Intramolecular Cycloaddition of Azomethine Ylides Activated by Aromatic Rings: Scope and Limitations

Article abstract of DOI:10.1007/s10593-016-1912-9

[Figure not available: see fulltext.] Simple aromatic substituents in the substrate molecule, including pyrimidine, pyridine, and benzene rings, directly facilitated the intramolecular cycloaddition of azomethine ylide to alkene. All of these aromatic substituents aided the formation of azomethine ylides, which then underwent highly diastereospecific sequential cycloaddition. It was shown that both the presence of an electron-deficient aromatic ring and a substituent at ortho position of the aromatic ring relative to the aminomethyl group enhanced the reactivity of azomethine ylides towards cycloaddition.

Full text of DOI:10.1007/s10593-016-1912-9

DOI 10.1007/s10593-016-1912-9
Chemistry of Heterocyclic Compounds 2016, 52(7), 484–492
Intramolecular cycloaddition of azomethine ylides activated
by aromatic rings: scope and limitations
Hongxiang Xie1, Bowen Gong1, Xinran Zhong1, Hongming Cui1, 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(7), 484–492
Submitted May 19, 2016
Accepted July 4, 2016
Simple aromatic substituents in the substrate molecule, including pyrimidine, pyridine, and benzene rings, directly facilitated the
intramolecular cycloaddition of azomethine ylide to alkene. All of these aromatic substituents aided the formation of azomethine ylides,
which then underwent highly diastereospecific sequential cycloaddition. It was shown that both the presence of an electron-deficient
aromatic ring and a substituent at ortho position of the aromatic ring relative to the aminomethyl group enhanced the reactivity of azo-
methine ylides towards cycloaddition.
Keywords: azomethine ylide, aromatic ring, 1,3-dipolar cycloaddition, facilitating group, intramolecular reactions, stereocontrol.
The 1,3-dipolar cycloaddition, defined as a reaction of a
dipolarophile with a 1,3-dipolar compound, is a classic tool
in organic chemistry1 and offers a reliable synthetic access
to five-membered heterocyclic rings.2 In particular, the
reaction of azomethine ylides with alkenes is a powerful
method for the preparation of substituted pyrrolidines,3
which are important building blocks in the synthesis of
many natural products and pharmaceuticals.4 Intramole-
cular azomethine ylide reactions can provide direct access
to polycyclic scaffolds of considerable complexity with
high to complete stereocontrol.5 Despite the abundance of
literature related to cycloadditions of azomethine ylides
stabilized by electron-withdrawing groups,3 only a few
cases of azomethine ylide reactions have been reported
involving amines fused with an aromatic ring that may
serve as a direct facilitating group.6
pyrimidine ring (Scheme 1).7 The stereochemical outcome
of this reaction is rationalized by an S-shaped azomethine
ylide intermediate. To the best of our knowledge, this is the
first reported intramolecular cycloaddition of an azomethine
ylide activated by a simple aromatic ring.6 Although the
preliminary scope of the intramolecular cycloaddition of
azomethine ylide activated by pyrimidine ring was studied
in our initial report, the effect of aromatic ring remained to
be investigated. Thus, a further investigation of the acti-
vating effect of substituents including pyrimidine, pyridine,
and benzene rings is warranted. Herein, the results of the
investigation are presented.
Azomethine ylide cycloaddition in a pyrimidine
system. To expand the scope of this new synthetic method,
a series of substituted pyrimidines 7b–g were prepared as
depicted in Scheme 2. The treatment of starting material 1a
with NaBH3CN followed by hydrogenation of the hydroxy-
methyl derivative 2a on Pd/C catalyst yielded compound 3a.
Recently, we reported a highly stereoselective intra-
molecular cycloaddition of azomethine ylide activated by
Scheme 1
0009-3122/16/52(7)-0484©2016 Springer Science+Business Media New York
484

Chemistry of Heterocyclic Compounds 2016, 52(7), 484–492]
Scheme 2
Cl
Cl
CHO
Cl
NaBH3CN, AcOH
H2, Pd/C, Et3N
N
OH
N
OH
N
EtOH
rt
EtOH
rt, 3 h
N
Cl
N
Cl
N
1a
2a (68%)
3a (75%)
Et3N, CHCl3
rt
MeHN
CH2
R1
Cl
N
Cl
N
CHO
MeHN
CHO
Cl
N
N
OH
NaBH3CN, AcOH
CH2
N
CH2
CH2
R2
N
EtOH
rt
R2
N
N
R2
Et3N, CHCl3
0–5°C, 30 min
Me
Me
5b R2 = Me (90%)
c R2 = Ph (89%)
4a R1 = H, R2 = H (89%)
b R1 = Cl, R2 = Me (89%)
c R1 = Cl, R2 = Ph (86%)
1b R2 = Me
c R2 = Ph
2) MeNH2, Et3N
EtOH, CH2Cl2, rt
1) SOCl2, CH2Cl2
i: NaOMe, THF, rt
rt
ii: PhSH, Et3N, THF, rt
iii: PhBr, Pd(PPh3)4,
Bis(pinacolato)diboron
KOAc, dioxane,
R1
N
R1
Cl
MeNH2, NaBH4
AcOH
CHO
CHO
N
N
NHMe
N
CH2
CH2
CH2
R2
N
N
EtOH
rt
N
N
N
Me
Me
Me
i: 6a R1 = MeO (72%)
ii: 6b R1 = PhS (95%)
iii: 6c R1 = Ph (74%)
7b R1 = H, R2 = H (50%)
c R1 = Cl, R2 = Me (72%)
d R1 = Cl, R2 = Ph (75%)
e R1 = MeO, R2 = H (74%)
f R1 = PhS, R2 = H (69%)
g R1 = Ph, R2 = H (72%)
5d
Condensation of compound 3a with N-methylprop-2-en-
1-amine formed the intermediate 4a. Intermediates 4b and
4c could be obtained from the starting materials 1b and 1c,
respectively. The nucleophilic substitution reactions of aryl
chlorides 1b,c with N-methylprop-2-en-1-amine furnished
compounds 5b,c. Reduction of aldehydes 5b,c with
NaBH3CN gave intermediates 4b,c. The alcohols 4a–c
were converted to the respective secondary amines 7b–d in
a two-step process involving chlorination of intermediates
4a–c using SOCl2, followed by the addition of methanamine.
Compounds 7e–g could be obtained from the starting
material 5d. Coupling of compound 5d with a nucleophile
(NaOMe and PhSH) or PhBr gave intermediates 6a–c,
which after condensation with N-methylprop-2-en-1-amine
afforded the respective compounds 7e–g.
Scheme 3
Compounds 7b–g were studied in cyclization reactions
with benzaldehyde under our previously reported condi-
tions of refluxing in toluene with a Dean–Stark trap, in
order to investigate the effects of substituents at the
pyrimidine ring and to increase the diversity of products
(Scheme 3).
As shown in Scheme 3, the reactions of substituted
pyrimidines 7a–g with benzaldehyde produced the desired
products 8a–g in moderate to good yields. In the previous
work, we have shown that the substrate 7a (R1 = Cl, R2 = H)
reacted with benzaldehyde to give the product 8a in 75%
yield as a pair of enantiomers.7 However, with R1 = H and
R2 = H, only 40% yield of product 8b was obtained.
485

Chemistry of Heterocyclic Compounds 2016, 52(7), 484–492]
The results suggested that the ortho-Cl substituent of
Scheme 5
substrate 7a had a significant influence on the ease of intra-
molecular cycloaddition. The 2-methyl-substituted com-
pound 7c and 2-phenyl-substituted compound 7d gave a
lower yield of the final products 8c,d compared to the
substrate 7a. These results indicated that the reaction was
sensitive to electronic effects and an electron-rich aromatic
ring was unfavorable for this azomethine ylide cyclo-
addition. A further survey of the electronic effects revealed
that the steric influence seems to be an important factor for
enhancing the reactivity (compounds 7e–g vs compound 7b).
All of the products 8b–g were characterized as configured
with the phenyl group and the two bridgehead hydrogen
atoms on the same side of the newly formed pyrrolidine
1
ring, based on the comparison of their H NMR spectra
with those of compound 8a, which had been unambi-
guously characterized by X-ray structural analysis in our
previous report.7
Azomethine ylide cycloaddition in pyridine and benzene
systems. As expected, the precursors 11a–f were prepared
via a two- or three-step sequence as depicted in Scheme 4.
Condensation of compounds 9a–c with N-methylprop-2-en-
1-amine in the presence of K2CO3 as a base formed the
respective products 10a–c, while products 10e,f were
obtained analogously from compounds 9d,e. Compound
10d was obtained by reacting the benzaldehyde derivative
10c with PhSH. Reductive amination of aldehydes 10a–f
with methanamine gave the precursors 11a–f.
groups were employed (compounds 11f vs 11b vs 11e).
The presence of an ortho substituent in anilines 11c,d led
to higher yields of the final products 12c,d compared to the
reactions of analogous aniline 11b. These results further
validated the assumption that the presence of ortho
substituents relative to the aminomethyl group enhanced
the reactivity of azomethine ylides towards cycloaddition.
In conclusion, we have obtained new data about intra-
molecular cycloadditions of azomethine ylides activated by
aromatic rings, including pyrimidine, pyridine, and ben-
zene. The utility of this reaction sequence has been demon-
strated by the synthesis of tricyclic derivatives containing
fused piperidine and pyrrolidine rings. The reactions were
completely stereocontrolled and yielded products in mode-
rate to good yields. The reactivity of azomethine ylides in
cycloaddition reactions was enhanced by both the presence
of electron-deficient aromatic rings and the presence of
ortho substituent relative to the aminomethyl group.
Scheme 4
Experimental
1H and 13C NMR spectra were acquired on a Varian
Mercury (300 MHz) NMR spectrometer with TMS as
internal standard and CDCl3 as solvent unless otherwise
stated. HRMS analysis was performed on an Agilent 1290-
micrOTOF-Q II mass spectrometer (ESI). Melting points
were determined on an XT5 melting point apparatus and
are uncorrected. Acetonitrile and dichloromethane were
dried over CaH2 and distilled. Toluene was dried over Na
and distilled. All other commercial reagents were
purchased from Energy Chemical and Sigma-Aldrich, and
were used without additional purification.
Precursors 11a–f were studied in reaction with benz-
aldehyde under the conditions described above to further
investigate the electronic effects due to the aromatic ring
(the ortho substituent effect), and to increase the diversity
of products (Scheme 5).
As shown in Scheme 5, pyridin-3-ylmethanamine 11a
and several substituted anilines 11b–f reacted with benz-
aldehyde to produce the desired products 12a–f in
moderate yields. The reaction seemed very sensitive to the
electronic effects of aromatic ring since higher yields were
obtained when anilines 11 with electron-withdrawing
(4,6-Dichloropyrimidin-5-yl)methanol (2a).8 A stirred
solution of 4,6-dichloro-5-formylpyrimidine (1a) (5.00 g,
28.2 mmol) in EtOH (50 ml) was treated with NaBH3CN
(2.66 g, 42.3 mmol), followed by AcOH (5 ml). After
486

Chemistry of Heterocyclic Compounds 2016, 52(7), 484–492]
complete consumption of the starting material 1a, as indi-
ArCH3); 2.89 (3H, s, NCH3); 4.30 (2H, d, J = 5.7,
CH2CH=CH2); 5.19–5.28 (2H, m, CH2CH=CH2); 5.80–
5.90 (1H, m, CH2CH=CH2); 10.33 (1H, s, CHO). 13C NMR
spectrum, δ, ppm: 26.1; 40.0; 54.6; 107.7; 118.7; 132.2;
161.4; 164.7; 168.1; 187.2. Found, m/z: 226.0751 [M+H]+.
C10H13ClN3O. Calculated, m/z: 226.0742.
cated by TLC, saturated aqueous NaHCO3 (14 ml) was
added to quench the reaction. The volatiles were removed
in vacuo, and saturated aqueous NaHCO3 (200 ml) was
added. The mixture was extracted with EtOAc (2 × 200 ml),
the combined organic layers were dried over Na2SO4 and
concentrated in vacuo. Purification by flash chro-
matography (5:1 petroleum ether–EtOAc, v/v) afforded the
desired product 2a as a white solid. Yield 3.44 g (68%), mp
93–95°C (mp 88–90°C8). 1H NMR spectrum, δ, ppm: 2.18
(1H, br. s, OH); 4.96 (2H, s, CH2); 8.74 (1H, s, H Ar). 13C
NMR spectrum (DMSO-d6), δ, ppm: 57.7; 131.3; 157.1;
161.7.
4-[Allyl(methyl)amino]-6-chloro-2-phenylpyrimidine-
5-carbaldehyde (5c). Yield 7.22 g (89%), white solid, mp
1
81–82°C. H NMR spectrum, δ, ppm (J, Hz): 2.97 (3H, s,
NCH3); 4.40 (2H, d, J = 6.0, CH2CH=CH2); 5.24–5.31 (2H,
m, CH2CH=CH2); 5.88–5.99 (1H, m, CH2CH=CH2); 7.43–
7.52 (3H, m, H Ar); 8.38–8.42 (2H, m, H Ar); 10.39 (1H, s,
CHO). 13C NMR spectrum, δ, ppm: 40.1; 54.9; 108.3;
118.8; 128.6; 129.2; 132.0; 132.4; 135.9; 161.7; 163.3;
165.5; 187.2. Found, m/z: 288.0899 [M+H]+. C15H15ClN3O.
Calculated, m/z: 288.0898.
(4-Chloropyrimidin-5-yl)methanol (3a). Triethylamine
(3 ml) and 10% Pd/C (330 mg) were added to a stirred
solution of compound 2a (3.33 g, 18.6 mmol) in EtOH
(30 ml). The mixture was stirred for 3 h under a hydrogen
atmosphere provided by a balloon. The Pd/C catalyst was
then removed by filtration and the resulting clear solution
was concentrated in vacuo. Purification by flash chromato-
graphy (4:1 to 1:1 petroleum ether–EtOAc, v/v) afforded
the starting material 2a (1.43 g) and the desired product 3a
as a white solid. Yield 1.15 g (75%), mp 62–63°C.
1H NMR spectrum, δ, ppm: 2.76 (1H, s, OH); 4.85 (2H, s,
CH2); 8.85 (1H, s, H Ar); 8.94 (1H, s, H Ar). 13C NMR
spectrum (DMSO-d6), δ, ppm: 57.9; 133.7; 156.8; 157.2;
158.2. Found, m/z: 145.0167 [M+H]+. C5H6ClN2O. Calcu-
lated, m/z: 145.0163.
Synthesis of compounds 4b,c (General method). A stirred
solution of compound 5b,c (2 mmol) in EtOH (5 ml) was
treated with NaBH3CN (189 mg, 3.0 mmol), followed by
AcOH (0.5 ml). After complete consumption of the starting
material 5b or 5c, as indicated by TLC, saturated aqueous
NaHCO3 (1.0 ml) was added to quench the reaction. The
volatiles were removed in vacuo, and saturated aqueous
NaHCO3 (20 ml) was added. The mixture was extracted
with EtOAc (2×20 ml), the combined organic layers were
dried over Na2SO4 and concentrated in vacuo. Purification
by flash column chromatography (5:1 to 3:1 petroleum
ether–EtOAc, v/v) afforded the desired product 4b or 4c.
{4-[Allyl(methyl)amino]-6-chloro-2-methylpyrimidin-
5-yl}methanol (4b). Yield 405 mg (89%), white solid, mp
75–76°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.08 (1H, br. s,
OH); 2.48 (3H, s, ArCH3); 3.16 (3H, s, NCH3); 4.21 (2H, d,
J = 5.1, CH2CH=CH2); 4.64 (2H, s, CH2OH); 5.24–5.30
(2H, m, CH2CH=CH2); 5.88–5.98 (1H, m, CH2CH=CH2).
13C NMR spectrum, δ, ppm: 25.5; 38.1; 55.3; 58.2; 110.9;
117.1; 133.8; 161.9; 165.0; 165.6. Found, m/z: 228.0902
[M+H]+. C10H15ClN3O. Calculated, m/z: 228.0898.
{4-[Allyl(methyl)amino]-6-chloro-2-phenylpyrimidin-
5-yl}methanol (4c). Yield 498 mg (86%), white solid, mp
75–76°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.95 (1H, br. s,
OH); 3.27 (3H, s, NCH3); 4.29 (2H, d, J = 5.1,
CH2CH=CH2); 4.70 (2H, s, CH2OH); 5.27–5.33 (2H, m,
CH2CH=CH2); 5.95–6.04 (1H, m, CH2CH=CH2); 7.41–
7.46 (3H, m, H Ar); 8.35–8.39 (2H, m, H Ar). 13C NMR
spectrum, δ, ppm: 38.2; 55.5; 58.6; 111.7; 117.3; 128.4; 128.5;
131.0; 133.8; 136.8; 161.8; 162.8; 165.1. Found, m/z: 290.1065
[M+H]+. C15H17ClN3O. Calculated, m/z: 290.1055.
{4-[Allyl(methyl)amino]pyrimidin-5-yl}methanol (4a).
A stirred solution of compound 3a (1.10 g, 7.6 mmol) in
CHCl3 (10 ml) was treated with N-methylprop-2-en-
1-amine (1.08 g, 15.2 mmol), followed by Et3N (1.6 ml,
11.4 mmol). The resulting solution was stirred for 12 h at
room temperature, then washed with saturated aqueous
NaHCO3 (10 ml). The aqueous phase was extracted with
CH2Cl2 (2×15 ml). The combined organic layer was dried
over MgSO4 and concentrated in vacuo. Purification by
flash chromatography (2:1 to 1:5 petroleum ether–EtOAc,
v/v) afforded the desired product 4a. Yield 1.21 g (89%),
pale-yellow oil. 1H NMR spectrum, δ, ppm: 2.94 (1H, br. s,
OH); 3.22 (3H, s, CH3); 4.27–4.30 (2H, m, CH2CH=CH2);
4.56 (2H, s, CH2OH); 5.13–5.24 (2H, m, CH2CH=CH2);
5.86–5.96 (1H, m, CH2CH=CH2); 8.01 (1H, s, H Ar); 8.50
(1H, s, H Ar). 13C NMR spectrum, δ, ppm: 37.6; 54.1; 61.0;
116.5; 117.3; 133.6; 156.5; 156.9; 162.0. Found, m/z:
180.1139 [M+H]+. C9H14N3O. Calculated, m/z: 180.1131.
Synthesis of compounds 5b,c (General method).
A solution of N-methylprop-2-en-1-amine (2.00 g, 28.2 mmol)
and Et3N (4.07 ml, 29.4 mmol) in CHCl3 (20 ml) was
added dropwise to a stirred solution of compound 1b or 1c
(28.2 mmol) in CHCl3 (40 ml) at 0°C. The resulting
solution was stirred for 0.5 h at 0–5°C, then washed with
H2O (30 ml) and saturated aqueous NaHCO3 (30 ml), dried
over anhydrous MgSO4, and concentrated in vacuo. Purifi-
cation by flash chromatography (20:1 to 5:1 petroleum
ether–EtOAc, v/v) afforded the desired product 5b,c.
4-[Allyl(methyl)amino]-6-chloro-2-methylpyrimidine-
5-carbaldehyde (5b). Yield 5.73 g (90%), white solid, mp
Synthesis of compounds 7b–d (General method).
A stirred solution of compound 4b–d (1.64 mmol) in
CH2Cl2 (10 ml) was treated with SOCl2 (0.48 ml, 6.6 mmol)
at room temperature. After complete consumption of the
starting material, as indicated by TLC, the volatiles were
removed in vacuo. The obtained crude chlorinated product
was dissolved in CH2Cl2 (5 ml), and this solution was
added dropwise at room temperature to a 30% solution of
methylamine in ethanol (3 ml) diluted with CH2Cl2 (5 ml).
After complete consumption of the chlorinated product, as
indicated by TLC, the reaction mixture was washed with
saturated aqueous NaHCO3 (10 ml). The aqueous layer was
1
55–56°C. H NMR spectrum, δ, ppm (J, Hz): 2.52 (3H, s,
487

Chemistry of Heterocyclic Compounds 2016, 52(7), 484–492]
extracted with CH2Cl2 (10 ml). The combined organic
temperature. The volatiles were removed in vacuo and
EtOAc (20 ml) was added. The organic layers were washed
with saturated aqueous NaHCO3 (10 ml), dried over
anhydrous MgSO4, and concentrated in vacuo. Purification
by flash chromatography (10:1 petroleum ether–EtOAc, v/v)
afforded the desired product 6b. Yield 1.08 g (95%), pale-
layers were dried over anhydrous MgSO4 and concentrated
in vacuo. Purification by flash column chromatography
(from 3:1 v/v petroleum ether–EtOAc to 100% EtOAc)
afforded the desired products 7b–d.
N-Allyl-N-methyl-5-[(methylamino)methyl]pyrimidin-
4-amine (7b). Yield 158 mg (50%), pale-yellow oil.
1H NMR spectrum, δ, ppm (J, Hz): 2.08 (1H, br. s, NH);
2.46 (3H, s, NHCH3); 3.17 (3H, s, NCH3); 3.62 (2H, s,
NHCH2); 4.29–4.32 (2H, m, CH2CH=CH2); 5.15–5.24 (2H,
m, CH2CH=CH2); 5.85–5.96 (1H, m, CH2CH=CH2); 8.11
(1H, s, H Ar); 8.54 (1H, s, H Ar). 13C NMR spectrum,
δ, ppm: 36.0; 37.5; 52.2; 54.3; 112.2; 116.2; 134.2; 156.8;
157.7; 162.6. Found, m/z: 193.1451 [M+H]+. C10H17N4.
Calculated, m/z: 193.1448.
1
yellow solid, mp 57–58°C. H NMR spectrum, δ, ppm
(J, Hz): 3.10 (3H, s, NCH3); 4.23 (2H, d, J = 5.1,
CH2CH=CH2); 5.24–5.32 (2H, m, CH2CH=CH2); 5.85–
5.94 (1H, m, CH2CH=CH2); 7.43–7.46 (3H, m, H Ar); 7.52–
7.57 (2H, m, H Ar); 8.23 (1H, s, H Ar); 10.23 (1H, s, CHO).
4-[Allyl(methyl)amino]-6-phenylpyrimidine-5-carb-
aldehyde (6c). Pd(PPh3)4 (316 mg, 0.27 mmol), KOAc
(1.60 g, 16.3 mmol), and bromobenzene (0.86 ml, 8.2 mmol)
were added under nitrogen atmosphere to a stirred solution
of bis(pinacolato)diboron (4.06 g, 16 mmol) in 1,4-dioxane
(100 ml). The resulting mixture was stirred for 10 h at
reflux. After cooling to room temperature, compound 5d
(1.50 g, 7.1 mmol) and saturated aqueous Na2CO3 solution
(16 ml) were added. The resulting mixture was stirred for
12 h at reflux. The volatiles were removed in vacuo, and
saturated aqueous NaHCO3 solution (40 ml) was added. The
aqueous layer was extracted with EtOAc (2×20 ml). The
combined organic layers were dried over anhydrous
Na2SO4 and concentrated in vacuo. Purification by flash
chromatography (5:1 petroleum ether–EtOAc, v/v)
afforded the desired product 6c. Yield 1.33 g (74%), pale-
N-Allyl-6-chloro-N,2-dimethyl-5-[(methylamino)methyl]-
pyrimidin-4-amine (7c). Yield 284 mg (72%), pale-yellow
1
oil. H NMR spectrum, δ, ppm (J, Hz): 1.64 (1H, br. s,
NH); 2.45 (3H, s, ArCH3); 2.46 (3H, s, NHCH3); 3.12 (3H,
s, NCH3); 3.55 (2H, s, NHCH2); 4.27 (2H, d, J = 4.8,
CH2CH=CH2); 5.21–5.28 (2H, m, CH2CH=CH2); 5.87–
5.97 (1H, m, CH2CH=CH2). 13C NMR spectrum, δ, ppm:
25.6; 36.7; 37.7; 49.2; 55.4; 111.1; 116.7; 134.4; 161.4;
165.0; 165.6. Found, m/z: 241.1224 [M+H]+. C11H18ClN4.
Calculated, m/z: 241.1215.
N-Allyl-6-chloro-N-methyl-5-[(methylamino)methyl]-
2-phenylpyrimidin-4-amine (7d). Yield 372 mg (75%),
pale-yellow solid, mp 89–90°C. 1H NMR spectrum, δ, ppm
(J, Hz): 1.76 (1H, br. s, NH); 2.49 (3H, s, NHCH3); 3.24
(3H, s, NCH3); 3.65 (2H, s, NHCH2); 4.36 (2H, d, J = 4.5,
CH2CH=CH2); 5.25–5.34 (2H, m, CH2CH=CH2); 5.95–
6.05 (1H, m, CH2CH=CH2); 7.41–7.46 (3H, m, H Ar); 8.34–
8.38 (2H, m, H Ar). 13C NMR spectrum, δ, ppm: 36.8;
37.8; 49.5; 55.5; 112.2; 116.8; 128.3; 128.4; 130.7; 134.5;
137.1; 161.3; 162.3; 165.6. Found, m/z: 303.1384 [M+H]+.
C16H20ClN4. Calculated, m/z: 303.1371.
4-[Allyl(methyl)amino]-6-methoxypyrimidine-5-carb-
aldehyde (6a). Sodium hydride (14.2 mmol, 60% disper-
sion in mineral oil) was added to a solution of MeOH (0.57 ml,
14.2 mmol) in THF (10 ml), followed by compound 5d
(1.50 g, 7.1 mmol). The resulting solution was stirred for
0.5 h at room temperature. The volatiles were removed in
vacuo and EtOAc (40 ml) was added. The organic layers
were washed with saturated aqueous NaHCO3 (20 ml) and
brine (15 ml), dried over anhydrous Na2SO4, and concen-
trated in vacuo. Purification by flash chromatography
(CH2Cl2) afforded the desired product 6a. Yield 1.065 g
(72%), pale-yellow oil. 1H NMR spectrum, δ, ppm (J, Hz):
2.92 (3H, s, NCH3); 4.04 (3H, s, OCH3); 4.25 (2H, d,
J = 5.1, CH2CH=CH2); 5.16–5.25 (2H, m, CH2CH=CH2);
5.81–5.95 (1H, m, CH2CH=CH2); 8.27 (1H, s, H Ar); 10.24
(1H, s, CHO). 13C NMR spectrum, δ, ppm: 39.9; 54.5; 54.7;
99.5; 118.1; 132.9; 137.0; 158.4; 172.8; 186.6. Found, m/z:
208.1089 [M+H]+. C10H14N3O2. Calculated, m/z: 208.1081.
4-[Allyl(methyl)amino]-6-(phenylsulfanyl)pyrimidine-
5-carbaldehyde (6b).9 A solution of compound 5d
(846 mg, 4.0 mmol) in THF (20 ml) was treated with PhSH
(0.62 ml, 6.0 mmol) followed by Et3N (0.83 ml, 6.0 mmol).
The resulting solution was stirred for 2 h at room
1
yellow solid, mp 36–37°C. H NMR spectrum, δ, ppm
(J, Hz): 3.07 (3H, s, NCH3); 4.38 (2H, d, J = 5.7,
CH2CH=CH2); 5.24–5.30 (2H, m, CH2CH=CH2); 5.89–5.98
(1H, m, CH2CH=CH2); 7.48–7.56 (3H, m, H Ar); 7.71–7.75
(2H, m, H Ar); 8.63 (1H, s, H Ar); 9.78 (1H, s, CHO). 13C
NMR spectrum, δ, ppm: 39.9; 54.5; 111.3; 118.5; 128.7;
130.8; 132.5; 134.8; 136.9; 158.1; 161.2; 173.0; 188.5. Found,
m/z: 254.1296 [M+H]+. C15H16N3O. Calculated, m/z: 254.1288.
Synthesis of compounds 7e–g (General method). A 30%
solution of methanamine in ethanol (4 ml) was added to a
stirred solution of compound 6a–c (2.5 mmol) in EtOH
(8 ml), followed by AcOH (1 drop). The resulting solution
was stirred for 2.5 h at room temperature. NaBH4 (190 mg,
5.0 mmol) was then added, and the mixture was stirred for
0.5 h at room temperature. Saturated aqueous NaHCO3
solution (1.0 ml) was added to quench the reaction. The
volatiles were removed in vacuo, and saturated aqueous
NaHCO3 solution (20 ml) was added again. The mixture
was extracted with EtOAc (2×20 ml). The combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. Purification by flash column chromatography
(EtOAc) afforded the desired product 7e–g.
N-Allyl-6-methoxy-N-methyl-5-[(methylamino)methyl]-
pyrimidin-4-amine (7e). Yield 411 mg (74%), pale-yellow
1
oil. H NMR spectrum, δ, ppm (J, Hz): 2.16 (1H, br. s,
NH); 2.45 (3H, s, NHCH3); 3.05 (3H, s, NCH3); 3.52 (2H,
s, NHCH2); 3.94 (3H, s, OCH3); 4.15 (2H, d, J = 3.3,
CH2CH=CH2); 5.20–5.29 (2H, m, CH2CH=CH2); 5.87–
5.99 (1H, m, CH2CH=CH2); 8.28 (1H, s, H Ar). 13C NMR
spectrum, δ, ppm: 36.8; 37.7; 46.4; 53.9; 55.9; 101.4;
116.5; 134.9; 155.0; 165.7; 169.3. Found, m/z: 223.1561
[M+H]+. C11H19N4O. Calculated, m/z: 223.1553.
488

Chemistry of Heterocyclic Compounds 2016, 52(7), 484–492]
N-Allyl-N-methyl-5-[(methylamino)methyl]-6-(phenyl-
at reflux. After cooling to room temperature, the reaction
mixture was extracted with Et2O (2×15 ml). The combined
Et2O layers were washed with 10% aqueous HCl (60 ml),
and the aqueous layer was washed with Et2O (15 ml). The
aqueous layer was made basic with 10% aqueous NaOH to
pH 10 and extracted with EtOAc (3×20 ml). The combined
EtOAc layers were washed with brine (30 ml), dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification
by flash column chromatography (50:1 petroleum ether–
EtOAc, v/v) afforded the desired product 10b. Yield 14.9 g
(90%), pale-yellow oil. 1H NMR spectrum, δ, ppm (J, Hz):
2.85 (3H, s, NCH3); 3.73 (2H, d, J = 5.7, CH2CH=CH2);
5.20–5.25 (2H, m, CH2CH=CH2); 5.84–5.90 (1H, m,
CH2CH=CH2); 6.99–7.10 (2H, m, H Ar); 7.42–7.49 (1H, m,
H Ar); 7.77 (1H, dd, J = 7.8, J = 1.8, H Ar); 10.26 (1H, s,
CHO).
2-[Allyl(methyl)amino]-6-chlorobenzaldehyde (10c).
A stirred solution of 2,6-dichlorobenzaldehyde (9c) (3.5 g,
20 mmol) in DMF (20 ml) was treated with N-methylprop-
2-en-1-amine (7 g, 98 mmol), followed by K2CO3 (4 g,
29 mmol). The resulting solution was stirred for 2 h at 120°C.
After cooling to room temperature, water (120 ml) was
added, and the mixture was extracted with EtOAc (3×30 ml).
The combined organic layers were washed with water (30 ml)
and concentrated in vacuo. The crude residue was
dissolved in 10% aqueous HCl (20 ml) and washed with
Et2O (2×20 ml). The aqueous layer was made basic with
10% aqueous NaOH to pH 10 and extracted with EtOAc
(2×30 ml). The combined EtOAc layers were dried over
MgSO4 and concentrated in vacuo. Purification by flash
column chromatography (30:1 petroleum ether–EtOAc, v/v)
afforded the desired product 10c. Yield 684 mg (16%), pale-
yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 2.83 (3H, s,
CH3); 3.73 (2H, d, J = 5.7, CH2CH=CH2); 5.19–5.30 (2H,
m, CH2CH=CH2); 5.85–5.95 (1H, m, CH2CH=CH2); 6.94–
6.98 (2H, m, H Ar); 7.30 (1H, t, J = 8.1, H Ar); 10.33 (1H,
s, CHO). 13C NMR spectrum, δ, ppm: 41.2; 60.5; 117.3;
118.2; 122.1; 123.6; 133.6; 133.7; 137.1; 155.4; 189.4.
Found, m/z: 210.0685 [M+H]+. C11H13ClNO. Calculated,
m/z: 210.0680.
2-[Allyl(methyl)amino]-6-(phenylsulfanyl)benzaldehyde
(10d). A solution of PhSH (0.182 ml, 1.8 mmol) in THF
(10 ml) was treated with NaH (1.8 mmol, 60% dispersion
in mineral oil), followed by the addition of compound 10c
(315 mg, 1.5 mmol). The resulting solution was stirred for
6 days at room temperature. The volatiles were removed
in vacuo, and EtOAc (20 ml) was added. The organic
layers were washed with saturated aqueous NaHCO3
solution (10 ml) and brine (10 ml), dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromato-
graphy (CH2Cl2) afforded the desired product 10d. Yield
318 mg (75%), pale-yellow oil. 1H NMR spectrum, δ, ppm
(J, Hz): 2.84 (3H, s, CH3); 3.71 (2H, d, J = 5.7, CH2CH=CH2);
5.21–5.30 (2H, m, CH2CH=CH2); 5.82–5.96 (1H, m,
CH2CH=CH2); 6.41 (1H, d, J = 8.1, H Ar); 6.84 (1H, d,
J = 8.1, H Ar); 7.17 (1H, t, J = 8.1, H Ar); 7.40–7.45 (3H,
m, H Ar); 7.53–7.57 (2H, m, H Ar); 10.40 (1H, s, CHO).
13C NMR spectrum, δ, ppm: 41.5; 62.1; 115.3; 118.2;
120.2; 124.5; 129.1; 129.7; 132.4; 133.2; 134.0; 135.5; 144.6;
sulfanyl)pyrimidin-4-amine (7f). Yield 518 mg (69%),
1
pale-yellow oil. H NMR spectrum, δ, ppm (J, Hz): 1.57
(1H, br. s, NH); 2.52 (3H, s, NHCH3); 3.10 (3H, s, NCH3);
3.68 (2H, s, NHCH2); 4.26 (2H, d, J = 5.1, CH2CH=CH2);
5.24–5.31 (2H, m, CH2CH=CH2); 5.91–6.00 (1H, m,
CH2CH=CH2); 7.40–7.43 (3H, m, H Ar); 7.50–7.54 (2H,
m, H Ar); 8.28 (1H, s, H Ar). 13C NMR spectrum, δ, ppm:
36.7; 37.5; 49.3; 55.5; 113.8; 116.4; 128.8; 129.0; 129.6;
134.5; 134.9; 155.3; 163.9; 168.1. Found, m/z: 301.1487
[M+H]+. C16H21N4S. Calculated, m/z: 301.1481.
N-Allyl-N-methyl-5-[(methylamino)methyl]-6-phenyl-
pyrimidin-4-amine (7g). Yield 483 mg (72%), pale-
1
yellow oil. H NMR spectrum, δ, ppm (J, Hz): 1.48 (1H,
br. s, NH); 2.13 (3H, s, NHCH3); 3.14 (3H, s, NCH3); 3.57
(2H, s, NHCH2); 4.27 (2H, d, J = 5.1, CH2CH=CH2); 5.23–
5.31 (2H, m, CH2CH=CH2); 5.89–6.02 (1H, m,
CH2CH=CH2); 7.41–7.55 (5H, m, H Ar); 8.60 (1H, s, H Ar).
13C NMR spectrum, δ, ppm: 36.0; 38.0; 49.4; 55.7; 115.5;
117.0; 128.5; 128.6; 128.9; 134.4; 139.7; 155.4; 165.2;
167.1. Found, m/z: 269.1773 [M+H]+. C16H21N4. Calcu-
lated, m/z: 269.1761.
Synthesis of compounds 10a,e,f (General method).
A stirred solution of compound 9a,d,e (13 mmol) in DMF
(20 ml) was treated with N-methylprop-2-en-1-amine (1.11 g,
15.6 mmol), followed by K2CO3 (2.70 g, 19.5 mmol). The
resulting solution was stirred for 2 h at 120°C. After
cooling to room temperature, water (120 ml) was added,
and the mixture was extracted with EtOAc (2×40 ml). The
combined organic layers were washed with water (30 ml),
dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification by flash column chromatography (20:1 petro-
leum ether–EtOAc, v/v) afforded the desired product 10a,e,f.
2-[Allyl(methyl)amino]nicotinaldehyde (10a).10 Yield
1
1.72 g (75%), pale-yellow oil. H NMR spectrum, δ, ppm
(J, Hz): 3.04 (3H, s, CH3); 4.12–4.14 (2H, m,
CH2CH=CH2); 5.23–5.31 (2H, m, CH2CH=CH2); 5.90–
6.00 (1H, m, CH2CH=CH2); 6.80 (1H, dd, J = 7.5, J = 4.8,
H Ar); 7.96 (1H, dd, J = 7.2, J = 1.5, H Ar); 8.32 (1H, dd,
J = 4.8, J = 2.1, H Ar); 9.99 (1H, s, CHO).
2-[Allyl(methyl)amino]-4-methoxybenzaldehyde (10e).11
1
Yield 2.37 g (89%), pale-yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 2.84 (3H, s, NCH3); 3.75 (2H, d, J = 5.7,
CH2CH=CH2); 3.86 (3H, s, OCH3); 5.21–5.31 (2H, m,
CH2CH=CH2); 5.87–6.00 (1H, m, CH2CH=CH2); 6.52–
6.58 (2H, m, H Ar); 7.77 (1H, d, J = 8.4, H Ar); 10.10 (1H,
s, CHO).
2-[Allyl(methyl)amino]-5-nitrobenzaldehyde (10f).11
1
Yield 2.52 g (88%), yellow oil. H NMR spectrum, δ, ppm
(J, Hz): 3.06 (3H, s, NCH3); 4.00–4.03 (2H, m,
CH2CH=CH2); 5.25–5.37 (2H, m, CH2CH=CH2); 5.86–
5.96 (1H, m, CH2CH=CH2); 6.99 (1H, d, J = 8.7, H Ar);
8.22 (1H, dd, J = 9.0, J = 2.4, H Ar); 8.62 (1H, d, J = 2.7,
H Ar); 10.02 (1H, s, CHO).
2-[Allyl(methyl)amino]benzaldehyde (10b).11 2-Fluoro-
benzaldehyde (9b) (10 ml, 94.4 mmol) was added to a
stirred solution of K2CO3 (13 g, 94.4 mmol) in water (100 ml),
followed by the addition of N-methylprop-2-en-1-amine
(8 g, 113 mmol). The resulting solution was stirred for 36 h
489

Chemistry of Heterocyclic Compounds 2016, 52(7), 484–492]
157.6; 191.2. Found, m/z: 284.1111 [M+H]+. C17H18NOS.
spectrum, δ, ppm (J, Hz): 2.19 (1H, br. s, NH); 2.42 (3H, s,
NHCH3); 2.64 (3H, s, NCH3); 3.49 (2H, d, J = 5.7,
CH2CH=CH2); 3.74 (2H, s, NHCH2); 3.79 (3H, s, OCH3);
5.14–5.27 (2H, m, CH2CH=CH2); 5.79–5.92 (1H, m,
CH2CH=CH2); 6.58 (1H, d, J = 8.1, H Ar); 6.66 (1H, s, H Ar);
7.22 (1H, d, J = 8.4, H Ar). 13C NMR spectrum, δ, ppm:
36.0; 41.4; 51.9; 55.3; 60.5; 107.5; 107.7; 117.2; 126.9;
130.9; 135.5; 153.4; 159.4. Found, m/z: 221.1657 [M+H]+.
C13H21N2O. Calculated, m/z: 221.1648.
Calculated, m/z: 284.1104.
Synthesis of compounds 11a–f (General method).
A stirred solution of compound 10a–f (2.5 mmol) in EtOH
(8 ml) was treated with a 30% solution of methylamine in
ethanol (4 ml), followed by AcOH (1 drop). The resulting
solution was stirred for 2.5 h at room temperature. NaBH4
(190 mg, 5.0 mmol) was added, and the mixture was stirred
for 0.5 h at room temperature. Saturated aqueous NaHCO3
solution (1.0 ml) was added to quench the reaction. The
volatiles were removed in vacuo, and saturated aqueous
NaHCO3 solution (20 ml) was added, after which the
mixture was extracted with EtOAc (2×20 ml). The com-
bined organic layers were dried over Na2SO4 and concen-
trated in vacuo. Purification by flash column chromato-
graphy (EtOAc) afforded the desired product 11.
N-Allyl-N-methyl-2-[(methylamino)methyl]-4-nitro-
1
aniline (11f). Yield 418 mg (71%), yellow oil. H NMR
spectrum, δ, ppm (J, Hz): 1.71 (1H, br. s, NH); 2.47 (3H, s,
NHCH3); 2.83 (3H, s, NCH3); 3.75 (2H, d, J = 5.7,
CH2CH=CH2); 3.78 (2H, s, NHCH2); 5.23–5.32 (2H, m,
CH2CH=CH2); 5.80–5.94 (1H, m, CH2CH=CH2); 7.00 (1H,
d, J = 9.0, H Ar); 8.05 (1H, dd, J = 8.7, J = 2.7, H Ar); 8.27
(1H, d, J = 3.0, H Ar).13C NMR spectrum, δ, ppm: 36.5;
40.2; 52.2; 59.2; 117.9; 118.4; 123.4; 125.9; 132.9; 134.2;
141.7; 157.6. Found, m/z: 236.1399 [M+H]+. C12H18N3O2.
Calculated, m/z: 236.1394.
N-Allyl-N-methyl-3-[(methylamino)methyl]pyridin-
2-amine (11a). Yield 387 mg (81%), pale-yellow oil.
1H NMR spectrum, δ, ppm (J, Hz): 1.81 (1H, br. s, NH);
2.43 (3H, s, NHCH3); 2.82 (3H, s, NCH3); 3.72 (2H, s,
NHCH2); 3.75 (2H, d, J = 5.7, CH2CH=CH2); 5.16–5.31
(2H, m, CH2CH=CH2); 5.87–5.98 (1H, m, CH2CH=CH2);
6.87 (1H, dd, J = 7.5, J = 4.8, H Ar); 7.61 (1H, dd, J = 7.5,
J = 1.8, H Ar); 8.18 (1H, dd, J = 4.8, J = 2.1, H Ar).
13C NMR spectrum, δ, ppm: 36.2; 38.9; 52.0; 57.7; 116.8;
117.3; 126.0; 135.4; 138.0; 146.0; 161.9. Found, m/z:
192.1498 [M+H]+. C11H18N3. Calculated, m/z: 192.1495.
N-Allyl-N-methyl-2-[(methylamino)methyl]aniline (11b).
Synthesis of compounds 8b–g and 12a–f (General
method). A stirred solution of compound 7b–g or 11a–f
(0.5 mmol) in toluene (2 ml) was treated with benz-
aldehyde (61 μl, 0.6 mmol). The resulting solution was
heated in an azeotropic distillation apparatus for 1.5–3 h
under N2 atmosphere. The volatiles were removed in
vacuo. Purification by flash column chromatography (5:1
to 2:1 petroleum ether–EtOAc, v/v) afforded the desired
product 8 or 12.
1
Yield 285 mg (60%), pale-yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 1.80 (1H, br. s, NH); 2.43 (3H, s, NHCH3);
2.66 (3H, s, NCH3); 3.49 (2H, d, J = 6.3, CH2CH=CH2);
3.80 (2H, s, NHCH2); 5.13–5.28 (2H, m, CH2CH=CH2);
5.82–5.91 (1H, m, CH2CH=CH2); 7.02–7.12 (2H, m, H Ar);
7.19–7.33 (2H, m, H Ar). 13C NMR spectrum, δ, ppm:
35.8; 41.5; 52.2; 60.5; 117.2; 120.7; 123.7; 127.7; 129.9;
134.6; 135.5; 152.1. Found, m/z: 191.1547 [M+H]+. C12H19N2.
Calculated, m/z: 191.1543.
(2R*,3aR*,9bR*)-1,5-Dimethyl-2-phenyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[2',3':4,5]pyrido[2,3-d]pyrimidine (8b).
1
Yield 56 mg (40%), pale-yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 2.03 (3H, s, 1-CH3); 2.16–2.35 (2H, m,
3-CH2); 2.61–2.69 (1H, m, 3a-CH); 3.18 (3H, s, 5-CH3);
3.28–3.42 (2H, m, 4-CH2); 3.97 (1H, d, J = 5.4, 9b-CH);
4.13 (1H, dd, J = 7.8, J = 6.0, 2-CH); 7.24–7.38 (5H, m,
H Ar); 7.94 (1H, s, H Ar); 8.52 (1H, s, H Ar). 13C NMR
spectrum, δ, ppm: 34.1; 35.2; 36.0; 37.5; 51.7; 60.0; 65.3;
112.0; 127.4; 128.5; 128.7; 142.6; 154.8; 157.6; 160.1. Found, m/z:
281.1769 [M+H]+. C17H21N4. Calculated, m/z: 281.1761.
(2R*,3aR*,9bR*)-9-Chloro-1,5,7-trimethyl-2-phenyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2',3':4,5]pyrido[2,3-d]-
pyrimidine (8c). Yield 109 mg (66%), pale-yellow solid,
N-Allyl-3-chloro-N-methyl-2-[(methylamino)methyl]-
aniline (11c). Yield 494 mg (88%), pale-yellow oil. 1H NMR
spectrum, δ, ppm (J, Hz): 2.28 (1H, br. s, NH); 2.43 (3H, s,
NHCH3); 2.68 (3H, s, NCH3); 3.90 (2H, d, J = 5.4,
CH2CH=CH2); 3.94 (2H, s, NHCH2); 5.15–5.30 (2H, m,
CH2CH=CH2); 5.80–5.91 (1H, m, CH2CH=CH2); 7.00 (1H,
dd, J = 7.8, J = 1.5, H Ar); 7.06–7.17 (2H, m, H Ar).
13C NMR spectrum, δ, ppm: 36.1; 41.4; 48.7; 60.8; 117.3;
119.2; 124.5; 128.4; 132.7; 135.2; 135.8; 154.5. Found, m/z:
225.1160 [M+H]+. C12H18ClN2. Calculated, m/z: 225.1153.
N-Allyl-N-methyl-2-[(methylamino)methyl]-3-(phenyl-
sulfanyl)aniline (11d). Yield 649 mg (87%), pale-yellow
1
mp 161–163°C. H NMR spectrum, δ, ppm (J, Hz): 2.12
(3H, s, 1-CH3); 2.21–2.26 (2H, m, 3-CH2); 2.46–2.54 (4H,
m, 3a-CH, 7-CH3); 3.14–3.47 (5H, m, 5-CH3, 4-CH2); 4.26–
4.31 (1H, m, 2-CH); 4.53 (1H, s, 9b-CH); 7.26–7.48 (5H,
m, H Ar).13C NMR spectrum, δ, ppm: 25.8; 33.5; 35.7;
36.5; 37.9; 51.0; 58.4; 65.0; 127.4; 128.3; 128.5; 129.8;
142.8; 159.2; 160.7; 166.3. Found, m/z: 329.1536 [M+H]+.
C18H22ClN4. Calculated, m/z: 329.1528.
1
oil. H NMR spectrum, δ, ppm (J, Hz): 2.20 (1H, br. s,
NH); 2.41 (3H, s, NHCH3); 2.69 (3H, s, NCH3); 3.59 (2H,
d, J = 6.3, CH2CH=CH2); 4.01 (2H, s, NHCH2); 5.15–5.29
(2H, m, CH2CH=CH2); 5.83–5.95 (1H, m, CH2CH=CH2);
6.99–7.31 (8H, m, H Ar). 13C NMR spectrum, δ, ppm: 36.4;
41.6; 49.3; 61.0; 117.2; 120.2; 126.7; 128.2 (2C); 129.0; 129.3;
130.3; 135.6; 136.3; 136.7; 153.9. Found, m/z: 299.1587
[M+H]+. C18H23N2S. Calculated, m/z: 299.1576.
(2R*,3aR*,9bR*)-9-Chloro-1,5-dimethyl-2,7-diphenyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2',3':4,5]pyrido[2,3-d]-
pyrimidine (8d). Yield 108 mg (55%), pale-yellow solid,
1
mp 154–155°C. H NMR spectrum, δ, ppm (J, Hz): 2.16
(3H, s, 1-CH3); 2.20–2.30 (2H, m, 3-CH2); 2.42–2.60 (1H,
m, 3a-CH); 3.25–3.34 (1H, m) and 3.40–3.65 (1H, m,
4-CH2); 3.34 (3H, s, 5-CH3); 4.20–4.34 (1H, m, 2-CH);
4.60 (1H, d, J = 4.5, 9b-CH); 7.32–7.45 (8H, m, H Ar);
N-Allyl-5-methoxy-N-methyl-2-[(methylamino)methyl]-
aniline (11e). Yield 485 mg (88%), pale-yellow oil. 1H NMR
490

Chemistry of Heterocyclic Compounds 2016, 52(7), 484–492]
8.38–8.41 (2H, m, H Ar). 13C NMR spectrum, δ, ppm:
3-CH2); 2.86 (3H, s, 5-CH3); 2.93–3.07 (3H, m, 3a-CH,
4-CH2); 3.90 (1H, t, J = 6.9, 2-CH); 4.13 (1H, d, J = 6.3,
9b-CH); 6.69–6.75 (2H, m, H Ar); 7.08 (1H, d, J = 7.8,
H Ar); 7.16–7.22 (1H, m, H Ar); 7.26–7.36 (5H, m, H Ar).
13C NMR spectrum, δ, ppm: 36.2; 37.8; 39.2; 40.0; 56.8;
62.5; 67.1; 112.1; 116.9; 122.8; 127.1; 127.2; 128.3; 128.4;
131.4; 143.1; 150.0. Found, m/z: 279.1865 [M+H]+. C19H23N2.
Calculated, m/z: 279.1856.
33.7; 35.8; 36.7; 38.2; 51.2; 58.5; 65.3; 106.7; 127.3;
128.2; 128.3; 128.4; 128.5; 130.7; 137.4; 143.4; 160.1;
160.8; 162.4. Found, m/z: 391.1690 [M+H]+. C23H24ClN4.
Calculated, m/z: 391.1684.
(2R*,3aR*,9bR*)-9-Methoxy-1,5-dimethyl-2-phenyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2',3':4,5]pyrido[2,3-d]-
pyrimidine (8e). Yield 93 mg (60%), pale-yellow solid,
1
mp 103–104°C. H NMR spectrum, δ, ppm (J, Hz): 2.03
(2R*,3aR*,9bR*)-9-Chloro-1,5-dimethyl-2-phenyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (12c).
(3H, s, 1-CH3); 2.11–2.33 (2H, m, 3-CH2); 2.44–2.50 (1H,
m, 3a-CH); 3.17 (3H, s, 5-CH3); 3.19–3.36 (2H, m, 4-CH2);
3.89 (3H, s, OCH3); 4.18 (1H, t, J = 7.8, 2-CH); 4.41 (1H,
d, J = 4.5, 9b-CH); 7.28–7.39 (5H, m, H Ar); 8.27 (1H, s,
H Ar). 13C NMR spectrum, δ, ppm: 33.8; 35.8; 36.7; 38.1;
51.7; 53.4; 55.9; 65.5; 127.2; 128.0; 128.4; 128.5; 143.2;
156.1; 161.3; 167.5. Found, m/z: 311.1874 [M+H]+.
C18H23N4O. Calculated, m/z: 311.1866.
1
Yield 88 mg (56%), pale-yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 2.07 (3H, s, 1-CH3); 2.24–2.33 (2H, m,
3-CH2); 2.79–2.82 (1H, m, 3a-CH); 2.90 (3H, s, 5-CH3);
3.01 (2H, d, J = 5.4, 4-CH2); 4.09–4.14 (1H, m, 2-CH);
4.79 (1H, s, 9b-CH); 6.64 (1H, d, J = 8.1, H Ar); 6.79 (1H,
d, J = 7.8, H Ar); 7.09 (1H, t, J = 8.1, H Ar); 7.41–7.44
(5H, m, H Ar).13C NMR (CDCl3) spectrum, δ, ppm:
36.4; 37.9; 40.0; 40.3; 56.1; 58.6; 67.8; 110.3; 118.5;
120.8; 127.0; 127.9; 128.4; 128.7; 136.5; 143.9; 151.0.
Found, m/z: 313.1472 [M+H]+. C19H22ClN2. Calculated, m/z:
313.1466.
(2R*,3aR*,9bR*)-1,5-Dimethyl-2-phenyl-9-(phenylsulfanyl)-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2',3':4,5]pyrido[2,3-d]-
pyrimidine (8f). Yield 173 mg (89%), pale-yellow
powder, mp 99–100°C. 1H NMR spectrum, δ, ppm (J, Hz):
2.21–2.25 (5H, m, 1-CH3, 3-CH2); 2.46–2.52 (1H, m,
3a-CH); 3.20 (3H, s, 5-CH3); 3.22–3.41 (2H, m, 4-CH2);
4.26 (1H, t, J = 8.4, 2-CH); 4.61 (1H, d, J = 4.2, 9b-CH);
7.29–7.32 (1H, m, H Ar); 7.36–7.43 (7H, m, H Ar); 7.50–
7.53 (2H, m, H Ar); 8.28 (1H, s, H Ar). 13C NMR
spectrum, δ, ppm: 34.1; 36.6; 36.8; 38.4; 51.1; 58.8; 65.7;
127.2; 127.9; 128.5; 128.6; 129.1; 129.8; 130.5; 134.8;
143.7; 156.6; 158.6; 165.9. Found, m/z: 389.1799 [M+H]+.
C23H25N4S. Calculated, m/z: 389.1794.
(2R*,3aR*,9bR*)-1,5-Dimethyl-2-phenyl-9-(phenylsulfanyl)-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (12d).
1
Yield 104 mg (54%), pale-yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 2.10 (3H, s, 1-CH3); 2.21–2.27 (2H, m,
3-CH2); 2.71–2.77 (1H, m, 3a-CH); 2.91 (3H, s, 5-CH3);
2.99–3.03 (2H, m, 4-CH2); 4.02–4.18 (1H, m, 2-CH); 4.85
(1H, s, 9b-CH); 6.62–6.66 (2H, m, H Ar); 7.07 (1H, t,
J = 7.5, H Ar); 7.21–7.35 (10H, m, H Ar). 13C NMR
spectrum, δ, ppm: 37.0; 38.3; 40.0; 40.1; 56.2; 59.3; 67.9;
110.6; 121.3; 123.8; 126.7; 126.9; 127.8; 128.4; 128.5;
129.1; 131.0; 136.9; 137.7; 144.0; 150.2. Found, m/z:
387.1893 [M+H]+. C25H27N2S. Calculated, m/z: 387.1889.
(2R*,3aR*,9bR*)-7-Methoxy-1,5-dimethyl-2-phenyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (12e).
Yield 29 mg (19%), pale-yellow solid, mp 104–105°C.
1H NMR spectrum, δ, ppm (J, Hz): 2.02 (3H, s, 1-CH3);
2.23–2.28 (2H, m, 3-CH2); 2.85 (3H, s, 5-CH3); 2.89–2.97
(1H, m, 3a-CH); 3.00–3.08 (2H, m, 4-CH2); 3.80 (3H, s,
OMe); 3.87 (1H, t, J = 7.4, 2-CH); 4.13 (1H, d, J = 8.4,
9b-CH); 6.27–6.30 (2H, m, H Ar); 7.00 (1H, d, J = 8.4,
H Ar); 7.25–7.35 (5H, m, H Ar). 13C NMR spectrum, δ,
ppm: 36.0; 37.4; 39.2; 39.9; 55.2; 56.4; 62.0; 66.9; 98.8;
101.2; 115.3; 127.0; 128.2; 128.3; 132.1; 143.1; 150.9;
159.9. Found, m/z: 309.1976 [M+H]+. C20H25N2O. Calcu-
lated, m/z: 309.1961.
(2R*,3aR*,9bR*)-1,5-Dimethyl-2,9-diphenyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[2',3':4,5]pyrido[2,3-d]pyrimidine
(8g). Yield 132 mg (74%), pale-yellow solid, mp 156–157°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.95–2.00 (1H, m) and
2.19–2.26 (1H, m, 3-CH2); 2.03 (3H, s, 1-CH3); 2.44–2.52
(1H, m, 3a-CH); 3.27 (3H, s, 5-CH3); 3.33–3.42 (2H, m,
4-CH2); 4.11 (1H, t, J = 6.9, 2-CH); 4.51 (1H, d, J = 3.3,
9b-CH); 7.20–7.33 (5H, m, H Ar); 7.40–7.49 (3H, m,
H Ar); 7.90 (2H, d, J = 6.6, H Ar); 8.62 (1H, s, H Ar).
13C NMR spectrum, δ, ppm: 35.1; 36.7; 38.6; 39.8; 51.2;
58.9; 67.1; 108.0; 127.0; 127.1; 128.1; 128.4; 129.0; 129.4;
138.4; 144.5; 156.9; 160.4; 163.3. Found, m/z: 357.2087
[M+H]+. C23H25N4. Calculated, m/z: 357.2074.
(2R*,3aR*,9bR*)-1,5-Dimethyl-2-phenyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3,2-c][1,8]naphthyridine (12a).
1
Yield 64 mg (46%), pale-yellow oil. H NMR spectrum,
δ, ppm (J, Hz): 2.02 (3H, s, 1-CH3); 2.22–2.27 (2H, m,
3-CH2); 2.79–2.87 (1H, m, 3a-CH); 3.10 (3H, s, 5-CH3);
3.23 (2H, d, J = 5.7, 4-CH2); 3.93 (1H, t, J = 7.2, 2-CH);
4.10 (1H, d, J = 6.3, 9b-CH); 7.54 (1H, dd, J = 7.5, J = 4.8,
H Ar); 7.23–7.36 (6H, m, H Ar); 8.10 (1H, dd, J = 5.4,
J = 1.8, H Ar). 13C NMR spectrum, δ, ppm: 35.7; 35.8;
37.3; 38.3; 53.6; 62.6; 66.1; 111.7; 115.5; 127.2; 128.2;
128.3; 138.4; 142.6; 146.9; 158.5. Found, m/z: 280.1816
[M+H]+. C18H22N3. Calculated, m/z: 280.1808.
(2R*,3aR*,9bR*)-1,5-Dimethyl-2-phenyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3,2-c]quinoline (12b). Yield 58 mg
(42%), pale-yellow solid, mp 69–70°C. 1H NMR spectrum,
δ, ppm (J, Hz): 2.02 (3H, s, 1-CH3); 2.25–2.34 (2H, m,
(2R*,3aR*,9bR*)-1,5-Dimethyl-8-nitro-2-phenyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (12f).
Yield 86 mg (53%), yellow solid, mp 159–160°C. 1H NMR
spectrum, δ, ppm (J, Hz): 2.04 (3H, s, 1-CH3); 2.17–2.35
(2H, m, 3-CH2); 2.67–2.78 (1H, m, 3a-CH); 3.07 (3H, s,
5-CH3); 3.24–3.39 (2H, m, 4-CH2); 4.03 (1H, d, J = 6.0,
9b-CH); 4.10 (1H, dd, J = 7.8, J = 6.6, 2-CH); 6.62 (1H, d,
J = 9.0, H Ar); 7.24–7.36 (5H, m, H Ar); 7.94 (1H, d,
J =2.7, H Ar); 8.07 (1H, dd, J = 9.0, J = 2.4, H Ar).
13C NMR spectrum, δ, ppm: 34.9; 35.3; 37.5; 39.4; 53.8;
61.8; 65.4; 110.0; 125.4; 127.3; 127.5; 127.6; 128.3; 128.9;
136.4; 142.5; 152.3. Found, m/z: 324.1715 [M+H]+.
C19H22N3O2. Calculated, m/z: 324.1707.
491

Chemistry of Heterocyclic Compounds 2016, 52(7), 484–492]
King, G.; Ohlmeyer, M. J.; Appell, K. C.; Webb, M. L.
The Supplementary information file containing NMR
spectra of all new compounds is available at http://
link.springer.com/journal/10593.
J. Med. Chem. 2009, 52, 1295. (c) Ueda, J.; Takagi, M.;
Shin-ya, K. J. Nat. Prod. 2009, 72, 2181. (d) Vartak, A. P.;
Nickell, J. R.; Chagkutip, J.; Dwoskin, L. P.; Crooks, P. A. J.
Med. Chem. 2009, 52, 7878. (e) Xue, F.; Kraus, J. M.;
Labby, K. J.; Ji, H.; Mataka, J.; Xia, G.; Li, H.; Delker, S. L.;
Roman, L. J.; Martásek, P.; Poulos, T. L.; Silverman, R. B. J.
Med. Chem. 2011, 54, 6399. (f) Lorthiois, E.; Breitenstein, W.;
Cumin, F.; Ehrhardt, C.; Francotte, E.; Jacoby, E.; Ostermann, N.;
Sellner, H.; Kosaka, T.; Webb, R. L.; Rigel, D. F.; Hassiepen, U.;
Richert, P.; Wagner, T.; Maibaum, J. J. Med. Chem. 2013, 56,
2207. (g) Krogsgaard-Larsen, N.; Storgaard, M.; Møller, C.;
Demmer, C. S.; Hansen, J.; Han, L.; Monrad, R. N.; Nielsen, B.;
Tapken, D.; Pickering, D. S.; Kastrup, J. S.; Frydenvang, K.;
Bunch, L. J. Med. Chem. 2015, 58, 6131.
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.
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