Iodine-catalyzed Friedel-Crafts alkylation of electron-rich arenes with aldehydes: efficient synthesis of triarylmethanes and diarylalkanes

Article abstract of DOI:10.1016/j.tetlet.2009.08.036

Iodine is shown to be an efficient catalyst for the Friedel-Crafts alkylation of arenes with a wide variety of aldehydes in toluene under 'open-flask' and mild conditions. In the presence of 10 mol % of iodine, the reaction of arenes with aromatic aldehyd

Full text of DOI:10.1016/j.tetlet.2009.08.036

Tetrahedron Letters 50 (2009) 6012–6015
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Iodine catalyzed Friedel–Crafts alkylation of electron-rich arenes with
aldehydes: efficient synthesis of triarylmethanes and diarylalkanes
a
a
b
Jaray Jaratjaroonphong a, , Supaporn Sathalalai , Prapapan Techasauvapak , Vichai Reutrakul
*
a Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
b Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodine is shown to be an efficient catalyst for the Friedel–Crafts alkylation of arenes with a wide variety of
aldehydes in toluene under ‘open-flask’ and mild conditions. In the presence of 10 mol % of iodine, the
reaction of arenes with aromatic aldehydes gives the corresponding triarylmethane derivatives (TRAMs),
regioselectively, in good to excellent yields. On the other hand, a series of diarylalkane derivatives is syn-
thesized smoothly by reaction with aliphatic aldehydes.
Received 5 June 2009
Revised 16 July 2009
Accepted 14 August 2009
Available online 20 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Triarylmethanes
Diarylalkanes
Iodine
Friedel–Crafts
Ar1
Ar1
Ar2
Ar2CHO
Triarylmethanes (TRAMs) and diarylalkanes have attracted con-
siderable attention1 due to their varied biological activity as antivi-
ral,2 antitumor,3 antitubercular,4 antifungal,5 and anti-
inflammatory agents.5 Moreover, these compounds have found
widespread application in the chemical industry.1a,6 Methods for
the synthesis of TRAMs and diarylalkanes have been developed7,8
which mainly centered on Friedel–Crafts alkylation of electron-rich
arenes with aldehydes and their imines using AuCl3/AgOTf,9 [Ir(-
COD)Cl]2–SnCl4,5,10 Cu(OTf)2/( )-BINAP,11 ZnBr2/SiO2,12 FeCl3,13
and Bi2(SO4)3/TMSCl14 as the Lewis acids. However, most of these
methods are multi-step processes, require harsh reaction condi-
tions and are limited to non-enolizable aldehydes.
Molecular iodine has received considerable attention in organic
and pharmaceutical syntheses due to its inexpensive, non-toxic,
and environmentally friendly characteristics.15 Iodine has a high
tolerance to air as well as moisture and can be easily removed from
reaction systems. Moreover, the mild Lewis acidity associated with
iodine has led to its use in various organic transformations in cat-
alytic to stoichiometric amounts. In this paper, we report the
molecular iodine catalyzed Friedel–Crafts alkylation of electron-
rich arenes using aromatic and enolizable aldehydes to generate
either TRAMs or diarylalkanes, respectively, in high yields under
mild reaction conditions (Scheme 1).
(Ar = aryl)
I2 (10 mol%)
2
Ar1-H
toluene, air
rt
1
Ar1
Ar1
RCHO
(R = alkyl)
R
3
Scheme 1. I2-catalyzed formation of TRAMs and diarylalkanes
(20 mol %) with a mixture of 1a (2 equiv) and benzaldehyde
(1 equiv) in CH2Cl2 afforded triarylmethane 2a, regioselectively,
in high yield (entry 1). By lowering the catalyst loading to
10 mol % (entry 2), the product 2a was also obtained in similar
yield, however, a longer reaction time was necessary. As antici-
pated, no reaction was observed in the absence of the iodine cata-
lyst and both starting materials were recovered in quantitative
yields (entry 3). The reaction under neat conditions (entry 4) gave
the product in 53% yield. Reactions in different organic solvents
and with propanal (entries 5–10) were studied. We found that a
remarkable solvent effect existed in our iodine catalyzed reaction.
Dichloromethane (entry 2) and toluene (entry 8) were the best sol-
vents for good transformation in the case of benzaldehyde accep-
tors, while the other solvents were less effective and lower
product yields of 39–81% were obtained (entries 5–7). Although
reaction of the enolizable aldehyde acceptor, propanal, in CH2Cl2
gave a low yield of the diarylalkane 3a, reaction in toluene was
accomplished to afford 3a in a high 89% yield.
We first examined the reaction of 1,2,4-trimethoxybenzene (1a)
with benzaldehyde using iodine as the catalyst in an open test-
tube at room temperature (Table 1). The initial reaction of iodine
* Corresponding author. Tel.: +66 038 10 3053; fax: +66 038 39 3494.
E-mail address: jaray@buu.ac.th (J. Jaratjaroonphong).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.036

J. Jaratjaroonphong et al. / Tetrahedron Letters 50 (2009) 6012–6015
6013
Table 1
Optimization studiesa
OMe
OMe
MeO
MeO
OMe
OMe
PhCHO
EtCHO
OMe
MeO
OMe
Ph OMe
2a
MeO
I2 , solvent
air,rt
OMe
OMe
1a
MeO
OMe
3a
Entry
Aldehyde
Catalyst (mol %)
Solvent
Time (h)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
EtCHO
EtCHO
20
10
—
10
10
10
10
10
10
10
CH2Cl2
CH2Cl2
CH2Cl2
—
CH3CN
THF
MeOH
Toluene
CH2Cl2
Toluene
48
72
72
18
72
72
72
72
72
72
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
90
92
—
c
d
53e
75
81
39
90
36
89
10
a
Reaction conditions: 1a (2 mmol), aldehyde (1 mmol), I2, solvent (1 mL), room temperature.
Isolated yield.
Reaction conducted in the absence of iodine.
No reaction based on TLC analysis.
b
c
d
e
The reaction mixture solidified after stirring for 18 h.
The generality of the reaction was studied through experiments
of 3,4-dimethoxybenzaldehyde, increasing the reaction tempera-
ture to 60 °C gave a significant increase in the yield of 2f in a short-
er reaction time (entries 6 and 7). Furthermore, the corresponding
diarylalkane adducts 3a–f were smoothly obtained in 80–99%
yields when various aliphatic aldehydes were used (entries 9–
14).16
with different aldehydes as electrophiles (Table 2) under the opti-
mum conditions (Table 1, entry 8).16 In the presence of 10 mol % of
I2, 1,2,4-trimethoxybenzene (2 equiv) reacted with a number of
aromatic aldehydes possessing either electron-withdrawing (F, Cl,
Br, and NO2) or electron-donating (OMe) substituents to give the
corresponding symmetric triarylmethanes 2b–g, selectively, in
good to excellent yields (entries 2–8). Due to the low reactivity
We next explored the iodine catalyzed Friedel–Crafts alkylation
of various arenes as well as 2-methylfuran with either aromatic or
aliphatic aldehydes for the synthesis of the corresponding TRAMs
or diarylalkanes, respectively. The results presented in Table 3
show that all the reactions gave selective formation of triarylme-
thane and diarylalkane derivatives. The reactions of mono-, di- or
trimethoxy substituted arenes with 4-nitrobenzaldehyde or 3-phe-
nylpropanal afforded the corresponding TRAMs 2h–j or diarylalk-
anes 3g–i, respectively, in moderate to high yields (entries 1–4
and 6–10). The reaction of heteroaromatic 2-methylfuran with 3-
phenylpropanal gave the alkylated diheteroarylalkane 3j in 84%
yield (entry 11). Additionally, the reaction of 2-methylfuran was
also performed in water as the reaction medium due to its many
advantages from economical, environmental, and safety stand-
points.17 Gratifyingly, the reaction succeeded to provide the de-
sired product 3j in an excellent 99% yield (entry 12). Compound
2k which has been reported to show significant antiviral activity5
was synthesized smoothly in an excellent 92% yield by condensa-
tion of phenol with 4-chlorobenzaldehyde (entry 5).
In summary, we have demonstrated an efficient molecular io-
dine catalyzed Friedel–Crafts alkylation of electron-rich arenes
with a wide variety of aldehydes in toluene under ‘open flask’
and mild conditions. Typically, the reaction of arenes with aro-
matic aldehydes provides the corresponding triarylmethane deriv-
atives (TRAMs), regioselectively, in good to excellent yields. In
addition, a series of diarylalkane derivatives has been smoothly
synthesized by reaction with aliphatic aldehydes. Further investi-
gations on the scope and limitations of this reaction are in
progress.
Table 2
I2-catalyzed reaction of arene 1a with various aldehydesa
OMe
OMe
OMe
OMe
MeO
OMe
MeO
I2 (10mol%)
+
RCHO
toluene,air
rt
OMe
MeO
R
1a
2 (R=aryl)
3 (R=alkyl)
Time (h)
Entry
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3-MeOC6H4
Et
PhCH2CH2
Me2CHCH2
Me2CH
2a
2b
2c
2d
2e
2f
72
72
72
72
72
120
48
72
72
72
72
72
130
72
90
97
88
98
99
72
90c
87
89
80
87
95
99
99
2f
2g
3a
3b
3c
3d
3e
3f
Ph(Me)CH
Cyclohexyl
a
Reaction conditions: 1a (2 mmol), aldehyde (1 mmol), I2 (10 mol %), toluene
(1 mL), room temperature.
b
Isolated yield.
The reaction was carried out at 60 °C.
c

6014
J. Jaratjaroonphong et al. / Tetrahedron Letters 50 (2009) 6012–6015
Table 3
I2-catalyzed reaction of various arenes with aliphatic and aromatic aldehydesa
I
2 (10 mol%)
Ar
Ar
Ar
H
+
RCHO
toluene, air
rt
R
1
2 (R = aryl)
3 (R = alkyl)
Entry
Ar-H
RCHO
Product
OMe OMe
Time (h)
Yieldb (%)
MeO
OMe
1
2
1,3,5-Trimethoxybenzene
1,3,5-Trimethoxybenzene
4-O2NC6H4CHO
4-O2NC6H4CHO
2h
2h
24
24
82
MeO
OMe
93c
NO2
MeO
OMe
OMe
MeO
MeO
3
1,2,3-Trimethoxybenzene
4-O2NC6H4CHO
2i
72
47c
OMe
NO2
MeO
MeO
OMe
OMe
4
1,2-Dimethoxybenzene
4-O2NC6H4CHO
2j
72
63c
NO2
HO
OH
5
Phenol
ClC6H4CHO
2k
12
92c
Cl
MeO
OMe
OMe
MeO
MeO
6
7
1,2,3-Trimethoxybenzene
1,2,3-Trimethoxybenzene
PhCH2CH2CHO
PhCH2CH2CHO
3g
3g
72
48
66
78c
OMe
Ph
MeO
MeO
OMe
OMe
8
9
1,2-Dimethoxybenzene
1,2-Dimethoxybenzene
PhCH2CH2CHO
PhCH2CH2CHO
3h
3h
72
24
49
78c
Ph
MeO
OMe
10
Anisole
PhCH2CH2CHO
3i
72
76
Ph
O
Me
Me
O
11
12
2-Methylfuran
2-Methylfuran
PhCH2CH2CHO
PhCH2CH2CHO
3j
3j
22
24
84
99d
Ph
a
b
c
Reaction conditions: arene 1 (2 mmol), aldehyde (1 mmol), I2 (10 mol %), toluene (1 mL), room temperature.
Isolated yield.
The reaction was carried out at 60 °C.
The reaction was carried out in H2O (1 mL).
d

J. Jaratjaroonphong et al. / Tetrahedron Letters 50 (2009) 6012–6015
6015
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Acknowledgements
We thank the Thailand Research Fund for financial support
MRG5280024 to J.J. Financial support from the Center for
Innovation in Chemistry (PERCH-CIC), Commission on Higher Edu-
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ence, Burapha University, Thailand are also gratefully
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a
toluene solution (1 mL) of arene
1
(2 mmol) and aldehyde (1 mmol) in
a
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