Stereoselective organocatalytic one-pot α,α-bifunctionalization of acetaldehyde by a tandem mannich reaction/electrophilic amination

Article abstract of DOI:10.1021/ol202340p

The first asymmetric organocatalyzed one-pot α,α- bifunctionalization of acetaldehyde with two different electrophiles is described. A diarylprolinol silyl ether-catalyzed reaction of acetaldehyde with an imine and di-tert-butyl azodicarboxylate affords s

Full text of DOI:10.1021/ol202340p

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5778–5781
Stereoselective Organocatalytic One-Pot
r,r-Bifunctionalization of Acetaldehyde
by a Tandem Mannich Reaction/
Electrophilic Amination
ꢀ ꢀ
Vincent Coeffard, Alaric Desmarchelier, Benedicte Morel, Xavier Moreau, and
Christine Greck*
ꢀ
Institut Lavoisier de Versailles, UMR CNRS 8180, Universite de Versailles-St-Quentin-en-
Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles cedex, France
ꢀ
greck@chimie.uvsq.fr
Received August 29, 2011
ABSTRACT
The first asymmetric organocatalyzed one-pot R,R-bifunctionalization of acetaldehyde with two different electrophiles is described. A
diarylprolinol silyl ether-catalyzed reaction of acetaldehyde with an imine and di-tert-butyl azodicarboxylate affords syn-2,3-diaminoalcohols
with excellent ee values of up to 98%. This methodology was successfully applied to the synthesis of a chiral R,β-diaminocarboxylic acid.
Asymmetric R-functionalization of aldehydes mediated
by enamine catalysis has attracted considerable attention
over the past decade.1 Recent approaches in this field lie in
the development of novel catalytic strategies aiming at
higher-yielding, more selective and complex chemical
transformations using simple substrates. Among carbonyl
compounds, acetaldehyde is the simplest enolizable nu-
cleophile but its use in organocatalysis has long been
hampered by difficulties in controlling its reactivity.2 In
2008, the research groups of List and Hayashi indepen-
dently reported the first general enantioselective transfor-
mationsof acetaldehyde under enamine catalysis.3 Follow-
ing these works, several research groups successfully devel-
oped organocatalytic transformations involving acetalde-
hyde as a substrate.4 In 2009, List et al. reported a highly
diastereo- and enantioselective proline-catalyzed double
Mannich reaction of acetaldehyde with N-Boc imines.4a
€
(1) (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-
VCH: Weinheim, 2005. (b) Enantioselective Organocatalysis; Dalko, P. I.,
Ed.; Wiley-VCH: Weinheim, 2007. (c) Organocatalysis; Reetz, M. T., List,
B., Jaroch, S., Weinmann, H., Eds.; Springer-Verlag: Berlin Heidelberg,
2008.
(4) For relevant examples, see: (a) Chandler, C.; Galzerano, P.;
Michrowska, A.; List, B. Angew. Chem., Int. Ed. 2009, 48, 1978. (b)
Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 3854. (c) Kano,
T.; Yamaguchi, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2009, 48, 1838.
(d) Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Chem.;Eur. J. 2009,
15, 6790. (e) Galzerano, P.; Agostino, D.; Bencivenni, G.; Sambri, L.;
Bartoli, G.; Melchiorre, P. Chem.;Eur. J. 2010, 16, 6069. (f) Enders, D.;
(2) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed. 2008, 47, 4632.
(3) (a) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B.
Nature 2008, 452, 453. (b) Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa,
H. Angew. Chem., Int. Ed. 2008, 47, 2082. (c) Garcıa-Garcıa, P.;
€
Krull, R.; Bettray, W. Synthesis 2010, 567. (g) Chen, W.-B.; Du, X.-L.;
ꢀ ^
Ladepeche, A.; Halder, R.; List, B. Angew. Chem., Int. Ed. 2008, 47,
Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2010, 66, 1441. (h)
Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Adv. Synth. Catal. 2010,
352, 1621. (i) Jin, M. Y.; Kim, S. M.; Han, H.; Ryu, D. H.; Yang, J. W.
Org. Lett. 2011, 13, 880. (j) Ishikawa, H.; Honma, M.; Hayashi, Y.
Angew. Chem., Int. Ed. 2011, 50, 2824. (k) Hu, S.; Zhang, L.; Li, J.; Luo,
S.; Cheng, J.-P. Eur. J. Org. Chem. 2011, 3347.
4719. (d) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew.
Chem., Int. Ed. 2008, 47, 4722. (e) Hayashi, Y.; Okano, T.; Itoh, T.;
Urushima, T.; Ishikawa, H.; Uchimaru, T. Angew. Chem., Int. Ed. 2008,
47, 9053. (f) Hayashi, Y.; Samanta, S.; Itoh, T.; Ishikawa, H. Org. Lett.
2008, 10, 5581.
r
10.1021/ol202340p
Published on Web 10/11/2011
2011 American Chemical Society

Despite this breakthrough, organocatalyzed R,R-bifunc-
tionalization of acetaldehyde with two different electro-
philes remains an untrodden process. As a part of our
ongoing research into organocatalyzed CꢀN bond
formation,5 we report herein a stereoselective one-pot
Mannich reaction/electrophilic amination of acetaldehyde
through double enamine catalysis (Scheme 1). This would
afford chiral R,β-diamino aldehydes which represent inter-
esting building blocks for the synthesis of vicinal diamine-
containing compounds.6
Dichloromethane and acetonitrile are good solvents for
R-amination of aldehydes using catalyst 2.5a,7,8 These were
tested in the Mannich reaction, and acetonitrile turned out
to be the best solvent affording 3 in 84% yield and 98% ee
(entries 5 and 6).
Table 1. Optimization of the Mannich Reactiona
Scheme 1. One-Pot R,R-Bifunctionalization of Acetaldehyde
entry
PG
solvent
yield (%)b
ee (%)c
1
Boc
Cbz
Bz
THF
n.r.
n.r.
68
n.d.
n.d.
98
2
THF
The successful implementation of a one-pot trans-
formation in a sequential approach requires the opti-
mization of the first step to make it compatible with the
subsequent ones. With this aim in mind, the first step
has to fulfill several criteria: (i) A quasi-equimolar ratio
of reagents is required. An excess of one substrate
might inhibit the subsequent reaction. (ii) The reaction
has to proceed in high yield without the formation of
any side products which could influence the following
transformation. (iii) Reaction conditions must be com-
patible with each transformation. Based on the recent
work of Hayashi et al.3e on the reaction of N-benzoyl-
N-benzylideneamine (1 equiv) with acetaldehyde
(5 equiv) catalyzed by the system diarylprolinol silyl ether
2/p-nitrobenzoic acid, we first embarked upon optimiza-
tion of the first step (Table 1). The reaction of acetaldehyde
(1.5 equiv) with N-protected-N-benzylideneamine 1a
(1 equiv) was chosen as the model reaction. Under these
conditions, N-Boc- and N-Cbz-N-benzylideneamines 1a
failed to react withacetaldehyde (entries 1 and 2). Reaction
of acetaldehyde with N-Bz imine 1a led to the desired
alcohol 3 in 68% yield and 98% ee after in situ reduction
(entry 3). It is worthwhile noting that decreasing the
amount of acetaldehyde only slightly affects the yield while
maintaining high enantioselectivity (entries 3 and 4).
3
THF
4d
5
Bz
THF
76
97
Bz
CH2Cl2
MeCN
60
82
6
Bz
84
98
a Unless otherwise noted, reactions were run with N-PG imine 1a (0.3
mmol), acetaldehyde (0.45 mmol) in solvent at 0 °C for 16 h. b Yield of
isolated product. c Determined by chiral HPLC analysis. d Reaction
carried out with 5 equiv of acetaldehyde.
With the optimized conditions for the Mannich reaction
in hand, we then turned our attention on the R-amination
step as part of a one-pot procedure (Scheme 2).
Scheme 2. R,R-Bifunctionalization of Acetaldehyde by
Sequential Addition of Reagents
The one-pot procedure consists of the reaction of acet-
aldehyde (1.5 equiv) with N-Bz imine 1a (1 equiv) catalyzed
by 10 mol % of 2/p-NO2C6H4CO2H. The reaction was
stirred at 0 °C for 16 h, at which point 1.5 equiv of di-tert-
butylazodicarboxylate was added. Monitoring of the reac-
tion showed that electrophilic amination did not occur at
0 °C under these conditions. Raising the temperature to
room temperature and further stirring for 24 h led to the
formation of 4a in 54% yield as a separable mixture of two
diastereoisomers (syn/anti = 90.5/9.5) after in situ reduction
and purification on silica gel. The above results prompted us
to investigate a procedure whereby all the reagents would be
present at the beginning of the reaction and a simple change
of temperature from 0 °C to room temperature would
promote electrophilic amination. Under these conditions,
reaction of 1a, di-tert-butylazodicarboxylate, and acetalde-
hyde for 16 h at 0 °C followed by further stirring at room
(5) For recent articles, see: (a) Ait-Youcef, R.; Sbargoud, K.;
Moreau, X.; Greck, C. Synlett 2009, 3007. (b) Kalch, D.; Ait-Youcef,
R.; Moreau, X.; Thomassigny, C.; Greck, C. Tetrahedron: Asymmetry
2010, 21, 2302. (c) Ait-Youcef, R.; Moreau, X.; Greck, C. J. Org. Chem.
2010, 75, 5312. (d) Desmarchelier, A.; Marrot, J.; Moreau, X.; Greck, C.
Org. Biomol. Chem. 2011, 9, 994. (e) Desmarchelier, A.; Yalgin, H.;
Coeffard, V.; Moreau, X.; Greck, C. Tetrahedron Lett. 2011, 52, 4430.
(6) For reviews, see: (a) Lucet, D.; Gall, T. L.; Mioskowski, C.
Angew. Chem., Int. Ed. 1998, 37, 2580. (b) Saibabu Kotti, S. R. S.;
Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101. (c) Kizirian,
J. C. Chem. Rev. 2008, 108, 140.
(7) For seminal reports on organocatalyzed R-amination of alde-
hydes, see: (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (b) Bøgevig, A.;
Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 1790.
(8) For relevant reviews on organocatalyzed R-amination, see: (a)
Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem. 2004, 1377.
(b) Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292. (c) Guillena, G.;
ꢀ
Ramon, D. J. Tetrahedron: Asymmetry 2006, 17, 1465. (d) Vilaivan, T.;
Bhanthumnavin, W. Molecules 2010, 15, 917.
Org. Lett., Vol. 13, No. 21, 2011
5779

Scheme 3. Proposed Catalytic Cycle for the Temperature-Controlled Tandem Mannich Reaction/Electrophilic Amination
temperature for 24 h gave rise to 4a after careful purifica-
tions on silica gel in 50% yield with excellent stereoselectiv-
ities (Table 2, entry 1).9 Decreasing the amount of di-tert-
butylazodicarboxylate (1 equiv) led to 4a in lower yield
(36%) and diastereoselectivity (syn/anti = 88/12) while
maintaining high enantioselectivity (ee for 4-syn = 96%).
levels of diastereo- and enantioselectivities were obtained
(entries 2ꢀ8). With respect to aryl substitution, para- and
meta-substituents were well tolerated leading to 4bꢀg in
32ꢀ51% yields and high enantioselectivities (entries 2ꢀ7).
A lower yield was obtained when an ortho-substituted
imine was employed as a substrate (entry 8). The proposed
catalytic cycle depicted above is suggested to explain the
selective formation of 4 through a temperature-controlled
tandem Mannich reaction/electrophilic amination (Scheme 3).
The reaction starts with the condensation of 2 with acet-
aldehyde to form the enamine A. Under acidic conditions,
A reacts with N-Bz imine 1 to furnish the iminum B.
Hydrolysis of this intermediate leads to the β-amino alde-
hyde Cand direct elimination of the catalyst 2. Reaction of 2
with C allows the formation of the enamine D. It should be
noted that formation of D from B cannot be ruled out at this
stage. Electrophilic amination of D by di-tert-butylazodi-
carboxylate furnishes the iminium E with a syn geometry as
the major intermediate. This could be explained by electro-
philic attack from the Si-face of the most stable anti-(E)-
enamine D.10 Hydrolysis of Eand subsequent reduction of F
afford 4 with syn-configuration as the major diastereoi-
somer. Starting from N-Bz imine 1b (R = 4-ClC6H4), ESI-
MS analyses were carried out to characterize the intermedi-
ates and to support the proposed catalytic cycle.11
Table 2. One-Pot R,R-Bifunctionalization of Acetaldehyde with
Various Iminesa
yield
ee
(%)c
entry
Ar
C6H5
4
syn/antib
4-syn(%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
94/6
50
45
32
41
40
51
35
23
96
98
98
90
97
96
96
88
4-ClC6H4
92/8
3-ClC6H4
90.5/8.5
93.5/6.5
88/12
88/12
91/9
4-MeC6H4
4-FC6H4
2-naphthyl
3-MeOC6H4
2-MeOC6H4
We then focused our attention on the application of this
tandem reaction to the synthesis of enantioenriched R,β-
diaminocarboxylic acids. These constitute an important
class of compounds found in a multitude of biologically
active synthetic and natural molecules.12 To assign the
absolute configuration of the obtained syn-diaminoalco-
hol 4, the developed methodology was successfully applied
4g
4h
96/4
a Reactions were run with N-Bz imine 1 (0.3 mmol), di-tert-butyla-
zodicarboxylate (0.45 mmol), and acetaldehyde (0.45 mmol) in MeCN at
0 °C for 16 h and then stirred at room temperature for 24 h. b Determined
by UHPLC-ESI of the crude product after workup. c Determined by
chiral HPLC analysis for the major syn-diastereoisomer.
ꢁ
(10) For mechanistic discussions, see: (a) Groselj, U.; Seebach, D.;
The one-pot procedure was then extended to a focus
selection of imines with the results summarized in Table 2.
Regardless of the substitution on the aromatic ring, high
Badine, D. M.; Schweizer, W. B.; Beck, A. K.; Krossing, I.; Klose, P.;
Hayashi, Y.; Uchimaru, T. Helv. Chim. Acta 2009, 92, 1225. (b) Nielsen,
M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen,
K. A. Chem. Commun. 2011, 47, 632.
(11) See Supporting Information for further details.
ꢀ
(12) (a) Viso, A.; Fernandez de la Pradilla, R.; Garcıa, A.; Flores, A.
(9) Under these conditions, reaction of imine N-Bz 1a with acetalde-
hyde and dibenzylazodicarboxylate afforded the desired compound
along with side products as an inseparable mixture.
ꢀ
Chem. Rev. 2005, 105, 3167. (b) Viso, A.; Fernandez de la Pradilla, R.;
Tortosa, M.; Garcıa, A.; Flores, A. Chem. Rev. 2011, 111, PR1.
5780
Org. Lett., Vol. 13, No. 21, 2011

Scheme 4. Synthesis of R,β-Diaminocarboxylic Acid 5 from Acetaldehyde
to the synthesis of the R,β-diaminocarboxylic acid 5, an
aminated analog of the taxol side chain (Scheme 4).13 The
synthetic sequence started with R,R-bifunctionalization of
acetaldehyde and imine 1a followed by in situ oxidation to
afford 6 with a diastereoselectivity similar to that pre-
viously observed for 4a (syn/anti = 92/8). Esterification of
6 led to 7 as a pure diastereoisomer in an overall yield of
26% from 1a. Cleavage of the hydrazine was carried out
through a two-step procedure: acidic cleavage of the
carbamates and hydrogenolysis of the hydrazine in the
presence of Raney Ni under sonication led to 8 in 77%
yield.14 Subsequent protection of the amine produced the
carbamate 9 in 88% yield. Hydrolysis of the ester group
yielded the N,N0-diprotected R,β-diaminocarboxylic acid 5
in 74% yield. By comparison of the optical rotation of 5
with the literature value,13 the absolute configuration was
confirmed to be (2S,3R).
a large amount of acetaldehyde (5ꢀ10 equiv) was
generally used in similar processes.4 Reaction of acet-
aldehyde with N-benzoyl imines 1 and di-tert-butyla-
zodicarboxylate enabled the one-pot synthesis of the
diamino compounds 4 with high levels of diastereo-
and enantioselectivity. From these results, a catalytic
cycle has been suggested to account for the selective
formation of 4. Furthermore, this methodology has
been successfully exploited for the stereoselective
synthesis of the R,β-diaminocarboxylic acid 5. We
anticipate that this transformation will find many
applications in stereoselective synthesis and will spur
further progress in the use of acetaldehyde in organo-
catalysis.
Acknowledgment. The authors thank CNRS, Univer-
sity of Versailles-St-Quentin-en-Yvelines, and MENRT
for a grant (A.D.) and for financial support. We also
warmly acknowledge Estelle Galmiche from the Institut
Lavoisier de Versailles for mass spectrum analyses.
In summary, we have disclosed the first asymmetric
organocatalyzed R,R-bifunctionalization of acetalde-
hyde with two different electrophiles. The organoca-
talytic transformations were successfully optimized by
lowering the amout of acetaldehyde to 1.5 equiv while
Supporting Information Available. Experimental pro-
cedures and compound characterization data including
NMR spectra, UHPLC-ESI data, and relevant HPLC
traces. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Rossi, F. M.; Powers, E. T.; Yoon, R.; Rosenberg, L.; Meinwald, J.
Tetrahedron 1996, 52, 10279–10286.
(14) It is important to note that reductive cleavage of the hydra-
zine carried out at room temperature for 24 h without sonication led
to 8 in 33% yield as an inseparable mixture of diastereoisomers (syn/
anti: 87/13).
Org. Lett., Vol. 13, No. 21, 2011
5781