Enantioselective allylation of aldehydes promoted by chiral sulfur reagents

Article abstract of DOI:10.1016/j.tetlet.2006.01.014

The addition of allylzinc bromide to aldehydes was studied with different chiral sulfur compounds acting as a catalyst. Yield differences and enantiomeric excesses were observed.

Full text of DOI:10.1016/j.tetlet.2006.01.014

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1829–1831
Enantioselective allylation of aldehydes promoted by chiral
sulfur reagents
Rosanne P. A. Melo,a Juliana A. Vale,a Gilson Zenib and Paulo H. Menezesa,*
aDepartamento de Quı´mica Fundamental—Universidade Federal de Pernambuco—CCEN, Recife-PE, Brazil
bLaborato´rio de Sı´ntese e Reatividade e Avaliac¸a˜o Toxicolo´gica e Farmacolo´gica de
ˆ
Organocalcogenios-CCNE—UFSM, Santa Maria-RS, Brazil
Received 14 September 2005; revised 27 December 2005; accepted 5 January 2006
Abstract—The addition of allylzinc bromide to aldehydes was studied with different chiral sulfur compounds acting as a catalyst.
Yield differences and enantiomeric excesses were observed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The availability of efficient synthetic methods for achiev-
ing absolute stereoselectivity by catalytic processes in
the production of enantiomerically pure compounds
are of considerable interest because such products can
be used as building blocks for the synthesis of valuable
chiral substances.1 Asymmetric allyl-transfer reactions
provide excellent stereoselective routes for converting
aldehydes into the corresponding homoallylic alcohols,
which are important building blocks for the synthesis
of many natural and biologically active compounds,2
and materials such as liquid crystals.3
We describe herein the results obtained in the asymmet-
ric allylation of aromatic and aliphatic aldehydes. The
catalysts investigated 2a–e (Table 1) consisting of
monodentated and bidentated ligands and were easily
prepared according to the literature procedures.10
Allylzinc bromide is also easily prepared by treatment of
allyl bromide with zinc powder and is compatible with
most functional groups.11
With the appropriate ligands, we then examined the
enantioselective allylation of benzaldehyde catalyzed
by different chiral sulfur reagents. The reactions were
performed under standard conditions: the allylzinc re-
agent was added to a solution of a catalytic amount of
the chiral ligand (2a–e) (0.5 mol %) in THF at À78 ꢁC
and stirred for 5 min followed by the addition of benzal-
dehyde (Scheme 1). Table 1 summarizes the results ob-
tained in the reaction.
The enantioselective addition of allylsilanes,4 allylstann-
anes,5 allylindium,6 and allylboranes7 to aldehydes has
been extensively studied using several catalysts devised
for this purpose.
Chiral sulfur compounds have been employed as effi-
cient stereochemical controllers in many classical key-
stone C–C bond-forming reactions.8 The efficacy of
sulfur compounds in diastereoselective auxiliary-in-
duced reactions is mainly due to the steric and stereo-
electronic differences existing between the substituents
of the stereogenic sulfur atom: a lone electron pair, an
oxygen, and two different carbon ligands, which are able
to differentiate the diastereotopic faces of a proximal or
even remote reaction center.9
The conversion was complete in 15 min, and alcohol 3a
was obtained in good yields in all cases but with modest
enantioselectivities (Table 1).
The majority of catalytic asymmetric reactions rely on
the use of chiral Lewis acids, which bind to the electro-
phile activating it toward nucleophilic attack.12 The chi-
ral Lewis bases catalyzed reactions are conceptually
distinct and involve the binding of the nucleophile with
the catalyst, which can further coordinate the electro-
phile. This dual mechanism of activation could provide
high reaction rates and excellent transfer of stereochemical
Keywords: Lewis base catalysis; Allylation; Enantioselective addition;
Chiral sulfur reagents.
*
Corresponding author. Tel.: +55 81 2126 8440; fax: +55 2126
8442; e-mail: pmenezes@ufpe.br
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.014

1830
R. P. A. Melo et al. / Tetrahedron Letters 47 (2006) 1829–1831
Table 1. Allylation of benzaldehyde with allylzinc using different chiral
sulfur compounds
cule and the nitrogen atom of the pyridine ring with
the zinc atom was found to be fairly effective for enhanc-
ing the ee of the reaction (Table 1, entry 5). In all cases,
the reactions took place smoothly and the ligands em-
ployed could be recovered at the end of the reaction.14
Additionally, it is worthwhile to note the allylzinc
reagent with relatively acidic functionalities of the
ligands such as the sulfinamide 2c and 2d, which are
also compatible.
Entry
2
Yield (%)a ee (%)b (confgn)c
O
S
1
80
24 (S)
O
p-Tol
2a
When the reaction was performed without the presence
of the catalysts, longer reaction times were required indi-
cating that the ligands are catalyzing the reaction.
O
S
2
3
82
75
15 (S)
13 (S)
p-Tol
2b
It is notable that increasing the catalyst loading
(2.0 mol %) proved to have no effect on the enantioselec-
tivity. Furthermore, increasing the temperature from the
original À78 ꢁC to room temperature or 0 ꢁC resulted
only in the decomposition of the allylzinc compound.
The use of toluene as a solvent in the reaction surpris-
ingly led to lower enantioselectivity. This fact is proba-
bly due to the low solubility of the allylzinc compound
as well as due to the ligands in this solvent.
O
S
H2N
p-Tol
2c
O
S
4
5
65
87
20 (S)
41 (S)
N
NH
p-Tol
p-Tol
Having optimized the reaction conditions, we extended
the enantioselective allylation to a variety of aldehydes
using the chiral ligand 2e as a catalyst. The results are
summarized in Table 2.
2d
O
S
N
As shown in Table 2, the methodology gave the desired
products in good yields after 15 min and with modest
ee’s in all cases.
2e
a Isolated yield.
b Determined by converting the obtained alcohol into the corre-
sponding MTPA-ester.
c Configuration assignment by comparison to the literature values of
optical rotations.
The electronic effects of the aldehyde were briefly stud-
ied. Both para-substituted aldehydes proved to have
Table 2. Allylation of aldehydes with allylzinc using the chiral ligand
2e
OH
OH
1) Zn*, THF, -78oC, 0.25h
Br
1) Zn*, THF, -78oC, 0.25h
Br
2) 2 (0.5 mol%), THF
R
-78oC then PhCHO
2) 2e (0.5 mol%), THF
1
3a
-78oC then RCHO
4a-d
1
Scheme 1.
Entry
Compound
R
Yield
(%)a
ee
(%)b (confgn)c
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
2-CN–C6H4
3-CN–C6H4
4-CN–C6H4
2-MeO–C6H4
4-Cl–C6H4
C6H5CH2CH2
2-Naphthyl
2-NO2–C6H4
4-NO2–C6H4
C3H7
80
80
85
68
86
80
78
—
—
70
75
20 (S)
7 (S)
10 (S)
42 (S)
17 (S)
26 (S)
21 (S)
—
information because the reaction proceeds through a
closed assembly transition state.13
Very different levels of enantiocontrol were observed in
the reaction. Although low stereoselectivities were ob-
served with monodentate ligands, a significantly higher
and more homogeneous enantiocontrol were found
when bidentate 2e ligand was used.
4g
4h
4i
9
10
11
—
0
0
4j
4k
This decrease in the enantioselectivity could be attrib-
uted to the interaction of monodentate catalysts 2a–c
via an oxygen coordination or via some unidentified
electronic effect (Table 1, entries 1–3). However, for
the more rigid N,O bidentade catalyst 2e a possible che-
lation between the oxygen atom of the sulfoxide mole-
C6H13
a Isolated yield.
b Determined by converting the obtained alcohol into the corre-
sponding MTPA-ester.
c Configuration assignment by comparison to the literature values of
optical rotations.

R. P. A. Melo et al. / Tetrahedron Letters 47 (2006) 1829–1831
1831
OH
References and notes
1) Zn*, THF, -78oC, 0.25h
1. (a) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew. Chem.,
Int. Ed. 2002, 41, 3701; (b) Hornberger, K. R.; Hamblett,
C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894;
(c) Felpin, F. X.; Lebreton, J. J. Org. Chem. 2002, 67,
9192.
Br
2) 2e (0.5 mol%), THF
-78oC then PhCHO
5
6
Scheme 2.
2. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
3. (a) North, M. Synlett 1993, 807; (b) Ohno, H.; Nitta, H.;
Tanaka, M. A.; Inoue, S. J. Org. Chem. 1992, 57, 6778.
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5. (a) Mukaiyama, T.; Harada, T. Chem. Lett. 1981, 1527;
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DeLaTorre, K.; Singaram, B. Tetrahedron Lett. 2005, 46,
2315.
similar reactivities giving the desired products in good
yields but low ee (Table 2, entries 3 and 5). Similar reac-
tivity but higher selectivity was observed with ortho-
substituted aldehydes 4a and 4d (Table 2, entries 1 and
4). Aliphatic aldehydes gave good chemical yields, but
no enantioselectivity was observed (Table 2, entries 10
and 11). It is also noteworthy that both o- and p-nitro-
benzaldehyde did not react at all (Table 2, entries 8
and 9).
7. (a) Kramer, G. W.; Brown, H. C. J. Org. Chem. 1977, 42,
2292; (b) Yamamoto, Y.; Hara, S.; Suzuki, A. Synlett
1996, 883.
Furthermore, this method is also useful for the allylation
of substituted allyl bromides. Crotyl bromide 5 was also
used as allylating agent and the reaction was found to be
regioselective, giving only the c-regioisomer 6 (Scheme
2). The reaction was, however, less diastereoselective,
giving an inseparable 6:4 mixture of syn- and anti-
diastereomers.
´
8. Mikolajczk, M.; Drabowicz, J.; Kielbasinski, P. Chiral
Sulfur Reagents; CRC Press, Boca Raton: New York, 1997.
9. Carreno, M. C. Chem. Rev. 1995, 95, 1717.
˜
10. For preparation of (À)-(S)-O-menthyl p-toluenesulfinate
´
see: (a) Mioskowski, C.; Solladie, G. Tetrahedron 1980, 36,
´
227; (b) Solladie, G. Synthesis 1981, 185; For preparation
of (+)-(R)-methyl p-tolyl sulfoxide see: (c) Andersen, K.
K. Tetrahedron Lett. 1962, 93; (d) Andersen, K. K.;
Gaffield, W.; Papanikolau, N. E.; Foley, J. W.; Perkins, R.
I. J. Am. Chem. Soc. 1964, 86, 5637; For preparation of
(+)-(S) p-toluenesulfinamide see: Davis, F. A.; Zhang, Y.;
Andemichael, Y.; Fang, T.; Fanelli, D. L.; Zhang, H.
J. Org. Chem. 1999, 64, 1403.
In summary, we have demonstrated the effectiveness of
the use of chiral sulfur compounds as chiral Lewis bases
in the enantioselective addition of allylzinc to aldehydes.
To the best of our knowledge, there are few precedents
dealing with the use of sulfoxides as chiral ligands in this
kind of reaction, with the reported enantioselectivity of
the process being very modest.15 The present methodol-
ogy provides the first example that utilizes chiral sulfox-
ides as ligands in a Lewis base catalyzed reaction.
Furthermore, the reaction was characterized by low cat-
alyst loading (0.5 mol %), high tolerance to certain alde-
hydes and short reaction time. Studies on the
mechanism of this reaction as well as the synthesis of
other chiral sulfoxides to further enhance the enantio-
selectivity are currently in progress.
11. Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
12. For reviews, see: (a) Denmark, S. E.; Almstead, N. G.
Allylation of Carbonyls: Methodology and Stereochemis-
try. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000; pp 299–402; (b) Denmark, S. E.;
Fu, J. Chem. Rev. 2003, 103, 2763.
13. Dennmark, S. E.; Fu, J. Chem. Commun. 2003, 167.
14. Representative procedure for the asymmetric allylation of
aldehydes: Zinc (100 mg; 1.5 mmol) in anhydrous THF was
activated successively with 1,2-dibromoethane and chloro-
trimethylsilane, which were stirred under argon for 5 min.
Allyl bromide (0.14 mL; 1.35 mmol) was added at À78 ꢁC
and the mixture was stirred for 10 min. Chiral ligand
(0.5 mol %) in THF was then added at À78 ꢁC and stirred
for 10 min, followed by aldehyde (1.2 mmol) addition at
À78 ꢁC. The reaction mixture was allowed to warm to
room temperature and was then quenched by the addition
of HCl (0.1 M). The mixture was then extracted with
AcOEt (2 · 10 mL) and the organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated in
vacuo. The crude product was purified by chromatography
using silica gel to yield the desired homoallylic alcohols.
15. Massa, A.; Malkov, A. V.; Kocˇovsky´, P.; Scettri, A.
Tetrahedron Lett. 2003, 44, 7179.
Acknowledgements
We gratefully acknowledge the financial support from
CNPq/PROFIX (54045/01-4), FACEPE and CAPES.
´
R.P.A.M. is grateful to Dr. Andre L. M. Porto (Univer-
sity of Sao Paulo) for his help in obtaining optical rota-
˜
tions. The authors also thank CNPq for their
Fellowships.