THE NIEMENTOWSKI REACTION. THE USE OF METHYL ANTHRANILATE OR ISATOIC ANHYDRIDE WITH SUBSTITUTED AMIDES OR AMIDINES I N THE FORMATION OF 3-SUBSTITUTED4-KETO-3,4-DIHYDROQUINAZOLINES. THE COURSE OF THE REACTION JOHN F. MEYERL* AND E. C. WAGNER Received Janwry 99, l O q S
The formation of substituted 4-keto-3,4-dihydroquinazolinesby interaction oflanthranilic acid or substituted anthranilic acids and amides may be designated as the Niementowski reaction:
0
0 C
Numerous variants of the essential synthesis have been described, using o-acylaminobenzamides (1), ammonium o-acylaminobenzoates (2), anthranilic acid and nitdes in the presence of acetic anhydride (3), o-acetaminobenzonitrile in the presence of acetic anhydride or alkaline hydrogen peroxide (4), and acetanthranils and primary amines ( 5 ) . The Niementowski procedure (using anthranilic acid and amides) has been found applicable to amides of the lower fatty acids, which show rapidly decreasing reactivities in this respect as the molecular weights increase. The usefulness of amides of acids of higher molecular weights has not been systematically studied, but is probably restricted by the fact that temperatures required for the ring closures cannot be attained or maintained without decarboxylation of anthranilic acid. The experiments described below mere undertaken to test several modifications and extensions of the Niementomski synthesis, viz., (a) the use of methyl anthranilate instead of anthranilic acid, in order to permit higher reaction temperatures, (b) the use of substituted amidines instead of amides, and (c) the use of isatoic anhydride and amidines instead of anthranilic acid and amides. All theise new procedures yielded the corresponding 4-keto-3 ,4-dihydroquinasoliner;. The last two procedures mere designed respectively to take advantage of the relatively high reactivities of certain diarylamidines in ring closures similar to that involved in the Niementowski reaction ( 6 ) , and of the notably high reactivity of isatoic anhydride as an agent which yields anthranoyl compounds by interaction with substances containing amino hydrogen. 1 This paper is constructed from the thesis submitted by John F. Meyer to the Graduate School of the University of Pennsylvania in partial satisfaction of the requirements for the degree of Doctor of Philosophy, September 1942. 2 Present address: Clarkson College of Technology, Potsdam, New York. 239
240
J. F. MEYER AND E. C. WAGNER
I. Salt formation during the Niementowski reaction. A preliminary study of the formation of quinazolone salts was necessitated by the observation that in the preparation of 3-phenyl-3 ,4-dihydroquinazolone-4 from anthranilic acid and formanilide the product was present in the reaction mixture in the form of its anthranilate. When the reaction mixture was extracted with aqueous alkali prior to isolation of the quinazolone no complication was encountered, but when the reaction mixture was a t once dissolved in alcohol the crystallized product was not the expected quinazolone but its anthranilate. The salt character of this compound was established by tcsts outlined in the experimental section. There were prepared also the formate, benzoate, phenylacetate, and salicylate of this quinazolone. It is probable that the conversion of quinazolone to stable anthranilate within the reaction mixture withdrew part of the anthranilic acid from participation in the intended ring closure and so decreased the yield. When two equivalents of anthranilic acid were used the yield of quinazolone was increased from 40% to 73%. Further study of salt formation as a possible interference in the Kiementowski synthesis indicated anthranilates of the other quinazolones tested to be not sufficiently stable to survive under reaction conditions. That this instability may be rather general is to be inferred from the facts that yields by the Nementowski reaction are in many cases satisfactorily high (7), and that salts of several quinazolones could be prepared only under special conditions (e.g., in indifferent solvents, or by fusion of the mixed solids) and could not be crystallized from alcohol without partial or complete separation into the components. The practical application of these findings is comprised in (a) a preliminary extraction of the reaction mixture with cold aqueous alkali or alkali carbonate13 to remove anthranilic acid whether uncombined or present as salt, and (b) the use of an excess (to two equivalents) of anthranilic acid in cases in which salt formation is suspected because yields are low and considerable anthranilic acid is recoverable from the alkaline extracts. 11. The use of methyl anthranilate in the Niementowski synthesis. The usefulness of the Niementowski synthesis is limited to some extent by the ease of thermal decarboxylation of anthranilic acid. Decarboxylation is rapid a t 180", and sustained heating a t 150" or above may lead to extensive decarboxylation, followed by interaction of the resulting aniline with the amide or anilide by amide exchange. Thus, Niementomski (8) obtained acetanilide from anthranilic acid and acetamide. This difficulty is avoided if anthranilic ester is used instead of the acid. hlethyl anthranilate is stable a t temperatures approaching its boiling point (260"),and i t was found to react with acetamide or with formanilide a t about 200" to form the expected quinazolones: 0 0
3
Ketodihydroquinazolines without substituents on nitrogen may be soluble in alkali.
24 1
THE NIEMENTOWSKI REACTION
The yield from formanilide reached 49% at 225". Acetamide and methyl anthranilate, heated together at 200", gave small amounts of 2-methyl-3,4dihydroquinazolone-4 and N-acetylanthranilic ester. Extension of this procedure to other amides showed that, while the aberrant reaction caused by decarboxylation of anthranilic acid was excluded, the synthesis was not improved with respect to yield or applicability. This must be due to the fact that in general the higher temperatures permitted by use of the ester do not compensate for its lower reactivity, the ring closure involving the aminolysis of an ester, which is relatively slower than the corresponding amide formation which is one step in the Niementowski reaction. The significance of the formation of N-acetylanthranilic ester is discussed in section V. 111. 'The use of amidines in the Niementowski synthesis. The previous demonstration (6) of a functional analogy between N,N'-disubstituted formamidines and acetamidines and carboxylic acids in certain ring closing reactions encouraged the belief that amidines could be used to replace amides (which are aquo-arnmono acids) in the Niementowski reaction, and experimental trials showed this to be the case. Interaction of diary1 formamidines or acetamidines with anthranilic acid at 135-150" or with methyl anthranilate a t 200-230" yielded the expected quinazolones with (respectively) amine and water or amine and methanol as by-products:
3.
0 o:coH(cH3)
HNAr +
2"
A!., II NAr
0 C
-3' P\
+
H2O (CH3OH) ArNH2
N
With anthranilic acid the reactions were rapid but yields were relatively low. Methyl anthranilate and disubstituted formamidines gave satisfactory yields of quinazolones, which were better than yields obtainable by the Niementowski reaction. Disubstituted acetamidines were found to react less readily than formamjdines, a result consistent with previous findings ( 6 ) . Results of these experiments appear in Table 11. IV. The use of isatoic anhydride in the Niementowski synthesis. In its most characteristic reactions (with ammonia or primary amines) isatoic anhydride serves essentially as an active agent for introduction of the anthranoyl group, probably thus : 0 C
H
0
0
CNHR
CNHR
\
OH
242
J. F. MEYER AND E. C. WAGSER
The similarity of the contribution of isatoic anhydride in such reactions and that of anthranilic acid in the Niementowski reaction suggested that the former might be useful as an active reagent in an extension of the synthesis. The use of isatoic anhydride with amides is excluded, because their interaction yields unidentified amorphous products (9). In contrast with this behavior of amides it was found that interaction of N,N'-diary1 formamidines and acetamidines with isatoic anhydride occurred smoothly at moderate temperatures (120-140"),with evolution the of carbon dioxide and formation of 3-aryl-4-keto-3,4-dihydroquinazolines, over-all reactions being:
c:-)z0 0 C
5.
0
HNAr
+
N
1 I1
+ coz + ArNHz
C-
NAr
H
This result is apparently inconsistent with the structural and functional analogies between amides and amidines (considered respectively as aquo-ammono-acids and ammono-acids) and requires explanation. The interaction of isatoic anhydride and primary amines yields substituted anthranilamides (equation 4). Interaction of isatoic anhydride and amides, e.g., acetamide, is perhaps initially similar, the amide functioning as a weak base:
0 6.
~
0
~
+ H~NCOCHS ) ~ ---f
N H
CYCNHC o + coz v\ O
NHz
The product shown, though capable of ring closure to yield a quinazolone, probably reacts more readily (as a primary amine) with isatoic anhydride, for the reaction yields no quinazolone, but only amorphous material. The alternative initial condensation, with the amide functioning as an aquo-ammono-acid, viz.,
0 7.
(f)Zo
0
+ HzNCOCHs N H
---+
07
+ coz
NHCOCH,
is an acylation, and it must be dismissed, for Weddige (1) found that o-acetamand inobenzamide is readily convertible into 2-methyl-3,4-dihydroquinazolone-4, it seems unlikely that it would react with isatoic anhydride more readily than
243
THE XIEMENTOWSKI REACTION
does acetamide and so escape conversion to the quinaxolone. Equation 6 may thereforebe accepted provisionally as representing the initial step when acetamide and isatoic anhydride react. By analogy the reaction of isatoic anhydride and an amidine may be represented by equation 8 (which may be considered as the first step in the synthesis represented by 5 ) :
0 C 8.
0:
Np
0
HNAr
+ o
A-
-+ Q C - y
NAr /I
+
C-
(20%
II
“2
H
NAr
The apparently “normal” reaction of isatoic anhydride with diaryl formamidines and ace tamidines to yield quinaxolones (equation 5 ) is actually more complicated than is obvious, since it has been found that formamidines may yield quinazolones by two distinct series of reactions, as is to be inferred from the following experimental results. When equivalent amounts of isatoic anhydride and diaryl formamidine were heated together (120-130°) the yields of 4-keto-3,4-dihydroquinaxolinewere high (80-90~0), and a corresponding quantity of amine (liberated in the reaction) was recoverable. Similar experiments in which diaryl acetamidines were used gave yields always less than SO%, and the reaction mixtures contained no free amine. These results were found to be explicable as follows. Interaction of isatoic anhydride and diarylformamidines yields 3-aryl-4-ketodihydroquinazolines by a reaction course not yet determined, but involving probab1;y reactions 5 and 8, vk.,
0
0 CH --+
N H
“2
+ c02 0 C
The liberated amine reacts rapidly with more isatoic anhydride (this reaction occurs at or below water-bath temperature, equation 10) to form the corresponding anthranilanilide, and this then reacts with diaryl formamidine, as shown
244
J. F. MEYER AND E. C. WAGNER
previously (6), to yield the quinazolone with liberation of two equivalents of amine. This amine reacts with more isatoic anhydride, and these opertitions are repeated until no isatoic anhydride remains :
10.
0
0
C
CNHAr
0:
ArNH,
\
CH
No :) H
0 C
The net result is involvement of equivalent amounts of isatoic anhydride and diaryl formamidine, with formation of the quinazolone andliberation of an equivalent amount of amine. There are thus two paths which lead to the finalproducts. To what extent the quinazolone is formed by each of these paths cannot be stated. The liberation of even a trace of amine by reaction 9 might start a reaction chain which could run to completion as shown in 10. The reality of reaction 9 is thus far inferential. Evidence that quinazolones can be formed in this may is afforded by the results obtained with diaryl acetamidines: less than 50% yields of quinazolone and no free amine. In this case no quinazolone is to be expected by reaction 10, for it was shown previously (6) that diphenylacetamidine and anthranilanilide do not react even at 190’. It may be concluded that the quinazolone obtained from isatoic anhydride and diaryl acetamidines must have been formed by reaction 9. Only half the isatoic anhydride is convertible to quinazolone, and no free amine persists, conclusions in full agreement with the experimental results. The secondary formation of anthranilanilide (equation 10) was demonstrated in an experiment in which isatoic anhydride and only one-half an equivalent of diphenylformamidine were heated at 125’. The evolved carbon dioxide was collected and weighed, its amount indicating that all of the isatoic anhydride had reacted. The reaction mixture yielded 3-phenyl-3,4-dihydroquinazolone-4 (72.7 yobased on formamidine) and also anthranilanilide (53% based on isatoic anhydride). The formation of 4-keto-3,4-dihydroquinazolines from isatoic anhydride and amidines is to be regarded as a new quinazoline synthesis rather than as modification of the Niementowski synthesis. V. The course of the Niementowski reaction. The only “mechanism” hitherto proposed is that of Bogert and Gotthelf (3):
245
THE NIEMENTOWSKI REACTION
0
0
0:
COH
11. (a)
+ CH3CONH2
0
0
u\ @OH
+ "s
NHCOCH9
2"
(lJ)
-0:
COH
-0:
CONHi
+
3"
NHCOCH3
NHcocHa
0
h"COCH3
-+
+
0 C O NHCOCH, N H 2
0
Reaction 11 (a) is an amide-exchange (or an ammonia-system acetylation), similar to the conversion of aniline to acetanilide by heating with acetamide (10). The conversion of ammonium-K-acetylanthranilate to 2-methyl-3,4dihydroquinazolone-4 [reaction 11 (e)] was reported by Bischler and Burkart (2). Equations 11 (a) and 11 (b) lack experimental support. The present study yielded experimental evidence rhich directly or collaterally supports the react>ion sequence suggested by Bogert and Gotthelf. An effort was made to demonstrate the intermediate formation of K-acetylanthranilic acid or of N-acetylanthranilamide [equations 11 (a) (e)] by heating anthranilic acid with acetamide at minimal temperature for incipient reaction, but these experiments either yielded no reaction products or gave the quinazolone which is the final product. It appeared that this difficulty might be overcome by use of anthranilic ester instead of the acid, since the reaction corresponding to equation 11 (b) would be expected to proceed more slowly with anthranilic ester than with the acid,4 thus favoring the survival of some of the N-acetyl4 Methyl anthranilate in methanol, treated with excess strong ammonium hydroxide, showed no evidence of reaction a t room temperature or on heating a t 100" in a pressurebottle.
246
J. F. MEYER AND E. C. WdGNER
anthranilic ester, a surmise which proved to be correct. When methyl anthranilate and acetamide were heated together the first evidence of reaction was the slow evolution of a little ammonia near 170". After three hours at 200" the mixture was worked up, yielding sufficient N-acetylanthranilic ester for identification. A similar experiment run for seven hours yielded 9.6% of N-acetylant,hranilic ester and 9.8% of 2-methyl-3 ,4-dihydroquinazolone-4. In both experiments most of the anthranilic ester was recovered unchanged. The evolution of ammonia, the formation of K-acetylanthranilic ester and the appearance of the quinazolone when the reaction period was prolonged, are results which are consistent with reactions 11 (a) (b) (c), extended to anthranilic ester, viz.,
0 12. (a)
0
0coca
+ CH3CONH2 + 0 C O C H 3
acoca-0,
NHCOCH3
2"
0
0
(b)
PNH2 +
+ M4
o r
0
0
NHCOCH3
C&OH
NHCOCHLl
NHCOCH3
(c)
+";I
+ H2O
-+
\ / N
Reaction 12 (a) is the acetylation of anthranilic ester by acetamide (aquo-ammono-acetic acid); it is obviously slow. Reaction 12 (b) (c), the conversion of by action of N-acetylanthranilic ester to 2-methyl-3,4-dihydroquinazolone-4 ammonia and heat, mas reported by Weddige (1). Reaction 12 (b) is the ammonolysis of an ester, for which the conditions cannot be considered favorable (11), and which is in part excluded by escape of ammonia from the mixture. Inferential support for this interpretation is provided by experiments using anthranilic ester and formanilide (section II), which compounds reacted to form the quinazolone in yields reaching 49%, a result considerably better than was obtained using acetamide. The greater effectiveness of formanilide may be attributed to its definitely acidic character, which probably favors the initial formylation, and to the fact that the aniline set free during the formylation does not escape from the reaction mixture, so that any N-formylanthranilic ester which forms will eventually react with aniline and undergo conversion to quinaz-
THE NIEMENTOWSKI REACTION
247
olone. The reaction of aniline with N-formylanthranilic ester to yield N-formylanthrtmilanilide (aminolysis of an ester) may be assumed t o be slow, so that aniline produced in the initial reaction may accumulate in the mixture, its presence retarding the first reaction, which is the reversible formylation of an amine by an aquo-ammono-acid. In any case the final ring closure [12 (c)] may safely be regarded as fairly rapid, as has been observed in similar closures of pyrimidine and imidazole rings. These considerations appear to account for the results with anthranilic ester and acetamide, and for those with anthranilic ester and formanilide, in a manner consistent with the series of reactions 12 (a) (b) (c), which is the counterpart of that suggested by Bogert and Gotthelf, the two principal steps having been realized separately. The extension of the indicated reaction course to the case of anthranilic acid (Le., to the Niementowski reaction) appears to involve no doubtful assumption. The principal obvious difference is that reaction 11 (b) (interaction of acid and ammonia) would occur much more rapidly than reaction 12 (b) (the ammonolysis of an ester), a conclusion in accord with the fact that in general the yields of quinazolones obtained from anthranilic acid and amides were higher than those from anthranilic ester and amides. EXPERIMENTAL
Diaryl formamidines were prepared from arylamines and ethyl orthoformate (12). Diaryl acetamidine5 were prepared from arylamines, acetylarylamines, and phosphorus pentachloride (13). Isatoic anhydride was prepared from anthranilic acid and phosgene (14). Other organic compounds were used (after identification) as supplied by the Eastman Kodak Company.
I . Salt formation during the Niementowski reaction S-Phenyl-S,4-dihydroquinazolone-4anthranilate. A mixture of 18.7 g. (0.1 mole) of anthranilic acid and 12.1 g. (0.1 mole) of formanilide was heated at 140" for ninety minutes. The cooled mixture was dissolved in hot alcohol. Dilution with water caused the separation of 7.5 g. (41.4%) of the crude salt, m.p. 120-124" obs. After two recrystallizations from dilute alcohol the product was pure, and melted a t 132.2"cor. The same compound resulted when 4.48 g. (0.02 mole) of 3-phenyl-3,4-dihydroquinazolone-4 and 2.76 g. (0.02mole) of anthranilic acid were dissolved together in the minimal hot alcohol. The total yield of salt, obtained in two crops (4.24g., m.p. 131" obs., and 2.57 g., m.p. 130' obs.) was 94%. After recrystallization the salt was colorless, highly crystalliine, and melted a t 132.2' cor. Anal Calc'd for C2,HL7P;303:S,11.7;neut. equiv., 359; sap. equiv., 120. Found: N , 11.36,11.40;neut. equiv., 364,365;sap. equiv., 129,122. The salt character of this compound was shown by the following results. (a) Cleavage by 5% aqueous sodium hydroxide solution, or by pyridine added to the solution in hot m.p. 139" cor. The filtrate dilute alcohol, yielded 3-phenyl-3,4-dihydroquinazolone-4, yielded anthranilic acid, m.p. 144'. Both compounds were identified by mixed melting point tests. (b) Cleavage by picric acid, of which an alcohol solution was added to one of the salt, yielded the crystalline quinazolone picrate, m.p. 179". Other quinazolone salts. These were made by the second method outlined above. I n several cases dissociation occurred in alcohol, and the salts were obtained by using inert solvents (ligroin, benzene). Results are presented in Table I.
248
J. F. MEYER AIiD E. C. WAGNER
ZZ. The use of methyl anthraniiate in the Niementowski reaction S-Phenyl-J,4-dihydroquinazolone-4.A mixture of 6.05 g. (0.05 mole) of formanilide and 7.60 g. (0.05 mole) of methyl anthranilate was heated a t 200" in an oil-bath for three hours. The oily mass was dissolved in hot 50% alcohol and the solution decolorized with charcoal. Upon chilling the filtered liquid the product separated; i t was recrystallized from 50% alcohol. The pure compound weighed 4.75 g. (42.8%), melted a t 137-138", and by mixed melting point test was shown to be identical with a specimen of 3-phenyl-3,4-dihydroquinazolone-4 made by the Niementowski reaction (4). A similar experiment a t higher temperature (225' for one hour) yielded 5.23 g. (49.0%) of 3-phenyldihydroquinazolone. TABLE I SALTS OF 3-ARYL-4-KETO-3,4-DIHYDROQ~INAZOLIXES
SALT
SOLVENT
~
YIELD,
%
M.P.,
ANALYSIS HITBOGEN
"c
FORMULA
'alc'd. 1 Found,
%
%
132.2
1.7
131-132
8.14
168-169
7.69
113-114
7.82
119-120
0.45
11.4 11.4 7.87 7.97 I 7.59 7.55 I 7.71 7.75 10.61 10.51 11.15 11.10
_
~L-
3-Phenyl-3,4-dihydroquin- ethanol 1 azolone-4 anthranilate " 3-Phenyl-3,4-dihydroquinazolone-4 benzoate IL 3-Phenyl-3,4-dihydroquinazolone-4 salicylate
