Ga(OTf)3-catalyzed direct substitution of alcohols with sulfur nucleophiles

Article abstract of DOI:10.1021/ol102565b

It is reported that Ga(OTf)₃ catalyzes the direct displacement of alcohols with sulfur nucleophiles. The products are versatile intermediates that can be utilized in carbon - carbon, carbon - sulfur bond formation or used in modified Julia olef

Full text of DOI:10.1021/ol102565b

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5780-5782
Ga(OTf)3-Catalyzed Direct Substitution of
Alcohols with Sulfur Nucleophiles
Xinping Han and Jimmy Wu*
Department of Chemistry, Dartmouth College, HanoVer,
New Hampshire 03755, United States
jimmy.wu@dartmouth.edu
Received October 22, 2010
ABSTRACT
It is reported that Ga(OTf)3 catalyzes the direct displacement of alcohols with sulfur nucleophiles. The products are versatile intermediates
that can be utilized in carbon-carbon, carbon-sulfur bond formation or used in modified Julia olefination reactions. The only byproduct
generated is water.
Sulfur-containing bioactive natural and pharmaceutical agents
are prevalent and, among others,1 include ꢀ-lactam and
sulfonamide antibiotics, selective COX-II inhibitors, H2-
receptor antagonists,2 pyrimidine thionucleosides,3 penicil-
lamine, glutathione, and immunoconjugates.4 Because of the
general availability and low cost of alcohols, the direct
substitution of the hydroxyl functional group with sulfur
nucleophiles is desirable. Although there are some examples
of substitutions promoted by excess Brønsted acids, with the
exception of a few reports,5 these reactions are characterized
by low yields, formation of undesired byproducts, and narrow
substrate scope.6 A limited number of Lewis acid promoted
reactions are also known, but these typically require sto-
ichiometric or near-stoichiometric amounts of catalyst.7 The
use of catalytic Lewis acids in the direct displacement of
alcohols with sulfur nucleophiles is rare. Kagan and co-
workers reported two examples in which SmCl3 catalyzed
the formation of thioethers from alcohols and thiols.8 Hidai
and Uemura demonstrated that cationic diruthenium com-
plexes can promote the displacement of propargyl alcohols
with thiols.9
Our own group reported the photochemically promoted
substitution of alcohols with phosphorothioic acid 1.10
However, this transformation was limited to γ,γ-disubstituted
allylic alcohols. Primary, secondary, and tertiary aliphatic
alcohols and benzyl alcohols did not participate.
(1) (a) Prinsep, M. R. Studies Nat. Prod. Chem. 2003, 28, 617. (b) Haq,
K.; Ali, M. In Sulphur in Plants; Abrol, Y. P., Ahmad, A., Eds.; Kluwer
Academics Publishers: Dordrecht, 2003; p 375. (c) Parry, R. J. Tetrahedron
1983, 39, 1215.
(2) (a) Black, J.; Durant, G.; Emmett, J.; Ganellin, C. Nature 1974, 248,
65.
(3) Miura, S.; Yoshimura, Y.; Endo, M.; Machida, H.; Matsuda, A.;
Tanaka, M.; Sasaki, T. Cancer Lett. 1998, 129, 103.
(4) Trail, P.; Willner, D.; Lasch, S.; Henderson, A.; Hofstead, S.;
Casazza, A.; Firestone, R.; Hellstro¨m, I.; Hellstro¨m, K. Science 1993, 261,
212.
Herein we report that Ga(OTf)3 catalyzes the direct
displacement of a wide range of alcohols with phospho-
rothioic acid 1 and phenyltetrazole 2 (eqs 1, 2). Ga(OTf)3 is
an inexpensive, hydrolytically stable, oxygen-tolerant Lewis
´
(5) (a) Sanz, R.; Mart´ınez, A.; Miguel, D.; Alvarez-Gutie´rrez, J. M.;
Rodr´ıguez, F. AdV. Synth. Catal. 2006, 348, 1841. (b) Zhang, X.; Rao, W.;
Chan, P. W. H. Synlett 2008, 2204.
10.1021/ol102565b  2010 American Chemical Society
Published on Web 11/22/2010

acid that was first utilized by Olah and Prakash,11 then
Kobayashi,12 in a variety of transformations. The present
work was inspired by Baba and co-workers who demon-
strated that In(III) salts are effective catalysts for the direct
substitution of alcohols with various carbon nucleophiles.13
We have previously shown that phosphorothioic esters 3 are
useful intermediates in transition-metal-free allylic alkyla-
tions10 with Grignard reagents and one-step syntheses of
thioethers.14 Furthermore, compounds 1 and 3 are odorless,
bench-stable compounds that are compatible with column
chromatography. Others have demonstrated that phospho-
rothioate esters can be transformed to the corresponding
alkenes15 or converted to thiols via hydrolysis16 or reduc-
tion.17 Sulfides 4 are valuable because they can be oxidized
to the corresponding sulfones and applied to Julia olefination
reactions.18
Table 1. Scope of Substitution with Phosphorothioic Acid, 1
We selected benzyl alcohol (5a) and diethyl phospho-
rothioic acid (1) as the initial test substrates for optimization.
When 1 and 5a were aged at rt in the presence of 10 mol %
Ga(OTf)3, no reaction was observed. However, increasing
the temperature to 60 °C in dichloroethane generated the
desired product in good yield. A control reaction in which
Ga(OTf)3 was omitted furnished no observable product. The
use of various In(III) catalysts resulted in inferior yields. With
optimized conditions in hand, we surveyed the scope of the
transformation (Table 1). The reaction is tolerant to oxygen,
sulfur, and nitrogen heterocycles (entries 5-6, 9-10). Both
primary and secondary alcohols are compatible if at least
a Isolated yield. b Conducted in dichloroethane at 60 °C. c 1% Ga (OTf)3
used. d Product decomposes upon standing. e Isolated as a 3:1 mixture of
regioisomers:
(6) (a) Haynes, R. K.; Katsifis, A. G.; Vonwiller, S. C.; Hambley, T. W.
J. Am. Chem. Soc. 1988, 110, 5423. (b) Parker, K. A.; Johnson, W. S. J. Am.
Chem. Soc. 1974, 96, 2556. (c) Sneen, R. A.; Kay, P. S. J. Am. Chem. Soc.
1972, 94, 6983.
(7) (a) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos,
A. L. J. Am. Chem. Soc. 2009, 131, 1753. (b) Furth, P. S.; Hwu, J. R.
J. Am. Chem. Soc. 1989, 111, 8842. (c) Firouzabadi, H.; Iranpoor, N.;
Jafarpour, M. Tetrahedron Lett. 2006, 47, 93. (d) Legoupy, S.; Cre´visy,
C.; Guillemin, J.-C.; Gre´e, R.; Toupet, L. Chem.sEur. J. 1998, 4, 11. (e)
Guindon, Y.; Frenette, R.; Fortin, R.; Rokach, J. J. Org. Chem. 1983, 48,
1357.
one of the substituents is aromatic or allylic. This method is
amenable to both electron-donating and -withdrawing sub-
stituents (entries 2-6). Alcohols with all alkyl substituents
participated only if they are tertiary (entry 14). For more
active substrates, heating was not necessary.
(8) Ouertani, M.; Collin, J.; Kagan, H. B. Tetrahedron 1985, 41, 3689.
(9) Inada, Y.; Nishibayashi, Y.; Hidai, M.; Uemura, S. J. Am. Chem.
Soc. 2002, 124, 15172.
Other than 6a, the alcohols in Table 1 do not undergo the
photochemically promoted substitution described in our
earlier publication.10 In that report, we observed more facile
substitution reactions for substrates in which cleavage of the
carbon-oxygen bond results in highly stabilized carboca-
tionic or radical intermediates. We suspect that the highly
electron-rich nature of the furan ring in 6a is why it is able
to successfully undergo photolytic displacement. When
geraniol (8), a γ,γ-disubstituted allylic alcohol, was subjected
to the UV-promoted substitution, significant decomposition
was observed.
(10) Han, X.; Zhang, Y.; Wu, J. J. Am. Chem. Soc. 2010, 132, 4104.
(11) (a) Olah, G. A.; Farooq, O.; Farnia, S. M. F.; Olah, J. A. J. Am.
Chem. Soc. 1988, 110, 2560. (b) Prakash, G. K. S.; Mathew, T.; Panja, C.;
Alconcel, S.; Vaghoo, H.; Do, C.; Olah, G. A. Proc. Natl. Acad. Sci. U.S.A.
2007, 104, 3703. (c) Prakash, G. K. S.; Mathew, T.; Panja, C.; Vaghoo,
H.; Venkataraman, K.; Olah, G. A. Org. Lett. 2007, 9, 179. (d) Yan, P.;
Batamack, P.; Prakash, G. K. S.; Olah, G. A. Catal. Lett. 2005, 103, 165.
(e) Parakash, G. K. S.; Yan, P.; To¨ro¨k, B.; Bucsi, I.; Tanaka, M.; Olah,
G. A. Catal. Lett. 2003, 85, 1.
(12) Kobayashi, S.; Komoto, I.; Matsuo, J.-I. AdV. Synth. Catal. 2001,
343, 71.
(13) (a) Nishimoto, Y.; Onishi, Y.; Yasuda, M.; Baba, A. Angew. Chem.,
Int. Ed. 2009, 48, 9131. (b) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem.,
Int. Ed. 2006, 45, 793. (c) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew.
Chem., Int. Ed. 2004, 43, 1414.
Interestingly, the use of regioisomeric alcohols (21 vs entry
12, Table 1) furnished identical products (eq 3). We also
demonstrated that phosphorothioate esters can be efficiently
hydrolyzed to the corresponding thiol with KOH in aqueous
THF.
(14) Robertson, F.; Wu, J. Org. Lett. 2010, 12, 2668.
(15) (a) Macia¸giewicz, I.; Dybowski, P.; Skowron˜ska, A. Tetrahedron
2003, 59, 6057. (b) Macia¸giewicz, I.; Dybowski, P.; Skowron˜ska, A.
Tetrahedron Lett. 1999, 40, 3791. (c) Krawczyk, E. Synthesis 2006, 716.
(d) Tanaka, K.; Uneme, H.; Ono, N.; Kaji, A. Chem. Lett. 1979, 1039. (e)
Tanaka, K.; Uneme, H.; Ono, N.; Kaji, A. Synthesis 1979, 890.
(16) (a) Fukuto, T. R.; Stafford, E. M. J. Am. Chem. Soc. 1957, 79,
6083. (b) Michalski, J.; Musierowicz, S. Rokzniki Chem. 1962, 36, 1655.
(17) Fabbri, D. Tetrahedron: Asymmetry 1993, 4, 1591.
(18) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(b) Blakemore, P. R.; Cole, W. J.; Kocien˜ski, P. J.; Morley, A. Synlett 1998,
26.
Org. Lett., Vol. 12, No. 24, 2010
5781

The substitution was extended to include phenyltetrazole
2 as the nucleophile (Table 2). As with phosphorothioic acid
The products obtained in Table 2 and Scheme 1 are
important because they can be further oxidized to the
corresponding sulfones for use in Julia-type olefination
reactions. Conventional methods for synthesizing these
sulfides typically employ the Mitsunobu reaction19 between
an alcohol and 2. However, the Mitsunobu reaction is an
inherently nonatom economical process which produces
stoichiometric amounts of hydrazine dicarboxylate and
triphenylphosphine oxide byproducts, of which the latter can
sometimes be difficult to separate from the desired product.
In contrast, the only byproduct generated in our method is
water.
Table 2. Scope of Substitution with Phenyltetrazole, 2
We then performed the Ga(OTf)3-catalyzed sulfur substi-
tution reaction on enantioenriched alcohol (S)-9 with both
phosphorothioic acid 1 and phenyltetrazole 2 under optimized
conditions (Scheme 2). In both instances, the expected
Scheme 2. Substitution with Enantioenriched Alcohol, (S)-9
product was isolated in good yield but in nearly racemic
form. These results, taken together with the fact that
regioisomeric starting materials converge to a single product
(eq 3 vs Table 1, entry 12), provide strong evidence that
prochiral carbocationic intermediates are involved in the
reaction.
a Isolated yield. b Conducted in DCM at rt. c Isolated as a 3:1 mixture
of regiosomers:
In summary, we have described the direct substitution of
alcohols with phosphorothioic acid 1, phenyltetrazole 2, and
other heteroaromatic thiols catalyzed by Ga(OTf)3. Broad
versatility has been demonstrated with respect to the alcohols
that participate in the reaction. This method provides an
alternative means for preparing two useful classes of sulfur-
containing compounds.
1, the reaction exhibited broad generality for a range of
alcohols. Electron-donating and -withdrawing functionality
as well as oxygen, sulfur, and nitrogen heterocycles, free
amines, and esters were well tolerated (entries 5-6). Three
other thiols commonly utilized in sulfone olefination reac-
tions were also examined (Scheme 1). In principle, this
Acknowledgment. The authors are grateful to Dartmouth
College and the Walter and Constance Burke Foundation
for their generous financial support.
Scheme 1. Substitution with Other Julia Olefination Thiols
Supporting Information Available: Experimental pro-
cedures and spectra for all previously unreported compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL102565B
methodology can be extended to sulfur nucleophiles other
than 1-2 and 31-33. These results will be reported in a
full paper.
(19) Hughes, D. L. The Mitsunobu Reaction. In Organic Reactions;
Paquette, L. A., Ed.; John Wiley & Sons, Inc.: New York, 1992; Vol. 42,
p 335.
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Org. Lett., Vol. 12, No. 24, 2010