Rh-Catalyzed Direct Carboxylation of Alkenyl C?H Bonds of Alkenylpyrazoles

Article abstract of DOI:10.1002/asia.202000476

The Rh-catalyzed direct carboxylation of alkenyl C?H bonds was achieved by using pyrazole as a removable directing group. In the presence of 5 mol% RhCl₃ ? 3H₂O, 6 mol% P(Mes)₃, and 2 equiv. of AlMe₂(OMe), the alkenyl C?H bond of various alkenylpyrazoles was directly carboxylated in good yields under CO₂ atmosphere. Furthermore, several useful transformations of the pyrazole moiety of the product were achieved to afford synthetically useful carboxylic acid derivatives in good yields.

Full text of DOI:10.1002/asia.202000476

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Rh-Catalyzed Direct Carboxylation of Alkenyl C–H Bonds of
Alkenylpyrazoles
Authors: Takanobu Saito, Yushu Jin, Kotaro Isobe, Takuya Suga, Jun
Takaya, and Nobuharu Iwasawa
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To be cited as: Chem. Asian J. 10.1002/asia.202000476
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10.1002/asia.202000476
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Rh-Catalyzed Direct Carboxylation of Alkenyl C–H Bonds of
Alkenylpyrazoles
Takanobu Saitou, Yushu Jin, Kotaro Isobe, Takuya Suga, Jun Takaya, Nobuharu Iwasawa*
Abstract: The Rh-catalyzed direct carboxylation of alkenyl C–H
cyclohexenylpyridine 1, 5 mol% [Rh(coe)2Cl]2 (10 mol% Rh metal),
molar amounts of
bonds was achieved by using pyrazole as a removable directing group. 12 mol% tricyclohexylphosphine, and
2
In the presence of 5 mol% RhCl3•3H2O, 6 mol% P(Mes)3, and 2 equiv.
of AlMe2(OMe), the alkenyl C-H bond of various alkenylpyrazoles was
directly carboxylated in good yields under CO2 atmosphere.
Furthermore, several useful transformations of the pyrazole moiety of
the product were achieved to afford synthetically useful carboxylic
acid derivatives in good yields.
AlMe2(OMe) was heated in DMA at 70 °C for 4 hours under 1 atm
of CO2, the desired carboxylated product 2 was obtained in 28%
yield, along with the direct methylated compound 3 in 20% yield
(Scheme 1a).
a) Initial Result
CO2 (1 atm, closed)
[Rh(coe)2Cl]2 (5.0 mol%)
PCy3 (12 mol%)
Transition metal-catalyzed direct C–H carboxylation reactions
have been attracting much attention as a useful method for the
utilization of carbon dioxide as a one-carbon source,[1,2] and
several approaches have recently been reported for the direct
carboxylation of aryl C–H bonds. For examples, Nolan’s group
along with Hou’s group reported gold(I) hydroxide or copper(I)
alkoxide-catalyzed direct carboxylation of aromatic compounds
having rather acidic hydrogens (pKa <30).[3,4] We also reported
rhodium(I)-catalyzed direct carboxylation of phenylpyridines and
phenylpyrazoles utilizing the oxidative addition of aryl C–H bonds
Me
H
COOH
AlMe2(OMe) (2.0 equiv.)
N
N
N
DMA, 70 °C, 4 h
1
2
3
28% yield
20% yield
b) Optimized Conditions
CO2 (1 atm, closed)
RhCl3•3H2O (5.0 mol%)
P(Mes)3 (6.0 mol%)
AlMe2(OMe) (2.0 equiv.)
CO2Me
N
H
by using
a methylaluminum reagent as a stoichiometric
TMSCHN2
reductant,[5a] and the reaction was further extended to the direct
carboxylation of simple aromatic compounds.[5b,c] In contrast to
the direct carboxylation of aryl C–H bonds, the transition metal-
catalyzed direct carboxylation of alkenyl C–H bonds based on C–
H bond activation has rarely been achieved partly because of the
increased difficulty due to possible side reactions such as further
conjugate addition to the produced a,b-unsaturated carboxylic
acid derivatives under the reaction conditions. Actually, only one
example has been reported for the transition metal-catalyzed
alkenyl C-H carboxylation reaction, that is, palladium(II)-catalyzed
direct carboxylation of o-hydroxystyrenes to give coumarins.[6]
However, this reaction was limited to o-hydroxystyrene
derivatives, and it is desirable to develop a new method which is
potentially applicable to alkenes in general.[7-10] In this regard, the
Rh(I)-catalyzed direct carboxylation of aryl C–H bonds developed
in our group is attractive because it would be applicable to the
reaction of alkenes. In this paper, we report a rhodium-catalyzed
direct carboxylation of alkenyl C−H bonds utilizing oxidative
addition of the sp2 C-H bond of alkenylpyrazole derivatives along
with further transformation of the product utilizing pyrazole as a
removable directing group.
N
N
N
DMA, 90 °C, 8 h
5
4
75% yield
Scheme 1. Optimization of reaction conditions.
To suppress the formation of the direct methylation product,
various directing groups were investigated. After examination of
representative directing groups and several other reaction
conditions,[11] it was found that when installing a pyrazole moiety
as the directing group, carboxylation of cyclohexenylpyrazole 4
proceeded smoothly in high yield without detection of methylation
product.[12] In addition, use of RhCl3•3H2O as a rhodium precursor
improved the yield to some extent. The olefinic ligand derived
from the Rh catalyst was thought to compete with the substrate to
coordinate to the rhodium metal resulting in decrease of the yield.
No carboxylation product was detected when the reaction was
conducted without the rhodium catalyst. Finally, the best result
was obtained by heating a mixture of cyclohexenylpyrazole 4, 5
mol% RhCl3•3H2O, 6 mol% trimesitylphosphine, and 2 molar
amounts of AlMe2(OMe) at 90 °C for 8 hours. The desired C–H
carboxylation product 5 was isolated in 75% yield after methyl
esterification with trimethylsilyldiazomethane. No undesired
methylation product was obtained under these conditions.
(Scheme 1b). It should be noted that despite the potential
reactivity of a,b-unsaturated carboxylic acid derivatives to
alkenylrhodium nucleophiles, the product remained intact under
the reaction conditions and decomposition or further reaction of
the product was not observed.
Initially, the reaction of cyclohexenylpyridine 1 was examined
under the best reaction conditions developed for the reaction of
phenylpyridine
derivatives.[5a]
When
a
mixture
of
[*]
T. Saitou, Dr. Y. Jin, K. Isobe, Dr. T. Suga, Dr. J. Takaya, Prof. Dr.
N. Iwasawa
Department of Chemistry
Tokyo Institute of Technology
2-12-1, O-Okayama, Meguro-ku, Tokyo, 152-8551 (Japan)
Fax: (+)81-3-5734-2931
E-mail: niwasawa@chem.titech.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
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10.1002/asia.202000476
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COMMUNICATION
Under the best reaction conditions, the generality of the reaction
was examined (Table 1). Cycloalkenylpyrazoles such as
cyclopentenyl (6a) and cycloheptenylpyrazoles (6b) gave the
corresponding products in good yield.
useful yields. In the reactions of these 1,1-disubstituted
alkenylpyrazoles, small amounts of (E)-alkenoates were also
obtained due to the partial isomerization of initially produced (Z)-
isomers under the reaction conditions in most cases. Finally, the
carboxylation of 1,2-disubstituted alkenylpyrazole (6l) also
proceeded selectively at the b-position by carrying out the
reaction at an elevated temperature (110 ˚C) to give (Z)-7l as the
major product, although the yield was moderate. It should be
noted that the alkene substrates were mostly consumed in these
reactions and several unidentified products were detected,
especially with acyclic substrates.
To exhibit the usefulness of this transformation, a gram scale
carboxylation of 6a was conducted (Scheme 2). To our delight,
the reaction proceeded smoothly even with a decreased catalyst
loading (1.0 mol%) at lower temperature (70˚C). After methyl
esterification, 7a was isolated in 70% yield, showing the strong
power of our Rh(I)-catalyst in this carboxylation (TON = 70).
Table 1. Generality of the reaction.a
R2
R2
CO2 (1 atm, closed)
RhCl3•3H2O (5.0 mol%)
P(Mes)3 (6.0 mol%)
AlMe2(OMe) (2.0 equiv.)
R1
R1
H
CO2Me
TMSCHN2
N
N
N
N
DMA, 90 °C, 8 h
7
6
n-Hex
CO2Me
CO2Me
CO2Me
N
N
N
N
N
N
CO2 (1 atm, closed)
RhCl3•3H2O (1.0 mol%)
7a 69%b
7c 64%
(E : Z = 4 : 96)
7b 78%
H
P(Mes)3 (1.2 mol%)
AlMe2(OMe) (2.0 equiv.)
CO2Me
TMSCHN2
N
N
N
DMA, 70 ˚C, 8 h
N
Ph
Ph
CO2Me
CO2Me
CO2Me
6a
1.0 g
7a
70% yield
N
N
N
N
N
N
7e 53%c
(E : Z = 8 : 92)
7d 69%
(E : Z = <5 : >95)
7f 64%
(E : Z = 3 : 97)
Scheme 2. Gram scale carboxylation of 6a using CO2.
OTIPS
( )
OTHP
( )
( )
Currently, the reaction is thought to proceed in a similar manner
to the reaction of phenylpyridines as shown in Scheme 3.[5a,c]
Initially, MeRh(I) species (A) is generated by the reaction of RhCl3
with AlMe2(OMe). Then, the pyrazole-directed oxidative addition
of the alkenyl C-H bond occurs to give MeH(alkenyl)Rh(III) (B),
which undergoes reductive elimination of methane to give
(alkenyl)Rh(I) species (C). Carboxylation occurs at this stage to
give Rh(I) carboxylate (D). Finally, transmetallation with
AlMe2(OMe) regenerates MeRh(I) species (A) along with
liberation of the aluminum carboxylate product.
Ph
3
CO2Me
CO2Me
CO2Me
3
2
N
N
N
N
N
N
7i 62%b
(E : Z = 4 : 96)
7h 51%
(E : Z = 11 : 89)
7g 48%
(E : Z = 3 : 97)
O
Ph
CO2Me
( )
( )3
N
CO2Me
CO2Me
3
N
CO2Me
N
N
N
O
N
N
(Z)-7l 45%
(E)-7l 7%
LnRh–Cl
7j 60%
(E : Z = 6 : 94)
7k 69%bd
(E : Z = 5 : 95)
AlMe2(OMe)
O[Al]
(E : Z = 13 : 87)de
H
O
N
AlMe(OMe)Cl
N
N
aAll reactions were conducted on a 0.3 mmol scale in DMA (3.0 mL)
at 90 ˚C for 8 hours unless otherwise noted. The yields shown are
isolated yields of major isomers. The E/Z ratio in parentheses were
determined according to the crude products. b4 h. c80 ˚C, 12 h. d110
˚C. e10 mol% RhCl3•3H2O,12 mol% P(Mes)3, the E/Z ratio was
calculated by isolated yield.
N
MeRhILn
(A)
AlMe2(OMe)
O
LnRhI–H
O
Me
RhILn
N
RhIII(Me)(H)Ln
N
N
N
N
Furthermore, acyclic 1,1-disubstituted alkenylpyrazoles such as
1-octen-2-ylpyrazole (6c), 1-cyclohexylethen-1-ylpyrazole (6d),
4-phenylbutene-2-ylpyrazole (6f) gave the corresponding direct
C−H carboxylation products 7c, 7d, 7f in good yields. Functional
groups such as OTHP (6h), silyl ether (6i), imide (6j), and ester
(6k) were tolerated under the reaction conditions and the
corresponding products 7h~k were obtained in synthetically
N
(B)
(D)
RhILn
(C)
N
CO2
N
CH4
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10.1002/asia.202000476
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COMMUNICATION
Scheme 3. Proposed mechanism.
acid derivatives in good yields. Application of this reaction to
simple alkenes is now in progress in our group.
Finally, replacement of the pyrazole moiety of the carboxylated
product 7e was examined to prepare synthetically useful
carboxylic acid derivatives. As summarized in Scheme 4,
methylation of the pyrazole moiety was found to be very important
for the transformations. Thus, methylation of the product followed
by hydrogenation gave saturated carboxylic ester 8 in quantitative
yield, while hydrogenation followed by methylation and base
treatment gave unsaturated carboxylic ester 9 in good yield
(Scheme 4, [Eq. (1) and (2)]). Replacement of the methylated
pyrazolium moiety of 10 with methyl or phenyl group was
successfully achieved by Rh(I)-catalyzed 1,4-addition reaction of
trimethylaluminum followed by elimination of N-methylpyrazole or
Ni-catalyzed coupling reaction with phenylboronic acid (Scheme
4, [Eq. (3) and (4)]).[13] Furthermore, pyridinecarboxylic acid
derivative 13 was obtained in reasonable yield on treatment of 10
with cesium carbonate (Scheme 4, [Eq. (5)]).[14] These results
clearly show the superiority of pyrazole as a removable directing
group for the C–H functionalization reactions.
Experimental Section
A DMA suspension (3.0 mL) of RhCl3•3H2O (4.0 mg, 0.015 mmol, 5.0
mol%), P(Mes)3 (7.0 mg, 0.018 mmol, 6.0 mol%) and 1-(cyclohex-1-en-1-
yl)-1H-pyrazole 4 (44.8 mg, 0.3 mmol) was stirred in a glass tube (ϕ = 1.7
cm, 18 cm) under an atmospheric pressure of CO2. AlMe2(OMe) (0.3 ml,
0.60 mmol, ca. 2.0 M in toluene) was added to the mixture at room
temperature and then the system was closed. The mixture was heated at
90 °C for 8 h. After the mixture was cooled to room temperature, 1N HCl
aq. (3.0 ml) was slowly added to the reaction mixture, which was stirred
until an evolution of gas ceased. Chloroform was added to the mixture to
induce separation of two layers. The mixture was kept stirring vigorously
for a certain period until both the organic and aqueous phase became
homogeneous. Adding more chloroform and/or 1N HCl aq. was allowed
when a small amount of precipitate remains undissolved after a long period.
The mixture was then extracted with chloroform five times. The combined
organic layer was added a small portion of NaHCO3 powder to neutralize
HCl and then dried over Na2SO4. After removal of the solvent under
reduced pressure, the residue was treated with TMSCHN2 (2.0 M sol. in
Et2O, 0.3 mL, 0.6 mmol) in Et2O/MeOH (3 : 1, 4.0 mL) at 0 °C in a 50 mL
round bottom flask under N2. After 1 h, all volatiles were removed under
reduced pressure and the residue was purified by preparative TLC plate
to give methyl 2-(1H-pyrazol-1-yl)cyclohex-1-ene-1-carboxylate 5 (46.5
mg, 0.23 mmol, 75%).
H2 (1 atm)
Pd/C (10 mol%)
MeOTf (1.0 equiv.)
DCM, r.t., 30 min
Ph
(1)
(2)
CO2Me
MeOH, r.t., 7 h
8
Ph
CO2Me
>99% yield from 7e
N
N
H2 (1 atm)
Pd/C (10 mol%)
1) MeOTf (1.55 equiv.)
DCM, r.t., 2.5 h
Ph
7e
CO2Me
Acknowledgements
MeOH, r.t., 3 h
2) DBU (1.0 equiv.)
DCM, r.t., 18 h
9
78% yield from 7e
(E isomer only)
This research was supported by Grant-in-Aid for Scientific
Research from MEXT, Japan (Grant No. 15H05800 and
17H06143), and ACT-C from JST (Grant No. JPMJCR12Y3). T.
S. thanks JSPS for a fellowship.
MeOTf (1.0 equiv.)
DCM, r.t., 30 min
97% yield
RhCl3•3H2O (5.0 mol%)
P(Mes)3 (6.0 mol%)
AlMe3 (2.0 equiv.)
Ph
CO2Me
(3)
DMA, 90 ˚C, 4 h
Me
11
Keywords: carboxylation• alkenyl C–H activation • pyrazole •
63% yield (E isomer, isolated)
(E : Z = 92 : 8 by crude NMR)
Rh(I) catalyst
Ni(cod)2 (10 mol%)
P(o-tol)3 (22 mol%)
Cs2CO3 (1.5 equiv.)
PhB(OH)2 (1.5 equiv.)
OTf
Ph
[1]
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compounds, see: a) Q. Liu, L. Wu, R. Jackstell, M. Beller, Nat. Commun.
2015, 6, 5933; b) R. Martin, A. Tortajada, F. Juliá-Hernández, M.
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4118.
Ph
CO2Me
CO2Me
(4)
N
Me
N
Ph
1,4-dioxane, 70 ºC, 6 h
12
75% yield
10
CO2Me
Cs2CO3 (1.0 equiv.)
Ph
NHMe
(5)
1,4-dioxane, 70 ˚C, 6 h
N
13
61% yield
[2]
[3]
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Scheme 4. Transformation of the product.
In conclusion, we have realized an efficient direct carboxylation of
the alkenyl C-H bonds of alkenylpyrazole derivatives. The
reaction is applicable to various cyclic and acyclic
alkenylpyrazoles containing functional groups to give the products
in good yield. Further transformations of the pyrazole moiety of
the product were achieved to afford synthetically useful carboxylic
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[11] For details of the examination of reaction conditions, see the supporting
information.
[12] a) T. Asaumi, N. Chatani, T. Matsuo, F. Kakiuchi, S. Murai, J. Org. Chem.
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2685.
[6]
[7]
K. Sasano, J. Takaya, N. Iwasawa, J. Am. Chem. Soc. 2013, 135,
10954–10957.
For examples of base promoted formal alkenyl C-H bond carboxylations,
see: a) Z. Zhang, L.-L. Liao, S.-S. Yan, L. Wang, Y.-Q. He, J.-H. Ye, J.
Li, Y.-G. Zhi, D.-G. Yu, Angew. Chem. Int. Ed. 2016, 55, 7068–7072;
Angew. Chem. 2016, 128, 7184–7188; b) Z. Zhang, T. Ju, M. Miao, J.-L.
Han, Y.-H. Zhang, X.-Y. Zhu, J.-H. Ye, D.-G. Yu, Y.-G. Zhi, Org. Lett.
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Song, J.-H. Ye, J. Li, D.-G. Yu, Chin. J. Chem. 2018, 36, 430–436; d) W.-
Z. Zhang, M.-W. Yang, X.-B. Lu, Green Chem. 2016, 18, 4181–4184; e)
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18732.
[13] S. B. Blakey, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 6046–
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[14] The reaction was thought to proceed as follows. See; A. Schmidt, N.
Münster, A. Dreger, Angew. Chem. Int. Ed. 2010, 49, 2790–2793; Angew.
Chem. 2010, 122, 2851– 2854.
OTf
CO2Me
Ph
Ph
NHMe
CO2Me
Me
[8]
For selected examples of Lewis acid-promoted electrophilic
carboxylation of alkenes, see: a) S. Tanaka, K. Watanabe, Y. Tanaka,
T. Hattori, Org. Lett. 2016, 18, 2576–2579; b) K. Nemoto, S. Tanaka, M.
Konno, S. Onozawa, M. Chiba, Y. Tanaka, Y. Sasaki, R. Okubo, T.
Hattori, Tetrahedron 2016, 72, 734–745. See also; c) Y. Suzuki, T.
Hattori, T. Okuzawa, S. Miyano, Chem. Lett. 2002, 31, 102–103; d) G.A.
Olah, B. Török, J. P. Joschek, I. Bucsi, P. M. Esteves, G. Rasul, G. K. S.
Prakash, J. Am. Chem. Soc. 2002, 124, 11379–11391; e) K. Nemoto, S.
Onozawa, N. Egusa, N. Morohashi, T. Hattori, Tetrahedron Lett. 2009,
50, 4512–4514; f) K. Nemoto, H. Yoshida, N. Egusa, N. Morohashi, T.
Hattori, J. Org. Chem. 2010, 75, 7855–7862; g) P. Munshi, E. J.
1.0 equiv. Cs2CO3
N
N
N
1,4-dioxane, 70 ºC, 6 h
base
Ph
Ph
CO2Me
NMe
Ph
CO2Me
Me
CO2Me
Me
N
CO2Me
Ph
N
N
N
N
N
•
N
Me
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10.1002/asia.202000476
Chemistry - An Asian Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
R2
1 atm CO2 (closed)
5 mol% RhCl3•3H2O
6 mol% P(Mes)3
Takanobu Saitou, Yushu Jin, Kotaro
Isobe, Takuya Suga, Jun Takaya,
Nobuharu Iwasawa*
R2
N
R1
R1
H
COOMe
TMSCHN2
2 equiv. AlMe2(OMe)
N
N
N
DMA, 90 °C, 8 h
Page No. – Page No.
Direct carboxylation of alkenyl C-H bonds was achieved.
Rh-Catalyzed Direct Carboxylation of
Alkenyl C–H Bonds of
Alkenylpyrazoles
The Rh-catalyzed direct carboxylation of alkenyl C–H bonds was achieved by using
pyrazole as a removable directing group. Furthermore, several useful
transformations of the product were achieved to replace the pyrazole moiety to
afford synthetically useful carboxylic acid derivatives in good yields.
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