N-(4-biphenylmethyl)imidazoles as potential therapeutics for the treatment of prostate cancer: Metabolic robustness due to fluorine substitution?

Article abstract of DOI:10.1002/hlca.200390217

3,3′,5,5′- And 2,2′,6,6′-tetrafluoro-substituted 1-[(1,1′-biphenyl]-4-yl)methyl]-1H-imidazoles were synthesized as inhibitors of 17α-hydroxylase-C17,20-lyase (P450 17, CYP 17). P450 17 is the key enzyme of androgen biosynthesis. Its inhibition is a novel

Full text of DOI:10.1002/hlca.200390217

Helvetica Chimica Acta Vol. 86 (2003)
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N-(4-Biphenylmethyl)imidazoles as Potential Therapeutics for the Treatment
of Prostate Cancer: Metabolic Robustness Due to Fluorine Substitution?
by Fre¬de¬ric Leroux*a), Tilman U. Hutschenreuterb), Ce¬line Charrie¡rea), Rosario Scopellitia),
and Rolf W. Hartmannb)
a
¬
¬ ¬
) Institut de chimie moleculaire et biologique, Ecole Polytechnique Federale de Lausanne,
BCH-LSCO, CH-1015 Lausanne
b) Saarland University, FR 8.5 Pharmaceutical and Medicinal Chemistry, POBox 151150,
D-66041 Saarbr¸cken
3,3',5,5'- And 2,2',6,6'-tetrafluoro-substituted 1-[(1,1'-biphenyl]-4-yl)methyl]-1H-imidazoles were synthe-
sized as inhibitors of 17a-hydroxylase-C17,20-lyase (P450 17, CYP 17). P450 17 is the key enzyme of androgen
biosynthesis. Its inhibition is a novel therapeutic approach for treatment of prostate cancer. To increase the so-far
insufficient in vivo lifetime of such compounds, the metabolically sensitive positions were blocked by F-
substitution. The meta- and ortho-F-substituted compounds were prepared by selective metallation or halogen/
metal permutation reactions performed on symmetrically substituted 1,1'-biphenyls. Compared with the
halogen-free compounds, the ortho-F-substituted derivatives did not match the activity, whereas the meta-F-
substituted isomers equaled or surpassed the latter.
1. Introduction.
17a-Hydroxylase-C17,20-lyase (P450 17, CYP 17, androgen
synthase), a cytochrome P450 monooxygenase, is the key enzyme of androgen
biosynthesis. It produces androstenedione and dehydroepiandrosterone from proges-
terone and pregnenolone, respectively. As androgens are implicated in the develop-
ment of prostatic cancer, it is a promising alternative to the treatment with
antiandrogens to develop selective inhibitors of this enzyme [1 7].
1-[([1,1'-Biphenyl]-4-yl)methyl]-substituted 1H-imidazoles 1 are highly potent
inhibitors of CYP 17 and of CYP19 (aromatase) [8 11]. Unfortunately, the very
encouraging in vitro results are contrasted by a lack of in vivo activity, due to rapid
degradation of the compounds by metabolic oxidation. We were able to isolate and
identify the major metabolites by means of biomimetic methods.
N
1a R = H
N
1b R = Me
1c R = MeO
1d R = HO
R
Fluorine, the only element capable of mimicking hydrogen by virtue of comparable
size (−isosterism×) [12][13], may not only induce very specific properties to molecules,
due to its electron-withdrawing power, but also confer metabolic stability, and, in
addition, enhance the lipophilicity, and, as a corollary, facilitate cell-membrane
permeation [14 20]. Thus, fluorine appeared to us to be the ideal molecular tool for
fine-tuning the mechanical and biological properties of these compounds [15].

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Therefore, we have embarked on the synthesis of fluorinated 1-[([1,1'-biphenyl]-4-
yl)methyl]-1H-imidazoles 2 (F in the meta-positions) and 3 (F in the ortho-positions),
wherein metabolically sensitive positions were blocked by F-atoms.
F
F
N
N
F
F
N
N
F
F
R
F
R
F
2a R = H
3a R = H
2b R = Me
2c R = MeO
2d R = HO
3b R = Me
3c R = MeO
3d R = HO
2. Results and Discussion.
Synthesis. The two series of dissymmetrically
substituted 1,1'-biphenyls 2 and 3 could be prepared by the classical cross-coupling
processes such as SuzukiÀMiyaura, Negishi, KumadaÀTamaoÀCorriu, or Stille
coupling [21], as we have shown in the case of the non-fluorinated parent compounds
[9]. In all these cases, an efficient access to the corresponding fluorinated aryl
nucleophiles and aryl halides is imperative. As this is not always the case, we decided to
develop a different approach, based on the development of specific organometallic
methods to transform symmetrically substituted 1,1'-biphenyls in dissymmetrically ones
[22]. The symmetrically substituted 1,1'-biphenyls were prepared according to a
modern modification [23 25] of the classical Ullmann reaction [26].
The crucial question was whether a symmetrically substituted 1,1'-biphenyl
undergoes selective metallation or selective Br/metal permutation. This kind of
reaction is far from being obvious, as one might expect a statistical mixture of zero-,
mono-, and dimetallated intermediates. Gilman et al. reported in 1940 that 4,4'-
dibromo-1,1'-biphenyl gives, after treatment with BuLi under various conditions,
roughly a 2 :1 mixture of the mono- and dicarboxylic acids after trapping with dry ice
[27]. In 1997, Ferreira and co-workers reported on the formation of 4'-bromo[1,1'-
biphenyl]-4-carbaldehyde after treatment of 4,4'-dibromo[1,1'-biphenyl] with BuLi in
THF at À758 and subsequent addition of DMF [28]. Applying these reaction
conditions, a 69 :31 mixture of the mono- and dicarbaldehyde, as determined by gas
chromatography, was obtained. Contrarily, when the Br/Li permutation was performed
in THF at À1008, followed by trapping of the aryllithium intermediate with DMF, the
aldehyde 4 was selectively formed in a ratio of 96 :4 for the mono- and dicarbaldehyde
(see Exper.Part ). After reduction of 4 to the alcohol 5 (96%), followed by conversion
to the sulfonate and condensation with 1H-imidazole, the target compound 1e was
obtained in a yield of 56% (Scheme 1).
Encouraged by these findings, we decided to prepare the m-F-substituted
compounds 2 by metallation of 3,3',5,5'-tetrafluoro[1,1'-biphenyl] (6; Scheme 2). In a
model reaction, with s-BuLi, in the presence of N,N,N',N'',N''-pentamethyldiethylene-
triamine (PMDTA) at À758 in THF, followed by addition of DMF as electrophile, a
mixture of mono- and dicarbaldehyde in a ratio of 94 :6 was obtained (see compound

Helvetica Chimica Acta Vol. 86 (2003)
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Scheme 1. Selective Br/Li Permutation Performed on 4,4'-Dibromo[1,1'-biphenyl]
O
H
OH
b)
Br
Br
4
5
a)
c)
Br
N
N
Br
Br
1e
a) 1. LiC4H9, THF, À1008; 2. DMF; 91%. b) NaBH4, MeOH/THF, 258, 12 h; 96%. c) 1. MeSO2Cl, Et3N, CH2Cl2,
08, 1 h; 2. 1H-Imidazole, K2CO3, 18-crown-6, acetone, reflux, 2 h; 56%.
8a in Exper.Part ). In the same way, the 1,1'-biphenyl core was functionalized by
trapping the organometallic intermediate with Me2SO4 to the methyl derivative 7a
(79%) or addition of FB(OMe)2 ¥ O Et , followed by oxidation to the phenol and
2
treatment with MeI to yield the MeOderivative 7b (64%). These 1,1'-biphenyls were
metallated for a second time, under the same reaction conditions. After addition of
DMF, the aldehydes 8b (82%) and 8c (87%) were obtained. The alcohols 9a 9c,
obtained after reduction with NaBH4 (up to 95%) were converted to the bromides 10a
(88%), 10b (89%), and 10c (83%). Condensation with 1H-imidazole resulted in the
target compounds 2a (74%), 2b (69%), and 2c (71%). The phenolic compound 2d was
synthesized from the corresponding MeO-substituted 1,1'-biphenyl 2c by ether
cleavage with Br3B in a yield of 62%.
To obtain the o-F-substituted compounds 3, 1-bromo-3,5-difluorobenzene was used
as the starting material. Metallation with lithium diisopropylamide (LDA) and
addition of I2 gave 5-bromo-1,3-difluoro-2-iodobenzene (11; 82%). I/Li exchange,
transmetallation, and oxidation yielded 4,4'-dibromo-2,2',6,6'-tetrafluoro[1,1'-biphen-
yl] (12; 79%; Scheme 3). Selective Br/Li permutation performed on 12 with BuLi in
Et2Oat À1008 and trapping of the organometallic intermediate with DMFafforded the
aldehyde 13 in a 92 :8 ratio for mono- and dicarbaldehyde (see Exper.Part ). After
reduction to the alcohol 14a (89%) and protection with the (i-Pr)3Si group to 15a
(92%), the 1,1'-biphenyl unit was further functionalized by Br/Li exchange and
interception of the lithiated intermediate with Me2SO4 or FB(OMe)2 ¥ O Et to yield the
2
Me- and MeO-substituted compounds 15b (74%) and 15c (63%), respectively.
Cleavage of the (i-Pr)3Si groups with Bu4NF gave the alcohols 14b (85%) and 14c
(83%), respectively. Bromination of the alcohols 14a, 14b, and 14c resulted in the
formation of the bromides 16a (81%), 16b (78%), and 16c (77%), respectively. After

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 2. Preparation of the m-F-Substituted Derivatives 2
F
O
F
F
OH
H
c)
F
F
F
R
R
F
F
F
F
8a R = H
8b R = Me
8c R = MeO
9a R = H
9b R = Me
9c R = MeO
b)
d)
F
F
Br
F
F
F
F
R
R
7a R = Me
7b R = MeO
10a R = H
10b R = Me
10c R = MeO
F
a') a)
e)
F
F
N
F
F
F
N
F
R
6
F
2a R = H
2b R = Me
2c R = MeO
2d R = HO
f)
a) 1. LiC(Me)Et, N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDTA), THF, À758, 2 h; 2. Me2SO4; 79% of
7a, a') 1. LiC(Me)Et, PMDTA, THF, À758, 2 h; 2. FB(OMe)2 ¥ O Et ; 3. NaOH, H2O2; 4. MeI, KOH, DMSO,
2
64% of 7b. b) 1. LiC(Me)Et, PMDTA, THF, À758, 2 h; 2. DMF; 75% of 8a; 82% of 8b; 87% of 8c. c) NaBH4,
MeOH/THF, 258, 12 h; 94% of 9a; 88% of 9b; 79% of 9c. d) Ph3P, Br2, MeCN, 508, 6 h; 88% of 10a; 89% of
10b; 83% of 10c. e) 1H-Imidazole, K2CO3, 18-crown-6, acetone, reflux, 2 h; 74% of 2a; 69% of 2b; 71% of 2c.
f) Br3B, CH2Cl2, 258, 12 h; 62%.
condensation with 1H-imidazole the 2,2',6,6'-tetrafluoro-substituted 1-[([1,1'-biphen-
yl]-4-yl)methyl]-1H-imidazoles 3b (62%), 3c (64%), and 3e (67%), respectively, were
obtained. The 4-Br-substituted compound 3e can be submitted to another Br/Li
permutation and, after addition of MeOH, the debrominated compound 3a was
obtained in a yield of 93%. Ether cleavage of the methoxy derivative 3c with Br3B gave
the alcohol 3d (64%).
These results show that, in the symmetrically substituted 1,1'-biphenyls 6 and 12, the
H- or Br-atoms play the role of a kind of joker, which can be successively replaced by

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Scheme 3. Preparation of the o-F-Substituted Derivatives 3
O
Br
F
F
H
F
F
F
a)
b)
I
F
F
F
Br
F
Br
Br
F
11
12
13
c)
Br
OR'
OR'
F
F
F
F
F
F
g)
e)
e')
F
F
F
R
F
R
Br
F
F
16a R = Br
16b R = Me
16c R = MeO
R' = (i-Pr)3Si
15b R = Me
15c R = MeO
14a R' = H
15a R' = (i-Pr)3Si
f)
d)
R' = H
14b R = Me
14c R = MeO
h)
N
N
F
F
3a R = H
3b R = Me
3c R = MeO
3d R = HO
3e R = Br
i)
F
F
j)
R
a) 1. BuLi, Et2O, À758; 2. CuBr2, 45 min; 3. nitrobenzene; 79%. b) 1. BuLi, Et2O, À1008; 2. DMF; 86%. c)
NaBH4, MeOH/THF, 258, 12 h; 89%. d) (i-Pr)3SiCl (TIPSCl), 1H-imidazole, DMF, 258, 20 h; 92%. e) 1. BuLi,
THF, À758; 2. Me2SO4; 74% of 15b. e') 1. BuLi, THF, À758; 2. FB(OMe)2 ¥ O Et ; 3. NaOH, H2O2; 4. MeI, KOH,
2
DMSO; 63% of 15c. f) Bu4NF, THF, 258, 15 min; 85% of 14b; 83% of 14c. g) Ph3P, Br2, MeCN, 508, 6 h; 81% of
16a; 78% of 16b; 77% of 16c. h) 1H-Imidazole, K2CO3, 18-crown-6, acetone, reflux, 2 h; 62% of 3b; 64% of 3c;
67% of 3e. i) 1. t-BuLi, THF, À1008; 2. MeOH; 93%. j) Br3B, CH2Cl2, 258, 12 h; 64%.
any electrophile, after selective metallation (H/metal interconversion) or Br/Li
permutation, opening access to dissymmetrically substituted biaryls.
X-Ray-Diffraction Studies. It makes a striking difference whether the two pairs of F-
atoms are introduced at the 2,2',6,6'- or the 3,3',5,5'-positions of the 1,1'-biphenyl core.
Although the oxidation potentials should be quite similar in both series, the structures
do not resemble each other. The unsubstituted 1,1'-biphenyl is twisted in the gas phase

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Helvetica Chimica Acta Vol. 86 (2003)
with a torsion angle of 458 [29]. In the solid state, the two phenyl rings are absolutely
coplanar [30 32].
The introduction of the F-atoms into the meta-positions of the phenyl ring should
change neither the form nor the shape of the molecules compared to the non-
fluorinated analogs. This prediction was supported by single-crystal X-ray-diffraction
studies (Fig.1 and Table 2 in Exper.Part ). The 1,1'-biphenyl core in compounds 2 is
only slightly twisted around the central CÀC axis. Compound 2c has a torsion angle
C(2)ÀC(1)ÀC(7)ÀC(12) of 11.1(5)8 and C(6)ÀC(1)ÀC(7)ÀC(8) of 12.3(5)8. The
torsional barriers of such 1,1'-biphenyls falls in the range of E=tors ꢀ 3 kcal/mol [32].
Fig. 1. X-Ray crystal structure of the m-F-substituted derivative 2c
By dislocating the F-atoms from the meta- to the ortho-positions, the two aryl rings
of the 1,1'-biphenyl unit are forced to occupy distinctly separated planes. Single-crystal
X-ray-diffraction studies of 3c (Fig.2 and Table 2 in Exper.Part ) revealed a torsion
angle C(2)ÀC(1)ÀC(7)ÀC(12) of 64.1(4)8 and C(6)ÀC(1)ÀC(7)ÀC(8) of 61.4(4)8.
This was anticipated by the torsion angle of 59.78 [33] for perfluoro[1,1'-biphenyl] and
even 57.68 [34] for 2,2'-difluoro[1,1'-biphenyl]. The barrier to planarization is too high
(E=tors ˆ 26 kcal/mol) to be surmounted at ambient temperature [35].
Fig. 2. X-Ray crystal structure of the o-F-substituted derivative 3c

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Biological Studies. The newly synthesized compounds were tested for their
inhibitory activity towards CYP 17 and CYP 19 by the methods described in [9][36],
and their inhibitory activities were compared with those of the non-fluorinated parent
compounds. When the inhibitory activities exceeded 80%, the IC50 values were
determined.
The derivatives, which have the best inhibitory activity towards CYP 17, were also
tested in a kinetic study for their in vitro stability [37]. Phenol and the unfluorinated
parent compound were used as reference substances. In these experiments, the
compounds were incubated with rat liver microsomes for 120 min, samples were taken
at stated time intervals, and the remaining concentrations of the parent compounds
were determined by high-pressure liquid chromatography.
Inhibition of CYP 19 and SAR. The fluorinated 1,1'-biphenyl derivatives exhibit
poor-to-moderate inhibitory activity towards CYP 19 (see Table 1). The influence of
the introduction of F-atoms in the meta- and ortho-positions of the 1,1'-biphenyl unit
was inconsistent. However, in two cases (3b and 3d) the introduction of the F-atoms in
the ortho-positions resulted in an increased activity of more than 20%, compared to the
non-fluorinated analogs.
Table 1. Inhibition of CYP 17 and CYP 19 by the Fluorinated ([1,1'-Biphenyl]ylmethyl)-1H-imidazoles in
Comparison to the Non-Fluorinated Parent Compounds
Compound
R
Inhibition of CYP 17 [%]
Inhibition of CYP 19b) [%]
(IC50 [mm])a)
1a [9]
2a
3a
1b [9]
2b
3b
H
H
H
Me
Me
Me
(0.96)
(0.37)
73
36
39
66
57
66
51
66
72
38
1c [9]
2c
3c
1d [9]
2d
3d
MeO43
MeO46
MeO4
OH
OH
O
62
53
48
(0.31)
(0.38)
H
31
29
68
49
40
75
1e
3e
Br
Br
27
16
b
a) 25 mm progesterone; 250 mm NADPH; 2.5 mm inhibitor ) 4.4 pm [1b2b3H]-testosterone ‡ 2.5 mm testoster-
one; 10 mm glucose-6-phosphate; 1 mm NADP+; 2 U/ml glucose-6-phosphate dehydrogenase; 25 mm inhibitor.
Inhibition of CYP 17 and SAR. The strongly twisted o-F-substituted 1,1'-biphenyls 3
did not match the activity of the halogen-free parent compounds. Only the poor
inhibitor 3b was as potent as its non-fluorinated congener. On the other hand, the
flattened m-F-substituted isomers 2 equaled or surpassed the inhibitory activity of the
non-fluorinated parent compounds (see Table 1). Compound 2a showed an almost
threefold higher activity towards CYP 17 (IC50 value of 0.37 mm), compared to the non-
fluorinated analogue 1a with an IC50 value of 0.96 mm.

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Already 1-[(3'-fluoro[1,1'-biphenyl]-4-yl)methyl]-1H-imidazole, a monofluorinat-
ed derivative, has an inhibitory activity of 0.66 mm towards CYP 17 [9]. Apparently, the
introduction of one or more F-atoms in the 3'-position of the 1,1'-biphenyl unit
increases the inhibitory activity significantly.
The introduction of a non-hydrophilic p-substituent decreases the inhibition
potency in the case of the non-fluorinated parent compounds as in the case of the
fluorinated derivatives. However, the introduction of the OH group at the para-
position increases the inhibition of CYP 17 by a factor of three. These observations are
identical to the results for the non-fluorinated compounds [9]. Thus, the introduction of
F-atoms in the meta-positions of the 1,1'-biphenyl unit has only marginal effects on the
inhibitory activity towards CYP 17. The inhibition potency is affected mainly by the
nature of the p-substituent.
These results indicate that the different torsion angles for the m- and o-F-
substituted 1,1'-biphenyls have a significant influence on the inhibitory activity. The o-
F-substituted 1,1'-biphenyls seem to be too −bulky× to interact well with the active site of
the target enzyme. In addition, the torsional barrier for planarization of the 1,1'-
biphenyl unit is to high to be surmounted in the enzyme pocket. On the other hand, the
effect of the F-atoms in the meta-positions are negligible if one looks at the in vitro
activity.
Effects of Fluorination on the Metabolic Stability. Next, we studied the effect of the
F-substitution on the metabolic stability of the [(biphenylyl)methyl]-1H-imidazoles.
Therefore, the two fluorinated OH isomers with the highest inhibitory activity towards
CYP 17 (2d and 3d) were tested for their metabolic stability in an in vitro study. Phenol
and the unsubstituted analogue were used as reference compounds (Fig.3 ).
Fig. 3. In vitro biodegradation of the m-F-substituted derivative 2d and the o-F-substituted derivative 3d
compared with the unfluorinated compound 1d and phenol (control experiments are without NADPH-
generating system)
Controls without added NADPH-generating system remained unaffected indicat-
ing no NADPH-independent reactions. The biodegradation of the (1H-imidazol-1-

Helvetica Chimica Acta Vol. 86 (2003)
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yl)methyl-substituted 1,1'-biphenyls is slower than the degradation of the reference
phenol, since most of the 1H-imidazol-1-yl-substituted compounds are inhibitors of
many hepatic CYPs [38 40]. As expected, the m-F-substituted derivative 2d showed a
significantly reduced in vitro metabolism (P < 0.005, n ˆ 6) compared to its non-
fluorinated congener 1d. Surprisingly, the o-F-substituted compound 3d was metab-
olized faster than the non-fluorinated parent compound 1d. In the HPLC chromato-
gram of the incubation of 1d, a catechol derivative (4'-[(1H-imidazol-1-yl)methyl][1,1'-
biphenyl]-3,4-diol) was detected (tR 3.8 min).
In phenolic compounds the ortho-position is susceptible to hydroxylation. In
addition, this position is acidified in compound 3d due to the neighboring F-atom. This
finding may explain the faster biodegradation of 3d in comparison to the non-
fluorinated analogue 1d. In the derivative 2d, however, this position is blocked by F-
substitution.
3. Conclusions.
Two sets of model compounds were investigated to control
metabolism of 1-[([1,1'-biphenyl]-4-yl)methyl]-1H-imidazoles. One set contained the
F-atoms in the meta-positions of the 1,1'-biphenyl unit and the second set in the ortho-
positions. All fluorinated 1,1'-biphenyl derivatives exhibit poor inhibitory activity
towards aromatase (CYP 19), but proved potent towards 17a-hydroxylase-C17,20-
lyase (CYP 17). Compared with the halogen-free compounds, the o-F-substituted
derivatives did not match the activity, whereas the m-F-substituted isomers equaled or
surpassed the latter. The phase-I metabolism of these compounds can be slowed down
by the introduction of F-atoms in the meta-positions.
The authors are indebted to the Swiss National Science Foundation (grant No. 20-63584-00), the COST-
D12 action 0004/98 and the Swiss Federal Institute of Technology Lausanne (EPFL) for financial support. F.L.
is much indebted to Prof. M.Schlosser , Lausanne, for countless precious advice.
Experimental Part
General. THFand Et2Owere distilled from sodium benzophenone and stored under N 2 in Schlenk burettes.
DMF was dried by azeotropic distillation with toluene. BuLi, s-BuLi, and t-BuLi were supplied by
CheMetall AG, D-38685 Langelsheim. Other reagents were obtained from commercial sources and checked
by comparison of refraction index for liquids and melting points for solids. Air- and moisture-sensitive
compounds were stored in Schlenk tubes or Schlenk burettes. Reactions at low temp. were performed by using
cold baths: H2O/ice at 08, EtOH/dry ice at À758, and Et2O/liquid N2 at À1008. The temp. EtOH/dry ice is
consistently indicated at À758 and −room temperature× as 258. Melting ranges (M.p.) are reproducible after
resolidification unless otherwise stated (dec.), and were corrected by using a calibration curve. 1H-NMR:
Bruker DPX-400; chemical shifts d in ppm relative to TMS (d ˆ 0.00) or relative to deuterated solvent.
Elementary analysis: Ilse Beetz, Microanalytisches Laboratorium, D-96301 Kronach, or F.Hoffmann-La Roche
AG, CH-4070 Basel.
4'-Bromo[1,1'-biphenyl]-4-carbaldehyde (4). At À1008, BuLi (0.10 mol) in hexanes (63 ml) was added
dropwise during 10 min to a soln. of 4,4'-dibromo[1,1'-biphenyl] (31 g, 0.10 mol) in THF (0.50 l). After 15 min,
DMF (7.7 ml, 7.3 g, 0.10 mmol) was added, and the mixture was allowed to reach 258. After addition of H2O
(50 ml) and extraction with Et2O(3 Â 50 ml), a 96 :4 mixture, according to GC (30 m, DB-1, 1808), of the
aldehyde 1 and the dicarbaldehyde was obtained. The combined org. layers were evaporated and crystallized from
AcOEt/hexanes to provide 4 (23.9 g, 91%). Colorless needles. M.p. 140 1428 ([41]: 137 1408). 1H-NMR (CDCl3,
400 MHz): 10.06 (s, 1 H); 7.95 (d, J ˆ 8.4, 2 H); 7.70 (d, J ˆ 8.3, 2 H); 7.61 (d, J ˆ 8.6, 2 H); 7.49 (d, J ˆ 8.5, 2 H).
4'-Bromo[1,1'-biphenyl]-4-methanol (5). NaBH4 (7.6 g, 0.20 mol) was added to 4 (13 g, 50 mmol) in MeOH/
THF 1:1 (v/v) (0.20 l). After 12 h at 258, a 2.0m aq. soln. of HCl (50 ml) was carefully added, followed by
extraction with Et2O(4 Â 50 ml). The org. layer was washed with brine (50 ml), dried, and evaporated.

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Crystallization from AcOEt/hexanes afforded 5 (12.6 g, 96%). Colorless needles. M.p. 130 1328 ([42]: 130.5
131.58). 1H-NMR (CDCl3, 400 MHz): 7.57 (d, J ˆ 8.5, 2 H); 7.55 (d, J ˆ 8.3, 2 H); 7.46 (d, J ˆ 8.7, 2 H); 7.43
(d, J ˆ 8.0, 2 H); 4.74 (s, 2 H); 1.76 (br. s, 1 H).
1-[(4'-bromo[1,1'-biphenyl]-4-yl)methyl]-1H-imidazole (1e). At 08, MsCl (3.9 ml, 5.7 g, 50 mmol) and Et3N
(10 ml, 7.6 g, 75 mmol) were added consecutively to 5 (6.6 g, 25 mmol) in CH2Cl2 (0.12 l). After 1 h, the volatiles
were removed in vacuo, and the residue was dissolved in dry acetone (0.12 l). 1H-Imidazole (6.9 g, 0.10 mol),
18-crown-6 (0.26 g, 1.0 mmol), and anh. K2CO3 (28 g, 0.20 mol) were added consecutively, and the mixture was
heated under reflux for 2 h. At 258, the precipitate was removed by filtration, washed with more acetone
(50 ml), and the combined filtrates were evaporated. After the addition of H2O(0.10 l), the mixture was
extracted with a 1:5 (v/v) mixture MeOH/AcOEt (2 Â 50 ml). The org. phase was extracted with a 0.10m aq.
soln. of HCl (5 Â 50ml). The combined aq. layers were alkalinized with a sat. aq. soln. of Na2CO3 (0.20 l) and
again extracted with a 1:5 (v/v) mixture MeOH/AcOEt (4 Â 50 ml). The combined org. layers were dried and
evaporated. The residue was crystallized from AcOEt/hexanes to afford 1e (4.38 g, 56%). Colorless needles.
M.p. 116 1178. 1H-NMR (CDCl3, 400 MHz): 7.59 (s, 1 H); 7.56 (d, J ˆ 8.5, 2 H); 7.53 (d, J ˆ 8.2, 2 H); 7.43
(d, J ˆ 8.5, 2 H); 7.22 (d, J ˆ 8.3, 2 H); 7.11 (s, 1 H); 6.95 (s, 1 H); 5.17 (s, 2 H). Anal. calc. for C16H13BrN2
(313.20): C 61.36, H 4.18; found: C 61.32, H 4.36.
3,3',5,5'-Tetrafluoro[1,1'-biphenyl] (6). At À758, 1-bromo-3,5-difluorobenzene (39 g, 0.20 mol), CuBr2
(45 g, 0.20 mol), and, 45 min later, PhNO2 (20 ml, 25 g, 0.20 ml) were added consecutively to a soln. of BuLi
(0.20 mol) in hexanes (0.11 l) and Et2O(0.40 l). The mixture was allowed to reach 25 8 during 2 h. The
suspension was poured into a 12% aq. solution of NH3 (0.20 l). The org. layer was separated, and the aq. phase
was extracted with Et2O(2 Â 0.20 l). The combined org. layers were dried and evaporated. Crystallization from
MeOH afforded 6 (19.9 g, 88%). Colorless needles. M.p. 86 888 ([43]: 85.5 878). 1H-NMR (CDCl3, 400 MHz):
7.06 (sym. m, 4 H); 6.85 (tt, J ˆ 8.9, 2.6, 2 H).
3,3',5,5'-Tetrafluoro-4-methyl[1,1'-biphenyl] (7a). At À1008, s-BuLi (50 mmol) in cyclohexane (39 ml) was
added dropwise during 15 min to 6 (11 g, 50 mmol) and N,N,N',N'',N''-pentamethyldiethylenetriamine
(PMDTA; 10 ml, 8.7 g, 50 mmol) in THF (0.25 l). After the addition was completed, the mixture was kept
2 h at À758, followed by the addition of Me2SO4 (4.8 ml, 6.3 g, 50 mmol). The volatiles were evaporated, and
H2O(50 ml) was added. After extraction with Et 2O(3 Â 50 ml), drying, and evaporation, the residue was
crystallized from MeOH to afford 7a (9.49 g, 79%). Colorless needles. M.p. 77 798. 1H-NMR (CDCl3,
400 MHz): 7.1 (m, 4 H); 6.82 (tt, J ˆ 8.8, 2.5, 1 H); 2.41 (t, J ˆ 1.7, 3 H). Anal. calc. for C13H8F4 (240.20): C 65.01,
H 3.36; found: C 65.18, H 3.26.
3,3',5,5'-Tetrafluoro-4-methoxy[1,1'-biphenyl] (7b). The reaction was initially conducted as described for
7a, Me2SO4 being replaced by FB(OMe)2 ¥ O Et [44][45] (9.4 ml, 8.2 g, 50 mmol). At 08, a 3.0m aq. soln. of
2
NaOH (18 ml) and a 30% aq. H2O2 soln. (5.0 ml, 1.7 g, 50 mmol) were added consecutively. The mixture was
neutralized with a 2.0m aq. soln. of HCl (50 ml) and extracted with Et2O(3 Â 50 ml). The combined org. layers
were washed with a 10% aq. soln. of Na2SO3 (50 ml), dried, and evaporated. The residue was dissolved in
Me2SO(0.10 l), before MeI (3.8 ml, 8.5 g, 60 mmol) and KOH powder (3.4 g, 60 mmol) were added. After 1 h,
H2O(0.25 l) was added, followed by extraction with Et 2O(3 Â 50 ml). The combined org. layers were washed
with brine (3 Â 50 ml), dried, and evaporated. Crystallization from EtOH gave 7b (8.20 g, 64%). Colorless
needles. M.p. 87 888. 1H-NMR (CDCl3, 400 MHz): 7.09 (d, J ˆ 9.3, 2 H); 7.01 (dd, J ˆ 8.4, 2.2, 2 H); 6.80 (tt, J ˆ
8.8, 2.3, 1 H); 4.05 (t, J ˆ 1.1, 3 H). Anal. calc. for C13H8F4O(256.20): C 60.95, H 3.15; found: C 61.13, H 2.99.
3,3',5,5'-Tetrafluoro[1,1'-biphenyl]-4-carbaldehyde (8a). The same metallation conditions described for 7a
were applied, followed by addition of DMF (3.2 ml, 3.0 g, 50 mmol). The mixture was allowed to reach 258. H2O
(50 ml) was added, followed by extraction with Et2O(3 Â 50 ml). A 96 :4 mixture of 8a and the dicarbaldehyde
was obtained (according to GC, 30 m, DB-1, 1508). Concentration and crystallization from AcOEt/hexanes gave
8a (9.53 g, 75%). Colorless needles. M.p. 128 1298. 1H-NMR (CDCl3, 400 MHz): 10.37 (s, 1 H); 7.20 (d, J ˆ 9.4,
2 H); 7.11 (sym. m, 2 H); 6.92 (tt, J ˆ 8.5, 2.3, 1 H). Anal. calc. for C13H6F4O(254.18): C 61.43, H 2.38; found:
C 61.35, H 2.53.
3,3',5,5'-Tetrafluoro-4'-methyl[1,1'-biphenyl]-4-carbaldehyde (8b). At À1008, s-BuLi (50 mmol) in cyclo-
hexane (39 ml) was added dropwise during 15 min to 7a (12 g, 50 mmol) and PMDTA (10 ml, 8.7 g, 50 mmol) in
THF (0.25 l). After the addition was completed, the mixture was kept 2 h at À758, followed by the addition
DMF (3.2 ml, 3.0 g, 50 mmol). The mixture was allowed to reach 258. H2O(50 ml) was added, followed by
extraction with Et2O(3 Â 50 ml). The org. layers were dried and evaporated. The residue was crystallized from
AcOEt/hexanes to afford 8b (11.0 g, 82%). Colorless needles. M.p. 143 1458. 1H-NMR (CDCl3, 400 MHz):
10.35 (s, 1 H); 7.17 (d, J ˆ 9.7, 2 H); 7.09 (d, J ˆ 8.0, 2 H); 2.27 (t, J ˆ 1.6, 3 H). Anal. calc. for C14H8F4O(268.21):
C 62.69, H 3.01; found: C 62.84, H 3.08.

Helvetica Chimica Acta Vol. 86 (2003)
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3,3',5,5'-Tetrafluoro-4'-methoxy[1,1'-biphenyl]-4-carbaldehyde- (8c). Compound 8c was obtained from 7b
(13 g, 50 mmol) as described above after crystallization from AcOEt/hexanes (12.4 g, 87%). Colorless needles.
M.p. 113 1148. 1H-NMR (CDCl3, 400 MHz): 10.37 (s, 1 H); 7.15 (d, J ˆ 9.5, 2 H); 7.12 (d, J ˆ 9.7, 2 H); 4.08
(t, J ˆ 1.5, 3 H). Anal. calc. for C14H8F4O2 (284.12): C 59.17, H 2.84; found: C 58.81, H 2.76.
3,3',5,5'-Tetrafluoro[1,1'-biphenyl]-4-methanol (9a). NaBH4 (7.6 g, 0.20 mol) was added to 8a (13 g,
50 mmol) in a 1:1 (v/v) mixture MeOH/THF (0.20 l). After 12 h at 258, a 2.0m aq. soln. of HCl (0.20 l) was
carefully added. The mixture was extracted with Et2O(4 Â 50 ml), and the combined org. layers were washed
with brine (50 ml), dried, and evaporated. Crystallization from AcOEt/hexanes afforded 9a (12.0 g, 94%).
Colorless needles. M.p. 106 1088. 1H-NMR (CDCl3, 400 MHz): 7.10 (d, J ˆ 8.3, 2 H); 7.04 (dd, J ˆ 8.4, 2.3, 2 H);
6.84 (tt, J ˆ 8.7, 2.4, 1 H); 4.81 (s, 2 H); 2.04 (s, 1 H). Anal. calc. for C13H8F4O(256.20): C 60.95, H 3.15; found:
C 60.58, H 3.33.
3,3',5,5'-Tetrafluoro-4'-methyl[1,1'-biphenyl]-4-methanol (9b). The same reaction and workup conditions as
described for 9a were applied to 8b (13 g, 50 mmol). Compound 9b was obtained after crystallization from
AcOEt/hexanes (11.9 g, 88%). Colorless needles. M.p. 151 1528. 1H-NMR (CDCl3, 400 MHz): 7.09 (d, J ˆ 8.3,
2 H); 7.03 (d, J ˆ 7.8, 2 H); 4.81 (s, 2 H); 2.22 (s, 3 H). Anal. calc. for C14H10F4O(270.23): C 62.23, H 3.73;
found: C 62.14, H 3.79.
3,3',5,5'-Tetrafluoro-4'-methoxy[1,1'-biphenyl]-4-methanol (9c). Compound 9c was obtained from 8c (14 g,
50 mmol) as described above after crystallization from AcOEt/hexanes (11.3 g, 79%). Colorless needles. M.p.
127 1288. 1H-NMR (CDCl3, 400 MHz): 7.09 (d, J ˆ 9.4, 2 H); 7.05 (d, J ˆ 8.3, 2 H); 4.81 (s, 2 H); 4.05 (s, 3 H).
Anal. calc. for C14H10F4O2 (286.23): C 58.75, H 3.52; found: C 58.86, H 3.43.
4-(Bromomethyl)-3,3',5,5'-tetrafluoro[1,1'-biphenyl] (10a). Br2 (1.5 ml, 4.8 g, 30 mmol) and 9a (7.7 g,
30 mmol) were added consecutively to a suspension of Ph3P (11 g, 30 mmol) in MeCN (0.15 ml). The mixture
was kept at 508 for 6 h. After evaporation, the residue was suspended in hexanes (0.10 l), filtered over a pad of
silica gel, and washed with more hexanes (0.10 l). Evaporation and crystallization from AcOEt/hexanes
afforded 10a (8.42 g, 88%). Colorless needles. M.p. 102 1048. 1H-NMR (CDCl3, 400 MHz): 7.11 (d, J ˆ 8.2,
2 H); 7.05 (dd, J ˆ 8.3, 2.2, 2 H); 6.86 (tt, J ˆ 8.6, 2.1, 1 H); 4.55 (s, 2 H). Anal. calc. for C13H7BrF4 (319.10):
C 48.93, H 2.21; found: C 48.93, H 2.11.
4-(Bromomethyl)-3,3',5,5'-tetrafluoro-4'-methyl[1,1'-biphenyl] (10b). Compound 10b was obtained from 9b
(8.11 g, 30 mmol) as described above after crystallization from AcOEt/hexanes (8.89 g, 89%). Colorless
needles. M.p. 104 1058. 1H-NMR (CDCl3, 400 MHz): 7.09 (d, J ˆ 8.2, 2 H); 7.03 (d, J ˆ 7.3, 2 H); 4.55 (s, 2 H);
2.23 (s, 3 H). Anal. calc. for C14H9BrF4 (333.12): C 50.48, H 2.72; found: C 50.43, H 2.61.
4-(Bromomethyl)-3,3',5,5'-tetrafluoro-4'-methoxy[1,1'-biphenyl] (10c). When the reaction and workup
conditions described above were applied to 9c (8.6 g, 30 mmol), the 10c (8.69 g, 83%) was obtained after
crystallization from AcOEt/hexanes. Colorless needles. M.p. 99 1018. 1H-NMR (CDCl3, 400 MHz): 7.09 (d, J ˆ
9.5, 2 H); 7.05 (d, J ˆ 8.4, 2 H); 4.55 (s, 2 H); 4.05 (s, 3 H). Anal. calc. for C14H9BrF4O(349.12): C 48.16, H 2.30;
found: C 48.40, H 2.51.
1-[(3,3',5,5'-Tetrafluoro[1,1'-biphenyl]-4-yl)methyl]-1H-imidazole (2a). 1H-Imidazole (6.8 g, 0.10 mol),
the 10a (8.0 g, 25 mmol), 18-crown-6 (0.26 g, 1.0 mmol), and anh. K2 CO3 (28 g, 0.20 mol) in dry acetone (0.12 l)
were heated under reflux for 2 h. At 258, the precipitate was removed by filtration, washed with more acetone
(50 ml), and the combined filtrates were evaporated. After the addition of H2O(0.10 l), the mixture was
extracted with a 1:5 (v/v) mixture MeOH/AcOEt (2 Â 50 ml). The org. phase was extracted with a 0.10m aq.
soln. of HCl (4 Â 50 ml). The combined aq. layers were alkalinized with a sat. aq. soln. of Na2CO3 (0.20 l) and
again extracted with a 1:5 (v/v) mixture MeOH/AcOEt (4 Â 50 ml). The combined org. layers were dried and
evaporated. The residue was crystallized from AcOEt/hexanes to afford 2a (5.67 g, 74%). Colorless needles.
1
M.p. 117 1188. H-NMR (CDCl3, 400 MHz): 7.62 (s, 1 H); 7.14 (d, J ˆ 8.3, 2 H); 7.0 (m, 4 H); 6.86 (tt, J ˆ 7.6,
2.3, 1 H); 5.21 (s, 2 H). Anal. calc. for C16H10F4N2 (306.26): C 62.75, H 3.29; found: C 62.65, H 3.21.
1-[(3,3',5,5'-Tetrafluoro-4'-methyl[1,1-biphenyl]-4-yl)methyl]-1H-imidazole (2b). When the same reaction
and workup conditions described above were applied to 10b (5.0 g, 15 mmol), 2b (3.32 g, 69%) was obtained
after crystallization from AcOEt/hexanes. Colorless needles. M.p. 112 1138. 1H-NMR (CDCl3, 400 MHz): 7.62
(s, 1 H); 7.11 (d, J ˆ 8.2, 2 H); 7.0 (m, 4 H); 5.20 (s, 2 H); 2.23 (s, 3 H). Anal. calc. for C17H12F4N2 (320.29):
C 63.75, H 3.78; found: C 63.62, H 3.72.
1-[(3,3',5,5'-Tetrafluoro-4'-methoxy[1,1'-biphenyl]-4-yl)methyl]-1H-imidazole (2c). When the same reac-
tion and workup conditions described above were applied to 10c (7.0 g, 20 mmol), 2c (4.78 g, 71%) was obtained
1
after crystallization from AcOEt/hexanes. Colorless cubes. M.p. 108 1118. H-NMR (CDCl3, 400 MHz): 7.61
(s, 1 H); 7.09 (d, J ˆ 8.2, 2 H); 7.06 (d, J ˆ 9.3, 2 H); 7.04 (s, 1 H); 7.00 (s, 1 H); 5.19 (s, 2 H); 4.04 (s, 3 H). Anal.
calc. for C17H12F4N2O(336.29): C 60.72, H 3.60; found: C 61.01, H 3.63.

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Helvetica Chimica Acta Vol. 86 (2003)
3,3',5,5'-Tetrafluoro-4'-[(1H-imidazole-1-yl)methyl][1,1'-biphenyl]-4-ol (2d). Br3B (0.95 ml, 2.5 g,
10 mmol) was added to a soln. of 2c (1.7 g, 5.0 mmol) in dry CH2Cl2 (25 ml). After 12 h at 258, MeOH
(5.0 ml) was added, and the volatiles were evaporated. A sat. aq. soln. of NaHCO3 (10 ml) was added, and the
product was collected by filtration. Crystallization from MeOH afforded 2d (1.00 g, 62%). Colorless cubes. M.p.
242 2448 (dec.). 1H-NMR (D3CCOCD3, 400 MHz): 7.67 (s, 1 H); 7.43 (d, J ˆ 8.4, 4 H); 7.11 (s, 1 H); 6.93
(s, 1 H); 5.36 (s, 2 H); 2.83 (s, 1 H). Anal. calc. for C16H10F4N2O(322.26): C 59.63, H 3.13; found: C 59.49,
H 3.22.
5-Bromo-1,3-difluoro-2-iodobenzene (11). At À758, (i-Pr)2NH (16 ml, 10 g, 0.10 mol) and 1-bromo-3,5-
difluorobenzene (12 ml, 19 g, 0.10 mol) were added consecutively to a soln. of BuLi (0.10 mol) in THF (0.20 l)
and hexanes (60 ml). After 2 h at À758, a soln. of I2 (25 g, 0.10 mol) in THF (50 ml) was added. The solvents
were evaporated, and the residue was dissolved in Et2O(0.10 l). After washing with a 10% aq. soln. of Na 2S2O3
(2 Â 50 ml), the org. layer was dried and evaporated. Crystallization from EtOH afforded 11 (26.1 g, 82%).
1
Colorless platelets. M.p. 41 438. H-NMR (CDCl3, 400 MHz): 7.08 (m, sym., 2 H). Anal. calc. for C6H2BrF2I
(318.85): C 22.60, H 0.63; found: C 22.76, H 0.78.
4,4'-Dibromo-2,2',6,6'-tetrafluoro[1,1'-biphenyl] (12). At À758, BuLi (0.10 mol) in hexanes (0.62 l), CuBr2
(22 g, 0.10 mol), and, 45 min later, PhNO2 (10 ml, 12 g, 0.10 mol) were added consecutively to a soln. of 11 (32 g,
0.10 mol) in Et2O(0.50 l). The mixture was allowed to reach 25 8 during 2 h. The suspension was poured into a
12% aq. soln. of NH3 (0.10 l). The org. layer was separated, and the aqueous phase was extracted with Et2O(2 Â
0.10 l). The combined org. layers were dried and evaporated. Crystallization from MeOH afforded 12 (15.2 g,
79%). Colorless platelets. M.p. 106 1088. 1H-NMR (CDCl3, 400 MHz): 7.22 (sym. m, 4 H). Anal. calc. for
C12H4Br2F4 (383.96): C 37.54, H 1.05; found: C 37.48, H 1.10.
4-Bromo-2,2',6,6'-tetrafluoro[1,1'-biphenyl]-4-carbaldehyde (13). At À1008, BuLi (0.10 mol) in hexanes
(63 ml) was added dropwise during 10 min to a suspension of 12 (38 g, 0.10 mol) in Et2O(0.50 l). After 15 min,
DMF (7.7 ml, 7.3 g, 0.10 mmol) was added, and the mixture was allowed to reach 258. After addition of H2O
(50 ml) and extraction with Et2O(3 Â 50 ml), a 92 :8 mixture (according to GC, 30 m, DB-1, 1008 (10 min) !
2008, heating rate 308/min) of 13 and the dicarbaldehyde was obtained. Concentration and crystallization from
AcOEt/hexanes gave 13 (28.6 g, 86%). Colorless needles. M.p. 94 968. 1H-NMR (CDCl3, 400 MHz): 10.00
(t, J ˆ 1.6, 1 H); 7.55 (d, J ˆ 6.8, 2 H); 7.26 (d, J ˆ 6.9, 2 H). Anal. calc. for C13H5BrF4 (333.08): C 46.88, H 1.51;
found: C 47.14, H 1.20.
4'-Bromo-2,2',6,6'-tetrafluoro-[1,1'-biphenyl]-4-methanol (14a). NaBH4 (7.6 g, 0.20 mol) was added to 13
(17 g, 50 mmol) in a 1:1 (v/v) mixture MeOH/THF (0.20 l). After 12 h at 258, a 2.0m aq. soln. of HCl (50 ml) was
carefully added, followed by extraction with Et2O(4 Â 50 ml). The combined org. layers were washed with brine
(50 ml), dried, and evaporated. Crystallization from AcOEt/hexanes afforded 14a (14.9 g, 89%). Colorless
needles. M.p. 74 758. 1H-NMR (CDCl3, 400 MHz): 7.21 (d, J ˆ 6.7, 2 H); 7.03 (d, J ˆ 8.2, 2 H); 4.74 (s, 2 H).
Anal. calc. for C13H7BrF4O(335.09): C 46.60, H 2.11; found: C 46.96, H 1.96.
Bromo-2,2',6,6'-tetrafluoro-4'-{[(triisopropylsilyl)oxy]methyl}[1,1'-biphenyl] (15a). The alcohol 14a (17 g,
50 mmol), (i-Pr)3SiCl (13 ml, 12 g, 60 mmol), and 1H-imidazole (8.8 g, 0.13 mol) were dissolved in DMF
(25 ml). After 20 h at 258, the mixture was poured into H2Oand extracted with CH 2Cl2 (3 Â 50 ml). The
volatiles were evaporated, and the residue was crystallized from MeOH to afford 15a (22.6 g, 92%). Colorless
needles. M.p. 57 598. 1H-NMR (CDCl3, 400 MHz): 7.21 (d, J ˆ 6.6, 2 H); 7.02 (d, J ˆ 8.3, 2 H); 4.85 (s, 2 H); 1.2
(m, 3 H); 1.11 (d, J ˆ 6.8, 18 H). Anal. calc. for C22H27BrF4OSi (491.44): C 53.77, H 5.54; found: C 53.91, H 5.35.
2,2',6,6'-Tetrafluoro-4-methyl-4'-{[(triisopropylsilyl)oxy]methyl}[1,1'-biphenyl] (15b). At À758, 15a (37 g,
75 mmol) and Me2SO4 (7.1 ml, 9.5 g, 75 mmol) were added consecutively to a soln. of BuLi (75 mmol) in
hexanes (33 ml) and THF (0.15 l). After evaporation, H2O(50 ml) was added, and the product was extracted
with Et2O(3 Â 50 ml). The combined extracts were dried and evaporated. Crystallization from MeOH afforded
15b (23.7 g, 74%). Colorless needles. M.p. 67 688. 1H-NMR (CDCl3, 400 MHz): 7.01 (d, J ˆ 8.3, 2 H); 6.83
(d, J ˆ 8.0, 2 H); 4.85 (s, 2 H); 2.40 (s, 3 H); 1.2 (m, 3 H); 1.11 (d, J ˆ 6.7, 18 H). Anal. calc. for C23H30F4OSi
(426.57): C 64.76, H 7.09; found: C 64.42, H 6.88.
2,2',6,6'-Tetrafluoro-4-methoxy-[4'-{[(triisopropylsilyl)ary]methyl[1,1'-biphenyl] (15c). The reaction was
conducted as described for 15b, Me2SO4 being replaced with FB(OMe)2 ¥ O Et [44][45] (14 ml, 12 g, 75 mmol).
2
At 08, a 3.0m aq. soln. of NaOH (27 ml) and 30% H2O2 (7.5 ml, 2.7 g, 75 mmol) were added consecutively. At
258, the mixture was acidified with 2.0m solution of HCl (0.10 l) and extracted with Et2O(3 Â 0.10 l). The
combined org. layers were washed with a 10% aq. soln. of Na2S2O3 (0.10 ml), dried, and evaporated. The residue
was dissolved in Me2SO(0.15 l) before MeI (5.6 ml, 13 g, 90 mmol) and KOH powder (5.0 g, 90 mmol) were
added consecutively. After 1 h, H2O(0.50 l) was added, and the product was extracted with Et O(3 Â 0.10 l).
2
The org. layers were dried and evaporated. Crystallization from MeOH afforded 15c (20.9 g, 63%). Colorless

Helvetica Chimica Acta Vol. 86 (2003)
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1
needles. M.p. 73 758. H-NMR (CDCl3, 400 MHz): 7.00 (d, J ˆ 8.2, 2 H); 6.58 (d, J ˆ 9.1, 2 H); 4.85 (s, 2 H);
3.84 (s, 3 H); 1.2 (m, 3 H); 1.11 (d, J ˆ 6.4, 18 H). Anal. calc. for C23H30F4O2Si (442.52): C 62.42, H 6.83; found:
C 62.50, H 6.71.
2,2',6,6'-Tetrafluoro-4'-methyl[1,1'-biphenyl]-4-methanol (14b). The protected alcohol 15b (11 g, 25 mmol)
was dissolved in THF (25 ml) and treated with a 1.0m soln. of Bu4NF (26 mmol) in THF (26 ml). After 15 min,
H2O(50 ml) was added, and the aq. layer was extracted with Et 2O(3 Â 50 ml). The combined org. layers were
dried and evaporated. Crystallization from AcOEt/hexanes gave 14b (5.74 g, 85%). Colorless needles. M.p. 92
948. 1H-NMR (CDCl3, 400 MHz): 7.03 (d, J ˆ 7.6, 2 H); 6.83 (d, J ˆ 8.2, 2 H); 4.75 (s, 2 H); 2.40 (s, 3 H). Anal.
calc. for C14H10F4O(270.23): C 62.23, H 3.73; found: C 62.31, H 3.67.
2,2',6,6'-Tetrafluoro-4'-methoxy[1,1'-biphenyl]-4-methanol (14c). When the reaction and workup conditions
described above were applied to 15c (11 g, 25 mmol), 14c (5.94 g, 83%) was obtained after crystallization from
AcOEt/hexanes. Colorless needles. M.p. 89 908. 1H-NMR (CDCl3, 400 MHz): 7.02 (d, J ˆ 8.0, 2 H); 6.57
(d, J ˆ 9.4, 2 H); 4.75 (s, 2 H); 3.84 (s, 3 H). Anal. calc. for C14H10F4O2 (286.22): C 58.75, H 3.52; found: C 58.77,
H 3.51.
4-Bromo-4'-(bromomethyl)-2,2',6,6'-tetrafluoro[1,1'-biphenyl] (16a). Br2 (1.5 ml, 4.8 g, 30 mmol) and 14a
(10 g, 30 mmol) were added consecutively to a suspension of Ph3P (11 g, 30 mmol) in (0.15 l). The mixture was
kept at 508 for 6 h. After evaporation, the residue was suspended in hexanes (0.15 l), filtered over a pad of silica
gel, and washed with more hexanes (0.10 l). After evaporation, the residue was crystallized from AcOEt/
hexanes to afford 16a (9.67 g, 81%). Colorless needles. M.p. 63 648. 1H-NMR (CDCl3, 400 MHz): 7.22 (d, J ˆ
6.8, 2 H); 7.07 (d, J ˆ 7.8, 2 H); 4.45 (s, 2 H). Anal. calc. for C13H6Br2F4 (397.99): C 39.23, H 1.52; found: C 39.42,
H 1.59.
4-(Bromomethyl)-2,2',6,6'-tetrafluoro-4'-methyl[1,1'-biphenyl] (16b). When the reaction and workup
conditions described above were applied to 14b (8.1 g, 30 mmol), 16b (7.79 g, 78%) was obtained after
crystallization from AcOEt/hexanes. Colorless needles. M.p. 92 938. 1H-NMR (CDCl3, 400 MHz): 7.05 (d, J ˆ
7.8, 2 H); 6.83 (d, J ˆ 8.3, 2 H); 4.45 (s, 2 H); 2.41 (s, 3 H). Anal. calc. for C14H9BrF4 (333.12): C 50.48, H 2.72;
found: C 50.46, H 2.62.
4-(Bromomethyl)-2,2',6,6'-tetrafluoro-4'-methoxy[1,1'-biphenyl] (16c). When the reaction and workup
conditions described above were applied to 14c (8.6 g, 30 mmol), 16c (8.06 g, 77%) was obtained after
crystallization from AcOEt/hexanes. Colorless needles. M.p. 91 928. 1H-NMR (CDCl3, 400 MHz): 7.04 (d, J ˆ
8.1, 2 H); 6.56 (d, J ˆ 9.3, 2 H); 4.44 (s, 2 H); 3.85 (s, 3 H). Anal. calc. for C14H9BrF4O(349.12): C 48.16, H 2.60;
found: C 48.41, H 2.58.
1-[(2,2',6,6'-Tetrafluoro-4'-methyl[1,1'-biphenyl]-4-yl)methyl]-1H-imidazole (3b). 1H-Imidazole (6.9 g,
0.10 mol), 16b (8.3 g, 25 mmol), 18-crown-6 (0.26 g, 1.0 mmol), and anh. K2CO3 (28 g, 0.20 mol) in dry acetone
(0.12 l) were heated under reflux for 2 h. At 258, the precipitate was removed by filtration, washed with more
acetone (50 ml), and the combined filtrates were evaporated. After the addition of H2O(0.10 l), the mixture
was extracted with a 1:5 (v/v) mixture MeOH/AcOEt (2 Â 50 ml). The org. phase was extracted with a 0.10m aq.
soln. of HCl (4 Â 50 ml). The combined aq. layers were alkalinized with a sat. aq. soln. of Na2CO3 (0.20 l) and
again extracted with a 1:5 (v/v) mixture MeOH/AcOEt (4 Â 50 ml). The combined org. layers were dried and
evaporated. The residue was crystallized from AcOEt/hexanes to afford 3b (4.96 g, 62%). Colorless needles.
M.p. 112 1138. 1H-NMR (CDCl3, 400 MHz): 7.59 (s, 1 H); 7.16 (s, 1 H); 6.96 (s, 1 H); 6.83 (d, J ˆ 8.3, 2 H); 6.75
(d, J ˆ 7.2, 2 H); 5.16 (s, 2 H); 2.39 (s, 3 H). Anal. calc. for C17H12F4N2 (320.29): calc. (%): C 63.75, H 3.78;
found: C 63.62, H 3.52.
1-[(2,2',6,6'-Tetrafluoro-4'-methoxy[1,1'-biphenyl]-4-yl)methyl]-1H-imidazole (3c). When the reaction and
workup conditions described for 3b were applied to 16c (7.0 g, 20 mmol), 3c (4.30 g, 64%) was obtained after
crystallization from AcOEt/hexanes. Colorless needles. M.p. 88 898. 1H-NMR (CDCl3, 400 MHz): 8.06
(s, 1 H); 7.21 (s, 1 H); 6.99 (s, 1H); 6.81 (d, J ˆ 8.1, 2 H); 6.57 (d, J ˆ 9.2, 2 H); 5.26 (s, 2 H); 3.83 (s, 3 H). Anal.
calc. for C17H12F4N2O(336.29): C 60.72, H 3.60; found: C 60.68, H 3.46.
1-[(4'-bromo-2,2',6,6'-tetrafluoro[1,1'-biphenyl]-4-yl)methyl]-1H-imidazole (3e). Compound 3e was ob-
tained from 16a (9.9 g, 25 mmol) and isolated as described above from AcOEt/hexanes (6.45 g, 67%). Colorless
needles. M.p. 120 1218. 1H-NMR (CDCl3, 400 MHz): 7.60 (s, 1 H); 7.22 (d, J ˆ 6.5, 2 H); 7.17 (s, 1 H); 6.96
(s, 1 H); 6.77 (d, J ˆ 7.3, 2 H); 5.19 (s, 2 H). Anal. calc. for C16H9BrF4N2 (385.16): C 49.90, H 2.36; found:
C 50.04, H 2.33.
1-[(2,2',6,6'-Tetrafluoro[1,1'-biphenyl]-4-yl)methyl]-1H-imidazole (3a). At À1008, 3e (1.9 g, 5.0 mmol) was
added to a soln. of t-BuLi (10 mmol) in Et2O(50 ml) and pentanes (7.1 ml). After 5 min, MeOH (0.50 ml) was
added, and the volatiles were evaporated. The residue was crystallized from AcOEt/hexanes to afford 3a (1.42 g,
93%). Colorless needles. M.p. 107 1098. 1H-NMR (CDCl3, 400 MHz): 8.20 (s, 1 H); 7.41 (m symm., 1 H); 7.22

2684
Helvetica Chimica Acta Vol. 86 (2003)
(s, 1 H); 7.02 (t, J ˆ 7.9, 2 H); 7.00 (s, 1 H); 5.30 (s, 2 H). Anal. calc. for C16H10F4N2 (306.26): C 62.75, H 3.29;
found: C 62.71, H 3.16.
2,2',6,6'-Tetrafluoro-4'-[(1H-imidazol-1-yl)methyl][1,1'-biphenyl]-4-ol (3d). Br3B (0.95 ml, 2.5 g, 10 mmol)
was added to 3c (1.7 g, 5.0 mmol) in dry CH2Cl2 (25 ml). The mixture was kept at 258 for 12 h. MeOH (5.0 ml)
was added, and the volatiles were evaporated. A sat. aq. soln. of NaHCO3 (10 ml) was added, and the product
was collected by filtration. Crystallization from MeOH afforded 3d (1.03 g, 64%). Colorless cubes. M.p. 228
1
2308 (dec.). H-NMR (D3CCOCD3, 400 MHz): 7.85 (s, 1 H); 7.27 (s, 1 H); 7.05 (d, J ˆ 7.9, 2 H); 7.04 (s, 1 H);
6.64 (d, J ˆ 9.3, 2 H); 5.42 (s, 2 H). Anal. calc. for C16H10F4N2O(322.26): C 59.63, H 3.13; found: C 59.53,
H 3.06.
Inhibition of CYP 17. The inhibition of human CYP 17 of the synthesized compounds was determined as
described in [9].
Inhibition of CYP 19. According to the method of Hartmann and Batzl [36], the compounds were tested for
their inhibitory activity toward CYP 19.
Preparation of Rat Liver Microsomes. Six adult male SpragueÀDawley rats were sacrificed by CO2. The
livers were removed, pooled, washed twice with an ice-cold 0.90% aq. soln. of NaCl, weighed, and frozen at
À708 until they were further processed.
The defrosted livers were homogenized in buffer (pH 7.4) containing 0.25m sucrose, 10 mm tris(hydrox-
ymethyl)aminomethane (Tris), and 1.0 mm ethylenediaminetetraacetic acid (EDTA; 3 ml per g tissue). The
homogenate was centrifuged at 1.2 ¥ 104 g for 30 min in order to remove cell debris and mitochondria. The
resulting supernatant was subsequently centrifuged at 1.0 ¥ 105 g for 1 h. The pelleted microsomes were washed
once with 0.10m Na3PO4 buffer (pH 7.4) and suspended in 0.10m Na3PO4 buffer containing 20% glycerol
(15 ml). All steps were carried out at 48 [1]. Protein concentrations were determined by the method of Lowry et
al. [46] with bovine serum albumin as standard. Cytochrome P450 concentrations were measured according to
the method described by Omura and Sato [47]. Aliquots of this enzyme preparation were frozen at À708 until
used.
Test of the in vitro Stability. Rat liver microsomal suspension containing 0.40 mm of P450 (0.41 nm of P450 ¥
(mg of protein)À1) and 1.0 mm of one of the compounds (1d, 2d, 3d, or phenol; dissolved in a 7:3 (v/v) mixture of
a 0.10m aq. HCl soln. and Me2SO, diluted 1:10) was mixed in 1440 ml of 50 mm Na3PO4 buffer (pH 7.4,
containing 1.0 mm MgCl2, 1.0 mm EDTA, and 0.10 mm dithiothreitol) at 48 in a 2.0-ml micro test tube. After
5 min of preincubation at 378, the reaction was started by the addition of 60 ml of NADPH-generating system
(2.0 U/ml glucose-6-phosphate dehydrogenase, 10 mm glucose-6-phosphate, and 1.0 mm NADP+ (pre-
incubated for 30 min at 378)) and vigorous mixing [37]. Control incubations were performed in absence of
the NADPH-generating system. At 0, 10, 20, 30, 45, 60, 90, and 120 min, samples of 150 ml were taken and
pipetted into 80 ml of a 91:9 (v/v) mixture of MeCN and AcOH to stop the reaction. After 15 min at 08, the
precipitated proteins were separated by microcentrifugation. Samples of 50 ml of the supernatant were
transferred into a safe-lock vial and stored at À708 until the HPLC analysis.
HPLC Analysis. The HPLC system consisted of an isocratic high-pressure pump (Jasco 870-PU, D-64823
Gro˚-Umstadt), an autosampler (Jasco 851-AS, D-64823 Gro˚-Umstadt), and a UV-detector (Jasco 870-UV, D-
64823 Gro˚-Umstadt). A CC 125 Â 3 mm Nucleodur Gravity 120-3 C18 column with column holder and an
analogue guard column (Macherey Nagel, D-52355 D¸ren) operated at ambient temp. was used to separate the
compounds at a flow rate of 0.85 ml/min. Different ratios of ammonium acetate buffer (20 mm, pH 4.0) and
MeCN were used as eluents (for 1d: 91 :9 (G/G), tR 7.9 min; for 2d, 3d, and phenol: 84 :16 (G/G), tR 7.5, 5.1, and
7.0 min, resp.). UV Absorbance was monitored at 254 nm.
X-Ray Crystal-Structure Determination of 2c and 3c (Table 2). Diffraction data were collected at 140 K (2c)
and 293 K (3c) with MoKa radiation on different equipments: an Oxford Diffraction diffractometer with a
kappa geometry equipped with a Sapphire CCD detector (2c) and a mar345 imaging plate detector (3c). Data
reduction was performed with CrysAlis RED 1.6.9b [48] and marHKL 1.9.1 [49]. Structure solutions were
determined with ab initio direct methods [50]. All structures were refined with full-matrix least-squares on F2
with all non-H-atoms anisotropically defined. The H-atoms were placed in calculated positions by the −riding
model× with Uiso ˆ aUeq(C) (where a is 1.5 for Me H-atoms and 1.2 for other atoms and C is the parent C-atom).
Space-group determination, structure refinement, geometric calculations, and graphical representations were
carried out on all structures with SHELXTL software package, release 5.1 [51]. Crystallographic data
(excluding structure factors) for the structures reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as deposition No. CCDC-203256 (2c) and deposition No. CCDC-203257 (3c).
Copies of the data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge
CB21EZ UK (fax: ‡44 (1223) 336033; e-mail: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta Vol. 86 (2003)
2685
Table 2. Crystallographic Data for the Compounds 2c and 3c
2c
3c
Empirical formula
Formula weight
Crystal size [mm]
Crystal system
Space group
a [ä]
b [ä]
c [ä]
b [8]
Volume [ä3]
Z
C17H12F4N2O
336.29
0.30 Â 0.13 Â 0.10
monoclinic
P21/n
16.0021(18)
4.2789(10)
21.648(3)
96.239(10)
1473.5(4)
C17H12F4N2O
336.29
0.20 Â 0.15 Â 0.12
monoclinic
P21/c
6.9734(14)
8.848(5)
24.125(8)
92.16(2)
1487.5(10)
4
4
Density [g mÀ3
Temp. [K]
]
1.516
140(2)
0.130
1.502
293(2)
0.129
3.42 to 25.02
Absorption coeff. [mmÀ1
q Range [8]
]
3.79 25.03
À 19 ! 18, À4 ! 4, À25 ! 25
7389
Index ranges
Refl. collected
À 7 ! 8, À10 ! 10, À28 ! 28
8589
Independent reflect.
Absorption correction
2477 (Rint ˆ 0.0607)
2495 (Rint ˆ 0.0489)
none
none
Data/restraints/parameters
Goodness-of-fit on F2
2477/0/218
1.144
2495/0/218
0.991
Final R indices [I > 2s(I)]
R Indices (all data)
Largest diff. peak/hole [e AÀ3
R1 ˆ 0.0715, wR2 ˆ 0.1508
R1 ˆ 0.0854, wR2 ˆ 0.1573
0.264 and À0.235
R1 ˆ 0.0590, wR2 ˆ 0.1600
R1 ˆ 0.0856, wR2 ˆ 0.1886
0.260 and À0.297
]
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Received February 14, 2003