Metal-free hydroamination of alkynes: A mild and concise synthesis of thiazolo[3,2- a ]indoles and their cytotoxic activity

Article abstract of DOI:10.1055/s-0039-1690680

A metal-free, mild and efficient method for the synthesis of thiazolo[3,2- a ]indoles has been developed starting from indoline-2-thiones. The reaction methodology involves first the formation of thermally labile 2-(prop-2-ynylthio)-1 H -indole intermedia

Full text of DOI:10.1055/s-0039-1690680

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
S. Short et al.
Paper
Synthesis
Metal-Free Hydroamination of Alkynes: A Mild and Concise
Synthesis of Thiazolo[3,2-a]indoles and their Cytotoxic Activity
Spencer Shorta
Steven Rhodesa
Vishakha S. Bhaveb
Ryoga Hojoa
0
0
0
0-0
0
0
2-6
8
3
9-1
5
6
8
R1
R
DMSO/KOH,
60 °C
S
S
N
R
K2CO3
H2O, rt
+
S
R
N
H
5-exo-dig
hydroamination
R1 = H/alkyl/aryl
N
H
R1
Mukund Jha*a
0
0
0
0-0
0
0
2-0
5
4
0-6
3
5
5
X
R1
19 examples
up to 91% yield
X = Cl/Br
a Department of Biology and Chemistry, Nipissing University,
100 College Drive, North Bay, ON P1B 8L7, Canada
mukundj@nipissingu.ca
b School of Pharmacy, Philadelphia College of Osteopathic
Medicine, Suwanee, GA 30024, USA
DMSO/KOH, rt then 60 o
R1
C
up to 56% yield
Br
Received: 08.07.2019
Accepted after revision: 29.08.2019
Published online: 24.09.2019
N
CHO
S
N
SCH3
S
S
DOI: 10.1055/s-0039-1690680; Art ID: ss-2019-m0384-op
N
N
N
H
2
H
1
3
Abstract A metal-free, mild and efficient method for the synthesis of
thiazolo[3,2-a]indoles has been developed starting from indoline-2-thi-
ones. The reaction methodology involves first the formation of thermal-
ly labile 2-(prop-2-ynylthio)-1H-indole intermediates, which undergo
base-mediated intramolecular hydroamination to produce the title
compounds in excellent yields.
HO
O
OH
S
R
S
N
R1
5
N
4
O
Figure 1 Representative examples of biologically active indole-fused
sulfur-containing tricyclic heterocycles
Key words indole-fused heterocycles, thiazolo[3,2-a]indoles, metal-
free hydroamination, indoline-2-thiones, intramolecular cyclization
oratory recently reported antiproliferative activity of
[1,3]thiazino[3,2-a]indol-4-ones 5 (Figure 1).10
Indole-fused heterocyclic frameworks are a highly de-
sirable class of organic compounds because they are often
found to possess biological and medicinal properties.1
Among them, polycyclic derivatives of indole have received
significant attention in recent years due to their role in
modulating biological processes.2 More specifically, indole-
annulated heterocycles containing one or two sulfur atoms
are of interest because several such compounds are known
to possess interesting properties. For instance, sulfur-con-
taining heterocycles have been found to exhibit activities
such as HIF-1 inhibition,3 selective estrogen receptor modu-
lators,4 LTB4 production inhibition,5 and analgesic, psycho-
analeptic and nootropic activities.6 Similarly, fused thi-
azoles are valuable structural motifs known for their anti-
cancer, antibacterial, antifungal, antiviral and other
pharmacological properties.7 Many indole-based sulfur-
containing tricyclic heterocycles are found among crucifer-
ous phytoalexins, including cyclobrassinin (1), brassilexin
(2) and brassicanal B (3), produced by plants as defense
chemicals (Figure 1).8 Similarly, fused indole derivatives, in-
cluding thiazoloindole 4, are also biologically relevant for
their potential to act as 5HT4 receptor antagonists.9 Our lab-
Considering the potential of these tricyclic heterocycles
to display bioactivity, their efficient synthesis and quick ac-
cess is highly sought after. Metal-catalyzed reactions have
played an important role in the development of syntheses
of thiazole-fused heterocycles.11–17 Particularly, strategies
based on S-propargylation followed by Sonogashira cou-
pling and subsequent intramolecular cyclization have led to
the synthesis of ring systems such as 3-benzylthiazolo[3,2-
a]benzimidazole12,14 and 6-benzylthiazolo[3,2-b]1,2,4-tri-
azoles.16 Related approaches, but under basic conditions,
have led to the synthesis of 3-benzylthiazolo[3,2-a]benzim-
idazole from benzimidazole-2-thione.18 However, only a
couple of reports are available for the synthesis of analo-
gous heterocycles fused with the biologically relevant in-
dole nucleus (i.e., thiazoloindole 9), each stemming from in-
doline-2-thiones 6.9,17 In the first instance, thione 6a was
converted into 2-((2,2-diethoxyethyl)thio)-1H-indole (8)
using bromoacetaldehyde diethyl acetal (7), which upon
treatment with polyphosphoric acid resulted in thiazo-
lo[3,2-a]indole (9) in an overall 25% yield (Scheme 1a).9 The
second report is based on the aforementioned sequential S-
propargylation–Sonogashira reaction coupled with an in-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
S. Short et al.
Paper
Synthesis
Previous reports
OEt
OEt
OEt
EtO
Br
polyphosphoric
acid, 130 °C
7
S
(a)
S
N
S
9
N
K2CO3/acetone
reflux
N
H
8
H
1 example
25%
6a
DCM, 1% NaOH
BTEAC, rt
+
(b)
R
S
R
S
N
11
N
10
H
H
I
6
X
Pd(PPh3)2Cl2
CuI
R1
Et3N, DMF
rt, 3 h
R
1 = EWG
12
R
S
N
Et3N, DMF
90 °C, 4 h
S
R
S
R1
R1
N
H
12a
13
Our work
R
R1
S
N
R
K2CO3
H2O, rt
DMSO/KOH
14
(c)
S
+
R
N
H
60 °C
5-exo-dig
N
H
R1
19 examples
up to 91% yield
R1 = H/alkyl/aryl
6
11
10
hydroamination
X
R1
1 h
X = Cl/Br
DMSO/KOH, rt then 60 °C
R1
up to 56% yield
Br
10
Scheme 1 (a) Literature synthesis of thiazolo[3,2-a]indole (9);9 (b) Transition-metal-catalyzed synthesis of 3-benzylthiazolo[3,2-a]indoles 1317 (EWG =
electron-withdrawing group); (c) Synthesis of thiazolo[3,2-a]indoles 14 (current work).
tramolecular cyclization approach (Scheme 1b).17 Thione 6
was first S-propargylated19 using propargyl bromide (10) to
produce 2-(prop-2-ynylthio)-1H-indole 11. Sonogashira
coupling of sulfide 11 with aryl iodides 12 in the presence
of bis(triphenylphosphine)palladium(II) chloride, CuI and
excess Et3N base resulted in 3-benzylthiazolo[3,2-a]indoles
13 in decent yields. Although this method allows for the
synthesis of tricyclic thiazoloindoles 13, it suffers from
some limitations. First, sulfide 11 is thermally unstable, and
when heated at 90 °C readily undergoes thio-Claisen rear-
rangement to yield 2,9-dihydrothiopyrano[2,3-b]indole,
which renders it unusable in high-temperature reactions.17
Secondly, the methodology lacks generality, as only sulfides
12a having electron-deficient arenes successfully under-
went intramolecular hydroamination (Scheme 1b). Thus,
only benzyl-substituted thiazolo[3,2-a]indoles 13 with elec-
tron-withdrawing groups could be furnished under these
conditions.
tion reactions.21 We have a long-standing interest in the
synthesis of functionalized indoles.22–26 Given the low ther-
mal stability of sulfides 11, we envisaged that they would
be more conducive to milder base-assisted hydroamination
conditions to furnish N-fused heterocycles. Towards that
end, herein, we report a general, metal-free, mild and effi-
cient method for the synthesis of thiazolo[3,2-a]indoles 14
exploiting the reactivity 2-(prop-2-ynylthio)-1H-indoles
11. The newly developed methodology primarily relies on
direct base-mediated intramolecular hydroamination of
sulfides 11, thus substantially expanding the scope and
synthetic utility of thermally labile 2-(prop-2-ynylthio)-
1H-indoles 11 (Scheme 1c).
The required precursor indoline-2-thiones 6, depicted
in Scheme 1c, were synthesized from commercially avail-
able indolin-2-ones using a literature procedure.22 The regi-
oselective propargylation of thiones 6 using propargyl bro-
mide in the presence of phase-transfer catalyst benzyltri-
Hydroamination reactions involving alkynes have
emerged as a powerful tool for the synthesis of nitrogen-
containing heterocycles.20,21 Metal catalyses have been em-
ployed extensively for achieving both inter- and intramo-
lecular hydroamination reactions.20 At the same time, more
economical base-mediated approaches have also been de-
veloped to expand the efficacy and scope of hydroamina-
ethylammonium chloride (BTEAC) is
a
well-known
method.19 However, we adopted slightly modified reaction
conditions for the propargylation of thiones which excludes
the need for the BTEAC catalyst. The cues for the new reac-
tion conditions were gathered from a recent literature re-
port describing the conjugate addition of thiophenols to
propiolate esters to produce vinyl sulfides.27 Following the
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

C
S. Short et al.
Paper
Synthesis
reported procedure, propargylation of thiones 6 was at-
tempted and achieved in aqueous K2CO3 medium using
commercially available propargyl halides 10 in near quanti-
tative yields, without compromising any reaction efficacy,
under the new and simplified conditions. Additional prop-
argyl halides 1-(3-bromoprop-1-yn-1-yl)-4-methoxyben-
zene and 1-(3-bromoprop-1-yn-1-yl)-4-nitrobenzene, de-
rivatives with an electron-donating (OCH3) and electron-
withdrawing (NO2) group, respectively, were synthesized
following a literature procedure28 to produce the corre-
sponding sulfides. The p-methoxy-substituted product 11q
was obtained in high yield while the p-nitro-substituted
propargyl halide failed to undergo the substitution reaction
under these conditions. The electron-withdrawing effect of
the nitro substituent could be detrimental for the desired
substitution step. It is worthwhile to mention that the sta-
bility of sulfides 11 is not ideal. At room temperature, these
sulfides undergo decomposition within 24 hours to multi-
ple undetermined products. Fortunately, this process is sig-
nificantly slowed by storing compounds of series 11 in re-
frigeration conditions. Additionally, decomposition of 11, to
undetermined products, was also observed on attempts to
purify them using column chromatography (silica gel).
Hence, to circumvent any loss in yields during the purifica-
tion process, sulfides 11 were freshly prepared and directly
taken to the next step in the crude form.
Next, we set out to explore the base-mediated hydro-
amination reaction using unsubstituted sulfide 11a as a
model reactant. The preliminary reaction conditions were
adopted based on literature reports describing KOH-assist-
ed hydroamination of substituted indoles and phenylacety-
lenes.21 2-(Prop-2-ynylthio)-1H-indole (11a) was subjected
to 0.5 equivalents of KOH in DMSO and the reaction mix-
ture was stirred at room temperature. However, no product
formation was detected for up to 12 hours. Stirring the re-
action mixture for a longer period resulted in decomposi-
tion of the starting sulfide 11a. In the following attempt,
the reaction temperature was incrementally increased to
70 °C. A nonpolar product spot, which turned purple under
UV light, was detected on TLC analysis. Once sulfide 11a
was completely consumed (30 min), the product was isolat-
ed and characterized using spectroscopic methods. We
were delighted to find that the desired hydroamination had
taken place to produce 3-methylthiazolo[3,2-a]indole (14a)
in 44% yield (Table 1, entry 1). Content with the success of
the desired reaction, we proceeded to optimize the condi-
tions by varying the reaction parameters, such as solvent,
base and temperature, to maximize the yield of 14a (Table
1). The use of mild organic base Et3N in place of KOH in sol-
vent DMSO was ineffective in facilitating the intramolecular
hydroamination reaction, and sulfide 11a remained unre-
active under these conditions (Table 1, entry 2). Increasing
the concentration of KOH in the reaction mixture had a fa-
vorable impact on reaction output. The reaction yield im-
proved dramatically in the presence of 1.5 equivalents of
KOH in DMSO at 60 °C, which resulted in 14a in 85% yield
(Table 1, entry 4). Further increase in the KOH concentra-
tion led to decreased yields (Table 1, entries 9 and 10).
Changing the solvent from DMSO to MeCN, DMF, MeOH or
THF was ineffective in enhancing the yield of product 14a
(Table 1, entries 5–8). These results are in agreement with
literature reports describing the DMSO/KOH mixture as
ideal conditions for the hydroamination of N-heterocycles
involving alkynes.21 Thus, after thorough screening, we es-
tablished the use of 1.5 equivalents of KOH in DMSO at
60 °C as the optimal conditions for the intramolecular
hydroamination reaction of 2-(prop-2-ynylthio)-1H-indole
(11a) to afford N-fused heterocycle thiazolo[3,2-a]indole 14a.
Table 1 Optimization of the Base-Mediated Synthesis of 14aa
base, solvent
S
S
N
temperature
N
H
11a
14a
Entry Solvent
Base (equiv)
Temp (°C) Time
(min)
Yield (%)b
of 14a
1
2
DMSO
DMSO
DMSO
DMSO
MeCN
MeOH
THF
KOH (0.5)
Et3N (1.0)
KOH (1.0)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (1.5)
KOH (2.0)
KOH (2.5)
70
70
70
60
60
60
60
60
60
60
30
30
45
45
45
45
45
45
45
30
44
ndc
60
3
4
85d
38
5
6
ndc
ndc
40
7
8
DMF
9
DMSO
DMSO
71
10
25
a Reaction conditions: 11a (0.34 mmol), base, solvent (2 mL).
b Isolated yield.
c Not detected.
d Optimized reaction conditions.
We next proceeded to examine the scope of the newly
developed hydroamination reaction under the optimized
reaction conditions by varying the substitutions on the in-
dole nucleus and the propargyl moiety. As summarized in
Scheme 2, sulfides 11a–q underwent cyclization smoothly
to produce thiazoloindoles 14a–q in excellent yields. The
substitutions on the indole ring did not cause any imped-
ance in the hydroamination reaction except in the case of
chloro-substituted sulfides 11i–l; the corresponding thi-
azoloindoles 14i–l were obtained in slightly lower yields
compared to other derivatives (Scheme 2). The loss in yield
could be attributed to low stability of the precursor chloro-
substituted indole sulfides 11i–l. Furthermore, we were de-
lighted to observe that the methodology under develop-
ment worked well with both internal and terminal alkyne
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

D
S. Short et al.
Paper
Synthesis
R
S
R
DMSO/KOH
60 °C
S
N
N
H
11a–q
14a–q
R1
R1
S
S
N
S
S
N
S
S
S
N
N
N
N
N
14a, 85%
14b, 78%
14c, 81%
14d, 85%
14e, 90%
14f, 80%
14g, 86%
Ph
S
S
S
S
S
S
S
F
F
N
N
N
N
N
N
N
Cl
Cl
Cl
Cl
14m, 80%
14n, 75%
14h, 80%
14i, 75%
14j, 65%
14k, 62%
14l, 68%
Ph
Ph
S
N
S
N
S
F
F
N
14o, 91%
14p, 85%
14q, 87%
Ph
O
Scheme 2 Synthesis of thiazolo[3,2-a]indoles 14a–q. Reagents and conditions: 11 (0.34 mmol), KOH (0.51 mmol), DMSO (2 mL); isolated yields.
functionality. The sulfide possessing an electron-donating
group (OCH3) produced p-methoxybenzyl-substituted thi-
azoloindole 14q in excellent yield.
from 6. Indoline-2-thione (6a) and propargyl bromide (10)
were allowed to react in the presence of KOH in DMSO, as
depicted in Scheme 3. Thione 6a was completely consumed
producing sulfide 11a within 15 minutes at room tempera-
ture (TLC analysis). The reaction temperature was then
gradually increased to 60 °C, which resulted in product 14a
formation. Although it was pleasing to find that 14 can be
obtained in a one-pot reaction, the isolated yield was unfor-
tunately somewhat compromised. Product 14a was ob-
tained in 45% yield. This loss in yield of the cyclized prod-
ucts was consistent with propargyl bromides having both
terminal and internal alkynes (Scheme 3). Gratifyingly, the
reaction of substituted thiones 6e and 6f (5-CH3 and 6-
CO2CH3) with p-nitrophenyl-substituted propargyl bromide
10f furnished the corresponding thiazoloindoles 14r and
14s in 56% and 48% yield, respectively, under KOH-mediated
one-pot conditions (Scheme 3). These results are in agree-
ment with previous observations which suggest the intra-
molecular hydroamination is facilitated in the presence of
alkynes conjugated with phenyl rings having electron-
withdrawing groups.17
The H/alkyl/phenyl/p-methoxyphenyl substitutions of
the propargyl moiety yielded the corresponding cyclized
products in high yields (Scheme 2). These results truly
demonstrate the generality of our newly developed meth-
odology. Until now, the synthesis of 14 with these substitu-
tions was not feasible via the currently known sequential S-
propargylation–Sonogashira coupling method for the syn-
thesis of the thiazolo[3,2-a]indole ring system (Scheme
1b).17 However, attempts to obtain cyclized products with
electron-withdrawing substituents were unsuccessful us-
ing the methodology under investigation. This is due to the
limitation of thiones 6 to undergo a substitution reaction
with propargyl halide tethered with an electron-withdraw-
ing substituent [e.g., 1-(3-bromoprop-1-yn-1-yl)-4-nitro-
benzene] in the presence of K2CO3. The divergent approach
using Sonogashira coupling followed by intramolecular cy-
clization17 could very well be used to generate further
structural diversity, particularly with electron-withdraw-
ing substituents, around the framework of 14. The ease of
synthesis and the structural makeup of the heterocyclic
skeleton thiazolo[3,2-a]indole 14 would be of tremendous
interest to the synthetic chemistry community as the most
nucleophilic site of 14, position 9,10 is available for further
functionalization using electrophiles.
S
R1
N
DMSO/KOH
rt–60 °C
S
R
R
+
Br
N
H
R1
10a R1 = H
14a R = R1 = H, 45%
6a R = H
6c R = 6-Cl
6e R = 5-CH3
10b R1 = CH3
14b R = H, R1 = CH3, 50%
14i R = 6-Cl, R1 = H, 48%
14r R = 7-CH3,
10f R1 = p-nitrophenyl
Given that propargylation of thiones 6 can be accom-
plished under basic conditions and the subsequent hydro-
amination step in this methodology is also base-mediated,
it was prudent to examine whether the synthesis of thiazo-
lo[3,2-a]indoles 14 can be carried out in one pot starting
6f R = 6-CO2CH3
R1 = p-nitrophenyl, 56%
14s R = 6-CO2CH3,
R1 = p-nitrophenyl, 48%
Scheme 3 One-pot synthesis of thiazolo[3,2-a]indoles 14
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

E
S. Short et al.
Paper
Synthesis
We believe the mechanism of intramolecular hydroami-
nation in the current work to be similar to previously re-
ported base-mediated hydroamination of analogous S-
propargylated substrates.14,17 Sulfide 11 first undergoes a
KOH-assisted 5-exo-dig cyclization to produce intermediate
15. Subsequent proton transfer followed by an isomeriza-
tion step could furnish the thiazoloindole ring system, as
outlined in Scheme 4.
FT-NMR 300 MHz spectrometer. 13C NMR spectra are fully decoupled.
High-resolution mass spectrometry was carried out using an Agilent
LC-MS 6545 quadrupole time-of-flight (qTOF) mass spectrometer. IR
was recorded using a Bruker ALPHA FT-IR spectrometer. Chemicals
obtained from commercial suppliers were used without further puri-
fication.
2-(Prop-2-ynylthio)-1H-indoles 11; General Procedure
In a clean, 50 mL, round-bottomed flask covered with tin foil, the
appropriate indoline-2-thione 6 (0.25 mmol) was mixed with water
(5 mL) followed by the addition of the propargyl halide (0.48 mmol)
and K2CO3 (0.84 mmol). The reaction mixture was stirred at room
temperature until the thione was consumed completely (as indicated
by TLC). The mixture was then diluted with water (15 mL) and ex-
tracted with EtOAc (2 × 30 mL). The organic layers were then com-
bined and washed with brine (10 mL), dried over Na2SO4 and concen-
trated in vacuo. In most cases, the crude residue containing product
11 was further dried under high vacuum for at least 20 min and then
immediately taken to the next step without any column purification.
To check the authenticity of the products, in select cases (11l, 11p and
11q) the sulfides were purified using flash column chromatography
(0.5% EtOAc in hexanes).
5-exo-dig
S
S
S
N
N
N
hydroamination
11
H
R
HO
R
R
H2O
H2O
S
S
S
N
N
OH
N
14
15
H
R
R
R
Scheme 4 Plausible mechanism for the base-mediated synthesis of 14
from 11
6-Chloro-2-((3-phenylprop-2-ynyl)thio)-1H-indole (11l)
Yield: 57 mg (0.19 mmol, 75%); reddish solid; mp 97–99 °C.
IR (neat): 3395, 3078, 2922, 1361, 1220, 1064, 818, 759, 691 cm–1
1H NMR (300 MHz, CDCl3):  = 8.37 (br s, 1 H, NH), 7.54–7.51 (d, J =
8.5 Hz, 1 H, Ar), 7.41–7.31 (m, 6 H, Ar), 7.15–7.11 (m, 1 H, Ar), 6.81–
6.80 (s, 1 H, Ar), 3.78 (s, 2 H, CH2).
13C NMR (75 MHz, CDCl3):  = 137.6, 131.7, 129.0, 128.6, 128.5, 128.3,
126.9, 122.6, 121.5, 121.1, 110.7, 110.3, 85.6, 84.7, 26.4.
HRMS (ESI): m/z [M + H]+ calcd for C17H12ClNS: 298.0379; found:
298.0453.
We have recently reported the cytotoxic activity of
compounds based on the [1,3]thiazino[3,2-a]indol-4-one 5
ring system against breast cancer cell lines.10 In light of
those results, the synthesized compounds 14a–p were
screened for cytotoxic activity; however, no appreciable ac-
tivity was detected for these compounds. The IC50 values
were >350 M (see the Supporting Information for more
details).
.
In conclusion, we have developed a mild, efficient and
versatile synthesis of thiazolo[3,2-a]indoles 14 via KOH-
mediated hydroamination of alkynes. The use of stronger
base appears to allow for a broader scope of substrates than
that previously reported, enabling the installation of a wide
variety of substitutions (H/alkyl/aryl) feasible on the thi-
azoloindole ring system. Furthermore, a one-pot synthesis
of 14 and analogues is also possible from indoline-2-thi-
ones 6, without the isolation of intermediate 11, at the
slight expense of loss in yields. The one-pot strategy is par-
ticularly amenable for the synthesis of 14 in the case of
propargyl halides substituted with electron-withdrawing
groups. In all, these findings underscore a milder method in
which the scope and synthetic utility of thermally labile 2-
(prop-2-ynylthio)-1H-indoles 11 can be exploited in the
construction of potentially bioactive indole-annulated scaf-
folds.
5-Fluoro-2-((3-phenylprop-2-ynyl)thio)-1H-indole (11p)
Yield: 50 mg (0.18 mmol, 71%); off-white solid; mp 82–88 °C.
IR (neat): 3422, 3136, 2922, 1146, 858, 794, 756 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.40 (br s, 1 H, NH), 7.40–7.22 (m, 7 H,
Ar), 7.10–6.99 (m, 1 H, Ar), 6.81 (s, 1 H, Ar), 3.80 (s, 2 H, CH2).
13C NMR (75 MHz, CDCl3):  = 158.0 (1JC–F = 235.3 Hz), 133.9, 131.7,
129.3, 128.7, 128.6, 128.5 (3JC–F = 9.3 Hz), 122.7, 111.7, 111.5 (3JC–F
=
10.5 Hz), 110.1 (4JC–F = 4.6 Hz), 105.3 (2JC–F = 23.3 Hz), 85.7, 84.7, 25.4.
HRMS (ESI): m/z [M + H]+ calcd for C17H12FNS: 282.0674; found:
282.0747.
2-((3-(4-Methoxyphenyl)prop-2-ynyl)thio)-5-methyl-1H-indole
(11q)
Yield: 50 mg (0.17 mmol, 68%); green oil.
IR (neat): 3116, 3080, 2964, 2837, 1622, 1585, 1118, 810 cm–1
1H NMR (300 MHz, DMSO-d6):  = 11.34 (s, 1 H, NH), 7.27–7.21 (m, 4
H, Ar), 6.94–6.86 (m, 3 H, Ar), 6.57 (s, 1 H, Ar), 3.98 (s, 2 H, CH2), 3.74
(s, 3 H, OCH3), 2.34 (s, 3 H, CH3).
.
Melting points were determined in open capillary tubes on a Electro-
thermal Mel-Temp automated melting point apparatus and are uncor-
rected. Reactions were monitored using TLC on 0.2 mm silica gel F254
plates. The chemical structures of final products were determined
from their NMR spectra (1H and 13C NMR) using a Bruker Fourier 300
13C NMR (75 MHz, DMSO-d6):  = 159.7, 136.3, 133.3, 128.6, 128.2,
127.7, 124.0, 119.7, 114.7, 111.1, 107.5, 84.9, 83.8, 55.7, 25.1, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H17NOS: 308.1031; found:
308.1110.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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S. Short et al.
Paper
Synthesis
Thiazolo[3,2-a]indoles 14; General Procedure
3,9-Dimethylthiazolo[3,2-a]indole (14e)
Yield: 62 mg (0.31 mmol, 90%); off-white solid; mp 81–84 °C.
IR (neat): 3092, 2906, 1550, 1458, 1226, 726 cm–1
1H NMR (300 MHz, CDCl3):  = 7.84 (d, J = 8.2 Hz, 1 H, Ar), 7.63 (d, J =
8.0 Hz, 1 H, Ar), 7.28 (dd, J = 7.4, 7.5 Hz, 1 H, Ar), 7.17 (dd, J = 7.7, 7.6
Hz, 1 H, Ar), 6.13 (s, 1 H, Ar), 2.73 (s, 3 H, CH3), 2.42 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 135.7, 132.6, 131.6, 130.1, 120.4, 118.7,
117.6, 110.8, 102.9, 99.4, 15.1, 9.4.
HRMS (ESI): m/z [M + H]+ calcd for C12H11NS: 202.0612; found:
The crude sulfide 11 (0.34 mmol) was mixed with KOH (0.51 mmol)
in DMSO (2 mL) in a screw-capped 20 mL vial covered with tin foil.
The reaction mixture was stirred at 60 °C until 11 was completely
consumed (as indicated by TLC). The mixture was then diluted with
water (10 mL) and extracted with EtOAc (2 × 15 mL). The organic lay-
ers were then combined and washed with brine (5 mL), dried over
Na2SO4 and concentrated in vacuo. The residue obtained was purified
using flash column chromatography (0.5% EtOAc in hexanes) to pro-
duce 14a–q.
.
202.0697.
3-Methylthiazolo[3,2-a]indole (14a)
Yield: 54 mg (0.29 mmol, 85%); light blue solid; mp 90–91 °C.
3-Ethyl-9-methylthiazolo[3,2-a]indole (14f)
IR (neat): 3094, 2920, 1459, 1434, 808, 716 cm–1
.
Yield: 59 mg (0.27 mmol, 80%); off-white solid; mp 66–73 °C.
IR (neat): 3114, 3043, 2973, 1452, 817, 726 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.89 (d, J = 8.2 Hz, 1 H, Ar), 7.69 (d, J =
8.0 Hz, 1 H, Ar), 7.30–7.25 (m, 1 H, Ar), 7.20–7.15 (m, 1 H, Ar), 6.58 (s,
1 H, Ar), 6.17 (s, 1 H, Ar), 2.76 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 138.9, 133.2, 131.4, 130.3, 121.0, 119.7,
118.9, 110.9, 103.7, 91.1, 15.1.
1H NMR (300 MHz, CDCl3):  = 7.78 (d, J = 8.3 Hz, 1 H, Ar), 7.61 (d, J =
8.0 Hz, 1 H, Ar), 7.29–7.22 (m, 1 H, Ar), 7.18–7.13 (m, 1 H, Ar), 6.13 (s,
1 H, Ar), 3.12 (q, J = 7.3 Hz, 2 H, CH2), 2.41 (s, 3 H, CH3), 1.48 (t, J = 7.3
Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 137.8, 135.9, 132.7, 129.8, 120.3, 118.7,
HRMS (ESI): m/z [M + H]+ calcd for C11H9NS: 188.0456; found:
117.5, 111.2, 101.5, 99.3, 22.3, 11.6, 9.3.
188.0532.
HRMS (ESI): m/z [M + H]+ calcd for C13H13NS: 216.0769; found:
3-Ethylthiazolo[3,2-a]indole (14b)
216.0833.
Yield: 53 mg (0.26 mmol, 78%); purple liquid.
9-Methyl-3-propylthiazolo[3,2-a]indole (14g)
IR (neat): 3119, 3047, 2972, 1500, 1455, 823, 737 cm–1
.
Yield: 67 mg (0.29 mmol, 86%); black solid; mp 60–67 °C.
1H NMR (300 MHz, CDCl3):  = 7.83 (d, J = 8.3 Hz, 1 H, Ar), 7.66 (d, J =
8.0 Hz, 1 H, Ar), 7.28–7.22 (m, 1 H, Ar), 7.18–7.12 (m, 1 H, Ar), 6.56 (s,
1 H, Ar), 6.18 (s, 1 H, Ar), 3.16 (q, J = 7.3 Hz, 2 H, CH2), 1.49 (t, J = 7.3
Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 139.0, 137.6, 133.3, 130.1, 120.9, 119.7,
118.9, 111.3, 102.2, 91.1, 22.3, 11.6.
IR (neat): 3127, 2960, 1553, 1451, 1224, 760 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.75 (d, J = 8.3 Hz, 1 H, Ar), 7.62 (d, J =
7.9 Hz, 1 H, Ar), 7.27 (dd, J = 6.9, 7.5 Hz, 1 H, Ar), 7.17 (dd, J = 7.3, 7.8
Hz, 1 H, Ar), 6.13 (s, 1 H, Ar), 3.04 (t, J = 7.5 Hz, 2 H, CH2), 2.41 (s, 3 H,
CH3), 1.97–1.85 (m, 2 H, CH2), 1.16 (t, J = 7.4 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 136.1, 136.0, 132.8, 129.8, 120.4, 118.7,
HRMS (ESI): m/z [M + H]+ calcd for C12H11NS: 202.0612; found:
117.6, 111.2, 102.2, 99.3, 30.8, 20.4, 13.9, 9.4.
202.0694.
HRMS (ESI): m/z [M + H]+ calcd for C14H15NS: 230.0925; found:
3-Propylthiazolo[3,2-a]indole (14c)
230.1003.
Yield: 60 mg (0.28 mmol, 81%); bluish-green oil.
3-Benzyl-9-methylthiazolo[3,2-a]indole (14h)
IR (neat): 3113, 3049, 2961, 1499, 834, 750, 725 cm–1
.
Yield: 75 mg (0.27 mmol, 80%); yellow solid; mp 67–79 °C.
1H NMR (300 MHz, CDCl3):  = 7.79 (d, J = 8.2 Hz, 1 H, Ar), 7.66 (d, J =
8.2 Hz, 1 H, Ar), 7.28–7.24 (m, 1 H, Ar), 7.21–7.15 (m, 1 H, Ar), 6.56 (s,
1 H, Ar), 6.17 (s, 1 H, Ar), 3.08 (t, J = 7.6 Hz, 2 H, CH2), 1.98–1.86 (m, 2
H, CH2), 1.16 (t, J = 7.3 Hz, 3 H, CH3).
IR (neat): 3096, 3029, 2914, 1449, 1222, 723 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.69 (d, J = 8.3 Hz, 1 H, Ar), 7.61 (d, J =
8.0 Hz, 1 H, Ar), 7.39–7.33 (m, 5 H, Ar), 7.25–7.22 (m, 1 H, Ar), 7.12–
7.07 (m, 1 H, Ar), 5.91 (s, 1 H, Ar), 4.42 (s, 2 H, CH2), 2.42 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 139.0, 135.9, 133.3, 130.0, 120.9, 119.7,
13C NMR (75 MHz, CDCl3):  = 136.1, 135.9, 135.0, 132.7, 129.8, 128.9,
128.9, 127.2, 120.4, 118.8, 117.5, 111.3, 105.1, 99.6, 35.1, 9.3.
118.9, 111.3, 102.9, 91.1, 30.8, 20.4, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C13H13NS: 216.0769; found:
HRMS (ESI): m/z [M + H]+ calcd for C18H15NS: 278.0925; found:
216.0844.
278.0993.
3-Benzylthiazolo[3,2-a]indole (14d)
Yield: 76 mg (0.29 mmol, 85%); off-white solid; mp 111–113 °C.
6-Chloro-3-methylthiazolo[3,2-a]indole (14i)
IR (neat): 3119, 3097, 2921, 1591, 1492, 725, 703 cm–1
.
Yield: 56 mg (0.25 mmol, 75%); green solid; mp 113–116 °C.
IR (neat): 3101, 2918, 1502, 1446, 1211, 800, 707 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.81–7.73 (m, 2 H, Ar), 7.48–7.38 (m, 5
H, Ar), 7.33–7.28 (m, 1 H, Ar), 7.19–7.14 (m, 1 H, Ar), 6.66 (s, 1 H, Ar),
5.94 (s, 1 H, Ar), 4.45 (s, 2 H, CH2).
1H NMR (300 MHz, CDCl3):  = 7.81 (s, 1 H, Ar), 7.54 (d, J = 8.5 Hz, 1 H,
Ar), 7.21 (d, J = 8.5 Hz, 1 H, Ar), 6.51 (s, 1 H, Ar), 6.17 (s, 1 H, Ar), 2.69
(s, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 139.1, 136.0, 135.0, 133.3, 130.1, 129.0,
13C NMR (75 MHz, CDCl3):  = 139.5, 131.5, 131.0, 130.1, 124.6, 121.6,
120.3, 110.9, 104.5, 91.2, 14.9.
127.4, 121.1, 119.8, 119.1, 111.5, 105.9, 91.4, 35.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H13NS: 264.0769; found:
264.0845.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C11H8ClNS: 222.0066; found:
222.0143.
1H NMR (300 MHz, CDCl3):  = 7.69 (dd, J = 9.0, 4.6 Hz, 1 H, Ar), 7.29
(dd, J = 9.6, 2.3 Hz, 1 H, Ar), 6.89 (dt, J = 9.1, 2.5 Hz, 1 H, Ar), 6.51 (s, 1
H, Ar), 6.16 (s, 1 H, Ar), 3.11–3.04 (q, J = 7.3 Hz, 2 H, CH2), 1.49–1.45 (t,
J = 7.4 Hz, 3 H, CH3).
6-Chloro-3-ethylthiazolo[3,2-a]indole (14j)
13C NMR (75 MHz, CDCl3):  = 158.4 (1JC–F = 236.2 Hz), 140.8, 137.5,
133.7 (3JC–F = 10.5 Hz), 126.8, 111.9 (3JC–F = 10.1 Hz), 107.0 (2JC–F = 26.3
Hz), 104.3 (2JC–F = 23.8 Hz), 102.3, 91.1 (4JC–F = 4.4 Hz), 22.2, 11.4.
HRMS (ESI): m/z [M + H]+ calcd for C12H10FNS: 220.0518; found:
220.0596.
Yield: 52 mg (0.22 mmol, 65%); bluish-green solid; mp 73–81 °C.
IR (neat): 3116, 2915, 1593, 1498, 1455, 929, 795 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.79 (s, 1 H, Ar), 7.54 (d, J = 8.5 Hz, 1 H,
Ar), 7.20 (d, J = 8.6 Hz, 1 H, Ar), 6.52 (s, 1 H, Ar), 6.20 (s, 1 H, Ar), 3.11
(q, J = 7.3 Hz, 2 H, CH2), 1.49 (t, J = 7.3 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 139.7, 137.2, 131.6, 129.9, 124.6, 121.5,
120.3, 111.3, 102.9, 91.2, 22.2, 11.4.
HRMS (ESI): m/z [M + H]+ calcd for C12H10ClNS: 236.0222; found:
236.0299.
7-Fluoro-3-propylthiazolo[3,2-a]indole (14o)
Yield: 72 mg (0.31 mmol, 91%); off-white solid; mp 70–74 °C.
IR (neat): 3117, 2961, 2929, 1617, 1456, 1165, 855, 703 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.67 (dd, J = 9.0, 4.4 Hz, 1 H, Ar), 7.30–
7.26 (m, 1 H, Ar), 6.92–6.85 (dt, J = 9.0, 2.4 Hz, 1 H, Ar), 6.51 (s, 1 H,
Ar), 6.18 (s, 1 H, Ar), 3.02 (t, J = 7.4 Hz, 2 H, CH2), 1.96–1.83 (m, 2 H,
CH2), 1.18–1.14 (t, J = 7.3 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 158.4 (1JC–F = 236.3 Hz), 140.8, 135.8,
133.7 (3JC–F = 10.6 Hz), 126.7, 111.8 (3JC–F = 9.9 Hz), 107.0 (2JC–F = 26.3
Hz), 104.3 (2JC–F = 23.7 Hz), 103.0, 91.1 (4JC–F = 4.5 Hz), 30.6, 20.3, 13.8.
6-Chloro-3-propylthiazolo[3,2-a]indole (14k)
Yield: 53 mg (0.21 mmol, 62%); bluish-green solid; mp 80–81 °C.
IR (neat): 3115, 2963, 1597, 1548, 1455, 803, 708 cm–1
1H NMR (300 MHz, CDCl3):  = 7.75 (s, 1 H, Ar), 7.54 (d, J = 8.5 Hz, 1 H,
Ar), 7.20 (d, J = 8.6 Hz, 1 H, Ar), 6.52 (s, 1 H, Ar), 6.19 (s, 1 H, Ar), 3.02
(t, J = 7.5 Hz, 2 H, CH2), 1.94–1.87 (m, 2 H, CH2), 1.17 (t, J = 7.3 Hz, 3 H,
CH3).
.
HRMS (ESI): m/z [M + H]+ calcd for C13H12FNS: 234.0674; found:
234.0750.
13C NMR (75 MHz, CDCl3):  = 139.6, 135.5, 131.6, 129.9, 124.6, 121.5,
120.3, 111.3, 103.6, 91.2, 30.6, 20.2, 13.8.
HRMS (ESI): m/z [M + H]+ calcd for C13H12ClNS: 250.0379; found:
250.0455.
3-Benzyl-7-fluorothiazolo[3,2-a]indole (14p)
Yield: 81 mg (0.29 mmol, 85%); yellow solid; mp 139–142 °C.
IR (neat): 3124, 3029, 1591, 1434, 1164, 849, 699 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.61 (dd, J = 9.0, 4.4 Hz, 1 H, Ar), 7.42–
7.25 (m, 6 H, Ar), 6.81 (dt, J = 9.1, 2.5 Hz, 1 H, Ar), 6.54 (s, 1 H, Ar), 5.96
(s, 1 H, Ar), 4.41 (s, 2 H, CH2).
3-Benzyl-6-chlorothiazolo[3,2-a]indole (14l)
Yield: 69 mg (0.23 mmol, 68%); yellow solid; mp 140–151 °C.
IR (neat): 3142, 2922, 1596, 1454, 943, 840, 827 cm–1
1H NMR (300 MHz, CDCl3):  = 7.73 (s, 1 H, Ar), 7.54 (d, J = 8.6 Hz, 1 H,
Ar), 7.44–7.28 (m, 5 H, Ar), 7.20–7.17 (d, J = 8.6 Hz, 1 H, Ar), 6.55 (s, 1
H, Ar), 5.91 (s, 1 H, Ar), 4.38 (s, 2 H, CH2).
13C NMR (75 MHz, CDCl3):  = 139.7, 135.5, 134.8, 131.5, 129.9, 129.0,
129.0, 127.5, 124.7, 121.7, 120.3, 111.5, 106.5, 91.4, 35.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H12ClNS: 298.0379; found:
.
13C NMR (75 MHz, CDCl3):  = 158.4 (1JC–F = 236.7 Hz), 140.8, 135.7,
134.7, 133.7 (3JC–F = 10.5 Hz), 129.0, 128.9, 127.4, 126.7, 112.0 (3JC–F
=
9.9 Hz), 107.2 (2JC–F = 26.3 Hz), 106.0, 104.3 (2JC–F = 23.6 Hz), 91.4
(4JC–F = 4.5 Hz), 35.0.
HRMS (ESI): m/z [M + H]+ calcd for C17H12FNS: 282.0674; found:
282.0752.
298.0427.
3-(4-Methoxybenzyl)-7-methylthiazolo[3,2-a]indole (14q)
Yield: 87 mg (0.29 mmol, 87%); pale green oil.
IR (neat): 3080, 3066, 2918, 2837, 1585, 1242, 1100, 807 cm–1
1H NMR (300 MHz, CDCl3):  = 7.61 (d, J = 8.5 Hz, 1 H, Ar), 7.42 (s, 1 H,
Ar), 7.25 (m, 2 H, Ar), 6.92–6.90 (m, 3 H, Ar), 6.48 (s, 1 H, Ar), 5.87 (s, 1
H, Ar), 4.36 (s, 2 H, CH2), 3.83 (s, 3 H, OCH3), 2.47 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 158.7, 139.0, 135.3, 133.5, 130.3, 130.0,
128.4, 127.9, 120.5, 119.3, 114.3, 111.1, 105.1, 90.8, 55.3, 34.3, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C19H17NOS: 308.1031; found:
308.1116.
7-Fluoro-3-methylthiazolo[3,2-a]indole (14m)
.
Yield: 56 mg (0.27 mmol, 80%); yellow-white solid; mp 102–106 °C.
IR (neat): 3137, 2958, 2921, 1593, 1456, 1162, 852, 789, 699 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.71 (dd, J = 9.0, 8.9 Hz, 1 H, Ar), 7.29
(dd, J = 9.8, 2.5 Hz, 1 H, Ar), 6.90 (dt, J = 9.1, 2.5 Hz, 1 H, Ar), 6.51 (s, 1
H, Ar), 6.16 (s, 1 H, Ar), 2.68 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 158.5 (1JC–F = 236.0 Hz), 140.7, 133.6
(3JC–F = 10.5 Hz), 131.3, 127.0, 111.5 (3JC–F = 10.1 Hz), 107.0 (2JC–F = 26.4
Hz), 104.3 (2JC–F = 23.8 Hz), 103.8, 91.1 (4JC–F = 4.4 Hz), 14.9.
HRMS (ESI): m/z [M + H]+ calcd for C11H8FNS: 206.0361; found:
206.0439.
One-Pot Synthesis of Thiazolo[3,2-a]indoles 14a, 14b, 14i, 14r and
14s; General Procedure
The appropriate indoline-2-thione 6 (0.18 mmol) was mixed with the
propargyl halide (0.48 mmol) and KOH (0.51 mmol) in DMSO (2 mL)
in a screw-capped 20 mL vial covered with tin foil. The reaction mix-
ture was stirred at room temperature until the thione was consumed
completely (as indicated by TLC), to form intermediate sulfide 11. The
reaction temperature was then increased to 60 °C and the mixture
was allowed to stir until the intermediate compound transformed to a
new product (as evidenced by TLC). The mixture was then diluted
3-Ethyl-7-fluorothiazolo[3,2-a]indole (14n)
Yield: 56 mg (0.25 mmol, 75%); purple solid; mp 90–96 °C.
IR (neat): 3126, 2967, 1617, 1455, 1164, 842, 773, 698 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

H
S. Short et al.
Paper
Synthesis
with water (10 mL) and extracted with EtOAc (2 × 15 mL). The organic
layers were then combined and washed with brine (5 mL), dried over
Na2SO4 and concentrated in vacuo. The residue obtained was purified
using flash column chromatography (0.5% EtOAc in hexanes) to pro-
duce 14a, 14b, 14i, 14r and 14s.
References
(1) For recent reviews, see: (a) Brahmachari, G. Asian J. Org. Chem.
2018, 7, 1982. (b) Passador, K.; Thorimbert, S.; Botuha, C. Syn-
thesis 2019, 51, 384. (c) Nemoto, T.; Harada, S.; Nakajima, M.
Asian J. Org. Chem. 2018, 7, 1730.
(2) Ciulla, M. G.; Zimmermann, S.; Kumar, K. Org. Biomol. Chem.
2019, 17, 413.
7-Methyl-3-(4-nitrobenzyl)thiazolo[3,2-a]indole (14r)
Yield: 32 mg (0.10 mmol, 56%); brown solid; mp 138–139 °C.
(3) Staab, A.; Loeffler, J.; Said, H. M.; Diehlmann, D.; Katzer, A.;
Beyer, M.; Fleischer, M.; Schwab, F.; Baier, K.; Einsele, H.;
Flentje, M.; Vordermark, D. BMC Cancer 2007, 7, 213.
(4) Ji, Q.; Gao, J.; Wang, J.; Yang, C.; Hui, X.; Yan, X.; Wu, X.; Xie, Y.;
Wang, M. Bioorg. Med. Chem. Lett. 2005, 15, 2891.
(5) Kuehm-Caubère, C.; Caubère, P.; Jamart-Grégoire, B.; Pfeiffer,
B.; Guardiola-Lemaître, B.; Manechez, D.; Renard, P. Eur. J. Med.
Chem. 1999, 34, 51.
(6) (a) Takada, S.; Makisumi, Y. Chem. Pharm. Bull. 1984, 32, 872.
(b) Takada, S.; Ishizuka, N.; Sasatani, T.; Makisumi, Y.; Jyoyama,
H.; Hatakeyama, H.; Asanuma, F.; Hirose, K. Chem. Pharm. Bull.
1984, 32, 877.
IR (neat): 3088, 2945, 2918, 1622, 1593, 1568, 1336, 1205, 1100, 834
cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 8.22 (d, J = 7.1 Hz, 2 H, Ar), 7.61 (d,
J = 8.3 Hz, 2 H, Ar), 7.55 (d, J = 8.3 Hz, 1 H, Ar), 7.34 (s, 1 H, Ar), 6.81 (d,
J = 8.4 Hz, 1 H, Ar), 6.55 (s, 1 H, Ar), 6.51 (s, 1 H, Ar), 4.68 (s, 2 H, CH2),
2.35 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6):  = 147.0, 145.5, 138.9, 133.3, 133.3,
130.3, 128.1, 124.3, 120.8, 119.4, 111.7, 107.5, 91.4, 33.7, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C18H14N2O2S: 323.0776; found:
323.0862.
(7) (a) Jin, Z. Nat. Prod. Rep. 2003, 20, 584. (b) Lewis, J. R. Nat. Prod.
Rep. 1999, 16, 389.
Methyl 3-(4-Nitrobenzyl)thiazolo[3,2-a]indole-6-carboxylate
(14s)
(8) Pedras, M. S.; Abdoli, A. RSC Adv. 2017, 7, 23633.
(9) Gaster, L. M.; Wyman, P. A. US Patent 5852014, 1998.
(10) Rhodes, S.; Short, S.; Sharma, S.; Kaur, R.; Jha, M. Org. Biomol.
Chem. 2019, 17, 3914.
(11) Balasubramanian, K. K.; Nagarajan, R. Synthesis 1976, 189.
(12) Heravi, M. M.; Keivanloo, A.; Rahimizadeh, M.; Bakavoli, M.;
Ghassemzadeh, M. Tetrahedron Lett. 2004, 45, 5747.
(13) Xiao, D.; Han, L.; Sun, Q.; Chen, Q.; Gong, N.; Lv, Y.; Suzenet, F.;
Guillaumet, G.; Cheng, T.; Li, R. RSC Adv. 2012, 2, 5054.
(14) Omar, M. A.; Frey, W.; Conrad, J.; Beifuss, U. J. Org. Chem. 2014,
79, 10367.
Yield: 31 mg (0.08 mmol, 48%); yellow solid; mp 142–143 °C.
IR (neat): 3255, 3089, 2998, 2930, 2880, 1692, 1626, 1590, 1569,
1414, 1275, 1118, 833, 753 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.37 (s, 1 H, Ar), 8.26 (d, J = 8.2 Hz, 2 H,
Ar), 7.89 (d, J = 8.4 Hz, 1 H, Ar), 7.63 (d, J = 8.4 Hz, 1 H, Ar), 7.56 (d, J =
8.2 Hz, 2 H, Ar), 6.65 (s, 1 H, Ar), 6.11 (s, 1 H, Ar), 4.61 (s, 2 H, CH2),
3.93 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3):  = 167.9, 147.4, 143.0, 142.7, 136.5, 133.4,
129.9, 129.0, 124.3, 122.3, 120.5, 119.1, 113.4, 107.7, 92.5, 52.0, 34.8.
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HRMS (ESI): m/z [M + H]+ calcd for C19H14N2O4S: 367.0674; found:
367.0752.
Funding Information
The authors gratefully acknowledge the financial support provided by
the Natural Sciences and Engineering Research Council of Canada
(NSERC), Nipissing University, the Canada Foundation for Innovation
(CFI) and the Northern Ontario Heritage Fund Corporation (NOHFC)
to conduct this research.()
(20) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Chem.
Rev. 2015, 115, 2596.
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52, 684. (c) Jha, M.; Enaohwo, O.; Marcellus, A. Tetrahedron Lett.
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Acknowledgment
Mass spectrometry was performed with the help of Ms Ashley Mar-
cellus.
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2015, 80, 5272.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690680.
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H