Sequential catalytic reactions for the synthesis of benzofulvenes using an iridium complex with dual function

Article abstract of DOI:10.1055/s-0029-1218575

The cationic iridium complex ([Ir(cod)₂]OTf + racBINAP) efficiently catalyzed a sequential process of ortho-C-H bond functionalization, cyclization and dehydration, leading to a concise preparation of 1 -methylene indene (benzofulvene) derivatives. The iridium complex operated as a catalyst in the ortho-C-H bond alkenylation of aryl ketones with alkynes and as a Lewis acid catalyst in the cyclization of the alkenylated product and the subsequent dehydration. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218575

LETTER
97
Sequential Catalytic Reactions for the Synthesis of Benzofulvenes Using an
Iridium Complex with Dual Function
S
ynthesis of Benzo
y
fulvenes Us
o
ing Iridium ji Tsuchikama, Mitsugu Kasagawa, Kohei Endo, Takanori Shibata*
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University,
Okubo, Shinjuku, Tokyo, 169-8555, Japan
Fax +81(3)52868098; E-mail: tshibata@waseda.jp
Received 21 October 2009
acetophenone (2a), providing the ortho-alkenylated ad-
duct in good yield (Scheme 1a).6a Whilst modifying this
catalyst, we found an unexpected cyclization occurred
when the counter anion of the iridium complex was
Abstract: The cationic iridium complex ([Ir(cod)2]OTf + rac-
BINAP) efficiently catalyzed a sequential process of ortho-C–H
bond functionalization, cyclization and dehydration, leading to a
concise preparation of 1-methylene indene (benzofulvene) deriva-
tives. The iridium complex operated as a catalyst in the ortho-C–H changed: when trifluoromethanesulfonate anion (OTf)
bond alkenylation of aryl ketones with alkynes and as a Lewis acid
catalyst in the cyclization of the alkenylated product and the subse-
quent dehydration.
was used, indenol 3aa¢ and benzofulvene 3aa were ob-
tained in high yield in place of the ortho-alkenylated prod-
uct (Scheme 1b). In the case of other counter anions, such
as PF6, SbF6, and B[3,5-(CF3)2C6H3]4 (BARF), the cy-
Key words: catalysis, cyclization, C–H bond functionalization,
indenes, iridium
clized product was not obtained and the ortho-alkenylated
product was the only detectable product.9
A sequence of catalytic reactions that can be performed in
(a) C–H alkenylation of arylketones (ref. 6a)
one pot from simple precursors is an efficient and envi-
Ph
Ph
ronmentally benign protocol for the preparation of syn-
thetic intermediates.1 Among various approaches toward
this end, consecutive reactions promoted by a single cata-
lyst are promising. Actually, mechanistically similar mul-
tiple transformations based on this concept are well
established.1,2 In contrast, using a single catalyst for a se-
quence of mechanistically distinct reactions is more in-
triguing and challenging.3 For example, a palladium
complex showed high catalytic activity in a consecutive
Mizoroki–Heck reaction, C–H bond arylation and hydro-
genation sequence.3d In recent work, a cationic rhodium
complex was found to catalyze three sequential reactions
of olefin isomerization, propargyl Claisen rearrangement
and carbonyl migration.3g Herein, we disclose a cationic
iridium-complex catalyzed sequence of ortho-C–H bond
functionalization, cyclization and dehydration. The iridi-
um complex showed dual functionality in the three reac-
tions: It behaved as a catalyst for the ortho-C–H bond
alkenylation of aryl ketones with alkynes4–6 and acted as a
Lewis acid catalyst7 in the cyclization and dehydration.
From the synthetic point of view, this protocol provides
easy access to the 1-methylene indene (benzofulvene)
framework.8
1a
O
[Ir(cod)2]BF4 (5 mol%)
rac-BINAP (5 mol%)
O
H
Me
Ph
DCE, reflux, 20 h
Me
Ph
75%
2a
(2 equiv)
(b) C–H alkenylation/cyclization sequence (this work)
[Ir(cod)2]OTf (5 mol%)
rac-BINAP (5 mol%)
1a
2a
DCE, reflux, 24 h
(2 equiv)
Me
OH
Ph
Ph
Ph
Ph
3aa 87% (NMR yield)
3aa' 4% (NMR yield)
Scheme 1
Several substituted aryl ketones were then subjected to the
present protocol at a higher temperature using 10 mol% of
the cationic iridium catalyst (Table 1). Ortho-substituents
on the aryl ketones had a significant influence on the
reactivity: o-methoxy acetophenone (2b) for example, af-
forded the benzofulvene 3ab in excellent yield,10 although
the presence of an o-methyl group lowered the conversion
of the substrates and the o-trifluoromethyl group com-
pletely prevented the reaction (entries 1–3). Meta-substi-
tuted acetophenones also gave the benzofulvene
derivatives in moderate to high yield, and the regioselec-
tivity varied depending on the substituents: m-methoxy
acetophenone (2e) reacted at the congested ortho-position
Our group has already disclosed a cationic iridium com-
plex that exhibits high catalytic activity in the carbonyl-
directed sp2 C–H bond alkenylation of aryl ketones. We
found that, in the presence of 5 mol% [Ir(cod)2]BF4 and
rac-BINAP in refluxing 1,2-dichloroethane (DCE),
diphenylacetylene (1a) added to the ortho-C–H bond of
SYNLETT 2010, No. 1, pp 0097–0100
x
x.
x
x.
2
0
1
0
Advanced online publication: 11.12.2009
DOI: 10.1055/s-0029-1218575; Art ID: U10609ST
© Georg Thieme Verlag Stuttgart · New York

98
K. Tsuchikama et al.
LETTER
OMe
Table 1 Iridium-Catalyzed Benzofulvene Synthesis from Diphenyl-
acetylene (1a) and Aryl Ketones 2
[Ir(cod)2]OTf (10 mol%)
R1
R2
2c
(2 equiv)
rac-BINAP (10 mol%)
R1
1b (R1 = Ph, R2 = Me)
1c (R1, R2 = n-Pr)
R2
O
PhCl, reflux, 24 h
R3
R2
R2
[Ir(cod)2]OTf (10 mol%)
1a
rac-BINAP (10 mol%)
+
R3
3bb: 50%
3cb: 11%
Ph
PhCl, reflux, 24 h
H
R1
2a
3
R1
Ph
Scheme 2
(2 equiv)
Entry R1
R2
R3
H
2
3
Yield of 3 (%)
between the methoxy and acetyl groups, whereas m-meth-
yl acetophenone (2f) and m-trifluoromethyl acetophenone
(2g) reacted at the less hindered ortho-position of the
acetyl group (entries 4–6).11 Both electron-donating and
electron-withdrawing groups could be installed at the
para-position of acetophenone and the corresponding
benzofulvenes were obtained in high yield (entries 7–9).
As a directing carbonyl group, ethanoyl and isopropanoyl
groups were also acceptable (entries 10 and 11). As for the
scope of alkynes, unsymmetrical alkyl, aryl-substituted
acetylene 1b also reacted with aryl ketone 2b and the cy-
clized product 3bb was obtained as a single regioisomer
in moderate yield,12,13 whereas 4-octyne (1c) afforded the
product 3cb in low yield (Scheme 2). These results illus-
trate that at least one aryl substituent on the alkyne termi-
nus was required for the alkyne to be a good coupling
partner.
1
2
o-OMe
o-Me
H
2b
2c
2d
2e
2f
2g
2h
2i
3ab
3ac
–
95
H
H
48
3
o-CF3
m-OMe
m-Me
m-CF3
p-Me
p-OMe
p-CF3
H
H
H
n.d.a
45b
88b
59b
88
4
H
H
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
5
H
H
6
H
H
7
H
H
8
H
H
82
9
H
H
2j
2k
2l
80
10
11
Me
Me
H
82c
71
H
Me
A possible mechanism for the present reaction is depicted
in Scheme 3. The ortho-C–H bond alkenylation should
proceed through iridium-catalyzed carbonyl-directed C–
a No product was detected.
b The structures are depicted below.
c The product was obtained as a single stereoisomer, although the
H bond cleavage followed by alkyne insertion.6a The sub- geometry was not determined.
sequent cyclization and dehydration would be promoted
by the Lewis acidity of the iridium catalyst.14 To probe the
Me
F3C
Ph
reaction mechanism, we subjected ortho-alkenylated ace-
Ph
Ph
tophenone to the present reaction conditions and found
Ph
Ph
Ph
that benzofulvene 3aa was obtained in good yield
(Scheme 4). This result strongly suggests that the Lewis
acid catalyzed cyclization of alkenylated product A is
more probable than intramolecular 1,2-addition of vinyl
iridium intermediate B, which could be generated in the
C–H bond alkenylation step.15 We also ascertained that
dehydration of the isolated indenol 3aa¢ efficiently pro-
ceeded only in the presence of the iridium catalyst; in the
absence of the catalyst, no dehydration was observed. Fur-
thermore, tert-butyl phenyl ketone (2m), which has no a-
proton adjacent to the carbonyl group, afforded methyl-
and isopropenyl-substituted indene 3am. This could be
explained by the generation of a tertiary cationic interme-
diate followed by a 1,2-methyl shift (Scheme 5). All these
results prove the Lewis acidity of the iridium catalyst.
OMe
3ae
3ag
3af
O
[Ir(cod)2]OTf (15 mol%)
rac-BINAP (15 mol%)
Me
Ph
3aa: 70%
PhCl, reflux, 24 h
Ph
Scheme 4
In conclusion, we have discovered that the Lewis acidity
of the cationic iridium-BINAP complex could be readily
tuned by the counter anion without being detrimental to
the catalytic activity of the C–H bond functionalization re-
action. This dual catalytic activity enabled a facile proto-
Me
R1
R1
Ir-catalyzed
C–H
alkenylation
Ir+
Me
Me
Ir+
R1
O
OH
cyclization
O
Ir+
R1
H
R1
O
H
R1
– H2O
R1
Me
R1
R1
R1
A
B
Scheme 3
Synlett 2010, No. 1, 97–100 © Thieme Stuttgart · New York

LETTER
Synthesis of Benzofulvenes Using Iridium
99
(5) For selected examples of Ir-catalyzed C–H bond
functionalization, see: (a) Aufdenblatten, R.; Diezi, S.;
Togni, A. Monatsh. Chem. 2000, 131, 1345.
O
H
Me
[Ir(cod)2]OTf (10 mol%)
rac-BINAP (10 mol%)
Me
Ph
t-Bu
1a
(b) Matsumoto, T.; Taube, D. J.; Periana, R. A.; Taube, H.;
Yoshida, H. J. Am. Chem. Soc. 2000, 122, 7414.
+
PhCl, reflux, 24 h
Ph
3am: 80%
2m
(c) Nishinaka, Y.; Satoh, T.; Miura, M.; Morisaka, H.;
Nomura, M.; Matsui, H.; Yamaguchi, C. Bull. Chem. Soc.
Jpn. 2001, 74, 1727. (d) Fukumoto, Y.; Sawada, K.;
Hagihara, M.; Chatani, N.; Murai, S. Angew. Chem. Int. Ed.
2002, 41, 2779. (e) Dorta, R.; Togni, A. Chem. Commun.
2003, 760. (f) Tenn, W. J.; Young, K. J. H.; Bhalla, G.;
Oxgaard, J.; Goddard, W. A.; Periana, R. A. J. Am. Chem.
Soc. 2005, 127, 14172. (g) Ishiyama, T.; Miyaura, N. Pure
Appl. Chem. 2006, 78, 1369. (h) Lu, B.; Falck, J. R. Angew.
Chem. Int. Ed. 2008, 47, 7508. (i) Join, B.; Yamamoto, T.;
Itami, K. Angew. Chem. Int. Ed. 2009, 48, 3644.
(2 equiv)
1,2-Me shift
Me
H
Me Me
Ir+
OH
Ph
Me
Me
Ph
Ph
Ph
(6) For our recent reports of cationic Ir-catalyzed C–H bond
functionalization, see: (a) Tsuchikama, K.; Kasagawa, M.;
Hashimoto, Y.; Endo, K.; Shibata, T. J. Organomet. Chem.
2008, 693, 3939. (b) Tsuchikama, K.; Kasagawa, M.; Endo,
K.; Shibata, T. Org. Lett. 2009, 11, 1821. (c) Tsuchikama,
K.; Hashimoto, Y.; Endo, K.; Shibata, T. Adv. Synth. Catal.
in press.
(7) For several reactions using Ir complexes as a Lewis acid
catalyst, see: Shibata, T. In Iridium Complexes in Organic
Synthesis; Oro, L. A.; Claver, C., Eds.; Wiley-VCH Verlag
GmbH: Weinheim, 2009, 277.
Scheme 5
col for the synthesis of benzofulvene derivatives via three
sequential reactions of C–H bond alkenylation, cycliza-
tion and dehydration. Further studies on the application of
the present catalyst are in progress.
Acknowledgment
(8) The synthesis of poly-benzofulvene and the analysis of its
physical properties have been reported, see: Cappelli, A.;
Galeazzi, S.; Giuliani, G.; Anzini, M.; Donati, A.; Zetta, L.;
Mendichi, R.; Aggravi, M.; Giorgi, G.; Paccagnini, E.;
Vomero, S. Macromolecules 2007, 40, 3005; and references
cited therein.
This work was supported by a Waseda University Grant for Special
Research Projects. We thank the Japan Society for the Promotion of
Science for the fellowship support to K.T. We appreciate Umicore
for the generous donation of [Ir(cod)2]BARF.
References and Notes
(9) For a review of ion-pairing effects in transition-metal
catalysis, see: Macchioni, A. Chem. Rev. 2005, 105, 2039.
(10) Typical experimental procedure (Table 1, entry 1):
[Ir(cod)2]OTf (10.9 mg, 20 mmol), rac-BINAP (12.6 mg, 20
mmol), and diphenylacetylene (1a; 37.7 mg, 0.21 mmol)
were placed in an oven-dried Schlenk tube, which was then
evacuated and backfilled with argon (× 3). To the reaction
vessel were added 2-methoxyacetophenone (2b; 60.1 mg,
0.40 mmol) and PhCl (0.2 mL, pretreated by argon bubbling
for 30 s) before the solution was stirred at 135 °C for 24 h.
The resultant mixture was cooled to room temperature and
filtered through a silica pad. After evaporation of the solvent,
the crude products were purified by thin-layer chromatog-
raphy (hexane–EtOAc, 10:1) to yield analytically pure
product 3ab (62.4 mg, 95%). Yellow solid; mp 95 °C. 1H
NMR (400 MHz): d = 3.98 (s, 3 H), 5.84 (d, J = 1.5 Hz, 1 H),
6.73 (d, J = 1.5 Hz, 1 H), 6.86 (d, J = 8.3 Hz, 1 H), 7.01 (d,
J = 7.6 Hz, 1 H), 7.18–7.28 (m, 11 H); 13C NMR (100 MHz):
d = 55.3, 109.0, 113.5, 119.8, 121.5, 126.8, 127.2, 127.9,
128.1, 129.0, 129.6, 130.9, 134.6, 134.7, 138.2, 140.7,
144.6, 146.5, 156.2; IR (KBr): 1599, 1442, 1260, 1083, 700
cm–1; HRMS (FAB+): m/z calcd for C23H18O: 310.1358;
found: 310.1351.
(11) Similar regioselectivity was observed in the Ru-catalyzed
ortho-C–H bond addition of meta-substituted acetophenones
to vinylsilanes, see: Kakiuchi, F.; Murai, S. Acc. Chem. Res.
2002, 35, 826.
(12) The geometry was determined by NOESY measurement.
(13) The relatively bulky phenyl group was situated at the
external position against the aromatic ring of the aryl ketone.
The same regioselectivity was also reported in the Ru-
catalyzed directed C–H alkenylation of aryl ketones with
unsymmetrical alkynes, see: Kakiuchi, F.; Yamamoto, Y.;
Chatani, N.; Murai, S. Chem. Lett. 1995, 681.
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K. Tsuchikama et al.
LETTER
(14) TsOH-catalyzed cyclization of ortho-alkenylated aromatic
ketones for the synthesis of benzofulvenes, see: Harris,
P. W. R.; Woodgate, P. D. Synth. Commun. 1997, 27, 4195.
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2005, 127, 13498. (b) Kuninobu, Y.; Nishina, Y.; Kawata,
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Synlett 2010, No. 1, 97–100 © Thieme Stuttgart · New York

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