Stille coupling of stereochemically defined α- sulfonamidoorganostannanes

Article abstract of DOI:10.1021/ja044354s

Addition of tributylstannylmetallics to (R)-tert-butanesulfonimine derivatives of arylaldehydes provides α-sulfinamidostannanes with high (>98% de) diastereoselectivities. Oxidation of these compounds with m-CPBA gives α-sulfonamidostannanes which undergo Pd/Cu-catalyzed Stille-type couplings with benzoyl chloride. Best yields are achieved using the electron-rich tris(2,4,6-trimethoxyphenyl)phosphine as the ligand. Inversion of configuration at the benzylic carbon is observed. Copyright

Full text of DOI:10.1021/ja044354s

Published on Web 11/11/2004
Stille Coupling of Stereochemically Defined r-Sulfonamidoorganostannanes
Kevin W. Kells and J. Michael Chong*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry,
UniVersity of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received September 16, 2004; E-mail: jmchong@uwaterloo.ca
Table 1. Addition of Bu3SnM to tert-Butanesulfinimines
The Stille coupling of organostannanes has emerged as an im-
portant tool in modern organic synthesis.1 Many applications have
been documented, particularly with aryl and vinylstannanes. For
vinylstannanes, overall retention of configuration has been well
established. In contrast, there are relatively few reports where groups
with an sp3-carbon attached to the tin atom are employed2 and even
fewer reports where a chiral, nonracemic group is transferred from
an organostannane. In fact, the only stereochemical studies pub-
lished in this area are with an R-deuteriobenzylstannane, wherein
inversion of stereochemistry was observed,3 and with an R-ben-
zoyloxyorganostannane, where “ca. 98% retention of configuration”
was noted.4
The use of stereochemically defined R-aminostannanes in Stille
couplings could significantly enhance this synthetic methodology,
allowing access to a wide variety of enantiomerically pure amine
derivatives, such as R-amino acids, R-amino ketones, and aryl-
methylamines. It is known that R-aminostannanes can undergo
Sn-Li exchange with retention of configuration,5 but the stereo-
chemistry of Sn-Pd exchange (as in Stille couplings) is not known.
Although it has been stated that R-amino- and R-alkoxystannanes
undergo couplings with retention of configuration and with a citation
to Falck’s work,6 retention of stereochemistry was only demon-
strated for an R-alkoxyalkyl group. In the report by Falck and co-
workers, the only R-amino derivative examined was a (racemic)
phthalimidoalkyl-tributylstannane, which gave a modest (45%) yield
of product along with considerable amounts (28%) of competing
butyl transfer. Poor results in attempted Stille couplings of
aminostannanes Bu3SnCH2NRR′ have also been noted by Merck
researchers who made elegant use of Vedejs’ stannatranes7 to
efficiently transfer a CH2NRR′ unit.8 We now report that stereo-
chemically defined R-sulfonamidobenzylstannanes can be readily
prepared and undergo Stille couplings with acid chlorides with
essentially complete inversion of configuration.
We have previously shown that additions of Bu3SnLi to imines
derived from (R)- or (S)-tert-butanesulfinamide9 and aliphatic
aldehydes proceed with high diastereoselectivities and are an
efficient means of accessing stereochemically defined R-aminostan-
nanes.10 Since benzylic R-aminostannanes are much more likely
to participate efficiently in Stille couplings, we examined the
addition of tributylstannylmetallics to tert-butanesulfinimine deriva-
tives of aryl aldehydes. Addition of Bu3SnLi to benzaldehyde-
derived imine 1a gave adduct 2a as a single diastereomer (Table
1). Other sulfinimines with electron-donating groups (EDGs) also
reacted with Bu3SnLi with high diastereoselectivities (entries 2-4),
but substrates with electron-withdrawing groups (EWGs) gave
disappointing results (entries 5, 7, and 9). Fortunately, use of
Bu3SnZnEt2Li, a reagent we had previously shown to react with
high selectivities (and the same sense of diastereoselection as
Bu3SnLi) with aliphatic sulfinimines, restored the high selectivities
(entries 6, 8, and 10) observed with other substrates. The stereo-
entry
X
M
product
yielda
drb
1
2
3
4
5
6
7
8
9
H
p-Me
p-OMe
p-NMe2
p-Cl
Li
Li
Li
Li
Li
ZnEt2Li
Li
ZnEt2Li
Li
2a
2b
2c
2d
2e
2e
2f
2f
2g
2g
73
77
84
91
80
94
25
59
0c
>99:<1
>99:<1
>99:<1
>99:<1
73:27
>99:<1
50:50
>99:<1
p-Br
p-CF3
10
ZnEt2Li
80
>99:<1
a Isolated yields (%) of chromatographed products. b Determined by 1H/
13C NMR spectroscopy. The “>99:<1” denotes that signals for only one
diastereomer were observed. c Compound 1g was consumed, but only
unidentifiable products were observed.
chemistry of Bu3SnLi addition to alkyl tert-butanesulfinimines can
be rationalized by a six-membered chair transition-state model,9
and it is reasonable to assume that the same model is operative
here, especially as it has been shown that alkyl and aryl groups
behave similarly in related reactions with organometallics.11
The difference in results observed with Bu3SnLi and
Bu3SnZnEt2Li may be due to a change in the reaction mech-
anism. Perhaps Bu3SnLi reacts with substrates 1a-d via an ionic
mechanism, while with imines 1e-g (which possess EWGs),
competing single electron-transfer processes12 give rise to lower
selectivities (1e), no selectivity (1f), or side reactions (1g). With
Bu3SnZnEt2Li, reactions occur exclusively via an ionic pathway
so high diastereoselectivities are observed.
Attempted coupling of sulfinamides 2 with a variety of electro-
philes under Stille-type conditions proved to be fruitless. Fortu-
nately, oxidation of sulfinamides 2 could be readily accomplished
(mCPBA)13 in high yields to produce sulfonamides 3, which could
be coerced to participate in Stille-type couplings. From a synthetic
viewpoint, it is relevant that stereochemically defined aminostan-
nanes 3 can be easily (three steps from commercially available
materials) prepared and are essentially amines protected with a tert-
butanesulfonyl (Bus) group, a functionality previously shown to
be a useful protecting group that can be removed under acidic
conditions.14
Stannane 3a could be coupled with benzoyl chloride under
conditions similar to those used by Falck in his work with R-amino-
and R-alkoxystannanes.4 With Ph3P as the ligand, a respectable 66%
yield of 4a was observed (Table 2, entry 1).
9
15666
J. AM. CHEM. SOC. 2004, 126, 15666-15667
10.1021/ja044354s CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Stille-type Coupling of Sulfonamides 3 with Benzoyl
Scheme 1
Chloridea
entry
X
ligandb
product
yieldc
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
H
H
H
p-Me
p-OMe
p-OMe
p-Cl
p-Cl
p-Cl
p-Cl
p-CF3
Ph3P
(o-tol)3P
dppe
PA-Ph
TTMPP
TTMPP
Ph3P
TTMPP
Ph3P
(Fu)3P
Ph3As
TTMPP
TTMPP
4a
4a
4a
4a
4a
4b
4c
4c
4e
4e
4e
4e
4g
66
17
0
75
90
98
80
85
63
23
37
86
78
Other acid chlorides (e.g., p-ClC6H4C(O)Cl, 77%;
n-C3H7C(O)Cl, 42%; PhCHdCHC(O)Cl, 58%) could be coupled
with 3a to yield the expected ketones, albeit in lower (unopti-
mized) yields.
The demonstration that R-sulfonamidobenzylstannanes can be
easily prepared in high enantiomeric purity and can undergo Stille-
type couplings with benzoyl chloride to give the expected ketones
in high yields and with inversion of stereochemistry at the benzylic
carbon is of synthetic and mechanistic interest. Efforts to expand
the scope of this chemistry to other R-heteroatom-substituted
stannanes and electrophiles are underway.
a Reactions were carried out with 5 mol % Pd2(dba)3, 5-10 mol %
CuCN, and 20 mol % ligand. b Ligands dppe ) 1,2-bis(diphenylphosphi-
no)ethane, (o-tol)3P ) tri(o-tolyl)phosphine, (Fu)3P ) tri(2-furyl)phosphine,
TTMPP ) tris(2,4,6-trimethoxyphenyl)phosphine, and PA-Ph ) 1,3,5,7-
tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane (ref 15). c Isolated
yields (%) of chromatographed products.
Acknowledgment. We thank the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) for financial support,
as well as NSERC and the Ontario Ministry of Colleges and
Training for postgraduate scholarships (to K.W.K.). We are grateful
to Professor Capretta for a generous gift of their phosphaadamantane
ligand.
By varying the ligand, the yield of 4a could be increased to 90%
(Table 2, entry 5). With trialkylphosphines (e.g., n-Bu3P, t-Bu3P),
considerable decomposition of 3a was observed, and with the
chelating diphosphine 1,2-bis(diphenylphosphino)ethane (dppe),
imine 5 was isolated in high yield. Imine 5, likely the product of
a â-hydride elimination process,16 was also isolated from reactions
that gave lower yields of 4a.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652.
(2) Notable exceptions are symmetrical stannanes, such as Me4Sn where
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systems, such as benzyl and allylstannanes: Milstein, D.; Stille, J. K. J.
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3636.
Other R-sulfonamidostannanes, including those with EDGs or
EWGs on the aryl ring, also couple well under these reaction
conditions (Table 2, entries 5-13). The most effective ligand for
these Stille couplings is the highly basic tris(2,4,6-trimethoxy-
phenyl)phosphine (TTMPP), whereas many Stille couplings are best
performed using ligands of lower donicity, such as (2-furyl)3P and
Ph3As.17 This may be because the less basic ligands facilitate the
Sn-Pd transmetalation step but do not help suppress the competitive
â-hydride elimination observed here.
Analysis of the enantiomeric purity of the sulfonamido ketones
4 by HPLC on a chiral column (ChiralCel OD) showed >98% ee
in all cases. Thus, there was <1% loss of stereochemical integrity
in the conversion of 3 f 4.
To determine the stereochemical outcome of these coupling
reactions, a sample of (R)-4a was prepared from (R)-phenylglycine
(Scheme 1).18 Comparison (HPLC, ChiralCel OD) of ketone 4a
prepared via Stille coupling (and originally derived from sulfinimine
1a) with this material showed that they were enantiomers. Thus,
the Stille coupling of stannane 3a proceeds with inversion of
stereochemistry. This is consistent with an SE2-type mechanism
for the Sn-Pd transmetalation step, as originally proposed by Stille
for benzylstannanes.3
(6) See ref 1, p 27.
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(16) â-hydride elimination is a common side reaction in cross-coupling reactions
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(17) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595.
(18) Partial racemization (as expected for manipulations of phenylglycine) gave
4a of lower enantiopurity (∼90% ee by HPLC) than material prepared
from 3a (>98% ee). See Supporting Information for full details.
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