Chemistry of aminophenols. Part 1: Remarkable additive effect on Sonogashira cross-coupling of 2-carboxamidoaryl triflates and application to novel synthesis of indoles

Article abstract of DOI:10.1016/S0040-4039(01)00965-0

A novel and general synthesis of indoles has been established by utilizing 2-aminophenols as the starting materials. The key step is a modified Pd(0)-Cu(I)-catalyzed cross-coupling of 1-alkynes with 2-carboxamidoaryl triflates in the presence of n-Bu₄NI as the additive. The 2-alkynylanilides obtained were subjected to an alkoxide-mediated cyclization to provide a number of indole containing compounds possessing substituents at the C2, C4, C5, and/or C6 position(s) in good overall yields.

Full text of DOI:10.1016/S0040-4039(01)00965-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5275–5278
Chemistry of aminophenols. Part 1: Remarkable additive effect
on Sonogashira cross-coupling of 2-carboxamidoaryl triflates and
application to novel synthesis of indoles
Wei-Min Dai,* Dian-Shun Guo and Li-Ping Sun
Combinatorial Chemistry Laboratory, The Biotechnology Research Institute and Department of Chemistry,
The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
Received 30 March 2001; accepted 1 June 2001
Abstract—A novel and general synthesis of indoles has been established by utilizing 2-aminophenols as the starting materials. The
key step is a modified Pd(0)–Cu(I)-catalyzed cross-coupling of 1-alkynes with 2-carboxamidoaryl triflates in the presence of
n-Bu4NI as the additive. The 2-alkynylanilides obtained were subjected to an alkoxide-mediated cyclization to provide a number
of indole containing compounds possessing substituents at the C2, C4, C5, and/or C6 position(s) in good overall yields. © 2001
Elsevier Science Ltd. All rights reserved.
Since the discovery and development of metal-catalyzed
cross-coupling reactions in the 1970s, this powerful
methodology has been widely used in synthetic organic
chemistry over the last 30 years.1 Among the active
metals, Ni(0) and Pd(0)2 complexes are the most popu-
larly used catalysts for cross-coupling reactions.
Numerous Pd(0) and Pd(II) complexes enjoy applica-
tions in the synthesis of heterocyclic compounds3 that
are biologically active and/or used as pharmaceutical
compositions. For example, the Sonogashira cross-coup-
ling reaction4 of 2-haloanilides 1 with 1-alkynes in the
2,3-disubstituted indoles.10 Moreover, 2,3-disubstituted
indoles can be obtained directly from 2-iodoaniline
derivatives 1 (Z=I) via the Pd(0)-catalyzed annulation
with internal alkynes, a process referred to as the
Larcok indole synthesis.11 We report here on a novel
synthesis of substituted indoles12 using 2-aminophenols
as the starting materials, and the remarkable effect of
iodide anion on Sonogashira cross-coupling reactions
of 2-carboxamidoaryl triflates with 1-alkynes.13
2-Alkynylanilides 2 are commonly synthesized from
2-iodoanilines which are prepared by iodination of
anilines with bis(pyridine)iodonium(I) tetrafluoroborate
(IPy2BF4).5p Sometimes, 2-bromoanilines can be used in
the cross-coupling reaction under rather harsh reaction
conditions with low yields.6b,f The electron-deficient
2-nitroaryl chlorides and bromides are alternative sub-
presence of Pd(0)–Cu(I) gives 2-alkynylanilides
2
(Scheme 1). The latter cyclize under various metal-,5
alkoxide-,6 fluoride-,7 or TMG (tetramethylguanidine)-8
mediated conditions to furnish indoles 3. On the other
hand, 2-alkynylanilides 2 can react further with aryl or
vinyl triflates9 under Pd(0)–Cu(I) catalysis to produce
R2
Pd(II), Cu(I),
X
TBAF, or base
X
X
Z
R2
R2
Pd(0), Cu(I), base
N
R1
NH
R1
NH
R1
Y
Y
Y
1
2
3
Z = Br, I;
R1 = H, acyl, BOC, CO2Et, SO2Me, SO2Ar
Scheme 1.
Keywords: coupling reactions; indoles; phenols; triflates.
* Corresponding author. Fax: +852 2358 1594; e-mail: chdai@ust.hk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00965-0

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W.-M. Dai et al. / Tetrahedron Letters 42 (2001) 5275–5278
strates which exhibit reasonably good reactivity toward
the Sonogashira cross-coupling reaction.14 To the best
of our knowledge, the commercially available 2-
aminophenols 4 have not been used for the general
synthesis of indoles. We took the advantage of the
structural diversity of 2-aminophenols and used them
as the starting materials for the design and synthesis of
indole compound libraries. Therefore, we explored this
synthetic approach, as illustrated in Scheme 2,15 which
consists of key cross-couplings of the triflates 6 with
1-alkynes. According to our previously reported proce-
dures,16 4 can be selectively N-acylated to give the
amides 5 in 89–98% yield by (i) heating with 3-butyryl-
1,3-thiazoline-2-thione in refluxing THF (Method A);
(ii) treating with NaH and butyryl chloride in THF at
20°C (Method B), and (iii) heating with butyryl chlo-
ride and pyridine in THF at 40–50°C (Method C).17
Treatment of the amides 5 with 1.1 equiv. of Tf2O and
1.3 equiv. of Et3N in CH2Cl2 at 0°C gave the corres-
ponding triflates 6 in 77–96% yield. Under these condi-
tions, sulfonylation at the amide nitrogen atom could
be avoided.
an additive (entry 1), reaction of 6a with phenyl-
acetylene initially proceeded in Et3N–CH3CN (1:5)13g at
20°C to form 7a, but it stopped at about 30% conver-
sion of 6a. When 1.0–1.5 equiv. of n-Bu4NBr was
added, the isolated yield of 7a increased from 29% to
ca. 60% (entries 2–3). Sharp rate acceleration was
observed when n-Bu4NI was used (entries 4–7). Conver-
sion of 6a completed within 24 h in the presence of over
1.0 equiv. of n-Bu4NI to provide 7a in 84–91% yield
(entries 5–7). These data indicated that iodide is a
better additive than bromide. We also examined other
palladium catalysts such as Pd(PPh3)2Cl2 (entry 8),
Pd(PhCN)2Cl2, and Pd(OAc)2 and found that the cross-
coupling reaction did not occur in the presence of
iodide or bromide without PPh3. A parallel experiment
with the meta analog of the triflate 6 (X=Y=H),
which underwent the cross-coupling reaction without
n-Bu4NI at 80°C, confirmed that the acyl group in 6 is
the origin of the additive effect. It is highly possible
that complexation of the acyl group with the Pd(II)
species possessing a triflate anion ligand, which was
formed in the oxidative addition step of the catalytic
cycle, modifies the chemical and/or physical properties
of the complex. Iodide anion may act by replacing the
triflate anion in the square-planar Pd(II) complex or to
form a new pentacoordinated anionic palladium spe-
cies,18 which makes the following transmetalation or
reductive elimination occur easily. It is clear that the
iodide anion does not activate the Pd(0) species for
oxidative addition to the triflates 6 because the cross-
coupling reaction proceeds without added iodide anion
in the initial stage. The catalyst became poisoned by the
triflate anion as the cross-coupling reaction progressed.
Aryl triflates have been reported to undergo the Sono-
gashira cross-coupling with 1-alkynes under the stan-
dard conditions of catalytic Pd(0) and Cu(I) plus an
excess amine base.13 A 2-alkoxycarbonyl group pre-
sented in the aryl and vinyl triflates did not show any
inhibitory effect on the cross-coupling reaction.13d,h
Selective stepwise cross-coupling of naphthalene 2,3-
bistriflate with two different 1-alkynes was also
achieved without difficulty.13b,c In 1996, Powell and
Rychnovsky reported an iodide acceleration phe-
nomenon in the Sonogashira cross-coupling of the sub-
stituted phenyl 1,2-bistriflates in the formation of
1,2-dialkynylbenzenes.13f Activation of Pd(0) catalyst
by iodide anion before oxidative addition to the triflate
was suggested. We observed a similar additive effect on
the cross-coupling reactions of the triflates 6. Some of
the results are summarized in Table 1. In the absence of
We synthesized a number of 2-alkynylanilides 7a–i in
71–98% yield from triflates 6a–g via the Pd(0)–Cu(I)-
catalyzed cross-coupling reaction in the presence of 1.5
equiv. of n-Bu4NI (Scheme 2 and Table 2). Electron-
rich substituents deactivated the triflates and the reac-
R2
X
X
X
OH
Z
R2
t-BuOK, NMP
ref. 16
3
Pd(PPh3)4, CuI
60 °C, 6 h
(R1 = H)
NH2
NH
NH
Y
Y
nBu4NI
Y
Et3N-CH3CN (1:5)
O
4
O
5: Z = OH
6: Z = OTf
Tf2O, Et3N
CH2Cl2, 0 °C, 4-6 h
7
Scheme 2.
Table 1. Effects of additives on the cross-coupling of triflate 6a (X=Y=H) with phenylacetylenea
Entry
Additive (mol%)
t (h)
7a (R2=Ph, %)
Entry
Additive (mol%)
t (h)
7a (R2=Ph, %)
1
2
3
4
Noneb
17
24
24
24
29
58
62
56
5
6
7
8
n-Bu4NI (100)
n-Bu4NI (150)
n-Bu4NI (300)b
n-Bu4NI (300)c
24
24
15
36
84
91
91
82
n-Bu4NBr (100)b
n-Bu4NBr (150)
n-Bu4NI (50)
a Carried out with 10 mol% Pd(PPh3)4 and 30 mol% CuI in Et3N–CH3CN (1:5) at 20°C under N2.
b 20% CuI was used.
c Pd(PPh3)2Cl2 was used to replace Pd(PPh3)4.

W.-M. Dai et al. / Tetrahedron Letters 42 (2001) 5275–5278
Table 2. Synthesis of 2-alkynylanilides 7a and indoles 3 (R1=H)
5277
Entry
X and Y;b R2
t (h), 7 (%)
3 (%)
Entry
X and Y;b R2
t (h), 7 (%)
3 (%)
1
2
3
4
5
a: H, H; Ph
24, 91
22, 96
2, 97c
24, 71c
10, 95
81
81
84
78
81
6
7
8
9
f: H, 6-Cl; Ph
g: H, 6-SO2Et; Ph
h: H, H; SiMe3
i: H, H; n-Pr
6, 94
3, 92
3, 94
3, 98
81
76
b: H, 5-Me; Ph
c: H, 6-Me; Ph
d: 4,6-Me2; Ph
e: 5,6-(CH2)4; Ph
93 (R2=H)
86
a Carried out with 10 mol% Pd(PPh3)4, 30 mol% CuI, and 150 mol% n-Bu4NI in Et3N–CH3CN (1:5) at 20°C under N2.
b Indole skeleton numbering was used here.
c The cross-coupling reactions were carried out at refluxing temperature. 7c was obtained in 67% yield at 20°C for 24 h.
tions proceeded on heating (entries 3 and 4). In con-
trast, electron-deficient substituents activated the tri-
flates so that the reaction times decreased from 24 h for
6a to 3–6 h for 6f,g at 20°C (entries 6 and 7). Cycliza-
tion of 7 occurred upon exposure to t-BuOK (1.2
equiv.)6e–g in 1-methyl-2-pyrrolidinone (NMP) at 60°C
to provide indoles 3 where the 1-acyl group was
removed presumably after the indole ring forma-
tion.6b,d,e We found that both N-benzoyl6b and benzyl-
oxyacetyl analogs of 7a gave the same indole 3a under
the basic conditions. The SiMe3 group in 7h was lost
during the indole ring closure to give 3h.6b,e,f Moreover,
TMG could be used to replace t-BuOK for indole ring
closure.8
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Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proc. Int.
1995, 27, 129. A recent example of intramolecular Sono-
gashira cross-coupling reaction, see: (d) Dai, W.-M.; Wu,
A. Tetrahedron Lett. 2001, 42, 81.
5. For Pd(II)-catalyzed cyclization of 2-alkynylanilines, see:
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In summary, we have successfully developed a novel
and general synthesis of substituted indoles from 2-
aminophenols. This approach enables indole compound
library synthesis by taking advantage of the structural
diversity of commercially available 2-aminophenols. A
remarkable rate enhancement was observed for the
Sonogashira cross-coupling reactions of 2-carboxamido-
aryl triflates 6 in the presence of iodide anion. This
finding is useful for understanding the reaction mecha-
nisms of the related cross-coupling reactions of signifi-
cance in contemporary organic synthesis. Transfer of
our indole synthesis from solution to solid supports is
underway in our laboratory.
Acknowledgements
This work is supported by the Innovation and Technol-
ogy Fund (ITS/119/00) from the Innovation and Tech-
nology Commission of the Hong Kong Special
Administration Region, China. We also thank HKUST
for providing a Post Doctoral Fellowship Matching
Fund (PDF99/00) to D.-S. Guo and Department of
Chemistry, HKUST for providing a scholarship to
L.-P. Sun.
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