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Syntheses of Heterocycles by Intramolecular Acylation of Nitrile-Hydrogen Halide Adducts.

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[62] E. L. Elief: Stereochemistry of Carbon Compounds. McGrawH111,New York 1962, p. 189; German Translation. Verlag Chemie,
Weinheim 1966. p. 233.
[63] a) In the fast acid hydrolyses of cyclic phosphates (Section 5.3).
phosphonates (Section 5.4) and in a slightly different manner, diethyl2-carboxyphenyl phosphonate [63 b, c] ria cyclic oxyphosphoranederivatives, an equatorial hydroxyl is formed from the phosphoryl oxygen
due to the constraints involved; b) M . Gordon, V A. Nataro, and C . E.
Grij'n, J. Amer Chem. Soc. 86, 1898 (1964); c) G . M Blackburn and
M . J . Brown, ibid. 91, 525 (1969).
[64] The literature on Berry pseudorotation was reviewed in Refs.
[2,29]. See also Refs. [65-671.
[65] G . M . Whitesides and H. L. Mitchell, J. Amer. Chem. SOC.91, 5384
(1969).
[66] Review articles: E. L. Muetterties, Accounts Chem. Res. 3. 266
(1970); Rec. Chem. Progr. 31, 51 (1970).
[67] D. Gorenstein and F . H . Westbeimer, J. Amer. Chem. SOC.92.
634 (1970).
[68] D. Bernard and R. Burgada, C. R. Acad. Sci. Paris 271(c),418 (1970).
[69] R . M . Smith and R. A . Alberty, J. Phys. Chem. 60, 180 (1956):
R. A. Alberty, J. Biol. Chem. 244, 3290 (1969); R. C . Phillips, P. George,
and R. J . Rutman, ibid. 244, 330 (1969); P. M! Schneider, H . Brintzinger,
and H. Erlenmeyer, Helv. Chim. Acta, 47, 992 (1964); C. A . Bunton,
D. R. Llewellyn, K . G . Oldham, and C . A . Vernon, J. Chem. Soc. 1958,
3574.
[70] P. D. Boyer and M . P . Stulberg, Proc. Nat. Acad. Sci. U. S . 44.92
(1958); M.Cohn and 1. Reuben, Accounts Chem. Res. 4,214 (1971)
[71] C. Liebecq and M . Jocquemotte-Louis, Bull. Soc. Chim. Biol 40.
759 (1958).
[72] Review article: H . Sigel and D. B. McCormick, Accounts Chem.
Res. 3, 201 (1970).
[73] J . I . Musher. J. Amer. Chem. Soc. 94, 5662 (1972)
Syntheses of Heterocycles by Intramolecular Acylation of
Nitrile-Hydrogen Halide Adducts
By Gerhard Simchen and Giinther Entenmann"]
Five-membered, six-membered, and seven-membered aza-, diaza-, and thiazaheterocycles
can be prepared by cyclization of w-cyano carboxylic acid halides in the presence of hydrogen
halides in aprotic solvents. Nitrite-hydrogen halide adducts occur as intermediates in this
novel heterocycle synthesis of wide application. The acylating cyclizations of nitriles in
protonic media, which proceed via imidic esters or amides, are not discussed.
1. Introduction
2. Nitrile-Hydrogen Halide Adducts
Heterocycle syntheses with nitriles as reactants are very
numerous. The nitrile group often acts only as an electrophile in these syntheses, i.e.only the carbon atom is incorporated into the ring system, with formation of amino-substituted heterocycles['.2! Ring closure reactions with
incorporation of the entire nitrile group are usually preceded by the conversion of this group into an imidic ester or a
carboxamide groupr3- 'I. Developments of the past 15 years
include syntheses of heterocycles from nitriles by 1,3dipolar cycloadditi~n[~I
and on the basis of nitrilium
These syntheses will not be discussed here.
Reaction products ofnitriles with hydrogen halides, though
discovered by Guutier['21in 1867, received little attention
until recently. In 1964, AZZenstein et u1.[13.141
succeeded in
establishing the structure of adducts of nitriles or thiocyanates with hydrogen chloride, bromide, and iodide. The
isolable, thermally unstable substances (the adduct of
acetonitrile and hydrogen chloride decomposes at 6 "C)
were found to be compounds of the imidium acid halide
halide (amide halide) type ( I ) . Their stability increases
with the acidity of the hydrogen halide.
The nitrile nitrogen is only weakly nucleophilic. Thus the
presence of Lewis acids is necessary for the formation of
alkylnitrilium and acylnitrilium salts[9].Only very reactive
acyl halides, such as malonyl chloride, react directly with
nitriles to form heterocycles['0.' 'I. An intramolecular
acylation leading to heterocycles is possible with hydrogen
halide adducts of w-cyanoacyl chlorides.
(I), X
= C1.
Br. I
Adducts with complex anions are more stable, comparable
with the "amide fluorides" (2)['51.
[*] Priv.-Doz. Dr G. Simchen and Dr. G. Entenmann
Institut fur Organische Chemie, Biochemie and Isotopenforschung
der Universitat
7 Stuttgart 1, Azenbergstrasse 14 (Germany)
Angers. Chvm rnrernnt Edii.
1 Yo/ 12
( i Y 7 3 ) f No. 2
119
Imidoyl halides having the structure ( 3 ) have not so far
been i~olated['~.''~.
The addition of one mole of HX evidently increases the basicity to such a degree that a further
NH
(3)
R-C:
X
mole of HX can be rapidly taken up. Imidoyl halides are
postulated not only for the formation of the "amide
halides" ( I ) but also for many reactions of nitriles that are
catalyzed by hydrogen halides. The adduct ( 4 ) of malodini-
to a heterocycle having a reactive haIogen atom. The
initially formed cyclic N-acylimidoyl halides (7) are
stabilized in many cases by prototropy (see Section 4).
3.1. 6-Halo-2-pyridones
Non-cyclic esters of P-keto acids react with cyanoacetic
acid to form esters of cis- and trans-P,y-unsaturated y-cyano
carboxylic acids" l,zzl, from which the acids are obtained
by hydrolysis, and the acyl chlorides (8a) are then obtained
as crude products by reaction with phosphorus pentachloride. The corresponding cycloalkanecarboxylic acids
give mixtures of the a$- (86) and P,y-unsaturated acyl
chloride ( 8 c ) in these reactions.
trile and hydrogen bromide deserves mentionLL8'.In this
case a 1 :1 adduct is stabilized, as it were, by tautomerization
to the a-bromoenamine.
Nitrile-hydrogen halide adducts of the type ( 1 ) react with
nucleophiles such as water, alcohols, and carboxylic
acids"91. The trimerization of nitriles to s-triazines may
also belong to this class of reactions.
The course of the synthesis of many heterocycles from
a,o-dinitriles with hydrogen halides is uncertain. Johnson
and Madronero[61have invoked nucleophilic attack of a
nitrile group on an "amide bromide" function in their
interpretation.
3. Electrophilic Reactions on Nitrile-Hydrogen
Halide Adducts
H
R = CH,, C & , (86). n
=
(8c), n = 3, 4, 5
3, 4, 5
The acyl chlorides (8a) and ( 8 b ) / ( 8 c ) in the pure form
remain unchanged in inert solvents. However, if hydrogen
chloride is passed into solutions of these substances in
etherldi-n-butyl ether, with subsequent heating to [email protected],
one obtains 6-chloro-2-pyridones (9 a) and (9 b)1223231
(Table I)[*].
Since the ring closure does not occur in the
absence of hydrogen chloride, the acylation must take place
on an intermediate hydrogen chloride adduct.
Table 1. 6-Chloro-2-pyridones ( 9 a ) and ( 9 b ) from ( 8 a ) and from
(86///8 c ) .
The increased nucleophilicity of the adducts in comparison
with the nitriles should facilitate electrophilic reactions on
the nitrogen. It should not, however, be overlooked that
such addition compounds are present only in low concentrations, particularly at elevated temperatures. The isolation of N-acylation products therefore depends on the
possibilities of stabilizing them.
Initial attempts to prepare N-acylimidoyl chlorides ( 5 )
by reaction of nitriles with acyl chlorides in the presence
of hydrogen chloride[z01were unsuccessful.
When this reaction was applied to o-cyanoacyl halides
(6), however, a novel synthesis of wide application was
found for five-membered, six-membered, and seven-membered heterocycles.Significantly,the synthesis leads directly
120
R/n
( 9 a ) , CH,
(Ya), C,H,
(9b), 3
(961% 4
Conditions
6h,50°C
6h,50°C
4 h, 60°C
7 h, 80°C
Yield
PA][a]
M.p.["C]
37
63
156- 158
166-168
182- 184
187-190
35
38
[a] The yields are based on the carboxylic acids from which ( 8 a ) and
(86//(8c) are derived.
Adducts with hydrogen bromide and with hydrogen iodide
are more nucleophilic and thermally more stable than those
with hydrogen chloride. This is confirmed by the extremely
fast cyclization of (8a) and (8b)/(8c) (15-30 min at O°C)
in the presence of hydrogen bromide or hydrogen iodide[z41.
The initial products are salt-like adducts of the hydrogen
halides with 6-bromo-2-pyridones and 6-iodo-2-pyridones.
The 6-halo-2-pyridones (IOa) and (IOb) are obtained
from the adducts by treatment with aqueous sodium
hydrogen carbonate solution (Table 2).
[*] It should he noted that the mixture (86)/(8c) is converted exclusively into ( 9 b ) .
Angew. Chem. infernat. Edit.
/ Vol. I2 ( 1 9 7 3 ) / Nu. 2
Table 3. 6-Chloro-5-aryl-3,4-dihydro-2(lH)-pyridinones (12) from
A
y
0
(11).
C1
Yield
Ar
[XI
..
80
79
88
85
Phenyl
4-Chlorophenyl
4-Methoxyphenyl
4-Nitrophenyl
H
-
M. p. ["C]
180- 184
193- 195
115-118
240-245
y-hydrogen in (11) is replaced by a methyl group, the ring
closure does not occur[251.
3.3. Halogenated Isoquinolines
1-1.5 HX
H
H
Table 2. 6-Halo-2-pyridones ( I O a ) and ( I O b ) from ( 8 a ) and from
(8bll(8c).
R/n
( I O a ) , CH,
( I O a ) , C6H5
( I O a ) , C,H5
11Ob/, 3
(lob), 4
(10b), 4
(lob), 5
X
Conditions
Br
Br
I
Br
Br
I
Br
30rnm,0°C
30 rnin, 0°C
15 rnin.O"C
30 min, 0°C
30 min, 0°C
15 min,O"C
30 min, 0°C
Yield [%][a]
24
80
61
24
38
40
32
M.p.["C]
149-151
114-116
199-201
114-115
195- 196
192-193
171
[a] The yields are based on the carboxylic acids from which ( 8 a ) and
( 8 6 ) / ( 8 c ) are derived.
3.2. 6-Chloro-3,4-dihydro-2(1H)-pyridinones
The N-acylimidoyl halides formulated as precursors of the
2-pyridones ( 9 ) and (10) are stabilized by formation of
the ring-conjugated pyridone system. The question whether
this is essential for the ring closure can be examined in the
reaction of 4-aryl-4-cyanobutyryl chlorides (11)[251with
hydrogen chloride. The compounds (11) can be distilled
unchanged at temperatures above 100°C. However, if
solutions of (11) in dioxane saturated with hydrogen
chloride are heated for 6 h at 60°C, 6-chloro-S-ary1-3,4dihydro-Z(1H)-pyridinones (I2 ) are formed in excellent
yieldsrzs1(Table 3).
The driving force of the cyclization is evidently the formation of the u-chloroenamide structure in (12). If the
In view of the great importance and the widespread use of
isoquinolines, it would be of interest to synthesize them
on the basis of the principle described. Most of the earlier
isoquinoline syntheses involve intramolecular electrophilic substitution on the benzene ring. Satisfactory yields
are therefore obtained only if the carbocyclic ring is activated by suitable + M or + I substituents[Z6-281.An
interesting method that was recently described for the
preparation of 1,3dichloroisoquinolines from arylacetonitriles and phosgene in the presence of hydrogen chloride
offers no
Isoquinoline derivatives with
activating substituents on C-8 were practically unknown in
the past, since the cyclization occurs almost exclusively in
position 4 with respect to the activating group['*]. Little
investigation has been devoted to syntheses that give isoquinolines in good yields irrespective of the nature and
position of the substituent; examples are the amidation
of i s o c o ~ m a r i n s [ the
~ ~ ~reaction
,
of homophthalic acids
with amine~['~],
and the cyclization of o-cyanomethylben~onitriles[~with hydrogen bromide, which leads to
1-bromo-3-aminoisoquinolines.
3.3.1. 3-Halo-I-isoquinolones
The starting materials for the cyclization are 2-cyanomethylbenzoyl chlorides (I4), which are obtained either from
phthalides by reaction with potassium cyanide[321and
then with phosphorus pentachloride or by Beckmann
rearrangement of the second kind[331from 2-oximino-Iindanones (13)r341. 2-Oximino-I-indanones are readily
obtainable by nitrosation of I-indanones with alkyI nitrites
in the presence of hydrochloric acidr341.
Saturation of solutions of 2-cyanomethylbenzoylchlorides
(14) in dioxane with hydrogen chloride and heating for a
few hours at 60--70°C leads to 3-chloro-I -isoquinolones
(15)[34*351
(Table 4).
- wHzcN
x
_-
X
$&)=NOH
PCIS
n
-POCI,
-HCI
COCl
H
I
Ar-C-CH,-CH,-COCl
&N
5
Anyew. Chem. internar. Edit.
Vol. 12 (1973)
c1
y
0
1 No. 2
121
Table 4. 3-Chloro-I -isoquinolones ( I S ) from 2-cyanomethylbenzoyl
chlorides (14).
X
Yield
H
5-Methyl
7-Methyl
5-Methoxy
6-Methoxy
7-Methoxy
7-Chloro
6,7-Dimethoxy
6,s-Dimethoxy
6,7,8-Trimethoxy
8-Chloro-5-methyl
5-Chloro-8-methyl
5,S-Dimethyl
7-Nitro
1x3 [a]
76
75
72
72
100
50
68
14
77
40
96
70
89
100
M.p.["C]
210-215
243.5
223-224
246 - 247
228-229
241
253-254
264-265
201 -202
211-212
250-251
281 -282
244 - 245
323-325
hydrogen chloride, and heating for a few hours at 60°C,
one obtains 3-chloro-I -isoquinolones (15) as intermediates. After further addition of an equimolar quantity of
phosphorus pentachloride and heating at 8 ~ 1 0 0 ° C the
,
components react to form 1,3dichIoroisoquinolines
(16)[361.
2-Cyanomethylbenzoicacid is used as the starting
material for the preparation of 1,3dichloroisoquinoline
(16a) (Table 5).
X
X
02
NOH
+2
HC!_
PC1,
0
QC1
"1
(16) L1
+ 2 POCI.3 + 2 HC1
- acl
[a] The yields of ( I S ) are based on 2-oximino-1-indanones (13)
+2
PC1,
HC'
The rate of the cyclization increases with the hydrogen
chloride concentration. If the reaction is carried out at low
hydrogen chloride concentrations, e.g. in di-n-butyl ether,
side reactions due to acylation of already formed (15) are
observed in the case of inert acyl chlorides (14)[34'.
+
2 POCl, + 2 HC1
Table 5. 1,3-Dichloroisoquinolines ( 1 6 ) from 2-oximino-I-indanones
(13)
X
Yield
[x]
H3C0eCH2C
61
H3C0
0
H [a1
5-Methyl
7-Methyl
5-Methoxy
6-Methoxy
7-Methoxy
7-Chloro
6,7-Dimethoxy
8-Chloro-5-methyl
5-Chloro-%methyl
5,S-DimethyI
7-Nitro
H3c0wc1
.
H3C0
.
0-CO
M.p.["C]
120
121
113-114
166 - 167
91- 93
169-170
166- 168
200-201
146-148
165-166
136- 137
176-1 80
85
80
80
57
62
77
76
90
70
44
64
H3c0eH2cN
[a] ( I 6 a ) ; prepared from 2-cyanomethylbenzoic acid.
OCH,
3.3.3. I-Halo-3-hydroxyisoquinolines
3-Bromo-I -isoquinolone (15a) and 3-iodo-1-isoquinolone
(15b) are obtained particularly readily and in quantitative yield from 2-cyanomethylbenzoylchloride with hydrogen bromide and hydrogen iodide respectively in ether at
0°Cr341(2 h and 20 min respectively).
CH2CN
acoc1
(15a)o
3.3.2. 1,3-Dichloroisoquinolines
By analogy with the synthesis of 3-chloro-I-isoquinolones
(IS), it seemed reasonable to attempt the preparation of
1,3-dichloroisoquinolines(16) by a "single-reactor method" from 2-oximino-I-indanones (13). By Beckmann
rearrangement of (13) with phosphorus pentachloride in
phosphorus oxide chloride as the solvent, saturation with
122
A feature common to all the syntheses described so far is
the electrophilic attack of chlorocarbonyl groups on hydrogen halide adducts of aliphatic nitriles, i.e. of compounds
whose cyano groups are not directly attached to an aromatic nucleus. Whether the much less stable hydrogen halide
adducts of aromatic nitriles can be acylated should be
shown by corresponding reactions with (2-cyanopheny1)acetyl chlorides. (2-Cyanopheny1)acetic acids ( I 7) are
obtained from oxindoles by alkaline hydrolysis followed
by a Sandmeyer reaction with copper(1) cyanide, or from
(2-nitropheny1)acetic acids, which are reduced and again
subjected to a Sandmeyer reaction13' - 391.
If (2-cyanopheny1)aceticacids ( I 7) are first converted into
the acyl chlorides by reaction with phosphorus pentachloride in di-n-butyl ether or etherldi-n-butyl ether at
20°C, followed by saturation of these solutions with hydrogen chloride and standing for about 12 h, l-chloro-3hydroxyisoquinolines (18) precipitate in excellent
In the preparation of I-bromo- (19) and 1iodo-3-hydroxyisoquinolines (20)r391,
after the reaction
of ( I 7) with phosphorus pentachloride, the phosphorus
oxide chloride and the solvent are first distilled off and
the crude product is taken up in ether. Hydrogen bromide
Angew. Chem. internat.
Edit. f Vol. 12 (1973) J N o . 2
or hydrogen iodide is introduced at 0°C until the solution
is saturated; after a few minutes, (19) or (20) is obtained
in the form of the hydrogen halide adduct (Table 6).
(21) 0
Yields above 50% were unobtainable; the reaction is an
equilibrium process.
3.5. Diazaheterocycles
As can be seen from the heterocycle syntheses described
(19), X
(20). x
=
Br
= I
Table 6. I-Halo-3-hydroxyisoquinolines (18)-(20) from (2-cyanopheny1)acetic acids (17).
X'
(IS),H
(191, H
(20), H
( 1 8 ) , 6-Methyl
(19). 6-Methyl
(ZO), 6-Methyl
( I S ) , 7-Methyl
(191, 7-Methyl
(18), 6-Chloro
( 1 9 ) , 6-Chloro
(IS)? 6-Bromo
(19). 6-Bromo
( 2 0 ) , 6-Bromo
(IS), 6-Methoxy
(19),6-Methoxy
(20). 6-Methoxy
( I S ) , 7-Methoxy
( I s ) , 6.7-Dimethoxy
(19), 6,7-Dimethoxy
(ZO), 6,7-Dimethoxy
X
Yield[%]
M.p.["C]
CI
Br
79
83
81
84
82
70
94
84
80
70
70
89
85
72
13
85
70
69
75
61
205-206
179-1 82
154-1 57
194-196
188-190
165-167
194-1 96
193-195
219-221
204-206
226-227
197-199
180-1 82
21 1
191-193
180-182
230-232
226-227
207-21 0
220-222
I
c1
Br
I
c1
Br
C1
Br
CI
Br
I
CI
Br
I
C1
C1
Br
I
in the foregoing sections, nitrile-hydrogen halide adducts
can be acylated on the nitrogen if stabilization of the cyclic
N-acylimidoyl halide is possible by tautomerization
(Sections 3.1 and 3.2) or by formation of a ring-conjugated
6a-electron system (Sections 3.3 and 3.4).
Substantial expansions of the synthesis result from variation of the acyl halide function. For example, stable
heterocycles should also be obtained on replacement of
the chlorocarbonyl group by a chlorocarbonylamino
group.
3.5.1. 4-Halo-2-quinazolones
Reaction of o-cyanophenyl isocyanates (22) with hydrogen
halide at room temperature in di-n-butyl ether leads first
to carbamoyl halides (23), which cyclize at about 70°C
in the presence of an excess of hydrogen halide to form
4-halo-2-quinazolones (24)[441
(Table 7).
Investigations on the reaction course showed that though
(18) is formed more slowly than the chlorine analog (16),
the differences are small and are not noticeable at high
hydrogen halide concentration^^^'^.
The syntheses described in Sections 3.3.1 to 3.3.3 all give
isoquinolines in equally good yields, irrespective of the
nature and position of the substituents in the aromatic
compounds. The isoquinoline derivatives in Tables 4 6
have not been described before or were hitherto obtainable
only with considerable difficulty.
3.4. 3-Chloro-2-benzazepin-1-one
In all the ring closure reactions discussed so far the final
product is stabilized by a proton shift (cf. Section 3.2).
The question whether the proton shift is a necessary criterion, i.e. whether cyclization does not also occur if bond
systems obeying the Hiickel rule are formally to be expected directly, has been investigated for the reaction of
2-(cis-2-cyanovinyl)benzoyl chloride with hydrogen chloride in dioxane (70"C, 5 h). The reaction did in fact lead
to the previously unknown 3-chloro-2-benzazepin-I-one
(benzazatropone) (21), which may be regarded as a heteroaromatic ~ y s t e r n [ ~ * . ~ ~ !
Angew. Chem. infernaf Edit.
1 Vol. 12 (1973) 1 N o . 2
X
(24) l!I
Table 7. 4-Halo-2-quinazolones ( 2 4 ) from (22).
X
R
Yield
Chloro
Bromo
Chloro
H
87
78
77-85
H
Bromo
PA]
M.p.["C]
21 3
[a1
250-255
[a] The compound is susceptible to hydrolysis. The melting points
found in several experiments range from 280 to 320°C.
The synthesis of 4-chloro-2-quinazolones can also be
carried out as a "one-reactor process" by introduction of
phosgene into a suspension of 2-cyanoanilinium chloride
in dibutyl ether at 120"C, followed by the introduction of
hydrogen chloride at 80°C.
Reference should be made at this point to the formally
similar reaction of nitriles with phosgene to form 6-chloro2,5-disubstituted 4-pyrimidones as described by Yanagida
however, the ring closure in this case is carried
et
out by intramolecular C-acylation of an enamine.
123
3.5.2. 4-Chloro-2-thioquinazolone
o-Cyanophenyl isothiocyanate, which is readily obtainable
from o-cyanoaniline and thiophosgene, can be cyclized
with hydrogen chloride in analogy with the reactions
described above to give 4-chloro-2-thioquinazolone(25).
The yield is 70%[441.
Table 9. 2-Chloro-1,3-thiazin-4-ones
of the type ( 2 9 ) .
Yield [ %]
R
c1
M. p. PC]
(25) H
3.6. 1,3-Thiazaheterocycles
Cyclization of @-unsaturated P-thiocyanatoacyl chlorides
with hydrogen halides should yield heterocycles that are
formally derived from 3-chloro-2-benzazepin-I-one (21) by
replacement of a vinylene grouping by sulfur.
cis-P-Thiocyanatoacrylicacid (28a) is formed by addition
of potassium thiocyanate to acetylenemonocarboxylic
acid in dilute sulfuric acid. The acids (28b) and (28c) are
prepared by reaction of 2-chloro-I-formyl-I-cyclopentene
and 2-chloro-l-formyl-l-cyclohexene,
respectively, with
potassium thiocyanate, followed by oxidation with chromium trioxide.
3.6.1. 2-Chloro-I ,3-benzothiazin-4-ones
When a solution of an o-thiocyanatobenzoyl chloride (26)
in an ether/dibutyl ether mixture saturated with hydrogen
chloride is heated (5 h, 70°C), 2-chloro-l,3-benzothiazin4-ones (27) are obtained in good yields1461(Table 8).
Similarly,
2-chloronaphtho[2,3-e]-[1,3]-thiazin-4-one
(27a) is obtained from 3-thiocyanato-2-naphthoyl chloride.
X
3.6.3. 2-Chloro-l,3-selenazin-4-ones
When 2-selenocyanatobenzoyl chloride (30) is heated for
5 hours in dioxane saturated with hydrogen chloride, one
obtains 2-chloro-l,3-benzoselenazin-4-one
(31) having a
melting point of 125-126°C in 59%
2-Chloroselenenylbenzoyl chloride is also formed by cleavage of
(30)[461.
X
Table 8. 2-Chlor-l,3-benzothiazin-4-ones
( 2 7 ) from (26)
X
H
7-Chloro
6-Chloro
7-Methoxy
6-Methoxy
7-Nitro
6-Nitro
(270)
Yield
PA]
74
13
74
88
61
73
80
16
M.P C"C1
-__
.-
115-1 17
149-1 50
178
164-165
162
188-190
14&142
116-1 78
The cyclization of $-selenocyanatoacryloyl chloride (32)
to form 2-chloro-l,3-selenazin-4-one
(33) proceeds in poor
yield with hydrogen chloride in dibutyl ether at 80°C.
The main reaction here is probably the cleavage of the
selenocyanate group to give selenenyl chloride and hydrogen cyanideL4'!
H
H
x
SeCN
COCl
N
(32)
The acyl chlorides (26) need not be isolated; the crude
products obtained by reaction of the o-thiocyanatobenzoic
acids with phosphorus pentachloride can be cyclized to
form (27).
After these investigations had been closed, we learned of
a method for the preparation of 2-chloro-1,3-benzothiazin-4-ones by reaction of 2-thiocyanatobenzoic acids with
thionyl chloride in the presence of catalytic quantities of
dimethylf~rmarnide~~~~.
3.6.2. 2-Chloro-1,3-thiazin-4-ones
On reaction of cis-P-thiocyanatoacrylic acid (28a) in
ether at 0°C with phosphorus pentachloride and introduction of dry hydrogen chloride into the solution, 2-chloro-I ,3-thiazin-4-one (29 a) precipitatesr4'l. The derivatives
(29 b) and (29 c) are obtained in a similar manner (Table 9).
124
ti
(33)
3.6.4. 2-Chloro-5,6dihydro-1,3-thiazin-4-one
If hydrogen chloride is led into a solution of P-thiocyanatopropionyl chloride (34) in ether at O T , 2-chloro-5,6dihydro-l,3-thiazin-4-one(35) crystallizes out after one
hourr4']. It was thus possible, by acylation of a nitrilehydrogen halide adduct, to synthesize a heterocyclic
HzC'
SCN
I
H2c'coc1
(34)
0
(35)
compound that is not stabilized by tautomerization or by
formation of a 6n-electron system. (35) is not very stable,
Angew. Chem. internat. Edit. 1 Vol. 12 (1973)
No. 2
and is reconverted into (34) on standing for several days
at room temperature. (35) also exhibits a number of
peculiarities in its reactions. Whereas the halogen in the
thiazinones (27) and (29) is smoothly replaced in reactions with nucleophiles, ring cleavage predominates in (35).
R = H, CH,
X = C,H5, CH,, C1
2 = CGH5, C1
Perhydro-l,3-thiazine-2,4-dione
is obtained by hydrolysis
of (35)1481or by reaction of P-thiocyanatopropionic acid
with thionyl chloride[491.
4. Course of the Reaction
3.6.5. 2-Chloro-4-thiazolones
Though many six-membered and seven-membered heterocycles have been synthesized, it is not yet known whether
smaller rings are also obtainable by cyclizing acylation of
nitrile-hydrogen halide adducts. As an example we chose
the cyclization of a-thiocyanatoacyl chlorides, partly
because of the interesting properties of the expected
4-thiazolones.
On saturation of a solution of a-thiocyanatopropionyl
chloride or of a-thiocyanatoisobutyryl chloride in absolute
ether with dry hydrogen chloride at -20 to 0 ° C the
5-substituted 2-chloro-4-thiazolone (36a) or (36 b ) crystallizes out after a short timef501[(36a), m.p. 55"C, yield
64%; (36b), m. p. 81-83"C, yield 74x1.
(36a). R
(36h). R
Detailed investigations on the mode of formation of 3-haloI-isoquinolones (15) have proved that nitrile-hydrogen
halide 1,2-adducts (39) occur as intermediates.
(39)
Since an electrophilic attack of the carbonyl group on the
imonium group is not very probable, we assume that ahaloenamines (40) occur as intermediates.
= H
= CH3
5,5-Dimethyl-2-chloro-4-thiazolone
(366) is a stable crystalline substance ; (36 a) decomposes on prolongebstanding at room temperature, with development of a yellow
color.
The existence of a-haloenamines has been detected e.g. by
D/H exchange on methyl [a,a-D2]-2-cyanomethylbenzoate
(41) with dry hydrogen chloride in dioxane at 50°C.
3.6.6. Ring Systems with Three Hetero Atoms
The extreme versatility of the cyclization reaction described
here is underlined by syntheses of other heterocyclic systems. Toldy and SohUrrS1'described the preparation of
3-chloro-5,6-dihydro-1,2,4-thiadiazine1,l-dioxides (37a)
and 3-chloro-5H-6,7-dihydro-l,2,4-thiadiazepine
1,l -dioxides (37 b) by heating o-(N-aryl-N-cyanamino)alkanesulfonyl chlorides. This reaction probably also proceeds via
intermediate nitrile-hydrogen halide adducts.
6 C H,
Intermediates having an analogous structure should also
be possible in the cyclization of a$-unsaturated P-thiocyanatoacyI chlorides to form (27) and (29a).
0
SCN
(37aj. n = 2
(37bj. n = 3
4-Chloro-3H-l,3,2-benzodiazaphosphorinium chlorides
(38) are obtained according to Schmidpeter and Schindler" by cyclization of 2-cyanoanilinophosphonium chlorides with hydrogen chloride.
Angew. Chem. inrernat. Edit. J Vol. 12 (1973) J
No. 2
X,OCl
- xsycl
- 2 HCI
COCl
C'
N
However, nitrile-hydrogen halide 1,l-adducts cannot be
ruled out as the true reactive intermediates at least in the
ring closure reactions leading to (18), (21), (24), and (25).
125
We thank Prof Dr. H . Bredereck for his generous support of
our work. Thanks are also due to the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie for
material aid.
Received: March 20,1972 [A 925 IE]
German version: Angew. Chem. 85,155 (1973)
Translated.by Express Translation Service, London
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/ No. 2
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