Acetic acid mediated coupling of 2-aminonicotinamides with ortho esters: A convenient, scalable synthesis of 2,3-substituted pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1055/s-2007-990878

Substituted pyrido[2,3-d]pyrimidines are synthesized in good to excellent yields by treatment of various 2-aminonicotinamides with triethyl orthopropionate or triethyl orthoacetate in the presence of acetic acid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990878

3678
PAPER
Acetic Acid Mediated Coupling of 2-Aminonicotinamides with Ortho Esters:
A Convenient, Scalable Synthesis of 2,3-Substituted Pyrido[2,3-d]pyrimidines
Synthesis
o
of 2,3-Substi
h
tuted
P
yrido
a
[2,3-
d
]
pyrim
n
idine
s
n Chan,*a Darin Gustin,b Evan Divirgilio,a Anil Guram,a Margaret M. Faula
a
Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
E-mail: johannc@amgen.com
b
Amgen San Francisco, 1020 Veterans Blvd., South San Francisco, CA 94080, USA
Received 29 May 2007; revised 30 August 2007
O
N
Abstract: Substituted pyrido[2,3-d]pyrimidines are synthesized in
good to excellent yields by treatment of various 2-aminonicotin-
amides with triethyl orthopropionate or triethyl orthoacetate in the
presence of acetic acid.
R2
aza-Wittig
O
N
O
N
O
P(R1)3
R2
R1
R2
N
Key words: pyrido[2,3-d]pyrimidines,
2-aminonicotinamides,
N
OH
NH2
X = N, C
acetic acid, oxazin-4-one
X
N
N
R1
O
O
N
The development of methodology for synthesis of hetero-
cycles is an important area of interest, as their structures
form the basis of many pharmaceutically active products.
In particular, quinazolinones draw significant attention
due to their vast array of biological activities ranging from
anticonvulsants to antihypertensives.1 While a significant
number of papers have been published describing differ-
ent approaches to quinazolinones,2 the pyrido[2,3-d]pyri-
midines have attracted far less attention. Nevertheless, the
synthesis of this heterocycle poses a significant challenge.
In analyzing methods toward quinazolinone synthesis, a
common approach involves the functionalization of an-
thralinic acids. However, application of quinazolinone
synthesis methodology using 2-aminonicotinic acids in
place of anthralinic acids is generally unsuccessful. Di-
minished reactivity is observed with 2-aminonicotinic
acids since the amidine moiety tends to exhibit low
nucleophilicity towards a variety of electrophiles. To ad-
dress this inherent reactivity issue, we have recently em-
ployed the aza-Wittig reaction3 to the synthesis of
pyrido[2,3-d]pyrimidines (Figure 1).4,5 While iminophos-
phoranes6 may exhibit greater reactivity, they are also
moisture-sensitive and generally can not be isolated in
large amounts without risk of decomposition.
N
R1
oxazin-4-one
Figure 1 Common approaches to pyrido[2,3-d]pyrimidines
As part of our program targeting biologically active N-
containing heterocycles, we required an efficient synthe-
sis of 2,3-substituted pyrido[2,3-d]pyrimidines. Attempts
at utilizing conventional methods afforded low yields and
required difficult purification procedures in order to reject
unwanted side products. Hence, we were required to de-
velop a synthesis of pyrido[2,3-d]pyrimidines that cir-
cumvents issues of scale and yield.
Our approach began with investigating pyrido[2,3-d]pyri-
midine formation by direct reactions with 2-aminonico-
tinamides. While isolated examples of the reaction between
2-aminonicotinamide itself and triethylorthoformate can
be found in the literature,9 to the best of our knowledge,
there are no reports of N-substituted 2-aminonicotin-
amides participating with orthoacetates or orthopropi-
onates to directly afford the corresponding 2,3-substituted
pyrido[2,3-d]pyrimidines. Herein we present our efforts
toward a generalized method to this class of compound.
A second approach to the pyrido[2,3-d]pyrimidines in-
volves the reaction of oxazin-4-ones with amines under
dehydrating conditions (Figure 1).7 However, the genera-
tion of oxazin-4-ones tend to be low-yielding owing to the
poor reactivity of 2-aminonicotinic acids. In addition,
when these reactions are conducted on a larger scale, we
have found that oxazin-4-ones are prone to hydrolysis.8
Consequently, there appears to be a lack of reliable, high-
yielding methods that generate pyrido[2,3-d]pyrimidines
on scale.
Based on an initial lead utilizing PPTS (pyidinium p-tolu-
enesulfonate), we screened different acids and were
pleased to find that the treatment of 2-aminonicotin-
amides with triethyl orthopropionate and acetic acid af-
forded the desired compound in 97% yield (Table 1).
Using 2-amino-N-(4-iodophenyl)nicotinamide (1) as our
test substrate, we found that acetic acid effected the trans-
formation, yielding full conversion into the desired com-
pound 2. Further optimization of reaction stoichiometries
led to lowering of the number of equivalents of acetic acid
and triethyl orthopropionate (Table 2).
SYNTHESIS 2007, No. 23, pp 3678–3682
x
x.
x
x
.
2
0
0
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Advanced online publication: 13.11.2007
DOI: 10.1055/s-2007-990878; Art ID: M03607SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2,3-Substituted Pyrido[2,3-d]pyrimidines
3679
With regard to reaction scope, aromatic groups are well
tolerated affording pyrido[2,3-d]pyrimidines in moderate
to excellent yields. N-Ortho substitutions are also compat-
ible, providing desired pyrido[2,3-d]pyrimidines in good
yield (entries 4 and 7). Alkyl substituents on the amide do
not make good substrates. For example, cyclization of the
nicotinamide derived from n-hexylamine affords a mix-
ture of starting material, a product resulting from coupling
of triethyl orthopropionate to the amidine of the nicotin-
amide, and approximately 20% of the desired cyclized
product.10 Interestingly, nicotinamides derived from cy-
clopropylamine (entry 7) participate well in the reaction
suggesting that even substituents with poor p-character
will undergo the reaction. Substituents on the pyridine
ring (entries 5, 11, 12) required more forcing conditions.
To test the scalability of the method, a reaction with amide
1 was conducted on a 950 g scale. An excellent yield of
92% (980 g) of the desired pyrido[2,3-d]pyrimidine (2)
(entry 2) was obtained in this scaled-up reaction.
Table 1 Influence of Different Acids in Pyrido[2,3-d]pyrimidine
Formation
I
I
O
O
acid
N
N
H
60 °C
N
NH2
N
N
1
2
Entry Solvent/Reagent
Acid
PPTS
H2SO4
AcOH
HCl
TFA
–
Yield (%)
1
2
3
4
5
6
7c
triethyl orthopropionate
triethyl orthopropionate
40a
<5
97b
<5
72b
–
triethyl orthopropionate
triethyl orthopropionate
triethyl orthopropionate
propionyl chloride
triethyl orthopropionate
–
–
Pyrido[2,3-d]pyrimidines can be elaborated as shown in
Scheme 1. Palladium-catalyzed cyanation of 2 afforded
benzonitrile 3 in 97% yield.11 Utilizing 1% Cl2Pd[P(Ph)(t-
Bu)2]2, our recently developed catalyst,12 4-cyanoboronic
acid was also successfully cross-coupled to afford biaryl
4 in 96% yield. Finally, halogenation at the 2-ethyl posi-
tion with NCS generated the secondary chloride 5 and
opens the possibility to eliminate to the olefin or conduct
nucleophilic displacements to further build molecular
complexity.
a Isolated yield.
b HPLC assay yield.
c Control experiment.
Table 2 Acetic Acid Mediated Synthesis of 2,3-Substituted Pyri-
do[2,3-d]pyrimidines
O
O
EtC(OEt)3
(9 equiv)
R1
R1
N
N
H
CN
AcOH (2 equiv)
60 °C
R3
Pd2(dba)3, dppf
O
R2
R2
N
N
N
NH2
Zn(CN)2, DMF
115 °C, 97%
N
Me
Entry
1
R1
R2
H
R3
Yield (%)
83a
92b
95
N
N
3
4-IC6H4
4-IC6H4
H
I
functionalize
O
N
2
H
Me
Me
Me
Me
Me
Me
Me
H
NCS, AcOH
40 °C, 97%
N
3
2-MeSC6H4
2-MeOC6H4
4-FC6H4
H
N
functionalize
4
H
74
2
H
I
Ar
O
N
O
N
5
Cl
H
71
N
6
2-naphthyl
c-Pr
77
Me
N
N
N
7
H
60
5
4
Cl
Cl2Pd[P(Ph)(t-Bu)2]2 (1 mol%)
4-cyanoboronic acid
dioxane–H2O (4:1)
K3PO4, 100 °C
8
2-MeC6H4
3,5-Me2C6H4
3,5-Me2C6H4
4-NCC6H4
4-NCC6H4
H
79
Ar = 4-NCC6H4
9
H
76a
86
96%
10
11
12
13
H
Me
Me
Me
Me
Scheme 1 Elaboration of 2,3-substituted pyrido[2,3-d]pyrimidines
Me
OMe
57c
95
In conclusion, we have developed a synthesis of 2,3-sub-
stituted pyrido[2,3-d]pyrimidines starting from 2-amino-
nicotinamides under mildly acidic conditions. We have
demonstrated that the reaction can be run reliably on a
large scale and products of the reaction can be elaborated
to different functionalized pyrido[2,3-d]pyrimidines in
excellent yields.
4-CF3CH2OC6H4
H
69
a Triethyl orthoacetate was used in place of triethyl orthopropionate.
b Reaction conducted on 950 g scale.
c Reaction conducted at 100 °C.
Synthesis 2007, No. 23, 3678–3682 © Thieme Stuttgart · New York

3680
J. Chan et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 8.98 (dd, J = 2.2, 4.7 Hz, 1 H),
8.59 (dd, J = 2.1, 7.8 Hz, 1 H), 7.50 (dt, J = 1.8, 8.2 Hz, 1 H), 7.40
(dd, J = 4.5, 7.8 Hz, 1 H), 7.21 (dd, J = 1.8, 7.8 Hz, 1 H), 7.12 (m,
2 H), 3.79 (s, 3 H), 2.47 (m, 2 H), 1.30 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 161.4, 161.2, 157.1, 155.8,
154.0, 135.8, 130.8, 129.5, 124.7, 122.1, 120.8, 115.2, 112.3, 55.6,
28.0, 10.1.
NMR spectra were recorded at 400 MHz for 1H and 100 MHz for
13C NMR. Chemical shifts are reported in d (ppm) referenced to
CHCl3, DMSO, or DMF. All starting materials necessary for the
preparation of 2,3-disubstituted pyrido[2,3-d]pyrimidines were de-
rived from EDC coupling of the respective amines with 2-amino-
nicotinic acids. Cl2Pd[P(t-Bu)2Ph]2 was prepared according to a
literature procedure.12
EI: m/z calcd for C16H15N3O2: 281.11643; found [M + H]:
282.12406.
Pyrido[2,3-d]pyrimidines; General Procedure
To a solution or slurry of the 2-aminonicotinamide (1; 5.0 mmol) in
triethyl orthopropionate (45 mmol, 9 mL) [or triethyl orthoacetate
(7.75 mL, 45 mmol) for Table 2, entries 1 and 9] was added glacial
AcOH (10 mmol, 0.55 mL). The mixture was heated to 60 °C for 4
h at which time the HPLC analysis revealed full consumption of
starting material. Two different workups were employed.
7-Chloro-2-ethyl-3-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-
4(3H)-one (Table 1, Entry 5)
Conducted on a 2.9 mmol scale. Workup A. Silica gel chromatog-
raphy using CH2Cl2–acetone (98:2 → 4:1); yield: 630 mg (71%).
IR (film): 2090, 3010, 1683, 1603, 1579, 1593, 1557, 1507, 1424,
Workup A: The mixture was diluted with aq 1 M HCl (5 mL) and
stirred for 5 min. The solution was made basic by the addition of
concd NH4OH and extracted with CH2Cl2 (3 × 50 mL). The organic
layers were combined, dried (MgSO4), filtered, and concentrated in
vacuo. Silica gel chromatography of the crude material (hexanes–
EtOAc, 30:70) afforded the desired pyrido[2,3-d]pyrimidines
(Table 2).
1368 1259, 1211 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.47 (d, J = 8.3 Hz, 1 H), 7.41 (d,
J = 8.3 Hz, 1 H), 7.30–7.23 (m, 4 H), 2.48 (q, J = 7.3 Hz, 2 H), 1.29
(t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 163.9, 162.5 (d, J = 147 Hz),
157.6, 157.5, 138.9 (d, J = 4.5 Hz), 132.1, 129.8 (d, J = 8.7 Hz),
123.2, 117.4, 117.2, 114.4, 29.7, 10.6.
Workup B: The mixture was diluted with hexanes (50 mL) and fil-
tered to afford the desired pyrido[2,3-d]pyrimidines (Table 2).
EI: m/z calcd for C15H11ClFN3O: 303.0653; found [M + H]:
304.0655.
3-(4-Iodophenyl)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one
(Table 1, Entry 1)
2-Ethyl-3-(naphthalene-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(Table 1, Entry 6)
Workup B; yield: 1.15 g (77%).
Workup B. Silica gel chromatography of the sticky solid (hexanes–
EtOAc, 30:70 → 100 EtOAc) afforded the title compound; yield:
1.51 g (83%).
IR (neat): 3058, 2984, 2934, 1690, 1585, 1431, 1368, 1248, 797
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.0 (s, 1 H), 8.52 (d, J = 7.4
Hz, 1 H), 8.07 (m, 4 H), 7.60 (m, 4 H), 2.43 (m, 2 H), 1.16 (t, J = 6.9
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.2, 161.3, 157.3, 156.0, 136.0,
134.5, 133.1, 132.7, 129.4, 128.1, 127.8, 127.4, 127.2, 126.9, 126.2,
122.3, 115.7, 29.1, 10.5.
IR (neat): 3063, 2982, 1681, 1593, 1566, 1431, 1274, 1003, 788
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.98 (dd, J = 1.8, 4.5 Hz, 1 H),
8.48 (d, J = 7.8 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 2 H), 7.54 (dd,
J = 4.7, 7.9 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 2 H), 2.18 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 161.7, 157.6, 157.2, 156.0,
138.4, 137.2, 135.9, 130.6, 122.1, 115.5, 95.7, 24.3.
EI: m/z calcd for C14H10IN3O: 362.9869; found [M + H]: 363.9952.
EI: m/z calcd for C19H15N3O: 301.12151; found [M + H]:
302.12879.
2-Ethyl-3-[3-(methylthio)phenyl]pyrido[2,3-d]pyrimidin-
4(3H)-one (Table 1, Entry 3)
Workup B; yield: 1.42 g (95%).
3-Cyclopropyl-2-ethylpyrido[2,3-d]pyrimidin-4(3H)-one
(Table 1, Entry 7)
IR (neat): 3059, 2984, 2933, 1690, 1573, 1562, 1432, 1247, 801,
705 cm–1.
1H NMR (400 MHz, DMF-d7): d = 9.04 (dd, J = 2.2, 4.7 Hz, 1 H),
8.55 (dd, J = 1.9, 7.8 Hz, 1 H), 7.59 (m, 3 H), 7.49 (d, J = 8.0 Hz, 1
H), 7.35 (d, J = 7.7 Hz, 1 H), 2.59 (s, 3 H), 2.50 (m, 2 H), 1.23 (t,
J = 7.3 Hz, 1 H).
13C NMR (100 MHz, DMF-d7): d = 163.1, 162.2, 158.6, 156.8,
141.6, 139.2, 136.7, 130.8, 127.3, 126.6, 125.8, 123.0, 116.8, 29.2,
15.1, 10.9
Reaction conducted on a 2.8 mmol scale. Workup B. Silica gel chro-
matography of the crude material (hexanes–EtOAc, 50:50 → 100
EtOAc); yield: 0.39 g (60%).
IR (neat): 3066, 2975, 2997, 2921, 1681, 1586, 1566, 1429, 1037,
808, 701 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.91 (dd, J = 1.9, 4.5 Hz, 1 H),
8.52 (dd, J = 1.9, 7.8 Hz, 1 H), 7.35 (dd, J = 4.5, 8.1 Hz, 1 H), 3.11
(q, J = 7.3 Hz, 2 H), 2.94 (m, 1 H), 1.46 (t, J = 7.3 Hz, 3 H), 1.34 (q,
J = 7.2 Hz, 2 H), 0.92 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 163.8, 162.6, 156.7, 155.4, 135.7,
121.8, 115.6, 27.6, 26.7, 10.6, 9.8.
EI: m/z calcd for C16H15N3OS: 297.09358; found [M + H]:
298.10086.
EI: m/z calcd for C12H13N3O: 215.10586; found [M + H]:
216.11322.
2-Ethyl-3-(2-methoxyphenyl)pyrido[2,3-d]pyrimidin-4(3H)-
one (Table 1, Entry 4)
Workup A. Silica gel chromatography of the crude material (hex-
anes–EtOAc, 30:70) afforded the title compound; yield: 1.07 g
(76%).
2-Ethyl-3-(o-tolyl)pyrido[2,3-d]pyrimidin-4(3H)-one (Table 1,
Entry 8)
Work-up A. Silica gel chromatography (hexanes–EtOAc, 30:70 →
100 EtOAc); yield: 1.05 g (79%).
IR (neat): 2977, 2942, 2844, 1682, 1583, 1496, 1431, 1241, 1023,
790 cm–1.
IR (neat): 3057, 2982, 2939, 1681, 1589, 1578, 1432, 1368, 1252,
903, 794 cm–1.
Synthesis 2007, No. 23, 3678–3682 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,3-Substituted Pyrido[2,3-d]pyrimidines
3681
1H NMR (400 MHz, CDCl3): d = 9.00 (dd, J = 2.3, 4.7 Hz, 1 H),
8.60 (dd, J = 1.9, 7.8 Hz, 1 H), 7.41 (m, 4 H), 7.15 (d, J = 7.4 Hz, 1
H), 2.40 (m, 2 H), 2.10 (s, 3 H), 1.30 (t, J = 7.4 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.36 (d, J = 8.6 Hz, 1 H), 7.88 (d,
J = 8.4 Hz, 2 H), 7.42 (d, J = 8.4 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 1
H), 4.10 (s, 3 H), 2.48 (q, J = 7.4 Hz, 2 H), 1.24 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.1, 161.9, 157.8, 156.2, 136.8,
135.8, 135.4, 131.7, 129.9, 128.0, 127.7, 122.2, 115.9, 29.2, 17.4,
10.7.
13C NMR (100 MHz, CDCl3): d = 168.2, 161.7, 161.0, 157.6, 140.9,
138.0, 133.6, 129.5, 117.4, 113.7, 112.4, 109.6, 54.4, 29.5, 11.4.
EI: m/z calcd for C17H14N4O2: 306.1117; found: 307.1199.
EI: m/z calcd for C16H15N3O: 265.12151; found [M + H]:
266.12870.
2-Ethyl-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrim-
idin-4(3H)-one (Table 1, Entry 13)
2-Methyl-3-(3,5-dimethylphenyl)pyrido[2,3-d]pyrimidin-
4(3H)-one (Table 1, Entry 9)
Workup A. Silica gel chromatography (hexanes–EtOAc, 30:70 →
100 EtOAc) afforded the title compound; yield: 1.07 g (76%).
Workup A. Silica gel chromatography (hexanes–EtOAc, 30:70 →
100 EtOAc) afforded the title compound; yield: 1.0 g (76%).
IR (neat): 3066, 2988, 2942, 1681, 1587, 1509, 1433, 1237, 1157,
1070, 966, 793, 656 cm–1.
IR (neat): 3065, 2997, 2921, 1683, 1586, 1566, 1427, 1039, 809,
701 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.97 (dd, J = 1.7, 4.5 Hz, 1 H),
8.48 (dd, J = 1.8, 7.8 Hz, 1 H), 7.54 (dd, J = 4.5, 7.9 Hz, 1 H), 7.16
(s, 1 H), 7.07 (s, 2 H), 2.34 (s, 6 H), 2.20 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 161.8, 158.0, 157.2, 155.9,
138.9, 137.2, 135.9, 130.4, 125.6, 122.1, 115.3, 24.2, 20.7.
1H NMR (400 MHz, CDCl3): d = 8.92 (dd, J = 1.9, 4.5 Hz, 1 H),
8.51 (dd, J = 2.0, 7.8 Hz, 1 H), 7.35 (dd, J = 4.5, 7.8 Hz, 1 H), 7.15
(d, J = 8.8 Hz, 2 H), 7.06 (d, J = 8.8 Hz, 2 H), 4.36 (q, J = 8.0 Hz,
2 H), 2.43 (q, J = 7.3 Hz, 2 H), 1.23 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.9, 161.8, 157.9, 157.6, 156.3,
136.7, 130.9, 129.6, 122.2, 116.3, 65.8 (q, J = 36.2 Hz), 29.7, 10.9.
EI: m/z calcd for C17H14F3N3O2: 349.30717; found [M + H]:
EI: m/z calcd for C16H15N3O: 265.12151; found [M + H]:
350.11146.
266.12879.
Large Scale Preparation of 2-Ethyl-3-(4-iodophenyl)pyri-
do[2,3-d]pyrimidin-4(3H)-one (2)
2-Ethyl-3-(3,5-dimethylphenyl)pyrido[2,3-d]pyrimidin-4(3H)-
one (Table 1, Entry 10)
Workup A. Silica gel chromatography (hexanes–EtOAc, 30:70 →
100 EtOAc) afforded the title compound; 1.2 g (86%).
A 20 L reactor was charged with 2-amino-N-(4-iodophenyl)nicotin-
amide (1; 950 g, 2.8 mol) under N2. Triethyl orthopropionate (5.0 L,
25.2 mol) was added and the stirring was commenced (no exotherm
observed). AcOH (320 mL, 5.6 mol) was added and the mixture was
heated to 60 °C for 3.5 h. The HPLC analysis at this time revealed
full conversion to the desired product. The mixture was cooled to
20 °C, charged slowly with heptanes (8.0 L), and stirred for an ad-
ditional 15 min before filtering through a sintered glass funnel (po-
rosity D). The filter cake was washed with heptanes (6.0 L) and air
dried (2–3 h). The filter cake was transferred to a vacuum oven and
dried (40 °C/2 Torr, 12 h) to afford 2; yield: 980 g (92%).
IR (neat): 3074, 2935, 2831, 1681, 1584, 1565, 1431, 1273, 1026,
801, 710 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.98 (d, J = 2.7 Hz, 1 H), 8.48
(d, J = 3.5 Hz, 1 H), 7.54 (dd, J = 4.5, 7.6 Hz, 1 H), 7.16 (s, 1 H),
7.06 (s, 2 H), 2.40 (q, J = 7.3 Hz, 2 H), 2.34 (s, 6 H), 1.15 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 161.9, 161.2, 157.1, 155.8,
138.9, 136.7, 135.9, 130.4, 125.8, 122.1, 155.5, 28.8, 20.6, 10.4.
IR (neat): 3060, 2982, 2936, 2873, 1682, 1590, 1566, 1431, 1271,
1115, 1008, 797, 707 cm–1.
EI: m/z calcd for C17H17N3O: 279.13716; found [M + H]:
1H NMR (400 MHz, DMSO-d6): d = 8.98 (dd, J = 2.1, 4.5 Hz, 1 H),
8.48 (dd, J = 2.0, 7.8 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 2 H), 7.55 (dd,
J = 4.5, 7.9 Hz, 1 H), 7.30 (d, J = 8.5 Hz, 2 H), 2.37 (q, J = 7.2 Hz,
2 H), 1.15 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 161.9, 160.8, 157.2, 155.9,
138.5, 136.8, 135.9, 130.9, 122.2, 115.6, 95.8, 29.0, 10.4.
280.14444.
4-(2-Ethyl-7-methyl-4-oxopyrido[2,3-d]pyrimidin-3(4H)-
yl)benzonitrile (Table 1, Entry 11)
Reaction conducted at 100 °C on a 27 mmol scale. Workup A. Sil-
ica gel chromatography using CH2Cl2–acetone (98:2 → 4:1) afford-
ed the title compound; 4.5 g (57%).
EI: m/z calcd for C15H12IN3O: 377.00251; found [M + H]:
378.01106.
IR (film): 3010 (br), 1701, 1681, 1592, 1567, 1503, 1411, 1373,
1270 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.43 (d, J = 8.04 Hz, 1 H), 7.88
(d, J = 8.4 Hz, 2 H), 7.42 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.04 Hz,
1 H), 2.75 (s, 3 H), 2.42 (q, J = 7.3 Hz, 2 H), 1.30 (t, J = 7.3 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 166.8, 162.1, 160.1, 157.0, 140.8,
136.2, 133.7, 129.5, 122.6; 117.4, 113.7, 112.9, 29.5, 25.3, 10.6.
Elaboration of Pyrido[2,3-d]pyrimidines
4-(2-Ethyl-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl)benzonitrile
(3)
To a slurry of iodide 2 (37.7 g, 100 mmol) in degassed DMF (95
mL) was added dppf (443 mg, 0.8 mmol) and Zn(CN)2 (6.1 g, 52
mmol). Pd2(dba)3 (366 mg, 0.4 mmol) was then added and the mix-
ture was heated to 115 °C for 3 h. After that, the HPLC analysis re-
vealed full conversion. The solution was cooled to r.t., poured into
H2O (0.5 L), and stirred for 0.5 h before filtering. The filter cake
was reslurried in toluene (100 mL) and filtered to afford 3; yield:
27.7 g (97%).
EI: m/z calcd for C17H14N4O: 290.1168; found [M + H]: 291.1250.
4-(2-Ethyl-7-methoxy-4-oxopyrido[2,3-d]pyrimidin-3(4H)-
yl)benzonitrile (Table 1, Entry 12)
Reaction conducted on a 3.1 mmol scale. Workup A. Silica gel
chromatography using CH2Cl2–acetone (98:2 → 4:1) afforded the
title compound; yield: 0.91 g (95%).
IR (neat): 3442, 3256, 2223, 1682, 1610, 1583, 1566, 1504, 1432,
1250, 1005, 815, 683 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.00 (dd, J = 1.7, 4.5 Hz, 1 H),
8.50 (dd, J = 1.7, 7.8 Hz, 1 H), 8.10 (d, J = 8.2 Hz, 2 H), 7.76 (d,
J = 8.2 Hz, 2 H), 7.56 (dd, J = 4.5, 7.9 Hz, 1 H), 2.34 (q, J = 7.3 Hz,
2 H), 1.15 (t, J = 7.2 Hz, 3 H).
IR (film): 2090, 3010, 1685, 1673, 1606, 1587, 1566, 1505, 1483,
1422, 1381, 1368, 1350, 1293, 1207 cm–1.
Synthesis 2007, No. 23, 3678–3682 © Thieme Stuttgart · New York

3682
J. Chan et al.
PAPER
13C NMR (100 MHz, DMSO-d6): d = 161.8, 160.3, 157.2, 156.1,
141.3, 135.9, 133.8, 130.1, 122.3, 118.2, 115.6, 112.2, 29.0, 10.3.
References
(1) (a) Nawrocka, W.; Statsko, J. J. Boll. Chim. Farm. 1998,
137, 35; Chem. Abstr. 2000, 132, 87507. (b) Corbett, J.
Prog. Med. Chem. 2002, 40, 63. (c) Nawrocka, W.; Statsko,
J. J. Boll. Chim. Farm. 2002, 140, 84; Chem. Abstr. 2002,
137, 59947. (d) Archana, S. Eur. J. Med. Chem. 2002, 37,
873. (e) White, D. C.; Greenwood, T. D.; Downey, A. L.;
Bloomquist, J. R.; Wolfe, J. F. Bioorg. Med. Chem. Lett.
2004, 12, 5711.
(2) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153; and references cited therein.
(3) (a) Shoji, E.; Matsushita, Y.; Yamashita, K. Org. Prep.
Proced. Int. 1992, 24, 209. (b) Ding, M. W.; Liu, Z. J. Chin.
J. Org. Chem. 2001, 21, 1; Chem. Abstr. 2001, 134, 207368.
(4) Chan, J.; Faul, M. Tetrahedron Lett. 2006, 47, 3361.
(5) For related work: Okawa, T.; Toda, M.; Eguchi, S.; Kakehi,
A. Synthesis 1998, 1467.
(6) (a) Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197.
(b) Wamhoff, H.; Richardt, G.; Stölben, S. Adv. Heterocycl.
Chem. 1995, 64, 159. (c) Fresneda, P. M.; Molina, P. Synlett
2004, 1.
(7) (a) Zografos, A. L.; Mitsos, C. A.; Igglessi-Markopoulou, O.
J. Org. Chem. 2001, 66, 4413. (b) Watkins, W. J.; Lemoine,
R. C.; Chong, L.; Cho, A.; Renau, T. E.; Kuo, B.; Wong, V.;
Ludwikow, M.; Garizi, N.; Iqbal, N.; Barnard, J.;
Jankowska, R.; Singh, R.; Madsen, D.; Lolans, K.;
Lomovskaya, O.; Oza, U.; Dudley, M. N. Bioorg. Med.
Chem. Lett. 2004, 14, 5133.
EI: m/z calcd for C16H12N4O: 276.10111; found [M + H]:
277.10825.
3-(4-Cyanophenyl)-2-ethylpyrido[2,3-d]pyrimidin-4(3H)-one
(4)
To a mixture of the iodide 2 (1.89 g, 5 mmol), 4-cyanophenylboron-
ic acid (822 mg, 5.75 mmol), and K3PO4 (2.13 g, 10 mmol) in diox-
ane–H2O (20:5 mL) was added Cl2Pd[P(Ph)(t-Bu)2]2 (31 mg, 0.05
mmol). The slurry was heated to 100 °C for 3 h. After that, the
HPLC analysis revealed full conversion. To the mixture was added
H2O (20 mL), MTBE (50 mL), and filtered. The filter cake was
washed with H2O (20 mL), MTBE (20 mL), and hexanes (20 mL).
The solids were transferred to a vacuum oven and dried to constant
mass; yield: 1.70 g (96%).
IR (neat): 3073, 3011, 2225, 1676, 1592, 1567, 1433, 1258, 1002,
791, 720 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.00 (dd, J = 1.9, 4.7 Hz, 1 H),
8.52 (dd, J = 2.0, 7.8 Hz, 1 H), 8.0 (m, 6 H), 7.64 (d, J = 8.4 Hz, 2
H), 7.56 (dd, J = 4.7, 7.9 Hz, 1 H), 2.43 (q, J = 7.4 Hz, 2 H), 1.19 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, DMF-d7): d = 161.5, 158.1, 156.3, 144.3,
139.8, 139.2, 138.3, 136.2, 133.3, 129.9, 128.7, 128.3, 122.5, 119.0,
116.3, 111.3, 67.0, 10.3.
EI: m/z calcd for C22H16N4O: 352.13241; found [M + H]:
353.14016.
(8) Decomposition of oxazin-4-ones was found to occur during
extraction with aq sat. NaHCO3 on a 150 g scale.
(9) (a) Gewald, K.; Hain, U.; Gruner, M. Chem. Ber. 1985, 118,
2198. (b) Gakhar, H. K.; Kaur, R.; Gupta, S. B. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1990, 29, 992.
(c) Kardiotonika, P. Pharmazie 1991, 46, 531. (d) Demina,
L. M.; Konshin, M. E. Chem. Heterocycl. Comp. (Engl.
Transl.) 1992, 28, 1179. (e) Paronikyan, E. G.; Sirakanyan,
S. N.; Noravyan, A. S. Chem. Heterocycl. Comp. (Engl.
Transl.) 1993, 29, 1454. (f) Ferrand, G.; Dumas, H.; Depin,
J.; Quentin, Y. Eur. J. Med. Chem. 1996, 31, 273.
(g) Rewcastle, G. W.; Palmer, B. D.; Thompson, A. M.;
Bridges, A. J.; Cody, D. R.; Zhou, H.; Fry, D. W.;
McMichael, A.; Denny, W. A. J. Med. Chem. 1996, 39,
1823.
2-(1-Chloroethyl)-3-(4-iodophenyl)pyrido[2,3-d]pyrimidin-
4(3H)-one (5)
To a solution of the iodide 2 (3.77 g, 10 mmol) in AcOH (10 mL)
was added NCS (1.46 g, 11 mmol) and the mixture was heated to 40
°C for 12 h. The mixture was diluted with H2O (100 mL) and fil-
tered. The solids were washed with aq sat. NaHCO3 (20 mL), H2O
(20 mL), and dried in a vacuum oven to constant mass to afford 5;
yield: 4.05 g (97%).
IR (neat): 3074, 3012, 1676, 1592, 1567, 1433, 1371, 1259, 1002,
791 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.04 (d, J = 4.3 Hz, 1 H), 8.54
(d, J = 7.9 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 2 H), 7.63 (dd, J = 4.5, 7.8
Hz, 1 H), 7.40 (d, J = 7.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.68
(q, J = 6.5 Hz, 1 H), 1.81 (d, J = 6.5 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 161.7, 157.2, 156.6, 156.3,
138.5, 138.1, 136.1, 135.3, 131.8, 130.8, 123.3, 116.3, 96.4, 53.2,
21.7. Restricted rotation observed.
(10) Determined by 1H NMR analysis of the crude reaction
mixture.
(11) Maligres, P. E.; Waters, M. S.; Fleitz, F.; Askin, D.
Tetrahedron Lett. 1999, 40, 8193.
(12) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel,
L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.;
Martinelli, M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787.
EI: m/z calcd for C15H11ClIN3O: 410.96353; found [M + H]:
411.97116.
Acknowledgment
We would like to thank Ken McRae for assistance in the scale-up
preparation of compound 2. We would also like to thank Paul
Schnier for assistance in obtaining HRMS.
Synthesis 2007, No. 23, 3678–3682 © Thieme Stuttgart · New York