Gold-Catalyzed Cascade Reaction of Skipped Diynes for the Construction of a Cyclohepta[b]pyrrole Scaffold

Article abstract of DOI:10.1021/acs.orglett.7b01759

A gold-catalyzed cascade reaction of skipped diynes (1,4-diynes) and pyrroles has been developed. This reaction proceeds by the consecutive regioselective hydroarylation of two alkynes with a pyrrole, followed by a 7-endo-dig cyclization to give 1,6-dihydrocyclohepta[b]pyrroles in good yields. The direct synthesis of cyclohepta[b]indoles using indole nucleophiles has also been reported.

Full text of DOI:10.1021/acs.orglett.7b01759

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Cascade Reaction of Skipped Diynes for the
Construction of a Cyclohepta[b]pyrrole Scaffold
Naoka Hamada, Yusuke Yoshida, Shinya Oishi, and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
S
* Supporting Information
ABSTRACT: A gold-catalyzed cascade reaction of skipped diynes (1,4-
diynes) and pyrroles has been developed. This reaction proceeds by the
consecutive regioselective hydroarylation of two alkynes with a pyrrole,
followed by a 7-endo-dig cyclization to give 1,6-dihydrocyclohepta[b]-
pyrroles in good yields. The direct synthesis of cyclohepta[b]indoles
using indole nucleophiles has also been reported.
kipped diynes (1,4-diynes) have been used extensively as
building blocks for the synthesis of polyunsaturated fatty
Scheme 1. Sequential Gold(I)-Catalyzed Hydroarylation of a
Diyne with a Pyrrole
S
acids (PUFAs).1,2 Following the pioneering work of Raphael and
Sandheimer, PUFAs are generally prepared by the reaction
between skipped diynes and metal acetylides used as a carbon
chain elongation strategy, followed by a partial reduction with
Lindlar’s catalyst. Skipped diynes are also recognized as versatile
synthons for the construction of various hetero- and carbocyclic
systems. For example, activated skipped diynes bearing an 3-oxo/
3-methylidene group or tetrasubstituted carbon at their 3-
position have been used to prepare pyrrole,3 pyridine,4 furan,5
benzene,6 pyrone,7 and 1,1′-bitriphenylene derivatives.8 Fur-
thermore, Czekelius and co-workers9 reported the development
of a gold-catalyzed reaction for the synthesis of carbocycles from
skipped diynes bearing a nucleophilic moiety at their
tetrasubstituted 3-position by the desymmetrization of two
alkynes. Despite considerable progress in this area, there have
been very few reports pertaining to cyclization reactions of this
type involving 3-unsubstituted 1,4-diynes. The lack of progress in
this area has been attributed in part to the importance of
disubstitution or a conjugated functional group at the 3-position
to the stabilization of these systems or the cyclization (i.e.,
Thorpe-Ingold effect10) of skipped 1,4-diynes. One important
exception to this observation is the Khand reaction reported by
Kerr and co-workers, where skipped diynes were stabilized in a
conformation that supported their cyclization via the formation
of a dicobalt complex.11
Homogenous gold catalysis has emerged as a powerful
synthetic tool for the activation of alkynes, thereby facilitating
nucleophilic addition to the alkyne bond to provide cyclization
products with high atom economy.12 Recent advances in this
area, including considerable contributions from Czekelius,9 have
shown that diynes are useful substrates for gold-catalyzed cascade
reactions.13,14 We recently reported the development of a gold-
catalyzed formal [4 + 2] reaction between 1,3-diynes and
pyrroles (Scheme 1A).15 This reaction proceeded through a
double hydroarylation cascade involving the initial intermolec-
ular hydroarylation of a 1,3-diyne at the 2-position of a pyrrole,
followed by an intramolecular hydroarylation to give a 4,7-
disubstituted indole.
Following on from this work, we switched our attention to the
reactivity of skipped diynes in the double hydroarylation cascade,
especially those not bearing a substituent at their 3-position. We
envisaged that the biggest challenge associated with this work
would be controlling the regioselectivity of both steps. For
example, intermolecular hydroarylation could occur at the 1-
position or the 2-position to give the corresponding regioiso-
meric enyne intermediates A and B (paths a and b, respectively).
Received: June 10, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01759
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The subsequent 7-endo-dig-type hydroarylation of intermediate
A·[Au+] (path c) would give cyclohepta[b]pyrrole 3, whereas the
generally favored 6-exo-dig cyclization16 of A·[Au+] (path d) or
6-endo-dig cyclization of B·[Au+] (path e), followed by an
aromatization step, would lead to the regioisomeric indoles 4 and
5, respectively. Notably, the use of unsymmetrical skipped diynes
could result in up to six isomeric products. The lack of any
positive effects associated with the substitution of the 3-position,
as described above, would also provide another challenging issue.
Herein, we report the regioselective formation of 1,6-
dihydrocyclohepta[b]pyrrole derivatives 3, which are homo-
logues of 4,7-disubstituted indoles, by the gold-catalyzed [5 + 2]
reaction of skipped diynes with pyrroles. We also report
consecutive hydroarylation reactions using an indole as a
nucleophile for the direct synthesis of cyclohepta[b]indoles,
which are important structural motifs found in numerous natural
products and pharmaceutical compounds.17
We initially examined the reaction of 1,5-diphenylpenta-1,4-
diyne (1a) with pyrrole (2a) (2 equiv) in the presence of various
gold catalysts (10 mol %) (Table 1). The use of IPrAuCl/AgSbF6
allowed for the formation of the [5 + 2] cyclization product 1,6-
dihydrocyclohepta[b]pyrrole (3a) (14%) along with a small
amount of the regioisomeric indoles 4a (1%) and 5a (2%) (entry
1). Although the use of PPh3, BrettPhos (L1), or JohnPhos (L2)
as a phosphine ligand did not lead to an improvement in the
efficiency of the catalyst (entries 2−4), the commercial gold
catalyst JohnPhosAu(MeCN)SbF6 led to a considerable
improvement in the yield of 3a to 69% (entry 5). After a series
of different solvents was screened under various reaction
temperatures with a 5 mol % loading of the catalyst (entries
6−11), we found that the use of toluene as a solvent at 80 °C led
to an increase in the yield of 3a (72%, entry 11). Finally, we
examined the stoichiometry of the reaction and found that
increasing the amount of pyrrole (10 equiv) had very little impact
on the reaction (entry 14). Furthermore, the use of a reduced
charge of pyrrole (1.1 equiv) only resulted in a slight reduction in
the yield of 3a (63%, entry 13). It is noteworthy that the second
hydroarylation proceeded preferentially via a 7-endo-dig pathway
(path c, Scheme 1) rather than a 6-exo-dig pathway (path d).
Furthermore, the first hydroarylation occurred regioselectively at
the terminal carbon of the skipped diyne moiety (path a).
Having established efficient conditions for the selective
synthesis of 1,6-dihydrocyclohepta[b]pyrrole 3a, we proceeded
to evaluate the substrate scope of this reaction (Table 2). Diaryl
Table 2. Reaction of Symmetrical Skipped Diynes Bearing
a
Various Substituents
a
Table 1. Optimization of Reaction Conditions
b
entry
substrate
R
time (h)
yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
3
3
71
80
64
32
72
72
80
C6H4(4-OMe)
C6H4(4-Br)
C6H4(4-CN)
C6H4(4-Me)
C6H4(3-Me)
C6H4(2-Me)
n-Bu
3
12
3
b
yield (%)
3
solvent
(0.1 M)
time
(h)
1g
1h
3
entry
catalysts (mol %)
3a
4a
5a
c
24
<24
1
2
3
4
5
6
7
8
9
10
IPrAuCl/AgSbF6 (10)
Ph3PAuCl/AgSbF6 (10)
L1AuCl/AgSbF6 (10)
L2AuCl/AgSbF6 (10)
L2Au(MeCN)SbF6 (10)
L2Au(MeCN)SbF6 (5)
L2Au(MeCN)SbF6 (5)
L2Au(MeCN)SbF6 (5)
L2Au(MeCN)SbF6 (5)
L2Au(MeCN)SbF6 (5)
L2Au(MeCN)SbF6 (5)
L2Au(MeCN)SbF6 (5)
L2Au(MeCN)SbF6 (5)
L2Au(MeCN)SbF6 (5)
DCE
24
24
24
24
18
18
18
24
24
24
3
14
4
1
2
1
a
Reactions were conducted using a mixture of 1, pyrrole 2a (2 equiv),
g
b
DCE
−
2
and catalyst (5 mol %) in toluene (0.1 M) at 80 °C. Isolated yields.
c
DCE
9
5
Contained inseparable impurities.
DCE
12
69
56
64
14
−
39
72
66
63
73
1
2
DCE
2
2
substituted skipped diyne 1b bearing an electron-donating
methoxy group at the 4-position of its phenyl rings reacted
smoothly to afford the corresponding [5 + 2] product 3b in 80%
yield within 3 h (entry 2). The 4-brominated derivative 1c also
reacted efficiently to produce 3c in 64% yield (entry 3), whereas
1d bearing cyano-substituted phenyl groups gave a much lower
yield (32% yield after 12 h, entry 4). The influence of the position
of the substituent on the phenyl ring was evaluated using tolyl
derivatives 1e−g. Interestingly, the reaction of the o-tolyl-
substituted skipped diyne 1g proceeded most efficiently to give
3g in 80% yield, whereas the p- and m-tolyl derivatives (1e and 1f,
respectively) gave slightly lower yields of the desired products
(72%). It is noteworthy that the aliphatic skipped diyne 1h
showed low reactivity toward the desired cyclization (entry 8).
These observations implied that electron-rich aryl groups
facilitated the formation of alkyne-gold complexes by stabilizing
the developing cationic charge to promote the desired
cyclization. In contrast, aliphatic and electron-deficient aryl
substituents failed to afford similar benefits (entries 4 and 8).
We then switched our focus to the reaction of unsymmetrical
skipped diynes (Table 3). In this case, we envisaged that the
regioselectivity of the first hydroarylation would determine the
DCE
2
1
toluene
MeCN
EtOH
THF
1
1
−
−
1
−
−
−
1
2
c
11
toluene
toluene
toluene
toluene
2
3
d
12
3
ce
,
13
14
6
2
1
cf
,
2
2
1
a
Unless otherwise noted, all of these reactions were carried out using
b
1a and 2 equiv of pyrrole 2a at 50 °C. Yields were determined by 1H
NMR analysis using dimethyl sulfone as an internal standard.
Reactions were carried out at 80 °C. Reaction was carried out at
100 °C. Reaction was conducted using 1.1 equiv of 2a. Reaction was
conducted using 10 equiv of 2a. Not detected.
c
d
e
f
g
B
DOI: 10.1021/acs.orglett.7b01759
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Reaction of Unsymmetrical Skipped Diynes Bearing Various Substituents
yield (%)
entry
substrate
R1
R2
3′
3″
ratio (3′/3″)
b
b
1
2
3
1′a
1′b
1′c
Ph
C6H4(4-OMe)
C6H4(4-OMe)
Ph
52
47
27
13
66:34
79:21
56:44
b
b
C6H4(4-CN)
c
c
Et
22
17
a
b
Reactions were conducted using a mixture of 1′, pyrrole 2a (2 equiv), and the catalyst (5 mol %) in toluene (0.1 M) at 80 °C. Determined by 1H
c
NMR analysis based on the combined isolated yields. Isolated yields.
distribution of the two possible products (i.e., 3′ vs 3″). Given
that the reactivity of the unsymmetrical skipped diynes could
vary depending on the electronic properties of their substituents,
we tested substrates 1′a−c bearing substituents with different
electronic properties. The reaction of unsymmetrical diaryl diyne
1′a (R1 = Ph, R2 = 4-anisyl) gave cyclohepta[b]pyrrole 3′a
(52%), along with the corresponding regioisomeric product 3″a
(27%).18 Skipped diyne 1′b, which was substituted with electron-
rich and -deficient aryl groups, led to an increase in the
regioselectivity of the reaction (79:21) in favor of 3′b (47%) over
3″b (13%). The major isomers 3′a,b were most likely formed as a
consequence of the first intermolecular hydroarylation occurring
at the more electron-rich triple bond of the diyne (i.e., the one
directly attached to the anisyl group). In contrast, the reaction of
diyne 1′c bearing phenyl and ethyl groups was less efficient,
leading to lower yields of 3′c (22%) and 3″c (17%), with very
little regioselectivity.
Scheme 2. Plausible Mechanism
Next, we investigated the effect of having a substituent on the
pyrrole ring using methylated pyrroles 2b−d (Table 4).
a
to form intermediate A. The subsequent 7-endo-dig hydro-
arylation of A would proceed via intermediate C to give 1,6-
dihydrocyclohepta[b]pyrrole 3. The remarkable high 7-endo-dig
selectivity in the second hydroarylation can be attributed in part
to the stabilization of the cation by the aryl group in positively
charged complex A·[Au+],19 as well as the five-membered ring
fusion in the transition states.20 However, further studies are
required to elucidate the observed regioselectivity.
Finally, we extended this cyclization to the synthesis of various
cyclohepta[b]indoles (Table 5). Cyclohepta[b]indole deriva-
tives have been reported to display a broad range of biological
activities,17 prompting considerable interest in the development
Table 4. Reaction with Substituted Pyrroles
b
entry
pyrrole
R
time (h)
product
yield (%)
1
2
3
4
2a
2b
2c
2d
H
3
9
3a
6b
6c
6d
71
25
57
19
1-Me
2-Me
3-Me
22
24
a
Reactions were conducted using a mixture of 1a, pyrrole (2 equiv),
and the catalyst (5 mol %) in toluene (0.1 M) at 80 °C. Isolated
b
a
Table 5. Reaction with Indoles
yields.
Although 2-methylpyrrole (2c) gave the corresponding
cyclohepta[b]pyrrole 6c in acceptable yield (57%, entry 3), the
N-methylpyrrole (2b) and 3-methylpyrrole (2d) gave much
lower yields of the desired products (19−25%, entries 2, 4).
These poor results were attributed to steric hindrance from the 1-
or 3-methyl group during the first or second hydroarylation, as
well as the unproductive nature of the first hydroarylation step at
the 2-position of 2d.
A plausible mechanism for the reaction is shown in Scheme 2.
As reported in our previous work,15 the cationic gold catalyst
would activate one of the triple bonds of skipped diyne 1 to
facilitate the first hydroarylation at the 2-position of pyrrole14f,15
b
entry
indole
R1
R2
time (h)
yield (%)
1
2
3
4
5
7a
7b
7c
7d
7e
H
H
15
6
74
88
70
56
75
OMe
Br
H
H
15
24
20
CO2Me
H
H
Me
a
Reaction conducted using a mixture of 1a, indole (2 equiv), and
b
catalyst (5 mol %) in toluene (0.1 M) at 80 °C. Isolated yields.
C
DOI: 10.1021/acs.orglett.7b01759
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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thus investigated the reaction of skipped diyne 1a with
unsubstituted indole 7a in the presence of PPh3AuNTf2.
Pleasingly, this reaction afforded the desired cyclohepta[b]indole
derivative 8a in 74% yield (entry 1). Several other indoles 7b−e,
including 5-methoxy, 5-bromo, 5-methoxycarbonyl, and N-
methyl-indole also reacted smoothly to give the corresponding
cyclohepta[b]indoles (entries 2−5). Among the indoles tested
(7a−e), 5-methoxyindole (7b) was discovered to be the most
reactive, affording the corresponding cyclohepta[b]indole 8b in
88% yield.
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In summary, we developed a gold-catalyzed cascade reaction
for the construction of the cyclohepta[b]pyrroles from skipped
diynes and pyrroles. Remarkably, the second hydroarylation
proceeded selectively in a 7-endo-dig manner. The use of an
indole as a nucleophile in this reaction allowed for the direct
synthesis of cyclohepta[b]indoles. Further studies toward the [5
+ 2] cyclization of skipped diynes and pyrroles, including
elucidating the regioselectivity of this reaction, are currently
underway in our laboratory.
(14) For selected papers, see: (a) Rao, W.; Chan, P. W. H. Chem. - Eur.
J. 2014, 20, 713−718. (b) Naoe, S.; Saito, T.; Uchiyama, M.; Oishi, S.;
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̈
̈
ASSOCIATED CONTENT
* Supporting Information
■
M.; Rudolph, M.; Wieteck, M.; Rominger, F.; Frey, W. Chem. - Eur. J.
S
2010, 16, 9846−9854. (e) Nosel, P.; dos Santos Comprido, L. N.;
̈
Lauterbach, T.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. J. Am.
Chem. Soc. 2013, 135, 15662−15666. (f) Naoe, S.; Suzuki, Y.; Hirano,
K.; Inaba, Y.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2012, 77, 4907−
4916.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01759.
Experimental procedures, characterization data for all new
compounds (PDF)
(15) Matsuda, Y.; Naoe, S.; Oishi, S.; Fujii, N.; Ohno, H. Chem. - Eur. J.
2015, 21, 1463−1467.
(16) (a) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180−3211.
AUTHOR INFORMATION
■
́
́
(b) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Commun. 2007, 333−
̃
Corresponding Author
*E-mail: hohno@pharm.kyoto-u.ac.jp
ORCID
346. (c) Shen, H. C. Tetrahedron 2008, 64, 3885−3903. (d) Patil, N. T.;
Singh, V. J. Organomet. Chem. 2011, 696, 419−432.
(17) (a) Stempel, E.; Gaich, T. Acc. Chem. Res. 2016, 49, 2390−2402.
(b) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351, 1517−
1522. (c) Xu, S.; Zhou, Y.; Xu, J.; Jiang, H.; Liu, H. Green Chem. 2013,
15, 718−726.
Shinya Oishi: 0000-0002-2833-2539
Hiroaki Ohno: 0000-0002-3246-4809
Notes
(18) The structures of the major isomers 3′ were confirmed by the
NOE between the pyrrole 3-H and the proton of R1 group. For more
details, see the Supporting Information.
The authors declare no competing financial interest.
(19) This rationalization is important when the formation of the
alkyne-gold(I) cationic complex is the rate-limiting step. Another
important aspect relevant to the observed endo-selectivity would be the
LOMO umpolung concept developed by Alabugin and co-workers,
which allows both endo and exo cyclization of the alkyne-gold complex,
see: (a) Gilmore, K.; Mohamed, R. K.; Alabugin, I. V. WIREs Comput.
Mol. Sci. 2016, 6, 487−514. (b) Alabugin, I. V.; Gilmore, K. Chem.
Commun. 2013, 49, 11246−11250.
ACKNOWLEDGMENTS
■
This work was supported by the JSPS KAKENHI (Grant Nos.
JP15KT0061 and JP17H03971), the Platform Project for
Supporting Drug Discovery and Life Science Research (Platform
for Drug Discovery, Informatics, and Structural Life Science)
from Japan Agency for Medical Research and Development
(AMED), and the Uehara Memorial Foundation.
(20) In our related study,14b a five-membered fusion favored 7-endo-dig
cyclization, whereas a six-membered ring fusion favored 6-exo-dig
cyclization.
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DOI: 10.1021/acs.orglett.7b01759
Org. Lett. XXXX, XXX, XXX−XXX