Implications of dynamic imine chemistry for the sustainable synthesis of nitrogen heterocycles via transimination followed by intramolecular cyclisation

Article abstract of DOI:10.1039/c5ob02670a

An exploration of a tandem approach to the sustainable synthesis of N-heterocycles from readily available N-aryl benzylamines or imines and ortho-substituted anilines is described, which demonstrates, for the first time, an important synthetic application of dynamic imine chemistry. The key features to the successful development of this protocol include the utilisation of N-aryl benzylamines as imine precursors in transimination, the occurrence of transimination in acetonitrile in the absence of any catalysts, an intramolecular nucleophilic addition occurring in the newly formed imine causing irreversible transimination, and the tandem event occurring under green conditions.

Full text of DOI:10.1039/c5ob02670a

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DOI: 10.1039/C5OB02670A
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Article
Implications of dynamic imine chemistry to the sustainable
synthesis of nitrogen heterocycles via transimination followed by
intramolecular cyclisation
Received 00th January 20xx,
Accepted 00th January 20xx
Joydev K. Laha,* K. S. Satyanarayana Tummalapalli, and Krupal P. Jethava
DOI: 10.1039/x0xx00000x
An exploration of a tandem approach to the sustainable synthesis of N-heterocycles from readily available N-aryl
benzylamines or imines and ortho-substituted anilines is described, which demonstrates, for the first time, an important
synthetic application of dynamic imine chemistry. The key features to the successive development of this protocol include
utilisation of N-aryl benzylamines as imine precursors in transimination, occurrence of transimination in acetonitrile in the
absence of any catalyst, an intramoleuclar nucleophilic addition occurred in newly formed imine causing irresversible
transimination, and the tandem event occurred under green conditions.
www.rsc.org/
Dynamic covalent chemistry (DCC) refers to a phenomenon of an intramolecular nucleophilic addition in the
covalent bond forming/breaking of components of a reversible
Ar2
N
Ar2
reaction in equilibrium.1 Imine (C=N) among few others
represents the occurrence of DCC.2 Transimination is defined
as the phenomenon of dynamic imine chemistry, wherein a
new imine and amine are formed upon reaction of a
preformed imine and an amine, often effected in the presence
of a transition-metal-catalyst (Scheme 1). Transimination
proceeds reversibly through the formation of a tetrahedral
aminal intermediate that subsequently transformed into a new
imine and amine. The position of the equilibrium depends on
the relative basicity of the amines and is generally favoured
toward the formation of the imine incorporating the most
basic amine. Taking advantage of these unique features of
transimination, dynamic imine chemistry has found wide
applications, in particular, to the preparation of dynamic
combinatorial libraries, macrocycles, molecular cages and
polymers.3 Despite these significant realisations in
transimination, the important elements currently lacking may
include a) rare demonstration to the preparation of nitrogen
heterocycles,4 b) often, use of preformed imines, c) imines
prepared invariably from an amine and aldehyde, and d)
limited investigations in the absence of a toxic metal-catalyst.5
To expand the scope of transimination in the synthesis of
nitrogen heterocycles, the following measures were taken into
consideration, a) in situ imine formation by oxidation of readily
available N-aryl benzylamines as opposed to preformed
imines, b) development of a new transimination reaction in
the absence of any proton or metal catalyst, c) occurrence of
N
+
Ar3NH2
+
Ar1NH2
Ar1
Ar3
Applications
Macrocycles
Molecular cages
Polymers
Known features of Transimination
Reversiblility
Preformed imine is used
Often effected in the presence of a metal catalyst
Concept
Ar2
NH2
N
Ar2
+
+
Ar1NH2
N
Ar1
Nu
Nu
or
their precursors
New application
Nitrogen
heterocycles
This work
N
Ar2
NH
N
Ar2
NHR
Ar1
K2S2O8
N
S
+
or
MeCN, 90 oC
Ar2
XH
O
N
or
Ar2
or
N
Ar2
X = CONH,
CH2NH, S
ArO2S
or
N
R
N
Ar2
Ar1
This work features
Irreversible transimination
R = H or alkyl
(imine precursor)
Imine or its precursor could be used
a.Department of Pharmaceutical Technology (Process Chemistry)
b.National Institute of Pharmaceutical Education and Research
c. S. A. S. Nagar, Punjab 160062, India
Under metal-free condtion
Scheme 1 Transimination of imines and subsequent applications
d.Email: jlaha@niper.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
newly formed imine that could facilitate irreversible
transimination, and d) development of a new sustainable
This journal is © The Royal Society of Chemistry 20xx
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tandem approach to the synthesis of nitrogen heterocycles via
transimination. Nevertheless, a defined objective considering
all these elements collectively would be a daunting challenge.
View Article Online
DOI: 10.1039/C5OB02670A
Recently, we described
a transition-metal free, K2S2O8
mediated intramolecular oxidative benzylic C(sp3)-H
nitrogenation/oxygenation and subsequent oxidation, which
afforded annulated nitrogen heterocycles including quinazolin-
4-ones, benzimidazoles, benoxazoles, and benoxazin-4-ones
under green conditions.6 Our continued interest on the
synthesis of nitrogen heterocycles7 drove us to embark on this
ambitious objective. Herein, we describe, distinct from our
previous report, development of a unified tandem approach to
the synthesis of N-heterocycles from readily available ortho-
substituted anilines and imines or their precursors under green
conditions via transimination followed by intramolecular
nucleophilic addition and subsequent oxidation. The protocol
features utilisation of preformed N-aryl or N-arylsulfonyl
imines, successful use of N-aryl benzylic amines as imine
precursors, transimination in the absence of any metal
catalyst, and event of an intramolecular nucleophilic addition
causing the transimination irreversible.
Entry
Oxidant
Solvent
Temp (ºC)
3 (%)b
1
2
3c
4d
5
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
DDQ
MeCN
MeCN
MeCN
MeCN
DCE
35
90
90
90
90
90
90
90
90
90
90
90
90
90
60
88
44
72
20
35
10
40
35
65
0
6
MeOH
Water
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
7
8
9
Oxone
(NH4)2S2O8
PhI(OAc)2
DTHP
10
11
12
13e
14f
Our initial investigation was largely focused on the utilisation
of an imine precursor, instead of a preformed imine, in
transimination reactions. To the best of our knowledge, N-aryl
benzylic amines have never been explored as imine precursors
in transimination reactions despite commercial availability or
preparative simplicity of N-aryl benzylic amines. Our study
commenced with the reaction of readily available 2-
0
K2S2O8
K2S2O8
0
<10
a 1 (0.5 mmol), 2 (0.5 mmol), K2S2O8 (1.0 mmol), solvent (4 mL), additive, if any
(0.1 -1.0 mmol), temp., 6 h; b Isolated yield, c K2S2O8 (0.5 mmol); d MeCN (2 mL); e
Base such as NaOH or K2CO3 (2 equiv); f Free radical quencher (2.5 mmol).
aminobenzamide (
of quinazolin-4-one
below 50 °C in the oxidative cyclisation of N-benzyl-2-
1
) and N-benzylaniline (
2) to the synthesis
Notably, an electron-donating group exerts deleterious effect
to the formation of the product. Thus, a substrate 11
containing three strong electron-donating OMe groups when
exposed to the optimised conditions yielded 21 in significantly
reduced yield (46%). The different substitutions on the aniline
3
. While K2S2O8 was practically ineffective
aminobenzamide to
significant reaction was observed at 35 °C in 1 h affording
and dihydro-quinazolin-4-one
3
observed in our previous study,6
a
3
4
in 60% and ca.10% isolated
ring were also tolerated yielding
3 in varying yields (Entries 8-
yields, respectively (Table 1, entry 1). A complete conversion
of starting materials was observed at 90 °C in 3 h yielding
10). It is worthy to note that various functional groups were
tolerated under the optimised condition, which could enable
further synthetic manipulations. More importantly, the current
protocol demonstrates a rare example of the synthesis of
quinazolin-4(3H)-ones under green conditions.
compound
stoichiometry (1 equiv) of K2S2O8 reduces the yield
substantially (Entry 3). Likewise, lower yield (72%) of was
3 in 88% yield (Entry 2). However, lower
3
obtained at higher concentration (Entry 4). Other solvents
produced inferior results (Entries 5-7). While many other
When
optimised conditions, compound
(90%) comparable to that obtained from
entry 1). This experiment reveals that imine 22 could form in
situ in the tandem reaction of and . Reaction of and aryl
imine 23 containing an ortho-carboxyl group under the
optimised conditions produced in 90% isolated yield.
1
and a preformed imine 22 were subjected to the
was obtained in a yield
and (Table 3,
3
oxidants used in this study gave
or DTHP did not produce (Entries 8-12). The oxidative
transformation was ineffective in the presence of a base (Entry
13). Exposure of and under the conditions (used in entry 2)
in the presence of TEMPO, a free radical quencher, could
markedly suppress the formation of , suggesting that a free
3 in varying yields, PhI(OAc)2
1
2
3
1
2
1
1
2
3
3
Notably, imine 23 independently did not undergo
intramolecular annulations to give the corresponding
benzoxazine heterocycle, due to the poor reactivity of the
carboxyl group. The arylsulfonyl imines remains unexplored
previously in transimination reactions despite their preparative
ease.9 Pleasingly, arylsulfonyl imines 24-27 were also viable
substrates resulting in the formation of 2-aryl quinazolin-4-
radical was involved in this reaction (Entry 14).
The scope of the tandem reaction was manifested in the
synthesis of 2-aryl quinazolin-4-ones8 using
1
and
commercially available N-aryl benzylic amines 5-14 (Table 2).
N-Aryl benzylic amines 5-6 containing a para-substitutent
reacted with
1 under the optimized conditions yielding
quinazolin-4-ones 15-16 in 60-95% yield (Entries 1-2). The
substrates 7-10 containing one or more substituents also
ones 3, 15-16, 19 in good to excellent yields. Interestingly,
reaction of imine 22 and 2-aminobenzylamine 28 under the
optimised conditions gave 2-phenylquinazoline 29 albeit in low
(40%) yield. Notably, the quinazoline 29 could form via homo-
reacted with 1 yielding 17-20 in varying yields (Entries 3-7).
Table 1 Optimization study for the synthesis of 3a
2 | J. Name., 2012, 00, 1-3
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transimination involving reaction of aryl amine in 28 or hetero- benzylaniline 35 that does not have a free-NHVrieewaAcrttieclde Olnelisnes
transimination involving alkyl amine in 28. Nevertheless, the efficiently with 1 affording 3
in low yield D(4O0I:%10)..1039/C5OB02670A
current protocol describes the preparation of 2-
arylquinazolines10 from 2-aminobenzylamines and imines via Table 3 Synthesis of substituted qunazolin-4(3H)-ones and
homo- or hetero-transimination. Thus, the protocol has a great quinazolines
potential to include other nucleophiles, warranting a broad
application to the synthesis of other N-heterocycles under
R2
N
Ph
NH2
NH2
N
R2
K2S2O8
MeCN, 90 oC, 6 h
green conditions.
N
+
N
Ar
NH
X
and
22-27
29
1, 28
O
3, 15-16, 19
Table 2 Synthesis of substituted qunazolin-4(3H)-ones
N-Benzylaniline
Product (% yield)
Entry
2-Aminobenzamide
R2
NH2
NH2
N
N
R2
K2S2O8
MeCN, 90 oC, 6 h
H
1
2
N
3 (90%)
3 (90%)
+
1
NH
15-21
R1
22
O
5-14
O
1
MeO
N
1
N-Benzylaniline
Entry
1,2
Product (% yield)
R
MeO
CO2H
R
23
H
N
N
O
R
R
NH
N
O
Me
3,4,5
1
O
15
16
NH
R = Me 95%
R = OMe 60%
5
6
R = Me
R = OMe
S
N
O
3
15
R = H (94%)
24 R = H
R = Me (86%)
H
N
25 R = Me
N
16 R = OMe (95%)
26 R = OMe
3
NH Cl
Cl
F
Me
O
19 (81%)
7
O
S
17 (78%)
6
1
N
O
H
27
N
N
R
R
4,5
NH
O
NH2
NH2
N
N
Ph
8
9
R = Me
R = F
18
19
R = Me 72%
R = F 83%
22
7
Me
Me
29
(40%)
28
Me
H
N
Me
N
NH Me
Table 4 Synthesis of substituted qunazolin-4(3H)-ones and 2-
6
7
Me
O
arylbenzothiazoles
10
20 (57%)
O
O
R/CH2Ar
NH
Bn
N
N
S
O
O
O
O
Ph
R
K2S2O8
MeCN, 90 oC, 6 h
H
N
N
3 and
N
+
Ar
N
R2
XH
1, 30-31, 36
or
37
2 or 35
NH
32-34
O
O
Entry
N-Benzylaniline
Product (% yield)
11
12
Anilines
21 (46%)
H
Bn
N
N
3 (66%)
3 (92%)
8
9
H
N
N
O
Cl
+
2
N
R
NH
R
NH2
R
1,2
O
H
O
Me
N
3
R = H 25%
33 R = Br 35%
32 R = H 36%
34 R = Br 46%
30 R = H
31 R = Br
Me
13
Et
N
3 (40%)
3
4
1
H
N
35
2
10
3
(90%)
N
NH2
SH
OMe
Ph
14
S
37 (74%)
Substituted benzamides 30-31 also reacted with
2
yielding 3
36
and 32 or 33 and 34 in a combined 61 and 81% yields,
respectively (Table 4, entries 1-2). Interestingly, N-
This experiment suggests that an iminium ion generated in situ
from 35 could participate in the tandem
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transimination/cyclisation reaction. Furthermore, reaction of A mixture of 1, 5 and 6 under the optimised condiVtiieownAsrtgicalevOenl1in5e
under the optimised conditions gave 2- and 16 in 45% and 34% yields, DOreI:s1p0e.1c0t3i9v/eCl5yO. B0W26h7i0lAe
2-aminothiol 36 and
2
phenylbenzthiazole 37 in 74% yield, warranting extended intramolecular tandem cyclised products 15 and 16 were
substrate scope. The current protocol complements the formed competitively, no intermolecular product was
approaches for the preparation of 2-arylbenzthiazoles that are observed. Similarly, a mixture of
currently available in the literature.11
1 and 36 when exposed to the
standard conditions in presence of only imine precursor
2, 3
Additional experiments were carried out to gain insights into and 37 formed competitively. Taken together, these
the reaction mechanism. The evidence for transimination was experiments reveal that K2S2O8 plays a pivotal role in the
observed in the reaction of an imine 23 containing an ortho- tandem oxidative conversion of N-arylbenzylic amines and
carboxyl group and aniline (Scheme 2). Because of the poor ortho-substituted anilines to the synthesis of N-heterocycles.
reactivity of carboxyl group toward nucleophilic addition,6 the
Based on the above results, a plausible mechanism for the
formation of 22 was observed in <10 min in this reaction. This tandem reaction is shown in Scheme 4. N-Benzylaniline is
experiment strongly indicates that transimination reaction oxidized to an iminium ion 38 via imine formation,6 which
occurs in our study. While
under the standard conditions, heating a reaction of
in acetonitrile at 90 °C for 6 h did not give in the absence of 40 or imine. The intramolecular nucleophilic addition to
K2S2O8. These experiments suggest that K2S2O8 does not have iminium ion followed by oxidation could give quinazolin-4-one
1
and preformed imine 22 gave
3
undergoes transimination through the formation of an aminal
1
and 22 39 that subsequently decomposes to give a new iminium ion
3
any apparent role in transimination reactions. However,
further detailed study is required to rule out this possibility.
Nevertheless, a crucial role of K2S2O8 in the overall tandem
3.
H
N
H
N
H
N
Fast
Ph
Ph
K2S2O8
Ph transimination
transformation of 1 and 22 to 3 is obvious.
HN
2
1
38
MeO
NH2
N
Ph
MeCN, 90 oC, 6 h
39 H2NOC
N
Ph
H
+
H
N
Nucleophilic
addition
N
Ph
MeO
CO2H
oxidation
3
K2S2O8
Ph
23
22 (observed in < 10 min
with or without K2S2O8)
NH
CONH2
O
40
MeCN, 90 oC, 6 h
4
(isolated)
N
3
or imine
Scheme 4 Plausible mechanism for tandem heterocycle synthesis
+
1
90% (with K2S2O8)
0% (without K2S2O8)
22
Scheme 2 Evidence for transimination
In conclusion, we have demonstrated development and
successful execution of a unified approach to the tandem
sustainable synthesis of N-heterocycles via transimination and
intramolecular cyclisation as the two key steps. The protocol
demonstrates, for the first time, the utilisation of N-aryl
benzylic amines as imine precursors in transimination
reactions. Incongruent to the multi-steps literature procedure,
the protocol described herein is convergent, operationally
simple, and produces non-toxic by-products, warranting
superior sustainability and environmental compatibility of the
protocol. The nitrogen heterocycles prepared herein takes
advantages of the mild-conditions of the protocol, transition-
metal-free green conditions and reagents that are eco-friendly.
An experiment containing equimolar mixture of
methoxybenzaldehyde, carried out under the standard
conditions, yielded and 16 in 47% and 11% yields,
1, 2 and 4-
3
respectively (Scheme 3). The two products are likely to form by
two different pathways before intramolecular cyclisations. The
imine, formed in situ by the condensation of amine
methoxybenzaldehyde, could undergo intramolecular
nucleophilic addition to form 16. Conversely, the formation of
from and , is likely to occur via tranimination resulting in
1 and 4-
3
1
2
faster formation of the compound 3.
R
OMe
N
O
K2S2O8
MeCN, 90 oC, 6 h
1
+ 2 +
EXPERIMENTAL SECTION
NH
General Methods: The commercially available reagents were
used as received. All the reactions were carried out using a
clean oven dried screw-capped reaction tube of 10 mL capacity
under air. The progress of the reaction was monitored by TLC
(Thin Layer Chromatography) where visualization was carried
out with UV light (254 nm) and/or I2 vapours. The reaction
mixture was purified by column chromatography on silica gel
100-200 mesh and the yields mentioned refer to pure isolated
products. 1H and 13C NMR spectra were recorded using
BRUKER-400MHz spectrometer with trimethylsilane as an
internal standard and CDCl3 or DMSO-d6 as the solvents. Mass
spectra were obtained on a Bruker maxis mass spectrometer.
CHO
3 R = H, (47%)
16
+
R = OMe, (11%)
R
R
NH2
NH2
N
K2S2O8
MeCN, 90 oC, 6 h
H
N
+
NH
O
O
1
15 R = Me, (45%) +
5 (R = Me) + 6 (R = OMe)
16
R = OMe, (34%)
K2S2O8
MeCN, 90 oC, 6 h
3 (60%) + 37 (27%)
(1 + 36) +
2
Scheme 3 Competition experiments
4 | J. Name., 2012, 00, 1-3
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1
Compounds
purchased from commercial vendors. Compounds
19 13 29 10d 30,6 and 3714 are known in literature.
1
,
2
,
9
,
12
,
22
,
24-26
,
28
,
35, and 36 were
N
-(2,4,6-trimethylbenzyl)aniline
(
10): Brown solid, H NMR: δ
View Article Online
3
-
4,6 6 12
,
7.29-7.23 (m, 2H), 6.94 (s, 2H), 6.77 (tt, J=7.3, 1.1 Hz, 1H), 6.73-
DOI: 10.1039/C5OB02670A
,
,
6.68 (m, 2H), 4.23 (s, 2H), 2.39 (s, 6H), 2.33 (s, 3H); 13C NMR: δ
General procedure for the preparation of 2-arylquinazolin- 148.6, 137.5, 137.3, 132.2, 129.3, 129.1, 117.2, 112.4, 42.3,
4(3 )-ones or 1-benzyl-2-phenylquinazolin-4(1 )-one or 2- 21.0, 19.4; HRMS: obsd 226.1600, calcd 226.1596 for C16H20N
phenylbenzo[ ]thiazole. A mixture of 2-aminobenzamide (0.5 (M+H).
mmol), or 2-(benzylamino)benzamide (0.5 mmol), or 2- -(3,4,5-trimethoxybenzyl)aniline
aminothiophenol (0.5 mmol), N-benzylaniline (0.5 mmol) and NMR: δ 7.25-7.18 (m, 2H), 6.79-6.74 (m, 1H), 6.70-6.66 (m,
K2S2O8 (1.0 mmol) in acetonitrile (4 mL) was heated at 90
for 2H), 6.64 (s, 2H), 4.29 (s, 2H), 3.86 (s, 9H); 13C NMR: δ 153.4,
H
H
d
N
(11):
Pale brown solid, 1H
℃
6 h in a screw-capped reaction tube. After completion of the 148.2, 137.1, 135.2, 129.3, 117.8, 112.9, 104.4, 60.9, 56.1,
reaction, water (25 mL) was added and the resulting mixture 48.8; HRMS: obsd 274.1429, calcd 274.1443 for C16H20NO3
was extracted with EtOAc (20 mL x 3), and then dried over (M+H).
anhydrous Na2SO4. Concentration under reduced pressure
N-benzyl-3,5-dimethylaniline (
13): Yellow liquid, 1H NMR: δ
followed by chromatography of the crude [silica gel, 30% 7.49-7.40 (m, 4H), 7.39-7.33 (m, 1H), 6.48 (d, J=0.4 Hz, 1H),
EtOAc:hexane] gave 2-arylquinazolin-4(3H)-one or 1-benzyl-2- 6.37(s, 2H), 4.38 (s, 2H), 2.33 (d, J=0.8 Hz, 6H); 13C NMR: δ
phenylquinazolin-4(1H)-one or 2-phenylbenzo[d]thiazole.
General procedure for the preparation
148.4, 139.8, 139.0, 128.7, 127.6, 127.2, 119.7, 110.8, 48.4,
of 2- 21.6; HRMS: obsd 212.1447, calcd 212.1439 for C15H18N
phenylquinazoline. A mixture of 2-(aminomethyl)aniline (0.5 (M+H).
mmol), or 2-aminobenzamide (0.5 mmol), N- -benzyl-3-methoxyaniline (
14): Brown liquid, 1H NMR: δ
N
benzylideneaniline (0.5 mmol), or N-benzylidene-4- 7.37-7.30 (m, 2H), 7.26-7.18 (m, 2H), 6.97-6.89 (m, 2H), 6.76
methylbenzenesulfonamide (0.5 mmol) and K2S2O8 (1.0 mmol) (tt, J=7.3, 1.1 Hz, 1H), 6.72-6.62 (m, 2H), 4.29 (s, 2H), 3.84 (s,
in acetonitrile (4 mL) was heated at 90
℃
for 6 h in a screw- 3H); 13C NMR: δ 158.9, 148.2, 131.4, 129.3, 128.8, 117.5,
capped reaction tube. After completion of the reaction, water 114.0, 112.9, 55.3, 47.8; HRMS: obsd 214.1241, calcd 214.1232
(25 mL) was added and the resulting mixture was extracted for C14H16NO (M+H).
with EtOAc (20 mL x 3), and then dried over anhydrous Na2SO4. 2-(4-Methylphenyl)quinazolin-4(3H)-one (15): Colourless
1
Concentration under reduced pressure followed by solid, mp: 181-183 °C, H NMR: δ 8.32 (d, J=8.4 Hz, 1H), 8.18
chromatography of the crude [silica gel, 5% EtOAc:hexane] (d, J=8.2 Hz, 2H), 7.76-7.82 (m, 2H), 7.4 (dt, J=8.1, 1.8 Hz, 1H),
gave 2-phenylquinazoline.
7.36 (d, J=8.0 Hz, 2H), 2.44 (s, 3H). 13C NMR: δ 164.1, 151.9,
General procedure for
N
-benzylaniline. The appropriate 149.7, 142.1, 134.8, 130.0, 129.7, 127.9, 127.4, 126.5, 126.3,
starting primary amine (2.0 mmol) and aldehyde (2.0 mmol) in 120.7, 21.5; HRMS: obsd 237.1021, calcd 237.1028 for
MeOH (5 mL) were stirred for 30 min at room temperature. C15H13N2O (M+H).
NaBH4 (3.5 mmol) and NaOH (0.4 mmol) in H2O (1 mL) were 2-(4-methoxyphenyl)quinazolin-4(3H)-one (16): Pale yellow
1
added to the reaction mixture, and the resulting solution was solid, mp: 230-232 °C, H NMR: δ 8.33 (d, J=7.6 Hz, 1H), 8.18
stirred for 6 h. The reaction was diluted with CH2Cl2 (200 mL) (d, J=6.9 Hz, 2H), 7.81 (m, 2H), 7.50 (m, 1H), 7.10 (d, J=6.9 Hz,
and washed with water (200 mL). The organic layer was 2H). 13C NMR: δ 163.5, 163.4, 151.2, 149.6, 134.8, 128.9,
filtered and dried over MgSO4, and the solvent was removed. 127.7, 126.4, 126.3, 125.0, 120.6, 114.4, 55.5; HRMS: obsd
The crude solid was used in the next cyclization step without 253.0971 calcd 253.0977 for C15H13N2O2 (M+H); IR (KBr): 3430,
purification.
-(4-methylbenzyl)aniline
2918, 2849, 1677, 1484, 1250 cm-1.
5): Yellow liquid, H NMR: δ 7.31 2-(2-chlorophenyl)quinazolin-4(3 )-one (17): Pale yellow
1
N
(
H
1
(d, J=8.0 Hz, 2H), 7.19-7.25 (m, 4H), 6.76 (tt, J=7.3, 0.9 Hz, 1H), solid, mp: 172-174 °C, H NMR: δ 8.32 (dt, J=7.0, 0.9 Hz, 1H),
6.68 (dd, J=7.6, 1.8 Hz, 2H), 4.33 (s, 2H), 2.40 (s, 3H); 13C NMR: 7.84 (m, 3H), 7.45-7.58 (m, 4H). 13C NMR: δ 161.8, 150.9,
δ 148.2, 136.9, 136.3, 129.3, 129.2, 127.5, 127.1, 117.5, 115.1, 148.9, 134.9, 132.6, 132.0, 131.8, 131.5, 130.6, 128.0, 127.5,
112.9, 48.1, 21.1; HRMS: obsd 198.1286 calcd 198.1283 for 127.4, 126.5, 121.1; HRMS: obsd 257.0475 calcd 257.0482 for
C14H16N (M+H).
C14H10ClN2O (M+H); IR (KBr): 3024, 1681, 1605, 1302, 875, 766
1
N
-(2-chlorobenzyl)aniline (7): Yellow liquid, H NMR: δ 7.40- cm-1.
7.46
(
m, 2H), 7.18-7.27 (m, 4H), 6.77 (t, J=7.3 Hz, 1H), 6.66 (dd, 2-(m-tolyl)quinazolin-4(3
H
)-one (18): Pale yellow solid, 1H
J=8.6, 0.9 Hz, 2H), 4.47 (s, 2H); 13C NMR: δ 147.7, 136.7, 133.2, NMR: δ 8.35 (dd, J=7.8, 0.7 Hz, 1H), 8.09 (s, 1H), 8.02 (d, J=7.7
132.1, 129.5, 129.3, 129.0, 128.6, 128.3, 127.1, 126.9, 117.7, Hz, 1H), 7.80-7.88 (m, 2H), 7.47-7.54 (m, 2H), 7.42 (d, J=7.5 Hz,
112.9, 112.6, 45.9; HRMS: obsd 218.0737, calcd 218.0737 for 1H), 2.53 (s, 3H). 13C NMR: δ 163.6, 151.8, 149.6, 138.9, 134.8,
C13H13ClN (M+H).
-(3-methylbenzyl)aniline
7.14 (m, 5H), 7.09 (d, J=7.5 Hz, 1H), 6.71 (tt, J=1.1, 7.3 Hz, 1H), (M+H), IR (KBr): 3052, 2918, 1677, 1470, 1311, 765 cm-1.
6.67-6.60 (m, 2H), 4.28 (s, 2H), 2.35 (s, 3H); 13C NMR: δ 148.3, 2-Mesitylquinazolin-4(3
)-one (20): Pale brown solid, mp:
139.4, 138.3, 129.3, 128.6, 128.3, 128.0, 124.6, 117.5, 112.9, 192-194 °C, 1H NMR: δ 8.27 (d, J=7.1 Hz, 1H), 7.81 (m, 2H), 7.54
48.4, 21.4; HRMS: obsd 198.1281 calcd 198.1283 for C14H16N (dt, J=6.0, 2.1 Hz, 1H), 6.96 (s, 2H), 2.34 (s, 3H), 2.25 (s, 6H). 13
132.7, 132.4, 128.9, 128.0, 127.9, 126.7, 126.8, 124.4, 120.9,
1
N
(8): Brown liquid, H NMR: δ 7.27- 21.5; HRMS: obsd 237.1028 calcd 237.1028 for C15H13N2O
H
C
(M+H).
NMR: δ 163.5, 153.5, 149.0, 139.8, 135.9, 134.8, 131.1, 128.7,
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J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
127.8, 127.0, 126.4, 120.8, 21.2, 19.4; HRMS: obsd 265.1347, We greatly appreciate the generous financial support from the
View Article Online
DOI: 10.1039/C5OB02670A
DST, New Delhi. KSST thanks the CSIR, New Delhi for the award
calcd 265.1341 for C17H17N2O (M+H).
2-(3,4,5-Trimethoxyphenyl)quinazolin-4(3H)-one (21): Pale of a senior research fellowship.
1
brown solid, H NMR: δ 8.26 (dd, J=8.0, 0.7 Hz, 1H), 7.81-7.88
(m, 2H), 7.55 (s, 2H), 7.51 (dt, J=6.7, 1.6 Hz, 1H), 4.08 (s, 6H),
3.98 (s, 3H). 13C NMR: δ 164.3, 153.6, 151.6, 149.5, 141.0,
135.0, 128.0, 126.7, 126.1, 120.6, 104.8, 61.0, 56.4, 56.0;
HRMS: obsd 313.1182 calcd 313.1188 for C17H17N2O4 (M+H); IR
(KBr): 3202, 2926, 2850, 1669, 1341, 1141 cm-1.
Notes and references
1. (a) K. Meguellati, S. Ladame, Top. Curr. Chem., 2012, 322, 291–314; (b) Y.
Jin, C. Yu, R. J. Denman, W. Zhang, Chem. Soc. Rev., 2013, 42, 6634–6654.
2. For review, see: (a) M. E. Belowich, J. F. Stoddart, Chem. Soc. Rev., 2012,
41, 2003–2024; Also see: (b) P. Kovaříček, J.-M. Lehn, J. Am. Chem. Soc.,
2012, 134, 9446–9455; (c) K. Ziach, A. Kulesza, J. Jurczak, Org. Biomol.
Chem., 2014, 12, 3827–3830;(d) A. Ciesielski, M. El Garah, S. Haar, P.
Kovaříček, J-M. Lehn, P. Samorì. Nat. Chem., 2014, 6, 1017–1023; (e) M.
Ciaccia, I. Tosi, L. Baldini, R. Cacciapaglia, L. Mandolini, S. Di Stefano, C. A.
Hunter, Chem. Sci., 2015, 6, 144–151.
2-(Benzylideneamino)-4,5-dimethoxybenzoic acid (23): Bright
1
yellow solid; mp: 204-206 °C; H NMR: δ 8.70 (s, 1H), 7.89 (d,
J=8.5 Hz, 2H), 7.79 (s, 1H), 7.53-7.63 (m, 3H), 6.92 (s, 1H), 3.98
(s, 3H), 3.92 (s, 3H); 13C NMR: δ 192.4, 167.2, 158.1, 155.6,
153.3, 149.3, 148.0, 140.7, 134.4, 133.8, 133.2, 129.7, 129.4,
129.0, 128.7, 117.6, 113.4, 112.9, 100.8, 99.2, 98.7, 56.3, 55.8;
HRMS: obsd 286.1072, calcd 286.1079 for C16H16NO4 (M+H).
3. Y. Jin, Q. Wang, P. Taynton, W. Zhang, Acc. Chem. Res., 2014, 47, 1575–
1586.
4. For selected references, see: (a) M. R. Fructos, E. Álvarez, M. M. Díaz-
Requejo, P. J. Pérez, J. Am. Chem. Soc., 2010, 132, 4600–4607; (b) A. D. J.
Calow, F. Fernández, A. Whiting Org. Biomol. Chem., 2014, 12, 3827–3830.
5. (a) M. Ciaccia, R. Cacciapaglia, P. Mencarelli, L. Mandolini, S. Di Stefano,
Chem. Sci., 2013, 4, 2253–2261; (b) M. Ciaccia, S. Pilati, R. Cacciapaglia, L.
Mandolini, S. Di Stefano, Org. Biomol. Chem., 2014, 12, 3282–3287; (c) M.
Ciaccia, S. Di Stefano, Org. Biomol. Chem., 2015, 13, 646–654.
N
-(3-fluorobenzylidene)-4-methylbenzenesulfonamide (27):
1
Pale yellow solid; H NMR: δ 9.02 (s, 1H), 7.90-7.92 (m, 2H),
7.66-7.70 (m, 2H), 7.48-7.53 (m, 1H), 7.37 (d, J=8.0 Hz, 2H),
7.30-7.35 (m, 1H), 13C NMR: 168.7, 168.6, 164.1, 161.6, 144.8,
134.7, 134.4 (d, J=7.0 Hz), 130.8 (d, J=7.0 Hz), 129.8, 128.2,
127.8, 127.7, 121.9 (d, J=22.0 Hz), 116.5 (d, J=22.0 Hz); HRMS:
obsd 278.0658, calcd 278.0651 for C14H13FNO2S (M+H).
2-(2-Bromobenzylamino)benzamide (31): Pale yellow solid;
mp: 162-164 °C; 1H NMR: δ 7.58 (dd, J=7.9, 1.1 Hz, 1H), 7.44
(dd, J=7.8, 1.4 Hz, 1H), 7.38 (td, J=7.7, 0.8 Hz, 1H), 7.23-7.29
(m, 2H), 7.13 (dt, J=7.4, 1.7 Hz, 1H), 6.63 (dt, J=8.0, 1.0 Hz, 1H),
6.56 (d, J=7.9 Hz, 1H), 4.51 (s, 2H); 13C NMR: δ 172.0, 149.9,
137.7, 133.6, 132.7, 128.5, 128.4, 128.2, 127.5, 123.0, 115.1,
113.2, 112.3, 47.1; HRMS: obsd 305.0278, calcd 305.0290 for
C14H14BrN2O (M+H).
6. J. K. Laha, K. S. S. Tummalapalli, A. Nair, N. Patel, J. Org. Chem., 2015, 80,
11351–11359 ; 7. (a) J. K. Laha, P. U. Shah, K. P. Jethava, Chem. Commun.,
2013, 49, 7623–7625; (b) J. K. Laha, K. S. S. Tummalapalli, A. Gupta, Eur. J.
Org. Chem., 2013, 8330–8335; (c) J. K. Laha, K. S. S. Tummalapalli, A.
Gupta, Org. Lett., 2014, 16, 4392–4395; (d) J. K. Laha, K. S. S. Tummalapalli,
A. Gupta, Eur. J. Org. Chem., 2014, 4773–4779; (e) J. K. Laha, N. Dayal, S.
Singh, R. Bhimpuria, Eur. J. Org. Chem., 2014, 5469–5475; (f) J. K. Laha,. K.
P. Jethava, N. Dayal, J. Org. Chem., 2014, 79, 8010–8019; (g) J. K. Laha, N.
Dayal, R. Jain, K. Patel, J. Org. Chem., 2014, 79, 10899–10907; (h) J. K.
Laha, N. Dayal, K. P. Jethava, D. V. Prajapati, Org. Lett., 2015, 17, 1296–
1299; (i) J. K. Laha, S. Sharma, N. Dayal, Eur. J. Org. Chem., 2015, 7885–
7891 ; (j) J. K. Laha, N. Dayal, Org. Lett., 2015, 17, 4742–4745.
N
-Benzyl-2-phenylquinazolin-4(1H)-one (32): Pale yellow
8. For very recent syntheses of quinazolin-4-ones, see: (a) A. J. A. Watson, A.
C. Maxwell, J. M. J. Williams, Org. Biomol. Chem., 2012, 10, 240–243; (b) Y.-
F. Wang, F.-L. Zhang, S. Chiba, Org. Lett., 2013, 15, 2842–2845. (c) X. Jiang,
T. Tang, J.-M. Wang, Z. Chen, Y.-M. Zhu, S.-J. Ji, J. Org. Chem.. 2014, 79,
5082–5087; (d) Q. Huang, Y. Li, T. Chen, Y. Zhou, Q. Xu, S.-F. Yin, L.-B.
Han, Org. Lett., 2014, 16, 3672–3675; (e) X. Gao, B. Yu, Z. Yang, Y. Zhao, H.
Zhang, L. Hao, B. Han, Z. Liu ACS Catal., 2015, 5, 6648–6652. 9. (a) R.
Patel, V. P. Srivastava, L. D. S. Yadav, Adv. Synth. Catal., 2010, 352, 1610–
1614; (b) G. S. Deng, J. Y. Zou, T. F. Sun, Chin. Chem. Lett., 2011, 22, 511–
514; (c) M. A. Zolfigol, M. Tavasoli, A. R. Moosavi-Zare, P. Arghavani-Hadi, A.
Zare, V. Khakyzadeh, RSC Adv., 2013, 3, 7692–7696.
1
semi-solid; H NMR: δ 8.46 (dd, J=7.9, 1.4 Hz, 1H), 7.64 (dt,
J=8.2, 1.4 Hz,1H), 7.55 (d, J=8.1 Hz, 2H), 7.46-7.50(m, 2H), 7.32-
7.40 (m, 5H), 7.28 (d, J=8.4 Hz, 1H) 7.10 (d, J=7.0 Hz,2H), 5.40
(s, 2H); 13C NMR: δ 168.7, 163.2, 140.9, 135.1, 134.6, 133.9,
130.6, 129.3, 128.8, 128.6, 128.4, 128.0, 126.3, 125.5, 120.6,
116.7, 53.0; HRMS: obsd 313.1337, calcd 313.1341 for
C21H17N2O(M+H).
2-(2-Bromophenyl)quinazolin-4(3H)-one (33): Light brown
solid; mp: 175-177 °C; 1H NMR: δ 9.95 (s, 1H), 8.33 (d, J=8.0 Hz,
1H), 7.85 (m, 2H), 7.72-7.75 (m, 2H), 7.49-7.56 (m, 2H), 7.44 (t,
J=7.8 Hz, 1H); 13C NMR: δ 161.9, 151.8, 148.9, 134.9, 134.8,
133.8, 132.1, 131.7, 129.0, 128.0, 126.5, 121.1, 120.7; HRMS:
obsd 300.9969, calcd 300.9971 for C14H10BrN2O (M+H).
10. For some selected recent references, see: (a) (b) (c) (d) (a) C. Wang, S. Li,
H. Liu, Y. Jiang, H. Fu, J. Org. Chem., 2010, 75, 7936-7938;(b) B. Han, X.-L.
Yang, C. Wang, Y.-W. Bai, T.-C. Pan, X. Chen, W. Yu, J. Org. Chem., 2012,
77, 1136–1142; (c) Z. Chen, J. Chen, M. Liu, J. Ding, W. Gao, X. Huang, H.
Wu, J. Org. Chem., 2013, 78, 11342–11348; (d) Q. Liu, Y. Zhao, H. Fu, C.
Cheng, Synlett, 2013, 24, 2089-2094; (e) J-P. Lin, F-H. Zhang,Ya-Qiu Long,
Org. Lett., 2014, 16, 2822–2825; (f) L. Xu, H. Li, Z. Liao, K. Lou, H. Xie, H. Li,
W. Wang, Org. Lett., 2015, 17, 3434–3437.
1-Benzyl-2-(2-bromophenyl)quinazolin-4(1H)-one (34): Brown
1
solid, mp: 228-230 °C, H NMR: δ 8.47 (dd, J=7.9, 1.5 Hz, 1H),
7.65 (m, 2H), 7.48-7.54 (m, 4H), 7.39 (m, 2H), 7.31 (t, J=7.5, 3.0
Hz, 1H), 7.23 (t, J=7.8, 1.6 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.97
(d, J=8.0 Hz, 1H), 5.36 (s, 2H). 13C NMR: δ 168.5, 163.1, 140.3,
134.5, 134.1, 134.0, 133.4, 130.7, 129.6, 128.7, 128.9, 128.2,
127.8, 127.1, 126.4, 121.6, 120.6, 116.2, 53.4; HRMS: obsd
391.0442, calcd 391.0446 for C21H16BrN2O (M+H).
11. For some selected recent references, see: (a) X. Zhang, W. Zeng, Y. Yang,
H. Huang, Y. Liang, Org. Lett., 2014, 16, 876–879; (b) G. Zhang, C. Liu, H. Yi,
Q. Meng, C. Bian, H. Chen, J-X. Jian, L.-Zhu Wu, A. Lei, J. Am. Chem. Soc.,
2015, 137, 9273–9280; (c) J. Shi, D. Qiu, J. Wang, H. Xu, Y. Li J. Am. Chem.
Soc., 2015, 137, 5670–5673; (d) Z. Li, J. Dong, X. Chen, Q. Li, Y. Zhou, S-F.
Yin J. Org. Chem., 2015, 80, 9392–9400. .
12. B. G. Das, P. Ghorai, Chem. Commun., 2012, 48, 8276–8278.
13. S. Guo, Y. Li, L. Tao, Z. Wenwen, X. Fan, RSC Adv. 2014, 4, 59289–59296.
14. W.-J.Yoo, H. Yuan, H. Miyamura, S. Kobayashi. Adv. Synth. Catal. 2011,
353, 3085–3089.
Acknowledgements
6 | J. Name., 2012, 00, 1-3
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