Synthesis of aromatic compounds containing a 1,1-dialkyl-2-trifluoromethyl group, a bioisostere of the tert-alkyl moiety

Article abstract of DOI:10.1016/j.bmcl.2007.09.053

1,1-Dialkyl-2-perfluoroalkyl compounds, which are potential metabolically stable bioisosteres of the tert-alkyl moiety, have been synthesized from the corresponding tertiary alcohols using titanium (IV) chloride-dimethylzinc or trimethylaluminium as the source of the methyl group. The synthetic methods proved to be versatile for synthesizing 1,1-dimethyl-2,2,2-trifluoroethyl compounds and analogs, including compounds containing aromatic and heterocyclic rings.

Full text of DOI:10.1016/j.bmcl.2007.09.053

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6079–6085
Synthesis of aromatic compounds containing a
1,1-dialkyl-2-trifluoromethyl group, a bioisostere
of the tert-alkyl moiety
Hirotaka Tanaka and Yuji Shishido*
Pfizer Global Research & Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan
Received 9 July 2007; revised 11 September 2007; accepted 13 September 2007
Available online 18 September 2007
Abstract—1,1-Dialkyl-2-perfluoroalkyl compounds, which are potential metabolically stable bioisosteres of the tert-alkyl moiety,
have been synthesized from the corresponding tertiary alcohols using titanium (IV) chloride—dimethylzinc or trimethylaluminium
as the source of the methyl group. The synthetic methods proved to be versatile for synthesizing 1,1-dimethyl-2,2,2-trifluoroethyl
compounds and analogs, including compounds containing aromatic and heterocyclic rings.
ꢀ 2007 Elsevier Ltd. All rights reserved.
In structure–activity relationship studies, bulky alkyl
groups, as exemplified by tert-butyls, are frequently crit-
ical for the biological activity,1 however, they often are
susceptible to rapid metabolic degradation such as
x-oxidation by P-450. In order to prevent this oxidative
metabolism, we have designed and synthesized fluori-
nated analogs such as the 1,1-dimethyl-2,2,2-trifluoro-
ethyl compounds which serve as metabolically stable
bioisosteres (Fig. 1).
crease of activity, possibly due to the electron-
withdrawing effect of the trifluoromethyl moiety. In
our neurokinin-1 antagonist program,2 we set out to
address the issue of rapid metabolism, i.e. clearance
in HLM, by the introduction of fluorine atoms di-
rectly on the tert-butyl moiety. Unfortunately, it was
found that mono- or di-fluorination of alcohol 1 or
aldehyde 4 by dimethylsulfur trifluoride (DAST)4 re-
sulted exclusively in the undesired compounds 3 and
6, respectively, as shown in Figure 3. The formation
of compound 3 and 6 can be explained by a migration
of the phenyl group to the adjacent carbon followed
by fluorination.4
In our neurokinin-1 and TRPV1 antagonist programs,
the 1,1-dimethyl-2,2,2-trifluoroethyl derivatives (B and
D) showed significantly improved stability in human
liver microsomes (HLM) while retaining the intrinsic
activity of the tert-butyl derivatives (A and C), as shown
in Figure 2. This report summarizes new synthetic
methods for the preparation of 1,1-dimethyl-2,2,2-triflu-
oroethyl compounds and related analogs, discovered
while prosecuting these two programs.2
Following this result, the preparation of 1,1-dimethyl-
2,2,2-trifluoroethyl compounds was investigated.
Methods for the trifluoromethylation5 of carboxylic
acid derivatives include direct fluorination using sulfur
tetrafluoride (SF4) or indirect fluorination via dithion-
ic acid (or esters) using xenon difluoride/bromo
trifluoride. However, neither of these reactions is prac-
tical on large scale. Consequently, our first attempt
was the direct geminal dimethylation of trifluorometh-
The sometimes unstable tert-butyl group has often
been replaced by the easily accessible and metaboli-
cally stable trifluoromethyl or trifluoromethoxy deriva-
tives3 as exemplified in Figure 2 for the TRPV1
antagonist program. However, in this case the modifi-
cation to a trifluoromethyl group resulted in a de-
ylketone
7 using dimethyltitanium dichloride, as
reported by Reetz,6 but the reaction provided mono-
methylated 8a instead as the major product without
any desired 9a, as shown in Figure 4. Since alcohol
8a is considered to be an intermediate of 9a, an addi-
tional step for the introduction of the second methyl
group was necessary. Thus, our efforts shifted toward
Keywords: Bioisostere; tert-Butyl; Dimethyltitanium dichloride; Tri-
methylaluminium; 1,1-Dimethyl-2,2,2-trifluoroethyl.
*
Corresponding author. E-mail: Yuji.Shishido@pfizer.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.09.053

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H. Tanaka, Y. Shishido / Bioorg. Med. Chem. Lett. 17 (2007) 6079–6085
Figure 1.
Figure 2.
Figure 3.
Figure 4.
the conversion of 8a to 9a. After several trials,7 it was
found that chlorination8 of the tertiary alcohol 8a
using titanium (IV) chloride (1 equiv) at 0 ꢁC followed
by displacement with a methyl group using the tita-
nium (IV) chloride (1 equiv)—dimethyl zinc (2 equiv)
combination7 at À78 ꢁC produced the desired product
9a in high combined yield (81%) for the two steps
(Method A). This reaction has been run on a 1 mole
scale to give 180 g of 9a, reproducibly.
limitation of this approach, as shown in Table 1.
While the methylation of non-cyclic analogs (entries
1 and 2) by method A proceeded smoothly, for cyclic
analogs elimination of hydrohalide or decomposition9
of intermediates 8e and 8f took place (entries 5 and
6). In order to address this issue, a one-pot method
(Method B) was found to be very effective in prevent-
ing the elimination reaction and instability during the
isolation. In entries 5 and 6, chlorination of the cyclic
tertiary alcohol using titanium (IV) chloride (2 equiv)
at À78 ꢁC followed by addition of dimethylzinc (2
equiv), all in one pot, afforded the desired products
This method was applied to a variety of tertiary alco-
hol analogs 8b–g in order to examine the scope and

H. Tanaka, Y. Shishido / Bioorg. Med. Chem. Lett. 17 (2007) 6079–6085
6081
Table 1. Methylation of tertiary alcohols using titanium (IV) chloride—dimethylzinc (Methods A and B)
Entry
Substrate
Product
Method (% yield)
HO
CF3
CF3
1
A (95), B (51)
MeO
MeO
8a
9a
HO
CF2CF3
CF2CF3
2
3
4
5
6
7
A (60)
MeO
MeO
9b
8b
HO
CF3
F
CF3
B (34)
MeO
MeO
F
9c
8c
F
OH
F
CF3
F
CF3
B (N.R.)
B (87)
MeO
MeO
F
MeO
MeO
8d
9d
9e
HO
CF3
CF3
CF3
8e
HO
CF3
B (92)
MeO
Br
MeO
Br
8f
9f
HO
CF3
CF3
N
B (N.R.)
N
9g
8g
tert-Alcohol derivatives 8a–g are prepared by trifluoromethylation of ketones using TMS-CF3 or Grignard reaction via corresponding halide and
1,1,1-trifluoroacetone.
(9e and 9f) in high yield.6 Method B is superior to
method A in terms of ease of operation as well as
yield. Entries 4 and 7 show the limitations of this pro-
tocol, since neither case gave appreciable amount of
expected product. Whether the failure of the reaction
is due to the stronger electron-withdrawing nature of
the aromatic ring, steric effects (entry 4), or in the case
of entry 7 the presence of an intramolecular hydrogen
bond, is unclear.
method A (entry 1) led to a mixture of recovered
starting material and alcohol 8d in a ratio of 1:4.
As shown in Table 2, other conditions (entries 2 and
8) also produced hydrolyzed product 8d as the major
product. It is assumed that 8d is formed via halogen–
metal exchange of 10d followed by hydrolysis during
the work-up without the insertion of the methyl
group. However, investigation of alternate conditions
resulted in the successful methylation of 10d: when
trimethylaluminium in cyclohexane was used as the
source of the methyl group (entry 6), the desired 9d
was obtained cleanly (Method C).
Methylation using method B (entry 4 in Table 1)
resulted in recovery of the starting material. Clearly,
a more drastic set of conditions for the chlorination
was needed. As expected, the reaction of 8d with
thionyl chloride (as the solvent) provided the desired
chloride 10d. However, the methylation of 10d using
The application of this method to 2-substituted het-
eroaryl derivatives using various reagents proved
difficult to implement since halogenation of the

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H. Tanaka, Y. Shishido / Bioorg. Med. Chem. Lett. 17 (2007) 6079–6085
Table 2. Methylation of tertiary chlorides using trimethylaluminium (Method C)
Entry
Lewis acid (2 equiv)
Me source (4 equiv)
Solvent
Productse
10d (chloride)
9d (desired)
8d (hydrolysis)
1a
2a
3a
4a
5b
6b
7b,c
8d
TiCl4
TiCl4
Me2Zn
Me3Al
Me3Al
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Tolueneg
Cyclohexane
THF
20
0
0
80
90
10
0
trace
AlCl3
BF3ÆEt2O
0
Me3Al
Me3Al
100
0
Majorf (72)
5
Me3Al
MeMgBr
MeMgBr
0
95f
20
0
0
50
40
30
60
HMPT
a Reaction condition; r.t. 16 h.
b Reaction condition; reflux, 16 h.
c LiBr (1.5 equiv) as an additive was added.
d Reaction condition; 110 ꢁC, 4 h.
e The reaction was analyzed by 1H NMR analysis of crude product.
f Isolated yield.
g Some toluene adducts were formed.
Table 3. Heteroaryl compounds
Entry
Substrate
Conditions
Solventa
Product
Yield (%)
Reagent (equiv)
Time (h) in rt
AlMe3 (4)
AlMe3(4)
Cyclohexane
CH2Cl2
1.5
1.5
6
80
Br
Br
Br
88
CF3
CF3
73% recoveryb
26% recoveryc
86
1
N
AlMe3 (1.2)
AlMe3 (2.2)
AlMe3 (2)
Cyclohexane (suspension)
Cyclohexane (suspension)
CH2Cl2
N
17
OMs
15
6
1.5
Br
CF3
CF3
Cl
2
3
Me2AlCl (4)
Me3Al (2)
CH2Cl2
CH2Cl2
1.5
1.5
95
91
N
N
OMs
18
15
CF3
CF3
N
N
19a
OMs
16a
Br
N
Br
CF3
CF3
CF3
4
5
Me3Al (2)
Me3Al (2)
CH2Cl2
Toluene
1.5
1.5
65d, 96d
N
19b
OMs
16b
CF3
I
I
57
OMs
16c
19c
Methylation of tertiary mesylates using aluminium reagents (Method D).
a All reactions were homogeneous solutions unless indicated.
b Mixture of 15 and 17 in a 98: <2 ratio.
c Mixture of 15 and 17 in a 94: <6 ratio.
d The conversion to 19b was carried out in 64% and 96% yield including olefine derivative of 4.5% and 10%, respectively.

H. Tanaka, Y. Shishido / Bioorg. Med. Chem. Lett. 17 (2007) 6079–6085
6083
Appendix A. General procedure
Method A: 1-methoxy-4-(2,2,2-trifluoro-1-chloro-1-
methylethyl)benzene (10a). To a stirred solution of
the alcohol 8a (5.00 g, 22.7 mmol) in dry dichlorometh-
ane (50 ml) was added titanium (IV) chloride
(2.37 ml ꢀ 4.09 g, 21.57 mmol) via a syringe with ice-
cooling. The reaction mixture was stirred at the same
temperature for 1.5 h. The mixture was poured into
ice-water (150 g) and stirred for 15 min. The organic
layer was separated, and the aqueous layer was ex-
tracted with dichloromethane (3·). The combined solu-
tion was washed with satd NaHCO3 aqueous solution,
brine, dried over anhydrous potassium carbonate, and
concentrated in vacuo to give the crude product
(5.31 g, 98%) as a yellow oil. 1H NMR (270 MHz,
CDCl3)d 2.12 (3H, s), 3.83 (3H, s), 6.83–6.96 (2H, m),
7.52–7.63 (2H, m).
Scheme 1. Reagents: (a) N(Me)OMe-HCl, HBTU, TEA, DMF,
90%; (b) MeMgBr, THF, 95%; (c) TMS-CF3, AcOLi (cat), DMF,
then dil HCl aq, THF, 96%; (d) NaH, methanesulfonyl chloride,
THF, 96%.
tert-alcohol moiety was unsuccessful (entry 7 in Table
1). Recently, however, we have found a sequence that
allows for the preparation of the 2-(1,1-dimethyl-2,2,2-
trifluoroethyl)pyridine and quinoline moiety. This was
accomplished by sequential O-mesylation of the ter-
tiary alcohol derivatives followed by methylation.
The typical O-mesyl derivative 15 was synthesized
from the corresponding carboxylic acid 11 in four
steps as shown in Scheme 1. Treatment of Weinreb
amide10 12 with methylmagnesium halide afforded ke-
tone 13, which was converted to the mesylate 15 by
the formation of the tertiary alcohol11 using Ruppert’s
reagent (TMS-CF3), followed by O-mesylation using
sodium hydride.
1-Methoxy-4-(2,2,2-trifluoro-1,1-dimethylethyl)benzene
(9a). To a stirred solution of titanium (IV) chloride
(111 ml, 1.02 mol) in dry dichloromethane (200 ml)
was added a solution of 1.0 M dimethylzinc in hexane
(2050 ml, 2.05 mol) over a period of 1 h at À78 ꢁC (inner
temperature; À78 to À60 ꢁC). After stirring for 20 min
at the same temperature, to this mixture was added a
solution of compound 10a (243 g, 1.02 mol) in dry
dichloromethane (150 ml) dropwise, keeping the inner
temperature below À50 ꢁC. After the cooling bath was
removed the reaction temperature climbed rapidly to
À 37 ꢁC, and the mixture was cooled again to keep the
temperature below À40 ꢁC. Finally the temperature of
the reaction mixture was raised to 0 ꢁC and the reaction
was quenched with water-saturated dichloromethane
(150 ml), then water (200 ml), all the while cooling in a
dry ice–methanol bath (inner temperature: À40 ꢁC).
After bringing the mixture to ambient temperature,
additional water (1 L) was added and the mixture was
stirred for 30 min. The organic layer was separated,
and the aqueous layer was extracted with dichlorometh-
ane. The combined organic solution was washed with
water, satd NaHCO3 aqueous solution, brine, dried over
sodium sulfate, and concentrated in vacuo to give the
crude product, which was distilled to give the main frac-
tion (180.9 g) at bp 88–90 ꢁC/2 ꢀ 4 mm Hg. The main
fraction solidified upon standing at room temperature;
mp 52–52.2 ꢁC (white solid). 1H NMR (270 MHz,
CDCl3)d 1.55 (6H, s), 3.81 (3H, s), 6.84–6.93 (2H, m),
7.35–7.45 (2H, m).
The methylation of substrate 15 was then investigated
using varying combinations of reagent and solvent, as
detailed in Table 3. A positive result was obtained
when 15 was treated with trimethylaluminium (2.0
equiv) in dichloromethane solution at 0 ꢁC to ambient
temperature, thus providing the expected 1,1-dimethyl-
2, 2, 2-trifluoroethyl derivative 17 in high yield
(Method D). Dichloromethane was superior over
hydrocarbon solvents since it allows a homogeneous
solution during the methylation step. Switching to
dimethylaluminium chloride as the potential methyl
source gave the chloride derivative 18 in 95% yield.
This method can also be applied to aromatic com-
pounds (entry 5), similarly to Method A.
The 1,1-dialkyl-2-perfluoroalkyl derivatives, which are
potentially useful as metabolically stable bioisosteres
of tert-alkyl compounds, can be synthesized from
various tertiary alcohol derivatives using titanium chlo-
ride—dimethylzinc or trimethylaluminium. The one-pot
(Method B) conversion of cyclic tertiary alcohols pro-
vides 1,1-dimethyl-2,2,2-trifluoroethyl analogs without
by-products, while the methylation of heteroaryls using
trimethylaluminium (Method D) is a convenient method
that does not require low temperature or the prepara-
tion of a reagent.
Method B: To a stirred solution of compound 8a
(1000 mg, 4.63 mmol) in dry dichloromethane (15 ml)
was added titanium (IV) chloride (1.00 ml, 9.25 mmol)
via a syringe at À78 ꢁC (dark yellow–yellow solution).
After 1.5 h at the same temperature, a 1.0 M dimethyl-
zinc in hexane solution (18.5 ml, 18.5 mmol) was added
dropwise at À78 ꢁC. The reaction mixture was allowed
to warm to ambient temperature and stirred for 3.5 h.
The reaction mixture was poured into ice-water and stir-
red for 15 min. The aqueous layer was extracted with
dichloromethane (3·) and the combined solution was
washed with brine (1·), dried over sodium sulfate,
and concentrated in vacuo to give the crude product.
Acknowledgments
The authors thank Mr. Kazuo Ando for performing
the bulk synthesis of compound 9a, Dr. Bernard
Hulin of ChemWrite for the editing of the manuscript,
and Dr. Kunio Satake for providing helpful advice.

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H. Tanaka, Y. Shishido / Bioorg. Med. Chem. Lett. 17 (2007) 6079–6085
The crude product was purified by column chromato-
graphy on silica gel (150 g) eluting with hexane–ethyl
acetate (100:1) to give compound 9a (515 mg, 51% yield)
as a white solid.
mixture was stirred at ambient temperature for
90 min. The mixture was quenched with satd NaHCO3
(3 ml), then brine (1 ml). The mixture was filtered
though a pad of celite and the filter cake was washed
with ethyl acetate. The filtrate and washings were
washed with brine, dried over sodium sulfate, and con-
centrated in vacuo to give crude product (133 mg).
The crude product was purified by column chromatog-
raphy on packaged silica gel L size (120 g) with hexane
only to furnish the compound 17 (103 mg, 86% yield)
1H NMR (270 MHz, CDCl3)d 1.55 (6H, s), 3.81 (3H, s),
6.84–6.93 (2H, m), 7.35–7.45 (2H, m). Anal. Calcd for
C11H13F3O: C, 60.54; H, 6.00. Found: C, 60.58; H, 6.03.
Method C: 2-(1-chloro-2,2,2-trifluoro-1-meyhylethyl)-
1,3-difluoro-5-methoxybenzene (10d). A thionyl chloride
(25 ml) solution of compound 8d (8.7 g, 34.1 mmol) and
pyridine (26 mg, 0.34 mmol) was stirred at 70 ꢁC for 3 h.
The reaction was concentrated in vacuo and diluted with
water carefully. The product was extracted with hexane
and the organic layer was dried over sodium sulfate, fil-
tered, and concentrated to furnish compound 10d
(8.84 g, 94% yield) as a colorless oil. 1H NMR
(270 MHz, CDCl3)d 2.24–2.29 (3H, m), 3.81 (3H, s),
6.44–6.54 (2H, m).
1
as a colorless oil. H NMR (300 MHz, CDCl3) d 1.72
(6H, s), 7.66 (1H, d, J = 8.8 Hz), 7.75–7.80 (1H, m),
7.96–8.00 (2H, m), 8.06 (1H, d, J = 8.8 Hz). MS
(ESI): m/z 318, 320 (M+H)+.
References and notes
1. References on TRPV-1 antagonists BCTC (a) Valenzano,
K. J.; Grant, E. R.; Wu, G.; Hachicha, M.; Schmid, L.;
Tafesse, L.; Sun, Q.; Rotshteyn, Y.; Francis, J.; Limberis,
J.; Malik, S.; Whittemore, E. R.; Hodges, D. J.
Pharmacol. Exp. Ther. 2003, 306, 377; AMG 9810 (b)
Gavva, N. R.; Tamir, R.; Qu, Y.; Klionsky, L.; Zhang,
T. J.; Immke, D.; Wang, J.; Zhu, D.; Vanderah, T. W.;
Porreca, F.; Doherty, E. M.; Norman, M. H.; Wild, K.
D.; Bannon, A. W.; Louis, J-C.; Treanor, J. J. S. J.
Pharmacol. Exp. Ther. 2005, 313, 474; N-(4-tert-Butyl-
phenyl)-4-(3-methylpyridine-2-yl)benzamide (c) Park,
H.-g.; Choi, J.-y.; Kim, M.-h.; Choi, S.-h.; Park, M.-k.;
Lee, J.; Suh, Y.-G.; Cho, H.; Oh, U.; Kim, H.-D.; Joo,
Y. H.; Shin, S. S.; Kim, J. K.; Jeong, Y. S.; Koh, H.-J.;
Park, Y.-H.; Jew, S.-s. Bioorg. Med. Chem. Lett. 2005,
15, 631; SC-0030 (d) Suh, Y.-G.; Lee, Y.-S.; Min, K.-H.;
Park, O.-H.; Seung, H.-S.; Kim, H.-D.; Park, H.-G.;
Choi, J.-Y.; Lee, J.; Kang, S.-W.; Oh, U.-t.; Koo, J.-y.;
Joo, Y.-H.; Kim, S.-Y.; Kim, J. K.; Park, Y.-H. Bioorg.
Med. Chem. Lett. 2003, 13, 4389; (e) References regard-
ing to NK-1 antagonists: Ito, F.; Kondo, H.; Shimada,
K.; Nakane, M.; Lowe, J. A. III; Rosen, T.J.; Yang, B.V.
WO 9221677 A1.
2. (a) Satake, K.; Shishido, Y.; Wakabayashi, H. WO
9708144 A1 (NK-1 antagonist in Pfizer); (b) Bakthavat-
chalam, R.; Blum, C. A.; Brielmann, H.; Darrow, J.W.;
De Lombaert, S.; Yoon, T.; Zheng, X. WO 2004056774;
(c) Park, H.-g.; Choi, J.-y.; Kim, M.-h.; Choi, S.-h.; Park,
M.-k.; Lee, J.; Suh, Y.-G.; Cho, H.; Oh, U.; Kim, H.-D.;
Joo, Y. H.; Shin, S. S.; Kim, J. K.; Jeong, Y. S.; Koh,
H.-J.; Park, Y.-H.; Jew, S.-s. Bioorg. Med. Chem. Lett
2005, 15, 631.
3. (a) Trafts, K. W., Jr. In Steric Effects in Organic
Chemistry; Newman, M. S., Ed.; John Wiley and Sons:
New York, 1965; p 556; (b) Macphee, J. A.; Panaye, A.;
Dubois, J.-E. Tetrahedron 1978, 34, 1616.
1,3-Difluoro-5-methoxy-2-(2,2,2-trifluoro-1,1-dimethyleth-
yl)benzene (9d). To a cyclohexane (100 ml) solution of
compound 10 d (8.84 g, 32.2 mmol) was added a 1.0 M
hexane solution of trimethylaluminium (129 ml,
129 mmol) at room temperature and the mixture was stir-
red at reflux for 4 h. The reaction was quenched with a
2 M hydrochloride aqueous solution, extracted with hex-
ane, followed by drying over sodium sulfate, filtration,
and evaporation to furnish 7.9 g (97% yield) of the title
compound as a colorless oil. 1H NMR (300 MHz,
CDCl3) d 1.71 (6H, s), 3.78 (3H, s), 6.39–6.49 (2H, m).
Method D: 1-(6-bromoquinolin-2-yl)-2,2,2-trifluoro-1-
methylethyl methanesulfonate (15). To a stirred sus-
pension of 60% sodium hydride (1.38 g, 34.5 mmol)
in tetrahydrofuran (25 ml) was added a solution of
compound 14 (5.52 g, 17.2 mmol) in tetrahydrofuran
(20 ml) dropwise with ice-cooling (after the removal
of ice-bath, hydrogen gas was generated). The reaction
mixture was stirred at ambient temperature for 1 h,
then 3 h at 40 ꢁC, and to this was added dropwise a
solution of methanesulfonyl chloride (3.95 g,
34.5 mmol) in tetrahydrofuran (30 ml) at ambient tem-
perature. After 1h at same temperature, the mixture
was heated at 40 ꢁC for 2 h. The mixture was
quenched with water (ca 50 ml; carefully), then satd
NaHCO3 solution, and extracted with ethyl acetate
(3·). The combined solution was washed with brine,
dried over sodium sulfate and concentrated in vacuo
to give crude product, which was purified by column
chromatography on silica gel (300 g) with hexane–ethyl
acetate (5:1–3:1) to furnish the compound 15 (6.57 g,
96% yield ) as a white solid. 1H NMR (300 MHz,
CDCl3) d 2.45 (3H, s), 3.24 (3H, s), 7.81–7.86 (2H,
m), 7.96–8.05 (2H, m), 8.17 (1H, d, J = 8.8 Hz). MS
(ESI): m/z 397, 399 (M+H)+.
4. Middleton, W. J. J. Org. Chem. 1975, 40, 574.
5. (a) Hasek, W. R.; Smith, W. C.; Engelhardt, V. A. J. Am.
Chem. Soc 1960, 82, 543; (b) Rozen, S.; Mishani, E.
J. Chem. Soc. Chem. Commun. 1994, 2081.
6. (a) Reetz, M. T.; Westermann, J.; Steinback, R. J. Chem.
Soc. Chem. Commun. 1981, 237; (b) Reetz, M. T.;
Westermann, J. J. Org. Chem. 1983, 48, 254; (c) Reetz,
M. T.; Westermann, J.; Steinback, R. Agnew. . Chem. Int.
Ed. Engel. 1980, 19, 1; (d) Reetz, M. T.; Westermann, J.;
Kyung, S.-h. Chem. Ber. 1985, 118, 1050.
6-Bromo-2-(2,2,2-trifluoro-1,1-dimethylethyl)quinoline
(17). To a stirred solution of compound 15 (150 mg,
0.37 mmol) in dry dichloromethane (3 ml) was added
dropwise a 2.0 M trimethylaluminium in hexane solu-
tion (377ll, 0.75 mmol) at ice-cooling. The reaction
7. At the beginning of the NK-1 project, the dimethyl-
zinc reagent was only available commercially as
toluene solution. In the course of the methylation by
a

H. Tanaka, Y. Shishido / Bioorg. Med. Chem. Lett. 17 (2007) 6079–6085
6085
dimethylzinc in toluene, some toluene adducts were
formed, but a 1:2 titanium chloride: dimethyl zinc
mixture gave the dimethyl derivatives without toluene
by-products. This problem has also been avoided
through the use of hexane as the solvent Bonnet-
Delpon, D.; Charpentier-Morize, M.; Jacquot, R. J.
Org. Chem. 1988, 53, 759.
9. The treatment of 5-methoxy-1-(trifluoromethyl)-2, 3-dihy-
dro-1H-inden-1-ol (12e) with PBr3 in dichloromethane
(40 ꢁC) gave the indene derivative in quantitative yield,
while reaction with TiCl4 (1 equiv) in dichloromethane
(0 ꢁC) resulted in decomposition during the workup.
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