Organic Letters
Letter
require stringent control over even very low levels of residual
metals. Thus, we embarked on the development of a metal-free
method for the N-alkylation of indoles that would complement
existing metal-based strategies. Furthermore, we sought a
method that would also be amendable to late-stage alkylation
of functionalized indoles to serve as a convenient method for
bioconjugation of biologically active indole-containing small
molecules relevant to medicinal chemistry efforts and cellular
target identification.
Table 1. Preliminary Substrate Scope Using Fmoc-Protected
Tryptophan and Various Aldehydes
Our approach was inspired from internal development
efforts to selectively alkylate indole 1 in the C3 position toward
a scalable synthetic route to beclabuvir. This tactic takes
advantage of the well-known fact that the most nucleophilic
position in unsubstituted indoles is the C3 position. Using the
21−23
method reported by Appleton,
we were able to alkylate
the C3 position of 1 using cyclohexanone in good yields.
However, a recurring formed impurity was determined to be
bis-alkylated product 3 where concomitant N-alkylation also
24
occurred (Scheme 1). This result suggested to us that with
Indoles Using Et SiH/TFA
3
a
b
c
Isolated via direct crystallization. On a 100 mmol scale. An
additional 0.6 equiv of aldehyde and 0.55 equiv of Et SiH were
3
d
needed to achieve full conversion. Reaction performed in toluene.
optimization, C3-alkylated indoles could serve as viable
substrates for achieving N-alkylation using carbonyl derivatives
Carbazoles performed well in this chemistry, with N-alkylated
3,6-dibromocarbazole 8e being of particular note as it was
alkylated using phenyl glyoxal and can serve as a potential
precursor to analogues of the P7C3 class of neuroprotective
agents. Furthermore, other carbonyl functional groups such
as ketones and amides were tolerated well as exemplified by
indoles 8g and 8h.
under these reductive amination-type conditions (Et SiH/
3
TFA).
Initial efforts to develop a general approach to the N-
alkylation of indoles began using a broad range of aldehydes
along with the methyl ester of Fmoc-protected tryptophan
26
(Fmoc-trp-OMe) 4. The results of these preliminary findings
are highlighted in Table 1. We were gratified to find that the
Several examples highlight the potential of this method
toward biologically relevant applications in medicinal chem-
istry and chemical biology (Scheme 2). For example, aldehyde
5a with a primary tosylate group can successfully N-alkylate
indoles as an electrophilic handle for downstream structure−
activity relationship (SAR) studies (as in 9). Furthermore,
aldehyde 5b with a primary azide could serve as a linker for
bioconjugation via click chemistry for cellular target identi-
fication studies with biologically active indoles. This concept is
demonstrated using Fmoc-protected tryptophan and the indole
core of the antihistamine drug latrepirdine to yield N-alkylated
indoles 10 and 11, respectively. In a related approach, the
direct N-alkylation of the selective serotonin agonist,
zolmitriptan, demonstrates the feasibility of late-stage N-
alkylation of advanced intermediates and APIs as in the case of
indole 12. Finally, starting with the indole fragment from
beclabuvir (1), we demonstrated the sequential one-pot C3-
alkylation/N-alkylation using cyclohexanone followed by p-
tolualdehyde to give bis-alkylated indole 8i in 55% yield.
conditions used to alkylate 1 (1.1 equiv of Et SiH, 5.0 equiv of
3
TFA, DCM, 0 °C) proved to be effective in each case to
provide synthetically useful yields of a diversified pool of N-
alkylated tryptophan derivatives without further optimization.
A particular example to highlight from Table 1 is N-methyl
derivative 6h, where paraformaldehyde was used as the
methylating agent providing a complementary and, in some
cases, a reactive yet safer alternative to traditional methylating
sources (i.e., CH I, dimethyl sulfate, and dimethyl carbo-
3
2
5
nate). In several cases, the N-alkylated products could be
isolated by direct crystallization from the crude reaction
mixture in good yields and purities. Moreover, using toluene in
place of DCM was also successful as in the case of indole 6k.
Finally, the method is readily scalable as 6c was isolated in 86%
yield on a 100 mmol scale.
Next, we turned our attention to diversity within the indole
core using a handful of selected aldehyde substrates. The
results obtained from these efforts are listed in Table 2.
3
234
Org. Lett. 2021, 23, 3233−3236
Clanton, Nicholas A.
