Secondary Interactions Arrest the Hemiaminal Intermediate to Invert the Modus Operandi of Schiff Base Reaction: A Route to Benzoxazinones

Article abstract of DOI:10.1021/acs.joc.7b00352

Discovered by Hugo Schiff, condensation between amine and aldehyde represents one of the most ubiquitous reactions in chemistry. This classical reaction is widely used to manufacture pharmaceuticals and fine chemicals. However, the rapid and reversible formation of Schiff base prohibits formation of alternative products, of which benzoxazinones are an important class. Therefore, manipulating the reactivity of two partners to invert the course of this reaction is an elusive target. Presented here is a synthetic strategy that regulates the sequence of Schiff base reaction via weak secondary interactions. Guided by the computational models, reaction between 2,3,4,5,6-pentafluoro-benzaldehyde with 2-amino-6-methylbenzoic acid revealed quantitative (99%) formation of 5-methyl-2-(perfluorophenyl)-1,2-dihydro-4H-benzo[d][1,3]oxazin-4-one (15). Electron donating and electron withdrawing ortho-substituents on 2-aminobenzoic acid resulted in the production of benzoxazinones 9-36. The mode of action was tracked using low temperature NMR, UV-vis spectroscopy, and isotopic (¹⁸O) labeling experiments. These spectroscopic mechanistic investigations revealed that the hemiaminal intermediate is arrested by the hydrogen-bonding motif to yield benzoxazinone. Thus, the mechanistic investigations and DFT calculations categorically rule out the possibility of in situ imine formation followed by ring-closing, but support instead hydrogen-bond assisted ring-closing to prodrugs. This unprecedented reaction represents an interesting and competitive alternative to metal catalyzed and classical methods of preparing benzoxazinone.

Full text of DOI:10.1021/acs.joc.7b00352

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Article
Secondary Interactions Arrest the Hemiaminal Intermediate to Invert the
Modus Operandi of Schiff Base Reaction: A Route to Benzoxazinones
Ketan Patel, SATEJ DESHMUKH, Dnyaneshwar Bodkhe, Manoj Mane, Kumar Vanka, Dinesh Shinde,
Pattuparambil R. Rajamohanan, Shyamapada Nandi, Ramanathan Vaidhyanathan, and Samir H. Chikkali
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00352 • Publication Date (Web): 05 Apr 2017
Downloaded from http://pubs.acs.org on April 6, 2017
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The Journal of Organic Chemistry
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Secondary Interactions Arrest the Hemiaminal Intermediate to
Invert the Modus Operandi of Schiff Base Reaction: A Route
to Benzoxazinones
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a†
a†
a†
b
b
Ketan Patel , Satej Deshmukh , Dnyaneshwar Bodkhe , Manoj Mane , Kumar Vanka , Dinesh
c
c
d
d
Shinde , Pattuparambil R. Rajamohanan , Shyamapada Nandi , Ramanathan Vaidhyanathan ,
Samir H. Chikkali
a,e*
a
Polyolefin Lab, Polymer Science and Engineering Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha
Road, Pune-411008, India.
b
Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-
411008, India.
c
Central NMR Facility, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411008, India.
d
Department of Chemistry, Indian Institute of Science, Education and Research, Dr. Homi Bhabha Road, Pune-
4
11008, India.
e
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, In-
dia.
*Correspondence to: s.chikkali@ncl.res.in
KEYWORDS (Secondary interaction, Amine, Aldehyde, Schiff-base, Hemiaminal, Benzoxazinone).
ABSTRACT: Discovered by Hugo Schiff, condensation between amine and aldehyde represents one of the most ubiqui-
tous reactions in chemistry. This classical reaction is widely used to manufacture pharmaceuticals and fine chemicals.
However, the rapid and reversible formation of Schiff-base prohibits formation of alternative products, of which Benzoxa-
zinones are an important class. Therefore, manipulating the reactivity of two partners to invert the course of this reaction
is an elusive target. Presented here is a synthetic strategy that regulates the sequence of Schiff-base reaction via weak sec-
ondary interactions. Guided by the computational models, reaction between 2,3,4,5,6-pentafluoro-benzaldehyde with 2-
amino-6-methylbenzoic acid revealed quantitative (99%) formation of 5-methyl-2-(perfluorophenyl)-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (15). Electron donating and electron withdrawing ortho-substituents on 2-aminobenzoic acid
resulted in the production of Benzoxazinones 9-36. The mode of action was tracked using low temperature NMR, UV-vis
1
8
spectroscopy and isotopic ( O) labelling experiments. These spectroscopic mechanistic investigations revealed that the
hemiaminal intermediate is arrested by the hydrogen-bonding motif to yield Benzoxazinone. Thus, the mechanistic inves-
tigations and DFT calculations categorically rule out the possibility of in-situ imine formation followed by ring-closing,
but support instead hydrogen-bond assisted ring-closing to prodrugs. This unprecedented reaction represents an interest-
ing and competitive alternative to metal catalyzed and classical methods of preparing Benzoxazinone.
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INTRODUCTION
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Reversible condensation of an aldehyde with an amine,
to construct a carbon-nitrogen double bond, represents
In spite of a plethora of applications of Schiff bases, the
structure-reactivity relationship between aldehyde and
amine is difficult to establish. The intrinsic reactivity of
the reaction partners is an interplay between various ef-
fects and is usually dominated by the inductive effect,
conjugative effects, steric effects and innate strains. The
structural changes (such as substitutions on the reac-
tants) can sometimes completely shut down the desired
reaction and enforce a completely different course of re-
activity. Therefore, altering the reactivity of an amine and
aldehyde in a condensation reaction requires judicious
tailoring of the reaction partners. It is known that the
amine-aldehyde condensation reaction proceeds via hem-
1,2
one of the most ubiquitous reaction steps in chemistry.
The seminal work of Hugo Schiff laid the foundation of
this reaction and his contribution has been rightly recog-
nized by the naming of this reaction after him. Tremen-
dous progress has been made and mechanistic details of
3
,4
5
this reaction have been well established. Depending on
the substitution, the condensation products are called
imines or Schiff bases or Salen’s. Schiff bases are widely
used as synthetic intermediates (such as the cycloaddition
reaction in Penicillin synthesis), ligands and catalysts,
in molecular recognition and nano-science , and they
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play a crucial role in deciding the activity of enzymes and
iaminal X (Fig. 1), which is intermediate to imine (Im).
11,12,13
proteins.
The synthetic applications of imines include,
The hemiaminal is highly unstable and NH, H-C-OH
fragments condense to liberate water and imine for-
14
but are not limited to, imine umpolung reactions, imine
15
16
2
multicomponent reactions, the formation of MOF and-
mation with sp -carbon is realized. Since altering the
17
COF.
amine group or the aldehyde functionality would com-
pletely shut down the reaction, we realized that the best
way to manipulate their reactivities would be to offer a
competitive proton in close proximity to the hydroxy
group to construct benzoxazinones (Bz) product with a
3
sp -carbon.
Recent approach
O
TMS
NR
O
+
+
CO2
Ar
H
OTf
N
R
Ar
Yoshida et al J. Am. Chem. Soc. 2006
O
N
O
CHO
R
COOH
OH
Ac2O
O
+
R1
NH2
Ar
N
Ar
Nikpour et al Chem. Lett. 2007
O
O
OH
R1
O
O
R1
PIDA
NaN3
N
N
Zhang et al J. Org. Chem. 2014
O
O
O
H2
O
[
L(Fe)]
N
H
Ar
N
Ar
Lu et al J. Am. Chem. Soc. 2015
This work
CHO
O
O
COOH
NH2
+
N
H
Ar
O
OH
N
H
Ar
Figure 1. Condensation of an amine and aldehyde to imine
(Schiff-base: path-I) and H-bonding assisted condensation
(path-II). Energy optimized structures of hemiaminal inter-
mediates; 2-aminobenzoic acid (bottom left-A), and 2-
amino-6-methylbenzoic acid (bottom right-B).
Figure 2. Recent synthetic methods for the synthesis of ben-
zoxazinones (top) and this work (bottom).
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Benzoxazinones have long medical history as biologi-
cally active compounds and are being currently used as
observed at 6.19 and 4.84 ppm. To our delight, structural
mapping of the condensation products using 2D NMR
(COSY, HSQC, HMBC) revealed the presence of a minor
(about 20%) amount of cyclized Benzoxazinone 5 (Chart 1
and Fig. S4-S8). In our endeavor to completely switch
over the reactivity to the annulation reaction, more elec-
trophilic benzaldehydes were employed, which lead to
enhanced formation of Benzoxazinones 6-9 (Chart 1). The
most electrophilic pentafluoro-benzaldehyde produced
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drug intermediates. Classical synthetic methods involve
20
multistep synthesis, but the most recent methods pro-
vide direct access to benzoxazinones (Fig. 2 top). Among
various approaches, Yoshida et al reported a straight for-
21
ward access to Benzoxazinones via aryne chemistry. In
007 Nikpour and coworkers reported synthesis of ben-
2
zoxazinones. The authors noted that a reaction between
anthranilic acid and benzaldehyde proceeds to imine,
which was found to be stable up to 3 hours under reflux
conditions. Further, it was found that the direct-
cyclization between amine and aldehyde to benzoxazi-
nones is disfavored and only in presence of acetic anhy-
48%
of
2-(perfluorophenyl)-1,2-dihydro-4H-
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benzo[d][1,3]oxazin-4-one 9. Our attempts to further im-
prove the yields of the Benzoxazinone, by screening reac-
tion parameters, were not very successful at this stage.
To identify the requirements of the condensation reac-
tion and to understand lower selectivity towards Benzox-
azinone, we turned our attention to DFT. The energy
minimized structures (Fig. 1 bottom) revealed that ortho-
substitution on the 2-aminobenzoic acid orients the car-
boxylic-OH in close proximity. Intermediate A without
any ortho-substitution displayed a C-HO---HOOC-Ar
distance of 1.86 Å, whereas the methyl substituted ana-
logue B revealed a shorter distance of 1.82 Å. Although
these distances are just indicative, the theoretical revela-
tions paved the way for experimental design and we set
out to evaluate the reactivity of 2-amino-6-methylbenzoic
acid. In fact, treatment of 2-amino-6-methylbenzoic acid
with benzaldehyde under identical conditions produced
the annulated Benzoxazinone product 11 with excellent
selectivity (86%) (Chart 1).
22
dride the reaction yields Benzoxazinones. In a recent C-
H activation strategy, Zhang et al utilized hypervalent
iodine compounds to access benzoxazinones in a single
23
step. Beller and co-workers adopted iron catalyzed
asymmetric hydrogenation reaction to prepare benzoxa-
24
zinones. We postulated that the reaction between
amine-aldehyde could be turned around via a H-
25
bonding assisted ring closing strategy (Fig.1, path-II), in
which the hemiaminal C-OH bond is selectively weak-
ened through a relatively acidic proton (compared to the
NH proton) located in close proximity. Thus, proposing a
simple, straight forward, selective and versatile synthetic
strategy to modulate the Schiff-base reaction would rep-
resent significant advancement in existing knowledge of
Schiff-base chemistry and create substantial interest in
this area.
Herein, we present a synthetic strategy that regulates
the reactivity of amine and aldehyde partners in a con-
densation reaction via weak secondary interactions. The
flipped reaction, which provides a simple selective metal
free alternative to the recent metal catalyzed coupling
Reaction Scope
Condensation of highly electrophilic 2,3,4,5,6-
pentafluoro-benzaldehyde with 2-amino-6-methylbenzoic
acid led to quantitative (99%) formation of Benzoxazi-
none 15. Benzoxazinone formation through condensation
reaction has been termed as “Benz”, where “Benz” stands
for Benzoxazinone. 2D C-H correlation NMR spectra re-
vealed cross-peaks that establish the connectivity be-
tween various protons and carbons in 15 (Fig. 3). The
NMR findings were further corroborated by IR and sup-
plemented by electrospray ionization (ESI) mass spec-
trum that disclosed a pseudo-molecular ion peak at m/z =
21,23,24
reactions,
establishes two new carbon-heteroatom
bonds bearing medicinally important Benzoxazinones.
The generality of the flipped reaction is demonstrated by
preparing a library of Benzoxazinones in a single step in-
verted condensation protocol. Mechanistic investigations
and density functional theory (DFT) calculations rule out
the possibility of in-situ imine formation followed by ring-
closing, but support instead hydrogen-bond assisted di-
rect ring-closing to produce Benzoxazinones.
+
+
330 [M+H] ; 352 [M+Na] Da. The identity of compound
15 (Chart 1) was unambiguously ascertained from a single
crystal X-ray diffraction (Fig. 3 bottom). Compound 15
crystalizes in a monoclinic unit cell in space group P1/c.
The molecular structure of 15 revealed a distinctly longer
C-N bond (N2-C24 = 1.430(5) Å) in comparison to the
RESULTS AND DISCUSSION
Synthesis of Benzoxazinone
We anticipated that the commercially available amino
acid - anthranilic acid - would be the most suitable candi-
date as it has the suitable acidity and the required direc-
tionality to facilitate the condensation reaction. To vali-
date our hypothesis, we selected benzaldehyde as an al-
dehyde partner with anthranilic acid. The condensation
reactions were performed in ethanol under reflux and the
substrates were activated using a catalytic amount of ace-
tic acid. Monitoring the progress of the reaction by pro-
ton NMR revealed the formation of imine as a major
2
6
regular imine (C=N 1.26-1.30) bond and thus categorical-
ly ruled out the existence of a C=N double bond. Interest-
ingly, the formed six member ring is not planar, but as-
sumes a half-boat conformation with one of the carbon
atoms pointing out of the plane. To the best of our
knowledge, this is the first example of an amine and alde-
hyde condensation reaction that efficiently produces 15 as
the only product. Similar structural features could be ob-
served for compound 14.
(
80%) product. In addition, two new resonances could be
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To evaluate the generality of this reaction, we investi- Benzoxazinone reaction. This followed a similar trend as
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gated the substrate scope and Chart 1 summarizes the
accessible product range. In general, electron poor alde-
hydes outperformed the electron rich aldehydes. The
electron withdrawing pentafluoro-benzaldehyde fur-
nished excellent selectivity (15, 99%), whereas the elec-
tron rich anisaldehyde displayed an inferior selectivity of
in the case of fluoro-substituted anthranilic acid and Ben-
zoxazinones could be obtained with good to excellent
selectivity (22-26; 30-96%). After having investigated the
effect of substituents ortho to the carboxylic group of an-
thranilic acid, we investigated effect of substitution ortho
to the amine group. Quite remarkably, the methyl ortho
to the amine did not pose any problem, but rather sur-
prisingly, an enhanced cyclization was observed. The re-
action of various benzaldehydes with 2-amino-3-
methylbenzoic acid resulted in quantitative production of
Benzoxazinones (27-31; 99%). The reaction does not dis-
criminate between the electron donating and electron
withdrawing aldehydes and both produced the “Benz”
product. The identity of resultant Benzoxazinones 27-31
was established using a combination of spectroscopic and
analytical methods. We attribute the enhanced annula-
tion process to the steric crowding around the amine in
5
3% only (compound 10). In order to investigate the in-
fluence of the ortho-substituent on the annulation pro-
cess, the methyl group was replaced with electron with-
drawing fluorine. Although counterintuitive, the outcome
was largely insensitive to changes in the electronic nature
of 2-aminobenzoic acid.
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the hemiaminal intermediate. An sp aldehyde was also
tested in this reaction, which produced Benzoxazinones
in excellent selectivity (32-36; 91-99%). The resultant Ben-
zoxazinones were isolated in excellent yields and their
identity was fully established using spectroscopic and
analytical tools. These observations suggest that steric
parameters dominate the annulation process irrespective
of the electronic effect of the two reaction partners. This
finding is particularly remarkable and is an additional
bonus that will aid the extension of the scope of the annu-
lation reaction. To demonstrate the synthetic utility of
this reaction, we performed the reaction on gram scale.
Treatment of 1 g of 2-methylanthranilic acid with two
equivalent of pentafluoro-benzaldehyde produced 2.03
grams of isolated 15 (92% yield). Thus, secondary interac-
tions seem to play a pivotal role and turn around the reac-
tivity of an amine and aldehyde to produce Benzoxazi-
nones, an important class of drug intermediates.
c
Diamond Demonstration Version
Diamond Demonstration Version
Diamond Dem
Diamond Dem
Diamond Dem
b
C23
Diamond Demonstration Version
O3 Diamond
Demonstration Version
C16
C17 N2
C24
Diamond Demonstration Version
Diamond Demonstration Version
Figure 3. A short range direct C-H correlation (HSQC) spec-
trum of compound 15 in CDCl (top) and molecular structure
3
(bottom) (hydrogen atoms except N-H and C-H have been
deleted for clarity and thermal ellipsoids are drawn at 50%
probability level).
The annulated product yields for 2-amino-6-
fluorobenzoic acid (21; 97%) and those obtained with 2-
amino-6-methylbenzoic acid (15; 99%) match closely.
Thus, the reaction of 2-amino-6-fluorobenzoic acid with
electron donating (aldehydes) substituents led to poor
performance (16; 37%), whereas electron withdrawing
substituents revealed excellent performance (18-21; 80-
9
4%). Encouraged by these findings, we examined the
effect of relatively less electronegative bromide in the
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Figure 5. Variable temperature stacked H NMR spectra of a
reaction between an aldehyde(I) and amine (*)(II) in CD CN;
3
ii) addition of 0.75 equivalent of II at 0°C; iii) NMR recorded
at 20°C; iv) NMR recorded at 40°C; v) NMR recorded at 60°C;
vi) addition of 0.25 equivalent of (II), NMR at 60°C; vii) addi-
tion of 0.25 equivalent of (II), NMR at 60°C.
Mechanistic Investigations
Unfolding the elementary steps in modulating the text-
book condensation reaction will be of great significance
for understanding the flipped reactivity and might unlock
the synthetic potential of this transformation. In a Schiff
base reaction, direct nucleophilic attack of amine on the
aldehydic carbocation leads to the generation of the cru-
cial hemiaminal intermediate. The underlying imine
mechanism with different rates (K -K ) has been investi-
Chart 1. Scope of the reaction with a library of Benzoxazi-
nones. Selectivity of benzoxazinone was calculated from H
NMR data.
1
1
5
28
27
gated in depth by Sayer and others. However, none of
these mechanistic proposals touch upon the reactivity
reversal and thus fail to explain the observed cyclization
(
Fig. 4). Therefore, a sixth rate constant (K ) is proposed.
6
The rate constant K can follow, at least theoretically,
three different pathways to arrive at Benzoxazinone (IV).
First, the possibility of rearrangement of imine (III) to
benzoxazinone (IV) (proposed by Nikpour, Azarifar
although the starting compounds employed in the pro-
posed mechanism were different) cannot be completely
ignored. In our attempts to understand the modus op-
erandi; we investigated this reaction using a set of NMR,
UV-vis spectroscopy and DFT calculations.
6
22
29
To nail down the possible intermediates, NMR tube re-
action of 2-amino-6-methylbenzoic acid with pentafluo-
ro-benzaldehyde was attempted and the progress of the
reaction was monitored by proton NMR spectroscopy.
Even at 0°C, instantaneous formation of Benzoxazinones
was observed with traces of imine (Fig. 5). As the temper-
ature of the reaction mixture was raised from 0°C to 60°C,
gradual decrease in the intensity of methyl (2.41 ppm *)
resonance in (II) and concomitant increase in the intensi-
ty of methyl group in (IV) at 2.60 ppm (■) was observed.
Interestingly, only traces of imine (8-9 ppm) could be
Figure 4. Proposed reaction pathways to Benzoxazinone
(
IV), (R = F ).
1 5
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observed (Fig. S130). These findings rule out the possibil-
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ity of formation of imine (route A) as the first step and
subsequent conversion of (III) to (IV) [D (K )]. The NMR
6
findings were corroborated by UV-vis, which revealed the
absence of a C=N charge transfer band (at 319 nm) and
attested to the formation of Benzoxazinone with a charac-
teristic band at 291 nm, which was confirmed by DFT (ESI
Fig. S136, S137 respectively). In order to differentiate be-
tween route B and C, we labeled the anthranilic acid oxy-
1
8
13
gen (with O-isotope). Tracking the progress by C NMR
revealed a resonance at 77.52 ppm, which clearly indicat-
ed retention of labeled oxygen in the Benzoxazinone
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8
13
product. The observed isotopic ( O) dependence of
C
3
0
chemical shift is in agreement with literature reports.
The NMR observations were further supplemented by
ESI-MS which revealed a pseudo-molecular ion peak at
m/z = 332.06 [M+H] , wherein the mass of oxygen is 18
Da. Therefore, it is very likely that route B is the most
preferred mechanistic pathway for the condensation reac-
tion.
+
Figure 6. DFT calculated (A, B, C) mechanistic pathways
with free energies (kcal.mol ) for various transition states
and (E) Benzoxazinone as an important building block for
drugs and prodrugs.
-1
The thus produced Benzoxazinones are pharmaceuti-
cally important molecules that are commercially used to
treat obesity (V), to lower cholesterol levels (VI) and as
Computational Insights
31
3
2
To obtain detailed insights in the benzoxazinone reac-
tion, we sought the assistance of DFT and the energies
associated with potential routes A, B and C was calculat-
ed. Figure 6 depicts the energy barriers for hemiaminal
formation and the rate determining dehydration reaction
for the three routes. The initial formation of hemiaminal
was identical for the three routes with a ΔG = 10.4
kcal/mol. As is evident, route B proved to be the preferred
pathway with the lowest barrier of 29.5 kcal/mol, as com-
pared to 51.1 kcal/mol (uphill by +21 kcal/mol) for Path-
way A and 64.9 kcal/mol (uphill by +35 kcal/mol) for
Pathway C (Fig. 6). The lowest barrier for route B is most
likely due to the secondary interaction between the acidic
proton of the carboxylic acid and the hydroxyl group of
the hemiaminal. The ortho-(to COOH) substituent likely
facilitates the spatial orientation of the acidic proton and
brings it to the close proximity of the hydroxyl group,
leading to the favored water elimination. The above DFT
results therefore complement the experimental findings
and reveal the existence of secondary interactions that
totally alter the course of the reaction to produce Benzox-
azinone via a mechanism that changes our perception of
Schiff condensation.
an anti-inflammatory prodrug (VII). We anticipate that
similar other reactions can be reengineered using second-
3
3
ary interactions.
CONCLUSIONS
In summary, we report on the first synthetic strategy
that regulates the reactivity of an amine and aldehyde via
secondary interactions. The strategic placement of an
ortho-substituent selectively suppresses the formation of
Schiff-base and increase the formation of Benzoxazi-
nones, which belongs to a class of prodrugs. Energy opti-
mized models of the hemiaminal intermediate revealed
that a ortho-substituent correctly orients the hydrogen
bonding motif at hemiaminal stage and promotes the
condensation reaction via weak secondary interactions.
Indeed, reaction of 2-amino-6-methylbenzoic acid with
benzaldehyde produced the desired Benzoxazinone 11
with 86% selectivity. To our delight, treating electrophilic
pentafluoro-benzaldehyde with 2-amino-6-methylbenzoic
acid revealed quantitative formation of Benzoxazinone 15.
The synthetic utility of this strategy was demonstrated by
preparing a library of 30 compounds and by scaling up the
reaction to gram scale. The benzoxazinone reaction was
found to be largely insensitive to the electronic changes
and yielded similar results for electron donating methyl-
substituent and electron withdrawing substituents. Quite
remarkably, a methyl-substituent ortho to amine yielded
Benzoxazinones in quantitative yield (27-31). Even the
aliphatic aldehyde such as cyclohexane carboxaldehyde
produced the corresponding Benzoxazinones in near
quantitative yield (32-36). Detailed mechanistic investiga-
tions using low temperature NMR, UV-vis and isotopic
18
(
O) labeling revealed that the reactions follows pathway
B and the possibility of route A and C was ruled out. The-
se experimental findings were corroborated by DFT calcu-
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The Journal of Organic Chemistry
4
1
lations, which indicated that pathway B is the lowest bar-
rier pathway, 20 kcal/mol lower than pathway A and 35
kcal/mol lower than pathway C.
were done with the M06-2X functional on the optimized
geometries. With regard to the transition states obtained
during the investigations of these reactions, care was tak-
en to ensure that the obtained transition state structures
possessed only one imaginary frequency corresponding to
the correct normal mode. For compounds (III) and (IV)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
EXPERIMENTAL SECTION
General methods and material
(
HOMO-LUMO calculation), calculations were per-
4
2
Starting materials were procured from commercial sup-
pliers and used without further purification. Solvents
were dried by standard procedures unless otherwise men-
tioned. 2-Amino benzoic acid was purchased from Loba
Chemie Pvt. Ltd. 2-Amino-6-methyl benzoic acid, 2-
amino-6-fluorobenzoic acid, 2-amino-3-methylbenzoic
acid, 2-amino-6-bromobenzoic acid, benzaldehyde, 4-
formed using the Gaussian 09 suite of programs with the
M062X functional and 6-31+G* basis set. The HOMO-
LUMO was calculated using the time-dependent (TD-
DFT) method based on the optimized ground-state struc-
ture at the M062X/6-31+G* level. Isovalue was set to 0.02
to draw orbitals.
3
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Single-crystal data was collected on a Bruker SMART
APEX four-circle diffractometer equipped with a CMOS
photon 100 detector (Bruker Systems Inc.) and with a Cu
Kα radiation (1.5418 Å). The incident X-ray beam was fo-
cused and monochromated using Microfocus (IµS). The
Flaky colourless crystals were mounted on nylon Cryo
loops with Paratone-N oil. Data was collected at 100(2) K.
Full data was integrated using Bruker SAINT Software
and absorption correction was done using SADABS.
Structure was solved by Intrinsic Phasing module of the
direct methods and refined using the SHELXTL 97 soft-
ware suite. All non-hydrogen atoms were located from
iterative examination of difference F-maps following
which the structure was refined using least-squares
method. All the non-Hydrogen atoms were refined aniso-
tropically. Hydrogen atoms were placed geometrically
and placed in a riding model.
methoxybenzaldehyde,
fluorobenzaldehyde, 2,6-difluorobenzaldehyde, 2,3,4,5,6-
pentafluorobenzaldehyde, cyclohexanecarboxaldehyde
were received from Sigma Aldrich. 2-Amino-6-
3-bromobenzaldehyde,
2-
1
8
bromobenzoic acid was purchased from Alfa Aesar.
O
1
8
labeled water (H O) and solvents (CDCl , CD CN) were
2
3
3
purchased from Sigma Aldrich. Ethanol (commercial
grade, 99.9%) was obtained from Brampton, Canada. All
other solvents were purchased from local suppliers (Spec-
trochem Pvt. Ltd.; Avra Synthesis Pvt. Ltd.).
Solution NMR spectra were recorded on a Bruker
Avance 200, 400 and 500 MHz instruments and internal-
ly referenced to residual solvent signals (note: CDCl ref-
3
erenced at δ 7.26 and 77.23 ppm and CD CN referenced at
3
δ 1.94 and 1.39 ppm respectively). Coupling constants are
given as absolute values. Multiplicities are given as fol-
lows- s: singlet, d: doublet, t: triplet, m: multiplet. Ben-
zoxazinone and imine are denoted as Bz and Im respec-
tively in NMR spectra of compounds. Mass spectra were
recorded on Thermo scientific Q-Exactive mass spec-
trometer (Quadrupole analyzer) with Hypersil gold C18
column (150 x 4.6 mm diameter 8 µm particle size mobile
phase used is 90% methanol + 10 % water + 0.1 % formic
acid). UV–visible spectrum was recorded at ambient tem-
perature on PerkinElmer 35 LAMDA instrument using the
General procedure for the synthesis of Benzoxazi-
nones
1 mmol of amine was dissolved in 20 mL ethanol and 2
mmol (2 equiv.) aldehyde was added to the above solu-
tion. Catalytic amount of acetic acid (0.2 equiv.) was add-
ed to the reaction mixture and the resulting reaction mix-
ture was refluxed for 6 hours. Next, the reaction mixture
was concentrated in vacuum to afford a crude semi-solid
residue. The thus obtained residue was washed with
hexane (10 mL × 2) to yield free flowing solid.
1
cm quartz cell. FT-IR spectra of the samples were rec-
orded using KBr pellet on the PerkinElmer instrument. C,
H and N analyses were carried out using PerkinElmer
2400.
The identity of the imine and the benzoxazinone
(
obtained via the proposed condensation) was established
The geometry optimizations were conducted employing
from various 1-2D NMR experiments and the NMR
spectra have been deposited in supporting information.
The product (benzoxazinone : imine) distribution was
determined from the proton NMR of above residue. Spec-
trum of respective compounds has been presented in
supporting information.
density functional theory (DFT) with the Turbomole 7.0
35
suite of programs. The Perdew, Burke, and Ernzerhof
36
(
PBE) functional was used for the geometry optimiza-
tion calculations. The triple-ζ basis set augmented by a
polarization function (Turbomole basis set TZVP) was
37
used for all the atoms. The resolution of identity (RI)
along with the multipole accelerated resolution of identi-
Benzoxazinones with more than 90% selectivity were
isolated and the yields have been reported.
38
ty (marij) approximations were employed for an accu-
rate and efficient treatment of the electronic Coulomb
term. Solvent effects were accounted for as follows: we
have done full geometry optimizations of all intermedi-
ates and transition state calculations using the COSMO
2-(3-bromophenyl)-5-methyl-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 12):
General procedure as above was followed and 2-
amino-6-methylbenzoic acid (0.151 g, 1 mmol, 1 equiv.)
and 3-bromobenzaldehyde (0.367 g, 2 mmol, 2 equiv.)
39
model with ethanol as a solvent. Moreover, dispersion
corrections (disp-3) were also included through these
40
calculations. Following this, single point calculations
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The Journal of Organic Chemistry
were used as reaction partners. The ratio of the two prod-
Page 8 of 12
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ucts was determined from a proton NMR and the respec-
tive spectrum is presented in figure S32. After hexane
wash benzoxazinone 12 was isolated as light yellow color
5
-methyl-2-(perfluorophenyl)-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 15):
General procedure as above was followed and 2-amino-
6-methylbenzoic acid (0.151 g, 1 mmol, 1 equiv.) and
,3,4,5,6-pentafluorobenzaldehyde (0.392 g, 2 mmol, 2
equiv.) were used as reaction partners. Compound 15 was
isolated in as pale yellow solid (0.315 g, 96%) after routine
hexane wash. The compound was crystalized by slow
evaporations from ethanol solution and molecular struc-
ture is presented in S56. Melting point (m.p.) = 196-
solid (0.288 g, 91%) Melting point (m.p.) = 132-134°C.
1
H NMR (500 MHz, CDCl , 298 K): δ = 7.79 (br s, 1H,
3
2
Ar), 7.57 (d, JH-H = 8.01 Hz, 1H, Ar), 7.53 (d, JH-H = 7.63 Hz,
1
6
1
H, Ar), 7.32-7.27 (m, 2H, Ar), 6.83 (d, J
.71 (d, JH-H = 8.39 Hz, 1H, Ar), 6.04 (d, JH-H = 2.29 Hz ,
= 7.63 Hz, Ar),
H-H
3
13
H, H ), 4.88 (br s, 1H, H ), 2.68 (s, 3H, CH ). C NMR
Bz a 3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
125 MHz, CDCl , 298 K) δ = 163.3 (C ), 148.5, 144.5, 138.1,
3 h
1
(
34.4, 133.3, 131, 130.4, 125.9, 124.7, 122.9, 114.2, 113.0, 85.5
+
197°C.
C ), 22.5 (CH ). HRMS (ESI) m/z: [M+H] Calcd for
Bz 3
1
+
H NMR (400 MHz, CDCl3, 298 K): δ = 7.34 (t, JH-H
=
C H O BrN 318.0124; Found 318.0122, [M +Na] Calcd for
1
5
13
2
7.82, 1H, Ar, H ), 6.92 (d, J
(d, JH-H = 8.07 Hz, 1H, Ar, H ), 6.47 (d, J
HBz), 5.03 (d, J = 3.42 Hz, 1H, H ), 2.70 (s, 3H, CH ). C
NMR (100 MHz, CDCl , 298 K) δ = 162.8 (C ), 147.9, 146.9,
144.7, 143.7, 139.1, 138.9, 136.9, 134.5, 125.8, 115.5, 115.3, 113.9,
110.7, 77.8 (CBz), 22.4 (CH ). F NMR (376 MHz, CDCl3,
= 7.34 Hz, 1H, Ar, H ), 6.77
C H O BrNNa 339.9944; Found 339.9937.
d
H-H
c
1
5
12
2
3
= 5.15 Hz, 1H,
e
H-H
2-(2-fluorophenyl)-5-methyl-1,2-dihydro-4H-
3
13
H-H
a
3
benzo[d][1,3]oxazin-4-one (compound 13):
3
h
General procedure as above was followed and 2-amino-
19
6
-methylbenzoic acid (0.151 g, 1 mmol, 1 equiv.) and 2-
3
fluorobenzaldehyde (0.248 g, 2 mmol, 2 equiv.) were used
as reaction partners. The ratio of the two products was
determined from a proton NMR and the respective spec-
trum is presented in figure S36. After hexane wash the
benzoxazinone 13 was isolated as light yellow color solid
2
98 K) δ -139.87 (d, JF-F = 16.02 Hz, 2F), -149.85 (d, JF-F
=
20.60 Hz, 1F), -160.16 (t, J = 18.54 Hz, 2F). HRMS (ESI)
F-F
+
m/z : [M+H] Calcd for C H O F N 330.0548; Found
15
9
2 5
3
3
5
30.0543. Elemental analysis For C H O F N (FW =
29.05) in %: Calcd.: C 54.72, H 2.45, N 4.25; Found: C
4.63, H 2.38, N 4.21. FT-IR (cm-1): 1705 (C=O), 1653, 1602,
15 8 2 5
(
0.226 g, 88%). Melting point (m.p.) = 98-100°C.
1
H NMR (500 MHz, CDCl , 298 K): δ = 7.76 (t, J
=
H-H
1504 (N-H (br.)), 1433, 1382, 1338 (C-N), 1274, 1201 (C-O),
1130 (C-O (br.)), 1044, 1003.
3
6
.87Hz, , 1H, Ar), 7.40 (m, 1H, Ar), 7.24 (m, 2H, Ar), 7.09
(
(
t, JH-H = 9.16, 1H, Ar), 6.79 (d, JH-H = 7.63 Hz, 1H, Ar), 6.67
2-(3-bromophenyl)-5-fluoro-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 18):
d, JH-H = 8.01 Hz, 1H, Ar), 6.39 (s, 1H, H ), 4.87 (br, s, 1H,
Bz
13
H ), 2.66 (s, 3H, CH ). C NMR (125 MHz, CDCl , 298 K) δ
=
a
3
3
3
General procedure as above was followed and, 2-amino-
6-fluorobenzoic acid (0.155 g, 1 mmol, 1 equiv.) and 3-
bromobenzaldehyde (0.370 g, 2 mmol, 2 equiv.) were used
as reaction partners. The resultant compound 18 was iso-
lated as light yellow color solid (0.289 g, 90% ). Melting
163.8, 161.6, 149.3, 144.7, 134.5, 132.4 (d, J = 8.58), 129.0,
C-F
2
3
1
25.0, 124.7, 116.1 (d, J = 20.98), 114.2, 112.9, 80.5 (d, J
=
C-F
C-F
+
4
.77 Hz), 22.6 (CH ). HRMS (ESI) m/z : [M+H] Calcd for
3
+
C H O NF 258.0925; Found 258.0922, [M+Na] Calcd for
C H O NFNa 280.0744; Found 280.0740.
15 13
2
15 12
2
point (m.p.) = 146-148°C.
2-(2,6-difluorophenyl)-5-methyl-1,2-dihydro-4H-
1
H NMR (200 MHz, CDCl , 298 K): δ = 7.78 (t, J
=
H-H
3
benzo[d][1,3]oxazin-4-one (compound 14):
1
6
.77, 1H, Ar), 7.62-7.50 (m, 2H, Ar), 7.46-7.28 (m, 2H, Ar),
3
General procedure as above was followed and 2-amino-
-methylbenzoic acid (0.151 g, 1 mmol, 1 equiv.) and 2,6-
.75-6.64 (m, 2H), 6.11 (d, J
= 3.03 Hz, 1H, H ), 5.02 (br
H-H Bz
13
6
s, 1H, H ). C NMR (125 MHz, CDCl , 298 K) δ = 164.0
a
3
3
difluorobenzaldehyde (0.284 g, 2 mmol, 2 equiv.) were
used as reaction partners. The ratio of the two products
was determined from proton NMR which is presented in
figure S40. The compound was crystalized by slow evapo-
rations from ethanol (Pure crystal, 0.231 g , 84%) and mo-
lecular structure is presented in Figure S41. Melting
(
C ), 161.0, 159.4, 150.5, 137.8, 135.2 (d, J = 11.45 Hz),
h
C
-
F
3
2
1
32.5, 130.0 (d, J = 7.6), 128.1, 126.0, 121.8, 106.1 (d, J
=
C-F
2
0.98 Hz), 126.2, 115.9, 115.3, 114.3, 111.2, 110.3, 84.9 (C ).
Bz
+
HRMS (ESI) m/z: [M+H] Calcd for C H O NFBr
1
4
10
2
3
21.9873; Found 321.9876.
-fluoro-2-(perfluorophenyl)-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 21):
5
point (m.p.) = 94-96°C.
1
H NMR (400 MHz, CDCl , 298 K): δ = 7.45-7.41 (m, 1H,
3
2
General procedure as above was followed and 2-amino-
6-fluorobenzoic acid (0.155 g, 1 mmol, 1 equiv.) and
2,3,4,5,6-pentafluorobenzaldehyde (0.392 g, 2 mmol, 2
equiv.) were used as reaction partners. Work-up of reac-
tion mixture produced pure 21 in light yellow color solid
Ar, H), 7.35-7.28 (m, 1H, Ar, H), 6.97 (t, J = 8.45, 2H, Ar,
H), 6.88 (m, JH-H = 7.58, 1H, Ar, H), 6.77 (d, JH-H = 8.07, 1H,
3
Ar, H), 6.49 (d, J
= 5.38, 1H, H ), 5.13 (br, s, 1H, H),
Bz
H-H
13
2
.70 (s, 3H, CH ). C NMR (100 MHz, CDCl , 298 K) δ =
63.7 (C ), 162.8 (d, J = 6.17 Hz, C), 160.3 (d, J = 6.17
Hz, C), 148.3 (C), 144.5 (C), 134.1 (C), 132.2 (t, J = 10.63
Hz, C), 125.3 (C), 115.7 (C), 114.3 (C), 114.5 (C), 112.2 (d, J
25.43 Hz, C), 78.3 (t, J = 3.85 Hz, J = 4.62 Hz, C ),
2.5 (CH ). HRMS (ESI) m/z: [M+H] Calcd for
C H O NF 276.0831; Found 276.0826, [M+Na] Calcd for
3
3
3
3
1
h
C-F
C-F
3
(0.306 g, 92%). Melting point (m.p.) = 184-186°C.
C-F
1
2
H NMR (200 MHz, CDCl , 298 K): δ = 7.53-7.42 (m, 1H,
3
C-F
3
3
3
Ar), 6.86-6.72 (m, 2H, Ar), 6.53 (d, J = 4.53 Hz, 1H,
H-H
=
C-F
Bz
13
+
H ), 5.16 (br, s, 1H). C NMR (100 MHz, CDCl , 298 K) δ =
2
Bz
3
3
3
+
1
1
64.4 (C ), 161.8, 158.8, 150.0, 135.9 ( J = 11.56 Hz), 131.3,
h C-F
1
5
12
2
2
4
2
13.3, 111.2 (d, J = 3.85), 109.5, 106.3 (d, J = 20.81), 101.3
C H O NF Na 298.0650; Found 298.0644.
C-F
C-F
1
5
11
2
2
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The Journal of Organic Chemistry
2
+
(
d, J = 11.56), 77.1 (C ). HRMS (ESI) m/z: [M+H] Calcd
5-methyl-2-(perfluorophenyl)-1,2-dihydro-4H-
C-F
Bz
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
for C H O NF 334.0297; Found 334.0293.
benzo[d][1,3]oxazin-4-one (compound 26):
1
4
6
2
6
5
-bromo-2-(3-bromophenyl)-1,2-dihydro-4H-
General procedure as above was followed and 2-amino-
6-bromobenzoic acid (0.216 g, 1 mmol, 1 equiv.) and
2,3,4,5,6-pentafluorobenzaldehyde (0.392 g, 2 mmol, 2
equiv.) were used as reaction partners. Compound 26 was
isolated as pale yellow color solid (0.355 g, 90%). Melting
benzo[d][1,3]oxazin-4-one (compound 23):
General procedure as above was followed and, 2-
amino-6-bromobenzoic acid (0.216 g, 1 mmol, 1 equiv.)
and 3-bromobenzaldehyde (0.370 g, 2 mmol, 2 equiv.)
were used as reaction partners. The ratio of the two prod-
ucts was determined from a proton NMR and the respec-
tive spectrum is presented in figure S79. After multiple
hexane wash compound 23 was isolated (0.344 g, 90%) as
point (m.p.) = 120-122°C.
1
H NMR (400 MHz, CDCl , 298 K): δ = 7.50-7.21 (m, 1H,
3
3
Ar), 6.82-6.72 (m, 1H, Ar), 6.52 (d, J
.48-6.38 (m, 1H, Ar), 5.22 (br, s), 1H). C NMR (125 MHz,
= 4.27 Hz, 1H, H ),
Bz
H-H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
6
light yellow solid. Melting point (m.p.) = 142-144°C.
CDCl , 298 K) δ = 169.8 (C ), 165.3, 162.8-162.7 (d, J = 7.7
3
h
1
H NMR (200 MHz, CDCl , 298 K): δ = 7.79 (br, s,
3
Hz), 159.1, 152.8, 148.4, 136.6-136.5 (d, J = 11.56 Hz), 135.6-
35.0 (d, J = 12.33 Hz), 77.5 (C ). HRMS (ESI) m/z: [M+H]
Ar, 1H , H), 7.65-7.52 (m, Ar, 2H), 7.35-7.28 (m, Ar, 2H, H;
H), 6.84-6.78 (m, 1H, Ar, H), 7.25-7.20(m, 1H, Ar, H),6.03
1
Bz
+
Calcd for C H O NF Br 393.9497; Found 393.9495.
1
4
6
2
5
3
13
(
(
d, J
= 2.75 Hz, 1H, H ), 4.90 (br, s, 1H, H ). C NMR
H-H Bz a
2-(4-methoxyphenyl)-8-methyl-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 27):
125 MHz, CDCl , 298 K): δ = 160.0 (C ), 148.7, 147.4, 137.2,
3
h
1
1
36.6, 134.8, 133.0, 131.0, 130.4, 130.04, 129.9, 127.9, 123.4,
General procedure as described in section 2.1 was fol-
lowed and 2-amino-3-methylbenzoic acid (0.151 g, 1 mmol,
1 equiv.) and 4-methoxybenzaldehyde (0.272 g, 2 mmol, 2
equiv.) were used as reaction partners. After multiple
hexane wash compound 23 was isolated (0.234 g, 87%) as
20.7, 117.9, 116.5, 115.0, 114.7 84.3 (C ).
Bz
5
-bromo-2-(2-fluorophenyl)-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 24):
General procedure as above was followed was followed
and 2-amino-6-bromobenzoic acid (0.216 g, 1 mmol, 1 eq)
and 2-fluorobenzaldehyde (0.248 g, 2 mmol, 2 eq) were
used as reaction partners. Multiple hexane wash resulted
in yellow color solid (0.283 g, 88%). Melting point (m.p.)
light yellow solid. Melting point (m.p.) = 145-147°C.
1
H NMR (500 MHz, CDCl , 298 K): δ = 7.92-7.86 (m, Ar,
3
1
6
(
H), 7.58 (br, s, Ar, 2H), 7.33 (d, JH-H = 6.10 Hz, 1H), 6.99-
.95 (m, Ar, 3H), 6.14 (br, s, 1H, H ), 4.51 (br, s, 1H), 3.86
Bz
13
OCH ), 2.20 (CH ). C NMR (125 MHz, CDCl , 298 K) δ =
3 3 3
=
96-98°C.
1
65.2 (C ), 161.3, 150.1, 136.3, 132.0, 130.4, 128.9, 128.6, 121.2,
h
1
H NMR (400 MHz, CDCl , 298 K): δ = 7.77 (t, J
=
3
H-H
116.1, 114.5, 86.8 (C ), 55.6 (OCH ), 21.2 (CH ). HRMS
Bz 3 3
+
6
7
.71 Hz, Ar, 1H, H), 7.43 (d, JH-H = 7.34 Hz, Ar, 1H, H), 7.23-
.19 (m, 2H, Ar, H; H), 7.13 (t, JH-H = 9.24 Hz, Ar, 1H, H),
6.813 (d, JH-H = 2.75 Hz, Ar, 1H, H), 7.02-6.98 (m, Ar, 1H,
(ESI) m/z: [M +H] Calcd for C H O N 270.1125; Found
1
6
16
3
+
270.1123, [M +Na] Calcd for C H O NNa 292.0944; Found
1
6
15
3
292.0941.
1
3
H), 6.43 (d, 1H, H ), 5.07 (br, s), 1H, H). C NMR (100
Bz
8-methyl-2-phenyl-1,2-dihydro-4H-
MHz, CDCl , 298 K) δ = 161.5 (C), 159.0.8, 150.1, 134.9, 133.2,
3
3
2
benzo[d][1,3]oxazin-4-one (compound 28):
132.2 ( J = 8.48 Hz, C), 128.7, 127.9, 124.9 ( J = 3.08 Hz),
C-F
2
2
General procedure as described in section 2.1 was fol-
lowed and 2-amino-3-methylbenzoic acid (0.151 g, 1 mmol,
123.5, 122.6 (d, J = 12.33), 116.1 (d, J = 21.58), 115.5, 81.2
( J = 4.62 Hz, C ). HRMS (ESI) m/z: [M+H] Calcd for
C-F
3
+
C-F
Bz
1
equiv.) and benzaldehyde (0.212 g, 2 mmol, 2 equiv.)
C H O NFBr 321.9873; Found 321.9870.
1
4
10
2
were used as reaction partners. Multiple hexane washing
led to pure compound 28, although with about 9% start-
ing 2-amino-3-methylbenzoic acid impurity. Melting
5
-bromo-2-(2,6-difluorophenyl)-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 25):
º
General procedure as above was followed and 2-amino-
point (m.p.): 160-162 C.
6
-bromobenzoic acid (0.216 g, 1 mmol, 1 equiv.) and 2,6-
1
H NMR (500 MHz, CDCl , 298 K): δ = 7.92-7.86 (m, Ar,
3
difluorobenzaldehyde (0.284 g, 2 mmol, 2 equiv.) were
used as reaction partners. Hexane washing led to the pro-
duction of 25 as light yellow color solid (0.312 g, 92%).
1H), 7.66 (br s, Ar, 2H), 7.48 (br s, 2H), 7.35 (d, JH-H = 6.87
Hz , Ar, 1H), 6.96 (t, JH-H = 7.25 Hz , 1H), 6.63 (t, JH-H = 7.44
Hz , 1H), 6.19 (s, 1H, H ), 4.55 (br, s, 1H, H ), 2.20 (CH ).
Bz
a
3
Melting point (m.p.) = 108-110°C.
13
C NMR (125 MHz, CDCl , 298 K) δ = 164.5 (C ), 149.6,
3
h
1
H NMR (500 MHz, CDCl , 298 K): δ = 7.54-7.44 (m, Ar,
3
145.4, 135.8, 130.0, 128.8, 126.9, 124.57, 123.0, 120.9, 115.7,
+
1
H), 7.33 (d, JH-H = 7.63 Hz, Ar, 1H), 7.23 (t, JH-H = 8.01 Hz,
114.3, 86.6 (C ). HRMS (ESI) m/z: [M+H]
Calcd for
Bz
+
Ar, 1H), 6.98 (t, JH-H = 8.50 Hz, Ar, 2H), 6.89 (d, JH-H = 8.01
C H O N 240.1019; Found 240.1016, [M+Na] Calcd for
15 14
2
3
3
Hz, Ar, 1H), 6.50 (d, J
=
= 5.34 Hz, 1H, H ), 5.34 (d, J
Bz H-H
H-H
C H O NNa 262.0838; Found 262.0835.
15 13 2
13
3.43 Hz, 1H ). C NMR (125 MHz, CDCl , 298 K) δ =
3
3
1
62.5 (C ), 161.4, 160.5, 149.4, 134.75, 132.6 (t, J = 10.48
h C-F
2
2
2-(3-bromophenyl)-8-methyl-1,2-dihydro-4H-
Hz), 128.7, 125.7, 117.2, 114.6, 112.5 (d, J = 12.33), 112. 5 (dd, J
=
[
3
3
3
benzo[d][1,3]oxazin-4-one (compound 29):
8.26), 77.9 ( J
= 4.29 Hz, C ). HRMS (ESI) m/z:
C-F Bz
+
M+H] Calcd for C H O NF Br m/z = 339.9779, Found
39.9775, [M+Na] Calcd for C H O NF BrNa m/z =
14 8 2 2
General procedure as described above was followed and
2-amino-3-methylbenzoic acid (0.151 g, 1 mmol, 1 equiv.)
and 3-bromobenzaldehyde (0.370 g, 2 mmol, 2 equiv.)
were used as reaction partners. Simple hexane wash pro-
1
4
9
2
2
+
61.9599, Found 361.9592.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Hz, 1H, H ), 4.85 (br, s, 1H, H), 1.98 (d, J
Page 10 of 12
= 10.68 Hz,
H-H
duced 29 as yellowish white color solid (0.295 g, 93%).
Melting point (m.p.): 94-96 C.
Bz
°
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1H, H), 1.84 (br, d, JH-H = 8.77 Hz, 4H, H), 1.73 (d, J
=
H-H
13
1
1
1.44 Hz, 1H, H), 1.32-1.23 (m, 5H, H;H). C NMR (125
H NMR (500 MHz, CDCl , 298 K): δ = 7.92 (d, J
.83 Hz, 1H, Ar), 7.84 (s, 1H, Ar), 7.60 (t, JH-H = 8.62 Hz,
H, Ar), 7.36 (t, 2H, Ar), 7.00 (t, JH-H = 7.80 Hz , 1H), 6.18
=
H-H
3
MHz, CDCl , 298 K) δ = 164.7 (C ), 162.7, 160.9, 149.6, 135.7
(
2
7
2
3
h
3
4
2
d, J = 11.44 Hz, C), 111.5 (d, J = 3.82 Hz, C), 107.9 (d, J =
0.98 Hz, C), 88.6 (C ), 40.7 (C), 27.57-26.40 (m, C).
(
d, JH-H = 4.88 Hz, 1H, H ), 4.45 (br, s, 1H, H ), 2.24 (CH ).
Bz
Bz
a
3
+
13
HRMS (ESI) m/z : [M +H] Calcd for C H O NF m/z =
C NMR (125 MHz, CDCl , 298 K) δ = 164.1, 144.9, 138.0,
36.0, 133.2, 130.4, 130. 1, 128.6, 125.6, 124.9, 122.8, 121.3,
14.6, 85.4 (C ), 16.4 (CH ). HRMS (ESI) m/z : [M+H]
Calcd for C H O NBr 318.0124; Found 318.0125, [M+Na]
14 17
2
3
2
50.1238, Found 250.1235.
5-bromo-2-cyclohexyl-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 35):
1
1
+
Bz
3
+
1
5
13
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Calcd for C H O NBrNa 339.9944; Found 339.9942.
1
5
12
2
General procedure as described above was followed and
2-amino-6-bromobenzoic acid (0.216 g, 1 mmol, 1 equiv.)
and cyclohexanecarbaldehyde (0.240 g, 2 mmol, 2 equiv.)
were used as reaction partners. Compound 35 was isolated
as light brownish color solid (0.298 g, 96%). Melting
2
-cyclohexyl-1,2-dihydro-4H-benzo[d][1,3]oxazin-4-
one (compound 32):
General procedure as described in section 2.1 was fol-
lowed and 2-aminobenzoic acid (0.137g, 1 mmol, 1 equiv.)
and cyclohexanecarbaldehyde (0.224g, 2 mmol, 2 equiv.)
were used as reaction partners. The ratio of the two prod-
ucts was determined from a proton NMR and the respec-
tive spectrum is presented in figure S110. Compound 32
was isolated as yellow color solid (0.203 g, 88%). Melting
º
point (m.p.) = 131-132 C.
1
H NMR (500 MHz, CDCl , 298 K): δ = 7.21-7.14 (m, 2H,
3
3
Ar), 6.80 (d, JH-H = 7.93 Hz,1H, Ar), 4.93 (d, J
= 4.40 Hz,
H-H
2H, HBz ; H ) , 1.98 (d, J
= 10.27 Hz, 1H), 1.84 (d, JH-H =
a
H-H
6.85 Hz, 4H), 1.74 (d, J
= 10.27 Hz, 1H), 1.34-1.20 (m,
H-H
°
13
point (m.p.): 160 C.
5H). C NMR (125 MHz, CDCl , 298 K) δ = 161.8 (C ),
3 h
1
50.0, 134.2, 127.0, 125.1, 115.5, 113.1, 87.9 (C ), 40.5, 27.5-
Bz
+
1
26.4 (m). HRMS (ESI) m/z: [M +H] Calcd for C14H
17
H NMR (500 MHz, CDCl , 298 K): δ = 7.96 (d, J
.63 Hz, Ar, H), 7.41 (t, JH-H = 7.25 Hz, Ar, H), 6.95 (t, JH-H
=
=
+
3
H-H
O NBr m/z = 310.0437, Found 310.0436, [M+Na] Calcd for
2
7
7
C H O NBrNa m/z = 332.0257, Found 332.0251. Ele-
14 16
2
.63 Hz, Ar, H), 6.82 (d, JH-H = 8.01 Hz, Ar, H), 5.02 (d, JH-H
4.58 Hz, H ), 4.73 (s, br, H), 1.98 (d, J = 9.92 Hz, 1H,
mental analysis. For C H O NBr (309.10) in % : Calcd C,
14 16
2
=
Bz
H-H
13
54.21; H, 5.20; N, 4.52; Found: C, 54.13; H, 5.14; N, 4.49
H), 1.84-1.27 (m, 10H, H). C NMR (125 MHz, CDCl , 298
3
K) δ = 165.1 (C), 147.6, 135.0, 130.7, 120.6, 116.1, 114.0, 89.2
+
(
C ), 40.9, 27.4-25.6. HRMS (ESI) m/z): [M+H] Calcd for
2-cyclohexyl-8-methyl-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 36):
Bz
+
C H O N m/z = 232.1332; Found 232.1330, [M+Na] Calcd
1
4
18
2
for C H O NNa 254.1152; Found 254.1148.
1
4
17
2
General procedure as described above was followed
and, 2-amino-3-methylbenzoic acid (0.151 g, 1 mmol, 1
equiv.) and cyclohexanecarbaldehyde (0.224 g, 2 mmol, 2
equiv.) were used as reaction partners. Compound 36 was
2
-cyclohexyl-5-methyl-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 33):
General procedure as described above was followed
and, 2-amino-6-methylbenzoic acid (0.151 g, 1 mmol, 1
equiv.) and cyclohexanecarbaldehyde (0.240 g, 2 mmol, 2
equiv.) were used as reaction partners. The resultant
compound 33 was isolated in excellent (0.237 g, 97%) iso-
isolated in 96% yield (0.235 g). Melting point (m.p.) =
°
1
00-101 C.
1
H NMR (500 MHz, CDCl , 298 K): δ = 7.85 (d, J
=
H-H
3
8.01 Hz, 1H, Ar), 7.29 (d, J
= 7.25 Hz, 1H, Ar), 6.90 (t, JH-
H-H
º
3
lated yields. Melting point (m.p.) = 122-124 C.
= 7.63 Hz, 1H), 5.00 (d, J
= 4.77 Hz, 1H, H ), 4.30 (br,
H
H-H
Bz
1
s, 1H, H ), 2.21 (CH ), 2.03 (d, J
= 9.92 Hz, 1H), 1.86 (m,
H NMR (500 MHz, CDCl , 298 K): δ = 7.23 (t, J
7.32, 1H, Ar), 6.75 (d, JH-H = 7.25 Hz, 1H, Ar), 6.65 (d, JH-H
=
=
a
3
H-H
3
H-H
13
4
H), 1.74 (d, JH-H = 11.83 Hz, 1H), 1.35-1.22 (m, 5H).
C
3
NMR (125 MHz, CDCl , 298 K) δ = 165.3 (C ), 145.6, 135.5,
8.01 Hz, 1H, Ar), 4.91 (d, J
= 4.58 Hz, 1H, H ), 4.64 (br
3
h
H-H
Bz
1
28.4, 124.6, 120.5, 114.5, 88.9 (C ), 40.9, 27.5-25.6 (m), 16.3
Bz
s, 1H, H ), 2.66 (s, 3H, CH ), 1.99 (d, J
H-H
= 11.06 Hz, 1H),
= 11.44 Hz, 1H),
a
3
+
(
CH ). HRMS (ESI) m/z: [M+H] Calcd for C H O N m/z
1.83 (br, d, JH-H = 8.01 Hz, 4H), 1.73 (d, J
3
15 20
2
H-H
13
=
246.1489, Found 246.1488.
1.29-1.19 (m, 5H). C NMR (125 MHz, CDCl , 298 K) δ =
3
164.7 (C ), 149.4, 144.5, 134.1, 124.2, 114.3, 113.3, 88.8 (C ),
h
Bz
41.3, 27.6-26.1, 22.8 (CH ).
3
Mechanistic investigations:
2
-cyclohexyl-5-fluoro-1,2-dihydro-4H-
benzo[d][1,3]oxazin-4-one (compound 34):
Tracking the progress by NMR spectroscopy
In an NMR tube experiment, 1 µmol (15 mg, 1 equiv.) of
-amino-6-methyl-benzoic acid was dissolved in 0.6 mL
deuterated acetonitrile and the NMR tube was cooled to -
°C. 0.75 µmol (14 mg, 0.75 equiv.) of 2,3,4,5,6-
pentafluoroaldehyde was added to the cold NMR tube
and a proton NMR was recorded immediately at 0°C.
Imine resonance (in the range of 8-9 ppm) could not be
observed at 0°C, but even at this low temperature a new
resonance at 2.60 ppm appeared, which can be easily as-
General procedure as described above was followed
and, 2-amino-6-fluorobenzoic acid (0.155 g, 1 mmol, 1
equiv.) and cyclohexanecarbaldehyde (0.240 g, 2 mmol, 2
equiv.) were used as reaction partners. Pure compound
2
5
(
9
34) was isolated as light yellow color solid (0.236 g,
º
5%). Melting point (m.p.) = 132-134 C.
1
H NMR (500 MHz, CDCl , 298 K): δ = 7.37-7.32 (m, 1H,
Ar, H), 6.64-6.60 (m, 2H, Ar, H ; H), 4.98 (d, JH-H = 3.43
3
3
ACS Paragon Plus Environment

Page 11 of 12
The Journal of Organic Chemistry
signed to methyl group in benzoxazinone (IV). Our at-
tempts to record the NMR at lower temperature (-10 to -
5°C) were not very successful as the amine and the alde-
S136). Absence of 319 nm band in the reaction mixture
(Fig. S137) clearly suggested that the reaction did not fol-
low Pathway A.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
hyde start precipitating out and very significant signal
broadening was observed. Subsequently, the temperature
of the probe was raised from 0°C to 20°C and proton NMR
was recorded. Likewise, proton NMR of the same sample
was recorded at 40°C and 60°C. To obtain full conversion,
another 0.25 equivalent of 2,3,4,5,6-pentafluoroaldehyde
was added to the NMR tube and proton NMR was record-
ed at 60°C. Finally excess (another 0.25 equivalent) was
Scale up
In order to demonstrate the synthetic utility of present
strategy, a gram scale synthesis was attempted. To a
stirred solution of 2-amino-6-methyl-benzoic acid (6.7
mmol, 1.01 g) in ethanol (50 mL), was added 2,3,4,5,6-
pentafluoroaldehyde (13.4 mmol, 2.62 g) in presence of
catalytic amount of acetic acid at room temperature. The
resulting reaction mixture was refluxed for 6 hours with
constant stirring and later concentrated in vacuo to afford
a crude semi-solid material. The residue was further
washed with hexane (100 mL × 3) to produce free flowing
crystalline compound (15) in 92% isolated yield (2.032 g).
In addition, excess aldehye and solvents (ethanol, hexane)
were recovered and reused.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2,3,4,5,6-pentafluoroaldehyde was necessary to fully con-
vert the 2-amino-6-methyl-benzoic acid and NMR was
recorded at 60°C. Figures 5, S130-S131 depict the variable
temperature proton NMR spectra.
18
Isotopic ( O) labeling investigation
As depicted in figure S132, 2-amino-6-methylbenzoic
4
3
acid was first converted to corresponding acid-chloride.
An oven dried Schlenk tube was charged with 1 equivalent
-amino-6-methyl-benzoic chloride (17 mg, 1 µmol, dark
2
1
2
8
red colored) and 2.5 equivalent labeled water (H O) was
ASSOCIATE CONTENT
Supporting information
Spectroscopic characterization of compound 4-36, molecular
structure 14 (CCDC: 1497807), 15 (CCDC: 1497808), full
mechanistic investigation, gram scale experiment and com-
putational details.
added. The dark color semisolid chloride immediately
1
8
turned into light yellow colored precipitate of O labeled
4
4
2
-amino-6-methyl-benzoic acid. The residue was then
dissolved in CD CN and 2 equivalent of 2,3,4,5,6-
3
pentafluorobenzaldehyde (40 mg, 2 µmol) was added.
Subsequently, the reaction mixture was refluxed for 6
hours and NMR spectra were recorded. Due to the pres-
AUTHOR INFORMATION
1
8
ence of O, the C-H carbon adjacent to the labelled oxy-
gen shifts up-field and appears at 77.52 ppm. Similar
Correspondence
1
8
changes in the chemical shift of O labelled C-H carbon
s.chikkali@ncl.res.in
3
0
have been reported. The 2D NMR spectroscopy further
Note
1
8
confirmed the existence of O in the cyclized product
1
3
16
(
IV) (Fig. S134). Figure S133 compares the C NMR of O
†These authors contributed equally. Patent application based
on the results presented here is filed (IN 2016/11002384). The
authors declare no competing financial interest.
1
8
benzoxazinone (bottom) and that of O labelled benzox-
azinone (top). ESI-MS analysis revealed molecular ion
peak at m/z = 332 [M+H] , which can be assigned to
+
18
O
ACKNOWLEDGMENT
labelled benoxazinone (Fig. S135).
Financial support from DST India (SR/S2/RJN-11/2012 and
SR/S1/IC-60/2012) is gratefully acknowledged. KP thanks
DST-India for the YSS/2015/001052. SSD, DB thanks UGC and
CSIR respectively, for the research fellowship. CSIR-NCL and
SPIRIT (DCPC) is gratefully acknowledged for additional
support. SHC is indebted to the AvH Foundation, Germany
for the equipment grant. KV acknowledges DST for funding.
Monitoring the reaction by UV-visible spectrosco-
py
UV-visible spectroscopy was used as a tool to further
investigate the reaction mechanism. Ground state optical
absorption of the aqueous solution was measured in a
quartz cell (light path 10 mm) on a UV-vis spectropho-
tometer (Perkin Elmer) equipped with a PTC-348WI tem-
perature controller. Stock solution of 2,3,4,5,6-
pentafluorobenzaldehyde (I) and 2-amino-6-methyl-
REFERENCES
-
3
(1) Advanced Organic Chemistry: Reactions, Mechanisms and
Structure; March, J. Eds.; John Wiley & Sons, Ltd, 2004.
benzoic acid (II) (1× 10 M ) was prepared in ethanol. Di-
-
5
lute solution of (3.8 × 10 M) aldehyde and acid was
mixed and the reaction mixture was monitored at differ-
ent time intervals (Fig. S137). In order to interpret the
experimental results of UV-visbile spectroscopy, the elec-
tronic absorption spectra of the cyclized (IV) and imine
(III) compounds were theoretically calculated using DFT.
The calculation has been carried out at the fixed geometry
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