Organic Letters
Letter
Excess silver salts are essential for amine-directed C−H
arylation reactions. Gaunt et al. realized the free amine-
directed C−H activation of steric hindered secondary amines
through this strategy.21 Very few free primary amine (NH2)-
directed intramolecular δ-C−H functionalization reactions
have been reported, which are still limited to bulky
amines.20e,22 The nonsteric NH2-directed C−H functionaliza-
tion was less realized23 and needs further investigation. In this
work, we report the nonsteric NH2-directed Pd(II)-catalyzed
intramolecular C(sp2)−H arylation that enables the efficient
synthesis of biologically important 2-aryltryptamines (up to
98% yield) in a regioselective manner via six-membered
cyclopalladated complex using tryptamines as substrates
(Scheme 2A). Of note, tryptamine substrates do not contain
Scheme 1. Routes to C-2 Arylated Tryptamines
Scheme 2. Nonsteric NH2-Directed Pd(II)-Catalyzed
Regioselective Intramolecular Direct C(sp2)−H Arylation
and Further Late-Stage Elaborations
preprotection, prefunctionalization, and deprotection make
this method tedious, thus reducing the synthetic utility. The
Pd(II)-catalyzed direct C−H phenylation reactions of
acetriptine for the synthesis of 2-aryltryptamines were
previously reported by Sames,10 Lavilla,11 and Vincent12
using different aryl coupling reagents. However, these methods
suffer from narrow substrate scope, low yields, the use of
protected substrates, etc. (Scheme 1b). Besides, Wood et al.
realized the synthesis of 2-aryltryptamine derivatives through
Rh(II)-catalyzed cyclopropanation reactions of Boc-protected
tryptamine with diazobenzene (Scheme 1c).13 This protocol
also utilizes protected tryptamine substrate and commercially
unavailable diazobenzene. The drawbacks referenced above
restrict the synthetic practicability of these protocols. Hence,
new protocols enabling the efficient synthesis of 2-aryltrypt-
amine derivatives are highly desirable.
The directing group (DG) assisted C−H activation has
become a promising synthetic strategy for its higher reactivity,
selectivity, and step economy, among which the use of native
substrates without covalently installing external DGs remains
one of the major challenges in directed C−H activation.14
Amines, an important class of functional groups, are frequently
found in pharmaceuticals,15 agrochemicals,16 and materials.17
The amine-derived DG strategy for C−H functionalization was
the most explored approach, involving the installation and
removal of DGs.18a Recently, transient directing groups have
been applied for C−H activation of amine substrates, avoiding
additional steps for DG installation and removal.18b,c Even
some of these approaches can enable reactivity on relatively
unhindered α-secondary, α-primary amines and realize the
more challenging C(sp3)−H functionalization.19 The use of
native amine functionality to promote C−H functionalization
is conceptually the most straightforward approach, as it does
not need any other exogenous DGs.18a However, due to the
formation of stable but unreactive bis-amine Pd(II) complexes,
oxidative degradation through β-hydride elimination, and N-
substitution reactions toward electrophiles, free amines are
challenging substrates for Pd-catalyzed C−H functionaliza-
tion.8,18 Thus, free aliphatic amine-directed C−H functional-
ization reactions are largely limited to bulky amines.20 It is
believed that the bulky groups adjacent to the free amine motif
favor dissociation of bis(amine)-Pd(II) complexes through
steric repulsion, hamper oxidative degradation by blocking the
β-position, and weaken the nucleophilicity of the amine group.
bulky substituents around the amine moiety, and no silver salts
are used. This approach further broadens the substrate scope
of the NH2-directed C−H functionalization and also improves
synthetic efficiency of 2-aryltryptamine. As valuable building
blocks, late-stage elaborations of 2-aryltryptamines were also
performed, affording the complex core scaffolds of natural
products such as aurantioclavine, chimonanthine, and
phalarine (Scheme 2B).
Tryptamine (1a) and p-chloro iodobenzene (2a) were used
as model substrates to optimize the reaction conditions.
Initially, several commonly used bases were screened (Table 1,
entries 1−10). To our satisfaction, compound 3a was obtained
in 65% isolated yield when the reaction was performed in
HFIP at 100 °C using K2CO3 as the base in the presence of 10
mol % Pd(OAc)2 (entry 1). In contrast, other bases gave
compound 3a in lower yields (entries 2−10), indicating that
K2CO3 was the optimal base for this conversion. Replacing
HFIP with other solvents such as DMF, DCE, AcOH, toluene,
and IPA caused significantly decreased yields (entries 11−15).
It has been reported that CO2 could facilitate C−H arylation
and hamper the oxidation of sensitive amine substrates.20c,f
Owing to the high hydrogen bonding donor ability, low
nucleophilicity, and high ionizing power,24 HFIP has been
commonly used in Pd-catalyzed C−H activation. We
speculated that carbonates could be decomposed in the
presence of acidic HFIP under the C−H activation conditions
to release CO2, which prevents oxidation of amine substrates.
Reactions were also performed under a CO2 atmosphere
(entries 1, 7−9), and the corresponding yields were improved
slightly. The effect of the reaction time on the yields was also
B
Org. Lett. XXXX, XXX, XXX−XXX