Synthetic development and mechanistic study on Pd(II)-catalyzed cyclization of enediynes to benzo[ a ]carbazoles

Article abstract of DOI:10.1021/ol1024458

Treatment of N,N-dimethyl 2-[2-(2-ethynylphenyl)ethynyl]anilines (1) with 10 mol % of palladium chloride and 2 equiv of cupric chloride in refluxing THF gave benzo[a]carbazoles (6) in good yields. A mechanistic study showed that this reaction must proceed

Full text of DOI:10.1021/ol1024458

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5652-5655
Synthetic Development and Mechanistic
Study on Pd(II)-Catalyzed Cyclization of
Enediynes to Benzo[a]carbazoles
Chin-Chau Chen,† Lin-Yu Chin,‡ Shyh-Chyun Yang,† and Ming-Jung Wu*,‡
School of Pharmacy, Kaohsiung Medical UniVersity, Kaohsiung, Taiwan, and
Department of Chemistry, National Sun Yat-sen UniVersity, Kaohsiung, Taiwan
mijuwu@faculty.nsysu.edu.tw
Received October 8, 2010
ABSTRACT
Treatment of N,N-dimethyl 2-[2-(2-ethynylphenyl)ethynyl]anilines (1) with 10 mol % of palladium chloride and 2 equiv of cupric chloride in
refluxing THF gave benzo[a]carbazoles (6) in good yields. A mechanistic study showed that this reaction must proceed through formation of
haloindole (7) followed by a palladium(II)-catalyzed atom transfer cyclization reaction to give the benzo[a]carbazoles.
The modes of cyclization of enediynes have attracted much
attention since the discovery of enediyne antitumor antibiot-
ics.1 Initially research focused on the Bergman2 and related
cyclization of enediynes to generate biradical intermediates
because they are the key intermediates for biological activi-
ties.3 Recently, attention has been turned to the nonclassical
thermal-type cyclization of enediynes to produce a variety
of aromatic and highly π-conjugated molecules. These
reactions involved the cyclization reaction of enediynes
promoted by electrophiles,4 nucleophiles,5 radicals,6 or
organometallics.7
Carbazoles are pharmaceutically important heterocycles8
and are attractive synthetic targets to many organic chemists.9
Recently, we reported the palladium-catalyzed cyclization of
enediynes to dibenzo[b,d]pyran-6-ones.10 Although the reaction
mechanism of that reaction is not clear, we anticipated that
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† Kaohsiung Medical University.
‡ National Sun Yat-sen University.
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Wu, M. J.; Lin, C. F.; Lu, W. D. J. Org. Chem. 2002, 67, 5907. (e) Lee,
C. Y.; Lin, C. F.; Lee, J. L.; Chiu, C. C.; Lu, W. D.; Wu, M. J. J. Org.
Chem. 2004, 69, 2106. (f) Chen, Z. Y.; Wu, M. J. Org. Lett. 2005, 7, 475.
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10.1021/ol1024458  2010 American Chemical Society
Published on Web 11/18/2010

carbazoles could be synthesized by the same strategy starting
from N,N-dimethyl 2-[6-substituted 3(Z)-hexen-1,5-diynyl]-
anilines. Herein, we report the synthesis of benzo[a]carbazoles
from N,N-dimethyl 2-[2-(2-ethynylphenyl)ethynyl]anilines cata-
lyzed by palladium and a mechanistic study of this reaction.
The synthesis of N,N-dimethyl 2-[2-(2-ethynylphenyl)-
ethynyl]aniline (1a) starting from N,N-dimethyl 2-iodoaniline
(2a) is outlined in Scheme 1. A Sonogashira coupling
mol % of PdCl2 and 2 equiv of CuCl2 in acetonitrile at room
temperature for 24 h, and benzo[a]carbazole 6a was obtained
in 72% yield (entry 1, Table 1). Upon heating the reaction
Table 1. Optimization of Reaction Conditions
Scheme 1
entry
solvent
temp(°C)
time(h)
products/yields (%)
1
2
3
4
5
6
CH3CN
CH3CN
DMF
THF
THF
Toluene
Toluene
CH3CN
CH3CN
rt
reflux
rt
rt
reflux
rt
reflux
rt
reflux
24
1
24
24
1
24
1
24
1
6a/72
6a/50
6a/21, 7a/24
6a/90
6a/90
6a/52, 7a/23
6a/76
7a/90
7
8a
9b
6a/trace
a Without PdCl2 catalyst. b Without CuCl2.
mixture at reflux, the yield of 6a drops to 50% (entry 2,
Table 1). To optimize the reaction conditions, we investigated
the solvent effects on this cyclization reaction by employing
different organic solvents. The results are summarized in
Table 1. THF was found to be the most suitable solvent in
this reaction. Upon heating the reaction mixture in refluxing
THF for 1 h, compound 6a was obtained in 90% yield (entry
5, Table 1). The structure of 6a was unambiguously
determined by X-ray crystallography (Figure 1).
reaction of 2a with trimethylsilylacetylene using Pd(PPh3)4
as the catalyst gave compound 3a in 95% yield. Desilylation
of 3a with methanol in the presence of potassium carbonate
gave 4a in 95% yield. Compound 4a was then coupled with
1,2-diiodobenzene under the Sonogashira coupling reaction
conditions to give 5a in 75% yield. Finally, compound 5a
was coupled with 1-pentyne using Pd(PPh3)2Cl2 as the
catalyst to give the desired product 1a in 75% yield.
Our first attempt for the cyclization of 1a followed the
reaction conditions used for the synthesis of dibenzo[b,d-
]pyran-6-ones.10 Thus, compound 1a was treated with 10
(9) (a) Kno¨lker, H.-J.; Kno¨ll, J. Chem. Commun. 2003, 1170. (b) Tsang,
W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560.
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Figure 1. ORTEP drawing of compound 6a.
Other N,N-dimethyl 2-[2-(2-ethynylphenyl)ethynyl]anilines
1b-m bearing different substituents on the terminal alkynes
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2008, 350, 1248.
Org. Lett., Vol. 12, No. 24, 2010
5653

have also been synthesized (Scheme 1) and subjected to the
cyclization reaction under the optimized reaction conditions.
The results are summarized in Table 2. These reactions gave
intermediates are not clear. We herein explore the reaction
mechanism of this carbazole formation reaction. Thus,
compound 1a was first converted to 7a using CuCl2 as the
halocyclization agent11 in acetonitrile at room temperature
for 24 h (eq 1). Compound 7a was then dissolved in THF,
and 10 mol % PdCl2 was added. The reaction mixture was
heated at reflux for 2 h. This led to the virtually complete
conversion of 7a to 6a (entry 1, Table 3). Similar results
Table 2. Synthesis of Benzo[a]carbazoles by Optimized
Reaction Conditions
Table 3. Study of Conversion from Indole to
Benzo[a]carbazoles
entry
compounds
product/yield (%)
1
2
3
4
5
6
7
8
9
1b, R1 ) H, R2 ) H, R3 ) i-Bu
6b/95
6d/89
6e/85
6f/76
6g/75
6h/94
6i/88
6j/85
6k/78
6l/96
6m/93
6n/92
1d, R1 ) H, R2 ) H, R3 ) 4-CH3OC6H4
1e, R1 ) H, R2 ) H, R3 ) 2-CH3C6H4
1f, R1 ) H, R2 ) H, R3 ) 3-CH3C6H4
1g, R1 ) H, R2 ) H, R3 ) 4-CH3C6H4
1h, R1 ) H, R2 ) H, R3 ) Ph
1i, R1 ) H, R2 ) H, R3 ) 4-ClC6H4
1j, R1 ) H, R2 ) H, R3 ) 4-BrC6H4
1k, R1 ) H, R2 ) H, R3 ) 4-CF3C6H4
time
(h)
products/
yields (%)
entry compd catalyst
additive
1
2
3
4
5
6
7
8
9
10
7a
7a
7a
7a
7a
7a
8a
8a
7h
7h
PdCl2
Pd(OAc)2 --
PdBr2
PdI2
Pd(PPh3)4 --
PtCl2 --
Pd(OAc)2 --
Pd(OAc)2 CuCl2(1 equiv)
PdCl2 --
Pd(OAc)2 --
--
2
2
2
2
24
2
2
2
2
2
6a/92
6a/88
10 1l, R1 ) H, R2 ) H, R3 ) 4-NO2C6H4
11 1m, R1 ) CH3, R2 ) CH3, R3 ) n-Pr
12 1n, R1 ) H, R2 ) CO2CH3, R3 ) n-Pr
--
--
6a/85a
6a/85b
6a/40c
6a/75
9a/90
6a/55, 9a/18
6h/93
the benzo[a]carbazoles in excellent yields (75-96%). How-
ever, under the optimized reaction conditions, cyclization of
1c gave only the monocyclization product 7c in 95% yield.
No expected benzo[a]carbazole 6c was formed. Compound
7c was then dissolved in THF and stirred with 10 mol % of
PdCl2 and 2 equiv of CuCl2 in refluxing THF for a prolonged
time of 72 h; benzo[a]carbazole 6c could then be obtained
in 40% yield, and there is a significant amount (50%) of 7c
that was recovered (Scheme 2). The slow cyclization rate of
6h/93
a A trace amount of 9a was observed by GC-MS. b A trace amount of
10a (X ) I) was observed by GC-MS. c Compound 7a was recovered in
25% yield.
were observed by employing electrophilic palladium salts,
such as Pd(OAc)2, PdBr2, and PdI2 (entries 2-4, Table 3).
When Pd(PPh3)4 was employed in this reaction, the reaction
took place very slowly. After stirring in refluxing THF for
24 h, carbazole 6a was isolated in only 40% yield and the
starting indole 7a was recovered in 25% yield (entry 5, Table
3). Platinum(II) was also employed in this reaction as a
catalyst, and 6a was obtained in 75% yield (entry 6, Table
3). The bromoindole 8a was prepared by the reaction of 1a
with CuBr2 in 85% yield (eq 1). Treatment of 8a with 10
mol % of Pd(OAc)2 in refluxing THF for 2 h gave 9a in
90% yield (entry 7, Table 3). In the presence of 1 equiv of
CuCl2, the above reaction led to the formation of 6a in 55%
yield and 9a in 18% yield (entry 8, Table 3). The phenyl
substituted compound 7h was also treated with 10 mol % of
PdCl2 and Pd(OAc)2, respectively. Both reactions gave
benzo[a]carbazole 6h in 93% yield (entries 9 and 10, Table
3).
Scheme 2
compound 7c must be because of the steric effect of the bulky
tert-butyl substituent.
(11) (a) Lu, W. D.; Wu, M. J. Tetrahedron 2007, 63, 356. (b) Liang,
Y.; Xie, Y. X.; Li, J. H. Synthesis 2007, 15, 400. (c) Chin, L. Y.; Lee,
C. Y.; Lo, Y. H.; Wu, M. J. J. Chin. Chem. Soc. 2008, 55, 643.
In our previous report,10 the presence of PdCl2 is crucial
to obtain the double cyclization adduct; however, the reaction
5654
Org. Lett., Vol. 12, No. 24, 2010

ates 10 and 7 could be formed in the first cyclization step.
If the palladated indole 10 is the case, the second step
cyclization should favor the 5-exodig pathway to give the
vinylpalladium 11 based on previous reports.4d,13 We
therefore excluded the possibility of this pathway. We believe
that compound 1 should react with CuX2 to form the
halogenated indole 7 initially. The Pd(II) could then coor-
dinate to the triple bond, followed by intramolecular
Friedel-Crafts cyclization to give 13. The released nucleo-
philic ligand would come back to kick out the halogenium
ion to give the palladated carbazole 12. Finally, intermediate
12 could be coverted to the final product 6 by reaction with
either CuX2 or XY. In entry 8 of Table 3, the reaction of
bromoindole 8a with Pd(OAc)2 in the presence of 1 equiv
of CuCl2 gave a mixture of bromocarbazole 9a and chloro-
carbazole 6a, establishing the possibility of this reaction
pathway.
Based upon the above experimental results, a proposed
reaction mechanism is outlined in Scheme 3. Since Pd(II)
Scheme 3
In conclusion, we have not only developed an efficient
synthetic method to convert N,N-dimethyl 2-[2-(2-ethy-
nylphenyl)ethynyl]anilines to halogenated benzo[a]carbazoles
but also proposed a unique electrophilic palladium- or
platinum-catalyzed atom transfer cyclization reaction of
1-halodienynes. Based upon this new type of cyclization
reaction, we should be able to develop new synthetic methods
to many carbocycles. These studies are currently under
investigation and will be reported in due course.
Acknowledgment. We thank the National Science Council
of the Republic of China for financial support.
Supporting Information Available: Experimental pro-
cedures and full spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
and Cu(II) both can catalyze the cyclization of 2-alkynyla-
nilines to give indole derivatives,11,12 two possible intermedi-
OL1024458
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