Dehydrogenative synthesis of C3-azolylindoles via copper-promoted annulative direct coupling of o -alkynylanilines

Article abstract of DOI:10.1055/s-0031-1290965

A copper-promoted annulative direct coupling of o-alkynylaniline derivatives with 1,3,4-oxadiazoles for the synthesis of C3-azolylindoles has been developed. The copper-based system provides a new protocol for the dehydrogenative construction of indole-oxadiazole conjugations from nonhalogenated and nonmetalated starting materials.

Full text of DOI:10.1055/s-0031-1290965

SPECIAL TOPIC
▌1515
sDpeecihal ytopdicrogenative Synthesis of C3-Azolylindoles via Copper-Promoted
Annulative Direct Coupling of o-Alkynylanilines
Synthesis of C3-Azolylindoles
Yoshiro Oda, Naoto Matsuyama, Koji Hirano,* Tetsuya Satoh, Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Fax +81(6)68797362; E-mail: k_hirano@chem.eng.osaka-u.ac.jp; E-mail: miura@chem.eng.osaka-u.ac.jp
Received: 29.02.201; Accepted: 15.03.2012
products were simply the cyclized NH and NMs indoles.
Subsequent investigations revealed that the substituent on
nitrogen was critical for the annulative coupling: the use
of benzoyl-substituted 1a-Bz increased the yield of 3aa
Abstract: A copper-promoted annulative direct coupling of o-al-
kynylaniline derivatives with 1,3,4-oxadiazoles for the synthesis of
C3-azolylindoles has been developed. The copper-based system
provides a new protocol for the dehydrogenative construction of
indole–oxadiazole conjugations from nonhalogenated and non- (entry 2), while the introduction of acetyl or pentafluoro-
metalated starting materials.
benzoyl groups completely inhibited the formation of 3aa
(entries 3 and 4). The delicate acidity of the aniline NH
would play a pivotal role in the oxidative coupling. Addi-
tional screening (entries 5–9)10 identified a 2-fluoroben-
zoyl substituent to be optimal (entry 9). Moreover, the
addition of MS 3Å was found to give a positive effect on
the reaction efficiency (entry 7 vs 8). Finally, with a
slightly higher loading of CuF2 and 2a relative to 1a-2F,
the target molecule 3aa was isolated in 64% yield (entry
10). Other reaction systems using CuCl2, Cu(OTf)2,
Cs2CO3, or toluene largely diminished the yield of 3aa
(data not shown).
Key words: copper, dehydrogenative coupling, indoles, C–H func-
tionalization, oxadiazoles
Since an indole–heteroarene conjugation frequently oc-
curs in natural products, medicines, and biologically ac-
tive compounds,1 the construction of this biheteroaryl
moiety has been one of long-standing central topics in
synthetic chemistry. The palladium-catalyzed dual C–H
functionalization that makes the indole–heteroarene link-
age directly is the most useful of these synthetic method-
ologies. To date, the palladium-based dehydrogenative
couplings of indoles with simple benzenes,2 polyfluoro-
arenes,3 pyridine N-oxides,4 and 1,3-azoles4b have been
reported.
Table 1 Optimization Studies for Copper-Promoted Annulative Di-
rect Coupling of o-Alkynylanilines 1 with 2-Phenyl-1,3,4-oxadiazole
(2a) for the Dehydrogenative Synthesis of 3aaa
Bu
N
N
N
N
Meanwhile, we have recently focused on the activity of
copper salts and complexes in the C–H functionalization
chemistry and succeeded in the copper-mediated direct
C–C5 and C–N6 bond forming reactions of some hetero-
arenes.7 In addition, as an alternative to the palladium-cat-
alyzed direct biaryl couplings mentioned above, we have
also developed a copper-promoted annulative direct cou-
pling of o-alkynylphenols with 1,3-azoles for the dehy-
drogenative synthesis of C3-azolylbenzofurans.8 In the
course of this study, we envisaged that the annulative di-
rect coupling protocol would be extended to the construc-
tion of C3-azolylindole skeletons, results of which are
reported herein.
On the basis of our previous work,8 the optimization stud-
ies commenced with N-mesyl-2-(hex-1-ynyl)aniline (1a-
Ms)9 and 2-phenyl-1,3,4-oxadiazole (2a) in a CuF2/1,10-
phenanthroline (phen)/K3PO4 system under ambient con-
ditions. Pleasingly, after 15 hours in DMF, the desired
2,3-disubstituted NH indole 3aa was formed, albeit in
only 8% yield (Table 1, entry 1). Notable is that the Ms
group on the indole nitrogen was spontaneously remov-
able during the reaction course. Detectable major by-
CuF2/phen
K3PO4
+
O
O
N
DMF, 65 °C
4–8 h, air
NH
2a
H
Bu
1
3aa
R
Yield (%)b of 3aa
Entry
1
R
1c
2
1a-Ms
1a-Bz
1a-Ac
SO2Me
Bz
(8)
33
0
3
Ac
4
COC6F5
0
1a-F5
5
6
CO(4-CF3C6H4)
CO(2-CF3C6H4)
CO(2-ClC6H4)
22
43
1a-4CF3
1a-2CF3
1a-2Cl
1a-2Cl
1a-2F
7
40
8d
9d
50
CO(2-FC6H4)
58
10d,e
11e
1a-2F
76 (64)
56
1a-2F
a Reaction conditions: 1 (0.30 mmol), 2a (0.60 mmol), CuF2 (0.60
mmol), phen (0.30 mmol), K3PO4 (0.90 mmol), DMF (2.0 mL).
b Estimated by 1H NMR analysis. Yield of isolated product is given in
parentheses.
c At r.t. for 15 h.
d With 200 mg of MS 3Å.
SYNTHESIS 2012, 44, 1515–1520
Advanced online publication: 19.04.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290965; Art ID: SS-2012-C0214-ST
© Georg Thieme Verlag Stuttgart · New York
e With 1a-2F (0.20 mmol), 2a (0.60 mmol), CuF2 (0.60 mmol), phen
(0.60 mmol), and K3PO4 (0.90 mmol).

1516
Y. Oda et al.
SPECIAL TOPIC
With the optimized conditions in hand, the annulative di- The scope of 1,3-azoles was next evaluated with 1b-2F as
rect coupling of various o-alkynylanilines 1 with 2a was an aniline coupling partner. Representative products are
performed (Table 2). In some cases, the addition of MS summarized in Figure 1. Electronically and sterically di-
3Å was not required for the successful conversion. At the verse 1,3,4-oxadiazoles coupled with 1b-2F effectively to
alkyne terminus, aromatic substituents were also tolerat- make the indole–azole conjugations with the synthetically
ed, and electron-neutral and -rich substrates gave the cor- useful level (3bb–bf). The oxadiazole that bears the alkyl
responding 2,3-diarylindoles 3ba–da in good yields side chain also could be employed (3bg). Attempts to ap-
(entries 1–3). On the other hand, an electron-deficient ply other 1,3-azoles such as oxazole and thiazole still re-
function diminished the yield (entry 4).11 A decrease of main unsuccessful. On the other hand, while preliminary,
the yield was also observed in the case of sterically de- triisopropylsilylacetylene was found to couple with 1b-
manding naphthyl-substituted aniline (entry 5). However, Ms by using CuBr2 instead of CuF2 under otherwise iden-
to our delight, the change of the substituent on nitrogen tical conditions to afford the corresponding C3-alkynylin-
into more electron-withdrawing 2-trifluoromethylbenzoyl dole 4 (Scheme 1). Although a similar two-step
group improved the reaction efficiency (entry 6). Interest- transformation of o-alkynylanilines with a special hyper-
ingly, such a trend was more remarkable in the reaction of valent iodine reagent is known to be catalyzed by a gold
aniline that bears much bulkier t-Bu substituent: the Ms catalyst,12 this dehydrogenative alternative with the termi-
group acted as a promising activator, while the 2-fluoro- nal alkyne and less expensive copper salt appears to be of
benzoyl group completely shut down the reaction (en- synthetic utility.
try 7 vs 8). The introduction of an electron-donating or
-withdrawing group to the benzene ring also influenced
N
N
the reaction outcome. The Me-substituted indole 3ha was
obtained in a satisfactory yield (entry 9), whereas the Cl
substituent largely led to a reduced yield (entry 10).
O
Me
N
H
N
N
3bb 63%
Table 2 Copper-Promoted Annulative Direct Coupling of Various
o-Alkynylanilines 1 with 2-Phenyl-1,3,4-oxadiazole (2a)a
O
OMe
N
H
R3
N
N
3bc 69%
R2
2a
R3
O
CuF2/phen
K3PO4, 3 Å MS
N
N
Cl
N
H
N
N
O
DMF, 65 °C
8 h, air
NH
R1
3bd 57%
N
1
3
H
R2
O
CF3
N
R1
R2
Ph
R3
Entry 1
Product 3,
H
yield (%)b
3be 56%
N
N
1
1b-2F
1c-2F
1d-2F
1e-2F
CO(2-FC6H4)
CO(2-FC6H4)
CO(2-FC6H4)
CO(2-FC6H4)
CO(2-FC6H4)
H
H
H
H
H
H
H
H
3ba, 92 (75)
3ca, 65 (63)
3da, 91 (76)
3ea, 43 (37)
3fa, 49
O
2c
3
4-MeC6H4
N
H
N
N
4-MeOC6H4
4-CF3C6H4
1-naphthyl
3bf 75%
O
4
N
H
5c
6c
7
1f-2F
3bg 43%
1f-2CF3
CO(2-CF3C6H4) 1-naphthyl
3fa, 62 (58)
3ga, 0
Figure 1 Copper-promoted annulative direct coupling of 1b-2F with
1g-2F
CO(2-FC6H4)
t-Bu
t-Bu
Ph
various 1,3,4-oxadiazole; yield of isolated product is shown
8
1g-Ms SO2Me
3ga, 75 (70)
9
1h-2F
1i-2F
CO(2-FC6H4)
CO(2-FC6H4)
Me 3ha, 64 (60)
Cl 3ia, 18 (18)
Ph
10
Ph
H
Si(i-Pr)3
Si(i-Pr)3
a Reaction conditions: 1 (0.20 mmol), 2a (0.60 mmol), CuF2 (0.60
mmol), phen (0.60 mmol), K3PO4 (0.90 mmol), DMF (2.0 mL).
b Estimated by 1H NMR analysis. Yield of isolated product is in pa-
rentheses.
CuBr2/phen, K3PO4
DMF, r.t., 24 h, air
N
NH
Ms
H
Ph
1b-Ms
4 60%
c Without MS 3Å.
Scheme 1 Copper-promoted annulative direct coupling of 1b-Ms
with triisopropylsilylacetylene
Synthesis 2012, 44, 1515–1520
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of C3-Azolylindoles
1517
Although the exact reaction mechanism is not clear at the All reactions were carried out under atmospheric conditions in dried
glassware. All starting materials were purchased from commercial-
ly suppliers and used without further purification, unless otherwise
noted. DMF was distilled from CaH2 and stored strictly under nitro-
gen on MS 4Å. o-Alkynylanilines 1 were readily accessible in two
present, we are tempted to assume the mechanism of the
copper-mediated dehydrogenative coupling as illustrated
in Scheme 2. A base-assisted direct cupration5,6,7c,l–n of the
oxadiazole initially forms a heteroarylcopper intermediate
steps: the Sonogashira coupling of the corresponding iodoanilines
5. Subsequent electrophilic activation of the alkynyl moi-
ety in the aniline 1 via a coordination to the π-acidic copper
center of 5 triggers an annulative cupration (aminocupra-
tion),9 leading to a di(heteroaryl)copper 6. Final reductive
elimination13 furnishes the corresponding N-protected in-
dole 7, the protection of which is spontaneously removed
under standard basic conditions to deliver the observed
NH form 3.14 The postulated pathway can account for the
substituent effect of 1 dependent on the alkyne terminus
(Table 1, entries 5 vs 6 and 7 vs 8). Namely, the increase
of acidity of the NH might accelerate the backside attack
with terminal alkynes and mesylation or benzoylation with appro-
priate sulfonyl or benzoyl chlorides.9c 1,3,4-Oxadiazoles 2 were
prepared according to the literature.16 MS 3Å was activated at 100
°C under high vacuum for 1 h prior to use. Silica gel column chro-
matography was performed using Wakogel 200 mesh from Wako
Pure Chemical Co. 1H and 13C NMR spectra were recorded at 400
or 600 MHz and 100 or 150 MHz, respectively, for CDCl3 or
DMSO-d6 solutions. MS data were obtained by EI. GC analysis was
carried out using a silicon OV-17 column (i. d. 2.6 mm × 1.5 m) or
a CBP-1 capillary column (i. d. 0.5 mm × 25 m). Gel permeation
chromatography (GPC) was performed by LC-6AD (Shimadzu,
two in-line Shodex, CHCl3, 3.5 mL/min, UV detector).
of pendant nitrogen nucleophile to accelerate the genera- C3-Azolylindoles; 2-(2-Butyl-1H-indol-3-yl)-5-phenyl-1,3,4-
oxadiazole (3aa); Typical Procedure
tion of di(heteroaryl)copper species, unless it is difficult
to obtain owing to steric factors associated with 1-naph-
CuF2 (61 mg, 0.60 mmol), 1,10-phenanthroline (109 mg, 0.60
mmol), K3PO4 (191 mg, 0.90 mmol), and MS 3Å (200 mg) were
thyl and t-Bu groups. An alternative mechanism involves
1) an initial annulation of 1 by CuF2 of π-acidic nature and
2) a copper-mediated indole15/oxadiazole direct biaryl
coupling. However, the possibility could be completely
excluded by control experiments shown in Scheme 3.
placed in a 20 mL two-necked reaction flask, with a drying tube
lined with CaCl2. DMF (1.0 mL) was then added to the flask, and
the suspension was stirred for 10 min at r.t. Finally, a solution of 2-
fluoro-N-2-[(hex-1-ynyl)phenyl]benzamide (1a-2F; 59 mg, 0.20
mmol) and 2-phenyl-1,3,4-oxadiazole (2a; 88 mg, 0.60 mmol) in
DMF (1.0 mL) was added dropwise. The solution was stirred at
65 °C for additional 8 h. The resulting mixture was then quenched
with H2O (10 mL). The mixture was extracted with EtOAc (3 × 10
mL), and the combined organic layers were dried (Na2SO4). Con-
centration in vacuo and subsequent column chromatography with
hexane–EtOAc (2:1, v/v) followed by GPC gave 3aa as a pale yel-
low powder; yield: 41 mg (0.13 mmol, 64%); mp 171–173 °C.
1H NMR (400 MHz, CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3 H), 1.39–
1.48 (m, 2 H), 1.77–1.84 (m, 2 H), 3.30 (t, J = 7.8 Hz, 2 H), 7.22–
7.31 (m, 2 H), 7.43 (d, J = 7.8 Hz, 1 H), 7.52–7.57 (m, 3 H), 8.13–
8.17 (m, 2 H), 8.27 (d, J = 7.8 Hz, 1 H), 9.30 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.8, 22.6, 27.7, 31.3, 97.5, 111.1,
120.3, 121.6, 122.6, 124.3, 126.0, 126.6, 129.1, 131.2, 135.2, 144.3,
162.6, 163.1.
2
1
N
N
phen, K3PO4
K3PO4
CuF2
XCu
C–H cupration
O
5
N
N
N
N
O
R2
N
N
XCu
Cu
O
O
reductive
elimination
N
R2
R1
spontaneous
removal of R1
R2
7
N
R1
H
N
R1
K3PO4
6
annulative cupration
3
HRMS: m/z (M+) calcd for C20H19N3O: 317.1528; found: 317.1529.
Scheme 2 Tentative reaction mechanism
2-Phenyl-5-(2-phenyl-1H-indol-3-yl)-1,3,4-oxadiazole (3ba)
Following the typical procedure for 3aa, the reaction was per-
formed with CuF2 (61 mg, 0.60 mmol), 1,10-phenanthroline (109
mg, 0.60 mmol), K3PO4 (191 mg, 0.90 mmol), MS 3Å (200 mg), 2-
fluoro-N-[2-(phenylethynyl)phenyl]benzamide (1b-2F; 63 mg,
0.20 mmol), and 2a (88 mg, 0.60 mmol) in DMF (2.0 mL) at 65 °C
for 8 h. The crude product was purified by column chromatography
on silica gel (hexane–EtOAc, 2:1, v/v) followed by GPC to give 3ba
as a white powder; yield: 51 mg (0.15 mmol, 75%); mp 208–
210 °C.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.38 (m, 2 H), 7.42–7.53 (m,
7 H), 7.74–7.78 (m, 2 H), 7.86–7.89 (m, 2 H), 8.44–8.46 (m, 1 H),
8.79 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 98.3, 111.2, 121.8, 122.2, 123.8,
124.2, 126.58, 126.61, 128.5, 128.9, 129.4, 129.5, 131.2, 131.5,
135.7, 140.3, 162.1, 162.8.
CuF2/phen
K3PO4, 3 Å MS
N
N
+
3ba
not detected
DMF, 65 °C
8 h, air
O
N
R
Ph
2a
R = H or CO(2-FC6H5)
Scheme 3 Control experiments
In conclusion, we have developed a copper-promoted an-
nulative direct coupling of o-alkynylanilines with 1,3,4-
oxadiazoles for the dehydrogenative synthesis of C3-azo-
lylindoles. The copper-based strategy can provide a
unique and convergent approach to the indole–azole con-
jugation from relatively simple, nonhalogenated and non-
metalated starting materials. Further studies to expand the
scope of azoles and make the reaction catalytic in copper
by elucidation of the mechanism and appropriate terminal
co-oxidants are in progress.
HRMS: m/z (M+) calcd for C22H15N3O: 337.1215; found: 337.1213.
2-[2-(4-Methylphenyl)-1H-indol-3-yl]-5-phenyl-1,3,4-oxadia-
zole (3ca)
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), 2-fluoro-N-[2-(4-methylphenyl)phenyl]benzamide
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1515–1520

1518
Y. Oda et al.
SPECIAL TOPIC
(1c-2F; 66 mg, 0.20 mmol), and 2a (88 mg, 0.60 mmol) in DMF
(2.0 mL) at 65 °C for 8 h. The crude product was purified by column
chromatography on silica gel (hexane–EtOAc, 2:1, v/v) followed by
GPC to give 3ca as a pale pink powder; yield: 44 mg (0.13 mmol,
63%); mp 190–192 °C.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 7.21 (d, J = 8.2 Hz,
2 H), 7.27–7.34 (m, 2 H), 7.40–7.49 (m, 4 H), 7.60 (d, J = 8.2 Hz,
2 H), 7.87 (d, J = 8.2 Hz, 2 H), 8.38 (d, J = 7.6 Hz, 1 H), 9.22 (br s,
1 H).
1H NMR (400 MHz, CDCl3): δ = 7.11–7.18 (m, 4 H), 7.28–7.40 (m,
4 H), 7.46 (t, J = 7.8 Hz, 1 H), 7.51–7.55 (m, 2 H), 7.66 (d, J = 6.4
Hz, 1 H), 7.74 (d, J = 8.7 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.99
(d, J = 8.2 Hz, 1 H), 8.52–8.55 (m, 1 H), 9.29 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 100.7, 111.4, 121.7, 122.2,
123.75, 123.79, 125.0, 125.6, 125.8, 126.2, 126.3, 127.0, 128.2,
128.5, 128.6, 129.5, 129.9, 130.8, 132.3, 133.4, 135.9, 138.5, 161.8,
162.4.
HRMS: m/z (M+) calcd for C26H17N3O: 387.1372; found: 387.1375.
13C NMR (100 MHz, CDCl3): δ = 21.4, 97.6, 111.4, 121.4, 122.0,
123.5, 124.2, 126.6, 126.7, 128.5, 128.9, 129.1, 129.2, 131.1, 135.8,
139.5, 140.9, 162.4, 162.8.
2-[2-(tert-Butyl)-1H-indol-3-yl]-5-phenyl-1,3,4-oxadiazole (3ga)
Following the typical procedure for 3aa, the reaction was per-
formed with CuF2 (61 mg, 0.60 mmol), 1,10-phenanthroline (109
mg, 0.60 mmol), K3PO4 (191 mg, 0.90 mmol), MS 3Å (200 mg), N-
[2-(3,3-dimethylbut-1-ynyl)phenyl]methanesulfonamide (1g-Ms;
50 mg, 0.20 mmol), and 2a (88 mg, 0.60 mmol) in DMF (2.0 mL)
at 65 °C for 8 h. The crude product was purified by column chroma-
tography on silica gel (hexane–EtOAc, 2:1, v/v) followed by GPC
to give 3ga as a pale yellow oil; yield: 45 mg (0.14 mmol, 70%).
1H NMR (400 MHz, CDCl3): δ = 1.66 (s, 9 H), 7.24–7.30 (m, 2 H),
7.43 (d, J = 7.3 Hz, 1 H), 7.54–7.55 (m, 3 H), 8.16–8.20 (m, 3 H),
8.70 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.9, 33.6, 96.3, 111.0, 120.5,
121.8, 122.7, 124.4, 126.6, 127.8, 129.1, 131.3, 133.4, 150.2, 162.7,
163.2.
HRMS: m/z (M+) calcd for C23H17N3O: 351.1372; found: 351.1367.
2-[2-(4-Methoxyphenyl)-1H-indol-3-yl]-5-phenyl-1,3,4-oxadia-
zole (3da)
Following the typical procedure for 3aa, the reaction was per-
formed with CuF2 (61 mg, 0.60 mmol), 1,10-phenanthroline (109
mg, 0.60 mmol), K3PO4 (191 mg, 0.90 mmol), MS 3Å (200 mg), 2-
fluoro-N-{2-[(4-methoxyphenyl)ethynyl]phenyl}benzamide (1d-
2F; 69 mg, 0.20 mmol), and 2a (88 mg, 0.60 mmol) in DMF (2.0
mL) at 65 °C for 8 h. The crude product was purified by column
chromatography on silica gel (hexane–EtOAc, 2:1, v/v) followed by
GPC to give 3da as a pale yellow powder; yield: 56 mg (0.15 mmol,
76%); mp 172–174 °C.
1H NMR (600 MHz, CDCl3): δ = 3.90 (s, 3 H), 7.05 (d, J = 8.8 Hz,
2 H), 7.26–7.37 (m, 2 H), 7.46–7.50 (m, 4 H), 7.72 (d, J = 7.9 Hz,
2 H), 7.94 (d, J = 7.9 Hz, 2 H), 7.42 (d, J = 7.0 Hz, 1 H), 8.59 (br s,
1 H).
HRMS: m/z (M+) calcd for C20H19N3O: 317.1528; found: 317.1525.
2-(5-Methyl-2-phenyl-1H-indol-3-yl)-5-phenyl-1,3,4-oxadia-
zole (3ha)
13C NMR (150 MHz, CDCl3): δ = 55.5, 97.8, 111.0, 114.0, 121.6,
122.1, 123.6, 123.7, 124.3, 126.6, 126.8, 128.9, 130.7, 131.1, 135.6,
140.4, 160.6, 162.2, 162.8.
HRMS: m/z (M+) calcd for C23H17N3O2: 367.1321; found:
367.1324.
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), 2-fluoro-N-[4-methyl-2-(phenylethynyl)phenyl]benz-
amide (1h-2F; 66 mg, 0.20 mmol), and 2a (88 mg, 0.60 mmol) in
DMF (2.0 mL) at 65 °C for 8 h. The crude product was purified by
column chromatography on silica gel (hexane–EtOAc, 2:1, v/v) fol-
lowed by GPC to give 3ha as a white powder; yield: 42 mg (0.12
mmol, 60%); mp >250 °C.
1H NMR (400 MHz, CDCl3): δ = 2.55 (s, 3 H), 7.18 (d, J = 8.7 Hz,
1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.42–7.50 (m, 3 H), 7.53–7.54 (m,
3 H), 7.73–7.75 (m, 2 H), 7.85–7.87 (m, 2 H), 8.27 (s, 1 H), 8.53 (br
s, 1 H).
2-Phenyl-5-{2-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}-
1,3,4-oxadiazole (3ea)
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), 2-fluoro-N-{2-[(4-(trifluoromethyl)phenyl)ethy-
nyl]pheny}benzamide (1e-2F; 77 mg, 0.20 mmol), and 2a (88 mg,
0.60 mmol) in DMF (2.0 mL) at 65 °C for 8 h. The crude product
was purified by column chromatography on silica gel (hexane–
EtOAc, 2:1, v/v) followed by GPC to give 3ea as a pale yellow pow-
der; yield: 30 mg (0.074 mmol, 37%); mp 227–229 °C.
13C NMR (100 MHz, CDCl3): δ = 21.7, 98.0, 110.7, 121.5, 124.3,
125.5, 126.6, 126.9, 128.5, 128.9, 129.3, 129.4, 131.1, 131.7, 131.8,
134.0, 140.2, 162.1, 162.7.
HRMS: m/z (M+) calcd for C23H17N3O: 351.1372; found: 351.1372.
1H NMR (400 MHz, DMSO-d6): δ = 7.29–7.36 (m, 2 H), 7.51–7.60
(m, 4 H), 7.79 (d, J = 7.6 Hz, 2 H), 7.95 (d, J = 8.2 Hz, 2 H), 8.07
(d, J = 8.2 Hz, 2 H), 8.25 (d, J = 6.8 Hz, 1 H), 12.5 (br s, 1 H).
2-(5-Chloro-2-phenyl-1H-indol-3-yl)-5-phenyl-1,3,4-oxadia-
zole (3ia)
13C NMR (100 MHz, DMSO-d6): δ = 97.3, 112.2, 120.8, 121.8,
123.6, 123.7, 124.2 (q, J = 271 Hz), 125.1 (q, J = 4.0 Hz), 125.8,
126.1, 129.336, 129.340 (q, J = 32 Hz), 130.6, 131.6, 135.4, 136.3,
138.9, 161.6, 162.0.
HRMS: m/z (M+) calcd for C23H14F3N3O: 405.1089; found:
405.1083.
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), N-[4-chloro-2-(phenylethynyl)phenyl]-2-fluorobenz-
amide (1i-2F; 70 mg, 0.20 mmol), and 2a (88 mg, 0.60 mmol) in
DMF (2.0 mL) at 65 °C for 8 h. The crude product was purified by
column chromatography on silica gel (hexane–EtOAc, 2:1, v/v) fol-
lowed by GPC to give 3ia as a pale yellow powder; yield: 13 mg
(0.035 mmol, 18%); mp >250 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.38 (dd, J = 1.8, 8.5 Hz, 1 H),
7.61–7.68 (m, 7 H), 7.82–7.85 (m, 2 H), 7.89–7.92 (m, 2 H), 8.30
(d, J = 1.8 Hz, 1 H), 12.6 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 96.1, 113.7, 119.9, 123.3,
123.6, 126.05, 126.09, 127.1, 128.4, 129.4, 129.70, 129.73, 130.8,
131.6, 134.7, 142.3, 161.4, 162.0.
2-[2-(1-Naphthyl)-1H-indol-3-yl]-5-phenyl-1,3,4-oxadiazole
(3fa)
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), N-[2-(naphthylethynyl)phenyl]-2-(trifluorometh-
yl)benzamide (1f-2CF3; 83 mg, 0.20 mmol), and 2a (88 mg, 0.60
mmol) in DMF (2.0 mL) at 65 °C for 8 h. The crude product was
purified by column chromatography on silica gel (hexane–EtOAc,
2:1, v/v) followed by GPC to give 3fa as a pale yellow oil; yield: 45
mg (0.12 mmol, 58%).
HRMS: m/z (M+) calcd for C22H14ClN3O: 371.0825; found:
371.0822.
Synthesis 2012, 44, 1515–1520
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of C3-Azolylindoles
1519
2-(4-Methylphenyl)-5-(2-phenyl-1H-indol-3-yl)-1,3,4-oxadia-
zole (3bb)
8 h. The crude product was purified by column chromatography on
silica gel (hexane–EtOAc, 2:1, v/v) followed by GPC to give 3be as
a pale yellow powder; yield: 45 mg (0.11 mmol, 56%); mp 237–
239 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.25–7.32 (m, 2 H), 7.50–7.62
(m, 4 H), 7.83–7.86 (m, 2 H), 7.92 (d, J = 8.2 Hz, 2 H), 7.99 (d,
J = 8.2 Hz, 2 H), 8.22–8.30 (m, 1 H), 12.3 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 90.3, 106.1, 114.7, 115.6,
117.2, 117.8 (q, J = 272 Hz), 120.0, 120.4 (q, J = 3.0 Hz), 120.8,
121.4, 122.3, 123.4, 123.7, 125.0 (q, J = 32 Hz), 125.1, 130.2,
135.3, 154.9, 156.5.
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), 2-fluoro-N-[2-(phenylethynyl)phenyl]benzamide (1b-
2F; 63 mg, 0.20 mmol), and 2-(4-methylphenyl)-1,3,4-oxadiazole
(2b; 96 mg, 0.60 mmol) in DMF (2.0 mL) at 65 °C for 8 h. The
crude product was purified by column chromatography on silica gel
(hexane–EtOAc, 2:1, v/v) followed by GPC to give gave 3bb as a
white powder; yield: 44 mg (0.13 mmol, 63%); mp 219–221 °C.
1H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3 H), 7.23 (d, J = 7.8 Hz,
2 H), 7.31–7.36 (m, 2 H), 7.47–7.50 (m, 4 H), 7.73–7.75 (m, 4 H),
8.41–8.44 (m, 1 H), 8.99 (br s, 1 H).
HRMS: m/z (M+) calcd for C23H14F3N3O: 405.1089; found:
405.1084.
13C NMR (100 MHz, CDCl3): δ = 21.6, 98.3, 111.2, 121.4, 121.7,
122.1, 123.7, 126.5, 126.6, 128.5 (overlapped), 129.4, 129.6, 131.6,
135.8, 140.3, 141.6, 161.9, 163.0.
2-(1-Naphthyl)-5-(2-phenyl-1H-indol-3-yl)-1,3,4-oxadiazole
(3bf)
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), 2-fluoro-N-[2-(phenylethynyl)phenyl]benzamide (1b-
2F; 63 mg, 0.20 mmol), and 2-(naphthyl)-1,3,4-oxadiazole (2f; 118
mg, 0.60 mmol) in DMF (2.0 mL) at 65 °C for 8 h. The crude prod-
uct was purified by column chromatography on silica gel (hexane–
EtOAc, 2:1, v/v) followed by GPC to give 3bf as a pale yellow oil;
yield: 58 mg (0.15 mmol, 75%).
HRMS: m/z (M+) calcd for C23H17N3O: 351.1372; found: 367.1366.
2-(4-Methoxyphenyl)-5-(2-phenyl-1H-indol-3-yl)-1,3,4-oxadia-
zole (3bc)
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), 2-fluoro-N-[2-(phenylethynyl)phenyl]benzamide (1b-
2F; 63 mg, 0.20 mmol), and 2-(4-methoxyphenyl)-1,3,4-oxadiazole
(2c; 106 mg, 0.60 mmol) in DMF (2.0 mL) at 65 °C for 8 h. The
crude product was purified by column chromatography on silica gel
(hexane–EtOAc, 2:1, v/v) followed by GPC to give 3bc as a pale
yellow powder; yield: 51 mg (0.14 mmol, 69%); mp 206–208 °C.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.36 (m, 2 H), 7.43–7.48 (m,
5 H), 7.52–7.59 (m, 2 H), 7.71–7.75 (m, 2 H), 7.87 (t, J = 7.3 Hz, 2
H), 7.95 (d, J = 8.2 Hz, 1 H), 8.46 (d, J = 7.8 Hz, 1 H), 9.03 (br s,
1 H), 9.21 (d, J = 8.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 98.0, 111.3, 120.6, 122.1, 123.7,
124.8, 126.4, 126.5, 126.6, 127.90, 127.92, 128.5 (overlapped),
129.37 (overlapped), 129.39, 129.9, 131.5, 132.0, 133.8, 135.8,
140.6, 161.7, 163.0.
1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 6.94 (d, J = 8.7 Hz,
2 H), 7.32–7.36 (m, 2 H), 7.47–7.51 (m, 4 H), 7.74–7.81 (m, 4 H),
8.42–8.44 (m, 1 H), 8.86 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 55.4, 98.4, 111.2, 114.4, 116.8,
121.8, 122.1, 123.8, 126.6, 128.3, 128.5, 129.37, 129.40, 131.6,
135.7, 140.1, 161.6, 161.9, 162.8.
HRMS: m/z (M+) calcd for C26H17N3O: 387.1372; found: 387.1369.
2-Phenethyl-5-(2-phenyl-1H-indol-3-yl)-1,3,4-oxadiazole (3bg)
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), 2-fluoro-N-[2-(phenylethynyl)phenyl]benzamide (1b-
2F; 63 mg, 0.20 mmol), and 2-phenethyl-1,3,4-oxadiazole (2g; 105
mg, 0.60 mmol) in DMF (2.0 mL) at 65 °C for 8 h. The crude prod-
uct was purified by column chromatography on silica gel (hexane–
EtOAc, 2:1, v/v) followed by GPC to give 3bg as a pale yellow
powder; yield: 31 mg (0.085 mmol, 43%); mp 185–187 °C.
1H NMR (600 MHz, CDCl3): δ = 3.03 (t, J = 7.3 Hz, 2 H), 3.12 (t,
J = 7.3 Hz, 2 H), 7.17 (d, J = 7.6 Hz, 2 H), 7.22 (t, J = 7.3 Hz, 1 H),
7.27–7.34 (m, 4 H), 7.44–7.49 (m, 4 H), 7.65–7.67 (m, 2 H), 8.25
(d, J = 7.6 Hz, 1 H), 8.68 (br s, 1 H).
HRMS: m/z (M+) calcd for C23H17N3O2: 367.1321; found:
367.1319.
2-(4-Chlorophenyl)-5-(2-phenyl-1H-indol-3-yl)-1,3,4-oxadia-
zole (3bd)
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), 2-fluoro-N-[2-(phenylethynyl)phenyl]benzamide (1b-
2F; 63 mg, 0.20 mmol), and 2-(4-chlorophenyl)-1,3,4-oxadiazole
(2d; 108 mg, 0.60 mmol) in DMF (2.0 mL) at 65 °C for 8 h. The
crude product was purified by column chromatography on silica gel
(hexane–EtOAc, 2:1, v/v) followed by GPC to give 3bd as a white
powder; yield: 42 mg (0.11 mmol, 57%); mp 223–225 °C.
13C NMR (150 MHz, CDCl3): δ = 27.1, 32.7, 98.2, 111.1, 121.6,
122.0, 123.7, 126.6, 126.7, 128.2, 128.5, 128.6, 129.2, 129.4, 131.4,
135.6, 139.7, 139.9, 162.2, 164.3.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.38 (m, 2 H), 7.42 (d,
J = 8.7 Hz, 2 H), 7.47–7.54 (m, 4 H), 7.73–7.79 (m, 4 H), 8.42–8.44
(m, 1 H), 8.76 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 111.2, 121.7, 122.3, 122.7, 123.9,
126.5, 127.8, 128.6, 129.3, 129.4 (overlapped), 129.6, 131.5, 135.7,
137.3, 140.5, 162.0, 162.2.
HRMS: m/z (M+) calcd for C24H19N3O: 365.1528; found: 365.1529.
C3-Alkynylindoles: 2-Phenyl-3-[(triisopropylsilyl)ethynyl]-1H-
indole (4); Typical Procedure
HRMS: m/z (M+) calcd for C22H14ClN3O: 371.0825; found:
371.0826.
CuBr2 (66 mg, 0.30 mmol), 1,10-phenanthroline (108 mg, 0.60
mmol), K3PO4 (191 mg, 0.90 mmol), N-mesyl-2-(phenylethy-
nyl)aniline (1b-Ms; 81 mg, 0.30 mmol) and dibenzyl (ca. 50 mg, in-
ternal standard) were placed in a 20 mL two-necked reaction flask.
A solution of triisopropylsilylacetylene (109 mg, 0.60 mmol) in
DMF (1.0 mL) was added, and the mixture was stirred for 24 h un-
der air. The resulting mixture was then poured into H2O (10 mL)
and extracted with EtOAc (3 × 10 mL), and the combined organic
layers were dried (Na2SO4). Concentration in vacuo followed by sil-
ica gel column purification with hexane–EtOAc (90:10, v/v) gave 4
as a yellow oil; yield: 67 mg (0.18 mmol, 60%).
2-(2-Phenyl-1H-indol-3-yl)-5-[4-(trifluoromethyl)phenyl]-
1,3,4-oxadiazole (3be)
Following the typical procedure for 3aa, but excluding the addition
of MS 3Å, the reaction was performed with CuF2 (61 mg, 0.60
mmol), 1,10-phenanthroline (109 mg, 0.60 mmol), K3PO4 (191 mg,
0.90 mmol), 2-fluoro-N-[2-(phenylethynyl)phenyl]benzamide (1b-
2F; 63 mg, 0.20 mmol), and 2-[4-(trifluoromethyl)phenyl]-1,3,4-
oxadiazole (2e; 108 mg, 0.60 mmol) in DMF (2.0 mL) at 65 °C for
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1515–1520

1520
Y. Oda et al.
SPECIAL TOPIC
1H NMR (400 MHz, CDCl3): δ = 1.18 (s, 21 H), 7.14–7.28 (m, 2 H),
7.28–7.38 (m, 2 H), 7.32–7.45 (t, J = 8.0 Hz, 2 H), 7.63 (d, J = 8.0
Hz, 1 H), 7.74–7.80 (m, 2 H), 8.27 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 11.5, 18.8, 95.1, 96.5, 101.3,
111.0, 120.1, 120.9, 123.5, 126.4, 128.3, 128.7, 130.8, 131.4, 135.1,
139.7.
Satoh, T.; Kowalczyk, R.; Bolm, C.; Miura, M. Org. Lett.
2011, 13, 359. (c) Matsuda, N.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2011, 13, 2860. (d) Oda, Y.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2011, 14, 664.
(7) Selected work on the copper-mediated direct C–H
functionalization: (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2006, 128, 56. (b) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu,
J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (c) Do, H.-Q.;
Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(d) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.;
Vicente, R. Org. Lett. 2008, 10, 3081. (e) Ban, I.; Sudo, T.;
Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 3607.
(f) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008,
130, 833. (g) Brasche, G.; Buchwald, S. L. Angew. Chem.
Int. Ed. 2008, 47, 1932. (h) Ueda, S.; Nagasawa, H. Angew.
Chem. Int. Ed. 2008, 47, 6411. (i) Phipps, R. J.; Grimster, N.
P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172.
(j) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org. Lett.
2009, 11, 1511. (k) Phipps, R. J.; Gaunt, M. J. Science 2009,
323, 1593. (l) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang,
L.; Gao, G.; You, J. Angew. Chem. Int. Ed. 2009, 48, 3296.
(m) Besseliévre, F.; Piguel, S. Angew. Chem. Int. Ed. 2009,
48, 9553. (n) Monguchi, D.; Fujiwara, T.; Furukawa, H.;
Mori, A. Org. Lett. 2009, 11, 1607. (o) Mousseau, J. J.; Bull,
J. A.; Charette, A. B. Angew. Chem. Int. Ed. 2010, 49, 1115.
(8) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2011, 13, 3076.
(9) For copper-mediated annulations of o-alkynylanilines,
reviews: (a) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008,
108, 3395. (b) Vicente, R. Org. Biomol. Chem. 2011, 9,
6469. Selected publications: (c) Hiroya, K.; Itoh, S.;
Sakamoto, T. J. Org. Chem. 2004, 69, 1126. (d) Swamy, N.
K.; Yazici, A.; Pyne, S. G. J. Org. Chem. 2010, 75, 3412.
(e) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2012, 77, 617.
(10) In all cases, the product was detected in the free NH form.
(11) The lower reactivity of 1e-2F can be attributed to a
competitive coordination of the amide moiety to the copper
center. A similar trend was observed in our related
annulative amination of o-alkynylanilines, see ref. 9e.
(12) (a) Brand, J. P.; Chevalley, C.; Waser, J. Beilstein J. Org.
Chem. 2011, 7, 565. See also: (b) Gu, Y.; Wang, X.-m.
Tetrahedron Lett. 2009, 50, 763. (c) Brand, J. P.;
HRMS: m/z (M+) calcd for C25H31NSi: 373.2226; found: 373.2224.
Acknowledgment
This work was supported by Grants-in-Aid for Scientific Research
from MEXT and JSPS, Japan. N.M. acknowledges JSPS for finan-
cial support. K.H. acknowledges Kansai Research Foundation for
the Promotion of Science for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.onmorinIfatgnonmSorti
i
npfurotIangSiuptor
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(13) (a) When the present reaction was carried out under the inert
atmosphere of N2, the simple annulation predominantly
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Synthesis 2012, 44, 1515–1520
© Georg Thieme Verlag Stuttgart · New York