Gold(III)-catalyzed annulation of 2-alkynylanilines: A mild and efficient synthesis of indoles and 3-haloindoles

Article abstract of DOI:10.1055/s-2004-815947

Gold(III)-catalyzed annulation of 2-alkynylanilines in EtOH or EtOH-water mixtures at room temperature gives indoles derivatives in good yields. One-flask protocol for the gold-catalyzed conversion of 2-alkynylanilines to 3-bromo and 3-iodoindoles is also reported.

Full text of DOI:10.1055/s-2004-815947

610
PAPER
Gold(III)-Catalyzed Annulation of 2-Alkynylanilines: A Mild and Efficient
Synthesis of Indoles and 3-Haloindoles
G
old(III)-Catalyze
n
dAnnulation
t
of 2-A
o
lkynylanilin
n
es io Arcadi, Gabriele Bianchi, Fabio Marinelli*
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Facoltà di Scienze, via Vetoio, 67100 L’Aquila, Italy
Fax +39(0862)433753; E-mail: fmarinel@univaq.it
Received 23 December 2003; revised 9 January 2004
significantly facilitate the Cu(II) or Pd(II)-mediated ring
Abstract: Gold(III)-catalyzed annulation of 2-alkynylanilines in
EtOH or EtOH–water mixtures at room temperature gives indoles
derivatives in good yields. One-flask protocol for the gold-cata-
lyzed conversion of 2-alkynylanilines to 3-bromo and 3-iodoin-
doles is also reported.
closure of the resin-bound 2-alkynylanilides.9 Syntheses
of 2-substituted indoles through copper10 or palladium11
catalyzed domino reactions of N-protected o-iodoaniline
derivatives with 1-alkynes have been also developed. 2,3-
Disubstituted indoles could be readily available by elec-
trophilic cyclization of 2-alkynylaniline derivatives as-
sisted by I212 or by -palladium complexes.13
Key words: 2-alkynylanilines, indoles, 5-endo-dig cyclization,
gold catalysis, halogenations
Our interest towards the development of resource-saving
and safe chemical processes14 led us to explore gold salts
as green catalysts.15 Until now, little attention has been
paid to gold-catalyzed cyclization of 2-alkynylanilines
derivatives. Only few examples of NaAuCl4-catalyzed cy-
clization of 1 or 2 in THF have been previously reported
by Utimoto and co-workers;16 moreover, it has been re-
cently shown that this catalyst is scarcely efficient in the
cyclization of 2-alkynyl-N-(alkoxycarbonyl)aniline to in-
doles in 1,2-dichloroethane at 100 °C (only one substrate
was tested).17 Consequently, the use of gold catalysis in
the conversion of o-alkynylanilines 1 to indoles 3 remains
largely unexplored.
The indole nucleus is found in many natural and synthetic
products that display a wide range of interesting biologi-
cal activity1 and is currently object of great synthetic ef-
forts.2 Besides classical methods (e.g. Fischer, Reissert
and Madelung reactions),3 many transition metals-assist-
ed protocols have been developed in the last two de-
cades,2c,10 with remarkable improvements in terms of
efficiency and functional group compatibility. In this area,
one of the most investigated approach to indoles is repre-
sented by the cyclization of 2-alkynylanilines 1 or their N-
substituted derivatives 2 (Scheme 1). Many reaction con-
ditions have been reported for this purpose.
Here we describe that a gold catalyst in EtOH or EtOH–
water mixture at room temperature can lead to indoles in
a very simple fashion. Indeed, with the aim to develop a
synthetic protocol involving the use of more environmen-
tally benign solvents and avoiding the need of protecting
groups and or harsh reaction conditions, we selected 2-
(phenylethynyl)aniline 1a as a model substrate to attempt
its cyclization in EtOH or EtOH–water mixtures at room
temperature by means of a variety of catalysts
(Equation 1). The results of this investigation are reported
in Table 1.
R
N
E
R
NHE
1 or 2
3
1 E = H
2 E = COCH3, COCF3, Tosyl, Mesyl
Scheme 1
Base-promoted cyclizations of 2-alkynylanilines4 1 or
their N-protected derivatives5 2 have been developed.
Nevertheless, many protocols rely on transition metal-cat-
alyzed processes. Pd(II)-catalyzed cyclizations of 1 and 2
to 2-substituted indoles 3 have been widely explored.6
Cu(II)-catalyzed cyclization of 1 and 2 occurs in refluxing
dichloroethane in the presence of 10% of catalyst,7 and a
Cu(I)-promoted conversion of 2-[(trimethylsilyl)ethy-
nyl]anilines to 2-unsubstituted indoles requires 2 equiva-
lents of CuI in DMF at 100 °C.8 Microwave-assisted
solid-phase organic synthesis has been demonstrated to
Ph
catalyst
r.t., 5h
N
H
Ph
NH2
3a
1a
Equation 1
According to our previous results,15 gold(III) catalysts
were very effective. From all catalysts screened,
NaAuCl4·2H2O in EtOH was the most efficient (entries 1,
6, 7) for the preparation of 3a. Other Pd, Pt or Cu catalysts
were much less effective than Au in promoting the cy-
clization (entries 8–14). Interestingly, the reaction can be
SYNTHESIS 2004, No. 4, pp 0610–0618
Advanced online publication: 03.02.2004
DOI: 10.1055/s-2004-815947; Art ID: Z18603SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
4

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Gold(III)-Catalyzed Annulation of 2-Alkynylanilines
611
Table 1 Transition Metals-Catalyzed Synthesis of 3a from 1aa
tive work-up. Interestingly, good results were obtained for
the synthesis of 2-unsubstitued indoles 3l–o (entries 15–
19); it is worth noting that these products have been pre-
viously isolated from the corresponding 2-alkynylanilines
in the presence of two-fold excess of CuI in hot DMF8 or
four-fold excess of t-BuOK in refluxing t-BuOH.5b The
failure in the formation of 3l by reacting 1l with a catalytic
amount (4 mol%) of PdCl2 in refluxing MeCN for 7 hours
gives further support to the advantage of the present pro-
tocol over the previously reported methodologies.6
Entry catalyst
Solvent
Yield%b
1
2
NaAuCl4·2H2O
EtOH
83
80
84
82
62
76
50
20
7
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
KAuCl4
EtOH–H2O, 95:5
EtOH–H2O, 66:33
EtOH–H2O, 50:50
EtOH–H2O, 33:66
EtOH
3
4
5
Since 3-haloindoles 4 represents versatile building-blocks
for the assembly of more complex structure,18 we also at-
tempted a one-flask gold-catalyzed conversion of 2-al-
kynylanilines 1 into 3-bromo and 3-iodoindoles 4.12
Considering that a variety of methods are available for the
-halogenation of indoles,19 we found that the derivatives
4 can be conveniently prepared in a single, practical oper-
ation by adding the halogen source (NBS can also be used
in place of Br2) to the reaction mixture after that the con-
version of 1 to 3 was observed by GC analysis
(Scheme 2).
6
7
AuCl
EtOH
8
PtCl4
EtOH
9
NaPdCl4
EtOH
10
11
12
13
14
Pd(OAc)2
PdCl2
EtOH
8
EtOH
6
PdCl2
EtOH
5c
10
0
Cu(OTf)2
Cu(OAc)2
EtOH
Br
Br2 or NBS
EtOH
EtOH
N
H
R
a Determined by GLC analysis.
b Reactions were carried out at r.t. under N2 for 5 h on a 0.26 mmol
scale with 0.01 mmol of catalyst in 1.5 mL of solvent.
c In the presence of 0.26 mmol of CuCl2·2H2O
R
4a-b
EtOH, r.t.
NaAuCl4·2H2O
N
H
R
NH2
1
3
I
carried out in EtOH–water mixtures without loss of effi-
ciency (entries 2–4); raising the amount of water of the
EtOH–water mixtures over 50% can result in a less satis-
factory yield of 3a because of the decreasing solubility of
1a (entry 5).
I2/KOH
N
R
H
4c-f
Scheme 2
Subsequently this gold-catalyzed protocol has been ex-
tended to various alkynylanilines 1 (Equation 2).
The results of this latter protocol are summarized in
Table 3. The alternative protocols12 requires sophisticated
iodonium source (Ipy2BF4·HBF4) at temperatures be-
tween –20 °C and –60 °C or N-protecting groups and the
use of excess of iodine (3 equiv), which could prove a dis-
advantage in relatively large scale preparations in terms of
work-up and by-product disposal.
R1
R4
R4
NaAuCl4·2H2O
N
H
R1
EtOH or EtOH/H2O, r.t.
R3
R3
NH2
60-94%
R2
R2
3
1
In conclusion, we have showen that gold catalysis can al-
low a mild and green procedure for the synthesis of in-
doles from 2-alkynylanilines. This approach is simple to
perform and requires neither use of bases, acids nor N-
protective group. One-flask gold-catalyzed conversion of
2-alkynylanilines into 3-haloindoles opens a clean and
synthetically competitive alternative to the established
procedures.
Equation 2
The results of Table 2 show that NaAuCl4·2H2O in EtOH
or EtOH–water mixtures affords indoles 3a–o at room
temperature in good to high yields. The gold-catalyzed
annulation reaction of 2-alkynylanilines 1 is general and
compatible with a large variety of functional groups. The
isolation of products is simple and does not require extrac-
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A. Arcadi et al.
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Table 2 Gold-Catalyzed Synthesis of Indoles 3 from 2-Alkynilanilines 1a
Entry
1
2-Alkynylaniline 1
Solvent,b Time (h)
EtOH (2.5)
Indole 3, Yield (%)
3b (80)
CH3
NH2
1b
nBu
2
3
95:5 (4)
3c (74)
3d (70)
NH2
1c
EtOH (4)
Ph
NH2
1d
1d
4
5
6
95:5 (4.5)
50:50 (7)
EtOH (2)
3d (78)
3d (75)
3e (83)
1d
tBu
NH2
1e
7
EtOH (4)
3f (80)
3f (90)
S
NH2
1f
1f
8
9
50:50 (2.5)
EtOH (3)
N
H
2
NH2
H2N
Cl
3g (70)d
3h (92)
1g
10
11
EtOH (6)
NH2
1h
EtOH (20)
3i (90)
Cl
NH2
Cl
1i
1i
12
95:5 (20)
3i (77)
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Gold(III)-Catalyzed Annulation of 2-Alkynylanilines
613
Table 2 Gold-Catalyzed Synthesis of Indoles 3 from 2-Alkynilanilines 1a (continued)
Entry
13
2-Alkynylaniline 1
Solvent,b Time (h)
50:50 (5.5)
Indole 3, Yield (%)
3j (75)
OCH3
Cl
NH2
Cl
1j
14
EtOH (5)
3k (91)e
Ph
O2N
NH2
Cl
1k
15
16
EtOH (7)
3l (79)
Cl
NH2
Cl
1l
EtOH (16)
3m (66)
O2N
NH2
Cl
1m
1m
17
18
50:50 (18)
EtOH (16)
3m (12)
3n (60)
NH2
F3C
1n
19
EtOH (16)
3o (58)
F
NH2
F
1o
a Reactions were carried out on a 0.35–0.75 mmol scale in 3–6 mL of solvent, at r.t. under N2 using the following molar ratios:
1/NaAuCl4·2H2O = 1:0.04.
b Numbers refer to ratio of EtOH–H2O.
c Yields refer to single runs and are for pure isolated products.
d 6 mL of EtOH.
e Carried out at 70 °C.
SiMe3
Melting points are uncorrected. 1H NMR (200 MHz) and 13C NMR
(50.3 MHz) spectra were recorded on a Bruker AC 200 spectrome-
R4
ter in CDCl3 (unless otherwise stated). EI (70 eV) mass spectra were
recorded on a Varian Saturn 2100T/GC apparatus. IR spectra were
R3
NH2
R2
recorded in KBr pellets or neat in NaCl disks using a Perkin-Elmer
6d
683 spectrometer. 2-Alkynylanilines 1a,c,d,f,g,4 and 1b,e
are
R2
Cl
R3
R4
compound
known products; 1h,6b 1i21 and 1k,l20 were prepared from 2-ethynyl-
anilines using reported procedures. 2-Ethynylanilines 1l–o were ob-
tained through desilylation of 2-ethynyltrimethylsilanyl anilines
1p–s (Figure 1) which were in turn obtained by the Sonogashira re-
action of commercially available 2-bromoanilines with ethynyltri-
methylsilane.21
1p
H
H
Cl
NO2
H
Cl
H
F
1q
1r
CF3
H
F
1s
Figure 1
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614
A. Arcadi et al.
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Table 3 One-Flask Synthesis of 3-Halogenoindoles 4a
2-Chloro-4-nitro-6-trimethylsilanylethynylaniline (1q)
Yield: 70%; mp 174–175 °C.
IR (KBr): 3500, 3390, 2140 cm–1.
1H NMR: = 8.13 (s, 2 H, Ar), 5.34 (br s, 2 H, NH2), 0.29 (s, 9 H,
SiCH3).
Entry Alkynyla- 3-Haloindole
Yield (%)b
niline 1
74 (75c)
Br
1
1a
13C NMR: = 149.7, 137.6, 126.9, 125.6, 117.4, 107.7 (Ar), 103.4,
98.2 (C≡C), –0.2 (SiCH3).
N
Ph
H
4a
Cl
MS: m/z (%) = 270 (14) [M+ + 2], 268 (46) [M+], 253 (100).
2
1l
80 (70c)
Br
5-Trifluoromethyl-2-trimethylsilanylethynylaniline (1r)
Yield: 66%; oil.
IR (neat): 3500, 3400, 2150 cm–1.
N
H
Cl
1H NMR: = 7.36 (d, J = 7.3 Hz, 1 H, Ar), 6.90–6.83 (m, 2 H, Ar),
4b
4.41 (br s, 2 H, NH2), 0.27 (s, 9 H, SiCH3).
3
4
1a
1l
66
64
I
13C NMR: = 148.3, 132.6, 131.5 (q, J = 32 Hz, C5), 123.9 (q, J =
270 Hz, CF3), 114.0 (q, J = 3.8 Hz), 111.5 (q, J = 4.0 Hz), 110.8
(Ar), 102.2, 100.3 (C≡C), –0.1 (SiCH3).
N
Ph
H
4c
Cl
MS: m/z (%) = 257 (100) [M+], 242 (65).
I
2,4-Difluoro-6-trimethylsilanylethynylaniline (1s)
Yield: 91%; oil.
N
H
Cl
IR (neat): 3510, 340, 2150 cm–1.
4d
4e
1H NMR: = 6.85–6.75 (m, 2 H, Ar), 4.08 (br s, 2 H, NH2), 0.27 (s,
9 H, SiCH3).
5
6
1c
1g
81
56
I
13C NMR: = 153.6 (dd, J1 = 237.8 Hz, J2 = 12.3 Hz, C4), 150.4 (dd,
J1 = 241.6 Hz, J2 = 12.6 Hz, C2), 133.7 (dd, J1 = 13.6 Hz, J2 = 2.8
Hz, C1), 113.3 (dd, J1 = 23.3 Hz, J2 = 3.6 Hz), 109.5 (dd, J1 = 10.8
Hz, J2 = 6.5 Hz), 104.9 (dd, J1 = 26.9 Hz, J2 = 22.7 Hz, Ar), 102.1,
99.3 (t, J = 4.0 Hz, C≡C), –0.1 (SiCH3).
N
H
nBu
I
H
N
MS: m/z (%) = 225 (70) [M+], 210 (100).
N
H
I
Preparation of 2-Ethynylanilines 1l,m; Typical Procedure
To a solution of 1p (0.570 g, 2.21 mmol) in MeOH (15 mL) was
added KF (0.320 g, 5.52 mmol). The mixture was stirred at r.t. for
3 h, then extracted with water (150 mL) and Et2O (2 × 50 mL). The
organic layer was dried (Na2SO4) and evaporated. Column chro-
matographic purification on silica gel (hexane–EtOAc, 95:5) af-
forded 2,4-dichloro-6-ethynylaniline (1l).
4f
a Reactions were carried out at r.t. under a N2 atmosphere using the
following molar ratios: 1/NaAuCl4·2H2O/Br2 = 1:0.04:1 or 1/
NaAuCl4·2H2O/I2/KOH = 1:0.04:1:2.5.
b Yields refer to single runs and are for pure isolated products.
c Carried out using NBS (1.1 equiv) in place of Br2
Yield: 0.351g (86%); mp 90–91 °C.
IR (KBr): 3430, 3300, 2090 cm–1.
1H NMR: = 7.23 (d, J = 2.3 Hz, 1 H, Ar), 7.20 (d, J = 2.3 Hz, 1 H,
Ar), 4.63 (br s, 2 H, NH2), 3.45 (s, 1 H, Csp-H).
Preparation of 2-Trimethylsilanylethynylanilines 1p–s: Typical
Procedure
13C NMR: = 143.9, 130.5, 129.8, 121.4, 119.1, 108.4 (Ar), 84.2,
To a solution of 2-bromo-4,6-dichloroaniline (1.363 g, 5.66 mmol)
in DMF (1 mL) and Et3N (4 mL) were added ethynyltrimethylsilane
(1.205 mL, 8.48 mmol), PdCl2(PPh3)2 (0.059 g, 0.084 mmol) and
CuI (0.016 g, 0.084 mmol). The mixture was stirred at 50 °C for 8
h under N2, then extracted with 0.1 M HCl (150 mL) and EtOAc (2
× 50 mL). The organic layer was dried (Na2SO4) and evaporated.
Column chromatographic purification on silica gel (hexane–
EtOAc, 98:2) afforded 2,4-dichloro-6-trimethylsilanylethynyl-
aniline (1p).
78.7(C≡C).
MS: m/z (%) = 189 (10) [M+ + 4], 187 (63) [M+ + 2], 185 (100)
[M+], 150 (31).
2-Chloro-6-ethynyl-4-nitroaniline (1m)
Yield: 78%; mp 189–190 °C.
IR (KBr): 3500, 3380, 3300, 2100 cm–1.
1H NMR (acetone-d6): = 8.14 (d, J = 2.5 Hz, 1 H, Ar), 8. 09 (d,
J = 2.5 Hz, 1 H, Ar), 6.32 (br s, 2 H, NH2), 4.10 (s, 1 H, Csp-H).
13C NMR (acetone-d6): = 152. 1, 137.7, 127.9, 126.6, 117.8, 107.0
(Ar), 87.1, 78.3 (C≡C).
Yield: 1.245g (85%); oil.
IR (neat): 3540, 3440, 2190 cm–1.
1H NMR: = 7.16 (s, 2 H, Ar), 4.58 (br s, 2 H, NH2), 0.26 (s, 9 H,
SiCH3).
13C NMR: = 143.5, 130.1, 129.4, 121.3, 118.9, 109.6 (Ar), 102.0,
MS: m/z (%) = 197 (37) [M+ + 2], 195 (100) [M+].
99.6 (C≡C), –0.1 (SiCH3).
Preparation of 2-Ethynylanilines 1n–o; Typical Procedure
To a solution of 1s (0.331 g, 1.29 mmol) in THF (5 mL) was added
TBAF (1.5 mL of a 1.2 M solution in THF). The mixture was stirred
MS: m/z (%) = 261 (14) [M+ + 4], 259 (71) [M+ + 2], 257 (100)
[M+], 207 (65).
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Gold(III)-Catalyzed Annulation of 2-Alkynylanilines
615
at r.t. for 0.5 h, then extracted with water (150 mL) and Et2O (2 ×
50 mL). The organic layer was dried (Na2SO4) and evaporated. Col-
umn chromatographic purification on silica gel (hexane–EtOAc,
95:5) afforded 2-ethynyl-5-(trifluoromethyl)aniline (1n).
13C NMR: = 143.1, 136.7, 135.0, 132.2, 130.0, 129.1, 127.9,
127.6, 126.8, 124.8, 121.6, 121.3, 119.0, 110.1(Ar, C=C), 94.3,
84.8(C≡C), 27.0 (CH2Ar), 23.7 (C=CCH2).
MS: m/z (%) = 317 (11) [M+ + 4], 315 (60) [M+ + 2], 313 (100)
Yield: 0.190 g (80%); oil.
[M+], 243(29).
IR (neat): 3500, 3400, 3310, 2090 cm–1.
1H NMR: = 7.37 (d, J = 8.3 Hz, 1 H, Ar), 6.88–6.84 (m, 2 H, Ar),
Preparation of 2-Alkynylanilines 1j,k: Typical Procedure
To a solution of 1l (0.146 g, 0.78 mmol) in DMF (1.2 mL) were add-
ed 4-iodoanisole (0.230 g, 0.98 mmol), piperidine (0.080 mL, 0.80
mmol), PdOAc2(PPh3)2 (0.012 g, 0.016 mmol), and CuI (0.06 g,
0.031 mmol). The mixture was stirred at 60 °C for 7 h under N2,
then extracted with 0.1 M HCl (150 mL) and EtOAc (3 × 50 mL).
The organic layer was dried (Na2SO4) and evaporated. Column
chromatographic purification on silica gel (hexane–EtOAc, 90:10)
afforded 2,4-dichloro-6-[(4-methoxyphenyl)ethynyl]aniline (1j).
4.14 (br s, 2 H, NH2), 3.46 (s, 1 H, Csp-H).
13C NMR: = 148.6, 133.0, 131.7 (q, J = 31.9 Hz, C5), 113.8 (q,
J = 3.8 Hz), 110.6 (q, J = 3.9 Hz), 109.6 (arom); 123.8 (q, J = 272
Hz, CF3), 84.4, 79.3 (C≡C).
MS: m/z (%) = 185 (100) [M+], 166 (20).
2-Ethynyl-4,6-difluoroaniline (1o)
Yield: 70%; liquid; bp 200 °C (dec).
IR (neat): 3500, 3400, 3310, 2100 cm–1.
Yield: 0.198g (87%); mp 81–82 °C.
IR (KBr): 3420, 3320, 2180 cm–1.
1H NMR: = 7.42 (d, J = 8.9 Hz, 2 H, Ar), 7.22 (d, J = 2.3 Hz, 1 H,
Ar), 7.18 (d, J = 2.3 Hz, 1 H, Ar), 6.86 (d, J = 8.9 Hz, 2 H, Ar), 4.61
(br s, 2 H, NH2), 3.80 (s, 3 H, OCH3).
13C NMR: = 160.0, 142.9, 133.1, 129.8, 128.9, 126.7, 121.6,
118.9, 114.1, 110.3 (Ar), 96.4, 82.7 (C≡C).
1H NMR: = 6.87–6.71 (m, 2 H, Ar), 4.14 (br s, 2 H, NH2), 3.45 (s,
1 H, Csp-H).
13C NMR: = 153.7 (dd, J1 = 237.7 Hz, J2 = 12.1 Hz, C4), 150.6 (dd,
J1 = 241.6 Hz, J2 = 12.6 Hz, C2), 134.2 (dd, J1 = 13.9 Hz, J2 = 2.9
Hz, C1), 113.7 (dd, J1 = 23.5 Hz, J2 = 3.7 Hz), 108.3 (dd, J1 = 10.9
Hz, J2 = 6.9 Hz), 105.3 (dd, J1 = 26.8 Hz, J2 = 22.6 Hz, Ar), 84.4,
78.6 (t, J = 4.1 Hz, C≡C).
MS: m/z (%) = 295 (9) [M+ + 4], 293 (44) [M+ + 2], 291 (72) [M+],
276 (100).
MS: m/z (%) = 153 (100) [M+].
2-Chloro-4-nitro-6-[(3E)-4-phenylbut-3-en-1-ynyl]aniline (1k)
Yield: 79%; mp 168–170 °C.
2-[(4-Chlorophenyl)ethynyl]aniline (1h)
IR (KBr): 3500, 3360, 2190 cm–1.
To a solution of 2-ethynylaniline (0.193 g, 1.65 mmol) in DMF (1
mL) and Et2NH (2 mL) were added 4-iodochlorobenzene (0.394 g,
1.65 mmol), Pd(PPh3)4 (0.038 g, 0.033 mmol) and CuI (0.013 g,
0.068 mmol). The mixture was stirred at r.t. for 4 h under N2, then
extracted with 0.1 M HCl (150 mL) and EtOAc (3 × 50 mL). The
organic layer was dried (Na2SO4) and evaporated. Column chro-
matographic purification on silica gel (hexane–EtOAc, 98:2) af-
forded 1h.
1H NMR (acetone-d6): = 8.14 (d, J = 2.5 Hz, 1 H, Ar), 8. 10 (d,
J = 2.5 Hz, 1 H, Ar), 7.58–7.53 (m, 2 H, Ar), 7.45–7.30 (m, 3 H,
Ar), 7.22 (d, J = 16.3 Hz, 1 H, C=CH), 6.61 (d, J = 16.3 Hz, 1 H,
C=CH), 6.52 (br s, 2 H, NH2).
13C NMR (acetone-d6): = 151.5, 143.5, 136.9, 129.9, 129.7, 129.5,
129.4, 127.4, 127.2, 126.0, 108.0 (Ar), 97.2, 86.0 (C≡C).
Yield: 0.310 g (82%); mp 116–117 °C.
IR (neat): 3460, 3360, 2200 cm–1.
1H NMR: = 7.40 (d, J = 8.7 Hz, 2 H, Ar), 7.35–7.30 (m, 1 H, Ar),
7.27 (d, J = 8.7 Hz, 2 H, Ar), 7.16–7.06 (m, 1 H, Ar), 6.73–6.64 (m,
2 H, Ar), 4.18 (br s, 2 H, NH2).
13C NMR: = 147.7, 134.0, 132.5, 132.1, 129.9, 128.6, 121.7,
117.9, 114.3, 107.4 (Ar), 93.5, 86.9 (C≡C).
MS: m/z (%) = 229 (34) [M+ + 2], 227 (100) [M+], 192 (11).
MS: m/z (%) = 300 (35) [M+ + 2], 298 (93) [M+], 251 (100).
Preparation of Indoles 3; Typical Procedure
To a solution of 2,4-dichloro-6-ethynylaniline (1l) (0.140 g, 0.75
mmol) in EtOH (6 mL) was added NaAuCl4·2H2O (0.012 g, 0.030
mmol). The mixture was stirred at r.t for 7 h under N2, then purified
by chromatography on silica gel (hexane–EtOAc, 98:2) to give 5,7-
dichloro-1H-indole (3l).
Yield: 0.110g (79%); mp 55–56 °C (Lit.22 53.5–54 °C).
IR (KBr): 3460, 1530 cm–1.
1H NMR: = 8.37 (br s, 1 H, NH), 7.51 (dd, J1 = 1.8 Hz, J2 = 0.7
Hz, 1 H), 7.28–7.25 (m, 1 H), 7.20 (dd, J1 = 1.8 Hz, J2 = 0.4 Hz, 1
H), 6.53 (dd, J1 = 3.2 Hz, J2 = 2.2 Hz, 1 H, H-3).
13C NMR: = 131.7, 129.6, 126.1, 125.3, 121.4. 118.9, 116.9, 103.4
(C-3).
2,4-Dichloro-6-(3,4-dihydronaphthalen-1-ylethynyl)aniline
(1i);Typical Procedure
To a solution of 1l (0.108 g, 0.58 mmol) in DMF (0.5 mL) and
Et2NH (2 mL) were added 3,4 dihydronaphthalen-1-yl triflate
(0.198 g, 0.71 mmol), PdCl2(PPh3)2 (0.008 g, 0.011 mmol) and CuI
(0.005 g, 0.026 mmol). The mixture was stirred at r.t. for 18 h under
N2, then extracted with 0.1 M HCl (150 mL) and EtOAc (3 × 50
mL). The organic layer was dried (Na2SO4) and evaporated. Col-
umn chromatographic purification on silica gel (hexane–EtOAc,
99:1) afforded 1i.
MS: m/z (%) = 189 (11) [M+ + 4], 187 (72) [M+ + 2], 185 (100)
[M+], 150 (23).
Anal. Calcd for C8H5Cl2N: C, 51.65; H, 2.71; N, 7.53. Found: C,
51.63; H, 2.72; N, 7.54.
Yield: 0.125g (69%); mp 79–80 °C.
IR (KBr): 3430, 3320, 2180 cm–1.
1H NMR: = 7.58 (d, J = 6.6 Hz, 1 H, Ar), 7.25–7.12 (m, 5 H, Ar),
6.57(t, J = 4.8 Hz, 1 H, C=CH), 4.63 (br s, 2 H, NH2), 2.82 (t, J =
8.0 Hz, 2 H, CH2Ar), 2.48–2.38 (m, 2 H, C=CCH2).
2-Phenyl-1H-indole (3a)
Mp 186–188 °C (Lit.5a 185–187 °C).
2-(4-Methylphenyl)-1H-indole (3b)
Mp 213–215 °C (Lit.6d 210–212 °C).
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2-Butyl-1H-indole (3c)
7-Chloro-5-nitro-1H-indole (3m)
Mp 176–177 °C.
Mp 29–31 °C (Lit.23 28–29.5 °C).
IR (KBr): 3360, 1530, 1320 cm–1.
2-[(E)-2-phenylvinyl]-1H-indole (3d)
1H NMR (acetone-d6): = 11.24 (br s, 1 H, NH), 8.55 (dd, J1 = 2.0
Hz, J2 = 0.7 Hz, 1 H), 8.05 (dd, J1 = 2.0 Hz, J2 = 0.3 Hz, 1 H), 7.67–
7.64 (m, 1 H), 6.87 (dd, J1 = 3.2 Hz, J2 = 1.9 Hz, 1 H, H-3).
Mp 197–199 °C (Lit.6d 198–201 °C).
2-(4-tert-butylcyclohex-1-enyl)-1H-indole (3e)
Mp 147–150 (Lit.6d 148–150 °C).
13C NMR (acetone-d6): = 143.1, 137.5, 130.8, 129.9, 118.0, 117.7,
117.3, 107.1 (C-3).
MS: m/z (%) = 198 (31) [M+ + 2], 196 (100) [M+], 150 (21).
2-(2-Thienyl)-1H-indole (3f)
Mp 165–167 °C (Lit.24 167–168 °C).
Anal. Calcd for C8H5ClN2O2: C, 48.88; H, 2.56; N, 14.25. Found:
C, 48.87; H, 2.57; N, 14.26.
2,2 -Bisindolyl 3g
Mp 294–296 °C (dec) [Lit.4 292–294 °C (dec)].
6-(Trifluoromethyl)-1H-indole (3n)
Mp 79–81 °C.
IR (KBr): 3420 cm–1 (Lit.4 3400 cm–1).
IR (KBr): 3420 cm–1.
2-(4-Chlorophenyl)-1H-indole 3h
Mp 209–211 °C (Lit.25 208–211).
1H NMR: = 8.32 (br s, 1 H, NH), 7.70 (dd, J1 = 8.3 Hz, J2 = 0.7
Hz, 1 H), 7.62–7.61 (m, 1 H), 7.35 (dd, J1 = 8.3 Hz, J2 = 1.6 H, 1 H),
7.31–7.28 (m, 1 H), 6.60–6.57 (m, 1 H, H-3).
13C NMR: = 132.8, 129.4, 126.8, 125.2 (q, J = 271 Hz, CF3) 121.1,
116.5 (q, J = 3.6 Hz), 108.6 (q, J = 4.4 Hz), 102.9 (C-3).
5,7-Dichloro-2-(3,4-dihydronaphthalen-1-yl)-1H-indole (3i)
Oil.
IR (neat): 3440 cm–1.
1H NMR: = 8.32 (br s, 1 H, NH), 7.47–7.46 (m, 1 H), 7.33–7.28
(m, 1 H), 7.24–7.19 (m, 3 H), 7.17 (d, J = 1.8 Hz, 1 H), 6.54 (d, J =
2.2 Hz, 1 H, H-3), 6.41 (t, J = 4.8 Hz, 1 H, C=CH), 2.84 (t, J = 7.4
Hz, 2 H, CH2Ar), 2.47–2.40 (m, 2 H, C=CCH2).
MS: m/z (%) = 185 (100) [M+], 166 (21).
Anal. Calcd for C9H6F3N: C, 58.38; H, 3.27; N, 7.57. Found: C,
58.40; H, 3.25; N, 7.58.
13C NMR: = 139.1, 136.9, 133.1, 131.1, 130.4, 129.9, 127.9,
127.8, 126.7, 125.5, 125.0, 121.3, 118.5, 116.5, 102.5 (C-3), 27.8
(CH2Ar), 23.3 (C=CCH2).
5,7-Difluoro-1H-indole (3o)
Liquid; bp 208 °C.
IR (neat): 3480, 1590 cm–1.
1H NMR: = 8.07 (br s, 1 H, NH), 6.94–6.90 (m, 1 H), 6.82 (dd,
J1 = 9.1 Hz, J2 = 2.2 Hz, 1 H), 6.52–6.39 (m, 1 H), 6.27–6.22 (m, 1
H, H-3).
13C NMR: = 157.2 (dd, J1 = 236.1 Hz, J2 = 9.9 Hz, C5), 148.9 (dd,
J1 = 246.0 Hz, J2 = 14.4 Hz, C7), 130.5 (dd, J1 = 11.6 Hz, J2 = 6.4
Hz), 126.5, 103.7 (dd, J1 = 4.9 Hz, J2 = 2.4 Hz), 101.4 (dd, J1 = 23.2
Hz, J2 = 3.9 Hz), 97.3 (dd, J1 = 20.3 Hz, J2 = 6.4 Hz).
MS: m/z (%) = 317 (12) [M+ + 4], 315 (64) [M+ + 2], 313 (100)
[M+], 278 (21).
Anal. Calcd for C18H13Cl2N: C, 68.81; H, 4.17; N, 4.46. Found: C,
68.78; H, 4.19; N, 4.47.
5,7-Dichloro-2-(4-methoxyphenyl)-1H-indole (3j)
Mp 158–159 °C.
IR (KBr): 3450, 1530 cm–1.
1H NMR: = 8.40 (br s, 1 H, NH), 7.58 (d, J = 8.9 Hz, 2 H), 7.44
(d, J = 1.5 Hz, 1 H), 7.14 (d, J = 1.5 Hz, 1 H), 6.98 (d, J = 8.9 Hz, 2
H), 6.65 (d, J = 1.5 Hz, 1 H, H-3), 3.86 (s, 3 H, OCH3).
MS: m/z (%) = 153 (100) [M+], 126 (27).
Anal. Calcd for C8H5F2N: C, 62.75; H, 3.29; N, 9.15. Found: C,
62.80; H, 3.27; N, 9.14.
13C NMR: = 159.9, 140.1, 131.1, 128.8, 126.8, 125.7, 124.0,
121.2, 118.4, 116.4, 114.6, 99.2 (C-3), 55.4 (OCH3).
Preparation of 3-Bromoindoles 4a,b; Typical Procedure
To a solution of 2,4-dichloro-6-ethynylaniline (1l) (0.099 g, 0.38
mmol) in EtOH (3 mL) was added NaAuCl4·2H2O (0.006 g, 0.015
mmol). The mixture was stirred under N2 at r.t. for 7 h, then a solu-
tion of Br2 (0.021 mL, 0.41 mmol) in EtOH (2 mL) was added drop-
wise. The mixture was stirred for further 2 h, then extracted with 5%
sodium thiosulfate (100 mL) and EtOAc (2 × 50 mL). The organic
phase was dried (Na2SO4) and evaporated. Column chromatograph-
ic purification on silica gel (hexane–EtOAc, 95:5) afforded 3-bro-
mo-5,7-dichloro-1H-indole (4b).
MS: m/z (%) = 295 (12) [M+ + 4], 293 (67) [M+ + 2], 291 (100)
[M+], 278 (59), 276 (81).
Anal. Calcd for C15H11Cl2NO: C, 61.67; H, 3.79; N, 4.79. Found: C,
61.68; H, 3.78; N, 4.78.
7-Chloro-5-nitro-2-[(E)-2-phenylvinyl]-1H-indole (3k)
Mp 158–159 °C.
IR (KBr): 3400, 1520, 1330 cm–1.
1H NMR (DMSO-d6): = 12.23 (br s, 1 H, NH), 8.48 (d, J = 2.0 Hz,
1 H), 8.01 (d, J = 2.0 Hz, 1 H), 7.61 (d, J = 16.5 Hz, 1 H), 7.63–7.59
(m, 2 H), 7.47–7.25 (m, 4 H), 6.98 (d, J = 1.7 Hz, 1 H, H-3).
13C NMR (DMSO-d6): = 142.3, 141.6, 137.7, 137.1, 131.9, 130.2,
129.5, 128.9, 127.2, 118.5, 116.8, 116.4, 116.1, 105.6 (C-3).
Yield: 0.103g (80%); mp 97–98 °C.
IR (KBr): 3450 cm–1.
1H NMR: = 8.42 (br s, 1 H, NH), 7.46 (dd, J1 = 1.8 Hz, J2 = 0.7
Hz, 1 H), 7.28 (d, J = 2.6 Hz, 1 H), 7.24 (d, J = 1.8 Hz, 1 H).
13C NMR: = 128.7, 126.5, 125.3, 122.8, 117.7, 117.2, 91.9 (C-3).
MS: m/z (%) = 300 [M+ + 2], 298 (100) [M+], 252 (41).
MS: m/z (%) = 269 (7), 267 (46), 265 (100), 263 (7).
Anal. Calcd for C8H4BrCl2N: C, 36.27; H, 1.52; N, 5.29. Found: C,
36.30; H, 1.53; N, 5.28.
Anal. Calcd for C16H11ClN2O2: C, 64.33; H, 3.71; N, 9.38. Found:
C, 64.35; H, 3.70; N, 9.39.
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Gold(III)-Catalyzed Annulation of 2-Alkynylanilines
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3-Bromo-2-phenyl-1H-indole (4a)
References
Mp 80–82 °C (Lit.19b 78–79 °C).
(1) (a) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17,
175. (b) Silvestri, R.; De Martino, G.; La Regina, G.; Artico,
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Preparation of 3-Iodoindoles 4c–f; Typical Procedure
To a solution of 2-hex-1-ynylaniline (1c) (0.070 g, 0.40 mmol) in
EtOH (1.5 mL) was added NaAuCl4·2H2O (0.006 g, 0.015 mmol).
The mixture was stirred under N2 at r.t. for 3.5 h, then KOH (0.057
g, 1.02 mmol) and a solution of I2 (0.104 g, 0.41mmol) in EtOH (1
mL) were added. The mixture was stirred for further 2 h, then ex-
tracted with 5% sodium thiosulfate (100 mL) and EtOAc (2 × 50
mL). The organic phase was dried (Na2SO4) and evaporated. Col-
umn chromatographic purification on silica gel (hexane–EtOAc,
95:5) afforded 2-butyl-3-iodo-1H-indole (4e).
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(b) Sundeberg, R. J. In Comprehensive Heterocyclic
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Yield: 0.098 g (81%); oil.
IR (neat): 3400 cm–1.
1H NMR: = 8.00 (br s, 1 H, NH), 7.40–7.33 (m, 1 H), 7.18–7.13
(m, 3 H), 2.71(t, J = 7.3 Hz, 2 H), 1.61–1.50 (m, 2 H), 1.40–1.29 (m,
2 H), 0.92 (t, J = 7.2 Hz, 3 H).
13C NMR: = 140.5, 135.9, 130.7, 122.3, 120.4, 120.3, 110.7, 58.6
(C-3) 31.3, 28.3, 22.2, 13.8.
MS: m/z (%) = 299 (100) [M+], 256 (70), 172 (14).
Anal. Calcd for C12H14IN: C, 48.18; H, 4.72; N, 4.68. Found: C,
48.15; H, 4.71; N, 4.70.
3-Iodo-2-phenyl-1H-indole (4c)
Mp 68–70 °C (Lit.19b 70–71 °C).
5,7-Dichloro-3-iodo-1H-indole 4d
Mp 142–143 °C.
IR (KBr): 3410, 1620 cm–1.
1H NMR (acetone-d6): = 11.25 (br s, 1 H, NH), 7.67 (s, 1 H), 7.33
(d, J = 1.8 Hz, 1 H), 7.30 (d, J = 1.8 Hz, 1 H).
(9) Dai, W. M.; Guo, D. S.; Sun, L. P.; Huang, X. H. Org. Lett.
2003, 5, 2919.
13C NMR (acetone-d6): = 133.2, 132.9, 132.7, 126.4, 122.6, 119.6,
118.0, 56.5(C-3).
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MS: m/z (%) = 315 (12) [M+ + 4], 313 (75) [M+ + 2], 311 (100)
[M+].
Anal. Calcd for C8H4Cl2IN:C, 30.80; H, 1.29; N, 4.49. Found: C,
30.85; H, 1.27; N, 4.47.
3,3 -Diiodo-1H,1 H-2,2 -biindole (4f)
Mp 125–126 °C (dec.).
IR (KBr): 3420 cm–1.
1H NMR (acetone-d6): = 11.78 (br s, 2 H, NH), 7.54–7.41 (m, 4
H), 7.31–7.14 (m, 4 H).
13C NMR (acetone-d6): = 133.8, 132.7, 131.4, 124.1, 121.4, 121.2,
112.7, 61.8 (C-3).
MS: m/z (%) = 484 (100) [M+], 357 (42), 230 (13)
Anal. Calcd for C16H10I2N2: C, 39.70; H, 2.08; N, 5.79. Found: C,
39.85; H, 2.10; N, 5.77.
Acknowledgment
This work was carried out in the framework of the National Project
‘La Catalisi dei Metalli di Transizione nello Sviluppo di Strategie
Sintetiche Innovative di Eterocicli’ supported by the Ministero
dell’Università e della Ricerca Scientifica e Tecnologica, Rome,
and by the University of L’Aquila.
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