Facile synthesis of dihydrochalcones via the AlCl3-promoted tandem Friedel-Crafts acylation and alkylation of arenes with 2-alkenoyl chlorides

Article abstract of DOI:10.1016/j.molcata.2012.09.005

Tandem Friedel-Crafts acylation and alkylation of arenes with 2-alkenoyl chlorides were investigated under the catalysis of Lewis acids. The cascade reaction affords dihydrochalcones in good yields accompanying 1-indanone derivatives in some cases, in the presence of anhydrous aluminum chloride. The scope, limitation, and mechanism of the tandem reaction were also explored. The intermolecular Friedel-Crafts alkylation for the formation of dihydrochalcones is more favorable than the intramolecular one for the generation of 1-indanones in the tandem reaction due to a stable six-membered ring transition state. The sequent process was further studied by the DFT computations at the M06-2X/6-31G(d) level, which are in great agreement with the experimental observation and support the proposed mechanism. The current method provides a convenient and economic method to synthesis of dihydrochalcones.

Full text of DOI:10.1016/j.molcata.2012.09.005

Journal of Molecular Catalysis A: Chemical 365 (2012) 203–211
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Facile synthesis of dihydrochalcones via the AlCl3-promoted tandem
Friedel–Crafts acylation and alkylation of arenes with 2-alkenoyl chlorides
Yang Zhou, Xinyao Li, Shili Hou, Jiaxi Xu∗
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing 100029, People’s
Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2012
Received in revised form 1 September 2012
Accepted 4 September 2012
Available online 12 September 2012
Tandem Friedel–Crafts acylation and alkylation of arenes with 2-alkenoyl chlorides were investigated
under the catalysis of Lewis acids. The cascade reaction affords dihydrochalcones in good yields accompa-
nying 1-indanone derivatives in some cases, in the presence of anhydrous aluminum chloride. The scope,
limitation, and mechanism of the tandem reaction were also explored. The intermolecular Friedel–Crafts
alkylation for the formation of dihydrochalcones is more favorable than the intramolecular one for the
generation of 1-indanones in the tandem reaction due to a stable six-membered ring transition state.
The sequent process was further studied by the DFT computations at the M06-2X/6-31G(d) level, which
are in great agreement with the experimental observation and support the proposed mechanism. The
current method provides a convenient and economic method to synthesis of dihydrochalcones.
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Arene
Aluminum chloride
Dihydrochalcone
Friedel–Crafts alkylation
Friedel–Crafts acylation
Tandem reaction
1. Introduction
Tandem reactions of ␣,␤-unsaturated acyl chlorides with phenols
have also been carried out to synthesize dihydrocoumarins
Friedel–Crafts acylation and alkylation are powerful and con-
venient methods for the preparation of acyl and alkyl substituted
arenes, respectively [1]. Tandem reactions have attracted much
attention and have been used widely in synthetic organic chem-
istry during recent two decades due to their high efficiency and
diversity [2,3]. It was reported that the reaction of benzaldehyde
and benzene produced diphenylmethanol, which further yielded
triphenylmethane under the catalysis of anhydrous aluminum
chloride [4]. This is an early example of tandem Friedel–Crafts
alkylations. Both aromatic and aliphatic aldehydes underwent
the tandem Friedel–Crafts alkylation with electron-rich arenes
to afford 1,1,1-triaryl/1,1-diarylalkanes in the presence of anhy-
drous aluminum chloride under solvent-free conditions [5]. LnCl3
(Ln = Pr, Dy, Er, Sm, Yb) and Yb(O3SCF3)3 catalyzed alkylation
of PhR (R = H, Me) with AcCl–PhCHO to give PhCH(CH6H4R)2
was also reported [6]. Strong proton acid-catalyzed tandem
Friedel–Crafts reactions of arenes with aromatic aldehydes
have been investigated as well [7]. Recently we discovered
the tandem Friedel–Crafts acylation and alkylation of arenes
with acyl chlorides and ␣,␤-unsaturated acyl chlorides in the
presence of anhydrous aluminum chloride, to afford 1,1-diaryl-1-
alkenes and indanone derivatives in good yields, respectively [8].
[9].
A
copper(II) triflate-catalyzed tandem Friedel–Crafts
alkylation/cyclization process was developed to prepare dihydroin-
denes [10]. Indenoindene-fused ␣-methylene-␥-butyrolactones
were synthesized via
a
tandem intra- and intermolecu-
lar Friedel–Crafts reaction [11]. The TFA-mediated tandem
Friedel–Crafts alkylation/cyclization/hydrogen transfer process
has been explored to provide an efficient approach to the synthesis
of flavylium compounds from chalcones and phenols [12]. When
this article was revised, the superacid catalyzed synthesis of trifluo-
romethylated dihydrochalcones, aryl vinyl ketones, and indanones
from arenes and 4,4,4-trifluoro/3-(trifluoromethyl)crotonic acids
was reported [13].
To further extend the application of the tandem Friedel–Crafts
acylation and alkylation of arenes with ␣,␤-unsaturated acyl
chlorides under the catalysis of Lewis acids (LAs), we systemati-
cally studied the reaction to prepare dihydrochalcone derivatives,
which are important intermediates in organic and pharmaceutical
syntheses [14]. Dihydrochalcone derivatives have been prepared
previously via the selective catalytic hydrogenation of chalcones
[15], via coupling of acetophenone and benzyl alcohol [16], via
coupling of cinnamaldehyde and aryl halides, [17] and via the
Suzuki cross-coupling of 3-phenylpropanoyl chloride [18] or cin-
namaldehyde [19] and phenylboronic acid, in which noble metals
were employed as catalysts and/or the reactions were conducted
under high pressure. Herein, we wish to report a facile synthesis
of dihydrochalcones via the AlCl3-promoted tandem Friedel–Crafts
∗
Corresponding author. Tel.: +86 10 6443 5565; fax: +86 10 6443 5565.
E-mail address: jxxu@mail.buct.edu.cn (J. Xu).
1381-1169/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2012.09.005

204
Y. Zhou et al. / Journal of Molecular Catalysis A: Chemical 365 (2012) 203–211
Table 1
Tandem Friedel–Crafts acylation and alkylation of acryloyl chloride with benzene.a
O
O
O
LA
+
+
Cl
1a
2a
3a
Entry
LA
LA (equiv.)
Benzene (mL)
Temp. (◦C)
Addition time
Reaction time
Isolated yield (%)
2a
3a
1
2
3
4
5
6
7
8
9
BF3 OEt2
ZnCl2
ZnCl2
ZnCl2
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
1.5
0.5
1.0
1.0
1.2
1.5
1.2
1.2
1.5
15
15
15
9
3
25
9
25–30
25–30
25–30
Reflux
25–30
25–30
Reflux
Reflux
Reflux
48 h
5 h
12 h
72 h
1 h
1 h
1 h
20 min
20 min
–
–
–
–
–
–
–
Trace
14b
52
35b
69
81
20b
12
1 h
20 min
1 h
15b
Trace
Trace
10
15
3.3 h
a
A solution of acryloyl chloride (0.95 g, 10 mmol) in benzene (8 mL) was added in a suspension of Lewis acid in benzene.
b
Yield obtained from 1H MNR analysis of a mixture of isolated products 2a and 3a.
acylation and alkylation of arenes with 2-alkenoyl chlorides and to
discuss its scope, limitation, and mechanism.
7.13–7.17 (m, 1H, ArH), 7.24–7.29 (m, 2H, ArH), 7.35–7.38 (m, 4H,
ArH), 7.42–7.53 (m, 2H, ArH), 7.80–7.82 (m, 2H, ArH).
3,3-Dimethyl-1-indanone (3c) [24]. Colorless oil, 1H NMR (CDCl3,
400 MHz): ı 1.43 (s, 6H, 2CH3), 2.59 (s, 2H, CH2), 7.35–7.39 (m, 1H,
ArH), 7.49–7.51 (m, 1H, ArH), 7.60–7.64 (m, 1H, ArH), 7.69–7.71 (m,
1H, ArH).
2. Experimental
General methods. Melting points were measured on a Yanaco
MP–500 melting point apparatus and are uncorrected. 1H NMR
and 13C NMR spectra were recorded on a Bruker 400 (400 MHz)
spectrometer in CDCl3 with TMS as an internal standard.
General procedure for the AlCl3-promoted tandem Friedel–Crafts
acylation and alkylation of arenes with 2-alkenoyl chlorides. To a stir-
ring mixture of anhydrous aluminum chloride (2.0 g, 15 mmol) and
arene (15 mL for the reaction under refluxing, 25 mL for the reac-
tion at RT) was added a solution of 2-alkenoyl chloride (10 mmol)
in the same arene (8 mL) dropwise during 3 h at 25–30 ◦C (RT) or
under refluxing. After addition, the resulting mixture was kept stir-
ring for 20 min and then allowed to cool to the room temperature.
It was poured into 150 mL of 1 mol/L HCl to decompose AlCl3 com-
plex. After phase separation, the aqueous phase was extracted with
ethyl acetate (3× 50 mL). After dried over Na2SO4 and evaporation
of the solvents, the residue was purified on silica gel column with a
mixture of petroleum ether (60–90 ◦C) and ethyl acetate (10:1, v/v)
as eluent to afford the desired product.
1,3,3-Triphenylpropan-1-one (2d) [25]. White solid, m.p. 93 ◦C,
(Lit. m.p. 88 ◦C). 1H NMR (400 MHz, CDCl3): ı 3.74 (d, J = 7.3 Hz, 2H,
CH2), 4.83 (t, J = 7.3 Hz, 1H, CH), 7.15–7.20 (m, 2H, ArH), 7.25–7.27
(m, 8H, ArH), 7.42–7.45 (m, 2H, ArH), 7.52–7.57 (m, 1H, ArH),
7.92–7.94 (m, 2H, ArH).
2-Methyl-1,3-diphenylpropan-1-one (2e) [26]. Colorless oil, 1H
NMR (400 MHz, CDCl3): ı 1.20 (d, J = 6.9 Hz, 3H, CH3), 2.69 (dd,
J = 7.9, 13.7 Hz, 1H in CH), 3.17 (dd, J = 6.3, 13.7 Hz, 1H in CH),
3.70–3.79 (m, 1H, CH), 7.15–7.20 (m, 3H, ArH), 7.24–7.28 (m, 2H,
ArH), 7.42–7.46 (m, 2H, ArH), 7.51–7.56 (m, 1H, ArH), 7.91–7.93 (m,
2H, ArH).
2-Methyl-1-indanone (3e) [27]. Colorless oil, 1H NMR (CDCl3,
400 MHz): ı 1.31 (d, J = 7.3 Hz, 3H, CH3), 2.67–2.76 (m, 2H, CH2),
3.40 (dd, J = 8.8, 17.9 Hz, 1H, CH), 7.37 (t, J = 7.4 Hz, 1H, ArH), 7.45
(d, J = 7.7 Hz, 1H, ArH), 7.58 (dt, J = 7.4, 1.2 Hz, 1H, ArH), 7.76 (d,
J = 7.7 Hz, 1H, ArH).
1,3-Di(-p-tolylpropan-)1-one (2g) and its isomers, light yellow
oil, 1H NMR (CDCl3, 400 MHz): ı 2.32–2.41 (m, 6H, 2CH3), 3.00–3.06
(m, 2H, CH2), 3.20–3.27 (m, 2H, CH2), 7.09–7.19 (m, 4H, ArH),
7.23–7.26 (m, 2H, ArH), 7.84–7.88 (m, 2H, ArH).
3-Methyl-1,3-di(-p-tolylbutan-)1-one (2h) and its isomers, light
yellow oil, 1H NMR (CDCl3, 400 MHz): ı 1.46–1.47 (m, 6H, 2CH3),
2.27–2.37 (m, 6H, 2CH3), 3.21–3.25 (m, 2H, CH2), 7.05–7.28 (m, 6H,
ArH), 7.72–7.75 (m, 2H, ArH).
1,3,3-Tri(-p-tolylpropan-)1-one (2i) and its isomers, colorless oil,
1H NMR (CDCl3, 400 MHz): ı 2.26–2.28, (m, 6H, 2CH3), 2.38 (s, 3H,
CH3), 3.65–3.68 (m, 2H, CH2), 4.72–4.75 (m, 1H, CH), 6.95–6.97 (m,
1H, CH), 7.05–7.07 (m, 4H, ArH), 7.12–7.15 (m, 3H, ArH), 7.20–7.22
(m, 2H, ArH), 7.82–7.84 (m, 2H, ArH).
1,3-Diphenylpropan-1-one (2a). Colorless crystals, m.p. 72–73 ◦C
(Lit. [20] m.p. 74–75 ◦C). 1H NMR (400 MHz, CDCl3): ı 3.07 (t,
J = 7.7 Hz, 2H, CH2), 3.30 (t, J = 7.7 Hz, 2H, CH2), 7.19–7.32 (m, 5H,
ArH), 7.43–7.47 (m, 2H, ArH), 7.53–7.57 (m, 1H, ArH), 7.96 (d,
J = 8.2 Hz, 2H, ArH).
1-Indanone (3a). Colorless crystals, m.p. 39–42 ◦C (Lit. [21] m.p.
39–41 ◦C). 1H NMR (400 MHz, CDCl3): ı 2.68 (t, J = 6.0 Hz, 2H,
CH2), 3.14 (t, J = 6.0 Hz, 2H, CH2), 7.34–7.38 (t, J = 7.42 Hz, 1H, ArH),
7.46–7.48 (d, J = 7.6 Hz, 1H, ArH), 7.56–7.60 (t, J = 7.42 Hz, 1H, ArH),
7.74–7.76 (d, J = 7.64 Hz, 1H, ArH).
1,3-Diphenylbutan-1-one (2b) [22]. Colorless oil, 1H NMR
(400 MHz, CDCl3): ı 1.34 (d, J = 6.9 Hz, 3H, CH3), 3.19 (dd, J = 8.3,
16.4 Hz, 1H in CH2), 3.30 (dd, J = 5.7, 16.4 Hz, 1H in CH2), 3.49–3.62
(m, 1H, CH), 7.18–7.35 (m, 5H, ArH), 7.42–7.50 (m, 2H, ArH),
7.52–7.60 (m, 1H, ArH), 7.93–7.97 (m, 2H, ArH).
1,3-Dimesitylpropan-1-one (2j) [28]. Colorless crystals, m.p.
80–82 ◦C (Lit. m.p. 80–81 ◦C). 1H NMR (400 MHz, CDCl3): ı 2.21 (s,
6H), 2.24 (s, 3H), 2.26 (s, 3H), 2.28 (s, 6H), 2.80 (t, J = 8.0 Hz, 2H), 3.02
(t, J = 8.0 Hz, 2H), 6.82 (s, 4H). 13C NMR (100 MHz, CDCl3): ı 19.1,
19.6, 20.8, 21.0, 23.1, 43.9, 128.5, 129.0, 132.3, 134.4, 135.4, 135.8,
138.3, 139.5, 210.3. HRMS (ESI) m/z: Calcd for C21H27O: 295.2056;
Found: 295.2053.
3-Methyl-1-indanone (3b) [8b]. Colorless oil, 1H NMR (400 MHz,
CDCl3): ı 1.41 (d, J = 7.1 Hz, 3H, CH3), 2.28 (dd, J = 3.5, 19.0 Hz, 1H
in CH), 2.94 (dd, J = 7.5, 19.0 Hz, 1H in CH), 3.40–3.48 (m, 1H, CH),
7.37 (t, J = 7.4, 1H, ArH), 7.51 (d, J = 7.7 Hz, 1H, ArH), 7.61 (t, J = 7.4,
1H, ArH), 7.73 (d, J = 7.7, 1H, ArH).
(E)-1-Mesitylbut-2-en-1-one (5b) [29]. Yellow oil, 1H NMR
(400 MHz, CDCl3): ı 1.90 (d, J = 6.8 Hz, 3H), 2.21 (s, 6H), 2.28 (s, 3H),
6.31 (d, J = 15.6 Hz, 1H), 6.50 (dq, J = 15.6 and 6.8 Hz, 1H), 6.83 (s, 2H).
3-Methyl-1,3-diphenylbutan-1-one (2c) [23]. Colorless oil, 1H
NMR (400 MHz, CDCl3): ı 1.50 (s, 6H, 2CH3), 3.30 (s, 2H, CH2),

Y. Zhou et al. / Journal of Molecular Catalysis A: Chemical 365 (2012) 203–211
205
Table 2
Tandem Friedel–Crafts acylation and alkylation of 2-alkenoyl chlorides with benzene.a
O
R1 R2
O
O
R1
AlCl3
+
R3
+
Cl
R2
Temp.
R3
R3
1
R1
R2
2
3
Entry
1
2-Alkenoyl chloride
Temp. (◦C)
Reflux
Isolated yield (%)
2
3
81
Trace
1a
2
3
30
52
12
Reflux
21b
39b
4
5
30
55
Trace
35b
Trace
12b
1b
6
Reflux
40
38
1c
7
8
30
77
50
–
–
Reflux
1d
9
30
63
Trace
74b
10
Reflux
21b
1e
11
12
30
34
19
–
Reflux
65 (2d)
1f
13
30
67 (2d)
–
a
A solution of 2-alkenoyl chloride (10 mmol) in benzene (8 mL) was added dropwise slowly in a suspension of aluminum chloride (2.0 g, 15 mmol) in benzene (15 mL)
under refluxing during 3.3 h. The resulting solution was further stirred for 20 min. Or a solution of 2-alkenoyl chloride (10 mmol) in benzene (8 mL) was added dropwise
slowly in a suspension of aluminum chloride (2.0 g, 15 mmol) in benzene (25 mL) at 25–30 ◦C (for acyl chloride 1b at 55 ◦C) during 3.3 h. The resulting solution was further
stirred for 1 h.
b
Yield obtained from 1H MNR analysis of a mixture of isolated products 2 and 3.
13C NMR (100 MHz, CDCl3): ı 18.4, 19.2, 21.0, 128.2, 133.8, 134.1,
137.2, 138.1, 147.8, 201.5.
characterized by only one imaginary vibrational mode. Solvation
energies were evaluated by a self-consistent reaction field (SCRF)
using the CPCM model, [35] where UFF radii were used. Solvation
calculations were carried out at M06-2X level on the gas-phase
optimized structures. The reported energies are zero-point energy-
corrected Gibbs free energies in benzene solution (ꢀGsol).
1-Mesityl-3-methylbut-2-en-1-one (5c) [29b]. Colorless oil, 1H
NMR (400 MHz, CDCl3): ı 1.93 (s, 3H), 2.09 (s, 3H), 2.19 (s, 6H),
2.27 (s, 3H), 6.22 (s, 1H), 6.82 (s, 2H). 13C NMR (100 MHz, CDCl3): ı
19.1, 20.5, 21.0, 28.0, 126.4, 128.4, 133.1, 137.9, 140.4, 156.1, 199.8.
(E)-1-Mesityl-3-phenylprop-2-en-1-one (5d) [30]. Yellow oil, 1
H
NMR (400 MHz, CDCl3): ı 2.19 (s, 6H), 2.32 (s, 3H), 6.89 (s, 2H), 6.93
(d, J = 16.4 Hz, 1H), 7.19 (d, J = 16.4 Hz, 1H), 7.36–7.39 (m, 3H, ArH),
7.49–7.52 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3): ı 19.3, 21.1,
128.4, 128.4, 128.5, 129.0, 130.8, 134.1, 134.5, 137.1, 138.3, 146.7,
201.4.
(E)-1-(2,5-Dimethylphenyl)but-2-en-1-one (5e) [31]. Colorless
oil, 1H NMR (400 MHz, CDCl3): ı 1.94 (dd, J = 6.8 and 1.6 Hz, 3H),
2.32 (s, 3H), 2.33 (s, 3H), 6.52 (dd, J = 15.6 and 1.6 Hz, 1H), 6.74 (dq,
J = 15.6 and 6.8 Hz, 1H), 7.09–7.15 (m, 2H), 7.17 (s, 1H).
4. Results and discussion
The tandem Friedel–Crafts acylation and alkylation of equiva-
lent arenes and 2-alkenoyl chlorides have been successfully used
to prepare indanone derivatives. The tandem reaction includes
Friedel–Crafts acylation of arenes with 2-alkenoyl chlorides
and subsequent intramolecular Friedel–Crafts alkylation or the
Nazarov cyclization [8b]. Additionally, Olah and his co-workers
reported that acrylic acid reacted with equivalent benzene in
dichloromethane to give rise to a mixture of 1-indanone and
dihydrochalcone under the catalysis of superacidic acid trifluo-
romethanesulfonic acid when they investigated the superacidic
trifluoromethanesulfonic acid-induced synthesis of 1-indanone
and 1-tetralone derivatives through the Friedel–Crafts cycli-
acyalkylation of aromatics with unsaturated carboxylic acids
[36]. These inspire us to attempt to synthesize dihydrochalcone
derivatives via intermolecular tandem Friedel–Crafts acylation and
alkylation of arenes with 2-alkenoyl chlorides under the catalysis
3. Calculational method
All calculations were performed with Gaussian 09 [32]. The
M06-2X level [33] with the 6-31G(d,p) basis set [34] was applied
for the optimization of all the stationary points in the gas phase.
Frequency calculations were performed at the M06-2X level to
confirm that each stationary point is either a minimum or a transi-
tion structure, which is confirmed by the vibrational analysis and

206
Y. Zhou et al. / Journal of Molecular Catalysis A: Chemical 365 (2012) 203–211
Table 3
Tandem Friedel–Crafts acylation and alkylation of 2-alkenoyl chlorides with arenes.a
O
R1
R1 R2
O
O
R1
R2
AlCl3
r.t.
Rn
+
+
Cl
R2
Rn
Rn
1
4
Rn
2
5
Entry
2-Alkenoyl chloride 1
ArH 4
2 or 5
2 or 5 yield (%)
O
O
Me
Me 2g
1
1a
4a
88
O
Me
Cl
Me 2h
2
1c
4a
4a
83
O
Cl
3
4
5
6
7
1f
2i
61
90
83
93
85
O
1a
4b
2j
O
O
O
1b
4b
4b
4b
5b
5c
O
O
Cl
Cl
1c
1d
5d
O
8
1b
4c
5e
65
a
A solution of 2-alkenoyl chloride (10 mmol) in arene (8 mL) was added dropwise slowly in a suspension of aluminum chloride (2.0 g, 15 mmol) in arene (25 mL) at 25–30 ◦
C
during 3 h. The resulting solution was further stirred for 1 h.
of Lewis acids. We envisioned that the synthesis could be realized
if the corresponding arenes were used in an excessive amount,
such as a solvent. We firstly used the reaction of acryloyl chloride
(1a) and benzene as a model reaction to optimize the reaction
conditions. To keep a high ratio of benzene:acryloyl chloride during
the whole reaction period, a solution of acryloyl chloride (1a) in
benzene was added dropwise slowly into benzene in the presence
of different Lewis acids. The results are summarized in Table 1. It
can be seen that no reaction occurred under the catalysis of either
boron trifluoride or zinc chloride (Table 1, entries 1–4). However,

Y. Zhou et al. / Journal of Molecular Catalysis A: Chemical 365 (2012) 203–211
207
AlCl3
AlCl3
HO
O
O
H
H3O+
Int2
Pathway A
AlCl3
Int3
2
H3O+
AlCl3
HO
O
O
AlCl3
Cl3Al
Ph
H
+
Pathway C
O
H
Int3
TS1
Int1
Cl
s-cis
1
TS2 Pathway B
AlCl3
AlCl3
AlCl3
AlCl3
O
O
O
O
HO
HCl
TS4
H3O+
H
3
Int4
H
H
TS3
H
Int5
Int6
s-tr ans
Scheme 1. Proposed mechanism for the AlCl3-promoted tandem Friedel–Crafts acylation and alkylation of arenes with 2-alkenoyl chlorides.
Cl3Al
H
O
Cl
H
ΔGsol
kcal/mol
TS4a
AlCl3
41.0
O
O
Cl3Al
Ph
H
H
H
TS3a
HCl
H
TS1a
32.3
Int5a
31.8
O
23.3
AlCl3
O
2a
O
15.3
AlCl3
O
3a
8.1
H
Int3a
4.2
AlCl3
HO
Int1a
Int4a
s-cis
s-trans
AlCl3
Int6a
0.0
-0.1
O
-0.6
AlCl3
HO
Pathway B
Pathway C
Fig. 1. DFT computed energy surface for the AlCl3-promoted tandem Friedel–Crafts acylation and alkylation of 2-acryloyl chloride with benzene at M06-2X/(CPCM)/6-
31G(d,p)//M06-2X/6-31G(d,p).

208
Y. Zhou et al. / Journal of Molecular Catalysis A: Chemical 365 (2012) 203–211
Fig. 2. Geometries (in Å) of transition state and intermediate structures in the AlCl3-promoted tandem Friedel–Crafts acylation and alkylation of 2-acryloyl chloride with
benzene, optimized at M06-2X/6-31G(d,p).
the reaction gave rise to a mixture of dihydrochalcone (2a) and
1-indanone (3a) under the catalysis of anhydrous aluminum chlo-
ride (Table 1, entries 5–7). 1-Indanone (3a) was obtained as major
product if acryloyl chloride (1a) and benzene were mixed directly
and stirred in the presence of aluminum chloride (Table 1, entry
5) due to high concentration of acryloyl chloride (1a) at the begin-
ning of the reaction. However, dihydrochalcone (2a) became the
major product (Table 1, entries 6 and 7), even almost sole product
(Table 1, entries 8 and 9), when acryloyl chloride (1a) was diluted
with benzene and the resulting solution was added dropwise into
the reaction system both at room temperature and under refluxing.
The results indicate that the dihydrochalcone (2a) was obtained in
the highest yield of 81% when a solution of acryloyl chloride (1a)
in benzene was added dropwise into a suspension of aluminum
chloride (1.5 equiv.) in benzene during 3.3 h and then the resulting
mixture was further stirred for 20 min under refluxing.
temperature (Table 2, entries 2, 5, 7, 9, 11, and 13). However,
under refluxing condition, aliphatic 2-alkenoyl chlorides 1a–c,e
generally yielded 1-indanones 2a, b, e as major products except
for 3-methyl-2-butenoyl chloride (1c) (Table 2, entries 3 and 10),
which generated dihydrochalcone 2c and 1-indanone 3c in sim-
ilar yields (Table 2, entry 6), while both cinnamoyl chloride (1d)
and 4-methylcinnamoyl chloride (1f) gave rise to dihydrochalcone
(2d) as sole product as well (Table 2, entries 8 and 12). It is noted
that cinnamoyl chloride (1d) and 4-methylcinnamoyl chloride (1f)
produced the same dihydrochalcone (2d) as product at room tem-
perature and under refluxing, revealing that the Friedel–Crafts
alkylation is facile and reversible in the presence of aluminum chlo-
ride (Table 2, entries 12, and 13).
The results promote us to further investigate the generality of
different arenes in the reaction. Three representative 2-alkenoyl
chlorides 1a, c, f were reacted with toluene at room temperature
to afford the dihydrochalcones 2g–i as chemoselective products
in good yields possibly due to the high reactivity of toluene
with an electron-donating methyl group on the benzene ring. For
both acryloyl chloride (1a) and 2-methylacryloyl chloride (1c),
a mixture of four different regiomeric dihydrochalcone deriva-
tives 2a,c were obtained because both ortho and para acylation
To extend the application of the AlCl3-promoted tandem
Friedel–Crafts acylation and alkylation, a series of 2-alkenoyl chlo-
rides 1 were reacted with benzene under the optimized reaction
conditions both at room temperature and under refluxing (Table 2).
The results indicate that all 2-alkenoyl chlorides 1 produced dihy-
drochalcone derivatives 2 as major or sole products at room

Y. Zhou et al. / Journal of Molecular Catalysis A: Chemical 365 (2012) 203–211
209
ΔGsol
kcal/mol
Cl3Al
H
O
Cl
H
O
Cl3Al
H
Ph
H
AlCl3
O
TS4e
TS1e
35.0
33.5
H
H
TS3e
HCl
O
28.1
O
Int5e
2e
16.3
AlCl3
AlCl3
16.3
O
3e
O
9.0
Int3e
4.0
AlCl3
Int1e
Int4e
s-cis
H
AlCl3
s-tr ans
0.0
Int6e
-4.5
HO
-0.3
O
AlCl3
HO
Pathway B
Pathway C
Fig. 3. DFT computed energy surface for the AlCl3-promoted tandem Friedel–Crafts acylation and alkylation of methacryloyl chloride with benzene at M06-2X/(CPCM)/6-
31G(d,p)//M06-2X/6-31G(d,p).
and alkylation occurred (Table 3, entries 1 and 2). However, 4-
methylcinnamoyl chloride (1f) reacted with toluene to give rise to
a mixture of 1,3,3-tri(4-methylphenyl)-1-propanone (2ipp) and 1-
(2-methylphenyl)-3,3-di(4-methylphenyl)-1-propanone (2iop) in
a ratio of 1.8:1.0, in which only para-alkylation occurred possibly
due to steric hindrance in the 3-position of 4-methylcinnamoyl
chloride (1f) (Table 3, entry 3). Treatment of 1a with mesitylene
(4b) also gave rise to the corresponding product 2j in 90% yield
exclusively. However, when 4b was reacted with substituted 2-
alkenoyl chlorides 1b–d, only the Friedel–Crafts acylation took
place, giving the acylation products 5b–d in good yields. This
is mainly attributed to the steric hindrance of the substituents
between 4b and 1b–d, making the consequent alkylation difficult.
Similarly, acylation product 5e was also synthesized by the acy-
lation of 1b and p-xylene (4c) in 65% yield. We also attempted the
reaction of acryloyl chloride (1a) and anisole with a strong electron-
donating group in anisole as the solvent and hoped to prepare the
corresponding dihydrochalcone in a good yield. Unfortunately, we
failed because of the strong coordination between the oxygen atom
in anisole and aluminum chloride. When aluminum chloride was
added into anisole, solid complex generated from aluminum chlo-
ride and anisole, resulting in no desired reaction occurred.
alkylation with another molecule of arenes involving the inter-
mediacy of Int2 and Int3 to afford dihydrochalcones 2 through
pathway A and an intramolecular of Friedel–Crafts alkylation
(or the Nazarov cyclization) via the transition states TS3 and
TS4 to yield 1-indanone 3 through pathway B in the reaction
system. In general, the intramolecular reactions are more pre-
dominant than the intermolecular reactions, especially for the
formation of five- and six-membered ring products. However,
in the current reaction system, intermolecular products, dihy-
drochalcones 2, were obtained as major or sole products in the
most cases. This attracts our attention to deep understand the
Friedel–Crafts alkylation mechanism. We presumed that the inter-
molecular Friedel–Crafts alkylation possibly undergoes a second
pathway via a six-membered ring transition state in the alkylation
reaction with relatively low energy barrier to facile the intermolec-
ular alkylation (pathway C). To verify the proposed mechanism, we
conducted the DFT calculation investigation into the intermolecu-
lar and intramolecular Friedel–Crafts alkylation at M06-2X level
with the 6-31G(d,p) basis set. For intermolecular Friedel–Crafts
alkylation, both acyclic and cyclic transition states were searched.
The reaction of acryloyl chloride (1a) and benzene was first
selected as a model reaction for the calculational investigation.
The energy surface was obtained and is shown in Fig. 1, in
which the energy of the intermediate Int1 was selected as the
reference. For the intermolecular Friedel–Crafts alkylation, no tran-
sition state was located in the acyclic pathway (Pathway A),
while the transition state was indeed located in the cyclic path-
way with an activation energy of 31.8 kcal/mol (Pathway C). The
While a precise reaction mechanism awaits further study, plau-
sible competitive pathways are shown in Scheme 1. 2-Alkenoyl
chlorides 1 and arenes initially undergo a Friedel–Crafts acylation in
the presence of aluminum chloride to yield aluminum-coordinated
1-aryl-1-alkanone intermediates Int1, which further undergo a
competitive process between an intermolecular Friedel–Crafts

210
Y. Zhou et al. / Journal of Molecular Catalysis A: Chemical 365 (2012) 203–211
Fig. 4. Geometries (in Å) of transition state structures in the AlCl3-promoted tandem Friedel–Crafts acylation and alkylation of methacryloyl chloride with benzene, optimized
at M06-2X/6-31G(d,p).
intermediate Int1a undergoes a six-membered ring transition state
TS1a to produce the aluminum chloride-coordinated enol interme-
diate Int3a with energy of 4.2 kcal/mol, which further generates the
final product dihydrochalcone (2a) upon hydrolysis. In the tran-
sition structure TS1a, the forming C C and O H bond distances
tandem reaction due to a stable six-membered ring transition state.
The current reaction provides a convenient, environment-friendly,
and practical route to the preparation of dihydrochalcone deriva-
tives from arenes and 2-alkenoyl chlorides directly.
˚
are 1.67 and 1.87 A, respectively, and the breaking C H bond dis-
Acknowledgments
˚
tance is 1.13 A, indicating that the alkylation occurs in a concerted
but asynchronous cyclic fashion (Fig. 2). For the formation of 1-
indanone (Pathway B), the intermediate Int1a needs first to rotate
its single C C bond to become s-trans isomer Int4a via a transition
state with low energy. The intermediate Int4a cyclizes via a five-
membered ring transition state TS3a with an activation free energy
The project was supported by National Natural Science Foun-
dation of China (Nos. 2011CBA00508, 21172017 and 20972013),
specialized Research Fund for the Doctoral Program of Higher Edu-
cation, Ministry of Education of China (No. 20110010110011), and
“CHEMCLOUDCOMPUTING” of Beijing University of Chemical Tech-
nology.
˚
of 32.3 kcal/mol and the forming C C bond distance of 1.92 A to
form an intermediate Int5a at energy of 23.3 kcal/mol, which fur-
ther undergoes H-migration with the assistance of HCl molecule
via a seven-membered ring transition state TS4a, requiring an
activation free energy of 41.0 kcal/mol to generate an aluminum
chloride-coordinated enol of 1-indanone Int6a at energy level of
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.molcata.2012.09.005.
−0.6 kcal/mol. In the transition structure TS4a, the forming Cl
H
˚
and O H bond distances are 2.37 and 1.03 A, respectively, and the
˚
breaking Cl H and C H bond distances are 2.07 and 1.15 A, respec-
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