Cyclopropanols, preparation

The procedure can be adapted to the preparation, in comparable yield, of a variety of 1-substituted cyclopropanols, alkyl as well as aryl. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Scheme 11.6. Routine and enantiose-lective preparation of 1,2-disubstituted cyclopropanols from esters and 2-substituted ethylmagnesium halides. For details, see Table 11.4.

This methodology offers the best means of preparing the key precursors to bicyclopro-pylidene (89) [59,60] and its bis-spirocyclopropanated analogue 92 [59], since methyl cyclopropanecarboxylate (87) and ethyl dispiro[2.0.2.1]heptane-7-carboxylate (90) are virtually quantitatively converted to 1-cyclopropylcyclopropanol (88) and l-(dispiro[2.0.2.1]-hept-7-yl)cyclopropanol (91), respectively (Scheme 11.25) [59]. The same approach has successfully been applied for the preparation of other strained bicyclopropylidene derivatives [72,121],... 

Progress has also been reported in applying titanium-mediated cydopropanation reactions as a key step in the preparation of natural products. For example, racemic stigmo-lone (8-hydroxy-2,5,8-trimethylnonan-4-one) 163, a pheromone of the myxobacterium Stigmatella aurantiaca, has been synthesized in 67% overall yield by the titanium-mediated hydroxycyclopropanation of 2-methyl-5-hexen-2-ol 161 with ethyl isovalerate 160 followed by base-induced ring-opening of the resulting 2-(3-hydroxy-3-methylbutyl)-1-isobutyl-l-cyclopropanol 162 (Scheme 11.41) [139]. 

The alkaloid whitasomnine 44 was prepared according two different routes. The first approach (route A) was based on the cyclization of the l-(3-chloropropyl)cyclopropanol 41 (Scheme 3). The final cyclization involved the reaction of 3-(3-chloropropyl)pyrazole 42 to form the final pyrazole 43 in 40% yield, which is then transformed to the natural product <1996TL1095>. The second approach (route B) is based on the radical cyclization of the substituted pyrazole 45 in the presence of Bu3SnH in acetonitrile under refluxing toluene. Whitasomnine 44 was isolated in 38% yield <2002TL4191>. 

DePuy, as early as 1966 [14], reported that cw-1-methyl-2-phenylcyclopropanol gave exclusively deuterated 4-phenyl-2-butenone in 0.1 M NaOD/D20/dioxane. However, homoenolates derived from simple cyclopropanols by base-induced proton abstraction fail to react with electrophiles such as aldehydes and ketones, which would afford directly 1,4-D systems. Lack of a reasonably general preparative method was another factor which impeded the studies of homoenolate chemistry. For this reason, in the past twenty years more elaborated cyclopropanols, which might be suitable precursors of "homoenolates", have been prepared and studied. 

This method for the preparation of exo/ewdo-7-norcaranol is an adaptation of that described by Schollkopf, Paust, Al-Azrak, and Schumacher. The method has been used by the submitters for the preparation of the following cyclopropanols exo/endo-6-hydroxybicyclo[3.1. OJhexane, exo/e do-8-hydroxybicyclo[5.1.0] octane, exo/cwdo-9-hydroxybicyclo[6.1.0]nonane, 2,2-dimethylcy-clopropanol, 2,2,3,3-tetramethylcyclopropanol,Im 5-2,3-dimethyl cyclopropanol, cw-2,3-dimethyl-cf5//ran5-cyclopropanol, cis/ [Pg.45]

The principal disadvantage of this procedure is that the olefin must be used in at least three- to fourfold excess in order to obtain reasonable yields. In case of rare olefins, or of olefins containing groups such as the carbonyl group which add organolithium compounds, other methods might be more advantageous. The method is also limited to the preparation of secondary cyclopropanols. 

The most satisfactory procedure for obtaining cyclopropanol itself is that of ( ottle which is also recommended for the synthesis of l-arylcyclopropanols. l-Alkylcyclopropanols are best prepared via the correspoiiding acetates which are obtained... 

Vicinally donor-acceptor-substituted cyclopropanol carboxylic esters have been proven to be versatile synthetic building blocks in organic synthesis [11]. They readily undergo a retroaldol reaction, thus creating a stable enolate that at the same time can be considered as a homoenolate in relation to the newly formed carbonyl function. Shimada et al. applied this strategy to the preparation of y-substituted lactones starting from cyclopropane 21 (Scheme 3) [12]. 

This reaction was applied to the synthesis of quinonoid natural products [34]. Propargyl bromides 62 a and 62b, which were prepared from prenyl bromide and phytyl bromide by a standard procedure, were converted to the corresponding aluminum reagents by reaction with powdered aluminum and a catalytic amount of mercuric chloride [35]. Then the iodomagnesium salt of cyclopropanol hemiacetal was treated with these reagents [36] affording the prenyl derivative 63 a and the phytyl derivative 63 b in 49 and 50% yield, respectively (Scheme 26). 

However, the real breakthrough came with the drastically facilitated preparation of 1-cyclopropylcyclopropanol (15) from methyl cyclopropanecarboxylate (19) applying the transformation of an alkoxycarbonyl group into a cyclopropanol fragment with ethylmagnesium bromide in the presence of Ti(zPrO)4 as developed by Kulinkovich et al. [13]. The optimized conversion of the alcohol 15 to the bromide 16 and its dehydrobromination makes the alkene 1 available in synthetically useful quantities of 40 -55 g within one week (Scheme 3) [ 14]. This sequence is also applicable to prepare substituted, especially spirocyclopropane-annelated, bicyclopropylidenes [ 14a]. 

Cyclopropylamines and cyclopropanols can be prepared from alkyknagnesium ha-lides. The reaction is catalyzed by titanium alcoholates and its mechanism includes the formation of a dialkoxytitanacyclopropane 270, which reacts with a carbonyl compound or nitrile (Scheme 22). The use of chiral titanium alcoholates allows the reaction to be performed with up to 78% ee (equation 171) . 

A very useful class of chiral auxiliaries has been developed for alkenes substituted with a heteroatom. These auxiliaries, attached to the heteroatom, allow for the preparation of enantiomerically enriched cyclopropanols, cyclopropylamines and cyclopropylboronic acids. Tai and coworkers have developed a method to efficiently generate substituted cyclopropanol derivatives using the cyclopropanation of a chiral enol ether (equation 78) . The reaction proceeds with very high diastereocontrol with five- to eight-membered ring sizes as well as with acyclic enol ethers. The potential problem with the latter is the control of the double bond geometry upon enol ether formation. A detailed mechanistic study involving two zinc centers in the transition structure has been reported. ... 

The chemistry of cyclopropanol [7] has long been studied in the context of electrophilic reactions, and these investigations have resulted in the preparation of some 3-mercurio ketones. As such mercury compounds are quite unreactive, they have failed to attract great interest in homoenolate chemistry. Only recent studies to exploit siloxycyclopropanes as precursors to homoenolates have led to the use of 3-mercurio ketones for the transition metal-catalyzed formation of new carbon-carbon bonds [8] (vide infra). 

Notes A reagent that allows for a unique preparation of cyclopropanol derivatives. 

A number of new methods for the preparation of cyclopropanols from carbonyl derivatives via 1,3-bond formation between the carbonyl and carbons have been developed. 7>ons-2-alkylcyclopropanols are stereoselectively produced from 2- or 3-substituted acrolein upon exposure to chromium(II) chloride in the presence of a catalytic amount of nickel chloride in DMF (equation 56)73. 2,3-Disubstituted acroleins are, in contrast, inert to the chromium reagent. Treatment of / -stannyl carbonyls with titanium(IV) chloride affords cyclopropanols in good yields when the substrates are ketones not bearing j -alkyl... 

A number of new methods for the preparation of cyclopropanols has been developed (see Sections II.B and II.E for the preparation of cyclopropanols via 1,3-bond formation see also Section III. A. 1). Treatment of carboxylic esters with ethylmagnesium bromide in the presence of Ti (OPr-z)4 affords 1-substituted cyclopropanols in excellent yields (equation 152)334. Similar transformation of carboxylic esters to cyclopropanols is realized by... 

Cyciopropanone ethyl hemiketalThis useful precursor to 1-cyclopropanols is readily prepared by a procedure (equation I) adapted from Ruhlmann s reaction (4, 537). 

Diastereoselective cyclopropanation of enol ethers preparation of cyclopropanol derivatives27 ... 

Nonetheless, there are some examples of cyclopropanol formation by straightforward P-hydrogen abstraction. The Diels-Alder adduct 100 prepared from o-quino-... 

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