Allylic disulfide rearrangement and desulfurization: Mild, electrophile-free thioether formation from thiols

Article abstract of DOI:10.1021/ol061381+

Secondary and tertiary allylic 2-pyridyl and 2-benzothiazolyl disulfides react with thiol groups at room temperature to give secondary and tertiary allyl alkyl disulfides. On the addition of a phosphine, a desulfurative sigmatropic rearrangement takes pla

Full text of DOI:10.1021/ol061381+

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3593-3596
Allylic Disulfide Rearrangement and
Desulfurization: Mild, Electrophile-Free
Thioether Formation from Thiols
David Crich,* Franck Brebion, and Venkataramanan Krishnamurthy
Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
dcrich@uic.edu
Received June 6, 2006
ABSTRACT
Secondary and tertiary allylic 2-pyridyl and 2-benzothiazolyl disulfides react with thiol groups at room temperature to give secondary and
tertiary allyl alkyl disulfides. On the addition of a phosphine, a desulfurative sigmatropic rearrangement takes place at room temperature to
give thioethers.
We recently reported a new functionalization method for
thiols and cysteine derivatives which proceeds at room
temperature in protic media. The chemistry involves the
deselenative [2,3]-sigmatropic rearrangement of allylic se-
lenosulfides (Scheme 1) and is best suited for the synthesis
As first described by Baldwin,2a allylic disulfides are in
equilibrium with allylic thiosulfoxides by virtue of a [2,3]-
sigmatropic rearrangement of undetermined stereoselectivity
(Scheme 2).2 The equilibrium, which strongly favors the
Scheme 2. Allylation of Thiols via Allylic Disulfides
Scheme 1. Chemical Ligation via Se-Allyl Selenosulfides
of tertiary allylic sulfides from primary selenosulfides as
exemplified by the introduction of linalyl and nerolydyl
groups.1
However, this method is not as well adapted for the
preparation of primary allyl sulfides because of complications
in the synthesis of the required tertiary selenosulfides. To
access primary allylic sulfides from thiols, we have now
examined and report on the analogous rearrangement of
allylic disulfides.
allylic disulfide, can be displaced toward the formation of
an allylic sulfide by the addition of a thiophilic agent. At 60
°C in benzene, rate constants for the rearrangement with
(2) (a) Ho¨fle, G.; Baldwin, J. E. J. Am. Chem. Soc. 1971, 93, 6307. (b)
Baechler, R. D.; Hummel, J. P.; Mislow, K. J. Am. Chem. Soc. 1973, 95,
4442. (c) Block, E.; Iyer, R.; Grisoni, S.; Saha, C.; Belman, S.; Lossing, F.
P. J. Am. Chem. Soc. 1988, 110, 7813. (d) Kutney, G. W.; Turnbull, K.
Chem. ReV. 1982, 82, 333. (e) Moore, C. G.; Trego, G. R. Tetrahedron
1962, 18, 205. (f) Evans, M. B.; Higgins, G. M. C.; Moore, C. G.; Porter,
M.; Saville, B.; Smith, J. F.; Trego, B. R.; Watson, A. A. Chem. Ind. 1960,
897. (g) Pilgram, K.; Phillips, D. D.; Korte, F. J. Org. Chem. 1964, 29,
1844.
(1) Crich, D.; Krishnamurthy, V.; Hutton, T. K. J. Am. Chem. Soc. 2006,
128, 2544.
10.1021/ol061381+ CCC: $33.50
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Published on Web 07/14/2006

transfer of sulfur to triphenylphosphine were found to be
strongly dependent on the substitution pattern.2a Whereas the
desulfurative rearrangement was reported to be slow for
primary allylic disulfides (R1,R2 ) H and R3,R4 ) H/alkyl;
k ) 0.7 × 10-4 to 8.6 10-4 s-1), a significant rate acceleration
was observed with secondary and tertiary allylic disulfides
(R1,R2 ) alkyl and R3,R4 ) H; k ) 1.4 × 10-2 to 1.9 10-2
s-1).2a On the basis of early observations,2a,e we reasoned
that use of polar solvents to stabilize the polar thiosulfoxide
intermediate would enable the reaction to be conducted at
room temperature, thereby providing a mild and selective
functionalization method for thiols, complementary to the
allylic selenosulfide methodology. We describe here the
successful realization of this concept and its application to
the functionalization of thiols under mild, electrophile-free
conditions and provide the first insights into the stereose-
lectivity of this process.
Scheme 4. Synthesis of Sulfenylating Agents from Allylic
Thiols
A series of secondary and tertiary allylic thiols were
prepared by exploiting the ease of formation of allylic
xanthates and thiocarbamates and their thermal [3,3]-sigma-
tropic rearrangement to dithiocarbonates and thiocarbamates
(Scheme 3).3
of this new functionalization method. It is noteworthy that
such sulfenylating agents, derived from hindered allylic
thiols, have drawn little attention so far and that only a
limited number of benzothiazolyl disulfides8 and thiosulfi-
nates9 have been reported.
Scheme 3. Synthesis of Secondary and Tertiary Allylic Thiols
Reaction of disulfide 7 with cysteine derivative 11 at room
temperature in CD3OD/CD3CN resulted in the formation of
expected disulfide 12 accompanied by only traces of rear-
ranged product 13 (Scheme 5).10
Scheme 5. Functionalization of a Cysteine Derivative
Thiols 4a-c were activated for disulfide formation by
conversion to their corresponding benzothiazolyl and pyridyl
disulfide derivatives (Scheme 4). Analogous sulfenylating
agents have found wide applications for the synthesis of
mixed disulfides, especially pyridyl derivatives owing to the
spectroscopic properties of pyridine-2-thiones which enable
successful monitoring of sulfydryl group modifications.4 For
4a, the benzothiazolyl derivative 5, as well as pyridyl
disulfides 6 and 7, were prepared and proved to be easily
purified and perfectly stable.5,6 The recent use of selenos-
ulfides for formation of disulfide-linked neoglycopeptides7
motivated us to prepare the selenosulfide 10 and compare
the efficiency of different sulfenylating agents in the context
Interestingly, during an attempt to purify 12 on silica gel,
a significant amount of 13 was obtained, thereby establishing
(3) (a) Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1972, 20, 2348. (b)
Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1972, 20, 2357. (c) Harano,
K.; Taguchi, T. Chem. Pharm. Bull. 1975, 23, 467. (d) Harano, K.; Ohizumi,
N.; Hisano, T. Tetrahedron Lett. 1985, 26, 4203. (e) Nakai, T.; Ari-Izumi,
A. Tetrahedron Lett. 1976, 17, 2335. (f) Nakai, T.; Mimura, T.; Ari-Izumi,
A. Tetrahedron Lett. 1977, 18, 2425. (g) Ueno, Y.; Sano, H.; Okawara, M.
Tetrahedron Lett. 1980, 21. 1767.
(4) (a) Talgoy, M. M.; Bell, A. W.; Duckworth, H. W. Can. J. Biochem.
1979, 57, 822. (b) Kimura, T.; Matsueda, R.; Nakagawa, Y.; Kaiser, E. T.
Anal. Biochem. 1982, 122, 274.
(5) For examples of preparation of benzothiazolyl disulfides and pyridyl
disulfides as well as their application to the synthesis of mixed disulfides,
see: (a) Brzezinska, E.; Ternay, A. L. J. Org. Chem. 1994, 59, 8239. (b)
Rabanal, F.; DeGrado, W. F.; Dutton, P. L. Tetrahedron Lett. 1996, 37,
1347. (c) Stoner, E. J.; Negro´n, G.; Gavin˜o, R. In Handbook of Reagents
for Organic Synthesis: Reagents for Glycoside, Nucleotide and Peptide
Synthesis; Crich, D., Ed.; Wiley: London, 2005; p 330. (d) Lundblad, R.
L. Chemical Reagents for Protein Modification, 3rd ed.; CRC Press: Boca
Raton, 2005.
(6) Disulfides 5-10 were kept at 0 °C for several months with no
evidence of rearrangement or degradation.
(7) Gamblin, D. P.; Garnier, P.; van Kasteren, S.; Oldham, N. J.;
Fairbanks, A. J.; Davis, B. G. Angew. Chem., Int. Ed. 2004, 43, 828.
(8) (a) Watson, A. A. J. Chem. Soc. (C) 1964, 2100. (b) Morrison, N. J.
J. Chem. Soc., Perkin Trans. 1 1984, 101.
(9) Braverman, S.; Pechenick, T. Tetrahedron Lett. 2002, 43, 499.
(10) Only traces of allylic sulfide 13, arising from the [2,3]-rearrangement
with loss of sulfur, were identified by NMR.
3594
Org. Lett., Vol. 8, No. 16, 2006

Table 1. Application to Thiols, Cysteine Derivatives, and Cysteine-Containing Peptides
a Ar ) 2-benzothiazolyl. b The double-bond configuration of 13, 18, 22, 23, 25, 26, and 28 was determined by a homonuclear spin decoupling experiment
(J ∼ 15 Hz). The E and Z isomers of 21 and 24 were separated by preparative HPLC, and double-bond configurations were determined on the basis of 13C
γ effects. c Reactions were performed in benzene at 0.05 M with 1.3 equiv of disulfide and 3 equiv of phosphine. Et3N (3 equiv) was added to accelerate
the disulfide bond formation (minutes instead of hours). The disulfide bond formation was carried out at room temperature, and the rearrangement was
carried out at reflux. d Reactions were performed at room temperature in MeCN/MeOH (1:1) at 0.05 M with 2 equiv of disulfide and 3 equiv of phosphine.
e PPh3 was used as the thiophile. f Ph2P(4-C6H4NMe2) was used as the thiophile. g Et3N (5 equiv) was added. h Reaction was performed at room temperature
in a mixture of Tris buffer/MeCN/THF (2:1:1) at 0.02 M with 3 equiv of disulfide and 5 equiv of phosphine.
that the rearrangement and the subsequent loss of sulfur can
be performed at room temperature.11 The addition of a
phosphine to a mixture of 12 and 13 resulted in the
desulfurization of the thiosulfoxide and led to the primary
allylic sulfide as a single E-isomer, without racemization of
the cysteine moiety.12 We next explored the possibility of
conducting the reaction in one pot, at room temperature,
using a mixture of methanol-acetonitrile as solvent. Fol-
Org. Lett., Vol. 8, No. 16, 2006
3595

lowing this strategy, the phosphine was simply added to the
reaction mixture after consumption of the cysteine derivative.
This protocol turned out to be not only more convenient but
also more efficient with yields up to 85% (Table 1, entry
4). The nature of the sulfenylating agent (5, 6, or 7), or of
the arylphosphine, has no significant impact on the yields,
which were optimum with 2 equiv of sulfenylating agents.
We next explored the functionalization of carbohydrate-
based thiols, cysteine derivatives, and small cysteine-
containing peptides with 1-thio-â-D-glucose tetraacetate 14,
Boc-L-Cys-OMe 11, Boc-(R-OMe)-γ-L-Glu-L-Cys-Gly-OMe
15, and Boc-L-Cys-L-Ala-L-Trp-OMe 161 (Table 1). These
reactions were conducted following the one-pot/two-step
procedure in various solvents, including protic ones. The
reaction involving cysteine residues could be performed at
room temperature, whereas the rearrangement of disulfides
derived from 1-thio-â-D-glucose tetraacetate 14 required a
higher temperature. Secondary disulfides 5-8 were employed
under neutral conditions, but the more hindered tertiary
disulfide 9 and the selenosulfide 10 required the addition of
Et3N to achieve the ligation to the cysteine derivatives. With
selenosulfide 10, the modified cysteine derivative 13 was
isolated as a mixture of isomers, presumably arising from
double-bond isomerization mediated by selenium-based
byproducts (Table 1, entry 6).13 The potential of this method
for the ligation of organic molecules to cysteine-containing
peptides was also demonstrated by allylation of free glu-
tathione (Table 1, entry 13). It is noteworthy that this
convenient and efficient thiol functionalization method is
highly selective and compatible with the indole ring in
tryptophan.
and 2). On the other hand, trisubstituted double bonds were
obtained with a modest E-selectivity (Table 1, entries 3, 5,
9, and 12). These results are consistent with features of other
[2,3]-shifts, such as the Evans-Mislow or [2,3]-Wittig
sigmatropic rearrangements.14,15
In summary, we describe a new and convenient function-
alization method of thiols, combining the use of stable and
easily prepared benzothiazolyl and pyridyl disulfides as
sulfenylating agents with a phosphine-promoted desulfurative
allylic rearrangement. As demonstrated by allylation of
unprotected glutathione, this method has potential for the
ligation to peptides and protein-based thiols, an area of
considerable current interest. The facile synthesis of the allyl
heteroaryl disulfides coupled with the applicability of the
method to native peptides renders the method highly
competitive with other routes to cysteine functionalized
peptides, all of which require the use of electrophilic reagents
or the prior derivatization of the peptide.16
Acknowledgment. We thank the Ministe`re des Affaires
EÄ trange`res, France, for a Lavoisier Fellowship (F.B.) and
the NIH (GM 62160) for their financial support.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061381+
(14) Stereoselectivity of the allylic sulfoxide rearrangement. Evans, D.
A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147.
(15) Stereoselectivity of [2,3]-Wittig rearrangement: (a) Nakai, T.;
Mikami, K. Chem. ReV. 1986, 86, 885. (b) Nakai, T.; Mikami, K. In Organic
Reactions; Paquette, L. A., Ed.; Wiley: New York, 1994; Vol. 46, p 105.
(c) Mikami, K.; Nakai, T. Synthesis 1991, 594.
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Chem. Soc. 2002, 124, 5954. (b) Zhu, Y.; Van Der Donk, W. A. Org. Lett.
2001, 3, 1189. (c) Cohen, S. B.; Halcomb, R. L. J. Am. Chem. Soc. 2002,
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Waldmann, H. Angew. Chem., Int. Ed. 2004, 43, 5839. (g) Thayer, D. A.;
Yu, H. N.; Galan, M. C.; Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44,
4596. (h) Pachamuthu, K.; Zhu, X.; Schmidt, R. R. J. Org. Chem. 2005,
70, 3720. (i) Palomo, J. M.; Lumbierres, M.; Waldmann, H. Angew. Chem.,
Int. Ed. 2006, 45, 477. (j) Jobron, L.; Hummel, G. Org. Lett. 2000, 2, 2265.
The results gathered in Table 1 give also the first insight
into the stereochemistry of the [2,3]-sigmatropic rearrange-
ment of allylic disulfides. At room temperature, high
selectivity was observed for the formation of E-disubstituted
double bonds, but the selectivity slightly decreased when the
rearrangement was performed at 80 °C (Table 1, entries 1
(11) Sulfur extrusion appears to be favored by the presence of acid in
the reaction mixture. In untreated CDCl3, the disulfide 12 partially rearranged
to allylic sulfide 13, even in the absence of phosphine.
(12) Rearrangement of 12 to 13 in the presence of PPh3 or 4-(Me2-
NC6H4)PPh2 was complete in 12-15 h. Racemization was excluded by a
reaction in CDCl3/CD3OD, with no deuterium incorporation.
(13) Light-induced alkene isomerization by diselenide. Barrett, A. G.
M.; Barton, D. H. R.; Johnson, G.; Nagubandi, S. Synthesis 1978, 741.
3596
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