The Reaction of Dialkyl Carbonates with o-Aminophenol Catalysed by K 2CO3: A Novel High-Yield Synthesis of N-Alkylbenzoxazol-2- ones

Article abstract of DOI:10.1055/s-2003-42464

At 130-150°C and in the presence of catalytic K₂CO ₃, o-aminophenol (1) readily reacts with dialkyl carbonates (2: ROCO₂R; 2a: R = Me, 2b: Et, 2c: Allyl, 2d: Bn) to give the corresponding N-alkylbenzoxazol-2-ones (3a-d) in high yields (88-98%). This reaction is a rare example where dialkyl carbonates may simultaneously act as carbonylating and alkylating agents likely through a B_Ac2/B _A12 sequence. Moreover, compounds 2a-c serve also as solvents. In the case of 2d, 1,2-dimethoxyethane (DME) is the reaction medium.

Full text of DOI:10.1055/s-2003-42464

2872
PAPER
The Reaction of Dialkyl Carbonates with o-Aminophenol Catalysed by K2CO3:
A Novel High-Yield Synthesis of N-Alkylbenzoxazol-2-ones
Reactionof Dialkyl
C
a
a
rbonates
w
u
ith
o
-Aminop
r
henol izio Selva*
Dipartimento di Scienze Ambientali dell’Università Ca’ Foscari, Calle Larga S. Marta 2137, 30123 Venezia, Italy
Fax +39(041)2348620; E-mail: selva@unive.it
Received 5 August 2003; revised 2 October 2003
NuCO2R + ROH
NuR + CO2 + ROH
Abstract: At 130–150 °C and in the presence of catalytic K2CO3,
o-aminophenol (1) readily reacts with dialkyl carbonates (2:
ROCO2R; 2a: R = Me, 2b: Et, 2c: Allyl, 2d: Bn) to give the corre-
(a)
(b)
(~90 °C)
(>120 °C)
sponding N-alkylbenzoxazol-2-ones (3a–d) in high yields (88–
98%). This reaction is a rare example where dialkyl carbonates may
NuH
base
simultaneously act as carbonylating and alkylating agents likely
through a BAc2/BAl2 sequence. Moreover, compounds 2a–c serve
also as solvents. In the case of 2d, 1,2-dimethoxyethane (DME) is
the reaction medium.
O
R
R
O
O
2
Key words: alkylations, allylations, benzylations, carbonylations,
catalysis
HON
R'
K2CO3
(c)
R"
5
R
N
R'
O
+ ROH + H2O
Introduction
O
6
R
N-alkylbenzoxazol-2-ones 3 are intermediates of wide-
spread use for the synthesis of analgesics, pesticides, her-
bicides, and more recently, of new classes of
anticonvulsants.1 In most cases, the preparation of com-
pounds 3 is achieved through a two steps sequence, i.e. the
carbonylation of o-aminophenol (1) with phosgene, urea
or CO, followed by the N-alkylation of the resulting benz-
oxazol-2-ones 4 with an alkyl halide (RX, Scheme 1).1,2
Scheme 2 Base-promoted reactions of dialkyl carbonates with a ge-
neric nucleophile [NuH: ArOH, ArOCH2X, ArCH2X, X = CN; CO2R;
path (a) and (b)] and with oximes [path (c)]
Dialkyl carbonates simultaneously act as alcoxycarbony-
lating and alkylating agents in only a few instances.
Among them, the case of oximes with an -CH2 group [5:
R CH2C(=NOH)R ] was reported by us for the synthesis
of N-alkyloxazolinones (6) [path (c)].7 Compounds 5 were
formed via two reactions of O-alkoxycarbonylation and
N-alkylation, respectively.
COCl2
H
R
OH
N
NH2CONH2, H+
CO, Se
N
RX
O
O
base
O
O
NH2
More recently, also the preparation of 3a (R = Me) from
o-aminophenol and dimethyl carbonate was claimed with
catalytic Pb(AcO)2, but this Lewis-acidic catalysis in-
volved a completely different mechanism.1b
3
4
1
Scheme 1 Conventional syntheses of N-alkylbenzoxazol-2-ones
(3); R = alkyl, allyl, benzyl
In this paper, we wish to report that in the presence of cat-
alytic K2CO3, the reaction of o-aminophenol (1) with di-
alkyl carbonates represents a novel example in which an
uncommon BAc2/BAl2 sequence [analogous to path (c) of
Scheme 2] takes place: N-alkylbenzoxazol-2-ones (3) are
obtained in high yields (88–98%) (Scheme 3).
These procedures, though efficient, pose environmental
and operational concerns since highly harmful and/or cor-
rosive reagents are used.3
A safer and eco-friendly alternative can be conceived with
the use of non toxic dialkyl carbonates (2: ROCO2R).4
These compounds are versatile electrophiles and may
serve for both alkylations and alcoxycarbonylations,3b,5
although however, these two reactions are often discrimi-
nated by the temperature [Scheme 2 path (a) and (b): BAl2
and BAc2 mechanisms, respectively].6
OH
O
N
K2CO3
O
+ 2 ROCO2R
+ 3 ROH + CO2
NH2
R
1
2a-d
3a-d
R = Me (3a), Et (3b), Allyl (3c), Bn (3d)
Scheme 3 The reaction of o-aminophenol with dialkylcarbonates
and K2CO3
SYNTHESIS 2003, No. 18, pp 2872–2876
x
x.
x
x
.
2
0
0
3
Advanced online publication: 04.11.2003
DOI: 10.1055/s-2003-42464; Art ID: T08603SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Reaction of Dialkyl Carbonates with o-Aminophenol
2873
The effect of the base was then investigated. Two sets of
Results and Discussion
reactions were performed using solutions of o-aminophe-
Initial experiments were carried out using the lightest nol (0.5 g, 4.6 mmol) in DMC (30 mL), to which different
compound in the carbonate series, dimethyl carbonate amounts of K2CO3 – in the range of 0.1–2.0 molar equiv-
(DMC, 2a: MeOCO2Me). A mixture of o-aminophenol alents with respect to the substrate – were added. Experi-
(0.5 g, 4.6 mmol), DMC (30 mL), and K2CO3 (1.27 g, 9.0 ments were run for 18 hours and 16 hours, at 90 °C and
mmol) was made to react at temperatures of 90 °C, 110 130 °C, respectively. At 130 °C, DME (5 mL) was always
°C, and 130 °C and for different time intervals. In partic- used as a co-solvent. Results are reported in Figure 1.
ular, reactions run above the boiling point of DMC (90
°C), were performed in a stainless steel autoclave of 150
mL. At 130 °C, two experiments were also carried out in
the presence of DME (5 mL) and N,N-dimethylformamide
(DMF, 5 mL) as co-solvents. Results are reported in
Table 1.
Table 1 The Reaction of o-Aminophenol with Dimethyl Carbonate
Entrya
Time
(h)
Temp
(°C)
Co-
solvent
Product Yieldb (%)
O
O
N
3a
Me
1
2
3
4
5
6
7
8
9
9
18
28
48
3
90
90
11
48
63
83
14
23
74
89
37
Figure 1 Isolated yield of 3a in the reaction of o-aminophenol and
DMC with different amounts of K2CO3
90
90
None
Under both conditions (90 °C and 130 °C), data clearly
show that the base can be used catalytically: when the mo-
lar ratio K2CO3/1 changes from 0.1 to 2, the yield of iso-
lated product 3a is in the range of 82–89% at 130 °C, and
of 48–55% at 90 °C. This behavior appears in line with the
modest solubility of K2CO3 in DMC.5a
110
130
130
130
130
3
15
27
15
DME
DMF
Based on the parallel with the reaction of oximes of
Scheme 2, a preliminary mechanistic hypothesis was for-
mulated as follows (Scheme 4).
a Entries 1–4: reactions run in a glass apparatus; entries 5–9: reactions
run in an autoclave; entries 8 and 9: DME (5 mL) and DMF (5 mL)
were used, respectively.
The reagent 1 undergoes a transesterification reaction
with DMC to yield the intermediate I1 (BAc2 reaction),
which in turn, gives the ring closure to the benzoxazol-2-
one (I2). The BAl2 N-methylation of I2 yields the final
product 3a through a reaction analogous to the known
DMC-mediated methylation of amides.9 The scheme indi-
cates the catalytic role of the base B (K2CO3). Still, the se-
quence BAc2/BAl2 of O-methoxycarbonylation and N-
methylation, needs to be demonstrated. Presently, the pro-
posed intermediates I1 and I2 have not been isolated nor
observed.
b Isolated yield of 3a.
At 90 °C, the effect of reaction time is evident (entries 1–
4): from 9–48 h, the yield of 3a increases progressively
from 11% to 83%. The enhancement of the temperature
allows faster reactions with unaltered selectivity: at 130
°C, after 15 hours, 3a is isolated as a sole product in a 74%
yield (entry 7). Under these conditions (130 °C, 15 h), a
further improvement is achieved in the presence of DME
as a co-solvent (entry 8: Y = 89%): this behavior is rea-
sonable due to a moderate increase of the solubility of the
base (K2CO3) and/or the reactant anion [(o-H2N)C6H4O–
K+] in the DMC–DME mixture with respect to DMC
alone.8 In the case of DMF co-solvent, the unsatisfactory
outcome (entry 9: Y = 37%), is not attributable to a drop
in the reaction conversion, but rather to the difficulty in
the separation of the high-boiling co-solvent from the
product.
o-Aminophenol was then made to react with higher homo-
logues of DMC, such as diethyl-, diallyl-, and dibenzyl-
carbonates (2b, 2c, and 2d, respectively). Previous exper-
iments indicated that the electrophilic reactivity of com-
pounds 2 followed the trend: 2a 2d ca. = 2c > 2b.10
Reaction conditions were chosen accordingly. In the case
of 2c and 2d, experiments were carried out at 130 °C,
while diethyl carbonate 2b was used at 150 °C. Liquid
carbonates 2b,c were used as solvents, while DME was
the reaction medium in the case of the solid 2d: solutions
of 1 (0.5 g, 4.6 mmol) in 2b or 2c (38 mL or 45 mL, re-
Synthesis 2003, No. 18, 2872–2876 © Thieme Stuttgart · New York

2874
M. Selva
PAPER
Scheme 4 Mechanistic hypothesis for the reaction of o-aminophenol and DMC. B: a base
spectively; molar ratio 2/1 = 70), and solutions of 1 (0.5 g, In summary, this study allows the following conclusions:
4.6 mmol) and 2d (2.8 g, 11. 6 mmol; molar ratio 2d/1 = i) the reaction of o-aminophenol with compounds 2a–d
2.5) in DME (25 mL) were used. The catalyst K2CO3 was represents a unusual example where dialkylcarbonates act
added in different amounts in the range of 0.1–2 molar at the same time as alkylating and carbonylating agents
equivalents with respect to 1. Reactions were always run through BAl2/BAc2 mechanisms; ii) the base K2CO3 is tru-
in a stainless steel autoclave of 150 mL. Results are re- ly catalytic and yields of N-alkylbenzoxazol-2-ones 3a–d
ported in Table 2.
are satisfactory in all cases; iii) in the range of 90–150 °C,
the increase of temperature allows for a faster reaction
while it does not affect the selectivity towards final com-
pounds 3 (reaction intermediates are not observed); iv) al-
though the method is rather energy-intensive because of
the relatively high reaction temperature, valuable environ-
mental and synthetic advantages are the use of non toxic
compounds and catalyst, and the fact that neither organic
nor inorganic by-products are formed.3
Table 2 shows that N-alkylbenzoxazol-2-ones (3b–d) are
obtained in good yields. As for DMC, the base can be used
in a catalytic amount: in the case of 2b and 2c, at compa-
rable reaction times, a very limited variation of the final
yield is observed when the molar ratio K2CO3/1 changes
from 0.1 to 2.
Table 2 Reactions of o-Aminophenol (1) with Dialkyl Carbonates 2b–d
Entry
ROCO2R/1a
K2CO3/1b
Temp (°C)
Time (h)
Product, Yield (%)c
(mol/mol)
(mol/mol)
O
O
N
R
1
2b (70)
2b (70)
2b (70)
2c (70)
2b (70)
2b (70)
2d (2.5)
2d (2.5)
2
150
150
150
130
130
130
130
130
28
26
26
16
16
16
16
26
3b: R = Et, 81
3b: R = Et, 98
3b: R = Et, 86
3c: R = Allyl, 98
3c: R = Allyl, 93
3c: R = Allyl, 89
3d: R = Bn, 69
3d: R = Bn, 88
3
0.5
0.1
2
4
5
6
0.5
0.1
2
7
8d
9d
2
a Molar ratio ROCO2R/1.
b Molar ratio K2CO3/1.
c Isolated Yield of compounds 3.
d Entries 8 and 9: Reactions in DME as a solvent (25 mL).
Synthesis 2003, No. 18, 2872–2876 © Thieme Stuttgart · New York

PAPER
Reaction of Dialkyl Carbonates with o-Aminophenol
2875
All compounds used were ACS grade and were employed without
further purification. H NMR spectra were recorded on 300 MHz
1H NMR (300 MHz, CDCl3): = 7.23–6.95 (m, 4 H, Ar), 3.89 (q,
J = 7.2 Hz, 2 H), 1.38 (t, J = 7.2 Hz, 3 H).
1
spectrometer using CDCl3 as solvent and TMS as internal standard.
GLC and GC–MS (70 eV) analyses were run using CPSil24CB and
HP5 capillary columns (30 m), respectively. Melting points are un-
corrected.
GC–MS (70 eV): m/z = 163 (100) [M+], 148 (61) [M+ – CH3], 135
(62) [M+ – CO], 106 (10) [M+ – CO – CH2CH3], 91 (15), 79 (23),
78 (10), 77 (18), 51 (9).
3c
Reaction of o-Aminophenol with DMC (2a); General Procedure
According to the reaction temperature, two different procedures A
and B were used.
Liquid (bp Lit12 75–76 °C/0.07 mmHg).
1H NMR (300 MHz, CDCl3): = 7.24–6.94 (m, 4 H, Ar), 5.91 (ddt,
Jtrans = 17.3 Hz, Jcis = 10.2 Hz, Ja = 5.5 Hz, 1 H), 5.31 (dd, Jtrans
=
Procedure A: At 90 °C, experiments were run at atmospheric pres-
sure. A two-necked, jacketed, 50 mL round-bottomed flask fitted
with a reflux condenser connected to a N2 reservoir (ca 1 L), a stop-
cock and a magnetic bar, was loaded with o-aminophenol (0.5 g, 4.6
mmol), DMC (30 mL), and K2CO3 (the molar ratio K2CO3/1 was
made to vary in the range of 0.1–2.0, see Table 1 and Figure 1).
Four cycles of vacuum/N2 were carried out. Then, the mixture was
kept under N2, heated at the reflux temperature of DMC (90 °C), and
vigorously stirred. After a particular time interval (9 h, 18 h, 28 h,
and 48 h), the flask was cooled to r.t., K2CO3 was filtered and
washed with EtOAc (8–10 mL), and finally, solvents were removed
by rotary-evaporation. To the solid residue was added a mixture (35
mL) of petroleum ether–EtOAc (35:1) and heated at the reflux tem-
perature for 30 min. The light suspension was allowed to settle and
at 50 °C the upper clear solution (containing the product) was de-
canted. After removal of solvents, N-methyl benzoxazol-2-one (3a)
was isolated and characterized as such (yields given in Table 1 and
Figure 1).
17.3 Hz, Jgem = 1.2 Hz, 1 H), 5.30 (dd, Jcis = 10.2 Hz, Jgem = 1.2 Hz,
1 H), 4.45 (d, Ja = 5.5 Hz, 2 H).
GC–MS (70 eV): m/z = 175 (100) [M+], 146 (9), 134 (57) [M+ –
CH2CHCH2], 130 (9), 120 (7), 106 (34) [M+ – CH2CHCH2 – CO],
78 (16), 77 (10), 41 (36) [M+ - C7H4NO2], 39 (14).
Reaction of o-Aminophenol with Dibenzyl Carbonate 2d; Typi-
cal Procedure
Procedure B was used. At 130 °C, solutions of 1 (0.5 g, 4.6 mmol)
and 2d (2.8 g, 11. 6 mmol; molar ratio 2d:1 = 2.5) in DME (25 mL)
were made to react in the presence of K2CO3 (1.3 g, 9.2 mmol;
K2CO3/1 in a 2:1 molar ratio) for time intervals in the range of 16–
26 h. Then, the autoclave was cooled to r.t. and K2CO3 was filtered.
The solution was distilled under reduced pressure to remove the co-
product benzyl alcohol (bp 40 °C/10 mm) and the unreacted DBnC
(2d: bp 90 °C/10 mm). The solid residue was treated as described
above (see procedure A) to isolate N-benzyl benzoxazol-2-one (3d:
yields given in Table 2), which was characterized as such.
Procedure B: At 110 °C and 130 °C (above the bp of DMC), reac-
tions were run in an autoclave. A stainless steel autoclave (150 mL)
fitted with a thermostatic jacket, a manometer, and a thermocouple,
was loaded with a mixture of o-aminophenol (0.5 g, 4.6 mmol),
DMC (30 mL), and K2CO3 (the molar ratio K2CO3/1 was made to
vary in the range of 0.1–2.0; see Table 1 and Figure 1). Before heat-
ing, the autoclave was purged with a N2 stream using two on/off
valves (fixed on the autoclave head). The mixture was kept under
magnetic stirring and made to react for time intervals in the range of
3d:
Recrystallized (EtOH); mp 102–4 °C (Lit.1c mp 123–124).
1H NMR (300 MHz, CDCl3): = 7.40–6.80 (m, 9 H, Ar), 5.01 (s, 2
H).
GC–MS (70 eV): m/z = 225 (44) [M+], 91 (100) [M+ – C7H4NO2].
3–18 h. Then, the apparatus was cooled to r.t. and K2CO3 filtered. Acknowledgment
The product 3a was isolated as described above for the procedure A.
MIUR (Italian Ministry of University) and INCA (Interuniversity
Two experiments were also run with procedure B (130 °C, auto-
clave), in the presence of DME (5 mL) or DMF (5 mL) as co-sol-
vents.
Consortium Chemistry for the Environment; grant ‘Piano Ambiente
Terrestre: Chimica per l’Ambiente’ Legge 488/92) are gratefully
acknowledged for financial support. Prof. Pietro Tundo is also ack-
nowledged for his comments and suggestions.
3a
Yellow solid; mp 79.1–80.3 °C (Lit.2b 83.0–83.5 °C).
References
1H NMR (300 MHz, CDCl3): = 7.23–6.92 (m, 4 H, Ar), 3.40 (s, 3
H).
(1) (a) Close, W. J.; Tiffany, B. D.; Spielman, M. A. J. Am.
Chem. Soc. 1949, 71, 1265. (b) Fu, Y.; Baba, T.; Ono, Y. J.
Catal. 2001, 197, 91. (c) Ucar, H.; Vanderpoorten, K.;
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(3) (a) Green Chemistry, Theory and Practice; Anastas, P. T.;
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GC–MS (70 eV): m/z = 149 (100) [M+], 134 (4) [M+ – CH3], 120
(40) [M+ – NH=CH2], 106 (9) [M+ – CH3 – CO], 93 (20) [M+ –
N=CH2 – CO], 92 (12), 78 (14), 51 (16).
Reaction of o-Aminophenol with Diethyl- and Diallyl Carbon-
ates 2b,c; General Procedure
Procedure B was used. Accordingly, solutions of 1 (0.5 g, 4.6
mmol) in 2b or 2c (38 mL or 45 mL, respectively; molar ratio 2:1 =
70), were loaded in a stainless steel autoclave of 150 mL, along with
the catalyst (K2CO3) added in the range of 0.1–2 molar equiv with
respect to 1. The reaction temperature was 150 °C and 130 °C, with
2b and 2c, respectively. Products 3b,c were isolated as described
above in procedure A (yields given in Table 2). N-Ethyl- and N-al-
lyl benzoxazol-2-ones were liquids at r.t.; mp 4 °C.
3b
Liquid (Lit.11 brown oil).
Synthesis 2003, No. 18, 2872–2876 © Thieme Stuttgart · New York

2876
M. Selva
PAPER
(5) (a) Selva, M.; Marques, C. A.; Tundo, P. J. Chem. Soc.,
Perkin Trans. 1 1994, 1323. (b) Tundo, P.; Selva, M.
CHEMTECH 1995, 25, 31. (c) Selva, M.; Marques, C. A.;
Tundo, P. J. Chem. Soc., Perkin Trans. 1 1995, 1889.
(d) Selva, M.; Tundo, P.; Perosa, A.; Memoli, S. J. Org.
Chem. 2002, 67, 1071.
(6) The alkylation reaction with 2 takes place only at a high
temperature [ 120 °C; Scheme 2, path (a)]. Under these
conditions, the alkylation is the sole possible process
because of the reversibility of path (b).
(8) DME has been reported by us as a good co-solvent also for
the DMC-mediated N-methylation reaction of p-
aminophenol: Selva, M.; Tundo, P.; Perosa, A. J. Org.
Chem. 2003, 68, 7374.
(9) Ben Taleb, A.; Jenner, G. J. Mol. Catal. 1993, 84, L131.
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Trans. 2 1992, 4, 519. (b) Perosa, A.; Selva, M.; Tundo, P.;
Zordan, F. Synlett 2000, 1, 272. (c) Selva, M.; Tundo, P.;
Perosa, A. J. Org. Chem. 2001, 66, 677.
(11) Anderson, G. W.; Bell, F. J. Chem. Soc. 1949, 2668.
(7) Marques, C. A.; Selva, M.; Tundo, P.; Montanari, F. J. Org.
Chem. 1993, 58, 5765.
Synthesis 2003, No. 18, 2872–2876 © Thieme Stuttgart · New York