An efficient and scalable synthesis of (2R,αS)-3,4-dihydro-2-[3-(1,1, 2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-α- (trifluoromethyl)-1(2H)-quinolineethanol: A potent CETP inhibitor

Article abstract of DOI:10.1002/jhet.488

An efficient and scalable synthesis of the potent CETP inhibitor, (2R,αS)-3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl] -5-[3-(trifluoromethoxy)phenyl]-α-(trifluoromethyl)-1(2H) -quinolineethanol 1, is described. One of the important intermediates,

Full text of DOI:10.1002/jhet.488

1406
An Efficient and Scalable Synthesis of (2R,aS)-3,4-Dihydro-2-
[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)-
phenyl]-a-(trifluoromethyl)-1(2H)-quinolineethanol: A Potent
CETP Inhibitor
Vol 47
Aihua Wang,* Yan Zhang, Songfeng Lu, William V. Murray,
and Gee-Hong Kuo
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C. Welsh &
McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477-0776
*E-mail: awang1@its.jnj.com
Received January 27, 2010
DOI 10.1002/jhet.488
Published online 30 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and scalable synthesis of the potent CETP inhibitor, (2R,aS)-3,4-dihydro-2-[3-(1,1,2,2-tet-
rafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)phenyl]-a-(trifluoromethyl)-1(2H)-quinolineethanol 1, is
described. One of the important intermediates, tetrahydroquinoline 10, was readily prepared by reductive
cyclization of nitroketone 9 in high yield. Asymmetric synthesis of 10 with high enantiomeric excess
(>80% ee) was also developed.
J. Heterocyclic Chem., 47, 1406 (2010).
INTRODUCTION
of CETP has been proposed as a strategy to raise HDL-
C level [10], thus increases the efficiency of RCT.
Low levels of high density lipoprotein-cholesterol
(HDL-C) and high levels of low density lipoprotein-cho-
lesterol (LDL-C) are independent risk factors for the de-
velopment of atherosclerosis and eventually coronary
heart disease (CHD), which remain the leading cause of
death in the developed countries [1–3]. HDL-C plays
important role in removal of excess cholesterol from pe-
ripheral cells to the liver for metabolic degradation in a
reverse cholesterol transport (RCT) process [4–6].
Therefore, the increase in HDL-C level offers a new
and promising therapeutical principle for treatment of
CHD [7]. Plasma protein cholesteryl ester (CE) transfer
protein (CETP) mediates the transfer of CE from HDL
to very low density lipoprotein (VLDL) and LDL in
exchange for triglyceride [8,9]. As a result, the disad-
vantage of this action is a reduction in HDL-C level and
with increase in VLDL-C and LDL-C levels. Inhibition
Compound 1 has been identified as a potent CETP in-
hibitor [11]. It showed IC50 in 34–44 nM range and
increased HDL-C in human CETP transgenic mice. The
original preparation of 1 [11c] was lengthy and involved
the use of some highly toxic and potentially explosive
chemicals. To supply a large quantity of material 1 for
further in vivo and toxicity studies, an efficient and scal-
able synthesis was required. In this article, we describe
the chemical synthesis that was used successfully in the
preparation of multigram quantities of compound 1.
As illustrated by the retrosynthetic analysis in Scheme
1, the feature of our strategy involved efficient construc-
tion of the piperidine ring. We envisioned that trans-
forming nitroketone 9 to tetrahydroquinoline 10 would
be the key step in achieving our goal. This could be
realized by reductive cyclization of nitroketone 9 to a
racemic mixture of 10 from which the (R)-enantiomer
C
V
2010 HeteroCorporation

November 2010 Efficient and Scalable Synthesis of (2R,aS)-3,4-Dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)
phenyl]-5-[3-(trifluoromethoxy)phenyl]-a-(trifluoromethyl)-1(2H)-quinolineethanol
1407
Scheme 1. Retrosynthetic analysis
yield, along with 5% of C,O-dialkylation by-product 8b.
Without separation of the two compounds, the mixture
was converted to the same nitroketone 9 upon treatment
with hydrochloric acid in hot acetic acid [15]. Under
normal catalytic hydrogenation conditions, reductive cy-
clization of nitroketone 9 occurred to form tetrahydro-
quinoline 10 in essentially quantitative yield. The (R)-10
was collected by chiral HPLC resolution of the racemic
mixture. The R configuration at the 2 position of the tet-
rahydroquinoline ring of (R)-10 was known by compar-
20
ing its optical rotation, [a]D –13.3ꢀ (c1.0, CHCl3),
20
with that of (R)-10, [a]D –12.9ꢀ (c 1.0, CHCl3),
obtained from an asymmetric synthesis shown below in
Scheme 4. In the presence of catalytic amount of Lewis
acid ytterbium trifluoromethanesulfonate, N-alkylation
of (R)-10 with commercially available ꢁ90% enriched
(S)-1,1,1-trifluoro-2,3-epoxypropane 11 occurred to pro-
duce the target 1 in 80% yield [16]. Under these condi-
tions, the ring opening of the epoxide proceeded with
complete regioselectivity.
Although this route is attractive due to its simplicity
and rapid access to 1, it suffers from the obvious need for
resolution of racemic tetrahydroquinoline 10 and econ-
omy of synthesis. We then turned our attention toward the
development of an asymmetric approach to (R)-10. It was
hoped that by controlling reaction conditions, the hydro-
genation of nitroketone 9 could stop at aminoketone or
cyclic-imine stage, and both of the materials could be
reduced to (R)-10 in high enantiomeric purity by subject-
ing to chiral sodium triacyloxyborohydride [17] as dem-
onstrated in our syntheses of similar analogues [18]. How-
ever, preliminary investigation by changing H2 pressure,
solvents, and catalysts only yielded a mixture of starting
material 9 and partially reduced intermediates. The strat-
egy of stepwise reduction of nitroketone 9 to aminoketone
and subsequently enantioselective reductive cyclization of
which to (R)-10 was also attempted by using inorganic
reducing reagents such as Na2S2O4, SnCl2, and FeSO3.
Unfortunately, it only resulted in the formation of quino-
line 12 (eq. 1):
could be isolated by chiral HPLC separation. (R)-10
might also be prepared in a stepwise fashion by asym-
metric reductive cyclization of 9. The nitroketone 9
could be derived from benzyl bromide 5 and b-keto
ester 7 by alkylation and decarboxylation. The synthons
5 and 7 should be easily assembled from commercially
available 5-bromo-6-methylnitrobenzene 2, 3-(trifluoro-
methoxy)phenyl-boronic acid 3, and 3-tetrafluoroethoxy-
benzoic acid 6, respectively.
The preparation of benzyl bromide 5 and b-keto ester 7
is shown in Scheme 2, and the reaction scale is given in
parentheses. Suzuki reaction [12] of 5-bromo-6-methylni-
trobenzene 2 with 3-(trifluoromethoxy)phenylboronic acid
3 provided 28 g of 4 in 96% yield. In a solvent-free system,
bromination [13] of 4 (26 g) with N-bromosuccimide and
AIBN at 90ꢀC for 5 h gave benzyl bromide 5 in 95% yield.
The b-keto ester 7 was synthesized by acylation of ethyl
hydrogen malonate with 3-tetrafluoroethoxybenzoyl chlo-
ride, followed by decarboxylation during acidic work-up
procedure [14]. The product was a mixture of b-keto ester
7a and its tautomer enol 7b in ꢁ3:1 ratio.
Scheme 2
With both building synthons 5 and 7 available, the
stage was set to generate the important intermediate 8a
by alkylation of b-keto ester 7 with benzyl bromide 5
(Scheme 3). However, the reaction was complicated by
the formation of 8a, C,O-dialkylation compound 8b, and
a,a-dialkylation by-product 8c. Different reaction condi-
tions were explored by varying a variety of bases (such
as NaN(SiMe3)2, NaH, n-BuLi, Cs2CO3, and K2CO3),
solvents (such as THF, DMF, CH3CN, and acetone),
reaction temperature, the order of reagent addition. It
was found that using K2CO3 in acetone was the best
conditions tried to give the desired product 8a in 87%
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. Wang, Y. Zhang, S. Lu, W. V. Murray, and G.-H. Kuo
Vol 47
Scheme 3
assigned based upon the precedent illustrated in Corey and
Helal’s article [19]. The hydroxyl group in 13 was then
converted to a good leaving group mesylate 14. Upon treat-
ment of 14 with SnCl2 in ethanol, the nitro group was
reduced to amino functionality [21] and followed by spon-
taneous intramolecular displacement of the mesylate to
yield the ring closed (R)-10 in 80–85% ee [20]. During this
transformation, the inversion of the original stereocenter
occurred to give the R absolute configuration at the 2 posi-
tion of the tetrahydroquinoline ring of 10. A small erosion
of ee was observed during the cyclization step due to a
competitive ionization pathway.
(1)
Alternatively, the required stereocenter was introduced
by utilizing Corey’s oxazaborolidine-borane methodology
[19]. Using the R-Me CBS oxazaborolidine reagent 15,
nitroketone 9 was enantioselectively reduced to (S)-alcohol
13 in 91% yield and >90% enantiomeric excess (% ee)
[20] (Scheme 4). The S configuration of alcohol 13 was
In conclusion, we have developed a very efficient, scal-
able, and high yielding synthesis of (2R,aS)-3,4-dihydro-2-
[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluorome-
thoxy)phenyl]-a-(trifluoromethyl)-1(2H)-quinolineethanol
1. This method provides access to 1 in multigram quanti-
ties reliably.
Scheme 4
EXPERIMENTAL
2-Methyl-3-nitro-30-trifluoromethoxy-biphenyl (4). A mix-
ture of 2-bromo-6-nitrotoluene 2 (21.5 g, 99.5 mmol), 3-tri-
fluoromethoxylbenzeneboronic acid 3 (27.0 g, 131.1 mmol),
Pd(PPh3)2Cl2 (3.50 g, 5.0 mmol), and 2.0M K2CO3 (120 mL,
240 mmol) in dioxane (330 mL) was degassed with N2 and
then heated at 100ꢀC for 3 h. After cooling to room tempera-
ture, the reaction mixture was passed through Celite and parti-
tioned between EtOAc and brine. The combined organic
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010 Efficient and Scalable Synthesis of (2R,aS)-3,4-Dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)
phenyl]-5-[3-(trifluoromethoxy)phenyl]-a-(trifluoromethyl)-1(2H)-quinolineethanol
1409
phases were dried (MgSO4), concentrated, and purified by flash
column chromatography (1–10% EtOAc in hexane) to give
28.27 g (96%) of 4 as a light yellow oil. H NMR (300 MHz,
chromatography (5–15% EtOAc in hexane) to give 22.5 g
(87%) of 8a as a yellow oil. 1H NMR (300 MHz, CDCl3) d
7.85 (dd, J ¼ 6.5, 2.7 Hz, 1 H), 7.59–7.54 (m, 2 H), 7.48–7.36
(m, 5 H), 7.26–7.21 (m, 2 H), 7.14 (s, 1 H), 5.92 (tt, J ¼ 53.0,
2.5 Hz, 1 H), 4.21 (t, J ¼ 7.0 Hz, 1 H), 4.02–3.82 (m, 2 H),
3.74–3.59 (m, 2 H), 0.96 (t, J ¼ 7.1 Hz, 3 H); MS (ES) m/z:
626 (MþNaþ). Anal. Calcd for C27H20F7NO7: C, 53.74; H,
3.34; N, 2.32. Found: C, 54.00; H, 3.02; N, 2.36.
1
CDCl3) d 7.85 (d, J ¼ 7.8 Hz, 1 H), 7.74–7.38 (m, 3 H),
7.31–7.23 (m, 2 H), 7.19 (s, 1 H), 2.37 (s, 3 H).
2-Bromomethyl-3-nitro-30-trifluoromethoxy-biphenyl (5). A
mixture of 4 (26.1 g, 87.8 mmol), NBS (20.3 g, 114 mmol), and
AIBN (1.44 g, 8.77 mmol) was degassed with N2 and then heated
at 85ꢀC. After 20 min, it began to react vigorously. After 2 h, the
temperature was raised to 90ꢀC, and the mixture was heated for 3
more hours. After cooling to room temperature, the reaction mix-
ture was diluted with hexane. The solid was filtered off, and the
filtrate was concentrated to give 31.47 g (95%) of 5 as a yellow
3-(3-Nitro-30-trifluoromethoxy-biphenyl-2-yl)-1-[3-(1, 1,2,2-
tetrafluoro-ethoxy)-phenyl]-propan-1-one (9). A solution of 8a
(22.5 g, 37.3 mmol) in concentrated HCl (85 mL) and HOAc
(140 mL) was heated at 100ꢀC for 9 h. TLC (20% EtOAc in hex-
ane) showed the completion of reaction. After cooling down to
room temperature, HOAc was evaporated through a rotary evapo-
rator. The residue was diluted with water (200 mL) and cooled in
an ice-bath. To the mixture was added 6N NaOH (ꢁ80 mL) until
basic judged by pH paper. The aqueous solution was extracted
with EtOAc (ꢂ3), and the combined organic layers were dried
(Na2SO4), concentrated, and purified by flash column chromatog-
raphy (10–20% EtOAc in hexane) to give 18.4 g (93%) of 9 as a
1
oil. H NMR (300 MHz, CDCl3) d 8.00 (dd, J ¼ 2.0, 2.0, 1 H),
7.58–7.49 (m, 3 H), 7.41–7.28 (m, 3 H), 4.69 (s, 2 H).
3-Oxo-3-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-propionic
acid ethyl ester (7). To an ice-cooled solution of 3-tetrafluor-
oethoxy-benzoic acid 6 (40.0 g, 0.168 mol) was added SOCl2
(59.0 mL, 0.809 mol) dropwise. After addition, the ice-bath
was removed, and the mixture was stirred at room temperature
for 3 h followed by heating at 50ꢀC for 2 h and 75ꢀC for 3 h.
The reaction mixture was left stirring at room temperature
overnight. After removing of SOCl2 in vacuo, to the residue
was added dry toluene and concentrated (20 mL ꢂ 3). After
on high vacuum line for 5 h, the acyl chloride was obtained as
a clear oil (41.0 g, 95%).
1
yellow oil. H NMR (400 MHz, CDCl3) d 7.90–7.84 (m, 1 H),
7.71–7.64 (m, 2 H), 7.50–7.37 (m, 5 H), 7.28–7.22 (m, 2 H), 7.17
(s, 1 H), 5.91 (tt, J ¼ 53.0, 2.7 Hz, 1 H), 3.21–3.08 (m, 4 H); MS
(ES) m/z: 554 (MþNaþ); HRMS (ESI) calcd for C24H16F7NO5
(M þ Hþ) m/z 532.0995, found m/z 532.0989. Anal. Calcd for
C24H16F7NO5: C, 54.25; H, 3.01; N, 2.64. Found: C, 54.38; H,
2.59; N, 2.89.
To a solution of EtOCOCH2CO2H (16.1 g, 0.122 mol) in THF
(120 mL) at –78ꢀC was added i-PrMgCl (2.0M in THF, 122 mL,
0.244 mol) dropwise through an additional funnel. After stirring
at –78ꢀC for 1 h, the above prepared acyl chloride (20.9 g, 0.0815
mol) in THF (80 mL) was added via an addition funnel. The reac-
tion mixture was stirred at –78ꢀC for 1 h and RT for 2 h.
The reaction flask was cooled in an ice-bath, and ꢁ100 mL
of 1N HCl was added dropwise until pH < 1. Upon addition
of 1N HCl, some precipitate formed and stirring became dif-
ficult. The precipitated solid gradually dissolved during further
addition of 1N HCl. The organic layer was separated and the
aqueous layer was extracted with EtOAc. The combined or-
ganic phases were dried, concentrated, and purified by flash
column chromatography (5–10% EtOAc in hexane) to give
21.8 g (83%) of 7 as a yellow oil.
2-[3-(1,1,2,2-Tetrafluoro-ethoxy)-phenyl]-5-(3-trifluorome-
thoxy-phenyl)-1,2,3,4-tetrahydro-quinoline (10). A mixture
of 9 (5.70 g, 10.7 mmol) and 10% Pd/C (615 mg) in EtOAc
(ꢁ100 mL) was shaken in a par-shaker under 50 psi H2 for 19
h. The reaction mixture was filtered through Celite and the
solid was washed with EtOAc. The filtrate was concentrated
and dried under vacuum to give 5.20 g (100%) of 10 as a yel-
low oil. 1H NMR (400 MHz, CDCl3) d 7.40–7.29 (m, 3 H),
7.28–7.23 (m, 2 H), 7.20–7.05 (m, 4 H), 6.61 (d, J ¼ 7.8 Hz,
2 H), 5.92 (tt, J ¼ 53.0, 2.8 Hz, 1 H), 4.50 (dd, J ¼ 8.9, 3.3
Hz, 1 H), 2.75 (ddd, J ¼ 16.4, 10.6, 5.1 Hz, 1 H), 2.51 (dt, J
¼ 16.5, 4.9 Hz, 1 H), 2.10–2.02 (m, 1 H), 1.91–1.81 (m, 1 H);
MS (ES) m/z: 486 (MþHþ). Anal. Calcd for C24H18F7NO2: C,
59.39; H, 3.74; N, 2.89. Found: C, 59.80; H, 3.50; N, 2.80.
(2R)-1,2,3,4-Tetrahydro-2-[3-(1,1,2,2-tetrafluoroethoxy)-
phenyl]-5-[3-(trifluoromethoxy)phenyl]quinoline (10). Chiral
HPLC resolution of racemate (6)-10: 16.5 g of (6)-10 was
separated by using Chiralcel OJ eluting with 80% heptane–
20% ethanol at 80 mL/min and wavelength 220 nm. A total of
1
7a. H NMR (300 MHz, CDCl3) d 7.89–7.85 (m, 1 H), 7.80
(s, 1 H), 7.56–7.51 (m, 1 H), 7.48–7.45 (m, 1 H), 5.95 (tt, J ¼
53.0, 2.5 Hz, 1 H), 4.23 (q, J ¼ 7.2 Hz, 2 H), 3.98 (s, 2 H),
1.27 (t, J ¼ 7.2 Hz, 3 H); MS (ES) m/z: 331 (MþNaþ); HRMS
(ESI) calcd for C13H12F4O4 (M þ Hþ) m/z 309.0750, found m/
z 309.0751.
6.46 g of (R)-10 and 5.91 g of (S)-10 were obtained in 99.99%
1
7b. H NMR (300 MHz, CDCl3) d 12.6 (s, 1 H), 7.71–7.68
20
and 99.5% ee, respectively. (R)-10: [a]D
CHCl3).
–13.3ꢀ (c1.0,
(m, 1 H), 7.63 (s, 1 H), 7.45–7.42 (m, 1 H), 7.34–7.31 (m, 1
H), 5.94 (tt, J ¼ 53.0, 2.5 Hz, 1 H), 5.68 (s, 1 H), 4.29 (q, J
¼ 7.2 Hz, 2 H), 1.35 (t, J ¼ 7.2 Hz, 3 H); MS (ES) m/z: 331
(MþNaþ).
Cyclization of (S)-14: A solution of 14 (105 mg, 0.172 mmol)
and EtOH (2 mL) was degassed under vacuum and then filled
.
with N2 for three times. To the solution SnCl2 2H2O (244 mg,
2-(3-Nitro-30-trifluoromethoxy-biphenyl-2-ylmethyl)-3-oxo-
3-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-propionic acid ethyl
ester (8a). To a mixture of b-keto ester 7 (13.5 g, 43.8 mmol)
and benzyl bromide 5 (15.7 g, 41.7 mmol) in 270 mL of ace-
tone was added K2CO3 (8.66 g, 62.6 mmol). After stirring at
room temperature for 1 h, TLC (15% EtOAc in hexane)
showed the completion of reaction. The reaction mixture was
filtered through Celite and the solid was washed with EtOAc.
The filtrate was concentrated and purified by flash column
1.08 mmol) was added and the reaction mixture was stirred at
room temperature under N2 for 4.5 h. After removal of EtOH
under vacuum, to the residue were added CH2Cl2 and saturated
NH4OH. The precipitated solid was filtered through Celite, and
rinsed with CH2Cl2 and EtOAc. The filtrate was separated and the
aqueous layer was extracted with CH2Cl2. The combined organic
phases were dried, concentrated in vacuo, and purified by flash
column chromatography (10–15% EtOAc in hexane) to give 46
1
mg (55%) of (R)-10 as an oil. H NMR (400 MHz, CDCl3) d
Journal of Heterocyclic Chemistry
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A. Wang, Y. Zhang, S. Lu, W. V. Murray, and G.-H. Kuo
Vol 47
7.42–7.30 (m, 3 H), 7.29–7.23 (m, 2 H), 7.21–7.07 (m, 4 H), 6.61
(d, J ¼ 7.8 Hz, 2 H), 5.91 (tt, J ¼ 53.1, 2.8 Hz, 1 H), 4.51 (dd, J
¼ 9.0, 3.4 Hz, 1 H), 4.20 (brs, 1 H), 2.76 (ddd, J ¼ 16.3, 10.6, 5.2
Hz, 1 H), 2.53 (dt, J ¼ 16.6, 5.0 Hz, 1 H), 2.11–2.04 (m, 1 H),
1.93–1.83 (m, 1 H); MS (ES) m/z: 486 (MþHþ); HRMS (ESI)
–12.9ꢀ (c 1.0, CHCl3). A total of 80–85% ee was analyzed by chi-
ral HPLC (Chiralcel OJ; isocratic elution 10/90 isopropanol/hex-
ane, 0.8 mL/min, area integration at 210 nm).
4.90 (t, J ¼ 4.4 Hz, 1 H), 4.46–4.41 (m, 1 H), 3.92 (d, J ¼
15.4 Hz, 1 H), 3.32 (dd, J ¼ 15.4, 9.6 Hz, 1 H), 2.49 (dt, J ¼
16.2, 4.6 Hz, 1 H), 2.41–2.34 (m, 2 H), 2.19–2.10 (m, 1 H),
2.00–1.94 (m, 1 H); MS (ES) m/z: 598 (MþHþ); HRMS (ESI)
calcd for C27H21F10NO3 m/z 597.1362, found m/z 597.1378.
Anal. Calcd for C27H21F10NO3: C, 54.28; H, 3.54; N, 2.34.
20
calcd for C24H18F7NO2 m/z 485.1226, found m/z 485.1219. [a]D
20
Found: C, 54.10; H, 3.40; N, 1.99. [a]D –112.0ꢀ (c1.0,
CHCl3).
(aS)-3-Nitro-a-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-30-(tri-
fluoromethoxy)-[1,10-biphenyl]-2-propanol (13). To a solu-
tion of THF (0.2 mL) and 1.0M (R)-2-methyl-CBS-oxazaboro-
lidine (0.186 mL, 0.186 mmol) in toluene was added 2.0M
Acknowledgment. The authors thank Sandra Damon for deter-
mining enantiomeric excess of some of the compounds.
.
BH3 SMe2 (0.137 mL, 0.274 mmol) in THF. After stirring at
REFERENCES AND NOTES
room temperature for 15 min, the mixture was cooled to –
25ꢀC and to which a solution of 9 (132 mg, 0.249 mmol) in
THF (2 mL) was added. The reaction mixture was stirred from
–20ꢀC to –10ꢀC for 3.5 h and then quenched with a few drops
of MeOH followed by a few drops of 1N HCl. The reaction
mixture was partitioned between CH2Cl2 and water. The or-
ganic layer was dried, concentrated, and purified by flash col-
umn chromatography (10–20% EtOAc in hexane) to provide
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114 mg (86%) of 13 as an oil. H NMR (300 MHz, CDCl3) d
7.88–7.77 (m, 1 H), 7.43–7.37 (m, 3 H), 7.28–7.23 (m, 2 H),
7.14–6.99 (m, 5 H), 5.90 (tt, J ¼ 53.1, 2.8 Hz, 1 H), 4.54 (brs,
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H), 1.73 (brs, 1 H); MS (ES) m/z: 556 (MþNaþ). Anal. Calcd
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integration at 210 nm).
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X.; Wang, A.; Ballentine, S. A.; Beauchamp, D. A.; Macphee, J.-M.;
Rammeloo, T. J. L.; Vanhoegaerden, T. J. PCT Int Appl WO
2008141077 A1 20081120, 2008.
(aS)-3-Nitro-a-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-30-(tri-
fluoromethoxy)-[1,10-biphenyl]-2-propanol methanesulfonate
(14). To a solution of 13 (220 mg, 0.413 mmol) and CH2Cl2 (3
mL) was added methanesulfonyl chloride (0.040 mL, 0.52 mmol)
and Et3N (0.086 mL, 0.62 mmol). After stirring at room tempera-
ture for 2 h, water was added and the mixture was acidified with
1N HCl until acidic by pH paper. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2. The combined
organic phases were dried and concentrated to give 250 mg
(99%) of 14 as a yellow oil. 1H NMR (400 MHz, CDCl3) d 7.88–
7.83 (m, 1 H), 7.49–7.45 (m, 1 H), 7.42 (d, J ¼ 4.6 Hz, 2 H),
7.36–7.29 (m, 2 H), 7.20–7.15 (m, 2 H), 7.09–7.07 (m, 2 H), 7.03
(s, 1 H), 5.92 (tt, J ¼ 53.0, 2.7 Hz, 1 H), 5.38 (dd, J ¼ 7.3, 5.8
Hz, 1 H), 2.85 (td, J ¼ 12.6, 4.8 Hz, 1 H), 2.72 (s, 3 H), 2.67 (dd,
J ¼ 13.1, 4.8 Hz, 1 H), 2.18–1.98 (m, 2 H); MS (ES) m/z: 634
(MþNaþ).
[12] Miyaura, N.; Suzuki, A. Chem Rev 1995, 95, 2457.
[13] Togo, H.; Hirai, T. Synlett 2003, 5, 702.
[14] Renau, T. E.; Sanchez, J. P.; Domagala, J. M. J Heterocycl
Chem 1996, 33, 1407.
[15] Balasankar, T.; Gopalakrishnan, M.; Nagarajan, S. Eur J
Med Chem 2005, 40, 728.
[16] Reinhard, E. J.; Wang, J. L.; Durley, R. C.; Fobian, Y. M.;
Grapperhaus, M. L.; Hickory, B. S.; Massa, M. A.; Norton, M. B.;
Promo, M. A.; Tollefson, M. B.; Vernier, W. F.; Connolly, D. T.;
Witherbee, B. J.; Melton, M. A.; Regina, K. J.; Smith, M. E.; Sikorski,
J. A. J Med Chem 2003, 46, 2152.
(2R,aS)-3,4-Dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-
5-[3-(trifluoromethoxy)phenyl]-a-(trifluoromethyl)-1(2H)-qui-
nolineethanol (1). To a mixture of (R)-10 (6.10 g, 10.2 mmol)
and 1,1,1-trifluoro-2,3-epoxypropane 11 (5.71 g, 51.0 mmol) in
CH2Cl2 (60 mL) under N2 was added Yb(OTf)3 (1.58 g, 2.55
mmol). The reaction mixture was heated at 50ꢀC for 48 h and
then cooled to ambient temperature. EtOAc was added and the
mixture was washed with saturated NaHCO3, H2O and brine,
dried, concentrated and purified by flash column chromatogra-
phy (5–15% EtOAc in hexane) to give 6.00 g (80%) of 1 as
an oil. 1H NMR (400 MHz, CDCl3) d 7.40–7.34 (m, 2 H),
7.25–7.12 (m, 6 H), 7.05 (s, 1 H), 6.74 (d, J ¼ 8.1 Hz, 1 H),
6.68 (d, J ¼ 7.3 Hz, 1 H), 5.89 (tt, J ¼ 53.1, 2.8 Hz, 1 H),
[17] Atarashi, S.; Tsurumi, H.; Fujiwara, T.; Hayakawa, I. J Het-
erocycl Chem 1991, 28, 329.
[18] Wang, A.; Prouty, C. P.; Pelton, P. D.; Yong, M.; Demar-
est, K. T.; Murray, W. V.; Kuo, G.-H. Bioorg Med Chem Lett 2010,
20, 1432.
[19] Corey, E. J.; Helal, C. J. Angew Chem Int Ed 1998, 37,
1986.
[20] Enantiomeric excess was determined by chiral HPLC (Chir-
alcel OJ; isocratic elution 10/90 isopropanol/hexane, 0.8 mL/min, area
integration at 210 nm).
[21] Bellamy, F. D.; Ou, K. Tetrahedron Lett 1984, 25, 839.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet