The Ru3(CO)12-catalyzed intermolecular [2+2+1] cyclocoupling of imines, alkenes or alkynes, and carbon monoxide: A new synthesis of functionalized γ-lactams

Article abstract of DOI:10.1055/s-2000-6295

The reaction of imines which contain N-heterocycles or an ester group with alkenes or alkynes and carbon monoxide in the presence of a catalytic amount of a ruthenium carbonyl results in [2+2+1] cyclocoupling to give γ- butyrolactams in good yields.

Full text of DOI:10.1055/s-2000-6295

PAPER
925
The Ru3(CO)12-Catalyzed Intermolecular [2+2+1] Cyclocoupling of Imines,
Alkenes or Alkynes, and Carbon Monoxide: A New Synthesis of
Functionalized g-Lactams
Naoto Chatani, Mamoru Tobisu, Taku Asaumi, Shinji Murai*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Fax +81(6)68797396; E-mail: murai@chem.eng.osaka-u.ac.jp
Received 1 February 2000
fins, and CO catalyzed by Ru3(CO)12, a reaction which
leads to the formation of g-butyrolactones bearing carbo-
nyl or N-heterocyclic groups at the g-position.7 This find-
ing prompted us to examine the possibility of using imines
in place of ketones for the synthesis of g-lactams, which
are of importance for use as pharmaceutical agents.8 Here-
in, we wish to report that the intermolecular [2+2+1] cy-
clocoupling of imines, alkene or alkynes, and CO can be
achieved catalytically, using Ru3(CO)12 as the catalyst.
Abstract: The reaction of imines which contain N-heterocycles or
an ester group with alkenes or alkynes and carbon monoxide in the
presence of a catalytic amount of a ruthenium carbonyl results in
[2+2+1] cyclocoupling to give g-butyrolactams in good yields.
Key words: ruthenium carbonyl, [2+2+1] cyclocoupling, cycload-
dition, imines, carbon monoxide
A [2+2+1] cycloaddition represents one of the most direct
and convenient strategies for the construction of five-
membered carbocyclic and heterocyclic carbonyl com-
pounds from simple acyclic building blocks.1 In particu-
lar, the Pauson-Khand reaction, in which an alkyne, an
alkene, and carbon monoxide are assembled into cyclo-
pentenones, mediated by Co2(CO)8 (Scheme 1, a), has
been a subject of great interest.2
We initially examined the reaction of an imine which con-
tained a 2-pyridyl group, since it has been reported that
such a group, when adjacent to a carbonyl group has an
accelerating effect in the ketone cycloadditions.7 We were
pleased to observe that the reaction proceeded smoothly
and efficiently. The reaction of imine 1a (1 mmol) with
ethylene (3 atmospheres) at 5 atmospheres of CO in tolu-
ene (3 mL) in the presence of Ru3(CO)12 (0.025 mmol) at
160 °C for 20 hours furnished the expected g-lactam 2a in
97% isolated yield, based on 1a (eq 1). The yields were
lower when a tert-butyl group (38%), or a benzyl group
(57%), or a p-toluenesulfonyl group (0%) were used as the
N-protecting groups of the imine moiety. The introduction
of an additional 2-pyridyl group at the imino carbon (i.e.
1b) resulted in the formation of the corresponding g-lac-
tam 2b in quantitative yield. Imine 1c (E-isomer only)
also underwent cycloaddition to give lactam 2c in a good
yield. In contrast, the use of benzoylpyridine-derived im-
ine 1d (1.4:1 stereoisomeric mixture) resulted in only
modest yields of lactam 2d. Since we have found that the
addition of P(4-CF3C6H4)3 enhances the efficiency of the
catalysis in the previously reported ketone cyclocou-
a)
b)
[ref 2]
C
O
O
O
X
X
[ref 3,4,5,7]
X = O
X = N
C
O
[ref 6] and
present work
[2+2+1] Cycloaddition approaches to the construction of five-mem-
bered carbonyl compounds
Scheme 1
It should be noted, however, that the application of the
[2+2+1] cycloaddition to the synthesis of heterocycles,
such as g-lactone and g-lactam derivatives (Scheme 1, b),
has met with limited success. In 1996, Crowe and Buch-
wald independently reported on the cyclocarbonylation of
olefinic aldehydes and ketones leading to bicyclic g-buty-
rolactones, mediated3,4 or catalyzed4 by a titanocene com-
plex. Subsequently, we reported on the Ru3(CO)12-
catalyzed cyclocarbonylation of yne-aldehydes5 and yne-
imines6 to give bicyclic g-lactones and g-lactams, respec-
tively. In these cases, a C=X moiety (X = O, N) and an
alkene or alkyne are incorporated in an intramolecular
manner. Quite recently, we reported the first example of
the intermolecular [2+2+1] cyclocoupling of ketones, ole-
Ru3(CO)12 2.5 mol%
ethylene (3 atm)
CO (5 atm)
toluene
160 °C, 20 h
R
R
N
N
ArN
NAr
O
Ar = p-MeOC6H4
1
2
a: R =
b: R =
c: R =
d: R =
97 %
H
2-pyridyl
CH3
99 %
78 %
42 % (88 %)*
Ph
* In the presence of P(4-CF3C6H4)3 (7.5 mol%)
Equation 1
Synthesis 2000, No. 7, 925–928 ISSN 0039-7881 © Thieme Stuttgart · New York

926
N. Chatani et al.
PAPER
pling,7 the cyclocoupling of 1d was conducted in the pres-
ence of this phosphine. As predicted, the yield of 2d was
increased to 88%.
Ru3(CO)12 2.5 mol %
P(4-CF3C6H4)3 7.5 mol%
CO (5 atm)
toluene
160 °C, 20 h
N
1a
+
ArN
Thiazole containing imines 3 were also applicable to the
[2+2+1] cycloaddition (eq 2). Since a thiazole ring can be
converted into a formyl group without interfering with the
functionality of lactam,9 thiazolyl lactams 4 represent po-
tentially useful intermediates for organic synthesis.
3 atm
O
7 87 % (64/36)
Equation 4
S
Ru3(CO)12 2.5 mol%
ethylene (3 atm)
CO (5 atm)
toluene
S
R
Alkynes were also examined as the two-carbon p-system.
Diphenylacetylene is an excellent coupling component
for this reaction (eq 5).
R
N
N
ArN
NAr
160 °C, 20 h
O
Ar = p-MeOC6H4
3
4
Ru3(CO)12 2.5 mol %
P(4-CF3C6H4)3 7.5 mol%
CO (5 atm)
a: R =
b: R =
92 %
54 % (78 %)*
H
Ph
Ph
CH3
N
1a
+
* In the presence of P(4-CF3C6H4)3 (7.5 mol%)
toluene
ArN
Ph
160 °C, 20 h
Ph
Equation 2
O
8
9 99 %
Equation 5
This new cycloaddition presumably proceeds via the ini-
tial formation of the s-N, s-N chelate ruthenium carbonyl
complex A or related complexes.10 This proposal led us to
test the reaction of the a-imino ester 5, which would be
expected to form a similar chelation complex B. Indeed,
the reaction of the imino ester 5 with ethylene and CO af-
forded the corresponding lactam 6 in good yield (eq 3).
Furthermore, mono-silylated alkynes can also serve as the
two-carbon unit. Since the desilylation of the primary
products occurred, to some extent, under the reaction con-
ditions employed here, the yields were determined after
the complete desilylation, by treatment of the crude
reaction mixture with p-TsOH (eq 6). This methodology
allows straightforward access to highly substituted
g-lactams.
EtO
N
O
(OC)3Ru
NAr
(OC)3Ru
NAr
Ru3(CO)12 2.5 mol %
P(4-CF3C6H4)3 7.5 mol%
A
B
R
p-TsOH
CO (5 atm)
toluene
160 °C, 20 h
1a
+
Structural Formula
wet. CH3CN
50 °C, 24 h
SiMe3
10a: R = Ph
10b: R = Me
Ru3(CO)12 2.5 mol%
P(4-CF3C6H4)3 7.5 mol%
ethylene (3 atm)
CO (5 atm)
toluene
160 °C, 20 h
R
EtO
N
N
EtO
+
ArN
ArN
R
O
O
ArN
O
O
NAr
11
12
O
Ar = p-MeOC6H4
a: R =
b: R =
97 % (92/8)
Ph
5
6 68 %
72 % (15/85)
Me
Equation 3
Equation 6
In conclusion, we demonstrate herein, the Ru3(CO)12-cat-
alyzed intermolecular [2+2+1] cycloaddition of imines,
alkenes or alkynes, and CO, which provides a new path-
way to the synthesis of functionalized g-lactam deriva-
tives.12
The use of propylene in place of ethylene afforded the me-
thyl-substituted lactam 7 with a high degree of regioselec-
tivity (eq 4).11
Synthesis 2000, No. 7, 925–928 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A New Synthesis of Functionalized g-Lactams
MS: m/z = 274 (M+).
927
1H NMR and 13C NMR were recorded on a JEOL JMN-270 spec-
trometer in CDCl3 using TMS as the internal standard. Infrared
spectra (IR) were obtained on a Hitachi 270-50 spectrometer. Mass
spectra were obtained on a Shimadzu GCMS-QP 5000 instrument
with ionization voltages of 70 eV. Column chromatography was
performed on Merk Silica Gel 60 (230-400 mesh). Ru3(CO)12 was
prepared according to the literature procedure13 and used after re-
crystallization from hexane. Imines were prepared by the reaction
of the corresponding aldehydes or ketones with p-anisidine and
used after distillation or recrystallization.
Anal. Calcd for C14H14N2O2S: C, 61.30; H, 5.14; N, 10.21; S, 11.24.
Found: C, 61.19; H, 5.15; N, 10.11; S, 11.22.
1-(4-Methoxyphenyl)-5-methyl-5-(2-thiazolyl)-2-pyrrolidinone
(4b)
Pale yellow crystal; mp 93-94 °C (hexane/EtOAc); Rf 0.17
(EtOAc).
IR (KBr): n = 1691 cm-1.
1H NMR: d = 1.77 (s, 3H), 2.25-2.36 (m, 1H), 2.57-2.68 (c, 2H),
2.90-3.04 (m, 1H), 3.73 (s, 3H), 6.78 (d, J = 9.1 Hz, 2H), 6.85 (d,
J = 9.1 Hz, 2H), 7.28 (d, J = 3.3 Hz, 1H),, 7.76 (d, J = 3.3 Hz, 1H).
13C NMR: d = 26.4, 30.0, 35.8, 55.3, 66.7, 114.1, 119.3, 128.4,
129.4, 142.6, 158.6, 174.1, 175.1.
Typical Procedure
A 50-mL stainless steel autoclave was charged with the imine 1a
(1 mmol, 212 mg), Ru3(CO)12 (0.025 mmol, 16 mg), and toluene (3
mL). After the system was flushed with 10 atm of ethylene three
times, it was pressurized with ethylene to 3 atm and then with CO
to an additional 5 atm. The autoclave was then immersed in an oil
bath at 160 °C. After 20 h it was removed from the oil bath, allowed
to cool for approx. 1 h, and the gases were then released. The con-
tents were transferred with toluene to a round-bottomed flask, and
the volatiles were removed in vacuo. The residue was subjected to
column chromatography on silica gel (EtOAc) to give 1-(4-methox-
yphenyl)-5-(2-pyridinyl)-2-pyrrolidinone (2a) (259 mg, 97% yield)
as a pale yellow solid. Recrystallization of the solid afforded the an-
alytically pure product.
MS: m/z = 288 (M+).
Anal. Calcd for C15H16N2O2S: C, 62.48; H, 5.59; N, 9.71; S, 11.12.
Found: C, 62.44; H, 5.61; N, 9.67; S, 11.07.
1-(4-Methoxyphenyl)-5-oxoproline Ethyl Ester (6)
White solid; mp 83-84 °C (hexane/EtOAc); Rf 0.14 (hexane/
EtOAc, 1:1).
IR (KBr): n = 1740, 1693 cm-1.
1H NMR: d = 1.19 (t, J = 7.3 Hz, 3H), 2.10-2.22 (m, 1H), 2.41-
2.59 (c, 2H), 2.64-2.78 (m, 1H), 3.78 (s, 3H), 4.15 (q, J = 7.3 Hz,
2H), 4.63 (dd, J = 8.6, 3.0 Hz, 1H), 6.88 (d, J = 8.9 Hz, 2H), 7.33
(d, J = 8.9 Hz, 2H).
13C NMR: d = 14.0, 23.2, 30.5, 55.4, 61.6, 62.4, 114.2, 124.4, 130.9,
157.5, 171.8, 174.3.
1-(4-Methoxyphenyl)-5-(2-pyridinyl)-2-pyrrolidinone (2a)
White solid; mp 130-131 °C (hexane/EtOAc); Rf 0.06 (EtOAc).
IR (KBr): n = 1676 cm-1.
1H NMR: d = 2.09-2.17 (m, 1H), 2.59-2.82 (c, 3H), 3.73 (s, 3H),
5.31 (dd, J = 7.8, 4.6 Hz, 1H), 6.78 (d, J = 8.9 Hz, 2H), 7.10-7.18
(c, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.59 (ddd, J = 7.8, 7.6, 1.6 Hz,
1H), 8.58 (d, J = 3.8 Hz, 1H).
13C NMR: d = 26.9, 30.9, 55.2, 65.5, 113.9, 120.4, 122.6, 123.8,
131.1, 136.9, 149.8, 156.8, 160.5, 174.8.
MS: m/z = 263 (M+).
Anal. Calcd for C14H17O4N: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.74; H, 6.44; N, 5.24.
MS: m/z = 268 (M+).
1-(4-methoxyphenyl)-4-methyl-5-(2-pyridinyl)-2-pyrrolidin-
one (7)
cis-isomer: White solid; mp 140-142 °C (hexane/EtOAc); Rf 0.20
(EtOAc).
Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C,
71.50; H, 6.08; N, 10.38.
IR (KBr): n = 1682 cm-1.
1-(4-Methoxyphenyl)-5-phenyl-5-(2-pyridinyl)-2-pyrrolidin-
one (2d)
White solid; mp 96-97 °C (hexane/EtOAc); Rf 0.31 (EtOAc).
IR (KBr): n = 1694 cm-1.
1H NMR: d = 2.50-2.67 (c, 3H), 3.39-3.46 (m, 1H), 3.67 (s, 3H),
6.61 (d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 7.06 (d, 1H), 7.16
(dd, J = 7.6, 5.0 Hz, 1H), 7.26-7.36 (c, 5H), 7.47 (dd, J = 8.3, 7.6
Hz, 1H), 8.65 (d, J = 5.0 Hz, 1H).
13C NMR: d = 30.1, 37.2, 55.2, 76.9, 113.5, 122.5, 124.6, 127.6,
128.1, 128.4, 130.1, 135.7, 142.1, 148.8, 157.5, 160.0, 175.9.
1H NMR: d = 0.72 (d, J = 6.9 Hz, 3H), 2.48-2.93 (c, 2H), 2.93-
3.05 (m, 1H), 3.68 (s, 3H), 5.21 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 8.9
Hz, 2H), 7.10 (d, J = 7.9 Hz, 1H), 7.16 (td, J = 6.3, 0.7 Hz, 1H),
7.37 (d, J = 8.9 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 8.58-8.60 (m,
1H).
13C NMR: d = 15.6, 32.0, 38.7, 55.1, 69.4, 113.7, 121.5, 122.4,
123.3, 131.4, 136.2, 149.4, 156.3, 157.4, 174.3.
MS: m/z = 282 (M+).
Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: C,
72.14; H, 6.32; N, 9.88.
MS: m/z = 344 (M+).
trans-isomer: White solid; mp 104-106 °C (hexane/EtOAc); Rf
Anal. Calcd for C22H20N2O2: C, 76.49; H, 5.82; N, 8.14. Found: C,
76.72; H, 5.85; N, 8.13.
0.14 (EtOAc).
IR (KBr): n = 1688 cm-1.
1-(4-Methoxyphenyl)-5-(2-thiazolyl)-2-pyrrolidinone (4a)
Pale yellow crystal; mp 95-96 °C (hexane/EtOAc); Rf 0.14 (hex-
ane/EtOAc, 1:2).
IR (KBr): n = 1681 cm-1.
1H NMR: d = 2.24-2.32 (m, 1H), 2.60-2.89 (c, 3H), 3.75 (s, 3H),
5.60 (dd, J = 7.8, 4.1 Hz, 1H), 6.83 (d, J = 8.9 Hz, 2H), 7.34 (d,
J = 3.2 Hz, 1H), 7.32 (d, J = 8.9 Hz, 2H), 7.70 (d, J = 3.2 Hz, 1H).
1H NMR: d = 1.32 (d, J = 6.6 Hz, 3H), 2.30 (dd, J = 16.5, 6.3 Hz,
1H), 2.42-2.52 (m, 1H), 2.92 (dd, J = 16.5, 7.9 Hz, 1H), 3.73 (s,
3H), 4.85 (d, J = 5.0 Hz, 1H), 6.77 (d, J = 9.1 Hz, 2H), 7.11-7.18
(c, 2H), 7.29 (d, J = 9.1 Hz, 2H), 7.58 (td, J = 7.6, 1.6 Hz, 1H),
8.55-8.58 (m, 1H).
13C NMR: d = 19.5, 35.6, 39.3, 55.3, 72.8, 113.8, 120.6, 122.6,
123.8, 131.1, 136.8, 149.5, 156.6, 159.6, 174.0.
MS: m/z = 282 (M+).
13C NMR: d = 27.2, 30.4, 62.0, 114.1, 119.5, 124.5, 130.3, 142.6,
157.3, 171.3, 174.0.
Synthesis 2000, No. 7, 925–928 ISSN 0039-7881 © Thieme Stuttgart · New York

928
N. Chatani et al.
PAPER
Anal. Calcd for C17H18N2O2: C, 72.32; H, 6.43; N, 9.92. Found: C,
72.29; H, 6.38; N, 9.91.
Acknowledgement
This work was supported, in part, by grants from Monbusho, Japan.
1,5-Dihydro-3,4-diphenyl-1-(4-methoxyphenyl)-5-(2-pyridi-
nyl)-2H-pyrrole-2-one (9)
Pale yellow solid; mp 180-182 °C (hexane/EtOAc); Rf 0.17 (hex-
ane/EtOAc, 4:3).
References
(1) For reviews on transition-metal-catalyzed cycloaddition
reactions, see: Schore, N. E. Chem. Rev. 1988, 88, 1081.
Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem.
Rev. 1996, 96, 635.
(2) Chung, Y. K. Coord. Chem. Rev. 1999, 188, 297.
(3) Crowe, W. E.; Vu, A. T. J. Am. Chem. Soc. 1996, 118, 1557.
(4) Kablaouni, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 5818.
IR (KBr): n = 1694 cm-1.
1H NMR: d = 3.72 (s, 3H), 6.26 (s, 1H), 6.80 (d, J = 9.2 Hz, 2H),
7.00-7.05 (m, 1H), 7.12-7.23 (c, 6H), 7.30-7.36 (c, 3H), 7.46-
7.53 (c, 3H), 7.57 (d, J = 9.2 Hz, 2H), 8.38-8.40 (m, 1H).
13C NMR: d = 55.3, 69.4, 113.9, 121.0, 123.0, 128.2, 128.7, 128.8,
129.7, 130.7, 131.1, 131.8, 132.4, 136.9, 149.0, 151.5, 156.2, 156.4,
169.1.
Kablaouni, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem
Soc. 1997, 119, 4424.
MS: m/z = 418 (M+).
Anal. Calcd for C28H22N2O2: C, 80.36; H, 5.30; N, 6.69. Found: C,
80.27; H, 5.37; N, 6.69.
(5) Chatani, N.; Morimoto, T.; Fukumoto, Y.; Murai, S. J. Am.
Chem. Soc. 1998, 120, 5335.
(6) Chatani, N.; Morimoto, T.; Kamitani, A.; Fukumoto, Y.;
Murai, S. J. Organomet. Chem. 1999, 579, 177.
(7) Chatani, N.; Tobisu, M.; Asaumi, T.; Fukumoto, Y.; Murai, S.
J. Am. Chem. Soc. 1999, 121, 7160.
(8) Gamzu, E. R.; Hoover, T. M.; Gracon, S. I. Drug. Dev. Res.
1989, 18, 177; and references cited therein.
1,5-Dihydro-1-(4-methoxyphenyl)-4-phenyl-5-(2-pyridinyl)-
2H-pyrrole-2-one (11a)
Pale yellow solid; mp 174-176 °C (hexane/EtOAc); Rf 0.46
(EtOAc).
IR (KBr): n = 1674 cm-1.
(9) Tejero, T.; Dondoni, A.; Rojo, I.; Merchàn, F. L.; Merino, P.
Tetrahedron 1997, 53, 3301.
1H NMR: d = 3.72 (s, 3H), 6.31 (s, 1H), 6.65 (s, 1H), 6.79 (d, J = 8.9
Hz, 2H), 7.04-7.09 (m, 1H), 7.13 (d, J = 7.9 Hz, 1H), 7.28-7.32 (c,
3H), 7.46-7.52 (c, 3H), 7.59-7.63 (m, 2H), 8.48 (d, J = 5.0 Hz,
1H).
13C NMR: d = 55.3, 69.9, 114.0, 120.9, 121.0, 123.2, 123.4, 127.2,
128.6, 130.0, 130.2, 130.6, 137.1, 149.1, 156.2, 156.5, 157.3, 169.9.
(10) Although the mechanism for the present catalytic reaction is
not clear, a similar stoichiometric reaction has been reported.
Feiken, N.; Schreuder, P.; Siebenlist, R.; Frühauf, H.-W.;
Vrieze, K.; Kooijman, H.; Veldman, N.; Spek, A. L.; Fraanje,
J.; Goubitz, K. Organometallics 1996, 15, 2148; and
references cited therein.
(11) A trace amount of the regioisomer of 7 was detected by GC.
(12) Supporting information including typical experimental
procedures and the details of spectral data of new compounds
are available on request to the author by e-mail or fax.
(13) Bruce, M. I.; Jensen, C. M.; Jones, N. L. Inorg. Synth. 1989,
26, 259.
MS: m/z = 342 (M+).
1,5-Dihydro-1-(4-methoxyphenyl)-3-phenyl-5-(2-pyridinyl)-
2H-pyrrole-2-one (12a)
Pale yellow solid; Rf 0.51 (EtOAc).
1H NMR: d = 3.75 (s, 3H), 5.91 (d, J = 2.3 Hz, 1H), 6.84 (d, J = 8.9
Hz, 2H), 7.05 (d, J = 7.9 Hz, 1H), 7.18 (ddd, J = 7.6, 5.0, 1.0 Hz,
1H), 7.35 (d, J = 2.3 Hz, 1H), 7.36-7.45 (c, 3H), 7.52-7.60 (c, 3H),
7.92-7.95 (m, 2H), 8.58 (dd, J = 5.0, 1.0 Hz, 1H).
Article Identifier:
1437-210X,E;2000,0,07,0925,0928,ftx,en;C00900SS.pdf
13C NMR: d = 55.4, 66.8, 114.1, 120.5, 122.6, 123.0, 127.2, 128.4,
128.8, 130.7, 131.0, 135.6, 137.3, 139.3, 149.6, 156.0, 156.4, 169.0.
Synthesis 2000, No. 7, 925–928 ISSN 0039-7881 © Thieme Stuttgart · New York