Pyrolysis of perhydro[1,2-c][1,3]oxazines: A green method of synthesizing 2,3-dehydropiperidine enamines

Article abstract of DOI:10.1016/j.tetlet.2005.06.067

Heat pyrolysis of the oxazines formed from 2-piperidineethanol produced 2,3-dehydropiperidine enamines. The same results were observed when these oxazines were irradiated with microwaves. Various 2-substituted perhydrooxazines were synthesized by allowing 2-piperidineethanol or 2-piperidinemethanol to react with aldehydes or ketones.

Full text of DOI:10.1016/j.tetlet.2005.06.067

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5451–5454
Pyrolysis of perhydro[1,2-c][1,3]oxazines: a green method
of synthesizing 2,3-dehydropiperidine enamines
*
A. Gilbert Cook, Christine A. Schering, Pauline A. Campbell and Samantha S. Hayes
Department of Chemistry, Valparaiso University, Valparaiso, IN 46383, USA
Received 7 June 2005; revised 10 June 2005; accepted 14 June 2005
Available online 5 July 2005
Abstract—Heat pyrolysis of the oxazines formed from 2-piperidineethanol produced 2,3-dehydropiperidine enamines. The same
results were observed when these oxazines were irradiated with microwaves. Various 2-substituted perhydrooxazines were synthe-
sized by allowing 2-piperidineethanol or 2-piperidinemethanol to react with aldehydes or ketones.
ꢀ
2005 Elsevier Ltd. All rights reserved.
1
The synthesis of 2,3-dehydropiperidine enamines has
typically been carried out by one of the following meth-
ods: oxidation of saturated piperidines with mercuric
lysis temperatures used were 600–750 ꢁC. For example,
when 3-oxa-1-azabicyclo[4.4.0]decane (1) was passed
8
9
through a pyrolysis apparatus, enamine 2 was pro-
duced in a 43% yield (Scheme 1). Upon standing this
2
3
acetate, reduction of aromatic heterocycles and
4
5
2
amides, addition of Grignard reagents to lactams,
and base catalyzed isomerizations of 1,2,5,6-tetrahydro-
enamine reacted to form dimer 3. These products were
shown to have identical physical and spectral properties
(IR, NMR and MS) as those obtained by base isomeri-
6
,7
pyridines.
6
zation of compound 4 (see Table 1). A similar result
was obtained by the use of microwave energy in a micro-
We have found that perhydro[1,2-c][1,3]oxazines are a
good source of various N-substituted 2,3-dehydropiperi-
dine enamines. These enamines can be produced using
only the ÔgreenÕ reactions of flash vacuum thermolysis
or microwave excitation of these oxazines. The thermo-
1
0
wave apparatus.
In a parallel reaction, 2-phenyl-3-oxa-1-azabicyclo-
1
[4.4.0]decane (5) was pyrolyzed to produce enamine
1
KOtBu
DMSO
6
00 ºC
or
N
O
microwave
N
N
CH
CH3
3
1
2
4
N
CH3
N
3
CH3
Scheme 1.
Keywords: Oxazines; Pyrolysis; Microwave; Enamines; Azomethine ylides.
*
Corresponding author. Tel.: +1 2194 645389; fax: +1 2194 645489; e-mail: Gil.Cook@valpo.edu
0
040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.067

5452
A. G. Cook et al. / Tetrahedron Letters 46 (2005) 5451–5454
Table 1. Yields, physical and spectral properties of bicyclo[4.4.0]decyl oxazines and enamines
N
O
R1
R2
À1 b
R
1
R
2
Oxazine Boiling
yield
Enamine % yield
Pyrolysis Microwave
Enamine mass IR (cm
spectra
)
N–C@C
%
point ꢁC
mmHg)
a
GC/MS
Monomer
Dimer
(
1
20 240 290
c
+
97(M )
H
CH
H
H
80
77
85–87 (0.6)
60–65 (1.5)
43
—
38
—
0
0
14
6
20
11
1645
—
1670
—
c
+
3
111(M )
6(base)
9
d
Ph
e
+
H
H
H
H
H
H
H
H
97
55
70
79
80
68
95
94
87
86
60
55–56
6
—
5
—
—
24
—
—
—
—
—
—
—
—
0
0
2
0
0
0
0
0
1
3
4
6
20
8
173(M )
1(base)
1642
1640
1643
—
—
9
f
e
+
p-MePh
64–65
187(M )
05(base)
—
1
g
e
+
p-ClPh
69–70
5
6
207(M )
25(base)
—
1
f
e
+
p-HOPh
156.5–157.5
—
13
—
—
—
20
13
17
0
5
189(M )
5(base)
—
5
f
e
+
p-MeOPh
64–65
19
8
58
17
3
203(M )
21(base)
1646
—
1673
—
1
f
+
m-MeOPh
82 (0.6)
203(M )
21(base)
1
g
e
+
p-O
m-O
Cyclohexyl
2
NPh
93–94
3
218(M )
5(base)
—
—
5
f
+
2
NPh
164–166 (0.2)
85–95 (0.5)
71–73 (0.1)
89–92 (0.2)
1
5
218(M )
5(base)
—
—
5
h
+
44
36
63
63
52
78
165(M )
22(base)
1644
1646
1642
1668
1673
1683
1
h
+
Cyclopentyl
151(M )
22(base)
1
f
+
Bicyclo[2.2.1]heptyl
16
177(M )
6(base)
9
a
b
c
A Phenomenex Zebron ZB-5 30-meter column in a Hewlett Packard BCD Plus GC–MS system was used.
Obtained as a liquid film using a Thermo Nicolet Nexus 670 FT-IR spectrophotometer.
Ref. 8.
Ref. 11.
d
e
Melting point.
Satisfactory elemental analysis was obtained. Performed by Schwarzkopf Microanalytical Laboratory, Woodside, NY.
f
g
h
Ref. 20.
Ref. 15.
N
O
KOtBu
DMSO
600 ºC
N
CH2
N
CH2
5
7
6
Scheme 2.
6
produced by isomerization of amine 7.
(Scheme 2). This enamine product was identical to that
1
did not significantly change these ratios. So these ratios
can be used to predict the amount of enamine obtain-
able by pyrolysis. Using these indicators it can be seen
from Table 1 that the p-methoxyphenyl, cyclohexyl,
cyclopentyl and bicyclo[2.2.1]heptyl oxazines have the
highest potential yields of enamines. This is important
because it indicates that, by varying pyrolysis condi-
tions, it should be possible to obtain much higher yields
of enamine products than we actually did obtain in these
limited experiments. Exploitation of the microwave
2
This type of pyrolysis also takes place in the injection
port of a gas chromatograph. By varying the tempera-
ture of the injection port, the yields of enamine would
vary. As the injection port temperature increased, the
ratio of enamine to oxazine starting material would
increase (see Table 1). Varying the ramping oven tem-
peratures of the gas chromatograph starting at 70 ꢁC

A. G. Cook et al. / Tetrahedron Letters 46 (2005) 5451–5454
5453
H
H
4
e–
+
CH3CHO
N
N
O
N
CH2
CH3
1
8
2
Scheme 3.
technique also shows great potential for increasing these
yields significantly as shown by the example of the
p-chlorophenyl substituted oxazine.
A good method for synthesizing oxazines is the reaction
of a secondary amine with an aldehyde or a ketone fol-
lowed by nucleophilic attack of the intermediate imin-
ium ion by an attached alcohol. This method forms
the basis of the production of 2-substituted-3-oxa-1-aza-
The mechanism for the formation of the enamine has as
the first step the formation of azomethine ylide 8 result-
8
,11,15,16
bicyclo[4.4.0]decanes
1-azabicyclo[4.3.0]nonanes.
and 2-substituted-3-oxa-
For example when
1
3
11,17–19
ing from the loss of acetaldehyde. This is followed by a
suprafacial [1,4]sigmatropic shift of a hydrogen to give
2-piperidineethanol (10) was allowed to react with
4-nitrobenzaldehyde (11), 2-(4-nitrophenyl)-3-oxa-1-
1
4
enamine 2 (Scheme 3).
2
0
azabicyclo[4.4.0]decane (12) was formed in a 95%
yield (Scheme 5).
Pyrolysis of the bicyclo[4.3.0]nonane oxazines such as
1
1
3
-oxa-1-azabicyclo[4.3.0]nonane (9) did not produce
an enamine product (Scheme 4). This was true of all
of the oxazines shown in Table 2.
The simple 3-oxa-1-azabicyclo[4.4.0]decane (1) exists as
an equilibrium mixture of the trans and O-inside cis iso-
mers in the amounts of 97% trans and 3% O-inside cis at
1
3
203 K. This was based upon some low-temperature
NMR spectroscopy measurements carried out by Crabb
C
2
1
6
00 ºC
and Ingate.
O
N
N
CH3
References and notes
9
2
1
. Haynes, L. W.; Cook, A. G. In Enamines: Synthesis,
Structure, andReactions ; Cook, A. G., Ed., 2nd ed.;
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Chemistry of Enamines, Part 1; Rapport, Z., Ed.; Wiley:
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Scheme 4.
Table 2. Yields and physical properties of bicyclo[4.3.0]nonyl oxazines
2
3
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4. Stevens, R. V.; Mehra, R. K.; Zimmerman, R. L. J. Chem.
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R
1
R
2
% Yield
Boiling point ꢁC (mmHg)
5
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a
Ph
p-ClPh
p-O NPh
p-Me
p-MeOPh
H
H
H
H
H
74
82
28
63
79
93–97 (0.4)
100 (0.06)
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a
a
b
2
64.5–65.5
b
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a
2
NPh
a
a
9. Flash vacuum thermolysis has been reviewed by: Wier-
sum, U. E. Recl. Trav. Chim. Pays-Bas. 1982, 101, 317.
The apparatus used consisted of a 530 · 25 mm quartz
pyrolysis tube filled with 6 · 6 mm pieces of quartz
packing, and a Lindbert/Blue M tube furnace with a
maximum temperature of 1100 ꢁC. A 0.1 mm of Hg
vacuum was used after flushing the apparatus with
nitrogen. The product was trapped at À78 ꢁC.
Satisfactory elemental analysis was obtained. Performed by
Schwarzkopf Microanalytical Laboratory, Woodside, NY.
Melting point.
b
CHO
N
O
1
0. Milestone ETHOS SYNTH Labstation with magnetic
stirring, ATC-FO Automatic Temperature Control, glass
reaction vial with Teflon cover and screw cap. It was held
at 160 C for 1 h and 200 C for 1 3/4 h using 500 W power.
+
CH2CH2OH
H2O
+
N
H
10
NO2
11. Rink, M.; Eich, H. W. Naturwissenschaften 1958, 45, 516.
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13. Najera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105.
1
NO2
1
1
1
2
1
4. Bureau, R.; Mortier, J.; Joucla, M. Bull. Soc. Chim. Fr.
1993, 130, 584.
Scheme 5.

5454
A. G. Cook et al. / Tetrahedron Letters 46 (2005) 5451–5454
1
1
5. Hess, K.; Corleis, W. Chem. Ber. 1921, 54B, 3010.
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7
1
1
233.