The homologation of carbonyl compounds by single carbon insertion reactions

This short review describes the methods of single carbon insertion reactions into carbonyl compounds.


Introduction
Carbon chain extension or ring expansion of carbonyl compounds by one-carbon unit is a frequently encountered synthetic objective.Carbon insertion reactions are the most straightforward and most commonly used strategy for this purpose.Classical insertion reactions utilizing diazo compounds are known for diazoalkanes as well as functionalized diazo compounds such as ethyl diazoacetate etc. (Scheme 1(i)).1a-j However, the use of diazo compounds is not usually possible on the large scale and many attempts have been made to find other insertion methods avoiding diazo compounds.

Single carbon insertion via β-oxido carbenoid intermediates
The Yamamoto method is presented in more detail in Scheme 2. This approach depends crucially on the generation in situ of dibromomethyllithium from methylene bromide and its addition to carbonyl compounds in the presence of lithium dialkylamide.Depending on the structure of the ketone the dibromomethyllithium carbonyl adduct may rapidly form the corresponding epoxide; to avoid this the reaction should be performed between -70 °C and -100°C.Although the dibromomethyllithium carbonyl adducts are extremely thermally unstable, several one-carbon homologated cyclic ketones were synthesized in high yields by this method (Scheme 2).

Scheme 2
The modification by Satoh and Yamakawa 3a-c of this method for the one-carbon homologation of carbonyl compounds is based on the rearrangement of β-oxido carbenoids 4 generated via ligand exchange of the sulfinyl group of α-chloro β-hydroxy sulfoxide 3 with t-BuLi to give homologated ketones 5 (Scheme 3): Table 1 shows examples where selective migration occurs to form a single regioisomer.Most insertions into cyclic ketones and aromatic or aliphatic aldehydes are regioselective with formation of single regioisomers; however, insertions into aryl-alkyl ketones lead to both aryl-and alkyl-migration.Recently, Satoh and Miyashita reported one-carbon homologations of cyclic ketones by treatment of adducts 2 derived from the 1-chloroalkyl sulfoxides 1 with t-BuMgCl or LDA followed by reaction with i-PrMgCl.Then the enolate intermediates 7 generated in situ from the rearrangement of 6 were trapped with an electrophile to give the α,α-disubstituted homologated ketones 8 (Scheme 4) (Table 2).3a

Single carbon insertion via α-lithioalkyl sulfone intermediates
Trost introduced a useful insertion methodology by reaction of α-lithioalkyl sulfones 10 with ketones 9 to form intermediates 11 followed by aluminium-based Lewis acid-induced ring expansion to α-phenylthio and α-methoxy ketones 12 as shown in Scheme 5 and Table 3 (entries  1 and 2).Published examples of this approach have all concerned cyclic or bicyclic ketones and α-thio or α-alkoxy sulfones.

4b,c
Later, Trost's sulfone homologation procedure for the transformation of ketones 9 into their higher homologues 12 was extended by Taylor to aryl-alkyl ketones, dialkyl ketones and novel cycloalkanones utilizing ZrCl 4 promoted conditions in the rearrangement step (Scheme 5 and Table 3; entries 3 and 4).
α-Lithioalkyl aryl sulfoxides and selenoxides are effective reagents for the ring expansion of a variety of cyclobutanones to cyclopentanones.4d Intermediates 15 produced from 14 and cyclobutanones 13 undergo rapid ring expansion upon treatment with potassium hydride to give 16 in good yields (Scheme 6 and Table 4).Using 14 the carbon atom inserted into the cyclobutanone can be unsubstituted, monosubstituted, or disubstituted.4d

General overview of benzotriazole-mediated single carbon insertion
Benzotriazole derivatives 17 may also be used in one-carbon homologation as shown in Scheme 7. 5a-d Carbonyl compounds that can be utilized as starting materials include aliphatic, aromatic aldehydes and many types of ketones (Table 5).Monosubstituted benzotriazolylmethanes 17, which can be successfully inserted include 1-(arylmethyl)-, 1-(heteroarylmethyl)-, 1-(alkenylmethyl)-, 1-(alkoxymethyl)-, and 1-[(phenylthio)methyl]-benzotriazoles, which allow the preparation of wide variety of α-functionalized ketones.The generality of our methodology is also exemplified by successful insertions of disubstituted methylene groups into carbonyl compounds when disubstituted reagents of type Bt-CHXY are utilized.Insertion into ketones can be performed by use of our procedure in a simple one-step operation.The lithium alcoholate 18 generated from 17 and a ketone undergoes a subsequent rearrangement catalyzed by zinc bromide to give the homologated ketones 19.An alternative two-step procedure includes the formation of benzotriazolyl alcohols 20, which undergo rearrangement via their lithium alcoholates 18 to give 19 (Scheme 7).

Bt-mediated insertion with C-linked substituents on the carbon atom α to Bt
A large variety of C-linked substituents can be carried by the carbon atom that is inserted next to carbonyl group.As shown in Scheme 7 and Table 6 these include vinyl groups, aryl groups and heteroaryl groups.Insertion of aryl-linked 6a,b and vinyl-linked 6c carbons into carbonyl compounds has previously been achieved by direct insertion of the corresponding diazo compounds, but, this procedure is limited by low regioselectivity and handling difficulties.An advantage of the benzotriazole-mediated methodology is the possibility of introducing a heteroaryl group attached to the inserted carbon; the 1-methyl-1H-indol-3-yl and 5-methylthiophene-2-yl groups, for example, were introduced in this way.5a-c

Bt-mediated insertion with Het-linked substituents on the carbon atom α to Bt
Similarly, a whole variety of heteroatom-linked substituents can be carried by the inserted carbon atom.As shown in Scheme 7 and Table 7 this can include various O-linked, S-linked and Nlinked groups.

Insertion with C-and Het-linked substituents on the carbon α to Bt
It is possible to insert a carbon atom carrying two substituents with a reagent of type 21 (Scheme 8).In these examples one substituent is an alkyl or aryl group and the other is an O-linked, Slinked or N-linked group.Examples of such insertion reactions to aromatic aldehydes and cyclic ketones to give higher homologues 22 are shown in Scheme 8 and Table 8.

Examples of bis-Bt insertion
One example missing from the above is the insertion of carbon carrying a single alkyl group.This is not easy using an alkylbenzotriazole because the acidity of the α-hydrogen is low and yields are poor.However, this limitation has been overcome by using (alkylidene)bisbenzotriazoles 23 (Scheme 9, Table 9).5d Insertion here gives the expected intermediate 24 containing two benzotriazole groups one of which is eliminated during the rearrangement to give ketone 25 and the other one can easily be eliminated by treatment with Zn metal to give functionalized ketone 26.7a Intermediates 25 with an α-benzotriazolyl group are of significant synthetic utility for transformations to diketones, 7b,c or olefins, 7d-g for directed regioselective α-alkylation, 7h and for heterocyclic ring synthesis.7i  Intermediates 30 and 35 can be isolated as corresponding alcohols or directly treated with Lewis acid to give inserted ketones 31 and 36 respectively.This method is valuable for the synthesis of 3-alkyl-3-aryl-2,3-dihydrobenzofuran-2-ones, which are important intermediates for the synthesis of the anti-cancer compound, diazonamide A, 8b,c analgesics 8d and antidepressants.8d

Selectivity in the rearrangement steps
If an unsymmetrical ketone is used as the starting material, then obviously two products 37 and 38 could occur from the rearrangement (Scheme 12).The mechanism of rearrangement was discussed in previous publications, 5a-c and involves zinc bromide-promoted oxirane ring-closurering-opening followed by migration of the group that can best stabilize an electron deficiency (Scheme 12).The selectivity of benzotriazole-mediated insertions is notable.5a-c In most cases, single regioisomers 37 were produced by migration of the R 1 shown in Scheme 12 and Table 10.Similar migration aptitudes were found in other pinacol-type rearrangements H>Ar>Alk; sec-Alk>n-Alk.9a,b To extend the synthetic utility of benzotriazolyl-mediated one carbon insertion, the migratory aptitude of π-electron-rich heterocycles of 2-benzotriazolyl alcohols 40 in the presence of alkyl and aryl groups has been investigated recently.5e It was demonstrated that electron rich heteroaryl groups migrate more easily than the methyl group but less easily than a phenyl group (Scheme 13 and Table 11).

Conclusions
Results compiled and discussed in this short review demonstrate the value of single carboninsertion methods for the homologation of carbonyl compounds in organic synthesis.The benzotriazole-mediated carbon-insertion method described in this review seems to be general, highly regioselective and applicable to most aldehydes and ketones allowing the introduction of a variety of substituents attached to the inserted carbon atom.

Table 6 .
C-linked substituents on the carbon atom α to Bt

Table 7 .
Het-linked substituents on the carbon atom α to Bt

Table 8 .
C-and Het-linked substituents on the carbon atom α to Bt

Table 9 .
Bis-Bt examplesIntramolecular reaction of the carbonyl group of adducts 29 or 34 with a benzotriazole-activated nucleophilic α-carbon to give intermediates 30 or 35 is also possible (Schemes 10 and 11).8a

Table 10 .
Selectivity of migration