Synergistic Cooperative Effect of Sodium borohydride-Iodine Towards Cascade C?N and C?S/Se Bond Formation: One-pot Regioselective Synthesis of 3-Sulfenyl/selenyl Indoles and Mechanistic Insight

Article abstract of DOI:10.1002/adsc.201701028

In this work, a new strategy to synthesize 3-sulfenyl/selenyl indole is reported wherein LC?MS reveals a novel insight into synergistic cooperative effect of NaBH₄-I₂ which allows cascade C?N and C?S/C?Se bond formations via reduction-nucleophilic cyclization-chalcogenylation, three steps in one-pot, towards regioselective synthesis of diverse 3-chalcogenyl indoles including 5-bromo-3-[(3,4,5-trimethoxyphenyl)thio]-1H-indole, a known lead anticancer compound, directly from 2-amino-phenacylchlorides and thiophenols or disulfides/diselenides in aqueous dioxane under transition-metal-free condition. (Figure presented.).

Full text of DOI:10.1002/adsc.201701028

Title: Synergistic Cooperative Effect of Sodium borohydride-Iodine
Towards Cascade C-N and C-S/Se Bond Formation: One-pot
Regioselective Synthesis of 3-Sulfenyl/selenyl Indoles and
Mechanistic Insight
Authors: ADITYA LAVEKAR, DANISH EQUBAL, SAIMA Malik, and
Arun Sinha
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701028
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10.1002/adsc.201701028
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synergistic Cooperative Effect of Sodium borohydride-Iodine Towards
Cascade C-N and C-S/Se Bond Formation: One-pot Regioselective Synthesis of
3-Sulfenyl/selenyl Indoles and Mechanistic Insight
Aditya G. Lavekar,a,b Danish Equbal,a Saimaa and Arun K Sinhaa,b
a.
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram
Extension, Sitapur Road, Lucknow-226031, Uttar Pradesh India; E-mail: aksinha08@rediffmail.com;
ak.sinha@cdri.res.in
Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
derivatives. In general, two synthetic routes[3,4] have
Abstract. In this work, a new strategy to synthesize 3-
sulfenyl/selenyl indole is reported wherein LC-MS
reveals a novel insight into synergistic cooperative effect
of NaBH4-I2 which allows cascade C-N and C-S/C-Se
bond formations via reduction-nucleophilic cyclization-
chalcogenylation, three steps in one-pot, towards
regioselective synthesis of diverse 3-chalcogenyl indoles
including 5-bromo-3-[(3,4,5-trimetoxyphenyl)thio]-1H-
indole, a known lead anticancer compound, directly from
been known in the literature for synthesis of
chalcogenylated indoles (Scheme 1) in which the first
route involves direct chalcogenylation of an existing
indole ring[3] with sulfenylating agents whereas other
route involves cascade electrophilic cyclization and
coupling reactions of various designer aniline
derivatives[4] (such as 2-alkynyl aniline or 2-vinyl
aniline) followed by subsequent chalcogenylation.
Despite the fact that there are a wide range of sulphur
sources (such as arylsulfenyl/sulfonyl halides,[3d,e] and
arylsulfonium salts[3i] which contribute immensely in
the first route during direct chalcogenylation of pre-
existing indoles with C-S bond formation (Scheme 1,
Route - 1), however, many commercially available
indole derivatives are either expensive or possessing
limited scope in structural diversity besides some of
sulphur sources requires some additional step to
prepare or are sensitive to moisture. Against this
milieu, the second cascade route offers advantage in a
way to design a mild, efficient and diversified method
for the simultaneously constructing the substituted
indole nucleus and subsequent chalcogenylation with
C-N and C-S bond formation in one manoeuvre
(Scheme 1, Route - 2). For example, Larock[4a,b] et al
2-amino-phenacylchlorides
and
thiophenols
or
disulfides/diselenides in aqueous dioxane under
transition-metal-free condition.
Keywords: cascade C-N and C-S/C-Se bond,cooperative
catalysis, heterocycles, LC-MS based reaction
mechanism, reduction-cyclization-chalcogenylation
The indole nucleus[1] is one of the most widespread
heterocycle compounds in the realm of
pharmaceuticals, agrochemicals and organic materials.
The excellent binding ability of indole to interact with
different biological targets makes them “privileged
structures” in drug design and development. Among
numerous indole nuclei, 3-chalcogenyl-indoles (3-
sulfenyl and 3-selenyl indoles) are one of such
attracting candidates possessing several potential
therapeutic uses[2] as antitumor, antibacterial, antiviral
activities (Figure 1).
Due to the special pharmacological properties,
much effort has been devised towards development of
efficient route to access indole-based sulfides and
their
Figure 1: Some examples of bioactive 3-sulfenylated
indole.
Scheme 1: Distinct synthetic approaches to 3-sulfenyl-
indoles.
1
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10.1002/adsc.201701028
Advanced Synthesis & Catalysis
reported a novel synthetic route to 3-chalcogenyl- selective chalcogenylation at 3-position of indole in
indoles by palladium/ copper catalyzed coupling of the same pot by comprising synergistic co-operative
N,N-dialkyl-o-iodoanilines and terminal alkynes effect of NaBH4-I2 which finally produces highly
followed
by electrophilic
cyclization
with effective and diversity oriented regioselective
arylsulfenyl(selenyl) chlorides in the presence of (n- synthesis of bioactive 3-sulfenyl/selenyl indoles
Bu)4NI.
utilizing and
2-amino-phenacylchlorides[8]
Similarly, Zhang[4d] et al provides another route for thiophenol[3c] as cheaper and versatile precursors in
synthesis of 3-sulfenylindoles by palladium-catalyzed aq.-dioxane. Moreover, LC-MS provides powerful
annulation of 2-(1-alkynyl)benzenamines with insights into the mechanistic aspects of the above
disulfides as a sulphur source (Scheme 1). At times, cascade reduction-cyclisation-sulfenylation reaction
the high cost and the toxicity of transition metals in one pot.
limits the utility of many synthetic routes. Most
At the beginning of our investigation, a model
importantly, Li[4e] and Du[4f] et al disclosed copper[4e] reaction of 4- bromo-2-amino phenacylchloride[7b] (1a,
or iodine/iron-mediated[4f] electrophilic annulation of 1 mmol) and thiophenol (2a, mmol) with NaBH4 (2
2-alkynyl-aniline[4f] derivatives with disulfides or mmol) in aqueous dioxane (4ml, 1:9), at reflux
diselenides
provides
corresponding
3- temperature was performed to optimize the reaction
sulfenyl/selenenyl indoles in moderate to excellent conditions and the results are summarized in Table 1
yields. Among various sulfenylation agents (such as (entries 1-14). Unfortunately, the desired product (3a)
arylsulfenyl chlorides or diaryldisulfide etc), sulfonyl
hydrazide[3f] being shelf-stable reagent, has received Table 1: Optimization of reaction conditionsa for 3-sulfenyl
considerable attention as a sulphur source. In this indoles via Sugasawa annulation-chalcogenylation.
context, Kuhakarn[4h] et al described the synthesis of
N-alkyl-3-sulfanylindoles
from
2-alkynyl-N,N-
dialkylanilines and sulfonyl hydrazides in the
presence of iodine and tert-butylhydroperoxide
(TBHP). While the second route provides indole
thioethers with N-protected indole and/or substituent
at 2nd position of indole core via electrophilic
cyclization of 2-alkynyl aniline derivatives[4a-4f]
(Scheme 1), 2-vinyl aniline derivative[4g] also surfaced
as one of the precursors which provides regioselective
synthesis of 3-chalcogenyl indoles with free NH
group via tandem electrophilic reactions of 2-(gem-
dibromo(chloro)vinyl)-N-methyl sulfonyl anilines and
disulfides/diselenides in the presence of t-BuOLi and
I2 in DMSO as solvent. Very recently, Fan[4c] et al
developed an oxidative nucleophilic cyclization of 2-
alkynylanilines with thiophenols towards the
construction of 3-chalcogenyl-indoles in the presence
of PhI(OAc)2 (Scheme1). Further, there is still scope
for development of new methodology and selection of
green catalyst for the titled compounds.
was not formed even after refluxing the reaction
mixture of 1a and 2a for 12 h or more (Table 1, entry
1) and TLC observation revealed the formation of
only intermediate indole[7a] via Sugasawa annulation
without subsequent sulfenylation with thiophenol as it
was initially presumed that in-situ generated NaOH
from NaBH4 would allow the sulfenylation in alkaline
medium. [3l] Further an increase in amount of NaBH4
(upt o 3 equiv.) and addition of external NaOH[3l] (1
equiv.) as co-catalyst could not allow the formation of
product 3a (entries 2-3). Hence, our attention moved
towards exploration of iodine[3l,q].as a compatible
cooperative catalyst with NaBH4 for subsequent
sulfenylation of indole in the same pot. To our
satisfaction, 1 equiv. of iodine provides the desired
product 3a in 41% yield (entry 4) along with some
amount of unreacted intermediate indole. Further
increase in amount of iodine upto 3 equiv. (entries 5-
7) wherein 2 equiv. of iodine (entry 6) successfully
provided the optimum yield of desired product 3a up
to 71% yield in shorter reaction time of 3.5 h without
any trace of unreacted intermediate indole. Replacing
New reactions provide new ways to think about
bond construction/breaking thereby achieving step
economic synthesis while selection of inexpensive
starting material, non-toxic solvent and non-metal
based catalyst, is highly desirable. In this context,
there has been rapidly expanding interest in the field
of cooperative catalysis which allows the construction
of several bonds in one pot due to synergistic-
cooperative[5] effect of both the catalysts otherwise
the desired products are not obtainable by the use of
one catalyst alone. As a part of our on-going interest
in green chemistry with emphasis on the use of
cooperative catalysis[3c,5f] and revisiting of some
classical named reactions[6] (Heck, [6a,b] Suzuki-Aldol,
[6c]
Knoevenagel-Perkin-Heck reactions[6d] in one pot)
towards concise synthesis of bioactive molecules, we
herein report first multiple C-N and C-S/C-Se bond
formation under transition metal free conditions via
cascade route for in situ generation of indole with free
-NH group by Sugasawa[7] annulation followed by
[3m]
the iodine with other oxidants[3] (such as NBS,
[3o]
PIDA[3n] and FeCl3 (entries 8-10) and aq-dioxane
2
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10.1002/adsc.201701028
Advanced Synthesis & Catalysis
by another solvents (entries 11-12) were found regioselective as only 3 position of indole is occupied
ineffective for the above cascade transformation. In during sulfenylation.
controlled experiments for which the above cascade
With the optimized conditions in hand (Table 1,
reaction was conducted with iodine alone (without entry 6), the substrate scope was studied by changing
NaBH4), the formation of 3a was not observed (entry the thiols (aromatic/heteroaromatic) and 2-amino
13), which clearly indicated the role of a NaBH4–I2 phenacylchloride derivatives and the desired 3-
combination as an activator for the cascade Sugasawa sulfenylated indoles (Table 2, 3a-3ac) were obtained
annulation-sulfenylation reaction. Further, 3 equiv. of in moderate to good yield without any much influence
thiophenol (2a) was used for the above cascade of electron-donating or electron-withdrawing groups
reaction, however, no further improvement in the present either on aromatic ring of thiol or 2- amino
yield of product 3a was noticed as well as 1HNMR of phenacylchloride derivative. Gratifyingly, 2/4-
the product showed no trace of 2,3 bis-sulfenylated aminothiophenols i.e. thiophenol (-SH) having
indole3b thus it confirmed that our protocol is a highly additional acidic proton (- NH2) also reacts
Table 2: Substrate scope of 3-sulfenyl-indoles a
successfully
with
2-amino
phenacylchloride 2518[2c] i.e. 5-bromo-3-[(3,4,5-trimetoxyphenyl)thio]-
derivative yielding products 3i-3j (Table 2) under 1H-indole (Table 2, entry 3ac) in one pot under
[9]
mild
reaction condition.
Unfortunately, metal-free condition, thus overall demonstrating the
dodecanethiol, an aliphatic thiol, did not provide the generality, greenness and robustness of our
corresponding desired product. Thus, this cooperative catalytic protocol.
chemoselectivity[3p] can be a significant addition to
the growing arsenal for substrate-selective
sulfenylation (aromatic versus aliphatic) in the total
synthesis of bioactive complex molecule bearing
indole core. [9] While implementing the study into the
substrate scope (Table 2, entries 3a-3ab), we further
got interested to react 3,4,5-trimethoxythiophenol
with 4-bromo-2-amino phenacylchloride (1a) which
successfully provided a lead antitumor compound RS
To properly address the synergism between
NaBH4 and I2 towards the formation of the product 3a,
LC-MS spectroscopy was used to visualize in situ
generation of the intermediates (A-F) (Scheme 2) as
well as to monitor the progress of the reaction to
provide deeper insight into the mechanism of the
reaction pathway for both steps. Towards this goal,
aliquots were taken after an time intervals of 15,30,
3
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10.1002/adsc.201701028
Advanced Synthesis & Catalysis
45 and 60 min (see S.I. for details) from reaction alcohol “C” (see S.I.). Next, iodination of 2a into
mixture of 1a and 2a and the outcome was reactive species i.e. phenylsulfenyl iodide "E"
rationalized by assuming reduction of 1a into (m/z=235) detected after 45 min of reaction which
intermediate "A" (m/z=250) which gets converted enters in the second stage of reaction i.e. sulfenylation
into indole “D” by two plausible paths (i) dehydration at the third position of indole with formation of an
of "A" into “B” (m/z = 234) via “B1” (m/z = 377) as ionic intermediate- “F” (m/z=430) which finally
detected after 15 min (ii) cyclization of "A" into 3- confirmed the formation of desired product 3a
hydroxyindoline "C" (m/z=214) after 30 min of marked as "G" (m/z =304) after 60 min of reaction
reaction. Interestingly, the cooperative role of iodine (see S.I.). Based on this analysis a plausible
appears crucial in Sugasawa annulation as evident mechanism is shown in scheme 2.
from LC-MS[10] wherein the intermediate indole “D”
With remarkable success towards synthesis of
sulfenylating agent. (Table 2, 29 examples of 3-
sulfenylated indoles),
(m/z 196) formed via “C1” (m/z=467) or “C2”
(m/z=340) involving iodine mediated dehydration of
Scheme 2: Plausible mechanism and LC-MS collage of reaction intermediates for cascade Sugasawa anuulation-
sulfenylation
now our attention turned towards further widening the is to mention that diaryldisulfide being odourless and
scope and compatibility of commercially available inexpensive, also appear as alternative sulfenyalting
agents towards formation of 3e. Further, few more
other
sulfenylating
agents[3d-k]
(such
as
diaryldisulfides (Table 3, 3ad-3ah) were investigated
with 2-amino phenacylchloride derivatives wherein
half equivalent of disulfides in comparison to thiol
was found sufficient to form the desired C-3
sulfenylated indoles 3ad-3ah (Table 3) via multiple
C-N and C-S bond formation in one pot.
sulfonylhydrazide, sulfonylchlorides, sulfinate and
disulfide derivatives) in optimized reaction condition
(Scheme 3). Among them, sulfonylhydrazide
provided 3e in poor yield (29%) whereas p-tolyl
disulfide appears as an effective sulphur source which
successfully reacts with 1a to provide the desired
product 3e in 67%yield (Scheme 3) which is
comparable in respect to yield of 3e as obtained using
thiophenol (68%, Table 2) as a sulfenylating agent. It
Further venturing into the robustness of our
Table 3: Substrate scope of 3 sulfenyl/selenyl indoles with
diaryldisulfides/diaryldiselenidea
Scheme 3: Comparative study of different sulfenylating
agents towards 3-sulfenylindole (3e)
4
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10.1002/adsc.201701028
Advanced Synthesis & Catalysis
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2-
amino
phenacylchloride derivative (1a’) was reacted with
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NaBH4-I2 catalyzed one-pot two-step reaction of 2-
amino-phenacylchlorides
and
thiophenols
or
diaryldisulfides/diaryldiselenide in which the
intermediate indole is formed by in situ nucleophilic
Sugasawa-annulation that becomes the starting
material
for
second
step
i.e.
C(sp2)–H
chalcogenylation thereby furnishing structurally
diverse 3-sulfenyl/selenyl indoles. The main
advantage of our protocol is cascade C-N and C-S/C-
Se bond formation under influence of cooperative
catalyst (NaBH4-I2) besides being milder reaction
condition, ample substrate scope with high
regioselectivity and high atom economy. Additional
investigations aimed at the exploring the biological
activities of the titled structurally diverse heterocyclic
compounds are underway in our laboratory.
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Experimental Section
2-Aminophenacyl chloride derivative (0.25 mmol) was
taken in aq. dioxane (4 ml) in a RBF and then a NaBH4
(0.5 mmol) and iodine (0.50 mmol) and thiophenol
(0.275mol) or diaryl disulfide/diaryl diselenide (0.14
mmol) were added and reaction mixture was refluxed for
duration of 3.5 h. After completion of the reaction, crude
reaction mixture was allowed to come to rt then conc. on
rotatory evaporator. Water was added to crude product and
then extracted with ethyl acetate (5 ml, 3 times) and
combined organic layer was washed with saturated
Na2S2O3 solution to remove any traces of iodine followed
by brine, dried over anhydrous Na2SO4 and conc. under
vacuum. Colum purification of crude product was
performed on silica gel (60/120 mesh) using ethyl acetate
in hexane as eluent to afford the different 3-sulfenyl/selenyl
indoles (3a-3al).
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Acknowledgements
AGL and DE are indebted to UGC New Delhi for the award of
research fellowships. We acknowledge Director CDRI, Lucknow
and grateful to SAIF-CDRI for providing spectroscopic data and
Mr D. N. Vishwakarma for LCMS data. CDRI Communication No.
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5
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10.1002/adsc.201701028
Advanced Synthesis & Catalysis
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cyclization-dehydration steps)7a of well reported Sugasawa
annulation is identified for the first time by LC-MS wherein
synergism of Iodine found crucial for the both Sugasawa
annulation as well as chalcogenylation to provide product 3a.
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10.1002/adsc.201701028
Advanced Synthesis & Catalysis
UPDATE
Synergistic Cooperative effect of Sodium
borohydride-Iodine Towards Cascade C-N and C-
S/Se Bond Formation: One-pot Regioselective
Synthesis of 3-Sulfenyl/selenyl Indoles and
Mechanistic Insight
Adv. Synth. Catal. Year, Volume, Page – Page
Aditya G. Lavekar,a,b Danish Equbal,a Saimaa and
Arun K Sinhaa,b*
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