Collective Synthesis of 3-Acylindoles, Indole-3-carboxylic Esters, Indole-3-sulfinic Acids, and 3-(Methylsulfonyl)indoles from Free (N-H) Indoles via Common N-Indolyl Triethylborate

Article abstract of DOI:10.1021/acs.orglett.6b01970

A general and direct C3 functionalization of free (N-H) indoles with readily available electrophiles such as acid chlorides, chloroformates, thionyl chloride, and methylsulfonyl chloride via a common N-indolyl triethylborate intermediate is reported. The reaction proceeds smoothly under mild conditions in up to 93% yield. Indoles with substituents at the C2, C4, C5, C6, and C7 positions are well tolerated. The easy accessibility of a variety of important 3-acylindoles, indole-3-carboxylic esters, indole-3-sulfinic acids, and 3-(methylsulfonyl)indoles demonstrates the high degree of compatibility and practicability of this method.

Full text of DOI:10.1021/acs.orglett.6b01970

Letter
pubs.acs.org/OrgLett
Collective Synthesis of 3‑Acylindoles, Indole-3-carboxylic Esters,
Indole-3-sulfinic Acids, and 3‑(Methylsulfonyl)indoles from Free
(N−H) Indoles via Common N‑Indolyl Triethylborate
Zhi-Wei Zhang,*,† Hong Xue,†,§ Hailing Li,†,§ Huaiping Kang,† Juan Feng,† Aijun Lin,‡
and Shouxin Liu*,†
†State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, College of Chemical &
Pharmaceutical Engineering, Hebei University of Science & Technology, Shijiazhuang 050018, P. R. China
‡State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, China Pharmaceutical University,
Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: A general and direct C3 functionalization of free (N−
H) indoles with readily available electrophiles such as acid chlorides,
chloroformates, thionyl chloride, and methylsulfonyl chloride via a
common N-indolyl triethylborate intermediate is reported. The
reaction proceeds smoothly under mild conditions in up to 93%
yield. Indoles with substituents at the C2, C4, C5, C6, and C7
positions are well tolerated. The easy accessibility of a variety of
important 3-acylindoles, indole-3-carboxylic esters, indole-3-sulfinic
acids, and 3-(methylsulfonyl)indoles demonstrates the high degree
of compatibility and practicability of this method.
ubstituted indoles are versatile structural motifs in bio-
logically active natural products and drug molecules1 and
via transition-metal-catalyzed or transition-metal-free reac-
tions.10 However, despite tremendous efforts to develop more
efficient strategies in these areas, drawbacks, such as harsh
conditions, side reactions, the need of expensive catalyst, and
poor selectivity especially on unprotected indole substrates, are
also obvious. A general and straightforward strategy to access all
of these interesting skeletons via a common intermediate from
free (N−H) indoles using readily available electrophiles remains
highly desirable.
S
have been considered as “privileged scaffolds” in drug discovery2
since they are capable of binding many receptors with high
affinity.3 3-Acylindoles and indole-3-carboxylic esters are among
the most useful fragments because of their privileged core and
their widespread applications in the synthesis of a broad range of
useful indole derivatives (Figure 1).4 3-Sulfurindole-based
Functionalization at the C3 position of free (N−H) indoles is
challenging because it often suffers from competing reactions at
N1 and C212 due to the inherent reactivity of the aromatic
system.13 For the electron-rich indoles, other side reactions, such
as polymerization and dimerization, also occur under acidic
conditions.9d,e The use of N-protecting groups and metal
indolides such as magnesium9a and zinc9b,14 is generally the
strategy for improving efficiency. However, the inefficient nature
of the protecting groups and moderate nucleophilicity of these
metal indolides made it necessary to develop more efficient
approaches.
In 2013, Yang and co-workers reported that N-indoly
triethylborate, prepared from potassium indole salt and
triethylborane, was a useful reagent for dearomatizing C3-
alkylation of 3-substituted indoles.15 Similar effects have also
been observed in palladium- and iridium-catalyzed C3 allylation
and benzylation reactions of indoles with trialkylborane as the
Figure 1. Examples of bioactive C3-functionalized compounds.
compounds also exhibited excellent activities against HIV,5
cancer,6 CNS disorders,7 heart disease,8 etc. Synthetic methods
for each of these C3-functionalized indoles have been intensely
studied in the past.9−11 Direct functionalization at the C3
position using various electrophiles is extremely attractive,9,11
and other elegant cyclization strategies have been also developed
Received: July 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01970
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
additive.16 Based on these important precedents, we envisioned
that N-indolyl triethylborate may be used as a nucleophile to
react with readily available electrophilic carbonyl reagents
regioselectively. Herein, we describe the extension of this
method and report that not only acid chloride but also
chloroformate, thionyl chloride, and methylsulfonyl chloride
could react with N-indolyl triethylborate under mild conditions
to provide a variety of C3 functionalized N−H indoles in high to
excellent yield (up to 93% yield). Arylsulfinic acids (salts) are
valuable functional groups since they could be easily converted to
aryl sulfones,17 sulfoxides,18 and sulfides,19 which have received
much attention in drug discovery.20 In this paper, we highlight
our results on the collective synthesis of unprotected 3-
acylindoles, indole-3-carboxylic esters, indole-3-sulfinic acids,
and 3-(methylsulfonyl)indoles employing N-indolyl triethylbo-
rate as a common intermediate.
Scheme 1. Acylation of Indoles with Aliphatic and Aromatic
Acid Chlorides
Our studies commenced with the acylation of indole 1a with
pivaloyl chloride under the established conditions (t-BuOK,
Et3B, 1,4-dioxane, rt).15 Gratifyingly, the desired 3-trimethyla-
cetylated indole 2a was formed in 55% yield along with N-
acylated product 3 in 30% yield (Table 1, entry 1). The solvents
Table 1. Optimization of C3 Acylation of Indole 1a
a
entry
solvent
temp (°C)
time (h)
2a/3 (%)
1
2
3
4
5
6
1,4-dioxane
THF
25
25
12
12
12
12
16
24
4
55/30
58/31
50/27
42/23
80/12
91/trace
0/89
toluene
CH2Cl2
THF
25
25
0
THF
−15
−15
b
7
THF
a
Reaction conditions: 1a (0.5 mmol), t-BuOK (1.1 equiv), Et3B (1.1
b
equiv), pivaloyl chloride (1.1 equiv) in 10 mL of solvent. In the
absence of Et3B.
a
Reactions of 1 run on 0.5 mmol scale with 1.1 equiv of t-BuOK and
b
1.1 equiv of Et3B. Reactions were conducted at 0 °C when aromatic
acid chlorides were used as electrophiles.
were briefly investigated, and THF was found to give a slightly
higher combined yield (89%) with same ratio of 2a/3 (entry 2−
4). Further screening revealed that the temperature has a crucial
effect on the regioselectivity. When the reaction was conducted
at 0 °C, 2a was obtained in 80% yield and 3 in 12% yield (entry
5). When performed at −15 °C, the reaction gave the best result
(entry 6), with a trace amount of 3 detected. A control
experiment showed that 3 was generated exclusively in the
absence of Et3B (entry 7).
With the optimized conditions in hand, we first sought to
explore the scope of C3 acylation reactions with aliphatic acyl
chlorides at −15 °C. As shown in Scheme 1, the more reactive
acetyl chloride and even chloroacetyl chloride could react
smoothly with indole 1a under the optimized conditions to give
2b and 2c, respectively, in high yield. Octanoyl chloride resulted
in a relatively low yield of 2d (51%). Because of the usefulness of
the α-chlorine for further synthetic manipulations, chloroacetyl
chloride was selected to test the scope of indole substrates.
Substituents at the 2-, 4-, 5-, and 6-positions on the indole ring
are well tolerated. Reactions of indoles substituted with methyl
(2e, 2f, and 2h), methoxy (2i), and chloro (2g) groups all
provided the corresponding 3-acylindoles in good to excellent
yield (79−90%). No alkylated product was observed in any of the
reactions. Notably, the dichloride substituents of compound 2g
may be used as handles to synthesize indoles of greater
complexity.21 Pivaloyl chloride and substituted indoles were
also compatible reaction partners, with 2j−l obtained in good
yield.
Compared to aliphatic acyl chlorides, less reactive aromatic
acyl chlorides needed higher temperature (0 °C) to complete the
reaction. Benzoyl chloride offered a modest yield of 2m (54%)
after 24 h at 0 °C under otherwise identical conditions. Electron-
rich aromatic acyl chlorides such as 3,4,5-trimethoxybenzoyl
chloride, 2-naphthoyl chloride, and α-furoyl chloride afforded
2n−p in 70−82% yield. 1H-Indole-2-carbonyl chloride was also
compatible with this reaction system, giving 2q in 75% yield. The
thiazole-2-carboxyl chloride provided a low yield of 2r (33%), a
natural 3-acylindole alkaloid (namely indothiazinone) isolated in
a culture of myxobacterial strain.22 Aryl acyl chlorides bearing
electron-withdrawing groups at the ortho, meta, and para
positions gave 2s−u in good yield. Indoles containing
substituents at various positions (C2, C4, C5, C6, and C7)
reacted to afford the desired 2w−ac in 58−89% yield. Acylated
B
DOI: 10.1021/acs.orglett.6b01970
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
product 2x could be easily transformed into the analgesic agent
pravadoline (Figure 1) in one step according to reported
method.23 However, reactions of indole 1a with phenylacetyl
chloride or cinnamoyl chloride gave inseparable mixtures in both
cases. N-Acylated product (not shown) was generated
exclusively when 2-phenyl-substituted indole 1b or indole-2-
carboxylic acid methyl ester 1c was used as the substrate,
presumably because of the difficulty of the formation of N-indolyl
triethylborate intermediate. Indole-5-carboxylic acid methyl
ester 1d was also an unsuitable substrate.
Scheme 3. Reactions of Indoles with Thionyl Chloride or
Methylsulfonyl Chloride
We next focused on the reaction of indoles with
chloroformates with the expectation that indole-3-carboxylic
esters (4, Scheme 2) would be formed. To our great delight, on
Scheme 2. Reactions of Indoles with Chloroformate
a
Reaction conditions: 1 (0.5 mmol), t-BuOK (1.1 equiv), Et3B (1.1
equiv), thionyl chloride or methylsulfonyl chloride (1.1 equiv) in 10
b
mL of THF. 0.5 equiv of SOCl2 was used.
fluorobenzenesulfonyl chloride proved to be unsuitable electro-
philes and gave complex mixtures.
In conclusion, we have demonstrated that N-indolyl
triethylborate reacted with a series of electrophiles to
regioselectively generate a wide range of C3-functionalized free
(N−H) indoles that are important building blocks in medicinal
and biological chemistry. 3-Acylindoles, indole-3-carboxylic
esters, indole-3-sulfinic acids, and 3-methylsulfonyl indoles
were easily produced in a direct and efficient manner utilizing
N-indolyl triethylborate. Further investigation of the scope of the
reaction is underway in our laboratory.
a
Reaction conditions: 1 (0.5 mmol), t-BuOK (1.1 equiv), Et3B (1.1
b
equiv), chloroformate (1.1 equiv) in 10 mL of THF. Reaction was
conducted at 0 °C.
treatment of the N-indolyl triethylborate of 1a with methyl
chloroformate, allyl chloroformate, and benzyl chloroformate,
respectively, the esters 4a−c were generated regioselectively in
excellent yield (90−93%). 5-Methyl-1H-indole and 6-methoxy-
1H-indole also showed good reactivity and regioselectivity in the
formation of the desired products 4d−h. Indoles bearing
substituents at the C2, C4, or C7 position proved to be
incompatible substrates and offered N-protected 3a−d as the
major products. Only a trace of the desired esters was obtained
for these cases.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01970.
Experimental procedures, product characterization, and
1H and 13 C NMR spectra for all compounds (PDF)
To further explore the reactivity (Scheme 3) of the N-indolyl
triethylborate reagent, thionyl chloride was used to react with
indole 1a. After the reaction was quenched with aqueous
ammonium chloride, indole-3-sulfinic acid 5a was produced in
80% yield. C2-, C4-, and C5-methylated indoles also gave the
desired sulfinic acid 5b−d in high yield. It is important to note
that when 0.5 equiv of thionyl chloride was used to react with
indole 1a, symmetric sulfoxide 5aa was formed in 69% yield. This
reaction demonstrates that arene sulfinyl chlorides are also
suitable electrophiles. Encouraged by this result, we turned our
attention to the sulfonylation reaction of indoles. Methylsulfonyl
chloride was first examined, which reacted with various indoles
smoothly to produce the 3-methylsulfonyl indoles 6a−g in 80−
92% yield. However, the arylsulfonyl chlorides including p-
toluenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, and p-
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhangzw@hebust.edu.cn.
*E-mail: chlsx@hebust.edu.cn.
Author Contributions
§H.X. and H.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Generous financial support from the National Natural Science
Foundation of China (21302039), the Natural Science
■
C
DOI: 10.1021/acs.orglett.6b01970
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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DOI: 10.1021/acs.orglett.6b01970
Org. Lett. XXXX, XXX, XXX−XXX