An efficient route to 4-aryl-5-pyrimidinylimidazoles via sequential functionalization of 2,4-dichloropyrimidine

Article abstract of DOI:10.1021/ol052663x

Starting from 2,4-dichloropyrimidine, a concise synthetic route to medicinally important 4-aryl-5-pyrimidinylimidazoles is described. Sequential substitution of the 4- and 2-chloro groups using a regioselective Sonogashira coupling, followed by nucleophil

Full text of DOI:10.1021/ol052663x

ORGANIC
LETTERS
2
006
Vol. 8, No. 2
69-272
An Efficient Route to
-Aryl-5-pyrimidinylimidazoles via
Sequential Functionalization of
,4-Dichloropyrimidine
2
4
2
Xiaohu Deng and Neelakandha S. Mani*
Johnson & Johnson Pharmaceutical Research & DeVelopment, LLC,
3210 Merryfield Row, San Diego, California 92121
nmani@prdus.jnj.com
Received November 2, 2005
ABSTRACT
Starting from 2,4-dichloropyrimidine, a concise synthetic route to medicinally important 4-aryl-5-pyrimidinylimidazoles is described. Sequential
substitution of the 4- and 2-chloro groups using a regioselective Sonogashira coupling, followed by nucleophilic substitution, led to
pyrimidinylalkyne derivatives, which were then oxidized to their corresponding 1,2-diketones. These 1,2-diketones, on cyclocondensation with
ammonium acetate and an aldehyde, furnished the desired pyrimidinyl imidazoles in good overall yields.
4,5-Diarylimidazoles, in which one of the aryl substituents
is a heteroaryl group such as a pyridine or pyrimidine, form
an important class of p38 MAPK (mitogen-activated protein
kinase) inhibitors, vigorously pursued by a number of pharm-
1-3
aceutical companies as antiinflammatory drugs (Figure 1).
Despite the heightened interest, preparation of these com-
pounds has relied largely upon just two synthetic strategies.
(1) Lee, J. C.; Laydon, J. T.; McDonnel, P. C.; Gallagher, T. F.; Kumar,
S.; Green, D.; McNulty, D.; Blumenthal, M. J.; Heys, J. R.; Landvatter, S.
W.; Strickler, J. E.; Mclaughlin, M. M.; Siemens, I. R.; Fisher, S. M.; Livi,
G. P.; White, J. R.; Adams, J. L.; Young, P. R. Nature (London) 1994,
3
72, 739-745.
(
2) (a) Badger, A. M.; Griswold, D. E.; Kapadia, R.; Blake, S.; Swift,
B. A.; Hoffman, S. J.; Stroup, G. B.; Webb, E.; Rieman, D. J.; Gowen, M.;
Boehm, J. C.; Adams, J. L.; Lee, J. C. Arthritis Rheum. 2000, 43, 175-
1
85. (b) Fullerton, T.; Sharma, A.; Prabhakar, U.; Tucci, M.; Boike, S.;
Davis, H.; Jorkasky, D.; Williams, W. Clin. Pharmacol. Ther. 2000, 67,
14.
3) McLay, I. M.; Halley, F.; Souness, J. E.; McKenna, J.; Benning, V.;
1
Figure 1. 4,5-Diarylimidazole class of p38 MAP kinase inhibitors.
(
Birrell, M.; Burton, B.; Belvisi, M.; Collis, A.; Constan, A.; Foster, M.;
Hele, D.; Jayyosi, Z.; Kelley, M.; Maslen, C.; Miller, G.; Ouldelhkim, M.-
L.; Page, K.; Phipps, S.; Pollock, K.; Porter, B.; Ratcliffe, A. J.; Redford,
E. J.; Webber, S.; Slater, B.; Thybaud, V.; Wilsher, N. Bioorg. Med. Chem.
4
5
Merck and Aventis scientists employed the cycloconden-
sation of substituted 1,2-dicarbonyl compounds with am-
2
001, 9, 537-554.
1
0.1021/ol052663x CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/30/2005

-11
monia and an aldehyde. Although this reaction is quite
efficient, preparation of the necessary pyrimidinyl-substituted
dicarbonyl derivatives requires a lengthy sequence starting
from 2-mercapto-4-methylpiperidine.
2-position.9 A variety of base and solvent combinations
were investigated, but we could not find synthetically useful
2-position selectivity. On a smaller scale (5-10 g), the two
regioisomers could be separated by column chromatography.
The 4-chloro regioisomer 10 was then coupled with 4-fluo-
rophenylacetylene, under standard Sonogashira coupling
A notably elegant approach, developed by the SKB group,6
involved the cycloaddition of substituted TosMIC with
7
12
aldimines, originally pioneered by van Leusen. More
conditions, to furnish the desired disubstituted acetylene
8
recently, Merck scientists have reported a promising one-
11a in 76% yield. Although we obtained diarylacetylene 11a
in two steps, the poor regioselectivity in the nucleophilic
substitution reaction rendered this approach impractical for
large-scale synthesis.
By reversing the order of the substitution steps, we
overcame the regioselectivity issues. A Sonogashira reaction
between 2,4-dichloropyrimidine and 1-ethynyl-4-fluoroben-
zene smoothly afforded the desired regioisomer 12 as the
major product in 65% isolated yield (Scheme 2). Unfortu-
pot synthesis of imidazoles based on the cyclocondensation
of an R-ketoamide with an amine, wherein the requisite
R-ketoamide is generated in situ by a Stetter reaction
involving an R-amidosulfone. In these cases also, access to
the suitably elaborated pyrimidines required multistep se-
quences. To successfully exploit the particularly efficient
condensation of 1,2-diketones bearing an electron-deficient
pyrimidine moiety with an aldehyde and ammonia, a more
succinct route to the requisite 1,2-diketone derivatives would
clearly be advantageous. Herein, we wish to disclose our
development of a novel approach to this important class of
compounds. Relative to existing methods, our synthetic route
is concise and appears suitable to provide ready access to a
range of structurally related 1,2-diketone and imidazole
analogues.
Scheme 2
To more readily access the desired 1,2-diketone intermedi-
ates, we considered the oxidation of disubstituted acetylene
compounds, which could be derived from the readily
available 2,4-dichloropyrimidine through sequential substitu-
tion reactions (Figure 2).
nately, treatment of 12 with tert-butylamine gave a mixture
of the desired compound 11a, along with the product of 1,2-
addition across the alkyne, 13. The structure of 13 was
13
ascertained by NOE experiments. To avoid this hydroami-
nation reaction, a variety of conditions, such as Na CO
2
3
/
(4) ) (a) Liverton, N. J.; Butcher, J. W.; Claiborne, C. F.; Claremon, D.
A.; Libby, B. E.; Nguyen, K. T.; Pitzenberger, S. M.; Selnick, H. G.;
Smith, G. R.; Tebben, A.; Vacca, J. P.; Varga, S. L.; Agarwal, L.; Dancheck,
K.; Forsyth, A. J.; Fletcher, D. S.; Frantz, B.; Hanlon, W. A.; Harper,
C. F.; Hofsess, S. J.; Kostura, M.; Lin, J.; Luell, S.; O’Neill, E. A.; Orevillo,
C. J.; Pang, M.; Parsons, J.; Rolando, A.; Sahly, Y.; Visco, D. M.; O’Keefe,
S. J. J. Med. Chem. 1999, 42, 2180-2190. (b) McIntyre, C. J.; Ponti-
cello, G. S.; Liverton, N. J.; O′Keefe, S. J.; O’Neill, E. A.; Pang, M.;
Schwartz, C. D.; Claremon, D. A. Bioorg. Med. Chem. Lett. 2002, 12, 689-
Figure 2. Retrosynthetic analysis.
692.
(5) ) (a) Collis, A. J.; Foster, M. L.; Halley, F.; Maslen, C.; McLay, I.
Our initial explorations into selective substitution, outlined
in Scheme 1, were not very encouraging. Reacting 2,4-
M.; Page, K. M.; Redford, E. J.; Souness, J. E.; Wilsher, N. E. Bioorg.
Med. Chem. Lett. 2001, 11, 693-696. (b) McKenna, J. F.; Halley, F.;
Souness, J. E.; McLay, I. M.; Pickett, S. D.; Collis, A. J.; Page, K.; Ahmed,
I. J. Med. Chem. 2002, 45, 2173-2184.
(6) ) Adams, J. L.; Boehm, J. C.; Gallagher, T. F.; Kassis, S.; Webb, E.
F.; Hall, R.; Sorenson, M.; Garigipati, R.; Griswold, D. E.; Lee, J. C. Bioorg.
Med. Chem. Lett. 2001, 11, 2867-2870 and literature cited therein.
Scheme 1
(
7) ) Van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem.
1
977, 42, 1153-1159.
8) ) Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. A.; Grabowski,
J. J. E.; Tillyer, R. D. Org. Lett. 2004, 6, 843-846.
9) Mylari, B. L.; Oates, P. J.; Beebe, D. A.; Brackett, N. S.; Coutcher,
(
(
J. B.; Dina, M. S.; Zembrowski, W. J. J. Med. Chem. 2001, 44, 2695-
2
700.
(10) Yoshida, K.; Taguchi, M. J. Chem. Soc., Perkin Trans. 1 1992, 7,
9
19-922.
(
11) Chu-Moyer, M. Y.; Ballinger, W. E.; Beebe, D. A.; Berger, R.;
Coutcher, J. B.; Day, W. W.; Li, J.; Mylari, B. L.; Oates, P. J.; Weekly, R.
M. J. Med. Chem. 2002, 45, 511-528.
dichloropyrimidine with tert-butylamine at 60 °C gave a
mixture of 4- and 2-substitution products in 65% and 26%
yield, respectively. This result clearly indicated that the
chloro group at the 4-position is more reactive (albeit slightly)
toward substitution with amine nucleophiles than the
(
12) ) Sonogashera, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
5
0, 4467-4470.
13) ) For the vinylic hydrogen, strong NOE was observed with
-pyrimidinyl hydrogen and weaker effect with the 2-and 6-hydrogens of
(
5
the 4-fluorophenyl. These aryl hydrogens, however, showed strong NOE
with t-butyl hydrogens. See the Supporting Information for the NOE spectra.
270
Org. Lett., Vol. 8, No. 2, 2006

t
3 2
EtOH, Et N/THF, NH Bu /THF, and Buchwald amination,
were investigated with limited success.
Table 1. Oxidation of 11a
We hypothesized that it might be possible to effect the
nucleophilic substitution on the pyrimidine nucleus prefer-
entially by changing the electronic and steric properties of
the alkyne. Based on this line of reasoning, a new route was
designed (Scheme 3). Sonogashira cross-coupling reaction
entry
1
conditions
KMnO4,/CH2Cl2, H2O, AcOH,
Adogen 64, reflux, 3 h
KMnO4/CH2Cl2, AcOH,
Adogen 64, reflux, 1.5 h18
results
Scheme 3
over-oxidationa
1
8
2
3
30%
45%
KMnO4/acetone, H2O, MgSO4,
1
9
NaHCO3, rt, 45 min
I2/DMSO, 150 °C, 16 h
2
0,21
over-oxidationa
53%
4
5
6
7
8
PdCl2/DMSO, 130 °C, 4 h22
2
2
b
NBS/DMSO, rt, 10 min
bromination
HBr/DMSO, 130 °C, 3 h
(CF3COO)2IPh, DMSO,
no reaction
SM and
over-oxidationa
no reaction
2
4
130 °C, 3 h
9
RuCl3/NaIO4, H2O/CH3CN/CCl4,
2
5,26
reflux, 2 h
of (trimethylsilyl)acetylene with 2,4-dichloropyrimidine af-
forded the requisite alkyne 14 in 87% yield. Heating this
intermediate in neat tert-butylamine at 80 °C gave exclu-
sively the desired substitution product. Desilylation followed
by another Sonogashira cross-coupling with 4-fluoroiodo-
benzene afforded compound 11a in very good overall yield.
This reaction sequence was performed successfully on
brominationb
10
OsO4, Me3NO, t-BuOH, H2O,
reflux, 5 h27,28
a
-Fluorobenzoic acid was isolated. b Based on MS, the product was
4
not isolated.
(
130 °C) to achieve reasonably good conversion. Lower Pd
loading caused incomplete reaction and raising the temper-
ature caused side reactions. A Pd on C/CuCl /DMSO system
produced similar results. These methods also required
column chromatography to purify the final product, making
them less well-suited for largescale preparations. Although
oxidation using KMnO was more promising in terms of
4
clean reaction and easy purification, over oxidation was a
major disadvantage. After screening numerous conditions,
2
0-40 g scale without the need for column chromatography.
It should be noted that accessing the intermediate 14 not
only affords a more efficient route to 11 but also allows for
a point of diversification for the design of new analogues.
With a reliable route to diaryl-substituted acetylenes 11
and 12 in hand, we set out to examine the key oxidation
reaction. Initially, we focused our attention on the oxidation
of 12, for it would allow the introduction of the amine
substituent after imidazole formation. Oxidation of diaryl-
substituted acetylene to diketone is well precedented and a
2
23
it was found that the key to obtaining good yields was to
29
use a very finely powdered form of KMnO
the reaction time in a, acetone/H
MgSO and NaHCO . Under these optimized conditions, the
4
and to control
1
4-16
wide array of reagent systems have been reported.
2
O solution buffered with
However, we soon realized that oxidation of a diarylacetylene
containing a pyrimidine group is far from trivial. Thus, in
the case of 12 all our attempts using a battery of reagent
systems resulted in no oxidation or over-oxidation. Gratify-
ingly, in the case of 11a, oxidation using KMnO or PdCl
DMSO went smoothly on small scale (Table 1, entries 3 and
). The stark reactivity difference between 11a and 12 could
4
3
(18) ) Lee, D. G.; Chang, V. S. J. Org. Chem. 1979, 44, 2726-2730.
(19) ) Srinivasan, N. S.; Lee, D. G. J. Org. Chem. 1979, 44, 1574.
1
7
(
20) ) D o¨ tz, F.; Brand, J. D.; Ito, S.; Gherghel, L.; M u¨ llen, K. J. Am.
Chem. Soc. 2000, 122, 7707-7717.
21) Ito, S.; Wehmeier, M.; Brand, J. D.; Kubel, C.; Epsch, R.; Rabe, J.
P.; Mullen, K. Chem.sEur. J. 2000, 6, 4327-4342.
22) ) Chi, K.-W.; Yusubov, M. S.; Filimonov, V. D. Synth. Commun.
1994, 24, 2119-2122.
23) Yusubov, M. S.; Filimonov, V. D.; Vasilyeva, V. P.; Chi, K.-W.
4
2
/
(
5
(
be due to the reduced electron deficiency of the triple bond
(
in compound 11a.
Synthesis 1995, 10, 1234-1236.
The oxidation procedures using KMnO
were then investigated carefully. Although both procedures
worked well on small scale, the PdCl /DMSO system
suffered several drawbacks, requiring high Pd loading
∼10%), prolonged reaction time, and elevated temperatures
4
and PdCl
2
/DMSO
(24) ) Kita, Y.; Yakura, T.; Terashi, H.; Haruta, J.; Tamura, Y. Chem.
Pharm. Bull. 1989, 37, 891-894.
(25) Sharpless, K. B.; Lauer, R. F.; Repic, O.; Teranishi, A. Y.; Williams,
2
D. R. J. Am. Chem. Soc. 1971, 93, 3303-3304.
(26) Pattenden, G.; Tankard, M.; Cherry, P. C. Tetrahedron Lett. 1993,
3
4, 2677-2680.
27) Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766-
68.
(28) Page, P. C. B.; Rosenthal, S. Tetrahedron Lett. 1986, 27, 1947-
1950.
(29) ) See ref 19. Permanganate reagent that worked best in our hands
(
(
7
(
(
(
14) Gopal, H.; Gordon, A. J. Tetrahedron Lett. 1971, 31, 2941-2944.
15) Walsh, C. J.; Mandal, B. K. J. Org. Chem. 1999, 64, 6102-6105.
16) Yusubov, M. S.; Zholobova, G. A.; Vasilevsky, S. F.; Tretyakov,
E. V.; Knight, D. W. Tetrahedron 2002, 58, 1607-1610.
was a finely powdered form of KMnO4 (Cairox M) purchased from Carus
Chemical Co.
(
17) 4-Fluorobenzoic acid was isolated and characterized.
Org. Lett., Vol. 8, No. 2, 2006
271

Using the method described above, isopropyl analogue 6b
was also prepared in good yield. Cyclocondensation of the
diketones with ammonium acetate and an aldehyde (Table
Table 2. Preparation of Imidazoles
2
) efficiently provided various pyrimidinyl-substituted imi-
dazoles.
In summary, we have developed a concise, six-step
sequence to synthesize 4-aryl-5-pyrimidinylimidazolessan
important scaffold useful in antiinflammatory drug research.
The methodology is well-suited to the preparation of a
number of related analogues.
no.
R1
R2
T (°C)/time (h)
yield (%)
1
7a
8a
9a
7b
8b
9b
t-Bu
t-Bu
t-Bu
i-Pr
i-Pr
i-Pr
H
65/4
65/48
rt/3
65/3
65/48
rt/3
56
68
60
52
62
58
Acknowledgment. We thank Dr. Jiejun Wu for NMR
experiments and mass spectra and Dr. James P. Edwards for
helpful discussions.
1
1
1
1
1
4-ClC6H4
(CH3O)2CH
H
4-ClC6H4
(CH3O)2CH
Supporting Information Available: Representative ex-
perimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
desired diketone 6a was obtained consistently in 65-70%
yields on 5 g scale after simple aqueous workup and without
column chromatography.
OL052663X
272
Org. Lett., Vol. 8, No. 2, 2006