Synthesis of fluorene and indenofluorene compounds: Tandem palladium-catalyzed suzuki cross-coupling and cyclization

Article abstract of DOI:10.1002/anie.201000327

Figure Presented "Fluor" it: Palladium-catalyzed tandem reactions, in which C(sp³)-H bond activation is the key step (see scheme; DMA = dimethylacetamide), lead to substituted fluorenes and indenofluorenes through annulation in high yield and i

Full text of DOI:10.1002/anie.201000327

Angewandte
Chemie
DOI: 10.1002/anie.201000327
Tandem Reactions
Synthesis of Fluorene and Indenofluorene Compounds: Tandem
Palladium-Catalyzed Suzuki Cross-Coupling and Cyclization**
Tao-Ping Liu, Chun-Hui Xing, and Qiao-Sheng Hu*
Table 1: Palladium-catalyzed cyclization of 1,2-dibromobenzene with 2-methylphenylboronic acid.[a]
Palladium-catalyzed carbon–carbon
bond-forming reactions proceeding
À
through
a
C H bond activation
strategy have recently emerged as
useful tools in organic synthesis.[1,2]
In our laboratory, we have initiated a
program to explore new tandem
Entry
Catalyst
Base
Solvent
T
[8C]
Conv.
[%]
A/B/C[b]
reactions[3] in which C H bond acti-
À
1
2
3
4
5
6
7
8
[Pd2(dba)3]/tBu3P
[Pd2(dba)3]/tBu3P
[Pd2(dba)3]/tBu3P
[Pd2(dba)3]/tBu3P
Pd(OAc)2/tBu3P
Pd(OAc)2
K3PO4
K3PO4
K3PO4
K2CO3
K2CO3/tBuCO2H
K2CO3
K2CO3/tBuCO2H
K2CO3
KF
K3PO4
K2CO3/tBuCO2H
K2CO3/tBuCO2H
KF/tBuCO2H
CsF/tBuCO2H
KOAc/tBuCO2H
K2CO3/tBuCO2H
THF
80
67
83
70
66
<1
79.5
55
40
51.5
63
99
96
70
97
14
99
28:72:0
76:24:0
11:89:0
27:73:0[c]
–
56:44:0
73:27:0
65:18:17
29:22:9
42:56:2
0:6:94
vation is the key reaction compo-
nent. In this context, we have
recently documented palladium-cat-
alyzed tandem reactions of 1,2-diha-
lobenzenes with hindered Grignard
reagents to form 4-methylfluorenes
(Scheme 1), in which Grignard
reagents served as both cross-cou-
pling partners and bases.[4] Although
these new tandem reactions pro-
vided efficient access to substituted
fluorenes, there are noticeable draw-
backs associated with them; for
example, Grignard reagents are air
and moisture sensitive, and more
importantly, the formed substituted
toluene
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
110
140
140
140
140
140
140
140
140
140
140
140
140
140
140
Pd(OAc)2
Pd(OAc)2/PCy3
Pd(OAc)2/PPh3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PPh3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
9
10
11
12
13
14
15
16
74:26:0
34:4:62
0:45:55
91:9:0
0:12:88
[a] Reaction conditions: Dibromide (1.0 equiv), arylboronic acid (1.1 equiv), palladium catalyst
(3 mol%), base (6 equiv), solvent (2 mL). [b] Ratio based on GC–MS analysis of the reaction mixture.
[c] 1,2-Diarylbenzene was observed. DMA=dimethylacetamide, dba=dibenzylideneacetone.
fluorenes always bear
a methyl
group at the C4 position because
the tandem reactions only worked
Scheme 1. Palladium-catalyzed tandem reactions of hindered Grignard
reagents with o-dihalobenzenes.
Scheme 2. Double cross-couplings versus cross-coupling and cyclization pro-
3
À
ceeding through C(sp ) H bond activation.
well with 2,6-dimethylphenylmagnesium halides. On the basis
of our understanding of the reaction mechanism depicted in
Scheme 2, in which the cross-coupling of I with organome-
tallic reagents (path a) competes with the cyclization pro-
[*] Dr. T.-P. Liu, Dr. C.-H. Xing, Prof. Dr. Q.-S. Hu
Department of Chemistry, College of Staten Island and
the Graduate Center of the City University of New York
Staten Island, New York, 10314 (USA)
Fax: (+1)718-872-3910
E-mail: qiaosheng.hu@csi.cuny.edu
À
ceeding through a C H activation process (path b), we
speculated that the requirement of the use of 2,6-dimethyl-
phenylmagnesium halides might result from the fast cross-
coupling of Grignard reagents with aryl halides. Therefore, we
wondered whether the use of less nucleophilic coupling
reagents, such as arylboronic acids, could circumvent this
drawback. In addition, arylboronic acids, which have been
demonstrated to be excellent cross-coupling reagents in
[**] We gratefully thank the NSF (CHE0719311 and CHE0911533) for
funding. Partial support from the PSC-CUNY Research Award
Programs is also acknowledged. We thank Frontier Scientific for its
generous gifts of Pd(OAc)2, arylboronic acids, and 1-bromo-2-
iodobenzene.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000327.
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Suzuki coupling reactions,[5] are readily available, air
Table 2: Palladium-catalyzed tandem reactions of 1,2-dihalobenzenes with 2-
methylphenylboronic acids.[a]
and moisture stable, and functional-group compat-
ible. Herein, we describe our results from our
investigation into Pd(OAc)2/PCy3-catalyzed tandem
reactions of 1,2-halobenzenes with 2-methylphenyl-
boronic acids to access substituted fluorenes and
indenofluorenes.[6–8]
Entry Dihalide
Boronic acid
Fluorene
Yield
[%][b]
We anticipated that the challenge to realize a
tandem Suzuki cross-coupling and cyclization pro-
1
2
3
4
5
6
91
À
ceeding through C H activation would require ach-
À
ieving the C H activation (Scheme 2; path b) while
78
minimizing double Suzuki cross-coupling reaction
(Scheme 2; path a). We reasoned that factors includ-
ing ligand, base, and reaction temperature would
influence the interaction of the PdII center of
92
À
intermediate I with the C H bond and impact the
81.5
90
3
À
cyclization proceeding through C(sp ) H bond acti-
vation. The bases used for the Suzuki cross-coupling
reaction are typically inorganic bases such as K3PO4,
KF, and K2CO3, which are not strong enough to
remove a proton on an sp3-hybridized carbon atom at
room temperature. These bases are typically used at
55[c]
À
7
85.5
84
elevated reaction temperatures for C H activation
processes.[1,2] We began by examining the tandem
reaction of 1,2-dibromobenzene with 2-methylphe-
nylboronic acid at elevated reaction temperatures.
We found that with a [Pd2(dba)3]/tBu3P catalyst
system, which has been demonstrated to be an
excellent catalyst for the tandem cross-coupling and
cyclization with hindered Grignard reagents as reac-
tion partners,[4a] no cyclization product was observed,
even with K2CO3/tBuCO2H as the base[9] at 1408C
(Table 1, entries 1–5). These results suggested that
tBu3P was not an effective ligand for the tandem
Suzuki cross-coupling and cyclization reaction. Fur-
thermore, testing revealed that by using Pd(OAc)2/
PCy3 as the catalyst and K2CO3/tBuCO2H as the base,
excellent yields of the desired cyclization product,
fluorene, were observed (Table 1, entries 7–12). A
screening of bases showed that Cs2CO3/tBuCO2H was
also effective (Table 1, entries 13–16). Therefore, by
using Pd(OAc)2/PCy3 as the catalyst and M2CO3/
tBuCO2H (M = K, Cs) as the base, it was possible to
8
9
79
10
11
74
81
12
13
14
93
96
83
(>99:1)[d]
(>99:1)[d]
(97:3)[d]
[a] Reaction conditions (not optimized): Dihalide (1.0 equiv), arylboronic acid
(1.1 equiv), 3 mol% Pd(OAc)2, 6 mol% PCy3, tBuCO2H (1 equiv), K2CO3 (6 equiv),
DMA (2 mL), 140–1508C, 5 h. [b] Yields of isolated products. [c] 5 mol% Pd-
(OAc)2, 10 mol% PCy3, tBuCO2H (2 equiv) at 308C for 4 h. [d] Ratio based on
1H NMR analysis.
realize the tandem Suzuki cross-coupling and cycli-
zation proceeding through C H activation.
Having established the feasibility of the tandem
reaction sequence, we next examined the tandem
[10,11]
À
reaction using other 1,2-dihalobenzenes and other 2-methyl-
phenylboronic acids (Table 2). We found that various 1,2-
dihalobenzenes including 1-bromo-2-iodobenzene, 1,2-dibro-
mobenzenes, 1-bromo-2-chlorobenzene, and 1,2-dichloroben-
zene all afforded the cyclization products in good to high
yields (Table 2, entries 1–9). Reaction of unsymmetrical 3-
bromo-4-chlorotoluene and 4-chloro3-iodotoluene with 2-
methyphenylboronic acids afforded predominantly 3-methyl-
fluorene (> 97%). The observation of 2-chloro-2’-methylbi-
phenyls as intermediates in these reactions suggested that the
tandem reaction occurred through cross-coupling and sub-
sequent cyclization as depicted in path b of Scheme 1.[12]
The excellent regioselectivity observed for 3-bromo-4-
chlorotoluene (Table 2, entries 10 and 11) implied that this
tandem reaction protocol could be extended for the prepa-
ration of other planar fluorene-related analogues such as
indenofluorenes. Therefore, when 1,4-dibromo-2,5-dichloro-
toluene was used as the starting material, indenofluorenes
could be obtained in good yields (Scheme 2). In addition, we
also accomplished the preparation of indenofluorene II, using
3-bromo-4-chlorotoluene as the starting material, through an
iterative tandem Suzuki cross-coupling and cyclization pro-
cess (Scheme 3).
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Chemie
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Scheme 3. Indenofluorene preparation by palladium-catalyzed tandem
Suzuki coupling and cyclization.
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In summary, we have demonstrated that tandem Suzuki
3
À
cross-coupling and cyclization proceeding through C(sp ) H
bond activation for 1,2-dihalobenzenes with 2-methylphenyl-
bronic acids could be efficiently achieved by employing
Pd(OAc)2/PCy3 as the catalyst system. This ring-forming
reaction overcame the drawbacks associated with the use of
Grignard reagents as reaction partners and allows efficient
access to a broad spectrum of potentially useful substituted
fluorenes and indenofluorenes. Our study has suggested that
other ladder-type fluorene-based analogues could be accessed
through an iterative approach, and work towards this is
underway.
[6] Fluorenes are typically prepared in more than one step. For
examples, see: a) I. A. Kashulin, I. E. Nifant’ev, J. Org. Chem.
2004, 69, 5476 – 5479; b) R. A. Abramovitch, T. Chellathurai,
I. T. McMaster, T. Takaya, C. I. Azogu, D. P. Vanderpool, J. Org.
Chem. 1977, 42, 2914 – 2919.
Experimental Section
General procedure for Pd(OAc)2/PCy3-catalyzed tandem Suzuki
coupling reactions of 2-methylarylboronic acids with o-dihaloben-
zenes: DMA (2 mL) was added to a vial containing o-dihalobenzene
(0.5 mmol), 2-methylarylboronic acid (0.55 mmol), K2CO3 (3 mmol),
À
[7] Synthesis of fluorenes through C H activation of halobiphenyls
has been reported: a) S. J. Hwang, H. J. Kim, S. Chang, Org. Lett.
2009, 11, 4588 – 4591; b) S. J. Hwang, S. H. Cho, S. Chang, J. Am.
Chem. Soc. 2008, 130, 16158 – 16159; c) K. Fuchibe, T. Akiyama,
J. Am. Chem. Soc. 2006, 128, 1434 – 1435. Also see: Y.-B. Zhao,
D. A. Mariampillai, B. Candito, M. Laleu, Li, M. Lautens,
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2009, 48, 1849 – 1852.
palladium(II)
acetate
(0.015 mmol),
tricyclohexylphosphine
(0.03 mmol), and trimethylacetic acid (0.5 mmol). After the reaction
mixture had been stirred at 140–1508C for 5 h, the mixture was cooled
down to room temperature. The reaction mixture was quenched by
adding water. The mixture was extracted with CH2Cl2. The organic
layer was washed with brine. After removal of the solvents the crude
reaction mixture was purified by column chromatography on silica gel
with hexanes as the eluent to afford the desired fluorene or
indenofluorene products.
[8] Fluorene- and indenofluorene-based molecules including poly-
mers have been established as promising sensors and light-
emitting materials. For examples: a) T.-C. Lin, C.-S. Hsu, C.-L.
Hu, Y.-F. Chen, W.-J. Huang, Tetrahedron Lett. 2009, 50, 182 –
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K. R. Carter, J. Am. Chem. Soc. 2001, 123, 6965 – 6972.
Received: January 19, 2010
Published online: March 19, 2010
À
Keywords: C H bond activation · cross-coupling · fluorenes ·
palladium · tandem reaction
.
[9] K2CO3/tBuCO2H has been established as a very effective base
À
system for bond formations by C H activation: a) M. Lafran-
À
[1] Recent reviews on C H activation: a) X. Chen, K. M. Engle, D.-
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Hutchby, C. D. Bailey, J. G. Ford, S. N. G. Tyler, M. R. Gagnꢀ,
[10] For examples on palladium-catalyzed tandem cross-coupling and
2
À
cyclization proceeding through aromatic C(sp ) H bond activa-
tion: a) L.-C. Campeau, M. Parisien, M. Leblanc, K. Fagnou, J.
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Communications
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[12] Two isomeric products in an almost 1:1 ratio were always
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Zhang, R. C. Larock, J. Am. Chem. Soc. 2005, 127, 15716 – 15717.
Also see Ref. [4b].
[11] For examples of palladium-catalyzed cyclization proceeding
3
À
through C(sp ) H activation: a) E. M. Ferreira, B. M. Stoltz, J.
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