The proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc imines

Article abstract of DOI:10.1002/anie.200806049

(Chemical Equation Presented) Double-cross: Proline catalyzes the double Mannich reaction of acetaldehyde with N-Boc imines in excellent yields (up to 99%; Boc = tert-butoxycarbonyl) and close to perfect diastereo- and enantioselectivities. Depending on t

Full text of DOI:10.1002/anie.200806049

Communications
DOI: 10.1002/anie.200806049
Organocatalysis
The Proline-Catalyzed Double Mannich Reaction of Acetaldehyde
with N-Boc Imines**
Carley Chandler, Patrizia Galzerano, Anna Michrowska, and Benjamin List*
Within the last decade, enamine catalysis has become a
powerful strategy, delivering several enantioselective trans-
formations of ketones and aldehydes.[1] Very recently, the
scope of this concept was further advanced with the utilization
of acetaldehyde, the simplest of all enolizable carbonyl
compounds, as a nucleophile. We have developed a proline-
catalyzed Mannich reaction of acetaldehyde with N-Boc-
imines, which gives a-unbranched b-aminoaldehydes with
near perfect enantioselectivities.[2–4] Independently, Hayashi
and co-workers reported the application of acetaldehyde in
cross-aldol reactions.[5] Acetaldehyde was also found to be a
suitable nucleophile in related Michael reactions with nitro-
alkenes.[6]
with an additional imine equivalent (Scheme 2).[7] Having
undergone two cycles of enamine activation during the course
of the reaction, this pseudo-C2-symmetric compound contains
a chirotopic nonstereogenic center embedded between two
new stereogenic centers.
Interestingly, the products derived from all these trans-
formations are a-unbranched aldehydes themselves and
should be suitable substrates for a separate enamine catalytic
activation. Moreover, enamine catalytic in situ sequences of
acetaldehyde with two electrophiles can be envisioned
(Scheme 1). Herein, we report the first successful realization
of this concept with a proline-catalyzed double Mannich
reaction of acetaldehyde with either a single or two different
N-Boc-imines.
Scheme 2. Double Mannich reaction of acetaldehyde with imine 2a.
Being the result of two concomitant highly enantioselec-
tive catalyst-controlled transformations,[8] we were not sur-
prised to find the enantiomeric ratio of bis-addition product
4a to be extremely high (@ 99:1 e.r.), challenging the
detection limits of our HPLC instruments. Realizing that
such aldehydes may be interesting precursors for various
chiral molecules including b,b’-diamino acids, we became
interested in optimizing the reaction towards the formation of
the double addition product. Indeed, if one equivalent of
acetaldehyde was treated with three equivalents of imine 2a,
compound 4a was obtained in essentially quantitative yield.
Careful HPLC analysis, including the determination of the
detection limit of the enantiomers, revealed an enantiomeric
ratio (e.r.) of 9905:1, corresponding to an ee value of 99.98%.
Remarkably, other diastereomers could not be detected by
NMR spectroscopy of the crude reaction mixture.
Scheme 1. Concept: in situ sequences of enamine-catalyzed reactions
of acetaldehyde with two electrophiles.
During our initial studies of the Mannich reaction of
acetaldehyde with N-Boc-imines, we detected traces of bis-
addition product 4a, resulting from the reaction of product 3,
Encouraged by this exciting result, we performed the
reaction under optimized conditions with a variety of N-Boc
imines to evaluate the scope of the double Mannich reaction
(Table 1). Aromatic ring substitution is well tolerated and
imines with differing electronic properties (Table 1, entries
1–5) provided products in high yields (76–99%) and
with exceptionally high diastereo- and enantioselectivities
(> 99:1 d.r., > 300:1 e.r.). A heteroaromatic thiophene-sub-
stituted imine also participated in the reaction, furnishing
product 4 f in 93% yield with similar stereoselectivity
(Table 1, entry 6). Even the aliphatic isovaleraldehyde-
derived N-Boc imine, which is much more difficult to
handle, gave the double Mannich adduct highly enantiose-
lectively (> 300:1 e.r.) albeit in moderate yield (30%) owing
to the instability of the imine (Table 1, entry 7).
[*] Dr. C. Chandler,[+] P. Galzerano,[+] Dr. A. Michrowska,[+]
Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
Fax: (+49)208-306-2999
E-mail: list@mpi-muelheim.mpg.de
[+] These authors contributed equally.
[**] We thank our HPLC department for accurate e.r. measurements.
Generous support by the Max-Planck-Society, the Deutsche For-
schungsgemeinschaft (SPP 1179, Organokatalyse), the University of
Bologna (Fellowship to P.G.), the Alexander von Humboldt Stiftung
(Fellowship to A.M.) and the Fonds der Chemischen Industrie is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200806049.
1978
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 1978 –1980

Angewandte
Chemie
Table 1: Double Mannich reactions of acetaldehyde.[a]
Table 2: Mannich reactions of compound 3 with different imines 2.
Entry
1[e]
Product
Yield [%][b] d.r.[c] e.r. (ee %)[d]
Entry
1[c]
Product
Yield [%][a]
61
d.r.[b]
99
86
90
85
76
93
>99:1 9905 (99.98)
>99:1 >300 (>99)
>99:1 >300 (>99)
>99:1 >300 (>99)
>99:1 >300 (>99)
>99:1 >300 (>99)
45:2:1:0
2
2[d]
59
58
60
53
70:2:1:0
>20:1:1:1
>20:1:1:1
>20:1:1:1
3
3[c,e]
4[d,e]
5[d]
4
5
[a] Yield of the isolated corresponding alcohol after in situ reduction.
[b] The d.r. refers to the ratio of the four possible diastereomers and was
determined by HPLC analysis of the corresponding crude alcohol mixture
after in situ reduction (entries 1 and 2) or following column chromatog-
raphy (entries 3–5). [c] Using (S)-proline. [d] Using (R)-proline. [e] Reac-
tion carried out with 1.3 equivalents of imine 2.
6[e]
7[f]
30
>99:1 >300 (>99)
proline, these reactions are essentially catalyst controlled.
Using (S)-proline, the reaction leads to products 5a and 5c
(Table 2, entries 1 and 3), resulting from the inherent syn
diastereoselectivity and imine si-facial enantioselectivity of
the (S)-proline-catalyzed Mannich reaction. In contrast, when
we used (R)-proline as the catalyst, diastereomers 5b and 5d
were obtained. In these cases, the two new stereogenic centers
were formed with the opposite configuration (Table 2,
entries 2 and 4).
[a] Unless otherwise noted, reactions were run with imine 2 (0.75 mmol)
and acetaldehyde (0.25 mmol) in CH3CN at 08C for 2 h and then allowed
to warm to room temperature for 18–22 h. [b] Yield of isolated product.
[c] Determined by NMR spectroscopy of the crude mixture. [d] Deter-
mined by HPLC analysis of the corresponding alcohol. [e] Reaction run at
08C for 24 h. [f] A solution of the N-Boc imine (0.31 mmol, 1 equiv) and
acetaldehyde (1.5 equiv) in CH3CN was added to a solution of (S)-proline
(0.2 equiv) in CH3CN at 08C. The solution was allowed to stir for 2 h at
08C before a second portion of freshly prepared N-Boc imine (1.5 equiv)
was added.
The strategy of utilizing first (S)-proline and then (R)-
proline in subsequent acetaldehyde Mannich reactions with
the same imine (2a) was used to afford the corresponding
meso product 5e highly diastereoselectively (Table 2,
entry 5). In this rather sophisticated symmetrization process,
two highly enantioselective catalytic reactions were
sequenced to create an achiral molecule.
Finally, aldehyde 4b was readily converted into the
corresponding diamino acid 6 by a straightforward two-step
oxidation–deprotection sequence in 73% overall yield
[Eq. (1)].[11]
We also made attempts at developing analogous cross-
Mannich reactions with two different imines by sequencing
their addition. Initial attempts lead to formation of both
homocoupling products, as well as the corresponding cross-
Mannich products under a variety of conditions.[9] However,
the desired products 5 were obtained when the initial mono-
addition products were first isolated and then subjected to a
second reaction, similar to our previously described condi-
tions.[10] Indeed, treating isolated Mannich product
3
(> 99:1 e.r.) with two different second aromatic N-Boc
imines in the presence of either (S)- or (R)-proline gave the
corresponding cross-Mannich products in reasonably good
yields and with high diastereoselectivities and, as anticipated,
with enantiomeric ratios greater than 99:1 (Table 2). Judging
from the high diastereoselectivity using either (R)- or (S)-
Angew. Chem. Int. Ed. 2009, 48, 1978 –1980
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1979

Communications
asymmetric Mannich reactions, see: c) A. Cꢁrdova, S. I. Wata-
nabe, F. Tanaka, W. Notz, C. F. Barbas III, J. Am. Chem. Soc.
2002, 124, 1866 – 1867; d) A. G. Wenzel, E. N. Jacobsen, J. Am.
Chem. Soc. 2002, 124, 12964 – 12965; e) Y. Hayashi, W. Tsuboi, I.
Ashimine, T. Urushima, M. Shoji, K. Sakai, Angew. Chem. 2003,
115, 3805 – 3808; Angew. Chem. Int. Ed. 2003, 42, 3677 – 3680;
f) A. Cꢁrdova, Chem. Eur. J. 2004, 10, 1987 – 1997; g) A. J. A.
Cobb, D. M. Shaw, S. V. Ley, Synlett 2004, 558; h) J. Franzꢂn, M.
Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjrsgaard, K. A.
Jørgensen, J. Am. Chem. Soc. 2005, 127, 18296 – 18304; i) B.
Westermann, C. Neuhaus, Angew. Chem. 2005, 117, 4145 – 4147;
Angew. Chem. Int. Ed. 2005, 44, 4077 – 4079; j) T. Kano, Y. Hato,
K. Maruoka, Tetrahedron Lett. 2006, 47, 8467 – 8469; k) D.
Enders, M. Vrettou, Synthesis 2006, 2155 – 2158; l) D. Enders, C.
Grondal, M. Vrettou, Synthesis 2006, 3597 – 3604; m) J. Song, Y.
Wang, L. Deng, J. Am. Chem. Soc. 2006, 128, 6048 – 6049; n) M.
Sickert, C. Schneider, Angew. Chem. 2008, 120, 3687 – 3690;
Angew. Chem. Int. Ed. 2008, 47, 3631 – 3634; o) B. T. Hahn, R.
Frꢃhlich, K. Harms, F. Glorius, Angew. Chem. 2008, 120, 10134 –
10137; Angew. Chem. Int. Ed. 2008, 47, 9985 – 9988; p) C.
Gianelli, L. Sambri, A. Carlone, G. Bartoli, P. Melchiorre,
Angew. Chem. 2008, 120, 8828 – 8830; Angew. Chem. Int. Ed.
2008, 47, 8700 – 8702.
In summary, a double enamine catalysis sequence using
acetaldehyde as the nucleophile has been realized. We
developed an efficient method for the one-pot catalytic
asymmetric synthesis of pseudo-C2-symmetric b,b’-diaminoal-
dehydes with extremely high stereoselectivities, starting from
acetaldehyde and either aromatic or aliphatic N-Boc imines.
The method was extended to cross-Mannich reactions,
furnishing b,b’-diamino aldehydes 5 containing stereotriads
(three adjacent stereogenic centers). The general strategy
should be of use for alternative double enamine catalysis
sequences using different reactions and even triple enamine
catalysis sequences of acetaldehyde.
Experimental Section
General procedure for the (S)-proline-catalyzed asymmetric homo
double Mannich reaction of acetaldehyde and aromatic N-Boc
imines: The N-Boc imine (0.75 mmol, 3 equivalents) was dissolved
in anhydrous CH3CN (3.75 mL) and stirred under an atmosphere of
argon. The solution was cooled to 08C and freshly distilled
acetaldehyde (0.25 mmol, 1 equivalent) and (S)-proline (0.05 mmol,
0.2 equivalents) were added. The reaction mixture was stirred for 2 h
at 08C and then allowed to warm to room temperature. After stirring
for 18–22 h, the reaction mixture was quenched with H2O (15 mL)
and extracted with CH2Cl2 (3 ꢀ 15 mL). The organic fractions were
dried over anhydrous MgSO4 and concentrated under reduced
pressure. Purification by flash column chromatography on silica gel
(hexane/ethyl acetate, 90:10) afforded 4a–f as white solids.
[4] Also see: a) A. Cꢁrdova, W. Notz, C. F. Barbas III, J. Org. Chem.
2002, 67, 301 – 303; A. Bogevig, N. Kumaragurubaran, K. A.
Jørgensen, Chem. Commun. 2002, 620 – 621.
[5] Y. Hayashi, T. Itoh, S. Aratake, H. Ishikawa, Angew. Chem. 2008,
120, 2112 – 2114; Angew. Chem. Int. Ed. 2008, 47, 2082 – 2084.
[6] a) P. Garcꢄa-Garcꢄa, A. LadꢂpÞche, R. Halder, B. List, Angew.
Chem. 2008, 120, 4797 – 4799; Angew. Chem. Int. Ed. 2008, 47,
4719 – 4721; b) Y. Hayashi, T. Itoh, M. Ohkubo, H. Ishikawa,
Angew. Chem. 2008, 120, 4800 – 4802; Angew. Chem. Int. Ed.
2008, 47, 4722 – 4724.
[7] In the context of developing an alternative catalyst, Hayashi
et al. also mentioned this side reaction, see: Y. Hayashi, T.
Okano, T. Itoh, T. Urushima, H. Ishikawa, T. Uchimaru, Angew.
Chem. 2008, 120, 9193 – 9198; Angew. Chem. Int. Ed. 2008, 47,
9053 – 9058.
Typical procedure for the (S)-proline-catalyzed asymmetric
double Mannich reaction of acetaldehyde and isovaleraldehyde-
derived N-Boc imine: A solution of the N-Boc imine (0.31 mmol,
1 equivalent) in CH3CN (1.3 mL) was added to a solution of (S)-
proline (0.062 mmol, 0.2 equivalents) in CH3CN (250 mL) at 08C.
Freshly distilled acetaldehyde (0.465 mmol, 1.5 equivalents) was
immediately added and the resulting solution was allowed to stir for
2 h at 08C.
A second solution of N-Boc imine (0.465 mmol,
[8] For an example of an auxiliary-mediated double aldol reaction
of an acetate nucleophile, see: a) A. Abiko, J. F. Liu, D. C.
Buske, S. Moriyama, S. Masamune, J. Am. Chem. Soc. 1999, 121,
7168 – 7169; b) H. Furuno, T. Inoue, A. Abiko, Tetrahedron Lett.
2002, 43, 8297 – 8299. For a non-asymmetric, stoichiometric,
base-mediated double Mannich reaction of acetonitrile and
esters with imines see: C. Ivanov, V. Dryanska, Dokl. Bolg.
Akad. Nauk 1969, 22, 423 – 426.
1.5 equivalents) in CH3CN (1 mL) was added and the mixture was
allowed to stir an additional 3 h at 08C. The reaction mixture was
quenched with H2O (15 mL) and extracted with CH2Cl2 (3 ꢀ 15 mL).
The organic fractions were dried over anhydrous MgSO4 and
concentrated under reduced pressure. Purification by flash column
chromatography on silica gel (hexane/ethyl acetate, 95:5) afforded 4g
as a white solid.
[9] A representative in situ attempt for the synthesis of cross double
Mannich products is as follows: A standard Mannich reaction
mixture of (S)-proline (20 mol%), imine 2a (1 equivalent), and
acetaldehyde (1.5 equivalents) was stirred for 3 h. N-Boc imine
2b (1.5 equivalents) was added, resulting in a complex mixture
of the two first Mannich adducts (3), the two homo double
Mannich products 4a and 4b, and the desired cross-Mannich
product (5). The ratio 4b/5 was close to 1:1 and could be slightly
improved to 0.6:1 by slowly adding imine 4b under dilute
conditions.
[10] J. W. Yang, M. Stadler, B. List, Angew. Chem. 2007, 119, 615 –
617; Angew. Chem. Int. Ed. 2007, 46, 609 – 611.
[11] For a multistep synthesis of similar b,b’-diamino acid derivatives,
see: A. A. Taubinger, D. Fenske, J. Podlech, Tetrahedron 2008,
64, 8659 – 8667.
Received: December 12, 2008
Published online: February 6, 2009
Keywords: aldehydes · diastereoselectivity · enantioselectivity ·
.
Mannich reaction · organocatalysis
[1] a) B. List, Synlett 2001, 1675 – 1686; b) B. List, Acc. Chem. Res.
2004, 37, 548 – 557; c) S. Mukherjee, J. W. Yang, S. Hoffmann, B.
List, Chem. Rev. 2007, 107, 5471 – 5569.
[2] J. W. Yang, C. Chandler, M. Stadler, D. Kampen, B. List, Nature
2008, 452, 453 – 455.
[3] For the discovery of the proline-catalyzed Mannich reaction,
see: a) B. List, J. Am. Chem. Soc. 2000, 122, 9336- 9337; b) B.
List, P. Pojarliev, W. T. Biller, H. J. Martin, J. Am. Chem. Soc.
2002, 124, 827 – 833. For examples of other organocatalytic
1980 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 1978 –1980