Trifluoroacetic acid-mediated nucleophilic substitution/smiles rearrangement cascade reaction: An alternative approach to constructing pyrrole-fused dihydropteridines

Article abstract of DOI:10.1007/s10593-016-1973-9

A trifluoroacetic acid-mediated cascade reaction involving nucleophilic substitution and Smiles rearrangement is described. The reaction of hydroxydihydrodiazepines with primary amines led to amino-substituted dihydrodiazepines, which readily underwent Smiles rearrangement to give pyrrolo[1,2-f]pteridine derivatives.

Full text of DOI:10.1007/s10593-016-1973-9

DOI 10.1007/s10593-016-1973-9
Chemistry of Heterocyclic Compounds 2016, 52(10), 831–835
Trifluoroacetic acid-mediated nucleophilic substitution /
Smiles rearrangement cascade reaction: An alternative approach
to constructing pyrrole-fused dihydropteridines
Tong Zhu1, Jinbao Xiang1*
1 The Center for Combinatorial Chemistry and Drug Discovery of Jilin University,
The School of Pharmaceutical Sciences, Jilin University,
1266 Fujin Road, Changchun, Jilin 130021, P. R. China; е-mail: jbxiang@jlu.edu.cn
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(10), 831–835
Submitted June 27, 2016
Accepted after revision August 18, 2016
A trifluoroacetic acid-mediated cascade reaction involving nucleophilic substitution and Smiles rearrangement is described. The reaction
of hydroxydihydrodiazepines with primary amines led to amino-substituted dihydrodiazepines, which readily underwent Smiles rear-
rangement to give pyrrolo[1,2-f]pteridine derivatives.
Keywords: dihydrodiazepines, pyrimidines, pyrrolo[1,2-f]pteridines, cascade reactions, nucleophilic substitution, Smiles rearrangement.
Cascade reactions have been of interest for organic
synthesis because they offer convenient and economical
methods for the preparation of various organic molecules.1
Smiles rearrangement is a type of intramolecular nucleo-
philic aromatic substitution, which has become a powerful
synthetic method.2 To date, several cascade reactions
involving Smiles rearrangement have been reported. For
example, the Ugi–Smiles rearrangement cascade reaction
was developed by Kaïm's group;3 a Smiles rearrangement /
nucleophilic substitution cascade reaction was reported by
the groups of Guillaumet,4 Shin,5 and Ma;6 an Ullmann
coupling / Smiles rearrangement / nucleophilic substitution
cascade reaction was achieved by Snieckus's group.7
In the past years, we reported a new cascade reaction
entailing an iminium cyclization followed by a Smiles
rearrangement in N-pyrrolopyrimidine and analogous
systems.8 As depicted in Scheme 1, the reaction of
aldehydes 2 with a primary amine yielded an exo iminium
cyclization products, dihydrodiazepines 4, under acidic
conditions; subsequently, dihydrodiazepines 4 underwent
Smiles rearrangement to produce pteridine derivatives 5. It
is noteworthy that the aldehydes 2 were unstable and
readily cyclized to give the hydroxydihydrodiazepines 3
during purification on a silica gel column.8a Thus it was
considered that hydroxydihydrodiazepines 3 may serve as
stable analogs of aldehydes 2 and can participate directly in
a cascade reaction under acidic conditions.
As part of our continuing efforts to provide further
insights into synthetically useful reactions8d and to develop
new cascade reactions involving Smiles rearrangement, we
speculated that the reaction of hydroxydihydrodiazepine 3
and primary amines may offer an alternative approach to
pteridine derivatives 5 via a cascade reaction involving
nucleophilic substitution9 / Smiles rearrangement under
acidic conditions (Scheme 1). Herein, the preliminary
results of the studies are reported.
Our studies began with the preparation of key precursor,
hydroxydihydrodiazepine 3, from amino alcohol 1 by a
sequence of oxidation/cyclization processes. The oxidation
of compounds 1 under the Parikh–Doering conditions
cleanly generated aldehydes 2, which were extracted from
aqueous solutions. Considering the reaction workup,
2-iodobenzoic acid (IBX) was regarded as an ideal oxidant,
as simple filtration of the reaction mixture provided the
aldehydes 2.10 The oxidation of compound 1a with IBX
followed by cyclization was investigated, and results are
summarized in Table 1. First, solvents (EtOAc, MeCN, and
1,2-dichloroethane (DCE)) were investigated in the
presence of TFA (entries 1–3). The best reaction solvent
was DCE, giving the desired product 3a in 50% yield
0009-3122/16/52(10)-0831©2016 Springer Science+Business Media New York
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Chemistry of Heterocyclic Compounds 2016, 52(10), 831–835
Scheme 1
Cl
Cl
Cl
N
R2
NH
N
N
R2NH2
N
Pyr·SO3
N
N
N
OH
O
DMSO, CH2Cl2
TFA, CH2Cl2
N
N
N
N
N
R1
1
R1
R1
2 (unstable)
4
R2NH2
Cl
Cl
N
N
N
N
N
N
H
N
OH
N
N
R1
R2
R1
3
5
R1 = alkyl
R2 = alkyl, alkoxy, aryl
Table 1. Optimization of the oxidation and cyclization conditions
Entry
1
Product
3a
R1
Solvent
EtOAc
MeCN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Acid (equiv)
Temp., °C
c2, M*
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.01
Time, h
1.0
Yield, %
37
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
TFA (0.5)
TFA (0.5)
TFA (0.5)
TsOH (0.5)
AcOH (0.5)
TFA (0.25)
TFA (1.0)
TFA (0.5)
TFA (0.5)
TFA (0.5)
TFA (0.5)
TFA (0.5)
80
80
80
80
80
80
80
60
25
80
80
80
2
2.5
21
3a
3
0.5
50
3a
4
1.5
20
3a
5
0.5
34
3a
6
0.5
43
3a
7
0.5
39
3a
8
1.5
30
3a
9
1.5
27
3a
10
11
12
0.5
71
3a
0.005
0.01
0.5
67
3a
0.2
65
3b
* c2 – the concentration of compound 2 based on assumed 100% conversion of amino alcohol 1 to aldehyde 2.
(entry 3). Other acids, including TsOH and AcOH, were
also screened, but neither produced a higher yield of
compound 3a (entries 4 and 5). The amount of TFA was
varied, but these changes did not improve the yield (entries
6 and 7). Finally, the reaction conditions were further
optimized with regard to the reaction temperature and the
concentration of aldehyde 2a (entries 8–11), and the
desired product 3a was obtained in 71% yield by using
0.01 M concentration of compound 2a at 80°C temperature
(entry 10). Moreover, a 65% yield of compound 3b was
also obtained under these optimal conditions (entry 12).
Initially, hydroxydihydrodiazepine 3a was treated with
4-chloroaniline under our previously reported reaction
conditions,8d giving an 83% yield of the desired product 5a
(entry 1, Table 2). It was noteworthy that no aldehyde 2a
was detected in the reaction mixture by both LC-MS and
thin-layer chromatography analysis during the cascade
reaction. Therefore, the results confirmed that diazepine 4a
was indeed produced via direct amine substitution of the
hydroxyl group in compound 3a (SN1 mechanism),8d not
iminium cyclization of aldehyde 2a with 4-chloroaniline.
The scope of this new cascade reaction was further
investigated with hydroxydiazepines 3a,b and various
amines, and the results are summarized in Table 2.
As shown in Table 2, aromatic amines effectively parti-
cipated in the current reaction and produced the desired
products in good to high yields (entries 1–12). The reaction
appeared to be somewhat sensitive to electronic effects in
832

Chemistry of Heterocyclic Compounds 2016, 52(10), 831–835
Table 2. Cascade reactions of compounds 3*
Experimental
1H and 13C NMR data were acquired on a Varian Mercury
300 NMR spectrometer (300 and 75 MHz, respectively).
TMS was used as internal standard and the solvent was
CDCl3, unless otherwise stated. HRMS analysis was
performed on an Agilent 1290-micrOTOF-Q II mass
spectrometer. Melting points were determined on an XT5
melting point apparatus and are uncorrected. All commer-
cial reagents were purchased from Energy Chemical and
Sigma-Aldrich, and used without additional purification.
Synthesis of compounds 3a,b (General method). IBX
(2.52 g, 9 mmol) was added to a stirred solution of com-
pound 1a,b (3 mmol) in DCE (42 ml). The reaction
mixture was stirred for 2.5 h at 80°C. When the solution
was cooled to 0°C, the precipitate was filtered off. The
resulting clear solution was then diluted with DCE to give a
solution of crude aldehyde 2 in DCE (300 ml). TFA (112 μl,
1.5 mmol) was then added to the solution. The mixture was
stirred for the appropriate time at 80°C, then washed with
saturated aqueous Na2CO3 solution, dried over anhydrous
MgSO4, and concentrated at reduced pressure. Purification
by flash chromatography (petroleum ether–EtOAc, 10:1 to
1:1) afforded the desired products 3a,b.
Entry
R1
R2
Time, h
Product
Yield, %
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
p-ClC6H4
p-O2NC6H4
p-NCC6H4
p-FC6H4
9
2
83
57
67
78
85
88
79
79
78
80
53
66
0
5a
5b
5c
5d
5e
5f
3
5.5
8
4
5
m,p-Cl2C6H3
p-BrC6H4
m-ClC6H4
Ph
8
6
9
7
9
5g
5h
5i
8
13
15
15
18
22
23
23
11
9
p-MeC6H4
m-MeC6H4
p-MeOC6H4
o-MeOC6H4
n-Bu
10
11
12
13
14
15
5j
5k
5l
1-Chloro-5-methyl-6,7-dihydro-5H-pyrimido[4,5-b]-
pyrrolo[1,2-d][1,4]diazepin-7-ol (3a). Yield 533 mg
1
(71%), white solid, mp 139–141°C. H NMR spectrum
5m
5n
5o
(DMSO-d6), δ, ppm (J, Hz): 3.02 (3H, s, CH3); 3.61 (1H,
dd, J = 12.6, J = 4.8) and 3.75 (1H, dd, J = 12.6, J = 2.7,
NCH2CHOH); 4.90 (1H, dd, J = 4.8, J = 2.7, NCH2CHOH);
6.10 (1H, dd, J = 3.3, J = 1.8, H Ar); 6.13 (1H, t, J = 3.3,
H Ar); 6.98 (1H, dd, J = 2.7, J = 1.8, H Ar); 8.29 (1H, s,
H Ar). 13C NMR spectrum (DMSO-d6), δ, ppm: 39.8; 62.7;
63.8; 105.6; 108.3; 118.8; 123.6; 134.3; 150.3; 152.9; 158.3.
Found, m/z: 251.0699 [M+H]+. C11H12ClN4O. Calculated,
m/z: 251.0694.
i-Pr
0
p-ClC6H4
85
* Intermediates 4 could be detected in the reaction mixture by mass
spectroscopy and thin-layer chromatography analysis during the reaction.
the aromatic amines. When either a moderate electron-
withdrawing or a mild electron-donating group (Cl, F, Br,
H and Me; entries 1 and 4–10) was present in the aromatic
amine, higher yields were obtained compared to those
aromatic amines with either a strong electron-withdrawing
group (R2 = p-NO2 or p-CN; entry 2 or 3) or a strong
electron-donating group (R2 = p-MeO, entry 11). On the
other hand, the reaction proceeded faster with aromatic
amines having an electron-withdrawing group compared to
those with an electron-donating group (entries 2–7 vs
entries 9–12). In contrast, aliphatic amines failed in this
reaction (entries 13 and 14). In addition, when hydroxy-
dihydrodiazepine 3b was treated with 4-chloroaniline, 85%
yield of the desired product 5o was obtained (entry 15).
The structures of compounds 5 were determined based on
5-Benzyl-1-chloro-6,7-dihydro-5H-pyrimido[4,5-b]-
pyrrolo[1,2-d][1,4]diazepin-7-ol (3b). Yield 637 mg (65%),
white solid, mp 171–173°C (171–173°C8a). 1H NMR
spectrum, δ, ppm (J, Hz): 3.68–3.82 (2H, m, NCH2CHOH);
4.67 (1H, d, J = 15.6) and 5.12 (1H, d, J = 15.3, NCH2Ph);
5.00 (1H, dd, J = 5.1, J = 2.1, NCH2CHOH); 6.16 (1H, dd,
J = 3.3, J = 1.5, H Ar); 6.23 (1H, t, J = 3.3, H Ar); 7.01
(1H, dd, J = 3.0, J = 1.5, H Ar); 7.24–7.36 (5H, m, H Ar);
8.25 (1H, s, H Ar).
Synthesis of 5,6-dihydropyrrolo[1,2-f]pteridines 5a–l,o
(General method). The appropriate amine (0.6 mmol) was
added to a stirred solution of compound 3 (0.5 mmol) in
DCE (20 ml), followed by TFA (78 μl, 1.05 mmol). The
mixture was stirred for the appropriate time at 60°C, then
washed with saturated aqueous Na2CO3 solution, dried over
anhydrous MgSO4, and concentrated at reduced pressure.
Purification by flash chromatography (4:1 to 2:1 petroleum
ether–EtOAc, v/v) afforded the desired products.
1
the 6-CH proton at 5.02−5.26 ppm (double doublet) in H
1
NMR spectra and the comparison of their H NMR spectra
with analogues reported in the literature.8a
In conclusion, a new cascade reaction involving nucleo-
philic substitution and Smiles rearrangement was
developed. The utility of this reaction sequence has been
demonstrated by the synthesis of pyrrolo[1,2-f]pteridine
derivatives. Futhermore, the proposed method represents a
promising approach that could be extended to the synthesis
of other practically relevant molecules.
1-[1-Chloro-5-(4-chlorophenyl)-5,6-dihydropyrrolo-
[1,2-f]pteridin-6-yl]-N-methylmethanamine (5a). Yield
150 mg (83%). Pale-yellow solid. Mp 86–87°C (86–87°C8a).
1H NMR spectrum, δ, ppm (J, Hz): 2.33 (3H, s, NCH3);
2.76–2.93 (2H, m, NCH2); 5.04 (1H, dd, J = 7.5, J = 4.2,
833

Chemistry of Heterocyclic Compounds 2016, 52(10), 831–835
NCH); 6.16 (1H, dd, J = 3.3, J = 1.2, H Ar); 6.44 (1H, t,
NCH2); 5.08 (1H, dd, J = 7.5, J = 4.2, NCH); 6.18 (1H, dd,
J = 3.3, J = 1.2, H Ar); 6.44 (1H, t, J = 3.3, H Ar); 7.28
(2H, d, J = 9.0, H Ar); 7.58 (2H, d, J = 8.7, H Ar); 7.97
(1H, dd, J = 3.0, J = 1.5, H Ar); 8.14 (1H, s, H Ar).
13C NMR spectrum, δ, ppm: 36.4; 54.5; 58.6; 106.5; 111.8;
116.8; 119.9; 120.8; 126.3; 128.5; 132.6; 140.7; 143.5;
152.0; 153.4. Found, m/z: 404.0282 [M+H]+. C17H16BrClN5.
Calculated, m/z: 404.0272.
J = 3.3, H Ar); 7.33 (2H, d, J = 8.7, H Ar); 7.43 (2H, d,
J = 8.7, H Ar); 7.98 (1H, dd, J = 3.0, J = 1.5, H Ar); 8.13
(1H, s, H Ar).
1-[1-Chloro-5-(4-nitrophenyl)-5,6-dihydropyrrolo[1,2-f]-
pteridin-6-yl]-N-methylmethanamine (5b). Yield 106 mg
1
(57%). Yellow solid. Mp 128–130°C. H NMR spectrum,
δ, ppm (J, Hz): 2.40 (3H, s, NCH3); 2.83 (1H, dd, J = 12.0,
J = 8.4) and 2.99 (1H, dd, J = 12.0, J = 4.8, NCH2); 5.24–
5.29 (1H, m, NCH); 6.21 (1H, d, J = 3.3, H Ar); 6.45 (1H,
t, J = 3.3, H Ar); 7.62 (2H, d, J = 9.0, H Ar); 7.94 (1H, dd,
J = 3.0, J = 1.2, H Ar); 8.25–8.31 (3H, m, H Ar). 13C NMR
spectrum, δ, ppm: 36.4; 54.5; 57.8; 107.1; 112.1; 118.6;
120.1; 124.3; 124.9; 126.5; 144.7; 145.2; 147.7; 152.0;
152.7. Found, m/z: 371.1025 [M+H]+. C17H16ClN6O2.
Calculated, m/z: 371.1018.
1-[1-Chloro-5-(3-chlorophenyl)-5,6-dihydropyrrolo-
[1,2-f]pteridin-6-yl]-N-methylmethanamine (5g). Yield
1
142 mg (79%). Pale-yellow solid. Mp 86–88°C. H NMR
spectrum, δ, ppm (J, Hz): 2.35 (3H, s, NCH3); 2.79 (1H,
dd, J = 11.7, J = 8.1) and 2.93 (1H, dd, J = 12.0, J = 4.2,
NCH2); 5.08 (1H, dd, J = 8.4, J = 3.9, NCH); 6.15–6.20
(1H, m, H Ar); 6.44 (1H, t, J = 3.3, H Ar); 7.28–7.32 (2H,
m, H Ar); 7.36–7.43 (2H, m, H Ar); 7.96–7.97 (1H, m, H Ar);
8.16 (1H, s, H Ar). 13C NMR spectrum, δ, ppm: 36.3; 54.5;
58.5; 106.6; 111.8; 117.0; 119.9; 124.7; 126.3; 126.8;
127.3; 130.3; 134.8; 142.8; 143.7; 152.0; 153.3. Found, m/z:
360.0779 [M+H]+. C17H16Cl2N5. Calculated, m/z: 360.0777.
1-(1-Chloro-5-phenyl-5,6-dihydropyrrolo[1,2-f]pteridin-
6-yl)-N-methylmethanamine (5h). Yield 129 mg (79%).
4-{1-Chloro-6-[(methylamino)methyl]pyrrolo[1,2-f]-
pteridin-5(6H)-yl}benzonitrile (5c). Yield 118 mg (67%).
1
Pale-yellow solid. Mp 154–155°C. H NMR spectrum,
δ, ppm (J, Hz): 2.37 (3H, s, NCH3); 2.80 (1H, dd, J = 12.3,
J = 7.8) and 2.94 (1H, dd, J = 12.0, J = 5.1, NCH2); 5.17
(1H, dd, J = 7.8, J = 5.1, NCH); 6.18 (1H, dd, J = 3.6,
J = 1.2, H Ar); 6.44 (1H, t, J = 3.3, H Ar); 7.56 (2H, d,
J = 9.0, H Ar); 7.71 (2H, d, J = 9.0, H Ar); 7.94 (1H, dd,
J = 3.3, J = 1.5, H Ar); 8.24 (1H, s, H Ar). 13C NMR
spectrum, δ, ppm: 36.3; 54.5; 57.9; 106.7; 109.0; 111.9;
118.1; 118.4; 119.8; 125.0; 126.5; 133.1; 144.7; 145.9;
151.8; 152.6. Found, m/z: 351.1127 [M+H]+. C18H16ClN6.
Calculated, m/z: 351.1119.
1
Pale-yellow solid. Mp 130–132°C. H NMR spectrum,
δ, ppm (J, Hz): 2.34 (3H, s, NCH3); 2.81 (1H, dd, J = 11.7,
J = 8.1) and 2.94 (1H, dd, J = 11.7, J = 4.2, NCH2); 5.08
(1H, dd, J = 7.8, J = 4.2, NCH); 6.17 (1H, dd, J = 3.3,
J = 1.2, H Ar); 6.44 (1H, t, J = 3.3, H Ar); 7.32–7.37 (3H,
m, H Ar); 7.44–7.51 (2H, m, H Ar); 7.98 (1H, dd, J = 3.0,
J = 1.5, H Ar); 8.13 (1H, s, H Ar). 13C NMR spectrum,
δ, ppm: 36.4; 54.6; 58.8; 106.4; 111.7; 116.6; 119.9; 126.5;
126.9; 127.4; 129.5; 141.7; 143.3; 152.1; 153.7. Found, m/z:
326.1172 [M+H]+. C17H17ClN5. Calculated, m/z: 326.1167.
1-[1-Chloro-5-(p-tolyl)-5,6-dihydropyrrolo[1,2-f]pteridin-
6-yl]-N-methylmethanamine (5i). Yield 133 mg (78%).
Pale-yellow solid. Mp 122–124°C (122–124°C8a). 1H NMR
spectrum, δ, ppm (J, Hz): 2.35 (3H, s, NCH3); 2.39 (3H, s,
CH3C6H4); 2.78–3.01 (2H, m, NCH2); 5.06–5.13 (1H, m,
NCH); 6.19 (1H, d, , J = 3.0, H Ar); 6.43 (1H, t, J = 3.3,
H Ar); 7.22–7.30 (4H, m, H Ar); 7.98 (1H, dd, J = 3.0,
J = 1.5, H Ar); 8.11 (1H, s, H Ar).
1-[1-Chloro-5-(4-fluorophenyl)-5,6-dihydropyrrolo-
[1,2-f]pteridin-6-yl]-N-methylmethanamine (5d). Yield
134 mg (78%). Pale-yellow oil. 1H NMR spectrum, δ, ppm
(J, Hz): 2.33 (3H, s, NCH3); 2.79 (1H, dd, J = 12.0, J = 7.8)
and 2.99 (1H, dd, J = 12.0, J = 4.2, NCH2); 5.11 (1H, dd,
J = 8.4, J = 4.2, NCH); 6.23 (1H, d, J = 2.4, H Ar); 6.42
(1H, t, J = 3.3, H Ar); 7.11–7.17 (2H, m, H Ar); 7.32–7.36
(2H, m, H Ar); 7.97 (1H, dd, J = 3.0, J = 1.5, H Ar); 8.10
(1H, s, H Ar). 13C NMR spectrum, δ, ppm: 36.4; 54.7; 59.1;
106.5; 111.9; 116.4; 116.7; 120.1; 126.5; 129.3; 129.4;
137.7; 143.4; 152.1; 153.9; 159.9; 163.2. Found, m/z: 344.1078
[M+H]+. C17H16ClFN5. Calculated, m/z: 344.1073.
1-[1-Chloro-5-(m-tolyl)-5,6-dihydropyrrolo[1,2-f]-
pteridin-6-yl]-N-methylmethanamine (5j). Yield 136 mg
(80%). Pale-yellow solid. Mp 56–58°C. 1H NMR spectrum,
δ, ppm (J, Hz): 2.35 (3H, s, NCH3); 2.39 (3H, s, CH3C6H4);
2.81 (1H, dd, J = 11.7, J = 8.1) and 2.96 (1H, dd, J = 11.7,
J = 3.9, NCH2); 5.08 (1H, dd, J = 7.8, J = 3.9, NCH); 6.15–
6.21 (1H, m, H Ar); 6.44 (1H, t, J = 3.3, H Ar); 7.13–7.19
(3H, m, H Ar); 7.32–7.38 (1H, m, H Ar); 7.97 (1H, dd,
J = 3.0, J = 1.5, H Ar); 8.13 (1H, s, H Ar). 13C NMR
spectrum (DMSO-d6), δ, ppm: 20.9; 36.2; 54.8; 58.2;
105.8; 111.7; 116.2; 118.8; 124.1; 127.4; 127.5; 127.8;
128.9; 138.7; 141.7; 141.8; 151.6; 153.7. Found, m/z:
340.1331 [M+H]+. C18H19ClN5. Calculated, m/z: 340.1323.
1-[1-Chloro-5-(4-methoxyphenyl)-5,6-dihydropyrrolo-
[1,2-f]pteridin-6-yl]-N-methylmethanamine (5k). Yield
94 mg (53%). Pale-yellow solid. Mp 104–106°C. 1H NMR
spectrum, δ, ppm (J, Hz): 2.33 (3H, s, NCH3); 2.81 (1H,
dd, J = 11.7, J = 8.1) and 2.95 (1H, dd, J = 11.7, J = 4.2,
NCH2); 3.84 (3H, s, OCH3); 5.04 (1H, dd, J = 7.8, J = 4.2,
1-[1-Chloro-5-(3,4-dichlorophenyl)-5,6-dihydropyrrolo-
[1,2-f]pteridin-6-yl]-N-methylmethanamine (5e). Yield
167 mg (85%). Pale-yellow solid. Mp 102–104°C.
1H NMR spectrum, δ, ppm (J, Hz): 2.34 (3H, s, NCH3);
2.78 (1H, dd, J = 12.0, J = 7.5) and 2.91 (1H, dd, J = 12.0,
J = 4.5, NCH2); 5.06 (1H, dd, J = 7.5, J = 4.5, NCH); 6.17
(1H, dd, J = 3.3, J = 1.2, H Ar); 6.44 (1H, t, J = 3.3, H Ar);
7.25–7.30 (1H, m, H Ar); 7.52 (1H, d, J = 8.7, H Ar); 7.55
(1H, d, J = 2.4, H Ar); 7.96 (1H, dd, J = 3.0, J = 1.5, H Ar);
8.17 (1H, s, H Ar). 13C NMR spectrum, δ, ppm: 36.3; 54.6;
58.6; 106.6; 110.3; 111.9; 117.1; 119.9; 126.0; 126.2;
128.5; 130.9; 133.1; 141.0; 143.8; 151.9; 153.1. Found, m/z:
394.0391 [M+H]+. C17H15Cl3N5. Calculated, m/z: 394.0388.
1-[5-(4-Bromophenyl)-1-chloro-5,6-dihydropyrrolo-
[1,2-f]pteridin-6-yl]-N-methylmethanamine (5f). Yield
1
178 mg (88%). Pale-yellow solid. Mp 68–70°C. H NMR
spectrum, δ, ppm (J, Hz): 2.34 (3H, s, NCH3); 2.79 (1H,
dd, J = 11.7, J = 7.8) and 2.93 (1H, dd, J = 11.7, J = 4.2,
834

Chemistry of Heterocyclic Compounds 2016, 52(10), 831–835
NCH); 6.18–6.20 (1H, m, H Ar); 6.44 (1H, t, J = 3.3,
This work was supported by a grant from the Sci-Tech
Development Project of Jilin Province in China
(No. 20160520039JH) and a grant from the Norman
Bethune Program of Jilin University (No. 2015330).
Additional support was provided by Changchun Discovery
Sciences, Ltd.
H Ar); 6.99 (2H, d, J = 9.0, H Ar); 7.28 (2H, d, J = 8.7,
H Ar); 7.98 (1H, dd, J = 3.0, J = 1.2, H Ar); 8.10 (1H, s,
H Ar). 13C NMR spectrum, δ, ppm: 36.3; 54.6; 55.6; 59.1;
106.4; 111.8; 115.0; 116.4; 120.1; 126.5; 128.9; 134.4;
143.1; 152.2; 154.2; 158.9. Found, m/z: 356.1282 [M+H]+.
C18H19ClN5O. Calculated, m/z: 356.1273.
References
1-[1-Chloro-5-(2-methoxyphenyl)-5,6-dihydropyrrolo-
[1,2-f]pteridin-6-yl]-N-methylmethanamine (5l). Yield
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1
117 mg (66%). Pale-yellow solid. Mp 99–100°C. H NMR
spectrum, δ, ppm (J, Hz): 2.30 (3H, s, NCH3); 2.79 (1H,
dd, J = 12.0, J = 7.2) and 2.86 (1H, dd, J = 12.0, J = 3.9,
NCH2); 3.79 (3H, s, OCH3); 4.99–5.04 (1H, m, NCH); 6.16
(1H, dd, J = 3.3, J = 1.2, H Ar); 6.43 (1H, t, J = 3.3, H Ar);
7.03–7.10 (2H, m, H Ar); 7.29–7.43 (2H, m, H Ar); 8.01
(1H, dd, J = 3.0, J = 1.5, H Ar); 8.05 (1H, s, H Ar).
13C NMR spectrum, δ, ppm: 36.2; 54.5; 55.6; 57.0; 106.0;
111.5; 112.4; 115.7; 119.7; 120.9; 124.8; 126.5; 128.7;
129.5; 130.9; 142.3; 151.8; 153.7. Found, m/z: 356.1280
[M+H]+. C18H19ClN5O. Calculated, m/z: 356.1273.
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The Supplementary information file containing NMR
spectra of all new compounds is available at http://
link.springer.com/journal/10593.
835