Catalytic asymmetric three-component acyl-strecker reaction

Article abstract of DOI:10.1021/ol0702674

(Chemical Equation Presented) The first organocatalytic asymmetric three-component Strecker reaction, the urea-catalyzed acylcyanation of in situ generated imines, has been developed. Different α-amido nitriles are formed in excellent yields and enantiosl

Full text of DOI:10.1021/ol0702674

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ORGANIC
LETTERS
2007
Vol. 9, No. 6
1149-1151
Catalytic Asymmetric Three-Component
Acyl-Strecker Reaction
Subhas Chandra Pan and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 Mu¨lheim an der Ruhr, Germany
list@mpi-muelheim.mpg.de
Received February 2, 2007
ABSTRACT
The first organocatalytic asymmetric three-component Strecker reaction, the urea-catalyzed acylcyanation of in situ generated imines, has
been developed. Different -amido nitriles are formed in excellent yields and enantioslectivities from aldehydes, amines, and acyl cyanides
r
in the presence of Jacobsen’s thiourea catalyst 5. Despite its obvious use for the synthesis of
r-amino acids and their derivatives, our
reaction may find use in diversity oriented synthesis and medicinal chemistry.
Catalytic asymmetric Strecker reactions are highly useful for
the preparation of chiral R-amino acid derivatives.1 Although
there are already a number of versatile indirect variants of
this transformation,2,3 only a single direct catalytic asym-
metric three-component Strecker reaction of aldehydes,
aromatic amines, and HCN has been described by Kobayashi
et al.4 Replacing the highly toxic and volatile HCN in such
catalytic asymmetric Strecker reactions with a more conve-
nient cyanide source and expanding the scope of the amine
component would clearly be desirable. We have recently
developed a novel variant of the Strecker reaction, the
Brønsted acid catalyzed acylcyanation of imines (acyl-
Strecker reaction) with commercially available acetyl cyanide
as an HCN equivalent (Scheme 1, eq 1).5,6 Previously, acetyl
(1) For reviews, see: (a) Gro¨ger, H. Chem. ReV. 2003, 103, 2795-2827.
(b) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875-877. (c) Spino, C. Angew.
Chem., Int. Ed. 2004, 43, 1764-1766. (d) Enders, D.; Shilvock, J. P. Chem.
Soc. ReV. 2000, 29, 359-373.
Scheme 1. Discussed Strecker Variants
(2) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120,
4901-4902. (b) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998,
120, 5315-5316. (c) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2000, 39, 1279-1281. (d) Vachal, P.; Jacobsen, E. N. Org.
Lett. 2000, 2, 867-870. (e) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 10012-10014. (f) Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E.
N. Synlett 2003, 1919-1922.
(3) (a) Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew. Chem., Int.
Ed. 1998, 37, 3186-3188. (b) Corey, E. J.; Grogan, M. J. Org. Lett. 1999,
1, 157-160. (c) Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun,
W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
1999, 121, 4284-4285. (d) Takamura, M.; Hamashima, Y.; Usuda, H.;
Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 1650-1652.
(e) Nakamura, S.; Sato, N.; Sugimoto, M.; Toru, T. Tetrahedron: Asymmetry
2004, 15, 1513-1516. (f) Banphavichit, V.; Mansawat, W.; Bhanthumnavin,
W.; Vilaivan, T. Tetrahedron 2004, 60, 10559-10568. (g) Ooi, T.; Uematsu,
Y.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2548-2549. (h) Berkessel,
A.; Mukherjee, S.; Lex, J. Synlett 2006, 41-44. (i) Rueping, M.; Sugiono,
E.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 2617-2619. (j) Herrera, R.
P.; Sgarzani, V.; Bernardi, L.; Fini, F.; Pettersen, D.; Ricci, A. J. Org. Chem.
2006, 71, 9869-9872.
cyanide and other cyanoformates have only been used in
catalytic enantioselective acylcyantions of carbonyl com-
10.1021/ol0702674 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/24/2007

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pounds.7 After investigating several chiral phosphoric acid
and thiourea catalysts,8,9 we identified Jacobsen thiourea 5
to be an effective and highly enantioselective catalyst of this
reaction.10 Our two-step protocol (imine formation, acetyl-
cyanation) may be considered a simplification of the Jacob-
sen-Strecker reaction where three operationssimine for-
mation, Strecker reaction, and amide formationsare required
to isolate a stable R-amido nitrile product (eq 2).2 We
reasoned that a further refinement of the reaction might be
possible by developing an attractive one-pot three-component
catalytic asymmetric acyl-Strecker reaction (eq 3).
Such a process would constitute the first organocatalytic
asymmetric three-component Strecker-type reaction. More-
over, as a three-component reaction, this methodology may
benefit diversity oriented synthesis. Here we report the
successful realization of this concept.
lectivity was observed after lowering the temperature to -40
°C (entry 6). Finally, we realized that the best result (98%
yield, 97:3 er) was obtained if the aldehyde was first mixed
with the amine and MS 5 Å for 2 h at rt before the catalyst
and acetyl cyanide were added subsequently at -40 °C
(entries 7 and 8). Decreasing the catalyst loading to 1 mol
% resulted in considerably lower yield and enantioselectivity.
With optimal reaction conditions established we initiated
a study to explore the scope of this new catalytic asymmetric
three-component reaction.11 First, the reaction of a variety
of different aldehydes 2 with benzyl amine (3a) as the amine
component and acetyl cyanide (1a) was examined (Table
2).12 Noteworthy, the reactions took place efficiently in good
Table 2. Catalytic Asymmetric Acylcyanation of Different
Initially we found that stirring benzaldehyde (2a), benzyl
amine (3a), MgSO4, catalyst 5, and acetyl cyanide (1a) at 0
°C for 24 h in toluene resulted in poor yield of the desired
product 4a and side product formation. Not unexpectedly, a
considerable amount of N-benzyl acetamide was formed
resulting from the direct reaction of benzyl amine with acetyl
cyanide. We hypothesized that to suppress this side reaction,
the order of reagent mixing may be crucial. Indeed, when
acetyl cyanide was added last, significant conversion to the
desired product could be realized (Table 1, entry 1).
Aldehydes with Acetyl Cyanide and Benzyl Amine
Table 1. Optimizing the Reaction Conditions
a Aldehyde 2 (0.5 mmol), benzyl amine (3a, 0.5 mmol), and molecular
sieves 5 Å (150 mg) were stirred at rt for 2 h in CH2Cl2 (2 mL). Catalyst
5 (0.025 mmol) and after cooling to -40 °C acetyl cyanide 1a (0.75 mmol)
were added and the mixture was stirred for 36 h before the usual workup.
b Determined by chiral HPLC. c With 10 mol % of catalyst 5.
to excellent yields with a high level of enantioselectivity for
all studied aldehydes. Particularly high enantioselectivities
were observed with aromatic aldehydes (entries 1-4) and
an R,â-unsaturated aldehyde (entry 5). But even an aliphatic
branched and an R-trisubstituted aldehyde gave excellent
enantioselectivities (entries 6 and 7). In the case of the most
challenging R-unbranched aldehydes (entries 8 and 9),
slightly lower er values were obtained. However, at least in
the case of 3,3-dimethylbutanal, the er could be significantly
increased (96:4) when we used 10 mol % of catalyst 5.
entrya
solvent
additive
temp (°C)
yield (%)
er
1
2
3
4
5
6
7b
8c
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MgSO4
MS 5 Å
none
MgSO4
MS 5 Å
MS 5 Å
MS 5 Å
MS 5 Å
0
0
0
0
0
84
10
63
68
66
83
85
98
57:43
80:20
74:26
78:22
87:13
94:6
-40
-40
-40
97:3
97:3
a Aldehyde, amine, additive, and catalyst were stirred for 2 h at 0 °C
before acetyl cyanide was added. b Aldehyde, amine, and additive were
stirred for 2 h at 0 °C before the catalyst and acetyl cyanide (at -40 °C)
were added. c Aldehyde, amine, and additive were stirred for 2 h at rt before
the catalyst and acetyl cyanide (at -40 °C) were added.
(4) (a) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2000, 122, 762-766. (b) Kobayashi, S.; Ishitani, H. Chirality
2000, 12, 540-543.
(5) Pan, S. C.; Zhou, J.; List, B. Synlett 2006, 3275-3276.
(6) For alternative non-enantioselective variants, see: (a) Dornow, A.;
Lu¨pfert, S. Chem. Ber. 1956, 89, 2718-2722. (b) Dornow, A.; Lu¨pfert, S.
Chem. Ber. 1957, 90, 1780-1786. (c) Dornow, A.; Lu¨pfert, S. U.S. patent
2849477, 1958. (d) Gardent, M. J.; Dele´pine, M. M. C. R. Acad. Sci. 1958,
247, 2153-2156. (e) Rai, M.; Krishan, K.; Singh, A. Indian J. Chem., Sect.
B 1978, 16, 834-835. (f) Sakamoto, M.; Akiyama, Y.; Furumi, N.; Ishii,
K.; Tomimatsu, Y.; Date, T. Chem. Pharm. Bull. 1983, 31, 2623-2631.
However, the product was formed with poor enantioselec-
tivity. Switching the drying reagent to 5 Å molecular sieves
and the solvent to dichloromethane significantly improved
the enantioselectivity (entries 2-5). Even higher enantiose-
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Org. Lett., Vol. 9, No. 6, 2007

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A variety of amines were probed next with benzaldehyde
(2a) as the aldehyde component (Table 3). It turned out that
component do not seem to influence the yield and enantio-
selectivity of the reaction. Furfuryl amine having an het-
eroaromatic moiety can also be employed (entry 4). Allyl
amine has also been used and still gave the desired product
in good results (entry 5). Moreover, the reaction also affords
the product with a simple alkyl amine although in slightly
lower enantioselectivity (entry 6). Apparently, the third
component of our reaction can be varied equally well. In
preliminary experiments we found that heptanoyl cyanide
reacts with benzaldehyde and benzyl amine to provide
product 4p in 84% yield and 94:6 er (entry 7).13 That the
reaction products (i.e., 4g) can readily be converted into
R-amino acids and their salts without racemization and in
high yields via acid-mediated hydrolysis and hydrogenolysis
has previously been established in our laboratories.10
In summary, we have developed the first organocatalytic
asymmetric variant of the classical three-component Strecker
reaction. The operational simplicity, practicability, and mild
reaction condition render it an attractive approach for the
generation of different R-amido nitriles. In comparison to
the Jacobsen-Strecker reaction, which uses the same cata-
lysts, the newly developed variant avoids highly toxic HCN,
does not require preformation of the imine intermediate, and
avoids derivatization with TFAA. Despite its obvious use
for the synthesis of R-amino acids and their derivatives, our
reaction may find use in diversity oriented synthesis and
medicinal chemistry.
Table 3. Catalytic Asymmetric Acylcyanation of Benzaldeyde
with Different Amines and Acyl Cyanides
a Reaction conditions as described in Table 2 were used. b Determined
by chiral HPLC.
three different benzyl amines can be used to give the products
in high yields and excellent enantioselectivities (entries 1-3).
The electronic properties of the aromatic system of the amine
(7) (a) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2002, 41, 3636-3638. (b) Tian, J.; Yamagiwa, N.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2003, 5, 3021-3024. (c) Yamagiwa,
N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
3413-3422. (d) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6295-
6196. (e) Casas, J.; Baeza, A.; Sansano, J. M.; Na´jera, C.; Saa´, J. M.
Tetrahedron: Asymmetry 2003, 14, 197-200. (f) Baeza, A.; Na´jera, C.;
Sansano, J. M.; Saa´, J. M. Tetrahedron: Asymmetry 2005, 16, 2385-2389.
(g) Belokon, Y. N.; Blacker, A. J.; Clutterbuck, L. A.; North, M. Org. Lett.
2003, 5, 4505-4507. (h) Belokon, Y. N.; Ishibashi, E.; Nombra, H.; North,
M. Chem. Commun. 2006, 16, 1775-1777. (i) Gou, S.; Wang, J.; Liu, X.;
Wang, W.; Chen, F.-X.; Feng, X. AdV. Synth. Catal. 2007, 349, 343-349.
For the first use of acetyl cyanide in an acylcyanation of aldehydes, see:
(j) Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C. J. Am. Chem.
Soc. 2005, 127, 11592-11593. (k) Lundgren, S.; Wingstrand, E.; Moberg,
C. AdV. Synth. Catal. 2007, 349, 364-372.
Acknowledgment. This work was funded in part by the
DFG (Priority program “Organocatalysis” SPP1179). Gener-
ous support by the Max-Planck-Society and by Novartis
(Young Investigator Award to B.L.) is gratefully acknowl-
edged. We also thank BASF, Degussa, Merck, Saltigo, and
Wacker for general support and for donating chemicals.
Supporting Information Available: Experimental and
analytical data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0702674
(8) For reviews, see: (a) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth.
Catal. 2006, 348, 999-1010. (b) Connon, S. J. Angew. Chem., Int. Ed.
2006, 45, 3909-3912.
(11) For a review on catalytic asymmetric multicomponent reactions,
see: Seayad, J.; List, B. In Multicomponent Reactions; Zhu, J., Bienayme´,
H., Eds.; WILEY-VCH: Weinheim, Germany, 2005; pp 277-298.
(12) If HCN was used rather than acetyl cyanide, under the same reaction
conditions, following standard in situ derivatization with trifluoroacetic acid
anhydride, the obtained product was essentially racemic.
(9) For reviews, see: (a) Schreiner, P. R. Chem. Soc. ReV. 2003, 32,
289-296. (b) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299-4306. (c)
Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520-
1543. (d) Connon, S. J. Chem. Eur. J. 2006, 12, 5418-5427. (e) Pihko, P.
M. Angew. Chem., Int. Ed. 2004, 43, 2062-2064.
(10) Pan, S. C.; Zhou, J.; List, B. Angew. Chem., Int. Ed. 2007, 46, 612-
614.
(13) No conversion was obtained when cyanoformate esters or benzoyl-
cyanide were used as the cyanide source.
Org. Lett., Vol. 9, No. 6, 2007
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