Selective metal-halogen exchange of 4,4′-dibromobiphenyl mediated by lithium tributylmagnesiate

Article abstract of DOI:10.1016/j.tet.2006.03.039

A selective metal-halogen exchange/electrophilic quench protocol on 4,4′-dibromobiphenyl 4 that proceeds under non-cryogenic conditions is reported. This method provides an economic alternative to traditional transition-metal catalyzed cross-coupling chemistry to prepare various biaryls 7a-g. This novel route to functionalized biaryls was used as the basis for the kg-scale preparation of a biphenyl ketone 1, a key intermediate in the synthesis of a potent cathepsin K inhibitor.

Full text of DOI:10.1016/j.tet.2006.03.039

Tetrahedron 62 (2006) 5092–5098
Selective metal-halogen exchange of 4,40-dibromobiphenyl
mediated by lithium tributylmagnesiate
a
a
b
Sarah J. Dolman,a, Francis Gosselin, Paul D. O’Shea and Ian W. Davies
*
aDepartment of Process Research, Merck Frosst Centre for Therapeutic Research 16711 route transcanadienne,
´
Kirkland, Quebec, Canada H9H 3L1
bDepartment of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 17 January 2006; revised 9 March 2006; accepted 10 March 2006
Available online 17 April 2006
Abstract—A selective metal–halogen exchange/electrophilic quench protocol on 4,40-dibromobiphenyl 4 that proceeds under non-cryogenic
conditions is reported. This method provides an economic alternative to traditional transition-metal catalyzed cross-coupling chemistry to
prepare various biaryls 7a–g. This novel route to functionalized biaryls was used as the basis for the kg-scale preparation of a biphenyl ketone
1, a key intermediate in the synthesis of a potent cathepsin K inhibitor.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of biphenyl ketone 1, a precursor to potent cathep-
sin K inhibitor I (Scheme 1).7 One obvious disconnection of
biphenyl ketone 1 would be the aryl–aryl bond, which could
be generated via a Suzuki–Miyaura3 cross-coupling between
boronic acid 2 and aryl bromide 3. While these materials are
commercially available, we felt that the price of the coupling
partners was not justified for a simple molecule such as
ketone 1. The cost of these materials compelled us to de-
velop an alternative strategy to ketone 1 that would avoid
the use of metal-catalyzed cross-coupling.
Transition-metal catalyzed reactions represent some of the
most widely used and powerful tools in synthetic organic
chemistry.1 Currently, these techniques are readily applied
to various C–C bond constructions, including aryl–aryl
bond formation.2 In particular, the Suzuki–Miyaura3 reac-
tion has gained widespread use throughout preparative and
medicinal chemistry due to the low toxicity and bench
stability of organoboron species. Recent examples of
pharmaceutically relevant molecules prepared utilizing this
chemistry include VLA-4 antagonists,4 angiotensin II
antagonists,5 and cathepsin K inhibitors.6
2. Results and discussion
During the course of our investigations on cathepsin K in-
hibitors, we sought to develop a cost-efficient and practical
From the outset we aimed to use low-cost, commercial mate-
rials to avoid the use of cryogenic temperatures throughout
CF3
B(OH)2
+
O
Me
Me
S
Me
Br
CF3
H
O O
CF3
2
3
N
CN
N
O
H
O
Me
Me
S
Br
S
I
O O
1
O O
Br
4
Scheme 1. Retrosynthetic analysis of cathepsin K inhibitor I.
* Corresponding author. Tel.: +1 514 428 3582; e-mail: sarah_dolman@merck.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.039

S. J. Dolman et al. / Tetrahedron 62 (2006) 5092–5098
5093
thisprocess. Weselected 4,40-dibromobiphenyl(4)asstarting
material since it is a readily available, inexpensive commod-
ity chemical. We sought to develop a protocol for stepwise
functionalization of 4 via controlled, selective mono-
metal–halogen exchange followed by electrophilic quench.
Lithium trialkylmagnesiates11 have been used as metal–
halogen exchange reagents for aryl and vinyl halides; the
resultant magnesiates were successfully used as nucleo-
philes.12 In fact, Oshima and co-workers have shown that
addition of 1.0 equiv of n-Bu3MgLi to dibromide 4, followed
by D2O addition resulted in metal–halogen exchange and
incorporation of deuterium at both the 4- and 40-positions.
Work within our own laboratories on 2,6-dibromopyridine
has shown that all three alkyl groups on trialkylmagnesiates
are active toward metal–halogen exchange and that direct
addition of the dihalide to magnesiate, atꢀ10 ꢁC, afforded
good mono- versus di-exchange selectivity.13 We there-
fore examined the addition of dibromide 4 to 0.33 equiv
n-Bu3MgLi, but were disappointed to observe poor selectiv-
ity (Table 2, entry 1, 4:5:6¼47:36:17). Gratifyingly, by add-
ing n-Bu3MgLi to a solution of 4, a substantial improvement
in selectivity was observed (Table 2, entry 2, 4:5:6¼
24:73:3). In order to drive the reaction to completion, we
tested the use of greater equivalents of reagent (Table 2, en-
tries 3–4). As much as 0.43 equiv of n-Bu3MgLi was needed
in order to consume >98% dibromide 4, however, at this
point selectivity was significantly diminished (4:5:6¼
1:89:10). We therefore settled upon the use of 0.40 equiv
of magnesiate as the optimal stoichiometry, for which high
conversion (94%) was obtained, and selectivity maintained
We investigated the selectivity of a variety of metal–halogen
exchange reagents by examination of the ratio of di-, mono-,
and non-brominated biphenyls (4, 5, and 6, respectively) re-
sulting from direct quench with 3 N aqueous HCl (Table 1).
Metal–halogen exchange using n-BuLi gave unsatisfactory
ratios of mono- to di-metallation in THF at ꢀ46 ꢁC, toluene
at 22 ꢁC, and toluene/THF (2:1) at ꢀ25 ꢁC (Table 1, entries
1–3). Modest selectivity was observed with n-BuLi in
MTBE, however a significant quantity of starting material
remained (Table 1, entry 4). Grignard reagents have been
used as an effective metal–halogen exchange reagents.8
However, i-PrMgCl was completely ineffective in both
THFandtoluene, evenafter16 h at55 ꢁC;theadditive lithium
chloride only marginally improved reactivity (Table 1,
entries 5–7). The more reactive dibutylmagnesium9 was
also ineffective for metal–halogen exchange (Table 1, entry
8). While the Grignard reagent could be prepared by heating
dibromide 4 with magnesium metal,10 acceptable selectivity
was not observed (Table 1, entry 10).
Table 1. Selectivity of various metal–halogen exchange reagents toward dibromobiphenyl 4
Br
Br
H
H
1) n equiv RM
2) 3N HCl/H2O
+
+
solvent, temp
Br
Br
Br
H
4
4
5
6
Entry
Reagent
Solvent
n (equiv)
Temperature (ꢁC)
Time (h)
HPLC area (%)
4
5
6
1
2
3
4
5
6
7
8
9
10
n-BuLi
n-BuLi
n-BuLi
n-BuLi
i-PrMgCl
i-PrMgCl
i-PrMgCl-LiCl
n-Bu2Mg
Mg
THF
1.0
1.0
1.0
1.0
2.0
2.0
1.1
1.0
1.5
1.5
ꢀ46
22
ꢀ25
ꢀ25
55
55
22
22
80
0.1
0.1
0.1
0.1
16
16
24
1
24
32
10
23
28
99
99
83
99
99
64
41
43
50
62
<1
<1
16
<1
<1
16
27
47
27
10
0
0
1
0
0
18
Toluene
Toluene/THF
MTBE
THF
Toluene
THF
Toluene
Toluene
THF
Mg
55
24
Table 2. Selectivity of n-Bu3MgLi toward metal–halogen exchange of dibromobiphenyla
Br
Br
H
+
H
1) n equiv n-Bu3MgLi
2) 3N HCl/H2O
+
THF [0.4 M]
temp
Br
Br
Br
H
4
4
5
6
Entry
Mode of addition
Addition time (min)
n (equiv)
Temperature (ꢁC)
Time (h)
HPLC area (%)
4
5
6
1
2
3
4
5
Direct
60
60
90
120
90
0.33
0.33
0.40
0.43
0.40
22
22
22
22
0
0.1
0.1
0.1
0.1
1.0
47
24
6
1
6
36
73
88
89
90
17
3
6
10
4
Inverse
Inverse
Inverse
Inverse
a
Reaction conditions: for direct addition, a THF solution (0.4 M) of dibromide 4 was added to a slurry of n-Bu3MgLi in THF. For inverse addition, n-Bu3MgLi
was added to a THF solution (0.4 M) of dibromide 4.

5094
S. J. Dolman et al. / Tetrahedron 62 (2006) 5092–5098
Br
Br
Y
1) 0.40 equiv n-Bu3MgLi, 0 °C
2) 1.1 equiv Me2S2, 0 °C
+
THF [0.4 M]
Br
MeS
X
4
7a
4 X=Y=Br
8 X=Y=SMe
5 X=H, Y=Br 9 X=H, Y=SMe
6 X=Y=H
82 % yield
Scheme 2. Trialkylmagnesiate mediated mono-metal–halogen exchange followed by Me2S2 quench.
(4:5:6¼6:88:6). Finally, we found that addition of magnesi-
ate at 0 ꢁC, followed by aging 1 h, provided optimal selectiv-
ity (Table 2, entry 5, 4:5:6¼6:90:4).
disulfide, biaryl 7a was obtained in 82% yield (Scheme 2).14
The crude organic stream was contaminated with several
biphenyl impurities (4–6, 8, and 9), as indicated by HPLC
analysis, however, these contaminants could be carried
through the process sequence without detrimental effect.
When addition of lithium tributylmagnesiate to dibromobi-
phenyl 4 was followed by addition of 1.1 equiv of methyl
With a successful method for mono-metal–halogen ex-
change/electrophilic quench in hand, we briefly investigated
the scope of addition to various electrophiles. We found that
direct addition of carbon dioxide and DMF afforded high
assay yields of the carboxylic acid and aldehyde derivatives,
respectively (Table 3, entries 2 and 3). Non-enolizable
ketones and aldehydes afforded both secondary and tertiary
alcohols in good yield (Table 3, entries 4 and 5). Addition to
acetic and trifluoroacetic anhydride necessitated the use of
inverse addition to the electrophile at ꢀ20 ꢁC to obtain
good yields of the corresponding ketones (Table 3, entries
6 and 7).
Table 3. Preparation of 4,40-disubstituted biphenyls via magnesiate-medi-
ated metal–halogen exchange and electrophilic quencha
Entry
Electrophile
Product
Yieldb (%)
82 (73)c
SMe
1
Me2S2
7a
Br
CO2H
CHO
2
3
CO2
91 (73)c
83 (60)c
7b
7c
Br
In order to complete the synthesis of ketone 1, we next inves-
tigated the introduction of the trifluoroacetyl moiety via
aryllithium addition to ethyl trifluoroacetate, Scheme 3.15
Metal–halogen exchange could be performed with n-BuLi
at room temperature in a toluene/MTBE (10:1) solvent mix-
ture. In the absence of MTBE as a co-solvent, exchange was
sluggish (<15% conversion in 1 h at room temperature). The
yield of thioketone 10 was found to be highly dependent
upon the mode of electrophile addition. Direct addition of
ethyl trifluoroacetate was not scalable; if the addition was
completed in <5 s, thioketone 10 was obtained in w80%
yield on gram-scale. However upon scale-up to multi-
gram, longer periods were needed for addition; greater
amounts of unidentified impurities and variable yields
were obtained. In contrast, slow addition of the aryllithium
slurry to a solution of ethyl trifluoroacetate at 0 ꢁC (inverse
addition), consistently afforded material of higher purity and
reproducibly in 85% yield on up to 50 g scale.
DMF
Br
OH
4
PhCHO
83 (55)c
7d
Br
OH
CF3
CF3
5
(CF3)2CO
93 (59)c
7e
Br
Me
O
6d
Ac2Od
75 (63)c
1) 1.37 equiv
n-BuLi, 22 °C
CF3
Br
7f
2) 1.47 equiv
CF3CO2Et, 0 °C
O
Br
Br
CF3
toluene/MTBE (10/1)
85 % yield
7a
10
O
MeS
MeS
7d
(CF3CO)2Od
79 (61)c
Scheme 3. Introduction of the trifluoroacetyl moiety.
7g
The crude organic stream containing thioketone 10 was used
directly for the tungstate-catalyzed oxidation16 to sulfone
1$H2O. Addition of 3.0 equiv H2O2 over 1.5–2 h to the
reaction mixture at 45 ꢁC, in the presence of 2 mol %
Na2WO4$2H2O and 5 mol % Bu4NHSO4, gave sulfone
hydrate 1$H2O in 85% assay yield within 6 h (Scheme
4).17 Azeotropic removal of water/toluene was used to drive
the material to >99% ketone 1, as determined by 19F NMR
a
Reaction conditions: 0.4 equiv n-Bu3MgLi added over 90 min to a THF
solution (0.4 M) of dibromide 4 at 0 ꢁC. The reaction mixture was stirred
1 h, then 1.1 equiv of requisite electrophile was added.
Assay yield determined by HPLC versus authentic standard.
Isolated yield after column chromatography.
Inverse addition was used: 0.4 equiv n-Bu3MgLi added over 90 min to
a THF solution (0.4 M) of dibromide 4 at 0 ꢁC; then the crude reaction
mixture was added over 60 min to a solution of the requisite electrophile
in THF at ꢀ20 ꢁC.
b
c
d

S. J. Dolman et al. / Tetrahedron 62 (2006) 5092–5098
5095
CF3
CF3
CF3
3.0 eq H2O2
2 mol % Na2WO4-2H2O
5 mol % Bu4NHSO4
O
OH
OH
O
1) Dehydrate by Dean-Stark
O
MeS
O
O
MeS
O
2) Concentrate
3) Add heptane
THF/Toluene/MTBE (10/10/1)
1·H2O
10
1
30 mL/g, 45 °C
MeS
80 % yield
Scheme 4. Oxidation to sulfone and isolation.
spectroscopy. The material was then crystallized from
toluene/heptane to afford desired ketone 1 in 80% yield
from thioketone 10.
was charged with anhydrous THF (3.21 L). n-BuMgCl
(1.31 L, 2.0 M in THF, 2.63 mol, 100 mol %) was charged
into the dropping-funnel, and added over 90 min at room
temperature. The reactor’s internal temperature rose from
20 ꢁC to 31 ꢁC during n-BuMgCl addition. Next n-BuLi
(2.05 L, 2.5 M in hexane, 5.13 mol, 195 mol %) was charged
to the dropping-funnel, and added to the reactor over 90 min.
During the initial stages of n-BuLi addition the internal tem-
perature rose from 30 ꢁC to 34 ꢁC, however, no external
cooling bath was used. Upon complete addition of n-BuLi,
a thin gray slurry formed, from which gray solids would set-
tle if stirring was ceased. The slurry was stirred for 5 min,
and then used to perform metal–halogen exchange. 1H
NMR (400 MHz, THF with an internal THF-d8 standard)
d 1.49 (m, 2H), 1.22 (m, 2H), 0.81 (t, J¼7.2, 3H), ꢀ0.79
(t, J¼8.0, 2H). For comparison, the spectrum of n-BuMgCl
In summary, we have developed a 3-step through process for
the preparation of ketone 1 that proceeds in w56% overall
yield from inexpensive dibromobiphenyl 4, without the use
of cryogenic methods. The process features a selective
mono-metal–halogen exchange of dibromobiphenyl 4,
mediated by lithium tributylmagnesiate. The metal–halogen
exchange/electrophilic quench protocol provides access to
a variety of functionalized biphenyls (7a–g) under non-cryo-
genic conditions and avoids the use of expensive transition-
metal catalyzed cross-coupling chemistry.
1
3. Experimental
3.1. General
is as follows: H NMR (400 MHz, THF with an internal
THF-d8 standard) d 1.34 (m, 2H), 1.67 (m, 2H), 0.68 (t,
J¼7.2, 3H), ꢀ0.80 (t, J¼8.0, 2H).
Reactions were carried out under an atmosphere of dry nitro-
gen. Reagents and solvents were used as received from
commercial sources. H NMR spectrum was recorded on
3.2.2. Conversion of dibromobiphenyl 4 to 4-Bromo-40-
methylsulfanyl-biphenyl (7a). 4,40-Dibromobiphenyl
(2.00 kg, 6.41 mol, 100 mol %) was charged to a clean
50-L round-bottom flask equipped with a dropping-funnel,
mechanical stirrer, thermocouple, nitrogen inlet and outlet.
Anhydrous THF (16.0 L) was added with stirring, and the
flask cooled to 0 ꢁC in an ice/acetone bath. The dropping-
funnel was charged with the n-Bu3MgLi slurry (6.57 L,
2.63 mol, 40 mol %), which was added to the reaction flask
over 2.25 h. The internal temperature rose from 0 ꢁC to
4.4 ꢁC during the addition of n-Bu3MgLi (initial 4.0 L).
The pale gray solution took on an amber color as n-Bu3MgLi
was added. Upon complete n-Bu3MgLi addition, the internal
temperature was 3.0 ꢁC. The resultant yellow solution was
aged for 60 min, while re-cooling to 0 ꢁC. HPLC analysis
of a crude aliquot (quenched into aqueous 3 N HCl/
MTBE) showed a mixture of biphenyl, 6, 40-bromobiphenyl,
5, and dibromobiphenyl, 4. (4:5:6¼6:84:3). A clean addition
funnel was replaced for the used addition funnel, and
charged with methyl disulfide (635 mL, 7.05 mol,
110 mol %), which was then added over 1.75 h. Addition
of methyl disulfide caused an exotherm from 1.1 ꢁC to
7.4 ꢁC. The solution became a yellow-white slurry after
500 mL of methyl disulfide had been added. The slurry
was aged for 15 h, then cooled with an external ice/acetone
bath to ꢀ2.0 ꢁC. Aqueous periodic acid (10 wt %, 4.04 L,
1.77 mol, 28 mol %) was added dropwise over 1 h into the
reaction flask, and the resultant biphasic mixture stirred
vigorously for 20 min. An exotherm was observed upon
addition to aqueous periodic acid (internal temperature rose
from ꢀ2.0 ꢁC to 7.4 ꢁC) and the mixture became deep-red.
Aqueous 3 N HCl (4.04 L, 12.1 mol, 190 mol %) was then
added dropwise over 1 h into the reaction flask, and the mix-
ture stirred for 1 h, which raised the internal temperature
1
a Bruker 400 (400 MHz) spectrometer. Chemical shifts are
reported in parts per million from tetramethylsilane with
the solvent resonance as the internal standard (acetone-d6:
d 2.06, DMSO-d6: d 2.49, THF-d8: d 3.65). Data are reported
as follow: chemical shift, multiplicity (s¼singlet, d¼
doublet, t¼triplet, q¼quartet, br¼broad, m¼multiplet), cou-
pling constants (Hz) and integration. 13C NMR spectrum
was recorded on a Bruker 400 (100 MHz) spectrometer
with complete proton decoupling. Chemical shifts are
reported in parts per million from tetramethylsilane with
the solvent as the internal reference (acetone-d6: d 206.0,
DMSO-d6: d 39.5, THF-d8: d 66.5). 19F NMR spectrum
was recorded on Bruker 400 (375 MHz) spectrometer with
complete proton decoupling. Chemical shifts are reported
in parts per million with a,a,a-trifluorotoluene added as an
internal reference (d ꢀ67.2). All compounds except 1, 7g,
and 10 were characterized using the same HPLC conditions:
Zorbax RX-C8 (4.6 mmꢂ25.0 cm) column, gradient elu-
tion: (0.1% H3PO4/CH3CN 50:10 to 10:90 over 7.5 min,
hold 2.5 min), flow rate¼2.0 mL/min, T¼35 ꢁC, UV detec-
tion at 220 nm. Compounds 1, 7g, and 10 were analyzed
by GC: HP-1 (30 m, 0.32 mm, 0.25 mm film) column, gradi-
ent elution (100 ꢁC–250 ꢁC at 15 ꢁC/min), flow rate¼
2.5 mL/min He, FID detection¼300 ꢁC. A 10 mL sample
was injected at 250 ꢁC.
3.2. Procedures
3.2.1. Preparation of lithium tri-n-butylmagnesiate. A
15-L round-bottom flask equipped with a dropping-funnel,
thermocouple, mechanical stirrer, nitrogen inlet and outlet,

5096
S. J. Dolman et al. / Tetrahedron 62 (2006) 5092–5098
from 3.6 ꢁC to 11.1 ꢁC. Agitation was stopped and the mix-
ture was transferred to a 50 L extractor; the flask was washed
with 1.0 L THF, which was added to the extractor. The mix-
ture was vigorously stirred, then allowed to settle for 5 min.
The bottom (aqueous) layer was removed. Aqueous sodium
thiosulfate (10 wt %, 8.1 L) was added to the extractor, caus-
ing the internal temperature to rise from 10 ꢁC to 23 ꢁC, the
mixture was vigorously stirred for 5 min, which became
pale-yellow. After agitation was stopped, the aqueous layer
was cut. Aqueous sodium thiosulfate (10 wt %, 4.0 L) and
toluene (5.0 L) were added to the extractor, and after vigor-
ous stirring for 5 min, the aqueous layer was separated. The
organic layer was then washed with water (2ꢂ4.0 L) and
collected. HPLC analysis showed 7a (15.95 kg at
9.16 wt % for a total of 1.46 kg, 5.24 mol, 82% assay yield).
The crude solution was concentrated in vacuo, flushed with
toluene (20 L), and re-concentrated to a thick beige slurry of
3.537 kg. Approximately 155 g of this slurry was dissolved
in toluene and used for the subsequent transformation.
An analytically pure sample was prepared by chromato-
graphy on silica gel, eluting with 5% MTBE in hexane.
1H NMR (400 MHz, acetone-d6) d 7.62 (m, 6H), 7.38 (d,
J¼8.0, 2H), 2.54 (s, 3H); mp¼144.0–146.4 ꢁC (lit.18
148–150 ꢁC). HPLC retention time: 6.79 min. Anal.
Calcd for C13H11BrS: C, 55.92; H, 3.97. Found: C,
55.65; H, 3.73.
An analytically pure sample was prepared by chromato-
graphy on silica gel, eluting with 25% MTBE in hexane.
1H NMR (400 MHz, acetone-d6) d 8.18 (d, J¼7.6, 2H),
7.98 (d, J¼7.6, 2H), 7.77 (d, J¼8.4, 2H), 7.43 (d, J¼8.4,
2H), 2.57 (s, 3H); 13C NMR (100 MHz, acetone-d6)
2
d 180.3 (q, JCF¼34), 148.2, 141.5, 135.7, 131.4, 129.1,
1
128.4, 128.0, 127.2, 117.7 (q, JCF¼289), 14.9; 19F NMR
(375 MHz, acetone-d6) dꢀ76.2; mp¼114.6–116.2 ꢁC. GC
retention time: 13.24 min. Anal. Calcd for C15H11F3OS: C,
60.80; H, 3.74; F, 19.24. Found: C, 60.56; H, 3.44; F, 19.19.
3.2.4. 2,2,2-Trifluoro-1-(40-methylsulfonyl-biphenyl-4-
yl)-ethanone (1). The crude thioketone 10 (18.0 wt % in
toluene, 327 g, 198 mmol, 100 mol %) was charged into a
visually clean, 2-L round-bottom flask equipped with a mag-
netic stirrer, reflux condenser, internal temperature probe,
nitrogen inlet and outlet. Toluene (300 mL), THF
(600 mL), Na2WO4$2H2O (22.8 g, 0.07 mol, 2 mol %),
and Bu4NHSO4 (58.2 g, 0.17 mol, 5 mol %) were added to
the reactor and the resultant mixture heated to 45 ꢁC in an
oil bath while stirring vigorously. Hydrogen peroxide
(67 mL, 30% aqueous, 594 mmol, 300 mol %) was then
added via syringe pump over 1.5 h, the resultant mixture
was stirred with heating for an additional 2 h and then cooled
to room temperature. (The internal temperature remained
below 59 ꢁC during peroxide addition.) Aqueous Na2S2O3$
5H2O (10 wt %, 300 mL) was added to the flask over 60 min
(temperature remained <25 ꢁC) and the mixture stirred for
5 min. At this point, starch-paper test indicated <10 mg/L
of peroxide remained. Methyl ethyl ketone (750 mL) was
added, and after 5 min stirring was stopped. The mixture
was transferred to a separatory funnel, the cloudy bottom
(aqueous) layer removed, and the organic solution collected.
GC analysis indicated ketone-hydrate 1$H2O (3.66 wt % of
1.68 kg, 61.5 g, 95.2% assay yield). The solution was con-
centrated and solvent-switched to toluene. Analysis by
19F NMR spectroscopy indicated a 10:1 mixture of 1$H2O
(ꢀ88.7 ppm) & 1 (ꢀ76.3 ppm). The material was diluted
to w1.0 L toluene, then dehydrated by water/toluene azeo-
trope in a Dean–Stark apparatus. After 1 h only the ketone
1 remained (19F NMR analysis). The toluene solution was
concentrated in vacuo to w643 g, whereupon white solids
began to form in the orange solution. The material was trans-
ferred to a 3-neck round-bottom flask equipped with
mechanical stirrer and addition funnel, then diluted with tol-
uene (12 mL). Heptane (675 mL) was added dropwise over
1 h to the vigorously stirred slurry. After stirring for an addi-
tional 45 min, the material was filtered to afford sulfone 1
(68.8 g at 75 wt % for 51.6 g, 80% assay yield, 91.9 A%
by GC). An analytically pure sample was prepared by chro-
matography on silica gel, eluting with 15% ethyl acetate in
3.2.3. 2,2,2-Trifluoro-1-(40-methylsulfanyl-biphenyl-4-
yl)-ethanone (10). A 2-L round-bottom flask equipped
with a magnetic stirrer, thermocouple, nitrogen inlet and
outlet, was charged with crude bromosulfide 7a (8.76 wt %
in toluene, 731 g, 230 mmol, 100 mol %) and MTBE
(80 mL). n-BuLi (130 mL, [2.5 M] 322 mmol, 140 mol %)
was via syringe pump over 0.5 h. The initial internal temper-
ature was observed as 20.7 ꢁC and increased to 37.7 ꢁC dur-
ing n-BuLi addition. Upon completion, a dark orange slurry
formed, from which white solids would settle very slowly if
stirring was ceased. HPLC analysis of a crude aliquot after
n-BuLi was added (quenched into aqueous 3 N HCl/
MTBE) showed >97% conversion to the aryllithium spe-
cies. The slurry was stirred for 2 h, and then transferred to
the apparatus described as follows. A second 2-L round-
bottom flask, equipped with a magnetic stirrer, thermocou-
ple, addition funnel, nitrogen inlet and outlet, was charged
with ethyl trifluoroacetate (41 mL, 345 mmol, 150 mol %)
and toluene (40 mL), and cooled in an ice/acetone bath.
The prepared slurry of aryllithium was charged to the addi-
tion funnel, and added to the reaction flask over 1.0 h. An
exotherm (internal temperature started at 4.4 ꢁC and rose
to 19.9 ꢁC) was observed during aryllithium addition.
Upon completion, a bright yellow-orange solution formed.
GC analysis of an aliquot immediately after addition was
complete indicated w81% conversion to the thioketone
(59.3 A% thioketone 10, 10.4 A% sulfide 9 by GC). The
slurry was aged for 30 min, then aqueous 3 N HCl
(350 mL) and THF (350 mL) were added into the reaction
flask. The resultant biphasic mixture stirred vigorously for
15 min, then allowed to settle. The bottom (aqueous) layer
was removed and the bright yellow organic phase washed
with aqueous 3 N HCl (200 mL) and collected. GC analysis
showed thioketone 10 (1.2 kg at 4.84 wt % for a total of
58.11 g, 85.9% assay yield). The crude organic solution
was concentrated in vacuo to 327 g of a yellow solution.
1
hexane. H NMR (400 MHz, acetone-d6) d 8.23 (d, J¼7.4,
2H), 8.11 (d, J¼8.2, 2H), 8.05 (m, 4H), 3.20 (s, 3H);
2
13C NMR (100 MHz, acetone-d6) d 180.3 (q, JCF¼34),
146.6, 144.3, 142.2, 131.3, 130.0, 128.9, 128.7, 117.4 (q,
1JCF¼289), 116.7, 44.0; 19F NMR (375 MHz, acetone-d6)
dꢀ76.3; mp¼157.9–158.8 ꢁC. GC retention time: 15.91
min. Anal. Calcd for C15H11F3O3S: C, 54.88; H, 3.38; F,
17.36. Found: C, 53.37; H, 3.60; F, 15.00.
3.2.5. 40-Bromo-biphenyl-4-carboxylic acid (7b). 1H NMR
(400 MHz, DMSO-d6) d 13.00 (br s, 1H), 8.01 (d, J¼8.0, 2H),
7.79 (d, J¼8.0, 2H), 7.68 (m, 4H); mp¼300.3–302.2 ꢁC

S. J. Dolman et al. / Tetrahedron 62 (2006) 5092–5098
5097
(lit.19 301.5–302.5 ꢁC). HPLC retention time: 3.96 min.
Anal. Calcd for C13H9BrO2: C, 56.34; H, 3.27. Found: C,
56.46; H, 3.34.
4. Hagmann, W. K.; Durette, P. L.; Lanza, T.; Kevin, N. J.; de
Laszlo, S. E.; Kopka, I. E.; Young, D.; Magriotis, P. A.; Li,
B.; Lin, L. S.; Yang, G.; Kamenecka, T.; Chang, L. L.; Wilson,
J.; MacCoss, M.; Mills, S. G.; Van Riper, G.; McCauley, E.;
Egger, L. A.; Kidambi, U.; Lyons, K.; Vincent, S.; Stearns,
R.; Colletti, A.; Teffera, J.; Tong, S.; Fenyk-Melody, J.; Owens,
K.; Levorse, D.; Kim, P.; Schmidt, J. A.; Mumford, R. A.
Bioorg. Med. Chem. Lett. 2001, 11, 2709–2713.
5. Larsen, R. D.; King, A. O.; Chen, C.-y.; Corley, E. G.; Foster,
B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer,
R. A.; Tschaen, D. M.; Verhoeven, R. R.; Reider, P. J. J. Org.
Chem. 1994, 59, 6391–6394.
3.2.6. 40-Bromo-biphenyl-4-carboxaldehyde (7c). 1H
NMR (400 MHz, acetone-d6) d 10.12 (s, 1H), 8.05 (d,
J¼8.0, 2H), 7.92 (d, J¼7.6, 2H), 7.73 (m, 4H);
mp¼159.1–161.4 ꢁC (lit.20 158 ꢁC). HPLC retention time:
5.27 min. Anal. Calcd for C13H9BrO: C, 59.80; H, 3.47.
Found: C, 45.33; H, 2.65.
3.2.7. (40-Bromo-biphenyl-4-yl)-phenyl-methanol (7d).
1H NMR (400 MHz, acetone-d6) d 7.58 (m, 6H), 7.53 (d,
J¼8.0, 2H), 7.48 (d, J¼7.2, 2H), 7.33 (t, J¼7.6, 2H), 7.24
(t, J¼7.4, 1H), 5.90 (d, J¼3.8, 1H), 4.97 (d, J¼3.8, 1H);
mp¼136.0–138.6 ꢁC (lit.21 115–116 ꢁC). HPLC retention
time: 5.76 min. Anal. Calcd for C19H15BrO: C, 67.27; H,
4.46. Found: C, 67.22; H, 4.17.
6. Robichaud, J.; Oballa, R.; Prasit, P.; Falgueyret, J.-P.; Percival,
M. D.; Wesolowski, G.; Rodan, S. B.; Kimmel, D.; Johnson, C.;
Bryant, C.; Venkatraman, S.; Setti, E.; Mendonca, R.; Palmer,
J. T. J. Med. Chem. 2003, 46, 3709–3727.
7. (a) Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J. P.;
´
Gauthier, J. Y.; Kimmel, D. B.; Leger, S.; Masse, F.; McKay,
D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; Somoza,
´
3.2.8. 2-(40-Bromo-biphenyl-4-yl)-1,1,1,3,3,3-hexafluoro-
propan-2-ol (7e). H NMR (400 MHz, acetone-d6) d 7.91
´
J.; Therien, M.; Truong, V.-L.; Wesolowski, G.; Zamboni, R.;
1
Black, W. C. Bioorg. Med. Chem. Lett. 2006, 16, 1985–1989;
(b) Roy, A.; Gosselin, F.; O’Shea, P. D.; Chen, C.-y. J. Org.
Chem., submitted for publication.
(d, J¼8.4, 2H), 7.84 (d, J¼8.4, 2H), 7.69 (m, 4H), 7.58 (s,
1H); 13C NMR (100 MHz, acetone-d6) d 142.0, 139.3,
1
8. Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem.,
Int. Ed. 2003, 42, 4302–4320.
9. Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999,
40, 7449–7453.
10. Grignard, V. Bull. Soc. Chim. 1910, 7, 453.
132.5, 130.7, 129.4, 128.0, 127.4, 123.7 (q, JCF¼286),
2
122.4, 77.9 (q, JCF¼30); 19F NMR (375 MHz, acetone-
d6) dꢀ79.5; mp¼44.8–45.5 ꢁC. HPLC retention time:
6.40 min. Anal. Calcd for C15H9F6BrO: C, 45.14; H, 2.27;
F, 28.56. Found: C, 44.53; H, 2.10; F, 27.24.
3.2.9. 1-(40-Bromo-biphenyl-4-yl)-ethanone (7f). 1H NMR
(400 MHz, acetone-d6) d 8.09 (d, J¼8.4, 2H), 7.82 (d,
J¼8.4, 2H), 7.70 (m, 4H), 2.63 (s, 3H); mp¼124.9–
127.5 ꢁC (lit.22 121–122.5 ꢁC). HPLC retention time:
5.38 min. Anal. Calcd for C14H11BrO: C, 61.11; H, 4.03.
Found: C, 61.29; H, 3.82.
11. First magnesiate synthesis: Wittig, G.; Meyer, F. J.; Lange, G.
Liebigs Ann. Chem. 1951, 571, 167–201; Representative struc-
tural studies: (a) Seitz, L. M.; Brown, T. L. J. Am. Chem. Soc.
1966, 88, 4140–4147; (b) Coates, G. E.; Heslop, J. A. J. Chem.
Soc. A 1968, 514–518; (c) Squiller, E. P.; Whittle, R. R.;
Richey, H. G., Jr. J. Am. Chem. Soc. 1985, 107, 432–435; (d)
Wagonner, K. M.; Power, P. P. Organometallics 1992, 11,
3209–3214; Synthetic applications: (e) Ashby, E. C.; Chao,
L.-C.; Laemmle, J. J. Org. Chem. 1974, 39, 3258–3263; (f)
Richey, H. G., Jr.; DeStephano, J. P. J. Org. Chem. 1990, 55,
3281–3286; (g) Richey, H. G., Jr.; Farkas, J., Jr. Tetrahedron
Lett. 1985, 26, 275–278; (h) Richey, H. G., Jr.; Farkas, J., Jr.
Organometallics 1990, 9, 1778–1784; (i) Bayh, O.; Awad,
3.2.10. 1-(40-Bromo-biphenyl-4-yl)-2,2,2-trifluoroetha-
none (7g). 1H NMR (400 MHz, acetone-d6) d 8.22 (d,
J¼8.4, 2H), 8.02 (d, J¼8.4, 2H), 7.79 (d, J¼8.4, 2H), 7.75
(d, J¼8.4, 2H); 19F NMR (375 MHz, acetone-d6) dꢀ76.2;
mp¼72.5–74.8 ꢁC (lit.23 75–77 ꢁC). GC retention time:
11.47 min. Anal. Calcd for C14H8F3BrO: C, 51.09; H,
2.45; F, 17.32. Found: C, 50.72; H, 2.38; F, 16.94.
´
´
H.; Mongin, F.; Hoarau, C.; Bischoff, L.; Trecourt, F.; Que-
guiner, G.; Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros,
R. J. Org. Chem. 2005, 70, 5190–5196.
References and notes
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14. Reaction between n-Bu3MgLi, dibromide 4 and Me2S2 leads to
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5098
S. J. Dolman et al. / Tetrahedron 62 (2006) 5092–5098
silica and alumina powders were ineffective at odor removal,
with slow addition (1 h) of peroxide. We attributed this to
a slow initiation step, which is difficult to control due to the
biphasic nature of the reaction mixture. Furthermore, the
exotherm was not always observed (particularly on smaller
scale) resulting in extended reaction times and incomplete con-
version to the sulfone. By performing the oxidation at 45 ꢁC,
the reaction was complete within 6 h, and the internal temper-
ature was maintained below 62 ꢁC.
even at 1 g/g loadings. Treatment of the crude solution with
aqueous copper salts (CuSO4, CuCl2, and CuCO3) or KOH was
also unsuccessful. Odor was effectively removed by treatment
with either 10% aqueous HIO3 or 1% aqueous NaOCl, however
oxidation of 7a to the corresponding sulfoxide (5–10%) was
observed. Treatment with 10% aqueous H5IO6 removed virtu-
ally all odor, with <2% oxidation to sulfoxide. Therefore, the
crude reaction was quenched by the direct addition of aqueous
periodic acid.
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