B(C6F5)3-catalyzed hydrogenation of oxime ethers without cleavage of the N-O bond

Article abstract of DOI:10.1002/anie.201407324

The hydrogenation of oximes and oxime ethers is usually hampered by N-O bond cleavage, hence affording amines rather than hydroxylamines. The boron Lewis acid B(C₆F₅)₃ is found to catalyze the chemoselective hydrogenation

Full text of DOI:10.1002/anie.201407324

Angewandte
Chemie
DOI: 10.1002/anie.201407324
Hydrogenation
B(C6F5)3-Catalyzed Hydrogenation of Oxime Ethers without Cleavage
ꢀ
of the N O Bond**
Jens Mohr and Martin Oestreich*
Abstract: The hydrogenation of oximes and oxime ethers is
We reasoned that reactions involving catalytic borohydride
generation would be perfectly suited to address the problem
ꢀ
usually hampered by N O bond cleavage, hence affording
ꢀ
amines rather than hydroxylamines. The boron Lewis acid
B(C6F5)3 is found to catalyze the chemoselective hydrogenation
of oxime ethers at elevated or even room temperature under
100 bar dihydrogen pressure. The use of the triisopropylsilyl
group as a protecting group allows for facile liberation of the
free hydroxylamines.
of catalytic oxime reduction while leaving the N O bond
intact. Borohydrides are key intermediates in reduction
processes catalyzed by B(C6F5)3 and related Lewis acids
with either hydrosilanes or dihydrogen used as reductants.[9]
ꢀ
Activation of the Si H bond was established by Piers and co-
workers, and successfully applied to catalytic imine hydro-
silylation.[10] Heterolytic splitting of the H H bond is
ꢀ
T
he catalytic reduction of oximes and its congeners to the
hydroxylamine oxidation level without cleavage of the weak
accomplished in a similar way by making use of the unique
reactivity of frustrated Lewis pairs (FLPs),[11] and several
systems for the hydrogenation[12] of imines have been
reported to date.[13] Electron-deficient boranes alone also
ꢀ
N O bond is still a challenge (I!II, Scheme 1). The
hydroxylamine motif is particularly prevalent among mole-
cules with a biological function,[1] and its formation from
ꢀ
bring about H H bond activation in the presence of the Lewis
basic imine.[14] With regard to potential applications of these
catalytic systems to oxime reduction, hydrosilylation will be
hampered by the oxophilicity of the silicon atom, and our own
experimental findings support this assumption.[15] The hydro-
genation approach looked more promising, and we disclose
here the B(C6F5)3-catalyzed hydrogenation of oxime ethers to
furnish O-alkylated or O-silylated N-monosubstituted
hydroxylamines with no overreduction.
We began our studies by attempting to hydrogenate the
acetophenone-derived oxime 1a by using catalytic amounts of
B(C6F5)3, but did not detect any conversion even at high
dihydrogen pressures (Table 1, entry 1). We reasoned that its
free hydroxy group intervenes, and we therefore prepared
Scheme 1. Reduction of oximes and its congeners: How to stop at the
hydroxylamine oxidation level?
readily available oxime precursors is desirable. A literature
survey revealed that the heterogeneous hydrogenation of
oximes had been described nearly a century ago,[2] but there
were issues with reproducing this work.[3] The homogeneous,
transition-metal-catalyzed hydrogenation of oximes is com-
monly plagued by deoxygenation to yield primary amines
(I!III, Scheme 1).[4] However, there is a single patent where
the hydrogenation of oxime ethers is reported to stop at the
corresponding hydroxylamine derivative (I!II, Scheme 1).[5]
The majority of methods that allow reliable reduction of
the oxime functional group to hydroxylamines with or
without substitution at the oxygen atom is based on the
stoichiometric use of borohydrides as reducing agents.[1,3,6–8]
Table 1: Hydrogenation of oximes to hydroxylamines: Effect of the
substituent at the oxygen atom.[a]
Entry Oxime
R
Hydroxyl- Pressure
t
Conv. Yield
amine
[bar]
[h] [%][b] [%][c]
1
2
1a
1b
1b
1c
1c
1d
1e
1 f
H
2a
2b
2b
2c
2c
2d
100
100
100
60
100
100
100
60
16
16
16
16
0
5
0
–
n.d.
–
Me
Me
tBu
tBu
SiEt3
3[d]
4
95 n.d.
[*] J. Mohr, Prof. Dr. M. Oestreich
5
6
18 >99 88
18
18
Institut fꢀr Chemie, Technische Universitꢁt Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
5
n.d.
7
SitBuMe2 2e
SiiPr3 2 f
27 n.d.
8[e]
16 >99 99
Homepage: http://www.organometallics.tu-berlin.de
[**] M.O. is indebted to the Einstein Foundation (Berlin) for an endowed
professorship. We thank Dr. Mustafa Durmaz (TU Berlin) for initial
contributions.
[a] Reactions were performed on a 90–145 mmol scale. [b] Determined by
GLC analysis. [c] Determined after purification by filtering through
a small plug of silica gel. [d] Reaction performed with addition of Mes3P
(5 mol%). [e] Reaction successfully performed on a 1.5 g scale.
n.d.=not determined.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407324.
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Table 2: Substrate scope of the hydrogenation of oxime ethers to O-protected hydroxylamines.[a]
methyl-substituted
oxime
1b.
Reduction to hydroxylamine 2b
indeed occurred, but no catalytic
turnover was achieved (entry 2).
This result is in agreement with
a similar observation by Stephan
and co-workers during the hydro-
genation of sterically less-demand-
ing imines.[13a] According to Pꢀpai
and co-workers, the formation of
stable Lewis pairs with sterically
unhindered amines that accumu-
late over the course of the reaction
inhibits the catalysis.[14c] As the
catalyst system B(C6F5)3/Mes3P
(Mes = mesityl), known to be supe-
rior to B(C6F5)3 in the reduction of
imines,[14a] showed no improvement
(entry 3), we decided to test oxime
ether 1c, which bears a tert-butyl
group at the oxygen atom. Gratify-
ingly, 1c showed 95% conversion at
a dihydrogen pressure of 60 bar at
room temperature (entry 4). The
reaction proved to be highly che-
Entry
Oxime
ether
R1
R2
R3
Hydroxyl-
amine
T
[8C]
Conv.
[%][b]
Yield
[%][c]
1
2
3c
3 f
Me
Me
tBu
SiiPr3
10c
10 f
25
60
>99
>99
80
99
3
4c
4 f
Me
Me
tBu
SiiPr3
11c
11 f
25
60
>99
>99
96
97
4[d]
5
5c
5 f
Et
Et
tBu
SiiPr3
12c
12 f
25
60
>99
>99
99
99
6[d]
7
8
6c
6 f
Me
Me
tBu
SiiPr3
13c
13 f
25
25
>99
>99
96
95
9[e]
10
7c
7 f
Me
Me
tBu
SiiPr3
14c
14 f
60
25
95
>99
94[f]
99
ꢀ
moselective. Neither N O bond
11[d]
12[d]
8c
8 f
tBu
SiiPr3
15c
15 f
60
60
90
50
66[f]
n.d.
fission nor other side reactions
were observed, with only hydroxyl-
amine 2c and remaining 1c
detected. Increasing the dihydro-
gen pressure to 100 bar resulted in
full conversion, and enabled the
isolation of 2c in excellent yield
(entry 5).[16] We then turned our
attention to O-silylated oximes,
which would allow us to subse-
quently liberate the unprotected
ꢀ
13
14
9c
9 f
tBu
SiiPr3
16c
16 f
60
60
>99
>99
n.d.[g]
99
[a] Reactions were performed on a 0.12–0.14 mmol scale. [b] Determined by GLC analysis. [c] Deter-
mined after purification by filtering through a small plug of silica gel. [d] Reaction was performed with
10 mol% B(C6F5)3. [e] Reaction was performed with 8.2 mol% B(C6F5)3. [f] Calculated yield, contains
starting material. [g] Not isolated because of its volatility. n.d.=not determined.
hydroxylamine by facile Si O bond cleavage. Again, the
steric demand of the substituent was the key to success.
Oxime ethers 1d (entry 6) and 1e (entry 7) were not fully
converted into the corresponding hydroxylamines, but hydro-
genation of triisopropylsilyl-substituted oxime 1 f (entry 8)
afforded hydroxylamine 2 f in quantitative yield at a dihydro-
gen pressure of 60 bar at room temperature. It is noteworthy
that neither 1e and 1 f nor tert-butyl-substituted 1c showed
adduct formation with B(C6F5)3 at room temperature, as
verified by 11B and 19F NMR spectroscopy.
electron-donating substituents (entries 3 and 4) were con-
verted into the corresponding hydroxylamines, with the O-
silyl oximes requiring elevated temperatures to reach full
conversion. Prolonged reaction times at room temperature
generally had little or no effect on the conversion. Even the
Lewis basic methoxy substituent in oxime ethers 4c and 4 f is
tolerated under these reaction conditions. Likewise, halogen-
ated (entries 5–8) and ortho-substituted substrates (entries 9
and 10) were successfully hydrogenated. No dehalogenation
was observed for chloro-substituted 5c/5 f and bromo-sub-
stituted 6c/6 f. Benzophenone-derived oxime ethers were far
less reactive (entries 11 and 12), not exceeding 50% con-
version in the case of O-silyl-substituted oxime 8 f even at
elevated temperature and higher catalyst loading. Aliphatic
oxime ethers 9c and 9 f reacted poorly at room temperature,
but showed complete conversion at 608C (entries 13 and 14).
Although the reduction of unprotected oximes had failed
(see Table 1, entry 1), the deprotection of O-silylated hydrox-
ylamines was considered to be a way to liberate the hydroxyl-
amine functionality. To illustrate its feasibility, we investi-
gated the removal of the silyl protecting group of O-silylated
To our surprise, related benzaldehyde-derived oxime
ethers were completely inert under these reaction conditions.
Lewis acid/base pairing was again excluded by means of NMR
spectroscopy. We think that aldehyde-based oxime ethers are
not sufficiently Lewis basic at the nitrogen atom to participate
in the cooperative dihydrogen activation.
With the optimal substituents at the oxygen atom
identified, we set out to explore the substrate scope of the
hydrogenation. Representative O-tert-butyl (3c–9c) and O-
triisopropylsilyl oxime ethers (3 f–9 f) were treated with
B(C6F5)3 at 100 bar dihydrogen pressure (Table 2). Oxime
ethers bearing electron-withdrawing (entries 1 and 2) or
ꢀ
2 f. Cleavage of the Si O bond was observed under acidic as
2
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[5] A homogeneous, rhodium-catalyzed hydrogenation of oxime
well as basic conditions (2 f!2a). However, depending on the
solvent, decomposition or in situ oxidation[17] to the free
oxime (2a!1a, not shown) thwarted the isolation of 2a.
Likewise, the use of tetra-n-butylammonium fluoride (TBAF)
in THF yielded a complex mixture. Finally, unprotected 2a
was obtained after treatment of 2 f with HF·pyridine in THF
at 08C (Scheme 2).
methyl ethers to afford the corresponding O-methylhydroxyl-
amines in an enantioenriched form is documented in a patent: R.
Kadyrov, T. Riermeier, J. Almena, A. Monsees, P. Groß, K.
Rossen (Evonik Degussa GmbH), EP 1 862 446A2, 2007.
[6] a) H. Feuer, B. F. Vincent, Jr., R. S. Bartlett, J. Org. Chem. 1965,
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[7] For stoichiometric Itsuno reductions, see: a) J. T. Dougherty,
J. R. Flisak, J. Hayes, I. Lantos, L. Liu, L. Tucker, Tetrahedron:
Asymmetry 1997, 8, 497 – 499; b) E. Fontaine, C. Namane, J.
Meneyrol, M. Geslin, L. Serva, E. Roussey, S. Tissandiꢂ, M.
Maftouh, P. Roger, Tetrahedron: Asymmetry 2001, 12, 2185 –
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´
2189; c) M. P. Krzeminski, M. Zaidlewicz, Tetrahedron: Asym-
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[8] The use of hydrosilanes in trifluoroacetic acid as reducing agents
is an alternative method: a) D. D. Sternbach, W. C. L. Jamison,
Tetrahedron Lett. 1981, 22, 3331 – 3334; b) M. Fujita, H. Oishi, T.
Hiyama, Chem. Lett. 1986, 837 – 838. Alternatively, reduction
can be mediated by BF3·OEt2 with Bu3SnH as the reductant: M.
Ueda, H. Miyabe, M. Namba, T. Nakabayashi, T. Naito,
Tetrahedron Lett. 2002, 43, 4369 – 4371.
In summary, we presented herein a catalytic method for
the reduction of O-alkyl and O-silyl oxime ethers to their
corresponding N-monosubstituted hydroxylamines. The
simple setup which employs dihydrogen as a reducing agent
and commercially available Lewis acid B(C6F5)3 as the
catalyst results in exceptionally clean reactions. These assets
distinguish the present approach from traditional ones[1] that
require stoichiometric amounts of boron hydrides.[6,7] It was
shown that desilylation of the resulting O-silylhydroxyl-
amines furnishes unprotected hydroxylamines, thereby
adding a new reaction to synthetic chemistsꢁ repertoire.
[9] For a review, see: W. E. Piers, A. J. V. Marwitz, L. G. Mercier,
Inorg. Chem. 2011, 50, 12252 – 12262.
[10] For imine hydrosilylation catalyzed by electron-deficient bor-
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Piers, Org. Lett. 2000, 2, 3921 – 3923; b) D. T. Hog, M. Oestreich,
Eur. J. Org. Chem. 2009, 5047 – 5056; c) D. Chen, V. Leich, F.
Pan, J. Klankermayer, Chem. Eur. J. 2012, 18, 5184 – 5187; d) M.
Mewald, M. Oestreich, Chem. Eur. J. 2012, 18, 14079 – 14084;
e) J. Hermeke, M. Mewald, M. Oestreich, J. Am. Chem. Soc.
2013, 135, 17537 – 17546.
Received: July 17, 2014
Published online: && &&, &&&&
[11] D. W. Stephan, G. Erker, Angew. Chem. Int. Ed. 2010, 49, 46 – 76;
Angew. Chem. 2010, 122, 50 – 81.
[12] For brief reviews of FLP-catalyzed hydrogenation, see: a) L. J.
Hounjet, D. W. Stephan, Org. Process Res. Dev. 2014, 18, 385 –
391; b) J. Paradies, Angew. Chem. Int. Ed. 2014, 53, 3552 – 3557;
Angew. Chem. 2014, 126, 3624 – 3629; c) J. Paradies, Synlett 2013,
777 – 780; d) D. W. Stephan, Org. Biomol. Chem. 2012, 10, 5740 –
5746.
[13] For imine hydrogenation catalyzed by FLPs, see: a) P. A. Chase,
G. C. Welch, T. Jurca, D. W. Stephan, Angew. Chem. Int. Ed.
2007, 46, 8050 – 8053; Angew. Chem. 2007, 119, 8196 – 8199; b) P.
Spies, S. Schwendemann, S. Lange, G. Kehr, R. Frçhlich, G.
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Atsumi, C. Wang, M. Nieger, M. Leskelꢃ, T. Repo, P. Pyykkç, B.
Keywords: boron · homogeneous catalysis · hydrogenation ·
Lewis acids · reduction
.
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[2] Vavon et al. published a series of papers on the heterogeneous,
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monosubstituted hydroxylamines, oximes must be derived
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to the primary amines, and aldoximes yield N,N-disubstituted
hydroxylamines. Seminal publications include: a) G. Vavon,
A. L. Berton, Bull. Soc. Chim. Fr. 1925, 37, 296 – 305; b) G.
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˝
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˝
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Chem. Commun. 2008, 2130 – 2131; c) T. A. Rokob, A. Hamza,
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tion of 1c, although we recently showed that this borane is
almost as Lewis acidic as B(C6F5)3 and performs equally well in
ꢀ
catalytic transformations involving Si H bond activation: J.
Mohr, M. Durmaz, E. Irran, M. Oestreich, Organometallics 2014,
33, 1108 – 1111. We assume that heterolytic splitting of the
ꢀ
shorter H H bond is prevented by steric repulsion of the
[15] The B(C6F5)3-catalyzed hydrosilylation of various acetophe-
none-derived oxime ethers produced a complex mixture, clearly
indicating that deoxygenation occurred. Moreover, N-ethylani-
line was detected in variable quantities as a result of a reductive
rearrangement that is related to the Beckmann rearrangment:
M. Ortiz-Marciales, L. D. Rivera, M. De Jesffls, S. Espinosa, J. A.
Benjamin, O. E. Casanova, I. G. Figueroa, S. Rodríguez, W.
Correa, J. Org. Chem. 2005, 70, 10132 – 10134.
naphthyl groups of this borane and the substrate. Indeed, the
reaction with Stephanꢁs borane B(2,3,5,6-F4C6H)3, which is
comparably Lewis acidic but smaller, showed full conversion
under the same reaction conditions. For the preparation of
B(2,3,5,6-F4C6H)3, see: M. Ullrich, A. J. Lough, D. W. Stephan, J.
Am. Chem. Soc. 2009, 131, 52 – 53.
[17] S. Horiyama, K. Suwa, M. Yamaki, H. Kataoka, T. Katagi, M.
Takayama, T. Takeuchi, Chem. Pharm. Bull. 2002, 50, 996 – 1000.
[16] We observed no conversion when employing tris(5,6,7,8-tetra-
fluoronaphthalen-2-yl)borane as the catalyst in the hydrogena-
4
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Hydrogenation
No NO cleavage: Transition-metal-free
hydrogenation of oxime ethers with bulky
groups at the oxygen atom (R=tBu and
SiiPr3) can be achieved at mild temper-
atures by using the electron-deficient
boron Lewis acid B(C6F5)3 as a catalyst.
The reduction is highly chemoselective,
J. Mohr, M. Oestreich*
&&&& — &&&&
B(C6F5)3-Catalyzed Hydrogenation of
Oxime Ethers without Cleavage of the N
O Bond
ꢀ
ꢀ
leaving the N O bond intact. Subsequent
ꢀ
fluoride-mediated cleavage of the Si O
bond (for R3 =SiiPr3) provides access to
the free hydroxylamines (see scheme).
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