The expedient synthesis of 4,2′-difluoro-5′-(7- trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile, a GABA α2/3 agonist

Article abstract of DOI:10.1021/op050217j

An expedient regioselective synthesis of a GABA α2/3 agonist 1 is described. The key step is an efficient regioselective palladium-catalyzed coupling of 7-trifluoromethylimidazo[1,2-a]pyrimidine (5) to 5′-chloro-4,2′-difluorobiphenyl-2-carbonitrile (15).

Full text of DOI:10.1021/op050217j

Organic Process Research & Development 2006, 10, 398−402
The Expedient Synthesis of 4,2′-Difluoro-5′-(7-trifluoromethyl-
imidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile, a GABA r2/3 Agonist
Mark Cameron,* Bruce S. Foster, Joseph E. Lynch, Yao-Jun. Shi, and Ulf-H. Dolling
Department of Process Research, Merck Research Laboratories, Merck & Co. Inc., P.O. Box 2000,
Rahway, New Jersey 07065, U.S.A.
Abstract:
we sought to make use of this observation in developing an
expedient synthesis of 1.
An expedient regioselective synthesis of a GABA r2/3 agonist
1
is described. The key step is an efficient regioselective
palladium-catalyzed coupling of 7-trifluoromethylimidazo[1,2-
a]pyrimidine (5) to 5′-chloro-4,2′-difluorobiphenyl-2-carbonitrile
Results and Discussion
The reaction between ethyl vinyl ether (6) and trifluoro-
(15). The efficiency of this step was affected by the choice of
acetic anhydride (7) gave trifluoromethyl ketone 8 (Scheme
solvent, ligand, and tetrabutylammonium salt additive.
6
3
) in 95% yield. Owing to degradation on storage, it was
used immediately after preparation and condensed with
commercially available 2-aminoimidazole hemisulfate (9) to
give 5, with high regioselectivity, in 85% yield. Alterna-
Introduction
7
General anxiety disorder is a disease that is estimated to
affect over 40 million patients in the U.S.A. Gamma amino
butyric acid (GABA) is the major inhibitory neurotransmitter
tively, 5 could be prepared from the reaction of 2-amino-
4
-trifluoropyrimidine (10) with bromoacetaldehyde diethyl
7
acetal (11), with similar regioselectivity, in 83% yield. With
efficient syntheses of 5 in hand, the palladium-catalyzed
coupling of 5 to the biaryl bromide 12 was investigated.
A
in the CNS where it binds to GABA receptors of which
the R2/3 subtype has been recognized as having anxiolytic
1
a
benefit. Our interest in this field necessitated the develop-
ment of an expedient synthesis of a potential GABA R2/3
agonist drug candidate 1.1b The synthesis was finalized
In polar aprotic solvents such as DMF, DMAc, and NMP
8
with Cs
2
CO
3
as the base and 2-5 mol % Pd(OAc)
2
/2 PPh
3
9
coupling of 5 to 12 gave the desired compound 1 (Scheme
). However, during the course of the reaction formation of
the regioisomer 13, formation of the bis-coupled product 14
occurred, while the concentration of 1 decreased. Presum-
ably, initial coupling occurred in the desired 3-position;
however, under these conditions isomerization via a Dimroth-
(
Scheme 1) by coupling intermediates 2 and 3 in 70% overall
yield.
Preparation of 3 (Scheme 2) was relatively laborious and
4
10
required the use of commercially expensive, atom-economy-
poor, bis(pinacolato)diboron reagent (4). More favourably,
2
was relatively straightforward to prepare (Scheme 3), with
1
1
type rearrangement (Scheme 5) occurred to give the
regioisomer 13 that in turn coupled to give 14.
electrophilic bromination of 5 occurring regioselectively to
afford 2 in good yield. Although, this route was amenable
to preparing gram quantities of 1, it was unsuitable for our
needs in preparing kilogram amounts to support drug trials.
The efficient palladium-catalyzed arylation of azole com-
pounds such as imidazoles, thiazoles, and oxazoles with aryl
No reaction was observed in either refluxing THF or
2-methyltetrahydrofuran; however, to our satisfaction, when
the reaction was performed in 1,4-dioxane at 90 °C, coupling
occurred, with minimal formation of 13, to give 1 in 80-
85% yield. Although it was gratifying to obtain 1 in high
yield, the preparation of 12 was inefficient for our purposes.
With the recent advances in ligand design efficient Heck
2-4
iodides and aryl bromides has been reported. Moreover,
5
our department recently reported the palladium-catalyzed
regioselective arylation of imidazo[1,2-a]pyrimidine with
arylbromides. Consequently, in our retrosynthetic analysis
(
5) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Javadi, G. J.; Cai, D.;
Larsen,. R. D.Org. Lett. 2003, 5, 4835-4837. Jensen, M. S.; Hoerrner, R.
S.; Li, W.; Nelson, D. P.; Javadi, G. J.; Dormer, P. G.; Cai, D.; Larsen, R.
D. J. Org. Chem. 2005, 70, 6034-6039.
*
To
mark_cameron@merck.com.
(
whom
correspondence
should
be
addressed.
E-mail:
1) (a) Mckernan, R. M.; Rosahl, T. W.; Reynolds, D. S.; Sur, C.; Wafford, K.
A.; Atack, J. R.; Farrar, S.; Myers, J.; Cook, G.; Ferris, P.; Garret, L.;
Bristow, L.; Marshall, G.; Macaulay, A.; Brown, N.; Howell, D. O.; Moore,
K. W.; Carling, R. W.; Street, L. J.; Castro, J. L.; Ragan, C. I.; Dawson, G.
R.; Whiting, P. J. Nat. Neurosci. 2000, 3, 587. (b) Chambers, M. S.;
Goodacre, S. C.; Hallet, D. J.; Jennings, A.; Jones, P.; Lewis, R. T.; Moore,
K. W.; Russell, M. G. N.; Street, L. J.; Szekeres, H. J. Imidazol-Pyrimidine
Derivatives as Ligands for GABA Receptors. World Patent WO 02/074773
A1, September 26, 2002.
(6) Colla, A.; Martins, A. P.; Clar.; G.; Krimmer, S.; Fischer, P. Synthesis 1991,
483-486.
(7) By HPLC assay. 5:5a ratio 24:1. 5a readily rejected by swishing 5 in heptane.
2 3 3 4 2 3 2 3
(8) Cs CO afforded significantly higher yields than K PO , Li CO , Na CO ,
or dicyclohexylmethylamine.
(9) Catalyst systems prepared from Pd(OAc)
2
were more efficient than those
, or Pd(O CCF
(10) HPLC analysis of the reaction mixture against authentic samples of 1 and
prepared from Pd(dba)
2
, Pd
2
(dba)
3
, PdCl
2
2
3 2
) .
1
(
2) Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma,
K.; Komatsu, J.; Seikine, K.; Miyafuji, A.; Kunoh, J.; Homma, R.; Akita,
Y.; Ohta, A. Heterocycles 1992, 33, 257-272.
3
13. Confirmed by H NMR, 400 MHz in CDCl signal for H2 (8.25 ppm)
and H3 (8.70 ppm). Bis-coupled product 14, LC/MS data, and absence of
1
H2 and H3 protons in H NMR spectrum.
(3) Pivsa-Art, S.; Satoh, T.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998,
(11) Dimroth, O. Annals 1909, 364, 183. Dimroth, O. Annals 1927, 459, 39.
Vaughen, K.; LaFrance, R. J.; Tang, Y. J. Heterocycl. Chem. 1991, 28,
1709-1713.
7
1, 467-473.
(
4) Kondo, Y.; Komine, T.; Sakamoto, T. Org. Lett. 2000, 2, 3111-3113.
3
98
•
Vol. 10, No. 3, 2006 / Organic Process Research & Development
10.1021/op050217j CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/17/2006

Scheme 1a
a
3 4 2 3 2
(i) Pd(PPh ) , Na CO , H O, THF, 65 °C.
Scheme 2a
a
Reagents and conditions: (i) Pd(dppf)
2
Cl
2
, KOAc, 1,4-dioxane, 90 °C. (ii) 2-Bromo-5-fluorobenzonitrile (17), Pd
Cl , KOAc, 1,4-dioxane.
2
(dba)
3
, P(t-Bu)
3 2 2
, KF, THF, 50 °C. (iii) H , PtO ,
EtOH, (iv) NaNO
2
, CuBr, HBr,1,4-dioxane. (v) diboronpinacolato Pd(dppf)
2
2
Scheme 3 a
Table 1. Comparison of yields for coupling 5 to 15, with
a
4
various ligands and Bu NX
ligand/
4
yieldd
(%)
ligand/
Bu NX
yieldd
(%)
entry
1b
Bu
NX
entry
4
21
<1
<1
3
10
22
25
36
63
88
2
4
6
22b
<1
3
4
20
20
26
50
75
85
b
b
3
Cl
2
Ni(PPh
3
)
2
23
25
b
5
24
c
c
7
Pd[(t-Bu)
3
P]
2
8
P(t-Bu)
3
c
26
20
10
19
b
c
12
19/Bu
19/Bu
20/Bu
20/Bu
4
4
4
4
NCl
NBr
NCl
NOAc
c
c
c
c
19/Bu
20/Bu
20/Bu
4
4
4
NI
NBr
NHSO
14
16
c
c
4
18
a
3 2 2 2
Reagents and conditions: (i) (CF CO) O (7), pyridine, CH Cl . (ii) guanidine
hydrochloride, EtOH, NaOH. (iii) 2-aminoimidazole hemisulfate (9), NaOMe,
EtOH. (iv) bromoacetaldehyde diethyl acetal (11), conc HBr, EtOH, reflux. (v)
Br , KBr, NaOAc, MeOH, 0-5 °C.
2
at -75 °C with in situ quenching of the anion with
1
4
B[O(i-Pr)]
9
6
3
, followed by an acidic work up to afford 16 in
0% yield (Scheme 6). Although, the corresponding 3-bromo-
-fluorobenzeneboronic acid could also be prepared in this
couplings to aryl chlorides12 have become possible. The
coupling of 5 with the biaryl chloride 15 was an attractive
option since 15 could easily be prepared in short order from
the coupling of the boronic acid 16 to commercially available
fashion in high yield, subsequent coupling to 17 resulted, as
one might expect, in a mixture of coupled products.
The initial results (Table 1, entries 1-13) for the coupling
of 5 to 15 with ligands 19 to 26 (Figure 1) were disappoint-
ing. Encouragingly, more favorable results were obtained
2-bromofluorobenzonitrile (17) to give 15 in 92% yield. The
boronic acid 16 itself was readily prepared from ortholithia-
13
tion of commercially available 4-chlorofluorobenzene (18)
by lithium 2,2,6,6-tetramethylpiperidine (LiTMP) in THF
15
under Jeffrey-type conditions. For ligand biphenyl-di-tert-
butylphosphine (19), yields increased upon the addition of
tetrabutylammonium salts (Table 1, entries 12-14). Interest-
ingly, no reaction was observed when Me NBr or Et BnNBr
4 3
(
12) Little, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10-11. Beller, M.; Zapf,
A. Synlett 1998, 792-793. Reetz, M. T.; Lohmer, G.; Schwickardi, R.
Angew. Chem., Int. Ed. 1998, 37, 481-483. Riermeier, T. H.; Zapf, T. H.;
Beller, M. Top Catal. 1997, 4, 301-309. Hermann, W. A.; Brossmer, C.;
Reisinger, C.-P.; Reirmeier, T. H.; Ofele, K.; Beller, M. Chem. Eur. J. 1997,
were used as additives. More synthetically useful yields
3
, 1357-1364. Hermann, W. A.; Brossmer, C.; Ofele, K.; Beller, M.;
Fischer, H. J. Mol. Catal. A 1995, 103, 133-146. Hermann, W. A.;
Brossmer, C.; Ofele, K.; Resinger, C.-P.; Priermeier, T.; Beller, M.; Fischer,
H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1844-1848. Herrmann, W. A.;
Elison, M.; Fischer, J.; K o¨ cher, C.; Artus, G. R. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2371-2374.
(13) Snieckus, V. Chem. ReV, 1990, 90, 879-933. Kalinin, A. V.; Bower, J. F.;
Riebel, P.; Snieckus, V. J. Org. Chem, 1999, 64, 2986-2987.
(14) Kristensen, J.; Lys e´ n, M.; Vesdø P.; Begtrup, M. Org. Lett, 2001, 3, 1435-
1437.
(15) Jeffrey, T. J. Chem. Soc., Chem. Commun, 1984, 1287-1289.
Vol. 10, No. 3, 2006 / Organic Process Research & Development
•
399

Scheme 4
Scheme 5
catalytic activity is observed. In conclusion, a convergent
six-step synthesis of our GABA R2/3 agonist 1 has been
developed via the regioselective palladium-catalyzed cou-
pling of 5 to 15 in 80-90% yield. Key to the efficiency of
this coupling was the use of 1,4-dioxane as solvent, Cs
as base, X-phos (20) as the ligand, and addition of 10 mol
Bu NOAc or Bu NHSO . The combination of X-phos (20)
and Bu NHSO was found to be useful for the coupling of
to challenging electron-rich aryl chlorides such as 4-
2 3
CO
%
4
4
4
4
4
5
chlorotoluene and 4-chloroanisole.
Scheme 6a
a
Reagents and conditions: (i) LiTMP, - 75 °C, THF, B[O(i-Pr)]
3
. (ii) 2 N
, KF, THF 0 to
HCl. (iii) 2-Bromo-5-fluorobenzonitrile (17), Pd[P(t-Bu)
0 °C.
3 2
]
2
(
Table 1, entries 16-18) were obtained with the ligand
X-phos 20 in combination with Bu NHSO , Bu NOAc, or
Bu NCl. Indeed the combination of 20 with Bu NHSO was
4
4
4
4
4
4
found particularly useful in coupling of 5 to challenging
electron-rich aryl chlorides such as 4-chlorotoluene and
4
-chloroanisole to give their relevant coupling products 27
and 28 (Scheme 4) in 72 and 77% yields, respectively. It is
not clear the exact role Bu NHSO plays when used in
4
4
Figure 1. Ligands employed in coupling 5 to 15.
conjunction with ligands such as 19 or 20. Little (<2%)
reaction was observed in the absence of either ligand, and it
seems unlikely that phase transfer catalysis is in play since
a beneficial effect was not observed for tetramethylammo-
nium or triethylbenzylammonium salts. More likely, addition
of the salt leads to the formation of a stabilized anionic
Experimental
General. For 19F NMR (H decoupled) δ values were
3
measured against CFCl as reference. The HPLC assay for
the determination of concentration and final purity of 1 was
performed with an YMC ODS AQ 5 µ (250 mm × 4.6 mm)
16
Pd(0) species, thus allowing sufficient turnover of the Heck
cycle to drive the reaction to completion before loss of
(16) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV, 2000, 100, 3009-3006.
400
•
Vol. 10, No. 3, 2006 / Organic Process Research & Development

column at 25 °C, and compounds were detected at 215 nm.
Separation was achieved by employing a gradient elution
δ 7.1 (1H, t, J ) 8.8 Hz), 7.43 (1H, ddd, J ) 2.8, 4.8, 8.8
19
Hz), 7.48 (1H, dd, J ) 2.8, 4.8 Hz), 8.37 (2H, br). F NMR
1
3
(90% A for 5 min, then to 10% A over 15 min, and then
(379 MHz, (CD
3 2
) SO) δ -107.5. C NMR (100 MHz,
held at 10% A for a further 15 min) of two mobile phases A
CD Cl) δ 164.4 (d, J ) 244.9 Hz), 135.4 (d, J ) 10.4 Hz),
135.0 (d, J ) 8.8 Hz), 131.7 (d, J ) 3.2 Hz), 125.5 (br),
117.5 (d, J ) 26.5 Hz).
3
-
1
and B at a flow rate of 1.0 mL min . Phase A consisted of
.1% phosphoric acid in water, and phase B consisted of
0
acetonitrile. Melting points were uncorrected.
Preparation of 7-Trifluoromethylimidazo[1,2-a]-
pyramidine (5). Method A. To a stirred mixture of 9 (1.7 g,
Preparation of 5-Chloro-4,2′-difluorobiphenyl-2-
carbonitrile (15). To a mixture of 16 (19.3 g, 110.6 mmol),
17 (20.0 g, 100.0 mmol), and potassium fluoride (15.5 g,
264.5 mmol) in THF (500 mL) at ambient temperature under
an atmosphere of nitrogen was added bis(tri-tert-butylphos-
phino)palladium (0.14 g, 0.3 mmol). The mixture stirred for
5 h. Isopropyl acetate (400 mL) was added and the mixture
12.7 mmol) and NaOMe (1.4 g, 13.1 mmol) in ethanol (17
mL) at 0 °C was added 8 (2.5 g, 15.2 mmol). The mixture
stirred for 1 h, and then was heated at reflux temperature
for 2 h. The mixture cooled to ambient temperature and was
filtered. The filter cake was washed with ethanol (40 mL),
and the organic filtrates were combined and volatiles
evaporated in vacuo. The residue was suspended in heptane
2
filtered through SiO . The filter cake washed with isopropyl
acetate (3 × 100 mL). The combined filtrate was evaporated
in vacuo and the residue suspended in heptane (200 mL).
The suspension stirred at ambient temperature for 30 min,
and the solid was collected, washed with heptane (100 mL),
(
30 mL) and stirred at ambient temperature for 16 h. The
suspension was filtered and the solid washed with heptane
5 mL) and dried to afford 4 (2.0 g, 10.8 mmol) in 85%
(
and dried and gave 15 (23.0 g, 92.4 mmol) in 92% yield.
1
1
yield. Mp 163-164 °C. H NMR (400 MHz, CD
3
Cl) δ 7.24
Mp ) 105.5-106.5 °C. H NMR (400 MHz, CD
2 2
Cl ) δ 7.20
(
1H, d, J ) 7.2 Hz), 7.77 (1H, d, J ) 1.2 Hz), 8.03 (1H, d,
(1H, t, J ) 7.2 Hz), 7.39 (1H, dd, J ) 2.4, 6.4 Hz), 7.41-
19
19
J ) 1.2 Hz), 8.72 (1H, d, J ) 7.2 Hz). F NMR (376 MHz,
CD
(
1
7.53 (4H, m). F NMR (376 MHz, CD
2
Cl
2
) -112.0, -118.7.
1
3
13
3
Cl) δ -68.78 (s). C NMR (100 MHz, CD
3
Cl) δ 147.0
C NMR (100 MHz, CD Cl ) δ 161.9 (d, J ) 251.4 Hz),
2 2
q, 2JCF ) 36.9 Hz), 138.3, 135.0, 120.5 (q, J ) 275.5 Hz)
12.1, 104.8 (q, J ) 2.4 Hz). HRMS calcd for (M + H)
88.0430, found 188.0437.
158.1 (d, J ) 248.2 Hz), 134.4 (d, J ) 3.2 Hz), 132.9 (dd,
J ) 1.6, 8.8 Hz), 131.0 (d, J ) 3.2 Hz), 130.9 (d, J ) 8.0
Hz), 129.4 (d, J ) 4.0 Hz), 126.6 (d, J ) 16.9 Hz), 120.6
(d, J ) 21.7 Hz), 120.1 (d, J ) 24.9 Hz), 117.6 (d, J ) 24.1
Hz), 116.5 (d, J ) 3.2 Hz), 114.3 (d, J ) 9.6 Hz). Anal.
Calcd for C13H ClFN: C, 62.54; H, 2.43; N, 5.61; Cl, 14.20;
6
F, 15.22. Found: C, 62.33; H, 2.32; N, 5.48; Cl, 14.20; F,
15.41.
Preparation of 4,2′-Difluoro-5′-(7-trifluoromethyl-
imidazo[1,2-a]pyrimidin-3-yl)-biphenyl-2-carbonitrile (1).
Under an atmosphere of nitrogen a well-stirred, degassed
mixture of 5 (5.0 g, 26.7 mmol), 15 (6.7 g, 26.7 mmol),
•
+
1
Method B. To a stirred suspension of 10 (101.8 g, 624.3
mmol) and 11 (120.0 mL, 773.6 mmol) in ethanol (600 mL)
was added concd HBr (50 mL). The mixture was heated at
reflux temperature for 3 h and then cooled to ambient
temperatue and stirred for a further 16 h. The mixture cooled
to 0 °C, and 50% NaOH was added slowly (50 mL) followed
by water (200 mL). The mixture was extracted with isopropyl
acetate (2 × 300 mL); the organic extracts were combined
and volatiles evaporated in vacuo. The residue was suspended
in heptane (600 mL) and stirred for 2 h at ambient
temperature. The suspension was filtered, and the solids were
washed with heptane (50 mL) and dried in vacuo to give 4
Bu
4
NHSO
4
(0.9 g, 2.7 mmol), Cs
2
CO
3
(13.1 g, 40.1 mmol),
(0.3 g, 1.3 mmol)
XPhos (1.4 g, 2.9 mmol), and Pd(OAc)
2
in 1,4-dioxane (140 mL) was heated at 90 °C for 8 h. The
mixture cooled to ambient temperature, and 1 was isolated
by quenching into water. The solid formed was isolated by
filtration and washed with water (100 mL) and gave 1 (11.6
g, 80 wt % pure, 23.2 mmol) in 87% yield. Pure material
(
97.0 g, 518.4 mmol) in 83% yield.
Preparation of 3-Chloro-6-fluorobenzeneboronic Acid
16). To a stirred solution of 2,2,6,6-tetramethylpiperidine
18.6 mL, 110.2 mmol) in dry THF (200 mL) at -50 °C,
(
(
under an atmosphere of nitrogen, was added hexyllithium
was obtained by recrystallization from ethanol (95%). Mp
1
2.3 M in hexane (47.8 mL, 109.9 mmol) slowly over 30 min
) 189 °C. H NMR (400 MHz, CD
2
Cl
2
) δ 7.29 (1H, d, J )
and was stirred for a further 45 min at -50 °C. The solution
was then chilled to -75 °C, and trisopropylborate (25.8 mL,
7.2 Hz), 7.43-7.49 (2H, m), 7.56 (1H, dd, J ) 2.4, 8.0 Hz),
7.60-7.70 (3H, m), 8.09 (1H, s), 8.99 (1H, d, J ) 7.2 Hz).
C NMR (100 MHz, CD Cl ) δ 162.1 (d, J ) 221.7 Hz),
2 2
1
3
111.8 mmol) was added slowly over 30 min. The solution
stirred at -75 °C for 15 min, and 18 (11.0 mL, 103.3 mmol)
was added dropwise; stirring continued at -75 °C for 5 h.
Glacial acetic acid (40 mL) was then added and the resulting
slurry warmed to ambient temperature. The mixture was
partitioned between water (950 mL) and isopropyl acetate
159.5 (d, J ) 218.4 Hz), 147.1, 146.4 (q, J ) 36.9 Hz),
136.8, 134.6 (d, J ) 4.0 Hz), 133.3 (dd, J ) 2.4, 8.8 Hz),
133.2, 131.4 (d, J ) 8.8 Hz), 130.9 (d, J ) 3.2 Hz), 126.2
(d, J ) 16.1 Hz), 124.3 (d, J ) 4.0 Hz), 124.1, 120.7 (q, J
) 274.7 Hz), 120.6 (d, J ) 21.7 Hz), 120.3 (d, J ) 25.7
Hz), 117.9 (d, J ) 23.3 Hz), 117.3 (d, J ) 3.2 Hz), 114.0
(d, J ) 9.6 Hz), 105.1 (q, J ) 1.6 Hz). HRMS calcd for (M
+ H) 401.0820, found 401.0825.
(150 mL). The two layers were separated, and the aqueous
phase was extracted with isopropyl acetate (100 mL). The
organic solutions were combined and volatiles evaporated
in vacuo to residue that was recrystallized from isopropyl
4-Methyl-(7-trifluoromethyl-imidazo[1,2-a]pyrimidin-
3-yl)benzene (27). This compound was obtained in 72%
yield from the reaction of 5 with 4-chlorotoluene. Pale-yellow
acetate/hexane and gave 16 (16.1 g, 92.7 mmol) in 90%
1
yield. Mp 206-207.5 °C. H NMR (400 MHz, (CD
3
)
2
SO)
Vol. 10, No. 3, 2006 / Organic Process Research & Development
•
401

1
solid: mp 192-193 °C; H NMR (400 MHz, CDCl
(
7
3
) δ 2.47
(376 MHz, CDCl
294.0848, found 294.0854. Anal. Calcd for C14H F
57.34; H, 3.44; N, 14.33; F, 19.71. Found: C, 57.29; H, 3.27;
N, 14.25; F, 19.71.
3
) δ -68.4. HRMS calcd for (M + H)
NO: C,
3H, s), 7.21 (1H, d, J ) 7.2 Hz), 7.38-7.40 (2H, m), 7.43-
10 3
1
3
.46 (2H, m), 8.05 (1H, s), 8.80 (1H, d, J ) 7.2 Hz).
) δ 146.1, 145.2 (q, J ) 36.9 Hz),
39.7, 136.4, 132.4, 130.4, 128.0, 125.7, 124.5, 120.6 (q, J
C
NMR (100 MHz, CDCl
3
1
)
19
275.5 Hz), 104.8 (q, J ) 2.4 Hz), 21.4. F NMR (376
) δ -68.7. HRMS calcd for (M + H) 278.0899,
found 278.0911. Anal. Calcd for C14 N: C, 60.65; H,
.64; N, 15.16; F, 20.55. Found: C, 60.65; H, 3.64; N, 15.11;
F, 21.03.
-Methoxy-(7-trifluoromethyl-imidazo[1,2-a]pyrimidin-
-yl)benzene (28). This compound was obtained in 77%
yield from the reaction of 5 with 4-chloroanisole. Yellow
Acknowledgment
MHz, CDCl
3
We thank Dr. D. J. Hallett, and Dr S. C. Goodacre (MSD,
Terlings Park, UK) for helpful discussions. We also thank
Dr. P. Dormer and Ms L. DiMichele for NMR assistance.
10 3
H F
3
4
Supporting Information Available
3
Copies of NMR data for compounds 1, 5, 15, 16, 27 and
28. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
solid: mp 173.5-174.0 °C. H NMR (400 MHz, CDCl
3
) δ
.90 (3H, s), 7.07-7.11 (2H, m), 7.21 (1H, d, J ) 7.2 Hz),
.46-7.49 (2H, m), 8.01 (1H, s), 8.76 (1H, d, J ) 7.2 Hz).
3
7
1
3
C NMR (100 MHz, CDCl
6.9 Hz), 136.1, 132.3, 129.5, 125.5, 121.1 (q, J ) 275.5
Hz), 119.5, 115.1, 104.7 (q, J ) 2.4 Hz), 55.5. F NMR
3
) δ 160.4, 146.7, 145.9 (q, J )
Received for review November 1, 2005.
OP050217J
3
19
402
•
Vol. 10, No. 3, 2006 / Organic Process Research & Development