Ytterbium triflate promoted one-pot three component synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3-oxazines

Article abstract of DOI:10.1007/s10562-011-0605-3

An efficient one-pot synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3- oxazines from acetylene dicarboxylates, aromatic and aliphatic amines, and formaldehyde is described. The six member N,O-heterocyclic nucleus was constructed via Yb(OTf)₃

Full text of DOI:10.1007/s10562-011-0605-3

Catal Lett (2011) 141:844–849
DOI 10.1007/s10562-011-0605-3
Ytterbium Triflate Promoted One-Pot Three Component
Synthesis of 3,4,5-Trisubstituted-3,6-dihydro-2H-1,3-oxazines
•
Francesco Epifano Caroline Pelucchini
•
•
Ornelio Rosati Salvatore Genovese
•
Massimo Curini
Received: 24 March 2011 / Accepted: 8 April 2011 / Published online: 26 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract An efficient one-pot synthesis of 3,4,5-trisub-
stituted-3,6-dihydro-2H-1,3-oxazines from acetylene dicar-
boxylates, aromatic and aliphatic amines, and formaldehyde
is described. The six member N,O-heterocyclic nucleus was
constructed via Yb(OTf)3 promoted domino hydroamina-
tion/Prins reaction/cyclization/dehydration reactions.
one of the most important C–C bond-forming reactions
for production of nitrogen-containing molecules [19–21].
1,3-Oxazine derivatives represent a group of compounds of
particular interest for their antibiotic [22–24], anticancer
[25], analgesic [26], and anticonvulsant [27] activities.
Although several different methods for the preparation of
title compounds have already been reported in the literature
[28–31], very few have been accomplished by means of a
the MCRs-based methodology. Recently Jiang and
coworkers reported the synthesis of 3,4,5-trisubstituted-
3,6-dihydro-2H-1,3-oxazines from alkynoates, anilines,
and formaldehyde via a Bronsted acid (e.g. HCl) promoted
domino hydroamination/Prins reaction/cyclization/dehy-
dration process [32]. A recent alternative to this process is
represented by the use of sulfamic acid as catalyst of the
title process [33]. However many of the proposed meth-
odologies suffer major or minor drawbacks such as harsh
reaction conditions, low yields, tedious work-up proce-
dures, low selectivity leading to mixture of differently
sized rings, co-occurrence of several side reactions, and
need of chromatography for purification of adducts.
Keywords Heterogeneous catalysis ꢀ Multicomponent
reactions ꢀ Lanthanides ꢀ Oxazine derivatives ꢀ
Ytterbium triflate
1 Introduction
The development of simple routes to widely used chemi-
cals is one of the most challenging task in organic synthesis
[1]. In this context, domino reactions including multi-
component processes have been employed as a powerful
mean to reach this goal [2–8]. Multicomponent reactions
(MCRs) in fact allow to get access to molecular structure
complexity and diversity from readily available starting
materials in the same reaction vessel by a one-step proce-
dure [9–17]. Despite the fact that it is approaching its
century ‘‘birthday’’ [18], the Mannich reaction still remains
During the last two decades, rare earth metal triflates
have been found to be unique Lewis acids since they are
water tolerant reusable catalysts and can effectively pro-
mote several carbon–carbon and carbon–heteroatom bonds
formation reactions in high yields, including MCRs [34]. In
the course of our investigations, we have recently seen that
rare earth metal triflates are able to efficiently promote a
variety of valuable and high yielding C–C bond-forming
reactions in the context of a green chemical approach [35].
In continuation of our ongoing studies aimed at developing
mild and practical protocols for the synthesis of useful
building blocks and/or biologically active compounds by
using lanthanides as catalysts, and employing water as the
solvent or solvent-free conditions, we wish to report herein
F. Epifano ꢀ S. Genovese
`
Dipartimento di Scienze del Farmaco, Universita ‘‘G.
D’Annunzio’’ Chieti-Pescara, Via dei Vestini 31, 66100 Chieti
Scalo, CH, Italy
C. Pelucchini ꢀ O. Rosati ꢀ M. Curini (&)
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di
`
Chimica Organica, Universita degli Studi di Perugia, Via del
Liceo, 06123 Perugia, Italy
e-mail: curmax@unipg.it
123

Synthesis of 1,3 Oxazines Promoted by Yb(OTf)3
845
that 1,3-oxazine derivatives can be effectively synthesized
by a MCR catalyzed by Yb(OTf)3 hydrate in satisfactory
yields using acetylene dicarboxylates, aromatic and ali-
phatic amines, and formaldehyde (Scheme 1).
with yields in oxazine derivative of 71, 69, 64, and 68%
respectively.
The same reaction was also performed by using other
metal triflates from the lanthanide series, but the results
were worse than those obtained with Yb(OTf)3. The reason
of this discrepancy of catalytic efficiency in the lanthanide
series could be explained by the fact that Yb3? is the
‘‘hardest’’ cation and thus the most oxophilic, due to its
smaller ionic radius [37].
2 Results and Discussion
In a preliminary experiment, dimethyl acetylene dicarbox-
ylate (R1 = Me) (1 equiv.), aniline (R2 = H) (1 equiv.),
and formaldehyde (2 equiv. of fresh 37% aqueous solution)
were added 10% mol Yb(OTf)3 hydrate. The resulting
reaction mixture was vigorously stirred at room temperature
for 6 h. After the addition of 1 N NaOH to precipitate
Yb3? as the hydroxide and filtration, the desired adduct
dimethyl 3-phenyl-3,6-dihydro-2H-1,3-oxazine-4,5-dicar-
boxylate (entry 1) was obtained in 72% yield after extrac-
tion with Et2O and purification by SiO2 gel column
chromatography. Saponification of the ester functions in the
adducts occurred to a very limited extent during the
described recovery procedure and was virtually undetect-
able. To investigate the advantages and limitations of our
methodology, other amines, having electron-withdrawing
and donating substituents in the aromatic ring (entries 2–6
and 10–14), as well as aliphatic ones like n-butylamine
(entries 7 and 15) or cyclohexylamine (entries 8 and 16),
and diethyl acetylene dicarboxylate (R1 = Et), as an alter-
native source of alkynoate were used as reactants. The
results of the performed condensations are reported in the
Table 1. See Sect. 1.
From a mechanistic point of view, it could be hypoth-
esized that Yb3? first coordinates the alkynoate thus
enhancing its reactivity towards the hydroamination reac-
tion, and subsequent coordination to the oxygen atom of
formaldehyde led to the formation of the desired adduct by
Prins reaction and consequent dehydration and cyclization.
The ‘‘hard’’ feature as a Lewis acid of Yb3? would result in
a great enhancement of the electrophilicity of the inter-
mediates involved in the steps of the MCR we are dealing
with all requiring a coordination to an oxygen atom.
3 Conclusions
As a conclusion, in this manuscript we have demonstrated
that dimethyl- or diethyl acetylene dicarboxylate, formal-
dehyde, and differently substituted aromatic and aliphatic
amines undergo an efficient condensation reaction under
the catalysis of Yb(OTf)3 hydrate yielding 1,3-oxazine
derivatives. The simple workup procedure, mild reaction
conditions, and satisfactory yields make our methodology a
valid and alternative contribution to the already existing
processes in the field of this kind of multicomponent pro-
cess. Moreover, this protocol introduces a practical and
viable technology of solvent-free reactions. Further inves-
tigations to broaden the scope of this methodology are in
progress in our laboratories and will be reported in due
course.
From data reported in the Table 1 it is evident that both
aromatic amines having electron donating or withdrawing
substituents as well as aliphatic aldehydes reacted nearly to
the same extent furnishing the desired adducts in yields
ranging from 50 to 72%. Compared to the existing meth-
odologies, our process is effective in avoiding the use of
strong mineral acids and an excess of HCHO. The catalyst
was always recovered by precipitation as Yb(OH)3, fil-
trated, and transformed into the triflate salt as already
described [36]. Recycled in this way, the catalyst could be
reused several times without any significant loss of activity.
For example the reaction leading to product of entry 1 was
repeated four additional times with the recovered Yb3?
4 Experimental
4.1 General Remarks
All reagents, including Yb(OTf)3 hydrate, were obtained
from commercial sources (Aldrich Chemical Co.) and used
without further purification. All solvents were of analytical
R1OOC
O
1
NH2
grade. All extracts were dried over anhydrous Na2SO4. H
COOR1
and 13C NMR spectra were recorded on a Bruker AC 200
(1H NMR, 200 MHz; 13C NMR, 50.32 MHz) CDCl3 was
used as the solvent and tetramethylsilane as an internal
standard. Chemical shifts are reported in d (ppm). Reac-
tions were routinely monitored by TLC using Merck silica
gel F254 plates and visualization of TLC spots with a
R1OOC
N
+
HCHO
+
COOR1
R2
R2
Scheme 1
123

846
F. Epifano et al.
Table 1 Yb(OTf)3 catalyzed synthesis of 1,3 oxazine derivatives
Entry
1
Alkynoate
R1 = Me
Amine
Product
Yield (%)a
NH2
MeOOC
72
O
O
MeOOC
N
N
R1 = Me
R1 = Me
R1 = Me
60
NH2
MeOOC
MeOOC
2
3
4
NO2
NH2
NO2
O
MeOOC
MeOOC
67
70
N
OCH3
NH2
OCH3
O
MeOOC
MeOOC
N
Br
Br
O
R1 = Me
R1 = Me
R1 = Me
R1 = Me
65
50
60
60
NH2
MeOOC
MeOOC
5
6
7
8
OCH3
N
OCH3
NH2
NO2
MeOOC
MeOOC
O
N
NO2
MeOOC
MeOOC
NH2
O
N
NH2
MeOOC
MeOOC
O
N
NH2
R1 = Et
R1 = Et
70
60
EtOOC
EtOOC
9
O
N
NH2
NO2
EtOOC
EtOOC
10
O
N
NO2
123

Synthesis of 1,3 Oxazines Promoted by Yb(OTf)3
847
Table 1 continued
Entry
Alkynoate
Amine
Product
Yield (%)a
R1 = Et
65
NH2
EtOOC
11
O
EtOOC
N
OCH3
NH2
OCH3
O
R1 = Et
68
EtOOC
EtOOC
12
N
Br
Br
O
R1 = Et
R1 = Et
R1 = Et
R1 = Et
58
60
60
60
NH2
EtOOC
13
14
15
16
OCH3
EtOOC
N
OCH3
NH2
EtOOC
EtOOC
O
NO2
N
NO2
EtOOC
EtOOC
NH2
O
N
NH2
EtOOC
EtOOC
O
N
a
1
Yields of pure isolated products, characterized by IR, elemental analysis, H NMR, and 13C NMR
freshly prepared 7% EtOH solution of phosphomolybdic
acid. Silica gel 40 (0.063–0.200 mm) from Merck was used
for column chromatography. Melting points were measured
on a Bu¨chi melting point apparatus and are uncorrected
prior crystallization with n-hexane. Elemental analyses
were carried out on a Carlo Erba 1106 elemental analyzer.
The purity of the intermediates and the final products was
confirmed by combustion analysis.
Na2SO4 and the solvent evaporated to dryness. The syrup
obtained was finally purified by SiO2 column chromatog-
raphy (eluent CH2Cl2/MeOH 99:1) yielding the desired
product.
4.2.1 Dimethyl 3-phenyl-3,6-dihydro-2H-1,3-oxazine-4,
5-dicarboxylate (1)
Pale yellow solid (m.p. = 191–192 °C). Analytical data
were in full agreement for those already reported in the
literature for the same compound [32]. Anal. Calcd. for
C14H15NO5 C 60.64; H 5.45; N 5.05; O 28.85. Found: C
60.59; H 5.43; N 5.01; O 28.81.
4.2 Synthesis of 1,3-Oxazine Derivatives. General
Procedure
Yb(OTf)3 hydrate (0.1 mmol) was added to a stirred sus-
pension of alkynoate (1.0 mmol), aromatic amine
(1.1 mmol), and formaldehyde 37% (2.1 mmol). The
resulting mixture was vigorously stirred for 6 h at room
temperature, few drops of a solution of NaOH 1 N were
added, and the precipitate formed was filtered under vac-
uum. The filtrate was extracted twice with Et2O (5 mL) and
the combined organic layers were dried over anhydrous
4.2.2 Dimethyl 3-(40-nitro)phenyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (2)
Orange solid (m.p. = 203–205 °C). Analytical data were
in full agreement for those already reported in the literature
for the same compound [32]. Anal. Calcd. for C14H14N2O7
123

848
F. Epifano et al.
4.2.8 Dimethyl 3-cyclohexyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (8)
C 52.18; H 4.38; N 8.69; O 34.75. Found: C 52.12; H 4.33;
N 8.61; O 34.78.
Pale yellow solid (m.p. = 191–192 °C). IR = 1,650 cm-1
.
4.2.3 Dimethyl 3-(40-methoxy)phenyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (3)
1H NMR 1.09–1.33 (m, 10H), 2.89–2.96 (m, 1H), 3.75 (s,
3H), 3.87 (s, 3H), 4.31 (s, 2H), 4.82 (s, 2H). 13C NMR d
25.6, 26.7, 32.7, 51.1, 52.3, 57.5, 67.2, 82.3, 110.7, 131.0,
163.9, 166.3. Anal. Calcd. for C14H21NO5 C 59.35; H 7.47;
N 4.94; O 28.24. Found: C 59.31; H 7.42; N 4.99; O 28.20.
Pale reddish solid (m.p. = 162–164 °C). Analytical data
were in full agreement for those already reported in the
literature for the same compound [32]. Anal. Calcd. for
C15H17NO6 C 58.63; H 5.45; N 4.56; O 31.24. Found: C
58.65; H 5.41; N 4.52; O 31.21.
4.2.9 Diethyl 3-phenyl-3,6-dihydro-2H-1,3-oxazine-4,
5-dicarboxylate (9)
4.2.4 Dimethyl 3-(40-bromo)phenyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (4)
Pale yellow solid (m.p. = 234–235 °C). Analytical data
were in full agreement for those already reported in the
literature for the same compound [32]. Anal. Calcd. for
C16H19NO5 C 62.94; H 6.27; N 4.59; O 26.20. Found: C
62.99; H 6.21; N 4.54; O 26.29.
Pale red solid (m.p. = 172–173 °C). Analytical data were
in full agreement for those already reported in the literature
for the same compound [32]. Anal. Calcd. for
C14H14BrNO5 C 47.21; H 3.96; N 3.93; O 22.46. Found: C
47.15; H 3.93; N 3.88; O 22.40.
4.2.10 Diethyl 3-(40-nitro)phenyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (10)
4.2.5 Dimethyl 3-(20-methoxy)phenyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (5)
Orange solid (m.p. = 245–247 °C). Analytical data were
in full agreement for those already reported in the literature
for the same compound [32]. Anal. Calcd. for C16H18N2O7
C 54.86; H 5.18; N 8.00; O 31.97. Found: C 54.80; H 5.21;
N 7.93; O 31.90.
Red solid (m.p. = 165–167 °C). IR = 1,650 cm-1
.
1H
NMR d 3.72 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.76 (s,
2H), 4.97 (s, 2H), 6.52–7.84 (m, 4H). 13C NMR d 51.1,
52.2, 55.7, 67.8, 83.0, 114.1, 116.7, 125.4, 126.2, 130.4,
130.9, 131.4, 132.4, 151.3, 166.2, 166.3. Anal. Calcd. for
C15H17NO6 C 58.63; H 5.45; N 4.56; O 31.24. Found: C
58.68; H 5.40; N 4.50; O 31.18.
4.2.11 Diethyl 3-(40-methoxy)phenyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (11)
Pale reddish solid (m.p. = 189–191 °C). Analytical data
were in full agreement for those already reported in the
literature for the same compound [32]. Anal. Calcd. for
C17H21NO6 C 60.89; H 6.31; N 4.18; O 28.63. Found: C
60.81; H 6.34; N 4.12; O 28.69.
4.2.6 Dimethyl 3-(20-nitro)phenyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (6)
Orange solid (m.p. = 186–188 °C). IR = 1650, 1550,
1
1305 cm-1. H NMR d 3.74 (s, 3H), 3.92 (s, 3H), 4.81 (s,
2H), 5.02 (s, 3H), 7.29–7.97 (m, 4H). 13C NMR d 51.2,
52.1, 67.4, 78.8, 115.8, 120.3, 127.0, 130.5, 131.0, 131.5,
135.8, 165.5, 166.8. Anal. Calcd. for C14H14N2O7 C 52.18;
H 4.38; N 8.69; O 34.75. Found: C 52.14; H 4.37; N 8.62;
O 34.70.
4.2.12 Diethyl 3-(40-bromo)phenyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (12)
Pale red solid (m.p. = 189–190 °C). Analytical data were
in full agreement for those already reported in the literature
for the same compound [32]. Anal. Calcd. for
C16H18BrNO5 C 50.02; H 4.72; N 3.65; O 20.82. Found: C
50.07; H 4.67; N 3.60; O 20.78.
4.2.7 Dimethyl 3-nbutyl-3,6-dihydro-2H-1,3-oxazine-4,
5-dicarboxylate (7)
Pale yellow solid (m.p. = 168–169 °C). IR = 1,650 cm-1
.
1H NMR d 0.94 (t, 3H, J = 5.1 Hz), 1.39 (m, 2H), 1.92 (m,
2H), 3.41 (t, 3H, J = 6.8 Hz), 3.74 (s, 3H), 3.90 (s, 3H),
4.17 (s, 2H), 4.81 (s, 2H). 13C NMR d 13.7, 20.1, 31.3,
51.2, 52.0, 52.3, 67.5, 84.3, 110.2, 131.9, 164.5, 166.3.
Anal. Calcd. for C12H19NO5 C 56.02; H 7.44; N 5.44; O
31.09. Found: C 56.00; H 7.38; N 5.39; O 31.02.
4.2.13 Diethyl 3-(20-methoxy)phenyl-3,6-dihydro-2H-1,
3-oxazine-4,5-dicarboxylate (13)
Red solid (m.p. = 171–173 °C. IR = 1,650 cm-1
.
1H
NMR d 1.19 (t, 3H, J = 7.1 Hz), 1.28 (t, 3H, J = 7.0 Hz),
3.86 (s, 3H), 4.11 (q, 2H, J = 7.1 Hz), 4.22 (q, 2H,
123

Synthesis of 1,3 Oxazines Promoted by Yb(OTf)3
849
References
J = 7.0 Hz), 4.75 (s, 2H), 4.92 (s, 2H), 6.50–7.78 (m, 4H).
13C NMR d 14.0, 14.1, 55.4, 60.2, 61.3, 68.0, 82.9, 113.7,
116.6, 125.4, 126.3, 130.5, 131.1, 131.4, 132.4, 151.3,
166.3, 166.5. Anal. Calcd. for C17H21NO6 C 60.89; H 6.31;
N 4.18; O 28.63. Found: C 60.85; H 6.37; N 4.11; O
28.65.
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1H NMR d 0.95 (t, 3H, J = 5.2 Hz), 1.20 (t, 3H,
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1H NMR d 1.10–1.95 (m, 10H), 1.18 (t, 3H, J = 7.1 Hz),
1.32 (t, 3H, J = 7.1 Hz), 2.92–2.96 (m, 1H), 4.10 (q, 2H,
J = 7.1 Hz), 4.22 (q, 2H, J = 7.1 Hz), 4.44 (s, 2H), 4.76
(s, 2H). 13C NMR d 14.0, 14.1, 25.4, 26.7, 32.9, 57.4, 60.2,
61.1, 67.3, 82.0, 111.4, 131.9, 164.5, 166.6. Anal. Calcd.
for C16H25NO5 C 61.72; H 8.09; N 4.50; O 25.69. Found: C
61.77; H 8.01; N 4.44; O 25.65.
36. Fieser M (1989) Reagents for organic synthesis, vol 14. Wiley-
Interscience, New York, p 188
37. Pitzer KS (1974) Acc Chem Res 12:271
Acknowledgment Financial support from MIUR PRIN 2008 ‘‘A
Green Approach to Process Intensification in Organic Synthesis’’ is
gratefully acknowledged.
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