Unsymmetrical Diarylketones from Electron-rich Heterocyclic Arenes

Article abstract of DOI:10.1007/s00706-002-0573-9

AlCl₃-mediated chlorocarbonylation of a first arene by oxalyl chloride followed by in situ Friedel-Crafts acylation of a second electron-rich arene expeditiously provides, in a one-pot procedure, either symmetrical or unsymmetrical benzophenones with yields ranging from 17-52%. Best results are obtained when the more activated substrate is used as the second arene. Another advantage is that the resultant benzophenone precipitates from the reaction mixture allowing facile workup.

Full text of DOI:10.1007/s00706-002-0573-9

Monatshefte f€ur Chemie 134, 823–830 (2003)
DOI 10.1007/s00706-002-0573-9
Unsymmetrical Diarylketones
from Electron-rich Heterocyclic Arenes
Jacques H. Poupaerta;ꢀ, Patrick Depreuxb, and Christopher R. McCurdyc
a
ꢀ
School of Pharmacy, Universite Catholique de Louvain, B-1200 Brussels, Belgium
ICPAL, Universite de Lille 2, F-59006 Lille Cedex, France
b
c
ꢀ
Department of Medicinal Chemistry, University of Mississippi, MS-38677, USA
Received October 4, 2002; accepted October 15, 2002
Published online March 6, 2003 # Springer-Verlag 2003
Summary. AlCl3-mediated chlorocarbonylation of a first arene by oxalyl chloride followed by in situ
Friedel-Crafts acylation of a second electron-rich arene expeditiously provides, in a one-pot procedure,
either symmetrical or unsymmetrical benzophenones with yields ranging from 17–52%. Best results
are obtained when the more activated substrate is used as the second arene. Another advantage is that
the resultant benzophenone precipitates from the reaction mixture allowing facile workup.
Keywords. Heterocycles; Lewis acids; Friedel-Crafts acylation; Benzophenone; 2(3H)-Benzoxazo-
lone; Oxalyl chloride.
Introduction
Diarylketones serve as useful synthons in the elaboration of pharmacological tools
and the diphenylmethane pharmacophore is encountered in numerous clinically
relevant drugs such as methadone, phenytoin, progabide, tolcapone, etc. In parti-
cular, diarylketones are very useful for the synthesis of 5,5-diarylhydantoins [1]. In
this connection, this scaffold was used recently with great success in the design of
CB1-cannabinoid receptor antagonists [2, 3]. In an effort to gain access to 5,5-
diarylhydantoins bearing electron-donating substituents on the aromatic moieties,
we have searched for a straightforward synthesis of diarylketones possessing the
above prerequisites. These compounds could then be utilized in the Bucherer-Berg
synthesis of such 5,5-diarylhydantoins as an advantageous alternative to the Biltz’s
synthesis of phenytoin [3]. Indeed, benzils substituted with electron-donating
groups in ortho- or para-position give poor yields of hydantoin when reacted with
urea in basic medium [4].
Whereas many synthetic methods are available to prepare such diarylketones,
in spite of numerous limitations, the Friedel-Crafts (FC) acylation of arenes by an
ꢀ
Corresponding author. E-mail: Poupaert@cmfa.ucl.ac.be

824
J. H. Poupaert et al.
aroyl halide in the presence of a Lewis acid catalyst remains the method of choice.
A paradoxical limitation of this method arises when the arene is electron-rich
because the extensive complexation of the aromatic substrate by the Lewis acid
drastically reduces the reactivity of the arene leading to low yields or no conversion
at all [5]. The problem is partially alleviated when the Lewis acid is complexed by
an appropriate Lewis base. In this context, the use of the AlCl3 ꢁ DMF complex as a
catalyst in the acylation of electron-rich aromatic substrates is well documented
[6–8]. A major practical limitation of this approach is that a considerable excess of
catalyst (up to 10-fold) is necessary to obtain good yields [9].
The AlCl3-mediated chlorocarbonylation of arenes has been known for many
years [10, 11]. There were a few reports of the in situ coupling of the intermediate
complexed aroyl chloride with an additional arene to prepare symmetrical benzo-
phenones [12, 13]. Recently, an interesting contribution to the synthesis of unsym-
metrical diarylketones was brought about by Taber and Sethuraman who made use
of the well-known AlCl3-mediated chlorocarbonylation of arenes to generate in situ
the aroyl halide species, which was coupled in a one-pot procedure with an arene to
prepare an unsymmetrical diarylketone [14]. This technique appears to be an effi-
cient approach for synthesizing both symmetrical and unsymmetrical diarylketones
with the advantage that the method does not require a huge excess of AlCl3. The
yields reported by these authors ranged from 54 to 77%.
In this paper, we report the results of the application of this method to electron-
rich heterocyclic systems such as 2(3H)-benzoxazolone, 2(3H)-benzothiazolone,
and 2-indolinone. This work was motivated also in part by the recent report that 6-
benzoyl-2(3H)-benzothiazolone is endowed with interesting analgesic properties
due to the release of opioid peptides in the periphery [15].
Results and Discussion
We first optimized the reaction by examining 2(3H)-benzoxazolone (1) as a model
electron-rich aromatic substrate used both as arene A and B (Scheme 1). Initial
attempts done using Taber’s conditions of solvent, temperature, and AlCl3=arene
ratio were met with poor success resulting in mediocre extent of arene consumption
and complex reaction mixtures. We anticipated that N-acylation could interfere in
the process as, during our exploration of the reaction under acidic conditions, when
we substituted AlCl3 with K10 montmorrillonite [16], we obtained in high yield 3-
benzoyl-2(3H)-benzoxazolone (2) by treatment of 1 with benzoic anhydride. An
authentic sample of 2 was obtained by treatment of 1 by benzoyl chloride and
triethylamine in refluxing THF, as previously described [17]. While 2 readily
Scheme 1

Unsymmetrical Diarylketones
825
undergoes N–C acyl migration at elevated temperature (165ꢂC) in the presence of a
Lewis acid such as AlCl3 [17], it is stable at room temperature and does not
rearrange to benzophenone 3 (Figure 1) under Taber’s conditions, or at 50ꢂC. Com-
pound 2 was smoothly converted to 3 by treatment with polyphosphoric acid (PPA)
when submitted to microwave irradiation. However, we were unable to isolate 2 as
an intermediate during direct acylation of 1 using either benzoyl chloride or ben-
zoic anhydride in the presence of AlCl3 ꢁ DMF.
To overcome the problems mentioned above, the model arene was switched
to 3-methyl-2(3H)benzoxazolone (4). Indeed, direct acylation of 1 using the
AlCl3 ꢁ DMF complex as catalyst always results in lower yields than 4. Owing to
previous experience, initial attempts were made at 85ꢂC using the AlCl3 ꢁ DMF
complex as catalyst. Again, complex reaction mixtures were obtained. The break-
trough came when lithium ions were added to the reaction medium. At first, lithium
chloride was used. The use of lithium ions as adjuvant in the FC reaction is well
illustrated in the literature by several recent reports [18–20]. The optimal condi-
tions for the synthesis of benzophenone 5 were obtained by running the reaction in
CH3NO2 in the presence of AlCl3 and LiClO4.
The structure of 5 was assigned on the basis of the following two arguments:
first, 13C NMR owing to the number of signals and their attribution clearly indi-
cated that we had obtained a symmetrical benzophenone; second, when the reaction
medium was quenched by water after short reaction times (typically 30–60 min), it
was possible to isolate 2,3-dihydro-3-methyl-2-oxo-benzoxazol-6-carboxylic
acid (6, 47% yield). The regioselectivity of the reaction was therefore established
since treating the known 6-acetyl-3-methyl-2(3H)-benzoxazolone (7) [21] with
NaClO (haloform reaction) produced the same acid 6 (Scheme 2). The same chloro-
carbonylation – FC coupling reaction was then reproduced with 3-benzyl-2(3H)-
benzoxazolone (8). The only product isolated was the corresponding symmetrical
benzophenone 9, indicating that under these reaction conditions no competing ac-
ylation took place on the N-benzyl moiety.
Next, we extended the investigation of the reaction sequence (Scheme 1) to un-
symmetrical benzophenones with arene A being either benzene (10) or chlorobenzene
(11) and arene B being either 2(3H)-benzoxazolone (1), 2(3H)-benzothiazolone (12),
3-methyl-2(3H)-benzoxazolone (4), 3-methyl-2(3H)-benzothiazolone (13), or 2-indo-
linone (14). The times and temperatures for the chlorocarbonylation and subsequent in
situ acylation for the successful conversions are reported in Table 1.
Scheme 2

826
J. H. Poupaert et al.
Table 1. Synthesis of benzophenones (cf. Scheme 1) via chlorocarbonylation (Step 1) and subsequent
in situ FC acylation (Step 2)
Arene A
Step 1
t=h, T=ꢂC
Arene B
Step 2
product (yield=%)
4
8
2, rt
4
8
5 (47)
9 (43)
2, rt
13
10
11
10
11
10
2, rt
13
4
20 (51)
15 (52)
16 (37)
17 (52)
18 (47)
19 (17)
0.5, 10
10, rt
0.5, 10
10, rt
0.5, 10
4
13
13
14
Fig. 1. Structures of compounds 1–9 and 12–20
With a less activated substrate such as chlorobenzene (11), the chlorocarbon-
ylation required longer reaction time and higher temperature. In each case, 1.3
equivalent of oxalyl chloride with respect to arene A were employed. It should
be emphasized that the yields reported are for reactions using a 1:1 molar ratio
of arene A and B, and this is in accordance with Taber’s report [14]. With the

Unsymmetrical Diarylketones
827
heterocycles bearing a free NH, the reaction either failed (for 1 and 12) or gave
very low yield (for 14, 17% yield). Attempts to run the reaction with meta-direct-
ing substituted substrates (as arene A) such as nitrobenzene or benzonitrile also
failed. Inverting arene A and B was unsuccessful, which clearly indicates that the
more activated substrate has to be used as the second arene.
Overall yields (Table 1) were found within the range of 17–52%. While these
yields can be considered as relatively low, it has to be taken into account that the
compounds were isolated by precipitation and recrystallization (not chromatogra-
phy) and that this one-pot procedure competes rather well with the classical ap-
proach involving the construction of the carboxylic acid, activation to aroyl halide,
and subsequent FC coupling. This approach, however, is not competitive for the
synthesis of symmetrical benzophenones as FC reaction of 4 with carbon tetra-
chloride in the presence of AlCl3 ꢁ DMF and in situ hydrolysis of the gem-dichloro-
methane intermediate gives 5 with a higher yield (80%) [9].
Conclusion
We have shown that Taber’s synthesis of benzophenones can be applied to hetero-
cyclic arenes. This process involves the AlCl3-mediated chlorocarbonylation of a
first arene (termed here arene A) by oxalyl chloride followed by the in situ Friedel-
Crafts acylation of a second electron-rich arene (termed arene B) and expeditiously
provides, in a one-pot procedure, either symmetrical or unsymmetrical benzophe-
nones with yields ranging from 17–52%. Best results are obtained when the more
activated substrate is used as second arene. The desired benzophenones precipitate
from the reaction mixture allowing for easy isolation by filtration and recrystalli-
zation. This reaction sequence is quite simple from the experimental point of view
and might prove useful for the elaboration of a sortiment of heterocyclic benzo-
phenones using a fast parallel synthesis technique.
Experimental Section
General Procedures
€
Melting points (uncorrected) were determined in open capillary tubes using a Buchi SMP 20 melting
point apparatus. IR spectra were recorded using a dispersion of the product in KBr disks by means of a
1
Perkin-Elmer Model 297 spectrometer. H and 13C NMR spectra were recorded using an AC 300 P
Bruker spectrometer. The NMR spectra were recorded at ambient temperature using tetramethylsilane
(TMS) as internal reference. Elemental analyses were obtained by courtesy of Prof. B. Masereel
1
(FUNDP, Namur, Belgium). All compounds reported had IR, H and 13C NMR, MS, and elemental
analysis data consistent with their structure. The experimental elemental analysis figures were found
within 0.4% of the calculated values. Thin layer chromatography analyses were performed on Merck
TLC plates (silica gel, 60 F 254, E. Merck, Darmstadt, ref. 5735). All compounds reported here were
found chromatographically homogenous in two standard solvents, i.e. acetone=toluene=cyclohexane
(5:2:3, v=v=v) and methanol=chloroform equilibrated with ammonia (1:9, v=v). High-performance
liquid chromatography conditions were: C-18, methanol:water (75:25, v=v), 1.5 ml=min. All com-
pounds reported were found homogenous under these HPLC conditions. All reagents were purchased
from Aldrich. Montmorrillonite K10 was a generous gift from Dr A. Mathy from the University of
ꢁ
Liege (Ulg) [16]. The times and temperatures for the chlorocarbonylation step (Step 1) and yields of

828
J. H. Poupaert et al.
the subsequent acylation (Step 2) are summarized in Table 1. Improved procedures for synthesis of
some reference compounds (2, 3, 7, and 19) or starting materials (8) are given hereunder. Other
reference compounds were available from previous studies [9, 17].
3-Benzoyl-2(3H)-benzoxazolone (2)
A solution of 1.35 g of 2(3H)-benzoxazolone (1, 10mmol) and 2.49 g of benzoic anhydride (11 mmol)
in 100 cm3 of anhydrous CH2Cl2 was treated with 1 g of K10 montmorrillonite and refluxed for 4 h.
After cooling, the mixture was diluted with 150 cm3 of CH2Cl2, filtered over a bed of celite, washed
with 5% Na2CO3 solution, H2O, dried over MgSO4, and evaporated in vacuo to give a residue which
was recrystallized from ethanol to give 1.98g (83%) of analytically pure 2 (TLC, HPLC, mp
170–172ꢂC, Ref. [17] 172–173ꢂC). This material had IR, 1H, and 13C NMR spectroscopic data
identical to those previously reported by Ucar [17] and Cotelle [22].
6-Benzoyl-2(3H)-benzoxazolone (3)
A dispersion of 2.39 g of 2 (10 mmol) in 25 g of PPA was irradiated at 300 W power in a regular
kitchen microwave oven at times 0, 1.5, 3, 6, 9, 12, and 15min for 30sec. The dark mixture was
allowed to stand aside for 1 h and was quenched with 500 cm3 of ice=H2O. The resulting precipitate
was stirred for 1 h, filtered off, washed with distilled water, dried, and recrystallized from ethanol to
give 2.06g (86%) of analytically pure 3 (TLC, HPLC, mp 168–170ꢂC, Ref. [17] 169–170ꢂC). This
1
material had IR, H, and 13C NMR spectroscopic data identical to those previously reported by Ucar
[17].
3-Benzyl-2(3H)-benzoxazolone (8)
A solution of 13.50 g of 1 (100 mmol) in 250 cm3 of n-butanol containing 10 g of PEG 600 and
100 cm3 of 10% NaOH solution was stirred mechanically at room temperature while 25.3g of benzyl
chloride (200 mmol) were added dropwise over 30min. The emulsion was stirred vigorously for 24h.
The organic phase was then separated and the solvent was evaporated in vacuo. The resulting waxy
residue was diluted in 250 cm3 of ethyl acetate and washed copiously with H2O, dried over MgSO4,
and evaporated in vacuo to afford a solid which was recrystallized from anhydrous ethanol. After
standing overnight in a refrigerator, 16.2g of 8 (72%) were collected (mp 123–125ꢂC, Ref. [23] 123–
1
124ꢂC). This material had IR, H, and 13C NMR spectroscopic data identical to those previously
reported by Ucar [9].
General Method for the Preparation of Diarylketones
In a 100 cm3 side-arm round-bottom flask, into 1.15cm3 of oxalyl chloride (13 mmol) were added in
one portion to a solution of 10mmol of the arene A and 6.60 g of LiClO4 (62 mmol) in 50cm3 of
CH3NO2 kept at 3–5ꢂC using an ice bath. AlCl3 (2.67 g, 20mmol) was then added portionwise over
5 min. The reaction mixture was allowed to warm up to room temperature during which time pro-
gressive dissolution of the solid, darkening of the solution, and gas evolution was observed. The
mixture was stirred at room temperature during the time reported for the chlorocarbonylation in Table
1. An equivalent of the arene B (10 mmol) along with an additional amount of AlCl3 (2.67 g, 20 mmol)
were then added portionwise. After 1 h at room temperature, the reaction mixture was heated for 12h at
50–55ꢂC, poured onto 500 cm3 of ice=H2O containing 25 cm3 of concentrated HCl, and stirred for 1 h.
The resulting precipitate was collected on a B€uchner funnel, washed with H2O, dried, and recrystal-
lized from ethanol.

Unsymmetrical Diarylketones
829
2,3-Dihydro-3-methyl-2-oxo-benzoxazole-6-carboxylic acid (6)
(a) Chlorocarbonylation method. To a mixture of 80g of AlCl3 (0.6mol) and 13cm3 of DMF, heated
and stirred mechanically at 85ꢂC (oil bath), 9.0 g of 3-methyl-2(3H)-benzoxazolone (4, 60 mmol) were
added in one portion. After a homogenous paste was obtained, 6.6 g of LiClO4 (62 mmol) were added
in one portion and 8.0 cm3 of oxalyl chloride (90 mmol) were added dropwise over 30min. The dark
red mixture was stirred for another 6 h at 85ꢂC and poured, while hot, onto 1 kg of ice containing
50cm3 of concentrated HCl. The resulting mixture was extracted three times with 250 cm3 of ethyl
acetate and the organic phase was then re-extracted with 3 ꢃ 50 cm3 of 5% NaOH solution. Acidifi-
cation of the aqueous phase gave a precipitate, which was filtered, dried, and recrystallized from
ethanol:water (80:20, v=v) to give 3.96 g (35%) of 7 (mp 270ꢂC dec). This material was identical in
all respects to that obtained by the haloform reaction (cf. (b)).
(b) Haloform reaction. To a solution of 20 g of NaOH (500mmol) in 100 cm3 of H2O at room
temperature 9.65g of 6-acetyl-3-methyl-2(3H)-benzoxazolone (7, 50 mmol) were added. The resulting
solution was treated with 400 cm3 of 12% NaClO solution and heated at 95ꢂC for 1 h. The reaction
mixture was acidified to pH ¼ 1 with concentrated HCl and the resulting precipitate was collected on a
filter, washed with distilled H2O, dried, and recrystallized from ethanol:water (80:20, v=v). Yield: 67%;
mp 270ꢂC dec; IR (KBr): ꢀꢂ¼ 3100–2400 (OH), 2950 (aliph. C–H), 1780 (het. C¼O), 1680 (car-
boxylic acid C¼O) cmÀ 1
;
1H NMR (DMSO-d6): ꢁ ¼ 13.00 (s, COOH), 7.88 (d, Jo ¼ 7.89 Hz,
Jm ¼ 1.50 Hz, 1H, H5), 7.78 (d, Jo ¼ 7.89Hz, H7), 7.35 (d, Jm ¼ 1.50Hz, H4), 3.37 (s, N–CH3) ppm.
5-Benzoyl-1,3-dihydro-2H-indol-2-one (19)
To a mixture of 53.3g of AlCl3 (0.4mol) and 8.6 cm3 of DMF (115mmol), heated and stirred me-
chanically at 50ꢂC (oil bath), 5.34 g of 2-indolinone (14, 40mmol) were added in one portion. After a
homogenous paste was obtained, 7.0 cm3 of benzoyl chloride (60 mmol) were added dropwise over
30min. When the addition was completed, the dark red mixture was stirred for another 3.5h at 85ꢂC
and poured, while hot, onto 1 kg of ice containing 50 cm3 of concentrated HCl. The resulting precip-
itate was stirred for 2 h, filtered, washed copiously with distilled H2O, dried, and recrystallized from
methanol to give 4.48 g (47%) of 19 (mp 205–206ꢂC, Ref. [25] 204–205ꢂC). IR (KBr): ꢀꢂ¼ 3308
1
(NH), 3062 (arom. CH), 2916 (aliph. CH), 1705 (ketone C¼O), 1641 (het. C¼O)cmÀ1; H NMR
(CDCl3): ꢁ ¼ 9.10 (s, NH), 7.70 (m, H4, H7, H1’, H5’), 7.50 (m, H3’), 6.90 (dd, J6–7 ¼ 8.0 Hz, J6–4
¼
0.9 Hz, H6), 3.55 (s, CH2) ppm.
6,60-Carbonyl bis[3-benzyl-2(3H)-benzoxazolone] (9)
IR (KBr) ꢀꢂ¼ 3010 (arom. CH), 2940 (aliph. CH), 1670 (het. C¼O), 1640 (ketone C¼O) cmÀ 1
;
13C
NMR (DMSO-d6): ꢁ ¼ 193.20 (ketone C¼O), 154.52 (het. C¼O), 143.28, 134.60, 131.25, 126.96,
110.62, 109.39 (het. arom. C), 142.71 (ipso), 134.75, 130.90, 127.65, 110.05 (benz. arom. C), 46.10
(CH2) ppm.
References
[1] Henze HR, Isbell AF (1954) J Am Chem Soc 76: 4152
[2] Kanyonyo M, Govaerts SJ, Hermans E, Poupaert JH, Lambert DM (1999) Bioorg Med Chem
Lett 15: 2233
[3] Ooms F, Wouters J, Oscari O, Happaerts T, Bouchard G, Carrupt PA, Testa B, Lambert DM
(2002) J Med Chem 45: 1748
[4] Poupaert JH, De Keyser JL, Vandervorst D, Dumont P (1984) Bull Soc Chim Belg 93: 49
[5] Yous S, Poupaert JH, Lesieur D, Depreux P, Lesieur D (1994) J Org Chem 59: 1574

830
J. H. Poupaert et al.: Unsymmetrical Diarylketones
[6] Aichaioui H, Poupaert JH, Lesieur D, Henichart JP (1991) Tetrahedron 47: 6649
[7] Poupaert JH, Kanyonyo M, Ucar H, Mouithys AM, Diouf O, Lesieur D (1996) Bull Soc Chim
Belg 105: 397
[8] Ucar H, Van Derpoorten K, Kanyonyo M, Isa M, Lambert D, Lesieur D, Poupaert JH (1996) Bull
Soc Chim Belg 105: 773
[9] Ucar H, Van Derpoorten K, Poupaert JH (1997) Heterocycles 45: 805
[10] Liebermann C (1912) Chem Ber 45: 1186
[11] Osman M (1982) Helv Chim Acta 65: 2448
[12] Zimmerman HE, Paskovich DH (1964) J Am Chem Soc 86: 2149
[13] Heitzler FR, Hopf H, Jones PG, Bubenitschek P, Lehne V (1993) J Org Chem 58: 2781
[14] Taber DF, Sethuraman MR (2000) J Org Chem 65: 254
[15] Ferreira SH, Lorenzotti BB, Devissaguet M, Lesieur D, Tsouderos Y (1995) Br J Pharmacol 114:
303
[16] Lazlo P, Mathy A (1987) Helv Chim Acta 70: 577
[17] Ucar H, Van Derpoorten K, Depovere P, Lesieur D, Isa M, Masereel B, Delarge J, Poupaert JH
(1998) Tetrahedron 54: 1763
[18] Chapman CJ, Frost CG, Hartley JP, Whittle AJ (2001) Tetrahedron Lett 42: 773
[19] Matsuo J, Odashima K, Kobayashi S (2000) Synlett 403
[20] Bartolli G, Bosco M, Marcantoni E, Massaccesi M, Rinaldi S, Sambri L (2002) Tetrahedron Lett
43: 6331
[21] Bonte JP, Lesieur D, Lespagnol C, Plat M., Cazin JC, Cazin M (1974) Eur J Med Chem 9:
491–496
[22] Cotelle N, Cotelle P, Lesieur D (1989) Synth Commun 19: 3259
[23] Ucar H, Van Derpoorten K, Cacciaguerra S, Spampinato S, Stables JP, Depovere P, Isa M,
Masereel B, Delarge J, Poupaert J (1998) J Med Chem 41: 1138
[24] Mukhamedov NS, Aliev NA, Kristallovich EL (1991) Uzb. Khim. Zh. 5: 39–42
[25] Welstead WJ Jr, Moran HW (1976), US Pat. 3975531