Selective sp3 C-H bond activation based on a carbocation relay: Friedel-Crafts reaction with alkanes as the alkylating component

Article abstract of DOI:10.1002/ejoc.201001118

A highly efficient and selective intramolecular Friedel-Crafts reaction of 3-methylbutyl or 4-methylpentyl-substituted aromatics has been developed using a carbocation relay strategy through selective sp³ C-H bond activation, providing a facile and cost-effective approach for the construction of benzocyclic compounds. A variety of 1,1-dimethylindane and naphthalene derivatives have been prepared from very simple starting materials in good yields with high selectivity. The present strategy has provided a new example of a Friedel-Crafts reaction with alkanes as the alkylating component and constitutes a convenient approach to selective C-H bond activation and functionalization of alkane derivatives. A highly efficient and selective intramolecular Friedel-Crafts reaction of 3-methylbutyl or 4-methylpentyl- substituted aromatics has been developed using a carbocation relay strategy through selective sp³ C-H bond activation. The approach provides a facile and cost-effective route to benzocyclic compounds. Copyright

Full text of DOI:10.1002/ejoc.201001118

FULL PAPER
DOI: 10.1002/ejoc.201001118
Selective sp3 C–H Bond Activation Based on a Carbocation Relay:
Friedel–Crafts Reaction with Alkanes as the Alkylating Component
Jie Wang,[a] Pengfei Zhou,[a] and Yang Wang*[a,b]
Keywords: C-H activation / Friedel-Crafts reaction / Lewis acids / Carbocations / Alkanes / Alkylation
A highly efficient and selective intramolecular Friedel–Crafts
reaction of 3-methylbutyl or 4-methylpentyl-substituted aro-
matics has been developed using a carbocation relay strategy
through selective sp3 C–H bond activation, providing a facile
and cost-effective approach for the construction of benzo-
cyclic compounds. A variety of 1,1-dimethylindane and
naphthalene derivatives have been prepared from very sim-
ple starting materials in good yields with high selectivity. The
present strategy has provided a new example of a Friedel–
Crafts reaction with alkanes as the alkylating component and
constitutes a convenient approach to selective C–H bond ac-
tivation and functionalization of alkane derivatives.
Introduction
Results and Discussion
As a synthetic route to the key intermediate, 4-methoxy-
1,1-dimethylindane (2a), which is used in the synthesis of
analogous anti-HIV molecules,[7] an intramolecular F–C
cyclization of 1-methoxy-2-(3-methyl-2-butenyl)benzene
(1a) in the presence of a Lewis acid was designed. The F–
C reaction of 1a was carried out under the catalysis of
AlCl3/HCl in cyclohexane at room temperature (Scheme 1).
As expected, the normal intramolecular F–C product 2a
was isolated in 30% yield. It is interesting to note that the
reductive product 1-methoxy-2-(3-methylbutyl)benzene
(3a), and cyclohexyl-substituted products 6-cyclohexyl-4-
methoxy-1,1-dimethylindane (4a) and 4-cyclohexyl-2-meth-
oxy-1-(3-methylbutyl)benzene (5a) were simultaneously ob-
tained in yields of 21, 15, and 5%, respectively. The forma-
tion of these by-products clearly indicates that the cyclo-
hexyl cation 8 must be involved in the course of reaction.
However, because neither cyclohexene nor cyclohexyl halide
(or alcohol) is present in the reaction system, it can be de-
duced that the formation of the cyclohexyl cation 8 origi-
nates from the reaction solvent cyclohexane, either by direct
C–H activation with AlCl3/HCl or by hydride abstraction
with an alternative cation. The pathway for direct C–H
bond activation of cyclohexane by AlCl3/HCl was easily ex-
cluded on the basis of experimental facts that no reaction
occurred for 2a or 3a in cyclohexane in the absence of ole-
fins such as cyclohexene or 1a. Therefore, the formation of
cyclohexyl cation 8 must be due to hydride abstraction by
cation 7 from a cyclohexane molecule. As depicted in
Scheme 2, the olefin 1a can be easily protonated in the pres-
ence of AlCl3/HCl to form carbocation 7, which might
either immediately undergo an intramolecular F–C alkyl-
ation to afford the expected cyclization product 2a, or pro-
ceed to hydride abstraction from solvent cyclohexane to af-
ford the reductive product 3a and the cyclohexyl cation 8.
Carbocations are electron-deficient species that are ex-
tremely important intermediates in organic reactions.[1] For
example, it is well-known that carbocations are the key in-
termediate in Friedel–Crafts (F–C) alkylations; alkyl ha-
lides, alkenes, and alcohols usually serve as the alkylating
reagents to form the carbocations under the catalysis of
various acids.[2] Although research into carbocations has
been developing for over 100 years, the field is still continu-
ing to be of major significance in both academia and indus-
try.[3] Recently, research on C–H bond activation has at-
tracted increasing interest.[4] However, most of the reported
work in this area has focused on C–H bond activation of
aromatics,[4] and only very few studies have centered on ac-
tivation of the alkane C–H bond.[5] On the other hand, the
isoparaffin-olefin alkylation catalyzed by various super ac-
ids is a very important process for producing high-octane
alkylates in the petrochemical industry;[6] in this process an
+
intermediate i-C8 cation abstracts a hydride from isobut-
ane to give excellent yields of products and the formed tert-
butyl cation keeps the catalytic cycle going.[6a] In the pres-
ent work, we would like to report a new example of a Frie-
del–Crafts reaction with alkane as the alkylating compo-
nent that operates through sp3 C–H bond activation and
involves a carbocation relay strategy.
[a] Department of Medicinal Chemistry, School of Pharmacy,
Fudan University,
826 Zhangheng Road, Shanghai 201203, P. R. of China
Fax: +86-21-5198-0115
E-mail: wangyang@shmu.edu.cn
ywang.spfdu@gmail.com
[b] State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, P. R. of China
264
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Selective C–H Bond Activation
Further intermolecular F–C alkylation of 8 with 3a and 2a/ uct (49%), the normal cyclized F–C product 4-hydroxy-1,1-
1a yields 5a and 4a, respectively (Scheme 2). On the basis dimethylindane (2b) in 20% yield, and the reductive prod-
of the experimental results mentioned above, it can be con- uct 2-(3-methylbutyl)phenol (3b) in 6% yield. Moreover,
cluded that, in the present reaction system, a carbocation two cyclohexyl-substituted products, 6-cyclohexyl-4-hy-
relay has occurred that involves intermolecular hydride ab- droxy-1,1-dimethylindane (4b) and 5-cyclohexyl-2-(3-meth-
straction from an sp3 C–H bond by a cation, providing an ylbutyl)phenol (5b) were also isolated, albeit with low yields
1
interesting and potentially useful strategy for C–H bond ac- (4 and 3%, respectively). In the H NMR spectrum of 5b,
tivation.
the presence of two doublets and one singlet at the aromatic
field implies that either the C4 or C5 position of the phenyl
ring was substituted by the cyclohexyl group. To identify
the exact position of the cyclohexyl group on the phenyl
ring in product 5b, HMBC spectra were further determined.
The proton of the phenyl ring at δ = 7.02 ppm (doublet)
could be correlated to C-1Ј at δ = 27.42 ppm in the 13C
NMR spectrum, which confirms that the cyclohexyl group
in 5b is situated at the C5-position of the phenyl ring. The
HMBC spectra of 4b clearly show that cyclohexyl substitu-
tion occurs at the meta-position relative to the hydroxyl
group. The formation of products 3b–5b in the reaction of
1b again supports the involvement of cyclohexyl cation 8 in
the reaction system, and this result suggests the possibility
of using alkanes as the alkylating reagent in the Friedel–
Crafts alkylation through a cation relay strategy.
Scheme 1. F–C reaction of the 1-substituted 2-(3-methyl-2-buten-
yl)benzenes 1a–c.
The observed phenomena of hydride abstraction by the
cation (Schemes 1 and 2) prompted us to carry out an intra-
molecular F–C reaction of alkane substrate, 1-methoxy-2-
(3-methylbutyl)benzene (3a), by activation of a sp3 C–H
bond through a cation relay. The formation of cation 8 was
realized by reaction of readily available cyclohexene with
AlCl3/HCl in hexane at room temperature. The cation 8,
generated in situ, was expected to abstract a hydride from
the alkyl aromatic substrate 3a to form the more stable ter-
tiary carbocation 7 and generate the reductive product cy-
clohexane. As shown in Scheme 3, under these experimental
conditions, two intramolecular cyclization products, 4-
methoxy-1,1-dimethylindane (2a) and 6-cyclohexyl-4-meth-
oxy-1,1-dimethylindane (4a), were obtained in 43 and 44%
isolated yields, respectively. In contrast, the intermolecular
‘normal’ alkylation product 5a was only afforded in 5%
Scheme 2. Proposed reaction pathway for the formation of unex-
pected products 3a, 4a, and 5a in the F–C reaction of 1a.
To investigate the generality of the above reaction sys- yield. Incidentally, purification of the products by flash sil-
tem, the F–C reactions of substrates 2-(3-methyl-2-butenyl)- ica gel chromatography could be problematic because TLC
phenol (1b) and 1-methyl-2-(3-methyl-2-butenyl)benzene analysis of compounds 3a/5a reveals almost the same Rf
(1c) were also carried out under the same experimental con- values, and products 2a/4a also exhibit very similar polari-
ditions. As shown in Scheme 1, the reaction of 1c affords ties. After initial attempts to separate the products by HPLC
the intramolecular F–C product 1,1,4-trimethylindane (2c) failed, the demethylation reactions were carried out with
selectively in 82% isolated yield and no other products were BBr3 in CH2Cl2 in good yields. Fortunately, the two de-
observed. On the other hand, the reaction of 1b furnished methylated derivatives could be separated from the mix-
the O-cyclized 2,2-dimethylchromane (6) as the major prod- tures.
Scheme 3. F–C reaction of 1-substituted 2-(3-methylbutyl)benzenes 3a–c by activation of an sp3 C–H bond through a cation relay.
Eur. J. Org. Chem. 2011, 264–270
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265

J. Wang, P. Zhou, Y. Wang
FULL PAPER
Under the reaction conditions described above, the F– none of the products were observed for the reaction of 3a in
C reaction of analogous alkyl aromatics 3b–c was further cyclohexane without cyclohexene under otherwise identical
investigated (Scheme 3). The cyclization of 3b gave the reaction conditions. This experiment further supports the
product 4-hydroxy-1,1-dimethylindane (2b), 6-cyclohexyl-4- involvement of cyclohexene and its related carbocation 8.
hydroxy-1,1-dimethylindane (4b), and 2,2-dimethylchroman The relatively unstable secondary cyclohexyl cation 8 is in-
(6) in the yields of 37, 24, and 15%, respectively. Similarly, clined to be transformed into a more stable tertiary carbo-
the F–C reaction of 3c afforded the cyclic product 2c and cation 7 and regenerate cyclohexane. The resultant carbo-
6-cyclohexyl-1,1,4-trimethylindane (4c) in yields of 46 and cation 7 subsequently undergoes intramolecular F–C alk-
28%, respectively.
ylation to afford cyclization product 2a and then further
In addition, the effect of a methoxy group on the phenyl intermolecular F–C reaction of 2a with cyclohexyl cation
ring on the product distribution was also examined by tak- 8.
ing 1-methoxy-4-(3-methylbutyl)benzene (3d) as the sub-
strate (Scheme 4). Under identical experimental conditions
to those described above, the reaction of 3d in the presence
of cyclohexene afforded two cyclized products, 6-methoxy-
1,1-dimethylindane (2d) and 4-cyclohexyl-6-methoxy-1,1-
dimethylindane (4d), as an inseparable mixture in 45 and
The total yields of the intramolecular F–C reaction of
3a–d using the cation relay strategy can be as high as 61–
87%, indicating the advantageous features of the present
strategy. These examples have provided solid support for
the mechanism of hydride abstraction proposed in
Scheme 5, which demonstrates that not only haloalkanes,
alkenes, and alkanols, but also alkanes can be utilized as
efficient alkylating partners in the F–C reactions.
1
39% yields (determined by H NMR spectroscopic analy-
sis), respectively.
As shown in Schemes 3 and 4, although the F–C reaction
of alkane substrates 3a–d catalyzed by AlCl3/HCl, in the
presence of cyclohexene, were able to give the cyclization
products 2a–d and 4a–d with total yields of 61–87% on
the basis of a cation relay strategy, the intermolecular F–C
reaction of alkane substrates 3 or the further F–C reaction
of primary intramolecular F–C cyclization product 2 with
cyclohexyl cation 8 is still a problematic issue in terms of
the chemoselectivity of the reaction. Therefore, in situ gen-
eration of a primordial carbocation with matched stability
and reactivity is particularly important for a good balance
between the carbocation relay with the alkane substrate and
intermolecular electrophilic reactivity towards aromatics.
Accordingly, we further optimized the olefin additives used
Scheme 4. F–C reaction of 1-methoxy-4-(3-methylbutyl)benzene
(3d) by activation of an sp3 C–H bond through a cation relay.
On the basis of the experimental results described above, to generate the primordial carbocation to improve the
the reaction pathway of 3a is outlined in Scheme 5. It is chemoselectivity of the reaction. As shown in Scheme 6, the
clear that the formation of cyclized products 2a and 4a can addition of either styrene (9a) or 1-hexene (9b) to the reac-
be attributed to the C–H bond activation of 3a by the cyclo- tion of 3a afforded only intermolecular F–C adducts 10a
hexyl cation 8 under the catalysis of AlCl3/HCl. In fact, and 10b (82 and 85%, respectively) without formation of
Scheme 5. Proposed reaction pathway for the F–C reaction of an alkane substrate 3a by activation of its sp3 C–H bond through a cation
relay of 8.
266
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Selective C–H Bond Activation
any of the expected intramolecular F–C cyclization product of AlCl3/HCl or CF3SO3H were applied (Table 1, entries 1
2a by a carbocation relay. It was pleasing to find that (+)- and 4). Notably, the yields of 2a greatly diminished (Ͻ32%)
α-pinene (9c) was able to work well as the primordial carbo- when the acid loading was decreased to 0.5 equiv. and be-
cation precursor in the reaction, affording the intramolecu- low (Table 1, entries 2, 5, and 6). The workup protocol was
lar F–C cyclization product 2a as the sole product, albeit also crucial for the isolated yield of 2a; treating the reaction
in 37% isolated yield with 50% recovery of 3a. The yield of mixture with NaHCO3 (aq.) at 0 °C was found to be better
2a was substantially improved to 81% with complete con- than treatment with H2O at room temperature (Table 1, en-
version of 3a by treating the reaction mixture at room tem- tries 4 and 3).
perature for 17 h then at reflux temperature for 5 h. This
Under the optimized reaction conditions [AlCl3/HCl as
result clearly indicates that the primordial carbocation from the catalyst and (+)-α-pinene as the olefin additives for the
α-pinene (9c) can effectively activate the tertiary C–H bond generation of primordial carbocation], the intramolecular
of 3a to realize the carbocation relay and consequently fur- F–C reaction of various alkyl-substituted benzenes 3b, 3c,
nish the intramolecular F–C reaction. The formation of and 3e were carried out to investigate the substituent effect,
intermolecular F–C product 10c was completely inhibited, affording the corresponding 1,1-dimethylindane derivatives
probably due to the steric hindrance and relatively low reac- 2b, 2c, and 2e in moderate yields without the formation of
tivity of the carbocation formed by α-pinene (9c) towards intermolecular products (Scheme 7). The relatively low
phenyl rings.
yields of 2c and 2e were due to the volatile properties of
their starting materials 3c and 3e.
Scheme 7. F–C reaction of 1-substituted 2-(3-methylbutyl)benzenes
3b, 3c, and 3e under the optimized conditions.
Finally, 1-methoxy-4-(4-methylpentyl)benzene (11), hav-
ing a six-carbon side chain, was examined as a substrate for
the F–C reaction to prepare the 1,2,3,4-tetrahydronaphth-
alene derivative under the optimized reaction conditions
Scheme 6. The influence of olefin additives on the chemoselectivity
of the reaction.
In the present catalytic system, the acid plays a key role
in both the catalytic activity and selectivity. A variety of
acids, including AlCl3/HCl, AlCl3, HCl(g), CH3SO3H,
TsOH, conc. H2SO4, CF3CO2H, CF3SO3H, and Sc(OTf)3
were examined for the reaction of 3a in the presence of α-
pinene (9c) as the primordial carbocation precursor. It was
found that, besides AlCl3/HCl, only CF3SO3H was effec-
tive, affording the expected intramolecular F–C product
(2a) in 60% yield.
The influence of the amount of acid used and of the
workup conditions on the yields of product 2a were also
investigated (Table 1). It was found that 2a was obtained in
Scheme 8. F–C reaction of 1-methoxy-4-(4-methylpentyl)benzene
satisfactory yields (60–81%) when stoichiometric amounts (11) under the optimized conditions.
Table 1. The influence of reaction conditions and workup on the yields of F–C reactions of the substrate 3a with (+)-α-pinene (2 equiv.)
catalyzed by AlCl3 or CF3SO3H.
Entry
Acid
Acid loading [equiv.]
Workup
Isolated yield of 2a [%]
1
2
3
4
5
6
AlCl3/HCl
AlCl3/HCl
CF3SO3H
CF3SO3H
CF3SO3H
1–3
0.5
1
1
20% HCl
20% HCl
H2O/r.t.
NaHCO3 (aq.)/0
NaHCO3 (aq.)/0
–
79–81
32
32
60
27
0.2
CF3SO3H/AlCl3
0.1–0.05/0.1
ND
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267

J. Wang, P. Zhou, Y. Wang
FULL PAPER
(m, 1 H, 3Ј-H), 2.59–2.63 (m, 2 H, 1Ј-H), 3.81 (s, 3 H, CH3O),
6.82–6.89 (m, 2 H, 4-H, 6-H), 7.12–7.22 (m, 2 H, 3-H, 5-H) ppm.
(Scheme 8). Surprisingly, only the naphthalene derivative 13
was isolated in 83% yield, and no expected product 12 was
obtained at all. It is assumed that compound 12 was proba-
bly generated as the primary product and then converted
into the final, stable product 13 after undergoing a methyl
shift and aromatization. When the reaction was carried out
under an argon atmosphere, a compound with molecular
ionic peak at m/z = 190 [M]+ corresponding to the interme-
diate 12 was indeed observed by GC–MS analysis. This ex-
perimental evidence confirmed the assumption discussed
above.
4-Cyclohexyl-2-methoxy-1-(3-methylbutyl)benzene (5a): 1H NMR
(300 MHz): δ = 0.93–0.97 (m, 6 H, CH3 of isopentyl), 1.24–1.48
(m, 7 H, 2Ј-H of isopentyl, 5 H of cyclohexyl), 1.54–1.61 (m, 1 H,
3Ј-H of isopentyl), 1.82–1.90 (m, 5 H of cyclohexyl), 2.37–2.52 (m,
1 H, 1Ј-H of cyclohexyl), 2.55–2.63 (m, 2 H, 1Ј-H of isopentyl),
3.81 (s, 3 H, CH3O), 6.69 (d, J = 7.5 Hz, 1 H, 3-H), 6.71–6.74 (m,
1 H, 5-H), 7.04 (d, J = 7.2 Hz, 1 H, 6-H) ppm. MS (EI): m/z (%)
= 260 (44.06) [M]+, 203 (100), 91 (21.51), 121 (28.76), 204 (16.88),
41 (12.17), 115 (11.25), 117 (10.02). HR-MS: calcd. for C18H28O
260.2140; found 260.2141.
In summary, a highly efficient and selective intramolecu-
lar Friedel–Crafts reaction of 3-methylbutyl-substituted
aromatics has been developed by using a carbocation relay
strategy through selective sp3 C–H bond activation, provid-
ing a facile and cost-effective approach to the construction
of benzocyclic compounds. The present strategy has pro-
vided a new example of a Friedel–Crafts reaction with al-
kanes as the alkylating component and represents a conve-
nient approach to selective C–H bond activation and func-
tionalization of alkane derivatives. Further studies on the
extension and application of these reactions are underway.
4-Methoxy-1,1-dimethylindane (2a):[9] 1H NMR (400 MHz): δ =
1.25 (s, 6 H, 1-CH3), 1.92 (t, J = 7.2 Hz, 2 H, 2-H), 2.84 (t, J =
7.2 Hz, 2 H, 3-H), 3.82 (s, 3 H, CH3O), 6.67 (d, J = 8.0 Hz, 1 H,
5-H), 6.77 (d, J = 7.6 Hz, 1 H, 7-H), 7.15–7.19 (m, 1 H, 6-H) ppm.
6-Cyclohexyl-4-methoxy-1,1-dimethylindane (4a): M.p. 65–67 °C.
1H NMR (300 MHz): δ = 1.25 (s, 6 H, 1-CH3), 1.32–1.51 (m, 5 H
of cyclohexyl), 1.73–1.93 (m, 7 H, 2-H, 5 H of cyclohexyl), 2.46–
2.54 (m, 1 H, 1Ј-H of cyclohexyl), 2.79 (t, J = 7.2 Hz, 2 H, 3-H),
3.83 (s, 3 H, CH3O), 6.54 (s, 1 H, 5-H), 6.63 (s, 1 H, 7-H) ppm.
MS (EI): m/z (%) = 258 (42.74) [M]+, 243 (100), 161 (21.51), 121
(19.50), 244 (19.43), 55 (11.64), 128 (9.65), 259 (9.19), 129 (7.90).
HR-MS: calcd. for C18H26O 258.1984; found 258.1980.
2-(3-Methylbutyl)phenol (3b):[10] Colorless oil. 1H NMR
(300 MHz): δ = 0.94–0.96 (m, 6 H, 1-CH3), 1.47–1.53 (m, 2 H, 2Ј-
H), 1.60–1.63 (m, 1 H, 3Ј-H), 2.59–2.63 (m, 2 H, 1Ј-H), 5.55 (br.,
1 H, OH), 6.75–6.77 (m, 1 H, 6-H), 6.84–6.86 (m, 1 H, 4-H), 7.03–
7.12 (m, 2 H, 3-H, 5-H) ppm.
Experimental Section
General Methods: Melting points were measured with an SGW X-
4 apparatus. Reactions were monitored by analytical thin-layer
chromatography (TLC) on 0.2 mm silica-gel plates, and visualiza-
tion of the developed chromatogram was enabled by UV ab-
sorbance or by using an ethanolic phosphomolybdic acid dip. Flash
chromatography was performed using silica gel (300–400 mesh)
1
5-Cyclohexyl-2-(3-methylbutyl)phenol (5b): Colorless oil. H NMR
(500 MHz): δ = 0.90–0.98 (m, 6 H, CH3), 1.24–1.38 (m, 5 H of
cyclohexyl), 1.45–1.51 (m, 2 H, 2Ј-H), 1.54–1.61 (m, 1 H, 3Ј-H),
1.71–1.85 (m, 5 H of cyclohexyl), 2.37–2.41 (m, 1 H, 1Ј-H of cyclo-
hexyl), 2.54–2.58 (m, 2 H, 1Ј-H), 3.69 (br., 1 H, OH), 6.60 (s, 1 H,
6-H), 6.70–6.73 (m, 1 H, 4-H), 7.02 (d, J = 7.6 Hz, 1 H, 3-H) ppm.
13C NMR (125 MHz): δ = 153.15, 147.36, 129.70, 126.00, 119.24,
113.72, 77.28, 77.02, 76.77, 44.07, 39.03, 34.44, 27.97, 27.42, 26.90,
26.18, 22.55 ppm. MS (EI): m/z (%) = 246 (45.11) [M]+, 189 (100),
107 (22.1), 190 (16.48), 133 (10.34), 247 (8.83), 176 (7.21), 108
(6.61). HR-MS: calcd. for C17H26O 246.1984; found 246.1979.
1
with the indicated solvent system. H NMR spectra were recorded
with a Varian Mercury 300, Varian 400 or Spect 500 spectrometer,
HMBC and 13C NMR spectra were recorded with a Drx 400 or
Spect 500 spectrometer; the solvent used was CDCl3 unless indi-
cated. All chemical shifts are reported in ppm on the δ scale relative
to an internal standard of TMS (1H) or the signals of the solvent
(13C). Mass spectra were recorded with an Agilent 5973N MSD
(EI) instrument. High-resolution mass spectra (HR-MS) were re-
corded with a Waters Micromass GCT spectrometer.
4-Hydroxy-1,1-dimethylindane (2b): White prismatic crystals; m.p.
1
88–89 °C (ref.[11] 88–88.5 °C). H NMR (400 MHz): δ = 1.24 (s, 6
H, 1-CH3), 1.96 (t, J = 6.9 Hz, 2 H, 2-H), 2.82 (t, J = 6.9 Hz, 2 H,
3-H), 4.55 (br., 1 H, OH), 6.63 (d, J = 7.5 Hz, 1 H, 5-H), 6.75 (d,
J = 7.5 Hz, 1 H, 7-H), 7.09 (t, J = 7.8 Hz, 1 H, 6-H) ppm.
Typical Procedure for Friedel–Crafts Reaction of 3-Methylbutenyl-
Substituted Aromatics: Cyclization was carried out in a three-
necked 250-mL flask equipped with an HCl(g) inlet tube and an
air condenser fitted with a CaCl2 drying tube. A cyclohexane solu-
tion of 1a (0.15 mL, 140 mg, 0.79 mmol) was added dropwise to a
stirred suspension of powdered aluminum chloride (120 mg,
0.9 mmol) in cyclohexane (25 mL) at r.t. in an atmosphere of
HCl(g). The reaction mixture was stirred for 3 h and then quenched
by slow addition of 1 n hydrochloric acid. The organic layer was
separated and the aqueous phase was extracted with EtOAc
(3ϫ10 mL). The combined organic phase was dried with anhy-
drous Na2SO4. After removal of the solvent in vacuo, the residue
was purified by flash column chromatography on silica gel (petro-
leum ether) to provide 3a as a colorless oil (29 mg, 21%), 5a as a
clear oil (11 mg, 5%), 2a as a clear oil (40 mg, 30%), and 4a as a
white powder (31 mg, 15%).
6-Cyclohexyl-4-hydroxy-1,1-dimethylindane (4b): White power; m.p.
74–76 °C. 1H NMR (400 MHz): δ = 1.24 (s, 6 H, 1-CH3), 1.35–
1.57 (m, 5 H of cyclohexyl), 1.71–1.88 (m, 5 H of cyclohexyl), 1.94
(t, J = 6.9 Hz, 2 H, 2-H), 2.46–2.54 (m, 1Ј-H of cyclohexyl), 2.76
(t, J = 6.9 Hz, 2 H, 3-H), 4.48 (br., 1 H, OH), 6.50 (s, 1 H, 5-H),
6.60 (s, 1 H, 7-H) ppm. 13C NMR (100 MHz): δ = 154.92, 151.33,
149.02, 125.09, 111.30, 77.34, 77.02, 76.71, 44.66, 44.49, 41.45,
34.67, 28.61, 26.96, 26.20, 25.64 ppm. MS (EI): m/z (%) = 244
(35.42) [M]+, 229 (100), 147 (30.55), 230 (19.99), 55 (15.67), 159
(15.00), 145 (14.62), 83 (12.58). HR-MS: calcd. for C17H24O
244.1827; found 244.1826.
1
2,2-Dimethylchroman (6):[12] Colorless oil. H NMR (400 MHz): δ
= 1.33 (s, 6 H, 2-CH3), 1.79 (t, J = 7.6 Hz, 2 H, 3-H), 2.77 (t, J =
7.6 Hz, 2 H, 4-H), 6.76–6.83 (m, 2 H, 6-H, 8-H), 7.04–7.09 (m, 2
1-Methoxy-2-(3-methylbutyl)benzene (3a):[8] 1H NMR (400 MHz):
δ = 0.92–0.95 (m, 6 H, CH3), 1.43–1.47 (m, 2 H, 2Ј-H), 1.56–1.61 H, 5-H, 7-H) ppm.
268
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Selective C–H Bond Activation
1,1,4-Trimethylindane (2c):[13] Colorless oil. H NMR (400 MHz):
1
3-H), 7.18–7.23 (m, 2 H, 4-H, 7-H), 7.25–7.30 (m, 2 H, 5-H, 6-
δ = 1.24 (s, 6 H, 1-CH3), 1.98–1.93 (m, 2 H, 2-H), 2.24 (s, 3 H, 4- H) ppm.
CH3), 2.80 (t, J = 7.42 Hz, 2 H, 3-H), 6.94–6.97 (m, 2 H, 7-H, 5-
7-Methoxy-1,2-dimethylnaphthalene (13):[16] Pale-yellow oil. 1H
NMR (400 MHz): δ = 2.49 (s, 3 H, CH3), 2.56 (s, 3 H, CH3), 3.96
Typical Procedure for Friedel–Crafts Reaction of 3-Methylbutyl- (s, 3 H, OCH3), 7.10 (dd, J = 8.6, 2.7 Hz, 1 H, 3-H), 7.18 (d, J =
H), 7.06–7.11 (m, 1 H, 6-H) ppm.
Substituted Aromatics: Cyclization was carried out in a three-
necked 250-mL flask equipped with an HCl(g) inlet tube and an
air condenser fitted with a CaCl2 drying tube. A hexane solution of
3a (0.17 mL, 150 mg, 0.84 mmol) and cyclohexene (0.16 g, 0.2 mL,
2.0 mmol) were added dropwise to a stirred suspension of pow-
dered aluminum chloride (120 mg, 0.9 mmol) in hexane (25 mL) at
r.t. in an atmosphere of HCl(g). The reaction mixture was stirred
for 19 h and then quenched by slow addition of 1 n hydrochloric
acid. The organic layer was separated and the aqueous phase was
extracted with EtOAc (3ϫ10 mL). The combined organic phase
was dried with anhydrous Na2SO4. After removal of the solvent in
vacuo, the residue was purified by flash column chromatography
on silica gel (petroleum ether) to provide 5a as a colorless oil
(10 mg, 5%), 2a as a colorless oil (65 mg, 43%), and 4a as a white
powder (95 mg, 44%).
6-Cyclohexyl-1,1,4-trimethylindane (4c): Colorless oil. 1H NMR
(400 MHz): δ = 1.24 (s, 6 H, 1-CH3), 1.30–1.49 (m, 5 H of cyclo-
hexyl), 1.81–1.93 (m, 7 H, 2-H, 5H of cyclohexyl), 2.23 (s, 3 H, 4-
CH3), 2.54–2.56 (m, 1 H, 1Ј-H of cyclohexyl), 2.76 (t, J = 7.2 Hz,
2 H, 3-H), 6.83 (s, 2 H, 5-H, 7-H) ppm. MS (EI): m/z (%) = 242
(53.59) [M]+, 241 (100), 243 (72.06), 43 (69.35), 55 (67.79), 41
(66.24), 244 (19.96), 44 (9.52). HR-MS: calcd. for C18H26 242.2035;
found 242.2030.
6-Methoxy-1,1-dimethylindane (2d):[14] Colorless oil. 1H NMR
(400 MHz): δ = 1.26 (s, 6 H, 1-CH3), 1.91–1.94 (m, 2 H, 2-H),
2.79–2.84 (m, 2 H, 3-H), 3.80 (s, 3 H, CH3O), 6.68–6.71 (m, 2 H,
5-H, 7-H), 7.08–7.11 (m, 1 H, 4-H) ppm.
4-Cyclohexyl-6-methoxy-1,1-dimethylindane (4d): Colorless oil. 1H
NMR (400 MHz): δ = 1.24 (s, 6 H, 1-CH3), 1.32–1.49 (m, 5 H of
cyclohexyl), 1.74–1.92 (m, 7 H, 2-H, 5H of cyclohexyl), 2.23 (s, 3
H, 4-CH3), 2.51–2.55 (m, 1 H, 1Ј-H of cyclohexyl), 2.79 (t, J =
7.2 Hz, 2 H, 3-H), 3.83 (s, 3 H, CH3O), 6.53 (s, 1 H, 7-H), 6.60 (s,
1 H, 5-H) ppm. MS (EI): m/z (%) = 258 (52.46) [M]+, 243 (100),
174 (30.24), 175 (29.98), 159 (23.32), 244 (19.16), 161 (16.74), 128
(13.74). HR-MS: calcd. for C18H26O 258.1984; found 258.1988.
8.2 Hz, 1 H, 6-H), 7.28 (d, J = 2.4 Hz, 1 H, 8-H), 7.56 (d, J =
8.8 Hz, 1 H, 4-H), 7.71 (d, J = 9.0 Hz, 1 H, 5-H) ppm.
Acknowledgments
Financial support from the National Natural Science Foundation
of China (grant number 20972033), the National Drug Innovative
Program (grant number 2009ZX09301-011), and the State Key
Laboratory of Drug Research, Shanghai Institute of Materia Med-
ica, Chinese Academy of Sciences is gratefully acknowledged.
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1-(3-Methylbutyl)-2-methoxy-4-(1-phenylethyl)benzene (10a): Col-
1
orless oil. H NMR (300 MHz): δ = 0.93 (s, 3 H, CH3), 0.95 (s, 3
H, CH3), 1.43–1.56 (m, 2 H, 2Ј-H), 1.59–1.64 (m, 4 H, 3Ј-H, CH3
of phenylethyl), 2.53–2.64 (m, 2 H, 1Ј-H), 3.81 (s, 3 H, CH3O),
4.03–4.11 (m, 1 H, 1Ј-H of phenylethyl), 6.67 (d, J = 8.4 Hz, 1 H,
5-H), 6.91 (d, J = 8.1 Hz, 1 H, 6-H), 6.97 (s, 1 H, 3-H), 7.15–7.30
(m, 5 H, phenyl of phenylethyl) ppm. MS (EI): m/z (%) = 282
(44.53) [M]+, 267 (100), 268 (21.78), 225 (19.80), 165 (16.89), 105
(14.55), 211 (13.29), 283 (10.08). HR-MS: calcd. for C20H26O
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1
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(42.55), 149 (36.05), 191 (29.14), 233 (28.47), 91 (18.43), 135
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269

J. Wang, P. Zhou, Y. Wang
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Received: August 9, 2010
Published Online: November 17, 2010
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