Multiple Roles of the Pyrimidyl Group in the Rhodium-Catalyzed Regioselective Synthesis and Functionalization of Indole-3-carboxylic Acid Esters

Article abstract of DOI:10.1002/adsc.201500769

A regioselective synthesis of indole-3-carboxylic acid esters from anilines and diazo compounds has been realized by making use of the pyrimidyl group-assisted rhodium-catalyzed C-H activation and C-N bond formation. The reaction proceeds under mild conditions, exhibits good functional group tolerance and scalability. Reutilization of the pyrimidyl directing group in the resulting products provided an efficient strategy for further C-7 functionalization of indoles. Moreover, the pyrimidyl moiety could be readily removed as a leaving group to offer various free N-H indoles.

Full text of DOI:10.1002/adsc.201500769

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DOI: 10.1002/adsc.201500769
Multiple Roles of the Pyrimidyl Group in the Rhodium-Catalyzed
Regioselective Synthesis and Functionalization of Indole-3-car-
boxylic Acid Esters
a
a
a
a
a,
a,
Hui Jiang, Shang Gao, Jinyi Xu, Xiaoming Wu, Aijun Lin, * and Hequan Yao *
a
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy,
China Pharmaceutical University, Nanjing 210009, Peopleꢀs Republic of China
Fax: (+86)-25-8327-1042; e-mail: ajlin@cpu.edu.cn or hyao@cpu.edu.cn
Received: August 16, 2015; Revised: October 15, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500769.
Abstract: A regioselective synthesis of indole-3-car-
boxylic acid esters from anilines and diazo com-
pounds has been realized by making use of the pyri-
midyl group-assisted rhodium-catalyzed CÀH acti-
vation and CÀN bond formation. The reaction pro-
and limited substrate scopes still hampered their fur-
ther applications to some extent. Therefore, the de-
velopment of a promising strategy to access various
indole-3-carboxylic acid esters from simple and readi-
ly available starting materials remains highly desirable
in modern organic chemistry.
ceeds under mild conditions, exhibits good function-
al group tolerance and scalability. Reutilization of
the pyrimidyl directing group in the resulting prod-
ucts provided an efficient strategy for further C-7
functionalization of indoles. Moreover, the pyrimid-
yl moiety could be readily removed as a leaving
group to offer various free NÀH indoles.
Recently, diazo compounds or related derivatives
as carbene precursors have played an important role
in CÀH activation for direct CÀC bond formation, in
[9]
particular in the synthesis of heterocycles. However,
to the best of our knowledge, CÀH activation involv-
ing diazo compounds is challenging. The diazo com-
pounds could easily undergo a classic nucleophilic in-
sertion reaction of metal carbenoids rather than inser-
tion into the challenging aromatic CÀH bond. Previ-
Keywords: CÀH activation; diazo compounds;
indole-3-carboxylic acid esters; pyrimidyl group;
rhodium catalysis
ously, Moody reported an indole-2-carboxylic acid
ester synthesis from N-methylanilines and a-diazo-b-
keto esters involving carbenoid insertion into the NÀ
H
bond followed by cyclization/condensation
[10]
(
Scheme 1).
In comparison, we wondered if we
Indole-3-carboxylic acid esters are one of the most
important structural motifs widely present in numer-
ous natural products, pharmaceuticals and bioactive
[
1]
[2]
[3]
compounds, such as Arbidol, Tropisetron, PD
0
[
4]
[5]
298029 and Grandilodine A (Figure 1). Conse-
quently, tremendous efforts have been devoted to the
synthesis and functionalization of indole-3-carboxylic
[
6]
acid esters. During the past two decades, transition
metal-catalyzed CÀH functionalization has emerged
as an economical and environmentally benign ap-
[7]
proach to achieve these structures. In 2008, Glorius
reported a Pd-catalyzed intramolecular oxidative cy-
clization to indole-3-carboxylic acid esters from N-
arylenamines. Later, the Jiao and Cao groups ach-
ieved the skeletons via a Pd-catalyzed sequential Mi-
chael-type addition and cross-dehydrogenative cou-
pling (CDC) reaction between anilines and electron-
[
8]
deficient alkynes. However, the preparation of pre- Figure 1. Examples of indole-3-carboxylic acid esters in bio-
activated substrates, the demand for excess oxidants, active compounds.
1
88
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Multiple Roles of the Pyrimidyl Group
[
a]
Table 1. Optimization of the reaction conditions.
Entry Ag Salt Additive
Solvent Time [h] Yield [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
AgSbF6
AgSbF6 CsOAc
AgSbF6 Cs CO
AgSbF6 HOAc
–
–
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
12
12
12
12
12
12
12
12
12
12
N.R.
N.R.
N.R.
81
N.R.
79
5
80
73
11
25
N.R.
74
86 (85 )
43
2
3
HOAc
AgNTf2 HOAc
Ag CO HOAc
2
3
AgSbF6 PivOH
AgSbF6 PhCOOH DCE
AgSbF6 HCOOH DCE
AgSbF6 HOAc
AgSbF6 HOAc
AgSbF6 HOAc
AgSbF6 HOAc
AgSbF6 HOAc
0
1
2
3
4
5
toluene 12
CH CN 12
3
MeOH 12
DCE
DCE
[
[
b]
c]
[d]
6
6
Scheme 1. Rhodium-catalyzed synthesis of indoles with ani-
lines and diazo compounds.
[
a]
Reaction conditions: 1a (0.25 mmol, 1.0 equiv.), 2a
0.50 mmol, 2.0 equiv.), [Cp*RhCl ] (2.5 mol%), Ag salt
(
2 2
(10.0 mol%) and additive (0.25 mmol, 1.0 equiv.) in sol-
vent (2 mL), 608C, under air. Yields were determined by
H NMR using dibromomethane as the internal standard.
HOAc (0.5 equiv.), 6 h.
1
could control the reaction pathway by introducing
[
11]
[b]
a directing group strategy, thus leading to preferen-
[
[
c]
tial aromatic CÀH bond activation instead of the nu-
[Cp*RhCl
]
2
(1.25 mol%), HOAc (0.5 equiv.), 6 h.
2
d]
Isolated yield.
cleophilic metal-carbene insertion to obtain different
types of products. In continuation of our studies on
the synthesis and applications of heterocycles via
[12]
transition metal-mediated CÀH functionalization,
tempted the reaction with [Cp*RhCl ] in the absence
2 2
herein, we report the rhodium(III)-catalyzed pyrimid- of AgSbF (Table 1, entry 5), which was completely
6
yl-directed sequential aromatic CÀH activation and unreactive. Based on the above results, we found that
CÀN bond formation for the regioselective synthesis a combination of an acid and a silver salt was indis-
of indole-3-carboxylic acid esters from anilines and pensable in this cyclization reaction. Subsequently,
diazo compounds. Reutilization of the pyrimidyl as the reaction conditions were further optimized by
a directing group in the resulting products provided screening of different silver salts, acids and solvents
an efficient strategy for further C-7 functionalization (Table 1, entries 6–13). All of them failed to give
of indoles. Moreover, the pyrimidyl group could be a better yield. The isolated yield could be improved
readily removed to offer various free NÀH indoles in to 85% when the reaction time was shortened to 6 h.
high efficiency.
Reducing the amount of [Cp*RhCl ] from 2.5 mol%
2 2
We initiated our study with N-(2-pyrimidyl)aniline to 1.25 mol% provided 3aa in a lower yield (Table 1,
a and ethyl 2-diazo-3-oxobutanoate 2a as substrates. entry 15).
1
When the reaction was performed in the presence of
With the optimized conditions in hand, we then ex-
[
Cp*RhCl ] (2.5 mol%), AgSbF (10.0 mol%) in 1,2- amined the substrates scope of arylamines, and the re-
2
2
6
dichloroethane (DCE, 2 mL) at 608C for 12 h, no de- sults are shown in Table 2. Most of the substrates of-
sired product was observed. Then we examined differ- fered the corresponding ethyl 2-methyl-1-(pyrimidin-
ent additives such as acids, bases and silver salts. With 2-yl)-1H-indole-3-carboxylates in good to excellent
HOAc as additive, the desired ethyl 2-methyl-1-(pyri- yields. Methyl or n-butyl substitution at the para-posi-
midin-2-yl)-1H-indole-3-carboxylate 3aa was obtained tion of the phenyl ring offered 3ba and 3ca, respec-
in 81% yield (Table 1, entry 4), and the structure was tively in 84% yield. With a methoxy group as substitu-
1
13
confirmed by H and C NMR spectroscopy, mass ent the reaction gave 3da in 67% yield. Halogen sub-
spectrometry, and single crystal X-ray analysis (see stituents led to 3ea–3ha in 64–75% yield, which could
[
13]
the Supporting Information for details). We also at- be subjected to further synthetic transformations. It
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189

Hui Jiang et al.
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[a,b]
Table 2. Scope of arylamines.
[a]
Reaction conditions: 1 (0.25 mmol, 1.0 equiv.), 2a (0.50 mmol, 2.0 equiv.), [Cp*RhCl ] (2.5 mol%), AgSbF (10.0 mol%)
2
2
6
and HOAc (0.5 equiv.) in DCE (2 mL) at 608C for 6 h under air atmosphere.
Isolated yields.
[
[
[
b]
c]
d]
8
5
08C.
mmol scale reaction.
was worth noting that the substrates with strong elec-
Next, the scope of diazo acetoacetates was investi-
tron-withdrawing groups such as the CF , CO Et, Ac gated, and the results are summarized in Table 3.
3
2
and NO could also offer the desired products 3ia–3la Methyl, tert-butyl and benzyl a-diazoacetoacetates
2
in 70–80% yield. ortho-Substituted arylamines 1n and 2b–2d afforded 3ab–3ad in 57–76% yield. When we
2
1
o provided the corresponding products 3na and 3oa changed the group R with ethyl and n-propyl, 3ae
in 78% and 66% yields, respectively. meta-Methyl and 3af were obtained in 68% and 88% yield, respec-
substituted 1p reacted exclusively at the less sterically tively. Phenyl-substitued 2g gave 3ag in 22% yield. 1-
hindered position and afforded 3pa in 75% yield. Diazo-1-tosylpropan-2-one 2h delivered C-3 sulfonyl-
Poly-substituted 1q and 1r gave 3qa in 80% yield and indole 3ah in 49% yield. Moreover, ethyl 2-diazo-3-
3
ra in 90% yield. N-(Naphthalen-1-yl)pyrimidin-2- oxopropanoate 2i was also suitable for this transfor-
amine 1s produced 3sa in 76% yield. A morpholinyl mation, giving the desired 3ai in 32% yield.
group at the para-position of the phenyl ring led to When a-diazo esters such as dimethyl malonic
ta in 71% yield. In addition, the reaction could be esters, methyl 2-diazo-2-(phenylsulfonyl)acetate and
conducted on a gram scale (5 mmol), and 3aa was ob- ethyl 2-diazo-2-(diethoxyphosphoryl)acetate were al-
tained in 82% yield (1.16 g). lowed to react with N-(2-pyrimidyl)aniline in the
3
1
90
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Multiple Roles of the Pyrimidyl Group
[a,b]
Table 3. Scope of diazo acetoacetates.
Scheme 2. Alkylation of N-(2-pyrimidyl)aniline with a-diazo
esters.
[a]
Reaction conditions: 1a (0.25 mmol, 1.0 equiv.),
2
cause the directing group was unnecessary in the final
10.0 mol%) and HOAc (0.5 equiv.) in DCE (2 mL) at target structures. The pyrimidyl group in the resulting
(
(
0.50 mmol, 2.0 equiv.), [Cp*RhCl ] (2.5 mol%), AgSbF
2
2
6
6
08C for 6 h under air atmosphere.
Isolated yields.
4 h.
product 3aa could be readily removed by treatment
with NaOEt in DMSO at 1008C for 24 h, providing
the unprotected ethyl 2-methyl-1H-indole-3-carboxyl-
ate 12 in 85% yield. Moreover, in our reaction, the C-
[
[
b]
c]
[21]
2
3
ester group could be removed, and the correspond-
ing product 13 was obtained in 82% yield, which
presence of [Cp*RhCl2]2 (2.5 mol%), AgSbF6 could be further hydrolyzed to afford 2-methyl-1H-
10.0 mol%) in 1,2-dichloroethane (DCE, 2 mL) at indole 14 in a yield of 80%. With regard to the C-7
08C for 24 h, all reactions afforded the monoalkylat- functionalized indole 5, it could also be successfully
(
6
ed products 4a–4c in 30–47% yield. The diazo deriva- hydrolyzed to afford 2,3,7-trisubstituted indole 15 in
tive of Meldrumꢀs acid could not give any alkylated 71% isolated yield (Scheme 4).
or annular product (Scheme 2).
To date, only few efficient protocols for direct C-7 ried out. It gave a K /K ratio of 1.6, thus indicating
Finally, a kinetic isotope effect experiment was car-
H
D
functionalization of indoles via CÀH activation have that CÀH cleavage might be involved in the rate-de-
[
14]
been reported. In our reaction, the pyrimidyl group termining step (Scheme 5, see the Supporting Infor-
in the resulting product 3aa could be reutilized as a di- mation for details).
[9i–m,19]
recting group for further C-7 functionalization via CÀ
Based on the previous studies,
we propose
H activation. For instance, transition metal-catalyzed a plausible reaction mechanism as illustrated in
[
15]
[16]
[17]
direct alkenylation,
amination,
acyloxylation,
Scheme 6. First, the rhodium complex would be acti-
[
18]
[9m]
[19]
cyanation,
alkylation,
amidation
and acyla- vated by AgSbF to generate electrophilic cationic
6
[
20]
tion all proceeded smoothly and offered the corre- complex Cp*Rh(III), which then participated in the
sponding products 5–11 in moderate to excellent directed CÀH cleavage to offer intermediate A. Sub-
yields (Scheme 3).
sequently, intermediate A reacted with diazo com-
Removing the directing groups under mild condi- pound 2aa to generate rhodium(III)-carbene inter-
tions is a common challenge in CÀH activation, be- mediate B. Migratory insertion into the rhodium-
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191

Hui Jiang et al.
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Scheme 3. Reutilization of the pyrimidyl as directing group for further C-7 functionalization of indoles.
the active rhodium(III) catalyst for the next catalytic
cycle. Enol intermediate E was formed through keto-
enol tautomerization, and the final product 3aa was
obtained by a dehydration process.
In summary, the pyrimidyl as a directing group
played a pivotal role in our rhodium(III)-catalyzed re-
gioselective synthesis of indole-3-carboxylic acid
esters from anilines and diazo compounds. The proce-
dure involved CÀH activation, carbene migration in-
sertion and CÀN bond formation, exhibited good
functional group tolerance and scalability. Reutiliza-
tion of the pyrimidyl as directing group in the result-
ing products provided an efficient strategy for further
C-7 functionalization of indoles. Moreover, the pyri-
midyl as leaving group could be readily removed to
offer free NÀH indoles under mild reaction condi-
tions. Further investigations on the construction of
complex functionalized heterocycles are in progress in
our laboratory.
Experimental Section
General Procedure
A
1
sealed tube was charged with pyrimidylarylamines
(0.25 mmol, 1.0 equiv.), [Cp*RhCl ] (3.9 mg, 2.5 mol%),
2
2
Scheme 4. Deprotection of pyrimidyl group to synthesize
free NÀH functionalized indoles.
AgSbF (8.6 mg, 10.0 mol%), HOAc (8 mL, 0.5 equiv.), diazo
6
compounds 2 (0.5 mmol, 2.0 equiv.) and DCE (2 mL). The
reaction mixture was vigorously stirred at 608C (oil bath
temperature) for 6 h. After cooling to room temperature,
the reaction mixture was diluted with EtOAc (20 mL) and
carbon bond produced the seven-membered rhodacy-
cle C. Upon protonation by acetic acid, the intermedi- filtered through a plug of celite. The solvent was evaporat-
ate D was achieved along with the regeneration of ed, and the residue was purified by flash chromatography on
1
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Multiple Roles of the Pyrimidyl Group
Scheme 5. Intermolecular kinetic isotope study.
Scheme 6. Proposed mechanism.
silica gel (petroleum ether/ethyl acetate) to afford the corre-
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