Possible competitive modes of decarboxylation in the annulation reactions ofortho-substituted anilines and arylglyoxylates

Article abstract of DOI:10.1039/d0ob00360c

Annulation reactions ofortho-substituted anilines and arylglyoxylates in the presence of K₂S₂O₈at 80 °C under metal-free neutral conditions have been investigated, which extended a platform for the tandem synthesis of nitrogen heterocycles. While arylglyoxylic acids are known to undergo decarboxylation to form an acyl radical in the presence of K₂S₂O₈and used in the Minisci acylation of electron-deficient (hetero)aromatics, their reactions with electron-richortho-substituted anilines to form nitrogen heterocycles have recently been studied. Depending upon the experimental conditions used in the reactions, the mechanism of the formation of heterocycles involving reactions of an acyl radical or aryl iminocarboxylic acids has been postulated. Given the subtle understanding of the mechanisms of annulation reactions of 2-substituted anilines and arylglyoxylates in the presence of K₂S₂O₈, an extensive mechanistic investigation was undertaken. In the current study, the various mechanistic pathways including the generation of acyl, imidoyl, aminal, and N,O-hemiketal radicals have been postulated based on different possible decarboxylation modes. Some of the proposed intermediates are supported based on the available analytical data. The protocol uses a single, inexpensive reagent K₂S₂O₈, which offers not only transition-metal-free conditions but also serves as the reagent for the key decarboxylation step. Taken together, this study complements the current development of the annulation reactions of 2-substituted anilines and arylglyoxylates in terms of synthesis and mechanistic understanding.

Full text of DOI:10.1039/d0ob00360c

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Possible competitive modes of decarboxylation in the annulation
reactions of ortho-substituted anilines and arylglyoxylates
Joydev K. Laha,*, Surabhi Panday, Monika Tomar, and Ketul V. Patel
Received 00th January 20xx,
Accepted 00th January 20xx
Annulation reactions of ortho-substituted anilines and arylglyoxylates in the presence of K2S2O8 at 80 oC under metal-free
neutral conditions have been investigated, which extended a platform for the tandem synthesis of nitrogen heterocycles.
While arylglyoxylic acids are known to undergo decarboxylation to form acyl radical in the presence of K2S2O8 and used in
the Minisci acylation of electron-deficient (hetero)aromatics, their reactions with electron-rich ortho-substituted anilines
to form the nitrogen heterocycles have recently been studied. Depending upon the experimental conditions used in the
reactions, the mechanism to the formation of heterocycles involving reactions of acyl radical or aryl iminocarboxylic acids
has been postulated. Given subtle understanding of the mechanisms of annulations reactions of 2-substituted anilines and
arylglyoxylates in the presence of K2S2O8, an extensive mechanistic investigation was undertaken. In the current study, the
various mechanistic pathways including the generation of acyl, imidoyl, aminal, and N,O-hemiketal radicals have been
postulated based on different possible decarboxylation modes. Some of the proposed intermediates are supported based
on available analytical data. The protocol uses a single, inexpensive reagent K2S2O8, which offers not only a transition-
metal-free condition, but also serves as the reagent for the key decarboxylation step. Taken together, this study
complements the current development of the annulations reactions of 2-substituted anilines and arylglyoxylates in terms
of synthesis and mechanistic understanding.
DOI: 10.1039/x0xx00000x
substituted anilines with a convenient acyl source such as,
arylaldehyde, arylmethanol, or even arylmethane, wherein
arylimines are often reported to form as the intermediates.2,4
INTRODUCTION
Benzodiazines, especially quinazolines (1,3-benzodiazines)
represent privileged nitrogen heterocycles ubiquitously found
in natural products, pharmaceuticals, and performance
materials.1 Because of their wide prevalence in chemical
entities that demonstrate significant antihypertensive,
antineoplastic, antidepressant, and antipsychotic activities, an
impressive armoury of diverse synthetic routes have been
developed for their synthesis.2 A related class of nitrogen
heterocycle, 2H-1,2,4-benzothiadiazine-1,1-dioxides, also
exhibits considerable biological and pharmaceutical
importance.3 These heterocycles have reportedly been
prepared by oxidative amidation although with a certain
limitation.4 Many of the previous reports to the synthesis of
these heterocycles involve oxidative annulations of ortho-
Since the discovery of Minisci acylation,5 arylglyoxylic acids
have been extensively studied as the source of acylating
agents in decarboxylative acylation reactions.6 The acyl
radical,7 generated from arylglyoxylic acids by reaction with
persulfate at an elevated temperature (>70 oC), undergoes
nucleophilic
substitution
on
the
electron-deficient
heterocycles yielding C-acylated products, often in high
regioisomeric ratios.5 While C-acylation of electron-deficient
heteroaromatics using arylglyoxylic acids merits extensive
discussion,6d,8 decarboxylative N-acylation using arylglyoxylic
acids largely remained unexplored until a seminal report
appeared recently. In 2014,
a
pioneering work on
decarboxylative N-acylation of electron-rich anilines using
arylglyoxylic acids under visible light mediated photoredox-
catalysis was reported by Lei et al.9 The annulation reactions of
ortho-substituted anilines and arylglyoxylic acids to the
synthesis of nitrogen heterocycles, although limited to few
examples, was demonstrated first time in this report (Scheme
1). Subsequent to the work of Lei et al., three research groups
independently reported the annulations of ortho-substituted
anilines and arylglyoxylic acids or salts to the synthesis of
nitrogen heterocycles in the same year 2016. Huang et al.
reported annulation reactions of o-phenylenediamine or 2-
aminothiophenol and arylglyoxylic acid using electrochemical
a.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
b.,c Department of Pharmaceutical Technology (Process Chemistry),
c. National Institute of Pharmaceutical Education and Research,
S. A. S. Nagar, Punjab 160062,
India
Electronic Supplementary Information
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
(ESI) available: [details of any
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method in aqueous medium demonstrating a convenient, wide
access to benzimidazoles and benzothiazoles.10 We
demonstrated an annulation reaction of ortho-substituted
anilines encompassing broad substrate scope with
arylglyoxylates to the synthesis of nitrogen heterocycles using
an inexpensive oxidant K2S2O8.11 Concurrently, Lenardao et al.
reported the annulation reactions using a niobium-catalyst,12
Lei et al (2014)9
O
N
R1
NH2
[Ru(phen)3]Cl2 (1 mol%)
OH
Ar
R1
R2
Y
DMSO, O2, 32 o
C
O
Y = NH, O, or S
X
Huang et al (June 2016)10
Pt-Pt cell, 5 mA
TFA (1.0 equiv)
O
N
NH2
R1
OH
Ar
R1
DIPEA (2.0 equiv)
0.2 M NH4ClO4
DMSO/H2O, rt
R2
Y
O
X
Y = NH and S
13
Our previous work (July 2016)11
and later in 2017 by Na2S2O5 to the general synthesis of
O
N
Y
N
O
Ar
R1
benzthiazoles, benoxazin-2-ones, and related heterocycles. A
copper-catalyzed reaction of 2-aminobenzenesulfonamide and
phenylglyoxylic acid is reported for the synthesis of 2H-1,2,4-
benzothiadiazine-1,1-dioxide albeit limited to only one
example.14 Subsequent to their earlier contributions, Lenardao
and Jacob et al. further demonstrated a niobium-catalyzed
annulation of ortho-phenelynediamines and phenylglyoxylic
acid to the synthesis of 3-arylquinoxalin-2(1H)-ones.15 Very
recently, Sharma et al. reported a transition-metal-free visible-
light mediated synthesis of benzothiazoles.16 The mechanistic
pathways involving reactions of acyl radical9,10,11 or aryl
iminocarboxylic acids10,12,13,15,16 have been postulated in these
reports. Although a large variety of ortho-substituted anilines
were covered in previous studies, annulation reactions of
ortho-substituted aniline containing another ortho-amine
functional group, such as 2-aminobenzylamine and
arylglyoxylic acid remains unexplored. Such an investigation
would be especially interesting and appealing in terms of
delivery of product, possibly different modes of annulations,
regioselective decarboxylative N-acylation that could occur at
K2S2O8
NH2
Ar
OK
R1
or
R1
R2
MeCN, 80 oC, 12 h
NH
O
Y = NH, O, or S
X
Lenardao et al. (October 2016)12
O
ammonium niobium oxalate
(10 mol%)
O
N
O
N
S
NH2
X
OH
R1
or
R1
Ar
R1
R2
PEG-400(1 mL), 100 o
C
O
Ar
Lenardao et al. (2017)13
O
N
NH2
Na2S2O5 (2equiv)
DMSO, 100 o
R1
OH
OH
Ar
R1
R2
X
Y
C
O
Y = S or Se
2
Chaskar et al. ( February 2019)14
N
Ph
NH
O
NH2
Cat. Cu(OAc)2, Cs2CO3
DMSO, O2, 110 0
S
O2
O
SO2NH2
C
ONLY example
Lenardao & Jacob et al. (October 2019)15
O
H
N
ammonium niobium oxalate
(5 mol%)
O
NH2
OH
R1
R1
R2
PEG-400, ultra sonication
O
N
Ar
NH2
Sharma et al (2020)16
O
NH2
OH
N
blue LED
R1
R1
R2
Ar
dioxane/water, H2O2, rt
O
S
SH
aniline or benzylamine nitrogen, and finding
mechanism to the product formation. Herein, we describe
annulation reactions of 2-aminobenzylamines and
a rational
Current Work X = CH2NH2, SO2NH2
O
N
Ar
NH
K2S2O8, MeCN, 80 0
C
NH2
N
OH
or
R1
R2
S
N
Ar
O
X
O2
arylglyoxylates in the presence of K2S2O8 to the tandem
preparation of 2-arylquinazolines. The extended substrate
scope of the current protocol has been demonstrated with 2-
aminobenzenesulfonamides that remained largely uncovered
in previous studies. Unlike mechanistic studies previously
reported, current mechanistic study reveals substantial
difference including K2S2O8 aided decarboxylation of
iminocarboxylic acids and substrate dependent mechanistic
pathway. Based on different possible decarboxylation modes,
the formation of reactive intermediates, such as acyl, imidoyl,
aminal, and N,O-hemiketal radicals have been proposed in the
mechanism. Perhaps most importantly, K2S2O8 serves as the
reagent for the key decarboxylation step.
Mechanism involving decarboxylation before or after the reaction with anilines
NH2
O
O
CO2
OH/K
N
X
XH
O
NH
acyl radical
NH2
XH
O
CO2
OH
N
N
O
NH
COOH
XH
-H2
O
X
iminocarboxylic acid
Scheme 1. Annulation of ortho-substituted anilines and arylglyoxylic acids or salts to
the synthesis of nitrogen heterocycles
RESULTS AND DISCUSSION
The readily available 2-aminobenzylamine
of phenylglyoxylic acid 2a were chosen for the annulation
reaction. Reaction of and 2a in a mixture of solvents
1 and potassium salt
1
[CH3CN/H2O (1:1)] in the presence of 3 equiv of K2S2O8 at 80 °C
gave 3a in 35% yield (Table 1, entry 1). When MeOH was used,
a slightly reduced yield of 3a was obtained (entry 2). However,
a significant improvement in the yield was observed in the
absence of any polar protic solvent. Thus, optimized reaction
conditions entailed heating
1 and 2a in the presence of K2S2O8
in CH3CN at 80 °C for 12 h, which afforded 3a in 89% yield
(entry 3). A subordinate amount of K2S2O8 was somewhat
detrimental (entry 4). Without K2S2O8, the reaction did not
give even a trace amount of 3a suggesting the crucial role of
2 | J. Name., 2012, 00, 1-3
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K2S2O8 in this tandem reaction (entry 5). Similar oxidants, such
as Na2S2O8 or oxone are comparatively less effective in the
tandem reaction (entries 6-7).
Table 1: Optimization for the synthesis of quinazoline 3aa
Entry
1
Oxidants
K2S2O8
Solvents (mL)
MeCN:H2O
(1:1)
Yield (%)b
35
2
3
K2S2O8
K2S2O8
MeOH
MeCN
MeCN
MeCN
MeCN
25
89
80
0
70
67
72
4c
5d
6e
7f
8
K2S2O8
-
Na2S2O8
Oxone
K2S2O8
MeCN
DMF
Scheme 2. Synthesis of substituted 2-(hetero)arylquinazolines and benzothiadiazine-
1,1-dioxides
aReaction conditions: 1 (0.3 mmol), 2a (0.36 mmol), oxidant (3 equiv), solvent (2
c
mL), 80 °C, 12 h. bIsolated yield. K2S2O8 (2 equiv). dNo K2S2O8 was used. eNa2S2O8
(3 equiv) was used. foxone (3 equiv) was used.
Furthermore, more substrate scope was investigated with
heterocycles containing an α-oxocarboxylic acid group. Thus,
thiophene-3-α-oxocarboxylate and furan-3-α-oxocarboxylate
were compatible under the optimized conditions yielding 3i
The effect of a polar aprotic solvent DMF is comparable to that
of CH3CN (entry 8). Perhaps most importantly, K2S2O8 was
identified as the effective reagent that could promote
heterocycle formation via decarboxylation. Despite
polymerization is often known to occur with anilines in the
and
3j
in
85-91%
yield.
Reaction
of
2-
aminobenzenesulfonamide
benzothiadiazine-1,1-dioxides
4
5
and 2a gave 2H-1,2,4-
under the optimized condition
presence of K2S2O8,17 reaction of 2-aminobenzylamine
1 and
with
a
little extended time. Thus, when
2-
phenylglyoxylate 2a in our optimized condition delivers 2-
arylquinazoline 3a overcoming such issues. Notably,
phenylglyoxylate is used in this annulation reaction in lieu of
phenylglyoxylic acid largely used in the literature.
The optimized condition was further utilized to investigate
the substrate scope that could participate in tandem
annulation reaction for the synthesis of quinazolines (Scheme
2). The arylglyoxylate containing a methyl group at the 2-
position also reacted eventfully under the optimized condition
affording quinazoline 3b in 83% yield. An arylglyoxylate
aminobenzenesulfonamide and some aryglyoxylates were
subjected to the modified condition, the corresponding
annulated products 5a, 5b, and 5c were isolated in 42-55%
yields.
Unlike arylglyoxylic acids were used in previous studies,9,10,12-
we invariably used arylglyoxylates in the annulations
16
reactions. To understand any difference in reactivity between
the free acid and salt in the annulations reactions, we carried
out annulation reactions of some ortho-substituted anilines
and phenyglyoxylic acid in the presence of K2S2O8. The yields of
the heterocycles obtained in the annulation reactions of ortho-
containing
a 3-OMe group is also compatible with the
developed condition affording 3c in 72% yield. An
arylglyoxylate with an electron-donating 4-Me group delivered
quinazoline 3d in 88% yield. The tandem transformation also
exhibited tolerance for halogen groups at 2- or 4-positions of
arylglyoxylates. 4-Chloro- and 4-fluoro-phenylglyoxylate also
substituted
anilines
and
phenylglyoxylic
acid
or
phenylglyoxylate are shown in Table 2. The observed yields of
the products clearly reflect the different reactivity of
phenylglyoxylic acid compared to its salt phenylglyoxylate. This
observation may be explained by considering ease of
decarboxylation of the free acid/ salt before or after the
reaction with aniline. Decarboxylation of arylglyoxylic acids is
reacted with
1 under the optimized conditions affording 3e
and 3f in 80-82% yield, whereas 2-bromo-phenylglyoxylate
afforded 3g in 72% yield. The halogen substituent in the
product could be utilized for further functionalizations. When
2-napthyl-α-oxocarboxylic acid salt was subjected to the
known to occur at temperature >70
℃ in the presence of
persulfate.18 In addition, the current literature supports the
relative ease of decarboxylation of arylglyoxylic acid salts
compared to their corresponding free acids.18 An interesting
feature of arylglyoxylic acids is that they could undergo
condensation with an amino group to form the corresponding
aryl iminocarboxylic acids.19 Because of low pH of the medium,
the free acids are likely to undergo condensation with ortho-
substituted anilines relatively easily than their salts. From
reaction with
1
under the optimized condition, 2-
napthylquinazoiline 3h was isolated in 82% yield.
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these results, it may be concluded that the reaction
mechanism of the annulations reactions involving ortho-
substituted anilines and arylglyoxylates could be dissimilar to
that of the annulations reactions involving ortho-substituted
anilines and arylglyoxylic acids.
Table 2. Comparison of the reactivity of phenylglyoxylic acid and
phenylglyoxylate towards reaction with ortho-substituted anilines
Scheme 3. Product suppression with radical inhibitors
Entry
1
X
Product
Yield (%)
Acid Salt
Based on the results of comparison of decarboxylation of free
acid vs. the corresponding salt, radical quenching experiments,
and gleaning from previous articulation,9-13,15-16 the two
possibilities including decarboxylation before or after the
reaction with anilines have been discussed in the following
mechanisms.
H
Trace
4811
6
2
CONH2
30
8511
7
3
4
CH2NH2
SO2NH2
40
30
89
3a
5a
55
5
6
NH2
SH
60
80
4011
7511
8
9
The following experiments were performed to understand
whether any radical was indeed involved in the annulation
reactions studied herein (Scheme 3). While the annulation
reaction of 2-aminobenzylamine and phenylglyoxylate under
the optimized condition is only partially affected by TEMPO, a
nearly complete inhibition of the reaction was observed with
BHT. In stark contrast, the annulation reaction of 2-
Scheme 4. Decarboxylation to form acyl radical before reaction with
aniline
The scheme 4 delineates decarboxylation of arylglyoxylate
occurs first to form an acyl radical,7 which upon subsequent
reaction with ortho-substituted aniline could give the
heterocycle.20 Initially, homolytic cleavage of K2S2O8 under
thermal conditions could generate a sulfate radical anion
(SO4˙ˉ),21 which upon reaction with phenylglyoxylate 2a could
produce acyl radical 10 via decarboxylation.6d The acyl radical
10 could react with ortho-substituted aniline via two different
pathways (A & B) leading to N-acylation of ortho-substituted
aniline. The aniline 1/4 could form a radical cation 11 by single
electron transfer (SET) to SO4˙ˉ.22 The benzoyl radical23 10
aminobenzensulfonamide
and
phenylglyoxylate
was
completely inhibited by both TEMPO and BHT. The annulations
reactions described herein showed ortho-substituted aniline
dependent radical inhibition effect with TEMPO and BHT.
Although attempted trapping of any radical in these reactions
was unsuccessful, the different inhibition effect of the two
radical inhibitors augurs possible mechanistic difference of the
two annulations reactions.
could react with anilines 1/4 to form N,O-hemiketal radical 12,
which upon oxidation could form an intermediate N-acylated
product 13/14 via a radical pathway A.9-11 The electron-rich
benzoyl radical23 10 could also react with the radical cation 11
followed by deprotonation to form amide 13/14/15. The acyl
radical also could form an acylium ion 16 24
or a similar
,
4 | J. Name., 2012, 00, 1-3
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electrophilic species benzoyl sulfate 1711 upon capture of a
sulfate radical anion (SO4˙ˉ), which could undergo nucleophilic
substitution with 1/4 to give 13/14 via an ionic pathway B.
The intramolecular cyclization of 13/14 in the presence of
-
bases like HSO4 or SO42-, generated in situ, followed by
oxidation could give the final product 3/5 25
.
Alternatively, the scheme 5 reveals that condensation of both
could occur before decarboxylation to form the
iminocarboxylate 18
.
Based on different modes of
decarboxylation, two possibilities that could lead to product
formation have been shown (pathways C & D). At this stage,
intramolecular cyclization of 18 could directly form a cyclized
intermediate 19, which upon decarboxylation could deliver an
aminal radical26 20 (pathway C). This aminal radical 20 could
give the final product on oxidation and deprotonation. A
competitive decarboxylation in 18 could yield imidoyl radical27
21, which upon oxidation could form iminol product 22
(pathway D). The tautomerization of 22 could give 13/14. The
intramolecular cyclization of N-acylated product 13/14 in the
Scheme 6. Competitive annulation reactions in the presence of electron-
deficient species
As acyl radical is known to react with electron-deficient
heteroarenes via Minisci acylation,5 or with methyl
acrylate,28acyl radical could undergo a competitive reaction in
these reactions leading to the lower yield of 3a. Indeed, 2,4-
dibenzoylated pyridine was isolated when 4-cyanopyridine was
1
used (see ESI for H NMR and a low-resolution mass data).29
This suggests that acyl radical was indeed involved in the
annulation reactions of 1.
-
presence of bases like HSO4 or SO42-, generated in situ,
To trap the formation of N-acylated product 13/14, we
performed mass studies of the reaction mixture with time
intervals. The reactions of 2-aminobenzylamine and
phenylglyoxylate in the presence of K2S2O8 in acetonitrile at 80
followed by oxidation could deliver the heterocycle 3/5
.
℃
for 1 h, 2 h, and 4 h were performed and mass data were
obtained for all the reaction mixtures. First of all, the mass
data of four reaction mixtures were nearly same. An observed
mass peak at m/z 226 [M+] corresponds to amide 13/15. The
other prominent peak observed at m/z 331 [M+H] identified as
dibenzoylated product of 2-aminobenzylamine. This
experiment could validate both possibilities of acyl radical
reactions (pathways A & B). As a radical quencher either
slightly or partially inhibits this annulation reaction (Scheme 3),
it is likely that acyl radical is transformed into acylium ion 1624
or 17 11
cyclization of 13/15 could give the final product
,
which drives the reaction further. The intramolecular
in the
3
2- 25
presence of a base like SO4
.
To understand whether decarboxylation of arylglyoxylate
occurs after reaction with ortho-substituted anilines (pathways
C & D), the following experiments were performed. A time
course mass analysis of the reaction mixture of 2-
aminobenzensulfonamide and phenylglyoxylate under the
optimized condition was performed. The mass data for all the
reaction mixtures at 1 h, 2 h, and 4 h were nearly same. The
mass analysis reveals a mass peak at m/z 304 [M + H], which
could correspond to the iminocarboxylate 18 (X = SO2NH2).
However, similar mass spectroscopic analysis of the reaction
Scheme 5. Decarboxylation occurs after reaction with anilines to form
iminocarboxylates
To understand whether decarboxylation occurs first to form an
acyl radical (pathway A and B), the following experiments were
performed. Firstly, the annulation reaction of 2-
aminobenzylamine and phenylglyoxylate under the optimized
condition in the presence of 2-acetylpyridine or 4-
cyanopyridine gave 2-phenylquinazoline albeit in low yield (10-
20%) (Scheme 6, upper panel). Secondly, the annulation
reaction of 2-aminobenzylamine and phenylglyoxylate under
the optimized condition in the presence of methyl acrylate also
gave 2-phenylquinazoline in <10% yield (Scheme 6, lower
panel).
mixture of 2-aminobenzylamine 1 and phenylglyoxylate 2a also
revealed a mass peak of iminocarboxylate 18 (X = CH2NH2) at
m/z 292 [M+]. These experiments encouraged us to explore
further the possibility of the iminocarboxylate formation in the
annulation reaction (Scheme 7). Thus, the aryl
iminocarboxylates 18 were prepared in situ by the
condensation of phenylglyoxylate and 2-aminobenzylamine
or 2-aminobenzensulfonamide at room temperature in the
absence of K2S2O8, which were further treated with K2S2O8 at
1
4
80
℃
. In so doing, two dissimilar observations were recorded.
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While the reaction involving 2-aminobenzylamine
phenylglyoxylate 2a gave 2-phenylquinazoline 3a only in <20% attempted to make 13 from 2-aminobenzylamine
yield, the reaction involving 2-aminobenzensulfonamide
1
and acylation of 4-aminobenzylamine under a critical pH (4.1),32 we
under
and similar pH controlled conditions. However, direct isolation of
1
4
phenylglyoxylate 2a gave the corresponding heterocycle in a an analytically pure 13 was unsuccessful in these experiments.
comparable yield to that obtained under the optimized Thus, the crude mixture after neutralization with NaOH was
condition. These experiments clearly suggest that treated with K2S2O8 in acetonitrile at 80
℃ for 12 h, which
iminocarboxylate 18 (X SO2NH2) might involve as an afforded quinazoline 3a. Based on these observations coupled
=
intermediate in the annulation of 2-aminobenzensulfonamide with mass studies, we believe that regioselective
and phenylglyoxylate. Subsequent to iminocarboxylate 18 decarboxylative N-acylation could occur at aryl amino group to
formation, it could undergo decarboxylation in the presence of furnish 13, which upon intramolecular cyclization and
sulfate radical anion to form either aminal radical 19 or imidoyl oxidation could give quinazoline 3a
radical 21 as shown in the scheme 4. Unlike in the reaction of
.
2-aminobenzylamine
1 and phenylglyoxylate, a careful mass
analysis of the reaction mixture of 2-aminobenzensulfonamide
and phenylglyoxylate does not reveal any mass peak
correspond to N-acylated product 14. Thus, the annulations
reaction is more likely to follow the pathway B through the
aminal radical.
Scheme 7. Annulation via in situ formation of iminocarboxylate
A radical quencher TEMPO used in this study largely inhibited
the annulation reaction of 2-aminobenzensulfonamide and
phenylglyoxylate possibly by forming adduct with the
proposed aminal radical. The tracking and characterization of
the adduct requires further investigation.
Scheme 8. Control experiments to understand the regioselective N-
acylation
A
regioselective N-acylation of 2-aminobenzylamine 1 is
Conclusions
currently unavailable in the literature. To check whether any
regioselective decarboxylative N-acylation takes place at
benzylic or aromatic amine of 2-aminobenzylamine
irrelevant in quinazoline synthesis, we carried out reactions
involving 2a and benzylamine, or 2a and aniline under the
optimized conditions. While attempted N-acylation of
benzylamine itself with 2a under the optimized condition did
not give decarboxylative N-acylated product, aniline yielded N-
In conclusion, annulation reactions of ortho-substituted
anilines and arylglyoxylates described herein feature K2S2O8
1 although
promoted
possible
competitive
decarboxylation
of
arylglyoxylates before or after the reactions with anilines. Our
study indicated that use of arylglyoxylic acid or its salt may
have different outcome in the annulations reactions. Based on
substrate dependent radical inhibition experiments and other
data available, two different proposed mechanistic pathways
are supported for the two substrates. However, it is difficult to
ascertain whether a single or competitive deacrboxylative
mode is in operational. Using our optimized condition, a
acylated product
6 of aniline via decarboxylation. Next, we
explored the possibility of conversion of the proposed
intermediate 13/15 to quinazoline 3a under the optimized
conditions. When N-benzoyl-2-aminobenzylamine 1530 was
exposed to our optimized condition, 3a didn’t form. Next, we
investigated the transformation of 13 into product under our
optimized condition. As regioselective benzoylation at aniline
regioselective
decarboxylative
N-acylation
of
2-
aminobenzylamines could be possible by reaction with
arylglyoxylate at the arylamino group. Taken together, the
current study is substantially different from the relevant
literature in terms substrate variation, product delivery, and
mechanistic understanding.
nitrogen of 1 posed challenging, we protected the benzylamine
nitrogen with a tert-butoxylcarbonyl (Boc) group. Following a
literature report, compound 23 was prepared,30 which was
subjected to benzoylation to obtain 24 31
. During deprotection
of 24 with TFA at room temperature, quinazoline 3a was
obtained directly. Following a literature for the regioselective
6 | J. Name., 2012, 00, 1-3
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ARTICLE
2-(4-Fluorophenyl)quinazoline (3f):5 (82% yield); a pale yellow
solid; mp 131-133 °C; 1H NMR (500 MHz, CDCl3): δ 9.44 (s, 1H),
8.63-8.61 (m, 2H), 8.07-8.06 (d, J = 8.44 Hz, 1H), 7.94-7.88 (m,
2H), 7.61-7.60 (t, J = 7.4 Hz, 1H), 7.20-7.18 (t, J = 8.76 Hz, 2H).
2-(2-Bromophenyl)quinazoline (3g):6 (72% yield); a yellow
solid; mp 124-126 °C; 1H NMR (400 MHz, CDCl3): δ 9.56 (s, 1H),
8.18-8.15 (d, J = 8.5 Hz, 1H), 8.06-7.97 (m, 2H), 7.83-
7.77(m,3H), 7.51-7.47 (dd, J = 7.5, 6.9 Hz,1H), 7.37-7.35 (dt, J =
15, 1.64 Hz, 1H). 13C NMR (400 MHz, CDCl3) δ 162.82, 160.28,
150.27, 140.16, 134.47, 133.72, 131.67, 130.44, 128.64,
128.12, 127.51, 127.19, 123.31, 121.91, 77.36, 77.04, 76.72,
29.72, 14.15.
Experimental Section
General Information
purchased from commercial vendors and used as received. 2-
Aminobenzylamine and 2-aminobenzenesulfonamide were
purchased from commercial vendors. Arylglyoxylates 2a-k 11
compound 15 30 and compound 2330 were prepared according
: All reagents and solvents were
1
4
,
,
to the literature procedures. Column chromatography was
performed using silica gel 60-120, 100-200, or 230-400 mesh.
13C
All 1H NMR and
NMR spectra were recorded with 400 MHz
and 100 MHz NMR spectrometers, respectively and are
reported in δ units. The coupling constants (J) are reported in
Hz.
2-(Naphthalen-2-yl)quinazoline
( a pale
3h):7 (82% yield);
General procedure for the synthesis of 2-arylquinazolines
1
yellow solid; mp 120-121°C; H NMR (400 MHz, CDCl3): δ 9.55
(s, 1H), 9.18 (s, 1H), 8.77-8.75 (dd, J = 8.64 Hz, 1.4 Hz, 1H),
8.18-8.16 (d, J = 8.40 Hz, 1H), 8.10-8.06 (m, 1H), 8.04-8.02 (d, J
= 6.6 Hz, 1H), 7.98-7.92 (dd, J = 15.3, 7.7 Hz, 3H), 7.69-7.65 (t, J
= 7.5 Hz, 1H), 7.60-7.55 (m, 2H). 13C NMR (400 MHz, CDCl3) δ
160.56, 134.24, 133.42, 129.29, 128.97, 128.50, 127.74,
127.59, 127.03, 126.26, 125.41, 77.34, 77.03, 76.71.
illustrated for 3a: In an oven-dried sealed tube, 2-
aminobenzylamine 1 (36.6 mg, 0.30 mmol), phenylglyoxylate
(78.5 mg, 0.36 mmol) and potassium persulphate (243.2 mg,
0.90 mmol) were dissolved in CH3CN (2 mL) and the mixture
was heated at 80
℃ for 12 h. After completion of the reaction,
water (20 mL) was added and the layers were separated. The
aqueous layer was extracted with ethyl acetate (3 x 20 mL) and
the combined organic layer was dried over Na2SO4. Removal of
the solvent with rotary evaporator afforded the crude product,
which upon purification by chromatography using
hexane/ethyl acetate (8:2) afforded a pale yellow solid.
2-(Thiophen-2-yl)quinazoline (
3i):7 (91% yield); a yellow solid;
mp 108–110 °C; 1H NMR (400 MHz, CDCl3): δ 9.38 (s, 1H), 8.18-
8.17 (d, J = 3.6 Hz, 1H), 8.05-8.02 (d, 8.80 Hz, 1H), 7.92–7.89
(m, 2H), 7.62-7.58 (t, J = 7.59 Hz, 1H), 7.55-7.54 (d, J = 5 Hz,
1H), 7.23-7.21 (m, 1H). 13C NMR (400 MHz, CDCl3) δ 160.55,
157.86, 150.63, 143.84, 134.38, 129.96, 129.23, 128.40,
2-Phenylquinazoline(
3a):2 (89% yield); white solid; mp 97-98
1
°C; H NMR (500 MHz, CDCl3) δ 9.47 (s, 1H), 8.62-8.60 (dd, J =
7.9, 1.6 Hz, 2H), 8.10-8.08 (d, J = 8.5 Hz, 1H), 7.94 – 7.91 (m,
2H), 7.61-7.60 (t, J = 7.5 Hz, 1H), 7.60 – 7.56 (m, 3H). 13C NMR
(500 MHz, CDCl3) δ 160.61, 134.24, 130.71, 128.70, 127.31,
77.36, 77.10, 76.85.
128.20, 127.29, 127.02, 123.38, 77.35, 77.04, 76.72.
1
2-(Furan-2-yl)quinazoline
(
3j):8 (85% yield); a yellow solid; H
NMR (500 MHz, CDCl3): δ 9.38 (s, 1H), 8.11-8.09 (d, J = 8.9 Hz,
1H), 7.93-7.88 (m, 2H), 7.69 (d, J = 0.8 Hz, 1H), 7.63-7.58 (m,
1H), 7.46 (d, J = 3.5 Hz, 1H), 6.62 (dd, J = 3.4 Hz, 1.8 Hz, 1H). 13C
NMR (500 MHz, CDCl3) δ 134.67, 128.49, 127.41, 114.23,
112.45, 77.33, 77.10, 76.85.
General procedure for the synthesis of 2H-1,2,4-
benzothiadiazine-1,1-dioxide illustrated for 5a: In an oven-
dried sealed tube, 2-aminobenzenesulphonamide (51.6 mg,
0.30 mmol), phenylglyoxylate (67.7 mg, 0.36 mmol) and
potassium persulfate (243.27 mg, 0.90 mmol) were dissolved
2-(o-Tolyl)quinazoline (
3b):3 (83% yield); a pale yellow solid;
1
mp 43-45 °C; H NMR (500 MHz, CDCl3) δ 9.50 (s, 1H), 8.10-
8.08 (d, J = 8.5 Hz, 1H), 7.99-7.86 (m, 3H), 7.66 (t, J = 7.4 Hz,
1H), 7.37-7.32 (dt, J = 13.1,6.4 Hz, 3H), 2.60 (s, 3H).
2-(3-Methoxyphenyl)quinazoline (
3c):4 (72% yield); a pale
1
yellow solid; mp 119-122°C; H NMR (400 MHz, CDCl3): δ 9.49
(s, 1H), 8.26-8.24 (d, J = 7.72 Hz, 1H), 8.22 (d, J = 2.3 Hz,1H),
8.13-8.11 (d, J = 8.44, 1H), 7.96-7.91 (m, 2H), 7.66-7.62 (t, J =
7.5 Hz, 1H), 7.49-7.46 (t, J = 7.9 Hz, 1H), 7.11-7.08 (dd, J = 8.12,
2.4 Hz, 1H), 3.98 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.28,
159.86, 159.46, 150.17, 138.93, 133.52, 129.06, 128.11,
126.63, 123.09, 120.60, 116.68, 112.48, 54.89, 31.36, 29.13,
22.12.
in CH3CN (2 mL) and the mixture was heated at 80
℃ for 16 h.
After completion of the reaction, water (20 mL) was added and
the layers were separated. The aqueous layer was extracted
with ethyl acetate (3 x 20 mL) and the combined organic layer
was dried over Na2SO4. Removal of the solvent with rotary
evaporator afforded the crude product, which upon
purification by chromatography using hexane/ethyl acetate
(3:7) afforded a dark yellow solid.
2-(p-Tolyl)quinazoline (
3d):5 (88% yield); a yellow solid; mp 97-
1
98 °C; H NMR (400 MHz, CDCl3): δ 9.48 (s, 1H), 8.54-8.52 (d, J
= 8.12 Hz, 2H), 8.10-8.09 (d, J = 8.44 Hz, 1H), 7.97-7.87 (m, 2H),
7.64-7.62 (t, J = 7.44 Hz, 2H), 7.38-7.36 (d, J = 8.0, 1H), 2.47 ( s,
3H). 13C NMR (500 MHz, CDCl3) δ 161.15, 160.46, 150.80,
140.89, 134.07, 129.44, 128.54, 127.10, 123.52, 21.55.
3-Phenyl-2H-benzo[e][1,2,4]thiadiazine1,1-dioxide (5a):6 (55%
1
yield); a dark yellow solid; mp. 308-310 °C; H NMR (400 MHz,
DMSO-d6): δ 12.2 (s, 1H), 8.06-8.04 (d, J = 7.32, 2H), 7.88-7.86
(d, J = 7.88, 1H), 7.77-7.69 (m, 2H), 7.65-7.62 (m, 3H), 7.53-
7.49 (t, J = 7.28 Hz, 1H).
2-(4-Chlorophenyl)quinazoline (
3e):5 (80% yield); a yellow
1
solid; mp 136-138 °C; H NMR (400 MHz, CDCl3): δ 9.48 (s,
1H), 8.61-8.59 (d, = 8.52 Hz, 2H), 8.11-8.09 (d, J = 8.44 Hz,
1H), 7.96-7.93 (m, 2H), 7.68-7.64 (t, = 7.5 Hz, 1H), 7.54-7.52
(d,
= 8.5 Hz, 2H).13C NMR (400 MHz, CDCl3) δ 160.57,
3-(3-Methoxyphenyl)-2H-benzo[e][1,2,4]thiadiazine
1,1-
J
dioxide (5b):6 (48% yield); a dark yellow solid; ; mp. 323-325
°C; 1H NMR (500 MHz, DMSO-d6): δ 12.13 (s, 1H), 7.84-7.82 (d,
J = 7.92, 1H), 7.77-7.73(m, 1H), 7.62-7.57 (m, 2H), 7.55-7.48
(m, 3H), 7.26-7.23 (m, 1H), 3.84 (s, 3H). 13C NMR (500 MHz,
J
J
136.85, 134.30, 129.90, 128.85, 128.60, 127.50, 127.18,
123.63, 77.34, 77.03, 76.71.
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J. Name., 2013, 00, 1-3 | 7
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ARTICLE
Journal Name
1
2
Shagufta and I. Ahmad, Med. Chem. Commun., 2017, 8, 871-
DMSO-d6) δ 133.6, 123.87, 121.00, 119.07, 113.87, 41.21,
40.08, 39.52.
885; (b) T. Gupta, A. Rohilla, A. Pathak, J. Akhtar, M. R.
Haider and M. S. Yar, Synth. Commun., 2018, 48, 1099-1127.
(a) T. Mathew, A. Á. Papp, F. Paknia, S. Fustero and G. K.
Surya Prakash, Chem. Soc. Rev., 2017, 46, 3060-3094. For
some most recent articles: (b) X. Wang, D. He, Y. Huang, Q.
Fan, W. Wu and H. Jiang, J. Org. Chem., 2018, 83, 5458-5466;
(c) T. Chatterjee, D. Kim and E. J. Cho, J. Org.
Chem., 2018, 83, 7423-7430; (d) C. Y. Chen, F. He, G. Tang, H.
3-(4-Bromophenyl)-2H-benzo[e][1,2,4]thiadiazine1,1-
dioxide(
5c):6 (42% yield); a dark yellow solid; mp236-238 °C; 1H
NMR (500 MHz, DMSO-d6): δ 12.21 (s, 1H), 7.97-7.96 (d, J =
8.56, 2H), 7.84-7.81 (m, 3H), 7.73-7.69 (t, J = 7.7 Hz, 1H), 7.60-
7.58 (m, 1H), 7.49-7.48 (t, J = 7.48 Hz, 1H). 13C NMR (500 MHz,
DMSO-d6) δ 123.74, 122.65, 109.4, 107.68, 72.78, 72.28, 72.09,
71.70.
Yuan, N. Li, J. Wang, and R. Faessler, J. Org. Chem., 2018, 83
,
2395-2401; (e) R. Gujjarappa, S. K. Maity, C. K. Hazra, N.
Vodnala, S. Dhiman, A. Kumar, U. Beifuss, and C. Malakar,
Eur. J. Org. Chem., 2018, 33, 4628-4638; (f) S. Parua, R. Sikari,
S. Sinha, G. Chakraborty, R. Mondal and N. D. Paul, J. Org.
Chem., 2018, 83, 11154-11166.
N-Phenylbenzamide (6):11 White solid; 1H NMR (400 MHz,
CDCl3): δ 7.8 (dd J = 7.9, 0.9 Hz, 2H), 7.83 (brs, 1H), 7.64 (dd, J =
8.6, 1.0 Hz, 2H), 7.56 (tt, J = 7.3, 1.3 Hz, 1H), 7.50-7.46 (m, 2H),
7.40-7.35 (m, 2H), 7.15 (tt, J = 7.4, 1.0 Hz, 1H).
3
4
S. Boverie, M.-H. Antoine, F. Somers, B. Becker, S.
Sebille, R. Ouedraogo, S. Counerotte, B. Pirotte, P.
Lebrun and P. Tullio, J. Med. Chem., 2005, 48, 3492-3503.
For some recent selected references, see: (a) A. J. A. Watson,
A. C. Maxwell and J. M. J. Williams, Org. Biomol. Chem.,
2012, 10, 240-243; (b) M. Sharif, J. Opalach, P. Langer, M.
Beller and X.-F. Wu, RSC Adv., 2014, 4, 8-17; (c) J. K. Laha; K.
S. S. Tummalapalli, A. Nair and N. Patel, J. Org.
Chem., 2015, 80, 11351–11359.
2-Phenylquinazolin-4(3H :
)-one (7) 11 White solid; 1H NMR (400
MHz, CDCl3) δ 11.69 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.29 (dd, J
= 6.3, 2.8 Hz, 2H), 7.93-7.74 (m, 2H), 7.64-7.59 (m, 3H), 7.54 (d,
J = 6.7 Hz, 1H).
11
2-Phenyl-1
H
-benzo[
d
]imidazole (8)
:
White solid; 1H NMR
(400 MHz, DMSO) δ 12.59 (s, 1H), 8.31 (d, J = 6.7 Hz, 2H), 7.85
(d, J = 7.9 Hz, 1H), 7.53 (dd, J = 21.7, 6.7 Hz, 4H), 7.34 (t, J = 8.1
Hz, 2H).
5
6
F. Fontana, F. Minisci, M. C. N. Barbosa and E. Vismara, J.
Org. Chem., 1991, 56, 2866-2869.
2-Phenylbenzo[d
]thiazole (9):11 White solid; 1H NMR (400
For some recent selected reviews, see: (a) X. F. Wu, Chem.
Eur. J., 2015, 21, 12252-12265; (b) L. N. Guo, H. Wang and X.
H. Duan, Org. Biomol. Chem., 2016, 14, 7380-7391; (c) J.
Schwarz and B. König, Green Chem., 2018, 20, 323-361; (d) F.
Penteado, E. F. Lopes, D. Alves, G. Perin, R.G. Jacob and E. J.
Lenardao, Chem. Rev., 2019, 119, 7113-7278.
(a) C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chem.
Rev., 1999, 99, 1991-2070; (b) R. Vanjarin and K. N. Singh,
Chem Soc. Rev., 2015, 44, 8062-8096; (c) A. Banerjee, L. Zhen
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(a) M. A. Duncton, Med Chem Comm., 2011, 2, 1135-1161;
(b) R. S. Proctor and R. J. Phipps, Angew. Chem. Int. Ed.,
2019, 58, 13666-13699.
J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan and A. Lei,
Angew. Chem. Int. Ed., 2014, 53, 502–506.
MHz, CDCl3) δ 8.12 (ddd, J = 9.7, 5.0, 3.3 Hz, 3H), 7.94 (dd, J =
8.0, 0.5 Hz, 1H), 7.56 – 7.49 (m, 4H), 7.45 – 7.39 (m, 1H).
Preparation of tert-butyl 2-benzamidobenzylcarbamate (24):
Following a literature,31 tert-butyl 2-aminobenzylcarbamate
2330 (444 mg, 2 mmol) and Et3N (0.2 mL, 1.72 mmol) were
7
dissolved in DCM (4 mL) at 0
1.72 mmol) was added dropwise at 0
℃
. Benzoyl chloride (0.19 mL,
. After 10 min,
℃
temperature of the reaction was raised to room temperature
and allowed to stir for 1 h. After the completion of the
reaction, the mixture was neutralized with aqueous saturated
NaHCO3 (10 mL) by constant stirring. It was further extracted
with DCM (20 mL x 2). The organic layer was dried (Na2SO4),
concentrated under reduced pressure, and purified by
chromatography to obtain the desired N-acylated product as a
8
9
10 H.-B. Wang and J.-M. Huang, Adv. Synth. Catal., 2016, 358
,
1975-1981.
1
11 J. K. Laha, K. V. Patel, K. S. S. Tummalapalli, and N. Dayal,
Chem. Comm., 2016, 52, 10245–10248.
white solid; (600 mg, 92% yield); H NMR (400 MHz, DMSO-
d6): δ 10.17 (s, 1H), 8.02-8.00 (d, J = 7.44 Hz, 2H), 7.62-7.59 (m,
1H), 7.55-7.45 (m, 4H), 7.31-7.21 (m, 3H), 4.17-4.15 (d, 8 Hz,
2H), 1.37 (s, 9H); 13C NMR (100 MHz, DMSO-d6): δ 165.9,
156.7, 135.9, 134.8, 132.1, 128.85, 128.5, 128.1, 127.5, 126.3,
126.1, 78.6, 28.6. HRMS (ESI) m/z calcd for C19H22N2O3 [M +
Na]+ 349.1528, found 349.1512.
12 F. Penteado, M. M. Vieira, G. Perin, D. Alves, R. G. Jacob, C.
Santi and E. J. Lenardão, Green Chem., 2016, 18, 6675-6680.
13 D. B. Lima, F. Penteado, M. M. Vieira, D. Alves, G. Perin, C.
Santi and E. J. Lenardão, Eur. J. Org. Chem., 2017, 3830-3836.
14 B. N. Patil, J. J. Lade, A. S. Karpe, B. Pownthurai, K. S.
Vadagaonkar, V. Mohanasrinivasan, and A. C. Chaskar,
Tetrahedron Lett., 2019, 60, 891-894.
15 C. Ebersol, N. Rocha, F. Penteado, M. S. Silva, D. Hartwig, E.
J. Lenardão, and R. G. Jacob, Green Chem., 2019, 21, 6154-
6160.
16 A. Monga, S. Bagchi, R. K. Soni, and A. Sharma, Adv. Synth.
Catal., 2020, 361, 3554-3559.
Conflicts of interest
There are no conflicts to declare.
17 (a) I. Sapurina and J. Stejskal, Polymer Int., 2008, 57, 1295-
1325; (b) J. X. Xie, Y. Zhang, W. Huang and S. Huang, J.
Environ. Sci. 2012, 24, 821-826.
18 A. J. L. Cooper, J, Z. Ginos and A. Meister, Chem. Rev., 1983,
83, 321-358.
19 (a) M. F. Aly and R. Grigg, JCS Chem Commun., 1985, 1523-
1524; (b) D. H. R. Barton, and F. Taran, Tetrahedron Lett.,
1998, 39, 4777-4780; (c) F. Collet, B. Song, F. Rudolphi and L.
J. Gooßan, Eur. J. Org. Chem., 2011, 6486-6501; (d) X-L. Xu,
Acknowledgements
The financial support from the CSIR, New Delhi is greatly
appreciated.
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8 | J. Name., 2012, 00, 1-3
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Journal Name
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Organic & Biomolecular Chemistry
Page 10 of 10
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DOI: 10.1039/D0OB00360C
Possible competitive modes of decarboxylation in the annulations reactions of ortho-
substituted anilines and arylglyoxylates
Joydev K. Laha,* Surabhi Panday, Monika Tomar, and Ketul V. Patel
O2
S
O
X
K2S2O8
N
NH2
NH
Ph
OH
MeCN, 80 0
C
or
Ph
yield up to 90%
+
N
NH2
N
O
-CO2
X = CH2 or SO2
Competitive decarboxylation, before or after reaction with anilines
Different outcome with free arylglyxoylic acid or salt
Substrate dependent inhibition of the reactions by radical quenchers
Annulation reactions of ortho-substituted anilines and arylglyoxylates in the presence of K2S2O8 at 80 oC
via decarboxylation before or after the reaction with anilines have been investigated, which extended a
platform for the tandem synthesis of nitrogen heterocycles.