Sulfate Radical Anion (SO4?-) Mediated C(sp3)-H Nitrogenation/Oxygenation in N-Aryl Benzylic Amines Expanded the Scope for the Synthesis of Benzamidine/Oxazine Heterocycles

Article abstract of DOI:10.1021/acs.joc.5b01872

A transition-metal-free, K₂S₂O₈-mediated intramolecular oxidative nitrogenation/oxygenation of C(sp³)-H in N-aryl benzylic amines followed by oxidation at the benzylic center has been developed for the synthesis of benzamidine/benzoxazine heterocycles, providing an expedient access to quinazolin-4(3H)-ones, N-aryl-2-arylbenzimidazoles, and 4H-3,1-benzoxazin-4-ones. A considerable amount of work dealing with the mechanistic study to understand the crucial intramolecular cyclization step largely favors an iminium ion as the key intermediate.

Full text of DOI:10.1021/acs.joc.5b01872

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Article
Sulfate Radical Anion (SO4#¯) Mediated C(sp3)-H Nitrogenation/
Oxygenation in N-Aryl Benzylic Amines Expanded the Scope
for the Synthesis of Benz-amidine/oxazine Heterocycles
Joydev K. Laha, K. S. Satyanarayana Tummalapalli, Akshay Nair, and Nidhi Patel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01872 • Publication Date (Web): 02 Nov 2015
Downloaded from http://pubs.acs.org on November 3, 2015
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Sulfate Radical Anion (SO4˙¯) Mediated C(sp3)-H Nitrogenation/Oxygenation in N-Aryl
Benzylic Amines Expanded the Scope for the Synthesis of Benz-amidine/oxazine
Heterocycles
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Joydev K. Laha,* K. S. Satyanarayana Tummalapalli, Akshay Nair, and Nidhi Patel
Department of Pharmaceutical Technology (Process Chemistry)
National Institute of Pharmaceutical Education and Research
S. A. S. Nagar, Punjab 160062
India
Email: jlaha@niper.ac.in
ABSTRACT.
H
N
H
N
Ar
N
Ar
XH
Ar
[O]
K2S2O8
MeCN, 90°C
X
X
X = CONH, SO2NH,
NAr, O, or CO2
Tandem C(sp3)-H f unctionalization/oxidation
Transition-metal-f ree
Operationally simple and fast
Diverse N-heterocycles
Including uncommon carboxyl group as nucleophile
A transitionꢀmetalꢀfree, K2S2O8 mediated intramolecular oxidative nitrogenation/oxygenation
of C(sp3)ꢀH in Nꢀaryl benzylic amines followed by oxidation at the benzylic center has been
developed for the synthesis of benzamidine/benzoxazine heterocycles providing an expedient
access to quinazolinꢀ4(3H)ꢀones, Nꢀarylꢀ2ꢀarylbenzimidazoles, and 4Hꢀ3,1ꢀbenzoxazinꢀ4ꢀ
ones. A considerable amount of work dealing with the mechanistic study to understand the
crucial intramolecular cyclization step largely favors an iminium ion as the key intermediate.
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INTRODUCTION
The nitrogenation/oxygenation of benzylic C(sp3)ꢀH has long proven didactic value in
organic transformation adding nitrogen/oxygen containing functionality to the benzylic
position.1 The αꢀfunctionalized benzylic amine is a central component of a wide range of
compounds including pharmaceuticals, agrochemicals, performance materials, and bioactive
natural products.2 The capacity of benzylic CꢀH nitrogenation/oxygenation in benzylic
amines to engender a unique structural feature with germinal carbonꢀhetero functionalities
(N,Nꢀacetal or N,Oꢀacetal) at the benzylic position has motivated synthetic chemists toward
the invention of a new, costꢀeffective, and environmentally benign approach. Further
oxidation at the benzylic center could provide benzꢀamidine/oxazine structural motifs that are
ubiquitously found in many natural products, pharmaceuticals, and materials.3 Historically,
nucleophilic additions to the aryl imines using a variety of nitrogen and oxygen nucleophiles
have rendered a circumlocutory approach to the nitrogenation/oxygenation of the benzylic Cꢀ
H in Nꢀaryl benzylic amines.4 The oxidative benzylic CꢀH functionalization in benzylic
amines, pioneered independently by Murahasi5 and Li,6 was largely explored on Nꢀaryl
tetrahydroisoquinolines and tertꢀNꢀalkyl anilines, generally in the presence of a transitionꢀ
metalꢀcatalyst and sacrificial oxidant (Scheme 1).7 Remarkably, a redoxꢀneutral
intramolecular cyclization,8a,8c discernible from an intramolecular oxidative approach,8b has
also been reported yielding various substituted fused Nꢀaryl tetrahydroisoquinolines. A
seminal contribution by Klussmann et al. has enabled inꢀdepth understanding of the
mechanism of these oxidative functionalizations, which relies on nucleophilic addition to the
resulting aryl iminium species.9 Conspicuously, an αꢀamino peroxide derivative was proposed
to be an intermediate in the benzylic functionalization of Nꢀphenyl tetrahydroisoquinoline
employing CuBr/TBHP as oxidant. However, the oxidative benzylic CꢀH
nitrogenation/oxygenation in Nꢀaryl secꢀbenzylic amines (an acyclic benzylic amine), often
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effected in the presence of transitionꢀmetal catalyst/oxidant, has been the subject of a few
reports.10ꢀ12 The intramolecular cyclization of imines, formed in situ under oxidation
conditions, paved the way to the synthesis of quinazolidinꢀ4ꢀones,10 benzimidazoles,11 and
related nitrogen heterocycles.12 Nonetheless, nucleophilic addition to the aryl imine or
iminium species is the only dependable mechanism currently available in the literature for the
functionalization of benzylic position in Nꢀaryl benzylic amines.
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Despite these significant advances, the important questions still remain are, whether: a) a
transitionꢀmetalꢀfree as opposed to transitionꢀmetalꢀcatalyzed oxidative approach could be
developed, b) a single, nonꢀtoxic, inorganic oxidant that is compatible with environmental
safety could execute a desired transformation, c) a wide scope of nitrogen and oxygen
nucleophiles including previously unexplored nucleophiles such as carboxyl group could be
employed, and d) a radical oxidative coupling mechanism distinct from nucleophilic addition
to aryl imine or iminium species could be operative, in case a single oxidant is used.
Therefore, development of
a
transitionꢀmetal free, nonꢀtoxic oxidant mediated
nitrogenation/oxygenation of benzylic CꢀH in Nꢀaryl benzylic amines and subsequent
oxidation to the nitrogen heterocycles containing amidine/oxazine structural motifs is of
paramount importance. Nevertheless, an objective considering these questions collectively
would be a formidable challenge.
Earlier, we demonstrated oxidative removal of benzylic methylene group and subsequent Cꢀ
N bond formation in Nꢀaryl benzylamine embedded in dibenzodiazepines utilizing a cheap,
environmentallyꢀfriendly powerful oxidant K2S2O8.13 Based on our previous experiences on
the synthesis of nitrogen heterocycles,14 we envisaged that intramolecular oxidative
nitrogenation/oxygenation in Nꢀaryl benzylamines, having an internal nucleophile substituted
at the orthoꢀposition in aniline ring, might be brought to fruition under transitionꢀmetalꢀfree
condition. Herein we describe, conceptually distinct from our previous report, a transitionꢀ
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metal free, single oxidant mediated15 novel intramolecular oxidative benzylic C(sp3)ꢀH
nitrogenation/oxygenation and subsequent oxidation, affording annulated nitrogen
heterocycles under green conditions. The protocol appears to be generally applicable in the
synthesis of nitrogen heterocycles including quinazolinꢀ4ꢀones, benzimidazoles, benoxazoles,
and benoxazinꢀ4ꢀones, warranting wide applications of this protocol. The mechanistic study
reveals that an iminium ion could be the key intermediate in the crucial intramolecular
cyclization step. Furthermore, a rarely used nucleophile, for example, a carboxyl group was
demonstrated to participate with the iminium ion cyclizations affording benoxazinꢀ4ꢀones.
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Scheme 1. Benzylic C-H Nitrogenation/Oxygenation in N-Aryl benzylic amines
Previous work :
imines or iminium ions
Benzylic Nitrogenation/Oxygenation through Nucleophilic addition to
cat., ox.
H
X
or
N
N
N
N
Ar
Ar
Ar
Ar
Ar
X
This work
N
CO2 H
X Nucleophilic
addition
(Formed competitively)
[O]
Ar
XH
H
H
H
N
Ar
N
Ar
N
N
Ar
XH
[O]
X
X
X = CONH, SO2NH,
NAr, O, or CO2
Applicable for diverse N-heterocycles
Operationally simple and fast
Transition-metal-free, K2S2O8 mediated
Demonstrated with carboxyl as a nucleophile
N
Ar
CONH2
(Not observed)
RESULTS AND DISCUSSION
Our study commenced with the oxidative cyclization of readily available Nꢀbenzylꢀ2ꢀ
aminobenzamide (1) to the corresponding dihydroquinazolinone 2 and its subsequent
oxidized product 3. K2S2O8 was a judicious choice, largely derived from our previous study,
as the primary oxidant for our optimization study.13 K2S2O8 was practically ineffective below
50 ºC (Table 1, entry 1). A significant reaction was observed at 70 ºC in 1 h affording 3 and
dihydroquinazolinone 2 in 40% and 15% isolated yields, respectively (Entry 2). A complete
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conversion of starting material was observed at 90 ºC in 3 h yielding compound 3 in 80%
yield (Entry 3). However, lower stoichiometry (1 equiv) of K2S2O8 reduces the yield (Entry
4). Likewise, compound 1 gave lower yield (55%) of 3 at higher concentration (Entry 5).
Other solvents produced inferior results (Entry 6ꢀ8). While many other oxidants used in our
study were ineffective, DDQ produced 3 in 50% yield (Entry 9). The oxidative
transformation was ineffective in the presence of a base (Entry 10). The oxidation of 1 in the
presence of allyl acetate, a wellꢀknown radical trap for SO4˙ꢁ,16 gave only a trace amount of 3
(Entry 11). The oxidation comes to a halt in the presence of a free radical quencher such as,
TEMPO or ascorbic acid suggesting that the reaction follows a radical pathway (Entry 12). A
comparable yield was obtained when the oxidation was carried out in the presence of 20
mol% AgOAc (Entry 3 vs. 13).17
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Table 1: Optimization Study for the Synthesis of 3a
H
N
H
N
Ph
NH2
Ph
and/or
N
O
Ph
NH
K2 S2O8
NH
additive, solvent
temp, 4 h
O
O
2
3
1
Entry Additive
Solvent Temp
(ºC)
3
(%)b
1
MeCN RTꢀ50 <10
2c
3
MeCN 70
MeCN 90
MeCN 90
MeCN 90
40
80
45
55
40
4d
5e
6
DCE
90
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MeOH 90
15
5
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8
9
8
Water
90
Trace
50
9f
MeCN 90
MeCN 90
MeCN 90
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10g
11h
12i
Base
0
Allyl acetate
Trace
0
Ascorbic acid MeCN 90
or TEMPO
13
20
mol% MeCN 90
79
AgOAc
a 1 (0.5 mmol), K2S2O8 (1.0 mmol), solvent (5 mL), additive, if any (0.1 ꢀ1.0 mmol), temp., 4
b
c
d
e
h; Isolated yield, Reaction was carried out for 1 h, K2S2O8 (0.5 mmol); MeCN (2.5
f
g
mL); Other oxidants such as TEMPO, PhI(OAc)2, oxone, (NH4)2S2O8, or DTHP; Base
h
i
such as NaOH or K2CO3 (2 equiv); Allyl acetate (2.0 mmol); Free radical quencher (1.0
mmol).
The scope of intramolecular oxidative C(sp3)ꢀN coupling was manifested in the synthesis of
quinazolinones18 and their sulfonyl analogues from the readily accessible substrates 4-16
(Scheme 2). Despite sulfonamide pharmacophores inhabited in many drugs display a
structural diversity, the general paucity of structurally related sulfonamide derivatives of
quinazolinones relies on poor accessibility to these scaffolds. The substrates 4-16 were
prepared by reacting 2ꢀaminobenzamides or –benzenesulfonamides with benzyl bromides in
the presence of tetraꢀbutylammonium bromide (TBAB) at 90 ºC for 6 h. Under the optimized
condition, Nꢀbenzylꢀ2ꢀaminobenzamide 4 participated in the reaction yielding benzosultam
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17 in 80% yield. The substrates 5-11 containing an electronꢀdonating or –withdrawing group
on the benzyl ring work eventfully affording various substituted quinazolinones or sulfonyl
analogues 18-24 in good to excellent yields. However, the substrates 12-15 when exposed to
the optimized condition for a longer period of time yielded the corresponding Nꢀoxides 25-28
due to rapid oxidation of the corresponding cyclized benzosultams. Intriguingly, Nꢀaryl tertꢀ
benzylamine 16 gave the oxidative cyclized product 29 in excellent yield (95%) under the
optimized conditions. It is worthy to note that various functional groups were tolerated under
the optimized condition, which could enable further synthetic manipulations.
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Scheme 2. Synthesis of Various Substituted Quinazolinones and Sulfonyl Analogs
Bn
R
N
Ph
Ar
NH2
N
N
X
Ar
K2S2O8
N
MeCN, 90 oC, 3-16 ha
NH
17-28
Substrate
X
4-16
29
O
Substrate
Product
OMe
Product
OMe
H
N
H
N
N
N
NH
NH2
S
NH
S
NH2
O
O
O
O
O
O
4
5
18 (72%)
17 (80%)
CF3
CF3
R
R
H
H
N
N
O
N
N
NH2
NH2
NH
X
19 X = CO (77%)
NH
X
6 X = CO
X = SO2
O
8b
9
21 R = Me (80%)c
20
X = SO2 (71%)
R = Me
7
R = CO2Me
22 R = CO2Me (90%)
Cl
Cl
H
N
H
N
N
N
NH2
S
NH
S
NH2 Br
NH Br
O
O
O
O
O
11
O
24 (55%)
10
23 (72%)
R
R
R
R
O
N
O
N
H
N
H
N
NH
NH
NH2
S
O
NH2
O
S
S
S
O
O
O
O
O
O
12 R = Me
13 R = OMe
27 R = Me (66%)
28 R = OMe (51%)
14 R = Me
15 R = OMe
25 R = Me (50%)
26 R = OMe (62%)
a
Time: 3-4 h for N-benzyl benzamides and12-16 h for N-benzyl benzenesulfonamides;
Formed in-situ from the reaction of 2-aminobenzamide and 4-methyl benzylbromide;
b
c Corresponds to the overall yield in two-steps (see one-pot synthesis)
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The expanded scope of the current protocol was further demonstrated in the synthesis of
benzimidazoles (Scheme 3).19 The starting substrates 30-38 were prepared from 2ꢀ
bromoanilines by baseꢀmediated Nꢀbenzylation followed by palladiumꢀcatalyzed N´ꢀ
arylation. Under the optimized condition, substrates 30-38 participated in the intramolecular
oxidative CꢀN/CꢀO bond formation, which upon further oxidation gave various substituted Nꢀ
arylꢀ2ꢀarylbenzimidazoles 39-47. However, attempted preparation of benzimidazole 40
containing a free NꢀH was unsuccessful. To our delight, Nꢀbenzylꢀ2ꢀaminophenol 38
undergoes intramolecular oxidative CꢀO coupling to form 2ꢀaryl benzoxazole 47 in 52%
yield.
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Scheme 3. Synthesis of Various Substituted Benzimidazoles and Benzoxazole
H
N
Ph
N
X
K2S2O8
Ph
R1
R1
MeCN, 90 oC, 4 h
NHR2/OH
30-38
39-47
Product
N
Substrate
Product
Substrate
H
N
Ph
H
N
Ph
Ph
N
N
N
R
Ph
R
NH
NH
R
R
Me
39
30 R = Ph
R = Ph (75%)
40 R = H (0%)
Me
Me
Me
31 R = H
32 R = H
33 R = Me
41 R = H (87%)
42 R = Me (90%)
H
N
Ph
H
N
Ph
N
N
Ph
Ph
N
R1
NH
N
Ph
46 (85%)
F
R1
F
NH
Ph
37
R2
43 R1 = Me, R2 = NO2 (95%)
35 R1 = F, R2 = NO2 44 R1 = F, R2 = NO2 (80%)
36 R1 = Me, R2 = F 45 R1 = Me, R2 = F (96%)
H
N
R2
Ph
N
34 R1 = Me, R2 = NO2
Ph
O
OH
38
47 (52%)
Because of poor nucleophilicity of an aryl carboxyl group, a nucleophilic addition to aryl
amines has been less successful to the synthesis of benzoxazinꢀ4ꢀones although they have
been prepared in multiꢀsteps.20 A direct access to benzoxazinꢀ4ꢀones from Nꢀaryl benzylic
amines is, to the best of our knowledge, unprecedented. The starting substrates 48-52 were
prepared from their corresponding 2ꢀaminobenzoic acids and aryl aldehydes using reductive
amination protocol and the crude substrates were used in the next cyclization step without
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purification. Notably, the crude substrates were sufficiently pure except compound 50 and
their characterization data were found satisfactory. Thus, Nꢀbenzylꢀ2ꢀaminobenzoic acid 48
gave benzoxazinꢀ4ꢀone 53 albeit in poor yield (15%) under oxidative condition (Scheme 4).
A brief survey of different substituents on two rings reveals their substantial influence in the
product formation. The presence of two strong electronꢀdonating groups in benzoic acid ring
improves the yield by about 4ꢀfold. However, the electronꢀdonating or ꢀwithdrawing groups
in benzyl ring have subordinate effect as observed in the synthesis of 55-57. Noticeably, aryl
aldehydes and 2ꢀaminobenzoic acids were the two major byꢀproducts in these reactions.
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Scheme 4. Synthesis of Substituted Benzoxazin-4-ones
Ph
NH
N
O
Ph
K2S2O8
R
R
MeCN, 90 oC, 8 h
O
CO2H
48-52
53-57
Substrate
Product
Substrate
Product
N
H
N
MeO
MeO
Ph
H
N
MeO
MeO
Ph
OH
N
O
O
OH
O
O
O
48
O
54
(60%)
49
53
R = H (15%)
R1
R2
R1
R2
H
N
MeO
MeO
N
O
MeO
MeO
50a
O
OH
O
55 R1 = NO2 , R2 = H (35%)b
56 R1 = Me, R2 = H (30%)
57 R1 = OH, R2 = OMe (trace)
R1 = NO2, R2 = H
51 R1 = Me, R2 = H
52 R1 = OH, R2 = OMe
a Used the crude product obtained from the reaction of the corresponding benzoic acid and
4-methyl benzylbromide; b Corresponds to the overall yield in two-steps.
A oneꢀpot synthesis of benzamidine heterocycles, exemplified in the synthesis of
quinazolinones 3 and 21 from their corresponding commercially available materials, was
achieved by reacting 2ꢀaminobenzamides and benzyl bromides in the presence of TBAB
followed by treating the reaction mixture with K2S2O8 under the optimized condition
(Scheme 5).
Scheme 5. One-pot Synthesis of Quinazolinones
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7
Br
NH2
NH3
1. TBAB, MeCN, 90 o
C
N
O
Ph
NH
2. K2S2O8, MeCN, 90 oC
+
One-pot synthesis
R
O
3 R = H (55%)
21 R = Me (80%)
Benzyl bromide R = H
4-Methylbenzyl bromide R = Me
8
9
The following mechanism involving a key intramolecular cyclization of iminium ion is
proposed in Scheme 6. Initially, reaction of 1 and sulphate radical anion (SO4˙ꢁ), generated in
situ from K2S2O8 under thermolysis,21 could form a benzyl radical 58, which upon subsequent
oxidation could generate an iminium ion 59. However, other pathways to form iminuim ion
59 are not ruled out.7 An intramolecular nucleophilic addition in 59, similar to that reported in
literature,7 followed by oxidation could give quinazolinone 3. In a competitive manner, the
iminium ion 59 could also produce αꢀamino benzyl sulfate 61 upon capture of a sulfate anion
10
11
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13
14
15
16
17
18
19
20
21
22
23
24
25
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29
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35
36
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀ
(SO4 ). Benzyl sulfate 61 could also give quinazolinone 3 via imine (60) formation followed
by intramolecular nucleophilic addition and subsequent oxidation. Other pathways that could
possibly form imine 60 are not ruled out.
Scheme 6. Proposed mechanism for the benzylic C-H functionalization
O
S
O
S
heat
2
O
O
O
O
K
K
OSO2O
K
O
O
H
N
H
N
H
Ph
NH
Ph
N
Ph
OSO2O
OSO2O
1
NH2
CONH2
58
59
O
2
O
2-
SO4
N
[O]
H
N
Ph
Ph
OSO2O
CONH2
60 (Not observed)
3
CONH2
61
Additional experiments were carried out to gain confidence on the proposed mechanism.
The reaction of 1 under the optimized conditions in the presence of excess allyl acetate,17
gave only a trace of 3 suggesting the direct participation of SO4˙ꢁ in these oxidative
transformations, disparate to Agꢀcatalyzed persulfate oxidation.18 Under the standard
conditions, an optically pure Nꢀbenzylaniline 63 resulted in a nearly quantitative recovery of
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starting 63 with extremely low optical purity (Scheme 7). The formation of a benzyl radical22
64 could cause racemization at the benzylic center. The presence of a considerable amount of
unreacted starting 63 in the recovered sample could account for the low optical purity.
Scheme 7. Evidence for the Formation of Benzyl Radical
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16
17
18
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21
22
23
24
25
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49
50
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52
53
54
55
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58
59
60
H
N
H
Ph
Me
N
Ph
K2S2O8
MeCN, 90 oC, 4 h
Me
63 (>99% ee)
64
racemization
H
N
Ph
Me
63 (35% ee)
Evidently, a benzyl sulfate might be formed in the following experiments (Scheme 8).
Under the standard conditions, reactions of Nꢀbenzylanilines 65-66 without having an orthoꢀ
functional group gave oxidized product Nꢀbenzoylanilines 67-68. While attempt isolation of
the benzyl sulfate (69-SULFATE) in the conversion of 65 to 67 was unsuccessful, a
hydrolyzed product 69 was evident from the HRMS data (See in the Supporting Information).
In the absence of any internal nucleophile, the benzyl sulfates, if formed, could give imine or
undergo further oxidation to Nꢀbenzoylanilines 67-68. Hydrolysis of imines could generate
the corresponding aldehydes that could account for nonꢀpolar products formed in these
reactions.
Scheme 8. Evidence for the Formation of Benzyl sulfate
R2
R3
H
N
H
N
K2S2O8
MeCN, 90 o C, 4 h
O
R1
R1
65 R1 = Cl, R2 = H
66 R1 = Cl, R2 = Br
67 70% (R1 = Cl, R2 = H)
68 45% (R1 = Cl, R2 = Br)
H
N
H
N
workup
OSO2O
OH
Cl
H
Cl
69
69-SULFATE
(Observed in HRMS)
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7
8
9
Notably, compounds 4, 9, and 35 appeared to be the most reactive substrates giving highest
yields of the cyclized products in the respective series. However, a competitive experiment
involving heating a mixture of 4, 9, and 35 (each 0.5 mmol) in the presence of K2S2O8 (1.0
mmol) in MeCN (5 mL) at 90 ºC for 12 h gave 2ꢀarylbenzimidazole 44 as major isolable
product in 78% yield, comparable to that obtained when 35 was reacted independently
(Scheme 9). This experiment reveals that compound 35 has the superior reactivity among the
three compounds. Probably, the enhanced nucleophilicity of nitrogen in NHAr group could
facilitate intramolecular nucleophilic addition to iminium ion in 35.
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48
49
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54
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58
59
60
Scheme 9. Competition Experiment
H
CO2Me
+
N
Ph
H
N
H
N
F
NH
+
NH2
NH2
S
4
O
O
O
9
NO2
35
(each 0.5 mmol)
K2S2O8 (1 mmol)
MeCN, 90 oC, 12 h
N
N
Ph
F
NO2
44 (78%)
To understand whether imine 60 was formed in the reaction, a time course of the reaction
at 70 ºC (30 min, 1 h, 2 h, and 4 h) was followed by TLC, GCꢀMS, and 1H NMR data. At any
time point, the data collected did not indicate the formation of aryl imine 60 (See the
I
overlapping H NMR spectra of the reaction mixture at a time point with 2 and 60, prepared
independently). Furthermore, a more close time point (every 5 min) in the 30 min to 1 h timeꢀ
block revealed the formation of unreacted starting material 1, compound 2 and quinazolinone
3 with a variable composition. Central to the mechanistic study was the finding that the
formation of aryl imine 60 was not observed in the conversion of 1 to quinazolinone 3. In
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stark contrast, aryl imine 62 and 4,5ꢀdimethoxyanthranilic acid were the two byꢀproducts
formed in the conversion of acid 49 to benoxazapinꢀ4ꢀone 54 (Scheme 4). More importantly,
attempted conversion of 62 to 54 under the standard conditions was unsuccessful (Eqn 1).
Therefore, formation of an iminum ion is likely involved in the reaction of 49, which upon
subsequent intramolecular cyclization could give 54.
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48
49
50
51
52
53
54
55
56
57
58
59
60
MeO
MeO
N
K2S2O8
MeO
MeO
N
Ph
Ph
Eqn 1
O
MeCN, 90 oC, 8 h
CO2H
62
O
54
Collectively, these experiments are intuitive for the SO4˙ꢁ mediated oxidative benzylic CꢀH
functionalization that favors the intramolecular cyclization via an iminium ion as the key
intermediate. The intramolecular cyclization in iminium ion 59 could give 2, which upon
further oxidation by SO4˙ꢁ forms quinazolinone 3. While tertꢀbenzylamine 16 gave 29 under
the optimized conditions, the reaction of 16 (0.5 mmol) and K2S2O8 (1 mmol) in
MeCN/MeOH (4 mL, 3:1) at 90 °C for 4 h gave 29 and 3 in 34% and 27% yields,
respectively. The intramolecular nucleophilic addition of iminium ion 70 could give 29. The
formation of compound 3 in this reaction could be explained by the external nucleophilic
attack of methanol. Thus, methanol could react with 70 to ultimately give 3 through a
sequence of reactions as shown in Scheme 10.
Scheme 10. Oxidative Functionalizations of tert-Benyzlamine 16 via nucleophilic
addition to iminium ion 70
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Bn
Bn
N
N
Ph
Ph
NH2
N
O
Ph
NH
K2S2O8
+
N
MeCN/MeOH (3:1)
90 oC, 4 h
6
O
O
7
29 (34%)
3 (27%)
16
8
9
Bn
N
H
N
10
11
12
13
14
15
16
17
18
19
20
21
22
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29
30
31
32
33
34
35
36
37
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
O
NH2
N
O
Ph
NH2
O
N
MeOH
Ph
OMe
N
Ph
OMe
N
Ph
O
70
OMe
71
73
72
MeOH
In conclusion, an intramolecular oxidative nitrogenation/oxygenation of benzylic C(sp3)ꢀH
bond, a widely sought yet elusive transformation, has been demonstrated in the synthesis of
diverse benzamidine/benzoxazine heterocycles. The protocol described herein proceeds
through a key step, intramolecular nucleophilic addition to imines followed by oxidation at
the benzylic center. While the intermediacy of an imine 60 was not observed, aryl imine 62
formed in the reaction. Furthermore, a carboxyl group, rarely used as nucleophile in related
iminium ion cyclizations, was used affording benoxazinꢀ4ꢀones. While our protocol augurs
interesting synthetic applications, developing an intermolecular version and subsequent
applications to the synthesis of an antiꢀpsychotic drug Clozapine, and understanding a
detailed mechanism are the subjects of further investigation.
EXPERIMENTAL SECTION
General Methods: Unless noted otherwise, all reagents and solvents were purchased from
commercial sources and used as received. All reactions were carried out using a clean oven
dried screwꢀcapped reaction tube of 10 mL capacity. The progress of the reaction was
monitored by TLC (Thin Layer Chromatography) wherein visualization was carried out with
UV light (254 nm) and/or I2 vapours. Column chromatography was performed on silica gel
[100ꢀ200 mesh]. H and 13C NMR spectra were obtained in CDCl3 or DMSOꢀd6 as solvent
1
using a 400 MHz spectrometer with Me4Si as an internal standard. Coupling constants (J
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values) are reported in Hz. High resolution mass spectra (HRMS) were obtained using
electron spray ionization technique (ESI) and as TOF mass analyzer. All melting points were
recorded using a melting point apparatus equipped with a calibrated thermometer and are
uncorrected. Compounds1,24 2,25 3,24 17,18a 30,13 39,26 47,11 and 6327 are known in literature.
Compounds 31, 38, 48, 53, and 65 were obtained from commercial suppliers.
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60
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Typical Procedure for the Preparation of 2-(Benzylamino)benzamides. A mixture of 2ꢀ
aminobenzamide (1.0 mmol), TBAB (2.5 mmol) and benzyl bromide (1.2 mmol) in
acetonitrile (4 mL) was heated at 90 ℃ for 6 h in a screwꢀcapped reaction tube. After
completion of the reaction, water (50 mL) was added to the reaction mixture. The mixture
was then extracted with EtOAc (50 mL x 3), dried (Na2SO4), and concentrated under reduced
pressure. Column chromatography [silica gel, EtOAc: hexane (1:4)] of the crude product
yielded 2ꢀ(benzylamino)benzamides.
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Typical Procedure for the Preparation of 2-Arylquinazolin-4(3H)-ones. A mixture of 2ꢀ
(benzylamino)benzamides (0.5 mmol) and K2S2O8 (1.0 mmol) in acetonitrile (5 mL) was
heated at 90 ℃ for 3ꢀ4 h in a screwꢀcapped reaction tube. After completion of the reaction
(monitored by TLC analysis), water (25 mL) was added and the resulting mixture was
extracted with EtOAc (20 mL x 3), and then dried over anhydrous Na2SO4. Concentration
under reduced pressure followed by chromatography of the crude [silica gel, 30% EtOAc:
hexane] gave 2ꢀarylquinazolinꢀ4(3H)ꢀones.
Typical Procedure for the Preparation of 2-(Benzylamino)benzenesulfonamides. A
mixture of 2ꢀaminobenzenesulfonamide (1.0 mmol), TBAB (2.5 mmol), and benzyl bromide
(1.2 mmol) in acetonitrile (4 mL) was heated at 90 ℃ for 6 h in a screwꢀcapped reaction tube.
After completion of the reaction, water (50 mL) was added to the reaction mixture. The
mixture was then extracted with EtOAc (50 mL x 3), dried (Na2SO4), and concentrated under
reduced pressure. Column chromatography [silica gel, EtOAc: hexane (2:3)] of the crude
product yielded 2ꢀ(benzylamino)benzenesulfonamide.
Typical Procedure for the Preparation of Sulfonyl Analogs of 2-Arylquinazolin-4(3H)-
ones. A mixture of 2ꢀ(benzylamino)benzenesulfonamide (0.5 mmol) and K2S2O8 (1.0 mmol)
in acetonitrile (5 mL) was heated at 90 ℃ for 12ꢀ16 h in a screwꢀcapped reaction tube. After
completion of the reaction (monitored by TLC analysis), water (50 mL) was added and the
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resulting mixture was extracted with EtOAc (30 mL x 3), and then dried over anhydrous
Na2SO4. Concentration under reduced pressure followed by chromatography of the crude
[silica gel, 60% EtOAc: hexane] and/or recrystallization from EtOAc: dichloromethane (1:2)
gave the title compound.
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49
50
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53
54
55
56
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58
59
60
Typical Procedure for the Preparation of N-Aryl-N´-benzyl-1,2-diaminobenzenes. To a
stirred suspension of 2ꢀbromoaniline (2 mmol), and NaH (2 mmol), benzyl bromide (2.4
mmol) in DMF (10 mL) was added dropwise at room temperature under argon and the
reaction mixture was allowed to stir at room temperature for 3 h. After completion of the
reaction, the reaction mixture was quenched with saturated aqueous NH4Cl followed by
addition of water (150 mL). The mixture was then extracted with EtOAc (50 mL x 4), and the
organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced
pressure. Chromatography [silica gel, EtOAc:hexane (5:95)] of the crude yielded Nꢀbenzylꢀ2ꢀ
bromoanilines.
A mixture of Nꢀbenzylꢀ2ꢀbromoaniline (1.5 mmol), aniline (1.5 mmol), Pd(OAc)2 (0.15
mmol), SꢀPhos (0.15 mmol), and Cs2CO3 (3.0 mmol) in anhydrous toluene (6 mL) was
o
degassed for about 5 min and then heated at 110 C for 16 h. The resulting mixture was
filtered through a Celite bed and the solid residue was washed with EtOAc (10 mL). Water
(50 mL) was added to the filtrate and the aqueous layer was extracted with EtOAc (50 mL x
3). The combined organic layer was collected and dried over anhydrous Na2SO4. The solvent
was evaporated under vacuum and the crude reaction mixture was purified by column
chromatography on silica gel using 10% EtOAc: hexane as eluent, which upon drying under
vacuum yielded the title compound.
Typical Procedure for the Preparation of 1,2-Diphenyl-1H-benzo[d]imidazoles. A
mixture of NꢀbenzylꢀN´ꢀphenylꢀ1,2ꢀdiaminobenzene (0.5 mmol) and K2S2O8 (1 mmol), in
acetonitrile (5 mL) was heated at 90 ℃ for 4ꢀ6 h in a screwꢀcapped reaction tube. After
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completion of the reaction, water (25 mL) was added and the resulting mixture was extracted
with EtOAc (25 mL x 3), and then dried over anhydrous Na2SO4. Concentration under
reduced pressure followed by chromatography of the crude [silica gel, 20% EtOAc: hexane]
9
1,2ꢀdiphenylꢀ1Hꢀbenzo[d] imidazoles
.
10
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Typical Procedure for the Preparation of 2-(Benzylamino)benzoic acids 48ꢀ52. The
appropriate starting primary amine (2.0 mmol) and aldehyde (2.0 mmol) in MeOH (5 mL)
were stirred for 30 min at room temperature. NaBH4 (3.5 mmol) and NaOH (0.4 mmol) in
H2O (1 mL) were added to the reaction mixture, and the resulting solution was stirred for 6 h.
The reaction was diluted with CH2Cl2 (200 mL) and washed with water (200 mL). The
organic layer was filtered and dried over MgSO4, and the solvent was removed. The crude
solid was used in the next cyclization step without purification.
Typical Procedure for the Preparation of Benzoxazin-4-ones. A mixture of 2ꢀ
(benzylamino)benzoic acids (0.5 mmol) and K2S2O8 (1.0 mmol) in acetonitrile (5 mL) was
heated at 90 ℃ for 8 h in a screwꢀcapped reaction tube. After completion of the reaction
(monitored by TLC analysis), water (50 mL) was added and the resulting mixture was
extracted with EtOAc (20 mL x 3), and then dried over anhydrous Na2SO4. Concentration
under reduced pressure followed by chromatography of the crude [silica gel, 20% EtOAc:
hexane] gave benzoxazinꢀ4ꢀones.
Typical Procedure for the Preparation of compounds 60 and 62. The appropriate starting
primary amines [2ꢀaminobenzamide or 4,5ꢀdimethoxyꢀ2ꢀaminobenzoic acid, 1.0 mmol] and
aldehyde (1.0 mmol) in CH2Cl2 or MeOH (2 mL) were stirred overnight at room
temperature. Concentration followed by recrystallization from methanol gave the compounds.
2-(Benzylamino)benzenesulfonamide (4): Yield 98% (256 mg); Pale yellow solid; mp: 98ꢀ
100 ºC; 1H NMR: δ 7.75 (dd, 7.7, 1.2Hz, 1H), 7.40 (m, 2H), 7.23ꢀ7.25 (m, 4H), 6.70 (m, 2H),
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4.49 (s, 2H); 13C NMR: δ 145.1, 138.8, 133.4, 128.2, 126.7, 126.6, 124.6, 115.3, 112.4, 46.5;
5
6
HRMS: obsd 263.0840 calcd. 263.0854 for C13H15N2O2S (M+H).
7
8
9
2-(3-Methoxybenzylamino)benzamide (5): Yield 99% (253mg); Colourless solid; mp: 133ꢀ
135 ºC; 1H NMR: δ 7.41 (dd, J=8.4, 1.4Hz, 1H), 7.24ꢀ7.29 (m, 3H), 6.97 (dd, J=7.5, 0.6Hz,
1H), 6.93 (s, 1H), 6.80 (dd, J=8.1, 2.2, 1H), 6.59ꢀ6.66 (m, 2H), 4.43 (s, 2H), 3.80 (s, 3H); 13C
NMR: δ 172.07, 159.9, 150.1, 140.8, 113.5, 129.6, 128.2, 119.2, 114.8, 113.1, 112.5, 112.4,
55.2, 47.2; HRMS: obsd 257.1288, calcd. 257.1290 for C15H17N2O2 (M+H).
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16
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(3-(Trifluoromethyl)benzylamino)benzamide (6): Yield 97% (285 mg); Pale brown
solid, mp: 126ꢀ128 ºC, 1H NMR : δ 7.62 (s, 1H), 7.56 (d, J=7.6, 1H), 7.52 (d, J=7.7Hz, 1H),
6.47 (dt, J=8.0, 1.4Hz, 2H), 7.26 (dt, J=8.1, 1.4Hz, 1H), 6.65 (dt, J=8.0, 1.2Hz, 1H), 6.55
(d, J=8.4Hz, 1H), 4.43 (s, 2H), 3.80 (s, 3H); 13C NMR: δ 172.1, 149.9, 149.3, 140.3, 133.5,
130.2, 129.1, 128.3 (q, J=261.0Hz), 127.1, 125.5, 123.9, 123.7 (q, J=16.0Hz), 117.4, 115.3,
113.3, 112.2,46.6 ; HRMS: obsd 295.1049, calcd. 295.1058 for C15H14F3N2O (M+H).
2-(3-(trifluoromethyl)benzylamino)benzenesulfonamide (7): Yield 98% (323 mg); Pale
1
brown solid; mp: 147ꢀ149 ºC; H NMR: δ 7.83 (dd, J=7.9, 1.5Hz, 1H), 7.62 (m, 2H), 7.45
(m, 2H), 7.33ꢀ7.39ꢀ (dt, J=7.1, 1.4Hz, 1H), 6.81 (dt, J=7.2, 0.9 Hz, 1H), 6.67 (d, J=8.2 Hz,
1H), 6.34 (br, 1H), 4.95 (s, 2H), 4.53 (d, J=5.6 Hz, 2H); 13C NMR: δ 145.1, 142.2, 134.6,
129.9, 129.6, 128.9 (q, J=280.0Hz), 127.1, 125.8(q, J=13.0Hz), 125.7, 124.1, 117.1, 113.0,
46.9 ; HRMS: obsd 330.0643 calcd. 330.0650 for C14H13F3N2O2S (M+).
Methyl 4-((2-carbamoylphenylamino)methyl)benzoate (9): Yield 99% (281 mg);
Yellowish white solid; mp: 152ꢀ153 ºC, 1H NMR: δ 8.0 (d, J=8.3Hz, 2H), 7.45 (m, 3H), 7.25
(dt, J=7.2, 1.5 Hz, 1H), 6.63 (t, J=8Hz, 1H), 6.59 (d, J=8.4Hz, 1H), 4.5 (s, 2H), 3.9 (s, 3H);
13C NMR: δ 172.1, 166.9, 149.5, 144.4, 133.5, 129.9, 129.0, 128.3, 126.9, 115.5, 113.6,
112.6, 52.0, 47.0; HRMS: obsd 285.1235, calcd 285.1239 for C16H17N2O3 (M+H).
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2-(4-Chlorobenzylamino)benzenesulfonamide (10): Yield 97% (287 mg); Pale yellow
1
solid; mp: 148ꢀ150 ºC; H NMR: δ 7.83 (dd, 7.9, 1.5 Hz, 1H), 7.27ꢀ7.39 (m, 5H), 6.81 (dt,
7
8
9
8.0, 0.9 Hz, 1H), 6.70 (d, 8.2 Hz, 1H), 6.25 (s, 1H), 4.89 (s, 2H), 4.43 (d, 5.2 Hz, 2H); 13C
NMR: δ 145.2, 136.5, 134.6, 133.2, 129.0, 128.8, 124.1, 117.0, 113.0, 46.7; HRMS: obsd
297.0453 calcd. 297.0465 for C13H14ClN2O2S (M+H).
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2-(2-Bromobenzylamino)benzamide (11): Yield 100% (304 mg); Pale yellow solid; mp:
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162ꢀ164 ºC; H NMR: δ 7.58 (dd, J=7.9, 1.1Hz, 1H), 7.44 (dd, J=7.8, 1.4Hz 1H), 7.38 (td,
J=7.7, 0.8Hz, 1H), 7.23ꢀ7.29 (m, 2H), 7.13 (dt, J=7.4, 1.7Hz, 1H), 6.63 (dt, J=8.0, 1.0Hz,
1H), 6.56 (d, J=7.9Hz, 1H), 4.51 (s, 2H); 13C NMR: δ 172.0, 149.9, 137.7, 133.6, 132.7,
128.5, 128.4, 128.2, 127.5, 123.0, 115.1, 113.2, 112.3, 47.1; HRMS: obsd 305.0278, calcd.
305.0290 for C14H14BrN2O (M+H).
2-(3-Methylbenzylamino)benzenesulfonamide (12): Yield 98% (270 mg); Colorless liquid;
1H NMR: δ 7.74 (dd, J=7.9, 1.4Hz, 1H), 7.35 (dt, J=7.3, 1.5Hz, 1H), 7.17 (t, J=7.8Hz, 1H),
7.07 (d, J=7.5Hz, 1H), 6.98 (m, 2H), 6.83 (dt, J=8.1, 1.0Hz, 1H), 6.78 (dd, J=8.1, 0.8Hz,
1H), 5.06 (t, 5.8Hz, 1H), 4.87 (s, 2H), 4.02 (d, J=6.2Hz, 2H); 13C NMR: δ 145.0, 138.3,
136.1, 134.2, 129.7, 128.6, 128.5, 128.3, 124.8, 121.6, 117.9, 117.7, 47.2, 21.2; HRMS: obsd
277.1011, calcd. 277.1007 for C14H17N2O2S (M+H).
2-(3-Methoxybenzylamino)benzenesulfonamide (13): Yield 97% (283 mg); Pale yellow
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semiꢀsolid; H NMR: δ 7.82 (dd, J=7.9, 1.6Hz, 1H), 7.38 (dt, J=7.3, 1.6Hz, 1H), 7.28 (m,
1H), 6.94 (dd, J=7.5, 0.5Hz, 1H), 6.90 (d, J=2Hz, 1H), 6.82 (m, 1H), 6.78 (t, J=7.8Hz, 2H);
13C NMR: δ 160.0, 159.7, 145.4, 139.7, 138.8, 134.5, 129.9, 129.6, 128.7, 124.1, 121.9,
119.2, 116.8, 114.9, 113.6, 113.1, 112.9, 112.6, 55.2, 47.4; HRMS: obsd 293.0947 calcd.
293.0960 for C14H17N2O3S (M+H).
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2-(4-Methylbenzylamino)benzenesulfonamide (14): Yield 99% (273 mg); Colorless liquid;
1H NMR: δ 7.75 (dd, J = 7.9, 1.4Hz, 1H), 7.35 (dt, J=7.3, 1.5Hz, 1H), 7.17 (t, J=7.8Hz, 1H),
7.07 (d, J=7.5Hz, 1H), 6.98 (m, 2H), 6.83 (dt, J=8.1, 1.0Hz, 1H), 6.78 (dd, J=8.1, 0.8Hz,
1H), 5.06 (t, 5.8Hz, 1H), 4.87 (s, 2H), 4.02 (d, J=6.2Hz, 2H); 13C NMR: δ 145.0, 138.3,
136.1, 134.2, 129.7, 128.6, 128.5, 128.3, 124.8, 121.6, 117.9, 117.7, 47.2, 21.2; HRMS: obsd
277.1007, calcd. 277.1011 for C14H17N2O2S (M+H).
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2-(4-Methoxybenzylamino)benzenesulfonamide (15): Yield 97% (283 mg); Colorless
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liquid; H NMR: δ = 7.74 (dd, J=8.0, 1.5 Hz, 1H), 7.35 (dt, J = 7.3, 1.5 Hz, 1H), 7.10 (m,
2H), 6.77ꢀ6.84 (m, 4H), 5.03 (t, J=5.0 Hz, 1H), 4.87 (s, 1H), 3.99 (d, J=5.8 Hz, 2H), 3.80 (s,
3H); 13C NMR: δ 159.2, 145.0, 134.2, 130.4, 129.7, 129.2, 129.0, 128.6, 128.4, 128.2, 121.5,
117.9, 117.7, 114.2, 114.1, 114.0, 113.8, 55.3, 46.8; HRMS: obsd 293.0956, calcd. 293.0960
for C14H17N2O3S (M+H).
2-(Dibenzylamino)benzamide (16): Yield 98% (309 mg); Yellow solid;
1H NMR: δ 8.21
(dd, J=7.8, 1.7Hz, 1H), 7.37 (dt, J=7.4, 1.6Hz, 1H), 7.29ꢀ7.31 (m, 6H), 7.23 (dt, J=8.1,
0.9Hz, 1H), 7.11ꢀ7.19 (m, 4H), 6.99 (d, J=8Hz, 1H), 4.14 (s, 4H), 5.40 (s, 2H); 13C NMR: δ
168.4, 149.0, 137.0, 131.9, 131.8, 130.6, 129.5, 129.1, 128.7, 128,3, 128.2, 128.1, 127.8,
127.7, 127.3, 124.0, 123.9; HRMS: obsd 317.1644, calcd. 317.1654 for C21H21N2O (M+H).
2-(3-Methoxyphenyl)quinazolin-4(3H)-one (18): Yield 72% (91 mg); Pale brown solid;
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mp: 195ꢀ197 ºC, H NMR: δ 11.53 (s, 1H), 8.33 (dd, J=7.8, 0.8Hz, 1H), 7.78ꢀ7.88 (m, 4H),
7.50ꢀ7.55 (m, 2H), 7.15 (dd, J=8.3, 2.4Hz, 1H), 3.98 (s, 3H); 13C NMR: δ 163.65, 160.19,
151.56, 149.44, 134.93, 134.17, 130.15, 128.06, 126.87, 126.36, 120.94, 119.53, 118.28,
112.25, 55.55; HRMS: obsd 253.0967, calcd 253.0972 for C15H13N2O2 (M+H).
2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (19): Yield 77% (112 mg); Colourless
solid; mp: 237ꢀ239 ºC; 1H NMR : δ 11.95 (s, 1H), 8.67 (s, 1H), 8.52 (d, J=7.9 Hz, 1H), 8.40
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(dd, J=7.6, 0.8 Hz, 1H), 7.87–7.89 (m, 3H), 7.76 (t, J=7.8 Hz 1H), 7.59 (dt, J=7.6, 2.16 Hz,
1H); 13C NMR: δ 162.09, 150.9, 148.4, 134.6, 133.6, 131.7, 129.8, 129.5, 129.2, 127.7, 127.6,
126.9(q, J=278.0Hz), 125.8, 125.0, 124.4(q, J=14.0Hz), 122.5, 121.1 ; HRMS: obsd
291.0739, calcd. for 291.0740 for C15H10F3N2O (M+H).
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3-(3-Trifluoromethylphenyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (20): Yield 71%
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(116 mg); Colourless solid, mp: >300 ºC, H NMR: δ 12.61 (s, 1H) 8.20 (m, 2H), 8.16 (d,
J=7.0Hz, 1H), 7.85 (t, J=8.2Hz, 1H), 7.75(d, J=8.0Hz, 1H), 7.63 (d, J=8.0Hz, 2H), 7.54 (t,
J=7.8Hz, 1H); 13C NMR: δ 154.1, 136.2, 135.8, 133.7, 130.1, 129.7, 127.4(q, J=230.0Hz),
126.2(q, J=10.0Hz), 126.1,123.8, 121.9, 119.1 ; HRMS: obsd 327.0411, calcd. 327.0415 for
C14H10F3N2O2S (M+H).
2-(4-Methylphenyl)quinazolin-4(3H)-one (21): Yield 80% (94 mg); Colourless solid, mp:
1
181ꢀ183 ºC, H NMR : δ 8.32 (d, J=8.4Hz, 1H), 8.18 (d, J=8.2Hz, 2H), 7.76ꢀ7.82 (m, 2H),
7.4 (dt, J=8.1, 1.8Hz, 1H), 7.36 (d, J=8.0Hz, 2H), 2.44 (s, 3H). 13C NMR: δ 164.1, 151.9,
149.7, 142.1, 134.8, 130.0, 129.7, 127.9, 127.4, 126.5, 126.3, 120.7, 21.5; HRMS: obsd.
237.1021, calcd. 237.1028 for C15H13N2O (M+H).
Methyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)benzoate (22): Yield 90% (126 mg);
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Colourless solid; mp: 254ꢀ256 ºC; H NMR : δ 12.75 (s, 1H), 8.31 (d, J=8.4Hz, 2H), 8.17
(dd, J=7.8,1.0Hz, 1H), 8.11 (d, J=8.4Hz 2H), 7.85 (dt, J=8.3, 1.4Hz, 1H), 7.78 (d, J=7.8Hz,
1H), 7.56 (dt, J=7.9, 0.8Hz , 1H), 3.90 (s,3H); 13C NMR: δ 166.1, 162.6, 151.9, 148.9,
137.3, 135.2, 132.2, 129.7, 128.6, 128.1, 127.5, 126.3, 121.6, 52.9; HRMS: obsd 281.0927,
calcd. 281.0926 for C16H13N2O3 (M+H); IR (KBr): 2922, 2851, 1732, 1673, 1282, 1114 cmꢀ1.
3-(4-Chlorophenyl)-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (23): Yield 72% (105 mg);
Pale yellow solid; mp: >300 ºC; 1H NMR: δ 8.07 (d, J = 7.0Hz, 2H), 7.87 (dd, J=7.9, 1.1Hz,
1H), 7.73 (m, 3H), 7.62 (d, J=8.0Hz, 1H), 7.52 (dt, J=7.8, 0.7Hz, 1H); 13C NMR: δ 153.7,
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137.7, 135.3, 133.2, 130.5, 130.1, 128.9, 126.8, 123.3, 121.3, 118.4; HRMS: obsd 293.0141,
calcd. 293.0152 for C13H10ClN2O2S (M+H).
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175ꢀ177 ºC; H NMR: δ 9.95 (s, 1H), 8.33 (d, J=8.0Hz, 1H), 7.85 (m, 2H), 7.72–7.75 (m,
2H), 7.49ꢀ7.56 (m, 2H), 7.44 (t, J=7.8Hz, 1H); 13C NMR: δ 161.9, 151.8, 148.9, 134.9,
134.8, 133.8, 132.1, 131.7, 129.0, 128.0, 126.5, 121.1, 120.7; HRMS: 300.9969, calcd.
300.9971 for C14H10BrN2O (M+H).
3-(m-Tolyl)-2H-benzo[e][1,2,4]thiadiazine 4-oxide 1,1-dioxide (25): Yield 50% (72 mg);
Brown solid; mp: 232 ºC; 1H NMR: δ 12.01 (s, 1H), 7.91 (d, J=8.0Hz, 1H), 7.86 (d, J=7.3Hz,
1H), 7.80 (d, J=8.2Hz, 1H), 7.61 (m, 3H), 7.44 (m, 2H); 13C NMR: δ 157.2, 138.0, 137.6,
134.1, 132.6, 131.8, 130.5, 128.4, 127.7, 127.3, 124.1, 122.9, 116.0, 21.3; HRMS: obsd
289.0643, calcd. 289.0647 for C14H13N2O3S (M+H).
3-(3-Methoxyphenyl)-2H-benzo[e][1,2,4]thiadiazine 4-oxide 1,1-dioxide (26): Yield 62%
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(94 mg); Pale brown solid; mp: 226–228 ºC; H NMR: δ 7.90 (dd, J=8.2, 1.2Hz, 1H), 7.85
(m, 1H), 7.79 (d, J=7.8Hz, 1H), 7.62 (t, J=7.8Hz, 1H), 7.47 (t, J=7.9Hz, 1H), 7.34 (m, 2H),
7.18 (ddd, J=8.2, 2.6, 1.0 Hz, 1H), 3.82 (s, 3H); 13C NMR: δ 159.0, 156.8, 137.5, 134.1,
133.0, 129.8, 127.8, 124.1, 122.8, 122.3, 117.7, 116.0, 115.2, 55.8; HRMS: obsd 305.0590,
calcd. 305.0596 for C14H13N2O4S (M+H)
3-(p-Tolyl)-2H-benzo[e][1,2,4]thiadiazine 4-oxide 1,1-dioxide (27): Yield 66% (95 mg);
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Pale brown solid; mp: 227ꢀ229 ºC; H NMR: δ 7.90 (d, J=8.2 Hz, 2H), 7.80 (dd, J=8.4,
0.7Hz, 1H), 7.75 (d, J=8.0Hz, 2H), 7.61 (dt, J=7.8, 1.1Hz, 1H), 7.37 (d, 8.0Hz, 2H), 2.40 (s,
3H); 13C NMR: δ 157.1, 142.4, 137.7, 134.1, 130.5, 129.1, 128.9, 127.7, 124.0, 122.9, 116.0,
21.5; HRMS: obsd 289.0638, calcd. 289.0647 for C14H13N2O3S (M+H); IR (KBr): 2670,
1590, 1392, 1323, 1186 cmꢀ1.
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3-(4-Methoxyphenyl)-2H-benzo[e][1,2,4]thiadiazine 4-oxide 1,1-dioxide (28): Yield 51%
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(77 mg); Brown solid; mp: 213–215 ºC; H NMR: δ 7.79ꢀ7.89 (m, 5H), 7.60 (dt, J=7.7,
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1.1Hz, 1H), 7.10 (dd, J=7.0, 2.0Hz, 2H), 3.85 (s, 3H), 13C NMR: δ 162.5, 156.7, 137.8,
134.0, 132.9, 127.6, 123.9, 123.5, 123.0, 116.1, 114.0, 55.9; HRMS: obsd 305.0589, calcd.
305.0596 for C14H13N2O4S (M+H).
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N-Benzyl-2-phenylquinazolin-4(1H)-one (29): Yield 95% (148 mg); Pale yellow semiꢀ
solid; 1H NMR: δ 8.46 (dd, J=7.9, 1.4Hz, 1H), 7.64 (dt, J=8.2, 1.4Hz, 1H), 7.55 (d, J=8.1Hz,
2H), 7.46ꢀ7.50(m, 2H), 7.32ꢀ7.40 (m, 5H), 7.28 (d, J=8.4Hz, 1H) 7.10 (d, J=7.0Hz, 2H),
5.40 (s, 2H); 13C NMR: δ 168.7, 163.2, 140.9, 135.1, 134.6, 133.9, 130.6, 129.3, 128.8, 128.6,
128.4, 128.0, 126.3, 125.5, 120.6, 116.7, 53.0; HRMS: obsd 313.1337, calcd. 313.1341 for
C21H17N2O (M+H).
N1-benzyl-N2-(3,5-dimethylphenyl)benzene-1,2-diamine (32): Yield 55% (249 mg);
Greenish yellow solid; mp: 79ꢀ81 ºC; 1H NMR: δ 7.34ꢀ7.37 (m, 5H), 7.15 (dd, J=7.5, 1.4Hz,
1H), 7.09 (dt, J=7.5, 1.4Hz 1H), 6.70ꢀ6.75 (m, 2H), 6.52 (s, 1H), 6.41 (s, 2H), 5.05 (s, 1H),
4.37 (s, 2H), 2.27 (s, 6H); 13C NMR: δ 145.7, 143.9, 139.5, 129.2, 128.6, 128.5, 127.5,
127.28, 126.3, 125.1, 121.2, 117.3, 113.0, 111.2, 47.8, 21.4; HRMS: obsd. 303.1855 calcd.
for 303.1861 for C21H23N2 (M+H).
N1-Benzyl-N2-(3,5-dimethylphenyl)-4-methylbenzene-1,2-diamine (33): Yield 62% (294
mg); Light Brown liquid; 1H NMR: δ 7.25ꢀ7.37 (m, 5H), 6.99 (s, 1H), 6.89 (d, J=8.1Hz, 1H),
6.62 (d, J=8.2Hz, 1H), 6.52 (s, 1H), 6.42 (s, 2H), 4.36 (s, 2H), 2.28 (s, 6H), 2.25 (s, 3H); 13C
NMR: δ 145.7, 141.4, 139.8, 139.0, 128.3, 128.1, 127.2, 127.0, 126.8, 126.3, 121.2, 113.2,
111.4, 48.2, 21.4, 20.4; HRMS: obsd 317.2010 calcd. 317.2018 for C22H25N2 (M+H).
N1-Benzyl-4-methyl-N2-(3-nitrophenyl)benzene-1,2-diamine (34): Yield 72% (359 mg);
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Yellow solid; mp: 117ꢀ119 ºC; H NMR: δ 7.64 (dd, J=8.0, 2.1Hz, 1H), 7.51 (t, J=2.2Hz,
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1H), 7.25ꢀ7.36 (m, 6H), 6.96ꢀ7.00 (m, 3H), 6.68 (d, J=8.8Hz, 1H), 5.45 (s, 1H), 4.36 (s, 2H),
2.28 (s, 3H); 13C NMR: δ 149.3, 147.1, 149.9, 139.3, 129.8, 128.6, 128.0, 127.2 127.1,
126.5, 125.9, 120.3, 113.6, 111.9, 108.9, 48.1, 20.3; HRMS: obsd 334.1546, calcd. 334.1556
for C20H20N3O2 (M+H).
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N1-Benzyl-4-fluoro-N2-(3-nitrophenyl)benzene-1,2-diamine (35): Yield 76% (384 mg);
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Red solid; mp: 98ꢀ100 ºC; H NMR: δ 7.69 (dd, J=8.0, 2.1Hz, 1H), 7.58 (t, J=2.2Hz, 1H),
7.29ꢀ7.39 (m, 6H), 7.07 (dd, J=8.1, 2.3Hz, 1H), 6.92 (dd, J=9.2, 2.8Hz, 1H), 6.85 (dt, J=8.4,
2.8Hz, 1H), 6.68 (dd, J=8.9, 5.2Hz, 1H), 5.54 (s, 1H), 4.34 (s, 2H); 13C NMR: δ155.8 (d,
J=236.0Hz), 149.3, 145.9, 139.7, 139.7, 130.1, 128.7, 127.4 (d, J=5.0Hz), 121.0, 114.4, 113.0
(d, J=22.0Hz), s112.8, 112.7, 111.6, 111.4, 109.7, 48.6 ; HRMS: obsd. 338.1318, calcd.
338.1305 for C19H17FN3O2 (M+H).
N1-Benzyl-N2-(3-fluorophenyl)-4-methylbenzene-1,2-diamine (36): Yield 56% (257 mg);
Brown solid; mp: 93ꢀ95 ºC; 1H NMR: δ 7.33 (m, 4H), 7.27ꢀ7.29 (m, 1H), 7.12ꢀ7.18 (m, 1H),
6.99 (d, J=1.6 Hz ,1H), 6.93 (dd, J=8.1, 1.4Hz 1H), 6.65 (d, J=8.1Hz, 1H), 6.50ꢀ6.54 (m,
2H), 6.44 (td, J=11.2, 2.2 Hz, 1H), 5.2 (br, 1H), 4.35 (s, 1H), 2.26 (s, 3H); 13C NMR: δ
164.0(d, J=242.0Hz),147.9, 147.8, 141.7, 139.5, 130.3, 130.2, 128.6, 128.3, 127.5, 127.3,
127.2, 127.0(d, J=4.0Hz),126.2, 111.7, 110.7, 110.6, 105.5(d, J=22Hz), 101.9, 101.7, 48.2;
HRMS: obsd 307.1601, calcd. 307.1611 for C20H20FN2 (M+H).
N1-Benzyl-4-fluoro-N2-phenylbenzene-1,2-diamine (37): Yield 64% (280 mg); Green
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liquid; H NMR: δ 7.27ꢀ7.35 (m, 8H), 6.88ꢀ6.98 (m, 3H), 6.66ꢀ6.74 (m, 2H), 5.29 (br, 1H),
4.34 (s, 2H); 13C NMR: δ 156.0(d, J=235.0Hz),144.1, 139.2, 138.3, 130.9, 130.8, 129.7,
128.0(d, J=3.0Hz),127.3, 120.5, 116.7, 115.8, 115.5, 113.7, 113.6, 112.6, 112.5, 110.3(d,
J=22.0Hz),109.14, 108.9, 103.4, 48.9; HRMS: obsd 293.1450, calcd. 293.1454 for
C19H18FN2 (M+H).
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1-(3,5-Dimethylphenyl)-2-phenyl-1H-benzo[d]imidazole (41): Yield 87% (130 mg);
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Brown solid; H NMR: δ 7.90 (d, J=7.9Hz, 1H), 7.63 (d, J=6.8Hz, 2H), 7.30ꢀ7.36 (m, 5H),
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7.26 (s, 1H), 7.11 (s, 1H), 6.94 (s, 2H), 2.36 (s, 6H); 13C NMR: δ 139.7, 129.9, 129.9, 128.2,
123.2, 122.9, 119.6, 110.6, 21.2; HRMS: obsd 299.1535, calcd. 299.1548 for C21H19N2
(M+H).
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1-(3,5-Dimethylphenyl)-6-methyl-2-phenyl-1H-benzo[d]imidazole (42): Yield 90% (140
mg); Light brown solid; mp: 136ꢀ139 ºC; 1H NMR: δ 7.76 (d, J=8.24Hz, 1H), 7.60ꢀ7.62 (dd,
J=8.3,1.8Hz, 2H), 7.30ꢀ7.35 (m, 3H), 7.16 (dd, J=8.2, 1.1Hz, 1H), 7.12 (d, J=0.6Hz, 1H),
7.02 (t, J=0.8Hz, 1H), 6.93 (d, J=0.4Hz, 2H), 2.47 (s, 3H), 2.35 (s, 6H); 13C NMR: δ 151.8,
140.9, 139.6, 137.6, 136.9, 133.2, 130.2, 129.2, 129.1, 128.1, 125.0, 124.4, 119.2, 110.3,
21.6, 21.1; HRMS: obsd 313.1695, calcd. 313.1705 for C22H21N2 (M+H).
6-Methyl-1-(3-nitrophenyl)-2-phenyl-1H-benzo[d]imidazole (43): Yield 95% (156 mg);
Reddish brown solid; mp: 136ꢀ139 ºC, 1H NMR: δ 8.34 (d, J=7.3Hz, 1H), 8.27 (t, J=2Hz,
1H), 7.81 (d, J=8.2Hz, 1H), 7.69 (t, J=8.0Hz, 1H), 7.60 (d, J=8.4, 1H), 7.51 (d, J=8.4Hz,
2H), 7.32ꢀ7.39 (m, 3H), 7.22 (d, J=8.2Hz, 1H), 7.05 (s, 1H); 13C NMR: δ 151.8, 149.0, 141.0,
138.3, 136.6, 134.2, 133.5, 130.8, 129.8, 129.4, 129.2, 128.6, 125.2, 123.2, 122.2, 119.8,
109.7, 21.8; HRMS: obsd 330.1232, calcd. 330.1243 for C20H16N3O2 (M+H); IR (KBr): 1613,
2924, 2854, 1536, 1464, 1348 cmꢀ1.
6-Fluoro-1-(3-nitrophenyl)-2-phenyl-1H-benzo[d]imidazole (44): Yield 80% (133 mg);
Reddish brown solid; mp: 198ꢀ201 ºC; 1H NMR: δ 8.36 (d, J=8.2Hz, 1H), 8.25 (t, J=2.0Hz,
2H), 7.86 (dd, J=8.8,4.8Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.63 (d, J=8.2Hz, 1H), 7.50ꢀ7.52
(dd, J=8.2,2.1Hz, 1H), 7.34ꢀ7.44 (m, 3H), 7.15ꢀ7.18 (dt, J=9.4,2.4Hz, 1H), 6.96 (dd, J=8.4,
2.3Hz, 1H); 13C NMR: δ δ 160.3(d, J=240.0Hz), 152.9, 149.0, 139.4, 137.9, 136.7, 136.5,
133.2, 131.0, 130.1, 129.3, 128.9, 128.7, 123.5, 122.1, 121.2(d, J=10.0Hz), 112.0(d,
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J=25.0Hz), 96.8(d, J=29.0Hz); HRMS: obsd 334.0983 , calcd. 334.0992 for C19H13FN3O2
(M+H); IR (KBr): 1621, 1537, 1475, 1349, 1156 cmꢀ1.
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1-(3-Fluorophenyl)-6-methyl-2-phenyl-1H-benzo[d]imidazole (45): Yield 96% (145 mg);
Reddish brown solid, mp: 173ꢀ175 ºC; 1H NMR: δ 8.00 (d, J=8.2Hz, 1H), 7.68 (d, J=7.3Hz,
2H), 7.54ꢀ7.60 (m, 1H), 7.48 (t, J=7.2Hz, 1H), 7.41 (t, J=9.1Hz, 2H), 7.31 (d, J=8.3Hz,
2H), 7.13ꢀ7.18 (m, 2H), 7.08 (s, 1H), 2.50 (s, 3H); 13C NMR: δ 163.1(d, J=250.0Hz), 149.8,
136.4, 136.3, 135.2, 131.8, 131.7, 131.5, 129.8, 127.1, 125.2, 123.7, 123.4(d,
J=3.0Hz),117.6, 117.2(d, J=21.0Hz), 115.0(d, J=23.0Hz),110.7, 21.9; HRMS: 303.1296,
calcd. 303.1298 for C20H16FN2 (M+H).
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6-Fluoro-1,2-diphenyl-1H-benzo[d]imidazole (46): Yield 85% (122 mg); Bright yellow
solid; mp: 120ꢀ122 ºC; 1H NMR: δ 7.83 (dd, J=8.7, 4.5Hz, 1H), 7.50ꢀ7.57 (m, 5H), 7.35ꢀ7.38
(m, 1H), 7.30ꢀ7.34 (m, 4H), 7.10 (dt, J=8.9, 2.5Hz, 1H), 6.95 (dd, J=8.6, 2.8Hz, 1H); 13C
NMR: δ 160.1(d, J=239.0Hz), 153.1, 159.2, 137.4, 137.2, 136.6, 130.0, 129.6, 129.5, 129.2,
128.6, 128.4, 127.1, 120.6, 120.5, 111.3(d, J=25.0Hz),97.2(d, J=28.0Hz); HRMS: obsd
289.1132; calcd. 289.1141 for C19H14FN2 (M+H).
2-(Benzylamino)-4,5-dimethoxybenzoic acid (49): Yield 98% (281 mg); Pale brown solid;
1H NMR: δ 7.45 (s, 1H), 7.34ꢀ7.42 (m, 4H), 7.29ꢀ7.32 (m, 1H), 6.1 (s, 1H), 4.50 (s, 1H), 3.84
(s, 3H), 3.76 (s, 3H); 13C NMR: δ 173.0, 156.0, 149.0, 139.6, 138.9, 128.7, 127.2, 126.9,
113.9, 99.9, 95.0, 56.3, 55.6, 47.4; HRMS: obsd 288.1229, calcd. 288.1236 for C16H18NO4
(M+H).
4,5-Dimethoxy-2-(4-methylbenzylamino)benzoic acid (51): Yield 97% (292 mg); Light
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brown solid; mp: 163ꢀ165 ºC; H NMR: δ 7.44 (s, 1H), 7.27 (d, J=7.9Hz, 2H), 7.17 (d,
J=7.9Hz, 2H), 6.12 (s, 1H), 4.45 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 2.36 (s, 3H); 13C NMR: δ
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173.0, 156.0, 149.0, 139.6, 138.9, 128.7, 127.2, 126.9, 113.9, 99.9, 95.0, 56.3, 55.6, 47.4;
HRMS: obsd 302.1388, calcd. 302.1392 for C17H20NO4 (M+H).
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2-(4-Hydroxy-3-methoxybenzylamino)-4,5-dimethoxybenzoic acid (52): Yield 96% (319
mg); Yellow solid; mp: 175ꢀ177 ºC; 1H NMR: δ 7.44 (s, 1H), 7.31 (d, J=8.5Hz, 1H), 6.90 (d,
J=8.6Hz, 2H), 6.13 (s, 1H), 4.42 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H); 13C NMR: δ
173.1, 158.8, 156.0, 149.0, 139.5, 130.8, 128.2, 114.15, 113.9, 100.0, 95.0, 56.4, 55.6, 55.3,
46.9; HRMS: obsd 334.1289, calcd. 334.1291 C17H20NO6 (M+H).
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6,7-Dimethoxy-2-phenyl-4H-benzo[d][1,3]oxazin-4-one
(54): Yield 60% (85 mg);
Colourless solid; mp: 217ꢀ219 ºC; 1H NMR: δ 8.30 (dd, J=8.5Hz, 1.5Hz, 2H), 7.50ꢀ7.59 (m,
4H), 7.14 (s, 1H), 4.06 (s, 3H), 4.02 (s, 3H); 13C NMR: δ 159.5, 156.6, 156.4, 149.7, 143.3,
132.3, 130.4, 128.8, 128.7, 109.6, 108.1, 107.6, 56.5, 56.4, 53.4; HRMS: obsd 284.0914,
calcd. 284.0923 for C16H14NO4 (M+H).
6,7-Dimethoxy-2-(4-nitrophenyl)-4H-benzo[d][1,3]oxazin-4-one (55): Yield 35% (57 mg);
Green solid, mp: 209ꢀ211 ºC; 1H NMR: δ 8.45 (d, J=7.0Hz, 2H), 8.35 (d, J=6.9Hz, 2H), 7.58
(s, 1H), 7.15 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H); 13C NMR: δ 158.7, 156.6, 154.3, 150.5,
142.6, 136.1, 128.8, 123.9, 109.3, 108.4, 107.7, 56.6, 56.5; HRMS: obsd 328.0686, calcd.
328.0695 for C16H12N2O6 (M+).
6,7-Dimethoxy-2-p-tolyl-4H-benzo[d][1,3]oxazin-4-one (56): Yield 30% (45 mg);
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Colourless solid; H NMR: δ 8.18 (d, J=8.2Hz, 2H), 7.57 (s, 1H), 7.32 (d, J=8.1Hz, 2H),
7.12 (s, 1H), 4.05 (s, 3H), 4.01(s, 3H), 2.46 (s, 3H); 13C NMR: δ 159.6, 156.8, 156.4, 149.5,
143.5, 143.0, 129.5, 128.0, 127.6, 109.5, 108.0, 107.6, 56.5, 56.4, 21.6; HRMS: obsd
298.1071, calcd. 298.1079 for C17H16NO4 (M+H); IR (KBr): 2918, 2579, 1645, 1521, 1231
cmꢀ1.
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2-(Benzylideneamino)benzamide (60): Yield 60% (134 mg); Colourless solid; mp: 200ꢀ202
ºC; 1H NMR: δ 8.48 (s, 1H), 8.35 (dd, J=7.9, 1.6Hz, 1H), 7.90 (dd , J=7.8, 1.7Hz, 2H), 7.53ꢀ
7.59(m, 4H), 7.40 (dt, J=7.8, 1.2Hz, 1H), 7.10 (dd, J=7.9,1.0Hz, 1H); 13C NMR: δ 167.8,
161.6, 149.8, 135.3, 134.4, 133.0, 132.9, 132.4, 131.6, 129.7, 129.1, 129.0, 127.9, 126.7,
126.0, 118.7, 117.4, 116.3, 113.8; HRMS: obsd 225.1021, calcd. 225.1028 for C14H13N2O
(M+H).
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2-(Benzylideneamino)-4,5-dimethoxybenzoic acid (62): Yield 80% (228 mg); Bright
yellow solid; mp: 204ꢀ206 ºC; 1H NMR: δ 8.70 (s, 1H), 7.89 (d, J=8.5Hz, 2H), 7.79 (s, 1H),
7.53ꢀ7.63(m, 3H), 6.92 (s, 1H), 3.98 (s, 3H), 3.92 (s, 3H); 13C NMR: δ 192.4, 167.2, 158.1,
155.6, 153.3, 149.3, 148.0, 140.7, 134.4, 133.8, 133.2, 129.7, 129.4, 129.0, 128.7, 117.6,
113.4, 112.9, 100.8, 99.2, 98.7, 56.3, 55.8; HRMS: obsd 286.1072, calcd. 286.1079 for
C16H16NO4 (M+H).
N-(4-Bromobenzyl)-4-chloroaniline (66): Yield 98% (288 mg); Pale yellow solid; mp: 82ꢀ
84 ºC; 1H NMR: δ 7.45 (d, J=6.7Hz, 2H), 7.21 (d, J=8.3Hz, 2H), 7.09 (d, J=8.8Hz, 2H), 6.50
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(d, J=6.8Hz, 2H); C NMR: δ 146.3, 138.0, 131.7, 129.1, 128.9, 122.1, 121.2, 113.9, 47.7;
HRMS: obsd 295.9849, calcd. 295.9842 for C13H12BrClN (M+H).
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N-(4-Chlorophenyl)benzamide (67): Yield 70% (81 mg); White solid; mp: 181ꢀ183 ºC; H
NMR: δ 7.88(m, 2H), 7.8 (s, 1H), 7.57ꢀ7.64 (m, 3H), 7.50 (m, 2H), 7.35 (dd, J=6.7, 2.0Hz,
2H); 13C NMR: δ 165.6, 136.5, 134.6, 132.0, 129.5, 129.1, 128.8, 126.9, 121.5; HRMS: obsd
232.0535, calcd. 232.0529 for C13H11ClNO (M+H).
4-Bromo-N-(4-chlorophenyl)benzamide (68): Yield 45% (70 mg); Brown solid; mp: 186ꢀ
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188 ºC; H NMR: δ 7.80 (s, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.64 (d, J=8.1Hz, 2H), 7.60 (d,
J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 13C NMR: δ 164.7, 136.2, 133.4, 132.1, 129.8, 129.1,
128.6, 126.8, 121.5; HRMS: obsd 308.9548, calcd. 308.9556 for C13H9BrClNO (M+).
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