Ru3(CO)12-catalyzed coupling reaction of sp3 C - H bonds adjacent to a nitrogen atom in alkylamines with alkenes

Article abstract of DOI:10.1021/ja011540e

Catalytic reactions which involve the cleavage of an sp³ C-H bond adjacent to a nitrogen atom in N-2-pyridynyl alkylamines are described. The use of Ru₃(CO)₁₂ as the catalyst results in the addition of the sp³ C

Full text of DOI:10.1021/ja011540e

J. Am. Chem. Soc. 2001, 123, 10935-10941
10935
Ru3(CO)12-Catalyzed Coupling Reaction of sp3 C-H Bonds Adjacent
to a Nitrogen Atom in Alkylamines with Alkenes
Naoto Chatani, Taku Asaumi, Shuhei Yorimitsu, Tsutomu Ikeda, Fumitoshi Kakiuchi, and
Shinji Murai*
Contribution from the Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita,
Osaka 565-0871, Japan
ReceiVed June 25, 2001
Abstract: Catalytic reactions which involve the cleavage of an sp3 C-H bond adjacent to a nitrogen atom in
N-2-pyridynyl alkylamines are described. The use of Ru3(CO)12 as the catalyst results in the addition of the
sp3 C-H bond across the alkene bond to give the coupling products. A variety of alkenes, including terminal,
internal, and cyclic alkenes, can be used for the coupling reaction. The presence of directing groups, such as
pyridine, pyrimidine, and an oxazoline ring, on the nitrogen of the amine is critical for a successful reaction.
This result indicates the importance of the coordination of the nitrogen atom to the ruthenium catalyst. In
addition, the nature of the substituents on the pyridine ring has a significant effect on the efficiency of the
reaction. Thus, the substitution of an electron-withdrawing group on the pyridine ring as well as a substitution
adjacent to the sp2 nitrogen in the pyridine ring dramatically retards the reaction. Cyclic amines are more
reactive than acyclic ones. The choice of solvent is also very important. Of the solvents examined, 2-propanol
is the solvent of choice.
Introduction
bonds, have been extended to a wide variety of aromatic and
olefinic substrates by a number of research groups.3-15 In
Recently, the development of catalytic reactions which
involve the cleavage of unreactive C-H bonds has been a
subject of considerable interest.1 For decades, it had been
generally believed that the cleavage of a C-H bond Via
oxidatiVe addition was a difficult process because of its strong
bond strength. Consequently, the majority of studies focused
on the cleavage of C-H bonds via the use of stoichiometric
amounts of transition metal complexes. However, since we
reported that the addition of the ortho C-H bond in aromatic
ketones to alkenes can be efficiently attained by the presence
of H2Ru(CO)(PPh3)3 as the catalyst,2 in addition to our finding
that the C-H bond cleavage step is not as difficult as had been
thought and is not a rate-determining step,3b a variety of similar
C-C bond formations, which involve the cleavage of C-H
(4) Trost, B. M.; Imi, K.; Davies, I. W. J. Am. Chem. Soc. 1995, 117,
5371.
(5) Guo, H.; Huang, D.; Weber, W. P. Polym. Prep. 1999, 40, 70.
Londergan, T. M.; Teng, C. J.; Weber, W. P. Polym. Prep. 1999, 40, 154.
Gupta, S.; Londergan, T. M.; Paulasaari, J. K.; Sargent, J. R.; Weber, W.
P. Polym. Mater. Sci. Eng. 1999, 80, 445. Gupta, S.; Kepler, C. L.; Weber,
W. P. Polym. Prep. 1999, 40, 837. Kepler, C. L.; Londergan, T. M.; Lu, J.;
Paulasaari, J.; Weber, W. P. Polymer 1999, 40, 765. Sargent, J. R.; Weber,
W. P. Polymer 1999, 40, 3795. Sargent, J. R.; Weber, W. P. J. Polym. Sci.,
Part A: Polym. Chem. 2000, 38, 482. Gupta, S.; Weber, W. P. Macro-
molecules 2000, 33, 108. Huang, D.; Yang, J.; Weber, W. P. Polym. Bull.
2000, 43, 465.
(6) Harris, P. W. R.; Woodgate, P. D. J. Organomet. Chem. 1996, 506,
339. Harris, P. W. R.; Woodgate, P. D. J. Organomet. Chem. 1997, 530,
211. Harris, P. W. R.; Rickard, C. E. F.; Woodgate, P. D. J. Organomet.
Chem. 1999, 589, 168.
(7) Grigg, R.; Savic, V. Tetrahedron Lett. 1997, 38, 5737.
(8) Lim, Y.-G.; Kim, Y. H.; Kang, J.-B. J. Chem. Soc., Chem. Commun.
1994, 2267. Lim, Y.-G.; Kang, J.-B.; Kim, Y. H. J. Chem. Soc., Perkin
Trans. 1 1996, 2201.
(9) Lim, Y.-G.; Kang, J.-B.; Kim, Y. H. Chem. Commun. 1996, 585.
Lim, Y.-G.; Kang, J.-B.; Kim, Y. H. J. Chem. Soc., Perkin Trans. 1 1998,
699. Lim, Y.-G.; Kang, J.-B.; Koo, B. T. Tetrahedron Lett. 1999, 40, 7691.
Lim, Y.-G.; Han, J.-S.; Koo, B. T.; Kang, J.-B. Bull. Korean Chem. Soc.
1999, 20, 1097. Lim, Y.-G.; Han, J.-S.; Koo, B. T.; Kang, J.-B. Polymer
2000, 41, 4351.
(10) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616.
(11) Guari, Y.; Sabo-Etienne, S.; Chaudret, B. J. Am. Chem. Soc. 1998,
120, 4228.
(12) Busch, S.; Leitner, W. Chem. Commun. 1999, 2305. Busch, S.;
Leitner, W. AdV. Synth. Catal. 2001, 343, 192.
(13) Halbritter, G.; Knoch, F.; Wolski, A.; Kisch, H. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1603. Halbritter, G.; Konch, F.; Kisch, H. J. Organomet.
Chem. 1995, 492, 87. Aulwurm, U. R.; Melchinger, J. U.; Kisch, H.
Organometallics 1995, 14, 3385. Du¨rr, U.; Heinemann, F. W.; Kisch, H. J.
Organomet. Chem. 1997, 541, 307. For a review, see: Du¨rr, U.; Kisch, H.
Synlett 1997, 1335. Du¨rr, U.; Heinemann, F. W.; Kisch, H. J. Organomet.
Chem. 1998, 558, 91.
(1) For a recent review, see: 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. Dyker, G. Angew. Chem., Int. Ed. 1999, 38,
1698.
(2) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature 1993, 366, 529.
(3) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Pure Appl. Chem. 1994, 66, 1527. (b) Kakiuchi,
F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N.; Murai,
S. Bull. Chem. Soc. Jpn. 1995, 68, 62. (c) Sonoda, M.; Kakiuchi, F.; Chatani,
N.; Murai, S. J. Organomet. Chem. 1995, 504, 151. (d) Sonoda, M.;
Kakiuchi, F.; Kamatani, A.; Chatani, N.; Murai, S. Chem. Lett. 1996, 109.
(e) Kakiuchi, F.; Yamauchi, M.; Chatani, N.; Murai, S. Chem. Lett. 1996,
111. (f) Murai, S.; Chatani, N.; Kakiuchi, F. Pure Appl. Chem. 1997, 69,
589. (g) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S. Bull. Chem. Soc.
Jpn. 1997, 70, 3117. (h) Kakiuchi, F.; Sato, T.; Tsujimoto, T.; Yamauchi,
M.; Chatani, N.; Murai, S. Chem. Lett. 1998, 1053. (i) Kakiuchi, F.; Sato,
T.; Yamauchi, M.; Chatani, N.; Murai, S. Chem. Lett. 1999, 19. (j) Kakiuchi,
F.; Sonoda, M.; Tsujimoto, T.; Chatani, N.; Murai, S. Chem. Lett. 1999,
1083. (k) Kakiuchi, F.; Matsumoto, M.; Sonoda, M.; Fukuyama, T.; Chatani,
N.; Murai, S. Chem. Lett. 2000, 750. (l) Kakiuchi, F.; Sato, T.; Igi, K.;
Chatani, N.; Murai, S. Chem. Lett. 2001, 386. (m) Kakiuchi, F.; Igi, K.;
Matsumoto, M.; Chatani, N.; Murai, S. Chem. Lett. 2001, 422. (n) Kakiuchi,
F.; Tsujimoto, T.; Sonoda, M.; Chatani, N.; Murai, S. Synlett 2001, 948.
(14) Jun, C.-H.; Hong, J.-B.; Kim, Y.-H.; Chung, K.-W. Angew. Chem.,
Int. Ed. 2000, 39, 3440.
(15) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001,
123, 2685.
10.1021/ja011540e CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/09/2001

10936 J. Am. Chem. Soc., Vol. 123, No. 44, 2001
Chatani et al.
addition, various functional groups were found to promote the
site-selective cleavage of C-H bonds as the directing group.
The catalytic cleavage of C-H bonds has also been extended
to direct carbonylation reactions at C-H bonds in substrates
which contain sp2-nitrogen atoms.16-21 At present, it has been
accepted that the cleavage of C-H bonds is not always a
difficult process and that the cleavage of a C-H bond is often
not the rate-determining step.22
These exchange reactions involve imine or iminium intermedi-
ates, which are formed by abstraction of hydrogen R to the
nitrogen in amines. Recently, we reported on the Rh4(CO)12-
catalyzed carbonylation of a C-H bond in the piperazine ring.
Although the reaction involves two cleavages of C-H bonds,
carbonylation took place after the initial formation of alkenes
via transfer hydrogenation.20 The results obtained from these
papers suggest the possibility of utilizing C-H bonds adjacent
to a nitrogen atom for C-H/CO/olefin coupling reactions or
C-H/olefin coupling reactions. We then examined the pos-
sibility of developing catalytic reactions which involve the
cleavage of a C-H bond adjacent to a nitrogen atom in the
presence of a wide variety of transition metal complexes as the
catalyst. In addition, based on our previous studies we chose
substrates with a directing group close to the C-H bond which
may react.3,17-20 Thus, our approach is again based on a
chelation-assisted cleavage of C-H bonds, a strategy that has
proved to be effective for the development of catalytic reactions
involving the cleavage of unreactive bonds, such as sp2
C-H,2-21 C-C,31,32 C-F,33 and C-O bonds.34 We now wish
to report that the reaction of N-2-pyridyldialkylamines with
alkenes in the presence of Ru3(CO)12 results in alkylation at
the carbon adjacent to the nitrogen atom (eq 1). Recently, Jun
reported a similar reaction: the Ru3(CO)12-catalyzed addition
of an sp3 C-H bond adjacent to a nitrogen atom in benzy-
lamine.35 In his reaction, the substrates were limited to N-
pyridylbenzylamines, in which only benzylic C-H bonds can
add to the alkenes.
However, essentially all of these reactions reported to date
involve the cleavage of sp2 C-H bonds, and catalytic reactions
involving the cleavage of the sp3 C-H bond are still rare.1,23,24
Our next project involved the exploration of catalytic reactions
which involve the cleavage of sp3 C-H bonds, which is believed
to be much more difficult than that of sp2 C-H bonds. It is
known that the cleavage of sp3 C-H bonds is kinetically and
thermodynamically unfavorable. On the basis of a recent
literature survey, sp3 C-H bonds which are adjacent to a
heteroatom are, however, more reactive than those surrounded
by carbon atoms. A few transition metal catalyzed reactions,
which involve the cleavage of sp3 C-H bonds adjacent to a
heteroatom, have recently been reported. The addition of a C-H
bond adjacent to an oxygen atom in 1,2-dimethoxytethane across
alkenes was achieved via an Ir-catalyzed reaction.25 The
tungsten-catalyzed addition of a C-H bond R to a nitrogen in
secondary amines has also been reported.26 Catalytic alkyl
exchange reactions of primary and secondary amines, in the
presence of Pd, were reported by Murahashi.27 Later, Ni,27c,28
Ru,27c,29,30 and other transition metal complexes27c,30 were also
reported to be active in the catalytic alkyl exchange reactions.
(16) 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.
(17) Chatani, N.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am. Chem.
Soc. 1996, 118, 493. Chatani, N.; Fukuyama, T.; Tatamidani, H.; Kakiuchi,
F.; Murai, S. J. Org. Chem. 2000, 65, 4039.
(18) Fukuyama, T.; Chatani, N.; Tatsumi, J.; Kakiuchi, F.; Murai, S. J.
Am. Chem. Soc. 1998, 120, 11522.
Results and Discussion
(19) (a) Chatani, N.; Ie, Y.; 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) Chatani, N.; Ishii, Y.; Ie, Y.; Kakiuchi, F.; Murai,
S. J. Org. Chem. 1998, 63, 5129. (d) Ie, Y.; Chatani, N.; Ogo, T.; Marshall,
D. R.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Org. Chem. 2000, 65, 1475.
(20) Ishii, Y.; Chatani, N.; Kakiuchi, F.; Murai, S. Organometallics 1997,
16, 3615. Ishii, Y.; Chatani, N.; Kakiuchi, F.; Murai, S. Tetrahedron Lett.
1997, 38, 7565.
The initial aim of the study was the carbonylation at sp3 C-H
bonds. However, it was not possible to explore the direct
carbonylation at an sp3 C-H bond when N-pyridyl cyclic amines
were used as the substrates with ruthenium complexes as the
catalyst.36 Instead, we found that the addition of a C-H bond
to alkenes was achieved by the use of Ru3(CO)12 as a catalyst.37
Thus, the reaction of 2-(1-pyrrolidinyl)pyridine (1a, 1 mmol)
with ethylene (initial pressure 10 atm at 25 °C in a 50-mL
stainless autoclave) at 1 atm (initial pressure at 25 °C) of CO
at 140 °C in toluene (2 mL) in the presence of Ru3(CO)12 (0.08
mmol) for 20 h in a 50-mL stainless steel autoclave gave 2-(2-
ethyl-1-pyrrolidinyl)pyridine (2a) in 22% isolated yield and
2-(2,5-diethyl-1-pyrrolidinyl)pyridine (3a) in 12% isolated yield,
along with a 25% yield of the starting material 1a after column
chromatography on silica gel (entry 1 in Table 1). No carbo-
(21) Szewczyk, J. W.; Zuckerman, R. L.; Bergman, R. G.; Ellman, J. A.
Angew. Chem., Int. Ed. 2001, 40, 216.
(22) Matsubara, T.; Koga, N.; Musaev, D. G.; Morokuma, K. Organo-
metallics 2000, 19, 2318.
(23) For a recent review on the cleavage of sp3 C-H bonds, see:
Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.; Peterson, T. H. Acc. Chem.
Res. 1995, 28, 154.
(24) For a recent paper on catalytic reaction involving the cleavage of
sp3 C-H bonds, see: Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F.
Science 2000, 287, 1995 and references therein. Liu, F.; Pak, E. B.; Singh,
B.; Jensen, C. M.; Goldman, A. S. J. Am. Chem. Soc. 1999, 121, 4086.
Quite recently, catalytic hydroxylation of amino acids was reported. Dangel,
B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001, 123, 8149.
(25) Lin, Y.; Ma, D.; Lu, X. Tetrahedron Lett. 1987, 28, 3249.
(26) Nugent, W. A.; Ovenall, D. W.; Holmes, S. J. Organometallics 1983,
2, 161.
(27) (a) Yoshimura, N.; Moritani, I.; Shimamura, T.; Murahashi, S.-I. J.
Am. Chem. Soc. 1973, 95, 3038. (b) Yoshimura, N.; Moritani, I.; Shimamura,
T.; Murahashi, S.-I. J. Chem. Soc., Chem. Commun. 1973, 307. (c)
Murahashi, S.-I.; Yoshimura, N.; Tsumiyama, T.; Kojima, T. J. Am. Chem.
Soc. 1983, 105, 5002.
(31) Jun, C.-H.; Lee, H. J. Am. Chem. Soc. 1999, 121, 880. Jun, C.-H.;
Lee, H.; Park, J.-B.; Lee, D.-Y. Org. Lett. 1999, 1, 2161. Jun, C. H.; Lee,
H.; Lim, S.-G. J. Am. Chem. Soc. 2001, 123, 751.
(32) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1999,
121, 8645.
(33) Ishii, Y.; Chatani, N.; Yorimitsu, S.; Murai, S. Chem. Lett. 1998,
157.
(34) Chatani, N.; Tatamidani, H.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Am.
Chem. Soc. 2001, 123, 4849.
(28) De Angelis, F.; Grgurina, I.; Nicoletti, R. Synthesis 1979, 70.
(29) (a) Bui-The-Khai, Concilio, C.; Porzi, G. J. Organomet. Chem. 1981,
208, 249. (b) Bui-The-Khai, Concilio, C.; Porzi, G. J. Org. Chem. 1981,
46, 1759.
(30) The catalytic alkyl exchange reaction of tertiary amines was found
to be catalyzed by Ru3(CO)12, Os3(CO)12, and Ir4(CO)12. Shvo, Y.; Laine,
R. M. J. Chem. Soc., Chem. Commun. 1980, 753. Laine, R. M.; Thomas,
D. W.; Cary, L. W. J. Am. Chem. Soc. 1982, 104, 1763. Wilson, R. B., Jr.;
Laine, R. M. J. Am. Chem. Soc. 1985, 107, 361.
(35) Jun, C.-H.; Hwang, D.-C.; Na, S.-J. Chem. Commun. 1998, 1405.
(36) Quite recently, we have found that carbonylation at sp3 C-H bonds
to the nitrogen atom in cyclic amines is attained by the use of a rhodium
complex as the catalyst. Chatani, N.; Asaumi, T.; Ikeda, T.; Yorimitsu, S.;
Ishii, Y.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12882.
(37) RuCl3‚3H2O and RuCl2(PPh3)3 showed less catalytic activity than
Ru3(CO)12. None of the complexes, such as PdCl2, Rh6(CO)16, Ir4(CO)12,
Os3(CO)12, Ru(acac)3, and RuH2(CO)(PPh3)3, were found to be active for
this coupling reaction.

Ru3(CO)12-Catalyzed Coupling Reaction
J. Am. Chem. Soc., Vol. 123, No. 44, 2001 10937
Table 2. Effect of Substituents on the Pyridine Ringa
Table 1. The Ru3(CO)12-Catalyzed Reaction of 1a with Ethylenea
yields, %b,c
yields, %b
R
2
3
recovery of 1
entry
solvent
2a
3a
recovery of 1a
H (1a)
3-Me (1b)
4-Me (1c)
5-Me (1d)
6-Me (1e)
3-OMe (1f)
6-OMe (1g)
5-CF3 (1h)
4-COOMe (1i)
0
0
0
0
39
0
11
0
92 (54:46)
76 (70:30)
90 (66:34)
93 (61:39)
11 (52:48)
86 (52:48)
0
0
0
0
0
35
0
77
0
nd
1
2
3
4
5
6
7
8
9
toluene
CH3CN
THF
dioxane
DMF
22
27
10
0
0
0
14
8
0
12
0
0
0
0
25
55
86
ndc
ndc
ndc
9
DMSO
MeOH
EtOH
0
31
86
92
94 (63:37)
0
0
iPrOH
no reaction
a Reaction conditions: 1 (1 mmol), Ru3(CO)12 (0.08 mmol), ethylene
(initial pressure 10 atm at 25 °C in a 50 mL stainless autoclave), CO
(1 atm) in 2-propanol (2 mL) at 140 °C for 20 h. b Isolated yields based
on 1. c The numbers in parenthesis are the stereoisomeric ratios.
a Reaction conditions: 1a (1 mmol), Ru3(CO)12 (0.08 mmol),
ethylene (initial pressure 10 atm at 25 °C in a 50 mL stainless
autoclave), CO (1 atm), solvent (2 mL) at 140 °C for 20 h. b Isolated
yields based on 1a. c 1a was recovered, but the amount was not
determined.
due to the low coordination ability of these functional groups
compared with the sp2 nitrogen in the pyridine ring.
nylation products were obtained, even when the reaction was
carried out at higher CO pressures and at higher reaction
temperatures. This finding led us to concentrate on the alkylation
at an sp3 C-H bond adjacent to a nitrogen atom. To optimize
the reaction conditions, a variety of solvents were examined. It
was found that the nature of solvents significantly affects the
efficiency of the coupling reaction. The use of CH3CN as a
solvent gave the mono-ethylation product 2a as a main product,
albeit in low yield (entry 2). Among the solvents examined,
2-propanol was found to be the best. With 2-propanol as the
solvent, the yield of 3a was dramatically increased to 92% (entry
9). Our solvent system enabled the addition of C-H bonds in
cyclic amines to alkenes. This result complements the work of
Jun, who reported that only the benzylic C-H bond reacted
with alkenes.35 The presence of CO is not essentially required,
but it was found to keep the reaction clean, putatively by
avoiding the decomposition of the catalyst. In fact, the yield of
3a was 77% when the reaction of 1a was carried out under N2
in place of CO.
The effect of substituents on the pyridine ring was next
examined. The results are shown in Table 2. We have already
observed that the electronic nature of the substituents on a
pyridine ring has a significant effect on the efficiency of a
carbonylation reaction at the C-H bonds reported thus far.19a
In most cases, the reaction did not stop at the mono-alkylation
stage. As expected the nature of the substituents on the pyridine
ring had a significant effect on the product yields. The
substitution at the 6-position, as in 1e and 1g, dramatically
decreased the reactivity of the substrates due to steric hindrance
around the pyridine ring. The substitution of the electron-
withdrawing group at the 4-position, as in 1i, resulted in no
reaction due to an electron deficiency on the pyridine nitrogen.
The decreased reactivity of 1e, 1g, and 1i clearly showed that
the coordination of the pyridine nitrogen to ruthenium is an
important step for the reaction to proceed. The cis/trans ratio
in 3 was not affected by either the nature or the position of the
substituents.
Various cyclic amines were found to be applicable to the
present alkylation. The results are summarized in Table 3. The
reaction of 2-(1-piperidinyl)pyridine (4) gave 2-(2,6-diethyl-1-
piperidinyl)pyridine (5) in high yield (entry 1), while the seven-
membered amine derivative 8 gave a mixture of mono-ethylation
9 and di-ethylation products 10 (entry 3), indicating that small
ring systems are more reactive than larger membered cyclic
amines (1 > 4 > 8) in the competition between the second
ethylene coupling and the dissociation of mono-ethylation
product from the metal center. The reaction of 15 gave 16 as a
major product and another di-ethylation product, in which two
molecules of ethylene had been incorporated; neither were
observed at the benzylic position (entry 6). A pyrimidine ring
also functioned as a good directing group in place of a pyridine
ring (entry 7).
While 2-(2-pyridinyl)-2,3-dihydro-1H-isoindole (13) gave the
corresponding di-ethylation product 14 in high yield (entry 5
in Table 3), the reaction of the dihydroindole derivative 19 gave
a mixture of the expected ethylation product 20 and its indole
derivative (eq 2). This suggests that compound 21 is formed
A variety of functional groups, as shown below, were
examined for their ability as directing groups, in place of a
pyridine ring, but they were unable to serve as such. This is

10938 J. Am. Chem. Soc., Vol. 123, No. 44, 2001
Chatani et al.
by dehydrogenation of an initial product 20. An alternative route
involving an initial aromatization of 19 to N-2-pyridylindole is
not likely, since the reaction of N-2-pyridylindole under the same
reaction conditions as those in eq 2 resulted in no reaction.
Table 3. Ru3(CO)12-Catalyzed Reaction of N-2-Pyridylamines with
Ethylenea
indicating that the reaction is limited to amines. Compared with
a C-H bond in a benzylic position, a C-H bond in an alkyl
group is less reactive. The alkylation of 24 took place to give
25 in 20% yield, along with unreacted 24 (57%) (eq 4). A
tertiary amine, such as N-benzyl-N-methyl-2-pyridylamine (26),
did not result in a selective alkylation reaction (eq 5). As a result,
the scope of this reaction appears to be limited to the addition
of C-H bonds in a benzylic position of secondary amines in
the case of acyclic amines, as had been reported by Jun.35
The results on the reaction of 1a with some alkenes are shown
in Table 4. In most cases, mixtures of mono-alkylation products
and di-alkylation products were obtained. Mono-alkylation
products were not obtained selectively, even when the reactions
were carried out for short reaction times with a smaller amount
of alkenes. The reaction of 1a with 1-hexene gave a mixture of
the linear products 30 and 31 in a total yield of 91%, and no
branched products were observed (entry 1). The similar
predominate formation of a linear product was observed when
2-hexene was employed as an alkene. The reaction of 1a with
2-hexene led to the formation of the corresponding linear
alkylation products 30 and 31, along with a 21% yield of
recovered 1a (entry 2). The reaction of 1a with hexene under
the reaction conditions (in toluene) employed by Jun35 gave 30
in 8% yield and 31 in 3%, along with 74% of 1a being recovered
after 20 h. This result again demonstrates the efficiency of
2-propanol as the solvent. The reaction of 1a with styrene gave
the di-alkylation product 34 in good yield; however, products
formed via hydroesterification and the polymerization of styrene
were also produced as contaminants (entry 4). A cyclic olefin,
such as cyclohexene, was also applicable to the present
alkylation (entry 5). Olefins with an electron-withdrawing group,
such as acrylonitrile and butyl vinyl ether, did not function as
an alkene partner. Isoprene and 1,5-cyclooctadiene also failed
a Reaction conditions: amine (1 mmol), Ru3(CO)12 (0.08 mmol),
ethylene (initial pressure 10 atm at 25 °C in a 50 mL stainless
autoclave), CO (1 atm) in 2-propanol (2 mL) at 140 °C for 20 h.
b Isolated yields based on amine. c The numbers in parenthesis are the
stereoisomeric ratios. d For a reaction time of 20 h.
Cyclic amines were found to serve as good substrates for
this alkylation reaction, as shown in Table 3. We then examined
the reaction of N-pyridyl acyclic amines (eqs 3-5). In the case
of secondary amines, such as 22 and 24, the reaction was not
carried out under CO, because the reaction of these substrates
in the presence of CO resulted in carbonylation at an N-H bond
to give formamides as byproducts. Substrate 22, which was
originally reported by Jun to react with alkenes efficiently in
the presence of Ru3(CO)12,35 also reacted with ethylene in
2-propanol to give 23 in high yield (eq 3). The corresponding
ether analogue of 22 failed to give an ethylation product,

Ru3(CO)12-Catalyzed Coupling Reaction
J. Am. Chem. Soc., Vol. 123, No. 44, 2001 10939
Table 4. The Ru3(CO)12-Catalyzed Reaction of 1a with Alkenesa
a Reaction conditions: 1a (1 mmol), alkene (10 mmol), Ru3(CO)12 (0.08 mmol), in 2-propanol (2 mL) at 140 °C in a 10 mL stainless vial.
b Isolated yields based on 1a. c The numbers in parentheses are the stereoisomeric ratios.
Scheme 1. A Proposed Reaction Mechanism
Scheme 2. An Alternative Mechanism (1) for the Cleavage
of a C-H Bond
the final product 40, with the Ru complex being regenerated.
Two possibilities for the step in which the C-H bond is cleaved
exist in addition to the direct oxidative addition, as has already
been shown in Scheme 1. One involves hydride elimination from
the 1,3-diaza-π-allyl Ru complex 41 to 42 (Scheme 2). The
C-H bond to be cleaved is doubly activated, the C-H bond
being next to nitrogen and located at the allylic position.
Another alternative mechanism, which involves the participa-
tion of an iminium intermediate, cannot be excluded (Scheme
3). Hydride abstraction from 37 gives an iminium intermediate
43, which undergoes intramolecular nucleophilic attack to give
38. A related mechanism in which, prior to the formation of 38
from 43, the insertion of an alkene into the H-Ru bond in 43
followed by intramolecular nucleophilic attack gives 39 is also
possible. In the transalkylation of amines, the intermediacy of
to react. Alkynes were also tested as a coupling partner instead
of alkenes, but none of the alkynes showed any reactivity.
While the precise reaction mechanism is not clear, a proposed
reaction mechanism is shown in Scheme 1. Coordination of the
nitrogen in 1a to ruthenium provides complex 37, in which the
C-H bond undergoes cleavage to give the Ru hydride complex
38. The insertion of an alkene into the H-Ru bond in 38 gives
the alkyl Ru complex 39, from which reductive elimination gives

10940 J. Am. Chem. Soc., Vol. 123, No. 44, 2001
Chatani et al.
Scheme 3. An Alternative Mechanism (2) for the Cleavage
of a C-H Bond
Next, the H/D exchange reaction was undertaken to obtain
information concerning the reaction mechanism. An H/D
exchange experiment provided good evidence for the revers-
ibility of C-H bonds between substrates and reactants (alkenes),
indicating that the cleavage of C-H bonds is not the rate-
determining step.3b,10 In the present case, however, H/D
exchange with the solvent took place even when the reaction
was carried out in the absence of ethylene. The treatment of 1a
under catalytic reaction conditions (in the absence of ethylene)
in 2-propanol-d8 showed deuterium incorporation to 1a at all
positions (eq 7). Although this result indicates that C-H bonds
in the substrate 1a can be cleaved in a nonselective manner, it
is noteworthy that the cleavage of C-H bonds is a facile
process.
Scheme 4
imine or iminium intermediates was invoked.27-30 Although we
have no experimental evidence at present, a direct oxidative
addition mechanism seems to be unlikely.
Alcohols were found to be effective solvents for the present
reaction. Of the alcohols examined, 2-propanol is the best
solvent. The exact role of 2-propanol is not clear at present,
but we speculate that its role involves protecting the ruthenium-
hydride species 38 from decomposition. If R-elimination from
38 takes place, a carbene complex 45 is formed, which is
susceptible to decomposition. However, the ruthenium hydride
species 38 can be regenerated by hydrogen donation from
2-propanol to 45, as shown in Scheme 4. Consequently, 38 has
a sufficiently long lifetime to react with alkenes. Recently, Lee,
Faller, and Crabtree observed a reversible R-elimination in
related iridium complexes.38
Summary
We have demonstrated herein that the addition of an sp3 C-H
bond in alkylamines to alkenes can be achieved via catalysis
by a ruthenium complex. The C-H bond next to a nitrogen
atom is selectively cleaved and adds to alkenes. The presence
of a pyridine ring on the nitrogen in cyclic amines is essential
for the reaction to proceed, suggesting the importance of the
coordination of pyridine nitrogen to the ruthenium. The use of
2-propanol is also critical for the reaction to proceed.
We have previously reported that the use of a rhodium
complex in the reaction of 1a with CO and ethylene gives
carbonylation products and that no alkylation products are
obtained.36 In contrast, carbonylation did not take place in the
case of an sp3 C-H bond when Ru3(CO)12 was used as the
catalyst, although Ru3(CO)12 has been found to be an active
catalyst for carbonylation at sp2 C-H bonds.16-21 While we
cannot provide a precise reason, we speculate that a backward
reaction exits in the case of the present Ru3(CO)12-catalyzed
reaction of alkylamines. In fact, the reaction of 46 under standard
reaction conditions gave 3a in 81% yield along with a small
amount of 47 (eq 6). This result shows that decarbonylation of
46 easily took place under these conditions to give 1a, which
then reacted with ethylene to afford 3a. A similar example of
the decarbonylation of ketones has been previously reported by
us.32
Experimental Section
Materials. 2-Propanol was distilled over sodium metal and stored
over 4 Å molecular sieves. Ru3(CO)12 was prepared according to
literature procedures39 and used after recrystallization from hexane.
Alkylamines 1a,40 1b,36 1d,36 1e,36 1f, 1g, 4, 6, 8, 11, 17, 19, 22, 24,
and 2641 were obtained from the corresponding substituted 2-bromopy-
ridines and amines according to the Pd-catalyzed amination procedure
reported by Buchwald.41 1h,36 1i, and 15 were prepared from the
corresponding substituted 2-chloropyridines or 2-chloropyrimidine and
pyrrolidine according to literature procedures.42 And 1c36 and 13 were
prepared from the corresponding substituted 2-aminopyridines and 1,4-
dichlorobutane, with slight modification of the literature procedure.43
(39) Bruce, M. I.; Jensen, C. M.; Jones, N. L. Inorg. Synth. 1989, 26,
259.
(40) Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron 1999, 55, 12829.
(41) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240.
(42) Hassher, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34,
2069.
(38) Lee, D.-H.; Chen, J.; Faller, J. W.; Crabtree, R. H. Chem. Commun.
2001, 213.
(43) Craig, L. C.; Hixon, R. M. J. Am. Chem. Soc. 1930, 52, 804.

Ru3(CO)12-Catalyzed Coupling Reaction
J. Am. Chem. Soc., Vol. 123, No. 44, 2001 10941
Typical Procedure for the Coupling of C-H Bonds r to the
Nitrogen Atom in Alkylamines with Ethylene. A 50-mL stainless
autoclave was charged with 2-(1-pyrrolidinyl)pyridine (1a) (1 mmol,
148 mg), 2-propanol (2 mL), and Ru3(CO)12 (0.08 mmol, 51 mg). After
the system was flushed with 10 atm of carbon monoxide three times,
it was pressurized with carbon monoxide to 1 atm and then with
ethylene to an additional 10 atm. The autoclave was then immersed in
an oil bath at 140 °C. After 20 h had elapsed, the autoclave was removed
from the oil bath and allowed to cool for ca. 1 h and the gases were
then released. The contents were transferred to a round-bottomed flask
with toluene, and the volatiles were removed in vacuo. The residue
was subjected to column chromatography on silica gel (eluent; hexane/
EtOAc ) 30/1) to give 2,5-diethyl-1-(2-pyrridinyl)pyrroridine (3a) (189
mg, 92% yield, 54/46 stereoisomeric mixture of cis/trans) as a colorless
oil. Purification by bulb-to-bulb distillation afforded the analytically
pure product.
2-Ethyl-1-(2-pyridinyl)pyrroridine (2a): colorless oil; bp 80 °C
(1 mmHg); Rf 0.14 (hexane/EtOAc ) 10/1); 1H NMR (CDCl3) δ 0.92
(t, J ) 7.6 Hz, 3H), 1.26-1.44 (m, 1H), 1.77-2.04 (c, 5H), 3.33-
3.56 (m, 2H), 3.85 (m, 1H), 6.33 (d, J ) 7.6 Hz, 1H), 6.48 (dd, J )
6.5 Hz, 5.1 Hz, 1H), 7.39 (ddd, J ) 7.6 Hz, 6.5 Hz, 1.9 Hz, 1H), 8.14
(d, J ) 5.1 Hz, 1H); 13C NMR (CDCl3) δ 10.60, 23.36, 25.66, 29.51,
47.30, 58.98, 106.63, 110.89, 136.66, 148.23, 157.09; IR (neat) 2968
s, 2876 m, 2024 w, 1942 m, 1600 s, 1559 s, 1495 s, 1443 s, 1383 s,
1304 m, 1248 m, 1155 m, 1092 m, 1050 m, 991 s; MS, m/z (relative
intensity, %) 176 (M+, 11), 147 (100), 119 (10), 78 (36), 51 (15). HRMS
Calcd for C11H16N2: 176.1313. Found: 176.1321.
m, 1599 s, 1559 m, 1494 s, 1443 s, 1381 s, 1297 m, 1155 m, 1092 w,
1050 w, 988 m; MS, m/z (relative intensity, %) 232 (M+, 9), 148 (12),
147 (100), 78 (18). HRMS Calcd for C15H24N2: 232.1939. Found:
232.1932.
2,5-Dihexyl-1-(2-pyridinyl)pyrrolidine (31). Spectral data were
obtained from a mixture of cis and trans isomer: yellow oil; bp 140
1
°C (1 mmHg); Rf 0.40 (hexane/EtOAc ) 10/1); H NMR (CDCl3) δ
0.81-0.94 (c, 6H), 1.06-1.31 (c, 18H), 1.77-2.38 (c, 6H), 3.92 (c,
2H), 6.24-6.34 (c, 1H), 6.41-6.51 (c, 1H), 7.34-7.38 (c, 1H), 8.12-
8.15 (c, 1H); 13C NMR (CDCl3) δ 14.11, [22.61 (minor), 22.64 (major)],
[26.47 (minor), 26.74 (major)], 27.35, [29.36 (minor), 29.51 (major)],
[31.90 (minor), 31.93 (major)], [57.45 (major), 59.18 (minor)], [106.45
(major), 107.96 (minor)], [110.33 (major), 110.87 (minor)], [136.33
(major), 136.48 (minor)], [148.12 (minor), 148.39 (major)], [155.90
(minor), 157.45 (major)]; IR (neat) 2960 s, 2926 s, 2858 s, 1596 s,
1559 m, 1484 s, 1441 s, 1378 s, 1297 m, 1246 w, 1206 w, 1157 m,
1091 w, 1051 w, 978 w; MS, m/z (relative intensity, %) [316 (M+, 4),
232 (18), 231 (100), 147 (12), 133 (11), 121 (12), 119 (11), 95 (15),
78 (16), 69 (10), 55 (17), major], [316 (M+, 6), 232 (17), 231 (100),
147 (19), 133 (17), 121 (13), 119 (17), 95 (18), 78 (20), 64 (12), 55
(20), minor]. Anal. Calcd for C21H36N2: C, 79.69; H, 11.46; N, 8.85.
Found: C, 79.77; H, 11.50; N, 8.90.
Procedure for the Backward Reaction from the Carbonylated
Product to the Alkylated product. A 50-mL stainless autoclave was
charged with 1-[1-(2-pyridinyl)-2-pyrrolidinyl]-1-propanone (46) (0.05
mmol, 10 mg), 2-propanol (1 mL), and Ru3(CO)12 (0.008 mmol, 5 mg).
After the system was flushed with 10 atm of carbon monoxide three
times, it was pressurized with carbon monoxide to 1 atm and then with
ethylene to an additional 10 atm. The autoclave was then immersed in
an oil bath at 160 °C. After 20 h had elapsed, the autoclave was removed
from the oil bath and allowed to cool for ca. 1 h and the gases were
then released. The contents were transferred to a round-bottomed flask
with toluene, and the volatiles were removed in vacuo. The residue
was subjected to column chromatography on silica gel (eluent; hexane/
EtOAc ) 5/1) to give 2,5-diethyl-1-(2-pyridinyl)pyrroridine (3a) and
1-[5-ethyl-1-(2-pyridinyl)-2-pyrrolidinyl]-1-propanone (47) as a mixture
(8 mg). The yields of 3a and 47 were determined by comparing the
integrations of the 6-H signals on the pyridine for 3a and 47 in the 1H
NMR spectrum of the mixture.
Procedure for the H/D Exchange Experiment in 2-Propanol-d8.
A 50-mL stainless autoclave was charged with 2-(1-pyrrolidinyl)-
pyridine (1a) (1 mmol, 148 mg), 2-propanol-d8 (2 mL), and Ru3(CO)12
(0.08 mmol, 51 mg). After the system was flushed with 10 atm of
carbon monoxide three times, it was pressurized with carbon monoxide
to 1 atm. The autoclave was then immersed in an oil bath at 140 °C.
After 20 h had elapsed, the autoclave was removed from the oil bath
and allowed to cool for ca. 1 h after which the gases were released.
The contents were transferred to a round-bottomed flask with toluene,
and the volatiles were removed in vacuo. The residue was subjected to
column chromatography on silica gel (eluent; hexane/EtOAc ) 5/1)
to give deuterized starting material (122 mg, 79% recovered) as a
colorless oil. After purification by bulb-to-bulb distillation, D-contents
in the recovered starting material were measured by 1H NMR with
cyclohexane as an external standard.
2,5-Diethyl-1-(2-pyridinyl)pyrroridine (3a). Spectral data were
obtained from a mixture of cis and trans isomer: colorless oil; bp 95
1
°C (1 mmHg); Rf 0.26 (hexane/EtOAc ) 10/1); H NMR (CDCl3) δ
0.86-0.96 (c, 6H), 1.20-1.42 (c, 2H), 1.76-2.05 (c, 6H), 3.81-3.92
(c, 2H), [6.26 (d, J ) 8.4 Hz, minor), 6.34 (d, J ) 8.6 Hz, major),
1H], 6.43-6.50 (c, 1H), 7.36-7.39 (c, 1H), 8.14 (dd, J ) 5.0 Hz, 2.0
Hz, 1H); 13C NMR (CDCl3) δ [10.67 (major), 10.92 (minor)] [24.34
(minor), 27.74 (major)], [26.95 (minor), 28.94 (major)], [59.02 (minor),
60.09 (major)], [106.66 (minor), 108.21 (minor)], [110.54 (major),
111.10 (minor)], [136.47 (minor), 136.60 (major)], [148.17 (major),
148.42 (minor)], [156.11 (major), 157.66 (minor)]; IR (neat) 3676 w,
3004 m, 2964 s, 2876 s, 1595 s, 1558 s, 1488 s, 1443 s, 1379 s, 1331
m, 1307 s, 1293 m, 1246 m, 1206 m, 1193 m, 1162 s, 1091 m, 1052
m, 1013 m, 989 s, 960 m, 932 w, 897 w, 879 m, 839 w; MS, m/z
(relative intensity, %) 204 (M+, 12), 176 (11), 175 (100), 147 (15),
121 (20), 119 (15), 107 (11), 95 (19), 79 (13), 78 (40), 55 (25), 51
(15). Anal. Calcd for C13H20N2: C, 76.42; H, 9.87; N, 13.71. Found:
C, 76.41; H, 9.92; N, 13.61.
Typical Procedure for the Coupling of C-H Bonds r to the
Nitrogen Atom in Alkylamines with Substituted Olefins. A 10-mL
stainless vial was charged with 2-(1-pyrrolidinyl)pyridine (1a) (1 mmol,
148 mg), 1-hexene (10 mmol, 842 mg), 2-propanol (2 mL), and Ru3-
(CO)12 (0.08 mmol, 51 mg) under nitrogen. The vial was then immersed
in an oil bath at 140 °C. After 60 h had elapsed, the vial was removed
from the oil bath and allowed to cool for ca. 1 h and the contents were
transferred to a round-bottomed flask with toluene, after which the
volatiles were removed in vacuo. The residue was subjected to column
chromatography on silica gel (eluent; hexane/EtOAc ) 30/1) to give
2-hexyl-1-(2-pyridinyl)pyrrolidine (30) (68 mg, 29% yield) and 2,5-
dihexyl-1-(2-pyridinyl)pyrrolidine (31) (168 mg, 53% yield, 52/48
stereoisomeric mixture of cis/trans) as colorless oils. Purification by
bulb-to-bulb distillation afforded analytically pure products.
2-Hexyl-1-(2-pyridinyl)pyrrolidine (30): colorless oil; bp 105 °C
(1 mmHg); Rf 0.17 (hexane/EtOAc ) 10/1); 1H NMR (CDCl3) δ 0.81-
0.89 (m, 3H), 1.20-1.40 (c, 9H), 1.72-2.07 (m, 5H), 3.32-3.42 (m,
1H), 3.46-3.58 (m, 1H), 3.82-3.92 (m, 1H), 6.32 (d, J ) 7.6 Hz,
1H), 6.47 (ddd, J ) 5.4 Hz, 4.9 Hz, 1.4 Hz, 1H), 7.39 (ddd, J ) 7.6
Hz, 5.4 Hz, 1.6 Hz, 1H), 8.15 (dd, J ) 4.9 Hz, 1.6 Hz, 1H); 13C NMR
(CDCl3) δ 14.09, 22.61, 23.33, 26.49, 29.44, 30.08, 31.90, 32.99, 47.14,
57.67, 106.96, 110.82, 136.64, 148.25, 157.02; IR (neat) 2928 s, 2856
Acknowledgment. This work was supported, in part, by
grants from Monbusho. T.A. acknowledges Research Fellow-
ships of Japan Society for the Promotion of Science for Young
Scientists. Thanks are given to the Instrumental Analysis Center,
Faculty of Engineering, Osaka University, for assistance in
obtaining MS, HRMS, 600-MHz NMR, and elemental analyses.
Supporting Information Available: Full characterization
data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA011540E