Synthesis of indenes via palladium-catalyzed carboannulation of diethyl 2-(2-(1-alkynyl)phenyl)malonate and organic halides

Article abstract of DOI:10.1021/jo0601361

Highly substituted indenes have been prepared in good yields by the palladium-catalyzed carboannulation of diethyl 2-(2-(1-alkynyl)phenyl)malonate with aryl, benzylic, and alkenyl halides. The reaction conditions and the scope of the process were examined, and a possible mechanism is proposed.

Full text of DOI:10.1021/jo0601361

SCHEME 1
SCHEME 2
Synthesis of Indenes via Palladium-Catalyzed
Carboannulation of Diethyl
2-(2-(1-alkynyl)phenyl)malonate and Organic
Halides
Li-Na Guo,† Xin-Hua Duan,† Hai-Peng Bi,†
Xue-Yuan Liu,† and Yong-Min Liang*,†,‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou
UniVersity, and State Key Laboratory of Solid Lubrication,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Science, Lanzhou 730000, People’s Republic of China
indenes by the palladium-catalyzed carboannulation of internal
alkynes with functionally substituted aryl halides (Scheme 1).6
The transition-metal-catalyzed cyclization of alkynes, which
possess nucleophilic centers in close proximity to the carbon-
carbon triple bond, by in situ coupling/cyclization reactions,7
and reactions promoted by vinylic, aryl, and alkynylpalladium
complexes,8 have also been shown to be extremely effective
for the synthesis of a wide variety of carbo- and heterocycles.
In our own laboratories, it has been demonstrated that palladium-
catalyzed annulation can be effectively employed for the
synthesis of furans.9 Herein, we wish to report that the
palladium-catalyzed annulation of diethyl 2-(2-(1-alkynyl)-
phenyl)malonate and a variety of organic halides offers an
efficient, direct route to highly substituted indenes (Scheme 2).
We started out our investigation of the reaction conditions
by using 1.0 equiv of diethyl 2-(2-(2-phenylethynyl)phenyl)-
malonate (1a; 0.2 mmol), 1.2 equiv of iodobenzene, 5 mol %
of Pd2(dba)3 as the catalyst, and 2.0 equiv of K2CO3 in DMF
as the solvent at 100 °C for 16 h under argon. The desired
product, diethyl 2,3-diphenyl-1H-indene-1,1-dicarboxylate (3aa)
was isolated in 36% yield. While using Pd(PPh3)4 as the catalyst,
the reaction afforded 3aa in 71% yield. We then screened
various bases using 1a and iodobenzene as the reactants and
Pd(PPh3)4 as the catalyst in DMF (Table 1). We found that K2-
CO3 was the most effective base (Table 1, entry 5). The use of
other inorganic bases such as K3PO4, KOAc, Cs2CO3, and KOt-
Bu failed to improve the yield of 3aa (Table 1, entries 3, 4, 6,
and 7). Triethylamine and tri-n-butylamine were ineffective
(Table 1, entries 1 and 2). The optimum reaction conditions
thus far developed employ 1.0 equiv of 1a, 1.2 equiv of the
liangym@lzu.edu.cn
ReceiVed January 21, 2006
Highly substituted indenes have been prepared in good yields
by the palladium-catalyzed carboannulation of diethyl 2-(2-
(1-alkynyl)phenyl)malonate with aryl, benzylic, and alkenyl
halides. The reaction conditions and the scope of the process
were examined, and a possible mechanism is proposed.
Indene derivatives, in particular, multiply-substituted ones,
have been attractive, and synthetically useful methods for their
synthesis have been developed.1 Among the most important
synthetic routes to such compounds are reduction/dehydration
of indanones,2 the cyclization of phenyl-substituted allylic
alcohols,3 and the ring expansion of substituted cyclopropenes.4
Recently, Gridnev et al. and Yamamoto et al. have reported
Pd-catalyzed or Pt-catalyzed intramolecular carbalkoxylation
reactions accompanied by an unprecedented 1,2-alkyl migration
to the synthesis of functionalized indenes.5 Very recently, Larock
et al. have reported a convenient method for the preparation of
(6) Zhang, D.; Yum, E. K.; Liu, Z.; Larock, R. C. Org. Lett. 2005, 7,
4963.
* Corresponding author. Fax: +86-931-8912582. Tel.: +86-931-8912593.
† Lanzhou University.
(7) For reviews, see: (a) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105,
2873. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104,
3079. For some recent examples, see: (c) Harmata, M.; Rayanil, K.-o.;
Gomes, M. G.; Zheng, P.; Calkins, N. L.; Kim, S.-Y.; Fan, Y.; Bumbu, V.;
Lee, D. R.; Wacharasindhu, S.; Hong, X. Org. Lett. 2005, 7, 143. (d) Roesch,
K. R.; Larock, R. C. Org. Lett. 1999, 1, 553. (e) Roesch, K. R.; Larock, R.
C. J. Org. Chem. 2002, 67, 86. (f) Zhang, H.; Larock, R. C. Org. Lett.
2001, 3, 3083. (g) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 7048.
(h) Kundu, N. G.; Khan, M. W. Tetrahedron. 2000, 56, 4777.
(8) For reviews, see: (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104,
2285. (b) Cacchi, S. J. Organomet. Chem. 1999, 576, 42 and references
therein. For some recent examples, see: (c) Bossharth, E.; Desbordes, P.;
Monteiro, N.; Balme, G. Org. Lett. 2003, 5, 2441. (d) Dai, G.; Larock, R.
C. Org. Lett. 2001, 3, 4035. (e) Dai, G.; Larock, R. C. J. Org. Chem. 2003,
68, 920. (f) Wei, L.-M.; Lin, C.-F.; Wu, M.-J. Tetrahedron Lett. 2000, 41,
1215.
‡ Chinese Academy of Science.
(1) (a) Xi, Z.; Guo, R.; Mito, S.; Yan, H.; Kanno, K.-i.; Nakajima, K.;
Takahashi, T. J. Org. Chem. 2003, 68, 1252 and references therein. (b)
Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. J. Am. Chem. Soc.
2000, 122, 7280. (c) Lautens, M.; Marquardt, T. J. Org. Chem. 2004, 69,
4607. (d) Chang, K.-J.; Rayabarapu, D. K.; Cheng, C.-H. J. Org. Chem.
2004, 69, 4781.
(2) (a) Prough, J.; Alberts, A.; Deanna, A.; Gilfillian, J.; Huff, R.; Smith,
J.; Wiggins, J. J. Med. Chem. 1990, 33, 758. (b) Ikeda, S.; Chatani, N.;
Kajikawa, Y.; Ohe, K.; Murai, S. J. Org. Chem. 1992, 57, 2. (c) Becker,
C.; McLaughlin, M. Synlett 1991, 642.
(3) Miller, W.; Pittman, C. J. Org. Chem. 1974, 39, 1955.
(4) Yoshida, H.; Kato, M.; Ogata, T. J. Org. Chem. 1985, 50, 1145.
(5) (a) Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.; Mizushima,
Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423. (b)
Nakamura, I.; Bajracharya, G. B.; Mizushima, Y.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2002, 41, 4328.
(9) Duan, X.-h.; Liu, X.-y.; Guo, L.-n.; Liao, M.-c.; Liu, W.-M.; Liang,
Y.-m. J. Org. Chem. 2005, 70, 6980.
10.1021/jo0601361 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/15/2006
J. Org. Chem. 2006, 71, 3325-3327
3325

TABLE 1. Effect of Base on the Reaction of 1a with Iodobenzenea
TABLE 3. Pd-Catalyzed Reaction of Diethyl
2-(2-(1-alkynyl)phenyl)malonate and Organic Halidesa
isolated yield of 3aab
entry
base
Et3N
(n-Bu)3N
K3PO4
(%)
1
2
3
4
5
6
7
no reaction
no reaction
15 (<2)
KOAc
20 (<2)
K2CO3
Cs2CO3
KOt-Bu
71 (<2)
66 (<2)
time
(h)
isolated yieldb
(%)
68 (<2)
entry
R1
3f
a All reactions were carried out using diethyl 2-(2-(2-phenylethynyl)phen-
yl)malonate (1a; 0.2 mmol), 1.2 equiv of iodobenzene, 5 mol % of Pd(PPh3)4
as the catalyst, and 2.0 equiv of base in DMF as the solvent at 100 °C for
16 h under argon. b The numbers in parentheses are the isolated yields of
the corresponding 2-substituted indene 4.
1
2
3
p-BrC6H4 (1b)
1-cyclohexenyl (1c)
n-pentyl (1d)
12
8
8
3bf
3cf
3df
60 (0)
67 (0)
70 (0)
a All reactions were carried out under the optimal conditions reported in
the text. b The numbers in parentheses are the isolated yields of the
corresponding 1,2-disubstituted indenes.
TABLE 2. Pd-Catalyzed Reaction of Diethyl
2-(2-(2-Phenylethynyl)phenyl)malonate and Organic Halidesa
alkynes 1a.10 Interestingly, the reactions of substrate 1a and
aryl iodides bearing an electron-withdrawing group or an
electron-donating group in the ortho position also led to good
yields of the desired 2,3-disubstituted indenes (Table 2, entries
10-13). Accordingly, steric hindrance did not appear to be a
major problem. 2-Iodothiophene also gave the indene 3an in
72% yield (Table 2, entry 14). In addition, the use of aryl
bromides also afforded desired products in good yields (Table
2, entries 15-18). But the reaction of aryl bromides were slower
than their corresponding aryl iodide counterparts. Benzylic
halides have also proven successful. For example, the reaction
of benzyl chloride produced a high 85% yield of the indene
product 3ao (Table 2, entry 19). Surprisingly, when a mixture
of â-bromostyrene (E/Z > 95:5) was employed in the reaction
with substrate 1a, no detectable amount of the Z-diethyl 2-
phenyl-3-styryl-1H-indene-1,1-dicarboxylate (3aq) was afforded,
but the E-styryl product was afforded in 70% yield (Table 2,
entry 20). We assumed that this was due to the isomerization
of the Z-styryl product to the corresponding trans isomer. To
prove this result, using â-bromostyrene (Z/E > 99:1) as
substrate, only the product containing the Z-styryl moiety was
isolated (Table 2, entry 21). The reason for this remained
unclear.11 However, when chlorobenzene was used as the
reactant, no desired product was observed.
We have also investigated the reactions of diethyl malonate
alkynes containing different R1 groups at the end of the triple
bond with an aryl iodide. With 4-iodoacetophenone, diethyl
malonate alkyne 1b was employed in the reaction (Table 3, entry
1), and the corresponding product, 3bf, was isolated in 60%
yield. Diethyl malonate alkyne 1c bearing a 1-cyclohexenyl
group afforded the corresponding 2,3-disubstituted indene 3cf
in a good yield of 67% (Table 3, entry 2). Diethyl malonate
alkyne 1d containing an n-pentyl group afforded the desired
product 3df in a 70% yield (Table 3, entry 3).
R2X
(2)
time
(h)
isolated
entry
R2 (3a)
Ph (3aa)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
PhI
16
16
24
10
6
6
6
6
6
71 (<2)
67 (3)
26 (5)
85 (0)
78 (0)
82 (0)
75 (<2)
82 (0)
p-CH3C6H4I
p-CH3OC6H4I
p-ClC6H4I
p-CH3C6H4 (3ab)
p-CH3OC6H4 (3ac)
p-ClC6H4 (3ad)
p-CNC6H4 (3ae)
p-CH3OCC6H4 (3af)
p-CH3O2CC6H4 (3ag)
p-NO2C6H4 (3ah)
p-CF3C6H4 (3ai)
o-CH3OCC6H4 (3aj)
o-NO2C6H4 (3ak)
o-CH3O2CC6H4 (3al)
o-CH3C6H4 (3am)
2-thienyl (3an)
p-CNC6H4I
p-CH3OCC6H4I
p-CH3O2CC6H4I
p-NO2C6H4I
p-CF3C6H4I
o-CH3OCC6H4I
o-NO2C6H4I
o-CH3O2CC6H4I
o-CH3C6H4I
2-iodothiophene
PhBr
p-CH3C6H4Br
p-CH3OCC6H4Br
p-NO2C6H4Br
benzyl chloride
â-bromostyrene
(E/Z > 95:5)
â-bromostyrene
(Z/E > 99:1)
87 (0)
8
8
8
65 (<2)
66 (<2)
72 (<2)
73 (0)
72 (<2)
67 (<2)
63 (<2)
77 (0)
12
12
24
24
12
12
12
16
Ph (3aa)
p-CH3C6H4 (3ab)
p-CH3OCC6H4 (3af)
p-NO2C6H4 (3ah)
benzyl (3ao)
80 (0)
85 (0)
70 (<2)
â-styryl (3ap)
(E/Z > 99:1)c
21
16
â-styryl (3aq)
73 (<2)
(Z/E > 99:1)c
a All reactions were carried out under the optimal conditions reported in
the text. b The numbers in parentheses are the isolated yields of the
corresponding 2-substituted indene 4. c The ratio was determined by 1H
NMR analysis of the product.
organic halide, 5 mol % of Pd(PPh3)4, and 2.0 equiv of K2CO3
in DMF at 100 °C.
Under the optimized reaction conditions above, the reactions
of 1a with a variety of aryl iodides afforded the corresponding
multiply-substituted indenes 3a in moderate to good yields
(Table 2, entries 1-13). Aryl iodides bearing an electron-
withdrawing group in the para position usually led to good to
high yields of the 2,3-disubstituted indenes (Table 2, entries
4-9). When 4-methyl-iodobenzene and 4-iodoanisole were
employed in the reaction with substrate 1a (Table 2, entries 2
and 3), the corresponding products 3ab and 3ac were isolated
in 67 and 26% yields along with low yields of the side product
diethyl 2-phenyl-1H-indene-1,1-dicarboxylate (4). Thus, strong
electron-rich aryl iodides gave poor results in this cyclization
chemistry. The 2-substituted indene 4 is believed to be formed
by the Pd(II)-catalyzed cyclization of the diethyl malonate
Meanwhile, diethyl malonate alkyne with different electron-
withdrawing groups, such as ethyl 2-(2-(2-phenylethynyl)-
phenyl)-2-(phenylsulfonyl)acetate (1e), has also been allowed
to react with 4-iodoacetophenone to afford a moderate yield of
the desired product 3ef (Scheme 3).
The mechanism shown in Scheme 4 is proposed for this
process. It consists of the following key steps: (1) oxidative
(10) Similar results were observed in a Pd-catalyzed coupling reaction,
see: ref 8d and ref 8e.
(11) A similar result was observed in a Pd-catalyzed coupling/cyclization
reaction, see: Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli, F.
Tetrahedron Lett. 1993, 34, 2813.
3326 J. Org. Chem., Vol. 71, No. 8, 2006

SCHEME 3
characterization of the starting material 1a-1e is described in the
Supporting Information. The preparation and characterization of
the other highly substituted indenes are included in Supporting
Information.
General Procedure for the Preparation of Substituted In-
denes. To a solution of diethyl 2-(2-(2-phenylethynyl)phenyl)-
malonate 1a (67.2 mg, 0.20 mmol) in DMF (2.0 mL) was added
K2CO3 (44.2 mg, 0.40 mmol). The mixture was stirred for 10 min
and Pd(PPh3)4 (11.5 mg, 0.01 mmol, 5 mol %) and organic halides
(0.24 mmol) was added. The resulting mixture was then heated
under an argon atmosphere at 100 °C. When the reaction was
considered complete, as determined by TLC analysis, the reaction
mixture was cooled to room temperature, quenched with a saturated
aqueous solution of ammonium chloride, and extracted with EtOAc.
The combined organic extracts were washed with water and
saturated brine. The organic layers were dried over Na2SO4 and
filtered. The solvents were evaporated under reduced pressure. The
residue was purified by chromatography on silica gel to afford the
corresponding 2,3-disubstituted indenes.
SCHEME 4
Diethyl 3-(4-methoxyphenyl)-2-phenyl-1H-indene-1,1-dicar-
boxylate, 3ac. The reaction mixture was chromatographed using
20:1 hexanes/EtOAc to afford 22.9 mg (26%) of the indicated
compound as a solid: mp 118-120 °C; 1H NMR (300 MHz,
CDCl3) δ 7.70-7.68 (d, J ) 6.9 Hz, 1H), 7.37-7.17 (m, 10H),
6.87-6.84 (d, J ) 8.7 Hz, 2H), 4.20-4.08 (m, 4H), 3.80 (s, 3H),
1.10-1.05 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 168.3, 159.0,
145.1, 144.3, 140.8, 139.7, 135.2, 130.8, 130.3, 128.6, 127.5, 127.1,
126.5, 126.4, 124.5, 121.2, 113.8, 72.6, 61.8, 55.1, 13.7; IR (KBr,
cm-1) 3450, 2927, 1730, 1511, 1464, 1247, 1041; HRMS (ESI)
calcd for C28H26O5 Na [M++ Na], 465.1672; found, 465.1668. Anal.
Calcd for C28H26O5: C, 76.00; H, 5.92. Found: C, 75.98; H, 6.08.
addition of the organic halide to the Pd(0) catalyst, (2)
coordination of the resulting palladium intermediate 5 to the
alkyne triple bond to form complex 6,8 (3) generation of a
carbanion by the base, (4) intramolecular nucleophilic attack
of the carbanion on the vinylic palladium intermediate to afford
a palladacyclic intermediate, 8,6 and (5) reductive elimination
of the intermediate to furnish the indene and regenerate the Pd-
(0) catalyst. If the diethyl malonate alkyne does not coordinate
well to the palladium(II) intermediate, 5, cyclization by Pd(II)
catalysis to the monosubstituted indene can occur.10 Therefore,
the selectivity between the mono- and disubstituted indenes is
determined by whether the triple bond of the diethyl malonate
alkyne coordinates the R2PdIIX intermediate, 5.
In conclusion, an efficient, palladium-catalyzed synthesis of
substituted indenes has been developed. A variety of aryl,
benzylic, and alkenyl halides undergo this process, giving the
desired products in moderate to good yields, particularly aryl
iodides with a substituted group in the ortho position, which
also produce the desired indenes.
Diethyl 3-(4-acetylphenyl)-2-phenyl-1H-indene-1,1-dicarboxy-
late, 3af. The reaction mixture was chromatographed using 20:1
hexanes/EtOAc to afford 74.5 mg (82%) of the indicated compound
as a solid: mp 143-145 °C; 1H NMR (300 MHz, CDCl3) δ 7.94-
7.91 (d, J ) 9.0 Hz, 2H), 7.73-7.70 (m, 1H), 7.45-7.43 (d, J )
8.1 Hz, 2H), 7.39-7.34 (m, 2H), 7.29-7.26 (m, 1H), 7.23-7.20
(m, 5H), 4.22-4.10 (m, 4H), 2.60 (s, 3H), 1.11-1.07 (t, J ) 7.2
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 197.7, 167.9, 144.3, 143.8,
141.8, 140.8, 139.3, 136.1, 134.5, 130.2, 129.8, 128.7, 128.4, 127.6,
127.5, 126.9, 124.7, 120.9, 72.9, 62.0, 26.6, 13.7; IR (KBr, cm-1
)
3451, 3351, 2983, 1730, 1684, 1464, 1362, 1248, 1046; HRMS
calcd for C29H27O5 [M + H]+, 455.1853; found, 455.1847. Anal.
Calcd for C29H26O5: C, 76.63; H, 5.77. Found: C, 76.47; H, 5.77.
For the characterization of the rest of the 2,3-disubstituted indenes,
see Supporting Information.
Acknowledgment. We thank the NSF (NSF-20021001,
NSF-20572038) and the “Hundred Scientist Program” from the
Chinese Academy of Sciences for financial support.
Supporting Information Available: Typical experimental
procedures and characterizations for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
Experimental Section
All reactions were performed under an argon atmosphere. Unless
otherwise stated, all aryl halides were purchased from commercial
suppliers and used without further purification. The preparation and
JO0601361
J. Org. Chem, Vol. 71, No. 8, 2006 3327