Efficient Friedel–Crafts benzoylation of aniline derivatives with 4-fluorobenzoyl chloride using copper triflate in the synthesis of aminobenzophenones

Article abstract of DOI:10.1080/00397911.2016.1148164

ABSTRACT: An efficient pathway for the synthesis of the aminobenzophenone derivatives via Friedel–Crafts benzoylation using copper triflate as catalyst is proposed. New derivatives are synthesized. The copper triflate could be easily recovered and reused without loss of catalytic activity. Both the use of ionic liquids and microwave heating turned out to be fruitful.

Full text of DOI:10.1080/00397911.2016.1148164

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Efficient Friedel–Crafts Benzoylation of Aniline
Derivatives with 4-fluorobenzoyl Chloride
Using Copper Triflate in the Synthesis of
Aminobenzophenones
Phuong Hoang Tran, Huy Quang Phung, Poul Erik Hansen, Hai Ngoc Tran &
Thach Ngoc Le
To cite this article: Phuong Hoang Tran, Huy Quang Phung, Poul Erik Hansen, Hai Ngoc Tran
& Thach Ngoc Le (2016): Efficient Friedel–Crafts Benzoylation of Aniline Derivatives with 4-
fluorobenzoyl Chloride Using Copper Triflate in the Synthesis of Aminobenzophenones,
Synthetic Communications, DOI: 10.1080/00397911.2016.1148164
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1148164
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Date: 19 February 2016, At: 15:12

Efficient Friedel–Crafts benzoylation of aniline derivatives with 4-fluorobenzoyl
chloride using copper triflate in the synthesis of aminobenzophenones
Phuong Hoang Tran1, Huy Quang Phung1, Poul Erik Hansen2, Hai Ngoc Tran1, Thach
Ngoc Le1
1Department of Organic Chemistry, Faculty of Chemistry, University of Science,
Vietnam National University, Ho Chi Minh City 70000, Vietnam2Department of Science,
Systems and Models, Roskilde University, DK-4000 Roskilde, Denmark
Corresponding author: Thach Ngoc Le Email: lenthach@yahoo.com
Supplemental data for this article can be accessed on the publisher’s website.
Abstract
An efficient pathway for the synthesis of the aminobenzophenone derivatives via
Friedel–Crafts benzoylation using copper triflate as catalyst is proposed. New derivatives
are synthesized. The copper triflate could be easily recovered and reused without loss of
catalytic activity. Both the use of ionic liquids and microwave heating turned out to be
fruitful.
KEYWORDS: Friedel–Crafts acylation, metal triflate, aminobenzophenone, microwave
heating, ionic liquid.
INTRODUCTION
Aminobenzophenone derivatives play a crucial role in organic synthesis and are known
as important groups for anticancer therapy [1-9]. Among these, 4-aminobenzophenones
are known as the precursors for the synthesis of a wide range of benzothiazole and
triazole derivatives [10, 11]. In addition, 2-aminobenzophenone derivatives have been
prepared by Fries rearrangement [12-16], from benzoisoxazole [17, 18], by ortho-
acylation of anilides with toluene derivatives [19], by addition of arylboronic acids [20],
or by cross-coupling of N-nitrosoanilines and toluene derivatives [21]. 4-
Aminobenzophenone derivatives have normally been prepared via Friedel–Crafts
acylation [22-24]. However, the well-known traditional catalysts such as AlCl3, FeCl3,
1

TiCl4,… are usually required in more than stoichiometric amounts and cannot be recycled
after aqueous work-up [25-27]. Besides, the use of volatile organic solvents in this
process may be dangerous to the environment, especially on an industrial scale [26]. The
direct Friedel–Crafts acylation of aniline derivatives is unsuccessful because N-acylation
is much more rapid than Friedel–Crafts acylation [28, 29]. Consequently, N-protection of
the amino group is necessary for the Friedel–Crafts acylation process, and 4-
aminobenzophenone derivatives are obtained after an acidic hydrolysis step. Moreover,
the Friedel–Crafts acylation of acylanilides using excess of AlCl3 afforded the
corresponding ketones in low yields due to the loss of the catalytic activity of the Lewis
acid in the presence of the basic nitrogen [25]. Recently, Kobayashi and co-workers
reported the use of gallium triflate in nitromethane and lithium perchlorate in the Friedel–
Crafts acylation of acylanilides. The yields of ketones were good to excellent testing a
range of aliphatic acid anhydrides and a couple of acid chlorides. In the latter case N-
methyl-N-methylsulfonylaniline was the substrate using methylene chloride as solvent
giving a yield of 90% or better for the acylation step [30]. We report here an efficient
procedure to synthesize 4-aminobenzophenone derivatives via Friedel–Crafts
benzoylation with 4-fluorobenzoyl chloride using copper triflate under solvent-free
condition. Aniline derivatives with electron-rich and electron-poor substituents are also
reactive with substituent selectively in the para-position.
RESULTS AND DISCUSSION
The proposed Friedel–Crafts benzoylation of 4-aminobenzophenone derivatives using
copper triflate is a procedure including three steps with moderate yields (overall yield 55-
2

75%): (i) the first step is to synthesize the amide derivatives (see Table 2) (ii) the second
step involves the Friedel–Crafts benzoylation reaction (iii) and the third step is the
hydrolysis of the amide derivatives in acidic solution (see Table 3). Three new
compounds were prepared from dichloroanilines and 4-fluorobenzoyl chloride: 4-amino-
2,5-dichloro-4’-fluorobenzophenone, 4-amino-2,6-dichloro-4’-fluorobenzophenone, 2-
amino-4,5-dichloro-4’-fluorobenzophenone.
Initially, the effect of metal triflates in the process using aniline as substrate with benzoyl
chloride was investigated. The Friedel–Crafts acylation of aniline derivatives catalyzed
by traditional Lewis acids is usually reported in low yield due to the formation the Lewis
acid-base adduct between the catalyst and the amine group of the aniline derivatives.
Metal triflates, a new type of Lewis acid, could avoid this problem. The most
characteristic feature of metal triflates can be used as catalyst without loss of activity in
the presence of many types of Lewis bases [31]. Initially, we examined the reaction and
the activity of metal triflates with aniline as the starting material and benzoyl chloride as
the acylating agent to find the best catalyst. Five rare-earth metal triflates (La, Pr, Nd, Ho
and Er) and four well-known metal triflates (Cu, In, Y, Bi) were chosen to test the
catalytic activity in the process. The Friedel–Crafts benzoylation was carried out at 150
oC for 2 hours in a thermostat-controlled oil bath, and copper triflate showed the highest
catalytic activity (Table 1, entry 1). 4-Aminobenzophenone was the major product. The
yield of product was overall 68% (in three steps) with 80% selectivity for the para-
position using copper triflate.
3

A Fries type rearrangement with copper triflate under the same condition was also tested.
Benzamide (1 mmol) isolated from step 1 with 100% purity (checked by GC-MS) was
allowed to react with Cu(OTf)2 (0.1 mmol). The reaction mixture was kept at 150 oC for
2 hours but aminobenzophenones were not formed and the benzamides still remained
(checked by GC-MS). Consequently, copper triflate catalyzes the Friedel-Crafts
benzoylation of benzamide but not the Fries type rearrangement.
After having optimized the reaction conditions, we also examined the reaction between
aniline derivatives containing methyl- or dichloro-substituents with 4-fluorobenzoyl
chloride catalyzed by copper triflate (Scheme 2). As reported by Cortez-Maya and
coworkers [32], these aminobenzophenone derivatives have potential anticancer activity.
The general synthesis to prepare aminobenzophenone derivatives in a mild and efficient
way is shown in Scheme 2. N-acylation of several aniline derivatives (A) with 4-
fluorobenzoyl chloride easily produced amide derivative (B) in 100% conversion (GC) at
100 oC for 5 min without the use of catalyst (Table 2). All products of this step are easily
isolated and used for the next step. The structures and purity were determined by 1H
NMR spectroscopy and GC-MS.
The benzoylated products (C) were obtained by Friedel–Crafts benzoylation of the
acylanilides using copper triflate. In this method, acylanilides (B) were used without
further purification. The following step was the deprotection of the amides to give the -
4

NH2 compounds under acidic condition (H2SO4:CH3COOH:H2O) at 150 oC for 60 min.
The yields of products (D) (steps ii, iii) are given in Table 3.
Most of the anilines with the methyl- or chloro- substituents gave high yields with high
selectivity towards the para-position (Table 3, entries 2-6). Although the use of copper
triflate required harsh reaction temperature over 150 oC, the reaction time is much shorter
than comparing with the previous report usually using 24 hrs. of reaction time [30].
Moreover, the present method is solvent free and consequently is an environment friendly
method for synthesis of aminobenzophenone derivatives [30]. The presence of electron-
withdrawing groups such as chlorine required higher temperatures and longer reaction
times (Table 3, entries 4-6). In general, the Friedel–Crafts benzoylation in position para
to -NHCOC6H4 group gave better yields while the products in ortho-substitution to the -
NHCOC6H4 group were obtained in moderate yields, presumably due to steric hindrance
(Table 3, entries 2-6). However, p-nitroaniline containing strong electron-withdrawing
substituent (-NO2) was not suitable in this method. The Friedel–Crafts benzoylation of 4-
fluoro-N-phenylbenzamide was also investigated in ionic liquid media under
conventional heating. The Friedel-Crafts benzoylation of 4-fluoro-N-phenylbenzamide
gave good yield using commercial imidazolium ionic liquids such as [BMIM]BF4 or
[BMIM]PF6 (Table 3, entry 1) and a shorter reaction time was achieved under solvent-
free microwave irradiation (Table 3, entry 1). The copper triflate was recovered and
reused in three consecutive cycles in the Friedel-Crafts benzoylation of 4-fluoro-N-
phenylbenzamide with 4-fluorobenzoyl chloride at 150 oC for 2 h under conventional
5

heating. The yields of product were only slightly decreased after each cycle (78, 75 and
74%).
CONCLUSIONS
This paper describes an efficient method to prepare 4-aminobenzophenone derivatives via
Friedel–Crafts acylation using copper triflate. The copper triflate catalyst was easily
recovered and reused without significant loss of its catalytic activity. The protection-
deprotection of the amino group was carried out in high yields with easy work-up. Three
new fluorine containing compounds with dichloro-substituents in the
aminobenzophenone ring are obtained. These may have potential anti-cancer activity.
Biological activity tests are now in progress.
EXPERIMENTAL
Chemicals And Supplies.
Aniline derivatives, 4-fluorobenzoyl chloride, ionic liquids and metal triflates were
purchased from Sigma-Aldrich and used without further purification. Solvents were
obtained from Labscan and Chemsol (Vietnam) and also used without purification. Silica
gel 60 (0.040-0.063 mm) was from Merck.
Instruments.
GC-MS analyses were performed on an Agilent GC System 7890 equipped with a mass
selective detector Agilent 5973N and a capillary DB-5MS column (30 m x 250 µm x 0.25
µm). The 1H and 13C NMR spectra were recorded on a Bruker Advance 500 using CDCl3
as solvent and solvent peaks or TMS as internal standards. HRMS (ESI) data were
6

recorded on a Bruker micrOTOF-QII MS at 80 eV. Conventional heating was performed
on an IKA-RET thermostat-controlled oil bath. Microwave irradiation was performed on
a CEM Discover BenchMate apparatus which offers microwave synthesis with safe
pressure regulation using a 10 mL pressurized glass tube with Teflon-coated septum and
vertically-focused IR temperature sensor controlling the reaction temperature. Flash
column chromatography (length 60 cm, internal diameter 1.5 cm) was performed on
silica gel.
GENERAL PROCEDURE.
(a) The first step. Protection of the amine group. 4-Fluoro-N-phenylbenzamide
derivatives were prepared from aniline derivatives (1 mmol) and 4-fluorobenzoyl
chloride (1.2 mmol) under solvent-free condition at 100 oC for 5 min. The reaction
mixture was cooled to room temperature and extracted with ethyl acetate (3 x 15 mL) and
quenched with sodium bicarbonate (2 x 20 ml), water (2 x 20 mL). The combined organic
layers were dried over magnesium sulfate and concentrated under vacuum. The crude
product was purified by flash column chromatography on silica gel (hexane : ethyl
acetate = 9:1) to obtain the desired product.
(b) The second step. The Friedel–Crafts benzoylation. 4-Fluoro-N-phenylbenzamide
derivative (1 mmol), 4-fluorobenzoyl chloride (2 mmol) and metal triflate (0.1 mmol)
were heated at appropriate temperature and time. The reaction mixture was extracted with
ethyl acetate/H2O. The ethyl acetate layer was dried and concentrated under vacuum. The
crude product was used for the next step without further purification. Attempts were
7

made to recover and reuse the copper triflate. After extraction the reaction mixture with
ethyl acetate the aqueous layer was evaporated under reduced pressure at 80 oC. Mass of
pure copper triflate (white powder) obtained: 0.0317 g, (86%, yield of recovery).
(c) The third step. The benzoylated product was added to a mixture of H2SO4,
CH3COOH and H2O (5:3.5:1 mL) and heated at 150 oC for 60 min. The reaction mixture
was extracted with ethyl acetate (3 x 15 mL), neutralized with sodium carbonate (2 x 100
mL), washed with water (2 x 50 mL). The organic layer was dried over magnesium
sulfate and concentrated under vacuum. The pure regioisomer was obtained after column
chromatography on silica gel (eluent, hexane followed by an appropriate volume of ethyl
acetate).
COMPOUNDS
The following new compounds were synthesized.
4-Amino-2,5-dichloro-4’-fluorobenzophenone
Yellow solid, m.p. 144-146 oC.
1H NMR (500 MHz, CDCl3): δ = 7.81 (dd, J = 8.8 Hz, 5.5 Hz, 2H), 7.35 (s, 1H), 7.13
(t, J = 8.6 Hz, 2H), 6.81 (s, 1H), 4.44 (br s, 2H).
8

13C NMR (125 MHz, CDCl3): δ = 191.2 (CO), 164.9 (d, J = 253.8 Hz), 144.9, 132.8 (d,
J = 2.8 Hz), 131.6 (d, J = 9.3 Hz), 130.8, 130.3, 126.7, 115.9, 115.1, 114.7 (d, J = 21.9
Hz).
MS (EI) m/z 283 (M+), 248, 188, 160, 133, 123, 95, 75.
HRMS (ESI) calcd for C13H8Cl2FNONa 305.9859 [M+Na]+, found 305.9863.
4-Amino-2,6-dichloro-4’-fluorobenzophenone
Brown liquid: b.p.: not determined, decomposed at 400 oC.
1H NMR (500 MHz, CDCl3): δ = 7.86 (dd, J = 8.8 Hz, 5.4 Hz, 2H), 7.13 (t, J = 8.6 Hz),
6.63 (s, 2H), 3.88 (br s, 2H).
13C NMR (125 MHz, CDCl3): δ = 191.1, 166.3 (d, J = 254.8 Hz), 148.8, 133.0 (d, J = 2.6
Hz), 132.5 (s, 2C), 132.4(d, J = 9.6 Hz), 126.4, 116.1 (d, J = 22.0 Hz), 113.9.
MS (EI) m/z 283 (M+), 247, 213, 188, 157, 133, 123, 109, 95,75, 63, 50.
HRMS (ESI) calcd for C13H8Cl2FNONa [M+Na]+ 305.9859, found 305.9876.
2-Amino-4,5-dicloro-4’-fluorobenzophenon
Yellow solid, m.p. 139-141oC.
9

1H NMR (500 MHz, CDCl3): δ = 7.66 (dd, J = 8.8 Hz, 5.4 Hz, 2H), δ = 7.47 (s, 1H), 7.17
(t, J = 8.6 Hz, 2H), 6.87 (s, 1H), 6.02 (br s).
13C NMR (125 MHz, CDCl3): δ = 194.7, 163.9 (d, J = 251.9 Hz), 148.8, 137.4, 134.1 (d,
J = 3.1 Hz), 133.7, 130.6 (d, J = 8.9 Hz), 117.5, 117.2, 116.6, 114.6 (d, J = 21.8 Hz).
MS (EI) m/z 283 (M)+, 266, 247, 219, 188, 160, 133, 123,109, 95, 75, 63, 50.
HRMS (ESI) calcd for C13H8Cl2FNO [M+H]+ 284.0039, found 284.0031.
ACKNOWLEDGEMENT
We are grateful to the Vietnam National University – Hochiminh City (Grant No. C2014-
18-08) for financial support.
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<END>
12

Scheme 1. Testing for Fries rearrangement
13

Scheme 2. Synthesis of aminobenzophenone derivatives via Friedel–Crafts benzoylation
14

Table 1. The effect of metal triflates in the synthesis of aminobenzophenone from aniline
with benzoyl chloride.a
Entry Metal triflate
Total yield (%)
o-/p-
Selectivity
20/80
17/83
28/72
16/84
19/81
20/80
21/79
22/78
20/80
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Y(OTf)3
In(OTf)3
La(OTf)3
Pr(OTf)3
Nd(OTf)3
Ho(OTf)3
Er(OTf)3
Bi(OTf)3
68
34
64
40
50
41
44
34
57
a The benzamide product was purified before using for the next steps. The Friedel–Crafts
benzoylation of benzamide was monitored by GC-MS. The benzoylated product was used
for the hydrolysis step without purification.
15

Table 2. Protection of amine group
Entry
Substrate (A) Product (B)
Conversion (%) Yield (%)
1
100
100
100
90
92
92
2
3
4
5
6
100
100
100
89
91
92
16

Table 3. Friedel–Crafts benzoylation of anilides and hydrolysis of amide groups
Entry (B)
Condition (B-C) Product (D)
Yield Isomeric
of D ratio
(%)
1
150 oC, 2 h
79
78
80
77
81
o-/p- =
21/79
a
[BMIM]PF6 ,
o-/p- =
22/79
150 oC, 1 h
b
[BMIM]BF4 ,
o-/p- =
20/80
150 oC, 1 h
MW, 150 oC, 0.5
h
o-/p- =
19/81
2
3
150 oC, 2 h
15/85b
150 oC, 2 h
70
25/75c
17

4
200 oC, 6 h
78
16/84d
5
6
200 oC, 6 h
200 oC, 6 h
71
63
30/70e
10/90f
a[BMIM]PF6: 1-butyl-3-methylimidazolium hexafluorophosphate, b[BMIM]BF4: 1-butyl-
3-methylimidazolium tetrafluoroborate.
bIsomeric ratio of (2-amino-3-methylphenyl)(4-fluorophenyl)methanone/(4-amino-3-
methylphenyl)(4-fluorophenyl)methanone.
cIsomeric ratio of (5-amino-2-methylphenyl)(4-fluorophenyl)methanone/(2-amino-5-
methylphenyl)(4-fluorophenyl)methanone.
dIsomeric ratio of (2-amino-3,6-dichlorophenyl)(4-fluorophenyl)methanone/4-amino-2,5-
dichlorophenyl)(4-fluorophenyl)methanone.
eIsomeric ratio of (2-amino-4,6-dichlorophenyl)(4-fluorophenyl)methanone/(4-amino-
2,6-dichlorophenyl)(4-fluorophenyl)methanone.
fIsomeric ratio of (6-amino-2,3-dichlorophenyl)(4-fluorophenyl)methanone/(2-amino-4,5-
dichlorophenyl)(4-fluorophenyl)methanone.
18