One-pot synthesis of highly substituted 4-acetonylindoles via sequential dearomatization and silver-catalyzed domino reaction

Article abstract of DOI:10.1021/ol501678v

Synthetically useful 4-acetonylindoles have been conveniently prepared from 2-alkynylanilines and silyl enol ethers using a dearomatization strategy. The two-step/one-pot protocol involves an iodosylbenzene-mediated oxidative dearomatization and a silver-

Full text of DOI:10.1021/ol501678v

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of Highly Substituted 4‑Acetonylindoles via
Sequential Dearomatization and Silver-Catalyzed Domino Reaction
Xin Feng,† Huiqing Wang,‡ Bo Yang,*,‡ and Renhua Fan*,†
†Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
‡Department of Urology, Changhai Hospital, 168 Changhai Road, Shanghai 200433, China
S
* Supporting Information
ABSTRACT: Synthetically useful 4-acetonylindoles have been
conveniently prepared from 2-alkynylanilines and silyl enol
ethers using a dearomatization strategy. The two-step/one-pot
protocol involves an iodosylbenzene-mediated oxidative dear-
omatization and a silver-catalyzed domino reaction.
Scheme 1. Synthesis of 4-Acetonylindoles from Aniline
Derivatives
4-Substituted indoles constitute a valuable class of compounds
because of their wide range of biological activities.1 4-
Acetonylindoles have found widespread use in the synthesis
of natural products containing a 4-substituted indole core, such
as dragmacidins D and E,2 welwitindolinones,3 and ergot
alkaloids.4 Accordingly, a variety of strategies have been
developed to prepare these synthetically useful intermediates.
Traditionally, 4-acetonylindoles are synthesized from 5-halo-4-
oxo-4,5,6,7-tetrahydroindoles and the dianion of acetoacetic
esters via 1,2-addition, dehydration, and dehydrohalogenation.5
The difficulty of this three-step synthesis has limited the
application of this method. 4-Halo-substituted indoles are
alternative precursors to prepare 4-acetonylindoles. Besides
palladium-catalyzed enolate arylation,6 4-halo-substituted in-
doles can be converted to lead(IV) 4-indolyl triacetates to react
with α-ketoester to form 4-acetonylindoles.7 However, the
direct electrophilic halogenation of the C-4 position of indoles
is not preferred. The preparation of 4-halo-substituted indoles
requires multistep synthesis. Additionally, Witkop photo-
cyclization,8 Rh-catalyzed C−H insertion by α-diazo ketone,9
and the addition of enolates onto an in situ generated indolyne
species10 have also been developed to construct 4-acetony-
lindoles, but these reactions only proceed in an intramolecular
way.
Recently, the Kerr group reported an elegant method for
synthesizing 4-acetonylindoles that relied on the [4 + 2]
cycloaddition of quinone imine ketals (QIK) and subsequent
oxidative olefin cleavage and cyclization (Scheme 1).11
Although a multistep process is required, the success of this
tactic leads us to speculate that 4-acetonylindoles might be
prepared from simple aniline derivatives using a dearomatiza-
tion strategy.12 Herein, we wish to present our success in this
regard. Highly substituted 4-acetonylindoles are rapidly
constructed from 2-alkynylanilines and silyl enol ethers
(Scheme 1). Our strategy involves a hypervalent iodine-
mediated oxidation to break the aromaticity of 2-alkynylani-
lines,13 a Michael-type addition with silyl enol ethers to install
the acetony group, and a tandem cyclization/aromatization to
build the indole ring.
2-Alkynylaniline 1 was conveniently prepared from p-
toluidine via an iodination and a Sonogashira coupling with
phenylacetylene. Many hypervalent iodine compounds could
mediate the oxidative dearomatization of compound 1, but
most of the reactions produced acidic metabolites, which are
harmful to subsequent reaction with silyl enol ethers.
Iodosylbenzene proved to be the best oxidant for this one-
pot synthesis. To avoid the decomposition of silyl enol ethers,
methanol was removed under a pressure-reducing condition
before adding silyl enol ethers. The catalytic activities of a
variety of metal salts in the formation of 4-acetonylindole 3
were evaluated (Table 1, entries 1−10). When Bi(III), In(III),
Zn(II), Cu(II), Au(III), Pd(II), or Pt(II) salt was used, the
reaction gave rise to a 4-methoxy-substituted indole as the
major product. When AuCl or AgOTf was used, the desired 4-
acetonylindole 3 was isolated in 43% or 50% yield, respectively.
Received: June 11, 2014
Published: June 25, 2014
© 2014 American Chemical Society
3600
dx.doi.org/10.1021/ol501678v | Org. Lett. 2014, 16, 3600−3603

Organic Letters
Letter
Table 1. Evaluation of Catalysts and Conditions
Table 2. Two-Step/One-Pot Synthesis of 4-Acetonylindoles
a
entry
catalyst (equiv)
conditions
3 (%)
1
Bi(OTf)3 (0.1)
In(OTf)3 (0.1)
Zn(OTf)2 (0.1)
Cu(OTf)2 (0.1)
CuCl2 (0.1)
AuCl3 (0.1)
THF, 25 °C, 3 h
THF, 25 °C, 3 h
THF, 25 °C, 3 h
THF, 25 °C, 3 h
THF, 25 °C, 3 h
THF, 25 °C, 3 h
THF, 25 °C, 3 h
THF, 25 °C, 3 h
THF, 25 °C, 3 h
THF, 25 °C, 3 h
DCM, 25 °C, 3 h
toluene, 25 °C, 3 h
dioxane, 25 °C, 3 h
CH3CN, 25 °C, 3 h
CH3CN, 25 °C, 3 h
CH3CN, 25 °C, 3 h
CH3CN, 25 °C, 2 h
CH3CN, 25 °C, 5 h
CH3CN, 0 °C, 8 h
0
0
2
3
0
4
<5
7
5
6
27
43
<5
<5
50
32
61
45
65
73
72
63
65
55
51
7
AuCl (0.1)
8
PdCl2 (0.1)
9
PtCl2 (0.1)
10
11
12
13
14
AgOTf (0.1)
AgOTf (0.1)
AgOTf (0.1)
AgOTf (0.1)
AgOTf (0.1)
AgOTf (0.1)
AgOTf (0.1)
AgOTf (0.2)
AgOTf (0.05)
AgOTf (0.1)
AgOTf (0.1)
b
15
c
16
17
18
19
20
CH3CN, reflux, 1 h
a
b
Reported yields are of the isolated products. Two equivalents of
c
compound 2 was used. Three equivalents of compound 2 was used.
A screening of solvents for the AgOTf-catalyzed reaction
revealed that acetonitrile was the best reaction media (Table 1,
entries 10−14). The best ratio of 2-alkynylaniline, silyl enol
ether, and catalyst was 1:2:0.1, increasing the yield to 73%
(Table 1, entry 15).
With the optimized conditions established, the two-step/
one-pot synthesis of 4-acetonylindoles was investigated, and the
results are presented in Table 2. A range of 2-alkynylanilines
bearing different substitutions were suitable substrates. The
structure of compound 10 was confirmed by its single-crystal
diffraction analysis (Figure 1).14 The protecting group of 2-
alkynylanilines played a significant role in the formation of 4-
acetonylindoles. For example, when the para substitution of 2-
alkynylaniline was a n-butyl group, the reaction of the N-Ts-
protected substrate gave rise to the 4-methoxy-substituted
indole as product. When the N-Bz-protected substrate was used
instead, the desired 4-acetonylindole was formed in 54% yield
(Table 2, entries 11 and 12). When the para substitution was a
phenyl group, the reaction was complex. For a series of silyl
enol ethers derived from aryl methyl (ethyl) ketones, the
reactions proceeded smoothly (Table 2, entries 15−22). The
yield was diminished when the enol silane bearing ortho
substitution was employed. For silyl enol ethers derived from
cyclic ketones, cyclopentanone-derived enol silane was a
suitable reaction partner (Table 2, entry 23). It is noteworthy
that when Danishefsky’s diene was used, the reaction produced
4-acetonylindole 27, and no Diels−Alder cycloaddition product
was isolated (Table 2, entry 25). With respect to other
(silyloxy)dienes, reactions of dienes bearing an electron-
donating group gave rise to products in higher yields compared
a
Reported yields are of the isolated products.
with those bearing an electron-withdrawing group (Table 2,
entries 26−31).
A plausible reaction pathway for this two-step/one-pot
synthesis is shown in Scheme 2. Iodosylbenzene mediates
oxidative dearomatization of para-substituted 2-alkynylaniline
in methanol to form 2-alkynylcyclohexadienimine. AgOTf
functions as a π acid to induce heterocyclization of 2-
alkynylcyclohexadienimine. The formed pyrrole-like intermedi-
3601
dx.doi.org/10.1021/ol501678v | Org. Lett. 2014, 16, 3600−3603

Organic Letters
Letter
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures, characterization data, copies of H
NMR and 13C NMR of new compounds, and crystallographic
data of compound 10 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: yangbochanghai@126.com.
*E-mail: rhfan@fudan.edu.cn.
Notes
Figure 1. X-ray diffraction structure of compound 10.
The authors declare no competing financial interest.
Scheme 2. Plausible Reaction Pathway
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation of
China (No. 21332009), Specialized Research Fund for the
Doctoral Program of Higher Education (No.
20120071110009), and Shanghai Science and Technology
Committee (13431900103) is gratefully acknowledged.
REFERENCES
■
(1) (a) Saxton, J. E. In The Chemistry of Heterocyclic Compounds;
Wiley: New York, 1983; Vol. 25, Part IV. (b) Horton, D. A.; Bourne,
G. T.; Smyth, M. L. Chem. Rev. 2003, 103, 893. (c) Cacchi, S.; Fabrizi,
G. Chem. Rev. 2005, 105, 2873. (d) Humphrey, G. R.; Kuethe, J. T.
Chem. Rev. 2006, 106, 2875. (e) Steven, A.; Overman, L. E. Angew.
Chem., Int. Ed. 2007, 46, 5488. (f) Mulzer, J.; Gaich, T.; Siengalewicz,
P. Angew. Chem., Int. Ed. 2008, 47, 8170. (g) Bandini, M.; Eichholzer,
A. Angew. Chem., Int. Ed. 2009, 48, 9608.
(2) (a) Yang, C.-G.; Wang, J.; Jiang, B. Tetrahedron Lett. 2002, 43,
1063. (b) Mandal, D.; Yamaguchi, A. D.; Yamaguchi, J.; Itami, K. J.
Am. Chem. Soc. 2011, 133, 19660.
(3) (a) Wood, J. L.; Moniz, G. A. Org. Lett. 1999, 1, 371. (b) Baran,
P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394. (c) Reisman,
S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J. L. J. Am. Chem.
Soc. 2006, 128, 1448.
(4) (a) Floss, H. G. Tetrahedron 1976, 32, 873. (b) Horwell, D. C.
Tetrahedron 1980, 36, 3123. (c) Kozikowski, A. P. Acc. Chem. Res.
1984, 17, 410.
ate is ready to undergo a Mukaiyama−Michael addition with
silyl enol ethers. The in situ generated Me3SiOTf promotes
aromatization. Subsequent protonation of the carbon−silver
bond by TfOH affords 4-acetonylindole and regenerates the
catalyst AgOTf.
(5) (a) Matsumoto, M.; Watanabe, N. Heterocycles 1986, 24, 3149.
(b) Rosenberg, M. L.; Aasheim, J. H. F.; Trebbin, M.; Uggerud, E.;
Hansen, T. Tetrahedron Lett. 2009, 50, 6506.
(6) (a) MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7,
3421. (b) Baudoux, J.; Blake, A. J.; Simpkins, N. S. Org. Lett. 2005, 7,
4087. (c) Hellal, M.; Singh, S.; Cuny, G. D. J. Org. Chem. 2012, 77,
4123.
Compound 15 could be easily converted to a 3,4-fused
tricyclic indole15 34 via a deprotection and a condensation with
paraformaldehyde (Scheme 3).
Scheme 3. Conversion of 4-Acetonylindole to
Oxepino[3,4,5-cd]indole Derivative
(7) Deng, H.; Konopelski, J. P. Org. Lett. 2001, 3, 3001.
(8) Feldman, K. S.; Ngernmeesri, P. Org. Lett. 2011, 13, 5704.
(9) Wood, J. L.; Holubec, A. A.; Stoltz, B. M.; Weiss, M. M.; Dixon, J.
A.; Doan, B. D.; Shamji, M. F.; Chen, J. M.; Heffron, T. P. J. Am.
Chem. Soc. 1999, 121, 6326.
(10) Huters, A. D.; Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J.
Am. Chem. Soc. 2011, 133, 15797.
(11) Banfield, S. C.; England, D. B.; Kerr, M. A. Org. Lett. 2001, 3,
3325.
(12) For reviews on dearomatization, see: (a) Pape, A. R.; Kaliappan,
In conclusion, we have developed a dearomatization strategy
for synthesis of highly substituted 4-acetonylindoles. The
process involves an oxidative dearomatization of 2-alkynylani-
lines followed by a silver-catalyzed domino reaction with silyl
enol ethers. The application of this method to the synthesis of
natural products is currently underway in our laboratory, and
these results will be forthcoming.
K. P.; Kundig, E. P. Chem. Rev. 2000, 100, 2917. (b) Magdziak, D.;
̈
Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383. (c) Lop
Ortiz, F.; Iglesias, M. J.; Fernandez, I.; Andujar Sanchez, C. M.;
Gomez, G. R. Chem. Rev. 2007, 107, 1580. (d) Quideau, S.; Pouysegu,
L.; Deffieux, D. Synlett 2008, 467. (e) Pouysegu, L.; Deffieux, D.;
́
ez
́
́
́
́
́
́
Quideau, S. Tetrahedron 2010, 66, 2235. (f) Roche, S. P.; Porco, J. A.,
Jr. Angew. Chem., Int. Ed. 2011, 50, 4068. (g) Zhuo, C.-X.; Zhang, W.;
3602
dx.doi.org/10.1021/ol501678v | Org. Lett. 2014, 16, 3600−3603

Organic Letters
Letter
You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662. (h) Ding, Q.; Ye, Y.;
Fan, R. Synthesis 2013, 45, 1.
(13) (a) Jackson, S. K.; Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7,
1215. (b) Quideau, S.; Pouyseg
Molecules. 2005, 10, 201. (c) Jean, A.; Cantat, J.; Ber
D.; Canesi, S. Org. Lett. 2007, 9, 2553. (d) Sabot, C.; Ber
Canesi, S. Org. Lett. 2008, 10, 4629. (e) Giroux, M.-A.; Guerard, K. C.;
́
u, L.; Ozanne, A.; Gagnepain, J.
ard, D.; Bouchu,
ard, D.;
́
́
́
Beaulieu, M.-A.; Sabot, C.; Canesi, S. Eur. J. Org. Chem. 2009, 3871.
(14) Crystallographic data for compound 10 is available free of
charge from the Cambridge Crystallographic Data Centre, accession
numbers CCDC 1007350.
(15) (a) Shan, D.; Gao, Y.; Jia, Y. Angew. Chem., Int. Ed. 2013, 52,
4902. (b) Breazzano, S. P.; Poudel, Y. B.; Boger, D. L. J. Am. Chem.
Soc. 2013, 135, 1600.
3603
dx.doi.org/10.1021/ol501678v | Org. Lett. 2014, 16, 3600−3603