Synthesis of fused polycycles from propargylic compounds with terminal alkynes via a palladium-catalyzed tandem C-H activation/biscyclization process

Article abstract of DOI:10.1021/ol702311z

Various benzo[b]fluorene and fluorene derivatives have been prepared from propargylic compounds with terminal alkynes through a novel palladium-catalyzed tandem biscyclization reaction. This reaction involved a sequence of carboannulation, coupling, C-H a

Full text of DOI:10.1021/ol702311z

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5425-5428
Synthesis of Fused Polycycles from
Propargylic Compounds with Terminal
Alkynes via a Palladium-Catalyzed
Tandem C−H Activation/Biscyclization
Process
Li-Na Guo,† Xin-Hua Duan,† Xue-Yuan Liu,† Jie Hu,† Hai-Peng Bi,† and
Yong-Min Liang*,†,‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity, Lanzhou
730000, China, and State Key Laboratory of Solid Lubrication, Lanzhou Institute of
Chemical Physics, Chinese Academy of Science, Lanzhou 730000, P.R. China
liangym@lzu.edu.cn
Received September 24, 2007
ABSTRACT
Various benzo[b]fluorene and fluorene derivatives have been prepared from propargylic compounds with terminal alkynes through a novel
palladium-catalyzed tandem biscyclization reaction. This reaction involved a sequence of carboannulation, coupling, C H activation and C
bond formation process. A plausible mechanism has been proposed that was consistent with the deuterium-labeling experiment.
−
−C
Palladium-catalyzed C-C bond formation via C-H bond
activation is a highly attractive method in organic synthesis
since it can give the products directly from readily available
and unreactive starting materials without forming copious
amounts of byproducts.1 Recently, palladium-catalyzed tan-
dem cyclization involving C-H bond functionalization has
received considerable attention.2 However, most of those
transformations were initiated with aryl halides. To the best
of our knowledge, there has been no report on the tandem
biscyclization reaction involving C-H bond activation
initiated by propargylic compounds with terminal alkynes.3
Herein, we wish to report a novel palladium-catalyzed
tandem reaction involving a sequence of carboannulation,
Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 7460. (d) Huang,
Q.; Campo, M. A.; Yao, T.; Tian, Q.; Larock, R. C. J. Org. Chem. 2004,
69, 8251. (e) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004,
126, 14475. (f) Bour, C.; Suffert, J. Org. Lett. 2005, 7, 653. (g) Zhao, J.;
Larock, R. C. Org. Lett. 2005, 7, 701. (h) Ohno, H.; Miyamura, K.; Mizutani,
T.; Kadoh, Y.; Takeoka, Y.; Hamaguchi, H.; Tanaka, T. Chem. Eur. J.
2005, 11, 3728 and references therein. (i) Ohno, H.; Yamamoto, M.; Iuchi,
M.; Tanaka, T. Angew. Chem., Int. Ed. 2005, 44, 5103 and references
therein. (j) Pinto, A.; Neuville, L.; Retailleau, P.; Zhu, J. Org. Lett. 2006,
8, 4927 and references therein. (k) Ackermann, L.; Althammer, A. Angew.
Chem., Int. Ed. 2007, 46, 1627. (l) Pinto, A.; Neuville, L.; Zhu, J. Angew.
Chem., Int. Ed. 2007, 46, 3291. (m) Zhao, J.; Yue, D.; Campo, M. A.;
Larock, R. C. J. Am. Chem. Soc. 2007, 129, 5288.
† Lanzhou University.
‡ Lanzhou Institute of Chemical Physics.
(1) For recent reviews on C-H activation, see: (a) Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc.
Chem. Res. 2001, 34, 633. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
ReV. 2002, 102, 1731. (d) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002,
35, 826. (e) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077.
(f) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (g) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174.
(2) For some recent tandem processes involving C-H funtionalization,
see: (a) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J. Am.
Chem. Soc. 2003, 125, 11506. (b) Cuny, G.; Bois-Choussy, M.; Zhu, J.
Angew. Chem., Int. Ed. 2003, 42, 4774. (c) Huang, Q.; Fazio, A.; Dai, G.;
(3) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. 1995, 34, 2589.
10.1021/ol702311z CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/22/2007

C-H activation, coupling, and carbopalladium cyclization.
In this process, more than one carbon-carbon bond can be
formed, and polycyclic aromatic rings can also be constructed
in a one-pot manner.
Table 1. Tandem C-H Activation/Biscyclization Reaction of
Propargylic Compounds with Terminal Alkynesa
We initially focused on palladium-catalyzed cyclization/
coupling reaction of propargylic carbonate 1a and pheny-
lacetylene (2a) to synthesize the highly substituted indene 4
(Scheme 1).4,5 Surprisingly, when compound 1a was treated
Scheme 1
with 2a at 60 °C in DMF in the presence of Pd(PPh3)4 (5
mol %) and CuI (10 mol %), using Et3N as a base, the 2,3-
disubstituted indene 4 was isolated in only 6% yield, and an
unexpected diethyl 5-benzyl 11H-benzo[b]fluorene-11,11-
dicarboxylate (3aa) was obtained as a major product. The
formation of polycyclic compound 3aa shows that this
tandem reaction involved a novel C-H activation process
in which three carbon-carbon bonds and two carbocycles
were constructed. This result encouraged us to extend our
protocol to investigate this novel C-H activation reaction.
Consequently, we investigated the tandem cyclization reac-
tion of 1a and 2a under various conditions.6 Pd(PPh3)4/CuI
and Pd(OAc)2/PPh3/CuI proved to be the best catalysts. Pd2-
(dba)3·CHCl3/CuI were less effective. DMF turned out to be
a better solvent than THF and dioxane. As a base, Et3N gave
the best result. It is noteworthy that the reaction in the
absence of CuI resulted in a dramatic decrease in the yield
of 3aa.
To evaluate the scope of this C-H activation process, a
number of different substrates were examined (Table 1). The
reaction of 1a with various substituted terminal alkynes often
led to good yields of the polycyclic carbocycles (entries
1-5). The use of tetrahydropyranyl propargyl ether (2f) gave
the desired product in 67% yield (entry 6). Secondary
carbonates 1b-e possessing various substituents at the
propargylic position also worked well to give the desired
products in good to excellent yields (entries 7-10). Prop-
argylic carbonate 1f with different electron-withdrawing
groups also afforded the desired product 3fa in 30% yield
(entry 11). Propargylic acetate 1g has also proven successful
a Reaction conditions: 1 (1.0 equiv), 2 (2.0 equiv), Et3N (5.0 equiv),
Pd(OAc)2 (5 mol %), PPh3 (10 mol %), and CuI (10 mol %), in DMF, at
60 °C. b Isolated yield.
and gave a similar yield to 1a (entry 12). To our delight,
propargylic tertiary acetates 1h and 1i also afforded the
products 3ha and 3ia in moderate yields after longer reaction
times, perhaps due to steric hindrance (entries 13 and 14).7
In addition, a secondary propargyl acetate bearing a het-
eroaromatic substituent such as a furyl group also proceeded
well in this tandem reaction (entry 15).
Although the NMR spectroscopic data support the forma-
tion of polycyclic compounds 3, the structure was unambigu-
ously confirmed through an X-ray crystal structure analysis
of compound 3ca (Figure 1).8
(7) For propargylic tertiary carbonate, the nucleophile is inhibited from
attacking the 3-position of the indene; see ref 4a.
(4) (a) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M.
Org. Lett. 2006, 8, 5777. (b) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-
Y.; Liang, Y.-M. J. Org. Chem. 2007, 72, 1538.
(5) For the coupling reaction of propargylic compounds and terminal
alkynes, see: (a) Mandai, T.; Nakata, T.; Murayama, H.; Yamaoki, H.;
Ogawa, M.; Kawada, M.; Tsuji, J. Tetrahedron Lett. 1990, 31, 7179. (b)
Mandai, T.; Murayama, H.; Nakata, T.; Yamaoki, H.; Ogawa, M.; Kawada,
M.; Tsuji, J. J. Organomet. Chem. 1991, 417, 305. (c) Hayashi, M.; Saigo,
K. Tetrahedron Lett. 1997, 38, 6241. (d) Yoshida, M.; Hayashi, M.;
Shishido, K. Org. Lett. 2007, 9, 1643.
(8) Crystal data for 3ca have been deposited in CCDC as deposition
number 658187: C30H25ClO4, MW ) 484.14, T ) 294(2) K, λ ) 0.71073
Å, triclinic space group, P1, a ) 11.9038(10) Å, b ) 14.2082(12) Å, c )
16.4475(13) Å, R ) 73.5420(10)°, â ) 80.3940(10)°, γ ) 87.3350(10)°,
V ) 2630.4(4) Å3, Z ) 2, Dc ) 1.279 mg/m3, µ ) 0.182 mm-1, F(000) )
1062, crystal size 0.26 × 0.24 × 0.22 mm, independent reflections 9585
[R(int) ) 0.0274], reflections collected 13757, refinement method, full-
matrix least-squares on F2, goodness-of-fit on F2 1.555, final R indices [I
> 2σ(I)] R1 ) 0.1194, wR2 ) 0.0927, R indices (all date) R1 ) 0.0651,
wR2 ) 0.0833, extinction coefficient 0.0043(2), largest diff peak and hole
(6) Detailed results are listed in the Supporting Information.
0.641 and -0.548 e Å-3
.
5426
Org. Lett., Vol. 9, No. 26, 2007

Figure 1. Structure of 3ca.
Furthermore, secondary carbonates having a vinyl or a
styryl group such as 5a and 5b were also employed in this
reaction (Scheme 2). Satisfactorily, the hydrogen on the
simple double bond can also be activated under the above-
terms of the following steps: (a) cyclization of propargylic
carbonate under palladium catalysis to give the palladium
Scheme 3
Scheme 2
optimized conditions. The reaction proceeded smoothly to
give the 9H-fluorene derivatives 6aa and 6ba in 61% and
52% yields, respectively.
To study the mechanism of this C-H activation process,
labeled 1a-D5 was used as a modified substrate (Scheme 3).
When compound 1a-D5 was treated with 2a under the
conditions used above, 3aa-D5 was isolated in 81% yield.
complex 7,3,4 (b) intramolecular proton transfer of the
palladium complex 7 to form the palladacycle intermediate
8,2f (c) reaction of 8 with the copper acetylide to give
intermediate 9,2f (d) intramolecular coupling to generate
intermediate 10, and (e) intramolecular carbopalladium
cyclization of 10 to produce intermediate 11, followed by
reductive elimination and isomerization to furnish the desired
product and regenerate the Pd(0) catalyst. When the pal-
ladium complex 7 picks up an active hydrogen from the
nucleophilic moiety or the reaction system, and then couples
1
In the H NMR spectra of 3aa-D5, it was obvious that one
of the deuteriums in the ortho position of benzene-d5 has
been transferred to the benzyl position of the product. The
result indicated that there is an intramolecular proton transfer
in this C-H activation process.
A plausible mechanism for this new C-H activation
process is outlined in Scheme 4. It may be rationalized in
Org. Lett., Vol. 9, No. 26, 2007
5427

In conclusion, we have developed a novel tandem biscy-
clization reaction of propargylic compounds with terminal
alkynes, which afforded a simple and efficient route to
polycyclic aromatic compounds. This study has demonstrated
for the first time that propargylic compounds can initiate a
tandem biscyclization process involving a C-H functional-
ization of benzene, heteroaromatic rings, or simple C-C
double bonds in the presence of a palladium catalyst. Further
investigation on the scope and the mechanism of the reaction
is process.
Scheme 4
Acknowledgment. We thank the NSF (NSF-20621091,
NSF-20672049) and the “Hundred Scientist Program”
from the Chinese Academy of Sciences for financial
support.
Supporting Information Available: Typical experimen-
tal procedure and characterization for all products and X-ray
data of 3ca (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
with the copper acetylide directly, side product 4 can be
formed.
OL702311Z
5428
Org. Lett., Vol. 9, No. 26, 2007