A facile synthesis of 4(3H)-Pteridinone derivatives by utilizing N-{3-[(N-substituted)carbamoyl]-2- -pyrazyl}iminophosphoranes

Article abstract of DOI:10.1055/s-1998-2122

The intermolecular aza-Wittig reaction of iminophosphoranes 4 derived from 3-aminopyrazine-2-(N-substituted)-carboxamide derivatives 2 with various acyl chlorides followed by heterocyclization provided an efficient synthetic route to 2,3-disubstituted 4(3H)-pteridinone derivatives 5.

Full text of DOI:10.1055/s-1998-2122

SYNTHESIS
August 1998
1185
A Facile Synthesis of 4(3H)-Pteridinone Derivatives by Utilizing N-{3-[(N-
Substituted)carbamoyl]-2-pyrazyl}iminophosphoranes
Tomohiro Okawa, Masaru Kawase, Shoji Eguchi*
Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-
01, Japan
Received 11 July 1997; 25 August 1997
Abstract: The intermolecular aza-Wittig reaction of iminophos-
phoranes 4 derived from 3-aminopyrazine-2-(N-substituted)-
carboxamide derivatives 2 with various acyl chlorides followed by
heterocyclization provided an efficient synthetic route to 2,3-di-
substituted 4(3H)-pteridinone derivatives 5.
ine-2-carboxylates or 2-arylpyrazino[2,3-d][3,1]oxazin-
4-ones.29 Also, we reported the synthetic route to 4(3H)-
pteridinone derivatives from the corresponding N-(2-
pyrazyl)iminophosphorane derivatives via intermolecular
aza-Wittig reaction followed by addition of alcohols or
amines for the desired heterocyclization.18, 19 As a part of
our continued research programs on the aza-Wittig reac-
tion, we wish to report here that the intermolecular aza-
Wittig reaction of iminophosphorane derivatives 4 with
various acyl chlorides followed by heterocyclization pro-
vides a facile and efficient synthetic route to 2,3-disubsti-
tuted 4(3H)-pteridinone derivatives 5.
Key words: iminophosphorane, intermolecular aza-Wittig reac-
tion, heterocyclization, 4(3H)-pteridinone
Over the past decade, the aza-Wittig methodology1–4 has
received increased attention for its utility in the formation
of C=N bonds and heterocumulene bonds. As well as
other workers we have also recently demonstrated that the
intramolecular aza-Wittig reaction is a powerful and
useful tool for the synthesis of 5–8 membered hetero-
cycles2, 5, 6 including natural products such as DC-81,7, 8
l-vasicinone,9 (–)-benzomalvin A,10 (–)-dendrobine,11
and (+)-fumiquinazoline G12 etc. On the other hand, the
intermolecular aza-Wittig reaction followed by electrocy-
clization, cycloaddition or heterocyclization, i.e., the tan-
dem aza-Wittig methodology, has been utilized for the
synthesis of many important heterocycles by Molina,3
Wamhoff,4 Quintela,13 Saito,14, 15 and Noguchi16, 17 and
co-workers. We were interested in the preparation and the
reactivity of the N-heteroaryliminophosphorane deriva-
tives because these species seem to have been less studied,
notwithstanding their promising role as building blocks
for synthesis of heterocyclic compounds. For example, we
have reported the facile synthesis of 4(3H)-pteridinone
derivatives via the intermolecular aza-Wittig reaction fol-
lowed by heterocyclization18,19 and pyrazino[2,3-e]-
[1,4]diazepin-5-one derivatives via the intramolecular
aza-Wittig reaction.20 In addition, the reaction of the imi-
nophosphorane derivatives with carboxylic acid chlorides
to give heterocyclic compounds has been reported by
Zbiral,21 Wamhoff22 and Molina23, 24 et al. They have
shown that upon warming or in the presence of tert-
amines, imidoyl chlorides are formed, which react with
internal nucleophiles to afford various heterocyclic com-
pounds such as oxazoles,21 3,1-oxazin-4-ones,22 1,2,4-tri-
azolo[5,1-c]-1,2,4-triazines23 and 6-substituted quinazoli-
no[4,3-b]-quinazolin-8-ones,24 etc.
At first, we investigated the synthesis of the correspond-
ing sec-amide derivatives 2, the precursors of N-heteroar-
yl iminophosphorane derivatives. These required amide
derivatives 2 were prepared by the condensation of 3-ami-
nopyrazine-2-carboxylic acid (1) and various primary
amines (glycine methyl ester, alkyl amines etc.) with the
aid of diethylphosphoryl cyanide (DEPC)30 or 2-chloro-
1,3-dimethylimidazolinium chloride (DMC) which are
two of the most powerful and useful condensation re-
agents (Scheme 1, Table 1). In the condensation of 3-amino-
pyrazine-2-carboxylic acid (1) and glycine methyl ester
hydrochloride (entries 1 and 2 in Table 1), the yield with
DEPC was somewhat better than that with DMC (78% vs.
74%).
Folic acid, methotrexate, L-biopterin25 and leucettidine,26
etc.areknownasnaturalproductshavingpteridineskeletons
which play an essential role in several biological process-
es and methotrexate has a long and distinguished history
(a) RNH2, condensation reagent, Et3N, DME, 0 °C, 1 h → 40 °C 1 h
Scheme 1
as an antineoplastic and an immunosuppressive drug. Al- Although the exchange reaction of ester 3 to tert-butyl
though several methods for the synthesis of these impor- amide derivative 2b was ineffective (see entry 5 in Table
tant skeletons, pteridine rings, have been reported,27, 28 2), a much better yield was obtained with DMC by the
new technologies that advance the field are still in de- condensation of 1 and tert-butylamine (see entries 3 and 4
mand. Recently, Wamhoff et al. reported the synthesis of in Table 1, 13% vs. 68%). Thus, 1 and 1-methylbut-3-enyl-
4(3H)-pteridinone derivatives from 3-aroylaminopyraz- amine, which was prepared from the corresponding alco-

SYNTHESIS
Papers
Table 1. Synthesis of sec-Amides 2a–2d by Condensation Reagents
1186
Entry R
Condensation Product Yield (%)a
Reagents
1
2
3
4
5
6
–CH2CO2CH3
–CH2CO2CH3
t-Bu
t-Bu
s-Bu
DEPCb
DMCc
DEPC
DMC
2a
2a
2b
2b
2c
2d
78
74
13
68
45
32
Scheme 2
DMC
–CH(CH3)CH2CH=CH2 DMC
entry 5 in Table 2, for the characterization of 2a–2g, see
Tables 3–5).
a Isolated yields.
b Diethylphosphoryl cyanide.
c 2-Chloro-1,3-dimethylimidazolinium chloride.
The synthesis of N-heteroaryliminophosphorane deriva-
tives 4a–4g was carried out by the Appel method, i.e. the
modified Kirsanov reaction.31 The sec-amide derivatives
2a–2g were easily and directly converted into the corre-
sponding iminophosphoranes 4a–4g by a triphenylphos-
phine/hexachloroethane/triethylamine reagent system in
benzene under reflux (Scheme 3, Table 6, for the charac-
terization of 4a–4g, see Tables 7–9).
hol by Mitsunobu reaction and Gabriel synthesis, were ef-
fectively condensed by using DMC (entries 5 and 6 in Ta-
ble 1).
The exchange reactions of ester 3 to sec-amide derivatives
2 proceeded using primary amines as solvent in the pres-
ence of various bases (Scheme 2, Table 2). When allyl
amine and sodium hydride were used at room tempera-
ture, the corresponding sec-amide derivative 2e was pro-
duced in only 18% yield together with an unidentified
product in 18% yield. When potassium hydroxide was
used at room temperature, the desired sec-amide 2e was
obtained in 51% yield. Also, when 1,8-diazabicyc-
lo[5.4.0]undec-7-ene (DBU) was used at room tempera-
ture, the desired sec-amide 2e was obtained in quantitative
yield. Thus, we decided to employ DBU as the base in the
exchange reactions of ester 3 to sec-amide derivatives 2b,
2c and 2e–2g. This reaction proceeded quantitatively with
allyl-, propyl-, isopropyl- and sec-butylamines. But it did
not proceed smoothly with hindered amines such as tert-
BuNH2, giving only 1% yield (3% based on consumed 3,
Scheme 3
Finally, the synthesis of 4(3H)-pteridinone derivatives
5a–5m (Scheme 4) was examined by the intermolecular
aza-Wittig reaction and heterocyclization as follows. To a
solution of the iminophosphorane derivative 4a in anhy-
drous toluene was added dropwise benzoyl chloride (2.0
equiv) and triethylamine (2.0 equiv). The mixture was
heated to reflux for 4 hours to provide the desired 4(3H)-
pteridinone derivative 5a. Moreover this reaction was per-
formed without triethylamine to realize the mechanism of
4(3H)-pteridinone formation (entry 2 in Table 10). As a
result, 4(3H)-pteridinone derivative 5a and the N-benzoyl
amide derivative 7a were obtained in 12% and 40% yield,
respectively (Scheme 5). Taking the isolation of the
N-benzoyl amide derivative 7a into consideration, imi-
doyl chloride 6 must participate as the key intermediate in
the consecutive reaction. The imidoyl chloride intermedi-
ate 6 could not be isolated due to its high reactivity.
Table 2. Exchange Reaction of Ester 3 to sec-Amides 2b, 2c, 2e–2g
Entry
R
Products
Yield (%)a
1
2
3
4
5
allyl
Pr
i-Pr
s-Bu
t-Bu
2e
2f
2g
2c
2b
100
100
90 (100)b
100
1 (3)b
a Isolated yield.
b Based on consumed 3.
Table 3. Characterization (mp, Rf, IR) of Compounds 2a–2g Prepared
Products
mp (°C)
Rf (A/H)a
IR (KBr or neat) ν (cm–1)
2a
2b
2c
2d
2e
2f
135–136
84–85
28
oil
63–66
oil
0.25
0.67
0.49
0.48
0.52
0.37
0.46
3416, 3382, 3258, 3154, 1757, 1740, 1667, 1616, 1534, 1514, 1213, 1169
3407, 2967, 1661, 1611, 1514, 1236, 932, 847, 814
3449, 1692, 1663, 1539, 1412, 1379, 1265, 1219, 1020, 777, 750
3387, 3324, 2975, 1655, 1597, 1516, 1435, 1235, 1163, 920, 816
3399, 3326, 1657, 1597, 1518, 1433, 1236, 1161, 993, 918, 814
3401, 3320, 2965, 1655, 1601, 1534, 1522, 1435, 1236, 1161, 814
3391, 3318, 2973, 1655, 1599, 1514, 1460, 1433, 1179, 959, 910, 810
2g
61–62
a EtOAc/hexane (A/H) (1:1).

SYNTHESIS
August 1998
1187
Table 4. Characterization (1H, 13C NMR) of Compounds 2a–2g Prepared
Product
1H NMR (CDCl3/TMS, 200 MHz), δ, J (Hz)
13C NMR (CDCl3/TMS, 50 MHz) δ
2a
8.32 (1H, br s, CONH), 8.17 (1H, d, J = 2.3, H-5), 7.83 (1H, d, J = 2.3, 170.57 (CO2), 166.81 (CONH), 155.46 (C-3), 147.42
H-6), 7.0–6.0 (2H, br, NH2), 4.22 (2H, d, J = 5.8, NHCH2CO), 3.80 (3H, (C-5), 132.31 (C-6), 126.32 (C-2), 52.62 (OCH3), 41.12
s, OCH3)
(NHCH2CO)
2b
2c
8.11 (1H, d, J = 2.4, H-5), 7.85 (1H, br s, CONH), 7.76 (1H, d, J = 2.4, 165.95 (CONH), 155.53 (C-3), 146.63 (C-5), 131.63
H-6), 7.2–5.5 (2H, br, NH2), 1.47 [9H, s, C(CH3)3]
(C-6), 127.86 (C-2), 51.19 [NHC(CH3)3], 28.87
[C(CH3)3]
8.14 (1H, d, J = 2.4, H-5), 7.78 (1H, d, J = 2.4, H-6), 7.75–7.69 (1H, br, 165.84 (CONH), 155.56 (C-3), 146.81 (C-5), 131.83
CONH), 7.3–5.5 (2H, br, NH2), 4.04 [1H, d-sextet, J = 9.0, 6.6, (C-6), 127.25 (C-2), 46.60 [NHCH(CH3)CH2], 29.82
NHCH(CH3)CH2], 1.59 (2H, qd, J = 7.4, 6.8, CHCH2CH3), 1.24 (3H, d, (CHCH2CH3), 20.53 (CHCH3), 10.49 (CH2CH3)
J = 6.8, CHCH3), 0.96 (3H, t, J = 7.4, CH2CH3)
2d
2e
8.13 (1H, d, J = 2.4, H-5), 7.78 (1H, d, J = 2.4, H-6), 7.82–7.67 (1H, br, 165.74 (CONH), 155.53 (C-3), 146.83 (C-5), 134.61
CONH), 7.3–6.0 (2H, br, NH2), 5.84 (1H, ddt, J = 17.1, 10.1, 7.2, (CH2CH=CH2), 131.87 (C-6), 127.11 (C-2), 118.29
CH2CH=CH2), 5.13 [1H, dq, J = 16.8, 1.2, CH=CH2 (trans)], 5.11 [1H, (CH=CH2),
44.69
[NHCH(CH3)CH2],
41.03
dq, J = 10.4, 1.1, CH=CH2 (cis)], 4.20 [1H, d-sextet, J = 8.6, 6.6, (CHCH2CH=CH2), 20.34 (CHCH3)
NHCH(CH3)CH2], 2.34 (2H, ddt, J = 7.2, 6.6, 1.3, CHCH2CH=CH2),
1.26 (3H, d, J = 7.0, CHCH3)
8.15 (1H, d, J = 2.4, H-5), 8.10–7.95 (1H, br, CONH), 7.80 (1H, d, J = 166.37 (CONH), 155.53 (C-3), 147.03 (C-5), 134.31
2.4, H-6), 7.4–5.9 (2H, br, NH2), 5.94 (1H, ddt, J = 17.2, 10.2, 5.4, (CH2CH=CH2), 131.94 (C-6), 126.88 (C-2), 116.78
CH2CH=CH2), 5.27 [1H, dq, J = 17.2, 1.6, CH=CH2 (trans)] 5.19 [1H, (CH=CH2), 41.61 (NHCH2CH=CH2)
dq, J = 10.2, 1.4, CH=CH2 (cis)], 4.06 (2H, ddt, J = 6.1, 5.5, 1.6,
NHCH2CH=CH2)
2f
8.14 (1H, d, J = 2.4, H-5), 8.05–7.85 (1H, br, CONH), 7.78 (1H, d, J =
2.4, H-6), 7.5–6.0 (2H, br, NH2), 3.39 (2H, td, J = 7.0, 6.2, NHCH2CH2), (C-6), 127.16 (C-2), 40.99 (NHCH2CH2), 22.93
1.65 (2H, sextet, J = 7.3, CH2CH2CH3), 0.99 (3H, t, J = 7.4, CH2CH3) (CH2CH2CH3), 11.48 (CH2CH3)
166.44 (CONH), 155.51 (C-3), 146.83 (C-5), 131.85
2g
8.13 (1H, d, J = 2.4, H-5), 7.78 (1H, d, J = 2.4, H-6), 7.83–7.65 (1H, br, 165.63 (CONH), 155.54 (C-3), 146.80 (C-5), 131.83
CONH), 7.2–6.3 (2H, br, NH2), 4.21 [1H, d-septet, J = 8.2, 6.6, (C-6), 127.23 (C-2), 41.30 [NHCH(CH3)2], 22.81
NHCH(CH3)2], 1.27 [6H, d, J = 6.6, CH(CH3)2]
[CH(CH3)2]
Table 5. Characterization (MS, HRMS) of Compounds 2a–2g Prepared
Products MS (70 eV), m/z (%)
HRMS (70 eV), m/z, Found (Formula, Calcd.)
2a
210 (71, M+), 178 (23), 167 (15), 151 (88), 123 (31), 122 (95), 95 (37), 94 (100), 210.0751 (C8H10N4O3, 210.0753)
68 (13), 67 (24)
2b
194 (45, M+), 180 (8), 179 (100), 138 (13), 122 (44), 95 (12), 94 (46), 68 (6),
67 (8)
194.1167 (C9H14N4O, 194.1167)
2c
194 (29, M+), 166 (8), 165 (100), 138 (6), 122 (70), 95 (8), 94 (50), 72 (30), 67 (8) 194.1167 (C9H14N4O, 194.1167)
2d
206 (3, M+), 166 (13), 165 (100), 138 (3), 123 (5), 122 (79), 95 (6), 94 (80), 68
(3), 67 (12)
206.1167 (C10H14N4O, 206.1168)
2e
2f
178 (100, M+), 163 (22), 162 (19), 161 (21), 160 (14), 150 (20), 133 (16), 123 178.0854 (C8H10N4O, 178.0855)
(10), 122 (18), 95 (90), 94 (87), 68 (49), 67 (47)
180 (62, M+), 167 (33), 151 (30), 149 (100), 122 (71), 95 (27), 94 (72), 85 (18), 180.1011 (C8H12N4O 180.1011)
83 (19), 81 (19), 71 (42), 70 (18), 69 (41)
2g
180 (55, M+), 165 (37), 122 (75), 95 (22), 94 (100), 68 (15), 67 (19)
180.1011 (C8H12N4O 180.1011)

SYNTHESIS
Papers
1188
Table 6. Synthesis of Iminophosphoranes 4a–4g by the Modified
Kirsanov Reaction
Entry
R
Products
Yield (%)a
Scheme 6
1
2
3
4
5
6
7
–CH2CO2CH3
t-Bu
s-Bu
–CH(CH3)CH2CH=CH2
allyl
Pr
4a
4b
4c
4d
4e
4f
100
96
72
89
100
83
even at room temperature in a few hours (entries 5 and 6
in Table 10). The reaction with isobutyroyl chloride pro-
duced the desired 4(3H)-pteridinone derivative 5d in a
moderate yield; however, that with acetyl chloride gave
only acetyl amide derivative 7b. The expected 3-(methoxy-
carbonylmethyl)-2-methyl-4(3H)-pteridinone (5e) was
not probably produced because it is sensitive to hydrolysis
due to less steric hindrance than the other 4(3H)-pteridi-
none derivatives 5a–5d. Further, the other iminophosphor-
ane derivatives 4c–4g (R were simple alkyl groups)
showed similar reactivity to afford the desired 4(3H)-pte-
ridinone derivatives 5f–5k, 5m in satisfactory yields (en-
tries 7–12 and 14 in Table 10). However, in the case of the
tert-butyl amide derivative 4b, the corresponding 4(3H)-
pteridinone derivatives 5l was produced in a low yield ac-
companied by a small amount of 2-phenyl-4(3H)-pteridin-
one (8) as a byproduct (entry 13 in Table 10). Because a
tert-butyl group is well known as very bulky and sensitive
to heat and acid to be removed as isobutene, the above-
mentioned side reaction must have occurred. Besides, the
reaction of iminophosphorane 4a and trifluoroacetic an-
hydride instead of acyl chloride resulted in the formation
of unidentified compounds, affording none of the desired
product. In the synthesis of a series of these 4(3H)-pteridin-
one derivatives 5, Chromatorex® (NH-DM-1020)32 was
used to isolate the desired compounds (e.g. 5h, 5k–5m)
because Rf values of these compounds on silica gel TLC
were the same as that of triphenylphosphine oxide, which
was the inevitable byproduct in the aza-Wittig reaction.
i-Pr
4g
93
a Isolated yield
Scheme 4
Scheme 5
In addition, N-benzoyl amide 7a was also produced in
72% yield by the reaction of sec-amide 2a with benzoyl
chloride in the presence of triethylamine at 120°C for 4
hours to confirm the given structure (Scheme 6).
In addition, we investigated the possibility of extended
ring construction of the 4(3H)-pteridinone derivative. The
reaction of iminophosphorane 4a and o-azidobenzoyl
chloride, which was derived from anthranilic acid in two
steps, led to the 4(3H)-pteridinone derivative 9 having an
azide function. This compound 9 was treated with tri-
phenylphosphine to give the corresponding iminophos-
The other aroyl chlorides were reactive as benzoyl chlo-
ride and the substituent effects were not observed (entries
1, 3 and 4 in Table 10). Alkyl acyl chlorides were found
to be more reactive than aroyl chlorides and the intermo-
lecular aza-Wittig reaction with acyl chlorides proceeded
Table 7. Characterization (mp, Rf, IR) of Compounds 4a–4g Prepared
Products
mp (°C)
Rf (EtOAc)
IR (KBr or neat) ν (cm–1)
4a
4b
4c
4d
4e
4f
55–56
194–200
162–165
45–50
132–135
60–61
0.09 (tailing)
0.10 (tailing)
0.10 (tailing)
0.10 (tailing)
0.10 (tailing)
0.10 (taling)
0.10 (tailing)
2973, 1750, 1665, 1549, 1512, 1451, 1400, 1219, 1171, 1115, 750, 723, 694
3422, 2967, 1665, 1551, 1512, 1439, 1400, 1115, 993, 750, 723, 693
2965, 1657, 1547, 1510, 1439, 1399, 1173, 1115, 993, 750, 723, 694
2967, 1657, 1547, 1439, 1399, 1171, 1115, 993, 750, 723, 693
3420, 3194, 1690, 1618, 1439, 1420, 1200, 654
3181, 2965, 1657, 1549, 1512, 1449, 1399, 1175, 1115, 995, 847, 721, 693
3428, 2971, 1657, 1545, 1439, 1399, 1161, 1115, 995, 721, 693
4g
202–208

SYNTHESIS
August 1998
1189
Table 8. Characterization (1H, 13C NMR) of Compounds 4a–4g Prepared
Product
1H NMR (CDCl3/TMS, 200 MHz), δ, J (Hz)
13C NMR (CDCl3/TMS, 50 MHz), δ, J (Hz)
4a
11.52 (1H, br s, CONH), 7.99 (1H, d, J = 2.4, H-5), 7.86–7.74 171.19 (CO2), 165.97 (CONH), 158.66 (d, J = 7.3, C-3), 143.33
(1H + 6H, m, H-6 + C6H5), 7.63–7.42 (9H, m, C6H5), 4.41 (2H, (C-5), 136.53 (d, J = 4.2, C-2), 133.75 (C-6), 133.45 (d, J = 9.9,
d, J = 5.6, NHCH2CO), 3.73 (3H, s, OCH3)
C-2′), 132.64 (d, J = 2.8, C-4′), 129.02 (d, J = 12.3, C-3′), 128.53
(d, J = 101.1, C-1′), 52.15 (OCH3), 41.78 (NHCH2CO)
4b
4c
10.52 (1H, br s, CONH), 7.96 (1H, d, J = 2.4, H-5), 7.80–7.69 164.62 (CONH), 158.22 (d, J = 7.5, C-3), 142.52 (C-5), 138.48
(1H + 6H, m, H-6 + C6H5), 7.64–7.41 (9H, m, C6H5), 1.43 [9H, (d, J = 19.6, C-2), 133.79 (C-6), 133.50 (d, J = 9.9, C-2′), 132.61
s, C(CH3)3]
(d, J = 2.6, C-4′), 128.98 (d, J = 12.3, C-3′), 128.84 (d, J = 101.0,
C-1′), 50.95 [C(CH3)3], 29.10 [C(CH3)3]
10.90 (1H, d, J = 8.2, CONH), 8.00 (1H, d, J = 2.4, H-5), 7.81– 164.91 (CONH), 158.41 (d, J = 7.6, C-3), 142.73 (C-5), 137.70
7.69 (1H + 6H, m, H-6 + C6H5), 7.63–7.43 (9H, m, C6H5), 4.25 (d, J = 19.1, C-2), 133.86 (C-6), 133.39 (d, J = 10.0, C′-2),
[1H, d-sextet, J = 8.2, 6.6, NHCH(CH3)CH2], 1.52 (2H, qd, J 132.68 (d, J = 2.8, C′-4), 129.03 (d, J = 12.4, C′-3), 128.74 (d, J
= 7.4, 6.6, CHCH2CH3), 1.21 (3H, d, J = 6.6, CHCH3), 0.87 = 101.1, C′-1), 46.52 [NHCH(CH3)CH2], 29.86 (CHCH2CH3),
(3H, t, J = 7.4, CH2CH3)
20.88 (CHCH3), 10.51 (CH2CH3)
4d
10.97 (1H, d, J = 8.0, CONHCH2), 8.00 (1H, d, J = 2.4, H-5), 164.80 (CONH), 158.31 (d, J = 7.4, C-3), 142.81 (C-5), 137.58
7.81–7.69 (1H + 6H, m, H-6 + C6H5), 7.65–7.43 (9H, m, (d, J = 19.2, C-2), 135.57 (CH2CH=CH2), 133.88 (C-6), 133.43
C6H5), 5.76 (1H, ddt, J = 18.0, 9.2. 7.1, CH2CH=CH2), 4.91 (d, J = 10.0, C′-2), 132.71 (d, J = 2.8, C′-4), 129.05 (d, J = 12.6,
[1H, dq, J = 9.2, 0.8, CH=CH2 (cis)], 4.89 [1H, dq, J = 18.0, C′-3), 128.72 (d, J = 101.3, C′-1), 117.32 (CH=CH2), 44.63
0.8, CH=CH2 (trans)], 4.44 [1H, d-sextet, J = 8.2, 6.6, [NHCH(CH3)CH2], 41.24 (CHCH2CH=CH2), 20.68 (CHCH3)
NHCH(CH3)CH2], 2.27 (2H, tt,
J
=
6.8, 1.2,
CHCH2CH=CH2), 1.22 (3H, d, J = 6.8, CHCH3)
4e
4f
11.26 (1H, br s, CONH), 8.01 (1H, d, J = 2.4, H-5), 7.81–7.69 165.58 (CONH), 158.39 (d, J = 7.5, C-3), 143.01 (C-5), 137.36
(1H + 6H, m, H-6 + C6H5), 7.63–7.41 (9H, m, C6H5), 6.01 (1H, (d, J = 19.1, C-2), 135.50 (CH2CH=CH2), 133.87 (C-6), 133.38
ddt, J = 17.2, 10.2, 5.8, CH2CH=CH2), 5.29 [1H, dq, J = 17.2, (d, J = 9.8, C′-2), 132.68 (d, J = 2.8, C′-4), 129.05 (d, J = 12.5,
1.6, CH=CH2 (trans)], 5.14 [1H, dq, J = 10.2, 1.5, CH=CH2 C′-3), 128.62 (d, J = 101.2, C′-1), 116.56 (CH=CH2), 42.59
(cis)], 4.23 (2H, tt, J = 5.7, 1.5, NHCH2CH=CH2)
(NHCH2CH=CH2)
11.09 (1H, br s, CONH), 8.00 (1H, d, J = 2.4, H-5), 7.81–7.69 165.65 (CONH), 158.29 (d, J = 7.8, C-3), 142.80 (C-5), 137.61
(1H + 6H, m, H-6 + C6H5), 7.64–7.43 (9H, m, C6H5), 3.52 (2H, (d, J = 19.2, C-2), 133.82 (C-6), 133.32 (d, J = 10.1, C′-2),
td, J = 7.0, 5.6, NHCH2CH2), 1.62 (2H, sextet, J = 7.3, 132.68 (d, J = 2.9, C′-4), 129.02 (d, J = 12.1, C′-3), 128.66 (d, J
CH2CH2CH3), 0.90 (3H, t, J = 7.4, CH2CH3)
= 101.1, C′-1), 41.63 (NHCH2CH2), 22.81 (CH2CH2CH3), 11.75
(CH2CH3)
4g
10.89 (1H, d, J = 7.6, CONHCH2), 7.99 (1H, d, J = 2.2, H-5), 164.72 (CONH), 158.29 (d, J = 7.5, C-3), 142.77 (C-5), 137.63
7.82–7.70 (1H + 6H, m, H-6 + C6H5), 7.64–7.43 (9H, m, (d, J = 19.1, C-2), 133.83 (C-6), 133.40 (d, J = 9.9, C′-2), 132.68
C6H5), 4.41 [1H, d-septet, J = 7.6, 6.6, NHCH(CH3)2], 1.23 (d, J = 2.8, C′-4), 129.03 (d, J = 12.5, C′-3), 128.72 (d, J = 101.2,
[6H, d, J = 6.6, CH(CH3)2]
C′-1), 41.22 [NHCH(CH3)2], 23.20 [CH(CH3)2]
Table 9. Characterization (MS, HRMS) of Compounds 4a–4g Prepared
Products MS (70 eV), m/z (%)
HRMS (70 eV), m/z, Found (Formula, Calcd.)
4a
4b
4c
4d
4e
4f
471 (26, M + 1), 470 (89, M+), 412 (11), 411 (42), 398 (7), 397 (27), 382 (7), 470.1497 (C26H23N4O3P, 470.1508)
355 (21), 354 (100), 352 (8), 262 (12), 201 (9), 183 (24)
455 (19, M + 1), 454 (62, M+), 440 (11), 439 (38), 398 (22), 397 (11), 382 (24), 454.1923 (C27H27N4OP, 454.1923)
355 (26), 354 (100), 262 (14), 212 (13), 183 (30)
455 (16, M + 1), 454 (52, M+), 425 (13), 383 (11), 382 (16), 355 (28), 354 (100), 454.1922 (C27H27N4OP, 454.1923)
262 (11), 208 (8), 183 (17)
466 (17, M+), 426 (14), 425 (50), 383 (10), 382 (30), 355 (22), 354 (100), 262 466.1922 (C28H27N4OP, 466.1923)
(15), 205 (9), 183 (25), 178 (11), 108 (9)
439 (18, M + 1), 438 (61, M+), 397 (12), 394 (9), 355 (25), 354 (100), 262 (12), 438.1607 (C26H23N4OP, 438.1609)
201 (9), 183 (22)
441 (19, M + 1), 440 (61, M+), 425 (6), 411 (8), 397 (12), 383 (7), 382 (7), 355 440.1766 (C26H25N4OP, 440.1766)
(27), 354 (100), 262 (10), 183 (21), 108 (6)
4g
441 (16, M + 1), 440 (54, M+), 397 (12), 355 (31), 354 (100), 183 (20)
440.1765 (C26H25N4OP, 440.1766)

SYNTHESIS
Papers
1190
Table 10. Synthesis of 4(3H)-Pteridinone Derivatives 5a–5m via the
Intermolecular Aza-Wittig Reaction Followed by Heterocyclization
Entry R
R′
Products Yield (%)a
1
2b
3
4
5
6
7
8
9
–CH2CO2CH3
Ph
Ph
5a
68
–CH2CO2CH3
–CH2CO2CH3
–CH2CO2CH3
–CH2CO2CH3
–CH2CO2CH3
–CH2CH=CH2
Pr
5a + 7ac 12 + 40
4-CH3OC6H4 5b
4-NO2C6H4 5c
i-Pr
CH3
Ph
52
61
47
5d
5e
5f
5g
5h
0d
89
53
91
Ph
Ph
i-Pr
10
i-Pr
i-Pr
s-Bu
t-Bu
4-CH3OC6H4 5i
4-NO2C6H4 5j
49
67
98
37 + 14
89
11
12
13
14
Ph
Ph
5k
5l + 8
5m
–CH(CH3)CH2CH=CH2 Ph
a Isolated yield.
b Absence of Et3N.
c Vide infra.
d Obtained compound was only 7b.
phorane intermediate 10 via Staudinger reaction, which was
then heated without purification to produce the seven mem-
bered ring compound 11, 4(3H)-pteridinone fused with a
1,4-benzodiazepine skeleton, via intramolecular aza-Wittig
reaction with the ester carbonyl function (Scheme 7).
Scheme 7
In conclusion, a facile and efficient method for synthesis
of 4(3H)-pteridinone derivatives via N-pyrazylimino-
phosphorane derivatives has been established.
carried out under N2 or argon. 3-Aminopyrazine-2-carboxylic acid (1)
and DMC were supplied by Nippon Soda Co., Ltd. and Shiratori Phar-
maceutical Co., Ltd., respectively. Methyl 3-aminopyrazine-2-car-
boxylate (3) and DEPC were purchased from Sigma–Aldrich Japan
K. K. and Tokyo Kasei Co., Ltd., respectively. These reagents were
used without further purification.
Mps were determined with a Yanagimoto micro-melting-point hot-
stage apparatus and were uncorrected. IR spectra were recorded on a
1
JASCO FT/IR 5300 spectrophotometer. H and 13C NMR spectra
3-Amino-N-(methoxycarbonylmethyl)pyrazine-2-carboxamide
(2a); Typical Procedure:
The condensation reaction (see Scheme 1).
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 an internal standard. Chemical shifts
were reported in ppm (δ). MS and HRMS were recorded on a JEOL
JMS-AX 505 HA mass spectrometer (EI and CI, 70 eV). Flash chro-
matography was performed with a silica gel column (Fuji–Davison
BW-300) and Chromatorex® (NH-DM-1020).32 TLC was performed
on Merck Kieselgel 60 F254 pre-coated silica plates (0.15 mm layer
thickness). All reactions except for amide exchange reactions were
To a mixture of 3-aminopyrazine-2-carboxylic acid (1) (714 mg,
5.13 mmol) and glycine methyl ester hydrochloride (773 mg,
6.16 mmol) in anhyd DME (30.0 mL) was added dropwise DEPC
(93%, 1.00 mL, 6.16 mmol) and Et3
N (1.70 mL, 12.2 mmol) respec-
tively 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 (500 mL)
Table 11. Characterization (mp, Rf, IR) of Compounds 5a–5m Prepared
Products
mp (°C)
Rf (Solvent)a
IR (KBr or neat) ν (cm–1)
5a
5b
5c
5d
5f
5g
5h
5i
178–179
228.5–229
86–90
0.08 (A/H 2:1)
0.27 (A)
0.41 (A)
0.29 (A)
0.29 (A)
0.24 (A)
0.10 (2:1)
0.30 (A)
0.30 (A)
0.19 (A/H 3:1)
3343, 1753, 1696, 1659, 1589, 1489, 1451, 1256, 704
1742, 1701, 1609, 1586, 1561, 1543, 1518, 1426, 1366, 1258, 1225, 1175
3007, 1752, 1705, 1580, 1543, 1524, 1420, 1350, 1229, 752
2978, 1752, 1701, 1588, 1561, 1543, 1464, 1424, 1373, 1217, 752
1686, 1543, 1408, 1366, 1337, 1265, 1217, 926, 704
2955, 1692, 1561, 1543, 1449, 1418, 1368, 1211, 1140, 704
2998, 2920, 1694, 1576, 1541, 1416, 1395, 1345, 1215, 1074, 745, 704
2932, 1692, 1607, 1561, 1537, 1510, 1418, 1294, 1260, 1073, 1032, 831, 750
3079, 1692, 1576, 1545, 1520, 1414, 1350, 1290, 1202, 1071, 858, 714
1699, 1578, 1439, 1416, 1395, 1343, 1194, 1121, 721, 696
oil
159–160
164–165
235
237.5–238
>300
5j
5k
160–166
5l
5m
277–285 (dec.)
127–131
0.36 (A)
0.36 (A)
3056, 1696, 1555, 1535, 1483, 1402, 1370, 1343, 1314, 1287, 675
3056, 1699, 1580, 1541, 1416, 1395, 1345, 1290, 1209, 1119, 914, 828, 698
a EtOAc (A) and hexane (H)

SYNTHESIS
August 1998
1191
Table 12. Characterization (1H, 13C NMR) of Compounds 5a–5m Prepared
Product 1H NMR (CDCl3/TMS, 200 MHz) δ, J (Hz)
13C NMR (CDCl3/TMS, 50 MHz) δ
5a
9.01 (1H, d, J = 2.0, H-7), 8.88 (1H, d, J = 2.0, H-6), 7.65– 168.12 (CO2), 161.59 (C-8a), 160.26 (C-4), 154.00 (C-2), 151.08
7.48 (5H, m, C6H5), 4.78 (2H, s, NCH2CO), 3.78 (3H, s, (C-7), 145.45 (C-6), 134.08 (C-4a), 132.53 (C′-1), 131.37 (C′-4),
OCH3)
129.36 (C′-2), 128.27 (C′-3), 53.06 (OCH3), 48.41 (NCH2CO)
5b
8.99 (1H, d, J = 2.0, H-7), 8.85 (1H, d, J = 2.0, H-6), 7.64– 168.34 (CO2), 162.22 (C′-4), 161.90 (C-4), 160.24 (C-8a), 154.10
7.57 (2H, m, C6H4), 7.06–6.99 (2H, m, C6H4), 4.82 (2H, s, (C-2), 151.05 (C-7), 145.23 (C-6), 132.41 (C-4a), 130.36 (C′-2),
NCH2CO), 3.89 (3H, s, C6H4OCH3), 3.80 (3H, s, CO2CH3)
126.32 (C′-1), 114.70 (C′-3), 55.67 (C6H4OCH3), 53.10 (CO2CH3),
48.79 (NCH2CO)
5c
5d
5f
9.05 (1H, d, J = 2.0, H-7), 8.93 (1H, d, J = 2.2, H-6), 8.45– 167.95 (CO2), 161.15 (C-4), 158.11 (C-8a), 153.77 (C-2), 151.31
8.38 (2H, m, C6H4), 7.89–7.83 (2H, m, C6H4), 4.73 (2H, s, (C-7), 149.61 (C′-4), 146.13 (C-6), 139.72 (C′-1), 132.78 (C-4a),
NCH2CO), 3.80 (3H, s, OCH3)
129.80 (C′-2), 124.63 (C′-3), 53.40 (OCH3), 48.15 (NCH2CO)
8.96 (1H, d, J = 2.0, H-7), 8.82 (1H, d, J = 2.0, H-6), 5.03 168.10 (CO2), 166.44 (C-8a), 161.70 (C-4), 154.09 (C-2), 150.83
(2H, s, NCH2CO), 3.83 (3H, s, OCH3), 2.98 [1H, septet, J = (C-7), 144.99 (C-6), 132.23 (C-4a), 53.24 (OCH3), 44.86
6.6, CH(CH3)2], 1.45 [6H, d, J = 6.6, CH(CH3)2]
(NCH2CO), 33.05 [CH(CH3)2], 21.05 [CH(CH3)2]
9.00 (1H, d, J = 2.2, H-7), 8.87 (1H, d, J = 2.0, H-6), 7.70– 161.58 (C-4), 161.04 (C-8a), 153.92 (C-2), 150.95 (C-7), 145.31
7.46 (5H, m, C6H5), 5.93 (1H, ddt, J = 17.3, 10.3, 5.2, (C-6), 134.62 (C′-1), 132.71 (C-4a), 131.69 (CH2CH=CH2), 131.08
CH2CH=CH2), 5.23 [1H, ddd, J = 10.4, 2.3, 1.5, CH=CH2 (C′-4), 128.92 (C′-2), 128.44 (C′-3), 118.88 (CH=CH2), 49.36
(cis)], 5.00 [1H, ddd, J = 17.2, 2.4, 1.6, CH=CH2 (trans)], (NCH2CH=CH2)
4.74 (2H, dt, J = 5.4, 1.6, NCH2CH=CH2)
5g
8.98 (1H, d, J = 2.0, H-7), 8.86 (1H, d, J = 2.0, H-6), 7.63– 161.76 (C-4), 161.00 (C-8a), 153.80 (C-2), 150.84 (C-7), 145.21
7.51 (5H, m, C6H5), 4.08 (2H, t, J = 7.7, NCH2CH2), 1.70 (C-6), 134.98 (C′-1), 132.72 (C-4a), 130.85 (C′-4), 129.09 (C′-2),
(2H, sextet, J = 7.6, CH2CH2CH3), 0.79 (3H, t, J = 7.5, 128.21 (C′-3), 48.58 (NCH2CH2), 21.90 (CH2CH2CH3), 11.08
CH2CH3)
(CH2CH3)
5h
5i
8.96 (1H, d, J = 2.0, H-7), 8.83 (1H, d, J = 2.0, H-6), 7.60– 161.93 (C-4), 161.29 (C-8a), 153.40 (C-2), 150.69 (C-7), 145.08
7.54 (5H, m, C6H5), 4.48 [1H, septet, J = 6.8, NCH(CH3)2], (C-6), 135.75 (C′-1), 133.51 (C-4a), 130.73 (C′-4), 129.21 (C′-2),
1.64 [6H, d, J = 6.8, CH(CH3)2]
127.72 (C′-3), 55.57 [NCH(CH3)2], 19.47 [CH(CH3)2]
8.94 (1H, d, J = 1.6, H-7), 8.80 (1H, d, J = 1.8, H-6), 7.62– 162.20 (C′-4), 161.74 (C-4), 161.28 (C-8a), 153.47 (C-2), 150.65
7.54 (2H, m, C6H4), 7.08–7.01 (2H, m, C6H4), 4.58 [1H, sep- (C-7), 144.86 (C-6), 133.36 (C-4a), 129.77 (C′-2), 127.96 (C′-1),
tet, J = 6.8, NCH(CH3)2], 3.90 (3H, s, OCH3), 1.67 [6H, d, J 114.51 (C′-3), 55.61 [OCH3 and NCH(CH3)2 may be overlapped],
= 6.8, CH(CH3)2]
19.65 [NCH(CH3)2]
5j
8.99 (1H, d, J = 2.0, H-7), 8.88 (1H, d, J = 2.2, H-6), 8.47– 161.51 (C-4), 158.98 (C-8a), 153.18 (C-2), 150.92 (C-7), 149.30
8.40 (2H, m, C6H4), 7.84–7.77 (2H, m, C6H4), 4.31 [1H, sep- (C′-4), 145.77 (C-6), 141.47 (C′-1), 133.75 (C-4a), 129.10 (C′-2),
tet, J = 6.8, NCH(CH3)2], 1.67 [6H, d, J = 6.8, CH(CH3)2]
124.61 (C′-3), 55.98 [NCH(CH3)2], 19.56 [NCH(CH3)2]
5k
8.96 (1H, d, J = 2.0, H-7), 8.84 (1H, d, J = 2.0, H-6), 7.75 161.74 (C-4), 161.64 (C-8a), 153.27 (C-2), 150.58 (C-7), 144.99
(5H, s, C6H5), 4.20 [1H, d-quintet, 9.0, 6.5, (C-6), 135.72 (C′-1), 133.22 (C-4a), 130.56 (C′-4), 129.11 (C′-2),
J
=
NCH(CH3)CH2], 2.36 (1H, d-quintet, J = 15.5, 7.5, 127.56 (C′-3), 61.68 [NCH(CH3)CH2], 25.99 (CHCH2CH3), 18.21
CHCH2CH3), 1.88 (1H, dqd, J = 14.0, 7.5, 6.5, CHCH2CH3), (CHCH3), 11.60 (CH2CH3)
1.67 (3H, d, J = 7.0, CHCH3), 0.73 (3H, t, J = 7.5, CH2CH3)
5l
8.90 (1H, d, J = 2.2, H-7), 8.77 (1H, d, J = 2.2, H-6), 7.71– 165.07 (C-4), 161.55 (C-8a), 152.41 (C-2), 150.34 (C-7), 144.58
7.66 (2H, m, C6H5), 7.55–7.45 (3H, m, C6H5), 1.55 [9H, s, (C-6), 140.06 (C′-1), 133.41 (C-4a), 130.98 (C′-4), 128.85 (C′-2),
C(CH3)3]
128.57 (C′-3) 65.71 [NC(CH3)3], 31.08 [C(CH3)3]
5m
8.96 (1H, d, J = 2.0, H-7), 8.83 (1H, d, J = 2.0, H-6), 7.55 161.97 (C-4), 161.75 (C-8a), 153.40 (C-2), 150.73 (C-7), 145.16
(5H, s, C6H5), 5.49 (1H, dddd, J = 17.0, 10.0, 8.4, 6.3, (C-6), 135.80 (C′-1), 134.34 (CH2CH=CH2), 133.39 (C-4a), 130.72
CH2CH=CH2), 4.97 [1H, dq, J = 16.8, 1.0, CH=CH2 (trans)], (C′-4), 129.22 (C′-2), 127.97 (C′-3), 118.92 (CH=CH2), 59.46
4.92 [1H, dq, J = 10.0, 1.0, CH=CH2 (cis)], 4.36 [1H, dqd, J [NCH(CH3)CH2], 36.99 (CHCH2CH=CH2), 18.00 (CHCH3)
= 9.1, 6.8, 6.1, NCH(CH3)CH2], 3.15 (1H, dddt, J = 14.2, 9.2,
8.4, 1.0, CHCH2CH=CH2), 2.53 (1H, dtt, J = 14.2, 6.3, 1.3,
CHCH2CH=CH2), 1.69 (3H, d, J = 6.8, CHCH3)
N-Allyl-3-aminopyrazine-2-carboxamide (2e); Typical Proce-
dure:
The exchange reactions of ester derivative 3 to sec-amide derivatives
(see Scheme 2).
Methyl 3-aminopyrazine-2-carboxylate (3) (308 mg, 2.01 mmol) was
dissolved in allylamine (10.0 mL) and to this solution was added
DBU (0.30 mL, 2.01 mmol). The resultant solution was stirred at r.t.
and washed with water (50 mL), sat. Na2CO3 (50 mL), water (50 mL)
and sat. brine (50 mL) successively. The combined organic layer was
dried (MgSO4) and evaporated under reduced pressure to afford the
crude product, which was purified by recrystallization from EtOAc
and hexane to give secondary amide derivative 2a (pale yellow nee-
dles, 841 mg, 78%). The other secondary amide derivatives 2b–2d
were also obtained by the similar method (see, Table 1).

SYNTHESIS
Papers
1192
Table 13. Characterization (MS, HRMS) of Compounds 5a–5m Prepared
Products MS (70 eV), m/z (%)
HRMS (70 eV), m/z, Found (Formula, Calcd.)
5a
5b
5c
5d
5f
297 (15, M + 1), 296 (100, M+), 295 (50), 264 (11), 263 (11), 237 (68), 236 (33), 296.0911 (C15H14N4O3, 296.0909)
235 (9), 209 (15), 165 (8), 79 (13)
327 (17, M + 1), 326 (100, M+), 325 (66), 294 (7), 293 (10), 267 (24), 266 (14), 326.1017 (C16H14N4O4, 326.1015)
265 (8), 252 (6), 239 (9), 133 (7), 79 (6)
342 (15, M + 1), 341 (100, M+), 340 (28), 311 (8), 310 (9), 295 (8), 294 (9), 282 341.0747 (C15H11N5O5, 314.0760)
(12), 281 (10), 236 (27), 79 (21)
263 (14, M + 1), 262 (80, M+), 248 (18), 247 (100), 234 (55), 231 (12), 203 (23), 262.1064 (C12H14N4O3, 262.1066)
189 (22), 177 (12), 175 (40), 79 (15)
265 (12, M + 1), 264 (74, M+), 263 (100), 249 (8), 235 (8), 187 (8), 181 (14), 132 264.1038 (C15H12N4O, 264.1011)
(7), 104 (9), 103 (14)
5g
5h
5i
267 (18, M + 1), 266 (100, M+), 265 (46), 238 (18), 225 (13), 224 (87), 223 (26), 266.1169 (C15H14N4O, 266.1168)
196 (12), 121 (21), 104 (12), 103 (12)
267 (16, M + 1), 266 (100, M+), 265 (86), 225 (13), 224 (76), 223 (28), 196 (15), 266.1168 (C15H14N4O, 266.1168)
195 (8), 121 (34), 104 (14), 103 (14), 93 (8)
297 (16, M + 1), 296 (100, M+), 295 (73), 255 (12), 254 (74), 253 (54), 223 (6), 296.1271 (C16H16N4O2, 296.1273)
211 (14), 134 (11), 133 (12), 121 (7)
5j
311 (52, M+), 310 (57), 295 (17), 294 (71), 270 (19), 269 (100), 268 (11), 264 311.1015 (C15H13N5O3, 311.1018)
(17), 239 (10), 223 (61), 195 (11), 121 (22)
5k
5l
280 (28, M+), 279 (12), 226 (6), 225 (50), 224 (100), 223 (18), 196 (13), 121 (26), 280.1326 (C16H16N4O, 280.1324)
104 (11), 103 (9)
280 (10, M+), 225 (31), 224 (100), 223 (20), 196 (14), 195 (5), 121 (26), 104 (7), 280.1322 (C16H16N4O, 280.1324)
103 (8), 93 (6), 77 (5)
5m
292 (22, M+), 291 (41), 251 (30), 226 (12), 225 (100), 224 (41), 223 (13), 207 292.1324 (C14H16N4O, 292.1324)
(8), 196 (8), 121 (10), 104 (8), 103 (8)
for 4 h. The mixture was diluted with water (50 mL) and extracted with
CHCl3 (3 × 50 mL) The combined organic layer was dried (MgSO4)
and evaporated under reduced pressure to afford the crude product,
which was purified on a silica gel column (EtOAc/hexane 1:2) to give
secondary amide derivative 2e (307 mg, 86%). Other sec-amide deriv-
atives 2b, 2c, 2f, 2g were also obtained by a similar method (Table 2).
The characterization data of 2a–2g are summarized in Tables 3–5.
(0.040 mL, 0.34 mmol) and Et3N (0.050 mL, 0.36 mmol). The mix-
ture was heated at reflux for 4 h. After completion of the reaction
(monitored by TLC), the mixture was diluted with water (10 mL) and
extracted with CHCl3 (2 × 30 mL ). The combined extracts were dried
(MgSO4) and evaporated under reduced pressure and the crude prod-
uct was purified on a silica gel column (EtOAc/hexane 1:1) to give the
4(3H)-pteridinone derivative 5a (37 mg, 68%). The other 4(3H)-pte-
ridinone derivatives 5b–5d, 5f–5m, 8, 9 were synthesized using sim-
ilar conditions (Table 10). The characterization data of 5a–5d, 5f–5m
are summarized in Tables 11–13.
N-(Methoxycarbonylmethyl)-3-(triphenylphosphoranylideneam-
ino)pyrazine-2-carboxamide (4a); Typical Procedure:
(see Scheme 3.)
To a stirred mixture of the corresponding 3-aminopyrazine-2-carbox-
amide 2a (360 mg, 1.71 mmol), hexachloroethane (405 mg, 1.71
mmol) and PPh3 (449 mg, 1.71 mmol) in anhyd benzene (20.0 mL)
was added dropwise Et3N (0.48 mL, 3.44 mmol). The resultant solu-
tion was heated at reflux for 2 h. After cooling, the mixture was fil-
tered under pressure in order to remove the precipitates and the filtrate
was evaporated under reduced pressure to give a solid residue, which
was purified on a silica gel column (EtOAc/hexane1:1 → 2:1 →
EtOAc only) to afford the iminophosphorane derivative 4a (795 mg,
99%). The other iminophosphorane derivatives 4b–4g were also ob-
tained by a similar method (Table 6). The characterization data of 4a–
4g are summarized in Tables 7–9.
2-(2-Azidophenyl)-3-(methoxycarbonylmethyl)-4(3H)-pteridinone
(9): pale yellow solid;
yield: 70%; Rf 0.17 (EtOAc/hexane 3:1); mp 188–192°C.
IR (KBr): ν = 2133, 1752, 1705, 1584, 1414, 1366, 1304, 1227,
752 cm–1.
1H NMR (CDCl3, 200 MHz): δ = 9.02 (1H, d, J = 2.0 Hz, H-7), 8.90
(1H, d, J = 2.0 Hz, H-6), 7.65–7.47 (2H, m, C6H4), 7.34–7.26 (2H, m,
C6H4), 5.22 (1H, d, J = 17.2 Hz, NCH2CO), 4.26 (1H, d, J = 17.2 Hz,
NCH2CO), 3.68 (3H, s, OCH3).
13C NMR (CDCl3, 50 MHz): δ = 167.82 (CO2), 161.16 (C-4), 157.66
(C-8a), 154.15 (C-2), 151.02 (C-7), 145.67 (C-6), 138.13 (C'-2),
132.87 (C-4a), 132.61 (C'-4 or C'-6), 130.69 (C'-4 or C'-6), 125.72
(C'-3 or C'-5), 125.43 (C'-1), 118.77 (C'-3 or C'-5), 52.95 (OCH3),
46.99 (NCH2CO).
3-(Methoxycarbonylmethyl)-2-phenyl-4(3H)-pteridinone (5a);
Typical Procedure:
(see Scheme 4.)
To a stirred solution of the iminophosphorane 4a (86 mg, 0.18 mmol)
in anhyd toluene (2.0 mL) was added dropwise benzoyl chloride
MS (EI): m/z (%) = (337.30) 310 (15, M+ – 28 + 1), 309 (90, M – 28),
277 (14), 251 (14), 250 (100), 222 (20), 221 (21), 168 (12), 129 (6),
102 (6).
MS (CI): 338 (MH).

SYNTHESIS
August 1998
1193
Table 14. Characterization (mp, Rf, IR) of Compounds 7a, 7b, 8 Prepared
Products
mp (°C)
Rf (Solvent)a
IR (KBr or neat) ν (cm–1)
7a
7b
8
188–189
149–151
217–218
0.17 (A/H 2:1)
0.10 (A/H 2:1)
0.13 (A)
1753, 1713, 1671, 1406, 1323, 1252, 1217, 1179, 982, 694
3382, 1744, 1715, 1665, 1589, 1530, 1491, 1445, 1370, 1233, 1190, 1121, 721, 696
1692, 1603, 1545, 1464, 1391, 1292, 1217, 833, 702
a EtOAc (A) and hexane (H).
Table 15. Characterization (1H, 13C NMR) of Compounds 7a, 7b, 8 Prepared
Product
1H NMR (CDCl3/TMS, 200 MHz) δ, J (Hz)
13C NMR (CDCl3/TMS, 50 MHz) δ
7a
12.70 (1H, br s, NHCOC6H5), 8.71 (1H, d, J = 2.4, H-5), 8.65 169.98 (CO2), 166.39 (NHCOPh), 165.15 (CONHCH2),
(1H, br s, CONHCH2), 8.29 (1H, d, J = 2.2, H-6), 8.14–8.07 150.27 (C-2), 147.41 (C-6), 137.27 (C-5), 134.66 (C′-1),
(2H, m, C6H5), 7.64–7.49 (3H, m, C6H5), 4.29 (2H, d, J = 5.6, 132.85 (C′-4), 129.34 (C-3), 129.26 (C′-2), 128.12 (C′-3),
NHCH2CO), 3.83 (3H, s, OCH3)
52.82 (OCH3), 41.32 (NHCH2CO)
7b
8a
11.70 (1H, br s, NHAc), 8.60 (1H, d, J = 2.4, H-5), 8.58 (1H, 169.98 (CO2), 169.55 (NHCOCH3), 166.07 (CONHCH2),
br s, CONHCH2), 8.24 (1H, d, J = 2.4, H-6), 4.24 (2H, d, J = 149.58 (C-2), 146.98 (C-6), 137.04 (C-5), 128.79 (C-3), 52.80
5.6, NHCH2CO), 3.83 (3H, s, OCH3)
(OCH3), 41.25 (NHCH2CO), 26.09 (COCH3)
13.09 (1H, br s, NH), 9.02 (1H, d, J = 2.2, H-7), 8.83 (1H, d, 161.93 (C-4), 156.28 (C-8a), 155.48 (C-2), 150.87 (C-7),
J = 2.0, H-6), 8.26–8.21 (2H, m, C6H5), 8.26–8.21 (3H, m, 144.50 (C-6), 133.52 (C′-1), 132.59 (C´-4), 132.37 (C-4a),
C6H5)
129.09 (C´-2), 128.63 (C´-3)
a This compound was measured by DMSO-d6/TMS.
Table 16. Characterization (MS, HRMS) of Compounds 7a, 7b, 8 Prepared
Products
MS (70 eV), m/z (%)
HRMS (70 eV), m/z, Found (Formula, Calcd.)
7a
315 (17, M + 1), 314 (100, M+), 282 (8), 254 (13), 226 (19), 198 (13), 197 (7), 314.1014 (C15H14N4O4, 314.1015)
106 (6), 105 (93), 77 (28)
7b
8
252 (38, M+), 211 (10), 210 (100), 193 (12), 178 (19), 167 (12), 164 (40), 151 252.0860 (C10H12N4O4, 252.0859)
(77), 136 (13), 123 (21), 122 (68), 120 (10), 95 (34), 94 (54), 67 (11)
225 (12, M + 1), 224 (100, M+), 223 (12), 196 (16), 180 (8), 121 (44), 104 (15), 224.0698 (C12H8N4O, 224.0698)
103 (11), 93 (18), 77 (16), 76 (4), 66 (4)
CHCl3 (2 × 30 mL). The combined extracts were dried (MgSO4) and
evaporated under reduced pressure and the crude product was purified
on a silica gel column (EtOAc/hexane 1:1) to give 7a (44 mg, 72%).
The characterization data of 7a, 7b and 8 are summarized in Tables
14–16.
HRMS calcd for C15H11N7O3 337.0923, C15H11N7O3 (–N2) 309.0862,
found 309.0866.
3-(Methoxycarbonylmethyl)-2-phenyl-4(3H)-pteridinone (5a)
and 3-(Benzoylamino)-N-(methoxycarbonylmethyl)pyrazine-2-
carboxamide (7a):
6-Methoxy-7H-1,4-benzodiazepino[5,4-b]pteridin-9-one (11):
(see Scheme 7.)
(see Scheme 5.)
To a stirred solution of the iminophosphorane 4a (53 mg, 0.11 mmol)
in anhyd toluene (2.0 mL) was added dropwise benzoyl chloride
(0.025 mL, 0.22 mmol). The mixture was heated at reflux for 4 h.
After completion of the reaction (monitored by TLC), the mixture
was diluted with water (10 mL) and extracted with CHCl3 (2 ×
30 mL). The combined extracts were dried (MgSO4) and evaporated
under reduced pressure and the crude product was purified on a silica
gel column (EtOAc/hexane 1:1) to give 5a (4.0 mg, 12%) and 7a
(14.0 mg, 40%).
The mixture of the 4(3H)-pteridinone derivative having an azide
function 9 (47.5 mg, 0.14 mmol) and PPh3 (41.0 mg, 0.16 mmol) was
stirred in benzene (5.0 mL) at r.t. for 2.5 h. After 9 disappeared (mon-
itored by TLC) to form the corresponding iminophosphorane 10, the
mixture was heated at reflux for 3 h to provide desired compound 11
whose Rf value on silica gel TLC was eventually almost the same as
10. The solvent was evaporated under reduced pressure and the crude
product was purified on a silica gel column (EtOAc/hexane 1:1 →
EtOAc only) to give 11 (32.1 mg, 78%); Rf = 0.27 (EtOAc); white
solid; mp 270–278°C (subl.).
3-(Benzoylamino)-N-(methoxycarbonylmethyl)pyrazine-2-car-
boxamide (7a):
(see Scheme 6.)
To a stirred solution of the sec-amide 2a (41 mg, 0.20 mmol) in anhyd
toluene (2.0 ml) was added dropwise benzoyl chloride (0.045 mL,
0.39 mmol) and Et3N (0.055 mL, 0.39 mmol). The mixture was heat-
ed at reflux for 4 h. After completion of the reaction (monitored by
TLC), the mixture was diluted with water (10 mL) and extracted with
IR (KBr): ν = 2943, 1690, 1665, 1572, 1537, 1441, 1410, 1379, 1265,
1219, 1128, 1020, 777, 654 cm–1.
1H NMR (CDCl3, 200 MHz): δ = 9.01 (1H, d, J = 2.0 Hz, H-12), 8.84
(1H, d, J = 2.0 Hz, H-11), 8.33 (1H, ddd, J = 8.0, 1.6, 0.4 Hz, H-1 or
H-4), 7.63 (1H, ddd, J = 7.8, 7.4, 1.5 Hz, H-2 or H-3), 7.36 (1H, ddd,
J = 8.0, 7.4, 1.2 Hz, H-2 or H-3), 7.31 (1H, ddd, J = 8.0, 1.4, 0.4 Hz,
H-1 or H-4), 5.89 (2H, br s, NCH2C), 3.95 (3H, s, OCH3).

SYNTHESIS
Papers
1194
13C NMR (CDCl3, 50 MHz) δ = 162.22 (C-9), 160.24 (C-6), 157.65
(C-13a), 154.43 (C-14a), 151.16 (C-12), 146.16 (C-4a), 144.89 (C-
11), 133.56 (C-1 or C-3), 132.67 (C-1 or C-3), 132.13 (C-9a), 127.25
(C-2 or C-4), 126.03 (C-14b), 125.34 (C-2 or C-4), 55.15 (OCH3),
41.30 (NCH2C).
(12) He, F.; Snider, B. B. Synlett 1997, 483.
(13) Peinador, C.; Moreira, M. J.; Quintela, J. M. Tetrahedron 1994,
50, 6705.
(14) Saito, T.; Tsuda, K.; Saito, Y. Tetrahedron Lett. 1996, 37, 209.
(15) Saito, T.; Tsuda, K. Tetrahedron Lett. 1996, 37, 9071.
(16) Watanabe, M.; Okada, H.; Teshima, T.; Noguchi, M.; Kakehi,
A. Tetrahedron 1996, 52, 2827.
MS (EI): m/z (%) = (293.29) 294 (12, M + 1), 293 (70, M+), 264 (16),
250 (7), 237 (14), 236 (100), 208 (5), 79 (7).
MS (CI): 294 (MH).
HRMS calcd for C15H11N5O2 293.0913, found 293.0907.
(17) Noguchi, M.; Okada, H.; Watanabe M.; Okuda, K.; Nakamura,
O. Tetrahedron 1996, 52, 6581.
(18) Okawa, T.; Eguchi, S. Synlett 1994, 555.
(19) Okawa, T.; Eguchi, S.; Kakehi, A. J. Chem. Soc., Perkin Trans.
1 1996, 247.
(20) Okawa, T.; Eguchi, S. Tetrahedron Lett. 1996, 37, 81.
(21) Zbiral, E.; Bauer, E.; Stroh, J. Monatsh. Chem. 1971, 102, 168.
(22) Wamhoff, H.; Herrmann, S.; Stölben, S.; Nieger, M. Tetrahe-
dron 1993, 49, 581.
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. A generous gift of 3-aminopyrazine-2-
carboxylic acid from Nippon Soda Co., Ltd. and DMC from Shiratori
Pharmaceutical Co., Ltd. is also acknowledged.
(23) Molina, P.; Alajarín, M.; Saez, J. R.; Foces-Foces, C.; Hernán-
dez Cano, F.; Claramunt, R. M.; Elguero, J. J. Chem. Soc., Per-
kin Trans. 1 1986, 2037.
(For reviews on the synthesis of heterocycles via the aza-Wittig reac-
tion, see: ref. 1–4.)
(24) Molina, P.; Conesa, C.; Velasco, M. D. Liebigs Ann. Chem.
1997, 107.
(25) Fernandez, A. M.; Duhamel, L. J. Org. Chem. 1996, 61, 8698
and references cited therein.
(26) Kakoi, H.; Tanino, H.; Okada, K.; Inoue, S. Heterocycles 1995,
41, 789.
(27) Brown, D. J. Fused Pyrimidines Part 3, Pteridines. In The
Chemistry of Heterocyclic Compounds, Vol. 24, Part 3;
Weissberger, A.; Taylor, E. C., Eds.; Wiley: New York, 1988.
(28) Tanino, H.; Takakura, H.; Kakoi, H.; Okada, K.; Inoue, S.
Heterocycles 1996, 42, 125 and references cited therein.
(29) Wamhoff, H.; Kroth, E. Synthesis 1994, 405.
(30) Takuma, S.; Hanada, Y.; Shioiri, T. Chem. Pharm. Bull. 1982,
30, 3147 and reference cited therein.
(1) Barluenga, F.; Palacios, F. Org. Prep. Proced. Int. 1991, 23, 1.
(2) Eguchi, S.; Matsushita, Y.;Yamashita, K. Org. Prep. Proced.
Int. 1992, 24, 209.
(3) Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197.
(4) Wamhoff, H.; Rechardt, G.; Stölben, S. Adv. Heterocycl. Chem.
1996, 64, 159.
(5) Okawa, T.; Sugimori, T.; Eguchi, S.; Kakehi, A. Chem. Lett.
1996, 843 and references cited therein.
(6) O'Neil, I. A.; Murray, C. L.; Potter, A. J.; Kalindjian, S. B.
Tetrahedron Lett. 1997, 38, 3609.
(7) Eguchi, S.; Yamashita, K.; Matsushita, Y.; Kakehi, A. J. Org.
Chem. 1995, 60, 4006.
(8) Molina, P.; Díaz, I.; Tárraga, A. Tetrahedron 1995, 51, 5617.
(9) Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y.; Yashima, E.;
Okamoto, Y. J. Org. Chem. 1996, 61, 7316.
(10) Sugimori, T.; Okawa, T.; Eguchi, S.; Yashima, E.; Okamoto, Y.
Chem. Lett. 1997, 869.
(11) Sha, C.-K.; Chiu, R.-T.; Yang, C.-F.; Yao, N.-T.; Tseng, W.-H.;
Liao, F.-L.; Wang, S.-L. J. Am. Chem. Soc. 1997, 119, 4130.
(31) Appel, R.; Halstenberg, M. In Organophosphorus Reagents in
Organic Synthesis; Cadogan, J. I. G. Ed.; Academic Press: Lon-
don, 1979. pp 378ff.
(32) Fuji Silysia Chemical Ltd.