Palladium-catalyzed reduction of N-(tert-Butoxycarbonyl)indoles by polymethylhydrosiloxane

Article abstract of DOI:10.1055/s-2007-966029

The palladium-catalyzed [10% Pd(OH)₂/C] reduction of N-(tert-butoxycarbonyl)indoles to the corresponding N-(tert-butoxycarbonyl) indolines is described. Polymethylhydrosiloxane was used as reducing agent and the reaction proceeded smoothly at r

Full text of DOI:10.1055/s-2007-966029

PAPER
1509
Palladium-Catalyzed Reduction of N-(tert-Butoxycarbonyl)indoles by
Polymethylhydrosiloxane1
Reduction of
N
r
-(tert-B
i
utoxyc
v
arbonyl)indo
a
les by Poly
r
methylhy
i
drosiloxane Chandrasekhar,* Debjit Basu, Ch. Raji Reddy
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: srivaric@iict.res.in
Received 14 February 2007; revised 9 March 2007
Initially, N-(tert-butoxycarbonyl)indole and polymethyl-
hydrosiloxane were stirred in the presence of different po-
tential activators such as tris(pentafluorophenyl)borane,
zinc(II) chloride, aluminum trichloride, tetrakis(triphe-
Abstract: The palladium-catalyzed [10% Pd(OH)2/C] reduction of
N-(tert-butoxycarbonyl)indoles to the corresponding N-(tert-
butoxycarbonyl)indolines is described. Polymethylhydrosiloxane
was used as reducing agent and the reaction proceeded smoothly at
room temperature in short reaction times giving the products in nylphosphine)palladium, and palladium on carbon
good yields.
(Table 1), but, to our disappointment, either no or hardly
any N-(tert-butoxycarbonyl)indoline formed (Table 1, en-
tries 1, 2, 4) or it formed in 60–80% yield only (entries 3,
5). A more careful study resulted in the identification of
10% palladium(II) hydroxide on carbon as an efficient ac-
tivator for the reduction of N-Boc-indoles. Thus, the reac-
tion of N-(tert-butoxycarbonyl)indole with polymethyl-
hydrosiloxane in the presence of a catalytic amount of
10% palladium(II) hydroxide on carbon in ethanol gave
the corresponding indoline product in 96% yield (Table 1,
entry 6).
Key words: palladium catalysis, reduction, indoles, polymethyl-
hydrosiloxane
The reduction of indoles to indolines is a commonly en-
countered reaction and a number of methods have been
developed for this conversion, including those involving
hydrogenation and hydride reductions.2 The reagents used
for this transformation have been sodium borohydride or
sodium cyanoborohydride in carboxylic acids,3 zinc boro-
hydride,4 magnesium in methanol,5 triethylsilane/trifluo-
roacetic acid,6 borane–pyridine in hydrogen chloride,7 and
hydrogen over catalysts,8 amongst others.9 While several
of these methods have seen wide use, chemists continue to
seek new protocols using safer reducing agents. Silanes
and siloxanes have been identified as alternative and safe
reducing agents when compared to conventional reduc-
tion procedures.10 In particular, polymethylhydrosiloxane
(PMHS) is gaining prominence as an inexpensive reagent
and is an air- and moisture-stable reducing agent.11 In-
deed, polymethylhydrosiloxane can be stored for longer
periods of time, and no special precautions are needed
when this reagent is used. Recent studies of polymethyl-
hydrosiloxane as a reducing agent by us12 and others13
suggest that additional opportunities may exist for its use
in indole reductions.
Table 1 Reduction of N-(tert-Butoxycarbonyl)indole with Poly-
methylhydrosiloxane in the Presence of Different Catalysts
Entry
Catalyst
B(C6F5)3
ZnCl2
Time (h)
Yield (%)
1
2
3
4
5
6
12
18
18
12
2
no reaction
10
AlCl3
60
Pd(PPh3)4
10% Pd/C
10% Pd(OH)2
no reaction
80
96
0.1
To explore the scope of the reaction, various N-Boc-in-
doles (Table 2, entries 1–8, 10, 11) were treated under the
reaction conditions described above to give the corre-
sponding N-Boc-indolines in good yields. In all these cas-
es, the reaction proceeded smoothly at room temperature
in 5–15 minutes (Table 2). The ester functionality is stable
(Table 2, entries 6, 8, 9) and, as expected, the carbonyl
and nitro functionalities were reduced (entries 4, 7, 11)
under these reaction conditions. The reduction of N-
acetylindole 9a was also achieved, giving the correspond-
ing indoline 9b in five minutes in 93% yield (Table 2, en-
try 9). N-Benzylindole (12a) did not change under the
described reduction conditions, which resulted in deben-
zylation to give the indole; instead, 12a was reduced with
a polymethylhydrosiloxane/aluminum trichloride system
to give N-benzylindoline (12b) in 85% yield (Table 2, en-
try 12). However, N-sulfonylindole 13a failed to give the
Accordingly, polymethylhydrosiloxane was used as an ef-
ficient reducing agent for the reduction of N-Boc-protect-
ed indoles to N-Boc-protected indolines in the presence of
10% palladium(II) hydroxide on carbon as a catalyst
(Scheme 1).
R1
R1
PMHS, 10% Pd(OH)2/C
EtOH, r.t., 5–15 min
R2
R2
N
N
Boc
Boc
Scheme 1
SYNTHESIS 2007, No. 10, pp 1509–1512
x
x.
x
x
.
2
0
0
7
Advanced online publication: 02.05.2007
DOI: 10.1055/s-2007-966029; Art ID: Z04207SS
© Georg Thieme Verlag Stuttgart · New York

1510
S. Chandrasekhar et al.
PAPER
Table 2 Reduction of N-Boc-Protected Indole Derivatives by Polymethylhydrosiloxane in the Presence of 10% Palladium(II) Hydroxide on
Carbon
Entry
1
Indole
Time (min)
5
Indoline
Yielda (%)
968b
1a
2a
3a
4a
1b
2b
3b
4b
N
N
Boc
Boc
2
3
4
10
10
15
928b
908b
8514
N
N
Boc
Boc
N
N
Boc
Boc
CHO
OH
N
N
Boc
Boc
OTBS
OTBS
5
6
5a
6a
15
10
5b
6b
88
92
N
N
Boc
Boc
COOEt
COOEt
N
N
Boc
Boc
BocHN
O2N
7b
8
7a
8a
10
5
7b
8b
86
N
N
Boc
Boc
888b
COOMe
COOMe
COOMe
COOMe
N
N
Boc
Boc
9
10
11
9a
10a
11a
10
10
10
9b
10b
11b
93
87
82
N
N
Ac
Ac
OAc
OAc
N
N
Boc
Boc
OH
O
N
N
Boc
Boc
12c
13
12a
13a
120
120
12b
8515
N
N
Bn
Bn
no reaction
–
–
N
Ts
a Isolated yields after purification by column chromatography. The literature references are given for the known products.
b After completion of the reduction, the reaction mixture was treated with Boc2O.
c AlCl3 was used as the catalyst, while in all other entries Pd(OH)2 was used.
Synthesis 2007, No. 10, 1509–1512 © Thieme Stuttgart · New York

PAPER
Reduction of N-(tert-Butoxycarbonyl)indoles by Polymethylhydrosiloxane
1511
3.48–3.40 (m, 1 H), 3.02–2.98 (m, 1 H), 2.45 (t, J = 6.74 Hz, 2 H),
2.21 (s, 3 H), 2.18–2.06 (m, 1 H), 1.96–188 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 172.7, 168.0, 142.6, 133.5, 128.1,
123.7, 123.5, 117.1, 54.6, 51.5, 39.1, 30.9, 30.2, 23.9.
corresponding indoline in the presence of polymethyl-
hydrosiloxane with either 10% palladium(II) hydroxide
on carbon or aluminum trichloride (Table 2, entry 13).
In summary, we have demonstrated a useful method for
the reduction of N-Boc-indoles to the corresponding indo-
lines using polymethylhydrosiloxane as a safe reducing
agent in the presence of a catalytic amount of 10% palla-
dium(II) hydroxide on carbon. We believe this method is
a useful addition to the existing protocols and may find
application in organic synthesis.
ESI-MS: m/z = 270 [M+ + Na].
tert-Butyl 3-(Acetoxymethyl)indoline-1-carboxylate (10b)
1H NMR (300 MHz, CDCl3): d = 7.70 (br s, 1 H), 7.10–7.01 (m, 2
H), 6.82–6.78 (m, 1 H), 4.16–4.10 (m, 1 H), 3.98–3.88 (m, 2 H),
3.70–3.60 (m, 1 H), 3.52–3.40 (m, 1 H), 1.94 (s, 3 H), 1.45 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 170.9, 152.5, 128.5, 124.6, 122.2,
114.9, 80.8, 66.5, 51.2, 39.2, 28.4, 20.8.
1H (300 MHz) and 13C (75 MHz) NMR spectra of samples in CDCl3
were recorded on a Bruker Avance 300 spectrometer. ESI-MS de-
terminations were carried out on an Agilent Technologies LC/MSD
trap SL spectrometer. Column chromatography was performed on
silica gel (Merck, 100–200 mesh). EtOH was dried over sodium
cake, EtOAc and hexanes (LR grade) were used as received com-
mercially. The N-Boc indoles were obtained trough standard pro-
ceedures using Boc2O. PMHS and Pd(OH)2/C were obtained from
Aldrich and used as received.
ESI-MS: m/z = 314 [M+ + Na].
tert-Butyl 3-Hydroxy-2,3,3a,8b-tetrahydrocyclopenta[b]indole-
4(1H)-carboxylate (11b)
1H NMR (300 MHz, CDCl3): d = 7.40 (br s, 1 H), 7.04–6.95 (m, 2
H), 6.82–6.78 (m, 1 H), 4.58–4.52 (m, 1 H), 4.26–4.19 (m, 1 H),
3.73–3.66 (m, 1 H), 1.98–1.88 (m, 2 H), 1.76–1.67 (m, 2 H), 1.50
(s, 9 H).
13C NMR (75 MHz, CDCl3): d = 152.2, 143.4, 135.2, 127.5, 124.0,
122.9, 114.9, 81.8, 76.5, 64.9, 43.5, 29.4, 29.1, 28.4, 20.6.
ESI-MS: m/z = 298 [M+ + Na].
Indolines 1b–12b; General Procedure
PMHS (180 mg, 3 mmol) was added to a stirred soln of one of in-
doles 1a–12a (1 mmol) in anhyd EtOH (5 mL). The mixture was
cooled to 0 °C and 10% Pd(OH)2/C (10 mg) was added. The mix-
ture was stirred vigorously for 5 min and, after completion of the re-
action (monitored by TLC), the mixture was filtered through a pad
of Celite. Volatiles were removed on a rotary evaporator, and the
residue was purified by subsequent column chromatography (silica
gel, EtOAc–hexane); this gave the corresponding indoline.
Acknowledgments
D.B. thanks CSIR, New Delhi for financial assistance.
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Synthesis 2007, No. 10, 1509–1512 © Thieme Stuttgart · New York

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Synthesis 2007, No. 10, 1509–1512 © Thieme Stuttgart · New York