Expedient parallel synthesis of 2-amino-4-heteroarylpyrimidines

Article abstract of DOI:10.1021/ol051339z

(Chemical Equation Presented) An expedient synthesis of diverse 2-amino-4-heteroarylpyrimidines via a 2-chloropyrimidine intermediate is described. A series of potentially biologically active analogues have been synthesized in two parallel steps to afford focused arrays.

Full text of DOI:10.1021/ol051339z

ORGANIC
LETTERS
2
005
Vol. 7, No. 19
113-4116
Expedient Parallel Synthesis of
-Amino-4-heteroarylpyrimidines
4
2
Matthew G. Bursavich,* Sabrina Lombardi, and Adam M. Gilbert
Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research,
401 North Middletown Road, Pearl RiVer, New York 10965
bursaVm@wyeth.com
Received June 8, 2005
ABSTRACT
An expedient synthesis of diverse 2-amino-4-heteroarylpyrimidines via a 2-chloropyrimidine intermediate is described. A series of potentially
biologically active analogues have been synthesized in two parallel steps to afford focused arrays.
In our efforts to pursue leads generated via HTS campaigns,
we have focused on developing expedient parallel syntheses.
Following one such HTS campaign, we needed to develop
a straightforward synthesis to both 2-anilino-4-heteroarylpy-
we envisioned forming these two key bonds sequentially
utilizing all commercially available starting materials (Figure
2). Key to our envisioned parallel synthesis was the initial
selective formation of the 4-pyrimidine-heteroaromatic
bond. Subsequently, we needed to develop methods for
1
rimidines 1 and 2-amino acid-4-heteroaryl pyrimidines 2.
Traditional approaches (Figure 1) suggested synthesis via
2
condensation of ketone 3 with either guanidine 4 or 5.
Unfortunately, formation of arylguanidine 4 and subsequent
cyclization is nontrivial as specific conditions are required
for guanidine formation with individual anilinessseemingly
counterproductive to developing an expedient parallel syn-
3
thesis. Synthesis of 2 via amino acid guanidine formation
and subsequent cyclization is also nontrivial, affording
complex reaction mixtures.
To develop an expedient parallel synthesis that explored
both the pyrimidine 2-amino- and 4-heterocycle substituent
(1) For a review of bioactive pyrimidines, see: Fabbro, D.; Ruetz, S.;
Buchdunger, E.; Cowan-Jacob, S. W.; Fendrich, G.; Liebetanz, J.; Mestan,
J.; O’Reilly, T.; Traxler, P.; Chaudhuri, B.; Fretz, H.; Zimmermann, J.;
Meyer, T.; Caravatti, G.; Furet, P.; Manley, P. W. Pharmacol. Therapeut.
Figure 1. Traditional retrosynthetic analysis of 2-anilino-4-
heteroaromatic pyrimidines.
2
002, 93, 79 and references contained therein. Tavares, F. X.; Boucheron,
J. A.; Dickerson, S. H.; Griffin, R. J.; Preugschat, F.; Thomson, S. A.; Wang,
T. Y.; Zhou, H.-Q. J. Med. Chem. 2004, 47, 4716.
1
0.1021/ol051339z CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/17/2005

including bases, solvents, additives, extended reaction times,
temperatures, and microwave irradiation. Several of these
conditions afforded some conversion of the starting materials
to the desired product but suffered from issues of generality
and reproducibility. After a more thorough literature inves-
tigation, we identified an acid-mediated approach to syn-
6
thesize 2-anilinopyrimidines. We found that refluxing 6a
with 1.2 equiv of several anilines in the presence of 0.8 equiv
p-TsOH in dioxane afforded the desired 2-aniline products
Figure 2. Envisioned 2-amino-4-heteroaromatic pyrimidine forma-
tion.
7a-c in good yields after isolation via flash chromatography
(
Scheme 2). Furthermore, this acid-mediated procedure
generating the 2-aminopyrimidine bond. Accomplishing these
two goals would provide a general, expedient route to a
potentially biologically important 2,4-disubstituted pyrimi-
dine scaffold.
Scheme 2
We decided to focus our efforts on the synthesis and
subsequent nucleophilic displacement of 2-chloro-4-het-
eroarylpyrimidines 6. We initially investigated Suzuki reac-
4
tions with 2,4-dichloropyrimidine to afford 6 but found this
reaction to be unsatisfactory with heteroarylboronic acids.
Fortunately, we were able to generate this key intermediate
5
via the method of Strekowski and co-workers. Nucleophilic
attack with several different heteroaryllithium anions gener-
ated in situ on commercially available 2-chloropyrimidine
afforded 6a-c after subsequent oxidative workup with DDQ
appeared to be general, reproducible, and amenable to parallel
synthesis.
(Scheme 1).
To demonstrate the scope of the acid-mediated, nucleo-
philic displacement of 2-chloro-4-heteroarylpyrimidines with
a variety of anilines, the compounds in Table 1 were
prepared. All three 4-heteroarylpyrimidines 6a-c were
successfully coupled with a variety of anilines. In addition
to reactions with aniline to give 7a,j,s in good yields,
couplings of anilines containing electron-donating groups to
give 7b,i,k,r,t,z went in high yields as determined by LC/
MS. Good isolated yields of these products were also
obtained. Whereas displacement reactions of 2-chloropyri-
midines with weakly nucleophilic anilines are problematic
under basic conditions, anilines with strong p-electron-
withdrawing groups gave good yields of 2-amino-4-het-
eroarylpyrimidines under the p-TsOH conditions (7d,f,g,m,o-
q,v,x,y). Ortho substitution on the aniline also appears to be
tolerated as o-toluidine couples effectively to give 7e,n,w.
We also wanted to synthesize 2-amino acid-4-heteroarylpy-
rimidines. There are limited literature reports on this type
Scheme 1
With the key intermediates 6a-c in hand, we focused on
identifying conditions to generate the 2-aminopyrimidine
bond with anilines. We investigated a variety of conditions
7
of biologically interesting scaffold. To our knowledge, there
is no literature procedure available to rapidly access ana-
logues of this scaffold. Our initial efforts to synthesize this
scaffold utilizing aminoguanidines (Figure 1) failed miserably
leading to complex reaction mixtures. Nucleophilic displace-
ment of 2-chloro-4-heteroarylpyrimidines with amino acids
under the acidic p-TsOH procedure also did not work. We
then investigated a variety of conditions including bases,
(
2) Paul, R.; Hallett, W. A.; Hanifin, J. W.; Reich, M. F.; Johnson, B.
D.; Lenhard, R. H.; Dusza, J. P.; Kerwar, S. S.; Lin, Y. I.; Pickett, W. C.;
Seifert, C. M.; Torley, L. W.; Tarrant, M. E.; Wrenn, S. J. Med. Chem.
993, 36, 2716. Drager, G.; Solodenko, W.; Messinger, J.; Schon, U.;
Kirschning, A. Tetrahedron Lett. 2002, 43, 1401. For other methods to
potentially access 2-amino-4-heteroarylpyrimidines, see: Collis, A. J.;
Foster, M. L.; Halley, F.; Maslen, C.; McLay, I. M.; Page, K. M.; Redford,
E. J.; Souness, J. E.; Wilsher, N. E. Bioorg. Med. Chem. Lett. 2001, 11,
1
6
93. Manley, P. J.; Balitza, A. E.; Bilodeau, M. T.; Coll, K. E.; Hartman,
G. E.; McFall, R. C.; Rickert, K. W.; Rodman, L. D.; Thomas, K. A. Bioorg.
Med. Chem. Lett. 2003, 13, 1673. Clark, M. P.; Laughlin, S. K.;
Laufersweiler, M. J.; Bookland, R. G.; Brugel, T. A.; Golebiowski, A.;
Sabat, M. P.; Townes, J. A.; VanRens, J. C.; Djung, J. F.; Natchus, M. G.;
De, B.; Hsieh, L. C.; Xu, S. C.; Walter, R. L.; Mekel, M. J.; Heitmeyer, S.
A.; Brown, K. K.; Juergens, K.; Taiwo, Y. O.; Janusz, M. J. J. Med. Chem.
(
5) Harden, D. B.; Mokrosz, M. J.; Strekowski, L. J. Org. Chem. 1988,
5
3, 4137. Strekowski, L.; Harden, D. B.; Grubb, W. B., III; Patterson, S.
E.; Czarny, A.; Mokrosz, M. J.; Cegla, M. T.; Wydra, R. L. J. Heterocycl.
Chem. 1990, 27, 1393.
(
6) Hattinger, G.; Stanetty, P.; Eberle, M. GB 2369359, 2002.
2
004, 47, 2724.
3) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org. Chem. 1992,
7, 2497.
4) Gong, Y.; Pauls, H. W. Synlett 2000, 829.
(7) A SciFinder search of the generic 2-amino acid-4-cyclic-pyrimidine
(
scaffold identified a total of only 18 patents and 2 publications. In ref 2,
Clark et al., one of the 30 compounds exemplified was a 2-Phe-OMe-4-
cyclic-pyrimidine.
5
(
4114
Org. Lett., Vol. 7, No. 19, 2005

Table 1. 2-Amino-4-heteroarylpyrimidines Prepared via
Schemes 1 and 2
Table 2. 2-Amino acid-4-heteroarylpyrimidines Prepared via
Schemes 1 and 3a
a
a
Reported yields determined via LC/MS analysis of the crude reaction
mixture using an internal standard. Yields in parentheses are isolated yields
after RP-HPLC purification using a Gilson HPLC instrument.
acids (Table 2). Both 4-heteroarylpyrimidines 6a and 6c were
successfully coupled with racemic leucine and serine to
8
afford 8a-d. The yields with the more sterically encum-
bered leucine (8a and 8b) were only moderate as determined
by LC/MS, but the yields with the less sterically encumbered,
more highly functionalized serine (8c and 8d) were good.
While the yields are good to moderate at best for 8a-d,
this synthetic strategy allows rapid, straightforward access
to potentially biologically interesting scaffolds for which
there are no efficient procedures known in the literature.
We also found the 2-amino acid-4-heteroarylpyrimidine
chemistry to be amenable to solid-phase techniques (Scheme
4
) utilizing an Fmoc-Gly Wang resin. The Fmoc group was
Scheme 4
a
Reported yields determined via LC/MS analysis of the crude reaction
mixture using an internal standard. Yields in parentheses are isolated yields
after RP-HPLC purification using a Gilson HPLC instrument. Yields with
*
are isolated yields after flash chromatography.
solvents, additives, extended reaction times, microwave
irradiation, and temperatures. We found that heating 6a with
1.5 equiv of the amino acid and 4 equiv of NaH in DMSO
afforded the desired 2-amino acid product 8 in moderate
yields and appeared to be general, reproducible, and ame-
nable to parallel synthesis (Scheme 3).
first removed to unmask the amino acid. Subsequent heating
of this resin with NaH and the desired 2-chloropyrimidine
in DMSO afforded, after acidic cleavage, the desired 2-amino
acid-4-heteroarylpyrimidine 9. Purification of this relatively
clean product via preparative HPLC afforded the desired
compound in moderate yield and excellent purity. One can
imagine cleavage of the product from the Wang resin under
different conditions to incorporate another site of diversity,
A simple 2 × 2 library was prepared via nucleophilic
displacement of 2-chloro-4-heteroarylpyrimidines with amino
Scheme 3
9
e.g., to produce amide analogues as well. Thus, in a single
(8) Resynthesis of 8a and 8c with the enantiomerically pure amino acids
and subsequent purification via preparatory HPLC revealed a minimal degree
of epimerization. The desired products 8a and 8c were isolated in 93% and
7
6% respective chiral purity.
9) Barn, D. R.; Morphy, J. R.; Rees, D. C. Tetrahedron Lett. 1996, 37,
213.
(
3
Org. Lett., Vol. 7, No. 19, 2005
4115

on-resin transformation multiple arrays of this potentially
biologically interesting scaffold could be generated with three
points of diversity.
In summary, we have developed an expedient parallel
synthesis to diverse 2-amino-4-heteroarylpyrimidines. These
potentially biologically important targets can be obtained in
two straightforward steps utilizing commercially available
starting materials. Synthetic arrays of both 2-anilino- and
heteroarylpyrimidine intermediate to access other biologically
interesting targets.
Acknowledgment. We thank Michael Kelly for helpful
discussions and insights on RP-HPLC purification using a
Gilson HPLC instrument. We also thank Mairead Young for
chiral sample analysis.
Supporting Information Available: Experimental pro-
1
cedures and H NMR and LC/MS data for intermediates and
2
2
-amino acid-pyrimidines can be derived from the same key
-chloro intermediate. We have also shown the utility of a
final products of chemistry validation and LC/MS data for
parallel synthesis array. This material is available free of
charge via the Internet at http://pubs.acs.org.
solid phase supported functionalization protocol for the
-amino acid-pyrimidine derivatives. We are currently
investigating other syntheses utilizing this key 2-chloro-4-
2
OL051339Z
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Org. Lett., Vol. 7, No. 19, 2005