Cyclization of substituted phenyl N-(2-hydroxybenzyl)carbamates in aprotic solvents. Synthesis of 4H-1,3-benzoxazin-2(3H)-ones

Article abstract of DOI:10.1135/cccc20001262

The kinetics of cyclization of substituted phenyl N-(2-hydroxybenzyl)carbamates and their N-methyl analogs, prepared by the reaction of 2-(aminomethyl)phenols with substituted phenyl chloroformates, was studied in dioxane or toluene at the temperatures 110-180 °C. Electron-withdrawing substituents in the leaving phenoxy group strongly accelerate the rate of cyclization (ρ = 2.45 ± 0.15) while the substituents in the other ring have virtually no effect. The cyclization was catalyzed with triethylamine in toluene but not in dioxane. On the basis of these results, the most convenient method for preparation of substituted 4H-1,3-benzoxazin-2(3H)-ones was a one-hour reflux of substituted 4-nitrophenyl N-(2-hydroxybenzyl)carbamates in dioxane. Based on the influence of substituents, solvents (dioxane and toluene) and triethylamine, the reaction mechanism and structure of the transition state were proposed.

Full text of DOI:10.1135/cccc20001262

1262
Mindl, Hrabík, Štěrba, Kaválek:
CYCLIZATION OF SUBSTITUTED PHENYL
N-(2-HYDROXYBENZYL)CARBAMATES IN APROTIC SOLVENTS.
SYNTHESIS OF 4H-1,3-BENZOXAZIN-2(3H)-ONES
1,
2
3
Jaromír MINDL *, Oldřich HRABÍK, Vojeslav ŠTĚRBA and Jaromír KAVÁLEK
Department of Organic Chemistry, University of Pardubice, 532 10 Pardubice, Czech Republic;
1
2
3
e-mail: jaromir.mindl@upce.cz, vojeslav.sterba@upce.cz, jaromir.kavalek@upce.cz
Received Jan uary 25, 2000
Accepted Jun e 12, 2000
Th e kin etics of cyclization of substituted ph en yl N-(2-h ydroxyben zyl)carbam ates an d th eir
N-m eth yl an alogs, prepared by th e reaction of 2-(am in om eth yl)ph en ols with substituted
ph en yl ch loroform ates, was studied in dioxan e or toluen e at th e tem peratures 110–180 °C.
Electron -with drawin g substituen ts in th e leavin g ph en oxy group stron gly accelerate th e
rate of cyclization (ρ = 2.45 ± 0.15) wh ile th e substituen ts in th e oth er rin g h ave virtually
n o effect. Th e cyclization was catalyzed with trieth ylam in e in toluen e but n ot in dioxan e.
On th e basis of th ese results, th e m ost con ven ien t m eth od for preparation of substituted
4H-1,3-ben zoxazin -2(3H)-on es was
a on e-h our reflux of substituted 4-n itroph en yl
N-(2-h ydroxyben zyl)carbam ates in dioxan e. Based on th e in fluen ce of substituen ts, solven ts
(dioxan e an d toluen e) an d trieth ylam in e, th e reaction m ech an ism an d structure of th e tran -
sition state were proposed.
Key w ord s: Carbam ates; Cyclization s; Kin etics; Ben zoxazin es; Ben zoxazin on es; Substituen t
effects.
4H-1,3-Ben zoxazin -2(3H)-on es 1 an d aryl N-ben zylcarbam ates 2 in h ibit th e
activity of acetylch olin esterase1 an d h en ce are biologically active com -
poun ds. Ben zoxazin -2-on es are ph osh odiesterase in h ibitors an d an ti-
th rom botic ph arm aceuticals2. Th e syn th eses of 4H-1,3-ben zoxazin -2(3H)-
on es 1 publish ed so far use 2-(am in om eth yl)ph en ols 3 cyclized with ph os-
gen e in th e presen ce of N,N-dim eth ylan ilin e3. A th erm al cyclization of
(2-h ydroxyph en yl)acetylazide to 4H-1,3-ben zoxazin -2(3H)-on e in ben zen e
solution was also described4. Th e in tram olecular reaction s of sim ilar com -
poun ds in water at 25 °C catalyzed by h ydroxide ion (Sch em e 1) was pub-
lish ed5,6. Th e rate con stan t of aryl N-(2-h ydroxyph en yl)carbam ates 4 is ca
ten tim es lower th an th at of N-m eth yl-N-(2-h ydroxyph en yl)carbam ates 5.
Th e autors5 estim ated th at th e cyclization of 4 is ca 8 order of m agn itudes
faster th e th e in term olecular reaction of N-(4-h ydroxyph en yl)carbam ates.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Synthesis of 4H-1,3-Benzoxazin-2(3H)-ones
1263
R
N
R
R
N
O
N
O
kc
HO
C
O
C
O
O
- PhO
O
Ph
O
H
Ph
O
5, R = CH3
4, R = H
SCHEME 1
Th e aim of th is work was to study a n ew two-step n on -ph osgen e syn th e-
sis of 4H-1,3-ben zoxazin -2(3H)-on es 1a–1g by cyclization of substituted
ph en yl N-(2-h ydroxyben zyl)carbam ates 2a–2o, prepared by reaction of
2-(am in om eth yl)ph en ols 3a–3g with substituted ph en yl ch loroform ates
6a–6e (Sch em e 2) an d th e kin etics of cyclization an d determ in ation of reac-
tion m ech an ism . Th e yields of oxazin es 1a–1g prepared by th is m eth od are
com pared with th e on e-step ph osgen ation m eth od.
5'
R5
6'
O
4'
1
6
3
7
R1
R2
R5
R4
1'
R1
R2
C
1
NHR3
O
C
N
R3
O
R4
3'
base
- HCl
2
5
2'
2
+
3
OH
Cl
O
4
OH
4
2
6
3
1
4
R3
O
R1
R2
100–180 oC
COCl2
base
N
2
- R4R5C6H3OH
3
O
1
R1 R2 R3
R4 R5
R1 R2 R3 R4 R5
R1 R2 R3 R4 R5
R1 R2 R3
3a
3b
3c
3d
3e
3f
6a
6b
6c
6d
6e
2a
2b
2c
2d
2e
2f
2i
2j
1a
1b
1c
1d
1e
1f
H
H
Br
H
H
H
H
H
Me
Me
H
Cl
H
H
H
Cl
H
H
H
H
H
H
H
H
H H
H H Cl
H H
H
H
H
Cl
H
H
Br
H
H
H
H
H
Me NO2 H
Me H NO2
Me H NO2
H
H
Br
NO2
H
H
H
H
H
H
Me
Me
Me
2k
2l
2m
2n
2o
H
Cl Me
NO2 H
NO2
H H NO2 H
Cl Me H NO2
NO2 Me H NO2
NO2 H Me
H
H
H
H H
H
NO2
H
H
Cl Me
NO2 Me
H
NO2 Me
Ph
H Me H
H Me Cl
H Me H Cl
NO2 H Me H NO2
H
H
H
3g
2g
2h
1g
H
H
Ph H NO2
Ph
SCHEME 2
EXPERIMENTAL
Meltin g poin ts were m easured on a Koffler in strum en t an d are n ot corrected. 1H (360 MHz)
an d 13C (90.56 MHz) NMR spectra were recorded usin g a Bruker AMX 360 spectrom eter as
saturated solution s in CDCl3. Th e 13C NMR ch em ical sh ifts were referen ced to th e solven t
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1264
Mindl, Hrabík, Štěrba, Kaválek:
sign al an d th is was recalculated in th e δ-scale (δ(13C) 77.00 ppm ). Th e δ(1H) ch em ical sh ifts
were referen ced to th e in tern al h exam eth yldisiloxan e (δ 0.05 ppm ) stan dard. Couplin g con -
stan ts 3J(H,H) are given in Hz. UV spectra were m easured on a Specord M40, Carl Zeiss Jen a
apparatus; λ are given in n m .
Syntheses
Syn th esis of Ph en yl N-(2-Hydroxyben zyl)carbam ates (2). Gen eral Procedure
A ph en yl ch loroform ate 6 (5 m m ol) in dieth yl eth er (3 m l) was added to a 2-(am in o-
m eth yl)ph en ol 3 (5 m m ol) an d trieth ylam in e (6 m m ol) in dieth yl eth er (3 m l) an d th e reac-
tion was m on itored by TLC. After stirrin g at room tem perature for 30 m in an d subsequen tly
saturatin g th e reaction m ixture with gaseous h ydrogen ch loride, th e precipitated
trieth ylam in e h ydroch loride was filtered off. Dieth yl eth er was distilled off an d th e crude
product was crystallized from a m ixture h eptan e–propan -2-ol (4 : 1).
Phenyl N-(2-hydroxybenzyl)carbamate (2a). From 3a an d 6a. Yield 61%, m .p. 78–80 °C. For
C14H13NO3 (243.3) calculated: 69.12% C, 5.44% H, 5.80% N; foun d: 69.40% C, 5.67% H,
5.86% N. 1H NMR (CDCl3): 7.95 b, 1 H (OH); 7.33 t, 2 H, J = 7.9 (H-3′,5′); 7.20 m (overlap),
1 H (H-4); 7.19 t (overlap), 1 H (H-4′); 7.13 d, 1 H, J = 8.0 (H-6); 7.08 d, 2 H, J = 7.4 (H-2′,6′);
6.90 d, 1 H, J = 8.0 (H-3); 6.86 t, 1 H, J = 7.4 (H-5); 5.79 b, 1 H (NH); 4.35 d, 2 H, J = 6.5
(H-7). UV (MeOH), λm ax (log ε): 203 (4.34), 274 (3.41).
3-Chlorophenyl N-(2-hydroxybenzyl)carbamate (2b ). From 3a an d 6b . Yield 68%, m .p.
98–99 °C. For C14H12ClNO3 (277.7) calculated: 60.58% C, 4.36% H, 5.02% N; foun d: 60.49% C,
4.41% H, 5.05% N. 1H NMR (CDCl3): 7.62 b, 1 H (OH); 7.26 t, J = 8.0 (H-5′); 7.21 m (over-
lap), 1 H (H-4); 7.18 m , 1 H (H-4′); 7.14 d (overlap), 1 H (H-6); 7.13 t, 1 H, 4J = 2.0 (H-2′);
7.00 m , 1 H (H-6′); 6.90 d, 1 H, J = 8.1 (H-3); 6.87 t, 1 H, J = 7.4 (H-5); 5.79 b, 1 H (NH);
4.37 d, 2 H, J = 6.5 (H-7). UV (MeOH), λm ax (log ε): 203 (4.66), 274 (3.44).
4-Chlorophenyl N-(2-hydroxybenzyl)carbamate (2c). From 3a an d 6c. Yield 69%, m .p.
125–127 °C. For C14H12ClNO3 (277.7) calculated: 60.58% C, 4.36% H, 5.02% N; foun d:
60.79% C, 4.42% H, 5.31% N. 1H NMR (CDCl3): 7.69 b, 1 H (OH); 7.28 AA′XX′-system , 2 H
(H-3′,5′); 7.21 t, 1 H, J = 7.8 (H-4); 7.14 d, 1 H, J = 7.5 (H-6); 7.03 AA′XX′-system , 2 H
(H-2′,6′); 6.90 d, 1 H, J = 8.1 (H-3); 6.86 t, 1 H, J = 7.5 (H-5); 5.78 b, 1 H (NH); 4.37 d, 2 H, J =
6.6 (H-7). UV (MeOH), λm ax (log ε): 202 (4.38), 219 (4.27), 274 (3.48).
3-Nitrophenyl N-(2-hydroxybenzyl)carbamate (2d ). From 3a an d 6d . Yield 72%, m .p. 113 °C
(dec.). For C14H12N2O5 (288.3) calculated: 58.29% C, 4.16% H, 9.72% N; foun d: 58.47% C,
4.22% H, 9.51% N. 1H NMR (CDCl3): 8.30 b, 1 H (OH); 8.10 m , 1 H (H-4′); 8.00 t, 1 H, 4J =
2.2 (H-2′); 7.52 t, 1 H, J = 7.9 (H-5′); 7.48 m , 1 H (H-6′); 7.22 t, 1 H, J = 7.6 (H-4); 7.18 d,
1 H, J = 7.1 (H-6); 6.90 d, 1 H, J = 7.6 (H-3); 6.89 t, 1 H, J = 7.6 (H-5); 5.87 b, 1 H (NH);
4.42 d, 2 H, J = 6.5 (H-7). UV (MeOH), λm ax (log ε): 202 (4.34), 265 (3.84).
4-Nitrophenyl N-(2-hydroxybenzyl)carbamate (2e). From 3a an d 6e. Yield 75%, m .p. 75 °C
(dec.). For C14H12N2O5 (288.3) calculated: 58.29% C, 4.16% H, 9.72% N; foun d: 58.22% C,
4,31% H, 9.51% N. 1H NMR (CDCl3): 8.25 b, 1 H (OH); 8.22 AA′XX′-system , 2 H (H-3′,5′);
7.29 AA′XX′-system , 2 H (H-2′,6′); 7.25 (overlap), 1 H (H-4); 7.18 d, 1 H, J = 7.0 (H-6); 6.92 d,
1 H, J = 8.0 (H-3); 8.89 t, 1 H, J = 7.5 (H-5); 5.89 b, 1 H (NH); 4.42 d, 2 H, J = 6.4 (H-7).
UV (MeOH), λm ax (log ε): 203 (4.40), 214 (4.18), 276 (4.08).
Phenyl N-(2-hydroxybenzyl)-N-methylcarbamate (2f). From 3b an d 6a. Yield 73%, m .p. 145–
147 °C. For C15H15NO3 (257.2) calculated: 70.06% C, 5.86% H, 5.42% N; foun d: 70.32% C,
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Synthesis of 4H-1,3-Benzoxazin-2(3H)-ones
1265
6.04% H, 5.56% N. 1H NMR (CDCl3): 8.65 b, 1 H (OH); 7.36 t, 2 H, J = 7.6 (H-3′,5′); 7.26 t,
1 H, J = 7.6 (H-4′); 7.22 m , 1 H (H-4); 7.15 d, 1 H, J = 7.8 (H-6); 7.09 d, 2 H, J = 7.6 (H-2′,6′);
6.96 d, 1 H, J = 8.0 (H-3); 6.85 t, 1 H, J = 7.5 (H-5); 4.34 s, 2 H (H-7); 3.13 s, 3 H (NCH3). UV
(MeOH), λm ax (log ε): 204 (4.34), 275 (3.41).
3-Chlorophenyl N-(2-hydroxybenzyl)-N-methylcarbamate (2g). From 3b an d 6b. Yield 57%,
m .p. 120.5–122.0 °C. For C15H14ClNO3 (291.7) calculated: 61.77% C, 4.83% H, 4.82% N;
foun d: 62.04% C, 4. 75% H, 4.64% N. 1H NMR (CDCl3): 8.47 b, 1 H (OH); 7.28 t, J = 8.0
(H-5′); 7.22 m (overlap), 1 H (H-4); 7.19 m , 1 H (H-4′); 7.15 d (overlap), 1 H (H-6); 7.12 t,
1 H, 4J = 1.8 (H-2′); 6.99 m , 1 H (H-6′); 6.92 d, 1 H, J = 8.0 (H-3); 4.40 s, 2 H (H-7), 3.07 s,
3 H (NCH3). UV (MeOH), λm ax (log ε): 204 (4.50), 275 (3.42).
4-Chlorophenyl N-(2-hydroxybenzyl)-N-methylcarbamate (2h ). From 3b an d 6c. Yield 47%,
m .p. 130.5–133.0 °C. For C15H14ClNO3 (291.7) calculated: 61.77% C, 4.83% H, 4.82% N;
foun d: 61.90% C, 4. 99% H, 4.74% N. 1H NMR (CDCl3): 8.50 b, 1 H (OH); 7.31 AA′XX′-sys-
tem , 2 H (H-3′,5′); 7.25 t, J = 7.5 (H-4); 7.15 d, 1 H, J = 7.5 (H-6); 7.04 AA′XX′-system , 2 H
(H-2′,6′); 6.95 d, J = 7.7 (H-3); 6.85 t, 1 H, J = 7.4 (H-5); 4.42 s, 2 H (H-7); 3.12 s, 3 H
(NCH3). UV (MeOH), λm ax (log ε): 203 (4.43), 219 (4.30), 275 (3.49).
3-Nitrophenyl N-(2-hydroxybenzyl)-N-methylcarbamate (2i). From 3b an d 6d . Yield 84%, m .p.
110 °C (dec.). For C15H14N2O5 (302.3) calculated: 59.59% C, 4.73% H, 9.33% N; foun d:
59.29% C, 4.53% H, 9.24% N. 1H NMR (CDCl3): 8.23 b, 1 H (OH); 8.09 d, 1 H, J = 7.4 (H-4′);
8.00 t, 1 H (H-2′); 7.54 t, 1 H, J = 7.8 (H-5′); 7.50 d, 1 H, J = 7.5 (H-6′); 7.26 t, 1 H, J = 7.4
(H-4); 7.17 d, 1 H, J = 7.0 (H-6); 6.96 d, 1 H, J = 7.7 (H-3); 6.85 t, J = 7.4 (H-5); 4.46 s, 2 H
(H-7); 3.16 s, 3 H (NCH3). UV (MeOH), λm ax (log ε): 203 (4.40), 265 (3.86).
4-Nitrophenyl N-(2-hydroxybenzyl)-N-methylcarbamate (2j). From 3b an d 6e. Yield 75%, m .p.
121 °C (dec.). For C15H14N2O5 (302.3) calculated: 59.59% C, 4.73% H, 9.33% N; foun d:
59.31% C, 4.67% H, 9.28% N. 1H NMR (CDCl3): 8.24 AA′XX′-system , 2 H (H-3′,5′); 8.23 b,
1 H (OH); 7.28 AA′XX′-system , 2 H (H-2′,6′); 7.26 (overlap), 1 H (H-4); 7.16 d, 1 H, J = 7.3
(H-6); 6.96 d, 1 H, J = 8.0 (H-3); 6.78 t, 1 H, J = 7.4 (H-5); 4.46 s, 2 H (H-7); 3.15 s, 3 H
(NCH3). UV (MeOH), λm ax (log ε): 204 (4.41), 214 (4.23), 277 (4.08).
4-Nitrophenyl N-(5-bromo-2-hydroxybenzyl)-N-methylcarbamate (2k). From 3c an d 6e. Yield
78%, m .p. 78 °C. (dec.). For C15H13BrN2O5 (381.2) calculated: 47.26% C, 3.42% H, 7.43% N;
foun d: 47.38% C, 3.32% H, 7.24% N. 1H NMR (CDCl3): 8.30 b, 1 H (OH); 8.24 AA′XX′-sys-
tem , 2 H (H-3′,5′); 7.32 dd, 1 H, 4J = 2.1 (H-4); 7.30 AA′XX′-system , 2 H (H-2′,6′); 7.28 d,
1 H, J = 7.5 (H-6); 6.83 d, 1 H, J = 8.7 (H-3); 4.40 s, 2 H (H-7); 3.17 s, 3 H (NCH3). UV
(MeOH), λm ax (log ε): 204 (4.41), 219 (4.34), 275 (4.05).
4-Nitrophenyl N-(2-hydroxy-4-chlorobenzyl)-N-methylcarbamate (2l). From 3d ·HCl an d 6e
in th e presen ce of double m olar excess of trieth ylam in e. Yield 43%, m .p. 131 °C (dec.). For
C
15H13ClN2O5 (336.1) calculated: 53.56% C, 3.87% H, 8.33% N; foun d: 53.39% C, 4.06% H,
8.30% N. 1H NMR (CDCl3): 8.40 b, 1 H (OH); 8.24 AA´XX´system , 2 H (H-3′,5′); 7.29
AA′XX′-system , 2 H (H-2′,6′); 7.08 d, 1 H, J = 7.9 (H-6); 6.95 m , 1 H (H-3); 6.85 t, 1 H (H-5);
4.41 s, 2 H (H-7); 3.14 s, 3 H (NCH3). 13C NMR (CDCl3): 156.45, 155.72, 155.40, 145.16,
135.74, 131.90, 126.09, 125.09, 122.15, 119.97, 49.54, 34.41. UV (MeOH), λm ax (log ε): 204
(4.67), 279 (3.67).
4-Nitrophenyl N-(2-hydroxy-4-nitrobenzyl)-N-methylcarbamate (2m ). From 3f·HCl an d 6e in
th e presen ce of double m olar excess of trieth ylam in e. Yield 86%, m .p. 137 °C. (dec.). For
C
15H13N3O7 (347.3) calculated: 51.92% C, 3.82% H, 12.09% N; foun d: 51.88% C, 3.71% H,
12.33% N. 1H NMR (CDCl3): 8.88 b, 1 H (OH); 8.26 AA′XX′-system , 2 H (H-3′,5′); 7.78 m ,
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

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Mindl, Hrabík, Štěrba, Kaválek:
1 H (H-3); 7.73 d, 1 H, J = 8.4 (H-5); 7.31 AA′XX′-system , 2 H (H-2′,6′); 7.30 (overlap), 1 H
(H-6); 4.53 s, 2 H (H-7); 3.19 s, 3 H (NCH3). UV (MeOH), λm ax (log ε): 203 (4.69), 283 (4.34).
4-Nitrophenyl N-(2-hydroxy-5-nitrobenzyl)-N-methylcarbamate (2n ). From 3e an d 6e. Yield
59%, m .p. 151 °C. (dec.). For C15H13N3O7 (347.3) calculated: 51.92% C, 3.82% H, 12.09% N;
foun d: 51.76% C, 3.64% H, 12.17% N. 1H NMR (CDCl3): 9.48 b, 1 H (OH); 8.26 AA′XX′-sys-
tem , 2 H (H-3′,5′); 8.17 dd, 1 H, 4J = 2.7 (H-4); 8.13 d, 1 H (H-6); 7.32 AA′XX′-system , 2 H
(H-2′,6′); 7.02 d, 1 H, J = 8.9 (H-3); 4.50 s, 2 H (H-7); 3.22 s, 3 H (NCH3). UV (MeOH), λm ax
(log ε): 203 (4.38), 283 (4.15).
4-Nitrophenyl N-(2-hydroxybenzyl)-N-phenylcarbamate (2o). From 3g an d 6e. Yield 86%, m .p.
115 °C. (dec.). For C20H16N2O5 (364.3) calculated: 65.93% C, 4.43% H, 7.69% N; foun d:
66.21% C, 4.37% H, 7.96% N. 1H NMR (CDCl3): 8.33 b, 1 H (OH); 8.16 AA′XX′-system , 2 H
(H-3′,5′); 7.30 m , 2 H (H-3,5-NPh ); 7.26 m , 1 H (H-4); 7.20 AA′XX′-system , 2 H (H-2′,6′); 7.17
(overlap), 1 H (H-4-NPh ); 7.15 m , 2 H (H-2,6-NPh ); 6.96 d, 1 H, J = 8.00 (H-6); 6.70 (over-
lap), 1 H (H-3); 6.70 (overlap), 1 H (H-5); 4.82 s, 2 H (H-7). 13C NMR (CDCl3): 158.24,
155.46, 152.03, 145.01, 139.91, 131.58, 130.27, 129.43, 128.21, 127.39, 124.88, 121.94,
121.49, 119.83, 51.69. UV (MeOH), λm ax (log ε): 203 (4.54), 276 (4.08).
Syn th esis of Substituted 4H-1,3-Ben zoxazin -2(3H)-on es (1). Gen eral Procedures
Procedure A. A solution of 5 m m ol of 4-n itroph en yl carbam ate 2e, 2j–2o in dioxan e (5 m l)
was h eated un der reflux for on e h our. After coolin g dich lorom eth an e (20 m l) was added an d
th e m ixture was extracted several tim es with 8% aqueous solution of am m on ium carbon ate
un til th e aqueous ph ase con tain ed n o yellow 4-n itroph en olate. Th en th e organ ic ph ase was
wash ed with water an d dried with an h ydrous sodium sulfate. Th e solven t was evaporated
an d th e residue was crystallized from toluen e.
4H-1,3-Benzoxazin-2(3H)-one (1a). From 2e. Yield 81%, m .p. 190–192 °C; ref.7 m .p. 193 °C.
UV (MeOH), λm ax (log ε): 203 (4.11), 268 (2.91). Th e form ation of 1a from carbam ates
2a–2d in 1 M dioxan e solution was verified by HPLC followin g th e reaction carried out at a
h igh er tem perature (°C) for th e given tim e (h ) with a yield (%): 2a, 180, 7, 93; 2b, 150, 7,
95; 2c, 170, 5, 94; 2d , 130, 1, 98.
3-Methyl-4H-1,3-benzoxazin-2(3H)-one (1b). From 2j. Yield 80%, m .p. 106–108 °C; ref.3
m .p. 106–108 °C. 13C NMR (CDCl3): 150.75, 149.79, 127.20, 125.23, 124.07, 116.99, 116,19,
49.38, 36.66. UV (MeOH), λm ax (log ε): 203 (4.08), 268 (2.95), 275 (2.89). Th e form ation of
1b from carbam ates 2f–2i in 1 M dioxan e solution was verified by HPLC followin g th e reac-
tion carried out at a h igh er tem perature (°C) for th e given tim e (h ) with a yield (%): 2f, 180,
4, 94; 2g, 150, 4, 95; 2h , 170, 5, 94; 2i, 120, 8, 97.
6-Bromo-3-methyl-4H-1,3-benzoxazin-2(3H)-one (1c). From 2k . Yield 77%, m .p. 148.5–
151 °C. For C9H8BrNO2 (242.1) calculated: 44.72% C, 3.28% H, 5.81% N; foun d: 44.84% C,
3.56% H, 5.66% N. 1H NMR (CDCl3): 7.32 dd, 1 H, 3J = 8.00, 4J = 2.1 (H-3); 7.20 d, 1 H, J =
8.0 (H-4); 7.00 d, 1 H, 4J = 2.3 (H-1); 4.35 s, 2 H (CH2); 3.12 s, 3 H (NCH3). 13C NMR
(CDCl3): 149.80, 148.61, 131.58, 127.86, 118.83, 116.16, 48.61, 36.14. UV (MeOH), λm ax
(log ε): 203 (4.32), 230 (3.87), 278 (3.04).
3-Methyl-6-nitro-4H-1,3-benzoxazin-2(3H)-one (1d ). From 2n . Yield 85%, m .p. 203–204 °C;
ref.3 m .p. 202.0–204.5 °C. UV (MeOH), λm ax (log ε): 202 (4.11), 284 (3.57).
7-Chloro-3-methyl-4H-1,3-benzoxazin-2(3H)-one (1e). From 2l. Yield 64%, m .p. 99.0–
101.5 °C. For C9H8ClNO2 (197.2) calculated: 54.77% C, 4.06% H, 7.01% N; foun d:
54.83% C, 3.86% H, 6.86% N. 1H NMR (CDCl3): 7.07 dd, 1 H, 3J = 8.1, 4J = 1.6 (H-2); 7.02 d,
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Synthesis of 4H-1,3-Benzoxazin-2(3H)-ones
1267
1 H, 4J = 2.1 (H-1); 7.01 d, 1 H, J = 8.1 (H-4); 4.43 s, 2 H (CH2); 3.11 s, 3 H (NCH3). UV
(MeOH), λm ax (log ε): 206 (4.25), 276 (3.06), 282 (3.05).
3-Methyl-7-nitro-4H-1,3-benzoxazin-2(3H)-one (1f). From 2m . Yield 72%, m .p. 157.5–
159.0 °C. For C9H8N2O4 (208.1) calculated: 51.90% C, 3.84% H, 6.72% N; foun d: 52.04% C,
3.66% H, 6.61% N. 1H NMR (CDCl3): 7.23 d, 1 H, J = 8.5 (H-2); 8.13 dd, 1 H, 4J = 1.8 (H-1);
7.07 d, 1 H, J = 8.9 (H-4); 4.51 s, 2 H (CH2); 3.17 s, 3 H (NCH3). UV (MeOH), λm ax (log ε):
204 (4.21), 284 (3.35).
3-Phenyl-4H-1,3-benzoxazin-2(3H)-one (1g). From 2o. Yield 81%, m .p. 144–145 °C
(2-propan ol); ref.8 m .p. 146 °C.
Procedure B. A solution of substituted 2-(am in om eth yl)ph en ol 2 (5 m m ol) an d dim eth yl-
an ilin e (10 m m ol) in a m ixture of toluen e (2 m l) an d dich lorom eth an e (2 m l) was added
dropwise to a solution of ph osgen e (7 m m ol) in toluen e (10 m l) with stirrin g at 0– 10 °C.
Th e m ixture was th en refluxed for 30 m in . After coolin g it was wash ed with 5% solution of
h ydroch loric acid an d th en with water. Th e organ ic ph ase was dried, evaporated an d th e
crude product crystallized from eth an ol–toluen e m ixtures. Oxazin e yields: 1a from 3a (74%);
1b from 3b (71%); 1c from 3c (69%); 1d from 3e (59%); 1g from 3g (69%).
Procedure C. To a solution of 2-(am in om eth yl)ph en ol 3a (5 m m ol) an d trim eth ylam in e
(5 m m ol) in dioxan e (5 m l) was added dropwise with stirrin g 4-n itroph en yl ch loroform ate
6e (5 m m ol) in dioxan e (5 m l) at room tem perature durin g 2 m in . After an oth er 5 m in
trieth ylam in e h ydroch loride was filtered off an d wash ed with dioxan e (5 m l). Th e dioxan e
solution was h eated to reflux for 1 h . Dioxan e was evaporated un der reduced pressure an d
solid residue was dissolved in dich lorom eth an e (15 m l). 4-Nitroph en ol was extracted with
8% aqueous am m on ium carbon ate. After evaporation of dich lorom eth an e 4H-1,3-
ben zoxazin -2(3H)-on es 1a was crystallized from toluen e. Yield 93%, m .p. 190–192 °C.
4-Ch loro-2-h ydroxy-N-m eth ylben zylam in e Hydroch loride (3d ·HCl)
From 4-ch loro-2-h ydroxyben zaldeh yde9 (7.80 g, 50 m m ol) by treatm en t of m eth ylam in e
(16 m l of 10% m eth an olic solution , 50 m m ol) for 20 m in at room tem perature. Th e solution
of im in e was m ixed with sodium boroh ydride (0.57 g, 55 m m ol) at room tem perature. After
30 m in th e m ixture was acidified with 5% aqueous h ydroch loric acid to pH 1. After th at th e
solution was alkalized with 5% aqueous sodium h ydroxide to pH 10. Th e organ ic ph ase was
extracted th ree tim es with 30 m l of eth er. Th e separated organ ic ph ase was wash ed th ree
tim es with water an d dried with an h ydrous sodium sulfate. Gaseous h ydrogen ch loride was
bubbled in to th e solution cooled to 10 °C for 2 m in . Th e separated product was filtered off
an d wash ed with eth er. Yield 3.0 g (36%), m .p. 191.0 °C (dec.). 1H NMR (D2O): 6.99 d, 1 H,
J = 8.1 (H-6); 6.70 d, 1 H, J = 1.9 (H-3); 6.68 dd, 1 H, 3J = 8.1, 4J = 1.9 (H-5); 3.88 s, 2 H
(CH2); 2.44 s, 3 H (CH3).
2-Hydroxy-N-m eth yl-4-n itroben zylam in e Hydroch loride (3f·HCl).
From 2-h ydroxy-4-n itroben zaldeh yde10 (8.35 g, 50 m m ol). Th e reaction was carried out in a
sim ilar way as in case of 3d ·HCl. Yield 2.7 g (25%), m .p. 243 °C (dec.). 1H NMR (D2O):
7.58 d, 1 H, J = 1.7 (H-3); 7.56 dd, 1 H, 3J = 8.0 (H-5); 7.21d, 1 H, J = 8.0 (H-6); 4.01 s, 2 H
(CH2); 2.49 s, 3 H (CH3).
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1268
Mindl, Hrabík, Štěrba, Kaválek:
Kinetic Measurements
Th e m easurem en ts of rate con stan ts were carried out spectroph otom etrically with a Specord
M40, Carl Zeiss Jen a apparatus. Ch rom atograph ic ch eckin g was perform ed usin g HPLC–
Escom apparatus on colum n SGC C18 with 60% aqueous m eth an ol at λ = 254 n m .
Ch rom atograph ic Meth od D
Th e 1 M solution s of carbam ates 2a–2d an d 2f–2i an d 1,4-dich loroben zen e (in tern al stan -
dard) in dry dioxan e in m icroam poules were h eated in an oil bath at con stan t tem perature
in th e ran ge 110–180 °C. Th e am poules were cooled at regular tim e periods, th e con ten ts di-
luted to 10–2 M usin g m eth an ol an d th en in jected to HPLC ch rom atograph . Rate con stan ts
kc (s–1) were calulated from th e decrease of con cen tration of th e startin g carbam ates 2.
Spectroph otom etric Meth od E
Th e 1·10–2 M solution s of 4-n itrocarbam ates 2e an d 2j–2n in dry dioxan e in m icroam poules
were term ostatted in an oil bath at 110 °C. Am poules were cooled in regular tim e periods
an d th eir con ten ts diluted to 5·10–5 M solution by addition of aqueous acetate buffer (pH 5.65).
4-Nitrocarbam ates 2e an d 2j were also m easured in toluen e an d were diluted to 5·10–5 M so-
lution by addition of m eth an ol. For evaluation of th e rate con stan ts kc, th e absorban ces of
th ese solution s were m easured in 1 cm cells at 280 n m (λm ax of 4-n itroph en ol) an d 350 n m ,
wh ere th e spectral differen ces of products an d startin g carbam ates were m axim al.
RESULTS AND DISCUSSION
Rate con stan ts of cyclization kc (s–1) of carbam ates 2 were m easured in
dioxan e. 4-Nitrocarbam ates 2e, 2j–2n form ed products wh ich were spec-
trally well distin guish ed from th e startin g carbam ates usin g m eth od E.
Spectral differen ces of oth er carbam ates an d th eir products of cyclization
were sm all an d th erefore it was n ecessary to in sert ch rom atograph ical sepa-
ration by m eth od D. Cyclization of som e carbam ates, wh ich proceed at
tem perature 110 °C very slowly, were carried out at h igh er tem peratures.
Th e obtain ed velocity con stan ts kc were recalculated to th is tem perature us-
in g th e Arrh en ius equation . A good agreem en t between th e exptrapolated
an d m easured value was verified for com poun d 2g (Table I). Reaction s were
first order with respect to substrate con cen tration . For carbam ates 2a–2e
(R3 = H) an d 2f–2j (R3 = Me) wh ere th ere was a ch an ge of th e substituen t in
th e ph en oxide leavin g group (R1 = R2 = H), electron -with drawin g substitu-
en ts in creased th e reaction rate, an d th e kin etics of cyclization were m ea-
sured at 110–180 °C. At th e h igh est tem peratures th ere was decom position
of th e product 1 (up to 7%).
Th e in fluen ce of substituen ts R1 an d R2 in th e am in om eth ylph en ol n u-
cleus was exam in ed in case of 4-n itroph en yl derivatives 2j–2n . In con trast
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Synthesis of 4H-1,3-Benzoxazin-2(3H)-ones
1269
to th e substituen ts on th e leavin g ph en oxy group, th e in fluen ce of substitu-
en ts R1 an d R2 on th e rate of cyclization was sm all an d all th e m easure-
m en ts could be carried out at th e sam e tem perature 110 °C (Table I). To
determ in e th e effect of th e substituen ts at th e leavin g ph en oxy group th e
values of kc m easured at h igh er tem peratures were extrapolated to 110 °C.
Th e depen den ce of log kc on T–1 was sim ilar for all substituen ts (–5.3 ±
0.3)·10–3 K–1, i.e. ∆H≠ values are th e sam e an d th e effect of th e substituen ts
is predom in an tly determ in ed by th e en tropy of activation .
TABLE I
Rate con stan ts kc (s–1
a
)
of cyclization of carbam ates 2 to oxazin es 1 in dioxan e solution
Com -
poun d
Com -
poun d
105 kc
105 kc
T, °C
Meth od
T, °C
Meth od
2a
2b
2c
89.1
26.3
0.67d
180
160
110
150
130
110
170
150
110
110
110
110
110
110
110
180
160
110
D
D
–
2g
129
37.1
8.84
8.9d
115
150
130
110
110
160
140
110
110
110
110
110
110
110
110
110
110
110
–
D
D
–
87.1
D
D
–
30.2
5.4d
2h
D
D
–
30.9
3.8d
38.0
138
D
D
–
36.3
2.1d
20.9
2i
2j
D
E
E
E
E
E
E
E
E
E
955
2d
2e
D
E
E
E
E
E
D
D
D
46.8b
234b,c
295b,c
389b
708
589
295b
571b,c
536b
567b
151
2k
2l
617
2f
2m
2n
794
42.7
1.4d
891
a
Reported rate con stan ts are th e m ean s of several determ in ation s an d are correct to ±5% in
b
c
dioxan e an d about ±10% in toluen e.
trieth ylam in e. Extrapolated value. With 2 equivalen ts of trieth ylam in e. With 4 equiva-
len ts of trieth ylam in e.
In toluen e solution .
W ith 1 equivalen t of
d
e
f
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1270
Mindl, Hrabík, Štěrba, Kaválek:
Th e slope of log kc on σ0 con stan ts (Fig. 1) h as th e value ρ = 2.50 ± 0.15
an d 2.40 ± 0.15 for N-H an d N-Me derivatives (th e kc values for 4-n itro de-
rivatives were n ot used for calculation of ρ con stan ts), respectively, but th e
cyclization rate of th e N-m eth yl derivatives is alm ost twice as h igh . On th e
basis of th e kin etic experim en ts a on e-h our reflux of 4-n itroph en yl carba-
m ates in dioxan e was foun d to be th e m ost suitable procedure for th e prep-
aration of th e substituted 4H-1,3-ben zoxazin -2(3H)-on es 1. Th e am oun t of
un reacted carbam ate was in all cases less th an 1%. Wh en th e carbam ate
form ed by th e reaction of substituted am in om eth ylph en ols with 4-n itro-
ph en yl form ate was isolated from th e reaction m ixture (procedure A) th e
m ean yield, based on am in om eth ylph en ol, was 62% an d by th e ph osgen e
m eth od (procedure B) 68%. Wh en th e preparation of th e product was car-
ried out with out isolation of carbam ate (procedure C), th e yield was alm ost
quan titative. Th e substituen ts in th e leavin g ph en oxy group effect th e rate
of cyclization con siderably (ρ = 2.45) th is m ean s th at th ere is a substan tial
splittin g of th e C–O bon d in th e tran sition state. However th e substituen ts
in th e secon d aryl n ucleus h ave little effect on th e rate of cyclization . Th is
m ay be caused by th e fact th at th e n ew C–O bon d is form ed on ly to a sm all
exten t or th at th ere is a sim ultan eous form ation of th e O–C an d splittin g of
th e O–H bon ds an d th e effect of substituen ts on both processes com pen -
sate: electron -with drawin g substituen ts m ake th e form ation of th e O–C
bon d difficult, but th ey facilitate th e splittin g of th e O–H bon d.
If th e cyclization proceeds by th is m ech an ism , th en th e presen ce of
trieth ylam in e, wh ich is m ore th an 10-orders of m agn itude a stron ger base
th an dioxan e, will in crease th e rate of cyclization . Th ere was actually n o
catalytic effect of added trieth ylam in e wh ich m ean s th at th ere is n o sub-
4-NO
2
–2
FIG. 1
Depen den ce of logarith m s of cyclization rate
con stan ts of substituted ph en yl N-(2-h ydroxy-
3-NO
–4
–6
2
ben zyl)carbam ates (ꢀ) an d substituted ph en yl
N-(2-h ydroxyben zyl)-N-m eth ylcarbam ates (ꢀ)
on σ0 con stan ts in dioxan e at 110 °C. For
4-nitrophenyl N-(2-hydroxybenzyl)carbamate (ꢀ)
and 4-nitrophenyl N-(2-hydroxybenzyl)-N-methyl-
carbam ate (◊) on σ– con stan t in dioxan e at
110 °C
3-Cl
4-Cl
H
0.0
0.4
0.8
1.2
–
0
σ
(σ )
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Synthesis of 4H-1,3-Benzoxazin-2(3H)-ones
1271
stan tial splittin g of th e O–H bon d in th e activated com plex. Th e tran sition
state can be stabilized by form ation of th e h ydrogen bon d between basic
solven t an d th e h ydrogen of th e O–H bon ds, if it is stron ger th an in th e
substrate11. Hydrogen bon d acceptin g ability of trieth ylam in e (β = 0.71) is
h igh er th an th at of dioxan e12 (β = 0.37), but its con cen tration is m ore th an
two orders of m agn itude sm aller h en ce it in fluen ces th e rate of cyclization
just sligh tly. Th erefore we m easured th e kin etics of cyclization of
4-n itroph en yl carbam ates 2e an d 2j in toluen e (β = 0.11) with an d with out
trieth ylam in e (Table I). Th e rate of cyclization with out trieth ylam in e in
case of N-H derivative 2e is ca twice an d th at of N-m eth yl derivatives 2j ca
twen ty tim es lower th an in dioxan e. After addin g trieth ylam in e th e values
kc gradually approach th e values in dioxan e. Th e in crease of rate is faster in
2j th an in 2e. In th e presen ce of excess trieth ylam in e all th e substrate is ob-
viously h ydrogen -bon ded to trieth ylam in e so th ere is n o m ore effect of fur-
th er addition of trieth ylam in e. Th is result is quite opposite to th e kin etics
of reaction of ph en ols with aryl isocyan ates13. In toluen e at 67 °C th e rate
of th e in term olecular reaction in creased lin early with th e con cen tration of
trieth ylam in e (k = 256 ± 15) l2 m ol–2 s–1 an d th ere was n o reaction in th e
absen ce of trieth ylam in e.
In con clusion , th e cyclization of carbam ates 2 in dioxan e is a con certed
reaction with breakin g of th e C–O bon d bein g m ore advan ced th an form a-
tion of th e O–C bon d. Th e reaction is accelerated by H-bon din g to a basic
solven t, wh ich is stron ger in th e tran sition state th an in th e substrate. Th e
un usual structure of tran sition state m ay be due to a large n um ber of reac-
tive con form ation s ch aracteristic of in tram olecular reaction s14.
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Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1272
Mindl, Hrabík, Štěrba, Kaválek:
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Collect. Czech. Chem. Commun. (Vol. 65) (2000)