Diazocarbonyl cycloaddition

Friedrichsen and co-workers (133) approached substituted benzotropolones from an aromatic substituted carbonyl ylide with a tethered alkyne as the intramolecular dipolarophUe (Scheme 4.67). Starting from an aromatic anhydride, Friedrichsen was able to make the tethered alkyne via addition of either pentyn-ol or hexyn-ol, then transform the recovered benzoic acid to the a-diazocarbonyl cycloaddition precursor. Addition of rhodium acetate resulted in the tandem formation of cyclic carbonyl ylide followed by cycloaddition of the tethered alkyne producing the tricyclic constrained ether 252. Addition of BF3 OEt2 opened the ether bridge, forming the benzotropylium ion, which subsequently rearranged to form the tricyclic benzotropolone (253). 

Azetidines are compounds of interest in the field of agricultural and pharmaceutical chemistry. They are also useful as monomers and cross-linkers in polymer industry. Due to ring strain associated with it, azetidines are also useful S5mthons in organic chemistry. The common methods for S5mthesis of azetidines are cyclizations of y-amino alcohols, y-amino halides, 3-amino allenes, reactions of 1,3-dielectrophiles with amines, metal-catalyzed cyclizations in diazocarbonyls, cycloaddition reactions, and reduction of 2-azetidinones. There are several reports in literature on the S5mthesis of azetidines in aqueous media. A diastereoselective synthesis of azetidines is reported by the reaction of azazirconacyclopentane derivatives with iodine followed by treatment with aqueous potassium carbonate [26]. 

An intermolecular 1,3-dipolar cycloaddition of diazocarbonyl compounds with alkynes was developed by using an InCl3-catalyzed cycloaddition in water. The reaction was found to proceed by a domino 1,3-dipolar cycloaddition-hydrogen (alkyl or aryl) migration (Eq. 12.68).146 The reaction is applicable to various a-diazocarbonyl compounds and alkynes with a carbonyl group at the neighboring position, and the success of the reaction was rationalized by decreasing the HOMO-LUMO of the reaction. 

Diazocarbonyl compounds readily undergo [3 + 2] cycloaddition to electron-poor alkenes 139). The 1-pyrazolines thus formed usually tautomerize to 2-pyrazolines if there is a hydrogen in an a-position to one of the nitrogen atoms otherwise, thermally induced ring contraction with evolution of nitrogen to give cyclopropanes can occur (Scheme 18). 

Based on a detailed investigation, it was concluded that the exceptional ability of the molybdenum compounds to promote cyclopropanation of electron-poor alkenes is not caused by intermediate nucleophilic metal carbenes, as one might assume at first glance. Rather, they seem to interfere with the reaction sequence of the uncatalyzed formation of 2-pyrazolines (Scheme 18) by preventing the 1-pyrazoline - 2-pyrazoline tautomerization from occurring. Thereby, the 1-pyrazoline has the opportunity to decompose purely thermally to cyclopropanes and formal vinylic C—H insertion products. This assumption is supported by the following facts a) Neither Mo(CO)6 nor Mo2(OAc)4 influence the rate of [3 + 2] cycloaddition of the diazocarbonyl compound to the alkene. b) Decomposition of ethyl diazoacetate is only weakly accelerated by the molybdenum compounds, c) The latter do not affect the decomposition rate of and product distribution from independently synthesized, representative 1-pyrazolines, and 2-pyrazolines are not at all decomposed in their presence at the given reaction temperature. 

The (ri" -diene tricarbonyliron)-substituted diazocarbonyl compounds 25 have been found to undergo 1,3-dipolar cycloaddition with methyl acrylate in high yield, but with little or no diastereoselectivity (56). Nevertheless, the facile chromatographic separation of the diastereomeric products 26a,b and 27a,b (Scheme 8.8), permits the synthesis of pure enantiomers when optically active diazo compounds (25) [enantiomeric excess (ee) >96%] are employed. When the reaction of 25 (R = C02Et) with methyl acrylate was carried out at 70 °C, cyclopropanes instead of A -pyrazolines were formed. The enantiomerically pure... 

Silyl-substituted diazoketones 29 cycloadd with aryl isocyanates to form 1,2,3-triazoles 194 (252) (Scheme 8.44). This reaction, which resembles the formation of 5-hydroxy-l,2,3-triazoles 190 in Scheme 8.43, has no analogy with other diazocarbonyl compounds. The beneficial effect of the silyl group in 29 can be seen from the fact that related diazomethyl-ketones do not react with phenyl isocyanate at 70 °C (252). Although the exact mechanistic details are unknown, one can speculate that the 2-siloxy-1-diazo-1-alkene isomer 30 [rather than 29 (see Section 8.1)] is involved in the cycloaddition step. With acyl isocyanates, diazoketones 29 cycloadd to give 5-acylamino-l,2,3-thiadiazoles 195 by addition across the C=S bond (252), in analogy with the behavior of diazomethyl-ketones and diazoacetates (5). 

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3+2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. A7-AUyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254—256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (xy2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

Photochemical or thermal extrusion of molecular nitrogen from ot-diazocarbonyl compounds generates a-carbonylcarbenes. These transient species possess a resonance contribution from a 1,3-dipolar (303, Scheme 8.74) or 1,3-diradical form, depending on their spin state. The three-atom moiety has been trapped in a [3 + 2] cycloaddition fashion, but this reaction is rare because of the predominance of a fast rearrangement of the ketocarbene into a ketene intermediate. There are a steadily increasing number of transition metal catalyzed reactions of diazocarbonyl compounds with carbon-carbon and carbon-heteroatom double bonds, that, instead of affording three-membered rings, furnish hve-membered heterocycles which... 

The reaction of a-diazocarbonyl compounds with nitriles produces 1,3-oxazoles under thermal (362,363) and photochemical (363) conditions. Catalysis by Lewis acids (364,365), or copper salts (366), and rhodium complexes (367) is usually much more effective. This latter transformation can be regarded as a formal [3 + 2] cycloaddition of the ketocarbene dipole across the C=N bond. More than likely, the reaction occurs in a stepwise manner. A nitrilium ylide (319) (Scheme 8.79) that undergoes 1,5-cyclization to form the 1,3-oxazole ring has been proposed as the key intermediate. 

The cyclic ylide intermediate 366, as a 1,3-dipole, is generated by intramolecular reaction of Rh-carbene with the ketone in 365, and undergoes cycloaddition with n-bonds to give the adduct 367 [121]. When a-diazocarbonyls have additional unsaturation, domino cyclizations occur to produce polycyclic compounds. The Rh-carbene method offers a powerful tool for the construction of complex polycyclic molecules in short steps, and has been applied to elegant syntheses of a number of complex natural products. 

Rhodium (Il)-catalysed 3 + 2- and 3 + 4-cycloaddition of diazocarbonyl compounds (7) with conjugated dienes (e.g. 2,3-dimethylbuta-l,3-diene) provides a simple and rapid route to dihydrofurans (8) and dihydrooxepins (9) in high yields. A stepwise mechanism involving delocalized zwitterions has been proposed for the formation of the cycloadducts (Scheme 2).3... 

The same salt from acetylene afforded similarly adducts with furan and 1,3-diphenyl i sobenzofuran. A number of alkynyl iodonium salts underwent also [2 + 3] cycloaddition with dipolarophiles such as a-diazocarbonyl compounds, nitrile oxides, etc., allowing the preparation of iodonium salts with an alkenyl or a heterocyclic moiety [7],... 

Diazo compounds have also been used as precursors in the preparation of pyrazoles and indazoles. The copper-promoted cycloaddition reaction of lithium acetylides 18 with diazocarbonyl compounds 19 provided a direct and efficient approach to the synthesis of pyrazoles 20 <07AG(I)3242>. A facile, efficient, and general method for the synthesis of 1-arylated indazoles 22 and A-unsubstituted indazoles 23 by the 1,3-dipolar cycloaddition of benzynes, generated from 21, with diazomethane derivatives has been reported <07AG(I)3323>. Reaction of diazo(trimethylsilyl)methylmagnesium bromide with aldehydes or ketones gave 2-diazo-2-(trimethylsilyl)ethanols, which were applied to the synthesis of di- and trisubstituted pyrazoles via [3+2] cycloaddition reaction with ethyl propiolate or dimethyl acetylenedicarboxylate <07S3371>. 

In consideration of conceivable strategies for the more direct construction of these derivatives, nitriles can be regarded as simple starting materials with which the 3+2 cycloaddition of acylcarbenes would, in a formal sense, provide the desired oxazoles. Oxazoles, in fact, have previously been obtained by the reaction of diazocarbonyl compounds with nitriles through the use of boron trifluoride etherate as a Lewis acid promoter. Other methods for attaining oxazoles involve thermal, photochemical, or metal-catalyzed conditions.12 Several recent studies have indicated that many types of rhodium-catalyzed reactions of diazocarbonyl compounds proceed via formation of electrophilic rhodium carbene complexes as key intermediates rather than free carbenes or other types of reactive intermediates.13 If this postulate holds for the reactions described here, then the mechanism outlined in Scheme 2 may be proposed, in which the carbene complex 3 and the adduct 4 are formed as intermediates.14... 

An interesting dichotomy of reaction paths was recently observed by Huisgen and coworkers in reactions of diazocarbonyl compounds with enamines While diazomonocarbonyl compounds react with 2,5-dimethyl-l-pyrrolidinocyclopentene 19 in a cycloaddition reaction to give 2-pyrazolines 20, dimethyl diazomalonate undergoes an azo coupling reaction and the hydrazone 21 is formed (12). This nicely... 

The use of diazocarbonyl compounds in the synthesis of O-bridged systems is the approach of choice. There are a few main synthetic strategies of bridged framework building based on this approach tandem cyclization with carbonyl ylide formation/cycloaddition, tandem cyclization with 0x0-nium ylide formation/sigmatropic shift, intramolecular cyclopropanation, and cyclization with single bond insertion. 

Some of the transformations listed above do not involve free carbenes. For example, heating an a-diazocarbonyl compound in the presence of an alkene may trigger a [3 + 2] cycloaddition reaction rather than formation of the acylcarbene. The resulting 4,5-dihydro-3//-pyrazole may undergo spontaneous ring contraction with concomitant loss of nitrogen. (For the transformation of 4,5-dihydro-3/f-pyrazoles to cyclopropanes, see Section 4.2.1.1.)... 

The formation of 1,2,3-triacylcyclopropanes, which are sometimes obtained in small amounts when a-diazocarbonyl compounds are decomposed thermally in the absence of additional substrates, is also rationalized by the intermediacy of a 4,5-dihydro-3//-pyrazole resulting from the [3 -f 2] cycloaddition of the diazo compound to the initially formed carbene dimer, e.g. formation of C/.S-24 via 23. ... 

Whether a cyclopropanation reaction is stereospecific or not, is often tested with (Z)- and ( )-but-2-ene, but of course, this problem also holds for other diastereomeric alkenes. The following carbenes, generated by direct irradiation of the corresponding a-diazocarbonyl compound, undergo stereospecific or highly stereoselective cycloaddition to (Z)- and ( )-but-2-ene methoxycarbonylcarbene, chloro-, bromo- and iodo(ethoxycarbonyl)carbene, ° eth-oxycarbonyl(trimethylsilyl)carbene, ethoxycarbonyl(trimethylgermyl)carbene, ethoxy-... 

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