Highly stereoselective vinylogous pummerer reaction mediated by Me 3SiX

Article abstract of DOI:10.1021/ol048054r

(Chemical Equation Presented) A highly stereoselective vinylogous Pummerer rearrangement involving 1,4-migration of the sulfinyl oxygen atom occurs when ortho-sulfinyl benzyl carbanions are treated with trimethylsilyl halides. The reaction proceeds in goo

Full text of DOI:10.1021/ol048054r

ORGANIC
LETTERS
2005
Vol. 7, No. 1
19-22
Highly Stereoselective Vinylogous
Pummerer Reaction Mediated by Me3SiX
Jose L. Garc´ıa Ruano,*,† Jose´ Alema´n,† M. Teresa Aranda,†
Mar´ıa J. Are´valo,‡ and Albert Padwa*,‡
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049-Madrid, Spain, and Department of Chemistry, Emory UniVersity,
Atlanta, Georgia 30322
joseluis.garcia.ruano@uam.es; chemap@emory.edu
Received September 24, 2004
ABSTRACT
A highly stereoselective vinylogous Pummerer rearrangement involving 1,4-migration of the sulfinyl oxygen atom occurs when ortho-sulfinyl
benzyl carbanions are treated with trimethylsilyl halides. The reaction proceeds in good yield and affords optically pure benzyl alcohols with
extremely high enantioselectivity (ee > 98%).
Since the initial report in 1909,1 the Pummerer reaction has
established itself as a very useful method for the preparation
of R-substituted sulfides. The reaction has been widely
studied and has received considerable attention as a valuable
synthetic process.2 Pummerer thionium ions are generally
formed by treating a sulfoxide bearing an R-hydrogen with
acetic anhydride.3 The finding that thionium ions may serve
as electrophiles in electrophilic substitution chemistry has
greatly extended the synthetic range of the Pummerer
reaction.4 Thus, both inter- and intramolecular versions of
the process have been used to prepare a wide assortment of
compounds.5 Currently, Pummerer-based transformations are
finding widespread application in carbo- and heterocyclic
synthesis by reaction of the initially generated thionium ion
with internally disposed nucleophiles.6
The related vinylogous Pummerer reaction of vinylic
sulfoxides also proceeds by an electrophilic thionium ion
intermediate formed by γ-proton loss followed by sulfoxide
S-O bond scission.7,8 The unsaturated thionium ion is then
intercepted by a nucleophile at the γ-position. Recently, our
two research groups discovered a new type of vinylogous
tin-Pummerer rearrangement that occurs with benzyl-tin
derivatives such as 1 that possess a sulfinyl group at the ortho
position of the aromatic ring.9 When treated with an acyl
chloride, the reaction proceeds by a halide-induced cleavage
of the Sn-C bond followed by nucleophilic attack of the
leaving carboxylate at the γ-position of the conjugated
† Universidad Auto´noma de Madrid.
‡ Emory University.
(1) Pummerer, R. Chem. Ber. 1909, 42, 2282.
(2) (a) De Lucchi, O.; Miotti, U.; Modena, G. In Organic Reactions;
Paquette, L. A., Ed.; Wiley: 1991; Chapter 3, p 157. (b) Grierson, D. S.;
Husson, H. P. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 6, p 909. (c) Kennedy, M.; McKervey, M.
A. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon:
Oxford, 1991; Vol. 7, p 193.
(5) (a) Padwa, A. Phosphorous, Sulfur, Silicon 1999, 153, 23. (b) Padwa,
A.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. J. Braz. Chem. Soc. 2001, 12,
571. (c) Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M.
Synlett 2002, 851.
(3) (a) Padwa, A.; Gunn, D. E.; Osterhout, H. M. Synthesis 1997, 1353.
(b) Padwa, A. Pure Appl. Chem. 2003, 75, 47.
(6) Bur, S. K.; Padwa, A. Chem. ReV. 2004, 104, 2401.
(7) Leading references to vinylogous Pummerer reactions can be found
in: (a) Padwa, A.; Kuethe, J. T. J. Org. Chem. 1998, 63, 4256. (b) Marino,
J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc. 1992, 114, 5566.
(8) For a new variant of the vinylogous Pummerer reaction, see: (a)
Feldman, K. S.; Vidulova, D. B. Org. Lett. 2004, 6, 1869. (b) Feldman, K.
S.; Karatjas, A. G. Org. Lett. 2004, 6, 2849.
(4) (a) Russell, G. A.; Mikol, G. J. In Mechanisms of Molecular
Migration; Thyagaragan, B. S., Ed.; Wiley: New York, 1968; Vol. 1, p
157. (b) Oae, S.; Numata, T. The Pummerer Type of Reactions. In Isotopes
in Organic Chemistry; Buncel, E., Lee, C. E., Eds.; Elsevier: New York,
1980; Vol. 5, Chapter 2. (c) Marino, J. P. In Topics in Sulfur Chemistry;
Senning, A., Ed.; George Thieme: Stuttgart, Germany, 1976; Vol. 1, p 1.
(9) Garc´ıa Ruano, J. L.; Alema´n, J.; Padwa, A. Org. Lett. 2004, 6, 1757.
10.1021/ol048054r CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/14/2004

occur with high stereoselectivity. In this communication, we
report results showing that optically pure benzylic alcohols
can be obtained with >98% enantioselectivity when ortho-
sulfinyl-substituted benzyl carbanions are treated with tri-
methylsilyl halides.
Scheme 1
The first model system we examined focused on the simple
sulfoxides 8 (R1 ) H) and 9 (R1 ) Me) (Table 1). The initial
Table 1. Reactions of 8 and 9 with Different Electrophiles
thionium ion (Scheme 1).10 Our continuing interest in this
reaction derives from the complete stereoselectivity observed
in the migration of the RCO2- group, thereby permitting the
synthesis of enantiomerically pure benzyl alcohols. Efficient
asymmetric syntheses of benzylic alcohols are of consider-
able interest because of their importance in biological systems
and their usefulness as chiral building blocks in organic
synthesis.11 The main drawback of the vinylogous tin-
Pummerer sequence shown in Scheme 1 is the need to
prepare the toxic benzyl tin derivative 1 in a diastereomeri-
cally pure form. We reasoned that generation of the key
intermediate 3 could also be accomplished by a simple
deprotonation at the benzylic position of an oxysulfonium
salt (i.e., 7) (Scheme 2). This modified reaction sequence
n value
in (O)n
entry
R1
X
product (R2)
yield
ee
1
2
3
4
5
6
7
8
9
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Cl
1
1
1
1
0
0
0
0
0
0
0
10 (TMS)
10 (TMS)
10 (TMS)
10 (TMS)
11 (OTMS)
11 (OTMS)
11 (OTMS)
11 (OTMS)
11 (OTMS)
11 (OTMS)
11 (OTMS)
43
57a
63
48
65
Cl
Br
I
Cl
Br
I
OTf
Cl
Cl
Cl
>98
>98
40
<10
<10
70a
30
>98
>98
10b
11c
a TMSCl redistilled. b Solvent: Et2O. c Solvent: CH2Cl2.
trial experiments involved treating 8 with several different
anhydrides. However, only (Tf)2O was capable of forming
the acyloxysulfonium salt (i.e., 7), but the TfO anion was
not basic enough to generate the benzylic carbanion 3. When
stronger bases were added to the salt, a complex reaction
mixture was obtained. Considering our lack of success using
these conditions, we decided to invert the order of addition
of the reagents. The use of LDA as a base is known to
efficiently lead to ortho-sulfinyl-substituted benzyl carban-
ions that can act as nucleophiles in many different reaction
pathways.12 The resulting benzyl carbanions are easily
recognized by the intense purple coloration of the solution.
The critical problem was to identify a proper electrophile
that would regioselectively react at the sulfinyl oxygen rather
than at the anionic carbon atom. We noted that the addition
of acyl halides13 resulted in a complex mixture of products.
After trying various electrophiles, we found that trimethyl-
Scheme 2
would allow for the synthesis of optically pure benzylic
alcohols provided one could find the necessary experimental
conditions to permit the 1,4-migration of the OE group to
(11) For some leading references, see: (a) Ponzo, V. L.; Kaufman, T.
S. Synlett 2002, 1128. (b) Hillier, M. C.; Desrosiers, J. N.; Marcoux, J. F.;
Grabowski, E. J. J. Org. Lett. 2004, 6, 573. (c) Nakamura, S.; Oda, M.;
Yasuda, H.; Toru, T. Tetrahedron 2001, 57, 8459.
(12) For reaction with carbonyl groups, see: (a) Garc´ıa Ruano, J. L.;
Aranda, M.; Carren˜o, M. C.; Toledo, M. A. Angew. Chem., Int. Ed. 2000,
39, 2736. For reaction with imines, see: (b) Garc´ıa Ruano, J. L.; Alema´n,
J.; Soriano, J. F. Org. Lett. 2003, 5, 677. (c) Garc´ıa Ruano, J. L.; Alema´n,
J. Org. Lett. 2003, 5, 4513.
(10) For some examples of the tin-Pummerer reaction, see: (a) Beddoes,
R. L.; MacLeod, D.; Moorcroft, D.; Quayle, P.; Zhao, Y.; Davies, G. M.
Tetrahedron Lett. 1992, 33, 417. (b) Pohmakotr, M.; Sithikanchanakul, S.
Tetrahedron Lett. 1989, 30, 6773.
20
Org. Lett., Vol. 7, No. 1, 2005

silylbromide produced the silylated product 10 in good yield
(63%). Other unidentifiable products were produced when
TMSCl or TMSI was used.14 The above result suggests that
the reactivity of the benzyl carbanion derived from 8 is higher
at the carbon atom than at the sulfinyl oxygen position.
Table 2. Alkylation Reactions of Compound 8
Most interestingly, when the closely related benzyl sul-
foxide 9 (R1 ) Me) was treated under an identical set of
conditions, trimethylsilyloxy-thioether 11 was the major
product isolated (entry 5, Table 1) and is the result of a
vinylogous Pummerer rearrangement.15 The exclusive forma-
tion of 11 suggests that the relative reactivity of the two
nucleophilic centers (carbon and oxygen) in the benzyl
carbanion derived from 9 is inverted with respect to the
situation encountered with the carbanion derived from 8. In
the case of sulfoxide 9, the sulfinyl oxygen atom corresponds
to the most reactive site of the sulfinyl benzyl carbanion.
Notably, the enantiomeric purity of the resulting product 11
has the remarkably high value of 98% ee. This value was
determined by cleavage of the Si-O bond using Bu4NF
followed by an examination of the NMR spectrum of the
Mosher ester derived from the corresponding alcohol.16 In
an attempt to improve the overall yield of the reaction, we
evaluated the role of different parameters such as concentra-
tion, solvent, and the nature of the silylated electrophile
(Table 1). TMSCl was found to be the most efficient
electrophile (entry 5), whereas TMSI and TMSOTF gave
much lower yields of product (entries 7 and 8). The optimal
conditions consisted of using redistilled TMSCl at a con-
centration of 0.1 M and at -78 °C (entry 9). Lower or higher
concentrations resulted in a diminished yield.
entry
alkyl halide
methyl iodide
ethyl bromide
ethyl iodide
benzyl bromide
2-phenylethyl bromide PhCH2CH2 (14)
2-phenylethyl iodide
2-(3,4-dimethoxy-
phenyl)ethyliodide
product (R)
CH3 (9)
CH3CH2 (12)
CH3CH2 (12)
PhCH2 (13)
yield (%)
1
2
3
4
5
6
7
98
85
92
93
59
81
85
PhCH2CH2 (14)
(3,4-dimethoxy-
phenyl)CH2CH2
(15)
starting material
starting material
CH2CHdCH2 (16)
CH2OMe (17)
8
9
2-bromopropane
1-bromoethylbenzene
allyl bromide
10
11
12
13
14
82
94
15
55
51
ICH2OMe
BrCH2CH2OTIPS
ICH2CH2OTIPS
ICH2CH2NPhta
CH2CH2OTIPS (18)
CH2CH2OTIPS (18)
CH2CH2NPht (19)
a Pht ) phthalimide.
bromides. It was not possible to carry out an alkylation using
secondary halides due to a competitive elimination.17 Inter-
estingly, when 2-phenethyl iodide or bromide was used, the
substitution product 14 (entry 5/6) was obtained and only
trace quantities of styrene were detected in the crude reaction
mixture.18 The last five entries in Table 2 demonstrate the
flexibility of the alkylation when more complicated halides
are used as the electrophiles.
With these sulfinyl compounds in hand, we proceeded to
investigate their vinylogous Pummerer behavior. Using the
conditions described in Table 1, the reactions were found to
occur rapidly and furnished a wide variety of benzylic
alcohols (Table 3) in yields ranging between 50 and 70%
for the three-step sequence. Complete stereoselectivity (ee
> 98%) was observed in all of the cases examined. The
presence of a heteroatom on the side chain was found to
influence the reaction course. Thus, 2-p-tolylsulfinyl styrene
(27) was the only product obtained starting from 17 (entry
8), thereby indicating that elimination of the methoxy group
is preferred over the rearrangement. In contrast, the homolo-
gous compound 18 afforded diol 26 in 56% yield under the
reaction conditions. Finally, the more heavily substituted
amide 19 failed to undergo the reaction.19
To further evaluate the scope and generality of the
asymmetric vinylogous Pummerer reaction, it became neces-
sary to prepare several more highly substituted sulfinyl
derivatives (i.e., 12-19). The method previously used to
synthesize 812a and 912b was based on the sulfinylation of
the Grignard derivatives derived from 2-bromotoluene and
2-bromoethylbenzene. This procedure is severely limited
using the more highly substituted bromides due to the
unavailability of the starting materials. Instead, we opted to
carry out a base-induced alkylation of ortho-sulfinyl toluene
8 that proceeded in high yield (Table 2). Thus, the reaction
of 8 with LDA in THF at -78 °C furnished the expected
anion, which readily reacted with various halides. The
reaction proceeded best when alkyl iodides were employed,
although the yield was respectable with the corresponding
(13) Garc´ıa Ruano, J. L.; Alema´n, J.; Aranda, M. T.; Ferna´ndez-Iba´n˜ez,
M. A.; Rodr´ıguez-Ferna´ndez, M. M.; Maestro, M. C. Tetrahedron 2004,
60, 10067.
(14) R3N and R3SiX have also been used in some cases to produce the
normal Pummerer reaction; see: Tokitoh, N.; Igarashi, Y.; Ando, W.
Tetrahedron Lett. 1987, 28, 5903.
(15) Under similar conditions, ethylphenylsulfoxide underwent C-sily-
lation; see: Miller, R. D.; Hassig, R. Tetrahedron Lett. 1984, 25, 5351. An
alternative vinylogous silicon-Pummerer rearrangement could have also been
invoked (see: Brook, A. G.; Anderson, D. G. Can. J. Chem. 1968, 46,
2115. Shainyan, B. A.; Kipichenko, S. V.; Freeman, F. J. Am. Chem. Soc.
2004, 124, 11456) to explain the stereochemical results encountered.
However, we could not obtain any evidence indicating the formation of a
C-silyl derivative, even when working in the presence of HMPA, which
would enhance the nucleophilicity at the carbon atom.
(17) This behavior is also found with the alkylation of other sulfinyl
carbanions; see: Drabowicz, J.; Kielbasinski, P.; Mikolajczky, M. In The
Chemistry of Sulphones and Sulphoxides; Patai, S., Rappoport, Z., Stirling,
C., Eds.; Wiley: Chichester, 1988; pp 305-317.
(18) There are some examples in the literature where substitution rather
than elimination was observed with phenylethyl-substituted systems; see:
Solladie´-Cavallo, A.; Martin-Cabrejas, L. M.; Caravatti, G.; Lang, M.
Tetrahedron: Asymmetry 2001, 12, 967.
(16) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(19) Stabilization of the carbanionic intermediate by the nitrogen atom
may be responsible for the lack of reactivity of 19.
Org. Lett., Vol. 7, No. 1, 2005
21

Scheme 3
Table 3. Scope of the Sila-Pummerer Reaction
entry
R (product)
yield (%)
69
67
51
54
58
65
56
ee (%)
1
2
3
4
5
6
7
8
9
CH3 (20)
>98
>98
>98
>98
>98
>98
>98
CH2CH3 (21)
CH2Ph (22)
CH2CH2Ph (23)
3,4-(OMe)2(C6H3)CH2CH2 (24)
CH2CHdCH2 (25)
CH2CH2OH (26)
CH2OMe
see text
no reaction
obtained. Although the failure to intramolecularly trap the
cationic center in 4 is consistent with a concerted migration,
it can also be attributed to the fact that the collapse of 4 to
24 is simply much faster than intramolecular cyclization.
In conclusion, we have described herein a highly stereo-
selective vinylogous Pummerer rearrangement that proceeds
by a 1,4-migration of the sulfinyl oxygen atom. The reaction
occurs in good yield and with high enantioselectivity when
ortho-sulfinyl-substituted benzyl carbanions are treated with
trimethylsilyl halides. The influence of the reaction conditions
and the nature of the electrophile suggests that the rear-
rangement proceeds by an intimate ion pair as a reaction
intermediate. The extremely high stereoselectivity achieved
(ee > 98%) allows for some interesting synthetic possibilities
for the synthesis of optically pure benzyl alcohols.
CH2CH2NPht
The observed stereochemical results can best be explained
by assuming that the benzyl lithiate intermediate 28 (gener-
ated from LDA) reacts with TMSCl at the benzylic carbon
position when the R substituent is a hydrogen atom (R )
H) to give 1020 (Scheme 3). However, when an alkyl
substituent is present (R * H) (i.e., 12-19), the oxygen atom
of the sulfoxide group preferentially reacts with TMSCl as
a consequence of the diminished nucleophilicity on the
carbon atom (more hindered position). The overall reaction
produces the trimethylsilyloxy sulfonium ion 3. This transient
species readily eliminates Me3SiO- and furnishes the con-
jugated thionium salt 4, which reacts further at the benzylic
position to give compounds 20-26. The complete stereo-
selectivity encountered in this reaction suggests that an
intimate ion pair is involved (Scheme 3). This species
maintains the Me3SiO- ion on the same face it originally
occupied in its most stable conformation and ultimately leads
to the (R)-alcohols by internal collapse. Alternatively, a
concerted migration of the Me3SiO- ion to the benzylic
position is also possible. An attempt to trap the conjugated
thionium ion intermediate 4 by using the activated 3,4-
dimethoxy-phenylethyl substituent (i.e., 15) failed to capture
the cation. Only the vinylogous Pummerer product 24 was
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, and M.J.A. wishes to thank the Fundacion Ramon
Areces for a postdoctoral fellowship at Emory University.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 8-27. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Compound 10 was recovered unchanged when heated at 60 °C (CH2-
Cl2) or at 120 °C (toluene) in a sealed reaction vessel, thereby indicating
that it does not undergo a thermal silicon-Pummerer rearrangement.
OL048054R
22
Org. Lett., Vol. 7, No. 1, 2005