Diazomethane cycloaddition

Cycloaddition reactions of the C(3)=N bond of azirines are common (Scheme 45) <71AHC(13)45, B-83MI 101-03,84CHEC-I(7)47>. Azirines can participate in [4 + 2] cycloadditions with dienes including cyclopentadienones, isobenzofurans, triazines, and tetrazines. They also participate in 1,3-dipolar cycloadditions with azomethine ylides, nitrile oxides, mesoionic compounds, and diazomethane. Cycloadditions with heterocumulenes, benzyne, and carbenes are known. Azirines also participate in other pericyclic reactions, such as ene reactions. 

A stereochemically interesting observation was made by Carrie s group (Vebrel et al., 1987) in their investigations of diazomethane cycloaddition to methyl l,2-dihydronaphthalene-3-carboxylates substituted at the 1- or 2-position by alkyl or phenyl groups. The 4,5-dihydro-3//-pyrazoles were isomerized into the l//-isomers for easier identification by NMR spectroscopy, in part also by X-ray analyses (6-33). 

The interesting observation mentioned above relates to diazomethane cycloaddition to the chromium (tricarbonyl) (methyl l,2-dihydro- xo"-2-methylnaphthalene-3-carboxylate) complex 6.82 (6-35). 

MBH adducts and their derivatives derived from methyl acrylate and aldehydes undergo stereoselective cycloadditions with diazomethane and benzonitrile oxide to give the corresponding cycloadducts in good yields (Scheme 3.214). The stereochemical outcome can be explained by the so-called inside alkoxy elfect theory.However, in the case of diazomethane cycloadditions, electrostatic factors play a reduced role compared to the corresponding nitrile oxide reactions, while steric elfects are of major importance in governing the stereoselectivity. This dilferent behavior of the two 1,3-dipoles has been rationalized by analysis of the atomic charges, as calculated at the RHF/3-21G level of theory, for the transition structure of these reactions. 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

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. 

Reactions of fluorinated dipolarophiles. Electron-deficient unsaturated species generally make better dipolarophiles, therefore, fluonnated alkenes become better dipolarophiles when vinylic fluonnes are replaced by perfluoroalkyl groups For example, perfluoro-2-butene is unreactive with diazomethane, but more highly substituted perfluoroalkenes, such as perfluoro-2-methyl-2-pentene, undergo cycloadditions in high yields [5] (equation 2) Note the regiospecificity that IS observed in this reaction... 

Cycloadditions ot diazomethane with fluonnated cyclobutenes provide insight into those factors that govern the reactivity and regioselectivity of such reactions Although 3,3,4,4-tetrafluorocyclobutene undergoes reactions at ambient temperature in 5 min [77, 72], complete reaction with the less reactive perfluorocyclobutene requires 14 days [7J] (equation 8). Note also the regioselectivity observed in the reaction of diazomethane with 3,3-difluorocyclobutene [14] (equation 9)... 

Reactions offluorinated dipoles. In recent years, much effort has been devoted to the preparation of tnfluoromethyl-substituted 1,3-dipoles with the goal of using them to introduce trifluoromethyl groups into five-membered nng heterocycles Fluorinated diazoalkanes were the first such 1,3-dipoles to be prepared and used in synthesis A number of reports of cycloadditions of mono- and bis(tnfluo-romethyl)diazomethane appeared prior to 1972 [9] Other types of fluonne-substi-tuted 1,3-dipoles were virtually unknown until only recently However, largely because of the efforts of Tanaka s group, a broad knowledge of the chemistry of tnfluoromethyl-substituted nitrile oxides, nitnle imines, nitnle ylides, and nitrones has been accumulated recently... 

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 ... 

The cycloaddition reaction of diazomethane 4 and an olefin, e.g. methyl acrylate 5, leads to a dihydropyrazole derivative 6 ... 

Strained bicyclic compounds can be obtained e.g. when cyclopropenes are used as dipolarophiles. Reaction of 3,3-dimethylcyclopropene 7 with diazomethane 4 gives the heterobicyclic cycloaddition product 8 in 85% yield ... 

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). 

The 4ne component in a (4tc + 2n) cycloaddition need be neither a four-atom system (as in 1,3-dienes), nor involve carbon atoms only, so long as the HOMO/LUMO symmetry requirements for a concerted pathway can be fulfilled. The most common of these non-dienic 4ne systems involve three atoms, and have one or more dipolar canonical structures, e.g. (34a), hence the term—1,3-dipolar addition. They need not, however, possess a large permanent, i.e. residual, dipole, cf. diazomethane (34a 34f>) ... 

More recently, [2+3] cycloaddition reaction of the tri-te/t-butylphenylphosphaethyne (25) has been reinvestigated, when in spite of the steric encumbrance of extremely bulky Mes group, the use of trimethylsilylated diazomethane (24) makes its cycloaddition successful, which is followed by SiMe3/H migration yielding bulky [l,2,4]diazaphospholes [33], Phosphaalkyne 25 reacts with 24 in a regioselective manner to form intermediate cycloadduct 26, which undergoes facile aromatization... 

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>. 

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