Ru-catalyzed hydroamidation of alkenes and cooperative aminocarboxylation procedure with chelating formamide

Article abstract of DOI:10.1021/ol034862r

(Matrix presented) A strategy of chelation-assisted activation of formamide was employed to achieve hydroamidation of alkenes to generate one-carbon-elongated amides in moderate to good selectivity and yields. Also reported is the two-metal-catalyzed cooperative aminocarboxylation of aryl iodides, in which Ru is presumed to catalyze decarbonylation of formamide to release carbon monoxide and amine for the subsequent Pd-catalyzed aminocarboxylation routes, thus enabling the net transformation to be performed in the absence of external CO pressure.

Full text of DOI:10.1021/ol034862r

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2687-2690
Ru-Catalyzed Hydroamidation of Alkenes
and Cooperative Aminocarboxylation
Procedure with Chelating Formamide
Sangwon Ko, Hoon Han, and Sukbok Chang*
Center for Molecular Design and Synthesis (CMDS), Department of Chemistry and
School of Molecular Science (BK21), Korea AdVanced Institute of Science and
Technology (KAIST), Daejeon 305-701, Korea
sbchang@mail.kaist.ac.kr
Received May 18, 2003
ABSTRACT
A strategy of chelation-assisted activation of formamide was employed to achieve hydroamidation of alkenes to generate one-carbon-elongated
amides in moderate to good selectivity and yields. Also reported is the two-metal-catalyzed cooperative aminocarboxylation of aryl iodides,
in which Ru is presumed to catalyze decarbonylation of formamide to release carbon monoxide and amine for the subsequent Pd-catalyzed
aminocarboxylation routes, thus enabling the net transformation to be performed in the absence of external CO pressure.
Metal-catalyzed C-H bond activation and subsequent ad-
dition of the activated species to unsaturated compounds
constitute one of the most economical and efficient methods
in organic synthesis.1 Among them, the method for insertion
of alkene or alkyne into the activated C-H bond of aldehyde,
resulting in the corresponding ketone moiety, is considered
highly useful.2 However, the use of hydroacylation in organic
synthesis is rather limited mainly due to facile decarbony-
lation of the activated hydroacyl intermediate under the
normally used conditions.3 Chelation strategy has been
elegantly utilized in transition metal-catalyzed organic
transformations to direct reaction pathways by virtue of
forming tight transition states.4 During the course of studies
on transition metal catalysis,5 we have recently demonstrated
that the chelation strategy could be employed to effectively
activate pyridyl group-containing formates to achieve ef-
ficient hydroesterification of alkenes.6 In this protocol, the
pyridyl moiety of formats serves as a directing group and
facilitates the formation of chelating species, thus effectively
suppressing decarbonylation of ruthenium acyl hydride
intermediates. It is surprising that whereas hydroesterification
(1) For recent examples of catalytic C-H bond activation, see: (a)
Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.; Peterson, T. H. Acc. Chem.
Res. 1995, 28, 154. (b) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997,
97, 2879. (c) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (d) Jia, C.;
Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (e) Kakiuchi,
F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (f) Ritleng, V.; Sirlin, C.;
Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(2) For selected examples of metal-catalyzed hydroacylation, see: (a)
Lochow, C. F.; Miller, R. G. J. Am. Chem. Soc. 1976, 98, 1281. (b) Marder,
T. B.; Roe, D. C.; Milstein, D. Organometallics 1988, 7, 1451. (c) Bosnich,
B. Acc. Chem. Res. 1998, 31, 667. (d) Tanaka, K.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 11492. (e) Jun, C.-H.; Lee, H.; Hong, J.-B.; Kwon, B.-I.
Angew. Chem., Int. Ed. 2002, 41, 2146. (f) Sato, Y.; Oonishi, Y.; Mori, M.
Angew. Chem., Int. Ed. 2002, 41, 1218.
(4) For some selected recent examples, see: (a) Murai, S.; Kakiuchi, F.;
Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993,
366, 529. (b) Gozin, M.; Weisman, A.; Ben-David, Y.; Milstein, D. Nature
1993, 364, 699. (c) Jun, C.-H.; Lee, H. J. Am. Chem. Soc. 1999, 121, 880.
(d) Itami, K.; Koike, T.; Yoshida, J.-i. J. Am. Chem. Soc. 2001, 123, 6957
and references therein.
(5) (a) Na, Y.; Chang, S. Org. Lett. 2000, 2, 1887. (b) Lee, M.; Chang,
S. Tetrahedron Lett. 2000, 41, 7507. (c) Lee, M.; Ko, S.; Chang, S. J. Am.
Chem. Soc. 2000, 122, 12011. (d) Chang, S.; Na, Y.; Choi, E.; Kim, S.
Org. Lett. 2001, 3, 2089. (e) Chang, S.; Yang, S. H.; Lee, P. H. Tetrahedron
Lett. 2001, 42, 4833. (f) Choi, E.; Lee, C.; Na, Y.; Chang, S. Org. Lett.
2002, 4, 2369.
(6) (a) Ko, S.; Na, Y.; Chang, S. J. Am. Chem. Soc. 2002, 124, 750. (b)
Ko, S.; Lee, C.; Choi, M.; Na, Y.; Chang, S. J. Org. Chem. 2003, 68, 1607.
(c) Na, Y.; Ko, S.; Hwang, L. K.; Chang, S. Tetrahedron Lett. 2003, 44,
4475.
(3) Bates, R. W. In ComprehensiVe Organometallic Chemistry II; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, UK, 1995;
Vol. 12, pp 373-378.
10.1021/ol034862r CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/25/2003

has been well studied previously,7 only a few examples of
hydroamidation, in which formamides are directly added to
alkenes, have been reported.8 Considering the high potential
utility of hydroamidation in organic synthesis, an efficient
and preparative method for the reaction is highly desirable.
Herein, we report our studies on the chelation-assisted
hydroamidation of alkenes via ruthenium catalysis and its
application in an aminocarboxylation of aryl halides by a
cooperative catalysis with two metal catalysts, ruthenium and
palladium.
As shown in our previous reports that low-valent ruthe-
nium carbonyl species can effectively activate formyl C-H
bond,6 hydroamidation of alkenes was initially scrutinized
with Ru3(CO)12 catalyst with various formamides, which
were readily prepared from the corresponding amines (Table
1).9
(15%).10 Among the various solvents examined, acetonitrile
was the most suitable for the reaction under the catalytic
system. For example, in DMF or 2-propanol, decarbonylation
became significant and only a low yield of the desired amide
could be obtained (entries 3 and 4). N-Methylated formamide
(1c) was almost inert to the transformation (entry 5).
Substituents near the pyridyl nitrogen of formamides turned
out to accelerate decarbonylation, thereby giving poor yields
of hydroamidation (entry 6). Reaction of formanilide (1e)
did not proceed under the conditions, clearly demonstrating
the crucial role of chelation on the reactivity (entry 7).
The chelation-assisted hydroamidation protocol could be
extended to a range of alkenes, and the corresponding one-
carbon-homologated amides could be obtained in moderate
to good yields (Table 2).11 The preference for the formation
Table 2. Ru-Catalyzed Hydroamidation of Alkenes with
N-(2-Pyridyl)formamide (1b)a
Table 1. Hydroamidation of 3,3-Dimethyl-1-butene with
Various Formamidesa
entry
R
R′
solvent
conversion (%)b
1
2
3
4
5
6
7
2-PyCH2
2-Py
2-Py
2-Py
2-Py
H (1a ) CH3CN
H (1b) CH3CN
H (1b) DMF
10 (<5)
>99 (80)
>99 (23)
>99 (9)
13 (<5)
79 (10)
H (1b) 2-propanol
Me (1c)
H (1d ) CH3CN
H (1e) CH3CN
CH3CN
(6-Me)-2-Py
Ph
<5 (<5)
a All reactions were carried out with formamide (1.0 mmol), alkene (3.0
mmol), and ruthenium catalyst (0.05 mmol) in the indicated solvent (1 mL).
b Conversion and product yields were calculated by 1H NMR using an
internal standard (anisole).
Contrary to the results of hydroesterification studies,6 in
which 2-pyridylmethy formate was the most efficient acyl
donor based on the reaction rates and selectivity, the
corresponding amide, N-(2-pyridylmethyl)formamide (1a),
reacted very slowly with alkene and almost no desired
product was obtained under the employed conditions (entry
1). In contrast, N-(2-pyridyl)formamide (1b) reacted much
more readily with alkene (entry 2), giving the one-carbon-
elongated amide in good yield in acetonitrile along with the
decarbonylated moiety (2-aminopyridine) in small portion
a Formamide (1b, 0.5 mmol), alkene (1.5 mmol), and Ru3(CO)12 (0.025
mmol) in CH3CN (1 mL). b Conversion was calculated by 1H NMR
integration using anisole as a standard. c Isolated yield after chromatography
and ratio of linear/branched isomer (parenthesis). d Ratio of exo/endo isomer
obtained by comparison to the literature.12
of linear formamide over branched isomer was observed for
all substrates examined, and the extent of the ratio turned
out to be dependent on the steric bulkiness of olefins. For
example, whereas a 4:1 ratio of linear/branched amide
product was observed with 1-hexene by the reaction of N-(2-
pyridyl)formamide (1b), the ratio was increased to 93:7 with
vinylcyclohexane and then up to >99:1 with 3,3-dimethyl-
1-butene (entries 1-3). Hydroamidation of aromatic olefins
with 1b proceeded with similar tendency compared to
aliphatic alkenes (entries 4-5). Allylsilane was also reacted
to afford N-(2-pyridyl)-4-trimethylsilyl butanamide, albeit in
(7) For selected examples of hydroesterification of alkenes using alkyl
formates, see: (a) Kondo, T.; Yoshii, S.; Tsuji, Y.; Watanabe, Y. J. Mol.
Catal. 1989, 50, 31. (b) Lugan, N.; Lavigne, G.; Soulie´, J. M.; Fabre, S.;
Kalck, P.; Saillard, J. Y.; Halet, J. F. Organometallics 1995, 14, 1712. (c)
Legrand, C.; Castanet, Y.; Mortreux, A.; Petit, F. J. Chem. Soc., Chem.
Commun. 1994, 1173. (d) Grevin, J.; Kalck, P. J. Organomet. Chem. 1994,
476, C23.
(8) (a) Tsuji, Y.; Yoshii, S.; Oshumi, T.; Kondo, T.; Watanabe, Y. J.
Organomet. Chem. 1987, 331, 379. (b) Kondo, T.; Okada, T.; Mitudo, T.-
a. Organometallics 1999, 18, 4123.
(9) Formamides (1a-e) were prepared by the reaction of acetic formic
anhydride with the corresponding amines in 86-95% yields up to a 10 g
scale. For a reference, see: Strazzolini, P.; Giumanini, A. G.; Cauci, S.
Tetrahedron 1990, 46, 1081.
(10) For ruthenium-catalyzed hydroamidation of olefins with primary
amines under high-pressure CO, see: Tsuji, Y.; Ohsumi, T.; Kondo, T.;
Watanabe, Y. J. Organomet. Chem. 1986, 309, 333.
(11) For experimental details, see Supporting Information.
2688
Org. Lett., Vol. 5, No. 15, 2003

moderate yield and selectivity (entry 6). However, reaction
of vinylsilane with 1b showed almost exclusive formation
of the linear product in satisfactory yield, presumably due
to steric reasons (entry 7). Reaction of norbornylene resulted
in preferential formation of exo-isomeric product in good
yield (entry 8).12 Although the ruthenium catalyst was used
in 5 mol % in this study, the amount of the catalyst could
be reduced to as low as 2 mol % without a significant
decrease in the efficiency. For example, when 3,3-dimethyl-
1-butene was allowed to react with 1b in the presence of 2
mol % Ru3(CO)12 under otherwise identical conditions, 71%
yield of the desired amide was obtained with the same
selectivity (6 h, linear/branched isomer, >99:1, compare
entry 3 of Table 2).
tigations have to be carried to get a precise mechanism of
the present reaction, an alternative pathway, ruthenium-
catalyzed decarbonylation of 1b and subsequent aminocar-
boxylation of alkenes with the released CO and 2-aminopy-
ridine, could be ruled out on the basis of the following result.
The aminocarboxylation of alkenes with CO and 2-
aminopyridine instead of 1b gave very low yields (<10%)
with the use of Ru3(CO)12 catalyst under identical conditions.
In the course of our studies on the hydroamidation of
alkenes, we found that with certain olefin substrates, decar-
bonylation of formamide 1b occurred much faster than
addition of the formamide to alkenes, which is especially
conspicuous with sterically bulky olefins. In fact, in the
absence of alkenes, decarbonylation of 1b was complete in
2 h at temperatures above 130 °C with Ru3(CO)12 catalyst
(3 mol %) in acetonitrile to give 2-aminopyridine quantita-
tively. The fact that palladium is known to be an excellent
catalyst for aminocarboxylation of aryl halides with CO and
amines led us to examine a cooperative coupling of forma-
mide 1b with aryl halides by the use of both ruthenium and
palladium catalysts (Table 3).14 Two sequential catalytic
On the basis of previous studies, including a crystal
structure analysis of a chelated Ru-pyridyl species,6 we
propose the following mechanism for the hydroamidation
of alkenes using 1b (Scheme 1, only a major isomeric
Scheme 1. Proposed Mechanism of the Ru-Catalyzed
Hydroamidation of Alkenes with N-(2-Pyridyl)formamide (1b)a
Table 3. Cooperative Catalytic Aminocarbonylation of Aryl
Iodides by the Combined Use of Pd and Ru Catalystsa
entry
Ar
t (h)
yield (%)b
1
2
3
4
5
6
7
C6H5
4
8
8
8
10
8
58
50
76
62
83
57
54
(3-Br)C6H4
(4-Me)C6H4
(4-MeO)C6H4
(4-Ac)C6H4
(6-HO)C6H4
1-naphthyl
10
a Only one plausible pathway for the formation of the linear
isomer is shown.
a Formamide (1b, 0.4 mmol), aryl iodides (0.8 mmol), and the indicated
ratio of NaHCO3, Pd, and Ru species in CH3CN (0.8 mL). b Isolated yields
after column chromatography.
pathway is shown). Although it is not clear at the present
stage whether ruthenium acts as a mononuclear or as a
cluster,13 it is presumed that the coordination of ruthenium
to the pyridyl nitrogen should facilitate the activation of the
formyl C-H bond, leading to a five-membered chelation
intermediate. The observation that formanilide (1e) does not
react under the identical conditions (Table 1, entry 7) may
support our assumption. In addition, such a chelation is
believed to be a driving force for the significant suppression
of the decarbonylation pathway during the catalytic hydro-
amidation cycles using 1b. Although more extensive inves-
routes were intended to combine, Ru-catalyzed decarbony-
lation of 1b to generate CO and 2-aminopyridine and
subsequent aminocarboxylation of aryl halides using the
released CO and amine in the presence of Pd catalyst. Among
several solvents examined, acetonitrile turned out to be most
suitable for the transformation in combination with sodium
bicarbonate. For example, from the reaction of 1b with
iodobenzene, the desired amide was isolated in 58, 20, and
50% yields in CH3CN (entry 1), toluene, and DMF,
respectively, under otherwise identical conditions.15 It should
be mentioned that N-(2-pyridyl)benzamide was produced
(12) Regioselectivity of exo/endo isomer was determined unambiguously
by comparison to the literature after hydrolysis of the obtained amide to
the corresponding carboxylic acid; see: Eda, M.; Takemoto, T.; Ono, S.-i.;
Okada, T.; Kosaka, K.; Gohda, M.; Matzno, S.; Nakamura, N.; Fukaya, C.
J. Med. Chem. 1994, 37, 1983.
(13) We isolated a triruthenium cluster bound to 2-pyridylmethanol from
the previous studies and showed that it was a stoichiometric reagent for
the hydroesterification of alkenes. For a reference, see ref 6b.
(14) For some recent examples of sequential catalytic reactions, see: (a)
Jeong, N.; Seo, S. D.; Shin, J. Y. J. Am. Chem. Soc. 2000, 122, 10220. (b)
Park, K. H.; Son, S. U.; Chung, Y. K. Org. Lett. 2002, 4, 4361.
(15) On the basis of this result, the possibility that DMF acts as a CO
source through decomposition of the solvent can be ruled out. For a reference
of a related example, see: Wan, Y.; Altermann, M.; Larhed, M.; Hallberg,
A. J. Org. Chem. 2002, 67, 6232.
Org. Lett., Vol. 5, No. 15, 2003
2689

only by the combined use of both Ru and Pd catalysts, and
that no desired product was obtained with any single metal
catalytic species examined under the present reaction condi-
tions. Whereas aryl chlorides and bromides were inert to the
coupling with 1b under the conditions, various aryl iodides
having different electronic properties were readily reacted
to afford benzamide derivatives in moderate to good yields.
Electron variation in aryl halides had little effect on the
reaction efficiency, and moderate to good yields were
obtained from the couplings (entries 2-5). Free hydroxyl
group was tolerant to the employed reaction conditions (entry
6). 1-Iodonaphthalene was also coupled with 1b, although
in moderate yield (entry 7). Although further studies have
to be carried out to elucidate detailed mechanistic pathways
of the present cooperative reaction, by the analogy of our
previous report on sequential alkoxycarboxylation protocol,6b
the reaction is believed to proceed via ruthenium-catalyzed
initial decarbonylation of formamide 1b to afford CO and
2-aminopyridine and then palladium-catalyzed subsequent
aminocarboxylation of aryl iodides with the released moi-
eties.16,17
one more carbon compared to the starting material. It should
be noted that the present hydroamidation and reduction
approach is highly comparable to the known Pd-catalyzed
hydroamination of alkenes,18 by which amines are produced
with the same number of carbons as in the olefinic starting
materials.
In summary, we have demonstrated that hydroamidation
of alkenes can be developed into a useful catalytic transfor-
mation by the assistance of chelation strategy with the use
of a readily prepared and hydrolyzable formamide. In
addition, in the absence of an external CO atmosphere, a
cooperative catalytic coupling of pyridyl formamide and aryl
iodides was realized by the combined use of ruthenium and
palladium catalyst in one pot to afford aminocarboxylation
adducts.
Acknowledgment. This research was supported by Korea
Science & Engineering Foundation (Grant No. R02-2002-
000-00140-0) through the Basic Research Program.
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data for all new
compounds obtained in this study. This material is available
free of charge via the Internet at http://pubs.acs.org.
Hydrolysis of the obtained N-(2-pyridyl) amides, repre-
sented by N-(2-pyridyl)-4,4-dimethyl pentanamide (2), could
be readily carried out under mild conditions to generate the
corresponding carboxylic acid (3) in almost quantitative yield
(eq 1). On the other hand, reduction of the pyridyl amide 2
with LAH afforded in high yield a pyridylamine (4) that bears
OL034862R
(16) Recent example of aminocarbonylation of aryl iodides using DMF
as an amide source: Hosoi, K.; Nozaki, K.; Hiyama, T. Org. Lett. 2002, 4,
2849.
(17) Use of aldehyde as a CO source in catalytic Pauson-Khand reaction
has been reported recently; see: (a) Morimoto, T.; Fuji, K.; Tsutsumi, K.;
Kakiuchi, K. J. Am. Chem. Soc. 2002, 124, 3806. (b) Shibata, T.; Toshida,
N.; Takagi, K. Org. Lett. 2002, 4, 1619.
(18) For recent reviews of hydroamination, see: (a) Gasc, M. B.; Lattes,
A.; Perie, J. J. Tetrahedron 1983, 39, 703. (b) Mu¨ller, T. E.; Beller, M.
Chem. ReV. 1998, 98, 675. (c) Nobis, M.; Driessen-Holscher, B. Angew.
Chem., Int. Ed. 2001, 40, 3983. (d) Mu¨ller, T. E.; Beller, M. In Transition
Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, Germany, 1998; Vol. 2, p 316.
2690
Org. Lett., Vol. 5, No. 15, 2003