Full Paper
Conclusions
We have realized an effective organocatalytic Mannich-type re-
action of N-Boc imines and sulfonyl acetonitriles, which allows
the production of a-unsubstituted b-amino nitriles in a highly
enantioselective fashion. The method demonstrates the effica-
cy of the ureidopeptide-based BB catalysts to perform the or-
ganocatalytic reaction and (2-naphthylsulfonyl)acetonitrile to
act as a synthetic equivalent of the acetonitrile anion. The pro-
cess offers a simple and efficient route for the catalytic enan-
tioselective synthesis of b-amino nitriles and also provides ex-
perimental evidence for the potential scope of this family of
BB catalysts.
[7] For recent reviews on (thio)urea-tertiary amines, see: a) S. J. Connon,
metric Organocatalysis 2, Brønsted Base and Acid Catalysis, and Addition-
al Topics, Science of Synthesis (Ed.: K. Maruoka), Thieme, Stuttgart, 2012,
pp. 119–168; d) T. Inokuma, Y. Takemoto, in Asymmetric Organocatalysis
2, Brønsted Base and Acid Catalysis, and Additional Topics, Science of Syn-
thesis (Ed.: K. Maruoka), Thieme, Stuttgart, 2012, pp. 437–497.
Experimental Section
Typical procedure for the Mannich reaction of N-Boc imine
9a and sulfonyl acetonitrile 10b (11a)
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cept, see: a) T. Marcelli, R. N. S. van der Hases, J. H. Van der Maarseveen,
7756; d) C.-J. Wang, X.-A. Dong, Z. H. Zhong, Z. Y. Xue, H.-L. Teng, J. Am.
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Sulfonyl acetonitrile 10b (0.150 g, 0.65 mmol, 1.3 equiv) was added
to a mixture of 9a (0.5 0mmol, 1 equiv) and catalyst D2 (0.034 g,
0.05 mmol, 0.10 equiv) in dry CH2Cl2 (3 mL) at À408C under a nitro-
gen atmosphere. The reaction mixture was stirred for 15 h, then
quenched with HCl (5 mL, 0.1n) and extracted with CH2Cl2 (3ꢂ
3 mL). The combined organic layers were washed with HCl (5 mL),
dried over MgSO4 and concentrated under reduced pressure. The
residue was dissolved in CH2Cl2/MeOH (1:1, 3 mL) and Mg (0.24 g,
10 mmol, 20 equiv), 1,2-dibromoethane (0.01 mL) and TMSCl
(0.01 mL) were added at 08C. The reaction mixture was stirred for
3–5 h at rt. The mixture was quenched with a saturated solution of
NH4Cl (5 mL) and filtered over Celite. The filtrate was diluted with
EtOAc (20 mL) and washed with brine (3ꢂ10 mL). The organic
layers were combined, dried over MgSO4 and concentrated under
reduced pressure to give the crude product, which was purified by
flash column chromatography on silica gel (90:10 hexane/Et2O) to
produce pure 11 a (0.095 g, 77%) as a white solid. M.p. 109–1138C;
1
[a]2D5 =À5.6 (c=0.6, EtOH); H NMR (300 MHz, CDCl3): d=7.41 (m,
5H), 5.17–4.92 (m, 2H), 3.11–2.85 (m, 2H), 1.50 ppm (s, 9H);
13C NMR (75 MHz, CDCl3): d=154.8, 138.5, 129.2, 128.7, 126.2,
116.9, 80.6, 51.3, 28.2, 25.2 ppm; chiral HPLC (Chiralpak IA; hexane/
iPrOH 95:5; 0.5 mLminÀ1, 210 nm): retention time (tR) minor=
27.8 min, tR (major)=31.8 min; 94% ee; HRMS (TOF, MS, CI): m/z
calcd for C10H11N2O: 174.0793 [M HÀC4H9O]+; found:174.0793.
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Acknowledgements
[17] For recent direct methods to produce a,a-disubstituted mercapto car-
boxylic acid derivatives, see: enamine-mediated Michael reaction of
Mannich reaction of a-sulfonyl lactones: b) S. Takechi, N. Kumagai, M.
c) H. Jiang, D. C. Cruz, Y. Li, V. H. Lauridsen, K. A. Jørgensen, J. Am. Chem.
doles: d) F. Zhou, X.-P. Zang, C. Wang, X.-L. Zhau, J. Zhou, Chem.
that dealt with the enantioselective allylation of thiazolones was pub-
[18] For a review of tertiary thiols, see: J. Clayden, P. MacLellan, Beilstein J.
Support has been provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22), Basque Government (GV
Grant No IT-291-07 and SAIOTEK 2012) and Ministerio de Cien-
cia e Innovaciꢀn (MICINN, Grant CTQ2010-21263-C02), Spain.
S.D. thanks MEC for a grant. We also thank S. Vera and A.
Puente for their help with some transformations.
Keywords: Brønsted bases
peptides · synthetic methods
· nitriles · organocatalysis ·
b) Comprehensive Enantioselective Organocatalysis: Catalysis, Reactions,
and Applications, Vols. 1–3 (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2013.
Chem. Eur. J. 2014, 20, 6526 – 6531
6530
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim