Furo[2,3-d]pyrimidines and Oxazolo[5,4-d]pyrimidines as Inhibitors of Receptor Tyrosine Kinases (RTK)

Article abstract of DOI:10.1002/hlca.200490089

Receptor tyrosine kinases such as VEGFR2 (vascular endothelial growth factor receptor 2, KDR) or EGFR (epidermal growth factor receptor) play crucial roles in a variety of diseases, such as cancer. Recently, some pyrrolopyrimidines were shown to be potent

Full text of DOI:10.1002/hlca.200490089

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Helvetica Chimica Acta Vol. 87 (2004)
Furo[2,3-d]pyrimidines and Oxazolo[5,4-d]pyrimidines as Inhibitors of
Receptor Tyrosine Kinases (RTK)
by Andreas Martin-Kohlera), Jˆrg Widmera), Guido Bold*b), Thomas Meyerb), Urs Se¬quin*a),
and Peter Traxlerb)
a) Departement Chemie der Universit‰t Basel, St. Johanns-Ring 19, CH-4056 Basel
(phone: ‡ 41612671110; fax: ‡ 41612671103; e-mail: urs.sequin@unibas.ch)
b) Novartis Pharma AG, Oncology Research, CH-4002 Basel
(phone: ‡ 41616962497; fax ‡ 41616966246; e-mail: guido.bold@pharma.novartis.com)
Receptor tyrosine kinases such as VEGFR2 (vascular endothelial growth factor receptor 2, KDR) or
EGFR (epidermal growth factor receptor) play crucial roles in a variety of diseases, such as cancer. Recently,
some pyrrolopyrimidines were shown to be potent EGFR inhibitors. Therefore, new types of oxazolo[5,4-
d]pyrimidines and furo[2,3-d]pyrimidines were synthesized (Schemes 1 and 2). Appropriately substituted
derivatives of these classes of compounds inhibited VEGFR2 and EGFR with IC50 values in the low nanomolar
range (see Table). Generally, the furopyrimidines were somewhat more active than the oxazolopyrimidines. The
best inhibitors, 20m, 20p, and 20r, had an IC50 of 3 nm towards EGFR and showed a good selectivity, being
distinctly less active towards VEGFR2.
Introduction. Uncontrolled receptor-tyrosine-kinase(RTK)-mediated signaling
plays an important role in many pathological conditions, especially in cancer [1][2].
Recently, this was most successfully established by the tremendous responses observed
in chronic myelogenous leukemia (CML) patients under treatment with GlivecTM [3].
Inhibitors for two other RTKs, vascular endothelial growth-factor receptor 2
(VEGFR2 or KDR; a receptor expressed in endothelial cells of blood vessels [4])
and the epidermal growth-factor receptor (EGFR or HER-1; in cancer cells frequently
overexpressed or mutated [5]), are undergoing clinical trials or have already been
launched recently. Signaling via KDR induces neovascularization of growing tumor
tissue, a process that is essential for the development of massive tumors [6]. Mutated
forms and/or overexpression of EGFR in cancer cells lead to uncontrolled EGFR
activity and, as a consequence, to development and progression of numerous human
tumors [5]. Much effort has been applied to the development of synthetic small-
molecule inhibitors against either VEGFR2 [7 13] or EGFR [14 18], such as
compounds 1 6 (Fig. 1).
The pyrrolopyrimidines 3 5 are potent inhibitors of the EGFR [21]. While sharing
many features with other inhibitors (Fig. 1), 3 5 idiosyncratically have a pyrrole ring
fused to the pyrimidine ring. The proper role of the pyrrolo NHmoiety of these
compounds for binding to the EGFR had not been fully determined. Methylation of the
pyrrolo NHleads to a significant drop in activity against EGFR as demonstrated for 7
(IC50 ˆ 27 nm) and 8 (IC50 ˆ 450 nm) [22]. Whether this is due to steric hindrance or
lack of a H-bond remained unclear. To address this issue, we synthesized compounds in
which this pyrrolo NHis replaced by an O-atom.

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957
Fig. 1. VEGFR or EGFR Kinase inhibitors. IC50 values are published as follows: ZD4190 [19], ZD1839 [15],
PKI 166 [17], and PTK 787 [20].
Fig. 2 depicts the general structure of the target furopyrimidines (Yˆ CH) or
oxazolopyrimidines (Yˆ N). Synthetic routes yielding oxazolopyrimidines (Yˆ N)
were described in [23][24], whereas for furopyrimidines (Yˆ CH), no viable synthetic
paradigm was available. Finally, variation of the substituents R1 R4 should allow
establishing some structure activity relationships (SAR).
Syntheses.
Oxazolo[5,4-d]pyrimidines. Two major routes to 2,7-disubstituted
oxazolo[5,4-d]pyrimidines have been discussed by Patil and Townsend [23]. For

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Helvetica Chimica Acta Vol. 87 (2004)
Fig. 2. General structure of target compounds lacking the
pyrrolo NH moiety: oxazolo[5,4-d]pyrimidines (Yˆ N) or
furo[2,3-d]pyrimidine (Yˆ CH)
stability reasons, these authors favored the methodology published by Ishidate and Yuki
[24], which we followed also. In the published syntheses [23][24], an N-acylation is
performed in the appropriate carboxylic anhydride as solvent as well as acylating agent.
In our case, the acylation (Scheme 1) was carried out with nitrobenzoyl chlorides in
pyridine as the solvent. Heating of the resulting intermediate in POCl3 led to
simultaneous ring closure to the oxazole system and substitution of the second OH
functionality by a Cl-atom, giving rise to 9 in moderate yield. Substitution of the Cl-
atom by any desirable aniline furnished compounds of type 10. These compounds
frequently exhibited extremely poor solubilities and were, therefore, often used in the
next steps without purification. Reduction of the NO2 group readily produced the
primary amines 11c i. Due to the poor solubilities of the nitro compounds 10, 1,3-
dimethylimidazolidin-2-one (dimethylethyleneurea, DMEU) was usually used as
solubilizer in this reduction step.
Furo[2,3-d]pyrimidines. Korte and Trautner [25] and Foley [26] discovered that,
after the condensation of cyanoacetates with a-chloro-b-keto esters under basic
conditions, the keto nitriles formed swiftly cyclized to stable trisubstituted furan
systems when there was a conjugating electron-withdrawing substituent at the C-atom
adjacent to the keto function, e.g. an ester group. Exploitation of this information
granted access to 4,6-disubstituted furo[2,3-d]pyrimidines, which were synthesized
according to Scheme 2: The key to the synthesis is the utilization of this furo-inducing
property of an ester group in the starting material 12a,b. The cyanoacetate
condensation was carried out according to Korte and Trautner [25]. However, to

Helvetica Chimica Acta Vol. 87 (2004)
959
Scheme 1. Synthesis of (2-Aminophenyl)-7-anilinooxazolo[5,4-d]pyrimidines 11c i. For substitution patterns
i, see the Table.
c
a) Reflux, pyridine. b) Reflux, POCl3; 56 73% (steps a and b). c) Reflux, BuOH, 3 equiv. of the suitably
substituted aniline; 52 84%. d) H2, Raney-Ni, THF (‡ DMEU); 26 82%.
prevent retro-Claisen condensation, EtOHas solvent was replaced by THF. Then, the
furans 13a,b were successfully condensed with formamide to yield the fused
furopyrimidines 14a,b [27]1). After saponification of the esters, the resulting carboxylic
acids 16a,b were decarboxylated to 17a,b in hot quinoline with Cu2O as the catalyst as
described by Cohen and Schambach [28]. Activation to the respective formal imidoyl
chlorides 18a,b and subsequent substitution of the Cl-atom by anilines produced
compounds of type 19. Reduction of the nitro group in the presence of Raney-Ni finally
yielded the corresponding amino derivatives 20.
1
)
In the 3-nitro series, reaction of ester 13b with the NH3 (resulting from the heat-induced degradation of
formamide) to amide 15 (Scheme 2) occurred to some extent. Yet 15, just as ester 14b, may be converted to
the carboxylate in aqueous NaOHsolution. Therefore, the crude mixture 14b/15 was used without
purification in the subsequent saponification.

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 2. Synthesis of Furopyrimidines 19k v and 20k v. For substitution patterns k v, see the Table.
a) THF, 308; 44%. b) Formamide/DMF/formic acid 4 :2 :1, 140 1508; ca. 20 40%. c) 5% aq. NaOHsoln.,
1008; 63 87%. d) Cu2O, quinoline, 180 2208, N2; ca. 49 70%. e) Reflux, POCl3; ca. 23%. f) Reflux, BuOH,
3 equiv. of the suitably substituted aniline or amine; 27 94%. g) H2, Raney-Ni in THF (‡ DMEU); 35 97%
(except for 20v: 5% due to poor hydrogenation selectivity between the two NO2 groups).

Helvetica Chimica Acta Vol. 87 (2004)
961
Results and Discussion. The IC50 values determined for the inhibitory activities
towards KDR and EGFR of the furopyrimidines and oxazolopyrimidines synthesized
are compiled in the Table. For comparison, the activities of the selective KDR inhibitor
PTK 787 (6), the selective EGFR inhibitor PKI 166 (3), and the known RTK inhibitors
1, 2, 4, and 5 were included. Many of the nitrophenyl-substituted compounds
synthesized, particularly the oxazolopyrimidines 10, proved to be inactive and were,
therefore, not included in the Table.
In contrast to what could have been expected from our former binding hypothesis
[22], compounds lacking the pyrrolo NHmoiety are indeed potent inhibitors of KDR
Table. IC50 Values for KDR and EGFR Inhibition by Compounds 1 6, 11c i, 19k p, and 20k
v
IC50 [mm]a)
Ring D
Ring C
R4 R5 R6
KDR
EGFR
Y
n
R1
R2
R3
1 [11]
2 [15]
3b)
4
0.03
0.023
0.3
0.5
0.4
0.04
0.3*
0.3*
0.5*
0.6*
4*
0.001
0.003
0.004
5
6c)
11c
d
> 10
0.2*
0.9*
0.07*
0.2*
0.06*
0.2*
N
N
N
N
N
N
N
C0H F
C0H F
CH
0
0
0
0
0
0
0
HOHH HNH
H
H
2
2
HOHMeO HNH
HOHH HH NH
HHOHHNH
e
f
g
h
2
2
HCl
HCl
HHCl
HCl
HCl
H HNH
H HH NH
HNH
HNO
HNH
H
H
2
7*
2
2
2
2
i
> 50
0.04
0.7*
> 5
0.2*
> 5
2*
> 10
5*
0.07
0.05*
> 5
1*
0.06*
1
18
0.02
0.01*
> 5
19k
20k
19l
20l
19m
20m
19n
20n
19o
20o
19p
20p
q
0
F
Cl
HH
H
NO
2
2
0.009* CH0
0.01 CH0
0.003* CH0
0.007 CH0
0.005* CH0
F
H
Cl
H NH
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
H
H
H
H
H H NO
H H NH
H NO
2
2
H
H
2
2
H NH
0.1
0.02*
0.01
CH0
CH0
CH1
OH MeO H H NO
OH MeO H H NH
2
2
H
H
H
H
H NO
H NH
H
H
H
H
2
2
2
2
0.003* CH1
0.02*
0.003
0.03*
0.04*
0.05*
CH0
CH0 OHH
CH0
CH0
CH0
OH Me
H NH
r
s
t
u
H
Cl NH
HHHNH
3*
0.06*
4*
H
H
H
H
NH
OH Me
2
2
2
2
H H NH
Cl
NO
H
Cl NH
HNHH
H
H
2
2
v
> 10*
0.005* CH0
a) Figures marked * are median values of at least three measurements. b) Selective EGFR inhibitor [17].
c) Selective KDR inhibitor [20].

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Helvetica Chimica Acta Vol. 87 (2004)
and EGFR. These findings are consistent with observations for the 4-anilinoquinazo-
line-structure class as exemplified by ZD4190 (1; KDR inhibitor [19]) or ZD1839 (2;
IressaTM; EGFR inhibitor [15]). Neither 1 and 2 possess a moiety enabling H-bond
donation. The space filled by the pyrrolo moiety in 4 or 5 is occupied by a benzo moiety
in 4-anilinoquinazolines. Conclusively, a H-bonding interaction at this position as
postulated for the binding mode of pyrrolopyrimidines is not mandatory for potent
kinase inhibition. This makes furo[2,3-d]pyrimidines and oxazolo[5,4-d]pyrimidines
good tyrosine-kinase inhibitors in general. Furopyrimidines are better inhibitors than
their oxazolopyrimidine counterparts. This is prominently demonstrated by the EGFR
inhibition of 20m in comparison to 11h, or by 20n in comparison to 11g. Apparently, the
N-atom in the oxazolo moiety (position Y, ring B) is not well tolerated by EGFR. We
reckon this to be an electronic effect characteristic to EGFR. Or, alternatively, an
intramolecular H-bond between the aniline NH functionality and the oxazole N-atom
(Fig. 3) could hold the molecule in an unfavorable conformation for binding to the
enzyme.
Fig. 3. Hypothetical intramolecular H-bond in anilino-substituted oxazo-
lo[5,4-d]pyrimidines
The best EGFR inhibitors from the oxazolo[5,4-d]pyrimidine series, 11e and 11g,
are significantly less active than PKI 166 (3). However, very potent inhibitors for both
kinases with IC50 values in the low nanomolar range, and thus comparing favorably with
PKI 166 (3) or PTK787 (6), were found in the furo[2,3-d]pyrimidine series. Among
them, some are able to selectively inhibit the EGFR, not influencing KDR at
concentrations below 1 mm (e.g., 19m, 19n, 19p, 20m, 20n, 20p, 20r, 20s, 20u, or 20v).
Others, such as 19k, 20o, 20q, or 20t are inhibitors of both, EGFR and KDR. Clearly,
the oxazolo[5,4-d]pyrimidines and furo[2,3-d]pyrimidines presented here make an
interesting addition to the known classes of RTK inhibitors.
We thank David Saladin and Franz W. B¸rgler for their contributions to the Exper. Part of this study.
Financial support by the Swiss National Science Foundation (grant no. 2000-063344) is gratefully acknowledged.
Experimental Part
General. Tetrahydrofuran (THF) was freshly distilled over Na under Ar. Flash column chromatography
(FC): distilled solvents, SiO2 (40 63 mm) Uetikon. M.p.: Kofler hot stage; uncorrected. IR Spectra: Perkin-
Elmer FT-IR 1600; KBr pellets; n in cmÀ1. NMR: Varian Gemini-300 (300 (1H) and 75 MHz (13C)), Varian VXR-
400 (400 (1H) and 101 MHz (13C)), Bruker VRX-500 (500 (1H) and 126 MHz (13C)); d in ppm, J in Hz. MS: VG
70-250 (EI, 70 eV); Finnigan MAT 312 (FAB; 3-nitrobenzyl alcohol); Finnigan-LCQ system (ESI); m/z (rel.
%). Elemental analyses: Microlaboratory at the Department of Chemistry of the University of Basel (W.
Kirsch).
Catalytic Reductions. Raney-Ni Actimet M (Engelhard Corporation; kindly provided by P. Schultheiss,
Hydrierlabor Novartis, Klybeck, CH-4002 Basel) was washed to neutrality, stored under EtOH (at 2 88), and
used as suspension directly. Reductions were carried out in THF soln., with 1,3-dimethylimidazolidin-2-one

Helvetica Chimica Acta Vol. 87 (2004)
963
(dimethylethylurea, DMEU) as emulsifier, in the dark under H2 atmosphere at standard pressure for at least
one night with shaking.
7-Chloro-2-(4-nitrophenyl)oxazolo[5,4-d]pyrimidine (9a). The mixture of 5-aminopyrimidine-4,6-diol
(6.83 g, 41.8 mmol) [24] and 4-nitrobenzoyl chloride (9.84 g, 52.9 mmol) in abs. pyridine (100 ml; the suspension
turned dark red) was refluxed for 1 h under Ar. The solvent was evaporated at 758. The dark red residue was
refluxed in POCl3 (75 ml) under Ar for 1 h. After cooling to r.t., the mixture was concentrated (<608) and
added slowly with constant stirring to a NaOAc/ice mixture. After complete melting of the ice (ca. 30 min), the
pHof the suspension was adjusted to 5 by adding NaOAc. The suspension was filtered with suction, washed with
H2O and EtOH, and dried under high vacuum. The residue was heated in EtOH (150 ml), filtered lukewarm
with suction, and dried under high vacuum. An amorphous, brown solid (6.5 g, 56%; m.p. 228 2308) was
obtained containing 9a, pure enough for further synthesis. FC (SiO2, pentane/AcOEt 90 :10 ! 75 :25) yielded
colorless to pale yellow needles. M.p. 2318. IR: 3103w, 1615s, 1585s, 1527s, 1482s, 1421s, 1348s, 1261s, 1160s,
1106s, 1048s, 989s, 912s, 868s, 711s. 1H-NMR (300 MHz, (CD3)2SO): 9.00 (s, HÀC(5)); 8.54 (d, J ˆ 9.3, 2 H); 8.47
(d, J ˆ 9.1, 2 H). 13C-NMR (75 MHz, (CD3)2SO): 165.2; 161.0; 154.2; 149.9; 149.7; 130.7; 130.3; 129.6; 124.7. EI-
‡
MS: 276 (100, M ), 246 (18), 230 (15), 218 (21), 202 (13), 186 (14), 140 (17), 101 (21), 88 (19), 76 (20), 62 (12),
50 (17). Anal. calc. for C11H5ClN4O3 (276.64): C 47.76, H1.82, N 20.25, O 17.35; found: C 47.54, H1.96, N 20.08,
O 17.23.
7-Chloro-2-(3-nitrophenyl)oxazolo[5,4-d]pyrimidine (9b). A mixture of 5-aminopyrimidine-4,6-diol
(2.25 g, 17.7 mmol) [24] and 3-nitrobenzoyl chloride (3.72 g, 20.0 mmol) in abs. pyridine (100 ml) was refluxed
for 1 h under Ar. After evaporation at 758, the residue was dried under high vacuum. The brown-red residue was
refluxed for 2 h in POCl3 (ca. 100 ml) under Ar. Most of the POCl3 was evaporated (<608), and the remaining
liquid was very carefully poured under stirring onto NaOAc/ice. After adjusting the pHto ca. 5 by adding
NaOAc, the suspension was left standing overnight and then filtered with suction. The residue was washed with
H2O, heated in a considerable amount of EtOH, and filtered. The filtrate was left at 2 88 for a week and then
filtered with suction and the residue dried under high vacuum: 9b (3.57 g, 73%) as an ochre, amorphous solid
(m.p. 133 1358), usually pure enough for further use. FC (AcOEt/pentane 1:0 2 :1) yielded colorless platelets.
M.p. 144 1478. IR: 3071w, 1622m, 1595s, 1545m, 1523m, 1431w, 1419w, 1375m, 1349s, 1306m, 1271w, 1238w,
1
1219w, 1164w, 1100m, 988m, 912m, 756s, 712s, 541w. H-NMR (300 MHz, (CD3)2SO): 9.02 (s, HÀC(5)); 8.93
(−t×, J ˆ 1.9, HÀC(2')); 8.72 (ddd, J ˆ 8.0, 2.3, 1.0, 1 arom. H); 8.59 (ddd, J ˆ 8.3, 2.4, 1.0, 1 arom. H); 8.01 (−t×, J ˆ
8.1, HÀC(5')). 13C-NMR (75 MHz, (CD3)2SO): 165.4; 161.1; 154.0; 149.6; 148.4; 134.0; 131.6; 130.8; 127.7; 126.5;
‡
122.4. EI-MS: 276 (100, M ), 248 (14), 230 (26), 202 (9), 186 (13), 140 (11), 101 (12), 76 (14). Anal. calc. for
C11H5ClN4O3 (276.64): C 47.76, H1.82, N 20.25, O 17.35; found: C 47.75, H2.10, N 20.03, O 17.33.
General Procedure 1 (GP 1): Reaction of Substituted Anilines with 7-Chlorooxazolo[5,4-d]pyrimidines or 4-
Chlorofuro[2,3-d]pyrimidines; 3-{[2-(3-Nitrophenyl)oxazolo[5,4-d]pyrimidin-7-yl]amino}phenol (10c). A sus-
pension of 9b (3.57 g, 12.9 mmol) and 3-aminophenol (4.27 g, 39.1 mmol) in BuOH(250 ml) was refluxed for
2 h (orange). After cooling to r.t., the mixture was filtered with suction and the solid washed twice with BuOH
and dried under high vacuum (no additional workup): 10c (2.34 g, 52%), pure enough for further synthesis.
M.p.: crystalline platelets above ca. 2908, which melted at 307 3138. IR: 3504w, 3336w, 3088m, 1635s, 1603s,
1529m, 1493s, 1475m, 1352s, 1313m, 1284w, 1181w, 1155m, 1088w, 1049w, 711m. 1H-NMR (300 MHz,
(CD3)2SO): 10.32, 9.45 (2s, NH, OH); 8.98 (−t×, J ˆ 2.0, HÀC(2'')); 8.58 (−d×, J ˆ 7.3, 1 H); 8.56 (s, HÀC(5'));
8.50 (m, 1 H); 7.97 (−t×, J ˆ 8.0, HÀC(5'')); 7.49 (−t×, J ˆ 2.0, HÀC(2)); 7.34 (m, 1 H); 7.16 (−t×, J ˆ 8.1, HÀC(5));
‡
6.55 (m, 1 H). EI-MS: 349 (100, M ), 333 (6), 319 (12), 302 (12), 275 (5), 241 (30), 211 (5), 195 (6), 93 (6), 76
‡
(8), 65 (8), 39 (6). HR-MS: 349.0812 (C17H11N5O4 ; calc. 349.0811).
2-Methoxy-5-{[2-(3-nitrophenyl)oxazolo[5,4-d]pyrimidin-7-yl]amino}phenol (10d). According to the GP
1, with 9b (866 mg, 3.13 mmol), 5-amino-2-methoxyphenol (1.36 g, 9.77 mmol), and BuOH(100 ml) for 2 h
(ochre suspension). Workup: Additional washing with BuOHuntil apparently all impurities stemming from 5-
amino-2-methoxyphenol were washed out and drying under high vacuum gave 10d (1.00 g, 84%). Pale, yellow-
brown-green, amorphous residue. M.p.: at ca. 2608 crystals, mostly needles, which melted at 323 3258. IR:
3468s, 3342m, 3095w, 2953w, 2848w, 1639s, 1608s, 1585m, 1535s, 1510s, 1475s, 1441m, 1351s, 1312m, 1286m,
1236m, 1181m, 1161m, 1075m, 1030m, 964w, 930w, 898w, 873m, 801m, 766w, 736w, 711m, 670w, 561m. 1H-NMR
(300 MHz, (CD3)2SO): 10.19, 9.07 (2s, NH, OH); 8.95 (−t×, J ˆ 1.8, HÀC(2'')); 8.57 (d, J ˆ 7.8, 1 H); 8.51 8.47
(m, 2 H); 7.96 (t, J ˆ 8.1, HÀC(5'')); 7.24 (d, J ˆ 2.6, HÀC(6)); 7.24 (dd, J ˆ 8.8, 2.6, HÀC(4)); 6.93 (d, J ˆ 8.8,
‡
HÀC(3)); 3.79 (s, Me). EI-MS: 379 (100, M ), 364 (50), 336 (10), 318 (10), 308 (17), 290 (11), 262 (13). Anal.
calc. for C18H13N5O5 (379.34): C 56.99, H3.45, N 18.46, O 21.09; found: C 56.91, H3.60, N 18.50, O 21.01.
3-{[2-(4-Nitrophenyl)oxazolo[5,4-d]pyrimidin-7-yl]amino}phenol (10e). According to the GP 1, with 9a
(452 mg, 1.64 mmol), 3-aminophenol (587 mg, 5.38 mmol), and BuOH(100 ml) for 90 min (orange suspension):

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Helvetica Chimica Acta Vol. 87 (2004)
10e (414 mg, 72%). Amorphous, violet residue. M.p. > 2508. IR: 3474m, 3336m, 3108w, 1622s, 1606s, 1518s,
1493s, 1406m, 1345s, 1294s, 1179m, 1154m, 1050m, 956w, 857m, 779w, 711m, 686m. 1H-NMR (300 MHz,
(CD3)2SO): 10.35, 9.44 (s, NH, OH); 8.52 (s, HÀC(5')); 8.45 (d, J ˆ 9.2, 2 H); 8.39 (d, J ˆ 9.2, 2 H); 7.46 (−t×, J ˆ
2.1, HÀC(2)); 7.31 (dd, J ˆ 8.1, 1.1, HÀC(4)); 7.14 (−t×, J ˆ 8.1, HÀC(5)); 6.53 (m, HÀC(6)). 13C-NMR
(75 MHz, (CD3)2SO): 164.3; 157.3; 156.7; 154.5; 152.7; 149.0; 139.8; 131.6; 129.1; 128.2; 124.6; 117.4; 112.2; 110.7;
‡
108.4. EI-MS: 349 (100, M ), 321 (15), 302 (18), 274 (5), 241 (38), 195 (12), 120 (6), 104 (7), 93 (8), 76 (9), 65
‡
(9), 39 (7). HR-MS: 349.0819 (C17H11N5O4 ; calc. 349.0811).
4-{[2-(4-Nitrophenyl)oxazolo[5,4-d]pyrimidin-7-yl]amino}phenol (10f). According to the GP 1, with 9a
(2.22 g, 8.0 mmol), 4-aminophenol (2.58 g, 23.6 mmol), and BuOH(350 ml) for 3 h. Workup: The crude product
(2.2 g; m.p. > 3008) was heated to 708 in 40 ml of 98% EtOH, filtered with suction, and dried under high
vacuum: 10f (2.0 g, 72%). Amorphous solid, pure enough for the intended purposes. M.p. > 3008. IR: 3360w,
3178w, 1630m, 1607m, 1518m, 1482w, 1348m, 1217m, 1079w, 1045w, 855w, 710w, 516w. 1H-NMR (400 MHz,
(CD3)2SO): 10.25, 9.32 (2s, NH, OH); 8.48 (d, J ˆ 9.2, 2 H); 8.45 (s, HÀC(5')); 8.40 (d, J ˆ 9.1, 2 H); 7.59 (d, J ˆ
‡
8.9, HÀC(3)); 6.78 (d, J ˆ 9.0, HÀC(2)). FAB-MS: 349 (100, M ), 321 (13), 302 (14), 241 (33), 195 (14), 120
‡
(10). HR-MS: 349.0809 (C17H11N5O4 ; calc. 349.0811).
N-[(3-Chlorophenyl)-2-(3-nitrophenyl)oxazolo[5,4-d]pyrimidin-7-amine (10g). According to the GP 1,
with 9b (7.14 g, 25.9 mmol), BuOH(300 ml), and 3-chloroaniline (8.1 ml, 77.1 mmol) for 2.5 h (yellow
suspension ! clear, pale yellow soln.). Workup: The filtrate was stored for 3 d at 2 88 and then filtered with
suction, and the resulting residue dried under high vacuum (0.86 g) and combined with the initially obtained
bright brown residue (1.81 g). FC (SiO2, CH2Cl2/MeOH99 :1 ! 96 :4) yielded 10g (125 mg, 1%). Amorphous,
off-white solid. M.p. 256 2608. IR: 3331w, 3093w, 1636s, 1616s, 1593s, 1528s, 1476m, 1427m, 1355s, 1320m,
1080w, 1046w, 929w, 870w, 784m, 710m, 679m, 564w. 1H-NMR (300 MHz, (CD3)2SO): 10.60 (s, NH); 8.96
(−t×, J ˆ 1.9, HÀC(2'')); 8.62 (s, HÀC(5)); 8.58 (d, J ˆ 7.7, 1 H); 8.49 (ddd, J ˆ 8.3, 2.3, 0.9, 1 H); 8.18 (−t×, J ˆ 2.0,
HÀC(2'')); 7.96 (−t×, J ˆ 8.0, HÀC(5'')); 7.88 (d, J ˆ 7.7, 1 H); 7.41 (−t×, J ˆ 8.1, 1 H); 7.17 (ddd, J ˆ 8.0, 2.0, 0.8,
‡
1 H). EI-MS: 367 (100, M ), 351 (8), 337 (12), 320 (10), 259 (41), 229 (6), 213 (8), 157 (5), 150 (7), 143(7), 138
(5), 111 (8), 104 (6), 76 (12). HR-MS: 367.0473 (calc. 367.0472). Anal. calc. for C17H10ClN5O3 (367.76): C 55.52,
H2.74, N 19.04, O 13.05; found: C 55.04, H2.93, N 19.07, O 12.80.
N-(3-Chlorophenyl)-2-(4-nitrophenyl)oxazolo[5,4-d]pyrimidin-7-amine (10h). According to the GP 1,
with 9a (150 mg, 0.54 mmol), 3-chloroaniline (0.17 ml, 1.6 mmol), and BuOH(30 ml) for 2 h (clear, pale yellow
soln.). No workup: 10h (118 mg, 59%), pure enough for the intended purposes. Golden platelets. M.p. 2858. IR:
3289w, 3202w, 3110w, 1641s, 1590s, 1524s, 1476s, 1410m, 1348s, 1314m, 1292m, 1051m, 856m, 785w, 712m.
1H-NMR (300 MHz, (CD3)2SO): 10.70 (s, NH); 8.62 (s, HÀC(5)); 8.49 (d, J ˆ 9.2, 2 H); 8.43 (d, J ˆ 9.2, 2 H);
8.16 (−t×, J ˆ 2.0, HÀC(2')); 7.87 (m, 1 H); 7.41 (−t×, J ˆ 8.1, HÀC(5')); 7.17 (ddd, J ˆ 8.0, 2.1, 0.9, 1 H). EI-MS:
‡
367 (100, M ), 339 (12), 320 (11), 259 (43), 213 (11), 150 (16), 104 (11), 76 (15). HR-MS: 367.0475 (calc.
367.0472). Anal. calc. for C17H10ClN5O3 (376.76): C 55.52, H2.74, N 19.04, O 13.05; found: C 55.15, H3.04, N
18.59, O 13.98.
N-(4-Chlorophenyl)-2-(4-nitrophenyl)oxazolo[5,4-d]pyrimidin-7-amine (10i). According to the GP 1, with
9a (1.99 g, 7.2 mmol), 4-chloroaniline (2.75 g, 21.6 mmol), and BuOH(300 ml) for 90 min. Workup: Washing
with little MeOHand much EtOH(instead of BuOH) and drying under high vacuum (1.14 g, m.p. > 3008). The
residue was heated in (CD3)2SO (ca. 400 ml) and filtered hot. From this filtrate, orange-golden platelets
crystallized and were dried under high vacuum: 10i (307 mg, 12%). M.p. ca. 3008. IR: 3286w, 3198w, 3080w,
3000w, 1635s, 1604m, 1591m, 1577s, 1513s, 1495s, 1472m, 1404m, 1342s, 1306m, 1289m, 1231m, 1105w, 1080m,
1
1051m, 1028m, 712m. H-NMR (300 MHz, (CD3)2SO): 10.6 (s, NH); 8.57 (s, HÀC(5)); 8.49 (d, J ˆ 7.0, 2 H);
‡
8.43 (d, J ˆ 7.5, 2 H); 7.98 (d, J ˆ 9.0, HÀC(2')); 7.44 (d, J ˆ 8.9, HÀC(3')). EI-MS: 367 (100, M ), 339 (15), 320
‡
(11), 259 (40), 213 (14), 111 (11), 104 (11), 76 (14). HR-MS: 367.0473 (C17H10N5O3 ; calc. 367.0472).
General Procedure 2 (GP 2): Raney-Nickel Reduction; 3-{[2-(3-Aminophenyl)oxazolo[5,4-d]pyrimidin-7-
yl]amino}phenol (11c). A mixture of 10c (1.8 g, 5.1 mmol), THF (ca. 100 ml), and some Raney-Ni was shaken
overnight and then filtered with suction through Celite. Workup: The filtrate was brought to precipitation by
adding H2O (ca. 100 ml). After overnight storage at 2 88, the suspension was filtered with suction. The residue
was submitted to FC (adsorption onto SiO2 (10 g); SiO2, CH2Cl2/MeOH100 :0 ! 95 :5): 11c (91.2 mg, 0.6%).
Fine, off-white needles. M.p. 274 2788 (partial dec.). IR: 3390w, 3307w, 1636s, 1602s, 1464s, 1319m, 1281m,
1184w, 1159w, 684m. 1H-NMR (300 MHz, (CD3)2SO): 10.18, 9.44 (2s, NH, OH); 8.49 (s, HÀC(5')); 7.47 (−t×, J ˆ
2.1, 1 H); 7.41 (−t×, J ˆ 1.9, 1 H); 7.39 7.25 (m, 3 H); 7.14 (−t×, J ˆ 8.1, HÀC(5)); 6.83 (ddd, J ˆ 8.0, 2.3, 1.0, 1 H);
6.52 (ddd, J ˆ 8.1, 2.4, 0.9, 1 H); 5.55 (s, NH2). 13C-NMR (75 MHz, (CD3)2SO): 164.1; 159.5; 157.4; 153.5; 152.3;
‡
149.5; 140.1; 129.9; 129.1; 126.5; 117.5; 117.2; 114.5; 112.1; 111.7; 110.5; 108.3. EI-MS: 319 (100, M ), 290 (6), 264

Helvetica Chimica Acta Vol. 87 (2004)
965
(13), 211 (42), 160 (5), 146 (5), 118 (6), 92 (9), 65 (9). Anal. calc. for C17H13N5O2 (319.33): C 63.94, H4.10, N
21.93, O 10.02; found: C 63.10, H4.31, N 21.84, O 10.26.
5-{[2-(3-Aminophenyl)oxazolo[5,4-d]pyrimidin-7-yl]amino}-2-methoxyphenol (11d). According to GP 2,
with 10d (813 mg, 2.14 mmol), THF (ca. 50 ml), and DMEU (20 ml), brown-green suspension. Workup: The
filtrate was concentrated and brought to precipitation with H2O (bright, yellow-green), left for 4 h at 2 88, and
filtered with suction. The residue was dried under high vacuum: 11d (615 mg, 82%). Pale green amorphous
solid. M.p. 254 2578. IR: 3376s, 3299m, 3092w, 1635s, 1590s, 1528s, 1478s, 1432s, 1410m, 1320m, 1283s, 1243s,
1
1214s, 1187m, 1163m, 1136w, 1080m, 1060w, 1033w, 970w, 926w, 901w, 869s, 788s, 682s, 574w, 511m. H-NMR
(300 MHz, (CD3)2SO): 10.02, 9.04 (2s, NH, OH); 8.42 (s, HÀC(5')); 7.40 7.34 (m, 3 H); 7.29 7.20 (m, 2 H );
6.93 (d, J ˆ 8.8, 1 H); 6.83 (dd, J ˆ 8.0, 1.0, 1 H); 5.53 (s, NH2); 3.78 (s, MeO). 13C-NMR (75 MHz, (CD3)2SO):
164.0; 159.2; 153.6; 152.4; 149.4; 146.2; 144.2; 132.4; 129.9; 126.5; 117.4; 116.8; 114.6; 112.6; 112.3; 111.8; 110.2;
‡
56.0. EI-MS: 349 (100, M ), 334 (50), 320 (6), 306 (11), 278 (19), 153 (5), 118 (5), 92 (6). Anal. calc. for
C18H15N5O3 (349.35): C 61.89, H4.33, N 20.05, O 13.74; found (after heating the product for 105 min at 190 8/
0.05 mbar): C 61.57, H4.45, N 19.93, O 13.83.
3-{[2-(4-Aminophenyl)oxazolo[5,4-d]pyrimidin-7-yl]amino}phenol (11e). According to GP 2, with 10e
(0.574 g, 1.64 mmol), and THF (20 ml). Workup: The filtrate was brought to precipitation by adding H2O (ca.
50 ml). After removal of the light brown precipitate, another dark brown precipitate formed, which was filtered
off with suction a few days later (17 mg). Another beige, amorphous precipitate containing 11e formed, which
was collected and dried under high vacuum: 214 mg (41%). M.p. ca. 2858. IR: 3476w, 3375m, 3230w, 1625s,
1608s, 1594s, 1560w, 1498m, 1475m, 1443w, 1323m, 1263w, 1174m, 1154w, 1088w, 1040w, 911w, 833w, 769w, 684w,
558w. 1H-NMR (300 MHz, (CD3)2SO): 9.96, 9.39 (2s, NH, OH); 8.41 (s, HÀC(5')); 7.88 (d, J ˆ 8.7, HÀC(3''));
7.47 (−t×, J ˆ 2.2, HÀC(2)); 7.30 (dd, J ˆ 8.1, 1.1, 1 H); 7.12 (−t×, J ˆ 8.1, HÀC(5)); 6.72 (d, J ˆ 8.8, HÀC(2'')); 6.48
(m, 1 H); 6.08 (s, NH2). 13C-NMR (75 MHz, (CD3)2SO): 163.9; 160.2; 157.4; 152.7; 152.4; 151.6; 140.4; 129.0;
‡
128.9; 117.5; 113.6; 112.1; 111.8; 110.2; 108.1. EI-MS: 319 (100, M ), 290 (6), 264 (44), 237 (16), 211 (50), 173
(7), 160 (10), 146 (10), 120 (7), 104 (11), 92 (10), 65 (16), 39 (8).
4-{[2-(4-Aminophenyl)oxazolo[5,4-d]pyrimidin-7-yl]amino}phenol (11f). According to the GP 2, with 10f
(350 mg, 1.0 mmol), THF (100 ml), and DMEU (20 ml) for 72 h (reddish soln.). Workup: The yellow-green
filtrate was concentrated and brought to precipitation by adding H2O (ca. 150 ml). This precipitate was
collected, washed with H2O, and dried under high vacuum: 296 mg (92%) of crude product as small needles
(m.p. > 3008). The crude product was dissolved in warm THF, the soln. immediately filtered and evaporated,
and the resulting reddish residue dried under high vacuum at r.t. and then at 1508 for 1 h: 11f (0.15 g, 47%).
Amorphous solid. M.p. > 2508. IR: 3446w, 3311w, 3194w, 1618s, 1509s, 1483s, 1439m, 1322m, 1312m, 1267m,
1225m, 1171w, 1080w. 1H-NMR (300 MHz, (CD3)2SO): 9.79, 9.21 (2s, NH, OH); 8.30 (s, HÀC(5')); 7.85 (d, J ˆ
8.7, 2 H); 7.58 (d, J ˆ 8.9, 2 H); 6.75 (d, J ˆ 8.8, 2 H); 6.71 (d, J ˆ 8.8, 2 H); 6.03 (s, NH2). 13C-NMR (101 MHz,
(CD3)2SO): 163.4; 159.5; 153.2; 152.3; 152.2; 151.6; 130.2; 128.4; 123.0; 116.5; 114.6; 113.4; 112.0. EI-MS: 319
‡
‡
(100, M ), 264 (37), 237 (10), 211 (30). HR-MS: 319.1072 (C17H13N5O2 ; calc. 319.1069).
2-(3-Aminophenyl)-N-(3-chlorophenyl)oxazolo[5,4-d]pyrimidin-7-amine (11g). According to GP 2, with
10g (0.46 g, 1.3 mmol), THF (100 ml), and DMEU (10 ml). Workup: The filtrate was evaporated and the
residue submitted to FC (SiO2, CH2Cl2/MeOH100 :0 ! 95 :5). The precipitate formed in the eluates was
washed with H2O and MeOHand dried under high vacuum: 11g (116 mg, 26%). Microscopically fine colorless
needles. M.p. 239 2428. IR: 3383m, 3316m, 3206w, 3011w, 1639s, 1589s, 1482s, 1408m, 1349m, 1318m, 1280m,
1232m, 1170w, 1104m, 1086m, 996w, 909m, 864m, 791m, 778m, 726m, 677m, 580m. 1H-NMR (300 MHz,
(CD3)2SO): 10.51 (s, NH); 8.56 (s, HÀC(5)); 8.71 (−t×, J ˆ 2.0, HÀC(2'')); 7.88 (ddd, J ˆ 8.3, 2.1, 0.9, 1 H); 7.43
7.36 (m, 3 H); 7.28 (−t×, J ˆ 7.8, HÀC(5')); 7.15 (ddd, J ˆ 8.0, 2.1, 0.9, 1 H); 6.84 (ddd, J ˆ 8.0, 2.3, 1.1, 1 H); 5.56
(s, NH2). 13C-NMR (75 MHz, (CD3)2SO): 164.2; 159.8; 153.5; 152.0; 149.5; 140.8; 132.8; 130.2; 129.9; 126.4;
‡
122.7; 120.3; 119.3; 117.6; 117.6; 114.6; 111.8. EI-MS: 337 (100, M ), 282 (12), 229 (48), 151 (14), 92 (14), 84
(12), 49 (15). Anal. calc. for C17H12ClN5O (337.77): C 60.45, H3.58, N 20.73, O 4.74; found: C 60.21, H3.76, N
20.79, O 4.85.
2-(4-Aminophenyl)-N-(3-chlorophenyl)-oxazolo[5,4-d]pyrimidin-7-amine Hydrochloride (11h ¥ HCl). To a
suspension of 10h (1.61 g, 4.4 mmol) in conc. HCl soln. (10 ml) and EtOH (10 ml) at r.t., SnCl2 (2.50 g) was
added and the mixture heated to ca. 808 (water bath). After 100 min, conc. HCl soln. (40 ml) was added and the
water bath removed. Once the suspension reached r.t., it was filtered with suction and the amorphous residue
dried under high vacuum (1.65 g; m.p. ca. 2458 (dec.). The residue was resuspended in H2O, left to stand
overnight, and filtered with suction. The resulting residue was dried under high vacuum: 11h ¥ HCl (1.01 g, 56%)
(note: we recommend the more feasible methodology of GP 2 rather than the SnCl2 procedure). M.p. 260 2708
(partial dec.). IR: 3373m, 3215w, 2863 m, 2591w, 1637s, 1592s, 1479s, 1426m, 1322w, 1178w, 1081w, 1045w, 789w,

966
Helvetica Chimica Acta Vol. 87 (2004)
732w, 684w. 1H-NMR (300 MHz, (CD3)2SO): 10.36 (s, NH); 8.50 (s, HÀC(5)); 8.16 (m, HÀC(2'')); 7.95 (d, J ˆ
8.7, HÀC(2')); 7.85 (dd, J ˆ 2, 0.9, 1 H); 7.34 (−t×, J ˆ 8.1, HÀC(5'')); 7.12 (ddd, J ˆ 6.3, 2, 0.9, 1 H); 6.9 (d, J ˆ 8.8,
HÀC(3')); NH2 signal probably overlapped by the br. H2O signal at d 6.4. 13C-NMR (75 MHz, (CD3)2SO):
164.2; 159.7; 152.8; 151.5; 146.3; 140.9; 132.8; 130.1; 128.9; 122.5; 120.1; 119.1; 117.8; 117.7; 117.1. FAB-MS: 338
‡
(100, M ), 120 (30), 57 (23), 43 (21).
2-(4-Aminophenyl)-N-(4-chlorophenyl)oxazolo[5,4-d]pyrimidin-7-amine (11i). According th the GP 2,
with 10i (0.536 g, 2.93 mmol), DMEU (15 ml), and THF (75 ml) for 22 h. Workup: The filtrate was
concentrated, brought to precipitation by adding H2O, and filtered with suction, the residue dried under high
vacuum and redissolved in THF, and the mixture brought to precipitation by adding MeOH. This suspension
was filtered with suction and the amorphous residue dried for 1 week under high vacuum: 11e (256 mg, 52%).
M.p.: crystals at ca. 2908, which melted at 296 3018. IR: 3412w, 3330w, 1647s, 1611s, 1594s, 1563m, 1495s, 1320m,
1286w, 1258m, 1180w, 1083w, 1042w, 818m. 1H-NMR (300 MHz, (CD3)2SO): 10.2 (s, OH); 8.43 (s, HÀC(5));
7.96 (d, J ˆ 8.8, 2 H); 7.87 (d, J ˆ 8.7, 2 H); 7.41 (d, J ˆ 8.9, 2 H); 6.71 (d, J ˆ 8.7, 2 H); 6.1 (s, NH2). 13C-NMR
(75 MHz, (CD3)2SO): 164.0; 160.4; 152.8; 152.3; 151.2; 138.4; 129.0; 128.3; 126.4; 122.2; 117.7; 113.6; 112.0. EI-
‡
‡
MS: 337 (100, M ), 282 (35), 229 (39), 151 (16), 120 (11). HR-MS: 337.0734 (C17H12ClN5 ; calc. 337.0730).
Ethyl 2-Chloro-3-(4-nitrophenyl)-3-oxopropanoate (12a). Previously described in [29] (and ref. cit.
therein); simplified procedure: Ethyl 3-(4-nitrophenyl)-3-oxopropanoate (100.2 g, 0.42 mol; 1.0 equiv.) was
suspended in toluene (350 ml) and treated with SO2Cl2 (45 ml, 75 g, 0.55 mol, 1.3 equiv.). The reaction was then
performed under slightly reduced pressure (ca. 900 hPa). The soln. was stirred on an oil bath (bath temp. ca. 808)
for 1 h, upon which the soln. cleared. The heating was switched off after this and the pressure slowly reduced
(gas development, slow boiling). After a few hours, the mixture was stored under ambient conditions overnight
and then quenched with ice. H2O was added, the mixture extracted several times with toluene, the combined org.
phase washed with H2O several times and washed neutral (pH ca. 7) with sat. NaHCO3 soln., dried (MgSO4),
and filtered with suction. The filtrate was evaporated and the residue dried under high vacuum: 12a (105.1 g,
92%) as a yellow, viscose oil (containing some needles), which was used without further purification.
Diethyl 2-Amino-5-(4-nitrophenyl)furan-3,4-dicarboxylate (13a). A soln. of 12a (105 g, 0.39 mol, 1 equiv.)
in freshly distilled THF (600 ml) was kept on a water bath at 358. Within 6.3 h, finely crushed sodium ethyl
cyanoacetate (49.4 g, 0.37 mol, 0.94 equiv.) [25] was added gradually ( ! orange soln.). The soln. was stirred
overnight under N2. Then, the solvent was evaporated and the residue extracted with H2O and CH2Cl2. The aq.
phase was extracted with CH2Cl2, the combined CH2Cl2 phase (2 l) washed with H2O, dried (MgSO4), and
evaporated giving rise to a highly viscose mixture, which was recrystallized from toluene (300 ml): 13a (59.5 g,
44%). Very bright orange needles that were readily soluble in DMF, formamide, acetone, and CH2Cl2, fairly
t
soluble (slowly or under mild heating) in BuOMe, 1,2-dichloroethane, MeCn > toluene, BuOH > EtOH >
MeOH(in decreasing order), poorly soluble in conc. HCl soln. and ligroin, and insoluble in 1 m HCl, sat.
NaHCO3 soln. 5% NaOHsoln., and hexane. M.p. 174 177 8. IR: 3450s, 3337s, 2983w, 1735s, 1681vs, 1654s,
1591vs, 1543s, 1511s, 1476s, 1458s, 1318vs, 1264s, 1221s, 1109s, 1067s, 1024s, 852m. 1H-NMR (300 MHz,
(CD3)2SO): 8.29 (d, J ˆ 8.9, arom. H); 7.75 (s, NH2); 7.58 (d, J ˆ 8.9, arom. H); 4.36, 4.17 (q, J ˆ 7.1, 2 MeCH2);
1.31, 1.23 (t, J ˆ 7.1, 2 MeCH3). 13C-NMR (75 MHz, (CD3)2SO): 164.3; 162.4; 145.3; 135.7; 135.2; 134.4; 124.7;
‡
‡
123.4; 118.7; 88.4; 61.8; 59.4; 14.3; 13.8. FAB-MS: 349 (100, [M ‡ H] ), 348 (90, M ), 332 (10), 303 (39), 287
‡
(6), 275 (14), 150 (17), 89 (10), 77 (19), 65 (18), 51 (16), 39 (32). FAB-MS (KCl): 387 (25, [M ‡ K] ), 371 (5),
‡
‡
349 (99, [M ‡ H] ), 348 (100, M ), 332 (11), 303 (43), 287 (7), 274 (11), 150 (15). Anal. calc. for C16H16N2O7
(348.32): C 55.17, H4.63, N 8.04, O 32.15; found: C 54.89, H4.67, N 7.86, O 32.42.
Diethyl 2-Amino-5-(3-nitrophenyl)furan-3,4-dicarboxylate (13b). Ethyl 3-(3-nitrophenyl)-3-oxopropa-
noate (25 g, 0.10 mol) was suspended in toluene (300 ml), and SO2Cl2 (12.8 ml, 0.15 mol) was added at r.t.
After 5 min, the mixture cleared. Another 10 min later, the reaction was quenched by adding H2O (150 ml) with
cooling in an ice/water bath. The org. layer was washed neutral (pH > 7) with sat. NaHCO3 soln. and H2O, dried
(MgSO4), and filtered with suction. Evaporation of the filtrate gave 12b (26.51 g, 92%) as an orange oil that was
used without further purification.
After dissolution of 12b (180 g) in THF (400 ml), finely crushed sodium ethyl cyanoacetate (79.6 g,
0.59 mol) was added in small portions with cooling in an ice bath [25] (orange ! red). After stirring at 258 for
3 h, the THF was removed and the oily residue taken up in CH2Cl2 and H2O. The org. phase was washed with
H2O (5Â). The first two H2O phases were combined and washed back with CH2Cl2. The combined org. phase
was dried (MgSO4) and filtered with suction, the filtrate evaporated, and the orange oil (227 g) precipitated
from p-xylene: 61.98 g (25% from ethyl 3-(3-nitrophenyl)-3-oxopropanoate) of 13b. Yellow, amorphous solid.
M.p. 1698. IR: 3419m, 3318m, 3092w, 2986w, 2904w, 1718s, 1678s, 1647s, 1553m, 1528s, 1452m, 1347s, 1329m,
1265s, 1112m, 1030m. 1H-NMR (300 MHz, (CD3)2SO): 8.23 (−t×, J ˆ 2.1, 1 H); 8.11 (ddd, J ˆ 8.0, 2.3, 1.2, 1 H);

Helvetica Chimica Acta Vol. 87 (2004)
967
7.81 7.70 (m, 2 H); 7.61 (s, NH2); 4.35, 4.17 (2q, J ˆ 7.1, 2 MeCH2); 1.31, 1.23 (2t, J ˆ 7.1, 2 MeCH2). 13C-NMR
(75 MHz, (CD3)2SO): 164.2; 162.4; 161.9; 148.2; 136.0; 130.7; 129.9; 129.0; 121.6; 117.6; 116.6; 87.6; 61.6; 59.2;
‡
14.2; 13.7. EI-MS: 348 (100, M ), 303 (22), 274 (90), 256 (21), 150 (56), 134 (22), 104 (18), 76 (12). Anal. calc.
for C16H16N2O7 (348.32): C 55.17, H4.63, N 8.04, O 32.15; found: C 55.15, H4.79, N 8.00, O 32.27.
Ethyl 4-Hydroxy-6-(4-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylate (14a). Diethyl ester 13a (7.34 g)
was stirred under N2 at 1408 for 14 h in formamide (40 ml), DMF (20 ml), and 98 100% formic acid (10 ml).
After cooling to r.t., crystals in a deep red to brown mother liquor were present. This mixture was further cooled
in an ice bath. The highly viscose mass was filtered, the residue washed with iPrOHand hexane, dried under high
vacuum (5.6 g), and then heated in EtOH(200 ml), and the hot soln. filtered with suction. The residue obtained
was dried under high vacuum: 14a (1.43 g, 21%). Microscopically small crystals of irregular shape. M.p. 279
2828. IR: 3084w, 2994w, 2829w, 1721s, 1684s, 1597m, 1551m, 1512s, 1492m, 1351s, 1322s, 1298m, 1231m, 1076m,
1041m, 858m, 750w. 1H-NMR (400 MHz, (CD3)2SO): 12.9 (s, NH); 8.36 (d, J ˆ 9.0, 1 H); 8.28 (s, HÀC(2)); 8.01
(d, J ˆ 9.1, 1 H); 4.39 (q, J ˆ 7.1, MeCH2); 1.31 (t, J ˆ 7.1, MeCH2). 13C-NMR (101 MHz, (CD3)2SO): 164.2;
‡
162.3; 156.8; 148.9; 147.5; 147.4; 133.5; 127.6; 124.1; 113.2; 107.0; 61.8; 13.7. EI-MS: 357 (19, [M ‡ 28] ), 329 (100,
‡
M ), 313 (11), 284 (47), 257 (70), 237 (15), 227 (17), 211 (13), 150 (35), 104 (23), 76 (14), 44 (13). FAB-MS
‡
‡
(KCl): 368 (35, [M ‡ K] ), 330 (79, [M ‡ H] ), 284 (35), 149 (39), 124 (12), 113 (12), 107 (43), 95 (12), 89 (33),
77 (62), 69 (32), 65 (49), 55 (52), 41 (100). Anal. calc. for C15H11N3O6 (329.27): C 54.72, H3.37, N 12.76, O 29.16;
found: C 54.66, H3.46, N 12.81, O 29.27.
Ethyl 4-Hydroxy-6-(3-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylate (14b) and 4-Hydroxy-6-(3-nitro-
phenyl)furo[2,3-d]pyrimidine-5-carboxamide (15). Diethyl ester 13b (72.9 g) was stirred in formamide
(200 ml), DMF (100 ml), and 98 100% formic acid (40 ml) under N2 at 1408 for 1 d. After cooling to r.t.,
the mixture was diluted with H2O to 2 l and allowed to stand overnight. The precipitate formed was filtered off
with suction, air-dried overnight, and then dried under high vacuum. This crude product (79 g) was boiled in
MeCN (300 ml), filtered off with suction, washed with ice-cold MeCN, and dried under high vacuum (45 g). The
residue was boiled in CH2Cl2 (200 ml), filtered off warm with suction, washed with CH2Cl2, and dried under high
vacuum: 14b/15 (32.2 g, 46%) as a bright, gray-brown, and sometimes almost black solid, which was used
without further purification. The by-product 15 could be obtained in pure form upon recrystallization from
DMF as gray microcrystals of inconsistent shape. From the mother liquors (MeCN, CH2Cl2), ca. 20% of starting
material 13b was recovered.
Data of 14b: M.p. 212 2208. IR: 3528w, 3246m, 3092m, 2985w, 1936w, 1721s, 1589m, 1543s, 1482m, 1429w,
1378s, 1352s, 1323m, 1287m, 1234m, 1196m, 1076m, 1042s. 1H-NMR (300 MHz, (CD3)2SO): 12.87 (s, NH , 1 H );
8.60 (s, HÀC(2')); 8.34 (dd, J ˆ 8.2, 2.2, 1 H); 8.28 (s, HÀC(2)); 8.21 (d, J ˆ 8.7, 1 H); 7.84 (−t×, J ˆ 8.0, HÀC(5'));
‡
4.38 (q, J ˆ 7.0, MeCH2); 1.29 (t, J ˆ 7.0, MeCH2). EI-MS: 329 (100, M ), 284 (40), 268 (12), 257 (84), 237 (17),
‡
211 (21), 150 (49), 134 (12), 127 (14), 104 (25), 76 (24). HR-MS: 329.0645 (C15H11N3O6 ; calc. 329.0648).
Data of 15: M.p.: needles at ca. 3308, prisms at ca. 3508, start of dec. at ca. 3808, melting at 3908 (dec.). IR:
3338m, 3180 2810w, 1708s, 1676s, 1589w, 1560m, 1526s, 1406w, 1348s, 1220w, 1105w, 1081w, 1041w, 920w, 899w,
880w, 803w, 740w, 676w. 1H-NMR (500 MHz, (CD3)2SO): 13.2 (s, 1 H, exchange with D2O, NH); 9.5 (s, 1 H ,
exchange with D2O, CONH2); 8.82 (−t×, J ˆ 2.0, HÀC(2')); 8.36 (s, HÀC(2)); 8.33 (dd, J ˆ 8.1, 2.0, HÀC(4'),
HÀC(6')); 7.80 (−t×, J ˆ 8.1, HÀC(5')); 7.7 (s, 1 H, exchange with D2O, CONH2). 13C-NMR (126 MHz,
(CD3)2SO; assigned by HETCOR): 163.9; 162.2; 159.8; 150.6; 148.2 (C(2)); 147.4; 135.1 (C(6') or C(4'));
‡
130.2 (C(5')); 129.8; 124.3 (C(4') or C(6')); 123.9 (C(2')); 115.1; 105.8. EI-MS: 299 (100, [M À H] ), 253 (41), 150
(35), 134 (27), 104 (27), 76 (23), 44 (29). Anal. calc. for C13H8N4O5 (300.23): C 52.01, H2.69, N 18.66, O 26.65;
found: C 51.90, H2.81, N 18.80, O 26.51.
4-Hydroxy-6-(4-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylic Acid (16a). A mixture of 14a (3.0 g,
9.1 mmol) and 5% NaOHsoln. ( ca. 50 ml) was boiled for 50 min. The clear, reddish, hot soln. was filtered with
suction and the residue discarded2). The filtrate was adjusted to pH1 by cautiously adding conc. HCl soln. (
ochre and precipitation). The precipitate was dried under high vacuum: 16a (2.4 g, 87%). Yellow to beige,
!
2
)
Sodium 4-hydroxy-6-(4-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylate can be obtained from this
filtrate: Upon cooling to 08, the salt precipitated as needles, which were collected by filtering over ice
and washing with ice-cold H2O. These yellow-orange needles were dried under high vacuum, upon which
they turned blood red. Yield 62%. M.p. > 2508 (dec.). IR: 3414m (br.), 1595vs, 1542s, 1508s, 1476m, 1345m,
1180w, 1099w, 1067w, 854w, 811w. 1H-NMR (300 MHz, D2O; d rel. to residual HDO (ˆ4.79 ppm)): 8.24
(d, J ˆ 9.2, 2 H); 8.08 (s, 1 H); 7.93 (d, J ˆ 9.2, 2 H). ESI-MS (sample dissolved in MeOH): 299.9 (100, [M À
Na]À), 255.9 (23, [M À CO2]À).

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Helvetica Chimica Acta Vol. 87 (2004)
amorphous solid, readily soluble in DMSO, pyridine, and hot 5% NaOHsoln., fairly to poorly soluble in 5%
NaOH soln. at r.t., and practically insoluble in acetone, toluene, benzene, MeOH, nitromethane, BuOH, 1,2-
dichloroethane, THF, and sym-collidine. M.p. 300 3028 (dec.). IR: 3089m, 2843m, 1686s, 1540vs, 1513vs, 1474m,
1436m, 1405m, 1341vs, 1226s, 1110m, 1070m, 1039m, 855m, 775m, 755s, 620m, 516m. 1H-NMR (300 MHz,
(CD3)2SO): 13.5 (br. s, COOH); 8.40 (s, HÀC(2)); 8.38 (d, J ˆ 7.0, arom. H); 8.17 (d, J ˆ 9.1, arom. H).
13C-NMR (101 MHz, (CD3)2SO): 164.0; 162.4; 159.3; 149.6; 148.8; 147.7; 133.6; 128.8; 123.9; 113.7; 106.7. EI-MS:
‡
301 (100, M ), 257 (70), 227 (67), 211 (20), 156 (17), 150 (24), 120 (22), 104 (20), 76 (15), 44 (19). HR-MS:
‡
301.0350 (C13H7N3O6 ; calc. 301.0335). Anal. calc. for C13H7N3O6 (301.22): C 51.84, H2.34, N 13.95, O 31.87;
found: C 51.70, H2.53, N 14.15, O 31.88.
4-Hydroxy-6-(3-nitrophenyl)furo[2,3-d]pyrimidine-5-carboxylic Acid (16b). A mixture of 14b (0.95 g,
3.2 mmol) and 5% NaOHsoln. (30 ml) was heated for 30 min to 100 8. The black mixture was filtered hot, the
residue discarded, and the filtrate allowed to cool. The pHof the filtrate was adjusted to 1 in an ice bath. The
brown precipitate formed was collected and dried under high vacuum. The brown, amorphous solid contained
16b (595 mg, 63%) and was used without further purification. M.p. > 3008. IR: 3448w, 3237m, 3088w, 1752s,
1
1734s, 1672s, 1531s, 1474m, 1407m, 1381m, 1346s, 1241m, 1211m. H-NMR (300 MHz, (CD3)2SO): 14.4 12.8
(s, COOH, OH); 8.82 (−t×, J ˆ 1.9, HÀC(2')); 8.42 (s, HÀC(2)); 8.37 8.34 (m, 2 H); 7.85 (−t×, J ˆ 8.1, HÀC(5')).
13C-NMR (75 MHz, (CD3)2SO): 163.7; 162.1; 159.8; 150.7; 148.6; 147.7; 134.2; 130.4; 129.1; 124.7; 122.8; 112.5;
‡
106.4. MS: 301 (23, M ), 257 (100), 211 (24), 156 (48), 150 (14), 128 (17), 104 (20), 101 (12), 76 (32), 63 (11), 52
(15), 50 (15), 44 (20).
6-(4-Nitrophenyl)furo[2,3-d]pyrimidin-4-ol (17a). Acid 16a (21 g) was dissolved in warm pyridine
(200 ml). The pyridine was subsequently evaporated at 808. The mixture of the residue, Cu2O (1 g), and
quinoline (500 ml; dried over MgSO4) was heated under constant N2 flow for 1 h at 1908. After cooling to r.t.,
the mixture was poured into 2.5m HCl (1 l), stirred, and filtered with suction. This residue was washed with conc.
NH3 soln. and H2O. The dark brown, muddy residue was left to dry first at r.t. and then dried under high vacuum:
crude 17a (13 g, ca. 70%). Due to low solubilities, the compound was used without further purification. M.p. >
3508. IR: 3073w, 2859w, 1678vs, 1599s, 1548s, 1514s, 1349vs, 1218m, 1189m, 1110m, 854m, 780m, 752w. 1H-NMR
(300 MHz, (CD3)2SO): 12.8 (s, NH); 8.33 (d, J ˆ 8.8, 2 arom. H); 8.23 (d, J ˆ 3.6, HÀC(2)); 8.12 (d, J ˆ 8.6,
‡
2 arom. H); 7.85 (s, HÀC(5)). EI-MS: 257 (100, M ), 241 (9), 227 (18), 211 (19), 156 (22), 128 (7), 104 (9), 52
‡
(7). HR-MS: 257.0429 (C12H7N3O4 ; calc. 257.0437).
6-(3-Nitrophenyl)furo[2,3-d]pyrimidin-4-ol (17b). As described for 17a, with 16b (25.5 g), pyridine
(250 ml), Cu2O (1 g), and quinoline (250 ml). After cooling, the mixture was poured into 2.5m HCl (1 l), stirred,
diluted to 2 l with H2O, and filtered with suction. The residue was washed with little H2O (this acidic filtrate was
discarded), conc. NH3 soln. (200 ml), and lots of H2O. The pHof this second (basic) filtrate was adjusted to 1
with conc. HCl, and the mixture filtered with suction. The residue was dried in an oven at 1008 (for at least one
night), then under high vacuum. This crude product (18.5 g) was stirred into a considerable amount of sat.
NaHCO3 soln. and stored overnight. The resulting precipitate was filtered off with suction and washed with
H2O: crude 17b (10.5 g, 49%), which was used without further purification (starting material 16b (2.3 g, 9%)
could be recovered by adjusting the pHof the last filtrate to 1 with conc. HCl soln., collecting the precipitate,
and drying it under high vacuum). IR: 3091w, 2853w, 1670vs, 1593w, 1527s, 1496w, 1475w, 1373w, 1348s, 1297w,
1202m, 938m, 900m, 783w, 740w, 703w, 622w. 1H-NMR (400 MHz, (CD3)2SO): 12.7 (s, NH); 8.58 (t, J ˆ 3.8,
HÀC(2')); 8.29 (ddd, J ˆ 7.8, 1.8, 1.0, 1 H); 8.20 (ddd, J ˆ 8.4, 2.3, 1.0, 1 H); 8.19 (d, J ˆ 3.5, HÀC(2)); 7.78
‡
(s, HÀC(5)); 7.77 (t, J ˆ 8.1, HÀC(5')). EI-MS: 257 (100, M ), 241 (7), 227 (8), 211 (22), 156 (23), 128 (7), 104
‡
(7), 76 (9), 52 (6). HR-MS: 257.0436 (C12H7N3O4 ; calc. 257.0437).
4-Chloro-6-(4-nitrophenyl)furo[2,3-d]pyrimidine (18a). Crude 17a (13.5 g) was refluxed in POCl3 (200 ml)
for 1.5 h. The mixture was left open at r.t.for three days and then poured very cautiously onto 4 kg of drip-dried
ice. After a few hours, the resulting bright brown suspension was filtered with suction. The residue was washed
with much H2O and then air-dried overnight. Additional drying under high vacuum gave crude 18a (13.8 g, 94%)
which was frequently used without purification. We recommend, however, that 18a be sublimed before use in
synthesis as impurities may not easily be removed at a later stage. Sublimation at ca. 2008/ca. 0.1 mbar yielded
18a. Bright yellow, noncrystalline needles that are somewhat soluble in DMF and hardly or not at all soluble in
acetone, toluene, EtOH, and 1,2-dichloroethane. M.p.: transformation to microscopically small, crystalline
needles just before melting at 2458 (dec.). IR: 3106w, 1593m, 1560s, 1515s, 1430w, 1376w, 1345m, 1250w, 1108w,
1030w, 973w, 914w, 858w, 782w, 752w. 1H-NMR (300 MHz, (CD3)2SO): 8.93 (s, HÀC(2)); 8.42, 8.33 (d, J ˆ 9.2,
‡
HÀC(2'), HÀC(3')); 8.12 (s, HÀC(5)). EI-MS: 275 (100, M ), 245 (16), 217 (16), 174 (32), 139 (14). HR-MS:
‡
275.0091 (C12H6ClN3O3 ; calc. 275.0097). Anal. calc. for C12H6ClN3O3 (275.65): C 52.29, H2.19, N 15.24, O 17.41;
found: C 52.28, H2.45, N 15.26, O 17.47.

Helvetica Chimica Acta Vol. 87 (2004)
969
4-Chloro-6-(3-nitrophenyl)furo[2,3-d]pyrimidine (18b). Crude 17b (11 g) was refluxed in POCl3 (340 ml)
for 4 h. The mixture was left to stand at r.t. overnight and then poured slowly and cautiously onto drip-dried ice
(5 kg). The resulting bright brown suspension was stored for a few hours under constant surveillance. The
precipitate was then filtered off with suction and washed extensively with H2O. The residue was left to dry under
ambient conditions overnight, dried under high vacuum, and subsequently sublimed at ca. 2008 under high
vacuum: 18b (2.73 g, 23%) as noncrystalline needles (the brown sublimation residue (8.0 g, > 72%) contained
mostly starting material 17b). M.p.: transformation to tiny crystalline needles at ca. 1908 which melted from 1968
to 2058. IR: 3114w, 3070m, 3009w, 2867w, 1618w, 1592m, 1565s, 1519vs, 1469w, 1429m, 1373s, 1359s, 1304m, 1255s,
1228w, 1206m, 1108w, 1046w, 972w, 923m, 900w, 878w, 807m, 780m, 753m, 740m, 677m. 1H-NMR (400 MHz,
(CD3)2SO): 8.87 (s, HÀC(2)); 8.78 (−t×, J ˆ 1.9, HÀC(2')); 8.46 (ddd, J ˆ 7.8, 1.8, 1.0, 1 H); 8.33 (ddd, J ˆ 8.1, 2.3,
‡
0.9, 1 H); 8.09 (s, HÀC(5)); 7.86 (−t×, J ˆ 8.1; HÀC(5')). EI-MS: 275 (100, M ), 229 (9), 217 (5), 201 (8), 174
(33), 165 (10), 139 (13). Anal. calc. for C12H6ClN3O3 (275.65): C 52.29, H2.19, N 15.24, O 17.41; found: C 52.18,
H2.33, N 15.49, O 17.51.
N-(4-Chloro-2-fluorophenyl)-6-(4-nitrophenyl)furo[2,3-d]pyrimidin-4-amine (19k). According to GP 1,
with 18a (1.65 g, 5.9 mmol), 4-chloro-2-fluoroaniline (2.2 ml) and BuOH(100 ml) for 4 h. Workup: The residue
t
was washed with BuOH, MeOH, and BuOMe, dried under high vacuum ( ! 1.5 g), and recrystallized from
AcOH: 19k (1.15 g, 51%). Yellow, microscopically fine needles that are well soluble in DMSO and CF3COOH,
fairly soluble in AcOH, and not at all or poorly soluble in acetone, MeOH, and H2O. M.p. > 2508. IR: 3386m,
3110w, 3065w, 1625m, 1599s, 1590s, 1576s, 1506s, 1476m, 1456m, 1414m, 1337s, 1312m, 1286m, 1188m, 1109w,
1
1067w, 1032w, 853w, 787w, 753w. H-NMR (500 MHz, (CD3)2SO): 10.0 (s, NH); 8.41 (s, HÀC(2)); 8.36 (d, J ˆ
9.1, HÀC(2'')); 8.08 (d, J ˆ 9.0, HÀC(3'')); 7.82 (−t×, J ˆ 8.6, HÀC(6')); 7.78 (s, HÀC(5)); 7.57 (dd, J ˆ 10.4, 2.4,
HÀC(3')); 7.35 (ddd, J ˆ 8.6, 2.4, 1.1, HÀC(5')). 13C-NMR (126 MHz, (CD3)2SO; assigned by HETCOR and
long-range HETCOR): 166.8 (C(7a)); 155.5 (d, J ˆ 250.2, C(2')); 155.4 (C(3)); 154.3 (C(2)); 149.0 (C(1'')); 147.0
(C(4'')); 134.6 (C(6)); 129.5 (d, J ˆ 9.9); 127.7 (d, J ˆ 2.1, C(6')); 125.3 (C(3'')); 125.2 (d, J ˆ 13.1); 124.6 (d, J ˆ
‡
3.5, C(5')); 124.5 (C(2'')); 116.5 (d, J ˆ 23.7, C(3')); 103.8 (C(4a)); 103.0 (C(5)). EI-MS: 384 (100, M ), 365 (86),
‡
354 (21), 349 (42), 319 (36), 303 (20), 247 (11), 180 (13), 156 (14). HR-MS: 384.0419 (C18H10ClFN4O3 ; calc.
384.0426). Anal. calc. for C18H10ClFN4O3 (384.75): C 56.19, H2.62, N 14.56, O 12.48; found: C 55.92, H2.89, N
14.63, O 12.46.
N-(4-Chloro-2-fluorophenyl)-6-(3-nitrophenyl)furo[2,3-d]pyrimidin-4-amine (19l). According to the GP 1,
with 18b (4.32 g, 16 mmol), 4-chloro-2-fluoroaniline (5 ml) and BuOH(200 ml) for 3 h (colorless suspension !
colorless soln. ! yellow suspension). Workup: the crude 19l (4.3 g, 70%), a very bright yellow cotton-wool-like
solid, was recrystallized from AcOHand then dried at 100 8/high vacuum overnight: microscopically small
needles. M.p.: transformation at ca. 2608 to somewhat larger needles that melted at 2698. IR: 3410m, 3110w,
1630s, 1610s, 1594s, 1582s, 1526vs, 1479m, 1458m, 1416m, 1356s, 1190m, 1108w, 1070w, 1043w, 934w, 904w, 844w,
809w, 782w, 741w, 536w. 1H-NMR (500 MHz, (CD3)2SO): 9.9 (s, NH); 8.56 (t, J ˆ 2.0, HÀC(2'')); 8.42
(s, HÀC(2)); 8.31 8.27 (m, HÀC(4'') and HÀC(6'')); 7.850 (−t×, J ˆ 8.0, HÀC(5'')); 7.847 (−t×, J ˆ 8.7, HÀC(6'));
‡
7.77 (s, HÀC(5)); 7.60 (dd, J ˆ 10.4, 2.4, HÀC(3')); 7.37 (ddd, J ˆ 8.7, 2.3, 1.0, HÀC(5')). EI-MS: 384 (100, M ),
365 (90), 354 (20), 349 (43), 335 (14), 319 (29), 303 (18), 247 (12), 180 (10), 156 (10), 151 (15). Anal. calc. for
C18H10ClFN4O3 (384.75): C 56.19, H2.62, N 14.56, O 12.48; found: C 56.04, H2.72, N 14.66, O 12.36.
N-(3-Chlorophenyl)-6-(4-nitrophenyl)furo[2,3-d]pyrimidin-4-amine (19m). According to GP 1, with 18a
(1.80 g, 6.5 mmol), 3-chloroaniline (2.6 ml, 2.55 g, 20.0 mmol) and BuOH(100 ml) for 2 h. No workup: 19m
(2.24 g, 94%). Intensively yellow, granular microcrystals of irregular shape. M.p. 2888. IR: 3278w, 3187w, 3112w,
3014w, 1627m, 1600m, 1584s, 1571s, 1524m, 1473m, 1425m, 1345s, 1313m, 1152w, 1112w, 1072w, 1023w, 926w,
852w, 770w, 750w. 1H-NMR (300 MHz, (CD3)2SO): 10.17 (s, NH); 8.57 (s, HÀC(2)); 8.38 (d, J ˆ 8.6, 1 H); 8.13
(−t×, J ˆ 2.0, HÀC(2')); 8.10 (d, J ˆ 8.5, 1 H); 7.86 (s, HÀC(5)); 7.75 7.12 (m, 1 H); 7.43 (t, J ˆ 8.0, HÀC(5'));
‡
7.18 7.14 (m, 1 H). EI-MS: 366 (100, M ), 350 (12), 336 (21), 319 (21), 258 (8), 229 (11), 142.5 (9), 115 (11),
111 (15), 75 (8). Anal. calc. for C18H11ClN4O3 (366.77): C 58.95, H3.02, N 15.28, O 13.09; found (after drying for
19 h at < 1508/high vacuum): C 58.76, H3.29, N 15.24, O 13.31.
N-(3-Chlorophenyl)-6-(3-nitrophenyl)furo[2,3-d]pyrimidin-4-amine (19n). According to GP 1, with 18b
(0.87 g, 3.2 mmol), 3-chloroaniline (1.0 ml, 1.2 g, 9.5 mmol), and BuOH(170 ml) for 3 h. Workup: The bright
yellow, cotton-wool-like residue was recrystallized from AcOH: 19n (0.85 g, 73%). Bright yellow, microscopi-
cally small, non-crystalline needles. M.p.: transformation to crystalline platelets just below the m.p. (268 2708).
IR: 3278w, 3186w, 3112w, 3009w, 1629s, 1583vs, 1523s, 1485s, 1432m, 1346s, 1309m, 1235m, 1150m, 938m, 772m.
1H-NMR (400 MHz, (CD3)2SO; d rel. to the solvent (ˆ2.52 ppm)): 10.06 (s, NH); 8.56 (s, HÀC(2)); 8.54
(−t×, J ˆ 2.0, HÀC(2'')); 8.27 (dd, J ˆ 8.1, 2.0, HÀC(4''), HÀC(6'')); 8.14 (t, J ˆ 2.0, HÀC(2')); 7.85 (−t×, J ˆ 8.0,
HÀC(5'')); 7.81 (s, HÀC(5)); 7.74 (ddd, J ˆ 8.3, 2.0, 1.0, 1 H); 7.44 (−t×, J ˆ 8.2, HÀC(5')); 7.16 (ddd, J ˆ 8.0, 2.0,

970
Helvetica Chimica Acta Vol. 87 (2004)
‡
0.8, 1 H). EI-MS: 366 (100, M ), 350 (24), 336 (16), 319 (24), 258 (12), 229 (15), 142.5 (19), 115 (13), 111 (13).
‡
HR-MS: 366.0503 (C18H11ClN4O3 ; calc. 366.0520). Anal. calc. for C18H11ClN4O3 (366.77): C 58.95, H3.02, N
15.28, O 13.09; found: C 58.76, H3.15, N 15.41, O 13.16.
2-Methoxy-5-{[6-(4-nitrophenyl)furo[2,3-d]pyrimidin-4-yl]amino}phenol (19o). According to GP 1, with
18a (1.96 g, 7.1 mmol), 5-amino-2-methoxyphenol (2.94 g, 21 mmol), and BuOH(100 ml) for 3 h. Workup:
Recrystallization from AcOHyielded 19o (1.88 g, 70%). Red brown, amorphous solid. M.p. 280 2858 (dec.).
IR: 3364m, 3104w, 2929w, 1621m, 1599m, 1579s, 1508s, 1460m, 1340s, 1286w, 1218w, 1180w. 1H-NMR (300 MHz,
(CD3)2SO): 9.80, 9.15 (2s, exchange with D2O, NH, OH); 8.43 (s, HÀC(2')); 8.37, 8.06 (d, J ˆ 9.0, HÀC(3''),
HÀC(2'')); 7.74 (br. s, HÀC(5'')); 7.31 (d, J ˆ 2.5, HÀC(6)); 7.14 (dd, J ˆ 8.7, 2.5, HÀC(4)); 6.94 (d, J ˆ 8.9,
‡
HÀC(3)); 3.78 (s, MeO). EI-MS: 378 (100, M ), 363 (72), 348 (17), 335 (20), 317 (27), 289 (22), 139 (12). HR-
MS: 378.0955 (calc. 378.0964). Anal. calc. for C19H14N4O5 (378.35): C 60.32, H3.73, N 14.81, O 21.14; found: C
60.22, H4.02, N 14.57, O 20.98.
6-(3-Nitrophenyl)-N-[(1R)-1-phenylethyl]furo[2,3-d]pyrimidin-4-amine (19p). According to GP 1, with
18b (2.43 g, 8.8 mmol), [(1R)-1-phenylethyl]amine (4.2 ml), and BuOH(75 ml) for 2.5 h. The clear reaction
soln. was concentrated (808/100 mbar) and then brought to precipitation by adding H2O (100 ml) and tBuOMe
(300 ml; shaking, brightly yellow precipitate). The two-phase mixture was filtered with suction and the residue
dried under high vacuum. Recrystallization from EtOHyielded 19p (1.78 g, 56%). Brightly yellow needles. M.p.
163 1658. IR: 3407m, 3390m, 3124w, 3086w, 3031w, 2970w, 2929w, 1603s, 1524s, 1490m, 1450m, 1346s, 1294m,
1138m, 1102w, 934w, 785w, 738w, 699w. 1H-NMR (400 MHz, (CD3)2SO): 8.56 (s, HÀC(2')); 8.39 (d, J ˆ 8.1,
NH); 8.23 (s, HÀC(2)); 8.20 8.15 (m, HÀC(4'), HÀC(6')); 7.77 (−t×, J ˆ 8.1, HÀC(5')); 7.71 (s, HÀC(5)); 7.42
(d, J ˆ 7.6, 2 H); 7.33 7.29 (m, 2 H); 7.21 (tt, J ˆ 7.3, 1.2, 1 H); 5.47 5.43 (−quint.×, J ˆ 7.2, MeCHN); 1.54 (d, J ˆ
‡
7.1, MeCHN). EI-MS: 360 (60, M ), 345 (37), 299 (9), 256 (42), 210 (7), 139 (5), 120 (46), 105 (100), 77 (15).
Anal. calc. for C20H16N4O3 (360.38): C 66.66, H4.48, N 15.55, O 13.32; found: C 66.43, H4.62, N 15.61, O 13.37.
2-Methyl-5-{[6-(3-nitrophenyl)furo[2,3-d]pyrimidin-4-yl]amino}phenol (19q). According to GP 1, with 18b
(2.43 g, 8.8 mmol), 5-amino-2-methylphenol (3.27 g, 27 mmol), and BuOH(200 ml) for 3 h. Workup: The
residue was recrystallized once from AcOHand twice from DMSO: 19q (869 mg, 27%). Yellow-orange crystals
of various shapes. M.p. 280 2858. IR: 3388m, 3122w, 2922w, 1614s, 1593s, 1526s, 1583m, 1465m, 1420m, 1352s,
1304m, 1178m, 1122m, 933w, 897w, 845w, 782m, 739m, 668w. 1H-NMR (400 MHz, (CD3)2SO): 9.72, 9.36 (2s, NH ,
OH); 8.50, 8.43 (s, HÀC(2''), HÀC(2')); 8.25 8.21 (m, HÀC(4''), HÀC(6'')); 7.81 (−t×, J ˆ 8.7, HÀC(5'')); 7.75
(s, HÀC(5')); 7.36 (d, J ˆ 1.8, HÀC(6)); 7.12 (dd, J ˆ 8.0, 1.8, HÀC(4)); 7.03 (d, J ˆ 8.3, HÀC(3)); 2.09 (s, Me).
‡
‡
EI-MS: 362 (100, M ), 346 (17), 332 (42), 315 (27), 77 (11). HR-MS: 362.1001 (C19H14N4O4 ; calc. 362.1001).
4-Chloro-2-{[6-(3-nitrophenyl)furo[2,3-d]pyrimidin-4-yl]amino}phenol (19r). According to GP 1, with 18b
(2.5 g, 9.0 mmol), 2-amino-4-chlorophenol (4 g, 28 mmol), and BuOH(100 ml) for 3.5 h. Workup: The residue
was dried under high vacuum (3.05 g) and recrystallized from AcOH: 19r (1.93 g, 55%). Clear, dark brown
prisms. M.p. ca. 2758 (dec.; sublimation just below the m.p.). 1H-NMR (400 MHz, (CD3)2SO): 9.25 (s, NH); 8.51
(t, J ˆ 1.9, HÀC(2'')); 8.42 (s, HÀC(2')); 8.22 (dd, J ˆ 8.2, 2.1, HÀC(4''), HÀC(6'')); 7.93 (d, J ˆ 2.5, HÀC(3));
7.85 (s, HÀC(5')); 7.79 (−t×, J ˆ 8.1, HÀC(5'')); 7.06 (dd, J ˆ 8.6, 2.5, HÀC(5)); 6.95 (d, J ˆ 8.6, HÀC(6)). EI-MS:
‡
382 (62, M ), 365 (56), 355 (100), 335 (21), 325 (45), 309 (37), 205 (34), 178 (15), 139 (17), 63 (21), 36 (17).
‡
HR-MS: 382.0460 (C18H11ClN4O4 ; calc. 382.0469).
N-(3-Nitrophenyl)-6-(4-nitrophenyl)furo[2,3-d]pyrimidin-4-amine (19s). According to the GP 1, with 18a
(2.1 g, 7.4 mmol), 3-nitroaniline (3.2 g, 23 mmol), and BuOH(200 ml) for 3 h. No workup: 19s (2.6 g, 93%).
Yellow, amorphous solid. M.p.: tiny needles at ca. 3008, m.p. > 3508. IR: 3394m, 3106w, 3078w, 1623s, 1595s,
1578s, 1534s, 1510vs, 1457m, 1346vs, 1285m, 1243w, 1219w, 1109w, 1070w, 1032w, 923w, 854m, 820w, 786w, 751w.
1H-NMR (400 MHz, (CD3)2SO): 10.41 (s, NH); 8.86 (−t×, J ˆ 2.1, HÀC(2')); 8.60 (s, HÀC(2)); 8.36 (d, J ˆ 8.6,
HÀC(2'')); 8.31 8.27 (m, 1 H); 8.09 (d, J ˆ 8.8, HÀC(3'')); 7.93 (dd, J ˆ 8.1, 1.5, 1 H); 7.84 (s, HÀC(5)); 7.68
‡
(−t×, J ˆ 8.1, HÀC(5')). EI-MS: 377 (100, M ), 361 (18), 329 (19), 285 (16), 229 (11). Anal. calc. for C18H11N5O5
(377.32): C 57.30, H2.94, N 18.56, O 21.20; found (after drying overnight at ca. 1758/high vacuum): C 57.03, H
3.18, N 18.36, O 21.35.
2-Methyl-5-{[6-(4-nitrophenyl)furo[2,3-d]pyrimidin-4-yl]amino}phenol (19t). According to the GP 1, with
18a (2.23 g, 8.1 mmol), 5-amino-2-methylphenol (3.03 g, 25 mmol), and BuOH(170 ml) for 3 h ( ! red). No
workup: 19t (2.60 g, 89%). Orange, microscopically small needles. M.p.: transformation at ca. 2758 (partial dec.)
to larger needles that melted at ca. 2958. IR: 3388m, 3110w, 2927w, 1619s, 1599s, 1578s, 1518m, 1473m, 1339vs,
1236w, 1172m, 1108w, 1032w, 926w, 853w, 784w, 751w. 1H-NMR (400 MHz, (CD3)2SO): 9.81, 9.37 (2s, NH , OH );
8.44 (s, HÀC(2')); 8.36 (d, J ˆ 9.1, HÀC(3''); 8.04 (d, J ˆ 9.1, HÀC(2'')); 7.80 (s, HÀC(5')); 7.35 (d, J ˆ 1.0,
‡
HÀC(6)); 7.11 (dd, J ˆ 8.1, 2.3, HÀC(4)); 7.03 (d, J ˆ 8.1, HÀC(3)); 2.09 (s, Me). EI-MS: 362 (100, M ), 346

Helvetica Chimica Acta Vol. 87 (2004)
971
(11), 332 (14), 315 (27), 107 (5), 77 (9). Anal. calc. for C19H14N4O4 (362.35): C 62.98, H3.89, N 15.46, O 17.66;
found (after drying overnight at ca. 1758/high vacuum): C 62.70, H3.97, N 15.48, O 17.86.
N-(3,5-Dichlorophenyl)-6-(3-nitrophenyl)furo[2,3-d]pyrimidin-4-amine (19u). According to GP 1, with
18b (0.82 g, 3.0 mmol), 3,5-dichloroaniline (3.5 g, 21 mmol, 7 equiv.), and BuOH(170 ml), reflux overnight.
The mixture was somewhat concentrated, allowed to cool, and then filtered (r.t.) with suction. The solid was
washed with BuOHand dried under high vacuum: 19u (0.68 g, 56%). Microcrystalline platelets. M.p. 212 2158.
IR: 3400m, 3118w, 1626m, 1611s, 1578s, 1527s, 1457s, 1353s, 1082m, 843m, 785m, 738s, 671m. 1H-NMR
(400 MHz, (CD3)2SO): 10.13 (s, NH); 8.59 (s, HÀC(2)); 8.52 (−t×, J ˆ 1.9, HÀC(2'')); 8.26 (dd, J ˆ 8.1, 2.0,
HÀC(4''), HÀC(6'')); 7.98 (d, J ˆ 1.8, HÀC(2')); 7.82 (−t×, J ˆ 8.1, HÀC(5'')); 7.75 (s, HÀC(5)); 7.26 (t, J ˆ 2.0,
‡
‡
HÀC(4')). EI-MS: 400 (100, M ), 384 (15), 370 (14), 353 (14), 159.5 (14). HR-MS: 400.0133 (C18H10Cl2N4O3 ;
calc. 400.0130).
N,6-Bis(3-nitrophenyl)furo[2,3-d]pyrimidin-4-amine (19v). According to GP 1, with 18b (1.1 g, 4.0 mmol),
3-nitroaniline (3.8 g, 28 mmol, 7 equiv.), and BuOH(300 ml). BuOH(100 ml) was distilled off and the mixture
allowed to cool and then filtered at r.t. with suction. The solid was washed with BuOHand dried under high
vacuum: 19v (1.28 g, 85%). Yellow powder. M.p. 3178. IR: 3375m, 3112w, 3068w, 1612s, 1594s, 1575s, 1526s,
1456s, 1437m, 1347s, 1244w, 1218w, 1068m, 937w, 801w, 788m, 742m, 671w. 1H-NMR (400 MHz, (CD3)2SO):
10.35 (s, NH); 8.87 (−t×, J ˆ 2.3, 1 H); 8.60 (s, HÀC(2)); 8.56 (−t×, J ˆ 1.9, 1 H); 8.30 8.26 (m, 3 H); 7.92 (ddd, J ˆ
‡
8.3, 2.3, 0.9, 1 H); 7.84 (−t×, J ˆ 8.1, 1 H); 7.82 (s, HÀC(5)); 7.68 (−t×, J ˆ 8.2, 1 H). EI-MS: 377 (100, M ), 361 (17),
347 (5), 330 (22), 285 (18), 257 (7), 229 (12), 197 (5), 139 (8), 115 (5), 76 (9). Anal. calc. for C18H11N5O5
(377.32): C 57.30, H2.94, N 18.56, O 21.20; found: C 57.19, H3.04, N 18.59, O 21.21.
6-(4-Aminophenyl)-N-(4-chloro-2-fluorophenyl)furo[2,3-d]pyrimidin-4-amine (20k). According to GP 2,
with 19k (0.95 g, 2.5 mmol), THF (50 ml), Et3N (2 ml; to neutralize traces of AcOHstemming from the
previous recrystallization), and DMEU (2 ml). Workup: The filtrate was concentrated and resuspended in H2O,
the pHadjusted to 10 by adding 5% NaOHsoln., and the mixture filtered with suction. The residue was washed
extensively with H2O and dried under high vacuum: 20k (560 mg, 63%). Pale orange amorphous solid that is
fairly soluble in DMSO > acetone > iPrOH > toluene, AcOEt > EtOH(in decreasing order) and poorly soluble
t
in BuOMe. For elemental analysis, the product was submitted to FC (acetone soln. adsorbed on SiO2; SiO2,
pentane/AcOEt 3 :2; all fluorescent fractions were collected). M.p.: transformation to microscopically small
needles just before melting at 229 2328. IR: 3440w, 3408w, 3325w, 3219w, 1625m, 1607s, 1586m, 1504s, 1458m,
1
1412w, 1356m, 1181m, 1067w, 827w, 753w, 507w. H-NMR (500 MHz, (CD3)2SO; assigned by HETCOR): 9.6
(s, NH); 8.27 (s, HÀC(2)); 7.81 (−t×, J ˆ 8.6, HÀC(6'')); 7.55 (dd, J ˆ 10.4, 2.2, HÀC(3'')); 7.51 (d, J ˆ 8.6,
HÀC(3')); 7.33 (dd, J ˆ 8.6, 1.3, HÀC(5'')); 7.10 (s, HÀC(5)); 6.68 (d, J ˆ 8.6, HÀC(2')); 5.64 (s, NH2).
13C-NMR (126 MHz, (CD3)2SO; assigned by HETCOR): 165.8 (C(7a)); 155.3 (d, J ˆ 249.7, C(2'')); 154.0; 153.2;
151.8 (C(2)); 150.1; 128.8 (d, J ˆ 9.6); 127.5 (d, J ˆ 2.4, C(6'')); 125.8 (C(2')); 125.7 (d, J ˆ 11.9); 124.5 (d, J ˆ 3.6,
‡
C(5'')); 116.4 (d, J ˆ 23.7, C(3'')); 115.9; 113.8 (C(3')); 104.4 (C(4a)); 93.9 (C(5)). EI-MS: 354 (100, M ), 335
(29), 319 (13), 279 (9), 177 (7), 167.5 (11), 155 (14), 120 (12), 92 (9), 65 (8). Anal. calc. for C18H12ClFN4O
(354.77): C 60.94, H3.41, N 15.79, O 4.51; found: C 60.89, H3.66, N 15.58, O 4.76.
6-(3-Aminophenyl)-N-(4-chloro-2-fluorophenyl)-furo[2,3-d]pyrimidin-4-amine (20l). According to GP 2,
with 19l (2.9 g), THF (80 ml), and DMEU (30 ml). Workup: H2O (300 ml) was added to the filtrate. The
resulting precipitate was filtered off with suction, washed with H2O, and dried under high vacuum: 20l (2.58 g,
97%). Colorless, cotton-wool-like solid. M.p. 2168. IR: 3402w, 3323w, 3317w, 3119w, 1624s, 1606s, 1588s, 1511s,
1466s, 1415m, 1400m, 1355w, 1267m, 1191m, 1066w, 940w, 856m, 779m. 1H-NMR (400 MHz, (CD3)2SO): 9.7
(s, NH); 8.31 (s, HÀC(2)); 7.80 (−t×, J ˆ 8.7, HÀC(6'')); 7.54 (dd, J ˆ 10.4, 2.3, HÀC(3'')); 7.34 (s, HÀC(5)); 7.33
(ddd, J ˆ 8.7, 2.3, 1.0, HÀC(5'')); 7.14 (−t×, J ˆ 7.8, HÀC(5')); 7.04 (−t×, J ˆ 1.9, HÀC(2')); 6.96 6.94 (m, HÀC(6')
or HÀC(4')); 6.61 (ddd, J ˆ 8.1, 2.3, 1.0, HÀC(4') or HÀC(6')); 5.34 (s, NH2). 13C-NMR (101 MHz, (CD3)2SO):
167.0; 156.3 (d, J ˆ 250.0); 155.7; 153.8; 153.3; 150.2; 130.6 (CH); 130.2; 130.1 (d, J ˆ 10); 128.6 (d, J ˆ 2.3); 126.5
(d, J ˆ 12.3); 125.4 (d, J ˆ 3.1), 117.4 (d, J ˆ 23.4); 115.7 (CH); 112.9 (CH); 110.2 (CH); 104.9; 98.8 (CH). EI-
‡
MS: 354 (100, M ), 335 (75), 319 (39), 177 (5), 167.5 (16), 155 (8), 120 (5), 92 (11), 65 (7). Anal. calc. for
C18H12ClFN4O (354.77): C 60.94, H3.41, N 15.79, O 4.51; found: C 60.70, H3.56, N 15.78, O 4.66.
6-(4-Aminophenyl)-N-(3-chlorophenyl)furo[2,3-d]pyrimidin-4-amine (20m). To a suspension of 19m
(1.98 g, 5.4 mmol) in DMEU (50 ml), some Raney-Ni suspension was added, and the mixture was shaken
overnight under H2 at 1 atm. The orange suspension was filtered with suction over Celite and the residue washed
with acetone and DMSO. To the combined filtrates, much acetone was added, and this mixture was then filtered
with suction. The resulting residue (0.3 g; consisting of a DMEU polymer pigment) was discarded. The volume
of the filtrate was doubled with H2O. The resulting beige, amorphous precipitate (0.94 g) was submitted to FC
(SiO2, acetone). Fluorescent fractions were filtered (removal of more DMEU polymer colloids), combined,

972
Helvetica Chimica Acta Vol. 87 (2004)
and evaporated. The residue was dried under high vacuum: 20m (0.65 g, 36%). (Note: we recommend the GP 2
instead of the one described). Bright brown, microscopically small needles. M.p. 2548 (dec.). IR: 3461m, 3370m,
3288w, 3198w, 3116w, 1623s, 1579s, 1518m, 1507w, 1477s, 1458s, 1425m, 1354m, 1296m, 1179m, 1149m, 1072m,
1027w, 920w, 832m, 776m. 1H-NMR (400 MHz, (CD3)2SO): 9.8 (s, NH); 8.40 (s, HÀC(2)); 8.11 (−t×, J ˆ 2.0,
HÀC(2'')); 7.72 (ddd, J ˆ 8.2, 2.2, 0.9, 1 H); 7.50 (d, J ˆ 8.6, 2 H); 7.37 (−t×, J ˆ 8.1, HÀC(5'')); 7.16 (s, HÀC(5));
‡
7.08 (ddd, J ˆ 7.9, 2.0, 0.9, 1 H); 6.67 (d, J ˆ 8.8, 2 H); 5.64 (s, NH2). EI-MS: 336 (100, M ), 280 (9), 246 (12),
‡
167.5 (6), 155 (8), 150.5 (7), 120 (6), 92 (5). HR-MS: 336.0782 (C18H13ClN4O ; calc. 336.0778). Anal. calc. for
C18H13ClN4O (336.78): C 64.20, H3.89, N 16.64, O 4.75; found: C 63.78, H4.17, N 16.46, O 5.12.
6-(3-Aminophenyl)-N-(3-chlorophenyl)furo[2,3-d]pyrimidin-4-amine (20n). According to GP 2, with 19n
(0.81 g, 2.7 mmol), THF (120 ml), and DMEU (8 ml). The residue on the Celite was washed with acetone and
H2O. Workup: The combined filtrates were evaporated (682 mg), the residue heated in EtOH, and the mixture
filtered with suction while still hot. From this filtrate, 20n (0.07 g, 8%) precipitated as amorphous, pale yellow
solid (m.p. 244 2458). When H2O was added at the boiling point of the mother liquor, further 20n (373 mg,
41%) crystallized as pale yellow, cotton-wool-like solid. IR: 3318w, 3201w, 3117w, 1618s, 1605s, 1582s, 1570s,
1512m, 1474s, 1424m, 1356m, 1305m, 1242m, 1150w, 1070w, 940w, 772m. 1H-NMR (400 MHz, (CD3)2SO): 9.90
(s, NH); 8.47 (s, HÀC(2)); 8.12 (−t×, J ˆ 2.0, HÀC(2')); 7.73 7.71 (m, 1 H); 7.42 (s, HÀC(5)); 7.39 (−t×, J ˆ 8.1,
1 H); 7.15 (−t×, J ˆ 7.8, 1 H); 7.12 7.09 (m, 1 H); 7.05 (−t×, J ˆ 1.8, 1 H); 6.96 (d, J ˆ 8.1, 1 H); 6.93 6.60 (m, 1 H );
5.35 (s, NH2). 13C-NMR (101 MHz, (CD3)2SO): 166.8; 154.9; 153.8; 153.4; 150.2; 142.0; 133.9; 131.2; 130.7;
‡
130.2; 123.2; 120.4; 119.4; 115.8; 112.8; 110.2; 105.4; 98.8. EI-MS: 335 (100, M ), 167.5 (10), 150.5 (11), 92 (6).
Anal. calc. for C18H13ClN4O (366.78): C 64.20, H3.89, N 16.64, O 4.75; found: C 63.80, H4.07, N 16.38, O 5.18.
5-{[6-(4-Aminophenyl)furo[2,3-d]pyrimidin-4-yl]amino}-2-methoxyphenol (20o). According to GP 2, with
19o (1.8 g, 4.8 mmol), THF (50 ml), Et3N (5 ml; added to neutralize traces of AcOHstemming from
recrystallization of the starting material), and DMEU (2 ml). The residue on the Celite was washed with acetone
and H2O. Workup: The combined filtrates were evaporated, and the crude product was precipitated with H2O.
The precipitate was dried under high vacuum and partly purified by FC (SiO2, acetone; due to its poor solubility,
the crude product (1.33 g) was put onto the column as a solid and then dissolved in situ by adding DMSO
(100 ml)): 20o (0.9 g, 54%). Fluorescent, bright brown, amorphous solid. M.p. 261 2638. IR: 3406w, 3329w,
3275w, 3186w, 3118w, 2835w, 1618s, 1594s, 1506s, 1474s, 1354m, 1288m, 1264m, 1214m, 1170m, 1137w, 1071w,
1030w, 923w, 849w, 778m. 1H-NMR (300 MHz, (CD3)2SO): 9.4, 9.1 (2s, NH, OH); 8.28 (s, HÀC(2')); 7.47 (d, J ˆ
8.7, HÀC(2'')); 7.31 (d, J ˆ 2.5, HÀC(6)); 7.13 (dd, J ˆ 8.7, 2.5, HÀC(4)); 7.05 (br. s, HÀC(5')); 6.91 (d, J ˆ 8.8,
‡
HÀC(3)); 6.67 (d, J ˆ 8.6, HÀC(3'')); 5.59 (s, NH2); 3.76 (s, Me). EI-MS: 348 (100, M ), 333 (50), 305 (12), 174
‡
(5), 155 (9). HR-MS: 348.1235 (C19H16N4O3 ; calc. 348.1222).
6-(3-Aminophenyl)-N-[(1R)-1-phenylethyl]furo[2,3-d]pyrimidin-4-amine (20p). According to GP 2, with
19p (1.47 g, 4.1 mmol) and THF (50 ml). Workup: The filtrate was evaporated, the residue taken up in tBuOMe
(note: better to use CH2Cl2 instead) and extracted with H2O, the org. phase dried (MgSO4) and evaporated, and
the residue dried under high vacuum. The crude product (1.33 g; bright yellow foam) thus obtained was taken up
in CH2Cl2 and extracted with 18% HCl soln. The aq. phase was neutralized with sat. NaHCO3 soln. and washed
with CH2Cl2. The combined org. phase was dried (MgSO4) and evaporated: 20p (1.14 g, 84%). Bright yellow
foam. M.p. > 648. IR: 3340m (br.), 3028w, 2972w, 1600s, 1570m, 1491m, 1466m, 1352m, 1303m, 1228w, 1141m,
941w, 776m, 700m, 551w. 1H-NMR (500 MHz, (CD3)2SO): 8.30 (d, J ˆ 8.0, NH); 8.20 (s, HÀC(2)); 7.44 (d, J ˆ
7.5, HÀC(2''), HÀ(6'')); 7.38 (s, HÀC(5)); 7.35 7.31 (m, HÀC(3''), HÀC(5'')); 7.23 (tt, J ˆ 7.3, 1.2, HÀC(4''));
7.15 (−t×, J ˆ 7.8, HÀC(5')); 6.94 (ddd, J ˆ 7.6, 1.6, 1.0, HÀC(6') or HÀC(4')); 6.61 (ddd, J ˆ 8.0, 2.2, 0.9, HÀC(4')
or HÀC(6')); 5.49 5.46 (−quint.×, J ˆ 7.0, MeCHN); 5.36 (s, NH2); 1.56 (d, J ˆ 7.0, MeCHN). 13C-NMR
(126 MHz, (CD3)2SO; assignments from HETCOR and APT): 165.6; 156.1; 153.4 (C(2)); 151.2; 149.3; 144.8;
129.68; 129.67 (C(5')); 128.3 (C(3'')); 126.7 (C(4'')); 126.0 (C(2'')); 114.4, 111.7 (C(4'), C(6')); 109.1 (C(2'));
‡
102.6; 98.2 (C(5)); 49.2 (CH); 26.8 (Me). EI-MS: 330 (100, M ), 315 (44), 226 (69), 199 (13), 155 (10), 120 (39),
‡
105 (61), 77 (13). HR-MS: 330.1479 (C20H18N4O ; calc. 330.1481).
5-{[6-(3-Aminophenyl)furo[2,3-d]pyrimidin-4-yl]amino}-2-methylphenol (20q). According to GP 2, with
19q (606 mg, 1.67 mmol), THF (90 ml), and DMEU (10 ml). Workup: After most of the solvent was removed,
the filtrate was brought to precipitation by adding H2O. The off-white precipitate was washed with H2O and
dried under high vacuum: 20q (431 mg, 78%). Microscopically small crystals. M.p. 233 2348. IR: 3361m, 3187m,
3027m, 1591vs, 1550vs, 1458s, 1437s, 1408s, 1320m, 1285m, 1244w, 1176m, 1119w, 1101w, 944w, 772m. 1H-NMR
(400 MHz, (CD3)2SO): 9.57, 9.33 (2s, OH, NH); 8.36 (s, HÀC(2')); 7.37 (s, 1 H); 7.36 (d, J ˆ 2.0, HÀC(6)); 7.14
(−t×, J ˆ 7.8, HÀC(5'')); 7.10 (dd, J ˆ 8.1, 2.0, HÀC(4)); 7.02 7.00 (m, 2 H); 6.94 6.92 (m, 1 H); 6.60 (ddd, J ˆ
‡
8.1, 2.3, 0.8, 1 H); 5.34 (s, NH2); 2.09 (s, Me). EI-MS: 332 (100, M ), 276 (5), 199 (9), 165.5 (6), 158.5 (12), 155
(5), 77 (5). HR-MS: 332.1268 (calc. 332.1273).

Helvetica Chimica Acta Vol. 87 (2004)
973
2-{[6-(3-Aminophenyl)furo[2,3-d]pyrimidin-4-yl]amino}-4-chlorophenol (20r). According to GP 2, with
19r (1.81 g, 4.7 mmol), THF (150 ml), DMEU (20 ml), and iPr2NH(6 ml; added to neutralize potential traces of
acid stemming from previous recrystallization). Workup: The dark green filtrate was concentrated and brought
to precipitation by adding H2O. The bright brown, grayish residue was dried under high vacuum: 20r (1.23 g,
74%). Recrystallization from EtOHgave brown-violet prisms in low yield. M.p. ca. 2408. IR: 3399m, 2968w,
2698w, 1612vs, 1580vs, 1522s, 1490m, 1461m, 1426s, 1359m, 1302w, 1265m, 1242w, 1194w, 1073w, 760m. 1H-NMR
(500 MHz, (CD3)2SO; assigned by COSY, HETCOR, and long-range HETCOR): 10.20, 9.17(2s, OH, NH); 8.37
(s, HÀC(2')); 7.86 (d, J ˆ 2.5, HÀC(3)); 7.39 (s, HÀC(5')); 7.15 (−t×, J ˆ 7.8, HÀC(5'')); 7.08 (dd, J ˆ 8.6, 2.6,
HÀC(5)); 7.04 (−t×, J ˆ 1.9, HÀC(2'')); 6.96 (m, HÀC(6), HÀC(6'')); 6.61 (dd, J ˆ 8.0, 2.0, HÀC(4'')); 5.37
(s, NH2). 13C-NMR (126 MHz, (CD3)2SO; assigned by COSY, HETCOR, and long-range HETCOR): 166.0
(C(7'a)); 154.9 (C(4'a)); 153.0 (C(2')); 152.1 (C(6')); 149.3 (C(3'') or C(1'')); 149.0 (C(1)); 129.7 (C(5'')); 129.4
(C(1'') or C(3'')); 127.5 (C(2)); 124.8 (C(5)); 124.4 (C(3)); 122.0 (C(4)); 116.9 (C(6)); 114.7 (C(4'')); 111.9
‡
(C(6'')); 109.2 (C(2'')); 103.9 (C(4')); 98.2 (C(5')). EI-MS: 352 (100, M ), 335 (37), 325 (100), 318 (32), 291
(32), 280 (11), 205 (17), 171 (10), 167.5 (13), 155 (15), 120 (10), 92 (14), 65 (10). HR-MS: 352.0733
‡
(C18H13ClN4O2 ; calc. 352.0727).
N-(3-Aminophenyl)-6-(4-aminophenyl)furo[2,3-d]pyrimidin-4-amine (20s). According to GP 2, with 19s
(2.4 g, 6.4 mmol), THF (120 ml), and DMEU (40 ml) for 5 d (every 24 h, further Raney-Ni was added).
Workup: The filtrate was concentrated and brought to precipitation by adding H2O. The residue was dried under
high vacuum (1.2 g) and suspended in conc. HCl soln. (immediate, intense violet color followed by slow
discoloring). To the suspension, H2O (150 200 ml) was added (pH1) and then EtOH(150 ml). This mixture
was refluxed for several hours and filtered hot with suction. The filtrate was basified with sat. Na2CO3 soln. After
removal of the EtOH, the suspension (r.t.) was filtered with suction. The beige, amorphous residue was dried
under high vacuum: 20s (0.72 g, 35%). M.p. 225 2308. IR: 3377m, 3217w, 3034w, 1622s, 1581s, 1523m, 1505s,
1460s, 1401w, 1358m, 1318w, 1287m, 1192w, 1164w, 1073w, 1029w, 922w, 875w, 836w, 770m, 684m. 1H-NMR
(300 MHz, (CD3)2SO): 9.39 (s, NH); 8.31 (s, HÀC(2)); 7.48 (d, J ˆ 8.7, HÀC(2'')); 7.12 (s, HÀC(5)); 7.07 7.06
(m, HÀC(2')); 6.99 (t, J ˆ 7.8, HÀC(5')); 6.94 6.91 (m, 1 H); 6.67 (d, J ˆ 8.7, HÀC(3'')); 6.33 6.29 (m, 1 H );
5.60, 5.10 (s, NH2). 13C-NMR (75 MHz, (CD3)2SO): 166.5; 155.0; 153.5; 152.8; 150.8; 149.9; 141.0; 129.7; 126.6;
‡
117.2; 114.8; 110.1; 109.7; 107.3; 105.1; 95.3. EI-MS: 317 (100, M ), 261 (11), 199 (4), 158 (4), 131 (5), 120 (4), 92
‡
(7), 65 (5). HR-MS: 317.1270 (C18H15N5O ; calc. 317.1277).
5-{6-(4-Aminophenyl)furo[2,3-d]pyrimidin-4-yl]amino}-2-methylphenol (20t). According to GP 2, with 19t
(2.46 g, 6.8 mmol) and THF (180 ml). Workup: To the filtrate, H2O was added and the forming precipitate was
collected. The residue was dried under high vacuum: 20t (2.11 g, 94%). Off-white, amorphous solid. M.p.:
transformation to needles and prisms at ca. 2658 that decomposed from ca. 2808 and melted at ca. 2908 (dec.).
IR: 3457w, 3389s, 3376s, 3232m, 1616vs, 1592vs, 1522s, 1505s, 1470s, 1419s, 1359s, 1299m, 1267m, 1173s, 1123m,
1072w, 1026w, 997w, 922m, 830w, 776m. 1H-NMR (300 MHz, (CD3)2SO): 9.48, 9.35 (2s, NH, OH); 8.33
(s, HÀC(2')); 7.51 (d, J ˆ 8.5, HÀC(2'')); 7.40 (d, J ˆ 1.7, HÀC(6)); 7.15 7.11 (m, HÀC(3), HÀC(5')); 7.03
‡
(d, J ˆ 8.2, HÀC(4)); 6.70 (d, J ˆ 8.5, HÀC(3'')); 5.62 (s, NH2); 2.12 (s, Me). EI-MS: 332 (100, M ), 276 (7), 262
(7), 199 (9), 158.5 (10), 155 (6), 42 (7). Anal. calc. for C19H16N4O2 (332.36): C 68.66, H4.85, N 16.86, O 9.63;
found: C 68.53, H5.09, N 16.55, O 9.90.
6-(3-Aminophenyl)-N-(3,5-dichlorophenyl)furo[2,3-d]pyrimidin-4-amine (20u). According to GP 2, with
19u (0.49 g, 1.2 mmol), THF (170 ml), and DMEU (12 ml). Workup: After evaporation of the filtrate, the
residue (446 mg) was heated in EtOHand filtered hot with suction (residue discarded). Upon cooling, this
filtrate was again filtered several times (residues discarded) and then evaporated. FC (SiO2, pentane/AcOEt
4 :1 ! 2 :3) of the residue (440 mg) yielded 322 mg that were dissolved in 1,2-dichloroethane/MeOH/H2O
(heating) and filtered cold (residue discarded). H2O (300 ml) was added to the filtrate, which was then stored
openly for a few days. Filtration with suction and washing of the resulting residue with EtOHgave 20u (48 mg,
11%) as a bright beige, amorphous solid (m.p. 120 1258). The H2O/EtOHfiltrate was filtered the next day,
yielding another 118 mg (26%) of 20u of acceptable purity (beige, pale gray, amorphous solid; m.p. 135 1378).
IR: 3386w, 3303w, 3201w, 3117w, 1629s, 1609s, 1579vs, 1460s, 1409m, 1354m, 1152w, 1115w, 1082m, 941w, 928w,
863w, 838w, 777m. 1H-NMR (400 MHz, (CD3)2SO): 10.03 (s, NH); 8.53 (s, HÀC(2)); 8.00 (d, J ˆ 2.0, HÀC(2''),
HÀC(6'')); 7.40 (s, HÀC(5)); 7.25 (t, J ˆ 1.9, HÀC(4'')); 7.16 (−t×, J ˆ 7.8, HÀC(5')); 7.06 (−t×, J ˆ 1.9, HÀC(2''));
‡
6.99 6.96 (m, 1 H); 6.26 (ddd, J ˆ 8.0, 2.3, 0.9, 1 H); 5.38 (s, NH2). EI-MS: 370 (100, M ), 184.5 (11), 92 (10).
‡
HR-MS: 370.0392 (C18H12Cl2N4O ; calc. 370.0388).
6-(3-Aminophenyl)-N-(3-nitrophenyl)furo[2,3-d]pyrimidin-4-amine (20v). According to GP 2, with 19v
(1.2 g, 3.2 mmol), THF (170 ml), and DMEU (20 ml). Workup: The filtrate was concentrated and brought to
precipitation by adding a considerable amount of H2O. The precipitate was dried under high vacuum (852 mg)

974
Helvetica Chimica Acta Vol. 87 (2004)
and submitted to FC (SiO2, AcOEt/tBuOMe 1:1): 20v (57 mg, 5%). Orange powder. M.p. > 2508. IR: 3462w,
3388m, 3329m, 3221m, 3114w, 2923m, 2853w, 1618s, 1586vs, 1522vs, 1487s, 1461s, 1396m, 1353s, 1248m, 1079m,
782m, 733m. 1H-NMR (400 MHz, (CD3)2SO): 10.21 (s, NH); 8.89 (−t×, J ˆ 2.3, 1 H); 8.52 (s, HÀC(2)); 8.29
(ddd, J ˆ 8.2, 2.1, 0.9, 1 H); 7.90 (ddd, J ˆ 8.2, 2.3, 0.9, 1 H); 7.67 (−t×, J ˆ 8.2, 1 H); 7.45 (s, HÀC(5)); 7.16 (−t×, J ˆ
7.8, 1 H); 7.06 (−t×, J ˆ 1.9, 1 H); 6.98 (ddd, J ˆ 7.6, 1.8, 1.0, 1 H); 6.62 (ddd, J ˆ 8.1, 2.3, 1.0, 1 H); 5.37 (s, NH2).
‡
‡
EI-MS: 347 (100, M ), 331 (12), 317 (20), 299 (15), 155 (14). HR-MS: 347.1023 (C18H13N5O3 ; calc. 347.1018).
Biological Tests. The baculovirus donor vector pfbgx3IGFlRcd was used to generate a recombinant
baculovirus that expresses the amino acid region amino acids 670 1210 of the intra-cytoplasmic kinase domains
of human HER-1 (EGFR). The HER-1 cDNA fragment was kindly provided by Dr. N. Hynes, FMI, Basel,
Switzerland. The amplified DNA fragments were fused to GST by cloning them into FBG1 as BamHI-EcoRI
insertions to yield FBG1-HER-1.
Cell extracts were prepared and loaded onto a glutathione-sepharose (Pharmacia) column. After washing,
the GST-tagged proteins were then eluted with a glutathione-containing buffer. Purified protein was stored at
À 708 in elution buffer.
¬
KDR Kinase domains were provided by the lab of Dr. D. Marme (Tumorbiologiezentrum, Freiburg,
Germany). The glutathione S-transferase (GST) gene from the pAcG1 vector (Pharmingen) was excised with
EcoRV and EcoRI and inserted into the cloning site of the Fast-Bac baculoviral vector (GIBCO) creating a
5530 bp vector with N-terminal cloning sites derived from the pAcG1 fusion vector (FBG0). The C-terminal
cloning site may be any cloning site (from the Fast-Bac vector) downstream of the N-terminal cloning site used.
Viruses for each of the kinases were made according to the protocol supplied by GIBCO. In brief, transfer
vectors containing the kinase domains were transfected into the DH10Bac cell line (GIBCO), plated on agar
plates containing the recommended concentrations of Blue-Gal, IPTG, kanamycin, tetracycline, and
gentamycin. Colonies without insertion of the fusion sequence into the viral genome (carried by the bacteria)
are blue. A single white colony was usually picked and viral DNA (bacmid) isolated from the bacteria by
standard plasmid mini prep procedures. Sf 9 cells or High Five cells (GIBCO) were then transfected in 25-cm2
flasks with the viral DNA using the cellfectin reagent and protocol supplied with the Bac-to-Bac kit (GIBCO).
Virus-containing media was collected from the transfected cell culture and used for infection to increase its titer.
Virus-containing media obtained after two rounds of infection was used for large-scale protein expression. For
large-scale protein expression, 100-cm2 round tissue culture plates were seeded with 5 Â 107 cells/plate and
infected with 1 ml of virus-containing media (about 5 MOIs). After 3 days, the cells were scraped off the plates
and centrifuged at 500 r.p.m. for 5 min.
Cell pellets from 10 20 100-cm2 plates were resuspended in 50 ml of ice-cold lysis buffer (25 mm Tris ¥ H Cl
(pH7.5), 2 m m EDTA, 1% NP-40, 1 mm DTT, 1 mm PMSF). The cells were stirred on ice for 15 min and then
centrifuged at 5000 r.p.m. for 20 min. The supernatant was loaded onto a 2-ml glutathione-sepharose column
and washed three times with 10 ml of 25 mm Tris ¥ HCl (pH 7.5), 2 mm EDTA, 1 mm DTT, and 200 mm NaCl.
The GST-tagged proteins were then eluted by 10 applications (1 ml each) of 25 mm Tris ¥ H Cl (pH 7.5), 10 mm
reduced glutathione, 100 mm NaCl, 1 mm DTT, and 10% glycerol and stored at À 708.
The assays of KDR contained in a final volume of 30 ml 200 1800 ng of enzyme protein (depending on the
specific activity), 20 mm Tris ¥ HCl (pH 7.6), 3 mm MnCl2, 3 mm MgCl2, 1 mm DTT, 10 mm Na3VO4, 3mg/ml of
poly(Glu,Tyr) 4 :1, and 8 mm ATP (g-[33P]-ATP 0.1 mCi). Assays with purified GST-HER-1 were carried out in a
final volume of 30 ml containing 20 mm Tris ¥ H Cl (pH 7.6), 10 mm MgCl2, 0.01 mm Na3VO4, 1% DMSO, 1 mm
DTT, 3 mg/ml of poly(Glu,Tyr) 4 :1, and 10 mm ATP (g-[33P]-ATP 0.1 mCi). The assay was performed in 96-well
plates for 20 min at r.t. and then stopped by addition of 25 ml of 0.25m EDTA (pH7.0). An aliquot of 40 ml was
spotted with a multichannel dispenser on Immobilon-P membranes mounted in a Millipore Microtiter filter
manifold connected to a low-vacuum source. After elimination of liquid, the membrane was transferred to a
sequence of four washing baths containing 0.5% H3PO4 soln. and one with EtOH(shaking incubation for 10 min
¾
each), dried, and mounted onto a Hewlett-Packard TopCount manifold, 10 ml of Microscint was added, and the
sample was counted with a TopCount NXT counter (Perkin-Elmer). IC50 values were calculated by linear
regression analysis of the percentage inhibition of each compound in duplicate, at four concentrations (usually,
0.01, 0.1, 1, and 10 mm).
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Received October 23, 2003