Base-Promoted Synthesis of Quinoline-4(1H)-thiones from o-Alkynylanilines and Aroyl Isothiocyanates

Article abstract of DOI:10.1021/acs.orglett.7b02993

A base-promoted synthesis of quinoline-4(1H)-thiones has been accomplished from the in situ generated o-alkynylthiourea, obtained by reacting o-alkynylanilines with aroyl/acyl isothiocyanates. A 6-exo-dig S-cyclization of the in situ generated thiourea is

Full text of DOI:10.1021/acs.orglett.7b02993

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Base-Promoted Synthesis of Quinoline-4(1H)‑thiones from
o‑Alkynylanilines and Aroyl Isothiocyanates
Anju Modi, Prasenjit Sau, and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati 781039, India
S
* Supporting Information
ABSTRACT: A base-promoted synthesis of quinoline-4(1H)-
thiones has been accomplished from the in situ generated o-
alkynylthiourea, obtained by reacting o-alkynylanilines with
aroyl/acyl isothiocyanates. A 6-exo-dig S-cyclization of the in
situ generated thiourea is followed by a rearrangement to give
quinoline-4(1H)-thiones.
Scheme 1. Differential Reactivity of o-Alkynylanilines with
Aryl and Aroyl Isothiocyanates
onstruction of heterocycles with privileged scaffolds,
Cwhich exhibit various biological activities, is in great
demand in the field of chemical genetics.1 Among numerous
efforts devoted toward the development of these compounds,
cascade reactions have emerged as a powerful synthetic tool in
modern synthetic organic chemistry.2 Compared to the
traditional stepwise synthesis, cascade reactions have the
advantage of sequential incorporation of multiple C−C and
C−heteroatom bonds in one pot, thereby increasing the overall
synthetic efficiency. Taking advantage of this strategy, several
alkyne-based substrates, possessing internal nucleophiles at
appropriate positions, are often utilized for the construction of
interesting heterocycles.3 Among various alkynes, o-alkynylani-
lines have been extensively employed for the construction of
molecular frameworks such as indole,4 quinoline,5 quinazoli-
none,6 benzoxazine,7 and 4H-benzo[d][1,3]thiazine8 using
various metal salts such as palladium, copper, and silver.
Aroyl isothiocyanates, apart from being used as acylating9a
and thiocyanating agents,9a,b have also been utilized for the
synthesis of many biologically important heterocycles.9c
Recently, we reported the synthesis of indolo[2,3-b]quinolines
from o-alkynylanilines and aryl isothiocyantes in the presence of
Ag2CO3 under microwave heating.10 Interestingly, replacement
of aryl isothiocyante with an aroyl isothiocyanate completely
changed the course of reaction and the product outcome, giving
a quinoline-4(1H)-thione (Scheme 1).
Encouraged by this interesting result, we further investigated
the reaction by reacting 2-(phenylethynyl)aniline (1) (1 equiv)
and benzoyl isothiocyanate (a) (1 equiv) in the presence of CuI
(10 mol %) and K2CO3 (4 equiv) in 1,4-dioxane at 110 °C
(Table 1, entry 1). Spectroscopic analysis (IR, 1HNMR,
13CNMR, and HRMS) of the isolated product indicated its
structure to be N-(3-phenyl-4-thioxo-1,4-dihydroquinolin-2-
yl)benzamide (1a). However, the exact structure of the product
was fully ascertained by single-crystal X-ray diffraction of one of
its derivative (3a) (Figure S1, see the Supporting Information),
thereby confirming its structure to be N-(3-phenyl-4-thioxo-
1,4-dihydroquinolin-2-yl)benzamide (1a). Interestingly, the
benzoyl thiourea generated in situ underwent a 6-exo-dig S-
attack onto the internal alkyne followed by rearrangement to
give the quinoline-4(1H)-thione moiety in 100% atom
economy. On the basis of recent studies, quinoline-4(1H)-
thione derivatives are found to be inhibitors of virulence factor
elastase of the human pathogen Pseudomonas aeruginosa (Figure
S2, I).11a,b Some of the quinoline-4(1H)-thione derivatives
(Figure S2, II) are reported to form oxovanadium complexes
with VO(acac)2, exhibiting cytotoxic activity and apoptosis in
human malignant cell lines.11c Despite the importance of the
quinoline-4(1H)-thione framework, there are only a few reports
of their synthesis which mainly involve thioketolization of the
preformed quinolin-4(1H)-ones with phosphorus pentasulfide
(P4S10) or with Lawesson’s reagent.11,12 To the best of our
knowledge, there is no report at this date for the synthesis of
quinoline-4(1H)-thiones from o-alkynylanilines and aroyl
isothiocyanate in the presence of base.
Encouraged by the synthesis of quinoline-4(1H)-thiones,
further optimization of the reaction parameters were tuned to
enhance the productivity of the reaction. Initially, a range of
other copper salts such as CuBr (52%), Cu(OAc)2 (41%), and
Cu(OTf)2 (37%) were examined, among which CuBr gave
better yield (52%) compared to CuI (47%) (Table 1, entries
Received: September 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02993
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Letter
a
temperature may be due to the decomposition or dimerization
of the product. It may be noted that on prolonged reaction time
(12 h) the obtained product oxidized, giving a dimeric (S−S
bond) product (Scheme S1, SI).
Table 1. Screening of the Reaction Conditions
The scope and generality of the base-promoted reaction was
extended to a variety of o-alkynylanilines and aroyl
isothiocyanates under the optimized reaction conditions
(Table 1, entry 20). At first, the effect of different aroyl/acyl
isothiocyanates (a−g) on 2-(phenylethynyl)aniline (1) was
examined, and the results are summarized in Scheme 2. The
d
entry
catalyst (mol %)
base (equiv)
solvent
yield (%)
1
CuI (10)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
K2CO3 (4)
Na2CO3 (4)
Cs2CO3 (4)
DBU (4)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
CH3CN
DMSO
DMF
47
52
41
37
18
9
2
CuBr (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
Ag2CO3 (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (20)
CuBr (5)
3
Scheme 2. Substrate Scope of 2-(Phenylethynyl)aniline with
4
a−c
Aroyl Isothiocyanates
5
6
7
68
29
11
64
69
66
77
13
83
48
53
0
8
9
DABCO (4)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (2)
Cs2CO3 (2)
10
11
12
13
14
15
16
17
18
CuBr (5)
CuBr (5)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
DCE
b
19
CH3CN
CH3CN
71
87
c
20
a
Reaction conditions: 1 (0.25 mmol), a (0.25 mmol), catalysts (mol
%), base (equiv), solvent (2 mL) under air at 110 °C for 6 h.
Reaction at 130 °C. Reaction at 80 °C. Yield of the isolated
a
Reaction conditions: 2-(phenylethynyl)aniline (1) (0.25 mmol),
aroyl isothiocyanates (a−g) (0.25 mmol), Cs2CO3 (0.5 mmol) in
b
c
d
b
c
product.
CH3CN (2 mL) under air at 80 °C for 6−8 h. Isolated yield. 1 mmol
scale.
1−4). The use alkyne activating silver salt viz. Ag2CO3 (18%),
in lieu of copper salt, was not so effective (Table 1, entry 5).
Other inorganic bases such as Na2CO3 and Cs2CO3 (Table 1,
entries 6 and 7) and organic bases such as DBU and DABCO
(Table 1, entries 8 and 9) were tested. Except Cs2CO3 (68%,
Table 1, entry 7), none of the bases tested gave satisfactory
results. Increasing the catalyst loading to 20 mol % was not
beneficial (Table 1, entry 10), while decreasing the catalyst
loading to 5 mol % (Table 1, entry 11) was equally effective to
that of higher catalyst loading (10 mol %). A comparable yield
of 66% was obtained when the amount of base used was
reduced to 2 equiv (Table 1, entry 12). Surprisingly, when the
reaction was carried out in absence of the catalyst under
otherwise identical condition, the product yield improved
considerably (77%), while in the absence of base only a trace
(13%) of the product was observed (Table 1, entries 13 and
14). This result suggests the noninvolvement of catalyst and the
essential requirement of base for this cascade reaction. Different
solvents such as CH3CN, DMSO, DMF, and DCE were
screened, and solvent CH3CN gave an improved yield of 83%,
whereas DMSO and DMF provided reduced yields of 48% and
53%, respectively (Table 1, entries 15−17). No product
formation was observed in DCE (Table 1, entry 18). To
check the effect of temperature, reactions were performed at an
elevated temperature (130 °C) and at lower temperature (80
°C). Unexpectedly, the increase in the reaction temperature
was detrimental to the product formation, giving only 71%
yield, whereas lowering the temperature provided an improved
yield of 87% (Table 1, entries 19 and 20). Lower yield at higher
phenyl ring of benzoyl isothiocyanates bearing electron-
donating groups such as p-CH3 (b) and p-OCH3 (c) provided
excellent yields of 1b (93%) and 1c (91%) compared to the
unsubstituted analogue 1a (87%). However, lower yields of
products 1d (83%) and 1e (78%) (Scheme 2) were obtained
when moderately electron-withdrawing p-F (d) and strongly
electron-withdrawing p-CF3 (e) groups were present on the
phenyl ring of benzoyl isothiocyanates. Acyclic as well as
heterocyclic carbonyl isothiocyantes such as cyclohexanecar-
bonyl isothiocyanate (f) and thiophene-2-carbonyl isothiocya-
nate (g) reacted competently with 1 to give good yields of the
product 1f (81%) and 1g (79%), respectively. These results
suggest that, irrespective of the substituents present on the
aroyl isothiocyanates, all reacted well with 1 to give the
corresponding products.
Next, the effect of the substituents R2 present on the alkyne
side of the phenyl ring in 2-(phenylethynyl)anilines (2−14)
was tested by reacting them with various benzoyl isothiocyantes
(a−h) (Scheme 3). 2-(Phenylethynyl)aniline derivatives,
bearing either electron-donating (p-CH3 (2), p-OCH3 (3),
and p-tBu (4)) or electron-withdrawing (p-F (5), p-NO2 (6))
groups on the alkyne side of the phenyl ring reacted efficiently
with benzoyl isothiocyanate (a) to give good yields of their
products (2a−6a) in the range of 89−95% yield. When both
the substituents R2 in alkynylaniline and R3 in aroyl
isothiocyanate were electron-donating, such as p-CH3 (2)/p-
CH3 (b) and p-OCH3 (3)/p-CH3 (b), excellent yields of their
product (2b, 93%) and (3b, 91%) were obtained. On the other
B
DOI: 10.1021/acs.orglett.7b02993
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Letter
drawing group such as p-CF3 (12), the yield dropped further to
57% (Scheme 3). Moreover, when all substituents R1, R2, and
R3 were either p-CH3 (13) or p-F (14), their products 13b and
13d were furnished in 87% and 73% yields, respectively. When
aliphatic groups like cyclopropyl and butyl were present instead
of phenyl rings on the alkyne side of 2-(phenylethynyl)aniline,
the intermediate thiourea generated did not undergo any
further reaction. To demonstrate the potential application of
the present method, a gram-scale reaction was carried out with
2-(phenylethynyl)aniline (1) (6.2 mmol, 1.19 g) and benzoyl
isothiocyanate (a) (6.2 mmol, 1.01 g) under the standard
reaction conditions. The reaction proceeded smoothly to afford
77% isolated yield of (1a).
Scheme 3. Substrate Scope for Substituted 2-
(Phenylethynyl)aniline and Benzoyl Isothiocyanates
a,b
On the basis of the literature reports, a plausible pathway has
been proposed for the base-promoted cascade reaction
(Scheme 4). Reaction of 2-(phenylethynyl)aniline (1) and
Scheme 4. Plausible Reaction Mechanism
a
Reaction conditions: 2-(phenylethynyl)aniline (2−13) (0.25 mmol),
benzoyl isothiocyanates (a−h) (0.25 mmol), Cs2CO3 (0.5 mmol) in
b
CH3CN (2 mL) under air at 80 °C for 6−8 h. Isolated yields.
hand, when substituent R2 was electron-donating and R3 was
electron-withdrawing, combinations such as p-CH3 (2)/p-F
(d), p-OCH3 (3)/p-F (d), and p-tBu (4)/p-Cl (h), the yields of
their products were slightly lower (2d, 87%; 3d, 85%; and 4h,
89%). However, when R2 was electron-withdrawing, i.e., p-F
(5), it gave comparatively higher yields of their products (5b,
96%) and (5d, 89%), irrespective of the nature of substituents
R3 (either electron-donating, p-CH3 (b) or electron-with-
drawing p-F (d)). 2-(Naphthalen-2-ylethynyl)aniline (7) and 2-
(pyridin-2-ylethynyl)aniline (8) also reacted efficiently with
benzoyl isothiocyanate (a) to give their respective products 7a
and 8a in 82 and 78% yields.
benzoyl isothiocyanate (a) generates an intermediate thiourea
A.13a,b A 6-exo-dig S-attack onto the internal alkyne is facilitated
via the abstraction of a thioamidic nitrogen proton attached to
the phenyl ring to give intermediate B.13a−c Abstraction of a
second proton from the intermediate B generates a
carbodiimide intermediate C. The thiolate C so generated
undergoes thioketolization, giving a diphenylethane thione
nucleophilic moiety D.13d Intramolecular nucleophilic attack of
the heterocumulene generates a cyclic anionic intermediate E,
which upon protonation gave F. Finally, a proton migration
produces the desired quinoline-4(1H)-thiones product (1a).
The reaction of aroyl isothiocyanate (a) with secondary amine
based o-alkynylanilines (15) gave product 15a in 92% yield
(Scheme 4). The inability of the product 15a to undergo
further ring opening cyclization is due to the absence second
NH proton, there by supporting our proposed mechanism.
Further, the effect of substituents R1 present on the amine-
bearing ring of 2-(phenylethynyl)anilines (9−12) was inves-
tigated. When the substituent R1 was electron-donating, such as
p-CH3 (9) and 2,4-di-CH3 (10), good yields of the products 9a
(81%), 9b (83%), 9d (78%), and 10h (79%) were obtained on
reaction with benzoyl isothiocyantes (a, b, d, and h). On the
other hand, when R1 was moderately electron-withdrawing such
as p-F (11), the products 11b and 11d were obtained in 76%
and 72% yields, respectively. With a strong electron-with-
C
DOI: 10.1021/acs.orglett.7b02993
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Organic Letters
Letter
(6) (a) Gimeno, A.; Medio-Simon
́
, M.; Ramirez de Arellano, C.;
In conclusion, we have demonstrated a metal-free approach
for the synthesis of quinoline-4(1H)-thione derivatives. This is
the first example of a base-promoted synthesis of quinoline-
4(1H)-thiones from o-alkynylanilines and aroyl isothiocyanate.
Through the cascade process, simultaneous formation of three
C−C, C−N, and C−S bonds has been accomplished. This
protocol shows wide functional group tolerance with good to
excellent yields of the product in 100% atom economy.
Asensio, G.; Cuenca, A. B. Org. Lett. 2010, 12, 1900. (b) Wang, H.;
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(8) Tang, R.-Y.; Luo, P.-S.; Zhang, X.-G.; Li, J.-H.; Zhong, P. Synlett
2010, 2010, 1345.
(9) (a) Modi, A.; Ali, W.; Patel, B. K. Org. Lett. 2017, 19, 432.
(b) Palsuledesai, C. C.; Murru, S.; Sahoo, S. K.; Patel, B. K. Org. Lett.
2009, 11, 3382. (c) Bedane, K. G.; Singh, G. S. ARKIVOC 2015, No. v,
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(10) Ali, W.; Dahiya, A.; Pandey, R.; Alam, T.; Patel, B. K. J. Org.
Chem. 2017, 82, 2089.
ASSOCIATED CONTENT
■
S
* Supporting Information
(11) (a) Szamosvar
Chem. Commun. 2016, 52, 13440. (b) Prothiwa, M.; Szamosvar
́
i, D.; Reichle, V. F.; Jureschi, M.; Bottcher, T.
̈
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02993.
́
i, D.;
Glasmacher, S.; Bottcher, T. Beilstein J. Org. Chem. 2016, 12, 2784.
̈
(c) Yamaguchi, T.; Watanabe, S.; Matsumura, Y.; Tokuoka, Y.;
Yokoyama, A. Chem. Pharm. Bull. 2012, 60, 508.
X-ray data for 3a (CIF)
(12) (a) Bergman, J.; Pettersson, B.; Hasimbegovic, V.; Svensson, P.
Experimental procedures, spectral and analytical data of
all products (PDF)
H. J. Org. Chem. 2011, 76, 1546. (b) Escribano, J.; Rivero-Hernan
C.; Rivera, H.; Barros, D.; Castro-Pichel, J.; Perez-Herran, E.;
Mendoza-Losana, A.; Angulo-Barture n, I.; Ferrer-Bazaga, S.;
Jimenez-Navarro, E.; Ballell, L. ChemMedChem 2011, 6, 2252.
́
dez,
́
́
AUTHOR INFORMATION
́
■
(13) (a) Ding, Q.; Wu, J. J. Comb. Chem. 2008, 10, 541. (b) Ding, Q.;
Cao, B.; Zong, Z.; Peng, Y. J. Comb. Chem. 2010, 12, 370. (c) Zhao, P.;
Liao, Q.; Gao, H.; Xi, C. Tetrahedron Lett. 2013, 54, 2357. (d) Wang,
B.; Sun, S.; Yu, J.-T.; Jiang, Y.; Cheng, J. Org. Lett. 2017, 19, 4319.
Corresponding Author
*E-mail: patel@iitg.ernet.in.
ORCID
Bhisma K. Patel: 0000-0002-4170-8166
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
B.K.P. acknowledges the support of this research by the
Department of Science and Technology (DST/SERB) (EMR/
2016/007042), DST-FIST, and MHRD: 5-5/2014-TS-VII.CIF,
IIT Guwahati for instrumental facilitities. A.M. thanks the CSIR
for a fellowship.
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DOI: 10.1021/acs.orglett.7b02993
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