Synthesis of 1,1-dimethyl-4-indanol derivatives

Article abstract of DOI:10.1080/00397910600764691

The synthesis of 1,1-dimethyl-4-indanols (3a,b) has been achieved by intramolecular Friedel-Crafts cyclization of 2-(3-methyl-2-butenyl)phenols (5a,b) or 1-methoxy-2-(3-methyl-2-butenyl)benzenes (6a,b) followed by demethylation, respectively. It was found that the solvent was critical for the formation of different products in the intramolecular Friedel-Crafts reactions of 6. The unexpected product 4-methoxy-1,1,6,6-tetramethyl-as-hydrindacene (11) was obtained from the Friedel-Crafts reactions of 6a and its structure was confirmed by X-ray diffraction analysis. The key intermediates 5a,b were prepared by ortho-alkenylation of phenols with 1-bromo-3-methyl-2-butene, and the reaction temperature exerted an obvious impact on the yield of 2-(3-methyl-2-butenyl)phenol (5a). Copyright Taylor & Francis Group, LLC.

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Synthesis of 1,1‐Dimethyl‐4‐indanol
Derivatives
Yang Wang a , Jiang Wu a & Peng Xia a
a Department of Medicinal Chemistry , School of Pharmacy, Fudan
University , Shanghai, China
Published online: 16 Feb 2007.
To cite this article: Yang Wang , Jiang Wu & Peng Xia (2006) Synthesis of 1,1‐Dimethyl‐4‐indanol Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:18, 2685-2698, DOI: 10.1080/00397910600764691
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Synthetic Communicationsw, 36: 2685–2698, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600764691
Synthesis of 1,1-Dimethyl-4-indanol
Derivatives
Yang Wang, Jiang Wu, and Peng Xia
Department of Medicinal Chemistry, School of Pharmacy,
Fudan University, Shanghai, China
Abstract: The synthesis of 1,1-dimethyl-4-indanols (3a,b) has been achieved by
intramolecular Friedel–Crafts cyclization of 2-(3-methyl-2-butenyl)phenols (5a,b)
or 1-methoxy-2-(3-methyl-2-butenyl)benzenes (6a,b) followed by demethylation,
respectively.It was found that the solvent was critical for the formation of different
products in the intramolecular Friedel–Crafts reactions of 6. The unexpected
product 4-methoxy-1,1,6,6-tetramethyl-as-hydrindacene (11) was obtained from the
Friedel–Crafts reactions of 6a, and its structure was confirmed by X-ray diffraction
analysis. The key intermediates 5a,b were prepared by ortho-alkenylation of phenols
with 1-bromo-3-methyl-2-butene, and the reaction temperature exerted an obvious
impact on the yield of 2-(3-methyl-2-butenyl)phenol (5a).
Keywords: 1,1-Dimethyl-4-indanols, intramolecular Friedel–Crafts reactions,
1-methoxy-2-(3-methyl-2-butenyl)benzenes, ortho-alkenylation of phenols
INTRODUCTION
30,40-Di-O-(2)-camphanoyl-(þ)-cis-khellactone (DCK, 1) and various its
analogs have been reported to demonstrate extremely potent inhibitory
activity against HIV-1 replication in H9 lymphocytic cells.[1–8] In our
recent study on the structural modification of DCK (1), the oxygen atom in
C ring and/or A ring of DCK have been replaced by other atoms, and
some of these new analogs, such as 7-thia- and 1-thia-DCK, also inhibited
potent anti-HIV activity.[5,6] Compared with DCK series, a different
Received in Japan December 18, 2005
Address correspondence to Peng Xia, Department of Medicinal Chemistry, School
of Pharmacy, Fudan University, Shanghai 200032, China. E-mail: pxia@shmu.edu.cn
2685

2686
Y. Wang, J. Wu, and P. Xia
structure–activity relationship was implied in these DCK bioisosteres. In a
continuing effort to identify the pharmacophores and clarify the mechanism
of action in this class of potent anti-HIV agents, a new series of DCK
analogs, namely 7-deoxy-DCK derivatives (2a,b) was designed, and the
effect of the 7-oxygen atom of DCK (1) on the anti-HIV activity can be
further explored. According to retrosynthetic analysis, 1,1-dimethyl-4-
indanols (3a,b) are the key intermediates for the synthesis of 2a,b. Addition-
ally, the indanols are also useful as antioxidants, and more importantly, the
indans are an important structural unit found in many natural and synthetic,
biologically active molecules.[9] Herein, we report our study on the
synthesis of 1,1-dimethyl-4-indanols (3a,b) (Fig. 1).
RESULTS AND DISCUSSION
As shown in Scheme 1, the synthetic route of 1,1-dimethyl-4-indanols (3a,b)
was designed and tried by starting from an ortho-prenylation reaction of
phenols (4a,b), followed by an intramolecular Friedel–Crafts cyclization of
2-(3-methyl-2-buteny1)phenols (5a,b). To avoid the formation of undesired
by-products (8a,b) in the cyclization step, an alternative synthetic route was
also examined. The phenol hydroxyl groups in compounds 5a,b can be first
blocked by the methyl group, and then cyclization of 6a,b by intramolecular
Figure 1. Structures of DCK (1), 7-deoxy-DCK analogs (2a,b), and 1,1-dimethyl-4-
indanols (3a,b).

Synthesis of 1,1-Dimethyl-4-indanol Derivatives
2687
Scheme 1. The synthetic route of 3a,b: (i) 1-bromo-3-methyl-2-butene, NaH,
toluene; (ii) CH3I, K2CO3/acetone, rt; (iii) HCl (g)/AlC13; (iv) LiAlH4/THF;
(v) BBr3/CH2Cl2.
F-C reaction can give 7a,b. The subsequent demethylation of 7a,b with boron
tribromide results in the convenient formation of target compounds 3a,b.
Although two more steps are needed in the later route, the chemo- and
regioselectivity of the reaction can be more easily controlled. A more
detailed investigation of the optimal conditions for these reactions is
discussed as follows.
ortho-Prenylation of Phenols (4a,b) and Intramolecular Friedel–
Crafts Cyclization of 2-(3-Methyl-2-butenyl) Phenols (5a,b)
The synthesis of ortho-prenylated phenols has been extensively studied
because of their broad range of pharmacological activity, including anti-
inflammatory, antifungal, antibacterial, antitumor, anti-HIV, and anti-
Alzheimer activity.[10] ortho-Prenylphenols have been synthesized with
many strategies, such as the Friedel–Crafts reaction of prenyl alcohols or
prenyl halides with phenols, and direct alkylation of phenols with prenyl
halides in the alkaline media or in the presence of an akali-metal catalyst.
Because of competing side reactions such as para-prenylation, bis-
prenylation, and oxygen-prenylation, ortho-prenylation of phenols proceeds
with only moderate yield and regioselectivity.[10]

2688
Y. Wang, J. Wu, and P. Xia
Following a literature method,[11] we tried the reaction of 1-bromo-3-
methyl-2-butene with phenol (4a) or 4-chlorophenol (4b) in the presence of
NaH in toluene at 358C for 30 h (Eq. (1)). It is worthwhile to note that the
reaction shows complete ortho-regioselectivity, but both mono- and dialkeny-
lated phenols were furnished (Table 1). The formation of dialkenylated
phenols might be attributed to the more electron-rich property of the aromatic
system after the first introduction of a prenyl residue. In the case of 4a as
substrate, 2,6-bis-(3-methyl-2-butenyl)phenol (9a) dominated compared with
mono-substituted phenol 5a, whereas 4-chloro-2-(3-methyl-2-butenyl)phenol
(5b) was the main product in the reaction of 4-chlorophenol (4b). The
decrease of bis-prenylation product 9b might be due to the weak electron-
withdrawing property of C1 atom. To improve the yield of desired product
5a, the reaction was then carried out at a lowered temperature (158C). As
expected, the mono-substituted phenol 5a was obtained in satisfactory yield
(60%), and the formation of dialkenylated phenol 9a could be significantly
reduced (23%).
The initial trial on the cyclization of 2-(3-methyl-2-buteny1)phenol (5a,b)
to 1,1-dimethyl-4-indanols (3a,b) in cyclohexane upon exposure to aluminum
chloride in an HCl (g) atmosphere[12] proved to be inefficient (only 15% yield
of 3a and 12% yield of 3b, respectively), mainly because of the formation of a
large amount of undesired isomer 8a (73%) and 8b (39%). However, this
process has provided an efficient method for the preparation of 2,2-dialkyl-
2H-benzopyran derivatives, which exhibited an even broader range of interest-
ing physiological properties.[13,14] Accordingly, we switched our attention
to the synthesis of compounds 3 through an alternative approach by the
protection of hydroxyl group of 5.
Table 1. Product distributions obtained in the o-prenylation of phenols
4a,b
Products (isolated yield %)
Temperature (8C)
5
9
Recovered 4
35
15
35
5a (28)
5a (60)
5b (63)
9a (40)
9a (23)
9b (5)
4a (29)
—
—

Synthesis of 1,1-Dimethyl-4-indanol Derivatives
2689
Synthesis of 1,1-Dimethyl-4-indanols (3a,b) by an Indirect Pathway
As mentioned previously, the formation of by-products 8 in the intramolecular
Friedel–Crafts cyclization of 5 is responsible for the low yields of 3. In
principle, the protection of the hydroxyl groups in 5 can completely avoid the
formation of by-products 8 and as a result might enhance the yields of
expected products. Accordingly, we subsequently tried an alternative stepwise
strategy involving the blocking of the phenol hydroxyl group in compounds
5a,b by the methyl group, followed by intramolecular Friedel–Crafts cycliza-
tion and demethylation reactions. Treatment of 5a,b with methyl iodide under
standard conditions (K2CO3/acetone) provided 6a,b in 84% and 80% yields
respectively as pale yellow oil. Fatope and Okogun reported that cyclization of
1-methoxy-2-(3-methyl-2-butenyl)benzene (6a) in the presence of aluminum
chloride in an HCl (g) atmosphere in benzene gave 1,1-dimethyl-4-methoxyin-
dan (7a) in 60% yield.[12] This result seems to be encouraging, but problems
were encountered when we repeated this process. To our surprise, the desired
7a was obtained in only 13% of yield using the literature procedure. However
1-methoxy-2-(3-methyl-3-phenylbutanyl)benzene (10a), an intermolecular
Friedel–Crafts product with solvent benzene, was obtained as the major
product (50% yield) [Eq. (2)]. A similar result was afforded in the cyclization
of 4-chloro-1-methoxy-2-(3-methyl-2-butenyl)benzene (6b), and the yields of
7b and 10b were 32% and 23%, respectively.
Consequently, we tried hexane, cyclohexane, or CS2 instead of benzene
as the reaction solvent, respectively. The effects of the solvents on the
yields and product distributions are summarized in Table 2. In case of
Table 2. Product distributions obtained in the cyclization of 6a–b
Products (isolated yield %)
Solvent
7
10
11
Benzene
Hexane
Cyclohexane
CS2
7a (13)
7a (8)
10a (50)
—
—
—
—
—
(3)
7a (19)
7a (38)
7b (32)
—
10b (23)
Benzene

2690
Y. Wang, J. Wu, and P. Xia
hexane or cyclohexane as the solvent, 7a was obtained in low yields of 8–19%,
probably due to their lower polarity and poor solubility of the substrates and
catalysts. CS2 seems to be the optimal solvent for the reaction, affording 7a
in 38% yield. It was found that low concentrations of the substrates 6a,b in
the reaction medium and rapid workup were preferable to avoid the intermo-
lecular reaction. Small quantities of tricyclic compound were also separated
from the reaction system in 3% yield, but it is difficult to determine its
1
structure as 11,12 or 13 simply on the basis of its H NMR, 13C NMR,
and MS spectra. Its structure was finally confirmed as 4-methoxy-
1,1,6,6-tetramethyl-as-hydrindacene (11) by the X-ray single crystal
diffraction analysis (Fig. 2), which was probably formed by the reverse F-C
reaction of 6a followed by cyclization of intermediate 14 (Scheme 2).
The dechlorination of 7b was also tried by using lithium aluminum hydride
(4 equiv.) in refluxing tetrahydrofuran for 72 h to provide 7a in 30% yield. As
reported in the literature,[15] the reductions of aromatic chlorides are more
Figure 2. X-ray diffraction analysis of compound 11.

Synthesis of 1,1-Dimethyl-4-indanol Derivatives
2691
Scheme 2. Possible mechanism for the formation of 11.
difficult than those of aromatic iodides or bromides, especially for the substrates
containing electron-donating substituents. Therefore, 4-methoxy in 7b would
be responsible for the slow reaction rate and low yield of product 7a.
Treatment of 7a,b with boron tribromide under standard conditions (CH2Cl2,
2788C to rt, 2 h) smoothly cleaved the methyl ether and provided the target
1,1-dimethyl-4-indanols (3a,b) in 91% and 93% yield, respectively.
CONCLUSION
In conclusion, two approaches for the synthesis of indanols 3a,b starting from
corresponding phenols have been examined, and some unreported or unex-
pected reaction details were explored. The effects of solvents on the cycliza-
tion of 6a and the reaction temperature on the yield of 5a were optimized.
We hope the results described in this work will be helpful for the synthesis
of biologically interesting compounds with the indanols 3 as intermediates.
EXPERIMENTAL
Melting points were uncorrected. Reactions were monitored by TLC on
0.2-mm silica-gel plates, and the spots were visualized by ultraviolet light.
Flash column chromatography was performed on silica-gel (300–400 mesh).
1H NMR and 13C NMR spectra were recorded on a Varian Mercury 300 spec-
trometer at 300.13 and 75.47 MHz, respectively, and the solvent used was

2692
Y. Wang, J. Wu, and P. Xia
CDCl3 unless otherwise indicated. All chemical shifts were reported in d units
with reference to TMS (1H) or the signals of the solvent (13C). Mass spectra
(EI) were taken on a Agilent 5973 N MSD spectrometer. HRMS data were
determined on a Kratos Concept 1H spectrometer, Bruker APEXIII 7.0 Tesla
FTMS or IonSpec 4.7 Tesla FTMS instrument.
2-(3-Methyl-2-butenyl)phenol (5a) and 2,6-bis-(3-Methyl-2-
butenyl)phenol (9a)
Phenol (5 g, 53.13 mmol), NaH (60%, 2.81 g, 116.89 mmol) in anhydrous
toluene (70 mL) was heated at 608C for 0.5 h under argon. After being
cooled to 158C, 1-bromo-3-methyl-2-butene (11.87 g, 79.65 mmol) was
added to the reaction mixture through a syringe. The mixture was stirred for
24 h and subsequently poured into water (200 mL). The mixture was
extracted with EtOAc (3 ꢀ 30 mL), and the combined organic phase was
washed with H2O (3 ꢀ 20 mL) and brine (20 mL) and dried over anhydrous
MgSO4. After removal of the volatiles in vacuo, the residue was purified by
flash column chromatography on silica gel (petroleum ether–EtOAc, 15:1)
to give compound 5a as a pale yellow oil (5.20 g, 60%): 1H NMR
(300 MHz, CDC13) d 1.83 (s, 6H, CH3), 3.41 (d, J ¼ 6.9 Hz, 2H, CH2),
5.36–5.41 (m, 2H, -OH, 55CH-), 6.83–6.97 (m, 2H, 4-H, 6-H), 7.12–7.18
(m, 2H, 3-H, 5-H). A by-product 9a was also obtained as a yellow oil
1
(2.80 g, 23%): H NMR (300 MHz, CDCl3,) d 1.76 (s, 12H, CH3), 3.34
(d, J ¼ 6.9 Hz, 4H, CH2), 5.28–5.35 (m, 2H, 55CH-), 5.36 (s, 1H, OH),
6.76–6.79 (m, 1H, 4-H), 6.96 (t, J ¼ 7.5 Hz, 2H, 3-H, 5-H).
4-Chloro-2-(3-methyl-2-butenyl)phenol (5b) and 4-Chloro-2,6-
bis-(3-methyl-2-butenyl)phenol (9b)
4-Chlorophenol (200 mg, 1.56 mmol), NaH (60%, 137 mg, 3.43 mmol) in
anhydrous toluene (5 mL) was heated at 608C for 2.5 h under argon. After
being cooled to 358C, 1-bromo-3-methyl-2-butene (349 mg, 2.34 mmol)
was added to the reaction mixture through a syringe. Following the same
workup procedure for 5a, 5b was obtained as a yellow oil (194 mg, 63%):
1H NMR (300 MHz, CDCl3) d 1.74 (s, 3H, CH3), 1.76 (s, 3H, CH3), 3.30
(d, J ¼ 6.9 Hz, 2H, CH2), 5.26–5.31 (m, 1H, 55CH-), 5.38 (br, 1H, -OH),
6.71 (d, J ¼ 8.4 Hz, 1H 6-H), 7.03–7.07 (m, 2H, 3-H, 5-H).13C NMR
(75 MHz, CDC13) d 154.01, 134.30, 129.81, 127.31, 126.99, 121.81,
120.65, 115.52, 29.40, 25.66, 17.70. Similarly, product 9b was yielded as a
1
yellow oil (21 mg, 5%): H NMR (300 MHz, CDC13) d 1.76 (s, 6H, CH3),
1.78 (s, 6H, CH3), 3.30 (d, J ¼ 7.5 Hz, 4H, CH2), 5.25–5.30 (m, 2H,
55CH-), 5.33 (s, lH, OH), 6.94 (s, 2H, 3-H, 5-H).

Synthesis of 1,1-Dimethyl-4-indanol Derivatives
2693
1-Methoxy-2-(3-methyl-2-butenyl)benzene (6a) and 4-Chloro-1-
methoxy-2-(3-methyl-2-butenyl)benzene(6b)
Anhydrous K2CO3 (5.54 g, 40.1 mmol) and methyl iodide (2.6 mL, 5.91 g,
41.7 mmol) were added to a stirring solution of 5a (2.60 g, 16.0 mmol) in
dry acetone (10 mL). The mixture was stirred at room temperature for 18 h.
The volatiles were removed in vacuo, and the residual solids were dissolved
in H2O (30 mL). The resulting mixture was extracted with EtOAc
(3 ꢀ 30 mL), and the combined organic phase was dried over anhydrous
Na2SO4. After the removal of the solvent, the residue was purified by flash
column chromatography on silica gel (petroleum ether) to yield 6a as a pale
1
yellow oil (2.36 g, 84%): H NMR (300 MHz, CDCl3) d 1.71 (s, 3H, CH3),
1.73 (s, 3H, CH3), 3.32 (d, J ¼ 7.5 Hz, 2H, CH2), 3.81 (s, 3H, CH3O),
5.28–5.33 (m, 1H, -CH55), 6.81–6.94 (m, 2H, 4-H, 6-H), 7.12–7.20
(m, 2H, 3-H, 5-H). Following the same procedure for the preparation of 6a,
6b was obtained from 5b as a pale yellow oil (yield, 80%): 1H NMR
(300 MHz, CDC13) d 1.70 (s, 3H, CH3), 1.76 (s, 3H, CH3), 3.28
(d, J ¼ 7.2 Hz, 2H, CH2), 3.81 (s, 3H, CH3O), 5.24–5.30 (m, 1H, -CH55),
6.74 (d, J¼ 8.4 Hz, lH, 6-H), 7.08–7.13 (m, 2H, 3-H, 5-H). MS (EI) m/z
(%): 210 (Mþ, 100.00), 195 (78.78), 175(87.06), 160 (95.09), 155 (62.56),
125 (53.73), 115 (35.57), 77 (47.92), 41 (81.65). HRMS: calcd. mass for
C12H15ClO 210.0811; found 210.0806.
1,1-Dimethyl-1-4-methoxyindan (7a) and 1-Methoxy-2-(3-methyl-3-
phenylbutanyl)benzene (10a)
Cyclization was carried out in a three-necked 250-mL flask equipped with an
HCl (g) inlet tube and an air condenser with a CaCl2 drying tube. The benzene
solution of 6a (1.80 g, 10.2 mmol) was added dropwise to a stirred suspension
of powdered aluminium chloride (1.36 g, 10.2 mmol) in sodium-dried
benzene (50 mL) at room temperature in an atmosphere of HCl (g).
(HCl (g) was generated by dropping conc. sulphuric acid into NACl.) The
reaction mixture was stirred for 2.5 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 (3 ꢀ 20 mL). The combined organic phase
was dried over anhydrous Na2SO4. After removal of the solvent in vacuo,
the residue was purified by flash column chromatography on silica gel
1
(petroleum ether) to provide 7a as a pale yellow oil (226 mg, 13%): H
NMR (300 MHz, CDCl3) d 1.26 (s, 6H, 1-CH3), 1.93 (t, J ¼ 6.9 Hz, 2H,
2-H), 2.85 (t, J ¼ 6.9 Hz, 2H, 3-H), 3.84 (s, 3H, 4-CH3O), 7.69
(d, J ¼ 8.4 Hz, 1H, 5-H), 6.79 (d, J¼ 7.5 HZ, 1H, 7-H), 7.19 (t, J¼ 8.1 Hz,
1H, 6-H). In addition to 7a, by-product 10a was also obtained as a yellow
1
oil (1.30 g, 50%): H NMR (300 MHz, CDCl3) d 1.38 (s, 6H, 30-CH3),
1.87–1.92 (m, 2H, 20-CH2), 2.35–2.40 (m, 2H, 10-CH2), 3.77 (s, 3H,

2694
Y. Wang, J. Wu, and P. Xia
1-CH3O), 6.79–6.87 (m, 2H, 4-H, 6-H), 7.03 (d, J ¼ 7.5 Hz, 1H, 5-H), 7.11–
7.22 (m, 2H, 400-H, 3-H), 7.31–7.36 (t, J ¼ 7.8 Hz, 2H, 300-H, 500-H), 7.43
(d, J ¼ 8.1 Hz, 2H 200-H, 600-H). MS (EI) m/z (%): 254 (Mþ, 43.95), 135
(71.96), 119 (91.72), 91 (100.00), 77 (21.08), 41 (21.09). HRMS (MALDI-
DHB) calcd. mass for C18H22O [Mþ þ Na] 277.15633; found 277.1570.
4-Methoxy-1,1,6,6-tetramethyl-as-hydrindacene (11)
Fllowing a similar procedure for the preparation of 7a, except for the use of
CS2 as the solvent instead of benzene, 7a was prepared in 38% yield, and 11
1
was obtained as colorless crystals (3%): mp 77–788C. H NMR (300 MHz,
CDCl3) d 1.26 (s, 6H, 1-CH3), 1.30 (s, 6H, 7-CH3), 1.90–1.96 (m, 4H, 2-H,
6-H), 2.80 (t, J ¼ 7.2 Hz, 2H, 3-H), 2.88 (t, J ¼ 7.2 Hz, 2H, 5-H), 3.83 (s, 3H,
4-CH3O), 6.51 (s, 1H, 8-H). I3C NMR (75 MHz, CDCl3) d 155.17, 153.49,
148.85, 129.25, 128.74, 102.36, 55.43, 55.31, 45.36, 43.51, 42.17, 42.13,
29.89, 28.98, 28.80, 27.46, 26.78. MS (EI) m/z (%): 244 (Mþ, 25.27), 229
(100.00), 173 (67.04), 161 (17.31), 143 (13.11), 128 (14.49). HRMS
(MALDI-DHB) calcd. mass for C17H24O [Mþ þ H] 245.1900; found 245.1902.
Single-Crystal X-ray Diffraction Data of 11
Compound 11 was dissolved in petroleum ether, and crystals were obtained by
slow evaporation at room temperature after several days. Crystal with dimen-
sions of 0.517 ꢀ 0.506 ꢀ 0.345 mm was selected and mounted on a Bruker
Smart CCD diffractometer with graphite monochromatized Mo Ka radiation
˚
(l ¼ 0.71073 A). Diffraction data were collected using v-2u scans at room
temperature (293 K). A perspective view of the structure is depicted in
Fig. 2. Empirical formula: C17H24O. Formula weight: 244.36. Crystal
system: monoclinic. Space group: P2(1)/n. Unit cell dimensions: a ¼ 9.1975
˚
˚
˚
(17) A, b ¼ 17.430 (3) A, c ¼ 9.5062 (17) A, b ¼ 108.468(3)8. V ¼ 1445.5
3
˚
(5) A . Theta range for data collection is from 2.34 to 26.008. Z ¼ 4.
Dc ¼ 1.123 Mg/m3. Absorption coefficient 0.067 mm21. F(000) ¼ 536.
Refinement method: full-matrix least-squares on F2. Goodness-of-fit on F2:
0.973. Final R indices [I.2s (I)]: R1 ¼ 0 0708, wR2 ¼ 0.1807. R indices
(all data); R1 ¼ 0.0931, wR2 ¼ 0.1964. Largest diff. peak and hole: 0.260
3
˚
and 20.240 e/A .
7-Chloro-1,1-dimethyl-4-methoxyindan (7b) and 4-Chloro-1-
methoxy-2-(3-methyl-3-phenylbutanyl)benzene (10b)
Following the same procedure for the preparation of 7a, with benzene as the
solvent, 7b was afforded as a colorless liquid in 32% yield: 1H NMR

Synthesis of 1,1-Dimethyl-4-indanol Derivatives
2695
(300 MHz, CDC13) d 1.41 (s, 6H, 1-CH3), 1.95 (t, J ¼ 7.5 Hz, 2H, 2-H), 2.82
(t, J ¼ 7.5 Hz, 2H, 3-H), 3.81 (s, 3H, 4-CH3O), 6.62 (d, J ¼ 8.7 Hz, 1H, 5-H),
7.09 (d, J ¼ 8.4 Hz, 1H, 6-H). MS (EI) m/z (%): 210 (Mþ, 28.46), 197
(34.66), 195 (100.00), 160 (53.67), 145 (10.56), 115 (11.39), 44 (13.93).
HRMS calcd. mass for C12H15OC1 210.0811; found 210.0823. By-product
1
10b was obtained as a colorless liquid (23%): H NMR (300 MHz, CDC13)
d 1.37 (s, 6H, 30-CH3), 1.83–1.88 (m 2H, 20-CH2), 2.29–2.34 (m, 2H, 10-
CH2), 3.74 (s, 3H, 1-CH3O), 6.68 (d, J ¼ 9.0 Hz, 1H, 6-H), 6.98
(d, J ¼ 2.7 Hz, 1H, 3-H), 7.05–7.09 (m, 1H, 5-H), 7.18–7.22 (m, 1H 400-
H), 7.30–7.42 (m, 4H, 200-H, 300-H, 500-H, 600-H). MS (EI) m/z (%): 288
(Mþ, 25.33), 169 (11.76), 119 (100.00), 91 (44.39), 77 (9.48), 41 (10.53).
HRMS (MALDI-DHB) calcd. mass for C18H21OC1 [Mþ þ Na] 311.1173;
found 311.1188.
1,1-Dimethyl-4-indanol (3a)
A solution of BBr3 (3.0 M, 7.9 mL, 23.8 mmol) in CH2Cl2 was added
dropwise to a cooled (2788C) solution of 7a (2.10 g, 11.9 mmol) in
anhydrous CH2Cl2 (10 mL). The mixture was warmed over 2 h to room temp-
erature, stirred for a further 1 h, and then decomposed by slow addition of
water carefully. The layers were separated, and the aqueous phase was
extracted with CH2Cl2 (3ꢀ 20 mL). The combined organic layers were
dried over anhydrous Na2SO4, and the solvent was removed in vacuo. The
resultant residue was purified by flash column chromatography on silica gel
(petroleum ether–EtOAc, 20:1) to give the title compound 3a as a pale
yellow solid. Recrystallization from petroleum ether afforded 3a as
1
colorless needles (1.75 g, 91%): mp 81–838C (lit.[16] mp 88–88.58C). H
NMR (300 MHz, CDCl3) d 1.25 (s, 6H, 1-CH3), 1.95 (t, J ¼ 7.2 Hz, 2H,
2-H), 2.82 (t, J ¼ 6.9 Hz, 2H, 3-H), 4.68 (br, 1H, 4-OH), 6.62 (d, J ¼
7.8 Hz, lH, 5-H), 6.75 (d, J ¼ 7.5 Hz, lH, 7-H), 7.09 (t, J ¼ 7.8 Hz, lH,
6-H). 13C NMR (75 MHz, CDC13) d 155.29, 151.80, 128.27, 127.83,
114.75, 112.86, 44.69, 41.31, 28.72, 26.05.
7-Chloro-1,1-dimethyl-4-indanol (3b)
Following a similar procedure for the preparation of 3a, 3b was obtained as a
1
yellow oil (93%): H NMR (300 MHz, CDC13) d 1.41 (s, 6H, 1-CH3), 1.96
(t, J ¼ 7.5 Hz, 2H, 2-H), 2.78 (t, J ¼ 7.5 HZ, 2H, 3-H), 4.96 (br, 1H, 4-OH),
6.56 (d, J ¼ 8.4 Hz, 1H, 5-H), 6.98 (t, J ¼ 8.4 Hz, 1H, 6-H). 13C NMR
(75 MHz, CDCl3) d 150.49, 149.05, 130.73, 129.24, 122.02, 114.45, 46.84,
41.88, 26.66, 26.04. MS (EI) m/z (%): 196 (Mþ, 31.80), 183 (31.82), 181
(100.00), 146 (60.11), 145 (21.93), 115 (18.73), 77 (17.51), 41 (10.53).
HRMS: calcd. mass for C11Hl3OC1 196.065; found 196.0654.

2696
Y. Wang, J. Wu, and P. Xia
2,2-Dimethylchroman (8a)
Following a similar procedure for the preparation of 7a, except for 5a as
the starting material and cyclohexane as the solvent, 3a was afforded in
15% yield and 8a was obtained as a colorless liquid (73%): 1H NMR
(300 MHz, CDCl3) d 1.31 (s, 6H, 2-CH3), 1.77 (t, J ¼ 6.6 Hz, 2H, 3-H),
2.74 (t, J ¼ 6.6 Hz, 2H, 4-H), 6.76–6.82 (m, 2H, 6-H, 8-H), 7.02–7.09
(m, 2H, 5-H, 7-H).
6-Chloro-2,2-dimethylchroman (8b)
Following a similar procedure for the preparation of 7a, except for 5b as the
starting material and cyclohexane as the solvent, 3b was afforded in 12%
1
yield, and 8b was obtained as a colorless liquid (39%): H NMR (300 MHz,
CDC13) d 1.31 (s, 6H, 2-CH3), 1.78 (t, J ¼ 6.6 Hz, 2H, 3-H), 2.74 (t, J ¼
6.6 Hz, 2H, 4-H), 6.70 (d, J ¼ 9.3 Hz, 1H, 8-H), 7.01–7.04 (m, 2H, 7-H, 5-H).
ACKNOWLEDGMENT
This research was supported by the grants from the National Natural Science
Foundation of China (No. 20272010 and 30200348) awarded to P. Xia and
Y. Chen, respectively, and the research grant (2002046069) for PhD program
from the National Education Administration of China awarded to P. Xia.
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