Reactions of dipivaloylketene and its dimer with NH 2 –nucleophiles. Formation of amides, hydrazides, ureides and pyrimidine-2,4-diones

Dipivaloylketene 1 and its dimer 2 add several NH 2 -nucleophiles affording the open-chain dipivaloylacetic acid derivatives 3 , 5 , 6 , 9 and 10 . With methylhydrazine as well as 2,6-dimethylaniline the 2:1 products 8 and 11 , respectively, are formed. The tetracarbonyl compounds 3a-c only undergo PPA-induced cyclocondensation, and with concomitant loss of one pivaloyl group the pyrimidine-2,4-diones 4a-c are obtained.


Introduction
Dipivaloylketene 1 is obtained in excellent yield by preparative flash vacuum pyrolysis (FVP) of the corresponding furan-2,3-dione. 1 It slowly dimerizes to afford the dioxinone derivative 2, still possessing an α -oxoketene moiety. 1,2Both compounds are remarkably stable and have been found to smoothly add OH-nucleophiles as well as aryl and alkyl amines under very mild reaction conditions. 3Furthermore, in strongly basic medium 1,3-diketones also add as Cnucleophiles. 4 As expected, from 1 and nucleophilic species the corresponding dipivaloylacetic acid derivatives are obtained in excellent yields, but the reaction products derived from dimer 2 and alcohols, water or primary electron rich arylamines represent the rather rare molecular skeleton of a concave, bridged bis-dioxine exhibiting axial chirality. 3In addition, these molecules can be easily transformed into functionalized 2,4,6,8-tetraoxaadamantanes by acidic hydrolysis (Scheme 1). 5

Scheme 1
These bridged bisdioxines as well as tetraoxaadamantanes may serve as chiral spacer units in macrocyclic ring systems. 6In order to widen the scope of such molecules with respect to their application as potential host-systems in the area of host-guest chemistry, we extended our investigations to a variety of NH 2 -nucleophiles, such as ureas, primary amides, hydrazines, semicarbazides as well as further primary heteroaromatic amines.

Results and Discussion
The reaction of α-oxoketenes 1 and 2 with urea and N-alkyl/aryl ureas were performed in acetonitrile at rt to afford the disubstituted open-chain ureas 3a-g in moderate to good yields (40-80%).Apart from correct elemental analyses and IR-spectra (for details see Experimental) by intramolecular hydrogen bridges. 8Furthermore, in order to establish that the primary Experimental) structural evidence for these compounds is given by their 1 H -NMR spectra which exhibit a signal at 5.65-5.95ppm highly characteristic of the CH-proton.In the 13 C NMR spectrum of 3a and 3g as examples, the CH-signals are found at 63.5 ( 1 J = 152.0Hz, 3a) and 64.5 ppm ( 1 J = 153.0Hz, 3g).Similar results were obtained for several other closely related dipivaloylacetic acid derivatives 3b, 7 and again make evident that these multi-carbonyl systems mostly avoid enolization in solution, although enols should be stabilized NH 2 -moiety had attacked the central ketene carbon, the 15 N NMR spectrum of e.g.3b was performed.Two antiphase doublets at -304.4 and -244.8 ppm confirmed the presence of two different NHmoieties, thus ruling out an attack of the NHR group.

Scheme 2
Attempts to cyclize the open-chain compounds 3 with the aid of polyphosphoric acid (PPA) at 110-120°C were successful only in case of 3a-c affording the pyrimidine-2,4-diones 4a-c, which represent the well-known uracil nucleus.Loss of one pivaloyl-group during the cyclization process in the strongly acidic medium is not surprising.Examples of such deacylation reactions under similar reaction conditions are well known. 9 Compound 4a had been prepared independently previously from 6-t-butyl-2-thiouracil and chloroacetic acid. 10, 11Structural confirmation of the pyrimidine-2,4-diones 4 is given by the singlets for the olefinic protons at 5.63 ( 4a ), 5.78 (4b) and 5.75 ppm (4c) in the 1 H NMR spectra.Furthermore, in the 13 C NMR spectrum of e.g.4b the carbonyls are found at 163.9 and 163.6, respectively, C-6 appeared at 153.0 and C-5 at 100.0 ppm ( 1 J= 135 Hz) , while its 15 N-NMR spectrum exhibited one antiphase doublet at -232.3 ppm ( with respect to nitromethane ).In order to extend this cyclization process to further compounds of type 3, the dipivaloylacetic acid derivatives 5a,b were prepared by simple addition of phenylsemicarbazide or cyclohexanone semicarbazone to dipivaloylketene 1.Unfortunately, ring closure of 5 into heterocyclic systems could not be achieved.

Scheme 3
Irrespective of employing α-oxoketene 1 or 2, the primary reaction product in all cases was the corresponding open-chain derivative of dipivaloylacetic acid 6a,b,c and 8, the latter being a 1: 2 product.Besides the expected signal pattern for the t-butyl and methyl groups the presence of CH-moieties in 6 and 8 was again unambiguously demonstrated by signals at 5.97 (6a), 5.75 (6b), 5.63 (6c) and 5.70 ppm (8), respectively, in the 1 H-NMR spectra.From the 13 C NMR spectrum of 8 an interesting structural detail became evident : while in the 1 H NMR spectrum the two slightly different CH-protons appear as one signal only ( 5.70 ppm ), there are two signals at 62.9 ( 1 J= 123.7 Hz) and 60.7 ppm ( 1 J= 123.7 Hz) found in the 13 C NMR spectrum.Taking into account the different coupling constants and line-widths all carbon atoms of 8 could be clearly assigned : the CH attached to the C=O-NH-group appeared as a broad signal due to strongly hindered rotation around the C -NH bond, a phenomenon well known from dynamic NMR studies. 12Similar line broadening is also found for the NH-C=O ( 164.0 ppm) as well as the adjoining pivaloyl-C=O's ( 206.1 ppm ).In strict contrast, a distinct set of sharp signals is observed for the related carbons attached to the N-Me -moiety ( 62. 9, 167.8 and 207.8 ppm, respectively ).Attempts to cyclize the dipivaloylacetamide 6a following the procedures successfully applied to 3a-c, failed.The deacylated open-chain compound 7 (43%) was obtained instead; its CH 2 protons appear at 3.87 ppm.
In continuation of our efforts to obtain compounds representing the bridged bisdioxine scaffold (see Introduction) several heteroaromatic amines were treated with oxoketenes 1 and 2, respectively, but again the corresponding dipivaloylacetamides 9 were obtained as the only reaction products (Scheme 4).However, when the sterically hindered 2,6-dimethylaniline was employed as the nucleophile, divergent results were obtained depending on whether the monomeric oxoketene 1 or the dimeric form 2 was the substrate: while 1 underwent a simple addition reaction as usual to afford the dipivaloylacetic derivative 10 , in the case of 2 the bisacylated amide 11 was formed.Its 13 C NMR spectrum made evident that 11 favours enolization ( no signal above 175 ppm ) due to the enolic form being stabilized by intramolecular hydrogen bonds.It is important to note that pure 10 could not be converted into 11 when treated with 1 under identical or similar reaction conditions.Obviously, compounds 10 and 11 were formed via different mechanistic pathways (see below).

Mechanistic considerations
The formation of open-chain dipivaloylacetic acid derivatives 3, 5, 6, 9 and 10 from dipivaloylketene 1 and the corresponding NH 2 -nucleophiles is the result of addition of the nucleophile to the ketene functionality to give 12 (Scheme 5).In case of the dimeric oxoketene 2, the primary attack of the nucleophile at the ketene moiety must be followed by a subsequent fragmentation of the dioxinone ring.Finally, two equivalents of the corresponding dipivaloylacetic acid derivatives should be formed via two consecutive elimination processes ( Scheme 5 ) 3b With methylhydrazine the dipivaloylketene molecule released during this process adds to the free NH-Me group in 12 ( R = NHMe) leading to 8.However, the reaction of 2 with 2,6-dimethylaniline affording 11 must proceed via a somewhat different reaction pathway, since there is experimental evidence that the mono-acylated 10 cannot be converted into 11 by addition of 1 ( see above ).An intermediate 13 which still contains an oxoketene moiety could be formed in the initial addition of the amine ( see Scheme 5 ).Subsequent intramolecular attack of the amide nitrogen atom on the ketene function in 13 would lead to 11.

Scheme 5
Experimental Section General Procedures.Melting points were determined on a Tottoli apparatus (Buechi).IR spectra were recorded on a Perkin-Elmer 298 spectrophotometer.Elemental analyses were obtained on a Carlo Erba 1106 elemental analyzer. 1H -and 13 C NMR spectra were obtained on Varian XL-200 Gemini (200 MHz), Bruker AMX 360 (360 MHz) and Bruker DRX Avance (500 MHz) spectrometers.The 15 N NMR spectra of 3b and 4b were recorded on a Bruker AMX 360 spectrometer.The mass spectrum of 11 was recorded on a Hewlett Packard LC/MSD instrument.The α-oxoketenes 1 and 2 1,2 and cyclohexanone semicarbazone 13 were prepared according to the literature.All other reagents were purchased from Aldrich Chemical Co. and used without further purification.The solvents (dichloromethane, acetonitrile) were distilled and stored over molecular sieves, the eluants used during chromatographic separations (n-hexane, ethyl acetate, methanol) were purchased in p.a. quality.