Regioselectivity change in the reaction of naphthalene and 2-naphthyl ethers with 1,3,5-triazines depending on reagent quantities

Article abstract of DOI:10.1055/s-0029-1216973

A new method for the synthesis of 4H-benzo[de]isoquinolin-4-ones has been developed, based on the reaction of 2-naphthyl ethers with an equimolar quantity of 1,3,5-triazines in polyphosphoric acid. With a 2.5 molar excess of 1,3,5-triazines in polyphospho

Full text of DOI:10.1055/s-0029-1216973

PAPER
3439
Regioselectivity Change in the Reaction of Naphthalene and 2-Naphthyl
Ethers with 1,3,5-Triazines Depending on Reagent Quantities
R
egioselectivity in
l
the Re
e
actionof
N
x
a
phthalenes
a
w
ith1,3,5-
n
Stavropol State University, Pushkina St. 1, Stavropol 355009, Russian Federation
Fax +7(8652)357023; E-mail: alexaks05@rambler.ru
Received 8 June 2009; revised 17 June 2009
or 4H-benzo[de]isoquinolin-4-ones 9a,b (if X = OR¢)
Abstract: A new method for the synthesis of 4H-benzo[de]isoquin-
olin-4-ones has been developed, based on the reaction of 2-naphthyl
ethers with an equimolar quantity of 1,3,5-triazines in polyphospho-
ric acid. With a 2.5 molar excess of 1,3,5-triazines in polyphospho-
ric acid, the products of 1,6-diacylation (diformylation) are formed.
Isoquino[6¢,5¢,4¢:10,5,6]anthra[2,1,9-def]isoquinoline is formed
upon reaction of a 1.5 molar excess of 1,3,5-triazine with naphtha-
lene in polyphosphoric acid at 130–140 °C.
may be formed (Scheme 2).
R
N
R
X
R
PPA
R
N
+
N
N
HN
X
R
N
R
Key words: 1,3,5-triazines, polyphosphoric acid, naphthalenes,
1 X = H
2a X = OMe
2b X = OEt
3a R = H
3b R = Me
acylation,
4H-benzo[de]isoquinolin-4-ones,
isoqui-
4a–d
no[6¢,5¢,4¢:10,5,6]anthra[2,1,9-def]isoquinoline
– RC(NH)NH2
NH2
The monoacylation of naphthalene derivatives has al-
ready become a very well studied classic reaction. In con-
trast, there are few examples of the diacylation and
diformylation of naphthalene derivatives.1
PPA
X
R
X
X
R
NH
N
+
R
R
N
R
R
N
N
R
N
R
It is well known that 1,3,5-triazine can undergo ring
cleavage upon treatment with nucleophilic reagents and
serve as a formyl group precursor. This property has been
extensively used in organic synthesis.2 Thus, forma-
midines,2a perimidines,2b benzimidazoles,2b benzothia-
5a–d
6a–d
7a–d
Scheme 1 Mechanism of the reaction of 1,3,5-triazines 3a,b with
naphthalene derivatives
zoles,2b
benzoxazoles,2b
purines,2b
pyridines,2c,d
pyrimidines2c,e,f and 1,6-naphthyridines2g–i have been ob-
tained utilizing different nucleophiles in reactions with
1,3,5-triazine (3a).
H2O
H2O
7a–d
X = OR'
X = R = H
O
O
R
N
O
R
Recently, we have reported the new reagent system of
1,3,5-triazines in polyphosphoric acid and have proved its
effectiveness for the acylation and formylation of
perimidine3a,b and substituted naphthalenes,3c and the
peri-annelation of carbocyclic3d and pyridine rings.3e In
the present paper we suggest methods for pyridine ring
annelation to naphthalenes and regioselective 1,6-diacyla-
tion (diformylation) of 2-naphthyl ethers.
On the basis of our previous work,3 we propose that in the
case of the reaction of 1,3,5-triazines with naphthalene
and its monosubstituted derivatives, an intermediate 4 is
formed, which is opened as for azanaphthalenes and in the
series of subsequent transformations gives off the cation 7
(Scheme 1).
9a = H
9b = Me
8
Scheme 2 Hydrolysis of cations 7a–d
Indeed, reaction of naphthalene (1) with 1,3,5-triazine
(3a) in polyphosphoric acid4 (reagent ratio 1:1.5, at 65–
70 °C for 3 h, then at 100–110 °C for 2 h), followed by
quenching of the reaction mixture with water, leads to
naphthalene-1,8-dicarbaldehyde (8) in 31% yield5
(Scheme 2; Table 1, entry 1). A byproduct, isoqui-
no[6¢,5¢,4¢:10,5,6]anthra[2,1,9-def]isoquinoline (10), is
formed in ~6% yield. It is likely that compound 10 is
formed by the mechanism shown in Scheme 3. Thus, se-
quential heating of naphthalene (1) with 1,3,5-triazine
(3a) at 65–70 °C for 3 hours, then at 130–140 °C for 6
hours, leads to the formation of 10 in 27% yield (Table 1,
entry 2).
The behavior of cations 7a–d depends on the nature of X.
As a result of hydrolysis, dicarbonyl compounds (e.g., 8)
In the case of the 2-naphthyl ethers 2a,b, reaction with an
equimolar quantity of 1,3,5-triazine (3a) in polyphospho-
ric acid at 110–115 °C leads to the formation of 4H-ben-
zo[de]isoquinolin-4-one (9a) in 36–64% yield
SYNTHESIS 2009, No. 20, pp 3439–3442
Advanced online publication: 28.08.2009
DOI: 10.1055/s-0029-1216973; Art ID: Z12009SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

3440
A. V. Aksenov et al.
PAPER
H2N
Table 1 Reaction Conditions
N
N
6a
X = R = H
Entry
R
X
Ratio Temp (°C),
(1:3 or time (h)
2:3)
Product:
yield (%) yield (%)
Product:
7a
X = R = H
– HN=CH-NH2
N
1
2
3
H
H
H
H
H
1:1.5 65–70, 3; then 8: 31
10: 6
100–110, 2
+
– H+
N
N
N
N
N
1:1.5 65–70, 3; then
130–140, 6
10: 27
11a: 9
OMe 1:1.1 40–45, 1; then 9a: 87
100–110, 3
O2
N
4
5
H
H
OMe 1:2.5 75–80, 5
9a: 8
11a: 88
11b: 7
OEt 1:1.1 40–45, 1; then 9a: 89
10
100–110, 3
Scheme 3 Mechanism of the formation of isoquino[6¢,5¢,4¢:10,5,6]an-
thra[2,1,9-def]isoquinoline (10)
6
7
H
OEt 1:2.5 75–80, 5
9a: 7
11b: 91
11c: 11
Me OEt 1:1.1 40–45, 1; then 9b: 67
O
110–115, 3
1) 3a,b, PPA
R
2a,b
9a,b
+
8
Me OEt 1:2.5 75–80, 5
9b: 6
11c: 68
2) H2O
X
simplicity and applicability to the synthesis of a broad
range of naphthalene derivatives.
11a X = OMe, R = H
11b X = OEt, R = H
11c X = OEt, R = Me
O
R
Scheme 4 Reaction of 2-naphthyl ethers 2a,b with 1,3,5-triazines
3a,b
Preparative column chromatography was performed on SDS flash
silica gel (35–70 mesh). Evaporation of solvent was carried out us-
ing a rotary evaporator under reduced pressure (2–400 mbar) with a
bath temperature of up to 60 °C. Thin-layer chromatography (TLC)
was performed on Silufol UV-254 silica gel plates. In general, the
course of reactions was followed by TLC. NMR spectra were ob-
tained on a Bruker AM-300 spectrometer at 300 MHz (1H) and 75
MHz (13C) using CF3CO2D, CDCl3 or DMSO-d6 as solvent. Chem-
ical shifts are expressed in ppm downfield from TMS, which was
used as an internal standard. IR spectra were recorded on a Perkin-
Elmer FTIR spectrophotometer. Mass spectra were recorded on a
Varian CH 7 spectrometer. Melting points of small samples were
obtained after recrystallization; solvents are given in parentheses.
Microanalyses were carried out on a CHN-1 Elemental Analyzer.
2,4,6-Trimethyl-1,3,5-triazine (3b) was obtained by a known proce-
dure.6 Other chemicals used in this study were commercially avail-
able.
(Scheme 2). 1,6-Diacylation (diformylation) products
11a,b are formed as byproducts (Scheme 4).
Probably, the formation of compounds 11a–c occurs as a
result of the reaction of intermediates 4b–d with triazines
3a,b (Scheme 5). Therefore, the formation of compound
11 would be stimulated by excess triazine 3, and the for-
mation of 9 would be the result of higher temperature.
R
N
R
N
3a,b
H2O
N
R
4b–d
11a–c
H
PPA
X
R
Naphthalene-1,8-dicarbaldehyde (8)
R
N
HN
A mixture of naphthalene (1; 0.128 g, 1 mmol) and 1,3,5-triazine
(3a; 0.12 g, 1.5 mmol) in PPA (3–4 g) was stirred at 65–70 °C for 3
h and then at 100–110 °C for 2 h. The reaction mixture was poured
into cold H2O (30 mL) with intense stirring. The resulting mixture
was extracted with EtOAc (3 × 50 mL). The solution was concen-
trated under reduced pressure; compound 8 was purified by flash
N
R
Scheme 5 Mechanism of the formation of compounds 11a–c
Accordingly, we were able to increase the yield of the 4H- chromatography on silica gel (EtOAc); yield: 0.057 g (31%); mp
139–141 °C (H2O) (Lit.5 140–141 °C). For spectroscopic data, see
benzo[de]isoquinolin-4-ones 9 up to 67–89% by heating
2-naphthyl ethers 2 with a 1.1 molar excess of triazines 3
Ref.1d
in polyphosphoric acid at 40–45 °C for one hour, then at
100–115 °C for three hours (Table 1, entries 3, 5 and 7).
Compounds 11 were obtained in 68–91% yield by the re-
action of compounds 2 with a 2.5 molar excess of triazines
3 at 75–80 °C for five hours (Table 1, entries 4, 6 and 8).
4H-Benzo[de]isoquinolin-4-ones 9a,b
A mixture of the 2-naphthyl ether 2a or 2b (1 mmol) and the corre-
sponding 1,3,5-triazine 3a,b (1.1 mmol) in PPA (3–4 g) was stirred
at 40–45 °C for 1 h and then at 100–110 °C for 3 h. The reaction
mixture was poured into cold H2O (30 mL) with intense stirring.
The resulting mixture was extracted with EtOAc (3 × 50 mL); com-
pounds 11 were extracted. The aqueous layer was basified with am-
monia to pH 8–9 and, after cooling, the precipitated crystals or oil
was extracted with EtOAc (3 × 50 mL). The solution was concen-
In conclusion, the advantages of the described methods
for 1,6-diacylation (diformylation) and [cd]pyridine cycle
peri-annelation include reagent availability, experimental
Synthesis 2009, No. 20, 3439–3442 © Thieme Stuttgart · New York

PAPER
Regioselectivity in the Reaction of Naphthalenes with 1,3,5-Triazines
3441
trated under reduced presssure, and the residue was purified by
crystallization.
2-Methoxynaphthalene-1,6-dicarbaldehyde (11a)
Yield: 0.188 g (88%) from 2a with 3a; light yellow crystals; mp
158–159 °C (EtOH).
4H-Benzo[de]isoquinolin-4-one (9a)
IR (KBr): 1691, 1682 (C=O) cm–1.
Yield: 0.158 g (87%) from 2a with 3a; yield: 0.161 g (89%) from
2b with 3a; yellow crystals; mp 169–171 °C (EtOAc; with sublima-
tion).
IR (KBr): 1654 (C=O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.71 (d, J = 9.9 Hz, 1 H, H-5),
7.87 (dd, J = 7.3, 8.0 Hz, 1 H, H-8), 8.07 (d, J = 9.9 Hz, 1 H, H-6),
8.22 (dd, J = 7.3, 0.8 Hz, 1 H, H-7), 8.40 (dd, J = 8.0, 0.8 Hz, 1 H,
H-9), 9.31 (s, 1 H, H-1), 9.71 (s, 1 H, H-3).
1H NMR (300 MHz, CDCl3): d = 4.07 (s, 3 H, Me), 7.36 (d, J = 9.1
Hz, 1 H, H-3), 8.01 (dd, J = 9.1, 1.8 Hz, 1 H, H-7), 8.16 (d, J = 9.1
Hz, 1 H, H-4), 8.20 (d, J = 1.8 Hz, 1 H, H-5), 9.31 (d, J = 9.1 Hz, 1
H, H-8), 10.07 (s, 1 H, 6-CHO), 10.81 (s, 1 H, 1-CHO).
13C NMR (75 MHz, DMSO-d6): d = 56.57, 113.53, 116.65, 125.72,
127.03, 127.49, 132.60, 133.49, 134.98, 138.71, 165.53, 191.45,
191.61.
Anal. Calcd for C13H10O3: C, 72.89; H, 4.71. Found: C, 73.01; H,
4.64.
13C NMR (75 MHz, DMSO-d6): d = 96.60, 128.84, 129.28, 130.38,
131.27, 135.01, 135.63, 136.91, 137.41, 141.77, 145.96, 191.12.
MS (EI): m/z (%) = 181 (100) [M+], 153 (98), 126 (32).
2-Ethoxynaphthalene-1,6-dicarbaldehyde (11b)
Yield: 0.207 g (91%) from 2b with 3a; light yellow crystals; mp
147–148 °C (EtOH).
IR (KBr): 1690, 1681 (C=O) cm–1.
Anal. Calcd for C12H7NO: C, 79.55; H, 3.89; N, 7.73. Found: C,
79.68; H, 3.82; N, 7.65.
1,3-Dimethyl-4H-benzo[de]isoquinolin-4-one (9b)
Yield: 0.14 g (67%) from 2b with 3b; yellow crystals; mp 186–
188 °C (EtOAc; with sublimation).
IR (KBr): 1656 (C=O) cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.01 (s, 3 H, 1-Me), 3.03 (s, 3
H, 3-Me), 6.66 (d, J = 9.9 Hz, 1 H, H-5), 7.79 (dd, J = 7.3, 8.4 Hz,
1 H, H-8), 7.96 (d, J = 9.9 Hz, 1 H, H-6), 8.15 (dd, J = 7.3, 0.8 Hz,
1 H, H-7), 8.48 (dd, J = 8.4, 0.8 Hz, 1 H, H-9).
1H NMR (300 MHz, CDCl3): d = 1.54 (t, J = 6.9 Hz, 3 H, MeCH2),
4.34 (q, J = 6.9 Hz, 2 H, MeCH2), 7.36 (d, J = 9.1 Hz, 1 H, H-3),
8.05 (dd, J = 9.1, 1.8 Hz, 1 H, H-7), 8.19 (d, J = 9.1 Hz, 1 H, H-4),
8.25 (d, J = 1.8 Hz, 1 H, H-5), 9.37 (d, J = 9.1 Hz, 1 H, H-8), 10.11
(s, 1 H, 6-CHO), 10.90 (s, 1 H, 1-CHO).
13C NMR (75 MHz, DMSO-d6): d = 14.42, 65.32, 115.44, 124.46,
124.89, 126.12, 127.00, 132.12, 133.91, 134.14, 139.11, 165.01,
190.93, 191.67.
Anal. Calcd for C14H11NO: C, 80.36; H, 5.30; N, 6.69. Found: C,
80.52; H, 5.22; N, 6.61.
MS (EI): m/z (%) = 228 (54) [M+], 199 (87), 171 (43), 144 (36), 115
(100).
Anal. Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.79; H,
5.24.
Isoquino[6¢,5¢,4¢:10,5,6]anthra[2,1,9-def]isoquinoline (10)
A mixture of naphthalene (1; 0.128 g, 1 mmol) and 1,3,5-triazine
(3a; 0.12 g, 1.5 mmol) in PPA (3–4 g) was stirred at 65–70 °C for 3
h and then at 130–140 °C for 6 h. The reaction mixture was poured
into cold H2O (30 mL) with intense stirring. The resulting mixture
was basified with ammonia to pH 8–9 and, after cooling, the precip-
itated crystals or oil was extracted with EtOAc (3 × 50 mL). The so-
lution was concentrated under reduced pressure, and the residue
was purified by crystallization from pyridine.
Yield: 0.044 g (27%); yellow crystals; mp 326–328 °C (Lit.7 326–
328 °C).
1H NMR (300 MHz, CDCl3): d = 8.19 (d, J = 9.5 Hz, 4 H, H-4/7/11/
14), 9.22 (d, J = 9.5 Hz, 4 H, H-5/6/12/13), 9.61 (s, 4 H, H-1/3/8/
10).
1,6-Diacetyl-2-ethoxynaphthalene (11c)
Yield: 0.173 g (68%) from 2b with 3b; light yellow crystals; mp
172–173 °C (EtOH).
IR (KBr): 1736, 1678 (C=O) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52 (t, J = 6.9 Hz, 3 H, MeCH2),
2.69 (s, 3 H, 6-COMe), 3.07 (s, 3 H, 1-COMe), 4.18 (q, J = 6.9 Hz,
2 H, MeCH2), 7.09 (d, J = 9.1 Hz, 1 H, H-3), 7.73 (d, J = 8.8 Hz, 1
H, H-8), 7.86 (d, J = 9.1 Hz, 1 H, H-4), 7.99 (dd, J = 8.8, 1.8 Hz, 1
H, H-7), 8.38 (d, J = 1.8 Hz, 1 H, H-5).
Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.11; H,
6.23.
13C NMR (75 MHz, CF3CO2D): d = 123.72, 128.23, 129.68,
130.21, 130.99, 132.61, 136.24.
MS (EI): m/z (%) = 328 (100) [M+].
Acknowledgment
The authors are thankful to Dr O. Nadein for his assistance with
editing this manuscript.
Anal. Calcd for C24H12N2: C, 87.79; H, 3.68; N, 8.53. Found: C,
87.94; H, 3.59; N, 8.47.
References
1,6-Dicarbonyl Compounds 11; General Procedure
A mixture of the 2-naphthyl ether 2a or 2b (1 mmol) and the corre-
sponding 1,3,5-triazine 3a,b (2.5 mmol) in PPA (3–4 g) was stirred
at 75–80 °C for 5 h. The reaction mixture was poured into cold H2O
(30 mL) with intense stirring. After cooling, the precipitate was col-
lected by filtration and purified by crystallization.
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Synthesis 2009, No. 20, 3439–3442 © Thieme Stuttgart · New York