DETERMINACIÓN DE LAS CARGAS Y MOMENTOS EN LA

This section, which is concerned once again with the generation o f carbenoid species and their reactivity in cyclopropanation, includes both an investigation into the patterns of reactivity discussed in the introduction and also our efforts to generate novel functionalised carbenoid precursors.

2.5.1 A Comparison of Organocopper and Organozine Carbenoids in Carboalkoxycyclopropanations

Carboalkoxycyclopropanes are routinely prepared by thermal, photochemical, and catalytic decomposition of a-diazo esters in the presence of alkenes/^'^^^'^^^ From a practical standpoint, as with many diazo compounds, this method is not very convenient since alkyl diazoacetates are toxic and potentially explosive. For example, methyl diazoacetate has been reported to explode with extreme intensity on heating.

There have been a few isolated examples of carboalkoxycyclopropanations which do not involve the use of diazo precursors. One of these involves ethyl diiodoacetate 146

and zinc copper couple in a Simmons-Smith type cyclopropanation. Under these conditions 1,1,4,4-tetramethylbutadiene 145 gave the vinylcyclopropane 147, albeit in low yield after a prolonged reaction time (Scheme 157a, vide supra 1.5.1).^^^ A more successful cyclopropanation of alkenes was achieved by reacting copper with alkyl dibromoacetates. For example, heating a mixture of copper powder, ethyl dibromoacetate 154 and cyclooctene in a non-polar solvent provided the cyclopropane

301 in a good yield (Scheme 157b, vide supra 1.5.3).^^ This is in sharp contrast, to the trend exhibited by the family of organocopper carbenoids, which have shown the ability to cyclopropanate electron deficient alkenes {vide supra 1.5.3).^®^

o + 145 146 O + Br- Zn/C u, TH F 50°C, 14 days Cu, benzene O E t 5 5OQ 50 h N < ^ C 0 2 E t 147 12% (a) / ■ Br 154 C O .E . 3 m p ,) 1.3:1 (exo'.endo) Scheme 157

In the light of the above results, it was therefore o f considerable interest to carry out a direct comparison o f the various forms o f activated zinc, which were widely used in Simmons-Smith cyclopropanation, and also to examine copper as the metal for

15) were also chosen to investigate the effect of the halogen atoms on the cyclopropanation. Thus, we were intrigued to see whether ethyl dibromoacetate 154

would react in the same manner as dibromomethane with LeG off s zinc copper c o u p l e , a n d in similar vein, whether ethyl chloroiodoacetate 302 would react as well as chloroiodomethane in Furukawa’s modified Simmons Smith reagent.^^ In addition, we also decided to study 3,3-dibromo-1,1,1 -trifluoropropane 303, because the trifluoromethyl group has proven valuable to the agrochemical industry. Finally, in this series, the a,a-dibromoketone 304 was also selected (Figure 15).

OEt OEt OEt 146 154 302 304 303 Figure 15

The generation of samarium carbenoids was avoided, due to the fact that they only react with allylic alcohols.^^ In addition, the generation o f aluminium carbenoids was also avoided in this study, due to the known literature reactions of trialkylaluminium reagents and esters to give either the corresponding alcohols in high y i e l d s o r aldehydes and ketones, albeit in lower yields.166

All of the required dihalo compounds were prepared by literature methods. Thus, ethyl dibromoacetate 154 was formed by refluxing phosphorus tribromide and bromine to give first the resulting dibromoacetyl bromide and then subsequent reaction with ethanol. A subsequent Finkelstein reaction with potassium iodide in ethanol provided the corresponding diiodo compound 146.^^^ Similarly, a Finkelstein reaction of ethyl dichloroacetate provided the somewhat unstable chloroiodoacetate 302,'^^ which could however be redistilled prior to use (Scheme 158).

KI, EtOH

OEt OEt

reflux, 60 h OH (ii) EtOH [excess]

146 84% 154

67%

KI, acetone

OEt reflux, 132 h OEt

302 41% Scheme 158

Having a reference sample of ethyl diiodoacetate 146, we also attempted an alternative preparation of this unstable compound.

Interestingly, Jung had reported that a,a-diiodotoluene 305 could be prepared from benzaldehyde using 2.2 equiv. of iodotrimethylsilane. The mechanism is shown below (Scheme 159).’^° 305 50% TM SI (2 equiv.), CHCI3 r.t., 30 min TM SI (1 equiv.) TM SO TM S .OTMS TM SI (1 equiv.) Scheme 159

Thus, by using iodotrimethylsilane, an alternative one step procedure for the synthesis of ethyl diiodoacetate 146 from ethyl glyoxalate was investigated.

Ethyl glyoxalate is in fact a polymeric material at room temperature, and is therefore supplied as a 50:50 mixture by weight in toluene. The compound can be de-

polymerised on heating, and the monomer distilled. However, the compound re- polymerises in a few hours at room temperature. We discovered however that a more effective depolymerisation can be achieved by microwave irradiation. Thus, the polymer-toluene mixture was firstly distilled at 150°C in order to remove the toluene and then subjected to 600 W microwave irradiation for 5 m i n u t e s . T h e resulting oil was then distilled, and the aldehyde was immediately used.

By using similar reaction conditions to those reported by Jung, freshly distilled de­ polymerised ethyl glyoxalate 306 was heated at 35°C with 2.2 equiv. of iodotrimethylsilane in deuterated chloroform. Both GC and NMR analysis, however showed no formation of ethyl diiodoacetate 146 over an 18 hour period, during which, polymerisation of the aldehyde 306 occurred (Scheme 160).

O OEt TMSI (2.2 equiv.) CDCI3, 35°C, 18 h \ --- O o 3 0 6 OEt 14 6 Scheme 160

3,3-Dibromo-1,1,1-trifluoropropane 303 was easily formed by bromination of 1,1,1- trifiuoroacetone.^Finally, 2,2-dibromo-1 -phenylethanone 304 was synthesised by reacting 1 -phenylacetylene with hypobromous acid, which was generated in situ from sodium bromate and sodium hydrogensulphite. Thus, the reaction is initiated by the addition to the alkyne to form the a-bromoenol 307. Subsequent addition of a second molecule to the enol 307 then forms the a,a-dibromoketone 304 via dehydration of 308 (Scheme 161).173

303 60% CF: r.t., 65 h 304 46% MeCN/H2 0, r.t., 2 h BrOH OH _{HQ ,0H} BrOH 308 307 Scheme 161

The results of a systematic study for the three ethyl dihaloacetates 154,146 and 302 in carboalkoxycyclopropanations of cyclooctene are summarised in Scheme 162. The reaction of ethyl dibromoacetate 154 and ethyl diiodoacetate 146 with copper powder in the presence of cycloctene gave the corresponding carboalkoxycyclopropane 301 in good y i e l d . H o w e v e r , the use of activated zinc dust,^^'^ Shank-Shechter’^^ or LeGoffs^^ zinc copper couple and diethylzinc^^ all gave extremely low yields. Clearly in these reactions, the dihalo reagents 154 and 146 were being readily consumed by the reaction mixture, and no progress was made in identifying the fate of the resulting intermediates. Decomposition of the intermediates appears to take place rapidly, and even when the zinc source is reacted with the dihalo reagent in cyclooctene as the solvent and at low temperature, only a slight improvement in the cyclopropane yield was noted. The observation that the zinc copper couple gives a slightly higher yield than the zinc itself, perhaps suggests that copper can play the vital role in the reaction mechanism. Interestingly, only a trace amount of cyclopropane was observed when copper or diethylzinc was used with the mixed dihalo reagent 302. This unreactivity could be due to the high instability of the reagent 302 (Scheme 162).

X + Reaction conditions [72 h] C u,“ l2,C<,H6, 55”C Z n ‘’ “, THF, reflux

Shank and Shechter's Zn/Cu Et2 0, reflux

L eG offs Zn/C u/^ Et20, reflux Et2Zn^’ in hexane, DCE, r.t. X=C1, Br, I OEt 60%" trace 175 1%" no reaction O OEt 146 51%" 3%" trace*’ C02Et 301 O Cl OEt 302 trace*’ no reaction no reaction trace*’

“ M ix tu re o f e x o and endo d ia stereo m e rs (1.3:1). D e tec te d b y G C . A 3 % (1 .3 :1 , exo.endo) o f p ro d u c t w as o b ta in e d w h en th e reactio n w as p e rfo rm ed w ith o u t the p re se n c e o f ether.

Scheme 162

Thus, the observed reactivity of the species in the carboalkoxy-cyclopropanation of cyclooctene are shown in Scheme 163.

OEt OEt OEt

Cu Cu ZnX

X =B r or I

Scheme 163

Having observed that copper was clearly the best metal for

carboalkoxycyclopropanation, we then focused on applying the copper carbenoid generation method to other dihalo compounds. Thus, heating a mixture of 3,3- dibromo-1,1,1-trifluoropropane 303 with copper powder and cyclooctene in benzene gave the cyclopropane 309 as a mixture o f diastereomers. The reaction is similar to using alkyl dihalo acetates in the sense that the trifluoromethyl group is also electron- withdrawing (Scheme 164).

O + Br- C u, b enzene ^ ^ 3 5 5 ° C ,7 2 h Br 303 COCF3 309 15%, 1.2:1 (dr) Scheme 164

However, applying this method to the acetophenone derivative 304 was unsuccessful with recovery of the dihalo compound. The failure of this reaction can be attributed to the feeble electron-withdrawing nature of the phenyl group and is illustrative of how the groups attached to the carbenoid can effect its reactivity (Scheme 165).

4- 304 C u, b en zen e 55°C , 72 h — V - COPh Scheme 165

2.5.2 The Generation of a Novel Geminal Alkoxy-Carboalkoxy Organocopper Carbenoid and Reactivity in Cyclopropanation

At this stage, we were also interested in expanding the array of carbenoid precursors, through the synthesis of novel dihalo compounds. Our initial study involved an investigation into the cleavage of the acetal^^^ and ester’ groups in methyl dimethoxyacetate 310 by using bromo- or iodotrimethylsilane reagents as this could eventually lead to the formation of novel silylated gem dihalo intermediates such as 311. A series of NMR experiments was performed in order to investigate possible synthesis for these compounds (Scheme 166).

OTMS