Rationalization of benzazole-2-carboxylate versus benzazine-3-one/ benzazine-2,3-dione selectivity switch during cyclocondensation of 2-aminothiophenols/phenols/anilines with 1,2-biselectrophiles in aqueous medium

Article abstract of DOI:10.1021/acs.joc.7b01548

The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as ethyl glyoxalate and diethyl oxalate in aqueous medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwin's rule. On the other hand, the reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with Baldwin's rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chemical calculations (density functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates versus benzazine-3-ones/ benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier.

Full text of DOI:10.1021/acs.joc.7b01548

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Article
Rationalisation of Benzazole-2-carboxylate vs Benzazine-3-one/
Benzazine-2,3-dione Selectivity Switch during Cyclocondensation of 2-Amino
thiophenols/phenols/anilines with 1,2-Biselectrophiles in Aqueous Medium
Tejas M Dhameliya, Sumit Sunil Chourasiya, Eshan Mishra,
Pradeep S. Jadhavar, Prasad V. Bharatam, and Asit K Chakraborti
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01548 • Publication Date (Web): 28 Aug 2017
Downloaded from http://pubs.acs.org on August 29, 2017
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Page 1 of 41
The Journal of Organic Chemistry
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Rationalisation of Benzazole-2-carboxylate vs
Benzazine-3-one/Benzazine-2,3-dione Selectivity
Switch during Cyclocondensation of 2-Amino
thiophenols/phenols/anilines with 1,2-
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Biselectrophiles in Aqueous Medium
Tejas M. Dhameliya, Sumit S. Chourasiya, Eshan Mishra, Pradeep S. Jadhavar,
Prasad V. Bharatam and Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Sector 67, S. A. S. Nagar, Punjab 160 062, India.
CORRESPONDING AUTHOR FOOTNOTE Department of Medicinal Chemistry, National
Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160
062, Punjab, India. Fax: 91-(0)-172 2214692; Tel: 91-(0)-172 2214683; E-mail:
akchakraborti@niper.ac.in; akchakraborti@rediffmail.com
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ABSTRACT.
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The cyclocondensation reaction of 2-amino thiophenols with the 1,2-biselectrophiles such as
ethyl glyoxalate and diethyl oxalate in aqueous medium leads to the formation of the
benzothiazole-2-carboxylates via the 5-endo-trig process contrary to the Baldwin’s rule. On
the other hand, the reaction of 2-amino phenols/anilines produced the corresponding
benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with the
Baldwin’s rule. The mechanistic insights of these cyclocondensation reactions using HSAB
principle, quantum chemical calculations (DFT), and orbital interaction studies rationalize the
benzothiazole-2-carboxylates versus benzazine-3-ones/benzazine-2,3-diones selectivity
switch. The presence of water facilitates these cyclocondensation reactions through lowering
of the energy barrier.
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The Journal of Organic Chemistry
INTRODUCTION
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The N-containing heterocyclic systems constitute 60% of the drug candidate molecules.1
Among these N-heterocyclic scaffolds, benzazoles (benzothiazole,2 benzimidazole,3 and
benzoxazole4) draw attention as important pharmacophoric features of various bioactive
compounds. The most straight forward strategy for the synthesis of benzazoles is the
cyclocondensation (ring closure) reaction involving 2-aminothiophenols/phenols/anilines with
appropriate electrophilic coupling partner. The ring closure reaction is one of key reactions
for the construction of heterocyclic scaffold.5 The transformation of acyclic precursor into the
desired cyclic scaffold selectively is a challenging task and Baldwin’s rule6,7 has been found
to be the most significant tool in the arsenal of synthetic chemists for understanding the
rational of ring closure reactions. 8-10
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However, there are many reactions which do not follow Baldwin’s rule and the revised and
extended observations on Baldwin’s rule have been reported recently.11 For ring closure
reactions that are not in compliance with the Baldwin’s rule, the Density Functional Theory
(DFT) has been widely used to rationalize the product selectivity with mechanistic insight.12-15
Under the scope of multiple-site interactions for inter/intra molecular cyclocondensations, the
local hard-soft acid-base (HSAB) principle provides the key insight to justify the unusual
behavior of the reaction.16
Herein, we report mechanistic insight for the selectivity switch of benzazole-2-carboxylate
vs benzazine-3-one/benzazine-2,3-dione formation during the cyclocondensation of 2-amino
thiophenols/phenols/anilines with 1,2-biselectrophiles (e.g., ethyl glyoxalate and diethyl
oxalate) in aqueous medium and rationalize the observations in the context of Baldwin’s rule,
HSAB principle, orbital interactions, and quantum chemical calculations using the DFT.
RESULTS AND DISCUSSION
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In our endeavor to find out benzo[d]thiazole-2-carboxamides as anti-mycobacterial
agents,17,18 the benzo[d]thiazole-2-carboxylates (3) were found to be the key intermediates for
the synthesis of the target compounds. These were conveniently prepared by the condensation
of 2-aminothiophenols (1) with ethyl glyoxalate (2) in water17,18 under the catalytic influence
of sodium dioctyl sulfosuccinate (SDOSS) as the dioxygen activator.19 We realized that the
ring closure reaction of 1 with the biselectrophilic agent 2 is expected to form two different
products: the benzazole-2-carboxylates (3) and the benzazine-3-ones (4) (Scheme 1). Thus, to
understand the influence of various reaction parameters on the selectivity of the formation of
3 and 4, the condensation of 1 with 2 was performed under different variation of the reaction
condition such as the use of various organic solvents, water in the absence and presence of
various surfactants, and under neat condition (Tables 1-2).
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Scheme 1. The reaction of o-amino thiophenols/phenols/anilines (1) with ethyl glyoxalate (2)
to form the benzazole-2-carboxylates (3) and the benzazine-3-ones (4).
The progress of the reaction of 2-aminothiophenol (1a) with 2 was monitored by GCMS
(Table 1) that revealed the formation of ethyl benzothiazole-2-carboxylate (3a), ethyl 2,3-
dihydrobenzothiazole-2-carboxylate (3a′) but the presence of 2H-benzo[b][1,4]thiazin-2-one
(4a) could not be detected in the reaction mixture. The cyclocondensation of o-amino
thiophenols with aldehydes generally proceeds through the intermediate formation of the
corresponding thiazolines which on subsequent oxidative transformation lead to the formation
of the thiozoles.19,20 Thus, a distinct advantage in the use of catalytic amount of SDOSS in
water was observed in the fact that 3a was obtained in 83% isolated yield, without any
accumulation of the intermediately formed 3a′ (Table 1, Entry 3), via dioxygen activation19
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The Journal of Organic Chemistry
that would depend on the oxygen uptake ability of the additive/surfactants and offer the
rationale for their differential catalytic potential.
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Table 1. Evaluation of the effect of various reaction parameters during the reaction of 1a with
2 towards the selective formation of 3a vs 4a.
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[4a]
%
Yieldd
41
Entry
Solvent
[1a]b
[3a]b
[3a′]b
[3a]:[3a′]c
1
2
Neat
Water
Watere
MeOH
EtOH
MeCN
PhMe
DCM
DMF
3
0
0
6
5
2
4
3
4
4
44
86
100
69
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48
62
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65
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14
0
0
0
0
0
0
0
0
0
0
0
45:55
86:14
100:0
73:27
47:48
58:42
49:51
64:36
64:36
68:32
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THF
a1a (1 mmol) was treated with 2 (1 mmol, 1.2 equiv) in the indicated solvent (2 mL except for entry
1) at rt for 5 h. The % conversion as determined by GCMS. Calculated on the basis of total
conversion to 3a and 3a′. dIsolated yield of 3a obtained after column chromatographic purification.
eThe reaction was carried in the presence of SDOSS (10 mol%).
b
c
However, when this reaction condition was extended for the condensation of 1,2-
diaminobenzene 1d with 2, the quinoxaline-3-one 4d was obtained in 98% yield instead of the
ethyl benzimidazole-2-carboxylate 3d (Table 2, Entry 1). The reactions of 1d with 2 were
found to be exothermic that was not observed for the reaction involving 1a. In order to find
out whether the use of an additive/surfactant in water would have any decisive role in
directing the 3d vs 4d selectivity, the reaction of 1d with 2 was carried out in water in the
presence of catalytic amount (10 mol%) of various anionic (e.g., SDOSS, SDC, and SDS),
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Page 6 of 41
neutral (such as span-80, tween 80, triton X-100, and β-cyclodextrin hydrate), and cationic
(e.g., CTAB, and cetrimide) surfactants (Table 2, Entries 2-10). All of these resulted in the
exclusive formation of 4d in 92-98%. As the reaction of 1d with 2 to form 4 proceeds through
condensation processes without the involvement of any redox process the product yield and
selectivity are independent on the nature of the additive/surfactant. The reaction of 1d with 2
was next carried out under neat condition and in various halogenated (DCM and DCE),
ethereal (THF, 1,4-dioxane), aprotic (MeCN, acetone, DMF), and protic (MeOH, EtOH,
water, HOAc, TFA) solvents (Table 2, Entries 11-26). However, all of these resulted in the
exclusive formation of 4d in 87-97%.
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Table 2. The influence of various reaction conditions on the cyclocondensation of 1d with 2
on the selectivity of formation of 3d and 4d.a
Yield (%)b
Time
Entry
Solvent
Water
Water
Water
Water
Water
Water
Water
Water
Water
Water
Neat
Additive (10 mol%)
(h)
3d
4d
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2
SDOSS
1
0
98
SDOSS
0.5
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98
92
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SDC
4
SDS
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5
Span 80
1
6
Tween 80
1
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Triton X-100
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β-Cyclodextrin hydrate
1
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CTAB
1
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11
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Cetrimide
1
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-
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Neat
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The Journal of Organic Chemistry
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DCM
DCE
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-
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-
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-
-
-
-
-
-
-
-
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1
0
0
0
0
0
0
0
0
0
0
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97
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87
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THF
1
1,4-Dioxane
MeCN
Acetone
DMF
1
1
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MeOH
EtOH
1
1
EtOH
0.5
1
Water
Water
HOAc
TFA
0.5
1
1
a1d (1 mmol) was treated with 2 (1 mmol, 1.2 equiv) in different solvents at rt. Isolated
yields.
b
To assess the effect of electron withdrawing/donating substituents on the product
selectivity, the reaction of 2 was carried out with various substituted o-amino thiophenols (1b-
c) and o-phenylene diamines (1e-l) and naphthalene-2,3-diamine 1m. The reaction of 4-
substituted 2-aminobenzenethiols (1b,c) with 2 was performed under similar conditions that
led to the formation of the 3b and 3c in 73 and 70% yields, respectively, (Table 3, Entries 2
and 3) without formation of the 2H-benzo[b][1,4]thiazin-2-ones (4b,c). For the reaction of
1f-m, the quinoxaline-3-ones (4f-m) were formed as the sole products (Table 2, Entries 6-13).
However, in case of the nitro derivative (1e), the benzazole-2-carboxylate 3e was also formed
in 30% yield (Table 3, Entry 5). Similarly, the condensation of various substituted 2-
aminophenols (1n-r) and 3-amino-2-naphthol 1s with 2 led to the formation of the 2H-
benzo[b][1,4]oxazin-2-ones (4n-s)21 as the sole/major products (Table 3, Entries 14-19).
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Herein also the reaction involving the nitro derivative (1q) was associated with the formation
of the ethyl benzoxazole-2-carboxylate 3q in 24% yield (Table 3, Entry 17).
Table 3. The selectivity switch for formation of 3 vs 4 during cyclocondensation of 1a-s with
2.a
Page 8 of 41
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Yield (%)b
3
83
Entry
1
Time (h)
4
0
1
1a: X = S; Y = C; R1, R2 = H
5
2
3
1b: X = S; Y = C; R1 = Cl, R2 = H
1c: X = S; Y = C; R1 = CF3, R2 = H
1d: X = NH; Y = C; R1, R2 = H
1e: X = NH; Y = C; R1 = NO2, R2 = H
1f: X = NH; Y = C; R1, R2 = Cl
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12
1
73
70
0
0
0
4
98
70
86
81
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81
92
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76
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91
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1
30
0
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1
7
1g: X = NH; Y = C; R1 = Cl, R2 = H
1h: X = NH; Y = N; R1, R2 = H
1i: X = NH; Y = C; R1 = COOH, R2 = H
1j: X = NH; Y = C; R1, R2 = Me
1k: X = NH; Y = C; R1 = F, R2 = H
1l: X = NH; Y = C; R1 = Br, R2 = H
1m: X = NH; Y = C; R1 = R2 = (CH)4
1n: X = O; Y = C; R1, R2 = H
1
0
8
2
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9
1.5
1
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0
1
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1
0
1
0
2
0
1o: X = O; Y = C; R1 = H, R2 = Me
1p: X = O; Y = C; R1 = Me, R2 = H
1q: X = O; Y = C; R1 = NO2, R2 = H
1r: X = O; Y = N; R1, R2 = H
2
0
2
0
1
24
0
3
1s: X = NH; Y = C; R1 = R2 = (CH)4
1
0
a1 (1mmol) was treated with 2 (1 mmol, 1.2 equiv) in the presence of SDOSS (10 mol%) in
water at rt. bIsolated yield.
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In order to find out whether the selectivity switch for the formation of 3 vs 4 during the
1
2
cyclocondensation of 2 with 2-aminothiophenols and o-phenylene diamines could be due to
the differential electrophilic character of the bis-electrophile 2, we planned to explore the
selectivity switch using symmetric biselectrophilic agent such as diethyl oxalate (5). Thus, the
condensation of various o-amino thiophenols/phenols/anilines (1) with 5 was next
investigated (Tables 4 and 5). The reaction of 1a with 5 in water at rt for 6 h in the presence
of SDOSS (10 mol%) afforded 3a as the only product in 39% yield (Table 4, Entry 1) in
conformity with the literature report. 22 An increase of the reaction temperature to 60 ˚C gave
3a in 93% yield in 1 h (Table 4, Entry 3). The use of water as the reaction medium in the
presence of SDOSS (10 mol%) at 60 °C for 1 h was found to be the best operative reaction
condition as inferior yields were obtained in performing the reaction in water in the absence
of SDOSS or in various organic solvents in the presence or absence of SDOSS (Table 4,
Entries 3-13). On the contrary, the reaction of 1d with 5 led to the exclusive formation of 6d
(Table 4, Entries 14-48) performed in water (in the presence or absence of surfactants),
organic solvents, and under neat condition. However, the use of water as the reaction medium
was found to be advantageous in providing better yield of 6d due to the hydrogen bond-
assisted dual activation role23-26 of water in the cyclocondensation.
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Table 4. The influence of various reaction conditions on the cyclocondensation of 1a/d with 5
on the selectivity for formation of 3a/d vs 6a/d.a
Yieldb (%)
Temp Time
Entry
1
Solvent
Additive (mol%)
(°C)
(h)
3
6
0
0
1
2
1a: X = S
1a: X = S
Water
Water
SDOSS (10)
SDOSS (10)
rt
6
6
39
95
60
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3
4
5
6
7
8
9
1a: X = S
1a: X = S
1a: X = S
1a: X = S
1a: X = S
1a: X = S
1a: X = S
Water
Water
Water
Water
EtOH
EtOH
MeOH
MeOH
MeCN
MeCN
Neat
SDOSS (10)
60
60
60
60
60
60
60
60
60
60
60
1
0.5
6
93
52
78
42
43
26
32
21
41
23
34
0
0
0
0
0
0
0
0
0
0
0
1
2
3
4
5
6
7
8
SDOSS (10)
-
-
1
SDOSS (10)
1
9
10
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12
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-
1
SDOSS (10)
1
10 1a: X = S
11 1a: X = S
12 1a: X = S
13 1a: X = S
-
1
SDOSS (10)
1
-
-
1
1
14 1a: X = S
15 1a: X = S
16 1a: X = S
17 1a: X = S
18 1a: X = S
19 1a: X = S
Water
Water
Water
Water
Water
Water
SDC (10)
SDS (10)
60
60
60
60
60
60
1
1
1
1
1
1
90
82
88
81
85
84
0
0
0
0
0
0
Span 80 (10)
Tween 80 (10)
Triton X-100 (10)
β-Cyclodextrin
hydrate (10)
20 1a: X = S
21 1a: X = S
Water
Water
CTAB (10)
60
60
1
1
89
79
0
0
Cetrimide (10)
22 1d: X = NH
23 1d: X = NH
24 1d: X = NH
25 1d: X = NH
26 1d: X = NH
27 1d: X = NH
28 1d: X = NH
29 1d: X = NH
30 1d: X = NH
Water
Water
Water
Water
Water
Water
Water
Water
Water
-
60
rt
2
2
0
0
0
0
0
0
0
0
0
91
37
93
85
54
94
93
39
89
-
-
reflux
60
2
-
1
-
60
0.5
2
SDOSS (10)
SDOSS (10)
SDOSS (10)
SDOSS (10)
reflux
60
2
rt
2
60
1
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31 1d: X = NH
Water
EtOH
Neat
SDOSS (10)
60
reflux
rt
0.5
4
0
0
0
0
0
0
0
0
0
0
0
0
56
89
67
89
45
51
69
45
59
0
1
2
3
4
5
6
7
8
32 1d: X = NH
33 1d: X = NH
34 1d: X = NH
35 1d: X = NH
36 1d: X = NH
37 1d: X = NH
38 1d: X = NH
39 1d: X = NH
40 1d: X = NH
41 1d: X = NH
42 1d: X = NH
-
-
-
-
-
-
-
-
-
-
-
2
Neat
60
rt
2
MeOH
EtOH
EtOH
MeCN
MeCN
DCM
2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
rt
2
60
rt
2
2
60
rt
2
2
Acetone
Hexane
rt
2
45
0
rt
2
1,4-
Dioxane
43 1d: X = NH
-
rt
2
0
35
44 1d: X = NH
45 1d: X = NH
46 1d: X = NH
47 1d: X = NH
48 1d: X = NH
DMF
DCE
THF
-
-
-
-
-
rt
rt
rt
rt
rt
2
2
2
2
2
0
0
0
0
0
21
0
0
HOAc
TFA
29
0
a1 (1 mmol) was treated with 5 (1 mmol, 1.2 equiv) in water at 60 ˚C. bIsolated yield.
As the cyclocondensation reaction of 5 with 1a and 1d to form the respective products 3a
and 6d don not involve any redox process it was felt worth to understand the necessity of the
use of a surfactant (e.g., SDOSS) for the reaction of 5 with 1a. We observed that 1a is
immiscible in water (at rt or 60 °C) but forms a homogenous pale yellow solution in water at
60 ˚C in the presence of SDOSS indicating the role of SDOSS being merely as the solubility
enhancer of 1a in aqueous medium. No significant difference in the yield of 3a was observed
in performing the reaction of 5 with 1a in water at 60 °C in the presence of other surfactants
suggesting the role of the surfactant as solubility aid only. On the other hand, the mixture of
1d and 5 in water at 60 ˚C was found to be homogenous in the absence of SDOSS justifying
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the independence of the presence of any surfactant for the reaction of 1d with 5 to form 6d.
The reaction of 1d with 5 in EtOH under reflux has been claimed to form 3d that was used for
subsequent reaction without any further characterization (e.g., IR, NMR, MS).27 However, on
our hand, the treatment of 1d with 5 in EtOH under reflux afforded 6d (IR, NMR, MS) in
89% yield (Table 4, Entry 32) instead of 3d. Performing the reaction under the reported
condition (reflux in EtOH for 4 h)28 or extending the reaction time to 12 h led to the exclusive
formation of 6d. Our result is in agreement with the finding of Vázquez et al. on the
microwave–assisted cyclocondensation of 1d and 5 to form 6d instead of 3d.28
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hence, the reaction of 4-substituted 2-aminobenzenethiols (1b and 1c) with 5 was
performed under similar conditions that led to the formation of the benzothiazole-2-
carboxylates 3b and 3c, respectively, in excellent yields (Table 5, Entries 2 and 3) without
any competitive formation of the 2H-benzo[b][1,4]thiazine-2,3(4H)-diones (6b,c). The
reaction of substituted 1,2-diaminobenzenes (1f-m) with 5 in water at 60 ˚C led to the
exclusive formation of the quinoxaline-2,3-diones (6f-m) (Table 5, Entries 7-16) without any
competitive formation of the benzo[d]imidazole-2-carboxylates (3f-m). However, the reaction
of the nitro derivative 1e with 5 afforded 6e in 72% yield along with 28% of 3e (Table 5,
Entry 5). The reaction of 2-aminophenols (1n-s, except 1q, Table 5) with 5 in water in the
presence of SDOSS (10 mol%) at 60 ˚C gave 6n-p,r,s in 77-92% yields. The 4-nitro-2-
aminophenol (1q) resulted in selectivity switch affording the benzoxazole-2-carboxylate (3q)
in 93% yield (Table 5, Entry 21). The final products (6) were isolated in pure form by diluting
the reaction mixture with ice cold water-EtOH (3:1) followed by filtration of the precipitated
residue and did not require further purification. This protocol represents a simple, efficient,
and greener methodology for the construction of the benzazine-2,3-diones 6 avoiding the use
of protic acid,29 toxic or corrosive reagents,30,31 catalyst,32 multi-step reactions sequence,33
hazardous solvent21 and oxidants34 (ESI: Table S1, Entries 1-7).
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Table 5. The selectivity switch for the formation of 3 vs 6 during the cyclocondensation of
1a-s with 5.a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield (%)b
Time
Additive
(mol%)
Entry
1
(h)
3
95
89
81
0
6
1a: X = S; Y = C; R1 = R2 = H
SDOSS (10)
1
1.5
2
0
1
2
1b: X = S; Y = C; R1 = Cl, R2 = H
1c: X = S; Y = C; R1 = CF3, R2 = H
1d: X = NH; Y = C; R1= R2 = H
1e: X = NH; Y = C; R1= NO2, R2 = H
1e: X = NH; Y = C; R1= NO2, R2 = H
1f: X = NH; Y = C; R1 = R2 = Cl
1g: X = NH; Y = C; R1 = Cl, R2 = H
1h: X = NH; Y = N; R1 = R2 = H
1i: X = NH; Y = C; R1 = COOH, R2 = H
1j: X = NH; Y = C; R1, R2 = Me
1j: X = NH; Y = C; R1, R2 = Me
1k: X = NH; Y = C; R1 = F, R2 = H
1l: X = NH; Y = C; R1 = Br, R2 = H
1m: X = NH; Y = C; R1 = R2 = (CH)4
1m: X = NH; Y = C; R1 = R2 = (CH)4
1n: X = O; Y = C; R1 = R2 = H
SDOSS (10)
0
3
SDOSS (10)
0
4
-
2
91
72
69
82
85
81
84
91
87
89
79
83
79
92
89
87
0
5
SDOSS (10)
1.5
1.5
1
28
31
0
6
-
7
-
8
-
1
0
9
-
2
0
10
11
12
13
14
15
16
17
18
19
20
-
1
0
SDOSS (10)
1
0
-
1
0
-
1
0
-
1
0
SDOSS (10)
2
0
-
2
0
-
2
0
1o: X = O; Y = C; R1 = H, R2 = Me
1p: X = O; Y = C; R1 = Me, R2 = H
1q: X = O; Y = C; R1 = NO2, R2 = H
-
2
0
-
2
0
SDOSS (10)
2.5
96
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1q: X = O; Y = C; R1 = NO2, R2 = H
-
-
-
2.5
3
93
0
0
21
22
23
1
2
3
4
1r: X = O; Y = N; R1, R2 = H
87
77
1s: X = NH; Y = C; R1 = R2 = (CH)4
2
0
5
6
7
8
9
a1 (1 mmol) was treated with 5 (1 mmol, 1.2 equiv) in water at 60 ˚C in the presence of
indicated additive (10 mol%). bIsolated yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To understand the origin of selectivity switch towards the formation of 3 vs 4/6 during the
cyclocondensation of 1 with the bis-electrophiles 2 and 5 it was felt prudent to dig into the
mechanistic course of the reactions. The reaction proceeds via the Schiff base
(azomethine/imine/aldimine, I) formation35 between the aldehyde 2 and the amine 1 followed
by addition-elimination sequence (Scheme 2). According to Baldwin’s rule the 5-endo-trig
cyclization of alkenes is disfavored7 because the attack of a reactive termini on olefinic
36
carbon is not in compliance with the Bürgi-Dunitz trajectory. Herein, the success of the 5-
endo-trig cyclization was attributed to the soft nucleophilicity of sulphur. The thiol group
(XH = SH, 1a) attacks at the C2 (iminic carbon) of I-1a leading to the benzothiazoles through
the 5-endo-trig pathway in contrary to the Baldwin’s rule14,37-39 (Scheme 2). However, in case
of the 1,2-diaminobenzene (X = NH, 1d) and the 2-aminophenol (X = O, 1n), the NH2 and
OH group attack at the C1 (carbonyl carbon) of I-1d/n leading to the ring closure via 6-exo-
trig pathway (Scheme 2). This is in compliance with the Baldwin’s rule that suggests 5-endo-
trig to be disfavoured and the 6-exo-trig as favoured processes.7,40 This mechanistic course is
also operative for the cyclocondensation of 1a-s with 5 which proceeds through the formation
of the amide intermediate (III, Scheme 3).
Scheme 2. Plausible mechanism for the selectivity switch for formation of 3 vs 4 during the
cyclocondensation of 1a, 1d, and 1n with 2.
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
The proposed nucleophile attack on the bis-electrophilic sites gains support by the HSAB
principle.41 Thiols being soft nucleophile42 prefer to react on the soft iminic (C2 in I-1a,
Scheme 2)/amide (C2 in III-1a, Scheme 3) carbon following the 5-endo-trig pathway and
hence leads to the benzothiazoles 3. However, as NH2 and OH are hard nucleophiles4342 the
reaction takes place at the hard carbonyl carbon of the ester (C1 in I-1d/n and III-1d/n,
Scheme 2 and 3 respectively) via 6-exo-trig process forming the benzazine-3-one/benzazine-
2,3-diones 4/6. The selectivity switch observed with the nitro substituted derivatives 1e and
1q with 2 (Table 3, Entries 5 and 17) and 5 (Table 5, Entries 6 and 22) could be attributed to
the electron withdrawing nature of the nitro group by rendering the amino/hydroxyl group of
1e and 1q less nucleophilic.
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Plausible mechanism of the selectivity switch for formation of 3 vs 6 by
cyclocondensation of 1a, 1d, and 1n with 5.
To understand the reaction mechanism and to explore the origin of the observed selectivity
switch, quantum chemical calculations were performed and density functional theory (DFT)
studies based on B3LYP43 method and 6-31+G(d) basis set were employed to carry out the
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study (ESI: Tables S2-4).44,45 Reactions of o-substituted aniline (1a, 1d, and 1n) with the bis-
electrophilic coupling partners 2 and 5 were chosen as models for detailed DFT exploration.
To start with, the reaction of 1a with 2 to give 3a via the imine intermediate I-1a was
analyzed under solvent free (gas phase calculations) conditions (Figure 1). The overall free
energy change associated with the formation of 3a was found to be endothermic (8.71
kcal/mol, Figure 1). Conformational search for the imine generated from the reaction of 1a
with 2 leads to the identification of I-1a as the global minimum conformer among other
possible conformational isomers (I-1a-1 to I-1a-7, ESI: Figure S1, Table S5). Since the
importance/involvement of the thiolate anion has been invoked earlier as the effective
nucleophile during addition to α,β-unsaturated enone46 such a pathway was also considered.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Energy labelled diagram for cyclocondensation of 1a with 2 following zwitterionic
pathway. The conversion of II-1a into 3a happens with the participation of SDOSS (shown
in dotted lines).19
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The Journal of Organic Chemistry
In the global minimum structure of imine I-1a, there is an intramolecular hydrogen bonding
between SH----N (1.91 Ǻ) which can help in the exchange of proton (pKa of 1a = 6.54)47
leading to the formation of zwitterion I-1a-8 consisting of a thiolate anion and an iminium
cation. Though the zwitterion is about 9.04 kcal/mol less stable than I-1a, it can adopt suitable
conformational arrangements for intramolecular C-S bond formation (Figure 1). Rotation
across N3-C4 bond in I-1a-8 (to give I-1a-9) is required to facilitate 5-endo-trig ring closure.
An additional C2-N3 rotation is required to give I-1a-10. Figure 2 provides the 3D structures
of the transition states TS2 and TS3 for the formation of 5-endo-trig and 6-exo-trig ring
closure products 3a and 3d, respectively. The activation energy for the 5-endo-trig ring
closure via TS2 from I-1a-8 was estimated to be 7.87 kcal/mol and for the 6-exo-trig ring
closure via TS3 from I-1a-8 is 25.57 kcal/mol. The overall barrier for the 5-endo-trig ring
closure product and the 6-endo-trig closure product are 20.12 and 37.92 kcal/mol,
respectively. The overall free energy change associated with the formation of the 5-endo-trig
cyclized product II-1a and the 6-exo-trig ring cyclized product 4a were found to be
exothermic by 0.64 and -0.28 kcal/mol respectively. Hence although on thermodynamic
counts the formation of both of these products appears to be equally possible the formation of
3a is preferred on kinetic grounds.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The importance of the participation of water was observed for the reaction of 1a with 2
(Table 1, Entries 1-3) as better yields were obtained in performing the reaction in water. Thus,
it was felt prudent to reanalyze the potential energy surface in the presence of an explicit
water molecule. The energy barrier for the C-S bond formation step from I-1a-9 via TS2w
(Figure 1) is marginally smaller by 1.42 kcal/mol (i.e. reduction to 2.30 from 3.72 kcal/mol)
in the presence of an explicit water molecule (denoted by green line) in comparison with that
of the solvent free condition (denoted by brown line). The role of water molecule to provide a
bridge between the reactive centres via the network of hydrogen bonds has been reported by
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our research group.23-26 The overall activation barrier, i.e., TS2 versus TS2w, is reduced by
8.48 kcal/mol in the presence of interfacial water molecule compared with the reaction in the
absence of water. This result suggests that the transition state involving water molecule
(TS2w) is a better hydrogen-bond acceptor than the transition state without water (TS2) and
the net effect enables the lowering of the transition barrier.48 This explains the observed
increase in the yield in the presence of water.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. 3D-structures of a few important transition states. The blue dotted lines indicate
distance between nucleophile and electrophile in Angstroms (Ǻ).
The same reaction pathway was also explored considering the thiolate anion I-1a-11 (via
TS4, ESI: Figure S2) as the reactive species. The energy barrier for the formation of the 5-
exo-trig cyclized product is 16.81 (from I-1a to TS2, Figure 1). This is reduced to 13.73
kcal/mol when the thiolate anion intermediate (I-1a-11) was considered. Hence, the
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zwitterionic pathway (Figure 1) as well as the ionic pathway (ESI: Figure S2) appear to be
1
2
3
equally feasible for the 5-endo-trig product formation.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Energy labelled diagram for cyclocondensation of 1d with 2 following proposed
reaction pathway. Free energies are given in kcal/mol with relative to reactants.
Similarly, the reaction pathway for the selective formation of quinoxaline-3-one (4d) over
the benzimidazole-2-carboxylate (3d) was explored (Figure 3). The overall free energy
change associated with the reaction of 1d with 2 to form the 6-exo-trig cyclized product 4d
was found to be exothermic by 14.51 kcal/mol (Figure 3). The conformational search for the
imine intermediate leads to the identification of I-1d as the global minimum conformer on
potential energy surface among the various possible conformers I-1d-1 to I-1d-6 (ESI: Figure
S3, Table S6). For the 5-endo-trig pathway, ‘bad alignment’5049 was observed in I-1d (Figure
4a) between the nucleophile lone pair and C=N π* orbital for the nucleophile-electrophile
approach within the plane and the orbital interaction moves ‘too far away’5049 from the imine
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carbon if it bends out of this plane (Figure 4b). For the 6-exo-trig pathway the interaction
between the nucleophile lone pair and C=O π* orbital encounters no problem as can be seen
by visualization of molecular orbitals.49 The increase of the chain length by one carbon
enables the nucleophile to find the electrophile to have orbital interaction in consonance with
reported literature40 (ESI: Figure S4).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. (a) The ‘Bad alignment’ observed between the lone pair on the nucleophile (N) and
π* orbital of C=N if nucleophile (N) approaches electrophile (C2) within the plane in I-1d. (b)
‘Too far away’ interaction observed between the lone pair on the nucleophile (N) and π*
orbital of C=N if nucleophile (N) bends out of the plane to react with iminic carbon (C2).
Figure 2 provides the 3D structures of the transition states TS5 and TS6 for the formation
of the 5-endo-trig and the 6-exo-trig cyclized products, respectively. The overall barriers for
the 5-endo-trig cyclized product 3d and the 6-exo-trig cyclized product 4d from I-1d are
34.41 and 15.93 kcal/mol, respectively. Considering that 4d is more stable than 3d (by 18.5
kcal/mol) and that the barrier for formation of 4d is smaller than that of 3d by 18.48 kcal/mol,
the selective formation of 4d for the reaction of 1d with 2 via exothermic pathway is justified
on thermodynamic as well as kinetic grounds.
The energy barrier for the conversion of I-1d-5 to TS6 in the presence of an explicit water
(i.e., I-1d-5w to TS6w, Figure 3) reduced from 7.58 to 1.47 kcal/mol. The overall activation
barrier, i.e., TS6 versus TS6w, is reduced by 14.69 kcal/mol in the presence of
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interfacial/explicit water molecule compared with the reaction under neat condition (Figure
3). The reduced energy barrier is attributed to the direct exposure of nucleophile lone pair of
NH2 and C=O π* orbital in TS6w (ESI, Figure S5), which is not observed in TS6 due to
intramolecular hydrogen bond between NH---O=C (2.03 Ǻ). Thus, explicit water molecule
facilitates the reaction via synergistic electrophilic and nucleophilic dual activation.25,26
Similar calculations were performed to justify the selectivity switch observed for the
reaction of 1n with 2 to account for the selective formation of the 6-exo-trig cyclized product
4n (Figure 5). The overall free energy change associated with the reaction of 1n with 2 to
form the benzoxazine-3-one 4n was found to be exothermic by 4.53 kcal/mol (Figure 5). The
conformational search for the imine (I-1n) derived from 1n has been carried out to derive the
energy minimum conformer (ESI: Figure S6, Table S7).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Energy labeled diagram for cyclocondensation of 1n with 2 following proposed
reaction pathway. Free energies are given in kcal/mol with relative to the reactants.
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The energy barrier for the conversion of I-1n-6 to TS8 under solvent free condition was
found to be 6.61 kcal/mol (Figure 5). However, in the presence of explicit water it reduced to
2.22 kcal/mol (I-1n-6w to TS8w, Figure 5) via cooperative network of hydrogen bonds
involving a water molecule.25,26 The overall activation barrier, i.e., TS8 versus TS8w, is
reduced by 13.88 kcal/mol in the presence of interfacial water molecule compared to that of
the reaction under neat condition (Figure 5). The presence of water molecule makes the small
change in 3D-orientation of OH group and ester group. In the TS8, the sp2 lone pair of OH is
suitably arranged towards the C=O π* whereas in the presence of explicit water (TS8w), the p
orbital of OH is perfectly orientated towards the electrophilic C=O π* orbital (ESI, Figure
S7). Thus, water plays a crucial role in facilitating the intramolecular cyclization process.
We could locate the transition states TS8 (Figure 2) corresponding to the C-O bond
formation with a barrier of 16.74 kcal/mol for the formation of the 6-exo-trig ring closured
product 4n whereas the energy barrier of 36.92 kcal/mol is required for the formation of the 5-
endo-trig product 3n (Figure 5). Considering that 4n is more stable (-4.53 kcal/mol) and also
that the barrier for the formation of 4n is smaller than that of 3n by 20.18 kcal/mol, the
selective formation of 4n is justified on thermodynamic as well as kinetic grounds. In
conclusion, formation of the 6-exo-trig ring closure products 4d and 4n is governed by
thermodynamic and kinetic parameters and that of the 5-endo-trig ring closure product 3a is
governed by the kinetics.
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Further, we analysed the reaction of 1a, 1d, and 1n with 5 using DFT calculations. The
reaction of 1a and 1n with the symmetrical 1,2-biselectrophile 5 may lead to the formation of
the N-acylated or S-/O-acylated amide depending upon the nucleophilic attack of the NH2 of
1a and 1n on the ester carbonyl carbon of 5. The S-/O-acylated intermediates have higher
energy than that of the N-acylated products of 1a and 1n (ESI: Table S4). Thus the formation
of only the N-acylated products (III-1a/n) can be expected under experimental condition in
consonance with the reported literature.50 Hence, in order to elucidate the reaction
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mechanism, we have considered the N-acylated products (III-1a/n) as the reactive
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intermediate.
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Figure 6. Plausible reaction pathway for the selective formation of 5-endo-trig cyclized
product 3a. Free energies are given in kcal/mol with relative to reactants (1a and 5).
The overall reaction for the formation of 3a from 1a and 5 is exothermic by 2.82 kcal/mol
(Figure 6). In III-1a-1, the hydrogen of the thiol group undergoes intramolecular hydrogen
bond formation with the carbonyl oxygen of the C2 center. After the internal proton transfer
from the thiol to the carbonyl oxygen, we tried to locate the TS for the attack of the thiolate
anion on the protonated carbonyl carbon. However, at potential energy surface, we observed
the formation of the cyclized intermediate IV-1a, which is 15.67 kcal/mol higher in energy
from III-1a. Subsequently IV-1a undergoes water elimination (with barrier of 26.95 via
TS10, ESI: Figure S8) to form 3a. On the other hand, the formation of the 6-exo-trig cyclized
product 6a required a barrier (TS9) of 22.62 kcal/mol. Hence, the reaction of 1a with 5 leads
to the formation of 3a.
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Figure 7. Plausible reaction pathway for selective formation of the 6-exo-trig cyclized
product 6d. Free energies given in the parenthesis are provided in kcal/mol relative to the
reactants (1d and 5).
Figure 8. The 3D-structure of the transition state TS11-14. The blue dotted lines indicate
distance between nucleophile and electrophile in Angstroms (Ǻ).
The reaction of 1d with 5 leading to the formation of 6d is exothermic by -9.70 kcal/mol
(Figure 7). Figure 8 provides the 3D structures of the transition states TS11 and TS12. The
barrier for formation of 3d from III-1d via TS11 is found to be 27.02 kcal/mol and the same
for formation of the 6d via TS12 was found to be 15.83 kcal/mol. Thus, the overall energy
required for the formation of 3d is 25.75 kcal/mol whereas the overall barrier for the
formation of 6d is 14.56 kcal/mol (Figure 7). Considering that 6d is thermodynamically more
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stable by 2.17 kcal/mol than 3d and also the barrier for formation of 6d is smaller than that of
3d by 11.19 kcal/mol the selective formation of 6d from the reaction of 1d with 5 is justified
on thermodynamic as well as kinetic grounds.
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Figure 9. Plausible reaction pathway for the selective formation of 6-exo-trig cyclized
product 6n. Free energies in parenthesis are given kcal/mol with relative to reactants (1n and
5).
In similar way, we explored the reaction of 1n with 5 leading to the formation of 6n which
was found to be endothermic by 0.21 kcal/mol (Figure 9). The barrier for the formation of 3n
from III-1n via TS13 (Figure 8) was found to be 31.3 kcal/mol whereas the barrier for the
formation of 6n from III-1n via TS14 found to be only 17.29 kcal/mol. Thus, the overall
energy required for the formation of 3n from III-1n is 28.58 kcal/mol, whereas the overall
barrier for the formation of 6n from III-1n is 14.57 kcal/mol (Figure 9). Considering that 6n
is more stable (2.93 kcal/mol) than 3n and the barrier for formation of 6n is smaller than that
of 3n by 14.01 kcal/mol the selective formation of 6n during the reaction of 1n with 5 is
justified on thermodynamic as well as kinetic grounds.
Further, NBO charge analysis of the intermediates (I and III, Table 6) were carried out to
justify the selective attack at the electrophilic centres (C1 and C2). The NBO charge analysis
reveals that C1 is much strongly positive (hard electrophile) than C2 (soft electrophile, Table
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6). In the intermediates I-1a-9 and III-1a-1, C2 center is closer to S (soft nucleophile) and
both are associated with soft-soft relation (Table 6, Entries 1-2 and 5). In the intermediates
III-1d/n, C1 is closer to the reactive centres N/O (hard nucleophile) indicating hard-hard
relation (Table 6, Entries 3-4 and 6-7). This is in accordance with the HSAB principle.49
These structural and electronic features drive the reaction for the 5-endo-trig or the 6-exo-trig
pathways selectively.
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Table 6. Calculated NBO charges of optimized intermediates.
NBO Charge
Entry
Intermediate
R
X
C2
C1
-0.149 (S-)
0.040 (SH)
-0.867 (NH2)
-0.709 (OH)
0.000 (SH)
-0.744 (NH2)
-0.707 (OH)
-0.035
-0.395
0.023
0.038
0.459
0.613
0.614
0.726
0.751
0.755
0.759
0.596
0.754
0.754
I-1a-9a
I-1a
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7
H
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-
I-1d-5
-
I-1n-6
-
III-1a-1
III-1d-1
III-1n-1
-
-
aIntermediate exist in zwitterionic forms.
In conclusions, this work provides mechanistic insight for ring closure reaction of o-amino
thiophenols/phenols/anilines with the ambiphilic electrophiles ethyl glyoxalate and diethyl
oxalate. The benzazole-2-carboxylate versus benzazine-3-one/benzazine-2,3-dione product
selectivity switch has been rationalized with reference to the Baldwin’s rules using HSAB
principle, DFT calculations, and orbital interactions. For experimentally observed products,
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less energy barrier is observed. The observed less energy barrier in the presence of explicit
water molecule justifies the role of water in the reaction.
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EXPERIMENTAL SECTION
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General: Chemicals and all solvents were commercially available and used without further
9
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purification. H NMR and C NMR spectra were recorded on spectrometer at 400 and 100
MHz, respectively, with TMS as an internal standard and using CDCl3/DMSO as solvent with
residual undeuterated solvent (CDCl3: 7.26/77.0) or (DMSO-d6: 2.5/39.5). Chemical shifts ()
and coupling constants (J) are reported in ppm and hertz (Hz), respectively. The 13C NMR
spectra were fully decoupled. For analysis of the results of NMR, software was used. The
abbreviations used to characterize the signals are as follows: s = singlet, m = multiplet, d =
doublet, dd = doublet of doublet, t = triplet, q = quartet. Column chromatography and thin
layer chromatography (TLC) were performed on silica gel. Mass spectra were measured in the
APCI mode at an ionization potential of 70 eV; Infra-red spectra were recorded on FT-IR
spectrometer in the range of 4000-600 cm-1 either as neat samples or using KBr for preparing
pellets for solid samples or in solvent. Compounds were routinely checked for their purity on
the silica gel GF-254 and visualized under UV at wavelength 254 nm. Melting points were
measured using Visual Melting Range Apparatus. Evaporation of solvent was performed at
reduced pressure, using a rotary evaporator. Elemental analyses were performed on organic
element analyzer and indicated by the symbols of the elements or functions were within ± 0.4
% of the theoretical values.
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Procedure for the determination of benzothiazole:benzothiazoline selectivity by
GCMS: To the magnetically stirred suspension of sodium dioctyl sulfosuccinate (0.044 g, 5
mol%) in water (2 mL) was added ethyl glyoxalate (0.24 g, 1.2 mmol) and 2-aminothiophenol
(0.13 g, 1 mmol) and the mixture was stirred magnetically at rt. After completion of reaction
(TLC, 5 h), the reaction mixture was diluted with EtOAc (2 mL). An aliquot portion (100 μL)
of the supernatant EtOAc layer was taken out and further diluted to 1 mL in EtOAc and
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progress of reaction was monitored by GCMS. In case of solvent study where organic solvent
used as medium, samples were submitted for GCMS after further dilution/addition by EtOAc.
Computational methods: Geometry optimization of all reactants, transition states,
intermediates, final products and their corresponding conformers have been carried out using
Gaussian09 suite of programs.43 To carry out geometry optimization using Density functional
theory (DFT)51 calculations, B3LYP/6-31+G(d)52 method was utilized. All the minima and
transition states on the reaction path were characterized after performing frequency analysis
(ESI: Tables S2-4). All the transition states were confirmed to have only one imaginary
frequency. The orbital interactions in the transition states/intermediates were visualized using
Chemcraft 1.8 software.
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General procedure for the synthesis of compounds (3/4)
To a magnetically stirred miceller solution of SDOSS (44 mg, 10 mol %) in demineralised
water (2 mL), was added with o-substituted aniline (1 equiv) and ethyl glyoxalate (1.2 equiv)
and the mixture was stirred at rt. After completion of the reaction (TLC), the reaction mixture
was extracted with EtOAc (4 × 15 mL). The combined EtOAc extracts were washed with
saturated brine (15 mL), dried (anhydrous Na2SO4), filtered and concentrated under vacuum
rotary evaporation. The crude products were purified by filtration of precipitated residue or by
passing through a column of silica gel (60-120 mesh) and eluted with hexane-EtOAc (70:30)
to afford the pure product.
°
Ethyl benzo[d]thiazole-2-carboxylate (3a)17,18: Yellow solid (172 mg, 83%). mp 68-72 C;
1
IR (KBr, cm-1): 1750; H NMR (400 MHz, CDCl3)  8.25 (d, J = 8.2 Hz, 1H), 7.97 (d, J =
7.9 Hz, 1H), 7.60-7.52 (m, 2H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1, 3H); 13C NMR (100
MHz, CDCl3)  160.7, 158.6, 153.2, 136.8, 127.5, 127.1, 125.5, 122.1, 63.1, 14.3; MS
(APCI) m/z 208.21 (M + H)+.
Ethyl 5-chlorobenzo[d]thiazole-2-carboxylate (3b)17,18: Yellowish solid (176 mg, 73%). mp
1
91-93 °C; IR (KBr, cm-1): 3334, 1743, 1583, 1330, 1164; H NMR (400 MHz, CDCl3) δ 8.24
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(d, J = 1.9 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.6, 1.96 Hz), 4.57 (q, J = 7.2 Hz,
2H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.3, 160.3, 154.0, 135.0,
133.3, 128.3, 125.1, 123.0, 63.4, 14.3; MS (ESI) (m/z) 242.23 (M)+.
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Ethyl 5-(trifluoromethyl)benzo[d]thiazole-2-carboxylate (3c)18,1917,18: White solid (193 mg,
70%). mp 73-75 °C; IR (KBr, cm-1) 3078, 2989, 1736, 1493, 1344, 1114; 1H NMR (400 MHz,
CDCl3) δ 8.53 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.79 (dd, J = 8.5, 1.3 Hz, 1H), 4.60 (q, J =
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7.1 Hz, 2H), 1.52 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3) δ 160.8, 160.0, 152.9,
139.9, 130.2, 129.9, 123.6, 122.8, 122.5, 63.2, 14.1; MS (APCI) (m/z) 275.97 (M+H)+.
Ethyl 5-nitro-1H-benzo[d]imidazole-2-carboxylate (3e): Pale yellow solid (70 mg, 30%).
1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 4.7 Hz, 1H),
13
7.07 (dd, J = 2.2, 8.3 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 160.0, 153.5, 139.3, 138.7, 137.6, 125.7, 121.7, 120.4, 64.1, 14.0; MS
(APCI) (m/z) 236.43 (M+H)+; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H10N3O4
236.0671; Found 236.0690.
°
Quinoxalin-2(1H)-one (4d)53: White solid (137 mg, 94%). mp 239-242 C. IR (KBr, cm-1)
1
3650, 2830, 1698, 1682, 1638, 897. H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.76 (d, J =
8.0 Hz, 1H), 7.55 (t, J = 7.2 Hz, 2H), 7.33-7.30 (m, 3H); 13C NMR (100 MHz, DMSO) δ
155.5, 151.7, 132.4, 131.9, 131.4, 129.2, 124.1, 116.2; MS (EI) (m/z) 146.28 (M)+.
1
6-Nitroquinoxalin-2(1H)-one (4e)54: Pale yellow solid (134 mg, 70%). H NMR (400 MHz,
DMSO) δ 8.34 (s, 1H), 8.09-8.04 (m, 3H), 8.00 (s, 1H). 13C NMR (100 MHz, DMSO) δ
155.9, 155.0, 148.0, 135.7, 132.8, 130.7, 117.9, 111.7; MS (EI) (m/z) 191.05 (M)+.
6,7-Dichloroquinoxalin-2(1H)-one (4f)54: Pale yellow solid 185 mg, 86%). High melting
solid (>350 °C); IR (KBr, cm-1) 2886, 1669, 1607, 1388, 916; 1H NMR (400 MHz, DMSO) δ
13
8.28 (s, 1H), 8.12 (s, 1H), 7.53 (s, 2H); C NMR (100 MHz, DMSO) δ 154.9, 153.8, 132.3,
132.3, 131.9, 130.2, 125.5, 117.3; MS (APCI) (m/z) 214.14 (M+H)+.
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