Iridium-catalyzed double incorporation reaction of N-benzylmaleimide to styrene via ortho-C-H bond activation, initiated by precoordination of the double bond of styrene to iridium

Article abstract of DOI:10.1016/j.tetlet.2005.04.092

Reaction of styrene with N-benzylmaleimide in the presence of [IrCl(cod)]₂ (5 mol %) and bpy (10 mol %) in an autoclave (1 MPa of Ar) at 150°C for 18 h stereoselectively led to the formation of a new cyclic product. The structure of the product suggests that a novel iridium-catalyzed double incorporation reaction takes place via a metallacyclopentane formed after ortho-C-H activation.

Full text of DOI:10.1016/j.tetlet.2005.04.092

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4279–4282
Iridium-catalyzed double incorporation reaction of
N-benzylmaleimide to styrene via ortho-C–H bond activation,
initiated by precoordination of the double bond of styrene to iridium
Syun-ichi Kiyooka* and Yushi Takeshita
Department of Material Science, Faculty of Science, Kochi University, Akebono-cho 2-5-1, Kochi 780-8520, Japan
Received 7 April 2005; revised 23 April 2005; accepted 27 April 2005
Abstract—Reaction of styrene with N-benzylmaleimide in the presence of [IrCl(cod)]2 (5 mol%) and bpy (10 mol%) in an autoclave
(1 MPa of Ar) at 150 ꢀC for 18 h stereoselectively led to the formation of a new cyclic product. The structure of the product suggests
that a novel iridium-catalyzed double incorporation reaction takes place via a metallacyclopentane formed after ortho-C–H
activation.
ꢁ 2005 Elsevier Ltd. All rights reserved.
Styrene having an aromatic double bond with conju-
N
N
gated extranuclear unsaturation provides an active diene
system capable of undergoing the Diels–Alder reaction.
Reaction of styrene with maleic anhydride, however,
gave only a copolymer.1 Transition metal-mediated
cycloaddition reactions,2 to our knowledge, are scarcely
found in which styrene directly participates. By consi-
dering the rapidly developing progress in the area of
transition metal-catalyzed C–H bond activation via
intramolecular coordination, especially assisted by a
variety of directing groups such as imines, pyridines,
and esters,3 we can expect the ortho-C–H bond activa-
tion of styrene and the sequential C–C bond formation
provided that an appropriate metal can precoordinate
to the olefinic moiety of styrene. Iridium complexes have
recently been reported to be effective for the reactions,
involving intra- and/or intermolecular C–H activation
and sequential insertion of alkenes.4 Then, the reaction
of styrene with N-benzylmaleimide was investigated as
a possible [4 + 2] reaction system in the presence of cat-
ionic iridium complex 1, produced in situ from [IrCl-
(cod)]2 and 2,20-bipyridine (bpy) (Scheme 1).5 We
disclose herein the first example of iridium-catalyzed
double incorporation reaction of N-benzylmaleimide
Cl
+
[IrCl(cod)]2
2
Ir
N
N
(bpy)
1
Scheme 1.
to styrene via C–H bond activation, initiated by pre-
coordination of iridium to olefin.6
Preliminary reactions in toluene were performed with
styrene 2 and N-benzylmaleimide 3 in a 5:1 molar ratio
(2 mmol scale of styrene) in the presence of [IrCl(cod)]2
(2.5 mol%) with bpy (5 mol%) as a bidentate ligand at
100 ꢀC for 18 h under Ar atmosphere. The initial result,
however, was miserable to give unknown polymeric
products with recovery of a large amount of the starting
materials. When the reaction was carried out in a stain-
less autoclave at 150 ꢀC for 18 h under Ar atmosphere
(1 MPa), a novel compound 47 (31%) was first obtained
with compounds, 5 (6%) and 67 (3%) (Scheme 2). Pro-
duct 4, constituted of one 2 and two 3, found to be a sin-
gle stereoisomer. The entire condensation process to 4
might be to proceed in a regio- and stereoselective man-
ner. Reduction of 3–5 suggests the intervention of Ir–H
intermediates.8 The minor product 6 is apparently
formed via the Diels–Alder reaction twice. Thermal
reaction of 2 and 3 (1:1 ratio) at 150 ꢀC for 18 h under
Ar (1 MPa) led to the formation of polymeric products
Keywords: Iridium-catalyzed double incorporation reaction; C–H
bond activation; Precoordination to olefin.
*
Corresponding author. Tel.: +81 88 844 8295; fax: +81 88 844
8359; e-mail: kiyooka@cc.kochi-u.ac.jp
0040-4039/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.092

4280
S. Kiyooka, Y. Takeshita / Tetrahedron Letters 46 (2005) 4279–4282
2.5 mol% of [IrCl(cod)]2
5 mol% of bpy
O
O
N
Toluene, Ar (1MPa)
150ºC, 18 h
Ph
2
3
O
Ph
N
O
O
N
O
Ph
O
O
N
O
O
N
N
Ph
O
O
5
6
4
Ph
Ph
copolymers
Scheme 2.
without any isolation of 4–6. Reaction in the presence of
only [IrCl(cod)]2 merely gave a small amount of 5 so
that the involvement of bpy in the catalyst precursor 1
is essential for achieving an actual catalyst,9 which is
presumably activated by releasing the cod ligand during
the reaction process. Furthermore, when the reaction
was conducted without 2, the starting 3 was almost
recovered with a small amount of 5 along with minute
quantities of copolymer. After these experiments, ratios
of 2 and 3 with ranges of reaction temperature and time
were surveyed in order to optimize the reaction condi-
tions (Table 1). When the reaction temperature was low-
ered from 150 ꢀC to 100 ꢀC, the yield of 4 was reduced
and the formation of 6 was not observed (entry 2). Reac-
tion of 2 and 3 in a 1:1 ratio led to improvement of the
yield of 4 up to 63 % for 3 days and the formation of 6
was relatively limited (entries 3 and 4). The reaction
path to 6 can be considered to be discrete from the
major path to 4 because the ratios of products, 4 and 6,
are consequently independent of the reaction conditions.
Additionally, the use of [RhCl(cod)]2, instead of
[IrCl(cod)]2, did not give any 4 although the starting 3
was consumed as to lead to unknown products with
copolymers.
relatively electron-rich double bond of styrene, com-
pared with that of N-benzylmaleimide, makes the
sequential reactions possible after the release of the
cod ligand (7:16e). At the position a to the tethered ole-
fin, activation of the ortho-C–H bond takes place by oxi-
dative addition to the coordinatively unsaturated Ir
center, leading to a hydride intermediate 8 (16e). Coor-
dination of the iridium intermediate 8 to N-benzylmalei-
mide allows to the first insertion of the double bond into
the Ir–H bond via 9 to give alkylated intermediate 10,
followed by intramolecular migration of the resulting
alkyl group to the iridium-coordinated double bond to
afford metallacycle 11.10 The next step involves
the second insertion of N-benzylmaleimide into the Ir–C
bond of 11 to give sequential metallacycle 13 via 12
(16e) as to furnish the final product 4. This key step
results in a completely endo-stereoselective manner, as
evidenced by the product stereochemistry. Thus, the
iridium-catalyzed double incorporation reaction can be
formulated. The minor route to 6 can be explained, as
follows. Substrates, 2 and 3, undergo the formal
metal-catalyzed [4 + 2] cycloaddition,11 as illustrated
by 14. Then, metallacycle intermediate 15, having an
isolated double bond and a conjugated diene, is formed.
The intermediate undergoes the following Diels–Alder
reaction with 3 to give 6 with perfect stereocontrol,
accompanied by reductive elimination. The iridium
cation species can be recycled in the above catalytic
cycles.
On the basis of these results, the following catalytic cy-
cles involving two different reaction pathways for the
formation of 4 and 6, as depicted in Scheme 3, were pro-
posed. The major route to 4 can be explained, as fol-
lows. Coordination of cationic iridium 1 to the
The reaction was successfully carried out as to prepare
carbocycle adducts, branching a succinimide moiety at
the a position to the aromatic ring with a range of sty-
rene congeners (Table 2). The yields as a whole, how-
ever, are prone to be lower owing to the formation of
considerable amounts of copolymers by thermal reac-
tions, which might be enhanced by the electron density
induced by the substituents in styrene congeners. How-
ever, reaction with 4-nitrostyrene did not work as to give
4. Stereoselective control is maintained even in reaction
of a-methylstyrene, in which a quaternary carbon is
formed at the a position (entry 1). Conversely, the b-
substituents in styrene congeners were demonstrated to
prevent the formation of the corresponding desired
Table 1. Iridium-catalyzed double incorporation reaction of N-benz-
ylmaleimide to styrene via C–H bond activation (Scheme 2)a
Entry
2/3
Conditions with 1 in toulene
Yieldb (%)
4
5
6
1
2
3
4
5:1
5:1
1:1
1:1
Ar/150 ꢀC/18 h
Ar/100 ꢀC/18 h
Ar/150 ꢀC/18 h
Ar/150 ꢀC/3 d
31
22
47
63
6
3
3
0
2
3
7
21
a Reactions were carried out in a stainless autoclave with stirring under
Ar (1 MPa).
b 1H NMR yields based on N-benzylmaleimide were determined after
short-path silica gel column chromatography.

S. Kiyooka, Y. Takeshita / Tetrahedron Letters 46 (2005) 4279–4282
Major path
4281
Ir
O
Ir
Ir
N
N
H
H
H
N
N
N
Ph
O
(16e)
8
7
(16e)
9
(18e)
O
Ph
N
+
+
Ir
O
O
N
Ph
Ir
O
11
10
Ph
O
O
+
Ph
O
N
N
O
O
4
Ir
+
O
Ir
N
"Ir" to a catalytic cycle
N
O
Ph
Ph
O
12 (16e)
13
Minor path
D-A reaction (endo manner)
3
O
6
O
+
Ir
+
Ir
N
"Ir" to a catalytic cycle
N
Ph
Ph
O
O
14
15
Scheme 3. Proposed reaction mechanism.
Table 2. Major products obtained in iridium-catalyzed double incor-
poration reaction of styrene congerners and N-benzylmaleimidea
Table 2 (continued)
Entry Styrene congeners
Major products (% yield)b
Entry
Styrene congeners
Major products (% yield)b
O
Ph
N
O
O
N
4
19 (25)
1
16 (13)
Ph
O
O
N
O
N
O
Ph
O
Ph
O
5
6
No desired product
Ph
N
O
O
Ph
2
17 (6)
N
O
O
N
20 (42)
O
Ph
Ph
O
O
N
N
O
O
Ph
a Reactions of styrene congeners and N-benzylmaleimide in a 1:1 molar
ratio were run with [IrCl(cod)]2 (2.5 mol%) and bpy (5 mol%) at
150 ꢀC for 18 h in toluene under Ar (1 MPa) unless otherwise noted.
b Isolated yields.
3
18 (35)
O
N
O
Ph

4282
S. Kiyooka, Y. Takeshita / Tetrahedron Letters 46 (2005) 4279–4282
7. Compound 4: mp 92 ꢀC.
products (entries 2 and 5). Their steric and electronic
properties presumably encumber the formation of the
important intermediate, for example, an analog of
metallacycle 11 in Scheme 3. The desired product 20
was also obtained in reaction of the substrate involving
a naphthyl moiety (entry 6).
O
H
N
Ph
3%
H
nOe
H
H
O
H
H
H
10%
H
6%
In summary, a novel iridium-catalyzed double incorpo-
ration reaction of N-benzylmaleimide to styrene was
found. The cationic iridium complex 1 has the ability,
as a catalyst precursor, to activate the ortho-C–H bond
of styrene after the precoordination of the metal center
to the olefinic moiety and to enable the subsequent reac-
tions. Styrene congeners also gave good results in the
catalytic transformation with some limitations. The
almost complete stereoselection with respect to the entire
transformation might provide a versatile methodology
for the construction of a novel skeleton like 4.
O
H
4
N
21%
Ph
10%
O
IR: 1770.3, 1699.9 cmꢀ1. H NMR (400 MHz): d 7.74 (d,
1H, J = 7.8), 7.34–7.23 (m, 11H), 6.92 (t, 1H, J = 7.8), 6.70
(d, 1H, J = 7.8), 4.65 (ABq, 2H, J = 14.3, m = 18.3), 4.64
(ABq, 2H, J = 14.3, m = 20.0), 3.94 (d, 1H, J = 9.0), 3.50
(ddd, 1H, J = 2.2, 2.9, 4.2), 3.18 (ddd, 1H, J = 5.6, 9.0,
9.7), 3.12 (ddd, 1H, J = 2.9, 5.6, 9.3), 2.69 (dd, 1H, J = 9.3,
18.0), 2.24 (dd, 1H, J = 5.6, 18.0), 2.21 (ddd, 1H, J = 2.2,
5.6, 13.6), 1.94 (ddd, 1H, J = 4.2, 9.7, 13.6). 13C NMR
(100 MHz): d 178.2, 178.0, 175.8, 175.3, 135.5, 135.3,
134.7, 130.6, 129.5, 128.9 (·2), 128.7 (·4), 128.6 (·2), 128.0
(·2), 127.8, 127.7, 127.3, 44.1, 42.8, 42.6, 42.5, 38.0, 36.6,
31.6, 29.5. Anal. Calcd for C30H26N2O4: C, 75.29; H, 5.48;
N, 5.85. Found: C, 75.48; H, 5.49; N, 5.91.
1
Acknowledgement
We thank a Grant-in-Aid for Scientific Research of
Japan Society for the Promotion of Science.
Compound 6: mp 94 ꢀC.
O
N
O
18%
H
H
References and notes
nOe
11%
H
1. Hudson, B. J. F.; Robinson, R. J. Chem. Soc. 1941, 715–
722.
2. (a) Wilke, G. Angew. Chem., Int. Ed. Engl. 1988, 27, 185–
206; (b) Schore, N. E. Chem. Rev. 1988, 88, 1081–1119; (c)
Lautens, M.; Klute, W. Chem. Rev. 1996, 96, 49–92; (d)
Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J.
Ph
O
H
H
H
5%
H
6
N
4%
O
Ph
8%
4%
IR: 1771.3, 1697.0 cmꢀ1 1H NMR (400 MHz): d 7.29–
.
7.21 (m, 10H), 5.68 (dd, 1H, J = 2.4, 7.1), 5.57 (dd, 1H,
J = 5.4, 8.1), 5.11 (dd, 1H, J = 5.6, 7.8), 4.51 (s, 2H), 4.46
(ABq, 2H, J = 14.4, m = 46.1), 3.73 (d, 1H, J = 5.6), 3.40
(dd, 1H, J = 2.4, 6.1), 3.22 (dd, 1H, J = 8.8, 9.0), 3.03
(ddd, 1H, J = 1.9, 5.8, 8.6), 2.88–2.80 (m, 3H), 2.33 (d, 1H,
J = 8.8), 2.03 (ddd, 1H, J = 2.4, 5.6, 15.1). 13C NMR
(100 MHz): d 178.5, 177.2, 177.1, 177.0, 140.5, 135.6,
131.9, 129.1 (·3), 128.8, 128.5 (·2), 128.4 (·2), 128.3 (·2),
127.8, 127.7, 117.4, 45.6, 43.8, 42.8, 42.4, 42.3, 40.5, 40.3,
35.7, 23.0. Anal. Calcd for C30H26N2O4: C, 75.29; H, 5.48;
N, 5.85. Found: C, 75.41; H, 5.60; N, 5.72.
Chem. Rev. 1996, 96, 635–662; (e) Fruhauf, H.-W. Chem.
¨
Rev. 1997, 97, 523–596; (f) Itoh, K.; Matsuda, I.;
Yamamoto, Y. J. Synth. Org. Chem. Jpn. 1999, 57, 912–
923.
3. (a) Bergman, R. G. Science 1984, 223, 902–908; (b)
Ryabov, A. D. Chem. Rev. 1990, 90, 403–424; (c)
Amdtsen, B. A.; Bergman, R. G.; Mobley, A.; Peterson,
T. H. Acc. Chem. Res. 1995, 28, 154–162; (d) Shilov, A. E.;
ShulÕpin, G. B. Chem. Rev. 1997, 97, 2879–2932; (e)
Kakiuchi, F.; Murai, S. Top. Organomet. Chem. 1999, 3,
47–79; (f) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002,
35, 826–834; (g) Dyker, G. Angew. Chem., Int. Ed. 1999,
38, 1699–1712; (h) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
Rev. 2002, 102, 1731–1769.
4. (a) Stoutland, P. O.; Bergman, R. G. J. Am. Chem. Soc.
1985, 107, 4581–4582; (b) Hermann, D.; Gandelman, M.;
Rozenberg, H.; Shimon, L. J. W.; Milstein, D. Organo-
metallics 2002, 21, 812–818; (c) Tan, K. L.; Bergman, R.
G.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 13964–
8. Reaction of N-benzylmaleimide without styrene led to the
production of 5 in a low yield with a large amount of the
recovered starting materials under the same conditions but
we failed in our attempt to detect the dehydrogenated
product, arising from the hydrogen source (N-benzyl-
maleimide).
9. When 1,2-bis(diphenylphosphino)ethane (dppe) was used
instead of bpy, products derived from both styrene and N-
benzylmaleimide could not be obtained.
´
13965; (d) Martın, M.; Sola, E.; Torres, O.; Plou, P.; Oro,
10. (a) A similar metallacyclopentane species was isolated
from the reaction of a diphenyl-iridium derivative with
L. A. Organometallics 2003, 22, 5406–5417; (e) DeBoef, B.;
Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126,
6556–6557; (f) Thalji, R. K.; Ellman, J. A.; Bergman, R.
G. J. Am. Chem. Soc. 2004, 126, 7192–7193; (g) Zhang, X.;
Kanzelberger, M.; Emge, T. J.; Goldman, A. S. J. Am.
Chem. Soc. 2004, 126, 13192–13193.
´
ethylene: Slugovc, C.; Padilla-Martınez, I.; Sirol, S.;
Carmona, E. Coord. Chem. Rev. 2001, 213, 129–157; (b)
´
Gutierrez-Puebla, E.; Monge, A.; Nicasio, M. C.; Perez, P.
´
´
J.; Poveda, M. L.; Carmona, E. Chem. Eur. J. 1998, 4,
´
2225–2236; (c) Gutierrez, E.; Monge, A.; Nicasio, M. C.;
5. (a) Green, M.; Kuc, T. A.; Taylor, S. H. J. Chem. Soc. (A)
1971, 2334–2337; (b) Ishiyama, T.; Takagi, J.; Ishita, K.;
Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem.
Soc. 2002, 124, 390–391.
6. The corresponding reaction using maleic anhydride was
also investigated to give different products, which were not
identified, compared with the case of N-benzylmaleimide.
Poveda, M. L.; Carmona, E. J. Am. Chem. Soc. 1994, 116,
791–792.
11. (a) Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T.
J. Am. Chem. Soc. 1990, 112, 4965–4966; (b) Matsuda, I.;
Shibata, M.; Sato, S.; Izumi, Y. Tetrahedron Lett. 1987,
28, 3361–3362.