MARCO TEÓRICO Y ESTADO DEL ARTE

The first generation of a geminal dizinc carbenoid 116 led to a highly stereoselective synthesis of 1,2,3-substituted cyclopropanes from allylic alcohols.^^ In all cases, ?isyn

relationship was obtained between the R] group and the hydroxymethyl substituent as shown in 119 (Scheme 68). This is because one o f the Lewis acidic zinc atoms o f the dizinc reagent 116 interacts with the proximal basic group as shown in the transition state intermediate 117, whilst the stereochemical outcome o f the directed reaction is governed by complexation of the zinc centre that is not involved in the electrophilic carbenoid delivery (Scheme 68).^^ The resulting cyclpropylzinc derivative 118 could then be trapped with an electrophile to furnish the tri-substituted cyclopropane 119.

OH 119 OH OH R^Zrt" 118 syn relatio n sh ip 1 1 7 Scheme 68

The geminal zinc carbenoids 116 were prepared by mixing iodoform with diethylzinc by two successive alkyl exchanges. A competing pathway involves the decomposition of the species to generate the zinc carbenoid 121. However, 121 can react further with

iodoform to generate the zinc carbenoid 120 (R^=I). Alternatively, EtZnI can also be used to generate the geminal zinc carbenoid 116 (R^=Et) (Scheme 69).92

CHI3 R^ZnCHl2 (R^Zn)2CHI R ^ = E torI J2 0 1 1 6 CHI, R^CHIZnl 121 Scheme 69

lodo-, bromo-, and phenylseleno-substituted 124 cyclopropanes were all prepared in good yields by reaction of the gem-dizinc carbenoid with the allylic alcohol and subsequent trapping o f the resulting cyclopropylzinc derivatives 123 with electrophiles. In all cases the syn diastereomer was formed exclusively (>99:1). Interestingly, when D2O was used as the electrophile, <5% o f the iodo-substituted cyclopropane was observed, indicating that the gem-dizinc carbenoid 116 is substantially more reactive than the carbenoid 120 (Scheme 70).^^

BnO- 122 -OBn ZnR DCM BnO- OBn BnO OBn 123 124 64-94% Scheme 70

1.3.4 Chloro-Alkyl and -Aryl Zinc Carbenoids

Motherwell reported an excellent method for the generation of chloro-alkyl zinc carbenoids such as 125 and 126 from carbonyl compounds using zinc amalgam and a silicon electrophile; either chlorotrimethylsilane or l,2-bis(chlorodimethylsilyl)ethane (Scheme 71).^^’^^ The mechanism mirrors the Clemmensen reduction, with the exception o f silicon acting as the electrophile instead of a proton. C-H insertion reaction were observed in cyclic ketones such as cyclohexanone (Scheme 71 a)^^ and in the presence o f benzaldehyde, the corresponding zinc carbenoid 126 reacts with benzaldehyde to give the dicarbonyl coupling product (Scheme 71b).

ZnCI C -H in sertio n 72% (a) 125 PhCHO Z n/H g, E t2 0 , r.t. 69% (b) ZnCI C]Me2SiCH2CH2SiMe2C] Ph' Ph' 126 Scheme 71

Moreover, the zinc carbenoid derived from /7ara-methoxybenzaldehyde using zinc and bis(cblorodimetbylsilyl)etbane could also be trapped with electron-rich alkenes such as eyelohexene to give the corresponding functionalised cyclopropane 127 in excellent yield and stereoselectivity/^ In similar fashion, unfunctionalised alkenes such as styrene gave good yields of the cis cyclopropane 128 with the zinc carbenoid derived from 3-methylbutenal (Scheme 72)/^

OMe MeO, MeO, OHO 127 98%, 15:1 ( e n d o - .e x o ) Ph ^ H + P h ^ ^ ^ 128 53%, c i s only

(i) Zn/H g, CIM e2S iC H2C H2S iM e2C], E t2Ü, reflux, 36 h. Scheme 72

This chemistry will of course be described in greater detail in the results and discussion section.

1.3.5 Magnesium Carbenoids

a-Iodoalkylmagnesium compounds 131 are also accessible by an iodine/magnesium exchange reaction. Treatment of the diiodo compound 129 with

diisopropylmagnesium 130 at -78°C for two hours followed by protonation with methanol affords 97% of the iodoalkane 132 (Scheme 73).^^

T H F Ph Ph 131 130 129 M eO H 132 Ph Scheme 73

Interestingly, studies showed that the above magnesium carbenoid 131 had no tendency to disproportionate into diisopropylmagenesium 130 and the bis-a- iodoalkylmagnesium 133. In a separate experiment it could be shown that the bis(iodoalkyl)magnesium 133 is not converted into 131 by addition of diisopropylmagnesium 130 (Scheme 74).^^ This stability o f the magnesium carbenoids 131 and 133 at -78°C clearly contrasts with the behaviour of the analogous dialkylzinc reagents, which rapidly comproportionate and disproportionate at -78°C in THF.'^ Likewise, the corresponding alkylzinc iodides also exhibit a rapid Schlenck equilibrium.^^ Interestingly, NMR chemical shifts suggest that a- iodoalkylmagnesium compounds have a carbenoid character in between that of a- haloalkyllithium and the corresponding zinc compounds. This is reflected in a significant downfield shift AS of the NMR signal of the carbenoid carbon which may be caused by substantial weakening of the carbon-halogen carbon in the magnesium carbenoids, as supported by ab initio calculations and EXAFS studies.^^ Unfortunately however, the reactivity of these species in cyclopropanation studies was not described.

1.4 Alkoxycarbenoids [YMCH(OR)X]

1.4.1 Zinc Carbenoids

Alkoxy zinc carbenoids 135 have been prepared by Motherwell, from orthoformates 134 in the presence of zinc amalgam, zinc chloride and chlorotrimethylsilane (Scheme 75a).^^ The resulting carbenoids 135 reacted with unfunctionalised alkenes to provide the corresponding alkoxycyclopropanes in moderate to good yields (Scheme 75b).^^

Z n, Z n C l2 H ZnCI

RO' 'OR ^®3SiCl R O '^ ^ C I

134 (a ) R=alkyl or aryl Z n, Z nC l2, M e^S iC l, Et2Ü (M eO )]C H , reflux, 48 h 135 OMe (b) 6 4 % , 2 :1

(cis'.trans)

Interestingly, whilst it could be reasoned that this carbenoid species would exhibit a more nucleophilic character and hence exhibit a chemoselective preference for an electron-deficient alkene, due to the electron-donating nature of the alkoxy group, experiments proved otherwise. Thus, as shown in Scheme 76, both the enol ester 136 and the acrylate 138 gave similar yields of the corresponding cyclopropane in the presence of the methoxy carbenoid 137. Moreover, the reaction of a direct competition experiment using the monoterpene ester 139 clearly shows that the more electron-rich alkene is favoured over the a c ry la te .T h u s, the alkoxy species like other traditional zinc carbenoids displays essentially electrophilic character.

-CI 1 3 7 MeO' ZnCI _46% 1 3 6 Bu Bu _MeO MeO Bu MeO' ZnCI Bu _43% 138 Etc EtO' ZnCI {Z!E, 3:1) 139 Scheme 76

The chemistry of these alkoxy carbenoids will be discussed in further detail in the results and discussion section.

1.4.2 Lithium Carbenoids

A range of alkoxycyclopropanes was also prepared by the use of a-haloalkyllithium carbenoid species generated via halogen lithium exchange o f a,a-dihalo e t h e r s . F o r example, Schollkopf reported that the carbenoid generated from 140 or 142 reacted with a variety of electron rich alkenes to give the corresponding alkoxycyclopropane

141 and 143 in moderate yield with the cis cyclopropane favoured (Scheme 11)?''

However, the use of a,a-dihalo ethers as cyclopropanating agents is limited due to their high toxicity.^^’^^

141 M eLi 36%, 3:1* Çl 142 ( 51%, 7.5:1* M eLi 143

m ajo r iso m er show n Scheme 77

In addition, lithium alkoxy carbenoids may also be prepared by the deprotonation of a-haloethers and these species are stabilised by the oxygen atom. Thus, the treatment of chloromethyl-P-chloroethyl ether 144 with the previously mentioned lithium 2,2,6,6-tetramethylpiperidide 105 led to the alkoxcyclopropanation of electron-rich alkenes such as eyelohexene (Scheme 78).99

144

58%, 7.5:1*

m ajo r isom er show n Scheme 78