A new convenient Friedel-Crafts alkylation of aromatic compounds with secondary alcohol methanesulfonates in the presence of scandium(III) trifluoromethanesulfonate or trifluoromethanesulfonic acid as the catalyst

Article abstract of DOI:10.1055/s-1999-3436

Scandium(III) triflate and triflic acid were both found to be efficient catalysts for the Friedel-Crafts alkylation of aromatic compounds using methanesulfonates derived from secondary alcohols as alkylating agents.

Full text of DOI:10.1055/s-1999-3436

PAPER
603
A New Convenient Friedel-Crafts Alkylation of Aromatic Compounds with
Secondary Alcohol Methanesulfonates in the Presence of Scandium(III)
Trifluoromethanesulfonate or Trifluoromethanesulfonic Acid as the Catalyst
Hiyoshizo Kotsuki,* Takeshi Ohishi, Motoshi Inoue, Tomoyuki Kojima
Department of Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Fax +81(888)448360; E-mail: kotsuki@cc.kochi-u.ac.jp
Received 27 August 1998; revised 12 October 1998
(Table 1, entry 4). Not surprisingly, the same reaction was
Abstract: Scandium(III) triflate and triflic acid were both found to
dramatically accelerated when 10 mol% TfOH was used
in place of Sc(OTf)3: the reaction was completed within
be efficient catalysts for the Friedel-Crafts alkylation of aromatic
compounds using methanesulfonates derived from secondary alco-
30 min and gave 91% yield of 2a (Table 1, entry 9). In
these reactions, the amount of catalyst strongly influenced
both the yield and the reaction rate (Table 1, entries 1-3,
9-11) and at lower temperatures the reaction progress
was significantly retarded. As expected, cyclohexyl bro-
mide was unreactive as an alkylating agent under both
Sc(OTf)3- and TfOH-catalyzed conditions (Table 1, en-
tries 12, 13). Cyclohexanol and cyclohexene reacted
slowly with benzene to afford 2a under the catalysis of
TfOH (Table 1, entries 14, 15).
hols as alkylating agents.
Key words: Friedel-Crafts alkylation, aromatic compounds, scan-
dium(III) triflate, triflic acid, secondary alcohol methanesulfonates
Since its discovery in 1877,1 Friedel-Crafts alkylation
has been recognized as one of the most important tools for
introducing alkyl substituents into an aromatic compound
ring system.2 Usually this type of reaction can be carried
out using a wide variety of alkylating agents in the pres-
ence of a Lewis acid such as AlCl3 and BF3◊OEt2.2 Instead
of these rather classic reagents, considerable attention has
recently been focused on the use of rare earth metal triflu-
oromethanesulfonates [rare earth metal triflates,
RE(OTf)3] as water-tolerant and recyclable Lewis acid
catalysts.3 In the course of our investigation of the synthe-
sis of biologically interesting natural products,4 we re-
quired an efficient method for performing aromatic
substitution by using an alkyl methanesulfonate (mesy-
late) as a convenient electrophile.5 In view of the increas-
ing demand to explore the synthetic versatility of
RE(OTf)3, it may be worthwhile confirming the feasibility
of using these catalysts in our targetting Friedel-Crafts
alkylation.6 In connection with this research project, we
have been also interested in characterizing similarities and
differences between RE(OTf)3 and trifluoromethane-
sulfonic acid (TfOH) as an extremely strong Brønsted ac-
id. Whereas several papers have been appeared in the
literature on the use of superacids, e.g., Nafion-H, as
closely related reagents,7 the applicability of TfOH in this
field is not well-established.8 Here, we describe the results
that led to the development of a facile Friedel-Crafts
alkylation, in particular, using either a catalytic amount of
scandium(III) triflate [Sc(OTf)3] or TfOH.
Table 1 Catalytic Activity of RE(OTf)3 or TfOH for Friedel Crafts
Cyclohexylation of Benzene under Various Conditionsa
Entry
1
Cat (mol %)
Time
(h)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
---e
Sc(OTf)3 (5)
Sc(OTf)3
Sc(OTf)3 (20)
Yb(OTf)3
La(OTf)3
Nd(OTf)3
Dy(OTf)3
Gd(OTf)3
TfOH
TfOH (5)
TfOH (20)
Sc(OTf)3
TfOH
3
4
4
6
3
4
3
4
0.5
5
64
92c
88
92c
65
72
87
85
91
79
88
0.5
15
24
4
NRd
NRd
86
TfOH
TfOH
4.5
68
a Conditions: Alkylating agent (2 mmol) and catalyst (10 mol%) in
To search for the catalytic activity of RE(OTf)3 and TfOH,
the cyclohexylation of benzene with various cyclohexanol
derivatives was examined (Table 1). Among several rare
earth metal triflates, we found that Sc(OTf)3 was the best
of choice. Thus, the reaction of cyclohexyl mesylate (1a)
in refluxing benzene in the presence of 10 mol% Sc(OTf)3
proceeded efficiently to give cyclohexylbenzene (2a) in
92% yield (Table 1, entry 2). Almost comparable catalytic
activity was achieved for Yb(OTf)3, albeit rather slowly
benzene (10 ml), 80 ºC.
b GLC yield.
c Isolated yield.
d No reaction.
e Cyclohexene was used as an alkylating agent.
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H. Kotsuki et al.
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These results clearly indicate that TfOH is a highly favor- observed for the reaction of anisole (Table 2, entries 13,
able catalyst to effect the present type of Friedel-Crafts 14). In spite of the great ortho-directing effect of a meth-
alkylation. Nevertheless, we cannot ignore the synthetic oxy group, the preferential para-alkylation under the
utility of Sc(OTf)3 with respect to its reusability. Namely, Sc(OTf)3-catalyzed conditions can only be explained by
this catalyst could be recovered simply by crystallization considering the steric effect at the ortho-position probably
from the aqueous phase by gradual evaporation of water through complexation of the catalyst. This also caused the
and was used repeatedly without a significant loss of ac- deactivation of the catalyst resulting in the lower product
tivity: 2nd run, 89%, 8 h; 3rd run, 83%, 12 h.9
yield (Table 2, entry 13).15 The nonreactivity of durene
might be ascribed to its severe steric hindrance (Table 2,
entries 7, 8). The less reactive nature of bromobenzene in
the Friedel-Crafts reaction is quite a common phenome-
non (Table 2, entries 11, 12).2 The reaction of benzene
with cycloheptyl mesylate (1c) gave phenylcycloheptane
(2j) in good yield without contamination of isomerized
products (Table 2, entries 17, 18).16 The use of 2-pentyl or
3-pentyl mesylate (1f or 1g) gave a mixture of 2-phenyl-
and 3-phenylpentane (2m) with the similar isomer distri-
bution, implying the spontaneous rearrangement of an in-
termediate carbocation species (Table 2, entries 23-26).
Despite extensive effort, the use of cyclooctyl mesylate as
an alkylating agent was fruitless, probably due to its seri-
ous steric repulsion.17 The mesylates derived from prima-
ry alcohols or the aromatic substrates having an electron-
withdrawing group, e.g., acetophenone and methyl ben-
zoate, were found to be completely unreactive under these
conditions.
We next examined the general applicability of above two
procedures in other systems and the results are summa-
rized in Table 2. In most cases, a large excess of aromatic
compound was used as a solvent. In the case of the aro-
matic compounds with high boiling points, such as du-
rene, naphthalene, bromobenzene, and anisole, the
reactions were conducted in refluxing 1,2-dichloroethane
or carbon tetrachloride using 1.5 equiv of the substrate
(Table 2, entries 7-14). Thus, the desired reactions pro-
ceeded quite smoothly in most cases with high yields. The
catalytic activity of TfOH was so strong compared with
Sc(OTf)3 that polyalkylation side reactions could not be
suppressed for the highly nucleophilic aromatic substrates
such as p-xylene and naphthalene (Table 2, entries 3, 4, 9,
10). The regioselectivity observed for toluene, naphtha-
lene, bromobenzene, and anisole indicates that this alky-
lation follows
a typical electrophilic substitution
mechanism (Table 2, entries 1, 2, 9-11, 13, 14).2, 14 Inter-
estingly, the completely reversed isomer distribution was
Table 2 Sc(OTf)3- and TfOH-Catalyzed Friedel Crafts Alkylation of Aromatic Compoundsa
En-
try
R–OMs
Ar–H
Catalyst
Time
(h)
Product(s)
Yield
(%)b
mp (°C) or bp (°C/Torr)c
Found
Reported
1
2
toluene
Sc(OTf)3
TfOH
3
0.5
98d
94d
115–119/18e
141–144/18
151–155/19
–
120–129/2010, e
135/1210
156/1910
–
3
4
p-xylene
mesitylene
durene
Sc(OTf)3
TfOH
1
0.25
84
61f
5
6
Sc(OTf)3
TfOH
2
0.5
93
90
7g
8g
Sc(OTf)3
TfOH
13
2
0
0
9g
naphthalene
Sc(OTf)3
TfOH
4
0.5
71i
56j
184–186/6 (1)
28–29 (2)
118–120/0.3
(1)11
10g
31 (2)11
11g
12g
bromoben-
zene
Sc(OTf)3
TfOH
5
1
36k
0
159/19 (o)
154/20 (p)
132/6 (o)12
85/1 (p)13
13g
14g
anisole
Sc(OTf)3
TfOH
1
0.2
60l
131–135/16 (o)
147–150/16 (p)
268–269.5 (o)11
114–116/4 (p)11
96m
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A New Convenient Friedel-Crafts Alkylation of Aromatic Compounds
605
Table 2 (continued)
En-
try
R–OMs
Ar–H
Catalyst
Time
(h)
Product(s)
Yield
(%)b
mp (°C) or bp (°C/Torr)c
Found
Reported
15
16
benzene
Sc(OTf)3
TfOH
1
0.5
87
96
98–102/20
130–135/17
149–153
116–117/3711
17
18
benzene
benzene
benzene
Sc(OTf)3
TfOH
1
0.5
69
81
135–136.5/1811
152–15311
69/2011
19
20
Sc(OTf)3
TfOH
1.5
1.5
94n
94n
21
22
Sc(OTf)3
TfOH
2
0.5
92
95
70–73/19
23
24
benzene
benzene
Sc(OTf)3
TfOH
2
0.5
93o
95o
76–81/20 (2)
79–82/20 (3)
191–193 (2)11
189 (3)11
25
26
Sc(OTf)3
TfOH
2
0.5
90o
98o
a Conditions: Unless otherwise noted, mesylate (2 mmol) and catalyst (10 mol%) in Ar-H (10 mL), 80 ºC.
b Isolated yelds. Yields are based on the starting mesylates.
c Data in parentheses indicate the substituted position.
d Isomer ratio was o : p = 50 : 50
e Bp of the regioisomeric mixture.
f 2,5-Dicyclohexyl-p-xylene [35%, mp 153–154.5ºC (lit. 10, 156–157 ºC)] was also obtained.
g Reaction was carried out in CH2ClCH2Cl (10 mL) by using 1.5 equiv of Ar-H at 80ºC.
h These isomers were separated by JAI Recycling Preparative HPLC LC-908 (CHCl3 as an eluent).
i Isomer ratio was a : b = 31 : 69.
j Isomer ratio was a : b = 33 : 67. Dialkylated compounds (32%) were also obtained.
k Isomer ratio was o : p = 46 : 54.
l Isomer ratio was o : p = 37 : 63.
m Isomer ratio was o : p = 54 : 46.
n GLC yield.
o Isomer ratio was 2- : 3- = 76 : 24.
Scheme 1
Cyclohexylation of p-cresol showed quite an interesting substrates bearing potential coordination sites within the
product distribution (Scheme 1). Except for the main molecule.
product 2n, the major dialkylated compound was 2p for
Sc(OTf)3 and 2o for TfOH, respectively. Similarly as de-
scribed for the reaction of anisole (vide supra), these re-
In conclusion, we have found a convenient new method
for alkylating aromatic compounds with mesylates de-
rived from secondary alcohols in the presence of a catalyt-
sults support the preferential coordination of Sc(OTf)3
ic amount of Sc(OTf)3 or TfOH.19 In most cases TfOH is
with a phenolic hydroxyl group. Unsuccessful transfor-
superior to Sc(OTf)3, despite the fact that polyalkylation
mation of the 4-hydroxyproline derivative 3 to 4 under ei-
side reaction was unavoidable for the reactive substrates.
We believe that the present method should be useful with
ther condition (Scheme 2) typically represents the
limitation of the present method.18 It seems to be true that
regard to its simplicity, convenience, and high efficiency.
neither Sc(OTf)3 nor TfOH had sufficient activity for the
Synthesis 1999, No. 4, 603–606 ISSN 0039-7881 © Thieme Stuttgart · New York

606
H. Kotsuki et al.
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See also: Kotsuki, H.; Shimanouchi, T.; Teraguchi, M.;
Kataoka, M.; Tatsukawa, A.; Nishizawa, H. Chem. Lett. 1994,
2159.
(5) For a preliminary report, see: Kotsuki, H.; Ohishi, T.; Inoue,
M. Synlett 1998, 255.
(6) For related examples: Matsui, M.; Yamamoto, H. Bull. Chem.
Soc. Jpn. 1995, 68, 2663.
Scheme 2
Matsui, M.; Karibe, N.; Hayashi, K.; Yamamoto, H. Bull.
Chem. Soc. Jpn. 1995, 68, 3569.
All reactions were carried out under N2. All aromatic substrates,
CCl4 and CH2ClCH2Cl were distilled from CaH2. Preparative TLC
was carried out on 2 mm thick Merck Kieselgel 60PF-254. Wakogel
C-300 was employed for column chromatography.
Tsuchimoto, T.; Hiyama, T.; Fukuzawa, S. Chem. Commun.
1996, 2345.
Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S. Synlett
1996, 557.
Fukuzawa, S.; Tsuchimoto, T.; Hiyama, T. J. Org. Chem.
1997, 62, 151.
Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S. J. Org.
Chem. 1997, 62, 6997.
All the starting mesylates were prepared from alcohols under the
usual conditions. Sc(OTf)3 was purchased from Pacific Metals Co.,
Ltd., Hachinohe, Aomori 031, Japan (Fax +81(178)227350) and
used without further purification.
(7) Reviews: Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis
1986, 513.
Preparation of Cyclohexylbenzene (2a); Typical Procedure
A solution of cyclohexyl mesylate (1a, 2.0 mmol) in benzene (10
ml) containing Sc(OTf)3 (0.2 mmol, 10 mol%) or TfOH (0.2 mmol,
10 mol%) was heated at 80 °C under N2. H2O was added to quench
the reaction and the organic layer was separated. The aqueous layer
was further extracted with Et2O. The combined extracts were dried
(Na2SO4) and concentrated in vacuo. The crude product was puri-
fied by preparative TLC to afford cyclohexylbenzene (2a) as a col-
orless oil; bp 107-110 °C/16 Torr (lit.11 235-236 °C).
Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids, Wiley-
Interscience: New York, 1992.
Yamato, T. J. Synth. Org. Chem. Jpn. 1995, 53, 487.
(8) Reviews: Howells, R. D.; Mc Cown, J. D. Chem. Rev. 1977,
77, 69.
Stang, P. J.; White, M. R. Aldrichimica Acta, 1983, 16, 15.
(9) The contaminating methanesulfonic acid was removed by
decantation.
(10) Hickinbottom, W. J.; Rogers, N. W. J. Chem. Soc. 1957, 4124.
(11) Dictionary of Organic Compounds, 6th ed.; Chapman & Hall:
London, 1996.
Alkylation of the other substrates were carried out as described
above. The alkylated products thus obtained were known com-
pounds and identified spectroscopically (1H and 13C NMR and IR).
The following are not listed in Table 2.
(12) Le Guen, M. M. J.; Taylor, R. J. Chem. Soc., Perkin Trans. 2,
1976, 559.
(13) Ohashi, M.; Miyake, K.; Tsujimoto, K. Bull. Chem. Soc. Jpn.
1980, 53, 1683.
(14) Even at room temperature anisole could react slowly with 1a
under the TfOH-catalyzed conditions (6 h, 79% yield of 2h),
but no significant improvement in regioselectivity was
observed (o: p = 59: 41).
2-Cyclohexyl-4-methylphenol (2n)
Bp 165-168 °C/18 Torr (lit.20, 156 °C/10 Torr).
2,6-Dicyclohexyl-4-methylphenol (2o)
Bp 193-196 °C/5 Torr (lit.20, 268 °C/50 Torr).
2,5-Dicyclohexyl-4-methylphenol (2p)
(15) In contrast, RE(OTf)3-catalyzed Friedel-Crafts acylation of
anisoles proceeds in quite high yields. See for example:
Kawada, A.; Mitamura, S.; Kobayashi, S. Synlett 1994, 545.
Kobayashi, S.; Moriwaki, M.; Hachiya, I. Synlett 1995, 1153.
Kobayashi, S.; Moriwaki, M.; Hachiya, I. J. Chem. Soc.,
Chem. Commun. 1995, 1527.
Mp 111-113 °C (lit.21, 109 °C).
Acknowledgement
This work was supported in part by Scientific Research Grants from
the Ministry of Education, Science, Sports and Culture, Japan. We
also thank Central Glass Co., Ltd., for generously supplying TfOH.
Kawada, A.; Mitamura, S.; Kobayashi, S. Chem. Commun.
1996, 183.
Mikami, K.; Kotera, O.; Motoyama, Y.; Sakaguchi, H.;
Maruta, M. Synlett 1996, 171.
Kobayashi, S.; Moriwaki, M.; Hachiya, I. Bull. Chem. Soc.
Jpn. 1997, 70, 267.
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significantly to lower its catalytic activity (Table 1, entry 10),
(2) hydrolysis of lanthanide compounds is very slow (see
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Synthesis 1999, No. 4, 603–606 ISSN 0039-7881 © Thieme Stuttgart · New York