Extending the Scope of the B(C6F5)3-Catalyzed C=N Bond Reduction: Hydrogenation of Oxime Ethers and Hydrazones

Article abstract of DOI:10.1002/chem.201503509

The B(C₆F₅)₃-catalyzed hydrogenation is applied to aldoxime triisopropylsilyl ethers and hydrazones bearing an easily removable phthaloyl protective group. The C=N reduction of aldehyde-derived substrates (oxime ethers and hydrazones) is enabled by using 1,4-dioxane as the solvent known to participate as the Lewis-basic component in FLP-type heterolytic dihydrogen splitting. More basic ketone-derived hydrazones act as Lewis bases themselves in the FLP-type dihydrogen activation and are therefore successfully hydrogenated in nondonating toluene. The difference in reactivity between aldehyde- and ketone-derived substrates is also reflected in the required catalyst loading and dihydrogen pressure.

Full text of DOI:10.1002/chem.201503509

DOI: 10.1002/chem.201503509
Communication
&
Hydrogenation
Extending the Scope of the B(C6F5)3-Catalyzed C=N Bond
Reduction: Hydrogenation of Oxime Ethers and Hydrazones
Jens Mohr, Digvijay Porwal, Indranil Chatterjee, and Martin Oestreich*[a]
Abstract: The B(C6F5)3-catalyzed hydrogenation is applied
to aldoxime triisopropylsilyl ethers and hydrazones bear-
ing an easily removable phthaloyl protective group. The
C=N reduction of aldehyde-derived substrates (oxime
ethers and hydrazones) is enabled by using 1,4-dioxane as
the solvent known to participate as the Lewis-basic com-
ponent in FLP-type heterolytic dihydrogen splitting. More
basic ketone-derived hydrazones act as Lewis bases them-
selves in the FLP-type dihydrogen activation and are
therefore successfully hydrogenated in nondonating tolu-
ene. The difference in reactivity between aldehyde- and
ketone-derived substrates is also reflected in the required
catalyst loading and dihydrogen pressure.
Scheme 1. Hydrogenation of C=N bonds catalyzed by electron-deficient tri-
arylboranes. Dipp=2,6-diisopropylphenyl; Ts=4-toluenesulfonyl.
Boron-based Lewis acids bearing electron-deficient aryl sub-
stituents have been utilized as catalysts for numerous reduc-
tion methods since Piers and co-workers reported the B(C6F5)3-
catalyzed hydrosilylation of carbonyl compounds nearly two
decades ago.[1] In particular, the field of metal-free hydrogena-
tion[2] is currently attracting considerable attention due to the
ability of B(C6F5)3 and its congeners to bring about the hetero-
lytic splitting of dihydrogen either in combination with
a Lewis-basic substrate[3] or as a component of a frustrated
Lewis pair (FLP).[4] Based on the seminal reports by the groups
of Stephan[5] and Klankermayer[6] on the B(C6F5)3-catalyzed hy-
drogenation of imines (Scheme 1, top), we recently elaborated
the related reduction of oxime ethers to N-monosubstituted
hydroxylamines, a transformation that cannot be reliably ach-
ieved by metal catalysis due to cleavage of the NÀO bond
(Scheme 1, bottom).[7] However, our protocol is limited to
ketone-derived oxime ethers. Being aware that ethereal sol-
vents are able to function as Lewis-base partners to promote
the FLP-type reduction of imines at lower reaction temperature
and dihydrogen pressure (Scheme 1, top),[8–10] we hoped that
employing ethers as (co-)solvents might also be beneficial in
the hydrogenation of aldehyde-derived oxime ethers. More-
over, we disclose herein the extension of this hydrogenation
method to hydrazones, a hitherto neglected substrate class in
catalytic metal-free reductions (Scheme 1, bottom).[11]
We began with benzaldehyde-derived O-silylated oxime
ether 1 to test whether ethereal solvents permit the B(C6F5)3-
catalyzed hydrogenation of aldoxime ethers. We had previous-
ly seen no reactivity of 1 in toluene and we attribute this to its
lack of basicity at the nitrogen atom, that is, its inability to par-
ticipate in the FLP-type heterolytic dihydrogen cleavage. An
ethereal solvent such as 1,4-dioxane could bypass this problem
in that it assumes the role of the Lewis base in the dihydrogen
activation. The resulting oxonium ion is in turn a strong
Brønsted acid that is able to protonate 1. The observation that
the acidity of these protonated ethers compensates for the
low basicity of substrates that themselves fail to act as Lewis
bases in the FLP-activation step had already been made by
Ashley and co-workers in the reduction of imines.[8] Treatment
of aldoxime ether 1 with a catalytic amount of B(C6F5)3 in 1,4-
dioxane at 608C under a dihydrogen pressure of 100 bar led to
full conversion to the corresponding N-monosubstituted hy-
droxylamine 7 (1!7, Table 1, entry 1). Mixtures of 1,4-dioxane
and toluene as well as THF were less effective (not shown). We
excluded Et2O from our solvent screening because of the ele-
vated temperatures needed for this transformation. The cata-
lyst loading of 10 mol% was required to obtain excellent
yields, and lower loadings afforded incomplete conversion.
Likewise, an aldoxime ether with an electron-rich aryl group re-
acted smoothly (2!8, entry 2) but substantially lower conver-
sion was observed with an electron-deficient aryl substituent
[a] J. Mohr,+ D. Porwal,+ Dr. I. Chatterjee, Prof. Dr. M. Oestreich
Institut für Chemie, Technische Universität Berlin
Straße des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
Homepage: http://www.organometallics.tu-berlin.de
[+] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/chem.201503509.
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and benzaldehyde-derived hydrazones 13 and 14 to our hy-
drogenation protocols in both toluene[7] and 1,4-dioxane (cf.
Table 1). However, the hydrogenation of N,N-dimethyl-substi-
tuted 13a emerged to be better in toluene than in 1,4-dioxane
(13a!15a, entries 1 and 2). Changing the substituents at the
nitrogen atom to sterically more demanding benzyl groups se-
cured full conversion of 13b independent of the solvent
(13b!15b, entries 3 and 4). Conversely, the corresponding
benzaldehyde-derived hydrazone 14b did not reach full con-
version even with increased catalyst loading (14b!16b, en-
tries 5 and 6). We then attempted the hydrogenation of phtha-
loyl-protected hydrazones 13c and 14c to arrive at hydrazines
with an easily removable protective group. Ketone-derived
13c reacted cleanly to the hydrazine in either solvent (13c!
15c, entries 7 and 8) but aldehyde-derived 14c again gave in-
ferior results with no catalytic reaction in toluene and higher
but still poor conversion in 1,4-dioxane (14c!16c, entries 9
and 10). Increasing the catalyst loading to 10 mol% was neces-
sary to secure full conversion of 14c to hydrazine 16c
(entry 11). Generally, more basic ketone-derived hydrazones as
well as previously reported oxime ethers[7] do not require the
aid of an external Lewis base such as 1,4-dioxane.
Table 1. B(C6F5)3-catalyzed hydrogenation of aldoxime ethers in 1,4-diox-
ane.[a]
Entry Oxime
ether
R
Hydroxylamine Conv.
[%][b]
Yield
[%][c]
1
2
1
2
7
8
>99
>99
95
89[d]
3
4
3
4
9
72
n.d.
91
10
>99
5
6
5
6
11
12
>99
>99
90
93
[a] Reactions were performed on a 0.16 mmol scale. [b] Determined by
GLC analysis. [c] Determined after purification by filtration through
a small plug of silica gel. [d] Determined after purification by flash
column chromatography on silica gel. n.d.=not determined.
We subsequently explored the reactivity of other ketone-de-
rived, phthaloyl-protected hydrazones (Table 3). As we did not
observe any particular solvent effect with hydrazone 13c, we
decided to perform the hydrogenations in toluene. The elec-
tronic and steric situation of the substituents at the hydrazone
carbon atom in 17c–20c had little effect, and hydrazines 21c–
24c were obtained in excellent isolated yields. It was possible
to lower the dihydrogen pressure from 100 to 50 bar in all
cases.
(3!9, entry 3). This is again consistent with the notion of sub-
strate basicity being crucial to achieve satisfactory reactivity.
Conversely, halogenation and steric hindrance were both toler-
ated (4!10 and 5!11, entries 4 and 5), and an alkyl-substi-
tuted aldoxime ether was also readily converted in high yield
(6!12, entry 6).
We next turned our attention to the B(C6F5)3-catalyzed re-
duction of hydrazones, a closely related functional group
(Table 2).[12] We subjected differently protected acetophenone-
Other aldehyde-derived hydrazones with the phthaloyl pro-
tective group were reduced under the same setup as for 14c
(Table 4). The hydrogenation method with 10 mol% catalyst in
1,4-dioxane converted hydra-
zones with electron-rich and -de-
ficient aryl groups (entries 1 and
Table 2. B(C6F5)3-catalyzed hydrogenation of hydrazones: Comparison of protective groups and effect of the
solvent.[a]
2) as well as alkyl substitution
(entry 3) into the desired hydra-
zines.
Finally, we demonstrated the
feasibility of the removal of the
phthaloyl protective group from
Entry
Hydrazone
R1
R2
R3
Hydrazine
Solvent
Conv. [%][b,c]
Yield [%][d]
the
formed
hydrazines
(Scheme 2).[17] This was achieved
by treating phthaloyl-protected
hydrazine 15c with hydrazine
hydrate. For more convenient
isolation, the free hydrazine was
reacted in situ with acetic acid
to afford acetyl-substituted hy-
drazine 15d in good isolated
yield.
1
2
3
4
5[e]
6[e]
7
8
9
13a
13a
13b
13b
14b
14b
13c
13c
14c
14c
14c
Me
Me
Me
Me
H
Me
Me
Bn
Bn
Bn
Bn
Phthaloyl
Phthaloyl
Phthaloyl
Phthaloyl
Phthaloyl
Me
Me
Bn
Bn
Bn
Bn
15a
15a
15b
15b
16b
16b
15c
15c
16c
16c
16c
toluene
1,4-dioxane
toluene
1,4-dioxane
toluene
1,4-dioxane
toluene
1,4-dioxane
toluene
1,4-dioxane
1,4-dioxane
>99
85
>99
>99
48
n.d.
n.d.
89
n.d.
n.d.
n.d.
95
n.d.
n.d.
n.d.
94
H
77
Me
Me
H
H
H
>99
>99
3
13
>99
10
11[e]
In summary, we established
the transition-metal-free catalytic
[a] Reactions were performed on a 0.15–0.17 mmol scale. [b] Determined by GLC analysis. [c] In those cases for
which reactions did not go to completion, conversions from different runs differed significantly; the reported
numbers represent the lowest obtained. [d] Determined after purification by filtration through a small plug of
silica gel. [e] Reaction performed with 10 mol% B(C6F5)3. n.d.=not determined.
hydrogenation
of
aldoxime
ethers to N-monosubstituted hy-
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hydrogen pressure in toluene, whereas less basic aldehyde-de-
rived hydrazones required the use of an ethereal sovent.
Table 3. B(C6F5)3-catalyzed hydrogenation of ketone-derived hydrazo-
nes.[a]
Acknowledgements
This research was supported by the German Academic Ex-
change Service (predoctoral fellowship to D.P. , 2014—2018)
and the Cluster of Excellence Unifying Concepts in Catalysis of
the Deutsche Forschungsgemeinschaft (EXC 314/2). M.O. is in-
debted to the Einstein Foundation (Berlin) for an endowed
professorship. We thank Banjo Single-Liertz (TU Berlin) for ini-
tial experiments.
Entry Hydrazone R1
R2 Hydrazine Conv. [%][b] Yield [%][c]
1
2
17c
18c
Me 21c
Me 22c
>99
>99
97
83
3
4
19c
20c
Me 23c
Et 24c
>99
>99
90
96
Keywords: boron · homogeneous catalysis · hydrogenation ·
Lewis acids · reduction
Et
[a] Reactions were performed on a 0.16 mmol scale. [b] Determined by
GLC analysis. [c] Determined after purification by filtration through
a small plug of silica gel.
[1] D. J. Parks, W. E. Piers, J. Am. Chem. Soc. 1996, 118, 9440–9441.
[2] For selected overviews, 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.
[3] For a recent overview of catalytic HÀH and SiÀH bond activations with
electron-deficient boranes, see: M. Oestreich, J. Hermeke, J. Mohr,
Chem. Soc. Rev. 2015, 44, 2202–2220.
Table 4. B(C6F5)3-catalyzed hydrogenation of aldehyde-derived hydrazo-
nes.[a]
[4] For authoritative reviews of FLP chemistry, see: a) D. W. Stephan, G.
Erker, Angew. Chem. Int. Ed. 2015, 54, 6400–6441; Angew. Chem. 2015,
127, 6498–6541; b) D. W. Stephan, G. Erker, Angew. Chem. Int. Ed. 2010,
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[5] P. A. Chase, T. Jurca, D. W. Stephan, Chem. Commun. 2008, 1701–1703.
[6] D. Chen, J. Klankermayer, Chem. Commun. 2008, 2130–2131.
[7] J. Mohr, M. Oestreich, Angew. Chem. Int. Ed. 2014, 53, 13278–13281;
Angew. Chem. 2014, 126, 13494–13497 and references therein.
[8] D. J. Scott, M. J. Fuchter, A. E. Ashley, Angew. Chem. Int. Ed. 2014, 53,
10218–10222; Angew. Chem. 2014, 126, 10382–10386.
Entry Hydrazone
R
Hydrazine Conv. [%][b] Yield [%][c]
1
25c
28c
>99
95
[9] The same trick also enabled the previously elusive FLP-type hydrogena-
tion of carbonyl compounds: a) D. J. Scott, M. J. Fuchter, A. E. Ashley, J.
Am. Chem. Soc. 2014, 136, 15813–15816; b) T. Mahdi, D. W. Stephan, J.
Am. Chem. Soc. 2014, 136, 15809–15812.
2
3
26c
27c
29c
30c
>99
>99
97
65[d]
[10] For the seminal report of the use of ethereal solvents as Lewis-basic
partners in FLP-type reductions, see: L. J. Hounjet, C. Bannwarth, C. N.
Garon, C. B. Caputo, S. Grimme, D. W. Stephan, Angew. Chem. Int. Ed.
2013, 52, 7492–7495; Angew. Chem. 2013, 125, 7640–7643.
[a] Reactions were performed on a 0.16 mmol scale. [b] Determined by
GLC analysis. [c] Determined after purification by filtration through
a small plug of silica gel. [d] Determined after purification by flash
column chromatography on silica gel.
[11] For stoichiometric hydrazone-to-hydrazine reductions, see: a) R. L.
Hinman, J. Chem. Soc. 1957, 79, 414–417 (LiAlH4); b) G. N. Walker, M. A.
Moore, B. N. Weaver, J. Org. Chem. 1961, 26, 2740–2747 (NaBH4); c) J. A.
Blair, R. J. Gardner, J. Chem. Soc. C 1970, 1714–1717 (diborane); d) P.-L.
Wu, S.-Y. Peng, J. Magrath, Synthesis 1995, 435–438 (Et3SiH/TFA); for ex-
amples of metal-catalyzed hydrazone hydrogenations, see: e) H. L. Yale,
K. Losee, J. Martins, M. Holsing, F. M. Perry, J. Bernstein, J. Am. Chem.
Soc. 1953, 75, 1933–1942 (platinum catalysis); f) A. Ebnçther, E. Jucker,
A. Lindenmann, E. Rissi, R. Steiner, R. Süess, A. Vogel, Helv. Chim. Acta
1959, 42, 533–563 (nickel catalysis); g) M. J. Burk, J. E. Feaster, J. Am.
Chem. Soc. 1992, 114, 6266–6267 (ruthenium catalysis); for a nickel-cat-
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Chuanprasit, H. Hirao, J. Zhou, Angew. Chem. Int. Ed. 2015, 54, 5112–
5116; Angew. Chem. 2015, 127, 5201–5205.
Scheme 2. Removal of the phthaloyl protective group.
droxylamines. The previous limitation to ketone-derived oxime
ethers was overcome by the use of 1,4-dioxane as the solvent.
The ethereal solvent fulfills the role of the Lewis-basic compo-
nent in FLP-type dihydrogen splitting, thereby allowing for the
reduction of less basic aldehyde-derived substrates. Moreover,
the related transition-metal-free catalytic reduction of hydra-
zones to hydrazines was accomplished. In the case of ketone-
derived hydrazones protected with the easy-to-remove phtha-
loyl group, the hydrogenation could be performed at lower di-
[12] We also attempted to reduce less basic aldehyde-derived hydrazones
by means of the mechanistically related B(C6F5)3-catalyzed hydrosilyla-
tion[13] and transfer hydrosilylation,[14] respectively. In contrast to oxime
ethers for which hydrosilylation of the C=N bond was thwarted by the
oxophilicity of hydrosilane reducing agent,[7] reduction of benzalde-
hyde-derived hydrazone 14c to its corresponding hydrazine was feasi-
ble with PhSiH3 and the cyclohexa-2,5-dien-1-yl-substituted surrogates
of Me3SiH[14] and SiH4.[15] However, the reactivity was poor and complex
mixtures were obtained, especially at higher temperatures. GLC-MS
analysis indicated deoxygenation of the phthaloyl protective group as
a competing pathway.[16]
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[13] For B(C6F5)3-catalyzed hydrosilylation of imines, see: J. M. Blackwell, E. R.
Sonmor, T. Scoccitti, W. E. Piers, Org. Lett. 2000, 2, 3921–3923.
[14] For B(C6F5)3-catalyzed transfer hydrosilylation of imines, see: S. Keess, A.
Simonneau, M. Oestreich, Organometallics 2015, 34, 790–799.
[15] For SiH4 surrogates in B(C6F5)3 catalysis, see: A. Simonneau, M. Oes-
treich, Nat. Chem. 2015, 7, 816–822.
Cantat, Chem. Commun. 2014, 50, 9349–9352; c) R. C. Chadwick, V. Kar-
delis, P. Lim, A. Adronov, J. Org. Chem. 2014, 79, 7728–7733.
[17] The deprotection of 16c is reported in: M. J. Hearn, E. R. Lucero, J. Het-
erocycl. Chem. 1982, 19, 1537–1539.
[16] For B(C6F5)3-catalyzed deoxygenation of amide functionalities, see: a) M.
Tan, Y. Zhang, Tetrahedron Lett. 2009, 50, 4912–4915; b) E. Blondiaux, T.
Received: September 3, 2015
Published online on October 22, 2015
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17586
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim