α-Metallated ortho-Methylphenyl Isocyanides

The second type of metallated isocyanides, widely used in organic synthesis, are substituted ortho-methylphenyl isocyanides. Ito, Saegusa et al. first achieved the smooth deprotonation of o-methylphenyl isocyanides 78 by means of lithium dialkylamides in diglyme and utilized the thus obtained lithiated isocyanides 79 in versatile syntheses of various substituted indoles (Scheme 20).^[56] When the reaction was carried out in THF or Et2O, the addition of lithium dialkylamide onto the isocyano group became a competing process, decreasing the yield of indoles. An unsubstituted methyl group is lithiated selectively in the presence of a substituted one. o-Methylphenyl isocyanides with R² = H afforded the respective 3-unsubstituted indoles in high yields (82−100%) when lithium diisopropylamide (LDA) was used as a base, whereas for isocyanides substituted at the benzylic positions, lithium 2,2,6,6-tetramethylpiperidide (LiTMP) was the base of choice to provide 3-substituted indoles in good yields (62−95%).

NC:

Scheme 20. Synthesis of indoles via lithiated o-methylphenyl isocyanides 79.^[56]

21

Using an excess of the base (2 equiv.) dramatically improved the yields of indoles which suggest, that the lithiation must be a reversible process. The tricyclic 1,3,4,5-tetrahydrobenz[c,d]indole 82 was obtained when 5,6,7,8-tetrahydronaphthalen-1-yl isocyanide 81 was used as a starting material.

Different sequential reactions including the in situ modification of the o-methylphenyl isocyanides and employing different electrophiles have also been reported by the same authors. Thus, the cyclization of 79 at temperatures below 25 °C followed by trapping of the reaction mixture with various electrophiles such as alkyl halides, acid chlorides trimethylsilyl chloride and epoxides provides N-substituted indoles 85 exclusively in moderate to good yields (Scheme 21).^[56b]

NC:

R¹ Li

N R¹

Li N

Li R¹

N R¹

R²

78 to 25 °C

R²X

79 83 84

85 5282%

R¹ = H, Me

R² = Me, nBu, CH₂CO₂Me, EtC(O), MeOC(O), Me₃Si X = Cl. Br, I

Scheme 21. Synthesis of 1,3-disubstituted indoles 85.^[56b]

Ito, Saegusa et al. reported, that acceptor-substituted o-methylphenyl isocyanidescan be conveniently converted into the corresponding 3-substituted indoles under Cu(I) catalysis (Scheme 22).^{[57, 58]}

NC: N

H Cu₂O

(15 mol%) benzene

80 °C, 2 h 80%

86 87

O O

Scheme 22. Cu2O-catalyzed synthesis of 3-acylindole 87.^[57,58]

22

This method usefully supplements the approach to substituted indoles via lithiated o-methylphenyl isocyanides (vide supra). Thus, in the Cu2O-catalyzed reaction some functional groups, such as keto carbonyl groups are tolerated (3-acylindoles of type 87, for example, could not be prepared by means of benzylic lithiation)^[58] while the base-mediated variant does not require acceptor substituents in the side chain of the aryl isocyanide.^[56] The key intermediate of this process is supposed to be an α-copper-substituted (acylmethyl) phenyl isocyanide, which undergoes an intramolecular insertion of the isocyano group into the newly formed C-Cu bond to provide, after isomerization and protonation, indoles of type 87. The evidences for intermolecular insertions of isocyanides into copper(I) complexes of "active hydrogen" compounds like acetylacetone, malonates and others^[59] support this assumption.

α,α-Disubstituted o-methylphenyl isocyanides of type 88 in turn furnished the respective 3,3-disubstituted-3H-indoles 89 in moderate to high yields (Scheme 23).^[57]

NC: N

Cu₂O (1 mol%) benzene 70 °C, 10 h

4388%

88 89

R¹

EWG EWG

R¹

EWG = CN, CO₂Me R¹ = Me, CH₂Ph, nBu CH₂CO₂Me, CH₂CH=CH₂

Scheme 23. Synthesis of 3,3-disubstituted 3H-indoles 89.^[57]

Various substituted o-methylphenyl isocyanides could be prepared by alkylation of o-(lithiomethyl)phenyl isocyanides with alkyl halides and reactions with other electrophiles, such as epoxides, trimethylsilyl chloride, dimethyl disulfide,^[56b] aldehydes (ketones),^[60] isocyanates and isothiocyanates, respectively.^[61] The corresponding adducts may be involved in subsequent base-promoted or Cu(I)-catalyzed cyclizations to furnish indoles and other benzoannelated heterocycles. Thus, adducts of type 90 of reaction of o-(lithiomethyl)phenyl isocyanide (97) with isocyanates can undergo two types of Cu2O- catalyzed cyclizations providing 3-substituted indoles 91, benzodiazepine-4-ones 92 or both of them depending on the substituents present (Scheme 24), while in a base-mediated cyclization of N-substituted o-(isocyanophenyl)acetamides 90 (and analogous thioacetamides), indoles of type 91 are obtained exclusively.^[61]

23

Scheme 24. Cu2O-catalyzed cyclizations of N-substituted o-isocyanophenylacetamides 90.^[61]

The reaction of o-(lithiomethyl)phenyl isocyanides 79 with aldehydes (ketones) at −78 °C, hydrolysis of the reaction mixture at the same temperature and subsequent Cu₂O-catalyzed cyclization of the respective isocyanoalcohols 93 prepared in this way, furnishes 4,5-dihydro-3,1-benzoxazepines 94 in high overall yields. An analogous cyclization of the adduct 95 of o-(lithiomethyl)phenyl isocyanide (97) with 1-butene epoxide leads to 4H-5,6-dihydro-3,1-benzoxacine 96 in 42% yield (Scheme 25).^[60]

NC

Scheme 25. Synthesis of 4,5-dihydro-3,1-benzoxazepines 94 and 4H-5,6-dihydro-3,1-benzoxacine 96.^[60]

24

Substituted o-methylphenyl isocyanides prepared by functionalization of o-(lithiomethyl)phenyl isocyanide 97 can undergo hydrolysis to provide anilines, and subsequent cyclization of the latter by the reaction with an adjacent keto or ester group provides 2-substituted indoles 99^[58] or 1,3,4,5-tetrahydro-2H-benzazepine-2-ones 101, respectively (Scheme 26).^{[ 62 ]} These representative examples show applications of isocyanides as masked amines.

Scheme 26. Synthesis of indole 99 and cyclic amide 101 from 97.^[58,52]

On the other hand, the adducts of 79 with aldehydes (ketones), isocyanoalcohols of type 93, have been reported to undergo a further Lewis-acid catalyzed rearrangement to N-formylindolines 103 (Scheme 27).^[63]

R²

Scheme 27. Synthesis of N-formylindolines 103 by Lewis-acid catalyzed isomerization of isocyanoalcohol 93.^[63]

25

The reaction is supposed to proceed with initial formation of the dihydro-3,1-benzoxazepines 94 by Lewis acid-catalyzed insertion of the isocyano group into the O-H linkage. This initial product undergoes heterolytic cycloreversion and re-cyclization of the zwitterionic intermediate of type 102 to yield the N-formylindolines 103. Dihydro-3,1-benzoxazepines 94 prepared independently, in turn undergo the same Lewis-acid catalyzed rearrangement to provide 103.^[63]

An interesting precedent of a catalytic C, H-activation on 2,6-dimethylphenyl isocyanide (104) and some other similar aryl isocyanides by ruthenium complexes 106 and 107 leading to indoles 105 has been reported by Jones et al.^{[ 64 ]} along with interesting mechanistic investigations of this transformation.^[64b] Unfortunately, this method implies harsh reaction conditions (140 °C, 94 h) and has only a very limited scope. Moreover, the thermal instability of o-methylphenyl isocyanides as well as (reversible) insertion of isocyanide into the N-H bond of the newly formed indole molecule decreases the yields of final products and prolongs the reaction times.^[64]

NC:

NH cat. 107

(20 mol%) 140 °C, 94 h C₆D₆ 70%

(isolated yield)

Ru P

PMe₂ Me₂P

H

Me2P

R Me₂

106, R = H

107, R = naphthyl

104 105

Scheme 28. A ruthenium-catalyzed formation of 7-methylindole 105.^[64]