Enantioselective organocatalytic formal allylation of α-branched aldehydes

Article abstract of DOI:10.1039/c1cc14909a

Heteroarylvinyl sulfone 1 has been successfully used as a new sulfonyl Michael acceptor in aminocatalytic reactions with branched aldehydes. Subsequent one-pot Julia-Kocienski olefination allows the challenging preparation of enantiomerically pure α-allylated aldehydes bearing C-α quaternary carbons.

Full text of DOI:10.1039/c1cc14909a

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COMMUNICATION
Enantioselective organocatalytic formal allylation of a-branched
aldehydesw
´ ´
´
Eduardo Rodrigo, Sara Morales, Sara Duce, Jose Luis Garcıa Ruano and M. Belen Cid*
Received 8th August 2011, Accepted 3rd September 2011
DOI: 10.1039/c1cc14909a
Heteroarylvinyl sulfone 1 has been successfully used as a new
sulfonyl Michael acceptor in aminocatalytic reactions with branched
aldehydes. Subsequent one-pot Julia–Kocienski olefination allows
the challenging preparation of enantiomerically pure a-allylated
aldehydes bearing C-a quaternary carbons.
The direct asymmetric intermolecular a-alkylation of aldehydes
remains a hot topic which has been even considered the ‘‘Holy
Grail’’ of organocatalysis.1 Although some brilliant strategies have
been described,2 there are a wide variety of substrates still out of
range of these methodologies. This is also the case of the a-allylation
of aldehydes. The formation of quaternary stereogenic centers has
also been recognized as one of the most challenging tasks in organic
chemistry.3 Thus, although several purely organocatalytic4 or
organocatalytic combined methods5,6 have provided bright solu-
tions for the a-allylation of aldehydes, the synthesis of enantio-
merically pure a-allylated aldehydes bearing quaternary stereogenic
centers at C-a remains elusive. This is an important task since there
are many natural and non-natural products with interesting
pharmaceutical properties containing quaternary carbon centres,7
many of them prepared in racemic form from allylated aldehydes.8
The only organocatalytic method reported so far for the
a-allylation of branched aldehydes involving the creation of
quaternary a-carbons is due to Mukherjee and List (Scheme 1).6
It is a powerful procedure that employs allylamines as
electrophiles and chiral Brønsted acids in combination with a
Pd-catalyst. The method is quite efficient for R3 = H, but only
two examples with R3 a H (Me, Ph) were reported, with
slightly lower yields and enantioselectivities.
Scheme 2 Formal regio- and enantioselective method for the
allylation of a-branched aldehydes by a sequential procedure.
We envisioned a complementary and fully organocatalytic
strategy based on the alkylation of branched aldehydes through
a Michael addition9 yielding compounds with moieties easily
transformed into allylic fragments. It would provide a flexible
method for the synthesis of a-allylated aldehydes containing a
quaternary centre and a wide range of substitutions using
aminocatalysis. In order to develop this modular approach,
heteroaryl vinyl sulfone 110 was identified as an appropriate
electrophile since the resulting heterosulfone moiety has been
successfully used in Julia–Kocienski olefinations,11 thus
making possible the introduction of a variety of substituents R3
from only one common electrophile (Scheme 2).
a,b-Unsaturated sulfones have proven to be excellent
Michael acceptors under different organocatalytic conditions,12
such as base promoted conjugate additions,13 phase transfer
type reactions,14 and Michael additions involving thiourea
activation.15 Activation of aldehydes via enamine has been the
most prolific method,16 although an additional electron-
withdrawing group (EWG) is mandatory in the alkene so that
the Michael addition takes place, hampering the possibility of
using the obtained adducts as substrates for olefination reactions.
We initiated the studies with the heteroarylvinyl sulfone 1
with the hope that its higher electron-withdrawing character17
was enough to confer to the double bond the appropriate
electrophilicity to react with branched aldehydes via enamine
activation without requiring the presence of additional EWG
groups at the alkene, thus making possible the sequential
Michael/Julia–Kocienski process shown in Scheme 2.
Scheme 1 Allylation of branched aldehydes using chiral Brønsted
We present herein the results obtained in these studies that
have allowed us to synthesise a variety of g,d-unsaturated
aldehydes containing a quaternary C-a and R3 = alkyl, aryl, H,
which constitutes a regio- and enantioselective indirect method
for the a-allylation of branched aldehydes.
acid and palladium-catalyst.
´
Department of Organic Chemistry, Universidad Autonoma de Madrid,
Cantoblanco 28049, Spain. E-mail: belen.cid@uam.es
w Electronic supplementary information (ESI) available: Experimental
details, spectra and chiral HPLC conditions. See DOI: 10.1039/
c1cc14909a
In order to find the optimal reaction conditions, we started
our research using phenylpropionaldehyde 2a as a model
c
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Chem. Commun., 2011, 47, 11267–11269 11267

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Table 1 Screening of different catalysts for the conjugate addition of
2-phenylpropionaldehyde 2a to heteroaryl vinyl sulfone 1
Table 2 Scope of the conjugate addition of aldehydes 2 to heteroaryl
vinyl sulfone 1
Entrya R1 R2
Aldehyde Time/h Yield (%) ee (%)
1
2
3
4
5
6
7
Me Ph
Me p-Br–C6H4–
Me p-CN–C6H4– 3c
Me p-CH3–C6H4– 3d
Me 2-Naphthyl
Me o-F–C6H4–
Me 2-Thiophenyl 3g
Me n-Pr
Me
Me Bn
Et Ph
3a
3b
48
48
48
48
48
72
72
96
96
96
120
76
71
65
60
83
30
68
48
46
62
50c
94
93
86
93
89
92
58
40
3e
3f
8b
9b
10b
11b
3h
3i
3j
3k
Conv.
(%)
Entrya Catalyst Solvent Additive
Time/h
eeb (%)
42
71
75–80c
1
2
3
4
5
6
7
8
I
II
CHCl3
DMSO
DMSO
CH2Cl2
Toluened
DMF
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
—
—
—
—
—
—
—
—
—
—
—
24
24
48
1
100
100
95
100
100
20c
30c
2c
a
Reactions carried out with 5 equiv. of aldehyde 2 unless otherwise
b
stated. 10 equiv. of aldehyde 2 and 50% of p-NO2–C6H4CO2H.
III
IV
IV
IV
IV
V
VI
VII
VIII
VII
VII
VII
74c
68c
—
c
See ESI.w
1
No reaction —
1
4
16
16
16
36
100
78c (86)e
18c
92
100
100
100
100
74f
substrates in the Michael addition to sulfone 1. As it is the case
in other organocatalytic examples,23 reactivity and enantio-
meric ratios were significantly lower (entries 8–9) but they
improved when R2 is Bn (entry 10). Not only 2-arylpropanals
were used and 2-phenylbutanal 2k was also tolerated (R1 = Et,
entry 11).
9
10
11
12
13
14g
95
86c
96
CHCl3 BzOH
CHCl3 p-NO2-BzOH 16
CHCl3 p-NO2-BzOH 48
100
76
96
94
a
Reactions carried out with 30 equiv. of aldehyde 2a unless otherwise
Once compounds 3 were obtained, we studied their trans-
formation into the a-allylated aldehydes using the model
aldehyde 3a. We thought that the low reactivity of the
a-dibranched aldehydes 3, due to steric hindrance, would make
unnecessary their protection before reacting with other aldehydes
under the mild conditions of the Julia–Kocienski olefination. In
fact, 3a reacts with benzaldehyde (4A) and propanal (4D) to
afford olefins 5aA (E/Z = 10 : 1) and 5aD (E/Z = 2:1) in 48%
and 15% yields, respectively. However, both yields and stereo-
selectivities were improved starting from protected aldehydes in
the Julia-Kocienski reaction, as indicated in Scheme 3. The easy
protocol involving protection/Julia–Kocienski olefination11/
deprotection was satisfactorily applied to a variety of aldehydes
with only one final chromatography.
b
stated. ee determined by HPLC. Opposite enantiomer of 3a was
e
obtained. With 5 equivalents of water. Reaction performed at
c
d
f
g
ꢀ30 1C. Yield. 5 equiv. of aldehyde 2a were used.
aldehyde and testing a variety of primary amines as catalysts
such as (S)-methylbenzylamine (I), aminoacids18,19 L-alanine (II)
and L-valine (III). The conjugate addition took place effectively but
with low enantioselectivity (Table 1, entries 1–3). Higher enantio-
selectivities were obtained with Jacobsen’s thiourea IV20 (entries
4–7). After testing several solvents and temperatures the best result
was achieved using CHCl3 as solvent at ꢀ30 1C (entry 7). Under
similar conditions squaramide V gave poorer enantioselectivities
(entry 8). Catalysts derived from cinchona alkaloids (VI–VIII)21
afforded better enantiocontrol (entries 9–11). In search of additives
to enhance both reactivity and selectivity, we found the optimal
balance when p-nitrobenzoic acid (20 mol %)22 and 9-amino-
(9-deoxi)-epiquinine VII were used (entry 14).
The best results were obtained with aromatic aldehydes.
Aldehyde 5aF, which has been used in the preparation of a
potential pharmaceutical agent for the treatment of depression
and related disorders,24 was obtained in lower yield (R3 = H).
However, it is noteworthy that formaldehyde is not a common
aldehyde used in Julia–Kocienski olefination.25 Furthermore,
we have used 5aF for establishing the absolute configuration at
The optimized conditions, which were also scaled up to 500 mg
of sulfone 1, were applied to a series of aldehydes (Table 2). It is
important to note that in all the cases the excess of aldehyde can
be recovered by flash chromatography.
Substituted aromatic aldehydes 2a–e afforded the Michael
adducts 3a–e in good yields (60–83%) and ees (86–94%) regardless
of the electronic nature of the substituents (entries 1–5). The
reaction seems to be sensitive to the ortho substitution and
aldehyde 2f afforded the corresponding adduct 3f with high ee
but lower yield (entry 6). The Michael addition of aldehyde with
2-thiophenyl substituent 2g was sluggish affording moderate
enantioselectivity (entry 7). Even the more challenging branched
aldehydes with two aliphatic substituents were suitable
Scheme 3 Julia one-pot reaction of adduct 3a with different aldehydes.
c
11268 Chem. Commun., 2011, 47, 11267–11269
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the stereogenic center by chemical correlation as R (see ESIw).
The configurations of the rest of aldehydes 3a–k and 5aA–5aF
were assigned by analogy.
M. G. Kulkarni, A. P. Dhondge, A. S. Borhade, D. D. Gaikwad,
S. W. Chavhan, Y. B. Shaikh, V. B. Ningdale, M. P. Desai,
D. R. Birhade and M. P. Shinde, Tetrahedron Lett., 2009, 50,
2411–2413; (c) (+)-Cuparene prepared in ref. 6 from an allylated
branched aldehyde.
In conclusion, we have developed a new modular method for
the enantioselective a-allylation of branched aldehydes involving
their Michael addition to heteroarylvinyl sulfone 1 catalyzed by
9-amino-(9-deoxi)-epiquinine VII followed by a Julia–Kocienski
olefination. We anticipate that this easy to perform new flexible
retrosynthetic disconnection––complementary to that reported by
List––will find application in the preparation of a variety of
allylated aldehydes 5 bearing quaternary centers, which are
interesting building blocks in the synthesis of biologically active
molecules. Moreover, this communication describes for the first
time the synthetic usefulness of a monoactivated vinyl sulfone in
organocatalysis via enamine activation.
9 Review articles on organocatalytic Michael addition, see:
(a) D. Almasi, D. A. Alonso and C. Najera, Tetrahedron: Asym-
metry, 2007, 18, 299–365; (b) S. B. Tsogoeva, Eur. J. Org. Chem.,
2007, 1701–1716; (c) J. L. Vicario, D. Badıa, L. Carrillo and
E. Reyes, ‘‘Organocatalytic Enantioselective Conjugate Additions’’,
RSC Book series on catalysis, RSC Publishing, Oxford, 2010.
10 Sulfone 1 was prepared in a multigram scale as reported in the ESIw.
11 For some reviews see: (a) M. Nielsen, C. B. Jacobsen,
M. W. Paixao, N. Holub and K. A. Jørgensen, Angew. Chem.,
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J. Chem., 2009, 62, 951–955.
12 For a review dealing with the use of vinylsulfones in organo-
catalysis, see: Q. Zhu and Y. Lu, Aust. J. Chem., 2009, 62, 951–955.
13 This activation allows the use of monoactivated vinylsulfones: (a) H. Li,
J. Song, X. Liu and L. Deng, J. Am. Chem. Soc., 2005, 127, 8948–8949;
(b) T. Y. Liu, J. Long, B. J. Li, L. Jiang, R. Li, Y. Wu, L. S. Ding and
Y. Chun Chen, Org. Biomol. Chem., 2006, 4, 2097–2099; (c) H. Li,
J. Song and L. Deng, Tetrahedron, 2009, 65, 3139–3148.
We thank the Spanish Government (CTQ-2009-12168),
CAM (AVANCAT CS2009/PPQ-1634) and UAM-CAM
(CCG10-UAM/PPQ-5769) for financial support. E.R., S.D.
and S.M. thank the CAM and Spanish Ministry for predoctoral
fellowships. We thank Dr Luca Bernardi for some interesting
suggestions.
14 J. Aleman, E. Reyes, B. Richter, J. Overgaard and
K. A. Jørgensen, Chem. Commun., 2007, 3921–3923.
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17 Heteroaromatic rings have never been used to activate vinylsulfones
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PCT Int. Appl. 0240459, 2002.
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c
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Chem. Commun., 2011, 47, 11267–11269 11269