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Novel Approaches to the Synthesis of Some Heterocycles Containing Nitrogen.

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the ionic radius of M (Fig. 6). The lattice parameters
of the solid solutions change linearly with the amount
of MO1.5 dissolved in the (Mo.S,Pao.5)02. The solubility
increases with increasing temperature. As in the
Li20/Pa205 system[1731, a fluorite phase also exists in
the Li20/U205 system1174,1751. Only in compounds of
5 30
5 35
51 0
Fig. 6. Solubility of MO1.5 in ( M ” ’ Pa
5 L5
” )02
5 50
5 55
versus lattice parameter.
the type Ba(MT,f,,Pa0.5)02.75 and Ba(Mif:,Pa0.5)03
with an ordered fluorite structure can a relationship of
protactinium to niobium and tantalum be seen; moreover, the uranium compounds of at least the lastmentioned type can also be prepared [1761.
7.4. Nitrides, Carbides, and Sulfides
Little information is available o n the Pa/N, Pa/C, and Pa/S
systems [1531. Thermal treatment of PaCls with H2S/CS2 at
900°C leads to the formation of PaOS, and treatment of
[I681 C. Keller, J. inorg. nuclear Chem. 27, 1233 (1965).
[I691 C. Keller, J. inorg. nuclear Chem. 27, 321 (1965).
[ I701 C. Keller and K . H . Walter, J. inorg. nuclear Chem. 27, 1253
( I 965).
[I711 C.Keller, L.Koch, and K . H. Walter, J. inorg. nuclear Chem.
27, 1255 (1965).
[I721 C. Keller, J. inorg. nuclear Chem. 27, 797 (1965).
[I731 P . N . Iyer and A . J. Smirh, see [lo].
[ I741 W . Riidorff, S. Keminler, and H. Leutner, Angew. Chem. 74,
429 (1962).
[I751 L. M . Kovba and A . N . Golirbenko, Zh. strukt. Khim. 1,390
PaC15 or PaCI4 with gaseous NH3 at 800°C to PaN2. The
identification of PaOS and PaN2 was made solely on the
basis of their isotypicity with the analogous uranium compounds. PaC can be prepared by the reaction of PaF4 with
Ba + C at 14OO0C.
7.5. Nitrato Complexes of Pa(V)
The reaction of N205 with or PaClS yields the
hexanitrato acid HPa(N03)6[1771, whose salts - e. g .
CsPa(NO& or [N(CH3)4]Pa(NO& - can also be prepared
by the reaction of the hexahaloprotactinates(V) with N2O5.
On the other hand, in the analogous reaction the hexahaloniobates and hexahalotantalates form only oxotetranitro
complexes, e. g . CsNbO(N03)4. All these compounds are
very sensitive to hydrolysis, and they were identified mainly
on the basis of their infrared spectra.
8. Outlook
Within the past few years our knowledge of the chemistry of protactinium has increased to such an extent
that many aspects are better known than for the
neighboring elements niobium and tantalum. In other
fields, however, such as metallurgy, phase diagrams of
multi-component systems, and other thermodynamic
data, no thorough investigations have yet been carried
out. However, this statement applies also to many of
the “well-known” elements. If the present interest in
protactinium continues and can be increased by the production of a larger amount of 23lPa, these gaps may
rapidly be closed, despite the element’s radiotoxicity.
Weighable amounts of 23lPa can be handled only in
airtight glove boxes (the maximum permissible concentration of 23lPa in air is 10-8 mg/m3; that of hydrogen
cyanide is 10 mg/m3).
Received: October lst, 1965
[A 4871265 IE]
German version: Angew. Chem. 78, 85 (1966)
Translated by Express Translation Service, London
[ I761 C. Keller and B. Kanellnkopulos, unpublished work.
[I771 P. J . Jones, see [lo].
Novel Approaches to the Synthesis of Some Heterocycles Containing Nitrogen
Some syntheses of heretofore unknown pyrimidines, tetrahydroquinarolines, and quinazolines
are described. These methods are uniquely simple one- or two-step reactions, general and
versatile in scope, and give high yields. Some interesting chemistry associated with these
heterocyclic systems is discussed.
FOI a number of years we have been involved in
the synthesis of new heterocyclic systems for biological
evaluation. This work has led to the preparation of a
variety of new heterocycles, amongst which are 5,6,7,8tetrahydrobenzothiazolin-2-ones111, 5,6,7,8-tetrahydrobenzoxazoles [2,31, 1,2,4,5 - tetrahydro - 1,3 - benzodiazepines [41, and pyrazolo[l,5-~]quinazolines
151. Recently
we have
Some new synthetic routes to y2disubstituted pyrimidinesI61,tetrahydroquinazolines [7y81,
Angew. Chem. interiint.
Edit. 1 Vol. 5 (1966) 1 No. I
and quinazolines W01, and it is the purpose of this review
to present this work in its entirety.
[ I ] G. destevens, A. Frutchey, A. Halamandaris, and H . 0 . Luts,
79, 5263
[21 G. destevens, US.-Pat. g57 394 (Oct. 2nd? 1958).
[3] G. deStevens and R . H . Sprague, US.-Pat. 2892837 (Sept.
22nd, 1959).
[4] G. deStevens and M.Dughi, J.Amer.chem.Soc.83,3087 (1961).
[5] G. deStevrns and H . M.Blatter, Angew.Chem. 74, 249 (1962).
1,2-Disubstituted Pyrimidines
observation in mind that we considered the condensation of ethyl p-anilinocrotonate ( I ) with benzoyl
isothiocyanate. It was anticipated that the primary
In a recent monograph 0'1 pyrimidines Brown [111 noted
product of this condensation reaction would be ethyl
that, although many mercaptopyrimidines have been
P-anilino-cr-benzoylthiocarbamoylcrotonate(2). Howprepared, only the 2-mercaptopyrimidines have been
ever, when these intermediates were allowed to react in
synthesized from a 3-carbon intermediate and an
ethyl ether or tetrahydrofuran under mild reflux a
appropriate condensing agent (e.g. ethyl cyanoacetate
bright yellow precipitate was obtained in 60 % yield.
and thiourea). The usual procedure employed to arrive
The elemental analysis of this compound indicated that
at the 4-mercaptopyrimidines involves the synthesis of
the elements of water had been eliminated from
the 4-hydroxy- or 4-chloropyrimidines, which are then
the intermediate (2).
allowed to react with phosphorus pentasulfide or
ultraviolet, infrared, and nuclear magnetic resonance
sodium hydrogen sulfide, respectively. This method has
along with the elemental analysis strongly
in the past been confined to pyrimidines unsubstituted
the assignment of structure (3) to this
in the 1-position. 1-Alkyl-4-oxopyrimidineshave been
compound. The alternative structure (4) was not conprepared in certain cases through alkylation of a 4sidered feasible since it required an amide-carbonyl
aminopyrimidine derivative. The resultant 1-alkyl-4interaction with the carbon bearing the vinyl proton
iminopyrimidine was hydrolysed to the 4-ox0 deriva[cf. (2u)], a reaction which is not favorable for the
Thus, a minimum of four steps is required in the
preparation of a l-alkyl-l,4-dihydro-4-thiopyrimidine elimination of water under the mild reaction conditions
from the condensation of an appropriate 3-carbon
intermediate (e.g. malononitrile) with an amidine. The
problem becomes even more acute if one considers the
synthesis of the previously unknown 1,Zdisubstituted
s= 0
and especially the 1,2HN-e-cSH5
diary1 compounds which are not available by conven(24
tional routes.
The investigations of Behrend et al. during the early part
This reaction has been applied to a variety of a$of this century served as a convenient starting point in
unsaturated amino-esters and acyl and aroyl isothiothe preparation of such compounds. Behrend [13,141
cyanatesI61. Several factors are worthy of note, The
found that the condensation of ethyl p-aminocrotonate
reaction conditions are very mild, condensation and ring
with phenyl isothiocyanate affords not only the anticlosure occurring in the absence of an acid or base
cipated product, 6-methy1-3-phenyl-2-thiouraci1,but
catalyst and at relatively low temperature (25-50 "C).
also ethyl P-amino-cr-phenylthiocarbamoylcrotonate. The reaction seems to be quite general although higher
The tendency of ethyl p-aminocrotonate to behave as an
yields of 4-thioxopyrimidines are obtained if the aroyl
enamine towards the isothiocyanate function under
isothiocyanate is substituted with an electron withcertain conditions was thus established. It was with this
drawing group (e.g. p-nitrobenzoyl isothiocyanate). On
the other hand, the condensation of ethyl p-anilinocrotonate with o-methoxybenzoyl isothiocyanate gives
a poor yield and a number of different by-products are
formed. These facts suggest the mechanism represented
by formulae(5) -(6)which requires an electron-deficient
carbonyl group to facilitate ring closure and subsequent
[6] G. deStevens, B. Smolinsky, and L . Dorfman, J. org. Chemistry 29, 1115 (1964).
[7] R . W. J. Carney, J. Wojtkunski, and G . desitevens, J. org.
Chemistry 29, 2887 (1964).
[8] H. M . Blatter and H. Lukaszewski, J. org. Chemistry, in press.
[9] H . M . Blatter and H . Lukaszewski, Tetrahedron Letters 1964,
1101 H . M . Blatter, H . Lukaszewski, and G . deStevens, J. org.
Chemistry 30, 1020 (1965).
[ I l l D. J. Brown: The Pyrimidines. Wiley, New York 1962.
[I21 D . J. Brown, E. Hoerger, and S. F. Mason, J. chem. SOC.
(London) 1955, 211; cf. also 121.
[13] R . Behrend, F. Meyer, and Y.Buchholz, Liebigs Ann. Chem.
314, 200 (1900).
1141 R . Behrend and P . Hesse, Liebigs Ann.Chem.329,341 (1903).
The isothiocyanate derivatives of aliphatic acids also
give good yields. Variations in the structure of the
crotonic ester do not significantly affect the course of
the reaction. However, condensation of the ethyl (3Angew. Chem. internnt. Edit.
VoI. 5 (1966)
No. I
methylaminocrotonate with benzoyl isothiocyanate in
diethyZ ether results in immediate reaction with precipitation of the uncyclized intermediate ethyl a-Nbenzoylthiocarbamoyl - p - methylaminocrotonate (7),
which dissolves in refluxing ethanol or tetrahydrofuran
to undergo ring closure with water elimination. A similar
phenomenon was observed with ethyl p-aminocrotonate.
However, this ester reacts with acylisothiocyanates in
tetrahydrofuran, to give the corresponding 4-thioxopyrimidines directly. Infrared and NMR spectrocsopy
were very useful in determining the stereochemistry of
(7) and related compounds.
The 1665 cm-1 band of ethyl p-aminocrotonate was
assigned to the ester carbonyl, and the carbonyl group
of the p-anilino derivative absorbs at 1655 cm-1. A cis
relationship between the amino and the ester groups
has previously been shown [151. This assignment is
supported by the chemical shifts observed in the NMR
spectrum [IS]. In addition, ethyl p - diethylaminocrotonate
gives two carbonyl bands, 1677 cm-1
(strong) and 1655 cm-1 (very weak). This fully alkylated
amine therefore is a mixture of cis and trans isomers,
with trans predominating.
The cis stereochemical relationship (i. e. the cisorientation of the amino and ester groups) thus apparently holds for the aroylcarbamoyl and thiocarbamoyl derivatives since the ester group absorption is
found at 1665-1672 cm-1 when the amino group is
unsubstituted and at 1657 cm-1 when it carries a
phenyl substituent. However, this stereochemical assignment has little if any influence on the ring closure reaction since a cis-trans equilibrium is feasible in solution.
Ring closure could then proceed rapidly through the
small amount of trans isomer that is always present.
1,ZDisubstituted 5,6,7,8-Tetrahydroquinazolines
Hiinig and Hiibner 1161 ieported the formation of 5,6,7,8tetrahydro-2-phenylbenzoxazine-4-thione
(9) in 50 %
yield from N-( 1-cyclohexeny1)morpholine (8) with
benzoyl isothiocyanate. Since 1,3-oxazin-4-ones bear
a formal resemblance to 1,4-pyrones with regard to the
disposition of the double bonds, and since 1,4-pyrones
upon heating with primary amines can readily be
transformed into 4-pyridones [171, we explored the reactivity of (9) towards such amines.
When (9) was refluxed in ethanol with excess aniline,
a yellow crystalline material (10) was obtained in 59 %
1151 C. F. Huebner, L. Dorfman, M . M . Robison, E. Donoghue,
W . G. Pierson, and P . Strachan, J. org. Chemistry 28, 3 134 ( I 963).
[I61 S . Hiinig and K . Hiibner, Chem. Ber. 95, 937 (1962).
[I71 L. F. Cavalieri, Chem. Rev. 41, 525 (1947).
Angew. Chem. iiiterwt. Edit. f Vol. 5 (1966)
1 No. I
yield. Elemental analysis indicated the product to
consist of the combined reactants minus water. The
ultraviolet absorption spectrum of (10) in ethanol shows
a shoulder at 254 m p and a maximum at 342-345 mp,
in marked contrast to that of compound (9), which has
maxima at 228-230 mp, 287 mp, and 333-335 m p in
dioxane. Evidently the chromophore of the heterocycle
(9) is substantially altered in this reaction. The absence
of NH, OH, or CO bands in the infrared spectrum further
suggested that we were dealing with a heterocyclic
compound rather than with a ring-opened cyclohexenyl
To substantiate the structure ( l o ) , anilinocyclohexene
(11) was treated with benzoyl isothiocyanate in tetrahydrofuran. The product was identical with compound
(10). However, in diethyl ether the benzoylthiocarbamoyl derivative (12) was obtained which, in turn, was
converted to (10) in refluxing tetrahydrofuran. The
isolation of (12) and its subsequent conversion to (10)
relates the mechanism of the formation of (10) from
(11) to the one illustrated for the pyrimidine synthesis.
Compound (9) reacts with a number of primary amines
to afford the previously unknown 1-substituted 5,6,7,8tetrahydro-2-phenylquinazoline-4-thiones.
Treatment of
(9) with ammonia gives 5,6,7,8-tetrahydro-2-phenylquinazoline-4-thione. These substances are readily
converted to the corresponding tetrahydroquinazolin-4ones with mercuric acetate.
The versatility of Hiinig's intermediate benzoxazine (9)
is illustrated further by its application to the synthesis of
tetrahydroquinazolinium salts (14) and (Id). The
reaction of (9) with methyl iodide yields the oxonium
salt (13) which readily condenses with primary amines
to form the 1,2-disubstituted tetrahydroquinazolinium
iodide in good yields.
The R groups at positions 1 and 4 in these compounds
are identical. However, to prepare compounds in which
the R groups at positions 1 and 4 are different, it is
necessary to treat N(1)-substituted 5,6,7,8-tetrahydroquinazolines with methyl iodide. The resulting salts (15)
are then condensed with a primary amine whose R
function is different from that already incorporated at
the 1-positionof the heterocycle. The 4-methylmercapto5,6,7,8-tetrahydroquinazolinium salts (15) also react
quite readily with the alkyl iodide salts of 2-methylsubstituted heterocycles, e.g. 2-methylbenzothiazole, to
afford compounds of the cyanine dye type.
(16), Y = 0, S, CH=CH
In the synthesis of compounds related to (9) with substituents in the 2-phenyl group, the use of appropriately substituted aroyl isothiocyanates, usually gave
intractable tars from which no distinct product
could be isolated. This unexpected result limited the
utility of the above route to 1-substituted 2-phenyl5,6,7,8-tetrahydroquinazoline-4-thiones.
For this reason
it was necessary to devise an alternate route of synthesis
of such compounds.
N-Arylimidoyl isothiocyanates had already been prepared in our laboratory in connection with another
project [9,181. For example, N-phenylbenzimidoylchloride (17), readily obtainable from benzanilide by the
This readily condenses with N-(1-cyclohexeny1)morpholine to give (10) in fair yield [81. In fact, this was then
found to be a general reaction regardless of the nature
of the substituent on the benzene ring. In this way a
number of 1,2-disubstituted 1,4,5,6,7,8-hexabydroquinazoline-4-thiones were prepared, which were unobtainable by other routes. These substituted iniidoyl
isothiocyanates also react with other enamines, e.g.
N-(2-methylprop-l-enyl)morpholine(19), to form dihydropyrimidine-4-thiones(20) [81.
2-Substituted Quinazolines
N-Phenylbenzimidoyl isothiocyanate ( I s ) readily cyclizes to 2-phenyl-3,4-dihydroquinazoline-4-thione
at temperatures as low as 80 “C (refluxing benzene 191).
This ring closure was carried out with a variety of
imidoyl isothiocyanates and represents a general
synthesis of 3,4-dihydroquinazoline-4-thionesthat enables one to circumvent the use of the often difficultly
accessible anthranilic acid derivatives. The reaction
occurs regardless of the presence of electron-withdrawing (e.g. NO2) or electron-releasing substituents (e.g.
OCH3) in either benzene ring and particularly in the
ring directly involved [191.
It seems likely,therefore, that cis-imidoylisothiocyanates
such as (18) undergo ring closure by a cyclic, concerted,
thermally induced reorganization of the a- and xelectrons. This would reversibly yield the less stable
valence isomer (in brackets) which could stabilize itself
through irreversible prototropic shift to form the
aromatic 3,4-dihydroquinazoline-4-thione.
Reactions of this type, which includes both the Claisen and
Cope rearrangements, have been designated as “no mechanism reactions” [211; referring to the difficulty, if not impossibility, of describing precisely the transition state or
states of such reactions. Such multicenter processes [z21 are
neither ionic nor free-radical. They are thermally induced,
[I91 The alternative possibility that monothioimides such as
(22a) are formed was ruled out by independent synthesis and
action of thionyl chloride, reacts with lead thiocyanate (in refluxing benzene for 2 h) to afford Nphenylbenzimidoyl isothiocyanate (18) in good yield.
[18] H . M . Blatter, 145th Meeting Amer. Chem. SOC.,New York,
September 1963; Abstracts of Papers 89 Q.
by the fact that such compounds are obtainable only in the
presence of Friedel-Crafts catalysts [20].
[20] P . A . S . Smith, J . Amer. chem. SOC.82, 4753 (1960).
[21] W. Y. E. Doering and W. R . Roth, Tetrahedron 18, 67 (1962).
1221 Review: S . J . Rhoads in P . de Mayo: Molecular Rearrangements. Interscience, New York, London 1963, Vol. I, p. 655.
Aiigew. Chem. interntit. Edii.
1 Vol. 5
I No. I
are independent of the extramolecular environment, and are
often insensitive t o internal structural variation. These criteria are fulfilled in the present case.
Usually a red, crystalline imidoyl isothiocyanate dimer
can also be isolated, albeit in poor yield. Structure
determination by means of analytical and spectral data
nitrile 1251 or ethyl iminobenzoate 125,261, dehydrogenation of 1,2-diphenyl-1,4,5,6,7,8-hexahydroquinazolin-4one and -thione with palladium on carbon in cymene,
it was decided that the least complicated and most
unambigous route to these compounds would be via
the imido ester (29) prepared by condensing methyl
salicylate with N-phenylbenzimidoyl chloride. Chapman rearrangement [271 of compound (29) according to
as well as independent synthesis has established the
dimer formed from N-methylbenzimidoyl isothiocyanate (23) to be the triazine (24) [231. Thus, all the
red, crystalline dimers have been assigned the corresponding triazine structures.
1,2-Disubstituted 1,4-Dihydroquinazolin-4-ones
and their 4-Thioxo Derivatives
Finally our attention was directed to the synthesis of
1,Zdisubstituted 1,4-dihydroquinazoline-4-thiones
their 4-OX0 derivatives. A survey of the literature surprisingly revealed that compounds of this type have
received little attention. Huang-Hsinrnan and Mann [241
reported that 2-hydroxy-3-oximino-1,2-diphenylindoline
(25), obtained from 3-amino-l,2-diphenylindole
atmospheric oxidation, is converted by means of
ethanolic hydrogen chloride, aqueous sodium hydroxide, or heat alone to a colorless, crystalline substance, m.p. 280-281 "C, whose molecular formula,
C20H14N20, corresponds to that of the quinazolinone
(27). These authors acknowledged the tenuity of their
structural assignments, and suggested the oxime (26) as
an alternative to (25).
the prodecure of Jamison and Turner [2*1 yields methyl
2-(N-benzoyl-N-pheny1amino)benzoate (30). Saponification of the ester, followed by conversion to the acid
chloride and subsequent amination, gives (31) [291.
Heating of this compound for a few minutes at 300 "C
gives almost quantitatively the desired 1,2-diphenyl-l,4dihydroquinazolin-4-one (32) [lo]; its conversion into
the thione (33) can be carried out by the conventional
Each of these steps gives high yields and is free from
complicating side reactions. The method is general and
versatile since the nature of the substituents on the
benzene rings of the quinazoline ring system and of
the 1,2-diphenyl groups is governed by the starting
materials, which are readily available commercially or
through synthesis.
Received: January Zlst, 1965
[A 482/262 IE]
German version: Angew. Chem. 78, 125 (1966)
[25] U'. Ried and W. Stephan, Chem. Ber. 95, 3042 (1962).
[26] W. Riedand W. Stephan, Chem. Ber. 96, 1218 (1963).
[27] P. G. Srecher: The Merck Index. 7th Edit., Merck, Rahway 1960.
[28] M. M . Jamison and E. H.Turner, J. chem. SOC.(London)
1937, 1954.
[29] The preparation of other substituted anthranilamides
through the application of the Chapman rearrangement to the
After a variety of methods to prepare (27) and related
substances was explored with little success, e.g. condensation of N-phenylanthranilic acid with benzo[23] H. M. Blatter and H. Lukasrewski, Tetrahedron Letters
1964, 1087.
[24] Huang-Hsinman and F. G . Mann, J. chem. SOC.(London)
1949, 2903.
Atigrw. Client. internut.
Edit. 1 Vol. 5 (1966)
/ No.
imido ester (34) is difficult since other products such as (35)
and (36) are sometimes also formed.
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