mechanistic pathway is also proposed on the basis of kinetic
isotope and Hammett studies.
sluggish in the absence of external ligands (entry 1).15
Whereas the use of biphenyl (L1) or ferrocene (L2) ligands
resulted in no improvement, (m-Tol)3P (L3) gave a moderate
increase of product yield (entries 4-5).
Recently, we have reported a Pd-catalyzed cyclization of
N-(2-halobenzyl)pyrroles to give pyrroloindoles.12 While the
scope and synthetic applicability were quite versatile, the
reaction has a notable mechanistic aspect in that it utilizes
metal-catalyzed activation of benzylic halides which had been
much less studied when compared to aryl or vinyl (pseudo)-
halides.13 Although one preliminary result of the synthesis
of a parent skeleton of 9H-fluorene was briefly shown in
the report using 2-phenylbenzyl bromide,12 its comprehensive
scope, mechanistic details, and synthetic applications were
not further investigated. This led us to initiate our efforts on
the detailed optimization of reaction conditions using 2-phe-
nylbenzyl (pseudo)halides as model substrates (Table 1).14
It was revealed that the employment of 2-phenylbenzyl
chloride (1b, X ) Cl) offered a dramatic improvement,
presumably due to the reluctance to the reductive dehalo-
genation when compared to the bromo- and iodo counter-
parts, with the use of L3 and NaHCO3 or Cs2CO3 in 1,2-
dimethoxyethane (entries 6-7). It was later found that the
reaction could be best run with rac-BINAP L4 as a ligand
and Cs2CO3 as a base, thereby allowing the use of only 2
mol % of Pd(OAc)2 to afford satisfactory yield of 2a (entry
8). In contrast, whereas 2-phenylbenzyl acetate (1c, X )
OAc) was inert to the conditions (entry 9), reaction of an
iodo analogue (1d, X ) I) gave poor product yield due to
reductive elimination leading to 2-phenyltoluene (entry 10).
On the other hand, in our previous study,12 the highest yield
of 2a was 55% when 1a (X ) Br) was used in the presence
of 5 mol % of Pd(OAc)2, ligand L1 (10 mol %), and Et3N
(2 equiv to 1a) in toluene (100 °C, 12 h).
Table 1. Cyclization of 2-Phenylbenzyl (Pseudo)halidesa
The present synthetic route to a fluorene motif was quite
general, thus allowing the cyclization of a wide range of
2-arylbenzyl chlorides to take place smoothly to furnish the
corresponding fluorene derivatives (Table 2). While sub-
strates having electron-rich substituents underwent the cy-
clization more efficiently (entries 2 and 3), those bearing
certain electron-withdrawing groups gave products in moder-
ate yields (entries 4 and 5), although this trend of the
electronic effects could not be generalized in some cases
(e.g., entry 6). Disubstituted fluorene compounds were also
easily obtained in high yields (entries 7 and 8). Functional
group tolerance to the reaction conditions turned out to be
quite high, thus producing fluorene derivatives having chloro,
acetyl, or fluoro substituents (entries 4, 5, and 9, respectively).
entry
X
Pd (mol %) ligand
5
base
solvent yieldb (%)
1
2
3
4
5
6
7
8
9
10
Br
Br
Br
Br
Br
Cl
Cl
Cl
OAc
I
NaHCO3 benzene
NaHCO3 benzene
NaHCO3 benzene
NaHCO3 benzene
NaHCO3 DME
<1
8
5
5
5
5
5
5
2
2
2
L1
L2
L3
L3
L3
L3
L4
L4
L4
<1
16
19
90
96
92
<1
5
NaHCO3 DME
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DME
DME
DME
DME
a Conditions: substrate (1, 0.2 mmol), Pd(OAc)2 (indicated mol %),
ligand (2 equiv to Pd), base (2 equiv to 1) in solvent (0.3 mL). b 1H NMR
yield (internal standard: 1,1,2,2-tetrachloroethane).
When 2-(1-naphthyl)benzyl chloride was employed, the
annulation took place readily to afford 7H-benzo[c]fluorene
(3) in excellent yield (entry 10). 4H-Indeno[1,2-b]thiophene
(4) was also obtained from 3-(chloromethyl)-2-phenylth-
iophene (entry 11). The present procedure was readily
operative even with a multigram scale (10 mmol) without
difficulty.15
(11) For recent reviews on the direct C-H functionalization, see: (a)
Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (b) Campeau,
L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (c) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (d) Satoh, T.; Miura, M.
Chem. Lett. 2007, 36, 200. (e) Seregin, I. V.; Gevorgyan, V. Chem. Soc.
ReV. 2007, 36, 1173. (f) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham,
Q.-N.; Lazareva, A. Synlett 2007, 3382. (g) Pascual, S.; de Mendoza, P.;
Echavarren, A. M. Org. Biomol. Chem. 2007, 5, 2727. (h) Li, B.-J.; Yang,
S.-D.; Shi, Z.-J. Synlett 2008, 949.
When 2-phenylbenzyl bromide (1a, X ) Br) was subjected
to our previous reaction conditions,12 the reaction was
(5) For selected recent examples, see: (a) Reisch, H.; Wiester, U.; Scherf,
U.; Tuytuylkov, N. Macromolecules 1996, 29, 8240. (b) Merlet, S.; Birau,
M.; Wang, Z. Y. Org. Lett. 2002, 4, 2157. (c) Wong, K.; Chi, L.; Huang,
S.; Liao, Y.; Wang, L. Y. Org. Lett. 2006, 8, 5029. (d) Clive, D. L. J.;
Sunasee, R. Org. Lett. 2007, 9, 2677.
(12) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130,
16158.
(6) (a) Campeau, L. C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 581. (b) Shimizu, M.; Mochida, K.; Hiyama, T. Angew.
Chem., Int. Ed. 2008, 47, 9760.
(13) (a) Lie´gault, B.; Renaud, J.-L.; Bruneau, C. Chem. Soc. ReV 2008,
37, 290. (b) Kuwano, R. Synthesis 2009, 1049.
(7) Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2006, 128, 1434.
(8) Dong, C.-G.; Hu, Q.-S. Angew. Chem., Int. Ed. 2006, 45, 2289.
(9) Tobisu, M.; Kita, Y.; Ano, Y.; Chatani, N. J. Am. Chem. Soc. 2008,
130, 15982.
(14) For relevant examples from this laboratory, see: (a) Ko, S.; Na,
Y.; Chang, S. J. Am. Chem. Soc. 2002, 124, 750. (b) Lee, J. M.; Na, Y.;
Han, H.; Chang, S. Chem. Soc. ReV. 2004, 33, 302. (c) Ko, S.; Kang, B.;
Chang, S. Angew. Chem., Int. Ed. 2005, 44, 455. (d) Lee, J. M.; Park, E. J.;
Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130, 7824. (e) Cho, S. H.;
Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254.
(15) For details, see the Supporting Information.
(10) (a) Gorin, D. J.; Watson, I. D.; Toste, F. D. J. Am. Chem. Soc.
2008, 130, 3736. (b) Zhao, Y.-B.; Mariampillai, B.; Candito, D. A.; Laleu,
B.; Li, M.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 1849.
Org. Lett., Vol. 11, No. 20, 2009
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