Rhodium-catalyzed methylthio transfer reaction between ketone α-positions: Reversible single-bond metathesis of C-S and C-H bonds

Article abstract of DOI:10.1021/ol802619e

(Chemical Equation Presented) In the presence of a catalytic amount of RhH(PPh₃)₄ and 1,2-bis(diphenylposphino)ethane (dppe), α-phenylthio ketones were methylthiolated with ρ-cyano-α- methylthioacetophenone giving α-phenylthio-α-meth

Full text of DOI:10.1021/ol802619e

ORGANIC
LETTERS
2009
Vol. 11, No. 3
625-627
Rhodium-Catalyzed Methylthio Transfer
Reaction between Ketone r-Positions:
Reversible Single-Bond Metathesis of
C-S and C-H Bonds
Mieko Arisawa, Katsunori Suwa, and Masahiko Yamaguchi*,†
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Sendai 980-8578, Japan
yama@mail.pharm.tohoku.ac.jp
Received November 19, 2008
ABSTRACT
In the presence of a catalytic amount of RhH(PPh3)4 and 1,2-bis(diphenylposphino)ethane (dppe), r-phenylthio ketones were methylthiolated
with p-cyano-r-methylthioacetophenone giving r-phenylthio-r-methylthio ketones. The methylthio transfer reaction between the ketone
r-positions was reversible and at equilibrium, and the methylthio group was transferred in preference to the phenylthio group. The reaction
of tertiary alkyl methylthiomethyl ketones proceeded in high yields; the reaction of diastereomeric 4-(tert-butyl)-2-phenylthiocyclohexanones
gave an axial 2-methylthiolated product.
Transition-metal-catalyzed reversible cleavage (or forma-
tion) of the C-S bond is a novel reaction that can be used
for the synthesis of organosulfur compounds. The orga-
nometallic intermediates possessing the C-M and/or M-S
structure formed by this process exhibit various reactivi-
ties, transferring either carbon or sulfur groups to other
organic molecules, and the overall processes result in the
formation of new C-S bonds as well as C-C, S-S, or
C-H bonds.1 The reversibility of the reaction broadens
the scope of the synthesis if the equilibrium can be shifted
to a desired product.
In addition, such reactions allow the organosulfur
synthesis to be carried out under mild conditions and in
an energy saving manner, when compared with the
conventional synthesis employing stoichiometric amounts
of bases and highly reactive sulfur reagents.To develop
such a novel and efficient method, understanding and control
of the reactivity of the C-M and/or M-S intermediates is
critical. During our investigations on the development of
rhodium-catalyzed transformations of organosulfur com-
pounds,2a we reported rhodium-catalyzed alkylthio exchange
reactions of 1-(alkylthio)alkynes2b and thioesters.2c The
reactions, a single-bond metathesis of C-S and S-S bonds,
contained reversible C-S bond cleavage and formation and
reached equilibrium rapidly. The C-C bond formation
reaction by the single-bond metathesis of C-S and C-S
bonds has also been developed.2d In this paper, we describe
a novel rhodium-catalyzed reaction containing reversible
C-S bond cleavage and C-H activation: the intermolecular
transfer of a methylthio group between the ketone R-positions
† WPI Research Center, Advanced Institute for Materials Research,
Tohoku University, Sendai 980-8577, Japan.
(1) Examples of metal-catalyzed reactions with C-S bond cleavage.
Dehydrosulfurization reaction. Review: (a) Sa´nchez-Delgado, R. A. Hy-
drodesulfurization and Hydrodenitrogeneation. In ComprehensiVe Orga-
nometallic Chemistry III; Crabtree, R. H., Mingos, D. M., Eds.; Elsevier:
Amsterdam, 2007; Vol. 1, p 759. Organometallic substitution reaction. (b)
Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem. Soc., Chem.
Commun. 1979, 637. (c) Okamura, H.; Miura, M.; Takei, H. Tetrahedron
Lett. 1979, 20, 43. (d) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S.
J. Am. Chem. Soc. 1999, 121, 9449. (e) Savarin, C.; Srogl, J.; Liebeskind,
L. S. Org. Lett. 2001, 3, 91. (f) Egi, M.; Liebeskind, L. S. Org. Lett. 2003,
5, 801. (g) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.;
Guillaumet, G. Org. Lett. 2003, 5, 803.
(2) (a) Arisawa, M.; Yamaguchi, M. Pure Appl. Chem. 2008, 80, 993.
(b) Arisawa, M.; Fujimoto, K.; Morinaka, S.; Yamaguchi, M. J. Am. Chem.
Soc. 2005, 127, 12226. (c) Arisawa, M.; Kubota, T.; Yamaguchi, M.
Tetrahedron Lett. 2008, 49, 1975. (d) Arisawa, M.; Tagami, Y.; Yamaguchi,
M. Tetrahedron Lett. 2008, 49, 1593.
10.1021/ol802619e CCC: $40.75
Published on Web 01/13/2009
2009 American Chemical Society

and a single bond metathesis of C-S and C-H bonds to
form C-H and C-S bonds (Scheme 1). R-Phenylthio
determined by the presence of NOE between the 2-methylthio
protons and the axial-6-proton. When the molar ratio ax-
1/2 was changed from 5 to 1, the yields of 3 and 5a decreased
(entries 2 and 3). The use of 3 equiv of 2a decreased the
yield of 3 and increased the yield of 6a, the methylthio
transfer product from 2a to another 2a (entry 1). Two
methylthio transfer processes, the transformation of ax-1 to
3 and 2a to 6a, appear to compete. These results indicate
the formation of a C-Rh species at the R-position of 1,
which underwent methylthiolation with 2a liberating 5a. The
formation of 5a in larger amounts compared with 3 may be
partly due to reduction by the phosphine.3
The reversibility of the methylthio transfer reaction was
then examined. When equimolar amounts of 3 and 5a were
treated with rhodium catalyst in refluxing THF for 4 h, 1
was obtained in 61% yield as a mixture of ax-1 and eq-1
(Scheme 2). Regarding the acetophenone derivative, 2a
Scheme 1
ketones underwent methylthiolation reaction at the R-position
giving R-phenylthio-R-methylthio ketones, and R-methylthio-
p-cyanoacetophenone was found to be an efficient methylthio
transfer reagent for this reaction. This study revealed a novel
reactivity of the C-Rh and/or Rh-S intermediates formed
by reversible C-S bond cleavage.
When (2R*,4S*)-4-(tert-butyl)-2-thiophenylcyclohexanone
ax-1 (5 equiv) and R-methylthio-p-cyanoacetophenone 2a
were reacted in the presence of RhH(PPh3)4 (4 mol %) and
dppe (8 mol %) in refluxing THF for 4 h, (2R*,4S*)-4-(tert-
butyl)-2-methythio-2-phenylthiocyclohexanone 3 was ob-
tained in 45% yield based on 2a and p-cyanoacetophenone
5a in 84% yield (Table 1, entry 5). A 3:2 mixture of ax-1
Scheme 2
Table 1. R-Methylthio Transfer Reaction of ax-1 and 2a
(17%) and 6a (9%) were obtained. Thus, the methylthio
transfer reaction between the ketone R-positions was con-
cluded to be an equilibrium. That 2a was formed from 5a
indicates the methylthio transfer reaction is not restricted to
the R-phenylthio ketones, and various carbonyl compounds
can be R-methylthiolated using appropriate combinations of
substrates and catalyst. The reaction of the equatorial isomer
eq-1 gave 3 in 30% yield along with 5a in 55% yield (Table
1, entry 4). That the same configuration of 3 was obtained
both from ax-1 and eq-1 indicated the involvement of the
same C-Rh intermediate. In addition, the methylthiolation
of the intermediate was shown to occur at the axial site. The
C-H activation and isomerization of 1 were confirmed to
be catalyzed by the rhodium complex. When ax-1 was treated
with RhH(PPh3)4 (2 mol %) in refluxing THF for 4 h, a 3:2
mixture of ax-1 and eq-1 was obtained (Scheme 3).4 No
yielda (%)
entry
1 (equiv)
3
5a
1b
4
2a
6a
1
2
0.33
1
3
12c
21
37
30
45
30c
58
70
55
84
79
85
87
94
92
7
1
2
5
1
48
35
40
43
11
19
10
6
7
4
3
4d
5
5
a Yield based on 2a. b Yield of 3:2 mixtures of ax-1 and eq-1 based on
1. c Yield based on 1. d The isomer eq-1 was used.
and eq-1 was recovered quantitatively, which was ac-
companied by a very small amount of R-methylthiolated
cyclohexanone 4 (1%), a methylthio exchanged product of
ax-1. Other products isolated include R,R-dimethylthioac-
etophenone 6a (4%) and the recovery of 2a (11%). The
phenylthio C-S bond of ax-1 was not affected, and only
the methylthio C-S bond reacted. The product 3 was
obtained as a single isomer, and its stereochemistry was
Scheme 3
626
Org. Lett., Vol. 11, No. 3, 2009

reaction occurred in the absence of the complex, and dppe
was not required for this reaction.
Scheme 4
To compare the methylthio transfer ability of other
ketones, several R-methylthioacetophenones with different
para substituents were reacted with ax-1 (5 equiv). When
R-methylthiolated acetophenenone 2d or p-methoxyace-
tophenone 2e was used, 3 was obtained in low yields (Table
2, entries 4 and 5). In the case of 2e, a substantial alkylthio
Table 2. Effect of the MethylthioTransfer Reagent
R-phenylthioacetophenone 8 (45%) and 5a (78%). Dithio-
acetals derived from 2a and p-methoxyacetophenone 5e were
not formed.
R,R-Dialkylthio ketones have been used as intermediates
in organic synthesis, and the conventional synthesis from
ketones and R-alkylthio ketones employed stoichiometric
amounts of bases to generate enolates or highly reactive
sulfenylating reagents such as sulfenyl sulfones.5 The
synthesis described herein has the advantage of not using
such high energy reagents, which irreversibly produce waste
byproducts. It should also be noted that unsymmetrical
thioacetals were obtained by this method.
A rhodium catalyst brings a single-bond metathesis reac-
tion of C-H and C-S bonds to equilibrium. Similar to
proton transfer at the ketone R-position via enol/enolates
under acidic/basic conditions, the methylthio group can be
transferred in an intramolecular fashion via rhodium inter-
mediates possessing C-Rh and/or Rh-S structures. We have
also shown that the methylthio group can be introduced to
and removed from organic molecules under equilibrium, and
studies to explore efficient methylthio transfer reagents,
catalysts, and systems to shift equilibrium are now underway.
yielda (%)
entry
X
3
5
1b
4
2
6
1
2
3
4
5
CN
CF3
Cl
H
MeO
a
b
c
d
e
45
38
17
6
84
74
30
67
29
55
85
89
82
88
1
11
17
65
4
6
12
8
trace
2
7(65)c
NDd
2
43e
26(44)c
NDd
a Yield based on 2. b Yield of 3:2 mixtures of ax-1 and eq-1 based on
1. c Yield of R-phenylthiolated acetophenone ArCOCH2SPh. d Not detected.
e A 6:1 mixture of 4 and its equatorial isomer.
exchange reaction took place, as indicated by the formation
of 4 (43%) and R-phenylthioacetophenone (44%). p-Trif-
luoromethylacetophenone 2b gave 3 in 38% yield (entry 2).
The results indicated a higher methylthio transfer ability of
the acetophenone derivatives with electron-withdrawing para
groups. The reaction of dimethyl disulfide (1 equiv) and ax-1
gave 3 only in 2% yield with the recovery of 1 in 79% as a
3:2 mixture of diastereomers, which was accompanied by a
5:2 mixture of 4 and its isomer (14%).
Acknowledgment. This work was supported by JSPS
(Nos. 16109001 and 17689001), and WPI Initiative, MEXT,
Japan. M.A. expresses her thanks for the Grant-in-Aid for
Scientific Research on Priority Areas, “Advanced Molecular
Transformation of Carbon Resources”, from MEXT (Nos.
18037005 and 19020008).
The reaction of adamantyl phenylthiomethyl ketone, tert-
butyl phenylthiomethyl ketone, and 1-methylcyclohexyl
phenylthiomethyl ketone with 2a gave the methylthiolated
products in 87%, 78%, and 84% yields, respectively (Scheme
4). Although the yields in this methylthiolation reaction were
under thermodynamic control, these products were obtained
in high yields. The reaction of 2a and p-methoxy-R-
phenylthioacetophenone 7 is an interesting example of the
selective methylthio transfer giving p-methoxy-R-methylthio-
Supporting Information Available: Detailed experimen-
tal procedures and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL802619E
(5) For examples: O2NC6H4SSMe. (a) Grossert, J. S.; Dubey, P. K.
Chem. Commun. 1982, 1183. (b) Tsunetsugu, J.; Ikeda, T.; Suzuki, N.;
Yaguchi, M.; Sato, M.; Ebine, S.; Morinaga, K. J. Chem. Soc., Perkin Trans.
1 1985, 785. (c) Trost, B. M.; Mao, M. K.-T.; Balkovec, J. M.; Buhlmayer,
P. J. Am. Chem. Soc. 1986, 108, 4965. (d) Sugihara, Y.; Wakabayashi, S.;
Saito, N.; Murata, I. J. Am. Chem. Soc. 1986, 108, 2773. RSTs. (e)
Woodward, R. B.; Pachter, I. J.; Scheinbaum, M. L. J. Org. Chem. 1971,
36, 1137. (f) Trost, B. M.; Hiroi, K.; Jungheim, L. N. J. Org. Chem. 1980,
45, 1839. (g) Tosaka, A.; Ito, S.; Miyazawa, N.; Shibuya, M.; Ogasawara,
K.; Iwabuchi, Y. Heterocycles 2006, 70, 153. Na2Te/disulfide. (i) Pad-
manabhan, S.; Ogawa, T.; Suzuki, H. Bull. Chem. Soc. Jpn. 1989, 62, 1358.
(3) When 2a was reacted with RhH(PPh3)4 (4 mol %) and dppe (8 mol
%) in refluxing THF for 4 h, 5a was obtained in 9% yield. No reaction
took place when Rh complex or phosphine was not added.
¨
(4) Related observation with 2-phenylthiocyclohexanone. (a) Ozbal, H.;
Zajac, W. W., Jr. Tetrahedron Lett. 1979, 20, 4821. Also see: (b) Trost,
B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887.
Org. Lett., Vol. 11, No. 3, 2009
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