Evaluation of electrophilic heteroaromatic substitution: Synthesis of heteroaromatic-fused pyrimidine derivatives via sequential three-component heterocyclization

Article abstract of DOI:10.1021/jo301463m

A new sequential three-component heterocyclization was developed by reacting aromatic and heterocyclic substrates, including aminobenzenes, 1-aminonaphthalene, 2-aminopyrazines, 5-aminopyrazoles, 3-aminopyridine, 5-aminopyrimidine, 5-aminoquinoline, and 8

Full text of DOI:10.1021/jo301463m

Article
pubs.acs.org/joc
Evaluation of Electrophilic Heteroaromatic Substitution: Synthesis of
Heteroaromatic-Fused Pyrimidine Derivatives via Sequential Three-
Component Heterocyclization
Fung Fuh Wong,* Yu-Ying Huang, and Chun-Hsi Chang
Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan 40402,
Republic of China
S
* Supporting Information
ABSTRACT: A new sequential three-component heterocyclization was developed by
reacting aromatic and heterocyclic substrates, including aminobenzenes, 1-amino-
naphthalene, 2-aminopyrazines, 5-aminopyrazoles, 3-aminopyridine, 5-aminopyrimidine,
5-aminoquinoline, and 8-aminoquinoline, with formamide in the presence of PBr3. The
reaction gave the corresponding pyrazolo[3,4-d]pyrimidines in good yields (59−96%),
except for aminobenzenes and 3-aminopyridine. A plausible reaction mechanism
involving amidination, electrophilic substitution imination, and oxidative cyclization in
three steps was proposed to account for the heterocyclization. The reactivity of the
reaction was found proportional to the electrophilicity of the aromatic or heterocyclic substrate.
INTRODUCTION
RESULTS AND DISCUSSION
Development of the Sequential Three-Component
Synthesis of Pyrazolo[3,4-d]pyrimidine Derivatives 17−
32 and Mechanism Study. Scheme 1 shows the typical
■
■
Electrophilic aromatic substitution reactions are widely applied
to the synthesis of various aromatic and heterocyclic
compounds with potential pharmacological applications.1,2
Most of the evaluations of aromatic or heterocyclic reactivity
can be said to have begun with the results of electrophilic
substitution processes.2 Therefore, the reaction of heterocycles
with electrophilic reagents is still extremely useful to construct
the fused heterocyclic ring, particularly fused pyrimidine
derivatives.3−5
Scheme 1
Fused pyrimidine derivatives are an important class of
compounds with remarkable pharmaceutical applications, for
example, antibacterial,6 antifungal,7,8 antioxidant,9 antitumor,10
herbicidal,11 and antivirus,12 and are effective inhibitors of
inflammatory mediators in intact cells.13 As a result, many
synthetic methods were enthusiastically developed to prepare
heteroaromatic-fused pyrimidine derivatives.14,15 However,
most of the methods are not straightforward and purification
is troublesome.
Recently, one-pot multicomponent processes have attracted
considerable academic, economic, and ecological interest, for
they address very fundamental principles of synthetic efficiency
and reaction-designed approach.16 Herein, we have developed
an efficient one-pot, three-component synthesis of hetero-
aromatic-fused pyrimidines by treating aminoaromatic or
aminoheterocyclic substrates with formamide using PBr3 as
the coupling agent. The activity of electrophilic aromatic and
heterocyclic substitution imination was also studied to
determine the difference in electrophilicity between aromatic
and heterocyclic substrates.
reaction condition of the new sequential three-component
heterocyclization for the synthesis of pyrazolo[3,4-d]-
pyrimidines 17−32. 5-Amino-1,3-disubstituted pyrazoles 1−
16, prepared by our previously developed method,17 were used
as the starting materials. To evaluate the reaction conditions, 5-
amino-1,3-diphenylpyrazole (1) was used as the model case.
Various coupling agents in different amounts were used to
search for the best reaction conditions. These agents include
benzoyl chloride (PhCOCl), oxalyl chloride (ClCOCOCl),
phosphorus tribromide (PBr3), phosphorus oxychloride
(POCl3), thionyl chloride (SOCl2), and p-toluenesulfonic
chloride (TsCl). Without the coupling agent, only the starting
material 1 was recovered after the reaction proceeded for 48 h
at 60 °C (see entry 1 in Table 1). When the compound 1 was
allowed to react with different amounts of coupling agents, such
as PBr3 and POCl3, the reaction gave the corresponding
Received: July 12, 2012
Published: September 5, 2012
© 2012 American Chemical Society
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Table 1. Study of Coupling Agents in the Sequential Three-
Component Reaction
Table 2. Results of the One-Pot Synthesis of Pyrazolo[3,4-
d]pyrimidines from 5-Aminopyrazoles, Formamide, and
PBr3
coupling agent
amt
(equiv)
yield of pyrazolo[3,4-d]pyrimidine 17
a
entry
agent
(%)
1
no base
PBr3
b
76
97
95
73
96
97
49
68
23
2
1
3
5
1
3
5
3
3
3
3
3
PBr3
4
PBr3
5
POCl3
POCl3
POCl3
SOCl2
ClCOCOCl
PhCOCl
TsCl
6
7
8
9
10
11
28
a
b
Based on the weight of 5-amino-1,3-diphenylpyrazole 17. The
starting material 1 was recovered.
pyrazolo[3,4-d]pyrimidine product 17 in 73−97% yields (see
entries 2−7 in Table 1).
On treatment with 3.0 equiv of PhCOCl, ClCOCOCl,
SOCl2, and TsCl, the reaction gave the corresponding
pyrazolo[3,4-d]pyrimidine 17 in lower yields (49−68%; see
entries 8−11 of Table 1). The unreactive starting material 1
was recovered by using these coupling agents. Following the
experimental results, we found that the use of 3.0 equiv of the
coupling agent PBr3 provided the best yield of the desired
pyrazolo[3,4-d]pyrimidine 17 (>96%; see entries 3 and 6 of
Table 1). As a result, a reliable procedure for the new
heterocyclization involved the treatment of 5-aminopyrazole 1
with 3.0 equiv of PBr3 in formamide solution at 60 °C for 0.5−
1.0 h. After aqueous workup and purification by column
chromatography on silica gel, the corresponding pyrazolo[3,4-
d]pyrimidine 17 was isolated in excellent yield (97%; see
Scheme 1 and Table 1).
intermediate 34 (see Scheme 2). Under strongly acidic
conditions, amidination intermediate 34 simultaneously reacted
with the second equivalent of 33 to perform the electrophilic
heteroaromatic substitution and generate imination intermedi-
ate 35. Intramolecular heterocyclization of intermediate 35
consequently took place to generate 36, which then gave the
final product 17 by elimination of the amino group.
For further investigation of the reaction mechanism, we
prepared the series of pyrazolylimidoformamides 37−4119 to
react with reactive species 33 generated from the reaction of
HCHO and PBr3. The reaction proceeds by an amidination
reaction to give the intermediate 42, which is expected as the
chemical synthetic equivalent to 35 (see Scheme 3). We also
obtained the corresponding pyrazolo[3,4-d]pyrimidines 28−32
in 91−97% yields (see Scheme 3 and Table 3). A similar
heterocyclization has been reported by Jachak et al., and the
spectroscopic data of compound 39 were consistent with those
reported by Jachak.20 As a result, N′-[4-(iminomethyl)-1H-
pyrazol-5-yl]formamidine 35 could be presumed as a important
key intermediate in this newly developed heterocyclization
reaction.
On application of the obtained reliable procedure to 5-
aminopyrazoles 2−11 bearing various N-1-substituents, includ-
ing o-MePh, o-ClPh, m-MePh, m-ClPh, m-NO2Ph, p-ClPh, p-
OMePh, 2-pyridinyl, and 2-quinolinyl, the one-pot hetero-
cyclization also proceeded smoothly to give the corresponding
pyrazolo[3,4-d]pyrimidines 18−27 in 87−97% yields (see
Scheme 1 and Table 2). For further investigation of the
substitution effect, the same reaction conditions were applied to
5-amino-1-phenyl-3-substituted pyrazoles 12−16, which con-
tained a methyl, tert-butyl, p-MePh, p-ClPh, or p-OMePh group
at the C-3 position of the pyrazole ring. The reaction also gave
the corresponding compounds 28−32 in 91−94% yields (see
Scheme 1 and Table 2). All pyrazolo[3,4-d]pyrimidines 17−32
were fully characterized by spectroscopic methods. For
example, compound 17 presented two singlet peaks at δ 9.02
1
and 9.31 ppm for the pyrimidine ring in H NMR. In the 13C
NMR spectrum, compound 17 possessed characteristic
absorptions at δ 155.0 ppm for the pyrimidine carbon
13
N CHNC, at δ 34.4 ppm for −13C(CH3)3, and at δ
30.0 ppm for −C(13CH3)3.
We proposed a plausible mechanism for the sequential three-
component heterocyclization reaction as shown in Scheme 2.
Formamide first reacted with the coupling agent PBr3 or POCl3
to form the Vilsmeier reactive species 33 in situ.18 In the model
case, 5-amino-1,3-diphenylpyrazole (1) with the reactive
species 33 underwent an amidination reaction to give the
Investigation of the Electrophilic Aromatic and
Heterocyclic Substitution Reactivity. For a further
investigation of the electrophilic substitution reactivity in
aminobenzene substrates, we applied the same reaction
conditions to compounds 43−49 with various substituents,
including H, o-Me, o-OMe, p-OMe, o-F, m-F, and p-F.
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Scheme 2
Scheme 3
Table 3. Mechanistic Study of the Cyclization of 5-Amino-4-
formylpyrazoles 37−41 with Formamide and PBr3 for
Synthesis of Pyrazolo[3,4-d]pyrimidines 28−32
Scheme 4
Table 4. Results of the Reactions of Aromatic Amines with
Formamide and PBr3
However, the reaction did not give the desired quinazoline
products 60 (see Scheme 5); only N,N′-bisphenylformamidines
50−56 were obtained in 91−97% yields (see Scheme 4 and
Table 4). The spectroscopic data of 50−56 were also consistent
with the data reported in the literature.21 For example,
compound 50 presented a singlet peak at δ 8.24 ppm for
formamidine in 1H NMR. In the 13C NMR spectrum,
compound 50 possessed a characterization absorption at δ
13
149.5 ppm for the formamidine carbon PhN CHNHPh.
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Scheme 5
Scheme 6
Following the above experimental results, we also proposed a
plausible reaction mechanism as shown in Scheme 5 to account
for the different reactivities between aminobenzenes and 5-
aminopyrazoles. At first, the reaction of formamide with PBr3
generates the reactive species bromomethyleniminium salts 33
in situ (see Scheme 5).18 In the model study, aniline 43 was
preliminarily reacted with the reactive iminium species 33 to
afford the amidination intermediate 57 (see Scheme 5). The
addition reaction of amidine intermediate 57 with the second
equivalent of aniline 43 then took place to provide the N,N′-
diphenylformamidine product 58. After workup, the reaction
gave the formamidine product 50. However, the conversion of
N,N′-diphenylformamidine 50 is straightforward without
carrying out the electrophilic aromatic substitution reaction
(57 → 59 → 60).
heterocyclization pyridoquinazoline products 66 and 67 were
obtained in 89% and 91% yields, respectively (see Scheme 6).
When 1-aminonaphthalene 61 was used as the substrate under
the same conditions, the reaction gave the cyclized
benzoquinazoline 64 in 59% yield with the unexpected
formamidine product 65 in 28% yield (see Scheme 6).
Following the above experimental results, quinolinamines 62
and 63 were more electrophilic than naphthalen-1-amine 61.
Furthermore, the bicyclic aromatic amines 61−63 were also
found to be more active than aminobenzene in performing the
new sequential heterocyclization reaction.
After screening various monocyclic heteroaromatic amines,
we selected 3-aminopyridine 68, 5-aminopyrimidine 69, and 2-
aminopyrazines 70−72 as the substrates to study the reaction
(see Scheme 7). For the 3-aminopyridine substrate 68, only the
The difference results between 5-aminopyrazoles 1−16 and
aminobenzenes 42−48 might come from the pyrazole’s π-
excessive properties which thus make the pyrazole derivatives
more reactive than benzene rings toward the electrophilic
aromatic substitution reaction.22 As a result, the expected
pyrazolo[3,4-d]pyrimidine products were produced. However,
benzene is more stable; further electrophilic substitution and
oxidative cyclization did not take place to give the expected
product quinazoline 60 (see Scheme 5).
Scheme 7
Consequently, we applied the reaction conditions to bicyclic
aromatic amines such as 1-aminonaphthalene (61), 5-amino-
quinoline (62), and 8-aminoquinoline (63) (see Scheme 6).
For 62 and 63 as the reactants, only the corresponding
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gradient elution using hexanes in ethyl acetate (EA) unless otherwise
stated.
N,N′-dipyridinylformamidine product 73 was detected, without
the formation of the corresponding cyclization product.
Although the electron density of 3-aminopyridine was proved
to be superior to that of the benzene ring,22,23 the
heterocyclization did not smoothly take place to give the
expected fused pyrimidine product. Treatment of 5-amino-
pyrimidine 69 and 2-aminopyrazines 71 and 72 with the
Vilsmeier reagent 33 successfully afforded the fused pyrimidine
products 74−77 in good yields (82−89%; see Table 5). Finally,
Standard Procedure for Synthesis of Pyrazolo[3,4-d]-
pyrimidines (17−32, 65, 66, and 73−76). The reliable procedure
involved the treatment of 5-aminopyrazoles (1−16; 1.0 equiv), 5-
amino-4-formylpyrazoles (37−41; 1.0 equiv), 5-aminoquinoline (61;
1.0 equiv), 8-aminoquinoline (62; 1.0 equiv), 5-aminopyrimidine (68;
1.0 equiv), or 2-aminopyrazines (69−71; 1.0 equiv) with PBr3 (∼3
equiv) in formamide solution (2 mL) at 50−60 °C over 0.5−1 h.
When the reaction was complete, the reaction mixture was added to
saturated sodium bicarbonate (15 mL) and extracted with dichloro-
methane (15 mL). The organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
solution was purified by column chromatography on silica gel to
give the corresponding aromatic or heterocyclic fused pyrimidine
products (17−32, 65, 66, and 73−76) in 82−96% yields.
Table 5. Results of the Reactions of Heterocyclic Amines
with Formamide and PBr3
1,3-Diphenyl-1H-pyrazolo[3,4-d]pyrimidine (17).24 The standard
procedure involved the treatment of 5-amino-1,3-diphenyl-1H-
pyrazole (1; 100 mg, 0.37 mmol, 1.0 equiv) with PBr3 (0.10 mL,
1.1 mmol, 3.0 equiv) in formamide solution (2 mL) at 50−60 °C over
0.5−1.0 h. The reaction mixture was then worked up, and the residue
was purified by chromatography on silica gel to give pure 17: 96%
yield (96 mg), light yellow solid; mp 157−158 °C (hexane−EtOAc).
1H NMR (CDCl3, 500 MHz): δ 7.29−7.36 (1H, m), 7.41−7.48 (1 h,
m), 7.48−7.56 4H, m), 7.97−8.07 (2H, m), 8.25−8.35 (2H, m), 9.09
(1H, s), 9.45 (1H, s). 13C NMR (125 MHz, CDCl3): δ 114.1, 121.2 (2
× C), 126.7, 127.2 (2 × C), 129.0 (2 × C), 129.1 (2 × C), 129.5,
131.4, 138.5, 144.8, 152.7, 153.2, 155.5. IR (KBr): 2364, 2331, 1589,
1498, 1417, 1369, 1219, 1093 cm−1. EIMS m/z (rel int): 272 (100,
M+). Anal. Calcd for C17H12N4: C, 74.98; H, 4.44; N, 20.58. Found: C,
74.96; H, 4.45; N, 20.61.
we found tha tthe phenyl and pyridinyl substrates cannot
undergo the new sequential heterocyclization reaction because
they possess poor electrophilicity and stable resonance ability.
1-(2-Methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (18).
The standard procedure involved the treatment of 5-amino-1-(2-
methylphenyl)-3-phenyl-1H-pyrazole (2; 101 mg, 0.35 mmol, 1.0
equiv) with PBr3 (0.10 mL, 1.1 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 18: 93% yield (93 mg), light yellow solid; mp
CONCLUSIONS
■
We have successfully developed a one-pot multicomponent
reaction to prepare pyrazolo[3,4-d]pyrimidines or heterocyclic
fused pyrimidines by treating 5-aminopyrazoles, 5-amino-
pyrimidine, 2-aminopyrazines, 5-aminoquinoline, and 8-amino-
quinoline with formamide in the presence of PBr3 as a coupling
agent. On the basis of the mechanistic study, N′-[4-
(iminomethyl)-1H-pyrazol-5-yl]formamidine (59) was demon-
strated to be a key intermediate in this one-pot heterocycliza-
tion reaction. When further applying the same reaction
conditions to phenyl- and pyridinylamines, we only obtained
the unexpected N,N′-diphenylformamidine products. This was
attributed to the fact that benzene and pyridine are more stable
and less reactive resonance rings. On the basis of experimental
results, the order of electrophilicity was 5-aminopyrazole ≥ 5-
aminopyrimidine and 2-aminopyrazines ≥ 5-aminoquinoline
and 8-aminoquinoline > 1-aminonaphthalene > 3-amino-
pyridine > aminobenzenes.
1
142−143 °C (hexane−EtOAc). H NMR (CDCl3, 500 MHz): δ 2.21
(3H, s), 7.33−7.43 (3H, m), 7.44−7.50 (2H, m), 7.51−7.57 (2H, m),
8.02−8.08 (2H, m), 9.05 (1H, s), 9.53 (1H, s). 13C NMR (125 MHz,
CDCl3): δ 18.2, 112.8, 126.7, 127.2 (2 × C), 127.6, 129.2 (2 × C),
129.5 (2 × C), 131.4, 131.7, 135.5, 136, 144.9, 152.8, 154.1, 155.8. IR
(KBr): 3053, 2922, 2360, 2339, 1579, 1556, 1498, 1222, 1085 cm−1.
EIMS m/z (rel int): 286 (100, M+). Anal. Calcd for C18H14N4: C,
75.50; H, 4.93; N, 19.57. Found: C, 75.53; H, 4.92; N, 19.58.
1-(2-Chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (19).
The standard procedure involved the treatment of 5-amino-1-(2-
chlorophenyl)-3-phenyl-1H-pyrazole (3; 99 mg, 0.32 mmol, 1.0 equiv)
with PBr3 (0.09 mL, 0.97 mmol, 3.0 equiv) in formamide solution (2
mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture was then
worked up, and the residue was purified by chromatography on silica
gel to give pure 19: 91% yield (89 mg), yellow solid; mp 142−143 °C
1
(hexane−EtOAc). H NMR (CDCl3, 500 MHz): δ 7.43−7.49 (3H,
m), 7.50−7.56 (2H, m), 7.57−7.65 (2H, m), 8.02−8.08 (2H, m), 9.07
(1H, s), 9.52 (1H, s). 13C NMR (125 MHz, CDCl3): δ 122.9, 127.3 (2
× C), 127.6, 129.2 (2 × C), 129.6 (2 × C), 130.7 (2 × C), 131.4,
132.1, 134.7, 145.6, 152.8, 154.5, 155.9. IR (KBr): 3061, 2924, 2370,
2349, 1581, 1557, 1516, 1497, 1304, 1223, 1088 cm−1. EIMS m/z (rel
int): 306 (89, M+). Anal. Calcd for C17H11ClN4: C, 66.56; H, 3.61; N,
18.26. Found: C, 66.59; H, 3.58; N, 18.22.
EXPERIMENTAL SECTION
■
General Procedure. All chemicals were reagent grade and were
used as purchased. All reactions were carried out under a nitrogen
atmosphere and monitored by TLC analysis. Commercially available
reagents were used without further purification unless otherwise noted.
1H NMR spectra were recorded at 200, 400, or 500 MHz, and 13C
NMR spectra were recorded at 50, 100, or 125 MHz, respectively, in
CDCl3, CH3OD, and DMSO-d6 as solvent. The standard abbreviations
s, d, t, q, and m refer to singlet, doublet, triplet, quartet, and multiplet,
respectively. Coupling constants (J), whenever discernible, have been
reported in Hz. Infrared spectra (IR) were recorded as neat solutions
or solids, and mass spectra were recorded using electron impact or
electrospray ionization techniques. The wavenumbers reported are
referenced to the polystyrene 1601 cm−1 absorption. Flash column
chromatography purification of compounds was carried out by
1-(3-Methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (20).
The standard procedure involved the treatment of 5-amino-1-(3-
methylphenyl)-3-phenyl-1H-pyrazole (4; 103 mg, 0.36 mmol, 1.0
equiv) with PBr3 (0.10 mL, 1.1 mmol, 3 equiv) in formamide solution
(2 mL) at 50−60 °C over 0.5−1 h. The reaction mixture was then
worked up, and the residue was purified by chromatography on silica
gel to give pure 20: 92% yield (94 mg), light yellow solid; mp 75−76
1
°C (hexane−EtOAc). H NMR (CDCl3, 500 MHz): δ 2.47 (3H, s),
7.12−7.18 (1H, m), 7.38−7.42 (1H, m), 7.43−7.49 (1H, m), 7.50−
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7.56 (2H, m), 8.00−8.06 (2H, m), 8.07−8.11 (2H, m), 9.10 (1H, s),
9.46 (1H, s). 13C NMR (125 MHz, CDCl3): δ 21.6, 114.1, 118.6,
122.0, 127.3 (2 × C), 127.6 (2 × C), 129.0, 129. (2 × C), 129.5, 131.5,
138.3, 139.2, 144.7, 152.7, 153.2, 155.5. IR (KBr): 3053, 2920, 1611,
1582, 1557, 1495, 1386, 1229, 1094 cm−1. EIMS m/z (rel int): 286
(100, M+). Anal. Calcd for C18H14N4: C, 75.50; H, 4.93; N, 19.57.
Found: C, 75.54; H, 4.96; N, 19.53.
1-(3-Chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (21).
The standard procedure involved the treatment of 5-amino-1-(3-
chlorophenyl)-3-phenyl-1H-pyrazole (5; 101 mg, 0.33 mmol, 1.0
equiv) with PBr3 (0.09 mL, 0.99 mmol, 3 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1 h. The reaction mixture was
then worked up, and the residue was purified by chromatography on
silica gel to give pure 21: 96% yield (97 mg), yellow solid; mp 188−
189 °C (hexane−EtOAc). 1H NMR (CDCl3, 500 MHz): δ 7.27−7.33
(1H, m), 7.43−7.48 (1H, m), 7.48−7.52 (1H, m), 7.53−7.59 (2H, m),
8.01−8.07 (2H, m), 8.32−8.36 (1H, m), 8.42−8.44 (1H, m), 9.14
(1H, s), 9.50 (1H, s). 13C NMR (125 MHz, CDCl3): δ 114.5, 118.9,
121.1, 126.6, 127.4 (2 × C), 129.3 (2 × C), 129.9, 130.2, 131.2, 135.0,
139.6, 145.4, 152.9, 153.6, 155.8. IR (KBr): 3099, 3062, 2922, 2851,
1585, 1491, 1406, 1215 cm−1. EIMS m/z (rel int): 306 (100, M+).
Anal. Calcd for C17H11ClN4: C, 66.56; H, 3.61; N, 18.26. Found: C,
66.58; H, 3.62; N, 18.29.
1-(4-Methoxylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(25). The standard procedure involved the treatment of 5-amino-1-(4-
methoxylphenyl)-3-phenyl-1H-pyrazole (9; 104 mg, 0.34 mmol, 1.0
equiv) with PBr3 (0.10 mL, 1.0 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 25: 89% yield (91 mg), yellow solid; mp
1
149−150 °C (hexane−EtOAc). H NMR (CDCl3, 500 MHz): δ 3.84
(3H, s), 7.00−7.06 (2H, m), 7.42−7.48 (1H, m), 7.50−7.54 (2H, m),
7.99−8.05 (2H, m), 8.09−8.13 (2H, m), 9.10 (1H, s), 9.45 (1H, s).
13C NMR (125 MHz, CDCl3): δ 55.5, 113.8, 114.3 (2 × C), 123.1 (2
× C), 127.2 (2 × C), 129.1 (2 × C), 129.4, 131.5, 131.6, 144.5, 152.7,
152.8, 155.4, 158.4. IR (KBr): 3053, 2836, 2347, 1580, 1555, 1514,
1416, 1366, 1250, 1219, 1177, 1088, 1034 cm−1. EIMS m/z (rel int):
302 (100, M+). Anal. Calcd for C18H14N4O: C, 71.51; H, 4.67; N,
18.53. Found: C, 71.49; H, 4.71; N, 18.51.
3-Phenyl-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (26). The
standard procedure involved the treatment of 5-amino-3-phenyl-1-
(pyridin-2-yl)-1H-pyrazole (10; 97 mg, 0.36 mmol, 1.0 equiv) with
PBr3 (0.10 mL, 1.1 mmol, 3.0 equiv) in formamide solution (2 mL) at
50−60 °C over 0.5−1.0 h. The reaction mixture was then worked up,
and the residue was purified by chromatography on silica gel to give
pure 26: 88% yield (84 mg), yellow solid; mp 206−207 °C (hexane−
1
1-(3-Nitrophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (22).
The standard procedure involved the treatment of 5-amino-1-(3-
nitrophenyl)-3-phenyl-1H-pyrazole (6; 98 mg, 0.31 mmol, 1.0 equiv)
with PBr3 (0.09 mL, 0.92 mmol, 3.0 equiv) in formamide solution (2
mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture was then
worked up, and the residue was purified by chromatography on silica
gel to give pure 22: 93% yield (93 mg), brown solid; mp 183−184 °C
EtOAc). H NMR (CDCl3, 500 MHz): δ 7.30−7.22 (1H, m), 7.55−
7.41 (3H, m), 7.91−7.83 (1H, m), 8.05−7.99 (2H, m), 8.26−8.20
(1H, m), 8.70−8.66 (1H, m), 9.19 (1H, s), 9.47 (1H, s). 13C NMR
(125 MHz, CDCl3): δ 114, 116, 122, 128 (2 × C), 129 (2 × C), 130,
131, 139, 146, 149, 151, 153, 154, 156. IR (KBr): 3049, 2920, 2851,
2380, 2349, 1593, 1481, 1452, 1368, 1265, 1219, 1080 cm−1. EIMS m/
z (rel int): 273 (100, M+). Anal. Calcd for C16H11N5: C, 70.32; H,
4.06; N, 25.63. Found: C,70.28; H, 4.09; N, 25.66.
1
(hexane−EtOAc). H NMR (CDCl3, 500 MHz): δ 7.50−7.61 (3H,
m), 7.67−7.73 (1H, m), 8.02−8.10 (2H, m), 8.14−8.20 (1H, m),
8.81−8.87 (1H, m), 9.18 (1H, s), 9.31−9.35 (1H, m), 9.52 (1H, s).
13C NMR (125 MHz, CDCl3): δ 114.7, 115.6, 120.8, 126.0, 127.5 (2 ×
C), 129.3 (2 × C), 130.1, 130.1, 130.8, 139.6, 146.0, 148.8, 153.1,
154.0, 156.0. IR (KBr): 2924, 2348, 1531, 1431, 1416, 1343, 1215,
1092 cm−1. EIMS m/z (rel int): 317 (100, M+). Anal. Calcd for
C17H11N5O2: C, 64.35; H, 3.49; N, 22.07. Found: C, 64.37; H, 3.51;
N, 22.03.
1-(4-Chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (23).
The standard procedure involved the treatment of 5-amino-1-(4-
chlorophenyl)-3-phenyl-1H-pyrazole (7; 106 mg, 0.35 mmol, 1.0
equiv) with PBr3 (0.10 mL, 1.0 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 23: 91% yield (97 mg), yellow solid; mp
144−145 °C (hexane−EtOAc). 1H NMR (CDCl3, 500 MHz): δ
7.46−7.52 (3H, m), 7.52−7.58 (2H, m), 8.00−8.06 (2H, m), 8.29−
8.35 (2H, m), 9.12 (1H, s), 9.49 (1H, s). 13C NMR (125 MHz,
CDCl3): δ 114.3, 122.2 (2 × C), 127.4 (2 × C), 129.2 (2 × C), 129.3
(2 × C), 129.8, 131.3, 132.1, 137.2, 145.2, 152.9, 153.4, 155.7. IR
(KBr): 3051, 2922, 2851, 2384, 2349, 1589, 1554, 1406, 1367, 1215
cm−1. EIMS m/z (rel int): 306 (100, M+). Anal. Calcd for
C17H11ClN4: C, 66.56; H, 3.61; N, 18.26. Found: C, 66.53; H, 3.58;
N, 18.23.
3-Phenyl-1-(quinolin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (27).
The standard procedure involved the treatment of 5-amino-3-
phenyl-1-(quinolin-2-yl)-1H-pyrazole (11; 101 mg, 0.31 mmol, 1.0
equiv) with PBr3 (90 μL, 0.94 mmol, 3.0 equiv) in formamide solution
(2 mL) at 50−60 °C over 0.5−1 h. The reaction mixture was then
worked up, and the residue was purified by chromatography on silica
gel to give pure 27: 93% yield (91 mg), yellow solid; mp 194−195 °C
1
(hexane−EtOAc). H NMR (CDCl3, 500 MHz): δ 7.59−7.49 (4H,
m), 7.79−7.75 (1H, m), 7.87−7.89 (1H, m), 8.13−8.11 (2H, m),
8.37−8.39 (1H, m), 8.47−8.49 (1H, m), 9.26 (1H, s), 9.55 (1H, s).
13C NMR (125 MHz, CDCl3): δ 114.9, 115.6, 126.8, 127.2, 127.5,
127.8 (2 × C), 129.2 (2 × C), 129.5, 130.4, 131.2, 139.0, 146.6, 147.0,
149.8, 153.0, 154.4, 156.4. IR (KBr): 3055, 2376, 2347, 1582, 1557,
1502, 1477, 1409, 1368, 1325, 1219, 1090 cm−1. EIMS m/z (rel int):
323 (100, M+). Anal. Calcd for C20H13N5: C, 74.29; H, 4.05; N, 21.66.
Found: C, 74.33; H, 3.98; N, 21.61.
3-Methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (28).24 The
standard procedure involved the treatment of 5-amino-3-methyl-1-
phenyl-1H-pyrazole (12; 103 mg, 0.49 mmol, 1.0 equiv) with PBr3
(0.14 mL, 1.5 mmol, 3.0 equiv) in formamide solution (2 mL) at 50−
60 °C over 0.5−1.0 h. The reaction mixture was then worked up, and
the residue was purified by chromatography on silica gel to give pure
28: 93% yield (96 mg), light yellow solid; mp 79−80 °C (hexane−
1
EtOAc). H NMR (CDCl3, 500 MHz): δ 2.63 (3H, s), 7.23−7.29
1-(4-Bromophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (24).
The standard procedure involved the treatment of 5-amino-1-(4-
bromophenyl)-3-phenyl-1H-pyrazole (8; 102 mg, 0.29 mmol, 1.0
equiv) with PBr3 (80 μL, 0.87 mmol, 3.0 equiv) in formamide solution
(2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture was then
worked up, and the residue was purified by chromatography on silica
gel to give pure 24: 95% yield (96 mg), yellow solid; mp 176−177 °C
(1H, m), 7.42−7.50 (2H, m), 8.13−8.19 (2H, m), 9.02 (1H, s), 9.10
(1H, s). 13C NMR (125 MHz, CDCl3): δ 12.4, 115.6, 120.8 (2 × C),
126.3, 129.1 (2 × C), 138.4, 143.2, 151.6, 152.6, 155.5. IR (KBr):
3051, 2922, 2852, 1593, 1562, 1508, 1440, 1355, 1211, 1066 cm−1.
EIMS m/z (rel int): 210 (100, M+). Anal. Calcd for C12H10N4: C,
68.56; H, 4.79; N, 26.65. Found: C, 68.58; H, 4.76; N, 26.61.
3-tert-Butyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (29). The
standard procedure involved the treatment of 5-amino-3-tert-butyl-1-
phenyl-1H-pyrazole (13; 108 mg, 0.43 mmol, 1.0 equiv) with PBr3
(0.12 mL, 1.3 mmol, 3.0 equiv) in formamide solution (2 mL) at 50−
60 °C over 0.5−1.0 h. The reaction mixture was then worked up, and
the residue was purified by chromatography on silica gel to give pure
29: 91% yield (99 mg), light yellow solid; mp 48−49 °C (hexane−
1
(hexane−EtOAc). H NMR (CDCl3, 500 MHz): δ 7.45−7.57 (3H,
m), 7.60−7.66 (2H, m), 7.98−8.06 (2H, m), 8.21−8.29 (2H, m), 9.10
(1H, s), 9.47 (1H, s). 13C NMR (125 MHz, CDCl3): δ 114.3, 120.0,
122.4 (2 × C), 127.3 (2 × C), 129.2 (2 × C), 130.0, 131.2, 132.2 (2 ×
C), 137.6, 145.2, 152.8, 153.4, 155.6. IR (KBr): 2374, 2347, 1585,
1495, 1398, 1389, 1215, 1072 cm−1. EIMS m/z (rel int): 350 (100,
M+). Anal. Calcd for C17H11BrN4: C, 58.14; H, 3.16; N, 15.95. Found:
C, 58.16; H, 3.18; N, 15.91.
1
EtOAc). H NMR (CDCl3, 500 MHz): δ 1.55 (9H, s), 7.23−7.29
(1H, m), 7.44−7.52 (2H, m), 8.19−8.12 (2H, m), 9.02 (1H, s), 9.31
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(1H, s). 13C NMR (125 MHz, CDCl3): δ 30.3 (3 × C), 34.4, 114.0,
121.0 (2 × C), 126.2, 129.0 (2 × C), 138.6, 152.8, 153.1, 154.8, 155.0.
IR (KBr): 3049, 2968, 2666, 1599, 1578, 1555, 1508, 1427, 1366,
1261, 1098 cm−1. EIMS m/z (rel int): 252 (44, M+). Anal. Calcd for
C15H16N4: C, 71.40; H, 6.39; N, 22.21. Found: C, 71.43; H, 6.35; N,
22.17.
worked up, and the residue was purified by chromatography on silica
gel to give pure 67: 91% yield (133 mg), light yellow solid; mp 171−
1
172 °C (CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ 7.13−
7.19 (1H, m), 7.46−7.51 (1H, m), 7.72−7.76 (1H, m), 7.82−7.86
(1H, m), 8.69−8.73 (1H, m), 9.12 (1H, s), 9.17 (1H, s). 13C NMR
(50 MHz, CDCl3): δ 119.3, 124.8, 126.6 (2 × C), 127.1, 133.8, 148.4,
152.3, 154.7. IR (KBr): 3047, 2924, 1612, 1582, 1503, 1431, 1356,
1254, 1219, 1092 cm−1. EIMS m/z (rel int): 181 (100, M+). Anal.
Calcd for C11H7N3: C, 72.92; H, 3.89; N, 23.19. Found: C, 72.88; H,
3.86; N, 23.22.
3-(4-Methylphenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (30).
The standard procedure involved the treatment of 5-amino-3-(4-
methylphenyl)-1-phenyl-1H-pyrazole (14; 102 mg, 0.36 mmol, 1.0
equiv) with PBr3 (0.10 mL, 1.1 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 30: 93% yield (96 mg), light yellow solid; mp
Pyrimido[5,4-d]pyrimidine (74).28 The standard procedure in-
volved the treatment of 5-aminopyrimidine (69; 51 mg, 0.65 mmol,
1.0 equiv) with PBr3 (0.18 mL, 2.0 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 74: 86% yield (74 mg), light yellow solid; mp
1
139−140 °C (hexane−EtOAc). H NMR (CDCl3, 500 MHz): δ 2.43
(3H, s), 7.32−7.42 (3H, m), 7.51−7.61 (2H, m), 7.86−8.02 (2H, m),
8.24−8.38 (2H, m), 9.11 (1H, s), 9.47 (1H, s). 13C NMR (125 MHz,
CDCl3): δ 21.4, 114.2, 121.3 (2 × C), 126.7, 127.2 (2 × C), 128.7,
129.2 (2 × C), 129.9 (2 × C), 138.5, 139.8, 145.0, 152.8, 153.3, 155.5.
IR (KBr): 3030, 2920, 2374, 2349, 2313, 1584, 1503, 1430, 1368, 1220
cm−1. EIMS m/z (rel int): 286 (100, M+). Anal. Calcd for C18H14N4:
C, 75.50; H, 4.93; N, 19.57. Found: C, 75.49; H, 4.91; N, 19.55.
3-(4-Chlorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(31).25 The standard procedure involved the treatment of 5-amino-3-
(4-chlorophenyl)-1-phenyl-1H-pyrazole (15; 99 mg, 0.32 mmol, 1.0
equiv) with PBr3 (90 μL, 0.97 mmol, 3 equiv) in formamide solution
(2 mL) at 50−60 °C over 0.5−1 h. The reaction mixture was then
worked up, and the residue was purified by chromatography on silica
gel to give pure 31: 91% yield (89 mg), light yellow solid; mp 196−
197 °C (hexane−EtOAc). 1H NMR (CDCl3, 500 MHz): δ 7.34−7.38
(1H, m), 7.48−7.58 (m, 4 H, ArH), 7.96−8.02 (2H, m), 8.24−8.30
(2H, m), 9.12 (1H, s), 9.46 (1H, s). 13C NMR (125 MHz, CDCl3): δ
114.0, 121.5 (2 × C), 127.0, 128.5 (2 × C), 129.3 (2 × C), 129.5 (2 ×
C), 130.0, 135.7, 138.4, 143.8, 152.6, 153.3, 155.7. IR (KBr): 3043,
2926, 2848, 1585, 1368, 1219, 1093 cm−1. EIMS m/z (rel int): 306
(100, M+). Anal. Calcd for C17H11ClN4: C, 66.56; H, 3.61; N, 18.26.
Found: C, 66.53; H, 3.62; N, 18.29.
1
126−127 °C (CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ
8.53 (1H, s), 8.61 (1H, s), 9.12 (1H, s), 9.18 (1H, s). 13C NMR (50
MHz, CDCl3): δ 136.7 (2 × C), 156.2, 156.6, 158.7, 159.1. IR (KBr):
3047, 2924, 1612, 1582, 1503, 1431, 1356, 1254, 1219, 1092 cm−1.
EIMS m/z (rel int): 132 (100, M+). Anal. Calcd for C6H4N4: C, 54.54;
H, 3.05; N, 42.41. Found: C, 54.51; H, 3.02; N, 42.37.
Pyrazino[2,3-d]pyrimidine (75).29 The standard procedure in-
volved the treatment of 2-aminopyrazine (70; 53 mg, 0.56 mmol, 1.0
equiv) with PBr3 (0.16 mL, 1.7 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 75: 82% yield (61 mg), light yellow solid; mp
1
136−137 °C (CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ
8.47 (2H, m), 8.73 (1H, s, ArH), 9.14 (1H, s). 13C NMR (50 MHz,
CDCl3): δ 133.7, 142.5 (2 × C), 149.8, 155.9, 158.2. IR (KBr): 3047,
2924, 1612, 1582, 1503, 1431, 1356, 1254, 1219, 1092 cm−1. EIMS m/
z (rel int): 132 (100, M+). Anal. Calcd for C6H4N4: C, 54.54; H, 3.05;
N, 42.41. Found: C, 54.53; H, 3.06; N, 42.43.
6-Bromopteridine (76). The standard procedure involved the
treatment of 5-bromo-2-aminopyrazine (71; 48 mg, 0.51 mmol, 1.0
equiv) with PBr3 (0.14 mL, 1.5 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 76: 89% yield (95 mg), yellow solid; mp
3-(4-Methoxylphenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(32). The standard procedure involved the treatment of 5-amino-3-(4-
methoxylphenyl)-1-phenyl-1H-pyrazole (16; 101 mg, 0.33 mmol, 1.0
equiv) with PBr3 (90 μL, 1.0 mmol, 3 equiv) in formamide solution (2
mL) at 50−60 °C over 0.5−1 h. The reaction mixture was then
worked up, and the residue was purified by chromatography on silica
gel to give pure 32: 94% yield (94 mg), yellow solid; mp 175−176 °C
(hexane−EtOAc). 1H NMR (CDCl3, 500 MHz): δ 3.87 (3H, s),
7.08−7.84 (2H, m), 7.32−7.36 (1H, m), 7.50−7.56 (2H, m), 7.95−
8.01 (2H, m), 8.28−8.32 (2H, m), 9.10 (1H, s), 9.45 (1H, s). 13C
NMR (125 MHz, CDCl3): δ 55.4 (CH3), 114.2, 114.6 (2 × C), 121.3
(2 × C), 124.1, 126.7, 128.7 (2 × C), 129.2 (2 × C), 138.6, 144.8,
152.8, 153.2, 155.5, 160.8. IR (KBr): 3047, 2924, 1612, 1582, 1503,
1431, 1356, 1254, 1219, 1092 cm−1. EIMS m/z (rel int): 302 (100,
M+). Anal. Calcd for C18H14N4O: C, 71.51; H, 4.67; N, 18.53. Found:
C, 71.48; H, 4.68; N, 18.50.
1
102−103 °C (CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ
8.96 (1H, s, ArH), 9.98 (1H, s, ArH), 10.17 (1H, s, ArH); 13C NMR
(50 MHz, CDCl3): δ 134.3, 146.2, 148.1, 155.3, 160.1, 164.6. IR
(KBr): 3047, 2924, 1612, 1582, 1503, 1431, 1356, 1254, 1219, 1092
cm−1. EIMS m/z (rel int): 209 (98, M+). Anal. Calcd for C6H3BrN4:
C, 34.15; H, 1.43; N, 26.55. Found: C, 34.17; H, 1.41; N, 26.58.
7-Chloropteridine (77).30 The standard procedure involved the
treatment of 6-chloro-2-aminopyrazine (72; 48 mg, 0.53 mmol, 1.0
equiv) with PBr3 (0.15 mL, 1.6 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 77: 87% yield (77 mg), light yellow solid; mp
96−97 °C (CH2Cl2−methanol). 1H NMR (CDCl3, 200 MHz): δ 8.96
(1H, s), 9.98 (1H, s), 10.17 (1H, s); 13C NMR (50 MHz, CDCl3): δ
134.3, 146.2, 148.1, 155.3, 160.1, 164.6. IR (KBr): 3047, 2924, 1612,
1582, 1503, 1431, 1356, 1254, 1219, 1092 cm−1. EIMS m/z (rel int):
166 (100, M+). Anal. Calcd for C6H3C1N4: C, 43.26; H, 1.82; N,
33.64. Found: C, 43.28; H, 1.81; N, 33.61.
Pyrido[2,3-h]quinazoline (66).26 The standard procedure involved
the treatment of 5-aminoquinoline (62; 101 mg, 0.85 mmol, 1.0 equiv)
with PBr3 (0.24 mL, 2.5 mmol, 3.0 equiv) in formamide solution (2
mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture was then
worked up, and the residue was purified by chromatography on silica
gel to give pure 66: 59% yield (91 mg), light yellow solid; mp 125−
1
126 °C (CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ 7.23−
Standard Procedure for Synthesis of N,N′-Diarylformami-
dines (50−56 and 73). The reliable procedure involved the
treatment of arylamines (43−49; 1.0 equiv) or 3-aminopyridine (68;
1.0 equiv) with PBr3 (∼3.0 equiv) in formamide solution (2 mL) at
50−60 °C over 0.5−1.0 h. When the reaction was complete, the crude
solid was triturated in cold n-pentane and filtered through a glass frit
with suction. Then the solid was washed with n-pentane and dried in
vacuo to give the crude formamidines (50−56 and 73). The crude
products were recrystallized from the mixture of acetone and
diisopropyl ether to give the corresponding N,N′-diarylformamidine
products (50−56 and 73) in 88−97% yields as white to light yellow
solids.
7.29 (1H, m), 7.57−7.61 (1H, m), 7.82−7.86 (1H, m), 7.98−8.02
(1H, m), 8.79−8.83 (1H, m), 9.13 (1H, s), 9.18 (1H, s). 13C NMR
(50 MHz, CDCl3): δ 119.8, 123.2, 125.9 (2 × C), 126.6, 131.1, 134.4,
148.2 (2 × C), 153.8, 155.2. IR (KBr): 3047, 2924, 1612, 1582, 1503,
1431, 1356, 1254, 1219, 1092 cm−1. EIMS m/z (rel int): 181 (100,
M+). Anal. Calcd for C11H7N3: C, 72.92; H, 3.89; N, 23.19. Found: C,
72.89; H, 3.92; N, 23.16.
Pyrido[3,2-h]quinazoline (67).27 The standard procedure involved
the treatment of 8-aminoquinoline (63; 97 mg, 0.81 mmol, 1.0 equiv)
with PBr3 (0.23 mL, 2.4 mmol, 3.0 equiv) in formamide solution (2
mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture was then
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N,N′-Diphenylformamidine (50)..20,31 The standard procedure
involved the treatment of aniline (43; 51 mg, 0.55 mmol, 1.0 equiv)
with PBr3 (0.16 mL, 1.7 mmol, 3.0 equiv) in formamide solution (2
mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture was then
worked up, and the residue was purified by chromatography on silica
gel to give pure 50: 96% yield (103 mg), light yellow solid; mp 138−
N,N′-Bis(3-fluorophenyl)formamidine (55).35 The standard proce-
dure involved the treatment of 3-fluoroaniline (48; 50 mg, 0.52 mmol,
1.0 equiv) with PBr3 (0.15 mL, 1.6 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 55: 93% yield (108 mg), yellow oil (CH2Cl2−
methanol). 1H NMR (CDCl3, 200 MHz): δ 6.22−6.28 (2H, m),
6.32−6.36 (1H, m), 7.14−7.18 (4H, m), 7.25−7.29 (1H, m), 7.48
(1H, s), 8.01 (1H, s). 13C NMR (50 MHz, CDCl3): δ 103.6, 106.5,
109.1, 111.8, 113.9, 118.6, 130.8 (2 × C), 143.6, 150.8, 163.0, 164.8,
165.2. IR (KBr): 3132, 2968, 2827, 1655, 1574, 1481, 1466, 1280,
1257, 1214, 1169, 1109, 1017 cm−1. EIMS m/z (rel int): 232 (100,
M+). Anal. Calcd for C13H10F2N2: C, 67.24; H, 4.32; N, 12.06. Found:
C, 67.20; H, 4.36; N, 12.02.
1
139 °C (CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ 7.09−
7.42 (10H, m), 8.24 (1H, s), 8.86 (1H, s). 13C NMR (50 MHz,
CDCl3): δ 119.1, 123.3, 129.3, 145.2, 149.5. IR (KBr): 3048, 2965,
1671, 1659, 1598, 1572, 1493, 1439, 1320, 1205, 1169 cm−1. EIMS m/
z (rel int): 196 (100, M+). Anal. Calcd for C13H12N2: C, 79.56; H,
6.16; N, 14.27. Found: C, 79.59; H, 6.13; N, 14.22.
N,N′-Bis(4-methylphenyl)formamidine (51).32 The standard pro-
cedure involved the treatment of 4-toluidine (44; 47 mg, 0.44 mmol,
1.0 equiv) with PBr3 (0.12 mL, 1.3 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 51: 91% yield (90 mg), light yellow solid; mp
N,N′-Bis(4-fluorophenyl)formamidine (56).35 The standard proce-
dure involved the treatment of 4-fluoroaniline (49; 49 mg, 0.51 mmol,
1.0 equiv) with PBr3 (0.14 mL, 1.5 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 56: 97% yield (115 mg), yellow solid; mp
1
140−141 °C (CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ
2.28 (3H, s), 2.30 (3H, s), 6.99−6.93 (2H, m), 7.14−7.06 (4H, m),
7.43−7.37 (2H, m), 8.29 (1H, s), 8.91 (1H, m) ; 13C NMR (50 MHz,
CDCl3): δ 20.7, 20.8, 119.0 (2 × C), 120.0 (2 × C), 129.4 (2 × C),
130.0 (2 × C), 134.2, 134.3, 135.0, 159.3, 163.1. IR (KBr): 3106, 2953,
2835, 1653, 1583, 1495, 1459, 1296, 1243, 1200, 1175, 1113, 1026,
996, 743 cm−1. EIMS m/z (rel int): 256 (31, M+). Anal. Calcd for
C15H16N2: C, 80.32; H, 7.19; N, 12.49. Found: C, 80.29; H, 7.16; N,
12.51.
1
142−144 °C (CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ
7.09−6.96 (8H, m), 8.02 (1H, s), 9.61 (1H, s). 13C NMR (50 MHz,
CDCl3): δ 161.8, 1573.0, 150.2, 141.2, 120.5, 120.4, 116.2, 115.8. IR
(KBr): 3428, 2928, 2862, 1671, 1603, 1502, 1380, 1313, 1202 cm−1.
EIMS m/z (rel int): 236 (100, M+). Anal. Calcd for C13H10F2N2: C,
67.24; H, 4.32; N, 12.06. Found: C, 67.23; H, 4.34; N, 12.07.
Pyrido[3,4-d]pyrimidine (73). The standard procedure involved the
treatment of 3-aminopyridine (68; 52 mg, 0.55 mmol, 1.0 equiv) with
PBr3 (0.16 mL, 1.7 mmol, 3.0 equiv) in formamide solution (2 mL) at
50−60 °C over 0.5−1.0 h. The reaction mixture was then worked up,
and the residue was purified by chromatography on silica gel to give
pure 73: 88% yield (96 mg), yellow solid; mp 130−131 °C (CH2Cl2−
methanol). 1H NMR (CDCl3, 200 MHz): δ 7.24−7.28 (1H, m),
8.47−8.53 2H, m), 8.69 (1H, s), 9.12 (1H, s). 13C NMR (50 MHz,
CDCl3): δ 115.3, 120.6, 139.7, 147.9, 148.2, 155.3, 156.4. IR (KBr):
3106, 2953, 2835, 1653, 1583, 1495, 1459, 1296, 1243, 1200, 1175,
1113, 1026 cm−1. EIMS m/z (rel int): 198 (100, M+). Anal. Calcd for
C11H10N4: C, 66.65; H, 5.08; N, 28.26. Found: C, 66.63; H, 5.04; N,
28.27.
N,N′-Bis(2-methoxyphenyl)formamidine (52)..20,33 The standard
procedure involved the treatment of 2-anisidine (45; 51 mg, 0.41
mmol, 1.0 equiv) with PBr3 (0.12 mL, 1.2 mmol, 3.0 equiv) in
formamide solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction
mixture was then worked up, and the residue was purified by
chromatography on silica gel to give pure 52: 95% yield (100 mg),
1
yellow solid; mp 82−84 °C (CH2Cl2−methanol). H NMR (CDCl3,
200 MHz): δ 3.67 (6H, s), 7.04−6.86 (8H, m), 7.95 (1H, s), 8.22 (1H,
s). 13C NMR (50 MHz, CDCl3): δ 55.6, 56.2, 110.9, 117.1 (2 × C),
121.0 (2 × C), 123.3 (2 × C), 134.5 (2 × C), 147.2, 150.1, 159.6,
162.7. IR (KBr): 3315, 3126, 3037, 2987, 2889, 2813, 1664, 1591,
1459, 1300, 1236, 1021 cm−1. EIMS m/z (rel int): 256 (31, M+). Anal.
Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.33;
H, 6.31; N, 10.96.
Standard Procedure for Synthesis of Benzo[h]quinazoline
(64) and N,N′-Dinaphthalenylformamidine (65). The reliable
procedure involved the treatment of 1-aminonaphthalene (61; 1.0
equiv) with PBr3 (∼3.0 equiv) in formamide solution (2 mL) at 50−
60 °C over 0.5−1.0 h. When the reaction was complete, the reaction
mixture was added to saturated sodium bicarbonate (15 mL) and
extracted with dichloromethane (15 mL). The organic extracts were
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue solution was purified by column chromatography on silica
gel to give the corresponding benzo[h]quinazoline as the major
product (64) in 59% yield and N,N′-dinaphthalenylformamidine (65)
as the minor product in 28% yield.
N,N′-Bis(4-methoxyphenyl)formamidine (53).34 The standard
procedure involved the treatment of 4-anisidine (46; 49 mg, 0.40
mmol, 1.0 equiv) with PBr3 (0.11 mL, 1.2 mmol, 3.0 equiv) in
formamide solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction
mixture was then worked up, and the residue was purified by
chromatography on silica gel to give pure 53: 92% yield (94 mg),
yellow solid; mp 118−119 °C (CH2Cl2−methanol). 1H NMR
(CDCl3, 200 MHz): δ 3.66 (6H, s), 6.54−7.26, (8H, m), 7.89 (1H,
s), 8.07 (1H, s). 13C NMR (50 MHz, CDCl3): δ 56.9, 57.8, 114.9,
115.2, 118.3 (2 × C), 124.3 (2 × C), 135.2 (2 × C), 139.8 (2 × C),
149.5, 160.1, 163.7. IR (KBr): 3313, 3136, 3022, 2991, 2886, 2804,
1675, 1577, 1465, 1301, 1247, 1036 cm−1. EIMS m/z (rel int): 256
(51, M+). Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93.
Found: C, 70.26; H, 6.32; N, 10.91.
Benzo[h]quinazoline (64).37 The standard procedure involved the
treatment of 1-naphthylamine (61; 99 mg, 0.79 mmol, 1.0 equiv) with
PBr3 (0.22 mL, 2.4 mmol, 3.0 equiv) in formamide solution (2 mL) at
50−60 °C over 0.5−1.0 h. The reaction mixture was then worked up,
and the residue was purified by chromatography on silica gel to give
pure 64: 59% yield (84 mg), light yellow solid; mp 101−102 °C
N,N′-Bis(2-fluorohenyl)formamidine (54).35 The standard proce-
dure involved the treatment of 2-fluoroaniline (47; 51 mg, 0.53 mmol,
1.0 equiv) with PBr3 (0.15 mL, 1.6 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 54: 91% yield (112 mg), yellow oil (CH2Cl2−
methanol). 1H NMR (CDCl3, 200 MHz): δ 6.42−6.46 (1H, m),
6.57−6.61 (1H, m), 6.70−6.76 (2H, m), 7.08−7.12 (2H, m), 7.21−
7.25 (2H, m), 7.61 (1H, s), 7.92 (1H, s). 13C NMR (50 MHz,
CDCl3): δ 114.3, 116.3, 118.4, 125.5, 124.4 (2 × C), 127.9 (2 × C),
128.1, 137.5, 153.9, 156.1, 162.8. IR (KBr): 3127, 2951, 2847, 1637,
1561, 1494, 1456, 1277, 1232, 1207, 1175, 1121, 1038 cm−1. EIMS m/
z (rel int): 232 (100, M+). Anal. Calcd for C13H10F2N2: C, 67.24; H,
4.32; N, 12.06. Found: C, 67.22; H, 4.31; N, 12.01.
1
(CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ 9.48 (1H, s),
9.31 (1H, s), 9.23 (1H, m), 7.84 (1H, m), 7.76 (1H, m), 7.71 −
D;7.68 (2H, m), 7.59 (1H, m). 13C NMR (50 MHz, CDCl3): δ 156.8,
153.2, 148.5, 135.3, 133.0, 128.1, 127.9 (2 × C), 127.3 (2 × C), 125.9,
125.9. EIMS m/z (rel int): 180 (100, M+). Anal. Calcd for C12H8N2:
C, 79.98; H, 4.47; N, 15.55. Found: C, 79.93; H, 4.43; N, 15.57.
N,N′-Dinaphthalenylformamidine (65).31 The standard procedure
involved the treatment of 1-naphthylamine (61; 99 mg, 0.79 mmol, 1.0
equiv) with PBr3 (0.22 mL, 2.4 mmol, 3.0 equiv) in formamide
solution (2 mL) at 50−60 °C over 0.5−1.0 h. The reaction mixture
was then worked up, and the residue was purified by chromatography
on silica gel to give pure 65: 28% yield (65 mg), light yellow solid; mp
1
202−203 °C (CH2Cl2−methanol). H NMR (CDCl3, 200 MHz): δ
8499
dx.doi.org/10.1021/jo301463m | J. Org. Chem. 2012, 77, 8492−8500

The Journal of Organic Chemistry
Article
7.19−7.06 (6H, m), 7.41−7.30 (4H, m), 8.30 (1H, s), 9.97 (1H, s).
13C NMR (50 MHz, CDCl3): δ 121.0, 123.3, 132.5, 147.2, 150.0. IR
(KBr): 3241, 1659, 1578, 1391, 1296, 1210 cm−1. EIMS m/z (rel int):
296 (31, M+). Anal. Calcd for C21H16N2: C, 85.11; H, 5.44; N, 9.45.
Found: C, 85.13; H, 5.46; N, 9.47.
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647−650.
ASSOCIATED CONTENT
■
S
* Supporting Information
(16) (a) Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000,
̈
1
Figures giving H NMR and 13C NMR spectra for products
37, 647−658. (b) Posner, G. H. Chem. Rev. 1986, 86, 831−844.
(c) Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366−374.
(17) Su, W.-N.; Lin, T.-P.; Cheng, K.-M.; Sung, K.-C.; Lin, S.-K.;
Wong, F. F. J. Heterocycl. Chem. 2010, 47, 831−837.
17−32, 54, 55, 66, 73, and 77. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) (a) Srivastava, V.; Negi, A. S.; Kumar, J. K.; Gupta, M. M.
Steroids 2006, 71, 632−638. (b) El-Shishtawy, R. M.; Almeida, P.
Tetrahedron 2006, 62, 7793−7798.
AUTHOR INFORMATION
■
Corresponding Author
(19) (a) Haufel, V. J.; Breitmaier, E. Angew. Chem. 1974, 86, 671−
̈
*Tel.: +886 4 2205 3366, ext. 5603. Fax: +886 4 2207 8083. E-
mail: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw.
672. (b) Mason, H. J.; Wu, X.; Schmitt, R.; Macor, J. E.; Yu, G.
Tetrahedron Lett. 2001, 42, 8931−8934.
Notes
(20) Jachak, M. N.; Avhale, A. B.; Medhane, V. J.; Toche, R. B. J.
Heterocycl. Chem. 2006, 43, 1169−1175.
The authors declare no competing financial interest.
(21) Hirano, K.; Urban, S.; Wang, C.; Glorius, F. Org. Lett. 2009, 11,
1019−1022.
ACKNOWLEDGMENTS
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(22) Eicher, T.; Hauptmann, S. In The Chemistry of Heterocycles:
Structure, Reactions, Syntheses, and Applications; Suschitzky, H.,
Suschitzky, J. (translators); Wiiey-VCH: Weinheim, Germany, 2003;
pp 179−184.
We are grateful to the National Science Council of Republic of
China for financial support (NSC-99-2320-B-039-014-MY3).
This study was also supported in part by the Taiwan
Department of Health Clinical Trial and Research Center of
Excellence (DOH100-TD-B-111-004).
(23) Wiehn, M. S.; Vinogradova, E. V.; Togni, A. J. Fluorine Chem.
2010, 131, 951−957.
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