Rapid synthesis of CDP840 with 2-pyrimidyl vinyl sulfide as a platform

Article abstract of DOI:10.1021/jo0510437

A rapid synthesis of CDP840 (a potential therapeutic agent for asthma), using 2-pyrimidyl vinyl sulfide as a platform, has been established. This method includes a stereoselective double Mizoroki-Heck-type arylation, a Liebeskind-Srogltype cross-coupling reaction, and a Pd/C-catalyzed hydrogenation.

Full text of DOI:10.1021/jo0510437

interesting photophysical properties.1b,c,2 Moreover, we
have finally developed a programmable synthesis of
tetraarylethenes through a Pd-catalyzed sequential tet-
raarylation of a vinyl 2-pyrimidyl sulfide platform.3 As
for our application to the synthesis of pharmaceutically
important molecules, we established a programmable
synthesis of tamoxifen-type tetrasubstituted olefins using
alkynyl(2-pyridyl)silane as a platform.4
Rapid Synthesis of CDP840 with
2-Pyrimidyl Vinyl Sulfide as a Platform
Nobuhiro Muraoka, Masahiro Mineno,
Kenichiro Itami,*,† and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological
Chemistry, Graduate School of Engineering, Kyoto
University, Nishikyo-ku, Kyoto 615-8510, Japan
During these investigations toward multisubstituted
olefins, we became aware that such olefins should also
be excellent precursors for multisubstituted ethane struc-
tures by functionalizing the remaining CdC core of
multisubstituted olefins (Scheme 1). As functionalizing
methods, for example, carbometalation (X ) C, Y ) M),
hydrometalation (H, M), hydrogenation (H, H), and
epoxidation (-O-) may be applicable. In this paper, we
report on a rapid synthesis of CDP840 (1) using 2-py-
rimidyl vinyl sulfide as a platform.
itami@chem.nagoya-u.ac.jp; yoshida@sbchem.kyoto-u.ac.jp
Received May 24, 2005
CDP840 (1), which has an interesting 1,1,2-triaryle-
thane structure, is a potential therapeutic agent for
asthma as a selective phosphodiesterase (PDE) IV inhibi-
tor.5 PDE IV is believed to be the dominant isozyme
present in inflammatory cells and airway smooth muscle.
Inhibition of PDE IV leads to an increase in the concen-
tration of cyclic GMP, and gives rise to suppression of
cellular function in inflammatory cells.
A rapid synthesis of CDP840 (a potential therapeutic agent
for asthma), using 2-pyrimidyl vinyl sulfide as a platform,
has been established. This method includes a stereoselective
double Mizoroki-Heck-type arylation, a Liebeskind-Srogl-
type cross-coupling reaction, and a Pd/C-catalyzed hydro-
genation.
The synthesis of densely substituted (functionalized)
organic structures has been an important subject in
organic synthesis. In view of their synthesis as well as
potential applications as functional materials and phar-
maceuticals, we have been investigating the chemistry
(synthesis and properties) of multisubstituted olefins
during the last several years. In particular, we have
developed a number of syntheses of multisubstituted
olefins based on a sequential installation of substituents
on a CdC or CtC core of an appropriate starting
material (platform).1-4
For example, we have developed a programmable
synthesis of triarylethenes through a Pd-catalyzed se-
quential triarylation using vinyl(2-pyridyl)silane or vi-
nylboronate as a platform.1,2 From the triarylethene-
based extended π-system library, we were able to find a
number of interesting fluorescent materials as well as
Several syntheses of CDP840 including both racemic
and asymmetric approaches were reported so far.6,7
However, they suffered from a relatively long procedure
(6-7 steps). We envisaged that the sequence of double
Mizoroki-Heck-type arylation and cross-coupling start-
ing from 2-pyrimidyl vinyl sulfide (2)3,8 followed by
hydrogenation of the CdC bond would afford CDP840 (1)
very rapidly (Scheme 2). Such a synthesis would offer
an opportunity for diversity-oriented synthesis, which
would enable the production and screening of a series of
CDP840-type triarylethanes.
(5) Celltech Therapeutics LTD, U.S. Patent No. 5,608, 070.
(6) Previous syntheses: (a) Celltech Therapeutics LTD, U.S. Patent
No. 5,622,977. (b) Houpis, I. N.; Molina, A.; Dorziotis, I.; Reamer, R.
A.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1997, 38, 7131. (c)
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. (d) 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. 2002, 12,
1451. (e) Aggarwal, V, K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams,
D. T. Angew. Chem., Int. Ed. 2003, 42, 3274.
† Present address: Research Center for Materials Science, Nagoya
University, Nagoya 464-8602, Japan.
(1) Vinyl(2-pyridyl)silane as a platform: (a) Itami, K.; Nokami, T.;
Ishimura, Y.; Mitsudo, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc.
2001, 123, 11577. (b) Itami, K.; Ushiogi, Y.; Nokami, T.; Ohashi, Y.;
Yoshida, J. Org. Lett. 2004, 6, 3695. (c) Itami, K.; Ohashi, Y.; Yoshida,
J. J. Org. Chem. 2005, 70, 2778. Also see: (d) Itami, K.; Mitsudo, K.;
Kamei, T.; Koike, T.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2000,
122, 12013. (e) Itami, K.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc.
2001, 123, 5600.
(2) Vinyl boronate pinacol ester as a platform: Itami, K.; Tonogaki,
K.; Ohashi, Y.; Yoshida, J. Org. Lett. 2004, 6, 4093.
(7) The configuration of the enantiomer that shows the activity is
R.6
(3) Vinyl 2-pyrimidyl sulfide as a platform: Itami, K.; Mineno, M.;
Muraoka, N.; Yoshida, J. J. Am. Chem. Soc. 2004, 126, 11778.
(4) Alkynyl(2-pyridyl)silane as a platform: (a) Itami, K.; Kamei, T.;
Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670. (b) Kamei, T.; Itami,
K.; Yoshida, J. Adv. Synth. Catal. 2004, 346, 1824.
(8) Vinyl sulfide 2 was easily prepared from 2-thiocyanatopyrimidine
(derived from 2-mercaptopyrimidine) and vinylmagnesium bromide:
(a) Miyashita, A.; Nagasaki, I.; Kawano, A.; Suzuki, Y.; Iwamoto, K.;
Higashino, T. Heterocycles 1997, 45, 745. (b) Nagasaki, I.; Matsumoto,
M.; Yamashita, M.; Miyashita, A. Heterocycles 1999, 51, 1015.
10.1021/jo0510437 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/22/2005
J. Org. Chem. 2005, 70, 6933-6936
6933

TABLE 1. Optimization of the Liebeskind-Srogl-type
Cross-Coupling Reaction of 4a with 4-Pyridylboronic
Acid
SCHEME 1. Synthetic Strategy for
Multisubstituted Ethane Structures through CdC
Functionalization of Multisubstituted Olefins
entry
solvent
5 (yield, %)
4a (recovery, %)
1
2
3
4
5
6
7
8a
THF
19
0
10
9
42
49
57
66
57
29
53
68
37
41
34
23
EtOH
t-BuOH
CH3CN
DMF
DMA
DMI
DMI
SCHEME 2. Synthetic Strategy for CDP840
a 3.0 equiv of 4-pyridylboronic acid and CuTC were employed.
With the requisite 4a in hand, we embarked on the
installation of the 4-pyridyl group onto the alkenyl-
sulfur bond.11 According to our previous synthesis of
multisubstituted olefins using Pd-catalyzed cross-cou-
pling reactions of alkenyl sulfides with Grignard reagents
as a final step,3 our initial choice was to use 4-pyridyl-
magnesium chloride as the coupling partner for 4a in the
synthesis of 5. However, no cross-coupling occurred
between 4a and 4-pyridylmagnesium chloride (3.0 equiv)
under our standard conditions (5 mol % Pd[P(t-Bu)3]2, 60
°C, toluene)3 and a considerable amount of 4a was
recovered. This may be partially due to the thermal
instability of 4-pyridylmagnesium chloride.12
As an alternative to this Pd-catalyzed procedure, we
have recently reported the iron-catalyzed cross-coupling
reaction of alkenyl sulfides with Grignard reagents.13
Since this reaction proceeds at room temperature in
many cases, we applied this protocol in the installation
of the 4-pyridyl group. Unfortunately, however, the
reaction of 4a with 4-pyridylmagnesium chloride (3.0
equiv) under the influence of Fe(acac)3 (5 mol %) in THF
at room temperture gave the desired product 5 only in
9% yield (68% recovery of 4a).
SCHEME 3. Stereoselective Synthesis of 4a by the
Double Mizoroki-Heck Reaction of 2
At first, double Mizoroki-Heck-type arylation of 2-py-
rimidyl vinyl sulfide (2) was investigated (Scheme 3). The
stereoselective installation of two aryl groups (phenyl and
3-cyclopentyloxy-4-methoxyphenyl groups) at the â-C-H
bonds of 2 was achieved by following the procedure
developed previously.3 Thus, a toluene solution of 2 (1.0
equiv), iodobenzene (1.0 equiv), Et3N (3.0 equiv), and Pd-
[P(t-Bu)3]2 (5 mol %) was stirred at 60 °C for 4 h to afford
monoarylated vinyl sulfide in situ.9 Thereafter, aryl
iodide 310 (1.1 equiv) was added to the solution and the
mixture was stirred for an additional 18 h at 90 °C to
give the desired â,â-diarylated vinyl sulfide 4a in 87%
isolated yield (Scheme 3). The stereochemistry of 4a was
determined to be 97% E as judged by NMR analysis.
Thus, we turned to the Liebeskind-Srogl-type cross-
coupling reaction (an alternative cross-coupling reaction
of sulfides with arylboronic acids as coupling partners).14
When the original conditions reported by Liebeskind (Pd-
(PPh3)4, CuTC,15 THF, 60 °C) were applied in the reaction
of 4a with 4-pyridylboronic acid, the cross-coupling
product 5 was obtained in 19% yield (Table 1, entry 1).
Subsequently we found that the choice of solvent is
(11) A review on metal-catalyzed cross-coupling reactions using
sulfides: Luh, T.-Y.; Ni, Z.-J. Synthesis 1990, 89.
(12) (a) Furukawa, N.; Shibutani, T.; Fujihara, H. Tetrahedron Lett.
1987, 28, 5845. (b) Tre´court, F.; Breton, G.; Bonnet, V.; Mongin, F.;
Marsais F.; Que´guiner, G. Tetrahedron 2000, 56, 1349.
(13) Itami, K.; Higashi, S.; Mineno, M.; Yoshida, J. Org. Lett. 2005,
7, 1219.
(14) (a) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3,
91. (b) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979. (c) Liebeskind,
L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(15) CuTC ) copper(I) thiophene-2-carboxylate. Allred, G. D.; Lie-
beskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748.
(9) Pd/P(t-Bu)3 catalyst for Mizoroki-Heck reactions: (a) Littke, A.
F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (b) Itami, K.;
Yamazaki, D.; Yoshida, J. Org. Lett. 2003, 5, 2161. (c) References 1b,
1c, 2, and 3.
(10) 3 was prepared in one step from 5-iodo-2-methoxyphenol. See
the Supporting Information.
6934 J. Org. Chem., Vol. 70, No. 17, 2005

TABLE 2. The Effect of Sulfur Substituent in the
SCHEME 4. Hydrogenation of 5
Liebeskind-Srogl Coupling Reaction
at the alkenyl-sulfur bond. As we previously found in
the iron-catalyzed cross-coupling of alkenyl 2-pyrimidyl
sulfides with Grignard reagents,13 the 2-pyrimidyl group
might be acting as a directing group to a certain metal
species (Pd or Cu) to help the reacting CdC bond to
participate effectively in the desired cross-coupling mani-
fold through a complex-induced proximity effect. The
substantial decrease in coupling efficiency caused by the
introduction of a bulky tert-butyl group on the pyrimidine
ring (4d), which should interrupt such an attractive
pyrimidyl-metal interaction, is in line with such a
directed cross-coupling scenario.
4 (recovery,
entry
Ar
5 (%)a 6 (%)a
%)
1
2-pyrimidyl (4a)
phenyl (4b)
57
2
4
62
4
4
34
95
95
59
53
2
3b
4
phenyl (4b)
2-pyridyl (4c)
2-(4-tert-butyl)pyrimidyl (4d)
28
27
31
50
5
a Isolated yields besed on the amount of 4 used. b 1.0 equiv of
pyrimidine was added.
critical in this cross-coupling reaction. Although the use
of CH3CN, EtOH, and t-BuOH had a detrimental effect
in the coupling efficiency (entries 2-4), the use of amide-
based solvents such as N,N-dimethylformamide (DMF),
N,N-dimethylacetamide (DMA), and 1,3-dimethyl-2-imi-
dazolidinone (DMI) furnished 5 in higher yields (entries
5-7). In particular, the use of DMI afforded the desired
5 in 66% yield when 3.0 equiv of 4-pyridylboronic acid
was employed (entry 8). Further screening of Pd catalysts
(e.g. PdCl2(PPh3)2, Pd(OAc)2/P(OPh)3, Pd[P(t-Bu)3]2) was
also investigated, but they all turned out to be less active
than Pd(PPh3)4 in this cross-coupling.
Initially, we introduced the catalyst-directing 2-pyrim-
idyl group on sulfur in the vinyl sulfide strucure to
accomplish a “hard-to-achieve” Pd-catalyzed double C-H
arylation (2 f 4).3 During the present investigation, we
found an additional bonus by attaching the 2-pyrimidyl
group on sulfur in the cross-coupling at the alkenyl-
sulfur bond with arylboronic acids. Listed in Table 2 are
the results of the Liebeskind-Srogl-type cross-coupling
reaction of various vinyl sulfides 4 with 4-pyridylboronic
acid.
As already mentioned, the reaction of 4a with 4-py-
ridylboronic acid afforded 5 in 57% yield under the
influence of Pd(PPh3)4 and CuTC (Table 2, entry 1).
4-Pyridyl-2-pyrimidine (6a), another possible cross-
coupling product, was also obtained in 62% yield. These
results clearly indicate that both alkenyl and pyrimidyl
groups on sulfur are transferred into the coupling prod-
uct. The reaction with the phenyl analogue 4b was totally
sluggish under otherwise identical conditions, giving 5
and 6b in very low yield (entry 2). The addition of
pyrimidine (1.0 equiv) into the reaction system did not
promote the reaction either (entry 3). Thus, it is obvious
that the pyrimidyl group should be attached to sulfur to
achieve the cross-coupling at the alkenyl-sulfur bond.
The 2-pyridyl analogue 4c was found to be a somewhat
better substrate than the phenyl analogue 4b (entry 4).
Interestingly, the introduction of a tert-butyl group at the
4-position of the pyrimidine ring (4d) had a pronounced
detrimental effect on the coupling efficiency (entry 5).
There may be two possible explanations for the ben-
eficial effect of a 2-pyrimidyl group in the cross-coupling
Alternatively, the cross-coupling at the 2-pyrimidyl-
sulfur bond might be faster than that at the desired
alkenyl-sulfur bond. Such a cross-coupling should gener-
ate a structurally less congested alkenyl thiolate (or
thiol), which can then participate in the cross-coupling.
In such circumstances, 2-pyrimidyl sulfide can be re-
garded as a “masked” thiol. The fact that the yields of 6
(aryl group transfer) are comparable or greater than
those of 5 (alkenyl group transfer) implicates such a
reactivity order (heteroaryl > aryl ≈ â,â-diarylvinyl).16
With the desired triarylethene 5 in hand, the reduction
of the CdC bond of 5 remained to be conducted for the
synthesis of CDP840 (Scheme 4). As was somewhat
expected from the nonplanar structure of triarylethenes,3
the reduction of the CdC core of 5 required harsh
conditions. All attempts to accomplish this task through
metal-complex-catalyzed (homogeneous) hydrogenation
or hydrometalation/protodemetalation sequence resulted
in failure. Finally we found that heating a suspension of
5 and Pd/C in EtOH at 100 °C under 100 atm of H2
afforded CDP840 (1) in 90% isolated yield (Scheme 4).
In summary, we have achieved a short synthesis of
CDP840 using 2-pyrimidyl vinyl sulfide as a platform (3
steps from 2, 52% overall yield). During these investiga-
tions, we found an additional bonus by attaching the
2-pyrimidyl group on the sulfur of the alkenyl sulfide
structure in the Liebeskind-Srogl-type cross-coupling
reaction. Although a racemic reduction was applied in
this work, the employment of an asymmetric catalyst in
the final step (hydrogenation) would straightforwardly
produce optically active CDP840. The asymmetric syn-
thesis will be reported elsewhere.
Experimental Section
E-2-(3-Cyclopentyloxy-4-methoxy)phenyl-2-phenylethe-
nyl 2-Pyrimidyl Sulfide (4a). To a solution of Pd[P(t-Bu)3]2
(38.3 mg, 0.075 mmol) in toluene (6 mL) were added iodobenzene
(306 mg, 1.50 mmol), Et3N (455 mg, 4.50 mmol), and 2 (207 mg,
1.50 mmol). The reaction mixture was stirred for 4 h at 60 °C.
(16) Liebeskind has already found that the transfer ability (from
sulfur) of a certain heteroaryl group (2-nitro-2-pyridyl group) is much
higher than that of the p-tolyl group in the Pd-catalyzed cross-coupling
using sulfides.14b
J. Org. Chem, Vol. 70, No. 17, 2005 6935

After the consumption of sulfide, 3 (525 mg, 1.65 mmol) was
added to the reaction mixture and the resultant mixture was
stirred for an additional 18 h at 90 °C. After the reaction mixture
was cooled to room temperature, it was filtered through a short
silica gel pad (eluent: EtOAc) and the filtrate was concentrated
in vacuo. The recrystallization of residual solids from hexane/
EtOAc (5/1) afforded 4a (525 mg, 87%, E:Z ) 97:3) as colorless
δ 150.4, 149.2 (2×), 147.2, 146.9, 145.0, 139.3, 134.9, 129.9 (2×),
128.6 (2×), 128.0, 123.6, 123.3 (2×), 120.6, 114.6, 114.4, 80.5,
56.1, 32.9 (2×), 24.2 (2×). LRMS (EI) m/z 371 (M+). HRMS (EI)
calcd for C25H25NO2 371.1883, found 371.1884.
2-(3-Cyclopentyloxy-4-methoxy)phenyl-2-phenyl-1-(4-
pyridyl)ethane (CDP840, 1). The mixture of 5 (45.1 mg, 0.121
mmol), Pd/C (25 mg, 5%), and EtOH (3 mL) was stirred at 100
°C for 21 h under H2 (100 atm) in an autoclave. After being
cooled to room temperature, the mixture was filtered and
concentrated. Purification of the residue by silica gel flash
column chromatography (eluent: hexane/EtOAc ) 5/3) afforded
CDP840 (1) (40.8 mg, 90%) as a colorless oil. IR (neat) 2959,
crystals. IR (KBr) 2961, 1260, 804 cm-1 1H NMR (400 MHz,
.
CDCl3) δ 8.53 (d, J ) 3.0 Hz, 2H), 7.62 (s, 1H), 7.42-7.32 (m,
5H), 6.98 (t, J ) 3.0 Hz, 1H), 6.88 (dd, J ) 5.3, 1.3 Hz, 1H), 6.84
(d, J ) 1.3 Hz), 6.79 (d, J ) 5.3 Hz, 1H), 4.69 (m, 1H), 3.84 (s,
3H), 1.87-1,78 (m, 6H), 1.58-1.54 (m, 2H). 13C NMR (100 Hz,
CDCl3) δ 170.5, 157.2, 149.6, 140.9, 136.3, 134.3, 129.5, 128.2,
127.7, 120.0, 117.0, 116.9, 114.6, 111.5, 80.5, 58.1, 32.9, 24.2.
LRMS (EI) m/z 404 (M+). HRMS (EI) calcd for C24H24N2O2S
404.1558, found 404.1556.
1
1262, 702 cm-1. H NMR (400 MHz, CDCl3) δ 8.37 (d, J ) 3.0
Hz, 2H), 7.27-7.23 (m, 2H), 7.18-7.15 (m, 3H), 6.92 (d, J ) 3.8
Hz, 2H), 6.73 (d, J ) 5.3 Hz, 1H), 6.68 (dd, J ) 5.3, 1.3 Hz, 1H),
6.64 (d, J ) 1.0 Hz, 1H), 4.65-4.62 (m, 1H), 4.14 (t, J ) 5.0 Hz,
1H), 3.78 (s, 3H), 1.82 (m, 6H), 1.57-1.55 (m, 2H). 13C NMR
(100 Hz, CDCl3) δ 149.4, 149.1 (2×), 148.5, 147.2, 143.8, 135.8,
128.3 (2×), 127.6 (2×), 126.3, 124.4 (2×), 119.9, 115.3, 111.9,
80.5, 56.1, 51.6, 41.7, 32.9, 32.8, 24.2 (2×). LRMS (EI) m/z 373
(M+). HRMS (EI) calcd for C25H27NO2 373.2043, found 373.2046.
E-2-(3-Cyclopentyloxy-4-methoxy)phenyl-2-phenyl-1-(4-
pyridyl)ethene (5). The mixture of Pd(PPh3)4 (11.6 mg, 0.010
mmol), 4a (80.9 mg, 0.200 mmol), 4-pyridylboronic acid (73.7
mg, 0.600 mmol), and copper thiophene-2-carboxylate (114.4 mg,
0.600 mmol) in 1,3-dimethyl-2-imidazolidinone (DMI) (1.5 mL)
was stirred for 18 h at 60 °C under argon. The resultant mixture
was cooled to room temperature and filtered through a short
silica gel pad (eluent: EtOAc). The filtrate was washed with 28%
aq NH3, water, and brine, dried over Na2SO4, filtered, and
concentrated. Purification of the residue by silica gel flash
column chromatography (eluent; hexane/EtOAc ) 5/2 to 5/3)
afforded 5 (49.0 mg, 66%) as a yellow gum and recovered 4a
Acknowledgment. This work was financially sup-
ported in part by a Grant-in-Aid for Scientific Research.
Supporting Information Available: Additional experi-
mental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
(18.6 mg, 23%). IR (neat) 3015, 2963, 1266, 812 cm-1. H NMR
(400 MHz, CDCl3) δ 8.31 (br s, 2H), 7.36-7.32 (m, 3H), 7.18-
7.15 (m, 2H), 6.85-6.78 (m, 6H), 4.70-4.66 (m, 1H), 3.85 (s, 3H),
1.85-1.80 (m, 6H), 1.58-1.52 (m, 2H). 13C NMR (100 Hz, CDCl3)
JO0510437
6936 J. Org. Chem., Vol. 70, No. 17, 2005