Pyrido[2,3-d]pyrimidine derivatives: Synthesis via the intermolecular aza-Wittig reaction/heterocyclization and the crystal structure

Article abstract of DOI:10.1055/s-1998-2170

Pyrido[2,3-d]pyrimidine derivatives 5 were synthesized by the intermolecular aza-Wittig reaction of 2- (triphenylphosphoranylidene)aminonicotinamides 3 derived from 2- aminonicotinic acid (1), with carboxylic acid chloride followed by heterocyclization vi

Full text of DOI:10.1055/s-1998-2170

SYNTHESIS
October 1998
1467
Pyrido[2,3-d]pyrimidine Derivatives: Synthesis via the Intermolecular Aza-Wittig
Reaction/Heterocyclization and the Crystal Structure
Tomohiro Okawa,a Mieko Toda,a Shoji Eguchi*a Akikazu Kakehib
a
Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-01,
Japan
Fax +81(52)7893199; E-mail: eguchi@apchem.nagoya-u.ac.jp
Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato 500, Nagano 380, Japan
b
Received 21 November 1977; revised 26 December 1997
heterocycloaddition and heterocyclization.13 Thus, we in-
vestigated another route for the synthesis of pyrido[2,3-
d]pyrimidine derivatives by utilizing iminophosphoranes
having sec-amide functions and carboxylic acid chlorides.
We wish to report here a facile and efficient synthetic
route to pyrido[2,3-d]pyrimidine derivatives 5 by the in-
termolecular aza-Wittig reaction of iminophosphorane
derivatives having sec-amide functions 3 with various
carboxylic acid chlorides followed by heterocyclization.
Abstract: Pyrido[2,3-d]pyrimidine derivatives 5 were synthesized
by the intermolecular aza-Wittig reaction of 2-(triphenylphospho-
ranylidene)aminonicotinamides 3 derived from 2-aminonicotinic
acid (1), with carboxylic acid chloride followed by heterocycliza-
tion via imidoyl chloride intermediate 4. The structure of 3-allyl-
2-(4-nitrophenyl)-4(3H)-pyrido[2,3-d]pyrimidinone (5b) was
established by X-ray crystallographic analysis. This methodology
has been applied also to a novel synthesis of 4(3H)-quinazolinone
14.
Key words: iminophosphoranes, intermolecular aza-Wittig reac-
tion, heterocyclization, 4(3H)-pyrido[2,3-d]pyrimidinone, X-ray
crystallographic analysis
At first, we investigated the preparation for the imino-
phosphorane derivatives as follows. The required sec-
amide derivatives 2a–e were prepared from 2-aminonico-
tinic acid (1), primary amines and DEPC14 (diethylphos-
phoryl cyanide) as condensation reagent in moderate
yields (Scheme 1 and Tables 1–3). In this reaction, the de-
sired compounds could not be obtained by using 1,3-cy-
clohexylcarbodiimide. Subsequently, sec-amides 2a–e
were converted into the corresponding iminophosphorane
derivatives 3a–e in good yield by triphenylphosphine/
hexachloroethane/triethylamine reagent system (the Ap-
pel method, i.e. the modified Kirsanov reaction)15
(Scheme 1 and Tables 4–6).
Pyrido[2,3-d]pyrimidine, 5-deaza analogues of pteridine
derivatives are known to be the fundamental skeleton of
5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF)1
and also the deaza derivatives of methotrexate (MTX).
MTX and DDATHF have been shown to possess antineo-
plastic and immunosuppressive activities, and the estab-
lishment of a facile and regioselective construction of
these fundamental heterocyclic skeletons is important.
The aza-Wittig reaction has been one of the most useful
methodologies for the formation of C=N bonds and aza-
heterocumulenes, which are useful intermediates for syn-
thesis of nitrogen heterocycles.2–5 We have been interest-
ed in the preparation and the reactivity of N-heteroarylim-
inophosphoranes because these species seem to have been
less studied, in spite of their promising potential as build-
ing blocks for the synthesis of heterocycles. For example,
we have reported the facile synthesis of 4(3H)-pteridin-
ones via the intermolecular aza-Wittig reaction and hetero-
cyclization,6,7 and pyrazino[2,3-e][1,4]diazepin-5-ones
via the intramolecular aza-Wittig reaction.8
Reagents and conditions: (a) RNH2/DEPC/Et3N/DME, 0°C; then 1 h
at r.t. (32–59%); (b) Ph3P/hexachloroethane/Et3N/benzene, reflux,
2 h (81–95%)
Scheme 1
In addition, the reaction of the iminophosphoranes with
carboxylic acid chlorides to give heterocyclic compounds
has been reported by Zbiral,9 Wamhoff10 and Molina et
al.11,12 They have shown that upon warming or in the pres-
ence of tert-amines, imidoyl chlorides are formed, which
react with internal nucleophiles to afford various hetero-
cycles such as oxazoles,9 3,1-oxazin-4-ones,10 1,2,4-triaz-
olo[5,1-c]-1,2,4-triazines11 and 6-substituted quinazoli-
no[4,3-b]quinazolin-8-ones,12 etc. As part of our contin-
ued research programs on the aza-Wittig reaction, we
unexpectedly obtained (2-oxo-1,2-dihydropyridin-3-yl)-
Finally, the synthesis of pyrido[2,3-d]pyrimidine deriva-
tives 5a–j was examined by the intermolecular aza-Wittig
reaction and heterocyclization by refluxing the imino-
phosphoranes 3 with acid chlorides in the presence of tri-
ethylamine in anhydrous toluene (Scheme 2 and Tables 7–
9). In the formation of pyrido[2,3-d]pyrimidines, imidoyl
chlorides 4 are assumed to be the key intermediates in the
consecutive reaction even though 4 could not be detected
due to its high reactivity.
1,3,5-triazine derivatives instead of pyrido[2,3-d]pyrimi- Furthermore, X-ray crystallographic analysis was per-
dine derivatives from methyl 2-(N-triphenylphosphor- formed to confirm the structure of pyrido[2,3-d]pyrimi-
anylidene)aminonicotinate, aryl isocyanates and primary dine 5b (Figure). As summarized in the Figure and Table
amines via the intermolecular aza-Wittig reaction, [4+2] 10, the presence of the pyrido[2,3-d]pyrimidine skeleton

SYNTHESIS
Papers
Table 1. Secondary Amides 2a–e Prepared
1468
Prod-
uct
R
Yield (%)a mp (°C)
Rfb
IR (KBr or neat), ν (cm–1)
2a
2b
2c
2d
2e
CH2=CHCH2 46
116–119
159–161
123–127
135–137
155–157
0.42
0.41
0.61
0.58
0.58
3439, 3297, 3148, 1630, 1578, 1534, 1453, 1254, 997, 766
3439, 3306, 3156, 2975, 1624, 1576, 1535, 1453, 1256, 764
3448, 3424, 3326, 1642, 1601, 1576, 1524, 1451, 1258, 777, 754, 702
3371, 3332, 3156, 2977, 1636, 1575, 1539, 1456, 1317, 1257, 1221, 775
3428, 3314, 3130, 1626, 1578, 1523, 1458, 1259, 1208, 1158, 1135, 1045, 834, 761
i-Pr
54
59
32
54
Bn
t-Bu
DMPMc
a Isolated yield.
b Eluent = EtOAc.
c DMPM = 2,4-dimethoxyphenylmethyl.
Table 2. 1H and 13C NMR Spectral Data of Compounds 2a–e
Product
1H NMR (CDCl3/TMS, 200 MHz); δ, J (Hz)
13C NMR (CDCl3/TMS, 50 MHz), δ
2a
4.05 (2 H, tt, J = 5.7, 1.5, NHCH2CH=CH2), 5.20 [1 H, dq, J = 10.2, 42.33 (NHCH2CH=CH2), 110.73 (C-3), 112.68 (C-5),
1.5, CH=CH2 (cis)], 5.26 [1 H, dq, J = 17.2, 1.5, CH=CH2 (trans)], 117.24 (CH=CH2), 134.31 (CH2CH=CH2), 135.84 (C-4),
5.93 (1 H, ddt, J = 17.2, 10.2, 5.7, CH2CH=CH2), 6.22 (1 H, br, 152.22 (C-6), 159.13 (C-2), 168.14 (CONH)
CONH), 6.38 (2 H, br, NH2), 6.60 (1 H, dd, J = 7.7, H-5), 7.64 (1
H, dd, J = 7.7, 1.8, H-4), 8.16 (1 H, dd, J = 4.9, 1.8, H-6)
2b
1.26 [6 H, d, J = 6.6, CH(CH3)2], 4.24 [1 H, d-septet, J = 7.8, 6.6, 22.87 [CH(CH3)2], 41.91 [NHCH(CH3)2], 111.27 (C-3),
NHCH(CH3)2], 5.87 (1 H, br, CONH), 6.31 (2 H, br, NH2), 6.59 (1 112.67 (C-5), 135.65 (C-4), 152.02 (C-6), 159.14 (C-2),
H, dd, J = 7.6, 4.9, H-5), 7.57 (1 H, dd, J = 7.6, 1.8, H-4), 8.15 (1 H, 167.57 (CONH)
dd, J = 4.9, 1.8, H-6)
2c
2d
2e
4.57 (2 H, d, J = 5.6, NHCH2C6H5), 6.37 (2 H, br, NH2), 6.54 (1 H, 43.96 (NHCH2C6H5), 110.60 (C-3), 112.65 (C-5), 128.05
dd, J = 7.8, 4.9, H-5), 6.51–6.58 (1 H, br, CONH), 7.24–7.41 (5 H, (C'-4), 128.17 (C'-2), 129.19 (C'-3), 135.88 (C-4), 138.30
m), 7.61 (1 H, dd, J = 7.8, 1.8, H-4), 8.12 (1 H, dd, J = 4.9, 1.8, H-6) (C'-1), 152.27 (C-6), 159.19 (C-2), 168.20 (CONH)
1.45 [9 H, s, C(CH3)3], 5.86 (1 H, br, CONH), 6.27 (2 H, br, NH2), 28.92 [C(CH3)3], 51.93 [NHC(CH3)3], 112.41 (C-3),
6.57 (1 H, dd, J = 7.7, 5.0, H-5), 7.53 (1 H, dd, J = 7.7, 1.8, H-4), 112.63 (C-5), 135.70 (C-4), 151.65 (C-6), 159.04 (C-2),
8.12 (1 H, dd, J = 5.0, 1.8, H-6)
168.05 (CONH)
3.81 (3 H, s, OCH3), 3.86 (3 H, s, OCH3), 4.51 (2 H, d, J = 5.6 Hz, 39.56 (NHCH2Ar), 55.61 (2 OCH3), 99.04 (C'-3), 104.35
NHCH2A), 6.33 (2 H, br, NH2), 6.57 (1 H, dd, J = 7.8, 4.9, H-5), (C'-5), 111.21 (C-3), 112.64 (C-5), 118.73 (C'-1), 131.08
6.43–7.27 (3 H + 1 H, m, C6H3 + CONH), 7.55 (1 H, dd, J = 7.8, (C'-6), 135.80 (C-4), 151.99 (C-6), 159.13 (C-2 and/or C'-
1.8, H-4), 8.13 (1 H, dd, J = 4.9, 1.8, H-6)
2 or C'-4), 161.17 (C'-2 and/or C'-4), 167.87 (CONH)
Table 3. MS and HRMS Data of Compounds 2a–e
Product
MS (70 eV), m/z (%)
HRMS (70 eV), m/z, found (formula, calc.)
2a
178 (8, M+ + 1), 177 (48, M+), 122 (19), 121 (100), 95 (4), 94 (25), 93 (56), 177.0904 (C9H11N3O, 177.0902)
92 (3), 67 (3), 66 (16)
2b
2c
2d
2e
180 (7, M+ + 1), 179 (55, M+), 178 (4), 164 (5), 137 (3), 122 (8), 121 (100), 179.1062 (C9H13N3O, 179.1059)
120 (8), 94 (11), 93 (38), 92 (3), 66 (9)
228 (13, M+ + 1), 227 (76, M+), 122 (5), 121 (45), 107 (17), 106 (100), 94 (21), 227.1059 (C13H13N3O, 227.1059)
93 (35), 91 (39), 79 (7), 66 (10), 65 (8)
194 (6, M+ + 1), 193 (43, M+), 178 (10), 137 (29), 122 (6), 121 (100), 120 (22), 193.1213 (C10H15N3O, 193.1215)
94 (17), 93 (30), 92 (3), 66 (12)
288 (4, M+ + 1), 287 (21, M+), 167 (8), 166 (100), 152 (3), 151 (22), 121 (15),
93 (4)
287.1271 (C15H17N3O3, 287.1270)
was confirmed. The structure of 4(3H)-pyrido[2,3-d]pyr- most perpendicular (C2–N2–C14–C15: 100.5° and C3–
imidinones by X-ray crystallographic analysis has not been N2–C14–C15: 83.0°, Figure and Table 10). Also, the phe-
reported previously to the best of our knowledge.16 The nyl ring and the pyrido[2,3-d]pyrimidine ring were at an
torsion angles of 5b indicated that the pyrido[2,3-d]pyrim- angle of about 65° (N1–C2–C8–C9: 113.7° and N2–C2–
idine skeleton was approximately planar, and the allyl C8–C9: 64.2°, Figure and Table 10). All pyrido[2,3-d]pyr-
function and the pyrido[2,3-d]pyrimidine ring were al- imidines 5 were purified by both silica gel (BW-300 and

SYNTHESIS
October 1998
1469
Table 4. Iminophosphoranes 3a–e Prepared
Product
R
Yield (%)a
mp (°C)
Rfb
IR (KBr or neat), ν (cm–1)
3030, 1647, 1537, 1420, 1321, 1109, 995, 721
3136, 1640, 1574, 1535, 1420, 1329, 1250, 1111, 1011, 997, 720
3158, 1647, 1578, 1543, 1422, 1329, 1248, 1111, 1011, 997, 720
3202, 1648, 1543, 1419, 1327, 1277, 1255, 1111, 995, 720
3426, 1644, 1577, 1542, 1508, 1420, 1329, 1262, 1111, 996, 719
3a
3b
3c
3d
3e
CH2=CHCH2
i-Pr
Bn
95
91
88
81
88
178–179
214–215
57–60
168–170
60–62
0.79
0.82
0.56
0.86
0.71
t-Bu
DMPMc
a Isolated yield.
b Eluents for 3a, b, d, e = EtOAc, for 3e = EtOAc/hexane (1:1).
c DMPM = 2,4-dimethoxyphenylmethyl.
Table 5. 1H and 13C NMR Data of Compounds 3a–e
Product
1H NMR (CDCl3/TMS, 200 MHz); δ, J (Hz)
13C NMR (CDCl3/TMS, 50 MHz); δ, J (Hz)
3a
4.17 (2 H, tt, J = 5.8, 1.6, NHCH2CH=CH2), 5.13 [1 H, 42.36 (NHCH2CH=CH2), 113.54 (C-5), 116.24 (CH=CH2), 118.68 (d,
dq, J = 10.1, 1.6, CH=CH2 (cis)], 5.29 [1 H, dq, J = J = 18.4, C-3), 128.84 (d, J = 12.1, C'-3), 129.72 (d, J = 100.0, C'-1),
17.2, 1.6, CH=CH2 (trans)], 6.01 (1 H, ddt, J = 17.2, 132.26 (d, J = 2.7, C'-4), 133.49 (d, J = 9.8, C'-2), 135.82
10.1, 5.8, CH2CH=CH2), 6.60 (1 H, dd, J = 7.6, 4.9, H- (CH2CH=CH2), 139.62 (d, J = 2.9, C-4), 149.46 (C-6), 161.47 (d, J =
5), 7.38–7.59 (9 H, m, C6H5), 7.71–7.82 (6 H, m, 7.3, C-2), 167.23 (CONH)
C6H5), 7.84 (1 H, ddd, J = 4.9, 2.1, 0.5, H-4), 8.43 (1 H,
ddd, J = 7.6, 2.6, 2.1, H-6), 11.44 (1 H, br s, CONH),
3b
3c
1.22 [6 H, d, J = 6.7, CH(CH3)2], 4.34 [1 H, septet, J = 23.27 [CH(CH3)2], 41.08 [NHCH(CH3)2], 113.59 (C-5), 118.98 (d, J
6.7, NHCH(CH3)2], 6.60 (1 H, dd, J = 7.7, 4.8, H-5), = 18.8, C-3), 128.83 (d, J = 12.4, C'-3), 129.86 (d, J = 101.0, C'-1),
7.40–7.60 (9 H, m, C6H5), 7.73–7.85 (1 H + 6 H, m, H- 132.27 (d, J = 2.7, C'-4), 133.55 (d, J = 9.8, C'-2), 139.58 (d, J = 2.9,
4 + C6H5), 8.43 (1 H, ddd, J = 7.7, 2.7, 2.2, H-6), 11.08 C-4), 149.21 (C-6), 161.42 (d, J = 7.3, C-2), 166.40 (CONH)
(1 H, d, J = 6.8, CONHCH)
4.74 (2 H, d, J = 5.8, NHCH2C6H5), 6.60 (1 H, dd, J = 43.69 (NHCH2C6H5), 113.56 (C-5), 118.57 (d, J = 18.4, C-3), 127.31
7.6, 4.8, H-5), 7.24–7.53 (9 H + 5 H, m, C6H5 + C6H5), (C''-4), 128.34 (C''-2), 128.78 (d, J = 12.2, C'-3), 128.85 (C''-3), 129.59
7.60–7.72 (6 H, m, C6H5), 7.84 (1 H, ddd, J = 4.8, 2.2, (d, J = 100.9, C'-1), 132.16 (d, J = 2.7, C'-4), 133.39 (d, J = 9.8, C'-2),
0.5, H-4), 8.47 (1 H, ddd, J = 7.6, 2.8, 2.2, H-6), 11.74 139.72 (d, J = 2.8, C-4), 140.03 (C''-1), 149.50 (C-6), 161.53 (d, J =
(1 H, br, CONH)
7.2, C-2), 167.52 (CONH)
3d
3e
1.41 [9 H, s, C(CH3)3], 6.58 (1 H, dd, J = 7.6, 4.8, H-5), 29.30 [C(CH3)3], 50.66 [NHC(CH3)3], 113.58 (C-5), 119.83 (d, J =
7.38–7.59 (9 H, m, C6H5), 7.71–7.83 (1 H + 6 H, m, H- 19.0, C-3), 128.77 (d, J = 12.0, C'-3), 129.90 (d, J = 100.9, C'-1),
4 + C6H5), 8.41 (1 H, ddd, J = 7.6, 2.6, 2.0, H-6), 10.86 132.19 (d, J = 2.7, C'-4), 133.61 (d, J = 9.6, C'-2), 139.32 (d, J = 2.9,
(1 H, br, CONH)
C-4), 148.93 (C-6), 161.48 (d, J = 7.5, C-2), 166.45 (d, J = 1.7, CONH)
3.55 (3 H, s, OCH3), 3.79 (3 H, s, OCH3), 4.65 (2 H, d, 38.69 (NHCH2Ar), 55.24 (OCH3), 55.53 (OCH3), 98.85 (C''-3),
J = 5.8, (NHCH2Ar), 6.36–6.43 (2 H, m, C6H3), 6.58 (1 104.12 (C''-5), 113.44 (C-5), 118.94 (d, J = 18.8, C-3), 120.40 (C''-1),
H, dd, J = 7.6, 4.8, H-5), 7.32–7.55 (1 H + 9 H, m, C6H3 128.78 (d, J = 12.5, C'-3), 129.82 (d, J = 100.8, C'-1), 130.76 (C''-6),
+ C6H5), 7.66–7.78 (6 H, m, C6H5), 7.81 (1 H, ddd, J = 132.09 (d, J = 2.8, C'-4), 133.43 (d, J = 9.7, C'-2), 139.64 (d, J = 2.8,
4.8, 2.1, 0.5, H-4), 8.44 (1 H, ddd, J = 7.6, 2.9, 2.1, H- C-4), 149.23 (C-6), 158.95 (C''-2 or C''-4), 160.41 (C''-2 or C''-4),
6), 11.48 (1 H, br, CONH)
161.53 (d, J = 7.4, C-2), 167.30 (CONH)
Figure. ORTEP Diagram of 3-Allyl-2-(4-nitrophenyl)-4(3H)-pyri-
do[2,3-d]pyrimidinone (5b)
Scheme 2

SYNTHESIS
Papers
Table 6. MS and HRMS Data of Compounds 3a–e
1470
Product
MS (70 eV), m/z (%)
HRMS (70 eV), m/z, found (formula, calc.)
3a
438 (24, M+ + 1), 437 (83, M+), 397 (11), 396 (40), 382 (24), 381 (41), 354 (22), 437.1660 (C27H24N3OP, 437.1657)
353 (100), 262 (14), 201 (20), 183 (36)
3b
3c
3d
3e
440 (10, M+ + 1), 439 (33, M+), 424 (13), 397 (18), 396 (63), 383 (23),382 (100), 439.1811 (C27H26N3OP, 439.1813)
381 (86), 354 (23), 353 (91), 262 (15), 201 (26), 183 (34)
488 (23, M+ + 1), 487 (70, M+), 396 (22), 383 (8), 382 (34), 354 (24), 353 (100), 487.1818 (C31H26N3OP, 487.1813)
201 (12), 183 (18)
453 (16, M+), 439 (9), 438 (29), 397 (16), 396 (54), 382 (23), 381 (100), 353 (8), 453.1968 (C28H28N3OP, 453.1970)
262 (10), 201 (16), 124 (24), 108 (5)
548 (25, M+ + 1), 547 (81, M+), 532 (7), 383 (10), 382 (48), 381 (43), 354 (24), 547.2024 (C33H30N3O3P, 547.2025)
353 (100), 262 (8), 201 (9), 183 (15)
Table 7. Pyrido[2,3-d]pyrimidines 5a–k Prepared
Product
R
R'
Yield (%)a mp (°C)
Rfb
IR (KBr or neat), ν (cm–1)
5a
CH2CH=CH2 Ph
86
154–157
140–144
201–203
272–274
154–156
201–203
0.11
2948, 1686, 1566, 1433, 1375, 1346, 1250, 1221, 1130, 968,
912, 799, 704
5b
5c
5d
5e
5f
CH2CH=CH2 4-NO2C6H4 72
0.45
0.52
0.64
0.58
0.59
3148, 1680, 1578, 1520, 1431, 1377, 1352, 1221, 1096, 860,
799, 704
i-Pr
i-Pr
Bn
Ph
73
3428, 3057, 1678, 1589, 1437, 1397, 1348, 1298, 1221,
1073, 802, 702
4-NO2C6H4 79
3426, 3056, 1680, 1582, 1522, 1437, 1395, 1348, 1289,
1219, 1175, 1071, 856, 710
Ph
69
3067, 1674, 1572, 1497, 1431, 1364, 1304, 1254, 1223,
1179, 806, 777, 704
Bn
4-NO2C6H4 74
3423, 1682, 1578, 1517, 1434, 1384, 1346, 1220, 1104, 859,
799, 698
5g
5h
t-Bu
t-Bu
Ph
24
143–146
296–300
0.44
0.31
2971, 1674, 1588, 1558, 1429, 1340, 1211, 1181, 795, 702
4-NO2C6H4 37
3445, 1678, 1588, 1559, 1522, 1431, 1352, 1290, 1177, 858,
797
5j
DMPMc
4-NO2C6H4 71
197–200
134–136
0.14
0.21
3435, 1685, 1575, 1523, 1437, 1350, 1302, 1209, 1103,
1034, 859, 795
5k
CH2CH=CH2 i-Pr
83
2962, 1675, 1582, 1437, 1392, 1308, 1226, 1100, 936, 802
a Isolated yield.
b Eluents for 5b–f = EtOAc, for 5a, g–k = EtOAc/hexane (1:1).
c DMPM = 2,4-dimethoxyphenylmethyl.
Chromatorex→ NH-DM-1020) column chromatogra-
phy and recrystallization from ethyl acetate and hexane
because Rf values of these compounds on TLC (silica
gel) were the same as that of triphenylphosphine oxide,
which was the inevitable byproduct in the aza-Wittig
reaction (see Experimental section). Besides, reaction
with isobutyryl chloride (R' = alkyl) produced the de-
sired pyrido[2,3-d]pyrimidine derivative 5j in the same
way (83% yield).
the amine 1, DEPC and a ten-fold excess of ammonium
chloride (46% yield).17 Subsequently, the corresponding
iminophosphorane 7 was prepared by the Appel method
(24% yield); however, the nitrile derivatives 8 and 9 were
produced as byproducts (22 and 10% yield, respectively).
The yield of 7 was determined by 1H NMR because of the
difficulty in separation of the product 7 from triphe-
nylphosphine oxide, the inevitable byproduct in the prep-
aration of iminophosphoranes. In this reaction, the tri-
phenylphosphine/hexachloroethane/triethylamine reagent
system worked also as a dehydrating reagent, affording
Moreover, the synthesis of 3H-pyrido[2,3-d]pyrimidine
derivatives using primary amides was studied (Scheme 3).
At first, the primary amide derivative 6 was prepared from the nitriles 8 and 9.

SYNTHESIS
October 1998
1471
Table 8. 1H and 13C NMR Data of Compounds 5a–j
Product
1H NMR (CDCl3/TMS, 200 MHz); δ, J (Hz)
13C NMR (CDCl3/TMS, 50 MHz), δ
5a
4.65 (2 Η, dt, J = 5.2, 1.4, NCH2CH=CH2), 4.98 [1 H, dq, J = 48.72 (NCH2CH=CH2), 116.20 (C-4a), 118.19 (CH=CH2),
17.2, 1.4, CH=CH2(trans)], 5.22 [1 H, dq, J = 10.4, 1.4, 122.86 (C-6), 128.52 (C'-2 or C'-3), 128.78 (C'-2 or C'-3),
CH=CH2(cis)], 5.90 (1 H, ddt, J = 17.2, 10.4, 5.2, 130.72 (C'-4), 132.20 (CH2CH=CH2), 135.04 (C'-1), 136.85
CH2CH=CH2), 7.47 (1 H, dd, J = 8.0, 4.6, H-6); 7.49–7.55 (3 (C-5), 156.86 (C-7), 157.73 (C-2 or C-8a), 160.14 (C-2 or C-
H, m, C6H5), 7.60–7.65 (2 H, m, C6H5), 8.67 (1 H, dd, J = 8.0, 8a), 162.93 (C-4)
2.1, H-5), 9.02 (1 H, dd, J = 4.6, 2.1, H-7)
5b
4.62 (2 H, dt, J = 5.2, 1.6, NCH2CH=CH2), 4.98 [1 H, dtd, J = 48.59 (NCH2CH=CH2), 116.46 (C-4a), 118.51 (CH=CH2),
17.4, 1.6, 0.7, CH=CH2 (trans)], 5.29 [1 H, dtd, J = 10.5, 1.6, 123.52 (C-6), 124.07 (C'-3), 129.88 (C'-2), 131.85
0.7, CH=CH2(cis)], 5.91 (1 H, ddt, J = 17.4, 10.5, 5.1, (CH2CH=CH2), 137.01 (C-5), 140.70 (C'-1), 149.26 (C'-4),
CH2CH=CH2), 7.53 (1 H, dd, J = 8.0, 4.5, H-6), 7.81–7.88 (2 157.09 (C-7), 157.36 (C-2 or C-8a), 157.89 (C-2 or C-8a),
H, m, C6H4), 8.35–8.41 (2 H, m, C6H4), 8.69 (1 H, dd, J = 8.0, 162.44 (C-4)
2.0, H-5), 9.05 (1 H, dd, J = 4.5, 2.0, H-7)
5c
5d
5e
1.60 [6 H, d, J = 6.8, CH(CH3)2], 4.47 [1 H, septet, J = 6.8, 19.66 [CH(CH3)2], 54.64 [NCH(CH3)2], 117.38 (C-4a), 122.66
NCH(CH3)2], 7.44 (1 H, dd, J = 8.0, 4.4, H-6), 7.49–7.61 (5 H, (C-6), 127.85 (C'-2), 129.07 (C'-3), 130.38 (C'-4), 136.24 (C'-
m, C6H5), 8.62 (1 H, dd, J = 8.0, 1.8, H-5), 8.98 (1 H, dd, J = 1), 136.47 (C-5), 156.56 (C-7), 157.36 (C-2 or C-8a), 160.48
4.4, 1.8, H-7)
(C-2 or C-8a), 163.15 (C-4)
1.63 [6 H, d, J = 6.8, CH(CH3)2], 4.29 [1 H, septet, J = 6.8, 19.44 [CH(CH3)2], 54.75 [NCH(CH3)2], 117.38 (C-4a), 123.04
NCH(CH3)2], 7.50 (1 H, dd, J = 8.0, 4.4, H-6), 7.76–7.83 (2 H, (C-6), 124.17 (C'-3), 128.91 (C'-2), 136.38 (C-5), 141.73 (C'-
m, C6H4), 8.34–8.44 (2 H, m, C6H4), 8.64 (1 H, dd, J = 8.0, 1.8, 1), 148.79 (C'-4), 156.52 (C-7), 156.72 (C-2 or C-8a), 157.88
H-5), 9.01 (1 H, dd, J = 4.4, 1.8, H-7)
(C-2 or C-8a), 162.76 (C-4)
5.32 (2 H, s, NCH2C6H5), 6.99–6.92 (2 H, m, C6H5), 7.19–7.27 49.37 (NCH2C6H5), 116.30 (C-4a), 122.93 (C-6), 127.28
(3 H, m, C6H5), 7.37–7.50 (5 H, m, C6H5), 7.48 (1 H, dd, J = (C6H5), 128.03 (C6H5), 128.60 (C6H5), 128.79 (C6H5), 129.01
8.0, 4.6, H-6), 8.68 (1 H, dd, J = 8.0, 2.0, H-5), 9.02 (1 H, dd, (C'-4 or C''-4), 130.65 (C'-4 or C''-4), 135.11 (C'-1 or C''-1),
J = 4.6, 2.0, H-7)
136.48 (C'-1 or C''-1), 137.06 (C-5), 156.94 (C-7), 157.76 (C-
2 or C-8a), 160.25 (C-2 or C-8a), 163.39 (C-4)
5f
5.28 (2 H, s, NCH2C6H5), 6.92–6.88 (2 H, m, C6H5), 7.22–7.29 49.17 (NCH2C6H5), 116.53 (C-4a), 123.61 (C-6), 123.96 (C'-3
(3 H, m, C6H5), 7.55 (1 H, dd, J = 8.0, 4.6, H-6), 7.54–7.61 (2 or C''-2), 126.95 (C'-3 or C''-2), 128.43 C''-4), 129.33 (C'-2 or
H, m, C6H4), 8.22–8.29 (2 H, m, C6H4), 8.73 (1 H, dd, J = 8.0, C''-3), 129.81 (C'-2 or C''-3), 135.86 (C''-1), 137.25 (C-5),
2.0, H-5), 9.06 (1 H, dd, J = 4.6, 2.0, H-7)
140.76 (C'-1), 149.08 (C'-4), 157.17 (C-7), 157.40 (C-2 or C-
8a), 158.06 (C-2 or C-8a), 162.97 (C-4)
5g
5h
5i
1.52 [9H, s, C (CH3)3], 7.38 (1 H, dd, J = 7.9, 4.6, H-6), 7.44– 31.13 [C(CH3)3], 64.72 [NC(CH3)3], 117.50 (C-4a), 122.25
7.52 (3 H, m, C6H5), 7.64–7.70 (2 H, m, C6H5), 8.54 (1 H, dd, (C-6), 128.57 (C-2' or C-3'), 128.70 (C-2' or C-3'), 130.52 (C'-
J = 7.9, 1.9, H-5), 8.92 (1 H, dd, J = 4.6, 1.9, H-7)
4), 136.45 (C-5), 140.57 (C'-1), 156.13 (C-7), 156.53 (C-2 or
C-8a), 160.71 (C-2 or C-8a), 166.74 (C-4)
1.54 [9 H, s, C(CH3)3], 7.46 (1 H, dd, J = 7.9, 4.6, H-6), 7.83– 31.22 [C(CH3)3], 64.91 [NC(CH3)3], 117.71 (C-4a), 123.06
7.90 (2 H, m, C6H4), 8.33–8.40 (2 H, m, C6H4), 8.57 (1 H, dd, (C-6), 124.09 (C'-3), 129.52 (C'-2), 136.68 (C-5), 146.28 (C'-
J = 7.9, 2.0, H-5), 8.97 (1 H, br, H-7)
1), 148.93 (C'-4), 156.07 (C-2 or C-8a), 156.38 (C-7), 158.37
(C-2 or C-8a), 166.14 (C-4)
3.53 (OCH3), 3.76 (OCH3), 5.19 (NCH2Ar), 6.30 (1 H, d, J = 44.98 (NCH2Ar), 55.16 (OCH3), 55.51 (OCH3), 98.53 (C''-3),
2.4, H'-3), 6.37 (1 H, dd, J = 8.2, 2.4, H'-5), 6.88 (1 H, d, J = 104.56 (C''-5), 116.10 (C''-1), 116.50 (C-4a), 123.33 (C-6),
8.2, H'-6), 7.51 (1 H, dd, J = 8.0, 4.6, H-6), 7.63–7.69 (2 H, m, 123.70 (C'-3), 129.47 (C''-6), 129.74 (C'-2), 137.11 (C-5),
C6H4), 8.23–8.29 (2 H, m, C6H4), 8.68 (1 H, dd, J = 8.0, 2.0, 141.19 (C'-1), 148.96 (C'-4), 156.89 (C-7), 157.40 (C-2 or C-
H-5), 9.03 (1 H, dd, J = 4.6, 2.0, H-7)
8a), 157.95 (C-2'' or C-4''), 158.44 (C-2 or C-8a), 161.17 (C-2''
or C-4''), 163.11 (C-4)
5j
1.43 [6 H, d, J = 6.6, CH(CH3)2], 3.18 [1 H, septet, J = 6.6, 21.45
[CH(CH3)2],
32.30
[CCH(CH3)2],
45.21
CCH(CH3)2], 4.85 (2 H, dt, J = 4.8, 1.8, NCH2CH=CH2), 5.07 (NCH2CH=CH2), 115.66 (C-4a), 117.29 (CH=CH2), 122.30
[1 H, dtd, J = 17.2, 1.8, 0.7, CH=CH2(trans)], 5.27 [1 H, dtd, J (C-6), 132.36 (CH2CH=CH2), 136.98 (C-5), 156.55 (C-7),
= 10.6, 1.8, 0.7, CH=CH2(cis)], 6.00 (1 H, ddt, J = 17.2, 10.6, 157.91 (C-2 or C-8a), 162.96 (C-2 or C-8a), 166.27 (C-4)
4.8, CH2CH=CH2), 7.41 (1 H, dd, J = 7.9, 4.6, H-6), 8.60 (1 H,
dd, J = 7.9, 2.0, H-5), 8.97 (1 H, br s, H-7)
Subsequently, reaction of the obtained iminophosphorane 1H NMR reacted with carboxylic acid chloride to give 8
7 with acid chloride to form 4H-pyrido[2,3-d]pyrimidines via 11. As an alternative route to 10, attempted deprotec-
10 was examined. However, the desired 4H-pyrido[2,3- tion of the 2,4-dimethoxyphenylmethyl (DMPM) func-
d]pyrimidines 10 could not be obtained at all, only the im- tion of pyrido[2,3-d]pyrimidine 5i with TFA,18 CAN19 or
inophosphorane with nitrile function 8 was formed exclu- DDQ20 resulted in failure, affording no trace of the de-
sively (Scheme 4). The tautomer 7' of 7 as detectable by sired compound. Thus, the synthesis of 3H-pyrido[2,3-d]-

SYNTHESIS
Papers
Table 9. MS and HRMS Data of Compounds 5a–j
1472
Product
MS (70 eV), m/z (%)
HRMS (70 eV), m/z, found (formula, calc.)
5a
264 (11, M+ + 1), 263 (64, M+), 262 (100), 248 (38), 234 (9), 180 (7), 131 (6), 263.1057 (C16H13N3O, 263.1059)
104 (7), 78 (7), 77 (7)
5b
5c
5d
309 (13, M+ + 1), 308 (74, M+), 307 (100), 294 (10), 293 (64), 291 (12), 261 (26), 308.0901 (C16H12N4O3, 308.0909)
186 (8), 131 (7), 78 (8)
266 (16, M+ + 1), 265 (92, M+), 264 (79), 224 (13), 223 (65), 222 (15), 209 (11), 265.1208 (C16H15N3O, 265.1215)
120 (100), 104 (10), 103 (9)
311 (13, M+ + 1), 310 (67, M+), 309 (60), 293 (17), 269 (15), 268 (90), 263 (12), 310.1064 (C16H14N4O3, 310.1066)
254 (13), 222 (51), 120 (100), 78 (11)
5e
5f
314 (17, M+ + 1), 313 (85, M+), 312 (100), 209 (6), 207 (5), 181 (9), 91 (29)
359 (17, M+ + 1), 358 (90, M+), 357 (100), 341 (6), 312 (7), 311 (18), 254 (6), 358.1068 (C20H14N4O3, 358.1066)
252 (8), 181 (10), 91 (70), 78 (6), 65 (6)
313.1205 (C20H15N3O, 313.1215)
5g
5h
279 (8, M+), 224 (28), 223 (99), 222 (6), 195 (4), 179 (4), 121 (6), 120 (100), 103 279.1372 (C17H17N3O, 279.1372)
(5), 93 (6), 92 (5), 77 (5)
324 (6, M+), 270 (6), 269 (44), 268 (100), 238 (8), 223 (7), 222 (26), 194 (6), 121 324.1220 (C17H16N4O3, 324.1222)
(5), 120 (62)
5i
5j
418 (15, M+), 281 (3), 280 (19), 209 (3), 152 (7), 151 (100), 121 (14), 91 (3)
229 (21, M+), 228 (18), 215 (12), 214 (100), 200 (8), 199 (7), 188 (13), 187 (14), 229.1218 (C13H15N3O, 229.1215)
186 (70), 174 (16), 78 (8)
418.1274 (C22H18N4O5, 418.1277)
Table 10. Selected Bond Angles, Bond Lengths and Torsion Angles of 5b
Bond Angles (°)a Bond Lengths (Å)a
Torsion Angles (°)b
C1-N1-C2 117.0(3) O1-C3-N2 120.4(3) O1-C3 1.225(4) N4-C11 1.487(5) (1)-(2)-(3)-(4)
(1)-(2)-(3)-(4)
C2-N2-C3 120.8(3) N2-C3-C4 114.5(3) O2-N4 1.201(5) C1-C4
C2-N2-C14 122.4(3) C1-C4-C3 120.2(3) O3-N4 1.223(5) C2-C8
C1-N3-C7 115.4(3) C3-C4-C5 120.8(3) N1-C1 1.383(4) C3-C4
N1-C1-N3 114.5(3) C4-C5-C6 117.8(4) N1-C2 1.293(4) C4-C5
N1-C2-N2 125.2(3) C5-C6-C7 119.4(4) N2-C2 1.395(4) C5-C6
N1-C2-C8 117.6(3) N3-C7-C6 125.2(4) N2-C3 1.397(4) C6-C7
N2-C14 1.489(4) C8-C9
1.395(4) O1-C3-N2-C2 –179.9 (3) N2-C2-N1-C1
–3.9(5)
–113.7(4)
64.2(4)
1.485(4) O1-C3-N2-C14
1.445(4) O1-C3-C4-C1
1.398(5) O1-C3-C4-C5
1.366(5) C1-N1-C2-N8
1.378(6) C4-C5-C6-C7
1.393(4) C4-C1-N3-C7
–3.4(4) N1-C1-C8-C9
176.0(3) N2-C2-C8-C9
–3.0(5) N2-C14-C15-C16 136.9(4)
173.8(6) C2-N2-C14-C15 –100.5(4)
–1.3(6) C3-N2-C14-C15
–1.1(5) C8-C2-N2-C14
83.0(4)
11.0(4)
N3-C1 1.357(4) C14-C15 1.500(5)
N3-C7 1.335(5) C15-C16 1.314(5)
a The estimated standard deviations in the least significant figure are given in parentheses.
b The sign is positive if when looking from atom (2) to atom (3) a clockwise motion of atom (1) would superimpose it on atom (4). The estimated
standard deviations in the least significant figure are given in parentheses.
Reagents and conditions: (a) NH4Cl/DEPC/Et3N/DME, 0°C; then 1 h
at r.t. (46%); (b) Ph3P/hexachloroethane/Et3N/benzene, reflux, 2 h (7,
24%; 8, 22%; 9, 10%)
Reagents and conditions: (a) CH2=CHCH2NH2/DEPC/Et3N/DME,
0°C; then 1 h at r.t. (91%); (b) Ph3P/hexachloroethane/Et3N/benzene,
reflux, 2 h (77%); (c) PhCOCl/Et3N/toluene, reflux, 2 h (54%)
Scheme 3
Scheme 4

SYNTHESIS
October 1998
1473
0.165 mL, 1.00 mmol) and Et3N (0.140 mL, 1.00 mmol), respectively
at 0°C. The resultant solution was stirred at 0°C for 1 h and at 40°C
for 1 h under N2. The mixture was diluted with EtOAc (100 mL) and
pyrimidines 10 was difficult to carry out by the present
method.
Finally, we investigated the synthesis of 4(3H)-quinazoli- washed successively with H2O (10 mL), satd aq NaHCO3 solution
(10 mL), H2O (10 mL) and brine (10 mL). The combined organic lay-
ers were dried (MgSO4) and evaporated under reduced pressure to af-
none derivatives by the same methodology as follows.
The iminophosphorane having a secondary amide func-
ford the crude product, which was purified by silica gel column chro-
tion 13 prepared from anthranilic acid in two steps was
matography using EtOAc and hexane (1:1 → 2:1, v/v) as eluent and
treated with benzoyl chloride similarly to afford 4(3H)-
subsequently recrystallized from a mixture of EtOAc and hexane to
quinazolinone 14 in 54% yield (Scheme 5). This com-
pound was easily purified by silica gel column chromatog-
raphy. This method provides a complement to syntheses
of 4(3H)-quinazolinones by the intramolecular aza-Wittig
version21 and the intermolecular aza-Wittig reaction with
isocyanates.22
give the secondary amide derivative 2a; white needles (80.8 mg,
0.46 mmol, 46%).
The other secondary amides 2b–e and the primary amide derivative 6
were also obtained by a similar method (see, Table 1 and Scheme 3).
Also, the secondary amide derivative 12 was prepared by the above
method (Scheme 5). The spectral data of 2a–e are given in Tables 1–3.
2-Aminonicotinamide (6): yield 46 %; Rf 0.22 (EtOAc); white solid;
mp 199–202°C.
IR (KBr): ν = 3463, 3351, 3275, 3167, 1672, 1622, 1578, 1562, 1453,
1410, 1252, 770, 754, 642 cm–1.
1H NMR (DMSO-d6, 200 MHz): δ = 6.56 (1H, dd, J = 7.7, 4.7 Hz, H-
5), 7.17 (2H, br s, NH2), 7.31 (1H, br, CONH2), 7.93 (1H + 1H, dd +
br, J = 7.7, 1.7 Hz, H-4 + CONH2), 8.07 (1H, dd, J = 4.8, 1.8 Hz, H-6).
13C NMR (DMSO-d6, 50 MHz): δ = 109.02 (C-3), 111.54 (C-5),
137.45 (C-4), 151.95 (C-6), 159.63 (C-2), 170.38 (CONH2).
MS (EI): m/z (%) = 138 (6, M++1), 137 (100, M+), 121 (11), 120 (20),
94 (17), 93 (30), 92 (11), 84 (12), 67 (3), 66 (25), 65 (4).
HRMS: m/z calcd for C6H7N3O 137.0589, found 137.0587.
Allyl Anthranilic Carboxamide (12): yield 91%; Rf 0.35 (EtOAc/hex-
ane, 1:2); white solid; mp 83–84°C.
Reagents and conditions: (a) CH2=CHCH2NH2/DEPC/Et3N/DME,
0°C, then 1 h at r.t. (91%); (b) Ph3P/hexachloroethane/Et3N/benzene,
reflux, 2 h (77%); (c) PhCOCl/Et3N/toluene, reflux, 2 h (54%)
IR (KBr): ν = 3422, 3297, 1620, 1588, 1530, 1302, 1262, 1157, 993,
930, 750 cm–1.
1H NMR (CDCl3, 200 MHz): δ = 4.04 (2H, tt, J = 5.7, 1.6 Hz,
NCH2CH=CH2), 5.18 [1H, dq, J = 10.2, 1.4 Hz, CH=CH2 (cis)], 5.26
[1H, dq, J = 17.2, 1.6 Hz, CH=CH2 (trans)], 5.52 (2H, br s, NH2), 5.94
(1H, ddt, J = 17.2, 10.2, 5.6 Hz, CH2CH=CH2), 6.16–6.17 (1H, br,
CONH), 6.61–6.71 (2H, m, C6H4), 7.21 (1H, ddd, J = 8.2, 7.2, 1.6 Hz,
C6H4), 7.34 (1H, dd, J = 7.8, 1.6 Hz, C6H4).
Scheme 5
In conclusion, this methodology by the intermolecular
aza-Wittig reaction with acid chloride followed by hetero-
cyclization provided a facile and efficient synthesis of
4(3H)-pyrido[2,3-d]pyrimidinones and 4(3H)-quinazoli-
nones via imidoyl chloride intermediates derived from N-
pyridyliminophosphorane and N-phenyliminophospho-
rane derivatives, respectively.
13C NMR (CDCl3, 50 MHz): δ = 42.14, 116.25, 116.84, 116.93,
117.68, 127.44, 132.73, 134.67, 149.21, 169.65.
MS (EI): m/z (%) = 177 (8, M++1), 176 (72, M+), 130 (3), 121 (11),
120 (100), 119 (33), 94 (3), 65 (28), 64 (3).
HRMS: m/z calcd for C10H12N2O 176.0950, found 176.0946.
Allyl 2-(Triphenylphosphoranylideneamino)nicotinamide (3a);
Typical Procedure:
TLC was performed on E. Merck Kieselgel 60F254 pre-coated silica
gel plates (0.25 mm layer thickness). Melting points were determined
with a Yanagimoto micro-melting-point hot stage apparatus and were
To a stirred mixture of 2a (102 mg, 0.57 mmol), hexachloroethane
(134 mg, 0.57 mmol, 1.0 equiv) and Ph3P (150 mg, 0.57 mmol,
1.0 equiv) in anhyd benzene (5.0 mL) was added dropwise Et3N
(0.16 mL, 1.15 mmol, 2.0 equiv). The resultant solution was heated at
reflux for 2 h. After cooling, the mixture was filtered under reduced
pressure in order to remove the precipitates and the filtrate was evap-
orated under reduced pressure to give a solid residue, which was
purified on a silica gel column using EtOAc and hexane (1:2 → 1:1,
v/v) as eluent to afford 3a (238 mg, 0.54 mmol, 95%).
The other iminophosphorane derivatives 3b–e were also obtained by
a similar method (Table 2). The synthesis of 7 and the preparation of
nitrile derivatives 8 and 9 were carried out by a similar method
(Scheme 3). Also, the iminophosphorane derivative 13 was synthe-
sized by the above method (Scheme 5). The spectral data of 3a–e are
assembled in Tables 4–6.
1
uncorrected. H and 13C NMR spectra were obtained with a Varian
GEMINI-200 or 500 spectrometer at 200 or 500 and 50 or 125 MHz,
respectively, for samples in CDCl3 or DMSO-d6 solution with TMS
as internal standard. Chemical shifts were reported in parts per million
(δ). IR were recorded on a JASCO FT/IR 5300 spectrophotometer.
MS and HRMS were recorded on a JEOL JMS-AX 505 HA spectrom-
eter (EI and CI, 70eV). Microanalyses were performed with a Perkin-
Elmer 2400S CHN elemental analyzer. Flash chromatography was
performed with a silica gel column (Fuji Davison BW-300 or Fuji
Silysia Chemical Ltd. Chromatorex® NH-DM-1020) eluting with
mixed solvents [EtOAc (A), hexane (H)].
Benzene and toluene were stored over Na. All reactions were carried
out under N2. 2-Aminonicotinic acid (1) was purchased from Tokyo
Kasei Co., Ltd. This reagent was used without further purification.
2-(Triphenylphosphoranylidene)aminonicotinamide (7): yield 32%;
Rf 0.12 (hexane/EtOAc, 1:1); white solid; mp 258–261°C.
IR (KBr): ν = 3218, 1657, 1578, 1455, 1421, 1308, 1244, 1112, 997,
718, 692 cm–1.
Allyl 2-Aminonicotinamide (2a); Typical Procedure:
To a suspension of 1 (138 mg, 1.00 mmol) in anhyd 1,2-dimethoxy-
ethane (DME) (10.0 mL) was added dropwise DEPC (93%,

SYNTHESIS
Papers
1474
1H NMR (CDCl3, 200 MHz): δ = 5.90 (1H, d, J = 5.0 Hz, CONH2),
6.60 (1H, dd, J = 7.6, 4.8 Hz, H-5), 7.40–7.82 (15H, m, C6H5), 7.87
(1H, dd, J = 4.3, 2.1 Hz, H-4), 8.40 (1H, ddd, J = 7.6, 2.8, 2.2 Hz, H-
6), 11.02 (1H, d, J = 2.6 Hz, CONH2).
3-Allyl-2-phenyl-4(3H)-pyrido[2,3-d]pyrimidinone (5a); Typical
Procedure:
To a stirred solution of 3a (263 mg, 0.60 mmol) in anhyd toluene
(5.0 mL) was added dropwise benzoyl chloride (0.14 mL, 1.20 mmol,
2.0 equiv) and Et3N (0.17 mL, 1.20 mmol, 2.0 equiv) and the mixture
was refluxed for 2 h. After completion of the reaction (monitored by
TLC), the mixture was diluted with H2O (20 mL) and extracted with
CHCl3 (2 × 50 mL). The combined extracts were dried (MgSO4) and
evaporated under reduced pressure and the crude product was purified
by column chromatography on silica gel using EtOAc and hexane
(1:2, v/v) as eluent, Chromatorex column chromatography using
EtOAc and hexane (1:10, v/v) as eluent and, subsequently, recrystalli-
zation from EtOAc and hexane to give 5a (136 mg, 0.52 mmol, 86 %).
The other pyrido[2,3-d]pyrimidine derivatives 5b–j were synthesized
following the same procedure as above (Tables 7–9). Furthermore,
the preparation of nitrile derivative 8 and the synthesis of 4(3H)-
quinazolinone derivative 14 were carried out by the same method
(Scheme 4 and Scheme 5, respectively). The spectral data of 5a–j are
given in Tables 7–9.
13C NMR (CDCl3, 50 MHz): δ = 113.47 (C-5), 118.18 (d, J = 19.0 Hz,
C-3), 128.89 (d, J = 12.4 Hz, C'-3), 129.71 (d, J = 101.0 Hz, C'-1),
132.73 (C'-4 coupling constant could not be detected because the oth-
er peak was concealed by Ph3P=O), 133.43 (d, J = 9.6 Hz, C'-2),
139.96 (d, J = 2.8 Hz, C-4), 150.12 (C-6), 162.02 (d, J = 7.3 Hz, C-2),
169.68 (CONH2).
MS (EI): m/z (%) = 398 (19, M++1), 397 (100, M+), 396 (17), 379
(18), 378 (7), 353 (18), 320 (15), 260 (9), 183 (37).
MS (CI): m/z = 397 (MH+).
HRMS: m/z calcd for C24H20N3OP 397.1344, found 397.1335.
2-(Triphenylphosphoranylidene)aminonicotinonitrile (8): yield 22%;
Rf 0.74 (hexane/EtOac, 1:1); pale yellow solid; mp 229–231°C.
IR (KBr): ν = 3435, 2214, 1580, 1549, 1431, 1342, 1256, 1113, 1014,
719, 692 cm–1.
1H NMR (CDCl3, 200 MHz): δ = 6.44 (1H, dd, J = 7.5, 4.9 Hz, H-5),
7.40–7.59 (9H, m, C6H5), 7.63 (1H, ddd, J = 7.5, 2.6, 1.9 Hz, H-4),
7.81–7.95 (1H + 6H, m, H-6 + C6H5).
X-ray Crystal Structure Analysis of 5b:
A pale prism crystal of C16H12N4O3 having approximate dimensions
of 0.180 × 0.980 × 1.000 mm was mounted on a glass fiber. All mea-
surements were made on a Rigaku AFC5S diffractometer with graph-
ite monochromated Mo-Kα radiation (λ = 0.71069 Å) and a 2 KW
stationary anode generator. Cell constants and an orientation matrix
for data collection, obtained from a least-squares refinement using the
setting angles of 24 carefully centered reflections in range 37.38° <
2θ < 39.95° corresponded to an orthorhombic cell with dimensions: a
= 27.380 (4) Å, b = 13.579 (3) Å, c = 7.871 (4) Å, V = 2927 (3) Å3, α
= 90°, β = 90°, γ = 90°. For Z = 8 and F. W. = 308.30, the calculated
density is 1.399 g/cm3. Based on the systematic absences of (0kl: k ≠
2n, h0l: l ≠ 2n, hk0: h ≠ 2n), and the successful solution and refine-
ment of the structure, the space group was determined to be Pbca
(#61). The data were collected at a temperature of 23 ± 1°C using the
ω-2θ scan technique to a maximum 2θ value of 55.0°. Omega scans
of several intense reflections, made prior to data collection, had an
average width at half-height of 0.20° with a take-off angle of 6.0°.
Scans of (0.97 + 0.30 tan θ)° were made at a speed of 16.0°/min. (in
omega). The weak reflections (I < 10.0σ (I)) were rescanned (maxi-
mum of 2 rescans) and the counts were accumulated to assure good
counting statistics. Stationary background counts were recorded on
each side of the reflection. The ratio of peak counting time to back-
ground counting time was 2:1. The diameter of the incident beam col-
limator was 0.5 mm and the crystal to detector distance was 40 cm. A
total of 3834 was collected. The intensities of three representative re-
flections which were measured after every 150 reflections remained
constant throughout data collection indicating crystal and electronic
stability (no decay correction was applied). The linear absorption co-
efficient for Mo Kα is 0.9 cm–1. Azimuthal scans of several reflec-
tions indicated no need for an absorption correction. The data were
corrected for Lorentz and polarization effects. A correction for sec-
ondary extinction was applied (coefficient = 0.19934 × 10–5). The
structure was solved by direct method.23 The non-hydrogen atoms
were refined anisotropically. The final cycle of full-matrix least-
squares refinement was based on 1543 observed reflections (I >
2.00σ (I)) and 257 variable parameters and converged (largest param-
eter shift was 0.01 times its esd) with unweighed and weighed agree-
ment factors of: R = 0.057 and Rw = 0.057. The standard deviation of
an observation of unit weight was 1.69. The weighing scheme was
based on counting statistics and included a factor (p = 0.03, p: p-fac-
tor) to downweight the intense reflections. Plots of Σw(|Fo|–|Fc|)2
versus |Fo|, reflection order in data collection, sinθ/γ, and various
classes of indices showed no unusual trends. The maximum and min-
imum peaks on the final difference Fourier map corresponded to 0.24
and 0.27 e-/Å3, respectively. Natural atom scattering factors were tak-
en from Cromer and Waber.24 Anomalous dispersion effects were
13C NMR (CDCl3, 50 MHz): δ = 101.03 (d, J = 25.3 Hz, CN), 111.62
(C-5), 119.86 (C-3), 128.81 (d, J = 12.5 Hz, C'-3), 129.49 (d, J = 100.6
Hz, C'-1), 132.29 (d, J = 2.9 Hz, C'-4), 133.60 (d, J = 9.9 Hz, C'-2),
141.88 (d, J = 3.7 Hz, C-4), 151.73 (C-6), 165.23 (d, J = 5.1 Hz, C-2).
MS (EI): m/z (%) = 380 (18, M++1), 379 (79, M+), 378 (100), 353 (9),
302 (9), 300 (3), 261 (4), 260 (18), 259 (4), 224 (3), 190 (6), 185 (4),
184 (3), 183 (29).
HRMS: m/z calcd for C24H18N3P 379.1238, found 379.1242.
2-Aminonicotinonitrile (9): yield 10%; Rf 0.37 (hexane/EtOAc, 1:1);
white solid; mp 103–106°C.
IR (KBr): ν = 3423, 3329, 3206, 2216, 1664, 1639, 1593, 1563, 1492,
1249, 762 cm–1.
1H NMR (CDCl3, 200 MHz): δ = 5.28 (2H, br, NH2), 6.72 (1H, dd, J
= 7.6, 5.0 Hz, H-5), 7.71 (1H, dd, J = 7.6, 1.8 Hz, H-4), 8.26 (1H, dd,
J = 5.0, 1.8 Hz, H-6).
13C NMR (CDCl3, 50 MHz): δ = 91.64 (CN), 113.80 (C-5), 116.84
(C-3), 141.84 (C-4), 153.34 (C-6), 159.75 (C-2).
MS (EI): m/z (%) = 120 (6 %, M++1), 119 (100, M+), 118 (3), 93 (3),
92 (59), 91 (3), 84 (4), 66 (5), 65 (4), 64 (4).
HRMS: m/z calcd for C6H5N3 119.0483, found 119.0486.
Allyl 2-(Triphenylphosphoranylidene)aminobenzoic Carboxam-
ide (13): yield 77%; Rf 0.12 (EtOAc/hexane, 1:2); pale yellow solid;
mp 213–215°C.
IR (KBr): ν = 3019, 1631, 1590, 1533, 1468, 1437, 1335, 1269, 1110,
1013, 997, 758, 722, 693 cm–1.
1H NMR (CDCl3, 200 MHz): δ = 4.08 (2H, tt, J = 5.7, 1.6 Hz,
NCH2CH=CH2), 4.98 [1H, dq, J = 10.0, 1.6 Hz, CH=CH2 (cis)],
5.14 [1H, dq, J = 17.2, 1.8 Hz, CH=CH2 (trans)], 5.86 (1H, ddt, J =
17.0, 10.2, 5.6 Hz, CH2CH=CH2), 6.45 (1H, dt, J = 8.0, 1.2 Hz,
C6H4), 6.75 (1H, td, J = 7.5, 1.2 Hz, C6H4), 6.90 (1H, ddd, J = 8.0,
7.2, 2.0 Hz, C6H4), 7.43–7.59 (9H, m, C6H5), 7.61–7.75 (6H, m,
C6H5), 8.30 (1H, dd, J = 7.8, 2.2 Hz, C6H4), 11.40 (1H, br t, J = 5.6
Hz, CONHCH2).
13C NMR (CDCl3, 50 MHz): δ = 42.18, 115.55, 117.99, 122.92 (d, J
= 12.0 Hz), 125.35 (d, J = 20.4 Hz), 129.36 (d, J = 12.2 Hz), 129.90
(d, J = 100.0 Hz), 131.13, 131.95 (d, J = 2.5 Hz), 132.68 (d, J = 2.8
Hz), 132.89 (d, J = 9.7 Hz), 136.00, 150.32 (d, J = 3.2 Hz), 168.34 (d,
J = 1.8 Hz).
MS (EI): m/z (%) = 437 (27, M++1), 436 (91, M+), 435 (13), 382 (7),
380 (82), 378 (7), 353 (19), 352 (100), 262 (13), 201 (19), 197 (7), 191
(7), 183 (33).
HRMS: m/z calcd for C28H25N2OP 436.1705, found 436.1709.

SYNTHESIS
October 1998
1475
included in Fcalc;25 the value for ∆f' and ∆f" were those of Cromer.26
All calculations were performed using the TEXSAN27 crystallograph-
ic software package of Molecular Structure Corporation. Atomic co-
ordinate bond lengths and angle, torsion angle and thermal parameters
of 5b have been deposited with the Cambridge Crystallographic Data
Centre.
(12) Molina, P.; Conesa, C.; Velasco, M.D. Liebigs Ann. Chem.
1997, 107.
(13) Okawa, T.; Osakada, N.; Eguchi, S.; Kakehi, A. Tetrahedron
1997, 53, 16061.
(14) Takuma, S.; Hanada, Y.; Shioiri, T. Chem. Pharm. Bull. 1982,
30, 3147, and references cited therein.
3-Allyl-2-phenyl-4(3H)-quinazolinone (14): yield 54 %; Rf 0.44 (A:H
1:2); white solid; mp 78–79 °C.
(15) Appel, R.; Halstenberg, M. In Organophosphorus Reagents in
Organic Synthesis; Cadogan, J.I.G., Ed.; Academic Press: Lon-
don, 1979, pp 378ff.
(16) X-Ray data of 4(3H)-pyrido[2,3-d]pyrimidinones have not been
reported; however, for X-ray data of 2,4-diaminopyrido[2,3-
d]pyrimidines, see:
Sutton, P.A.; Cody, V. J. Am. Chem. Soc. 1988, 110, 6219.
(17) When an equivalent of NH4Cl was used, the desired compound
6 could not be obtained.
(18) DeShong, P.; Ramesh, S.; Elango, V.; Perez, J .J. J. Am. Chem.
Soc. 1985, 107, 5219.
(19) Overman, L.E.; Osawa, T. J. Am. Chem. Soc. 1985, 107, 1698.
(20) Mori, S.; Iwakura, H.; Takechi, S. Tetrahedron Lett. 1988, 29,
5391.
(21) Takeuchi, H.; Eguchi, S. Tetrahedron Lett. 1989, 30, 3313.
Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45,
6375.
IR (KBr): ν = 3065, 1680, 1605, 1588, 1566, 1472, 1427, 1375, 1333,
1252, 772, 698 cm–1.
1H NMR (CDCl3, 200 MHz): δ = 4.64 (2H, dt, J = 5.2, 1.7 Hz,
NCH2CH=CH2), 4.94 [1H, dq, J = 17.2, 1.5 Hz, CH=CH2 (trans)],
5.17 [1H, dq, J = 10.4, 1.3 Hz, CH=CH2 (cis)], 5.88 (1H, ddt, J = 17.2,
10.2, 5.2 Hz, CH2CH=CH2), 7.44–7.59 (1H + 5H, m, C6H4 + C6H5),
7.75–7.79 (2H, m, C6H4), 8.35 (1H, ddd, J = 8.0, 1.3, 1.0 Hz, C6H4).
13C NMR (CDCl3, 50 MHz): δ = 48.38, 117.68, 120.98, 127.04,
127.26, 127.71, 128.12, 128.79, 130.16, 132.37, 134.64, 135.42,
147.43, 156.45, 162.16.
MS (EI): m/z (%) = 263 (10 M++1), 262 (61, M+), 261 (100), 248 (6),
247 (43), 245 (4), 233 (4), 208 (3), 205 (3), 185 (4), 179 (4), 77 (4).
HRMS: m/z calcd for C17H14N2O 262.1106, found 262.1103.
Support by a Grant-in-Aid for Scientific Research (No. 07555285)
from the Ministry of Education, Science, Sports and Culture of Japan
is gratefully acknowledged.
(22) For the synthesis of 2-amino-4(3H)-quinazolinone, see:
Molina, P.; Alajarin, M.; Vidal, A.; Foces-Foces, C.; Cano, F.H.
Tetrahedron 1989, 45, 4263.
(23) Structure solution methods:
(1) For related references, see:
MITHRIL:
Taylor, E.C.; Dowling, J.E. J. Org. Chem. 1997, 62, 1599, and
references cited therein.
Gilmore; C.J., MITHRIL- An Integrated Direct Methods Com-
puter Program, J. Appl. Cryt. 1984, 17, 42.
(2) Barluenga, F.; Palacios, F. Org. Prep. Proced. Intl. 1991, 23, 1.
(3) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep. Proced.
Intl. 1992, 24, 209.
(4) Molina, P.; Vilaplana, M.J. Synthesis 1994, 1197.
(5) Wamhoff, H.; Rechardt, G.; Stölben, S. Adv. Heterocycl. Chem.
1996, 64, 159.
DIRDIF
Beurskens, P.T., DIRDIF: Direct Methods for Difference Struc-
tures- An Automatic Procedure for Phase Extension and Re-
finement of Difference Structure Factors, Technical Report
1984/1 Crystallographic laboratory, Toernooiveld, 6525 Ed
Nijmegen, Netherlands.
(6) Okawa, T.; Eguchi, S. Synlett 1994, 555.
(7) Okawa, T.; Eguchi, S.; Kakehi, A. J.Chem. Soc., Perkin. Trans.
1 1996, 247.
(24) Cromer, D.T.; Waber, J.T. International Tables for X-ray Cry-
stallography, Vol. IV; The Kynoch Press: Birmingham, 1974;
Table 2.2 A.
(8) Okawa, T.; Eguchi, S. Tetrahedron Lett. 1996, 37, 81.
(9) Zbiral, E.; Bauer, E.; Stroh, J. Monatsh. Chem. 1971, 102, 168.
(10) Wamhoff, H.; Hermann, S.; Stölben, S.; Nieger, M. Tetrahe-
dron 1993, 49, 581.
(11) Molina, P.; Alajarin, M.; Saez, J. R.; Foces-Foces, C.; Hernán-
dez Cano, F.; Claramunt, R.M.; Elguero, J. J.Chem. Soc., Perkin
Trans. 1 1986, 2037.
(25) Ibers, J.A.; Hamilton, W.C. Acta Crystallogr. 1964, 17, 781.
(26) Cromer, D.T. International Tables for X-ray Crystallography,
Vol. IV; The Kynoch Press: Birmingham, 1974; Table 2.3.1.
(27) TEXSAN-TEXRAY Structure Analysis Package, Molecular
Structure Corporation, 1985.