Synthesis and reactivity of N-hydroxy-2-amino-3-arylindoles

Article abstract of DOI:10.1055/s-2007-990969

Catalytic hydrogenation of 2-nitrophenylacetonitriles bearing an aromatic substituent α to the nitrile group, using Pd/C and (Ph₃P) ₄Pd, affords unstable N-hydroxy-2-amino-3-arylindoles which, after autoxidation, yields 2-amino-3-ary

Full text of DOI:10.1055/s-2007-990969

LETTER
2991
Synthesis and Reactivity of N-Hydroxy-2-Amino-3-Arylindoles
S
ynthesis and Reactivi
i
ty of
N
c
-Hydroxy-
2
h
-Amino-3-A
e
rylindoles l Belley,* Daniel Beaudoin, Petar Duspara, Effiette Sauer, Gabriel St-Pierre, Laird A. Trimble
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Highway, Kirkland, QC,
H9H 3L1, Canada
E-mail: belley@merck.com
Received 24 July 2007
Y
Y
Abstract: Catalytic hydrogenation of 2-nitrophenylacetonitriles
bearing an aromatic substituent a to the nitrile group, using Pd/C
and (Ph3P)4Pd, affords unstable N-hydroxy-2-amino-3-arylindoles
which, after autoxidation, yields 2-amino-3-aryl-3H-indol-3-ol 1-
oxides.
H2 (1 atm)
CN
NO2
CN
NHOH
10% Pd/C
Pd(PPh3)4
EtOAc–AcOH (4:1)
X
X
Key words: N-hydroxyindoles, N-methoxyindoles, reductive cy-
clization, tetrakis(triphenylphosphine)palladium, catalytic hydro-
genation
H
2 (1 atm)
10% Pd/C
EtOAc–AcOH (4:1)
Y
Y
NH2
The recent discovery of naturally occurring and bioactive
N-hydroxyindoles, such as nocathiacin I,1 stephacidin B,2
and coproverdine,3 has sparked the interest of the scientif-
ic community.4,5 In addition, their use in synthesis, their
hypothetical existence as metabolites in the enzymatic
functionalization of indoles and the presence of many N-
methoxyindoles (such as methoxybrassinin, paniculidine
B, lespedamine and convolutindole A) in nature, makes
the exploration of new routes for their preparation more
attractive. However, there are very few reports in the lit-
erature on the formation of N-hydroxy-2-aminoindoles6
and their biological activity is unknown, although they
have been used as intermediates in the synthesis of potent
anticonvulsant and antiarrhythmic agents.6a,7
N
X
N
H
X
OH
Y = CN, CO2R, SO2R
54–94%
Scheme 1 Synthesis of N-hydroxy-2-aminoindoles with an EWG at
position 3
ford stable N-methoxyindoles or oxidized by air to give 2-
amino-3-aryl-3H-indol-3-ol 1-oxides in excellent yields.
The 2-nitrophenylacetonitriles 1 (Table 1) were all pre-
pared in good yields by nucleophilic aromatic substitution
on the corresponding chloro- or fluoronitrobenzene with
an arylacetonitrile using sodium hydroxide and tetrabutyl-
ammonium hydrogen sulfate in toluene at room tempera-
ture.9 They were then treated with an atmosphere of
hydrogen over Pd/C containing Pd(PPh3)4 as a co-catalyst
to form the N-hydroxy-2-amino-3-arylindoles 2 in excel-
lent yields (Table 1). The presence of electron-donating or
-withdrawing substituents on either of the aromatic
groups did not seem to affect this reductive cyclization
and the conditions used were mild enough so that a benzyl
ether substituent (substrate 1g) was not cleaved.
We recently reported that catalytic hydrogenation of 2-ni-
trophenylacetonitriles bearing an electron-withdrawing
group (EWG) a to the nitrile group, using a mixture of Pd/
C and (Ph3P)4Pd, affords N-hydroxy-2-aminoindoles in
good to excellent yields (Scheme 1).8 In the absence of the
EWG, we mentioned that the reductive cyclization to
form the indole ring does not occur. Instead, we isolated
mixtures of anilines and hydroxylamines originating from
the reduction of the nitro group. The role of the co-cata-
lyst, (Ph3P)4Pd, has been found to be two-fold: it acts as a
poisoning agent towards the Pd/C catalyst and it catalyzes
the ring closure of the hydroxylamine intermediate onto
the cyano group. In the absence of (Ph3P)4Pd, the reduc-
tive cyclization follows a different pathway leading to the
formation of indoles that are unsubstituted on positions 1
and 2.
The critical role of the co-catalyst (Ph3P)4Pd in this trans-
formation was confirmed as follows: In its presence, the
reductive cyclization of 1f provided exclusively 2f
(Table 1), while in its absence, the 1,2-unsubstituted in-
dole 310 was obtained selectively (Scheme 2), without
traces of 2f detected during the reaction.
Depending on the reaction time and the quality of the Pd
catalysts, we were able to detect by TLC and sometimes
isolate the intermediate hydroxylamines in variable
yields. For example, the diarylacetonitrile 1c afforded
70% of the N-hydroxyindole 2c, along with 22% of the
hydroxylamine 411 (Table 1). This hydroxylamine was
found to remain unchanged for two hours when dissolved
into the solvent of the reaction (EtOAc–AcOH, 4:1).
However, in the presence of (Ph3P)4Pd, it cyclized com-
We wish to report here that the EWG can be replaced with
an aromatic substituent to yield unstable N-hydroxy-2-
amino-3-arylindoles, which can then be methylated to af-
SYNLETT 2007, No. 19, pp 2991–2994
x
x
.x
x
.2
0
0
7
Advanced online publication: 08.11.2007
DOI: 10.1055/s-2007-990969; Art ID: S05407ST
© Georg Thieme Verlag Stuttgart · New York

2992
M. Belley et al.
LETTER
Et
The instability of the N-hydroxy-2-amino-3-arylindoles 2
was due to their oxidation in the presence of air to give
crystalline derivatives to which structure 6 was assigned
(Table 1). Their structure was confirmed by NMR, IR,
MS and elemental analysis, but all our attempts to obtain
good crystals for X-ray diffraction studies failed. Howev-
er, similar oxidations of indoles possessing a heteroatom
in position 212 and of N-hydroxy-2-phenylindoles13 have
been reported to give close analogues of the N-oxides 6.
H2 (1 atm)
10% Pd/C
EtOAc–AcOH (4:1)
r.t. 20 h
1f
3
86%
N
F3C
H
OMe
Indirect confirmations of structure were obtained from the
high polarity of the 2-amino-3-aryl-3H-indol-3-ol 1-ox-
ides 6, which suggested a zwitterionic nature, and their
unreactivity towards diazomethane, which confirmed the
absence of a N-hydroxyindole functionality. More impor-
tantly, their basic hydrolysis yielded N,3-dihydroxyin-
dolinones 7 (Scheme 3), the structure of which was
confirmed by NMR analysis of 7b (600 MHz, NOE,
NOESY, gHMBC and gHSQC) and by its synthesis via an
alternative route involving the addition of a Grignard re-
agent to an N-hydroxyisatin (Scheme 4).14
Pd(PPh3)4
EtOAc–AcOH (4:1)
CN
2c
84%
F3C
NHOH
4
Scheme 2
pletely within those two hours to the N-hydroxyindole 2c
(Scheme 2), thus confirming its catalytic role in the ring
closure.
With NaOH at higher temperatures, the N-oxides 6 and
the N,3-dihydroxyindolinones 7 were found to be hydro-
lyzed to benzisoxazoles 8 (Scheme 3). The trifluorometh-
ylated derivative 8a was identical to a sample prepared
from 3-nitrobenzotrifluoride and phenylacetonitrile in the
presence of MgCl2 and DBU.15
Solutions containing the N-hydroxy-2-amino-3-arylin-
doles 2 were found to be unstable. However, treatment of
2 with diazomethane afforded the more stable N-meth-
oxyindoles 5 in good to excellent yields (Table 1). Other
methylation methods were also effective. For example, re-
action of the hydroxyindole 2e with methyl iodide or di-
methyl sulfate at room temperature for two hours in
acetone in the presence of K2CO3 gave 5e in 74% and 89%
yields, respectively.
Finally, the N,3-dihydroxyindolinone 7b was methylated
with diazomethane to afford compound 9, whose structure
was confirmed from 600 MHz NOESY NMR studies.
Table 1 Reductive Cyclization of 2-Nitrophenylacetonitriles16
Ar
NH2
X
Ar
CH2N2
Ar
N
H2 (1 atm)
1
2
5
OMe
CN
NO2
5
X
NH2
X
10% Pd/C
Pd(PPh3)4
EtOAc–AcOH (4:1)
N
4
Ar
O2
OH
NH2
OH
2
1
X
N+
O–
6
Substrate
X
Ar
Ph
2, Yield (%)
5, Yield (%)
6, Yield (%)
1a
1b
1c
1d
1e
1f
4-CF3
4-Cl
93
76
70b
95
83
86
70
71a
92
86
84
87
39c
–
66a
73
87
67
75
76
64
4-ClPh
4-CF3
4-CF3
4-F
4-(MeO)Ph
4-CF3Ph
4-(CN)Ph
4-EtPh
4-CF3
5-BnO
1g
4-CF3Ph
a Overall yield from 1, without isolation of 2.
b The hydroxylamine intermediate 4 was also isolated in 22% yield.
c Compound 6f was also isolated in 22% yield.
Synlett 2007, No. 19, 2991–2994 © Thieme Stuttgart · New York

LETTER
Synthesis and Reactivity of N-Hydroxy-2-Amino-3-Arylindoles
2993
Cantone, J. L.; Drexler, D.; Dalterio, R. A.; Lam, K. S. J.
Antibiot. 2003, 56, 232.
R
R
(2) Qian-Cutrone, J.; Huang, S.; Shu, Y.-Z.; Vyas, D.; Fairchild,
C.; Menendez, A.; Krampitz, K.; Dalterio, R.; Klohr, S. E.;
Gao, Q. J. Am. Chem. Soc. 2002, 124, 14556.
(3) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278.
(4) For reviews on N-hydroxyindoles, see: (a) Somei, M. Adv.
Heterocycl. Chem. 2002, 82, 101. (b) Somei, M.
OH
NH2
N+
O-
OH
NaOH
O
MeOH–THF
reflux
X
N
X
OH
Heterocycles 1999, 50, 1157.
6a,b
(5) Wong, A.; Kuethe, J. T.; Davies, I. W. J. Org. Chem. 2003,
68, 9865; and references cited therein.
7a, R = H, X = CF3 94%
7b, R = Cl, X = Cl 62%
R
(6) (a) Munshi, K. L.; Kohl, H.; de Souza, N. J. J. Heterocycl.
Chem. 1977, 14, 1145. (b) Showalter, H. D. H.; Bridges, A.
J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D. W. J.
Med. Chem. 1999, 42, 5464. (c) Stephensen, H.; Zaragoza,
F. Tetrahedron Lett. 1999, 40, 5799.
(7) Munshi, K. L.; Bhattacharyya, B. K.; Dohadwalla, A. H. N.;
de Souza, N. J.; Kohl, H. Indian Patent Appl. 75BO108,
1975; Chem. Abstr. 1980, 92, 163840.
(8) Belley, M.; Sauer, E.; Beaudoin, D.; Duspara, P.; Trimble, L.
A.; Dubé, P. Tetrahedron Lett. 2006, 47, 159.
(9) Makosza, M.; Tomashewskij, A. A. J. Org. Chem. 1995, 60,
5425.
NaOH
CH2N2
66%
MeOH–THF
90 °C 16 h
Cl
O
N
X
OH
O
8a, R = H, X = CF3 33%
8b, R = Cl, X = Cl 50%
N
Cl
OMe
(10) 3-(4-Ethylphenyl)-6-(trifluoromethyl)-1H-indole (3): 1H
NMR (400 MHz, acetone-d6): d = 8.10 (d, J = 10.5 Hz, 1 H),
7.89 (s, 1 H), 7.83 (s, 1 H), 7.66 (d, J = 11.0 Hz, 2 H), 7.42
(d, J = 10.5 Hz, 1 H), 7.34 (d, J = 11.0 Hz, 2 H), 2.71 (q, J =
8.0 Hz, 2 H), 1.28 (t, J = 8.0 Hz, 3 H). IR (neat): 3393, 2972,
2923, 1549, 1511, 1127 cm–1. MS (APCI, –ve): m/z = 287.9
[M – 1].
(11) [2-(Hydroxyamino)-4-(trifluoromethyl)phenyl](4-
methoxyphenyl)acetonitrile (4): 1H NMR (500 MHz,
acetone-d6): d = 8.12 (s, 1 H), 7.92 (s, 1 H), 7.67 (s, 1 H),
7.59 (d, J = 11.0 Hz, 1 H), 7.35 (m, 3 H), 7.00 (d, J = 9.0 Hz,
2 H), 6.68 (s, 1 H), 3.83 (s, 3 H). IR (neat): 2800–3500 (br),
2225 (CN) cm–1. MS (ESI, –ve): m/z = 381.1 [M + AcO–],
321.2 [M – 1], 303.1, 288.2.
9
Scheme 3 Basic hydrolysis of the 2-amino-3-aryl-3H-indol-3-ol 1-
oxides 6
O
N–
1) SOCl2
2) CH2N2
CO2H
NO2
N+
50%
Cl
Cl
NO2
O
HCO2H
50 °C, 1.5 h
4-ClC6H4MgBr
THF, –10 °C
O
7b
22%
N
45%
Cl
(12) Nakagawa, M.; Yamaguchi, H.; Hino, T. Tetrahedron Lett.
OH
1970, 11, 4035.
Scheme 4 Alternative synthesis of the N,3-dihydroxyindolinone 7b
(13) Berti, C.; Greci, L.; Poloni, M.; Andreeti, G. D.; Bocelli, G.;
Sgarabotto, P. J. Chem. Soc., Perkin Trans. 2 1980, 339.
(14) 6-Chloro-1-hydroxyisatin (Scheme 4) was prepared by the
method mentioned in: Giovanini, E.; Portmann, P. Helv.
Chim. Acta 1948, 31, 1381.
(15) Wrobel, Z. Polish J. Chem. 1998, 72, 2384.
(16) Typical Experimental Procedures:
In summary, we have given here examples of a new reduc-
tive cyclization of o-nitrophenylacetonitriles 1 leading to
the formation of N-hydroxy-2-amino-3-arylindoles 2.
This transformation requires only a simple hydrogenation
over Pd/C in the presence of (Ph3P)4Pd as a co-catalyst.
We have also shown how to prepare the more stable meth-
oxy derivatives 5 and we have identified the products 6
arising from autoxidation of the N-hydroxyindoles 2. Fi-
nally, we have hydrolyzed the oxidized products 6 to yield
interesting N,3-dihydroxyoxindoles 7 and benzisoxazoles
8.
4-(2-Amino-6-fluoro-1-hydroxy-1H-indol-3-yl)benzo-
nitrile (2e): To a solution of 4-[cyano(4-fluoro-2-nitro-
phenyl)methyl]benzonitrile (1e; 210 mg, 0.75 mmol) in a
mixture of EtOAc–AcOH (4:1, 12 mL) were added 10% Pd/
C (40 mg, 0.05 equiv) and (Ph3P)4Pd (13 mg, 0.015 equiv).
This mixture was degassed and stirred under an atmosphere
of hydrogen for 4 h. The solids were removed by a filtration
through Celite and the solvents were evaporated. Flash
chromatography of the residue on silica gel using a gradient
from 5% to 40% EtOAc–hexane afforded 2e (162 mg, 81%
yield) as a light orange powder; mp 146–147 °C (dec.). 1H
NMR (400 MHz, acetone-d6): d = 10.21 (s, 1 H), 7.76 (m, 4
H), 7.57 (dd, J = 4.9, 8.6 Hz, 1 H), 7.02 (br s, 1 H), 6.82 (br
s, 1 H), 5.66 (br s, 2 H). IR (KBr): 3348, 3210, 2923, 2226,
1670, 1631, 1601, 1510, 1493, 1479, 1466 cm–1. MS (ESI,
–ve): m/z = 532.8 (2 × M – 1), 266.1 (M – 1), 248.1.
4-(2-Amino-6-fluoro-3-hydroxy-1-oxido-3H-indol-3-
yl)benzonitrile (6e): The N-hydroxyindole 2e (78.9 mg,
0.216 mmol) was dissolved in EtOAc (2.5 mL) and this
solution was stirred for 3 d at r.t. under open air. The solid 6e
(44.3 mg) was separated by filtration and the residue from
Acknowledgment
The authors would like to thank the Natural Sciences and Enginee-
ring Research Council of Canada for an undergraduate research
award granted to E. Sauer.
References and Notes
(1) (a) Li, W.; Leet, J. E.; Ax, H. A.; Gustavson, D. R.; Brown,
D. M.; Turner, L.; Brown, K.; Clark, J.; Yang, H.; Fung-
Tomc, J.; Lam, K. S. J. Antibiot. 2003, 56, 226. (b) Leet, J.
E.; Li, W.; Ax, H. A.; Matson, J. A.; Huang, S.; Huang, R.;
Synlett 2007, No. 19, 2991–2994 © Thieme Stuttgart · New York

2994
M. Belley et al.
LETTER
heated to reflux (65 °C) for 16 h. The reaction was then
the filtrate was purified by flash chromatography on silica
gel eluting with 10% MeOH–CH2Cl2 to afford a second crop
of 6e (18.3 mg, overall yield 75%) as a white solid; mp
188.5–189.5 °C (dec.). 1H NMR (400 MHz, MeOH-d4): d =
7.78 (d, J = 10.5 Hz, 2 H), 7.60 (d, J = 10.5 Hz, 2 H), 7.05–
7.25 (m, 2 H), 6.91 (dd, J = 1.8, 11.0 Hz, 1 H), 4.61 (br s, 1
quenched with sat. NH4Cl, extracted with isopropyl acetate,
dried over Na2SO4 and concentrated. Trituration of the
residue in dichloromethane afforded 7b (92 mg, 62% yield)
as a yellow solid; mp 162–163 °C (dec.). 1H NMR (500
MHz, DMSO-d6): d = 11.10 (s, 1 H), 7.43 (d, J = 8.5 Hz, 2
H), 7.30 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 1 H), 7.12
(dd, J = 1.7, 8.0 Hz, 1 H), 7.07 (m, 2 H). 13C NMR (100
MHz, acetone-d6): d = 173.05, 144.95, 140.01, 135.91,
134.33, 129.19, 128.27, 126.68, 123.78, 108.93, 76.39,
14.60. IR: 3140, 1710, 1610 cm–1. MS (APCI, –ve): m/z =
310.1, 308.1 [M – 1], 272.1.
6-Chloro-3-(4-chlorophenyl)-2,1-benzisoxazole (8b): The
oxindole 7b (50 mg, 0.161 mmol) was dissolved in MeOH–
THF–H2O (3:1:2, 4.5 mL). Addition of 10 N NaOH (90 mL,
5.6 equiv) resulted in a clear yellow solution that was heated
to 90 °C overnight in a sealed tube. The reaction was then
quenched with sat. NH4Cl, extracted with isopropyl acetate,
dried over Na2SO4 and concentrated. Purification by flash
chromatography on silica gel eluting with 2% EtOAc–
hexanes afforded 8b (21 mg, 50% yield) as a yellow solid;
mp 152.0–153.5 °C. 1H NMR (500 MHz, acetone-d6): d =
8.17 (d, J = 7.8 Hz, 2 H), 8.12 (d, J = 9.1 Hz, 1 H), 7.75 (d,
J = 1.8 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 2 H), 7.17 (dd, J = 1.8,
9.1 Hz, 1 H). IR (KBr): 1640 cm–1. MS (ESI, +ve): m/z =
266.1, 264.1 [M + 1].
6-Chloro-3-(4-chlorophenyl)-3-hydroxy-1-methoxy-1,3-
dihydro-2H-indol-2-one (9): The oxindole 7b (39.9 mg,
0.129 mmol) was dissolved in THF (2 mL) and treated with
an ethereal solution of diazomethane at r.t. for 2.5 h. The
excess CH2N2 was quenched with AcOH, the solvents were
evaporated and the residue was purified by flash chromatog-
raphy on silica gel eluting with 10% EtOAc–toluene to
obtain 9 (27.8 mg, 66% yield) as an oil. 1H NMR (500 MHz,
acetone-d6): d = 7.46 (d, J = 8.6 Hz, 2 H), 7.41 (d, J = 8.6 Hz,
2 H), 7.30 (d, J = 7.0 Hz, 1 H), 7.20 (dd, J = 2.0, 7.0 Hz, 1
H), 7.18 (d, J = 2.0 Hz, 1 H), 6.06 (s, 1 H), 4.05 (s, 3 H). MS
(ESI, –ve): m/z = 384.2, 382.1 [M + AcO–], 324.1, 322.1
[M – 1], 290.2 [M – MeOH – 1].
H). 13C NMR (100 MHz, DMSO-d6): d = 163.92 (d, JC–F
243.3 Hz), 157.30, 148.30 (d, JC–F = 11.7 Hz), 146.24,
=
133.03 (2 × C), 130.72, 126.80 (2 × C), 124.24 (d, JC–F = 9.5
Hz), 119.05, 111.28, 111.02 (d, JC–F = 23.0 Hz), 99.34 (d,
JC–F = 27.8 Hz), 77.65. IR (KBr): 3287, 2233, 1699, 1630,
1610, 1491, 1183 cm–1. MS (ESI, +ve): m/z = 283.8 [M + 1].
Anal. Calcd for C15H10N3FO2·0.4EtOAc: C, 62.60; H, 4.18;
N, 13.19. Found: C, 62.24; H, 3.82; N, 12.80. HRMS: m/z
[M + H] calcd for C15H11N3FO2: 284.0830; found: 284.0837.
4-(2-Amino-6-fluoro-1-methoxy-1H-indol-3-yl)benzo-
nitrile (5e): To a solution of the N-hydroxyindole 2e (78.9
mg, 0.216 mmol) in EtOAc (2.5 mL) was added an ethereal
solution of CH2N2. This mixture was stirred at r.t. for about
30 min and the excess CH2N2 was quenched with AcOH.
The solvents were evaporated and the residue was purified
by flash chromatography on silica gel with 10% EtOAc–
toluene to obtain 5e (73.3 mg, 87%) as a yellow solid; mp
136–137 °C (dec.). 1H NMR (400 MHz, acetone-d6): d =
7.70–7.90 (m, 4 H), 7.50–7.65 (m, 1 H), 7.12 (dd, J = 1.1, 9.5
Hz, 1 H), 6.88 (dd, J = 2.4, 9.5 Hz, 1 H), 5.82 (br s, 2 H), 4.15
(s, 3 H). 13C NMR (100 MHz, acetone-d6): d = 158.28 (d,
JC–F = 232.8 Hz), 141.84, 140.76, 132.53 (2 × C), 130.19 (d,
JC–F = 11.9 Hz), 127.15 (2 × C), 119.56, 119.10, 116.81 (d,
JC–F = 9.2 Hz), 108.21 (d, JC–F = 23.3 Hz), 106.56, 94.50 (d,
JC–F = 27.7 Hz), 88.32, 64.27. IR (KBr): 3457, 3353, 2222,
1620, 1599 cm–1. MS (ESI, +ve): m/z = 282.1 [M + 1]. Anal.
Calcd for C16H12N3FO: C, 68.32; H, 4.30; N, 14.94. Found:
C, 68.40; H, 4.08; N, 14.86.
6-Chloro-3-(4-chlorophenyl)-1,3-dihydroxy-1,3-
dihydro-2H-indol-2-one (7b): 2-Amino-6-chloro-3-(4-
chlorophenyl)-3H-indol-3-ol 1-oxide (6b; 149 mg, 0.481
mmol) was diluted into MeOH–THF–H2O (3:1:2, 13.5 mL)
to give a cloudy yellow mixture. Addition of 10 N NaOH
(0.27 mL, 5.6 equiv) resulted in a clear red solution that was
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