Novel approach to 3,3-dimethyl-4-morpholino-3,4-dihydrocoumarins via hetero-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tet.2014.06.083

A new four-step synthetic procedure has been developed to prepare 3,3-dimethyl-4-morpholino-3,4-dihydrocoumarins from substituted salicylaldehydes, morpholine, and isobutyraldehyde. It involves aminal formation, deamination, enamine formation, hetero-Diel

Full text of DOI:10.1016/j.tet.2014.06.083

Tetrahedron 70 (2014) 5608e5618
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel approach to 3,3-dimethyl-4-morpholino-3,4-
dihydrocoumarins via hetero-DielseAlder reaction
,
,
*
Divya Mathur a b, Ashok K. Prasad b, T. Stanley Cameron c, Amitabh Jha a
a Department of Chemistry, Acadia University, Wolfville, NS, Canada
b Department of Chemistry, University of Delhi, Delhi, India
c Department of Chemistry, Dalhousie University, Halifax, NS, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2014
Received in revised form 13 June 2014
Accepted 19 June 2014
Available online 26 June 2014
A new four-step synthetic procedure has been developed to prepare 3,3-dimethyl-4-morpholino-3,4-
dihydrocoumarins from substituted salicylaldehydes, morpholine, and isobutyraldehyde. It involves
aminal formation, deamination, enamine formation, hetero-DielseAlder reaction, hydrolysis, and oxi-
dation. The aminal formation, subsequent one-pot domino deamination, enamine formation, and hetero-
DielseAlder reaction were achieved in microwave-assisted catalyst-free conditions. The following hy-
drolysis and oxidation steps, performed conventionally, gave quantitative yields.
Dedicated to Professor John M. Roscoe
(Acadia University) on the occasion of his
70th birthday
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
3,4-Dihydrocoumarins
Hetero-DielseAlder
Inverse electron demand
Cyclization
Cascade reaction
1. Introduction
Natural products undoubtedly are rich in chemical diversity,
biological specificity, and pharmacological properties inspiring
drug development. Among natural products, coumarins and dihy-
drocoumarins are privileged scaffolds found to possess important
biological activities.1 Their therapeutic potential attracted re-
searchers toward their isolation from natural resources as well as to
their chemical synthesis.2 Dihydrocoumarins are widely prevalent
in nature3 and have received considerable attention due to their
interesting biological activities,4 including inhibition of silent in-
formation regulator 2 (sir2)5 and aldose reductase,6 antioxidant,
immunomodulatory,7 and antitrypanosomal activities8 (Fig. 1).
Because of the importance of 3,4-dihydrocoumarins, their syn-
theses have been widely investigated. Several straightforward pro-
cesses include cyclocondensation of phenols and cinnamic acids and
cyclization of aryl cinnamates,9 hydrogenation,10 or enzymatic re-
duction of corresponding coumarins,11 redox lactonization of o-
hydroxycinnamaldehydes,12 Ir-based oxidative lactonization of 2-(3-
Fig. 1. Molecular structures of several bioactive dihydrocoumarins (highlighted in red).
hydroxypropyl)phenol,13 and oxidative cyclization of 3-
arylpropionic acids.14 Another report utilized Au(III)-catalyzed tan-
dem sigmatropic rearrangement/cyclization of (E)-2-(aryloxymethyl)
* Corresponding author. Tel.: þ1 902 585 1515; fax: þ1 902 585 1114; e-mail
address: ajha@acadiau.ca (A. Jha).
http://dx.doi.org/10.1016/j.tet.2014.06.083
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
5609
alk-2-enoates to synthesize 3,4-dihydrocoumarin derivatives.15 [4þ2]
Cycloaddition reaction of ortho-quinone methides with silyl ketene
acetals leading to the formation of alkyl- and aryl-substituted dihy-
drocoumarins is also been documented.16 Reaction of alkenyl Fischer
carbene chromium(0) complexes and ketene acetals are known to
furnish 4-aryl-3,4-dihydrocoumarins.17 Recently, double de-
carboxylationprocess has been used forthe synthesis of 4-substituted
3,4-dihydrocoumarins.18 Asymmetric tandem organocatalytic Mi-
chael additionehemiacetalization between aliphatic aldehydes and
(E)-2-(2-nitrovinyl)phenols has been used to synthesize chroman-2-
ols, which were further oxidized to dihydrocoumarins.19 Asymmetric
synthesis of decorated 3,4-dihydrocoumarins has been achieved via
a Rh-catalyzed reaction of 3-(2-hydroxyphenyl)cyclobutanones and
acrylate analogs.20 Multi-component reactions using Meldrum’s acid,
salicylaldehydes, isonitriles, and alcohols have been employed for the
synthesis of highly functionalized dihydrocoumarins.21 A deal-
koxycarbonylationeMichael addition sequence for the preparation of
3,4-dihydrocoumarins is also reported.22
hexane, sonication, and vacuum filtration to isolate the pure solid
aminal 1a in 98% yield.
Based on our previous experience from this lab,25 compound 1a
(1 equiv) was reacted with isobutyraldehyde (1 equiv) and p-TSA
ꢀ
(5 mol %) as catalyst in the presence of 4 A activated molecular
sieves in toluene at 80 ꢀC in a microwave reactor for 70 min. The
desired 3,3-dimethyl-2,4-dimorpholinochroman (2a) was obtained
in 42% isolated yield along with w20e25% unreacted aminal 1a,
w15% chroman-2-ol 3a, and some unidentified products in trace
amounts. Encouraged by the formation of the desired product 2a,
albeit in relatively low yield, we proceeded to optimize the re-
actions conditions with respect to stoichiometry, catalyst, solvent,
temperature, and reaction time. For these experiments, 1a and
isobutyraldehyde were chosen as model substrates for the
microwave-assisted reaction (Table 1).
The reaction temperature was maintained at 80 ꢀC or higher
because at lower temperatures the reaction was very slow and the
desired product was not obtained in reasonable amount. The vol-
atility of isobutyraldehyde (bp 63 ꢀC) was considered responsible
for the lower yield of the reaction when 1:1 ratio of iso-
butyraldehyde and 1a was used. At the reaction temperature
(80 ꢀC), it is likely that isobutyraldehyde is not entirely present in
the solution to ensure quantitative in situ generation of 4-(2-
methylpropenyl)morpholine from the liberated amine. Increasing
the molar equivalent of isobutyraldehyde to 2.5 with respect to 1a
resulted in the formation of 2a in 48% yield with consumption of
the starting material (Table 1, entry 1). Further increase in iso-
butyraldehyde concentration in the reaction did not affect the yield
of 2a. In order to improve the chemical yield of the desired product,
we further investigated the use of Brønsted/Lewis acid catalysts
(Table 1). Brønsted acids appeared to work better than Lewis acids
with p-TSA, TFA, and AcOH furnishing 48, 47, and 43% product
yields, respectively (Table 1, entries 1, 3, and 10). Other catalysts
resulted in either low yields or virtually no reaction. Interestingly,
the control reaction (without any catalyst) resulted in the forma-
tion of 2a in 53% yield (Table 1, entry 11).
While many of the reactions described above are efficient and/or
mechanistically interesting in producing
a variety of 3,4-
dihydrocoumarins, some suffer from one of more disadvantages
such as harsh reaction conditions, poor yields, expensive transition
metal catalysts, corrosive reagents, and/or laborious multistep
procedures.9,13,15,17,20,22 Thus, there is a need to further improve the
synthetic procedure and introduce further diversity on the 3,4-
dihydrocoumarin core.
In the past decade exploration of the potential of microwave-
based synthesis has resulted in many novel synthetically useful
transformations including the synthesis of coumarins.23 With the
above mentioned background in view and as part of our on-going
research program for the synthesis of biologically active pharma-
cophores,24 we delineate herein the synthesis of 3,3-dimethyl-4-
morpholino-3,4-dihydrocoumarins via microwave-assisted het-
ero-DielseAlder reaction, hydrolysis, and oxidation reaction se-
quence (Scheme 1).
Thus, we concluded that acid-catalysis is not a requirement for
the reaction and proceeded with the rest of the optimization ex-
periments without using any catalyst in the reaction. Subsequently,
a number of common laboratory solvents were screened to assess
their effect on the product yield. As indicated in Table 1, the yield of
2a was found to be the highest in toluene among the solvents
tested, followed by chlorobenzene and THF (Table 1, entries 11, 15,
and 18). This suggests that non-polar solvents worked better for the
cascade process in question. No reaction was observed under
solvent-free conditions (Table 1, entry 20).
With the optimized stoichiometry and solvent, the effect of
temperature and reaction time was studied simultaneously for
this catalyst-free process (Table 1). Experiments were carried out
at five temperature points starting at 80 ꢀC with a regular in-
crement of 10 ꢀC. The best result, i.e., 57% isolated yield of 2a
(Table 1, entry 22), was obtained at 100 ꢀC in 50 min. Increasing
the temperature to 110 ꢀC with decreased reaction time (45 min)
resulted in lower yield (Table 1, entry 23). On further increasing
the temperature to 120 ꢀC, the aminal 1a decomposed with no
product formation (Table 1, entry 24). This study indicated that
the reaction temperature for this reaction should not be any
higher than 100 ꢀC. It is also worth mentioning that when the
same reaction was performed in refluxing toluene under con-
ventional heating method for 24 h, product 2a was formed only in
36% yield. This indicated that the closed-vessel microwave-
assisted procedure is a superior option. Thus, microwave irradi-
ation at 100 ꢀC for 50 min in toluene under catalyst-free condi-
tions was established as the optimal condition for the synthesis of
compound 2a from 2-(dimorpholinomethyl)phenol (1a) and iso-
butyraldehyde (Scheme 2).
Scheme 1. Retrosynthetic analysis of 3,3-dimethyl-4-morpholino-3,4-dihydrocou
marins.
2. Results and discussion
We envisioned an approach to construct the benzopyran moiety
utilizing [4þ2] inverse-demand hetero-DielseAlder reaction be-
tween an ortho-quinone methide and an enamine (Scheme 1).25
The putative ortho-quinone methide can be thermally generated
in situ from 2-(dimorpholinomethyl)-phenols.26 Interestingly, re-
action between salicylaldehydes and enamines is known to directly
afford structurally related 2-dialkylamino-4- chromanols.27 As
depicted in the retrosynthetic analysis (Scheme 1), we initiated our
synthetic expedition with the synthesis of an aminal, i.e., 2-
(dimorpholinomethyl)-phenol (1a) from salicylaldehyde and
2 equiv of morpholine in a solvent-less microwave-assisted re-
action (Scheme 2). The purification simply involved addition of

5610
D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
Scheme 2. Synthesis of aminals 1, 3,3-dimethyl-2,4-dimorpholinochromans (2), 3,3-dimethyl-4-morpholinochroman-2-ols (3), and 3,3-dimethyl-4-morpholino-3,4-
dihydrocoumarins (4).
Table 1
Optimization of catalyst, solvent, temperature, and time for the synthesis of 3,3-dimethyl-2,4-dimorpholinochroman (2a)a
Entry
Catalyst (5 mol %)
Solvent
Temperature (ꢀC)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
pTSA
TMSCl
TFA
CuI
ScOTf3
InCl3
ZnCl2
AlCl3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
1,2-Dimethoxyethane
DMSO
Chlorobenzene
Acetonitrile
Methanol
THF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
65
50
45
30
48
No reactionc
47
23
31
26
Tracec
Tracec
Tracec
43
9
BF3$Et2O
AcOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
No catalyst
53
18
33
17
49
31
26
45
80
80
80
DCM
30
No solvent
Toluene
Toluene
Toluene
Toluene
N.Rc
54
90d
100d
110d
110d
57
50
Tracesc
a
ꢀ
Reaction conditions: 1a (1.50 mmol), isobutyraldehyde (3.75 mmol), catalyst (if any, 5 mol %), and 4 A activated molecular sieves (0.5 g) in solvent, temperatures, and times
as stated.
b
c
Isolated yields by column chromatography.
As indicated by thin layer chromatography.
TLC was taken after every 5 min till the disappearance of starting material.
d
As mentioned at the outset, we envisaged that 3,3-dialkyl-2,4-
order to hydrolyze compound 2a, we attempted several condi-
tions (Table 2) and found that selective hydrolysis at position-2
efficiently proceeded in just 30 min at room temperature in THF/
H2O (1:1, v/v) with dropwise addition of concd HCl (w2 equiv;
Table 2, entry 4). The chroman-2-ol 3a was obtained in 92% iso-
lated yield.
Considering the near quantitative conversion of 2a to 3a, we
decided to perform hydrolytic step separately rather than opti-
mizing conditions for direct conversion of 1a to 3a.
dimorpholinochromans (2) can be selectively hydrolyzed to 4-
morpholinochroman-2-ols (3). It was observed that in the re-
action of 1a with isobutyraldehyde, apart from 2a, chroman-2-ol
3a was invariably formed in w10e20% yield. We tried direct
microwave synthesis of chroman-2-ol 3a from 2-(dimorpholino-
methyl)phenol (1a) and isobutyraldehyde at temperatures rang-
ing from 80 ꢀC to 120 ꢀC in THF/H2O using p-TSA, AcOH, and HCl
but could not achieve exclusive formation of chroman-2-ol 3a. In

D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
5611
Table 2
2-(dimorpholinomethyl)-phenols (1bei) were examined. As in-
dicated in Table 3 and Scheme 2, the reactions proceeded smoothly
to functionalized dihydrobenzopyrans 2aei in moderate to good
yields. Generally speaking, the yields of the desired products from
aminals bearing electron-withdrawing halo substituents (Br, Cl,
and F; Table 3, entries 6e9) were comparatively higher than those
from aminals with electron releasing alkyl or alkoxy substituents
(Table 3, entries 2e5). This observation is consistent with the likely
mechanism of inverse-demand hetero-DielseAlder reaction where
the diene should be electron-poor (vide infra).
Hydrolysis of 3,3-dimethyl-2,4-dimorpholinochroman to afford 3,3-dimethyl-4-
morpholinochroman-2-ola
To assess the generality of the reaction with respect to amine
and alkyl substituents on the pyran ring, several reactions were
carried out under the optimized conditions. When aminal 1a was
Entry
Reaction condition
Timeb
Yieldc (%)
1
2
3
4
THF/H2O (1:1); AcOH
AcCN/H2O (1:1); AcOH
THF/H2O (1:1); p-TSA
THF/H2O (1:1); HCl
8 h
7 h
12 h
30 min
73
69
64
92
reacted with other
a,a-disubstituted acetaldehydes such as 2-
ethylbutyraldehyde and cyclohexanecarboxaldehyde in place of
isobutyraldehyde, no product formation was observed. This lack of
reactivity was attributed to the increase in steric bulk in the alkyl
chain. Also, using the optimized reaction conditions, 2-(dipiper-
idin-1-ylmethyl)phenol (1j) and 2-(bis(4-methylpiperazin-1-yl)
methyl)phenol (1k) were reacted with isobutyraldehyde but sur-
prisingly, the desired products were not obtained (Scheme 2). We
do not have an explanation of this behavior, however, we note that
morpholine is comparatively less basic than piperidine and N-
methylpiperazine.31
Subsequently, 3,3-dimethyl-4-morpholinochroman-2-ols (3bei)
were synthesized from 3,3-dimethyl-2,4-dimorpholinochroman
(2bei) in 88e94% yield using the established hydrolysis procedure
for 2a (Scheme 2, Table 3). Further oxidation of chroman-2-ols 3bei
using DesseMartin periodinane resulted in near quantitative yields
of 3,3-dimethyl-4-morpholino-3,4-dihydrocoumarins (4bei).
All products were characterized by detailed spectroscopic anal-
ysis. It should be noted that 3,3-dimethyl-4-morpholinochroman-2-
ols (3aei) are capable of existing in several forms, viz. mixture of
chroman-2-ol diastereomers and acyclic phenolic aldehyde. Al-
though the 1H and 13C NMR spectra (Figs. 2 and 3) of these com-
pounds suffered with broad and missing peaks at room temperature
due to morpholine-induced molecular dynamics,32 it indicated that
the product existed as a mixture of chroman-2-ol diastereomers. As
expected in cases of cyclic amine containing compounds showing
molecular dynamics on NMR time scale, the 1H and 13C spectra of
compound 3a showed strong temperature dependence. Morpholine
interconverts into its two equivalent chair conformers (Fig. 2) and
a
Reaction conditions: compound 2a (1.5 mmol) in 6 mL solvent followed by
addition of acid until the disappearance of turbidity.
b
As indicated by thin layer chromatography.
Isolated yields by column chromatography.
c
Finally, oxidation of chroman-2-ol 3a was attempted under
three separate conditions. Oxidation by Jones reagent28 in acetone
readily yielded 3,3-dimethyl-4-morpholinodihydrocoumarins (4a)
as a racemate in 74% yield. Use of silica-supported Jones reagent in
DCM gave marginally better result (80% yield). We then switched
to using commercially available DesseMartin periodinane,29
which yielded the expected 3,4-dihydrocoumarins 4a in 95% iso-
lated yield (Scheme 2). The procedure was found to be extremely
efficient and user-friendly.30 In the simple work-up procedure, the
periodinane species resulting from the reduction of DesseMartin
reagent was further reduced to o-iodobenzoic acid by sodium
thiosulphate.
Once the optimal protocol for the synthesis of 3,3-dimethyl-4-
morpholino-3,4-dihydrocoumarins (4a) starting from salicylalde-
hyde was established, we proceeded to investigate the scope of this
reaction using substituted salicylaldehydes (Scheme 2). Eight 2-
(dimorpholinomethyl)phenols (1bei) and two other 2-(bis-(dia-
lkylamino)methyl)phenols (1j and 1k) were synthesized from
substituted salicylaldehydes under the same reaction conditions as
those for 1a. The desired products were obtained in excellent to
quantitative yields (Table 3). Subsequently, the scope and limita-
tions of the reaction of isobutyraldehyde with variously substituted
Table 3
Isolated yields of 2-(dimorpholinomethyl)-phenols (1), 3,3-dimethyl-2,4-dimorpholinochromans (2), 3,3-dimethyl-4-morpholinochroman-2-ols (3), and 3,3-dimethyl-4-
morpholino-3,4-dihydrocoumarins (4)
Entry
R
R1
Yielda (%)
Series 1
Series 2
Series 3
Series 4
1.
2.
3.
4.
5.
6.
7.
8.
9.
H
H
Me
H
H
Br
Cl
F
H
Me
H
OMe
OEt
H
H
H
Cl
1a
1b
1c
1d
1e
1f
1g
1h
1i
98
95
94
91
96
98
97
98
96
2a
2b
2c
2d
2e
2f
2g
2h
2i
57
47
46
31
36
65
60
55
50
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
89
92
88
91
94
94
93
93
4a
4b
4c
4d
4e
4f
4g
4h
4i
95
94
94
94
95
96
95
95
94
Cl
a
Isolated yields by column chromatography.

5612
D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
Fig. 2. Variable temperature 1H NMR study of 3,3-dimethyl-4-morpholinochroman-2-ol (3a).
Fig. 3. Variable temperature 13C NMR study of 3,3-dimethyl-4-morpholinochroman-2-ol (3a).
when this exchange is faster than the NMR time scale, average of the
two conformations is observed. At low temperature this in-
terconversion is slowed down or prevented with the morpholino
substituent adopting the most stable chair conformation and as
a consequence the axial and equatorial hydrogen atoms can be
differentiated. Variable temperature 1H NMR experiments were
conducted on compound 3a at five temperature points: 234.6, 253.2,
273.0, 296.7, and 325.7 K. The stack plot of these spectra is presented
in Fig. 2.
At room temperature (296 K), we observed that the hydrogen
atoms of morpholine ring were not only indistinguishable, but they
also gave broad signals. Increase in temperature to 325.7 K led to
somewhat better resolution but peaks were still broad. On de-
creasing the temperature to 273.0, 253.2, and 234.6 K sequentially
led to marked improvement in resolution and all eight protons of
the morpholine ring showed discrete peaks with reasonably clear
peak splitting. This indicated that the symmetry of the morpholine
ring was lost in the conformationally frozen form at lower tem-
perature. All other peaks appeared as expected. The C-2H, which
dymanics.32 However, the spectrum recorded at 233 K not only
resulted in better resolved peaks but also showed distinct peaks for
each eOCH2 of the morpholine ring. This was another indication
that the magnetic equivalence of the two pairs of methylene car-
bons of morpholine ring is destroyed in the conformationally fro-
zen form at 233 K (Fig. 3).
The structure of a representative compound, 6-bromo-3,3-
dimethyl-2,4-dimorpholinochroman (2f) was unambiguously
established by single X-ray crystal analysis (Fig. 4a). All products
bear two stereogenic centers and therefore are capable of forming
four stereoisomers. However, the TLC behavior, NMR data, as well
as the ORTEP diagram clearly show that one pair of enantiomers
were exclusively formed. The two morpholino substituents were
found to be trans to each other (rac-2, Scheme 3). This is again
consistent with the concerted (or nearly concerted) cycloaddition
mechanism proposed for this reaction (vide infra). As expected, the
1H and 13C NMR spectra of 3,4-dihydrocoumarins (4aei) were
much simpler as compared to their chroman-2-ol precursors. To
settle any ambiguity surrounding the selectivity of hydrolysis and
subsequent oxidation step taking place at the C-2 position of the
chroman ring, X-ray crystallography was undertaken for a repre-
sentative compound 4g (Fig. 4b).
The rearrangement of one morpholine ring from the salicy-
laldehyde aminal in the product offers clue to the possible course of
the reaction mechanism (Scheme 3). We suggest that there occurs
a deamination process by the phenolic proton transfer from 1 to the
nitrogen of the morpholine. This results in dissociation of 1 and
formation of the ortho-quinone methide A. The dissociated mor-
pholine combines with isobutyraldehyde to produce enamine B.
Generally, the formation enamine is equilibrium driven that
was at
d 4.50 in 2a shifted downfield to d 5.14 in 3a indicating the
hydrolysis at C-2 position. Moreover, in the low temperature 1H
NMR spectrum of 3a at 235 K, C-2H and OH each appeared as two
close peaks (presumably due to existence of diastereomeric pairs)
at
d 5.16 and 9.15, respectively, further confirmed that hydrolysis
occurred at C-2 position (Fig. 2).
Change in the shape and position of the peak in the range
d
8.00e9.50 was also indicative of it belonging to the chromanol
eOH group. The room temperature 13C NMR spectra of 3a, on the
other hand, had the eNCH2 carbon peaks of morpholine ring
missing (Fig. 3). This is common in compounds showing molecular

D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
5613
Fig. 4. ORTEP diagram showing crystallographic atom numbering and solid-state conformation for: A. 6-bromo-3,3-dimethyl-2,4-dimorpholinochroman (2f; CCDC-941743) and B.
6-chloro-3,3-dimethyl-4-morpholinochroman-2-one (4g; CCDC-941742). Crystallographic data have been deposited with the Cambridge Crystallographic Data.
Thus, in essence this reaction is a one-pot cascade process in-
volving sequential deamination, enamine formation, and regio- and
diastereoselective hetero-DielseAlder reaction. Subsequent hy-
drolysis and oxidation steps leading to target dihydrocoumarins
follow straightforward mechanisms.
3. Conclusion
In conclusion, we have devised a mild and efficient protocol for
the synthesis of 3,3-dimethyl-4-morpholino-3,4-dihydrocoumarins
starting from simple and readily available starting materials via
microwave-assisted hetero-DielseAlder reaction, hydrolysis and,
oxidation sequence. One-pot catalyst-free cascade process involving
sequential deamination, enamine formation, and regio- and dia-
stereoselective hetero-DielseAlder reaction furnishing 3,3-
dimethyl-2,4-dimorpholinochromans is particularly interesting. In
addition, high yielding synthesis of chroman-2-ols and 3,4-
dihydrocoumarins in remarkably short reaction time by hydrolysis
and oxidation reactions further corroborated this methodology as
an efficient approach to benzopyran derivatives. We were able to
synthesize 3,4-dihydrocoumarins with both electron-withdrawing
and electron-donating groups on the aromatic ring. The facile syn-
Scheme 3. Plausible mechanism for the synthesis of 3,3-dimethyl-2,4-dimorpho
linochromans.
thetic strategy developed by us provides access to products having
potentially broad therapeutic application. Further applications of
this methodology for the synthesis of useful heterocycles are in
progress and will be reported in due course.
requires long reaction time, acid catalysts, continuous removal of
water, and high temperature.33 But the in situ generation of en-
amine B without an acid catalyst in this reaction suggests that the
subsequent steps in this cascade process are fast. Further, the ortho-
quinone methide A and enamine B undergo inverse electron de-
mand [4þ2] cycloaddition to produce substituted 3,3-dimethyl-
2,4-dimorpholinochromans (2aei). Most inverse electron demand
DielseAlder reactions are not as synchronous as standard Diel-
seAlder reaction but in most cases, the time difference in bond
scission and formation is very small rendering the mechanism to be
almost concerted.34 Also, as evident in most DielseAlder as well as
inverse electron demand DielseAlder reactions, the stereochemical
outcome obeys ‘endo’ selection rule where the electron-donating
amine on the dienophile approaches endo, with respect to the
electron-poor diene maximizing the secondary orbital overlap.35
Regioselectivity in this reaction is as predicted by the electrostatic
control based on interactions with resonance contributors.36
4. Experimental
4.1. General information
The 1H NMR and 13C NMR spectra were recorded on a Bruker
AC-300 Avance spectrometer or Bruker ARX-300 spectrometer at
300 and at 75.5 MHz, respectively. The chemical shift values are on
d
scale and the coupling constants (J) are in hertz (Hz). HRMS were
recorded in positive ion mode on an Ion Spec Fourier transform
mass spectrometer. CEM Discover S-class microwave reactor was
used for the synthesis of compounds. Melting points were de-
termined on a MEL-TEMP II apparatus. The IR spectra for the
synthesized compounds were recorded neat on a Nicolet AVATAR
300 FT-IR instrument. All chemicals used were purchased either
from Aldrich Chemical Co. or Fluka Chemicals Co., Canada and

5614
D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
used without further purification. Analytical TLCs were performed
on pre-coated Merck silica gel 60F254 plates; the spots were
detected under UV light. Silica gel (100e200 mesh) and basic
alumina were used for column chromatography. After column
chromatography, fraction-containing products were evaporated
under reduced pressure and dried under high vacuum to give the
desired product.
(75.5 MHz, CDCl3):
122.5, 147.4, 147.7.
d 15.2, 50.1, 64.9, 67.3, 89.4, 113.9, 118.4, 118.8,
4.2.6. 4-Bromo-2-(dimorpholinomethyl)-phenol (1f). Light yellow
crystalline solid; yield 98%. Experimental data were in agreement
with already reported in the literature.37
4.2.7. 4-Chloro-2-(dimorpholinomethyl)-phenol (1g). Light yellow
crystalline solid; yield 97%. Experimental data were in agreement
with already reported in the literature.38
4.2. General procedure for the synthesis of 2-(dimorpholi-
nomethyl)-phenols 1aei, 2-(dipiperidin-1-ylmethyl)-phenol
(1j) and 2-(bis(4-methylpiperazin-1-yl)methyl)-phenol (1k)
4.2.8. 2-(Dimorpholinomethyl)-4-fluorophenol (1h). Light orange
crystalline solid; yield 98%; mp 80 ꢀC (decomposition). IR (neat)
nmax 3439, 2960, 2852, 2360, 2248, 1491, 1456, 1268, 1245, 1197,
In a closed microwave process vial (2e5 mL) equipped with
1118, 1016, 922, 876, 767, 732 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
a magnetic stirrer bead, substituted salicylaldehydes (5 mmol),
d
2.56 (br s, 8H, 4ꢂeNCH2), 3.71 (br s, 9H, 4ꢂeOCH2 and -CH), 6.55
ꢀ
secondary amine (10 mmol), and 4 A activated molecular sieves
3 4
(dd, JHeF¼8.40 Hz and JHeH¼2.70 Hz, 1H, C-3H), 6.73 (dd,
(0.5 g) were added. The sealed vial was microwave irradiated at
a set temperature of 50 ꢀC for 20 min. After completion of irradi-
ation time, the reaction mixture was cooled to room temperature
through rapid gas jet cooling. Dichloromethane was added and
reaction mixture was filtered to remove molecular sieves. The fil-
trate was evaporated under reduced pressure and to the residue so
obtained; hexane was added and scratched with glass rod to obtain
desired compounds 1ae1k.
3JHeH¼8.70 Hz and JHeF¼4.50 Hz, 1H, C-6H), 6.87 (ddd,
4
3JHeH¼8.70 Hz, JHeF¼8.10 Hz and 4JHeH¼2.70 Hz, 1H, C-5H), 10.78
3
(br s, 1H, eOH). 13C NMR (75.5 MHz, CDCl3):
d 50.0, 67.2, 89.7, 116.0,
116.2, 116.3, 116.5, 117.5, 117.6, 118.6, 153.5, 154.6, 157.7.
4.2.9. 2,4-Dichloro-6-(dimorpholinomethyl)-phenol (1i). Light yel-
low crystalline solid; 96%. Experimental data were in agreement
with already reported in the literature.38
4.2.1. 2-(Dimorpholinomethyl)-phenol (1a). Pale yellow crystalline
solid; yield 98%. Experimental data was in agreement with already
reported in the literature.37
4.2.10. 2-(Dipiperidin-1-ylmethyl)-phenol (1j). Pale yellow crystal-
line solid; yield 98%. Experimental data was in agreement with
already reported in the literature.39
4.2.2. 2-(Dimorpholinomethyl)-6-methylphenol (1b). Yellow crys-
talline solid; yield 95%; mp 100 ꢀC (decomposition). IR (neat) nmax
3435, 2964, 2856, 2360, 2251, 1650, 1455, 1384, 1269, 1118, 1015,
4.2.11. 2-(Bis(4-methylpiperazin-1-yl)methyl)-phenol (1k). Pale yel-
low crystalline solid; yield 94%; mp 80 ꢀC (decomposition).1H NMR
(300 MHz, acetone-d6):
d
2.28e2.95 (m, 22H, 8ꢂeNCH2 and
909, 733 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 2.23 (s, 3H, PheCH3),
2ꢂCH3), 3.90 (s, 1H, eCH), 6.72e6.82 (m, 2H, C-3H, C-5H),
6.99e6.96 (m, 1H, C-6H), 7.13e7.18 (m, 1H, C-4H), 11.05 (br s, 1H,
2.57 (br s, 8H, 4ꢂeNCH2), 3.72 (br s, 8H, 4ꢂeOCH2), 3.77 (s, 1H,
eOH). 13C NMR (75.5 MHz, acetone-d6):
d 45.6, 49.2, 55.5, 88.8,
eCH), 6.69e6.76 (m, 2H, C-4H, C-5H), 7.10e7.08 (m, 1H, C-3H), 11.14
(s, 1H, eOH). 13C NMR (75.5 MHz, CDCl3):
d 16.1, 50.1, 67.3, 90.3,
116.2, 118.5, 118.9, 129.0, 130.4, 158.1.
116.9, 118.7, 125.5, 128.1, 130.9, 155.6.
4.3. General procedure for the synthesis of 3,3-dimethyl-2,4-
dimorpholinochromans (2)
4.2.3. 2-(Dimorpholinomethyl)-4-methylphenol (1c). Light orange
crystalline solid; yield 93.5%; mp 100 ꢀC (decomposition). IR (neat)
nmax 3449, 3155, 2967, 2918, 2858, 2252, 1657, 1497, 1455, 1384,
In a closed microwave process vial (2e5 mL) equipped with
1267, 1117, 1015, 909, 734, 650 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
a magnetic stirrer bead, substituted 2-(dimorpholinomethyl)-phe-
ꢀ
d
2.26 (s, 3H, Ph-CH3), 2.57 (br s, 8H, 4ꢂeNCH2), 3.71 (br s, 9H,
nol (1, 1.50 mmol), isobutyraldehyde (3.75 mmol), and 4 A activated
4ꢂeOCH2, eCH), 6.64 (s, 1H, C-3H), 6.71 (d, J¼8.40 Hz, 1H, C-6H),
molecular sieves (0.5 g) were added followed by toluene (3 mL). The
sealed vial was microwave irradiated at a set temperature of 100 ꢀC
for 50 min. After completion of irradiation time, the reaction mix-
ture was cooled to room temperature through rapid gas jet cooling.
The reaction mixture was filtered and the filtrate was evaporated
under reduced pressure. The residue so obtained was purified by
column chromatography on basic alumina using 8e12% EtOAc/
hexane mixture as an eluent to afford the desired compounds 2.
6.99 (d, J¼7.80 Hz, 1H, C-5H), 10.74 (br s, 1H, eOH). 13C NMR
(75.5 MHz, CDCl3):
130.8, 155.1.
d 20.8, 50.0, 67.3, 90.2, 116.5, 117.3, 128.3, 130.3,
4.2.4. 2-(Dimorpholinomethyl)-6-methoxyphenol (1d). Yellow crys-
talline solid; yield 91%; mp 80 ꢀC (decomposition). IR (neat) nmax
3446, 3156, 2964, 2917, 2856, 2252, 1588, 1456, 1409, 1268, 1249,
1117, 1069, 1015, 910, 733 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 2.56
(br s, 8H, 4ꢂeNCH2), 3.67e3.72 (m, 8H, 4ꢂeOCH2), 3.79 (s, 1H,
eCH), 3.86 (s, 3H, PheOCH3), 6.46 (d, J¼6.9 Hz, 1H, C-5H),
6.75e6.84 (m, 2H, C-3H, C-4H), 11.21 (br s, 1H, eOH). 13C NMR
4.3.1. 3,3-Dimethyl-2,4-dimorpholinochroman (2a). Pale yellow
crystalline solid; yield 57%; mp 95e97 ꢀC. IR (neat) nmax 3155, 2965,
2857, 2253, 1643, 1606, 1484, 1384, 1265, 1165, 909 cmꢁ1. 1H NMR
(75.5 MHz, CDCl3):
147.0, 148.5.
d
50.1, 56.3, 67.3, 89.6, 112.2, 118.2, 118.9, 122.3,
(300 MHz, CDCl3) d 0.87 (s, 3H, gem-CH3),1.21 (s, 3H, gem-CH3), 2.47
(br s, 4H, 2ꢂeNCH2), 2.78e2.85 (m, 2H, eNCH2), 2.98 (s, 1H, C-4H),
3.03e3.10 (m, 2H, eNCH2), 3.62 (t, J¼4.2 Hz, 4H, 2ꢂeOCH2),
3.73e3.74 (m, 4H, 2ꢂeOCH2), 4.50 (s, 1H, C-2H), 6.81e6.88 (m, 2H,
4.2.5. 2-(Dimorpholinomethyl)-6-ethoxyphenol (1e). Orange crys-
talline solid; 96%; mp 120 ꢀC (decomposition). IR (neat) nmax 3451,
3155, 2967, 2918, 2857, 2360, 2251, 1660, 1586, 1469, 1455, 1410,
1384, 1268, 1117, 1015, 908, 732 cmꢁ1. 1H NMR (300 MHz, CDCl3):
C-7H, C-8H), 6.97e7.01 (m, 1H, C-6H), 7.16e7.21 (m, 1H, C-5H). 13
C
NMR (75.5 MHz, CDCl3) d 22.5, 22.7, 39.8, 50.6, 55.2, 67.7, 68.0, 73.6,
95.2, 116.3, 119.6, 119.9, 129.1, 131.4, 155.5. HR-ESI-TOF-MS m/z calcd
d
1.44 (t, J¼6.9 Hz, 3H, PheOCH2CH3), 2.57 (br s, 8H, 4ꢂeNCH2),
for [C19H28N2O3þH]þ 333.2100, found 333.2173.
3.65e3.75 (m, 8H, 4ꢂeOCH2), 3.80 (s, 1H, eCH), 4.04 (q, J¼6.9 Hz,
2H, PheOCH2CH3), 6.46 (d, J¼7.5 Hz, 1H, C-5H), 6.72e6.78 (m, 1H,
C-4H), 6.82 (d, J¼8.1 Hz, 1H, C-3H), 11.02 (br s, 1H, eOH). 13C NMR
4.3.2. 3,3,8-Trimethyl-2,4-dimorpholinochroman (2b). Light yellow
solid; yield 47%; mp 93e95 ꢀC. IR (neat) nmax 3290, 2959, 2851,

D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
5615
2245, 1728, 1596, 1471, 1384, 1265, 1229, 1119, 1078, 979, 912 cmꢁ1
1H NMR (300 MHz, CDCl3):
0.85 (s, 3H, gem-CH3), 1.21 (s, 3H, gem-
.
(s, 3H, gem-CH3), 2.48 (br s, 4H, 2ꢂeNCH2), 2.75e2.82 (m, 2H,
eNCH2), 2.93 (s, 1H, C-4H), 3.01e3.08 (m, 2H, eNCH2), 3.62 (t,
J¼4.5 Hz, 4H, 2ꢂeOCH2), 3.73e3.74 (m, 4H, 2ꢂeOCH2), 4.49 (s, 1H,
C-2H), 6.74 (d, J¼8.7 Hz, 1H, C-8H), 6.97 (d, J¼2.1 Hz, 1H, C-5H), 7.11
d
CH3), 2.22 (s, 3H, Ph-CH3), 2.47 (br s, 4H, 2ꢂeNCH2), 2.81e2.88 (m,
2H, eNCH2), 2.96 (s, 1H, C-4H), 3.06e3.13 (m, 2H, eNCH2), 3.62 (t,
J¼4.5 Hz, 4H, 2ꢂeOCH2), 3.75e3.77 (m, 4H, 2ꢂeOCH2), 4.52 (s, 1H,
C-2H), 6.73e6.84 (m, 2H, C-6H, C-7H), 7.03 (d, J¼7.2 Hz, 1H, C-5H).
(dd, J¼8.7 and 2.4 Hz, 1H, C-7H). 13C NMR (75.5 MHz, CDCl3):
d 22.4,
22.6, 39.8, 50.5, 55.1, 67.7, 67.9, 73.3, 95.7, 117.6, 121.4, 124.6, 129.2,
130.6, 154.2. HR-ESI-TOF-MS m/z calcd for [C19H27ClN2O3þH]þ
367.1710, found 367.1783.
13C NMR (75.5 MHz, CDCl3):
d 15.9, 22.5, 22.7, 39.8, 50.8, 55.3, 67.8,
68.2, 73.8, 95.5, 119.2, 119.3, 125.7, 129.1, 130.1, 153.3. HR-ESI-TOF-
MS m/z calcd for [C20H30N2O3þH]þ 347.2256, found 347.2329.
4.3.8. 6-Fluoro-3,3-dimethyl-2,4-dimorpholinochroman (2h). White
crystalline solid; yield 55%; mp 80e82 ꢀC. IR (neat) nmax 3850, 3289,
2960, 2851, 2359, 2341, 1651, 1493, 1454, 1384, 1118, 732 cmꢁ1. 1H
4.3.3. 3,3,6-Trimethyl-2,4-dimorpholinochroman (2c). Light orange
solid; yield 46%; mp 95e97 ꢀC. IR (neat) nmax 3734, 3292, 2959,
2850, 2360, 2341, 1727, 1652, 1498, 1453, 1384, 1118, 982 cmꢁ1. 1H
NMR (300 MHz, CDCl3):
d 0.87 (s, 3H, gem-CH3), 1.20 (s, 3H, gem-
NMR (300 MHz, CDCl3):
d
0.86 (s, 3H, gem-CH3), 1.20 (s, 3H, gem-
CH3), 2.49 (br s, 4H, 2ꢂeNCH2), 2.78e2.83 (m, 2H, eNCH2), 2.94 (s,
1H, C-4H), 3.03e3.07 (m, 2H, eNCH2), 3.63 (t, J¼4.2 Hz, 4H,
2ꢂeOCH2), 3.73 (br s, 4H, 2ꢂeOCH2), 4.47 (s, 1H, C-2H), 6.69e6.78
(m, 2H, C-5H, C-8H), 6.86e6.92 (m, 1H, C-7H). 13C NMR (75.5 MHz,
CH3), 2.27 (s, 3H, PheCH3), 2.46 (br s, 4H, 2ꢂeNCH2), 2.78e2.83 (m,
2H, eNCH2), 2.92 (s, 1H, C-4H), 3.03e3.07 (m, 2H, eNCH2),
3.63e3.64 (m, 4H, 2ꢂeOCH2), 3.73 (br s, 4H, 2ꢂeOCH2), 4.46 (s, 1H,
C-2H), 6.69 (d, J¼8.4 Hz, 1H, C-8H), 6.77 (s, 1H, C-5H), 6.96 (d,
CDCl3):
d 22.4, 22.6, 39.7, 50.5, 55.1, 67.7, 68.0, 73.4, 95.4, 115.9,
J¼8.1 Hz, 1H, C-7H). 13C NMR (75.5 MHz, CDCl3):
d
20.8, 22.5, 22.7,
116.2,116.7,117.2, 119.1, 120.7, 151.6,155.1,158.1. HR-ESI-TOF-MS m/z
40.0, 50.7, 55.3, 67.8, 68.1, 73.7, 95.2, 116.0, 119.6, 128.7, 129.87, 131.7,
153.4. HR-ESI-TOF-MS m/z calcd for [C20H30N2O3þH]þ 347.2256,
found 347.2329.
calcd for [C19H27FN2O3þH]þ 351.2006, found 351.2078.
4.3.9. 6,8-Dichloro-3,3-dimethyl-2,4-dimorpholinochroman
(2i). White crystalline solid; yield 50%; mp 120e122 ꢀC. IR (neat)
nmax 3292, 2922, 2361, 2253, 1650, 1462, 1401, 1384, 1258, 1117, 908,
4.3.4. 8-Methoxy-3,3-dimethyl-2,4-dimorpholinochroman
(2d). Yellow oil; yield 31%. IR (neat) nmax 3271, 2963, 2856, 2361,
733 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 0.85 (s, 3H, gem-CH3), 1.21
2341, 2251, 1586, 1485, 1454, 1384, 1264, 1116, 909, 733 cmꢁ1
.
1H
(s, 3H, gem-CH3), 2.47 (br s, 4H, 2ꢂeNCH2), 2.84e2.90 (m, 2H,
eNCH2), 2.95 (s, 1H, C-4H), 3.08e3.13 (m, 2H, eNCH2), 3.63 (t,
J¼4.2 Hz, 4H, 2ꢂeOCH2), 3.74e3.76 (m, 4H, 2ꢂeOCH2), 4.60 (s, 1H,
C-2H), 6.90 (s, 1H, C-5H), 7.28 (s, 1H, C-7H). 13C NMR (75.5 MHz,
NMR (300 MHz, CDCl3):
d 0.89 (s, 3H, gem-CH3), 1.21 (s, 3H, gem-
CH3), 2.47 (br s, 4H, 2ꢂeNCH2), 2.85e2.91 (m, 2H, eNCH2), 2.99 (s,
1H, C-4H), 3.08e3.14 (m, 2H, eNCH2), 3.61 (t, J¼4.2 Hz, 4H,
2ꢂeOCH2), 3.75 (br s, 4H, 2ꢂeOCH2), 3.85 (s, 3H, PheOCH3), 4.56
(s, 1H, C-2H), 6.60e6.63 (m, 1H, H-7), 6.78e6.80 (m, 2H, C-5H, C-
CDCl3):
d 22.4, 22.6, 39.6, 50.6, 55.1, 67.6, 67.9, 73.3, 96.8, 122.5,
124.2, 129.1, 129.4, 149.0. HR-ESI-TOF-MS m/z calcd for
6H). 13C NMR (75.5 MHz, CDCl3):
d 22.6, 22.7, 39.7, 50.6, 55.1, 56.9,
[C19H26Cl2N2O3þNa]þ 423.1320, found 423.1213.
67.8, 68.1, 73.5, 95.7, 112.5, 119.2, 120.7, 123.7, 145.5, 148.6. HR-ESI-
TOF-MS m/z calcd for [C20H30N2O4þNa]þ 385.2206, found
385.2098.
4.4. General procedure for the synthesis of 3,3-dimethyl-4-
morpholinochroman-2-ol (3)
4.3.5. 8-Ethoxy-3,3-dimethyl-2,4-dimorpholinochroman (2e). White
crystalline solid; yield 36%; mp 110e112 ꢀC. IR (neat) nmax 3851,
3733, 3271, 2983, 2857, 2359, 2253, 1265, 908, 734 cmꢁ1. 1H NMR
To a solution of 3,3-dimethyl-2,4-dimorpholinochromans (2,
1.5 mmol) in THF/H2O (1:1, v/v), concd HCl was added till the dis-
appearance of turbidity and the solution was stirred for 30 min at
room temperature. The progress of the reaction was monitored on
TLC. After completion of the reaction, solvent was completely
evaporated under reduced pressure and the residue thus obtained
was extracted with ethylacetate (4ꢂ50 mL) and washed with
NaHCO3 solution (4ꢂ20 mL). Organic layer was separated and dried
over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the obtained crude product was purified by column
chromatography on silica gel using EtOAc/hexane as an eluent to
obtain pure product 3. The product thus obtained was a racemic
mixture in which one diastereomer predominated as indicated by
the NMR analysis.
(300 MHz, CDCl3):
d 0.88 (s, 3H, gem-CH3), 1.21 (s, 3H, gem-CH3),
1.41 (t, J¼6.9 Hz, 3H, PheOCH2CH3), 2.47 (br s, 4H, 2ꢂeNCH2),
2.83e2.90 (m, 2H, eNCH2), 2.98 (s, 1H, C-4H), 3.08e3.15 (m, 2H,
eNCH2), 3.61 (t, J¼4.2 Hz, 4H, 2ꢂeOCH2), 3.75e3.76 (m, 4H,
2ꢂeOCH2), 4.01 (q, J¼6.9, 14.1 Hz, 2H, PheOCH2CH3), 4.57 (s, 1H, C-
2H), 6.61 (d, J¼7.2 Hz, 1H, C-7H), 6.74e6.82 (m, 2H, C-5H, C-6H). 13
C
NMR (75.5 MHz, CDCl3): d 15.4, 22.6, 22.7, 39.7, 50.8, 55.1, 65.8, 67.8,
68.1, 73.5, 95.6, 115.2, 119.1, 120.9, 124.1, 146.1, 147.7. HR-ESI-TOF-MS
m/z calcd for [C21H32N2O4þH]þ 399.2362, found 399.2254.
4.3.6. 6-Bromo-3,3-dimethyl-2,4-dimorpholinochroman (2f). White
crystalline solid; yield 65%; mp 135e137 ꢀC. IR (neat) nmax 3280,
2965, 2917, 2857, 2252, 1598, 1477, 1453, 1384, 1265, 1116, 909,
4.4.1. 3,3-Dimethyl-4-morpholinochroman-2-ol (3a). White crys-
talline solid; yield 92%; mp 130e132 ꢀC. IR (neat) nmax 3156, 3053,
2986, 2919, 2857, 2253, 1609, 1588, 1489, 1456, 1384, 1256, 1117,
734 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 0.86 (s, 3H, gem-CH3), 1.20
(s, 3H, gem-CH3), 2.48 (br s, 4H, 2ꢂeNCH2), 2.75e2.82 (m, 2H,
eNCH2), 2.93 (s, 1H, C-4H), 3.01e3.08 (m, 2H, eNCH2), 3.63 (t,
J¼4.5 Hz, 4H, 2ꢂeOCH2), 3.72e3.74 (m, 4H, 2ꢂeOCH2), 4.48 (s, 1H,
C-2H), 6.69 (d, J¼8.7 Hz, 1H, C-8H), 7.11 (d, J¼2.1 Hz, 1H, C-5H), 7.25
909, 735 cmꢁ1. 1H NMR (300 MHz, CDCl3, 296 K):
d 0.90 (s, 3H, gem-
CH3), 1.44 (s, 3H, gem-CH3), 2.18e2.60 (br m, 4H, 2ꢂeNCH2), 3.31 (s,
1H, C-4H), 3.68 (br s, 4H, 2ꢂeOCH2), 5.14 (s, 1H, C-2H), 6.87e6.93
(m, 2H, C-7H, C-8H), 6.97 (d, J¼7.2 Hz, 1H, C-6H), 7.23e7.28 (m, 1H,
(dd, J¼8.7 and 2.4 Hz, 1H, C-7H). 13C NMR (75.5 MHz, CDCl3):
d 22.4,
22.6, 39.7, 50.5, 55.1, 67.7, 67.9, 73.2, 95.7, 111.7, 118.1, 122.1, 132.1,
133.6, 154.7. HR-ESI-TOF-MS m/z calcd for [C19H27BrN2O3þH]þ
411.1205, found 411.1278.
C-5H), 8.61 (br s, 1H, eOH). 13C NMR (75.5 MHz, CDCl3):
d 23.68,
25.02, 36.75, 54.16, 55.32, 67.63, 69.60, 101.64, 117.36, 118.76,
120.29, 130.31, 132.13, 152.06. 1H NMR (300 MHz, CDCl3, 234 K):
d
0.89 (s, 3H, gem-CH3), 1.45 (s, 3H, gem-CH3), 1.99 (d, J¼11.7 Hz, 1H,
4.3.7. 6-Chloro-3,3-dimethyl-2,4-dimorpholinochroman (2g). White
crystalline solid; yield 59%; mp 138e140 ꢀC. IR (neat) nmax 3289,
3053, 2966, 2917, 2858, 2360, 2341, 2253, 1480, 1265, 1116, 908,
eNH), 2.18e2.26 (m, 1H, eNH), 2.62e2.69 (m, 1H, eNH), 3.08 (d,
J¼11.4 Hz, 1H, eNH), 3.35 (s, 1H, C-4H), 3.38e3.46 (m, 1H, eOCH),
3.62e3.74 (m, 2H, eOCH2), 3.83 (d, J¼11.1 Hz, 1H, eOCH), 5.16 (d,
J¼7.5 Hz, 1H, C-2H), 6.88e6.95 (m, 2H, C-7H, C-8H), 6.99 (d, J¼6.3,
734 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 0.86 (s, 3H, gem-CH3), 1.20

5616
D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
1H, C-6H), 7.24e7.29 (m, 1H, C-5H), 9.15 (d, J¼8.4 Hz, 1H, eOH). 13
C
2965, 2857, 2360, 2341, 2253,1480,1411, 1317,1264, 1224,1185, 1118,
1090, 1021, 989, 908, 734, 650 cmꢁ1 1H NMR (300 MHz, CDCl3):
0.88 (s, 3H, gem-CH3), 0.97 (s, 0.41H, gem-CH3, minor di-
NMR (75.5 MHz, CDCl3):
d
24.1, 25.1, 36.4, 52.5, 57.7, 67.3, 68.2,
.
68.80, 101.6, 117.5, 118.5, 120.7, 130.6, 132.5, 151.4. HR-ESI-TOF-MS
d
m/z calcd for [C15H21NO3þH]þ 264.1521, found 264.1594.
astereomer), 1.13 (s, 0.40H, gem-CH3, minor diastereomer), 1.42 (s,
3H, gem-CH3), 2.35e2.65 (br m, 4H, 2ꢂeNCH2), 3.24 (s, 1H, C-4H),
3.47e3.68 (br m, 4H, 2ꢂeOCH2), 5.11 (s, 1H, C-2H), 6.76 (d, J¼8.7 Hz,
1H, C-8H), 7.11 (d, J¼2.1 Hz,1H, C-5H), 7.32 (dd, J¼8.7 and 2.4 Hz,1H,
4.4.2. 3,3,8-Trimethyl-4-morpholinochroman-2-ol (3b). Light yel-
low solid; yield 89%; mp 121e123 ꢀC. IR (neat) nmax 3168, 2983,
2923, 2873, 2850, 2819, 2769, 2361, 1727, 1595, 1467, 1435, 1366,
1286, 1222, 1119, 1088, 1021, 920 cmꢁ1. 1H NMR (300 MHz, CDCl3):
C-7H), 8.41 (br s, 1H, eOH). 13C NMR (75.5 MHz, CDCl3):
d 23.4, 24.9,
36.6, 53.84, 55.1, 67.6, 68.1, 69.2,101.8,112.3,119.2,121.0,133.2,134.3,
151.3; (minor diastereomer) 20.7, 21.6, 40.0, 99.2, 118.5, 123.7, 131.8,
132.6. HR-ESI-TOF-MS m/z calcd for [C15H20BrNO3þH]þ 342.0627,
found 342.0699.
d
0.87 (s, 3H, gem-CH3), 0.90 (s, 1.10H, gem-CH3, minor di-
astereomer), 1.17 (s, 0.97H, gem-CH3, minor diastereomer), 1.44 (s,
3H, gem-CH3), 2.20e2.56 (br m, 4H, 2ꢂeNCH2), 2.23 (s, 3H, Ph-
CH3), 3.28 (s, 1H, C-4H), 3.63 (t, J¼4.5 Hz, 4H, 2ꢂeOCH2), 5.18 (s, 1H,
C-2H), 6.79e6.81 (m, 2H, C-6H, C-7H), 7.01e7.12 (m, 1H, C-5H), 8.62
4.4.7. 6-Chloro-3,3-dimethyl-4-morpholinochroman-2-ol (3g). White
crystalline solid; yield 94%; mp 168e170 ꢀC. IR (neat) nmax 3150, 2967,
1484, 1415, 1326, 1227, 1188, 1115, 1085, 1020, 977, 828 cmꢁ1. 1H NMR
(br s, 1H, eOH). 13C NMR (75.5 MHz, CDCl3):
d 16.2, 23.7, 25.1, 36.6,
54.2, 55.1, 67.7, 68.1, 69.8, 101.6, 118.2, 119.6, 126.3, 129.7, 131.3,
150.1; (minor diastereomer) 20.1, 21.6, 39.54, 98.6, 120.0, 120.3,
125.5, 128.1, 130.06, 151.5. HR-ESI-TOF-MS m/z calcd for
[C16H23NO3þH]þ 278.1678, found 278.1751.
(300 MHz, CDCl3):
d 0.87 (s, 3H, gem-CH3), 0.97 (s, 0.46H, gem-CH3,
minor diastereomer), 1.13 (s, 0.48H, gem-CH3, minor diastereomer),
1.42 (s, 3H, gem-CH3), 2.35e2.65 (br m, 4H, 2ꢂeNCH2), 3.24 (s,1H, C-
4H), 3.47e3.67 (br m, 4H, 2ꢂeOCH2), 5.10 (s, 1H, C-2H), 6.80 (d,
J¼8.7 Hz, 1H, C-8H), 6.97 (d, J¼2.1 Hz, 1H, C-5H), 7.18 (dd, J¼8.7 and
2.1 Hz, 1H, C-7H), 8.39 (d, J¼6.6 Hz, 1H, eOH). 13C NMR (75.5 MHz,
4.4.3. 3,3,6-Trimethyl-4-morpholinochroman-2-ol (3c). Light yellow
solid; yield 91%; mp 152e154 ꢀC. IR (neat) nmax 3290, 2963, 2919,
2850, 2818, 2361, 1650, 1499, 1384, 1326, 1255, 1116, 1074, 1023,
CDCl3): d 23.5, 24.9, 36.6, 53.8, 55.0, 67.6, 68.1, 69.2,101.8,118.7,120.4,
990, 889, 823, 736 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
0.89 (s, 3H,
125.1, 130.3, 131.4, 150.7; (minor diastereomer) 20.8, 21.6, 99.2, 118.1,
128.9, 129.6. HR-ESI-TOF-MS m/z calcd for [C15H20ClNO3þH]þ
298.1132, found 298.1204.
gem-CH3), 1.26 (s, 1.20H, gem-CH3, minor diastereomer), 1.43 (s, 3H,
gem-CH3), 2.29 (s, 3H, Ph-CH3), 2.57e2.80 (br m, 4H, 2ꢂeNCH2),
3.24 (s, 1H, C-4H), 3.68 (br s, 4H, 2ꢂeOCH2), 5.11 (s, 1H, C-2H),
6.76e6.79 (m, 2H, C-5H, C-8H), 7.04 (d, J¼8.1 Hz, 1H, C-7H), 8.78 (br
4.4.8. 6-Fluoro-3,3-dimethyl-4-morpholinochroman-2-ol (3h). White
crystalline solid; yield 93%; mp 131e133 ꢀC. IR (neat) nmax 3190, 2947,
s, 1H, eOH). 13C NMR (75.5 MHz, CDCl3):
d 20.6, 23.6, 25.0, 36.8,
54.2, 55.4, 67.6, 68.0, 69.8, 101.5, 117.1, 118.4, 129.4, 131.0, 132.3,
149.9; (minor diastereomer) 20.2, 22.8, 25.5, 40.0, 66.5, 98.5, 116.1,
129.7, 130.9, 151.0. HR-ESI-TOF-MS m/z calcd for [C16H23NO3þH]þ
278.1678, found 278.1751.
2847, 1493, 1428, 1206, 1115, 982, 960 cmꢁ1 1H NMR (300 MHz,
.
CDCl3):
d 0.88 (s, 3H, gem-CH3), 0.99 (s, 0.48H, gem-CH3, minor di-
astereomer), 1.11 (s, 0.48H, gem-CH3, minor diastereomer), 1.41 (s,
3H, gem-CH3), 2.35e2.67 (br m, 4H, 2ꢂeNCH2), 3.24 (s, 1H, C-4H),
3.51e3.67 (br m, 4H, 2ꢂeOCH2), 5.09 (s, 1H, C-2H), 6.69 (d, J¼6.0 Hz,
1H, C-5H), 6.79e6.84 (m, 1H, C-8H), 6.93e6.98 (m, 1H, C-7H), 8.34
4.4.4. 8-Methoxy-3,3-dimethyl-4-morpholinochroman-2-ol
(3d). Yellow oil; yield 88%. IR (neat) nmax 3293, 2960, 2253, 1728,
1588, 1485, 1384, 1264, 1118, 1081, 1031, 991, 919, 732 cmꢁ1. 1H NMR
(br s, 1H, eOH). 13C NMR (75.5 MHz, CDCl3):
d 23.3, 24.9, 36.7, 53.7,
55.0, 67.6, 68.1, 69.4, 101.6, 116.9, 117.3, 117.5, 117.8, 118.2, 118.3, 119.7,
119.8, 148.1, 155.0, 158.2; (minor diastereomer) 20.8, 21.6, 99.3, 115.4,
115.7, 115.9, 123.0. HR-ESI-TOF-MS m/z calcd for [C15H20FNO3þH]þ
282.1427, found 282.1500.
(300 MHz, CDCl3):
d 0.92 (s, 3H, gem-CH3), 1.17 (s, 0.57H, gem-CH3,
minor diastereomer), 1.24 (s, 0.54H, gem-CH3, minor diastereomer),
1.44 (s, 3H, gem-CH3), 2.18e2.64 (br m, 4H, 2ꢂeNCH2), 3.31 (s, 1H,
C-4H), 3.66 (br s, 4H, 2ꢂeOCH2), 3.87 (s, 3H, PheOCH3), 5.26 (s, 1H,
C-2H), 6.58 (dd, J¼5.70 and 3.00 Hz,1H, C-7H), 6.85e6.87 (m, 2H, C-
5H and C-6H), 8.57 (br s, 1H, eOH). 13C NMR (75.5 MHz, CDCl3):
4.4.9. 6,8-Dichloro-3,3-dimethyl-4-morpholinochroman-2-ol
(3i). White crystalline solid; yield 93%; mp 178e180 ꢀC. IR (neat)
nmax 3292, 2922, 2361, 2340, 2253, 1650, 1462, 1401, 1384, 1258,
d
23.6, 25.0, 36.6, 54.1, 55.0, 56.3, 67.7, 68.2, 69.3, 101.8, 112.2, 119.4,
119.9, 124.1, 141.6, 148.7; (minor diastereomer) 20.4, 21.6, 39.5, 99.1,
110.9, 120.2, 122.3. HR-ESI-TOF-MS m/z calcd for [C16H23NO4þH]þ
294.1627, found 294.1700.
1117, 908, 733 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 0.89 (s, 3H, gem-
CH3), 1.02 (s, 0.62H, gem-CH3, minor diastereomer), 1.14 (s, 0.66H,
gem-CH3, minor diastereomer), 1.45 (s, 3H, gem-CH3), 2.18e2.68 (br
m, 4H, 2ꢂeNCH2), 3.28 (s, 1H, C-4H), 3.69 (br s, 4H, 2ꢂeOCH2), 5.27
(s, 1H, C-2H), 6.91 (s, 1H, C-5H), 7.36 (s, 1H, C-7H), 8.46 (br s, 1H,
4.4.5. 8-Ethoxy-3,3-dimethyl-4-morpholinochroman-2-ol
(3e). White crystalline solid; yield 91%; mp 102e104 ꢀC. IR (neat)
nmax: 3155, 2966, 2917, 2857, 2252, 1587, 1485, 1474, 1395, 1319,
eOH). 13C NMR (75.5 MHz, CDCl3):
d 23.2, 24.8, 36.7, 53.7, 55.1, 67.5,
68.1, 69.4, 102.4, 121.6, 123.2, 124.9, 129.8, 130.6, 147.1; (minor di-
astereomer) 21.1, 21.6, 39.5, 100.0, 122.5, 124.7, 125.6, 128.0, 129.1,
147.7. HR-ESI-TOF-MS m/z calcd for [C15H19Cl2NO3þH]þ 332.0742,
found 332.0815.
1264, 1117, 1078, 988, 908, 733 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
0.90 (s, 3H, gem-CH3), 0.95 (s, 0.37H, gem-CH3, minor di-
astereomer), 1.16 (s, 0.38H, gem-CH3, minor diastereomer),
1.42e1.47 (m, 6H, gem-CH3 and PheOCH2CH3), 2.35e2.60 (br m,
4H, 2ꢂeNCH2), 3.28 (s,1H, C-4H), 3.63 (br s, 4H, 2ꢂeOCH2), 4.06 (q,
J¼6.9 Hz, 2H, PheOCH2CH3), 5.24 (s, 1H, C-2H), 6.55 (dd, J¼6.3 and
2.1 Hz, 1H, C-7H), 6.79e6.83 (m, 2H, C-5H, C-6H), 8.48 (br s, 1H,
4.5. General procedure for the synthesis of 3,3-dimethyl-4-
morpholino-3,4-dihydrocoumarins (4)
eOH). 13C NMR (75.5 MHz, CDCl3):
d
15.1, 23.6, 25.1, 36.6, 54.0, 55.0,
To a solution of 3,3-dimethyl-4-morpholinochroman-2-ol (3,
0.50 mmol) in 3 mL dichloromethane, DesseMartin periodinane
(0.75 mmol) was added and the reaction mixture was stirred for
appropriate time at room temperature till the starting compound
was consumed. After completion of the reaction, as indicated by
TLC, 5 mL Na2S2O3 solution followed by NaHCO3 solution (5 mL)
was added and reaction mixture was stirred for 15 min. Organic
layer was separated, washed with water, and dried over anhydrous
65.1, 67.7, 68.1, 69.4, 101.6, 114.4, 119.6, 119.8, 124.2, 142.2, 148.0;
(minor diastereomer) 20.5, 21.7, 39.5, 69.1, 99.0, 113.0, 120.0, 122.1,
122.5, 143.3, 147.6. HR-ESI-TOF-MS m/z calcd for [C17H25NO4þH]þ
308.1784, found 308.1856.
4.4.6. 6-Bromo-3,3-dimethyl-4-morpholinochroman-2-ol (3f). White
crystalline solid; yield 94%; mp 170e172 ꢀC. IR (neat) nmax 3155,

D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
5617
Na2SO4. The solvent was removed under reduced pressure to obtain
the crude product, which was purified by column chromatography
on silica gel using EtOAc/hexane as an eluent to obtain pure product
4 in high yields.
735 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
1.9 (s, 3H, gem-CH3), 1.50 (s,
3H, gem-CH3), 2.22e2.26 (m, 2H, eNCH2), 2.46e2.50 (m, 2H,
eNCH2), 3.32 (s, 1H, C-4H), 3.64 (t, J¼4.5 Hz, 4H, 2ꢂeOCH2), 6.97 (d,
J¼8.7 Hz, 1H, C-8H), 7.28 (s, 1H, C-5H), 7.47 (d, J¼8.4 Hz, 1H, C-7H).
13C NMR (75.5 MHz, CDCl3):
d 21.4, 26.3, 41.2, 49.4, 67.2, 70.9, 117.0,
4.5.1. 3,3-Dimethyl-4-morpholino-3,4-dihydrocoumarin (4a). White
crystalline solid; yield 95%; mp 113e115 ꢀC. IR (neat) nmax 3288,
2982, 2932, 2860, 2360, 2341, 2253, 1753, 1612, 1589, 1484, 1455,
1384, 1265, 1118, 1096, 908, 733 cmꢁ1. 1H NMR (300 MHz, CDCl3):
118.5, 120.8, 132.8, 150.9, 173.3. HR-ESI-TOF-MS m/z calcd for
[C15H18BrNO3þNa]þ 362.0470, found 362.0362.
4.5.7. 6-Chloro-3,3-dimethyl-4-morpholino-3,4-dihydrocoumarin
(4g). White crystalline solid; yield 95%; mp 113e115 ꢀC. IR (neat)
nmax 3156, 3053, 2985, 2253,1762,1604, 1477,1410,1384,1265,1116,
d
1.18 (s, 3H, gem-CH3), 1.51 (s, 3H, gem-CH3), 2.21e2.25 (br m, 2H,
eNCH2), 2.46e2.50 (br m, 2H, eNCH2), 3.35 (s, 1H, C-4H), 3.62 (t,
J¼4.5 Hz, 4H, 2ꢂeOCH2), 7.07e7.20 (m, 3H, C-7H, C-8H, C-6H),
1099, 909, 735 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.18 (s, 3H, gem-
7.33e7.43 (m, 1H, C-5H). 13C NMR (75.5 MHz, CDCl3):
d
21.5, 26.3,
CH3), 1.49 (s, 3H, gem-CH3), 2.20e2.26 (m, 2H, eNCH2), 2.44e2.51
(m, 2H, eNCH2), 3.31 (s, 1H, C-4H), 3.63 (t, J¼4.5 Hz, 4H, 2ꢂeOCH2),
7.02 (d, J¼8.7 Hz, 1H, C-8H), 7.12 (d, J¼2.4 Hz, 1H, C-5H), 7.31 (dd,
41.4, 49.5, 67.3, 71.1, 116.7, 118.7, 124.3, 129.8, 130.3, 151.9, 174.1. HR-
ESI-TOF-MS m/z calcd for [C15H19NO3þH]þ 262.1365, found
262.1438.
J¼8.7 and 2.4 Hz,1H, C-7H). 13C NMR (75.5 MHz, CDCl3):
d 21.3, 26.3,
41.2, 49.4, 67.2, 71.0, 118.1, 120.5, 129.6, 129.8, 129.9, 150.4, 173.4.
HR-ESI-TOF-MS m/z calcd for [C15H18ClNO3þNa]þ 318.0975, found
318.0867.
4.5.2. 3,3,8-Trimethyl-4-morpholino-3,4-dihydrocoumarin (4b). Light
yellow solid; yield 94%; mp 86e88 ꢀC. IR (neat) nmax 3293, 2958,
2930, 2855, 2360, 2341, 1762, 1593, 1470, 1384, 1328, 1289, 1266,
1202, 1117, 1021, 920 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
1.17 (s, 3H,
4.5.8. 6-Fluoro-3,3-dimethyl-4-morpholino-3,4-dihydrocoumarin
(4h). White crystalline solid; yield 95%; mp 115e117 ꢀC. IR (neat)
nmax 3270, 2925, 2857, 2359, 2253, 1755, 1600, 1492, 1462, 1429,
1384, 1201, 1115, 1096, 908, 734 cmꢁ1. 1H NMR (300 MHz, CDCl3):
gem-CH3), 1.50 (s, 3H, gem-CH3), 2.20e2.23 (m, 2H, eNCH2), 2.33 (s,
3H, PheCH3), 2.46e2.49 (m, 2H, eNCH2), 3.32 (s, 1H, C-4H), 3.62 (t,
J¼4.5 Hz, 4H, 2ꢂeOCH2), 6.93 (d, J¼7.2, 1H, C-7H), 7.03e7.08 (m, 1H,
C-6H), 7.18 (d, J¼7.5 Hz,1H, C-5H). 13C NMR (75.5 MHz, CDCl3):
d
16.0,
d 1.19 (s, 3H, gem-CH3), 1.50 (s, 3H, gem-CH3), 2.20e2.27 (m, 2H,
21.6, 26.4, 41.4, 49.8, 67.4, 71.5, 118.6, 123.8, 126.0, 128.0, 131.4, 150.2,
174.2. HR-ESI-TOF-MS m/z calcd for [C16H21NO3þNa]þ 298.1521,
found 298.1414.
eNCH2), 2.45e2.52 (m, 2H, eNCH2), 3.31 (s, 1H, C-4H), 3.63 (t,
J¼4.8 Hz, 4H, 2ꢂeOCH2), 6.84 (m, 1H, C-5H), 7.05e7.07 (m, 2H, C-
7H, C-8H). 13C NMR (75.5 MHz, CDCl3):
d 21.5, 26.38, 41.3, 49.7, 67.3,
71.4, 116.5,116.8,118.1,118.2,120.5,148.1,157.6,160.8,173.6. HR-ESI-
4.5.3. 3,3,6-Trimethyl-4-morpholino-3,4-dihydrocoumarin
(4c). Light yellow solid; yield 94%; mp 113e115 ꢀC. IR (neat) nmax
3285, 2984, 2348, 2253, 1752, 1612, 1384, 1265, 909, 735 cmꢁ1. 1H
TOF-MS m/z calcd for [C15H18FNO3þH]þ 280.1271, found 280.1343.
4.5.9. 6,8-Dichloro-3,3-dimethyl-4-morpholino-3,4-dihy-
drocoumarin (4i). White crystalline solid; yield 94%; mp
164e166 ꢀC. IR (neat) nmax 3305, 2959, 2931, 2856, 2360, 2341, 1774,
NMR (300 MHz, CDCl3):
d 1.17 (s, 3H, gem-CH3), 1.49 (s, 3H, gem-
CH3), 2.21e2.24 (m, 2H, eNCH2), 2.37 (s, 3H, PheCH3), 2.44e2.51
(m, 2H, eNCH2), 3.28 (s, 1H, C-4H), 3.62 (t, J¼4.5 Hz, 4H, 2ꢂeOCH2),
6.91 (s, 1H, C-5H), 6.95 (d, J¼8.4 Hz, 1H, C-8H), 7.12 (d, J¼8.1 Hz, 1H,
1732, 1456, 1384, 1118, 1081 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.18
(s, 3H, gem-CH3), 1.49 (s, 3H, gem-CH3), 2.18e2.24 (m, 2H, eNCH2),
2.42e2.48 (m, 2H, eNCH2), 3.32 (s, 1H, C-4H), 3.61 (t, J¼4.5 Hz, 4H,
2ꢂeOCH2), 7.01 (d, J¼2.1 Hz, 1H, C-5H), 7.43 (d, J¼2.1 Hz, 1H, C-7H).
C-7H). 13C NMR (75.5 MHz, CDCl3):
d 21.0, 21.5, 26.3, 41.4, 49.6, 67.3,
71.3, 116.4, 118.5, 130.3, 130.6, 133.8, 149.9, 174.2. HR-ESI-TOF-MS m/
z calcd for [C16H21NO3þH]þ 276.1521, found 276.1594.
13C NMR (75.5 MHz, CDCl3):
d 21.4, 26.3, 41.3, 49.6, 67.2, 71.4, 121.7,
123.0, 128.3, 129.5, 130.4, 146.5, 172.2. HR-ESI-TOF-MS m/z calcd for
4.5.4. 8-Methoxy-3,3-dimethyl-4-morpholino-3,4-dihydrocoumarin
(4d). Colorless oil; yield 94%. IR (neat) nmax 3290, 2964, 2934, 2860,
2362, 2341, 2253,1762,1615,1589,1484, 1460,1384,1276,1116, 908,
[C15H17Cl2NO3þH]þ 330.0585, found 330.0815.
Acknowledgements
734 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.20 (s, 3H, gem-CH3), 1.50
(s, 3H, gem-CH3), 2.25 (br s, 2H, eNCH2), 2.48e2.51 (m, 2H, eNCH2),
3.34 (s, 1H, C-4H), 3.63 (br s, 4H, 2ꢂeOCH2), 3.91 (s, 3H, PheOCH3),
6.70 (d, J¼7.2 Hz, 1H, C-7H), 6.94e6.97 (m, 1H, C-6H), 7.09e7.12 (m,
The authors sincerely thank Natural Sciences and Engineering
Research Council of Canada (NSERC) for research funding. D.M.
thanks the Canadian Bureau for International Education for
awarding Canadian Commonwealth Scholarship and University
Grants Commission (India) for providing research fellowship.
1H, C-5H). 13C NMR (75.5 MHz, CDCl3):
d 21.5, 26.3, 41.2, 49.6, 56.5,
67.3, 71.4, 112.8, 119.7, 121.9, 124.1, 141.2, 147.6, 173.4. HR-ESI-TOF-
MS m/z calcd for [C16H21NO4þH]þ 292.1471, found 292.1543.
Supplementary data
4.5.5. 8-Ethoxy-3,3-dimethyl-4-morpholino-3,4-dihydrocoumarin
(4e). White crystalline solid; yield 95%; mp 121e123 ꢀC. IR (neat)
nmax 3293, 3053, 2985, 2253, 1758, 1603, 1473, 1421, 1384, 1265,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.06.083.
1115, 909, 734, 650 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.18 (s, 3H,
gem-CH3), 1.44e1.48 (m, 6H, gem-CH3, PheOCH2CH3), 2.19e2.25
(m, 2H, eNCH2), 2.45e2.51 (m, 2H, eNCH2), 3.31 (s, 1H, C-4H), 3.60
(t, J¼4.5 Hz, 4H, 2ꢂeOCH2), 4.08 (q, J¼6.9 Hz, 2H, PheOCH2CH3),
6.66 (d, J¼7.5 Hz, 1H, C-7H), 6.91 (m, 1H, C-6H), 7.04e7.09 (m, 1H, C-
References and notes
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5H). 13C NMR (75.5 MHz, CDCl3):
d 15.0, 21.5, 26.3, 41.2, 49.7, 65.4,
67.3, 71.5, 114.5, 119.8, 122.0, 124.1, 141.6, 146.9, 173.6. HR-ESI-TOF-
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4.5.6. 6-Bromo-3,3-dimethyl-4-morpholino-3,4-dihydrocoumarin
(4f). White crystalline solid; yield 96%; mp 156e158 ꢀC. IR (neat)
nmax 3284, 2985, 2253, 1761, 1643, 1476, 1384, 1265, 1115, 1098, 909,

5618
D. Mathur et al. / Tetrahedron 70 (2014) 5608e5618
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