1,3-Dihydro-1,3-diacetyl-2H-benzimidazol-2-one: A new versatile and selective acetylating agent

Article abstract of DOI:10.3987/com-99-8779

1,3-Dihydro-1,3-diacetyl-2H-benzimidazol-2-one (4, DABI) was proven to be a versatile and selective acetylating agent for amines. Selectivity and reactivity are not only superior than those of other known acetylating agents, but also products could be easily separated with excellent yield.

Full text of DOI:10.3987/com-99-8779

HETEROCYCLES, Vol.53, No.3, 2000, pp. 529 - 533, Received, 12th October, 1999
1,3-DIHYDRO-1,3-DIACETYL-2H-BENZIMIDA-
ZOL-2-ONE : A NEW VERSATILE AND SELEC-
TIVE ACETYLATING AGENT
In Hwa Chung,1,2 Ki Suk Cha,3 Jae Hong Seo,1
Joong Hyup Kim,1 Bong Young Chung,2 and Choong Sup Kim*1
1Biochemicals Research Center, Korea Institute of Science and
2
Technology, P.O.Box 131, Seoul 130-650, Korea, Department
3
of Chemistry, Korea University, Seoul 136-701, Korea, ISu
Chemical Co., LTd, Ulsan 689-890, Korea
Abstract - 1,3-Dihydro-1,3-diacetyl-2H-benzimidazol-2-one (4,
DABI) was proven to be a versatile and selective acetylating
agent for amines. Selectivity and reactivity are not only superior
than those of other known acetylating agents, but also products
could be easily separated with excellent yield.
The acetylation of amines is one of the most fundamental reactions in organic synthesis.1 Especially,
selective acetylation is important reaction in diamino or polyamino compounds. Numerous studies have
been performed to obtain more efficient acetylating agents or to extend the application of the existing
ones.2
During the study on imidazolone derivatives which are useful and important building blocks in medicinal
chemistry, 3 we have found that N-acetyl group could be easily removed by nucleophiles such as amines.
From this result, we have synthesized several 1,3-dihydro-1,3-diacetyl-1H-imidazolone derivatives
(Figure 1) to consider their acetyl transfer reactivity to amine.4
H3C
H3C
H3C
H3C
O
O
O
O
C2H5O2C
CH3
CH3
CH3
N
N
N
N
O
O
O
O
N
N
N
N
O
O
O
O
H3C
H3C
H3C
H3C
3
4
1
2
Figure 1. 1,3-Dihydro-1,3-diacetylimidazole-2-one derivatives
All of the compounds (1-4) showed excellent acetyl transferring properties (Tables 1 and 2). Among these,

4 showed the best reactivity. Compound (4) also has an additional advantage in its facile preparation
(Scheme 1) through acetylation of commercially available 1,3-dihydro-2H-benzimidazol-2-one (5) with a
corresponding acetyl chloride or acetic anhydride. N-Acetylated benzylamine and piperazine were
efficiently separated by filtration of 1,3-dihydro-1-acetyl-2H-benzimidazol-2-one (6) by virtue of its low
solubility in most organic solvents.
Table 1. Reactivity of 1,3-diacetylimidazolone derivatives with benzylamine
Agents
Amine
Conditions
Product
Yield(%)a
1
Benzylamine
Benzylamine
Benzylamine
Benzylamine
CH2Cl2, rt, 3 h
CH2Cl2, rt, 2.5 h
CH2Cl2, rt, 1.5 h
CH2Cl2, rt, 1.5 h
N-Ac-benzylamine
N-Ac-benzylamine
N-Ac-benzylamine
N-Ac-benzylamine
91
92
95
96
2
3
4
a) Isolated yield
Table 2. Reactivity of 1,3-diacetylimidazolone derivatives with piperazine
Agents
1
Amine
Conditions
Product
Yield(%)a
85
Piperazine
CH2Cl2, rt, 2.5 h
N-Ac-piperazine
2
3
4
Piperazine
Piperazine
Piperazine
CH2Cl2, rt, 2.5 h
CH2Cl2, rt, 1.3 h
CH2Cl2, rt, 1.4 h
N-Ac-piperazine
N-Ac-piperazine
N-Ac-piperazine
88
94
93
a) Isolated yield
Scheme 1. Preparation of 4 and reaction with benzylamine
Ac
N
H
N
H
N
a
b
+
O
O
O
NHAc
N
H
N
N
Ac
Ac
5
4
6
Reagents and conditions ; a) Ac2O, reflux, 6 h, 97 %; AcCl (2.05 eq), (C2H5)3N, reflux, 5 h, 94 %
b) benzylamine (1 eq), CH2Cl2, rt, 1.5 h, 96 %
In order to confirm the selectivity and reactivity of 4, three other known acetylating agents, N-acetyl-N-
acyl-3-aminoquinazoline (A), 2a 2-trifluoromethyl-N,N-diacetylaniline (B) 2b and N-methoxydiacetamide
(C) 2f were compared with 4. Although B showed good selectivity, its reaction condition and yield were
not recommendable. 4 also have advantages on the aspect of facile product isolation.
It was important to confirm the diacetyl transfering ability of 4 to various amine. The monoacetyl and
diacetyl transferring abilities of 4 to various amines are summarized in Table 3. All of the amines required
harsh conditions with 0.5 equivalent of 4 but proceeded under mild conditions with 1.0 equivalent.

In general, primary and secondary aliphatic amines including cyclic amines (Entries 1 and 4) were easily
acetylated in quantitative yield. Aromatic amines (Entry 2) and sterically hindered aliphatic amines
Table 3. Reaction of 1,3-dihydro-1,3-diacetyl-2H-benzimidazol-2-one ( DABI ) with amines*
Entry
Amine
Product
DABI(0.5 eq)a),Yield(%)b)
DABI(1 eq) c), Yield(%)b)
NH
NHAc
2
1
rt, 6 h, 95
25 min, 99
NH2
NHAc
2
3
30 h, 93
60 h, 48.
150 min, 94
4 h, 97
CH
CH
3 NH
3 NAc
CH3
N
NH
CH3
N
NAc
4
5
5 h, 96
30 min, 98
NH2
NHAc
25 h, 97
120 min, 96
* All experiments were carried out in reagent grade THF. a)The mixture was refluxed. b)Isolated yield. c)The reaction
proceeded at room temperature.
(Entry 5) required slightly harsher reaction conditions. In contrast, sterically hindered N- methylaniline
(Entry 3) was incompletely acetylated with 0.5 equivalent of reagent, but proceeded completely under
mild conditions with the 1.0 equivalent. The substantial reactivity difference depending on the
nucleophilicity and steric hindrance of amines encouraged us to examine selective acetylation in a series
of structurally diverse diamino compounds possessing aromatic and aliphatic, or primary and secondary
amino groups (Table 4). As shown in Table 4, the aliphatic amino group was selectively acetylated in the
presence of aromatic amines (Entries 6, 7, 5 8, and 9). In the case of aliphatic diamino compounds
consisting of primary and secondary amino moieties, monoacetamides of primary amino groups were
selectively obtained in good yields (Entries 14, 15, 6 and 16). Compound (4) showed good regio- and
chemoselectivity (Entry 17), and transferred acetyl group to imidazole7 itself (Entry 11). From this result,
we have found compound (4) has more powerful acetyl transfer reactivity than those of imidazole.
Table 4. Reaction of 1,3-dihydro-1,3-diacetyl-2H-benzimidazol-2-one (DABI) with diamines*
Entry
Amines
Product
DABI(0.5 eq) a), Yield(%)b) DABI(1 eq) a), Yield(%)b)
NH2
NHAc
6
15 h, 97
25 min, 97
H2N
H2N
H
H
N
N
NH2
NH2
NHAc
NHAc
7
8
12 h, 96
20 min, 96
12 h, 95
12 h, 93
20 min, 95
18 min, 93
N
N
H
H
NH
NHAc
H CO
2
CH O
3
3
9
N
N
H
H

H2N
AcHN
10
48 h, 95
120 min, 95
N
N
H
H
N
N
11
12
reflux, 12 h, 75
12 h, 75
20 min, 80
20 min, 95
N
H
N
Ac
HN NH
CH
HN NAc
CH
3
3
HN NH
CH
HN NAc
CH
13
reflux, 6 h, 95
18 min, 98
3
3
H
N
H
N
CH3
CH3
14
15
CH3
CH3
5 h, 96
6 h, 97
15 min, 96
15 min, 97
NH2
NH2
NHAc
NHAc
H
N
H
N
CH3
CH3
CH3
CH3
NH2
NHAc
16
17
7 h, 95
6 h, 94
18 min, 95
15 min, 94
CH
CH
3 NH2
3 NH2
H
N
H
N
HO
NH2
HO
NHAc
* All experiments were carried out in reagent grade THF. a)Reaction was performed at room temperature. b)Isolated yield.
In conclusion, 1,3-dihydro-1,3-diacetyl-2H-benzimidazol-2-one (4) is a convenient regio- and
chemoselective acetylating reagent with many advantages due to its facile preparation, good reactivity,
stability and easy work-up process.
REFERENCES AND NOTES
1. T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc.,
New York, 1991, pp. 349-352.
2. a) Y. Nagao, K. Seno, and K. Kawabata, Chem. Pharm. Bull., 1984, 32, 2687; b) Y. Musakami, K.
Kondo, K. Miki, Y. Akiyama, T. Watanabe, and, Y. Yokoyama, Tetrahedron Lett., 1997, 38, 3751; c) S.
Y. Kim, N. D. Sung, J. -K. Choi, and S. S. Kim, Tetrahedron Lett., 1999, 40, 117; d) J. H. Lee and J. D.
Kim, Bull. Korean Chem. Soc., 1997, 18, 442; e) S. Robert, E. B. Atkinson, and T. S. Michael, Chem.
Commun., 1996, 1051; f) Y. Kikugawa, K. Mitsui, T. Sakamoto, M. Kasase, and H. Tamiya,
Tetrahedron Lett., 1990, 31, 243.
3. N. A. Meanwell, S. Y. Sit, J. Gao, H. S. Wong. Q. Gao, R. St. L. Denis, and B. Neelakantan, J.
Org. Chem., 1995, 60, 1565.
4. R. Duchinsky and L. A. Dolan, J. Am. Chem. Soc., 1946, 68, 2350; B. B. Corson and D. Blum,
Chem. Ber., 1957, 90, 391.
5. All new compounds exhibited satisfactory analytical and spectroscopic data. Selected data for 7 :
brown oil; 1H NMR (300 MHz, CDCl3 ) δ 6.61-7.21 (m, 5H), 5.91 (br s, NH), 4.01 (br s, NH), 3.48
(t,
J = 5.7 Hz, 2H), 3.28 (t, J = 5.7 Hz, 2H ), 1.98 ( s, 3H ); MS m/z 178 (M+); HRMS m/z [M]+ calcd for

C10H14N2O, 178.1106, found 178.1106.
6. Selected data for 15 : yellow oil; 1H NMR (300 MHz, CDCl3 ) δ 6.21 (br s, NH), 3.33(q, J = 5.7 Hz,
2H), 2.78 (m, 1H), 2.72 ( q, J = 5.7 Hz, 2H ), 1.97 ( s, 3H ), 1.59 ( br s, NH ), 1.04 ( d, J = 6.4 Hz,
6H); HRMS m/z [M]+ calcd for C7H16N2O, 144.1262, found 144.1261.
7. R. Paul and G. W. Andonon, J. Am. Chem. Soc., 1960, 82, 4596; H. A. Staab, Angew. Chem. Int.,
Ed. Engl., 1962, 7, 351; A. Saito and B. Shimizu, Bull. Chem. Soc. Jpn., 1983, 56, 2974.