An easy-to-operate n-carbonylation of indoles with diaryl carbonates as reagent and Na2CO3 as catalyst

Article abstract of DOI:10.1080/00397911.2020.1758143

Na₂CO₃ catalyzed N-carbonylation of indoles using diaryl carbonates as acylation reagent have been developed. It provided an efficient and simple method for the utilization of carbonates and the synthesis of N-carbonyl indoles. The reaction can be operated easily with Na₂CO₃ as catalyst in CH₃CN and the corresponding products were isolated with good to excellent yields.

Full text of DOI:10.1080/00397911.2020.1758143

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
An easy-to-operate n-carbonylation of indoles
with diaryl carbonates as reagent and Na CO as
2
3
catalyst
Xiao-Yu Zhou & Xia Chen
To cite this article: Xiao-Yu Zhou & Xia Chen (2020): An easy-to-operate n-carbonylation of
indoles with diaryl carbonates as reagent and Na CO as catalyst, Synthetic Communications, DOI:
2
3
10.1080/00397911.2020.1758143
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SYNTHETIC COMMUNICATIONS
https://doi.org/10.1080/00397911.2020.1758143
An easy-to-operate n-carbonylation of indoles with diaryl
carbonates as reagent and Na CO as catalyst
2
3
Xiao-Yu Zhou and Xia Chen
School of Chemistry and Materials Engineering, Liupanshui Normal University, Liupanshui, China
ABSTRACT
ARTICLE HISTORY
Na CO
2 3
catalyzed N-carbonylation of indoles using diaryl carbonates
Received 7 November 2019
as acylation reagent have been developed. It provided an efficient
and simple method for the utilization of carbonates and the synthe-
sis of N-carbonyl indoles. The reaction can be operated easily with
Na CO as catalyst in CH CN and the corresponding products were
KEYWORDS
Sodium carbonate; catalysis;
carbonylation;
2
3
3
isolated with good to excellent yields.
indole; carbonates
GRAPHICAL ABSTRACT
R
R
O
R'
Na2 O3 (2 mol%)
R'
C
0
+
N
Ar
Ar
Ar
N
H
o
O
O
CH3 N, 120 C
C
O
O
™
™
™
™
N-Aryloxyformylation of Indoles
Inorganic Base as catalyst
High Regioselectivity
Good to Excellent Yields
The functionalization of indoles have always been the topics in organic methodology
because indole and its derivatives as essential moieties play important roles in the syn-
[
1]
thesis of natural products, pharmaceuticals and fine chemicals . And much attention
[
2]
[3]
have been devoted to its Friedel-Crafts reactions, cross-coupling reactions, C–H
[
4]
[5]
[6]
[7]
bond activation, nucleophilic addition, reduction, oxidation . Besides, the con-
[
8]
trolling of regioselectivity is still a prominent problem . A lot of meaningful work
[
9]
[10]
[11]
[12]
[13]
[14]
have been achieved on the regulation of 1-, 2-,
tionalization of indoles.
3-,
4-,
6-
and 7-
func-
Acylation is a valuable approach for the N-protection and N-functionalization of
indoles and the development of novel acylation reagents is an effective strategy. For
[
15]
[16]
[17]
example, acyl chlorides,
nitriles
anhydrides, amino acid derivatives,
anilines
and
[
18]
were used for the 3-acylation of indoles, respectively. Notably, there are a few
reports on the highly regioselective N-acylation or 2-acylation of indoles. The prepar-
ation of N-Boc indoles is a representative example via a 4-(N,N-dimethylamino)pyridine
(DMAP) catalyzed highly regioselective acylation of indoles with di-tert-butyl dicarbon-
ate ((Boc) O) as reagent, but this method is limited to the N-tert-butoxycarbonylation
2
CONTACT Xiao-Yu Zhou
Zhouxiaoyu20062006@126.com
School of Chemistry and Materials Engineering,
Liupanshui Normal University, Liupanshui, China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
X-Y. ZHOU AND X. CHEN
Scheme 1. N-Acylation of indoles.
Scheme 2. Na CO catalyzed N-carbonylation of indoles.
2
3
[
19]
of indoles (Scheme 1, path A)
.
Another widely used method is the
N-benzenesulfonylation, N-acetylation, N-methylation or N-benzylation of indoles in the
[
20]
presence of NaOH, KOH or NEt (Scheme 1, path B) . However, 3-acylindoles are
3
normal by-products in the synthesis of N-acylindoles and the conditions are difficult to
control in our practical experience.
Therefore, a highly regioselective method for N-acylation of indoles is needed to be
developed urgently. A great deal of work had been conducted and the previous
researches had confirmed that carbonic acid diesters could be used for the N-alkyl-
[
21]
[22]
ation
and N-acylation
of aza-heterocyclic compounds. And a superbase promoted
direct N-carbonylation of pyrrole with stoichiometric alkali and large excess carbonic
[
23]
acid diesters had been developed as well . Most recently, a Na CO -catalyzed N-acyl-
2
3
ation of indoles with alkenyl carboxylates as acyl source was accomplished in our
[
24]
laboratory and high regioselectivity was achieved (Scheme 1, path C) . In order to
expand the base-catalyzed N-acylation strategy to a wide range of acylation reagents,
Na CO -catalyzed regioselective N-carbonylation of indoles with diaryl carboxylates as
2
3
acyl source was achieved (Scheme 2). The results are reported in the current work.
Our study began by evaluating the N-carbonylation of indole (1a) with diphenyl car-
bonate (2a, Table 1). After some experiments, we found that inorganic base-catalyzed
ꢀ
protocol consisting of Na CO (20 mol%) in acetonitrile (CH CN) at 120 C afforded
2
3
3
phenyl 1H-indole-1-carboxylate (3aa) in >99% isolated yield (Entry 1). Subsequently,
the effects of catalyst, solvent and temperature were screened. Na CO (20 mol%) as
2
3
catalyst was more effective than K CO , DMAP and NaHCO (70%, 90% and 77%
2
3
3
yields, entries 2–4). By controlling the reaction condition, it was found that Na CO3
2
was necessary due to the yield decreased dramatically to 48% (Entry 5). Moreover, 1,4-
dioxane and toluene as solvent led to lower yields, presumably due to the poor solubil-
ity of Na CO (Entries 6–8). In especial, almost no product was detected when ethanol
2
3
was examined. The reasons were speculated that the transesterification of diphenyl

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SYNTHETIC COMMUNICATIONS
3
a
Table 1. Conditions optimization .
b
Entry
Deviation standard conditions
Yield (%)
1
2
3
4
5
6
7
8
9
1
a
None
CO
DMAP (12.2 mg, 20 mol%) instead of Na
NaHCO (4.2 mg, 10 mol%) instead of Na
Without Na CO
EtOH instead of CH
1,4-dioxane instead of CH
>99
70
90
77
48
–
46
32
96
91
K
2
3
(13.8 mg, 20 mol%) instead of Na
2
CO
CO
CO
3
(10.6 mg, 20 mol%)
(10.6 mg, 20 mol%)
3
(10.6 mg, 10 mol%)
2
3
3
2
2
3
3
CN
3
CN
Toluene instead of CH
3
CN
ꢀ
Reacted at 100 C
ꢀ
0
Reacted at 140 C
Reaction conditions: 1a (59 mg, 0.50 mmol), 2a (219 mg, 1.2 equiv, 0.60 mmol), Na
2
CO
3
(10.6 mg, 0.10 mmol, 20 mol%),
ꢀ
CH
3
CN (3.0 mL), 120 C, 24 h.
b
Isolated yield.
carbonate with ethanol occurred. Lastly, the temperature had been tested and the results
ꢀ
showed that 120 C was the best choice (Entries 9 and 10).
With these conditions in hand, we next turned our attention to evaluating the
scope of this reaction. As evident from the results compiled in Table 2, the
Na CO -catalyzed N-carbonylation can be applied to a wide number of indoles with
2
3
diphenyl carbonate 2a. N-carbonylated indoles were obtained in good to excellent
yields with indoles possessing alkyl, chloro, bromo or alkoxy substituents at either
C2, C3 and/or C5 (1 b, 1d-1g and 1i-1o, entries 2, 4–7 and 9–15). No target prod-
ucts can be detected when N-carbonylation of 2-phenyl-1H-indole 1c and 1,2,3,9-tet-
rahydro-4H-carbazol-4-one 1h (Entries 3 and 8) were chosen as the starting
materials. Theoretical analysis holds that these indoles with higher steric hindrance
may be the main factor.
Subsequently, the N-carbonylation of indole 1a with diaryl carbonates 2b–2g were
conducted under the optimal reaction conditions to screen the scope of starting materi-
als 2, as shown in Table 3. The results showed that the N-carbonylation with bis(2-
methoxyphenyl) carbonate 2b and bis(4-methoxyphenyl) carbonate 2c could proceed
smoothly and the good yields were obtained (entries 2-3). When bis(4-nitrophenyl) car-
bonate 2d and bis(perfluorophenyl) carbonate 2e with electron-withdrawing group were
used as carbonylation reagents, there were no products to be detected and the carbo-
nates were decomposed under the standard conditions (entries 4 and 5). Lastly, the
dimethyl carbonate 2f and diethyl carbonate 2g (Entries 6 and 7) were tested to screen
the substrate scope and the results were agreed with our previous analysis that dialkyl
carbonates were not suitable for the N-carbonylation of indole.
In summary, using diaryl carbonates as reagents, the highly regioselective N-carbony-
lation of indoles is achieved and the approach allows for a wide range of indoles with
good to excellent yields. Additional application of base-catalyzed N-functionalization of

4
X-Y. ZHOU AND X. CHEN
a
Table 2. Screening on the scope of substrate 1 .
b
Entry
Substrate 1
Product 3
Yield (%)
1
> 99
1
a
3aa
2
3
83
1
b
3
ba
NA
1
c
3
ca
4
5
--
1
d
3da
80
1
e
3ea
6
7
67
46
1
f
3fa
1
g
3ga
8
9
--
1
h
3
ha
83
86
93
93
97
91
85
1
i
3
ia
1
0
1
1
j
3
ja
1
1
k
3ka
1
1
1
1
2
3
4
5
1
l
3
la
1
m
3ma
1
n
3na
1
o
3oa
a
Unless other stated, all reactions are carried out with 1 (0.50 mmol), 2a
(
(
219 mg, 0.60 mmol, 1.2 equiv), Na
3.0 mL), 120 C, 24 h.
2
CO
3
(10.6 mg, 0.10 mmol, 20 mol%), CH
3
CN
ꢀ
b
Isolated yield.

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SYNTHETIC COMMUNICATIONS
5
a
Table 3. Screening on the scope of substrate 2 .
Entry
Substrate 2
Product 3
Yield (%)b
1
> 99
2
a
3
aa
2
3
4
73
84
--
2
b
3
ab
2
c
3
ac
2
d
3
ad
5
6
7
--
--
--
2
e
3
ae
2
f
3
af
2
g
3
ag
a
Unless other stated, all reactions are carried out with 1a (59 mg, 0.50 mmol), 2 (0.60 mmol,
ꢀ
1.2 equiv), Na
2
CO
3
(10.6 mg, 0.10 mmol, 20 mol%), CH
3
CN (3.0 mL), 120 C, 24 h.
b
Isolated yield.
indoles are under active investigation in our laboratory and will be disclosed in
due course.
Experimental section
General methods
Commercially available reagents were used throughout without further purification
other than those detailed below. The other solvents were purchased and without further
1
purification. The chemical shifts for H NMR were recorded in ppm downfield from
tetramethylsilane (TMS) with the solvent resonance as the internal standard. The chem-
1
3
ical shifts for C NMR were recorded in ppm downfield using the central peak of d-
chloroform (77.23 ppm) as the internal standard. Coupling constants (J) are reported in
Hz and refer to apparent peak multiplications. Flash column chromatography was per-
formed on silica gel (200–300 mesh). TLC analysis was performed using glass-backed
plates coated with 0.2 mm silica.

6
X-Y. ZHOU AND X. CHEN
The typical procedure for Na CO -catalyzed N-carbonylation of indoles
2
3
A mixture of indole 1 (0.50 mmol), Na CO (10.6 mg, 0.10 mmol, 20 mol%) and diaryl
2
3
carboxylate 2 (0.60 mmol, 1.2 equiv) in CH CN (3 mL) was added into a Schlenk flask
3
ꢀ
(
25 mL) and stirred at room temperature. The mixture was stirred at 120 C until the
reaction was finished. Then the solvent was evaporated under reduced pressure and the
residue was purified by column chromatography (petroleum ether:ethyl acetate 50:1
to 10:1).
Phenyl 1H-indole-1-carboxylate (3aa)
Yield: >99%, 117.5 mg, white solid, m.p. 80–82 C. H NMR (600 MHz, CDCl ) d 8.33 (d,
ꢀ
1
3
J¼ 5.4 Hz, 1H), 7.82 (d, J ¼ 3.7 Hz, 1H), 7.68 (d, J ¼ 7.8 Hz, 1H), 7.57–7.50 (m, 2H),
1
3
7
(
.48–7.43 (m, 1H), 7.36 (dd, J ¼ 4.6, 3.5 Hz, 4H), 6.75 (d, J ¼ 3.7 Hz, 1H); C NMR
151 MHz, CDCl ) d 150.2, 129.6, 129.5, 126.4, 126.2, 124.8, 123.4, 121.5, 121.1, 120.8,
3
1
15.3, 108.9; IR (KBr) 2975, 2926, 2870, 1734, 1590, 1476, 1450, 1370, 1335, 1317, 1257,
ꢁ
1
1221, 1163, 1133, 1098, 851, 804, 767 cm ; HRMS Calcd for C H NO Na: 260.0687
15
11
2
þ
1
13
[
M þ Na] ; found: 260.0689.Full experimental detail, H and C NMR spectra. This
material can be found via the “Supplementary Content” section of this article’s webpage.
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