A novel route to 2,4-dianilino-substituted pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2009.11.094

A method is described to couple sterically-hindered electron-poor anilines to the 4-position of the pyrimidine core using a pyrimidine-2,4-bis(trifluoromethanesulfonate).

Full text of DOI:10.1016/j.tetlet.2009.11.094

Tetrahedron Letters 51 (2010) 543–544
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel route to 2,4-dianilino-substituted pyrimidines q
b
c
b
Ruben Leenders a, , Jan Heeres , Jérôme Guillemont , Paul Lewi
*
a Mercachem BV, Kerkenbos 10-13, 6546 BB Nijmegen, The Netherlands
b Janssen Research Foundation, Center for Molecular Design, Antwerpsesteenweg 37, B-2350 Vosselaar, Belgium
c Johnson and Johnson Pharmaceutical Research and Development, Medicinal Chemistry Department, Campus de Maigremont BP315, F-27106 Val de Reuil Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A method is described to couple sterically-hindered electron-poor anilines to the 4-position of the pyrim-
idine core using a pyrimidine-2,4-bis(trifluoromethanesulfonate).
Ó 2009 Elsevier Ltd. All rights reserved.
Received 22 September 2009
Revised 9 November 2009
Accepted 20 November 2009
Available online 26 November 2009
In our continuing search toward HIV-inhibiting pyrimidines,1,2
we have prepared a series of 2,4-anilino disubstituted pyrimidines
derived from orotic acid (1, Scheme 1). These compounds act as
non-nucleoside reverse transcriptase inhibitors (NNRTIs). In the
present Letter we outline this synthesis.
Using route A (Scheme 1), in the first step, 2,6-dichloropyrimi-
dine-4-carboxylic acid methyl ester (3)3 was functionalized selec-
tively at the 4-position with an aniline yielding structure A. Next,
the 2-position was substituted with 4-cyanoaniline under acidic
conditions to furnish B.
This route, however, did not work where R1 was an electron-
withdrawing group, for example, 2,6-dimethyl-4-cyanoaniline did
not react with dichloride 3 under any of the conditions tested.4
In addition, we prepared amides of 2,6-dimethyl-4-cyanoaniline
(acetate, trifluoroacetate, and benzoate) to enable abstraction of
the remaining –NH and making the aniline more nucleophilic,
Scheme 1. Route A. Reagents and conditions: (i) MeOH, H2SO4, (MeO)2CO, reflux, 48 h (96%); (ii) POCl3, reflux, 16 h (80%); (iii) R1 = Me: 2,4,6-trimethylaniline, DIPEA, THF, rt,
48 h (81%); and (iv) R1 = Me: 4-cyanoaniline, BuOH, HCl, H2O, 100 °C, 16 h (98%).
Scheme 2. Route B. Reagents and conditions: (i) 4-[(tert-butyldimethylsilyloxy)methyl]-2,6-dimethylaniline, DIPEA, THF, reflux, 48 h (26%); (ii) MeOH, PPTS, reflux, 30 min;
(iii) acetone, MnO2, rt, 1 h (41% over two steps); (iv) hydroxylamine–HCl, Et3N, MeCN, rt, 16 h; and (v) Burgess reagent, THF, reflux, 4 h (30% over two steps).
q
See Ref. 1.
* Corresponding author. Tel.: +31 (0) 24 372 3321; fax: +31 (0) 24 372 3305.
E-mail addresses: ruben.leenders@mercachem.com, rggleenders@gmail.com (R. Leenders).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.094

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R. Leenders et al. / Tetrahedron Letters 51 (2010) 543–544
Scheme 3. Route C. Reagents and conditions: (i)5 Tf2O, Et3N, CH2Cl2, 0 °C to rt, 16 h (50%); (ii) R1R2R3-substituted aniline, THF, reflux, 16 h (10–40%); and (iii)6 carbon
monoxide, MeOH, Pd(OAc)2dppf, Et3N, DMF, 80 °C, 4–16 h (60–80%).
performed in good yields (60–80%).6 This is a rarely described pro-
Table 1
cess in the literature.7
List of products of type A and C
References and notes
1. Some of the compounds described in this Letter were claimed in Kukla, M. J.;
Ludovici, D. W.; Kavash, R. W.; De Corte, B. L. D.; Heeres, J.; Janssen, P. A. J.;
Koymans, L. M. H.; De Jonge, M. R.; Van Aken, K. J. A.; Krief, A.; Leenders, R. G. G.
U.S. 7276510, 2007; Chem. Abstr. 2001, 135, 371765. The synthesis of the
compounds from route C (Scheme 3) were not described in this patent.
2. (a) Ludovici, D. W.; De Corte, B. L.; Kukla, M. J.; Ye, H.; Ho, C. Y.; Lichtenstein, M.
A.; Kavash, R. W.; Andries, K.; de Béthune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P.
Entry
Route
Product
R1
R2
R3
Yield (%)
J.; Heeres, J.; Koymans, L. M. H.; De Jonge, M. R.; Van Aken, K. J. A.; Daeyaert, F. F.
D.; Das, K.; Arnold, E.; Janssen, P. A. J. Bioorg. Med. Chem. Lett. 2001, 11, 2235; (b)
De Corte, B.; De Jonge, M. R.; Heeres, J.; Ho, C. Y.; Janssen, P. A. J.; Kavash, R. W.;
Koymans, L. M. H.; Kukla, M. J.; Ludovici, D. W.; Van Aken, K. J. A. WO 2000/
27825; Chem. Abstr. 2000, 132, 347578.; (c) Kukla, M. J.; Ludovici, D. W.; Kavash,
R. W.; De Corte, B. L. D.; Heeres, J.; Janssen, P. A. J.; Koymans, L. M. H.; De Jonge,
M. R.; Van Aken, K. J. A.; Krief, A. U.S. 7034019; Chem. Abstr. 2001, 135, 371756.;
(d) Schils, D. P. R.; Willems, J. J. M.; Medaer, B. P. A. M.; Pasquier, E. T. J.; Janssen,
P. A. J.; Heeres, J.; Leenders, R. G. G. WO 2004/016581; Chem. Abstr. 2004, 140,
199342.; (e) Guillemont, J. E. G.; Paugam, M.; Delest, B. F. M. Patent WO 2007/
113254; Chem. Abstr. 2007, 147, 427364.; (f) Guillemont, J.; Pasquier, E.;
Palandjian, P.; Vernier, D.; Gaurrand, S.; Lewi, P. J.; Heeres, J.; De Jonge, M. R.;
Koymans, L. M. H.; Daeyaert, F. F. D.; Vinkers, M. H.; Arnold, E.; Das, K.; Pauwels,
R.; Andries, K.; De Béthune, M.-P.; Bettens, E.; Hertogs, K.; Wigerinck, P.;
Timmerman, P.; Janssen, P. A. J. J. Med. Chem. 2005, 48, 2072; (g) Mordant, C.;
Schmitt, B.; Pasquier, E.; Demestre, C.; Queguiner, L.; Masungi, C.; Peeters, A.;
Smeulders, L.; Bettens, E.; Hertogs, K.; Heeres, J.; Lewi, P.; Guillemont, J. Eur. J.
Med. Chem. 2007, 42, 567.
1
2
3
4
5
6
7
8
9
A
A
A
B
B
C
C
C
C
A
A
A
A
A
C
C
C
C
Me
CH2CN
CH2CH2CN
CN
CH@CHCN
CH@CHCN
CH@CHCN
CH@CHCN
CH@C(Me)CN
Me
Me
Me
Me
Me
Me
Cl
Me
Me
Me
Me
Me
OMe
OMe
H
81a
26a
20a
26b
26b,c
20d
11d
28d
36d
Me
Me
Me
a
b
c
Yield of 3 to A, Scheme 1.
Yield of 3 to 4, Scheme 2.
From 5 (Scheme 2) this product is prepared via a Wittig reaction with diethyl
cyanomethylphosphonate (76% yield).
d
Yield of 8 to C, Scheme 3.
3. Miltschitzky, S.; Michlova, V.; Stadlbauer, S.; Koenig, B. Heterocycles 2006, 67,
135.
4. We tested different organic and inorganic bases in THF, DME, dioxane, DMF, or
DMAc, microwave irradiation, and Buchwald–Hartwig coupling conditions
[Pd(OAc)2, BINAP, Cs2CO3, toluene, 80 °C]. However, no trace of the desired
product was found using any of these conditions.
5. Synthesis of 8: 3.64 g of 7 was stirred in 150 mL of dry CH2Cl2 and 4.45 mL of
Et3N (2 equiv) for 2 h and then cooled to 0 °C. Next, 9.0 g of Tf2O (2 equiv) in
50 mL of CH2Cl2 was added slowly to the substrate and the resulting mixture
was stirred overnight while the temperature was allowed to reach rt. The
reaction was washed with H2O (1 Â 200 mL) (when satd aq NaHCO3 was used
instead of H2O, the product decomposed), the organic layer was dried and the
solvent was evaporated leaving 3.9 g (50%) of a creamy solid behind. Rf = 0.45
(SiO2, heptane–EtOAc, 3:1); 1H NMR (300 MHz, CDCl3): d = 6.38 (s, 1H), 7.70 (br
s, 4H). The product was used as such.
6. Typical procedure: 1.73 mmol of triflate C, 6 mol % of dppf and 3 mol % of
Pd(OAc)2 were dissolved in 25 mL of dry DMF and the mixture was degassed by
bubbling a flow of nitrogen through the solution. Next, 50 equiv of MeOH and
3 equiv of Et3N were added and CO was bubbled through the solution until
saturation. The reaction vessel was closed and heated at 80 °C. When the
reaction was complete (4–12 h) it was cooled to rt, flushed with nitrogen and
partitioned between H2O and EtOAc. The organic extract was dried, evaporated
and the residue was purified by column chromatography (EtOAc–heptane) to
give the product methyl esters D in 60–80% yield.
however, coupling with 3 did not proceed. Alternatively, following
route B (Scheme 2), we were able to prepare the desired coupled
product 6. In this route, protected benzyl alcohol intermediate 4
was transformed into the corresponding aldehyde and then to
the oxime which was dehydrated to give the nitrile 6.
As this route was quite laborious and the yields were low, we
developed an alternative route. In route C (Scheme 3), 4,6-dihy-
droxypyrimidine 72a was converted into ditriflate 8. One of the tri-
flate groups was substituted with an aniline moiety to give
intermediate C and the remaining triflate group was transformed
into a methyl ester by palladium-mediated carbonylation in the
presence of methanol to afford D.
This synthesis shows that the highly reactive ditriflate 85 is a
valuable synthon in pyrimidine synthesis. One triflate group can
even be replaced with a bis-ortho-substituted electron-poor aniline
such as 2,6-dimethyl-4-cyanoaniline, whereas the corresponding
chloride did not react at all. See Table 1 for a list of the compounds
prepared. Carbonylation of the remaining triflate group was
7. Breuninger, D.; Bastiaans, H. M. M.; Von Deyn, W.; Langewald, J. WO 2008/
125410; Chem. Abstr. 2008, 149, 464751.