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N-Heterocyclic Carbene-Catalyzed Umpolung of Imines for the Enantioselective Synthesis of Dihydroquinoxalines Tamal Kanti Das, Avik Ghosh, Kuruva Balanna, PRADIPTA BEHERA, Rajesh G. Gonnade, Udaya Kiran Marelli, Abhijit Kumar Das, and Akkattu T. Biju ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00737 • Publication Date (Web): 28 Mar 2019 Downloaded from http://pubs.acs.org on March 28, 2019
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ACS Catalysis
N-Heterocyclic Carbene-Catalyzed Umpolung of Imines for the Enantioselective Synthesis of Dihydroquinoxalines Tamal Kanti Das,†,∥ Avik Ghosh,‡ Kuruva Balanna,§ Pradipta Behera,§ Rajesh G. Gonnade,ǂ Udaya Kiran Marelli,†,∥ Abhijit Kumar Das‡ and Akkattu T. Biju*,§ Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411008, India of Scientific and Innovative Research (AcSIR), New Delhi 110020, India ‡ School of Mathematical/Computational Sciences, Indian Association for the Cultivation of Science, Kolkata-700032, India § Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, India ǂ Centre for Materials Characterization, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411008, India. †
∥ Academy
ABSTRACT: N-heterocyclic carbene (NHC) organocatalysis is widely employed for the umpolung of aldehydes, and recently to the umpolung of Michael acceptors and aldimines. Described herein is the NHC-organocatalyzed umpolung of aldimines for the enantioselective synthesis of nitrogen heterocycles. The bisimines generated from the condensation of 1,2-phenylene diamines and salicylaldehydes undergo intramolecular cyclization in the presence of a chiral NHC catalyst resulting in the formation of dihydroquinoxalines in moderate to good yields and er values. Detailed DFT studies shed light on the role of –OH groups in stabilizing the initially generated aza-Breslow intermediates via intramolecular hydrogen bonds. Preliminary photophysical studies on the synthesized dihydroquinoxalines revealed that these molecules can be used for the sensing of various acids and bases. KEYWORDS. N-Heterocyclic Carbenes, Organocatalysis, Umpolung, Imines, Dihydroquinoxalines.
The reversal of normal mode of reactivity (umpolung concept) has opened up new synthetic avenues for forging carbon-carbon bonds.1 One of the earliest examples of the umpolung concept dates back to 1832 when the cyanidecatalyzed benzaldehyde coupling to benzoin was uncovered by Wöhler and Liebig.2 Later, N-heterocyclic carbenes (NHCs) are recognized as the catalytically active species for the umpolung of aldehydes.3 These reactions proceed via the generation of nucleophilic Breslow intermediates,4 and the two important transformations include the benzoin condensation5 and the Stetter reaction.6 Moreover, in 2004, this umpolung concept was extended to -unsaturated aldehydes for the generation of homoenolate intermediates independently by Glorius7 and Bode groups.8,9 In addition, NHCs are useful for the umpolung of Michael acceptors for inter/intramolecular reactions.10 In 1928, the Strain group extended the cyanide-catalyzed polarity reversal to aldimines for the synthesis of -amino imines (Scheme 1, eq 1).11,12 Additionally, the Miller group developed the intramolecular cyanide-catalyzed oxidative cyclization of the bisimines via the polarity reversal for the synthesis of 2,3-diaryl quinoxalines (eq 2).13 These reactions are considered as the nitrogen analogue of the benzoin condensation.14 Furthermore, recently, the Shi15 and Deng16 groups reported the organocatalytic imine umpolung for enantioselective transformations using chiral base or chiral phase transfer catalysts (PTC, eq 3). These reactions proceed via the generation of 2-azaallyl anions. The intramolecular addition of NHCs to aldimines leading to the formation of aza-Breslow intermediates was disclosed by Douthwaite and co-workers.17 Moreover, the intermolecular aza-Breslow intermediate isolation from NHCs and iminium salts was reported by Rovis and co-workers.18 In an effort to employ the aza-Breslow intermediates in catalytic
transformations, we have recently demonstrated the NHCcatalyzed Scheme 1. Organocatalytic Umpolung of Imines Strain (1928)
Miller (2004)
Ar1 N Ar CN+ Ar N Ar1
Ar1 HN
Ar
Ar
N
OH (2)
NHC-catalyzed umpolung of aldimines R = H or E R R1 R2 N
H+ or E
COR
COR NHC
Ar
(3)
N
N H
Ar
Ar
Enantioselective, NHC-catalyzed umpolung of aldimines HO N N HO
HO R
N
N Ar1
chiral organic base catalyst or chiral PTC
R2
N HO
OH
Shi (2011), Deng (2012) R1
CN
N
N
(1) HO
* NHC
(this work) R
N N H H HO
R
N N
Ar (4)
Mes R
N
N O H H H bond (5) N R R H bond H via. O
umpolung of aldimines leading to the synthesis of 2,3disubstituted indoles (eq 4).19,20 Further, this NHC-catalyzed aldimine umpolung was applied to the synthesis of 4difluoromethyl quinolines.21 Interestingly, however, the NHCcatalyzed aldimine umpolung has not been explored for enantioselective transformations. Herein, we report the NHCcatalyzed umpolung of aldimines for the enantioselective synthesis of dihydroquinoxalines. The NHC-catalyzed intramolecular cyclization of the bisimines afforded the nitrogen heterocycles in moderate to good yield and er values (eq 5). Moreover, using DFT studies, an insight on the role of –
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OH groups in intramolecular hydrogen bonding, thereby stabilizing the aza-Breslow intermediates is also provided. The present studies were initiated by treating the salicylaldehyde-derived bisimine 1a with carbene generated from the chiral triazolium salt 322 using K2CO3 as the base in DMF from 0 °C to rt. Interestingly, under these conditions, the dihydroquinoxalines derivative 2a was isolated in 98% yield and 99:1 er (Table 1, entry 1). Presumably, the reaction proceeds via the addition of NHC to the imine moiety generating the aza-Breslow intermediate, which adds to the second imine functionality to afford the desired product. The reactions performed using low catalyst loading or reduced reaction time resulted in less reactivity although the enantioselectivity was maintained (entries 2,3). Compared to the NHC generated from 3, carbenes generated from other chiral triazolium salts 4-6, which are usually used in NHCcatalyzed aldehyde umpolung are found to be less efficient under the present conditions (entries 4-6). The reaction performed in Cs2CO3 furnished 2a in 86% yield and 98:2 er (entry 7) whereas reactions carried out using other bases provided inferior results (entries 7-10). Screening various solvents indicated that DMF is the best solvent for this imine umpolung; the reaction did not work at all when conducted in toluene or 1,4-dioxane (entries 11,12). The reaction produced 50% of the corresponding quinoxaline (via the oxidation of 2a) in addition to 28% of 2a when performed in DMSO (entry 13). The use of 4Å MS as additive was essential for this reaction as the reaction done without 4Å MS returned 2a in only 85% yield (entry 14).23 Table 1. Optimization of Reaction
Conditionsa
O N
Cl
HO
N HO 1a
entry 1 2 3 4 5d 6 7 8 9 10 11 12 13e 14
N O
N
N N
4
a Standard
HO R
HO R1
N
N H H HO
N H H HO
2a
er of 2a (%)c 99:1 99:1
condition: 1a (0.25 mmol), 3 (10 mol %), K2CO3 (1.0 equiv), 4Å MS (200 mg), DMF (2.0 mL), 0 °C to rt, 24 h. b Yield of chromatographically purified product is given. c Determined by HPLC analysis on a chiral column. d Reaction mixture stirred for 36 h. e The corresponding quinoxaline was also isolated in 50% yield.
R R3
N H H HO
N N H H HO R2 R6
N
N Br
N H H HO
R6
2n, R6 = R7 = Me 65%, 79:21 erb 2o, R6 = R7 = F 88%, 72:28 erc
HO
N
R7 R7
N H H HO
R 2l, R4 = Br, R5 = Me 85%, 91:9 er 2m, R4 = R5 = Cl 62%, 56:44 er
HO Br +
N N H H HO
2q, 52%, 96:4 er, 2q', 29%, 98:2 erf
2p, 89%, 97:3 er HO F
R2
4
N H H HO
R
HO
R5 R5
HO
Cl
N H H HO
HO
N 3
2h, R3 = OMe, 90%, 97:3 er 2i, R3 = Me, 98%, 93:7 er 2j, R3 = Br, 77%, 87:13 er 2k, R3 = Cl, 55%, 86:14 er
Cl
2
2d, R2 = OMe, 98%, 98:2 er 2e, R2 = Me, 97%, 97:3 erc 2f, R2 = allyl, 88%, 90:10 er 2g, R2 = Cl, 90%, 97:3 er R4 HO
HO
N H H HO
1
2a, R1 = H, 98% , 99:1 er 2b, R1 = OMe, 54%, 96:4 erb,c 2c, R1 = OBn, 64%, 92:8 erb,d,e
R1
N
R
K2CO3 (1.0 equiv) DMF, 4Å MS 0 °C to rt, 24 h
R
R
N
3 (10 mol %)
HO
97:3 91:9 97:3 -nd98:2 -nd87:13 -nd-nd-nd94:6 96:4
F
6
5
1
HO
46 86 81
