Equatorial preference in the C-H activation of cycloalkanes: GaCl 3-catalyzed aromatic alkylation reaction

Article abstract of DOI:10.1021/jo030093d

GaCl₃ catalyzes the aromatic alkylation of naphthalene or phenanthrene using cycloalkanes. The C-C bond formation predominantly takes place at the least hindered positions of the substrates, and equatorial isomers regarding the cycloalkane moiety are generally obtained. The reaction of bicyclo[4.4.0]decane and naphthalene occurs at the 2-position of naphthalene and at the 2- or 3-carbons of the cycloalkane, and the products possess a trans configuration at the junctures and an equatorial configuration at the naphthyl groups. Notably, cis-bicyclo[4.4.0]decane turns out to be much more reactive than the trans isomer, and a turnover number "TON" up to 20 based on GaCl₃ is attained. 1,2-Dimethylcyclohexane reacts similarly, and the cis isomer is more reactive than the trans isomer. Monoalkylcycloalkanes react at the secondary carbons provided that the alkyl group is smaller than tert-butyl. Adamantanes react at the tertiary 1-position. The alkylation reaction is considered to involve the C-H activation of cycloalkanes with GaCl₃ at the tertiary center followed by the migration of carbocations and electrophilic aromatic substitution yielding thermodynamically stable products. The stereochemistry of the reaction reveals that GaCl ₃ activates the equatorial tertiary C-H bond rather than the axial tertiary C-H bond.

Full text of DOI:10.1021/jo030093d

Equ a tor ia l P r efer en ce in th e C-H Activa tion of Cycloa lk a n es:
Ga Cl3-Ca ta lyzed Ar om a tic Alk yla tion Rea ction
Fumi Yonehara, Yoshiyuki Kido, Hiraku Sugimoto, Satoshi Morita, and
Masahiko Yamaguchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aoba, Sendai 980-8578, J apan
yama@mail.pharm.tohoku.ac.jp
Received March 14, 2003
GaCl3 catalyzes the aromatic alkylation of naphthalene or phenanthrene using cycloalkanes. The
C-C bond formation predominantly takes place at the least hindered positions of the substrates,
and equatorial isomers regarding the cycloalkane moiety are generally obtained. The reaction of
bicyclo[4.4.0]decane and naphthalene occurs at the 2-position of naphthalene and at the 2- or
3-carbons of the cycloalkane, and the products possess a trans configuration at the junctures and
an equatorial configuration at the naphthyl groups. Notably, cis-bicyclo[4.4.0]decane turns out to
be much more reactive than the trans isomer, and a turnover number “TON” up to 20 based on
GaCl3 is attained. 1,2-Dimethylcyclohexane reacts similarly, and the cis isomer is more reactive
than the trans isomer. Monoalkylcycloalkanes react at the secondary carbons provided that the
alkyl group is smaller than tert-butyl. Adamantanes react at the tertiary 1-position. The alkylation
reaction is considered to involve the C-H activation of cycloalkanes with GaCl3 at the tertiary
center followed by the migration of carbocations and electrophilic aromatic substitution yielding
thermodynamically stable products. The stereochemistry of the reaction reveals that GaCl3 activates
the equatorial tertiary C-H bond rather than the axial tertiary C-H bond.
Aromatic hydrocarbons are generally alkylated using
alkenes or alkyl halides in the presence of a protic acid,
a Lewis acid,1 or a transition-metal complex2 as catalyst.
The alkylation of arenes with alkanes, which converts
an aliphatic C-H bond to a C-Ar bond, is more conve-
nient, if it can be performed effectively. Such reactions
in the presence of stoichiometric amounts of sacrificing
reagents, organohalogen compounds or alkenes, have
been reported.3 For example, the reaction of benzene,
methylcyclohexane, and 1,2-dichloro-2-methylpropane in
the presence of a catalytic amount of AlCl3 yields meth-
ylphenylcyclohexanes in which the organohalogen com-
pound serves as a hydride acceptor. Aromatic alkylation,
which proceeds via the C-C bond cleavage of alkane, is
known as “destructive alkylation”:4 2,2,4-trimethylpen-
tane and benzene react in the presence of a catalytic
amount of AlCl3 to yield tert-butylbenzene and isobutane.
A few examples of the direct arylation of alkanes, which
do not use a sacrificing reagent or a “destructive alky-
lation” methodology, have been reported.5-9 For example,
treating a mixture of benzene and isopentane with CuCl2
and AlCl3 gives pentylbenzenes.7 Benzene is alkylated
with C1-C5 alkanes in the presence of anhydrous fluo-
roantimonic acid (HF-SbF5).6 The efficiencies of these
reactions, however, are not high; more than stoichiomet-
ric amounts of a Lewis acid or protic acid promoter are
employed. During our studies on the development of
novel aromatic C-C bond-forming reactions using GaCl3,10
we found that the gallium compound catalyzes aromatic
alkylation using cycloalkanes.11 GaCl3 activates the
equatorial tertiary C-H bond of cycloalkanes to generate
tertiary cations, which after migration undergo electro-
philic substitution with aromatic hydrocarbons.
(5) (a) Miethchen, R.; Kro¨ger, C.-F., Z. Chem. 1975, 135-141. (b)
Miethchen, R.; Steege, S.; Kro¨ger, C.-F. J . Prakt. Chem. 1983, 325,
823-834. Also see references cited therein.
(6) Olah, G. A.; Schilling, P.; Staral, J . S.; Halpern, Y.; Olah. J . A.
J . Am. Chem. Soc. 1975, 97, 6807-6810.
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P.; Mathy, A.; Me´tra, P. Helv. Chim. Acta 1985, 68, 1196-1203.
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Chem. 1997, 33, 689-693.
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New York, 1973. (b) Taylor, R. Electrophilic Aromatic Substitution;
J ohn Wiley & Sons: New York, 1990.
(2) Recent examples: (a) Matsumoto, T.; Taube, D. J .; Periana, R.
A.; Taube, H.; Yoshida, H. J . Am. Chem. Soc. 2000, 122, 7414-7415.
(b) Nishiyama, Y.; Kakushou, F.; Sonoda, N. Bull. Chem. Soc. J pn.
2000, 73, 2779-2782. (c) Singh, R. P.; Kamble, R. M.; Chandra, K. L.;
Saravanan, P.; Singh, V. K. Tetrahedron 2001, 57, 241-247.
(3) (a) Schmerling, L.; Welch, R. W.; West, J . P. J . Am. Chem. Soc.
1956, 78, 5406-5409. (b) Schmerling, L.; Welch, R. W.; Luvisi, J . P. J .
Am. Chem. Soc. 1957, 79, 2636-2642. Also see references cited.
(4) (a) Grosse, A. V.; Ipatieff, V. N. J . Am. Chem. Soc. 1935, 57,
2415-2419. (b) Grosse, A. V.; Ipatieff, V. N. J . Org. Chem. 1937, 2,
447-458. (c) Grosse, A. V.; Mavity, J . M.; Ipatieff, V. N. J . Org. Chem.
1938, 3, 137-145. (d) Sugahara, Y.; Hayami, J .; Sera, A.; Goto, R..
Bull. Chem. Soc. J pn. 1969, 42, 2656-2662.
(10) (a) Yamaguchi, M.; Kido, Y.; Hayashi, A.; Hirama, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1313-1315. (b) Kido, Y.; Yamaguchi,
M. J . Org. Chem. 1998, 63, 8086-8087. (c) Kido, Y.; Yoshimura, S.;
Yamaguchi, M.; Uchimaru, T. Bull. Chem. Soc. J pn. 1999, 72, 1445-
1458. (d) Yonehara, F.; Kido, Y.; Yamaguchi, M. Chem. Commun. 2000,
1189-1190. (f) Kido, Y.; Yonehara, F.; Yamaguchi, M. Tetrahedron
2001, 57, 827-833.
(11) Preliminary publication: Yonehara, F.; Kido, Y.; Morita, S.;
Yamaguchi, M. J . Am. Chem. Soc. 2001, 123, 11310-11311.
10.1021/jo030093d CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/31/2003
6752
J . Org. Chem. 2003, 68, 6752-6759

Equatorial Preference in the C-H Activation of Cycloalkanes
SCHEME 1 a
SCHEME 2
a
Key: (a) The yield is based on GaCl3. The yield based on 2 is
shown in parentheses. (b) GaCl3 (5 mol %) was used. (c) GaCl3
(2.5 mol %) was used.
2) at 70 °C for 12 h, monoalkylated products 3 and 4
(4:1) were obtained in 1188% yield and dialkylated
products in 423% yield, “TON” 20.3 (Scheme 1). In
contrast, trans-1 gave 3 and 4 in only 11% yield, “TON”
0.1, which indicates that cis-1 is much more reactive in
this C-C bond formation than trans-1. Despite the
different stereochemistries of the starting materials, cis-1
or trans-1, the same products 3 and 4 with trans
configurations at the juncture were obtained. This ob-
servation strongly suggests that the initially activated
bond is one of the two tertiary C-H bonds in cis-1 and
the migration of the resulting carbocations takes place
during the reaction. In accordance, cis-1 isomerized to
A 2:1 mixture of bicyclo[4.4.0]decane 1 (a 1:1 mixture
of cis-1 and trans-1) and naphthalene 2 was heated at
70 °C with GaCl3 (5 mol % based on 2) for 40 h. After
aqueous workup, the crude product was heated in re-
fluxing 1-methylnaphthalene 6 in the presence of Pd/C
in order to dehydrogenate small amounts of tetrahy-
dronaphthalenes formed; for example, ca. 170% (based
on GaCl3) of 1,2,3,4-tetrahydronaphthalene was de-
tected in the crude product. (Decahydronaphthyl)naph-
thalenes 3 and 4 (590% yield based on GaCl3, 30% yield
based on 2) were obtained in a 6:1 ratio and were
accompanied by bis(decahydronaphthyl)naphthalenes 5
(237% based on GaCl3, 12% yield based on 2) (Scheme
1).12 No product derived from the reaction at the tertiary
carbon atom of 1 was detected. It should be noted that
the turnover number “TON” of the reaction based on
GaCl3 is 10.6, if that of the dialkylation is calculated to
be 2. In the following part of this paper, the yield
based on GaCl3 and the “TON” are used for discussion.
Some part of hydrogen that is formed from 1 and 2
may be incorporated in tetrahydronaphthalene. The
contamination of small amounts of cycloalkenes in 1 is
excluded, since the hydrocarbon washed with concen-
trated sulfuric acid also undergoes the same reaction. The
molecular formula of the 3/4 mixture was confirmed by
elemental analysis. The treatment of the mixture with
excess 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
in refluxing toluene for 3 h yielded 2,2′-binaphthalene
(27%) and 1,2′-binaphthalene (12%). This result indicates
that C-C bond formation predominantly occurs at the
2-position of 2 and at the 3-position of 1, which is
accompanied by a minor product that reacts at the
2-position of 1. The coupling constants (tt, J ) 12.0, 3.6
Hz) of the benzylic proton of 3 and those (td, J ) 11.6,
2.8 Hz) of 4 show the equatorial configurations of the
naphthyl groups. The juncture stereochemistry of 3 was
determined by comparison with an authentic compound.
A mixture of 3 and its 3-epimer was obtained from trans-
2-decalone13 and 2-naphthylmagnesium bromide followed
by reduction using triethylsilane and boron trifluoride
(Scheme 2). The cis isomers were also synthesized for
comparison.
14
trans-1 in the presence of a catalytic amount of GaCl3.
When a solution of GaCl3 (2.5 mol %) in cis-1 was heated
at 70 °C for 40 h, a 1.3:1.0 mixture of cis-1 and trans-1
was obtained, and a 1.0:14.2 mixture was obtained after
heating for 70 h.
The alkylation of methylnaphthalenes 6 and 8, 2-chlo-
ronaphthalene 11, and phenanthrene 12 using 1 (cis/
trans ) 1:1) was also conducted (Table 1). Monoalky-
lated products were obtained in more than 400% yield,
and their “TON” exceeded 7 in all cases. The reac-
tions takes place at the 3-position of 1 preferentially
and at the â-positions of naphthalenes giving thermo-
dynamically stable compounds: 6 reacts at the 3-posi-
tion predominantly giving 7 (entry 1); 8 at the 6-
and 7-positions in a 2:1 ratio (entry 2); 12 at the 2-
and 3-positions in a 1:2 ratio (entry 4). It was pre-
sumed that 11 reacted at the 6- and 7-positions by
analogy to the reaction with adamantane (vide infra). The
structures of the major products were determined un-
ambiguously by converting the products to partially
dehydrogenated compounds of single isomers. For ex-
ample, the treatment of monoalkylated product 7 derived
(12) We previously reported that the monoalkylated products ob-
tained from 1 and 2 are a 1:2.4 mixture of two isomers and that the
major compound was 2-(cis-decahydronaphthalen-3-yl)naphthalene 3.11
Detailed investigations shown in the present work revealed that the
two isomers are 3 and 4.
(13) Trimethyl[trans-(3,4,4a,5,6,7,8,8a-octahydro-2-naphthalenyl)-
oxyl]silane was synthesized by the reported method. Crabtree, S. R.;
Mander, L. N.; Sethi, S. P.; Org. Synth. 1992, 70, 256-264. trans-2-
Decalone was obtained by the hydrolysis of the silyl enol ether using
tetrabutylammonium fluoride in THF and water. cis-2-Decalone was
synthesized by the hydrogenation of 2-naphthol. Gream, G. E.; Laffer,
M. H.; Serelis, A. K. Aust. J . Chem. 1978, 31, 803-833.
When isomerically pure cis-1 was reacted with 2 (molar
ratio 2:1) in the presence of GaCl3 (2.5 mol % based on
J . Org. Chem, Vol. 68, No. 17, 2003 6753

Yonehara et al.
SCHEME 3 a
TABLE 1. Ga Cl3 Ca ta lyzed Ar yla tion of 1 w ith
Su bstitu ted Na p h th a len e
a
Key: (a) The reaction was carried out with irradiation using
a high-pressure mercury lamp (400 W). (b) The yield is based on
GaCl3. The yield based on 16 is shown in parentheses.
Alkylation using monoalkylcyclohexanes was examined
(Table 2). The reaction of methylcyclohexane 18 and 2
(molar ratio 4.7:1.0) gave a mixture of monoalkylated
naphthalenes 19, 20, and 21 (246%) in a ratio of 1:5:4,
which were isomers in terms of the 2-, 3-, and 4-positions
of the cycloalkane, respectively. Dialkylated naphtha-
lenes (42%) were also formed, “TON” 3.3 (entry 1). The
treatment of the monoalkylated compounds with excess
DDQ in refluxing toluene for 0.5 h gave a mixture of
2-(methylphenyl)naphthalenes (o/m/p ) 1:3:1), the struc-
tures of which were confirmed by comparison with those
of the authentic samples prepared from 2-bromonaph-
thalene and tolylmagnesium bromides. 1H NMR indi-
cated that all the naphthyl groups of 19, 20, and 21
occupy the equatorial position (benzylic H, J ) ca. 10 Hz).
Since previous 13C NMR studies of methylcyclohexanes
have revealed that equatorial methyl carbons are gener-
ally observed at >δ 20,15 the methyl groups of 19, 20,
and 21 observed at δ 21.0, 22.9, 23.8, respectively, are
likely to have the equatorial orientation.
The yield decreases as the alkyl group on the alkylcy-
clohexane becomes bulky from methyl to isopropyl, and
essentially no reaction occurs with tert-butylcyclohexane
24 (entries 1-4). The reactivity may be correlated to the
amount of axial conformers that possess tertiary equato-
rial protons (vide infra). Since neopentylcyclohexane 25
is also unreactive (entry 5), the low reactivity of 24 may
not be due to the steric hindrances at the vicinity of the
tertiary C-H bonds. Methylcyclopentane 26 and meth-
ylcycloheptane 27 exhibit reactivity similarly to 18
(entries 6 and 7). In contrast, the reaction of cyclohexane
28 gave a very low yield of naphthylcyclohexane 29,
which confirms that the tertiary C-H bond is necessary
for the present reaction.
a
The yield is based on GaCl3. The yield based on naphthalene
b
is shown in parentheses. The structure of the major isomer is
shown. c cis-1 was used.
The reaction of acyclic hydrocarbons was examined
using 2,3-dimethylbutane, isobutane, and methane (Table
3). The reaction of excess isobutane and 2 gave 2-(tert-
butyl)naphthalene in 20% yield and bis(tert-butyl)naph-
thalene in 2% yield (entry 1). Addition of oxygen slightly
increased the yield of the product (entry 2), which again
suggests the partial radical feature of the present reac-
tion. Alkylation of 2 with 2,3-dimethylbutane gave 2,3-
dimethyl-2-(2-naphthyl)butane 30 in 28% yield (entry 3).
These reactions competed with the oligomerization of 2.
The C-C bond formation occurred at the tertiary carbon
from 1 and 6 with DDQ in refluxing toluene for 1 h gave
3-(5,6,7,8-tetrahydro-2-naphthyl)-1-methylnaphthalene 15
as the major product, the structure of which was deter-
mined by NOE.
The condensed benzene ring system is required for the
effective reaction, and only a trace amount (2%) of
monoalkylated product 17 was obtained by the reaction
of 1 and m-xylene 16 (Scheme 3). 16 reacts at the least
hindered 5-position and gives 17 with an equatorial aryl
group (benzylic H, tt, J ) 12.0, 3.6 Hz). The juncture
trans stereochemistry of 17 was determined by compari-
son with an authentic compound prepared by the method
shown in Scheme 2. Irradiation with UV light improves
the yield of 17 to 26%, which suggests a partial radical
feature of this reaction.
(14) (a) Zelinsky, N.; Turowa-Pollak, M. Ber. 1932, 65B, 1299-1301.
(b) Davies, G. F.; Gilbert, E. C. J . Am. Chem. Soc. 1941, 63, 1585-1586.
(15) (a) Dalling, D. K.; Grant, D. M. J . Am. Chem. Soc. 1967, 89,
6612-6622. (b) Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectros-
copy, 3rd completely revised ed.; VCH: Weinheim, 1987. (c) Schneider,
H.-J .; Price, R.; Keller, T. Angew. Chem. 1971, 83, 759-760. (d)
Schneider, H.-J .; Hoppen, V. J . Org. Chem. 1978, 43, 3866-3873.
6754 J . Org. Chem., Vol. 68, No. 17, 2003

Equatorial Preference in the C-H Activation of Cycloalkanes
TABLE 2. Na p h th yla tion of Mon oa lk ylcycloa lk en es
TABLE 3. Na p h th yla tion of Acyclic Alk a n es
a
b
The yield is based on GaCl3. A 1:1 mixture of 2,6- and 2,7-
bis(tert-butyl)naphthalene was formed in 2%. c O2 (ca 0.3 mol) was
added. Benzene was used as solvent. e The yield was determined
d
by GC.
hexanes were examined (Table 4). When 2 and 1,2-
dimethylcyclohexane 31 (cis/trans ) 1:1) were reacted
with GaCl3 (5 mol %), monoalkylated products containing
2-(3,4-dimethylcyclohexyl)naphthalene 32 and 2-(2,3-
dimethylcyclohexyl)naphthalene 33 were obtained in
517% yield, which was accompanied by dialkylated
products in 124% yield, “TON” 7.7 (entry 1). The
monoalkylation products were 4 major isomers in a 5:2:
2:1 ratio as determined by GC, namely, 32, 33, and their
stereoisomers. Their regiochemistry was determined by
dehydrogenation to give a mixture of 2-(3,4-dimethyl-
phenyl)naphthalene and 2-(2,3-dimethylphenyl)naphtha-
lene in a 3.6:1 ratio in 48% yield. Their stereostructures
were determined by NMR. The benzylic protons of all the
four isomers exhibited coupling constants J ) ca. 12 Hz,
which indicated the equatorial orientation of the naph-
thyl groups. The methyl groups of the monoalkylated
products appeared at δ 20-25 indicating the equatorial
configuration, and small peaks at δ 14.3 and 17.7
suggested the presence of axial isomers. Thus, the major
isomers should be 32 and 33 with an all equatorial
configuration. As in the reaction of 1, cis-31 gave products
with “TON” 7.9 (entry 2), while trans-31 gave monoalky-
lated products in only 37% yield, “TON” 0.4 (entry 3).
GC analysis indicated that the cis-31 and trans-31 gave
the same composition of the products.
a
The yield is based on GaCl3. The yield based on naphthalene
b
is shown in parentheses. Isomer ratio regarding the methyl
position of cycloalkanes. c GaCl3 (10 mol %) was used. GaCl3 (5
d
mol %) was used. e GaCl3 (200 mol %) was used.
When 1,3-dimethylcyclohexane 34 (cis/trans ) 1:1) and
2 were reacted with GaCl3 (10 mol %), monoalkylated
products were obtained in 176% yield, which was ac-
companied by dialkylated products in 18% yield, “TON”
2.1 (entry 4). The dehydrogenation of monoalkylated
naphthalenes provided a mixture of 2-(3,5-dimethylphe-
nyl)naphthalene and 2-(2,4-dimethylphenyl)naphthalene
in a 5.4:1 ratio in 31% yield. The monoalkylated product
contained six isomers in a ratio of 10:5:2:2:1:1, as
determined by GC; the most major isomer was 2-(3,5-
in both cases, and no product reacted at the methyl
moiety was detected. In terms of “TON”, acyclic alkanes
are less reactive than cyclic alkanes, even though they
both possess tertiary C-H bonds. The presence of not
only the tertiary C-H bond but also the configurationally
fixed adjacent C-C bond appears to be critical for
effective C-H activation. It may be noted that a small
amount of 2-methylnaphthalene was detected, when 2
was treated with methane (190 atm) at 180 °C in benzene
(entry 4).16
(16) See the following for a related reaction, which is considered to
proceed via a radical mechanism. He, S. J . X.; Long, M. A.; Attalla, M.
I.; Wilson, M. A. Energy Fuels 1992, 6, 498-502.
To probe the effect of stereochemistry at the tertiary
C-H bond of cycloalkanes, the reactions of dialkylcyclo-
J . Org. Chem, Vol. 68, No. 17, 2003 6755

Yonehara et al.
TABLE 4. Na p h th yla tion of Dia lk ylcycloa lk en es
The reaction of 1,4-dimethylcyclohexane 37 (cis/trans
) 1:1) gave a monoalkylated product 38 in 190% yield
as a single isomer and dialkylated products in 23% yield,
1
“TON” 2.4 (entry 7). The H NMR of 38 at the benzylic
proton (td, J ) 11.2, 3.2 Hz) and the 13C NMR of the
5-methyl δ 22.7 showed that both naphthyl and methyl
groups occupied the equatorial positions. cis-37 gave the
products at a higher “TON” than trans-37. Thus, all these
experiments using dimethylcyclohexanes reveal that the
substrates with an axial methyl group, that is, those with
an equatorial tertiary C-H bonds are more reactive.
The reaction of 1-(tert-butyl)-4-methylcyclohexane 39
(cis/trans ) 1:1) and 2 gave a monoalkylated product 40
in 188% yield as a single isomer (entry 10). The C-C
bond formation takes place at the less hindered secondary
1
carbon, and the H NMR of the benzylic proton (td, J )
11.2, 3.6 Hz) indicates the equatorial configuration of
both methyl and naphthyl groups. Since the tert-butyl
group should be equatorial, 40 possesses an all equatorial
configuration.
The reactivity of adamantane 41 was considered
interesting, since all the tertiary C-H bonds of 41 occupy
an equatorial position (Table 5). An equimolar amount
of 2 and 41 in cyclohexane was reacted in the presence
of GaCl3 (5 mol %) at 70 °C for 12 h, and the crude
products were heated for 4 h in refluxing 1-methylnaph-
thalene 6 in the presence of Pd/C for dehydrogenation.
2-(1-Adamanty)naphthalene 42 was obtained in 267%
yield, and 2,7-bis(1-adamantly)naphthalene 43 in 11%
yield, “TON” 2.9 (entry 1). Since 41 has a relatively high
melting point, cyclohexane was used as a solvent, which
was inert to the arylation reaction (Table 2, entry 8). C-C
bond formation occurred at the 2-position of 2 and at the
1-position of 41. The structure of 43 was determined by
the presence of six aromatic 13C NMR peaks: The 2,6-
isomer should exhibit five peaks. Notably, 41 reacts only
at the tertiary C-H bond, which is different from the
reactions of cycloalkanes at the secondary carbons. The
regioselectivity of the reaction may be ascribed to the low
tendency of a 1-adamantyl cation to isomerize to a
secondary cation.17 Methyladamantanes 44, 46, and 48
react analogously at tertiary centers (entries 2-4). In the
reaction of 2-chloronaphthalene 11 and 41, the crude
product was treated with DDQ for dehydrogenation
instead of Pd/C in order to avoid hydrogenolysis of the
C-Cl bond (entry 5). A 1:1 mixture of 6-chloro and
7-chloro derivatives 50 and 51 was obtained, the struc-
tures of which were determined by careful 1H NMR
analysis. The results of the adamantane reactions are
consistent with the mechanism that GaCl3 activates the
tertiary equatorial C-H bond to generate carbocations.
The reactivity of the substituted cyclohexanes in the
present arylation reaction is summarized in Figure 1. The
disubstituted cyclohexanes possessing the equatorial
C-H bonds exhibit higher “TON”s than the isomers:
cis-1 . trans-1; cis-31 . trans-31; trans-34 > cis-34; cis-
37 > trans-37. That the reactivity of monosubstituted
cyclohexanes decreases as the bulkiness of the substitu-
ent increases is consistent with the explanation. It may
a
The yield is based on GaCl3. The yield based on aromatic
b
compound is shown in parentheses. The structure of the
major isomer is shown. c GaCl3 (5 mol %) was used. A 1:1 mixture
d
of cis isomer and trans isomer was used. e GaCl3 (5 mol %) was
used.
dimethylcyclohexyl)naphthalene 35 with an all equatorial
configuration, and the second major isomer was 2-(2,4-
dimethylcyclohexyl)naphthalene 36. The benzylic proton
of 35 was observed as a tt (J ) 12.0, 3.6 Hz) and that of
36 as a td (J ) 12.0, 3.6 Hz). 13C NMR indicated that
the methyl groups of 35 and 36 occupied equatorial
positions: 35 at δ 22.8; 36 at δ 20.9 and 22.9. As for the
effect of stereochemistry, trans-34 gave the monoalky-
lated naphthalenes in 264% yield and the dialkylated
naphthalenes in 15%, “TON” 2.9 (entry 6), while cis-34
gave the same monoalkylated naphthalenes in 84% yield,
“TON” 0.8 (entry 5). Thus, trans-34 is more reactive than
cis-34, which is contrasted to the higher reactivity of cis-
31 than of trans-31.
(17) (a) Schleyer, P. v. R.; Lam, L. K. M.; Raber, D. J .; Fry, J . L.;
McKervey, M. A.; Alford, J . R.; Cuddy, B. D.; Keizer, V. G.; Geluk, H.
W.; Schlatmann, J . L. M. A. J . Am. Chem. Soc. 1970, 92, 5246-5247.
(b) Aubry, C.; Holmes, J . L.; Walton, J . C. J . Phys. Chem. A 1998, 102,
1389-1393.
6756 J . Org. Chem., Vol. 68, No. 17, 2003

Equatorial Preference in the C-H Activation of Cycloalkanes
TABLE 5. Na p h th yla tion of Ad a m a n ta n es
F IGURE 1. Reactivity of substituted cycloalkanes.
SCHEME 4
a
The yield is based on GaCl3. The yield based on 2 is shown in
parentheses. b 2,7-Bis(1-adamantyl)naphthalene 43 was formed in
11(0.6%) yield.
-
ates the tertiary cation 52 with a counteranion HGaCl3
.
be likely that small amounts of axial conformers with the
equatorial C-H are the reactive species in the reactions
of 18, 22, and 23. The low reactivity of 24 and 25 can be
attributed to the extremely low concentration of axial
conformers. It was noted that the presence of adjacent
tertiary carbons with the cis-configuration enhances
reactivity: cis-1 and cis-31 are more reactive than trans-
34 and cis-37. This may be rationalized by cation migra-
tion, which readily takes place between adjacent tertiary
carbons.18
Our previous studies suggest that, in the presence of
GaCl3, otherwise unstable carbocations gain a longer
lifetime.10 The interaction of the gallate anion probably
stabilized the cation center. Then, 52 isomerizes to the
secondary cation 53, which is attacked by aromatic
hydrocarbons to give the arenium cation 54. GaCl3 is
-
regenerated by the hydride attack of HGaCl3 at the
acidic proton of 54 giving the aromatized 3 and hydrogen.
When the hydride attacks 54 at the aromatic ring,
partially hydrogenated products are formed. The cy-
cloalkyl group can also migrate as well as the carbocation
under the present conditions: The treatment of 1-(1-
methylcyclohexyl)-naphthalene with GaCl3 (40 mol %) in
cyclohexane for 40 h at 70 °C gave 2-(methylcyclohexyl)-
naphthalenes in 50% yield based on GaCl3 as a mixture
of three isomers in a 1:3:2 ratio (Scheme 5). The product
A possible mechanism of the present arylation reaction
is shown in Scheme 4. The initial activation of the
equatorial tertiary C-H bond of cis-1 with GaCl3 gener-
(18) (a) Olah, G. A.; Lukas, J . J . Am. Chem. Soc. 1968, 90, 933-
938. (b) Olah, G. A.; Liang, G.; Westerman, P. W. J . Org. Chem. 1974,
39, 367-369.
J . Org. Chem, Vol. 68, No. 17, 2003 6757

Yonehara et al.
SCHEME 5
ratio and the stereochemistry are identical to those
obtained from methylcyclohexane 18 and 2 (Table 2,
entry 1). Another C-H activation mechanism involves
the protonation of cis-1 via HGaCl4 formed from small
amounts of HCl and GaCl3. In this case, the counteran-
-
ions for 52, 53, and 54 should be GaCl4
.
An interesting aspect of the present reaction is the
origin of the selective C-H activation being the equato-
rial tertiary C-H bond, and several possible explanations
are presented (Figure 2). (1) If it can be assumed that
GaCl3 (or HGaCl4) gains access to the tertiary C-H bond
via a similar trajectory with transition metals,19 an
approach from the side of C-H, the axial C-H may be
more hindered by the 1,3-diaxial repulsions than the
equatorial C-H. (2) The tertiary cation derived from cis-1
can be more stable because of hyperconjugative stabiliza-
tion by the adjacent C-C bond, and therefore, the
transition state for the hydride abstraction from the
equatorial site is preferred.20 (3) The different reactivities
of cis- and trans-1 can be attributed to the different
F IGURE 2. Possible explanations of the equatorial selectivity.
SCHEME 6
-
stabilities of the carbocation/HGaCl3 (or GaCl4-) ion
TABLE 6. Deu ter a tion of 1-Meth yln a p h th a len e 6
pairs. Such ion-pair effect was suggested in the solvolysis
of cis- and trans-9-chlorodecalins yielding different prod-
ucts.21 A preference for the equatorial C-H activation
in C-H oxidation has precedents: cis-1 is hydroxylated
with p-nitroperbenzoic acid 1.5 times faster than trans-
1;22 cis-1 reacts with methyl(trifluoromethyl)dioxirane
twice faster than trans-1.23 The equatorial selectivity in
the present reaction, however, is much higher.
total
partial deuteration ratiob (%)
GaCl3 yield deuteration
(equiv) (%)
ratioa/%
2-H 3-H 4-H 5-H 6,7-H 8-H
Although the above cycloalkane activation mechanism
appears likely at present, an alternative mechanism is
conceivable, which involves the initial activation of arene
by GaCl3. GaCl3 is known to interact with aromatic
hydrocarbons as indicated by multinuclear NMR, Raman,
and UV/vis spectroscopies.24 We noticed a novel deute-
riation reaction of GaCl3-complexed arene. A solution of
naphthalene 2 and GaCl3 (molar ratio 1:2) in methylcy-
clohexane was stirred for 1 h at room temperature, and
was then treated with D2O. 2-d was recovered in 36%
yield with 270% deuteriation at both R- and â-positions
1.0
3.0
77
87
156 (135)
218 (202)
22
30
25
38
27
33
22
32
40
60
20
30
a
Determined by 1H NMR. The ratio obtained by 2H NMR is
shown in parentheses. Determined by 1H NMR.
b
also gave 2-d in 48% yield and deuteriation in 228% (R/â
) 1:1). Accordingly, this deuteriation is not the result of
a known aromatic H-D exchange25 under acidic condition
but is likely to be derived from the protiodegallation of
the C-Ga bond. Quenching with THF followed by D2O
treatment gave no deuterated naphthalene, which may
be consistent with the above explanation. The relatively
low yields of 2-d are due to competitive oligomerization.
When the alkaline deuteriation experiment was con-
ducted with 6 in cyclohexane, the yield improved (Table
6). All the aromatic hydrogens on the naphthalene ring
2
(1:1) as determined by H NMR (Scheme 6). Addition of
the reaction mixture to 2 M sodium deuterioxide in D2O
(19) (a) Williams, J . M.; Brown, R. K.; Schultz, A. J .; Stucky, G. D.;
Ittel, S. D. J . Am. Chem. Soc. 1978, 100, 7407-7409. (b) Crabtree, R.
H.; Holt, E. M.; Lavin, M.; Morehouse, S. M. Inorg. Chem. 1985, 24,
1986-1992. Also see references cited therein.
(20) Gonza´lez-Nu´n˜ez, M. E.; Castellano, G.; Andreu, C.; Royo, J .;
Ba´guena, M.; Mello, R.; Asensio, G. J . Am. Chem. Soc. 2001, 123,
7487-7491. Also see references cited therein.
(21) (a) Boschung, A. F.; Geisel, M.; Grob, C. A. Tetrahedron Lett.
1968, 50, 5169-5172. (b) Gream, G. E. Aust. J . Chem. 1972, 25, 1051-
1079.
1
were equally deuterated as determined by H NMR and
2H NMR spectroscopies employing 1,3,5-trimethylben-
zene and dimethyl sulfoxide-d6 as internal standards,
respectively. The methyl group was not deuterated as
indicated by 2H NMR. Analogously, the reaction of
(22) Schneider, H.-J .; Mu¨ller, W. J . Org. Chem. 1985, 50, 4609-
4615.
(23) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J . Am. Chem. Soc.
1989, 111, 6749-6757.
(24) Ulvenlund, S.; Wheatley. A.; Bengtsson. L. A. J . Chem. Soc.,
Dalton Trans. 1995, 255-263.
(25) (a) Mackor, E. L.; Smit, P. J .; van der Waals, J . H.; Trans.
Faraday. Soc. 1957, 53, 1309-1316. (b) Lauer, W. M.; Matson, G. W.;
Stedman, G. J . Am. Chem. Soc. 1958, 80, 6433-6437, 6437-6439. Also
see ref 1.
6758 J . Org. Chem., Vol. 68, No. 17, 2003

Equatorial Preference in the C-H Activation of Cycloalkanes
7.75-7.80 (m); 13C NMR (100 MHz, CDCl3) δ 23.5, 26.77, 26.83,
26.9, 31.4, 34.0, 34.1, 34.37, 34.40, 34.6, 35.9, 41.8, 43.1, 43.4,
43.5, 44.7, 48.0, 51.3, 124.4, 124.8, 124.9, 125.6, 126.1, 127.3,
127.40, 127.44, 127.6, 132.0, 132.1, 133.5, 133.6, 143.8, 145.0;
IR (neat) 3053, 2917, 2849, 1633, 1600, 1506, 1446, 852, 815,
742 cm-1; MS (EI, 70 eV) m/z 264 (100, M+), 154 (71), 142 (26),
128 (20); HRMS (EI, 70 eV) calcd for C20H24 264.1877, found
TABLE 7. Deu ter a tion of 1-Meth yln a p h th a len e 6
264.1877 (M+). Anal. Calcd for C20H24
: C, 90.85; H, 9.15.
Found: C, 90.81; H, 9.13. The trans stereochemistry at the
ring juncture was determined by comparison with an authentic
sample, the synthesis of which is described in the Supporting
Information. Dialkylated products 5: 1H NMR (400 MHz,
CDCl3) δ 0.69-0.83 (m), 0.92-1.36 (m), 1.42-1.88 (m), 1.95
(dq, J ) 12.8, 2.4 Hz), 2.31 (br t, J ) 10.4 Hz), 2.71 (br t, J )
12.0 Hz), 7.21-7.34 (m), 7.51 (s), 7.57 (s), 7.70 (dd, J ) 8.4,
3.2 Hz); 13C NMR (100 MHz, CDCl3) δ 15.8, 26.8, 26.9, 31.4,
34.0, 34.1, 34.39, 34.43, 34.5, 34.6, 35.9, 41.8, 43.1, 43.4, 43.5,
44.6, 44.7, 48.1, 51.3, 51.4, 123.96, 124.04, 124.1, 125.16,
125.23, 125.9, 127.18, 127.23, 127.3, 130.65, 130.71, 132.1,
132.19, 132.24, 133.7, 133.8, 142.86, 142.93, 143.65, 143.70,
144.1, 144.2, 144.89, 144.91; IR (neat) 3050, 2919, 2850, 1634,
1605, 1510, 1455, 1374, 837, 813 cm-1; MS (EI, 70 eV) m/z
400 (100, M+), 137 (14), 95 (16), 81 (12); HRMS (EI, 70 eV)
calcd for C30H40 400.3128, found 400.3136 (M+). Anal. Calcd
for C30H40: C, 89.93; H, 10.07. Found: C, 89.89; H, 10.33.
When isomerically pure cis-1 (19.4 mmol) was reacted with 2
(10 mmol) in the presence of GaCl3 (2.5 mol % based on 2) at
70 °C for 12 h, the monoalkylated products (3/4 ) 4:1) were
obtained in 1188% yield and dialkylated products in 423%
yield. trans-1 gave the monoalkylated products (3/4 ) 2:1) in
11% yield.
1,2′-Bin a p h th yl a n d 2,2′-Bin a p h th yl. Under an argon
atmosphere, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)
(1703 mg, 7.5 mmol) was added to a mixture of 2-(decahy-
dronaphthalenyl)naphthalenes 3 and 4 (79 mg, 0.3 mmol, 4:1)
in dry toluene (3 mL), and the mixture was heated at reflux
for 3 h. After the mixture was cooled to room temperature,
saturated aqueous NaHCO3 was added, and the insoluble
materials were removed by passing through Celite. The organic
layer was separated, washed with water, and dried over
MgSO4. Solvents were removed in vacuo, and the residue was
purified by flash column chromatography (silica gel, hexane)
giving 2,2′-binaphthyl (21 mg, 27%) and 1,2′-binaphthyl (9 mg,
12%). The structures were confirmed by comparison with the
authentic samples, the synthesis of which is described in the
Supporting Information.
total
partial deuteration ratiob (%)
GaCl3
(equiv)
yield deuteration
(%)
ratioa(%)
orthoc
metac
para
1.0
3.0
91
95
123 (103)
248 (226)
25
50
24
49
25
50
Determined by 1H NMR. The ratio obtained by 2H NMR is
a
b
shown in parentheses. Determined by 1H NMR. c Normalized
value based on the presence of two protons.
1-phenylhexane resulted in equal extent of deuteriation
at the benzene ring, and no deuteriation at the hexyl
group (Table 7). The lack of selectivity for aromatic
deuteriation suggests the involvement of the protiode-
gallation of GaCl3-arene complexes. Although it is
unclear whether the observation has some relation to the
present aromatic alkylation, it is an interesting property
of GaCl3-arene complexes.
In summary, the arylation of cycloalkanes with aro-
matic hydrocarbons occurs in the presence of a catalytic
amount of GaCl3. This is a novel catalytic reaction that
forms a C-C bond between aromatic and aliphatic
hydrocarbons.
Exp er im en ta l Section
Rea ction of Na p h th a len e 2 a n d Bicyclo[4.4.0]d eca n e
(Deca h yd r on a p h th a len e) 1. Under an argon atmosphere,
a 1.0 M solution of GaCl3 (0.25 mmol) in 1 (cis/trans ) 1:1)
was added to a solution of 2 (640 mg, 5.0 mmol) in 1 (cis/trans
) 1:1) (1.25 mL). The mixture was heated to 70 °C and stirred
for 40 h at that temperature. After the reaction was quenched
by addition of water, the organic layer was separated, washed
with saturated aqueous NH4Cl and water, and dried over
MgSO4. Solvents were removed in vacuo, and the residue was
heated with Pd/C (5%, 530 mg) in refluxing 1-methylnaph-
thalene 6 (0.7 mL) for 2 h. The mixture was diluted with ether
and filtered by passing through Celite. The solvents were
removed in vacuo, and the residue was purified by flash
column chromatography (silica gel, hexane) and GPC giving
monoalkylated products 3 and 4 (390 mg, 590% based on
GaCl3) and dialkylated products 5 (237 mg, 237% based on
GaCl3). 3 and 4:26 GC analysis indicated the presence of the
two isomers in a 6:1 ratio; 1H NMR (400 MHz, CDCl3) δ 0.76-
0.82 (m), 0.99-1.35 (m), 1.47-1.78 (m), 1.81-1.87 (m), 1.94-
1.99 (m), 2.35 (td, J ) 11.6, 2.8 Hz), 2.74 (tt, J ) 12.0, 3.6 Hz),
7.32 (dd, J ) 8.4, 1.6 Hz), 7.36-7.45 (m), 7.57 (s), 7.62 (s),
Ack n ow led gm en t . This work was supportedby
grants from J SPS. Fellowship to F.Y. from J SPS for
young J apanese scientists and the Hayashi Memorial
Foundation for Female Natural Scientists are also
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures and analytical data, references, and H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(26) Gysin, E. Helv. Chim. Acta 1926, 9, 59-67.
J O030093D
J . Org. Chem, Vol. 68, No. 17, 2003 6759