Palladium-catalyzed carbonylative bis(indolyl)methanes synthesis with TFBen as the CO source

Article abstract of DOI:10.1016/j.jcat.2018.03.028

An efficient and convenient palladium-catalyzed carbonylative procedure for the synthesis of bis(indolyl)methanes has been established for the first time. With TFBen (benzene-1,3,5-triyl triformate) as the solid CO source, aryl iodides and indoles were tr

Full text of DOI:10.1016/j.jcat.2018.03.028

Journal of Catalysis 362 (2018) 74–77
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Priority Communication
Palladium-catalyzed carbonylative bis(indolyl)methanes synthesis
with TFBen as the CO source
Xinxin Qi a, Han-Jun Ai a, Ning Zhang a, Jin-Bao Peng a, Jun Ying a, Xiao-Feng Wu a,b,
⇑
a Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China
b Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient palladium-catalyzed carbonylative procedure for the synthesis of bis(indolyl)
methanes has been established for the first time. With TFBen (benzene-1,3,5-triyl triformate) as the solid
CO source, aryl iodides and indoles were transformed into the corresponding bis(indolyl)methane deriva-
Received 20 February 2018
Revised 22 March 2018
Accepted 26 March 2018
tives in moderate to excellent yields
.
Ó 2018 Elsevier Inc. All rights reserved.
Keywords:
Carbonylation
Palladium catalyst
Domino reaction
Indoles
CO surrogate
Indoles represent an important group of N-heterocycles, which
are known to have potent pharmaceutical and biological properties
[1]. Among them, bis(indolyl)methanes (BIMs) are frequently
found in natural products, drugs and biological molecules (Fig. 1)
[2]. These compounds shown a broad biological activities, such as
anticancer, antimicrobial, antifungal, anti-flammatory, and etc
[3]. Due to their wide applications in medicinal chemistry and
functional materials, the synthesis of BIMs have continuously gain-
ing attentions from synthetic chemists and numerous methods
were developed. In general, the most commonly used method for
BIMs preparation rely on the addition of two molecules of indoles
to an aldehyde or ketone [4].
On the other hand, palladium-catalyzed carbonylation reactions
have been proven to be a class of powerful procedures on carbonyl-
containing compounds preparation [5]. During the past decades,
lots of interests have been attracted from synthetic community
and numbers of novel carbonylation processes were accomplished.
Nevertheless, carbon monoxide gas is usually required. Although
CO gas stills the best choice for industrial scale applications, the
gaseous property of CO together with its high toxicity and odorless
characters hindered CO gas-based carbonylations been applied at
the laboratory scales. Hence, efforts have been put in the construc-
tion of CO-free systems and many effective CO surrogates have
been explored [6]. Our group has been attracted by this topic as
well and a series of carbonylation reaction with formic acid as
CO precursor have been estabilished [7]. Meanwhile, benzene-
1,3,5-triyl triformate (TFBen) as a an efficient and non-reacting
CO surrogate was developed in our group as well [8]. Herein, we
wish to report our new results on palladium-catalyzed carbonyla-
tive synthesis of bis(indolyl)methanes from aryl iodides and
indoles. TFBen has been applied as the CO source here, and the cor-
responding bis(indolyl)methane derivatives were isolated in mod-
erate to excellent yields.
Initially, iodobenzene and 1-methyl-1H-indole were chosen as
model substrates. The reaction was conducted in acetonitrile at
80 °C with PdCl2(PPh3)2 as the catalyst and Et3N as the base,
employing formic acid as the CO source and DCC as the activator.
To our delight, 20% yield of desired product was observed (Table 1,
entry 1). The yield of the desired product can be increased to 44%
with DMSO as the solvent (Table 1, entry 2) and toluene can pro-
vided the same rang of yield (Table 1, entry 3), while only trace
amount of the target product was detected with THF as the media
(Table 1, entry 4). Then the reaction temperature was varied. Lower
yield was detected when the temperature was increased to 90 °C
(Table 1, entry 5). 56% Yield of the final product was obtained by
performing the reaction at 70 °C (Table 1, entry 6), and the reaction
efficiency decreased dramatically by further decrease the reaction
temperature to 60 °C (Table 1, entry 7). Notably, the amount of
HCO2H showed significant influence to the reaction, and 72% yield
of the final product can be formed with the addition of 3.5 equiv-
alents of formic acid (Table 1, entry 8). Subsequently, various
⇑
Corresponding author at: Department of Chemistry, Zhejiang Sci-Tech
University, Xiasha Campus, Hangzhou 310018, People’s Republic of China.
https://doi.org/10.1016/j.jcat.2018.03.028
0021-9517/Ó 2018 Elsevier Inc. All rights reserved.

X. Qi et al. / Journal of Catalysis 362 (2018) 74–77
75
such as methoxy, tert-butyl, ethyl, and methyl groups, the corre-
sponding products were obtained in excellent yields (3ab–3ae).
Here, para- and meta-methyl groups on iodobenzene resulted in
higher yield than ortho-methyl group, probably due to the steric
hindrance effect (3ae and 3af vs. 3ag). Those substrates with di-
substitutions, such as 2,4-dimethyl, 3,4-dimethyl groups gave the
final products in very high yields (3ah–3ai). It noteworthy that
electronic properties of the substituents have obvious influence
on the reaction result, and compare to electron-rich groups,
electron-poor groups provided the target products in relatively
lower yields (3aj–3am). Moreover, halogen groups, including
fluoro-, bromo- and chloro-substituents smoothly participated in
the reaction to afford the corresponding products in good yields
(3am–3ap). Naphthyl substrates can be applied as well, and gave
the desired products in moderate yields (3ar–3as). In addition, het-
eroaryl group such as 3-thienyl moiety can also take place to deli-
ver the desired product in 85% yield (3at).
Encouraged by above results, we next turn our attention to
indole moieties (Table 3). 1,2-Methyl-1H-indole was tolerated well
to give the target product in excellent yield (3ba). Notably, when
1,3-methyl-1H-indole was used, no reaction occurred (3ca). This
indicated that the reaction has a very good regioselectivity. Indoles
with other substitution at N atom, such as 1-propyl and 1-
cyclopropylmethyl, can also give the corresponding products in
95% and 65% isolated yields (3da–3ea). Remarkably, NH-free
indoles can be applied as the substrates under identical conditions.
The target products were isolated in excellent yields with perfect
selectivity (3fa–3ia).
In order to get some insight into the reaction mechanism of
this carbonylation process, several control experiments were
conducted (Scheme 1). In the absence of 1-methyl-1H-indole,
41% yield of benzaldehyde can be produced from iodobenzene
under the standard reaction conditions (Eq. (1)). Subsequently,
the reaction between 1-methyl-1H-indole and benzaldehyde
occurs in the presence of formic acid, and gave 66% yield of
the product 3aa (Eq. (2)). These results indicate that benzalde-
hyde act as an important intermediate in this carbonylative pro-
cess. In addition, no product could be detected without formic
acid under standard condition (Eq. 3). Hence we believe formic
acid has several roles in this catalytic system: (1) as proton
source in the reductive carbonylation for aldehyde production;
(2) as promotor for the reaction of the in situ formed aldehydes
and indoles to give the finial products; (3) forms equilibrium
with NH-free indoles to avoid the nucleophilic attack of NH to
acylpalladium intermediate.
Based on these results, the possible reaction mechanism is pro-
posed in Scheme 2. The reaction system can be divided into two
parts: the first part is the reductive carbonylation of aryl iodides
to produce benzaldehydes in situ; the second part is the formic
acid promoted nucleophilic addition of indoles to benzaldehydes
to give the final products. Here it’s also important to mention that
the yields decreasing with electron-withdrawing group substituted
aryl iodides is due to the decreased yields of the corresponding
aldehydes production. And which can be explained by the slowed
carbon monoxide insertion step and also the decreased stability of
the formed benzoyl palladium intermediate, due to the presence of
the electron-withdrawing groups.
Fig. 1. Selected examples of bio-active BIMs derivatives.
ligands were examined. Bidentate phosphine ligands, such as
DPPB, DPPE, DPPP, and Xantphos afford the target product in
67%, 37%, 80% and 5% yields, respectively (Table 1, entries 13–
16). Compare to bidentate phosphine ligands, monodentate phos-
phine ligands showed higher reactivity (Table 1, entries 9–12).
Delightly, P(o-tolyl)3 gave a very good result of 93% (Table 1, entry
11). The screening of palladium precursors showed that PdCl2
(PPh3)2 is the optimal catalyst (Table 1, entries 17–18). Additionally,
only trace amount of the product could be observed when using
acetic anhydride as the activator of formic acid instead of DCC
(Table 1, entry 19). Finally, TFBen as our developed solid CO
surrogate was tested, and 95% yield of the desired product was
formed (Table 1, entry 20). It’s important to mention that the load-
ing of palladium catalyst was varied as well; decreased reaction
efficiency was observed with lower loading of palladium catalyst
(For more details, see supporting information).
With the best reaction conditions in hand, we next studied the
substrate scope on a variety of aryl iodides. The results were sum-
marized in Table 2. Aryl iodides with electron-donating groups,
Table 1
Screening of reaction conditions.a.
Entry
Ligand
Solvent
Temp.
Yield[b]
1
2
3
4
5
6
7
–
–
–
–
–
–
–
–
CH3CN
DMSO
Toluene
THF
80 °C
80 °C
80 °C
80 °C
90 °C
70 °C
60 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
18%
44%
40%
trace
25%
56%
30%
72%
48%
83%
93%
89%
67%
37%
80%
5%
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
8[c]
9[c]
10[c]
11[c]
12[c]
13[c]
14[c]
15[c]
16[c]
17[d]
18[e]
19[f]
20[g]
PCy3
P(o-anisyl)3
P(o-tolyl)3
PPh3
DPPB
DPPE
DPPP
Xantphos
P(o-tolyl)3
P(o-tolyl)3
P(o-tolyl)3
P(o-tolyl)3
57%
9%
trace
95%
In conclusion, an interesting palladium-catalyzed carbonyla-
tive synthesis of bis(indolyl)methanes from aryl iodides and
indoles has been established. With TFBen as the CO source, a
wide range of bis(indolyl)methanes have been prepared in mod-
erate to excellent yields. In addition to the broad scope of aryl
iodides, both N-substituted and NH-free indoles can be applied
without any problem. The several roles of formic acid have been
explained as well.
a
Reaction conditions: iodobenzene (1.2 mmol), 1-methyl-1H-indole (1.0 mmol),
PdCl2(PPh3)2 (0.1 mmol), ligand (0.1 mmol for monodentate ligand; 0.05 mmol for
bidentate ligand), Et3N (1.0 mmol), HCO2H (2.5 mmol), DCC (2.0 mmol), solvent
(2.0 mL), 24 h. [b] Yield were determined by 1H NMR with CH3NO2 as the internal
standard. [c] HCO2H (3.5 mmol). [d] PdCl2. [e] Pd(OAc)2. [f] HCO2H (3.5 mmol),
acetic anhydride (2.0 mmol), Et3N (5.0 mmol). [g] HCO2H (1.5 mmol), TFBen
(0.5 mmol).

76
X. Qi et al. / Journal of Catalysis 362 (2018) 74–77
Table 2
Table 3
Substrate scope on aryl iodides.a.
Substrate scope on indoles.a.
a
Reaction conditions: iodobenzene (1.2 mmol), indoles (1.0 mmol), PdCl2(PPh3)2
(10 mol%), P(o-tolyl)3 (10 mol%), Et3N (1.0 mmol), HCO2H (1.5 mmol), TFBen
(0.5 mmol), DMSO (2.0 mL), 24 h. isolated yield.
a
Reaction conditions: aryl iodides (1.2 mmol), 1-methylindole (1.0 mmol),
PdCl2(PPh3)2 (0.1 mmol), P(o-tolyl)3 (0.1 mmol), Et3N (1.0 mmol), HCO2H (1.5
mmol), TFBen (0.5 mmol), DMSO (2.0 mL), 24 h, isolated yield.
Scheme 1. Control experiments.

X. Qi et al. / Journal of Catalysis 362 (2018) 74–77
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