Synthesis of 1-[aryl-(pyrimidin-2-ylamino)-methyl]-naphthalen-2-ols by p-toluenesulfonic acid catalysed reaction between 2-naphthol, aromatic aldehydes and 2-aminopyrimidine

Article abstract of DOI:10.3184/030823409X401781

Three-component reaction between 2-naphthol, an aromatic aldehyde and 2-aminopyrimidine catalysed by p-toluenesulfonic acid provided a simple and efficient one-pot route for the synthesis of 1-[aryl-(pyrimidin-2-ylamino)- methyl]-naphthalen-2-ol derivativ

Full text of DOI:10.3184/030823409X401781

JOURNAL OF CHEMICAL RESEARCH 2009
MARCH, 143-145
RESEARCH PAPER
143
Synthesis of 1-[aryl-(pyrimidin-2-ylamino)-methyl]-naphthalen-2-ols by
p-toluenesulfonic acid catalysed reaction between 2-naphthol, aromatic
aldehydes and 2-aminopyrimidine
Mohammad Anary-Abbasinejad*, Mahboobeh Akhavan and Alireza Hassanabadi
Department of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
Three-component
p-toluenesulfonic
ylamino)-methyl]-naphthalen-2-ol
reaction between 2-naphthol, an aromatic aldehyde and 2-aminopyrimidine
acid provided simple and efficient one-pot route for the synthesis of 1-[aryl-(pyrimidin-2-
derivatives in excellent yields.
catalysed by
a
Keywords: 2-naphthol, aromatic aldehydes, 2-aminopyrimidine, three-component reaction,p-toluenesulfonic acid
Multi-component reactions (MCRs) have emerged as an
important tool in organic synthesis in which carbon-carbon
and carbon-heteroatom bond formation takes place in a
tandem manner.l-S
derivatives with 2-naphthol and 2-aminopyrimidine in the
presence of p- TSA catalyst under these reaction conditions.
We prepared
a range of 1-[aryl-(pyrimidin-2-ylamino)-
methyl]-naphthalen-2-01 derivatives under the optimised
reaction conditions: 2-naphthol (1 mmol), aryl aldehydes
(1 mmol), and 2-aminopyrimidine (1.1 mmol) in the presence
of p- TSA (0.05 mmol). In all cases, aromatic aldehydes with
either electron-donating or electron-withdrawing groups gave
the desired products in 90-97% yields after 3 h. We also
examined the reaction between 2-naphthol, aliphatic aldehydes
and 2-aminopyridine in the presence ofp- TSA under the same
conditions, but no products were isolated.
Products 4a-h were all new compounds and their
structures were deduced from their elemental analyses and
spectroscopic data. The Mass spectrum of compound 4h
showed the molecular ion peak at 357. The I H NMR spectrum
The reaction of 2-naphthol with aromatic aldehydes in
the presence of p- TSA, a Bronsted acid gives ortho quinone
methides (o-QMs), which have been used in the building up
of dibenzoxanthenes.6 The same o-QMs, generated in situ,
also react with amides7 or acetonitrile8 to form amidoalkyl
naphthols. However, it has been reported7,9 that no products
were obtained from the reaction of o-QMs with anilines.
In continuation of our previous work on three-component
reactions between an aldehyde, an enolic system, such as
substituted 2-naphthols, 4-hydroxycoumarin or acetophenone
derivatives and a nuc1eophile,8,10,11we now report that a
three-component reaction between 2-naphthol, aromatic
aldehydes and 2-aminopyrimidine in the presence of catalytic
amounts ofp-toluenesulfonic acid (P-TSA) afforded l-[aryl-
(pyrimidin-2-ylamino )-methyl]-naphthalen-2-01 derivatives in
good yields. Thus, reaction between 2-naphthol, benzaldehyde
and 2-aminopyrimidine in the presence of 0.1 equiv of p- TSA
in refluxing 1,2-dichloroethane after 3 h afforded l-[phenyl-
(pyrimidin-2-ylamino)-methyl]-naphthalen-2-01 (4a) in 94%
yield (Scheme 1). To determine the optimum quantity of p-
TSA that was required, the reaction of 2-naphthol (1 equiv),
benzaldehyde (1 equiv), and 2-aminopyrimidine (1 equiv)
was carried out under the above conditions using different
quantities of catalyst. The use of 5 mol% of catalyst resulted in
the highest yield in 3 h. A slight excess of 2-aminopyrimidine
was found to be advantageous, therefore the molar ratio of
2-naphthol, aldehyde, and 2-aminopyrimidine was kept at
1: 1: 1.1. Then, we examined the reaction of benzaldehyde
of compound 4h displayed a sharp singlet at 0
for the methoxy protons, along with characteristic signals at
= 6.65-8.07 ppm for the aromatic protons. The methine and
=
3.34 ppm
o
NH protons were coupled to each other and two doublets were
observed for them at 6.91 and 7.38 ppm, respectively. When
the I H NMR spectrum was recorded after addition of some
D20 to the d6-DMSO solution of 4h the doublet assigned
to the NH proton disappeared and the doublet assigned to
the methine proton was converted to a singlet. A singlet was
observed at 0
=
9.90 ppm, and assigned to an OH proton
disappeared on addition of D20. The 13CNMR spectrum of
compound 4h showed 21 distinct signals in agreement with
the proposed structure. The methoxy and methine carbons
resonated at 0 55.6 and 46.8 ppm, respectively.
A
possible mechanism for the formation of l-[aryl-
(pyrimidin-2-ylamino)-methyl]-naphthalen-2-01s
4a-h has
cv~OR
p-TSA
..
I
+
ArCRO
+
",.::;
",.::;
CH
2
CICH CI' reflux, 3 h
2
2
4
4
b
d
h
a
c
e
9
Ar
%Yield*
Ph 4-CIPh 4-BrPh 2-CIPh 3-N02Ph 4-N02Ph 4-CH30Ph
94 93 95 90 93 95 90
*Yields refer to the pure isolated products.
2-CH30Ph
97
Scheme
1
* Correspondent. E-mail: mohammadanary@yahoo.com

144 JOURNAL OF CHEMICAL RESEARCH 2009
1-[4-Bromophenyl-(pyrimidin-2-ylamino )-methyl}-naphthalen-2-
01 (4c): White powder, m.p. 216-218°C, IR (KEr) (vrnox em"): 3423,
1629, 1592, 1571, 1525. Analyses: Calcd for C2,H'6BrNP: C, 62.08;
H, 3.97; N, 10.34. Found: C, 62.21; H, 4.07; N, 10.25%. MS (m/z, %):
405 (M'+, 8). 'H NMR (500 MHz, d6-DMSO): 1) 6.61 (1 H, t, 3JHH
been proposed in Scheme 2. As reported in the literature,17.21
reaction of2-naphthol with aromatic aldehydes in the presence
of an acid catalyst gives orthoquinone methides (o-QMs). The
same o-QMs, generated in situ, react with 2-aminopyrimidine
by
a
conjugate
addition
to form
1-[aryl-(pyrimidin-2-
=
5 Hz, pyrimidine), 7.21 (I H, d, 3JHH
8 Hz, NH), 8.32 (2 H, d, 3JHH = 5 Hz, pyrimidine), 7.23-7.31
(6 H, m, 6 CH of naphthol and phenyl), 7.74 (I H, d, 3JHH 8 Hz,
CH of naphthol), 7.76 (I H, d, 3JHH 8 Hz, CH of naphthol), 7.44
(2 H, t, 3JHH 8 Hz, 2 CH of phenyl), 10.28 (I H, broad s, OH). l3C
= 8 Hz, NCH), 8.03 (I H, d,
3JHH
=
ylamino )-methy 1]-naphthalen- 2-01 derivatives.
=
In summary, we report a simple and efficient one-pot synthesis
=
of
1-[aryl-(pyrimidin-2-ylamino
)-methyl]-naphthalen-2-01
=
derivatives by a three-component
reaction between 2-naphthol,
NMR (125.8 MHz, d6-DMSO): 1) 50.53 (CH), 111.98, 119.56, 119.85,
123.34, 123.52, 127.76, 128.83, 128.86, 129.25, 129.58, 130.36,
an aromatic aldehyde and 2-aminopyrimidine
catalysed by
131.64,133.11,143.07,153.92,159.17
and 162.63 (aromatic).
p-toluenesulfonic acid. The advantages of this method are
1-[2-Chlorophenyl-(pyrimidin-2-ylamino )-methyl}-naphthalen-2-
01 (4d): White powder, m.p. 201-203°C, IR (KEr) (vrnox em"): 3405,
1621,1595,1566,1514. Analyses: Calcd for C2,H'6CINP: C, 69.71;
H, 4.46; N, 11.61. Found: C, 69.93; H, 4.62; N, 11.75%. MS (m/z, %):
readily available starting materials, short reaction times, an
easy and clean work-up and excellent yields.
361 (M'+, 6). 'H NMR (500 MHz, d6-DMSO): 1) 6.60 (1 H, t, 3JHH
5 Hz, pyrimidine), 7.16 (I H, d, 3JHH 8 Hz, NCH), 8.11 (1 H, d,
8 Hz, NH), 8.29 (2 H, d, 3JHH = 5 Hz, pyrimidine), 7.23-7.42
(7 H, m, 7 CH of naphthol and phenyl), 7.62 (I H, d, 3JHH 8 Hz,
CH of naphthol), 7.75 (I H, d, 3JHH 8 Hz, CH of naphthol), 7.80
(1 H, d, 3JHH 8 Hz, CH of naphthol moiety), 10.01 (I H, broad
s, OH). l3C NMR (125.8 MHz, d6-DMSO): 1) 50.51 (CH), 111.80,
118.34, 119.63, 123.25, 123.65, 127.25, 127.34, 129.13, 129.32,
129.50, 130.15, 130.34, 130.66, 133.49, 133.56, 140.74, 154.55,
158.98 and 162.23 (aromatic).
1-[3-Nitrophenyl-(pyrimidin-2-ylamino )-methyl} -naphthalen-2-o1
(4e): White powder, m.p. 234-236°C, IR (KEr) (vrnox em"): 3395,
1625, 1594, 1571, 1522. Analyses: Calcd for C2,H'6N403: C, 67.73;
H, 4.33; N, 15.05. Found: C, 67.88; H, 4.50; N, 15.25%. MS (m/z,
%): 372 (M'+, 10) 'H NMR (500 MHz, d6-DMSO): 1) 6.68 (1 H, t,
=
Experimental
=
All melting points are uncorrected. Elemental analyses were
performed using a Heraeus CRN-O-Rapid analyser. Mass spectra
were recorded on a Fiunigan-MAT 8430 mass spectrometer operating
at an ionisation potential of 70 eV. IR spectra were recorded on a
Shimadzu IR-470 spectrometer. 'H, and l3C NMR spectra were
recorded on Broker DRX-500 Avance spectrometer at 500.1 and
125.8 MHz, respectively. 'H, and l3C NMR spectra were obtained on
solution in d,;-DMSO using TMS as internal standard. The chemicals
used in this work purchased from Fluka (Buchs, Switzerland) and
were used without further purification.
3JHH
=
=
=
=
General procedure
A magnetically stirred solution of 2-aminopyrimidine (1.1 mmol),
2-naphthol (1 mmol), aldehyde (1 mmol) and p-TSA (0.05 mmol)
in 1,2-dichloroethane (15 mL) was refluxed for 3 h. The mixture
was poured into water (50 mL). The solid product was filtered and
recrystallised from ethyl acetate/hexane mixture to give the pure
product.
3JHH
(1 H, d, 3JHH
=
5 Hz, pyrimidine), 7.25 (1 H, d, 3JHH
=
8 Hz, NCH), 8.06
5 Hz, pyrimidine),
=
8 Hz, NH), 8.36 (2 H, d, 3JHH
=
7.32 (I H, t, 3JHH = 8 Hz, CH of naphthol), 7.45 (1 H, d, 3JHH
CH of naphthol), 7.54 (I H, t, 3JHH 8 Hz, CH of naphthol), 7.61
(1 H, d, 3JHH 8 Hz, CH of naphthol), 7.82 (1 H, d, 3JHH 8 Hz, CH
of naphthol), 7.85 (I H, d, 3JHH = 8 Hz, CH of naphthol), 7.50 (1 H, t,
3JHH = 8 Hz, CH of phenyl), 7.68 (I H, d, 3JHH = 8 Hz, CH of phenyl),
= 8 Hz,
=
=
=
1-[Phenyl-(pyrimidin-2-ylamino)-methyl}-naphthalen-2-o1
(4a):
8.14 (2 H, d, 3JHH
= 8 Hz, 2 CH of phenyl), 10.39(1 H, broad s, OH).
White powder, m.p. 231-233°C, IR (KEr) (vrnox em"): 3480,1621,
1591,1567, 1507. Analyses: Calcd for C2,H17NP: C, 77.04; H, 5.23;
N, 12.84. Found: C, 77.22; H, 5.11; N, 13.05%. MS (m/z, %): 327
(M'+, 6). 'HNMR (500 MHz, d6-DMSO): 1) 6.63 (I H, t, 3JHH = 5 Hz,
l3C NMR (125.8 MHz, d6-DMSO): 1) 50.71 (CH), 112.22, 119.28,
119.47, 121.39, 122.28, 123.28, 123.67, 127.93, 129.23, 129.61,
130.60, 130.79, 132.94, 133.77, 146.59, 148.62, 154.08, 159.18 and
162.58 (aromatic).
1-[4-Nitrophenyl-(pyrimidin-2-ylamino )-methyl} -naphthalen-2-o1
(4f): White powder, m.p. 238-240°C, IR (KEr) (vrnox em"): 3420,
1627, 1592, 1568, 1513. Analyses: Calcd for C2,H'6N403: C, 67.73;
H, 4.33; N, 15.05. Found: C, 67.56; H, 4.30; N, 15.00%. MS (m/z,
%): 372 (M'+, 8). 'H NMR (500 MHz, d6-DMSO): 1) 6.68 (1 H, t,
3JHH
(1 H, d, 3JHH
7.32 (I H, t, 3JHH
of naphthol and phenyl), 7.82 (I H, d, 3JHH
7.84 (1 H, d, 3JHH = 8 Hz, CH of naphthol), 8.13 (2 H, d, 3JHH = 8 Hz,
2 CH of phenyl), 10.37 (I H, broad s, OH). l3C NMR (125.8 MHz,
d6-DMSO): 1) 50.71 (CH), 112.21, 119.37, 119.43, 123.33, 123.64,
124.22, 128.03, 128.13, 129.25, 129.61, 130.68, 132.96, 146.90,
152.32,154.07,159.19 and 162.58 (aromatic).
1-[4-Methoxyphenyl-(pyrimidin-2-ylamino )-methyl}-naphthalen-
2-01 (4g): White powder, m.p. 211-213°C, IR (KEr) (vrnox em"):
3455, 1624, 1597, 1566, 1523. Analyses: Calcd for C22H19N302:
C, 73.93; H, 5.36; N, 11.76. Found: C, 74.11; H, 5.19; N, 11.92%.
MS (m/z, %): 357 (M'+, 6). 'H NMR (500 MHz, d,;-DMSO): 1) 3.67
(3 H, s, OCH3), 6.61 (1 H, t, 3JHH
d, 3JHH
d, 3JHH
pyrimidine), 7.23 (I H, d, 3JHH
Hz, NH), 8.33 (2 H, d, 3JHH = 5 Hz, pyrimidine), 7.28-7.32 (3 H, m,
3 CH of naphthol), 7.38 (I H, d, 3JHH 8 Hz, CH of naphthol), 7.78
(I H, d, 3JHH = 8 Hz, CH of naphthol), 7.83 (I H, d, 3JHH 8 Hz, CH
of naphthol), 7.16 (1 H, t, 3JHH 8 Hz, CH of phenyl), 7.22-7.25 (2
H, m, 2 CH of phenyl), 7.49 (2 H, d, 3JHH 8 Hz, 2 CH of phenyl),
= 8 Hz, NCH), 8.11 (1 H, d, 3JHH = 8
=
=
=
=
=
5 Hz, pyrimidine), 7.25 (1 H, d, 3JHH
=
8 Hz, NCH), 8.09
5 Hz, pyrimidine),
10.25 (1 H, broad s, OH). l3C NMR (125.8 MHz, d,;-DMSO):
1) 51.96 (CH), 108.35, 111.78, 119.57, 120.32, 123.49, 126.92,
127.10, 127.72, 128.94, 129.21, 129.49, 130.08, 133.11, 143.91,
153.88, 159.14 and 162.71 (aromatic).
1-[4-Chlorophenyl-(pyrimidin-2-ylamino )-methyl} -naphthalen-2-
01 (4b): White powder, m.p. 228-230°C, IR (KEr) (vrnox em"): 3420,
1628, 1596, 1570, 1527. Analyses: Calcd for C2,H'6CINP: C, 69.71;
H, 4.46; N, 11.61. Found: C, 69.93; H, 4.62; N, 11.75%. MS (m/z, %):
=
8 Hz, NH), 8.35 (2 H, d, 3JHH
=
=
8 Hz, CH of naphthol), 7.43-7.54 (5 H, m, 5 CH
8 Hz, CH of naphthol),
=
361 (M'+, 9). 'H NMR (500 MHz, d,;-DMSO): 1) 6.60 (I H, t, 3JHH
5 Hz, pyrimidine), 7.20 (1 H, d, 3JHH 8 Hz, NCH), 8.05 (I H, d,
8 Hz, NH), 8.30 (2 H, d, 3JHH 5 Hz, pyrimidine), 7.21-7.32
(6 H, m, 6 CH of naphthol and phenyl), 7.75 (1 H, d, 3JHH = 8 Hz, CH
of naphthol), 7.78 (1 H, d, 3JHH 8 Hz, CH of naphthol), 7.46 (2 H,
t, 3JHH 8 Hz, 2 CH of phenyl), 10.26(1 H, broad s, OH). l3C NMR
=
=
3JHH
=
=
=
=
5 Hz, pyrimidine), 7.20 (I H,
8 Hz, NCH), 8.09 (1 H, d, 3JHH 8 Hz, NH), 8.32 (2 H,
5 Hz, pyrimidine), 6.80-6.82 (2 H, m, 2 CH of naphthol),
=
=
=
(125.8 MHz, d6-DMSO): 1) 50.55 (CH), 111.95, 119.53, 119.87,
=
123.32, 123.55, 127.78, 128.81, 128.89, 129.23, 129.55, 130.31,
7.22-7.59 (6 H, m, 6 CH of naphthol and phenyl), 7.75 (1 H, d, 3JHH
131.69,133.01,143.02,153.94,159.13
and 162.61 (aromatic).
=
8 Hz, CH of naphthol), 7.81 (I H, d, 3JHH = 8 Hz, CH of naphthol),
~NH
A r £ H
~2
0& N --':::N
p-TSA. I ~
0
U
•
4
h -
h -
Scheme 2

JOURNAL OF CHEMICAL RESEARCH 2009 145
10.42 (1 H, broad s, OH). l3CNMR (125.8 MHz, d -DMSO): 1) 50.72
6
Received 14 November 2008; accepted 10 December 2008
Paper 08/0296 doi: 10.3184/030823409X401781
Published online: 3 April 2009
(CH), 55.84 (OCH3), 111.63, 114.35, 119.82, 120.23, 123.32, 123.52,
127.54, 128.17, 129.08, 129.45, 129.86, 133.09, 135.86, 154.19,
158.66, 159.01 and 162.67(aromatie).
1-{2-Methoxyphenyl-(pyrimidin-2-ylamino
)-methyl} -naphthalen-
References
2-ol (4h): White powder, m.p. 207-209°C, IR (KEr) (vrnex em"):
3420, 1620, 1593, 1568, 1516. Analyses: Calcd for C22H19N302:
C, 73.93; H, 5.36; N, 11.76. Found: C, 73.65; H, 5.41; N, 11.99%.
MS (m/z, %): 357 (M'+, 9). 'H NMR (500 MHz, ~-DMSO): 1) 3.34
1
2
3
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(3 H, s, OCH3), 6.36 (1 H, t, 3JHH
=
5 Hz, pyrimidine), 6.91 (1 H,
8 Hz, NCR), 7.38 (1 H, d, 3JHH 8 Hz, NR), 8.07 (2 H,
5 Hz, pyrimidine), 6.65-6.68 (2 H, m, 2 CH ofnaphtbo1),
d, 3JHH
d, 3JHH
=
=
=
6.93-7.27 (5 H, m, 5 CH of naphthol and phenyl), 7.48 (1 H, d, 3JHH
= 8 Hz, CH of naphthol) , 7.57 (1 H, d, 3JHH 8 Hz, CH ofnaphtbo1),
8.15 (1 H, d, 3JHH 8 Hz, CH of phenyl), 9.90 (1 H, broad s, OH).
l3C NMR (125.8 MHz, -DMSO): 1) 46.80 (CH), 55.60 (OCH3),
=
9
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