Ruthenium-catalyzed C-H/CO/olefin coupling reaction of N-arylpyrazoles. Extraordinary reactivity of N-arylpyrazoles toward carbonylation at C-H bonds

Article abstract of DOI:10.1021/jo0343127

The reaction of 1-arylpyrazoles with CO and ethylene in the presence of Ru₃(CO)₁₂ resulted in regioselective carbonylation at the ortho C-H bonds. While it is found that the pyrazole ring also functions as the directing group for C-H

Full text of DOI:10.1021/jo0343127

2
Ru th en iu m -Ca ta lyzed C-H/CO/Olefin
Cou p lin g Rea ction of N-Ar ylp yr a zoles.
Extr a or d in a r y Rea ctivity of
N-Ar ylp yr a zoles tow a r d Ca r bon yla tion a t
C-H Bon d s
the coordination of the sp nitrogen to Ru or Rh is an
important determinant for the efficiency of the carbony-
lation reaction. In fact, we have observed a correlation
a
values of conjugate acids of heterocycles
directing group) and the efficiency of carbonylation at
C-H bonds R and â to the sp nitrogen.
the pK is, the more reactive is the molecule. When
substrates with a lower pK are employed, the reaction
must be carried out under lower CO pressure for the
reaction to proceed efficiently, because the coordination
of the substrates to metal competes with CO. As a result,
between the pK
(
2
6f,h
The higher
a
Taku Asaumi, Naoto Chatani,* Takuya Matsuo,
Fumitoshi Kakiuchi, and Shinji Murai
a
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, Suita, Osaka 565-0871, J apan
a
pK values are good indicators of the substrates to be
chatani@chem.eng.osaka-u.ac.jp
Received March 10, 2003
employed. We found that pyrazole also functions as a
directing group for carbonylation at C-H bonds in a
benzene ring. However, it shows a higher reactivity that
a
would be expected from its pK value. In this paper, we
Abstr a ct: The reaction of 1-arylpyrazoles with CO and
ethylene in the presence of Ru3(CO)12 resulted in regiose-
lective carbonylation at the ortho C-H bonds. While it is
found that the pyrazole ring also functions as the directing
group for C-H bond cleavage, the efficiency of the reaction
depends on the position of the pyrazole ring.
3
wish to report on the Ru (CO)12-catalyzed reaction of
N-arylpyrazoles 1 with CO and ethylene.7
The reaction of 1-phenyl-1H-pyrazole (1a , 2 mmol) with
CO (20 atm) and ethylene (7 atm) in toluene (6 mL) in
3
the presence of Ru (CO)12 (0.05 mmol) at 160 °C for 20 h
8
gave 1-[2-(1H-pyrazolyl)phenyl]-1-propanone (2a ) in 62%
yield, along with 20% of recovered 1a . Carbonylation did
not take place at a C-H bond on the pyrazole ring,
although such a reaction has previously been reported
The catalytic formation of a C-C bond from C-H
bonds has been extensively studied and it is now recog-
nized as a new synthetic route for the construction of
6h
by us. No second carbonylation products were detected.
1
organic molecules. Utilizing the chelation-assistance
While investigating the solvent effect, we observed a
significant improvement when aprotic polar solvents,
such as DMF and DMA (N,N-dimethylacetamide), were
used. The yield increased dramatically to 94% when DMA
2
strategy, a variety of catalytic additions of C-H bonds
to alkenes or alkynes have been successfully developed.3
Various types of catalytic carbonylation reactions at C-H
bonds have also been reported.5 All substrates which
are applicable to direct carbonylation at C-H bonds2
catalyzed by ruthenium or rhodium involve the sp
nitrogen atom as a directing group. This indicates that
,4
,6
9
was used as a solvent (eq 1). The use of common solvents,
(1) Kakiuchi, F.; Murai, S. In Activation of Unreactive Bonds and
Organic Synthesis; Murai, S., Ed.; Springer: Berlin, Germany, 1999;
pp 47-79. Guari, Y.; Sabo-Etienne, S.; Chaudret, B. Eur. J . Inorg.
Chem. 1999, 1047.
(
2) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
307.
3) For our recent review, see: Kakiuchi, F.; Murai, S. Acc. Chem.
Res. 2002, 35, 826.
1
(
however, had no effect on the yield of 2a (55% yield (28%
1
a recovered) in THF; 48% (20%) in dioxane; 42% (33%)
(
4) For recent papers on C-H/olefin coupling, see: J un, C.-H.; Moon,
in CH CN).
3
C. W.; Hong, J .-B.; Lim, S.-G.; Chung, K.-Y.; Kim, Y.-H. Chem. Eur.
J . 2002, 8, 485. Gupta, S. K.; Weber, W. P. Macromolecules 2002, 35,
Some results of reactions with N-arylpyrazoles are
shown in Table 1. The substitution of an electron-
withdrawing group, as in the case of 1d and 1f, led to a
low conversion, even when the reaction time was ex-
tended. The reaction of meta-substituted substrates 1e
3
2
369. Tan, K. L.; Bergman, R. G.; Ellman, J . A. J . Am. Chem. Soc.
002, 124, 13964.
(
5) For our papers on direct carbonylation at C-H bonds in a
benzene ring catalyzed by Ru (CO)12, see: (a) Chatani, N.; Ie, Y.;
3
Kakiuchi, F.; Murai, S. J . Org. Chem. 1997, 62, 2604. (b) Fukuyama,
T.; Chatani, N.; Kakiuchi, F.; Murai, S. J . Org. Chem. 1997, 62, 5647.
(
c) Ie, Y.; Chatani, N.; Ogo, T.; Marshall, D. R.; Fukuyama, T.;
Kakiuchi, F.; Murai, S. J . Org. Chem. 2000, 65, 1475.
6) For papers on chelation-assisted carbonylation at C-H bonds
(7) Ellman and Bergman reported on a combinatorial study of the
(
Ru
ous types of sp nitrogen containing aromatic heterocycles. It was
concluded that N-phenylpyrazole is a poor substrate for Ru (CO)12
3
(CO)12-catalyzed carbonylation reactions at C-H bonds with vari-
2
in a heterocyclic ring, see: (a) Moore, E. J .; Pretzer, W. R.; O’Connell,
T. J .; Harris, J .; LaBounty, L.; Chou, L.; Grimmer, S. S. J . Am. Chem.
Soc. 1992, 114, 5888. (b) Chatani, N.; Fukuyama, T.; Kakiuchi, F.;
Murai, S. J . Am. Chem. Soc. 1996, 118, 493. (c) Ishii, Y.; Chatani, N.;
Kakiuchi, F.; Murai, S. Organometallics 1997, 16, 3615. (d) Ishii, Y.;
Chatani, N.; Kakiuchi, F.; Murai, S. Tetrahedron Lett. 1997, 38, 7565.
3
-
catalyzed reactions with CO and tert-butylethylene. See ref 6g. We also
found that tert-butylethylene did not function as an olefin partner, in
contrast to ethylene, which has a high reactivity.
(8) All compounds were characterized by NMR, IR, and mass
spectral data. For new compounds, elemental analyses or high-
resolution mass data were obtained. For full characterization of new
compounds, see the Supporting Information.
(9) While the precise role of DMA is not clear, DMA has been shown
3
to be a superior solvent in some Ru (CO)12-catalyzed carbonylation
reactions. Mitsudo, T.; Suzuki, N.; Kobayashi, T.; Kondo, T. J . Mol.
Catal. A 1999, 137, 253. Kondo, T.; Suzuki, N.; Okada, T.; Mitsudo, T.
J . Am. Chem. Soc. 1997, 119, 6187. We also observed a DMA effect on
carbonylation at C-H bonds. See ref 6j.
(e) Chatani, N.; Ishii, Y.; Ie, Y.; Kakiuchi, F.; Murai, S. J . Org. Chem.
1
998, 63, 5129. (f) Fukuyama, T.; Chatani, N.; Tatsumi, J .; Kakiuchi,
F.; Murai, S. J . Am. Chem. Soc. 1998, 120, 11522. (g) Szewczyk, J . W.;
Zuckerman, R. L.; Bergman, R. G.; Ellman, J . A. Angew. Chem., Int.
Ed. 2001, 40, 216. (h) Chatani, N.; Fukuyama, T.; Tatamidani, H.;
Kakiuchi, F.; Murai, S. J . Org. Chem. 2000, 65, 4039. (i) Chatani, N.;
Asaumi, T.: Ikeda, T.; Yorimitsu, S.; Ishii, Y.; Kakiuchi, F.; Murai, S.
J . Am. Chem. Soc. 2000, 122, 12882. (j) Chatani, N.; Yorimitsu, S.;
Asaumi, T.; Kakiuchi, F.; Murai, S. J . Org. Chem. 2002, 67, 7557.
1
0.1021/jo0343127 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/26/2003
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J . Org. Chem. 2003, 68, 7538-7540

TABLE 1. Th e Ru 3(CO)12-Ca ta lyzed Ca r bon yla tion a t
a
C-H Bon d s in N-Ar ylp yr a zoles
values of the conjugate acids of heterocycles (directing
group). Thus, the higher the pK is, the more reactive it
will be.6 In fact, the reactivity decreased in the order
a
f,h
1
1
12
2
2
-phenylpyridine (5.25) > 2-phenylthiazole (2.44)
>
-phenyloxazole (0.8)13 in the carbonylation at C-H
1
4
bonds in a benzene ring. It should be noted that the
reaction of 1-methyl-3-phenyl-1H-pyrazole (3) under
identical reaction conditions gave the corresponding
ketone 4 in 28% isolated yield (eq 2).
SCHEME 1. A P r op osed Mech a n ism
A proposed mechanism is shown in Scheme 1. The
2
coordination of the sp nitrogen atom in the pyrazole ring
in 1a to Ru directs the metal complex to a desirable C-H
bond. The regioselective cleavage of an ortho C-H bond
is achieved to give the five-membered ruthenacycle 6. The
hydrometalation of ethylene leads to the formation of an
ethyl ruthenium complex 7, and the insertion of carbon
monoxide into the ethyl-Ru bond gives the acyl-Ru
intermediate 8. The reductive elimination from 8 gives
2
a . We propose that the reductive elimination proceeds
via the nucleophilic attack of a phenyl group on the
carbonyl carbon leading to the formation of a tetrahedral
intermediate 9,15 from which the cleavage of the C-Ru
bond takes place to give the product 2a , with the
regeneration of the active Ru species. This mechanism
rationalizes the unexpectedly high reactivity of N-arylpyra-
zoles, in which the electron-donating nature of the
nitrogen in the pyrazole ring attached to the benzene ring
facilitates the reductive elimination. The significant effect
of DMA on product yield can also be rationalized by
understanding that the tetrahedral intermediate 9 is
a
Reaction conditions: N-arylpyrazole (2 mmol), ethylene (7
atm), CO (20 atm), Ru3(CO)12 (0.05 mmol) in DMA (6 mL) at 160
°
b
C for 20 h. Isolated yields based on N-arylpyrazole.
(
a
10) The pK value is that of the conjugate acid of 1-methylpyrazole.
and 1f resulted in site-selective carbonylation. Thus,
carbonylation occurred exclusively at the less hindered
C-H bond, irrespective of the electronic nature of the
substituents.
Reedijk, J . In Comprehensive Coordination Chemistry; Wilkinson, G.,
Ed.; Pergamon Press: Oxford, UK, 1987; Vol. 2, p 73.
(
D. R., Ed. CRC Handbook of Chemistry and Physics; CRC Press: Boca
Raton, FL, 1990; Section 8.
a
11) The pK value is that of the conjugate acid of pyridine. Lide,
The carbonylation of N-phenylpyrazoles 1 was found
to proceed smoothly. This result is surprising since it was
anticipated that N-phenylpyrazole might not undergo
chelation-assisted direct carbonylation at C-H bonds
(12) The pKa value is that of the conjugate acid of 2-ethylthiazole.
(
13) The pK
azole. Brown, D. J .; Ghosh, P. B. J . Chem. Soc. B 1969, 270.
14) Asaumi, T.; Matsuo T.; Chatani, N. Unpublished data.
a
value is that of the conjugate acid of 2,4-dimethylox-
(
(15) A reductive elimination initiated by the inner-sphere attack of
one ligand at the π-bond of the other ligand was independently
proposed by Hartwig and Buchwald. Hartwig, J . F. Acc. Chem. Res.
998, 31, 852. Widenhoefer, R. A.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 6504.
value of the pyrazole ring (2.5).10
judging from the pK
a
We previously observed a correlation between the ef-
ficiency of carbonylation at C-H bonds and the pK
1
a
J . Org. Chem, Vol. 68, No. 19, 2003 7539

stabilized by a polar solvent. In addition, the trend in
electronic effects of substituents on the benzene ring, in
which the electron-donating substituents enhance the
reactivity of the substrates, supports this view.
In summary, a pyrazole ring also functions in the direct
carbonylation of C-H bonds in a benzene ring. In
addition, the unexpectedly higher reactivity of N-phe-
nylpyrazoles is due to the facilitation of reductive elimi-
nation by the presence of a nitrogen, which is capable of
accelerating a nucleophilic attack. Detailed studies of the
mechanism of this carbonylation and an examination of
new types of substrates for use in carbonylation reactions
involving the cleavage of C-H bonds are currently
underway.
Ack n ow led gm en t. This work was supported, in
part, by grants from Monbukagakusho. T.A. acknowl-
edges Research Fellowships of J .S.P.S. for Young Sci-
entists. We thank the Instrumental Analysis Center,
Faculty of Engineering, Osaka University, for assistance
in obtaining MS, HRMS, and elemental analyses.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and full characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0343127
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