Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis

Tetrahedron xxx (2017) 1e10

Contents lists available at ScienceDirect

Tetrahedron journal homepage: www.elsevier.com/locate/tet

Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis Renming Pan a, Jiaxing Zhang b, Changwu Zheng b, Hongyu Wang b, Dongdong Cao b, Weiguo Cao a, **, Gang Zhao b, * a

Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai, 200444, People's Republic of China Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, People's Republic of China b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 22 January 2017 Received in revised form 24 February 2017 Accepted 3 March 2017 Available online xxx

Quaternary phosphonium ion-pair or a salt derived from amino acid has been developed to catalyze the Mannich-type reaction of a-substituted ethyl cyanoacetates and 2-(2-nitrophenyl) acetonitrile to N-Boc imines. Experiments shown that more active cyanoacetates could be catalyzed by the gentle phosphonium ion-pair catalysis, while 2-(2-nitrophenyl) acetonitrile as the substrate has to be activated by quaternary phosphonium salts and strong base. All the reactions gave the corresponding highly functionalized chiral b-amino nitriles products with good yields, high diastereo- and enantioselectivities in mild conditions. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Asymmetric Mannich reaction Dual-reagent catalysis Quaternary phosphonium Organocatalysis

1. Introduction Cyanoalkyl moieties have been found as popular structural motifs in several nitrile-containing natural products and important drugs.1 One of the direct approaches to introduce nitrile group into molecules through the nucleophilic addition, however, usually in need of generation of carbanions from simple alkyl nitriles by strong bases or Lewis acids.2 Recently, alternative method to access this kind of products, especially the chiral species,4 has been achieved by employing activated functionalized acetonitrile under mild conditions.3 So far as we know, the related well developed asymmetric reactions were majorly limited in the conjugated reaction and were catalyzed by metallic catalysis.4 During the past decades, organophosphine as a versatile catalyst in enantioselective addition reactions has been successfully applied in a variety of organic synthesis to make useful compounds.5 Recently, our group has developed amino acid-derived chiral phosphine6 to catalyze Mannich-type reactions of dimethyl 2fluoromalonates with N-Boc imines or nitroalkanes with

* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (W. Cao), [email protected] (G. Zhao).

amidosulfone.7 The reaction of 2-fluoromalonates with N-Boc imines was demonstrated with the asymmetric dual-reagent catalysis by the phosphine catalyst and methyl acrylate. While the reaction of nitroalkanes with amidosulfone required bifunctional phosphonium phase-transfer catalyst to achieve excellent enantioselective control. In light of this work, we are very interested in testing alternative nucleophiles like substituted phenylacetonitriles in the Mannich reactions.8 Herein, we would like to report the reaction with N-Boc imines catalyzed by quaternary phosphonium catalysis. 2. Results and discussion Initially, we performed the catalyst evaluation in the model reaction between N-Boc imine 1a and ethyl 2-cyano-2phenylacetate 2a (Table 1). And the first catalytic system we tried was similar to the reaction of 2-fluoromalonates with N-Boc imines under dual-reagent catalysis. When the reaction was carried out in CH2Cl2 at room temperature in the presence of chiral phosphine 4f, the desired product 3a was obtained in 5 min with 1:1 dr and only 5% ee (Table 1, entry 1). Lowering the reaction temperature from
20  C to
78  C, we found that both diastereoselectivity and enantioselectivity of the corresponding product could be greatly increased as well as high yield achieved (Table 1, entries 2e3). It

http://dx.doi.org/10.1016/j.tet.2017.03.005 0040-4020/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005

2

R. Pan et al. / Tetrahedron xxx (2017) 1e10

Table 1 Optimization of conditions and evaluation of chiral catalysts.a

Entry

Catalyst

Solvent

T/ C

t/min

Yield (%)b

drc

ee (%)d

1 2 3 4e 5 6 7 8 9 10 11 12 13

4f 4f 4f 4f 4a 4b 4c 4d 4e 4g 4f 4f 4f

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene Et2O THF

rt
20
78
78
78
78
78
78
78
78
78
78
78

5 5 10 10 10 10 10 10 10 10 10 10 10

96 96 96 93 95 96 96 95 96 95 95 94 95

50:50 90:10 94:6 90:10 49:51 71:29 83:17 90:10 92:8 94:6 93:7 94:6 64:36

5 70 99 81 0 6 15 74 87 75 92 96 5

a Reactions were carried out with 1a (0.15 mmol), 2a (0.1 mmol), and methyl acrylate (0.01 mmol) in the presence of chiral phosphine 4 (0.01 mmol) in solvent (1.0 mL) at the specified temperature. b Isolated yield. c The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of the crude mixtures. d The ee value was determined by chiral HPLC analysis. e The reaction was carried out with 5 mol % of 4f and 5 mol % of methyl acrylate. Boc ¼ tert-butoxycarbonyl, Bn ¼ benzyl.

should be noted that the reaction was still very fast under pretty low temperature. We also investigated a set of H-bonding type of bifunctional chiral phosphine catalysts 4a-e and 4g and run these reactions in CH2Cl2 at
78  C (Table 1, entries 5e10). Among these catalysts, we observed the thiourea-phosphine 4e derived from Lphenyl alanine gave a better result (Table 1, entry 9), whereas the catalysts 4c-4d derived from other amino acids gave inferior selectivities (Table 1, entries 7e8). Reactions with single H-bonding 4a and urea catalyst 4b almost gave the racemic products (Table 1, entries 6e7). Electron-donating substituents on the thiourea had the bad effect on the reaction (Table 1, entries 10). Further examination of the solvent was conducted in the presence of chiral phosphine 4f and showed the reaction was best run in CH2Cl2 at
78  C (Table 1, 11e13). With the optimized condition in hand, we then examined the generality of this reaction with a variety of N-Boc protected aldimines and alkylnitriles. As shown in Table 2, all the reactions were complete within 10 min. The desired products 3 were obtained in high yields and excellent diastereoselectivities (90:10e98:2). Regardless of the electronic nature and steric effects of the substituents on the aryl groups, good to high enantioselectivities of 3 were also obtained (Table 2, 3a-3j). Ethyl ester replaced by methyl or benzyl groups also gave good results (Table 2, 3l, 3m) and replacement of the phenyl of alkylnitriles with benzyl or allyl had little effect on the selectivity (Table 2, 3n, 3o). Moreover, good yield and selectivity were also present when we used cyclohexyl instead of phenyl aldimine (Table 2, 3k). During our investigation of the generality of the reaction, we

also evaluated several less activated acetonitriles such as phenyl acetonitrile to test the catalytic ability of the system. However, none of them gave satisfied yields or enantioselectivities except 2nitrophenyl acetonitrile which gave the corresponding product rac-6a with an acceptable 60% yield (Table 3, entry 1). Further efforts to improve the selectivity of the reaction between 1a and 5a with the above dual-reagent catalytic system were not satisfactory (Table 3, entry 2, for details see the Supporting Information Table S1, entry 2). We presumed that the activity of 2-nitrophenyl acetonitrile was much close to the nitroalkane which we have studied in the reaction with amidosulfone by bifunctional phosphonium phase-transfer catalyst.7 Inspired by this work, we then tentatively screened a number of conditions including the catalysts, solvents, temperature and bases and finally we got the product 6a in high yield and good enantioselectivity in the presence of phosphonium catalyst 4k. The diastereoselectivity was also improved to 82:18 (Table 3, entries 3e6, for details see the Supporting Information Table S1, entries, 3e5, 18). Under these optimized conditions, various substituted N-Boc protected aldimines were tested with 2-nitrophenyl acetonitrile. All the reactions took place smoothly and afforded the corresponding addition products 6 in good yields and high-to-excellent enantioselectivities irrespective of the electronic nature of the substituents or substitution types (Table 4, 6a-6r). Little effect on the yield and selectivity was observed when cyclohexyl group was introduced instead of phenyl in aldimine (Table 4, 6r). Although both 3-nitrobenzylcyanide and 4-nitrobenzylcyanide also gave the products with good yields, poor enantioselectivities were obtained for these two substrates which

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005

R. Pan et al. / Tetrahedron xxx (2017) 1e10

3

Table 2 Scope of the Mannich reaction Catalyzed by the dual-reagent Catalysis.a

Although the mechanism of this novel catalyst system is not completely clear, a possible transition state can be considered (Fig. 1A and B for the two substrates). With the more activated cyanoacetate, the reaction is preferably catalyzed by the dualreagent catalysis, in which, the zwitterion was generated upon the mixing of organophosphine and methyl acrylate and then behaved as a Lewis base to activate ethyl 2-cyano-2-phenylacetate. With the less activated phenyl acetonitrile, the reaction is preferably catalyzed by phosphonium salt, in which, 2-nitrophenyl acetonitrile was deprotonated by the phosphonium phasetransfer catalyst and base and was directed to approach the aldimines from the Si face.

Table 3 Chiral catalysts for the asymmetric Mannich reaction of 1a and 5a.a

3. Conclusion Entry

Catalyst

T ( C)

t (h)

Yield (%)c

dr (%)d

Ee (%)e

1b 2b 3 4 5 6

4f 4h 4i 4j 4k 4k

rt rt rt rt rt
20

12 6 6 6 6 24

60 55 90 85 90 80

50:50 68:32 62:38 50:50 66:34 82:18

0 60/52 74/50 0 77/53 96/74

a Reactions were carried out in dichloromethane (1.0 mL) with 1a (0.15 mmol) and 5a (0.1 mmol) in the presence of 5 mol% of catalyst. b Reaction was carried out with methyl acrylate (0.01 mmol) without K2CO3. c Isolated yield. d The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of the crude product. e The ee value was determined by chiral HPLC analysis.

demonstrated the nitro group at the ortho position not only activate the methylene in the acetonitrile but also directed the reaction to control the enantioselectivity (Table 4, 6s- 6t).

In summary, we have successfully expanded the organophosphine catalyst into the Mannich-type reactions with the functionalized acetonitrile as the substrates. Both wildly used cyanoacetate and less active phenyl acetonitrile was evaluated under our catalytic reactions. Under the dual-reagent catalysis, the reactions with cyanoacetates took place very smoothly. The reaction was finished in minutes and good to excellent diastereo- and enantioselectivities were obtained. Under phosphonium catalysis, the reactions with phenyl acetonitrile also gave the corresponding products with good to high enantioselecitivities. 4. Experimental 4.1. General information 1 H NMR and 13C NMR spectra were recorded at 400 MHz for 1H and 100 MHz for 13C respectively. Chemical shifts (d) are reported in

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005

4

R. Pan et al. / Tetrahedron xxx (2017) 1e10

Table 4 Scope study with different N-Boc protected aldimines.a

4.2. Preparation of catalysts

Fig. 1. Possible mechanism of the reaction.

parts per million relative to the residual solvent signals of tetramethylsilane (TMS), and coupling constants (J) are reported in hertz. High-resolution ESI mass spectra were obtained from a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer, an RF-only hexapole ion guide, and an external electrospray ion source. IR spectra were measured for samples as KBr pellets or film in a FT-IR spectrophotometer. HPLC chromatograms were obtained on an apparatus with HPLC Pump, UVevis Detector and Optical rotations were measured with a polarimeter at 589 nm. All regents purchased from commercial sources were purified by standard techniques prior to use. Preparation and characterization of the catalysts 4a-4h4a, 4f, 4i, 4i-4j, 4m and 4o 5b, 4 were reported in the published literature.

To a solution of the corresponding a-amino acid-derives bifunctional phosphine (1.0 equiv) in anhydrous toluene was added the corresponding benzylic halide (1.2 equiv), and the resulting mixture was stirred at 110  C for 8 h. Then, the mixture was allowed to cool to ambient temperature and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography to afford the desired phase-transfer catalyst (CH2Cl2/MeOH ¼ 20: 1). 4.2.1. (S)-(2-(3,5-bis(trifluoromethyl)benzamido)-3phenylpropyl)(3-nitrobenzyl)diphenylphosphonium bromide (4k) ¼
17.6 Yield: 75%; white solid; m.p. ¼ 126e127  C; [a]23.2 D (c ¼ 0.75, CHCl3); 1H NMR(CDCl3, 400 MHz) d 9.40e9.42 (m, 1H), 8.27 (s, 2H), 7.89e7.27 (m, 19H), 5.15 (t, J ¼ 14.8 Hz, 1H), 4.92e5.11

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005

R. Pan et al. / Tetrahedron xxx (2017) 1e10

(m, 1H), 4.75e5.07 (m, 2H), 3.33e3.36 (m, 1H), 3.13e3.19 (m, 1H), 2.91 (t, J ¼ 14.0 Hz, 1H), 2.64 (s, 1H); 13C NMR (CDCl3, 100 MHz) d 21.90 (d, JC-P ¼ 51.3 Hz), 29.70 (d, JC-P ¼ 46.5 Hz), 42.92 (d, JCP ¼ 13.9 Hz), 46.31 (d, JC-P ¼ 4.6 Hz), 113.17, 115.78, 116.60, 116.85, 117.11, 117.21, 117.93, 118.41, 118.53, 126.31 (d, JC-P ¼ 8.2 Hz), 127.12, 128.05, 128.53 (d, JC-P ¼ 3.8 Hz), 128.96, 129.03 (d, JC-P ¼ 2.2 Hz), 129.63, 129.75 (d, JC-P ¼ 1.3 Hz), 129.87, 130.11 (d, JC-P ¼ 5.4 Hz), 133.02(q, JC-F ¼ 11.4 Hz), 134.02, 134.19, 134.35(d, JC-P ¼ 2.9 Hz), 134.53(d, JC-P ¼ 2.9 Hz), 137.16, 161.05, 169.80; 19F NMR (CDCl3, 282 MHz) d
62.61; 31P NMR (CDCl3, 163 MHz) d 22.43; IR (KBr) v 3226, 3058, 2941, 2863, 2786, 1656, 1623, 1594, 1537, 1495, 1455, 1437, 1373, 1346, 1279, 1176, 1137, 986, 919, 901, 842, 740, 702, 683; HRMS (MALDI): calcd. For [M-Br]þ (C35H31F2NOP) requires 695.1898, found 695.1877. 4.2.2. (S)-benzyl(2-(3,5-bis(trifluoromethyl)benzamido)-2phenylethyl)diphenylphosphonium bromide (4l) Yield: 70%; white solid; m.p. ¼ 135e137  C; [a]23.1 ¼
13.3 D (c ¼ 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz) d 9.96 (d, J ¼ 5.2 Hz, 1H), 8.42 (s, 2H), 7.88e7.37 (m, 16H), 7.23 (t, J ¼ 7.2 Hz, 2H), 6.98 (d, J ¼ 6.8 Hz, 2H), 5.80 (dd, J ¼ 26.4 Hz, 12.8 Hz, 1H), 5.63 (dd, J ¼ 20.4 Hz, 8.4 Hz, 1H), 4.92 (t, J ¼ 14.8 Hz, 1H), 4.26 (t, J ¼ 14.4 Hz, 1H), 2.79 (t, J ¼ 13.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 24.98, 25.45, 29.56, 29.79 (d, JC-P ¼ 46.3 Hz), 48.56, 48.59, 53.52, 116.05, 116.98 (d, JC-P ¼ 20.3 Hz), 118.92, 122.99 (q, JC-F ¼ 272.0 Hz), 126.46 (d, JC-P ¼ 8.3 Hz), 126.98, 128.24, 128.64, 129.08, 129.09 (d, JCP ¼ 3.2 Hz), 129.88 (q, JC-P ¼ 11.2 Hz), 130.29 (d, JC-P ¼ 5.5 Hz), 131.08 (q, JC-F ¼ 33.5 Hz), 133.64 (d, JC-P ¼ 10.1 Hz), 134.62 (d, JC-P ¼ 2.6 Hz), 134.86 (d, JC-P ¼ 2.6 Hz), 141.08 (d, JC-P ¼ 34.0 Hz), 163.16; 19F NMR (CDCl3, 282 MHz) d
62.56; 31P NMR (CDCl3, 163 MHz) d 22.34; IR (KBr) v 3218, 3071, 3028, 2933, 2859, 2799, 1663, 1604, 1527, 1483, 1442, 1378, 1350, 1277, 1260, 1179, 1142, 1103, 749; HRMS (MALDI): calcd. For [M-Br]þ (C36H29F6NOP) requires 636.1885, found 636.1903. 4.2.3. (S)-benzyl(2-(3,5-difluorobenzamido)-3-phenylpropyl) diphenylphosphonium bromide (4n) ¼
14.7 Yield: 72%; white solid; m.p. ¼ 125e127  C; [a]23.2 D (c ¼ 0.9, CHCl3); 1H NMR(CDCl3, 400 MHz) d 9.14 (m, 1H), 7.41e6.76 (m, 23H), 4.94e4.97 (m, 1H), 4.75e4.91 (m, 1H), 4.57e4.72 (m, 1H), 4.31e4.38 (m, 1H), 3.27e3.31 (m, 1H), 3.09 (t, J ¼ 13.2 Hz, 1H), 2.59 (t, J ¼ 14.4 Hz, 1H); 13C NMR (CDCl3, 100 Hz) d 22.16 (d, JCP ¼ 51.2 Hz), 29.31 (d, JC-P ¼ 46.2 Hz), 42.73, 42.87, 46.94, 46.98, 53.55, 106.51 (t, JC-P ¼ 25.1 Hz), 110.90, 116.16, 117.44, 126.42 (d, JCP ¼ 8.2 Hz), 126.99, 128.43 (d, JC-P ¼ 3.6 Hz), 128.84, 128.95 (d, JCP ¼ 3.2 Hz), 129.53, 129.61 (d, JC-P ¼ 4.5 Hz), 129.73 (d, JC-P ¼ 4.3 Hz), 130.11 (d, JC-P ¼ 5.5 Hz), 133.22 (q, JC-P ¼ 4.2 Hz), 134.29 (d, JCP ¼ 2.9 Hz), 134.50 (d, JC-P ¼ 2.9 Hz), 135.61 (t, JC-P ¼ 8.6 Hz), 160.95 (d, JC-F ¼ 12.0 Hz), 163.43 (d, JC-F ¼ 11.9 Hz), 163.84; 19F NMR (CDCl3, 282 MHz) d
108.81 to
108.89 (m, 2F); 31P NMR (CDCl3, 163 MHz) d 22.43; IR (KBr) v 3225, 3058, 2928, 2863, 2799, 1656, 1623, 1594, 1537, 1495, 1455, 1437, 1373, 1346, 1279, 1176, 1137, 986, 919, 901, 842, 739, 702, 683; HRMS (MALDI): calcd. For [M-Br]þ (C35H31F2NOP) requires 550.2106, found 550.2129. 4.2.4. (S)-(3,5-bis(trifluoromethyl)benzyl)(2-(4-nitrobenzamido)3-phenylpropyl)diphenylphosphonium bromide (4p) Yield: 68%; yellow solid; m.p. ¼ 138e139  C; [a]23.2 ¼
12.6 D (c ¼ 1.05, CHCl3); 1H NMR(CDCl3, 400 MHz) d 9.17 (d, J ¼ 8.4 Hz, 1H), 8.19 (dd, J ¼ 24.8 Hz, 8.4 Hz, 4H), 7.81 (dd, J ¼ 12.8 Hz, 7.2 Hz, 2H), 7.70 (s, 1H), 7.65 (t, J ¼ 7.6 Hz, 1H), 7.46e7.18 (m, 12H), 7.02 (dd, J ¼ 12.4 Hz, 7.6 Hz, 2H), 5.21e5.31 (m, 2H), 4.58e4.59 (m, 1H), 4.35 (t, J ¼ 14.8 Hz, 1H), 3.28e3.32 (m, 1H), 2.93 (t, J ¼ 11.2 Hz, 1H), 2.62 (t, J ¼ 14.4 Hz, 1H); 13C NMR (CDCl3, 100 Hz) d 14.02, 20.89, 22.97 (d, JC-P ¼ 50.0 Hz), 29.64 (d, JC-P ¼ 46.5 Hz), 42.53 (d, JC-P ¼ 14.0 Hz),

5

47.10(d, JC-P ¼ 4.4 Hz), 60.24, 114.90, 115.76 (d, JC-P ¼ 5.3 Hz), 122.48 (q, JC-F ¼ 271.8 Hz), 122.90, 128.77, 129.36, 129.99 (t, JC-P ¼ 12.7 Hz), 130.41, 130.57, 131.83, 131.98 (q, JC-F ¼ 30.5 Hz), 133.19 (d, JCP ¼ 9.3 Hz), 133.58 (d, JC-P ¼ 9.7 Hz), 135.02, 136.80, 137.69, 149.29, 164.36, 171.03; 19F NMR (CDCl3, 282 MHz) d
63.17; 31P NMR (CDCl3, 163 MHz) d 24.06; IR (KBr) v 3235, 3058, 3032, 2933, 2863, 2790, 1657, 1622, 1594, 1537, 1494, 1455, 1438, 1373, 1346, 1279, 1176, 1137, 986, 749, 702, 683; HRMS (MALDI): calcd. For [M-Br]þ (C37H30F6N2O3P) requires 695.1893, found 695.1879. 4.3. Asymmetric dual-reagent catalyzed Mannich-type reactions

To a solution of the correspongding catalyst (10 mol%) in solvent (1.0 mL) was added methyl acrylate (10 mol%), and the mixture was stirred at room temperature for 10 min, and then the ethyl 2-cyano2-phenylacetate (0.10 mmol) was added. The resulting mixture was vigorously stirred for 10 min at room temperature, and then was cooled to
78  C before the imine (0.12 mmol) was introduced. When the reaction was finished (determined by TLC analysis), the crude mixture was warmed to the room temperature and purified by flash column chromatography (silica gel: petroleum ether/ AcOEt ¼ 10: 1) to afford the products. 4.4. Characterization data of products 3a-3o 4.4.1. (2S,3R)-ethyl 3-((tert-butoxycarbonyl)amino)-2-cyano-2,3diphenylpropanoate (3a) Yield: 95%; white solid; m.p. ¼ 152e155  C; [a]22.4 ¼
32.7 D (c ¼ 0.6, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.48e7.46 (m, 2H), 7.30e7.29 (m, 3H), 7.20e7.13 (m, 5H), 5.73 (s, 1H, NHBoc), 5.68 (s, 1H, CHNHBoc), 4.26e4.35 (m, 2H, CH2CH3), 1.37 (s, 9H, CO2C(CH3)3), 1.29 (t, J ¼ 7.2 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 13.83 (CH2CH3), 28.21 CO2C(CH3)3, 60.08 (CHNHBoc), 61.23 (CCN), 63.63 (CH2CH3), 80.45 (CO2C(CH3)3), 117.19, 127.07, 127.84, 128.13, 128.37, 128.88, 129.11, 131.63, 136.04, 154.20, 166.25; IR (KBr) v 3374, 2980, 2850, 1730, 1712, 1518, 1494, 1470, 1453, 1371, 1244; HRMS (MALDI): calcd. For [MþH]þ (C23H27N2O4) requires 395.1971, found 395.1962; HPLC analysis: AD-HþAS-H, hexane/iPrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 12.5 min (minor), tR ¼ 24.4 min (major), 99% ee, dr ¼ 94:6. 4.4.2. (2S,3R)-ethyl,3-(4-bromophenyl)-3-((tert-butoxycarbonyl) amino)-2-cyano-2-phenylpropanoate (3b) Yield: 95%; white solid; m.p. ¼ 49e51  C; [a]23.3 ¼
81.7 D (c ¼ 0.5, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.50e7.48 (m, 2H), 7.31e7.29 (m, 5H), 6.99 (d, J ¼ 8.4 Hz, 2H), 5.68 (s, 1H, NHBoc), 5.63 (s, 1H, CHNHBoc), 4.26e4.35 (m, 2H, CH2CH3), 1.37 (s, 9H, CO2C(CH3)3), 1.29 (t, J ¼ 7.2 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 13.82 (CH2CH3), 28.19 CO2C(CH3)3, 59.61 (CHNHBoc), 60.90 (CCN), 63.77 (CH2CH3), 80.69 (CO2C(CH3)3), 116.90, 122.62, 126.98, 129.06, 129.35, 129.51, 131.29, 132.46, 135.20, 154.09, 166.02; IR (KBr) v 3447, 3360, 3066, 2979, 2932, 2254, 1747, 1721, 1596, 1490, 1450, 1407, 1392, 1367, 1339, 1235, 1165, 1074, 1010, 877, 740; HRMS (MALDI): calcd. For [MþNH4]þ (C23H29BrN3O4) requires 490.1341, found 490.1334. HPLC analysis: AD-H, hexane/iPrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 6.9 min (minor), tR ¼ 52.7 min (major), 86% ee, dr ¼ 94:6.

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005

6

R. Pan et al. / Tetrahedron xxx (2017) 1e10

4.4.3. (2S,3R)-ethyl3-((tert-butoxycarbonyl)amino)-2-cyano-2phenyl-3-(p-tolyl)propanoate (3c) Yield: 95%; white solid; m.p. ¼ 50e52  C; [a]23.7 ¼
41.6 (c ¼ 0.6, D CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.50e7.48 (m, 2H), 7.31e7.29 (m, 3H), 7.02 (d, J ¼ 7.2 Hz, 2H), 6.97 (d, J ¼ 8.4 Hz, 2H), 5.70 (s, 1H, NHBoc), 5.65 (s, 1H, CHNHBoc), 4.25e4.32 (m, 2H, CH2CH3), 2.24 (s, 3H, ArCH3), 1.36 (s, 9H, CO2C(CH3)3), 1.28 (t, J ¼ 7.2 Hz, 3H, CH2CH3); 13 C NMR (CDCl3, 100 MHz) d 13.83 (CH2CH3), 21.03 (ArCH3), 28.21 CO2C(CH3)3, 59.90 (CHNHBoc), 61.32 (CCN), 63.55 (CH2CH3), 80.33 (CO2C(CH3)3), 117.27, 127.13, 127.70, 128.82, 128.84, 129.05, 131.76, 133.10, 138.13, 154.18, 166.33; IR (KBr) v 3442, 3355, 2978, 2927, 2859, 2254, 1745, 1720, 1598, 1497, 1450, 1392, 1367, 1298, 1236, 1166, 1095, 1016, 880, 735; HRMS (MALDI): calcd. For [MþH]þ (C24H29N2O4) requires 409.2127, found 409.2123; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 7.6 min (minor), tR ¼ 31.1 min (major), 87% ee, dr ¼ 94:6. 4.4.4. (2S,3R)-ethyl,3-((tert-butoxycarbonyl)amino)-3-(4chlorophenyl)-2-cyano-2-phenylpropanoate (3d) Yield: 94%; white solid; m.p. ¼ 48e50  C; [a]24.5 ¼
4.7 D (c ¼ 0.25, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.48e7.45 (m, 2H), 7.33e7.31 (m, 3H), 7.14 (d, J ¼ 8.4 Hz, 2H), 7.06 (d, J ¼ 8.4 Hz, 2H), 5.68 (s, 1H, NHBoc), 5.64 (s, 1H, CHNHBoc), 4.26e4.34 (m, 2H, CH2CH3), 1.37 (s, 9H, CO2C(CH3)3), 1.29 (t, J ¼ 7.2 Hz, 3H, CH2CH3); 13 C NMR (CDCl3, 100 MHz) d 13.82 (CH2CH3), 28.19 CO2C(CH3)3, 59.56 (CHNHBoc), 60.97 (CCN), 63.76 (CH2CH3), 80.68 (CO2C(CH3)3), 116.92, 126.98, 128.34, 129.05, 129.20, 129.33, 131.33, 134.40, 134.68, 154.11, 166.04; IR (KBr) v 3351, 3071, 2978, 2926, 2854, 2250, 1744, 1720, 1597, 1493, 1450, 1414, 1392, 1367, 1300, 1236, 1166, 1092, 1015, 952, 880, 841, 727; HRMS (MALDI): calcd. For [MþH]þ (C23H26ClN2O4) requires 429.1581, found 429.1574; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 6.8 min (minor), tR ¼ 50.6 min (major), 86% ee, dr ¼ 94:6. 4.4.5. (2S,3R)-ethyl,3-(3-bromophenyl)-3-((tert-butoxycarbonyl) amino)-2-cyano-2-phenylpropanoate (3e) Yield: 94%; white solid; m.p. ¼ 130e132  C; [a]22.2 ¼
44.8 D (c ¼ 0.5, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.47e7.45 (m, 2H), 7.34e7.33 (m, 4H), 7.21 (s, 1H), 7.10e7.03 (m, 2H), 5.69 (s, 1H, NHBoc), 5.62 (s, 1H, CHNHBoc), 4.25e4.32 (m, 2H, CH2CH3), 1.37 (s, 9H, CO2C(CH3)3), 1.30 (t, J ¼ 8.4 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 13.83 (CH2CH3), 28.19 CO2C(CH3)3, 59.62 (CHNHBoc), 60.85 (CCN), 63.81 (CH2CH3), 80.76 (CO2C(CH3)3), 116.82, 122.19, 126.50, 126.97, 129.06, 129.39, 129.64, 131.00, 131.29, 131.53, 138.34, 154.09, 166.00; IR (KBr) v 3360, 3066, 2978, 2929, 2859, 2250, 1744, 1704, 1571, 1596, 1571, 1498, 1477, 1450, 1392, 1367, 1298, 1236, 1165, 1076, 1015, 883, 859, 777, 713; HRMS (MALDI): calcd. For [MþH]þ (C23H26BrN2O4) requires 473.1076, found 473.1071; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 5.8 min (minor), tR ¼ 15.3 min (major), 77% ee, dr ¼ 90:10. 4.4.6. (2S,3R)-ethyl,3-((tert-butoxycarbonyl)amino)-3-(4-(tertbutyl)phenyl)-2-cyano-2-phenylpropanoate (3f) Yield: 95%; white solid; m.p. ¼ 50e52  C; [a]22.4 ¼
40.8 D (c ¼ 0.6, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.48e7.47 (m, 2H), 7.31e7.29 (m, 3H), 7.19 (d, J ¼ 8.0 Hz, 2H), 7.07 (d, J ¼ 8.0 Hz, 2H), 5.73 (s, 1H, NHBoc), 5.64 (s, 1H, CHNHBoc), 4.22e4.29 (m, 2H, CH2CH3), 1.35 (s, 9H, CO2C(CH3)3), 1.27 (t, J ¼ 8.4 Hz, 3H, CH2CH3), 1.24 (s, 9H, PhC(CH3)3); 13C NMR (CDCl3, 100 MHz) (13.82 (CH2CH3), 28.21 CO2C(CH3)3, 31.19 (PhC(CH3)3), 34.46 (PhC(CH3)3), 59.80 (CHNHBoc), 61.23 (CCN), 63.51 (CH2CH3), 80.28 (CO2C(CH3)3), 115.61, 117.42, 125.03, 127.14, 127.48, 128.78, 129.01, 131.85, 151.31, 154.19, 166.34; IR (KBr) v 3455, 3352, 3062, 2966, 2870, 2263, 1745, 1720, 1450, 1498, 1392, 1366, 1298, 1235, 1168, 1108, 1016, 882, 843, 701; HRMS (MALDI): calcd. For [MþH]þ (C27H35N2O4) requires

451.2597, found 451.2589; HPLC analysis: AD-H, hexane/iPrOH ¼ 90/10, 1.0 mL/min, 220 nm, tR ¼ 5.8 min (minor), tR ¼ 16.7 min (major), 94% ee, dr ¼ 98:2. 4.4.7. (2S,3R)-ethyl3-((tert-butoxycarbonyl)amino)-2-cyano-2phenyl-3-(m-tolyl)propanoate (3g) Yield: 94%; white solid; m.p. ¼ 105e107  C; [a]22.5 ¼
61.6 D (c ¼ 0.6, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.48e7.46 (m, 2H), 7.30e7.29 (m, 3H), 7.06e6.90 (m, 4H), 5.71 (s, 1H, NHBoc), 5.63 (s, 1H, CHNHBoc), 4.25e4.35 (m, 2H, CH2CH3), 2.21 (s, 3H, PhCH3), 1.37 (s, 9H, CO2C(CH3)3), 1.29 (t, J ¼ 8.4 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 13.83 (CH2CH3), 21.25 (ArCH3), 28.21 CO2C(CH3)3, 60.13 (CHNHBoc), 61.24 (CCN), 63.56 (CH2CH3), 80.37 (CO2C(CH3)3), 117.20, 124.79, 127.12, 128.00, 128.68, 128.79, 129.03, 129.08, 131.76, 135.91, 137.72, 154.20, 166.30; IR (KBr) v 3354, 2964, 2926, 2876, 1745, 1721, 1607, 1494, 1450, 1392, 1366, 1299, 1235, 1163, 1081, 1017, 967, 867, 778; HRMS (MALDI): calcd. For [MþH]þ (C24H29N2O4) requires 409.2127, found 409.2120; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 220 nm, tR ¼ 5.7 min (minor), tR ¼ 13.1 min (major), 86% ee, dr ¼ 93:7. 4.4.8. (2S,3R)-ethyl,3-((tert-butoxycarbonyl)amino)-2-cyano-2phenyl-3-(o-tolyl)propanoate (3h) ¼
8.6 Yield: 94%; white solid; m.p. ¼ 85e87  C; [a]22.6 D (c ¼ 0.75, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.56 (d, J ¼ 7.6 Hz, 1H), 7.39e7.37 (m, 2H), 7.26e67.10 (m, 5H), 6.95 (d, J ¼ 7.6 Hz, 1H), 5.96 (s, 1H, NHBoc), 5.69 (s, 1H, CHNHBoc), 4.31e4.39 (m, 2H, CH2CH3), 2.10 (s, 3H, PhCH3), 1.36 (s, 9H, CO2C(CH3)3), 1.33 (t, J ¼ 8.0 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 13.86 (CH2CH3), 19.53 (ArCH3), 28.21 CO2C(CH3)3, 55.17 (CHNHBoc), 60.53 (CCN), 63.68 (CH2CH3), 80.31 (CO2C(CH3)3), 117.70, 126.25, 126.30, 127.05, 128.26, 128.63, 129.02, 130.52, 131.61, 135.43, 136.92, 154.20, 166.47; IR (KBr) v 3354, 2963, 2926, 2859, 1745, 1600, 1493, 1367, 1234, 1165, 1081, 1017, 967, 867, 778; HRMS (MALDI): calcd. For [MþH]þ(C24H29N2O4) requires 409.2127, found 409.2119; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 220 nm, tR ¼ 6.6 min (minor), tR ¼ 12.4 min (major), 88% ee, dr ¼ 93:7. 4.4.9. (2S,3R)-ethyl,3-((tert-butoxycarbonyl)amino)-2-cyano-2phenyl-3-(thiophen-2-yl)propanoate (3i) Yield: 95%; white solid; m.p. ¼ 52e54  C; [a]22.9 ¼
6.6 (c ¼ 0.5, D CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.58e7.56 (m, 2H), 7.37e7.36 (m, 3H), 7.12 (d, J ¼ 8.0 Hz, 1H), 6.86e6.82 (m, 2H), 5.99 (s, 1H, NHBoc), 5.637 (s, 1H, CHNHBoc), 4.25e4.34 (m, 2H, CH2CH3), 1.38 (s, 9H, CO2C(CH3)3), 1.29 (t, J ¼ 8.4 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 13.80 (CH2CH3), 28.16 CO2C(CH3)3, 56.31 (CHNHBoc), 61.54 (CCN), 63.72 (CH2CH3), 80.66 (CO2C(CH3)3), 117.02, 125.58, 126.56, 126.66, 127.09, 129.03, 129.36, 131.36, 139.13, 154.02, 166.02; IR (KBr) v 3438, 3351, 2071, 2979, 2259, 1746, 1719, 1602, 1496, 1450, 1392, 1367, 1303, 1237, 1161, 1095, 1018, 854, 696; HRMS (MALDI): calcd. For [MþH]þ(C21H25N2O4S) requires 401.1535, found 401.1523; HPLC analysis: AD-H, hexane/iPrOH ¼ 90/10, 1.0 mL/min, 220 nm, tR ¼ 6.6 min (minor), tR ¼ 12.4 min (major), 85% ee, dr ¼ 92:8. 4.4.10. (2S,3R)-ethyl,3-((tert-butoxycarbonyl)amino)-2-cyano-3(naphthalen-1-yl)-2-phenylpropanoate (3j) Yield: 98%; white solid; m.p. ¼ 65e67  C; [a]22.1 ¼
35.3 D (c ¼ 0.75, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.75e7.28 (m, 12H), 5.84 (s, 2H), 4.29e435 (m, 2H, CH2CH3), 1.37 (s, 9H, CO2C(CH3)3), 1.29 (t, J ¼ 8.0 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 13.84 (CH2CH3), 28.21 CO2C(CH3)3, 60.18 (CHNHBoc), 61.21 (CCN), 63.69 (CH2CH3), 80.53 (CO2C(CH3)3), 117.14, 117.24, 125.27, 1126.22, 26.41, 127.09, 127.49, 128.21, 128.92, 129.16, 154.23, 166.30; IR (KBr) v 3374, 2976, 2924, 2855, 1727, 1713, 1524, 1488, 1468, 1455, 1367,

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005

R. Pan et al. / Tetrahedron xxx (2017) 1e10

1332, 1245, 1166, 1069, 1047, 967, 867, 778; HRMS (MALDI): calcd. For [MþH]þ (C27H29N2O4) requires 445.2127, found 445.2118; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 6.0 min (minor), tR ¼ 39.3 min (major), 95% ee, dr ¼ 95:5. 4.4.11. (2S,3R)-ethyl,3-((tert-butoxycarbonyl)amino)-2-cyano-3cyclohexyl-2-phenylpropanoate (3k) Yield: 94%; white solid; m.p. ¼ 63e65  C; [a]23.0 ¼
0.82 D (c ¼ 0.5, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.57 (d, J ¼ 8.4 Hz, 2H), 7.36e7.31 (m, 3H), 5.04 (d, J ¼ 7.6 Hz, 1H), 4.50 (d, J ¼ 10.8 Hz, 1H), 4.11e4.15 (m, 2H, CH2CH3), 1.33 (s, 9H, CO2C(CH3)3), 1.75e1.18 (m, 10H); 13C NMR (CDCl3, 100 MHz) d 13.78 (CH2CH3), 25.79, 25.86, 26.15, 27.23, 28.26 CO2C(CH3)3, 29.69, 31.74, 39.93, 59.48 (CHNHBoc), 60.07 (CCN), 63.42 (CH2CH3), 79.84 (CO2C(CH3)3), 117.94, 126.95, 129.06, 132.24, 136.51, 155.03, 166.76; IR (KBr) v 3354, 2932, 2861, 1706, 1455, 1367, 1248, 1168, 1081, 1017, 967, 867, 778; HRMS (MALDI): calcd. For [MþH]þ (C23H33N2O4) requires 401.2440, found 401.2432; HPLC analysis: AD-H, hexane/iPrOH ¼ 90/10, 1.0 mL/min, 220 nm, tR ¼ 5.9 min (minor), tR ¼ 17.0 min (major), 80% ee, dr ¼ 90:10. 4.4.12. (2S,3R)-methyl 3-((tert-butoxycarbonyl)amino)-2-cyano2,3-diphenylpropanoate (3l) Yield: 95%; white solid; m.p. ¼ 54e56  C; [a]23.1 D ¼
27.1 (c ¼ 0.5, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.41e7.39 (m, 2H), 7.23e7.22 (m, 3H), 7.11e7.04 (m, 5H), 5.71 (s, 1H, NHBoc), 5.55 (s, 1H, CHNHBoc), 3.84 (s, 3H), 1.37 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.17 CO2C(CH3)3, 54.14 (CHNHBoc), 60.03 (CO2CH3), 60.10 (CCN), 80.50 (CO2C(CH3)3), 117.49, 126.99, 127.89, 128.04, 128.24, 128.81, 128.97, 131.97, 136.24, 154.20, 165.03; IR (KBr) v 3386, 3063, 3036, 2980, 2928, 2852, 2254, 1746, 1714, 1604, 1587, 1496, 1451, 1435, 1392, 1367, 1327, 1245, 1166, 1046, 1021, 738, 698; HRMS (MALDI): calcd. For [MþH]þ (C22H25N2O4) requires 381.1814, found 381.1808; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 220 nm, tR ¼ 5.2 min (minor), tR ¼ 16.7 min (major), 80% ee, dr ¼ 90:10. 4.4.13. (2S,3R)-tert-butyl,3-((tert-butoxycarbonyl)amino)-2-cyano2,3-diphenylpropanoate (3m) Yield: 94%; white solid; m.p. ¼ 55e57  C; [a]23.1 ¼
4.2 (c ¼ 0.5, D CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.46 (d, J ¼ 2.8 Hz, 2H), 7.30e7.29 (m, 3H), 7.19e7.14 (m, 5H), 5.69e5.72 (m, 1H, NHBoc), 5.55e5.57 (m, 1H, CHNHBoc), 1.42 (s, 9H, NHCO2C(CH3)3), 1.30 (s, 9H, CCO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 27.62 (CCO2C(CH3)3), 28.25 CO2C(CH3)3, 29.69, 59.98 (CHNHBoc), 80.30 (NHCO2C(CH3)3), 85.28 (CCO2C(CH3)3), 117.49, 126.99, 127.87, 128.04, 128.24, 128.82, 128.97, 131.97, 136.24, 154.20, 165.03; IR (KBr) v 3066, 3022, 2976, 2926, 2855, 2254, 1738, 1586, 1494, 1453, 1393, 1369, 1248, 1156, 1021, 878, 838, 803, 699; HRMS (MALDI): calcd. For [MþH]þ (C25H31N2O4) requires 423.2284, found 423.2275; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/ min, 254 nm, tR ¼ 7.2 min (minor), tR ¼ 62.6 min (major), 86% ee, dr ¼ 93:7. 4.4.14. (2S,3R)-ethyl,2-benzyl-3-((tert-butoxycarbonyl)amino)-2cyano-3-phenylpropanoate (3n) Yield: 94%; white solid; m.p. ¼ 60e62  C; [a]22.0 ¼
3.5 (c ¼ 0.5, D CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.45e7.20 (m, 10H), 5.79 (d, J ¼ 7.6 Hz, 1H, NHBoc), 5.27 (d, J ¼ 8.0 Hz, 1H, CHNHBoc), 4.09 (dd, J ¼ 14.0 Hz, J ¼ 6.8 Hz, 2H, CH2CH3), 3.26 (d, J ¼ 12.4 Hz, 1H, PhCH2), 2.75 (d, J ¼ 11.8 Hz, 1H, PhCH2), 1.41 (s, 9H, CO2C(CH3)3), 1.08 (t, J ¼ 8.0 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 13.74 (CH2CH3), 28.21 CO2C(CH3)3, 40.87 (CH2Ph), 57.84 (CHNHBoc), 58.95 (CCN), 63.05 (CH2CH3), 80.50 (CO2C(CH3)3), 117.53, 127.72, 127.88, 128.55, 128.83, 128.96, 129.83, 154.33, 167.34; IR (KBr) v

7

3075, 3028, 2984, 2863, 2241, 1738, 1583, 1494, 1451, 1399, 1369, 1247, 1156, 803, 699; HRMS (MALDI): calcd. For [MþH]þ (C24H29N2O4) requires 409.2127, found 409.2121; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 220 nm, tR ¼ 6.7 min (minor), tR ¼ 30.7 min (major), 85% ee, dr ¼ 93:7. 4.4.15. (S)-ethyl,2-((R)-((tert-butoxycarbonyl)amino)(phenyl) methyl)-2-cyanopent-4-enoate (3o) Yield: 94%; white solid; m.p. ¼ 58e60  C; [a]23.1 D ¼
33.1 (c ¼ 0.4, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.38e7.39 (m, 5H), 5.69e5.79 (m, 2H, CH2]CH), 5.15e5.18 (m, 2H), 5.20e5.22 (m, 1H), 4.20e4.25 (m, 2H, CH2CH3), 2.66e2.71 (m, 1H), 2.25e2.28 (m, 1H), 1.40 (s, 9H, CO2C(CH3)3), 1.25 (t, J ¼ 8.4 Hz, 3H, CH2CH3); 13C NMR (CDCl3, 100 MHz) d 13.96 (CH2CH3), 28.22 CO2C(CH3)3, 39.40 (CH2CH] CH2), 58.33 (CHNHBoc), 63.17 (CH2CH3), 80.50 (CO2C(CH3)3), 121.28, 127.63, 128.81, 128.93, 129.98, 159.65, 167.44; IR (KBr) v 3447, 3358, 3066, 2984, 2926, 2863, 2250, 1749, 1721, 1496, 1451, 1397, 1367, 1313, 1229, 1167, 1097, 1045, 1015, 928, 880, 704; HRMS (MALDI): calcd. For [MþH]þ (C20H26N2O4) requires 359.1971, found 359.1966; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 220 nm, tR ¼ 6.6 min (minor), tR ¼ 19.3 min (major), 81% ee, dr ¼ 90:10. 4.5. Asymmetric quaternary phosphonium salts catalyzed Mannich-type reaction

To a solution of the correspongding catalyst 4k (5 mol%), K2CO3 (2 equiv) and 2-(2-nitrophenyl)acetonitrile (0.10 mmol) in CH2Cl2 (1.0 mL), and then was cooled to
20  C before the imines (0.12 mmol) was introduced. When the reaction was finished (determined by TLC analysis), the crude mixture was warmed to room temperature and purified by flash column chromatography (silica gel: petroleum ether/AcOEt ¼ 5:1) to afford the products. 4.6. Characterization data of products 6a-6t 4.6.1. tert-butyl ((1S,2R)-2-cyano-2-(2-nitrophenyl)-1-phenylethyl) carbamate (6a) Yield: 80%; light red solid; m.p. ¼ 53e55  C; [a]26.7 ¼ þ28.9 D (c ¼ 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.04e8.17 (m, 1H), 7.82e7.31 (m, 8H), 5.42e5.48 (m, 1H, CHNHBoc), 5.20e5.23 (m, 1H, NHBoc), 5.17e5.18 (m, 1H, CHCN), 1.29 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.10, 40.39 (CHCN, minor), 43.16 (CHCN, major), 56.34, 80.42, 118.25, 125.29, 126.23, 127.11, 128.66, 129.11, 129.76, 131.64, 133.72, 137.19, 147.70, 154.28; IR (KBr) v 3352, 3253, 3075, 2989, 2933, 2876, 2254, 1702, 1609, 1581, 1531, 1496, 1453, 1367, 1347,1244, 1164, 1075, 1049, 1013, 862, 790 cm
1; HRMS (MALDI): calcd. For [MþNa]þ (C20H21N3O4Na) requires 390.1430, found 390.1436; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 11.2 min (major), tR ¼ 28.8 min (minor), 96%/74% ee, dr ¼ 82:18. 4.6.2. tert-butyl ((1S,2R)-2-cyano-1-(4-fluorophenyl)-2-(2nitrophenyl)ethyl)carbamate (6b) ¼ þ13.7 Yield: 80%; light red solid; m.p. ¼ 56e57  C; [a]26.9 D (c ¼ 0.75, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.06e8.20 (m, 1H), 7.81e7.04 (m, 7H), 5.47e5.50 (m, 1H, CHNHBoc), 5.36e5.38 (m, 1H,

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005

8

R. Pan et al. / Tetrahedron xxx (2017) 1e10

NHBoc), 5.19e5.20 (m, 1H, CHCN), 1.29 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.05 (C(CH3)3, major), 29.67 (C(CH3)3, minor), 40.40 (CHCN, minor), 43.33 (CHCN, major), 55.63, 80.57, 116.04 (d, J ¼ 21.6 Hz), 125.37, 126.17, 128.00 (d, J ¼ 8.2 Hz), 128.88 (d, J ¼ 8.3 Hz), 129.86 131.49, 133.09 (d, J ¼ 3.3 Hz), 133.60, 133.85, 147.52, 162.67 (d, J ¼ 247 Hz); 19F NMR (CDCl3, 282 MHz) d
116 (m, minor),
117.74 (m, major); IR (KBr) v 3360, 3084, 2980, 2929, 2850, 2371, 2332, 2259, 1704, 1607, 1530, 1511, 1392, 1367, 1347, 1233, 1161, 1103, 1054, 1017, 842, 785, 725; HRMS (MALDI): calcd. For [MþNa]þ (C20H20FN3O4Na) requires 408.1336, found 408.1318; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 14.3 min (major), tR ¼ 35.0 min (minor), 94%/79% ee, dr ¼ 76:24. 4.6.3. tert-butyl ((1S,2R)-2-cyano-1-(3-fluorophenyl)-2-(2nitrophenyl)ethyl)carbamate (6c) Yield: 70%; light red solid; m.p. ¼ 52e53  C; [a]27.2 ¼ þ5.8 D (c ¼ 1.25, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.07e8.21 (m, 1H), 7.82e7.04 (m, 7H), 5.50e5.52 (m, 1H, CHNHBoc), 5.38e5.40 (m, 1H, NHBoc), 5.17e5.23 (m, 1H, CHCN), 1.29 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.08 (C(CH3)3, major), 29.70 (C(CH3)3, minor), 40.16 (CHCN, minor), 43.11 (CHCN, major), 55.78, 80.72, 113.66 (d, J ¼ 22.6 Hz), 114.42 (d, J ¼ 22.2 Hz), 115.78 (d, J ¼ 20.9 Hz), 116.21 (d, J ¼ 20.9 Hz), 122.82, 125.42, 128.22, 129.94, 130.84 (d, J ¼ 8.3 Hz), 131.52, 133.89, 139.61 (d, J ¼ 6.9 Hz), 147.58, 163.06 (d, J ¼ 247 Hz); 19F NMR (CDCl3, 282 MHz) d
111.05 (m, minor),
111.24 (m, major); IR (KBr) v 3350, 3084, 2977, 2926, 2854, 2250, 1704, 1610, 1592, 1530, 1489, 1450, 1367, 1348, 1245, 1162, 1078, 1047, 1017, 968, 862, 785, 724, 709; HRMS (MALDI): calcd. For [MþNa]þ (C20H20FN3O4Na) requires 408.1336, found 408.1324; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 9.5 min (major), tR ¼ 17.2 min (minor), 92%/48% ee, dr ¼ 73:27. 4.6.4. tert-butyl ((1S,2R)-2-cyano-1-(2-fluorophenyl)-2-(2nitrophenyl)ethyl)carbamate (6d) Yield: 65%; light red solid; m.p. ¼ 50e52  C; [a]26.5 ¼
9.2 D (c ¼ 0.75, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.04e8.06 (m, 1H), 7.70e7.04 (m, 7H), 5.58e5.71 (m, 1H, CHNHBoc), 5.55e5.56 (m, 1H, NHBoc), 5.30e5.48 (m, 1H, CHCN), 1.32 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.05 (C(CH3)3, major), 29.69 (C(CH3)3, minor), 39.33 (CHCN, minor), 41.21 (CHCN, major), 54.05, 80.64, 116.60, 117.88, 124.79 (d, J ¼ 3.3 Hz), 125.74, 127.97, 129.04, 129.82, 130.69 (d, J ¼ 8.6 Hz), 131.40, 133.84, 136.38 (d, J ¼ 9.3 Hz), 147.95, 154.55, 161.75 (d, J ¼ 243 Hz); 19F NMR (CDCl3, 282 MHz) d
119.68 (m, major),
121.22 (m, minor); IR (KBr) v 3352, 3161, 3084, 2989, 2937, 2850, 2259, 1704, 1611, 1578, 1531, 1491, 1456, 1392, 1367, 1349, 1247, 1165, 1093, 1049, 1019, 877, 857, 759; HRMS (MALDI): calcd. For [MþNa]þ (C20H20FN3O4Na) requires 408.1336, found 408.1320; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/ min, 254 nm, tR ¼ 11.3 min (major), tR ¼ 25.4 min (minor), 76%/59% ee, dr ¼ 64:36. 4.6.5. tert-butyl ((1S,2R)-2-cyano-2-(2-nitrophenyl)-1-(p-tolyl) ethyl)carbamate (6e) Yield: 85%; light red solid; m.p. ¼ 65e67  C; [a]27.0 ¼ þ21.9 D (c ¼ 1.25, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.03e8.16 (m, 1H), 7.80e7.17 (m, 7H), 5.38e5.45 (m, 2H), 5.12e5021 (m, 1H), 2.37 (s, 2.4H; major, ArCH3), 2.35 (s, 0.6H; minor, ArCH3), 1.28 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 21.10, 28.11 (C(CH3)3, major), 29.68 (C(CH3)3, minor), 40.42 (CHCN, minor), 43.19 (CHCN, major), 56.18, 80.34, 118.00, 125.23, 126.09, 126.96, 128.62, 129.73, 131.15, 133.68, 134.76, 138.50, 147.75, 154.53; IR (KBr) v 3352, 3153, 2977, 2937, 2876, 2250, 1704, 1615, 1581, 1529, 1391, 1366, 1347, 1244, 1165, 1054, 1017, 855, 810, 792, 724; HRMS (MALDI): calcd. For [MþNa]þ (C21H23N3O4Na) requires 404.1586, found 404.1591; HPLC

analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 11.5 min (major), tR ¼ 31.6 min (minor), 98%/85% ee, dr ¼ 84:16. 4.6.6. tert-butyl ((1S,2R)-2-cyano-2-(2-nitrophenyl)-1-(m-tolyl) ethyl)carbamate (6f) Yield: 80%; light red solid; m.p. ¼ 109e110  C; [a]27.2 ¼ þ28.5 D (c ¼ 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.02e8.16 (m, 1H), 7.81e7.11 (m, 7H), 5.40e5.43 (m, 2H), 5.20e5.22 (m, 1H), 2.40 (s, 2.4H; major, ArCH3), 2.35 (s, 0.6H; minor, ArCH3), 1.28 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 21.51, 28.10 (C(CH3)3, major), 29.70 (C(CH3)3, minor), 40.34 (CHCN, minor), 43.16 (CHCN, major), 56.31, 80.38, 118.01, 123.21, 126.04, 126.93, 128.99, 129.42, 129.71, 131.15, 131.67, 133.71, 137.59, 138.91, 147,72, 154.55; IR (KBr) v 3360, 3261, 3153, 2977, 2933, 2881, 2384, 2323, 2250, 1703, 1607, 1581, 1529, 1391, 1366, 1347, 1245, 1163, 1099, 1056, 1021, 864, 786, 723, 708; HRMS (MALDI): calcd. For [MþNa]þ (C21H23N3O4Na) requires 404.1586, found 404.1590; HPLC analysis: AD-H, hexane/iPrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 9.4 min (major), tR ¼ 17.5 min (minor), 98%/79% ee, dr ¼ 85:15. 4.6.7. tert-butyl ((1S,2R)-2-cyano-2-(2-nitrophenyl)-1-(o-tolyl) ethyl)carbamate (6g) Yield: 70%; light red solid; m.p. ¼ 54e55  C; [a]27.1 ¼
110.0 D (c ¼ 1.25, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.90e8.02 (m, 1H), 7.67e7.15 (m, 7H), 5.57e5.59 (m, 1H, CHNHBoc), 5.52e5.54 (m, 1H, NHBoc), 5.08e5.26 (m, 1H, CHCN), 2.30 (s, 2.3H; major, ArCH3), 2.26 (s, 0.7H; minor, ArCH3), 1.31e1.26 (s, 9H, CO2C(CH3)3);13C NMR (CDCl3, 100 MHz) d 19.29, 28.07 (C(CH3)3, major), 29.70 (C(CH3)3, minor), 39.49 (CHCN, minor), 40.53 (CHCN, major), 52.93, 80.42, 118.61, 125.21, 125.55, 126.75, 127.07, 128.53, 128.65, 129.69, 131.25, 131.67, 133.78, 136.06, 147.87, 154.55; IR (KBr) v 3356, 3257, 3149, 3066, 2977, 2931, 2250, 1704, 1607, 1578, 1530, 1492, 1456, 1350, 1285, 1245, 1164, 1045, 1016, 877, 862, 785, 729, 703; HRMS (MALDI): calcd. For [MþH]þ (C21H24N3O4) requires 382.1767, found 382.1759; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/ min, 254 nm, tR ¼ 10.0 min (major), tR ¼ 20.9 min (minor), 83%/46% ee, dr ¼ 72:28. 4.6.8. tert-butyl,((1S,2R)-2-cyano-1-(4-methoxyphenyl)-2-(2nitrophenyl)ethyl)carbamate (6h) Yield: 85%; light red solid; m.p. ¼ 48e50  C; [a]26.8 ¼ þ17.5 D (c ¼ 0.6, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.02e8.15 (m, 1H), 7.85e6.86 (m, 7H), 5.40e5.42 (m, 2H), 5.20 (s, 1H), 3.82 (s, 3H; ArCH3), 1.28 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.26 (C(CH3)3, major), 29.70 (C(CH3)3, minor), 43.24, 55.34, 57.68, 80.35, 114.35, 118.09, 118.36, 125.24, 128.31, 129.67, 131.66, 147.74, 148.53, 154.27, 160.03, 164.65; IR (KBr) v 3373, 3153, 3071, 2977, 2933, 2846, 2254, 1703, 1611, 1579, 1529, 1391, 1366, 1347, 1297, 1251, 1164, 1114, 1031, 836, 785, 725; HRMS (MALDI): calcd. For [MþNa]þ(C21H23N3O5Na) requires 420.1535, found 420.1537; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 15.9 min (major), tR ¼ 42.5 min (minor), 96%/79% ee, dr ¼ 86:14. 4.6.9. tert-butyl,((1S,2R)-2-cyano-1-(3-methoxyphenyl)-2-(2nitrophenyl)ethyl)carbamate (6i) Yield: 85%; light red solid; m.p. ¼ 49e51  C; [a]27.1 ¼ þ45.1 D (c ¼ 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.03e8.16 (m, 1H), 7.81e6.83 (m, 7H), 5.23e5.44 (m, 2H), 5.14e5.16 (m, 1H, CHCN), 4.2 (s, 2.3H; major, ArOCH3), 3.92 (s, 0.7H; minor, ArOCH3), 1.28 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.10 (C(CH3)3, major), 29.70 (C(CH3)3, minor), 40.29 (CHCN, minor), 43.07 (CHCN, major), 55.37, 56.32, 80.43, 112.16, 114.13, 118.30, 126.08, 128.53, 129.77, 130.20, 131.12, 131.63, 133.75, 139.20, 147.68, 154.54, 160.11; IR (KBr) v 3373, 2989, 2937, 2833, 2246, 1703, 1603, 1586, 1529, 1491, 1455,

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005

R. Pan et al. / Tetrahedron xxx (2017) 1e10

1366, 1348, 1265, 1246, 1163, 1044, 862, 788, 726, 704; HRMS (MALDI): calcd. For [MþNa]þ(C21H23N3O5Na) requires 420.1535, found 420.1537; HPLC analysis: AS-HþOD-H, hexane/i-PrOH ¼ 90/ 10, 1.0 mL/min, 254 nm, tR ¼ 32.7 min (major), tR ¼ 44.3 min (minor), 92%/66% ee, dr ¼ 76:24. 4.6.10. tert-butyl,((1S,2R)-2-cyano-1-(2-methoxyphenyl)-2-(2nitrophenyl)ethyl)carbamate (6j) Yield: 85%; light red solid; m.p. ¼ 43e45  C; [a]27.2 ¼
8.0 D (c ¼ 1.25, CHCl3); 1H NMR(CDCl3, 400 MHz) d 7.35e8.12 (m, 6H), 6.79e6.94 (m, 2H), 6.07e6.10 (m, 1H, CHNHBoc), 5.43e5.64 (m, 1H, NHBoc), 5.19e5.28 (m, 1H, CHCN), 3.91 (s, 3H, ArCH3), 1.28 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.07 (C(CH3)3, major), 28.31 (C(CH3)3, minor), 37.83 (CHCN, minor), 39.16 (CHCN, major), 55.32, 57.15, 80.28, 111.26, 118.57, 120.84, 125.06, 128.17, 129,38, 130.13, 130.36, 130.93, 131.44, 133.38, 148.49, 154.87, 156.93; IR (KBr) v 3460, 3365, 3071, 2977, 2846, 2250, 1715, 1603, 1531, 1493, 1464, 1392, 1350, 1283, 1284, 1164, 1047, 1023, 890, 857, 755; HRMS (MALDI): calcd. For [MþNa]þ (C21H23N3O5Na) requires 420.1535, found 420.1536; HPLC analysis: AS-HþOD-H, hexane/i-PrOH ¼ 90/ 10, 1.0 mL/min, 254 nm, tR ¼ 21.8 min (major), tR ¼ 27.9 min (minor), 95%/55% ee, dr ¼ 55:45. 4.6.11. tert-butyl,((1S,2R)-1-(4-(tert-butyl)phenyl)-2-cyano-2-(2nitrophenyl)ethyl)carbamate (6k) Yield: 90%; light red solid; m.p. ¼ 48e50  C; [a]26.4 ¼ þ5.2 D (c ¼ 0.75, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.03e8.17 (m, 1H), 7.82e7.38 (m, 7H), 5.41e5.43 (m, 2H), 5.15e5.21 (m, 1H, CHCN), 1.33 (s, 9H, CO2C(CH3)3), 1.31 (s, 9H, ArC(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.08 (C(CH3)3, major), 29.35 (C(CH3)3, minor), 31.26 (ArC(CH3), major), 34.63 (ArC(CH3)3, minor), 40.39 (CHCN, minor), 43.20 (CHCN, major), 56.09, 80.31, 118.14, 125.21, 125.92, 126.72, 128.68, 129.67, 131.10, 133.69, 134.67, 147.69, 151.77, 154.52; IR (KBr) v 3356, 2965, 2246, 1704, 1609, 1579, 1530, 1366, 1347, 1269, 1243, 1165, 1047, 1016, 855, 785, 734, 709; HRMS (MALDI): calcd. For [MþNH4]þ (C24H33N4O4) requires 441.2052, found 441.2490; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 8.1 min (major), tR ¼ 15.8 min (minor), 95%/68% ee, dr ¼ 78:22. 4.6.12. tert-butyl ((1S,2R)-1-(4-chlorophenyl)-2-cyano-2-(2nitrophenyl)ethyl)carbamate (6l) ¼ þ44.8 Yield: 85%; light red solid; m.p. ¼ 45e47  C; [a]27.1 D (c ¼ 1.25, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.05e8.19 (m, 1H), 7.80e7.33 (m, 7H), 5.43e5.47 (m, 2H), 5.19 (s, 1H), 1.28 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.09 (C(CH3)3, major), 29.35 (C(CH3)3, minor), 40.28 (CHCN, minor), 43.16 (CHCN, major), 55.73, 80.66, 117.70, 126.21, 127.66, 128.53, 129.29, 129.94, 131.08, 133.93, 134.65, 136.32, 147.58, 154.45; IR (KBr) v 3356, 3265, 3153, 3075, 2978, 2933, 2876, 2246, 1704, 1530, 1613, 1581, 1493, 1455, 1392, 1367, 1347, 1245, 1163, 1092, 1054, 1014, 785, 734, 708; HRMS (MALDI): calcd. For [MþNa]þ (C20H20ClN3O4Na) requires 424.1486, found 424.1474; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 13.4 min (major), tR ¼ 30.4 min (minor), 90%/67% ee, dr ¼ 80:20. 4.6.13. tert-butyl ((1S,2R)-1-(4-bromophenyl)-2-cyano-2-(2nitrophenyl)ethyl)carbamate (6m) Yield: 85%; light red solid; m.p. ¼ 50e52  C; [a]23.0 ¼ þ23.8 D (c ¼ 0.1, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.06e8.19 (m, 1H), 7.80e7.18 (m, 7H), 5.35e5.48 (m, 2H), 5.19 (s, 1H), 1.28 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.10 (C(CH3)3, major), 29.69 (C(CH3)3, minor), 29.70, 55.78, 80.70, 117.66, 122.81, 126.23, 127.94, 128.21, 129.95, 131.07, 132.27, 133.93, 136.82, 147.57, 154.42; IR (KBr) v 2958, 2920, 2850, 1993, 1956, 1920, 1842, 1773, 1732, 1682, 1658, 1630, 1557, 1544, 1505, 1455, 1438, 1421, 1265, 1179,

9

1144, 1080; HRMS (MALDI): calcd. For [MþH]þ (C20H21BrN3O4) requires 446.0637, found 446.2118; HPLC analysis: AD-H, hexane/iPrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 15.6 min (major), tR ¼ 40.0 min (minor), 97%/56% ee, dr ¼ 80:20. 4.6.14. tert-butyl ((1S,2R)-1-(3-bromophenyl)-2-cyano-2-(2nitrophenyl)ethyl)carbamate (6n) Yield: 80%; light red solid; m.p. ¼ 51e53  C; [a]26.5 ¼ þ55.9 D (c ¼ 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.07e8.20 (m, 1H), 7.81e7.30 (m, 7H), 5.64e5.66 (m, 1H, CHNHBoc), 5.48e5.51 (m, 1H, NHBoc), 5.25e5.35 (m, 1H, CHCN), 1.28 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.04 (C(CH3)3, major), 29.69 (C(CH3)3, minor), 40.13 (CHCN, minor), 43.15 (CHCN, major), 55.59, 80.68, 117.60, 123.16, 124.90, 126.26, 128.10, 129.37, 129.96, 130.64, 131.05, 131.80, 133.96, 139.90, 147.45, 154.38; IR (KBr) v 3347, 3265, 3162, 3075, 2978, 2933, 2868, 2250, 1703, 1615, 1574, 1529,1476, 1392, 1367, 1347, 1244, 1163, 1075, 1052, 1017, 859, 786, 704; HRMS (MALDI): calcd. For [MþNH4]þ (C20H24BrN4O4) requires 463.0981, found 463.0965; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 11.5 min (major), tR ¼ 29.5 min (minor), 95%/65% ee, dr ¼ 80:20. 4.6.15. tert-butyl ((1S,2R)-2-cyano-2-(2-nitrophenyl)-1-(thiophen2-yl)ethyl)carbamate (6o) Yield: 78%; light red solid; m.p. ¼ 48e50  C; [a]27.2 ¼ þ29.2 D (c ¼ 1.25, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.05e8.20 (m, 1H), 7.82e6.98 (m, 6H), 5.69e5.71 (m, 1H, CHNHBoc), 5.47e5.51 (m, 1H, NHBoc), 5.17e5.35 (m, 1H, CHCN), 1.29 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.08 (C(CH3)3, major), 29.68 (C(CH3)3, minor), 41.15 (CHCN, minor), 43.60 (CHCN, major), 53.17, 80.65, 117.78, 125.06, 125.50, 126.20, 127.42, 129.94, 130.94, 131.48, 133.89, 147.47, 154.26; IR (KBr) v 3339, 3110, 3084, 2978, 2872, 2246, 1715, 1613, 1576, 1529, 1392, 1367, 1346, 1245, 1163, 1054, 1019, 705; HRMS (MALDI): calcd. For [MþNa]þ (C18H19N3O4SNa) requires 396.0994, found 396.0983; HPLC analysis: AD-H, hexane/iPrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 13.9 min (major), tR ¼ 37.2 min (minor), 93%/63% ee, dr ¼ 73:27. 4.6.16. tert-butyl ((1S,2R)-2-cyano-2-(2-nitrophenyl)-1-(4nitrophenyl)ethyl)carbamate (6p) Yield: 85%; light red solid; m.p. ¼ 66e68  C; [a]26.6 ¼ þ9.8 D (c ¼ 0.5, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.24e8.32 (m, 1H), 8.11e7.51 (m, 7H), 5.63e5.66 (m, 1H, CHNHBoc), 5.48e5.51 (m, 1H, NHBoc), 5.26e5.41 (m, 1H, CHCN), 1.29 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.03 (C(CH3)3, major), 29.68 (C(CH3)3, minor), 39.97 (CHCN, minor), 43.06 (CHCN, major), 55.68, 81.06, 117.27, 124.30, 126.46, 127.39, 128.30, 130.26, 131.32, 134.22, 144.71, 147.95, 148.29, 154.31; IR (KBr) v 3386, 3123, 3084, 2980, 2937, 2868, 2254, 1704, 1608, 1528, 1392, 1349, 1246, 1163, 1110, 1049, 1015, 856, 736, 706; HRMS (MALDI): calcd. For [MþNH4]þ (C20H24N5O6) requires 430.1727, found 430.1714; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 16.1 min (major), tR ¼ 34.8 min (minor), 94%/17% ee, dr ¼ 78:22. 4.6.17. tert-butyl((1S,2R)-2-cyano-1-(naphthalen-1-yl)-2-(2nitrophenyl)ethyl)carbamate (6q) Yield: 90%; light red solid; m.p. ¼ 55e57  C; [a]27.1 ¼ þ23.0 D (c ¼ þ1.25, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.05e8.19 (m, 1H), 7.93e7.51 (m, 10H), 5.66e5.68 (m, 1H, CHNHBoc), 5.54e5.56 (m, 1H, NHBoc), 5.34e5.35 (m, 1H, CHCN), 1.30 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 28.07 (C(CH3)3, major), 29.69 (C(CH3)3, minor), 40.28 (CHCN, minor), 43.24 (CHCN, major), 56.31, 80.48, 117.96, 122.74, 123.85, 124.11, 125.27, 126.17, 126.64, 127.70, 128.21, 129.11, 129.79, 131.11, 133.15, 133.84, 134.40, 134.94, 147.56, 154.54; IR (KBr) v 3352, 3157, 3062, 2978, 2933, 2881, 2246, 1703, 1609,

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005

10

R. Pan et al. / Tetrahedron xxx (2017) 1e10

1581, 1529, 1507, 1455, 1391, 1367, 1346, 1245, 1164, 1047, 1017, 961, 858, 815, 785, 741, 721; HRMS (MALDI): calcd. For [MþNH4]þ (C24H27N4O4) requires 435.2032, found 435.2024; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 20.7 min (major), tR ¼ 48.6 min (minor), 97%/90% ee, dr ¼ 82:18. 4.6.18. tert-butyl ((1S,2R)-2-cyano-1-cyclohexyl-2-(2-nitrophenyl) ethyl)carbamate (6r) Yield: 85%; light red solid; m.p. ¼ 55e57  C; [a]23.2 ¼
18.5 D (c ¼ 0.75, CHCl3); 1H NMR(CDCl3, 400 MHz) d 8.14e7.47 (m, 4H), 4.98e5.23 (m, 1H), 4.56e4.65 (m, 1H), 3.93e4.11 (m, 1H), 2.04e0.99 (m, 10H), 1.20 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) d 25.91, 28.10 (C(CH3)3, major), 28.34 (C(CH3)3, minor), 30.63, 35.21, 38.09, 40.05, 41.29, 57.74, 58.86, 79.73, 118.23, 126.01, 129.11, 129.27, 131.55, 134.08, 147.34, 154.91; IR (KBr) v 3451, 3355, 2984, 2928, 2854, 2246, 1705, 1609, 1578, 1530, 1450, 1393, 1367, 1347, 1302, 1244, 1169, 1056, 1012, 855, 785, 711; HRMS (MALDI): calcd. For [MþNH4]þ (C20H31N4O4) requires 391.2345, found 391.2332; HPLC analysis: AD-H, hexane/i-PrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 10.4 min (major), tR ¼ 31.6 min (minor), 87%/78% ee, dr ¼ 56:44. 4.6.19. tert-butyl ((1S,2R)-2-cyano-2-(3-nitrophenyl)-1phenylethyl)carbamate (6s) Yield: 80%; light red solid; m.p. ¼ 150e151  C; 1H NMR(CDCl3, 400 MHz) d 8.21e8.24 (m, 1H), 8.09e8.10 (m, 1H), 7.52e7.56 (m, 2H), 7.36e7.38 (m, 3H), 7.16e7.17 (m, 2H), 5.20e5.22 (m, 2), 5.57 (s, 1), 1.38 (s, 9H); 13C NMR (CDCl3, 100 MHz) d 28.24, 43.81, 59.13, 81.01, 117.84, 123.32, 123.39, 127.35, 128.92, 129.30, 129.76, 134.23, 134.42, 134.63, 148.16, 155.12; IR (KBr) v 3388, 3093, 3073, 2982, 2246, 1707, 1531, 1497, 1453, 1355, 1242, 1169 cm
1; HRMS (MALDI): calcd. For [MþNa]þ (C20H21N3O4Na) requires 390.1424, found 390.1426; HPLC analysis: IC, hexane/i-PrOH ¼ 95/5, 0.8 mL/min, 254 nm, tR ¼ 28.4 min (major), tR ¼ 25.9 min (minor), 25%/7% ee, dr ¼ 57:43. 4.6.20. tert-butyl ((1S,2R)-2-cyano-2-(4-nitrophenyl)-1phenylethyl)carbamate (6t) Yield: 80%; light red solid; m.p. ¼ 63e64  C; 1H NMR(CDCl3, 400 MHz) d 8.19e8.21 (m, 1H), 8.10e8.12 (m, 1H), 7.25e7.42 (m, 5H), 7.15e7.18 (m, 1H), 7.06e7.07 (1 m, 1H), 5.37e5.38 (m, 0.5H), 5.21 (s, 1H), 4.95 (s, 0.5H), 4.87e4.90 (m, 0.5H), 5.54 (s, 0.5H), 1.48 (s, 5H), 1.38 (s, 4H); 13C NMR (CDCl3, 100 MHz) d 28.16, 28.28, 44.01, 44.45, 57.90, 59.31, 80.94, 81.13, 117.53, 117.76, 123.83, 123.84, 126.66, 127.32, 128.91, 129.00, 129.04, 129.25, 129.32, 129.61, 134.44, 136.47, 139.28, 139.33, 147.74, 147.94, 155.13; IR (KBr) v 3354, 2978, 2930, 2245, 1701, 1607, 1525, 1497, 1453, 1367, 1347, 1247, 1167 cm
1; HRMS (MALDI): calcd. For [MþNa]þ (C20H21N3O4Na) requires 390.1424, found 390.1425; HPLC analysis: OD-H, hexane/iPrOH ¼ 90/10, 1.0 mL/min, 254 nm, tR ¼ 10.3 min (major), tR ¼ 30.0 min (minor), 0%/0% ee, dr ¼ 50:50. Acknowledgement Research support from the Chinese Academy of Sciences (XDB 20020100) and National Natural Science Foundation of China (Nos.

21272247, 21572247, 21290184) is gratefully acknowledged. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.03.005. References 1. (a) Fleming FF. Nat Prod Rep. 1999;16:597e606; (b) Fleming FF, Yao L, Ravikumar PC, Funk L, Shook BC. J Med Chem. 2010;53: 7902e7917. 2. (a) Kisanga P, McLeod D, D'Sa B, Verkade J. J Org Chem. 1999;64:3090e3094; (b) You J, Verkade JG. Angew Chem Int Ed. 2003;42:5051e5053; (c) Suto Y, Kumagai N, Matsunaga S, Kanai M, Shibasaki M. Org Lett. 2003;5: 3147e3150; (d) Kumagai N, Matsunaga S, Shibasaki M. Chem Commun. 2005:3600e3602; (e) Culkin DA, Hartwig JF. Acc Chem Res. 2005;36:234e245; (f) Goto A, Endo K, Ukai Y, Irle S, Saito S. Chem Commun. 2008:2212e2214; (g) Wu T, Mu X, Liu G. Angew Chem Int Ed. 2011;50:12578e12581; (h) Wang GW, Zhou AX, Wang JJ, Hu RB, Yang SD. Org Lett. 2013;15:5270e5273; (i) Chakraborty S, Patel YJ, Krause JA, Guan H. Angew Chem Int Ed. 2013;52: 7523e7526; (j) Sureshkumar D, Ganesh V, Kumagai N, Shibasaki M. Chem Eur J. 2014;20: 15723e15726. 3. (a) Suto Y, Kumagai N, Matsunaga S, Kanai M, Shibasaki M. Org Lett. 2003;5: 3147e3150; (b) Kumagai N, Matsunaga S, Shibasaki M. J Am Chem Soc. 2004;126: 13632e13633;  KJ. Org Lett. 2008;10:5175e5178; (c) Aydin J, Conrad CS, Szabo (d) Hyodo K, Nakamura S, Tsuji K, Ogawa T, Funahashi Y, Shibata N. Adv Synth Catal. 2011;353:3385e3390; (e) Kawato Y, Kumagai N, Shibasaki M. Chem Commun. 2013;49:11227e11229.  P. Organometallics. 2014;33:5492e5508; 4. (a) Melanie M, Wolfgang F, Rene (b) Trost BM, Mahapatra S, Hansen M. Angew Chem Int Ed. 2015;54:6032e6036. 5. For recent reviews, see. (a) Denmark SE, Beutner GL. Angew Chem Int Ed. 2008;47:1560e1638; (b) Cowen BJ, Miller SJ. Chem Soc Rev. 2009;38:3102e3116; (c) Wang S, Han X, Zhong F, Wang Y, Lu Y. Synlett. 2011;19:2766e2778; (d) Marinetti A, Voituriez A. Synlett. 2010;2:174e194; (e) Zhao Q, Lian Z, Weri Y, Shi M. Chem Commun. 2012;48:1724e1732; (f) Fan Y, Kwon O. Chem Commun. 2013;49:11588e11619. 6. (a) Xiao H, Chai Z, Zheng CW, et al. Angew Chem Int Ed. 2010;49:4467e4470; (b) Han X, Wang Y, Zhong F, Lu Y. Org Biomol Chem. 2011;9:6734e6740; (c) Zhong F, Wang Y, Han X, Huang KW, Lu Y. Org Lett. 2011;13:1310e1313; (d) Gong JJ, Li TZ, Pan K, Wu XY. Chem Commun. 2011;47:1491e1493; (e) Han X, Wang Y, Zhong F, Lu Y. J Am Chem Soc. 2011;133:1726e1729; (f) Xiao H, Chai Z, Wang HF, et al. Chem Eur J. 2011;17:10562e10565; (g) Takizawa S, Nguyen T, Grossmann A, Enders D, Sasai H. Angew Chem Int Ed. 2012;51:5423e5426; (h) Han X, Zhong F, Wang Y, Lu Y. Angew Chem Int Ed. 2012;51:767e770; (i) Xiao H, Chai Z, Cao DD, Wang H, Chen J, Zhao G. Org Biomol Chem. 2012;10: 3195e3201; (j) Wu XY, Liu Q, Liu Y, et al. Adv Synth Catal. 2013;355:2701e2706; (k) Chen J, Cai YP, Zhao G. Adv Synth Catal. 2014;356:359e363; (l) Wang T, Yao W, Zhong F, Pang GH. Lu Y Angew Chem Int Ed. 2014;53: 2964e2968; (m) Han X, Yao WJ, Wang T, et al. Angew Chem Int Ed. 2014;53:5643e5647; (n) Lou YP, Zheng CW, Pan RM, Jin QW, Zhao G, Li Z. Org Lett. 2015;17:688e691; (o) Zhang JX, Cao DD, Wang HY, Zhao G, Shang YJ. Tetrahedron. 2015;71: 1785e1791; (p) Cao DD, Zhang JX, Wang HY, Zhao G. Chem Eur J. 2015;21:9998e10002; (q) Dong X, Liang L, Li E, Huang Y. Angew Chem Int Ed. 2015;54:1621e1624. 7. (a) Cao DD, Chai Z, Zhang JX, et al. Chem Commun. 2013;49:5972e5974; (b) Wang HY, Zhang K, Zheng CW, et al. Angew Chem Int Ed. 2015;54:1775e1779; (c) Wang HY, Zheng CW, Chai Z, Zhang JX, Zhao G. Nat Commun. 2016;7:12720. 8. (a) Cid MB, Duce S, Morales S, Rodrigo E, Garca-Ruano JL. Org Lett. 2010;12: 3586e3589; (b) Do J, Kim SG. Tetrahedron Lett. 2011;52:2353e2355; (c) Culkin DA, Hartwig JF. Acc Chem Res. 2005;36:234e245.

Please cite this article in press as: Pan R, et al., Enantioselective direct Mannich reaction of functionalized acetonitrile to N-Boc imines catalyzed by quaternary phosphonium catalysis, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.03.005