Sulfur ylides via decarboxylation of carboxymethylsulfonium betaines: A novel and mild protocol for the preparation of oxiranes

Article abstract of DOI:10.1021/ol034612a

(Matrix presented) A novel protocol for the generation of sulfur ylides is described. The overall process involves thermal decarboxylation of a carboxymethyl-sulfonium betaine to give a sulfur ylide that, in the presence of an aldehyde, affords the corresponding terminal oxirane. Yields were found to correlate with the electron deficiency of the aryl aldehyde. In situ generation of betaine in the presence of an aldehyde successfully afforded the desired oxirane in moderate yield, thus demonstrating the feasibility of a catalytic process.

Full text of DOI:10.1021/ol034612a

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2283-2286
Sulfur Ylides via Decarboxylation of
Carboxymethylsulfonium Betaines: A
Novel and Mild Protocol for the
Preparation of Oxiranes
,†
,‡
David C. Forbes,* Michael C. Standen,* and Derrick L. Lewis†
Department of Chemistry, UniVersity of South Alabama, Mobile, Alabama 36688,
Synthetech, Albany, Oregon 97321
dforbes@jaguar1.usouthal.edu; mikes@synthetech.com.
Received April 9, 2003
ABSTRACT
A novel protocol for the generation of sulfur ylides is described. The overall process involves thermal decarboxylation of a carboxymethyl-
sulfonium betaine to give a sulfur ylide that, in the presence of an aldehyde, affords the corresponding terminal oxirane. Yields were found
to correlate with the electron deficiency of the aryl aldehyde. In situ generation of betaine in the presence of an aldehyde successfully
afforded the desired oxirane in moderate yield, thus demonstrating the feasibility of a catalytic process.
The construction of oxiranes represents an extremely useful
synthetic transformation for the introduction of functionality
into organic molecules.1 Of the two common disconnections
(Figure 1), the sulfur ylide approach offers potential advan-
compounds such as aziridines3 and cyclopropanes4,5 via
methylidene transfer to the appropriate π acceptors such as
suitably activated imines and conjugated olefins.6
A number of methods are available for the generation of
sulfur ylides.7,8 The classic method involves a stepwise
(1) (a) Rao, A. S. In ComprehensiVe Organic Synthesis: Oxidation; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Chapter 3.1. (b)
Plesnicar, B. In Oxidation in Organic Chemistry; Trahanovski, W. S., Ed.;
Academic Press: New York, 1978; Chapter III.
(2) (a) Aggarwal, V. K. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Heidel-
berg, 1999; Vol. II, pp 679-693. (b) Li, A.-H.; Dai, L.-X.; Aggarwal, V.
K. Chem. ReV. 1997, 97, 2341.
Figure 1. Strategic disconnections in oxirane formation.
(3) For the use of sulfonium and sulfoxonium ylides in aziridination
chemistry, see: (a) Aggarwal, V. K.; Ferrara, M.; O’Brien, C. J.; Thompson,
A.; Jones, R. V. H.; Fieldhouse, R. J. Chem. Soc., Perkin Trans. 1 2001,
1635. (b) Li, A.-H.; Zhou, Y.-G.; Dai, L.-X.; Hou, X.-L.; Xia, L.-J.; Lin,
L. J. Org. Chem. 1998, 63, 4338. (c) Garc´ıa-Ruano, J. L.; Fernandez, I.;
Prado Catalina, M.; Cruz, A. A. Tetrahedron: Asymmetry 1996, 7, 3407.
(4) For general discussions on the use of sulfur ylides in cyclopropanation
chemistry, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; Wiley-Interscience: New York, 1998; Chapter
7. (b) Nitrogen Oxygen and Sulfur Ylides in Synthesis: A Practical
Approach; Clark, J. S., Ed.; Oxford Press: Oxford, 2002.
tages in terms of atom efficiency and facility for stereo-
control.2 In addition to epoxide formation, sulfur ylides can
be used to prepare a wide range of synthetically valuable
* Corresponding authors.
† University of South Alabama.
‡ Synthetech.
10.1021/ol034612a CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/24/2003

sequence of (1) alkylation of a dialkyl sulfide to form a
sulfonium salt and (2) treatment of the sulfonium salt with
strong base to form the ylide. Aggarwal and co-workers have
demonstrated and refined an ingenious catalytic asymmetric
approach to homochiral epoxides and aziridines based on
the generation of S-ylides via reaction of chiral sulfides with
rhodium metallocarbenes.9 Through this approach, a range
of substituted epoxides can be generated in high yield and
with excellent control of both absolute and relative stereo-
chemistry.10 The same author has also demonstrated a similar
catalytic cycle using Simmons-Smith reagents (Et2Zn/
ClCH2I) as S-ylide precursors.11 In yet another approach,
Tanzawa and co-workers reported the generation of S-
benzylsulfonium ylides via fluoride-mediated desilylation of
trimethylsilylmethylbenzyl sulfonium precursors under es-
sentially nonbasic conditions.12 The generation of sulfur
ylides under mild conditions has been shown to be particu-
larly beneficial in situations where base-sensitive aldehydes
are employed.13
in most commonly used organic solvents of medium to even
low polarity.
Handling the carboxymethylsulfonium betaines was found
to be problematic at temperatures higher than 40°C or when
dissolved in nonpolar aprotic media.17 However, when (1)
kept in solution using either methanol and/or water or (2)
stored in crystalline form in the refrigerator, betaine 2 can
be stored for months without appreciable decomposition.
Significantly, use of solvents such as chloroform revealed a
half-life of approximately 5 h at room temperature, whereas
when placed in nitrobenzene, gas evolution (CO2) was
observed immediately at room temperature.
It was anticipated that the rate of decarboxylation and
therefore the efficiency of methylidene transfer would be
strongly solvent dependent.17 For example, highly polar and
protic solvents would likely provide good solvation for the
charged betaine relative to the transition state and thereby
raise the effective activation barrier for decarboxylation. At
the other extreme, nonpolar aprotic solvents would be
expected to facilitate decarboxylation by providing minimal
solvation, althougth the extent of bond breaking in the
transition state will also be an important factor.
In our search for alternative mild protocols for S-ylide
generation that might be capable of sustaining catalytic
methylidene tranfers, we were intrigued by the possibility
of the decarboxylation of carboxymethyl-substituted sulfo-
nium salts. Our initial search of the literature revealed a key
paper by Burness,14 who described the decarboxylation of
carboxymethyldodecylmethyl sulfonium tosylate in reflux-
ing acetone using catalytic piperidine (Scheme 1). This
(7) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(b) For a current listing of the current applications of dimethylsulfoxonium
methylide chemistry, see: Ng, J. S.; Liu, C. In Encyclopedia of Reagents
in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol.
3, p 2159. (c) Sulfur Ylides: Emerging Synthetic Intermediates; Trost, B.
M., Ed., Academic Press: New York, 1975; Chapter 9. (d) Forrester, J.;
Jones, R. V. H.; Preston, P. N.; Simpson, E. S. C. J. Chem. Soc, Perkin
Trans. I 1993, 17, 1937.
(8) (a) Li, A.-H.; Dai, L.-X.; Hou, X.-L.; Huang, Y.-Z.; Li, F.-W. J.
Org. Chem. 1996, 61, 489. (b) LaRochelle, R. W.; Trost, B. M.; Krepski,
L. J. Org. Chem. 1971, 36, 1126. (c) Trost, B. M.; Bogdanowicz, M. J. J.
Am. Chem. Soc. 1973, 95, 5298.
Scheme 1a
(9) (a) Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem.
Soc. 2002, 124, 5747. (b) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon,
K. M.; Palmer, M. J.; Porcelloni; M.; Studley, J. R. Angew. Chem., Int. Ed.
2001, 41, 1430. (c) Aggarwal, V. K.; Ford, J. G.; Thompson, A.; Jones, R.
V. H.; Standen, M. C. H. J. Am. Chem. Soc. 1996, 118, 7004.
(10) (a) Aggarwal, V. K.; Ford, J. G.; Thompson, A.; Studley, J.; Jones,
R. V. H.; Fieldhouse, R. In Current Trends in Organic Synthesis; Scolastico,
C., Nicotra, F., Eds.; Academic Press: New York, 1999; pp 191-199. (b)
Aggarwal, V. K.; Ford, J. G.; Thompson, A.; Jones, R. V. H.; Standen, M.
C. H. In SelectiVe Reactions of Metal-ActiVated Molecules; Werner, H.,
Schreier, P., Eds.; Vieweg: Gottingen, Germany, 1998; pp 13-24.
(11) (a) Aggarwal, V. K.; Coogan, M. P.; Stenson, R. A.; Jones, R. V.
H.; Fieldhouse, R.; Blacker, J. Eur. J. Org. Chem. 2002, 319. (b) Aggarwal,
V. K.; Stenson, R. A.; Jones, R. V. H.; Fieldhouse, R.; Blacker, J.
Tetrahedron Lett. 2001, 42, 1587.
a R ) n-alkyl (C7H15-C16H33 and -(CH2)n-).
reaction furnished the corresponding dimethyl-dodecyl-
sulfonium tosylate in 94% yield. It occurred to us that this
process involves the intermediacy of a sulfur ylide.
We now wish to report a new protocol for the generation
of sulfur ylides based on the decarboxylation of carboxy-
methylsulfonium betaines under aprotic conditions (Scheme
2), as well as their trapping with aldehydes to form
epoxides.15
(12) Tanzawa, T.; Shiria, N.; Sato, Y.; Hatano, K.; Kurono, Y. J. Chem.
Soc., Perkin Trans. 1 1995, 2845.
(13) Aggarwal, V. K.; Abdel-Rahman, H.; Jones, R. V. H.; Standen, M.
C. H. Tetrahedron Lett. 1995, 36, 1731.
(14) Burness, D. J. Org. Chem. 1959, 24, 849.
(15) Representative Reaction Procedure. An oven-dried round-
bottomed flask was equipped with a stir bar, septum, and drying tube. To
this system was added aldehyde (1.0 equiv) and 1,2-dichloroethane (0.1
M, 3.0 mL). The system was externally heated to 60 °C (sand bath) at
which time a solution of betaine (2.0 equiv) in 1,2-dichloroethane (0.1 M,
4.0 mL) was added via syringe pump over a period of 1.0 h. The reaction
mixture was allowed to stir for an additional period of 2.0 h. After cooling
to room temperature, the reaction mixture was concentrated in vacuo and
immediately purified by silica gel chromatography using a gradient eluent
system of hexanes and EtOAc (3 column equiv per solvent combination)
to afford analytically pure oxirane [hexanes/EtOAc, 100:0, 64:1, 32:1, 16:
1, 10 × 30 mm SiO2, 10 mL fractions].
The key betaine reagent 2 was readily prepared from the
corresponding thetin bromide 1 according to the known
method of Ratts and Yao.16 The choice of the relatively
lipophilic betaine 2 was driven by its high level of solubility
(5) For the use of sulfur mediators in cyclopropanation chemistry, see:
(a) Aggarwal, V. K.; Smith, H. W.; Hynd, G.; Jones, R. V. H.; Fieldhouse,
R.; Spey, S. E. J. Chem. Soc., Perkin Trans. 1 2000, 3267. (b) Solladie´-
Cavallo, A.; Diep-Vohuule, A.; Isarno, T. Angew. Chem., Int. Ed. 1998,
37, 1689. (c) Pyne, S. G.; Dong, Z.; Skelton, B. W.; White, A. H. J. Org.
Chem. 1997, 62, 2337.
(6) For a general discussion on the construction of three-membered rings
using ylides, see: Dai, L.-X.; Hou, X.-L.; Zhou, Y.-G. Pure Appl. Chem.
1999, 71, 369 and references therein.
(16) Ratts, K. W.; Yao, A. N. J. Org. Chem. 1966, 31, 1185.
(17) We are currently looking into a more detailed study on the
decarboxylative process in terms of solvent dielectric strength. See: Grate,
J.; McGill, R.; Andrew, H. J. Am. Chem. Soc. 1993, 115, 8577. Adams, J.;
Hoffman, L.; Trost, B. M. J. Org. Chem. 1970, 35, 1600.
2284
Org. Lett., Vol. 5, No. 13, 2003

Scheme 2
Using 4-nitrobenzaldehyde and carboxymethylsulfonium
unstabilized sulfur ylides are known to have short half-lives
in solution, typically on the order of a few minutes even at
room temperature.7a,8b,c Therefore, under our experimental
conditions, we propose that benzophenone is unable to
compete with rapid decomposition of the ylide. Likely
decomposition pathways for methylides include dispropor-
tionation, protonation, and elimination.7a,8b,c Efforts toward
isolating byproducts formed in systems that did not have
good to moderate levels of conversion to oxirane were both
unsuccessful and deemed secondary.
One final study involved the in situ generation of both
sulfonium bromide 1 and sulfonium betaine 2. Reaction of
methyl octyl sulfide with bromoacetic acid in the presence
of both 4-nitrobenzaldehyde and silver(I) carbonate on Celite
(approximately 2 equiv) in a hot solution of 1,2-dichloro-
ethane (0.1 M, 60 °C) afforded the desired oxirane (40%
conversion) and some unreacted aldehyde. The product was
identified by GC and its structure confirmed by NMR. This
single result demonstrated not only the feasibility of in situ
preparation of sulfur ylide using commercial reagents but
also the possibility of performing these reactions using only
a catalytic quantity of sulfide.
betaine 2 in dichloroethane as our benchmark, we began
optimization studies focusing on stoichiometry and temper-
ature. Results from these studies were then used as a basis
for exploring the scope of this reaction in terms of substrate
generality and also to explore the feasibility of an in situ
protocol based on the use of commercially readily available
materials (sulfides, halocarboxylic acids, etc).
Starting with a ratio of aldehyde to betaine of 1:1, we
studied a total of five temperatures in order to test the
efficiency of methylene transfer. Because appreciable de-
composition was first observed at 40 °C, this temperature
was used as a starting point and increasing intervals of 10
°C were used for each subsequent run ending at a temperature
of 80 °C. Reaction progress was expressed as a ratio of
aldehyde to oxirane (by GC area). The optimal temperature
was 60 °C, yielding a ratio of 16:84 aldehyde to oxirane. It
is important to note that all reactions were clean as judged
by GC with aldehyde (recovered), oxirane (isolated), and
sulfide the only significant components.
In terms of stoichiometry, a 1:2 ratio of aldehyde to betaine
was optimal and gave the best conversions to oxirane.
However, background decomposition of the betaine does lead
to inefficiency in methylene transfer and presumably affords
byproducts that are relatively nonvolatile. Using a 1:2 ratio
of aldehyde to betaine and a reaction temperature of 60 °C,
crude GC analysis showed complete consumption of the
aldehyde, resulting in an 84% isolated yield of oxirane.
Aldehyde to betaine ratios of 1:1 and 2:1 resulted in
incomplete consumption of the aldehyde. With these results
at hand, a study on substrate generality was carried out and
is presented below.
In view of the very short half-lives expected for unstabi-
lized sulfur ylides at temperatures approaching 60 °C and
in order to improve the efficiency of the betaine decarbox-
Table 1. Carboxymethylsulfonium Betaine-Promoted Oxirane
Formation
Table 1 reveals some interesting trends. Overall, electron-
deficient aryl aldehydes (entries 1-4) were superior to
aliphatic and electron-rich aryl aldehydes (entries 5 and 6)
and benzophenone (entry 7). Several attempts varying
reaction conditions with these and other carbonyl derivatives
were made that consistently resulted in very low yields of
the desired oxirane. With each substrate that did not afford
the desired oxirane, the starting carbonyl derivative was
isolated and recovered in >95%, thus confirming the poor
efficiency of methylene transfer.
The absence of oxirane products in entries 6 and 7 is
worthy of comment. Benzophenone epoxidation with di-
methylsulfonium methylide has been achieved in excellent
yields using protocols based on dimsylsodium7a (84%) and
KOH7d (78%). Both procedures operate at or close to room
temperature. In the present case, however, epoxidations are
carried out at 60 °C, a temperature necessary to achieve
acceptable rates of decarboxylation/ylide formation. Further,
a Isolated yields of chromatographically homogeneous spectroscopically
pure products are reported. b Desired oxirane not isolated; carbonyl deriva-
tive recovered in >95%.
Org. Lett., Vol. 5, No. 13, 2003
2285

ylation process and minimize side reactions during epoxi-
dation, part of our research is geared to finding inherently
less stable betaines that decarboxylate at lower temperatures.
To do this, we have prepared some aryl-substituted betaines,
and we will report results using these fourth-generation
compounds in due course.
has also been demonstrated using 4-nitrobenzaldehyde as a
carbonyl acceptor. Our continued research in this area will
explore (1) solvation effects on betaine decarboxylation, (2)
the use of chiral nonracemic sulfur templates, (3) the
development of ultralabile betaines, and (4) the extension
of this methodology to aziridines via use of activated imines.
In summary, a novel approach has been developed that
permits the transformation of aldehyde functionality to
oxirane in good yield using carboxymethylsulfonium betaine
2 as a promoter. The latter is a stable crystalline compound
that decarboxylates on heating in solvent to give ylid and
CO2 (“ylide in a bottle”). Ylide generation and trapping of
aldehyde to give oxirane occurs under mild and metal-free
conditions. Electron-deficient aryl aldehydes provided the
highest conversion to the desired oxirane. The basis of a
process involving in situ generation of betaine and S-ylide
Acknowledgment. D.C.F. would like to thank the
Research Corporation for partial funding of this research.
M.C.S. would like to thank the University of South Alabama.
Supporting Information Available: Synthetic and ex-
perimental procedures, analytical data, and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL034612A
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Org. Lett., Vol. 5, No. 13, 2003