Pd/C-catalyzed cyclizative cross-coupling of two ortho-alkynylanilines under aerobic conditions: Synthesis of 2,3′-bisindoles

Article abstract of DOI:10.1002/chem.201501020

Abstract A palladium-catalyzed cyclizative cross-coupling of two o-alkynylanilines to 2,3′-bisindoles under aerobic oxidative conditions was developed. Mechanistic studies suggested that the two catalytic cycles, namely the formation of 3-alkynylindoles 8

Full text of DOI:10.1002/chem.201501020

DOI: 10.1002/chem.201501020
Communication
&
Palladium Catalysis
Pd/C-Catalyzed Cyclizative Cross-Coupling of Two ortho-
Alkynylanilines under Aerobic Conditions:
Synthesis of 2,3’-Bisindoles
Bo Yao, Qian Wang, and Jieping Zhu*[a]
Abstract: A palladium-catalyzed cyclizative cross-coupling
of two o-alkynylanilines to 2,3’-bisindoles under aerobic
oxidative conditions was developed. Mechanistic studies
suggested that the two catalytic cycles, namely the forma-
tion of 3-alkynylindoles 8 and their subsequent cyclization
to bisindoles 5, are temporally separated. The aminopalla-
dation of 3-alkynylindoles 8 occurred only after all the
N,N-dialkyl-o-alkynylanilines were consumed. The solid
support (activated charcoal) played a crucial role in the
second intramolecular aminopalladation process.
Bisindoles are important structural motifs found in bioactive
natural products,[1] pharmaceuticals,[2] and functional materi-
als.[3] Different synthetic methodologies including Pd-catalyzed
cross-coupling of two appropriate functionalized indoles,[4]
double cyclization of 1,4-di-(o-aminophenyl)-1,3-diynes,[5]
homo-dimerization of indoles,[6] and cyclizative homo-dimeriza-
tion of o-alkynylanilines 1 to bisindoles 2 ([Eq. (1)], Scheme 1)[7]
have been developed.[8] Except for the cross-coupling method-
ology, most of the one-step protocols allow access to 3,3’- and
2,2’-bisindoles rather than the 2,3’-bisindoles. Synthesis of un-
symmetrical 2,3’-bisindoles directly from two different linear
starting materials has, to the best of our knowledge, never
been reported.
Palladium-catalyzed cyclization of N,N-dimethyl o-alkynylani-
lines is an efficient strategy for the synthesis of indoles.[9]
Scheme 1. Strategies for the synthesis of bisindoles.
Taking advantage of their high propensity to undergo Pd-cata-
lyzed oxidative cyclization under aerobic conditions, we have
recently reported a cross-cyclizative dimerization between o-al-
kynylanilines and o-alkynylbenzamides for the synthesis of bis-
heterocycles tethered by a double bond.[10,11] As a continuation
of this work, we report herein the synthesis of 2,3’-bisindoles
by a cyclizative cross-coupling of two o-alkynylaniline deriva-
tives 3 and 4 ([Eq. (2)], Scheme 1). The underlying principle is
shown in Scheme 1. Selective aminopalladation of 3 would
afford the s-indolylpalladium(II) intermediate 6 that upon
ligand exchange would provide 7. Reductive elimination fol-
lowed by N-demethylation would then furnish 3-alkynylindole
8 and Pd8.[12] Oxidation of Pd8 to PdII followed by a second
aminopalladation would afford 9 that upon proto-demetalla-
tion, was expected to deliver the 2,3’-bisindole 5. To ensure
the smooth occurrence of the desired domino process, the fol-
lowing competitive reaction pathways needed to be circum-
vented: a) the protonation and dimerization of intermediate 6;
b) the sequence initiated by PdII-catalyzed aminopalladation of
alkynes 4; c) Glaser type oxidative dimerization of terminal
alkyne 4,[13] and d) the dimerization of intermediate 9.
The reaction between N,N-dimethyl-2-(p-tolylethynyl)aniline
(3a; 1.0 equiv) and o-ethynylanline derivative 4 (2.0 equiv)
with different N-protecting groups was first examined to find
the best-matched reaction partners. Under our previous opti-
mized conditions [Pd(OAc)2 (0.05 equiv), nBu4NI (1.0 equiv),
HOAc (1.0 equiv), DMSO, air, 808C], reaction of 3a with 4a
[a] Dr. B. Yao, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: Jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
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(R1 =R2 =H) provided the desired bisindole 5a in about 40%
yield (based on NMR spectroscopy). On the other hand, reac-
tion of 4b (R1 =Me, R2 =H) or 4c (R1 =Bn, R2 =H) with 3a af-
forded a complex reaction mixture.[14] The most promising
result was obtained by reaction of 3a with 4d (R1 =Ac, R2 =H)
affording bisindole 5b in 43% isolated yield. Therefore, the re-
action between 3a and 4d was chosen for further survey of
the reaction conditions (Table 1). The key results are summar-
scope of o-alkynylanilines 3, both aromatic and aliphatic sub-
stituents attached on the Csp carbon atom (R5 =aryl or alkyl)
were well tolerated. The reaction was insensitive to the elec-
tronic properties of the aniline moieties of the two starting
materials. When N-methyl-N-alkylanilines 3 (R4 =alkyl) were
used as substrates, the reaction delivered the N-demethylated
bisindoles selectively (5ab, 5ac). Finally, a variety of functional
groups including fluoride, chloride, bromide, hydroxyl, amide,
and ester were compatible with the reaction conditions to pro-
vide bisindoles with a handle for further transformations.
The indolyl N-protecting groups can be removed under stan-
dard conditions (Scheme 2). Hydrolysis of the N-acetyl bisin-
Table 1. Survey of conditions for the cyclizative cross-coupling reaction.
Entry Pd [equiv]
Additive [equiv] Time [h] Yield [%] (ratio)[b]
1
2
3
4
5
6
7
8
Pd(OAc)2 (0.025)
nBu4NI (0.25)
nBu4NBr (0.25)
nBu4NI (0.25)
nBu4NBr (0.25)
nBu4NBr (0.5)
LiBr (1.0)
KBr (0.5)
nBu4NCl (0.5)
nBu4NBr (0.5)
24
33
52
26
23
44
44
24
21
21
21
59 (2.5:1)
–
Pd(OAc)2 (0.05)
Pd/C (0.025)
Pd/C (0.025)
Pd/C (0.025)
Pd/C (0.05)
Pd/C (0.025)
Pd/C (0.025)
[Na2PdCl4] (0.05)
41 (2:1)
69 (3:1)
77 (5:1)[c]
67 (5:1)
72 (4:1)
n.d.[d]
31 (0.8:1)
40 (1: 1)
50 (1:1)
9
10
11
[Pd(PPh3)2Cl2] (0.05) nBu4NBr (0.5)
[Pd2(dba)3] (0.025) nBu4NBr (0.5)
[a] Conditions: 3a (0.05 mmol), 4d (0.15 mmol), Pd catalyst, additive,
HOAc (1.0 equiv), DMSO (0.5 mL), air (1 atm), 808C, 700 rpm. [b] NMR
yields of 5b and ratios of 5b to 2b (in parentheses) were calculated
based on 1H NMR spectra using CH2Br2 as the internal standard. [c] 70%
isolated yield of 5b. [d] 5b was not detected.
ized as follows: a) nBu4NI was a better additive than nBu4NBr
when Pd(OAc)2 was used as a catalyst (Table 1, entries 1 vs. 2);
b) Pd/C was an excellent pre-catalyst and interestingly,
nBu4NBr was a better additive (Table 1, entry 4) than nBu4NI
(Table 1, entry 3) in this case. LiBr and KBr were also effective
additives (Table 1, entries 6, 7), while addition of nBu4NCl com-
pletely inhibited the desired transformation (Table 1,
entry 8);[15] c) other PdII (Table 1, entries 9, 10) and Pd8 species
(Table 1, entry 11) can also catalyze the reaction, albeit with re-
duced catalytic efficiency relative to Pd/C. Overall, the opti-
mized conditions consisted of heating a DMSO (c=0.1m) solu-
tion of 3a (0.05 mmol) and 4d (3.0 equiv) in the presence of
Pd/C (0.025 equiv, 10 wt% on activated charcoal), nBu4NBr
(0.5 equiv), and HOAc (1.0 equiv) at 808C under air (sealed
tube). Under these reaction conditions, the cyclizative cross-
coupling product 5b was isolated in 70% yield together with
2b, a homo-dimer of 3a, in 14% yield (5b/2b=5:1). We note
that there are only a few examples of using Pd/C as a pre-cata-
lyst for PdII-catalyzed oxidative transformations.[16]
Scheme 2. Selective N-deprotection of bisindoles 5.
dole 5b under basic conditions delivered 2,3’-bisindole 5a in
86% yield,[17] while cleavage of the N-Boc-bisindole 5o under
acidic conditions gave 5a in 89% yield.[18] The N-methoxycar-
bonylethyl protecting group in 5ac was selectively removed
under basic conditions through a retro-Michael reaction to
afford 10 in 66% yield.[19]
There are two catalytic cycles according to our working hy-
pothesis: formation of 3-alkynylindoles 8 and their subsequent
conversion to bisindoles 5 (see Scheme 1). To gain mechanistic
insights on this novel transformation, the reaction between 3a
and 4d was carefully monitored. As shown in Figure 1, cycliza-
tive alkynylation of 3a with 4d took place rapidly to deliver 3-
alkynylindole 8b. Only after the total consumption of aniline
3a (6 h) was the cyclization of 8b initiated to afford, after an-
other 16 h, the bisindole 5b. This kinetic data clearly suggest-
ed a temporal separation of the two catalytic cycles.[20] The
aminopalladation of N,N-dimethyl-2-(p-tolylethynyl)aniline (3a)
is apparently much faster than that of the acetanilide 8b due
presumably to the higher nucleophilicity of the aniline nitro-
gen.[21] We note here that in DMSO, acetic acid is not acidic
With the optimum conditions in hand, the scope of the reac-
tion was next examined (Table 2). These conditions were appli-
cable not only to N-acetyl-o-ethynylanilines, but also to N-ben-
zoyl- (5n) and N-Boc-o-ethynylanilines with N-Boc-o-ethynylani-
lines being in general the best substrates. With respect to the
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Table 2. Scope of cyclizative cross-coupling between o-alkynylanilines 3 and o-ethynylaniline derivatives 4.[a,b]
[a] Reaction conditions: 3 (0.05 mmol), 4 (0.15 mmol), Pd/C (0.025 equiv, 1.33 mg, 10 wt% on activated charcoal), nBu4NBr (0.5 equiv, 8.1 mg), HOAc
(1.0 equiv, 2.9 mL) and DMSO (0.5 mL) were heated at 808C under air atmosphere (1 atm) at the stirring speed of 700 rpm. [b] Yields of isolated products.
After 3.5 h, the filtrate showed a conversion and yield of 8b
similar to that of the parallel experiment without filtration.
However, after 23 h, the filtrate delivered 8b (66%) together
with only a trace amount of 5b. These results suggested that
PdII, leached into the solution, can catalyze the reaction be-
tween 3a and 4d leading to 3-alkynylindole 8b, but was ineffi-
cient in catalyzing the aminopalladation of 8b in the absence
of solid support. This last assumption was born out by the fol-
lowing control experiments. In two parallel reactions of 3a
with 4d, the one catalyzed by Pd(OAc)2 and activated charcoal
afforded, after 44 h, the 2,3’-bisindole 5b as the major isolable
Figure 1. Kinetic profile for the reaction of 3a with 4d.
product in 30% yield, while the other one catalyzed by
Pd(OAc)2 alone afforded only a trace amount of 5b.
enough to protonate the N,N-dimethylaniline.[22] The role of
the solid support in the reaction was next explored by hot fil-
tration experiments.[23] The reaction mixture of 3a with 4d at
28% conversion (23% yield of 8b) was filtered through a short
pad of Celite and the evolution of the filtrate was monitored.
In conclusion, we developed a novel palladium-catalyzed cy-
clizative cross-coupling reaction between two different o-alky-
nylanilines under aerobic oxidative conditions for the synthesis
of unsymmetrical 2,3’-bisindoles. Mechanistic studies suggest-
ed that the reaction went through cyclizative alkynylation to
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Experimental Section
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General procedure for the synthesis of 2,3’-bisindoles: A vial
(5.0 mL) was charged with 3a (12.8 mg, 0.05 mmol), 4d (23.8 mg,
0.15 mmol), Pd/C (1.33 mg, 2.5 mol%, 10 wt%), nBu4NBr (8.1 mg,
0.5 equiv), acetic acid (2.9 mL, 1.0 equiv), and DMSO (0.5 mL). The
reaction mixture was heated at 808C under air (1 atm). The reac-
tion mixture was quenched with water, and the aqueous phase
was extracted with EtOAc. The combined organic extracts were
washed with brine, dried over sodium sulfate, filtered, and concen-
trated in vacuo. The crude product was purified by flash column
chromatography (silica gel, petroleum ether/dichloromethane=
2/1) to give the desired product 5b as a foam (13.7 mg, 70%
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1
yield). H NMR (400 MHz, CDCl3): d=8.40 (d, J=8.2 Hz, 1H), 7.52–
7.49 (m, 1H), 7.36–7.21 (m, 6H), 7.21–7.10 (m, 3H), 6.56 (s, 1H),
3.73 (s, 3H), 2.44 (s, 3H), 2.36 (s, 3H), 2.06 ppm (s, 3H); 13C NMR
(101 MHz, CDCl3): d=171.6, 139.8, 138.6, 137.4, 135.8, 133.2, 130.6,
130.1, 129.6, 129.5, 128.7, 127.9, 124.5 (two carbons overlapped),
123.4, 120.0, 119.0, 116.6, 113.2, 109.7, 106.8, 31.6, 26.0, 21.6,
~
21.5 ppm; ATR-IR: n=1699 (w), 1450 (w), 1366 (m), 1302 (m), 908
(w), 823 (w), 794 (w), 730 cmÀ1 (s); HRMS (ESI) calcd for C27H25N2O+
[M+H]+ 393.1961; found 393.1947.
Acknowledgement
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Keywords: aerobic oxidative conditions
·
bisindoles
·
cyclizative cross-coupling · o-alkynylaniline · palladium
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Published online on && &&, 0000
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COMMUNICATION
&
Palladium Catalysis
B. Yao, Q. Wang, J. Zhu*
&& – &&
Pd/C-Catalyzed Cyclizative Cross-
Coupling of Two ortho-Alkynylanilines
under Aerobic Conditions: Synthesis
of 2,3’-Bisindoles
Good to excellent yields of the 2,3’-bi-
sindoles 3 were obtained, through the
formation of three chemical bonds (two
CÀN, one CÀC), in the Pd-catalyzed re-
action of two o-alkynylanilines 1 and 2
under mild aerobic conditions. Mecha-
nistic studies suggested that the two
catalytic cycles leading to two indole
rings were temporally separated. The
aminopalladation of 3-alkynylindoles,
the product of the first catalytic cycle
occurred only after all the N,N-dialkyl-o-
alkynylanilines 1 were consumed. This
work represents a rare example in
which Pd/C was used as a pre-catalyst
for the PdII-catalyzed oxidative transfor-
mations.
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