Introduction of a clean and promising protocol for the synthesis of β-amino-acrylates and 1,4-benzoheterocycles: An emerging innovation

Article abstract of DOI:10.1039/c1gc15701a

A highly efficient, elegant and simple procedure with exceptionally mild conditions has been proposed for the synthesis of β-amino-acrylate derivatives and an array of biologically and pharmaceutically active benzoheterocycles. The protocol offers a valua

Full text of DOI:10.1039/c1gc15701a

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PAPER
Introduction of a clean and promising protocol for the synthesis of
b-amino-acrylates and 1,4-benzoheterocycles: an emerging innovation†
Garima Choudhary and Rama Krishna Peddinti*
Received 15th June 2011, Accepted 11th August 2011
DOI: 10.1039/c1gc15701a
A highly efficient, elegant and simple procedure with exceptionally mild conditions has been
proposed for the synthesis of b-amino-acrylate derivatives and an array of biologically and
pharmaceutically active benzoheterocycles. The protocol offers a valuable alternative to known
methods and will find applications in the field of green synthesis. The regio- and stereo-chemistry
of the products were established by IR, NMR and single crystal X-ray analysis.
diseases.12 Michael adducts or vinylic amines bearing ester
Introduction
functionalities formed by the 1,4-addition of amines to DMAD
Over the last two decades, globalization has been driving
or DEAD are valuable intermediates for various important
the chemistry community to adopt green and environmentally
chemical transformations. For example, they can be converted
benign syntheses that circumvent the problems of human or
into indoles, bioactive heterocycles under Pd(OAc)2 catalysis13
ecological toxicity and safety.1 Various applications of green
and can also be used in the synthesis of quinolone ethers,
chemistry have shown that materials can be made friendly to
which enhance monoclonal antibody production in mammalian
the environment by designing chemical processes in a way that
cell cultures.14 These are also biologically and pharmaceutically
can diminish or obviate the use and production of hazardous
acceptable agents.15
substances.2 Due to the toxic, flammable and expensive nature
Several procedures have been reported in the literature
of organic solvents,3 special emphasis has been placed towards
for the synthesis of benzoxazinones that involve the use of
solvent-free reactions. As a result of the novelty, effectiveness and
triphenylphosphine in toluene,16 palladium catalysis,17 CuO
selectivity of the concept, researchers have been very attentive in
nanoparticles as a catalyst18 and microwave assistance.19 Re-
rendering their reactions free of solvents to achieve the ultimate
cently, benzoheterocycles were also synthesized in water with
goal of waste-free, hazard-free and energy-efficient synthesis.4
heating20 and in PEG as a reaction medium.21 Traditional
Heterocycles are of immense chemical and biological interest.
syntheses repeatedly involve the use of organic solvents such as
Benzoheterocycles, as synthesized in this study, belong to an
important class of compounds amid N-heterocycles. Due to their
methanol or petroleum-based solvents such as toluene. Most
syntheses required recrystallization, extraction or chromato-
wide range of biological,5 pharmacological6 and agricultural
graphic purification to further isolate or purify the desired
activity,7 benzoheterocycles have captured the attention of syn-
product. Some methods also required heating and nearly all
thetic organic chemists. For instance, the benzoxazine nucleus,
required stirring of the reaction components. Encouraged by the
found in rubradirin and rubradirin B antibiotics, represents
excellent performance of our catalyst-free and solvent-free green
a unique class of ansamycin-related products.8 Benzoxazine
approach for the synthesis of nitroamines and nitrosulfides,22
also shows resistance factors against insects and microbial
we have carried out the conjugate addition of aliphatic and
diseases. Similarly, the quinoxaline framework is present in a
aromatic amines and thiophenols to acetylenecarboxylates and
variety of biologically active compounds that show anticancer9
acetylenedicarboxylates. Herein, we report a facile and clean
and antiviral activities.10 Like benzoxazine and quinoxaline
derivatives, benzothiazine derivatives exhibit antitumor, antihy-
pertensive, antifungal and immune stimulating activities.11 These
procedure for the synthesis of b-amino-acrylates, and benzox-
azinone, benzothiazinone and quinoxalinone derivatives under
catalyst-free and solvent-free conditions.
heterocycles are also active on Parkinson’s and Alzheimer’s
Results and discussion
Department of Chemistry, Indian Institute of Technology, Roorkee, 247
667, Uttarakhand, India
Reaction between aliphatic/aromatic amines and
acetylenedicarboxylates (DMAD/DEAD)/
acetylenecarboxylates
† Electronic supplementary information (ESI) available: Spectral data,
table of selected IR and NMR data, copies of 1H NMR (500 MHz),
13C NMR (125 MHz) spectra of all the products, and 2D NMR
spectra of 23a and 23b. CCDC reference number 827294. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1gc15701a
Initially we focused on the direct synthesis of b-amino-acrylates
from aliphatic amines and dialkyl acetylenedicarboxylates or
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Table 1 Reaction between aromatic/aliphatic amines and DMAD/DEAD/methyl propiolate/ethyl propiolatea,b
Entry Amine derivative
R
Reaction time/min Product
Yieldc (%)
1
2
Me
Et
3 + 5
4 + 5
1a
1b
98
97
3
4
Me
Et
2 + 5
3 + 5
2a
2b
99
99
5
6
Me
Et
4 + 5
5 + 5
3a
3b
98
97
7
8
Me
Et
3 + 5
4 + 5
4a
4b
100
100
9
10
Me
Et
3 + 5
4 + 5
5a
5b
100
100
11
12
Me
Et
3 + 5
3 + 5
6a
6b
100
100
13
14
Me
Et
3 + 5
4 + 5
7a
7b
98
97
15
16
Me
Et
3 + 0
3 + 0
8a
8b
100
100
17
18
Me
Et
3 + 0
3 + 0
9a
9b
100
100
19
20
Me
Et
2 + 0
2 + 0
10a
10b
100
100
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Table 1 (Contd.)
Entry Amine derivative
R
Reaction time/min Product
Yieldc (%)
21
22
Me
Et
2 + 0
2 + 0
11a
11b
100
100
a All reactions were carried out with an equimolar (2 mM) ratio of donor and acceptor. 2.4 mM (1.2 equiv.) of methyl/ethyl propiolate was used in
entries 19–22. b Mixing of reactants with a spatula in a Petri dish for 2–5 min followed by allowing the mixture to stand for up to 5 min if necessary.
c Of pure Michael product.
alkyl propiolates. Most of the earlier proposed procedures for
the generation of these enamines were carried out in various
organic solvents, such as methanol, benzene, dry THF and ether,
under reflux conditions.23 The synthesis of these compounds
was reported recently by performing the reaction in water as
a solvent24 However, all of these chemical processes required a
long reaction time (hours) along with purification steps. When
we mixed equimolar quantities of aniline and DMAD together
in a Petri dish for 3 min at room temperature with the help
of a spatula, surprisingly, the reaction started immediately after
mixing with gentle heat production. The progress of the reaction
was monitored by thin layer chromatography and the reaction
mixture was allowed to stand for 5 min to obtain product
1a in quantitative yield. Excited by the above result, a range
of b-amino-acrylate derivatives were synthesized by the simple
mixing of aromatic and aliphatic amines with DMAD/DEAD
or methyl/ethyl propiolate at room temperature; the results are
summarized in Table 1. All of the products were obtained in
quantitative yield in analytically pure form without any further
purification. Of the possible two diastereomeric forms, E and
Z, only Z-isomers were obtained in the reactions between
aromatic/aliphatic amines and DMAD/DEAD (Table 1, entries
1–18). The reactions of alkyl propiolates with aliphatic amines
provided E-isomers (Table 1, entries 19–22). While, the reactions
of aniline derivatives required a standing time of 5 min after
mixing, the reactions of aliphatic amines such as morpholine,
piperidine and n-propylamine were very quick and reached
completion within 2 to 3 min of mixing and required no standing
time. When we extended this solvent-free and catalyst-free
protocol to the reaction between 4-chloroaniline and DEAD,
a mixture of E- and Z-diastereomers were formed in a ratio
of 19 : 81, respectively (not shown in the table), in quantitative
yield.
The mixing of equimolar quantities of fine powdered 2-
aminophenol and DMAD was carried out in a similar way in a
Petri dish with the help of a spatula. The reaction proceeded
with melting of the 2-aminophenol followed by immediate
solidification. Within 4 min, a perfectly yellow colour solid,
12a, of melting point 166–168 ◦C was obtained. In this case,
no standing was required. In order to further examine the
effect of the solvent and the regiochemistry of the product,
we carried out the reaction in different solvents such as
methanol, acetonitrile, THF, toluene, dichloromethane and even
in water (Table 2). It was found that the product was obtained
with the same regiochemistry; however, some variation of the
chemical yield was observed. Later, we investigated the scope
of the reaction with a variety of o-aminophenols and related
systems by simply mixing them with DMAD/DEAD under
the same reaction conditions to furnish the corresponding
benzoheterocycles. In all the cases, the products were obtained in
quantitative yield with spectroscopic purity without any purifi-
cation steps such as column chromatography or recrystallization
(Table 3).
The data reported in Table 3 show that the procedure worked
well with o-aminophenols bearing a variety of substituents.
The effect of substitution on the 2-aminophenol was examined,
and it was found that the nature of the substituent gave only
minor variations in the rate of the reaction. For instance,
on going from chloro to alkyl substituents (13/14/17/18 to
15/16), the reaction time increases from 2 to 5 min at room
temperature. The aza-benzoxazinone derivatives 19a and 19b
were also synthesized based on this protocol. At this junc-
ture, the reaction of o-phenylenediamine was performed with
DMAD. Once again, the reaction took place spontaneously,
and within 1 min of mixing it generated a yellow-colored
solid product, 20a, which decomposed at 227 ◦C. Similarly,
clean product 20b was formed in a quantitative yield from
the reaction between o-phenylenediamine and DEAD. The
4-bromo derivative of o-phenylenediamine provided quinox-
alinone derivatives 21a and 21b as a mixture of regioiso-
mers in each case. dl-Cyclohexane-1,2-diamine reacted under
these conditions to provide the corresponding heterocycles 22a
and 22b.
Reaction between 2-aminophenols/2-aminophenylamines and
DMAD or DEAD
After successfully performing the Michael addition of different
amines with DMAD/DEAD under solvent-free and catalyst-
free conditions, we extended this protocol to o-aminophenols.
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Table 2 Effect of solvents on the reaction of o-aminophenol with dimethyl acetylenedicarboxylatea
Entry
Solvent
Time/min
Yield (%)b
Entry
Solvent
Time/min
Yield (%)b
1
2
3
4
5
MeOH
MeCN
THF
Dioxane
Diethyl ether
5
5
5
5
5
63
60
45
37
41
6
7
8
9
Acetone
Toluene
CH2Cl2
Water
—
5
5
5
5
5
54
31
47
62
99c
10
a All reactions were performed for 5 min at room temperature. The solid obtained from the reactions in MeOH and water was purified either by
washing with cold MeOH (entry 1) or by recrystallization (entry 9). In all other cases (except entry 10), the reaction mixture was concentrated
and subjected to silica gel column chromatography (90 : 10 hexanes/EtOAc). b Of pure and isolated product. c The reaction was performed under
solvent-free conditions and no purification methods were applied.
Table 3 Reaction between o-aminophenols/o-phenylenediamines and DMAD/DEADa
Entry
Amine derivative
R
Reaction time/min
Product
Yieldb (%)
1
2
Me
Et
4
5
12a
12b
100
100
3
4
Me
Et
2
3
13a
13b
100
100
5
6
Me
Et
2
3
14a
14b
100
100
7
8
Me
Et
4
5
15a
15b
98
99
9
10
Me
Et
4
5
16a
16b
100
99
11
12
Me
Et
2
3
17a
17b
100
100
13
14
Me
Et
2
3
18a
18b
100
100
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Table 3 (Contd.)
Entry
Amine derivative
R
Reaction time/min
Product
Yieldb (%)
15
16
Me
Et
4
5
19a
19b
98
97
17
18
Me
Et
1
2
20a
20b
100
100
19
20
Me
Et
3
4
21a
21b
100c
100c
21
22
Me
Et
1
2
22a
22b
98d
97d
a All reactions were carried out with an equimolar (2 mM) ratio of donor and acceptor by mixing the reactants with a spatula in a Petri dish for
1–5 min. b Of pure product. c Combined yield of regioisomers. d Pure product was obtained after washing with a few drops of methanol.
Reaction between 2-aminothiophenols and DMAD or DEAD
bond. A similar trend is also present for products 7a,b and 9a,b,
derived from benzylamine and propylamine, respectively. The
absence of hydrogen bonding is clearly visible in products 8a,b,
10a,b and 11a,b, derived from morpholine and piperidine, where
the b-carbonyl absorbs in the range 1692–1699 cm-1. The vinylic
proton of compounds 1a,b and 3a,b, derived from aniline and
4-bromoaniline, resonates in the range d 5.39–5.45 in 1H NMR
spectra. The major Z-isomer and the minor E-isomer of the
Michael adduct derived from 4-chloroaniline resonate at d 5.44
and 5.31, respectively. Substitutions, such as methoxy or alkyl
groups on the arene residue, shifted the vinylic protons of the
Z-isomers (2 and 4–6) upfield into the range d 5.29–5.36. The
vinylic protons on the a-carbon of enamines 10a,b and 11a,b
resonate in the range d 7.35–7.39. Selected spectroscopic data
of some of the products are shown in Fig. 1 (for a table of
selected data of coupling constants of the vinylic protons, and
absorption frequencies of the vinylic C C and carbonyl bonds,
see the ESI†).
Encouraged by the results obtained from the reac-
tion of dialkyl acetylenedicarboxylates with 2-aminophenol
and o-phenylenediamine, we then investigated the reac-
tion of 2-aminothiophenol with DMAD/DEAD. When 2-
aminothiophenol (liquid) was mixed with DMAD (liquid)
at room temperature, within minutes yellow coloured solids,
23a/23b, were obtained in 97% yield. The chloro derivative of
2-aminothiophenol also reacted smoothly with the acetylene
derivatives to afford benzothiazinone derivatives 24a and 24b
(Table 4).
Structure elucidation
The assigned structures of the products are based on spectro-
1
scopic evidence, such as IR, H NMR (500 MHz), 13C NMR
(125 MHz) and MS data. The presence of signals for two
1
methyl/ethyl groups in the H NMR spectra of compounds
There is ambiguity in previous literature reports regarding
the regiochemistry of the products derived from 2-aminophenols
and 2-aminothiophenols in reactions with DMAD/DEAD (Fig.
2). Some reports present structures A as the products from
2-aminophenol and DMAD/DEAD, where an initial attack
of nitrogen takes place on the sp carbon of the electrophile,
followed by ring closure through the attack of the phenolic
oxygen on the a-carbonyl carbon; others report its regioisomer,
1a,b–9a,b indicates the two ester functionalities in each product
derived from DMAD/DEAD. The olefinic C C bond of
products 1a,b–7a,b, derived from anilines, absorbs in the range
1591–1617 cm-1, whereas the ester carbonyls absorb at 1662–
1681 and 1734–1742 cm-1. The absorption of the b-carbonyl
at a low frequency is due to hydrogen bonding between the
carbonyl oxygen and the hydrogen atom connected to the
nitrogen atom, confirming the Z-stereochemistry of the double
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Table 4 Reaction between o-aminothiophenols and DMAD/DEADa
Entry
o-Aminothiophenol
R
Reaction time/min
Product
Yieldb (%)
1
2
Me
Et
2
2
23a
23b
97
97
3
4
Me
Et
3
3
24a
24b
97
96
a All reactions were carried out with an equimolar (2 mM) ratio of donor and acceptor by mixing the reactants with a spatula in a Petri dish for 2–3
min. b Of pure product obtained after washing with a few drops of methanol.
Fig. 1 Absorption frequencies (n in cm-1) of the vinylic C C and carbonyl bonds, and chemical shifts (d in ppm) of the vinylic protons of selected
products.
C. Structure B was reported for the products from the reaction
between 2-aminothiophenols and DMAD/DEAD, where the
initial attack of sulfur takes place on the sp carbon of the
acetylene derivative, followed by ring closure through the attack
of the nitrogen of the amino functionality on the a-carbonyl
carbon; other reports present regioisomeric structure D.
Benzoxazinone can exist in two tautomeric forms, A and E
(Fig. 3). It has been reported that in acidic media, both the
enamine and imine forms are equilibrated.25 The tautomeric
equilibrium is strongly affected by the solvent; it shifts from
structure A towards structure E from CDCl3 to trifluoroacetic
acid (TFA). Such a shift can be easily followed by NMR (Fig.
4). For instance, the 1H NMR spectrum of compound 12a,
when measured in TFA, shows evidence of both methylene at
d 4.23 and methine at d 6.00 proton signals. Broadening of
the CH signal is observed in TFA due to rapid exchange of
the methine and methylene protons, and the methine signal
disappeared in CF3COOD due to deuteration of the methine
proton (see the ESI†). Whereas, in the NMR spectra of 12a
and other benzoxazinone derivatives recorded in CDCl3, there
is no evidence of methylene protons; a lower field proton signal,
d 5.94, shows the existence of A as the only tautomer of
12a in CDCl3 with an exo double bond and intramolecular
hydrogen bonding between the NH and the oxygen atom of the
ester carbonyl. This was further confirmed by a marked lower
frequency shift, 1660 cm-1, in the carbonyl band when compared
to normal a,b-unsaturated ester carbonyls at ~1700 cm-1 and
a broad maximum at 3464 cm-1 corresponding to the N–H
bond stretching frequency in the IR spectrum of compound
12a.
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Fig. 5 The X-ray crystal structure of compound 17b.
Fig.
2
Regioisomeric structures of 1,4-benzoxazinones and 1,4-
donor (p,p-conjugation) and acceptor (on account of vacant
orbitals) properties in the sulfur atom partially cancel each
other out. This effect of sulfur is clearly visible in the NMR
spectra of these compounds. The vinylic CH of these heterocyclic
benzothiazinones.
1
compounds resonates in the region d 6.89–6.92 in H NMR
spectra and at around d 114 ppm in 13C NMR spectra. A
singlet of the methine hydrogen appearing at d 6.93 in the
1H NMR spectrum of product 23a (Fig. 6) indicates that the
cyclic compound could have either structure B or D (Fig. 7).
1
A careful analysis of the crude material by H NMR and 13C
Fig.
3
Structures A and E of 1,4-benzoxazinones, representing
NMR spectroscopy revealed that mixing 2-aminothiophenol
with DMAD generates B as the only product, which was further
supported by the NMR spectra acquired in TFA and high-field
two-dimensional NMR spectroscopy HMBC (proton-detected
multiple bond coherence) experiments discussed below. No sign
enamine–imine tautomerism.
Furthermore, the assigned structure of benzoxazinone 17b
in the solid state was also confirmed by single crystal X-
ray analysis (Fig. 5).† Thus, the spectroscopic data, including
NMR experiments and crystallographic analysis, of compound
17b unambiguously confirm the assigned structures of these
benzoxazinone derivatives.
In benzothiazinone derivatives 23 and 24, the absorption
frequencies of the ester carbonyl bond are in the range 1663–
1670 cm-1, whereas those of the ring carbonyl are in the range
1583–1590 cm-1 and the C C bond absorbs in the range 1557–
1563 cm-1. Due to its greater size, the sulfur shows a lower
tendency for lone pair conjugation in heteroatom-substituted
vinylic compounds in comparison with oxygen or nitrogen
atoms which are smaller in size. The simultaneous presence of
1
of enamine–imine tautomerization was seen when a H NMR
spectrum was recorded in TFA. Both spectra obtained in TFA
and DMSO-d6 look similar, except for a slight shift of the
chemical shifts due to the solvent effect. This points out the
absence of a C C bond adjacent to the NH group, which is
required to switch the hydrogen between the imine and enamine
tautomers. This clearly indicates the correct structure as being
regioisomer B.
With the help of HSQC two-dimensional NMR experiments,
peak assignments for benzothiazinone compound 23a were
carried out (ESI†). The HMBC analysis, a two-dimensional
Fig. 4 1H NMR spectra of compound 12a in CDCl3 and CF3COOH (TFA).
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Fig. 6 1H NMR spectra of compound 23a recorded in DMSO-d6 and TFA.
Fig. 7 Structures of 1,4-benzothiazines B, and enamine–imine tautomers D and F.
Scheme 1 Proposed mechanistic approach for the synthesis of benzoxazinones (X = O) and quinoxalinones (X = NH).
NMR experiment, provided diagnostic proton–carbon corre-
lations over multiple bonds, which were found to be extremely
helpful for confirming the structure of the product. Fig. 7 shows
a two-bond H(N)–(C O) and a three-bond H(N)–C–(C CH)
correlation in structure B. Meanwhile, structure D holds an extra
three-bond H(N)–C–(C CH) correlation, along with a two-
bond H(N)–C and a three-bond H(N)–C(C O) correlation.
The HMBC spectrum of product 23b (ESI†), obtained by the
reaction of 2-aminothiophenol with DEAD, shows peaks for a
two-bond H(N)–C and a three-bond H(N)–C correlation, and
no peak was found for a H(N)–CH correlation, which reveals
that the structure of the product is identical to that of B. On the
basis of the above spectroscopic analysis, the structure of the
product was assigned as B.
the phenolic oxygen on the a-carbonyl carbon, leading to the
formation of benzoxazinone derivatives (Scheme 1).
For the formation of benzothiazinone products from the
reaction between 2-aminothiophenols and DMAD/DEAD, the
initial attack of sulfur takes place on the sp carbon of the
acetylene derivative, followed by ring closure through attack
of the nitrogen of the amino functionality on the a-carbonyl
carbon (Scheme 2).
Conclusion
In conclusion, we have established a fast, cleaner, safer, energy
efficient and environmentally sustainable approach by carrying
out all our reactions at exceptionally mild reaction conditions
such as, ambient temperature and pressure, open to air, solvent-
free, catalyst-free and without using any external energy (heat
source) which produces high purity products with excellent to
quantitative yields. By means of this new methodology a number
of b-amino-acrylate derivatives and benzoheterocycles were
Herein, we propose the following mechanism for the forma-
tion of the title heterocyclic compounds. The reaction between
2-aminophenol and dialkyl acetylenedicarboxylate commences
with an initial attack of nitrogen on the sp carbon of the
electrophile, followed by the ring closure through attack of
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Scheme 2 Proposed mechanistic approach for the generation of benzothiazinones.
synthesized under the tenet of “green technologies” by eliminat-
ing the use of highly volatile and hazardous conventional organic
solvents, and purification steps such as column chromatography
or crystallization. We have eradicated the ambiguity over the
structures of the products generated by the reaction of 2-
aminophenols and 2-aminothiophenols with DMAD/DEAD.
The structures were unambiguously determined by the analytical
tools such as IR, 1D and 2D NMR, GC-MS and X-ray
crystallographic analysis.
methanol. All the products were solids and no standing was
required. The progress of the reaction was monitored by TLC.
Acknowledgements
We are indebted to Professor V. R. Pedireddi, Indian Institute
of Technology, Bhubaneswar for carrying out the X-ray crystal
analysis. We thank MHRD (Scheme B) for financial assistance.
G. C. thanks CSIR, New Delhi for a research fellowship.
Experimental
References
We were not involved in any incidents while carrying out these
reactions on the scale chosen. However, as the Michael addition
of the substrate combinations presented herein are exothermic,
slow addition of the Michael acceptor DMAD/DEAD is
recommended.
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Reaction between amines and dialkyl
acetylenedicarboxylates/alykl propriolates
The solid reactants were powdered to fine particles prior to
their reaction. Amine (2 mmol) was taken in a pre-weighed
Petri dish, and dialkyl acetylenedicarboxylate (2 mmol) was then
added slowly with thorough mixing for 2–5 min with the help
of a spatula to form a homogeneous paste. Then, the reaction
mixture was allowed to stand (if required) at room temperature
for 5 min to obtain the product in quantitative yield. In the cases
of the more volatile amines, 1.2 equiv. of amine was used (Table
1, entries 15–22). The progress of the reaction was monitored by
TLC.
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Reaction between aminophenols/aminothiophenols/diamines
and dialkyl acetylenedicarboxylates
The aminophenol/aminothiophenol/diamine (2 mmol) was
taken in a pre-weighed Petri dish, dialkyl acetylenedicarboxylate
(2 mmol) was then added slowly with thorough mixing for 1–5
min with the help of a spatula to form a homogeneous paste.
The reaction was complete within minutes and afforded a solid
product. The thus obtained products were either opened to the
air or transferred to a round-bottomed flask and vacuum was
applied to remove the traces of MeOH/EtOH formed during
the reaction. Products 22–24 were obtained in analytically pure
form after washing the reaction mixture with a few drops of
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