New method for the direct electrophilic amination of aromatic compounds and its use in the annelation of the pyrimidine ring

Article abstract of DOI:10.1007/s10593-011-0661-z

A method has been developed for the synthesis of aromatic amines by the amination of the corresponding aromatic compounds using sodium azide in PPA. A method for the synthesis of quinazolines and benzo[h]quinazolines using this reaction and the subsequent reaction of the intermediates with 1,3,5-triazines has been developed.

Full text of DOI:10.1007/s10593-011-0661-z

Chemistry of Heterocyclic Compounds, Vol. 46, No. 10, 2011
NEW METHOD FOR THE DIRECT ELECTROPHILIC
AMINATION OF AROMATIC COMPOUNDS AND ITS
USE IN THE ANNELATION OF THE PYRIMIDINE RING
A. V. Aksenov1*, A. S. Lyakhovnenko1, and M. M. Kugutov1
A method has been developed for the synthesis of aromatic amines by the amination of the
corresponding aromatic compounds using sodium azide in PPA. A method for the synthesis of
quinazolines and benzo[h]quinazolines using this reaction and the subsequent reaction of the
intermediates with 1,3,5-triazines has been developed.
Keywords: sodium azide, arenes, aromatic amines, benzo[h]quinazolines, perimidines, PPA, 1,3,5-triazines,
quinazolines, amination.
In previous work [1, 2], we discovered a new reagent system for the electrophilic amination of aromatic
compounds and shown its applicability for perimidines. In the present work, we have extended this method for
the synthesis of other aromatic amines and shown its applicability in combination with 1,3,5-triazines for the
annelation of the pyrimidine ring to aromatic compounds.
As noted in our previous work [1, 2], the reaction of perimidines with a threefold excess of PPA at
80-90°C leads to the corresponding 6(7)-aminoperimidines in high yield. The PPA sample used containing
86% P2O5 was obtained according to Uhlig [3].
We might have assumed that this reagent system would be applicable for the amination of other
aromatic compounds. Indeed, we showed that the reaction proceeds analogously with naphthalene to give
1-naphthylamine (2a) in 31% yield. The low yield is mostly a consequence of sublimation of naphthalene from
the reaction mixture.
NH2
1) NaN3/PPA
2) H2O
2a
1a
_______
* To whom correspondence should be addressed, e-mail: biochem-org@stavsu.ru.
1Stavropol State University, Stavropol 355009, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1559-1562, October, 2010.
Original article submitted February 2, 2010.
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0009-3122/11/4610-1262©2011 Springer Science+Business Media, Inc.

The reaction proceeds with much greater facility with anisole 1b and phenol 1c. A 1.1-fold excess of
sodium azide is sufficient for PPA with 86% P2O5 content, while a 1.5-fold excess is sufficient for PPA with
80% P2O5 content. A lower temperature of 66-60°C is required. The yield of p-anisidine (2b) was 86%, while
the yield of p-aminophenol 2c was 74%.
X
X
1) NaN3/PPA
2) H2O
NH2
1b,c
2b,c
1, 2 b X = OMe, c X = OH
The reaction does not proceed at all with arenes containing weaker electron-donor substituents such as
toluene or acetanilide.
The reaction mechanism is probably analogous to the mechanism presented in our previous work [1, 2]
and involves the formation of intermediates 3, which presumably may not only undergo protonation but also
react with other electrophilic reagents such as 1,3,5-triazines. In this case, the reaction should proceed as shown
in the following scheme.
R
N
N
R
N
N
N
R
N
R
N
O
R
O
R
NaN3
PPA
+
4a,b
N
Ar
1a–c
...O
P
N
N
N
Ar
...O
P
N
H
H
OH
OH
3
R
R
+
NH2
R
H+
N
–N2
N
R
N
Ar
N
R
N
Ar
H
–PPA
H
N
N
R
N
NH2
X
X
N
N
–HN=CHNH2
N
N
H
R
5a,b
R
N
N
NH2
R
N
N
R
N
–HN=CRNH2
R
6a,b
4, 6 a R = H, b R = Me; 5 a X = OMe, b X = OH; Ar = 1-C10H7, 4-MeOC6H4, 4-HOC6H4
1,3,5-Triazine (4a) is added to the reaction mixture obtained from anisole 1b or phenol 1c and heated for
4 h at 90-100°C to give quinolines 5a,b* in 54% and 49% yield respectively.
_______
* Reported in our preliminary communication [4].
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1) NaN3/PPA
1a–c
5a,b, 6a,b
2) 4a,b/PPA
The reaction proceeds similarly if naphthalene 1a is used as the starting compound.
Thus, a convenient method has been developed for the amination of aromatic compounds. An advantage
of this method is the possibility of its combination with ring annelation. In this work, we have demonstrated the
feasibility of annelating the pyrimidine ring to benzene and naphthalene.
EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker WP-200 spectrometer at 200 MHz with TMS as the
internal standard. The reaction course and purity of the products were monitored by thin-layer chromatography
on Silufol UV-254 plates using 3:1 ethyl acetate–ethanol as the eluent.
A commercial sample of 1,3,5-triazine (4a) was obtained from Aldrich, while 2,4,6-trimethyl-1,3,5-triazine
(4b) was prepared according to Schaefer [5].
Amination of Aromatic Compounds (General Method). A mixture of corresponding aromatic
compound 1a-c (1 mmol), sodium azide (in the case of naphthalene 1a, 0.195 g, 3 mmol) or (in the case of
arenes 1b and 1c, 0.071 g, 1.1 mmol) in PPA (2-3 g) was heated to 75-80°C (in the case of naphthalene 1a) or
55-60°C (in the case of the other arenes) with vigorous stirring for 5 h. The reaction mixture was treated with
50 ml water, filtered, and extracted with three 50-ml ethyl acetate portions. The aqueous layer was brought to
pH 9-10 by adding ammonium hydroxide. The precipitate or oil formed was extracted with three 50 ml ethyl
acetate portions. The solvent was evaporated off. The residue was dissolved in 5 ml ethanol and the solution
obtained was saturated with dry gaseous HCl. The precipitate formed of the hydrochloride salt was purified by
recrystallization from ethanol.
1
1-Naphthylamine (2a) was obtained in 34% yield (0.049 g); mp 48-50°C (mp 48-49°C [6]). H NMR
spectrum in CDCl3, , ppm (J, Hz): 4.09 (2H, br. s, NH2); 6.80 (1H, dd, J = 6.6, J = 1.8, H-4); 7.31-7.41 (2H, m,
H Ar); 7.46-7.54 (2H, m, H Ar); 7.80-7.89 (2H, m, H Ar). Found, %: C 84.02; H 6.27; N 9.71. C10H9N.
Calculated, %: C 83.88; H 6.34; N 9.78.
1
4-Anisidine (2b) was obtained in 86% yield (0.106 g); mp 57-59°C (mp 56-59°C [7]). The H NMR
spectrum was identical to the spectrum given by Casarini [7].
4-Aminophenol (2c) was obtained in 74% yield (0.081 g); mp 188-191°C (aqueous ethanol)
1
(mp 187-190°C [8]). Hydrochloride salt: mp 240-242°C (ethanol). H NMR spectrum in DMSO-d6, , ppm (J,
Hz): 6.87 (2H, d, J = 7.6, H-3,5); 7.21 (2H, d, J = 7.6, H-2,6); 9.88 (1H, br. s, OH); 10.19 (3H, br. s, NH3).
Synthesis of Quinazolines 5a and 5b and Benzo[h]quinazolines 6a,b (General Method). A mixture
of aromatic compound 1a-c (1 mmol), sodium azide (0.195 g, 3 mmol, in the case of naphthalene 1a) or
(0.071 g, 1.1 mmol, in the case of arenes 1b and 1c) in PPA (2-3 g) was heated at 75-80°C (in the case of
naphthalene 1a) or 55-60°C (in the case of the other arenes) with vigorous stirring for 5 h. Then, the temperature
was raised to 90-100°C, corresponding triazine 4a or 4b (1.1 mmol) was added, and stirring was continued at
this temperature for 5 h. The reaction mixture was treated with 50 ml water, filtered, and extracted with three
50-ml ethyl acetate portions. The solvent was evaporated off and the residue was purified by recrystallization or
sublimation.
6-Hydroxyquinazoline (5a) was obtained in 49% yield (0.072 g); mp 237-239°C (water) (mp 239°C
[9]). The 1H NMR spectrum was given in our previous work [4].
6-Methoxyquinazoline (5b) was obtained in 54% yield (0.086 g); mp 71-72°C (petroleum ether)
(mp 71°C [9]). The 1H NMR spectrum was given in our previous work [4].
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Benzo[h]quinazoline (6a) was obtained in 26% yield (0.047 g); mp 101-103°C (chloroform–ethanol)
(mp 102-103°C [10]). The 1H NMR spectrum corresponded to the spectrum given by Koyama et al. [10].
2,4-Dimethylbenzo[h]quinazoline (6b) was obtained in 22% yield (0.046 g); mp 119-121°C (ethanol)
(mp 119-121°C [11]). The 1H NMR spectrum corresponded to the spectrum given by Petterson et al. [11].
This work was carried out with the financial support of the Russian Basic Research Fund
(Grant 10-03-00193a).
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