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Cite this: DOI: 10.1039/c5cc08118a Received 29th September 2015, Accepted 2nd November 2015
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Carbamoyl anion-initiated cascade reaction for stereoselective synthesis of substituted a-hydroxy-b-amino amides† Chao-Yang Lin,‡a Peng-Ju Ma,‡a Zhao Sun,b Chong-Dao Lu*ab and Yan-Jun Xu*a
DOI: 10.1039/c5cc08118a www.rsc.org/chemcomm
A carbamoyl anion-initiated cascade reaction with acylsilanes and imines has been used to rapidly construct substituted a-hydroxy-bamino amides. The Brook rearrangement-mediated cascade allows the formation of two C–C bonds and one O–Si bond in a single pot. Using this approach, a range of a-aryl a-hydroxy-b-amino amides has been synthesized in high yields with excellent diastereoselectivities.
Acylsilanes are well-known linchpin reagents that participate in 1,2-silyl migration-mediated three-component coupling reactions with nucleophiles and electrophiles (Scheme 1).1 Through such coupling reactions, modular combination of acylsilanes with appropriate coupling partners allows the construction of diverse functionalized tertiary silyl alcohols. Numerous nucleophiles have been used in this approach, including common organolithium, magnesium, and zinc reagents,2 as well as functionalized organometallic reagents such as metal enolates/aza-enolates generated from ketones,3 ketimines,4 esters,5 amides,6 and imidates.7 However, to the best of our knowledge, there have been no reports on the use of carbonyl anions in the acylsilanemediated coupling reaction.8 A three-component coupling cascade triggered by carbonyl anions would provide novel access to functionalized glycolic acid derivatives (Scheme 1, Nu = carbonyl anions), which might serve as an alternative to the protocols based on silyl glyoxylates (Scheme 1, R = esters) pioneered by Johnson and co-workers.1d The functionalized glycolic acid a-hydroxy-b-amino acid9,10 is an important structural motif found in several bioactive agents including taxoids.11 Recently, we developed a silyl glyoxylate-mediated coupling reaction involving Grignard reagents (or methyllithium) and imines a
The Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences, Urumqi 830011, China. E-mail: [email protected], [email protected] b Department of Chemistry and Applied Chemistry, Changji University, Changji 831100, China † Electronic supplementary information (ESI) available: Experimental details and spectral data. CCDC 1427984 (6o) and 1427986 (9). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc08118a ‡ These authors contributed equally.
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Scheme 1 imines.
Carbonyl anion-initiated cascade reaction with acylsilanes and
for the construction of a-substituted a-hydroxy acid derivatives.2g As an alternative to that method, we reasoned that using azomethines as electrophiles (Scheme 1, E+ = azomethines) to intercept the predicted carbamoyl anion12-triggered cascade would allow the construction of two C–C bonds and one O–Si bond in a one-pot operation, generating a-substituted a-hydroxyb-amino amides. We tried to achieve the predicted cascade reaction by adding lithium diisopropylamide (LDA) to a mixture of formamide 1a and phenyl acylsilane PhC(O)SiMe3 (2a) in THF at 78 1C. Subsequently we introduced N-diphenylphosphinylimine (N-DPP) 3a to the reaction mixture. To our delight, the expected threecomponent coupling proceeded smoothly to give substituted a-hydroxy-b-amino amide 4a in 90% yield, albeit with a low diastereomeric ratio (1.7 : 1 dr; Table 1, entry 1). Screening phenyl acylsilanes (entries 2–4) showed that bulky silyl groups improve the diastereoselectivity: using acylsilane 2b (SiR3 = SiPhMe2) led to 5 : 1 dr; 2c (SiR3 = SiEt3), to 11 : 1 dr; and 2d (SiR3 = Si-tBuMe2), to 420 : 1 dr.13 Surprisingly, replacing N-DPP imine 3a with N-tosylimine (PMPCH = NTs) in the coupling reaction of 1a and 2d dramatically reduced dr from 420 : 1 to o1.5 : 1.14 These results indicate that both the silyl group on the acylsilane and the N-substituent on the azomethine
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Table 1 Improving diastereoselectivity by tuning the silyl groups on phenyl acylsilanesa
Entry
NR2 SiR3 Entry (formamide) (acylsilane)
4
Yield (%)
1 2 3 4 5 6 7
4a 4b 4c 4d 4e 4f 4g
90 1.7 : 1 99 5:1 93 11 : 1 99 420 : 1 93 420 : 1 Quantd (99) 420 : 1 (420 : 1)d 42 420 : 1
N(CH2)5 (1a) N(CH2)5 (1a) N(CH2)5 (1a) N(CH2)5 (1a) NMe2 (1b) NEt2 (1c) NiPr2 (1d)
SiMe3 (2a) SiPhMe2 (2b) SiEt3 (2c) SitBuMe2 (2d) SitBuMe2 (2d) SitBuMe2 (2d) SitBuMe2 (2d)
b
c
dr
a Formamide 1 (0.40 mmol), acysilane 2 (0.40 mmol), LDA (0.48 mmol), and imine (0.20 mmol) in anhydrous THF under argon at 78 1C. b Isolated yield after silica gel chromatography. c Determined by 1 H NMR analysis of crude reaction mixtures. d Reaction on the 1 gram scale.
are critical for high diastereoselectivity. Formamides bearing various N-substitutions underwent coupling reactions with consistently excellent diastereocontrol (entries 5–7), although using sterically hindered formamide 1d led to lower yield. Using 1c in the coupling reaction led to nearly 100% yield, and the reaction was scaled up to 1 gram without losing yield or diastereoselectivity (entry 6). Next we investigated the substrate scope of the reaction (Table 2). The reaction worked well for N-DPP imines derived from a range of aryl and heteroaryl aldehydes, affording the desired products in high yields ranging from 73% to quantitative yield (entries 1–11). However, imines derived from pivaldehyde, cyclohexanecarboxaldehyde, and acetophenone did not react under standard conditions, and most of these imines were recovered after quenching the reactions. Several aryl acylsilanes proved to be good coupling partners, furnishing a-aryl-a-hydroxyb-amino amides 6l–q in excellent yields (90% – quantitative; entries 12–17). In contrast, electron-rich aryl or heteroaryl acylsilanes 5h–j gave diminished yields even when formamide and acylsilanes were present in large excess (5.0 equiv.; entries 18–20). Enolizable acylsilanes such as EtC(O)SiPhMe2 and iPrC(O)SiEt3 did not participate in the cascade transformation; no desired products were detected. High diastereoselectivities were observed for all products 6a–t in Table 2. The relative configuration of product 6o was assigned to be anti based on X-ray crystallography,15 and the configuration of other products was assigned by analogy. Next we explored the asymmetric variation in this cascade reaction by using chiral tert-butanesulfinylimine16 (tBS-imine). The chiral tBS-imine 7 proved to be a suitable coupling partner to give the desired products 8/8 0 in high yields (Scheme 2a). Only two anti-diastereomers of the imine adducts were observed; they had absolute configurations of (2R, 3R, RS) and (2S, 3S, RS).17
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Table 2 Diastereoselective synthesis of a-aryl a-hydroxy-b-amino amides via cascade couplinga
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Acylsilane (Ar) c
5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5b (4-MeC6H4) 5c (3-MeOC6H4) 5d (4-FC6H4) 5e (4-tBuC6H4) 5f (3,4-diMeC6H4) 5g (2-naphthyl) 5h (4-Me2NC6H4) 5i (2-furyl) 5j (2-thienyl)
Imine (Ar 0 ) 3a (4-MeOC6H4) 3b (Ph) 3c (4-MeC6H4) 3d (3-MeC6H4) 3e (2-MeC6H4) 3f (4-FC6H4) 3g (4-ClC6H4) 3h (3-MeOC6H4) 3i (1-naphthyl) 3j (2-furyl) 3k (2-thienyl) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4)
Product d
6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n 6o 6p 6q 6r 6s 6t
Yieldb Quant 99% 93% 94% 89% 90% 94% 93% 73% 87% 90% 90% 92% Quant Quant Quant 95% 76%e 84%e 63%e
a All reactions were carried out in THF with 2.0 equiv. of formamide 1, 2.0 equiv. of acylsilane 2 and 2.4 equiv. of LDA at 78 1C under argon, unless otherwise noted. Diastereomeric ratios (drs) were determined by 1 H NMR analysis of crude reaction mixtures. b Isolated yield after silica gel chromatography. c 5a = 2d. d 6a = 4f. e 5.0 equiv. of 1c, 5.0 equiv. of acylsilane and 6.0 equiv. of LDA were used.
Using acylsilane 2d (SiR3 = TBS) or 2a (SiR3 = TMS) led to major diastereomers with different configurations, suggesting that the steric hindrance of the silyl groups affects facial selectivity during the chiral imine addition reaction.18 Absolute configurations of the a-hydroxy-b-amino amide products 8 and 8 0 were deduced from the following reaction results (Scheme 2b). (1) Desilylation of 8a and 8d using tetrabutylammonium fluoride (TBAF) afforded the same alcohol 9, the configuration of which was determined to be (2R, 3R, RS) by X-ray crystallography.19 (2) Desilylation of 8 0 a and 8 0 d gave the same product 9 0 . (3) Using meta-chloroperoxybenzoic acid (m-CPBA) to oxidize the stereogenic sulfur centers in 8a and 8 0 a gave enantiomers 10 and 10 0 , respectively. The two enantiomers showed identical NMR spectra and melting point but opposite optical activity. Having worked out an efficient route toward the stereoselective synthesis of substituted a-hydroxy-b-amino amides, we next focused on removing substituents on the hydroxy and amino groups (Scheme 3). TBAF-induced desilylation of 4f gave free tertiary alcohol 11 in 93% yield. The phosphinyl group on nitrogen was then removed under acidic conditions, providing 12 in 99% yield. Mechanistically, the carbamoyl anion adds to acylsilane and then undergoes Brook rearrangement to generate an Z-enolate20
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bearing bulkier silyl groups gave higher anti-selectivities (Table 1, entries 1–4). In conclusion, we have developed an efficient three-component coupling reaction of formamides, acylsilanes and N-DPP imines. This appears to be the first report of cascade transformations initiated by carbamoyl anions and mediated by acylsilanes. The coupling reaction provides rapid access to substituted a-hydroxy-bamino amides in high yields with excellent diastereoselectivities. Excellent diastereocontrol requires appropriate silyl groups on the acylsilanes and appropriate N-substituted groups on the imines. Financial support of this work by the National Natural Science Foundation of China (U1403301, 21372255, and 21572262), the YCSTTC Project of Xinjiang Uygur Autonomous Region (2013711017), the Recruitment Program of Global Experts (Xinjiang Program) and the Director Foundation of XTIPC (2015RC014) is gratefully acknowledged.
Notes and references
Scheme 2 Coupling reactions with (RS)-tert-butanesulfinylimines, stereochemical model and assignment of absolute configurations of products.
Scheme 3
Removal of silyl and phosphinyl groups from product 4f.
of a-aryl-a-silyloxy amides (Scheme 4). The silyloxy enolate intermediate then reacts via the open transition state TS-1 to minimize nonbonding interactions between its silyoxy groups and the bulky N-DPP group of the imine, ultimately affording anti-a-hydroxy-b-amino amides 4 and 6. This proposed transition state model would explain why we observed that acylsilanes
Scheme 4
Proposed mechanism and stereochemical model.
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1 For reviews of Brook rearrangement and its applications in synthesis, see: (a) A. G. Brook, Acc. Chem. Res., 1974, 7, 77; (b) P. C. Bulman Page, S. S. Klair and S. Rosenthal, Chem. Soc. Rev., 1990, 19, 147; (c) W. H. Moser, Tetrahedron, 2001, 57, 2065; (d) G. R. Boyce, S. N. Greszler, J. S. Johnson, X. Linghu, J. T. Malinowski, D. A. Nicewicz, A. D. Satterfield, D. C. Schmitt and K. M. Steward, J. Org. Chem., 2012, 77, 4503; (e) G. Eppe, D. Didier and I. Marek, Chem. Rev., 2015, 115, 9175. 2 For selected examples of acylsilane-mediated cascade reactions initiated by alkyl, aryl, alkenyl, or alkynyl organometallic reagents, see: (a) R. Unger, T. Cohen and I. Marek, Org. Lett., 2005, 7, 5313; (b) D. A. Nicewicz and J. S. Johnson, J. Am. Chem. Soc., 2005, 127, 6170; (c) D. A. Nicewicz, A. D. Satterfield, D. S. Schmitt and J. S. Johnson, J. Am. Chem. Soc., 2008, 130, 17281; (d) G. R. Boyce and J. S. Johnson, Angew. Chem., Int. Ed., 2010, 49, 8930; (e) D. C. Schmitt and J. S. Johnson, Org. Lett., 2010, 12, 944; ( f ) M. Sasaki, Y. Kondo, M. Kawahata, K. Yamaguchi and K. Takeda, Angew. Chem., Int. Ed., 2011, 50, 6375; ( g) G. R. Boyce, S. Liu and J. S. Johnson, Org. Lett., 2012, 14, 652; (h) M. C. Slade and J. S. Johnson, Beilstein J. Org. Chem., 2013, 9, 166; (i) P. Smirnov, J. Mathew, A. Nijs, E. Katan, M. Karni, C. Bolm, Y. Apeloig and I. Marek, Angew. Chem., Int. Ed., 2013, 52, 13717; ( j) P. Smirnov, E. Katan, J. Mathew, A. Kostenko, M. Karni, A. Nijs, C. Bolm, Y. Apeloig and I. Marek, J. Org. Chem., 2014, 79, 12122; (k) J.-L. Jiang, M. Yao and C.-D. Lu, Org. Lett., 2014, 16, 318; (l ) M. Sasaki, Y. Kondo, T. Moto-ishi, M. Kawahata, K. Yamaguchi and K. Takeda, Org. Lett., 2015, 17, 1280; (m) C. Tan, W. Chen, X. Mu, Q. Chen, J. Gong, T. Luo and Z. Yang, Org. Lett., 2015, 17, 2338. 3 (a) K. Takeda, J. Nakatani, H. Nakamura, K. Sako, E. Yoshii and K. Yamaguchi, Synlett, 1993, 841; (b) M. Sasaki, K. Oyamada and K. Takeda, J. Org. Chem., 2010, 75, 3941, and references cited therein. 4 B. Liu and C.-D. Lu, J. Org. Chem., 2011, 76, 4205. 5 (a) S. N. Greszler, J. T. Malinowski and J. S. Johnson, J. Am. Chem. Soc., 2010, 132, 17393; (b) S. N. Greszler, J. T. Malinowski and J. S. Johnson, Org. Lett., 2011, 13, 3206; (c) D. C. Schmitt, L. Lam and J. S. Johnson, Org. Lett., 2011, 13, 5136; (d) D. C. Schmitt, E. J. Malow and J. S. Johnson, J. Org. Chem., 2012, 77, 3246. 6 (a) R. B. Lettan, T. E. Reynolds, C. V. Galliford and K. A. Scheidt, J. Am. Chem. Soc., 2006, 128, 15566; (b) R. B. Lettan, C. C. Woodward and K. A. Scheidt, Angew. Chem., Int. Ed., 2008, 47, 2294; (c) R. B. Lettan, C. V. Galliford, C. C. Woodward and K. A. Scheidt, J. Am. Chem. Soc., 2009, 131, 8805; (d) C. V. Galliford and K. A. Scheidt, Chem. Commun., 2008, 1926. 7 M. Yao and C.-D. Lu, Org. Lett., 2011, 13, 2782. 8 Nucleophiles such as metal cyanides, metallophosphites, and N-heterocyclic carbenes have been reported to initiate Brook rearrangement and subsequent nucleophilic transformations. For selected examples, see: (a) X. Linghu, C. C. Bausch and J. S. Johnson, J. Am. Chem. Soc., 2005, 127, 1833; (b) M. R. Garrett, J. C. Tarr and J. S. Johnson, J. Am. Chem. Soc., 2007, 129, 12944; (c) A. E. Mattson,
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10
11 12
13
A. R. Bharadwaj, A. M. Zuhl and K. A. Scheidt, J. Org. Chem., 2006, 71, 5715. These nucleophiles are usually used in catalytic amounts and are not present in the reaction intermediates. For reviews of b-amino acids, see: (a) P. Spiteller and F. von Nussbaum, b-Amino Acids in Natural Products, in Enantioselective Synthesis of b-Amino acids, ed. E. Juaristi and V. A. Soloshonok, Wiley & Sons, Hoboken, New Jersey, 2nd edn, 2005, p. 19; (b) G. Cardillo and C. Tomasini, Chem. Soc. Rev., 1996, 117. Selected examples of the synthesis of a-tertiary a-hydroxy-b-amino acid derivatives are presented. For direct addition of a-substituted a-hydroxy acid derivatives to imines, see: (a) A. Clerici, L. Clerici and O. Porta, Tetrahedron Lett., 1995, 36, 5955; (b) A. Clerici, N. Pastori and O. Porta, J. Org. Chem., 2005, 70, 4174; (c) A. Guerrini, G. Varchi and A. Battaglia, J. Org. Chem., 2006, 71, 6785; (d) A. Guerrini, G. Varchi, R. Daniele, C. Samori and A. Battaglia, Tetrahedron, 2007, 63, 7949. For Rh(II)-catalyzed three-component coupling of a-diazo esters, alcohols and imines, see: (e) C.-D. Lu, H. Liu, Z.-Y. Chen, W.-H. Hu and A.-Q. Mi, Org. Lett., 2005, 7, 83; ( f ) W. Hu, X. Xu, J. Zhou, W.-J. Liu, H. Huang, L. Yang and L.-Z. Gong, J. Am. Chem. Soc., 2008, 130, 7782; (g) Y. Qian, C. Jing, J. Ji, M. Tang, J. Zhou, C. Zhai and W. Hu, ChemCatChem, 2011, 3, 653; (h) X. Guo and W. Hu, Acc. Chem. Res., 2013, 46, 2427. For a recent review of the synthesis of the a-hydroxy-b-amino acid side chain of taxoids, see: J. C. Borah, J. Boruva and N. C. Barua, Curr. Org. Synth., 2007, 4, 175. We focused on the carbamoyl anion for building the predicted cascade reaction because it is among the stablest types of carbonyl anion. For recent examples of carbamoyl anion addition to azomethine electrophiles, see: (a) J. T. Reeves, Z. Tan, M. A. Herbage, Z. S. Han, M. A. Marsini, Z. Li, G. Li, Y. Xu, K. R. Fandrick, N. C. Gonnella, S. C. Campbell, S. Ma, N. Grinberg, H. Lee, B. Z. Lu and C. H. Senanayake, J. Am. Chem. Soc., 2013, 135, 5565; (b) J. T. Reeves, C. Lorenc, K. Camara, Z. Li, H. Lee, C. A. Busacca and C. H. Senanayake, J. Org. Chem., 2014, 79, 5895; (c) C. W. Seifert, S. Pindi and G. Li, J. Org. Chem., 2015, 80, 447. Desilylation of the major diastereomers of 4a–d gave identical products.
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ChemComm 14 The reaction using N-Ts imine derived from 4-methoxybenzaldehyde gave a three-component coupling product (13) in 99% yield with 1.5 : 1 dr. 15 Single crystals of compound 6o were recrystallized from benzene. Crystal data: C42H57N2O4PSi, M = 721.96, triclinic, a = 11.473(4) Å, b = 13.299(5) Å, c = 13.766(5) Å, V = 2086.5(12) Å3, T = 296 K, space group P1% , Z = 2, 12 527 reflections measured, 8916 unique (Rint = 0.0449), which were used in all calculations. The final R1 was 0.0750 (I Z 2s(I)) and wR2 was 0.2528 (all data), CCDC 1427984. See the ESI† for the single-crystal structure of compound 6o. 16 For reviews of the synthetic applications of tert-butanesulfinamide, see: (a) F. Ferreira, C. Botuha, F. Chemla and A. Perez-Luna, Chem. Soc. Rev., 2009, 38, 1162; (b) M. T. Robak, M. A. Herbage and J. A. Ellman, Chem. Rev., 2010, 110, 3600. 17 Adding 3.0 or 10.0 equiv. of boron trifluoride etherate (BF3Et2O) to the reactions did not improve the diastereoselectivity. 18 For facial selectivity of the chiral tBS-imine addition reaction via the chelated chair-like 6/4-membered bicyclic transition state, see: (a) F. A. Davis, R. T. Reddy and R. E. Reddy, J. Org. Chem., 1992, 57, 6387; (b) T. P. Tang and J. A. Ellman, J. Org. Chem., 1999, 64, 12; (c) T. P. Tang and J. A. Ellman, J. Org. Chem., 2002, 67, 7819. For facial selectivity via a non-chelated open transition state, see: (d) T. Fujisawa, Y. Kooriyama and M. Shimizu, Tetrahedron Lett., 1996, 37, 3881. 19 Single crystals of compound 9 were obtained from acetonitrile by slow solvent evaporation. Crystal data: C24H31BrN2O3S, M = 507.48, orthorhombic, a = 9.891(13) Å, b = 16.14(2) Å, c = 16.21(2) Å, V = 2588(6) Å3, T = 296 K, space group P212121, Z = 4, 15 227 reflections measured, 5656 unique (Rint = 0.0964), which were used in all calculations. The final R1 was 0.0672 (I Z 2s(I)) and wR2 was 0.2260 (all data), CCDC 1427986. See the ESI† for the single-crystal structure of compound 9. 20 The formation of (Z)-lithium silyloxy enolates in lithium enolateinitiated Brook rearrangements of silyl glyoxylates was documented by Johnson and co-workers in ref. 1c and 2e, in which Claisen rearrangement of the formed silyloxy enolate intermediates was used as a stereochemical probe for enolate geometry. In our case, the formation of E-enolate intermediate cannot be ruled out completely at this time.
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Cite this: DOI: 10.1039/c5cc08118a Received 29th September 2015, Accepted 2nd November 2015
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Carbamoyl anion-initiated cascade reaction for stereoselective synthesis of substituted a-hydroxy-b-amino amides† Chao-Yang Lin,‡a Peng-Ju Ma,‡a Zhao Sun,b Chong-Dao Lu*ab and Yan-Jun Xu*a
DOI: 10.1039/c5cc08118a www.rsc.org/chemcomm
A carbamoyl anion-initiated cascade reaction with acylsilanes and imines has been used to rapidly construct substituted a-hydroxy-bamino amides. The Brook rearrangement-mediated cascade allows the formation of two C–C bonds and one O–Si bond in a single pot. Using this approach, a range of a-aryl a-hydroxy-b-amino amides has been synthesized in high yields with excellent diastereoselectivities.
Acylsilanes are well-known linchpin reagents that participate in 1,2-silyl migration-mediated three-component coupling reactions with nucleophiles and electrophiles (Scheme 1).1 Through such coupling reactions, modular combination of acylsilanes with appropriate coupling partners allows the construction of diverse functionalized tertiary silyl alcohols. Numerous nucleophiles have been used in this approach, including common organolithium, magnesium, and zinc reagents,2 as well as functionalized organometallic reagents such as metal enolates/aza-enolates generated from ketones,3 ketimines,4 esters,5 amides,6 and imidates.7 However, to the best of our knowledge, there have been no reports on the use of carbonyl anions in the acylsilanemediated coupling reaction.8 A three-component coupling cascade triggered by carbonyl anions would provide novel access to functionalized glycolic acid derivatives (Scheme 1, Nu = carbonyl anions), which might serve as an alternative to the protocols based on silyl glyoxylates (Scheme 1, R = esters) pioneered by Johnson and co-workers.1d The functionalized glycolic acid a-hydroxy-b-amino acid9,10 is an important structural motif found in several bioactive agents including taxoids.11 Recently, we developed a silyl glyoxylate-mediated coupling reaction involving Grignard reagents (or methyllithium) and imines a
The Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences, Urumqi 830011, China. E-mail: [email protected], [email protected] b Department of Chemistry and Applied Chemistry, Changji University, Changji 831100, China † Electronic supplementary information (ESI) available: Experimental details and spectral data. CCDC 1427984 (6o) and 1427986 (9). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc08118a ‡ These authors contributed equally.
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Scheme 1 imines.
Carbonyl anion-initiated cascade reaction with acylsilanes and
for the construction of a-substituted a-hydroxy acid derivatives.2g As an alternative to that method, we reasoned that using azomethines as electrophiles (Scheme 1, E+ = azomethines) to intercept the predicted carbamoyl anion12-triggered cascade would allow the construction of two C–C bonds and one O–Si bond in a one-pot operation, generating a-substituted a-hydroxyb-amino amides. We tried to achieve the predicted cascade reaction by adding lithium diisopropylamide (LDA) to a mixture of formamide 1a and phenyl acylsilane PhC(O)SiMe3 (2a) in THF at 78 1C. Subsequently we introduced N-diphenylphosphinylimine (N-DPP) 3a to the reaction mixture. To our delight, the expected threecomponent coupling proceeded smoothly to give substituted a-hydroxy-b-amino amide 4a in 90% yield, albeit with a low diastereomeric ratio (1.7 : 1 dr; Table 1, entry 1). Screening phenyl acylsilanes (entries 2–4) showed that bulky silyl groups improve the diastereoselectivity: using acylsilane 2b (SiR3 = SiPhMe2) led to 5 : 1 dr; 2c (SiR3 = SiEt3), to 11 : 1 dr; and 2d (SiR3 = Si-tBuMe2), to 420 : 1 dr.13 Surprisingly, replacing N-DPP imine 3a with N-tosylimine (PMPCH = NTs) in the coupling reaction of 1a and 2d dramatically reduced dr from 420 : 1 to o1.5 : 1.14 These results indicate that both the silyl group on the acylsilane and the N-substituent on the azomethine
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Table 1 Improving diastereoselectivity by tuning the silyl groups on phenyl acylsilanesa
Entry
NR2 SiR3 Entry (formamide) (acylsilane)
4
Yield (%)
1 2 3 4 5 6 7
4a 4b 4c 4d 4e 4f 4g
90 1.7 : 1 99 5:1 93 11 : 1 99 420 : 1 93 420 : 1 Quantd (99) 420 : 1 (420 : 1)d 42 420 : 1
N(CH2)5 (1a) N(CH2)5 (1a) N(CH2)5 (1a) N(CH2)5 (1a) NMe2 (1b) NEt2 (1c) NiPr2 (1d)
SiMe3 (2a) SiPhMe2 (2b) SiEt3 (2c) SitBuMe2 (2d) SitBuMe2 (2d) SitBuMe2 (2d) SitBuMe2 (2d)
b
c
dr
a Formamide 1 (0.40 mmol), acysilane 2 (0.40 mmol), LDA (0.48 mmol), and imine (0.20 mmol) in anhydrous THF under argon at 78 1C. b Isolated yield after silica gel chromatography. c Determined by 1 H NMR analysis of crude reaction mixtures. d Reaction on the 1 gram scale.
are critical for high diastereoselectivity. Formamides bearing various N-substitutions underwent coupling reactions with consistently excellent diastereocontrol (entries 5–7), although using sterically hindered formamide 1d led to lower yield. Using 1c in the coupling reaction led to nearly 100% yield, and the reaction was scaled up to 1 gram without losing yield or diastereoselectivity (entry 6). Next we investigated the substrate scope of the reaction (Table 2). The reaction worked well for N-DPP imines derived from a range of aryl and heteroaryl aldehydes, affording the desired products in high yields ranging from 73% to quantitative yield (entries 1–11). However, imines derived from pivaldehyde, cyclohexanecarboxaldehyde, and acetophenone did not react under standard conditions, and most of these imines were recovered after quenching the reactions. Several aryl acylsilanes proved to be good coupling partners, furnishing a-aryl-a-hydroxyb-amino amides 6l–q in excellent yields (90% – quantitative; entries 12–17). In contrast, electron-rich aryl or heteroaryl acylsilanes 5h–j gave diminished yields even when formamide and acylsilanes were present in large excess (5.0 equiv.; entries 18–20). Enolizable acylsilanes such as EtC(O)SiPhMe2 and iPrC(O)SiEt3 did not participate in the cascade transformation; no desired products were detected. High diastereoselectivities were observed for all products 6a–t in Table 2. The relative configuration of product 6o was assigned to be anti based on X-ray crystallography,15 and the configuration of other products was assigned by analogy. Next we explored the asymmetric variation in this cascade reaction by using chiral tert-butanesulfinylimine16 (tBS-imine). The chiral tBS-imine 7 proved to be a suitable coupling partner to give the desired products 8/8 0 in high yields (Scheme 2a). Only two anti-diastereomers of the imine adducts were observed; they had absolute configurations of (2R, 3R, RS) and (2S, 3S, RS).17
Chem. Commun.
Table 2 Diastereoselective synthesis of a-aryl a-hydroxy-b-amino amides via cascade couplinga
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Acylsilane (Ar) c
5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5a (Ph) 5b (4-MeC6H4) 5c (3-MeOC6H4) 5d (4-FC6H4) 5e (4-tBuC6H4) 5f (3,4-diMeC6H4) 5g (2-naphthyl) 5h (4-Me2NC6H4) 5i (2-furyl) 5j (2-thienyl)
Imine (Ar 0 ) 3a (4-MeOC6H4) 3b (Ph) 3c (4-MeC6H4) 3d (3-MeC6H4) 3e (2-MeC6H4) 3f (4-FC6H4) 3g (4-ClC6H4) 3h (3-MeOC6H4) 3i (1-naphthyl) 3j (2-furyl) 3k (2-thienyl) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4) 3a (4-MeOC6H4)
Product d
6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n 6o 6p 6q 6r 6s 6t
Yieldb Quant 99% 93% 94% 89% 90% 94% 93% 73% 87% 90% 90% 92% Quant Quant Quant 95% 76%e 84%e 63%e
a All reactions were carried out in THF with 2.0 equiv. of formamide 1, 2.0 equiv. of acylsilane 2 and 2.4 equiv. of LDA at 78 1C under argon, unless otherwise noted. Diastereomeric ratios (drs) were determined by 1 H NMR analysis of crude reaction mixtures. b Isolated yield after silica gel chromatography. c 5a = 2d. d 6a = 4f. e 5.0 equiv. of 1c, 5.0 equiv. of acylsilane and 6.0 equiv. of LDA were used.
Using acylsilane 2d (SiR3 = TBS) or 2a (SiR3 = TMS) led to major diastereomers with different configurations, suggesting that the steric hindrance of the silyl groups affects facial selectivity during the chiral imine addition reaction.18 Absolute configurations of the a-hydroxy-b-amino amide products 8 and 8 0 were deduced from the following reaction results (Scheme 2b). (1) Desilylation of 8a and 8d using tetrabutylammonium fluoride (TBAF) afforded the same alcohol 9, the configuration of which was determined to be (2R, 3R, RS) by X-ray crystallography.19 (2) Desilylation of 8 0 a and 8 0 d gave the same product 9 0 . (3) Using meta-chloroperoxybenzoic acid (m-CPBA) to oxidize the stereogenic sulfur centers in 8a and 8 0 a gave enantiomers 10 and 10 0 , respectively. The two enantiomers showed identical NMR spectra and melting point but opposite optical activity. Having worked out an efficient route toward the stereoselective synthesis of substituted a-hydroxy-b-amino amides, we next focused on removing substituents on the hydroxy and amino groups (Scheme 3). TBAF-induced desilylation of 4f gave free tertiary alcohol 11 in 93% yield. The phosphinyl group on nitrogen was then removed under acidic conditions, providing 12 in 99% yield. Mechanistically, the carbamoyl anion adds to acylsilane and then undergoes Brook rearrangement to generate an Z-enolate20
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bearing bulkier silyl groups gave higher anti-selectivities (Table 1, entries 1–4). In conclusion, we have developed an efficient three-component coupling reaction of formamides, acylsilanes and N-DPP imines. This appears to be the first report of cascade transformations initiated by carbamoyl anions and mediated by acylsilanes. The coupling reaction provides rapid access to substituted a-hydroxy-bamino amides in high yields with excellent diastereoselectivities. Excellent diastereocontrol requires appropriate silyl groups on the acylsilanes and appropriate N-substituted groups on the imines. Financial support of this work by the National Natural Science Foundation of China (U1403301, 21372255, and 21572262), the YCSTTC Project of Xinjiang Uygur Autonomous Region (2013711017), the Recruitment Program of Global Experts (Xinjiang Program) and the Director Foundation of XTIPC (2015RC014) is gratefully acknowledged.
Notes and references
Scheme 2 Coupling reactions with (RS)-tert-butanesulfinylimines, stereochemical model and assignment of absolute configurations of products.
Scheme 3
Removal of silyl and phosphinyl groups from product 4f.
of a-aryl-a-silyloxy amides (Scheme 4). The silyloxy enolate intermediate then reacts via the open transition state TS-1 to minimize nonbonding interactions between its silyoxy groups and the bulky N-DPP group of the imine, ultimately affording anti-a-hydroxy-b-amino amides 4 and 6. This proposed transition state model would explain why we observed that acylsilanes
Scheme 4
Proposed mechanism and stereochemical model.
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1 For reviews of Brook rearrangement and its applications in synthesis, see: (a) A. G. Brook, Acc. Chem. Res., 1974, 7, 77; (b) P. C. Bulman Page, S. S. Klair and S. Rosenthal, Chem. Soc. Rev., 1990, 19, 147; (c) W. H. Moser, Tetrahedron, 2001, 57, 2065; (d) G. R. Boyce, S. N. Greszler, J. S. Johnson, X. Linghu, J. T. Malinowski, D. A. Nicewicz, A. D. Satterfield, D. C. Schmitt and K. M. Steward, J. Org. Chem., 2012, 77, 4503; (e) G. Eppe, D. Didier and I. Marek, Chem. Rev., 2015, 115, 9175. 2 For selected examples of acylsilane-mediated cascade reactions initiated by alkyl, aryl, alkenyl, or alkynyl organometallic reagents, see: (a) R. Unger, T. Cohen and I. Marek, Org. Lett., 2005, 7, 5313; (b) D. A. Nicewicz and J. S. Johnson, J. Am. Chem. Soc., 2005, 127, 6170; (c) D. A. Nicewicz, A. D. Satterfield, D. S. Schmitt and J. S. Johnson, J. Am. Chem. Soc., 2008, 130, 17281; (d) G. R. Boyce and J. S. Johnson, Angew. Chem., Int. Ed., 2010, 49, 8930; (e) D. C. Schmitt and J. S. Johnson, Org. Lett., 2010, 12, 944; ( f ) M. Sasaki, Y. Kondo, M. Kawahata, K. Yamaguchi and K. Takeda, Angew. Chem., Int. Ed., 2011, 50, 6375; ( g) G. R. Boyce, S. Liu and J. S. Johnson, Org. Lett., 2012, 14, 652; (h) M. C. Slade and J. S. Johnson, Beilstein J. Org. Chem., 2013, 9, 166; (i) P. Smirnov, J. Mathew, A. Nijs, E. Katan, M. Karni, C. Bolm, Y. Apeloig and I. Marek, Angew. Chem., Int. Ed., 2013, 52, 13717; ( j) P. Smirnov, E. Katan, J. Mathew, A. Kostenko, M. Karni, A. Nijs, C. Bolm, Y. Apeloig and I. Marek, J. Org. Chem., 2014, 79, 12122; (k) J.-L. Jiang, M. Yao and C.-D. Lu, Org. Lett., 2014, 16, 318; (l ) M. Sasaki, Y. Kondo, T. Moto-ishi, M. Kawahata, K. Yamaguchi and K. Takeda, Org. Lett., 2015, 17, 1280; (m) C. Tan, W. Chen, X. Mu, Q. Chen, J. Gong, T. Luo and Z. Yang, Org. Lett., 2015, 17, 2338. 3 (a) K. Takeda, J. Nakatani, H. Nakamura, K. Sako, E. Yoshii and K. Yamaguchi, Synlett, 1993, 841; (b) M. Sasaki, K. Oyamada and K. Takeda, J. Org. Chem., 2010, 75, 3941, and references cited therein. 4 B. Liu and C.-D. Lu, J. Org. Chem., 2011, 76, 4205. 5 (a) S. N. Greszler, J. T. Malinowski and J. S. Johnson, J. Am. Chem. Soc., 2010, 132, 17393; (b) S. N. Greszler, J. T. Malinowski and J. S. Johnson, Org. Lett., 2011, 13, 3206; (c) D. C. Schmitt, L. Lam and J. S. Johnson, Org. Lett., 2011, 13, 5136; (d) D. C. Schmitt, E. J. Malow and J. S. Johnson, J. Org. Chem., 2012, 77, 3246. 6 (a) R. B. Lettan, T. E. Reynolds, C. V. Galliford and K. A. Scheidt, J. Am. Chem. Soc., 2006, 128, 15566; (b) R. B. Lettan, C. C. Woodward and K. A. Scheidt, Angew. Chem., Int. Ed., 2008, 47, 2294; (c) R. B. Lettan, C. V. Galliford, C. C. Woodward and K. A. Scheidt, J. Am. Chem. Soc., 2009, 131, 8805; (d) C. V. Galliford and K. A. Scheidt, Chem. Commun., 2008, 1926. 7 M. Yao and C.-D. Lu, Org. Lett., 2011, 13, 2782. 8 Nucleophiles such as metal cyanides, metallophosphites, and N-heterocyclic carbenes have been reported to initiate Brook rearrangement and subsequent nucleophilic transformations. For selected examples, see: (a) X. Linghu, C. C. Bausch and J. S. Johnson, J. Am. Chem. Soc., 2005, 127, 1833; (b) M. R. Garrett, J. C. Tarr and J. S. Johnson, J. Am. Chem. Soc., 2007, 129, 12944; (c) A. E. Mattson,
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A. R. Bharadwaj, A. M. Zuhl and K. A. Scheidt, J. Org. Chem., 2006, 71, 5715. These nucleophiles are usually used in catalytic amounts and are not present in the reaction intermediates. For reviews of b-amino acids, see: (a) P. Spiteller and F. von Nussbaum, b-Amino Acids in Natural Products, in Enantioselective Synthesis of b-Amino acids, ed. E. Juaristi and V. A. Soloshonok, Wiley & Sons, Hoboken, New Jersey, 2nd edn, 2005, p. 19; (b) G. Cardillo and C. Tomasini, Chem. Soc. Rev., 1996, 117. Selected examples of the synthesis of a-tertiary a-hydroxy-b-amino acid derivatives are presented. For direct addition of a-substituted a-hydroxy acid derivatives to imines, see: (a) A. Clerici, L. Clerici and O. Porta, Tetrahedron Lett., 1995, 36, 5955; (b) A. Clerici, N. Pastori and O. Porta, J. Org. Chem., 2005, 70, 4174; (c) A. Guerrini, G. Varchi and A. Battaglia, J. Org. Chem., 2006, 71, 6785; (d) A. Guerrini, G. Varchi, R. Daniele, C. Samori and A. Battaglia, Tetrahedron, 2007, 63, 7949. For Rh(II)-catalyzed three-component coupling of a-diazo esters, alcohols and imines, see: (e) C.-D. Lu, H. Liu, Z.-Y. Chen, W.-H. Hu and A.-Q. Mi, Org. Lett., 2005, 7, 83; ( f ) W. Hu, X. Xu, J. Zhou, W.-J. Liu, H. Huang, L. Yang and L.-Z. Gong, J. Am. Chem. Soc., 2008, 130, 7782; (g) Y. Qian, C. Jing, J. Ji, M. Tang, J. Zhou, C. Zhai and W. Hu, ChemCatChem, 2011, 3, 653; (h) X. Guo and W. Hu, Acc. Chem. Res., 2013, 46, 2427. For a recent review of the synthesis of the a-hydroxy-b-amino acid side chain of taxoids, see: J. C. Borah, J. Boruva and N. C. Barua, Curr. Org. Synth., 2007, 4, 175. We focused on the carbamoyl anion for building the predicted cascade reaction because it is among the stablest types of carbonyl anion. For recent examples of carbamoyl anion addition to azomethine electrophiles, see: (a) J. T. Reeves, Z. Tan, M. A. Herbage, Z. S. Han, M. A. Marsini, Z. Li, G. Li, Y. Xu, K. R. Fandrick, N. C. Gonnella, S. C. Campbell, S. Ma, N. Grinberg, H. Lee, B. Z. Lu and C. H. Senanayake, J. Am. Chem. Soc., 2013, 135, 5565; (b) J. T. Reeves, C. Lorenc, K. Camara, Z. Li, H. Lee, C. A. Busacca and C. H. Senanayake, J. Org. Chem., 2014, 79, 5895; (c) C. W. Seifert, S. Pindi and G. Li, J. Org. Chem., 2015, 80, 447. Desilylation of the major diastereomers of 4a–d gave identical products.
Chem. Commun.
ChemComm 14 The reaction using N-Ts imine derived from 4-methoxybenzaldehyde gave a three-component coupling product (13) in 99% yield with 1.5 : 1 dr. 15 Single crystals of compound 6o were recrystallized from benzene. Crystal data: C42H57N2O4PSi, M = 721.96, triclinic, a = 11.473(4) Å, b = 13.299(5) Å, c = 13.766(5) Å, V = 2086.5(12) Å3, T = 296 K, space group P1% , Z = 2, 12 527 reflections measured, 8916 unique (Rint = 0.0449), which were used in all calculations. The final R1 was 0.0750 (I Z 2s(I)) and wR2 was 0.2528 (all data), CCDC 1427984. See the ESI† for the single-crystal structure of compound 6o. 16 For reviews of the synthetic applications of tert-butanesulfinamide, see: (a) F. Ferreira, C. Botuha, F. Chemla and A. Perez-Luna, Chem. Soc. Rev., 2009, 38, 1162; (b) M. T. Robak, M. A. Herbage and J. A. Ellman, Chem. Rev., 2010, 110, 3600. 17 Adding 3.0 or 10.0 equiv. of boron trifluoride etherate (BF3Et2O) to the reactions did not improve the diastereoselectivity. 18 For facial selectivity of the chiral tBS-imine addition reaction via the chelated chair-like 6/4-membered bicyclic transition state, see: (a) F. A. Davis, R. T. Reddy and R. E. Reddy, J. Org. Chem., 1992, 57, 6387; (b) T. P. Tang and J. A. Ellman, J. Org. Chem., 1999, 64, 12; (c) T. P. Tang and J. A. Ellman, J. Org. Chem., 2002, 67, 7819. For facial selectivity via a non-chelated open transition state, see: (d) T. Fujisawa, Y. Kooriyama and M. Shimizu, Tetrahedron Lett., 1996, 37, 3881. 19 Single crystals of compound 9 were obtained from acetonitrile by slow solvent evaporation. Crystal data: C24H31BrN2O3S, M = 507.48, orthorhombic, a = 9.891(13) Å, b = 16.14(2) Å, c = 16.21(2) Å, V = 2588(6) Å3, T = 296 K, space group P212121, Z = 4, 15 227 reflections measured, 5656 unique (Rint = 0.0964), which were used in all calculations. The final R1 was 0.0672 (I Z 2s(I)) and wR2 was 0.2260 (all data), CCDC 1427986. See the ESI† for the single-crystal structure of compound 9. 20 The formation of (Z)-lithium silyloxy enolates in lithium enolateinitiated Brook rearrangements of silyl glyoxylates was documented by Johnson and co-workers in ref. 1c and 2e, in which Claisen rearrangement of the formed silyloxy enolate intermediates was used as a stereochemical probe for enolate geometry. In our case, the formation of E-enolate intermediate cannot be ruled out completely at this time.
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