Cu(I)-mediated deoxygenation of N-oxides to amines

Article abstract of DOI:10.1016/j.tet.2006.10.031

A mild and highly efficient deoxygenation of variety of N-oxides using an inexpensive CuX, or a CuX-Zn or CuX-Al couple is described.

Full text of DOI:10.1016/j.tet.2006.10.031

Tetrahedron 63 (2007) 126–130
Cu(I)-mediated deoxygenation of N-oxides to amines*
*
Sunil Kumar Singh, M. Srinivasa Reddy, Mangesh Mangle and K. Ravi Ganesh
Discovery Chemistry, Discovery Research-Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
Received 28 July 2006; revised 25 September 2006; accepted 12 October 2006
Available online 30 October 2006
Abstract—A mild and highly efficient deoxygenation of variety of N-oxides using an inexpensive CuX, or a CuX–Zn or CuX–Al couple is
described.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
preparations32c at ambient temperature. But, they are highly
expensive for large scale conversions. Thus, there still re-
mains a need for developing simple, cheap and environment
friendly reagents for the exclusive deoxygenation of various
amine N-oxides to corresponding amines.
Organic N-oxides are important species in chemical as well
as biological studies. While many chemical transformations
essentially require N-oxide intermediates,1 often they are
formed as unwanted side products. These species are also
formed during biochemical oxidation of nitrogen containing
drug substances2a and serve as a major source of drug metab-
olism studies.2b Search for suitable deoxygenating agents for
various N-oxides continued for many years. The first gener-
ation reagents for this purpose include Pd–C combinations,3
H2SO3,4 Ni–Al alloy,5 metals,6 alkali metal hydrides,7
NaHTe,8 phosphorus compounds,9 S and Se compounds,10
aluminium halides,11 TiCl3,12 silanes,13 CrCl2,14 R3N–SO2
complex15 and acetic formic anhydride.16 But, most of these
reagents and reaction conditions are harsh, and affect other
sensitive groups in the substrate to yield unwanted products.
Therefore, milder and specific reagents such as Zn–
NH4Cl,17a Zn–HCO2NH4,17b TiCl4–SnCl2,18a TiCl4–Zn,18b
TiCl4–Mg,18c TiCl4–NaI,18d TiCl4–NaBH4 complex,18e bis-
(cyclopentadienyl)titanium(IV)dichloride–In,18f titanocene
2. Results and discussion
Apart from several other uses, cuprous iodide is known to be
a prime component of C–C and C–N bond formation reac-
tions.33 During the development of a drug candidate in our
laboratory, an extremely safe reagent was desired for the
deoxygenation of its N-oxide intermediate to afford an impu-
rity-free active pharmaceutical ingredient (API) under mild
reaction conditions. We experimented with many of the re-
ported reagents, and found a novel use of cuprous iodide
(CuI) as a highly effective reagent for the deoxygenation
of N-oxide. To the best of our knowledge, there is no report
on such kind of use of this reagent in the literature. In an
extensive study, this reagent was able to reduce a variety of
aliphatic and aromatic N-oxides to corresponding free
amines in high yield with excellent chemoselectivity
(Scheme 1, Table 1). Hence, in this report, we describe the
experimental conditions, which led to the identification of
CuX (Cl, I), CuX–Zn and CuX–Al as highly effective de-
oxygenating agents for various N-oxides.
methylidene complex,18g tributyltinhydride,19 SmI2 and
20
tetrathiomolybdate21 have been developed in recent years
to overcome the above problems. Very recently, more
specific and environmentally benign reagents such as
ZrCl4–NaBH4,22a LiCl–NaBH4,22b InCl3 (X¼Cl, Br),23a
In–NH4Cl,23b polymethylhydrosiloxane (PMHS),24 Ph3P–
oxorhenium(V) catalyst,25 NaOEt,26 MoO2Cl2(dmf)2,27
RuCl3$xH2O,28
Mo(CO)6,29
Zn/Cu–triflates30
and
CuI - base
CoCl2$6H2O–In31 have been investigated for the purpose.
But, most of these reagents are costly, partially selective, un-
known to the environment and require special preparation.
The deoxygenation of N-oxides is also catalyzed by mi-
crobes,32a haem moiety of cytochrome P-45032b and rat liver
X
X
THF, 25-60 °C
N
N
O
Scheme 1.
The reaction conditions were optimized by varying the sol-
vent, temperature, base and cuprous salt using a representa-
tive aliphatic N-oxide (entry 12). Among the solvents, THF,
MeCN and Me2SO were found to be suitable to favour the
reaction at room temperature. Other solvents required high
*
DRL publication no. 588.
Keywords: Deoxygenation; Cuprous halides; Zinc; Aluminium; Amine
N-oxides; Nitrones; Azoxybenzes; Heteroarene N-oxides.
* Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304 5438/
5007; e-mail: sunilkumarsingh@drreddys.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.031

S. K. Singh et al. / Tetrahedron 63 (2007) 126–130
127
Table 1. Deoxygenation of amine N-oxidesa
Entry
Substrate
Base
Temp (ꢀC)
25–30
Time (h)
1.5
Yield (%)
95
Product
(Et)3N
b
(Et)3N
O
1
O
b
d
2
3
25–30
25–30
1.5
1.0
95
98
O
N
O
O
N
N
O
O
S
S
NO2
NO2
N
N
S
S
NO2
NO2
O
O
O
N
O
O
d
d
4
5
6
25–30
25–30
35–40
1.0
2.0
3.0
98
97
96
O
O
F
F
O
NO2
N
N
NO2
N
N
O
d
d
NO2
N
N
NO2
N
O
N
NO2
NO2
7
35–40
3.0
97
F
F
F
F
O
N
c
8
9
25–30
35–40
2.0
3.0
95
96
NO2
NH2
N
N
NO2
NH2
F
F
O
N
d
O
N
O
O
S
N3
N
c
S
10
N3
35–40
3.0
95
O
O
F
F
d
d
c
11
12
25–30
35–40
35–40
2.0
2.0
3.0
97
95
97
N
N
O
CO2Me
CO2Me
N
N
N
O
O
N
13
F
F
a
All the reactions were carried out in THF using CuI.
Without base.
Triethylamine (1.0 equiv).
N,N0-diisopropylethylamine (1.0 equiv).
b
c
d
temperature and afforded only partially deoxygenated prod-
uct even after extended duration. Addition of organic base
such as triethylamine or N,N0-diisopropylethylamine further
reduced the reaction time from 2–3 h to 0.5–1.0 h, and this
reaction when heated to 50–60 ꢀC, was over within 30 min.
Other cuprous salts, viz. CuBr, CuCl, CuCN and Cu2O were
also tried. While CuCl was found to be as effective as CuI
and worked at room temperature, CuBr required higher
temperature for completion. Only 60–70% conversion was
observed in case of CuCN and Cu2O even after heating
overnight.
While simple warming (30–50 ꢀC) of aliphatic and aromatic
N-oxides with CuI in above solvents afforded quantitative
yields of corresponding amines (Table 1), the deoxygen-
ation of nitrone 1430,34a and azoxybenzene 1630,34b essen-
tially required one of the above bases and heating at
higher temperature for long time. But, this set of conditions
failed to deoxygenate heteroarene N-oxide (entry 18).
Different solvents such as MeCN, DMF and DMSO, bases
(triethylamine or N,N0-diisopropylethylamine) and elevated
temperatures (50–100 ꢀC) also did not lead to better
conversion. Even benzyl alcohol, a recently reported

128
S. K. Singh et al. / Tetrahedron 63 (2007) 126–130
reaction medium,35 could not assist the CuI mediated
deoxygenation.
1630 (Scheme 3), aliphatic and aromatic N-oxides (entries
1–13, Table 1) were deoxygenated by these two reagents
in quantitative yields, but no deoxygenation of heteroarene
N-oxides was observed on changing the solvent from ethanol
to THF, MeCN or DMSO even after addition of above bases.
Presumably, the CuX mediated deoxygenation process is
a simple reduction–oxidation reaction where lower valent
Cu(I) reduces the N-oxides, and itself gets oxidized to higher
valent Cu(II) salt. Though few metals and their alloys have
been used along with suitable reagents for similar conver-
sion, there was no report of pure metals, viz. Zn and Al being
used for the purpose in neutral medium. We selected these
metals because they are known to have high affinity for oxy-
gen. Pyridine N-oxide (entry 18) and the aliphatic N-oxide
(entry 12) when refluxed in ethanol, alone with these metals
(in 1:1 molar proportion), were partially reduced (10–15%)
to the corresponding amines after 10–12 h. However,
the CuI–Zn and CuI–Al combinations turned out to be ex-
tremely efficient, and caused the deoxygenation of these
substrates within 2 h. Many heteroarene N-oxides (entries
18–26, Table 2), nitrone 1430 (Scheme 2), azoxybenzene
F
F
O
N
CuI-Zn/Al, EtOH
50-60 C, 2h, 97%
Me
N
°
Me
14
15
Scheme 2.
F
F
F
F
O
N
CuI-Zn/Al, EtOH
50-60 C, 2h, 95%
N
N
N
°
F
F
F
F
16
17
Table 2. Deoxygenation of heteroarene N-oxidesa
Scheme 3.
Entry
Substrate
Time (h)
Yield (%)
Product
Since most of the N-oxides were prepared from correspond-
ing amines,36 the progress of reaction was monitored on
TLC to cross-match the reaction mixture with authentic sam-
ples. The starting materials (generated by standard methods)
and products were characterized by spectroscopic methods
where an upward chemical shift (w1 ppm) for all the protons
18
2.0
96
N
O
N
1
in their H NMR spectra was observed on conversion of
N-oxides to corresponding amines.
Me
19
20
21
N
O
1.5
1.5
2.5
96
95
95
M
e
N
Under the described reaction conditions, while the potential
sensitive functional groups such as nitro, amino, azide, ester,
amide, sulfone, fluoro and methyl remained unaffected, a mi-
nor de-chlorinated product (10–15%) was observed during
the deoxygenation of 2-chloro and 2,6-dichloropyridine N-
oxides (entries 22–23, Table 2). However, surprisingly, there
was no such incidence observed in the case of 2-chloroqui-
noline N-oxide (entry 26, Table 2).
OMe
OMe
NH2
N
O
N
N
O
O
O
O
NH2
N
O
Cl
22
23
24
25
3.0
3.0
2.0
2.0
3.0
70b
75b
96
N
O
3. Conclusion
C
l
N
In conclusion, we have described use of inexpensive CuX
(X¼Cl, I), CuX–Zn and CuX–Al in deoxygenation of vari-
ous N-oxides. The protocol offers an attractive alternative
to currently used reagents. Though CuX alone effectively
deoxygenates the aliphatic and aromatic N-oxides in aprotic
solvents at lower temperature (30–50 ꢀC), the CuX–Zn
and CuX–Al systems require refluxing the substrates, viz.
nitrone, azoxybenzene and heteroarene N-oxides in ethanol
at 50–60 ꢀC. The reagents are mild, efficient, safe to deli-
cated groups, environmentally benign, and do not involve
any prior preparation.
Cl
Cl
N
Cl
C
l
N
O
N
O
N
Me
Cl
N
O
95
M
e
N
4. Experimental
4.1. General
26
95
N
O
C
l
N
a
Solvents and reagents (LR grade) were used in the reactions
without distillation/purification. Reactions were monitored
All the reactions were performed using representative condition.
Partial de-chlorination (10–15%) was observed.
b

S. K. Singh et al. / Tetrahedron 63 (2007) 126–130
129
by thin-layer chromatography (TLC) using silica gel plates
(60 F254; Merck), visualizing with ultraviolet light or iodine
spray. The yields are un-optimized. IR spectra were recorded
on Perkin–Elmer FT-IR 1650 spectrometer. 1H NMR exper-
iments were performed at Varian Gemini 200 spectrometer
and their chemical shifts are reported in d units with respect
to TMS as an internal standard. Mass spectra were recorded
on HP-5989A spectrometer. All the analyses were per-
formed at Analytical Research Division of Discovery-
Research, Dr. Reddy’s Laboratories Ltd.
(c) entry 9 [2632-65-7], (d) entry 11 [824-21-5], (e) entry 12
[933-94-8], (f) entry 13 [702-11-4].
4.1.7. Representative procedure for the deoxygenation
of nitrones, azoxybenzenes and heteroarene N-oxides
(Table 2 and Schemes 2 and 3). Quinaldine N-oxide (en-
try 25; 500 mg, 3.14 mmol), dissolved in absolute ethanol
(5 ml), was added with CuI (597 mg, 3.14 mmol) and Zn-
powder (204 mg, 3.14 mmol), and the reaction mixture
was refluxed at 55–60 ꢀC for 2 h. After completion, the
reaction was brought to room temperature and the content
was filtered. The filtrate was poured over ice-water, stirred
with aqueous ammonia and extracted with ethyl acetate.
The combined organic layers were washed with water, dried
(anhydrous Na2SO4) and evaporated to afford a viscous
mass, which on trituration with minimum quantity of
petroleum ether afforded pure quinaldine (427 mg, 95%).
Similar results were obtained when the same molar
proportion of aluminium was used in the reaction. All the
products were confirmed by spectroscopic analyses (IR, 1H
NMR and MS) and by comparing the data available in the
literature.36
4.1.1. 4-(4-Nitrophenyl) thiomorpholine 1,1-dioxide36a
(representative procedure for the deoxygenation of ali-
phatic and aromatic N-oxides, Table 1). 4-(4-Nitrophenyl)
thiomorpholine 1,1,4-trioxide (entry 3, 500 mg, 1.83 mmol),
dissolved in THF (5 mL), was added with CuI (350 mg,
1.83 mmol) and N,N-diisopropylethylamine (237 mg,
1.83 mmol), and the reaction mixture was stirred at 25–
30 ꢀC for 1 h. The reaction mixture was filtered and washed
with THF (3 mL). The filtrate was concentrated and the
gummy mass was stirred with a mixture of ice-water and
ammonia (1:1; 2.0 mL) for 0.5 h. The content was extracted
with ethyl acetate and the combined organic layers were
washed with water, dried (anhydrous Na2SO4) and evapo-
rated to afford a viscous mass, which on trituration with a
minimum quantity of dichloromethane and petroleum ether
(1:1) afforded pure 4-(4-nitrophenyl) thiomorpholine 1,1-
dioxide (423 mg, 90%). IR (KBr) 2955, 1518, 1468, 1367,
4.1.8. (4-Fluoro-benzylidene)-p-tolyl-amine 15.30 IR
(Neat) 3015, 2141, 1565, 1503, 1317 cmꢁ1 1H NMR
.
(200 MHz, CDCl3) d 8.05 (s, 1H), 7.35–7.24 (m, 4H, Ar),
7.02 (d, J¼7.6 Hz, 2H, Ar), 6.78 (d, J¼7.6 Hz, 2H), 2.16
(s, 3H). MS (CI method) 214 (M+H)+, 105.
1
1334, 1305 cmꢁ1. H NMR (200 MHz, CDCl3) d 8.32 (d,
J¼8.4 Hz, 2H, Ar), 7.18 (d, J¼8.4 Hz, 2H, Ar), 4.05–3.85
(m, 4H), 3.00–2.80 (m, 4H). MS (CI method) 257
(M+H)+, 238, 185, 141.
4.1.9. Bis-(3,4-difluorophenyl) diazene 17.30 IR (KBr)
1
2945, 2125, 1548, 1402, 1343 cmꢁ1. H NMR (200 MHz,
CDCl3) d 7.60–7.50 (m, 4H, Ar), 7.15–7.05 (m, 2H, Ar).
MS (CI method) 255 (M+H)+, 128.
4.1.2. 4-(2-Fluoro-4-nitrophenyl) thiomorpholine 1,1-di-
oxide.36b Product obtained in entry 4. IR (KBr) 3102,
4.1.10. CAS nos. of the products. CAS nos. of the product
obtained in: (a) entry 19 [109-06-8], (b) entry 20 [2459-07-
6], (c) entry 21 [1452-77-3], (d) entry 22 [109-09-1], (e)
entry 23 [2402-78-0], (f) entry 24 [91-22-5], (g) entry 25
[91-63-4], (h) entry 26 [612-62-4].
1
3012, 2952, 1539, 1470, 1368, 1330, 1298 cmꢁ1. H NMR
(200 MHz, CDCl3) d 8.06–7.95 (m, 2H, Ar), 7.02 (t,
J¼9.0 Hz, 1H, Ar), 3.82 (t, J¼5.6 Hz, 2H), 3.22 (t, J¼5.6 Hz,
2H). MS (CI method) 275 (M+H)+, 259, 245, 209, 163.
4.1.3. 1-(2-Fluoro-4-nitrophenyl) pyrrolidine.36b Product
obtained in entry 7. IR (KBr) 2955, 1517, 1458, 1347,
Acknowledgements
1308 cmꢁ1
.
1H NMR (200 MHz, CDCl3) d 8.00 (t,
J¼8.8 Hz, 1H, Ar), 7.45–7.40 (m, 1H), 6.95–6.90 (m, 1H),
2.89–2.75 (m, 4H), 1.98–1.72 (m, 4H). MS (CI method)
211 (M+H)+, 178, 139.
We sincerely acknowledge Dr. K. Anji Reddy, Chairman-
DRL, for his kind encouragement and the Analytical Depart-
ment-DR, for providing spectral support.
4.1.4. 1-(2,6-Difluoro-4-nitrophenyl) pyrrolidine.36b
Product obtained in entry 8. IR (Neat) 2978, 2855, 1603,
References and notes
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1515, 1335 cmꢁ1. H NMR (200 MHz, CDCl3) d 8.05 (t,
J¼8.6 Hz, 1H, Ar), 6.95 (t, J¼8.8 Hz, 1H, Ar), 3.30 (m,
4H), 1.85–1.60 (m, 4H). MS (CI method) 229 (M+H)+,
219, 208, 177, 167, 137.
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