Rhodium-Catalyzed Regioselective C7-Functionalization of Indole Derivatives with Acrylates by Using an N-Imino Directing Group

Article abstract of DOI:10.1055/s-0036-1588530

An efficient rhodium-catalyzed method for C-H olefination at the C7 position of indoles has been developed. The N-imino directing group was shown to be crucial for high regioselectivity and reactivity of the metal catalyst. The utility of this protocol was further demonstrated through a concise, four-step synthesis of pyroquilon from indole.

Full text of DOI:10.1055/s-0036-1588530

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
L. Xu et al.
Letter
Synlett
Rhodium-Catalyzed Regioselective C7-Functionalization of Indole
Derivatives with Acrylates by Using an N-Imino Directing Group
Lanting Xua
Lushi Tan*b
Dawei Ma*c
R
N
Zn
H
X
R
R
4 examples
70–85% yield
a Shanghai Research Institute of Fragrance and Flavor Industry,
480 Nanning Road, Shanghai 200232, P. R. of China
b Merck Research Laboratories, P.O. Box 2000, RY800-D280,
Rahway, NJ 07065-0900, USA
1 mol% [Cp*RhCl2]2
4 mol% AgSbF6
NH4Cl
CO2R'
R
CO2R'
+
N
N
X
Cu(OAc)2•H2O
X
N
N
Raney-Ni
H2
lushi_tan@merck.com
c State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
P. R. of China
N
H
CO2R'
X
4 examples
68–78% yield
19 examples
42–85% yield
CO2R'
madw@sioc.ac.cn
Dedicated to Professor Victor Snieckus on the occasion of his
80th birthday
Received: 07.06.2017
Accepted after revision: 06.07.2017
Published online: 17.08.2017
Pd(II)-catalyzed C7-regioselective arylation of indoles with
the aid of a N-P(O)tBu2 directing group.12 More recently,
Chang’s group and our group respectively described the
direct C7-amination of N-pivaloylindole by employing
[Cp*IrCl2]2 as precatalyst and sulfonoazides as the nitrogen
source.13 Two other strategies are frequently used to
achieve direct functionalization at the 7-position of indole,
within which C2-sustituent indoles or indoline derivatives
were used as alternative substrates.9a,14 Despite the great
progress that has been made in regioselective direct C7-
functionalization of indoles, it is still highly desirable to ex-
plore a new generation of directing groups with the criteri-
ons of convenient introduction and cleavage, accurate di-
recting ability to the C7-position, and broad applications in
diverse reactions.
DOI: 10.1055/s-0036-1588530; Art ID: st-2017-r0441-l
Abstract An efficient rhodium-catalyzed method for C–H olefination
at the C7 position of indoles has been developed. The N-imino directing
group was shown to be crucial for high regioselectivity and reactivity of
the metal catalyst. The utility of this protocol was further demonstrated
through a concise, four-step synthesis of pyroquilon from indole.
Key words indoles, C7 regioselectivity, C–H activation, rhodium, ole-
fination
The substituted indole skeleton probably represents one
of the most significant units in medicinal chemistry and
has been referred to as a ‘privileged structure’ owing to its
excellent binding ability to many receptors.1–3 Motivated by
the widespread applications of this skeleton in the pharma-
ceutical field, many methods have been developed for their
preparation.4 Among a variety of well-established methods
for assembling substituted indoles, the transition-metal-
catalyzed C–H bond functionalization of simple indoles has
provided one of the most efficient, straightforward and
atom-economic approaches for assembling substituted in-
doles.5–9 Nevertheless, due to the higher electron density of
the C2 and C3 positions,6b,10 selective direct functionaliza-
tion at the 7-position of indoles remains challenging.
The first regioselective C7-functionalization of indole
that has no protecting group or substituent at C2 or C3 po-
sition was achieved by Hartwig in 2011.9b This seminal
work showed that high C7-selectivity could be realized by
using N-silyl as a directing group under Ir catalysis via a
five-membered metallocycle 2. Further work on the Rh(III)-
catalyzed regioselective C7-functionalization of indole by
using N-pivaloylindole was later reported by our team in
2016.11 Shortly after this, Shi and co-workers developed the
Previous works
[Ir]
N
N
1)
2)
Et
Et
HSi
Et
Si
Ir
Et
1
2
[Rh], [Pd] or [Ir]
N
N
X
X
Y
Y
M
O
O
3
4
This work
[M]
unfavored
[M]
M
N
N
N
favored
N
N
N
M
R
6
5
7
R
R
C7-selectivity
Scheme 1 Design of directing groups for regioselective C–H bond
cleavage
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
L. Xu et al.
Letter
Synlett
In a continuation of our recent effort on the transition-
metal-catalyzed regioselective C–H functionalization reac-
tion,11,13b,15 We postulated that using N-aminoindoles such
as 5 would allow C–H bond cleavage to occur at the 7-posi-
tion through a more stable five-membered metallocycle 6
and would disfavor C2-functionalization that could only oc-
cur through a less stable, four-membered metallocycle 7
(Scheme 1). With the idea in mind, we prepared N-amino-
indole by treatment of indole with potassium tert-butylate
and hydroxylamine-O-sulfonic acid.16 Unfortunately, all of
our attempted couplings of N-aminoindole with methyl ac-
rylate failed to provide any of the desired product in the
presence of a Rh catalyst under various conditions.17 We
then surveyed a variety of N-protected N-aminoindoles un-
der the same conditions. As summarized in Table 1, only a
complex mixture was obtained (entries 1 and 2) with N-
acetylamino indole 8a and N-methanesulfonamino indole
8b, likely due to weak coordination of the catalyst by the
electron-withdrawing amide/sulfonamide groups. In the
case of N-nitrosoindole 8c, we observed cleavage of the N–
N bond and no substitution at the desired position (entry
3). To our delight, imine 8d, derived from N-aminoindole
and trimethylacetaldehyde, gave the desired olefination
product 10d as a single regioisomer in 20% isolated yield
(entry 4). This result indicated that the sp2-hybridized N
atom might provide an effective handle to direct the cata-
lyst to the C7 position, so a range of imino-derivatives were
screened. In the case of benzylidene-protected N-aminoin-
dole 8e, alkenylation took place at the ortho-position of the
phenyl group rather than the indole (entry 5). To overcome
this problem, the phenyl group was replaced with 2,6-
disubstituted phenyl groups and significantly improved
yields were observed in the case of 2,6-difluorobenzalde-
hyde and 2,4,6-trimethylbenzaldehyde imines 8f and 8g
(entries 6 and 7). The best result was obtained by using 2,6-
dimethylbenzaldehyde derived imine 8ha (entry 8).18
With the coupling of 8ha and methyl acrylate as a mod-
el reaction, a range of catalysts, oxidants, and solvents were
then tested to improve the reaction yield (Table 2). Control
reactions confirmed that [Cp*RhCl2]2 as catalyst and AgSbF6
as counter-ion donor were both indispensable for the reac-
tion (entries 1 vs. 2 and 3) and that copper acetate could re-
generate the rhodium catalyst by oxidation (entries 1 vs. 4).
Iridium(III) could also promote this reaction but with lower
yield (entry 5). Further screening revealed the importance
of solvent (entries 6–11), with a significantly improved 85%
yield achieved in dichloromethane. Other copper and silver
salts as oxidants were also tested but none were more effi-
cient (entries 12–14).
With the optimized conditions in hand, we next ex-
plored the substrate scope and functional group tolerance
of the reaction. As shown in Table 3, a series of indole deriv-
Table 2 Optimization of Reaction Conditionsa
1.0 mol% catalyst
N
N
N
N
4.0 mol% AgSbF6
+
CO2Me
solvent, oxidant
O
OMe
Table 1 Effect of N-Protecting Group on the C7 Alkenylation of Indole
8ha
10ha
9a
with Methyl Acrylatea
Entry
Catalyst
Oxidant
Solvent
Yield (%)b
[Cp*RhCl2]2, Cu(OAc)2•H2O,
.
AgSbF6, t-AmyOH
1
2
[Cp*RhCl2]2
none
Cu(OAc)2 H2O
t-AmyOH
t-AmyOH
t-AmyOH
t-AmyOH
t-AmyOH
DME
52
n.d.
n.d.
<5
31
54
42
36
15
<5
85
<5
14
71
N
+
CO2Me
.
X
N
X
130 °C
Cu(OAc)2 H2O
3c
4
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*IrCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
Cu(OAc)2 H2O
.
8
9a
10
CO2Me
none
Entry
X
Product
Yield (%)b
.
5
Cu(OAc)2 H2O
1
NHAc (8a)
NHMs (8b)
nitroso (8c)
–
n.d.
n.d.
n.d.
20
.
6
Cu(OAc)2 H2O
2
–
.
7
Cu(OAc)2 H2O
1,4-dioxane
CH2Br2
3c
4
–
.
8
Cu(OAc)2 H2O
tert-butylmethyleneamino (8d)
phenylmethyleneamino (8e)
10d
–
.
9
Cu(OAc)2 H2O
DCE
5d
6
n.d.
42
.
10
11
12
13
14
Cu(OAc)2 H2O
MeCN
2,6-difluorobenzyleneamino (8f)
2,4,6-trimethylbenzyleneamino (8g)
2,6-dimethylbenzyleneamino (8ha)
10f
10g
10ha
.
Cu(OAc)2 H2O
CH2Cl2
7
44
Ag2CO3
AgOAc
CH2Cl2
8
52
CH2Cl2
a Reaction conditions: 8 (0.25 mmol), 9a (1.0 mmol), [Cp*RhCl2]2 (1 mol%),
AgSbF6 (4 mol%), Cu(OAc)2·H2O (0.525 mmol), t-AmyOH (1.0 mL), 130 °C,
d
Cu(EH)2
CH2Cl2
48 h.
a Reaction conditions: 8ha (0.25 mmol), 9a (1.0 mmol), catalyst (1 mol%),
AgSbF6 (4 mol%), oxidant (0.525 mmol), solvent (1.0 mL), 130 °C, 48 h.
b Yield of isolated product.
b Yield of isolated product; n.d. = not detected.
c 76% indole was obtained.
d The ortho-position of benzylidene alkenylation product (30%) was ob-
tained.
c AgSbF6 was not added.
d Cu(EH)2 = copper(II) 2-ethylhexanoate.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
L. Xu et al.
Letter
Synlett
atives with various substituents were subjected to olefina-
tion with methyl acrylate, and moderate to good yields
were obtained.19,20 Substrates with electron-donating
groups and halogens at the C4 position gave good yields
(entries 1–6); but strongly electron-withdrawing groups
such as CN at the C4 position completely shut down the re-
action (entry 7). The tolerance of halogens at C4, C5, and C6
provides evidence that the oxidative addition of the metal
catalyst is suppressed under the current conditions and,
furthermore, furnishes these products with a convenient
handle for functional elaboration (entries 4–6, 10–12, and
14). Substituents at the C6 position led to lower yields, pos-
sibly due to steric hindrance (entries 13 and 14). Pharma-
ceutically useful compounds such as tryptamine and tryp-
tophol derivatives also reacted smoothly at the C7 position
by employing the current method (entries 16 and 17). Un-
fortunately, attempts to vary the olefin all met with failure,
including styrene, α-methylacrylate and α,β-unsaturated
ketones. Only acrylic acid or its esters worked well (entries
18–20).
Interestingly, N–N bond cleavage occurred during the
olefination when tetrahydrocarbazole derivative 14b and
its analogue 14a were used under the same C–H bond-func-
tionalization conditions, giving olefins 15 directly in mod-
erate yields (Scheme 2). This may be a result of the in-
creased steric bulk in these olefination products; such a
phenomenon has not been observed in other substrates.
Table 3 Scope of the Reactiona
R
R
n
n
X
X
1.0 mol% [Cp*RhCl2]2
4.0 mol% AgSbF6
N
N
1.0 mol% [Cp*RhCl2]2
4.0 mol% AgSbF6
N
N
N
+
CO2R'
N
N
H
+
CO2Me
Cu(OAc)2•H2O,
CH2Cl2, 120–140 °C
Cu(OAc)2•H2O,
t-AmylOH, CH2Cl2,
120–140 °C
O
OR'
10ha
O
OM
8h
9
Yield (%)b
14a: n = 1
14b: n = 2
15a: n = 1, 48%
15b: n = 2, 50%
Entry
X
R
R′
Product
9a
1
2
4-Me
4-OBn
4-OMe
4-Cl
4-Br
4-F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
10hb
10hc
10hd
10he
10hf
10hg
–
85
80
73
64
61
60
NR
72
70
72
70
69
49
52
69
70
72
78
75
42
Scheme 2 Reagents and conditions: 14 (0.25 mmol), 9a (1.0 mmol),
[Cp*RhCl2]2 (1 mol%), AgSbF6 (4 mol%), Cu(OAc)2·H2O (0.525 mmol),
CH2Cl2/t-AmylOH (1:1), 140 °C.
3
4
The N-imino directing group was conveniently removed
from the products by reduction with Zn/NH4Cl to afford
α,β-unsturated esters 1121 (Scheme 3), or by Raney Ni-cata-
lyzed hydrogenation to give saturated esters 12.22 Under
more forcing conditions (70 °C, 40 kg/cm2 H2), 10ha was
converted directly into indoline lactam 1323 (pyroquilon) in
95% yield, through hydrogenolysis, hydrogenation of both
acrylate and the indole 5-membered ring followed by intra-
molecular amidation. Pyroquilon is a widely used agro-
chemical developed by Pfizer to prevent rice blast through
blocking biosynthetic access to velanin.24 Recent studies
also suggest that some compounds with this pyroquilon
core structure are potent and selective CYP11B1 inhibitors,
and are useful for the treatment of Cushing’s syndrome.25
Our present method (four-step synthesis from indole) pro-
vides a valuable tool for preparing pyroquilon analogues for
further biological testing.
In conclusion, we have developed a highly efficient
method for rhodium-catalyzed, C7 selective alkenylation of
indole derivatives by employing N-imino directing groups.
This protocol features low catalyst loading, diverse func-
tional group tolerance, and provides a straightforward
strategy to access privileged structural motifs in agrochem-
icals and pharmaceuticals.
5
6
7
4-CN
5-OMe
5-Me
5-Cl
5-Br
5-F
8
10hh
10hi
10hj
10hk
10hl
10hm
10hn
10ho
10hp
10hq
10hr
10hs
10ht
9
10
11
12
13c
14c
15d
16d
17d
18
19
20
6-Me
6-Cl
H
H
(CH2)2NPhth
(CH2)2OTBS
Me
Me
Bn
Et
H
H
H
H
H
H
H
H
a Reaction conditions: 8 (0.25 mmol), 9 (1.0 mmol), [Cp*RhCl2]2 (1 mol%),
AgSbF6 (4 mol%), Cu(OAc)2·H2O (0.525 mmol), CH2Cl2 (1.0 mL), 130 °C, 48–
72 h.
b Yield of isolated product. NR = no reaction.
c The reaction was carried out at 140 °C.
d t-AmylOH and CH2Cl2 were used as co-solvent in 1:1 volume ratio.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
L. Xu et al.
Letter
Synlett
Biol. 2008, 4, 313. (h) Fujita, M.; Ueda, T.; Iwata, M. Int. J. Pharm.
2010, 386, 195. (i) Yeung, K.-S.; Qiu, Z.; Xue, Q.; Fang, H.; Yang,
Z.; Zadjura, L.; D’Arienzo, C. J.; Eggers, B. J.; Riccardi, K.; Shi, P.-Y.;
Gong, Y.-F.; Browning, M. R.; Gao, Q.; Hansel, S.; Santone, K.; Lin,
P.-F.; Meanwell, N. A.; Kadow, J. F. Bioorg. Med. Chem. Lett. 2013,
23, 198. (j) Yeung, K.-S.; Qiu, Z.; Yin, Z.; Trehan, A.; Fang, H.;
Pearce, B.; Yang, Z.; Zadjura, L.; D’Arienzo, C. J.; Riccardi, K.; Shi,
P.-Y.; Spicer, T. P.; Gong, Y.-F.; Browning, M. R.; Hansel, S.;
Santone, K.; Barker, J.; Coulter, T.; Lin, P.-F.; Meanwell, N. A.;
Kadow, J. F. Bioorg. Med. Chem. Lett. 2013, 23, 203.
R
R
R
a) Zn, NH4Cl
b) Raney-Ni, H2
50 °C, 24 h
N
N
N
H
H
X
X
X
THF, r.t. to 50 °C
24–48 h
N
CO2Me
CO2Me
CO2Me
10h
11a: R = X = H, 85%
11b: R = H, X = 4-Me, 78%
11c: R = H, X = 4-F, 77%
12a: R = X = H, 78%
12b: R = H, X = 5-Br, 72%
12c: R = H, X = 4-F, 75%
12d: R = 3-(CH2)2OTBS,
X = H, 68%
11d: R = 3-(CH2)2OTBS, X = H, 70%
(3) (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
1172. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893. (c) Chen, F.-E.; Huang, J. Chem. Rev. 2005, 105,
4671. (d) de Sá Alves, F. R.; Barreiro, E. J.; Fraga, M.; Alberto, C.
Mini-Rev. Med. Chem. 2009, 9, 782. (e) Xu, H.; Lv, M. Curr. Pharm.
Des. 2009, 15, 2120. (f) Sharma, V.; Kumar, P.; Pathak, D. J. Het-
erocycl. Chem. 2010, 47, 491. (g) Lal, S.; Snape, T. J. Curr. Med.
Chem. 2012, 19, 4828.
c) Raney-Ni, H2
N
N
O
70 °C, 6 h
95%
N
CO2Me
10ha
13 (Pyroquilon)
(4) For books and reviews, see: (a) Cacchi, S.; Fabrizi, G. Chem. Rev.
2005, 105, 2873. (b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875. (c) Bandini, M.; Eichholzer, A. Angew. Chem.
Int. Ed. 2009, 48, 9608. (d) Joucla, L.; Djakovitch, L. Adv. Synth.
Catal. 2009, 351, 673. (e) Gribble, G. W.; Badenock, J. C. Hetero-
cyclic Scaffolds II: Reactions and Applications of Indoles;
Springer: Berlin, 2010. (f) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011,
111, PR215–PR283. (g) Inman, M.; Moody, C. J. Chem. Sci. 2013,
4, 29. (h) Bartoli, G.; Dalpozzo, R.; Nardi, M. Chem. Soc. Rev.
2014, 43, 4728.
Scheme 3 Reagents and conditions: (a) Zn, THF/NH4Cl (1:1), r.t. to 50 °C,
24–48 h; (b) Raney-Ni, H2, 50 °C, 24 h; (c) Raney-Ni, H2 (40 kg/cm2),
70 °C, 6 h.
Funding Information
We are grateful to the Shanghai Sailing Program (17YF1418900) and
Merck for their financial support.
)(
(5) (a) Yoshikai, N.; Wei, Y. Asian J. Org. Chem. 2013, 2, 466.
(b) Sandtorv, A. H. Adv. Synth. Catal. 2015, 357, 2403. (c) Guo, T.;
Huang, F.; Yu, L.; Yu, Z. Tetrahedron Lett. 2015, 56, 296.
Supporting Information
(6) For selected Pd-catalyzed direct C–H bond functionalization of
indole, see: (a) Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun.
2005, 1854. (b) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.;
Gaunt, M. J. Angew. Chem. Int. Ed. 2005, 44, 3125. (c) Stuart, D.
R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072.
(d) García-Rubia, A.; Arrayás, R. G.; Carretero, J. C. Angew. Chem.
Int. Ed. 2009, 48, 6511. (e) Choy, P. Y.; Lau, C. P.; Kwong, F. Y. J.
Org. Chem. 2010, 76, 80. (f) Liu, Q.; Li, Q.; Ma, Y.; Jia, Y. Org. Lett.
2013, 15, 4528. (g) Wu, J.; Lan, J.; Guo, S.; You, J. Org. Lett. 2014,
16, 5862. (h) Mantenuto, S.; Ciccolini, C.; Lucarini, S.; Piersanti,
G.; Favi, G.; Mantellini, F. Org. Lett. 2017, 19, 608.
(7) For selected Rh-catalyzed direct C–H bond functionalization of
indole, see: (a) Schipper, D. J.; Hutchinson, M.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 6910. (b) Patureau, F. W.; Besset, T.;
Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 1064. (c) Shi, J.; Zhou,
B.; Yang, Y.; Li, Y. Org. Biomol. Chem. 2012, 10, 8953. (d) Zhou, B.;
Li, J.; Hu, F.; Shi, B.-F. Org. Lett. 2013, 15, 3460. (e) Xie, F.; Qi, Z.;
Yu, S.; Li, X. J. Am. Chem. Soc. 2014, 136, 4780. (f) Shi, J.; Zhao, G.;
Wang, X.; Xu, H. E.; Yi, W. Org. Biomol. Chem. 2014, 12, 6831.
(g) Zhang, L.; Qiu, R.; Xue, X.; Pan, Y.; Xu, C.; Wang, D.; Wang, X.;
Xu, L.; Li, H. Chem. Commun. 2014, 12385. (h) Lu, M.-Z.; Lu, P.;
Xu, Y.-H.; Loh, T.-P. Org. Lett. 2014, 16, 2614. (i) Wang, Q.; Xie, F.;
Li, X. J. Org. Chem. 2015, 80, 8361.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588530.
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References and Notes
(1) For books and reviews, see: (a) Sundberg, R. J. Indoles; Academic
Press: New York, 1970. (b) Ban, Y.; Murakami, Y.; Iwasawa, Y.;
Tsuchiya, M.; Takano, N. Med. Res. Rev. 1988, 8, 231. (c) Pindur,
U.; Lemster, T. Curr. Med. Chem. 2001, 8, 1681. (d) Ramirez, A.;
Garcia-Rubio, S. Curr. Med. Chem. 2003, 10, 10. (e) Kochanowska-
Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489.
(f) Zhang, M.-Z.; Chen, Q.; Yang, G.-F. Eur. J. Med. Chem. 2015, 89,
421. (g) Stempel, E.; Gaich, T. Acc. Chem. Res. 2016, 49, 2390.
(2) For the application of C7-substituted indoles, see: (a) Humber,
L. G.; Ferdinandi, E.; Demerson, C. A.; Ahmed, S.; Shah, U.;
Mobilio, D.; Sabatucci, J.; Lange, B. De.; Labbadia, F. J. Med.
Chem. 1988, 31, 1712. (b) Zhang, B.; Salituro, G.; Szalkowski, D.;
Li, Z.; Zhang, Y.; Royo, I.; Vilella, D.; Díez, M. T.; Pelaez, F.; Ruby,
C.; Kendall, R. L.; Mao, X.; Griffin, P.; Calaycay, J.; Zierath, J. R.;
Heck, J. V.; Smith, R. G.; Moller, D. E. Science 1999, 284, 974.
(c) Jones, R. A. Inflammopharmacology 2001, 9, 63. (d) Teng, X.;
Degterev, A.; Jagtap, P.; Xing, X.; Choi, S.; Denu, R.; Yuan, J.;
Cuny, G. D. Bioorg. Med. Chem. Lett. 2005, 15, 5039. (e) Pirrung,
M. C.; Liu, Y.; Deng, L.; Halstead, D. K.; Li, Z.; May, J. F.; Wedel,
M.; Austin, D. A.; Webster, N. J. G. J. Am. Chem. Soc. 2005, 127,
4609. (f) Omachi, A.; Ishioka, K.; Uozumi, A.; Kamikawa, A.;
Toda, C.; Kimura, K.; Saito, M. Res. Vet. Sci. 2007, 83, 5.
(g) Degterev, A.; Hitomi, J.; Germscheid, M.; Ch’en, I. L.; Korkina,
O.; Teng, X.; Abbott, D.; Cuny, G. D.; Yuan, C.; Wagner, G.;
Hedrick, S. M.; Gerber, S. A.; Lugovskoy, A.; Yuan, J. Nat. Chem.
(8) For selected Ru-catalyzed direct C–H bond functionalization of
indole, see: (a) Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 6262.
(b) Li, B.; Ma, J.; Xie, W.; Song, H.; Xu, S.; Wang, B. J. Org. Chem.
2013, 78, 9345. (c) Liang, L.; Fu, S.; Lin, D.; Zhang, X.-Q.; Deng,
Y.; Jiang, H.; Zeng, W. J. Org. Chem. 2014, 79, 9472. (d) Lanke, V.;
Bettadapur, K. R.; Prabhu, K. R. Org. Lett. 2015, 17, 4664.
(e) Leitch, J. A.; Mcmullin, C. L.; Mahon, M.; Bhonoah, Y.; Frost,
C. G. ACS Catal. 2017, 7, 2616.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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(9) See selected Ir-catalyzed direct C–H bond functionalization of
indole, see: (a) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.;
Maleczka, R. E.; Smith, M. R. J. Am. Chem. Soc. 2006, 128, 15552.
(b) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 4068. (c) Pan, S.; Ryu, N.; Shibata, T. J. Am. Chem. Soc.
2012, 134, 17474. (d) Loach, R. P.; Fenton, O. S.; Amaike, K.;
Siegel, D. S.; Ozkal, E.; Movassaghi, M. J. Org. Chem. 2014, 79,
11254. (e) Zhou, S.; Jia, Y. Org. Lett. 2014, 16, 3416.
(10) (a) Murakami, Y.; Yokoyama, Y.; Aoki, T. Heterocycles 1984, 22,
1493. (b) Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999,
1, 2097. (c) Yokoyama, Y.; Tsuruta, K.; Murakami, Y. Heterocycles
2002, 56, 525. (d) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.;
Miyaura, N. Tetrahedron Lett. 2002, 43, 5649. (e) Maehara, A.;
Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1159.
(f) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936.
(11) Xu, L.; Zhang, C.; He, Y.; Tan, L.; Ma, D. Angew. Chem. Int. Ed.
2016, 55, 321.
1 H), 7.81 (d, J = 8.3 Hz, 1 H), 7.76 (d, J = 3.6 Hz, 1 H), 7.66 (d, J =
7.9 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.25–7.20 (m, 2 H), 7.17 (d,
J = 7.5 Hz, 2 H), 6.74 (d, J = 3.4 Hz, 1 H), 2.64 (s, 6 H); 13C NMR
(125 MHz, CDCl3): δ = 144.42, 138.11, 136.58, 130.93, 129.26,
129.17, 126.88, 123.44, 121.15, 121.02, 116.08, 110.81, 104.13,
21.84; HRMS (ESI): m/z [M + H]+ calcd for C17H17N2: 249.1386;
found: 249.1383.
(E)-1-(2,6-Dimethylphenyl)-N-(5-methoxy-1H-indol-1-
yl)methanimine (8hh): Yield: 2.4 g (88%); brown solid; Rf =
0.46 (5% EtOAc/petroleum ether). 1H NMR (400 MHz, CDCl3): δ =
8.76 (s, 1 H), 7.72 (d, J = 3.6 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H),
7.23–7.19 (m, 1 H), 7.15 (d, J = 7.6 Hz, 2 H), 7.09 (d, J = 2.4 Hz,
1 H), 6.99 (dd, J = 8.9, 2.4 Hz, 1 H), 6.64 (d, J = 3.5 Hz, 1 H), 3.88
(s, 3 H), 2.61 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 155.23,
144.11, 138.07, 131.82, 130.96, 129.21, 129.17, 127.21, 116.40,
113.51, 111.55, 103.71, 102.81, 56.01, 21.84; HRMS (ESI): m/z
[M + H]+ calcd for C18H19ON2: 279.1492; found: 279.1488.
(20) General Experimental Procedure for the Synthesis of C7-
Alkenylated Indole Derivatives 10ha–ht, 15a and 15b: A
sealed tube (10.0 mL) was charged with indole substrates 8
(0.25 mmol), [RhCp*Cl2]2 (1.5 mg, 1 mol%), Cu(OAc)2·H2O (104
mg, 0.53 mmol), and AgSbF6 (3.1 mg, 4 mol%). The tube was
evacuated and backfilled with argon before acrylate (1.0 mmol)
and dichloromethane (1.0 mL) were added. The reaction
mixture was stirred at 120–140 °C for 48–72 h. After cooling to
room temperature, the mixture was diluted with dichlorometh-
ane, filtered through a plug of diatomite, concentrated under
vacuum and the residue was purified by chromatography on
silica with a gradient eluent of petroleum ether and ethyl
acetate to give the corresponding products.
(12) Yang, Y.; Qiu, X.; Zhao, Y.; Mu, Y.; Shi, Z. J. Am. Chem. Soc. 2016,
138, 495.
(13) (a) Kim, Y.; Park, J.; Chang, S. Org. Lett. 2016, 18, 1892. (b) Xu, L.;
Tan, L.; Ma, D. J. Org. Chem. 2016, 81, 10476.
(14) (a) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett.
2003, 5, 1899. (b) Urones, B.; Arrayas, R. G.; Carretero, J. C. Org.
Lett. 2013, 15, 1120. (c) Jiao, L.; Oestreich, M. Org. Lett. 2013, 15,
5374. (d) Song, Z.; Samanta, R.; Antonchick, A. P. Org. Lett. 2013,
15, 5662. (e) Kim, M.; Mishra, N. K.; Park, J.; Han, S.; Shin, Y.;
Sharma, S.; Lee, E.; Lee, E.-K.; Kwak, J. H.; Kim, I. S. Chem.
Commun. 2014, 14249. (f) Pan, S.; Wakaki, T.; Ryu, N.; Shibata, T.
Chem. Asian J. 2014, 9, 1257. (g) Ai, W.; Yang, X.; Wu, Y.; Wang,
X.; Li, Y.; Yang, Y.; Zhou, B. Chem. Eur. J. 2014, 20, 17653. (h) Pan,
S.; Ryu, N.; Shibata, T. Adv. Synth. Catal. 2014, 356, 929. (i) Wu,
Y.; Yang, Y.; Zhou, B.; Li, Y. J. Org. Chem. 2015, 80, 1946. (j) Yang,
X.; Hu, X.; Loh, T. Org. Lett. 2015, 17, 1481. (k) Jin, N.; Pan, C.;
Zhang, H.; Xu, P.; Cheng, Y.; Zhu, C. Adv. Synth. Catal. 2015, 357,
1149. (l) Hou, W.; Yang, Y.; Ai, W.; Wu, Y.; Wang, X.; Zhou, B.; Li,
Y. Eur. J. Org. Chem. 2015, 395.
Methyl (E)-3-(1-{[(E)-2,6-Dimethylbenzylidene]amino}-1H-
indol-7-yl)acrylate (10ha): Yield: 70 mg (85%); white solid; Rf =
0.25 (10% EtOAc/petroleum ether). 1H NMR (400 MHz, CDCl3):
δ = 9.01 (d, J = 16.0 Hz, 1 H), 8.72 (s, 1 H), 7.68 (d, J = 3.7 Hz,
1 H), 7.58 (d, J = 7.5 Hz, 1 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.16–7.05
(m, 4 H), 6.65 (d, J = 3.6 Hz, 1 H), 6.36 (d, J = 16.0 Hz, 1 H), 3.66
(s, 3 H), 2.52 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ = 167.56,
146.83, 143.25, 138.45, 133.06, 130.60, 129.68, 129.07, 128.61,
123.37, 122.76, 121.04, 121.03, 117.95, 117.67, 104.47, 51.52,
(15) (a) Fan, M.; Ma, D. Angew. Chem. Int. Ed. 2013, 52, 12152. (b) He,
Y.-P.; Zhang, C.; Fan, M.; Wu, Z.; Ma, D. Org. Lett. 2015, 17, 496.
(c) Wang, X.; Niu, S.; Xu, L.; Zhang, C.; Meng, L.; Zhang, X.; Ma,
D. Org. Lett. 2017, 19, 246.
21.44; HRMS (ESI): m/z [M
+
H]+ calcd for C21H21O2N2:
(16) Weiberth, F. J.; Hanna, R. G.; Lee, G. E.; Polverine, Y.; Klein, J. T.
Org. Process Res. Dev. 2011, 15, 704.
333.1598; found: 333.1601.
Methyl (E)-3-(1-{[(E)-2,6-Dimethylbenzylidene]amino}-3-[2-
(1,3-dioxoisoindolin-2-yl)ethyl]-1H-indol-7-yl)acrylate (10hp):
Yield: 88 mg (70%); white solid; Rf = 0.17 (25% EtOAc/petroleum
ether). 1H NMR (400 MHz, CDCl3): δ = 9.06 (d, J = 16.0 Hz, 1 H),
8.75 (s, 1 H), 7.86–7.84 (m, 2 H), 7.77–7.71 (m, 4 H), 7.56 (d, J =
7.5 Hz, 1 H), 7.24–7.14 (m, 4 H), 6.42 (d, J = 16.0 Hz, 1 H), 4.10 (t,
J = 7.4 Hz, 2 H), 3.75 (s, 3 H), 3.24 (t, J = 7.3 Hz, 2 H), 2.61 (s,
6 H); 13C NMR (100 MHz, CDCl3): δ = 168.51, 167.55, 146.04,
143.22, 138.40, 134.17, 133.42, 132.23, 130.74, 129.52, 129.02,
128.23, 123.42, 122.99, 121.21, 121.03, 120.83, 117.98, 115.68,
114.45, 51.53, 37.96, 24.52, 21.46; HRMS (ESI): m/z [M + H]+
calcd for C31H28O4N3: 506.2074; found: 506.2068.
(17) (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008,
41, 1013. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2009, 110, 624. (c) Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16,
11212. (d) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A.
Acc. Chem. Res. 2011, 45, 814. (e) Song, G.; Wang, F.; Li, X. Chem.
Soc. Rev. 2012, 41, 3651.
(18) The structure of 10ha was confirmed by X-ray crystal analysis;
details are given in the Supporting Information.
(19) General Experimental Procedure for the Synthesis of N-
Imino Indole Substrates 8ha–hv, 14a and 14b: A sealed tube
(50.0 mL) was charged with N-aminoindoles (10.0 mmol) and
2,6-dimethylbenzaldehyde (1.34 g, 10.0 mmol). The tube was
evacuated and backfilled with argon before DCE (3.0 mL) was
added. The reaction mixture was stirred at 120–130 °C for 4 h.
After the reaction mixture was cooled to room temperature, the
solvent was distilled off under ambient pressure by simple dis-
tillation. Purification of the residual oil by flash chromatogra-
phy gave the desired products.
(21) General Experimental Procedure for the Synthesis of 11a–d:
A suspension of indole derivatives 10h (0.1 mmol) and activated
Zn powder (5.0 mmol) in a 1:1 mixture of THF and saturated
NH4Cl solution (2.0 mL) was stirred at room temperature to
50 °C until consumption of the starting material as monitored
by TLC. The mixture was diluted with EtOAc and filtered
through a plug of diatomite. The filtrate was extracted with
EtOAc and washed with brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. Residue was puri-
fied by chromatography on silica with a gradient eluent of
(E)-1-(2,6-Dimethylphenyl)-N-(1H-indol-1-yl)methanimine
(8ha): Yield: 2.3 g (92%); light-yellow solid; Rf = 0.72 (5%
EtOAc/petroleum ether). 1H NMR (500 MHz, CDCl3): δ = 8.81 (s,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
L. Xu et al.
Letter
Synlett
petroleum ether and ethyl acetate to give the corresponding
products.
(23) Procedure for the Synthesis of Pyroquilon: In a test tube C7-
alkenylated indole derivative 10ha (0.1 mmol) was dissolved in
EtOH (3 mL), and then an excess amount of Raney Ni slurry was
added. The test tube was placed in a stainless steel autoclave,
and autoclave was sealed under N2 before purging with hydro-
gen for three times. The autoclave was charged with hydrogen
(40 kg/cm2), and the reaction mixture was stirred at 70 °C for 6
h. After cooling to room temperature, the remaining hydrogen
was released. The mixture was filtered through a plug of
diatomite and extracted with EtOAc, and washed with brine.
The organic layer was dried over anhydrous Na2SO4 and concen-
trated in vacuo. Residue was purified by chromatography on
silica with a gradient eluent of petroleum ether and ethyl
acetate to give pyroquilon.
Methyl (E)-3-(1H-Indol-7-yl)acrylate (11a): Yield: 17 mg
(85%); white solid; Rf = 0.38 (25% EtOAc/petroleum ether). 1H
NMR (500 MHz, CDCl3): δ = 8.64 (br s, 1 H), 8.07 (d, J = 16.0 Hz,
1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.43 (d, J = 7.4 Hz, 1 H), 7.28 (t, J =
2.9 Hz, 1 H), 7.17 (t, J = 7.7 Hz, 1 H), 6.62 (dd, J = 3.2, 2.0 Hz, 1 H),
6.54 (d, J = 16.0 Hz, 1 H), 3.85 (s, 3 H); 13C NMR (125 MHz,
CDCl3): δ = 167.85, 141.47, 134.45, 129.06, 124.95, 123.59,
122.47, 120.30, 118.32, 117.71, 103.55, 51.95; HRMS (ESI): m/z
[M + H]+ calcd for C12H12O2N: 202.0863; found: 202.0862.
(22) General Experimental Procedure for the Synthesis of 12a–d:
C7-alkenylation of indole derivatives 10h (0.1 mmol) was dis-
solved in EtOH (3.0 mL). To the solution, an excess amount of
Raney Ni slurry was added and the resulting mixture was
stirred under H2 atmosphere (1 atm) at 50 °C until consumption
of the starting material as monitored by TLC. The mixture was
filtered through a plug of diatomite and extracted with EtOAc,
and washed with brine. The organic layer was dried over anhy-
drous Na2SO4 and concentrated in vacuo. Residue was purified
by chromatography on silica with a gradient eluent of petro-
leum ether and ethyl acetate to give the corresponding prod-
ucts.
1,2,5,6-Tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (13):
Yield: 16 mg (95%); white solid; Rf = 0.14 (25% EtOAc/petroleum
ether). 1H NMR (400 MHz, CDCl3): δ = 7.08 (d, J = 7.3 Hz, 1 H),
7.00 (d, J = 7.4 Hz, 1 H), 6.94 (t, J = 7.4 Hz, 1 H), 4.10 (t, J = 8.4 Hz,
2 H), 3.21 (t, J = 8.4 Hz, 2 H), 2.99 (t, J = 7.6 Hz, 2 H), 2.70 (t, J =
7.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ = 167.82, 141.47,
129.07, 125.46, 123.42, 123.39, 120.35, 45.29, 31.80, 27.91,
24.53; HRMS (ESI): m/z [M + H]+ calcd for C11H12ON: 174.0913;
found: 174.0913.
Methyl 3-(1H-Indol-7-yl)propanoate (12a): Yield: 16 mg
(78%); white solid; Rf = 0.20 (25% EtOAc/petroleum ether). 1H
NMR (400 MHz, CDCl3): δ = 8.86 (br s, 1 H), 7.54 (d, J = 7.8 Hz,
1 H), 7.24 (t, J = 2.8 Hz, 1 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.00 (d, J =
6.9 Hz, 1 H), 6.56 (dd, J = 3.1, 2 Hz, 1 H), 3.68 (s, 3 H), 3.22 (t, J =
7.0 Hz, 2 H), 2.79 (t, J = 7.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3):
δ = 175.09, 135.01, 128.17, 124.42, 123.71, 121.77, 120.06,
119.25, 102.93, 52.07, 34.77, 26.43; HRMS (ESI): m/z [M + H]+
calcd for C12H14O2N: 204.1019; found: 204.1017.
(24) (a) Bass, R. J.; Koch, R. C.; Richards, H. C.; Thorpe, J. E. US Patent
3917838, 1975. (b) Bass, R. J.; Koch, R. C.; Richards, H. C.;
Thorpe, J. E. J. Agric. Food Chem. 1981, 29, 576. (c) Woloshuk, C.
P.; Wolkow, P. M.; Sisler, H. D. Pestic. Sci. 1981, 12, 86.
(d) Prabhu, A.; Filippi, M. Int. J. Pest Manage. 1993, 39, 347.
(e) Wheeler, M. H.; Klich, M. A. Pestic. Biochem. Physiol. 1995,
52, 125.
(25) Yin, L.; Lucas, S.; Maurer, F.; Kazmaier, U.; Hu, Q.; Hartmann, R.
W. J. Med. Chem. 2012, 55, 6629.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F