Efficient construction of five-membered aromatic and nonaromatic heterocycles from 1,6-enynes by a palladium-catalyzed domino coupling/cycloisomerization process

Article abstract of DOI:10.1021/jo9020776

(Chemical Equation Presented) General and efficient methods for the construction of five-membered aromatic and nonaromatic heterocycles by palladium-catalyzed coupling/cycloisomerization of 1,6-enynes and aryl halides have been developed. Results indicate that substituents at the terminus of the alkynes have a significant effect on the selective formation of the products.

Full text of DOI:10.1021/jo9020776

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Efficient Construction of Five-Membered Aromatic and Nonaromatic
Heterocycles from 1,6-Enynes by a Palladium-Catalyzed Domino
Coupling/Cycloisomerization Process
Tuan-jie Meng,† Yimin Hu,*,† and Shaowu Wang*,†,‡
†Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based
Materials, Institute of Organic Chemistry, School of Chemistry and Materials Science, Anhui Normal
University, Wuhu, Anhui 241000, China and ‡State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Shanghai 200032, China
yiminhu@mail.ahnu.edu.cn; swwang@mail.ahnu.edu.cn
Received September 25, 2009
General and efficient methods for the construction of five-membered aromatic and nonaromatic
heterocycles by palladium-catalyzed coupling/cycloisomerization of 1,6-enynes and aryl halides have
been developed. Results indicate that substituents at the terminus of the alkynes have a significant
effect on the selective formation of the products.
Introduction
Palladium-catalyzed cyclization reactions of enynes and
coupling with other synthetic units have been reported, such
as CO (Pauson-Khand reaction),3 aryl boronic acids,4
bimetallic reagents,5 hydrides,6 and acetic acid.7 These can
be separated into those that form a π-allyl palladium inter-
mediate previous to the enyne cyclization4 and those that
“trap” the alkenylpalladium product of the enyne cycli-
zation.3,5-7 Furthermore, alkenylrhodium compounds are
important intermediates in coupling/cyclization reactions of
acetylenic compounds with organometallic reagents because
of the mild reaction conditions.8 Despite the extensive
Five-membered heterocycles are important synthetic tar-
gets as a result of their occurrence in numerous natural
products, their important roles in diverse living processes,
and their utility as versatile intermediates.1 As a conse-
quence, the development of synthetic routes for the con-
struction of these heterocycles has been a major research
objective for decades. Although several general approaches
are presently available, the search for new methodologies
proceeding more efficiently and involving readily available
starting materials still remains an important area of research.
Recently, there has been much attention focused on the
transformations of enynes catalyzed by transition metals for
the syntheses of potentially important heterocyclic com-
pounds.2 Palladium is the most versatile catalyst among
the transition metals used in enyne cyclization reactions.
(3) (a) Tang, Y.; Deng, L.; Zhang, Y.; Dong, G.; Chen, J.; Yang, Z. Org.
Lett. 2005, 7, 1657. (b) Deng, L.; Liu, J.; Huang, J.; Hu, Y.; Chen, M.; Lan,
Y.; Chen, J.; Lei, A.; Yang, Z. Synthesis 2007, 2565.
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C. H.; Lim, Y. M. Tetrahedron Lett. 2003, 44, 267.
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Wakamatsu, H.; Mori, M. J. Organomet. Chem. 2003, 687, 392. (c) Onozawa,
S.-Y.; Hatanaka, Y.; Choi, N.; Tanaka, M. Organometallics 1997, 16, 5389.
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S.; Shimamoto, T.; Chimori, M.; Yamamoto, K. Chem. Lett. 2005, 34, 160.
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Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604. (c) Lu, X.; Zhang, Q. Pure
Appl. Chem. 2001, 73, 247.
(1) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
1984; Vol. 4. (c) Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, 1997; Vol. 2. (d)
Comprehensive Heterocyclic Chemistry III; Katritzky, A. R., Taylor, R. J. K.,
Ramsden, C. A., Scriven, E. F. V., Eds.; Elsevier: Oxford, 2008; Vol. 3.
(2) (a) Fairlamb, I. J. S. Angew. Chem., Int. Ed. 2004, 43, 1048. (b) Zhang,
Z.; Zhu, G.; Tong, X.; Wang, F.; Xie, X.; Wang, J.; Jiang, L. Curr. Org.
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Chem. 2006, 10, 1457. (c) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew.
Chem., Int. Ed. 2008, 47, 4268. (d) Diver, S. T.; Giessert, A. J. Chem. Rev.
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Chem. Soc. 2001, 123, 9918. (b) Shintani, R.; Yamagami, T.; Hayashi, T. Org.
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J. Am. Chem. Soc. 2005, 127, 1094. (e) Miura, T.; Sasaki, T.; Nakazawa, H.;
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ꢀ
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Echavarren, A. M. Chem.;Eur. J. 2006, 12, 5916. (f ) Bruneau, C. Angew.
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582 J. Org. Chem. 2010, 75, 582–588
Published on Web 12/23/2009
DOI: 10.1021/jo9020776
r
2009 American Chemical Society

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TABLE 1. Palladium-Catalyzed Reaction for Construction of the Heterocyclesa
entry
[Pd] (mol %)
base (equiv)
solvent
time (h)
temp (°C)b
yield (%)c
1
2
3
4
5
6
7
8
[Pd(OAc)2]/PPh3 (1:2)
[Pd(OAc)2]/PPh3 (3:6)
[Pd(OAc)2]/PPh3 (3:6)
[Pd(OAc)2]/PPh3 (3:6)
[Pd(OAc)2]/PPh3 (3:6)
[Pd(OAc)2]/PPh3 (3:6)
[Pd(OAc)2]/PPh3 (3:6)
[Pd(OAc)2]/PPh3 (3:6)
[Pd(OAc)2]/PPh3 (2:4)
[Pd(dba)2] (2)
(n-Bu)3N (2)
(n-Bu)3N (2)
(n-Bu)3N (2)
(n-Bu)3N (2)
(n-Bu)3N (2)
K2CO3 (2)
(n-Bu)3N (2)
(n-Bu)3N (2)
(n-Bu)3N (2)
(n-Bu)3N (2)
(n-Bu)3N (2)
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
toluene
DMF
DMF
DMF
15
20
20
18
20
20
22
20
20
25
20
100
120
130
140
150
140
100
130
140
140
140
0
15
45
75
75
7
0
20
63
12
17
9
10
11
[Pd(PPh3)4] (2)
aAll reactions were carried out under argon using 1 (1.0 equiv), ethyl 4-bromobenzoate (1.2 equiv), Pd(OAc)2 (3 mol %), PPh3, base, and solvent
(5 mL) at indicated temperature. bOil bath temperature. cIsolated yield.
precedent on five-membered heterocycle syntheses,2 palladium-
catalyzed cyclization and coupling of enynes with aryl halides
has been less explored. In continuing our studies on 1,6-diene
compounds,9 we found that the cyclization reactions between
1,6-enynes and aryl bromides proceeded by a different pathway
to give unexpected cyclic products. Herein we wish to report
the palladium-catalyzed cyclization between enynes and aryl
bromides to form five-membered heterocycles.
in a decrease of product yields from 75% to 63% (Table 1,
entries 5 and 9). Other palladium catalysts such as Pd(dba)2 and
Pd(PPh3)4 exhibited catalytic activity lower than that of Pd-
(OAc)2 with regard to the isolated yields of the product (Table 1,
entries 10 and 11). The optimized reaction conditions use Pd-
(OAc)2 (3 mol %) as the catalyst, PPh3 (6 mol %) as the ligand,
tributylamine as a base, DMF as the solvent, 20 h for the reaction
time, and 140 °C for the reaction temperature. These conditions
were used in the following studies unless otherwise noted.
With the optimized conditions in hand, we then examined the
scope and limitations of this methodology. The reactions of
substrates N-allyl-4-methyl-N-(3-phenylprop-2-ynyl)benzene-
sulfonamide (1) and (3-(allyloxy)prop-1-ynyl)benzene (2) with
a number of aryl halides were performed, and the results are
compiled in Table 2. It was found that the reaction of the aryl
halides having electron-withdrawing groups, such as methox-
ycarbonyl, formyl, chloro, sulfonyl, cyano, and acetyl, with 1 or
2 gave the five-membered aromatic heterocycles in moderate to
good yields. In general, higher yields of the five-membered
aromatic heterocycles were obtained when the benzene ring of
the aryl halide was more electronic-deficient. As a consequence,
the reaction of 1 with 1-bromo-4-chlorobenzene gave the
product in 43% yield (entry 5), while the reaction of 1 with
4-bromophenyl methyl sulfone or 4-bromobenzonitrile gave the
corresponding products in 76% and 80% yield, respectively
(entries 7 and 8). However, the corresponding five-membered
aromatic heterocycles were not isolated when aryl halides such
as 4-bromotoluene and 1-bromo-4-methoxybenzene, which
incorporated electron-donating substituents on the benzene
ring, reacted with either 1 or 2. Instead unidentified products
were detected, indicating that the electronic properties of the
aryl halides have a strong effect on the reaction.
Results and Discussion
The reaction conditions using N-allyl-4-methyl-N-(3-phe-
nylprop-2-ynyl)benzenesulfonamide (1) and ethyl 4-bromo-
benzoate as representative substrates in the presence of a
catalytic palladium system was surveyed (Table 1). No desired
product was observed when the reaction was performed at
100 °C, and most of the staring material remained unchanged
(Table 1, entry 1). The product 1a could be obtained in 75%
yield when the reaction temperature was raised to 140 °C
(Table 1, entry 4) in the presence of 3 mol % of Pd(OAc)2, 6
mol % of PPh3, and 2 equiv of base (nBu)3N. However, no
significant increase in the yield of product 1a was observed as
the reaction temperature was raised from 140 to 150 °C
(Table 1, entries 4 and 5). Therefore, the reaction temperature
was fixed at 140 °C for subsequent experiments. The base
additive plays an important role in the overall efficiency of the
reaction; we discovered that the isolated yields of 1a dropped
from 75% to 7% when the base was changed from tributyla-
mine to potassium carbonate. (Table 1, entries 5 and 6).
Different organic solvents, such as CH3CN, toluene, and
DMF, were tested in the synthesis of 1a under the standard
conditions (140 °C, 3 mol % Pd(OAc)2, 6 mol % PPh3, 2 equiv
of (nBu)3N). As shown in Table 1 (entries 5, 7, and 8), we can
see that the best results were obtained in DMF. Further
lowering of the catalyst loadings from 3 to 2 mol % resulted
To further broaden the scope of this reaction, we tested re-
actions of N-allyl-4-methyl-N-(but-2-ynyl)benzenesulfonamide
(3) with aryl halides under the aforementioned conditions.
The reactions also proceeded smoothly; however, the desired
1,3,4-substituted pyrroles were not isolated. Instead, a series of
1,3,4-substituted 3-pyrrolines were obtained in good yields
(9) (a) Hu, Y. M.; Yu, C. L.; Ren, D.; Hu, Q.; Zhang, L. D.; Cheng, D.
Angew. Chem., Int. Ed. 2009, 48, 5448. (b) Hu, Y. M.; Ouyang, Y.; Qu, Y.;
Hu, Q.; Yao, H. Chem. Commun. 2009, 4575. (c) Hu, Y. M.; Song, F. F.; Wu,
F. H.; Cheng, D.; Wang, S. Chem.;Eur. J. 2008, 14, 3110.
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TABLE 2. Synthesis of Five-Membered Aromatic Heterocyclesa
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TABLE 2. Continued
aReaction conditions: 3 mol % Pd(OAc)2, 6 mol % PPh3, 2 equiv of n-Bu3N, 1.2 equiv of ArX, DMF, 140 °C, in an atmosphere of argon. bIsolated
yields.
SCHEME 1. Proposed Mechanistic Pathways for the Formation of Different Heterocyclic Compounds
(Table 3, entries 1-7). Similarly, reactions of N-allyl-N-ben-
zylbut-2-ynamide (4) led to the 1,3,4-substituted 3-pyrroline-2-
ones in good yields at lower temperatures and shorter reaction
times (Table 3, entries 9-15). Again, reactions of 4 with aryl
halides having electron-withdrawing groups led to the desired
product in higher yields, whereas reactions of 4 with aryl
halides having electron-donating groups did not afford the
products. Reaction of 4 with bromobenzene gave a much
lower yield of the product than aryl halides having electron-
withdrawing groups (entries 8 and 16). When aryl halides with
bothC-BrandC-Clbonds onthe benzene ring were reacted,
the C-Br bond coupled selectively with the 1,6-enynes
(entries 5, 13, and 14).
All the resulting heterocyclic compounds were confirmed
1
by H NMR, 13C NMR, and HR-MS analyses. The repre-
sentative compounds of 1h was additionally characterized by
X-ray crystallography analysis.10
Mechanism. On the basis of the above observations, plau-
sible mechanisms for the selective formation of five-mem-
bered aromatic heterocycles and nonaromatic heterocycles
are proposed in Scheme 1. Different substituents at the
terminus of the alkynes give rise to the formation of different
products. (1) When the terminus was a phenyl group, inser-
tion of arylpalladium(II) halide into an alkyne moiety pro-
duced the intermediate 5, which then reacted with the
carbon-carbon double bond through a carbopalladation
reaction to afford 6. After β-elimination, 6 produced HPdBr
and 7, which then led to five-membered aromatic hetero-
cycles through isomerization of exocyclic double bonds. A
reductive elimination assisted by tributylamine regene-
rated Pd(0). (2) When the terminus alkyne bore a methyl
(10) (a) Sheldrick, G. M. SHELXL97, Program for Crystal Structure
€
€
Refinement; University of Gottingen: Gottingen, Germany, 1997. (b) Sheldrick,
G. M. SHELXS97, Program for Crystal Structure Refinement; University of
€
€
Gottingen: Gottingen, Germany, 1997. (c) Sheldrick, G. M. Acta Crystallogr. A
1990, 46, 467.
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TABLE 3. Synthesis of Five-Membered Nonaromatic Heterocyclesa
586 J. Org. Chem. Vol. 75, No. 3, 2010

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TABLE 3. Continued
aReaction conditions: 3 mol % Pd(OAc)2, 6 mol % PPh3, 2 equiv of n-Bu3N, 1.2 equiv of ArX, DMF, 140 °C in an atmosphere of argon. bIsolated
yields. c120 °C, 4 h.
group, the carbon-carbon triple bond isomerizated to give
intermediate 8,11 which inserted to the Ar-Pd bond and led
to π-allyl palladium intermediate 9. Then another carbon-
carbon double bond inserted to the C-Pd bond of 9 to afford
intermediate 10, which gave intermediate 11 via classical β-H
elimination. Five-membered nonaromatic heterocycles were
obtained through isomerization of carbon-carbon double
bond of 11. To provide evidence for the mechanism via
intermediate 8, the reaction of N-allyl-4-methyl-N-(but-2,3-
dien)benzenesulfonamide with ethyl 4-bromobenzoate un-
der the same conditions was examined, and 1a was obtained
in 15% yield. The yield is lower, most probably because of
the polymerization of N-allyl-4-methyl-N-(but-2,3-dien)-
benzenesulfonamide at high temperature.12 Other possible
reaction pathways cannot be ruled out.
This process provides a new and general methodology for
the synthesis of aromatic and nonaromatic heterocycle deri-
vatives from 1,6-enynes by changing substituents at the
terminus of the alkynes. The results obtained demonstrated
that multiple carbon-carbon bond-forming processes can
operate with a single catalytic system using palladium.
Further studies into the scope, mechanism, and synthetic
application of this reaction are being carried out in our
laboratory.
Experimental Section
Typical Procedure for the Palladium-Catalyzed Cyclization
Reaction of 1,6-Dienynes with Aryl Halides. Enyne 1 (1.0 equiv),
4-bromobenzonitrile (1.2 equiv), Pd(OAc)2 (3 mol %), and PPh3
(6 mol %) were added to a degassed solution of (nBu)3N
(2 equiv) in DMF (5 mL), and the mixture was stirred at room
temperature for 0.5 h and then heated at 140 °C for 20 h. The
reaction mixture was then cooled, quenched with water, and
extracted with ethyl acetate (2 Â 10 mL). The combined organic
layers were washed with hydrochloric acid (5%, 20 mL), sodium
carbonate (5%, 20 mL), and saturated sodium chloride solution,
dried over MgSO4, and concentrated. The residue wes purified
by flash column chromatography on a silica gel eluting with
Conclusion
We present an efficient method for the synthesis of five-
membered heterocycles by treatment of readily available 1,
6-enynes with aryl halides bearing electron-withdrawing
substituents via a domino coupling/cycloisomerization pro-
cess in the presence of a catalytic amount of palladium cata-
lyst. The electron-withdrawing groups could be methoxy-
carbonyl, formyl, chloro, sulfonyl, cyano, and acetyl.
1
petroleum ether and ethyl acetate to give 1h (80%). H NMR
(300 MHz, CDCl3): δ 7.66 (d, J = 8.4 Hz, 2 H), 7.56 (d, J = 7.8
Hz, 2 H), 7.31-7.24 (m, 5H), 7.18 (d, J = 8.1 Hz, 2 H), 7.02 (d,
J = 7.8 Hz, 2 H), 6.91 (s, 1 H), 6.43 (s, 1 H), 5.19 (s, 1 H), 2.43
(s, 3 H), 1.68 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 148.3,
144.8, 141.2, 136.1, 132.3, 131.2, 129.9, 129.6, 128.7, 127.1,
126.8, 124.1, 120.3, 119.2, 118.9, 110.5, 48.6, 21.7, 10.5; FT-IR
(KBr): νmax 2224, 1597, 1371, 1170, 1072, 812, 667 cm-1. HRMS
(EI) m/z: calcd for C26H22N2O2S: 426.1402, found 426.1397.
(11) (a) Jacobs, T. L.; Akawie, R.; Cooper, R. G. J. Am. Chem. Soc. 1951,
73, 1273. (b) Macaulay, S. R. J. Org. Chem. 1980, 45, 734.
(12) (a) Mochizuki, K.; Tomita, I. Macromolecules 2006, 39, 6336. (b)
Kino, T.; Taguchi, M.; Tazawa, A.; Tomita, I. Macromolecules 2006, 39,
7474.
J. Org. Chem. Vol. 75, No. 3, 2010 587

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Acknowledgment. The work was supported by the National
Science Foundation of China (20872002, 20832001) and the Edu-
cation Department of Anhui Province (TD200707). The authors
are grateful to Prof. J. Hu for assistance in running NMR spectra.
Supporting Information Available: Experimental details,
X-ray CIF data of 1h, and other spectral data for the cyclization
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
588 J. Org. Chem. Vol. 75, No. 3, 2010