Aza-Baylis–Hillman Reactions Catalyzed by Chiral Thiourea Derivatives
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13C NMR (100 MHz, CDCl3): d¼172.62, 150.84, 144.43,
136.06, 131.96, 129.97, 129.62, 129.41, 124.59; LR-MS (ApCI):
m/z¼291.0 (5%) [MþH]þ, 261.0 (100%) [MꢀNOþ]þ.
(d, J¼10.3 Hz 1H), 8.07 (d, J¼8.3 Hz, 2H), 7.79 (d, J¼
8.3 Hz, 2H), 7.18 (d, J¼4.9 Hz, 2H), 6.95–7.10 (m, 3H), 4.93
(dd, J¼6.0, 10.5 Hz, 1H), 4.16 (d, J¼13.2 Hz, 1H), 3.72–3.91
(m, 7H), 3.70 (s, 3H), 3.42–3.63 (m, 6H), 2.90 (m, 1H); 13C
NMR (100 MHz, DMSO-d6): d¼170.97, 149.69, 146.80,
136.04, 128.93, 128.80, 128.62, 127.95, 124.56, 61.69, 59.24,
53.62, 51.10, 46.24, 43.45; LR-MS (ESI): m/z¼489.2 (100%)
General Procedure for the Asymmetric Aza-Baylis–
Hillman Reaction
þ
[Mꢀ2 H Cl] .
2-[(4-Nitrobenzenesulfonylamino)-(S)-phenylmethyl]-
acrylic acid methyl ester (7a): An oven-dried vial was charged
Base-Mediated Elimination of 10a
with
N-benzylidene-4-nitro-benzenesulfonamide
(6a,
1 equiv.), catalyst 1c (10 mol %), DABCO (1 equiv.), and acti-
vated 3 MS. The vial was evacuated and purged with N2. Pre-
cooled, freshly distilled, anhydrous xylenes (0.15 M) and meth-
yl acrylate (8 equivs.) were added via syringe at 48C, and the
mixture stirred for 36 h. The mixture was diluted with anhy-
drous MeOHand then quenched immediately with 4 N HCl
in dioxane. The crude adduct was purified by flash chromatog-
raphy (100% CH2Cl2) to afford the pure aza-Baylis–Hillman
adduct as a white solid. The ee of this material was determined
to be 95% [ChiralPak AS, 1.0 mL/min, 280 nm, 40% IPA/hex-
anes, tr(major)¼11.566 min, tr(minor)¼17.618 min]; [a]2D3:
þ27.78 (c 2, EtOH); FT-IR (CH2Cl2 thin film): n¼3293 (br),
3108 (w), 3068 (w), 1720 (s), 1632 (w), 1607 (w), 1531 (s),
1440 (m), 1350 (s), 1312 (m), 1166 (s), 1091 (m), 1062 (m),
2-[(4-Nitrobenzenesulfonylamino)-(S)-phenylmethyl]-
acrylic acid methyl ester (7a, from10a): A flame-dried, 5-mL
round-bottom flask was charged with dihydrochloride salt
(10a from above, 150 mg, 0.267 mmol) which was dissolved in
anhydrous DMSO (2 mL) or MeOH(2 mL) at room tempera-
ture. Freshly distilled DBU (84 mL, 0.560 mmol) was added via
syringe, and the reaction mixture stirred for 16 h. The mixture
was then diluted with 5 mL CH2Cl2, 1 N HCl (5 mL) was added
with vigorous stirring, the layers were allowed to separate, and
the organic layer removed. The aqueous layer was extracted
with 3ꢁ10 mL CH2Cl2, dried over Na2SO4, and concentrated
under vacuum to afford the crude aza-Baylis–Hillman adduct
(7a), which matched the 1HNMR and 13C NMR spectra as pre-
viously reported (vide supra). As discussed, ees of this product
were substantially depressed, and generally obtained in a range
of 30–40%.
1
855 (m), 738 cmꢀ1 (s); HNMR (500 MHz, CDCl 3): d¼8.22
(d, J¼8.8 Hz, 2H), 7.92 (d, J¼8.8, 3 Hz, 2H), 7.14–7.27 (m,
5H), 6.23 (s, 1H), 6.15 (d, J¼9.3 Hz, 1H), 5.82 (s, 1H), 5.40
(d, J¼9.3 Hz, 1H), 3.64 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼165.96, 150.08, 146.74, 138.49, 138.01, 128.94, 128.50,
128.41, 128.32, 126.64, 124.30, 59.86, 52.50; LR-MS (ApCI):
m/z¼377.0 (2%) [MþH]þ, 347.0 (30%) [MꢀNOþ]þ, 330.0
(32%) [MꢀNO2]þ, 175.0 (100%) [Mꢀsulfonamide]þ.
Acknowledgements
This work was supported by the NIGMS through GM-43214
and P50 GM069721 and by predoctoral fellowship support to
I. T. R. from the NSF. The authors also gratefully acknowledge
the Harvard University Mass Spectrometry facility for assis-
tance in the characterization of 10a.
Isolation of Aza-Baylis–Hillman Intermediate as the
Dihydrochloride Salt (10a)
A flame-dried, 10-mL round-bottom flask was charged with a
stir bar, imine 6a (75 mg, 0.259 mmol), thiourea catalyst 1c
(15.6 mg, 0.026 mmol), and DABCO (29 mg, 0.259 mmol).
The flask was cooled to 48C, and charged with pre-cooled,
freshly distilled xylenes (1.75 mL) and methyl acrylate
(187 mL, 2.07 mmol). The mixture was allowed to stir for 12 h
at 48C, over which time a bright yellow precipitate formed.
Distilled H2O (1.75 mL) was added, and the biphasic mixture
was stirred vigorously for an additional 3–6 h at 48C. HCl
(200 mL, 4 N in dioxane) was added. Additional 5 mL H2O
were added, and the reaction mixture was stirred vigorously
for 5 min. The layers were allowed to separate, and the organic
layer removed. The aqueous layer was extracted with CH2Cl2
(3ꢁ20 mL) and the combined organic layers were back-ex-
tracted with 3ꢁ5 mL H2O. The combined aqueous layers
were concentrated directly under vacuum at 608C. The result-
ing clear oil was further subjected to high vacuum for 24 h to
remove residual H2O, affording the dihydrochloride salt of
the aza-Baylis–Hillman intermediate (10a) as a glassy solid;
yield: 61.2 mg (42%); FTIR (CH2Cl2 thin film): n¼1734 (s),
1630 (w), 1530 (s), 1459 (w), 1438 (w), 1351 (s), 1313 (w),
1166 (s), 1089 (w), 853 (w), 739 cmꢀ1 (m); 1HNMR
(500 MHz, DMSO-d6, 10–16:1 mixture of diastereomers,
with signals corresponding to major form indicated): d¼9.72
References and Notes
[1] For reviews, see: a) D. Basavaiah, A. J. Rao, T. Satyanar-
ayana, Chem. Rev. 2003, 103, 811–892; b) E. Ciganek, in:
Organic Reactions, Vol. 51, (Ed.: L. A. Paquette), Wiley,
New York, 1997, pp. 201–350; c) D. Basavaiah, P. D.
Rao, R. S. Hyma, Tetrahedron 1996, 52, 8001–8062;
b) S. E. Drewes, G. H. P. Roos, Tetrahedron 1988, 44,
4653–4670.
[2] a) K. Matsui, S. Takizawa, H. Sasai, J. Am. Chem. Soc.
2005, 127, 3680–3681; b) M. Shi, L.-H. Chen, C.-Q. Li,
J. Am. Chem. Soc. 2005, 127, 3790–3800; c) M. Shi, L.-
H. Chen, C.-Q. Li, Tetrahedron: Asymmetry 2005, 16,
1385–1391; d) M. Shi, G.-L. Zhao, Adv. Synth. Catal.
2004, 346, 1205–1219; e) M. Shi, Y.-M. Xu, Eur. J. Org.
Chem. 2002, 696–701; f) M. Shi, L.-H. Chen, Chem.
Commun. 2003, 1310; g) M. Shi, Y.-M. Xu, Angew.
Chem. Int. Ed. 2002, 41, 4507–4510; h) D. Balan, H.
Adolfsson, Tetrahedron Lett. 2003, 44, 2521; i) S. Kawa-
hara, A. Nakano, T. Esumi, Y. Iwabuchi, S. Hataketya-
ma, Org. Lett. 2003, 5, 3103.
Adv. Synth. Catal. 2005, 347, 1701 – 1708
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