Trifluoromethyl substitution reactions

FIGURE 5.34. Plot of log (PRF) for methyl (O) and trifluoromethyl ( ) substitution reactions of aromatic hydrocarbon. Data from Ref. 12. 

Because the carbon atom attached to the ring is positively polarized a carbonyl group behaves m much the same way as a trifluoromethyl group and destabilizes all the cyclo hexadienyl cation intermediates m electrophilic aromatic substitution reactions Attack at any nng position m benzaldehyde is slower than attack m benzene The intermediates for ortho and para substitution are particularly unstable because each has a resonance structure m which there is a positive charge on the carbon that bears the electron withdrawing substituent The intermediate for meta substitution avoids this unfavorable juxtaposition of positive charges is not as unstable and gives rise to most of the product... 

The use of trifluoromethyl-substituted a-pyrones in Diels-Alder reactions with all types of dienophiles provides an interesting route to trifluoromethyl-benzenes [I/Sj (equation 98)... 

As the last reaction of equation 99 suggests, trifluoromethyl substituted furans are themselves reactive Diels-Alder dienes [722] (equation 102)... 

Bis(trifluoromethyl)-substituted pyrimidines are also available fromtrifluoro-acetonitrde on reaction with enamines and ynamines [d ] With dimethylami-nocrotonates, a cyclocondensation takes place to give 2-pyridones. 5-Cyano-6-trifluoromethyluracil is available via a similar route [95] (equation 18)... 

Three skeleton atoms of a hetero-l,3-diene are incorporated into a five-membered ring system on reaction with 1,2 [n,n] compounds (e.g., hydrazines, reaction type 4, equation 10). On further heating in the presence of azobisiso-butyronitrile (AIBN), the bis(trifluoromethyl)-substituted 1,2,4-triazolines are transformed into 5-tnfluoromethyl-l,2,4-triazoles in high yield [t02 (equation 22). 

Perfluoroalkyl groups adjacent to multiple bond systems lower the frontier molecular orbitals (FMOs) Therefore, cycloaddition reactions preferentially occur with electron-rich multiple-bond systems The preference of bis(trifluoromethyl)-substituted hetero-l,3-dienes for polar reacuons makes them excellent model compounds for developing new types of diene reactions deviating from the well documented Diels-Alder scheme (pathway 1) A systematic study of the reactions of diene (1 =2-3=4)-dienophile (5=6) combinations reveals new synthetic possibilities that have not yet been fully exploited as tools for preparative organic cherrustry (equation 25)... 

Trifluoromethyl-substituted diazonium betaines [176]. Synthetic routes to trifluoromethyl-substituted diazo alkanes, such as 2,2,2-trifluorodiazoethane [ 177, 7 78, 179] and alkyl 3,3,3-trifluoro-2-diazopropionates [24], have been developed Rhodium-catalyzed decomposition of 3,3,3-tnfluoro-2-diazopropionates offers a simple preparative route to highly reactive carbene complexes, which have an enormous synthetic potential [24] [3-1-2] Cycloaddition reactions were observed on reaction with nitnles to give 5-alkoxy-4-tnfluoromethyloxazoles [750] (equation 41)... 

Trifluoromethyl-substituted 1,3-dipoles of the allyl type. Trifluoromethyl-substituted azomethine imines ate readily available on reaction of hexafluo-... 

Trifluoromethyl-substituted nitrones have been prepared [184, 185, 186] and used for [3+2] cycloaddition reactions [iS5, 186] (equation 42). 

Cycloaddition reactions where bis(trifluoromethyl)-substituted hetero-1,3-dienes act as dienophiles have been descnbed for open-chain and cyclic dienes [115, 126, 127] The balance of the diene -dienophile activity of bis(tnfluoro-methyl)-substituted hetero-l,3-dienes can be influenced strongly by the substituents bonded to the inuno nitrogen atom For instance, A/-(arylsulfonyl) denvatives of tnfluoroacetaldimine and hexafluoroacetone imine do not act as dienes but exhibit only the dienophile reactivity of electron deficient imines [5 229, 234,235, 236 237] (equation 52)... 

Cycloaddition Reactions with Trifluoromethyl-Substituted Hetero-1,3-dienes... 

Bis(trifluoromethyl)-substituted heterodienes are electron-deficient species They therefore react preferentially with electron-rich multiple bond systems to give [4+2] cycloadducts (Diels-Alder reaction with inverse electron demand) [238]... 

The reaction conditions (neutral, acidic or basic) do have an affect on the regioselectivity of the reaction. Acidic reaction conditions have also been shown to preferentially provide one regioisomer over basic conditions for reactions of aryl hydrazines. Extensive studies with 2-perfluoroacylcycloalkanones and mono-substituted hydrazines were studied to determine the selectivity of various alkyl-, aryl-, and heteroaryl-substituted hydrazines. Reactions of the aryl hydrazine 21 with the trifluoromethyl-substituted cycloalkanone 22 under neutral conditions (methanol, reflux) gave a mixture of isomers 23 and 24, whereas the reaction of the pyridyl hydrazine 25 was shown to give exclusively 26. 

The triethylamine-induced reaction of benzohydroximinoyl chlorides, precursors of nitrile oxides, with P-trifluoromethyl-substituted acetylenic esters gives rise to three products 5-trifluoromethyl-4-isoxazolecarboxylates, 213 (R1 =CF3,... 

No major developments in the area have been reported recently. Wu et al. have described a novel application of the ring closure reaction to pyrazolo[5,l -d l, 2,3,5]tctrazine-4(3//)-ones for trifluoromethyl substituted derivatives <2006JFC409>. The transformations were found to proceed in high yields (70-95%). 

When reacted with trialkyl phosphite in benzene for 1 hr, dialkyl magnates (364, X = F) gave a mixture of amino(trifluoromethyl)methylene-malonates (365) (20% yields), dialkyl trifluoromethyl(substituted amino)-methylenemalonates (366) (40-45% yields), and dialkyl chlorophosphate (-20%) (86ZOB805). The reactions of dialkyl malonates (364, X = F, Cl) and triphenylphosphine in the presence of triethylamine in diethyl ether for 1 hr gave trihalomethyl(substituted amino)methylenemalonates (367) in 87-95% yields. The treatment of a solution of dialkyl trifluoromethyl-(substituted amino)methylenemalonates (366, R1 = Et) in benzene with aqueous hydrochloric acid gave amino(trifluoromethyl)methylene-malonates (368) in 82-84% yields (86ZOB805) (Scheme 32). 

As part of ongoing research into the behavior of (vinylcarbene)iron complexes,119120 Mitsudo and Watanabe found that the trifluoromethyl-substituted vinylcarbene 174 exhibited a reactivity different from that of both 166 and 169.107 Upon treatment of the complex 174 with triphenylphos-phine the vinylketene complex 175 is formed, a reaction identical to that seen in the series of vinylcarbene complexes 166 (R = H). However, when the vinylcarbene 174 is exposed to a high pressure of carbon monoxide, it is converted cleanly to the ferracyclopentenone 176. Remember that when the vinylcarbene complex 166 (R = H) was treated in the same manner, conversion stopped at the vinylketene complex 167 Even when exposed to a pressure of 80 atmospheres of CO(g), no further reaction was seen to occur. An electron donating ligand (L = PR3) is required for conversion to cyclopentenone structure 168. Conversely, when the more electron-rich vinylcarbene 169 is exposed to carbon monoxide in the same manner, the pyrone complex 172 is formed. 

There is another substitution reaction, not involving transition-metal complexes, namely, reaction of trifluoromethyl bromide with sulphur dioxide anion radicals (165) (Andrieux et al., 1990a) (this is an interesting route... 

From the investigation of all these data it is clear that the aromaticity of phosphinine is nearly equal to that of benzene. Their chemical reactivity, however, is different. Most important is the effect of the in-plane phosphorus lone pair, which (i) is able to form a complex and (ii) can be attacked by electrophiles to form A -phosphinines. Thus, electrophilic substitution reaction on the ring carbon is impossible. In Diels—Alder reactions, phosphinines behave as dienes, providing similar products to benzene but under less forcing condition (the reaction with bis(trifluoromethyl) acetylene takes place at 100 °C with 3, while for benzene 200 °C is required). 

Reaction of 3-trifluoromethyl-substituted 1,2-oxazine 5 with lithium diisopropylamide (LDA) resulted in smooth deprotonation at C-4 and allowed subsequent alkylation with various electrophiles. Reaction of 5 with Mel furnished the 4-methyl-l,2-oxazine 54 in good yield and with excellent r-diastereoselectivity, whereas carbonyl compounds could not be employed successfully as electrophiles <1996JFC( 80)21 1 reatment of 3,4,6-trisubstituted l,2"Oxazine... 

The fluoro substituents proved to induce changes in the reactivities of the methyl- (X = H) and trifluoromethyl-substituted (X = F) pyrido[3, 2 4,5]furo[3,2- [l,3]oxazin-4(47r)-ones 105 with nucleophiles. When methyl-substituted compounds 105 (X = H) were reacted with piperidine in toluene, Wacetylamino carboxamides 106 were formed by nucleophilic attack at the carbonyl group of the l,3-oxazin-4-one ring (Scheme 16). However, the similar reactions of the trifluoromethyl-substituted analogs 105 (X = F) resulted in formation of amidino carboxylic acids 107 by attack at electron-poor position 2 <1995JFC(74)1>. 

In accordance with expectations, the isolable trifluoromethyl substituted ketene imines (186-188) were found to react readily with nucleophilic agents. In the case of 186, the reaction with methanol and aniline led to lactim ether 187a and amidine 187b, respectively (137). 

Trifluoromethyl-substituted pyrazoles are easily obtained using trifluoromethyl-alkynes as dipolarophiles (Table 8.2, entry 9). Thus, treatment of 4,4,4-trifluorobut-2-ynoic acid with excess diazomethane gave methyl 4-(trifluoromethyl)pyrazole-4-carboxylate (45%) accompanied by its N - (32%) and -methylated (6.5%) derivatives (267). Another convenient route to CF3-substituted pyrazoles involves dipolar cycloaddition of appropriately CF3-substituted alkenes followed by eliminative aromatization (76,77,268). For example, the reaction of alkenes such as (CF3)2C=C(H)COAr with ethyl diazoacetate gave 4-aroyl-5-trifluoromethylpyra-zole-3-carboxylates (268). 

Adamantanecarboxylic acids with a carboxylic group at a bridgehead position, e.g. adaman-tane-1-carboxylic acid (8),111 react with sulfur tetrafluoride in the conventional way giving high yields of the corresponding trifluoromethyl-substituted adamantanes. l-(Trifluoromethyl)-adamantane (9) can also be formed in one step from adamantane by treatment with a mixture of sulfur tetrafluoride, hydrogen fluoride and formic acid the latter serves as a source of carbon monoxide. The reaction is believed to proceed via carbonylation of an intermediate carbocat-... 

In substitution reactions of the carbonyl oxygen, boron trifluoride has been used as a reagent. 4-Fluorobenzoyl chloride (5) can be converted to the corresponding fluoride 6 in addition to remarkable amounts of l-fluoro-4-(trifluoromethyl)benzene (7),10 however, this conversion does not appear to be generally useful. 

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