The 'Eenie-Meenie reaction'. Displacement reactions of bisanilinopyrimidines

Article abstract of DOI:10.1016/S0040-4039(01)02362-0

A novel acid-catalysed nucleophilic displacement reaction of pyrimidines is described, involving quinone-methide type chemistry. A wide range of nucleophiles can be tolerated. A similar mechanism is also applied to the synthesis of a tricyclic system.

Full text of DOI:10.1016/S0040-4039(01)02362-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1303–1306
The ‘Eenie–Meenie reaction’.
Displacement reactions of bisanilinopyrimidines
Stuart E. Pearson* and Robin Wood
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 25 September 2001; revised 6 December 2001; accepted 13 December 2001
Abstract—A novel acid-catalysed nucleophilic displacement reaction of pyrimidines is described, involving quinone–methide type
chemistry. A wide range of nucleophiles can be tolerated. A similar mechanism is also applied to the synthesis of a tricyclic system.
© 2002 Elsevier Science Ltd. All rights reserved.
During our quest to find a novel anti-cancer agent, we
have discovered an unexpected and previously unre-
ported reaction of 5-substituted 2,4-bisanilinopyrimidi-
nes. Few methods are described for the preparation of
these compounds. We wished to explore this area fur-
ther, with the aim of developing new pharmacologically
active molecules.
this is the first example of quinone–methide type chem-
istry applied to a heteroaromatic system.
2,4-Bisanilino-5-(ethoxymethyl)pyrimidine 1 is easily
prepared by sequential nucleophilic displacements of
the known 2,4-dichloro-5-(ethoxymethyl)pyrimidine2 in
a two stage process with optionally substituted anilines
(Scheme 2).
We have found that 5-(alkoxymethyl)-2,4-bisanilino-
pyrimidines1,2 undergo acid-catalysed displacement with
a wide range of nucleophiles (Scheme 1).
Treatment of 1 with nucleophiles in the appropriate
solvents under acidic catalysis at 100°C gives novel
5-substituted pyrimidines.4,6 A wide range of nucleo-
philes is tolerated, including alcohols, amides, ureas,
anilines, various substituted heterocycles and amines
(Table 1).
The intermediate cation is stabilised by the mesomeric
donating effects of the two anilines. This stabilised
species contains ene and iminium functionalities; there-
fore, we have named this process ‘the Eenie–Meenie
reaction’. Similar nucleophilic displacements have been
described for 4,4%-dimethoxybenzhydrol.3 We believe
A similar ‘Eenie–Meenie’ mechanism can be applied to
pyrimidines bearing hydroxymethyl anilines in the 2- or
Scheme 1. R1=H, Ph; R2=H, alkyl.
* Corresponding author. Tel.: +44 1625 518216; fax: +44 1625 513910; e-mail: stuart.pearson@astrazeneca.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02362-0

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S. E. Pearson, R. Wood / Tetrahedron Letters 43 (2002) 1303–1306
Reaction of 16 with 2-aminobenzyl alcohol in n-
butanol under acidic catalysis generates a similar
‘Eenie–Meenie’ intermediate, which undergoes electro-
cyclic rearrangement to generate the novel pyrido-
quinazoline system 18 (Scheme 4). The regioselectivity
1
of the cyclisation was confirmed by NOE H NMR.
A strong NOE is seen from Ha to Hb and Hc; the
alternative isomer 19 would only show one NOE,
from Hd to He. Formation of 19 was not observed,
presumably due to the lower electron density on the
3-nitrogen relative to the 1-nitrogen of the pyrimidine
ring.
Scheme 2. Reagents and conditions: (i) PhNH2, EtiPr2N, n-
BuOH, 100°C, 16 h; (ii) p-H2NC6H4OCH2CH(OH)-
CH2NMe2·2HCl, n-BuOH, MeOH, 100°C, 16 h; (iii) EtOH,
100°C, 16 h; (iv) nucleophile, Et2O·HCl, 100°C.
The reaction of 1 with 3-aminobenzyl alcohol under
the same conditions gave only formation of the initial
bisanilinopyrimidine, as there can be no mesomeric
stabilisation of the benzylic cation at the 3-position.
4-positions. Treatment of 16 with 4-aminobenzyl alco-
hol in n-butanol under acidic catalysis gave 17.5 We
propose the following mechanism (Scheme 3).
Further applications of this reaction will appear in
future publications.
Table 1. Reactions of 1 with various nucleophiles

S. E. Pearson, R. Wood / Tetrahedron Letters 43 (2002) 1303–1306
1305
Scheme 3. Reaction with 4-aminobenzyl alcohol.
Scheme 4. Reaction with 2-aminobenzyl alcohol.

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S. E. Pearson, R. Wood / Tetrahedron Letters 43 (2002) 1303–1306
6. Selected data: Chemical shifts are reported relative to
References
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1
1. Ple´, N.; Turck, A.; Martin, P.; Barbey, S.; Que´guiner, G.
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Hertz. 1: H NMR (CDCl3): l=1.28 (3H, t, J=6.5), 2.33
(6H, s), 2.3–2.6 (2H, m), 3.54 (2H, q, J=6.5), 3.97 (2H, d,
J=4.4), 4.07 (1H, m), 4.48 (2H, s), 6.87 (2H, d, J=8.5),
6.89 (1H, s), 7.08 (1H, t, J=7.0), 7.31 (2H, dd, J=7.0,
8.1), 7.44 (2H, d, J=8.5), 7.57 (2H, d, J=8.1), 7.87 (1H,
s), 7.93 (1H, br. s); MS (M+H+) 438.5. 3: 1H NMR
(CDCl3): l=2.34 (6H, s), 2.3–2.6 (2H, m), 3.63 (2H, t,
J=5.0), 3.73 (1H, s), 3.86 (2H, t, J=5.0), 3.96 (2H, d,
J=4.5), 4.08 (1H, m), 4.54 (2H, s), 6.86 (2H, d, J=8.5),
6.88 (1H, s), 7.08 (1H, t, J=7.0), 7.30 (2H, dd, J=7.0,
7.4), 7.43 (2H, d, J=8.5), 7.58 (2H, d, J=7.4), 7.88 (2H,
m); MS (M+H+) 454.3. 9: 1H NMR (CDCl3): l=2.20 (6H,
s), 2.25–2.5 (2H, m), 3.75–3.9 (3H, m), 4.79 (1H, br. s),
5.06 (2H, s), 6.05 (1H, d, J=2.5), 6.80 (2H, d, J=8.3),
7.02 (1H, t, J=7.3), 7.29 (2H, dd, J=7.3, 7.9), 7.50 (2H, d,
J=8.3), 7.70 (2H, dd, J=7.9), 8.05 (1H, s), 8.54 (1H, d,
J=2.5), 8.73 (1H, s), 9.07 (1H, s); MS (M+H+) 477.5. 17:
1H NMR (DMSO-d6): l=0.87 (3H, t, J=6.7), 1.31 (2H,
tq, J=6.7, 6.7), 1.49 (2H, tt, J=6.7, 6.7), 3.36 (2H, t,
J=6.7), 4.31 (2H, s), 7.07 (2H, d, J=7.8), 7.13 (1H, t,
J=7.4), 7.35 (2H, dd, J=7.4, 8.1), 7.54 (2H, d, J=8.1),
7.60 (2H, d, J=7.8), 8.20 (1H, s), 8.75 (1H, s), 9.30 (1H,
s); MS (M+H+) 427.3, 429.3. 18: 1H NMR (DMSO-d6):
l=4.92 (2H, s), 6.85–6.95 (3H, m), 6.95–7.0 (2H, m), 7.12
(1H, d, J=6.9) 7.15–7.25 (3H, m), 7.69 (1H, s), 10.0 (1H,
br. s); MS (M+H+) 352.9, 354.9.
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4. In a typical procedure, the nucleophile (0.50 mmol) and
Et2O·HCl (0.50 mmol) were added to a solution of
bisanilinopyrimidine 1 (0.25 mmol) in 3 ml N-methyl
pyrrolidinone, and the mixture was heated to 100°C for 2
h. The reaction was monitored by TLC. The solution was
cooled to room temperature and 30 ml Et2O were added,
causing a solid or gum to fall out of solution. The super-
natant was decanted off and the residue purified by flash
chromatography (MeOH/DCM system, containing 0.5%
conc. aqueous ammonia).
5. 4-Anilino-5-bromo-2-chloropyrimidine (626 mg, 2.20
mmol) and 4-aminobenzyl alcohol (246 mg, 2.00 mmol)
were dissolved in n-butanol (20 ml). Ethereal HCl (1 M,
4.00 ml, 4.00 mmol) was added at room temperature, and
the solution heated at 100°C for 16 h. The yellow solid,
which precipitated was removed by filtration, and the
filtrate was concentrated in vacuo. The crude product was
twice purified by flash chromatography (firstly eluting with
DCM, then eluting with 0–15% EtOAc in iso-hexane).
Product (17) (270 mg, 32%) was obtained as a white solid.