Fluorinated Alcohol-Mediated SN1-Type Reaction of Indolyl Alcohols with Diverse Nucleophiles

Article abstract of DOI:10.1002/adsc.201500500

This paper describes an efficient S_N1-type reaction of 3-indolylmethanols with miscellaneous nucleophiles, featuring a catalyst-free procedure, low cost, wide substrate scope and mild reaction conditions. This approach provides green and efficient methods for the synthesis of diverse 3-substituted indolyl derivatives as well as unsymmetrical bisindolylmethanes and triarylmethanes.

Full text of DOI:10.1002/adsc.201500500

UPDATES
DOI: 10.1002/adsc.201500500
Very Important Publication
Fluorinated Alcohol-Mediated SN1-Type Reaction of Indolyl
Alcohols with Diverse Nucleophiles
Hao Wen,+a Liang Wang,+b Lubin Xu,b Zhihui Hao,b Chang-Lun Shao,a,*
Chang-Yun Wang,a and Jian Xiaob,*
a
Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean
University of China, Qingdao 266003, Peopleꢀs Republic of China
E-mail: shaochanglun@163.com
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, Peopleꢀs Republic
b
of China
E-mail: chemjianxiao@163.com
+
These authors contributed equally to this work.
Received: May 25, 2015; Revised: July 31, 2015; Published online: October 21, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500500.
Abstract: This paper describes an efficient SN1-type
reaction of 3-indolylmethanols with miscellaneous
nucleophiles, featuring a catalyst-free procedure,
low cost, wide substrate scope and mild reaction
conditions. This approach provides green and effi-
cient methods for the synthesis of diverse 3-substi-
tuted indolyl derivatives as well as unsymmetrical
bisindolylmethanes and triarylmethanes.
logical activities. For example, mucronatins A and B
were isolated from the bark of Tetrapterys mucronata
and exhibit acetylcholinesterase inhibitory activity.
The bis- and tris-indole alkaloids C–F, isolated from
the New Caledonian sponge, Gellius sp. exhibited an-
tiserotonin activity and have strong affinity for soma-
tostatin and neuropeptide Y receptors (Figure 1).[5]
These bioactivity profiles and drug-like characteris-
tics have attracted great attention from synthetic
chemists and pharmacologists. However, to the best
of our knowledge, most of the reported methods are
related to synthesis of symmetrical bisindolylme-
thanes, whereas the synthesis of unsymmetrical bisin-
dolylmethanes or triarylmethanes is still rare and re-
mains a great challenge.[6] Only sporadic examples
were reported for the synthesis of unsymmetrical bis-
indolylmethanes, all of which suffered from the em-
Keywords: arylmethanes; fluorinated alcohols; in-
doles; 3-indolylmethanol; SN1-type reaction
Introduction
The indole scaffold represents one of the privileged ployment of environmentally harmful Lewis acid or
structures and is frequently encountered in a vast Brønsted acid catalysts, the formation of large
number of natural alkaloids, pharmaceuticals, agro- amounts of waste or by-products, the use of anhy-
chemicals as well as materials.[1] Among the family of drous conditions and high catalyst loadings as well as
indole derivatives, 3-substituted indole-based diaryl- limited substrate scope.[7] Therefore, it is highly desir-
methanes or triarylmethanes have proven to be highly able to develop efficient and green methods for syn-
promising as potential drug candidates for treatment thesis of unsymmetrical bisindolylmethanes or triaryl-
of bacterial infections and diabetes.[2] Remarkably, methanes for further structure–activity relationship
these compounds exhibit strong cytotoxicity against (SAR) investigations.
an array of cancer cell lines such as breast, prostate
Recently, 3-substituted indoles can be facilely ac-
and endometrial cancer.[3] In particular, symmetrical cessed via alkylideneindoleninium ion or alkylide-
p-phenyl-substituted bisindolylmethanes and bis(indo- neindolenine intermediates, providing much synthetic
lyl)indolin-2-ones are core structures of many biologi- flexibility for the preparation of 3-indolyl deriva-
cally active compounds possessing significant anti-in- tives.[8] As one of the most versatile reagents, 3-indo-
flammatory and antitumor activities.[4] In contrast, un- lylmethanols have been employed to generate alkyli-
symmetrical bisindole derivatives also exist in a multi- deneindoleninium ions under acidic conditions, lead-
tude of natural products and manifest significant bio- ing to various C-3 functionalizations of indoles.[9]
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Hao Wen et al.
Scheme 1. Reaction of 3-indolylmethanol with diverse nucle-
ophiles.
Results and Discussion
Initially, indole 2a was exploited as a nucleophile for
reaction with 2-phenyl-3-indolyl-methanol 1a. Various
protonic solvents such as EtOH, TFE and HFIP and
aprotic solvents such as toulene, DCE, DMF and
DMSO were examined. As expected, the desired
product could be afforded in TFE in 96% yield in 8 h
Figure 1. Natural products containing unsymmetrical bisin- (Table 1, entry 1). Although this reaction proceeded
dolylmethanes.
much faster in more acidic hexafluoroisopropyl alco-
hol (HFIP), the yield was a little bit lower (Table 1,
entry 2). To our surprise, the desired product 3a could
However, the acid catalysts employed are environ- also be furnished in the general alcohols such as
mentally detrimental and troublesome when removing EtOH and isopropyl alcohol in moderate to good
impurities, especially for pharmaceutical applications. yields (Table 1, entries 3 and 4). Intriguingly, this reac-
Fluorinated alcohols have unique properties such as tion could proceed smoothly in less polar aprotic sol-
high H-bonding donor ability, high ionizing power vents such as DCE and toluene, furnishing the desired
and low nucleophilicity, enabling them to easily gener- products in good yields (Table 1, entries 5 and 6). In
ate cationic intermediates through hydrogen bonding contrast, the more polar aprotic solvents such as
interactions, thus promoting reactions in the absence DMSO and DMF, could not give rise to the desired
of Lewis acid or Brønsted acid catalysts.[10,11] In this product (Table 1, entries 7 and 8). Among these sol-
context, we have developed the first acid-free inter- vents, TFE was shown to be the best in terms of yield
molecular a-alkylation of aldehydes using trifluoroe- and reaction efficiency.
thanol as a solvent.[12] As part of our continuing work
With the optimized reaction conditions in hand,
in this area, herein we present the catalyst-free SN1- a variety of electronically and sterically diverse 3-in-
type reaction of 3-indolylmethanols with diverse nu- dolylmethanols and indoles were subjected to this re-
cleophiles in trifluoroethanol (TFE), which affords action to investigate the generality of this protocol.
versatile 3-substitued indolyl derivatives in high At the outset, 2-phenyl-3-indolylmethanol 1a was se-
yields, including unsymmetrical diarylmethanes and lected as precursor of the alkylideneindoleninium ion
triarylmethanes. This strategy features catalyst-free, to react with various substituted indoles (Scheme 2).
mild reaction conditions, low cost, wide substrate All the products could be obtained in excellent yields
scope and convenient work-up (Scheme 1).
(3a–3l). When C-2 substituted indoles were used, ex-
cellent yields still could be obtained although bulky
substituents might cause steric hindrance for the nu-
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Fluorinated Alcohol-Mediated SN1-Type Reaction of Indolyl Alcohols
Table 1. Optimization of the reaction conditions.[a]
thus resulting in higher yield. The success of reaction
of non-C-2 substituted 3-indolylmethanols with in-
doles should be ascribed to the unique properties of
TFE.
The active methylene compounds have been used
as versatile soft nucleophiles in miscellaneous reac-
tions, however, to the best of our knowledge, they
have never been exploited as nucleophiles for SN1-
type reactions of 3-indolylmethanols to construct
Yield [%][b] indole derivatives. To further validate the power of
Entry
Solvent
Time [h]
this strategy, a variety of active methylene compounds
was tested (Scheme 3). Gratifyingly, the common
active methylene compounds such as 1,3-dicarbonyls,
45
1
2
3
4
5
6
7
8
CF3CH2OH
(CF3)2CHOH
EtOH
isopropyl alcohol
DCE
toluene
DMSO
DMF
8
96
91
0.5
24
24
24
24
48
48
ethyl cyanoacetate and malononitrile were all well
tolerated and could be conveniently merged into
indole skeletons, furnishing the desired products 5a–
5e in high yields. When pharmacologically intriguing
4-hydroxycoumarin was examined as a nucleophile,
the desired product 5f was afforded in good yield, as
a hybrid of indole and coumarin, both of which are
pharmaceutically significant moieties. Nitromethane
furnished product 6 in moderate yield at 908C, which
was only synthesized under harsh conditions in prece-
80
73
65
trace
trace
[a]
Reaction conditions: room temperature, 1a (0.2 mmol),
2a (0.3 mmol) in 2 mL solvent.
Isolated yield after column chromatography.
[b]
cleophilic attack (3a–3c). Electron-withdrawing dent reports.[8] In this reaction, a considerable amount
groups and electron-donating groups on the benzene of side product 7 was detected, resulting from the re-
ring of indoles were all well tolerated (3f–3i) and vari- action of 3-indolylmethanol with TFE.
ous nitrogen protecting groups of indoles had a trivial
To further expand the substrate scope of this proto-
impact on the yield (3j–3l), but use of unprotected col, silyl enol ether 8 was investigated and the desired
indole decreased the yield significantly (3za). It is product 9 was obtained in 85% yield after 8 h at
noteworthy that more than 190 predicted C-G pro- room temperature. However, for less nucleophilic an-
tein-coupled receptor (GPCR) targets have 3-substi- throne 10, a higher temperature (908C) was indispen-
tuted 2-phenylindole units,[13] this methodology can sable to obtain a decent yield (Scheme 4).
produce pharmaceutically significant 3-substituted 2-
Subsequently, arenes were also checked for this re-
phenylindoles in excellent yields under mild condi- action. For instance, phenol 12 reacted with 1a at
tions. 3-Indolylmethanols without C-2 substitution are 908C to furnish the desired product 13 in 65% yield.
problematic substrates for nucleophilic substitutions When electron-rich 1,3,5-trimethoxybenzene 14 was
since low yields and low selectivities are always ob- used,[15] the desired product 15 was obtained in 25%
tained due to side reactions continuously occurring at yield with a considerable amount of side product 7
the electron-rich C-2 carbon.[14] However, in our (Scheme 5).
system, good to excellent yields were furnished for re-
Sulfur is an elementary constituent in many phar-
actions of non-C-2 substituted 3-indolylmethanols maceuticals and its selective incorporation into com-
À
with various indoles (3m–3z). Protection of N H with plex frameworks is highly significant in medicinal
a tosyl group resulted in a higher yield than that ob- chemistry.[15] Therefore, thiol 16 and thiophenol 18
tained with the unprotected 3-indolylmethanol (3m were tested as nucleophiles, aiming to construct
and 3n). An electron-donating group on the phenyl sulfur-containing 3-indolyl derivatives. Not surprising-
ring was beneficial to the yield (3o), whereas elec- ly, the desired products 17 and 19 were obtained in
tron-withdrawing groups were detrimental to the high yields, which might be ascribed to the strong nu-
yields (3p–3t). The reaction mixture had to be heated cleophilicity of thiol and thiophenol (Scheme 6).
to 608C to obtain decent yields for substrates with
Finally, nitrogenated nucleophiles such as ammonia,
electron-withdrawing groups (3r–3t). These phenom- aniline, p-methoxyaniline, hydrazine, tosylamide, pyr-
ena might be rationalized by the fact that the cationic rolidine, NaN3 as well as TMSN3 were subjected to
alkylideneindoleninium intermediate can be stabilized this reaction, however, all the reactions were messy
by electron-donating substituents and destabilized by and no desired product could be isolated. Hence it
electron-withdrawing substituents. The same tendency can be concluded that nitrogenized 3-indolyl deriva-
was also observed when different indoles were exam- tives are unable to be synthesized via this strategy.
ined, even for 2-substituted indoles (3u–3x). The elec-
Mechanistically, dual H-bonds might be formed be-
tron-rich groups increase the nucleophilicity of indole, tween TFE and 3-indolylmethanol as shown in transi-
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Hao Wen et al.
Scheme 2. Substrate scope of the SN1-type reaction of 3-indolylmethanols with indoles.
tion state A (Scheme 7).[16] In this transition state, the to the decrease of the reaction barrier and stabiliza-
hydroxy hydrogen in TFE forms the hydrogen bond tion of this transition state.[16c] The dual H-bonding in-
with the oxygen of the OH group in compound 1, teractions decrease the electron density of the oxygen
À
while the fluorine forms a hydrogen bond with the hy- of the departing OH moiety, thus the C O bond is
drogen of the departing OH moiety. Therefore, TFE significantly weakened and can be easily cleaved to
serves as a complementary charge template, leading generate alkylideneindoleninium intermediate B. The
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Fluorinated Alcohol-Mediated SN1-Type Reaction of Indolyl Alcohols
Scheme 5. Arenes used as nucleophiles.
Scheme 3. The active methylene compounds used as nucleo-
philes.
Scheme 6. Thiol and thiophenol used as nucleophiles.
weak or no hydrogen bond can be formed between
compound 1 and solvents, therefore, 3-indolylmetha-
nol itself serves as both H-bond donor and acceptor,
forming a dimer D via dual H-bonds between two 3-
À
indolylmethanols. In this case, the C O bond can be
readily cleaved to furnish electrophilic intermediate
E. Under activation of H2O, indole attacks intermedi-
ate E to produce product 3. In sharp contrast, DMSO
or DMF are considerably stronger hydrogen accept-
ors, 3-indolylmethanol would preferentially form the
hydrogen bond with the solvent molecule rather than
Scheme 4. Silyl enol ether and anthrone used as nucleo-
philes.
high dielectric constant of TFE also helps to stabilize with itself (F and G). In fact the formed singular H-
À
intermediate B. Finally, intermediate B is attacked by bond cannot weaken the C O bond enough for fur-
nucleophiles to give product 3. In the presence of ther cleavage, hence intermediate E cannot be pro-
weak nucleophiles, TFE plays the role of nucleophile, duced at all.
competing for electrophilic intermediate B with weak
nucleophiles, furnishing side product C.
The antibacterial activities of bisindole derivatives
were evaluated against a variety of Gram-positive and
The phenomenon that this SN1-type reaction works Gram-negative bacteria using a standard screening
fairly well in less polar or even non-polar solvents can protocol.[17] Compounds 5e, 5f, 13 and 15 exhibited
be rationalized by transition state D (Scheme 8). important inhibitory activities against Bacillus megate-
When less polar or non-polar solvents are used, either rium and Micrococcus lysodeikticus (Table 2). Espe-
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Hao Wen et al.
Table 2. Antibacterial activities evaluation of compounds 5e,
5f, 13, and 15.[a]
Compounds
MIC [mM]
M. lysodeikticus
B. megaterium
5e
5f
13
15
33.5
13.5
8.36
52.9
3.16
2.10
3.35
4.18
33.6
0.049
ciprofloxacin[b]
[a]
Data are expressd in MIC values (mM).
Ciprofloxacin was used as a positive control.
[b]
of the positive control ciprofloxacin (MIC=3.13 mM).
Moreover, 5e, 5f and 13 showed obvious antibacterial
activities against M. lysodeikticus with MIC values of
2.10, 3.35 and 4.18 mM, respectively. These results
demonstrate that these synthetic compounds might be
exploited as promising lead compounds for further
modification and commercial application.
Scheme 7. Proposed mechanism for the SN1-type reaction in
TFE.
Conclusions
In summary, we have developed an efficient SN1-type
reaction of 3-indolylmethanols with diverse nucleo-
philes in TFE, featuring a catalyst-free procedure, low
cost, wide substrate scope and mild reaction condi-
tions. With readily available 3-indolylmethanols, mis-
cellaneous nucleophiles such as indole, dicarbonyl
compounds, nitromethanes, arenes and thiols could be
readily introduced to the indole skeleton, furnishing
the coupled products in good to excellent yields. No-
tably, all these reactions do not work very well under
common acid catalysts. This methodology overcomes
the difficulties in acid-catalyzed 3-indolylmethanol-in-
volved reactions, which contributes greatly to the
chemistry of 3-indolylmethanols. Lastly, this approach
offers green and efficient methods for synthesis of 3-
substitued indolyl derivatives as well as unsymmetri-
cal bisindolylmethanes and triarylmethanes.
Experimental Section
General Materials and Methods
Reagents were purchased from chemical companies. Sol-
vents used in reactions described here were dried over ap-
propriate drying agents (Na for THF, Na for toluene). All
the reactions were performed in sealed tubes and monitored
by TLC (0.2 mm silica gel-coated HSGF 254 plates). The
products were purified by flash column chromatography
(200–300 mesh silica gel) eluted with a gradient of petrole-
um ether and ethyl acetate. Proton nuclear magnetic reso-
Scheme 8. Explanation of the reactivity in other solvents.
cially, 13 and 5f showed strong antibacterial activities
against B. megaterium with MIC values of 8.36 and
nance spectra (1H NMR) were recorded on
a Bruker
13.5 mM, respectively, which were comparable to that 500 MHz NMR spectrometer (CDCl3 or DMSO-d6 as sol-
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Fluorinated Alcohol-Mediated SN1-Type Reaction of Indolyl Alcohols
vent). The chemical shifts are reported in parts per million
(ppm), downfield from SiMe4 (d=0.0) and relative to the
signal of chloroform-d (d=7.26, singlet) or dimethyl sulfox-
ide-d6 (d=2.54, singlet). Multiplicities are given as: s (sin-
glet); d (doublet); t (triplet); q (quartet); dd (doublets of
doublet) or m (multiplets). The number of protons for
a given resonance is indicated by nH. Coupling constants
are reported as a J value in Hz. Carbon nuclear magnetic
resonance spectra (13C NMR) are reported in ppm using sol-
vent CDCl3 (d=77.16 ppm) as an internal standard. HR-MS
analyses were performed on a Waters XEVO QTOF mass
spectrometer.
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General Experimental Procedure
A 15-mL sealed tube was charged with 1 (0.2 mmol) and 2
(0.3 mmol). Then CF3CH2OH (2 mL) was added and the re-
sulting mixture was stirred at room temperature or a suitable
temperature. The reaction was monitored by TLC until
starting material had disappeared. Then the solvent was re-
moved under vacuum and the residue was purified by flash
chromatography to give the desired product 3.
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Acknowledgements
We are grateful to the National Natural Science Foundation
of China (Nos. 21102142, 41322037, and 41130858) and the
Program of Natural Science Foundation of Shandong Prov-
ince of China (No. JQ201510). Financial support from Tal-
ents of High Level Scientific Research Foundation of Qing-
dao Agricultural University (Nos. 6631112323, 6631115015)
is also gratefully acknowledged. We thank Prof. Teck-Peng
Loh (University of Science and Technology of China and Na-
nyang Technological University for HR-MS determination.
We are also grateful to Prof. Jon C. Antilla (University of
South Florida) for proof reading of this manuscript.
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