Synthesis and reactivity of N-hydroxy-2-aminoindoles

Article abstract of DOI:10.1016/j.tetlet.2005.10.165

Catalytic hydrogenation of (2-nitrophenyl)acetonitriles bearing an electron-withdrawing substituent α to the nitrile, using Pd/C and (Ph ₃P)₄Pd, affords N-hydroxy-2-aminoindoles in good to excellent yields. (Ph₃P)₄Pd decreases the reduction rate of the intermediate hydroxylamine and acts as a catalyst during the cyclization onto the nitrile.

Full text of DOI:10.1016/j.tetlet.2005.10.165

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 159–162
Synthesis and reactivity of N-hydroxy-2-aminoindoles
Michel Belley,* Effiette Sauer, Daniel Beaudoin, Petar Duspara, Laird A. Trimble
´
and Pascal Dube
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Que´bec, Canada H9R 4P8
Received 29 September 2005; revised 28 October 2005; accepted 31 October 2005
Available online 17 November 2005
Abstract—Catalytic hydrogenation of (2-nitrophenyl)acetonitriles bearing an electron-withdrawing substituent a to the nitrile, using
Pd/C and (Ph3P)4Pd, affords N-hydroxy-2-aminoindoles in good to excellent yields. (Ph3P)4Pd decreases the reduction rate of the
intermediate hydroxylamine and acts as a catalyst during the cyclization onto the nitrile.
Ó 2005 Elsevier Ltd. All rights reserved.
CO2R
CN
CO2R
or
The synthesis of N-hydroxyindoles has received consid-
erable attention in recent years and their biological roles
are still under investigation.1,2 Some of them have been
isolated from natural sources and others have been pos-
tulated as intermediates in the enzymatic functionaliza-
tion of indoles. However, there are very few reports in
the literature on the formation of N-hydroxy-2-amino-
indoles3 and their biological activity is unknown,
although they were used as intermediates in the synthesis
of potent anticonvulsant and antiarrhythmic agents.3a,4
H2 Pd/C
EtOAc
N
N
H
NO2
H
2
3
1
NC
CO2Et
Ph
1) H2 Pd/C
EtOH:toluene
2) PhCHO
Zn
AcOH
N
H
4
CO2R
CO2R
NH2
2-Cyano-2-(2-nitrophenyl)acetates 1 have been used
extensively as key intermediates in the synthesis of
indole derivatives (Scheme 1). Catalytic hydrogenation
of 1 over Pd/C in EtOAc affords indole-3-carboxylates
25 or, when R is a benzyl group, 2,3-unsubstituted
indoles 3.6 Hydrogenation of 1 (R = Et) over Pd/C in
toluene–EtOH yields the corresponding aniline, which
can then react with benzaldehyde to give the indoline
4.7 Reduction of 1 with zinc powder in acetic acid at
80–100 °C generates 2-aminoindole-3-carboxylates 5.8
However, when this reduction is performed at lower
temperature (or when SnCl2 is used as the reducing
agent),3c N-hydroxy-2-aminoindoles 6 are obtained as
major products in 20–66% yields.3a,b
and/or
NH2
N
OH
N
H
5
6
Scheme 1.
(Ph3P)4Pd no longer affords indoles 2. Instead, N-hydro-
xy-2-aminoindoles 6 are obtained almost exclusively.
We wish to report herein this new and unprecedented
method for the synthesis of 6, along with its mechanism.
Results from experiments on the reactivity of N-hydro-
xy-2-aminoindoles 6 will also be discussed.
In order to explore the scope of this novel reductive
cyclization, several analogs of 1 were prepared from
the reaction of 2-nitrofluorobenzenes or 2-nitrochloro-
benzenes with the anions of ethyl cyanoacetate, cyano-
methyl sulfones or malononitrile, using either NaH in
DMF (1a–g)3a,9 or NaOH and Bu4NHSO4 in toluene
(1h–j).10,11 Catalytic hydrogenation of these (2-nitro-
phenyl)acetonitriles over Pd/C in the presence of
During the course of our research, we found that catal-
ytic hydrogenation of 1 over Pd/C in the presence of
Keywords: Reductive cyclization; N-Hydroxy-2-aminoindole; Catalytic
hydrogenation; Tetrakis(triphenylphosphine)palladium(0); (Ph3P)4Pd.
*
Corresponding author. Tel.: +1 514 428 3075; fax: +1 514 428
4900; e-mail: belley@merck.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.165

160
M. Belley et al. / Tetrahedron Letters 47 (2006) 159–162
Table 1. Reductive cyclization of (2-nitrophenyl)acetonitriles to N-
hydroxy-2-aminoindoles
Replacement of (Ph3P)4Pd with PdCl2(dppf) did not
affect the course of the reaction since 6b could still be
obtained in 70% yield. On the other hand, only traces
of 6b were detected when (Ph3P)4Pd was substituted
with Pd2(dba)3 for the reductive cyclization. This result
suggests that the palladium ligand is possibly poisoning
the Pd/C catalyst. Although addition of triphenylphos-
phine to Pd/C did not interfere with the reduction of
1b to the indole 2 (R = Et), heating Pd/C in a solution
of Ph3P in EtOAc for 15 min at 75 °C prior to the
hydrogenation produced the N-hydroxy-2-aminoindole
6b in 53% yield. The poisoning effect of (Ph3P)4Pd might
be due to a Pd(0) catalyzed Ph3P transfer to the Pd/C
catalyst.
Y
Y
H2 (1 atm.)
CN
NO2
NH2
N
OR
10 % Pd/C
Pd(PPh3)4
X
X
EtOAc:AcOH 4:1
r.t. 3 h
1a-j
6a-j R = H
7a,c,d,e,g R = Me
CH2N2
Substrate no
X
Y
6, Yield (%) 7, Yield (%)
1a
1b
1c
1d
1e
1f
CF3
H
MeO
Cl
CO2Et
CO2Et
CO2Et
CO2Et
78
86
72
75
54
75c
98
91d
94, 96d
69a
MeSO2 CO2Et
AcNH
CF3
CF3
F
CO2Et
SO2Me 72
SO2Ph
SO2Ph
CN
In addition, Pd(PPh3)4 catalyzes the ring closure of the
hydroxylamine intermediate onto the cyano group. This
second role was confirmed when the unstable reaction
intermediate 14 readily cyclized in the presence of
Pd(PPh3)4 to generate 6i (82% yield, Scheme 3). The
hydroxylamine 14, which decomposed in EtOAc and
AcOH solutions in the absence of catalyst, was synthe-
sized by reduction of the (nitrophenyl)acetonitrile 1i
with sodium hypophosphite.14
1g
1h
1i
55d
90
94c
64b,c
1j
CF3
a Overall yield from 1, without purification of 6.
b The tetrabutylammonium salt of the (2-nitrophenyl)malononitrile
was used as the starting material.
c Reaction time 5 h.
d Methylation with MeI and DBU (3 equiv each) in THF at rt for
1.5 h.
N-Hydroxy-2-aminoindoles 6 are usually stable when
stored at 5 °C. However, derivatization or reduction of
N-hydroxy functionality has been found to increase
the stability of these compounds. For example, the
N-hydroxy-2-aminoindole 6b can be reduced to the
2-aminoindole 5b by catalytic hydrogenation in ethanol
under pressure15 (Scheme 4). N-Hydroxy substituent can
also be alkylated with an alkyl or a benzyl bromide
(Scheme 4),4 or methylated with diazomethane at room
temperature (Table 1). Finally, it can be acylated with
acetic anhydride in pyridine.3a However, the resulting
N-acylated compound 15c is not very stable and can
be hydrolyzed easily to afford 6a (in the refrigerator over
a period of weeks or by refluxing in methanol for
10 min).
(Ph3P)4Pd gave N-hydroxy-2-aminoindoles 6a–j in good
to excellent yields (Table 1).12,13 O-Methylation of 6,
with diazomethane (rt, 15 min) or MeI and DBU, affor-
ded N-methoxy-2-aminoindoles 7 as more stable deriva-
tives (vide infra).
The reductive cyclization proceeded well when the sub-
stituent a to the nitrile Y (Table 1) is an electron-with-
drawing group. However, when Y is a hydrogen or a
methyl group, the corresponding N-hydroxy-2-amino-
indoles were not detected. The cyclization leading to
the formation of indole did not occur and the major
products isolated were the anilines and/or the hydroxyl-
amines resulting from the reduction of the nitro group
(Scheme 2).
The 2-amino functionality is fairly unreactive under
basic conditions. N-Alkylation does not occur when
the N-hydroxy substituent is alkylated, even in the pres-
ence of a large excess of alkylating agent at high temper-
atures. Furthermore, acylation of 7d proceeded only
The presence of Pd(PPh3)4 is crucial for the reaction and
it serves two purposes. First, it acts as a poisoning agent
towards the Pd/C catalyst by modifying the chemoselec-
tivity of the reduction of the nitro functionality. When
3-nitrobenzotrifluoride 11 is hydrogenated over Pd/C,
the nitro group is completely reduced to the aniline 12
(Fig. 1). However, treatment of 11 with (Ph3P)4Pd under
the same reaction conditions afforded the hydroxyl-
amine 13 in 38% yield, along with some aniline 12.
CF3
NH2
CF3
NHOH
CF3
NO2
12
13
11
Figure 1.
H2 (1 atm.)
CN
CN
NO2
H2PO2Na
10% Pd/C
SO2Ph
CN
10 % Pd/C
Pd(PPh3)4
EtOAc;AcOH 4:1
r.t.
NHR
X
X
1i
6i
THF:H2O
r.t. 4.5 h
56%
8
9
X = R = H 24%
X = CF3; R = H 31%
10 X = CF3; R = OH 33%
1k X = H
1l1 X = CF3
Pd(PPh3)4
EtOAc:AcOH 4:1
r.t. 1 h
NHOH
F
14
Scheme 2.
Scheme 3.

M. Belley et al. / Tetrahedron Letters 47 (2006) 159–162
161
HCl in pyridine.18 Moreover, reaction of 17a–c with ace-
tyl chloride in THF at rt for 3 days afforded the N-acyl-
ated derivative 16 in 53% unoptimized yield.
H2 (40 psi)
Pd/C
CO2Et
NH2
5b
6b
N
EtOH:AcOH
79 %
H
In summary, we have demonstrated that N-hydroxy-2-
aminoindoles bearing an electron-withdrawing substitu-
ent in position 3 can be prepared in good yields via hydro-
genation with a modified Pd/C catalyst. The addition of
Pd(Ph3P)4 to the hydrogenation mixture was found to
alter the chemoselectivity of the reaction, an effect that,
to our knowledge, has not been reported previously.
CO2Et
NH2
N
OR
RBr / DBU / THF
r.t. o.n.
6a-b
or Ac2O / pyridine
r.t. 1 day
X
15a X = H R = (4-MeOPh)CH2 100 %
15b X = H R = Pr
15c X = CF3 R = Ac
97 %
68 %
New applications of this reaction towards the synthesis
of hydroxylamines and other N-hydroxyindoles are cur-
rently under investigation.
CO2Et
NHAc
Ac2O
16
7d
Acknowledgements
N
DMAP
pyridine
100 oC 2 h
67 %
Cl
O
The authors would like to thank the Natural Sciences
and Engineering Research Council of Canada
(NSERC), for undergraduate student research awards
Scheme 4.
´
given to P. Dube, P. Duspara, E. Sauer, and Julie Far-
and, for critical comments on the manuscript.
Ph
CO2Et
Ph
Supplementary data
NH
Physical data for all the new compounds described in
this article can be found in the online version. Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2005.10.165.
N
Cl
O
17a (major)
Ph
CO2Et
Ph
+
CO2Et
a
c
H
N
O
7d
References and notes
N
O
Ph
N
O
Cl
Cl
b
Ph
1. Wong, A.; Kuethe, J. T.; Davies, I. W. J. Org. Chem. 2003,
68, 9865–9866, and references cited therein.
2. For reviews on N-hydroxyindoles, see: (b) Somei, M. Adv.
Heterocycl. Chem. 2002, 82, 101–155; (c) Somei, M.
Heterocycles 1999, 50, 1157–1211.
17b
18
+
CO2Et
N
3. (a) Munshi, K. L.; Kohl, H.; de Souza, N. J. J. Heterocycl.
Chem. 1977, 14, 1145–1146; (b) Showalter, H. D. H.;
Bridges, A. J.; Zhou, H.; Sercel, A. D.; McMichael, A.;
Fry, D. W. J. Med. Chem. 1999, 42, 5464–5474; (c)
Stephensen, H.; Zaragoza, F. Tetrahedron Lett. 1999, 40,
5799–5802.
4. Munshi, K. L.; Bhattacharyya, B. K.; Dohadwalla, A. H.
N.; de Souza, N. J.; Kohl, H. Indian Pat. Appl. 75-BO108,
1975; Chem. Abstr. 1980, 92, 163840.
N
O
Ph
Cl
Ph
17c
Scheme 5. Reagents and conditions: (a) Ph2CHOH, cat. H2SO4,
AcOH, rt, 16 h, 80%; (b) aq HCl, THF; (c) 2 N HCl, pyridine, rt,
4 days, 83%.
under forceful conditions (Scheme 4). These results sug-
gest that this amine reacts more like a vinylogous carba-
mate than like an arylamine.
´
5. (a) Belley, M.; Scheigetz, J.; Dube, P.; Dolman, S. Synlett
2001, 222–225; (b) Snyder, H. R.; Merica, E. P.; Force, C.
G.; White, E. G. J. Am. Chem. Soc. 1958, 80, 4622–4625,
and references cited therein; for similar reductions, see: (c)
Bourdais, J.; Germain, C. Tetrahedron Lett. 1970, 11, 195–
198, and references cited therein.
Acid-catalyzed alkylation of amides, carbamates and
anilines with diarylcarbinols has been reported to occur
readily in acetic acid at room temperature.16 The result-
ing diarylmethyl substituents were used as protecting
groups in synthesis.16b Reaction of 7d with diphenyl-
carbinol under these acid-catalyzed conditions yielded
a mixture of three inseparable compounds 17a–c (single
peak on HPLC, Scheme 5), which are in equilibrium
with each other in solution.17 These products could be
hydrolyzed back to the starting material with HCl in
THF or converted to the oxindole 18 with aqueous
6. Walkington, A.; Gray, M.; Hossner, F.; Kitteringham, J.;
Voyle, M. Synth. Commun. 2003, 33, 2229–2233.
7. Dijkink, J.; Zonjee, J. N.; de Jong, B. S.; Speckamp, W. N.
Heterocycles 1983, 20, 1255–1258.
8. (a) Forbes, I. T.; Morgan, H. K. A.; Thompson, M. Synth.
Commun. 1996, 26, 745–754; (b) Glushkov, R. G.;
Volokova, V. A.; Yu, O. Khim. Farm. Zh. 1967, 1, 25–
32; Chem. Abstr. 1968, 68, 105143f; (c) Reduction with
SnCl2 and HCl in ether has also been reported to yield 2-
aminoindoles.5b

162
M. Belley et al. / Tetrahedron Letters 47 (2006) 159–162
9. (a) Grob, C. A.; Weissbach, O. Helv. Chim. Acta 1961, 44,
14. The unstable intermediate [4-fluoro-2-(hydroxyamino)-
phenyl](phenylsulfonyl)acetonitrile 14 was prepared using
the method of Entwistle, I. D.; Gilkerson, T.; Johnstone,
R. A. W.; Telford, R. P. Tetrahedron 1978, 34, 213–215,
The crude product was purified by flash chromatography
on silica, with each fraction collected being cooled down
to À78 °C and kept under N2 as much as possible.
Concentration of the fractions containing 14 was done in
vacuo without heating above 20 °C.
1748–1753; (b) Scobie, M.; Tennant, G. J. Chem. Soc.,
Chem. Commun. 1993, 1756–1757.
10. Makosza, M.; Tomashewskij, A. A. J. Org. Chem. 1995,
60, 5425–5429.
11. Tetrabutylammonium
dicyano[2-nitro-4-(trifluoro-
methyl)phenyl]methanide 1j was prepared by treating 1-
chloro-2-nitro-4-(trifluoromethyl)benzene (8.9 mmol) with
malononitrile (1 equiv), Bu4NHSO4 (1 equiv) and 10 N
NaOH (6.8 equiv) in toluene (30 mL) at 70 °C for 4.3 h.10
When the reaction was complete, water was added and the
tetrabutylammonium salt 1j was extracted with EtOAc
and purified by flash chromatography on silica (10%
MeOH/CH2Cl2) to afford a bright red powder (82% yield).
12. General procedure for the formation of N-hydroxy-2-
aminoindoles. To a solution of (2-nitrophenyl)acetonitrile
1a–j (0.70 mmol) in EtOAc–AcOH 4:1 (5 mL) was added
10% Pd/C (22 mg, 2.0 mol %) and Pd(PPh3)4 (12 mg,
1.5 mol %) and this mixture was stirred under an atmo-
sphere of hydrogen for 3 h. The catalyst was removed by
filtration through Celite and the solvents were evaporated
in vacuo. The crude product was purified by flash
chromatography.
15. For similar reduction of N-hydroxyindoles, see: Penoni,
A.; Volkmann, J.; Nicholas, K. M. Org. Lett. 2002, 4, 699–
701.
16. (a) Henneuse, C.; Boxus, T.; Tesolin, L.; Pantano, G.;
Marchand-Brynaert, J. Synthesis 1996, 495–501; (b) Lau-
rent, M.; Marchand-Brynaert, J. Synthesis 2000, 667–672,
and references cited therein.
17. 1H NMR spectra in methanol-d4, acetone-d6 and DMSO-
d6 solutions display many broad peaks, which coalesce to
a smaller number of broad peaks at higher temperature
(100 °C in DMSO-d6). The structure of the major isomer
ethyl 6-chloro-3-(diphenylmethyl)-2-imino-1-methoxyind-
oline-3-carboxylate 17a was fully established by perform-
ing ROESY NMR studies (600 MHz, in DMSO-d6 with
some TFA to give sharp peaks).
13. Physical data for compounds 6b–d,f are in good agreement
with the published data.3a The novel N-hydroxy-2-amino-
indoles and their derivatives were characterized by 1H
NMR, 13C NMR, IR, MS, elemental analysis and/or
HRMS.
18. The structure of ethyl 6-chloro-3-(diphenylmethyl)-1-
methoxy-2-oxoindoline-3-carboxylate 18 was fully estab-
lished from 600 MHz NMR studies (NOESY, gCOSY,
gHSQC and gHMBC).