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Bischler-napieralski reaction by means of polyphosphate esters and synthesis of 5H-2-benzazepine derivatives
Tetrahedron Letters No.35, pp. 2119-2422, 1964. Pergamon Press Ltd. Printed in Great Britain.
BISCHLER-NAPIERAISKIREACTION BY iQ%NS OF FOLYPEOS'HATE ESTERS AND SYNTHEXS OF 5H-2-BENZAZFPINE DERIVATIVF3+'++
Yuichi Kanaoka, Eisuke Sate, Osamu Yonemitsu and Yoshio Ban Faculty of Pharmaceutical Sciences, Bokkaido University, Sapporo. Japan (Received 7 July 1964)
The recent report from our laboratory pointed out that polyphosphate esters 1 (PPE) may be useful as an agent for many condensation reactions. This communication describes the Bischler-Napieralskireaction by means of PPE in the synthesis of some dihydroisoquinolinestogether with the extensive application of this reaction in the synthesis of some 5%2-benzaeepine derivatives which have been rarely encountered in literatures as synthesized by cyclization of this type.2.3 PPE was prepared from phosphorous pentoxide and diethyl ether in chloroform solution and used -in situ 194.5 Amides of phenethylamine derivatives (Ia-d) were heated with 5 parts of PPE to afford corresponding dihydroisoquinolines (IIa-d) as shown in the Table 1.
Amides possessing benzene ring activated by substitu-
tion with methoxyl groups (Ia-b) were cyclised under extremely mild conditions. &substituted amides (Ic-d) were also cyclised under moderate conditions in good yields. PPE is thus shown to be a very good agent for conventional BischlerNapieralski reaction.6.7 In a similar manner, amides ofr-(3,4-dimethoryphenyl)-propylamine (IIIa-c)
l
l
Presented at the 19th Annual Meeting of the Pharmaceutical Society of Japan, April, 1964, Tokyo. *
Polyphosphate Esters as Synthetic Agent. Part II. Part I. ref. 1.
2419
2420
Bischler-Napieralski reaction
w
No.35
Rl = Me0
; R2 = Me
a
:
b
: Rl = Me0 i R2 = F'h
c
:
Rl =
H
; R2 = Me
H
;R2=Ph
N
d:Rl=
R2
were cyclixd to afford corresponding bases (IVa-c) as shown in the Table 1. Subsequent treatment of them with sodium borohydride gave reduced bases (Va-c). Infrared spectra of the bases (IVa-c) showed maxima at 1605 - 1630 cm-1 range (C= -1 N), which shifted to 1640 - 1660 cm range on salt formation. Ultraviolet spec-
Table 1. Bischler- Napieralski Reaction Products
Temp. ('c)'
Time (hr.)
Yields ($)
IIa
in chloroform refl.
0.5
78
IIb
in chloroform refl.
0.5
85
IIC
120
1.5
82
IId
120
1
89
IVa
120
1.5
76
IV-D
120
1
63
IVC
120
1
go**
l l
bath temp. * crude yield
No.35
trum patterns
of
in the Table
them and their These
2.
bathochromic
spectroscopic
change
behaviors
Table Ultraviolet Free
log
on protonation
the bases
are
IVtJ
263 297
3.70 3.68
301 346
3.77 3.81
IVC
239 305
4.27 3.67
270 380
4.10 3.80
with
in ethanol
those
in their
the cyclized
structures
indicated
the presence
of
singlets)
also
accord
in good
containing
hydrochloric
NMRspectra
(IVa-c).
two isolated with
aromatic
the structural
Table
Free Base
Picrate
166
197 -
198
Iv-b
140 143 ib.P.3)
183 -
184
222 (dec.)
Va
172 -
173
197 -
19e
Vb
115 120 (b.p.3)
163 -
165
VC
114 -
l
m.p.,
115
uncorrected
protons
the bases (3.15
assignment.
-
Perchlorate 234 (dec.) 190 -
191
246 - 247 (dec.)
and
(IV and V)
3.832
range,
These results
3.
165 -
oil
of
analogs’
of Benzazepines*
IVa
IVC
acid
6,7-dimethoxy-3,4-dihydroisoquinoline
Properties Compounds
in
logE
mP
4.05 4.14 4.09
in ethanol
definitely
Protonated**
E
246 326 363
**
described
the Benzazeipines
4.19 4.16 3.91
l
are
2.
of
236 273 312
IVa
confirm
Spectra
of
Base*
mp
parallel
2421
Bischler-Napieralski reaction
Methiodide 182 -
185
190 -
191
206 - 206.5 (dec.)
two
Birrchler-Napieralski reaction
2122
No.35
demonstra'iethat PPE is a reagent of choice for the synthesis of 3,4-dihydro-5A2-benzaeepine derivatives by the extended Bischler-Napieralskireaction. Physxal properties of 7,S-dimethoxy-3,4-dihydro-5A-2-benzazepines (IV), 7,8-dimethoxy-l,2,3,4-tetrahydro-5H-2-benzazapines (V) and the derivatives are listed in the Table 3.
Satisfactory results were obtained for all new compounds
on elemeni:alanalysis.
Acknowletiement
We are grateful to Professor Bn. S. Sugasawa for his valuable
advice. this work was supported by Grant-in-Aid for Developmental Scientific Research from Ministry of Education of Japan and Grant (MI 03187-01) from the National Xstitutes of Health, United States Public Health Service, which are gratefully acknowledged.
References 1. Y. Kanaoka, 0. Yonemitsu, K. Tanieaua and Y. Ban, Chsm. Pharm. Bull. g, in press. 2.
5. Uyoo, 19th IUPAC Absts. A, London, p. 12 (1963).
3.
IL Tonita and S. Minaai, Takwaku Zasshi 2,
4.
G. Schramm, H. Groetsch and W. Pollmann, Anu. Chem. Int. Rdn. A, 1 (1962).
1022 (1%3).
5. W. Po:.lmannand C. Schramm, Biochim. Biouhys. Acta 80, 1 (1964). 6. W. M. Whaley and T. T. Covindachari, Oruanic Reactions Vol. VI, p. 74 (19511. 7.
8. R. Snyder and F. X. Yerber, J. Am. Chem. Sot. &
8.
Y. Ban, 0. Yonemitsu and M. Terashima. Chem. Pharm. Bull. 2, 194 (1960).
2962 (1950).
BISCHLER-NAPIERAISKIREACTION BY iQ%NS OF FOLYPEOS'HATE ESTERS AND SYNTHEXS OF 5H-2-BENZAZFPINE DERIVATIVF3+'++
Yuichi Kanaoka, Eisuke Sate, Osamu Yonemitsu and Yoshio Ban Faculty of Pharmaceutical Sciences, Bokkaido University, Sapporo. Japan (Received 7 July 1964)
The recent report from our laboratory pointed out that polyphosphate esters 1 (PPE) may be useful as an agent for many condensation reactions. This communication describes the Bischler-Napieralskireaction by means of PPE in the synthesis of some dihydroisoquinolinestogether with the extensive application of this reaction in the synthesis of some 5%2-benzaeepine derivatives which have been rarely encountered in literatures as synthesized by cyclization of this type.2.3 PPE was prepared from phosphorous pentoxide and diethyl ether in chloroform solution and used -in situ 194.5 Amides of phenethylamine derivatives (Ia-d) were heated with 5 parts of PPE to afford corresponding dihydroisoquinolines (IIa-d) as shown in the Table 1.
Amides possessing benzene ring activated by substitu-
tion with methoxyl groups (Ia-b) were cyclised under extremely mild conditions. &substituted amides (Ic-d) were also cyclised under moderate conditions in good yields. PPE is thus shown to be a very good agent for conventional BischlerNapieralski reaction.6.7 In a similar manner, amides ofr-(3,4-dimethoryphenyl)-propylamine (IIIa-c)
l
l
Presented at the 19th Annual Meeting of the Pharmaceutical Society of Japan, April, 1964, Tokyo. *
Polyphosphate Esters as Synthetic Agent. Part II. Part I. ref. 1.
2419
2420
Bischler-Napieralski reaction
w
No.35
Rl = Me0
; R2 = Me
a
:
b
: Rl = Me0 i R2 = F'h
c
:
Rl =
H
; R2 = Me
H
;R2=Ph
N
d:Rl=
R2
were cyclixd to afford corresponding bases (IVa-c) as shown in the Table 1. Subsequent treatment of them with sodium borohydride gave reduced bases (Va-c). Infrared spectra of the bases (IVa-c) showed maxima at 1605 - 1630 cm-1 range (C= -1 N), which shifted to 1640 - 1660 cm range on salt formation. Ultraviolet spec-
Table 1. Bischler- Napieralski Reaction Products
Temp. ('c)'
Time (hr.)
Yields ($)
IIa
in chloroform refl.
0.5
78
IIb
in chloroform refl.
0.5
85
IIC
120
1.5
82
IId
120
1
89
IVa
120
1.5
76
IV-D
120
1
63
IVC
120
1
go**
l l
bath temp. * crude yield
No.35
trum patterns
of
in the Table
them and their These
2.
bathochromic
spectroscopic
change
behaviors
Table Ultraviolet Free
log
on protonation
the bases
are
IVtJ
263 297
3.70 3.68
301 346
3.77 3.81
IVC
239 305
4.27 3.67
270 380
4.10 3.80
with
in ethanol
those
in their
the cyclized
structures
indicated
the presence
of
singlets)
also
accord
in good
containing
hydrochloric
NMRspectra
(IVa-c).
two isolated with
aromatic
the structural
Table
Free Base
Picrate
166
197 -
198
Iv-b
140 143 ib.P.3)
183 -
184
222 (dec.)
Va
172 -
173
197 -
19e
Vb
115 120 (b.p.3)
163 -
165
VC
114 -
l
m.p.,
115
uncorrected
protons
the bases (3.15
assignment.
-
Perchlorate 234 (dec.) 190 -
191
246 - 247 (dec.)
and
(IV and V)
3.832
range,
These results
3.
165 -
oil
of
analogs’
of Benzazepines*
IVa
IVC
acid
6,7-dimethoxy-3,4-dihydroisoquinoline
Properties Compounds
in
logE
mP
4.05 4.14 4.09
in ethanol
definitely
Protonated**
E
246 326 363
**
described
the Benzazeipines
4.19 4.16 3.91
l
are
2.
of
236 273 312
IVa
confirm
Spectra
of
Base*
mp
parallel
2421
Bischler-Napieralski reaction
Methiodide 182 -
185
190 -
191
206 - 206.5 (dec.)
two
Birrchler-Napieralski reaction
2122
No.35
demonstra'iethat PPE is a reagent of choice for the synthesis of 3,4-dihydro-5A2-benzaeepine derivatives by the extended Bischler-Napieralskireaction. Physxal properties of 7,S-dimethoxy-3,4-dihydro-5A-2-benzazepines (IV), 7,8-dimethoxy-l,2,3,4-tetrahydro-5H-2-benzazapines (V) and the derivatives are listed in the Table 3.
Satisfactory results were obtained for all new compounds
on elemeni:alanalysis.
Acknowletiement
We are grateful to Professor Bn. S. Sugasawa for his valuable
advice. this work was supported by Grant-in-Aid for Developmental Scientific Research from Ministry of Education of Japan and Grant (MI 03187-01) from the National Xstitutes of Health, United States Public Health Service, which are gratefully acknowledged.
References 1. Y. Kanaoka, 0. Yonemitsu, K. Tanieaua and Y. Ban, Chsm. Pharm. Bull. g, in press. 2.
5. Uyoo, 19th IUPAC Absts. A, London, p. 12 (1963).
3.
IL Tonita and S. Minaai, Takwaku Zasshi 2,
4.
G. Schramm, H. Groetsch and W. Pollmann, Anu. Chem. Int. Rdn. A, 1 (1962).
1022 (1%3).
5. W. Po:.lmannand C. Schramm, Biochim. Biouhys. Acta 80, 1 (1964). 6. W. M. Whaley and T. T. Covindachari, Oruanic Reactions Vol. VI, p. 74 (19511. 7.
8. R. Snyder and F. X. Yerber, J. Am. Chem. Sot. &
8.
Y. Ban, 0. Yonemitsu and M. Terashima. Chem. Pharm. Bull. 2, 194 (1960).
2962 (1950).