Diazomethane, 1,3-dipolar cycloaddition

The reaction of cyclohexene with the diazopyruvate 25 gives unexpectedly ethyl 3-cyclohexenyl malonate (26), involving Wolff rearrangement. No cyclo-propanation takes place[28]. 1,3-Dipolar cycloaddition takes place by the reaction of acrylonitrile with diazoacetate to afford the oxazole derivative 27[29]. Bis(trimethylstannyl)diazomethane (28) undergoes Pd(0)-catalyzed rearrangement to give the A -stannylcarbodiimide 29 under mild conditions[30]. 

Since 1,3-dipolar cycloadditions of diazomethane are HOMO (diazomethane)-LUMO (dipolarophile) controlled, enamines and ynamines with their high LUMO energies do not react (79JA3647). However, introduction of carbonyl functions into diazomethane makes the reaction feasible in these cases. Thus methyl diazoacetate and 1-diethylaminopropyne furnished the aminopyrazole (620) in high yield. 

The interaction of diazomethane with 1-azirines was the first example of a 1,3-dipolar cycloaddition with this ring system (64JOC3049, 68JOC4316). 1,3-Dipolar addition produces the triazoline adduct (87). This material can exist in equilibrium with its valence tautomer (88), and allylic azides (89) and (90) can be produced from these triazolines by ring cleavage. 

The stereochemistry of the 1,3-dipolar cycloaddition reaction is analogous to that of the Diels-Alder reaction and is a stereospecific syn addition. Diazomethane, for example, adds stereospecifically to the diesters 43 and 44 to yield the pyrazolines 45 and 46, respectively. 

The regioselectivity of 1,3-dipolar cycloadditions can also be analyzed by MO calculations on transition-state models. For example, there are two possible regioisomers from the reaction of diazomethane and methyl vinyl ether, but only the 3-methoxy isomer is formed. 

In general, reaction of diazomethane with a, -unsaturated carbonyl compounds affords pyrazolines in which the nucleophilic methylene group is attached to the carbon atom of the carbonyl compound. According to Huisgen, the reactions belong to the general class of 1,3-dipolar cycloadditions. 

Using dioxolane as a substituent in the 1,3-dipolar cycloaddition of diazomethane with olefinic double bonds, it was found that the bulky dioxolane ring plays a major role in the diastereoselection [OOJOC388]. 

Mechanistically the 1,3-dipolar cycloaddition reaction very likely is a concerted one-step process via a cyclic transition state. The transition state is less symmetric and more polar as for a Diels-Alder reaction however the symmetry of the frontier orbitals is similar. In order to describe the bonding of the 1,3-dipolar compound, e.g. diazomethane 4, several Lewis structures can be drawn that are resonance structures ... 

With excess of diazomethane in ether 12% of l-(4-nitrophenyl)tetrazole are formed in a 1,3-dipolar cycloaddition (see Zollinger, 1995, Sec. 6.5). 

The first [3S+2C] cycloaddition reaction using a Fischer carbene complex was accomplished by Fischer et al. in 1973 when they reported the reaction of the pentacarbonyl(ethoxy)(phenylethynyl)carbene complex of tungsten and diazomethane to give a pyrazole derivative [45]. But it was 13 years later when Chan and Wulff demonstrated that in fact this was the first example of a 1,3-dipolar cycloaddition reaction [46,47a]. The introduction of a bulky trime-thylsilyl group on the diazomethane in order to prevent carbene-carbon olefi-nation leads to the corresponding pyrazole carbene complexes in better yields (Scheme 15). 

Pyrazolopyrazolopyrazines can be prepared from a stereoselective dipolar cycloaddition between the alkene group of 284 and diazomethane (Equation 45). Ten equivalents of diazomethane are used in this reaction when only 1 equiv is used, the corresponding methyl ester of the starting material was formed <20020L773>. 

Dipolar cycloaddition of diazomethane to aldehydes can successfully be used for the preparation of tetrahy-drooxadiazole derivatives. Photochemical interconversion of 3-acylamino-l,2,5-oxadiazole derivatives leads to 1,3,4-oxadiazoles, though the method suffers from lack of selectivity. Many reports concentrate only on the synthesis and applications of new 1,3,4-oxadiazoles substituted with a wide variety of groups without introducing much of new chemistry. 

Ester formation by dimethylsulfate or diazomethane is not satisfactory because the microgels become insoluble when the reaction proceeds to higher conversions. With diazomethane part of the unsaturated groups is involved in a side reaction of a 1,3-dipolar cycloaddition [132]. A more efficient method for ester formation of microgels is the reaction with 0-alkyl-N,N -bisisopropyl isoureas of the alcohols. The alkyl ureas are easily separated from solutions in methanol [294-296]. The esterified microgels were isolated by precipitation and freeze-drying. Depending on the alcohol used for ester formation, the yields of... 

The 1,3-dipolar cycloaddition of diazomethane to MFA (24) occurred exclusively at the C2-C3 Jt-bond to give 4-(fluoromethylene)pyrazolines. The methylene group of diazomethane was regioselectively attached to the C2 carbon atom of 24 with a syw.anti ratio of 88 12 [72b], DFA (25) similarly reacted with diazomethane to give 4-(difluoromethylene)pyrazoline 89 selectively [72b, 86], The cycloaddition reaction of bulkier 2-diazopropane with DFA was less regioselective. 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

The transition metal-catalyzed reaction of diazoalkanes with acceptor-substituted alkenes is far more intricate than reaction with simple alkenes. With acceptor-substituted alkenes the diazoalkane can undergo (transition metal-catalyzed) 1,3-dipolar cycloaddition to the olefin [651-654]. The resulting 3//-pyrazolines can either be stable or can isomerize to l//-pyrazolines. 3//-Pyrazolines can also eliminate nitrogen and collapse to cyclopropanes, even at low temperatures. Despite these potential side-reactions, several examples of catalyzed cyclopropanations of acceptor-substituted alkenes with diazoalkanes have been reported [648,655]. Substituted 2-cyclohexenones or cinnamates [642,656] have been cyclopropanated in excellent yields by treatment with diazomethane/palladium(II) acetate. Maleates, fumarates, or acrylates [642,657], on the other hand, cannot, however, be cyclopropanated under these conditions. 

When planning reactions of thiocarbonyl compounds with electrophilic carbene complexes it should be taken into aceount that thiocarbonyl compounds can undergo uncatalyzed 1,3-dipolar cycloaddition with acceptor-substituted diazomethanes to yield 1,3,4-thiadiazoles. These can either be stable or eliminate nitrogen to yield thiiranes or other products similar to those resulting from thiocarbonyl ylides [1338]. 

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

A very similar reaction to that of Pechmann and Nold but which probably does not proceed through a dipolar cycloaddition manifold is the formation of 1,2,3-thiadiazole (6) via a thionoester and lithium trimethylsilyldiazomethane (Equation (17)) <86H(24)589>. Lithium trimethylsilyl-diazomethane also reacts with thioketones to produce 1,2,3-thiadiazoles <87H(26)1467>. 

A second well-known dipolar cycloaddition reaction which is useful for the synthesis of thia-diazoles utilizes diazomethane and its derivatives. 

Reactions of aliphatic thiones (139) with diazomethane yields a mixture of isomers via a 1,3-dipolar cycloaddition reaction. Larger R groups lead to the formation of 1,3,4-thiadiazolines... 

Amino-l,2,4-thiadiazoles 191 are obtained when ether is used (249), while 5-alkylthio-1,2,3-triazoles 192 result when the reaction is carried out in THF (250). Reaction of 3 with carbon disulfide leads to 5-alkylthio-l,2,3-thiadiazoles 193 (251). While 3 can act as a synthetic equivalent of the RC—N—N synthon (R = H, SiMea) in all these reactions, it should be emphasized that it does not react by a concerted 1,3-dipolar cycloaddition but rather by a stepwise polar mechanism. The highly nucleophilic character of 3 can account for why diazomethane and... 

Trifluoromethyl-substituted pyrazoles are easily obtained using trifluoromethyl-alkynes as dipolarophiles (Table 8.2, entry 9). Thus, treatment of 4,4,4-trifluorobut-2-ynoic acid with excess diazomethane gave methyl 4-(trifluoromethyl)pyrazole-4-carboxylate (45%) accompanied by its N - (32%) and -methylated (6.5%) derivatives (267). Another convenient route to CF3-substituted pyrazoles involves dipolar cycloaddition of appropriately CF3-substituted alkenes followed by eliminative aromatization (76,77,268). For example, the reaction of alkenes such as (CF3)2C=C(H)COAr with ethyl diazoacetate gave 4-aroyl-5-trifluoromethylpyra-zole-3-carboxylates (268). 

If the C=N function is attached to an electron-withdrawing group, 1,3-dipolar cycloaddition with diazoalkanes occurs leading to 1,2,3-triazoles (5, 276). When diazomethane is used, the initially formed NH-triazole is not isolated due to a rapid subsequent NH deprotonation followed by N-methylation. Consequently, a mixture of the three Wmethyltriazoles is formed when methyl cyanoformate (71) (216) or trichloroacetonitrile (276) (217) is treated with excess diazomethane (Scheme 8.51). Huisgen and co-workers found that methyl diazoacetate reacts with TCNE by a 1,3-dipolar cycloaddition at the C=C bond and not, as published earlier by other authors, at one of the nitrile functions (72). 

Diazomethane reacts with 4-nitrobenzenediazonium chloride to give the 1-aryltetrazole 218 (Scheme 8.52) in addition to other products (277). This long-known reaction was revisited when the dipolarophUic character of the arenediazo-nium salt was realized (278). The tetrazole probably arises by a concerted 1,3-dipolar cycloaddition rather than by a two-step process. However, the observed regiochemistry is difficult to reconcile with either mechanism. 

The 1,3-dipolar cycloaddition reaction of diazoalkanes with alkenes has also been reported (395). Kanemasa and Kanai (395) used the chiral DBFOX-Ph ligand with various metals such as Ni, Zn, and Mg for the preparation of 255a-c. The reaction of TMS-diazomethane 171 with alkene 241 was catalyzed by 10 mol% of 255b to afford the 1,3-dipolar cycloaddition product 296 in good yields and enantioselectivities of up to 99% ee (Scheme 12.96). Also, the Ni-catalyst 255a and the Mg-catalyst 255c were excellent catalysts for the reaction, resulting in >90% ee in both cases. 

The exocyclic double bond of 4-arylidene-5(47/)oxazolones 383 reacts with diazomethane in a 1,3-dipolar cycloaddition reaction to give the corresponding... 

Dipolar Cycloaddition Reactions. Dehydroamino acid derivatives behave as dipolarophiles in 1,3-dipolar cycloaddition reactions that leads to a variety of interesting compounds. For example, 1,3-dipolar cycloaddition of diazomethane to dehydroamino acid esters 475 and 481 gives the corresponding pyrazolines 476 and... 

TABLE 7.47. OXAZOLONE SPIROCYCLOPROPANES FROM 1,3-DIPOLAR CYCLOADDITION REACTION OF UNSATURATED 5(4/7)-OXAZOLONES WITH DIAZOMETHANE... 

---