Highly regioselective synthesis of benz[a]anthracene derivatives via a Pd-catalyzed tandem C-H activation/biscyclization reaction

Article abstract of DOI:10.1021/jo802712n

A palladium-catalyzed tandem C-H activation/biscyclization reaction of propargylic carbonates with terminal alkynes was determined, which allowed the tetracyclic benz[a]anthracene framework to be constructed with high regioselectivity. A possible mechanis

Full text of DOI:10.1021/jo802712n

SCHEME 1
Highly Regioselective Synthesis of
Benz[a]anthracene Derivatives via a Pd-Catalyzed
Tandem C-H Activation/Biscyclization Reaction
Zhi-Hui Ren, Zheng-Hui Guan, and Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou
UniVersity, Lanzhou 730000, People’s Republic of China
liangym@lzu.edu.cn
The activation of propargylic compounds with palladium
catalysts is well established for the construction of carbon-carbon
and carbon-heteroatom bonds.7 Recently, we have reported an
efficient tandem cyclization reaction for the synthesis of highly
substituted indenes8 and spirocyclic compounds9 from propar-
gylic compounds. Furthermore, when the cyclization was
performed in the presence of alkynes, the reaction underwent a
tandem C-H activation/biscyclization process affording fluorene
derivatives (Scheme 1).10 Very recently, Gevorgyan reported a
Pd-catalyzed hydroarylation of o-alkynyl biaryls proceeding via
direct aromatic C-H activation pathways.11 Thus we envisioned
that the analogues of compound 1, which differ from our
previous substrates I by one carbon elongation, may be used to
construct the tetracyclic skeleton of benz[a]anthracene via a
tandem C-H activation/biscyclization reaction.
However, the execution of the sequential steps in this
biscyclization reaction represents a formidable challenge for the
following two reasons: (1) formation of allenyl indene deriva-
tives from intramolecular carboannulation reaction is faster than
intermolecular coupling (Scheme 2)8b-d,9 and (2) subsequent
biscyclization products could not be obtained if the following
C-H activation process is not sufficiently fast. In this paper,
we present a palladium-catalyzed tandem C-H activation/
biscyclization reaction of propargylic carbonates with terminal
alkynes to offer an efficient and direct route to the tetracyclic
benz[a]anthracene framework. The mechanistic studies indicated
that this tandem C-H activation/biscyclization reaction proceeds
from a different pathway than reported in our previous paper.10
We first investigated the reaction of propargylic carbonate
1a with phenylacetylene 2a. To our delight, the desired
tetracyclic product 3aa was isolated in 78% yield when
Pd(OAc)2/PPh3 and CuI were used as the catalysts (Table 1,
entry 1). The structure of this product was unambiguously
ReceiVed December 10, 2008
A palladium-catalyzed tandem C-H activation/biscyclization
reaction of propargylic carbonates with terminal alkynes was
determined, which allowed the tetracyclic benz[a]anthracene
framework to be constructed with high regioselectivity. A
possible mechanism for this tandem C-H activation/biscy-
clization process was discussed.
Transition metal-catalyzed C-C bond formation via C-H
bond activation has been intensively investigated.1,2 Recently,
the palladium-catalyzed tandem cyclization involving C-H bond
functionalization has also received considerable attention be-
cause of the possibilities to construct complex structural motifs
from relatively simple starting materials.3 However, highly
selective intermolecular tandem reactions for the preparation
of polycyclic aromatic compounds via C-H bond activation
remain challenging.4-6
(1) (a) Chatani, N. Directed Metallation. In Topics in Organometallic
Chemistry; Springer: Berlin, Germany, 2007. (b) Handbook of C-H Transforma-
tions; Dyker, G., Ed.; Wiley-VCH: Weinheim, Germany, 2005.
(2) (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (b)
Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (c) Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698. (d) Shilov, A. E.; Shul’pin, G. B. Chem. ReV.
1997, 97, 2879.
(3) For some recent tandem processes involving C-H funtionalization, see:
(a) Zhao, J.; Yue, D.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2007,
129, 5288. (b) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006, 8,
4927. (c) Bour, C.; Suffert, J. Org. Lett. 2005, 7, 653. (d) Cuny, G.; Bois-Choussy,
M.; Zhu, J. J. Am. Chem. Soc. 2004, 126, 14475. (e) Huang, Q.; Fazio, A.; Dai,
G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460. (f) Campo,
M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J. Am. Chem. Soc. 2003,
125, 11506.
(6) (a) Bergman, R. G. Nature 2007, 446, 391. (b) Godula, K.; Sames, D.
Science 2006, 312, 67. (c) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507.
(7) For reviews on the palladium-catalyzed reactions of propargylic com-
pounds, see: (a) Tsuji, J. Palladium Reagents and Catalysis: InnoVation in
Organic Synthesis; John Wiley & Sons Ltd: Chichester, England, 2004; pp 543-
562. (b) Tsuji, J. Acc. Chem. Res. 1969, 2, 144.
(8) (a) Guan, Z.-H.; Ren, Z.-H.; Zhao, L.-B.; Liang, Y.-M. Org. Biomol.
Chem. 2008, 6, 1040. (b) Bi, H.-P.; Guo, L.-N.; Gou, F.-R.; Duan, X.-H.; Liu,
X.-Y.; Liang, Y.-M. J. Org. Chem. 2008, 73, 4713. (c) Gou, F.-R.; Bi, H.-P.;
Guo, L.-N.; Guan, Z.-H.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2008, 73,
3837. (d) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan, X.-H.; Liang,
Y.-M. Org. Lett. 2007, 9, 3527. (e) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu,
X.-Y.; Liang, Y.-M. J. Org. Chem. 2007, 72, 1538. (f) Duan, X.-H.; Guo, L.-
N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2006, 8, 5777.
(9) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.; Guo, L.-N.; Duan, X.-H.; Shu, X.-Z.;
Liang, Y.-M. Angew. Chem., Int. Ed. 2007, 46, 7068.
(4) (a) Miller, T. J. J. Topics in Organometallic Chemistry; Springer:
Heidelberg, Germany, 2006; pp 149-205. (b) Tietze, L. F.; Haunert, F. In
Stimulating Concepts in Chemistry; Wiley-VCH: Weinheim, Germany, 2000;
pp 39-64. (c) Ho, T.-L. Tandem Organic Reactions; Wiley-Interscience: New
York, 1992.
(5) (a) Carren˜o, M. C.; Urbano, A. Synlett 2005, 1. (b) Negishi, E.; Coperet,
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Chem. ReV. 1996, 96, 115.
(10) Guo, L.-N.; Duan, X.-H.; Liu, X.-Y.; Hu, J.; Bi, H.-P.; Liang, Y.-M.
Org. Lett. 2007, 9, 5425.
(11) Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 5636.
10.1021/jo802712n CCC: $40.75
Published on Web 03/13/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3145–3147 3145

TABLE 2. Palladium-Catalyzed Tandem C-H Activation/
SCHEME 2
Biscyclization of Propargylic Carbonates with Terminal Alkynesa
entry
1 (R1)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
2 (R2)
2a (C6H5)
3
yield (%)
1
2
3
4
5
6
7
8
9
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ba
3ca
3da
3ea
86
87
83
77
43
52
53
40
86
80
72
69
2b (p-ClC6H4)
2c (p-BrC6H4)
2d (p-MeOC6H4)
2e (n-propyl)
2f (n-pentyl)
2g (THPOCH2)
2h (PhCH2OCH2)
2a (C6H5)
1a (H)
TABLE 1. Optimization of the C-H Activation/Biscyclization
Reactiona
1b (p-CH3)
1c (p-Cl)
1d (p-Br)
1e (o-Cl)
10
11
12
2a (C6H5)
2a (C6H5)
2a (C6H5)
a Reaction conditions: 1 (0.2 mmol), 2 (2.0 equiv), Et3N (5.0 equiv),
Pd(OAc)2 (5 mol %), PPh3 (10 mol %), and CuI (10 mol %), in DMF (2
mL), at 60 °C for 2 h.
SCHEME 3
entry
catalyst
base
Et3N
Et3N
Et3N
solvent
yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2/PPh3, CuI
Pd(OAc)2/PPh3, CuI
Pd(OAc)2/PPh3, CuI
Pd(OAc)2/PPh3, CuI
Pd(OAc)2/PPh3, CuI
Pd(OAc)2/PPh3, CuI
Pd(PPh3)4, CuI
THF
78
86
51
DMF
CH3CN
toluene
DMF
DMF
DMF
DMF
DMF
DMF
Et3N
62
K2CO3
Cs2CO3
Et3N
Et3N
Et3N
58 (54)b
43 (40)b
81
5
Pd2(dba)3, CuI
Pd(OAc)2/PPh3
10
of 1a with various aryl alkynes often led to excellent yields of
the desired products (entries 1-4). In this transformation,
electron-deficient aryl alkynes showed more reactivity and gave
slightly higher yields than electron-rich aryl alkynes (entries
2-4). Aliphatic alkynes can also be used successfully in this
tandem C-H activation/biscyclization process, even with lower
yields (entries 5 and 6). Additionally, propargyl ethers were
tolerated in this reaction and 3ag-ah were given in moderate
yields (entries 7and 8). Secondary carbonates 1b-e possessing
various substituents at the propargylic position also worked well,
and gave good to excellent yields of the desired products,
respectively. In the reaction, secondary carbonates with electron-
rich arene substituents gave better results than those bearing
electron-deficient substrates (entries 9-12). Notably, the Cl and
Br groups on the aromatic substituents were tolerated in these
transformations and no cross-coupling side products were
observed (entries 10-12).13 In this manner, the resulting halide-
substituted products could be further expanded to a wider variety
of functionalized tetracyclic benz[a]anthracene derivatives by
undergoing cross-coupling reactions.
10
CuI
Et3N
nrc
a Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv), base (5.0
equiv), Pd (5 mol %), PPh3 (10 mol %), and CuI (10 mol %), in solvent
(2 mL), at 60 °C for 2 h. b 2.0 equiv of base was used. c No reaction.
established as the tetracyclic product 3aa by X-ray diffraction
analysis.12 Screening of reaction conditions showed that DMF
was better than THF for this reaction (entry 2). Other solvents,
such as CH3CN and toluene, gave relatively lower yields (entries
3 and 4). Changing the base from Et3N to K2CO3 or Cs2CO3
did not improve the yield of 3aa (entries 5 and 6). The
Pd(PPh3)4/CuI catalytic system was also effective for this
reaction (entry 7), but lower conversion was observed when
Pd2(dba)3/CuI was employed (entry 8). In the absence of CuI,
the reaction resulted in a dramatic decrease in the yield of 3aa
(enty 9). And no reaction occurred without the palladium catalyst
(entry 10). These results indicated that both Pd and CuI played
a crucial role in this transformation.
Having gained an understanding of the factors that influence
the biscyclization process, we have explored the scope of this
reaction. The results are summarized in Table 2. The reaction
Furthermore, secondary carbonate 1f possessing a styryl group
was also investigated (Scheme 3). The tandem reaction pro-
ceeded well to give the desired product 3fa in 50% yield.
However, the reactions of secondary carbonates, having a
propenyl group or an alkyl group such as ethyl and propyl,
resulted in a complex mixture.14
(12) Crystal data for 3aa: C31H28O4, MW ) 464.53, T ) 296(2) K, λ )
0.71073 Å, triclinic space group, P1, a ) 10.160(6) Å, b ) 23.332(14) Å, c )
10.763(6) Å, R ) 90.00°, ꢀ ) 110.534(9)°, γ ) 90.00 °, V ) 2390(2) Å3, Z )
4, Dc ) 1.291 mg/m3, µ ) 0.084 mm-1, F(000) ) 984, crystal size 0.24 × 0.23
× 0.20 mm3, independent reflections 5483 [R(int) ) 0.0298], reflections collected
13981; refinement method full-matrix least-squares on F2, goodness-of-fit on
F2 1.020, final R indices [I > 2σ(I)] R1 ) 0.0475, wR2 ) 0.1392, R indices (all
date) R1 ) 0.0704, wR2 ) 0.1582, largest difference peak and hole 0.243 and-
(13) Chinchilla, R.; Najera, C. Chem. ReV. 2007, 107, 874.
(14) The reasons for this difference in reactivity are unclear at this time and
are currently under investigation.
0.225 e Å-3
.
3146 J. Org. Chem. Vol. 74, No. 8, 2009

SCHEME 4
of five-membered indene derivative was in agreement with our
previous results.8b-d,9 The result indicated that path b was less
likely to be the operating mechanism. Next, deuterium labeled
1a-D5 was used as a modified substrate to distinguish between
paths c and d (Scheme 5, eq 2). When the reaction proceeded
though path d, one of the deuterium atoms in the ortho position
of benzene-d5 should be transferred completely to the benzyl
position of the product. However, product loss of deuterium
wasobservedinthebiscyclization.16Additionally,theFriedel-Crafts-
type electrophilic cyclization of intermediate E was considered
to be less likely based on the higher propensity of the electron-
deficient alkynes toward this cyclization reaction. So we
proposed that path c may be the most likely route to the product.
In conclusion, we have developed an efficient palladium-
catalyzed tandem C-H activation/biscyclization reaction of pro-
pargylic carbonates with terminal alkynes. In this process, three
carbon-carbon bonds were formed, and high regioselectivity was
achieved. The reaction provided an efficient route for construction
of the complex tetracyclic benz[a]anthracene derivatives. The
possible mechanism was discussed in detail in this paper.
Experimental Section
Typical Procedure for the Synthesis of Propargylic
Carbonates 1. Ethyl chloroformate (0.87 g, 8.0 mmol) was added
to a solution of propargylic alcohol (2.0 mmol), pyridine (0.63 g,
8.0 mmol), and DMAP (44.8 mg, 0.4 mmol) in CH2Cl2 (10 mL) at
0 °C. The reaction was quenched with H2O (30 mL) after being
stirred for 2 h at room temperature. Then, the solution was extracted
with CH2Cl2 (3 × 30 mL). The combined CH2Cl2 solution was
washed with a saturated aqueous copper sulfate solution followed
by concentration. The residue was purified by column chromatog-
raphy on silica gel to afford the corresponding propargylic
carbonates 1.
Typical Procedure for the Synthesis of Benz[a]anthracene
Derivatives 3. Pd(OAc)2 (2.2 mg, 0.01 mmol, 5 mol %), PPh3 (5.2
mg, 0.02 mmol, 10 mol %), and CuI (3.8 mg, 0.02 mmol, 10 mol
%) were added to a solution of propargylic carbonates 1 (0.20
mmol), terminal alkynes 2 (0.40 mmol), and Et3N (101.0 mg, 1.0
mmol) in DMF (2.0 mL) under an argon atmosphere. Then, the
reaction mixture was stirred at 60 °C for 2 h. When the reaction
was completed, the reaction was quenched with H2O (5 mL) and
extracted with EtOAc (3 × 5 mL). The combined organic layer
was dried over Na2SO4 followed by concentration. The residue was
purified by chromatography on silica gel to afford the corresponding
product 3.
SCHEME 5
Spectroscopic data for product 3aa: 80 mg, 0.17 mmol, 86%;
1
mp 132-134 °C; H NMR (400 MHz, CDCl3) δ 7.81-7.79 (d, J
) 8.4 Hz, 2H), 7.68 (s, 1H), 7.42-7.40 (m, 2H), 7.36-7.28 (m,
4H), 7.22-7.16 (m, 4H), 7.09-7.05 (m, 1H), 4.73 (s, 2H), 4.18
(s, 4H), 3.50 (s, 2H), 1.13 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
170.4, 141.6, 134.9, 134.5, 134.2, 133.3, 133.1, 132.6, 131.6, 128.7,
128.5, 128.4, 128.3, 127.6, 126.8, 126.5, 125.9, 125.8, 125.7, 124.7,
61.7, 61.5, 37.7, 37.1, 13.9; HRMS (ESI) calcd for C31H28O4 (M
+ Na) 487.1880, found (M + Na) 487.1894.
The plausible mechanism for this tandem biscyclization is
summarized in Scheme 4. The key intermediate E can be formed
by two different ways. Path a involves coupling of A with
copper(I) acetylide followed by carboannulation of B, while path
b involves carboannulation of A followed by coupling of C with
copper(I) acetylide.7-10,15 Following the intermediate E, the
desired product 3 could be formed via a C-H activation step
by path c or d (occurring either at Pd(0) or at Pd(II)).3,11
To gain insight into the mechanism, several experiments were
carried out. As depicted in Scheme 5 (eq 1), when diethyl
malonate was used as the nucleophile, the allene product 4 was
obtained exclusively in 85% yield. The regioselective formation
Acknowledgment. We thank the NSF (NSF-20872052) and
the “111 project” for financial support.
Supporting Information Available: Typical experimental
procedures and characterization for all products and X-ray data
of 3aa (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JO802712N
(16) Biscyclization of 1a-D5 produced 3aa-D5 in 80% yield with 34%
deuterium incorporated at the benzyl position (see the Supporting Information
for details).
(15) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. ReV. 2000,
100, 3067.
J. Org. Chem. Vol. 74, No. 8, 2009 3147