Rhodium-catalyzed carbene-transfer reactions via thienylcarbene complexes generated from thiocarbamoyl-ene-yne compounds

Article abstract of DOI:10.1055/s-0030-1259559

Catalytic thienylcarbene-transfer reactions have been developed. The rhodium-catalyzed reaction of alkenes, furans, and thiophenes with a thiocarbamoyl-ene-yne compound as a carbene source gave the cyclopropanation products or ring-opened products of heterocycles. These processes provide efficient synthetic methods for thiophene-containing complex molecules. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259559

LETTER
655
Rhodium-Catalyzed Carbene-Transfer Reactions via Thienylcarbene
Complexes Generated from Thiocarbamoyl-ene-yne Compounds
R
hodium-Catalyze
s
d
Carbene
u
-Transfer Re
k
actions a Tsuneishi, Kazuhiro Okamoto, Yuji Ikeda, Masahito Murai, Koji Miki, Kouichi Ohe*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University,
Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
Fax +81(75)3832499; E-mail: ohe@scl.kyoto-u.ac.jp
Received 18 December 2010
thienylcyclopropane 2a in 84% yield (Table 1, entry
1).9,10 It turned out that the major diastereomer of product
2a was a cis-isomer (cis/trans = 81:19). The reaction of 1
with styrene gave 91% yield of 2b, which was in turn a
Abstract: Catalytic thienylcarbene-transfer reactions have been de-
veloped. The rhodium-catalyzed reaction of alkenes, furans, and
thiophenes with a thiocarbamoyl-ene-yne compound as a carbene
source gave the cyclopropanation products or ring-opened products
of heterocycles. These processes provide efficient synthetic meth- trans-rich mixture (cis/trans = 30:70; Table 1, entry 2).
ods for thiophene-containing complex molecules.
The reaction with 1,1-diphenylethylene also gave the cor-
responding cyclopropane 2c in 80% yield (Table 1, entry
3).
Key words: thiocarbamoyl-ene-yne, rhodium, carbene complex,
cyclopropanation, ring-opening reaction
In the reaction of furans with carbene complexes, we have
to consider several pathways including cyclopropanation,
C–O insertion, and ring opening of furans.11 In some cas-
es, the selective ring-opening reaction proceeds. A thie-
nylcarbene complex generated from thiocarbamoyl-ene-
yne is also expected to react with furans. Indeed, 2-meth-
oxyfuran reacted with thiocarbamoyl-ene-yne 1 to give
thienyldienoate 3a in 90% yield (Table 2, entry 1).12 This
reaction is applicable to various 2-substituted furans to
give the corresponding ring-opening products in the opti-
mized solvents (THF or DCE). In the case of 2-alkyl-
furans, the products were obtained only in moderate
yields (Table 2, entries 2 and 3). The reaction with aro-
matic-substituted furans at 2-position gave the dienone
3b–g in high yields (Table 2, entries 4–9).
Transition-metal-catalyzed transformations involving
carbene complexes are powerful methods especially for
carbon–carbon bond formation.1 Although diazoalkanes
have been widely used as some of the most common pre-
cursors for carbenoid generation,2 such compounds must
be handled carefully because of their explosive nature.
The activation of alkynes by transition-metal catalysts
giving carbene complexes with cyclization or rearrange-
ment has emerged as an alternative method.3 Among
them, reactions involving carbene complexes generated
with the formation of furan or pyrrole rings as a driving
force are efficient processes in terms of atom efficiency
(Scheme 1, Y = O, NR2).4 However, no such reaction with
the formation of thiophene rings has been reported
(Scheme 1, Y = S). Here we report the catalytic carbene-
transfer reactions via thienylcarbene complexes generated
from thiocarbonyl-ene-yne compounds.
We next examined the ring-opening reactions of
thiophenes, which are anticipated to be less reactive than
furans because of their resonance stability.13 Under the
above reaction conditions, the reaction of thiocarbamoyl-
ene-yne 1 with 2-methoxythiophene gave the ring-open-
ing product 4a in 62% yield (Table 3, entry 1).14,15 The in-
stability of the methoxythiocarbonyl group of the product
4a resulted in a low yield. Therefore, we employed 2-ami-
nothiophenes,16 which were expected to provide more sta-
ble products having thioamide moieties. As expected, the
use of pyrrolidino-, piperidino-, diethylamino-, and mor-
Since thioaldehydes and thioketones are generally unsta-
ble, we employed an ene-yne compound with a thiocar-
bamoyl moiety (1)5–8 as a substrate for the rhodium-
catalyzed cyclopropanation of alkenes, which was report-
ed by us using carbonyl-ene-ynes or imino-ene-ynes as
carbene sources.4 The reaction of thiocarbamoyl-ene-yne
1 with tert-butyl vinyl ether in the presence of 2.5 mol%
of [Rh(OAc)2]2 at room temperature gave the expected
R1
R1
R1
Y
R1
Y
[M]
Y
Y
[M]
–[M]
[M]
Y = O, NR2, S
Scheme 1 Cyclization-induced generation of carbene complexes
SYNLETT 2011, No. 5, pp 0655–0658
x
x.
x
x.
2
0
1
1
Advanced online publication: 11.02.2011
DOI: 10.1055/s-0030-1259559; Art ID: U11510ST
© Georg Thieme Verlag Stuttgart · New York

656
A. Tsuneishi et al.
LETTER
reaction with 2-aminothiophenes. As shown in Scheme 2,
we examined the reaction of 2-pyrrolidinothiophene with
ethyl diazoacetate under the above conditions, and found
that C–H insertion17 products were obtained as major
products in 64% yield (3-substituted/5-substituted = 67:33).
Other carbene sources were also examined.18 Carbonyl-
ene-yne compound 7,4a,c a previously reported carbene
source, was also reacted with 2-pyrrolidinothiophene.
However, the yield of ring-opening product 8 was only
67% (Scheme 3).
Table 1 Rhodium-Catalyzed Cyclopropanation of Alkenes via a
Thienylcarbene Complexa
NMe2
S
NMe2
1
+
R1
[Rh(OAc)2]2 (2.5 mol%)
S
THF, r.t., 2 h
R1
R2
R2
5.0 equiv
2
N2
Entry
R1
R2
Product
2a
Yield (%)b (cis/trans)c
84 (81:19)
91 (30:70)
80
[Rh(OAc)2]2 (2.5 mol%)
OEt
+
H
1
2
3
Ot-Bu
Ph
H
N
THF, r.t., 12 h
S
O
2.0 equiv
H
2b
CO2Et
Ph
Ph
2c
EtO2C
+
a The reaction was carried out with 1 (0.30 mmol), alkene (0.5 mmol),
and [Rh(OAc)2]2 (2.5 mol%) in THF (3.0 mL) at r.t. for 2 h.
b Isolated yield.
N
S
N
S
5
6
c Determined by 1H NMR.
64% (5/6 = 67:33)
Scheme 2 Ring-opening reaction with ethyl diazoacetate
Table 2 Rhodium-Catalyzed Ring-Opening Reaction of Furansa
NMe2
Ph
O
S
NMe2
1
[Rh(OAc)2]2 (2.5 mol%)
+
S
Ph
DCE, r.t., 2 h
7
+
[Rh(OAc)2]2 (2.5 mol%)
O
R
O
THF, r.t., 24 h
3
5.0 equiv
R
N
O
S
N
2.0 equiv
Entry
R
Product
3a
Yield (%)b
S
1
2
3
4
5
6
7
8
9
OMe
90
48c
64c
80
97
94
96
94
89
8 67% (EE/EZ = 67:33)
Scheme 3 Ring-opening reaction with carbonyl-ene-yne compound 7
Me
3b
Et
3c
In summary, we have developed catalytic carbene-trans-
fer reactions via a thienylcarbene complex from thiocar-
bamoyl-ene-yne 1. This type of carbene source was
applicable to not only cyclopropanation reaction, which
has been achieved by the use of furyl- or pyrrolylcarbene
complexes, but also ring-opening reactions of furans and
thiophenes. Especially, the ring opening of 2-ami-
nothiophenes succeeded specifically in the reaction of
thiocarbamoyl-ene-yne 1, while other carbene sources re-
sulted in lower yields of ring-opening products or in the
formation of C–H insertion products. Synthetic applica-
tions of thienylcarbene complexes to preparation of con-
jugated heterocycles are under way in our laboratory.
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-NCC6H4
4-F3CC6H4
3d
3e
3f
3g
3h
3i
a The reaction was carried out with 1 (0.30 mmol), furan (1.5 mmol),
and [Rh(OAc)2]2 (2.5 mol%) in DCE (3.0 mL) at r.t. for 2 h.
b Isolated yield.
c In THF.
Acknowledgment
pholinothiophene resulted in high yields of the ring-open-
ing products (Table 3, entries 2–5).12
This work is supported by Grant-in-Aid for Scientific Research on
Priority Areas ‘Synergistic Effects for Creation of Functional Mo-
lecules’ (Area 459, No. 19027027) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
Interestingly, ethyl diazoacetate, which is widely used as
a common carbene source, showed a different reactivity
from thiocarbamoyl-ene-yne 1 in the rhodium-catalyzed
Synlett 2011, No. 5, 655–658 © Thieme Stuttgart · New York

LETTER
Rhodium-Catalyzed Carbene-Transfer Reactions
657
Table 3 Rhodium-Catalyzed Ring-Opening Reaction of Thiophenesa
NMe2
NMe2
[Rh(OAc)2]2 (2.5 mol%)
DCE, r.t., 2 h
S
+
S
R
S
2.0 equiv
R
S
Entry
R
Time (h)
Product
4a
Yield (%)b
1
2
3
4
5
OMe
16
8
62
pyrrolidino
piperidino
diethylamino
morpholino
4b
91c
88c
94c
76
8
4c
6
4d
12
4e
a The reaction was carried out with 1 (0.30 mmol), thiophene (0.60 mmol), and [Rh(OAc)2]2 (2.5 mol%) in DCE (3.0 mL) at r.t. for 2 h.
b Isolated yield.
c In THF.
2 H). 13C NMR (75 MHz, CDCl3): d = –0.1, 21.8, 24.1, 31.7,
36.3, 98.3, 104.9, 121.4, 129.8.
(8) Synthesis of N,N-Dimethyl 2-Ethynyl-1-cyclohexene-
thiocarboxamide (1)
References and Notes
(1) (a) Zaragozasm Dörward, F. Metal Carbenes in Organic
Synthesis; Wiley-VCH: Weinheim, 1999. (b) Metal
Carbenes in Organic Synthesis, In Topics in Organometallic
Chemistry, Vol. 13; Dötz, K. H., Ed.; Springer: Berlin, 2004.
(2) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds;
Wiley-Interscience: New York, 1998.
(3) (a) Miki, K.; Uemura, S.; Ohe, K. Chem. Lett. 2005, 34,
1068. (b) Kusama, H.; Iwasawa, N. Chem. Lett. 2006, 35,
1082. (c) Ohe, K. Bull. Korean Chem. Soc. 2007, 28, 2153.
(d) Ohe, K.; Miki, K. J. Synth. Org. Chem. Jpn. 2009, 67,
1161.
(4) (a) Miki, K.; Nishino, F.; Ohe, K.; Uemura, S. J. Am. Chem.
Soc. 2002, 124, 5260. (b) Nishino, F.; Miki, K.; Kato, Y.;
Ohe, K.; Uemura, S. Org. Lett. 2003, 5, 2615. (c) Miki, K.;
Yokoi, T.; Nishino, F.; Kato, Y.; Washitake, Y.; Ohe, K.;
Uemura, S. J. Org. Chem. 2004, 69, 1557.
(5) Thiocarbamoyl moiety was also used for the generation of
vinylcarbene complexes. See: Ikeda, Y.; Murai, M.; Abo, T.;
Miki, K.; Ohe, K. Tetrahedron Lett. 2007, 48, 6651.
(6) Thiocarbamoyl-ene-yne 1 was synthesized in two steps from
1,2-dibromocyclohexene, which was prepared according to
the known procedure. See: Voigt, K.; von Zezschwitz, P.;
Rosauer, K.; Lansky, A.; Adams, A.; Reiser, O.; de Meijere,
A. Eur. J. Org. Chem. 1998, 1521.
To a solution of 1-bromo-2-trimethylsilylethynylcyclohex-
1-ene (2.56g, 10 mmol) in THF (20 mL) was added dropwise
n-BuLi (7.5 mL, 12.0 mmol) at –78 °C under N2. The
mixture was stirred at –78 °C for 30 min, and then N,N-
dimethylthiocarbamoyl chloride (1.5g, 15.0 mmol) was
added to it. After further stirring at r.t. for 2 h, the organic
solution was washed with H2O, and the aquous phase was
extracted with Et2O (3 × 10 mL). The combined organic
phase was dried over MgSO4. The solvent was removed
under reduced pressure. The residue was filtered through a
pad of silica gel. The filtrate was removed under reduced
pressure. To a solution of the residue in DMSO (20 mL)
were added KF (0.59 g, 10 mmol) and H2O (1 mL). The
mixture was stirred at r.t. for 2 h. The reaction mixture was
poured into H2O, and the aqueous phase was extracted with
Et2O (3 × 10 mL). The combined organic phase was dried
over MgSO4. The solvent was removed under reduce
pressure, and the residue was purified by column chroma-
tography on silica gel with hexane–EtOAc (v/v = 4:1) as an
eluent to afford N,N-dimethyl 2-ethynyl-1-cyclohexenethio-
carboxamide (640 mg, 3.3 mmol 33% yield) as a dark brown
solid; mp 42.1–43.0 °C. IR (KBr): 1061, 1123, 1140, 1395,
1520, 2858, 2931, 3223 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.60–1.79 (m, 4 H), 2.01–2.07 (m, 1 H), 2.20–2.26
(m, 2 H), 2.68–2.78 (m, 1 H), 3.04 (s, 1 H), 3.28 (s, 3 H), 3.47
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 21.7, 21.8, 28.7,
29.0, 41.8, 41.9, 80.7, 82.4, 113.29, 147.7, 201.0. HRMS–
FAB: m/z calcd for C11H16NS [M + H+], 194.1003; found:
194.1003.
(7) Synthesis of 1-Bromo-2-trimethylsilylethynylcyclohex-1-
ene
To a solution of trimethylsilylacetylene (1.96 g, 20 mmol) in
toluene (40 mL) were added tert-butylamine (5 mL) and 1,2-
dibromocyclohexene (9.6 g, 40 mmol) at r.t. under N2. CuI
(0.68 g, 3.6 mmol) and Pd(PPh3)4 (1.35 g 1.2 mmol) were
added to the solution, and the mixture was stirred at 60 °C
for 2 h. The reaction mixture was filtered through a pad of
silica gel with Et2O. The filtrate was removed under reduced
pressure, and the residue was purified by column chromatog-
raphy on silica gel with hexane to afford 1-bromo-2-
trimethylsilylethynylcyclohex-1-ene (4.6 g. 18 mmol, 45%)
as a colorless oil. 1H NMR (300 MHz, CDCl3): d = 0.21 (s,
9 H), 1.55–1.75 (m, 4 H), 2.21–2.26 (m, 2 H), 2.50–2.55 (m,
(9) In sharp contrast, the reaction of carbamoyl-ene-yne
compounds with a chromium complex gives not furyl
carbene–chromium complexes but pyranylidene–chromium
complexes. Theoretical investigations are in progress and
will be published in due course. See: (a) Ohe, K.; Miki, K.;
Yokoi, T.; Nishino, F.; Uemura, S. Organometallics 2000,
19, 5525. (b) Miki, K.; Yokoi, T.; Nishino, F.; Ohe, K.;
Uemura, S. J. Organomet. Chem. 2002, 645, 228.
Synlett 2011, No. 5, 655–658 © Thieme Stuttgart · New York

658
A. Tsuneishi et al.
LETTER
(10) The use of platinum or gold catalyst precursors (PtCl2, AuCl,
AuCl3) was not effective in this reaction.
d = 23.1, 23.1, 25.2, 25.4, 44.8, 50.1, 112.7, 119.8, 123.9,
124.3, 133.0, 140.9, 146.0, 155.3, 167.4. Anal. Calcd for
C16H21NO2S: C, 65.95; H, 7.26. Found: C, 66.06; H, 7.22.
Compound 4e
Red solid; yield 76%; mp 79.0–80.0 °C. IR (KBr): 1119,
1269, 1396, 1558 cm–1. 1H NMR (400 MHz, CDCl3): d =
1.60–1.75 (m, 4 H), 2.50–2.55 (m, 2 H), 2.68–2.77 (m, 2 H),
2.80 (s, 6 H), 3.78 (br s, 8 H), 4.20–4.40 (m, 2 H,), 6.45 (t,
J = 13.2 Hz, 1 H), 6.52 (d, J = 14.2 Hz, 1 H), 7.03 (d,
J = 15.1 Hz, 1 H), 7.73 (t, J = 12.7 Hz, 1 H). 13C NMR (100
MHz, CDCl3): d = 15.2, 22.9, 23.2, 25.2, 25.5, 44.7, 50.3,
65.8, 66.6, 121.5, 123.3, 124.0, 124.7, 131.9, 141.1, 147.9,
154.8, 194.9. HRMS–FAB: m/z calcd for C19H26N2OS2
[M+]: 362.1487; found: 362.1473.
(11) (a) Pirrung, M. C.; Zhang, J.; Lackey, K.; Strenbach, D. D.;
Brown, F. J. Org. Chem. 1995, 60, 2112. (b) Shieh, C. P.;
Ong, C. W. Tetrahedron 2001, 57, 7303. (c) Miki, K.;
Fujita, M.; Kato, Y.; Uemura, S.; Ohe, K. Org. Lett. 2006, 8,
1741.
(12) Typical Procedure for Rhodium-Catalyzed Ring-
Opening Reaction of Thiocarbamoyl-ene-yne 1 with 2-
Methoxyfuran
To a solution of [Rh(OAc)2]2 (3.3 mg, 0.0075 mmol) in
anhyd DCE (3.0 mL) were added thiocarbamoyl-ene-yne 1
(59 mg. 0.30 mmol) and 2-methoxyfuran (150 mg, 1.50
mmol) under N2. The mixture was stirred at r.t. for
appropriate time. The mixture was diluted with EtOAc (10
mL), and the solution was evaporated under reduced
pressure. The residue was purified by column
(13) Katritzky, A. R.; Ramsden, C. A.; Joule, J. A.; Zhdankin,
V. V. Handbook of Heterocyclic Chemistry, 3rd ed.;
Elsevier: Amsterdam, 2010, 126–128.
chromatography on silica gel with hexane–EtOAc (v/v =
10:1).
Compound 3a
Orange solid; yield 90%; 1E,4E/1Z,4E = 99:1; mp 108.5–
109.5 °C. IR (KBr): 877, 1008, 1237, 1332, 1394, 1590,
1701, 2831, 2938 cm–1.
(14) Rhodium-catalyzed ring-opening reaction of 2-methoxy-
thiophene with ethyl diazoacetate has been reported. See:
Tranmer, G. K.; Capreta, A. Tetrahedron 1998, 54, 15499.
(15) Catalytic ring-opening reaction of 2-methoxythiophene with
propargyl acetates as carbene sources has been reported. See
ref. 11c.
Compound (1E,4E)-3a: 1H NMR (300 MHz, CDCl3): d =
1.63–1.78 (m, 4 H), 2.41–2.56 (m, 2 H), 2.62–2.71 (m, 2 H),
2.79 (s, 6 H), 3.73 (s, 3 H), 5.80 (d, J = 15.0 Hz, 1 H), 6.38
(dd, J = 15.0, 11.3 Hz, 1 H), 6.96 (d, J = 15.0 Hz, 1 H), 7.39
(dd, J = 15.0, 11.3 Hz, 1 H). 13C NMR (75.5 MHz, CDCl3):
d = 22.9, 23.2, 25.2, 25.4, 44.7, 51.2, 116.7, 120.5, 123.5,
124.5, 132.1, 140.9, 145.7, 154.9, 167.9.
(16) 2-Aminothiophenes were synthesized according reported
procedures. See: Lu, Z.; Twieg, R. J. Tetrahedron 2005, 61,
903.
(17) (a) Gillespie, R. J.; Porter, A. E. A. J. Chem. Soc., Perkin
Trans. 1 1979, 2624. (b) Lee, Y. R.; Cho, B. S. Bull. Korean
Chem. Soc. 2002, 23, 779.
(18) The reaction of 1,1-dimethyl-2-propynyl acetate and 2-
pyrrolidinothiophene in the presence of [RuCl2(CO)3]2 or
PtCl2 as a catalyst gave no ring-opening product. Compared
with ref. 13, the reactivity of 2-aminothiophenes towards
ring opening seems to be lower than that of furans or 2-
methoxythiophene.
Compound (1Z,4E)-3a: 1H NMR (300 MHz, CDCl3): d =
1.63–1.78 (m, 4 H), 2.41–2.56 (m, 2 H), 2.62–2.71 (m, 2 H),
2.82 (s, 6 H), 3.76 (s, 3 H), 5.51 (d, J = 11.5 Hz, 1 H), 6.66
(dd, J = 11.5, 11.5 Hz, 1 H), 6.89 (d, J = 15.0 Hz, 1 H), 7.69
(dd, J = 15.0, 11.5 Hz, 1 H). 13C NMR (75.5 MHz, CDCl3):
Synlett 2011, No. 5, 655–658 © Thieme Stuttgart · New York

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