Análisis económico y medio ambiental

Following the report of the formation of 2-ethoxy-2-phenylacetic acid 79 from 2,2,2- trichloro-1-phenylethan-1-ol 23 (Scheme 65),20 the scope of oxygen nucleophiles in Jocic-type reactions has been widely explored.

Scheme 65 First reported synthesis of an α-ethoxy acids.

Shortly after, the scope of these conditions was demonstrated as a range of α-alkoxy acids were prepared with alkyl trichlorocarbinols.21 Esterification of these α-alkoxy acids to their corresponding α-alkoxy esters demonstrated a simple route for the synthesis of these class of compounds.21 In 1947, as a consequence of the attempted preparation of 2-ethoxy-2-phenylacetic acid 79 the synthesis of ethyl 2-ethoxy-2- penylacetate 80 was reported (Scheme 66).9 This provided a new route for the direct synthesis of α-alkoxy esters from trichlorocarbinols, removing the requirement of the esterification step.

Scheme 66 First preparation of α-ethoxy esters.

In 1950, Bergmann explored the scope of the previously reported chemistry21 with reactions of substituted aryl trichlorocarbinols.22 The successful synthesis of α-ethoxy and α-butoxyarylacetic acids, from the o-chloro,m-methoxy andp-methyl derivatives of 2,2,2-trichloro-1-phenylethan-1-ol 23, were reported.22 Additionally, α- methoxynaphthylacetic acids and derivatives were prepared from 2,2,2-trichloro- naphthyl alcohols using similar conditions.23

Reeve and coworkers made an advance in the field by the development of a ‘one-step’ synthesis for the preparation of α-methoxyarylacetic acids from aldehydes,24, 25

which were previously unreactive using the conditions reported by Bargellini.3 The procedure described by Reeve brings together the synthesis of trihalocarbinols and the Jocic-type chemistry of these substrates (Scheme 67). The scope of this chemistry was explored further by Reeve24and Benner,25where several more analogues were prepared.

Scheme 67‘One-step’ synthesis ofα-methoxyarylacetic acids.

As previously described the reactions reported by Bargellini involve the formation of saturated heterocycles via the in situ trapping of the acid chloride species in the reaction.3 An extension to the formation of saturated heterocycles using Jocic-type chemistry was reported by Gukasyan and coworkers in which 2-aminophenol and o- hydroxyphenol were reacted to form benzo[1,4]oxazin-3-ones and benzo[1,4]dioxin-3- ones (Scheme 68).26

Scheme 68Jocic-type reactions with 2-aminophenol ando-hydroxyphenol. More recently, this methodology was used for the synthesis of a key intermediate of a novel Factor Xa inhibitor81,27, 28using modified conditions from the literature.26

OH CCl3 CN O NH O CN O N O HN NH2 N ( )5 NaH DMSO HO NH2HCl 81, Factor Xa inhibitor 17 %

Scheme 69Synthesis of a key intermediate of a Factor Xa inhibitor using a Jocic-type reaction.

In 1991, Fechtel and coworkers used a variety of phenolate nucleophiles for the preparation of α-phenoxy methoxy esters (Table 6).29

R1 R2 R3 Yield % H H H 41 H H CH3 45 H CH3 H 27 CH3 H H 28 Cl H H 19 Cl H Cl 9

Table 6Yields of Jocic-type reactions with substituted phenolate nucleophiles. There are several examples of Jocic-type reactions of symmetrical and unsymmetrical tertiary trichlorocarbinols using oxygen nucleophiles in the literature.30-34

The transformation of 1,1,1-trichloro-3,3,3-trifluoropropan-2-ol 82 into α- (trifluoromethyl)-lactic acid precursors exploits Jocic-type chemistry.35 This is particularly important since derivatives of α-(trifluoromethyl)lactic acid are highly desirable intermediates in the pharmaceutical industry and opto-electronic materials science.30 Furthermore, the scope of this reaction in this field provided an industrial synthetic route for the synthesis of Mosher’s acid 83 (Scheme 70), a valuable chiral derivatising agent, which can be used for enantiomeric excess determination and in some cases absolute stereochemistry assignment of chiral alcohols and amines.36, 37

The preparation of a series of 2-(4-halophenoxy)-2-methylpropanoic acids was reported in 1989 by reacting 1,1,1-trichloro-2-methyl-2-propanol 71with sodium hydroxide and the relevant substituted phenol (Scheme 71).31Further examples of substituted and non- substituted α-(methoxyphenoxy)alkanoic acids are reported in the literature.38-40

Scheme 71Synthesis of 2-(4-halophenoxy)-2-methylpropanoic acids.

The introduction of thegem-dimethyl41 group as well as carboxylic acids42 and esters43 into drug molecules is particularly attractive. There are several examples in the literature where Jocic-type chemistry has been used to introduce these desirable functionalities into potential drug molecules. For example, a class of peroxisome proliferator-activated receptor (PPAR) related drugs have utilised this type of chemistry in synthesis of desired targets,32, 33 which include Clofibric acid, Fenofibric acid and Bezofibrate (Figure 35).34

Figure 35PPAR related drugs that use Jocic-type chemistry in their synthesis. The synthesis of a dual PPAR α/γ agonist 85 by Merck illustrates the Jocic-reaction on kilogram scale giving the desired product in an excellent 95 % yield (Scheme 72).44The

reaction demonstrates use of a highly hindered phenol 84, which highlights the scope and scalability of this class of reaction.

Scheme 72Jocic-type reaction using a highly hindered phenol.

There are several other reports of medicinally relevant compounds that make use of Jocic-type reactions with oxygen nucleophiles for the synthesis of key intermediates.45-

52

In addition to the traditional Jocic-type conditions with oxygen nucleophiles starting from trichlorocarbinols, there are many reports using the ‘one-pot’ conditions described by Bargellini, starting with ketones.3Some examples include the initial development of Clofibrate-related drugs,53 the synthesis of the antidepressant Efaproxiral sodium54 and reactions on hindered macrocycles.55 Further scope of this chemistry is shown by the synthesis of ano-substituted phenoxyalkanoic acid87in good yield from the reaction of 2-hydroxy-N-methylbenzamide86(Scheme 73).56

N H O O CO2H 87, 62 % N H O OH CHCl3 NaOH acetone 86

Scheme 73‘One-pot’ Jocic-type reactions ofo-substituted phenols.

In addition to the many examples of racemic Jocic-type reactions with oxygen nucleophiles which have been discussed there are a few examples of stereospecific versions, which will be discussed in section2.1.4.