Generation and trapping of non-aromatic cycloimines via diazotization/dediazotization of N-amino cyclic amines: theoretical and experimental results

Article abstract of DOI:10.1007/s11224-020-01567-z

A theoretical investigation of the model diazotization/dediazotization of N-aminopiperidine and N-aminomorpholine at the DFT (B3LYP/6-31+G(d)) level indicated that the corresponding cycloimines can be generated transiently, which can be trapped with dimethyl acetylenedicarboxylate (DMAD) to form a 1,4-dipole followed by cycloaddition of the latter with a second molecule of DMAD to give the corresponding pyrido-annelated products. All steps have low activation free energy barriers and are thermodynamically favoured. Based on the theoretical results, we carried out successfully diazotization of N-amino cyclic amines, namely N-aminopiperidine, 4-aminomorpholine and 1-amino-4-methylpiperazine with tert.-butyl nitrite followed by dediazotization to generate transiently the corresponding cycloimines, which could be trapped with dimethyl acetylenedicarboxylate. to afford new annelated pyridine derivatives, namely tetramethyl 9H-5,6,7,8-tetrahydroquinolizine-1,2,3,4-tetracarboxylate, tetramethyl 5,6,8,9-tetrahydropyrido[2,1-c][1,4]oxazine-1,2,3,4-tetracarboxylate and tetramethyl 9H-5,6,7,8-tetrahydro-7-methylpyrido[1,2-a]pyrazine-1,2,3,4-tetracarboxylate which were duly characterized.

Full text of DOI:10.1007/s11224-020-01567-z

Structural Chemistry
https://doi.org/10.1007/s11224-020-01567-z
ORIGINAL RESEARCH
Generation and trapping of non-aromatic cycloimines via
diazotization/dediazotization of N-amino cyclic amines: theoretical
and experimental results
Minita Ojha1 & Raj K. Bansal1
Received: 7 May 2020 /Accepted: 12 June 2020
#
Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
A theoretical investigation of the model diazotization/dediazotization of N-aminopiperidine and N-aminomorpholine at the DFT
(B3LYP/6-31+G(d)) level indicated that the corresponding cycloimines can be generated transiently, which can be trapped with
dimethyl acetylenedicarboxylate (DMAD) to form a 1,4-dipole followed by cycloaddition of the latter with a second molecule of
DMAD to give the corresponding pyrido-annelated products. All steps have low activation free energy barriers and are thermo-
dynamically favoured. Based on the theoretical results, we carried out successfully diazotization of N-amino cyclic amines,
namely N-aminopiperidine, 4-aminomorpholine and 1-amino-4-methylpiperazine with tert.-butyl nitrite followed by
dediazotization to generate transiently the corresponding cycloimines, which could be trapped with dimethyl
acetylenedicarboxylate. to afford new annelated pyridine derivatives, namely tetramethyl 9H-5,6,7,8-tetrahydroquinolizine-
1,2,3,4-tetracarboxylate, tetramethyl 5,6,8,9-tetrahydropyrido[2,1-c][1,4]oxazine-1,2,3,4-tetracarboxylate and tetramethyl 9H-
5,6,7,8-tetrahydro-7-methylpyrido[1,2-a]pyrazine-1,2,3,4-tetracarboxylate which were duly characterized.
.
.
.
Keywords 1,4-Dipoles Annelated pyridines Tetramethyl 9H-5,6,7,8-tetrahydroquinolizine-1,2,3,4-tetracarboxylate
.
Tetramethyl 5,6,8,9-tetrahydropyrido[2,1-c][1,4]oxazine-1,2,3,4-tetracarboxylate Tetramethyl
.
9H-5,6,7,8-tetrahydro-7-methylpyrido[1,2-a]pyrazine-1,2,3,4-tetracarboxylate DFT calculations
Introduction
subsequently reacted with a second molecule of DMAD act-
ing as dipolarophile to afford the final product (3) (Scheme 1)
[5, 6].
Furthermore, it was pointed out that in contrast to 1,3-di-
poles, 1,4-dipoles are not isolable and are produced in situ
from the reaction of a nucleophilic substrate (a = b) with an
electrophilic reagent (c = d) followed by the reaction with the
dipolarophile e = f (Scheme 2) [5, 6].
Diels and Alder [1] in 1932 reported the formation of an un-
stable red product from the reaction of pyridine with dimethyl
acetylenedicarboxylate (DMAD), whose correct structure as
tetramethyl 4H-quinolizine-1,2,3,4-tetracarboxylate (3) could
be assigned almost three decades later by Acheson and co-
workers [2–4]. However, Huisgen and co-workers [5, 6] for
the first time postulated it as an example of 1,4-dipolar cyclo-
addition reaction wherein a 1,4-dipole (1) was generated in
situ from the reaction of pyridine with DMAD which
a C=N-
Imine (
) is such a nucleophilic component which
has been frequently used for generating 1,4-dipoles that subse-
quently undergo 1,4-dipolar cycloaddition to afford a variety of
N-heterocyclic products. Nair and co-workers [7] have
reviewed these reactions in a systematic manner. A close look
at the types of imines employed for producing 1,4-dipoles re-
veals that they belong either to the acyclic category [8, 9] or the
aromatic N-heterocycles, such as pyridines [10, 11],
isoquinoline [12–15], quinoline [16–18], benzothiazoles
[19–22] and other similar systems [23, 24]. However, we could
not find a report about the use of non-aromatic cycloimines,
possibly due to their non-availability commercially.
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11224-020-01567-z) contains supplementary
material, which is available to authorized users.
* Raj K. Bansal
bansal56@gmail.com
1
Department of Chemistry, The IIS University, Jaipur 302020, India

Struct Chem
Scheme 1 Generation of 1,4-
dipole and its subsequent 1,4-
dipolar cycloaddition with
DMAD
N
..
N
C
N
C
MeO2C
CO2Me
C
C
MeO2C
C
MeO2C
C
CO2Me
CO2Me
1,4-dipole
1
DMAD
1,4-Dipolar cycloaddition
H
1,5-H shift
CO2Me
CO2Me
N
N
H
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
3
2
On looking in the literature, we found that unsubstituted
2,3,4,5-tetrahydropyridine (also named as Δ1-piperideine) is
unstable and changes into its trimer immediately [25]. The
methods for synthesizing substituted 2,3,4,5-
tetrahydropyridine are cumbersome and involve multiple
steps [26].
theoretical results, studied reactions of three N-amino cyclic
amines; the results are presented here.
Computational details
We recently reported generation of the nitrenium ion in situ
from diazotization/dediazotization of 4-amino-1,2,4-triazole-
5-thione followed by loss of nitrogen, which subsequently
underwent tandem S-S coupling, 1,2-proton migration and
reduction to afford a disulfide [27]. It has been reported earlier
that the nitrenium ion may get stabilized through 1,2-alkyl or
hydride shift to generate an imine [28–30]. With this back-
ground, we perceived that initially produced nitrenium ion
from diazotization/dediazotization of 2-unsubstituted N-ami-
no cyclic amine might get stabilized through a 1,2-prototropic
shift to generate cycloiminium ion, which in the presence of a
base would change into cycloimine. First, we investigated the
veracity of this hypothesis theoretically and then guided by the
Gaussian 016 suite of programs was used for all calculations
[31].
Geometries of the reactants, transition structures, interme-
diates and the product involved in the model reaction were
optimized in the gas phase at the B3LYP/6-31+G(d) level of
theory. Frequency calculations were done at the same level to
characterize the energy minimum or the first saddle point in
the presence of no imaginary and only one imaginary frequen-
cy, respectively.
The intrinsic reaction coordinate (IRC) calculations [32,
33] starting from the transition structure were carried out at
the same theory level to confirm its relation to the respective
reactants and the intermediate/product. The total enthalpy was
Scheme 2 Formation of 1,4-
dipole and its subsequent 1,4-
dipolar cycloaddition
a
b
c
f
e=f
a=b + c=d
a=b-c-d
a-b-c-d
e
d

Struct Chem
calculated by adding thermal corrections to the sum of the
electronic and thermal enthalpy. The free energy ΔG at a tem-
perature of 298.15 K was calculated as follows:
Results and discussion
Theoretical results
ΔG ¼ ΔH–TΔS
We computed the following model sequence of reactions
starting from the piperidinediazonium ion generated from
the reaction of 1-aminopiperidine with t-butyl nitrite
[34–37], the reagent actually used for diazotization as de-
scribed later, at the DFT (B3LYP/6-31+G(d)) level (Fig. 1).
ΔH ¼ relative enthalpy
ΔS ¼ relative entropy
T ¼ 298:15 K
Optimized geometries
Experimental details
The B3LYP/6-31+G(d) optimized geometries of the transition
structures TS1a-6a are given in Fig. 2. The Cartesian coordi-
nates of the optimized geometries of other species are given in
the Supplementary Material.
General
1-Aminopiperidine, 4-aminomorpholine, 1-amino-4-
methylpiperazine and t-butyl nitrite were purchased from
Sigma Aldrich and were used as such. Solvents were freshly
dried and distilled.
IR spectra were recorded on a Brucker or Perkin-Elmer
spectrometer in KBr pellet. NMR spectra were recorded in
CDCl3 on a Jeol- 400-MHz spectrometer, 1H NMR at a fre-
quency of 399.78 MHz using TMS as the internal reference.
The C, H, N elemental analyses were done on a FLASH Ea
1112 series CHN analyser.
Although it has been possible to locate the transition struc-
ture TS2a involved in 1,2-prototropic shift in the nitrenium
ion 5a to produce iminium ion 6a, the former was not found to
be a global minimum as it had one imaginary frequency at
− 48.6 cm−1. On computing IRC calculations of TS2a in the
reverse direction, a ring contracted species 12a was obtained
as the global minimum. As TS2a could be located successful-
ly, it seems probable that nitrenium ion 5a is generated tran-
siently, which changes rapidly into thermodynamically more
stable iminium ion 6a before it can rearrange to 12a through
ring contraction. The latter change, i.e. change of 5a to 12a is
expected to be a higher energy path as it involves cleavage of
the C–C bond in contrast to the C–H cleavage during the
change of 5a to 6a (Fig. 3).
Diazotization and reaction with DMAD: general
procedure
To a solution of N-amino cyclic amine (4 mmol; 1-
aminopiperidine 400 mg, 430 μL; 4-aminomorpholine
409 mg, 386 μL; 1-amino-4-methylpiperazine 461 mg,
481 μL) in acetonitrile (5 mL), taken in a 25 mL Round
Bottom (RB) flask and cooled to − 5 °C, was added t-butyl
nitrite (4.8 mmol, 494 mg, 570 μL) under a nitrogen atmo-
sphere with continuous stirring. After the addition was com-
plete, stirring was continued for another half an hour main-
taining the temperature at − 5 °C to 0 °C. Thereafter, a solution
of DMAD (8 mmol, 1136 mg, 980 μL) in acetonitrile (2 mL)
was added dropwise with continuous stirring and allowing the
reaction mixture to warm up to r.t. (~ 25 °C). Progress of the
reaction was monitored by TLC; it was complete after ca. 11–
16 h. The reaction mixture was concentrated and a few drops
of diethyl ether were added and kept in refrigerator. A
coloured solid settled down, which was separated and dried
under vacuum. In the case of the reaction with 1-
aminopiperidine and 1-amino-4-methylpiperazine, it was
chromatographed over a column of silica gel, eluent: EtOAc/
CHCl3, 0.2:9.8 v/v % and MeOH/CHCl3, 0.1:9.9, v/v% re-
spectively. The elute was concentrated and left in refrigerator
whereupon a pale yellow crystalline solid deposited, which
was separated and dried under vacuum.
Energetics
The thermodynamic data of different species are given in
Table 1.
Dediazotization of piperidinediazonium ion 4a to generate
the nitrenium ion 5a has expectedly a small activation free
energy barrier of 11.07 kcal mol−1 only. As discussed earlier,
the nitrenium ion 5a undergoes preferentially a 1,2-
prototropic shift to produce the iminium ion 6a. Such 1,2-
prototropic shifts in the nitrenium ions have been reported
earlier [28–30]. It may be noted that conversion of 5a into
6a is exergonic (ΔG° = − 63.62 kcal mol−1) and hence is ex-
pected to occur spontaneously. In the presence of a strong base
(−OtBu) produced during diazotization with BuONO
t
[34–37], iminium ion 6a undergoes deprotonation to generate
imine, i.e. 2,3,4,5-tetrahydropyridine 7a. The latter reacts sub-
sequently with DMAD to produce 1,4-dipole 8a. The reaction
has low activation enthalpy barrier (ΔH# = 12.05 kcal mol−1),
but as it is accompanied by a decrease in entropy, the activa-
tion free energy ΔG# is raised to 24.50 kcal mol−1. The for-
mation of the 1,4-dipole 8a is endergonic (ΔG° =
21.47 kcal mol−1), and hence, this step is expected to be slow.

Struct Chem
X
X
Fig. 1 Model sequence of
reactions computed at the
B3LYP/6-31+G(d) level
1,2-prototropic shift
H
H
TS1
TS2
-N2
N
N
N
5
N
4
X
X
X
tBuO-
-tBuOH
DMAD
TS3
N
N
N
H
7
MeO2C
6
CO2Me
8
1,4-Dipole
X
X
DMAD
TS5
H
TS4
CO2Me
CO2Me
N
N
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
10
9
X
1,5-H Shift
CO2Me
TS6
N
H
MeO2C
CO2Me
a X = CH2
b X = O
CO2Me
11
The next step involves a reaction between 1,4-dipole 8a
and the second molecule of DMAD. Here, another question
comes into picture, i.e. whether it follows a concerted mech-
anism like 1,3-dipolar cycloaddition reactions [38] or a step-
wise mechanism. Huisgen et al. for the first time predicted the
possibility of stepwise mechanism for these reactions [6].
Recently, a stepwise mechanism was established on the basis
of a theoretical investigation of 1,4-dipolar cycloaddition be-
tween propa-1,2-diene and imines catalysed by PBu3 [39].
Our results also support a stepwise mechanism on two
counts: firstly, all attempts to locate a concerted transition
structure on the PES failed, and secondly, in the HOMO of
the 1,4-dipole 8a (reproduced in Fig. 4), coefficient of the p-
orbital at the C2 atom is almost negligible, whereas at the β-
carbon atom, it is quite large. Thus, it can be perceived judi-
ciously that 1,4-dipole 8a reacts with a second molecule of
DMAD to produce zwitterion 9a. This step is found to be
barrier-less in terms of activation enthalpy (ΔH# = −
3.33 kcal mol−1). Activation free energy value (ΔG# =
10.06 kcal mol−1) for this step is also small. Intramolecular
cyclization of 9a to afford 10a is also barrier-less in terms of
activation enthalpy (ΔH# = − 0.27 kcal mol−1), with a small
activation free energy (ΔG# = 5.05 kcal mol−1). Furthermore,
it may be noted that cyclization of 9a to 10a is an exergonic
process with a standard free energy ΔG° value of − 53.49
kcal mol−1.
As regards the 1,5-prototropic shift, our theoretical as well
as experimental (1H NMR discussed later) results indicate that
in contrast to the reaction of pyridine with DMAD wherein
initially formed product undergoes 1,5-protoropic shift to af-
ford the final product, tetramethyl 4H-quinolizine-1,2,3,4-
tetracarboxylate (3) [2–4], no such shift occurs in the present

Struct Chem
Fig. 2 Geometries of the
transition structures TS1a-6a op-
timized at the B3LYP/6-31+G(d)
level
Ta S2
TS1a
TS3a
TS4a
TS5a
TS6a
case. A high activation free energy barrier (ΔG# =
42.06 kcal mol−1) for the 1,5-protoropic shift in 10a to give
11a makes it improbable. In fact, induction of the extended
conjugation in tetramethyl 4H-quinolizine-1,2,3,4-
tetracarboxylate (3) resulting from 1,5-protoropic shift in the
initially formed adduct of pyridine with DMAD (2) appears to
be the driving force. However, this kind of driving force is
missing in the present case. It is supported by the standard free
energy (ΔG°) values in the two cases calculated at the B3LYP/
6-31+G(d) level (Scheme 3).
ion (4b), which indicates that a CH2/O exchange in the piperidine
ring at 4-position does not affect course of the reaction.
Experimental results
Traditionally, nitrous acid (NaNO2+HCl) is used for diazoti-
zation of the primary amines. However, this reagent suffers
from several disadvantages: acidic conditions, poor functional
group tolerance and formation of undesirable side products. In
recent years, alkyl nitrites, particularly t-butyl nitrite and amyl
nitrite, have emerged as the reagents of choice for diazotiza-
tion as these reagents can be used under neutral conditions
also [34–37]. In view of this, particularly when N-
It may be noted from Table 1 that activation energies of dif-
ferent steps in the reaction sequence of piperidiniumdiazonium
ion (4a) are almost parallel to those of morpholiniumdiazonium

Struct Chem
aminomorpholine was to be diazotized, we preferred the use
of the commercially available t-butyl nitrite. Thus, successive
diazotization of N-aminocyclic amines 13a-c with t-butyl ni-
trite, warming up to r.t. and reaction with DMAD (2 equiv.)
afforded the products 15a-c (Scheme 4).
The compounds 15a-c are pale yellow crystalline solids
soluble in common organic solvents, such as dichlorometh-
ane, chloroform and ethyl acetate. The structures could be
established on the basis of elemental analysis and spectral
studies. For example in the case of tetramethyl 9H-5,6,7,8-
tetrahydroquinolizine-1,2,3,4-tetracarboxylate (15a), strong
absorption bands at 1727 cm−1 (C=O str.) and 1207 cm−1
(C(O)-O str.) in the IR spectrum confirm the presence of the
ester groups. In the 1H NMR spectrum, a triplet at δ 4.55 ppm
(3JHH = 6.0 Hz) can be assigned to the methylene protons at
the C5 atom. As discussed earlier, in contrast to tetramethyl
9H-quinolizine-1,2,3,4-tetracarboxylate, 1,5-prototropic shift
does not occur in the present case. It is confirmed by the
presence of a triplet at δ 3.94 (3JHH = 6.0 Hz), which partially
overlaps with the signals resulting from the OCH3 protons of
the ester groups, due to the C(9)H proton. The methoxy pro-
tons give a singlet at δ 3.91. The methylene protons at the C6
Fig. 3 Comparative energy paths for the ring contraction (path A) and
isomerization to iminium ion (path B) of the nitrenium ion 5a
Table 1 Thermodynamic data of different species computed in the gas phase at the B3LYP/6-31+G(d) level
Species Total
enthalpy
Entropy cal Activation enthalpy Activation entropy
Activation free
Standard enthalpy Standard free
mol−1 K−1 ΔH# (kcal mol−1
)
ΔS# (Cal mol−1 K−1
)
energy ΔG#
ΔH° (kcal mol−1
)
energy ΔG°
(a.u.)
(kcal mol−1
)
(kcal mol−1
)
4a
− 360.156120
85.125
85.643
45.785
72.973
72.741
74.103
73.613
106.451
138.303
133.789
195.346
192.653
174.810
181.314
180.281
181.161
83.954
84.305
72.072
71.599
72.898
72.567
136.105
132.482
193.236
189.595
–
–
11.22
–
–
–
–
–
–
–
–
–
TS1a − 360.138234
N2
5a
TS2a − 250.600114
6a
7a
0.518
–
–
− 0.232
–
–
–
11.07
–
–
37.52
–
–
–
24.50
–
10.06
–
5.05
–
42.06
–
–
8.96
–
–
–
–
26.06
–
11.40
–
–
–
− 109.511987
− 250.659797
− 9.83
–
− 63.28
–
–
–
7.67
–
− 26.86
–
− 56.88
–
− 2.27
–
–
− 19.78
–
− 51.48
–
–
9.70
–
− 25.88
–
−60.40
–
−11.51
− 19.86
–
− 63.62
–
–
–
21.47
–
− 12.67
–
− 53.49
–
− 2.23
–
37.45
–
–
–
12.05
–
− 3.33
–
− 0.27
–
41.75
–
–
9.07
–
48.06
–
–
13.27
–
− 2.22
–
− 250.760643
− 250.414332
DMAD − 532.845835
TS3a − 783.240969
−41.761
8a
TS4a − 1316.099082
9a − 1316.136575
TS5a − 1316.137007
10a − 1316.227218
TS6a − 1316.160681
− 783.247940
–
− 44.894
–
− 17.843
–
−1.033
–
–
0.352
–
− 0.472
–
11a
4b
− 1316.230835
− 396.085933
TS1b − 396.071478
5b − 286.605475
TS2b − 286.528880
6b
7b
TS3b − 819.178840
8b −819.184526
TS4b − 1352.033905
9b
TS5ba
10b
–
− 29.89
–
− 51.73
–
–
23.57
–
− 11.17
–
−58.11
–
− 11.17
− 286.687511
− 286.354153
–
− 42.913
–
− 45.697
− 1352.071598
–
− 1352.167850
–
–
–
–
181.924
179.066
180.786
–
− 2.858
–
TS6b − 1352.096794
11b
44.59
–
45.44
–
− 1352.186189
a Could not be located

Struct Chem
Fig. 4 Kohn-Sham Frontier
Molecular Orbitals of 1,4-dipole
8a and DMAD
and C8 carbon atoms give partially overlapping quintet and
quartet at δ 1.93 (3JHH = 6.0 Hz) and δ 1.89 (3JHH = 6.0 Hz)
respectively. The methylene protons at the C7 atom give a
quintet at δ 1.77 (3JHH = 5.6 Hz). The structure was unambig-
uously confirmed by recording a 1H-13C correlated 2D NMR
spectrum (reproduced in the Supplementary Material).
Scheme 3 Standard free energies
for the 1,5-prototropic shift in the
annelated pyridine- and piperi-
H
CO2Me
CO2Me
dine derivatives calculated at the
B3LYP/6-31+G(d) level
N
N
-1
°
H
= -18.48 kcal mol
G
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
2
3
H
CO2Me
CO2Me
N
N
-1
°
G
= -2.22 kcal mol
H
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
10a
11a

Struct Chem
X
Scheme 4 Generation and
trapping of non-aromatic
cycloimines with DMAD
X
X
tBuONO
°
-5 to 0 C
N
N
N
NH2
N2 OtBu
14a-c
13a-c
7
X
6
8
9
2 DMAD
r.t.
H
CO2Me
5
1
N
2
4
MeO2C
CO2Me
3
c
a
b
CO2Me
CH2
X
O
N-Me
15a-c
3
Tetramethyl 9H-5,6,7,8-tetrahydroquinolizine-1,2,3,4-
tetracarboxylate 15a: From 1-aminopiperidine and DMAD;
Light yellow crystalline solid; mp 68–70 °C; yield 52%;
[found; C, 55.61;H, 5.79;N, 3.80; C17H21NO8 requires C,
55.58; H, 5.76; N, 3.81]; Rf (20%EtOAc/Chloroform) 0.81;
νmax (KBr, ν cm−1) 1727 (s, C=O str.), 1509 (s, C=C str.),
OCH3), 3.77 (s, 3H, N-CH3), 1.90 (t, JHH = 6.0 Hz, 2H,
C(6)H2), 1.77 (d, 3JHH = 4.8 Hz, 2H, C(8)H2).
Conclusions
1
1207 (s, C(O)-O str.), and 1010 (s, C-N str.); H NMR
A model reaction computed at the DFT (B3LYP/6-31+
G(d)) level indicated that the diazonium ion produced
from diazotization of an N-amino cyclic amine undergoes
dediazotization to generate the nitrenium ion with low
activation free energy barrier. The nitrenium ion so pro-
duced undergoes 1,2-prototropic shift to form iminium
ion. The latter loses a proton to generate cycloimine tran-
siently, which reacts with DMAD to form a 1,4-dipole
with low activation free energy barrier. The 1,4-dipole
so formed reacts with a second molecule of DMAD to
produce annelated pyridine derivatives, which are ther-
modynamically stable. The theoretical results could be
verified experimentally when three N-amino cyclic
amines, namely 1-aminopiperidine, 4-aminomorpholine
and 1-amino-4-methylpiperazine were diazotized with t-
butyl nitrite, and the cycloimines so generated could be
t r a p p e d w i t h D M A D t o g i v e 9 H - 5 , 6 , 7 , 8 -
tetrahydroquinolizine derivatives.
(400 MHz, CDCl3, δ ppm, J Hz): 4.55 (t, 3JHH = 6.0 Hz, 2H,
3
C(5)H2) 3.94 (t, JHH = 6.0 Hz, 1H, C(9)H), 3.91 (s, 12H,
3
OCH3), 1.93 (quint., JHH = 6.0 Hz, 2H, C(6)H2), 1.89 (q.,
3
3JHH = 6.0 Hz, 2H, C(8)H2),1.77 (quint., JHH = 5.6 Hz, 2H,
C(7)H2).
Tetramethyl 5,6,8,9-tetrahydropyrido[2,1-c][1,4]oxazine-
1,2,3,4-tetracarboxylate 15b: From 4-aminomorpholine and
DMAD; Yellow coloured crystalline solid; mp 83–85 °C;
yield 50%; [found; C, 52.09;H, 5.22;N, 3.75; C16H19NO9 re-
quires C, 52.03; H, 5.19; N, 3.79]; Rf (20%EtOAc/
Chloroform) 0.65; νmax (KBr, ν cm−1) 1700 (s, C=O str.),
1615 (s, C=C str.), 1279 (s, C(O)-O str.), 1213 (s, C(O)-O
str.), and 1098 (w, C-N str.); 1H NMR (400 MHz, CDCl3, δ
ppm, J Hz): 4.70 (t, 3JHH = 5.2 Hz, 2H, C(5)H2), 3.97 (unre-
solved triplets, 4H, C(6)H2 and C(8)H2), 3.93, 3.92, 3.91, 3.90
(closely spaced singlets, 12H, four OCH3), 3.88 (t,
3JHH = 6.0 Hz, 1H, C(9)H).
Tetramethyl 9H-5,6,7,8-tetrahydro-7-methylpyrido[1,2-
a]pyrazine-1,2,3,4-tetracarboxylate 15c: From 1-amino-4-
methylpiperazine and DMAD; brown coloured solid; mp
138–139 °C (decomposed); yield 53%; [found; C, 53.45; H,
5.86; N, 7.28; C17H22N2O8 requires C, 53.40; H, 5.80; N,
7.33]; Rf (4%MeOH/Chloroform) 0.49; νmax (KBr, ν cm−1)
1732 (s, C=O str.), 1624 (s, C=C str.), and 1216 (s, C(O)-O
str.), 977 (w, C-N str.); 1H NMR (400 MHz, CDCl3, δ ppm, J
Acknowledgements We acknowledge the support of the authorities of
the IIS (deemed to be University), Jaipur (India) for providing research
facilities. We thank the anonymous reviewer for giving valuable
suggestions.
Compliance with ethical standards
3
3
Hz): 4.54 (t, JHH = 6.0 Hz, 2H, C(5)H2), 3.99 (t, JHH
=
Conflict of interest The authors declare that they have no conflict of
4.8 Hz, 1H, C(9)H), 3.94, 3.93, 3.91, 3.90 (s, 12H, 4
interest.

Struct Chem
Human and animal studies This article does not contain any studies
with human participants or animals performed by any of the authors.
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