Reaction of dialkyl 2-butynoate with aniline and formaldehyde: revision of the structure of the product

Article abstract of DOI:10.1016/j.tet.2010.03.084

Dimethyl 3-(aryl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate structure assigned for the products obtained in the Bronsted acid catalyzed reaction of dimethyl but-2-ynoates with anilines and an excess of formaldehyde in methanol has been revised to methy

Full text of DOI:10.1016/j.tet.2010.03.084

Tetrahedron 66 (2010) 3651–3654
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reaction of dialkyl 2-butynoate with aniline and formaldehyde:
revision of the structure of the product
*
A. Srikrishna , M. Sridharan, K.R. Prasad
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 March 2010
Received in revised form 20 March 2010
Accepted 23 March 2010
Available online 27 March 2010
Dimethyl 3-(aryl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate structure assigned for the products
obtained in the Bronsted acid catalyzed reaction of dimethyl but-2-ynoates with anilines and an excess of
formaldehyde in methanol has been revised to methyl 1-(aryl)-3-(methoxymethyl)-4,5-dioxopyrroli-
dine-3-carboxylate.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Domino reactions
Dialkyl 2-butynoates
1,3-Dioxazines
Tetrahydropyrimidines
3-oxo-2-Pyrrolidinones
Structure revision
Multi-component reaction
1. Introduction
as the reactions may take different mechanistic pathway. Herein,
we report the structure revision of the dihydro-1,3-oxazines
Domino reactions including multi-component reactions have
become very popular among synthetic chemists as a powerful
tool to accomplish molecular complexity and diversity from
readily accessible starting materials in one single operation.1
Transition-metal-catalyzed multi-component reactions have
attracted considerable attention due to the fact that complicated
organic molecules including lead compounds for drugs can be
easily prepared from simple compounds in one reaction se-
quence. The development of new multi-component reactions
that allow assembly of polysubstituted heterocycles in a regio-
selective manner is in high demand, particularly, those avoiding
transition metal catalysts and/or harsh conditions. In this con-
text, three and four-component domino reactions involving
dialkyl 2-butynoates with amines and aldehydes have generated
useful heterocyclic systems, such as dihydropyrimidines and tri
and tetrasubstituted pyrrolidinones. However, analogous ex-
trapolation of a set of reactions, e.g., formation of azahetero-
cycles, to other set, e.g., formation of oxaheterocycles, without
proper analysis of the spectral data may lead to wrong structures,
reported to be generated in the Bronsted acid catalyzed re-
action of dialkyl 2-butynoates with one equivalent of aniline and
an excess of formaldehyde.
2. Results and discussion
Reaction of dialkyl 2-butynoates with amines and aldehydes
generated a number of products depending upon the ratio of the
reagents involved and also the catalysts and conditions employed
including solvents.2–6 For example, reaction of dialkyl butynoate 1
with one equivalent of aniline 2 (or a primary or secondary amine)
in the absence of formaldehyde generates simple Michael addition
product 3 (Eq. 1). Potassium hydroxide catalyzed reaction of 1 with
one equivalent of aniline (or amine) and one equivalent of an al-
dehyde 4 in aqueous acetonitrile leads to the formation of 1,3-
oxazin-6-ones 5 (Eq. 2), whereas with two equivalents of aniline
forms the 1,3-pyrimidin-4-ones 6 (Eq. 3). Acetic acid catalyzed
reaction of 1 with two equivalents aniline 2 and three equivalents
of formaldehyde generates the 1,3-diaryl tetrahydropyr-
imidinedicarboxylate 7 (Eq. 4). Unsymmetrically substituted tet-
rahydropyrimidines 8 and 9 could also be generated by employing
one equivalent of aniline 2 and one equivalent of an amine, e.g.,
benzylamine, by altering the sequence of addition of amines in
refluxing DMF (Eqs. 5 and 6).
* Corresponding author. Tel.: þ91 80 22932215; fax: þ91 80 23600529; e-mail
address: ask@orgchem.iisc.ernet.in (A. Srikrishna).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.084

3652
COOR
A. Srikrishna et al. / Tetrahedron 66 (2010) 3651–3654
ROOC
ROOC
COOR
NH2
COOR
O
NH2
O
O
COOR
+
+
HCl
(1)
+
N
H
H
ROOC
N
H
COOR
O
N
COOR
RO
1
2
1
2
3
( 1 : 1 : 4 )
11
10
O
N
Table 1
COOR
O
NH2
Spectral data reported7 for the compound 10 (R¼Me)
O
KOH
+
+
ROOC
R
(2)
R
MeCN-H2O
IR (KBr) nmax/cmꢀ1
1H NMR (400 MHz,
13C NMR (100 MHz,
H
COOR
CDCl3) ppm
d
CDCl3)
d ppm
R = H or Ph
3395, 3045,
2858,
1769, 1700,
1457, 1091,
753
7.86 (2H, d, J¼8 Hz)
193.2,
166.4, 156.2,
1
2
4
5
7.47 (2H, d, J¼8 Hz)
7.31 (1H, t, J¼7.2 Hz)
4.52 (1H, d, J¼10.8 Hz)
4.27 (1H, d, J¼10 Hz)
4.00 (1H, d, J¼9.2 Hz)
3.89 (1H, d, J¼9.2 Hz)
3.77 (3H, s) and 3.32 (3H, s)
138.3, 129.3,
127.1, 119.5,
O
72.8, 59.6, 55.1,
53.7, 48.9
COOR
N
NH2
O
KOH
+
+
ROOC
N
R
(3)
R
MeCN-H2O
H
COOR
R = H or Ph
For example, all the compounds exhibited a carbonyl absorption
band at around 1770 cmꢀ1 (absent in 7) in the IR spectra, which is
not accountable for the structure 10. The absorption band at
1770 cmꢀ1 is generally due to either a strained ketone (e.g., 7-
ketonorbornane) or a butyrolactone or an aryl ester or a pyruvic
acid derivative, and cannot be due to a conjugated ester as in 10. In
the 1H NMR spectra, two protons of the aromatic moiety resonated
1
2
4
6
ROOC
ROOC
at
responding pyrimidine 7. The C-2 methylene in 10 resonated up-
field at w4.5 and 4.3 when compared to the C-2 methylene in the
dihydropyrimidines 7 ( w4.8 ppm), instead of shifting to down
d w7.8 ppm, in contrast to those appeared at d 7.23 in the cor-
COOR
N
NH2
O
AcOH
+
+
N
(4)
d
H
H
COOR
d
field (as it is now attached to one oxygen and one nitrogen in 10,
1
2
7
instead of two nitrogens as in 7). Most strikingly, 13C NMR spectra
contained a signal at
a ketone carbon) and an extra aliphatic quaternary carbon signal at
w55 ppm for the compounds 10. The most down field aliphatic
methylene carbon in 10 was resonated at w72 ppm ( w69 ppm
d w193 ppm (resonance most probably due to
d
d
d
in 7 for the C-2 carbon), whereas an aliphatic carbon attached to
oxygen and nitrogen (C-2 in 10) is expected to resonate in the range
of w80–90 ppm. These spectral data clearly established that the
structure 10 proposed for the product is wrong.
ROOC
ROOC
NH2
COOR
NH2
N
O
+
+
+
DMF
N
H
H
(5)
COOR
8
1
2
Based on the spectroscopic data, initially, an alternate structure
11 containing a strained ketone (similar to 7-ketonorbornane) and
a quaternary aliphatic carbon in addition to an orthoester type
carbon (expected to resonate around 120–130 ppm) was consid-
ered as a possibility, since it satisfies all the spectral data. However,
it is very unlikely that such a strained orthoester will be able to
exist under the reaction conditions (presence of aqueous HCl). In
order to unambiguously establish the structure of the product, the
reaction was reinvestigated. Chloroaniline 2a was opted as the
aniline component, and the reaction was performed employing
the conditions described7 by Jiang et al. Thus, reaction of one
equivalent of dimethyl acetylenedicarboxylate 1a with one equiv-
alent of p-chloroaniline 2a in the presence of a catalytic amount of
hydrochloric acid in methanol, followed by addition of five equiv-
alents of aqueous formaldehyde, under unoptimized conditions,
furnished a mixture of two compounds, which were separated by
column chromatography on silica gel. The less polar compound was
identified as the tetrahydropyrimidine diester 7a by comparing the
spectral data with that reported in the literature.6 The polar com-
pound 12 exhibited spectral data (IR, 1H and 13C NMR) identical to
that reported7 by Jiang et al. for the 1,4-oxazine diester 10a.
As mentioned earlier, based on the spectral data a logical
structure could not be assigned. In order to unambiguously estab-
lish the structure of the product, a single crystal X-ray diffraction
ROOC
ROOC
NH2
COOR
NH2
N
O
DMF
+
+
+
(6)
N
H
H
COOR
9
1
2
Recently, as an extrapolation of these studies, Jiang et al. reported7
an efficient synthesis (70–85% yield) of a number of 3,6-dihydro-
(2H)-1,3-oxazinedicarboxylates 10 by employing one equivalent of
the diester 1, one equivalent of an aniline 2 and an excess of
formaldehyde in methanol in the presence of a catalytic amount of
hydrochloric acid. However, perusal of the reported7 spectral data
(cf. Table 1) for the compounds 10 revealed several anomalies, in
particular, in comparison with their aza-analogues, the corre-
sponding tetrahydropyrimidines 7 (cf. Eq. 4).

A. Srikrishna et al. / Tetrahedron 66 (2010) 3651–3654
3653
analysis was carried out. Thus, recrystallization of the compound 12
from a mixture of methylene chloride and hexane, followed by
single crystal X-ray diffraction analysis (an ORTEP diagram is
depicted in Fig 1) revealed the structure of the product as methyl
1-(4-chlorophenyl)-3-(methoxymethyl)-4,5-dioxopyrrolidine-3-
A tentative mechanism for the formation of the ester 12, con-
sidering that the product is formed when only one equivalent of
aniline is employed, is depicted in Scheme 1. Initial Michael addi-
tion of aniline 2 to the diester 1 generates the enamine 3. An aza
ene type (or Prins type) addition of the enamine 3 to the oxonium
Cl
MeO
O
MeOOC
MeOOC
MeOOC
NH2
N
COOMe
O
HCl
N
O
N
+
+
+
H
H
COOMe
Cl
2a
1a
Cl
Cl
7a
12
Figure 1. ORTEP diagram of molecule B drawn at 30% probability displacement ellipsoids (the minor occupied site (35%) of the disordered carbonyl oxygen is omitted for clarity;
also the hydrogen positions on the disordered carbon atom are not refined).
H+
Me
Me
H+
OH
Me
HCHO + MeOH
ArNH2
O
O
13
COOMe
+
O
MeOOC
MeOOC
OMe
Me
O
COOMe
1
NH COOMe
NH COOMe
2
Ar
OMe
3
Ar
MeOOC
14
MeOOC
OMe
N
Ar
COOMe
16
MeO
H+
N
Ar
COOMe
15
OMe
MeO
COOMe
MeOOC
OMe
H
COOMe
O
Ar
N
N
O
Ar
MeO
N
Ar
COOMe
O
O
:OH2
17
12
Scheme 1.
carboxylate 12. All the spectral data (IR, 1H and 13C NMR) is con-
sistent with the dioxopyrrolidine8 structure 12, such as the pres-
ence of ketone of pyruvate in a five membered ring system (IR and
13C NMR), two isolated methylenes (one attached to oxygen and
other attached to nitrogen), a quaternary aliphatic carbon (C-3),
shift in the aromatic signals due to the acyl group on nitrogen.
ion 13, derived from formaldehyde and methanol, followed by
isomerisation of the imine to enamine generates the new enamine
14. Coupling of the nitrogen in 14 with one more equivalent of 13
produces 15, which on elimination of methanol yields the iminium
ion 16. Michael addition of water to the conjugated ester in 16
followed by cyclisation leads to the azetidine 17. Generation of the

3654
A. Srikrishna et al. / Tetrahedron 66 (2010) 3651–3654
ketone via cleavage of the C–N bond in 17 followed by intra-
molecular lactamisation furnishes the product 12.
129.2 (2C, CH), 126.2 (C), 126.0 (2C, CH), 119.1 (2C, CH), 101.4 (C, C-
5), 68.9 (CH2, C-2), 52.7 (CH3), 51.7 (CH3), 47.4 (CH2, C-6). Further
elution of the column with ethyl acetate/hexane (1:4) furnished
methyl 1-(4-chlorophenyl)-3-(methoxymethyl)-4,5-dioxopyrroli-
dine-3-carboxylate 12 (105 mg, 34%) as a white solid, which was
recrystallised from a mixture of methylene chloride and hexane.
Mp 164–166 ꢂC; [Found: C, 53.57; H, 4.66; N, 4.83. C14H14ClNO5
requires C, 53.94; H, 4.53; N, 4.49%]; Rf (30% EtOAc/hexane) 0.4; IR
(KBr): nmax/cmꢀ1 3112, 2955, 1776, 1739, 1714, 1495, 1455, 1435,
1309, 1330, 1232, 1100, 1002, 825, 734; 1H NMR (400 MHz, CDCl3):
3. Conclusions and summary
The 1,3-oxazine based structure 10 assigned for the product
obtained in the Bronsted acid catalyzed reaction of dialkyl but-2-y-
noates with anilines and an excess of formaldehyde in methanol
was deduced to be wrong. The new structure 12 based on 2,3-
dioxopyrrolidine-3-carboxylate was established through single
crystal X-ray diffraction analysis of the product obtained. A tenta-
tive mechanism is proposed for the formation of 12 via the Michael
addition product 3.
d
7.84 and 7.44 (4H, 2ꢁd, J¼8.9 Hz, Ar–H), 4.51 and 4.24 (2H, 2ꢁd,
J¼10.4 Hz, CH2OMe), 4.01 and 3.89 (2H, 2ꢁd, J¼9.0 Hz, H-2), 3.78
(3H, s, COOCH3), 3.32 (3H, s, CH2OCH3); 13C NMR (100 MHz, CDCl3):
d
192.7 (C, C]O), 166.2 (C, OC]O), 156.1 (C, NC]O), 136.9 (C), 132.4
4. Experimental section
(C), 129.4 (2C, CH), 120.6 (2C, CH), 72.8 (CH2, CH2OMe), 59.6 (CH3,
OCH3), 55.0 (C, C-3), 53.7 (CH3, OCH3), 48.8 (CH2, C-2).
4.1. General
Crystal data for the compound 12: X-ray data were collected at
291 K on a SMART CCD-BRUKER diffractometer with graphite-
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on
a Brucker AMX 400 spectrometers. The chemical shifts (
monochromated Mo K
a
radiation (
l
¼0.71073 Å). The structure was
d
ppm) and
solved by direct methods (SIR 92). Refinement was by full-matrix
least-squares procedures on F2 using SHELXL-97. The non-hydrogen
atoms were refined anisotropically whereas hydrogen atoms were
refined isotropically. Mol. For. C14H14ClNO5; MW¼311.71; colourless;
Crystal system: Triclinic; Space group P-1; cell parameters,
coupling constants (Hz) are reported in the standard fashion with
reference to either internal tetramethylsilane (for 1H) or the central
line(77.0 ppm) ofCDCl3 (for13C). Inthe13C NMR spectra, the natureof
the carbons (C, CH, CH2, or CH3) was determined by recording the
DEPT-135 spectra, and is given in parentheses. Elemental analyses
were carried out using Carlo Erba 1106 CHN analyzer at the De-
partment ofOrganic Chemistry, Indian Institute of Science, Bangalore.
a¼6.5900(2) Å, b¼7.8571(3) Å, c¼15.5749(5) Å;
a
78.882(2),
b
88.220(2),
g
65.933(2), V¼721.50(4) Å3, Z¼2, Dc¼1.435 g cmꢀ3
,
F(000)¼324,
m
¼0.285 mmꢀ1. Total number of l.s. parameters¼203,
R1¼0.0508 for 2235 F0>2
s(F0) and 0.0921 for all 3761 data.
4.1.1. Dimethyl 1,3-bis(4-chlorophenyl)-1,2,3,6-tetrahydropyrimidine-
4,5-dicarboxylate (7a) and methyl 1-(4-chlorophenyl)-3-(methoxy-
methyl)-4,5-dioxopyrrolidine-3-carboxylate (12). To a magnetically
stirred solution of p-chloroaniline 2a (127 mg,1 mmol) in methanol
(3 mL) was added dimethyl acetylenedicarboxylate 1a (142 mg,
1 mmol). The reaction mixture was stirred for 10 min at rt. To the
reaction mixture 0.01 M HCl (2 mL), followed by formaldehyde
(39% aqueous solution, 0.4 mL, 5 mmol) were added and stirred for
30 min. The solvent was removed under reduced pressure, water
(10 mL) was then added to the reaction mixture and extracted with
ether (3ꢁ5 mL). The ether extract was washed with brine and dried
(Na2SO4). Evaporation of the solvent and purification of the residue
on a silica gel column using ethyl acetate/hexane (1:9) as eluent
first furnished dimethyl 1,3-bis(4-chlorophenyl)-1,2,3,6-tetrahy-
dropyrimidine-4,5-dicarboxylate 7a (110 mg, 52%) as white solid.
Mp 127–129 ꢂC; [Found: C, 57.04; H, 4.50; N, 6.93. C20H18ClN2O4
requires C, 57.02; H, 4.31; N, 6.65%]; Rf (30% EtOAc/hexane) 0.5; IR
(KBr): nmax/cmꢀ1 2951, 1743, 1703, 1588, 1495, 1435, 1260, 1232,
wR2¼0.1285, GOF¼1.207, restrained GOF¼1.207 forall data. AnORTEP
diagram is depicted in Figure 1. Crystallographic data has been de-
posited with Cambridge Crystallographic Data Centre (CCDC 767892).
Acknowledgements
We thank Ms. S. Brinda, CCD Facility, Indian Institute of Science
for the X-ray diffraction analysis, and Council of Scientific and In-
dustrial Research, New Delhi for the award of a research associate
position to MS.
References and notes
1. (a) Multi-Component Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Wein-
heim, 2005; (b) Domino Reactions in Organic Synthesis; Tietze, L. F., Brasche, G.,
Gericke, K., Eds.; Wiley-VCH: Weinheim, 2006.
2. Zhang, M.; Jiang, H.-F.; Wang, A. Z. Synlett 2007, 3214.
3. Zhang, M.; Jiang, H.-F. J.; Liu, H. L.; Zhu, Q. H. Org. Lett. 2007, 9, 4111.
4. Cao, H.; Wang, X. J.; Jiang, H.-F.; Zhu, Q. H.; Zhang, M.; Liu, H. Y. Chem.dEur. J.
2008, 14, 11623.
5. Zhu, Q.; Jiang, H.-F.; Li, J.; Liu, S.; Xia, C.; Zhang, M. J. Comb. Chem. 2009, 11, 685.
6. Zhu, Q.; Jiang, H.-F.; Li, J.; Zhang, M.; Wang, X.; Qi, W. Tetrahedron 2009, 65, 4604.
7. Cao, H.; Jiang, H.-F.; Qi, C.-R.; Yao, W.-J.; Chen, H.-J. Tetrahedron Lett. 2009, 50,
1209.
8. Mohri, K.; Yokoyama, K.; Komiya, H.; Watanabe, Y.; Yoshida, Y.; Isobe, K.; Tsuda, Y.
Chem. Pharm. Bull. 2003, 51, 502.
1214, 1115, 1094, 832; 1H NMR (400 MHz, CDCl3):
d 7.23 (2H, d,
J¼8.7 Hz), 7.18 (2H, d, J¼8.7 Hz), 6.90 (2H, d, J¼8.7 Hz), 6.80 (2H, d,
J¼8.7 Hz), 4.84 (2H, s, H-2), 4.21 (2H, s, H-6), 3.74 (3H, s, OCH3), 3.60
(3H, s, OCH3); 13C NMR (100 MHz, CDCl3):
d 165.7 (C, OC]O), 164.2
(C, OC]O), 146.6 (C), 145.9 (C), 142.0 (C), 132.1 (C), 129.5 (2C, CH),