Regio- and stereoselective copper-catalyzed carbozincation reactions of alkynyl sulfoximines and sulfones

Article abstract of DOI:10.1021/ol070070b

Stereochemically pure polysubstituted vinyl sulfoximines and sulfones are easily prepared by a copper-catalyzed syn carbozincation reaction of the corresponding alkynyl derivatives.

Full text of DOI:10.1021/ol070070b

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1259-1261
Regio- and Stereoselective
Copper-Catalyzed Carbozincation
Reactions of Alkynyl Sulfoximines and
Sulfones
Genia Sklute,† Carsten Bolm,‡ and Ilan Marek*,†
The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry
and The Lise Meitner-MinerVa Center for Computational Quantum Chemistry,
Technion-Israel Institute of Technology, Haifa 32 000, Israel
chilanm@tx.technion.ac.il
Received January 10, 2007 (Revised Manuscript Received March 4, 2007)
ABSTRACT
Stereochemically pure polysubstituted vinyl sulfoximines and sulfones are easily prepared by a copper-catalyzed syn carbozincation reaction
of the corresponding alkynyl derivatives.
Nonracemic sulfoximines having a stereogenic sulfur atom
are well-known in asymmetric synthesis.1 Particularly, vinyl
sulfoximines are an interesting class of compounds, which
were used in a large variety of asymmetric transformations
such as conjugate additions1b,2 and pericyclic reactions3 and
as precursors for allylic sulfoximines.4
E-Substituted vinyl sulfoximines are easily prepared either
by an “in situ Peterson” reaction5 (Scheme 1, path A) or via
Scheme 1. General Preparation of E-Substituted Vinyl
Sulfoximines
† Technion-Israel Institute of Technology.
‡ Institute of Organic Chemistry, RWTH Aachen University, Landoltweg
1, D-52056, Germany.
(1) (a) For recent reviews on the use of sulfoximines in asymmetric
catalysis, see: (a) Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482. (b)
Harmata, M. Chemtracts 2003, 16, 660. (c) For a general overview on the
chemistry of sulfoximines, see: Reggelin, M.; Zur, C. Synthesis 2000, 1.
(2) (a) Pyne, S. G. J. Org. Chem. 1986, 51, 81. (b) Pyne, S. G.
Tetrahedron Lett. 1986, 27, 1691. (c) Annunziata, R.; Cinquini, M. J. Chem.
Soc., Perkin Trans. 1 1979, 1684. (d) Pyne, S. G. J. Chem. Soc., Chem.
Commun. 1986, 1686.
(3) (a) David, D. M.; Bakavoli, M.; Pyne, S. G.; Skelton, B. W.; White,
A. H. Tetrahedron 1995, 51, 12393. (b) Craig, D.; Geach, N. J. Tetrahe-
dron: Asymmetry 1991, 2, 1177. (c) Glass, R. S.; Reineke, K.; Shankli, M.
J. Org. Chem. 1984, 49, 1527. (d) Craig, D.; Geach, N. J.; Pearson, C. J.;
Slawin, A. M. Z.; White, A. J. P.; Williams, D. J. Tetrahedron 1995, 51,
6071.
(4) (a) Erdelmeier, I.; Gais, H.-J.; Lindner, H. J. Angew. Chem., Int. Ed.
Engl. 1986, 25, 935. (b) Gu¨nther, M.; Gais, H.-J. J. Org. Chem. 2003, 68,
8037. (c) Schleusner, M.; Gais, H.-J.; Koep, S.; Raabe, G. J. Am. Chem.
Soc. 2002, 124, 7789. (d) Koep, S.; Gais, H.-J.; Raabe, G. J. Am. Chem.
Soc. 2003, 125, 13243. (e) Tiwari, S. K.; Gais, H.-J.; Lindernmaier, A.;
Babu, G. S.; Raabe, G.; Reddy, L. R.; Ko¨hler, F.; Gu¨nter, M.; Koep, S.;
Iska, V. B. R. J. Am. Chem. Soc. 2006, 128, 7360.
metalated hydroxyphosphonate derivatives6 (Scheme 1, path
B). In both cases, yields and E-selectivities were excellent
(80% yield, >92% E). Besides these two protocols, few more
preparations of E-vinyl-substituted sulfoximines, relying on
hydroxyalkylation-elimination sequences of metalated alkyl
sulfoximines, were also reported.7 Surprisingly, straightfor-
(5) Erdelmeier, I.; Gais, H. J. Tetrahedron Lett. 1985, 26, 4359.
(6) Craig, D.; Geach, N. J. Synlett 1992, 299.
10.1021/ol070070b CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/10/2007

ward routes to stereodefined R,â,â′-trisubstituted vinyl
sulfoximines of general structure 1 remain unknown. In this
communication, we would like to report our preliminary
results for an easy preparation of stereodefined polysubsti-
tuted vinylsulfoximine derivatives 1.
Table 1. Carbometalation Reaction of Alkynyl Sulfoximine 3a
temp (°C),
time (h)
Z/E
yield
(%)d
entry
EtM
solvent
ratioe
1
2
3
4
5
6
7
EtCu
THF
-40, 4
-40, 4
-70, 1
-70, 0.5
-50, 1
-60, 0.5
0, 3
6:1
2:1
4:1
1:1
3:1
2:1
1:1
80
70
72
71
90
85
50
EtCu
Et2O
Our retrosynthetic analysis for the preparation of 1 shows
that it should be easily prepared by a regiospecific syn
bisalkylation of substituents R1 and R2 on the triple bond of
alkynyl sulfoximines 3 (Scheme 1, path C). Accordingly, a
regio- and stereoselective carbometalation reaction of 3,
followed by trapping the resulting vinylic organometallic 2
with an electrophile R2-X, should be the key reaction for
the preparation of tetrasubstituted alkenyl derivatives 1.
Among all the possible candidates for the carbometalation
reactions of heterosubstituted alkynes,8 organocopper deriva-
tives are usually the best candidates9 because organocopper
species are known for their high stereo- and chemoselectivity,
which enable them to add smoothly to a large variety of
alkynes with high tolerance to many functional groups.10
However, sulfoximines can be taken as the aza-analogues
of sulfones, and the literature shows that the carbocupration
of alkynyl sulfones generally leads to two isomers in a
variable ratio.11 The carbometalation reaction of alkynyl
sulfoximines 3 was investigated in detail. Our starting
material was easily obtained in high yield12 by reaction of
[N-(p-tolylsulfinyl)imino]phenyliodinane (PhIdNTs)13 on
alkynyl sulfoxide in the presence of a catalytic amount of a
copper(II) salt. This imination is stereospecific and occurs
with retention of configuration at the sulfur atom.14 We
initially started our investigation by the classical carbocu-
pration reaction of 3a (Scheme 2 and Table 1). When
EtCua
THF
EtCua
Et2O
EtCua
THF/NMPb
THF
Et2Cu, MgBrc
RMgBr, CuI
(10 mol %)
Et2Zn, CuI
(10 mol %)
Et2Zn, CuI
(10 mol %)
THF
8
9
THF
Et2O
0, 2
100:0
100:0
82
80
rt, 6
a The reaction was performed with an excess of CuBr11a (CuBr/EtMgBr
) 3:1). b THF/NMP ) 3:1. c The structure reflects the stoichiometry rather
than the real organometallic species. d Yield determined after purification
by chromatography on silica gel. e Ratio determined by 1H NMR spectros-
copy of the crude mixture.
(Table 1, entry 1). The formation of these two isomers is
indeed reminiscent of the carbocupration of acetylenic
sulfones.11
When the same reaction was performed in a less polar
solvent such as Et2O, the reaction still proceeded but in a
2:1 ratio (Table 1, entry 2). When organocopper (in the
presence of excess copper salt,11a,15 in THF, Et2O, or a
mixture of THF and NMP; Table 1, entries 3, 4, and 5,
respectively), alkyl cuprate (Table 1, entry 6), or a copper-
catalyzed ethylmagnesiation reaction (Table 1, entry 7) was
used, the stereoselectivity was not improved. The two
isomers result formally from a syn and anti addition of the
organocopper reagent on the triple bond although a subse-
quent isomerization of the resulting sp2 organocopper deriva-
tive (2a into 2b) cannot be excluded.
Careful analyses of chiral HPLC of racemic and enan-
tioenriched vinyl sulfoximines show that the sulfoximine unit
is not racemized in this isomerization process. Only the
copper-catalyzed carbozincation16 reaction led to a single
stereoisomer via a syn addition under mild conditions in
either THF or Et2O (Table 1, entries 8 and 9, respectively).
The scope of the reaction is broad in terms of reactive
organozinc species which can be used (Scheme 3 and Table
2).
Scheme 2. Carbometalation Reaction of Alkynyl Sulfoximine
3
Copper-catalyzed carbozincation reaction proceeds simi-
larly when dialkylzinc (Table 2, entry 1) or alkylzinc halide
was used, prepared either from dialkylzinc and 1 equiv of
iodine (Table 1, entry 2) or by insertion of zinc dust into
ethylcopper (prepared from EtMgBr and CuI) was added to
alkynyl sulfoximine 3a in THF at -40 °C, the carbocupration
reaction occurred, but two isomers were formed in a 6:1 ratio
(11) (a) Meijer, J.; Vermeer, P. Recl. TraV. Chim. Pays-Bas 1975, 94,
14. (b) Fiandanese, V.; Marchese, G.; Naso, F. Tetrahedron Lett. 1978, 19,
5131. (c) Eisch, J. J.; Behrooz, M.; Galle, J. E. Tetrahedron Lett. 1984, 25,
4851. (d) Eisch, J. J.; Behrooz, M.; Dua, S. K. J. Organomet. Chem. 1985,
285, 121. (e) Xie, M.; Huang, X. Synlett 2003, 477. (f) Xie, M.; Wang, J.;
Gu, X.; Sun, Y.; Wang, S. Org. Lett. 2006, 8, 431.
(12) (a) Lacote, E.; Amatore, M.; Fensterbank, L.; Malacria, M. Synlett
2002, 116. (b) For alternative sulfoxide imination procedures, see: Garc`ıa-
Manchen˜o, O.; Bolm, C. Org. Lett. 2006, 8, 2349 and references therein.
(13) Taylor, S.; Gullick, J.; McMorn, P.; Bethell, D.; Bulman Page, P.
C.; Hancock, F. E.; King, F.; Hutchings, G. J. Top. Catal. 2003, 24, 43.
(14) See experimental procedure for HPLC or GC analyses using chiral
stationary phases.
(7) (a) Craig, D.; Geach, N. J. Synlett 1993, 481. (b) Bailey, P. L.; Clegg,
W.; Jackson, R. F. W.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans. 1 1993,
343. (c) Paley, R. S.; Snow, S. R. Tetrahedron Lett. 1990, 31, 5853.
(8) For recent reviews on carbometalation, see: (a) Marek, I.; Chinkov,
N.; Banon-Tene, D. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; p 395.
(b) Banon-Tenne, D.; Marek, I. In Carbometalation Reactions of Zinc
Enolate Derivatives. In Transition Metals for Organic Synthesis, 2nd ed.;
Beller, M., Bolm, C., Eds.; Wiley-VCH: New York, 2004; p 563. (c) Marek,
I. J. Chem. Soc., Perkin Trans. 1 1999, 535.
(9) (a) Chechik-Lankin, H.; Marek, I. Org. Lett. 2003, 5, 5087. (b)
Chechik-Lankin, H.; Livshin, S.; Marek, I. Synlett 2005, 2098.
(10) Normant, J. F.; Alexakis, A. Synthesis 1981, 841.
(15) Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry 1990, 1, 477.
(16) Maezaki, N.; Sawamoto, H.; Yoshigami, R.; Suzuki, T.; Tanaka,
T. Org. Lett. 2003, 5, 1345.
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Org. Lett., Vol. 9, No. 7, 2007

dienyl sulfoximines in 72% yield as unique stereoisomer
(Table 2, entry 14). In contrast, the addition of alkynylzinc
species to alkynylsulfoximine is sluggish and only 18% of
the isolated product has been obtained (Table 2, entry 15).
The unique stereochemistry of the product was determined
by NOE measurement of 1d and is easily rationalized by a
copper-catalyzed syn addition of the organozinc species
across the triple bond of the alkynyl sulfoximine.
Scheme 3. Copper-Catalyzed Carbozincation Reaction of
Alkynyl Sulfoximines
Having in hand an easy and reproducible protocol for the
carbometalation reaction of alkynyl sulfoximines, we decided
to investigate also the case of alkynyl sulfones, known to
give two isomers by carbocupration reactions.11 We were
pleased to observe that alkynyl sulfones also reacted cleanly
with the copper-catalyzed addition of alkylzinc derivatives
to lead to a single regio- and stereoisomer in good isolated
yields as described in Table 3. Primary and secondary
the carbon-iodine bond (Table 2, entry 3). Similarly, the
copper-catalyzed carbozincation can be performed from a
Grignard reagent or an alkyllithium species if these latters
Table 2. Copper-Catalyzed Carbozincation Reaction
yield
entry
R
R1ZnY
E-X
HCl
E
product
(%)a
1
2
3a Et2Zn
H
1a
1a
1b
1a
1c
1d
1e
1f
82
90
55
75
80
83
85
92
80
90
55
78
65
72
Table 3. Copper-Catalyzed Carbozincation of Alkynyl
Sulfones
3a EtZnIb
3a OctZnIc
3a EtZnBrd
3a i-PrZnBrd
3a Me2Zn
3a PhZnBrd
3b Bu2Zne
3b BuZnBrf
3b Et2Zn
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
H
H
H
H
H
H
H
H
H
H
I
3
4
5
6
7
8
9
1f
yield
10
11
12
13
14
1g
1h
1i
entry
RZnX
E-X
HCl
E
product
(%)a
3a MeOCO(CH2)3ZnIc HCl
3a Et2Zn
3a Et2Zn
3a
I2
1
2
3
4
5
6
Bu2Zn
Et2Zn
H
5a
5b
5c
5d
5e
5f
70
72
92
55
65
60
allylBr allyl
1j
HCl
HCl
HCl
I2
H
HCl
H
1k
i-PrZnBrb
MeOCO(CH2)3ZnIc
Et2Zn
H
H
I
15
3a Hex-CC-ZnBrf
HCl
H
1l
18
Et2Zn
allylBr
allyl
a
Yields determined after purification by chromatography on silica gel.
b Prepared from Et2Zn and I2. c Prepared from the corresponding alkyl iodide
a
Yields determined after purification by chromatography on silica gel.
b Generated from the corresponding Grignard reagent and ZnBr2. c Prepared
from the corresponding alkyl iodide and zinc dust.
d
and zinc dust. Generated from the corresponding Grignard reagent and
e
f
ZnBr2. In the presence of CuCN‚2LiCl, 10 mol %. Prepared from the
g
corresponding alkyllithium and ZnBr2. Prepared from the corresponding
vinyl iodide followed by a iodine-lithium exchange and transmetalation
with ZnBr2.
functionalized derivatives react regio- and stereoselectively
with alkynyl sulfones.
In conclusion, polysubstituted vinyl sulfoximines and
sulfones were easily prepared as unique isomers by totally
regio- and stereoselective copper-catalyzed carbozincation
reactions. The addition is syn, and the resulting sp2 organo-
metallic can easily react with classical electrophiles. Several
applications of this new class of compounds is now underway
in our laboratory.
are transmetalated into an organozinc species (Table 1, entries
4 and 9, respectively).
Therefore, most of the classical methods for the preparation
of alkylzinc halide derivatives17 were tested (with different
associated salts), and all of them led to the carbometalation
reaction of alkynylsulfoximines in very good yields. The
nature of the alkyl groups can be extended to secondary alkyl
groups (Table 2, entry 5) as well as to the more sluggish
methyl and aryl groups (Table 2, entries 6 and 7). Even
functionalized alkylzinc iodides undergo the copper-catalyzed
carbozincation reaction (Table 2, entry 11).17 The formation
of a discrete organometallic species was checked by iodi-
nolysis and allylation as depicted in Table 2, entries 12 and
13 (formation of 1i and 1j, respectively). The allylation
reaction implies that the copper salt is used not only as a
catalyst for the carbozincation reaction but also for the
reaction with electrophiles. The E-vinylzinc species, gener-
ated by an iodine-lithium exchange followed by a trans-
metalation reaction with ZnBr2, undergoes the copper-
catalyzed carbozincation to lead to the corresponding (E,E)-
Acknowledgment. This research was supported by a
grant from the G.I.F., the German-Israeli Foundation for
scientific research and development (I-871-62.5/2005), by
the Israel Science Foundation administrated by the Israel
Academy of Sciences and Humanities (459/04), and by the
Fund for the promotion of research at the Technion. I.M. is
the holder of the Sir Michael and Lady Sobell Academic
Chair.
Supporting Information Available: Experimental pro-
1
cedures with a description of H and 13C NMR data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117.
Org. Lett., Vol. 9, No. 7, 2007
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