First use of HEH in oxazine synthesis: Hydroxy-substituted 2 H-1,4-benzoxazine derivatives

Article abstract of DOI:10.1055/s-0029-1218380

The synthesis of 2H-1,4-benzoxazine derivatives from 1,2-epoxy-3-(2- nitroaryloxy)propanes in the presence of Hantzsch 1,4-dihydropyridine (HEH) and Pd/C as a catalyst was achieved. The nitro group was reduced before the epoxide functionality, leading to attack of the amino group on the epoxide moiety in a 6-exo-fashion. By introducing a methyl group at the 1-position, the 7-endo ring-closed product could also be formed. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218380

LETTER
3283
First Use of HEH in Oxazine Synthesis:
Hydroxy-Substituted 2H-1,4-Benzoxazine Derivatives
H
ydroxy-Substitut
i
e
d
2
H
-
n
g
zine
D
eriva
t
-
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. of China
Fax +86(931)8625657; E-mail: liuqiang@lzu.edu.cn
Received 29 July 2009
which plays a pivotal role in biochemical redox processes.
HEH is a safe and easy-to-handle reagent for the reduction
of organic functional groups, and can be synthesized in a
simple way.9 We have found the reducibility of HEH was
Abstract: The synthesis of 2H-1,4-benzoxazine derivatives from
1,2-epoxy-3-(2-nitroaryloxy)propanes in the presence of Hantzsch
1,4-dihydropyridine (HEH) and Pd/C as a catalyst was achieved.
The nitro group was reduced before the epoxide functionality, lead-
ing to attack of the amino group on the epoxide moiety in a 6-exo- dramatically enhanced in the presence of Pd/C and even
electron-rich olefins can be reduced to saturated alkanes.10
Herein, we report the selective reduction of a nitro group
fashion. By introducing a methyl group at the 1-position, the 7-endo
ring-closed product could also be formed.
Key words: Hantzsch 1,4-dihydropyridine ester, organic reductant,
hydrogen transfer, benzoxazine derivatives, domino reaction
in the presence of an epoxy group with HEH and Pd/C, to
obtain hydroxy-substituted 2,3-dihydro-1,4-benzoxazine
derivatives in one pot. In addition, this approach repre-
sents the first application of this coenzyme NAD(P)H
The 2H-1,4-benzoxazine1 scaffold is a structural subunit model compound in the synthesis of oxazinic compounds.
in many naturally occurring compounds. For example,
At the outset, we realized that 1,2-epoxy-3-phenoxypro-
various glycosides bearing a 2-hydroxy-2H-1,4-benzoxa-
pane (2a) could be reduced to the corresponding alcohol
zine skeleton have been found in gramineous plants such
using HEH catalyzed by Pd/C (Scheme 1). At the same
as maize, wheat, and rice, and they have been suggested
time, the same reductive reagents could also be used to re-
to act as plant resistance factors against microbial diseases
duce nitrobenzene (1a) to afford the corresponding
and insects.2 Derivatives of 2H-1,4-benzoxazine have
anilines.11
shown interesting pharmaceutical properties, including
potassium channel modulators,3 antihypertensive agents,4
NO2
H
H
NH2
or antirheumatic agents.5 Hydroxy-substituted 1,4-benz-
oxazine is one of the most important intermediates for the
construction of complex 1, 4-benzoxazine derivatives be-
cause the hydroxy group can be easily converted into the
corresponding tosylate or amino compounds.6
EtO2C
Me
CO2Et
Me
Pd/C, EtOH
reflux
+ HEH
N
H
1a
1b
HEH
OH
O
Synthesis of hydroxy-substituted 1,4-benzoxazines was
accomplished through the intermolecular ring-opening of
epoxides with arylsulfonamides followed by cyclization
of the corresponding hydroxysulfonamides,7 or through
the tandem reduction–oxirane ring-opening of substituted
2-nitrophenoxymethyloxiranes.8 Obviously, the latter
procedure is more advantageous because the reductive cy-
clization proceeded in a very simple and efficient way.
However, there are still some limitations with the method.
For instance, the need for metallic reducing agents and
acidic reaction media restricts its use in further applica-
tions. In particular, the regioselectivity of the intramolec-
ular ring-opening of epoxides was not known. It seems
that the development of an efficient procedure that can ad-
dress this issue could be of practical use.
O
O
Pd/C, EtOH
reflux
+
HEH
2a
2b
Scheme 1 Reactions of nitrobenzene and 1,2-epoxy-3-phenoxypro-
pane with HEH and Pd/C
Interestingly, when we carried out the reduction in the
presence of nitrobenzene (1a) and 1,2-epoxy-3-phenoxy-
propane (2a) together, aniline (1b) was obtained as the
major product (Scheme 2). Most of the 1,2-epoxy-3-phe-
noxypropane was recovered unchanged. In addition, some
epoxide ring-opening product 2c,12 formed from attack by
the amino group on the epoxide ring, was found; the prod-
uct ratio of 1b/2b/2c was 73:6:21 (isolated yield).
Hantzsch 1,4-dihydropyridine (HEH) has been widely
used as a model compound for the coenzyme NAD(P)H,
With these results in mind, we decided to use 1,2-epoxy-
3-(2-nitrophenoxy)propane (3a) as the starting material,
with the expectation that reduction of the nitro group
would occur first, to form the corresponding amino com-
pound, which would be followed by ring-opening of the
epoxide by the amino group in a domino process. Indeed,
SYNLETT 2009, No. 20, pp 3283–3286
x
x
.x
x
.2
0
0
9
Advanced online publication: 18.11.2009
DOI: 10.1055/s-0029-1218380; Art ID: W11909ST
© Georg Thieme Verlag Stuttgart · New York

3284
Q.-y. Meng et al.
LETTER
Table 1 Effect of Different Organic Reductive Reagents on the
Synthesis of 2,3-Dihydro-3-hydroxymethyl-1,4-benzoxazinea
NO2
O
O
Pd/C, EtOH
reflux
+
+
+
HEH
Entry
Hydrogen donor
Yield (%)b
2a
1a
H
H
EtO2C
Me
CO2Et
Me
NH2
OH
O
OH
O
1
84
H
N
N
H
+
Ph
H
1b
2b
2c
EtO2C
Me
CO2Et
Me
2
3
N.Rc
Scheme 2 Reaction of nitrobenzene and 1,2-epoxy-3-phenoxypro-
pane in the presence of HEH and Pd/C in one pot
N
H
CONH2
O
O
N.Rc,d
O
Pd/C, EtOH
reflux
OH
N
+
HEH
N
H
NO2
(BNAH)
Me
CH2Ph
3a
4a
N
4
5
44d
30
Scheme 3 Synthesis of 2,3-dihydro-3-hydroxymethyl[1,4]benz-
oxazine
Ph
(PDMBI)
N
Me
it was gratifying to observe that 2,3-dihydro-3-hydroxy-
methyl-1,4-benzoxazine (4a) was formed (Scheme 3).
We then carried out the reduction using other NAD(P)H
model compounds (Table 1). When a phenyl group was
attached to the 4-position of HEH (entry 2), no reaction
took place. BNAH also failed to serve as a reductive re-
agent (entry 3). On the other hand, PDMBI (entry 4) and
1,4-cyclohexadiene (entry 5) both gave the target product
in moderate and poor yields, respectively. Obviously,
HEH furnished the desired heterocycle in highest yield
and was thus used for further study.
a Reaction conditions: 3a (0.5 mmol), hydrogen donor (1.85 mmol),
10% Pd/C (5% wt of hydrogen donor), reflux, 12 h under N2.
b Isolated yields.
c No reaction.
d Hydrogen donor (3.7 mmol).
the epoxide led only to the 6-exo product (4k). It seemed
that the 6-exo mode of attack was more facile because of
the hindrance of the two methyl groups (entry 9). Howev-
er, 7-endo attack could be achieved by controlling the po-
sition of the substituent. Hence, 1,2-epoxy-2-methyl-3-(2-
nitrophenoxy)propane (3j) afforded the seven-membered
heterocycle 4l in good yield (entry 10). A good result was
also achieved when cyclohexene oxide was used. Howev-
er, cyclopentene oxide gave the corresponding oxazine in
a low yield (entry 12).
Further studies were performed to determine the substrate
scope of this reaction (Table 2).13 To our delight, sub-
strates with electron-donating substituents at the 4-posi-
tion of the aromatic ring could also undergo the reaction,
to give the corresponding product in a high yield (entries
2–4). However, the presence of electron-withdrawing
substituents at the 4-position of the substrate had a nega-
tive effect on the formation of the cyclization product. In
this case, the nitro group was reduced to the amino group,
but the epoxide moiety was also reduced at the same time.
It seemed that the presence of the ethoxycarbonyl group
retarded the rate of reduction of the nitro group to such an
extent that the ring-opening of the epoxide then proceeded
with a comparable rate to give the alcohol compound that
could not be cyclized (entry 5). Nevertheless, the reaction
proceeded satisfactorily when the 5-position of the aro-
matic ring was substituted by a methyl group (entry 6), or
when the ethoxycarbonyl group was substituted at the 3-
position (entry 7).
In summary, we have successfully developed a domino
reaction in which benzoxazine derivatives were obtained
from 1,2-epoxy-3-(2-nitroaryloxy)propanes using the or-
ganic reductive reagent HEH in the presence of Pd/C. Se-
lective reduction of the nitro group was observed,
followed by a 6-exo attack on the epoxide ring. However,
the 7-endo mode of attack could be obtained through sub-
stitution at the epoxide position. This novel catalytic sys-
tem not only provides an efficient method with which to
prepare various benzoxazine derivatives, but may also in-
spire other uses for the combination of HEH and Pd/C in
reductive chemistry.
To further evaluate the scope of this reaction, a variety of
substituted epoxides were employed. To our surprise,
when 2,3-epoxy-1-(2-nitrophenoxy)butane (3h) was used
as substrate, both 6-exo (4i) and 7-endo (4j) products were
obtained (entry 8). Adding an additional methyl group to
Supporting Information for this article is available online at
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Synlett 2009, No. 20, 3283–3286 © Thieme Stuttgart · New York

LETTER
Hydroxy-Substituted 2H-1,4-Benzoxazine Derivatives
3285
Table 2 The Synthesis of 2,3-Dihydro-1,4-benzoxazine Derivativesa
Entry
Substrate
Product
Yield (%)b
84
O
O
O
1
OH
N
H
NO2
4a
3a
O
O
O
2
3
4
5
87
83
90
59
OH
OH
OH
Me
N
H
Me
NO2
4b
3b
O
O
O
t-Bu
N
H
t-Bu
NO2
4c
3c
O
O
O
MeO
N
H
MeO
NO2
4d
3d
O
O
O
OH
EtO2C
N
H
EtO2C
NO2
3e
4e
OH
O
22
EtO2C
NH2
4f
O
Me
O
Me
O
6
7
8
80
74
33
57c
86
OH
N
H
NO2
4g
3f
EtO2C
O
O
EtO2C
O
OH
N
NO2
O
H
3g
3h
4h
4i
O
O
OH
N
H
NO2
O
OH
N
H
4j
O
O
O
OH
9
N
H
NO2
3i
4k
Synlett 2009, No. 20, 3283–3286 © Thieme Stuttgart · New York

3286
Q.-y. Meng et al.
LETTER
Table 2 The Synthesis of 2,3-Dihydro-1,4-benzoxazine Derivativesa (continued)
Entry
10
Substrate
Product
Yield (%)b
O
O
OH
O
86
N
H
NO2
O
4l
3j
O
11
12
92c
52c
N
H
O
NO2
OH
4m
4n
3k
3l
O
O
N
H
O
NO2
OH
a Reaction conditions: 3a (0.5 mmol), HEH (1.85 mmol), 10% Pd/C (5% wt of HEH), reflux, EtOH (30 mL), 12 h under N2.
b Isolated yield.
c The relative stereostructure of compounds was determined by NOSEY NMR spectrum.
(6) Zhou, D. H.; Harrison, B. L.; Shah, U.; Andree, T. H.;
Acknowledgment
Hornby, G. A.; Scerni, R.; Schechter, L. E.; Smith, D. L.;
Sullivan, K. M.; Mewshaw, R. E. Bioorg. Med. Chem. Lett.
2006, 16, 1338.
We thank the National Natural Science Foundation of China (Grant
No. 20702023 and 20621091), the 111 Project and Program for
New Century Excellent Talents in University (NCET-06-0906) and
the Special Fund for Doctoral Program from the Ministry of Educa-
(7) Albanese, D.; Landini, D.; Lupi, V.; Penso, M. Ind. Eng.
Chem. Res. 2003, 42, 680.
(8) Jiao, P.-F.; Zhao, B.-X.; Wang, W.-W.; He, Q.-X.; Wan,
tion of China (Grant No. 20070730040) for financial support.
M.-S.; Shin, D.-S.; Miao, J.-Y. Bioorg. Med. Chem. Lett.
2006, 16, 2862.
(9) Zolfigol, M. A.; Safaiee, M. Synlett 2004, 827.
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