A novel asymmetric vinylogous tin-pummerer rearrangement

Article abstract of DOI:10.1021/ol0495725

Matrix presented. A new type of vinylogous tin-Pummerer rearrangement reaction was observed when benzyl tin derivatives containing a sulfinyl group at the ortho position were allowed to react with acyl chlorides or TPAA. The reaction is thought to proceed by nucleophilic attack of the leaving carboxylate at the γ-position of the conjugated thionium ion. The enantioselectivity (ee) of the reaction can reach values as high as 98%. The observed stereoselectivity is related to the nature of the solvent, the temperature employed, and the stability of the migrating carboxylate anion.

Full text of DOI:10.1021/ol0495725

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1757-1760
A Novel Asymmetric Vinylogous
Tin-Pummerer Rearrangement
,†
,‡
Jose´ Luis Garc´ıa Ruano,* Jose´ Aleman,† and Albert Padwa*
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain, and Deparment of Chemistry, Emory UniVersity,
Atlanta, Georgia 30322
joseluis.garcia.ruano@uam.es; chemap@emory.com
Received March 8, 2004
ABSTRACT
A new type of vinylogous tin-Pummerer rearrangement reaction was observed when benzyl tin derivatives containing a sulfinyl group at the
ortho position were allowed to react with acyl chlorides or TFAA. The reaction is thought to proceed by nucleophilic attack of the leaving
carboxylate at the γ-position of the conjugated thionium ion. The enantioselectivity (ee) of the reaction can reach values as high as 98%. The
observed stereoselectivity is related to the nature of the solvent, the temperature employed, and the stability of the migrating carboxylate
anion.
The Pummerer rearrangement has been widely studied and
has received considerable attention as a synthetically useful
process.1 The initial step of the reaction involves acylation
of the sulfoxide oxygen to form an acyloxysulfonium salt,
thereby converting this oxygen to a good leaving group.
Removal of a proton from the R-carbon with elimination of
the acyloxy group generates a thionium ion, which is trapped
by one of the nucleophilic species present in the reaction
medium. The intramolecular trapping of the R-acyl thionium
ions has been used for the synthesis of a variety of
heterocyclic ring systems.2 The related vinylogous Pummerer
reaction of vinylic sulfoxides also proceeds by an electro-
philic thionium ion intermediate formed by γ-proton loss
followed by sulfoxide S-O bond scission.3 The resulting
unsaturated thionium ion is then intercepted by a nucleophile
at the γ-position (Figure 1). The above reactions require the
presence of an R- or γ-hydrogen in order to allow the
formation of the thionium ion. Although the sila-Pummerer
rearrangement has also proven to be a synthetically useful
method,4 examples of the analogous tin-Pummerer reaction
are rare.5
During the course of our studies dealing with remote
stereoselective functionalization mediated by aryl sulfox-
ides,6,7 a novel example of this little studied reaction was
observed. As part of our general program dealing with chiral
sulfoxides, we had been investigating the coupling reaction
of the tin derivative 7 with acetyl chloride in the presence
of a either a palladium(0)8 or rhodium(I) catalyst.9 Under
† Universidad Auto´noma de Madrid.
(3) Kuethe, T.; Padwa, A. J. Org. Chem. 1998, 63, 4256.
(4) Block, E.; Aslam, M. Tetrahedron 1988, 44, 284 and references
therein.
‡ Emory University.
(1) (a) Pummerer, R. Chem Ber. 1909, 42, 2282. (b) DeLucchi, O.; Miotti,
U.; Modena, G. Organic Reactions; Paquette, L. A., Ed.; Wiley: 1991;
Chapter 3, pp 157-184. (c) Grierson, D. S.; Husson, H. P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 6, pp
909-947. (d) Kennedy, M.; McKervey, M. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 7, pp 193-
217.
(5) (a) Beddoes, R. L.; Macleod, D.; Moorcroft, D.; Queayle, P.; Zhao,
Y.; Davies, G. M. Tetrahedron Lett. 1992, 33, 417. (b) Pohmakotr, M.;
Sithikanchanakul, S. Tetrahedron Lett. 1989, 30, 6773.
(6) For reaction with carbonyl groups, see: Garc´ıa Ruano, J. L.; Aranda,
M.; Carren˜o, M. C.; Toledo, M. A. Angew. Chem., Int. Ed. 2000, 39, 2736.
(7) For reaction with imines, see: (a) Garc´ıa Ruano, J. L.; Alema´n, J.;
Soriano, J. F. Org. Lett. 2003, 5, 677. (b) Garcia Ruano, J. L.; Alema´n J.
Org. Lett. 2003, 5, 4513.
(2) (a) Padwa, A.; Gunn, D. E.; Osterhout, H. M. Synthesis 1997, 1353.
(b) Padwa, A.; Pure Appl. Chem. 2003, 75, 47.
10.1021/ol0495725 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/27/2004

Scheme 2
The results obtained for the reactions of the tin derivative
10 with a variety of different electrophiles are depicted in
Table 1. Different acyl chlorides (methyl, vinyl, benzyl, and
Figure 1. Mechanism of the Pummerer and Vinylogous Pummerer
reaction.
Table 1. Reactions of 10 with Different Electrophiles
the reported conditions for coupling we observed the
exclusive formation of the acetoxy derivative 9 instead of
the expected ketone 8 (Scheme 1). The formation of 9, which
Scheme 1
yield
entry
reagent
MeCOCl
CH2dCHCOCl
PhCH2COCl
PhCOCl
TFAA
TFAA
Ac2O
SOCl2
SOBr2
product (X)
9 (OCOMe)
(%)
1
2
3
4
5
6
7
8
9
61
72
78
67
72
76a
13 (OCOCHdCH2)
14 (OCOCH2Ph)
15 (OCOPh)
16 (OCOCF3)
16 (OCOCF3)
no reaction
is also observed in the absence of any catalyst, is the result
of the simultaneous oxidation at the benzylic position (γ with
respect to sulfur) with concomitant reduction at the sulfur
atom. In this communication, we report our results dealing
with this unprecedented vinylogous tin-Pummerer rearrange-
ment.
17 (Cl)
18 (Br)
85
81
a Solvent-free conditions.
The synthesis of the tin derivatives 7 and 10 were carried
out starting from sulfoxides 117a and 126 following a method
previously used to introduce various electrophilic groups at
the benzylic position.6 Thus, sulfoxides 11 and 12 were
treated with 1.2 equiv of LDA at -78 °C in THF. To the
resulting solution (purple color indicates formation of the
desired anion) was added 3 equiv of Bu3SnCl. Compound 7
was obtained in 90% yield (after purification), while 10 was
isolated in 82% yield as a mixture of epimers which could
easily be separated by silica gel chromatography (Scheme
2). The highest diastereomeric ratio (90:10) was obtained at
-78 °C (1 mmol scale). The stereoselectivity decreased
somewhat (80:20) when the reaction was carried out at the
10 mmol scale, and these latter conditions were used to obtain
the minor epimer. The relative configuration of both epimers
10 and 10′ has not been unequivocally established. Neverthe-
less, we assume the S configuration at the benzylic carbon
for the major epimer 10 (Scheme 2) on the basis of
stereochemical results that we have encountered with other
electrophiles in our earlier studies.6,7
phenyl) show similar behavior, furnishing acyloxy thioethers
9 and 13-16 in 60-80% isolated yield (entries 1-4). The
reactions are very clean, and only Bu3SnCl was detected in
addition to the acyloxy thioethers in the crude reaction
mixture. Better yields were obtained in reactions with SOCl2
and SOBr2 (entries 8 and 9), which afforded the chloro (17)
and bromo (18) derivatives.
By contrast, the reaction of 7 with Ac2O only resulted in
recovered starting material, even when the temperature was
increased (CH2Cl2 reflux, entry 7). However, the reaction
of 7 with TFAA did proceed smoothly, giving rise to
trifluoroacetate 16 in good yield (entry 5). We also studied
the reaction of 7 with TFAA in the absence of solvent, which
proceeded to give 16 in 76% yield (entry 6).
To rationalize the experimental results, we propose a four-
step reaction mechanism. Initially, the sulfinyl oxygen reacts
with the added electrophile (Ac2O is not reactive enough)
to afford the acyloxy (19) (entries 1-6) or the corresponding
halosulfinyloxy sulfonium salt (entries 8 and 9). The coun-
terion of these salts (i.e., halide or trifluoroacetate) acts as a
nucleophile in the second step and attacks the tin, producing
a benzyl carbanion (20). This reactive intermediate then
furnishes a thionium intermediate (21 or 22,10 Figure 2) by
(8) Labadie, J. W.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129.
(9) Shie, J. Y.; Lin, Y. C.; Wang, Y. J. Organomet. Chem. 1989, 3, 383
and references therein.
1758
Org. Lett., Vol. 6, No. 11, 2004

Table 2. Reaction of 10 with Different Electrophiles
yield
(%)b
ee
(%)c
entry
reagent
MeCOCl
MeCOCl
CH2dCH-COCl
PhCH2COCl
PhCOCl
TFAA
product (X)
1
2
3
4
5
6
7
8
9
23 (OCOMe)
23 (OCOMe)
24 (OCOCHdCH2)
25 (OCOCH2Ph)
26 (OCOPh)
27 (OCOCF3)
27 (OCOCF3)
28 (Cl)
73
79a
80
70
75
63
71a
70
71
>98
>98
66
81
40
2
TFAA
SOCl2
SOBr2
6
2
1
29 (Br)
a Solvent free conditions. b All reactions were carried out at room
temperature except entries 3 and 5, which were done at refluxing CH2Cl2.
c Entries 1-7 were determined from the Mosher ester and entries 8 and 9
by HPLC.
Figure 2. Mechanistic proposal for the reaction of 7 with various
acid chlorides.
the yield and stereoselectivity slightly increased (compare
entries 1 and 2 or 6 and 7). Reactions with SOX2 proceeded
with exceptionally low stereoselectivity (entries 8 and 9).
The stereochemical results outlined in Table 2 can be
explained by assuming the formation of an intimate ion pair
such as 32 (Figure 3) from compounds possessing the S
-
elimination of the RCO2 or X- group (resulting in the
-
extrusion of SO2 from XSO2 ). Steps 2 and 3 may or may
not occur simultaneously. The final step involves nucleophilic
addition of the acyloxy or halide ion onto the benzylic
γ-carbon of the intermediate, thereby restoring the aroma-
ticity of the system. The overall reaction can best be
considered as a vinylogous tin-Pummerer rearrangement.
We have also studied the behavior of the tin-derivative
10 under similar conditions in order to ascertain the stereo-
selectivity of the reaction as well as to extend the scope of
its synthetic applications. The results obtained are collected
in Table 2. All the reactions proceed rapidly at room
temperature (less than 15 min) and are instantaneous when
TFAA is used. The enantiomeric excess of compounds 23-
27 was established by reduction to the corresponding alcohol
with LiAlH4 and a subsequent transformation into its Mosher
ester.11 By means of this procedure, we were able to
demonstrate that the major (or exclusive) enantiomer formed
in these reactions possesses the R configuration. Enantiose-
lectivity for the halo-derivatives 28 and 29 was determined
by chiral HPLC (Chiralpak AD column).
Figure 3. Stereochemical reaction of 10 with acid chlorides.
The main feature of the results outlined in Table 2 centers
around the stereoselectivity of the tin-Pummerer rearrange-
ment. Interestingly, the enantioselectivity (ee) was found to
decrease when the stability of the carboxylate anion increases
configuration at sulfur. This transient species has the anion
occupying the pro-R face about the planar o-quinone methide
cation because the acyloxy group of precursors 30 or 31 is
oriented toward this face in its most stable conformation
around the C-S bond. Internal collapse of the intimate ion
pair affords the acyloxy derivative with the R configuration.
Separation of the ions will lead to the formation of the achiral
thionium intermediate 33, whose subsequent conversion into
both enantiomers would account for the incomplete stereo-
selectivity of many of these reactions. The low ee observed
for 28 and 29 is not unexpected since the departing halide
is not influenced by the proximal thionium ion, thus
precluding the formation of an intimate ion pair.
-
-
(i.e., ee for AcO- > PhCH2CO2 > CH2dCHCO2
>
-
PhCO2- > CF3CO2 ). When the reactions of 10 with AcCl
or TFAA were carried out in the absence of solvent, both
(10) Reactions involving the stereoselective formation of cyclobutanes
from precursors of 1,4-zwitterionic species have been widely reported
(see: Taylor, R. E.; Engelhardt, C. F.; Schmitt, M. J. Tetrahedron 2003,
59, 5623 and references therein). They are electronically similar to those
involving the direct transformation of 19 into 22 in just one step.
(11) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
Org. Lett., Vol. 6, No. 11, 2004
1759

in agreement with that expected from the stereochemical
proposal of Figure 3. A similar influence of the solvent can
be seen in the reactions of 10 with TFAA. In CH2Cl2 at room
temperature, essentially racemic 27 was obtained (entry 4),
whereas significant ee was observed at lower temperatures
(18% at -78 °C, entry 5) and by using a less polar solvent
(33% in CCl4 at room temperature, entry 6). The simulta-
neous use of an apolar solvent and low temperatures did not
improve the stereoselectivity (entry 7), probably a conse-
quence of the low reactivity (much longer reaction times are
required). The stereoselectivity of the reaction using 2-phe-
nylacetyl chloride (80% ee at room temperature in CH2Cl2,
entry 8) also increases by decreasing the temperature (94%
at -15 °C, entry 9). Reactions conducted in CCl4 did not
work (entry 10), even under refluxing conditions.
In summary, we have described herein the stereoselective
stannylation of benzylic positions mediated by sulfinyl
groups at the adjacent ortho position. The reaction of these
tin derivatives with acyl chlorides affording chiral benzyl
alcohols constitutes the first example of a novel vinylogous
tin-Pummerer reaction. The high stereoselectivity that can
be achieved with acetyl chloride allows for some interesting
synthetic perspectives in the synthesis of optically pure
benzyl alcohols. The influence of the reaction conditions and
the nature of the electrophile on the observed stereoselectivity
suggests that the reaction proceeds by an intimate ion pair
as a reaction intermediate. Further studies oriented toward
the intramolecular capture of the conjugated thionium ion
intermediate as well as a search for analogous reactions using
2-p-tolylsulfinyl alkylbenzenes are in progress and will be
reported at a later date.
Table 3. Influence of Solvent Polarity and Temperature on the
Stereoselective Rearrangement of Tin Derivative 10
enantiomeric ratio
entry
electrophile
temp
solvent
R:S
1
2
3
4
5
MeCOCl
MeCOCl
MeCOCl
TFAA
TFAA
TFAA
reflux
rt
rt
rt
-78°C
rt
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CCl4
97:3
>99:1
72:28
51:49
59:41
6
67:33
7
8
9
10
TFAA
-40°C
rt
-15°C
rt
CCl4
64:36
90:10
97:3
BnCOCl
BnCOCl
BnCOCl
CH2Cl2
CH2Cl2
CCl4
no reaction
According to the above proposal, those factors which
control the shift of the equilibrium between species 32 and
33 will be responsible for the observed enantioselectivity.
Species 32 should be favored with the less stable carboxylates
(i.e., higher density of charge and therefore higher electro-
static attraction with the cation). Factors that disperse the
charge at the anion will favor dissociation of the intimate
ion pair (electrostatic attraction will be lower).
To provide some support for this proposal, we have studied
the influence of different factors that affect the equilibrium
between species 32 and 33, such as the polarity of the solvent
as well as the temperature. Polar solvents would be expected
to favor the separate ion pair and therefore would decrease
the overall stereoselectivity.
The results obtained from these studies are depicted in
Table 3. The reaction of 10 with acetyl chloride, which
normally proceeds with complete control of stereoselectivity
at room temperature, was found to result in a slight decrease
in ee by increasing the temperature (compare entries 1 and
2). In contrast, when CH3CN was used instead of CH2Cl2 as
the solvent, the ee of 23 was strongly diminished (entry 3),
Acknowledgment. J.L.G.R. thanks the Spanish Govern-
ment (Grants BQU2003-04012 and PR2003-0025) and A.P.
thanks the National Science Foundation (Grant CHE-
0132651) for financial support. J.A. thanks the Spanish
Ministerio de Ciencia y Tecnolog´ıa for a predoctoral fel-
lowship.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 7, 10, 13-
19, and 23-29. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0495725
1760
Org. Lett., Vol. 6, No. 11, 2004