Novel Use of Substituted 1,4-Dihydrobenzoxazin-2-ones in the Synthesis of Important Aminomethyl o-Nitroanilines

Full text of DOI:10.1021/jo9707491

J . Org. Chem. 1997, 62, 9331-9334
9331
Sch em e 1. Syn th esis of Ben zyla m in es (2) Usin g
Ben zyl Alcoh ols (1) u n d er Mitsu n obu Rea ction
Con d ition s
Novel Use of Su bstitu ted
1,4-Dih yd r oben z[d ][1,3]oxa zin -2-on es in th e
Syn th esis of Im p or ta n t Am in om eth yl
o-Nitr oa n ilin es
Sham S. Nikam,* Po-Wai Yuen, Brian E. Kornberg,
Brian Tobias, and Michael F. Rafferty
Department of Chemistry, Parke-Davis Pharmaceutical
Division/ Warner-Lambert Company, 2800 Plymouth Road,
Ann Arbor, Michigan 48105
Sch em e 2. Nitr a tion of o-Am in oben zyl Alcoh ol
Received April 28, 1997 (Revised Manuscript Received October
24, 1997 )
In tr od u ction
Multifunctional o-nitroanilines are important inter-
mediates in the synthesis of a variety of nitrogen
heterocycles.1 However, there are very few efficient
methods to synthesize heteroalkyl side chains ortho to
the amino group, which give the corresponding peri
position substitution in the resultant nitrogen hetero-
cycle. Earlier, we standardized a novel method for the
synthesis of benzylamine derivatives 2 with an amino-
methyl side chain ortho to the amino group of the
o-nitroaniline derivative via a modified Mitsunobu reac-
tion (Scheme 1)2 starting from the substituted benzyl
alcohol 1. This synthesis had a few limitations with
regard to the amines that could be used and moderate
yield of the starting benzyl alcohol 1 from commercially
available 6-methylanthranilic acid.3 Our continued in-
terest in a variety of aminomethyl-substituted o-nitroa-
nilines and their tremendous utility in the synthesis of
several nitrogen heterocycles prompted us to investigate
other versatile and efficient methodologies for their
synthesis. We would like to report here the synthesis of
aminomethyl-substituted o-nitroanilines 9 starting from
novel 6-bromo-5-methyl-8-nitro-1,4-dihydrobenzo[d][1,3]-
oxazin-2-one (6).
give the 6-bromo derivative 5, which was subsequently
nitrated using potassium nitrate in sulfuric acid to give
the desired 6-bromo-5-methyl-8-nitro-1,4-dihydrobenz[d]-
[1,3]oxazin-2-one (6) in excellent isolated yields. Bromi-
nation step to give 6-bromo derivative 5 was necessary
as direct nitration of 4 gave a mixture of 6-nitro (7) and
8-nitro (8) regioisomers (∼4:6). Further, the bromine
substituent can be penultimately removed, as required
via catalytic hydrogenation. The structure of the regio-
isomer (7) was confirmed by 1H NOE NMR studies
(Scheme 3).
The benz[d][1,3]oxazin-2-one derivative 6 was directly
treated with nucleophilic amines to give the correspond-
ing aminoalkyl derivatives 9 (Table 1) in modest to good
yields (Scheme 4). Thus, in a typical reaction 6-bromo-
5-methyl-8-nitro-1,4-dihydrobenz[d][1,3]oxazin-2-one (6)
was treated with various amines (>6 equiv), neat or in a
high-boiling solvent such as dimethylformamide. The
reaction mixture was heated to reflux or >140 °C for
about 8 h. The products were isolated by crystallization
or column chromatography. The various substituted
aminomethyl o-nitroanilines synthesized are listed in
Table 1. Unlike the Mitsunobu method,2 which worked
only with amines having pKa > 9, the present method
was found to be more general with respect to a variety
of amines. For example, 2-(methylamino)ethanol, me-
thylaminoacetaldehyde dimethyl acetal, and morpholine
(Table 1, entries 1, 2, 9, respectively) gave the desired
benzylamines in modest to good yields. These amines
did not give the desired product on reaction with benzyl
alcohol 1 under Mitsunobu conditions. In general, amines
with pKa > 8 gave the desired products, whereas weakly
basic amines such as aniline did not give the desired
product. The reaction also appears to be dependent on
the steric bulk of the amines. Thus, dibenzylamine
(Table 1, entry 6) and N-isopropylbenzylamine (Table 1,
entry 5) gave the desired product in low yield, whereas
the N-methylbenzylamine (Table 1, entry 3) and N-
ethylbenzylamine (Table 1, entry 4) gave the product in
good yield.
Resu lts a n d Discu ssion
Synthesis of the benzyl alcohol 1 involved nitration of
o-aminobenzyl alcohol 3 in acetic anhydride using con-
centrated nitric acid3 (Scheme 2). The desired nitro
derivative 1 was isolated in about 40% yield from a
mixture of regioisomers. The moderate yields of this
starting material and the need for a variety of substituted
aminomethyl o-nitroanilines 2 led us to optimize the
synthesis of this starting material (Scheme 3). Thus
o-aminobenzyl alcohol 3 was cyclized to form the 5-meth-
yl-1,4-dihydrobenz[d][1,3]oxazin-2-one (4) by treating 3
with phosgene in the presence of triethylamine in THF.
The benz[d][1,3]oxazin-2-one derivative 4 was bromi-
nated using bromine in an acetic acid-TFA mixture to
* Corresponding author. Phone (313)-996-7452. Fax: (313)-996-
5165. E-mail: nikams@aa.wl.com.
(1) For reviews on chemistry of various nitrogen heterocycles from
o-nitroanilines, see: Preston, P. N.; Smith, D. M.; Tennant, G.
Heterocycl. Compds. 1981, 40. Cheeseman, G. W. H.; Werstiuk, E. S.
G. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Boulton,
A. J ., Eds.; Academic Press: New York, 1978; Vol. 22, pp 368-425.
Cheeseman, G. W. H.; Cookson, R. F. In Chemistry of Heterocyclic
Compounds; Weissburger, A., Taylor, E. C., Eds.; Academic Press: New
York, 1977; pp 1-261.
(2) Nikam, S. S.; Kornberg, B. E.; Rafferty, M. F. J . Org. Chem. 1997,
62, 3754.
(3) Utaka, M.; Takatsu, M.; Takeda, A. Bull. Chem. Soc. J pn. 1977,
50, 3276.
Initially, the mechanism proposed for this reaction was
the nucleophilic ring opening of the cyclic carbamate via
an SN2 mechanism. However, on careful investigation
and with our prior experience with the Mitsunobu
reaction, we postulated that the reaction probably pro-
S0022-3263(97)00749-4 CCC: $14.00 © 1997 American Chemical Society

9332 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
Sch em e 3. Syn th esis of 6-Br om o-5-m eth yl-8-n itr o-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e a n d Obser ved NOEs
for Regioisom er 7
Ta ble 1. Su bstitu ted Ben zyla m in es 9 fr om Su bstitu ted
Sch em e 6. P r op osed Mech a n ism In volvin g
Aza qu in od im eth a n e In ter m ed ia te
1,4-Dih yd r oben z[d ][1,3]oxa zin -2-on e (6)
entry
-NR1R2
yield (%)a
1
2
3
4
5
2-(methylamino)ethanol
methylaminoacetaldehyde dimethyl acetal
N-methylbenzylamine
N-ethylbenzylamine
N-isopropylbenzylamine
dibenzylamine
28
78
70
57
12
6
7
11 (50)b
76
pyrrolidine
8
piperidine
67
9
morpholine
71
10
11
3-azaspiro[5.5]undecane
sarcosine ethyl ester
51
34
a
b
Isolated yields. Reaction of 10 with dibenzylamine.
Sch em e 4
reflux to give 11. Heating 10 in DMF to 130 °C in the
absence of excess piperidine did not give 11, indicating
that excess amine is required to convert 10 to 11 and
the process is not an intramolecular process. This result
was important as the piperidinyl carbamate 10 could now
be used to synthesize benzylamines which could not be
synthesized in good yields directly by heating 6 with the
amine. For example, treatment of 10 with an excess of
dibenzylamine at 160 °C gave the corresponding diben-
zylamino derivative (Table 1, entry 6) in 50% yield.
These results also indicate that the yield-limiting step
is the initial amine attack at the carbamate carbonyl
group, which is dependent on the steric bulk and basicity
of the amines as discussed earlier in this paper. Heating
the benz[d][1,3]oxazin-2-one derivative 6 to reflux in
DMF, 2,2,6,6-tetramethylpiperidine, or TEA gave back
the starting material confirming that the temperature
or basicity was not the only criterion for the generation
of the azaquinodimethane intermediate and the overall
success of the reaction.
Sch em e 5
The mechanism was further investigated by exploring
the reactivity of other derivatives of 6 (Table 2) with
piperidine at reflux. There was no reaction with the
unsubstituted (Table 2, entry 1) or the 8-amino- (Table
2, entry 2) derivatives of 1, whereas the 8-nitro- and 6,8-
dibromo-1,4-dihydrobenz[d][1,3]oxazin-2-ones (Table 2,
entries 5, 6) gave the desired product indicating the
importance of the electron-withdrawing group ortho to
the amine functionality, which is critical for the base-
induced elimination to give the azaquinodimethane
intermediate. The proximity of the electron-withdrawing
group is also important for the success of the reaction.
The benz[d][1,3]oxazin-2-one derivatives having a bromo
ceeds via the azaquinodimethane intermediate 12 (Scheme
6). Thus, the reaction of benz[d][1,3]oxazin-2-one deriva-
tive 6 with piperidine was investigated at various tem-
peratures. At rt, the product isolated was the corre-
sponding acyclic piperidinyl carbamate 10 in very good
yield (Scheme 5). This intermediate is then proposed to
undergo base-induced elimination to form the azaquino-
dimethane intermediate 12 followed by conjugate addi-
tion of the amine to give the desired piperidinyl-
substituted o-nitroaniline 11 (Scheme 6). In a separate
experiment 10 was treated with excess piperidine at

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9333
Ta ble 2. Rea ction s of P ip er id in e Differ en tia lly
Su bstitu ted Ben z[d ][1,3]oxa zin -2-on es
added phosgene solution in toluene (1.93 M, 1.86 L, 3.6 mol)
slowly over 1 h keeping the temperature below 10 °C. The
reaction mixture was allowed to warm to rt and was stirred for
16 h. Cold water (150 mL) and aq NH4OH (10%, 200 mL) were
added under stirring followed by EtOAc (12 L). The EtOAc
extracts were washed with water and brine and dried over
MgSO4. The product (buff solid) was crystallized from EtOAc:
yield 536 g, 94%; mp 224-226 °C; 1H NMR (DMSO-d6) δ 2.19
(s, 3H), 5.31 (s, 2H), 6.66 (d, J ) 8.1 Hz, 1H), 6.82 (d, J ) 8.1
Hz, 1H), 7.1 (dd, J ) 7.8 Hz, 1H), 8.82 (bs, 1H); MS (CI) m/z
163 (M + H). Anal. Calcd for C9H9NO2: C, 66.25; H, 5.56; N,
8.61. Found: C, 66.34; H, 5.63; N, 8.61.
entry
X
Y
yield (%)a
6-Br om o-5-m e t h yl-1,4-d ih yd r ob e n z[d ][1,3]oxa zin -2-
on e (5). To a solution of 5-methyl-1,4-dihydrobenz[d][1,3]oxazin-
2-one (4) (400 g, 2.45 mol) in glacial acetic acid (2.5 L) and TFA
(1 L) was gradually added a solution of Br2 (151 mL, 468 g, 2.93
mol) in TFA (500 mL) over 1 h at 5 °C under stirring. The
reaction mixture was stirred for an additional 5 h and poured
into ice-water (12 L). The yellow precipitate was filtered,
washed with water until neutral, and dried: yield 558 g, 94%;
mp 287-288 °C; 1H NMR (DMSO-d6) δ 2.18 (s, 3H), 5.31 (s, 2H),
6.6 (d, J ) 8.8 Hz, 1H), 7.41 (d, J ) 8.8 Hz, 1H), 10.16 (s, 1H);
MS (CI) m/z 242, 243, 244 (M + H, M + 2H, M + 3H). Anal.
Calcd for C9H8BrNO2: C, 44.66; H, 3.33; N, 5.79. Found: C,
44.92; H, 3.28; N, 5.69.
1
2
3
4
5
6
7
H
H
H
NH2
H
H
NO2
Br
no rxn
no rxn
no rxn
no rxn
84
Br
NO2
H
Br
Br
36
NO2
67b
a
b
Isolated yields. Entry 8 in Table 1.
or nitro moiety para to the carbamoyl NH (Table 2,
entries 3, 4, respectively) did not give the desired ben-
zylamine derivative on treatment of piperidine under
reaction conditions mentioned above. These results can
be attributed to the acidity of the amine group protons,
with o-nitroaniline (pKa ) -0.25) being more acidic than
6-Br om o-5-m eth yl-8-n itr o-1,4-dih ydr oben z[d][1,3]oxazin -
2-on e (6). To a cooled (5 °C) solution of 6-bromo-5-methyl-1,4-
dihydrobenz[d][1,3]oxazin-2-one (5) (556 g, 2.3 mol) in concen-
trated H2SO4 (1200 mL) was added KNO3 (242 g, 2.39 mol)
portionwise keeping the temperature below 5 °C. Reaction
mixture was allowed to warm to rt and stirred for 18 h. The
viscous liquid was poured into ice-water (12 L) with stirring.
The yellow precipitate was filtered, washed with water until
p-nitroaniline (pKa ) 1.05) or p-bromoaniline (pKa
)
3.89).4 The mechanism proposed is analogous to that
postulated for the Mitsunobu method, but the present
methodology is more broadly applicable to the prepara-
tion of highly functionalized 6-(aminomethyl)-o-nitro-
anilines. Generation of an azaquinodimethane or aza-
o-xylylene intermediate via CO2 extrusion under high
temperatures or high-vacuum pyrolysis and trapping of
this intermediate by a dienophile to give the adduct have
been discussed earlier.5,6 Our mechanism adds a new
dimension to this area, in that the intermediate aza-
quinodimethane 12 can be generated under milder condi-
tions from appropriately substituted and readily synthe-
sizable benz[d][1,3]oxazin-2-ones.
1
neutral, and air-dried: yield 656 g, 99%; mp 187 °C; H NMR
(DMSO-d6) δ 2.32 (s, 3H), 5.47 (s, 2H), 8.23 (s, 1H), 9.76 (bs,
1H); MS (CI) m/z 287, 289 (M + H, M + 2H). Anal. Calcd for
C9H7BrN2O4: C, 37.66; H, 2.46; N, 9.76. Found: C, 37.44; H,
2.57; N, 9.56.
6-Nitr o-5-m eth yl-1,4-dih ydr oben z[d][1,3]oxazin -2-on e (7)
a n d 8-Nitr o-5-m eth yl-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e
(8). To a solution of 5-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-
one (4) (1.62 g, 10 mmol) in acetic anhydride (15 mL) was added
concentrated HNO3 (70%, 2 mL) at 15 °C under stirring. The
reaction mixture was warmed to 40 °C for 3 h and poured into
crushed ice. An off-white solid separated, which was filtered.
The sticky solid was triturated with EtOAc (∼250 mL) and
filtered. A buff-colored solid was obtained (0.711 g, 34%) which
was confirmed to be the 6-nitro-5-methyl-1,4-dihydrobenz[d]-
[1,3]oxazin-2-one (7) by 1H NMR and NOE studies: 1H NMR
(DMSO-d6) δ 2.27 (s, 3H), 5.4 (s, 2H), 7.04 (d, J ) 8.7 Hz, 1H),
7.95 (d, J ) 8.7 Hz, 1H), 9.67 (s, 1H); MS (CI) m/z 209 (M + H).
Anal. Calcd for C9H8N2O4: C, 51.93; H, 3.87; N, 13.46. Found:
C, 52.12; H, 3.73; N, 13.28.
The mother liquor was partially evaporated to give yellow
crystals of 8-nitro-5-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one
(8): yield, 0.964 g, 46%; 1H NMR (DMSO-d6) δ 2.27 (s, 3H), 5.39
(s, 2H), 6.81 (d, J ) 8.7 Hz, 1H), 7.85 (d, J ) 8.7 Hz, 1H), 10.61
(s, 1H); MS (CI) m/z 209 (M + 1). Anal. Calcd for C9H8N2O4:
C, 51.93; H, 3.87; N, 13.46. Found: C, 51.63; H, 3.84; N, 13.37.
8,6-Dibr om o-5-m eth yl-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-
on e (sta r tin g m a ter ia l for en tr y 6 in Ta ble 2). To a solution
of 5-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one (4; 9 g, 55.2
mmol) in acetic acid (40 mL) was added Br2 (19.2 g, 120 mmol)
dropwise (∼15 min). The reaction mixture was stirred for 16 h
and the reaction quenched with ice water. The yellow precipitate
was washed with water till neutral and dried: yield 16.8 g, 95%;
1H NMR (DMSO-d6) δ 2.24 (s, 3H), 5.31 (s, 2H), 7.26 (bs, 1H),
7.65 (s, 1H); MS (CI) m/z 320, 322 (M + H, M + 3H). Anal.
Calcd for C9H7Br2N1O2: C, 33.68; H, 2.2; N, 4.36. Found: C,
33.9; H, 2.22; N, 4.36.
Con clu sion
A new methodology for the synthesis of substituted
aminomethyl o-nitroanilines 9 via the novel intermediate
6-bromo-5-methyl-8-nitro-1,4-dihydrobenz[d][1,3]oxazin-
2-one (6) has been developed. The probable generation
of the azaquinodimethane intermediate 12 from 6-bromo-
5-methyl-8-nitro-1,4-dihydrobenz[d][1,3]oxazin-2-one (6)
under mild conditions is new and could have broad utility
in organic synthesis especially in synthesizing substi-
tuted nitrogen heterocycles.
Exp er im en ta l Section
Ma ter ia ls. All chemicals were purchased from Aldrich and
used without additional purification. Phosgene solution in
toluene (1.93 M) was purchased from Fluka AG. 1H NMR
spectra and 1H NOE NMR studies were recorded at 400 MHz
in CDCl3 or DMSO-d6. Chemical shifts are referenced to the
residual proton signal for CDCl3 (7.26 ppm) or DMSO-d6 (2.49
ppm). The starting benzyl alcohol 1 was synthesized from
6-methylanthranilic acid as reported earlier.3
5-Meth yl-1,4-d ih yd r oben z[d ][1,3]oxa zin -2-on e (4). To a
solution of (2-amino-6-methylphenyl)methanol (3) (478 g, 3.49
mol) and triethylamine (884 g, 8.75 mol) in THF (10 L) was
Gen er a l P r oced u r e for th e Syn th esis of Su bstitu ted
Am in om eth yl o-Nitr oa n ilin es (9) Sta r tin g fr om 6-Br om o-
5-m eth yl-8-n itr o-1,4-dih ydr ben z[d][1,3]oxazin -2-on e (6) (r ep-
r esen t a t ive exa m p le w it h NR 1R 2 ) p ip er id in e a s t h e
a m in e). A stirred solution of 6-bromo-5-methyl-8-nitro-1,4-
dihydrobenz[d][1,3]oxazin-2-one (6; 10 g, 35 mmol) in piperidine
(50 mL) was heated to reflux for 8 h. The dark reaction mixture
was cooled, and volatile material was evaporated on a rotary
(4) Albert, A.; Serjeant, E. P. The Determination of Ionization
Constants; 1984; pp 137-217.
(5) Mao, Y.; Boekelheide, V. J . Org. Chem. 1980, 45, 1547.
(6) Consonni, R.; Croce, P. D.; Ferraccioli, R.; La Rossa, C. J . Chem.
Soc., Perkin Trans. 1 1996, 1809.

9334 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
evaporator to give a viscous oil. The dark oil was triturated with
ethyl acetate with warming to form a solution. On cooling the
product (Table 1, entry 6) crystallized to give a yellow solid: yield
En tr y 11: 1H NMR (CDCl3) δ 1.26 (t, J ) 7.1 Hz, 3H), 2.28
(s, 3H), 2.42 (s, 3H), 3.28 (s, 2H), 3.76 (s, 2H), 4.18 (q, J ) 7, 7.1
Hz, 2H), 7.85 (bs, 2H), 8.31 (s, 1H); MS (CI) m/z 360, 362 (M +
H, M + 3H). Anal. Calcd for C13H18BrN3O4: C, 43.35; H, 5.04;
N, 11.67. Found: C, 44.36; H, 4.96; N, 11.16.
R ea ct ion of P ip er id in e w it h 8-Nit r o-5-m et h yl-1,4-
d ih yd r oben z[d ][1,3]oxa zin -2-on e (7) (Ta ble 2, en tr y 5) a n d
8,6-Dib r om o-5-m et h yl-1,4-d ih yd r ob en z[d ][1,3]oxa zin -2-
on e (Ta ble 2, en tr y 6). The reactions were carried as described
above in the general procedure for the synthesis of substituted
aminomethyl o-nitroanilines. Spectral and analytical data for
the compounds are listed in Table 2.
3-Meth yl-2-(p ip er id in -1-ylm eth yl)-6-n itr op h en yla m in e
(en tr y 5): 1H NMR (CDCl3) δ 1.53 (bs, 2H), 1.54-1.58 (m, 4H),
2.31 (s, 3H), 2.39 (bs, 4H), 3.56 (s, 2H), 6.45 (d, J ) 8.9 Hz, 1H),
7.87 (bs, 2H), 7.95 (d, J ) 8.9 Hz, 1H); MS (CI) m/z 250 (M +
H). Anal. Calcd for C13H19N3O2: C, 62.63; H, 7.68; N, 16.85.
Found: C, 62.63; H, 7.73; N, 16.61.
4,6-Dib r om o-3-m et h yl-2-(p ip er id in -1-ylm et h yl)p h en yl-
a m in e (en tr y 6): 1H NMR (CDCl3) δ 1.42 (bs, 2H), 1.55-1.59
(m, 4H), 2.34 (s, 3H), 2.38 (bs, 4H), 3.85 (s, 2H), 5.42 (bs, 2H),
7.58 (s, 1H); MS (CI) m/z 360.8, 362.8, 364.8 (M, M + 2H, M +
4H). Anal. Calcd for C13H18Br2N2: C, 43.12; H, 5.01; N, 7.74.
Found: C, 42.75; H, 4.85; N, 7.64.
1
7.58 g, 67%; H NMR (CDCl3) δ 1.43-1.55 (m, 6H), 2.36-2.45
(m, 4H), 2.41 (s, 3H), 3.59 (s, 2H), 7.84 (bs, 2H), 8.27 (s, 1H);
MS (CI) m/z 328 (M + H). Anal. Calcd for C13H18BrN3O2: C,
47.57; H, 5.53; N, 12.8. Found: C, 47.81; H, 5.44; N, 12.6.
Spectral and analytical data for the compounds (entry num-
bers) synthesized and listed in Table 1 are as follows.
En tr y 1: 1H NMR (CDCl3) δ 2.26 (s, 3H), 2.43 (s, 3H), 2.61
(m, 2H), 3.74 (m, 4H), 7.58 (bs, 2H), 8.3 (s, 1H); MS (CI) m/z
319, 320 (M + H, M + 2H). Anal. Calcd for C11H16BrN3O3: C,
41.52; H, 5.07; N, 13.21. Found: C, 41.72; H, 4.9; N, 12.79.
En tr y 2: 1H NMR (CDCl3) δ 2.2 (s, 3H), 2.42 (s, 3H), 3.33 (s,
6H), 3.67 (s, 2H), 4.54 (bs, 1H), 7.7 (bs, 2H), 8.29 (s, 1H); MS
(CI) m/z 362, 363 (M + H, M + 2H). Anal. Calcd for C13H20
-
BrN3O4: C, 43.11; H, 5.57; N, 11.60. Found: C, 42.85; H, 5.43;
N, 11.31.
En tr y 3: 1H NMR (CDCl3) δ 2.02 (s, 3H), 2.39 (s, 3H), 3.47
(s, 2H), 3.67 (s, 2H), 7.2-7.31 (m, 5H), 7.75 (bs, 2H), 8.09 (s,
1H); MS (CI) m/z 364, 365 (M + H, M + 2H). Anal. Calcd for
C
16H18BrN3O2: C, 52.76; H, 4.98; N, 11.54. Found: C, 52.22;
H, 4.87; N, 11.11.
En tr y 4: 1H NMR (CDCl3) δ 1.08 (t, J ) 7.8 Hz, 3H), 2.43 (s,
3H), 3.47 (q, J ) 7.33 Hz, 2H), 3.49 (s, 2H), 3.72 (s, 2H), 7.19-
7.29 (m, 5H), 7.72 (bs, 2H), 8.26 (s, 1H); MS (CI) m/z 378, 380
(M + H, M + 2H). Anal. Calcd for C17H20BrN3O2: C, 53.98; H,
5.33; N, 11.1. Found: C, 54; H, 5.22; N, 11.08.
P ip er id in e-1-ca r boxylic Acid 2-Am in o-5-br om o-6-m eth -
yl-3-n itr oben zyl Ester (10). 6-Bromo-5-methyl-8-nitro-1,4-
dihydrobenz[d][1,3]oxazin-2-one (6; 8.61 g, 30 mmol) was dis-
solved in THF (50 mL), and piperidine (6.65 g, 90 mmol) was
added keeping the temperature below 25 °C. The reaction
mixture was stirred for 8 h at rt, monitored by TLC (SiO2,
petroleum ether:EtOAc, 1:1), and filtered. A dark solid was
obtained, which was dissolved in CHCl3 (200 mL), washed with
dilute HCl (5%), aq NaHCO3, and water, and dried over MgSO4.
The solvent was evaporated to give a yellow residue, which was
triturated with petroleum ether:EtOAc (7:3, 50 mL), filtered, and
dried: yield 7.46 g, 67%; 1H NMR (CDCl3) δ 1.56 (m, 6H), 3.4
(m, 4H), 5.26 (s, 2H), 7.26 (bs, 2H), 8.38 (s, 1H); MS (CI) m/z
373, 374, 375 (M + H, M + 2H, M + 3H). Anal. Calcd for
En tr y 5: 1H NMR (CDCl3) δ 1.1 (d, 6H), 2.45 (s, 3H), 2.86
(septet, 1H), 3.73 (s, 2H), 7.2-7.31 (m, 5H), 7.63 (bs, 2H), 8.22
(s, 1H); MS (CI) m/z 308, 310 (M + H, M + 2H). Anal. Calcd
for C18H22BrN3O2: C, 55.10; H, 5.61; N, 10.71. Found: C, 55.13;
H, 5.58; N, 10.54.
En tr y 6: 1H NMR (CDCl3) δ 2.46 (s, 3H), 3.49 (s, 4H), 3.68
(s, 2H), 7.2-7.41 (m, 2H), 8.24 (s, 1H); MS (CI) m/z 440, 442 (M
+ H, M + 2H). Anal. Calcd for C22H22BrN3O2: C, 60.01; H,
5.04; N, 9.54. Found: C, 60.35; H, 5.18; N, 9.28.
En tr y 7: 1H NMR (CDCl3) δ 1.75 (m, 4H), 2.44 (s, 3H), 2.48
(m, 4H), 3.76 (bs, 2H), 7.83 (bs, 2H), 8.28 (s, 1H); MS (APCI)
m/z 315, 316 (M + H, M + 2H). Anal. Calcd for C12H16BrN3O2:
C, 45.87; H, 5.13; N, 13.37. Found: C, 45.88; H, 5.05; N, 13.27.
En tr y 8: 1H NMR (CDCl3) δ 1.43-1.52 (m, 6H), 2.37-2.45
(m, 4H), 2.41 (s, 3H), 3.59 (s, 2H), 7.85 (bs, 2H), 8.27 (s, 1H);
MS (CI) m/z 328, 329 (M + H, M + 2H). Anal. Calcd for
C
14H18BrN3O4: C, 45.18; H, 4.87; N, 11.29. Found: C, 44.98;
H, 4.64; N, 10.71.
Rea ction of P ip er id in e-1-ca r boxylic Acid 2-Am in o-5-
br om o-6-m eth yl-3-n itr oben zyl Ester (10) w ith Am in es. A
solution of piperidine-1-carboxylic acid 2-amino-5-bromo-6-meth-
yl-3-nitrobenzyl ester (10; 3.72 g, 10 mmol) was dissolved in
dibenzylamine (7.88 g, 40 mmol). The solution was heated to
160 °C for 18 h. The reaction mixture was cooled and the dark
oil triturated with methanol to give a yellow-brown crystalline
solid. The solid was filtered, washed with methanol, and dried:
C
13H18BrN3O2: C, 47.57; H, 5.53; N, 12.8. Found: C, 47.81; H,
5.44; N, 12.6.
En tr y 9: 1H NMR (CDCl3) δ 2.48 (s, 3H), 2.51 (bs, 4H), 3.71
(bs, 6H), 7.67 (bs, 2H), 8.34 (s, 1H); MS (CI) m/z 330, 331 (M +
H, M + 2H). Anal. Calcd for C12H16BrN3O3: C, 43.65; H, 4.88;
N, 12.73. Found: C, 43.31; H, 4.76; N, 12.42.
1
yield 2.06 g, 50%. The product had identical H NMR and TLC
(SiO2, petroleum ether:EtOAc, 1:1) to the product isolated from
the reaction of 1 with dibenzylamine. (Table 1, entry 4).
Similarly, the reaction of carbamate 10 with piperidine gave the
corresponding product (Table 1, entry 6) in 86% yield.
En tr y 10: 1H NMR (CDCl3) δ 1.24 (bs, 4H), 1.3 (bs, 10H),
2.31 (bs, 4H), 2.36 (s, 3H), 3.59 (s, 2H), 7.79 (bs, 2H), 8.08 (s,
1H); MS (CI) m/z 397, 398 (M + H, M + 2H). Anal. Calcd for
C
18H26BrN3O2: C, 54.55; H, 6.61; N, 10.6. Found: C, 54.51; H,
6.54; N, 10.43.
J O9707491