Direct construction of fused indoles by gold-catalyzed cascade cyclization of conjugated diynes

Article abstract of DOI:10.1021/acs.orglett.5b00550

A gold-catalyzed cascade cyclization of aniline derivatives bearing a conjugated diyne moiety was developed. Following the 5-endo-dig indole formation, subsequent 7-endo-dig cyclization predominated over 6-exo-dig cyclization to give the indole fused with a seven-membered ring in good yields.

Full text of DOI:10.1021/acs.orglett.5b00550

Letter
pubs.acs.org/OrgLett
Direct Construction of Fused Indoles by Gold-Catalyzed Cascade
Cyclization of Conjugated Diynes
Saori Naoe,† Tatsuo Saito,‡ Masanobu Uchiyama,*,‡ Shinya Oishi,† Nobutaka Fujii,† and Hiroaki Ohno*,†
†Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
‡Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: A gold-catalyzed cascade cyclization of aniline
derivatives bearing a conjugated diyne moiety was developed.
Following the 5-endo-dig indole formation, subsequent 7-endo-
dig cyclization predominated over 6-exo-dig cyclization to give
the indole fused with a seven-membered ring in good yields.
Scheme 1. Gold(I)-Catalyzed Intramolecular Consecutive
Cyclization of a Conjugated Diyne
omogeneous gold catalysis has recently garnered much
1
Hinterest in organic chemistry. The versatile reactivity of
gold catalysts enables the design of cascade reactions for atom-
and step-economical direct syntheses of complex molecules.2
Although many gold-catalyzed cascade reactions of alkynes have
been reported,3 there have been few studies of the reactions of
conjugated diynes. Recently, some useful gold-catalyzed
reactions of conjugated diynes have been reported, including
[4 + 3] annulation of conjugated diynyl esters,4 double
nucleophilic addition for pyrrole/furan syntheses,5 and double
hydroarylation to form highly fused rings.6 Banwell et al.
reported a gold-catalyzed consecutive hydroamination of
phenylurea derivatives bearing a terminal conjugated diyne
moiety at the ortho-position.7 This reaction proceeds through
indole formation followed by 5-exo- or 6-endo-dig cyclization,
depending on the substrate structure. Gold-catalyzed reactions of
conjugated diynes have great potential for ring construction
including indoles.8a However, to the best of our knowledge, 7-
endo selective cyclization using conjugated diynes is unprece-
dented.
by a gold catalyst. Here, we report a gold-catalyzed synthesis of
oxepino- and diazepino[1,7-a]indole derivatives 2. These are
important structural motifs found in hepatitis C virus polymer-
ase14 and dopamine receptor-binding compounds.15 The
reaction proceeds through regioselective 7-endo-dig cyclization
starting from conjugated diynes 1.
On initiation of this work, no information was available on the
reactivity of conjugated diynes toward indole formation. For a
feasibility study of the working hypothesis, the gold-catalyzed
reaction of the conjugated diyne 6 bearing an N-methylamino
group was examined. Indole formation proceeded smoothly to
give the alkynylindole 7 in 86% yield after treatment of 6 with
IPrAuCl/AgOTf (5 mol %) in DCE at rt for 1.5 min.
Interestingly, indole formation from 2-alkynylaniline 8 was
significantly faster than that from 6, which reached completion
within 1.0 min under identical conditions.17 This is in contrast to
the steric effect, where conjugated diyne derivatives would have a
positive effect on the coordination to gold catalysts compared to
2-(phenylethynyl)anilines. The relatively lower reactivity of
We recently developed a gold-catalyzed nucleophilic addition
and hydroarylation cascade using unconjugated diynes for
construction of fused rings such as carbazoles and naphthale-
nes.8b−e When the reactions were applied to polyyne derivatives,
highly fused rings were efficiently produced.9 Given our interest
in the reactivity of conjugated diynes, we designed a gold-
catalyzed intramolecular consecutive cyclization of conjugated
diyne 1 bearing two nucleophilic functionalities, such as an
amino alcohol and diamine (Scheme 1). The potential issues
associated with this reaction were regioselectivity in the second
cyclization (6-exo-dig vs 7-endo-dig) and reactivity of conjugated
diynes toward indole formation. It is well-known that gold-
catalyzed cyclizations of alkynes usually favor 6-exo-dig over 7-
endo-dig,10 except for some limited cases using terminal11,12 and
arylated alkynes.13 In the reaction of the intermediate 5, the 6-exo
cyclization might be promoted by the electron-donating nature
of the indole ring, which can effectively stabilize a developing
positive charge at the neighboring alkyne carbon when activated
Received: February 23, 2015
Published: March 12, 2015
© 2015 American Chemical Society
1774
DOI: 10.1021/acs.orglett.5b00550
Org. Lett. 2015, 17, 1774−1777

Organic Letters
Letter
a
diyne 6 compared with alkyne 8 toward indole formation can be
more clearly seen in the competition experiment shown in
Scheme 2.
Table 1. Optimization of the Reaction Conditions
Scheme 2. Comparison of the Reactivities toward Indole
Formation between Diynyl- and (Phenylethynyl)anilines
ab
,
c
% yield (%)
solvent
time
(h)
2a/3a
b
entry
catalysts (5 mol %)
(0.1 M)
(ratio )
10a
56
14
1
Ph3PAuCl/AgOTf
L1AuCl/AgOTf
L2AuCl/AgOTf
L3AuCl/AgOTf
L3Au(MeCN)SbF6
IPrAuCl/AgOTf
IPrAuCl/AgNTf2
IPrAuCl/AgOTs
IPrAuCl/AgBF4
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
AgOTf
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
MeCN
EtOH
DCE
DCE
DCE
DCE
DCE
5
10
5
28 (85/15)
48 (91/9)
27 (85/15)
76 (93/7)
3 (93/7)
86 (88/12)
32 (85/15)
57 (95/5)
29 (98/2)
<47 (93/7)
trace
2
3
43
4
2
−
39
5
5
6
2
−
ca. 33
7
8
8
6
−
trace
−
9
5
10
11
12
2
6
trace
2
<17 (93/7)
73 (92/8)
−
−
trace
58
d
13
8
e
a
b
1
14
24
4
Ratios were determined by H NMR. The competition experiment
e
f
15
e
AuCl
N.R.
was conducted with IPrAuCl/AgOTf (5 mol %) in DCE at −20 °C.
c
The horizontal axis indicates the time of NMR measurement.16
f
16
AuCl3
4
N.R.
e
f
17
PtCl4
4
N.R.
a
Reaction was carried out using 1a (0.15 mmol) and catalyst (5 mol
b
%) at 0.1 M at 50 °C. Ratios were determined by 1H NMR analysis.
The conjugated diyne has a sufficient level of reactivity for
gold-catalyzed indole formation, although it is relatively lower
than that of the isolated alkyne. A search for suitable catalysts and
solvents for the intramolecular consecutive cyclization of 1a was
then conducted (Table 1). When conjugated diyne 1a was
treated with PPh3AuCl/AgOTf (5 mol %) in DCE at 50 °C, the
desired fused indole derivatives 2a/3a and alkynylindole
derivative 10a were obtained in 28% and 56% yields, respectively
(entry 1). The ratio of 2a/3a was determined by 1H NMR after
purification of 2a/3a as an isomeric mixture. Surprisingly, 7-endo-
dig cyclization preferentially proceeded in the second cyclization
(2a/3a = 85/15). The reactions using XPhos (L1) or BrettPhos
(L2) in place of PPh3 gave the fused indoles 2a/3a in 48% and
27% yield, respectively (entries 2 and 3). Use of JohnPhos (L3)
resulted in efficient conversion to give a good yield of fused
indoles 2a/3a (76%, entry 4). The most efficient conversion was
observed when an N-heterocyclic carbene ligand, IPr, was used
(86%, entry 6). Compared with AgOTf (entry 6), other silver
salts such as AgNTf2, AgOTs, and AgBF4 were less effective
(entries 7−9). Of the four solvents tested (DCE, toluene,
MeCN, and EtOH), DCE was the best (entries 6 and 10−12).
The reaction at lower temperature (rt) reduced the yield slightly
(73%, entry 13). Use of AgOTf alone produced the alkynylindole
10a in 58% yield (entry 14). The reactions using AuCl, AuCl3
without any phosphine or carbene ligands, or PtCl4 were
unsuccessful (entries 15−17).
c
d
e
(Combined) isolated yields. The reaction was conducted at rt. 0.1
f
mmol of 1a was used. N.R. = No reaction.
(88%), respectively (entries 2 and 3). In both cases, the 7-endo
product was obtained with good selectivities (>90/10). A range
of substituents at the conjugated diyne terminus (R2) were
tolerated, including benzene rings bearing an electron-donating
or -withdrawing group (entries 4 and 5). The observed low
regioselectivity of the reaction of 1e (R2 = 4-(MeO2C)C6H4)
might result from the activation of 6-exo cyclization by the
electron-deficient phenyl group. Interestingly, use of 1f bearing
an alkyl group exclusively afforded the 7-endo-product 2f in 78%
yield (entry 6).
Preliminary results of the reaction of diamine derivatives 11
are shown in Table 3. These reactions required an increased
loading of the catalyst (10 mol %) and higher temperature (80
°C) because of the low reactivity. The reaction of 11a bearing a
free primary amino group (R2 = H) was unsuccessful and
produced a complex mixture of unidentified products (entry 1).
The reaction of the corresponding carbamate derivative 11b (R2
= Boc) was slow to give the alkynylindoles 14b (entry 2). Due to
With the conditions optimized (Table 1, entry 6), the cascade
reaction was investigated using various substrates (Table 2). The
reaction of 1b and 1c with electron-donating or -withdrawing
groups at the para-position of the amino group (R1) gave the
desired double cyclization products 2b/3b (86%) and 2c/3c
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Letter
a
Table 2. Reaction of Various Conjugated Diynes
b
c
entry
subst.
R1
R2
time (h)
yield (%)
ratio (2/3)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
Ph
Ph
Ph
2
86
86
88
90
88/12
OCF3
CO2Me
H
2
91/9
1.5
2
90/10
4-(MeO)C6H4
4-(MeO2C)C6H4
n-Pr
94/6
d
H
1
71−92
78
56−61/44−39
100/0
H
1
a
b
c
1
Reaction conditions: IPrAuCl/AgOTf (5 mol %) in DCE (0.1 M) at 50 °C. Combined isolated yields. Ratios were determined by H NMR
d
analysis after purification of the isomeric mixture. Low reproducibility due to the products instability.
a
density functional theory (DFT) based exploration of the origin
Table 3. Reaction of Ethylenediamine-Type Substrates
of the regioselectivity (Figure 1). The energy diagram clearly
b
c
% yield (ratio )
time
(h)
entry subst.
R1
Ph
R2
12/13
14
Figure 1. DFT calculations on cyclization of 10a [M06-2X/6-31G(d,p)
&SDD(Au)].
1
2
3
11a
11b
11c
H
24
24
8
complex mixture
Ph
Boc
Boc
trace
79
d
n-Pr
49−73 (82−85/18−15)
−
suggests that the kinetically and thermodynamically more
favorable pathway is the 7-endo-dig cyclization. Both cyclizations
from the starting complex 10a·AuPMe319 proceed smoothly, and
7-endo-dig cyclization requires a lower activation energy (14.0
kcal/mol) than that of 6-exo-dig (17.3 kcal/mol). However, the
cyclizations are remarkably both highly endothermic processes
and retro-cyclizations should occur very smoothly. Thus, an
equilibration between INT-1 and INT-2 via 10a·AuPMe3 should
exist and the seven-membered ring formation proceeds
preferentially through INT-2, which is more stable than INT-1
by 1.7 kcal/mol.
We assumed that the thermodynamic preference for INT-2
may result from ring strain of the six-membered ring in INT-1
fused with the indole ring. To evaluate this possibility, we
investigated the reaction of alkynylbenzene derivative 15
(Scheme 4, a benzene congener of the alkynylindole
intermediate 10a). In this case, the ring strain for the 6-exo-
cyclization would be considerably less compared with that from
10a. As expected, the 6-exo-dig cyclization product 17 was
preferentially produced (16/17 = 13/87) from 15, which
partially supports our assumption. However, at the present stage
a
Reaction conditions: IPrAuCl/AgOTf (10 mol %) in DCE (0.1 M) at
80 °C. Combined isolated yields. Ratios were determined by H
NMR analysis. Low reproducibility due to the products instability.
b
c
1
d
speculation that steric repulsion between R1 and R2 groups
obstructs progress of the second cyclization, the reaction of the
aliphatic diyne derivative 11c was examined (R1 = n-Pr). This
reaction led to the desired fused indole products 12c/13c in 49−
73% yields (entry 3). The observed low reproducibility is because
of the instability of 12c/13c bearing a sterically congested
enamine structure. Thus, the 1,2-diamine derivatives have
proven to be less suitable substrates for the present gold-
catalyzed cascade cyclization.
To obtain some insight of the reaction mechanism and
regioselectivity, we investigated the second cyclization of the
possible intermediate 10a (Scheme 3). Also in this case, the
seven-membered ring formation predominated to give a mixture
of 2a and 3a in an 89:11 ratio, essentially the same as the original
reaction of diyne 1a (entry 1, Table 2).18 We then undertook a
Scheme 3. Reaction of the Possible Intermediate 10a
Scheme 4. Reaction of the Benzene Congener 15
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Organic Letters
Letter
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of our understanding, we cannot rule out another possibility that
the protodeauration step might control the regioselectivity of the
second cyclization. Further calculations to elucidate the
protodeauration pathways from INT-1 and INT-2 are now
underway.
In summary, a novel gold-catalyzed cascade cyclization of
conjugated diynes was developed. This reaction provides direct
access to oxepino[1,7-a]indole derivatives with good functional
group tolerance. The observed 7-endo-selectivity was well
rationalized by DFT calculations: the second ring formation
proceeds through a more stable intermediate. Further develop-
ment and application of this transformation in natural product
syntheses are underway in our laboratory.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(12) For related 7-endo-dig cyclization using other metals, see: (a) Bera,
M.; Roy, S. J. Org. Chem. 2009, 74, 8814−8817. (b) Tsukano, C.;
Yokouchi, S.; Girard, A.-L.; Kuribayashi, T.; Sakamoto, S.; Enomoto, T.;
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L.; Enomoto, T.; Yokouchi, S.; Tsukano, C.; Takemoto, Y. Chem.
Asian J. 2011, 6, 1321−1324.
Experimental procedures, characterization data for all new
compounds, details of kinetic experiments, and computational
investigations. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) (a) Zhang, L.; Ye, D.; Zhou, Y.; Liu, G.; Feng, E.; Jiang, H.; Liu, H.
J. Org. Chem. 2010, 75, 3671−3677. (b) Pan, B.; Lu, X.; Wang, C.; Hu,
Y.; Wu, F.; Wan, B. Org. Lett. 2014, 16, 2244−2247.
AUTHOR INFORMATION
Corresponding Authors
■
(14) (a) Ikegashira, K.; Oka, T.; Hirashima, S.; Noji, S.; Yamanaka, H.;
Hara, Y.; Adachi, T.; Tsuruha, J.; Doi, S.; Hase, Y.; Noguchi, T.; Ando, I.;
Ogura, N.; Ikeda, S.; Hashimoto, H. J. Med. Chem. 2006, 49, 6950−6953.
(b) Zheng, X.; Hudyma, T. W.; Martin, S. W.; Bergstrom, C.; Ding, M.;
He, F.; Romine, J.; Poss, M. A.; Kadow, J. F.; Chang, C.-H.; Wan, J.;
Witmer, M. R.; Morin, P.; Camac, D. M.; Sheriff, S.; Beno, B. R.; Rigat,
K. L.; Wang, Y.-K.; Fridell, R.; Lemm, J.; Qiu, D.; Liu, M.; Voss, S.;
Pelosi, L.; Roberts, S. B.; Gao, M.; Knipe, J.; Gentles, R. G. Bioorg. Med.
Chem. Lett. 2011, 21, 2925−2929. (c) Sofia, M. J.; Chang, W.; Furman,
P. A.; Mosley, R. T.; Ross, B. S. J. Med. Chem. 2012, 55, 2481−2531.
(d) Ding, M.; He, F.; Hudyma, T. W.; Zheng, X.; Poss, M. A.; Kadow, J.
F.; Beno, B. R.; Rigat, K. L.; Wang, Y.-K.; Fridell, R. A.; Lemm, J. A.; Qiu,
D.; Liu, M.; Voss, S.; Pelosi, L. A.; Roberts, S. B.; Gao, M.; Knipe, J.;
Gentles, R. G. Bioorg. Med. Chem. Lett. 2012, 22, 2866−2871.
*E-mail: uchiyama@mol.f.u-tokyo.ac.jp (M.U.).
*E-mail: hohno@pharm.kyoto-u.ac.jp (H.O.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for the Encourage-
ment of Young Scientists (A) (to H.O.) and Scientific Research
(S) (to M.U.), as well as the Platform for Drug Design,
Discovery, and Development from the MEXT, Japan. S.N. is
grateful for Research Fellowships from the Japan Society for the
Promotion of Science (JSPS) for Young Scientists.
(15) Kraxner, J.; Hubner, H.; Gmeiner, P. Arch. Pharm. Pharm. Med.
̈
Chem. 2000, 333, 287−292.
(16) Because the reaction partially proceeds before the NMR
measurement even when the catalyst was added at a low temperature,
the ratio at the zero time is slightly variable for every experiment.
(17) For a review on gold-catalyzed indole formation of alkynylaniline
derivatives, see: (a) Abbiati, G.; Marinelli, F.; Rossi, E.; Arcadi, A. Isr. J.
Chem. 2013, 53, 856−868. For trapping of vinyl gold intermediates in
related reactions, see: (b) Hashmi, A. S. K.; Ramamurthi, T. D.;
Romingera, F. Adv. Synth. Catal. 2010, 352, 971−975.
(18) The reaction of a possible intermediate 14c showed slightly low
regioselectivity (12c:13c = 75:25; see Supporting Information).
(19) We confirmed that Me3PAuCl/AgOTf shows similar regiose-
lectivity (2a:3a = 82:18) although the reactivity was considerably
decreased (<6% yield of 2a/3a; 45% of 10a after 24 h at 50 °C).
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