Mol Divers DOI 10.1007/s11030-015-9596-0
COMPREHENSIVE REVIEW
Transition metal-free one-pot synthesis of nitrogen-containing heterocycles Simpal Kumari1 · Dharma Kishore2 · Sarvesh Paliwal1 · Rajani Chauhan1 · Jaya Dwivedi2 · Aakanksha Mishra2
Received: 11 April 2014 / Accepted: 2 April 2015 © Springer International Publishing Switzerland 2015
Graphical abstract
m
e ber em
d red be em rm fou
ee thr
me mb ere d
Transition metal-free one-pot synthesis of nitrogen-containing heterocycles
five
seven membered
Abstract One-pot heterocyclic synthesis is an exciting research area as it can open routes for the development of otherwise complex transformations in organic synthesis. Heterocyclic compounds show wide spectrum of applications in medicinal chemistry, chemical biology, and materials science. These heterocycles can be generated very efficiently through highly economical and viable routes using one-pot synthesis. In particular, the metal-free one-pot synthetic protocols are highly fascinating due to several advantages for the industrial production of heterocyclic frameworks. This comprehensive review is devoted to the transition metal-free one-pot synthesis of nitrogen-containing heterocycles from the period 2010–2013.
six
me mb er e d
Keywords Heterocycles · Metal-free synthesis · One-pot reactions · Reviews
B
Introduction Simpal Kumari
[email protected]
1
Department of Pharmacy, Banasthali University, Banasthali 304022, Rajasthan, India
2
Department of Chemistry, Banasthali University, Banasthali 304022, Rajasthan, India
Nitrogen-containing heterocyclic compounds have attracted considerable attention due to their broad range of physicochemical and pharmacological properties. Heterocyclic compounds offer a high degree of structural diversity and are proven to be useful as therapeutic agents [1]. Conventional
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Mol Divers
methods for the preparation of heterocycles are continuously being updated and replaced by new, more efficient and sustainable synthetic routes. The development of environmental, practical, and highly economic procedures for the preparation of heterocyclic compounds continues to be a challengining area for organic chemists [2]. One-pot synthetic pathways are remarkably advantageous to access diversely functionalized molecules which are useful as fine chemicals, chiral catalysts, ligands, drug candidates and drug intermediates [3–6]. One-pot reactions have been extensively studied for the synthesis of heterocyclic compounds [7–10]. In comparision to multi-step synthetic procedures, these reactions are highly economical to construct varyingly substituted molecules in just one reactor by avoiding the separation and purification of intermediates. Even though transition metalcatalyzed one-pot reactions are well-established approaches for the synthesis of heterocyclic compounds [11–13], there is a large number of reactions reported where no metal is needed to catalyze the reaction resulting in the production of biologically active agents without transition metal (TM) contamination [14]. This certainly increases the interest of TM-free one-pot reactions in the near future. In the last decade, many review articles have been published on one-pot heterocyclic synthesis [15–19]. Yet, no review has covered a range of metal-free one-pot procedures for the synthesis of nitrogen-containing heterocycles such as aziridines, azetidines, and azepines together with five- and six-membered heterocycles. Thus, considering the scant availability of such a review in the literature, herein we present a systematic entry to TM-free one-pot reactions to construct three-, four-, five-, six- and seven-membered heterocycles. This review covers recent literature from 2010 to 2013.
Three-membered ring compounds Aziridines represent a key structural motif in a large number of compounds used as pharmaceuticals, agrochemicals, and dyes [20]. They are also useful building blocks in the synthesis of nitrogen-containing compounds due to their highly regio- and stereo-selective ring-opening reactions with nucleophiles [21]. Buckley et al. [23] modified the two-step aziridine synthetic protocol of Xu et al. by a one-pot route involving the Wenker cyclization of amino alcohols 1 [22]. The advantages of this reaction are low-cost, simplicity, and high enantiopurity of desired products (Scheme 1). An exclusive one-pot synthesis of chiral 2aziridinylpropanol derivatives involving desulfonylation of amidosulfone 3 and aldehydes 4 followed by a Mannich reaction and a reduction in the presence of sodiumborohydride was reported by Hayashi et al. [24]. It was noticed that when
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Ph
H N
(i) ClSO3H, toluene, 0 oC, 2h OH (ii) 6M aq. NaOH and heat, 18h
1
N
Ph
2 (62 %)
Scheme 1 Chlorosulfonic acid-catalyzed synthesis of aziridines
the amount of NaHCO3 (in first step) was increased 3 times, an aziridinyl-aldehyde derivative was formed which upon further reduction provided desired aziridine 5. The enantioselectivity of the products was maintained, although a slight decrease in yield was noticed (Scheme 2). The advantages of this methodology are good product yields and excellent enantioselectivity. An exquisite methodology for the synthesis of aziridines has been published by Bull et al. [25]. N-Boc-protected imines 6 in the presence of diiodomethyllithium (LiHMDS) undergo an addition reaction to provide an intermediate amino gem-diiodides which in turn cyclizes into cis-iodoaziridine derivatives 7. This protocol provides a wide range of substrate scope with overall good yields (Scheme 3). Synthesis of highly functionalized trans-2,3-diphenyl Narylsulfonylaziridines 10 through the one-pot reaction of chloramines T (8) and trans-stilbenes 9 using a phase-transfer catalyst, trimethylphenylammonium tribromide (PTAB), has been described by Joshi et al. [26] (Scheme 4). The synthesis of fused aziridines 13 containing a sydnone moiety was reported by Hegde et al. [27] from 2,3-dibromo-1-(3arylsydnon-4-yl)-3-arylpropan-1-one 11 and 1,2-diaminoethane 12 in the presence of triethyl amine (TEA) and ethanol (Scheme 5). The sonocatalyzed synthesis of 2,2-dichloro-1,3diarylaziridines 15 through the reaction of Schiff bases 14 with dichlorocarbene and chloroform in the presence of sodium hydroxide has been discussed [28]. This process is an efficient green method to synthesize dichloro aziridines (Scheme 7).
Four-membered ring compounds Synthesis of azitidine Azetidine and its derivatives are of high interest due to their versatility in medicinal chemistry as well as in synthetic chemistry [29,30]. Antibiotics containing azetidine have been known for decades for their unsurpassed clinical efficacy and safety. The Spartan architecture of these heterocycles has been acknowledged as classical building blocks in the synthesis of other heterocyclic compounds [31].
Mol Divers Scheme 2 Base-catalyzed synthesis of aziridines
HN Cl
O
Ts
H
+ SO2Ph
R
3
TsN
NaHCO3 (1.2 mmol)
NaBH4
1,4 dioxane, 0 oC
MeOH, rt.
OH 5 (upto 99% ee)
4 F3C
R = CH3, CH2CH3, i-Pr, n-Pr, Bn, OBn, -CH2CH2CH=CHC2H5, CH2 C C Ph R1 = H, TMS
A=
Ar
6
Ts
Ar
X = Boc, Ts
OR1
CF3
X N
3 eq. CH2I2, 2.6 eq. LiHMDS THF/Et2O (3:1)
N X
CF3 CF3
N H
Scheme 3 Aziridines from N-Boc-protected imines
R
I
7
(>95% de) (20 examples up to 92% yields)
Ar = Ph, 2 or 4-CH3Ph, 4-FPh, 4-ClPh, 4-t-BuPh, 4-BrPh, 4FPh3, 4-OCH3Ph, 4-CF3Ph, 3-pyridyl, 4-tolyl, 2-tolyl, 2-napthyl
R
Ar O Cl + S N Na H O 8
H
PTAB, CH3CN, rt Ar
9
Ar
O O S R N H
12 h H
Ar1
Ar2
Ar 10
Cl
Cl
CH3Cl, NaOH
N
H2O ultrasonic irradiation
N
Ar1
Ar2
15
14
92-98 % yield yield
R = Ph, 4-CH3Ph, 4-Cl-C6Ph
Ar1 = Ph, 4-ClPh, 4-NO2Ph, 4-CH3Ph Ar2 = Ph. 4-BrPh, 4-CH3Ph, 4-ClPh
Scheme 4 Synthesis of aziridines in the presence of phase-transfer catalyst
Scheme 6 Sonocatalyzed synthesis of aziridines
Recently, a highly stereoselective synthesis of azitidine derivatives 18 was reported by Miao et al. [32] in the presence of tetramethylguanidine (TMG), comprising iodine catalyzed condensation of Michael adduct formed in situ from [2 + 2] cycloaddition of α-amidomalonates 16 and enones 17. Separately, Feula et al. [33] reported a facile synthetic protocol for the preperation of azitidines 20 via the iodocyclization of homoallylamines 19 in the presence of iodine and NaHCO3 . It was concluded from this study that the use of a different base, such as Li/Ba/K hydroxide and acetate in place of NaHCO3 , does not facilitate the synthesis Scheme 5 One-pot synthesis of aziridines
of azitidines; however, this leads to the formation of pyrrolidine derivatives. It was also noteworthy that both protocols utilize iodine as catalyst, although the iodocyclization of allylamines needed a large amount of catalyst and long reaction time (Path B) in contrast to Miao’s process (Path A) as shown in Scheme 6. In continuation of Fujioka’s interest in the chemistry of acetals [34], the synthesis of highly substituted azitidines 23 from O,P-acetals 21 was described through a one-pot protocol [35]. A number of trials were undertaken for the
Br O Ar Br
O 11
O N N R
O O
H2N TEA/ethanol
+ H2N 12
Ar N
N
N N R
13 (12 compounds upto 68% yields)
Ar = Ph, 4-ClPh, 4-BrPh, 3,4-methylenedioxyphenyl; R = H, CH3, OCH3
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Mol Divers Scheme 7 Iodine-catalyzed synthesis of azitidines
O
OC2H5 OC2H5
O +
O
R2OCHN
R1
R 17
16
C2H5OOC C2H5OOC
(i) 0.1 eq. TMG, 1h (ii) 1.2 eq. I2, 2.4 eq. TMG, THF, 4-6h
N
R2
R
R1
O 18 (19 derivatives in 33-76% yields)
Path A
R2 = Ph, CH3, 4-CH3OPh, 4-CH3Ph, 4-ClPh, pyridyl, PhCH=CH; R1 = Ph, CH3, 3 or 4-NO2Ph, furyl, butyl, 4-ClPh, 4-CH3OPh; R = Ts, Ms, PhCOR2 R1
3 eq. I2, 5 eq. NaHCO3
N H
CH3CN, 16 h 19
Path B
N R2
R1 20 (18 derivatives)
R1 = PMB, Bn, PTB, Cy, n-Pr, 3-Py; R2 = Ph, 3-Py, PNP, ONP, 3 or 4-OCH3Ph, 1-Naph, 3-furyl, 2-BrPh, t-Bu
O BnN P (OMe)2 R1 COOCH3 R2
(i) 3 eq. LDA and TMEDA (ii) 1.5 eq. R3CHO 22 THF, 0 oC, upto 1h
21
BnN R1
R3
R2
O 23 (yield up to 81%)
R1, R2 = CH3, -(CH2)5-; R3 =Ph, 4-OCH3Ph
Scheme 8 Azitidines from O,P-acetals
base-mediated cyclization of O,P-acetals 21 to furnish intermediate phosphono-oxetanone which was not isolated. This, followed by the addition of aldehydes, leads to the formation of azitidine derivatives 23 via a Horner Wadsworth-Emmons (HWE) olefination reaction as indicated in Scheme 8. Among all the bases studied for the cyclization reaction, LDA with tetramethylethylenediamine (TMEDA) at 0 ◦ C provided good results. The authors also studied the effects of substrates structure on the yield of the product. Although various aromatic and non-aromatic aldehydes were employed, only unsubstituted aromatic aldehydes provided the desired azitidines in high yield. A first report on the utilization of a Baylis–Hillman adduct in the synthesis of fully substituted nitroazitidines was published by Rai and Yadav [36]. Initially N -aryl/ tosylphosphoramidates (A) were treated with sodium hydride in tetrahydrofuran to generate a phosphoramidate anion which in situ added to Baylis-Hillman adducts 24a–b and cyclized into azitidine derivatives 25a–b. In the case of aldehyde 24b, the addition of ionic liquid [bmim][X-Y] provided a higher nucleophilicity to the phosphoramidate anion and the high affinity of phosphorus for oxygen leads to an annulation via formation of an iminium ion intermediate. The authors proposed trans geometry of the azitidine isomers with complete diastereoselectivity (Scheme 9).
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Five-membered ring compounds Five-membered heterocyclic compounds showed favorable interactions with various receptor sites on enzymes involved in many physiological responses. Due to such responses, the chemistry of these heterocyclic compounds has received a great focus of attention. For example, five-membered heterocycles are present in more than hundred drugs available in the market and approximately thousands of heterocyclic derivatives are under clinical trials [37]. Apart from this, they have also been known for their catalytic [38,39], fluorescent [40–42], and dying properties [43,44].
Five-membered ring compounds with one nitrogen heteroatom Synthesis of pyrroles The presence of the pyrrole nucleus in the life-sustaining heme and chlorophyll as well as in many pharmaceuticals retained its unsurpassed importance. Thus, development of new methodologies for the synthesis of pyrroles is still attracting the interest of many researchers [45]. membered ring compounds with one nitrogenValizadeh et al. [46] reported a base-catalyzed expedient condensation of dimethylacetylene dicarboxylate 26, Nmethylhydroxylamine 27, and acylchlorides 28 in anhydrous dichloromethane leading to the formation of N-methyl3-acyl-pyrroles 29 in good overall yields (Scheme 10). Recently, an interesting synthesis of N-aryl pyrroles 32 was accomplished via the regioselective Diels-Alder reaction of boronodiene 30 and arylnitroso derivatives 31 in methanol (Scheme 11). The expected pathway of the pyrrole formation was suggested via a [4 + 2] cycloaddition/ring contrac-
Mol Divers Scheme 9 Azitidine from Baylis–Hillman adducts
NO2 A (1 eq.)
OH
Ar
Ar N Ar1 25a (10 compounds 82-91% yields)
NO2
NaH, THF
24a or
A=
O NHAr1 EtO P EtO
NO2 Ar
A (1 eq.)
O
Y-X
1 eq. [bmin][Y-X],THF
NO2
X-Y = SCN, NO3, SPh
24b
N Ar1 25b
Ar
(12 compounds in 81-93% yields) Ar = Ph, 2 or 4-ClPh, 2 or 4-CH3OPh, 3-furyl Ar1 = Ph, 4-FPh, Ts
COOCH3
R
27 +
COOCH3
Cl
40 oC
28
26
R
R
33 +
CH2Cl2, KHCO3
O R
O
O
CH3NHOH.HCl
N CH3
O
R
(21 examples yield = 60-98%)
34 R = CH3; R1 = Ph, -CH2Ph, 3-ClPh,3-OCH3Ph, 2-CF3Ph, 2 or 3-NH2Ph, 3-COOHPh, cyclic amines
R = CH3, Ph, 4-ClPh, 2-MeOPh, 4-NO2Ph
Scheme 12 One-pot synthesis of pyrroles COOEt
x
O +
B 30
O
Ar N=O 31
CH3OH, rt 13 examples
X = CH3, H Ar = Ph, 4-ClPh, 4-BrPh, 4-COOEtPh, 2-CH3Ph,
R
N R1 35
CH3CN, rt
R1NH2
29 (53-81%)
Scheme 10 Base-catalyzed synthesis of pyrroles
NIBTS (0.15 mmol) or TCBDA (0.042 mmol)
NH2
N Ar 32
R
36
Ar
O
H + O
37
COOEt 5 mmol Py, CH3CN, reflux 12h
Br 38
(34-82%)
Scheme 11 N-aryl pyrroles from Diels-Alder reaction
tion rather than a classical nitroso-Diels-Alder cycloaddition [47]. Dicarbonyl compounds have been known to undergo Paul–Knorr pyrrole synthesis [48]. A new series of pyrroles 35 were synthesized by Ghorbani-Vaghei and Veisi [49] using 1,4-dicarbonyl compounds 33 and amine derivatives 34 in the presence of catalytic reagent N,N,N ,N tetrachlorobenzene-1,3-disulfonamide (TCBDA) or N,N diiodo-N,N -1,2-ethanediylbis( p-toluenesulfonamide) (NIB TS) through a one-pot Paul-Knorr synthesis. Both catalysts are reusable and proven to retain their efficiency after several reaction cycles (Scheme 12). Lin et al. [50] developed a facile route for synthesis of substituted pyrroles 39 through the one-pot, threecomponent coupling of amines 36, ethyl glyoxalate 37, and 2-bromoacetophenone derivatives 38. The reaction is promoted by pyridine (Py) under mild reaction conditions providing good overall yields (Scheme 13). This type of
Ar Ar
N R
O
39 (32-70%)
R = Ph, 4-CH3OPh, 4-CH3Ph, 4-ClPh, 4-BrPh, Bn, n-Bu, cyclohexyl; Ar = Ph, 4-BrPh, 4-CH3Ph, 4-ClPh
Scheme 13 Pyridine-catalyzed synthesis of pyrroles
polysubstituted pyrroles was utilized for the synthesis of benz[g]indoles [50]. Tetrasubstituted pyrroles 42 can be synthesized from a green one-pot reaction of arylglyoxal hydrates 40, βdicarbonyl compounds 41 with ammonium acetate and hydrazine hydrate in water under ultrasonic irradiation (Scheme 14) [51]. To date, only a few reports have appeared in the literature on the synthesis of 3H-pyrroles. Recently, Mukhopadhyay and coworkers [52] reported an attractive one-pot threecomponent synthesis of 3H-pyrroles 46 from inexpensive starting materials ketones 44, thiols 43, and malononitrile 45 under highly basic conditions. The pathway for the synthesis involves the Knoevenagel condensation of ketones and malononitrile followed by a nucleophilic attack of malononitrile/cheletropic addition of malononitrile and then tautomerization. This method can serve as an excellent alternative of existing 3H-pyyrrole syntheses (Scheme 15).
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Mol Divers Scheme 14 Pyrrole synthesis under ultrasonic irradiation
O OH
Ar 40
HO
O OH
+
COR
H3C
NH4OAc, NH2NH2 water
Ar
41
N H
CH3
42 (>90% yields)
Ar = Ph, 4-NO2Ph, 4-BrPh, 4-ClPh R = CH3, OCH3, OEt, O-t-Bu Scheme 15 Substituted pyrroles from ketones, thiols, and malononitrile
COR
R2
SH
O R2 +
+ R1 44
R3
NC
CN
20 mol% Et3N H2O, 100 oC
R3
CN
R1 NH2 N
S
45
46
43
(25 examples with yield upto 94%)
R1 =CH3, -CH2CH3, -CH2Ph; R2 = Ph, 3-ClPh, 3,4-OCH3Ph, thiophene; R3 = CH3, Cl, -C(CH2)2
NC NC 45
O
O
+ Ar
+ H
Ph
48
Ar
NC H N
Et3N, 70 oC Ts
CF3CH2OH, 12h
47
Ph H2N
N H
O
49 Ar = Ph, 3-ClPh, pyridine
Scheme 16 One-pot synthesis of 2-amino-pyrroles
Wang and Domling [53] have synthesized 2-aminopyrroles 49 through a one-pot multi-component reaction of malonodinitrile 45, aromatic aldehydes 47, and aminoacetophenone sulfonamides 48. They reported the synthesis of 14 highly substituted pyrroles with good overall yield (Scheme 16). A first report On regioselective intermolecular addition of in situ generated O-vinyl oximes to activated alkynes in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) followed by thermal rearrangement has been reported by Ngwerume et al. [54], which lead to the formation of pyrrole derivatives 51 through a one-pot assembly (Scheme 17). 1,2,4-Trisubstituted and several fused pyrrole derivatives 54 were successfully furnished by the Morita–Baylis– Hillman (MBH) reaction of acetates 52 with azide derivatives 53 in THF-H2 O using triphenylphosphine (PPh3 ) as catalyst at room temperature (Scheme 18). When sodium azide was used in place of alkyl azides, NH-pyrroles were obtained [55]. An efficient aza-Michael addition of amines 55 to a series of ynones 56 was carried out using tripotassium phosphate in DMSO at room temperature. This, followed by intramolecular condensation under nitrogen atmosphere, leads to the formation of pyrrole derivatives 57 (Scheme 19) [56]. 1,2-Diaza-1,3-dienes (DDs) have been studied in the preparation of libraries of several heterocyclic compounds
123
[57–59]. Utilizing the application of 1,2-diaza-1,3-dienes in the synthesis of diverse heterocycles, Attanasi et al. [60] achieved the solvent- and catalyst-free synthesis of pyrrole derivatives 61 via the condensation/aza-annulation of 1,2-diaza-1,3-dienes 58, primary aliphatic amines 59, and diketone derivatives 60. Electron-withdrawing groups at R4 and R5 including dimethyl-methylphosphonate provided desired products in good to moderate yield (Scheme 20). A combination of acetonitrile, water, and pyridine (80:15:5) was employed in a three-component, one-pot reaction of diversely substituted thiophenols 43, isocyanides 62, and gem-diactivated olefins 63 to produce highly substituted pyrroles 64 as shown in Scheme 21 [61]. An expedient Ugi-Aldol sequence allows the formation of biologically useful pyrrolinones 69. This strategy starts from readily accessible aldehydes, benzylamines, carboxylic acid derivatives, and isonitriles (65, 66, 67, and 68). The process involves a one-pot two-step Ugi–Aldol four-component condensation and cyclization of respective substrates. The first step is completed after overnight stirring in methanol, and then the solvent was removed and changed to DMF to trigger the cyclization step under microwave irradiation in the presence of diisopropylamine (DIPA). The generality of the protocol was proven by synthesizing a good range of pyrrolinone derivatives [62] (Scheme 22). Georgescu et al. [63] have synthesized a diverse library of regioselective pyrrolo[1,2-c]pyrimidine derivatives 74 from pyrimidines 70, 2-bromoacetophenones 71, and electrondeficient alkynes 72 in the presence of propylene oxide or 1,2-epoxybutane 73 (Scheme 23). The formation of pyrrolo[1,2-c]pyrimidine derivatives proceeded through a 1,3-dipolar cycloaddition forming an intermediate pyrimidinium salt which further reacted with alkyne derivatives (Scheme 23). All the synthesized products were isolated by
Mol Divers Scheme 17 Microwave-assisted regioselective synthesis of pyrroles
COOCH3 + R
R1
COOCH3 26
COOCH3
R1
(i) 10% DABCO, toluene MW, 8-10 min (ii) MW, 45 min, 170 oC toluene
N OH
R
COOCH3
N H 51
50
R =Ph, pyridine; R1 = -CH2Ph, -CH2Br, -CH2CH3 Scheme 18 Phosphine-mediated cascade synthesis of pyrroles
O O AcO
OMe OCH3 n
R2
+
PPh3, rt, stirring
N3
n
53
52
R3
N
THF-H2O
n = 1, 2 R1
Ph
54 R2 (upto 95%)
R1 = Ph, 2-thiophenyl, n-propyl, 4-CH3OPh, 4-NO2Ph
Scheme 19 Tripotassium phosphate-catalyzed synthesis of pyrroles
R2 R3
R1
+
R2 55
O
N H
K3PO4 (1 mmol) (i)DMSO, rt (ii)140 oC, N2
R
56
R1
R3
N R 57
(27 examples yield 40-91%) R = H, CH3, n-Bu; R1 = H, Ph, 3,4-OCH3Ph, 4-CF3Ph, 4-t-BuPh, 2 or 4-CH3Ph, 4-ClPh; R2 = Ph, 3,4-OCH3Ph, 4-CF3Ph, 4-t-BuPh, 2 or 4-CH3Ph, 4-ClPh, 4-FPh, 4-t-BuPh, thiophen-2-, cyclohexyl-, isopropyl-; R3 = Ph, 2 or 3 or4-CH3Ph, 4-ClPh, 4-FPh, nBu, t-Bu
Scheme 20 Pyrroles from 1,2-diaza-1,3-dienes
NH2R R2
O
N
O
N
R1
58
no catalyst no solvent rt, stirring
59 R5
+ O
R3
R3
O 60
R5
R4
R2
N R
61 (26 examples yields upto 26-87%)
R4
R = CH2Ph, CH3(CH2)n-; R1 = Ot-Bu, OCH3; R2 = H, Ph, CH3, -CH2COOCH; R3 = CH3, -CH2CH3; R4 = NEt2, OCH3,OEt, t-Bu,-O(CH2)2CH3, morpholine, 3ClPh, 3-OCH3Ph; R5 = morpholine, OCH3, -NEt2, -NH-Ph, OEt
Scheme 21 One-pot synthesis of substituted 2-amino-pyrroles
SH NC + R4 NC + R3
62
43
R3
R2
R1
R2
MeCN : H2O : Py R1
rt 63
S
N R4
NH2
64 (25-91%)
R1 = Ph, 3-CH3OPh, 4-ClPh, i-Pr, c-C6H11; R2 = CN, COOEt R3 =Cl, CH3; R4 = c-C6H11, (CH2)2OCH3, c-C5H9, cyclohexyl-, adamantyl
simple crystallization and found to have a wide spectrum of drug-like properties. A three-component, one-pot method for the regioselective synthesis of thieno[2,3-c]-pyrroles 78 was investigated by
Hong et al. [64]. The methodology involves the cyclization of 2-acetyl-3-thiophenecarboxaldehyde, thiols, and variously substituted amines (75, 76, 77) as shown in Scheme 26. The reaction proceeds efficiently in methanol in the absence of
123
Mol Divers Scheme 22 Microwave-assisted synthesis of pyrroles
O
O
R
CHO
R1 NH2
65
(i) rt, methanol, overnight
66
+
(ii) MW, 160 oC, DIPA
R R1 N
NC R3
COOH
R2
R3 NH
69
68
67
R2
O
(9 examples, 72-82% yields) R = CH3, Ph; R1 = Bn, 2-ClBn, 2,4-CH3OPh, 2furylmethyl, 4-BrPh, 4-ClPh; R2 = 2,4-ClPh, 3,4CH3OPh, 3,5-CF3Ph, 3,5-FPh
Scheme 23 Three-Component synthesis of pyrrolo[1,2-c]pyrimidines
R3 BrH2C
R1
O
O
CH O
N
+ R3
+
N
R2
70
O
N
reflux, 8h
R
72
71
O
R4 73
N
R1
74 (74 examples, 39-55 % yield)
R2 = H, CH3, OCH3, F, Br, Ph, and fused six member rings R1 = CH3Ph, 2,4-CH3Ph, OCH3Ph, 2,4-CH3Ph, 3,4-CH3Ph, 2,3,4-triCH3Ph R3 = CH3,OCH3,OC2H5 R4 = CH3, CH2CH3
Scheme 24 Regio-controlled synthesis of thieno[2,3-c]-pyrroles
O
S R 1
H + SH R1 + NH2 R 76 77
S 75
O
23 oC solvent free or CH3OH
N R S 78 (54-98%)
R = -(CH2)NHCOCH3, -(CH2)2pyrollidine, (CH2)2pyridine, -CH2CH2=CH2, -CH2CH Ph -(CH2)2COOH, -(CH2)2Ph, CH2Ph, -CH2C C, (CH2)2CH3, -(CH2)2indole OH R1 = CH2Ph, -(CH2)NHCOCH3, Ph, -(CH2)2COOH, CH2COOCH3, H2C OH CH3
Scheme 25 Diastereoselective synthesis of fused pyrroles
O
O O
COOH +
R1 79
O Ar C H 80
H2N R3 82 Ugi-4CR/Michael addition CH3OH, rt
R2 N CH 81
Ar = pyridine; R1 = H, CH3, OCH3, Cl R2= n-Pr, Cy, t-Bu; R3 = Ph, CH3Ph, OCH3Ph, ClPh
catalyst; moreover, the authors also explored this process in solvent-free conditions (Scheme 24). A sequential Ugi/Michael addition reaction provides a simple and an efficient method for the construction of chromeno[3, 4-c]pyrrole-3,4-diones 83 from coumarin3-carboxylic acid 79, aldehydes 80, isonitriles 81, and aryl amine derivatives 82. In this domino protocol the Ugi/intramolecular Michael reaction is applied ingeniously
123
O
O
N
R3 Ar O
HN R1
R2 83 (55-82%)
for highly functionalized molecules as shown below in Scheme 25 [65]. Synthesis of indoles Substituted indole derivatives have been prepared by Hong et al. [66]. Scheme 26 depicts a PPh3 - and CsF-mediated one-pot reaction of ethyl 2-azido-3-arylacrylate 84 and
Mol Divers Scheme 26 Substituted indoles from a one-pot reaction of azidoacrylates and ortho-silyl aryltriflates
EtOOC
TMS
N3 + R1 R 84
OTf
0.5 mmol PPh3 1.5 mmol CsF MeCN/PhMe, air
85
R R1
COOEt N H 86 (26 examples)
R = Ph, 3-NO2Ph, 4-Br or ClPh, 4-PhC6H4, 4-PhCH2OC6H4, 2-naphthyl, 4-OCH3Ph, 4-CH3Ph, 4-PhCH2OC6H4, 2-ClC6H4CH=CH, 2-CH3OC6H4CH=CH, 2-NO2C6H4CH=CH, PhCH=CH; R1 = CH3, 3,4-dimethyl, dioxolane (fused), Ph(fused)
Ph
Ph
OH
R
+ N Ts H 87
O
monohydrate 91, and N-substituted enamines 92, under microwave heating, provide the desired indole derivatives 93 in the absence of any catalyst and solvent (Scheme 28). When two equivalents of enamines 95 and arylglyoxal monohydrate 94 in the presence of acetic acid were allowed to react, the formation of bis-indole derivatives 96 took place (Scheme 29). Tu et al. [69] reported in 2013 another interesting microwave-assisted three-component domino bis-indole synthesis (100a and 100b). This microwave-assisted operation involves the reaction of N-aryl enaminones 97, arylglyoxals 98, and various indole derivatives 99 in acidic medium. The suggested mechanistic pathway for this prestigious reaction includes a selective [3 + 2] heterocyclization forming three sigma bonds simultaneously (Scheme 30). A catalyst-free, one-pot synthesis of indole derivatives has been described by Pramanik et al. [70]. The prominent domino process involves an annulation followed by the aromatization between enamines 101 and arylglyoxals 102 in acetonitrile and ethanol to give 7-ethoxy-1,2-diaryl-1,5,6,7tetrahydroindol-4-ones 103 and 1,2-substituted-1H -indol-4ol 104 in moderate yield (Scheme 31). An efficient regio- and stereo-selective three-component pathway using 2,2-dihydroxyindene-1,3-diones 105, enaminones 106, and arylamines 107 for the synthesis of functionalized tetracyclic indeno[1,2-b]indoles has been devised. The first pathway involves a novel sequential methyl migration, aromatization, and esterification, while a second reaction in acetic acid as shown in path A leads to the formation of the product 108 (Scheme 32). On the other hand, when 105
O
TfOH (10%)
R
DCE, 80 oC
88
89
N Ts
(31 examples, 41-95% yield) R = H, CH3, n-Bu, 2-CF3Ph, 2-OCH3Ph, 2,3-benzoPh, 2,4,6-tri-iPrPh, 4FPh, 4-BrPh, Cy, Cpent, -(CH2)2COOEt, (CH2)2COOCy, or 88 = O
O
O
O
Scheme 27 Synthesis of indoles from aminobenzyl alcohols and furans
ortho-silylaryltriflate 85 to provide substituted indoles 86 in moderate yields. The key steps in this transformation are (i) formation of iminophosphorane and benzynes and (ii) double cyclization, hydrolysis, and air-oxidation. Recently, the synthesis of diversely substituted indoles derivatives 89 was reported through an excellent one-pot reaction of precursor α-aminobenzyl alcohols 87 and furans 88. This transformation takes place via the formation of an aminobenzylfuran intermediate in the presence of trifluoromethanesulfonic acid (TfOH) in dichloroethane (DCE). The generality of the protocol was assessed using 20 different furans and aminobenzyl alcohols [67]. The author predicted that the resulting indoles can be transformed into 2,3- and 1,2-fused indoles having an α, β-unsaturated ketone moiety. A domino three-component reaction for the synthesis of indoles and bis-indoles 93 was developed by Tu and coworkers [68]. Various aliphatic carboxylic acids 90, arylglyoxal Scheme 28 Microwave-assisted synthesis of indoles
O O O
O R
HO 90
+ HO OH 91
MW, 120 oC
Ar1 + R1 R1
N H
Ar2
15-30 min
R1 R1 O
92
Ar1 N Ar2
O R
93
Ar1 = Ph, Benzo[1,3]dioxole R1 = CH3, R = CH3, -CH2CH3, -CH2CH2CH3, -CH2-(CH3)2, Ar2 = Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-CH3Ph, 4-CH3OPh
123
Mol Divers Scheme 29 Acetic acid-catalyzed synthesis of indoles
O O O 2 eq.
OH
HO OH
Ar1 + 2 eq. R1 R1
N H
95
94
Ar1 N Ar 2
HOAc
Ar2
R1 R1
Ar1 96
N Ar2
R1 = H; Ar2 = Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-CH3Ph, 4-CH3OPh; Ar1 = Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-CH3Ph, 4-CH3OPh, Benzo[d][1,3]dioxol-6-yl
Scheme 30 Microwave-assisted synthesis of indole derivatives
O
R2
R1 R1
N H
97 O HO
R2
Ar2 O
R2 HOAc MW
R3
+ N H
Ar1
99
OH
HN
R1 R1
Ar1
or
N Ar2
R1 R1
R3 Ar1 N Ar2
100b
100a
98
NH O
R2 = CH3, Ph
R2 = H R1 = H, CH3; Ar1 = Ph. 4-CH3Ph, 2-CH3OPh, 4-FPh, 4-BrPh, 4-ClPh, 4-NO2Ph; Ar2 = Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-CH3Ph, 4-CH3OPh,
Scheme 31 Efficient one-pot synthesis of indoles
O Ar
C2H5OH
N OC2H5R1 103
R1 HN
OH
O +
6-8 h O 101
OH
Ar
OH 102
(50-60%)
CH3CN
Ar
6-8 h 104
N R1
(40-60%)
R1 = Ar, Bn, alkyl; R2 = Ph, 4-NO2Ph, 4-ClPh, -OCH3Ph, 4-FPh
and 106 were treated with ester 109, tetracyclic indeno[1,2b]indole derivatives 110 were isolated (Path B [71]). Synthesis of pyrrolidines Pyrrolidines play an important role in the synthesis of biologically active substances. The presence of the methylpyrrolidinyl fragment in several enzymatic inhibitors and antagonists has placed this cyclic amine among valuable structural motifs. Thus, it is of high importance to search new and efficient methods to synthesize pyrrolidine derivatives. Recently, Lima et al. [72] introduced a process for the synthesis of pyrrolidine amides 113. This method features the initial formation of acid chloride from carboxylic acid 111 and trichloroisocyanuric acid 112 (TCICA) in the presence of PPh3 and CH2 Cl2 followed by the addition of amines or alcohol in the presence of triethyl amine, resulting in
123
the formation of pyrrolidine amides or esters, respectively (Scheme 33). N-Methylpyrrolidone (NMP) has been utilized in many industries for a long time. Besides its numerous applications in the paint and polymer industries, it is also a solvent of high interest for many reactions because of its strong solubilizing properties [73]. Owing to its versatile applications and consumption in various industries, NMP is commercially synthesized by reacting butyrolactone with methylamine at high temperature. However, due to the hazardous nature of methylamine (corrosive and flammable), there is a need to develop highly efficient and less toxic methods to generate NMP. It is shown in Schemes 34 and 35 that NMP can be prepared by the methylation of 2-pyrrolidone in situ obtained from the cyclization of γ -aminobutyric acid 114 (GABA) through a bio-based one-pot reaction. This method circumvents some of the problems and limitations associated
Mol Divers O O R1 R1
O HO N HN Ar R 108
NH2 Ar 107 R1 HOAc, MW R1 120 oC Path B
O
O OH OH
R + N H
R2
O 106
105
O
O
O R2 109 MW 120 oC Path A
O
R2
O
R1
N R R1 110
R = CH3, CH2CH3, 4-FPh; R1 = H, CH3; R2 = Me, Ph, 2- or 4-CH3 OPh, 3- or 4-CH3Ph, 4-FPh, 4-ClPh, 4-BrPh, cyclopropyl; Ar = Ph, 4-ClPh, 4-CH3Ph, 4-BrPh
Scheme 32 Microwave-assisted acid-catalyzed synthesis of indoles Scheme 33 One-pot synthesis of pyrrolidines from carboxylic acids and trichloroisocyanuric acid
O
Cl N
O +
OH NHBoc
Cl
N
N O
N O
(ii) H-L-Pro-OBn.HCl/Et3N Cl 3.0 eq. Et N, 1-2 h 3
NHBoc 113
112
111
Scheme 34 NMP from GABA CH3 N O
O A or B H2N
OH
250 oC
114
Scheme 35 Synthesis of pyrrolidines under ultrasonic irradiation
OBn
(i) PPh3, CH2Cl2 0 oC-rt
O
115
A = methylating agent = CH3OH catalyst = ammonium bromide, ammonium iodide or CTAB ( 90% selectivity) B= methylating agent = dimethyl carbonate (DMC) catalyst =NaY zeolite B = ( 67% selectivity)
O R1 116
O
R1 + R2
NH2 117
solvent and catalyst free
R1 = CH3, Ph R2 =
CH
O
O rt
Ph CH3 CH Ph napthalene
with other reported procedures, employs readily available materials, and provides excellent selectivity and good yields [74]. Amara et al. [75] have studied the double aza-Michael reaction (DAM) of bis-α, β-unsaturated carbonyl compounds 116 and amines 117 to get analogs of Lobelia alkaloids containing pyrrolidine. Very impressively, all the products were recovered in high yield (>98 %) in solvent-free conditions under ultrasonic irradiation (Scheme 35). On the other hand, the yield of the desired products decreased in the presence of protic or aprotic solvents. An efficient and a convenient route investigated by Lu et al. [76] has paved the way for the synthesis of fused pyrrolidine compounds under microwave irradiation. Their
CH
Ph OH
CH
Ph CH3
R1
N R2 118 (dr.>95:5)
R1
CH
process provides an excellent example of a double intermolecular [3 + 2] cycloaddition including the condensation of aminoesters 119, aldehydes 120, and maleimides 121. The process provides a convergent pathway for the synthesis of tetracyclic pyrrolidine derivatives 122 in a short time period with high stereoselectivity and good yields (Scheme 36). Liu et al. [77] have reported the stereoselective synthesis of substituted pyrrolidine derivatives 125 in quantitative yields via a pseudo four-component 1,3-cycloaddition between isatin derivatives 123, malononitrile 45, and sarcosine 124 in methanol. This highly stereoselective process provides highly functionalized spiropyrrolidines under mild reaction conditions (Scheme 37).
123
Scheme 36 One-pot synthesis of tetracyclic pyrrolidines under microwave irradiation
O
O O
O H2N
. HCl OCH3 + R1
MW, 180
O N
R2
N O
oC
N
O
O
120
119
R2
TEA, PhMe N R2
H +
COOCH3
Mol Divers
R1
R1
122 (11 examples yield 10-80%)
121
R1 = 2-furanyl, 4-BrPh, 4-CH3Ph, 2,4-ClPh, 4-CH3OPh, Ph, 2-thiophenyl, 4-NO2Ph; R2 = C2H5, C2H5Ph
Scheme 37 One-pot synthesis of pyrrolidines
R2 R OO 2 N N
O R1 O +
2 eq. N R2
CN
H N
COOH + 124
CN
CH3OH heating R1
45
R1
N NC CN 125
123
(>90% ee, yield 82-91%) R1 = H, CH3, Cl, Br, F; R2 = H, CH3
Scheme 38 Synthesis of 2-substituted 3-alkoxyisoindolin-1-imines
CHO + R1NH2
R CN 126
EtOH CH3COOH, reflux
OEt N R1
R
127 128
NH
R = H, 3-OCH3, 4-NO; R1 = Bn, Pr, i-Pr, 4-CH3OPhCH2, 4-ClPhCH2 4-FC6H4(CH2)2, 3,4-(CH3O)2C6H3(CH2)2, 2-furylmethyl, cyclopropyl, 3-pyridyl,
Synthesis of indolines Isoindole analogs are the key structural components in many therapeutic potent agents [78]. Their biological activities, such as anti-proliferative, thrombin receptor inhibitor, NMDA receptor antagonists, have attracted the attention of many research groups [79–82]. The existing methods are limited due to the problems associated with them. The condensation of 2-cyanobenzaldehydes 126 and amines 127 in alcohol resulted in 2-substituted 3-alkoxyisoindolin-1-imine 128 through an acid-catalyzed one-pot reaction (Scheme 38). Acid catalysts such as 4-toluenesulfonic acid, L-proline, sulfamic acid, and acetic acid were evaluated for their catalytic activity to provide a wide range of alkoxyisoindolin-1-imines in good to excellent yields, with acetic acid (0.5 eq.) providing the highest yield [83]. Notably, the ready availability of the starting materials and the practicability of the reaction make this approach an attractive complementary method for the access to isoidolin derivatives.
123
O R1 X + R2
R4 R3
129
R1 N N
(i) TsNHNH2, 131 (ii) NaOH , reflux (ii) C2H5I, NaOH
130
R2
R4
R3 132
R1 = Ph-CH2-, CH3-CH2-, alkene, propargylamine, Ph C O X = Br, Cl, I R2 = Ph; R3= H, CH3, R4 = H, Ph Scheme 39 Synthesis of 1,4-substituted pyrazoles
Five-membered ring compounds with two nitrogen heteroatoms The two highly acknowledged cyclic compounds in this class are pyrazole and imidazole. Many biological products containing these cyclic systems are present in the market [84,85].
Mol Divers Scheme 40 Synthesis of 1,4-substituted pyrazoles
R1
H
+ R3
NO2
HN N
R1 = 3-NO2Ph, 3-OCH3Ph, 2-ClPh, 2-BrPh R2 = H, CH3, Ph; R3 = Ph, CH3, 3-OCH3Ph, furan Scheme 41 One-pot two-step synthesis of pyrroles
R3
R3 + R1
R1
134
133
H N N
K2CO3, DABCO THF
R2
NNHTs
R2 R2 135a 135b major minor (19 examples upto 89% yields)
Ph Ph
O CN
Ph
(i) PhNHNH2. reflux H2N
136
N
(ii) RCOCl 138
N Ph
O
HN R
N N Ph 139
137
(25 derivatives, yield 70-90%) R = aryl or heteroaryl
Scheme 42 Base-catalyzed pyrazole synthesis
N O
O 140
O P OC2H5 OC2H5 + P OC2H5 O OC2H5
RNHNH2-HCl 141
C2H5OH
O C2H5O C2H5O P
NaOAc, NaBH4 (0.6 mmol)
N
Ar OH
O P C2H5O OC2H5 142 (19 derivatives, yield 61-94%)
R = Ph, 2- or 3- or 4-CH3Ph, 3,5-di-C2H5-Ph, 3- or 4-FPh, 2- or 3- or 5-ClPh, 2- or 3- or 5-BrPh, 2- or 4-CF3, 4-CNPh, 4-OCH3Ph, 4-OCF3Ph
Synthesis of pyrazoles O
Classical methods of pyrazole synthesis involve the condensation of 1,3-diketones and hydrazine [86,87]. Although a large number of methods for the regio- and stereo-selective synthesis of substituted pyrazoles have been reported, new and simple approaches are of high interest in comparison to the contemporary collection of synthetic approaches due to the continued importance of the pyrazole nucleus in both biological and chemical fields. In 2013, Tang et al. [88] synthesized several 1,4-substituted pyrazole derivatives in good to excellent yields via a one-pot three-component 1,3-dipolar cycloaddition of halides 129, enones 130, and hydrazides 131 (Scheme 39). Later on, in the same year, Tan published another process for the synthesis of substituted pyrazoles 135a, 135b from tosylhydrazones 133 and nitroalkenes 134 using a base and DABCO. The pathway for this pyrazole formation was belived to happen via a Baylis–Hillman mechanism followed by an intermolecular cyclization (Scheme 40) [89]. The convenient reaction conditions shown in Scheme 40 provide the desired products in good yields (70–90 %) under solvent-free conditions. The straightforward procedure involves cyclization of benzoylacetonitrile 136 and phenylhydrazine to give 5-amino-1,3-diphenyl pyrazole 137
C
R1 143
R2
R3 N N
R3NHNH2 144 ethanol, rt, 30 min upto 96%
R1
R2
145
R1 = CH3, Ph, 2-FPh, 2- or 4-ClPh, 4-BrPh,4-CH3Ph, 4-CH3OPh, 3,4-di-CH3OPh, PhCH2-; R2 = H, Ph, 4-FPh; R3 = H, Ph
Scheme 43 Pyrazoles from 1,2-allenic ketones
which upon acylation with acetyl chloride provides N-(1,3diphenyl-1H-pyrazol-5-yl)amides 139 [90] (Scheme 41). Xiang et al. [91] have described the synthesis of tetrasubstituted pyrazoles 142 containing bisphosphonate esters by reacting tetraethyl 2-(4-oxo-4H-chromen-3-yl)ethene1,1-diyldiphosphonate 140 and the hydrochloride salt of substituted hydrazine 141 catalyzed by NaOAc in ethanol (Scheme 42). An efficient strategy for synthesis of 1,3,5-trisubstituted pyrazole has been devised by the cyclocondensation of 1,2allenic ketones 143 and hydrazine hydrates 144 in adequate conditions through a one-step reaction (Scheme 43). This method is advantageous in terms of simplicity, mildness, and produces trisubstituted pyrazoles 145 in high yields in less than 1 h [92].
123
Mol Divers
N NH N
S +
O
O
RNHNH2 148 KOH, EtOH
S
N
Cl 146
N N
N N
R
149
147
R = Ph, 2- or 3- or 4-ClPh, 4-BrPh, 4-FPh, 4-CH3OPh
Scheme 44 Pyrazoles from thiones and chloro derivatives of 1,2diketones
Whang et al. [93] described the reaction of thiones 146 and chloro derivatives of 1,2-diketones 147 with hydrazine hydrate 148 in ethanolic KOH to provide a pyrazolecontaining molecules 149 as shown in Scheme 44. The synthesis of highly functionalized pyrazole derivatives 152 has been achieved from low-cost starting materials such as substituted aldehydes 150, malononitrile 45, and hydrazines 151 in the presence of molecular iodine (Scheme 45). Among all the solvents examined for this reaction water yielded the desired pyrazoles with the highest yield (92 %) and THF with the lowest yields (15 %) [94]. An alternate method for the synthesis of trisubstituted pyrazoles 152 was developed by Pan et al. [95] involving the condensation of aldehydes 150, hydrazines 151, and alkynes 153 via a sequence of Mannich-type cyclization/oxidation reaction in the presence of p-toluenesulfonic acid monohydrate (PTSA). This method proved to have wider substrate scope and higher functional group tolerance in order to make desired pyrazoles. Synthesis of imidazoles Functionalized silica has been emerged as a green catalyst for synthesis of imidazole derivatives. Ziarani et al. [96] have reported a simple path for the synthesis of fully substituted imidazoles 158 facilitated by acidic silica catalyst from benzils, ammonium acetate, aldehydes, and amines (154, 155, 156, 157) under solvent-free conditions (Scheme 46, Path A). Phosphorus pentoxide supported on silicon dioxide was also utilized as green and reusable catalyst in the Scheme 45 One-pot synthesis of substituted pyrazoles
NC
O R1 C H 150
CN 45
+
R2
H N
151
NH2
synthesis of 1,4,5-tetrasubstituted imidazoles (Scheme 46, Path B) [97]. These two protocols are highly economical and straightforward, and require no toxic solvent and harsh reaction conditions. A molecular iodine-mediated one-pot three-component reaction of aryl alcohols or aryl halides, arylaldehydes, and hexamethyldisilazane in the presence of trimethyl amine was investigated for the synthesis of 2,4,5triaryl-1H-imidazoles with a wide range of substrate compatibility and high yields (Scheme 46, Path C). This reaction was also performed under solvent-free conditions with a reported loss in the yield of desired products [98]. A four-component condensations in ionic liquid 1-butyl-3-methylimidazolium bromide has been illustrated in Scheme 46 (Path D), where the products were generated in 5 min in excellent yields under microwave irradiation; however, conventional heating requires more than 2 h in order to complete this reaction [99]. Keggin Heteropoly acid (H6 PAlMo11 O40 ) or acidic ionic liquids (IL) can also serve as green catalysts in the synthesis of tetrasubstituted imidazoles under microwave irradiation (Scheme 46, Path E) [100]. A three-component synthesis of imidazoles 160 under ultrasonic irradiation has recently been reported by Jourshari et al. [101]. The reaction utilizes easily available substrates like benzils 154, aldehydes 159, and ammonium acetate 155 and proceeds in the presence of supported ionic liquid-like phases (SILLP) catalyst under conventional condition and ultrasonic irradiation. A wide range of aldehydes containing either electron-withdrawing or electron-donating groups effectively participate in this reaction (Scheme 47, Path A). This type of conversion has also been observed in the presence of lipase [102], tannic acid [103], [BPy]H2 PO4 [104], PEG-400 [105], CAN [106], p-toluene sulfonic acid (PTSA) [107], morpholinium hydrogen sulfate [108] as well as in the presence of NH4 H2 PO4 −SiO2 [109], and trichloromelamine under solvent-free condition [110]. Another procedure has been developed for the preparation of 1H-imidazole, which consists of the condensation of aldehydes or alcohols 161 and hexamethyldisilazane 162 in the presence of molten tetrabutylammonium bromide (TBAB) ionic liquid as catalyst (Scheme 48, Path A). The procedure is admirable in respect of easy workup, non-hazardous
20 mol% I2 60 oC, H2O Path A 15-92% yield 14 examples
N R1
N
R2 NH2
NC 152
R2NHNH2 150 PTSA (20 mol%) CH2Cl2, rt, 6h Path B 71-86% yield 31 examples
Path A: R1 = 4-CH3Ph, Ph, 2- or 4-OCH3Ph, 1-OHPh, 4-N,N-dimethylPh, 3-CNPh, 3-NO2Ph, 3,4-di-OCH 3Ph; R2 = Ph Path B: R3 = Ph, 2- or 4-CH3OPh, 4-FPh, -CH3Ph, 4-BrPh, n-Bu; R4 = H, TMS, Ph R1 = Ph, 4-CH3OPh, 4-ClPh, thienyl, 4-NO2Ph; R2 = Ph, 4-CH3OPh, 4-NO2Ph
123
149 + R3
R4 153
Mol Divers (31 examples, yield 72-98%) 158 solvent free Path B (P2O5/SiO2) heat
(17 examples, yield 70-96%) 158 CH3CN I2, 120 oC Me3Si NH SiMe3
Path C
O
[Bmin]Br, M.W Path D
N Ar
Path D
140 oC, 200 W
158 (28 examples, yield 82-93%)
R1
Ar
NH4OAc SiO2 Pr SO3H 155 + 140 oC R1NH2 O 157 Ar O solvent free R C H 154 156 Path A Ar
R N 158 (up to 99%)
10 mol% IL or 5 mol% HPA MW, 10 min. solvent free
158 (20 examples, yield 85-92%)
Path A: R = 4-ClPh, 3-NO2Ph, 4-OCH3Ph, 4-CH3Ph, 4-OHPh, 4-N,N-dimethylPh, 3,4-(OCH3)2Ph; R1 = Ph, -CH2Ph Ar = Ph Path B: R = Ph, 2- or 4-CH3Ph, 2- or 4-OCH3Ph, 3,4-(OCH3)2Ph, 2- or 4-OHPh, 2,4-OHPh, 3NO2, 6OH-Ph, 2- or 3-ClPh, 2,4-Cl2Ph, 4-ClPh, 3- or 4-NO2Ph, 2NO2, 4,5-OCH3Ph, 2- or 4-BrPh, 4-FPh, 4-(CH 3)2PhPh, 2-furanPh, 2-OH-4OCH3Ph, 4-SCH3Ph, thiophene, furan, 3,4,5-OCH3Ph, 3-OCH3,4-OHPh; R1 = CH3, Ph, -CH2Ph, C2H5, -CH2(CH3)2, Ar =Ph Path C: R = Ph, 2- or 4-CH 3OPh, 4-CH3Ph, 2- or 4-ClPh, 3- or 4-NO 2Ph, 2- or 4-CH3O-C6H4CH2OH, 4-Cl-C6H4CH2OH, 2-furfural, 4-NO2-C6H4CH2OH, PhCH2Br,PhCH2Cl, Ar = Ph Path D: R = Ph, 4-CH3Ph, 4-BrPh, 4-ClPh, 3- or 4-NO2Ph, 3-OCH3Ph, 2-furyl, 2-thienyl, 3-indolyl, 4-CH(CH3)2Ph, 3-OHPh, 4-CNPh, 4-OHPh; R1 = CH3, Ph, 4-CH3Ph, iso-C4H9, 4-ClPh, 4-FPh, cyclohexyl, PhCH2-, 4-OHPh, C2H5 Ar = CH3, Ph Path E: R1 =Ph, 2- or 4-CH 3Ph, 3,4-(OCH3)2C6H3, 4-ClPh, 4-EtPh, 3-BrPh, 4-NO2Ph, 2,5-(CH3)2Ph, 2,6-Cl2Ph R2 = CH3, Ph, PhCH2-, CH3CH2, 4-NO2Ph; Ar = Ph, 4-CH3Ph
Scheme 46 One-pot synthesis of N-substituted imidazoles Scheme 47 One-pot synthesis of imidazoles
O
O
Ar
+ Ar
O R C
154
H
159
NH4OAc 155 SILLP, C2H5OH 50 oC or ultrasound 40 kHz Path A
Lipase, ethanol 45 oC, 9h Path B (160, yield 67-87%)
Ar
H N R
N 160
[Bpy]H2PO4 (10 mol%)
7.5 mol% tannic acid ethanol, reflux Path C (160, yield 87-90%)
SILLP =
Ar
Path D (160, yield 77-96%)
CH Cl 3 N N CH3
black ball represents Merrifield resin 47a: R =Ph, 2- or 4-CH3O2CPh, 4-ClPh, 4-FPh, 4-CH3O2CPh, 4-OHPh, substituted pyrazole; Ar =Ph 47b: R = 2- or 4-ClPh, 2- or 4-OCH 3Ph, 3-NO2Ph, 4-CNPh, 3-CH3Ph, 2-pyridyl, 2-thiophenyl; Ar = CH3, Ph, substituted phenyl
condition, and excellent yield. Two catalysts namely trifluoromethanesulfonic acid adsorbed on silica gel and bismuth (III) nitrate pentahydrate have also been utilized in this study for facile synthesis of imidazoles 163 as illustrated in (Scheme 48, Path B) [111]. Chen et al. [112] have developed an environmental benign approach for the synthesis of tri- and tetra-substituted
imidazoles 167 via one-pot multi-component cyclocondensation of alkyne 164, aldehydes 165, or aniline 166 (or N-substituted derivatives) at 140 ◦ C in the presence of pivalic acid. The reaction provides satisfactory results with various aromatic compounds containing electron-donating and electron-withdrawing groups (Scheme 49).
123
Mol Divers Scheme 48 One-pot synthesis of trisubstituted imidazoles
Ar
molten TBAB TfOH-SiO2
ArX + HMDS
100 oC, 2.5-5h
X = CHO
Ar
Path A (yield = upto 95%)
161, 162
Bi(NO3)3, 5H2O molten TBAB
NH Ar
N 163
ArX 161 + HMDS 162
5-10h, 100 oC Path B (yield = upto 92%)
X= CH2OH, CH2Cl, CH2Br Ar = Ph, 2- or 4-ClPh, 3- or 4-O2NPh, 2-ClPh, 2-furyl, 4-CH3Ph, 4-CH3OPh Scheme 49 Acid-catalyzed multi-component reaction of imidazoles
Ar1
Ar2 NH2 166
O +
R
H
Ar2
165
Ar 164
R
PivOH ((1.0 mmol), NH4OAc (4 mmol) DMSO/H2O 1:1, air
N Ar
N
aniline, if desired compound is tetra subtituted imidazole
Ar 167
(35 examples yields 68-90%) Ar = Ph, 3-OCH3Ph; Ar1 = Ph, 2- or 3- or 4-OCH3Ph, 3,4,5-OCH3Ph, thiophene, R = H, Ph, 4-CH3Ph, CH2CH3, CH2(CH3)2, furan, 4-OCH3Ph, 4-NO2Ph, 4-ClPh, 4-BrPh, 4-OCH3Ph; Ar2 = H, CH3, Ph, 4-Br-Ph
Scheme 50 Synthesis of tetrasubstituted pyrazoles
R3
O +
N3
R4 168
R2
N
R1 H
169
MgSO4, DCE
R2
Path A 26 examples yields 41-98%
R4
R1 N
170
N 170
R3
O
N
R2
R3NHOH
R1
MgSO4
H
CH3CN Path B
169
23 examples yields 23-95%
171 + R4CHO 172
Path A: R1 = Ph, 4-CH3Ph, 4-BrPh, 2-furyl; R2 = Ph, CH3, 3- or 4-ClPh, 2- or 4-CH3Ph, C2H5CH2; R3 = Ph, H, 3,4,5-tri-CH3OC6H2, 3,4-CH3OPh, 2- or 3- or 4-CH3OPh, 3- or 4CH3C6H4, 4-BrPh, 4-FPh, 4-CF3Ph, 3-CPh, PhCH2-, ; R4 = CO2Et, CO2CH3, CHO Path B: R3 = CH3, Ph, 4-CH3Ph, 4-ClPh; R4 = Ph, 4-BrPh, 4-CH3Ph, 4-OCH3Ph; R1 = COOEt, R2 = 4-BrPh, 4-CH3Ph, 3,4-OCH3Ph, 3,4,5-OCH3Ph, 4-BrPh, 4-FPh, 4-CF3Ph, 2-OCH3Ph, -CH2Ph
Azido acrylates 168 play an important role in the one-pot synthesis of N-heterocycles under catalyst-free conditions [113–115]. The synthesis of imidazoles 170 in good to excellent yield has been reported via a domino two-component reaction of 2-azidoacrylates 168 and nitrones 169 under mild reaction conditions (Scheme 50, Path A) [116]. Syntheses of a variety of pyrazoles were attempted to assure the scope of the method; a good range of azidoacrylates and nitrones participated smoothly to give desired imidazoles in excellent yields. Ai et al. [117], in 2012, introduced a modified process which features the in situ formation of nitrones from hydroxylamines and aldehydes (171, 172) and further react with 2-azidoacrylates to give imidazole derivatives as shown in Scheme 50 (Path B). Diacetoxyiodobenzene (DIB)-mediated oxidation of 1,2diamino-arenes (173) and subsequent addition of Vilsmeier reagents 174 facilitated the synthesis of 2-amino-imidazoles 175. This process could serve as an excellent alternative to existing methods because of its mild reaction condition and
123
diverse range of substrate acceptability to produce imidazoles in overall good yield (Scheme 51) [118].
Synthesis of benzimidazole The synthesis of imidazole fused 6-membered heterocycles has attracted considerable attention in past several decades due to the potential biological activities, such as antitumor, antiparasitic, analgesics, antifungal, antiviral, antihistamine, and antihypertensives antidiabetics [119]. The synthesis of benzimidazoles 178 from o-phenylenediamine 176 and diversely substituted alcohols 177 in the presence of 2-iodoxybenzoic acid (IBX) in DMSO has been reported by Moorthy et al. (Scheme 52, Path A) [120]. Similarly, benzimidazole derivatives have also been reported by the reaction of o-phenylenediamine 176 and aldehyde derivatives 179 in the presence of silica-supported periodic acid (H5 IO6 -SiO2 ) at 20 ◦ C (Scheme 52, Path B).
Mol Divers Scheme 51 One-pot synthesis of 2-amino-imidazoles
R2
NH2
R1
NH R3
R4 N
Cl
.HCl R5
DIB (1,1 eq.), 20 oC DCM-CH3CN
R2
N
R1
N R3
174
173
R4 N R5
175 20 examples, yield = 55-97 %
R1, R2 = CN, fused phenyl ring, dihydropyrimidine R3 = H, n-Pr, CH3; R4 = (CH2)2CH3, CH(CH3)3; R5 = (CH2)2CH3, CH3 R4, R5 = pyrrolidine, N-cbz-piperazine
R2 NH2 182 + O R1 C H 183
NO2 F 181
DMSO, 130 oC, 3h Path D NH2 R
+ NH2 176
R1 CH2OH IBX (1.1 equiv), DMSO R or 20 oC R2 CH2Br (30-84%) 177 Path A
0.5 M Na2S2O4 (15 examples in yields upto 91%) N
N 178 R2
NH2 R1 H5IO6-SiO2 (20mol%) R rt, 12-30 min (up to 95%) Path B
O + R1 C H NH2 183
179
HClO4–SiO2 (0.5mol%) (20 examples) 1-3h, rt Path C R1 N
N
R2
180 Path A: R = H, R1 = Ph, 4-OCH3Ph, (CH3)2-NPh, 4-BrPh, 4-CF3Ph, 2-IPh, 4-NO2Ph, pyridine, furnan, thiophene, naphthaline, hexane, PhC; R1=CH2, R2 = 4-BrPh, 4-OCH3Ph, 4-NO2Ph, 2,4,5-CH3Ph, naphthaline, coumarin, pyridiniumbromide. Path B: R = H, COOH, COPh, R1 = Ph, 2- or 3- or 4-NO2Ph, 2-OHPh, 2,6-Cl2Ph, 4-ClPh, 3-OH,4-OCH3Ph, Path C: R = H, R1 = H, 4-CH3Ph, 4-OCH3Ph, 4-N(CH3)2, 4-ClPh, 4BrPh, 4-CF3Ph, Ph-4-OCH3Ph, 4-NO2Ph, benzo[1,3]dioxole, naphthaline, thiophene, furan, pyridine, indole, hexane, -(CH3)2, (CH3)3CH2, (CH3)2 Path D: R = H, R1 = Ph, 4-OCH3Ph, 4-OHPh, 4-FPh, 4-BrPh, 4-CNPh, PhCH2-, N-(CH3)2Ph, PhCOR2 = Ph, 4-ClPh, 4-OCH3Ph, 4-CH3Ph, 2-NH2Ph
Scheme 52 Synthesis of N-substituted benzimidazoles
The reaction has also been employed at higher temperatures but a considerable decrease in the products yield was observed [121]. Apart from this, 1,2-disubstituted benzimidazoles 180 have selectively synthesized from aryl or heteroarylaldehydes 179 and o-phenylenediamine 176 in the presence of 0.5mol% HClO4 immersed on SiO2 (Scheme 52, Path C) [122]. Recently, an expedient onepot three-component synthesis of benzimidazoles 178 has been reported by Pramanik et al. [123] from easily available substrates 1-fluoro-2-nitro-benzene 181, amines 182, and aldehydes 183, following a sequence of reactions
namely coupling, reduction, and cyclization in the presence of Na2 S2 O4 (Scheme 52, Path D). The method provides good yield (up to 91 %) and a wide scope of substrates. A dynamic piece of molecular architecture was introduced by Xu et al. [124] consisting unique combination of Ugithree-component reaction of Boc-protected isocyanide 184, aldehydes or ketones 185, and amine derivatives 186 at room temperature followed by a cyclodehydration reaction under microwave irradiation as indicated in Scheme 53.
123
Mol Divers O R3
NHBoc
O
R1
186 (i) TFE, rt, overnight
HN
R3 (ii)TFA/DCE (10mol%) HN O MW, 120 oC, NHBoc
187
188
+ NC
COOH
184
R2
R2
185
O
O
R1
R3
R2
R1
R2
R3
N
NH
O NH2 189
R1 = substituted aryl and hetroaryls
Scheme 53 Microwave-assisted synthesis of benzimidazoles Scheme 54 Metal-free synthesis of fused imidazoles
COOCH3 COOCH3 H2N R1
Metal free R
+
CHO
H2N
190
C6H5CH3, reflux
176
R1
N R N 191
(17 derivatives, yield 50-90%)
R N 192
+ X NH2 193
R1
NaHCO3 (2 eq.) DMF, 120 oC
N R
N 194
X = Br, Cl
R1
(yield upto 86%)
area of high interest [128–130]. A facile three-component synthesis of imidazopyridinium ions 202 (heterocyclic carbenes) by coupling of picolinaldehydes 199, formaldehyde 200, and amines 201, in polar solvents with HCl, has been reported by Hutt et al. [131] as shown in (Scheme 57)
R = H, CH3, Cl, COOCH; R1 = Ph, 4-CH3Ph, 4BrPh, 3- or 4-OCH3Ph, 2-ClPh
Scheme 55 One-pot synthesis of imidazo[1,2-a]pyridines
Five-membered ring compounds with three and four nitrogen heteroatoms
Other fused imidazoles
Synthesis of triazoles
Polycyclic benzimidazoles 191 having fluorescence properties have been synthesized by Samanta et al. [125] by the one-pot reaction of o-phenylenediamine 176 and esters derivatives 190. This reaction proceeded under mild conditions without the assistance of any metal, acid, or base (Scheme 54). Wu et al. [126] have developed a simple and an efficient one-pot synthesis of imidazo[1,2-a]pyridines 194 by the reaction of 2-aminopyridines 192 and acetylene derivatives 193 in the presence of sodium carbonate in overall good yields (Scheme 55). An efficient cascade protocol enables the asymmetric synthesis of pyridine-fused derivatives of imidazole (Scheme 56). This asymmetric process involves the [3 + 2] annulation of trans-2-enals 195 and substituted 2-aminopyridine 197 in the presence of organocatalyst 196. The utility of this protocol has been generalized for the synthesis of almost 20 derivatives under optimized reaction conditions [127]. Nonracemic N-heterocyclic carbenes are vital ligands due to their importance in homogeneous catalysis. Hence, the development of new efficient and straightforward protocols for their synthesis with economical advantages remains an
A very few mild and selective one-pot methods for synthesis of triazoles are available. Many existing methodologies generally utilize metal catalysts or any other expensive materials [132–134]. Here, we are summarizing some metalfree one-pot approaches for the synthesis of this privileged heterocyclic ring. A highly economical transition metalfree reaction of aryl azides and terminal alkynes (203, 204) has been introduced to generate disubstituted 1,2,3triazoles 205 in excellent yields using aq. NMe4 OH in DMSO (Scheme 58). This reaction is an excellent alternative to copper-catalyzed azide-alkyne cycloaddition reaction for triazole synthesis [135]. Valizadeh et al. [136] have developed an efficient route toward the synthesis of N-substituted triazoles 208 in excellent yields by reacting an azide (in situ generated from aniline 206) and 1,3-diketones 207 in the presence of ionic liquid. This reaction proceeds easily at 5–10 ◦ C to generate corresponding target triazoles in excellent yield and purity (Scheme 59). Staben and Blaquiere [137] in 2010 published a study on the Pd-catalyzed, highly regioselective synthesis of 1,2,4triazoles. Later in the same year, the authors added an
123
Mol Divers Scheme 56 One-pot synthesis of fused imidazoles
(i) 1.3 eq. H2O2 or TsNHOTs NH2 (iii) Ar Ar (ii) X N 196 N X H OTMs 197 (0.7mol%) C6H5CH3 60 oC C6H5CH3, rt
O
R
N N
R R 198 (35 derivatives uptp 98% yield)
195 Ar = 3,5-(CF3)2-C6H3-
R = CH3, hexyl, pentyl, Pr, iPr, E-hex-3-enyl, Z-hex-3-enyl, CH2CH2Ph, CH2OBn, C6H13-; Ar = 3,5-(CF3)2-C6H3-; X = H, CH3, NC, F, Br, COOCH3; R = Hex,Pen, Pr, iPr, Me, E-Hex-3-enyl, Z-Hex-3-enyl, CH2CH2Ph, CH2OBn
Scheme 57 Metal-free one-pot synthesis of imidazoles
R1
R1 O +
N R1 199
HCl CH2O 200 water or ethanol
N R1
NH2 R 201
N R H
Cl
202 (23 examples upto 92 % yield)
R1 = H, CH3
R = Ph, -(CH2)2CH3, -CH2Ph, -CH2pyridine, -(CH2)2NHCH3, -C(CH3)3, 4-CNPh, 4-OCH3Ph, 2,4,6-CH3Ph, nBu, 4-NH2Ph, -(CH2)2NH2, -(CH2)2SCH3, -(CH2)2Br NH2
Ph H2N other amines are =
R1 10 mol% NMe4OH N R DMSO, rt N N 205
N N N R + R1 203
204
R = Ph, 4-NO2Ph, COOEtPh, 2-C(CH3)2Ph, 4-COOt-BuPh, 2 or 3-OCH3Ph, 2 or 4-BrPh, pyridine, 2,4,6-CH3Ph; R1 = Ph, pyridine, 4-NO2Ph, 4-BrPh, 4-CNPh, thiophene, napthaline, 4C2H3N3Ph Scheme 58 Base-catalyzed one-pot synthesis of triazoles R3
NH2
R2
(i)IL-1 (1.5 eq.), IL-2 (1.5eq.), HCl (ii) R1 206
R2
R3 O O 207
O N N
OCH3 O
OH
NH2
NH2 H2N H2N
NH2
Synthesis of fused triazoles A series of bicyclic[1,2,3]triazole derivatives 214 have been synthesized via intramolecular [2+3] cycloaddition of azidealkyne derivatives 213 under microwave heating through metal-free one-pot reaction. The reaction was also performed by conventional heating under same reaction conditions, and it has been observed that microwave synthesis provides comparatively high yields even at large scale. This process is environmentally benign and provides quick access to diverse triazole derivatives (Scheme 61) [139].
R1
N
208 (78-90%)
IL-1 = [bmim]NO2], IL-2= [bmim]N3 R1 = H, CH3, NO2, Cl,I, F; R2 = CH3, Ph; R3 = CH3, OC2H5, Ph
Scheme 59 Ionic liquid-catalyzed synthesis of triazoles
excellent metal-free complementary one-pot method for the synthesis of trisubstituted 1,2,4-triazoles 212, from the reaction of carboxylic acid 209, primary amidines 210, and hydrazine 211. A wide range of diversely substituted triazoles were synthesized in 25–84 % yield from this efficient method as shown in Scheme 60 [138].
Synthesis of tetrazoles Tetrazoles and their fused-ring derivatives have widespread applications in organic synthesis, materials science (in explosive and information recording systems), and co-ordination chemistry as ligands. Although many procedures for tetrazole synthesis have been reported, there is still dearth of efficient processes [140]. A first report on the environment friendly one-pot synthesis of tetrazoles containing pyrazine from oxalaldehydes 215 and diaminomaleonitrile 216 in the presence of catalyst sodium azide 217 has been discussed [141]. The reaction is sensitive to the amount of catalyst and time; if the amount of catalyst and reaction time increased at constant tempera-
123
Mol Divers Scheme 60 Synthesis of 1,3,5-substituted 1,2,4-triazoles
(i) 1.1 eq. HATU, 3-4 eq. DIPEA O R2 DMF, 25 oC, 18h + R1 OH HN NH2 (ii)1.5 eq. NH2NHR3 (211) 10 eq. HOAc, 1-3 h 209 210
R2 N R1
N N R3
212 (23 examples yields 30-78%)
R1 = alkyl, aryl and hetroaryl; R2 = CH3, Ph, 4-NH2Ph,-CH2OCH3, -(C(CH3)2, 4-OCH3Ph,COOCH3, pyridine, 2-OCF3Ph, cyclopropane, 2-CH3-thiazole; R3 = -(C(CH3)2, -(C(CH3)3, -CH2CF3, 4-OCH3Ph, 4-ClPh, -CH2COOEt, 2,4-FPh, -(CH2)2N(CH3)2, hexane, bromopyridine, indole, quinoxaline
Scheme 61 Synthesis of fused triazoles under microwave irradiation
OH n
OH or R
n
R
n = 1 and 2 213a
( )n
n
213b
N N N R 214a
[(PhO2)PON3], DBU DMF, MW (150 oC), 20 min
N N N 214b
or
R
(34 compounds 40-85 % yields) R = Ph, 2-NH2Ph, 2-CF3Ph, 2 or 4-OCH3Ph, 2 or 4-NO2Ph, -CH2CH=CH2, 2-FPh, 4-C2H5Ph, -(CH2)2CH3
Scheme 62 Synthesis of tetrazoles catalyzed by sodium azide
R1
O
H2N
CN
H2N
CN
+ O
R2 215
NaN3 DMSO, 100 oC 3h
216
N
CN
N
CN
R1
N
R2
N
217
CN N N HN N
218
R1, R2 = H, Ph
O 219
R1 NH2 220 + R2 NC COOCH3 221
(i) TMSN3 222 CH3OH, rt
O
R1 N
(ii) TFA, DCE, rt
N N N N R2
223
(37 examples) R1 = Ph-CH2-, benzo[1,3]dioxole-CH2-, 4-OCH3Ph-CH2-, -CH2CH2OCH3,2, 3-(OCH3)2Ph -(CH2)2-, phenylmoprholine, 2,5-(OCH3)2Ph-CH2-, 2,6-Cl2Ph-CH2-, -CH2-thiphene, furan-CH2-, pyridine-CH2-, 3-CF3Ph-CH2-, 3,4-(OCH3)2Ph-CH2-4-F-PhCH2-, 4-OCH3Ph-CH2-, 4-CH3Ph-CH2-, 3,4-(OCH3)2-Ph-CH2CH2-, -4-CH3Ph-(CH2)2-, 2-FPh-(CH2)2-, CF3, -(CH2)2-OCH3, -CH2-hexyl, -(CH2)3-imidazole, (CH2)3-morpholine, hexyl, cyclopropane, -(CH2)2-imidazole, 1-benzyl-piperidine, 2,3-dihydro-benzo[1,4]dioxine; R2 = Ph, Ph-CH2-, 2,3-dihydro-benzo[1,4]dioxine, -(CH2)3CH3, 2,6-(CH3)2Ph
Scheme 63 Three-component Ugi-azide reaction for synthesis of pyrrolidinone tetrazoles
ture, second tetrazole ring is formed at free CN of pyrazine (Scheme 62). Scheme 63 depicts synthesis of substituted tetrazoles 222 from methyl levulinate 219, primary amines 220, isocyanides 221, and azidotrimethylsilane 222 (TMSN3 ). The reaction proceeded via a trifluoroacetic acid-catalyzed Ugiazide reaction. A wide range of substituted tetrazoles were prepared in good to high yield (40–83 %) [142].
123
X 224
S N C + R NH2 225
HN R
DMF I2, Et3N
N N N N
NaN3/DMF
226 (upto 85%)
X, R = H, Cl, Br, CH3, NO2 Scheme 64 Iodine-catalyzed synthesis of tetrazoles
X
Mol Divers Scheme 65 Synthesis of 1,5-disubstituted tetrazoles catalyzed by chlorotrimethylsilane
O
R
N 227
N H
R
CH3CN or CH3OH 1 eq.TMSCl 1 eq. NaN3
Ph + NC R1 228
O
N N H
R1
Ph N N N N 229 (16 compounds with 71-99% yields) iPr OTBS
R = H, CH3, OCH3, Cl, t-Bu, t-Oct, c-Hex, Ph, 4-CH3Ph, 4-BrPh, 4-NO2Ph,
H N R
N H
O O
(i) POCl3 (ii) NaN3/DMF
230 R = H, CH3, Cl, Br, NO2
Scheme 66 One-pot quinoxalines
synthesis
of
O
N N N N
NC 45
R N N N N 231 (77-84%)
bistetrazolo-[1,5-a:5 ,1 -c]-
CN
R2
R3 232
(ii) CH3CN, reflux
O
CN R2 N N N N 233 (52-71%)
R N
Catalyst = N
Among the various tetrazole derivatives, aminotetrazoles have aroused great interest in recent years because of their wide spectrum biological activities and their importance in explosives and propellants [143]. Yella et al. [144] proposed a novel regioselective one-pot pathway for synthesis of tetrazole derivatives 226 via condensation of isothiocyanates 224, amine derivatives 225, and sodium azide in the presence of catalytic amount of iodine as shown in Scheme 64. All the compounds were obtained in overall good yield and excellent regioselectivity. An expedient one-pot multi-component synthesis of tetrazole 229 containing tetrahydroisoquinoline skeleton has been described through the reaction of C,N-cyclic-N acylazomethine imines 227, isocyanides 228 catalyzed by chlorotrimethylsilane (TMSCl), and sodium azide in DCM or MeOH at room temperature (Scheme 65). The electronic effect of isocynide affects the time required and the yields of the respective product [145]. A one-pot synthesis for the synthesis of tetrazoles was developed as two-step reaction involving an POCl3 -mediated chlorination of quinoxaline-2,3-diones 230 followed by condensation with sodium azide (Scheme 66) [146]. A first organocatalytic approach to asymmetric synthesis of fused tetrazoles 233 has been investigated by Huang et al. [147]. Functionalized α, β-unsaturated ketones 232 and malononitrile 45 undergo an asymmetric Michael addition and subsequent intramolecular 1,3-dipolar cycloaddition reaction under optimized reaction conditions as described in Scheme 67. Fourteen derivatives were synthesized in high enantioselectivity and in good yield in the presence of 20 mol% organocatalyst.
R3
(i) Catalyst (20 mol%), TFA (40 mol%), DCM, 20 oC
+
R1
R = H, OCH3; R1 = NH2, OH; R2 = H, Br, Cl R3 = CH3, Ph, 4-CH3Ph, 4-BrPh, 4-ClPh
Scheme 67 One-pot two-step synthesis of tricyclic tetrazoles
Six-membered ring compounds with one nitrogen heteroatom Synthesis of pyridines Pyridine is one of the most prevalent heterocycles, well known in agro and pharmaceutical industries, and does not require any introduction to chemical community. Ricinine, Aricoline, Nicotinic acid, Paraquat, Chlorpyrifos, and Gleevec are some representative pyridine-containing molecules, which show potential therapeutic actions [148]. For such potential scaffolds many contemporary methods for their preparation are available. Many of the existing methods suffer from certain limitations with respect to workup, multistep strategies, or reaction condition and formation of byproducts [149]. Due to the potential biological activities, great attention is still devoted to the development of novel and operationally simple methods for their synthesis. In a recent report, Stark et al. [150] illustrated a twocomponent reaction of α, β-unsaturated ketimines 234 and N-sulfonyl compounds 235 in the presence of pivaloyl chloride ((CH3 )3 CCOCl) to afford 2,4,6-trisubstituted pyridines 236 in good yield. A number of events, namely deprotonation of sulfonyl compound, intermolecular Michael addition, lactamization, thiophenyl elimination, and N- to O-sulfonyl migration subsequently take place interestingly at high tem-
123
Mol Divers Scheme 68 One-pot synthesis of functionalized pyridines
COOR
COOR (i) 1.5 eq. (CH3)3CCOCl 1.5 eq. Pr2NEt, THF
SPh + Ph
N SO2Ar 234
HO
(ii) 20 mol DHPB 1 eq. Pr2NEt, 80 oC
O 235
Ph
N 236
SO2Ar
DHPB = (3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole) Ar = NO2, CN, CF3, F, Cl, CH3, OCH3 substituted aryl; R = CH3, C2H5, Bn
Scheme 69 Acid-catalyzed one-pot synthesis of pyridines
Ar1 O
O +
Ar1
Ar1 237
Ar2
CH3 238
NH4OAc CH3COOH Ar1
N
Ar2
239 (12 derivatives upto 85% yield)
Ar1 = 4-FPh; Ar2 = Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-OCH3Ph, 4-NO2Ph, 4-NH2Ph, 3 or 4- OHPh, 2,4-(OH)2Ph, 2,4-ClPh, 3,4-(CH3)2Ph
NH2 COOEt 240
PhMe or EtOH, AcOH 120 oC
+ O Ph 241
EtOOC N
Ph
242
Scheme 70 Synthesis of pyridines in a continuous flow microwave reactor
perature in THF, through a one-pot operation. At lower temperature (< 80 ◦ C) a mixture of pyridone and desired pyridine was obtained (Scheme 68). These pyridine derivatives were found biologically active against COX-2 (i.e., COX-2 inhibitors). In addition, the synthesis of 2,4,6-triaryl pyridines 239 has also been reported by Samshuddin et al. [151] from the one-pot condensation of 4,4 -difluoro chalcones 237, acetophenones 238, and ammonium acetate using acetic acid as solvent (Scheme 69). Continuous flow multi-step synthesis is a significant tool for the preparation of fine chemicals and pharmaceuticals at large scale [152]. Bagley et al. [153] have synthesized trisubstituted pyridines 242 from ethyl β-aminocrotonate 240 and ethynyl ketone 241 via an acid-catalyzed Michael addition and Bohlmann–Rahtz cyclodehydration reaction (Scheme 70). Desired pyridines were synthesized through a continuous flow reactor under microwave irradiation or conductive heating. Microwave heating provides higher yields in comparison to conductive heating and delivers regioselelective Bohlmann-Rahtz pyridines rapidly in a single operation. A one-pot three-component reaction of chalcone derivatives 243, ammonium acetate 155, and malononitrile 45 provides pyridines 244. Initially all the reactants were grinded and the same were introduced to ultrasonic irradiation in the absence of any additional catalyst [154]. The process is simple in operation and provides 2-amino-3cyano-4,6-diarylpyridines 244 in 81–86 % yields as shown in Scheme 71.
123
Enders et al. [155] reported that α, β-unsaturated aldehydes 246 and enaminones 245 react excellently to give tetrahydropyridin-2-ols 247, 1,4-dihydropyridines 248, and 3,4-dihydropyridin-2-ones 249 using Jørgensen-Hayashi catalyst in a one-pot reaction. The author suggested that electron-donating groups serving at R2 and R3 are essential for high enantioselectivity. The mechanistic sequence involves Michael addition-hemiaminalization followed by dehydration or oxidation using sodium sulfate or pyridinium chlorochromate (PCC), respectively, to get corresponding 1,4-dihydropyridines or 3,4-dihydropyridin-2-ones in good yields (Scheme 72). 3-Aza-1,5-enynes 250 are prone to undergo cyclization reaction to give pyridine derivatives, although most of the process involves metal catalyst for cyclization [156–159]. Recently, Xin et al. [160] have reported an efficient metal-free process for synthesis of pyridine derivatives 251 under mild reaction condition in two easy steps. 3-Aza-1,5-enynes were heated at 140 ◦ C for 10 h. in ethanol and then in DMF for 4 h. (by replacing ethanol to DMF). The product was obtained in good to excellent yield for a varying range of substrates. The key step for pyridine formation is an aza-Claisen rearrangement followed by electrocyclization and elimination of aryl sulfinic acid (Scheme 73). In addition, Bagley et al. [153] have developed an elegant pathway for synthesis of some Hantzsch 1,4-dihydropyridines 254 in excellent yield and regioselectivity by the onepot three-component reaction of ethyl acetoacetate 252, 3-substituted propargyl aldehydes 253, and ammonia under certain reaction conditions as shown in Scheme 74. Dicarbonyl compounds and their analogs are well known in the synthesis of pyridines [161,162]. Owing to the utility of dicarbonyls, Dong et al. [163] have developed a new route for the synthesis of highly substituted pyridines 258 via four-
Mol Divers Scheme 71 Pyridine synthesis under ultrasonic irradiation
CH3COONH4 155
O Ar
Ar1
243
CH2(CN)2
+
45
(i) grinding (ii) ultrasonic irradiation, ethanol <30 min. Ar1
Ar CN N
NH2
244
Ar = Ph, 4-ClPh, 4-OCH3Ph, 4-FPh; Ar1 = Ph, 4-ClPh, 4-BrPh
Scheme 72 Synthesis of dihydropyridines from aldehydes and enaminones
R1
O R2
N R3 248 (er = 85:15)
(i) 20 mol% catalyst 10 mol% PhCO2H EtOAc, rt
R3 HN +
O
(ii) 2 eq.Na2SO4 1eq. TMSCl, rt
R1
O
R2 245
R1
O R2
15 examples
N H
R2 N R3 249 (er = 90:10)
N R3 247 (upto >99:1 er)
catalyst =
O
O
HO
246
R1
(ii) 1 eq. PCC, rt
Ar Ar OTMS
R1 = Ph, 4-ClPh, 2 or 4-OCH3Ph; R2 = Ph, 4-OCH3Ph, 4-FPh, 4-CH3Ph R3 = Ph, 4-ClPh, 4-c-HexylPh, 4-MePh
Scheme 73 Synthesis of pyridines from aza-1,5-enynes
R2 COOCH3 R1
N
COOCH3
SO2R3 250
(i) C2H5OH, heat, argon 16-48h (ii) DMF, heat, 4h, argon
R2 COOCH3 R1
N
COOCH3
251 (21 examples 44-99%)
R1= Ph, 1-naphthyl, 2 or 3 or 4-CH3Ph, 2-CF3Ph, 4-FPh, 2-ClPh, 2-BrPh; R2 = Ph, n-Bu, n-Pr, 2 or 3 or 4-CH3Ph, 4-CH3OPh, 4-FPh, 4-ClPh; R3 = Ph, 4-CH3Ph, 2-ClPh
R
O 2 eq. 252 R
COOEt
+ 253 O
NH3 PhMe-AcOH microwave reactor
O
O
EtO
OEt N H 254 (up to 98%)
R = Ph, SiMe3
Scheme 74 One-pot synthesis of 1,4-dihydropyridines
component reaction of 1,3-dicarbonyls, aldehydes, alcohols, and malononitrile (255–257, 45) in the presence of sodium hydroxide. Among all the alcohols and bases employed in this reaction, ethanol with sodium hydroxide was found suitable.
Similar transformation was also observed by Shaikh et al. [164] for synthesis of pyridine derivatives in the presence of ammonia solution (Scheme 75). Talea et al. [165] have developed a synthetic route to obtain 1,4-dihydropyridines 261 from aldehydes 259, 1,3dicarbonyls 260, and ammonium acetate 155 over silicasupported 2,4,6-trichloro-1,3,5-triazine through Hantzsch synthetic route under solvent-free condition (Scheme 76, Path A). Shengrong et al. [166] developed the multicomponent synthesis of Hantzsch dihydropyridines 261 under ultrasonic irradiation by the condensation of substituted aldehydes 259, 1,3-dicarbonyls 260, and ammonium acetate in the presence of efficient organocatalyst
123
Mol Divers Scheme 75 Synthesis of pyridines from 1,3-dicarbonyls, aldehydes, malononitrile, and alcohol
O R1 C 256
O O 255
H
O
+
R
NaOH, rt
R2 OH 257
R1 CN
R N
O
R2
258 (23 compounds upto 89% yield)
NCCH2CN 45
R = PhNH-, 2 or 4-CH3PhNH-, 2 or 4-CH3OPhNH-, OC2H5, CH3 R1 = Ph, 4-subsPh, 2-CH3OPh;R2 = C2H5, CH3, n-C4H9, CH(CH3)2 O O
NH4OAc (155) silica-TCT rt, stirring
O
R CHO + 260
259
Path B
OR1
ultrasound irradiation 10 mol% L-Proline EtOH at 60 oC
Path A
R
O
R1O
OR1
N H 261 12 examples with 70-84 % yield Path D 5 mol% MTSA 3-4hr
Path C Triton X-100
261 261 261 (7 examples with yield upto 96%) (26 examples yield upto 96%) (16 examples upto 94% yields)
Path A: R = Ph, 4-CH3OPh, 3,4-(CH3O)2Ph, 4-OHPh, 4-OH-3-CH3OPh, 4-(CH3)2NPh, 4-ClPh,4-CH3Ph, 4-BrPh, 2- or 3- or 4-NO2; R1 = C2H5 Path B: R = Ph, 3- or 4-FPh, 4-CH3Ph, 4-CH3OPh, 2-Cl, 6-CH3Ph, 3-CH3, 4-FPh, 2,5-di-FPh; R1 = C2H5 Path C: R = subs. phenyl, 2-furyl, 2-pyridyl, n-propyl, Ph, R = C2H5 Path D: R= Ph, 4-OCH3Ph, 4-CH3Ph, 4-NO2Ph, 3- or 4-ClPh, 3- or 4-OHPh, furan, thiophine; R1 = C2H5, CH3
Scheme 76 One-pot three-component synthesis of dihydropyridines
L-proline (Scheme 76, Path B). The author also discussed some other catalysts for this conversion, among them Lasparatic acid, L-glutamic acid, and L-histidine provided quite favorable results. Rajeshwari et al. [167] synthesized 1,4-dihydropyridines by stereoselective pathway through coupling reaction of aldehyde, ethyl acetoacetate, and ammonium acetate in the presence of chlorosulfonic acid on simple grinding. Recently, Triton X-100 was also studied for the synthesis of 1,4-dihydropyridine in aqueous medium at room temperature [168] (Scheme 76, Path C). Giving an extension to their study on melamine trisulfonic acid (MTSA) catalyst, Mansoor et al. [169] reported a solvent-free one-pot threecomponent reaction of aromatic aldehydes, acetoacetate, and ammonium acetate to afford 1,4-dihydropyridines. 5 mol% MTSA was employed in this transformation to synthesize 16 diverse derivatives in excellent yield (Scheme 76, Path D). Synthesis of quinolines and other pyridine condensed compounds Quinolines are found in many natural products and also treated as medicinally important compounds having numerous biological activities [170]. Thus, this class of nitrogencontaining heterocycles has attracted the attention of many
123
R + O 262
NC
CN
R1OH 264 Na MW, 320W, 4-8 min
263
R CN N
O
R1
265 (upto 95%)
R = Ph, 4-CH3Ph, 4-ClPh, 4-FPh, 4-OHPh, 4-OCH3Ph; R1 = CH3, C2H5
Scheme 77 Sodium-catalyzed synthesis of pyridines
chemists to develop new and operationally simple methods for their synthesis. A practical approach for the synthesis of hydroquinolines has been described by Dodiya et al. [171]. The method consists of microwave-assisted reaction of cyclohexanone 262 and arylidene malononitrile derivatives 263 in the presence of alcohol 264 containing sodium as catalyst [171] (Scheme 77). Similarly, quinolines 269 were synthesized through microwave-assisted domino a reaction described by Kulkarni et al. in 2010 [172]. The pathway utilizes efficiency of acidic clay montmorillonite K-10 as catalyst for condensation of aldehydes 266, anilines 267, and terminal aryl alkynes 268. The process involves a series of chemical events such as intermolecular addition of alkyne to in situ generated imine/ring-closure followed by oxidative aromatization (Scheme 78).
Mol Divers Scheme 78 Microwave-assisted domino synthesis of quinolines
NH2
E K-10, MW,15 min, 80 oC R1 72-96%
O H
R2
+ R
266
+ E 268
267
N 269
R2
(27 examples in 56-96 % yields) R = H, CH3, C2H5, CF3, Cl, Br, F, NO2, CN; R2 = Ph, 4-CH3Ph, 4-NO2Ph, 4-FPh, 4-CNPh, 2-BrPh, 3,4-ClPh, PhCO-, hexane; E = 4-COOCH3Ph, 4-CH3Ph, 4-FPh
Scheme 79 One-pot synthesis of fused quinolines
Ph
O R 281
Ph + R 1 NH2
10 mol% CAN O CH3OH, rt R R2 2h, 84 %
O
282
P2O5/SiO2 80 oC Scheme 82a solvent free, 15-40 min
R2 N 283
R1
10 mol % Scheme-8 2b Li(OTf),m 80 oC 10-35 min. 283 (11 derivatives upto 96%)
283 (upto 93 %, 15 derivatives)
82. R1 = COOCl, R2 = COOEt 82a. R2 = COOEt, COOCH3, COPh, COCH3, R1 = CH3, H, R = Cl, H; R1, R2 = cyclohexanone, cyclopentanone, 1,3-cyclohexanedione, 5-tert-butyl-cyclohexane-1,3-dione 82b. R2 = COOEt, COOCH3, COOBn, R1 =COCH2Cl, COCH3,R = H, Cl, R1, R2 = dimedone, cyclohexanone
Scheme 80 Sulfamic acid-catalyzed synthesis of quinolines
+
R 273
NH2
2 eq. R1
O 274
10 mol% sulfamic acid neat, 80 oC solvent-free
R R
R1 N 275 (12 derivatives, yield = 63-86%)
R = H, CH3, OCH3, Cl, Br; R1= Ph, Et, PhCH2, 4-BrPh, CH2=CH2(CH2)n-
An operationally simple and metal-free methodology for synthesis of tetracyclic-fused quinolines has been introduced by Gao et al. [173] involving the Friedlander reaction of benzophenone derivatives 270 and substituted ethylacetoacetates 271 (Scheme 79, Path A). Silica-supported P2 O5 catalytic system was developed for synthesis of quinoline derivatives via the Friedlander annulation reaction of benzophenones 270 and ethylacetoacetates 271 in 15–40 min. The reaction was also performed in various solvents but solvent-free protocol provided the highest yield (Scheme 79, Path B) [174]. The synthesis of ethyl quinoline derivatives 272 was also studied by Atar et al. [175] using Li(OTf) at 80◦ C in neat condition (Scheme 79, Path C). The catalyst is reproducible and can be utilized up to 4 cycles with only a slight decrease in product yield. A series of quinoline derivatives 275 have been synthesized by two-component reaction of substituted anilines 273 and aldehydes 274 using sulfamic acid as catalyst (Scheme 80). The catalyst can be reused without any loss in the product yield, and provide regioselective quinolines when dis-symmetrical arylamines were employed in the reaction [176].
Furthermore, quinoline derivatives have also been synthesized from substituted aminoketones 276 and acetylene derivatives 277. Asghari et al. [177] synthesized 4arylquinolines 278 by an intramolecular Wittig reaction of phosphoranes in situ generated from addition of acetylenic derivatives 276 to aminess 277 in the presence of triphenylphosphine followed by oxidation of functionalized phosphoranes. The yields of the product depend upon the substituent present on aromatic amines and acetylenes (Scheme 81, Path A). Base-catalyzed Pfitzinger reaction has been considerably known in the literature for designing many quinoline4-carboxylic acid compounds. Recently, Lv et al. [178] reported a modified Pfitzinger cyclization in two steps from isatin derivatives 279 and ketone derivatives 280 in water. The first step is a traditional base-catalyzed isatin ringopening and the second step involves an acid catalysis to form desired quinolines. Among the acids used for optimization of reaction conditions, p-TsOH and CAN provided desired quinoline-4-carboxylic acids in good to high yield (Scheme 81 Path B).
123
Mol Divers R
O R PPh , toluene R 3 1 reflux NH
R2 C C R3 + R1 276
277
2
Path A
O R2
N 278 (65-90%)
R3
R2
(i) KOH/H2O
O R3 280
(ii) 1, 3-cyclohexandione TsOH or CAN Path B
+ R1
O 279
N H
R = COOH; R1 = H; R2 = CH3, OCH3, cyclic amines; R3 = CH3
R = Ar, R1 = H, Cl; R2, R3 = COOCH3, COOC2H5
Scheme 81 Quinoline derivatives synthesized from aminoketones and acetylene derivatives Scheme 82 One-pot two-step synthesis of quinolines
R''
O R1
R
O + R2
(ii) 1N HCl, 5 min.
282
281
O
(i) 10 mol PPh3, CH3CN R rt, 1.5-19 h
R'
N 283 (24 compounds in 88-99% yields)
R = H, CF3, 4-F, 4-OCH3, 4, 5-OCH3, 4,5-F, fused phenyl ring; R1 = CH3, Ph, cyclohexane, cyclopropane; R2 = CH3, Ph, -OCH3, 2-FPh, 4-BrPh, 3,4-ClPh, 3-CNPh, 3-NO2Ph, 3,4-OCH3Ph, thiophene, naphtheline, -SO2Ph, PhCOCH2C
Scheme 83 Iodine-catalyzed synthesis of diiodoquinolines
R2
R2 Y
5 eq. electropilic reagent (Y) R1 N3
R3
R1
CH3NO2, 0.5-42h
285
284
N
R3
(25 examples yields up to 99%) R1 = H, Br, Cl; R2 = H, OAc; R3 = Ph, 4-CH3Ph, 3,5-FPh, CH3, cyclohexane, 1-azido-2-(2-propynyl)benzene; Y = I2, Br2, ICl, NBS, NIS, and HNTf2 I
R2 0.10 mmol I2 R1 NC 286
CHCl3, 4h
R2 R1 N
I
287 (11 examples in 46-96% yields)
R1 = H, CH3, CF3; R2 = Ph, 4-OCH3Ph, 4-CH3Ph, 4-ClPh, 4-FPh, 4-NO2Ph, CH3(CH2)3-, TMS, cyclohexene
In 2012, Khong and Kwon [179] published their work on utilization of phosphine, substituted aldehydes 281, and acetylenes 282 for the synthesis of 3-acetylated quinolines (Scheme 82). The synthesis is completed in two steps involving a Michael addition followed by an Aldol cyclization in the first step to generate N-tosyldihydroquinoline intermediate, which in the presence of aqueous HCl is then transformed into desired quinolines 283 all in a one-pot reaction. Substituted 1-azido-2-(2-propynyl)benzene 284 undergoes intramolecular cyclization in the presence of halogenated electrophilic reagent in nitromethane to produce substituted quinolines 285 as shown in Scheme 83. A vari-
123
ety of electrophilic reagents (halogen containing) in various solvents were subjected to electrophilic cyclization. All halogenated reagents provide desired quinolines in good yield. The reactivity order of these electrophilic reagents is as follows: Br2 > NIS > NBS > ICl > I2 [180]. It was observed that some of reactants gave desired products after 60 h of heating which is generally unfavorable. In this respect this opens a new challenge in the electrophilic cyclization reactions to be developed in coming years. Recently, Mitamura et al. [181] devised another expedient approach involving the intramolecular cyclization of oalkynylaryl isocyanides 286 to provide 2,4-diiodoquinolines
Mol Divers
(i) stirring, 3-4h CH3COOH, rt.
EtO
+
R
(ii) reflux 3-4h
NH2 288
derivatives 291, secondary amines 292, and Friedlander substrate o-aminoarylcarbaldehydes 294 [185]. The four-membered ring system 3-ethoxycyclobutanones 296 undergoes [3 + 3] annulation reaction with substituted aromatic amines 297, and provides a facile route for the regioselective synthesis of 2-alkylquinolines 298 in very good yield as shown in Scheme 86. BF3 .OEt2 (0.5–1 eq.) was optimized as catalyst of choice for the annulation in dichloromethane at room temperature providing overall good results in 8–12 h [186].
R
289
N 290 (upto 72%)
R = H, CH3, OCH3, CF3,Br, F, Cl Scheme 84 2-Methylquinolines from substituted anilines and ethyl vinyl ether
287 in moderate yields. In this process iodine serves as excellent catalyst in chloroform under photoirradiation conditions (Scheme 83). This process also overcomes the problem arising in Huo’s process (long reaction time) but some loss in the overall yield was observed. 2-Methylquinolines have been known as valuable intermediates in synthesis of natural and synthetic products [182,183]. In this regard, simple and economical synthetic methodologies for their synthesis remain an area of high interest. Recently, Mahadevan and coworkers [184] developed an efficient two-component synthesis of 2-methylquinolines 290 from substituted anilines 288 and ethyl vinyl ether 289 through an aza-Diels-Alder reaction in the presence of acetic acid (Scheme 84). Scheme 85 depicts the synthesis of biologically active 3aminoquinolines 295 from the two-step reaction of bromo Br
CH2(OEt)2 or O
R''
R
HN R1 Br 292
+
291
(i) K2CO3, KI, CH3COCH3 reflux (ii) conc. HCl in CH3OH, reflux R2 = Ph, H,
Others Gordon et al. [187] reported a simple, one-pot protocol for the preparation of quinolin-2-(1H)-ones 303 via the four-component Ugi–Knoevenagel reaction of aldehydes 299 (containing only electron-donating group), aminophenylketones 300, cyanoacetic acid 301, and aliphatic isocyanides 302 (Scheme 87). Aldehydes containing electronwithdrawing groups and aromatic isocynides were not found suitable for the formation of desired quinolin derivatives. Instead, an α-amino amide derivative was formed through 3-component Ugi-reaction. Raval and co workers [188] synthesized a series of imidazole fused quinoline derivatives from equimolar amount of enaminones 304, aldehydes 305, and malononitrile 45 using 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate (ionic liquid) and methanol (co-solvent). The reaction was carried out
(294) N R (iii) o-aminoarylcarbaldehyde R1 NaOH, C2H5OH, reflux R2 O F3C 293
Br
R N N
R1
R2
295
(21 derivatives, 15-89%) NHRR1 = piperazine, subs-piperazine, morpholine, pyrollidine, piperidine
Scheme 85 One-pot synthesis of substituted quinolines Scheme 86 One-pot regioselective synthesis of regioselective synthesis of 2-alkylquinolines
O
R1 R 2
NH2 BF3.OEt2 , DCM, rt R4
+ R3
296
OC2H5
R3 R4
R2
N 298
297
R1
(32 examples with yield 43-97%)
R1 = H, R2 = Bn, Pr, C2H5, cyclic ring R3 = H, CH3; R4 = CH3, OCH3, Br, NO2, -COPh
Scheme 87 Four-component Ugi-Knoevenagel reaction for synthesis of quinolines
O
300
Ar
O O R 299 NC OH + 301 NH2 C N R1 302
O NC CH3OH, rt, 3h
R
H N
N
R1
O
R
303 (49-71%)
R =CH3, Ph; R1 = C6H14, C4H8O2, C9H20,C5H14Si, Ph, cyclohexane
123
Mol Divers Scheme 88 Fused quinolines in the presence of ionic liquid
CN
NC O
45
H
+ 304
O
O
R
[DBU][Ac] (6.25 mol%) CH3OH
R 305
CN N
NHCH2COOH 306
NH O
R = Ph, 4-(CH3)2N-Ph, 3,4,5-(OCH3)3Ph, 2- or 3- or 4-NO 2Ph
O R O
O OEt
+
308
O
NH4OAc (155) DES, 60 oC, 20 min
C H 307
R COOEt
stirring O
O 309
60 oC Path B
N H
Path A
310 (80-95%)
NC
NH4OAc 5 mol% MTSA
+ O
O 309
CN 45
R
CHO 311
R = Ph, ClPh, OHPh, FPh, NO2Ph
R = CH3, C2H5, n-C4H9, 3-O2NPh, 4-(CH3)2N(C6H4), 2-ClPh, 4-CH3Ph, Ph
Scheme 89 One-pot multi-component synthesis of dihydropyridines Scheme 90 Microwave-assisted domino Knoevenagel-Michaelcyclization reaction
O Ar CN
C 312 +
CN 45
H HN O
O
N H 313
MW, DMF 250 W, 120 ºC or DAHP, H2O:EtOH (2:1) NH2 reflux
Ar
O
CN
HN O
N H
N
NH2
314
Ar = Ph, 2-ClPh, 2,4-Cl2Ph, 3-OHPh, 4-OCH3Ph, 4-CH3Ph, 4-NO2Ph
under ultrasound irradiation to afford all the products in good to high yield in less than 2 h (Scheme 88). Ever since the phenomena of deep eutectic solvents emerged in 2003, it has been studied for organic synthesis, natural products research, and biological applications [189,190]. Recently, a group of deep eutectic solvents (DES) was studied for the synthesis of dihydropyridine 310 from simple starting substrates like substituted aldehydes 307, dimedone 309, ethyl acetoacetate 308, and ammonium acetate 155 at 60 ◦ C. The reaction was completed in 20 min and the product was recovered by adding water to the obtained solid mass and filtering the product [191]. Similar pyridine derivatives have been synthesized under solventfree condition at 60 ◦ C via Hantzsch reaction in the presence of 5 mol% melamine trisulfonic acid (MTSA) as shown in Scheme 89 (Path B) [192]. Balalaie et al. [193] published an efficient three-component synthesis of pyrimidine fused pyridines through a domino Knoevenagel–Michael–cyclization reaction of aromatic aldehydes 312, 4(6)-aminouracil 313, and malononitrile 45 under microwave irradiation at 120 ◦ C (Scheme 90). This reaction was also conducted in aqueous media using 10 mol% diammonium hydrogen phosphate. The value of this
123
approach lies in the functional group tolerance and the operational ease of the method. Synthesis of piperidines Piperidines are found extensively in many natural compounds and pharmaceuticals. This privileged pharmacologically active moiety plays a crucial role in leading drug development and has emerged as strong candidates for future drug discovery [194]. A variety of methods have been developed for the preparation of piperidines in the past few decades. Despite these achievements, it is still highly desirable to develop more flexible, operationally simple methods with broad functional group tolerance. Phenylboronic acid-catalyzed, one-pot, three-component synthesis of highly substituted piperidines has been devised by reaction of 1,3- dicarbonyl compounds 315, aromatic aldehydes 316, and anilines 317 (Scheme 91, Path A). Other catalysts such as ZnCl2 , L-proline, and iodine were also studied but the yield observed in these cases was low in comparision to the phenylboronic acid-catalyzed approach [195]. Tetrabutylammonium tribromide (TBATB) has been utilized in the synthesis of 318 from 1,3-dicarbonyls, aromatic alde-
Mol Divers Scheme 91 One-pot synthesis of piperidines
(44-89%) 318
(27 examples with 67-93% yield) 318 Path D CH3COOH, rt
Path E
p-TsOH-H2O ethanol
R O O 2 NH R1 C H 10 mol% R3 O O 316 phenylboronic acid R4 + R4 R3 Path A R1 N R1 R2NH2 315 317 R2 318 TBATB Path C [K+PEG]Br3Path B C2H5OH, rt 318 (18 examples, 30-82%)
318 (14 examples, 30-90%)
Path A: R1 = R2 = substituted phenyl; R3 = H, R4 = OCH3, OC2H5 Path B: R1 = Ph, 4-CH3Ph, 4-BrPh, 4-ClPh, 3,4,5-OCH3Ph, 3- or 4-NO2Ph; R2 = Ph, 4-BrPh, 4-OCH3Ph, 4-CH3Ph; R3 =H, CH2CH3; R4 = OCH3, OC2H5 Path C: R1 = Ph, 4-CH3Ph 4-OCH3Ph, 4-NO2Ph, 4-ClPh; R 2 = Ph, 4-CH3Ph, 4-OCH3Ph; R3 = H; R4 = OCH3, OC2H5 Path D: R1 = Ph, 4-CH3Ph, 4-ClPh, 4-FPh, 4-BrPh, 4-OCH3Ph, 4-NO2Ph, 2-thienyl; R2 = Ph, 4-CH3Ph, 4-ClPh, 4-FPh, 4-BrPh, 4-OCH3Ph, 4-NO2Ph; R 3 = H; R 4 = CH3, C2H5 Path E: R1 = R2 = 4-MePh, 4-ClPh, 4-FPh, 4-BrPh, 4-OCH 3Ph, 4-NO2Ph; R3 = H; R4 = OCH3, OC2H5
Scheme 92 Synthesis of piperidines catalyzed by N-heterocyclic carbene
R1 O
O R2
R3 +
NHC-DBU (20 mol%) THF, stirring at rt.
O
R2 O
N
R1 319
O
Ph
N O
320
R3 Ph
321 (19 example, yields 76-96%)
R1 = Ph, 4-CH3Ph, 4-OCH3Ph, 4-ClPh, 4-BrPh, 4NO2Ph; R2 = H, CN, NO2; R3 = H, CH3
O R2 322
O H
(i) 5 mol% catalyst R2 toluene, rt.
+ R1
NO2
(ii) R3 H
R1 NO2 324
323 catalyst = N H
N
Ns
OH R2
325 K2CO3 R1 1,4-dioxane, rt. removel of solvent
Ph Ph OTMS
N
O Ns TsOH R3
NO2 326
R2
N
allylalcohol R 1
Ns R3
NO2 327
13 compounds upto 88% yields and 99 % ee
R1 = Ph, 4-OCH3Ph, 4-BrPh, furan; R2 = CH3,-CH2CH2CH3, -CH2CH3 R3 = Ph, 4-OCH3Ph, 4-BrPh
Scheme 93 Substituted piperidines from aldehydes, nitroalkenes, and imine derivatives
hydes, and amines at room temperature (Scheme 91, Path B) [196]. A PEG-embedded catalytic system [K+ PEG]Br− 3 has been devised by Jain and coworkers [197] for the onepot three-component synthesis of substituted piperidines 318 (Scheme 91, Path C). The catalyst can be regenerated by treating the residue of reaction with molecular bromine. It should
be mentioned that the electron-donating groups on aniline facilitated the reaction and provided good to excellent yield of desired products where as electron-withdrawing groups on aniline or aldehyde dramatically decreased the yield. Very recently, Lashkari [198] reported synthesis of 318 via intramolecular Mannich reaction of 1,3-dicarbonyls 315, aro-
123
Mol Divers
R1 EtO 328
O
(i) LDA, THF, -50 oC 1h (ii) THF, -50 oC, 3-4h O R N 3 (329) R2 (iii) sat. solution of NH4Cl
OH
ene (DBU) in THF provided the highest yield (upto 86 %) and N,N-diisopropylethylamine (DIPEA, a poor nucleophile) and potassium tert-butoxide (t-BuOK) provided the lowest. A slight decrease in the amount of catalyst showed a remarkable decrease in the yield of corresponding piperidines (Scheme 92). A combination of multiple transformations through a domino one-pot reaction allowed the synthesis of fully substituted piperidines from aldehydes 322, nitroalkenes 323, and imine derivatives 324. The reaction takes place in three successive steps— Michael reaction, aza-Henry reaction/hemiaminalization reaction followed by allylation in the presence of toluene, 1,4-dioxane and dichloromethane, respectively. The organocatalyst in the first step and a base (K2 CO3 ) in the second step are TsOH in allylation reaction in catalytic amounts were required to generate desired piperidines with high enantio- and diastereo-selectivity. The plausible reaction sequence is described in Scheme 93 [202]. Ghorai et al. [203] reported a highly enantio- and diasterioselective synthesis of highly substituted piperidines 330 via an imino-Aldol-aza-Michael pathway catalyzed by LDA. The methodology was applied to several α-arylmethylideneβ-keto esters 328 and aryl aldimines 329 to assess the generality of the process. The stereochemistry of the compounds was established on the basis of spectral and crystal data (Scheme 94). Kumar et al. [204] reported a novel and highly stereoselective [4 + 2] annulation process for synthesis of 2,3disubstituted piperidines 333. The whole transformation was realized through a cascade Mannich-reductive cyclization of glutaraldehyde 331 and aldimines 332 as described in Scheme 95. The electron-donating groups on the imines were not found favorable for this conversion.
COOEt R1
N R3 330
R2
(yield upto 70% with >99 dr) R1 = Ph, 3-BrPh, 2 or 4-ClPh, 4-CH3Ph, 4-OCH3Ph, 4-NO2Ph R2 = Ph, 4-CNPh; R3 = Ts, SO2Ph
Scheme 94 Imino-aldol-aza-Michael pathway for piperidine synthesis
matic aldehydes 316, and amines 317 in the presence of acetic acid which behaves as a solvent as well as catalyst at room temperature. The process is simple and provides a wide range of substrate scope with electron-withdrawing and electrondonating groups present on aniline and aldehyde (Scheme 91, Path D). p-Toluenesulfonic acid monohydrate in ethanol was also found as a suitable catalyst for the intramolecular Mannich needed for the preparation of piperidines (Scheme 91, Path E) [199]. Several other catalysts like trityl chloride for the synthesis of substituted piperidines from anilines, aldehydes, and 1,3-dicarbonyl compounds have also been discussed [200]. In late 2012, Yadav et al. [201] demonstrated a diastereoselective synthesis of piperidines in the presence of an organocatalyst N-heterocyclic carbene (NHC, generated from imidazolium salt) and a base. This organocatalytic transformation was applied to a range of α, β-unsaturated aldehydes 319 and azalactones 320 to produce substituted piperidines 321. The suggested mechanism involved in this transformations is an azalactone ring-opening reaction followed by piperidine ring-closing. The reaction was optimized with various bases in different solvents, among them non-nucleophilic base 1,8-diazabicyclo[5.4.0]undec-7Scheme 95 Piperidines from glutaraldehyde and aldimines
PMP
OHC
+
(i) 10 mol% L-proline and DMSO at 10 oC
N
OHC
R
331
332
OH N R PMP
(ii) 100 mol % CH3COOH NaBH4, H2O, rt.
333 (26 examples in 58-90% yield and up to >99% ee)
R = CH3, aryl, heteroaryl, alkenyl
Scheme 96 Stereoselective one-pot synthesis of pipecolic acids
O
R
HN Tr 334
O
(i) TFA, CH2Cl2 (ii) PhCHO, Et 3N THF, 4A mol. seives COOCH3 (iii) NaBH3CN, CH3OH, rt
R
N Bn 335
COOCH3
R = Ph, -(CH2)2Ph, 4-CH3Ph, 3-NO2Ph, i-Bu, CH3, 4-OCH3Ph, 4-BrPh, 4-(3' -NO2C6H4)Ph
123
Mol Divers Scheme 97 Meldrum’s acid containing piperidines from Meldrum’s acid, aromatic aldehydes, nitrostyrenes, and ammonium acetate
Ar1 O
O O
O
NH4OAc 155 Et3N (2 equiv), EtOH
+ Ar2
336
O
337
O2N
45 oC
NO2
Ar2
338
Ar1 O O O O Ar2
N H 339
Ar1 = 4-ClPh, 3- or 4-CH3Ph, 4- or 5-OCH3Ph, 3-OH-Ph, 4-FPh, thiophene, 3-F-Ph-O-Ph, 4-CF3Ph, 2-(4-ClPh)O; Ar2 = Ph, 4-CH3Ph, 4- or 5-OCH3Ph, 4-FPh, 2- or 4-NO 2Ph, 4-BrPh
Ph N 343
N N C R
(i) CH3O, HCl H3CO
NH.HCl (ii) NH3, CH3ONa
H2N
N
PF6
R
NaOEt
R 342
R 341
340
NH
Ph N 344
R = cyclohexane, piperazine, pyridine, 4-NO2Ph, 2-OCH3PhCH2-, PhCH2N-piperazine, 3-OHPh, 2-Cl-pyridin-CH2-, CH3CH2OCH2-
Scheme 98 One-pot synthesis of pyrimidines NC
CN 45
345
+
RCHO
R Path A P2O5, ethanol
X H2N
346
NH2
reflux
HX
(9 examples 80-92%)
Path B
CN
N
NH
Et3N, 4 eq. H2O, rt N 348
NH2 (23 examples, 35-83%)
X = S, O R = Ph, 2 or 3 or 4-ClPh, 4-N,N-(CH3)2Ph, 2 or 3-NO2Ph, 3,4-(OCH3)Ph, Ph-CH=CH-
XH + 45
H2N 347
XH = S-CH3, S-C2H5, S-PhCH2, S-n-Bu, S-Allyl R = alkyl, aryl, hetroaryl R1 = CH3, C2H5, Ph, cyclopentyl, n-Bu, allyl, PhCH2
Scheme 99 One-pot synthesis of substituted pyrimidines
Naturally occurring pipecolic acid is an important amino acid found in many metabolites in plants, microorganisms, and animals and is an important substrate of many synthetic peptides. It is also an important constituent of many synthetic bioactive entities. This vast area of pipecolic acid importance has gained the attention of many chemists to develop cheap and operationally simple methods to generate pipecolic acid [205,206]. Fowler et al. [207] developed a method for the preparation of pipecolic acid by a stereoselective one-pot three-step reaction of E-enones 334 (Scheme 96). The scope of the process was explored with limited substrates. In first step removal of the trityl-protecting group of E-enones 334 takes place using trifluroacetic acid in the presence of DCM followed by the reaction with benzaladehyde to afford an intermediate imine (not isolated); subsequent reduction and cyclization in the third step provided 2,6-trans-6-substituted-4-oxo-Lpipecolic acids 335 in good yields (Scheme 96). Meldrum’s acid containing piperidines 339 have been synthesized from five-component reaction of Meldrum’s acid
R1
x
CHO
+ HN
NH2 . HCl 349
R2
Br 350
Et3N, reflux dioxane
N
R1
N R2 351 (22 compounds yields 74-95%) X
X = H, CH3, Ph, 4-CF3Ph, 4-ClPh, 4-CH3Ph, pyridin-4-yl; R1 = H, cycloalkyl; R2 = Ph, 4-ClPh, 4-CH3Ph, -(CH2)4-
Scheme 100 Dihydropyrimidinone from amidine hydrochlorides and bromovinyl aldehydes
336, aromatic aldehydes 337, substituted β-nitrostyrenes 338, and ammonium acetate 155 involving a sequence of reactions—(i) Michael addition, (ii) aza-Mannich reaction, (iii) formation of acyclic imines followed by intermolecular aza-Mannich reaction. The whole transformation takes place in a one-pot reaction and tolerates a wide range of substrates for the synthesis of pharmacologically important piperidine derivatives [208] (Scheme 97).
123
Mol Divers Scheme 101 Ionic liquid-catalyzed synthesis of pyrimidines
Scheme 102 Three-component Biginelli-type reaction for the synthesis of pyrimidines
R1
R1CHO
OR [DABCO](SO3H)2Cl2(IL) HN C2H5OH H2N NH2 N X OR + H 354 352 355 (14 compounds upto 96% yield) X = O, S; R = CH3, C2H5; R1 = subs-phenyl O
X
353
O
R1 NH2 R
N
+
356
toluene, reflux CF3SO3H R1CHO R 357
N
N +
N
R2
ketone 358
359a major upto 69%
N
R2 R1 359b minor upto 8% R
R1
R = pyridine,3-Cl-pyridine, 3-COOEt-pyridine, 3-piperidine-pyridine; R1 = Ph, 4-ClPh, 4-NO2Ph, 4-OCH3Ph, 2 or 3 or 4-CH3Ph, thiophene-CH2-, PhCH2-, pyridine, CH3(CH2)3-, CH3(CH2)2-, cyclohexane-CH2-, cyclopentane-CH2-; ketone or aldehydes = cyclohexanone, phenyl-acetaldehyde, pentan-3-one, acetophenone, 1,2-diphenyl-ethanone, pentanal, cyclopentanone, Cycloheptanone
Scheme 103 Pyrazolopyrimidines from substituted pyrazoles
O
CN N
POCl3 N R1
NH2
NH
N
R2COOH 361
N R1
360
N
R
362
R1 = H, n-Bu, 2,6-Cl2-4-CF3Ph, 4-OCH3Ph, 2,4-(NO2)2Ph, 2,4,6-(Cl)3Ph, 2-ClPh, R2 = H, CH3, -CH2CH3,
Six-membered ring compounds with two nitrogen heteroatoms Synthesis of pyrimidines Recently, a report on pyrimidines synthesis from nitriles 340 and vinamidinium salt 343 was published. This practically controlled approach involves the formation of amidine 342 intermediates by reaction of ammonia and imidates 341 (a hydrochloride salt of imidate ester formed in the presence of HCl and methanol from nitriles 340) and finally a competitive reaction of vinamidinium salt 343 with amidines 342 gives pyrimidines (Scheme 98). The selectivity of vinamidinium salt for the amidate formation is crucial for the selective synthesis of substituted pyrimidines 344 [209]. Another important methodology reported for pyrimidine synthesis involves the three-component reaction of aldehydes 345 with malononitrile 45 and thiourea/urea 346 in the presence of phosphorus pentoxide [210]. Highly substituted pyrimidines were also furnished by the catalysis of SDS or triethylamine. It was noteworthy that SDS requires an additional base to facilitate the reaction while triethylamine alone
123
H N N N 363
NH2
+
RCHO 364 NC
45
CN
NH2 NaOH, C2H5OH 1h
N
N
CN
N
R N H 365 (35-88%)
R = 4-CH3Ph, 3,4-2-CH3OPh, 3-HOPh, 4-FPh, 4-BrPh, 2 or 4-ClPh, 2,4-ClPh, 4-O2NPh, 4-(CH3)2NPh, 3 or 4-pyridyl
Scheme 104 Synthesis of triazole fused pyrimidines under ultrasound irradiation
does not and provides good results as shown in Scheme 99 (Path B) [211]. Triethylamine was also studied by Yan et al. [212] for the condensation reaction of amidine hydrochlorides 349 and β-bromovinyl aldehydes 350 to produce pyrimidines 351 (Scheme 100) in good to excellent yields. Dihydropyrimidinone derivatives 355 have been synthesized from the reaction of ethyl acetoacetate derivatives 352, aldehydes, and thiourea/urea (353, 354) through a Biginelli-type reaction in the presence of acid functionalized ionic liquid derived from
Mol Divers Scheme 105 One-pot synthesis of dihydrotetrazolo[1,5a]pyrimidines
H N
H2N
N N 366
R1
RCHO 367 R1
+
N
5 mol.% TBBDA, 100 oC
N
N N N
O 368
N H
R
369 (16 examples, yield 82-98%)
R = H, CH3, Cl; R1 = H, CH3, OCH3,COCH3, Cl, F
Scheme 106 Three-component water-promoted synthesis of chromenopyrimidine
CHO R2 R
+
N H
R3
R2
R1
CN R1
O
R3 N
372
370
N
water, heat 80 °C, 8-10h O
N
R
373 (10 examples 77-90%)
NH
371
R = Ph, 2-OHPh, 4-CH3Ph, 4-ClPh, 4-CF3Ph, 2-OH-5-ClPh, 2-OH-5-BrPh, 2-OH-5-OCH3Ph, 2-OH-4-OCH3Ph; R1 = H, Cl, Br, OCH3; R2= Ph, CH3, Et; R3 = CH3, Et
DABCO as an effective catalyst in ethanol (Scheme 101) [213]. The three-component Biginelli-type condensation of 2aminopyridines 356, aldehydes 357, and ketones 358 in the presence of 0.5 equivalent trifluoromethanesulfonic acid (CF3 SO3 H) provides 4H-pyrido[1,2-a]pyrimidines 359 (Scheme 102). A broad range of aromatic and aliphatic ketones and aldehydes were introduced in this study to know the generality of the reaction and the results were found in good agreement [214]. Pyrazolopyrimidines 362 have been synthesized from the reaction of substituted pyrazoles 360 and aliphatic acids 361 in the presence of POCl3 [215] (Scheme 103). A fused pyrimidine-triazole system 365 has been constructed from triazole 363, malononitrile 45, and aldehydes 364 through a facile process under ultrasound irradiation at 25–30 ◦ C in the presence of 20 mol% NaOH. Solvents including acetonitrile and water were also employed, but only ethanol afforded products in high yields [216] (Scheme 104). Ghorbani-Vaghei et al. [217] directly heated a mixture of tetrazole 366, aldehydes 367, and ketones 368 (or dicarbonyl compounds) in the presence of N,N,N ,N tetrabromobenzene-1,3-disulfonylamide (TBBDA) catalyst under solvent-free conditions resulting in the formation of dihydrotetrazolo[1,5-a]pyrimidines 369 in good yield. The catalyst can be easily recovered and reused without any significant loss in catalytic activity even after three cycles (Scheme 105). Recently, the one-pot three-component water-promoted synthesis of chromenopyrimidine 373 has been devised by Zonouzi et al. [218] by heating aldehydes 370,
R1 SeO2Ph + 374
R2
NHR1'
catalyst solvent, 0 oC-rt, 15h
NHR2' 375
R1 R2
R1' N N R2' 376
R1, R2 = Ph R1', R2' = H, Ts
catalyst = NaH, DBU solvent = DCM, toluene
Scheme 107 One-pot synthesis of piperazines
iminocoumarines 371, and secondary amines 372 at 80 ◦ C. The process is highly environmental benign, which proceeds in water in the absence of catalyst (Scheme 106). Amine derivatives 370 can be replaced by alcohol derivatives or malononitrile giving rise to the formation of respective pyrimidine derivatives. Synthesis of piperazines Piperazine has received great attention in synthetic organic chemistry as well as in medicinal chemistry due to its presence in a wide range of drugs with biological activities such as antihistaminic, antipsychotic, antidepressant, antianginal, etc. [219]. Because of its versatility, various methods for the synthesis of piperazines have been developed and there still is considerable demand for more economic and versatile synthetic routes. In this direction, Bagnoli et al. [220] have described a facile TM-free one-pot method for the synthesis of pharmacologically important piperazines 376. The method utilizes a strong base as catalyst for a Michael addition and ring-closure reaction of vinyl selenone 374
123
Mol Divers O R2
H
R1
R N
Br 377 +
378
CF3CH2OH rt, Et3N N R3
H
R2
R
N H
(up to 87%)
N
379 captodative aminoenone
R3
OCH3 384
OH O
N
R1 N
OCH3
H2N
O
R2
NO2
CH3OH, 60 oC
R1
CF3COOH, 60 (41-66%)
380
R NC
+
oC
382
R3 383
R1
O R2 381
R, R3 = Et, i-Pr, Bn, cyclohexyl, allyl, CH3OCH2CH2
R = Cy, 4-ClBn, CH2CO2CH3 R1 = i-Bu, Ph, (CH2)4 , Et, 4-ClPh R2 = H, Et; R3 = H, CH3, OCH3, Cl
R1= CF3; R2 = Ph, 4-MePh, 2,5-(MeO)2Ph, 3-MePh, 3-MeOPh
Scheme 108 Efficient one-pot synthesis of piperazin-2-ones Scheme 109 Synthesis of piperazines from aziridines
MgBr2 CH3CN, 60 oC
R N Ar
H
R N
R N
H +
Ar' Ar N H N R H R Ar' 386b 386a (13 examples yield 70-80%) Ar
385
Ar = 4-ClCPh, 2- or 4-BrPh, 3- or 4-OCH3Ph, 2-CH3Ph, 2,4,6-(CH3)3Ph, 2-Naphthyl 2-(CH2)CHCH2)Ph, 3- or 4-CF3Ph, 2-n-PrPh, 2-CH3-5FPh
Scheme 110 Synthesis of piperazines from aldehydes with amines, carboxylic acids, and isocyanides
O
O
R2 H 387
+
R3 NH2 388
R1
O OH
389
CH3OH, rt.
R1
N R4
R4 NC 390
N
R3 R2
O 391 (11 examples yield = 12-55%)
R1 =Ph, benzoyl, 4-CH3OPh, 4-Cl-benzoyl; R2 = Ph, 2-ClPh, 2-IPh, 4-FPh, 2BrPh; R3 = Bn, Ph, 4-CH3OBn, hetroaryl; R4 = tosylmethyl
Scheme 111 One-pot synthesis of synthesis of 1,2-dihydropyrrolo[1,2a]pyrazin-3(4H)-ones
NH2 O 392
+
R
(a) EDCl.HCl, NMM CH2Cl2, -15 oC OH (b)HCl, CH3COOH, rt.
393
(c) aq. NaHCO3,reflux
O BocHN
NH N
O R 394 (yield = 70-92%)
R = H, Pr, CH3, -CH2-S-CH3, 4-OHPh, indole
and N-protected-1,2-diamines 375. This piperazine synthesis needed the presence of two different bases, namely sodium hydride in dichloromethane and 1,8-diazabicycloundec-7ene (DBU) in toluene (Scheme 107). Very recently, Rulev et al. [221] revealed an exclusive process for the synthesis of piperazin-2-ones in trifluoroethanol via the formation of captodative aminoenone intermediates 379 generated from the corresponding trifluorobromoenones 377 and N ,N -disubstituted ethylenediamines 378 at room temperature (Scheme 108, Path A). An effi-
123
cient four-component Ugi-reaction has been studied for the preparation of piperazines 380 from diversely substituted aldehydes, cyanides, phenols, and aminoacetaldehyde dimethyl acetal (381, 382, 383, 384, respectively) under mild reaction condition as shown in Scheme 108 (Path B). Intermediate enamines were formed in first step which further underwent a Smiles rearrangement resulting in the formation of substituted piperazines in good yield [222]. Another protocol for piperazines synthesis has been reported by Trinchera et al. [223] via the Lewis acid-
Mol Divers O
O O
H
+ O
X
Ar
O
NH2NH2 Ar H2O, 20-40 min. N ice bath
396
395
N
A four-component one-pot reaction of aldehydes, amines, carboxylic acids, and isocyanides 387–390 resulted in the formation of biologically important piperazine derivatives 390. This highly admirable transformation takes place through Ugi-reaction by forming an acyclic intermediate which in turn gives cyclic piperazines via 1,4-Michael addition (Scheme 110) [224]. Bhowmik et al. [225] have reported the synthesis of 1,2-dihydropyrrolo[1,2-a]pyrazin-3(4H)-ones 394 from 2,5disubstituted furans 392 and Boc-protected amino acids 393. The whole synthesis was carried out in three successive operations namely acid-catalyzed furan ring-opening, removal of protecting group, and intramolecular cyclization to afford target product through one-pot assembly (Scheme 111).
X 397
(18 examples yield 50-93%) X = CH2, C(CH3)2; Ar = Ph, 4-BrPh, 4-ClPh, 4-FPh, 4-NO2Ph, 4-CO3Ph, 3,4-OCH3Ph, 3-OH,4-OCH3Ph, 1,3-benzodioxole
Scheme 112 Regioselective synthesis of 7,8-dihydrocinnoline-5(6H)ones
O
O O N H 398
+ R O
K2CO3 NH2 THF, triphosgene 399
R
N N H
O
400 (13 derivatives, yields=44-71%)
Synthesis of cinnolines
R = CH3, -CH2CH3, Ph, cyclohexane, morpholine, piperazine
Cinnolines, containing a N=N double bond in a six-membered cyclic ring, have been found to exhibit for anti-inflammatory, anti-fungal, anti-bacterial, insecticidal, anti-allergic, antiasthmatic, and anti-cancer potential [226]. These diverse activities of cinnolines explain the continuing interest of synthetic chemists to develop new, efficient, and cost-effective methods to synthesize cinnolines. Khalafy et al. [227] have developed an efficient, catalystfree three-component, highly regioselective one-pot reaction of 1,3-cyclohexanediones or dimedones 395, arylglyoxals 396, and hydrazine hydrate for the synthesis of 3-aryl substituted-7,8-dihydrocinnolin-5(6H)-ones 397 in good to high yields. This protocol is highly environmental benign and time saving (Scheme 112).
Scheme 113 One-pot two-component synthesis of quinazoline-2,4diones
catalyzed dimerization of aziridines. A wide range of Lewis acids have been applied in this study to find the most suitable catalyst to facilitate the reaction under varying reaction conditions. Easily separable diastereomers (386a and 386b) of piperazine were synthesized using MgBr2 at 60 ◦ C in good yield. It is noteworthy to mention that substituents at the aziridine nitrogens, such as naphthyl 385, 4-tetrafluoro, methyl, and halogen-substituted phenyl yielded excellent desired products under the optimized conditions (Scheme 109). Scheme 114 Three-component synthesis of quinazolines
O R2
R1
NH2
+ R3CHO 402
NH4OAc (155) maltose-DMU-NH4Cl air, heat
R3
N R1
N
R2 403 (45 examples yield 82-93%)
401
R1 = Ph, CH3, 2-ClPh; R2 = H, Cl, NO2; R3 = Ph, 2 or 3 or 4-ClPh, 2,4-Cl2Ph, 3- or 4-BrPh, 3- or 4-FPh, 3- or 4-CF3Ph, 2- or 4-NO 2Ph, 3,4-(OCH3)2Ph, 4-OCH3Ph, 4-CH3Ph, 3-pyridyl, 2-thienyl
Scheme 115 Microwaveassisted synthesis of dihydroquinazolines
Ar
O Ar
R1
NH2 404
+ R2CHO 405
CO(NH2)2 solvent free 406 R1 + or MW, 540 W, 4 min. NH4OAc 155
N N H 407
R2
R2 = Ph, 4-CH3Ph, CH3-, -C4H3S-, C4H3O-, CH3(CH2)2–, (CH3)2CH-, 3-BrPh; R1 = NO2, F, Cl
123
Mol Divers Scheme 116 Green synthesis of isoindolo[2,1-a]quinazoline
O
O
O O
+
N H
OH
O
R-NH2 409 montmorillonite K10
R
N
C2H5OH
O
O
408
397
N
410 (12 examples upto 93% yield)
R = Ph, CH3, CH2CH3, n-Pr, C6H12, CH2C6H5, cyclopropane, -CH2CH2OH
Scheme 117 One-pot synthesis of quinoxalines
NH2 O R
R1
X 411
NH2 O
R2
X = C, N 412
R1
N 413
R2
R
H2O, rt. Path A
X
Path C 5% ENPFSA
HFIP or trifluoro ethanol, rt
Path B
N
1 mol% ([2-MPyH]OTf
+
413 (82-88% yields, 20 examples)
413 (80-97% yields 16 axamples)
Path A: R = H, 4-CH3, 4,5-diCH3, 4-NO2; 412 = benzil, acenaphthylene1,2-dione, 1,2-Bis(4-fluorophenyl)ethane-1,2-dione, 1,2-di(furan-2yl)ethane-1,2-dione, phenanthrene-9,10-dione, 1,2-di-p-tolylethane-1,2dione Path B: R =H, 3-CH3, 3-Cl, 3-Br, 3,4-diCH3; 412 = benzil, acenaphthylene-1,2-dione, 1,2-di-furan-2-yl-ethane-1,2-dione, 1H-Indole2,3-dione Path C: R = H, CH3, NO2, Cl, R1, R2 = Ph, 4-CH3Ph, 2-furyl, 2-thenyl, phenanthrene-9,10-dione; 412 = benzil O R2 Y R
+ X
Z
414
CH3CN, 3.5 eq. Cs2CO3
HN R1HN
O
(72-99% yield)
Br
N
R2
R2 +
CH3CN, heat, 12h R 2
R X
415
N R1 416
X = CH, N R = NO2, CN, CF3, F, CH3, AcNH R1 = Et, Pr, i-Pr, c-hex, Bn, 4-FPh, 4-ClPh, 4-CH3Ph, 4-BrPh, 4-OCH3Ph; Y = F, Cl; Z = NO2, Cl, F
O
(88-93% yield)
O O419
417
NH2
R X
NH2
418 R = H, CH3, NO2, 3,4-diCH3; R1 = H R2 = COOCH3, COOC2H5, COOt-Bu
Scheme 118 One-pot metal-free synthesis of pyrrolo[1,2-a]quinoxalines
Synthesis of quinazolines An efficient method for the synthesis of quinazoline-2,4diones has been reported by Li et al. [228]. Initially isatoic anhydride 398 was treated with primary amines 399 in THF at room temperature in which triphosgene was added in the presence of a base to afford respective quinazoline derivatives 400 (Scheme 113). A series of solvents were evaluated for the optimization of catalyst-free, three-component synthesis of quinazolines
123
403 under aerobic oxidation (Scheme 114). Substituted 2-aminoaryl ketone 401, aldehydes 402, and ammonium acetate 155 were selected as starting material due to their availability and economic viability. Initially the reaction was performed in water but only traces of the quinazoline were obtained. In order to get targeted quinazolines in good yield many protic and aprotic solvents were studied but no significant increase in the product yield was observed, then various low melting mixtures of solvents were used and the results were found quite satisfactory, where the highest yield was
Mol Divers Scheme 119 One-pot synthesis of triazines R
NH2
O 421
+
O 420
O
Cl
NHNH2
DMF
NH NH
N
reflux, 26-30h
R 422 (67-85 %)
HZ
R=
CH2
6
HE
CH2 4
Scheme 120 Three-component synthesis of triazines from ammonium thiocyanate, acid chlorides, and 2-aminopyridines
Cl +
Ar 424
423
11
CH2
R
O NH4SCN +
5
H3C
OH
6
3
11
Br
OH CH2
H
H3C
5
R N
N
3h stirring, rt.
NH2
Ar
425
N N
S
426 (90-98%)
Ar = Ph, 4-NO2Ph, 3-NO2Ph, 2-CH3Ph; R = CH3
Scheme 121 One-pot synthesis of azepines
R6 R3OOC
COOR4
COOR4
(i) DCM
427 + R1 NH R2
Ar R6
(ii) BF3Et2O, 4A MS OH R5 Ar R6 429
428
COOR3 N R1
R2
430 (24 examples yield 17-81%)
R3, R4= CH3, C2H5; R1, R2 = CH3, CH2CH3, Ph, CH2Ph, cyclic secondary amine pyrollidine, piperidine, morpholine; R5, R6 = Ph, aryl
R3OOC + H3CO
O 29
427
OCH3
COOR4 R2NH2 431
COOR4 PEG-400 catalyst free
H2 N
COOR3
R3
N
Scheme 122 PEG-catalyzed synthesis of azepines
obtained in the case of using maltose-dimethylurea (DMU– NH4 Cl as the solvent system. A total of 45 derivatives of quinazolines were reported with yields ranging from 82 to 93 % [229]. A microwave-assisted solvent-free, three-component, onepot reaction of various 2-aminobenzophenones 404, aldehydes 405, and urea derivatives 406 was developed by Sarma et al. [230] to give dihydroquinozolines 407 in a short reaction time (3–4 min) as shown in Scheme 115. Montmorillonite has been studied in a number of important organic transformations in one-pot reactions [231–233]. On the other hand, the efficiency of the 2,3-dihydroquinazolin4(1H)-one structural motif in inflammation treatment has attracted many research groups [234,235]. Thus, utiliz-
R3
(a) ethylacetate, rt. (b) toluene, reflux
O OR1 433
NH
R2 O 436 (15 derivatives 40-65%)
N R2
NH N N
NH2 O
rt, ethanol
N
432
R5 435
O
R2
R3, R4 = CH3, C2H5; R2 = aryl, hetroaryl
R4
O N R1O
NH2
N 437 (5 derivatives 47-71%) R2
H2 N 434
R1 = CH3, CH2CH3; R2 = Ot-Bu, NHPh; R3 = CH3; R4, R5 = H, CH3
Scheme 123 One-pot carboxylates
synthesis
of
5H-1,4-benzodiazepine-3-
ing the catalytic efficacy of montmorillonite, Kumar et al. [236] developed the synthesis of potent antinflammatory isoindolo[2,1-a]quinazoline 410 derivatives through the onepot reaction of isatoic anhydride 397, 2-formylbenzoic acid 408, and diverse substituted amines 409 under mild reaction conditions as shown in Scheme 116.
123
Mol Divers R1
NH2
1 mol% ([2-MPyH]OTf
+
R NH2
H N
O
R2
R
R2
H2O, rt,
N
439
438
R1 R2
440
ClCH2CO2H R1 reflux
R1
NH2
O R2
+ R
NH2 442
441
R = H, CH3; R` = R2 = CH3, C3H5, -(CH2)5-, -(CH2)6-
R = CH3, 4,5-(CH3)2, 4-NO2; R1 = CH3, -CHCH3CH3 R2 = CH3, -CHCH3CH3, CH2CH3 and cyclic ketones
Scheme 124 One-pot synthesis of 1,5-benzodiazepines Scheme 125 Stereoselective synthesis of cis-2,3-dihydro-4perfluoroalkyl-1H-1,5benzodiazepines
R1
NH2
R4CHO 444
+ R2
C2H5OH, reflux
R3
443
COOCH3 R2
NH2
N H 446
COOCH3 445
R3
N
R1
R4
(22 examples, yields 50-90%)
R3 = CF3, C2F5, n-C3F7; R1, R2 =H, CH3; R4 = Ph,C9H18O2, C9H18O2, 4-CH3Ph, 4-NO2Ph, 4-BrPh, 4-OCH3Ph, 4-FPh, 2-Furanyl, 3-1H-Indolyl
Scheme 126 Synthesis of benzodiazepines from aminophenylketones, carboxylic acids, isocyanides, and glycinal
O C R
R3COOH 448 R1 +
NH2 447
R2 NC 449
OHC NHBoc 450
O
R3O
(i)CH3OH (ii)DCE (10% TFA), 40 oC overnight
R2 N H
N NH
O 451 (39 derivatives upto 69% yields)
R = H, 4-Cl; R1 = Ph, CH3, 2-ClPh, 2F-Ph; R2 = t-Bu, Bn, cyclohexyl, benzyl, mesityl R3 = CH3, CH2OH,n-Pr, cyclobutyl, cyclohexyl, 4-FPh, cyclopropenyl
R3 N C
NH2
454 O
+ NH2 452
p-TsOH.H2O, CH3OH TMSN3 or NaN3
R1
N N N N R H R1 3 N
rt, 10h R2
453
N H
R2 R1 R2
455 (upto 95%)
R1,R2,R3 = aliphatic, alicyclic and aromatic groups
Scheme 127 Synthesis of diazepine–tetrazoles via a condensation reaction
Synthesis of quinoxalines Several methods for the synthesis of quinoxalines using diverse reaction conditions and versatile reagents and substrates have been reported [237]. Recently, Alinezhad et al. [238] developed a methodology for the synthesis of quinoxalines 413 from the cyclization of o-phenylenediamine 411 and 1,2-diketone derivatives 412 in the presence of ionic liquid 2-methylpyridinium trifluoromethanesulfonate ([2-MPyH]OTf) (Scheme 117, Path A).
123
Another ionic liquid, 1-methyl-3-(2-(sulfoxy)-ethyl)-1Himidazol-3-ium-chloride, was also used to furnish substituted quinoxalines in high yields (upto 99%) at room temperature [239]. The synthesis of 413 has also been reported in the presence of halogenated solvents such as hexafluoroisopropanol (HFIP) or trifluoroethanol at room temperature in the absence of any additional catalyst (Scheme 117, Path B) [240]. Epoxidized novolac phenol formaldehyde resin modified sulfanilic acid (ENPFSA) catalyzed reaction of 1,2diamines and 1,2-dicarbonyl compounds was also used for the synthesis of biologically active quinoxalines in ethanol at both room temperature and reflux. As expected, at reflux the reaction time is shorter than at room temperature. In addition, a slight increase in the amount of catalyst also shows resuts in a small increase in the yield of the desired products (Scheme 117, Path C) [241]. Synthesis of fused quinoxalines A simple and regioselective metal-free synthetic approach has been reported by Huang et al. [242] for the synthesis of pyrrolo[1,2-a]quinoxalines 416 derivatives by the reaction of 1,2-dihalobenzenes or 2-halonitroarenes 414 with pyrrole-2-carboxamides 415 in acetonitrile. It was reported that electron-withdrawing
Mol Divers Scheme 128 One-pot synthesis of quinazolino[1,2,3]triazolo[1,4]benzodiazepines
O N3 R1
N H NH2 456
+
O R3
R2
N N N
N I2, CH3OH reflux
457
R1 N HR3 R2 458 (11-71%)
R1 = H, Br, OCH3; R2 = H, OH, CH3; R3 = H, OCH3
groups on substrate 414 resulted in the formation of prodering the importance of this class of compounds, a series of ucts with higher yields than with electron-donating groups dihydroazepines 430 have been produced by Yin et al. [258] (Scheme 118). Apart from pyrrolo[1,2-a]quinoxalines derivthrough the one-pot three-component TM-free reaction of 2atives, several indolo[1,2-a]quinoxalines were also synthebutynedioates 427, secondary amines 428, and propargylic sized under the same reaction conditions. Another approach alcohols 429 via the formation of 1,3,4-pentatrien-1-amine for the synthesis of pyrrolo[1,2-a]quinoxalines derivatives intermediate. The nature of the secondary amines plays a 416 involves the three-component reaction of dialkyl acetylenedi- crucial role in product selectivity (Scheme 121). The use carboxylates 417, 1,2-diamino benzene or ethylenediamines of Lewis acid catalyst BF3 Et2 O (1 mmol) with 4A molecular sieves (MS) was required to facilitate the synthesis of 418, and ethyl bromopyruvate 419 in the presence of acethese dihydroazepine derivatives. Polyethylene glycol (PEG) tonitrile by simple heating. A nitro group at the 3-position serves as an efficient medium for the synthesis of azepines of 1,2-diamino benzene 418 was not favorable as the desired 432 in high yields at 60 ◦ C from 2-butynedioates, arylamines product was not obtained even after 24 h of heating [243]. and 2,5-dimethoxytetrahydrofuran in the absence of a catalyst (Scheme 122) [259]. Six-membered ring compounds with three nitrogen heteroatoms Synthesis of diazepines Synthesis of triazines 1,2-Diaza-1,3-dienes 446 are prone to undergo nucleophillic Triazines are an important class of compounds known for a addition leading to the formation of a variety of heterocycles long time due to their versatile activities, such as antifungal [260]. As an extension to their study on 1,2-diaza-1,3[244], anti-HIV [245,246], anti-cancer [247], anti-anxiety dienes, Crescentini et al. [261] have reported the divergent [248], anti-tubercular [249], anti-inflammatory [250], and behavior of two different nucleophilic substrates toward 1,2anti-convulsant [251] as well as for their use in industry as diaza-1,3-dienes (DDs) in the synthesis of 1,4-diazepines reactive dyes [252]. An efficient method for the preparation from DDs and 2-aminobenzylamine 447 or N-unsubstituted of biologically active triazine 422 from fatty acid hydrazides aliphatic1,3-diamines 448 via 1,4-conjugate addition and 420 and chloroacetamide 421 has been developed by Farshori exo-cyclization. When DDs were treated with aliphatic 1,3et al. [253] as shown in Scheme 119. diamines in alcohol, the corresponding 3-substituted 2,5,6,7Mohebat and Saeedi [254] have developed the one-pot tetrahydro-1H-1,4-diazepin-2-ones 449 were obtained, and three-component reaction of ammonium thiocyanate 423, when 1,3-diamines were employed in ethyl acetate, 5H-1,4acid chlorides 424, and 2-aminopyridines 425 allowing the benzodiazepine-3-carboxylates 450 were furnished in overall preparation of fused triazine derivatives 426 in excellent good yields. yields at room temperature in the absence of solvent and A two-component reaction in ionic liquid 2catalyst (Scheme 120). methylpyridinium trifluoromethanesulfonate has also been studied for the synthesis of 1,5-benzodiazepines as illustrated in Scheme 124. The authors have reported diamines Seven-membered ring compounds with one and and ketone derivatives (438, 439) as suitable substrates for two nitrogen heteroatoms the expedient synthesis of benzodiazepines at room temperature using water as green solvent. Similarly, Sandhar and Synthesis of azepines Singh [262] have reported the synthesis of diazepines 440 in refluxing water in the presence of chloroacetic acid using Azepine scaffolds are of particular interest in organic synthevarious ketones 441 and o-phenylenediamine 442. sis as they have been associated with a wide range of medi1,5-Benzodiazepines 446 can also be readily obtained cinal and therapeutic applications [255–257]. Thus, considfrom 443, 444, and 445 in refluxing ethanol under catalyst-
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Mol Divers
free conditions (Scheme 125). The scope of the protocol was explored by taking diversely substituted diamines and aldehydes with fluoroacetylenic ester 445 to obtain 19 different 4-perfluoroalkylated-1,5-benzodiazepines. The electronic effect of substituents efficiently alters the yield of the ectron-withdesired product. Electron-releasing groups on aldehydes provide much better results than electronwithdrawing groups [263]. A novel, convenient four-component reaction of substituted aminophenylketones 447, carboxylic acids 448, isocyanides 449, and Boc-protected glycinal or glycines 450 afforded benzodiazepines 451 through a domino twostep Ugi/cyclization mechanism under a balance set of conditions. However, the time needed for the reaction to complete was quite long. In order to reduce the reaction time, microwave irradiation was used providing favorable results [264] (Scheme 126). Mofakham et al. [265] discovered an interesting pathway for the synthesis of substituted diazepines from easily available substituted diamines 452, ketones 453, isocyanides 454, and trimethylsilyl azide (TMSN3 ) in methanol as shown in Scheme 127. The synthesis of quinazolino[1,2,3]triazolo[1,4]benzodiazepines 458 was accomplished by an atom-economical one-pot procedure using catalytic amounts of iodine in methanol via sequential quinazolinone ring-forming condensation and an intramolecular azide-alkyne 1,3-dipolar cycloaddition reaction. Different substituted o-amino-N-(prop-2-yn-1-yl) benzamines 456 and azide derivatives 457 were used to assess the substrate scope of the reaction (Scheme 128) [266].
Conclusion This review summarizes recent advances made in heterocyclization reactions without involving transition metal catalysts in one-pot pathways. These protocols paved the way of synthesizing many useful heterocycles of immense interest through facile, time saving, and atom-economical procedures. We have included miscellaneous reports published on transition metal-free one-pot synthesis of heterocyclic compounds between 2010 and 2013. These protocols showed advantages over the transition metal-catalyzed procedures for one-pot synthesis of heterocycles.
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