A One-Pot Synthesis of 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-amino-4- pyrimidinyl)-imidazole: A Potent Inhibitor of P38 MAP Kinase

Full text of DOI:10.1021/jo980248v

J . Org. Chem. 1998, 63, 4529-4531
4529
Sch em e 1
A On e-P ot Syn th esis of
1-(2,2,6,6-tetr a m eth yl-4-p ip er id in yl)-4-
(4-flu or op h en yl)-5-(2-a m in o-4-p yr im id in yl)-
im id a zole: A P oten t In h ibitor of P 38 MAP
Kin a se
J oseph Sisko
SmithKline Beecham Pharmaceuticals,
Synthetic Chemistry Department, P.O. Box 1539,
King of Prussia, Pennsylvania 19406
Received February 10, 1998
The 1,4,5-trisubstituted imidazole 1 is representative
of a general class of compounds which exhibit potent
binding affinities for p38 MAP kinase, a recently discov-
ered protein kinase which appears to be involved in an
inflammation regulatory pathway.1 As part of the de-
velopment of compounds of this class for the treatment
of arthritis, a flexible route capable of preparing kilogram
quantities of imidazole 1, as well as analogues, was
required.
Sch em e 2
Of the methods considered for the synthesis of 1,2 the
van Leusen method3 for preparing imidazoles by annu-
lation of TosMIC derivatives with imines seemed best
suited for our purposes. In fact, a similar strategy has
already been reported for the synthesis of the analogous
5-pyridinyl-substituted imidazoles.4 The commercial
availability of the various pyridine aldehydes required
for that series of compounds, however, had streamlined
and simplified their preparation.
Adapting the van Leusen strategy for the synthesis for
1 involved base-promoted annulation of imine 3 with
tosyl isonitrile 45 to provide the 1,4,5-trisubstituted
imidazole (Scheme 1).6 While the yield for this trans-
formation on a small scale routinely exceeded 65%, the
overall strategy was plagued with several problems which
would likely be compounded on scale-up. Most notable
was that pyrimidine aldehyde 2,7 which served as the
precursor to the requisite imine 3, was prone to polym-
erization and difficult to isolate due to its appreciable
water solubility.
(1) Lee, J . C.; Laydon, J . L.; McDonnel, P. C.; Gallagher, T. F.;
Kumar, S.; Green, D.; McNulty, D.; Blumenthal, M. J .; Heyes, J . R.;
Landvatter, S. W.; Strickler, J . F.; McLaughlin, M. M.; Siemens, I. R.;
Fisher, S. M.; Livi, G. P.; White, J . R.; Adams, J . L.; Young, P. R. Nature
(London) 1994, 372, 739.
(2) For examples, see: Lantos, I.; Zhang, W.-Y.; Shui, Z.; Eggleston,
D. S.; J . Org. Chem. 1993, 58, 7092. Nunami, K.; Yamada, M.; Fukui,
T.; Matsumoto, K. J . Org. Chem. 1994, 59, 7635. Hunt, J . T.; Bartlett,
P. A. Synthesis 1978, 741. Bredereck, H.; Theilig, G. Chem. Ber. 1953,
86, 88. Murakami, T.; Otsuka, M.; Ohno, M. Tetrahedron Lett. 1982,
23, 4729. See also: Grimmett, M. R. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Boulton, A. J ., Eds.; Academic: New York,
1970; Vol. 12.
An alternative approach to 1 that avoids aldehyde 2
was devised which targeted the 5-acetylimidazole 10 as
a key intermediate (Scheme 2). Although no general
procedure for the preparation of this class of compounds
could be found in the literature,8 the van Leusen TosMIC
chemistry3 again appeared to be the most promising
approach. The unprecedented reaction of an R-ketoaldi-
mine (9) with isonitrile 4 would be the pivotal reaction,
providing a novel and concise route to the imidazole 10.
Elaboration of the methyl ketone of 10 using the Bred-
erick procedure7 would complete the synthesis of 1.
(3) van Leusen, A. M.; Wildeman, J .; Oldenziel, O. H. J . Org. Chem.
1977, 42, 1153.
(4) Boehm, J . C.; Smientana, J . M.; Sorenson, M. E.; Garigipati, R.
S.; Gallagher, T. F.; Sheldrake, P. L.; Bradbeer, J .; Badger, A. M.;
Laydon, J . T.; Lee, J . C.; Hillegass, L. M.; Griswold, D. E.; Breton, J .
J .; Chabot-Fletcher, M. C.; Adams, J . L. J . Med. Chem. 1996, 39, 3929.
(5) Sisko, J .; Mellinger, M.; Sheldrake, P. W.; Baine, N. H. Tetra-
hedron Lett. 1996, 37, 8113.
(6) The details of this general approach to 1 will be published
separately.
(7) Bredereck, H.; Sell, R.; Effenberger, F. Chem. Ber. 1964, 97, 3407.
(8) Acetylimidazole syntheses have been reported. However, these
methods would not be suitable for the synthesis of 10. See: Reiter, L.
A. J . Org. Chem. 1987, 52, 2714 and references therein. Rahman, A.;
Ila, H.; J unjappa, H. J . Chem. Soc., Chem. Commun. 1984, 430.
Veronese, A. C.; Cavicchioni, G.; Servadio, G.; Vecchiati, G. J . Hetero-
cycl. Chem. 1980, 17, 1723. Bierer, D. E.; O′Connell, J . F.; Parquette,
J . R.; Thompson, C. M.; Rapoport, H. J . Org. Chem. 1992, 57, 1390.
S0022-3263(98)00248-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/05/1998

4530 J . Org. Chem., Vol. 63, No. 13, 1998
Notes
Resu lts a n d Discu ssion
4 and K2CO3 produced a solution of the imidazole 10, still
containing water from the 40% aqueous pyruvaldehyde
solution. This solution was easily dried by adding
toluene and distilling the water/toluene azeotrope under
vacuum prior to adding the DMFDMA to avoid its
hydrolysis. The resulting solution was heated with
DMFDMA to produce the vinylogous amide 11 which was
treated directly with guanidine‚HCl and K2CO3. After
7 h of heating at 100 °C the imidazole 1 was produced in
36% yield on the basis of isonitrile 4 in a single pot.
In conclusion, a novel and concise route to the antiin-
flammatory agent 1 was developed which employs the
annulation of the isonitrile 4 with an R-ketoaldimine as
the key reaction. This reaction is remarkably tolerant
of water and reactive functional groups, such as the
unprotected piperidine of 8. These considerations high-
light the potential of this method to prepare a wide array
of analogous imidazoles. Further examination of sub-
stituted TosMIC reagents, such as 4, reacting with
functionalized imines under partially aqueous conditions
is underway and these results will be reported in due
course.
Since their first reported preparation in 1978,9 R-ke-
toaldimines (6) have found little use in synthesis.10 In
that seminal report, van Koten showed that condensation
of tert-butylamine with pyruvaldehyde (5) produced the
imine 6 (R ) t-Bu) in 70% isolated yield (eq 1).9 This
result contrasted earlier reports11 in which less sterically
demanding amines, such as methylamine, reacted with
pyruvaldehyde to produce the R-diimines 7 (R ) Me)
exclusively. The success of this approach relied on the
ability to selectively prepare the monoimine when the
aminopiperidine required for 1 was used. It was gratify-
ing, therefore, to find that addition of 2,2,6,6-tetramethyl-
4-aminopiperidine (8) with pyruvaldehyde (5) in TBME
led to a 71% isolated yield of the monoimine 9 with none
of the corresponding R-diimine detected in the reaction
mixture. More importantly, reaction of imine 9 with tosyl
isonitrile 4 and K2CO3 produced a 78% isolated yield of
the ketone 10 on the first attempt.
Concerns about the stability of imine 9 led us to pursue
the construction of imidazole 10 in a single pot, without
isolation of the imine 9. This strategy had several
potential pitfalls. First, generation of the anion of
isonitrile 4 would have to be conducted in the presence
of a considerable amount of water since pyruvaldehyde
is only available as a 40% aqueous solution. In addition,
complete conversion of pyruvaldehyde to the imine 9
would be imperative since any residual aldehyde would
also react with 4 to produce the oxazole 12.12 These
concerns proved to be unwarranted. Combining equal
portions of amine 8 and pyruvaldehyde in DMF for 10-
20 min followed by the addition of the isonitrile 4 and
K2CO3 produced an 80% isolated yield of the imidazole
10, and <5% of the oxazole 12. Attempts to remove
water from the reaction medium by adding MgSO4 or
molecular sieves had little effect on the yield or purity
of the product.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, solvents and reagents were
obtained from commercial suppliers and used without further
purification. Unless otherwise noted, reagents were added by
syringe. Filtrations through silica were done using Merck 60
(230-400 mesh) silica gel. Unless otherwise noted, NMR spectra
were measured as solutions in CDCl3 and chemical shifts are
expressed in ppm relative to internal CHCl3 (7.26 ppm). 1H
NMR spectra were recorded at 300 MHz, and 13C NMR spectra
were recorded at 75 MHz.
r-(p-Tolu en esu lfon yl)-4-flu or oben zylison itr ile (4). To a
stirred suspension of R-(p-toluenesulfonyl)-4-fluorobenzylforma-
mide5 (20 g, 65 mmol) in THF (150 mL) was added POCl3 (12.2
mL, 130 mmol). The solution was stirred for 10-15 min and
then cooled to between -5 and 0 °C. Triethylamine (55 mL,
390 mmol) was added dropwise to the slurry over 45 min at such
a rate as to keep the reaction temperature below 0 °C but above
-5 °C. After complete Et3N addition, the yellow slurry was
stirred for 30 min at 0 °C. The reaction was diluted with EtOAc
(100 mL) and water (50 mL), stirred for 10 min at ∼10 °C, and
transferred to a separatory funnel. The aqueous layer was
removed, and the organic phase was washed with water (2 ×
100 mL), a saturated NaHCO3 solution (100 mL), and water (100
mL) again. The organic phase was concentrated under vacuum
until about 10-15% of the initial volume remained. 1-Propanol
(100 mL) was added, and the solution was concentrated again
under vacuum at 35 °C until about 10% of the initial volume
remained. The solution was allowed to stand for 30-45 min at
0 °C, and the fine, yellow precipitate which formed was collected
by suction filtration and rinsed with 1-propanol (20 mL). The
off-white solid was dried to a constant weight at 30-40 °C/<1
mm to give 15.1 g (80%) of the title compound. WARNING:
The isonitrile 4 is thermally unstable at temperatures above 80
°C. To obtain a margin of safety, isonitrile 4 should not be dried
or used at temperatures >40 °C: IR (KBr) 3077, 2998, 2137,
Completion of the synthesis of 1 required conversion
of the methyl ketone of 10 to a 2-aminopyrimidine ring.7
Heating 10 with an excess of N,N-dimethylformamide
dimethyl acetal (DMFDMA) produced the vinylogous
amide 11 which was reacted directly with guanidine
hydrochloride and NaOMe at 80 °C. In this manner, the
pyrimidine 1 could be prepared in 72% isolated yield from
10.
The synthesis of 1 was ultimately demonstrated in one
pot starting from pyruvaldehyde. Mixing pyruvaldehyde
and the amine 8 in DMSO prior to adding the isonitrile
1335 cm-1 1H NMR δ 7.62 (2H, d, J ) 6.7 Hz), 7.46 (4H, m),
;
7.08 (2H, t, J ) 8.6 Hz), 5.62 (1H, s), 2.46 (3H, s); 13C NMR δ
166.7, 164.1 (d, J ) 250 Hz), 146.8, 130.5 (d, J ) 6.6 Hz), 130.4,
130.1, 129.9, 122.6, 116.0 (d, J ) 22.1 Hz), 75.7, 21.8. Anal.
Calcd for C15H12NO2FS: C, 62.3; H, 4.2; N, 4.8. Found: C, 62.5;
H, 4.1; N, 4.6.
(9) van der Poel, H.; van Koten, G. Synth. Commun. 1978, 8, 305.
(10) For example, see: van Wijnkoop, M.; Siebenlist, R.; Ernsting,
J . M.; de Lange, P. P. M.; Fruhauf, H.-W.; Horn, E.; Spek, A. L. J .
Organomet. Chem. 1994, 482, 99. van Wijnkoop, M.; Siebenlist, R.; de
Lange, P. P. M.; Fruhauf, H.-W., Vrieze, K.; Smeets, W. J . J .; Spek, A.
L. Organometallics 1993, 12, 4172. van Vliet, M. R. P.; van Koten, G.;
de Keijser, M. S.; Vrieze, K. Organometallics 1987, 6, 1652 and
references therein. Krow, G. R.; J ohnson, C.; Boyle, M. Tetrahedron
Lett. 1978, 1971.
(11) tom Kieck, H.; Renk, I. W. Chem. Ber. 1971, 104, 110. Krum-
holz, P.; Serra, O. A.; Paoli, M. A. Inorg. Chim. Acta 1975, 15, 25.
(12) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron
Lett. 1972, 2369.
2,2,6,6-Tet r a m et h yl-4-(2-oxop r op ylid en e)a m in op ip er i-
d in e (9). To a solution of pyruvaldehyde (40% w/w solution in
water, 2.68 mL, 17.5 mmol) in 30 mL of TBME at room
temperature was added 2,2,6,6-tetramethyl-4-aminopiperidine
(2.0 mL, 14.0 mmol). After 30 min, the solution was diluted with
50 mL of TBME and washed with 3 × 25 mL of water and 25
mL of brine. The solution was concentrated in vacuo to yield
2.1 g (71%) of the imine product as an oil which was used as

Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4531
such in the subsequent step: IR (neat) 3310, 1685, 1630, 1360
1-(2,2,6,6-Tetr a m eth yl-4-p ip er id in yl)-4-(4-flu or op h en yl)-
5-(2-a m in o)-4-p yr im id in yl)im id a zole (1) fr om Keton e 10.
A solution of ketone 10 (8.5 g, 24.8 mmol) in N,N-dimethylfor-
mamide dimethyl acetal (6.6 mL, 49.5 mmol) was heated at 100
°C for 6 h. The solution was cooled to 80 °C, and 1-PrOH (25
mL), guanidine‚HCl (3.55 g, 37.1 mmol), and NaOMe (25% w/w
in MeOH, 8.5 mL, 37.1 mmol) were added. After 17 h, the
solution was cooled to room temperature, diluted with 200 mL
of EtOAc, and washed with a 10% NaOH solution (2 × 100 mL).
The organics were washed with 150 mL of 3 N HCl, and the
separated aqueous layer was made basic with 50% NaOH to pH
11-12. The aqueous layer was extracted with TBME (200 mL)
and concentrated to 100 mL in vacuo. The solution was diluted
with 50 mL of hexane, and after 30 min the crystals that formed
were filtered to give 7.0 g (72%) of the title compound: mp )
cm-1 1H NMR δ 7.60 (1H, s), 3.67 (1H, tt, J ) 4.0, 11.5 Hz),
;
2.30 (3H, s), 1.57 (2H, dd, J ) 4.0, 13.0 Hz), 1.28 (2H, dd, J )
11.5, 13.0 Hz), 1.17 (6H, s), 1.10 (6H, s); 13C NMR δ 200.1, 158.4,
62.3, 50.2, 45.2, 34.9, 28.8, 24.5.
1-(2,2,6,6-Tetr a m eth yl-4-p ip er id in yl)-4-(4-flu or op h en yl)-
5-a cetylim id a zole (10) fr om Im in e 9. To a solution of imine
9 (2.50 g, 11.9 mmol) in 30 mL of DMF at room temperature
were added isonitrile 4 (3.12 g, 10.8 mmol) and K2CO3 (1.64 g,
11.9 mmol). After 16 h, the solution was diluted with 100 mL
of EtOAc and washed with 2 × 75 mL of 3 N HCl. The aqueous
layers were combined and made basic with excess solid K2CO3
to pH 10-11. The aqueous layer was transferred to a separatory
funnel and extracted with 2 × 100 mL of EtOAc. The combined
organics were washed with 3 × 100 mL of water, concentrated
in vacuo, and recrystallized from CHCl3/hexanes to give the title
compound 10 (2.90 g, 78%): mp ) 134-136 °C; IR (KBr) 3430,
221-222 °C; IR (KBr) 3345, 3319, 3155, 1645, 1562 cm-1 1H
;
1
3144, 1659, 1653, 1219 cm-1; H NMR δ 7.76 (1H, s), 7.43 (2H,
NMR δ 8.17 (1H, d, J ) 5.2 Hz), 7.72 (1H, s), 7.45 (2H, m), 7.00
(2H, t, J ) 8.7 Hz), 6.49 (1H, d, J ) 5.2 Hz), 5.30 (1H, tt, J )
3.2, 12.6 Hz), 5.12 (2H, br s), 2.04 (2H, dd, J ) 3.2, 12.4 Hz),
1.48 (2H, dd, J ) 12.4, 12.6 Hz), 1.24 (6H, s), 1.17 (6H, s); 13C
NMR (DMSO-d6) δ 163.7, 161.1 (d, J ) 242.4 Hz), 158.8, 158.5,
138.7, 135.4, 130.9, 128.9 (d, J ) 8.0 Hz), 125.1, 115.0 (d, J )
21.1 Hz), 111.0, 50.8, 48.7, 44.7, 34.1, 28.1. Anal. Calcd for
C22H27N6F: C, 67.0; H, 6.9; N, 21.3. Found: C, 67.4; H, 6.9; N,
21.4.
m), 7.12 (2H, t, J ) 8.7 Hz), 5.39 (1H, tt, J ) 3.1, 12.5 Hz), 2.11
(3H, s), 2.10 (2H, dd, J ) 3.1, 11.9), 1.50 (2H, dd, J ) 11.9, 12.5
Hz), 1.37 (6H, s), 1.22 (6H, s); 13C NMR δ 190.8, 163.0 (d, J )
246.5 Hz), 149.8, 137.4, 131.4 (d, J ) 8.1 Hz), 131.4, 127.0, 115.4
(d, J ) 21.6 Hz), 52.0, 50.6, 46.2, 34.6, 30.5, 28.1. Anal. Calcd
for C20H26N3OF: C, 69.9; H, 7.6; N, 12.2. Found: C, 69.6; H,
7.6; N, 12.1.
1-(2,2,6,6-Tetr a m eth yl-4-p ip er id in yl)-4-(4-flu or op h en yl)-
5-a cetylim id a zole (10) fr om P yr u va ld eh yd e (5). To a
solution of pyruvaldehyde (40% w/w solution in water, 1.34 mL,
8.74 mmol) in 12 mL of DMSO at room temperature was added
2,2,6,6-tetramethyl-4-aminopiperidine (1.50 mL, 8.74 mmol).
After 10 min, isonitrile 4 (1.69 g, 5.83 mmol) and K2CO3 (0.81
g, 5.85 mmol) were added. After 16 h, the solution was diluted
with 100 mL of EtOAc and washed with 2 × 75 mL of 3 N HCl.
The aqueous layers were combined and made basic with excess
solid K2CO3 to pH 10-11. The aqueous layer was transferred
to a separatory funnel and extracted with 2 × 100 mL of EtOAc.
The combined organics were washed with 3 × 50 mL of water
and concentrated in vacuo to give 10 as a brown oil. This
material was recrystallized from CHCl3/hexanes to give 10 (1.61
g, 80%) whose spectra were identical to those listed for 10 above.
1-(2,2,6,6-Tetr a m eth yl-4-p ip er id in yl)-4-(4-flu or op h en yl)-
5-(3-N,N-d im eth yla m in o-tr a n s-2-p r op en -1-on e)im id a zole
(11). The ketone 10 (0.75 g, 2.18 mmol) and N,N-dimethylfor-
mamide dimethyl acetal (0.43 mL, 3.28 mmol) were dissolved
in 10 mL of toluene and heated at 110 °C for 20 h. The solution
was cooled to room temperature, and the solvents were removed
under vacuum. The residue was eluted through a short plug of
silica gel with EtOAc/MeOH (1:1) and concentrated to give the
title compound (0.65 g 76%) as a waxy solid: IR (neat) 3300,
1-(2,2,6,6-Tetr a m eth yl-4-p ip er id in yl)-4-(4-flu or op h en yl)-
5-(2-a m in o)-4-p yr im id in yl)im id a zole (1) fr om P yr u va ld e-
h yd e (5). To a solution of pyruvaldehyde (40% w/w solution in
water, 5.82 mL, 38.04 mmol) in 70 mL of DMSO at room
temperature was added 2,2,6,6-tetramethyl-4-aminopiperidine
(6.52 mL, 38.04 mmol). After 15-20 min, isonitrile 4 (10 g, 34.6
mmol) and K2CO3 (5.02 g, 36.3 mmol) were added. After 19 h,
30 mL of toluene was added and the solution was heated at 65
°C while the toluene/water azeotrope was removed under
vacuum. The toluene addition/distillation was repeated two
times more. N,N-dimethylformamide dimethyl acetal (DM-
FDMA) (9.2 mL, 69.2 mmol) was added, and the solution was
heated at 100 °C for 8-10 h. Guanidine‚HCl (6.61 g, 69.2 mmol)
and K2CO3 (9.56 g, 69.2 mmol) were added, and the resulting
solution was heated at 100 °C for 6-7 h. After being cooled to
room temperature, the solution was filtered through a pad of
Celite, diluted with 250 mL of EtOAc, and washed with 4 × 200
mL of 3 N HCl. The aqueous layers were combined and made
basic with solid KOH to pH ) 12. The aqueous layer was
transferred to a separatory funnel and extracted with EtOAc (3
× 200 mL). The combined organics were washed with 3 × 100
mL of a 3 N KOH solution and 50 mL of brine, dried over Na2-
SO4 and activated charcoal, filtered through Celite, and con-
centrated in vacuo. The residue was dissolved in 50 mL of
MeOH, and the crystals that formed were filtered and washed
with 100 mL of EtOAc to yield the title compound (4.89 g, 36%)
as a tan solid whose spectra matched those listed above.
1630, 1550, 1530 cm-1 1H NMR δ 7.65 (1H, s), 7.56 (2H, m),
;
7.46 (1H, d, J ) 12.4 Hz), 7.01 (2H, t, J ) 8.8 Hz), 5.32 (1H, tt,
J ) 3.1, 12.4 Hz), 5.01 (1H, d, J ) 12.4 Hz), 2.96 (3H, br s), 2.48
(3H, br s), 2.09 (2H, dd, J ) 3.1, 12.2 Hz), 1.44 (2H, dd, J )
12.2, 12.4 Hz), 1.31 (6H, s), 1.17 (6H, s); 13C NMR δ 182.3, 162.4
(d, J ) 244.8 Hz), 153.2, 143.0, 135.4, 131.7, 131.0 (d, J ) 7.9
Hz), 128.0, 114.7 (d, J ) 21.2 Hz), 98.5, 51.7, 49.6, 46.4, 44.7,
36.8, 34.7, 28.2; HRMS calcd for C23H31N4OF 398.2481, found
398.2481.
J O980248V