A new general synthesis of N-hydroxyindoles

Article abstract of DOI:10.1055/s-2007-990970

Catalytic hydrogenation of 2-nitrobenzyl aldehydes, ketones and amides, using Pd/C and (Ph₃P)₄Pd, affords N-hydroxyindoles in good to excellent overall yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990970

LETTER
2999
A New General Synthesis of N-Hydroxyindoles
A
New General
S
ynthe
i
sis of
N
c
-Hydroxy
hindoles el Belley,* Daniel Beaudoin, Gabriel St-Pierre
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 30 August 2007
it catalyzes the ring closure of the hydroxylamine interme-
diate onto the cyano group. In the absence of (Ph3P)4Pd,
the reductive cyclization follows a different pathway lead-
ing exclusively to the formation of indoles that are unsub-
stituted at positions 1 and 2.
Abstract: Catalytic hydrogenation of 2-nitrobenzyl aldehydes, ke-
tones and amides, using Pd/C and (Ph3P)4Pd, affords N-hydroxyin-
doles in good to excellent overall yields.
Key words: N-hydroxyindoles, N-methoxyindoles, reductive cy-
clization, tetrakis(triphenylphosphine)palladium, catalytic hydro-
genation
Y
Y
H2 (1 atm)
CN
NO2
CN
NHOH
The recent discovery of naturally occurring, bioactive N-
hydroxyindoles such as nocathiacin I,1 stephacidin B2 and
coproverdine,3 and N-methoxyindoles (such as methoxy-
brassinin, paniculidine B, lespedamine and convolutin-
dole A) has sparked the interest of the scientific
community towards their synthesis.4 In addition, the use
of N-hydroxyindoles as intermediates and their hypothet-
ical existence as metabolites in the enzymatic functional-
ization of indoles make the exploration of new routes for
their preparation more attractive.
10% Pd/C
Pd(PPh3)4
X
X
EtOAc–AcOH (4:1)
H
2 (1 atm)
10% Pd/C
EtOAc–AcOH (4:1)
Y
Y
NH2
N
X
N
H
X
OH
A variety of approaches have been reported to yield N-hy-
droxyindoles. Many of them rely on the reductive cycliza-
tion of o-nitrobenzyl aldehydes, ketones, esters, amides,
Y = Ph, CN, CO2R, SO2R
54–95%
Scheme 1 Synthesis of N-hydroxy-2-aminoindoles having an elec-
nitriles or enamines using reagents such as Zn/AcOH,5 tron-withdrawing substituent or an aryl group at position 3.
SnCl2,6 H2/Rh/C,7 H2/Pd,8 NaBH4/Pd or Pb/TEAF9
(TEAF = triethylammonium formate). Also widely used
We wish to report herein new applications of this catalytic
are the base-promoted cyclization of o-nitroarylethane10
hydrogenation in which the cyclization occurs on amides,
and oxidations of indolines with H2O2/NaWO4.4 Finally,
aldehydes and ketones, even in the presence of a nitrile
the coupling reactions between isonitriles and b-nitrosty-
group, to form a variety of N-hydroxyindoles in excellent
renes,11 as well as between nitrosoarenes and alkynes,12
yields.
are noteworthy. All these methods have their merits, but
While exploring the scope of the reductive cyclization and
some are marred by issues such as lack of generality, poor
replacing the EWG a to the nitrile of 2-nitrophenylaceto-
chemoselectivity and yields, use of toxic heavy metals or
high temperature at which N-hydroxyindoles are unstable.
nitriles with amides,14 we found that the reaction pro-
gressed via a different route (Table 1). Instead of
We recently reported that catalytic hydrogenation of 2-ni-
cyclizing on the nitrile, the intermediate hydroxylamine
trophenylacetonitriles bearing an electron-withdrawing
reacted with the amide, forming an unstable 1,2-dihy-
group (EWG) or an aryl substituent a to the nitrile, using
droxy-3-cyanoindole 2 that could not be isolated cleanly.
However, treatment of the crude reaction mixture with di-
azomethane afforded pure 1,2-dimethoxyindoles 3. A
similar reaction was also observed with the amidoester 4,
providing the 1,2-dimethoxyindole-3-carboxylate 6 in ex-
cellent yield (Scheme 2). This chemoselectivity towards
a mixture of Pd/C and (Ph3P)4Pd, afforded N-hydroxy-2-
aminoindoles in good to excellent yields (Scheme 1).13 In
the absence of the EWG, we observed that the reductive
cyclization to form the indole ring does not occur. Instead,
we isolated mixtures of anilines and hydroxylamines orig-
inating from the reduction of the nitro group. The role of
the amide was a bit surprising in view of the fact that the
the co-catalyst (Ph3P)4Pd has been found to be two-fold:
reduction of the cyanoamide 7, using zinc in AcOH, was
It acts as a poisoning agent towards the Pd/C catalyst and
reported to yield the 2-aminoindole 8, with the amide in-
tact at position 3 (Scheme 2).5c Moreover, catalytic hydro-
genation of the cyanoamide 1b and its analogues over Pd/
SYNLETT 2007, No. 19, pp 2999–3002
Advanced online publication: 08.11.2007
DOI: 10.1055/s-2007-990970; Art ID: S06607ST
x
x
.x
x
.2
0
0
7
C yields anilines or indole-3-carboxamides, depending on
the temperature of the reaction.15b
© Georg Thieme Verlag Stuttgart · New York

3000
M. Belley et al.
LETTER
CO2Et
Table 1 Synthesis of 1,2-Dimethoxy-3-cyanoindoles
CO2Et
CONH2
NO2
H2, Pd/C
(Ph3P)4Pd
CN
CN
OH
N
H2, Pd/C
EtOAc–AcOH
(4:1), 4 h
1
F3C
5
4
(Ph3P)4Pd
F3C
X
OH
OH
R
R
5
4
EtOAc–AcOH
(4:1)
N
NO2
CO2Et
OH
2
1
CH2N2
OMe
N
CN
F3C
80% overall yield
CH2N2
OMe
OMe
OMe
6
R
N
3
O
O
N
O
N
O
Cyanoamide R
X
Reaction time 3, Yield
Zn, AcOH
(h)
(%)
CN
NH2
PhMe, 80 °C
75%
N
1a
1b
1c
4-CF3
4-CF3
5-Me
CONH2
6.5
65
H
NO2
7
8
CONHPh
CON(CH2)5
3
45
Scheme 2
23
61
Table 2 Synthesis of N-Hydroxy-3-cyanoindoles17
hydes 12 (Table 3). Treatment of 12a with diazomethane
afforded the natural product N-methoxyindole-3-carbal-
dehyde (13a) in two steps with an unoptimized overall
yield of 60%. This compound has been isolated from the
Cruciferae family of plants16 and is an intermediate in the
synthesis of many other natural products, including meth-
oxybrassinin, paniculidine B and lespedamine.4
CN
COR'
H2, Pd/C
5
(Ph3P)4Pd
CN
NO2
R'
R
R
6
EtOAc–AcOH
(4:1), 4–6 h
N
OH
9
10
We have reported that in order for the reductive cycliza-
tion to occur on the nitrile, either an EWG or an aromatic
substituent a to the nitrile function was necessary. With
ketones, that substituent is no longer required, as exempli-
fied in Scheme 3 with the synthesis of N-hydroxyindoles
18 and 21. Noteworthy was the hydrogenation of the un-
saturated aldehyde 14 where the double bond was also re-
duced to afford N-hydroxy-3-methylindole (15).
Cyanoketone
R
R¢
10, Yield (%)
9a
9b
9c
5-Me
6-CF3
6-F
Me
t-Bu
Ph
92
96
98
Table 3 Synthesis of N-Hydroxyindole-3-carboxaldehydes
CHO
CHO
The role of the co-catalyst (Ph3P)4Pd in all the transforma-
tions shown here might be slightly different from what we
have published previously with o-nitrophenylacetoni-
triles. For example, the reductive cyclization of the cy-
anoketone 9b over Pd/C and the co-catalyst (Ph3P)4Pd
yielded exclusively 10b17 (Table 2 and Scheme 4). How-
ever, in the absence (Ph3P)4Pd, a mixture of the tert-butyl
indole 23 and the N-hydroxyindole 10b was obtained. Us-
ing the same conditions with nitriles, the unsubstituted in-
doles were produced exclusively. The intermediate
hydroxylamines probably react readily with aldehydes
and ketones and (Ph3P)4Pd is not likely catalyzing this cy-
clization to afford the N-hydroxyindoles. The major role
of the co-catalyst might be to reduce the speed of the re-
duction of the nitro group to the amine, so that the hydrox-
ylamine intermediate would survive longer in the reaction
medium and have more time to cyclize onto the carbonyl
H2, Pd/C
(Ph3P)4Pd
CHO
R
R
6
EtOAc–AcOH
(4:1), 7 h
N
NO2
OH
12
11
CHO
5
CH2N2
R
6
N
OMe
13
Dialdehyde
11a
R
H
12, Yield (%) 13, Yield (%)
80
59
43
75
81
75
11b
5-Cl
6-MeO
11c
Table 2 summarizes the results obtained with ketones as functionality.
the EWG. Reductive cyclization of cyanoketones 9 pro-
In summary, we have given here examples of a new reduc-
vided N-hydroxy-3-cyanoindoles 10, substituted at C-2 by
an alkyl or an aryl group, in excellent yields. The o-nitro-
phenyl malonaldehydes 11 were found to react in the
same manner, providing N-hydroxyindole-3-carbalde-
tive cyclization of o-nitrobenzyl amides, aldehydes and
ketones leading to the generation of a large variety of N-
hydroxyindoles in good to excellent yields. This transfor-
mation, which requires only a simple hydrogenation over
Synlett 2007, No. 19, 2999–3002 © Thieme Stuttgart · New York

LETTER
A New General Synthesis of N-Hydroxyindoles
3001
H2, Pd/C
(Ph3P)4Pd
CH2N2
CHO
NO2
EtOAc–AcOH
(4:1), 6.5 h
N
N
OMe
OH
16, 29%
14
15, 72%
H2, Pd/C
(Ph3P)4Pd
MeI, DBU
EtOAc–AcOH
(4:1), 6 h
O
N
N
NO2
OH
OMe
17
19, 55%
18, 100%
H2, Pd/C
(Ph3P)4Pd
CH2N2
O
N
N
EtOAc–AcOH
(4:1), 4 h
MeO2C
MeO2C
MeO2C
NO2
OH
OMe
20
21, 90%
22, 91%
Scheme 3 Reductive cyclization on o-nitrobenzyl ketones
Zaragoza, F. Tetrahedron Lett. 1999, 40, 5799.
CN
(d) Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem. 2001, 66,
3474.
(7) Akao, A.; Nonoyama, N.; Mase, T.; Yasuda, N. Org.
Process Res. Dev. 2006, 10, 1178.
H2, Pd/C
t-Bu
23
9b
+
10b
EtOAc–AcOH
(4:1)
N
F3C
H
(8) Jiang, Y.; Zhao, J.; Hu, L. Tetrahedron Lett. 2002, 43, 4589.
(9) Wong, A.; Kuethe, J. T.; Davies, I. W. J. Org. Chem. 2003,
68, 9865; and references cited therein.
without (Ph3P)4Pd, 6 h
with (Ph3P)4Pd, 4 h
58%
35%
96%
(10) Wrobel, Z.; Makosza, M. Tetrahedron 1997, 53, 5501.
(11) Foucaud, A.; Razorilalana-Rabearivony, C.; Loukakou, E.;
Person, H. J. Org. Chem. 1983, 48, 3639.
Scheme 4
(12) Penoni, A.; Palmisano, G.; Broggini, G.; Kadowaki, A.;
Nicholas, K. M. J. Org. Chem. 2006, 71, 823.
(13) (a) Belley, M.; Sauer, E.; Beaudoin, D.; Duspara, P.;
Trimble, L. A.; Dubé, P. Tetrahedron Lett. 2006, 47, 159.
(b) Belley, M.; Beaudoin, D.; Duspara, P.; Sauer, E.; St-
Pierre, G.; Trimble, L. A. Synlett 2007, in press.
(14) Most of the substrates used for the reductive cyclization
were prepared by aromatic electrophilic substitution, either
with NaH in DMF15 (1a–c, 4 and 9c) or NaOH/TBAHS/
toluene18 (9a,b). Compounds 11a–c, 14 and 17 were
commercially available and 20 was prepared via a Pd-
catalyzed arylation of a ketone enolate.9
(15) (a) Grob, C. A.; Weissbach, O. Helv. Chim. Acta 1961, 44,
1748. (b) Bourdais, J.; Germain, C. Tetrahedron Lett. 1970,
11, 195.
Pd/C in the presence of (Ph3P)4Pd as a co-catalyst, was
also applied successfully to the synthesis of the naturally
occurring N-methoxyindole-3-carbaldehyde (13a).
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.;
Cantone, J. L.; Drexler, D.; Dalterio, R. A.; Lam, K. S. J.
Antibiot. 2003, 56, 232. (c) Naidu, B. N.; Sorenson, M. E.;
Matiskella, J. D.; Li, W.; Sausker, J. B.; Zhang, Y.; Connoly,
T. P.; Lam, K. S.; Bronson, J. J.; Pucci, M. J.; Yang, H.;
Ueda, Y. Bioorg. Med. Chem. Lett. 2006, 16, 3545.
(2) (a) 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.
(b) Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.;
Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006,
128, 8678.
(16) Monde, K.; Takasugi, M.; Shirata, A. Phytochemistry 1995,
39, 581.
(17) Typical Experimental Procedures:
2-tert-Butyl-1-hydroxy-6-(trifluoromethyl)-1H-indole-3-
carbonitrile (10b): To a solution of 4,4-dimethyl-2-[2-
nitro-4-(trifluoromethyl)phenyl]-3-oxopentanenitrile (9b;
236 mg, 0.75 mmol) in a mixture of EtOAc and 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 of EtOAc–hexane (0–
25%) as eluent afforded 10b (204 mg, 96% yield) as a light
beige powder; mp 144 °C (dec.). 1H NMR (400 MHz,
acetone-d6): d = 11.07 (s, 1 H), 7.84 (s, 1 H), 7.81 (d, J = 8.3
(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.
Heterocycles 1999, 50, 1157.
(5) (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) Erba, E.; Gelmi, M. L.;
Pocar, D. Tetrahedron 2000, 56, 9991.
(6) (a) Nicolaou, K. C.; Estrada, A. A.; Hyup Lee, S.; Freestone,
G. C. Angew. Chem. Int. Ed. 2006, 45, 5364. (b) Wu, Z.;
Ede, N. J. Org. Lett. 2003, 5, 2935. (c) Stephensen, H.;
Hz, 1 H), 7.58 (dd, J = 1.3, 8.3 Hz, 1 H), 1.69 (s, 9 H). 13
C
NMR (100 MHz, acetone-d6): d = 153.78, 133.02, 126.60,
125.14 (q, JC–F = 32 Hz), 124.91 (q, JC–F = 269 Hz), 119.19,
Synlett 2007, No. 19, 2999–3002 © Thieme Stuttgart · New York

3002
M. Belley et al.
LETTER
118.34 (q, JC–F = 4 Hz), 115.47, 106.68 (q, JC–F = 4 Hz),
78.60, 34.48, 28.51. IR (KBr): 3127, 2977, 2229 (CN), 1365,
1324, 1272, 1119 cm–1. MS (ESI, +ve): m/z = 283.0 [M + 1].
Anal. Calcd for C14H13F3N2O: C, 59.57; H, 4.64; N, 9.92.
Found: C, 59.47; H, 4.68; N, 9.55.
EtOAc–hexane (0–10%) as eluent to give dimethoxyindole
6 (191 mg, 80%) as a light beige powder; mp 76 °C. 1H NMR
(400 MHz, acetone-d6): d = 8.25 (d, J = 8.4 Hz, 1 H), 7.78 (s,
1 H), 7.52 (dd, J = 1.3, 8.4 Hz, 1 H), 4.40 (q, J = 7.1 Hz, 2
H), 4.38 (s, 3 H), 4.24 (s, 3 H), 1.43 (t, J = 7.1 Hz, 3 H). 13
C
Ethyl 1,2-Dimethoxy-6-(trifluoromethyl)-1H-indole-3-
carboxylate (6): The reductive cyclization of ethyl 3-amino-
2-[2-nitro-4-(trifluoromethyl)phenyl]-3-oxopropanoate (4;
270 mg, 0.75 mmol) was performed as described above. The
crude material obtained after filtration was redissolved into
THF and treated with an ethereal solution of CH2N2 at r.t. for
45 min. The excess CH2N2 was quenched with AcOH, the
solvents were evaporated and the residue was purified by
flash chromatography on silica gel using a gradient of
NMR (100 MHz, acetone-d6): d = 162.69, 155.17, 126.75,
125.10 (q, JC–F = 269 Hz), 123.91 (q, JC–F = 32 Hz), 123.75,
121.65, 118.50 (q, JC–F = 4 Hz), 105.28 (q, JC–F = 4 Hz),
88.54, 66.29, 63.39, 59.53, 13.90. IR (KBr): 2987, 2949,
1703, 1555, 1459 cm–1. MS (ESI, +ve): m/z = 318.0 [M + 1],
289.1, 229.0. Anal. Calcd for C14H14F3NO4: C, 53.00; H,
4.45; N, 4.41. Found: C, 53.20; H, 4.13; N, 4.30.
(18) Makosza, M.; Tomashewskij, A. A. J. Org. Chem. 1995, 60,
5425.
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