Cycloaddition of tert-butylcyanoketene to isocyanides

The reaction of tert-butylcyanoketene with a series of isocyanides results in an unusual mode of addition involving the carbonyl bond of the ketene. The scope and mechanism of these cycloadditions are discussed.

filtrate was concentrated, dissolved in a small volume of 2 -b ~tanol-14 M formic acid (7030), and flash chromatographed on silica gel (60 g, 3 X 15 em, EM silica gel 60,4043 pm) eluted with the same solvent.Compounds 5a and 5b were eluted in the yellow fractions 15-35 mL after the void volume while 4a and 4b were eluted in the pale yellow fractions 35-80 mL after the void volume.The eluate containing 5a and 5b was concentrated, dissolved in water, cautiously basified to pH 6.0 with 1 M NaHC03, filtered through Dowex 2-X8 Cl-(2 mL, 20-50 mesh), and extracted twice with ether.The aqueous phase was concentrated, triturated with 95% EtOH, filtered through Celite, and concentrated, redissolved in 95% EtOH (2 mL), treated with chloroform (2 mL), and filtered.The fdtrate was concentrated to afford 100 mg (37% yield) of a reddish solid, a 1:l mixture of 5a and 5b.LC, TLC, 'H NMR, and 13C NMR revealed no impurities other than a small amount of formate.
Such products result from a reaction mode in which the cycloaddition takes place across the carbonyl bond of the ketene components.This is unusual since all other reported examples of ketene/isocyanide cycloadditions give products arising from reactions involving addition to the alkene bond of the cumulene.For example, the l-imino-2,4-cyclopentanedione (1) was obtained in 90% yield when benzyl isocyanide was treated with diphenylketene at -20 oc.1 oc.1 The cycloadditions reported here were accomplished by the addition of a benzene solution of TBCK2 to a slight excess of the isocyanides a t ambient temperature.The reactions were complete within a few minutes and the products isolated by standard methods.Although the yields differed slightly, the same products were obtained when the mode of addition was reversed or if the temperature of the reaction was maintained at -20 OC.In one case, the ketene was slowly added to an excess of neat tert-butylisocyanide in an attempt to obtain products incorporating more than 1 equiv of the isocyanide.However,  Although several stereoisomers are possible for 5a-e, only one is formed in the cycloadditions.On the basis of steric arguments, the stereochemistry of these products is assumed to be that represented by structures 5a-e.
The structures of compounds 5a-e are based primarily upon spectral and analytical data (Tables I and 11).Their IR spectra all show a weak absorption between 1745 and 1755 cm-' for the strained imidate group.Also, strong absorptions for the conjugated nitriles appear at 2210 cm-', and the polar double bonds absorb between 1635 and 1675 cm-'.Their 'H NMR spectra all show the appropriate absorptions for the tert-butyl and R substituents, and their 13C NMR spectra reveal the required number of sp, sp2, and sp3 carbon atoms.Finally, their mass spectra gave the appropriate molecular ion (M+) and an intense (100%) peak corresponding to M+ -TBCK.
The most reasonable explanation accounting for the formation of 5 involves the initial formation of zwitterion 3. Interception of this by another molecule of the ketene, 2, would give 4 as the penultimate precursor to 5 (Scheme I).It is noteworthy that an intermediate analogous to 3 was proposed in the previously mentioned cycloaddition of diphenylketene to isocyanides.'However, unlike the transformation of 3 to 4, this zwitterion undergoes acylation at carbon rather than oxygen to afford ultimately the iminocyclopentanediones, e.g., 1.That such a transformation is not observed with TBCK is most likely due to the steric congestion imparted by the bulky tert-butyl group.In order to investigate the possibility that 5 represents the kinetic products in these cycloadditions, we also studied the thermal chemistry of 5a.Here it was observed that 5a rearranges to 6 (82%) after 72 h in refluxing benzene.Clearly this must involve equilibration of 5a with  Cycloaddition of tert-Butylcyanoketene 4a.The thermodynamically more stable 6 then results from C-iminolation of the enolate moiety of 4a (Scheme 11).A most interesting additional thermolysis pathway was observed when 6 was heated at 145 "C in o-dichlorobenzene for 50 min.Under these conditions, de-tert-butylation occurred to give the butenolide 7 in 95% yield.This is viewed as arising via a retroene reaction as outlined in Scheme 11.
Finally, brief mention is made of a comparative study of the cycloaddition of chlor~cyanoketene~ to tert-butyl isocyanide.This ketene, unlike its tert-butyl analogue, readily undergoes self-condensation and thus must be generated in situ.When this was accomplished by the thermolysis of 4-azido-3-chloro-5-methoxy-2(5H)-furanone in refluxing benzene containing an excess of tert-butyl isocyanide, an entirely different reaction course was encountered.Rather than imino lactone, butenolide, or iminocyclopentanedione products, a 3:l adduct was isolated in 49% yield.The only reasonable structures that can be considered for a 3:l adduct are 8 or 9, and the latter is J. Reaction of tert-Butylcyanoketene with (p-Tolyl-sulfony1)methyl Isocyanide.A solution of 6 mmol of tertbutylcyanoketene was prepared by refluxing 0.906 g (3 mmol) of 2,5-diazido-3,6-di-tert-benzoquinone in 25 mL of anhydrous benzene for 75 min.The benzene solution was cooled to room temperature and then was added dropwise to a solution of 0.585 g (3 mmol) of (p-tolylsulfony1)methyl isocyanide in 15 mL of benzene.The reaction mixture was stirred for 1 h.After removal of the solvent, the reaction residue was chromatographed on silica gel to give 1.18 g (89%) of compound 5e.Recrystallization in hexane-chloroform provided the analytical sample: Anal.Calcd for C23H2,N304S: C, 62.59; H, 6.12.Found: C, 62.62; H, 6.14.
Thermolysis of Compound 5a.A benzene solution of 0.329 g (1 mmol) of compound 5a in 25 mL of anhydrous benzene was heated at 85 "C under nitrogen for 3 days.After removal of the solvent, the solid material was purified by crystallization from 30 mL of hexane-benzene.This procedure afforded 0.27 g (82%) of the pure compound 6: mp 162-163 "C dec; mass spectrum (CI), m/e (relative intensity) 330 (M + 1,5), 275 (7), 274 (40), 218 (5), 207 (12), 181 (12), 180 (loo), 166 (lo), 124 (8); 13C NMR (CDC13) Reaction of Chlorocyanoketene with tert-Butyl Isocyanide.A solution of 0.57 g (3 mmol) of 4-azido-3-chloro-5methoxy-2(5H)-furanone and 0.75 g (9 mmol) of tert-butyl isocyanide in 10 mL of anhydrous benzene was well stirred under nitrogen at 60 "C for 1 day.After removal of the volatile components in vacuo, the reaction residue was chromatographed on favored on the basis of spectral data.The IR spectrum shows a conjugate nitrile absorption at 2205 cm-' and the imine absorption as a multiplet a t 1720 cm-'.The ' H NMR spectrum shows only absorptions for the three tert-butyl groups.The I3C NMR spectrum provides significant structural information in that it reveals the required 12 absorptions, and six of these are in the sp2 region of the spectrum.Specifically, the absorptions for the tert-butyl groups appear at 6 60.5,59.9,56.8,29.6,28.8, and 28.7.The remaining sp2 carbons appear a t 6 157.4,146.9,144.0, 135.9, 114.6, and 87.1.This adduct is presumably favored over the previously described examples since, under the conditions utilized, the ketene would be in very low concentration relative to that of the isocyanide.Thus, the initially formed zwitterion analogous to 3 reacts further with additional isocyanide rather than ketene.In any regard, the synthesis of analogues of 9 by this method appears limited in scope since complex product mixtures were obtained when chlorocyanoketene was generated in the presenc of less bulky isocyanides, e.g., benzyl and (p-tolylsulfony1)methyl isocyanide.

Experimental Section
Reaction of tert-Butylcyanoketene with tert-Butyl Isocyanide.A solution of 6 mmol of tert-butylcyanoketene was prepared by refluxing 0.906 g (3 mmol) of 2,5-diazido-3,6-ditert-butyl-l,4-benzoquinone in 25 mL of anhydrous benzene for 75 min.The benzene solution was cooled to room temperature and 1.494 g (18 m o l ) of tert-butyl isocyanide was added dropwise.The reaction mixture was stirred for 10 min, and then the volatile components were removed in vacuo at room temperature.The crude reaction residue was chromatographed on silica gel, and 0.956 g (97%) of compound 5a was obtained.Recrystallization in ether-hexane (2080) afforded the analytical sample: mp    The syntheses of cu,p-fluoro amines from the reaction of secondary aziridines with either Olah's reagent (HF, pyridine) or anhydrous hydrogen fluoride and of N-activated aziridines with partially neutralized Olah's reagent (NR3-nHF) are reported.The stereochemistry of these reactions is highly dependent on the structure of the starting compound and on the fluorinating agent.From the same aziridine it is thw possible to synthesize selectively each diastereoisomeric fluoro amine by proper choice of fluorination conditions.
Fluorine compounds are widely used as drugs in pharmacology and ~hemotherapy.'-~However, a convenient synthetic route to a,@-fluoro amines, particularly those with a primary amine function, does not exist.These compounds exhibit biological activity on the central nervous ~y s t e m .~ A new synthetic route to fluoro amines has recently been reported by Kollonitsch and co-workers.6This method, however, needs special handling of sulfur tetrafluoride, a very toxic reagent.More frequently used fluorinating reagents are fluoroalkylamines,' metallic and nonmetallic fluorides: and trifluoromethyl hypofl~orite.~Fluorodesulfurization'O and diazotizationll reactions have also been carried out in this connection.Finally, the possible replacement of the chlorine atom by an amine function in a,B-chlorofluoro compounds should be mentioned.I2 The fact that the hydrogen fluoride addition to epoxides is a very clean and good method for preparing a,@-fluoro alcohol^'^ led us to investigate the same type of reaction