Bronsted acid catalyzed cyclization of propargylic alcohols with thioamides. Facile synthesis of Di- and trisubstituted thiazoles

Article abstract of DOI:10.1021/jo101292r

Figure presented. A general and efficient method to prepare 2,4-di- and trisubstituted thiazoles via p-TsOH·H₂O-catalyzed cyclization of trisubstituted propargylic alcohols with thioamides is described. The reaction was accomplished in moderate to excellent product yields under mild conditions that did not require the exclusion of air and moisture and offers an operationally simplistic and convenient route to this synthetically useful aromatic heterocycle.

Full text of DOI:10.1021/jo101292r

pubs.acs.org/joc
methodologies to functionalized thiazoles with selective
Brønsted Acid Catalyzed Cyclization of Propargylic
Alcohols with Thioamides. Facile Synthesis of Di- and
Trisubstituted Thiazoles
control of substitution patterns are still needed. This is all
the more so if it can be accomplished with low cost and
readily available starting materials and catalysts that follow
the principles of atom economy.5 One such synthetic strategy
has been to replace the electrophile in these reactions with a
propargylic alcohol in the presence of a Lewis acid catalyst.4,6
According to the seminal reports by the groups of Zhan4a
and Yoshimatsu,4b these catalytic systems are thought
to proceed via either an allenic or propargylic cationic
species that underwent the [3 þ 2] cycloaddition process.
Although shown to be efficient, producing H2O as poten-
tially the only byproduct, this was countered by the like-
lihood of forming metal impurities that lessened the poten-
tial of this approach for scale-up applications. Added to this
is a substrate scope that is limited to ones containing func-
tional groups that cannot take part in strong metal co-
ordination. In this regard, we reasoned that these drawbacks
could be readdressed by developing a Brønsted acid-cata-
lyzed version of this regioselective thiazole forming reac-
tion. An inexpensive and commercially available reagent
class that has a high tolerance to air and moisture, Brønsted
acids have been shown to mediate a wide variety of organic
transformations in an efficient and selective manner.7-9
Recently, this has included stereoselective C-X (X = C,
N, O, S) bond formation strategies that combine the use of
Brønsted acid catalysis with alcohol pro-electrophiles such
as allylic, benzylic, and propargylic alcohols.8,9 For example,
we recently reported TfOH to be a highly efficient catalyst
Xiaoxiang Zhang, Wan Teng Teo, Sally, and
Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of
Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637616, Singapore
waihong@ntu.edu.sg
Received June 30, 2010
A general and efficient method to prepare 2,4-di- and
trisubstituted thiazoles via p-TsOH H2O-catalyzed cycli-
3
zation of trisubstituted propargylic alcohols with thioa-
mides is described. The reaction was accomplished in
moderate to excellent product yields under mild condi-
tions that did not require the exclusion of air and moisture
and offers an operationally simplistic and convenient
route to this synthetically useful aromatic heterocycle.
(2) For selected recent examples, see: (a) Shi, B.; Blake, A. J.; Lewis, W.;
Campbell, I. B.; Judkins, B. D.; Moody, C. J. J. Org. Chem. 2010, 75, 152.
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Kirsch, G.; Seck, P. Tetrahedron 2009, 65, 2982. (c) Kaleta, Z.; Makowski,
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Org. Lett. 2004, 6, 3083. (f) Rivkin, A.; Cho, S. S.; Gabarda, A. E.;
Yoshimura, F.; Danishefsky, S. J. J. Nat. Prod. 2004, 67, 139. (g) Ganesh,
T.; Schilling, J. K.; Palakodety, R. K.; Ravindra, R.; Shanker, N.; Bane, S.;
Kingston, D. G. I. Tetrahedron 2003, 59, 9979. (h) DeRoy, P. L.; Charette,
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(3) Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20, 3118.
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Chem. 2010, 8, 3259. (b) Yoshimatsu, M.; Yamamoto, T.; Sawa, A.; Kato, T.;
Tanabe, G.; Muraoka, O. Org. Lett. 2009, 11, 2952.
Thiazoles are important structural moieties found in many
natural products and compounds of current biological and
material interest as well as versatile building blocks in
organic synthesis.1-4 Among the myriad reactions devoted
to the construction of this aromatic heterocycle,1-4 the most
often relied upon synthetic method is the Hantzsch thiazole
synthesis,3 which makes use of R-halo ketones and thioa-
mides as the substrates. While recent efforts have led to a
number of advances made in the development of this
reaction,1,4 the establishment of more versatile and flexible
(5) (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (b) Trost, B. M. Science
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(6) For reviews on the use of alcohols as pro-electrophiles, see:
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N.; Kann, N. Angew. Chem., Int. Ed. 2009, 48, 642. (c) Muzart, J. Tetrahedron
2008, 64, 5815. (d) Muzart, J. Eur. J. Org. Chem. 2007, 3077. (e) Muzart, J.
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Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999.
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(b) Chen, B.; Heal, W. Five-Membered Rings with Two Heteroatoms, Each
with Their Fused Carbocyclic Derivatives. In Comprehensive Heterocyclic
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Eds.; Pergamon: New York, 2008; Vol. 4, p 635. (c) Wu, Y.-J.; Yang, B. V.
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Published on Web 08/26/2010
DOI: 10.1021/jo101292r
r
2010 American Chemical Society

Zhang et al.
JOCNote
SCHEME 1. p-TsOH H2O-Catalyzed Formation of 2,4-Di-
and Trisubstituted Thiazoles from Propargylic Alcohols and
Thioamides
TABLE 1. Optimization of the Reaction Conditionsa
3
entry
catalyst
solvent
yield (%)
1
p-TsOH H2O
3
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
MeNO2
MeCN
1,4-dioxane
PhMe
MeNO2
MeNO2
MeNO2
90
86
39
81
87
25
86
73
70
59
2
p-TsOH H2Ob
p-TsOH H2O
3
3c
4
3
p-TsOH H2O
p-TsOH H2O
3
for the regioselective formation of conjugated enynes based
on nucleophilic ring-opening of 1-cyclopropyl-2-propyn-1-
ols with alcohols.8b As part of an ongoing program exploring
the utility of alcohol pro-electrophiles in organic synthesis,8b,9
5
6
7
8
9
10
3
p-TsOH H2O
p-TsOH H2O
3
3
TfOH
TFA
H3PO4
d
we report herein p-TsOH H2O-catalyzed cyclization of
3
aUnless stated otherwise, all reactions were performed at 100 °C for
trisubstituted propargylic alcohols with thioamides that
did not require air- and moisture-free conditions (Scheme 1).
The 2,4-di- and trisubstituted thiazole products were ob-
tained as a single regioisomer in moderate to excellent yields
comparable to those noted for the closely related metal-
promoted approaches to this aromatic heterocycle.4 To our
knowledge, a synthetic approach to thiazoles from trisub-
stituted propargylic alcohols catalyzed by a Brønsted acid is
not known.
5 h with a catalyst/1a/2a ratio of 1:10:20. bReaction conducted with
5 mol % of p-TsOH H2O. cReaction conducted at room temperature.
3
dUsed as a 80% solution in H2O.
ging the solvent from 1,2-dichloroethane to MeNO2, MeCN,
1,4-dioxane, or toluene (entries 3-7). A similar outcome was
found when stronger Brønsted acid catalysts in place of
p-TsOH H2O were examined (entries 8-10). In these latter
3
reactions, the use of 10 mol % of TfOH, TFA, and H3PO4 in
MeNO2 gave 3a in lower yields of 59-73%. On the basis
of these studies, reaction of 1a with 2a in the presence of
We began by choosing 1,1,3-triphenylprop-2-yn-1-ol 1a
and thioacetamide 2a as the model substrates to establish the
reaction conditions (Table 1). This initially revealed that
subjecting 1 equiv of 1a and 2 equiv of 2a to 10 mol % of p-
5 mol % of p-TsOH H2O in 1,2-dichloroethane at 100 °C
3
for 5 h was deemed to provide the optimal conditions. By
applying these conditions, we were pleased to find that a
product yield of 927 mg (77%) could be afforded when the
reaction was repeated on a large scale with 1 g (3.52 mmol) of
1a and 0.53 g (7.04 mmol) of 2a.
TsOH H2O in 1,2-dichloroethane at 100 °C for 5 h gave the
3
best result (entry 1). Under these conditions, 4-benzhydryl-2-
methyl-5-phenylthiazole 3a was afforded in 90% yield, com-
parable to those obtained for the closely related Sc- and Ag-
catalyzed reactions.4 The structure and regiochemistry of
1
To define the generality of the present procedure, we next
examined a series of propargylic alcohols 1b-w and thioa-
mides 2a-h (Table 2). Reactions of propargylic alcohols
bearing either an electron-withdrawing or electron-donating
group on the carbinol or alkyne carbon with 2a gave the
corresponding thiazoles in good to excellent yields (entries
1-13). Similarly, the analogous cyclizations with starting
alcohols containing either an alkyl functional group at R1 or
R3 or a terminal alkyne moiety afforded 3o-q in 54-79%
yield, albeit requiring a catalyst loading of 30 mol % (entries
14, 15, and 17). In contrast, recovery of both the propargylic
alcohol and thioamide was found when both substituents on
the carbinol carbon of the alcohol substrate were an alkyl
functional group as in 1q (entry 16). A propargylic alcohol
containing an acid-sensitive acetylenic ketone moiety was
also examined under the standard conditions but was found
to give a mixture of decomposition products that could not
be identified by 1H NMR analysis of the crude mixture
(entry 22). On the other hand, propargylic alcohols bearing
a nitrile, thiophene, or carboxamide moiety were found to
proceed well under the present conditions and give the corre-
sponding thiazoles 3e, 3r, and 3s (at a catalyst loading of
30 mol %) in excellent yields (entries 4, 18, and 19). Addi-
tionally, reactions of starting alcohols 1a and 1c with other
thioamide nucleophiles were found to give the corresponding
thiazoles in moderate to excellent yields (entries 23-29). This
included one example of a cyclic thioamide (2b) that gave 3t
the thiazole product were determined on the basis of H
NMR measurements and X-ray crystallographic analysis (see
Figure S33 in the Supporting Information).10 A slightly lower
product yield of 86% was obtained on decreasing the catalyst
loading from 10 to 5 mol % (entry 2). In contrast, lower pro-
duct yields were found when the reaction was repeated with
10 mol % of p-TsOH H2O at room temperature or on chan-
3
(8) For selected examples on Brønsted acid-catalyzed reactions with
alcohol pro-electrophiles, see: (a) Jin, T.; Himuro, M.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2009, 48, 5893. (b) Mothe, S. R.; Chan, P. W. H.
J. Org. Chem. 2009, 74, 5887. (c) Bras, J. L.; Muzart, J. Tetrahedron 2007, 63,
ꢀ
ꢀ
7942. (d) Sanz, R.; Martınez, A.; Guilarte, V.; Alvarez-Gutierrez, J. M.;
Rodrıguez, F. Eur. J. Org. Chem. 2007, 4642. (e) Sanz, R.; Miguel, D.;
ꢀ
ꢀ
Martınez, A.; Alvarez-Gutierrez, J. M.; Rodrıguez, F. Org. Lett. 2007, 9,
2027. (f) Sanz, R.; Martınez, A.; Miguel, D.; Alvarez-Gutierrez, J. M.;
ꢀ
ꢀ
Rodrıguez, F. Org. Lett. 2007, 9, 727. (g) Shirakawa, S.; Kobayashi, S.
ꢀ
Org. Lett. 2007, 9, 311. (h) Sanz, R.; Martınez, A.; Miguel, D.; Alvarez-
ꢀ
Gutierrez, J. M.; Rodrıguez, F. Adv. Synth. Catal. 2006, 348, 1841.
(i) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda,
ꢀ
K. Angew. Chem., Int. Ed. 2006, 45, 2605. (j) Sanz, R.; Martınez, A.; Alvarez-
ꢀ
Gutierrez, J. M.; Rodrıguez, F. Eur. J. Org. Chem. 2006, 1383. (k) Young,
J.-J.; Jung, L.-J.; Cheng, K.-M. Tetrahedron Lett. 2000, 41, 3415.
(9) For selected recent works by us see: (a) Kothandaraman, P.; Rao, W.;
Foo, S. J.; Chan, P. W. H. Angew. Chem., Int. Ed. 2010, 49, 4619. (b)
Kothandaraman, P.; Foo, S. J.; Chan, P. W. H. J. Org. Chem. 2009, 74, 5947.
(c) Zhang, X.; Teo, W. T.; Chan, P. W. H. Org. Lett. 2009, 11, 4990. (d) Rao, W.;
Zhang, X.; Sze, E. M. L.; Chan, P. W. H. J. Org. Chem. 2009, 74, 1740. (e) Rao,
W.; Chan, P. W. H. Chem.;Eur. J. 2008, 14, 10486.
(10) CCDC 753779-753780 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
J. Org. Chem. Vol. 75, No. 18, 2010 6291

Zhang et al.
JOCNote
TABLE 2. Synthesis of Substituted Thiazoles 3b-z Catalyzed by
SCHEME 2. Tentative Mechanism for p-TsOH H2O-Cata-
lyzed Cyclization of 1 with 2
3
p-TsOH H2Oa
3
yield
(%)
entry
1, R1/R2/R3
2, R4
2a, Me
3
1
2
3
4
5
6
7
8
9
1b, 4-FC6H4/Ph/Ph
1c, 4-ClC6H4/Ph/Ph
1d, 4-BrC6H4/Ph/Ph
1e, 4-CNC6H4/Ph/Ph
1f, 4-MeC6H4/Ph/Ph
1g, 4-FC6H4/4-FC6H4/Ph
1h, 4-ClC6H4/4-ClC6H4/Ph
1i, 4-BrC6H4/4-BrC6H4/Ph
1j, 4-MeC6H4/4-MeC6H4/Ph
3b
3c
3d
3e
3f
3g
3h
3i
96
98
93
98
79
94
85
88
74
86
87
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3j
3k
3l
10 1k, Ph/Ph/4-FC6H4
11 1l, Ph/Ph/4-ClC6H4
12 1m, Ph/Ph/4-MeC6H4
13 1n, Ph/Ph/4-MeOC6H4
14b 1o, i-Pr/Ph/Ph
3m 89
3n
3o
3p
69
76
79
c
54
96
78
75
72
d
15b 1p, Ph/Ph/n-Bu
16 1q, Me/Me/Ph
17b 1r, Ph/Ph/H
3q
3r
3s
4a
4b
18 1s, 4-ClC6H4/4-ClC6H4/2-thienyl 2a
unfavorable steric interactions between the incoming nu-
cleophile and these substituents of the cationic species.12
Indeed, our earlier findings showing the exclusive formation
of the N-propargylation adduct in cases where less sterically
demanding secondary alcohols were examined would be
consistent with the influence of such steric interactions on
the regioselectivities found (entries 20 and 21 in Table 2). We
surmise the origin of the chloro-substituted thiazole 3t could
be due to ring-opening of the iminium cation D0 by a chloride
anion generated in situ from the 1,2-dichloroethane solvent
under the acidic conditions.
In summary, we have developed a Brønsted acid-catalyzed
method for the cyclization of tertiary propargylic alcohols
with thioamides as an efficient approach to 2,4-di- and tri-
substituted thiazoles under conditions that did not require
the exclusion of air and moisture. The reaction was shown
to be applicable to a broad substrate scope that compliments
the metal-mediated versions of this transformation.4 More-
over, the possibility of the present operationally simplistic
method as a potential regioselective scale-up strategy for thi-
azole synthesis was exemplified by the large-scale prepara-
tion of one example in excellent yield. This is notable given
the recent demand for more rapid and direct atom economic-
al chemical processes that can make use of low cost and
readily available reagents and catalysts.
19b 1t, Ph/Ph/(CH2)2CONHPh
20 1u, H/Ph/Ph
21 1v, H/4-FC6H4/4-BrC6H4
2a
2a
2a
2a
22 1w, Ph/Ph/COCtCPh
23 1a
24 1c
25 1c
26 1c
27 1c
28 1c
29 1c
2b, -(CH2CH2)- 3t
2c, Ph
2d, 4-FC6H4
2e, 4-ClC6H4
2f, 2-ClC6H4
2g, 4-BrC6H4
30
91
92
3u
3v
3w 90
3x
3y
93
93
97
2h, 4-MeOC6H4 3z
aAll reactions were performed at 100 °C for 1.5-24 h with
p-TsOH H2O/1/2 ratio = 1:20:40.11 bReaction conducted at 30 mol %
3
catalyst loading. cNo reaction based on TLC and 1H NMR analysis of the
crude mixture after a reaction time of 24 h. dMixture of side products obtained
that could not be identified by 1H NMR analysis of the crude mixture.
and the structure of which was confirmed by X-ray crystal-
lography (entry 23 and Figure S34 in Supporting Information-
).10 In our hands, reactions of secondary alcohols 1u and 1v were
the only instances where the corresponding N-propargylation
products 4a and 4b were preferentially obtained as the sole
product in 75 and 72% yield, respectively (entries 20-21). This
contrasts markedly to a recent work reporting p-TsOH H2O to
3
catalyze the reaction of a closely related secondary propargylic
alcohol and thioamide in chlorobenzene giving the correspond-
ing thiazole in 12% yield.4a
We tentatively propose the mechanism of the present
reaction to proceed in a manner similar to that described
for the analogous metal-catalyzed cyclizations of di- and
trisubstituted propargylic alcohols with thioamides.4 As
depicted in Scheme 2, this could involve Brønsted acid-
mediated dehydration of 1 to deliver alkynyl cation species
B and its allenic resonance form C. Subsequent attack by the
thioamide at the sterically less hindered acetylenic carbon
center of B or allenic carbcation center C when followed by
5-exo-trig cyclization of the newly formed intermediate D
would then provide the thiazole product. It might be antici-
pated that trapping at the sterically less hindered carbon
center of B or C when R1 and/or R2 = aryl would limit any
Experimental Section
Representative Procedure for p-TsOH H2O-Catalyzed Synth-
esis of 2,4-Di- and Trisubstituted Thiazoles 3. To a 5 mL round-
bottom flask containing 1,2-dichloroethane (3 mL) were successively
added 1a (0.25mmol),2a (0.5 mmol) and p-TsOH H2O(12.5μmol).
3
3
The resultant reaction mixture was heated to 100 °C and stirred for
(11) See the Supporting Information for the reaction times.
(12) For similar regioselectivties observed in other reactions with pro-
pargylic cations, see refs 8f, 9c, and: (a) Huang, W.; Shen, Q. S.; Wang, J. L.;
Zhou, X. G. J. Org. Chem. 2008, 73, 1586. (b) Ishikawa, T.; Aikawa, T.;
Mori, Y.; Saito, S. Org. Lett. 2003, 5, 51. (c) Ishikawa, T.; Okano, M.;
Aikawa, T.; Saito, S. J. Org. Chem. 2001, 66, 4635. (d) Edens, M.; Boerner,
D.; Chase, C. R.; Nass, D.; Schiavelli, M. D. J. Org. Chem. 1977, 42, 3403.
6292 J. Org. Chem. Vol. 75, No. 18, 2010

Zhang et al.
JOCNote
5 h. On cooling to room temperature, the reaction mixture was
concentrated under reduced pressure, and the residue obtained was
directly purified by flash column chromatography on silica gel
(eluent: n-hexane/EtOAc = 8:1) to give the title compound.
4-Benzhydryl-2-methyl-5-phenylthiazole (3a): white solid; mp
163-164 °C; 1H NMR (CDCl3, 400 MHz) δH 2.65 (s, 3H), 5.51
(s, 1H), 7.17-7.19 (m, 2H), 7.20-7.27 (m, 8H), 7.36-7.37 (m,
5H); 13C NMR (CDCl3, 100 MHz) δC 19.5, 50.0, 126.4, 128.1,
128.3, 128.7, 129.2, 129.9, 132.0, 133.3, 143.4, 151.6, 163.9; IR
(neat) 3019, 1599, 1533, 1493, 1215, 1074, 1030, 669, 634, 617,
584, 507 cm-1; MS (ESI) m/z 342 [M þ H]þ; HRMS (ESI) calcd
for C23H20NS 342.1316, found 342.1316.
Acknowledgment. This work is supported by a University
Research Committee Grant (RG55/06) from Nanyang
Technological University and Science and Engineering
Research Council Grant (092 1010 053) from A*STAR,
Singapore.
Supporting Information Available: Characterization data
and 1H and 13C NMR spectra for the starting alcohols 1, thia-
zole products 3, and N-propargylation adducts 4 and X-ray data
for compounds 3a and 3t (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 18, 2010 6293