Palladium-Catalyzed Cyclocarbonylation of o-Iodophenols and 2-Hydroxy-3-iodopyridine with Heterocumulenes: Regioselective Synthesis of Benzo[e]-1,3-oxazin-4-one and Pyrido[3,2-e]-1,3-oxazin-4-one Derivatives

Article abstract of DOI:10.1021/jo991256u

Benzo[e]-1,3-oxazin-2-imine-4-ones (3) were synthesized by cyclocarbonylation of o-iodophenols with carbodiimides in the presence of a catalytic amount of a palladium catalyst and 1,4-bis-(diphenylphosphino)butane under CO pressure. Product yields are dep

Full text of DOI:10.1021/jo991256u

9194
J . Org. Chem. 1999, 64, 9194-9200
P a lla d iu m -Ca ta lyzed Cycloca r bon yla tion of o-Iod op h en ols a n d
2-Hyd r oxy-3-iod op yr id in e w ith Heter ocu m u len es: Regioselective
Syn th esis of Ben zo[e]-1,3-oxa zin -4-on e a n d
P yr id o[3,2-e]-1,3-oxa zin -4-on e Der iva tives
Chitchamai Larksarp and Howard Alper*
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received August 9, 1999
Benzo[e]-1,3-oxazin-2-imine-4-ones (3) were synthesized by cyclocarbonylation of o-iodophenols with
carbodiimides in the presence of a catalytic amount of a palladium catalyst and 1,4-bis-
(diphenylphosphino)butane under CO pressure. Product yields are dependent on the nature of the
substrate, catalyst, solvent, and base as well as phosphine ligand. Reaction of o-iodophenols with
unsymmetrical carbodiimides affords benzo[e]-1,3-oxazin-2-imine-4-ones (11a -g) in good yield and
usually in a completely regioselective manner. Benzo[e]-1,3-oxazin-2,4-diones (5) were obtained in
good to excellent yields using the same procedure and a 1:2 ratio of o-iodophenol/isocyanate. Pyrido-
[3,2-e]-1,3-oxazin-4-ones (16) were isolated in fine yield using 2-hydroxy-3-iodopyridine instead of
an iodophenol as reactant. The reaction mechanism is believed to involve in situ formation of a
carbamate ester followed by palladium-catalyzed carbonylative amidation.
Sch em e 1
In tr od u ction
The palladium-catalyzed carbonylation of aryl halides
is an important, convenient, and highly effective method
for the synthesis of aromatic-containing carbonyl com-
pounds.1 The reactions are well established to proceed
by initial oxidative addition of palladium(0) to a carbon-
halogen bond, followed by carbon monoxide insertion.
There are many publications on the inter- and intramo-
lecular palladium-catalyzed cross-coupling reactions of
aromatic halides with a variety of unsaturated com-
pounds [e.g., olefins,2 alkynes,3 and allenes4 (Scheme 1)].
(1) (a) Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: New York, 1985. (b) Colquhoun, H. M.; Thompson,
D. J .; Twigg, M. V. Carbonylation; Plenum Press: New York, 1991.
(c) Tsuji, J . Palladium Reagents and Catalysts; J ohn Wiley & Sons:
New York, 1995. (d) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94,
1047.
(2) (a) Negishi, E.; Cope´ret, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour,
J . M. J . Am. Chem. Soc. 1996, 118, 5904. (b) Negishi, E.; Ma, S.;
Amanfu, J .; Cope´ret, C.; Miller, J . A.; Tour, J . M. J . Am. Chem. Soc.
1996, 118, 5919. (c) Grigg, R.; Putnikovic, B.; Urch, C. J . Tetrahedron
Lett. 1996, 37, 695. (d) Grigg, R.; Redpath, J .; Sridharan, V.; Wilson,
D. Tetrahedron Lett. 1994, 35, 7661. (e) Negishi, E.; Cope´ret, C.;
Sugihara, T.; Shimoyama, I.; Zhang, Y.; Wu, G.; Tour, J . M. Tetrahe-
dron 1994, 50, 425. (f) Cotellani, M.; Chiusoli, G. P. Gazz. Chim. Ital.
1996, 126, 57. (g) Anacardio, R.; Arcadi, A.; Anniballe, G. D.; Marinelli,
F. Synthesis 1995, 831. (h) Negishi, E.; Tour, J . M. Tetrahedron Lett.
1986, 27, 4869. (i) Shimoyama, I.; Zhang, Y.; Wu, G.; Negishi, E.
Tetrahedron Lett. 1990, 31, 2841. (j) Negishi, E.; Wu, G.; Tour, J . M.
Tetrahedron Lett. 1988, 29, 6745. (k) Wu, G.; Shimoyama, I.; Negishi,
E. J . Org. Chem. 1991, 56, 6506.
(3) (a) Cope´ret, C.; Sugihara, T.; Negishi, E. Tetrahedron Lett. 1995,
36, 1771. (b) Cope´ret, C.; Sugihara, T.; Wu, G.; Shimoyama, I.; Negishi,
E. J . Am. Chem. Soc. 1995, 117, 3422. (c) Torii, S.; Okumoto, H.; Xu,
L. H. Tetrahedron Lett. 1991, 32, 237. (d) Kalinin, V. N.; Shostakovsky,
M. V.; Ponomaryov, A. B. Tetrahedron Lett. 1992, 33, 373. (e) Ciatini,
P. G.; Morera, E.; Ortar, G.; Rossi, S. S. Tetrahedron 1991, 47, 6449.
(f) Kobayashi, T.; Tanaka, M. J . Chem. Soc., Chem. Commun. 1981,
333. (g) Kalinin, V. N.; Shostakovsky, M. V.; Ponomaryov, A. B.
Tetrahedron Lett. 1990, 31, 4073. (h) Reference 2f. (i) Cope´ret, C.; Ma,
S.; Sugihara, T.; Negishi, E. Tetrahedron 1996, 52, 11529. (j) Arcadi,
A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron 1994, 50, 437.
(k) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J . Org. Chem.
1992, 57, 4754. (l) Bishop, B. C.; Cottrell, J . F.; Hands, D. Synthesis
1997, 1315. (m) Torii, S.; Okumoto, H.; Xu, L. H.; Sadakane, M.
Tetrahedron 1993, 49, 6773.
We previously reported the use of heterocumulenes
such as carbodiimides and isocyanates in cycloaddition
ring-expansion reactions catalyzed by palladium com-
plexes.5 Palladium-catalyzed ring opening of vinyloxi-
ranes5a,b and vinyloxetanes5c resulted in the formation
of π-allylpalladium intermediates containing an anionic
oxygen moiety. Nucleophilic addition of the anion to the
carbon of the heterocumulene, followed by nucleophilic
addition on the π-allyl palladium moiety, afforded het-
erocyclic compounds (Scheme 2).
To our knowledge, no carbonylative coupling reactions
have been described of aromatic halides with cumulenes
containing heteroatoms when catalyzed by transition
metal complexes. We reasoned that o-iodophenols could
undergo palladium catalyzed cyclocarbonylation with
(4) (a) Grigg, R.; Sridharan, V.; Terrier, C. Tetrahedron Lett. 1996,
37, 4221. (b) Walkup, R. D.; Guan, L.; Kim, Y. S.; Kim, S. W.
Tetrahedron. Lett. 1995, 36, 3805. (c) Larock, R. C.; Berrios-Pen˜a, N.
G.; Fried, C. A. J . Org. Chem. 1991, 56, 2615. (d) Larock, R. C.; Zenner,
J . M. Synthesis 1995, 60, 482.
(5) (a) Larksarp, C.; Alper, H. J . Am. Chem. Soc. 1997, 119, 3709.
(b) Larksarp, C.; Alper, H. J . Org. Chem. 1998, 63, 6229. (c) Larksarp,
C.; Alper, H. J . Org. Chem. 1999, 64, 4152. (d) Beag, J . O.; Bensimon,
C.; Alper, H. J . Am. Chem. Soc. 1995, 117, 4700. (e) Beag, J . O.; Alper,
H. J . Org. Chem. 1992, 57, 157. (f) Beag, J . O.; Alper, H. J . Am. Chem.
Soc. 1994, 116, 1220. (g) Beag, J . O.; Alper, H. J . Org. Chem. 1995,
60, 3092. (h) Beag, J . O.; Alper, H. J . Org. Chem. 1995, 60, 253.
10.1021/jo991256u CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/11/1999

Pd-Catalyzed Cyclocarbonylation of o-Iodophenols
J . Org. Chem., Vol. 64, No. 25, 1999 9195
Ta ble 1. Effect of Solven t on th e Cycloca r bon yla tion of
o-Iod op h en ol (1a ) w ith Bis(p-ch lor op h en yl)ca r bod iim id e
(2a ) in th e P r esen ce of a P a lla d iu m Com p lex a n d d p p ba
Sch em e 2
isolated yield of 3a b (%)
0.05 mmol of
Pd(OAc)2 and
0.05 mmol of
Pd2(dba)3‚CHCl3
entry solvent
0.05 mmol of dppbc and 0.05 mmol of dppbd
1
2
3
4
benzene
THF
DME
80
69
36
61
81
82
77
35
Sch em e 3
DMF
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), (i-Pr)2NEt (1.5
b
mmol), solvent (5 mL), CO (300 psi), 100 °C. Isolated yield.
c Reaction time was 24 h. Reaction time was 48 h.
d
of dppb in anhydrous benzene. After the mixture was
stirred under N2 at room temperature for 15 min, 1 mmol
each of 1a and 2a and 1.5 mmol of (i-Pr)2NEt were added,
and the reaction mixture was stirred at 100 °C under
300 psi carbon monoxide for 24 h, resulting in the
formation of N-(p-chlorophenyl)-3-(p-chlorophenyl)benzo-
[e]-1,3-oxazin-2-imin-4-one (3a ) in 80% isolated yield (eq
1).
heterocumulenes to form benzo[e]-1,3-oxazin-4-ones and
their derivatives (Scheme 3). These types of compounds
are reported to have pharmaceutically interesting prop-
erties; for example, compounds of class I have potential
analgesic properties6 while II are effective against serine
proteases7 such as trypsin, thrombin, and plasmin (Fig-
ure 1).
The influence of palladium complex, solvent, base, and
substrate/catalyst ratio was then investigated. When
Pd2(dba)3‚CHCl3 (0.025 mmol) was used instead of
Pd(OAc)2, 81% of 3a was obtained; however, the complete
conversion of the carbodiimide required 48 h. Benzene
proved to be the best solvent for the reaction (Table 1)
utilizing Pd(OAc)2 (entry 1), whereas THF, benzene, and
DME gave similar results for Pd2(dba)3‚CHCl3 (entries
1-3). Note that, of course, no carbonyl-containing prod-
ucts were detected when palladium-catalyzed reaction
was run in the absence of carbon monoxide. The
o-iodophenol (1a ) was recovered unchanged, and the
carbodiimide gave a mixture of unidentified products.
Table 2 shows the influence of different bases on the
reactions. Using Pd(OAc)2 as the catalyst, diisopropyl-
ethylamine was the best base (entry 1, Table 2), while
K2CO3 was superior when using Pd2(dba)3‚CHCl3 (entry
6). Cycloaddition of o-iodophenol (1a ) with 2a proceeds
using other bases such as Et3N, pyridine, Proton Sponge,
and Na2CO3, but in lower product yields (entries 2-5).
Slightly lower yields of 3a were obtained in the reaction
of 1a with 2a and K2CO3 under 300 psi CO in the
presence of 2.5 mol % of Pd2(dba)3‚CHCl3 in THF using
dppp (94%), dppe (91%), PPh3 (95%), or PCy3 (84%)
compared with the same reaction employing dppb (96%)
as the added ligand. Performing the reaction using only
2.5 mol % of Pd2(dba)3‚CHCl3 and in the absence of
phosphine ligand afforded 62% of 3a .
F igu r e 1. Structure of pharmaceutically active benzo[e]-1,3-
oxazin-4-one derivatives.
Herein, we describe a simple and novel method for the
synthesis of benzo[e]-1,3-oxazin-4-ones and benzo[e]-1,3-
oxazin-2-imine-4-ones by palladium-catalyzed cyclocar-
bonylation of o-iodophenols with heterocumulenes. The
anticipated products are formed in excellent yields and
regioselectivity. Application of this strategy to the reac-
tion of 2-hydroxy-3-iodopyridine with carbodiimides af-
fords pyrido[3,2-e]-1,3-oxazin-2-imin-4-ones.
Resu lts a n d Discu ssion
We started our investigation by treatment of o-iodo-
phenol (1a , R ) H) with bis (p-chlorophenyl)carbodiimide
(2a ) using reaction conditions similar to those previously
reported by one of us8 for the carbonylation of o-iodophe-
nols with allenes. The palladium(0)-1,4-bis(diphenylphos-
phino)butane (dppb) catalyst system was generated in
situ by the reaction of 0.05 mmol of Pd(OAc)2 with 1 equiv
(6) (a) Palazzo, S.; Giannola, L. I. Atii Acad. Sci., Lett. Arti Palermo,
Parte 1 1976, 34, 83. (b) Palazzo, S.; Giannola, L. I. Chem Abstr. 1978,
89, 43276z.
(7) Wagner, G.; Wunderlich, I. Pharmazie 1978, 33, 15.
(8) Okuro, K.; Alper, H. J . Org. Chem. 1997, 62, 1566.

9196 J . Org. Chem., Vol. 64, No. 25, 1999
Larksarp and Alper
Ta ble 2. Effect of Ba se on th e Cycloca r bon yla tion of
o-Iod op h en ol (1a ) w ith Bis(p-ch lor op h en yl)ca r bod iim id e
(2a ) in th e P r esen ce of a P a lla d iu m Com p lex a n d d p p ba
Ta ble 3. Deter m in a tion of th e Op tim u m Am ou n t of
P a lla d iu m Ca ta lyst Requ ir ed for th e Cycloca r bon yla tion
of o-Iod op h en ol (1a ) a n d w ith Bis(p-ch lor op h en yl)Ca r bo-
d iim id e (2a ) in th e P r esen ce of 1:1 P d 2(d ba )3‚CHCl3/d p p ba
isolated yield of 3a (%)b
ratio of substrate/
palladium catalyst
% isolated
0.05 mmol of
Pd(OAc)2 and
0.05 mmol of
Pd2(dba)3‚CHCl3
entry
yield of 3a b
0.05 mmol of dppb and 0.05 mmol of
1
2
3
4
5
6
20:1 (0.05 mmol Pd)
96 (80)c
94 (87)c
94
90
76
entry
base
in benzenec
dppb in THFd
100:1 (0.01 mmol Pd)
172.5:1 (0.006 mmol Pd)
250:1 (0.004 mmol Pd)
500:1 (0.002 mmol Pd)
1000:1 (0.001 mmol Pd)
1
2
3
4
5
6
(i-Pr)2NEt
NEt3
pyridine
Proton Sponge
Na2CO3
80
38
60
46
47
34
81
65
80
67
92
96
70
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), base (1.5
mmol), solvent (5 mL), CO (300 psi), 100 °C, 48 h. b 3a was purified
by SiO2 column chromatography. c Isolated yield of 3a from the
reaction using Pd (OAc)2-dppb after 24 h.
K2CO3
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), base (1.5
b
mmol), solvent (5 mL), CO (300 psi), 100 °C. 3a was purified by
SiO2 column Chromatography. c Reaction time was 24 h. Reac-
d
Ta ble 4. Cycloca r bon yla tion of o-Iod op h en ols (1) w ith
Ca r bod iim id es (2) Ca ta lyzed by a P a lla d iu m Com p lex
a n d d p p ba
tion time was 48 h.
The results in Table 3 show that 3a was obtained in
70-76% yield at a 500-1000:1 ratio of 1a and 2a /
palladium catalyst (Table 3, entries 5 and 6). Isolated
yields of 3a , of at least 90%, resulted using a 20-250/1
ratio of 1a /Pd2(dba)3‚CHCl3 (entries 1-4). Somewhat
lower yields were obtained with Pd(OAc)2 as catalyst. A
ratio of 200/1 was used for subsequent experiments.
As a consequence of the above results, the best reaction
conditions for the cyclocarbonylation of o-iodophenols (1)
with heterocumulenes involve use of 1 mmol each of 1
and 2, 1.5 mmol of base [(i-Pr)2EtN, for Pd(OAc)2), K2CO3
for Pd2(dba)3‚CHCl3)], 0.005 mmol Pd, and 1 equiv of
dppb relative to palladium in THF. Benzene was used
as the solvent for Pd(OAc)2.
A series of carbodiimides (2) were used for the Pd-
catalyzed cyclocarbonylation reaction with o-iodophenols
(1) (eq 2). The reactions were stirred at 100 °C under 300
psi CO, and after complete conversion of carbodiimide,
the reaction mixture was purified affording 3 in good to
excellent yields (Table 4).
isolated
R′NdCd
NR′, 2 product
yield
entry
1
catalystb (mmol)
of 3f (%)
1
2
3
4
5
6
7
8
9
1a
1a
1b
1c
1a
1a
1b
1c
1a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2d
2d
2e
2e
2f
3a
3a
3b
3c
3d
3d
3e
3f
3g
3g
3h
3i
3i
3j
3j
3k
3k
3l
3m
3n
3n
3o
Pd2(dba)3‚CHCl3(0.0025)
Pd(OAc)2 (0.005)
Pd2(dba)3‚CHCl3(0.0025)
Pd2(dba)3‚CHCl3(0.0025)
Pd2(dba)3‚CHCl3(0.0025)
Pd(OAc)2 (0.005)
Pd2(dba)3‚CHCl3(0.0025)
Pd2(dba)3‚CHCl3(0.0025)
Pd2(dba)3‚CHCl3(0.0025)
Pd(OAc)2 (0.005)
Pd2(dba)3‚CHCl3(0.0025)
Pd2(dba)3‚CHCl3(0.0025)
Pd(OAc)2 (0.005)
96
80
94
89
96
85
95
95
95
45
90
94
78
62
10
93
66
93
93
94
57
91
10 1a
11 1b
11 1a
12 1a
13 1a
14 1a
15 1a
16 1a
17 1b
18 1c
19 1b
20 1b
21 1c
Pd2(dba)3‚CHCl3(0.0025)
Pd(OAc)2 (0.005)
Pd(OAc)2 (0.025)c
2f
2f
2f
2g
2g
2g
Pd2(dba)3‚CHCl3(0.0125)d
Pd(OAc)2 (0.025)e
Pd(OAc)2 (0.025)e
Pd(OAc)2 (0.025)e
Pd2(dba)3‚CHCl3(0.0125)d
Pd(OAc)2(0.025)e
a
Reaction conditions: refer to the Experimental Section for the
General Procedure for the Cyclocarbonylation of o-Iodophenols (1)
b
with Carbodiimides (2). Reaction time was 48 h for Pd2(dba)3‚
c
CHCl3 and 24 h for Pd(OAc)2 respectively. Reaction time was 36
d
h. Reaction time was 72 h. e Reaction time was 48 h. f The
products (3) were purified by silica gel column chromatography.
bodiimides (2f and 2g). Furthermore, for the reactions
using 2f and 2g, 2.5 mol % of palladium catalyst was
needed since the reaction proceeded very slowly when
0.25 mol % of Pd was used, resulting in low product
yields.
Good to excellent yields of 3k -o were achieved from
the reaction of 2f and 2g with 1a -c in the presence of
2.5 mol % Pd(OAc)2 and 5 mol % dppb in 5 mL of benzene
after 24 h at 100 °C under 300 psi CO (entries 15, 17,
18, 19, and 21).
o-Iodophenols bearing either electron-donating (R )
CH3) or electron-withdrawing (R ) Cl) substituents on
the aromatic ring were converted to 3 in good yields.
4-Methyl-2-iodophenol (1b) reacted with heterocumu-
lenes in an analogous manner to 1a giving rise to the
anticipated heterocycles in high isolated yields (Table 4,
entries 3, 7, 11, 17, and 19). When 4-chloro-2-iodophenol
(1c) was used as the substrate, oxidative addition of
palladium occurred only into the C-I bond (not C-Cl)
to form 3 in high yield (entries 4, 8, 18, and 21).
When diarylcarbodiimides (2a -e) were utilized for the
reaction, Pd2(dba)3‚CHCl3 afforded 3 in higher yields than
Pd(OAc)2. The reverse is true (i.e., Pd(OAc)2 gives 3 in
higher yields than Pd2(dba)3‚CHCl3) utilizing dialkylcar-
Benzo[e]-1,3-oxazin-2,4-diones (5) were obtained by the
reaction of o-iodophenols (1) with isocyanates (4) and
carbon monoxide catalyzed by Pd2(dba)3‚CHCl3 and dppb
in THF, and the results are summarized in Table 5. A
mixture of Pd2(dba)3‚CHCl3 (0.0025 mmol) and dppb
(0.005 mmol) was stirred under N2 for 15 min, and then
1 mmol each of 1b and 4a and 1.5 mmol of K2CO3 were
added to the resulting solution. After the mixture was
stirred at 80 °C under 300 psi CO for 12 h, complete

Pd-Catalyzed Cyclocarbonylation of o-Iodophenols
J . Org. Chem., Vol. 64, No. 25, 1999 9197
Ta ble 5. Cycloca r bon yla tion of o-Iod op h en ols (1) w ith
Isocya n a tes (4) Usin g P d 2(d ba )3‚CHCl3-d p p ba
Sch em e 4. P r op osed Mech a n ism for th e
Cycloca r bon yla tion of o-Iod op h en ols w ith
Heter ocu m u len es via a n Ar oylp a lla d iu m
In ter m ed ia te
isolated
ratio yield of
entry
1
OdCdNR′, 4
product of 1:4 5b (%)
1
2
3
4
5
6
7
8
9
1a OdCdNC6H4Cl-p, 4a
1b 4a
1b 4a
1b OdCdNC6H4Br-p, 4b
1c 4b
1c 4b
1a OdCdNC6H4CH3-p, 4c
1c 4c
1c 4c
1b OdCdNC6H4OCH3-p, 4d
1a OdCdNCH2C6H5, 4e
5a
5b
5b
5c
5d
5d
5e
5f
1:2
1:2
1:1
1:2
1:2
1:1
1:2
1:2
1:1
1:2
1:2
79
84
4
77
58
0
81
52
0
5f
5g
5h
10
11
82
79c
a
Reaction conditions: 1/4/K2CO3/Pd2(dba)3‚CHCl3/dppb 1:2:1.5:
0.0025:0.005 mmol in 5 mL of THF, 80 °C, 300 psi CO, 12 h.
Isolated by silica gel column chromatography. c 0.005 mmol
b
and the arylpalladium iodide moiety of 7, followed by CO
insertion to give 9.
Pd(OAc)2 was used instead of Pd2(dba)3‚CHCl3.
To prove that the carbamate ester was formed first
before entering the catalytic cycle, 6a was synthesized
from the reaction of o-iodophenol (1a ) with p-chlorophe-
nylisocyanate (4a ) in benzene. The resulting carbamate
(1 mmol) was then used in the carbonylation reaction
using 0.01 mmol Pd(OAc)2, 0.01 mmol dppb, and 1.5
mmol (i-Pr)2NEt in benzene under 300 psi CO (eq 3).
After 12 h at 100 °C, complete conversion of the carbam-
ate was detected by TLC and 45% of 5a was isolated.
Performing the reaction in a similar manner but adding
an extra 1 mmol of 4a to the reaction mixture resulted
in the formation of 68% of 4a .13 This result also shows
the importance of using excess isocyanate in palladium-
catalyzed cyclocarbonylation with o-iodophenols in which
the equilibrium for the formation of the corresponding
carbamate ester was driven in such a manner as to give
more 6, which enters the catalytic cycle.
conversion of isocyanate was observed and afforded 5b
but in only 4% yield (entry 3, Table 5). Performing the
reaction under the same conditions but at a 2:1 ratio of
4a /1b gave 5b in 84% yield. No reaction occurred when
a 1:1 ratio of 4/1 was used as in the case of 4b (entry 6)
and 4c (entry 9); however, 5d and 5f were isolated in
52-58% yield by doubling the amount of the reactant
isocyanates (entries 5 and 8). Those reactions that afford
lower product yields may be a result of the presence of
base in the reaction, which induces dimer or trimer
formation of the isocyanates.9 Good yields of benzo[e]-
1,3-oxazin-2,4-diones (5) were attained by using 1/4/
K2CO3 in a ratio of 1:2:1.5 in the presence of 0.25 mol %
of Pd2(dba)3‚CHCl3 and 0.5 mol % of dppb in THF under
300 psi CO at 80 °C for 12 h. An important application
of this reaction is for the synthesis of 3-(benzyl)benzo-
[e]-1,3-oxazin-2,4-dione (5h , entry 11), which may be
effective against serine proteases. Note that Pd(OAc)2-
dppb was used instead of Pd2(dba)3‚CHCl3-dppb in order
to obtain 5h in better yield.10
The mechanism of this reaction can be explained by
the pathway outlined in Scheme 4. First the carbamate
(6) may be formed in situ by reaction between
o-iodophenols (1) with heterocumulenes. The latter un-
dergo oxidative addition to [PdL2]11 and carbonyl inser-
tion, affording aroylpalladium intermediates (8). Coor-
dination of the amine moiety to aroylpalladium halide12
to form intermediate 9 followed by HI neutralization, and
reductive elimination would result in the formation of
benzo[e]-1,3-oxazin-4-one derivatives. It is conceivable
that intramolecular coupling occurs between the nitrogen
The cycloaddition reaction was also applied to unsym-
metrical carbodiimides, and the results are listed in Table
6. We first used N-n-butyl-N′-phenylcarbodiimide (10a ,
1 mmol) for the reaction with 1a (1 mmol) in the presence
of 0.0025 mmol of Pd2(dba)3‚CHCl3, dppb (0.005 mmol),
and 1.5 mmol of K2CO3 in THF (5 mL). The reaction was
stirred under 300 psi CO at 100 °C for 48 h. After
(9) Dimerization and trimerization of isocyanates were observed in
the presence of base for the reaction at elevated temperature. See:
Hofmann, A. W. Ber. 1860, 3, 761. Snape, H. L. J . Chem. Soc. 1886,
49, 254. Hofmann, A. W. Ber. 1885, 18, 764.
(10) When the reaction of 1a with 4e was performed by using the
Pd2(dba)3‚CHCl3-dppb catalyst system, 5h was obtained in a small
amount with byproducts.
(11) For the mechanism of oxidative addition of aryl halides to
palladium complexes; see: Stille, J . K.; Lau, K.S. Y. Acc. Chem. Res.
1976, 10, 434.
(12) Inter- and intramolecular coordination of amine to palladium
aryl halide complexes was shown to enhance the acidity of the NH
bond. See: (a) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1995,
117, 4708. (b) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1997,
197, 88232. (c) Louie, J .; Paul, F.; Hartwig, J . F. Organometallics 1996,
15, 2794.
(13) 5a was obtained in 65% isolated yield when 1 mmol of 1a and
2 mmol of 4a . A 1.5 mmol portion of (i-Pr)2NEt was reacted in the
presence of 1 mol % Pd(OAc)2 and 1 mol % dppb under 300 psi CO in
benzene at 100 °C for 12 h.

9198 J . Org. Chem., Vol. 64, No. 25, 1999
Larksarp and Alper
Sch em e 5. P r op osed Mech a n ism for th e
Regioselective F or m a tion of 11d
F igu r e 2. X-ray structure of 11d .
Ta ble 6. Cycloca r bon yla tion of o-Iod op h en ols (1) w ith
Un sym m etr ica l Ca r bod iim id es (10) Ca ta lyzed by
P d 2(d ba )3‚CHCl3 a n d d p p b in THF a
isolated
yield of
entry
1
R′dCdNR′′, 10
product 11b (%)
1
2
3
4
5
6
7
1a C6H5NdCdNC4H9, 10a
1c 10a
1b C6H5NdCdNC6H11, 10b
1c 10b
1a p-FC6H4NdCdNC6H11, 10c
1b 10c
1a 2,6(CH3)2C6H3NdCdNC4H9, 10d
11a
11b
11c
11d
11e
11f
11g
94
77
94
92
82
82
93
a
Reaction conditions: 1 (1 mmol), 10 (1 mmol), K2CO3 (1.5
of formation of 12 compared to 13. Reductive elimination
of intermediate 14 and HI neutralization would furnish
11d (Scheme 5).
b
mmol), THF (5 mL), CO (300 psi), 100 °C, 48 h. Isolated yield by
silica gel chromatography.
When 3-iodo-2-hydroxypyridine (15) was employed for
the cyclocarbonylation with carbodiimides in the presence
of a catalytic amount of a palladium-dppb complex (eq
4), pyrido[3,2-e]-1,3-oxazin-4-ones were obtained in good
yields (see Table 7).
purification of the solution, only one regioisomer was
obtained in 94% yield (entry 1). Complete regioselectivity
also resulted using either o-iodophenols or carbodiimides
containing a substituent on the phenyl ring as reactants.
For instance, only 11b was formed using 1c in reaction
with 10a (entry 2). Reaction of 1a -c with 10b-d gave
only one isomer in high isolated yields (entries 3-7).
Two isomers are possible from reactions involving
unsymmetrical carbodiimides, one with an aromatic
substituent on the nitrogen of the oxazine ring (11) and
the other with an alkyl group attached to the oxazine
nitrogen (11′).
Pd(OAc)2 (entries 1 and 3) is superior to Pd2(dba)3‚
CHCl3 (entries 2 and 4) for the reaction of 3-iodo-2-
hydroxypyridine (15) with heterocumulenes to form 16.
A mixture of regioisomers of 16c, in a ratio of 2:1,
resulted from the reaction using unsymmetrical carbo-
diimides (10e) (entry 5). No product was obtained in the
reaction of 15 with p-chlorophenylisocyanate (4a ), per-
haps because the pyridine acts as reagent in the dimer
formation of isocyanate.14
To prove the structure of the products, an X-ray
determination of 11d was performed. The ORTEP dia-
gram shows that 11d contains a phenyl group on the
nitrogen of the oxazine ring (Figure 2), which contrasts
with the major (not exclusive) isomer resulting from the
reaction of the same carbodiimide with vinyloxirane.5b
Only one isomer was obtained from the cyclocarbony-
lation of o-iodophenol (1) with unsymmetrical carbodi-
imides (10a -d ). The selectivity may be due to the ease
In conclusion, a novel method has been developed for
the synthesis of benzo[e]-1,3-oxazin-4-ones and deriva-
tives by the cyclocarbonylation of o-iodophenols with
(14) The dimerization of isocyanates catalyzed by pyridine and its
derivatives was described by: Wiley, P. F. J . Am. Chem. Soc. 1949,
71, 3746.

Pd-Catalyzed Cyclocarbonylation of o-Iodophenols
J . Org. Chem., Vol. 64, No. 25, 1999 9199
Ta ble 7. Cycloca r bon yla tion of 3-Iod o-2-h yd r oxyp yr id in e (15) w ith Heter ocu m u len es (2a -b, 4a , 10e) Ca ta lyzed by a
P a lla d iu m Com p lex a n d d p p b u n d er 300 p si COa
entry
XdCdY
product
16a
catalyst
Pd(OAc)2
Pd2(dba)3‚CHCl3
Pd(OAc)2
Pd2(dba)3‚CHCl3
Pd(OAc)2
Pd(OAc)2
isolated yield (%)
1
2
3
4
5
6
p-ClC6H4NdCdNC6H4Cl-p, 2a
64b
60c
p-CH3C6H4NdCdNC6H4CH3-p, 2b
16b
50b,c
30c
p-ClC6H4NdCdNC4H9, 10e
p-ClC6H4NdCdO, 4a
16c and 16′c
65 (2:1)e
0
ndf
a
Reaction Conditions: 15 (1 mmol), 2 or 10 (1 mmol), 1.5 mmol of base [K2CO3 for Pd2(dba)3‚CHCl3, (i-Pr)2NEt for Pd(OAc)2], 0.005
b
mmol of Pd, 0.005 mmol of dppb, 300 psi CO, in 5 mL of solvent [THF for Pd2(dba)3‚CHCl3, benzene for Pd(OAc)2] at 100 °C. Reaction
time was 24 h. c Reaction time was 48 h. Isolated yield of 16b after complete conversion of 15 after 24 h. e The ratio of 16c:16′c was
d
determined by GC. f The ratio of 15:4a was 1:2 and complete conversion of the isocyanate occurred after 12 h at 80 °C; however, no
desired produce was isolated.
mp ) 164-165 °C; IR (CdN) 1671, (CdO) 1715 cm-1 1H
;
heterocumulenes using a palladium complex and a bi-
dentate phosphine. The yields are good to excellent, and
the reaction proceeds with complete regioselectivity. Of
particular note is the application of this reaction to the
facile synthesis of a relative of a serine protease inhibitor.
(CDCl3, 200 MHz) δ 2.33 (s, 3H), 6.82-7.79 (m, 11H); 13C
(CDCl3, 75 MHz) δ 20.66, 114.19, 115.52, 124.08, 127.94,
128.64, 128.81, 129.71, 129.95, 134.40, 134.62, 134.94, 136.90,
142.71, 143.03, 150.91, 159.68; MS m/e 396 [M - 1]+, 397 [M]+.
Anal. Calcd for C21H14Cl2N2O2: C, 63.49; H, 3.55; N, 7.05.
Found: C, 63.28; H, 3.45;, N, 6.95.
Exp er im en ta l Section
N-n -Bu tyl-3-p h en ylben zo[e]-1,3-oxa zin -2-im in e-4-on e
(11a ) (R ) H, R′ ) C6H5, R′′ ) C4H9): mp ) 107-108 °C; IR
Gen er a l Meth od s. Pd(OAc)2, phosphine ligands, 2-io-
dophenol (1a ), dicyclohexylcarbodiimide (2f), diisopropylcar-
bodiimide (2g), isocyanates (4), and 3-iodo-2-ohydroxypyridine
(15) were purchased from commercial sources and were used
as received. Carbodiimides (2a -e),15 unsymmetrical carbodi-
imides16 (10a -e), 4-methyl-2-iodophenol17 (1b), 4-chloro-2-
1
(CdN) 1652, (CdO) 1711 cm-1; H (CDCl3, 200 MHz) δ 1.12
(d, 6H J ) 6.33 Hz), 1.47 (d, 6H, J ) 6.92 Hz), 4.03 (Sept, 1H,
J ) 6.3 Hz), 5.20 (Sept, 1H, J ) 6.9 Hz) 6.99 (m, 1H), 7.43 (m,
1H), 7.88 (m,1H); 13C (CDCl3, 75 MHz) δ 13.59, 19.77, 31.68,
41.20, 119.79, 123.20, 124.38, 126.25, 128.97, 130.04, 131.85,
138.03, 147.68, 154.76, 164.15; MS m/e 293 [M - 1]+, 294 [M]+;
Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52.
Found: C, 73.20; H, 5.98; N, 9.11.
iodophenol17 (1c), and Pd2(dba)3‚CHCl3 were prepared ac-
18
cording to literature procedures. Organic solvents were dried
and distilled prior to use.
N-n -Bu tyl-3-ph en ylben zo[e]-6-ch lor o-1,3-oxazin -2-im in -
4-on e (11b) (R ) Cl, R′ ) C6H5, R′′ ) C4H9): mp ) 126-127
°C; IR (CdN) 1672, (CdO) 1714 cm-1; 1H (CDCl3, 200 MHz) δ
0.86 (t, 3H), 1.18-1.62 (m, 4H), 3.362. (dd, 2H, J ) 6.96 and
6.86 Hz), 7.11-8.00 (m, 8H); 13C (CDCl3, 75 MHz) δ 13.88,
20.44, 32.64, 45.50, 116.16, 117.03, 127.79, 128.43, 128.51,
129.29, 129.60, 135.37, 136.13, 141.49, 151.75, 159.84; MS m/e
327 [M - 1]+, 328 [M]+. Anal. Calcd for C18H17ClN2O2: C,
65.75; H, 5.21; N, 8.52. Found: C, 65.74; H, 5.04; N, 8.50.
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Cy-
cloca r bon yla tion of o-Iod op h en ols (1) w ith Isocya n a tes
4a -e. The cyclocarbonylation reactions of o-iodophenols with
isocyanates were performed in a manner similar to that with
carbodiimides but 2 equiv of isocyanate was used in order to
obtain higher product yield. The reaction mixtures were stirred
in an oil bath at 80 °C for 12 h. After filtration and rotary
evaporation of the filtrate, the residue was purified by silica
gel column chromatography (using 1:1, ethyl acetate/n-pentane
as eluant). Melting points, IR, NMR, MS, and analytical data
for selected example 5 are as follows (see the Supporting
Information for all other data for 5).
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Cy-
cloca r b on yla t ion of o-Iod op h en ols (1) w it h Ca r b od i-
im id es (2a -g, 10a -d ). An autoclave, its glass liner, and a
magnetic stirring bar were dried in an oven and then cooled
in a desiccator before use. The liner was charged with the
palladium catalyst 0.5 mol % (unless otherwise noted in each
case), 1 equiv of bidentate phosphine ligand relative to
palladium was used, and 3 mL of dried solvent (THF for
Pd2(dba)3‚CHCl3 or benzene for Pd(OAc)2) was added. After
the mixture was stirred under nitrogen for 15 min, o-iodophe-
nol (1, 1 mmol), carbodiimide (2 or 10, 1 mmol), 1.5 mmol of
base [K2CO3 for Pd2(dba)3‚CHCl3 or (i-Pr)2NEt for Pd(OAc)2],
and another 2 mL of solvent was added to the mixture. The
autoclave was then flushed three times with CO and pressur-
ized to 300 psi. After 24 or 48 h [48 h for Pd2(dba)3‚CHCl3, 24
h for Pd(OAc)2, unless otherwise stated] in an oil bath at 100
°C, the autoclave was removed from the oil bath and allowed
to cool to room temperature. The excess gas was discharged
and the system disassembled. The reaction mixture was
filtered, and the filtrate was concentrated and purified by
column chromatography on silica gel (1:1 ether/n-pentane).
Melting points, IR, NMR, MS, and analytical data for selected
samples of 3 and 11 are as follows (see the Supporting
Information for all other data for 3 and 11).
3-(p-Ch lor op h en yl)ben zo[e]-1,3-oxa zin -2,4-d ion e (5a )
(R ) H, R′ ) p-ClC6H4): mp ) 236-238 °C; IR (CdO) 1705,
1770 cm-1 1H (CDCl3, 200 MHz) δ 7.20-8.12 (m, 8H); 13C
;
(CDCl3, 75 MHz) δ 114.15, 116.66, 125.76, 128.48, 129.49,
129.87, 132.53, 136.68, 152.69, 160.48; MS m/e 273 [M]+. Anal.
Calcd for C14H8ClNO3: C, 76.81; H, 4.91; N, 8.53. Found: C,
76.60; H, 4.73; N, 8.49.
N-p-Ch lor oph en yl-3-p-ch lor oph en ylben zo[e]-1,3-oxazin -
2-im in -4-on e (3a ) (R ) H, R′) p-ClC6H4): mp ) 161-162
°C; IR (CdN) 1669, (CdO) 1710 cm-1; 1H (CDCl3, 200 MHz) δ
6.90-8.12 (m, 12H); 13C (CDCl3, 75 MHz) δ 114.57, 115.76,
124.02, 124.95, 128.32, 128.66, 128.86, 129.72, 129.91, 134.26,
134.65, 136.02, 142.23, 142.91, 152.78, 159.50; MS m/e 382
[M]+. Anal. Calcd for C20H12Cl2N2O2: C, 62.68; H, 3.16; N, 7.31.
Found: C, 62.82; H, 3.29; N, 7.26.
3-(p-Ch lor op h en yl)ben zo[e]-6-m eth yl-1,3-oxa zin e-2,4-
d ion es (5b) (R ) CH3, R′ ) p-ClC6H4): mp ) 190-191 °C; IR
1
(CdO) 1704, 1759 cm-1; H (CDCl3, 200 MHz) δ 2.43 (s, 3H),
7.21-7.88 (m, 7H); 13C (CDCl3, 75 MHz) δ 20.71, 113.75,
116.39, 127.95, 129.51, 129.82, 132.67, 135.30, 135.83, 137.59,
147.86, 150.78, 160.61; MS m/e 287 [M]+. Anal. Calcd for
N-p -Ch lor op h en yl-3-p -ch lor op h en ylb en zo[e]-6-m et h -
yl-1,3-oxa zin -2-im in -4-on e (3b) (R ) CH3, R′) p-ClC6H4):
C
15H10ClNO3: C, 62.62; H, 3.50; N, 4.87. Found: C, 62.45; H,
3.40; N, 4.80.
(15) Campbell, T. W.; Monagle, J . J . Foldi, V. J . Am. Chem. Soc.
1962, 84, 3673.
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Cy-
cloca r bon yla tion of 3-Iod o-2-h yd r oxyp yr id in e (15) w ith
Heter ocu m u len es. The cyclocarbonylation reactions of 3-iodo-
2-hydroxypyridine with heterocumulenes (2a ,b, 4a , 10e) were
performed following the same procedure as that used for the
(16) Palomo, C.; Mestres, R. Synthesis 1981, 373.
(17) Dains, F. B.; Eberly, F. Organic Syntheses; Wiley: New York,
1943; Collect. Vol. 2, p 355.
(18) Ukai, T.; Kawazura, H.; Ishii, Y. J . Organomet. Chem. 1974,
65, 253.

9200 J . Org. Chem., Vol. 64, No. 25, 1999
Larksarp and Alper
reaction of o-iodophenols with carbodiimides and isocyanates.
Melting points, IR, NMR, MS, and analytical data of 16 after
purification by silica gel column chromatography are shown
below.
1H, J ) 7.9 and 1.4 Hz); 13C (CDCl3, 75 MHz) δ 90.68, 120.05,
123.28, 127.73, 129.13, 129.48, 135.73, 139.37, 150.47; MS m/e
373 [M]+; HRMS calcd for C13H9ClINO2 372.9367, found
372.9353.
N-p-Ch lor op h en yl-3-p -ch lor op h en ylp yr id o[3,2-e]-1,3-
oxa zin -2-im in -4-on e (16a ) (X ) Y ) p-ClC6H4N): mp ) 221-
P a lla d iu m Ca ta lyzed Cycloca r bon yla tion of Ca r ba m -
a te 6a . To a 45-mL Parr autoclave fitted with a glass liner
and a stirring bar were added Pd(OAc)2 (0.01 mmol), dppb
(0.01 mmol), 6a (1 mmol), N,N-diisopropylethylamine (1.5
mmol), and dried benzene (5 mL). The autoclave was fill-
vented three times with CO and pressurized to 300 psi CO.
The reaction mixture was stirred at 100 °C for 12 h. The excess
CO was released, and the resulting reaction mixture was
separated by silica gel column chromatography, affording 5a
in 45% isolated yield. Performing the same reaction but in the
added presence of 4a (1 mmol) afforded 5a in 68% yield.
Sin gle-Cr ysta l Diffr a ction Stu d y of 11d . Suitable crys-
tals of 11d were selected and mounted on thin glass fibers
using epoxy cement. Data were collected on a Bruker AX
SMART 1k CCD diffractometer using 0.3° ω-scans at 0, 90,
and 180° in φ. Unit-cell parameters were determined from 60
data frames collected at different sections of the Ewald sphere.
No absorption corrections were required (µeff ) 2.24 cm-1).
Systematic absences in the diffraction data and unit-cell
parameters were uniquely consistent with the reported space
group. The structure was solved by direct methods, completed
with difference Fourier syntheses, and refined with full-matrix
least-squares procedures based on F2. The Flack parameter
refined to nil, indicating that the true hand of the data has
been determined correctly. All non-hydrogen atoms were
refined with anisotropic displacement parameters. All hydro-
gen atoms were treated as idealized contributions. All scat-
tering factors and anomalous dispersion factors are contained
in the SHEXTL 5.03 program library (Sheldrick, 1997, WI).
223 °C; IR (CdN) 1674, (CdO) 1728 cm-1 1H (CDCl3, 200
;
MHz) δ 6.86 (m, 2H), 7.24-7.61 (m, 8H), 8.66 (m, 1H); 13C
(CDCl3, 75 MHz) δ 123.81, 124.41, 128.73, 129.18, 129.64,
129.79, 131.98, 133.99, 134.85, 141.21, 142.40, 147.49, 150.63,
157.94; MS m/e 383 [M - 1]+, 384 [M]+. Anal. Calcd for C19H11
-
Cl2N3O2: C, 59.39; H, 2.89; N, 10.94. Found: C, 59.04; H, 2.88;
N, 10.88.
N-p -Tolyl-3-p -t olylp yr id o[3,2-e]-1,3-oxa zin -2-im in -4-
on e (16b) (X ) Y ) p-CH3C6H4N): mp ) 233-235 °C; IR
1
(CdN) 1671, (CdO) 1713 cm-1; H (CDCl3, 200 MHz) δ 2.29
(s, 3H), 2.40 (s, 3H), 6.84-7.52 (m, 10H), 8.65 (m, 1H); 13C
(CDCl3, 75 MHz) δ 20.82, 21.25, 122.30, 124.29, 128.00, 129.14,
129.26, 130.15, 132.32, 133.14, 138.66, 140.83, 141.46, 147.08,
150.70, 158.31; MS m/e 342 [M-1]+, 343 [M]+. Anal. Calcd for
C
21H17N3O2: C, 73.45; H, 4.99;, N, 12.24. Found: C, 73.56; H,
5.07; N, 12.07.
N-n -Bu tyl-3-p-ch lor op h en ylp yr id o[3,2-e]-1,3-oxa zin -2-
im in -4-on e (16c) (X ) p-ClC6H4N, Y ) C4H9N): mp ) 157-
159 °C; IR (CdN) 1681, (CdO) 1717 cm-1 1H (CDCl3, 200
;
MHz) δ 0.86 (t, 3H), 1.23-1.47 (m, 4H), 3.37 (t, 3H), 7.21 (m,
2H), 7.41 (m, 2H), 7.56 (m, 2H), 8.63 (m, 1H); 13C (CDCl3, 75
MHz) δ 13.83, 20.41, 32.58, 45.54, 124.04, 129.31, 129.58,
129.87, 132.25, 134.38, 134.54, 140.62, 146.83, 150.89, 158.25;
MS m/e 328 [M - 1]+, 329 [M]+. Anal. Calcd for C17H16
-
ClN3O2: C, 61.91; H, 4.89; N, 12.74. Found: C, 62.04; H, 5.07;
N, 12.48.
N-p-Ch lor op h en yl-3-n -bu tylp yr id o[3,2-e]-1,3-oxa zin -2-
im in -4-on e (16c′) (X ) C4H9N, Y ) p-ClC6H4N): mp ) 118-
120 °C; IR (CdN) 1665, (CdO) 1719 cm-1 1H (CDCl3, 200
;
Ack n ow led gm en t. We are grateful to the NSERC
of Canada for support of this research. Dr. Glenn P. A.
Yap is gratefully acknowledged for the X-ray diffraction
study of compound 11d .
MHz) δ 0.93 (t, 3H) 1.41 (m,2H), 1.75 (m, 2H), 4.21 (t, 2H),
6.97 (m, 2H), 7.29 (m, 2H), 7.49 (m, 2H), 8.62 (m, 1H); 13C
(CDCl3, 75 MHz) δ 13.83, 20.09, 28.98, 43.46, 123.99, 124.11,
128.87, 129.10, 132.06, 140.45, 146.02, 147.26, 150.26, 157.94;
MS m/e 328 [M - 1]+, 329 [M]+; HRMS calcd for C17H16ClN3O2
329.0931, found 329.0907.
Su p p or tin g In for m a tion Ava ila ble: Spectral data of
compounds 3c-o, 5c-h , and 11-11g; 1H and 13C NMR
spectra of compounds 3n , 6a , 11g, 16′c; text giving full details
of the X-ray structure of 11d including the experimental
procedures, tables of crystal data, structure refinements,
atomic coordination parameters, bond lengths, bond angles,
anisotropic displacement parameters, and hydrogen coordina-
tion parameters. This material is available free of charge via
the Internet at http:/pubs.acs.org.
P r ep a r a tion of Ca r ba m a te Ester 6a . In a 50-mL round-
bottom flask equipped with a stirring bar was added dropwise
o-iodophenol 1a (1 g, 4.5 mmol) in benzene (5 mL) to a 10 mL
solution of 0.7 g (4.5 mmol) of p-chlorophenylisocyanate 4a .
After the mixture was stirred at room temperature under N2
overnight, the resulting solution was concentrated and purified
by silica gel column chromatography. Carbamate ester 6a was
obtained (1.22 g, 71%).
Carbamate 6a : mp ) 123-125 °C; IR (CdO) 1727 cm-1
1H (CDCl3, 200 MHz) δ 6.97 (m, 1H), 7.35 (m, 7H), 7.80 (dd,
;
J O991256U