Synthesis of 1-{6-(2-methylbenzoyl)-N-ethylcarbazole- 3-yl}-ethane-1-one oxime O-acetate

Article abstract of DOI:10.1007/s11164-011-0329-4

1-{6-(2-Methylbenzoyl)-N-ethylcarbazole-3-yl}-ethane-1-one oxime O-acetate, an excellent two-photon carbazole photoinitiator, was synthesized with moderate yield (76.9%) starting from the successive o-methyl benzoylation and acetylation of N-ethylcarbazole, followed by oximation and esterification in the article. The structure was confirmed by ¹H-NMR, ¹³C-NMR, and IR. The by-product acetic acid in the neutralization of hydroxylamine hydrochloride is effectively utilized in esterification with the aid of the one-pot process. In particular, the phase transfer technique is applied to overcome the deficiency of low reaction rate caused by heterogeneous reaction conditions in esterification. Springer Science+Business Media B.V. 2011.

Full text of DOI:10.1007/s11164-011-0329-4

Res Chem Intermed (2012) 38:105–111
DOI 10.1007/s11164-011-0329-4
Synthesis of 1-{6-(2-methylbenzoyl)-N-ethylcarbazole-
3-yl}-ethane-1-one oxime O-acetate
•
Liang Zhao Chao Qian Ling Gong Xin-zhi Chen
•
•
Received: 24 February 2011 / Accepted: 20 May 2011 / Published online: 3 June 2011
Ó Springer Science+Business Media B.V. 2011
Abstract 1-{6-(2-Methylbenzoyl)-N-ethylcarbazole-3-yl}-ethane-1-one
oxime
O-acetate, an excellent two-photon carbazole photoinitiator, was synthesized with
moderate yield (76.9%) starting from the successive o-methyl benzoylation
and acetylation of N-ethylcarbazole, followed by oximation and esterification in
the article. The structure was confirmed by 1H-NMR, 13C-NMR, and IR. The
by-product acetic acid in the neutralization of hydroxylamine hydrochloride is
effectively utilized in esterification with the aid of the one-pot process. In particular,
the phase transfer technique is applied to overcome the deficiency of low reaction
rate caused by heterogeneous reaction conditions in esterification.
Keywords Photoinitiator Á One-pot Á Phase transfer Á Green chemistry
Introduction
The photoinitiator of UV-curing system can be divided into radical polymerization
and cationic polymerization photoinitiators [1–8] according to the reaction
mechanism. Two-photon photoinitiators rapidly received widespread attention for
their particular properties such as good two-photon absorption, rigidity conjugate
plane and electron delocalization. Good progress [9–11] has recently been made in
the design and synthesis of a two-photon photoinitiator with large absorption cross-
section.
Carbazole proxetil is a new class of carbazole-based two-photon photoinitiator,
which typically have the following general formula [12] (Fig. 1).
L. Zhao Á C. Qian (&) Á L. Gong Á X. Chen
Department of Chemical and Biochemical Engineering, State Key Laboratory of Chemical
Engineering, Zhejiang University, No.38 Zheda Road, Hangzhou 310027, China
e-mail: supmoney@163.com
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L. Zhao et al.
Fig. 1 Chemical structure
formula of carbazole proxetil;
where, R1, R2, and R3 are alkyl
or cycloalkyl, etc.; Ar represents
aryl
O
R2
O
O
Ar
N
R3
N
R1
O
O
Ar
R2
ArCOCl
NH2OH HCl
N
R2COCl
R1
N
R1
O
R2
O
R3
O
R2
Ar
N
Ar
N
OH
O
R3COCl
N
N
R1
R1
Scheme 1 General synthetic process of carbazole oxime ester
Many typical synthetic methods for carbazole oxime ester photoinitiator [13, 14]
have been reported with the general process as shown in Scheme 1. In such a process,
by-products with the symmetrical acyl group are easily produced during acylation,
and they are very hard to separate from each other because of their similar structures.
Acyl chloride is usually utilized as an esterification reagent which produces much
chlorine as a by-product and has an unfriendly effect on the environment.
1-{6-(2-Methylbenzoyl)-N-ethylcarbazole-3-yl}-ethane-1-one oxime O-acetate 5
can be obtained from N-ethylcarbazole 1, through successive o-methyl benzoyla-
tion and acetylation, then oximation of the acetyl and its esterification. In our
previous study [13], the side reaction of diacylation at the 3- and 6-positions of
N-ethylcarbazole is effectively inhibited by reaction-condition control. This study
focuses on the steps of oximation and esterification. In the oximation, hydroxyl-
amine hydrochloride is utilized as the reagent, with addition of sodium acetate as the
base, while the acetic acid produced as the by-product in the oximation is utilized as
the resource in the succeeding esterification step (Scheme 2).
Results and discussion
Base affecting oximation
Within appropriate pH conditions, acetyl would be oximated first, caused by the
conjugate function of the o-methylbenzoyl, though 3-acetyl-6-(o-methylbenzoyl)-
N-ethylcarbazole has two carbonyl groups. Furthermore, the hydroxylamine
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1-{6-(2-Methylbenzoyl)-N-ethylcarbazole-3-yl}-ethane-1-one oxime O-acetate
107
O
O
O
Cl
CH3COCl
2.
1.
N
AlCl3
N
(1)
O
(2)
OH
+
N
CH3COONa
NH2OH HCl
N(C4H9)4Br
CH3COOH +
(4)
H2O
+
NaCl +
N
(3)
O
O
N
O
SO3H
N
(5)
Scheme 2 Synthesis of 1-{6-(2-methylbenzoyl)-N-ethylcarbazole-3-yl}-ethane-1-one oxime O-acetate
hydrochlorides need to be neutralized to release hydroxylamine under alkaline
conditions to bring about the oximation. Therefore, modulation of the pH by adding
a suitable base is very important.
Four kinds of base were used for neutralizing the hydroxylamine hydrochloride
and regulating the pH. As seen in Table 1, substrate 3-acetyl-6-(o-methylbenzoyl)-
N-ethylcarbazole could be converted completely only when the sodium acetate was
added.
When sodium hydroxide was added, the strong alkaline condition that was
formed made hydroxylamine decompose easily, and consequently the substrate was
converted incompletely; carbon dioxide is produced and escapes easily after the
addition of sodium carbonate. This made the pH higher and higher resulting in the
reaction condition no longer being advantageous for oximation. Ammonia itself
volatilized easily and makes the hydroxylamine disassociate incompletely, so the
conversion was low. With the addition of sodium acetate, the CH3COOH/
Table 1 Affection of different base on oximation
Base
Material 3 converted completely or not
Purify of product (%)
Sodium hydroxide
Sodium carbonate
Sodium acetate
Ammonia
No
No
Yes
No
55.3
68.9
97.6
81.2
Base:hydroxylamine hydrochloride:3-acetyl-6-(o-methylbenzoyl)-N-ethylcarbazole = 1.2:1.15:1 (molar
ratio), solvent was ethyl alcohol, reacted at 70 °C for 4 h, detected by TLC
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CH3COONa buffer solution formed, maintaining pH 5–7 which was very
appropriate for oximation. Especially, the by-product acetic acid, through adding
sodium acetate, could be used as the esterification reagent in the one-pot process.
This design of introducing sodium acetate is not only helpful in accomplishing the
oximation but also significant in protecting the environment. The reaction route is
totally in accord with the atom-economy of green chemistry.
Phase transfer process in one-pot
Based on the fact that the by-product acetic acid in the neutralization of
hydroxylamine hydrochloride could be utilized as the esterification reagent, the
esterification was taken out in the one-pot process without intermediate purification.
This stops the carbonyl chloride consumption of the traditional method [14, 15], and
consequently cuts off the root of contamination.
By applying the one-pot process, choosing the solvent appropriate for both
oximation and esterification was difficult and complex. Alcohol would react with
the esterification reagent acetate, while ketone and ester could be oximated by
hydroxylamine. If the substrate and product were both benign photoinitiators, the
easily polymerizable solvent, i.e., acetonitrile, would polymerize itself. Heating to
reflux pulls out the produced water and accelerates esterification which was
essential when esterification was ongoing, and therefore the aromatic was not
suitable because of its high boiling point.
In summary, 1,2-dichloroethane is a relatively appropriate solvent for such a one-
pot process. We used a phase transfer catalyst to accelerate the reaction in a
heterogeneous system where hydroxylamine cannot dissolve in 1,2-dichloroethane.
This phase transfer catalyzing method could make a heterogeneous reaction, which
usually goes slowly or needs a liqour condition, become relatively fast and with a
high yield. Because it was no more homogeneous for oximation with 1,2-
dichloroethane as solvent, we investigated the effect of different reaction times on
oximation when tetrabutylammonium bromide was utilized as the phase transfer
catalyst. According to the results detected by TLC, the substrate could be converted
completely in 7 h.
Conclusion
1-{6-(2-Methylbenzoyl)-N-ethylcarbazole-3-yl}-ethane-1-one oxime O-acetate is
synthesized from successive o-methyl benzoylation and acetylation of N-ethylcar-
bazole, then oximation of the acetyl and its esterification. The appropriate
technological condition is as follows. o-Methylbenzoyl chloride: ethylcarbazole is
1:1 (molar ratio), molar amount of AlCl3 is 0.7 times that of N-ethylcarbazole and
the reaction at 0 °C. In acetylation acetyl chloride: N-ethylcarbazole is 1.2:1 (molar
ratio), molar amount of additive AlCl3 is 0.5 times that of N-ethylcarbazole and the
reaction at 20 °C.
Sodium acetate:hydroxylamine hydrochloride:3-acetyl-6-(o-methylbenzoyl)-N-
ethylcarbazole is 1.2:1.15:1 (molar ratio), mass amount of tetrabutylammonium
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1-{6-(2-Methylbenzoyl)-N-ethylcarbazole-3-yl}-ethane-1-one oxime O-acetate
109
bromide is 0.05 times that of 3-acetyl-6-(o-methylbenzoyl)-N-ethylcarbazole and
the reaction at 70 °C for 7 h. In esterification, the mass amount of additive catalyst
p-toluenesulphonic acid is 0.05 times that of 3-acetyl-6-(o-methylbenzoyl)-N-
ethylcarbazole and the mixture is heated to reflux removing the produced water for
6 h.
Experimental
Materials
All reagents were commercially obtained without further purification. Reaction
processes were monitored by thin-layer chromatography (TLC), and the developing
solvent is petroleum ether/ethyl acetate = 5/1 for selective acylation and petroleum
ether/ethyl acetate = 1/1 for oximation and esterification. Melting points were
1
tested by WRS-I melting point apparatus and were uncorrected. 13C-NMR and H-
NMR data were recorded on Bruker 400 MHz spectrometer operating near 400 (1H)
or 100 (13C) MHz in CDCl3 solvents, and TMS was used as internal standard.
Synthesis of 1-{6-(2-methylbenzoyl)-N-ethylcarbazole-3-yl}-ethane-1-one
oxime O-acetate
One-pot successive o-methyl benzoylation and acetylation
Key intermediate 3-acetyl-6-(o-methylbenzoyl)-N-ethylcarbazole was synthesized
from N-ethylcarbazole referring to our previous study [13].
o-Methyl benzoylation:AlCl3 (4.6 g, 0.035 mol), N-ethylcarbazole (9.75 g,
0.05 mol), and 1,2-dichloroethane(65 mL) were added to a 250-mL four-necked
flask equipped with a mechanical stirrer, condenser (connected with an inverted
funnel for absorbing HCl), constant pressure drop funnel and a thermometer, which
was placed in thermostat bath controlled at 0 °C. To the content, a mixture of
o-methylbenzoyl chloride (6.5 mL, 0.05 mol) and 1,2-dichloroethane (15 mL) was
added dropwise within 0.5 h with stirring, and after that the reaction was kept at the
temperature for another 0.5 h.
Acetylation: the reaction temperature was slowly warmed to 20 °C. Then,
another AlCl3 (3.4 g, 0.025 mol) was added to the reaction mixture. Acetyl chloride
(4.5 mL, 0.06 mol) was dropped in within about 0.5 h.
Once the reaction finished, 80 mL ice water was added to the reaction mixture
with stirring. THe organic layer was separated and washed with saturated sodium
carbonate solution and water to acid-free. The solvent was removed under reduced
pressure. 50 mL acetone was added to the residue and the mixture was heated to
reflux, and then cooled in an ice bath. The solid precipitate was filtered off, washed
with water and dried in the air, giving the crystalline powder of 3-acetyl-6-
(o-methylbenzoyl)-N-ethylcarbazole (15.2 g, 85.6% yield), m.p. 162.1–163.2 °C.
IR(KBr) rmax (cm-1): 1244, 1257, 1306 (C–N), 1457, 1484, 1590 (Ar), 1654,
1664 (C=O), 2894, 2966, 3056 (C–H).
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1H-NMR (400 MHz, CDCl3): 8.68 (d, 1 H, J = 0.6 Hz, Ar–H); 8.54 (d, 1 H,
J = 0.6 Hz, Ar–H); 8.14–8.17 (m, 1 H, Ar–H); 8.09–8.11 (m, 1 H, Ar–H);
7.29–7.48 (m, 6 H, Ar–H); 4.42 (q, 2 H, J = 7.2 Hz –CH2–CH3); 2.70 (s, 3 H, –
CO–CH3); 2.35 (s, 3 H, Ar-CH3); 1.48 (t, 3 H, J = 7.2 Hz –CH2–CH3).
13C-NMR (100 MHz, CDCl3): 13.81, 19.83, 26.69, 38.16, 108.69, 108.82,
122.08, 122.90, 122.93, 124.21, 125.30, 127.07, 127.97, 128.63, 129.71, 129.83,
129.93, 130.89, 136.16, 139.48, 143.37, 143.53, 197.50, 198.17.
One-pot oximation and esterification
To a well-stirred reaction vessel, which was equipped with a condenser, constant
pressure drop funnel and thermometer, was added 3-acetyl-6-(o-methylbenzoyl)-
N-ethylcarbazole (3.55 g, 0.01 mol), hydroxylamine hydrochloride (0.8 g, 0.0115 mol),
tetrabutylammonium bromide (0.2 g) and 1,2-dichloroethane (65 mL). Upon
completion, the reaction temperature was slowly warmed to 70 °C, and then the
solution of sodium acetate (1 g, 0.012 mol) and deionized water (10 mL) was added
dropwise into the content.
After the addition was done, the reaction was kept at this temperature for 7 h.
Then, p-toluenesulphonic acid (0.2 g) was added and the mixture was heated to
reflux. With the aid of dichloroethane-water azeotrope, the produced water could be
removed and the esterification was accelerated. After 6 h, there was no more water
in the vapored liquid. Detected by TLC, substrate 3-acetyl-6-(o-methylbenzoyl)-N-
ethylcarbazole was no longer in the mixture which meant it was completely
converted.
The mixture was evaporated under reduced pressure and the residue was washed
with deionized water. Then, 1-{6-(2-methylbenzoyl)-N-ethylcarbazole-3-yl}-eth-
ane-1-one oxime O-acetate was recrystallized in the alcohol and dried as a white
solid (3.7 g, 89.8% yield), mp. 125.5–126.1 °C (lit. 110–113 °C) [15].
IR(KBr) rmax (cm-1): 1131 (C–O), 1256, 1271, 1307 (C–N), 1487, 1590 (Ar),
1653 (C=N), 1623, 1765 (C=O), 2843, 2927 (–C–H).
1H-NMR (400 MHz, CDCl3): 1.47 (t, 3 H, J = 7.2 Hz –CH2–CH3); 2.29 (s, 3 H,
–C(=NOH)–CH3); 2.36 (s, 3 H, –CO–CH3); 2.51 (s, 3 H, Ar–CH3); 4.41 (q, 2 H,
J = 7.2 Hz –CH2–CH3); 7.29–7.35 (m, 6 H, Ar–H); 7.97 (d, 1 H, J = 4.6 Hz Ar–H);
8.11 (d, 1 H, J = 4.4 Hz, Ar–H); 8.43 (s, 1 H, Ar–H); 8.52 (s, 1 H, Ar–H).
13C-NMR (100 MHz, CDCl3): 13.85, 14.73, 19.87, 19.90, 38.09, 108.67, 109.04,
120.02, 122.63, 123.20, 124.43, 125.35, 125.51, 126.66, 127.97, 128.40, 129.58,
129.78, 130.91, 136.15, 139.67, 141.96, 143.31, 162.90, 168.97, 198.33.
Acknowledgments We gratefully acknowledge the generous financial support by grants from the
National Natural Science Foundation of China (No. 21076183, 21006087) and the Natural Science
Foundation of the Zhejiang Province (No. Y4100147).
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