General and facial synthesis of 2-amino-5-halogenpyrimidine-4-carboxylic acids and their derivatives

Article abstract of DOI:10.1080/00397910701396930

A facile synthetic approach to 2-amino-5-halogen-pyrimidine-4-carboxylic acids from 5-halogen-2-methylsulfonylpyrimidine-4-carboxylic acid by nucleophilic displacement of the methylsulfonyl group with primary and secondary aliphatic amines has been develo

Full text of DOI:10.1080/00397910701396930

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General and Facial Synthesis of
2‐Amino‐5‐halogenpyrimidine‐4‐carboxylic
Acids and Their Derivatives
Evgeniy V. Blyumin a , Hans Neunhoeffer a & Yulian V. Volovenko b
a Darmstadt University of Technology, Institute of Organic Chemistry ,
Darmstadt, Germany
b Kiev Taras Schevchenko University, Chemical Department , Kiev, Ukraine
Published online: 03 Jul 2007.
To cite this article: Evgeniy V. Blyumin , Hans Neunhoeffer & Yulian V. Volovenko (2007) General and
Facial Synthesis of 2‐Amino‐5‐halogenpyrimidine‐4‐carboxylic Acids and Their Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:13,
2231-2241, DOI: 10.1080/00397910701396930
To link to this article: http://dx.doi.org/10.1080/00397910701396930
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Synthetic Communicationsw, 37: 2231–2241, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701396930
General and Facial Synthesis of 2-Amino-
5-halogenpyrimidine-4-carboxylic Acids
and Their Derivatives
Evgeniy V. Blyumin and Hans Neunhoeffer
Darmstadt University of Technology, Institute of Organic Chemistry,
Darmstadt, Germany
Yulian V. Volovenko
Kiev Taras Schevchenko University, Chemical Department, Kiev,
Ukraine
Abstract: A facile synthetic approach to 2-amino-5-halogen-pyrimidine-4-carboxylic
acids from 5-halogen-2-methylsulfonylpyrimidine-4-carboxylic acid by nucleophilic
displacement of the methylsulfonyl group with primary and secondary aliphatic
amines has been developed. The titled amino acids underwent decarboxylation,
yielding 2-amino-5-halogenpyrimidines. Starting from 2-amino-5-chloropyrimidine-
4-carboxylic acid chlorides, 2-[5-chloro-2-(amino)-4-pyrimidinyl]-2-oxo-1-(2-
pyridyl)-ethyl cyanides were obtained in excellent yields.
Keywords: amino acids, aminopyrimidines, nucleophilic substitution, regioselectivity
INTRODUCTION
In the field of medicinal chemistry, substituted 2-aminopyrimidines are one
of the most important structural motifs, existing within many pharmaceuti-
cally useful compounds. For example, Trimethoprim and Tetroxoprim are
famous bactericides,[1a] and Mizolastine is known as an effective histamine
H1-receptor antagonist.[1b,c] Substituted 2-amino-5-halogen-pyrimidine-4-
Received in Poland November 4, 2006
Address correspondence to Evgeniy V. Blyumin, DSM Nutritional Products Ltd.,
NRD/CP 205/318, P. O. Box 3255, CH-4002 Basel, Switzerland. E-mail:
yevgen.blyumin@dsm.com
2231

2232
E. V. Blyumin, H. Neunhoeffer, and Y. V. Volovenko
Scheme 1.
carboxylic acid derivatives have been shown to possess anti-AIDS,[2] bacteri-
cidal,[3] antihypertensive, and antithrombozytic activity[4] and are known as
effective uridine phosphorylase and DHO DHase inhibitors.[5,6] Furthermore,
these compounds have also been used as starting materials in the synthesis of
new anti-Alzheimer’s pharmaceuticals[7] and other biologically active
compounds.[3,8]
Known routes for preparing the titled compounds are limited to primary
pyrimidine-ring synthesis,[9] oxidation of the alkyl groups on the C-4(6)
position,[10] or functionalization of an NH2-group in 2-amino-5-halogen-
pyrimidine-4-carboxylic acid.[3] Therefore, only a few representatives of
this class of amino acids are known. Recently, we have developed a flexible
and general approach to cyanides 2 using nucleophilic displacement of the
methylsulfonyl group in 1 by amines (Scheme 1).[11–13]
In the case of the pyridine derivative, the reaction afforded condensed pyr-
idopyrimidines 3 as the only isolable products.[12] This fact prompted us to look
for alternative approaches to compounds 4, based on 2-amino-5-halogen-
pyrimidine-4-carboxylic acids 5 as starting materials. Because of the lack of
a general method for the synthesis of amino acids 5, herein we describe our
results for a facile synthesis and synthetic application of these compounds.
RESULTS AND DISCUSSION
It is known that the methylsulfonyl group in the second position of the
pyrimidine ring can be readily substituted by nucleophiles.[14] Moreover,
such substitution occurs easily and faster when compared to 2-chloro- and
2-(alkyl)mercaptopyrimidines, and this was successfully applied in the so-
called sulfinate catalysis.[15–17] Therefore, our approach was based on func-
tional group manipulations of existing pyrimidine derivatives (Scheme 2).
The starting 5-halogen-2-methylsulfonyl-pyrimidine-4-carboxylic acids 6a,b

2-Amino-5-halogenpyrimidine-4-carboxylic Acids
2233
Scheme 2.
were obtained by condensation of S-methylisothiourea with mucochloric (or
mucobromic) acid,[18,19] followed by oxidation of the methylmercapto
group[19,20] to give 6a,b in 75% overall yield. Treatment of 6a,b with
aliphatic amines in dimethylformamide at ambient temperature afforded the
amino acids 5a–l. Thus, the reaction occurs regioselectively with substitution
of the methylsulfonyl group, yielding desired products in synthetically useful
yields (Table 1). Gratifyingly, the procedure was scalable, and we were able to
conduct this reaction on a 25 mmol scale, generating 4.87 g (80% isolated
yield) of 5h. In spite of their simple structures, all synthesized compounds
5a–l are hitherto unknown representatives of 2-amino-5-halogen-pyrimidine-
4-carboxylic acids.[21]
The compounds 5a–l were fully characterized by their analytical and spec-
troscopic properties. Their 1H NMR spectra revealed signals of an amine moiety
along with a one-proton singlet at 8.42–8.48 ppm assigned to the proton at the
C-6 position of the pyrimidine ring. The location of an amine moiety at the C-2
position of the ring was uniquely confirmed by two-dimensional NMR exper-
iments, namely heteronuclear multiple bond correlation (HMBC) and hetero-
nuclear single quantum correlation (HSQC). The IR spectra of compounds
5a–l showed absorption bands at 1720–1700 cm21. This indicated that in the
solid state amino acids 5 presumably exist in their acid and not in the betaine
form. All substances 5a–l decomposed with release of a gas during melting-
point determination. The crystals formed after cooling did not dissolve in
NaHCO3 solution. Because pyrimidine-2- and 4-carboxylic acids are known
to undergo thermal decarboxylation,[14,19] we assumed that the acids 5 were
undergoing a decarboxylation. This decarboxylation was also observed under
heating in toluene with a catalytic amount of tripropylamine. This led to the
spectroscopically pure aminopyrimidines 7a–c in almost quantitative yields
(Scheme 2). Therefore the procedure described represents a new and simple
synthetic method of 2-amino-5-halogenpyrimidines, which were reported to
possess a variety of biological activities.[22–24]
The acids 5g,h were reacted with thionyl chloride in chloroform and
afforded acid chlorides 8a,b quantitatively. When compounds 8a,b were
treated with pyridine-2-yl-acetonotrile 9 in the presence of pyridine in dioxane,

2234
E. V. Blyumin, H. Neunhoeffer, and Y. V. Volovenko
Scheme 3.
Table 1. Substituents for compounds 4, 5, and 7a
Compound
NR1R2
5a, 7b
5b
5c
5d, 7b
5e
5f
5g, 7c, 8a, 4a
5h, I, 8b, 4b
5i
5j
5k
aHal ¼ Br for 5l; for other compounds Hal ¼ Cl.

2-Amino-5-halogenpyrimidine-4-carboxylic Acids
2235
the desired 2-[5-chloro-2-(amino)-4-pyrimidinyl]-2-oxo-1-(2-pyridyl)-ethyl
cyanides 4a,b were obtained as the only products in excellent yields (Scheme 3).
To test the generality of this approach, other 2-azahetarylacetonitriles
(e.g., 1-methyl-benzimidazol-2-yl-acetonitrile and benzothiazol-2-yl-
acetonitrile) were studied. In all cases, C-acylated derivatives of type 2
(Scheme 1) were obtained. Hence, this method represents an alternative
synthetic approach toward the earlier described 2-[5-chloro-2-(amino)-4-
pyrimidinyl]-2-oxo-1-(2-hetaryl)-ethyl cyanides.[11,12]
In conclusion, our investigation has successfully provided a general and
facile synthesis of substituted 2-amino-5-halogen-pyrimidine-4-carboxylic
acids that is amenable to the preparation of a variety of 2-amino-pyrimidine
derivatives. This study also established a new strategy for the synthesis
of cyanides 2 and represents the only method available for the preparation of
substituted 2-[5-chloro-2-(amino)-4-pyrimidinyl]-2-oxo-1-(2-pyridyl)-ethyl
cyanides 4. These reactions are also readily scaled, generating multigram quan-
tities of the 2-amino-pyrimidine derivatives, compounds that can be used as
synthetic building blocks and as scaffolds for combinatorial synthesis.
EXPERIMENTAL
Melting points were determined using an Electrothermal melting-point
apparatus and are uncorrected. IR spectra were obtained on a Nicolet
impact 400 spectrometer. 1H and 13C NMR spectra were recorded on a
Bruker AC-300 or Bruker Avance 500 spectrometer. MS were determined
on a Varian 212 instrument at 70 eV. Elemental analyses (C, H, N) were
conducted using the Perkin-Elmer CHN 240 A or 240 B.
General Procedure for Preparation of Substituted 2-Amino-
5-halogen-pyrimidine-4-carboxylic acids 5a–l
To a solution of the corresponding 2-methylsulfonyl-5-halogen-pyrimidine-4-
carboxylic acid 6a,b (5 mmol) in dimethylformamide (10 mL), an appropriate
amine (15 mmol) was added, and the mixture was stirred at room temperature
for 12 h. The solvent was then removed in vacuo (temperature of the water
bath did not to exceed 708C). The residue was dissolved in water (5–
10 mL), neutralized with 0.2 N HCl, and left overnight at 8–108C. The preci-
pitated crystals were collected by filtration and washed with cold water (2 mL)
to give usually pure compounds. For further purification (if necessary), the
acids were recrystallized from a water–ethanol (4 : 6) mixture.
Data
2-Benzylamino-5-chloropyrimidine-4-carboxylic acid 5a. Yield (75%).
1
Pale yellow crystals, mp 161–1628C (dec.). H NMR (500 MHz, DMSO-

2236
E. V. Blyumin, H. Neunhoeffer, and Y. V. Volovenko
d6): d ¼ 8.42 (1H, s, pyrim-H), 8.26 (1H, br. s, NH), 7.40–7.20 (5H, m, ArH),
4.62 (2H, d, J 6.26 Hz, -CH2-NH). (COOH proton was not observed, probably
due to exchange with water in DMSO-d6). 13C NMR (125 MHz, DMSO-d6):
d ¼ 164.5, 159.8, 158.0, 140.9, 127.8, 127.7, 126.6, 126.2, 112.0, 43.7. IR
nmax (KBr): 3290 (NH), 1710 (COOH) cm21
. Anal. calcd. for
C12H10ClN3O2: C, 54.66;H, 3.82; N, 15.94. Found: C, 54.83; H, 3.65; N,
15.80.
5-Chloro-2-(phenylethylamino)-pyrimidine-4-carboxylic acid 5b. Yield
1
(83%). Pale yellow crystals, mp 171.5–172.58C (dec.). H NMR (300 MHz,
DMSO-d6): d ¼ 9.96 (1H, br. s, COOH), 8.43 (1H, s, pyrim.-H), 7.83 (1H,
br. s, NH), 7.26 (5H, m, ArH), 3.46 (2H, m, CH2CH2-NH), 2.83 (2H, t,
J 7.2 Hz, CH2CH2-NH). 13C NMR (75 MHz, DMSO-d6): d ¼ 164.9, 160.1,
158.3, 157.1, 139.4, 128.7, 128.6, 126.0, 112.0, 42.5, 34.5. IR nmax (KBr):
3290 (NH), 1710 (COOH) cm21. Anal. calcd. for C13H12ClN3O2: C, 56.23;
H, 4.36; N, 15.13. Found: C, 56.02; H, 4.37; N, 14.98.
2-Butylamino-5-chloropyrimidine-4-carboxylic acid 5c. Yield (60%). Pale
1
yellow crystals, mp 110–111.58C (dec.). H NMR (300 MHz, DMSO-d6):
d ¼ 9.79 (1H, br. s, COOH), 8.44 (1H, s, pyrim.-H), 7.84 (1H, br. s, NH),
3.11 (2H, m, -CH2CH2-NH), 1.48 (2H, m, -CH2CH2), 1.27 (2H, m,
-CH2CH3), 0.87 (3H, t, J 7.2 Hz, CH3). 13C NMR (75 MHz, DMSO-d6):
d ¼ 165.1, 160.2, 158.4, 156.9, 111.6, 40.5, 30.6, 19.5, 13.6. IR nmax (KBr):
3280 (NH), 1710 (COOH) cm21. Anal. calcd. for C9H12ClN3O2: C, 47.07;
H, 5.27; N, 18.30. Found: C, 47.38; H, 5.59; N, 18.28.
5-Chloro-2-diethylaminopyrimidine-4-carboxylic acid 5d. Yield (76%).
1
Pale yellow crystals, mp 116–1178C (dec.). H NMR (300 MHz, acetone-
d6): d ¼ 10.05 (1H, br. s, COOH), 8.44 (1H, s, pyrim.-H), 3.65 (4H, q,
J 7.3 Hz, CH2CH3), 1.17 (6H, t, J 7.3 Hz, CH2CH3). 13C NMR (75 MHz,
acetone-d6): d ¼ 165.1, 158.1, 157.4, 156.5, 111.6, 40.5, 19.5. IR nmax
(KBr): 1710 (COOH) cm21. MS (EI): m/z (%): 229 (31) [Mþ], 214 (100),
200 (14), 183 (33), 168 (26), 154 (16), 140 (40), 128 (12), 56 (13). Anal.
calcd. for C9H12ClN3O2: C, 47.07; H, 5.27; N, 18.30. Found: C, 47.11; H,
5.27; N, 18.34.
5-Chloro-2-dipropylamino-pyrimidine-4-carboxylic acid 5e. Yield (62%),
mp 105–106.58C (dec.). 1H NMR (300 MHz, acetone-d6): d ¼ 10.09 (1H, br.
s, COOH), 8.42 (1H, s, pyrim.-H), 3.57 (4H, m, CH2-N-CH2), 1.65 (4H, m,
CH2CH3), 0.90 (6H, t, J 7.2 Hz, CH2CH3). IR nmax (KBr): 1710 (COOH)
cm21. Anal. calcd. for C11H16ClN3O2: C, 51.27; H, 6.26; N, 16.30. Found:
C, 51.41; H, 6.50; N, 16.44.
5-Chloro-2-(pyrrolidin-1-yl)-pyrimidine-4-carboxylic acid 5f. Yield
1
(78%). Pale yellow crystals, mp 160–1618C (dec.). H NMR (300 MHz,
DMSO-d6): d ¼ 13.12 (1H, br. s, COOH), 8.47 (1H, s, pyrim.-H), 3.45 (4H,
m, CH2-N-CH2), 1.92 (4H, m, -CH2CH2-). 13C NMR (75 MHz, DMSO-d6):

2-Amino-5-halogenpyrimidine-4-carboxylic Acids
2237
d ¼ 165.1, 158.1, 157.6, 156.7, 111.5, 46.6, 24.9. IR nmax (KBr): 1710
(COOH) cm21. Anal. calcd. for C9H10ClN3O2: C, 47.48; H, 4.43; N, 18.46.
Found: C, 47.67; H, 4.12; N, 18.50.
5-Chloro-2-(piperidin-1-yl)-pyrimidine-4-carboxylic acid 5g. Yield (78%).
Pale yellow crystals, mp 127.5–128.58C (dec.). 1H NMR (500 MHz,
DMSO-d6): d ¼ 14.10 (1H, br. s, COOH), 8.48 (1H, s, pyrim.-H), 3.71
(4H, m, CH2-N-CH2), 1.63 (4H, m, 2CH2), 1.52 (2H, m, CH2). 13C
NMR (125 MHz, DMSO-d6): d ¼ 165.0, 158.8, 158.4, 156.5, 111.6, 44.5,
25.1, 24.0. IR nmax (KBr): 1710 (COOH) cm21. Anal. calcd. for
C10H12ClN3O2: C, 49.70; H, 5.00; N, 17.39. Found: C, 49.79; H, 4.90;
N, 17.39.
5-Chloro-2-(morpholin-4-yl)-pyrimidine-4-carboxylic acid 5h. Yield
1
(77%). Pale yellow crystals, mp 119.5–120.58C (dec.). H NMR (300 MHz,
DMSO-d6): d ¼ 13.70 (1H, br. s, COOH), 8.48 (1H, s, pyrim.-H), 3.67 (8H,
m, morph.-H). (COOH proton was not observed, probably due to exchange
with water in acetone-d6). 13C NMR (75 MHz, DMSO-d6): d ¼ 164.9,
158.9, 158.5, 156.5, 112.7, 65.7, 43.9. IR nmax (KBr): 1705 (COOH) cm21
.
Anal. calcd. for C9H10ClN3O3: C, 44.37; H, 4.14; N, 17.25. Found: C,
44.30; H, 4.26; N, 16.99.
2-(4-Carbamoylpiperidin-1-yl)-5-chloropyrimidine-4-carboxylic acid 5i.
Yield (84%). Pale yellow crystals, mp 121.5–122.58C (dec.). 1H NMR
(300 MHz, DMSO-d6): d ¼ 13.90 (1H, br. s, COOH), 8.45 (1H, s, pyrim.
-H), 7.30 (1H, s, CONH), 6.82 (1H, s, CONH), 4.54 (1H, m, piper.-H), 2.93
(2H, m, piper.-H), 2.39 (2H, m, piper.-H), 1.80 (2H, m, piper.-H), 1.44 (2H,
m, piper.-H). 13C NMR (75 MHz, DMSO-d6): d ¼ 175.9, 165.0, 158.8, 158.
5, 156.6, 111.9, 44.3, 41.4, 27.9. IR nmax (KBr): 1715 (COOH) cm21. Anal.
calcd. for C11H13ClN4O3: C, 46.41; H, 4.60; N, 19.68. Found: C, 46.59; H,
4.76; N, 19.70.
5-Chloro-2-(4-benzylpiperidin-1-yl)-pyrimidine-4-carboxylic acid 5j.
Yield (54%). Pale yellow crystals, mp 111–1128C (dec.). 1H NMR
(100 MHz, acetone-d6): d ¼ 8.43 (1H, s, pyrim.-H), 7.34–7.1 (5H, m,
ArH), 5.20 (2H, m, CH2Ph), 4.63 (2H, m, piper.-H), 2.90 (2H, m, piper.-H),
2.56 (2H, m, piper.-H), 1.77 (2H, m, piper.-H), 1.27 (1H, m, piper.-H).
(COOH proton was not observed, probably due to exchange with water in
acetone-d6). IR nmax (KBr): 1720 (COOH) cm21. Anal. calcd. for
C17H18ClN3O2: C, 61.54; H, 5.47; N, 12.66. Found: C, 61.55; H, 5.21; N,
12.72.
2-(1-Azepanyl)-5-chloropyrimidine-4-carboxylic acid 5k. Yield (64%).
Pale yellow crystals, mp 133.5–134.58C (dec.). 1H NMR (100 MHz,
acetone-d6): d ¼ 8.44 (1H, s, pyrim.-H), 3.85–3.7 (4H, m, CH2-N-CH2),
1.90–1.45 (8H, m, -(CH2)4-). (COOH proton was not observed, probably
due to exchange with water in acetone-d6). IR nmax (KBr): 1715 (COOH)

2238
E. V. Blyumin, H. Neunhoeffer, and Y. V. Volovenko
cm21. Anal. calcd. for C11H14ClN3O2: C, 51.67; H, 5.52; N, 16.43. Found: C,
51.54; H, 5.41; N, 16.12.
5-Bromo-2-(morpholin-4-yl)-pyrimidine-4-carboxylic acid 5l. Yield
1
(76%). Pale yellow crystals, mp 131.5–132.58C (dec.). H NMR (100 MHz,
acetone-d6): d ¼ 8.56 (1H, s, pyrim.-H), 3.74 (8H, m, morph.-H). (COOH
proton was not observed, probably due to exchange with water in acetone-
d6). 13C NMR (75 MHz, DMSO-d6): d ¼ 164.9, 158.9, 158.5, 156.5, 112.7,
65.7, 43.9. IR nmax (KBr): 1705 (COOH) cm21. Anal. calcd. for
C9H10BrN3O3: C, 37.52; H, 3.50; N, 14.59. Found.: C, 37.39; H, 3.34; N,
14.55.
Decarboxylation of Acids 6: General Procedure for Preparation of
2-Amino-5-chloropyrimidines 7a–c
To solution of corresponding 2-amino-5-chloro-pyrimidine-4-carboxylic acid
5 (2 mmol) in toluene (10 mL), tripropylamin (0.1 mL) was added. The
mixture was refluxed for 30 min. After solvent evaporation, the product was
obtained as a yellowish solid, which as shown by NMR and TLC, does not
require further purification.
Data
1
Benzylamino-5-chloropyrimidine 7a. Yield (99%), mp 1098C. H NMR
(300 MHz, DMSO-d6): d ¼ 8.36 (2H, s, pyrim.-H), 7.41-7.23 (5H, m,
ArH), 6.70 (1H, d, J 6.2 Hz, NH), 4.62 (2H, d, J 6.2 Hz, -CH2-NH). Anal.
calcd. for C11H10ClN3: C, 60.14; H, 4.59; N, 19.13. Found: C, 60.27; H,
4.55; N, 18.97.
5-Chloro-2-diethylaminopyrimidine 7b. Yield (99%). Yellowish crystals,
1
mp 868C. H NMR (300 MHz, DMSO-d6): d ¼ 8.37 (2H, s, pyrim.-H), 3.65
(4H, q, J 7.3 Hz, CH2CH3), 1.17 (6H, t, J 7.3 Hz, CH2CH3). Anal. calcd. for
C8H12ClN3: C, 51.76; H, 6.52; N, 22.63. Found: C, 51.85; H, 6.79; N, 22.69.
5-Chloro-2-(piperidin-1-yl)-pyrimidine 7c. Yield (99%). Yellowish
crystals, mp 968C. 1H NMR (500 MHz, DMSO-d6): d ¼ 8.36 (2H, s,
pyrim.-H), 3.70 (4H, m, CH2-N-CH2), 1.63–1.49 [6H, 2 m, -(CH2)3-). 13C
NMR (125 MHz, DMSO-d6): d ¼ 159.8, 156.2, 117.0, 44.8, 25.5, 24.5. MS
(EI) m/z (%): 197 (Mþ) (100), 182 (49), 168 (73), 154 (44), 142 (25), 114
(32), 84 (19). Anal. calcd. for C8H12 ClN3: C, 54.69; H, 6.12; N, 21.26.
Found: C, 54.75; H, 6.12; N, 21.41.
5-Chloro-2-(piperidin-1-yl)-pyrimidine-4-carboxylic acid chloride 8a. To
a suspension of 5-chloro-2-(piperidin-1-yl)-pyrimidine-4-carboxylic acid

2-Amino-5-halogenpyrimidine-4-carboxylic Acids
2239
(5g) (2.41 g, 10 mmol) in benzene (20 mL), thionylchloride (2.38 g, 20 mmol)
was added, and the mixture was refluxed for 2 h. After solvent evaporation, the
product was obtained as a yellow solid, which was used in further transform-
ations without purification. Yield 2.57 g (99%), mp 94–958C. 1H NMR
(100 MHz, CDCl3): d ¼ 8.42 (1H, s, pyrim.-H), 3.87–3.73 (4H, m, CH2-N-
CH2), 1.75–1.45 [6H, m, -(CH2)3-].
5-Chloro-2-(morpholin-4-yl)-pyrimidine-4-carboxylic acid chloride 8b.
According to the procedure for 8a, compound 8b was obtained as a yellow
1
solid. Yield (100%), mp 97–988C. H NMR (100 MHz, CDCl3): d ¼ 8.43
(1H, s, pyrim.-H), 3.80 (8H, m, morph.-H).
2-[5-Chloro-2-(piperidin-1-yl)-pyrimidin-4-yl]-2-oxo-1-(pyridin-2-yl)-
propio-nitrile 4a. To a solution of pyridin-2-yl-acetonitrile 9 (240 mg,
2 mmol) and pyridine (2.2 mmol, 0.180 mL) in anhydrous dioxane (20 mL),
8a (0.52 g, 2 mmol) was added. The reaction mixture was heated to 80–
908C for 1.5 h. After cooling, the solvent was removed in vacuo, and the
residue was treated with water, filtered, dried, and recrystallized from
1
dioxane to yield 0.65 g (95%) of 4a as a yellow solid, mp 232–2338C. H
NMR (100 MHz, DMSO-d6): d ¼ 15.4 (1H, br. s, chelat.-H), 8.52 (1H, s,
pyrim.-H), 8.49 (1H, br. t, a-pyridine-H), 8.25 (1H, ddd, J 8.8, 7.4, 1.5 Hz,
g-pyridine-H), 7.46 (1H, d, J 8.8 Hz, pyridine-H), 7.43 (1H, dd, J 7.4,
5.6 Hz, pyridine-H), 3.77-3.69 (4H, m, CH2-N-CH2), 1.75–1.45 [6H, m,
-(CH2)3-]. IR nmax (KBr): 2195 (CN) cm21. Anal. calcd. for C17H16ClN5O:
C, 59.74; H, 4.72; N, 20.49. Found: C, 59.71; H, 4.97; N, 20.61.
2-[5-Chloro-2-(morpholin-4-yl)-pyrimidin-4-yl]-2-oxo-1-(pyridin-2-yl)-
propio-nitrile 4b. According to the procedure for 4a, compound 4b was
obtained as a yellow solid. Yield (84%), mp 247–2488C. 1H NMR
(100 MHz, DMSO-d6): d ¼ 15.40 (1H, br. s, chelat.-H), 8.53 (1H, s, pyrim.
-H), 8.49 (1H, br. t, a-pyridine-H), 8.25 (1H, ddd, J 8.8, 7.4, 1.5 Hz,
g-pyridine-H), 7.46 (1H, d, J 8.8 Hz, pyridine-H), 7.43 (1H, dd, J 7.4, 5.
6 Hz, pyridine-H), 3.69 (8H, m, morph.-CH2). IR nmax (KBr): 2195 (CN)
cm21. MS (EI) m/z (%): 343 (Mþ) (98), 308 (100), 285 (76), 250 (16), 197
(14), 145 (55), 117 (21), 90 (16). Anal. calcd. for C16H14ClN5O2: C, 55.90;
H, 4.10; N, 20.37. Found: C, 55.93; H, 4.15; N, 20.21.
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