Base-Induced Cyclization of Active Methylene Isocyanides with Xanthate Esters: An Efficient Method for the Synthesis of 5-Alkoxy-4-(tosyl/ethoxycarbonyl)-1,3-thiazoles

Article abstract of DOI:10.1055/s-0036-1590811

Sodium hydride-induced cyclization of 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene or ethyl isocyanoacetate with various xanthate esters gave 5-alkoxy-4-tosylthiazoles or ethyl 5-alkoxythiazol-4-ylcarboxylates, respectively, in good to excellent yields. The xanthate ester S -methyl O -phenyl dithiocarbonate gave 5-(methylsulfanyl)-4-tosyl-1,3-thiazole when treated with 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene under similar conditions.

Full text of DOI:10.1055/s-0036-1590811

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
N. Rajeev et al.
Letter
Synlett
Base-Induced Cyclization of Active Methylene Isocyanides with
Xanthate Esters: An Efficient Method for the Synthesis of 5-
Alkoxy-4-(tosyl/ethoxycarbonyl)-1,3-thiazoles
Narasimhamurthy Rajeeva
Toreshettahally R. Swaroopb
Seegehalli M. Anila
Yadaganahalli K. Bommegowdaa
0
0
0
0
0-
0
0
2
0-
1
7
4
2-
9
2
5
Kanchugarakoppal S. Rangappa*a,c
Marilinganadoddi P. Sadashiva*a,c
a Department of Studies in Chemistry, University of Mysore,
Manasagangothri, Mysuru, Karnataka 570 006, India
b Department of Studies in Organic Chemistry, University of
Mysore, Manasagangothri, Mysuru, Karnataka 570 006, India
c Institution of Excellence, Vijnana Bhavan, University of
Mysore, Manasagangothri, Mysuru, Karnataka 570 006, India
mpsadashiva@gmail.com
rangappaks@gmail.com
Received: 15.04.2017
Accepted after revision: 02.06.2017
Published online: 13.07.2017
with thioamides,16 and others.17 Despite the availability of
these methods, more synthetic routes for the synthesis of
thiazole are still in demand, because the above-mentioned
methods suffer from limitations such as difficulties in han-
dling α-halocarbonyl compounds,11 the use of nonecof-
riendly solvents such as chloroform,12 the use of less-stable
substrates such as isothiocyanates,13 or the need for high
temperatures or long reaction times.15
DOI: 10.1055/s-0036-1590811; Art ID: st-2017-b0262-l
Abstract Sodium hydride-induced cyclization of 1-[(isocyanometh-
yl)sulfonyl]-4-methylbenzene or ethyl isocyanoacetate with various
xanthate esters gave 5-alkoxy-4-tosylthiazoles or ethyl 5-alkoxythiazol-
4-ylcarboxylates, respectively, in good to excellent yields. The xanthate
ester S-methyl O-phenyl dithiocarbonate gave 5-(methylsulfanyl)-4-to-
syl-1,3-thiazole when treated with 1-[(isocyanomethyl)sulfonyl]-4-
methylbenzene under similar conditions.
Thiazoles unsubstituted in the 2-position can be syn-
thesized by cycloaddition of isocyanides with carbon disul-
fide,18a,b thiono esters,18c isothiocyanates,18d,e or car-
boxymethyl dithioates.18f In this context, we have reported
the synthesis of 2,4-disubstituted thiazoles from methyl
dithiocarboxylates and active methylene isocyanides.19 On
the other hand, xanthate esters are well known substrates
that are used in Tschugaeff reactions,20 Barton–McCombie
reactions,21 and Claisen rearrangements22 as well as in syn-
theses of natural products.23 They are also useful interme-
diates in syntheses of thiols,24 thiocarbonates,25 carban-
ions,26 or photosensitizers.27 However, the applications of
these reagents in cycloaddition reactions with isocyanides
have not yet been explored. In continuation of our work on
the development of new methods for the synthesis of het-
erocyclic compounds,19,28 we report the cyclization of active
methylene isocyanides such as 1-[(isocyanomethyl)sulfo-
nyl]-4-methylbenzene or ethyl isocyanoacetate with xan-
thate esters in the presence of a base to give thiazoles with
diverse substituents. The required xanthate esters 2a–g
were synthesized in high yields by the reaction of the corre-
sponding alcohols 1 with carbon disulfide in the presence
of sodium hydroxide and methyl iodide in THF (Scheme 1).
Key words thiazoles, isocyanides, xanthate esters, cyclization
Thiazoles are an important class of heterocyclic com-
pounds because of their applications as antimicrobial
agents,1 antiprotozoal agents,2 antimalarial agents,3 anti-
mycobacterial antitubercular agents,4 microtubule-target-
ing drugs,5 and anticancer agents.6 They also exhibit inhibi-
tory activities against histone acetyltransferase,7 PIN1,8
platelet aggregation,9 rho kinase,10 and tubulin polymeriza-
tion.11. Because of these properties, the development of
new synthetic methods for thiazoles is an area of para-
mount importance. The most commonly used method is
the Hantzsch synthesis, which involves the reaction be-
tween α-halocarbonyl compounds and thioureas or thio-
amides.11 Other methods include the reaction of aryl N,N-
diformylaminomethyl ketones with phosphorus pentasul-
fide in chloroform,12 coupling of oxime acetates with iso-
thiocyanates catalyzed by copper,13 the reaction of propar-
gyl bromides with thioureas,14 the reaction of α-amido β-
keto esters with Lawesson’s reagent,15 the reaction of 1H-1-
(alkyn-1-yl)-5-methyl-1,2,3-benziodoxathiole 3,3-dioxides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
N. Rajeev et al.
Letter
Synlett
R1
O
S
(i) CS2/NaOH/THF
(ii) MeI
2–3 h
R1
S
N
S
R1
H
NaH/DMF
C
O
O
SMe
R1
R2
N
O
SMe
2a–f
0 °C-RT, 10–20 min
R2
1
2
4a–f
4g–i
R
2 = Ts, 3a
R2 = CO2Et, 3b
S
S
S
O
SMe
O
SMe
O
SMe
MeO
S
S
S
O
O
O
OMe
2a (94%)
2b (90 %)
2c (84%)
N
N
N
S
S
S
O
O
O
S
S
O
S
O
O
4a (92%)
4b (82%)
4c (88%)
O
SMe
O
SMe
O
SMe
Br
Br
2d (88%)
2e (90%)
2f (92%)
S
S
S
O
O
S
O
S
N
N
N
S
S
O
O
SMe
O
O
O
O
O
2g (94%)
4d (84%)
4e (91%)
4f (92%)
Scheme 1 Synthesis of xanthate esters 2a–g
We started with the cycloaddition reaction of O-benzyl
S-methyl dithiocarbonate (2a) with 1-[(isocyanometh-
yl)sulfonyl]-4-methylbenzene (3a) in the presence of sodi-
um hydride as the base of choice in various solvents (DMF,
THF, acetonitrile, toluene, DMSO, or 1,4-dioxane) to give 5-
(benzyloxy)-4-tosyl-1,3-thiazole (4a) (Scheme 2). The reac-
tion proceeded smoothly in DMF or acetonitrile in 15 min-
utes and eight hours, respectively to give thiazole 4a in 92%
and 73% yield, respectively. Thus, preliminary screening
suggested that DMF is the best solvent for carrying out the
reaction. Next, we started exploring the general applicabili-
ty of this method by using various O-arylmethyl S-methyl
dithiocarbonates. Thus, O-arylmethyl S-methyl dithiocar-
bonates 2b–d with a methyl, methoxy, or bromo substitu-
ent at the 2-, 3-, or 4-position of the aryl ring smoothly un-
derwent cyclization with isocyanide 3a to give the corre-
sponding thiazoles 4b–d in 82–88% yield (Scheme 2).
Furthermore, O-butyl S-methyl dithiocarbonate (2e) and O-
(3-methylcyclohexyl)-S-methyl dithiocarbonate (2f) simi-
larly gave the respective 5-(alkoxy)-4-tosyl-1,3-thiazoles 4e
and 4f in 91% and 92% yield, respectively (Scheme 2).
In the next stage, we replaced 1-[(isocyanomethyl)sulfo-
nyl]-4-methylbenzene (3a) with ethyl isocyanoacetate (3b)
in the cyclization reaction under similar condition. Thus,
xanthate esters 2a, 2c, and 2e gave the thiazolecarboxylates
4g, 4h, and 4i, respectively, in 63–70% yield (Scheme 2).
Finally, cyclization of 1-[(isocyanomethyl)sulfonyl]-4-
methylbenzene (3a) with S-methyl O-phenyl dithiocarbon-
ate gave 5-(methylsulfanyl)-4-tosyl-1,3-thiazole (4j) in 94%
yield under the optimized reaction conditions (Scheme 3).
The ORTEP diagram for 5-[(4-bromobenzyl)oxy]-4-to-
syl-1,3-thiazole (4d)29 is shown in Figure 1.
MeO
S
S
S
O
O
O
N
N
N
EtO
EtO
EtO
O
O
O
4g (70%)
4h (68%)
4i (63%)
Scheme 2 Synthesis of 5-(alkoxy)-4-(tosyl/ethoxycarbonyl)-1,3-thi-
azoles 4a–i
S
S
NaH/DMF
MeS
C
+
Ph
0 °C-RT, 10–20 min
Ts
N
N
O
SMe
Ts
4j (94%)
2g
3a
Scheme 3 Reaction of O-phenyl S-methyl dithiocarbonate with 1-[(iso-
cyanomethyl)sulfonyl]-4-methylbenzene (3a)
A probable mechanism for the formation of the thi-
azoles is depicted in Scheme 4. It involves abstraction of a
proton from the active methylene group of isocyanide 3 to
give a stable carbanion 5, which undergo condensation
with xanthate ester 2 to give intermediate 6. Abstraction of
another acidic proton from 6 gives a resonance-stabilized
carbanion 7 that undergoes cyclization to give the thiazole
carbanion 8. Protonation of 8 during workup yields the thi-
azole 4.18f A similar cyclization mechanism can be proposed
for the formation of thiazole 4j, except that phenol is a by-
product from the condensation step.
In conclusion, we have reported the cyclization of 5-[(4-
bromobenzyl)oxy]-4-tosyl-1,3-thiazole or ethyl isocyano-
acetate with xanthate esters30 induced by sodium hydride
in DMF solvent to give 5-alkoxy-4-(tosyl/ethoxycarbonyl)-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
N. Rajeev et al.
Letter
Synlett
S
S
S
R1O
SMe
R1O
C
R1O
NaH
–H2
C
NaH
–H2
2
C
C
R2
N
N
R2
N
N
–MeS
R2
7
R2
3
5
6
S
R1O
R1O
H+
R1O
C
S
N
S
N
N
R2
R2
R2
4a–i
8
7
Scheme 4 Probable mechanism for the formation of thiazoles
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590811.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References and Notes
(1) Liaras, A.; Geronikaki, A.; Glamočlija, J.; Ćirić, A.; Soković, M.
Bioorg. Med. Chem. 2011, 19, 3135.
(2) (a) Verge, J. P.; Roffey, P. J. Med. Chem. 1975, 18, 794. (b) Nava-
Zuazo, C.; Chávez-Silva, F.; Moo-Puc, R.; Chan-Bacab, M. J.;
Ortega-Morales, B. O.; Moreno-Diaz, H.; Díaz-Coutiño, D.;
Hernández-Núñez, E.; Navarrete-Vázquez, G. Bioorg. Med. Chem.
2014, 22, 1626.
(3) Hamzé, A.; Rubi, E.; Arnal, P.; Boisbrun, M.; Carcel, C.; Salom-
Roig, X.; Maynadier, M.; Wein, S.; Vial, H.; Calas, M. J. Med. Chem.
2005, 48, 3639.
(4) Shiradkar, M. R.; Murahari, K. K.; Gangadasu, H. R.; Suresh, T.;
Kalyan, C. A.; Panchal, D.; Kaur, R.; Barange, P.; Ghogare, J.;
Mokale, V.; Raut, M. Bioorg. Med. Chem. 2007, 15, 3997.
(5) Romagnoli, R.; Baraldi, P. G.; Brancale, A.; Ricci, A.; Hamel, E.;
Bortolozzi, R.; Basso, G.; Viola, G. J. Med. Chem. 2011, 54, 5144.
(6) (a) Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Camacho, M. E.;
Preti, D.; Tabrizi, M. A.; Bassetto, M.; Brancale, A.; Ernest, H.;
Bortolozzi, R.; Basso, G.; Viola, G. Bioorg. Med. Chem. 2012, 20,
7083. (b) Lu, Y.; Li, C.-M.; Wang, Z.; Ross, C. R. II.; Chen, J.;
Dalton, J. T.; Li, W.; Miller, D. D. J. Med. Chem. 2009, 52, 1701.
(7) Secci, D.; Carradori, S.; Bizzarri, B.; Bolasco, A.; Ballario, P.;
Patramani, Z.; Fragapane, P.; Vernarecci, S.; Canzonetta, C.;
Filetici, P. Bioorg. Med. Chem. 2014, 22, 1680.
Figure 1 ORTEP diagram for 5-[(4-bromobenzyl)oxy]-4-tosyl-1,3-thi-
azole (4d)
1,3-thiazoles.31 During the aromatization, methanethiol is
regioselectively eliminated to give the corresponding thi-
azoles. However, in the cyclization of 5-[(4-bromoben-
zyl)oxy]-4-tosyl-1,3-thiazole with S-methyl O-phenyl dith-
iocarbonate gave 5-(methylsulfanyl)-4-tosyl-thiazole with
highly regioselective elimination of phenol in the aromati-
zation–elimination step. As the protocol provides a rapid
synthesis of thiazoles, it can be considered as a base-in-
duced click reaction, similar to our earlier reported meth-
od.19
(8) Zhao, H.; Cui, G.; Jin, J.; Chen, X.; Xu, B. Bioorg. Med. Chem. 2016,
24, 5911.
(9) Rynbrandt, R. H.; Nishizawa, E. E.; Balogoyen, D. P.; Mendoza, R.;
Annis, K. A. J. Med. Chem. 1981, 24, 1507.
(10) Green, J.; Cao, J.; Bandarage, U. K.; Lao, H.; Court, J.; Marhefka,
C.; Jacobs, M.; Taslimi, P.; Newson, D.; Nakayama, T.; Shah, S.;
Rodems, S. J. Med. Chem. 2015, 58, 5028.
Acknowledgment
(11) Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20, 3118.
(12) Sheldrake, P. W.; Matteucci, M.; McDonald, E. Synlett 2006, 460.
(13) Tang, X.; Zhu, Z.; Qi, C.; Wu, W.; Jiang, H. Org. Lett. 2016, 18, 180.
(14) Castagnolo, M.; Pagano, M.; Bernardini, M.; Botta, M. Synlett
2009, 2093.
N.R. thanks the UGC for providing a fellowship. The authors are grate-
ful to IOE, University of Mysore, for performing the spectral charac-
terization. N.R. thanks the UGC for providing an RGNF. M.P.S. thanks
UGC-SAP DRS III for financial support.
(15) Sanz-Cervera, J. F.; Blasco, R.; Piera, J.; Cynamon, M.; Ibáñez, M.;
Murguía, M.; Fustero, S. J. Org. Chem. 2009, 74, 8988.
(16) Ishiwata, Y.; Togo, H. Synlett 2008, 2637.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
N. Rajeev et al.
Letter
Synlett
(17) (a) Narender, M.; Reddy, M. S.; Kumar, V. P.; Srinivas, R. S.;
Nageswar, Y. V. D.; Rao, K. R. Synthesis 2007, 3469. (b) Mustafa,
S. M.; Nair, V. A.; Chittoor, J. P.; Krishnapillai, S. Mini-Rev. Org.
Chem. 2004, 1, 375.
(30) O-Benzyl S-Methyl Dithiocarbonates 2a–g: General Proce-
dure
The appropriate benzylic alcohol 1a–g (10 mmol) was added to
a solution of NaOH (20 mmol) in THF (10 mL), and the mixture
was stirred at r.t. for 10 mins. The mixture was then cooled to
0 °C, CS2 (10 mmol) was added, and the mixture was stirred for
10 min. MeI (10 mmol) was then added at 0 °C, and the mixture
was stirred at r.t. for a further 2–3 h until the reaction was com-
plete (TLC). Ice-cold H2O (25 mL) was added, and the mixture
was extracted with EtOAc (2 × 25 mL). The organic layers were
combined, washed with H2O (25 mL) and brine (25 mL), dried
(Na2SO4), and concentrated under reduced pressure to give the
crude product that was purified by column chromatography
[silica gel, EtOAc–hexane, (1:9)].
(18) (a) Wildeman, J.; van Leusen, A. M. Synthesis 1979, 733.
(b) Schöllkopf, U.; Porsch, P.-H.; Blume, E. Justus Liebigs Ann.
Chem. 1976, 2122. (c) Hartman, G. D.; Weinstock, L. M. Synthesis
1976, 681. (d) Suzuki, M.; Moyira, T.; Matsumoto, K.; Miyoshi,
M. Synthesis 1982, 874. (e) van Nipsen, S. P. J. M.; Bregman, J. H.;
van Engen, D. G.; van Leusen, A. M.; Saikachi, H.; Kitagawa, T.;
Sasaki, H. Recl. Trav. Chim. Pays-Bas 1982, 101, 28. (f) Oldenziel,
O. H.; van Leusen, A. M. Tetrahedron Lett. 1972, 13, 2777.
(19) Lingaraju, G. S.; Swaroop, T. R.; Vinayaka, A. C.; Sharath Kumar,
K. S.; Sadashiva, M. P.; Rangappa, K. S. Synthesis 2012, 44, 1373.
(20) (a) Wells, P. R. Chem. Rev. 1963, 63, 171. (b) Koskikallio, J. Acta
Chem. Scand. 1969, 23, 1490. (c) Tschugaeff, L. Ber. Dtsch. Chem.
Ges. 1899, 32, 3332.
O-Benzyl S-Methyl Dithiocarbonate (2a)
Yellow viscous liquid; yield: 1.861 g (94%). IR (KBr): 622, 1051,
1185, 1203, 1609, 2920 cm–1 1H NMR (400 MHz, CDCl3):
.
(21) (a) Clive, D. L. J.; Wang, J. J. Org. Chem. 2002, 67, 1192.
(b) Barton, D. H. R.; Chen, M.; Jaszberenyi, J. C.; Rattingan, B.;
Tang, D. Tetrahedron Lett. 1994, 35, 6457.
(22) (a) Ferrier, R. J.; Vethavisar, N. J. Chem. Soc. D 1970, 1385.
(b) Hoefle, G. A.; Baldwin, J. E. J. Am. Chem. Soc. 1971, 93, 6307.
(23) (a) Curren, D. P. Synthesis 1988, 417. (b) Curren, D. P. Synthesis
1988, 489.
δ = 2.57 (s, 3 H, SMe), 5.63 (s, 2 H, CH2), 7.24–7.40 (m, 5 H, Ar-
H). 13C NMR (100 MHz, CDCl3): δ = 19.0, 75.1, 128.5, 128.6,
130.0, 134.7, 215.7. HRMS: m/z [M + H]+ calcd for C9H11OS2:
199.0000; found: 199.0173.
(31) 5-Alkoxy-4-(tosyl/ethoxycarbonyl)-1,3-thiazoles (4a–i) and
4-(Methylsulfanyl)-4-tosyl-1,3-thiazole (4j); General Proce-
dure
(24) Isola, M.; Ciuffarin, E.; Sagramora, L. Synthesis 1976, 326.
(25) (a) Degani, I.; Fochi, R.; Regondi, V. Synthesis 1981, 149.
(b) Baker, R.; O’Mahony, M.; Swain, C. J. J. Chem. Soc., Perkin
Trans 1 1987, 1623.
(26) (a) Degani, I.; Fochi, R.; Regondi, V. Synthesis 1979, 178.
(b) Tanaka, K.; Yamagishi, N.; Tanikaga, R.; Kaji, A. Bull Soc.
Chem. Jpn. 1979, 52, 3619.
A mixture of the appropriate xanthate ester 2 (2 mmol) and
active methylene isocyanide 3 (2 mmol) in DMF (1.5 mL) was
added dropwise to NaH (60% suspension in paraffin; 4 mmol) in
DMF (1.5 mL) at 0 °C. The mixture was stirred at r.t. for 10–20
min until the reaction was complete (TLC) then poured into sat.
aq NH4Cl (20 mL). The mixture was extracted with EtOAc (2 × 20
mL), and the EtOAc layers were combined, washed with H2O (20
mL) and brine (20 mL), dried (Na2SO4), and concentrated under
reduced pressure to give the crude product, which was purified
by column chromatography [silica gel, EtOA–hexane (2:8)].
5-(Benzyloxy)-4-tosyl-1,3-thiazole (4a)
(27) Okatawa, M.; Nakai, T.; Otsuji, Y.; Imoto, E. J. Org. Chem. 1965,
30, 2025.
(28) (a) Swaroop, T. R.; Roopashree, R.; Ila, H.; Rangappa, K. S. Tetra-
hedron Lett. 2013, 54, 147. (b) Swaroop, T. R.; Ila, H.; Rangappa,
K. S. Tetrahedron Lett. 2013, 54, 5288. (c) Vinayaka, A. C.;
Swaroop, T. R.; Prasanna Kumara, C.; Rangappa, K. S.; Sadashiva,
M. P. RSC Adv. 2016, 6, 11528. (d) Vinay Kumar, K. S.; Swaroop,
T. R.; Rajeev, N.; Vinayaka, A. C.; Lingaraju, G. S.; Rangappa, K. S.;
Sadashiva, M. P. Synlett 2016, 27, 1363.
(29) CCDC 1543222 contains the supplementary crystallographic
data for compound 4d. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
White solid; yield: 0.635 g (92%); mp 130–132 °C; IR (KBr): 626,
983, 1040, 1318, 1593, 2920 cm–1 1H NMR (400 MHz, CDCl3):
.
δ = 2.39 (s, 3 H, Ar-Me), 5.24 (s, 2 H, CH2), 7.26 (d, J = 8.0 Hz, 2 H,
Ar-H), 7.37–7.41 (m, 5 H, Ar-H), 7.92 (dd, J = 6.8, 2.0 Hz, 2 H, Ar-
H), 8.14 (s, 1 H, Ar-H). 13C NMR (100 MHz, CDCl3): δ = 21.6, 80.0,
127.9, 128.1, 128.8, 129.2, 129.6, 133.6, 135.0, 138.2, 140.3,
144.3, 163.7. HRMS: m/z [M + H]+ calcd for C17H16NO3S2:
346.0000; found: 346.0493.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D