Nucleophilic Displacement at Benzhydryl Centers: Asymmetric Synthesis of 1,1-Diarylalkyl Derivatives

Article abstract of DOI:10.1021/ol0361655

(Equation presented) Activation of substituted 1,1-diarylmethanols as their corresponding toluenesulfonates and subsequent displacement with a range of carbon, nitrogen, oxygen, and sulfur nucleophiles proceeds in 81-96% yield. Enantiomerically enriched d

Full text of DOI:10.1021/ol0361655

ORGANIC
LETTERS
2004
Vol. 6, No. 1
111-114
Nucleophilic Displacement at Benzhydryl
Centers: Asymmetric Synthesis of
1,1-Diarylalkyl Derivatives
Yuri Bolshan,†,‡ Cheng-yi Chen,§ Jennifer R. Chilenski,§ Francis Gosselin,†
,†
David J. Mathre,§ Paul D. O’Shea,* Ame´lie Roy,† and Richard D. Tillyer§
Department of Process Research, Merck Frosst Centre for Therapeutic Research,
P.O. Box 1005, Pointe Claire-DorVal, Que´bec, H9R 4P8, Canada, and
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065, USA
paul_oshea@merck.com
Received November 5, 2003
ABSTRACT
Activation of substituted 1,1-diarylmethanols as their corresponding toluenesulfonates and subsequent displacement with a range of carbon,
nitrogen, oxygen, and sulfur nucleophiles proceeds in 81−96% yield. Enantiomerically enriched diarylmethanols 8a−c were activated and
displaced with pyridine acetate enolate with complete stereochemical inversion at carbon to yield 1,1-diarylalkyl derivatives 10a−c without
loss of optical purity.
Substituted 1,1-diarylalkyl derivatives form the core structure
of a number of pharmacologically active compounds. For
example, the 1,1-diarylalkyl structural element is found in
compounds with reported activity as antimuscarinics,1 anti-
depressants,2 and endothelin antagonists.3 As such, there is
a need for practical synthetic methodologies for the prepara-
tion of a wide variety of compounds of this type, especially
in optically pure form.
metric C-H insertion of rhodium carbenoids derived from
aryl diazoacetates into cyclohexadienes,5 aryl cuprate addition
to chiral cyclopropane dicarboxylates,6 and diastereoselective
and enantioselective conjugate addition of organometallic
reagents to cinnamate derivatives7 (Scheme 1).
Scheme 1. Synthetic Approaches to 1,1-Diarylalkyl Derivatives
The asymmetric synthesis of the 1,1-diarylalkyl skeleton
poses some interesting challenges. Reported syntheses
include methods based on asymmetric epoxidation of a
trisubstituted alkene or chiral sulfur-ylide,4 catalytic asym-
† Merck Frosst Centre for Therapeutic Research.
‡ Merck Frosst undergraduate coop student from the University of
Waterloo, Ontario, Canada.
§ Merck Research Laboratories, Rahway.
(1) Nilvebrant, L.; Andersson, K.-E.; Gillberg, P.-G.; Stahl, M.; Sparf,
B. Eur. J. Pharmacol. 1997, 327, 195.
(2) Welch, W. M.; Kraska, A. R.; Sarges, R.; Coe, K. B. J. Med. Chem.
1984, 27, 1508.
(3) Astles, P. C.; Brown, T. J.; Halley, F.; Handscombe, C. M.; Harris,
N. V.; Majid, T. N.; McCarthy, C.; McLay, I. M.; Morley, A.; Porter, B.;
Roach, A. G.; Sargent, C.; Smith, C.; Walsh, R. J. A. J. Med. Chem. 2000,
43, 900.
Our interest in this structural motif originated from the
discovery of CDP-8408 and compound I9 as potent and
10.1021/ol0361655 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/13/2003

selective phosphodiesterase IV (PDE-IV) inhibitors (Figure
1). Selective PDE-IV inhibitors are currently under investiga-
for the rapid synthesis of 1,1-diarylalkyl derivatives in both
racemic and enantioenriched form.
We initially focused our efforts on developing a suitable
electrophile for alkylation by the lithium enolate of ethyl
4-pyridyl acetate using 1,1-diarylmethanols such as 1 (Scheme
2). Although racemic chloride and bromide derivatives 2a
Scheme 2 a
Figure 1. PDE-IV Inhibitors.
tion as potential therapeutic agents for the treatment of
asthma and chronic obstructive pulmonary disease (COPD),
and a number of these compounds have entered clinical
trials.10
a Conditions: (a) Activation. (b) Ethyl 4-pyridylacetate, LiN-
(SiMe3)2, THF, DMPU, -40 °C.
We sought to develop a practical methodology that would
allow access to a large number of racemic analogues of I
that also had the potential to be developed into an asymmetric
synthesis. We reasoned that a protocol based on nucleophilic
displacement of suitably activated benzhydryl alcohol deriva-
tives could provide access to a wide variety of 1,1-diaryl
substituted products in a minimal number of steps from
readily available, simple starting materials. With the excep-
tion of bromides and chlorides, the synthetic utility of
activated benzhydryl derivatives has received scant attention
in the literature. This may be a consequence of the general
expectation that diaryl-substituted electrophiles may be
exceedingly prone to ionization, racemization, and decom-
position and therefore not synthetically useful.
were previously demonstrated to be reasonably good sub-
strates for nucleophilic displacement with pyridinyl eno-
lates,9,11 our attempts to prepare chlorides and bromides from
the corresponding optically enriched alcohols were unsuc-
cessful because of extensive racemization during their
formation. Other activating groups were thus screened.
Phosphate leaving groups 2b (R) Et, i-Pr) could be readily
prepared but were unreactive toward lithium enolates.
Attempted preparation of methanesulfonate 2c using meth-
anesulfonyl chloride led exclusively to the corresponding
chloride, while use of methanesulfonic anhydride led to
decomposition of the starting benzhydrol. Similarly, attempts
In this communication, we describe our efforts to identify
a suitable leaving group and develop a synthetic methodology
(4) (a) Lynch, J. E.; Choi, W.-B.; Churchill, H. R. O.; Volante, R. P.;
Reamer, R. A.; Ball, R. G. J. Org. Chem. 1997, 62, 9223. (b) Aggarwal,
V. K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams, D. T.; Angew. Chem.,
Int. Ed. 2003, 42, 3274.
Table 1. Displacement of Benzhydrol Toluenesulfonates with
Lithium Enolate of Ethyl 4-Pyridyl Acetatea
(5) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 2,
233.
(6) Corey, E. J.; Gant, G. T. Tetrahedron Lett. 1994, 35, 5373.
(7) (a) Frey, L. F.; Tillyer, R. D.; Caille, A.-S.; Tschaen, D. M.; Dolling,
U.-H.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1998, 63, 3120. (b)
Xu, F.; Tillyer, R. D.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
Tetrahedron: Asymmetry 1998, 9, 1651. (c) Asano, Y.; Iida A.; Tomioka,
K. Chem. Pharm. Bull. 1998, 46, 184. (d) Houpis, I. N.; Lee, J.; Dorziotis,
I.; Molina, A.; Reamer, B.; Volante, R. P.; Reider, P. J. Tetrahedron 1998,
54, 1185.
(8) Alexander, R. P.; Warrellow, G. J.; Eaton, M. A. W.; Boyd, E. C.;
Head, J. C.; Porter, J. R.; Brown, J. A.; Reuberson, J. T.; Hutchinson, B.;
Turner, P.; Boyce, B.; Barnes, D.; Mason, B.; Cannell, A.; Taylor, R. J.;
Zomaya, A.; Millican, A.; Leonard, J.; Morphy, R.; Wales, M.; Perry, M.;
Allen, R. A.; Gozzard, N.; Hughes, B.; Higgs, G. Bioorg. Med. Chem. Lett.
2002, 12, 1451.
(9) Guay, D.; Hamel, P.; Blouin, M.; Brideau, C.; Chan, C. C.; Chauret,
N.; Ducharme, Y.; Huang, Z.; Girard, M.; Jones, T. R.; Laliberte´, F.;
Masson, P.; McAuliffe, M.; Piechuta, H.; Silva, J.; Young, R. N.; Girard,
Y. Bioorg. Med. Chem. Lett. 2002, 12, 1457.
(10) (a) Huang, Z.; Ducharme, Y.; MacDonald, D.; Robichaud, A. Curr.
Opin. Chem. Biol. 2001, 5, 432. (b) Martin, T. J. IDrugs 2001, 4, 312. (c)
Nell, H.; Louw, C.; Leichtl, S.; Rathgeb, F.; Neuhauser, M.; Bardin, P. G.
Am. J. Respir. Crit. Care Med. 2000, 161, A200. (d) Timmer, W.; Leclerc,
V.; Birraux, G.; Neuhauser, M.; Hatzelmann, A.; Bethke, T.; Wurst, W.
Am. J. Respir. Crit. Care Med. 2000, 161, A505.
entry
Ar
product
yield (%)
1
2
3
4
5
6
7
8
9
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
3,5-MeOC6H3
C6H5
4-CF3C6H4
3-CF3C6H4
2-CF3C6H4
3,5-CF3C6H3
3,4-MeOC6H3
3,4-HCF2OC6H3
5a
5b
5c
5d
5e
5f
5g
5h
5i
68
73
15
28
76
74
68
<5
94
<5
73
10
11
5j
5k
a Conditions: (a) n-BuLi or LiN(SiMe3)2, THF, -78 °C; Ts2O, THF;
ethyl 4-pyridyl acetate, LiN(SiMe3)2, THF, DMPU, -40 °C.
112
Org. Lett., Vol. 6, No. 1, 2004

Table 2. Displacement of Benzhydrol Toluenesulfonate 6 with
Various Nucleophiles
Table 3. Nucleophilic Displacement of Optically Enriched
Benzhydryl Toluenesulfonatesa
entry
8
ee (%)
10
ee (%)
yield (%)
1
2
3
8a
8b
8c
87
91
94
10a
10b
10c
87
91
94
93
81
94
a Conditions: (a) LiN(SiMe3)2, THF, -78 °C; Ts2O, THF, -20 °C; ethyl
4-pyridyl acetate, LiN(SiMe3)2, THF, DMPU, -20 °C. (b) LiOH, MeOH,
THF, H2O, 60 °C. (c) 6 N HCl, rt.
In general, electron-donating and withdrawing substituents
are well tolerated. However, substituents in the ortho position
(entries 3, 8) gave lower yields, presumably due to steric
hindrance. The reaction proved to be more difficult on
substrates with electron-donating groups in both the 3,5-
positions (entry 4), suggesting a problem with the stability
of the tosylate intermediate. By comparison, substrates with
electron-withdrawing groups in the same positions gave the
desired product in 94% yield (entry 9). Interestingly, replac-
ing electron-donating 3,4-methoxy groups with 3,4-difluo-
romethoxy groups increased the yield from <5% to 73%
(entries 10, 11).
In an effort to determine the scope and limitations of the
reaction, we investigated the displacement of 3,5-bis-
(trifluoromethyl)phenylmethyltoluenesulfonate with a range
of nucleophiles (Table 2).
a Additives: 15-crown-5 (6.5 equiv) and CH3CN (0.06 M). b Additive:
15-crown-5 (6.5 equiv).
Thus, treatment of toluenesulfonate 6 with phenoxide,
thiolate, lithiated acetonitrile, and acetylide nucleophiles gave
the expected products 7a-h in uniformly excellent yields.
By comparison, a number of nitrogen nucleophiles were
screened and only azide ion gave the desired product (Table
2, entry 8). No reaction was observed when primary or
secondary amines were used as nucleophiles.14
Finally, we investigated the activation and displacement
of optically enriched substituted benzhydrols. Diarylmetha-
nols 8a-c were conveniently prepared by the catalyzed
addition of diphenylzinc to the corresponding aldehydes in
the presence of a chiral ferrocene ligand as described by
Bolm et al.15 The treatment of secondary lithium alkoxides
to prepare toluenesulfonate 2d using p-toluenesulfonyl
chloride were unsuccessful.12 We were thus delighted to find
that treatment of a lithium alkoxide of 1 in THF at -78 °C
with p-toluenesulfonic anhydride (Ts2O) followed by addition
of the lithium enolate of ethyl 4-pyridyl acetate gave the
desired displacement product 3 in ∼90% yield.
To further explore this chemistry, a series of benzhydrols
4a-k containing both electron-donating and electron-
withdrawing substituents were prepared. Activation as tolu-
enesulfonates and nucleophilic displacement with the lithium
enolate of ethyl 4-pyridyl acetate gave adducts 5a-k (Table
1).
(13) In the cases of heteroatom nucleophiles, the reaction mixture was
heterogeneous after their addition. Addition of 15-crown-5 (in conjunction
with CH3CN for phenoxides) improved the solubility and in all cases
significantly increased the yield of the reaction.
(14) When tosylate 6 was treated with the lithium anion of either aniline,
n-butylamine, or indole, the corresponding ketone product was obtained,
presumably via abstraction of the benzylic proton and elimination of
toluenesulfinate anion. The use of less basic phthalimide anions resulted in
recovery of starting materials.
(11) Frenette, R.; Blouin, M.; Brideau, C.; Chauret, N.; Ducharme, Y.;
Friesen, R. W.; Hamel, P.; Jones, T. R.; Laliberte´, F.; Li, C.; Masson, P.;
McAuliffe, M.; Girard, Y. Bioorg. Med. Chem. Lett. 2002, 12, 3009.
(12) Preparation of benzhydryl toluenesulfonate has been reported: (a)
Ledwith, A.; Morris, D. G. J. Chem. Soc. 1964, 508. (b) Hoffmann, H. M.
R. J. Chem. Soc. 1965, 6748. (c) Coates, R. M.; Chen, J. P. Tetrahedron
Lett. 1969, 32, 2705.
Org. Lett., Vol. 6, No. 1, 2004
113

of 8a-c with p-toluenesulfonic anhydride followed by
addition of the lithium enolate of ethyl 4-pyridyl acetate led
to the expected ester products 9a-c in excellent yields. Ester
hydrolysis with lithium hydroxide and decarboxylation upon
treatment with aqueous 6 N HCl gave the corresponding 1,1-
diarylalkylpyridines 10a-c in excellent overall yield with
no loss of optical purity across the entire sequence as verified
by chiral HPLC (Table 3).16 The stereochemical outcome
of the nucleophilic displacement was confirmed by single-
crystal X-ray crystallographic analysis of alcohol 8c and
pyridine 10c as its bisulfate salt.
In summary we have developed a practical methodology
for the preparation of a variety of 1,1-diaryl-substituted
products in racemic or enantioenriched form via nucleophilic
displacement of activated benzhydryl derivatives. We are
currently investigating the mechanism of the nucleophilic
displacement and the displacement of optically enriched
benzhydryls with heteroatom-based nucleophiles.
(15) (a) Bolm, C.; Mun˜iz, K. Chem. Commun. 1999, 1295. (b) Angew.
Chem, Int. Ed. 2000, 39, 3465. (c) Bolm, C.; Rudolph, J. J. Am. Chem.
Soc. 2002, 124, 14850.
(16) Typical Procedure. To a solution of alcohol 8c (331 mg, 1.31 mmol,
94% ee) and (4-phenylazo)diphenylamine indicator (4 mg, 0.0131 mmol)
in THF (3.3 mL) at -78 °C under N2 was added dropwise LiN(SiMe3)2
(1.4 mL, 1.4 mmol, 1M in THF) until the solution turned deep pink. The
solution was aged at -78 °C for 10 min, and a solution of Ts2O (513 mg,
1.57 mmol) in THF (3.6 mL) was added dropwise. The reaction mixture
was warmed to -20 °C and aged for 1.5 h. In a separate flask, a solution
of ethyl 4-pyridyl acetate (1.08 g, 6.55 mmol) in THF (6.6 mL) and DMPU
(2.2 mL) was cooled to -50 °C, and LiN(SiMe3)2 (6.4 mL, 6.4 mmol, 1 M
in THF) was added dropwise. The enolate mixture was warmed to -30 °C
and aged for 1 h prior to its transfer via cannula to the flask containing the
toluenesulfonate. The reaction mixture was aged at -25 °C for 16 h,
quenched with 1 N HCl (10.5 mL, 10.5 mmol), and extracted with toluene
(30 mL). The organic layer was washed with water (5 × 10 mL) and
concentrated. The residue was diluted with THF/MeOH/H2O (24 mL:8 mL:8
mL), and 2 N LiOH (6 mL, 11.79 mmol) was added. The green reaction
mixture was heated to 60 °C under N2 for 2.5 h. After cooling to room
temperature, the solution was acidified to pH 1.5 with 6 N HCl (∼5 mL).
The volatiles were removed under reduced pressure, and the residue was
basified with 5 N NaOH (∼ 5 mL) and extracted with MTBE (30 mL).
The organic layer was washed with brine (10 mL), dried over Na2SO4,
filtered, and concentrated. The residue was purified by flash chromatography
(EtOAc/hexane 1:1) to afford pyridine 10c as a clear oil (403 mg, 94%
yield, 94% ee): [R]20D -18.9 (c 8.9, MeOH); 1H NMR (500 MHz, CDCl3)
δ 8.41 (dd, 2H, J ) 1.5, 4.5 Hz), 7.33-7.27 (m, 4H), 7.24-7.20 (tm, 1H,
J ) 7.3 Hz), 7.15 (m, 2H), 7.01 (dd, 1H, J ) 2.1, 8.3 Hz), 6.92 (m, 2H),
4.19 (t, 1H, J ) 7.9 Hz), 3.34 (dd, 1H, J ) 13.7, 7.9 Hz), 3.29 (dd, 1H, J
) 13.7, 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 149.4, 148.1, 143.7, 142.0,
132.2, 130.2, 129.5, 128.5, 127.5, 127.1, 126.8, 124.1, 50.9, 40.7; IR (neat,
cm-1) 3065, 3030, 2945, 1602, 1471, 1135, 1031, 803; LRMS calcd for
C19H15Cl2N 327.06, found 328.0 [M + 1]; chiral SFC-HPLC Chiralpak
OD 250 × 4.6 mm column, gradient 5-15% MeOH at 1%/min, 2.0 mL/
min, 300 bar, λ ) 215 nm, 35 °C; tr minor ) 14.5 min, tr major ) 15.1 min
(94% ee).
Acknowledgment. The authors wish to thank Mr. Phil-
ippe Dagneau and Dr. Xin Wang for preliminary experi-
ments.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 5a,b,d-
g,i,k, 7a-k, 8a-c, and 10a,b and X-ray crystallographic
data for compounds 8c and 10c. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0361655
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