Synthesis of 2,3-dihydro-6H-1-oxa-3a-aza-phenalene and its benzo/hetero-fused analog

Article abstract of DOI:10.1002/jhet.680

A simple and efficient method for the synthesis of highly substituted benzo- and hetero-fused analog of 2, 3-dihydro-6H-oxa-3a-aza-phenalene was developed using 2H-1, 4-benzoxazine and α-oxoketene dithio-acetals.

Full text of DOI:10.1002/jhet.680

September 2011
Synthesis of 2,3-Dihydro-6H-1-oxa-3a-aza-phenalene and Its
Benzo/Hetero-Fused Analog
1187
Pushpak Mizar,a,b* Mecadon Hormi,b Mantu Rajbangshi,b
and Bekington Myrbohb*
aNagaland University, Hqrs:Lumami, Mokokchung 798601, Nagaland, India
bNorth Eastern Hill University, Mawlai-Mawkynroh, Shillong 793022, Meghalaya, India
*E-mail: pushpakmizar@gmail.com (or) bmyrboh@nehu.ac.in
Received March 6, 2010
DOI 10.1002/jhet.680
Published online 5 May 2011 in Wiley Online Library (wileyonlinelibrary.com).
A simple and efficient method for the synthesis of highly substituted benzo- and hetero-fused analog
of 2, 3-dihydro-6H-oxa-3a-aza-phenalene was developed using 2H-1, 4-benzoxazine and a-oxoketene
dithio-acetals.
J. Heterocyclic Chem., 48, 1187 (2011).
INTRODUCTION
with benzyl propanoate and subsequent reduction and
cyclization. The other by reaction of benzoxazine and a-
oxoketene dithio-acetal to give the S,N-acetal, which
when reacted with Vilsmeier reagent provides a versatile
route to highly functionalized 2H-1,4-benzoxazine and
their benzo- and hetero-fused analogs [9–11].
The 2H-1,4-benzoxazine derivatives have been exten-
sively used as precursors for the synthesis of a variety
of biologically active compounds. They have shown to
be long-acting positive inotropes and peripheral vasodi-
lator [1] with potential intracellular calcium activity [2].
Tricyclic analogs with a fused additional ring on the
nitrogen atom of the benzoxazine moiety have been pre-
pared and evaluated for their cardiovascular effects and
RESULTS AND DISCUSSION
´
as potential antihypertensive agents. Recently, Merour
As part of our earlier work aimed at synthesizing ben-
zoxazine derivatives of biological interest,14 we wanted
to develop new and simpler routes for the synthesis of
benzo/hetero-fused analogs. The first step employed was
the N-alkylation of benzoxaxine 1 with 3-bromo-propi-
onic acid benzyl ester in presence of K2CO3 to obtain
3-(6,7-Dialkyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propi-
onic acid benzyl ester 2a–j. 2a–j when subjected to
reduction and subsequent cyclization using trifluoroace-
tic anhydride in dichloromethane at room temperature
yielded the desired products 3a–j (Scheme 1).
The use of a-oxoketene dithio-acetals in the synthesis
of various heterocyclic molecules is well documented in
the literature [12,13]. However, there is no report about
its uses in the synthesis of tricyclic analogs of benzoxa-
zines. We report here a simple procedure for the synthe-
sis of this class of compounds starting from benzoxazine
and a-oxoketene dithio-acetals. Benzoxaxine 1 when
treated with aryl-oxoketene dithioacetal 4 in presence of
n-BuLi in tetrahydofuran (THF) [14] gave the aryl-
and coworkers have used the benzoxazine framework
for the synthesis of number of imidazolinic derivatives,
which showed pronounced cardiovascular effects on
both blood pressure and heart rate either after intraperi-
toneal (ip) or oral (po) administration. Among them,
6-fluoro-2-(4,5-dihydro-1H-imidazol-2-yl)-4-methyl-3,4-
dihydro-2H-1,4-benzoxazine was considered to be a
potential antihypertensive agent [3]. Some tricylic
benzoxazines are synthetic analogs of antibacterial
fluoroquinolones, exemplified by norfloxacin and cipro-
floxacin [4–8]. Although numerous methods for the
synthesis of substituted 2H-1,4-benzoxazine and their
corresponding benzo/hetero-fused derivatives have been
developed, the search for new and efficient synthetic
routes for these classes of compounds continues to
attract a lot of attention.
This work describes two general methods for the syn-
thesis of 2,3-dihydro-6H-1-oxa-3a-aza-phenalene, one
involving the general N-alkylation of the benzoxazines
C
V
2011 HeteroCorporation

1188
P. Mizar, M. Hormi, M. Rajbangshi, and B. Myrboh
Vol 48
Scheme 1. Synthesis of substituted 2,3-dihydro-6H-oxa-3a-aza-
phenalene.
Scheme 2. Synthesis of substituted 2,3-dihydro-6H-oxa-3a-aza-
phenalene.
oxoketene-N,S-2H-1,4 benzoxazinoacetal 5 by displace-
ment of one of the methyl thiol groups of 4 (Scheme 2).
Vilsmeier cyclization of 5a–j afforded the tricyclic ana-
log 6a–j, which on subsequent reduction using Raney-
Ni yielded the final products 7a–j (Table 1).
It was observed that the yields of the products in the
second method (7) varied significantly with the nature
of the substituent. The presence of a methoxy or a
hydroxyl group in the aromatic ring system significantly
increases the yield as compared to an alkyl substituent.
Thus, for obtaining an alkyl substituted product, the pro-
cedure shown in scheme 1 was preferred.
which on further treatment with n-butylamine yielded
the desired products 9a–j. This process provided a sim-
ple and general route for the synthesis of highly func-
tionalized tricyclic analogs of benzoxazine. The reaction
proceeded under mild conditions, when an alkyl amine
is used; however, for aryl amine groups more drastic
conditions were necessary. Here, again the yield varied
with the bulkiness of the substituent (Table 2).
The 2-methylthiol group in 2,3-dihydro-6H-1-oxa-3a-
aza-phenalene 6a was oxidized with m-chloroperbenzoic
acid to afford the corresponding 2-(methylsulfonyl) of
2,3-dihydro-6H-1-oxa-3a-aza-phenalene 8 (Scheme 3),
Interestingly, when 6j was treated with ethyl amine in
presence of Pd(dppf)Cl2 and K2CO3 under microwave,
the reaction did not undergo simple substitution but
Table 1
Substituted 2,3-dihydro-6H-1-oxa-3a-aza-phenalene.
Product(3)
Product (7)
Entry
Yield (%) (3)
Yield (%) (7)
a
b
c
d
e
f
g
h
i
R1¼H, R2¼H
82
84
86
56
49
41
46
40
42
50
R1¼H, R2¼H, R3¼Ph
92
80
86
66
52
73
87
66
86
84
R1¼CH3, R2¼H
R1¼CH3, R2¼CH3
R1¼OCH3, R2¼H
R1¼H, R2¼OCH3
R1¼OCF3, R2¼H
R1¼Cl, R2¼H
R1¼H, R2¼OCH3, R3¼Ph
R1¼OCH3, R2¼H, R3¼Ph
R1¼CH3, R2¼H, R3¼2-BrPh
R1¼CH3, R2¼CH3, R3¼Ph
R1¼CF3, R2¼H, R3¼Ph
R1¼Cl, R2¼H, R3¼Ph
R1¼F, R2¼H
R1¼F, R2¼H, R3¼Ph
R1¼CH2OH, R2¼H
R1¼OCH3, R2¼CH3
R1¼OH, R2¼H, R3¼Ph
R1¼H, R2¼H, R3¼2-BrPh
j
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis of 2,3-Dihydro-6H-1-oxa-3a-aza-phenalene
and Its Benzo/Hetero Fused Analogue
1189
Scheme 3. Synthesis of highly substituted 2,3-dihydro-6H-oxa-3a-aza-
phenalene.
Scheme 4. Microwave assisted synthesis of hetero-fused analog of 2,3-
dihydro-6H-oxa-3a-aza-phenalene.
further coupled to yield the cyclized product 11 (65%)
as shown in Scheme 4.
EXPERIMENTAL
fied by column chromatography using silica gel as the solid
phase and dichloromethane (DCM) as the mobile phase. The
product was further subjected to reduction following the
method described above to yield the final product 3a.
2,3,4,6-Tetrahydro-6H-oxa-3a-aza-phenalene (3a). Yield 82%;
1
oil; IR (film) absence of mNH stretching. H NMR (CDCl3, 400
MHz) d ppm 1.95 (m, 3H), 2.79 (t, 2H, J ¼ 6.5 Hz), 3.08 (t, 2H,
J ¼ 6 Hz), 3.94 (t, 2H, J ¼ 5 Hz), 4.31 (t, 2H, J ¼ 4.5 Hz), 6.48–
6.54 (m, 3H, ArH). 13C NMR (CDCl3, 100 MHz) 30.1, 34.5,
58.7, 60.2 (NCH2), 73.1 (OCH2), 112.8, 116.8, 117.3, 119.5,
140.1, 130.2. MS (ESI) m/z ¼ 176.21. Calcd. for C11H13NO: C,
75.40; H, 7.48; N, 7.99 found: C, 75.42; H, 7.49; N, 8.01.
Carbon, hydrogen, and nitrogen analysis were performed
with a PerkinElmer 2400 series II instrument. IR spectra in
BOMEM DA-8 Fourier transform infrared (FTIR) spectropho-
tometer. The 1H and 13C nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker AMX 400 spectrometer.
Positive-ion and negative-ion electrospray ionization (ESI)
mass spectra were measured on an ion trap analyzer Esquire
3000 (Bruker Daltonics).
2,3,4,6-Tetrahydro-6H-oxa-3a-aza-phenalene (3a). Amine
1 (7 mmol) and dry K2CO3 (15 mmol) were dissolved in dry
dimethylformamide (DMF) (15 mL), then an alkyl halide (8.6
mmol) was added. The reaction mixture was stirred at room
temperature overnight. After completion of the reaction (moni-
tored by thin layer chromatography (TLC)), crushed ice was
added and the product extracted with ethyl acetate. The com-
bined organic extract was dried (Na2SO4), concentrated, and
purified by passing over silica gel and eluting with ethyl ace-
tate/hexane (1:15) to obtain the pure product. The N-substi-
tuted product (3.4 mmol) was then dissolved in ethanol (15
mL) containing Pd/C 10% (0.3 mmol) and the mixture stirred
under 1 atm of H2 for 4 h. It was then filtered under pressure,
and the filtrate evaporated to give brownish oil. [IR (film)
m(cmꢀ1) 3540 (mOH)]. This was dissolved in dichloroethane
and cooled to 0ꢁC. To this solution, trifluoroacetic anhydride
(9 mmol) was added and the mixture stirred overnight at room
temperature. The pH of the reaction mixture was adjusted to
9–10 by addition of 4N NaOH. Extraction with ethyl acetate,
washing of the organic layer with water, drying over Na2SO4,
and evaporation yield the crude product that was further puri-
8-Methyl-2,3,5,6-tetrahydro-4H-1-oxa-3a-aza-phenalene
(3b). Yield 84%; oil IR (film) absence of mNH stretching. 1H
NMR (CDCl3, 400 MHz) d ppm 1.90 (m, 3H), 2.21 (s, 3H),
2.61 (t, 2H, J ¼ 6.2 Hz), 3.25 (t, 2H, J ¼ 6.4 Hz), 3.61 (t, 2H,
J ¼ 5.7 Hz), 4.24 (t, 2H, J ¼ 4.9 Hz), 6.41 (s, 1H, ArH), 6.55
(s, 1H, ArH). 13C NMR (CDCl3, 100 MHz); 20.1, 25.9, 30.6,
53.1, 61.1 (NCH2), 73.6 (OCH2), 112.3, 121.1, 123.2, 127.1,
129.1, 142.5. MS (ESI) m/z ¼ 190.52. Calcd. for C12H15NO:
C, 76.16; H, 7.99; N, 7.40 found: C, 76.21; H, 8.09; N, 7.41.
8,9-Dimethyl-2,3,5,6-tetrahydro-4H-1-oxa-3a-aza-phenalene
(3c). Yield 86%; oil IR (film) absence of mNH stretching. 1H
NMR (CDCl3, 400 MHz) d ppm 1.87 (m, 3H), 2.28 (s, 6H),
2.72 (t, 2H, J ¼ 6.4 Hz), 3.17 (t, 2H, J ¼ 6.7 Hz), 3.60 (t, 2H,
J ¼ 5.3 Hz), 4.21 (t, 2H, J ¼ 4.7 Hz), 6.54 (s, 1H, ArH). 13C
NMR (CDCl3, 100 MHz) 12.4, 19.5, 21.1, 24.5, 46.6, 60.2
(NCH2), 73.9 (OCH2), 112.5, 121.9, 125.2, 127.1, 128.5,
140.1. MS (ESI) m/z ¼ 204.12. Calcd. for C13H17NO: C,
76.81; H, 8.43; N, 6.89 found: C, 76.86; H, 8.48; N, 6.85.
8-Methoxy-2,3,5,6-tetrahydro-4H-1-oxa-3a-aza-phenalene
(3d). Yield 56%; oil. IR (film) absence of mNH stretching. 1H
NMR (CDCl3, 400 MHz) d ppm 1.91 (m, 3H), 2.65 (t, 2H, J
¼ 6.4 Hz), 3.26 (t, 2H, J ¼ 6.2 Hz), 3.41 (s, 3H), 3.75 (t, 2H,
J ¼ 5.5 Hz), 4.19 (t, 2H, J ¼ 4.5 Hz), 6.21 (s, 1H, ArH), 6.35
(s, 1H, ArH). 13C NMR (CDCl3, 100 MHz); 20.5, 31.1, 50.5,
56.5, 60.7 (NCH2), 73.6 (OCH2), 99.7, 105.8, 121.1, 126.1,
140.5, 149.3. MS (ESI) m/z ¼ 206.1. Calcd. for C12H15NO2:
C, 70.22; H, 7.37; N, 6.82; found: C, 70.21; H, 7.39; N, 6.76.
9-Methoxy-2,3,5,6-tetrahydro-4H-1-oxa-3a-aza-phenalene
(3e). Yield 49%; oil. IR (film) absence of mNH stretching. 1H
NMR (CDCl3, 400 MHz) d ppm 1.96 (m, 3H), 2.72 (t, 2H, J ¼
6.8 Hz), 3.31 (t, 2H, J ¼ 6.7 Hz), 3.54 (s, 3H), 3.79 (t, 2H, J ¼ 6.5
Hz), 4.22 (t, 2H, J ¼ 5.5 Hz), 6.25 (d, 1H, J ¼ 7.1 Hz), 6.54 (d,
1H, J ¼ 7.1 Hz). 13C NMR (CDCl3, 100 MHz); 20.1, 26.1, 50.2,
56.9, 60.5 (NCH2), 73.1 (OCH2), 104.9, 110.1, 114.5, 131.1,
Table 2
Highly substituted 2, 3-dihydro-6H-1-oxa-3a-aza-phenalene.
Entry (9)
R1
R2
R3
R4
Yield %
a
b
c
d
e
f
g
h
i
H
H
H
Cl
H
H
H
Ph
2-Br Ph
Ph
Ph
Ph
n-Butyl
Ph
PhCH2
n-Butyl
Ph
82
75
85
70
72
70
80
68
65
67
H
H
Ph
Ph
H
H
Cl
H
H
2-BrPh
2-Br Ph
2-Br Ph
Ph
OCH3
OCH3
H
H
Ph
Ph
Ph
H
CH3
j
Ph
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1190
P. Mizar, M. Hormi, M. Rajbangshi, and B. Myrboh
Vol 48
134.5, 149.9. MS (ESI) m/z ¼ 206.12. Calcd. for C12H15NO2: C,
70.22; H, 7.37; N, 6.82; found: C, 70.26; H, 7.43; N, 6.78.
8-Trifluoromethoxy-2,3,5,6-tetrahydro-4H-1-oxa-3a-aza-phe-
nalene (3f). Yield 41%; oil IR (film) absence of mNH stretch-
umn chromatography over silica gel using hexanes-EtOAc (6:1)
as eluent to yield the pure product of 82%.
IR (KBr), m (cmꢀ1). 2925, 1614. 1H NMR (CDCl3, 400
MHz) d ppm 2.45 (s, 3H), 3.25(t, 2H, J ¼ 7.7 Hz), 4.07 (t,
2H, J ¼ 8.6 Hz), 5.89 (s, 1H), 6.46–6.65 (m, 4H, ArH), 7.42–
7.54 (m, 5H, ArH). 13C NMR (CDCl3, 100 MHz); 12.6
(SCH3), 60.2 (NCH2), 73.1 (OCH2), 87.1, 112.8, 116.8, 117.3,
119.5, 129.1, 130.2, 130.2, 134.3, 137.0, 140.1, 166.7, 187.8.
MS (ESI) m/z ¼ 310.41. Calcd. for C18H17NO2S: C, 69.43; H,
5.50; N, 4.50; found: C, 69.52; H, 5.49; N, 4.51.
1
ing. H NMR (CDCl3, 400 MHz) d ppm 1.89 (m, 3H), 2.64 (t,
2H, J ¼ 6.0 Hz), 3.29 (t, 2H, J ¼ 6.3 Hz), 3.73 (t, 2H, J ¼
5.7 Hz), 4.26 (t, 2H, J ¼ 5.0 Hz), 6.15 (s, 1H, ArH), 6.32 (s,
1H, ArH). 13C NMR (CDCl3, 100 MHz); 19.7, 29.6, 52.7,
60.7 (NCH2), 72.9 (OCH2), 98.7, 105.1, 121.7, 122.9, 126.1,
143.1, 151.2. MS (ESI) m/z
C12H12F3NO2: C, 55.60; H, 4.67; N, 5.40; found: C, 55.65; H,
4. 73; N, 5.45.
¼
260.02. Calcd. for
3-(6-Methoxy-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-methyl-
sulfanyl-1-phenyl-propenone (5b). Yellowish solid. Yield
1
8-Chloro-2,3,5,6-tetrahydro-4H-1-oxa-3a-aza-phenalene
(3g). Yield 46%; oil. IR (film) absence of mNH stretching. 1H
NMR (CDCl3, 400 MHz) d ppm 2.01 (m, 3H), 2.61 (t, 2H, J
¼ 6.0 Hz), 3.27 (t, 2H, J ¼ 6.2 Hz), 3.86 (t, 2H, J ¼ 5.5 Hz),
4.22 (t, 2H, J ¼ 4.5 Hz), 7.11 (s, 1H, ArH), 7.36 (s, 1H, ArH).
13C NMR (CDCl3, 100 MHz); 23.0, 30.9, 53.2, 61.1 (NCH2),
73.5 (OCH2), 113.1, 119.9, 121.9, 124.1, 129.5, 141.2. MS
(ESI) m/z ¼ 210.5 Calcd. for C11H12ClNO: C, 63.01; H, 5.77;
N, 6.68; found: C, 63.06; H, 5.82; N, 6.75.
78%; IR (KBr), m (cmꢀ1). 1627 H NMR (CDCl3, 400 MHz)
d ppm 2.41 (s, 3H), 3.31(t, 2H, J ¼ 7.5 Hz), 3.51 (s, 3H), 4.05
(t, 2H, J ¼ 6.7 Hz), 5.75 (s, 1H), 5.92(s, H), 6.15 (d, 1H, J ¼
8.5 Hz), 6.56 (d, 1H, J ¼ 8.5Hz) 7.62–7.84 (m, 5H, ArH). 13C
NMR (CDCl3, 100 MHz); 12.7 (SCH3), 59.9 (NCH2), 61.5,
73.6 (OCH2), 89.2, 96.5, 102.7, 116.5, 128.7, 130.4, 132.7,
133.5, 134.1, 137.3, 152.1, 165.9, 188.2. MS (ESI) m/z ¼
342.32. Calcd. for C19H19NO3S: C, 66.84; H, 5.61; N, 4.10;
found: C, 66.82; H, 5.59; N, 4.12.
8-Fluoro-2,3,5,6-tetrahydro-4H-1-oxa-3a-aza-phenalene
1
1-(2-Bromo-phenyl)-3-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-
3-methylsulfanyl-propenone (5j). Solid. Yield 77%; IR
(KBr), m (cmꢀ1). 1645 1H NMR (CDCl3, 400 MHz) d ppm
2.46 (s, 3H), 3.2(t, 2H, J ¼ 7.2 Hz), 4.11 (t, 2H, J ¼ 7.1 Hz),
5.95 (s, 1H), 5.92(s, H), 6.51–6.67 (m, 4H, ArH) 7.32–7.41
(m, 5H, ArH). 13C NMR (CDCl3, 100 MHz); 12.9 (SCH3),
60.4 (NCH2), 73.8 (OCH2), 90.2, 114.7, 116.1, 118.2, 120.6,
121.9, 128.1, 130.1, 131.4, 132.5, 136.9, 139.4, 141.1, 164.9,
188.6. MS (ESI) m/z ¼ 389.15. Calcd. for C18H16BrNO2S: C,
55.39; H, 4.13; N, 3.59; found: C, 55.42; H, 4.15; N, 3.56.
(4-Methylsulfanyl-2,3-dihydro-6H-1-oxa-3a-aza-phenalen-
5-yl)-phenyl-methanone (6a). To a solution of 5a (3 mmol)
in DMF was added drop wise a solution of Vilsmeier reagent
at 0ꢁC [prepared from POCl3 (5 mmol) and DMF (5 mmol) at
0–5ꢁC] under nitrogen atmosphere and stirred for 4 h at room
temperature. The reaction mixture was then heated at 90ꢁC for
3 h. The reaction mixture was poured into ice cold saturated
NaHCO3 solution (20 mL) and extracted with chloroform (2 ꢂ
25 mL). The combined organic extract was dried over Na2SO4
and then evaporated under reduced pressure. The pure product
was obtained by column chromatography over silica gel using
hexane-EtOAc as eluent (4.1).
(3h). Yield 40%; oil. IR (film) absence of mNH stretching. H
NMR (CDCl3, 400 MHz) d ppm 2.05 (m, 3H), 2.63 (t, 2H, J
¼ 6.4 Hz), 3.32 (t, 2H, J ¼ 6.7 Hz), 3.79 (t, 2H, J ¼ 6.0 Hz),
4.27 (t, 2H, J ¼ 5.7 Hz), 6.54 (s, 1H, ArH), 6.67 (s, 1H, ArH).
13C NMR (CDCl3, 100 MHz); 22.6, 31.2, 53.7, 61.4 (NCH2),
73.5 (OCH2), 101.3, 108.1, 123.9, 125.7, 143.7, 152.8. MS
(ESI) m/z ¼ 194.05 Calcd. for C11H12FNO: C, 68.38; H, 6.26;
N, 7.25; found: C, 68.43; H, 6.20; N, 7.29.
(2,3,4,6-Tetrahydro-6H-oxa-3a-aza-phenalene) methanol
(3i). Yield 42%; oil. IR (film) absence of mNH stretching. 1H
NMR (CDCl3, 400 MHz) d ppm 1.97 (m, 3H), 2.67 (t, 2H, J
¼ 6.8 Hz), 3.39 (t, 2H, J ¼ 6.9 Hz), 3.72 (t, 2H, J ¼ 6.2 Hz),
4.23 (t, 2H, J ¼ 5.9 Hz), 4.62 (s, 2H), 5.21 (s, OH), 6.59 (s,
1H, ArH), 6.72 (s, 1H, ArH). 13C NMR (CDCl3, 100 MHz);
21.9, 30.7, 50.1, 60.9 (NCH2), 67.7, 72.8 (OCH2), 110.7,
121.3, 123.5, 129.6, 132.5, 143.2. MS (ESI) m/z ¼ 206.10.
Calcd. for C12H15NO2: C, 70.22; H, 7.37; N, 6.82; found: C,
70.26; H, 7.42; N, 6.87.
8-Methoxy-9-methyl-2,3,5,6-tetrahydro-4H-1-oxa-3a-aza-phe-
nalene (3j). Yield 50 %; oil. IR (film) absence of mNH stretching.
1H NMR (CDCl3, 400 MHz) d ppm 1.88 (m, 3H), 2.28 (s,3H),
2.59 (t, 2H, J ¼ 6.7 Hz), 3.39 (t, 2H, J ¼ 6.1 Hz), 3.62 (s, 3H),
3.81 (t, 2H, J ¼ 5.9 Hz), 4.23 (t, 2H, J ¼ 5.9 Hz), 6.22 (s, 1H,
ArH). 13C NMR (CDCl3, 100 MHz); 9.7, 20.7, 26.7, 51.2, 56.1,
60.1 (NCH2), 73.0 (OCH2), 98.9, 115.3, 122.8, 124.6, 140.9,
149.1. MS (ESI) m/z ¼ 206.1. Calcd. for C13H17NO2: C, 71.21;
H, 7.81; N, 6.39; found: C, 71.16; H, 7.87; N, 6.45.
3-(2,3-Dihydro-benzo[1,4]oxazin-4-yl)-3-methylsulfanyl-1-
phenyl-propenone (5a). To a solution of 3,4-dihydro-2H-1,4-
benzoxazines (7 mmol) in dry THF (30 mL) was added n-BuLi
(9 mmol) drop wise under nitrogen atmosphere at ꢀ78ꢁC, it
was then allowed to attain room temperature and further stirred
for 30 min. To the reaction mixture a solution of the phenyl
oxoketene-S,S-acetal (4) (8 mmol) in dry THF (25 mL) was
added at 0ꢁC, stirred at room temperature for 1 h, and refluxed.
The reaction mixture was then cooled, quenched with saturated
NH4Cl solution, evaporated in vacuum, and extracted with
CHCl3. The combined organic extract was dried over Na2SO4
and evaporated to give a solid mass, which was purified by col-
Yield 90% (0.849 g). 1H NMR (CDCl3, 400 MHz) d ppm
2.34 (s, 3H), 3.21 (s, 2H), 3.35(t, 2H, J ¼ 6.1 Hz), 4.07 (t,
2H, J ¼ 5.6 Hz), 6.46–6.65 (m, 3H, ArH), 7.42–7.54 (m, 5H,
ArH). 13C NMR (CDCl3, 100 MHz); 12.1 (SCH3), 27.9, 60.1
(NCH2), 73.5 (OCH2), 96.1, 112.5, 116.3, 117.1, 119.2, 129.8,
130.5, 130.2, 134.3, 137.0, 140.1, 156.7, 186.8. MS (ESI) m/z
¼ 322.21. Calcd. for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33;
found: C, 70.60; H, 5.35; N, 4.31.
(8-Methoxy-4-methylsulfanyl-2,3-dihydro-6H-1-oxa-3a-aza-
phenalen-5-yl)-phenyl-methanone (6c). Dirty yellow solid.
1
Yield 82%; H NMR (CDCl3, 400 MHz) d ppm 2.35 (s, 3H),
3.19(s, 2H), 3.41(t, 2H, J ¼ 6.2 Hz), 3.56 (s, 3H), 4.16 (t, 2H,
J ¼5.9 Hz), 5.76 (s, 1H, ArH), 6.03 (s, 1H, ArH), 7.42–7.51
(m, 5H, ArH). 13C NMR (CDCl3, 100 MHz); 12.5 (SCH3),
28.7, 54.9, 60.1 (NCH2), 73.5 (OCH2), 95.9, 98.1, 104.8,
122.7, 128.4, 129.1, 132.9, 134.8, 138.1, 141.4, 149.1, 158.9,
180.6. MS (ESI) m/z ¼ 354.1. Calcd. for C20H19NO3S: C,
67.97; H, 5.42; N, 3.96; found: C, 67.94; H, 5.40; N, 3.98.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Synthesis of 2,3-Dihydro-6H-1-oxa-3a-aza-phenalene
and Its Benzo/Hetero Fused Analogue
1191
which was then sealed with septum and purged with N2.
K2CO3 (5.75 mmol) and Pd(dppf)Cl2 (0.23 mmol) were intro-
duced and the reaction mixture was again purged with N2. It
was then heated in the microwave synthesizer for 10 min at
100ꢁC and allowed to cool to room temperature. The content
of the vessel was filtered through celite and washed with
CH2Cl2 (3 ꢂ 5 mL). The combined organic extracts was fur-
ther washed with saturated aqueous NaHCO3 and evaporated
to yield the crude product (11), which was purified by column
chromatography using EtOAc–Hexane (1:5) as an eluent.
(8-Fluoro-4-methylsulfanyl-2,3-dihydro-6H-1-oxa-3a-aza-
phenalen-5-yl)-phenyl-methanone (6h). Solid. Yield 68%;
1H NMR (CDCl3, 400 MHz) d ppm 2.31 (s, 3H), 3.26(s, 2H),
3.45(t, 2H, J ¼ 6.5 Hz), 4.21 (t, 2H, J ¼7.1 Hz), 6.15 (s, 1H,
ArH), 6.21 (s, 1H, ArH), 7.21–7.42 (m, 5H, ArH). 13C NMR
(CDCl3, 100 MHz); 12.8 (SCH3), 28.9, 60.3 (NCH2), 73.8
(OCH2), 96.7, 100.9, 107.8, 124.7, 128.9, 129.2, 134.1, 136.9,
138.2, 142.1, 150.1, 158.6, 189.8. MS (ESI) m/z ¼ 340.52.
Calcd. for C19H16FNO2S: C, 66.84; H, 4.72; N, 4.10; found:
C, 66.87; H, 4.73; N, 4.13.
(8-Chloro-2,3-dihydro-6H-1-oxa-3a-aza-phenalen-5-yl)-phe-
nyl-methanone (7g). Reduction using Raney-Ni. To a solu-
tion of 6g (6.4 mmol) in ethanol was added Raney-Ni (three times
by weight) and the suspension refluxed for 2 h. The reaction mix-
ture was then cooled and filtered through sintered funnel. The res-
idue washed with ethanol (3 ꢂ 10 mL) and the filtrate evaporated
to give 7g which was further purified by column chromatography
over silica gel using EtOAc–Hexane (1:10) as eluent.
Yield 87% (1.99 g); 1H NMR (CDCl3, 400 MHz) d ppm 3.15
(s, 3H), 3.41 (t, 2H, J ¼ 6 Hz), 4.03 (t, 2H, J ¼ 7.1 Hz), 3.41(s,
3H), 4.05 (t, 2H, J ¼ 5.5 Hz), 6.15 (s, 1H, ArH), 6.21 (s, 1H,
ArH). 6.54 (s, 1H), 7.32–7.45 (m, 5H, ArH). 13C NMR (CDCl3,
100 MHz) 31.5, 61.7 (NCH2), 73.8 (OCH2), 111.9, 113.6,
119.5, 120.1, 127.3, 127.8, 128.1, 129.1, 132.1, 135.2, 136.3,
141.1, 165.3. MS (ESI) m/z ¼ 312.82. Calcd. for C18H14ClNO2:
C, 69.35; H, 4.53; N, 4.49; found: C, 69.41; H, 4.59; N, 4.42.
2-(Methylsulfonyl) of 2,3-dihydro-6H-1-oxa-3a-aza-phe-
nalene (8). To a solution of 6j (2.5 mmol) in dry DCM (30
mL) was added a solution of meta-chloroperbenzoic acid
(mCPBA) (5.0 mmol) dropwise over a period of 15 min and
stirred at room temperature for 3 h. The reaction mixture was
then neutralized with saturated NaHCO3 (2 ꢂ 25 mL) and
washed with brine, dried over anhydrous NaSO4, and evapo-
rated to yield the crude product, which was purified by column
chromatography using EtOAc–Hexane (1:20) as eluent.
Yield 65% (0.65 g); IR (KBr) 1712 cmꢀ1 1H NMR
.
(CDCl3, 400 MHz) d ppm 1.09 (t, 3H, J ¼ 3.6 Hz), 2.98 (q,
2H, J ¼ 3.5 Hz), 3.18 (s, 2H), 3.54 (t, 2H, J ¼ 6.5 Hz), 4.21
(t, 2H, J ¼ 6.4 Hz), 6.48–6.54 (m, 3H, ArH), 7.12–7.34 (m,
4H, ArH). 13C NMR (CDCl3, 100 MHz) 13.1, 26.2, 44.5, 55.2
(NCH2), 74.1 (OCH2), 84.1, 111.4, 112.4, 117.1, 117.9, 120.5,
121.3, 122.4, 129.2, 130.4, 135.6, 142.1, 144.6, 155.2, 179.6.
MS (ESI) m/z ¼ 317.41. Calcd. for C20H18N2O2: C, 75.45; H,
5.70; N, 8.80; found: C, 75.42; H, 5.69; N, 8.81.
Acknowledgment. The author (P.M) thanks CSIR for awarding
research fellowship; SAIF, NEHU Shillong, IISc Bangalore, and
CIF-IIT Guwahati for spectral analysis; Nagaland University and
UGC for SAP Programmes.
REFERENCES AND NOTES
[1] Combs, D. W.; Rampulla, M. S.; Bell, S. C.; Klaubert, D.
H.; Tobia, A. J.; Falotico, R.; Haertlein, B.; Weiss, L. C., Moore, J. B.
J Med Chem. 1990, 33, 380.
´
[2] Bourlot, A. S.; Sanchez, I.; Dureng, G.; Guillaumet, G.;
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Massingham, R.; Monteil, A.; Winslow, E. M.; Pujol, D., Merour, J.
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[3] Touzeau, F.; Arrault, A.; Guillaumet, G.; Scalbert, E.; Pfeiffer,
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B.; Rettori, M. C.; Renard, P., Merour, J. Y. J Med Chem 2003, 46, 1962.
Yield 80% (0.892 g); 1H NMR (CDCl3, 400 MHz) d ppm
3.21 (s, 2H), 3.34 (s, 3H), 3.45(t, 2H, J ¼ 6.3 Hz), 4.14 (t,
2H, J ¼ 6.7 Hz), 6.56–6.65 (m, 3H, ArH), 7.39–7.64 (m, 5H,
ArH).. 13C NMR (CDCl3, 100 MHz); 27.9, 38.5, 59.1 (NCH2),
74.9 (OCH2), 95.9, 112.8, 118.3, 120.6, 121.9, 122.8, 128.7,
131.2, 132.6, 136.5, 138.9, 140.1, 141.5, 160.3, 191.1. MS
(ESI) m/z ¼ 435.31. Calcd. for C19H16BrNO4S: C, 52.54; H,
3.71; N, 3.23; found: C, 52.57; H, 3.73; N, 3.21.
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Synthesis of 4-phenylamino-2,3-dihydro-6H-1-oxa-3a-aza-
phenalene (9a). A solution of 8a (3 mmol) and n-butyl amine (15
mmol) was refluxed for 6 h in dry THF (toluene for aryl amine).
The reaction mixture was cooled and THF evaporated off to yield
a yellow solid, which was further purified by column chromatog-
raphy on silica gel using EtOAc–Hexane (1:2) as an eluent.
Yield 82% (0.87 g). IR (KBr), m (cmꢀ1), 3316, 1342. 1H
NMR (DMSO-d6, 400 MHz) d ppm 3.16 (s, 2H), 3.54 (t, 2H,
J ¼ 6.5 Hz), 4.21 (t, 2H, J ¼ 6.4 Hz), 6.35–6.42 (m, 3H,
ArH), 6.62 (b, 1H), 6.98–7.14 (m, 4H, ArH), 7.42–7.54 (m,
4H, ArH). 13C NMR (CDCl3, 100 MHz); 26.1, 58.6 (NCH2),
75.4 (OCH2), 82.9, 111.5, 115.9, 117.3, 119.3, 121.3, 123.1,
128.9, 129.2, 130.1, 135.2, 138.7, 140.9, 141.8, 144.8, 156.3,
190.5. MS (ESI) m/z ¼ 367.41. Calcd. for C24H20N2O2: C,
78.24; H, 5.47; N, 7.60; found: C, 78.21; H, 5.50; N, 7.61.
Synthesis of 13-ethyl-1,2,7,13-tetrahydro-3-oxa-13,13b-
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(11). (2-Bromo-phenyl)-(4-
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Junjappa, H. J Org Chem 2003, 68, 3966.
methanesulfonyl-2,3-dihydro-6H-1-oxa-3a-aza-phenalen-5-yl)-
methanone (10) (2.3 mmol) was taken in a 25 mL container,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet