Orthoamides and iminium salts, LXXIII 1 Contributions to the cleavage of carboxylic acid orthoamides – a new access to N,N,N‘,N‘-tetraalkyl-carboxamidinium salts

Abstract


Introduction
By definition three amino functionalities are linked to one carbon atom in an orthoamide group.The stability of orthoamides depends on one hand on the nature of the N-substituents and on the other hand on the degree of substitution in α-position to the orthoamide function.With the aid of N,N,N',N',N'',N''-hexamethylguanidinium salts 8 orthoamide molecules 9 can be prepared easily since these salts react with complex hydrides as well as with metalorganic compounds to give the corresponding orthoamides 9. [8][9][10][11][12][13] Scheme 4. Orthoamides 9 from guanidinium chloride 8a and metalorganic compounds.
In conventional orthoamide synthesis an amide function is activated by electrophilic reagents.The iminium compounds thus formed are converted to amidinium salts whichas described abovecan be transformed to the desired orthoamide compounds.In contrast to these methods, the orthoamide function is not constructed step by step.In the guanidinium salt procedure the orthoamide molecule is formed by a simple C,C-bond connecting reaction.As a consequence, orthoamides are now easily obtainable even with a quite complicated pattern of substituents.This prompted us to investigate if these new orthoamides can serve as starting materials for amidinium salts, which are not easily available by other methods.

Cleavage of orthoamides with benzoyl chloride
The preparation of derivatives of propiolamidinium salts by conventional methods was regarded to be not trivial for several reasons. 9,13The cleavage of the corresponding orthoamides could deliver a solution for the problem.Indeed N,N,N',N'-tetramethyl-phenylpropiolamidinium chloride (13a) was prepared for the first time in pure state with 84% yield by the action of benzoyl chloride on 3,3,3-tris(dimethylamino)-1-phenyl-prop-1-yne. 9Later on, a series of propiolamidinium salts could be obtained by the same procedure. 13In these studies the very hygroscopic amidinium chlorides 13 were isolated as tetraphenylborates 14.However, this method is not applicable for the cleavage of trialkylsilyl substituted alkynyl orthoamides. 13In these cases triethylsilyl trifluoromethanesulfonate is the reagent of choice, which can be generally used for the transformation of orthoamides to the corresponding amidinium triflates 15. 13 Trimethylsilyl halides are not as effective in orthoamide cleavage reactions as trialkylsilyl triflates. 13he preparation of imidazole-2-carboxamidinium salts of type 17, starting from imidazole-2carboxamides seems also to be difficult, according to established procedures, since the electrophilic reagents usually used for the activation of the amide function, would very likely attack the nitrogen atoms of the imidazole system.However, the imidazole-2-carboxamidinium salt 17 could be prepared from the corresponding orthoamide derivative 16 and benzoyl chloride. 12We now found that the dihydro-4H-pyrane-carboxamidinium salt 19 can be obtained from the orthoamide derivate 18 by the same procedure.In order to evaluate the scope of this method we reacted the earlier described 7,9,20 orthoamides 7b-h with benzoylchloride in ether.From the orthoamides 7b-d the strongly hygroscopic corresponding amidinium chlorides 13b-d could be obtained, which were isolated as tetraphenylborates 14b-d.The amidinium chloride 13e forms extremely hygroscopic colorless crystals, which could be characterized by NMR.A further characterization as a tetraphenylborate by elemental analysis was not possible, since the tetraphenylborate 14e, prepared from 13e could not be obtained in crystalline state.From the reactions of the orthoamides 7f-h with benzoyl chloride resulted tarry products in which the presence of the guanidinium chloride 8a could be detected.Obviously, these orthoamides are cleaved by another, hitherto unknown mechanism.This deviating reaction path is observed when the substituent pattern of the substrate 7 does not fit to the cleaving reagent.Thus the orthoamide 7g is not converted into the corresponding amidinium chloride 13g by benzoylchloride, however, the treatment of 7g with triethylsilyl triflate affords the salt 15g. 13eavage of the orthoamide 7a by acetic acid anhydride We tried to cleave the orthoamides 7a and 25 by other reagents.From the results of these reactions we expected to get insight into side reactions which can compete with the cleavage of the orthoamide function.When 7a was treated with acetic acid anhydride in excess, we obtained with 63% yield a yellowish distillable oil, which turned out to be the ketene aminal 23.Scheme 7. Cleavage of 1,1,1-tris(dimethylamino)-3-phenyl-2-propyne (7a) by acetic acid anhydride.
The formation of the ketene aminal 23 can be explained in the following way.In the first step the amidinium acetate 21 is formed from 7a and acetic acid anhydride.The addition of the acetate ion on the triple bond of the phenylpropiolamidinium ion affords the allene 22, which delivers the ketene aminal 23 by elimination of ketene.The result of this cleavage reaction reminds of the known acetolysis of 7a which also affords the ketene aminal 23 as main product.The acrylamidinium salt 24 was isolated as a side product.The allene 22 was assumed to be an intermediate 6 in explaining the formation of the reaction products.Scheme 8. Cleavage of 1,1,1-tris(dimethylamino)-3-phenyl-2-propyne (7a) by acetic acid.

Cleavage of the orthoamide 25 by chloroform
It is well known that hydrogen chloride can be abstracted from chloroform by strong bases delivering dichlorocarbene via α-elimination.Assuming that the orthoamide 25 can produce dichlorocarbene from chloroform, the hydrogen chloride formed should cleave the orthoamide function of 25 to give the propiolamidinium salt 26a, which we expected to be trapped the trichloromethyl-anion formed from chloroform.After stirring 25 in chloroform for 24 h at room temperature, the chloroform was removed in vacuo.The residual yellow oil crystallized on treatment with diethylether.After recrystallization from acetonitrile/ethyl acetate, a colorless hygroscopic salt with mp 186-187 °C resulted.This could be identified as the hygroscopic vinylogous guanidinium chloride 27, which was transformed into the slightly hygroscopic tetraphenylborate 28.For the trichloromethyl anion in 26a, two reaction paths exist.On one hand it can add on the propiolamidinium ion, on the other hand it can lose a chloride ion forming dichlorocarbene.Very likely, the addition of the trichloromethyl anion on the propiolamidinium ion is reversible.Thus in equilibrium trichlormethyl anions are always present, which are completely decomposed to chloride ions and dichlorocarbene in the end.So finally, the salt 26a is completely converted into the salt 26b, on which dimethylamine can add to give the salt 27.

Hydrolysis of the orthoamide 7a
Since nothing is known on the hydrolysis of orthoamides 7 we heated 7a with diluted sodium hydroxide solution for 2 h under reflux.The reaction mixture was neutralized with diluted HCl and then extracted with dichloromethane.After further work up procedures we obtained colorless crystals with mp 75-77 °C with 72% yield which were identified as N,N-dimethyl-2benzoylacetamide (31A) in equilibrium with the corresponding Z-enol-isomer 31B.The compound forms an intensive red-violet colored iron complex when an aqueous solution of iron-III-chloride is added to a methanol solution of 31.The compound 31A was prepared by Oishi and Ochiai by benzoylation of N,N-dimethylacetamide dimethylacetal. 18heme 10.Hydrolysis of 1,1,1-tris(dimethylamino)-3-phenyl-2-propyne (7a).
The propiolamidinium hydroxide 29 is probably formed in the first step from 7a and water.Addition of the hydroxide ion gives the enol 30 which tautomerizes to afford the ketene aminal 23, which in turn delivers the keto/enol-mixture 31A, 31B on hydrolysis.
Butadiene derivates 32 are mainly obtained as reaction products from condensation reactions of orthoamides 7 with CH2-acidic compounds. 11,12,19These results were explained by the assumption that in the first step propiolamidinium ions and carbanions are formed from the starting compounds by loss of dimethylamine.The ketene aminals 32 result from the ionic species thus formed via conjugated addition.The propiolamidinium salt 13a can be prepared in pure state. 9So it was possible to confirm that nucleophiles enter propiolamidinium salts in 3-position.When the chloride 13a was treated with butylamine and secondary amines, the reaction products were the very hygroscopic 3amino-acrylamidinium chlorides 33, isolated as the tetraphenylborates 34.The compound 34d is known.It was obtained directly from the tetraphenylborate 14a and morpholine. 13heme 12. Addition of amines onto the phenylpropiolamidinium salt 13a.

Conclusions
The present investigations have enlarged the number of methods for the cleavage of orthoamide functions in orthoamides of alkyne carboxylic acids.Thus further examples have been reported for the transformation of orthoamides 7b-d to propiolamidinium salts 13 and 14 resp.by benzoyl chloride.The method is not applicable for the cleavage of orthoamides 7e-h since in these orthoamides additional functional groups are present, which can induce undesired side reactions.The reaction of 7a with acetic acid anhydride demonstrates that orthoamides as 7a can be converted for example to acylated ketene aminals as 23.The orthoamide group in 25 is cleaved by chloroform even at room temperature to give the vinylogous guanidinium salt 27.Thus the NMR spectra of orthoamides should not be recorded in chloroform solutions.The hydrolysis reaction of an orthoamide of compound type 7 has been reported for the first time.The β-ketocarboxylic acid amide 31 was isolated as reaction product.In total it could be shown that the orthoamides 7 can serve as starting materials for the preparation of amidinium salts of alkyne carboxylic acids, acylketene aminals, vinylogous guanidinium salts and β-keto-carboxylic acid amides.

Experimental Section
General.Melting points were measured with a Büchi 510 apparatus.IR spectra were recorded on a Perkin Elmer Spectrometer 457. 1 H-NMR spectra were recorded with a Varian T60 (60 MHz), a Bruker WP80 (90 MHz) and a Bruker AMX500 (500 MHz) spectrometer. 13C NMR spectra were recorded with a Bruker AMX500 (125 MHz) spectrometer.Solvents were dried by standard procedures.All reactionsexcept the hydrolysis reactionwere performed under exclusion of moisture (KOH) drying tubes.

Cleavage of orthoamides 7 with benzoyl chloridegeneral procedure
A solution of the corresponding orthoamide 7 in dry diethylether was added dropwise with stirring to a solution of benzoylchloride in dry diethylether under cooling with ice.After 0.5-1 h stirring, the precipitated salt was filtered off in vacuo with exclusion of moisture.The hygroscopic colorless salts were dried in an oil-pump vacuum.From not too extreme hygroscopic products could be recorded.In other cases the crude product was dissolved in dry acetonitrile.An equimolar amount of sodium tetraphenylborate in dry acetonitrile was added to this solution.The mixture was boiled for a short time and then freed from the sodium chloride by filtration of the hot solution.The filtrate was concentrated in a rotatory evaporator.The precipitated crystals were isolated by filtration and recrystallized from dry acetonitrile.Preparation procedures are described for all orthoamide derivatives 7a, 6,7,9 7b-h 20 and 18 9 which were used in the present study.

Addition of amines to N,N,N',N'-tetramethyl-3-phenyl-propiolamidinium-chloride (13a
)general procedure.The corresponding amine (2.1 mmol) was added slowly to a solution of 0.5 g (2.1 mmol) 13a in 20 ml acetonitrile.After 15-20 min a solution of 0.68 g (2.1 mmol) sodium tetraphenylborate in 10 ml acetonitrile was added.The mixture was heated upto 70 °C and filtered hot.The filtrate was evaporated.Treatment of the residual oily or solid compounds with diethylether afforded crystalline compounds, which were isolated by filtration.
The chloride 19 was converted into the tetraphenylborate 20 for analytical characterization.