1 , 2-Bis ( phenylsulfonyl )-1 H-indole as an acceptor of organocuprate nucleophiles

1,2-Bis(phenylsulfonyl)-1H-indole is a novel example of an electron-deficient indole that undergoes nucleophilic attack at C-3. Though a variety of other organometallic nucleophiles fail to engender nucleophilic substitution, organocuprates produce 3-substituted 2-(phenylsulfonyl)1H-indoles. These reactions contribute to the growing number of examples of nucleophilic addition to the indole core.


Introduction
While the electron-rich indole is typically reactive towards electrophilic reagents, electrondeficient indoles allow access to the divergent utility of nucleophiles. 1 Indeed, several electronwithdrawing functionalities permit nucleophilic addition to the indole nucleus, with recent examples favoring the use of nitro groups. 2 In most cases, the presence of a leaving group is necessary for this reactivity, resulting in a formal S N 2' or addition-elimination mechanism to give the substituted indole.Nucleophilic substitution at C-3 is especially appealing because these transformations are almost entirely contrary to the traditional reactivity of indole.To effect C-H substitution, leaving groups may be placed at N-1 as discussed in the review by Joule. 3 Early examples employed 1-hydroxy-and 1-methoxy-substituted indoles to enable substitution, while more recent techniques have favored the phenylsulfonyl group. 2,4The phenylsulfonyl group is a versatile moiety capable of acting as a powerful electron-withdrawing group, direct-metalation group, and leaving group. 5Noting these advantages, we investigated 1,2-bis(phenylsulfonyl)-1Hindole 1 as an electron-deficient indole capable of undergoing nucleophilic substitution at C-3.As an initial comparison, the addition of lithium dimethylcuprate to 1 produced favorable yields (67% vs. 31%) of 3-methylated product.To verify the structure of 6a, Na(Hg) was employed to reductively cleave the sulfonyl moiety, producing skatole; this transformation highlights an additional advantage of the C-2 phenylsulfonyl group.

Results and Discussion
With preliminary results in hand, we screened various sources of organometallic methyl nucleophiles.Grignard and organozinc reagents offered no reaction and allowed clean recovery of starting material.Methyllithium showed a slight inclination towards C-3 nucleophilic attack, but produced a mixture of other products as well as starting material.Gilman reagents were generated from methyllithium and copper bromide dimethylsulfide complex. 7While these cuprates readily produced 6a as the major product at -78 °C, reactions at higher temperatures were less consistent and favored sulfone 7a.Formation of 7a is presumed to result from attack on the N-protecting phenylsulfonyl group.However, the corresponding unprotected 3-methyl-2-(phenylsulfonyl)-1H-indole was never isolated under these reaction conditions.Reaction time beyond 2 hours did not significantly increase yields of either product.Following the success of lithium dimethylcuprate, we examined a series of Gilman reagents to determine the generality of this reaction.While the n-butyl derivative gave results in line with our previous reactions, the other cuprates showed varied selectivity.The structure, reactivity, and stability of organocuprates can be expected to vary as a function of solvent, temperature, counter ion, as well as alkyl ligand. 8In this case, the results from Table 2 suggest a sensitivity to the structure or dynamics of the copper complex, rather than a steric effect.As sulfone formation presumably cannibalizes the yield of these processes, the more hindered and less labile 'isitylsulfonyl' protecting group was examined (isityl = 2',4',6'triisopropylphenyl).1-(Isitylsulfonyl)-2-(phenylsulfonyl)-1H-indole 9 was produced in the same manner as 1 (Scheme 3).

Experimental Section
General.A Varian XL-300 Fourier transform NMR spectrometer was used to record 1 H and 13 C NMR spectra.Chemical shifts (δ) are reported using the solvent's residual proton or carbon signal (CDCl 3 : δ H 7.27, δ C 77.23) as an internal reference.Melting points were determined using open capillary tubes with a Laboratory Devices Mel Temp.High-resolution mass spectrometry (HRMS) was performed at the University of Illinois (Urbana-Champaign) mass spectrometry laboratory.Tetrahydrofuran (THF) and diethyl ether were dried over alumina columns as described by Grubbs. 9All alkyllithium reagents were purchased from either Aldrich or Acros, and were titrated with 3,5-dimethoxybenzyl alcohol in dilute THF prior to use.

Table 1 .
Addition of organometallic methyl nucleophiles to 1

Table 2 .
Nucleophilic addition of lithium dialkyl cuprates to 1 Conclusions1,2-Bis(phenylsulfonyl)-1H-indole 1 has provided new examples of nucleophilic attack on the indole nucleus.Organocuprates effect C-H substitution at C-3 by an addition-elimination mechanism via expulsion of phenylsulfinate.Though the selectivity of cuprate addition varies by alkyl ligand, side product formation can be blocked by the use of a highly hindered isitylsulfonyl protecting group.