Dihydrobenzoxazines and Tetrahydroquinoxalines by a Tandem Reduction-Reductive Amination Reaction

Article abstract of DOI:10.1002/jhet.5570400611

A tandem reduction-reductive amination reaction has been applied to the synthesis of 3,4-dihydro-2H-1,4-benzoxazines and 1-acetyl-1,2,3,4-tetrahydroquinoxalines. The nitroketones required for the benzoxazine ring closures were prepared by (A) alkylation of the anion derived from 2-nitrophenol with an allylic halide or (B) nucleophilic aromatic substitution of an allylic alkoxide on 2-fluoro-1-nitrobenzene followed by ozonolysis. Precursors for the quinoxalines were prepared by alkylation of the anion of 2-nitroacetanilide with an allylic halide followed by ozonolysis. Catalytic hydrogenation of the nitroketones using 5% palladium-on-carbon in methanol then gave the target heterocycles by a reduction-reductive amination sequence. The N-methyl derivatives for both ring systems were easily prepared by adding 5-10 equivalents of aqueous formaldehyde prior to the reduction. The dihydrobenzoxazines were isolated in high yield following purification by chromatographic methods; tetrahydroquinoxalines were isolated in a similar manner and possessed differentiated functionality on the two nitrogens.

Full text of DOI:10.1002/jhet.5570400611

Nov-Dec 2003
1031
Dihydrobenzoxazines and Tetrahydroquinoxalines by a
Tandem Reduction-Reductive Amination Reaction
Richard A. Bunce,* Derrick M. Herron [1] and Lu Y. Hale
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
Received August 6, 2003
Dedicated to the Memory of our Colleague and Friend Professor Elizabeth M. Holt
A tandem reduction-reductive amination reaction has been applied to the synthesis of 3,4-dihydro-2H-1,4-
benzoxazines and 1-acetyl-1,2,3,4-tetrahydroquinoxalines. The nitroketones required for the benzoxazine
ring closures were prepared by (A) alkylation of the anion derived from 2-nitrophenol with an allylic halide
or (B) nucleophilic aromatic substitution of an allylic alkoxide on 2-fluoro-1-nitrobenzene followed by
ozonolysis. Precursors for the quinoxalines were prepared by alkylation of the anion of 2-nitroacetanilide
with an allylic halide followed by ozonolysis. Catalytic hydrogenation of the nitroketones using 5% palla-
dium-on-carbon in methanol then gave the target heterocycles by a reduction-reductive amination sequence.
The N-methyl derivatives for both ring systems were easily prepared by adding 5-10 equivalents of aqueous
formaldehyde prior to the reduction. The dihydrobenzoxazines were isolated in high yield following purifi-
cation by chromatographic methods; tetrahydroquinoxalines were isolated in a similar manner and possessed
differentiated functionality on the two nitrogens.
J. Heterocyclic Chem., 40, 1031 (2003).
Introduction.
Quinoxaline precursors were available using a strategy
similar to Method A (Scheme 1). Deprotonation of
2-nitroacetanilide (7) and treatment with allylic halides
2a-d gave the N-alkylated amides 8a-d in 86-94% yields.
The tandem reduction-reductive amination sequence has
recently proven useful and selective in the formation of a
variety of heterocyclic systems [2]. As part of our effort to
develop efficient new methods for the preparation of bio-
logically active molecules, we wished to extend this
methodology to the synthesis of 3,4-dihydro-2H-1,4-ben-
zoxazines [3] and 1,2,3,4-tetrahydroquinoxalines [4].
Several known dihydrobenzoxazines have been shown to
possess significant activity as antihypertensives [5], as
serotonin receptor antagonists [6], and as neuroprotective
agents [7]. Tetrahydroquinoxalines are known to possess
diuretic properties [8] and have, more recently, been
explored as cell adhesion agents [9]. Access to new deriv-
atives of these structures would likely result in additional
compounds with valuable biological activities. We
describe here a short, high-yield synthesis of (±)-3-alkyl-
3,4-dihydro-2H-1,4-benzoxazines and (±)-1-acetyl-3-
alkyl-1,2,3,4-tetrahydroquinoxalines as well as their
N-methyl derivatives.
Results and Discussion.
The benzoxazine precursors were prepared in two steps
via allyl nitrophenyl ethers 5 that were available by two
routes (Scheme 1). Method A, used for the preparation of
5a and 5b, involved deprotonation of 2-nitrophenol (1) and
alkylation with allylic halides 2 (a: R = CH ; b: R =
3
t-C H ) [10]. Method B provided 5c and 5d by nucle-
4
9
ophilic aromatic substitution of 2-fluoro-1-nitrobenzene
(3) with allylic alkoxides 4 (c: R = n-C H ; d: R = C H )
4
9
6 5
[11a]. Both of these procedures proceeded in 90-96%
yields. In the second step, ozonolysis of 5a-d followed by
reductive workup and treatment with acid gave the α-(2-
nitrophenoxy)ketones 6a-d in greater than 93% yields.

1032
R. A. Bunce, D. M. Herron and L. Y. Hale
Vol. 40
Ozonolysis of 8a-d and workup as above then delivered
the ketones 9a-d in 88-94% yields. The use of the anilide
rather than the aniline permitted the use of 1:1 stoichio-
metric conditions [12] which gave higher yields and
cleaner products. Additionally, the presence of the
N-acetyl group precluded amine oxidation in the ozonoly-
sis step and provided differentiated functionality on the
nitrogens of the final product.
Precursors 11 and 12 for the unsubstituted parent ring
systems 21 and 24-26 were synthesized by alkylation of 1
and 7 with allyl bromide (10) using Method A (Scheme 2).
Compounds 14 and 15, for the generation of angular-fused
tricyclic structures 27 and 29, were similarly prepared
using 1-(bromomethyl)-1-cyclopentene (13).
The results of our cyclization studies are summarized in
Scheme 3. Hydrogenation of ketones 6 and 9 initiated a
sequence involving (1) reduction of the nitro group to the
hydroxylamine or amino group, (2) condensation of this
nitrogen intermediate with the side chain carbonyl, and (3)
reduction of the resulting imine to give the target heterocy-
cles 16 and 18. All of the reactions proceeded cleanly to
give products that were either crystalline or easily purified
by column chromatography.
Reactions to prepare the N-methyl derivatives 17 or 19
were performed by adding 5-10 equivalents of formalde-
hyde (37% in water) to the solution of 6 or 9 before hydro-
genation. These transformations proceeded as above with
an additional reductive amination as part of the reaction
sequence. All substrates provided good yields except for
the tert-butyl cases, 6b and 9b, where mixtures of meth-
ylated and unmethylated cyclization products were
obtained. Increasing the amount of formaldehyde to 35
equivalents in the reaction of 9b did not significantly
increase the yield of 19b, but instead resulted in competi-
tive formation of the uncyclized N,N-dimethylaniline
derivative 20.
procedure, while more direct, was complicated by the
presence of formaldehyde generated as the second ozonol-
ysis product. To minimize reaction between the initial het-
erocyclic product and formaldehyde, 3 equivalents of
nitrobenzene were added prior to the hydrogenation. This
nitrobenzene was converted to aniline during the cycliza-
tion and served to scavenge much of the formaldehyde.
Following removal of the excess aniline and N-methylani-
line under high vacuum, chromatographic purification
gave 21 and 24 in 66% and 64% yields, respectively.
Finally, the N-methyl derivatives 25 and 26 were prepared
from 11 and 12 using the standard protocol (Scheme 4).
Conversion of 14 and 15 to angular-fused heterocycles
was also accomplished without isolating the intermediate
aldehydes (Scheme 4). Following double bond cleavage,
hydrogenation initiated a reduction-double reductive ami-
nation sequence to produce 27 and 29 in 80% and 68%
yields, respectively. In each case, 10-15% of a second
product (i.e. 28 or 30), arising from oxidation of the alde-
hyde (during the ozonolysis) and a single reductive ring
closure, was also produced [13]. Overall, however, this
two-step sequence provided a very efficient synthesis for
the angular-fused systems.
The aldehyde products from the ozonolysis of 11 and 12
were too unstable to isolate, and thus, the reductive ring
closure was carried out on the crude ozonolysate. This

Nov-Dec 2003
Dihydrobenzoxazines and Tetrahydroquinoxalines
1033
EXPERIMENTAL
The catalytic reduction of the nitroketones was carried
out as described previously in methanol using 4 atmos-
pheres of hydrogen and 20 weight percent (relative to sub-
strate) of 5% palladium-on-carbon [2]. The presence of
multiple heteroatoms in the substrates did not noticeably
decrease catalyst efficiency. Competing reduction of the
phenyl ketones in substrates 6d and 9d was not observed.
Finally, in the quinoxaline synthesis, it was noted that
cyclization always occurred with the side chain ketone; the
less reactive amide did not participate in the reaction
despite being closer to the nucleophilic aniline nitrogen.
The fact that the N-methylated heterocycles were
formed so cleanly suggests that the reaction chronology
involves six-membered ring closure prior to N-methyla-
tion. If this was not the case, a higher proportion of the
uncyclized N,N-dimethylaniline would have been pro-
duced since formaldehyde is highly reactive in reductive
aminations. Only upon addition of more than 20 equiva-
lents of formaldehyde did measurable amounts of the
dimethylaniline form. These observations suggest that
intramolecular reductive amination occurs significantly
faster than the intermolecular reaction in the current reduc-
tive cyclizations [14].
In summary, we have developed a simple and efficient
synthesis of several new 3,4-dihydro-2H-1,4-benzoxazine
and 1-acetyl-1,2,3,4-tetrahydroquinoxaline derivatives.
Each synthesis requires three steps and affords the target
heterocycle in high overall yield. The products are easily
purified by crystallization or chromatography. The reaction
can be extended to the synthesis of the N-methyl deriva-
tives by adding 5-10 equivalents of formaldehyde to the
reaction prior to the final hydrogenation step. Presumably,
other simple alkyl groups could be added using different
aldehydes. We are continuing to explore this cyclization
strategy for the synthesis of other nitrogen heterocycles.
N,N-Dimethylformamide, from a freshly opened bottle, was
dried over 4 Å molecular sieves under nitrogen and transferred
by syringe into reactions where it was used. All reactions were
run under dry nitrogen in oven-dried glassware. Reactions were
monitored by thin layer chromatography on silica gel GF plates.
Preparative separations were performed using flash column chro-
matography [15] on silica gel (grade 62, 60-200 mesh) mixed
with ultraviolet-active phosphor (Sorbent Technologies UV-5) or
thin layer chromatography on 20-cm x 20-cm silica gel GF
plates; band elution was monitored using a hand-held ultraviolet
lamp. Melting points were uncorrected. Infrared spectra were
run as thin films on sodium chloride disks and were referenced to
1
13
polystyrene. H and C Nuclear magnetic resonance spectra
were measured in deuteriochloroform at 300 MHz and 75 MHz,
respectively, and were referenced to internal tetramethylsilane;
coupling constants (J) have been given in hertz. High-resolution
mass spectra (electron impact/direct probe) were obtained at 70
electron volts.
Caution: Though we never experienced any problems, addi-
tion of 5% palladium-on-carbon to methanol can cause fires.
This operation should be performed under a nitrogen atmosphere.
Representative Procedure for the Preparation of Allyl
Nitroaromatic Ethers. Method A— Alkylation of 2-Nitrophenol:
2-[(2-Methyl-2-propenyl)oxy]-1-nitrobenzene (5a).
To a suspension of 0.26 g (11.0 mmoles) of oil-free sodium
hydride in 15 mL of N,N-dimethylformamide was added 1.39 g
(10.0 mmoles) of 1 in 15 mL of N,N-dimethylformamide. The
reaction mixture was stirred at room temperature for 30 minutes
before a solution of 1.49 g (11.0 mmoles) of 2a in 5 mL of N,N-
dimethylformamide was added. The reaction mixture was stirred
at room temperature for 6 hours, then added to 50 mL of satu-
rated ammonium chloride and extracted with ether (three times).
The combined ether extracts were washed with 1 M sodium
hydroxide (until the aqueous washes remained colorless) and sat-
urated sodium chloride, then dried (magnesium sulfate) and con-
centrated under vacuum. The crude product was purified by flash

1034
R. A. Bunce, D. M. Herron and L. Y. Hale
Vol. 40
13
chromatography on a 50 cm x 2 cm silica gel column using 5%
ether in hexanes to give 1.74 g (9.04 mmoles, 90%) of 5a. The
spectral data matched those reported previously [10].
(d, 1H, J = 14.8), 1.90 (s, 3H), 1.76 (s, 3H); C nmr: 169.7,
δ
140.4, 133.9, 131.9, 129.4, 129.0, 125.3, 115.0, 112.7, 54.9, 22.6,
20.4; hrms: m/z Calcd. for C
234.1006.
H N O : 234.1005; Found:
12 14 2 3
2-{[2-(tert-Butyl)-2-propenyl]oxy}-1-nitrobenzene (5b).
Anal. Calcd. for C
H N O : C, 61.54; H, 5.98; N, 11.97.
12 14 2 3
This compound (Method A; 2.58 g, 11.0 mmoles, 88%) was
Found: C, 61.82; H, 6.07; N, 12.08.
-1
1
isolated as a light yellow oil; ir: 1642, 1524, 1351 cm ; H nmr:
δ 7.84 (dd, 1H, J = 8.1, 1.8), 7.51 (ddd, 1H, J = 8.5, 7.4, 1.8), 7.07
(dd, 1H, J = 8.5, 1.2), 7.02 (ddd, 1H, J = 8.1, 7.4, 1.2), 5.26 (m,
N-[2-(tert-Butyl)-2-propenyl]-N-(2-nitrophenyl)acetamide (8b).
This compound (2.44 g, 8.84 mmoles, 88%) was isolated as a
13
-1
1
1H), 5.14 (m, 1H), 4.71 (t, 2H, J = 1.2), 1.17 (s, 9H); C nmr: δ
light yellow oil; ir: 1675, 1648, 1531, 1358 cm ; H nmr (major
152.1, 150.5, 139.9, 134.0, 125.6, 120.2, 114.5, 110.5, 69.6, 34.8,
rotamer): δ 7.97 (m, 1H), 7.64 (m, 1H), 7.55 (m, 1H), 7.44 (m,
29.4 (3); hrms: m/z Calcd. for C
235.1207.
H NO : 235.1208; Found:
1H), 5.24 (d, 1H, J = 16.1), 5.03 (s, 1H), 4.81 (s, 1H), 3.57 (d, 1H,
13 17 3
13
J = 16.1), 1.90 (s, 3H), 0.98 (s, 9H); C nmr (major rotamer):
δ
Anal. Calcd. for C
H NO : C, 66.38; H, 7.23; N, 5.96.
169.9, 151.4, 142.1, 136.4, 133.7, 131.9, 127.6, 125.5, 109.3,
13 17 3
Found: C, 66.57; H, 7.29; N, 5.91.
50.1, 35.3, 28.6 (3), 22.5; hrms: m/z Calcd. for C
276.1476; Found: 276.1473.
H N O :
15 20 2 3
Method B—Nucleophilic Aromatic Substitution of 2-Fluoro-1-
nitrobenzene by Allylic Alkoxides: 2-[(2-Butyl-2-propenyl)-
oxy]-1-nitrobenzene (5c).
Anal. Calcd. for C
H N O : C, 65.21; H, 7.25; N, 10.14.
15 20 2 3
Found: C, 65.43; H, 7.32; N, 9.97.
N-(2-Butyl-2-propenyl)-N-(2-nitrophenyl)acetamide (8c).
This compound (1.77 g, 6.36 mmoles, 84%) was isolated as a
The alkoxide from 0.85 g (7.50 mmoles) of 2-butyl-2-propen-
1-ol [16] was reacted with 0.71 g (5.00 mmoles) of 3 according to
our published procedure [11a]. The crude product was chro-
matographed on a 50 cm x 2 cm silica gel column using 5% ether
in hexanes to afford 1.13 g (4.81 mmoles, 96%) of 5c as a light
yellow oil. The spectral data matched those reported previously
[11a].
-1
1
light yellow oil; ir: 1674, 1654, 1531, 1354 cm ; H nmr (major
rotamer): 7.99 (dd, 1H, J = 8.1, 1.6), 7.66 (td, 1H, J = 7.7, 1.6),
δ
7.55 (td, 1H, J = 8.1, 1.6), 7.31 (dd, 1H, J = 7.7, 1.6), 4.80 (s, 1H),
4.68 (d, 1H, J = 14.7), 4.61 (s, 1H), 3.69 (d, 1H, J = 14.7), 2.01 (t,
2H, J = 7.5), 1.89 (s, 3H), 1.41 (m, 2H), 1.32 (sextet, 2H, J = 7.1),
13
0.90 (t, 3H, J = 7.1); C nmr (major rotamer): 169.9, 144.5,
δ
2-[(2-Phenyl-2-propenyl)oxy]-1-nitrobenzene (5d).
136.0, 133.9, 132.0, 129.4, 128.7, 125.2, 113.8, 53.6, 33.3, 29.8,
This compound (Method B; 1.17 g, 4.59 mmoles, 92%) was
isolated as a light yellow solid, mp 53-54° (ether-hexanes) [17].
The spectral data matched those reported previously [11a].
22.6, 22.4, 13.9; hrms: m/z Calcd. for C
Found: 276.1475.
H N O : 276.1474;
15 20 2 3
Anal. Calcd. for C
H N O : C, 65.22; H, 7.25; N, 10.14.
15 20 2 3
Found: C, 65.49; H, 7.34; N, 9.91.
2-(2-Propenyloxy)-1-nitrobenzene (11).
This compound (Method A; 1.61 g, 9.02 mmoles, 90%) was
isolated as a light yellow oil. The spectral data matched those
reported previously [18].
N-(2-Nitrophenyl)-N-(2-phenyl-2-propenyl)acetamide (8d).
This compound (3.08 g, 10.4 mmoles, 94%) was isolated as a
-1
1
viscous yellow oil [21]; ir: 1672, 1635, 1530, 1351 cm ;
H
2-(1-Cyclopentenylmethoxy)-1-nitrobenzene (14).
nmr (major rotamer): 7.96 (m, 1H), 7.47 (m, 2H), 7,40-7.28
δ
(complex, 5H), 6.74 (m, 1H), 5.65 (dd, 1H, J = 15.0, 1.0), 5.34 (s,
This compound (Method A; 1.02 g, 4.66 mmoles, 93%) was
isolated as a light yellow oil [19]. The spectral data matched
those reported previously [20].
13
1H), 4.98 (s, 1H), 3.92 (d, 1H, J = 15.0), 1.81 (s, 3H); C nmr:
δ
169.9, 143.0, 137.9, 135.0, 133.5, 132.6, 129.4, 128.7, 128.5,
128.1, 126.2, 125.4, 117.5, 50.9, 22.7; hrms: m/z Calcd. for
Representative Procedure for the Alkylation of 2-Nitro-
acetanilide: N-(2-Methyl-2-propenyl)-N-(2-nitrophenyl)-
acetamide (8a).
C
H N O : 296.1161; Found: 296.1161.
17 16 2 3
Anal. Calcd. for C
H N O : C, 68.92; H, 5.41; N, 9.46.
17 16 2 3
Found: C, 69.11; H, 5.50; N, 9.32.
To a suspension of 0.26 g (11.0 mmoles) of oil-free sodium
hydride in 15 mL of N,N-dimethylformamide was added 1.80 g
(10.0 mmoles) of 7 in 15 mL of N,N-dimethylformamide. The
reaction mixture was stirred for 30 minutes before a solution of
1.49 g (11.0 mmoles) of 2a in 5 mL of N,N-dimethylformamide
was added. The reaction mixture was stirred at room temperature
for 8 hours, then added to 50 mL of saturated ammonium chlo-
ride and extracted with ether (three times). The combined ether
layers were washed with saturated sodium chloride, dried (mag-
nesium sulfate) and concentrated under vacuum. The crude prod-
uct was purified by flash chromatography on a 50 cm x 2.5 cm
silica gel column eluted with increasing concentrations of ether
in hexanes. The major band eluted with 30% ether in hexanes to
afford 2.01 g (8.59 mmoles, 86%) of 8a as a yellow oil; ir: 3078,
N-(2-Nitrophenyl)-N-(2-propenyl)acetamide (12).
This compound (1.87 g, 8.51 mmoles, 85%) was isolated as a
light yellow oil. The spectral data matched those reported previ-
ously [20].
N-(1-Cyclopentenylmethyl)-N-(2-nitrophenyl)acetamide (15).
This compound (3.38 g, 13.0 mmoles, 87%) was isolated as a
light yellow solid, mp 77-78° (ether-petroleum ether); ir: 1671,
-1
1
1527, 1353 cm ; H nmr (major rotamer): 7.96 (dd, 1H, J =
δ
8.1, 1.5), 7.68 (td, 1H, J = 7.7, 1.5), 7.56 (td, 1H, J = 8.1, 1.5),
7.31 (dd, 1H, J = 7.7, 1.5), 5.31 (m, 1H), 4.54 (d, 1H, J = 14.7),
4.02 (d, 1H, J = 14.7), 2.36 (m, 1H), 2.24 (m, 3H), 1.83 (m, 2H),
13
1.89 (s, 3H);
C nmr (major rotamer): 169.7, 147.4, 139.0,
δ
-1
1
1674, 1528, 1351 cm ; H nmr: δ 7.99 (dd, 1H, J = 8.1, 1.6),
7.67 (td, 1H, J = 7.8, 1.6), 7.56 (td, 1H, J = 7.8, 1.5), 7.32 (dd, 1H,
J = 7.8, 1.5), 4.81(s, 1H), 4.63 (d, 1H, J = 14.8), 4.60 (s, 1H), 3.67
136.12, 133.9, 131.8, 130.2, 129.3, 125.4, 49.1, 33.7, 32.3, 23.5,
22.6; hrms: m/z Calcd. for C
260.1160.
H N O : 260.1161; Found:
14 16 2 3

Nov-Dec 2003
Dihydrobenzoxazines and Tetrahydroquinoxalines
1035
Anal. Calcd. for C
Found: C, 64.97; H, 6.22; N, 9.23.
H
N O : C, 64.61; H, 6.15; N, 9.29.
134.3, 134.0, 133.9, 128.9, 128.2, 125.9, 121.5, 115.2, 72.0;
hrms: m/z Calcd. for C H NO : 257.0688; Found: 257.0685.
14 16
2 3
14 11
4
Anal. Calcd. for C
Found: C, 65.52; H, 4.36; N, 5.31.
H NO : C, 65.37; H, 4.28; N, 5.45.
14 11 4
Representative Procedure for the Ozonolysis of Allyl Ethers and
Anilides: (2-Nitrophenoxy)-2-propanone (6a).
N-(2-Nitrophenyl)-N-(2-oxopropyl)acetamide (9a).
A solution of 1.00 g (5.18 mmoles) of 5a in 150 mL of
methanol at –78° was treated with ozone until thin layer chro-
matography indicated complete consumption of starting material.
[Note: For the less soluble substrate 5d, 150 mL of a 6:1 mixture
of methanol and dichloromethane was used as the solvent.]
Excess ozone was purged on a stream of dry nitrogen, and 5.08 g
(6.00 mL, 84.9 mmoles) of dimethyl sulfide was added. The
reaction mixture was warmed to room temperature, stirred for 4
hours and the solvent was removed under vacuum. The resulting
yellow oil was dissolved in acetone, and the solution was stirred
at room temperature for 12 hours with 5.00 g of wet amberlyst-
15. The solvent was removed under vacuum and the product was
dissolved in ether and dried (magnesium sulfate). Concentration
afforded a yellow solid that was recrystallized from ether-petro-
leum ether to give 0.94 g (4.82 mmoles, 93%) of 6a as a light yel-
This compound (1.14 g, 4.83 mmoles, 94%) was isolated as a
light yellow solid, mp 107-109° (ether-petroleum ether); ir:
-1
1
1728, 1670, 1528, 1352 cm ; H nmr: δ 7.96 (dd, 1H, J = 8.1,
1.6), 7.82 (dd, 1H, J = 8.0, 1.5), 7.69 (td, 1H, J = 8.0, 1.6), 7.57
(td, 1H, J = 8.1, 1.5), 5.10 (d, 1H, J = 18.0), 3.75 (d, 1H, J = 18.0),
13
2.18 (s, 3H), 1.85 (s, 3H); C nmr: δ 202.1, 169.9, 147.1, 136.0,
134.2, 132.6, 129.8, 125.1, 58.7, 27.1, 21.7; hrms: m/z Calcd. for
C H N O : 236.0728; Found: 236.0728.
11 12
2 4
Anal. Calcd. for C H N O : C, 55.93; H, 5.08; N, 11.86.
11 12
2 4
Found: C, 56.17; H, 5.18; N, 11.75.
N-(3,3-Dimethyl-2-oxobutyl)-N-(2-nitrophenyl)acetamide (9b).
This compound (1.83 g, 6.58 mmoles, 87%) was obtained as a
light yellow solid, mp 115-117° (ether-petroleum ether); ir:
-1
1
-1
1
low solid, mp 61-62°; ir: 1725, 1521, 1348 cm ; H nmr: δ 7.91
(dd, 1H, J = 8.1, 1.5), 7.55 (ddd, 1H, J = 8.4, 7.5, 1.8), 7.12 (ddd,
1H, J = 8.1, 7.5, 1.2), 6.95 (dd, 1H, J = 8.4, 0.9), 4.63, (s, 2H),
1718, 1674, 1531, 1351 cm ; H nmr: δ 7.95 (dd, 1H, J = 8.0,
1.6), 7.88 (dd, 1H, J = 8.0, 1.5), 7.67 (td, 1H, J = 7.6, 1.6), 7.56
(td, 1H, J = 7.6, 1.5), 5.31 (d, 1H, J = 17.8), 3.77 (d, 1H, J = 17.8),
13
13
2.38 (s, 3H); C nmr: δ 204.9, 164.8, 151.0, 134.3, 126.1, 121.6,
1.85 (s, 3H), 1.20 (s, 9H); C nmr: δ 209.7, 169.7, 147.3, 136.3,
114.5, 73.7, 27.0; hrms: m/z Calcd. for C H NO : 195.0531.
134.2, 132.7, 129.6, 125.0, 54.4, 43.4, 26.3 (3), 21.8; hrms: m/z
9
9
4
Found: 195.0529.
Anal. Calcd. for C H NO : C, 55.38; H, 4.62; N, 7.18. Found:
Calcd. for C H N O : 278.1267; Found: 278.1269.
14 18 2 4
Anal. Calcd. for C
H N O : C, 60.43; H, 6.47; N, 10.07.
14 18 2 4
9
9
4
C, 55.54; H, 4.69; N, 7.09.
Found: C, 60.71; H, 6.55; N, 9.93.
3,3-Dimethyl-1-(2-nitrophenoxy)-2-butanone (6b).
N-(2-Nitrophenyl)-N-(2-oxohexyl)acetamide (9c).
This compound (1.66 g, 7.00 mmoles, 98%) was isolated as a
light yellow solid, mp 54-55° (ether-petroleum ether); ir: 1722,
1524, 1354 cm ; H nmr: δ 7.86 (dd, 1H, J = 8.1, 1.8), 7.48 (ddd,
This compound (0.96 g, 4.06 mmoles, 92%) was isolated as a
light yellow oil that solidified on standing at 0°. The solid was
triturated with petroleum ether at 0° and filtered, mp 43-45°; ir:
-1
1
-1
1
1H, J = 8.5, 7.5, 1.8), 7.07 (ddd, 1H, J = 8.1, 7.5, 1.2), 6.84 (dd,
1728, 1674, 1531, 1351 cm ; H nmr: δ 7.95 (dd, 1H, J = 8.1,
1.6), 7.85 (dd, 1H, J = 8.0, 1.5), 7.68 (td, 1H, J = 8.0, 1.6), 5.09
(d, 1H, J = 17.8), 3.70 (d, 1H, J = 17.8), 2.52 (ddd, 1H, J = 16.8,
8.2, 6.6), 2.37 (ddd, 1H, J = 16.8, 8.2, 6.6), 1.85 (s, 3H), 1.58 (m,
13
1H, J = 8.5, 1.2), 5.04 (s, 2H), 1.26 (s, 9H); C nmr: δ 208.2,
151.6, 140.4, 133.9, 125.8, 121.6, 115.1, 70.3, 43.2, 26.2 (3);
hrms: m/z Calcd. for C H NO : 237.1001; Found: 237.1000.
12 15
4
13
Anal. Calcd. for C
H
NO : C, 60.76; H, 6.32; N, 5.91.
2H), 1.32 (sextet, 2H, J = 7.4), 0.90 (t, 3H, J = 7.4); C nmr: δ
12 15
4
204.9, 169.8, 147.3, 136.2, 134.2, 132.7, 129.7, 125.1, 58.2, 39.7,
Found: 61.01; H, 6.39; N, 5.82.
25.5, 22.2, 21.7, 13.8; hrms: m/z Calcd. for C
278.1267; Found: 278.1266.
H N O :
14 18 2 4
1-(2-Nitrophenoxy)-2-hexanone (6c).
This compound (1.73 g, 7.30 mmoles, 95%) was isolated as a
light yellow oil that solidified on standing at 0°. The solid was
triturated with petroleum ether at 0° and filtered, mp 37-38°; ir:
Anal. Calcd. for C
Found: C, 60.70; H, 6.52; N, 9.96.
H N O : C, 60.43; H, 6.47; N, 10.07.
14 18 2 4
N-(2-Nitrophenyl)-N-(2-oxo-2-phenylethyl)acetamide (9d).
-1
1
1724, 1524, 1351 cm ; H nmr: δ 7.90 (dd, 1H, J = 8.2, 1.8),
7.54 (td, 1H, J = 7.5, 1.8), 7.11 (td, 1H, J = 7.5, 1.1), 6.95 (dd, 1H,
J = 8.2, 1.1), 4.65, (s, 2H), 2.70 (t, 2H, J = 7.2), 1.62 (quintet, 2H,
This compound (2.08 g, 6.98 mmoles, 88%) was isolated as a
yellow solid, mp 88-90° (ether-petroleum ether); ir: 1699, 1669
13
-1
1
J = 7.2), 1.37 (sextet, 2H, J = 7.2), 0.92 (t, 3H, J = 7.2); C nmr:
cm ; H nmr: δ 8.00-7.94 (complex, 4H), 7.70 (td, 1H, J = 7.5,
δ 206.6, 151.1, 140.1, 134.3, 126.0, 121.5, 114.5, 73.5, 38.9,
1.6), 7.56 (m, 2H), 7.47 (m, 2H), 5.84 (d, 1H, J = 17.8), 4.35 (d,
13
25.0, 22.2, 13.8; hrms: m/z Calcd. for C
Found: 237.0998.
H
NO : 237.1001;
1H, J = 17.8), 1.92 (s, 3H);
C nmr: δ 193.4, 169.9, 147.2,
12 15
4
136.2, 134.8, 134.2, 133.7, 132.9, 129.8, 128.7, 128.0, 125.2,
Anal. Calcd. for C
Found: C, 60.88; H, 6.37; N, 5.86.
H
NO : C, 60.76; H, 6.33; N, 5.91.
55.7, 21.9; hrms: m/z Calcd. for C
Found: 298.0953.
H N O : 298.0954;
12 15
4
16 14 2 4
Anal. Calcd. for C
Found: C, 64.71; H, 4.82; N, 9.23.
H N O : C, 64.42; H, 4.70; N, 9.40.
16 14 2 4
2-(2-Nitrophenoxy)-1-phenyl-1-ethanone (6d).
This compound (1.47 g, 5.72 mmoles, 98%) was isolated as a
light yellow solid, mp 113-114° (ether-petroleum ether); ir:
Representative Procedure for the Tandem Reduction-Reductive
Amination: 3-Methyl-3,4-dihydro-2H-1,4-benzoxazine (16a).
-1
1
1699, 1689, 1521, 1351 cm ; H nmr: δ 8.02-7.98 (complex,
2H), 7.87 (dd, 1H, J = 8.1, 1.6), 7.64 (tt, 1H, J = 7.4, 1.3), 7.55-
7.44 (complex, 3H), 7.07 (ddd, 1H, J = 8.1, 7.4, 1.2), 6.97 (dd,
To a solution of 0.50 g (2.56 mmoles) of 6a in 150 mL of
methanol in a stainless steel reaction vessel was added 125 mg of
5% palladium-on-carbon and the mixture was shaken under 4
13
1H, J = 8.5, 1.0), 5.45 (s, 2H); C nmr: δ 193.3, 151.5, 140.3,

1036
R. A. Bunce, D. M. Herron and L. Y. Hale
Vol. 40
atmospheres of hydrogen at 25° for 6 hours. [Note: For the less
soluble substrate 6d, 150 mL of a 6:1 mixture of methanol and
tetrahydrofuran was used as the solvent.] The solvent was
removed, the residue was diluted with ether, and the suspension
was filtered through a pad of Celite topped with a layer of anhy-
drous magnesium sulfate to separate the catalyst. Concentration
under vacuum gave a yellow oil that was purified by preparative
thin layer chromatography using 25% ether in hexanes to give
0.35 g (2.35 mmoles, 92%) of 16a as a light yellow oil; ir: 3372
114.1, 47.9, 44.8, 22.6, 19.9; hrms: m/z Calcd. for C H N O:
11 14 2
190.1107; Found: 190.1104.
Anal. Calcd. for C H N O: C, 69.47; H, 7.37; N, 14.74.
11 14
2
Found: C, 69.59; H, 7.41; N, 14.62.
1-Acetyl-3-(tert-butyl)-1,2,3,4-tetrahydroquinoxaline (18b).
This compound (0.39 g, 1.91 mmoles, 84%) was isolated as a
light yellow solid, mp 98-99° (ether-hexanes); ir: 3365, 1644
-1
1
cm ; H nmr: δ 6.99 (m, 2H), 6.63 (m, 2H), 4.62 (br d, 1H, J =
-1
1
cm ; H nmr: δ 6.77 (m, 2H), 6.65 (td, 1H, J = 7.7, 1.8), 6.57
(dd, 1H, J = 7.7, 1.8), 4.18 (dd, 1H, J = 10.3, 2.8), 3.77 (dd, 1H,
J = 10.3, 8.0), 3.65 (br s, 1H), 3.53 (m, 1H), 1.17 (d, 3H, J = 6.3);
10.6), 4.09 (br s, 1H) 3.14 (dd, 1H, J = 4.0, 1.3), 2.91 (br t, 1H,
13
J = 11.5), 2.25 (s, 3H), 0.99 (s, 9H); C nmr: δ 169.7, 138.8,
126.2, 125.0, 124.0, 115.9, 114.2, 61.0, 40.2, 33.4, 25.8 (3),
13
C nmr: δ 143.6, 133.4, 121.3, 118.7, 116.4, 115.3, 70.7, 45.1,
22.7; hrms: m/z Calcd. for C
232.1574.
H N O: 232.1576; Found:
14 20 2
17.6; hrms: m/z Calcd. for C H NO: 149.0841; Found:
9
11
149.0839.
Anal. Calcd. for C
H N O: C, 72.41; H, 8.62; N, 12.07.
14 20 2
Anal. Calcd. for C H NO: C, 73.62; H, 7.98; N, 8.59. Found:
Found: C, 72.62; H, 8.69; N, 11.96.
9
11
C, 73.44; H, 7.95; N, 8.70.
1-Acetyl-3-butyl-1,2,3,4-tetrahydroquinoxaline (18c).
This compound (0.45 g, 1.94 mmoles, 90%) was isolated as a
3-(tert-Butyl)-3,4-dihydro-2H-1,4-benzoxazine (16b).
This compound (0.44 g, 2.30 mmoles, 97%) was isolated as a
-1
1
white solid, mp 68-69° (ether-hexanes); ir: 3350, 1643 cm ;
H
-1
white solid, mp 68-69° (ether-petroleum ether); ir: 3392 cm ;
nmr: δ 6.98 (t, 2H, J = 7.1), 6.63 (t, 1H, J = 7.5), 6.58 (d, 1H, J =
8.2), 4.34 (br d, 1H, J = 11.2), 4.03 (br s, 1H), 3.42 (m, 1H), 3.10
(br t, 1H, J = 10.3), 2.28 (s, 3H), 1.55-1.32 (complex, 6H), 0.93
1
H nmr: δ 6.75 (m, 2H), 6.61 (m, 2H), 4.27 (dd, 1H, J = 10.6,
2.9), 3.93 (dd, 1H, J = 10.6, 8.3), 3.77 (br s, 1H), 3.10 (dd, 1H, J =
13
13
8.3, 2.9), 0.99 (s, 9H);
C nmr: δ 143.8, 134.3, 121.3, 118.2,
(t, 3H, J = 6.9); C nmr: δ 169.4, 138.0, 126.2, 124.5, 124.2,
116.2, 115.1, 66.5, 58.0, 32.6, 26.0 (3); hrms: m/z Calcd. for
NO: 191.1310; Found: 191.1310.
115.8, 114.0, 52.3, 43.3, 34.1, 27.6, 22.6 (2), 13.9; hrms: m/z
C
H
12 17
Calcd. for C
H N O: 232.1576; Found: 232.1575.
14 20 2
Anal. Calcd. for C
H NO: C, 75.39; H, 8.90; N, 7.33.
12 17
Anal. Calcd. for C
H N O: C, 72.41; H, 8.62; N, 12.07.
14 20 2
Found: C, 75.17; H, 8.83; N, 7.33.
Found: C, 72.58; H, 8.67; N, 11.97.
3-Butyl-3,4-dihydro-2H-1,4-benzoxazine (16c).
This compound (0.50 g, 2.61 mmoles, 97%) was isolated as a
1-Acetyl-3-phenyl-1,2,3,4-tetrahydroquinoxaline (18d).
This compound (0.39 g, 1.54 mmoles, 92%) was isolated as a
white foam; ir: 3339, 1648 cm ; H nmr: δ 7.36-7.30 (complex,
5H), 7.03 (br t, 2H, J = 7.9), 6.70 (br t, 1H, J = 7.4), 6.68 (br d,
-1
1
light yellow oil; ir: 3372 cm ; H nmr: δ 6.76 (m, 2H), 6.64 (td,
1H, J = 7.6, 1.8), 6.58 (dd, 1H, J = 7.8, 1.8), 4.21 (dd, 1H, J =
10.4, 2.8), 3.84 (dd, 1H, J = 10.4, 7.7), 3.73 (br s, 1H), 3.37 (m,
-1
1
1H, J = 7.8), 4.57 (m, 2H), 4.37 (br s, 1H), 3.25 (br t, 1H, J =
13
1H), 1.53-1.34 (complex, 6H), 0.93 (t, 3H, J = 6.9); C nmr: δ
13
10.2), 2.23 (br s, 3H);
C nmr: δ 169.5, 140.7, 137.9, 128.7,
143.9, 133.4, 121.3, 118.6, 116.4, 115.3, 69.5, 49.6, 32.0, 27.6,
128.1, 126.5, 126.3, 124.4, 116.3, 114.2, 56.4, 45.5, 22.4; hrms:
m/z Calcd. for C N O: 252.1263; Found: 252.1260.
22.7, 14.0; hrms: m/z Calcd. for C
191.1311.
H NO: 191.1310; Found:
12 17
H
16 16
2
Anal. Calcd. for C
H N O: C, 76.69; H, 6.77; N, 10.53.
16 16 2
Anal. Calcd. for C
H NO: C, 75.39; H, 8.90; N, 7.33.
12 17
Found: C, 76.41; H, 6.68; N, 10.69.
Found: C, 75.11; H, 8.87; N, 7.39.
Representative Procedure for the Tandem Reduction-Double
Reductive Amination to Prepare N-Methyl Heterocycles: 3,4-
Dimethyl-3,4-dihydro-2H-1,4-benzoxazine (17a).
3-Phenyl-3,4-dihydro-2H-1,4-benzoxazine (16d).
This compound (0.21 g, 1.00 mmole, 76%) was isolated as a
colorless oil that solidified on standing at 0°. The white solid was
triturated with petroleum ether at 0° and filtered, mp 38-40°; ir:
A solution of 0.50 g (2.56 mmoles) of 6a in 150 mL of
methanol was ozonized as described above. The crude
ozonolysate was transferred to a stainless steel reaction vessel,
1.05 g of 37% aqueous formaldehyde (0.39 g, 13.0 mmoles of
formaldehyde) and 125 mg of 5% palladium-on-carbon were
added and the mixture was shaken under 4 atmospheres of
hydrogen at 25° for 6 hours. Workup as described above and
purification by preparative thin layer chromatography using
10% ether in hexanes gave 0.38 g (2.33 mmoles, 91%) of 17a
-1
1
3358 cm ; H nmr: δ 7.40-7.32 (complex, 5H), 6.86-6.80 (com-
plex, 2H), 6.78-6.64 (complex, 2H), 4.48 (dd, 1H, J = 8.6, 2.9),
4.27 (dd, 1H, J = 10.6, 2.9), 3.98 (superimposed br s, 1H and dd,
13
1H, J = 10.6, 8.6); C nmr: δ 143.5, 139.1, 133.8, 128.8, 128.3,
127.1, 121.4, 118.9, 116.5, 115.3, 70.9, 54.1; hrms: m/z Calcd.
for C
H NO: 211.0997; Found: 211.0994.
14 13
Anal. Calcd. for C
H NO: C, 79.62; H, 6.16; N, 6.64.
14 13
Found: C, 79.43; H, 6.13; N, 6.68.
-1
1
as a light yellow oil; ir: 1602, 1505, 739 cm ; H nmr: δ 6.85
(td, 1H, J = 7.7, 1.5), 6.77 (dd, 1H, J = 8.1, 1.6), 6.62 (m, 2H),
4.20 (dd, 1H, J = 10.5, 2.5), 4.00 (dd, 1H, J = 10.5, 3.4), 3.35
1-Acetyl-3-methyl-1,2,3,4-tetrahydroquinoxaline (18a).
This compound (0.40 g, 2.09 mmoles, 82%) was isolated as an
off-white solid, mp 172-174° (ether-hexanes); ir: 3345, 1640
13
(m, 1H), 2.86 (s, 3H), 1.18 (d, 3H, J = 6.5); C nmr: δ 143.6,
135.5, 121.7, 117.3, 115.6, 112.2, 69.3, 52.1, 36.1, 14.1; hrms:
-1
1
cm ; H nmr: δ 6.98 (t, 2H, J = 7.7), 6.63 (t, 1H, J = 7.7), 6.57
m/z Calcd. for C
H NO: 163.0997; Found: 163.0995.
(dd, 1H, J = 8.2, 1.3), 4.44 (br d, 1H, J = 11.3), 3.94 (br s, 1H),
10 13
Anal. Calcd. for C
H NO: C, 73.62; H, 7.98; N, 8.59.
10 13
3.58 (m, 1H), 2.91 (br t, 1H, J = 8.9), 2.28 (s, 3H), 1.21 (d, 3H,
13
Found: C, 73.77; H, 8.01; N, 8.55.
J = 6.3);
C nmr: δ 169.6, 157.1, 156.9, 126.2, 124.4, 116.0,

Nov-Dec 2003
Dihydrobenzoxazines and Tetrahydroquinoxalines
1037
3-(tert-Butyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (17b).
gave 0.19 g (0.77 mmoles, 41%) of 19b as a light yellow oil; ir:
1652 cm ; H nmr: δ 7.09 (apparent td, 1H, J = 8.5, 1.5), 6.94 (br
d, 1H, J = 6.3), 6.71 (dd, 1H, J = 8.5, 1.3), 6.64 (ddd, 1H, J = 7.8,
-1
1
When the above procedure was run on 0.57 g (2.38 mmoles) of
5b, 0.41 g of a mixture of the N-methylated (17b, 39%) and
unmethylated (16b, 50%) products was isolated. Separation by
preparative thin layer chromatography using 10% ether in hex-
anes gave 0.18 g (0.88 mmoles, 37%) of 17b as a light yellow oil;
7.4, 1.3), 5.07 (br d, 1H, J = 12.5), 3.12 (s, 3H), 3.05 (dd, 1H, J =
13
4.4, 1.6), 2.74 (br d, 1H, J = 10.9), 2.30 (s, 3H), 0.93 (s, 9H);
C
nmr: δ 169.0, 139.7, 125.7, 124.3, 122.8, 114.9, 111.9, 69.2, 44.1,
37.7 (2), 27.8 (3), 23.5; hrms: m/z Calcd. for C
246.1733; Found: 246.1730.
H N O:
15 22 2
-1
1
ir: 1606, 1507, 739 cm ; H nmr: δ 6.86 (ddd, 1H, J = 8.1, 7.2,
1.5), 6.76 (dd, 1H, J = 7.8, 1.5), 6.66 (dd, 1H, J = 8.1, 1.5), 6.57
(ddd, 1H, J = 7.8, 7.2, 1.5), 4.47 (dd, 1H, J = 11.2, 1.0), 3.76 (dd,
1H, J = 11.2, 3.4), 3.09 (s, 3H), 2.80 (dd, 1H, J = 3.4, 1.0), 0.98 (s,
Anal. Calcd. for C
H N O: C, 73.17; H, 8.94; N, 11.38.
15 22 2
Found: C, 73.24; H, 8.99; N, 11.23.
13
N-[2-(Dimethylamino)phenyl]-N-(3,3-dimethyl-2-oxobutyl)-
acetamide (20).
9H); C nmr: δ 143.3, 136.3, 121.6, 116.1, 115.7, 112.0, 67.4,
63.1, 43.0, 37.8, 27.8 (3); hrms: m/z Calcd. for C
205.1467; Found: 205.1465.
H NO:
13 19
This compound (0.17 g, 0.60 mmoles, 32%) was isolated as a
Anal. Calcd. for C
H NO: C, 76.10; H, 9.27; N, 6.83.
-1
1
13 19
light yellow oil; ir: 1721, 1662 cm ; H nmr: 7.39 (dd, 1H,
δ
Found: C, 75.90; H, 9.19; N, 6.91.
J = 7.8, 1.6), 7.24 (ddd, 1H, J = 8.2, 7.4, 1.3), 6.97 (m, 2H), 5.21
(d, 1H, J = 17.5), 4.01 (d, 1H, J = 17.5), 2.74 (s, 6H), 1.99 (s,
3-Butyl-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (17c).
This compound (0.38 g, 1.85 mmoles, 85%) was isolated as a
13
3H), 1.16 (s, 9H); C nmr: 209.6, 171.1, 148.6, 135.1, 130.9,
δ
128.6, 122.0, 118.8, 51.9, 43.3, 42.9 (2), 26.3 (3), 21.8; hrms:
-1
1
light yellow oil; ir: 1606, 1503, 738 cm ; H nmr: δ 6.85 (ddd, 1H,
J = 7.8, 7.4, 1.6), 6.77 (dm, 1H, J = 7.5), 6.60 (td, 1H, J = 7.5, 1.6),
6.58 (d, 1H, J = 7.5), 4.19 (dd, 1H, J = 10.6, 2.2), 4.07 (dd, 1H, J =
10.6, 2.6), 3.14 (ddt, 1H, J = 8.1, 5.9, 2.4), 2.91 (s, 3H), 1.58 (m,
m/z Calcd. for C
H N O : 276.1838; Found: 276.1839.
16 24 2 2
Anal. Calcd. for C
H N O : C, 69.57; H, 8.70; N, 10.14.
16 24 2 2
Found: C, 69.81; H, 8.81; N, 9.97.
13
2H), 1.34 (m, 4H), 0.91 (t, 3H, J = 6.8); C nmr: δ 143.5, 135.3,
1-Acetyl-3-butyl-4-methyl-1,2,3,4-tetrahydroquinoxaline (19c).
This compound (0.39 g, 1.58 mmoles, 80%) was isolated as a
121.7, 116.8, 115.6, 111.8, 66.1, 57.5, 37.3, 28.4, 28.2, 22.8, 14.1;
hrms: m/z Calcd. for C H NO: 205.1467; Found: 205.1466.
13 19
-1
1
light yellow oil; ir: 1654 cm ; H nmr: 7.08 (apparent td, 1H,
δ
Anal. Calcd. for C
H NO: C, 76.10; H, 9.27; N, 6.83.
13 19
J = 7.7, 1.5), 6.96 (br d, 1H, J = 7.7), 6.62 (m, 2H), 4.64 (br d, 1H,
J = 12.5), 3.33 (m, 1H), 3.06 (br d, 1H, J = 12.5), 2.95 (s, 3H),
Found: C, 76.19; H, 9.29; N, 6.81.
2.29 (s, 3H), 1.57 (m, 1H), 1.50-1.20 (complex, 5H), 0.91 (t, 3H,
4-Methyl-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (17d).
13
J = 6.9);
C nmr: 169.3, 139.3, 126.4, 125.0, 123.5, 114.7,
δ
This compound (0.21 g, 0.93 mmoles, 72%) was isolated as a
white solid, mp 96-98° (ether-petroleum ether); ir: 1606, 1500,
110.5, 60.3, 41.0, 36.9, 31.6, 28.1, 22.7, 22.3, 13.9; hrms: m/z
Calcd. for C N O: 246.1733; Found: 246.1733.
H
15 22
2
-1
1
739, 699 cm ; H nmr: δ 7.38-7.23 (complex, 5H), 6.92 (ddd,
1H, J = 8.0, 7.2, 1.5), 6.82 (dd, 1H, J = 7.9, 1.6), 6.79 (dd, 1H, J =
8.0, 1.5), 6.68 (ddd, 1H, J = 7.8, 7.2, 1.6), 4.32-4.10 (ABX, 3H:
Anal. Calcd. for C
H N O: C, 73.17; H, 8.94; N, 11.38.
15 22 2
Found: C, 73.46; H, 9.01; N, 11.26.
ν
= 4.30, ν = 4.26, ν = 4.13; J = 3.1, J
= 6.3, J
=
1-Acetyl-4-methyl-3-phenyl-1,2,3,4-tetrahydroquinoxaline
(19d).
A
B
X
AB
AX
BX
13
10.8), 2.77 (s, 3H); C nmr: δ 144.2, 139.1, 136.9, 128.7, 127.9,
127.3, 122.0, 117.6, 116.0, 112.4, 70.1, 61.5, 36.4; hrms: m/z
Calcd. for C
This compound (0.34 g, 1.28 mmoles, 76%) was isolated as a
H NO: 225.1154; Found: 225.1152.
15 15
-1
1
light yellow oil; ir: 1658 cm ; H nmr: 7.39-7.31 (complex,
δ
Anal. Calcd. for C
H NO: C, 80.00; H, 6.67; N, 6.22.
15 15
3H), 7.12-7.04 (complex, 3H), 7.00 (d, 1H, J = 7.8), 6.77 (dd, 1H,
J = 8.1, 1.0), 6.70 (t, 1H, J = 7.5), 4.57 (m, 1H), 4.13 (dd, 1H, J =
Found: C, 79.74; H, 6.59; N, 6.30.
1-Acetyl-3,4-dimethyl-1,2,3,4-tetrahydroquinoxaline (19a).
This compound (0.33 g, 1.62 mmoles, 85%) was isolated as a
light yellow oil; ir: 1655 cm ; H nmr: δ 7.08 (apparent td, 1H,
J = 8.2, 1.3), 6.97 (br, d, 1H, J = 6.8), 6.64 (m, 2H), 4.35 (br d,
12.6, 5.1), 3.86 (dd, 1H, J = 12.6, 3.7), 2.87 (s, 3H), 2.13 (s, 3H);
13
C nmr: 169.1, 140.3 (2), 128.5, 127.8, 126.7, 126.5, 125.9,
δ
124.0, 115.5, 111.0, 63.8, 46.2, 36.7, 22.0; hrms: m/z Calcd. for
-1
1
C
H N O: 266.1420: Found: 266.1419.
17 18 2
Anal. Calcd. for C
H N O: C, 76.69; H, 6.77; N, 10.53.
17 18 2
1H, J = 12.5), 3.55 (m, 1H), 3.31 (br d, 1H, J = 11.8), 2.93 (s, 3H),
13
Found: C, 76.41; H, 6.68; N, 10.69.
2.29 (s, 3H), 1.14 (d, 3H, J = 6.3);
C nmr: δ 169.5, 139.6,
126.5, 125.3, 123.7, 115.0, 110.8, 55.2, 44.3, 35.9, 22.3, 17.8;
Representative Procedure for the Preparation of Heterocycles
without Isolation of the Ozonolysis Product: 3,4-Dihydro-2H-
1,4-benzoxazine (21).
hrms: m/z Calcd. for C
H N O: 204.1263; Found: 204.1261.
12 16 2
Anal. Calcd. for C
H N O: C, 70.59; H, 7.84; N, 13.73.
12 16 2
Found: C, 70.37; H, 7.76; N, 13.84.
A solution of 0.50 g (2.79 mmoles) of 11 in 150 mL of
methanol was ozonized as described for the preparation of 6a.
The crude ozonolysate was transferred to a stainless steel reac-
tion vessel, 3 equivalents of nitrobenzene and 200 mg of 5% pal-
ladium-on-carbon were added and the mixture was shaken under
4 atmospheres of hydrogen at 25° for 6 hours. Following workup
as described above, most of the aniline and N-methylaniline was
removed under high vacuum. Final purification by preparative
thin layer chromatography using 25% ether in hexanes afforded
three bands. Band 1 gave a mixture of N-methylaniline (22) and
1-Acetyl-3-(tert-butyl)-4-methyl-1,2,3,4-tetrahydroquinoxaline
(19b).
When the above procedure was run on 0.52 g (1.87 mmoles) of
9b, 0.36 g of a mixture of the N-methylated (19b, 35%) and
unmethylated (18b, 44%) products was isolated. When the amount
of formaldehyde was increased to 35 equivalents, 0.39 g of a mix-
ture of 19b (44%) and the unclosed N,N-dimethylaniline derivative
20 (35%) was obtained. Separation of this second mixture by
preparative thin layer chromatography using 10% ether in hexanes

1038
R. A. Bunce, D. M. Herron and L. Y. Hale
Vol. 40
a small amount of 4-methyl-3,4-dihydro-2H-1,4-benzoxazine
(25); band 2 gave aniline (23); and band 3 gave 0.25 g (1.85
mmoles, 66%) of 21 as a light yellow oil. The spectral data for
21 matched those reported previously [3e].
Methyl 4-(3,4-Dihydro-2H-1,4-benzoxazin-3-yl)butanoate (28).
This compound (0.08 g, 0.35 mmoles, 13%) was isolated as a
light tan solid that was triturated with petroleum ether and fil-
-1
1
tered, mp 84-85°; ir: 3372, 1735 cm ; H nmr: δ 6.80-6.73
(complex, 2H), 6.68-6.57 (complex, 2H), 4.20 (dd, 1H, J = 10.5,
2.7), 3.86 (dd, 1H, J = 10.6, 7.2), 3.80 (br s, 1H), 3.68 (s, 3H),
1-Acetyl-1,2,3,4-tetrahydroquinoxaline (24).
This compound (0.26 g, 1.48 mmoles, 64%) was isolated as a
light tan oil using preparative thin layer chromatography eluted
3.39 (qd, 1H, J = 7.2, 2.7), 2.38 (t, 2H, J = 7.2), 1.76 (m, 2H),
13
1.53 (m, 2H);
C nmr: δ 173.7, 143.7, 133.1, 121.4, 118.7,
-1
1
with 50% ether in hexanes; band 3; ir: 3351, 1640 cm ;
H
116.5, 115.5, 69.1, 51.6, 49.2, 33.7, 31.7, 20.8; hrms: m/z Calcd.
for C NO : 235.1208; Found: 235.1206.
nmr: δ 6.98 (br t, 2H, J = 7.5), 6.64 (td, 1H, J = 7.7, 1.3), 6.59 (dd,
H
13 17
3
1H, J = 8.2, 1.3), 4.20 (br s, 1H), 3.84 (br t, 2H, J = 4.7), 3.43 (m,
Anal. Calcd. for C
H NO : C, 66.38; H, 7.23; N, 5.96.
13 17 3
13
2H), 2.27 (s, 3H); C nmr: δ 169.4, 137.9, 129.6, 126.2, 124.5,
Found: C, 66.54; H, 7.16; N, 6.02.
116.0, 114.3, 42.4, 38.4, 22.6; hrms: m/z Calcd. for C
H N O:
10 12 2
Ozonolysis and Cyclization of 15.
176.0950; Found: 176.0950.
Anal. Calcd. for C
Found: C, 68.32; H, 6.85; N, 15.87.
H N O: C, 68.18; H, 6.81; N, 15.91.
10 12 2
Ozonolysis as described for the preparation of 6a and reduc-
tive ring closure as described for the preparation of 16a were per-
formed on 0.60 g (2.31 mmoles) of 15. Preparative thin layer
chromatography using 10% ether in hexanes gave two major
bands. Band 1 (fastest moving) contained product 29; band 2
contained 30.
4-Methyl-3,4-dihydro-2H-1,4-benzoxazine (25).
A solution of 0.50 g (2.79 mmoles) of 11 in 150 mL of
methanol was ozonized as described for the preparation of 6a.
The crude ozonolysate was transferred to a stainless steel reac-
tion vessel, 1.15 g of 37% aqueous formaldehyde (0.43 g, 14.2
mmol of formaldehyde) and 150 mg of 5% palladium-on carbon
were added and the mixture was hydrogenated as described for
the preparation of 17a. Purification by preparative thin layer
chromatography using 10% ether in hexanes gave 0.29 g (1.95
mmoles, 70%) of 25 as a light yellow oil. The spectral data
matched those reported previously [3g].
5-Acetyl-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline
(29).
This compound (0.36 g, 1.57 mmoles, 68%) was isolated as a
-1
1
light yellow oil; ir: 1653 cm ; H nmr: δ 7.05 (td, 1H, J = 7.8,
1.5), 6.96 (br d, 1H, J = 5.6), 6.84 (dd, 1H, J = 8.4,1.2), 6.67 (td,
1H, J = 7.8, 1.2), 4.31 (br d, 1H, J = 10.2), 3.94 (dm, 1H, J =
12.8), 3.31 (dd, 1H, J = 10.4, 7.8), 3.08 (m, 1H), 2.80 (td, 1H, J =
14.7, 2.4), 2.23 (s, 3H), 1.87 (dm, 1H, J = 12.4), 1.75 (dm, 2H, J
1-Acetyl-4-methyl-1,2,3,4-tetrahydroquinoxaline (26).
13
= 12.4), 1.64-1.38 (complex, 2H), 1.30 (m, 1H);
C nmr: δ
This compound (0.42 g, 2.21 mmoles, 65%) was isolated as a
169.4, 140.7, 127.3, 126.5, 124.5, 116.5, 113.0, 57.1, 47.7, 46.1,
-1
1
light yellow oil; ir: 1651 cm ; H nmr: δ 7.09 (apparent td, 1H,
J = 7.9, 1.3), 6.98 (br d, 1H, J = 4.0), 6.67 (dd, 1H, J = 8.2, 1.2),
6.65 (td, 1H, J = 7.5, 1.2), 3.89 (t, 2H, J = 5.4), 3.37 (t, 2H, J =
30.1, 25.4, 23.8, 22.5; hrms: m/z Calcd. for C
230.1420; Found: 230.1420.
H N O:
14 15 2
Anal. Calcd. for C
H N O: C, 73.04; H, 6.52; N, 12.17.
14 15 2
13
5.4), 2.95 (s, 3H), 2.23 (s, 3H); C nmr: δ 169.4, 140.0, 126.7,
Found: C, 72.92; H, 6.62; N, 12.31.
125.6, 124.2, 115.4, 111.0, 50.7, 39.3, 37.8, 22.5; hrms: m/z
Methyl 4-(1-Acetyl-1,2,3,4-tetrahydroquinoxalin-3-yl)butanoate
(30).
Calcd. for C H N O: 190.1107; Found: 190.1106.
11 14
2
Anal. Calcd. for C H N O: C, 69.47; H, 7.37; N, 14.74.
11 14
2
Found: C, 69.55; H, 7.41; N, 14.66.
This compound (0.07 g, 0.25 mmoles, 11%) was isolated as a
-1
1
yellow oil; ir: 3354, 1735, 1644 cm ; H nmr: δ 6.98 (t, 1H, J =
7.2), 6.66 (t, 1H, J = 7.7), 6.59 (dd, 1H, J = 8.2, 1.3), 4.18 (br d,
2H, J = 8.5), 3.68 (s, 3H), 3.45 (m, 1H), 3.29 (dd, 1H, J = 12.2,
8.5), 2.37 (t, 2H, J = 7.2), 2.28 (s, 3H), 1.77 (m, 2H), 1.53 (m,
Ozonolysis and Cyclization of 14.
Ozonolysis as described for the preparation of 6a and reduc-
tive ring closure as described for the preparation of 16a were per-
formed on 0.60 g (2.74 mmoles) of 14. Preparative thin layer
chromatography using 10% ether in hexanes gave two major
bands. Band 1 (fastest moving) contained product 27; band 2
contained 28.
13
2H); C nmr: δ 173.7, 169.5, 137.9, 126.3, 124.5, 124.2, 116.1,
114.2, 52.0, 51.6, 43.0, 33.9, 33.6, 22.5, 20.7; hrms: m/z Calcd.
for C
H N O : 276.1474; Found: 276.1473.
15 20 2 3
Anal. Calcd. for C
H N O : C, 65.21; H, 7.25; N, 10.14.
15 20 2 3
Found: C, 65.37; H, 7.22; N, 10.01.
6,6a,7,8,9,10-Hexahydropyrido[2,1-c][1,4]benzoxazine (27).
Acknowledgement.
This compound (0.41 g, 2.19 mmoles, 80%) was isolated as a
white solid that was triturated with petroleum ether and filtered,
We wish to thank the Oklahoma Center for the Advancement
of Science and Technology (HR01-015) for support of this
research. D. M. H. wishes to thank Oklahoma State University
for a Wentz Project Scholarship and the Chemistry Department
for a Skinner Scholarship. Funds for the 300 and 400 MHz NMR
spectrometers of the Oklahoma Statewide Shared NMR Facility
were provided by the NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education, the W. M. Keck Foundation, and
Conoco, Inc. Partial support for our mass spectrometers by the
NSF and the Oklahoma Center for the Advancement of Science
and Technology is also appreciated.
-1
1
mp 71-72°; ir: 1602, 1499, 739 cm ; H nmr: δ 6.83 (m, 2H),
6.76 (dm, 1H, J = 8.0), 6.68 (m, 1H), 4.15 (dd, 1H, J = 10.6, 2.8),
3.98 (dd, 1H, J = 10.6, 8.5), 3.82 (dm, 1H, J = 12.0), 2.94 (qt, 1H,
J = 8.5, 2.8), 2.54 (td, 1H, J = 12.2, 3.1), 1.85 (m, 2H), 1.65 (m,
2H), 1.43 (qt, 1H, J = 12.7, 3.4), 1.24 (ddd, 1H, J = 16.0, 12.7,
13
3.4); C nmr: δ 145.1, 136.0, 121.2, 119.0, 116.3, 113.1, 70.0,
53.3, 46.5, 27.2, 25.1, 23.2; hrms: m/z Calcd. for C
H NO:
12 15
189.1154; Found: 189.1155.
Anal. Calcd. for C
H NO: C, 76.19; H, 7.94; N, 7.41.
12 15
Found: C, 75.98; H, 7.99; N, 7.43.

Nov-Dec 2003
Dihydrobenzoxazines and Tetrahydroquinoxalines
1039
REFERENCES AND NOTES
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