Four-membered rings from isocyanides: Developments since the mid 1980s

Reactions of isocyanides with open-chain and cyclic substrates leading to four-membered rings are reviewed. The survey is intended to be illustrative rather than encyclopedic.


Introduction
Within the wide area of cyclizations involving the isocyano group the direct formation of fourmembered rings constitutes an especially intriguing process because of elements of serendipity.The first discoveries date back to the 1960s and were summarized at the end of the decade. 1 The period till 1985, however, proved prolific to such an extent as to warrant a second review. 2Since that time again new results have emerged in great number; this may justify the present survey. 3iewing the rich material, two features stand out: (i) The ring-forming principles have almost trebled so as to exclude an introductory graphic of the kind shown in ref. 2 ; (ii) regarding the type of products, a plethora of element-organic rings have arisen. 4dhering to style and format of the earlier review, 2 presentation of all new material will be arranged according to starting compounds rather than to products or actual mechanisms.

Reaction of isocyanides with open-chain substrates 2.1. [1+1+2] Cycloaddition of isocyanides to double and triple bond systems
Alkenes: While a methylenemalononitrile bearing two acceptor groups like the derivative 2a reacts with tert-butyl isocyanide to produce the cyclobutanediimine 1 (Scheme 1), 1 benzylidene analogs (even though substituted with a nitro or fluoro group at the phenyl ligand) were shown to take up three molecules of the isocyanide to yield the five-membered ring 3 instead. 5hough not being an open-chain substrate, the behavior of the benzocyclobutadiene complex 4 may be compared to that of 2a.When two equivalents of tert-butyl isocyanide were added to 4, the reagent underwent smooth insertion into both Zr-C bonds to eventually afford the Dewarnaphthalene 5, the structure of which was established by X-ray diffraction. 6Double insertion of tert-butyl isocyanide had been observed before also with the cyclobutene analog of 4, but in that case the carbon atoms of the two isocyanides did not couple to give a four-membered ring. 7

Scheme 1
Alkynes: Open-chain representatives devoid of an acceptor or donor group are usually inert towards isocyanides.As an exception, a [1+1+2] cycloaddition took place very readily when diphenylethyne was treated with trifluoromethyl isocyanide to afford the cyclobutenediimine 6 (Scheme 2).The structure of this material was determined by an X-ray structure analysis, showing that the imino functions are E and Z configured.Traces of a (mono)ketone arise unless the solvent is rigorously dried. 8Similar reactions of this isocyanide were reportedbut without experimental detailsfor but-2-yne and ethoxyethyne, whereas hexafluorobutyne and fluoroalkenes were said to be inert. 9owever, transition metal-induced [1+1+2] cycloadditions are relatively frequent (cf.ref. 2 ); more recent examples include the following: (i) When oct-4-yne was heated with tert-butyl isocyanide and a catalytic amount of dicarbonylcyclopentadienylcobalt(I), the cyclobutenediimine 7 was obtained. 10Yet, on addingas a fourth componenttrimethylsilyl cyanide (which equilibrates with the isocyanide in situ), the pyrrole 8 resulted (or its N-unsubstituted congener if tertbutyl isocyanide was replaced with cyclohexyl isocyanide).(ii) When the cationic molybdenum complex 9 was treated with six equivalents of 2,6-dimethylphenyl isocyanide, alkyne-isocyanide coupling gave rise to the four-membered ring 10. 11 According to the X-ray analysis, the imino groups are configured as observed earlier with the product 6. 8 -For a further example following the formal [1+1+2] cycloaddition pattern, cf.Section 3.2.

Scheme 2
Alkylidene-, imino-, aminoboranes: Compounds of the type 11 and 13 were shown to take up two isocyanide molecules very readily (Scheme 3).Treatment of the allene-type system 11 with tertbutyl isocyanide afforded the boretanediimine 12, even when using less than two equivalents of the isocyanide. 12Accordingly, action of 2,6-dimethylphenyl isocyanide on the iminoborane 13 led to the 1,2-azaboretidinediimine 14; 13 the structure of the product was investigated by X-ray diffraction (a study of 12 is lacking).Analogous behavior was shown by the aminoborane 15; the product 16, however, was accompanied by compound 17 which resulted from attack of unconsumed 15 on the four-membered ring; its amount increased as the reaction was prolonged. 14

Scheme 3
Imines, thioimidates: A new example for addition of two isocyanide molecules across the C=N double bond of an imine is represented by the process 18  19 (Scheme 4).The experiment has been carried out along with studies on ,-unsaturated imines which, however, afforded aminopyrrole derivatives instead of analogs of 19. 15 The thioimidate unit of the salts 20a,b could be converted into an azetidine using tert-butyl and isopropyl isocyanide ( 21a-c).But a competing reaction gave the 2-aminoimidazoles 22a-e (by involvement of the HC=NR'2 moiety of 20). 16

[1+2] Cycloaddition of isocyanides to double bond systems and subsequent reactions
Diphosphenes: Experiments with this class showed that the resultant ring type depends on the substituents (Scheme 5): 23a reacts with methyl or trifluoromethyl isocyanide to give the stable diphosphiranimines 24a,b, whereas bis [2,4,6-tri-(tert-butyl)phenyl]diphosphene combines with the latter isocyanide in a 1:3 ratio to afford a 1,3-azaphospholidine derivative instead. 17Threemembered rings like 24c,d were also isolated when the metal-substituted diphosphene 23b was reacted with phenyl or trifluoromethyl isocyanide; the same holds for the reaction of the latter component with the analogous substrate (23c  24e). 18However, treatment of 23c with several aryl 18 and alkyl isocyanides 19 led directly to 1,3-diphosphetanediimines like 25a-f; the transient compounds 24f-k, being prone to P-P fission (cf.Section 3.1), were detected spectroscopically.

Scheme 4
Silenes: Photolysis of the acylsilane 26a using 360-nm radiation generated the silene derivative 27a (Scheme 6).In the presence of one equivalent of tert-butyl isocyanide (a) this compound underwent a [1+2] cycloaddition to give the siliranimine 28a which in turn rearranged into the azasiliridine 29a. 20,21When a mixture of this material and 2,6-dimethylphenyl isocyanide (b) was photolyzed, the 1,3-azasiletidin-2-imine 30a resulted. 22Extending the experiments to the couples 27a + (a), 27b + (a), and 27b + (b), the expected azasiliridines 29b-d were formed, but these compounds, while eluding isolation, reacted with unconsumed isocyanide and produced the azasiletidines 30b-d.However, under nonphotochemical conditions (-70 °C; dark) preformed 27a and 2,6-dimethylphenyl isocyanide (b) gave rise to a mixture of the compounds 29b and 30b; this contrasts with the behavior of 27a towards alkyl isocyanides (cf.above and ref. 20 ), which leads exclusively to the type 29.-Detailed NMR spectroscopic investigations of the products 30a-d have shown the occurrence of two stereoisomers each for a and b, but only one for c and d.An X-ray diffraction study of the major isomer of 30b has revealed a Z / E symmetry (C=N / C=C group) as depicted; for brevity, this stereo formula was used here for 30a,c,d as well.Yields of 30a-d were not disclosed throughout. 22

Scheme 5
A later example of this kind of conversion constitutes the reaction of the neopentyl-substituted silene 27c.This substrateprepared from (dimesitylfluorosilyl)ethene and tert-butyllithiumgave the silazetidine 30e on treatment with two equivalents of tert-butyl isocyanide. 23t might be added that azasiliridines related to 29 were obtained very recently from isocyanides and a disilene like R2Si=SiRPh [R = 2,4,6-(i-Pr)3C6H2], but, remarkably, these products (which have a semicyclic C=Si bond instead of a C=C bond) did not undergo isocyanide insertion to give four-membered rings, i.e. silylidene analogs of 30. 24ospa-, arsasilenes: Unique derivatives of the type 30, i.e. compounds like 32a-c, arose quantitatively on exposure of the 'heterosilenes' 31a 25 and 31b 26 to mesityl and cyclohexyl isocyanide (Scheme 7).The reaction was assumed to follow the pattern of the preceding paragraph.Treatment of the products 32b,c with hydrogen chloride (or fluoride), however, met with surprise in that arsasilete derivatives 33a,b were isolated; X-ray crystallography served to establish the structures of both 32c and 33b. 26Extending their ring forming experiments to 1,6-diisocyanohexane, the authors succeeded in converting 31a,b into the corresponding macroheterocycles; of these new products, the arsa representative has also been studied by X-ray diffraction. 27Scheme 6 Scheme 7

Scheme 9
Nitrones: The known cyclization 2 of the nitrone 49 with cyclohexyl isocyanide to give the 1,2oxazetidin-4-imine 50 has recently been duplicated for mechanistic purposes (Scheme 10). 35To rationalize their synthesis of α-oxoamides from N-alkylhydroxylamines and aliphatic aldehydes under the conditions of the Ugi reaction, the authors thought of 50 as one possible intermediate and submitted this model to their procedure.But, being aware of an old observation, 36 they confirmed that N-O cleavage in 50 occurred with deprotonation of the N-methyl group ( 51), not at C(3) which would be necessary for the production of an α-oxoamide.

Scheme 10
Diphosphinoketenimines: Although representing no classical 1,3-dipoles, the title substrates 52 were shown to behave as such (Scheme 11).In the presence of water they reacted with isocyanides to give compounds of the type 54 that were proposed to arise via four-membered rings like 53/53'.Labeling experiments demonstrated that the oxygen and ring-attached hydrogen of 54 originate from the external water; in a rigorously dried medium no reaction occurred. 37

Addition of isocyanides to carbenes (including analogs) and subsequent reactions
Carbenes: The phosphino(silyl)carbene 55a, generated from the corresponding diazo precursor, reacted with pentafluorophenyl isocyanide to give the dihydro-1,2-azaphosphete 57a, which was established by an X-ray analysis (Scheme 12).The process was explained to involve a transient ketenimine (56a) that undergoes a P/C/ migration of one NR2 group, followed by electrocyclization of the resultant 1-aza-4-phosphabutadiene. 38,39When reacting the arylsubstituted carbene 55b with tert-butyl isocyanide, the respective ketenimine 56b could be characterized spectroscopically, but at room temperature it rearranged slowly into the analogous ring system 57b. 40

Scheme 12
Silylenes: Photolysis of the trisilirane 58 in the presence of isocyanides has been shown to afford disiletanediimines of the type 61 and 62 (Scheme 13).These compounds arose by coupling of the silylene 59 with the isocyanide to give the silaketenimine 60 which in turn cyclodimerized.The reaction was performed with phenyl 41 and sterically crowded aryl isocyanides, 42 but also with isocyanides bearing electron-withdrawing groups. 43As expected, head-to-tail cyclodimerization prevails; only when using 2,6-diisopropylphenyl isocyanide the head-to-head mode occurred too, giving minor amounts of the derivative 62c. 42While no yield figure was disclosed in that work, it was later detailed that the derivatives 61c and 62c were isolated in a ratio of ca.10:1 (regardless of the reaction conditions) and that they were not interconverted photochemically. 44[43]

Scheme 13
Surprising behavior was encountered with the (stable) silylene 63.On treatment with cyclohexyl isocyanide two competing reactions occurred (Scheme 14): (i) α-addition of the CN and c-C6H11 moieties of the fragmented reagent furnished the carbonitrile 64; (ii) linear coupling of intact isocyanide led to the silaketenimine 65; this intermediate, in contrast to species 60 (cf.Scheme 13), took up another isocyanide to generate a four-membered ring ( 66); stabilization of its carbene function by uptake of a third isocyanide, followed by hydrogen migration from the cyclohexylimino group, gave the product 67, the structure of which was established by the X-ray method. 45rylenes: An interesting borylene-to-isocyanide transfer resulting in the final formation of the four-membered rings 70a,b happened when the chromium complex 68 was treated with certain aryl isocyanides (Scheme 15).The reaction assumedly involved a [1+2] cycloadduct (69) that was susceptive to isocyanide insertion.The molecular structure of 70a was elucidated by X-ray diffraction. 46

Addition of isocyanides to Fischer carbene complexes and subsequent reactions
Isocyanides combine with Fischer-type carbenes to generate ketenimine complexes of the type A (Scheme 17).The mechanism of the process has recently been studied, showing that A is formed via a metallacyclopropanimine followed by isomerization and 1,2-metallotropic rearrangement. 49reparatively, these species have turned out to be valuable building blocks for a variety of four-, five-, and six-membered rings (for reviews, see refs. 50,51).Concentrating on the first mentioned class, this section will describe applications of the synthetic principles outlined below.Beyond that, mention will be made of the ring contraction of a single [2+3] cycloadduct obtained from A.

Scheme 17
Dimerization: Carbene complexes such as 75 react with alkyl isocyanides to give the corresponding ketenimine complexes 76 (Scheme 18).3][54] The symmetrical [2+2] cycloaddition which is unusual for free ketenimines is template-induced and thought to proceed through an intermediate like 77.Part of this remarkable reaction has been reviewed earlier. 2 Intramolecular cycloaddition: Ketenimine complexes bearing an alk-3-enyl moiety at the carbon atom like the derivatives 80a-c undergo, once generated from the precursor 79, an intramolecular [2s+2a] cycloaddition (Scheme 18).Owing to the involvement of the cycloheptatrienyl ligand, the cyclobutanimine unit becomes part of a tricyclic system, as illustrated by the products 81a-c.Of these materials, two stereoisomers were found; the structure of anti-81c has been determined by X-ray crystallography.Attempts to demetalate this derivative with pyridine caused fragmentation of the four-membered ring. 55

Scheme 18
Addition of isocyanides: Ketenimine complexes exhibit 1,3-dipolaroid properties.Using isocyanides as dipolarophiles, 4-iminoazetidin-2-ylidene complexes can arise (Scheme 19).Success and extent of this reaction depend primarily on the metal.Thus, starting from the iron carbene complex 82a, the desired products, e.g.84a-d, were obtained in high yield regardless of the nature of the isocyanide; the intermediary ketenimine complexes 83a-d were not observed. 56,57Yet, in the case of the tungsten complex 82b, the [1+3] cycloaddition became a side reaction: Employing benzyl isocyanide, 84e was accompanied by the indanediimine 86a and the complex 87a, 57 and using alkenyl isocyanides, relatively high quantities of the 2H-pyrroles 88a,b were isolated besides the azetidinylidene complexes 84f,g. 58As the compounds 84 readily undergo oxidative demetalation, they are useful precursors to functionalized -lactams ( 85a-c,f). 56,58

Scheme 19
Further derivatives 84 could be prepared from the manganese complex 82c (Scheme 20). 59his species is less reactive towards isocyanides than the substrates 82a,b.Moreover, the excess isocyanide which is necessary for ring closure tends to displace the metal from the ketenimine complex 83 to leave a mixture of the isocyanide complex 87 and the free ketenimine 89.As a consequence of this competing process, the 'regular' products 84h-j were accompanied by [2+2] cycloadducts like 90a-c; the proportions varied with the conditions and the kind of isocyanide.Since the conversion 83  84 proceeds more slowly than the step 82c  83, it was also possible to construct azetidinylidene complexes 84 (including the type 90) from two different isocyanides; this is exemplified by the couples 84k / 90d and 84l / 90e.Representatives of both ring series such as 84h,i and 90a,b could be demetalated with permanganate salt to give the lactams 85a,b and 91a,b, respectively. 59

Scheme 21
Addition of alkynes: a) Alk-1-ynes: Two types of 4-ylideneazetidin-2-ylidene complexes arise, when the second isocyanide that effects ring closure to 84 and 90 (cf.Scheme 19, 20) is replaced with a 1-unsubstituted alk-1-yne (94) (Scheme 22).Heating an equimolar mixture of 82b, cyclohexyl isocyanide, and (trimethylsilyl)ethyne (94a), the four-membered rings 95a and 97a were formed (isolated as the silicon-free derivatives b).While the process leading to 95 can be compared to that giving 84, the formation of 97 resembles the route to series 90; the vinylidene complexes 96putative intermediatesmay arise directly from 82b.Using alkynes like 94b,c, only the derivatives 97c,d were found, with the Z isomer predominating. 62Mechanistically, the reaction was understood as proceeding through an adduct of the type 98; in this species a hydrogen transfer from the CHR2 group to the central keteniminium carbon took place to generate the intermediate 98' which underwent electrocyclization.In the case of 98b, a second mode was operative, i.e. intramolecular [2+2] cycloaddition to the 1,4-dihydroazetidine complex 100 which on work-up was hydrolyzed to the -lactam 101 (no yield). 63ng contraction (Addendum): An unexpected formation of a four-membered ring was encountered when the [2+3] cycloadduct 102 from the ketenimine complex 83h (for prepration, see Scheme 20) and carbon disulfide was oxidized with aqueous permanganate (Scheme 23).Besides the regular productthe thiazolidin-5-one 103small amounts of the 3-iminothietane-2thione 104 were detected; formally, this material arose through ring contraction of 'deoxygenated' 103.Both compounds were formed in a 20:1 ratio with a total yield of 96% (crude). 64Scheme 23

Miscellaneous
Functionalized phosphino(phosphonio)carbene: Treatment of the salt 105 with two equivalents of tert-butyl isocyanide gave rise to the 1,3-diphosphetanium ring as in 108 (no yield); employment of only one equivalent led to the recovery of 50% of the starting substrate (Scheme 24). 65he reaction commenced with formation of the ketenimine 106; but, while stable when unprotonated (cf.ref. 66 ), this species rapidly inserts the second isocyanide into the P-H bond to give an intermediate like 107 which underwent ring closure through elimination of diisopropylamine.
Butynedioic acid ester: It is known that reactions of isocyanides with dimethyl butynedioate (DMAD) do not follow the pattern of Section 2.1, i.e. giving cyclobutenediimines. 2 However, a four-membered ring may arise from that reagent by another route.Indeed, a more recent study using cyclohexyl isocyanide has shown thatbesides the cyclopenta[b]pyridine 109 (including minor quantities of an isomer and a 1-azaspiro [4.4]nonatriene)the cyclohepta-anellated azetidinimine 110 was formed (Scheme 25). 67,68As a direct precursor the 3:1 cycloadduct of DMAD and the isocyanide, i.e. the cycloheptatrienimine 111, has been invoked. 67To rationalize its conversion into 110, a transient species like 112 is added here tentatively.Ensuing work of other authors concentrated on the preparation of 109 (including an X-ray study of the product); additional compounds were not reported. 69

Scheme 25
Oligosilanes: Insertion of isocyanides into the Si-Si bond involving a unique skeletal rearrangement has been encountered when the tetrasilanes 113a-c and the hexasilane 113d were reacted with certain aryl isocyanides in the presence of a palladium catalyst and 1,1,3,3-tetramethylbutyl isocyanide (115) (Scheme 26).This procedure gave the 1,2,4-azadisiletanes 114a-g and 114h, respectively. 70,71The structures of 114c 70 and 114h 71 have been elucidated by X-ray crystallography.Regarding the tert-alkyl isocyanide 115, this additive, without entering the four-membered ring, has proved an effective promotor in most cases as evidenced by comparison of the yields. 71

Scheme 26
Organoaluminum compounds: tert-Butyl isocyanide was found to undergo double insertion into one Al-C bond of tris(tetramethylcyclopentadienyl)aluminum (116) to form the four-membered ring 117 (Scheme 27).The cyclic structure has been elucidated by X-ray diffraction.The strong Al-N linkage seems to be the driving force behind the twofold insertion which is favored to such an extent as to leave unreacted 116 when working with less than two equivalents of isocyanide. 72nsertion of isocyanides into the Al-Al bond of the dialane 118 resulted in the formation of a three-or four-membered ring, depending on the reagent and conditions.Using one equivalent of tert-butyl isocyanide, compound 119a was obtained as the single product.However, phenyl isocyanide not only afforded the expected derivative 119b, but also gave 17% of the product of double insertion, i.e. the bicyclic system 120.Hence, on repeating the experiment with two equivalents of this isocyanide, compound 120 was isolated exclusively.An analogous run with tertbutyl isocyanide was not reported. 73he aluminum(I) complex 121 (dealt with in this section for practical reasons) was found to react very readily with two equivalents of 2,6-diisopropylphenyl isocyanide.When this reagent was added neat to a suspension of 121 in a minimum amount of solvent, the remarkable compound 122 was isolated.Its formation was thought to proceed through consecutive coupling of both isocyanides leaving a four-membered ring, the carbenic C(4) of which interfered with the adjacent isopropyl group to give the stable product 122.When working in a dilute medium, compound 123 arose, possibly via insertion of the two isocyanides into one of the Al-C bonds to be followed by a skeletal rearrangement of the resultant eight-membered ring.The structures of 122 and 123 have been determined by X-ray crystallography. 74

Scheme 27
(Diaminoboryl)silanes: Insertion of an aryl isocyanide into the Si-B bond of the borylsilanes 124 generates (boryl)(silyl)iminomethanes (125) (Scheme 28).Compounds of this type, e.g.125a (R= Me, Ar = 3,5-Me2C6H3), are obtained in high yield when working at room temperature.However, in refluxing toluene an unexpected rearrangement took place, consisting in a 1,2-shift of the silyl group to leave an (amino)(boryl)carbene species which engaged an adjacent isopropyl group to form the 1,2-azaboretidine 126a. 75The reaction was shown to be limited to isocyanides having a free ortho-position.Thus, while the reaction of 124a with 2,6-dimethylphenyl isocyanide even at 110 °C did not go beyond the stage of insertion (125), four-membered rings like 126b-d were formed readily from a range of 2-alkynylphenyl isocyanides.Extending the experiments to 1,2-diisocyanobenzenes, only one -N=C group reacted with the substrate to give the benzimidazolyl substituted azaboretidines 127a-c; the two derivatives a,b having R'' = H were obtained at room temperature.X-ray crystallographic data are available for the products 126d and 127a. 75ris(trimethylsilyl)silyllithium: The silyllithium substrate 128 was found to react smoothly with two molecules of 2,6-dimethylphenyl isocyanide to form, in the presence of N,N,N',N'-tetramethylethylenediamine (tmeda), the 1,2-dihydro-1,2-azasilete derivative 129 (Scheme 29). 76The process assumedly started with the formation of a lithioaldimine followed by migration of one silyl group to generate a silene species which incorporated the second isocyanide via electrocyclization.Quenching of 129 with trimethylsilyl triflate afforded the derivate 130, 76 while treatment with cyclopentadiene yielded the conjugated acid 131. 77Moreover, reacting 128 in the presence of the soft 1,2-bis(dimethylphosphino)ethane gave a product 129 having THF instead of tmeda. 77Detailed X-ray diffraction studies have been conducted with both 129 and 131. 76,77

Scheme 28
Dilithium tert-butylarsinide and -phosphinide: Action of the arsenic compound 132a on cyclohexyl isocyanide caused trimerization of the latter to form the product 133 which was isolated after addition of cyclohexane and diglyme (Scheme 30).By contrast, usage of the phosphorus analog 133b led to an engagement of six equivalents of the isocyanide to generate the more complicated structure 134 and, as a side product, an open-chain material originating from cyclohexylnitrene.The constitution of both cyclic products has been established by X-ray analyses. 78RKAT-USA, Inc.

Scheme 30
Tetragermabutadiene: Studies on the behavior towards the heavy chalcogens selenium and tellurium have revealed that the title substrate 135 (Scheme 31) is capable of undergoing [1+4] cycloadditions or Ge-Ge bond scissions, depending on the reagents.The former mode was followed by selenium, whereas treatment with tellurium caused fragmentation of the substrate.In this context the reaction with 2-methoxyphenyl isocyanide was probed too, showing that one Ge-Ge bond was broken: while the extruded germylene dimerized, the residual Ge3 chain cyclized to the 1,4-dihydrotrigermet-4-imine 136 which was characterized by X-ray crystallography. 79Scheme 31

Insertion of isocyanides into three-membered rings
Triafulvenes: In a fashion similar to the behavior of cyclopropenones towards isocyanides, 2 the triafulvenes 137a-c underwent ring expansion to the 2-ylidenecyclobutenimines 138a-h when treated with the respective isocyanides in an aprotic medium (Scheme 32). 80rom the substrates 137d,e, however, four-membered rings such as 138i-m could not be obtained.In this instance two equivalents of the isocyanide were engaged to afford, depending on the substituents R 1 , R 2 , and R 3 , (i) the cyclopentenediimine 139 or the azapentalenes 140a,b (which were formed through intramolecular dehydrogenation of a precursor like 139 having CH2Ph and CH2CO2Et instead of t-Bu), and (ii) the furo[b]pyridine derivatives 141a,b when reacting the benzoyl-containing triafulvene 137e.
Cyclopropenylioborates: Studies on this class 81 led to the discovery of another insertion of an isocyanide into a cyclopropene ring (Scheme 33): Compound 143easily prepared from 142 82 or its product of hydrolysis (144) reacted with tert-butyl isocyanide to give the cyclobutenimine 145 in good or reasonable yield.The molecular geometry was determined by X-ray diffraction. 83clopropanedicarboxylic acid esters: A lanthanide-catalyzed insertion of aryl isocyanides into bis-acceptor activated cyclopropanes like 146 has been reported to lead directly to the cyclopentene derivatives 148 (Scheme 34).Substrates devoid of the Ar 1 ligand (which functions as an additional activator) failed to react.The conversion was viewed as proceeding via fourmembered rings like 147, but these species could not be observed for their high proclivity to insert an isocyanide themselves (as exemplified for Ar 1 = Ph / Ar 2 = 4-MeOC6H4). 84Hence, the reaction of 146 parallels the behavior of oxiranes, 85 viz. the occurrence of double isocyanide insertion, with the failure to detect a four-membered ring, 85 which belies the quotation made in ref. 84 .

Scheme 33 Scheme 34
1H-Aluminirene: tert-Butyl isocyanide was found to insert under very mild conditions into the aluminirene unit of the spiro substrate 149 to form the unique molecule 150.Of this compound stable E and Z isomers were detected by NMR spectroscopy.Crystallization gave a solid in 57% yield that, according to X-ray diffraction, represented the Z configured form.It may be added by analogy that carbon monoxide transformed 149 into the corresponding aluminetimine. 86

Scheme 35
-Lactams: The conversion of this class into imino-substituted -lactams through reaction with isocyanides is well established. 2In a more recent work a stereochemical aspect was investigated (Scheme 36). 87Heating the enantiomer (R)-151 with tert-butyl isocyanide gave rise to a -lactam like (E,R*)-153 of unknown absolute configuration (low enantiomeric excess), i.e. the stereochemical information got almost lost (if not fully).This was rationalized by considering the behavior of the zwitterionic intermediate (R)-152: this species, formed with inversion at C(3), did not cyclize directly [which must have led to (E,R)-153], but in a competing step it underwent a 1/3/hydrogen shift to generate the ketenimine 154 which would yield racemic (E)-153.

Scheme 36
Siliranes: The insertion of isocyanides into siliranes was found to affect the Si-C bond.The first known examples originated from experiments with substrates like 155a-c and aryl isocyanides which gave the siletan-2-imines 156a-c (Scheme 37).Of these products the derivative 156b has been studied by X-ray diffraction, showing a practically planar four-membered ring with elongated Si-C and C-C bonds and a Z configured imine function. 88Soon thereafter other authors 89 investigated regioselectivity and stereospecificity: (i) Studying the behavior of the monosubstituted siliranes 155d-f towards tert-butyl isocyanide, they found that insertion occurred at the more substituted Si-C bond ( 156d-f), but this regioselectivity was gradually eroded as the substituent R 1 became bulkier.(ii) Reactions of cis-and trans-155g with p-tolyl and tert-butyl isocyanide revealed that the formation of the respective siletan-2-imines 156g,h proceeded with stereospecific retention of configuration.As for the reactivity of these compounds, it was observed inter alia that both cis-and trans-156g,h tautomerize to 2-amino-1,4-dihydrosiletes on heating. 89

Scheme 37
Thiirene S-oxides: Isocyanide insertion into the thiirene half-ring of 157 has been accomplished with 4-nitrophenyl isocyanide (Scheme 38). 90However, as observed with the cyclopropane derivative 146 (cf.Scheme 34), the reaction did not stop at the four-membered ring (158), but proceeded with double insertion to give a thiophenediimine 159 which, depending on the conditions, was obtained as S-oxide (n = 1) or deoxygenated (n = 0).Since four equivalents of the isocyanide were applied in both experiments, it is open whether 158 constitutes an elusive species.

Scheme 38
Azoniaboranuidacyclopropane: The title substrate 160 was found to react readily with tosyl and benzyl isocyanide to give in excellent yield the 1-azonia-3-boranuidacyclobutanimines 161a and b, respectively (Scheme 39).The structure of 161a has been elucidated by X-ray diffraction. 91

Scheme 39
Azasiliridines: For preparative reasons this class of compounds is dealt with in Section 2.2.

2H-Azaphosphirene:
In the presence of a stoichiometric amount of triflic acid the azaphosphirene complex 162 underwent rapid insertion of cyclohexyl isocyanide (Scheme 40).When the reaction was quenched with triethylamine after five minutes, the dihydro-1,3-azaphosphete complex 163 was obtained in high yield.Its structural parameters have been determined by the X-ray method.Interestingly, the 3-(2-thienyl)-substituted analog of 162 did not form the corresponding product 163 (2-thienyl instead of Ph), but was converted into a 2H-azaphosphole derivative. 92phosphiranes, diphosphirenium: The insertion of isocyanides into the P-P bond of diphosphiranes appears as a consequence of decomposition rather than representing a preparative concept (Scheme 40). 93Substrates like 164a-d (made from isocyanide dichlorides and alkali diphosph-ides) proved partially labile, depending on the Ar substituent: The derivatives a and b having sterically less demanding ligands released isocyanide within a few hours that reacted with residual 164a,b to give mixtures of the E-and Z-configured 1,3-diphosphetane-2,4-diimines 165a,b; in the case of the derivatives 164c,d, the bulkier substituents caused the respective conversion ( 165c,d) to occur much more slowly. 93nother example of P-P bond breaking by an isocyanide was observed on treatment of the diphosphirenium salt 166 with tert-butyl isocyanide.As the product of insertion the 1,2-dihydro-1,3-diphosphetium derivative 167 resulted, which was characterized also by X-ray diffraction. 94

Scheme 40
Azadiboriridine: Isocyanides were found capable of breaking the B-B bond of the azadiboridine 168 (Scheme 41).The nature of the products depends on the R ligand of the reagent: Usage of the sterically demanding 2,6-dimethylphenyl isocyanide (one equivalent only!) gave rise to the 1,2,4-azadiboretidin-3-imine 169a, whereas the analogous products from methyl and ethyl isocyanide, i.e. 169b,c, eluded isolation by undergoing a [3+3] cyclodimerization which led to the tricycles 170b,c.Of these derivatives, 170b has been submitted to an X-ray diffraction study. 95isilirane, trigermirane: Three-membered cycles having silicon or germanium as the sole ring atoms readily incorporate isocyanides (Scheme 42).Thus, on heating 171 with an aryl isocyanide the trisiletanimines 172a-d 96 and 172e-g 97 were formed.Regarding 1,4-diisocyanobenzene, less than one equivalent led to the 'bis' derivative 173 which is also accessible stepwise via 172c; this product 96 as well as compound 172f 97 has been studied by X-ray diffraction.The same kind of conversion occurred with the trigermirane 174 when treated with phenyl isocyanide ( 175). 98

Scheme 42
Trisilirenes: The behavior of this class of compounds towards isocyanides is characterized by two competing reaction modes, i.e. insertion into the three-membered ring and [1+2] cycloaddition across the double bond. 99Starting from the substrates 176a,b, the trisiletimines 177a,b and the trisilabicyclo[1.1.1]butanes178a-c were prepared (Scheme 43).According to a DFT study on the models 177 and 178 having R = SiMe3 / R' = c-C6H11 and 2,6-Me2C6H3, the derivatives 178 were found higher in energy by 2.4 and 5.1 kcal/mol, showing that they arise under kinetic control.This is best demonstrated by the reaction of 176a with tert-butyl isocyanide: At room temperature a mixture of 177a and 178a was formed immediately; on standing, the latter component slowly rearranged to 177a; yet, working at -94 °C, only compound 178a was observed.-X-ray diffraction studies have been performed with 177a,b and 178b,c (b: adduct with hexane). 99n certain cases the isocyanide opened the Si-Si bridge in 178 to give a trisilabicyclo[1.1.1]pentane179.This occurred on prolonged treatment of 176b with two equivalents of cyclohexyl isocyanide ( 179a); using 2,6-dimethylphenyl isocyanide, the formation of 179b took place even in five minutes, the intermediate 178d being undetectable. 99Scheme 43

Migratory insertion of isocyanides into metallacycles
Titanacyclobutanes: A synthetically useful synthesis of cyclobutanimines has been developed by starting from the titanacycles 180 and 183a-d (Scheme 44). 100 Treatment of compound 180 with tert-butyl and cyclohexyl isocyanide gave, respectively, the titanacyclopentanimines 181a and b in ≥ 90% yield.Moderate heating of the latter induced ring contraction with demetalation to afford the cyclobutanimine 182 in 72% yield (or 94% when working in the presence of ethene).

Scheme 44
The tert-butyl analog 181a, however, reverted to the starting ring 180 when submitted to either procedure.In a second series of experiments the authors reacted the disubstituted (transconfigured) substrates 183a-d with a threefold excess of 2,6-dimethylphenyl isocyanide.Here the intermediary five-membered rings were not isolated, but in a stereocontrolled manner directly converted into the cyclobutanimines 184a-d. 100© ARKAT-USA, Inc.

Scheme 45
1-Zirconacyclopent-3-ynes: Another, rather unexpected migratory insertion of an isocyanide was observed with the zirconacycles 185a-c (Scheme 45).At slightly elevated temperature two equivalents of tert-butyl isocyanide were inserted into the -Zr-C bonds, followed by a skeletal rearrangement to form the bicyclic compounds 186a-c with a four-membered half-ring.Methanolysis of the derivative 186c gave the monocycle 187 which, like the products 186b,c, was studied by X-ray crystallography. 101-The mechanism was the subject of extensive speculations, among which the assumption of an equilibrium between structure 185 and the isomeric butatriene complex placed the reaction into the neighborhood of the process 4  5 shown in Scheme 1. 101

Ring transformations
3H-1,2-Dithiole-3-thiones: Under mild conditions dithiolethiones like 188a-h were transformed into the 1,3-dithietan-2-imines 189a-h on treatment with the respective isocyanides (Scheme 46).The reaction was shown to be reversible, especially at elevated temperature.Studying the scope, the authors found that substrates 188 lacking electron-withdrawing substituents were unreactive, nor did a reagent like benzyl isocyanide enter the process. 102The same kind of reaction occurred with the fused systems 190a-h to give the derivatives 191a-h. 102,103These examples demonstrate that a dithiolone moiety (as present in 190a-e) is not affected and, second, that in the case of the bis(thioxodithiolo) fused thiazines 190f-h only one of the two five-membered anellands will be involved.Moreover, replacement of the central thiazine ring in 190 with a 6 cycle like pyrrole (which on ring transformation would lose its aromaticity) resulted in total loss of reactivity. 102

Conclusions
In the preceding pages we have tried to demonstrate the growing importance of isocyanides for the construction of four-membered rings.Meanwhile their diversity has gained an imposing width, as summarized below (Chart 1).Quite a number of these rings are formed with exceptional ease and are difficult to obtain by other methods.Yet, the synthetic potential of several reactions has not been fully exploited; certain transformations wait for mechanistic studies.An additional target might be the cyclic tetramerization of isocyanides to give tetraaza [4]radialenesa pattern that is formally present in the 'four-over-one' helix (41) of poly(isocyanides). 107

Scheme 22 b
Scheme 22