Automated multistep continuous flow synthesis of 2-(1H-indol-3-yl)thiazole derivatives

Article abstract of DOI:10.1055/s-0031-1290953

The multistep continuous flow assembly of 2-(1H-indol-3-yl)thiazoles using a Syrris AFRICA synthesis station is reported. Sequential Hantzsch thiazole synthesis, deketalization, and Fischer indole synthesis provides rapid and efficient access to highly functionalized, pharmacologically significant 2-(1H-indol-3-yl)thiazoles. These complex drug-like small molecules are generated in reaction times of less than 15 minutes and in high yields (38-82% over three chemical steps without isolation of intermediates). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290953

SPECIAL TOPIC
▌2537
sApeuciatlotompicated Multistep Continuous Flow Synthesis of 2-(1H-Indol-3-yl)thiazole
Derivatives
Nicholas Pagano,a Marintha L. Heil,b Nicholas D. P. Cosford*a
a
Apoptosis and Cell Death Research Program & Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute,
10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA
b
Southern Research Institute, Drug Development Division, 431 Aviation Way, Frederick, MD 21701, USA
Fax +1(858)7955221; E-mail: ncosford@sanfordburnham.org
Received: 01.03.2012; Accepted: 15.03.2012
R1
Abstract: The multistep continuous flow assembly of 2-(1H-indol-
3-yl)thiazoles using a Syrris AFRICA® synthesis station is reported.
N
Sequential Hantzsch thiazole synthesis, deketalization, and Fischer
indole synthesis provides rapid and efficient access to highly func-
tionalized, pharmacologically significant 2-(1H-indol-3-yl)thia-
zoles. These complex drug-like small molecules are generated in
reaction times of less than 15 minutes and in high yields (38–82%
over three chemical steps without isolation of intermediates).
S
R2
O
S
R1
S
A
O
O
N
N
R3
1
NH2
2
3
Key words: heterocycles, indoles, condensation, tandem reactions,
microreactor, microfluidic synthesis
N
O
S
Me
O
NH2
N
N
S
O
O
N
R
The interaction of small molecule compounds with specif-
ic human proteins, such as enzymes, receptors, or ion
channels, is one of the fundamental principles upon which
the discovery of new medicines is based. Advantages of
low molecular weight drugs include the potential for oral
bioavailability, efficient tissue (e.g., brain) penetration
and low cost of manufacture, among others. The vast ma-
jority of low molecular weight drugs are heterocyclic
compounds, often comprising several connected hetero-
cyclic rings. This is not surprising considering the propen-
sity of heteroatoms within drug scaffolds to form
reversible interactions (electrostatic, H-bonds etc.) within
the active sites of proteins, thereby exerting a modulatory
effect. High-throughput screening is one of the most com-
mon and effective methods to identify small molecule
compounds with activity against the target protein of in-
terest. Invariably, however, the initial hit structure identi-
fied in a screening campaign exhibits relatively low
potency and selectivity for the target protein, in addition
to sub-optimal physicochemical (drug-like) properties.
Therefore, the development of new synthetic chemistry
methods for the rapid and efficient generation of ana-
logues for in vitro testing is critical for the hit-to-lead op-
timization of screening hits.1–8 Accordingly, we have
established a research program focused on developing au-
tomated flow chemistry methods to rapidly access com-
plex, drug-like compounds from readily available
precursors. More specifically, we are developing highly
efficient flow chemistry methods that combine multiple
chemical transformations into single, continuous processes.
B
H2N
N
O
camalexin
N
N
O
Me
H
BE 10988
O
Tadalafil
Scheme 1 (a) Indolylthiazoles 1 from intermediate β-ketothiazoles 2
and prepared thioamide 3. (b) Marketed indole Tadalafil and biologi-
cally active natural products camalexin and BE 10988.
Advantages of this technology include optimal heat trans-
fer, enhanced reagent mixing, precise reaction times,
small reaction volumes, and the ability to conduct multi-
step reactions in a single, unbroken microreactor se-
quence.9 Thus, flow processes are safe, environmentally
friendly, and cost effective on a manufacturing scale. To
demonstrate the utility of flow synthesis, we have previ-
ously reported the continuous flow preparation of bis-sub-
stituted 1,2,4-oxadiazoles,5 functionalized imidazo[1,2-a]
heterocycles,6 pyrrole-3-carboxylic acid derivatives,7 and
5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-ones.8 We
now report a methodology for consecutive heterocycle
formation reactions to access 2-(1H-indol-3-yl)thiazoles
(indolylthiazoles, 1), which are privileged scaffolds with
demonstrated biological activity, using an uninterrupted
continuous flow microreactor sequence. In this unique
continuous process, sequential thiazole formation, deke-
talization, and Fischer indole synthesis provides rapid and
efficient access to novel indolylthiazole derivatives 1.
These structures, which are generated from β-ketothia-
zoles 2 and prepared thioamide 3 (Scheme 1), are formed
cleanly and without isolation of intermediates.
SYNTHESIS 2012, 44, 2537–2546
Advanced online publication: 25.05.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290953; Art ID: SS-2012-C0222-ST
© Georg Thieme Verlag Stuttgart · New York

2538
N. Pagano et al.
SPECIAL TOPIC
S
32.5 µL/min
32.5 µL/min
O
O
NH2
250 µL
3, 0.75 M DMF
O
S
R1
N
O
2 (49–91%)a
Br
150 °C
R1
3.75 min
5, 0.75 M DMF
R1
N
R2
1000 µL
H
O
S
N
N
H
200 °C
10 min
O
O
32.5 µL/min
4 (39–46%)a
+
R2
6, 0.9 M DMF
H
H2N
NH2
7, 0.9 M DMF
Scheme 2 Microfluidic synthesis of 5-(thiazol-2-yl)-3,4-dihydropyrimidin-2(1H)-ones 4. Yields for one-chip reactions determined using 5 min
retention times and 1 equiv of water. a Refer to ref.8 for complete details of this study.
Indoles constitute a ubiquitous structural motif present in in high yield (39–46%) over three chemical steps. This au-
a broad range of biologically active small molecules and tomated process comprised Hantzsch thiazole synthesis of
natural products. These heterocycles are present in inves- thioamide 3 with α-bromoketones 5 liberating molar
tigational and approved drugs such as Tadalafil, an inhib- equivalents of HBr and water, triggering removal of the
itor of phosphodiesterase 5 (PDE5) (Scheme 1).10 1,3-dioxane protecting group to generate intermediate β-
Tadalafil is currently indicated for the treatment of both ketothiazoles 2. The released acid was then further uti-
erectile dysfunction (Cialis®) and pulmonary arterial hy- lized to catalyze the subsequent Biginelli multicomponent
pertension (Adcirca®). Indolylthiazole derivatives also reaction with aldehydes 6 and urea 7. Knowing that the
constitute a large family of medicinally significant com- Fischer indole synthesis is also promoted by acid, we hy-
pounds displaying a wide range of pharmacological prop- pothesized that replacement of the aldehyde and urea
erties. For example, the camalexin class of natural components with hydrazines would provide a viable route
products has received much attention in recent years be- to the 2-(1H-indol-3-yl)thiazole core (1).
cause of its antifungal and antiviral activity (Scheme 1).11
In addition, closely related thiazolyl indolequinones, such
as the natural product BE 10988, have been identified as
At the outset of our experiments, we prepared the ketal-
protected thioamide 3 (Scheme 3) from commercially
available acetoacetamide 8 in two steps. First, ketone 8
was heated at reflux in the presence of neopentyl glycol
potent topoisomerase II inhibitors and have been shown to
possess promising anticancer activity (Scheme 1).12 Due
and chlorotrimethylsilane in anhydrous dichloromethane
to this broad spectrum of therapeutic areas, methods for
the high-throughput synthesis of connected heterocyclic
derivatives, such as the indolylthiazoles, are of significant
interest.
to furnish known ketal-protected amide 9 in excellent
yield (89%).15 Compound 9 was then carefully treated
with just over one-half equivalent of Lawesson’s reagent
at 0 °C in anhydrous tetrahydrofuran (THF) to generate
Although continuous flow methods for the synthesis of protected thioamide 3 in 43% yield. In our hands, the nec-
simple indoles have been reported separately by Watts13 essary ketone required a protecting group for acceptable
and Seeberger,14 the inspiration for our multistep flow thioamide production. This reaction process is amenable
assembly of indolylthiazoles 1 stems from our recently to scale-up procedures, with crystalline 3 easily isolated
reported synthesis of 5-(thiazol-2-yl)-3,4-dihydropyrimi- by precipitation from toluene. Furthermore, this key
din-2(1H)-ones 4 (Scheme 2).8 In this method, intermedi- building block can be stored at room temperature without
ate β-ketothiazoles 2 from ketal-protected thioamide 3 significant decomposition and is stable in the N,N-dimeth-
provided access to a novel class of connected heterocycles
Lawesson's
reagent
O
O
S
O
OH OH
O
O
O
O
NH2
NH2
NH2
THF, 2 h
(43%)
TMSCl, CH2Cl2
reflux, 2 d
(89%)
8
9
3
Scheme 3 Synthesis of thioamide 3
Synthesis 2012, 44, 2537–2546
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Flow Synthesis of 2-(1H-Indol-3-yl)thiazoles
2539
ylformamide (DMF) solutions used for all the microfluid- (entries 2, 3 and 4), electron-withdrawing (entries 10 and
ic experiments described herein.
11), or halogen substitution (entries 7, 8 and 9) as well as
2-naphthyl (entry 6) and heteroaromatic (entry 12) were
found to be suitable for this process. Importantly, these
data largely represent the current supply of commercially
available α-bromoketones yielding complex drug-like
compounds for extensive biological evaluation and/or
continued chemistry.
With freshly prepared thioamide 3 in hand, we next fo-
cused our efforts on using this building block for the mi-
crofluidic synthesis of indolylthiazoles 1 (Scheme 4). For
this continuous multistep process, the setup was identical
to that shown in Scheme 2 except that aldehydes 6 and
urea 7 were exchanged for hydrazines 10. As with the
Biginelli process, we envisioned that the liberated HBr We next investigated the reaction scope with respect to
utilized to unmask the ketone intermediates could be har- hydrazines 10; the multistep continuous flow synthesis of
nessed to catalyze the subsequent Fischer indole synthe- indolylthiazoles 1m–v is presented in Table 2. For all en-
sis. Gratifyingly, we found that the two-chip flow tries, a DMF solution of 2-bromoacetophenone (5a) was
synthesis of indolylthiazoles 1 proceeded efficiently un- pumped into the first microreactor chip. The overall yields
der the conditions shown in Scheme 4. Initially, 0.50 M for the three-step, two-chip sequence were also high (38–
solutions of thioamide 3 and α-bromoketones 5 in DMF 82%) when using free-base hydrazines or arylhydrazine
were pumped (32.5 μL/min) into a 250 μL reactor heated hydrochlorides, again averaging at least 70% yield for
to 150 °C for 3.75 minutes.
each chemical transformation. Hydrazine substrates bear-
ing either electron-donating (entries 1 and 6), alkyl (en-
tries 7 and 8), or halogen substituents (entries 2, 3 and 4)
were found to be suitable for this process. Whereas ex-
tended aromatic systems such as 1-naphthyl (entry 9) pro-
ceeded in excellent yield, hydrazine substrates bearing
electron-withdrawing groups such as 4-cyano or 4-trifluo-
romethyl (not shown) failed to furnish sufficient quanti-
ties of the desired indolylthiazole product for isolation.
Not surprisingly, this reaction sequence also proved futile
with batch-mode standard heating using an oil bath and
longer reaction times. Importantly, nitrogen-substituted
hydrazines such as methyl and benzyl (entries 5 and 10)
are also viable using this process. Since free-base hydra-
zines are known to be unstable, freshly opened bottles
were used for these experiments. It should also be noted
that hydrazines 10b and 10c, which were used to generate
1m and 1n, respectively, were not soluble in neat DMF
and, therefore, stock solutions were prepared in 1:1 mix-
tures of DMF and ethylene glycol.
This reaction concentration was chosen as a compromise
between general solubility and optimal yield for the se-
quence. The generated ketothiazole intermediate 2 was
then introduced to a separate stream (32.5 μL/min) of hy-
drazine hydrochlorides 10 (0.50 M, DMF). The combined
flow (97.5 μL/min) was pumped into a 1000 μL reactor
heated to 200 °C. Overall, each continuous two-chip mi-
crofluidic sequence required less than one hour for com-
pletion from start to finish (injection, reaction, and 1000
μL collection).
The multistep continuous flow synthesis of indolylthia-
zoles 1a–l is presented in Table 1. For all entries, a DMF
solution of phenylhydrazine hydrochloride (10a) was
pumped into the second chip in order to study the reaction
scope with respect to α-bromoketones 5. The overall
yields for the three-step, two-chip sequence were high
(43–65%) when using aromatic α-bromoketones 5, aver-
aging at least 70% yield for each chemical transformation.
Acetophenone substrates bearing either electron-donating
S
32.5 µL/min
32.5 µL/min
O
O
NH2
250 µL
R1
3, 0.50 M DMF
(HBr)
O
N
O
S
R1
Br
2
150 °C
3.75 min
R1
5, 0.50 M DMF
N
1000 µL
S
R2
N
R3
R3
200 °C
10 min
1
N
32.5 µL/min
NH3
Cl
R2
10, 0.50 M, DMF
Scheme 4 Final microfluidic setup for the synthesis of indolylthiazoles 1
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2537–2546

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N. Pagano et al.
SPECIAL TOPIC
Table 1 Synthesis of Indolylthiazoles 1a–l; Scope of α-Bromoketones
Entrya Product
Yield Entrya Product
(%)
Yield Entrya Product
(%)
Yield Entrya Product
(%)
Yield
(%)
F3C
F
N
N
N
N
S
1
50b
4
49
7
49
10
43
S
S
S
N
H
N
H
N
H
N
H
1a
1d
1g
1j
N
Cl
Ph
OH
N
N
N
S
N
2
65
5
44
8
46
11
48
S
S
S
N
H
N
H
N
H
N
H
1b
1e
1h
1k
MeO
Br
S
N
N
N
S
N
3
49
6
44
9
46
12
41
S
S
S
N
H
N
N
H
N
H
H
1l
1i
1c
1f
a Refer to Supporting Information for structures of α-bromoketones 5a–l.
b Isolated yields based on 1000 μL collection volumes and following silica gel chromatography.
Each of the indolylthiazoles (1a–v) thus far described was
a derivative of 2-methylindole as a direct result of using
O
OEt
OEt
O
O
thioamide 3 in the experiments. To broaden the scope of
the methodology and increase the structural diversity of
the scaffold, we became interested in methods that could
be used to rapidly prepare 2-(1H-indol-3-yl)thiazoles
lacking a 2-methyl group. In addition to enhancing the
utility of our methodology, functionalization of the 2-po-
sition of an indole heterocycle is well-established16 and
would provide access to highly complex and valuable in-
termediates for continued chemistry. Thus, we envisioned
that a dioxane-protected thioamide precursor such as 11
might accomplish this goal (Scheme 5).
OH OH
NH4OH
(55%)
EtO
EtO
O
TsOH
(95%)
12
13
O
O
S
O
O
Lawesson's reagent
H2N
O
THF, 0 °C
(81%)
H2N
14
11
Scheme 5 Batch synthesis of acetyl-protected thioamide 11
tative yield (95%).17 Treatment with aqueous ammonium
hydroxide (28–30% ammonia) under ambient conditions
then afforded amide 14 in 55% yield. Lastly, reaction with
Beginning from commercially available ethyl ester 12, re-
action with neopentyl glycol in the presence of a catalytic
amount of acid (TsOH) provided acetal 13 in near quanti-
Synthesis 2012, 44, 2537–2546
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SPECIAL TOPIC
Flow Synthesis of 2-(1H-Indol-3-yl)thiazoles
2541
Table 2 Synthesis of Indolylthiazoles 1m–v; Scope of Hydrazines
Entrya
Product
Yield (%)
Entrya
Product
Yield (%)
N
N
O
MeO
1m
F
S
S
1
51b
6
38
N
H
N
H
1r
1s
1t
N
N
S
S
2
3
4
47
54
44
7
8
9
57
53
82
N
H
N
H
1n
Cl
N
N
S
S
N
N
H
H
1o
Br
N
N
S
S
N
H
N
H
1p
1u
N
N
63c
10
44c
S
S
5
N
N
Me
Bn
1v
1q
a Refer to Supporting Information for structures of hydrazines 10a–k.
b Isolated yields based on 1000 μL collection volumes and following silica gel chromatography.
c Freshly opened free-base hydrazines were used.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2537–2546

2542
N. Pagano et al.
SPECIAL TOPIC
Lawesson’s reagent furnished the target dioxane-protect-
ed thioamide 11 in high yield (81%) following column
chromatography. Taken together, thioamide 11 was ac-
cessed in three steps in an overall yield of 42% with only
one purification step necessary. Similar to thioamide 3, 11
can be stored at room temperature without significant de-
composition and is stable in both organic and aqueous so-
lutions used for all the experiments described herein.
O
Br
5a
1. AcOH, 50 °C, 10 min
O
S
N
O
NH2
2.
H
N
S
11
R
NH3
Cl
N
With building block 11 in hand, we turned our attention to
the flow synthesis of 2-H-indolylthiazoles. To start, we
simply exchanged thioamide 3 with 11 and used the same
setup and reaction conditions shown in Scheme 4. Unfor-
tunately, the liberated equivalents of HBr and water fol-
lowing thiazole formation proved insufficient to release
the masked aldehyde necessary for the Fischer indole syn-
thesis.
R
H
10
15 a–c
H2SO4 (4%), 100 °C
N
N
S
N
MeO
F
S
S
Higher microreactor temperatures, longer reaction times,
acid additives, and increased water equivalents all failed
to remove the 1,3-dioxane protection group. Thus, it be-
came clear to us that a completely aqueous reaction envi-
ronment would be necessary for deprotection. While this
would likely preclude development of a continuous flow
method using the AFRICA synthesis station due to de-
creased solubility, a one-pot procedure in batch mode re-
mained an attractive option. In 1989, Speckamp and co-
workers developed a one-pot deacetalation/Fischer indole
reaction in their total synthesis of the Aristotelia alkaloid
peduncularine.18 For this, they heated 4% aqueous sulfu-
ric acid at reflux for 16 hours in the presence of phenylhy-
drazine hydrochloride.
N
N
H
N
H
H
15a (61%)
15b (41%)
15c (46%)
15 h
5 h
3 h
Scheme 6 One-pot batch synthesis of 2-H-indolylthiazoles 15
All reactions were carried out using oven-dried glassware and con-
ducted under a positive pressure of nitrogen unless otherwise spec-
ified. NMR spectra were recorded with a 400 MHz spectrometer.
All NMR samples were prepared using DMSO-d6. High-resolution
mass spectrometry data were obtained with a time of flight mass
spectrometer (MS-TOF) using electrospray ionization at the
Sanford-Burnham Medical Research Institute (SBMRI). LC/MS
analyses were carried out using a 5 micron C18 column (50 × 2.1
mmID). Silica gel purifications were accomplished using pre-
packed columns. All reagents and solvents were used as received
from standard suppliers. Microfluidic experiments were conducted
using a Syrris AFRICA® synthesis station.
The one-pot batch synthesis of 2-H-indolylthiazoles 15
from acetyl-protected thioamide 11 is outlined in Scheme
6. For all experiments, 2-bromoacetophenone (5a) was
first heated together with thioamide 11 for 10 minutes in
water-soluble acetic acid. A solution of hydrazine 10 in
sulfuric acid (4% aq) was then added and the progress of
the reaction at reflux was monitored. Gratifyingly, hydra-
zines 10 bearing electron-donating, unsubstituted, or elec-
tron-withdrawing halogen substitution were all found to
be suitable for this process (requiring 5, 3, and 15 h for
Synthesis of Indolylthiazoles (1a–l); General Procedure
All reactions were conducted in DMF under a positive pressure of
nitrogen. Streams of the thioamide 3 (32.5 μL/min, 0.50 M in DMF,
1 equiv) and a solution of α-bromoketone 5 (32.5 μL/min, 0.50 M
in DMF, 1 equiv) were mixed in a 250 μL glass reactor heated to
completion, respectively). As expected, precipitates read- 150 °C (3.75 min). After exiting the chip, the combined flow (65.0
μL/min) was introduced to a single stream (32.5 μL/min, 0.50 M in
DMF, 1 equiv) of phenylhydrazine hydrochloride (10a) in a
1000 μL glass reactor heated to 200 °C (10 min). The reaction flow
was then collected (1000 μL) after passing though a back-pressure
ily formed in the AFRICA chip during the course of all re-
actions, making such transformations impractical within
our microfluidic chips.
regulator. These reactions were carried out with a back-pressure of
6.0 bar. The crude reaction mixtures were then adsorbed onto silica
gel, loaded onto a pre-packed silica gel column (12 g), and purified
by chromatography (hexanes–EtOAc; 30 mL/min, 100% hexanes
for 2 min then ramped to 40% EtOAc in hexanes over 18 min).
In conclusion, we have engineered consecutive heterocy-
cle formation reactions using an automated continuous
flow process that allows efficient access to a novel class
of indolylthiazoles 1. These complex heterocyclic scaf-
folds are constructed rapidly and in high yield, allowing
the facile synthesis of libraries of biologically active ana-
logues. We have also developed an efficient one-pot
(batch) procedure for the synthesis of related 2-H-indolyl-
thiazoles. Further applications of both the continuous flow
and batch methods to the generation of analogues with op-
timal biological activity are in progress.
2-(2-Methyl-1H-indol-3-yl)-4-phenylthiazole (1a)
Yield: 0.024 g (50%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.68 (s, 1 H), 8.24 (dd, J =
6.4, 1.8 Hz, 1 H), 8.08 (dd, J = 8.5, 1.1 Hz, 1 H), 7.98 (s, 1 H), 7.48
(m, 2 H), 7.41–7.33 (m, 2 H), 7.17 (m, 2 H), 2.78 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.6, 153.5, 137.6, 135.0,
134.5, 128.8, 127.9, 126.0, 125.8, 121.6, 120.5, 119.5, 111.2, 110.2,
107.0, 14.1.
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SPECIAL TOPIC
Flow Synthesis of 2-(1H-Indol-3-yl)thiazoles
2543
HRMS (ESI): m/z [M + H]+ calcd for C18H15N2S: 291.0950; found:
291.0965.
1H NMR (400 MHz, DMSO-d6): δ = 11.70 (s, 1 H), 8.23 (dd, J =
6.0, 2.3 Hz, 1 H), 8.13 (m, 2 H), 7.98 (s, 1 H), 7.41 (m, 1 H), 7.32
(m, 2 H), 7.18 (m, 2 H), 2.78 (s, 3 H).
3-[2-(2-Methyl-1H-indol-3-yl)thiazol-4-yl]phenol (1b)
Yield: 0.033 g (65%); yellow-brown amorphous solid.
13C NMR (100 MHz, DMSO-d6): δ = 162.8, 161.8 (d, JC–F
=
245.4 Hz), 152.4, 137.7, 135.0, 131.1, 128.0 (d, JC–F = 8.6 Hz),
125.7, 121.6, 120.5, 119.5, 115.6 (d, JC–F = 21.1 Hz), 111.2, 110.0,
106.9, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C18H14FN2S: 309.0856; found:
1H NMR (400 MHz, DMSO-d6): δ = 11.67 (s, 1 H), 9.52 (s, 1 H),
8.24 (dd, J = 6.4, 2.8 Hz, 1 H), 7.89 (s, 1 H), 7.52 (m, 1 H), 7.48 (m,
1 H), 7.40 (m, 1 H), 7.25 (t, J = 7.8 Hz, 1 H), 7.17 (m, 2 H), 6.75
(ddd, J = 7.8, 2.3, 0.9 Hz, 1 H), 2.77 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.4, 157.7, 153.6, 137.5,
135.7, 135.0, 129.7, 125.8, 121.6, 120.5, 119.6, 116.8, 114.9, 113.0,
111.1, 110.1, 107.0, 14.0.
309.0866.
4-(4-Chlorophenyl)-2-(2-methyl-1H-indol-3-yl)thiazole (1h)
Yield: 0.025 g (46%); yellow-brown amorphous solid.
HRMS (ESI): m/z [M + H]+ calcd for C18H15N2OS: 307.0900;
found: 307.0931.
1H NMR (400 MHz, DMSO-d6): δ = 11.70 (s, 1 H), 8.22 (dd, J =
6.0, 2.3 Hz, 1 H), 8.10 (m, 2 H), 8.06 (s, 1 H), 7.54 (m, 2 H), 7.40
(m, 1 H), 7.17 (m, 2 H), 2.77 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.9, 152.2, 137.8, 135.0,
133.3, 132.3, 128.8, 127.7, 125.7, 121.7, 120.6, 119.5, 111.2, 111.0,
106.8, 14.1.
4-(4-Methoxyphenyl)-2-(2-methyl-1H-indol-3-yl)thiazole (1c)
Yield: 0.026 g (49%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.66 (s, 1 H), 8.23 (dd, J =
6.0, 2.3 Hz, 1 H), 8.00 (m, 2 H), 7.81 (s, 1 H), 7.40 (m, 1 H), 7.17
(m, 2 H), 7.04 (m, 2 H), 3.80 (s, 3 H), 2.78 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.4, 159.0, 153.4, 137.4,
135.0, 127.4, 125.8, 121.6, 120.5, 119.5, 114.1, 111.1, 108.2, 107.0,
55.1, 14.0, one hidden carbon.
HRMS (ESI): m/z [M + H]+ calcd for C18H14ClN2S: 325.0561;
found: 325.0568.
4-(4-Bromophenyl)-2-(2-methyl-1H-indol-3-yl)thiazole (1i)
Yield: 0.028 g (46%); yellow-brown amorphous solid.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2OS: 321.1056;
found: 321.1081.
1H NMR (400 MHz, DMSO-d6): δ = 11.71 (s, 1 H), 8.23 (dd, J =
6.4, 2.8 Hz, 1 H), 8.07 (s, 1 H), 8.04 (m, 2 H), 7.68 (m, 2 H), 7.41
(m, 1 H), 7.18 (m, 2 H), 2.78 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.9, 152.3, 137.8, 135.0,
133.7, 131.7, 128.0, 125.7, 121.7, 120.9, 120.6, 119.5, 111.2, 111.0,
106.8, 14.1.
2-(2-Methyl-1H-indol-3-yl)-4-(p-tolyl)thiazole (1d)
Yield: 0.025 g (49%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.67 (s, 1 H), 8.23 (dd, J =
6.4, 1.8 Hz, 1 H), 7.97 (m, 2 H), 7.92 (s, 1 H), 7.40 (m, 1 H), 7.29
(d, J = 8.2 Hz, 2 H), 7.18 (m, 2 H), 2.78 (s, 3 H), 2.35 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.5, 153.6, 137.5, 137.1,
135.0, 131.8, 129.3, 126.0, 125.8, 121.6, 120.5, 119.5, 111.1, 109.3,
107.0, 20.9, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H14BrN2S: 371.0036;
found: 371.0045.
2-(2-Methyl-1H-indol-3-yl)-4-[4-(trifluoromethyl)phenyl]thia-
zole (1j)
Yield: 0.026 g (43%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.73 (s, 1 H), 8.31–8.23 (m,
4 H), 7.85 (d, J = 8.2 Hz, 2 H), 7.41 (m, 1 H), 7.19 (m, 2 H), 2.79
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.2, 151.9, 138.2, 137.9,
135.0, 126.6, 125.8, 125.8, 125.7, 121.7, 120.6, 119.5, 112.9, 111.2,
106.8, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2S: 305.1107; found:
305.1113.
4-[(1,1′-Biphenyl)-4-yl]-2-(2-methyl-1H-indol-3-yl)thiazole (1e)
Yield: 0.027 g (44%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.68 (s, 1 H), 8.24 (dd, J =
6.4, 1.8 Hz, 1 H), 8.15 (m, 2 H), 8.03 (s, 1 H), 7.77 (m, 2 H), 7.71
(m, 2 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.16 (m, 2 H), 7.39–7.33 (m,
2 H), 2.77 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.7, 153.1, 139.7, 139.4,
137.7, 135.0, 133.6, 129.0, 127.5, 127.0, 126.6, 126.6, 125.8, 121.7,
120.6, 119.5, 111.2, 110.4, 107.0, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C19H14F3N2S: 359.0824;
found: 359.0840.
4-[2-(2-Methyl-1H-indol-3-yl)thiazol-4-yl]benzonitrile (1k)
Yield: 0.025 g (48%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.74 (s, 1 H), 8.28–8.21 (m,
4 H), 7.94 (m, 2 H), 7.40 (m, 1 H), 7.18 (m, 1 H), 2.77 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C24H19N2S: 367.1263; found:
367.1265.
13C NMR (100 MHz, DMSO-d6): δ = 163.2, 151.7, 138.5, 138.1,
135.0, 132.9, 126.6, 125.7, 121.7, 120.7, 119.5, 113.7, 111.2, 110.0,
106.7, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C19H14N3S: 316.0903; found:
316.0907.
2-(2-Methyl-1H-indol-3-yl)-4-(naphthalen-2-yl)thiazole (1f)
Yield: 0.025 g (44%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.71 (s, 1 H), 8.62 (s, 1 H),
8.29 (d, J = 7.3 Hz, 1 H), 8.22 (dd, J = 8.7, 1.8 Hz, 1 H), 8.14 (s,
1 H), 8.03–8.00 (m, 2 H), 7.93 (d, J = 7.3 Hz, 1 H), 7.53 (m, 2 H),
7.41 (d, J = 7.3, 1 H), 7.20 (m, 2 H), 2.82 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.8, 153.5, 137.7, 135.0,
133.2, 132.6, 132.0, 128.3, 128.2, 127.6, 126.4, 126.1, 125.8, 124.6,
124.4, 121.6, 120.6, 119.6, 111.2, 110.9, 107.0, 14.1.
2-(2-Methyl-1H-indol-3-yl)-4-(thiophen-2-yl)thiazole (1l)
Yield: 0.020 g (41%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.71 (s, 1 H), 8.22 (s, 1 H),
7.82 (s, 1 H), 7.63 (dd, J = 3.4, 1.1 Hz, 1 H), 7.53 (dd, J = 5.0,
0.9 Hz, 1 H), 7.40 (m, 1 H), 7.19–7.13 (m, 3 H), 2.75 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H17N2S: 341.1107; found:
13C NMR (100 MHz, DMSO-d6): δ = 162.7, 148.2, 138.6, 137.8,
135.0, 128.0, 125.7, 123.8, 121.7, 120.6, 119.5, 111.2, 108.4, 106.6,
13.9.
341.1103.
4-(4-Fluorophenyl)-2-(2-methyl-1H-indol-3-yl)thiazole (1g)
Yield: 0.025 g (49%); yellow-brown amorphous solid.
HRMS (ESI): m/z [M + H]+ calcd for C16H13N2S2: 297.0515; found:
297.0516.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2537–2546

2544
N. Pagano et al.
SPECIAL TOPIC
Synthesis of Indolylthiazoles 1m–v; General Procedure
All reactions were conducted in DMF under a positive pressure of
nitrogen. Streams of thioamide 3 (32.5 μL/min, 0.50 M in DMF, 1
equiv) and a solution of 2-bromoacetophenone (5a; 32.5 μL/min,
0.50 M in DMF, 1 equiv) were mixed in a 250 μL glass reactor heat-
ed to 150 °C (3.75 min). After exiting the chip, the combined flow
(65.0 μL/min) was introduced to a single stream (32.5 μL/min, 0.50
M in DMF, 1 equiv) of hydrazines (10d–k) in a 1000 μL glass reac-
tor heated to 200 °C (10 min). Streams of hydrazines 10b and 10c
(0.50 M) were prepared using 1:1 DMF/ethylene glycol. The reac-
tion flow was then collected (1000 μL) after passing though a back-
pressure regulator. These reactions were carried out with a back
pressure of 6.0 bar. The crude reaction mixtures were then adsorbed
onto silica gel, loaded onto a pre-packed silica gel column (12 g),
and purified by chromatography (hexanes–EtOAc; 30 mL/min,
100% hexanes for 2 min then ramped to 40% EtOAc in hexanes
over 18 min).
2-(1,2-Dimethyl-1H-indol-3-yl)-4-phenylthiazole (1q)
Yield: 0.032 g (63%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 8.21 (m, 1 H), 8.07 (m, 2 H),
8.01 (s, 1 H), 7.55 (m, 1 H), 7.48 (m, 2 H), 7.35 (m, 1 H), 7.23 (m,
2 H), 3.78 (s, 3 H), 2.86 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.5, 153.5, 138.7, 136.4,
134.4, 128.8, 127.9, 126.0, 124.9, 121.7, 120.8, 119.2, 110.5, 110.0,
106.8, 29.7, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2S: 305.1107; found:
305.1121.
2-[5-(Benzyloxy)-2-methyl-1H-indol-3-yl]-4-phenylthiazole (1r)
Yield: 0.024 g (38%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 8.23 (dd, J = 6.9, 1.4 Hz, 1 H),
8.05 (m, 2 H), 8.03 (s, 1 H), 7.52 (m, 1 H), 7.45 (m, 2 H), 7.34–7.18
(m, 6 H), 7.03 (m, 2 H), 5.55 (s, 2 H), 2.79 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.2, 153.6, 138.3, 137.5,
136.3, 134.4, 128.8, 128.8, 128.0, 127.3, 126.2, 126.1, 125.1, 122.1,
121.1, 119.5, 110.9, 110.4, 107.6, 39.9, 12.1.
HRMS (ESI): m/z [M + H]+ calcd for C25H21N2OS: 397.1369;
found: 397.1388.
2-(5-Methoxy-2-methyl-1H-indol-3-yl)-4-phenylthiazole (1m)
Yield: 0.027 g (51%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.55 (s, 1 H), 8.08 (d, J =
7.8 Hz, 2 H), 7.96 (s, 1 H), 7.81 (d, J = 2.8 Hz, 1 H), 7.48 (t, J =
7.8 Hz, 2 H), 7.35 (m, 1 H), 7.30 (d, J = 8.7 Hz, 1 H), 6.82 (dd, J =
8.7, 2.3 Hz, 1 H), 3.84 (s, 3 H), 2.74 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.7, 154.5, 153.4, 138.0,
134.5, 129.9, 128.8, 127.8, 126.4, 126.0, 111.8, 110.8, 109.9, 107.0,
102.3, 55.2, 14.1.
2-(2,5-Dimethyl-1H-indol-3-yl)-4-phenylthiazole (1s)
Yield: 0.029 g (57%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.60 (s, 1 H), 8.11 (m, 2 H),
8.02 (s, 1 H), 8.00 (s, 1 H), 7.52 (m, 2 H), 7.39 (m, 1 H), 7.32 (d, J =
8.2 Hz, 1 H), 7.03 (dd, J = 8.5, 2.1 Hz, 1 H), 2.81 (s, 3 H), 2.49 (s,
3 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2OS: 321.1056;
found: 321.1060.
13C NMR (100 MHz, DMSO-d6): δ = 162.8, 153.5, 137.7, 134.5,
133.3, 129.1, 128.8, 127.9, 126.0, 126.0, 123.0, 119.1, 110.9, 110.1,
106.5, 21.6, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2S: 305.1107; found:
305.1121.
2-(5-Fluoro-2-methyl-1H-indol-3-yl)-4-phenylthiazole (1n)
Yield: 0.024 g (47%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.81 (s, 1 H), 8.07 (m, 2 H),
8.00 (s, 1 H), 7.99 (dd, J = 10.0, 2.8 Hz, 1 H), 7.49 (m, 2 H), 7.40
(dd, J = 8.7, 4.6 Hz, 1 H), 7.36 (m, 1 H), 7.02 (m, 1 H), 2.75 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.2, 157.9 (d, JC–F
232.9 Hz), 153.5, 139.5, 134.4, 131.6, 128.8, 127.9, 126.2 (d, JC–F
10.5 Hz), 126.0, 112.2 (d, JC–F = 9.6 Hz), 110.4, 109.5 (d, JC–F
25.9 Hz), 107.4, 104.7 (d, JC–F = 24.9 Hz), 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C18H14FN2S: 309.0856; found:
309.0863.
=
=
=
2-[5-(tert-Butyl)-2-methyl-1H-indol-3-yl]-4-phenylthiazole (1t)
Yield: 0.031 g (53%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.51 (s, 1 H), 8.30 (d, J =
1.4 Hz, 1 H), 8.06 (m, 2 H), 7.94 (s, 1 H), 7.44 (m, 2 H), 7.33 (m,
1 H), 7.29 (d, J = 8.7 Hz, 1 H), 7.28 (s, 1 H), 7.22 (dd, J = 8.7,
1.8 Hz, 1 H), 2.73 (s, 3 H), 1.36 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.7, 153.3, 142.8, 137.5,
134.6, 133.1, 128.8, 127.9, 126.0, 125.6, 119.7, 115.4, 110.6, 110.0,
107.1, 34.4, 31.8, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C22H23N2S: 347.1576; found:
347.1583.
2-(5-Chloro-2-methyl-1H-indol-3-yl)-4-phenylthiazole (1o)
Yield: 0.029 g (54%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.90 (s, 1 H), 8.27 (d, J =
1.8 Hz, 1 H), 8.06 (m, 2 H), 8.02 (s, 1 H), 7.49 (m, 2 H), 7.42 (d, J =
8.2 Hz, 1 H), 7.36 (m, 1 H), 7.18 (dd, J = 8.5, 2.1 Hz, 1 H), 2.76 (s,
3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.0, 153.6, 139.3, 134.4,
133.5, 128.8, 128.0, 126.9, 126.0, 125.1, 121.6, 118.9, 112.7, 110.6,
106.9, 14.0.
2-(2-Methyl-1H-benzo[g]indol-3-yl)-4-phenylthiazole (1u)
Yield: 0.047 mg (82%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 12.40 (s, 1 H), 8.40 (d, J =
8.7 Hz, 1 H), 8.35 (d, J = 8.2 Hz, 1 H), 8.08 (d, J = 6.9 Hz, 1 H),
8.06 (m, 2 H), 8.01 (s, 1 H), 7.93 (d, J = 8.2 Hz, 1 H), 7.63 (d, J =
8.7 Hz, 1 H), 7.55 (t, J = 7.3 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 2 H), 7.41
(t, J = 7.3 Hz, 1 H), 7.34 (t, J = 7.3 Hz, 1 H), 2.84 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.6, 153.7, 135.3, 134.5,
129.7, 129.4, 128.8, 128.4, 127.9, 126.1, 125.7, 123.9, 121.7, 121.3,
121.1, 120.6, 119.9, 110.7, 108.9, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H14ClN2S: 325.0566;
found: 325.0564.
2-(5-Bromo-2-methyl-1H-indol-3-yl)-4-phenylthiazole (1p)
Yield: 0.027 g (44%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.92 (s, 1 H), 8.42 (d, J =
1.1 Hz, 1 H), 8.06 (dd, J = 8.2, 1.4 Hz, 2 H), 8.03 (s, 1 H), 7.50 (t,
J = 7.8 Hz, 2 H), 7.40–7.35 (m, 2 H), 7.30 (dd, J = 8.7, 1.8 Hz, 1 H),
2.76 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H17N2S: 341.1107; found:
341.1109.
13C NMR (100 MHz, DMSO-d6): δ = 162.0, 153.6, 139.1, 134.4,
133.7, 128.8, 128.0, 127.5, 126.0, 124.1, 121.9, 113.2, 113.1, 110.7,
106.7, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H14BrN2S: 371.0036;
found: 371.0064.
2-(1-Benzyl-2-methyl-1H-indol-3-yl)-4-phenylthiazole (1v)
Yield: 0.028 mg (44%); yellow-brown amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 8.26 (dd, J = 8.2, 1.4 Hz, 1 H),
8.07 (m, 2 H), 8.04 (s, 1 H), 7.55 (dd, J = 7.1, 1.1 Hz, 1 H), 7.47 (m,
2 H), 7.37–7.20 (m, 9 H), 7.05 (m, 2 H), 5.57 (s, 2 H), 2.82 (s, 3 H).
Synthesis 2012, 44, 2537–2546
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Flow Synthesis of 2-(1H-Indol-3-yl)thiazoles
2545
13C NMR (100 MHz, DMSO-d6): δ = 162.3, 153.6, 138.3, 137.5,
136.2, 134.4, 128.8, 128.7, 127.9, 127.3, 126.2, 126.0, 125.1, 122.1,
121.1, 119.5, 110.8, 110.4, 107.6, 39.9, 12.1.
13C NMR (100 MHz, DMSO-d6): δ = 162.9, 153.9, 136.6, 134.4,
128.8, 127.9, 126.7, 126.0, 124.3, 122.4, 120.8, 120.4, 112.2, 110.6,
110.5.
HRMS (ESI): m/z [M + H]+ calcd for C25H21N2S: 381.1420; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H13N2S: 277.0794; found:
381.1439.
277.0791.
2-(5,5-Dimethyl-1,3-dioxan-2-yl)acetamide (14)
2-(5-Methoxy-1H-indol-3-yl)-4-phenylthiazole (15b)
A solution of solution 13 (4.6 g, 22.8 mmol, 1 equiv) in aqueous am-
monium hydroxide (28–30% ammonia, 50 mL) was sealed and
stirred vigorously at r.t. overnight. The resulting pale-yellow reac-
tion mixture was extracted with CH2Cl2 (2 × 100 mL). The com-
bined organic layers were then washed with brine (100 mL), dried
using Na2SO4, and concentrated to dryness in vacuo to provide am-
ide 14.
Yield: 0.034 g (41%); light yellow amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.62 (s, 1 H), 8.07 (m, 3 H),
7.91 (s, 1 H), 7.84 (d, J = 2.8 Hz, 1 H), 7.48 (t, J = 7.3 Hz, 2 H),
7.40–7.33 (m, 2 H), 6.88 (dd, J = 8.7, 2.3 Hz, 1 H), 3.85 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.0, 154.6, 153.8, 134.4,
131.6, 128.8, 127.8, 127.1, 125.9, 124.9, 112.9, 112.2, 110.3, 110.2,
102.4, 55.3.
Yield: 2.16 g (55%); white solid.
HRMS (ESI): m/z [M + H]+ calcd for C18H15N2OS: 307.0900;
found: 307.0902.
1H NMR (400 MHz, DMSO-d6): δ = 6.39 (s, 1 H), 6.08 (s, 1 H),
4.73 (t, J = 4.6 Hz, 1 H), 3.60 (d, J = 11.5 Hz, 2 H), 3.44 (d, J =
11.0 Hz, 2 H), 2.56 (d, J = 4.6 Hz, 2 H), 1.15 (s, 3 H), 0.70 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 171.4, 98.7, 41.8, 30.0, 22.9,
21.6.
HRMS (ESI): m/z [M + Na]+ calcd for C8H15NNaO3: 196.0944;
found: 196.0945.
2-(5-Fluoro-1H-indol-3-yl)-4-phenylthiazole (15c)
Yield: 0.036 g (46%); light yellow amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.87 (s, 1 H), 8.21 (d, J =
1.8 Hz, 1 H), 8.06 (m, 2 H), 8.03 (dd, J = 10.1, 2.8 Hz, 1 H), 7.92
(s, 1 H), 7.51–7.46 (m, 3 H), 7.35 (t, J = 7.3 Hz, 1 H), 7.09 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.6, 158.0 (d, JC–F
232.9 Hz), 154.0, 134.3, 133.2, 128.8, 128.6, 127.9, 126.0, 124.6 (d,
=
2-(5,5-Dimethyl-1,3-dioxan-2-yl)ethanethioamide (11)
A solution of amide 14 (1.0 g, 5.78 mmol, 1 equiv) in anhydrous
THF (30 mL) was prepared and cooled to 0 °C. Lawesson’s reagent
(1.3 g, 3.18 mmol, 0.55 equiv) was then added and the resulting yel-
low suspension was allowed to warm to r.t., stirring for a total of
2 h. The resulting light-yellow solution was concentrated in vacuo
and re-dissolved in EtOAc (100 mL). The organic phase was
washed with sat. aq NaHCO3 (100 mL) followed by brine (100 mL),
dried using Na2SO4, and concentrated to dryness in vacuo. The
crude material was adsorbed onto silica gel, loaded onto a pre-
packed silica gel column (80 g), and purified by chromatography
(hexanes–EtOAc; 60 mL/min, 0% EtOAc to 30% EtOAc over 45
min). Following concentration of product eluents, 11 was isolated.
JC–F = 10.5 Hz), 113.4 (d, JC–F = 10.5 Hz), 110.7, 110.7 (d, JC–F
26.8 Hz), 110.6, 105.2 (d, JC–F = 24.0 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C17H12FN2S: 295.0700; found:
=
295.0696.
Acknowledgment
This work was supported by National Institutes of Health grant nos.
AI078048, CA140427, HG005033, GM079590, and GM081261.
The MS-TOF instrument was awarded through the Bankhead-Coley
Florida Biomedical Cancer Research Program shared instrument
grant 09BE-02.
Yield: 0.88 g (81%); off-white solid.
1H NMR (400 MHz, DMSO-d6): δ = 7.96 (s, 1 H), 7.71 (s, 1 H),
4.75 (m, 1 H), 3.64 (d, J = 11.0 Hz, 2 H), 3.47 (d, J = 11.0 Hz, 2 H),
3.09 (m, 2 H), 1.18 (s, 3 H), 0.73 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 203.9, 99.4, 49.7, 29.9, 22.8,
21.4.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are NMR spectra for final compounds and the structures of α-bro-
moketones 5a–l and hydrazines 10a–k.SnoIufproi
m
tgioSrantnugIifoop
r
imaotrtn
HRMS (ESI): m/z [M + H]+ calcd for C8H16NO2S: 190.0896; found:
190.0906.
References
Synthesis of Indolylthiazoles 15a–c; General Procedure
(1) (a) Chighine, A.; Sechi, G.; Bradley, M. Drug Discovery
Today 2007, 12, 459. (b) Huryn, D. M.; Cosford, N. D. P.
Annu. Rep. Med. Chem. 2007, 42, 401.
(2) (a) Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.;
Smith, C. D. Microreactors in Organic Synthesis and
Catalysis; Wirth, T., Ed.; Wiley-VCH: Weinheim, 2008.
(b) Ehrfeld, W.; Hessel, V.; Lowe, H. Microreactors: New
Technology for Modern Chemistry; Wiley-VCH: Weinheim,
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(3) For recent selected reviews, see: (a) Glasnov, T. N.; Kappe,
C. O. J. Heterocycl. Chem. 2011, 48, 11. (b) Webb, D.;
Jamison, T. F. Chem. Sci. 2010, 1, 675. (c) Geyer, K.;
Gustafsson, T.; Seeberger, P. H. Synlett 2009, 2382.
(d) Mak, X. Y.; Laurino, P.; Seeberger, P. H. Beilstein J.
Org. Chem. 2009, 5, No. 19. (e) Weiler, A.; Junkers, M.
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An aqueous solution of 4% sulfuric acid (2.5 mL) was heated to
50 °C following a thorough purge with nitrogen gas. Hydrazines 10
(0.294 mmol, 1.1 equiv) were then added to the reaction mixture
and dissolved by heating for an additional 10 min. At the same time,
a mixture of thioamide 11 (50 mg, 0.267 mmol, 1 equiv) and 2-bro-
moacetophenone (5a; 54 mg, 0.267 mmol, 1 equiv) in acetic acid
(0.65 mL) was purged with nitrogen and then heated to 50 °C for 10
min. Lastly, the separate reaction mixtures were combined and
monitored at reflux (105 °C). Each resulting suspension was ex-
tracted with EtOAc (2 × 50 mL), adsorbed onto silica gel, loaded
onto a pre-packed silica gel column (12 g), and purified by chroma-
tography (hexanes–EtOAc; 30 mL/min, 100% hexanes for 2 min
then ramped to 40% EtOAc in hexanes over 18 min).
2-(1H-Indol-3-yl)-4-phenylthiazole (15a)
Yield: 0.045 g (61%); light yellow amorphous solid.
1H NMR (400 MHz, DMSO-d6): δ = 11.76 (s, 1 H), 8.33 (m, 1 H),
8.14 (d, J = 2.8 Hz, 1 H), 8.08 (d, J = 7.3 Hz, 2 H), 7.91 (s, 1 H),
7.51–7.46 (m, 3 H), 7.35 (t, J = 7.3 Hz, 1 H), 7.23 (s, 2 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2537–2546

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N. Pagano et al.
SPECIAL TOPIC
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Synthesis 2012, 44, 2537–2546
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