Synthesis of indoles through Rh(III)-catalyzed C-H cross-coupling with allyl carbonates

Article abstract of DOI:10.1016/j.tetlet.2013.11.065

A practical Rh-catalyzed reaction was developed to achieve 2-alkyl-substituted indole synthesis. The reaction can tolerate a variety of synthetically important functional groups. The indole products can also be transformed into other important skeletons. Two bioactive compounds, that is indomethacin and pravadoline were prepared using the new method.

Full text of DOI:10.1016/j.tetlet.2013.11.065

Tetrahedron Letters 55 (2014) 1859–1862
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Tetrahedron Letters
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Synthesis of indoles through Rh(III)-catalyzed C–H cross-coupling
with allyl carbonates
⇑
Tian-Jun Gong, Wan-Min Cheng, Wei Su, Bin Xiao, Yao Fu
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical Rh-catalyzed reaction was developed to achieve 2-alkyl-substituted indole synthesis. The
reaction can tolerate a variety of synthetically important functional groups. The indole products can also
be transformed into other important skeletons. Two bioactive compounds, that is indomethacin and pra-
vadoline were prepared using the new method.
Received 23 September 2013
Revised 5 November 2013
Accepted 14 November 2013
Available online 22 November 2013
Ó 2014 Published by Elsevier Ltd.
Keywords:
Rh(III)-catalyzed
C–H activation
Indoles
The indole ring system represents a key structural component
that occurs ubiquitously in biologically active natural and unnatu-
ral compounds.1 As a result, the development of new synthetic
strategies for the synthesis of functionalized indoles2 has been
intensively studied in synthetic organic chemistry. Recently, an
increasing number of examples have appeared in the literature fea-
turing transition metal (Pd,3 Rh,4 Cu,5 Ru6 Fe,7 Au,8 Ni9) catalyzed
oxidative C–H bond functionalization event as a fundamental step
in the synthesis of various indoles. Despite these advances, further
development of methods for synthesis of indoles is needed to ex-
pand the scope and utility of this category of synthetically valuable
transformations. Herein, we developed a Rh(III)-catalyzed C–H
activation with allyl carbonates for the synthesis of 2-aliphatic-
substituted indoles.10–12 This process allows quick assembly of in-
dole rings from inexpensive and readily available amides and allyl
carbonates and tolerates a broad range of functional groups (aryl-
Br, heterocycle, amino acid).
Initially, we chose acetanilide (1a) and allyl acetate (2a) as
model substrates to screen the reaction conditions (Table 1). When
the substrates were treated with [RhCp⁄Cl2]2, AgSbF6, and Cu(OAc)2
in dioxane at 110 °C for 24 h, we were delighted to obtain the de-
sired product 3a in 67% yield (Table 1, entry 1). To improve the
yield we tested other solvents (i.e., DMF, DMSO, PhCl, DCE, and
THP), where little product was obtained in DMF and DMSO (entries
2 and 3) whereas moderate yields were obtained in THP, PhCl, and
DCE (60%, 53%, and 34%, entries 4–6). By changing the oxidants we
then found that AgOAc, Ag2CO3, Ag2O, and Cu(OTFA)2 diminished
the reactivity (entries 7–10). When Cu(OAc)2 (1 equiv)/Ag2CO3
(1 equiv) was used the yield increased to 80% (entry 11). The yield
was further improved to 88% by using allyl carbonate (2b) instead
of allyl acetate (2a) (entries 12). The present reaction does not pro-
ceed by using allyl bromide (2c) (entry 13). Moreover, we carried
out control experiments (entry 14 and 15), finding that the present
reaction does not proceed with [IrCp⁄Cl2]2 and [Ru(p-cymene)Cl2]2.
Furthermore, without adding [RhCp⁄Cl2]2 catalyst we obtained no
product (entry 16).
With the optimized reaction conditions in hand ([RhCp⁄Cl2]2,
AgSbF6, and Cu(OAc)2/Ag2CO3 in dioxane at 110 °C for 24 h), a vari-
ety of amides were examined to test the scope of the reaction
(Table 2). Both electron-donating and withdrawing groups could
be tolerated in this reaction. Electron-donating groups (3b–d)
including 4-OMe, OAc, and OPiv gave isolated yields of 77%, 52%,
and 50%, respectively. Electron withdrawing groups, such as 4-
CF3, 4-CN, and 4-SO2Me can also be tolerated in the reaction (3e–
g). Moreover, the aryl-halogen (Cl, Br, F) and OTs groups were well
compatible with the Rh-catalyzed processes (3h–k), which made
additional functionalization possible at these positions. When
3-substituted derivative was used, we saw the production of a less
sterically crowded isomer in 50% yield (3l) and 74% yield (3m). In
addition, acetanilides containing alkyl carboxylate, alkyl chloride,
alkyl phosphate ester, and alkyl toluenesulfonate side chains
(3n–q) were well tolerated in the reaction. Also interestingly,
disubstituted acetanilides were also successfully tolerated in the
reaction, with high regioselectivity (3r, 3s).
Heterocycle compounds are highly interesting building blocks
in the drug design. Accordingly we were interested in using hetero-
cycle substituted acetanilides. We were delighted to find that kinds
⇑
Corresponding author.
E-mail address: fuyao@ustc.edu.cn (Y. Fu).
http://dx.doi.org/10.1016/j.tetlet.2013.11.065
0040-4039/Ó 2014 Published by Elsevier Ltd.

1860
T.-J. Gong et al. / Tetrahedron Letters 55 (2014) 1859–1862
Table 1
because amino acids are highly important skeletons in the biolog-
ically active compounds.
Optimization of the reaction conditionsa
H
Ac
N
Other substituted allyl carbonates were used in the reaction.
Unfortunately, only very low yields of product were obtained
(3y, 3z).
To demonstrate the synthetic utility of our reaction, we first
tested and found that the reaction could be scaled up to a gram-
scale (Scheme 1). Moreover, the products were converted to a
number of important molecules. Direct cyanation of indole with
N-cyano-N-phenyl-p-toluenesulfonamide (NCTS)13 by using
Wang’s conditions13b was developed. Moreover, Lewis acid pro-
moted highly regioselective electrophilic substitution of indoles
[RhCp*Cl2]2/AgSbF6
oxidant / solvent
N
LG
2 equiv
+
O
H
110°C, 24h, Ar
2a LG= OAc
1a 0.2mmol
2b
3a
LG=OCOOMe
2c LG=Br
Entry
2
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2b
2b
2b
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
Cu(OAc)2 (2 equiv)
AgOAc (2 equiv)
Ag2O (2 equiv)
Dioxane
DMF
DMSO
THP
PhCl
67
8
0
60
53
34
12
30
40
48
80
88
0
with N-acetylated
a,b-dehydroalanine methyl ester synthesis of
-amino acids can successfully proceed.14 An Rh(II) cat-
DCE
3-indolyl-
a
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
alyzed [3+2] reaction was also reported, by using Davies’s condi-
tions.15 Finally, NaBH3CN reduction of the 2-methylindole can
give indoline 7.16 Such conversions are important for the synthesis
of biologically active compounds.
To further show the utility of the 2-aliphatic-substituted indole
process, this method allowed quick access to a number of drug
molecules (Scheme 2). Product 3b was converted to indomethacin
10, an nonsteroidal anti-inflammatory drug, in four steps:17 First,
removal of acetyl protecting group; Second, introduction of a sub-
stituent at the 3-position on the indole ring was accomplished by
9
Cu(TFA)2 (2 equiv)
Ag2CO3 (2 equiv)
10
11
12
13
14c
15d
16e
Cu(OAc)2 (1 equiv) Ag2CO3 (1 equiv)
Cu(OAc)2 (1 equiv) Ag2CO3 (1 equiv)
Cu(OAc)2 (1 equiv) Ag2CO3 (1 equiv)3
Cu(OAc)2 (1 equiv) Ag2CO3 (1 equiv)
Cu(OAc)2 (1 equiv) Ag2CO3 (1 equiv)
Cu(OAc)2 (1equiv) Ag2CO3 (1 equiv)
0
<5
0
a
All the reactions were carried out with 5 mol % [RhCp⁄Cl2]2, 20 mol % AgSbF6
0.2 mmol of 1a, and 0.4 mmol of 2, in 1 mL solvent, 110 °C.
b
Isolated yield.
c
[IrCp⁄Cl2]2 instead of [RhCp⁄Cl2]2.
d
[Ru(p-cymene)Cl2]2 instead of [RhCp⁄Cl2]2.
e
Without using [RhCp⁄Cl2]2.
CN
MeO
MeOOC
N
4
87%
of heterocycle substituted acetanilides can successfully proceed in
the reaction. Carbazole substituted acetanilides can afford the de-
sired products 3t in 58% yield. We obtained the indole product
3u in 55% yield when phthalimide substituted acetanilides was
used, high regioselectivity was observed. We also found that C–H
activation indole synthesis process can be applied to valerolactone
and acetal substituted acetanilides (3v, 3w). Finally, we were sur-
prised to find that an amino acid group can smoothly survive the
indole synthesis process (3x). This finding is synthetically useful
NHAc
H
N
a, b, c
5
80%
a, b, d
Br
Optimal
R
R
conditions
1
2
+
COOMe
3mmol scale
a, b, e
MeO
N
Ac
R = H
77%
OCOOMe
R = OMe 71%
NHAc
a, f
MeO
N
H
6
71%
N
H
7
80%
Scheme 1. Further transformation of 2-methyl indoles. Reaction conditions: (a)
KOH, EtOH, THF, reflux; (b) THF, NaH, then MeI; (c) NCTS, BF3ÁOEt2, DCE, 80 °C, 12 h;
(d) (E)-methyl 4-(4-bromophenyl)-2-diazobut-3-enoate, Rh2(S-DOSP)4, toluene,
Table 2
Scope of acetanilides and allyl carbonatesa
À45 °C; (e) N-acetylated
a-dehydroalanine methyl ester, ZrCl4 (2 equiv), CH2Cl2,
0 °C to rt, 12 h; (f) NaBH3CN (3 equiv), HOAc.
R
3b R = OMe 77%
3g R = SO2Me 70%
3c
3h
R = OTs 55%
R = OAc 52%
3d R = OPiv 50%
3e R = CF3 65%
3i R = Br 79%
3j R = Cl 57%
N
Ac
N
Ac
R
3f
3k
R = F 60%
R = CN 57%
3l R = Me
50%
MeO
R
3m
R = OCF3 74%
a
a
OEt
P
O
TsO
N
H
N
N
H
EtO
Cl
EtOOC
Ac
e 78%
N
Ac
N
N
Ac
b 68%
3a R=H
Ac
OMe
O
3b R=OMe
3n 41%
3o 45%
3p
44%
COOEt
O
6
R
Et
N
MeO
11
60%
OMe
N
Ac
N
N
Ac
8
Br
N
H
N
H
f
3r R = Me 56%
3q 54%
Ac
3t 58%
c
90%
3s R = OEt 46%
COOEt
COOH
O
O
F
MeO
MeO
O
F
N
O
O
O
N
N
N
N
N
d 89%
Ac
O
Ac
Ac
O
O
3w
3u 55%
3v 71%
37%
N
9
MeOOC
Br
MeO
Indomethacin 10
nonsteroidal
N
Cl
Cl
Pravadoline 12
O
NHAc
3x 49%
antiinflammatory drug
analgesic agent
N
Ac
N
N
Ac
Ac
3z 18%
3y 23%
Scheme 2. Application to the synthesis of indomethacin and pravadoline. Reaction
conditions: (a) KOH, EtOH, THF, reflux; (b) BrCH2CO2Et, n-BuLi, ZnCl2, THF, 0 °C to
rt; (c) 4-ClC6H4COCl, t-BuOK, THF, rt; (d) LiOH (10 equiv), H2O, THF, 25 °C, 6 h; (e)
MeMgBr, CH2Cl2, Et2O, then 4-OMeC6H4COCl; (f) ClCH2CH2-4-morpholinyl, KOH,
DMSO.
a
Reactions were carried out at 110 °C for 24 h on a 0.2 mmol scale. Isolated
yields.

T.-J. Gong et al. / Tetrahedron Letters 55 (2014) 1859–1862
1861
a) Kinetic Isotopic Effect
Experimental
H
OCOOMe
N
1H NMR spectra were recorded at 400 MHz on an ARX 400
Bruker spectrometer. Chemical shifts are reported in parts per
million referenced to the residual proton resonances of the
solvents. Coupling constants are expressed in Hertz.
[RhCp*Cl2]2 / AgSbF6
Cu(OAc)2 / Ag2CO3
Dioxane, 110°C, 1h
N
Ac
O
D
KIE= 2.85
H/D
H
N
OCOOMe
[RhCp*Cl2]2 / AgSbF6
Cu(OAc)2 / Ag2CO3
Dioxane, 110°C, 20min
N
O
D4 / H4
D5 / H5
kH / kD= 2.3
Ac
1 : 1
General procedure for rhodium-catalyzed indoles synthesis
b)
[RhCp*Cl2]2 / AgSbF6
Cu(OAc)2 / Ag2CO3
NHAc
A
10 mL Schlenk tube equipped with a magnetic stirrer
r.t.
25%
was charged with [RhCp⁄Cl2]2(5 mol %), AgSbF6(20 mol %),
Cu(OAc)2(1 equiv), Ag2CO3(1 equiv), and sub-stituted acetanilides
1 (0.2 mmol). The tube was evacuated and backfilled with argon
three times. Then allyl carbonate (0.4 mmol) in dioxane (1 mL)
was added. After addition of all substrates, the reaction mixture
was stirred and heated at 110 °C for 24 h. Then reaction was cooled
to room temperature. Solvent and volatile reagents were removed
by rotary evaporation and the residue was purified by flash column
chromatography on silica gel to give the target product.
N
Ac
110°C 60%
Dioxane, T°C, 12h
without [Rh] 0%
Scheme 3. Mechanism experiments.
H
N
RhIII
N
O
H
Cu+, Ag0
Cu2+, Ag+
Ac
3a
1a
H
N
1-(2-Methyl-1H-indol-1-yl)ethanone (3a)
RhIII
O
RhIII
N
Ac
III
O
I
1H NMR (400 MHz, CDCl3) d 7.97 (d, J = 7.8, 1H), 7.51–7.38 (m,
1H), 7.31–7.14 (m, 2H), 6.35 (s, 1H), 2.70 (s, 3H), 2.62 (s, 3H). 13C
NMR (101 MHz, CDCl3) d 170.42, 137.44, 136.66, 129.90, 123.68,
123.25, 119.96, 115.39, 109.86, 27.46, 17.74.
OMe
O
Rh
OCOOMe
2b
O
N
H
II
Figure 1. Proposed mechanism.
1-(5-Methoxy-2-methyl-1H-indol-1-yl)ethanone (3b)
1H NMR (400 MHz, CDCl3) d 7.91 (d, J = 9.1, 1H), 6.92 (d, J = 2.6,
1H), 6.84 (dd, J = 9.1, 2.6, 1H), 6.32–6.24 (m, 1H), 3.84 (s, 3H), 2.68
(s, 3H), 2.61 (d, J = 1.0, 3H).
conventional 3-alkylation; Third, 4-chlorobenzoylation to give
product 9 and Fourth, subsequent hydrolysis led to 10. Along the
same line, product 3a was converted to Pravadoline 12, an analge-
sic agent, in three steps:18 removal of the acetyl protecting group,
the C-3 aroyl group was introduced to give 11 followed by N-alkyl-
ation to afford the target 12.
To comprehend the mechanism of the reaction we carried out
the kinetic isotope effect experiment.19a First, an intramolecular ki-
netic isotope effect (kH/D = 2.85) was observed (Scheme 3). More-
over, an intramolecular kinetic isotope effect (kH/kD = 2.3) was
also observed. This observation indicates that C–H bond activation
is the rate-determining step in the catalytic cycle.19 We prepared
the 2-allylacetanilide (possible reaction intermediates).20 2-Ally-
lacetanilide can be converted to the indole product, even under
room temperature, which is consistent with Saá’s work.11 Further-
more, no product was obtained without using RhIII catalyst, RhIII is
necessary for the oxidant oxidative cyclization step.
1-Acetyl-2-methyl-1H-indol-5-yl acetate (3c)
1H NMR (400 MHz, CDCl3) d 8.01 (d, J = 9.0, 1H), 7.16 (d, J = 2.4,
1H), 6.95 (dd, J = 9.0, 2.4, 1H), 6.34 (s, 1H), 2.69 (s, 3H), 2.61 (d,
J = 0.9, 3H), 2.31 (s, 3H).
1-Acetyl-2-methyl-1H-indol-5-yl pivalate (3d)
1H NMR (400 MHz, CDCl3) d 8.01 (d, J = 9.0, 1H), 7.13 (d, J = 2.4,
1H), 6.91 (dd, J = 9.0, 2.4, 1H), 6.32 (s, 1H), 2.69 (s, 3H), 2.61 (d,
J = 1.0, 3H), 1.37 (s, 9H).
1-(5-Trifluoromethyl-2-methyl-1H-indol-1-yl)ethanone (3e)
On the basis of experiments we proposed that the mechanism is
as follows (Fig. 1): First, the Rh(III) catalyst reacted with the sub-
strate (1a) through a rate-determining C–H activation step (mostly
likely via a concerted metalation–deprotonation process) to gener-
ate a six-membered rhodacycle(III) intermediate (I). Second, Rh(III)
in I reacts with allyl carbonates to produce Rh(III) species II, fol-
lowed by decarboxylative b-oxygen elimination.21 Finally, oxida-
tive cyclization took place to generate the target product (3a).
The Rh(III) complex then went back to the catalytic cycle.
In summary, we have developed an unprecedented Rh-cata-
lyzed C–H activation with allyl carbonate synthesis of 2-ali-
phatic-substituted indoles. The reaction tolerated a variety of
synthetically important functional groups (e.g., aryl-Br, heterocy-
cle, amino acid). The indoles can be readily converted to many syn-
thetically useful skeletons, and the present reaction may provide a
practical tool for rapid synthesis of functional molecules (indo-
methacin and pravadoline). Further exploration of the synthetic
utilities of this chemistry and in-depth mechanistic study are cur-
rently in progress.
1H NMR (400 MHz, CDCl3) d 8.06 (d, J = 8.8, 1H), 7.63 (s, 1H),
7.40 (dd, J = 8.8, 1.4, 1H), 6.35 (s, 1H), 2.65 (s, 3H), 2.57 (d, J = 0.9,
3H).
Diethyl (1-acetyl-2-methyl-1H-indol-5-yl)methylphosphonate
(3n)
1H NMR (400 MHz, CDCl3) d 7.85 (d, J = 8.6, 1H), 7.32 (s, 1H),
7.10 (d, J = 8.6, 1H), 6.26 (s, 1H), 4.02–3.82 (m, 4H), 3.15 (d,
J = 21.3, 2H), 2.64 (s, 3H), 2.55 (s, 3H), 1.16 (t, J = 7.1, 6H).
2-(1-Acetyl-2-methyl-1H-indol-5-yl)ethyl 4-methylben-
zenesulfonate (3o)
1H NMR (400 MHz, CDCl3) d 7.86 (d, J = 8.6, 1H), 7.66 (d, J = 8.3,
2H), 7.22 (d, J = 8.0, 2H), 7.17 (d, J = 1.2, 1H), 6.97 (dd, J = 8.6, 1.7,
1H), 6.28 (s, 1H), 4.23 (t, J = 7.1, 2H), 3.01 (t, J = 7.0, 2H), 2.70 (s,
3H), 2.63 (d, J = 0.7, 3H), 2.40 (s, 3H).

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T.-J. Gong et al. / Tetrahedron Letters 55 (2014) 1859–1862
18326; (c) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. Angew. Chem., Int. Ed.
2011, 50, 1338; (d) Wang, C.; Sun, H.; Fang, Y.; Huang, Y. Angew. Chem., Int. Ed.
2013, 52, 5795.
1-(5-(6-Chlorohexyloxy)-2-methyl-1H-indol-1-yl)ethanone (3q)
1H NMR (400 MHz, CDCl3) d 7.89 (d, J = 9.1, 1H), 6.91 (d, J = 2.5,
1H), 6.83 (dd, J = 9.1, 2.6, 1H), 6.28 (s, 1H), 3.99 (t, J = 6.4, 2H), 3.54
(t, J = 6.7, 2H), 2.67 (s, 3H), 2.60 (d, J = 1.0, 3H), 1.81 (m, 4H), 1.56–
1.47 (m, 4H).
5. For Cu-catalyzed direct C–H indoles synthesis, for see: (a) Bernini, R.; Fabrizi,
G.; Sferrazza, A.; Cacchi, S. Angew. Chem., Int. Ed. 2009, 48, 8078–8081; (b) Li, Y.-
M.; Sun, M.; Wang, H.-L.; Tian, Q.-P.; Yang, S.-D. Angew. Chem., Int. Ed. 2013, 52,
3972.
6. For Ru-catalyzed direct C–H indoles synthesis, see: Ackermann, L.; Lygin, A. V.
Org. Lett. 2013, 15, 3670.
7. For Fe-catalyzed direct C–H indoles synthesis, see: Guan, Z.-H.; Yan, Z.-Y.; Ren,
Z.-H.; Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2010, 2823.
8. For Au-catalyzed direct C–H indoles synthesis, see: Wang, Y.; Ye, L.; Zhang, L.
Chem. Commun. 2011, 7815.
9. For Ni-catalyzed direct C–H indoles synthesis, see: Song, W.; Ackermann, L.
Chem. Commun. 2013, 6638.
10. For Rh(III)-catalyzed direct C–H allylation of arenes with allylic carbonates,
see: (a) Wang, H.; Schröder, N.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 5386;
(b) Feng, C.; Feng, D.; Loh, T.-P. Org. Lett. 2012, 14, 764.
11. During the preparation of our manuscript, we noted a similar study has been
published: Cajaraville, A.; López, S.; Varela, J. A.; Saá, C. Org. Lett. 2013, 15,
4576.
12. (a) Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212; (b) Colby, D. A.; Tsai, A. S.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814; (c) Song, G.; Wang,
F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.
13. (a) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 519;
(b) Gong, T.-J.; Xiao, B.; Cheng, W.-M.; Su, W.; Xu, J.; Liu, Z.-J.; Liu, L.; Fu, Y. J.
Am. Chem. Soc. 2013, 135, 10630.
(S)-Methyl 2-acetamido-3-(1-acetyl-2-methyl-1H-indol-5-
yl)propanoate (3x)
1H NMR (400 MHz, CDCl3) d 7.84 (d, J = 8.5, 1H), 7.10 (s, 1H),
6.89 (d, J = 8.5, 1H), 6.24 (s, 1H), 5.94 (d, J = 7.5, 1H), 4.82 (dd,
J = 13.5, 5.8, 1H), 3.65 (s, 3H), 3.10 (m, 2H), 2.62 (s, 3H), 2.54 (s,
3H), 1.90 (s, 3H).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
11.065.
14. Angelini, E.; Balsamini, C.; Bartoccini, F.; Lucarini, S.; Piersanti, G. J. Org. Chem.
2008, 73, 5654.
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