HC=C-CHO
I I
CH
3HCONH
2(CH )
3N
2LXV
N"VCH
3HCON(CH )
32LXVI
Since the separation of the methylpyrimidine from dimethylforma
mide cannot be effected by distillation—it must be separated in the form of a HgCl2 complex—we converted the propionaldehyde acetal into a-methyl-/?-diethylaminoacrolein with the diethylformamide-phosgene complex. 5-Methylpyrimidine and diethylformamide can be separated by distillation, and an 85% yield of 5-methylpyrimidine is obtained. If a-alkyl-substituted /?-chlorovinylaldehydes (LXVII) (52) are used, good yields of 4,5-substituted pyrimidines (LXVIII) are obtained (50). This conversion corresponds to the reaction between /?-chlorovinylketones and formamide, described above.
R-C=C-CHO LXVII
HCONH
2ft?
N LXVIII
Further syntheses, including those of 2,5-disubstituted pyrimidines, are still in progress.
2 , 4 - a n d 2 , 4 , 6 - S u b s t i t u t e d P y r i m i d i n e s
Although the conversion of diketones cannot be carried out with higher amides, these will effect the conversion of the more reactive fi-chlorovinylketones. Table 14 shows the 2-substituted pyrimidines ob
tained from /?-chlorovinylketones and acetamide, propionamide, and butyramide (53).
T A B L E 14 2-Substituted Pyrimidines
0-Chlorovinyl ketone Acid amide Pyrimidine Yield (%)
l-Chlorohex-l-en-3-one Acetamide 2-Methyl-4-propyl- 40
1 -Chlorohex-1 -en-3 -one Propionamide 2-Ethyl-4-propyl- 23
l-Chlorohex-l-en-3-one Butyramide 2,4-Dipropyl- .21
l-Phenyl-3-chloroprop-2-en-l-one Acetamide 2-Methyl-4-phenyl- 41 4-Chlorooct-3-en-2-one Acetamide 2,4-Dimethyl-6->? -butyl- 42 5-Chloronon-4-en-3-one Acetamide 2-Methyl-4-ethyl-6-« -butyl- 47
S y n t h e s i s o f P y r i m i d i n e
The synthesis of pyrimidine, accessible thus far with difficulty, merited special interest; we succeeded in obtaining it from
malondialde-hyde acetal ( L X I X ) , /?-dialkylaminoacrolein ( L X X ) , /?-alkoxyacrolein acetal ( L X X I ) , and propargyl aldehyde acetal (LXXII) (48,49,54).
R ON O R
yC H - C Ht- C H x RjeN-C H = C H - C H O
R O L X I X ° R L X X
/ O R O R R ' 0 - C H = C H - C H C H = C - C H
O R O R L X X I L X X I I
Compounds L X I X and L X X afforded yields of 60-65%. A mixture of the compound to be converted and formamide can be passed in a con
tinuous process over a contact catalyst (aluminum oxide or aluminum silicate) heated to 200° (54). The method developed for the preparation of pyrimidine and 4-methylpyrimidine affords yields of approximately 70%.
R e a c t i o n s o f Pyrimidine (54)
Pyrimidine forms numerous salts with inorganic acids, and addition compounds with metallic salts. It can, for example, be quaternized with dimethyl sulfate and oxidation with acetic acid/perhydrol gives an N-oxide; the latter reacts with acetic anhydride to yield an acetyl com
pound, probably 4-acetoxypyrimidine.
Organometallic compounds, e.g. phenyllithium, substitute at C4. 0 + c«h'l' (y 1. H j O 2. Oxidation N
1 ^ - C . H ,
N N C , H6 N
Li L X X I I I a L X X I I I b
The 4-substituted pyrimidines which we have prepared by this route are shown in Table 15.
T A B L E 15
4-Substitnted Pyrimidines from Pyrimidine and Organolithium Compounds
4-Substituted pyrimidine Yield (%)
Phenyl- 51
A-Tolyl- 51
p -Methoxy pheny 1- 45
2-Thienyl- 46
2-Furyl- 53
2-Thiazolyl- 30
Mesityl- 25
2,6-Dimethoxyphenyl- 18
2-Benzothiazolyl- 27
Pyrimidine, in the form of its hydrochloride, can be brominated to give a 5-bromopyrimidine. The bromine is comparatively readily re
placed by an alkoxy or ethylmercapto group, with ethoxide and ethyl-mercaptide, respectively.
Acid Amides a n d Halogen Compounds
F o r m a m i d e a n d H a l o g e n C o m p o u n d s
Following upon the reactions between a-haloketones and formamide yielding imidazoles and oxazoles (see above), we allowed a large number of halogen compounds to react with formamide at 150° (55). The results are summarized in Table 16.
The halogen compounds yield either formylamino compounds ( = N -substituted formamides, L X X I V ) according to Eq. (a), or formates
( L X X V ) according to Eq. ( b ) .
( a ) R—Hal + 2 H C O N H , R - N H - C H O + CO + N H4H a l L X X I V
( b ) R—Hal + 2 H C O N Ht - > R - O C H O + H C N + N H4H a l L X X V
The amounts of carbon monoxide and ammonium chloride found agree with those demanded by Eq. (a).
The hydrogen cyanide formed according to Eq. (b) is polymerized at the elevated reaction temperature, and results in the darkening of the solution.
Small quantities of a-hydroxyesters are found as by-product in the preparation of the a-formoxyesters (Table 16). On the assumption that these hydroxyl compounds are intermediates in the formation of the formoxy esters, we investigated the behavior of hydroxyl compounds towards formamide at various temperatures. The formation of formic esters does not occur below 160°, and proceeds readily at 180° (55)
(Table 17).
This proves that at our reaction temperature of 150°, the formoxy -esters are not formed simply by the action of formamide on the hydroxy-esters assumed to be initially produced. It is more probably a case of the joint reaction with formamide and the hydrogen halide liberated during the course of the reaction (see p. 276).
The preparation of the hydroxyl compounds from the halogen com
pounds, and hence the proof that they occur as intermediates, is accom
plished by the addition of substances which inhibit the formation of formates, e.g. water, formic acid, ammonium formate, finely divided nickel, or urotropine (see below).
T A B L E 16
Halogen Compounds and Formamide
Halogen compound Reaction product Yield (%)
Octyl bromide Octyl formate 92
Benzyl chloride Benzyl formate 74
N -Benzylformamide 5
Benzyl bromide Benzyl formate 27.5
N -Benzylformamide 44.5
Benzyl iodide Benzyl formate 15
N -Benzylformamide 47.5
/>-Methoxybenzyl chloride N -(/>-Methoxybenzyl)formamide 36 2,4,6-Trimethylbenzyl chloride N -(2,4,6-Trimethylbenzyl)formamide 31
Benzhydryl chloride N -Benzhydrylformamide 95
Triphenylmethyl chloride N -Triphenylmethylformamide 94
Benzotrichloride Benzoic acid 80
Diphenyldichloromethane Benzophenone 50
a,a' -Hexabromo-/)-xylene Terephthalic acid 63
p -Nitrochlorobenzene
-2,4-Dinitrochlorobenzene 2,4-Dinitroamune 55
a -Bromobutyric acid a -Hydroxybutyric acid 30
Phenylchloroacetic acid Mandelic acid 13
Diphenylchloroacetic acid N -Benzhydrylformamide 88
Ethyl chloroacetate Ethyl 0-formylglycolate 69
Ethyl a -bromopropionate Ethyl O-formyllactate 72 Ethyl a -bromobutyrate Ethyl or-formoxybutyrate 72 Ethyl a -bromocaproate Ethyl a-formoxycaproate 82 Ethyl a -bromoenanthate Ethyl a-formoxyenanthate 84 Ethyl diphenylchloroacetate Ethyl diphenyl- N-formylglycine 85 Chloromethyl w-propyl ether Bisformylaminomethane 50
Benzoyl chloride Benzoic acid 82
The conversion of haloesters into hydroxyesters (55) with forma-mide in the presence of water is shown in Table 18. It is noteworthy that the ester grouping remains unattacked during the replacement of the halogen by the formoxy or hydroxyl group. This allows a simplified
T A B L E 17 Hydroxy Compounds and Formamide
Hydroxy compound Reaction product Yield (%)
Octyl alcohol Octyl formate 100
Cyclohexanol Cyclohexyl formate 100
Benzyl alcohol Benzyl formate 100
P -Methoxybenzyl alcohol p-Methoxybenzyl formate 40
N -(/>-Methoxybenzyl)formamide 60
Benzhydrol N -Benzhydrylformamide 95
Triphenylmethyl carbinol N -Triphenylmethylformamide 100 or-Hydroxybutyric acid a -Hydroxybutyr amide 100
preparation of the hydroxyesters. The formoxyesters were previously unknown.
The experimental results show that the nature of the compounds produced depends on the structure of the halogen compound. The ability of the alkyl halide to form a relatively stable carbonium ion is an
essen-T A B L E 18
a-Hydroxy Esters from a-Halo Esters
Halo ester Hydroxy ester Yield (%)
Ethyl chloroacetate Ethyl glycolate 62
Ethyl a -bromopropionate Ethyl lactate 61
Ethyl nr-bromobutyrate Ethyl a-hydroxybutyrate 91 Ethyl a -bromoisovalerate Ethyl or-hydroxy iso valerate 55 Ethyl or -bromocaproate Ethyl a -hydroxycaproate 73 Ethyl a-bromoenanthate Ethyl a-hydroxyenanthate 76
tial prerequisite for the formation of a formylamine [reaction ( a ) ] . This dissociation is favored by the formamide (dielectric constant 113.5). For the conversion of trityl chloride [LXXVI, Tr = C ( C6H5)3] , we postulate the following reaction course (55-57):
T r - C l T r © + CI©
L X X V I
... 0
T r ® + N H2C H O ^ T r — N H2C H O
© . © T r - N H2C H O + ! N H2C H O < _ 1 T r - N H C H O + H C O N H3
L X X I V a
©
H C O N H j —> CO + N H4©
This scheme is supported by the fact that higher amides yield the
e
corresponding diacyl amides, since the H3NCOR cannot, in this case, dissociate (see below).
The formation of formate is capable of a twofold explanation (57).
Firstly, dissociation of the halogen compound R-Hal can be postulated.
Due to a lack of mesomeric stabilization, however, the unstable
car-R—Hal ^ ± R © + H a l ©
. © R® f H C O N H j , ^Z. R - 0 - C H = N H2
© . © R - 0 - C H = N H2- l - H C O N H2 ^ 3 R - 0 - C H = N H + H C O N H ,
L X X V I I R - 0 - C H = N H — > R O H + H C N
L X X I I L X X V I I I
©
R O H + H C O N H j + H a l © — > R O C H O + N H4H a l
L X X V I I I L X X V
bonium ion reacts immediately with the formamide oxygen, being the atom possessing the highest electron density.
Like reaction (a), this too is an SN1 reaction. The end-product is nevertheless different from that in reaction (a), due to differences in the type of reaction undergone by unstable carbonium ions. The second explanation interprets the formation of formate as an SN2 reaction; in carboxylic acid amides the oxygen is more nucleophilic than the nitrogen.
/ O l0 / O R H a l . O - R H a l © H C ^ + R—Hal ^ ± H C ^ — > H C ^ i
N H , N H , N H ,
© © © LXXH (Hydrochloride)
Both explanations include the formation of the iminoester LXXVII, which dissociates at the elevated reaction temperature. The formate constitutes a secondary product, formed by the formylation with forma-mide/hydrogen halide of the hydroxyl compound LXXVIII initially produced. Finely divided nickel or urotropine remove the hydrogen halide liberated and thus inhibit the formylation.
More thorough investigations have revealed that most halogen com
pounds in reaction (b) favor the SN1 mechanism (57).
In the presence of water or water-releasing substances, the reaction course depends on the actual quantity of the water {55). Addition of 1 mole of H20 per mole of haloester results in the formation of a formoxy-ester, and, at the high temperature obtaining, the hydrocyanic acid produced is immediately saponified by water to formamide or even formic acid. If 2 moles of water are added, hydroxyesters are formed almost exclusively; the water first causes the saponification of the hy
drocyanic acid, and, second, prevents the further formylation of the hydroxyester.
H i g h e r A c i d A m i d e s a n d C o m p o u n d s o f the T r i p h e n y l m e t h y l C h l o r i d e T y p e (56)
Corresponding to the preparation of N-tritylformamide, the higher acid amides (acetamide, propionamide, isobutyramide) also give N-trityl compounds ( L X X I X ) in very good yield. These preparations, however, necessitate a large excess of acid amide, elevated temperatures (210-220°) and prolonged reaction times (4-6 hr). These differences in reac
tion conditions are readily explained theoretically, as shown in the scheme below:
. ©
Tr® + | N H2C O C H3 T r - N H2- C O C H3
© . 0 T r - N H2- C O C H3 + | N H2C O C H , ^ ± T r - N H - C O C H3 + C H „ C O N H3
L X X I X
C H 3 C O N H 3 -f C H3C O N H2 ^ C H 3 - C - N H , N H2- C O C H3
©
| 0 |9
I © . © C H8- C - N H j ^ZL C H3C O N H2C O C H3 + N H ,
I
N H2- C O C H3
©
C H3C O N H2C O C H3 + N H , ^ ± C H3C O N H C O C H3 + N H4© L X X X
Whereas the reaction with formamide (see above) involves the
e
irreversible decomposition of the protonated formamide HCONH3 into CO and the ammonium salt, with the consequent displacement of the equilibrium in favor of the N-tritylformamide, formation of an am
monium salt in the case of the higher acid amides can only be effected with the assistance of a second amide molecule. Since the subsequent reactions are equilibria, and no longer irreversible reactions, such as those found with formamide, good yields of higher N-trityl amides are only obtained with an excess of acid amide, elevated temperatures, and pro
longed reaction times. In accordance with this scheme we were successful in isolating good yields of the diacyl amides (e.g. L X X X ) .
N-Trityl amides are also obtained from trityl perchlorate, trityl car-binol, trityl methyl, and trityl ethyl ether. In these cases the trityl carbonium ion is also initially formed.
Being another compound capable of forming a relatively stable car
bonium ion, xanthydrol was allowed to react with acid amides in the molten state. N-Xanthyl amides (e.g. L X X X I I ) are obtained in good yield after short reaction times (Table 19).
T A B L E 19
N-Xanlhyl Amides from Xanthydrol and Acid Amides
Acid amide N-Xanthyl amide Yield (%)
Formamide -formamide 86
Acetamide -acetamide 95
Isobutyramide -isobutyramide 88
Benzamlde -benzamlde 94
p -Nitrobenzamide - p-nitrobenzamide 79
Dixanthyl ether ( L X X X I I I ) also reacts very readily with formamide at 140° to give N-xanthylformamide. We postulate the following mecha
nism for this reaction:
L X X X I I I L X X X I I
Following upon the dissociation of the ether, formamide reacts with the xanthylium ion. The proton liberated combines with the alkoxide group to give xanthydrol ( L X X X I ) , which dissociates anew and reacts with formamide to give N-xanthylformamide ( L X X X I I ) .
It is interesting to note that p,p'-bisdimethylaminobenzhydrol (Mich-ler's hydrol) no longer reacts with acid amides. The melt merely becomes green, presumably due to the formation of the carbonium ion, which is strongly stabilized by resonance. Its electrophilic character is of such a low order that formamide no longer acts in a substituting capacity but as a reducing agent.
Formamide a n d Mannich-type Compounds
In reactions between keto Mannich bases (e.g. L X X X I V ) and form
amide, the amino group is replaced by formylamino (58). While the aliphatic Mannich compounds react best in the presence of metallic sodium, aromatic and heterocyclic compounds are advantageously al
lowed to react as their hydrochlorides (Table 20).
T A B L E 20
Formamide and Mannich Compounds
Mannich compound Reaction product Yield (%)
1 -Diethy lamino- 3 -butanone l-Formylamino-3-butanone (LXXXVI) 27 l-Dimethylamino-2-methyl-3-butanone 1 - For my lamino-2-methyl-3-butanone 33 /9-Dimethylaminopropiophenone /3 - For my laminopr opiophenone 14 0-Dimethylaminopropiophenone
hydrochloride (i - For my laminopropiophenone 42 /3-Dimethy
lamino-/)-methyl-propiophenone hydrochloride /3-Formylamino-/> -methyl propiophenone 40 /3Dimethy lamino/) methoxy
-propiophenone hydrochloride /3-Formylamino-/) -methoxy propiophenone 66 /3-Dimethy lamino-/)
-bromo-propiophenone hydrochloride 3-Formylamino-/) -bromo propiophenone 23 2-Naphthyl - /3-dimethylaminoethyl 2-Naphthyl /3-formylaminoethyl ketone 22
ketone hydrochloride
The course of the reaction can be explained by the initial formation of a,/?-unsaturated ketones (e.g. L X X X V ) , followed by the addition of formamide to their double bond.
C F V - C O - C H J - C H J N C C J H , ) , C HS— C O — C H = C H , + H N ( C , H , ) , L X X X I V L X X X V : H , - C O - C H = C H J - | - H C O N H J C H . - C O - C H j - C H j - N H - C H O
L X X X V L X X X V I
In accordance with this hypothesis, formamide will add to a,/3-un-saturated ketones to form monosubstituted formamides (Table 21).
T A B L E 21
Formamide and a, 3 - Unsaturated Ketones
Ketone Reaction product Yield (%)
Methyl vinyl ketone 1 - For my lamino- 3 -butanone 38 Methyl propenyl ketone 1 - For my lamino -1-methyl-3-butanone 50 Mesityl oxide 1 - For my lamino-1,1 -dimethy 1-3-butanone 18 Phenyl vinyl ketone 3 - For my laminopr opiophenone 32
N-Chloromethylphthalimide ( L X X X V I I ) can formally also be re
garded as a Mannich base. Reaction with formamide yields N-formoxy-methylphthalimide ( L X X X V I I I ) and diphthalimidodimethyl ether
( L X X X I X ) .
co
\
N - C Ht- C l N - C H2© + C1©
CO L X X X V I I
(X ) N - CH ' OCHO + 0
CO CO , N - C H2O H
L X X X V I I I
CO
+ LjIx ^ N - C H j C l CO
Uk / N - C H . - 0 - C H . - N ^
CO CO L X X X I X
According to this scheme, an unstable carbonium ion (the free elec
tron pair at the N is claimed by both CO groups) is formed initially; it then attacks the formamide oxygen (an SN2 mechanism gives the same result). If N-chloromethylphthalimide is replaced by diethylamino-methyl-p-tolyl sulfide ( X C ) , formaminodiethylamino-methyl-p-tolyl sulfide ( X C I ) is produced exclusively. Since the carbonium ion (XCa) is stabilized by mesomerism, only N-substitution can occur during the reaction with
formamide.
p - C H3- CeH4- S - C H2- Nx
By allowing halogen compounds to react with thioformamide in ethereal solution (59), we obtained the previously little known thioform-iminoester hydrohalides (Table 22).
T A B L E 22
Harogen Compounds and Thioformamide
Halogen compound Reaction product
Methyl iodide Thioformiminomethyl ester hydriodide Ethyl iodide Thioformiminoethyl ester hydriodide n -Butyl iodide Thioformimino-;/-butyl ester hydriodide Benzyl bromide Thioformiminobenzyl ester hydrobromide Benzhydryl bromide Thioformiminobenzhydryl ester hydrobromide Trityl chloride Thioformiminotrityl ester-thioformamide adduct
Unlike the reaction with formamide, that with thioformamide in
variably occurs at the sulfur atom. The thioformiminoesters correspond to the isothiouronium salts obtained from the reaction with thiourea.
Differences between thioformamide and thiourea become manifest in their behavior towards a-haloesters. Whereas thioformamide yields the salts of the thioformiminoesters ( = a-iminoformylmercaptoesters, XCII) as anticipated, thiourea gives pseudothiohydantoins (XCIII). The a-im
inoformylmercaptoesters are converted into a-mercaptoesters (XCIV) with water or alcohol.
The formation of the salts of the thioformiminoesters in ether requires 5-10 hr. If their isolation is dispensed with, and the reaction effected in boiling alcohol (95%), the previously unknown a-mercaptoesters are obtained after approximately 10 min (Table 23). These compounds are also formed by the reaction between haloesters, formamide, and phos
phorus pentasulfide, with thioformamide occurring as intermediate.
T A B L E 23
a-Mercapto Esters from Halo Esters and Thioformamide in Boiling Ethanol
a-Mercapto acid ethyl ester Yield (%)«
Thioglycolic 46 (58)
Thiolactic 82 (53)
a -Mercaptobutyric 78 (57)
a -Mercaptoisovaleric 78
a -Mercaptocaproic 63
a -Mercaptocaprylic 50
a The figures in parentheses refer to the reaction between or-halo esters, formamide, and PJSJ.
The thioformiminoesters correspond to the formiminoesters postulated as intermediates in the analogous reaction with formamide. The fact that the former can be isolated may be due to the lower reaction temperature (below 60°) compared to that of the formamide reaction (150°). At 150°
the thioformiminoesters (XCII) also decompose (in formamide solu
tion) into the a-mercaptoesters (XCIV).
R - C H - C O O R '
Hal© + H C O N H2 -> R - C H - C O O R ' + ( H C N )x
S H + C O + N H4H a l S
I
C H = N H2 J
X C I I X C I V
This reaction corresponds to the conversion of a-haloesters to a-hy-droxyesters with formamide (see above). In this instance too, the darken
ing of the reaction solution is due to the formation of polymeric hydro
cyanic acid.
Whereas both the reactions of thioformamide discussed above, and the previously known reactions of the higher thioamides (60) occur at the thioamide sulfur atom, the reaction between higher thioamides and trityl chloride in pyridine yields N-tritylthioamides (56) (Table 24).
T A B L E 24 Thioamides and Trityl Chloride
Thioamide Reaction product Yield (%)
Thioacet amide N -Tritylthioacetamide 38
Thiobenzamide N -Tritylthiobenzamide 32
4-Methylthiobenzamide N -Trityl-4-methylthiobenzamide 36 4-Methoxythiobenzamide N -Trityl-4-methoxythiobenzamide 37 Pheny It hioac etamide N -Tritylphenylthioacetamide 30
A reaction occurring at the nitrogen atom is also encountered in the reaction between xanthydrol and thioamides in xylene (80°) in the presence of anhydrous zinc chloride. The N-xanthyl thioamides formed are obtained in very good yield (56) and can be used in the detection of thioamides.
Synthesis of Trisformylaminomethane (&0
The thioformiminoesters discussed above and the formiminoesters postulated as intermediates in the reaction between halogen compounds and formamide are S- and O-alkylation products of thioformamide and formamide, respectively. It was therefore obvious that the preparation of the formiminoesters from formamide and alkylating agents be at
tempted at lower temperatures.
While the unambiguous synthesis of the formiminoester cannot be accomplished with a molar proportion of formamide: dimethyl sulfate
= 1:1, the reaction using an excess of formamide (2 moles) yields the methyl sulfate salt of formamidine ( X C V ) ; this crystallizes out together with other reaction products (ammonium methyl sulfate, trisformamino-methane) from the mixture of formamide and dimethyl sulfate warmed for a few hours at 50-60°. Unlike our previous assumption (61), the preparation of the pure formamidine salt has thus far not proved possible.
0 . O C H3 HCONHo
H CN + ( C H3)2S 04 — > HC^ C H3S 04©
N H2 N H , ®
N H ; N H2
C H3S 04© + HCOOCR, X C V
The proof of the correctness of this reaction course can be demon
strated by the reaction between the formiminoethyl ester hydrochloride and 1 mole of formamide; ethyl formate and formamidine hydrochloride are produced.
The ready formation of formamidine from formamide and dimethyl sulfate explains why the formiminoester cannot be obtained.
The reaction between formamide and dimethyl sulfate does not stop at the formamidine stage when the proportion of formamide is raised to a five- to tenfold excess. Methyl formate is eliminated on warming, and the hitherto unknown trisformylaminomethane (XCVI) crystallizes on cooling. In accordance with the reaction course depicted below, trisformyl
aminomethane can be obtained from both formiminoester hydrochloride and formamidine methyl sulfate.
H CX + ( C H3)2S 04
The structure of the new compound can be established by its forma
tion from orthoformic ester (XCVII) and formamide.
H C ( O C2H5)3 + 3 H C O N H2
X C V I I
H C ( N H C H O )3 + 3 C2H5O H X C V I
Trisformylaminomethane can be prepared quite generally from formamide and alkylating agents. Thus, the compound is obtained with dialkyl sulfates (including diethyl and diisopropyl sulfate), alkyl sul
fonates (benzenesulfonic esters, p-toluenesulfonic esters), and alkyl halides (ethyl iodide, isopropyl, and allyl bromide). Of the more powerful alkylating agents, triethyloxonium fluoborate can be used; with this reagent the reaction proceeds even at room temperature.
The fact that, apart from many halogen compounds, acid chlorides also attack the formamide oxygen atom (see above), explains why tris
formylaminomethane is also obtained from reactions between formamide and acylating agents (acid chlorides). The acid chlorides we utilized include acetyl chloride, benzoyl chloride, chloroformic ester, phosphorus oxychloride, phosphorus trichloride, and sulfuryl chloride. The reaction then proceeds via the compound corresponding to the formiminoester.
One such compound (XCVIII), for example, can be isolated in the form of a hygroscopic, crystalline product from an ethereal solution of form
amide and benzoyl chloride.
Trisformylaminomethane represents the formylated amide of the hypothetical orthoformic acid. A few of the reactions undergone by this reactive compound are cited briefly.
Reaction with acid anhydrides (acetic anhydride, propionic anhy
dride, butyric anhydride, benzoic anhydride) results in acylation (62).
( R C O ) , 0
H C ( N H - C H O )3 - — • H C ( N H - C O - R )3
X C V I X C I X
If trisformylaminomethane is heated above its melting point (165-167°, dec.), s-triazine (CI) is formed (62). This reaction proceeds par
ticularly readily in formamide (63), and s-triazine has thus become con
veniently accessible. We postulate the following reaction course: Initially, either formylformamidine (C) or formamidine is formed.
H C ( N H C K O )3
^ X C V I
H C ^ + H C O N H2 + CO
N H C H O N H C
The fact that triazine can be formed from formamidine is known (64)- With formylformamidine, the reaction must be formulated as follows:
N + N H , N N
H CX C H O H C C H
N H2 N
C CI
(For reasons of clarity, we formulate the following equations via formylformamidine as intermediate).
The reaction between trisformylaminomethane and benzaldehyde yields benzylidene bisformamide (CII) (65), also obtainable from form
amide and benzaldehyde (66).
H C ( N H C H O )3 + CeH5C H O -> C6H5- C H ( N H C H O )2
X C V I CII
With acetophenone, 4-phenylpyrimidine ( C M ) is obtained (65). If the reaction is carried out in formamide in the presence of an acid catalyst (p-toluenesulfonic acid), a yield of 72% is obtained. This syn
thesis can again be regarded as proceeding via the postulated formyl
formamidine intermediate.
C H O
N C H3 N NC H
II + 1 > II I HC O C - C6H6 H CX ^ C - C , H6
N H , N
c c m This reaction constitutes a new route for the synthesis of 2-unsub
stituted pyrimidines. 4-Phenylpyrimidine can be prepared directly from
formamide, dimethyl sulfate (which, together, yield trisformylamino
methane), and acetophenone, without isolation of the trisformylamino
methane (65). This new synthesis also allows the preparation of 4,5- and 5-substituted pyrimidines. It can be effected with aliphatic, cycloaliphatic, aromatic, and heterocyclic ketones (Table 25).
T A B L E 25
Pyrimidines from Trisformylaminomethane and Ketones
Ketone Pyrimidine Yield (%)
Acetone 4-Methyl- 39
Isobutyl methyl ketone 4-Isobutyl- 35
Pinacolone 4-terf-Buthyl- 17
Acetophenone 4-Phenyl- 72
2-Methyl-5-acetylpyridine 4-(2'-'ethyl-5'-pyridyl)- 43
Methyl ethyl ketone 4,5-Dimethyl- 47
Diethyl ketone 4-Ethyl-5-methyl- 37
Cy c lopentanone 4,5-Trimethylene- 52
Cyclohexanone 4,5-Tetramethylene- 36
Propiophenone 4-Phenyl-5-methyl- 53
Butyrophenone 4-Phenyl-5-ethyl- 26
In the reaction between trisformylaminomethane and methyl ethyl ketone or methyl isobutyl ketone, the question arises whether reaction occurs at the C H3 or the C H2 group of the ketone. While the C H2 group reacts in the case of methyl ethyl ketone—4,5-dimethylpyrimidine is formed exclusively—this is not so in the case of methyl isobutyl ketone, presumably on account of steric hindrance due to the isopropyl group, and the C H3 group reacts to give 4-isobutylpyrimidine (CIV) (65).
/ C H O
N C H3 N CH
II + I — * II I
H CN C O - C H2- C H ( C H3)2 HC C - C H2- C H ( C H3)2
N H , N
c CIV
Two other reactions may also proceed via N-formylformamidine.
With malonic ester, 4-hydroxypyrimidine-5-carboxylic acid ester (CV) is formed (66a).
/ C H O CH N H2C - C O O R / V C O O R N
H CX o i - O R H C J-OH
N H2 V
c c v
With guanidine carbonate, a good yield of amino-s-triazine (CVI) is obtained (63); this compound had previously been prepared in low yield
by Grundmann (67) from formylguanidine and formamide in the pres
ence of a little alkali hydroxide.
/ CH O H C H N
N | * l / Si
II + C - N H , || |
*
n hv
c v;
The reaction between trisformylaminomethane and benzoins at 140°
The reaction between trisformylaminomethane and benzoins at 140°