Gold-catalyzed deacylative cycloisomerization reactions of 3-acylindole/ynes: A new approach for carbazole synthesis

Article abstract of DOI:10.1021/ol2012154

The synthesis of functionalized carbazoles through gold-catalyzed deacylative cycloisomerization of 3-acylindole/ynes is described. A mechanistic proposal for these transformations involving a novel carbonyl group facilitated heterolytic fragmentation upo

Full text of DOI:10.1021/ol2012154

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3786–3789
Gold-Catalyzed Deacylative
Cycloisomerization Reactions
of 3-Acylindole/ynes: A New Approach
for Carbazole Synthesis
Lu Wang, Guijie Li, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s
Republic of China
yhliu@mail.sioc.ac.cn
Received May 7, 2011
ABSTRACT
The synthesis of functionalized carbazoles through gold-catalyzed deacylative cycloisomerization of 3-acylindole/ynes is described. A
mechanistic proposal for these transformations involving a novel carbonyl group facilitated heterolytic fragmentation upon the loss of an
acylium ion intermediate is presented. The eliminated acylium ion species could be trapped by the organogold intermediate to afford
acylcarbazoles.
In recent years, gold complexes have emerged as power-
ful homogeneous catalysts for inducing a wide variety of
transformation reactions.1 In particular, gold catalysts
have been proven to be efficient alkynophilic Lewis acids
to activate the π-systems toward nucleophilic attack. In
this regard, gold-catalyzed inter- or intramolecular cyclo-
isomerization of indolyl-tethered alkynes is of particular
interest,2 since these methodologies offer rapid access to
indole-fused polycyclic structures which frequently occur
in numerous natural products and indole-containing scaf-
folds with important biological and pharmaceutical prop-
erties. For example, Echavarren and co-workers reported
that intramolecular cyclization of indoles with alkynes
in the presence of gold catalysts led to the formation of
azepino[4,5-b]indoles and indoloazocines.2aꢀc Padwa et al.
developed a gold-catalyzed cycloisomerization of
N-propargylamides to β-carbolinones.2d,e Cyclization of 2,
3-disubstituted indoles to tetracyclic indolines2f and a novel
1,2-indole migration2g to indenyl indoles have also been
reported. We have recently shown that indoles could
undergo cascade FriedelꢀCrafts/hydroarylation reactions
with(Z)-enynols catalyzed by gold.3a Soon after this study,
we found a new gold-catalyzed cyclization of indole/ynes
possessing hydroxyl groups3b through a heterolytic
(1) For recent reviews on gold-catalyzed reactions, see: (a) Hashmi,
A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896. (b) Gorin,
D. J.; Toste, F. D. Nature 2007, 446, 395. (c) Hashmi, A. S. K. Chem. Rev.
€
2007, 107, 3180. (d) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed.
ꢀ
ꢀ~
2007, 46, 3410. (e) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Commun.
2007, 333. (f) Lipshutz, B. H.; Yamamoto, Y. Chem. Rev. 2008, 108, 2793.
ꢀ
ꢀ~
(g) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326.
(h) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351.
(i) Arcadi, A. Chem. Rev. 2008, 108, 3266. (j) Patil, N. T.; Yamamoto, Y.
Chem. Rev. 2008, 108, 3395. (k) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008,
108, 3239. (l) Muzart, J. Tetrahedron 2008, 64, 5815. (m) Shen, H. C.
Tetrahedron 2008, 64, 3885. (n) Shapiro, N.; Toste, D. Synlett 2010, 675.
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(o) Corma, A.; Leyva-Perez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657.
(p) Bandini, M. Chem. Soc. Rev. 2011, 40, 1358.
(2) (a) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45,
1105. (b) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.;Eur. J.
2007, 13, 1358. (c) Ferrer, C.; Escribano-Cuesta, A.; Echavarren, A. M.
Tetrahedron 2009, 65, 9015. (d) England, D. B.; Padwa, A. Org. Lett.
2008, 10, 3631. (e) Verniest, G.; England, D.; De Kimpe, N.; Padwa, A.
Tetrahedron 2010, 66, 1496. (f) Liu, Y.; Xu, W.; Wang, X. Org. Lett.
2010, 7, 1448. (g) Sanz, R.; Miguel, D.; Rodrıguez, F. Angew. Chem., Int.
Ed. 2008, 47, 7354. (h) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am.
Chem. Soc. 2008, 130, 1814. (i) Zhang, L. J. Am. Chem. Soc. 2005, 127,
16804.
(3) (a) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351,
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r
10.1021/ol2012154
Published on Web 07/06/2011
2011 American Chemical Society

fragmentation, which results in 1,5-indole migration and
C-3 allenylation of the indole nucleus (Scheme 1, eq 1). In
this reaction, the hydroxyl group R to the indole ring was
found to play an important role in initiating the CꢀC bond
cleavage reactions.4 We hypothesized that the fragmenta-
tion reactions might be facilitated by other nucleophilic
substituents such as ꢀCOR, ꢀNHR, or ꢀSR groups bearing
electron lone pairs on their heteroatoms. We then became
interested in exploring further possibilities for the assembly of
diverse indole-containing skeletons through heterolytic frag-
mentation reactions. Herein, we report a new Au-catalyzed
deacylative cycloisomerization of 3-acylindole/ynes into car-
bazole derivatives5 and demonstrating that a carbonyl group
can be utilized for inducing fragmentation reactions6
(Scheme 1, eq 2).
works well with aryl and even alkyl groups with acidic
R-protons as carbonyl substituents (R3). It is noted that
there is no report for ketone directed lateral lithiation of
the indole system.7 The methodology described here repre-
sents the first example of this type of reaction, and it is
expected to be applicable for the synthesis of a wide variety
of functionalized indoles through the reactions of lithium
intermediates with various electrophiles.
Scheme 2
Scheme 1
With indoleꢀynes 3 in hand, we were interested in
exploring the feasibility of 3 in gold-catalyzed cycloisome-
rization reactions. Indoleꢀyne 3a bearing an isopropyl-
carbonyl group was chosen as a model substrate for
optimization studies. After examination of the reaction
conditions, we were pleased to find that the reaction
proceeded smoothly and provided a 73% yield of the
carbazole 4a at 60 °C in the presence of 5 mol % of
(p-CF3C6H4)3PAuOTf (Table 1, entry 1). (PPh3)AuOTf
afforded 4a in a lower yield of 66%. When AgOTf alone
was used as a catalyst, only a trace amount of the antici-
pated 4a was observed. The results indicated that 4 was
formed by attack of the indolyl C-3-position onto the
activated triple bond, and a deacylation occurred during
the cyclization. It was noted that the presence of a phenyl
group as the carbonyl substituent (R3) in 3b significantly
decreased the yield of 4a to 31%, possibly due to the
weaker nucleophilicity of the indolyl C-3 position in this
case (entry 2). Thus, 3-acylindoles 3 with an isopropyl
group as R3 were used as substrates in most cases. The
effects of aryl substituents on the alkyne terminus (R4)
were first examined. The reaction proceeded satisfactorily
with both electron-rich and electron-deficient substituents,
furnishing the corresponding carbazoles 4cꢀe in 69ꢀ86%
yields (entries 3ꢀ5), in which a better yield was observed
with an electron-rich group (ꢀMe). A thienyl group was
also compatible under the cyclization conditions, leading
to 4f in 84% yield (entry 6). Alkyl-substituted alkyne 3g
afforded the corresponding carbazole 4g in a good yield of
76% (entry 7). The 5-MeO functionality on the indole ring
can alsobeincorporated intothe reactionprocess(entry 8).
N-allyl- and N-benzyl-protected indoles 3iꢀj were both
found to be suitable for this reaction, as well as the
nonprotected indole 3k (entries 9ꢀ11). The structure of
To test this hypothesis, we designed the 3-acylindoles 3
for the cyclization reactions. Compound 3 was synthesized
through a heteroatom-facilitated lateral lithiation of
2-methyl-3-acylindole 1 (Scheme 2). Treatment of ketone
1 with LDA freshly prepared by diisopropylamine/n-BuLi
combination in THF at ꢀ78 °C resulted in the lithiation
of the 2-methyl group to give a lithiated intermediate 2.
Subsequent reaction with acetylenic aldehyde afforded the
substituted indoles 3 in 48ꢀ79% yields. The reaction
(4) For hydroxy-group induced fragmentation, see: (a) Grob, C. A.;
Schiess, P. W. Angew. Chem., Int. Ed. 1967, 6, 1. (b) Paquette, L. A.;
Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542.
(5) For transition-metal-catalyzed synthesis of carbazoles, see:
€
(a) Hans-Knolker, J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303. (b) Liu,
Z.; Larock, R. C. Org. Lett. 2004, 6, 3739. (c) Cai, X.; Snieckus, V. Org.
Lett. 2004, 6, 2293. (d) Kuwahara, A.; Nakano, K.; Nozaki, K. J. Org.
Chem. 2005, 70, 413. (e) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 701.
(f) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 14560. (g) Kong, A.; Han, X.; Lu, X. Org. Lett. 2006, 8, 1339. (h) Jean,
D. J., St. Jr.; Poon, S. F.; Schwarzbach, J. L. Org. Lett. 2007, 9, 4897.
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(i) Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org.
Chem. 2008, 73, 5022. (j)Jordan-Hore, J. A.;Carin, C. C.;Gulias, M.;Beck,
E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (k) Tsang,
W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S. L. J. Org.
Chem. 2008, 73, 7603. (l) Ueno, K.; Kitawaki, T.; Chida, N.Org. Lett. 2008,
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10, 1999. (m) Stokes, B. J.; Jovanovic, B.; Dong, H.; Richert, K. J.; Riell,
R. D.; Driver, T. G. J. Org. Chem. 2009, 74, 3225. (n) Kong, W.; Fu, C.; Ma,
S. Chem. Commun. 2009, 4572. (o) Hirano, K.; Inaba, Y.; Takahashi, N.;
Shimano, M.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 1212.
For recent paper on gold-catalyzed cyclization of 2-(enynyl)indoles to
carbazoles, see: (p) Praveen, C.; Perumal, P. T. Synlett 2011, 521.
(6) For carbonyl group-induced fragmentation reaction under the
reductive conditions, see: (a) Molander, G. A.; Le Huerou, Y.; Brown,
G. A. J. Org. Chem. 2001, 66, 4511. (b) Prantz, K.; Mulzer, J. Chem.;
Eur. J. 2010, 16, 485. For reviews, see: (c) Prantz, K.; Mulzer, J. Chem.
Rev. 2010, 110, 3741.
(7) For lithiation of 2-alkylindoles by lithium carbamate protec-
tionꢀactivation, see: (a) Katritzky, A. R.; Akutagawa, K. J. Am. Chem.
Soc. 1986, 108, 6808. For C-3 carboxylate induced lateral lithiations of
2-alkyl derivatives, see: (b) Vedejs, E.; Mullins, M. J.; Renga, J. M.; Singer,
S. P. Tetrahedron Lett. 1978, 19, 519. For review on lateral lithiation
reactions promoted by heteroatomic substituents, see: (c) Clark, R. D.;
Jahangir, A. Org. React. 1995, 47, 1–314.
Org. Lett., Vol. 13, No. 15, 2011
3787

Table 1. Gold-Catalyzed Deacylative Cyclization of 3-Acylin-
dole/ynes 3
Table 2. Gold-Catalyzed Formation of 2-Hydroxycarbazoles 6
entry substrate R1
R2 R3
R4
products yielda (%)
entry substrate R1
R2 R3
R4
products yielda (%)
1
2
5a
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
Me iPr Ph
Me iPr Ph
Me Ph Ph
6a
6a
6a
6c
6d
6e
6f
80
30b
85c
86
1
2
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
Me iPr Ph
Me Ph Ph
Me iPr p-CH3C6H4
Me iPr p-ClC6H4
Me iPr p-BrC6H4
Me iPr 2-thienyl
Me iPr n-C6H13
4a
4a
4c
4d
4e
4f
73
31
86
69
71
84
76
80
48
64
56
3
4
Me iPr p-CH3C6H4
Me iPr p-ClC6H4
Me iPr 2-thienyl
Me iPr n-C6H13
3
5
82
4
6
81
5
7
58d
73
6
8
5g
5h
5i
5-OMe Me iPr Ph
6g
6h
6i
7
3g
3h
3i
4g
4h
4i
i
5-OMe Me iPr Ph
9
H
H
allyl Pr Ph
Bn iPr Ph
79c
78c
8
i
10
9
H
H
H
allyl Pr Ph
Bn iPr Ph
10
11
3j
4j
a Isolatedyields. b Without H2O. Reaction timeis 24 h. c Reaction time
iPr Ph
4k
is 5 h. d The C-3 acylated carbazole 7a was also isolated in 34% yield.
3k
H
a Isolated yields. All reactions were carried out in a sealed tube.
It occurred to us that trapping the organogold inter-
mediate through the reaction with the in situ formed
acylium ion is feasible according to the results shown in
Table 2, entry 7, which allows for the assembly of 2-hydroxy-
3-acylcarbazoles. To this end, the possible cycloisomeriza-
tion of ynone 5f to acylcarbazole was tested in the presence
of different gold catalysts. Best results were obtained upon
treatment of 5f with 5 mol % of Echavarren’s catalyst in
DCM, affording 3-acylcarbazole 7a in 63% yield (Table 3,
entry 1). To our surprise, 1-acylcarbazole 8a was also
isolated in 13% yield, which can be easily separated from
the main product by column chromatography. Representa-
tive results are summarized in Table 3. The reaction accom-
modated various alkyl substituents on the alkyne terminus,
such as n-hexyl, n-propyl, (CH2)2Ph, or benzyloxyethyl
groups, and the desired 3-acylcarbazoles 7aꢀf could be
obtained in moderate to good yields. In addition, the
corresponding 1-acylcarbazoles 8aꢀf were also isolated in
13ꢀ27% yields (entries 1ꢀ6). Aryl- or heteroaryl-substi-
tuted alkynes worked well under the cyclization condi-
tions, delivering a mixture of 3- and 1-acylated products
7 and 8 which could not be separated from each other
through chromatography (entries 7 and 8). The struc-
tures of carbazoles 7a and 8c have been verified by X-ray
crystallography.8
carbazole 4h was unambiguously confirmed by X-ray
crystallographic analysis.8
Encouraged by these results, we next prepared the ynones
5 with the enhanced electrophilicity of the alkyne moiety via
DMP oxidation to examine their cyclization reactions. To
our delight, we found that the desired 6-endo-dig cyclization
reactions took place efficiently at room temperature in the
presence of 5 mol % of (p-CF3C6H4)3PAuOTf and 5 equiv
of H2O, yielding the 2-hydroxycarbazole 6a as the exclusive
product in 80% yield within 2 h (Table 2, entry 1). It is
noteworthy that the employment of water for this cyclo-
isomerization reaction is essential. In the absence of water, 6a
was formed in 30% yield after 24 h (entry 2). The increased
reaction rate in the presence of water was attributed to the
facile demetalation facilitated by water. As shown in Table 2,
the reactions tolerated a wide range of alkyne substitution
with both aryl and alkyl groups, producing the cyclization
products 6 in generally high yields at room temperature.
Replacing the alkylcarbonyl group with a phenylcarbonyl
group did not influence the efficiency of the reaction in this
cyclization, leading to 6a in 85% yield, albeit with a longer
reaction time of 5 h (entry 3). Interestingly, when alkyl
alkyne 5f was used as a substrate, in addition to the major
product of 6f, a side product of C-3-acylated carbazole 7a
(see Table 3) resulting from a competing acylation was also
isolated in 34% yield (entry 7). 2-Hydroxycarbazoles and its
derivatives are of significant interest, as they exist as the
core structures in a number of biologically active natural
products;9 for example, 3,6-disubstituted 2-hydroxycarba-
zoles exhibit HIV-inhibitory activity.10
A possible reaction mechanism for the transformation
of indolyl alkyne 5 into the 2-hydroxycarbazole 6 is shown
in Scheme 3. In the first step, activation of the triple bond
in 5 by forming a π-complex 9 with LAuþ enhances the
electrophilicity of the alkyne moiety, which facilitates a
nucleophilic attack by the indole ring. Thus, the subse-
quent 6-endo-dig ring closure occurs to afford the inter-
mediate 10. Electron donation by the carbonyl oxygen lone
(8) See the Supporting Information.
€
(9) Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(10) Meragelman, K. M.; McKee, T. C.; Boyd, M. R. J. Nat. Prod.
(11) For the generation of acylium ions by fragmentation of the
amide bond, see: (a) Li, G.; Huang, X.; Zhang, L. Angew. Chem., Int. Ed.
2008, 47, 346. (b) Peng, Y.; Yu, M.; Zhang, L. Org. Lett. 2008, 10, 5187.
2000, 63, 427.
3788
Org. Lett., Vol. 13, No. 15, 2011

Table 3. Gold-Catalyzed Formation of 3-Acyl- or 1 -Acylcarbazoles 7 and 8
entry
substrate
R3
iPr
R4
n-C6H13
time (h)
yield (%) of 7a
7a
yield (%) of 8a
8a
1
2
3
4
5
6
7
8
5f
1
2
1
1
1
1
4
6
63
58
48
67
81
71
13
21
27
19
15
20
5j
Ph
n-C6H13
n-C6H13
n-C3H7
7b
7c
7d
7e
7f
8b
8c
8d
8e
8f
i
5k
5l
CH2 Pr
iPr
5m
5n
5a
5e
iPr
(CH2)2Ph
(CH2)2OCH2Ph
Ph
iPr
iPr
7g þ 8g 68(1:1.7)b,c
iPr
2-thienyl
7h þ 8h 67(1.1:1)b
a Isolated yields. b A mixture of two inseparable products were obtained. The ratio of the two products is shown in parentheses. c In this case, 8g is the
major product.
pair triggers the heterolytic fragmentation to give the
gold species 12 along with the loss of an acylium ion.11
Tautomerization of 12 facilitated by a proton or metal ion
Scheme 3
delivers the aryl gold species 13; this is followed by
deauration to furnish the carbazole 6 and regenerate the
gold catalyst.12 In a similar catalytic cycle to acylated
carbazoles, reaction of the AuꢀC bond in gold intermedi-
ate 13 with the highly electrophilic acylium ion would give
the 3-acylcarbazole 7. We speculate that the byproduct of
1-acylcarbazole 8 might be formed by competitive acyla-
tion on the C-1 position of the carbazolyl gold species 13.13
In summary, we have developed a gold-catalyzed cyclo-
isomerization of 3-acylindole/ynes for the synthesis of multi-
ply substituted carbazoles, which are very important build-
ing blocks in natural product synthesis9,14 and material
science.15 A mechanism involving a novel reaction pattern
of carbonyl group facilitated heterolytic fragmentation is
proposed. Clarification of the reaction mechanism and
further application of this chemistry are in progress.
(12) As suggested by one reviewer, we also tried the gold-catalyzed
Acknowledgment. We thank the National Natural
Science Foundation of China (Grant Nos. 20872163,
20732008, 20821002), Chinese Academy of Science,
and the Major State Basic Research Development
Program (Grant No. 2011CB808700) for financial
support.
cyclization of 5a in the presence of 5 equiv of D2O in a sealed tube. The
amounts of deuterium incorporation on C-1 and C-3 are 65% and 37%,
respectively. The results indicated that a hydrogenꢀdeuterium exchange
occurred during ketoꢀenol tautomerization. The low deuterium incorpora-
tion on C-3 might be due to the fast demetalation by Hþ produced in situ.
(13) At present, a mechanism that involves the acylation of the
neutral final product 6 by an acylium ion for the formation of 7 and 8
cannot be ruled out.
€
(14) (a) Knolker, H.-J. Top. Curr. Chem. 2005, 244, 115. (b) Chakraborty,
D. P.; Roy, S. In Progress in the Chemistry of Organic Natural Products; Herz,
W., Kirby, G. W., Steglich, W., Tamm, C., Eds.; Springer-Verlag: New York, 1991;
Vol. 57, pp 72ꢀ152.
Supporting Information Available. Experimental de-
tails, spectroscopic characterization of all new com-
pounds, and X-ray crystallography of compounds 4h,
6g, 7a, and 8c. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) (a) Zhang, Y.; Wada, T.; Sasabe, H. J. Mater. Chem. 1998, 8, 809.
(b) Grazulevicius, J. V.; Strohriegl, P.; Pielichowski, J.; Pielichowski, K.
Prog. Polym. Sci. 2003, 28, 1297. (c) Thomas, K. R. J.; Lin, J. T.; Tao, Y.-T.;
Ko, C.-W. J. Am. Chem. Soc. 2001, 123, 9404. (d) Dıaz, J. L.; Dobarro, A.;
Villacampa, B.; Velasco, D. Chem. Mater. 2001, 13, 2528.
Org. Lett., Vol. 13, No. 15, 2011
3789