Pd(OAc)2-catalyzed domino reactions of 1,2-dihaloarenes and 2-haloaryl arenesulfonates with Grignard reagents: efficient synthesis of substituted fluorenes

Article abstract of DOI:10.1016/j.tet.2008.01.020

Pd(OAc)₂-catalyzed domino reactions of 1,2-dihalobenzenes and 2-haloaryl arenesulfonates with hindered Grignard reagents to form substituted fluorenes, which are believed to occur through palladium associated aryne intermediates, are described. Such palladium associated aryne reaction pathway was found to be favored by omitting the use of phosphine and N-heterocyclic carbene ligands for palladium catalysts and with better leaving groups. Our study suggested that Pd(leaving group)X associated arynes should be formed first and the sp³ C-H activation preferentially occurred at benzylic C-(1°)H bonds. The work described here provides a high yield, one-step access to substituted fluorenes from readily available 1,2-dihalobenzenes and 2-haloaryl arenesulfonates and hindered Grignard reagents, and this substituted fluorene-making method may find applications in the preparation of substituted fluorene-containing molecules including polymers.

Full text of DOI:10.1016/j.tet.2008.01.020

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2537e2552
www.elsevier.com/locate/tet
Pd(OAc)2-catalyzed domino reactions of 1,2-dihaloarenes
and 2-haloaryl arenesulfonates with Grignard reagents:
efficient synthesis of substituted fluorenes
*
Cheng-Guo Dong, Qiao-Sheng Hu
Department of Chemistry, College of Staten Island and the Graduate Center of the City University of New York, Staten Island, NY 10314, United States
Received 2 December 2007; received in revised form 30 December 2007; accepted 4 January 2008
Available online 11 January 2008
Abstract
Pd(OAc)2-catalyzed domino reactions of 1,2-dihalobenzenes and 2-haloaryl arenesulfonates with hindered Grignard reagents to form
substituted fluorenes, which are believed to occur through palladium associated aryne intermediates, are described. Such palladium associated
aryne reaction pathway was found to be favored by omitting the use of phosphine and N-heterocyclic carbene ligands for palladium catalysts and
with better leaving groups. Our study suggested that Pd(leaving group)X associated arynes should be formed first and the sp3 CeH activation
preferentially occurred at benzylic Ce(1ꢀ)H bonds. The work described here provides a high yield, one-step access to substituted fluorenes from
readily available 1,2-dihalobenzenes and 2-haloaryl arenesulfonates and hindered Grignard reagents, and this substituted fluorene-making
method may find applications in the preparation of substituted fluorene-containing molecules including polymers.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 1,2-Dihalobenzenes; Domino reactions; Grignard reagents; 2-Haloaryl arenesulfonates; Palladium; Substituted fluorenes
1. Introduction
regenerate the Pd(0) catalyst (Fig. 1). Based on our under-
standing of the general mechanism depicted in Figure 1, we
envisioned that the individual elementary steps in each cata-
lytic cycle might be controlled. Such a control, especially
combined with other bond forming processes, might provide
us excellent opportunities to develop new reactions/processes
and thus could make the already powerful transition metal-
catalyzed cross-coupling reactions even more powerful for
organic synthesis. Toward this end, we have recently docu-
mented Pd(0)/t-Bu3P-catalyzed Suzuki cross-coupling of
Over the past decades, palladium-catalyzed cross-coupling
reactions, e.g., the Suzuki coupling, the Kumada coupling, the
Stille coupling, the Sonogashira coupling, and the amination
of aryl halides with amines, etc., have become powerful tools
for organic synthesis.1 They have been extensively employed
to synthesize a wide variety of organic compounds ranging
from small organic molecules to macromolecules.1,2 Extensive
study established that there are three key elementary steps in
the catalytic cycles of Pd(0)-catalyzed cross-coupling reac-
tions:1 oxidative addition of Pd(0) with an aryl halide to
form Pd(II) complex; transmetalation of the Pd(II) complex
with an organometallic reagent to form an diorganopalladiu-
m(II) complex; and reductive elimination of the diorganopal-
ladium(II) complex to form the cross-coupling product and
Ar-X
Ar-Ar'
Reductive Elimination
Pd(0)
Oxidative Addition
Ar Pd(II)
X
Ar Pd(II) Ar'
Transmetalation
M-X
Ar'-M
* Corresponding author. Fax: þ1 718 982 3910.
Figure 1. Generalized mechanism for Pd(0)-catalyzed cross-coupling
reactions.
E-mail address: qiaohu@mail.csi.cuny.edu (Q.-S. Hu).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.020

2538
C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
M
Rn
Rn
Rn
A
Direct
Cross-Coupling
Pd
X
X
Pd(0)
Rn
Rn
M
Rn
II
Rn
B
I
Cyclization
via C-H Activation
Scheme 1. Controlling competition between direct cross-coupling and cyclization via sp3 CeH bond activation.
R1
R2
R1
R2
X
R
1.5% Pd2(dba)3/6% t-Bu3P
R
+
BrMg
THF, r.t., 20 h
Br/I
X = Br: 89-99% yield
X = Cl: < 5% yield
Scheme 2. Pd(0)/t-Bu3P-catalyzed tandem reactions of 1,2-dihalobenzenes with hindered Grignard reagents.
dihaloarenes with arylboronic acids,3 a process that relies on
the control of oxidative addition step. We have also reported
Pd(0)/t-Bu3P-catalyzed reaction of 2-bromobiphenyl with hin-
dered Grignard reagents to form substituted fluorenes (Scheme
1),4e6 a cyclization process that combines the control of the
transmetalation step with sp3 CeH activation (Scheme 1).7e9
We have further incorporated a cross-coupling step into the
latter type of reaction and developed a new type of tandem re-
action that combines the cross-coupling strategy and cycliza-
tion via sp3 CeH activation strategy (Scheme 2).4,10,11 With
Pd(0)/t-Bu3P as catalyst, substituted fluorenes could be easily
prepared in excellent yields from 1,2-dibromobenzenes and 1-
bromo-2-iodobenzene.
associated aryne forming pathway including the ligand effect
and leaving group effect. We also investigated the substrates
other than 1,2-dibromobenzenes and 1-iodo-2-bromobenzene,
i.e., 1-chloro-2-halobenzenes, 1-bromo-2-fluorobezene, 2-
haloaryl tosylates, and benzenesulfonates for the reaction.
Herein, our detailed study is reported.12
2. Results and discussions
2.1. Palladium associated arynes as intermediates for the
reaction of 1,2-dihalobenzenes with Grignard reagents:
ligand effect and leaving group effect
Although Pd(0)/t-Bu3P has been demonstrated to be
a highly efficient catalyst system for the tandem reaction of
1,2-dibromobenzenes and 1-bromo-2-iodobenzene to form
substituted fluorenes, we reasoned that further improvement
of this new substituted fluorene-making process could be pos-
sible. For example, the air-sensitivity of t-Bu3P makes the han-
dling of the catalyst very stringent. In addition and more
importantly, Pd(0)/t-Bu3P catalyst system was ineffective for
substrates other than 1,2-dibromobenzenes and 1-bromo-2-
iodobenzene, e.g., 1-chloro-2-halobenzenes. To expand the
substrate scope and explore more practical catalyst systems,
we envisioned a pathway other than the cross-coupling-cycli-
zation (via sp3 CeH activation) strategy, namely palladium as-
sociated aryne forming pathway. We investigated factors that
could influence the reaction to proceed via the palladium
Our mechanistic study in Pd(0)/t-Bu3P catalyst system sug-
gested that the key obstacle to employ 1-chloro-2-haloben-
zenes as substrates for the reaction is the reluctance of the
CeCl bond in I to undergo oxidative addition with Pd(0) cat-
alyst (Scheme 3).4 We thus envisaged that if no oxidative ad-
dition of CeCl bond with Pd(0) was involved in the formation
of ArPd(II)Cl (II), these substrates could then be suitable sub-
strates for the new type of annulative tandem reactions. Recog-
nizing that halo groups are known to function as leaving
groups, we reasoned that this could be possible: as depicted
in Scheme 4, ortho-leaving group (LG) bearing o-aryl(LG)pal-
ladium(II) halides (IV), in addition to undergoing transmetala-
tion with organometallic reagents to form I (Scheme 4, path
Aa), could undergo b-LG-elimination to form palladium asso-
ciated arynes (V) (Scheme 4, path Ab). The generated
a
Pd
X
X
Pd(0) (X = Br)
X
X
Pd(0)
Rn
Rn
b
X
X'
PdX'
II
X' = Br, I
I
Pd(0) (X = Cl)
Scheme 3. Pd(0)/t-Bu3P-catalyzed tandem reactions of 1,2-dihalobenzenes with bulky Grignard reagents.

C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
2539
Pd(0)
LG = Br, I
LG
Pd
LG
Ar
ArM
(Transme-
talation)
Ar'
Ar'
Ar
I
Path Aa
X
Br, I
ArM
Pd(0)
VII
LG
=
(Cross-Coupling)
Pd
Ar
LG
LG
LG
Pd(0)
X
Pd
X
(Cross-Coupling
via C-H Activation)
II
IV
X = Br, I, Cl
LG
X
ArM
BrMg
LG = Br, Cl, F,
Pd
OTs, etc.
R
V
Path Ab
ArM
(Transmetalation)
R
III
ArM
or
LG
Ar
Pd
Carbopalladation
VI
Scheme 4. Outline for 1-halo-2-(leaving group)benzenes for domino reactions via palladium(II)(LG)X associated aryne intermediates.
Pd(II)(LG)X associated arynes could then undergo transmata-
lation followed by carbopalladation to form intermediate II,
which could further undergo other transformations (Scheme
4, path Ab). Therefore, through palladium associated aryne in-
termediates, intermediate II could be formed without undergo-
ing the oxidative addition of CeLG bond with Pd(0), thus
making it possible to employ 1-chloro-2-halobenzenes as suit-
able substrates for the domino reaction.
tandem/domino reactions. Therefore, exploration of this palla-
dium associated aryne generation strategy could be fundamen-
tally interesting and synthetically useful.
As depicted in Scheme 4, the direct transmetalation of
o-aryl(LG)palladium(II) halides (IV) to form cross-coupling
product I (Scheme 4, path Aa) would compete with the forma-
tion of Pd(II)(LG)X associated benzynes (path Ab). Therefore,
factors that could influence the transmetalation and/or the b-
leaving group elimination of o-aryl(LG)Pd(II) halides, e.g.,
the steric hindrance and nucleophilicity of organometallic re-
agents, LG leaving ability, ligand effect, basicity of the base,
and reaction temperature, etc., were expected to affect the gen-
eration of Pd-associated arynes. We reasoned that for a given
type of o-aryl(LG)Pd(II) halides with the same LG and a given
type of organometallic regents such as Grignard reagents at
a certain reaction temperature, the influential factors could be
narrowed down to steric hindrance and ligand effect. Since in-
creasing the steric hindrance of Grignard reagents has been es-
tablished to slow down the transmetalation process, we thus
began our study by examining the ligand influence. The reaction
of 1-bromo-2-chlorobenzene with bulky 2-mesitylmagnesium
bromide was employed as the model reaction. As the initial ox-
idative addition was believed to occur at the CeBr bond18,19 and
2-chloro-20,40,60-trimethylbiphenyl (Ia, LG¼Cl) was found to
be inert under Pd(OAc)2/Grignard reagent condition (Scheme
5), we expected that the domino reaction product 2,4-dimethyl-
fluorene would be expected if the reaction proceeded via ben-
zyne intermediate (path Ab). The reaction product would be
2-chloro-20,40,60-trimethylbiphenyl if the reaction occurred via
Arynes are very reactive and have recently been demon-
strated as useful substrates for palladium-catalyzed carbone
carbon bond forming reactions.13e17 Careful examination of
aryne chemistry showed that the aryne generation strategy in re-
ported reactions, in which arynes were generated in situ from ex-
pensive o-trimethylsilylaryl triflates, often does not work well
with the use of catalytic amount of palladium because short-
lived arynes needed to search for inherently unstable palladium
intermediates for reactions to occur. Consequently, large excess
of o-trimethylsilylaryl triflates were often required to achieve
good yields. The pathway to generate arynes depicted in Scheme
4 (path Ab) could employ widely available o-halo(LG)benzenes
including 1,2-dihaloarenes as substrates with the assurance of
every generated aryne associated with a palladium. More impor-
tantly, in this strategy, because the formation of II does not in-
volve the oxidative addition of C-leaving group bond, e.g.,
CeCl bond, with Pd(0) species, the overall reactivity of o-
halo(LG)benzenes would be governed by the reactivity of
C-halo bonds that undergo the initial oxidative addition with
Pd(0) catalysts. Thus, substrates that bear leaving groups other
than Br and I groups might also be suitable substrates for
3% Pd(OAc)2
BrMg
+
THF, 60 °C, 20 h
< 5%
X
X = Cl, F
Scheme 5. Pd(OAc)2-catalyzed reactions of 2-halo-20,40,60-trimethylbiphenyls with 2-mesitylmagnesium bromide.

2540
C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
transmetalation followed by reductive elimination (path Aa).
We screened a number of ligands and palladium source and
our results are listed in Table 1. We found that with monodentate
PPh3, PCy3, t-Bu3P, an N-heterocyclic carbene (NHC),20 or bi-
dentate DPPE, DPPB, and BINAP as ligands, 2-chlorobiaryl
was obtained as the major product (Table 1, entries 1e8), sug-
gesting the reactions proceeded predominately through path Aa.
However, 2,4-dimethylfluorene was observed as the major
product with PdCl2, Pd2(dba)3, Pd(OAc)2, Pd(PhCN)2Cl2, or
Pd/C (10% weight) as catalysts (Table 1, entries 9e13), imply-
ing that the reaction proceeded predominately through path Ab
and Pd-associated benzynes were involved.
The ligand effect on reaction pathways was further confirmed
by the reaction results of 1-bromo-2-chlorobenzene with less
sterically hindered p-tolylmagnesium bromide. We expected
that 4,400-dimethyl-(1,10,20,100)-terphenyl (VII) would be the
product if the reaction occurs via palladium associated aryne
pathway (path Ab) and 2-chloro-40-methylbiphenyl (Ia,
LG¼Cl) would be the product via transmetalation followed by
reductive elimination (path Aa) (Scheme 4). Our results showed
that with t-Bu3P as ligand, 4,400-dimethyl-(1,10,20,100)-terphenyl
and 2-chloro-40-methylbiphenyl were formed in a ratio of 7:93
(based on 1H NMR), suggesting that path Aa should be the major
pathway. However, with only Pd(OAc)2 as the catalyst, 4,400-
dimethyl-(1,10,20,100)-terphenyl was obtained as the major prod-
uct (Scheme 6). These results further suggested that the absence
of tert-butylphosphine favored the reaction occur via palladium
associated aryne intermediates. Comparing these results with
the reaction result of 1-bromo-2-chlorobenzene with 2-mesityl-
magnesium magnesium (Table 1, entry 11) further showed that
increasing the steric hindrance of Grignard reagents would slow
down the transmetalation process and favor the reaction to
proceed via the aryne pathway.
To gage the leaving group effect on the reaction pathways,
we chose 2-mesitylmagnesium bromide as the reagent and
studied 1,2-dihalobenzenes with different leaving groups. We
first examined 1-bromo-2-halobenzenes (halo¼F, Cl, Br) as
the substrates and found that the better the leaving group,
Table 1
Ligand effect on palladium-catalyzed reactions of 1-bromo-2-chlorobenzene with Grignard reagentsa
Cl
Cl
Pd catalyst
+
BrMg
+
THF, 60 °C, 20 h
Br
I
III
Entry
Catalyst
Conversion (%)
Ratio (%)b
I
III
31
1
2
3
4
1.5% Pd2(dba)3þ6% Ph3P
1.5% Pd2(dba)3þ6% Cy3P
1.5% Pd2(dba)3þ6% t-Bu3P
3% Pd(PPh3)4
99
99
99
99
69
91
90
88
9
10
12
+
5
1.5% Pd2(dba)3þ6%
N
N
22
99
<1
Cl-
6
1.5% Pd2(dba)3þ3% DPPE
1.5% Pd2(dba)3þ3% DPPB
1.5% Pd2(dba)3þ3% BINAP
1.5% Pd2(dba)3
5
27
8
99
99
<1
<1
7
8
99
<1
9
99
99
99
93
11
0
<3
<3
<3
<3
<3
d
>97
>97
>97
>97
>97
d
10
11
12
13
14
a
3% Pd(PhCN)2Cl2
3% Pd(OAc)2
3% PdCl2
3% Pd/C (10% weight)
None
Reaction conditions: 1-bromo-2-chlorobenzene (1.0 equiv), Grignard reagent (2.5 equiv), THF (2 ml).
Ratio based on 1H NMR.
b
Cl
Cl
Br
Pd catalyst
BrMg
+
+
THF, 60 °C, 20 h
99% conversion
1.5% Pd2(dba)3 + 6% t-Bu3P
93
48
:
:
7
3% Pd(OAc)2
52
Scheme 6. Pd(OAc)2-catalyzed reactions of 1-bromo-2-chlorobenzene with p-tolylmagnesium bromide.

C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
2541
the higher the ratio of III:I, suggesting benzyne intermediates
formed easier with better leaving group (Table 2, entries 1e4).
With 1-fluoro-2-halobenzenes as substrates, as 2-fluoro-
20,40,60-trimethylbiphenyl (Ib) was found to be also inert under
Pd(OAc)2/Grignard reagent condition (Scheme 5),21 formation
of 2,4-dimethylfluorene would be expected if the reaction pro-
ceeded via benzyne intermediate (path Ab). With a bromo
group as the leaving group, the reaction occurred smoothly
at room temperature with exclusive formation of 2,4-dimethyl-
fluorene (for the establishment of palladium associated ben-
zyne pathway, see the section that describes the reactions of
1,2-dibromobenzenes with hindered Grignard reagents (vide
infra)). For comparison purpose, room temperature reaction
of 1-bromo-2-chlorobenzene with 2-mesitylmagnesium bro-
mide was also tested, a conversion of 61% was observed. As
the oxidative addition of CeBr bond with Pd(0) for 1-
bromo-2-chlorobenzene is expected to occur at the same rate
as or higher than that of 1,2-dibromobenzene because of the
more electron-withdrawing nature of Cl group than Br group,
the lower conversion for 1-bromo-2-chlorobenzene suggested
that the benzyne formation occurred slower with a Cl leaving
group than that with a Br leaving group.
We have also carried out the reactions of 1-chloro-2-fluoro-
benzene and 1,2-dichlorobenzene with 2-mesitylmagnesium
bromide. Our results showed that higher ratio of III:I was ob-
served for 1,2-dichlorobenzene than that for 1-chloro-2-fluoro-
benzene (Table 2, entries 5 and 6), and thus further confirmed
that benzyne intermediates formed easier with better leaving
groups. The higher conversion for 1-chloro-2-fluorobenzene
than that of 1,2-dichlorobenzene might be explained by think-
ing of the CeCl bond in 1-chloro-2-fluorobenzene being more
activated than that in 1,2-dichlorobenzene because a fluoro
group is more electron-withdrawing than a Cl group.
next examined other 1-chloro-2-halobenzenes and hindered
Grignard reagents. Our results are listed in Table 3. We found
that all tested 1-chloro-2-halobenzenes including 1,2-dichloro-
benzene gave good to excellent yields of substituted fluorene
products. For 1,2-dichlorobenzene, higher reaction tempera-
ture and longer reaction time are needed to achieve good yield,
likely because the initial oxidative addition of CeCl bond with
Pd(0) is more difficulty than CeBr bonds. We have also em-
ployed 1-bromo-2-fluorobenzene as substrate and a good yield
of 2,4-dimethylfluorene was obtained (Table 3, entry 11).
The palladium associated benzyne intermediates could be
formed via several possible pathways, e.g., transmetalation
followed by benzyne formation (path A), transmetalation
and benzyne formation occurred simultaneously (path B), or
benzyne formation first followed by transmetalation (path C)
(Scheme 7). We reasoned that the results with unsymmetrical
1-halo-2-chlorobenzenes as substrates could be used to differ-
entiate these pathways as different ratio of isomeric substituted
fluorenes would be obtained for these pathways. Both path A
and B would give a mixture of fluorene products in a ratio re-
lated to oxidative addition rate difference between CeX bond
and CeCl bond. The third pathway, path C, is expected to give
the ratio of products related to the transmetalation rates be-
tween PdeCl and PdeX. Previous study on the reaction of
1-bromo-4-chlorobenzene with phenylboronic acid showed
that the oxidative addition of Pd(0) occurred almost exclu-
sively at CeBr bond (ꢁ97%).19 Path A or B would yield
the two isomeric fluorenes in a ratio of 97:3 or higher for
unsymmetrical 1-bromo-2-chlorobenzenes. Our results with
3-bromo-4-chlorotoluene and 3-bromo-4-chloroanisole as sub-
strates showed that the two isomeric fluorenes were formed in
about 4:1 ratio (Table 3, entries 6e8),22 suggesting that the
benzyne intermediates formed first followed by transmetala-
tion. Since CeI bond has also been established to have higher
oxidative addition rate than CeBr bond,1,20 o-chloroiodoben-
zenes would yield two isomeric fluorenes in a ratio close to
100:0 if the reaction proceeded via path A or B. Our result
with 3-chloro-4-iodotoluene as the substrate showed that the
two isomeric fluorenes were formed in about 85:15. This ob-
servation was consistent with that the palladium associated
benzyne intermediates were formed via path C. Comparison
2.2. Pd(OAc)2-catalyzed annulative reactions of 1-chloro-
2-haloarenes and 1-bromo-2-fluorobenzene with hindered
Grignard reagents via palladium associated arynes
After establishing Pd(OAc)2, Pd2(dba)3, and Pd(PhCN)2Cl2
as excellent catalysts for 1-bromo-2-chlorobenzene to undergo
annualtive reaction with 2-mesitylmagnesium bromide, we
Table 2
Pd(OAc)2-catalyzed reactions of 1,2-dihalobenzenes with 2-mesitylmagnesium bromidea
X
X'
3% Pd(OAc)2
BrMg
+
THF, 20 h
+
X
I
III
Entry
X
X0
Temperature
Conversion (%)
I:IIIb
1
2
3
4
5
6
a
F
Br
Br
Br
Br
Cl
Cl
60 ꢀC
60 ꢀC
rt
84
99
73
99
72
24
17:83
<3:>97
<3:>97
0:100
Cl
Cl
Br
F
rt
60 ꢀC
60 ꢀC
63:37
3:97
Cl
Reaction conditions: 1,2-dihalobenzene (1.0 equiv), Grignard reagent (2.5 equiv), THF (2 ml).
Ratio based on 1H NMR.
b

2542
C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
Table 3
Pd(OAc)2-catalyzed cross-couplings of 1-chloro-2-halobenzenes and 1-bromo-2-fluorobenzene with hindered Grignard reagentsa
R1
R2
Cl
X
R1
R2
3% Pd(OAc)2
+
BrMg
R
THF, 60 °C., 20 h
R
Entry
Dihalide
Product
Yieldb,c (%)
R
BrMg
Cl
Br
BrMg
1
2
3
4
5
6
7
8
9
10
95
86
89
93
92
84d
89d
86
82
Cl
Br
BrMg
Cl
Br
BrMg
BrMg
Cl
I
Cl
I
BrMg
Cl
Br
Cl
Br
Cl
Br
Cl
(77:23)e
(80:20)e
(78:22)e
(85:15)e
BrMg
BrMg
MeO
BrMg
MeO
MeO
BrMg
I
Cl
61f
BrMg
BrMg
Cl
F
11
59g
Br
a
Reaction conditions (not optimized): 1,2-dihalobenzene (1.0 equiv), Grignard reagent (2.5 equiv), Pd(OAc)2 (3%), THF (2 ml).
Isolated yields.
b
c
d
e
f
2-Chlorobiaryls were observed in less than 5% yields.
1.5% Pd2(dba)3 as catalyst.
Ratio based on 1H NMR.
Refluxing in THF, 40 h, 16% 2-chloro-20,40,60-trimethylbiphenyl was observed.
2-Fluoro-20,40,60-trimethylbiphenyl of 17% was observed.
g
of results of 3-bromo-4-chlorotoluene with that of 3-chloro-4-
flipping (dissociation followed by recoordination in a reversed
way). Otherwise, substituted fluorenes with the same ratio
would be observed for 3-bromo-4-chlorotoluene and 3-
chloro-4-iodotoluene.
iodotoluene indicated that the first CeC bond formed mainly
at the more reactive CeBr or CeI bond, suggesting that the
formed benzyne species (VI) did not undergo coordination

C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
2543
Cl
R
R
Pd
X
Ar
ArM
Path A
R'
Pd
Ar
R'
R
Ar
X
Ar
R
R
Pd
Pd
R'
Pd
X
R'
R'
R
Cl
R
R
Pd
X
Cl
X
Cl
Pd(0)
ArM
Path B
Carbopalladation
+
R'
Pd
X
R'
R'
R
R
Pd
Ar
Cl
R
Cl
Ar
IV
R'
R'
R'
R
Cl
X
ArM
(Transmetalation)
Pd
II
VI
Path C
R'
V
Scheme 7. Possible pathways for the formation of palladium(II)ClX associated aryne intermediates.
The observation of the formation of two isomeric fluorenes
with 0.5 equiv of 2-mesitylmagnesium bromide. Our result
showed that no I was observed with Pd(OAc)2 as catalyst
(Table 5, entry 1). In contrary, 7% of I was observed with
Pd(0)/t-Bu3P as catalyst (Table 5, entry 2). The reaction of
3,4-dibromotoluenewith 0.5 equiv of 2-mesitylmagnesium bro-
mide gave similar results: I was not detected with Pd(OAc)2 as
catalysts, and 12% I observed with Pd(0)/t-Bu3P as catalyst
(Table 5, entries 3 and 4). In combination with our results that
no reaction was observed when mixing I with 2-mesitylmagne-
sium bromide in the presence of Pd(OAc)2 (Scheme 8), the
absence of I strongly suggests that the pathway for the
Pd(OAc)2-catalyzed reaction of 1,2-dibromobenzenes as well
as 1-bromo-2-iodobenzenewith bulky Grignard reagents should
be benzyne formation pathway, rather than the cross-coupling
followed by CeH activation pathway.
To understand whether other types of carbonehydrogen
bonds (nonbenzylic Ce(1ꢀ)H bonds, benzylic Ce(2ꢀ)H bonds,
and benzylic Ce(3ꢀ)H bonds) could also be activated under
our condition, we tested 2-ethyl-6-methylphenylmagnesium
bromide and 2-isopropyl-6-methylphenylmagnesium bromide
for the domino reaction. We found that the reaction with ste-
rically more hindered Grignard reagent underwent slower
than that with less sterically hindered Grignard reagent
(Table 6, entries 1e3). Such a slower reaction could be im-
proved by raising the reaction temperature (Table 6, entries
3 and 4). We also found that the sp3 CeH activation occurred
at the benzylic methyl groups, suggesting that benzylic
Ce(1ꢀ)H bonds preferentially be activated over nonbenzylic
Ce(1ꢀ)H bonds (nonbenzylic methyl group), benzylic Ce
(2ꢀ)H bonds, and Ce(3ꢀ)H bonds (Table 4, entry 2, Table 6,
entries 1 and 2). This observation was further confirmed by
the fact that no reaction was observed for 2,6-diethylphenyl-
magnesium bromide (Table 6, entry 4).
in a similar ratio (4e5:1) for 3-bromo-4-chlorotoluene, 3-
bromo-4-chloroanisole, and 3-chloro-4-iodotoluene (Table 3,
entries 6e9) suggested that the transmetalation rates for
PdeBr and PdeI bonds with hindered Grignard reagents
were comparable to each other.
2.3. Pd(OAc)2-catalyzed annulative reactions of
1,2-dibromoarenes and 1-bromo-2-iodobenzene with
hindered Grignard reagents
Our study on the leaving group ability effect suggested that
1,2-dibromobenzenes should also be excellent substrates for
the Pd(OAc)2-catalyzed annulative reaction. We have thus
also employed 1,2-dibromobenzenes as substrates for the reac-
tion and our results are listed in Table 4. We found with
Pd(OAc)2 as catalyst, the reaction could proceed at room tem-
perature for 1,2-dibromobenzene and 3,4-dibromotoluene, and
excellent yields of substituted fluorenes were obtained. Un-
symmetrical 3,4-dibromotoluene gave two isomeric fluorenes
in 42:58 ratio, suggesting that the reactivity of two CeBr
bonds is close to each other. For 1,2-dibromo-4,5-dimethyl-
benzene, heating to 60 ꢀC was necessary to achieve high
yields, likely because of slower initial oxidative addition of
CeBr with Pd(0) species. We have also tested 1-bromo-2-
iodobenzene as substrate and found it was also an excellent
one for the reaction. Our study showed that Pd(OAc)2 was
a highly efficient, operationally convenient catalyst for this
reaction.
However, no cyclization product was observed with 2,3-
dibromopyridine as the substrate (Table 4, entry 9).
To establish that the Pd(OAc)2-catalyzed annulative reac-
tions of 1,2-dibromobenzenes with hindered Grignard reagents
did not proceed via cross-coupling followed by CeH activa-
tion pathway, we adopted the same strategy we used for
Pd(0)/t-Bu3P catalyst system: to detect the existence of the
intermediate I by interrupting the reactions before their
completion by using limited amount of Grignard reagent. 2-
Bromo-20,40,60-trimethylbiphenyl (I) was found to be inert un-
der the reaction condition (Scheme 8) and has been established
to be detectable by GCeMS.4 We thus reasoned that it could
be detected if it was formed in the reaction as the intermediate.
We have thus carried out the reaction of 1,2-dibromobenzene
2.4. Pd(OAc)2-catalyzed annulative reactions of hindered
Grignard reagents with 2-haloaryl arenesulfonates
Based on the hypothesis that the reactions of 1,2-dihaloben-
zenes proceeded with hindered Grignard reagents could
proceed via palladium associated aryne intermediates, we
found by omitting the use of phosphine and NHC ligands for
palladium catalysts, a broad range of 1,2-dihalobenzenes includ-
ing 1,2-dibromobenzenes, 1-bromo-2-iodobenzene, 1-chloro-2-

2544
C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
Table 4
Pd-catalyzed cross-couplings of 1,2-dibromobenzenes and 1-bromo-2-iodobenzene with hindered Grignard reagentsa
R1
R2
R1
R2
Br
R
3% Pd(OAc)2
THF, r.t., 20 h
R
+
BrMg
Br/I
Entry
Dihalide
Substituted fluorene
Yieldb (%)
R
BrMg
Br
Br
1
2
99
99
BrMg
Br
Br
BrMg
Br
Br
3
4
92
BrMg
BrMg
BrMg
Br
Br
99 (42/58)c
Br
5
6
7
8
97d
94d
99
Br
Br
Br
BrMg
Br
BrMg
BrMg
I
Br
I
99
Br
Br
9
0
BrMg
N
N
a
Reaction conditions (not optimized): 1,2-dihalobenzene (1.0 equiv), Grignard reagent (2.5 equiv), 3% Pd catalyst, THF (2 ml), rt.
Isolated yields.
Ratio based on 1H NMR.
Reaction temperature: 60 ꢀC.
b
c
d
halobenzenes, and 1-bromo-2-fluorobenzene could be suitable
substrates for the preparation of substituted fluorenes. Our pal-
ladium associated aryne hypothesis suggested that other types
of o-halo(LG)arenes, such as 2-haloaryl tosylates (Ts) and
benzenesulfonates (Bs), which contain very inert CeOTs or
CeOBs bonds, should also be suitable substrates for the dom-
ino reaction because the oxidative addition of Pd(0) with the
very inert CeOTs or CeOBs bond would not be involved
and the OTs/OBs group would only serve as a leaving group.
We thus tested 2-haloaryl tosylates and benzenesulfonates,
which are readily available from 2-halophenols,23 as substrates
for the domino reactions (Table 7). We found that with Pd(OAc)2
as catalyst, good to excellent yields of substituted fluorenes
were obtained for 2-iodoaryl tosylates/benzenesulfonates and
3% Pd(OAc)2
+
BrMg
THF, rt, 20 h
Br
< 5%
Scheme 8. Pd-catalyzed reactions of 2-bromo-20,40,60-trimethylbiphenyls with
2-mesitylmagnesium bromide.

C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
2545
Table 5
Pd-catalyzed reactions of 1,2-dibromobenzenes with limited amount of 2-mesitylmagnesium bromidea
Br
R
R
Br
Br
R
Pd catalyst
+ BrMg
+
THF, room temperature, 20 h
III
1 equiv. : 0.5 equiv.
I
Entry
X
R
Pd catalyst
Conversion (%)
Ratio (%)
I
III
1
2
3
4
a
Br
Br
Br
Br
H
3% Pd(OAc)2
46
48
49
45
0
7
100
93
H
1.5% Pd2(dba)3/t-Bu3P
3% Pd(OAc)2
1.5% Pd2(dba)3/t-Bu3P
CH3
CH3
0
12
100
88
Reaction conditions: 1,2-dibromobenzene (1.0 equiv), Grignard reagent (0.5 equiv), 3% Pd catalyst, THF (2 ml), rt, 20 h. Ratios of I to III were based on
GCeMS data.
2-bromoaryl tosylates/benzenesulfonates (Table 7, entries
(Table 7, entries 6, 7, and 14) revealed that 2-iodo-4-methyl-
phenyl tosylate was a better substrate than 2-bromo-4-methyl-
phenyl tosylate and 2-chloro-4-methylphenyl tosylate was
virtually inactive. As these substrates only differ in their halo
groups and chloro group was more electron-withdrawing than
Br or I group, our results suggested that the initial oxidative ad-
dition should occur at the CeX bond, rather than at the CeOTs
bond. Otherwise, 2-chloro-4-methylphenyl tosylate would be
the better substrate than 2-bromo-4-methylphenyl tosylate and
2-iodo-4-methylphenyl tosylate. This thinking was further con-
firmed by the fact that no reaction was observedfor pyrocatechol
ditosylate (Table 7, entry 15). Thus, the reluctance of the CeCl
bond in 2-chloro-4-methylphenyl tosylate to undergo the initial
oxidative addition with Pd(0) species excluded it as a suitable
substrate for the domino reaction. The observation of two iso-
mers, rather than only one, in similar ratio for 2-bromophenyl
tosylates/benzenesulfonates, 2-iodo-4-methylphenyl tosylate,
and 1-bromo-2-naphthyl tosylate/benzenesulfonate (Table 7,
entries 6e13) further suggested that the transmetalation oc-
curred with comparable transmetalation rates for PdeBr and
PdeI bonds.
Aryl tosylates have been demonstrated to undergo cross-
couplings with para-substituted phenylmagnesium bromides
and ortho-tolymagnesium bromide when catalyzed by Pd(0)/
Josiphos ligand.24 We have carried out the reaction of phenyl
tosylate with 2-mesitylmagnesium bromide in the presence of
5% Pd(OAc)2 at 60 ꢀC for 20 h. We found that the cross-cou-
pling product was formed in less than 5% yield, suggesting
that Pd(OAc)2 cannot catalyze the cross-coupling of aryl tosy-
lates with hindered Grignard reagents efficiently (Scheme 9).
We also found that 2-(20,40,60-trimethyl)-4-methylphenyl tosy-
late, intermediate that would be formed if the domino reaction
proceeded via cross-coupling-oxidative addition-sp3 CeH acti-
vation mechanism, was unable to be converted to 2,4,6-trime-
thylfluorene under Pd(OAc)2/Grignard reagent or Pd(OAc)2/
MgCl2/Grignard reagent condition (Scheme 10). We have fur-
ther carried out the Pd2(dba)3/t-Bu3P-catalyzed reaction of
2-bromo-4-methylphenyl tosylate with 2-mesitylmagnesium
bromide and 2-(20,40,60-trimethyl)-4-methylphenyl tosylate
was isolated in 82% yield with no cyclized fluorene being ob-
served (Scheme 11). These results strongly suggested that
1e13). However, 2-chloro-4-methylphenyl tosylate was found
to be a poor substrate (Table 7, entry 14). Comparingthe reaction
results with 2-halo-4-methylphenyl tosylates as substrates
Table 6
Pd-catalyzed cross-couplings of 1,2-dibromobenzene with hindered Grignard
reagentsa
R3
R3
Br
Br
R1
R2
R
3% Pd(OAc)2
THF, r.t., 20 h
+
BrMg
R
R
Entry
Substituted fluorene
Yieldb (%)
BrMg
1
2
99
68
BrMg
BrMg
3
4
29
BrMg
72c
BrMg
BrMg
5
<1
a
Reaction conditions (not optimized): dihalide (1.0 equiv), Grignard reagent
(2.5 equiv), 3% Pd(OAc)2, THF (2 ml), rt.
b
Isolated yields.
Reaction temperature: 60 ꢀC.
c

2546
C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
Table 7
Pd(OAc)2-catalyzed reactions of 2-haloaryl arenesulfonates with hindered Grignard reagentsa
R1
R1
R2
OAs
+
X
3% Pd(OAc)2
BrMg
R
THF, reflux, 20 h
R
R2
Entry
1
Tosylate
OTs
ArMgBr
Product
Yieldb (%)
92
BrMg
I
OTs
I
2
3
4
5
6
7
8
87
83
95
86
92
82
74
BrMg
OTs
I
BrMg
BrMg
OBs
I
OBs
I
BrMg
BrMg
BrMg
OTs
I
(62:38)c
(58:42)c
(63:37)c
OTs
Br
OTs
Br
BrMg
MeO
OTs
9
(58:42)c
(71:29)c
69
49
BrMg
BrMg
Br
MeO
MeO
OBs
Br
10
Br
Br
OTs
11
12
(65:35)c
79
71
BrMg
(68:32)c
OTs
BrMg

C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
2547
Table 7 (continued)
Entry
Tosylate
ArMgBr
Product
Yieldb (%)
Br
(55:45)c
47
OBs
13
14
BrMg
OTs
<2
<2
BrMg
BrMg
Cl
OTs
OTs
15
a
Reaction conditions (not optimized): 2-haloaryl arenesulfonate (1.0 equiv), Grignard reagent (2.5 equiv), Pd(OAc)2 (3%), THF (2 ml), reflux.
Isolated yields.
Ratio based on 1H NMR.
b
c
OTs
Pd(OAc)2-catalyzed domino reactions of 2-haloaryl arenesulfo-
nates with hindered Grignard reagents did not proceed through
the cross-coupling-oxidative addition-sp3 CeH activation
mechanism.
OTs
3% Pd2(dba)3/t-Bu3P
+
BrMg
THF, reflux, 20 h
Br
82%
Scheme 11. Pd(0)/t-Bu3P-catalyzed reaction of 2-bromo-4-methylphenyl tosy-
late with 2-mesitylmagnesium bromide.
OTs
3% Pd(OAc)2
With or without MgCl2
THF, reflux, 20 h
BrMg
+
Our study was based on the hypothesis that two mechanistic
pathways might be possible for the reaction of 1,2-dihaloben-
zenes with Grignard reagents, namely (a) the pathway that in-
volves the cross-coupling of 1,2-dihalobenzenes with Grignard
reagents to form 2-halobiphenyls followed by oxidative addi-
tion and sp3 CeH activation, and (b) the pathway that involves
the oxidative addition of 1,2-dihalobenzenes to form 2-halo-
arylPd(II)X complexes followed by b-halo elimination to form
palladium associated arynes, transmetalation, carbopallada-
tion, and sp3 CeH activation. We explored the ligand effect
and leaving group effect on these two pathways. We found
that these two pathways were highly ligand dependent and
the reaction pathway involving palladium associated arynes
as intermediates could be controlled by omitting the use of
phosphine and NHC ligands for palladium catalysts. We also
found that a better leaving halo group favored the benzyne
forming pathway and the sp3 CeH activation preferentially
occurred at benzylic Ce(1ꢀ)H bonds over nonbenzylic Ce
(1ꢀ)H bonds (nonbenzylic methyl group), benzylic Ce(2ꢀ)H
bonds, and benzylic Ce(3ꢀ)H bonds. Our palladium
associated aryne hypothesis allowed us to identify simple pal-
ladium complexes, e.g., Pd(OAc)2, as the catalyst and a broad
range of 1,2-dihalobenzenes including previously unsuitable
1-chloro-2-halobenzenes and 2-haloaryl arenesulfonates as
< 5%
Scheme 9. Pd(OAc)2-catalyzed reaction of phenyl tosylate with 2-mesitylmag-
nesium bromide.
As our results supported that the initial oxidative addition
should not occur at the CeOTs bond, the similar ratio of the
substituted fluorenes observed for unsymmetrical 2-bromoaryl
tosylates/benzenesulfonates, 2-iodo-4-methylphenyl tosylate,
and 1-bromo-2-naphthyl tosylate/benzenesulfonate excluded
the pathway that the transmetalation occurs first followed by
aryne formation, in which only one isomer of substituted
fluorenes would be expected. Our study further suggested
that the pathway to form Pd(LG)X associated arynes first
followed by transmetalation should be predominant, if not
the only one.25
3. Summary
We demonstrated that simple palladium complexes such as
Pd(OAc)2 were excellent catalysts for 1,2-dihalobenzenes and
2-haloaryl arenesulfonates to undergo annulative reactions
with hindered Grignard reagents to form substituted fluorenes.
OTs
3% Pd(OAc)2
BrMg
+
With or without MgCl2
THF, reflux, 20 h
< 2%
Scheme 10. Pd(OAc)2-catalyzed reaction of 2-(20,40,60-trimethyl)-4-methylphenyl tosylate with 2-mesitylmagnesium bromide.

2548
C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
substrates for high yield synthesis of substituted fluorenes. Our
study also suggested that 2-(leaving group)arylPd(II) com-
plexes most likely formed Pd(leaving group)X associated
arynes first followed by transmetalation with Grignard
reagents and carbopalladation, rather than undergo transmeta-
lation with Grignard reagent first following by aryne formation
and carbopalladation. The work described here provides a high
yield, one-step access to substituted fluorenes from readily
available 1,2-dihalobenzenes and 2-haloaryl arenesulfonates
and hindered Grignard reagents, and our method may find ap-
plications in the preparation of substituted fluorene-containing
molecules including polymers.
NMR analysis of the reaction mixture gave the conversion
of the reaction, and the ratio of the products.
4.3. General procedure of the leaving group effect on domino
reactions of 1,2-dihalobenzenes with Grignard reagents
In a glove box with N2-atmosphere, to a mixture of 1,2-
halobenzene (1.0 mmol) and 2.0 ml THF (in a Schlenk flask)
was added Pd(OAc)2 (0.015 mmol). After stirred for 5e
10 min, 2-mesitylmagnesium bromide (2.5 ml, 1 M in THF,
2.5 mmol) was added. The mixture was allowed to stir at
60 ꢀC or at room temperature for 20 h. After quenched with wa-
ter, the reaction mixture was extracted with ethyl acetate twice.
The organic layer was washed with brine and the solvent was
4. Experimental section
1
evaporated under vacuum. H NMR analysis of the reaction
mixture gave the conversion of the reaction, and the ratio of
the products.
4.1. General
NMR spectra were recorded on Varian 200 MHz or
600 MHz spectrometers. GCeMS experiments were carried
out using an Agilent GC/MS instrument consisting of
a 6890N series GC and a 5973 Mass Selective Detector Sys-
tem. All yields reported refer to isolated yields (average of
two runs) unless otherwise indicated, and the product purity
4.4. General procedure for Pd-catalyzed domino reactions of
1,2-dihalobenzenes with hindered Grignard reagents
In a glove box with N2-atmosphere, to a mixture of 1,2-di-
halobenzenes (1.0 mmol) and 1.0 ml THF (in a Schlenk flask)
was added palladium acetate (0.03 mmol) or Pd2(dba)3
(0.015 mmol). After stirred for 5e10 min, Grignard reagent
(2.5 ml, 1 M in THF, 2.5 mmol) was added. The mixture
was allowed to stir at room temperature or 60 ꢀC for 20 h. Af-
ter being quenched with water, the reaction mixture was ex-
tracted with ethyl acetate. The organic layer was washed
with brine and the solvent was evaporated under vacuum.
Flash chromatography on silica gel (hexane/ethyl acetate¼
100:0e90:10) gave the products.
1
was estimated to be greater than 95% as determined by H
NMR. Compounds described in the literature were character-
1
ized by comparison of their melting points, H NMR, and
13C NMR spectra to reported data. Some of the new com-
pounds were also characterized by elemental analysis.
THF was dried with sodium/benzophenone. 2,6-Dimethyl-
phenylmagnesium bromide, 2-mesitylmagnesium bromide,
and p-tolylmagnesium bromide were purchased from Aldrich
Chemical Co. and used directly. Pd2(dba)3 and t-Bu3P were pur-
chased from Strem and used as received. Pd(OAc)2 was obtained
as a gift from Frontier Scientific, Inc. 3-Bromo-4-chloroto-
luene,26 3-chloro-4-iodotoluene,27 and 2-iodo-4-methylphe-
nol28 were prepared according to literature procedures. Aryl
tosylates and benzenesulfonates were prepared by treating the
corresponding phenols with p-toluenesulfonyl chloride or ben-
zenesulfonyl chloride in dichloromethane containing excess of
triethylamine at room temperature overnight. Bromopentame-
thylbenzene and pentamethyl phenylmagnesium bromide were
prepared according to literature.29,30 Other chemical reagents
were purchased from Alfa Aesar and used directly.
4.5. General procedure for Pd(OAc)2-catalyzed domino
reaction of 2-haloaryl tosylates with hindered Grignard
reagents
In a glove box with N2-atmosphere, to a mixture of 2-
haloaryl tosylate (1.0 mmol) and 1.0 ml THF (in a Schlenk
flask) was added palladium acetate (6.7 mg, 0.03 mmol). After
stirred for 5e10 min, Grignard reagent (2.5 ml, 1 M in THF,
2.5 mmol) was added. The mixture was allowed to stir under
refluxing for 20 h. After quenched with water, the reaction
mixture was extracted with ethyl acetate. The organic layer
was washed with brine and the solvent was evaporated under
vacuum. Flash chromatography on silica gel (hexane/ethyl
acetate¼100:0e90:10) gave the products.
4.2. General procedure of the ligand effect on domino
reactions of 1-bromo-2-chlorobenzene with Grignard
reagents
In a glove box with N2-atmosphere, to a mixture of 1-
bromo-2-chlorobenzene (1.0 mmol) and 2.0 ml THF (in
a Schlenk flask) were added palladium source (0.015 mmol)
and phosphine ligands (0.06 mmol). After stirred for 5e
10 min, Grignard reagent (2.5 ml, 1 M in THF, 2.5 mmol)
was added. The mixture was allowed to stir under 60 ꢀC for
20 h. After quenched with water, the reaction mixture was ex-
tracted with ethyl acetate twice. The organic layer was washed
4.5.1. 2,4-Dimethylfluorene31
White solid. Mp: 66.5e67.5 ꢀC. 1H NMR (CDCl3,
600 MHz): d 7.87 (d, J¼7.2 Hz, 1H), 7.53 (d, J¼7.2 Hz,
1H), 7.36 (t, J¼7.8 Hz, 1H), 7.27 (t, J¼7.2 Hz, 1H), 7.21 (s,
1H), 6.97 (s, 1H), 3.86 (s, 2H), 2.69 (s, 3H), 2.39 (s,
3H) ppm. 13C NMR (CDCl3, 151 MHz): d 143.9, 143.5,
142.7, 137.16, 136.2, 132.7, 129.9, 126.5, 125.6, 124.8,
123.1, 122.6, 36.9, 21.3, 20.9 ppm.
1
with brine and the solvent was evaporated under vacuum. H

C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
2549
4.5.2. 4-Methylfluorene32
4.5.7. The structure of 3,5-dimethylfluorene was established
by NOE effect
Recrystallization of the mixture of 2,5-dimethylfluorene/
1
White solid. Mp: 69e71 ꢀC. H NMR (CDCl3, 600 MHz):
d 7.93 (d, J¼7.8 Hz, 1H), 7.56 (d, J¼7.2 Hz, 1H), 7.39 (t,
J¼7.2 Hz, 1H), 7.38 (d, J¼7.8 Hz, 1H), 7.30 (t, J¼7.2 Hz,
1H), 7.22 (t, J¼7.8 Hz, 1H), 7.15 (d, J¼7.8 Hz, 1H), 3.91 (s,
2H), 2.73 (s, 3H) ppm. 13C NMR (CDCl3, 151 MHz):
d 143.7, 143.6, 142.7, 139.8, 133.0, 129.0, 126.6, 126.4,
126.0, 124.9, 123.1, 122.4, 37.1, 21.1 ppm.
3,5-dimethylfluorene by hexanes gave >95% pure 3,5-dime-
1
thylfluorene. Mp: 77e78.5 ꢀC. H NMR (CDCl3, 600 MHz):
d 7.73 (s, 1H), 7.43 (d, J¼8.4 Hz, 1H), 7.38 (d, J¼7.8 Hz,
1H), 7.19 (t, J¼8.4 Hz, 1H), 7.13 (m, 2H), 3.85 (s, 2H),
2.73 (s, 3H), 2.47 (s, 3H) ppm. 13C NMR (CDCl3,
150.855 MHz): d 144.0, 142.9, 140.7, 139.8, 136.1, 133.0,
128.9, 126.9, 126.2, 124.5, 123.8, 122.4, 36.7, 21.8,
21.2 ppm. NOE effect observed when the peak at 3.85
(s) ppm was irradiated: 2.9% for the peak with chemical shift
of 7.43 ppm and 2.5% for the peak with chemical shift of
7.38 ppm.
4.5.3. 1,2,3,4-Tetramethylfluorene33
White solid. Mp: 121.5e122.5 ꢀC. 1H NMR (CDCl3,
600 MHz): d 7.97 (d, J¼8.4 Hz, 1H), 7.53 (d, J¼7.8 Hz, 1H),
7.34 (dd, J¼8.4, 0.6 Hz, 1H), 7.25 (dd, J¼8.4, 0.6 Hz, 1H),
3.76 (s, 2H), 2.66 (s, 3H), 2.32 (s, 6H), 2.29 (s, 3H) ppm. 13C
NMR (CDCl3, 151 MHz): d 143.7, 143.6, 139.9, 137.0, 133.7,
133.5, 129.4, 129.1, 126.4, 125.3, 124.7, 123.1, 36.6, 16.8,
16.5, 16.5, 16.2 ppm. Anal. Calcd for C17H18: C, 91.84%; H,
8.16%. Found: C, 91.58%; H, 8.19%.
4.5.8. 3-Methoxy-5-methylfluorene/2-methoxy-5-
methylfluorene
Compound was obtained as a mixture with a ratio of 78:22.
The structure of 3-methoxy-5-methylfluorene was established
by NOE effect. Recrystallization from the mixture of 3-me-
thoxy-5-methylfluorene and 2-methoxy-5-methylfluorene in
hexanes gave 3-methoxy-5-methylfluorene as a white solid.
Mp: 70e71 ꢀC. 1H NMR (CDCl3, 600 MHz): d 7.49 (d,
J¼2.4 Hz, 1H), 7.45 (d, J¼8.4 Hz, 1H), 7.38 (d, J¼7.2 Hz,
1H), 7.20 (t, J¼7.2 Hz, 1H), 7.14 (d, J¼7.8 Hz, 1H), 7.87 (dd,
J1¼8.4, 2.4 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 2H), 2.72 (s, 3H).
13C NMR (CDCl3, 151 MHz): d 158.8, 144.7, 143.9, 139.6,
135.8, 133.0, 128.9, 126.5, 125.1, 122.5, 111.3, 109.4, 55.6,
36.3, 21.0 ppm. NOE effect observed when the peak at
d 3.84 ppm was irradiated: 7.45 (d, 0.3%), 7.38 (d, 0.3%).
4.5.4. 2,4,6-Trimethylfluorene/2,4,7-trimethylfluorene
Off-white solid. Mp: 43e57 ꢀC. 1H NMR (CDCl3,
600 MHz): d 7.74 (d, J¼7.8 Hz, 1H), 7.68 (s, 1H), 7.40 (d,
J¼7.8 Hz, 1H), 7.34 (s, 1H), 7.19 (s, 1H), 7.18 (s, 1H),
7.18e7.16 (m, 2H), 7.08 (d, J¼7.2 Hz, 1H), 6.95 (s, 1H),
3.81 (s, 4H), 2.69 (s, 4H), 2.66 (s, 2H), 2.46 (s, 4H), 2.42 (s,
2H), 2.38 (s, 6H) ppm. 13C NMR (CDCl3, 151 MHz):
d 144.4, 143.8, 143.7, 142.9, 140.6, 140.1, 137.2, 137.2,
136.0, 136.0, 135.7, 135.3, 132.6, 132.2, 129.8, 129.8,
127.3, 126.4, 125.6, 124.4, 123.4, 123.1, 123.1, 122.3, 36.7,
36.5, 21.8, 21.4, 21.3, 21.3, 21.0, 20.8 ppm. Anal. Calcd for
C16H16: C, 92.26%; H, 7.74%. Found: C, 91.93%; H, 7.78%.
4.5.9. 2,3,5,7-Tetramethylfluorene
White solid. Mp: 104e105 ꢀC. 1H NMR (CDCl3,
600 MHz): d 7.64 (s, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 6.94
(s, 1H), 3.79 (s, 2H), 2.68 (s, 3H), 2.38 (s, 3H), 2.37 (s,
3H), 2.33 (s, 3H). 13C NMR (CDCl3, 150.871 MHz):
d 144.0, 141.2, 140.6, 137.4, 135.6, 134.5, 134.0, 132.2,
129.7, 126.0, 123.8, 123.1, 36.5, 21.3, 20.9, 20.3, 20.0 ppm.
4.5.5. The structure of 2,4,6-trimethylfluorene was
established by NOE effect
Recrystallization on the mixture of 2,4,7-trimethylfluorene/
2,4,6-trimethylfluorene by hexanes gave >90% pure 2,4,6-tri-
1
methylfluorene. H NMR (CDCl3, 600 MHz): d 7.68 (s, 1H),
7.40 (d, J¼7.8 Hz, 1H), 7.19 (s, 1H), 7.08 (d, J¼7.8 Hz,
1H), 6.95 (s, 1H), 3.80 (s, 2H), 2.68 (s, 3H), 2.46 (s, 3H),
2.38 (s, 3H) ppm. 13C NMR (CDCl3, 151 MHz): d 144.4,
142.9, 140.6, 137.2, 136.1, 136.0, 132.6, 129.8, 126.4,
124.4, 123.4, 123.1, 36.5, 21.8, 21.3, 21.0 ppm. NOE effect
observed when the peak at 3.80 ppm was irradiated: 3.5%
for the peak with chemical shift of 7.40 ppm and 3.4% for
the peak with chemical shift of 7.19 ppm.
4.5.10. 2,3,5-Trimethylfluorene
White solid. Mp: 86.5e87.5 ꢀC. 1H NMR (CDCl3,
600 MHz): d 7.68 (s, 1H), 7.36 (d, J¼7.2 Hz, 1H), 7.32 (s,
1H), 7.16 (t, J¼7.2 Hz, 1H), 7.11 (d, J¼7.2 Hz, 1H), 3.82 (s,
2H), 2.71 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H). 13C NMR
(CDCl3, 150.871 MHz): d 143.6, 141.4, 140.6, 140.0, 134.6,
134.5, 132.5, 128.8, 126.0, 125.8, 124.2, 122.3, 36.6, 21.1,
20.3, 20.0 ppm.
4.5.6. 3,5-Dimethylfluorene/2,5-dimethylfluorene
Off-white solid. Mp: 43e62 ꢀC. 1H NMR (CDCl3,
600 MHz): d 7.78 (d, J¼7.8 Hz, 1H), 7.72 (s, 1H), 7.42 (d,
J¼7.8 Hz, 1H), 7.36e7.36 (m, 1H), 7.21e7.15 (m, 1H),
7.13e7.11 (m, 1H), 3.84 (s, 2H), 2.72 (s, 3H), 2.70 (s, 3H),
2.46 (s, 3H), 2.42 (s, 3H) ppm. 13C NMR (CDCl3,
151 MHz): d 144.0, 143.9, 143.4, 142.9, 140.7, 140.0, 139.8,
139.8, 136.04, 135.8, 133.0, 132.6, 128.9, 128.8, 127.4,
126.9, 126.2, 125.9, 125.6, 124.5, 123.8, 122.8, 122.4,
122.3, 36.9, 36.7, 21.8, 21.4, 21.2, 21.0 ppm.
4.5.11. 4-Ethylfluorene34
1
White solid. Mp: 35e36 ꢀC. H NMR (CDCl3, 600 MHz):
d 7.92 (d, J¼7.8 Hz, 1H), 7.57 (d, J¼7.2 Hz, 1H), 7.41 (t,
J¼7.2 Hz, 1H), 7.39 (d, J¼7.8 Hz, 1H), 7.31 (t, J¼7.2 Hz,
1H), 7.27e7.24 (m, 1H), 7.19 (d, J¼7.2 Hz, 1H), 3.92 (s,
2H), 3.12 (q, J¼7.2 Hz, 2H), 1.39 (t, J¼7.2 Hz, 3H). 13C
NMR (CDCl3, 150 MHz): d 143.9, 143.7, 142.1, 139.4,
139.0, 127.1, 126.7, 126.6, 126.0, 124.9, 123.2, 122.5, 37.1,
27.2, 14.3 ppm.

2550
C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
4.5.12. 4-Isopropylfluorene34
1H), 4.17 (s, 2H), 2.80 (s, 3H). 13C NMR (CDCl3,
150 MHz): d 143.6, 140.7, 140.3, 140.0, 132.5, 132.0, 130.4,
129.2, 128.6, 127.4, 126.3, 126.0, 125.3, 124.1, 122.4,
121.8, 35.7, 21.0 ppm. NOE effect observed when the peak
at d 4.17 ppm was irradiated: 8.10 (d, 0.9%), 7.47 (s, 0.3%).
1
Colorless liquid. H NMR (CDCl3, 600 MHz): d 7.97 (d,
J¼7.8 Hz, 1H), 7.55 (d, J¼7.2 Hz, 1H), 7.39 (d, J¼6.0 Hz,
1H), 7.38 (t, J¼7.8 Hz, 1H), 7.33 (d, J¼7.8 Hz, 1H), 7.30 (t,
J¼6.0 Hz, 2H), 3.90 (s, 2H), 3.84 (m, 1H), 1.41 (d,
J¼6.6 Hz, 6H). 13C NMR (CDCl3, 150 MHz): d 144.3,
143.9, 143.8, 142.0, 138.5, 126.7, 126.6, 125.9, 124.9,
123.6, 123.0, 122.4, 37.1, 29.5, 22.8 ppm.
4.5.16. 11-Methyl-7H-benzo[a]fluorene
Off-white solid. Obtained from the mother liquid of the
mixture of 11-methyl-7H-benzo[c]fluorene and 7-methyl-
11H-benzo[a]fluorene by using hexanes as solvent with
>85% purity. 1H NMR (CDCl3, 600 MHz): d 8.51 (d,
J¼8.4 Hz, 1H), 7.91 (d, J¼8.4 Hz, 1H), 7.80 (d, J¼8.4 Hz,
1H), 7.62 (d, J¼8.4 Hz, 1H), 7.51 (t, J¼7.2 Hz, 1H), 7.46 (t,
J¼7.2 Hz, 1H), 7.42 (d, J¼7.2 Hz, 1H), 7.26 (t, J¼8.4 Hz,
1H), 7.25 (d, J¼7.2 Hz, 1H), 3.97 (s, 2H), 2.86 (s, 3H). 13C
NMR (CDCl3, 150 MHz): d 144.7, 142.7, 141.6, 138.3,
133.7, 132.0, 130.6, 128.8, 128.6, 128.6, 127.9, 126.8,
125.9, 124.6, 123.0, 122.0, 38.2, 25.1 ppm. NOE effect was
observed when the peak at d 3.97 ppm was irradiated: 7.62
(d, 0.3%), 7.42 (s, 0.2%).
4.5.13. 7,9-Dimethyl-11H-benzo[a]fluorene and
9,11-dimethyl-7H-benzo[c]fluorene
Anal. Calcd for C19H16: C, 93.40%; H, 6.60%. Found: C,
93.60%; H, 6.54%. The structure of 7,9-dimethyl-11H-ben-
zo[a]fluorene was established by NOE effect. Recrystalliza-
tion from the mixture of 7,9-dimethyl-11H-benzo[a]fluorene
and 9,11-dimethyl-7H-benzo[c]fluorene by using hexanes as
solvent gave 7,9-dimethyl-11H-benzo[a]fluorene as a white
solid. 1H NMR (CDCl3, 600 MHz): d 8.07 (d, J¼8.4 Hz,
1H), 8.00 (d, J¼8.4 Hz, 1H), 7.90 (d, J¼7.8 Hz, 1H), 7.85
(d, J¼8.4 Hz, 1H), 7.53 (t, J¼7.8 Hz, 1H), 7.45 (t,
J¼7.8 Hz, 1H), 7.29 (s, 1H), 7.00 (s, 1H), 4.14 (s, 2H), 2.77
(s, 3H), 2.42 (s, 3H). 13C NMR (CDCl3, 150 MHz): d 144.0,
140.1, 139.9, 138.1, 135.9, 132.1, 131.9, 130.5, 130.1,
128.6, 127.3, 126.2, 125.1, 124.0, 123.2, 121.6, 35.6, 21.3,
20.8 ppm. NOE effect was observed when irradiated at the
peak at d 4.14 ppm: 8.00 (d, 0.5%), 7.29 (s, 0.3%). NOE effect
observed when the peak at d 2.77 ppm was irradiated: 8.07
(d, 0.5%), 7.00 (s, 0.29%). NOE effect observed when the
peak at d 2.42 ppm was irradiated: 7.29 (d, 0.22%), 7.00
(s, 0.19%).
4.6. Pd(OAc)2-catalyzed reaction of 2-halo-20,40,60-
trimethylbiphenyl with 2-mesitylmagnesium bromide
In a glove box with nitrogen atmosphere, to a mixture of 2-
chloro-20,40,60-trimethylbiphenyl or 2-fluoro-20,40,60-trimethyl-
biphenyl (0.1 mmol) and 0.5 ml THF (in a Schlenk flask) was
added Pd(OAc)2 (0.7 mg, 0.003 mmol). After stirred for 5e
10 min, Grignard reagent THF solution (0.25 ml, 1 M in
THF, 0.25 mmol) was added. The mixture was allowed to
stir under 60 ꢀC for 20 h. After quenched with water, the reac-
tion mixture was extracted with ethyl acetate. The organic
layer was washed with brine and the solvent was evaporated
4.5.14. 9,11-Dimethyl-7H-benzo[c]fluorene
Off-white solid. Obtained from the mother liquid of the re-
crystallization of the mixture of 7,9-dimethyl-11H-benzo[a]-
fluorene and 9,11-dimethyl-7H-benzo[c]fluorene with >90%
purity. 1H NMR (CDCl3, 600 MHz): d 8.51 (d, J¼8.4 Hz,
1H), 7.88 (d, J¼8.4 Hz, 1H), 7.76 (d, J¼7.8 Hz, 1H), 7.58
(d, J¼7.8 Hz, 1H), 7.48 (t, J¼7.8 Hz, 1H), 7.43 (t, J¼
7.8 Hz, 1H), 7.21 (s, 1H), 7.07 (s, 1H), 3.90 (s, 2H), 2.82 (s,
3H), 2.39 (s, 3H). 13C NMR (CDCl3, 150 MHz): d 145.1,
142.3, 139.0, 138.4, 135.7, 133.7, 131.6, 131.4, 128.7,
128.6, 127.4, 126.8, 124.5, 124.5, 123.0, 122.9, 38.0, 25.1,
21.0 ppm. NOE effect observed when the peak at
d 3.90 ppm was irradiated: 7.58 (d, 0.5%), 7.21 (s, 0.3%).
1
under vacuum. No reaction was observed by H NMR.
4.7. Pd(OAc)2-catalyzed reaction of phenyl tosylate with
2-mesitylmagnesium bromide
In a glove box with nitrogen atmosphere, to a mixture of
phenyl tosylate (62 mg, 0.25 mmol) and 0.5 ml THF (in
a Schlenk flask) was added palladium acetate (1.7 mg,
0.007 mmol). After stirred for 5e10 min, 2-mesitylmagne-
sium bromide THF solution (0.6 ml, 1 M in THF, 0.6 mmol)
was added. The mixture was allowed to stir under 60 ꢀC for
20 h. After quenched with water, the reaction mixture was ex-
tracted with ethyl acetate. The organic layer was washed with
brine and the solvent was evaporated under vacuum. 1H NMR
showed that the yield of the cross-coupling product was less
than 5%.
4.5.15. 7-Methyl-11H-benzo[a]fluorene and 11-methyl-7H-
benzo[c]fluorene
Anal. Calcd for C18H14: C, 93.87%; H, 6.13%. Found: C,
93.69%; H, 6.01%. The structure of 7-methyl-11H-benzo[a]-
fluorene was established by NOE effect. Recrystallization
from the mixture of 7-methyl-11H-benzo[a]fluorene and 11-
methyl-7H-benzo[c]fluorene by using hexanes as solvent
gave 7-methyl-11H-benzo[a]fluorene as a white solid. 1H
NMR (CDCl3, 600 MHz): d 8.10 (d, J¼8.4 Hz, 1H), 8.01 (d,
J¼8.4 Hz, 1H), 7.90 (d, J¼8.4 Hz, 1H), 7.86 (d, J¼8.4 Hz,
1H), 7.53 (t, J¼7.8 Hz, 1H), 7.47 (d, J¼7.2 Hz, 1H), 7.47 (t,
J¼7.2 Hz, 1H), 7.22 (t, J¼7.8 Hz, 1H), 7.17 (d, J¼7.8 Hz,
4.8. Pd(OAc)2-catalyzed reaction of 2-chloro-5-methylphenyl
tosylate with 2-mesitylmagnesium bromide
In a glove box with nitrogen atmosphere, to a mixture of 2-
chloro-5-methylphenyl tosylate (0.25 mmol) and 0.5 ml THF
(in a Schlenk flask) was added Pd(OAc)2 (1.7 mg,
0.0075 mmol). After stirred for 5e10 min, Grignard reagent

C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
2551
(0.65 ml, 1 M in THF, 0.65 mmol) was added. The mixture
Supplementary data
was allowed to stir under refluxing for 20 h. After quenched
with water, the reaction mixture was extracted with ethyl ace-
tate. The organic layer was washed with brine and the solvent
was evaporated under vacuum. No reaction was observed by
1H NMR.
NMR spectra of the products of palladium-catalyzed annu-
lative reactions. Supplementary data associated with this arti-
cle can be found in the online version, at doi:10.1016/
j.tet.2008.01.020.
References and notes
4.9. Pd2(dba)3/t-Bu3P-catalyzed reaction of 2-bromo-4-
methylphenyl tosylate with 2-mesitylmagnesium bromide
1. (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reac-
tions, 2nd ed.; Wiley-VCH: New York, NY, 2004; (b) Beller, M.; Bolm,
C. Transition Metals for Organic Synthesis; Wiley-VCH: New York,
NY, 1998; (c) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke,
R. G. Principles and Applications of Organotransition Metal Chemistry;
University Science Books: Mill Valley, CA, 1987.
In a glove box with N2-atmosphere, to a mixture of 2-
bromo-4-methylphenyl tosylate (170.5 mg, 0.5 mmol) and
1.0 ml THF (in a Schlenk flask) were added Pd2(dba)3
(6.9 mg, 0.0075 mmol) and t-Bu3P (6.1 mg, 0.03 mmol). After
stirred for 5e10 min, 2-mesitylmagnesium bromide (1.25 ml,
1 M in THF, 1.25 mmol) was added. The mixture was allowed
to stir under refluxing for 20 h. After quenched with water, the
reaction mixture was extracted with ethyl acetate twice. The
organic layer was washed with brine and the solvent was evap-
orated under vacuum. Flash chromatography on silica gel
(hexane/ethyl acetate¼100:0e90:15) gave the cross-coupling
product 2-(20,40,60-trimethylphenyl)-4-methylphenyl tosylate
in 82% yield. White solid. Mp: 75e76 ꢀC. 1H NMR
(CDCl3, 600 MHz): d 7.31 (d, J¼7.8 Hz, 1H), 7.25 (d,
J¼8.4 Hz, 2H), 7.15 (dd, J¼7.8, 1.8 Hz, 1H), 7.07 (d,
J¼8.4 Hz, 2H), 6.94 (d, J¼1.8 Hz, 1H), 6.80 (s, 2H), 2.40
(s, 3H), 2.35 (s, 3H), 2.32 (s, 3H), 1.86 (s, 6H) ppm. 13C
NMR (CDCl3, 151 MHz): d 144.8, 144.3, 136.9, 136.6,
136.6, 133.7, 133.6, 133.1, 132.3, 129.2, 129.0, 127.9,
127.7, 122.6, 21.6, 21.0, 20.9, 20.3 ppm.
2. Hu, Q.-S. Synthetic Methods for Step-Growth Polymers; Rogers, M., Long,
T., Eds.; Wiley: Hoboken, New Jersey, NJ, 2003; pp 467e526.
3. Dong, C.-G.; Hu, Q.-S. J. Am. Chem. Soc. 2005, 127, 10006e10007.
4. Dong, C.-G.; Hu, Q.-S. Angew. Chem., Int. Ed. 2006, 45, 2289e2292.
5. Fluorenes are typically prepared via more than one step, for example, see:
Kashulin, I. A.; Nifant’ev, I. E. J. Org. Chem. 2004, 69, 5476e5479. For
a recent one-step synthesis of fluorenes, see: Fuchibe, K.; Akiyama, T.
J. Am. Chem. Soc. 2006, 128, 1434e1435. Also see Ref. 4.
6. Fluorene is the core structure of biologically active molecules, sensors and
light-emitting materials. For examples, see: (a) Rathore, R.; Chebny, V. J.;
Abdelwahed, S. H. J. Am. Chem. Soc. 2005, 127, 8012e8013; (b) Sulsky,
R.; Robl, J. A.; Biller, S. A.; Harrity, T. W.; Wetterau, J.; Connolly, F.;
Jolibois, K.; Kunselman, L. Bioorg. Med. Chem. Lett. 2004, 14, 5067e
5070; (c) Marsitzky, D.; Vestberg, R.; Blainey, P.; Tang, B. T.; Hawker,
C. J.; Carter, K. R. J. Am. Chem. Soc. 2001, 123, 6965e6972.
7. For recent examples on CeH bond activations, see: (a) Chen, X.;
Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634e12635;
(b) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 78e79; (c) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M.
J. Am. Chem. Soc. 2006, 128, 9048e9049; (d) Wang, D.-H.; Hao, X.-S.;
Wu, D.-F.; Yu, J.-Q. Org. Lett. 2006, 8, 3387e3390; (e) Zhou, C.; Larock,
R. C. J. Org. Chem. 2006, 71, 3551e3558; (f) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2005, 127, 3672e3673; (g) Shi, L.; Tu, Y.-Q.; Wang, M.;
Zhang, F.-M.; Fan, C.-A.; Zhao, Y.-M.; Xia, W.-J. J. Am. Chem. Soc.
2005, 127, 10836e10837; (h) Shabashov, D.; Daugulis, O. Org. Lett.
2005, 7, 3657e3659; (i) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685e4696; (j) Desai,
L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542e
9543.
8. Pd-catalyzed cyclizations via sp3 CeH activation are rare: Ref. 4. Also
see: (a) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem., Int. Ed.
2003, 42, 5736e5740; (b) Suau, R.; Lopez-Romero, J. M.; Rico, R. D.
Tetrahedron Lett. 1996, 37, 9357e9360; (c) Dyker, G. J. Org. Chem.
1993, 58, 6426e6428; (d) Dyker, G. Angew. Chem., Int. Ed. Engl.
1994, 33, 103e105; (e) Dyker, G. Angew. Chem., Int. Ed. Engl. 1992,
31, 1023e1025.
4.10. Palladium-catalyzed reaction of 2-(20,40,60-trimethyl)-4-
methylphenyl tosylate with 2-mesitylmagnesium bromide
In a glovebox with N2-atmosphere, to a mixture of 2-(20,40,60-
trimethyl)-4-methylphenyl tosylate (95 mg, 0.25 mmol) and
0.5 ml THF (in a Schlenk flask) was added Pd(OAc)2 (1.7 mg,
0.0075 mmol). After stirred for 5e10 min, 2-mesitylmagne-
sium bromide (0.65 ml, 1 M in THF, 0.65 mmol) was added.
The mixture was allowed to stir under refluxing for 20 h. After
quenched with water, the reaction mixture was extracted with
ethyl acetate. The organic layer was washed with brine and
the solvent was evaporated under vacuum. No 2,4,6-trimethyl-
fluorene was observed by 1H NMR.
9. For examples on Pd-catalyzed tandem/domino cross-coupling-cyclization
via aromatic CeH bond activation, see: (a) Pinto, A.; Neuville, L.; Retail-
leau, P.; Zhu, J. Org. Lett. 2006, 8, 4927e4930; (b) Wegner, H. A.; Scott,
L. T.; de Meijere, A. J. Org. Chem. 2003, 68, 883e887; (c) Larock, R. C.;
Tian, Q. J. Org. Chem. 2001, 66, 7372e7379.
Acknowledgements
10. For recent general reviews on tandem/domino reactions, see: (a) Tietze,
L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967e1983; (b)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
551e564; (c) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev.
1996, 96, 195e206; (d) Tietze, L. F. Chem. Rev. 1996, 96, 115e136.
11. Recent examples of annulative tandem reactions based on transition
metal-catalyzed addition/cross-coupling strategies: (a) Ney, J. E.; Wolfe,
J. P. J. Am. Chem. Soc. 2005, 127, 8644e8651; (b) Huang, Q.; Fazio,
A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004,
126, 7460e7461; (c) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc.
We gratefully thank the National Institutes of Health
(GM69704) and NSF (CHE0719311) for funding. Partial sup-
port from the donors of the Petroleum Research Fund, admin-
istered by the American Chemical Society (44428-AC1), and
the PSC-CUNY Research Award Programs is also gratefully
acknowledged. We also thank Prof. Alec Greer at Brooklyn
College of CUNY for his help on GCeMS analysis, and Fron-
tier Scientific for its generous gifts of Pd(OAc)2.

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C.-G. Dong, Q.-S. Hu / Tetrahedron 64 (2008) 2537e2552
2004, 126, 1620e1621; (d) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004,
tylmagnesium bromide in THF at 60 ꢀC gave low yield of 2,4-dimethyl-
fluorene (24%, much lower than the 95% yield observed for 1-bromo-
2-chlorobenzene under the same reaction condition), indicating that
the initial oxidative addition at the CeCl bond occurred very slowly.
This observation suggested that with 1-bromo-2-chlorobenzene as
substrate, the initial oxidative addition should mainly take place at the
CeBr bond.
126, 13906e13907; (e) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed.
2004, 43, 3605e3608; (f) Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am.
Chem. Soc. 2004, 126, 7601e7607; (g) Cauble, D. F.; Gipson, J. D.;
Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110e1111.
12. A portion of this study has been communicated: Dong, C.-G.; Hu, Q.-S.
Org. Lett. 2006, 8, 5057e5060. Also see: Hu, Q.-S. Synlett 2007,
1331e1345.
19. For a recent review, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
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13. Recent examples of Pd-catalyzed reactions via carbopalladation of arynes:
(a) Henderson, J. L.; Edwards, A. S.; Greaney, M. F. Org. Lett. 2007, 9,
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20. Recent reviews for N-heterocyclic carbenes as Pd(0) ligands: (a)
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Bahmanyar, S.; Borer, B. C.; Kim, Y. M.; Kurtz, D. M.; Yu, S. Org. Lett.
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22. Two isomeric products in close to 1:1 ratio were always observed with
unsymmetrical arynes in the reported aryne generation strategy from
o-trimethylsilylaryl triflates, see Ref. 13.
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~
´
´
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bond in Pd(OAc)2-catalyzed reaction of 1-chloro-2-bromobenzene with
2-mesitylmagnesium bromide based on the following experiments:
Pd(OAc)2-catalyzed reaction of 1,2-dichlorobenzene with 2-mesi-
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