Angewandte
Communications
Chemie
Indoles bearing electron-donating substituents including
methyl and methoxy at the C3, C5, and C6 positions
underwent facile phosphonylation affording the correspond-
ing products 3b, 3e, 3 f, 3n, and 3o in 60–80% yields, where
methoxy functional group at C5 enhanced the regioselectivity
to 92:8. The halogen-containing motifs were well-tolerated in
the C4-phosphonylation (3h–3j and 3l–3m). Indoles sub-
strates containing electron-deficient substituents such as
ester, cyanomethyl, cyano and trifluoromethyl were con-
verted in 58–73% yields with good C4 selectivity (3c–3d, 3g,
3k, and 3p). Notably, C5-substituted indoles that exert steric
effect to C4 position were also converted in good efficiency.
More importantly, tryptophan (Trp) and Trp-containing
dipeptides reacted smoothly at the C4 position, providing
3q and 3r in 78% and 43% yield, respectively.
Remote reactivity at C6 of an indole has been only
sparingly observed.[10,14,16] Unexpectedly, C6-phosphonylated
indoles 6 were obtained through blocking of the C4 position
under the same standard conditions, albeit with a slightly
lower regioselectivity and conversion (Table 3). Both elec-
Table 3: Scope for the C6-selective phosphonylation.[a]
Scheme 2. Mechanistic experiments.
pound was observed. (Scheme 2a). The radical scavenger 1,1-
diphenylethylene trapped CPO(OEt)2 directly to generate 7 in
47% yield (Scheme 2b). These results showed that the
reaction proceeded via a radical pathway. In addition, the
intermolecular competition experiment indicated that elec-
tron-rich indole substrates reacted preferentially (Scheme S4
in the Supporting Information).
Subsequently, methyl and phenyl functional groups in C7
position did not yield C4-phosphonylated products, and the
only material obtained was the recovered starting materials
(Scheme 2c). These results suggested that the key intermedi-
ate may not be formed with a blocking group in C7 position.
Also, the reaction between 1a and 2a was performed in the
presence of D2O (Scheme S5 in the Supporting Information).
However, no incorporated deuterium was observed at C7
position, presumably because H-atom in C7 was transferred
to the O-atom in Lewis basic phosphinoyl DG in concerted
metalation-deprotonation process (CMD). As expected on
the basis of this hypothesis, 23% [Dn]-1a and 60% [Dn]-3a
were isolated in the presence of CH3COOD (10.0 equiv)
(Scheme 2d). Deuterium was incorporated into the C7
position in significant quantities (23%, 24%), while there
was no deuterium at C2. Also, when [D1]-1a was treated with
2a in the presence of H2O or CH3COOH (10.0 equiv), no
deuterium loss was observed (Scheme 2e). This highlights
that the reaction is most likely not accessed through C2
insertion as observed in Frostꢀs work,[14] but through a C7-
cyclometalation/remote-activation pathway. Furthermore,
intermolecular kinetic experiments with substrates 1a and
[a] Conditions: 5 (0.1 mmol), 2 (3.0 equiv), Pd(OPiv)2 (10 mol%), L1
(20 mol%), (NH4)2SO4 (1.0 equiv), Ag3PO4 (1.5 equiv), and K2S2O8
(2.0 equiv) in MeCN (1 mL), under Ar at 858C for 12 h. Isolated yield.
Values in parentheses indicate the C6:C3 ratios, which were determined
by NMR using CH2Br2 as the internal standard. [b] Using Pd(OAc)2
(10 mol%), L3 (20 mol%).
tron-donating (6a, 6b, 6d, and 6 f) and electron-deficient (6c
and 6e) substituents were converted to the corresponding C6-
phosphonylated products in 30–61% yields. Moreover, differ-
ent P(O)H compounds were well-tolerated, affording the
desired products 6bb–6be in satisfied yields with good C6-
selectivity. Additionally, the 3-methyl-4-methoxy disubsti-
tuted indole was also transformed to the corresponding
product 6 f in 61% yield. And the molecular structure could
be verified by X-ray crystallography of 6a.[15]
Given the unique features of the unprecedented palla-
dium-catalyzed remote C4/C6-H activation, various experi-
ments were conducted to elucidate the reaction mechanism
(Scheme 2). The reaction was completely inhibited when the
radical scavenger TEMPO or BHT was added under the
standard conditions. As expected, the TEMPO-trapped com-
À
[D4]-1a suggested that C H cleavage is not kinetically
relevant (Scheme S8 in the Supporting Information). In
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
ꢀ 2021 Wiley-VCH GmbH
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