From tosylhydrazone salts

The sulfur ylide-mediated epoxidation of aldehydes has been thoroughly investigated [70, 71]. The chiral sulfur ylides reported by Aggarwal have been most broadly applicable, and a catalytic, asymmetric process yielding aromatic transepoxides has been developed [72]. In this process, the sulfur ylides are produced in situ from diazo compounds, generated in turn from tosylhydrazone salts (Scheme 9.15) [73],... 

As in the epoxidation reactions, the diazo compound could be generated in situ from tosylhydrazone salts (see Scheme 10.16) [79, 80]. This addressed the major... 

This chapter focuses on the generation of carbenes by extrusion of nitrogen (Tables 91.1 through 91.8). Several other methods are possible, such as the formation from tosylhydrazone salts, oxiranes, aziridines, dioxolanes, and pyrazolenines from cyclopropanes by photocydoehmination, from transition-metal carbene complexes or by a-elimination, from ot,a-dihalogen compounds, or from base treatment of N-nitrosocarbamate. ... 

The best results starting from tosylhydrazone salts are summarized in Table 7.21 [170]... 

Of course, the key limitation of the ylide-mediated methods discussed so far is the use of stoichiometric amounts of the chiral reagent. Building on their success with catalytic asymmetric ylide-mediated epoxidation (see Section 1.2.1.2), Aggarwal and co-workers have reported an aza version that provides a highly efficient catalytic asymmetric synthesis of trans-aziridines from imines and diazo compounds or the corresponding tosylhydrazone salts (Scheme 1.43) [68-70]. 

Thus, the 1,2-C pathway dominates when 84 is generated by the thermolysis of a tosylhydrazone salt, but a 1,2-H shift to cyclopropylethene is the major pathway when 84 is generated from either a hydrocarbon precursor or via the atomic carbon abstraction of oxygen from cyclopropylmethylketone at —196°C.U1... 

Throughout this chapter, we have almost always ignored the role of the carbene precursor. Carbenes are generally made from diazo compounds, or from a variety of surrogate diazo compounds including diazirines, tosylhydrazone salts, and aziridyl imines, all of which probably decompose through nonisolable diazo compounds. Not surprisingly, it turns out that diazo compounds have a rich chemistry of their own, especially when irradiated. Moreover, that chemistry often closely resembles the reactions of carbenes. Much of intramolecular carbene chemistry is, in fact, diazo compound chemistry. 

The present procedure uses sodium methoxide in methanol for generation of the tosylhydrazone salt. This procedure gives the highest reported yield and, unlike other procedures, also gives pure diazo compounds free from solvents. This vacuum pyrolysis method appears applicable to the formation of relatively volatile aryldiazomethanes from aromatic aldehydes. Table I gives yields of diazo compounds produced by this vacuum pyrolysis method. The yields have not been optimized. The relatively volatile diazo esters, ethyl a-... 

The major limitation of the vacuum pyrolysis method appears to be thermal decomposition of less volatile diazo compounds during the pyrolysis. The vacuum pyrolysis method was unsuccessful for the preparation of 1-naphthyl diazomethane and 3,5-dichlorophenyldiazomethane. However, such diazo compounds could be prepared from the corresponding tosylhydrazone salts by pyrolysi s in ethylene glycol and extraction of the aryldiazomethane into... 

A major improvement addressing the issue of practicability and safety by avoidance of the direct use of (potentially) explosive diazo compounds was recently reported by Aggarwal and co-workers [82, 83], The direct addition of diazo compounds was replaced by use of suitable precursors which form the desired diazo compound in situ. The Aggarwal group developed this concept for the corresponding sulfur ylide type epoxidation (see Section 6.8) [82], and successfully extended it to aziridination [83]. Starting from the tosylhydrazone salt 66 the diazo compound is formed in situ under conditions (phase-transfer-catalysis at 40 °C) which were found to be compatible with the sulfur ylide type aziridination [82, 83], The concept of this improved method, for which sulfide 67 (Scheme 5.41) is the most efficient catalyst, is shown in Scheme 5.40. 

Figure 10.2 illustrates selected examples of these epoxide products. Aromatic and heteroaromatic aldehydes proved to be excellent substrates, regardless of steric or electronic effects, with the exception of pyridine carboxaldehydes. Yields of aliphatic and a,/ -unsaturated aldehydes were more varied, though the enantio-selectivities were always excellent. The scope of tosylhydrazone salts that could be reacted with benzaldehyde was also tested (Fig. 10.3) [29]. Electron-rich aromatic tosylhydrazones gave epoxides in excellent selectivity and good yield, except for the mesitaldehyde-derived hydrazone. Heteroaromatic, electron-poor aromatic and a,/ -unsaturated-derived hydrazones gave more varied results, and some substrates were not compatible with the catalytic conditions described. The use of stoichiometric amounts of preformed sulfonium salt derived from 4 has been shown to be suitable for a wider range of substrates, including those that are incompatible with the catalytic cycle, and the sulfide can be recovered quantitatively afterwards [31]. Overall, the demonstrated scope of this in situ protocol is wider than that of the alkylation/deprotonation protocol, and the extensive substrate...

The reaction of p-chlorobenzaldehyde with phenyldiazomethane in the presence of (MeOlsP and catalytic amounts of meso-tetraphenylporphyrin iron chloride (ClFeTPP) resulted in the formation of the corresponding alkenes with an /Z-selectivity of 86 14, but the yield was low (30%). When phenyldiazomethane is generated in situ from the corresponding potassium tosylhydrazone salt, the olefin yield increases to 92% with E/Z-selectivity of 97 3. Thus, high levels of -selectivity are obtained with semistabilized ylides by this method . This process is applied to a wide range of aldehydes and is practical as compared to standard Wittig reaction, and therefore finds applications in industry, o... 

Borden, W. T., Concannon, P. W., Phillips, D. I. Synthesis and pyrolysis of carbonate tosylhydrazone salts derived from vicinal glycols. Tetrahedron Lett. 1973, 3161-3164. 

Norbornyldiazomethane (1) was prepared by gentle heating (90-100 °C) of the corresponding tosylhydrazone salt, obtained from bicyclo[2.2.1]heptane-l-carbaldehyde, in a Kugelrohr apparatus. 1-Norbornyldiazomethane (1) is an unstable orange-yellow liquid and was immediately dissolved in a solvent prior to use. Irradiation of a benzene solution of 1-norbor-nyldiazomethane (1) in the presence of ( )- or (Z)-but-2-ene for 2 hours at 25 C led to cyclopropanated products 2 and 3/4 in addition to dimeric products of the precursor carbene. The addition of the monoalkylcarbene is stereospecific with a singlet reaction state. 

Thermal decomposition of a tosylhydrazone salt has also been demonstrated as one of only few examples of methods for the generation of 1-substituted 1-vinylcyclopropanes from diazoalkenes. Heating the dilithiotosylhydrazone 26 in xylene in the presence of dimethyl fumarate generates the pentacyclic carbon skeleton 27 via two stereospecific cyclopropanations. ... 

Thus photolysis of the tosylhydrazone sodium salt of 5//-dibenzo[a,c]cyclohepten-5-one (14) at — 60 °C in the presence of cyclopentadiene or furan with tetrahydrofuran as cosolvent gave the cyclopropene Diels-Alder adducts 17 and 18 in 73 and 47% yields, respectively. If the photolysis was stopped shortly after all the tosylhydrazone salt had decomposed, adduct 17 was the only isomer found in the cyclopentadiene reaction. In the formation of the furan adduct 18, the reaction was not so clean and a number of unidentified products were also formed. Unfortunately, adduct 18 is thermally unstable at the temperature necessary for thermal formation of carbene 15. No trace of adduct 18 was detected when the arylcarbene 19 was generated directly from its tosylhydrazone salt in the presence of furan. ... 

Diazo-compounds can in turn be generated photochemically from sodium salts of toluenesulphonyl hydrazones. Irradiation of the cyclobutane tosylhydrazone (44) gave trans-tricyclo[5.1.0.0 ]-octane (45 R=Me) by the pathway shown in Scheme 4 44 the tricycle (45 R=H) can also be obtained by photoelimination of nitrogen from the diazatricyclo[ 5.2.1.0 4]decene (46). The unexpected conversion of the anthracenocycloheptatriene derivative (47) into triptycene with loss of one carbon atom was observed on irradiation in tetrahydrofuran 4 the mechanism of this unusual reaction remains obscure and merits further investigation, but neither 1-triptycenyl nor 2-triptycenyl carbene appears to be an intermediate in this transformation. 

This effect is even more pronounced in the phenanthryl series where, starting from the tosylhydrazone salt of 54, the cyclopropane 55 was trapped in up to 73% yield using cyclopentadiene [Eq. (15)]. 

Another surprising result was the observation 55,56) that good yields (20—70%) of cyanocyclopentadiene could be obtained by pyrolysis of 2-, 3-, and 4-(5-tetra-zolyl) p37ridines as well as of 3- and 4-pyridyldiazomethanes, the latter generated from the tosylhydrazone salts 55). 

The most commonly used synthesis of [l,2,3]triazolo[l,5-fl]pyridines remains that from the hydrazones of 2-p) idyl-carboxaldehydes or -ketones by oxidation. Some hydrazones give triazolop) dines when boiled in methanol in the presence of air, but all other reported cases require an added oxidant. The use of the most common oxidants illustrates the versatility of the synthesis. Nickel peroxide, potassium ferrocyanide and bicarbonate, air and a copper-II salt, manganese dioxide or (diacetoxyiodo)benzene have been used (02AHC1). An alternative route from tosylhydrazones of 2-pyridyl-carboxaldehydes or ketones by treatment with base, usually morpholine, has been used for high yields of sensitive materials (02AHC1). 

In an attempt to reach an isomeric [5.5.5.5]fenestrane, Luyten and Keese prepared the epimeric ketolactone 82 from dicyclopentadiene. Here decomposition of the tosylhydrazone salt led only to olefin 83. Once again the high-temperature palladium and hydrogen process was effective, but the product was 78 rather than the desired (la,4a,7a,10)5)-[5.5.5.5]fenestrane According to molecular mechanics calculations this latter unknown isomer should be about 13 kcal mol more strained than 78 . 

Reaction of 2,6-dimethyl-l,4-benzoquinone with the quinomethyl carbanion derived from 2,3-dimethyl-1,4-naphthoquinone is reported to give the tricyclo-[6,3,l,0 ]dodecane derivative (749). Pyrolysis of the sodium salt of the tosyl-hydrazone of 7-cycloheptatrienylmethyl methyl ketone in diglyme at 150 C afforded (750 7%) similar pyrolysis of the tosylhydrazone salt from l-(7-cycloheptatrienyl)-ethyl methyl ketone gave (751 9 %). Both compounds are examples of the previously... 

A liimtation of the current protocol is the use of diazo compounds, which are potentially explosive and not readily available. The inherent hazards in handling these diazo compounds severely limit the practical apphcation of this methodology. In 2001, Aggarwal and coworkers disclosed a modified Bamford-Stevens reaction [29] for the in situ generation of diazo compound from N-tosylhydrazone salts. The addition of BnEtsN CT as a phase-transfer catalyst can enable the diazo compound to be produced at 30-40°C (Scheme 20.12) [30]. 

The method of in situ generation of diazo compounds from N-tosylhydrazone salts proved to be quite efficient for aziridination. When sulfide 19 was employed as a catalyst, moderate to good yields and excellent enantioselectivities were obtained with a range of aromatic imines. The trans cis ratios of the products varied in the range of 2-8 1, dependent on the N-protecting group of imines. Notably, the aziridinations of aliphatic imines (cyclohexyl imine, tert-butyl imine) and benzophenone-imine also proceeded well, giving the aziridine products in 50-53% yields and 73-98% ee [39]. 

Diazo compounds can be dediazonized by transition metal complexes to generate metallocarbenes, which are important intermediates in various transformations [45-48]. Since tosylhydrazones have been found to be readily available precursors of diazo compounds through the Bamford-Stevens reaction, a series of transition metal-catalyzed reactions of aldehyde tosylhydrazone salts in the presence of base and phase transfer catalyst (PTC) have been reported since 2000 [49-53]. It has been considered that metal carbenes generated from the in situ generated diazo compounds are involved in the catalytic cycle of these reactions -see (7). 

Thermolysis and/or photolysis of tosylhydrazone salts, accessible by condensation of p-toluene-sulfonyl-hydrazine with aldehydes or ketone, gives rise to elimination of the sulfinate salts and forms the intermediate diazo compound (Scheme 18). Generation of free carbenes by this method is sometimes in doubt and, as a consequence, this method is not included in this chapter except when generation of a carbene from the diazirine or diazo compound is not available. 

The same type of reaction occurs in the work of Hauptman (76T1293), who, studying the chemistry of diethynylcarbenes, found that the pyrolysis of the lithium salts of diethynylketone tosylhydrazones 5 (140-150°C) in the presence of olefins leads to cyclopropanes. This process results in the formation of the corresponding 3-ethynylpyrazoles. The formation of l-p-tolylsulfonyl-3-alkynylpyrazoles from hydrazone runs in milder conditions (50°C, 14 h) (Scheme 24). 

Diazocycloheptatriene (1), generated from the sodium salt of tropone tosylhydrazone, reacts with electron-deficient acetylenes to give H- 1,2-benzodiazepines 4 in moderate yield. It is suggested that the primary adducts 2 rearrange via the intermediates 3 to the products 4.114... 

The sodium salt of the tosylhydrazone of 2-(diphcnylmethylene)cyclopentanone (4.99 g, 11 mmol) was boiled under reflux with cyclohexane (150mL) for 25 h and the precipitated sodium p-toluenesulfinate was filtered off. The filtrate was evaporated under reduced pressure and the residue was crystallized (EtOH) to give the product (2.38 g). An additional 0.13 g (total yield 80%) was obtained from the filtrate by chromatography (silica gel) yellow crystals mp 159-160 °C. 

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