3-Bromocyclohexane-1,2-dione as a useful reagent for Hantzsch synthesis of thiazoles and the synthesis of related heterocycles

Article abstract of DOI:10.1016/j.tetlet.2011.05.028

We describe the use of 3-bromocyclohexane-1,2-dione, an air stable, versatile reagent for the Hantzsch thiazole synthesis and the synthesis of other closely related heterocycles.

Full text of DOI:10.1016/j.tetlet.2011.05.028

Tetrahedron Letters 52 (2011) 3633–3635
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Tetrahedron Letters
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3-Bromocyclohexane-1,2-dione as a useful reagent for Hantzsch synthesis
of thiazoles and the synthesis of related heterocycles
⇑
Jason M. Guernon , Yong-Jin Wu
Department of Neuroscience Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the use of 3-bromocyclohexane-1,2-dione, an air stable, versatile reagent for the Hantzsch
thiazole synthesis and the synthesis of other closely related heterocycles.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 15 April 2011
Revised 29 April 2011
Accepted 5 May 2011
Available online 17 May 2011
Keywords:
3-Bromocyclohexan-1,2-dione
Hantzsch
Thiazole
Thiazoles are ubiquitous building blocks in medicinal chemistry
and can be found in numerous natural products (e.g., epothilone)
and biologically important compounds including the anticancer
drug dasatinib, antiviral clinical candidate TMC435350, and antidi-
abetic drug candidate MB06322.1–4 For a recent medicinal chemis-
try program, we looked to extend the utility of thiazoles to a
bicyclic thiazole ring system. In this context, we required the inter-
mediate 6,7-dihydrobenzo[d]thiazol-4(5H)-one 1 ( Fig. 1). Com-
pound 1 where R is methyl had previously been prepared via a
multi-step synthesis from diethyl 2-oxoheptanedioate 2.5 As this
method was not amenable to the rapid synthesis of various ana-
logs, we designed a more expedient route to 1 using a Hantzsch
reaction of 3-bromocyclohexane-1,2-dione 3 with appropriately
substituted thioamides. This reaction has not been investigated
in detail, although one example of Hantzsch thiazole synthesis
using bromodiketone 3 and thioamides 4 was described by Denon-
ne et al. in a patent application, but the yield was reported to be
only 20%.6 In contrast, 2-bromocyclohexane-1,3-dione 5 is widely
known to undergo Hantzsch reaction with various thioureas and
thioamides to give the regioisomeric 5,6-dihydrobenzo[d]thiazol-
7(4H)-ones 6.7–9 We, therefore, undertook a series of studies in-
tended to optimize the synthesis of bicyclic thiazoles 1. This report
describes the synthesis of pure bromodiketone 3 and its use in the
preparation of bicyclic thiazoles and related heterocycles.
typical conditions (EtOH, reflux) as we were concerned about the
stability of 3. We did obtain the desired 6,7-dihydrobenzo[d]thia-
zol-4(5H)-ones 1, but the yields were generally modest. We also
explored the Hantzsch thiazole synthesis using bromodiketone 3
generated in situ following the procedure of Denonne et. al.6 and
again the yields were unsatisfactory. For example, only 21% yield
of 2-(pyridin-4-yl)-6,7-dihydrobenzo[d]thiazol-4(5H)-one was
obtained from pyridine-4-carbothioamide. During the optimization
O
O
O
O
4 steps
O
O
2
Ref. 5
S
N
S
R
O
+
H2N
R
O
Br
3
4
S
1
6
O
N
S
In our initial investigation, we prepared 3-bromocyclohexane-
1,2-dione 3 from 1,2-cyclohexanedione using bromine (1 equiv) in
carbon tetrachloride at 0 °C. The crude product after removal of
the solvent was used immediately for the Hantzsch reactions under
R
Br
O
+
H2N
R
O
5
4
⇑
Corresponding author. Tel.: +1 203 677 7287; fax: +1 203 677 7702.
E-mail address: jason.guernon@bms.com (J.M. Guernon).
Figure 1. Hantzsch thiazole synthesis using bromodiketones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.028

3634
J. M. Guernon, Y.-J. Wu / Tetrahedron Letters 52 (2011) 3633–3635
process, we observed by 1H NMR analysis that the crude bromodik-
etone 3 was contaminated with several unidentifiedside products as
well as a trace amount of hydrogen bromide and that it decomposed
slowly even at À40 °C. This observation suggested that the yield
could be improved if the decomposition was avoided. Preparation
of pure 3 required considerable experimentation, and eventually
we found that the crude material could be purified using a pad of
Silica gel, eluting with 2.5% MeOH/CHCl3 followed by trituration of
the resulting white powder with minimal diethyl ether to give pure
3-bromocyclohexane-1,2-dione 3 as a white, crystalline solid as
determined by 1H NMR.10 This purified material was found to be sta-
ble, with no special handling required. After one month in a clear vial
at room temperature on the bench (no nitrogen flush), no degrada-
tion was detected by 1H NMR analysis.
Table 1
With pure bromodiketone 3 in hand, we examined its reaction
with pyridine-4-carbothioamide in refluxing ethanol. Under condi-
tions optimized for this substrate (1.5 equiv bromide 3, 0.3 M in
EtOH, reflux 15 h),11 2-(pyridin-4-yl)-6,7-dihydrobenzo[d]thiazol-
4(5H)-one (Table 1, entry 1) was isolated in 76% yield, which is a
significant improvement over that obtained using crude 3 follow-
ing the patented procedure (vide supra; 21%). A similar yield was
obtained from pyridine-2-carbothioamide (Table 1, entry 2), while
Hantzsch reaction of 3 with thioamides and thioureas
O
S
N
S
EtOH, reflux
15 h
R
O
+
H2N
R
O
Br
3
1
Entry
R
Yielda,b (%)
1
2
3
4-Pyridyl
2-Pyridyl
3-Pyridyl
76
76
54
Table 2
Reaction of 3 with ureas
N
O
R
O
O
N
4
76
O
EtOH, reflux
15 h
NH
R
N
O
+
H2N
N
H
N
S
Br
5
6
68
80
O
3
7
N
Entry
R
Yielda,b (%)
H
N
1
2
3
4
5
Methyl
Benzyl
Phenyl
2-Pyridyl
41
72
60
Trace
Trace
7
50
N
Phenyl
2,4-Dichlorophenyl
Mesityl
4-Methoxyphenyl
8
9
10
11
73
72
67
53
2-Chloroethyl
a
Isolated yield.
Yields not optimized.
b
O
12c
72
O
tert-Butyl
Ethyl
Cyclopropyl
Benzyl
Table 3
Tricyclic imidazole formation
13
14
15
16
51
30
29
33
O
N
N
EtOH, reflux
Y
O
+
Y
N
N
8
15 h
17
18
83
64
H2N
N
H
Br
O
3
Y = O, S, CH=CH
N
Entry
Aminoheterocycle
Product
Yielda,b (%)
O
19
20
49
71
HN
NH2
N
N
H2N
O
O
1
53
52
N
21
22
51
64
O
N
O
N
H2N
S
S
O
S
Cl
2
3
N
O
O
O
25d
N
23
24
O
N
H2N
S
N
N
CN
Trace
S
Trace
a
b
c
Isolated yield.
Yields not optimized.
a
Run in MeOH instead of EtOH due to transesterification.
Small amount of BOC deprotected product also observed.
Isolated yield.
Yields not optimized.
d
b

J. M. Guernon, Y.-J. Wu / Tetrahedron Letters 52 (2011) 3633–3635
3635
pyridine-3-carbothioamide gave a somewhat lower yield (Table 1,
References and notes
entry 3). In addition to pyridine thioamides, reactions of 3 with
pyrazine, isoxazole, thiazole, and imidazole thioamides also pro-
ceeded smoothly to afford heteroaryl substituted bicyclic thiazoles
in good yields (Table 1, entries 4–7). When phenyl and substituted
phenyl thioamides were used in these Hantzsch reactions, the
yields were comparable to those from heteroaryl thioamides.
Among several simple alkyl thioamides evaluated, tert-butylthioa-
mide gave the highest yield (51%, Table 1, entry 13), and ethyl,
cyclopropyl, and benzyl thioamides afforded modest yields (ca.
30%, Table 1, entries 14–16). Hantzsch-type cyclizations also pro-
ceeded efficiently for thiourea substrates, with the highest yield
obtained from 1-(pyridin-4-yl)thiourea (Table 1, entry 17). A sali-
ent feature of this chemistry is that ester, sulfone, and N-BOC func-
tional groups are well tolerated (Table 1, entries 12, 21–23). While
the N-BOC pyrrolidine derivative (Table 1, entry 23) gave only a
modest yield, this result is comparable to the other alkyl deriva-
tives. However, only a trace amount of the desired product was ob-
served in the reaction with 2-cyanoethanethioamide (Table 1,
entry 24).
1. For a recent review on thiazole synthesis, see: Wu, Y.-J.; Yang, B. V. In Progress
in Heterocyclic Chemistry; Gribble, G. W., Joule, J. A., Eds.; Elsevier: New York,
2010. Vol. 22 pp. 259-348.
2. Doggrell, S. A. Expert Opin. Invest. Drugs 2005, 14, 89.
3. Lin, T. I.; Lenz, O.; Fanning, G.; Verbinnen, T.; Delouvroy, F.; Scholliers, A.;
Vermeiren, K.; Rosenquist, A.; Edlund, M.; Samuelson, B.; Vrang, L.; de Kock, H.;
Wigerinck, P.; Raboisson, P.; Simmen, K. Antimicrob. Agents Chemother. 2009,
53, 1377.
4. Dang, Q.; Kasibhatla, S. R.; Jiang, T.; Fen, K.; Liu, Y.; Taplin, F.; Schulz, W.;
Cashion, D. K.; Reddy, K. R.; van Poelje, P. D.; Fujitaki, J. M.; Potter, S. C.; Erion,
M. D. J. Med. Chem. 2008, 51, 4331.
5. Maillard, J.; Delaunay, P.; Langlois, M.; Portevin, B.; Legeai, J.; Manuel, C. Eur. J.
Med. Chem. 1984, 19(5), 451.
6. Denonne, F.; Celanire, S.; Provins, L.; Defays, S. PCT Int. Appl.
WO2008012010A1.
7. McIntyre, N. A.; McInnes, C.; Griffiths, G.; Barnett, A. L.; Kontopidis, G.; Slaqin,
A. M. Z.; Jackson, W.; Thomas, M.; Zheleva, D. I.; Wang, S.; Blake, D. G.;
Westwood, N. J.; Fischer, P. M. J. Med. Chem. 2010, 53, 2136.
8. Zhang, N.; Ayral-Kaloustian, S.; Mansour, T.S.; Nguyen, T.H.; Niu, C.; Rosfjord,
E.C.; Suayan, R.; Tsou, H.-R. PCT Int. Appl. WO2009120826A1.
9. Perry, B.; Alexander, R.; Bennett, G.; Buckley, G.; Ceska, T.; Crabbe, T.; Dale, V.;
Gowers, L.; Horsley, H.; James, L.; Jendins, K.; Crepy, K.; Kulisa, C.; Lightfoot, H.;
Lock, C.; Mack, S.; Morgan, T.; Nicolas, A.-L.; Pitt, W.; Sabin, V.; Wright, S. Bioorg.
Med. Chem. Lett. 2008, 18, 4700.
With the Hantzsch thiazole synthesis well established, we ex-
tended this methodology to the synthesis of bicyclic aminooxaz-
oles. Exposure of bromodiketone 3 to methyl, benzyl, and phenyl
ureas furnished the expected 2-aminooxazoles in good yields (Ta-
ble 2, entries 1–3). In the cases of 2-pyridyl urea and 2-chloroeeth-
ylurea, only a small amount of the desired 2-aminooxazole was
formed.
Finally, we utilized bromodiketone 3 for the synthesis of some
unique tricyclic imidazoles 8 (Table 3). Treatment of 3-bromocy-
clohexane-1,2-dione 3 with 2-aminopyridine and 2-aminothiazole
in refluxing ethanol resulted in the formation of their respective
tricyclic imidazole compounds in good yields (Table 3), although
the 2-aminobenzothiazole gave only a trace amount of the desired
product.
In summary, we have developed a convenient synthesis of pure,
air-stable 3-bromocyclohexane-1,2-dione 3. This bromide was
shown to be a versatile reagent for the Hantzsch thiazole synthesis
and the synthesis of other closely related heterocycles. The meth-
odology described has been successfully applied to the synthesis of
biologically active bicyclic thiazoles, and these compounds will be
reported in due course. With the wide variety of commercially
available thioamides, thioureas, amides, 2-aminothiazoles, and 2-
aminopyridines, we anticipate widespread application of this pro-
cedure to the synthesis of various bicyclic thiazoles and oxazoles,
as well as tricyclic imidazoles.
10. Modified procedure for the preparation of 3-bromocyclohexane-1,2-dione 3. To a
solution of 1,2-cyclohexanedione (5.1 g, 45.5 mmol) in diethyl ether (46 mL) at
0 °C was added Br2 (2.34 mL, 7.27 g, 45.5 mmol) dropwise over 10 min. When
the addition was complete, the reaction was allowed to come to room
temperature and stir for 15 min., at which time the reaction mixture was
concentrated in vacuo. The resulting dark oil was taken up in 2.5% MeOH/CHCl3
and run through a pad of silica gel, eluting with the same solvent mixture. The
solvent was then removed in vacuo and the resulting yellow solid was
triturated with minimal cold diethyl ether (approx. 15 mL). Filtration gave 3-
bromocyclohexane-1,2-dione as a white crystalline solid (4.1 g, 47%). 1H NMR
(500 MHz, CDCl3) d 6.43 (s, 1H), 2.90 (t, J = 6.0 Hz, 2H), 2.62–2.54 (m, 2H), 2.09
(dt, J = 13.0, 6.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) d 191.7, 146.0, 119.4, 35.5,
34.5, 22.9. The carbon data as well as an hmqc experiment which showed no
cross peak of a carbon with the 6.43 ppm proton indicate that in solution, the
dione 3 exists exclusively in the enol form.
O
O
OH
Br
O
Br
11. Typical procedure for coupling of 3-bromocyclohexane-1,2-dione 3 in Hantzsch
and related reactions. A mixture of 3-bromocyclohexane-1,2-dione 3 (50 mg,
0.26 mmol) and pyridine-4-carbothioamide (24.1 mg, 0.17 mmol) in EtOH
(0.69 mL) was heated to reflux and stirred for 15 h. The reaction mixture was
diluted with DMSO (0.5 mL) to completely dissolve all solids and the resulting
mixture was purified by directly injecting the reaction mixture into
a
preparatory HPLC (C18, water/acetonitrile/ammonium acetate buffer) to give
2-(pyridin-4-yl)-6,7-dihydrobenzo[d]thiazol-4(5H)-one (30.4 mg, 0.13 mmol,
76%) (Table 1, entry 1). LC-MS (M+H)+ = 231.1. 1H NMR (500 MHz, CDCl3) d
8.80–8.69 (m, 2H), 7.95–7.80 (m, 2H), 3.22 (t, J = 6.1 Hz, 2H), 2.76 (dd, J = 7.2,
6.0 Hz, 2H), 2.38–2.29 (m, 2H). 13C NMR (126 MHz, CDCl3) d 190.9, 163.3,
152.7, 150.9, 150.5, 139.7, 120.8, 38.3, 24.6, 23.9.
Acknowledgments
We would like to thank Dr. Lorin A. Thompson and Dr. John E.
Macor for their encouragement.