Effective conversion of heteroaromatic ketones into primary amines via hydrogenation of intermediate ketoximes

Article abstract of DOI:10.1055/s-0034-1379538

A process to access heteroaromatic primary amines from the corresponding heteroaromatic ketones has been developed. A broad range of previously reported methods to convert ketones to primary amines was examined on heterocyclic ketones without success, including Leuckart-Wallach conditions, borane reductions, and transition-metal-catalyzed hydrogenations. Unique among the catalysts examined, Raney cobalt produced the desired primary heterocyclic amine. Raney cobalt hydrogenation of structurally varied heterocyclic ketoximes was demonstrated to form primary amines in good selectivity under mild conditions, and the products are easily isolated in high yield. Additionally, this is the first report of a systematic evaluation of the capabilities of Raney cobalt as an oxime hydrogenation catalyst.

Full text of DOI:10.1055/s-0034-1379538

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 201–204
letter
201
K. D. Baucom et al.
Letter
Synlett
Effective Conversion of Heteroaromatic Ketones into Primary
Amines via Hydrogenation of Intermediate Ketoximes
Kyle D. Baucom
Anil S. Guram
O
NOH
NH2
R
R
R
Christopher J. Borths*
X
Z
X
Z
X
Z
Y
Y
Y
Chemical Process Research and Development, Amgen, Inc.,
One Amgen Center Drive, Thousand Oaks, CA 91320, USA
cborths@amgen.com
>90%
45–98%
10 examples
+
1
8
(
0
5
3
)
7
5
4
5
3
2
Received: 29.09.2014
Accepted: 20.10.2014
Published online: 02.12.2014
DOI: 10.1055/s-0034-1379538; Art ID: st-2014-r0821-l
tion and only produced trace amounts of the desired
amine.4 Other reductive amination conditions investigated
produced the primary amine in poor to modest yields (40–
60%) with the remainder of the mass balance forming the
secondary amine (formed from two equivalents of the par-
ent ketone) or alcohol.5
Abstract A process to access heteroaromatic primary amines from the
corresponding heteroaromatic ketones has been developed. A broad
range of previously reported methods to convert ketones to primary
amines was examined on heterocyclic ketones without success, includ-
ing Leuckart–Wallach conditions, borane reductions, and transition-
metal-catalyzed hydrogenations. Unique among the catalysts exam-
ined, Raney cobalt produced the desired primary heterocyclic amine.
Raney cobalt hydrogenation of structurally varied heterocyclic ketoxim-
es was demonstrated to form primary amines in good selectivity under
mild conditions, and the products are easily isolated in high yield. Addi-
tionally, this is the first report of a systematic evaluation of the capabili-
ties of Raney cobalt as an oxime hydrogenation catalyst.
O
NH2
CH3
CH3
N
R
N
N
R
OH
+
+
CH3
R
Key words hydrogenation, Raney cobalt, heterogeneous catalysis,
CH3 CH3
amines, reduction, heterocycles
N
H
The conversion of ketones to the corresponding primary
amine is a common and useful transformation in organic
synthesis. This transformation is typically achieved by re-
ductive amination via reduction of an imine or enamine de-
rived from the corresponding ketone.1 Alternately, the re-
duction of oximes and nitriles can lead to the same prod-
ucts, typically requiring stoichiometric reductants such as
Mg, Na, Zn, Fe plus a hydride source or borane reagents.
These procedures can be expensive, pose environmental
concerns and involve complicated workup procedures.2 Sol-
id-supported metals like Pd, Ni or Rh can be used as hydro-
genation catalysts, avoiding expensive stoichiometric re-
agents and complex isolation protocols.3 However, oxime
reductions using these systems can be incompatible with
heteroaromatic functionalities due to complexation of the
metal catalyst by the heteroatom-containing substrates and
halogen-containing substrates due to dehalogenation.
N
R
R
N
Scheme 1 Synthesis of an amine from a ketone containing a coordi-
nating heterocycle and associated reaction side products
Encouraged by reports from Shan where oxime ethers
were readily reduced in the presence of stoichiometric bo-
rane reagents, we pursued amine formation through oxime
reduction.6 A model chelating heteroaromatic ketone 1 was
converted into a ketoxime 2 to examine the feasibility of
this approach (Scheme 2).
O
NOH
CH3
H2NOH•HCl
CH3
NaOAc
EtOH, reflux
95%
F
N
F
N
1
2
N
N
Scheme 2 Model oxime synthesis for reduction studies
As part of a program to develop an improved synthesis
towards an advanced intermediate of a kinase inhibitor, we
sought to transform a heteroaromatic ketone into the corre-
sponding primary amine (Scheme 1). Conventional direct
amination methods were explored with little success.
Leuckart–Wallach conditions led to significant decomposi-
A variety of borane reagents failed to reduce 2 to the de-
sired amine 3. Instead, the starting oxime was recovered
unchanged; prolonged reaction times led to complex degra-
dation. Zinc- and magnesium-mediated reductions gave
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 201–204

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K. D. Baucom et al.
Letter
Synlett
poor conversions to the desired amine even after extended
reaction times and forcing conditions.2a,e We then turned
our attention to hydrogenation of the oxime moiety.7 After
screening a variety of heterogeneous catalysts (Table 1), we
found that palladium and platinum gave no desired amine.
Pd- and Pt-catalyzed the reduction of the C–N double bond
yielding the hydroxy amine derived from 2. Ruthenium and
rhodium gave only low conversion (<5%), presumably due
to chelation-induced deactivation of the metal catalyst by
the bipyridyl functionality of the substrate. Raney nickel
showed consumption of the oxime 2, but produced a com-
plex mixture of products with little to no desired amine ob-
served.
However, Raney cobalt 2724 reduced oxime 2 to prima-
ry amine 3 in >95% yield and excellent purity, suppressing
the secondary amine formation to <1% (Table 1, entry 6).
The amine product could easily be isolated from this reac-
tion by filtering off the heterogeneous catalyst then adding
HCl to precipitate the product as a salt. This reaction was
subsequently demonstrated on >10 gram scale.
Table 1 Examination of Heterogeneous Catalysts in the Reduction of
Oxime 2
NOH
CH3
NH2
CH3
catalyst
THF–MeOH
H2 (60 psi)
50 °C, 12 h
F
N
F
N
2
3
N
N
Entry
Catalyst
Yield
1
2
3
4
5
6
5% Ru/C
5% Rh/C
5% Pt/C
5% Pd/C
<5%, recovered oxime
<5%, recovered oxime
hydroxy amine
hydroxy amine
decomposition
>95%
Raney Nia
Raney Co 2724a,b
a Raney catalysts are stored and charged as a slurry in H2O. The slurry was
charged at 100 wt% relative to oxime.
b Purchased from W. R. Grace and Co.
A few isolated reports of oxime reduction by Raney co-
balt were present in the literature.8 However, to the best of
the authors’ knowledge, this report represents the first sys-
tematic study of a high-yielding oxime reduction by this
underutilized heterogeneous catalyst.
The scope of the Raney cobalt 2724 catalyst was then
examined using the process developed for the model sub-
strate (Table 2). Sterically encumbered oximes were well
tolerated (Table 2, entries 2–6). Substrates expected to
strongly coordinate cobalt did not interfere with the reac-
tion (Table 2, entries 1 and 7), and aromatic halide-contain-
ing oximes could be reduced without significant dehaloge-
nation (Table 2, entries 10 and 11). Competitive secondary
amine formation was an issue for less sterically congested
substrates (Table 2, entries 2, 8, 12, and 13 and Scheme 3).
In particular, aldoximes preferentially formed dimeric sec-
ondary amines and yielded very little primary amine prod-
uct (Table 2, entries 12 and 13). The formation of secondary
amines during oxime and nitrile formation has been previ-
ously observed and reported. Specifically, Müller has ob-
served that the choice of catalyst can influence the selectiv-
ity of amine formation.8b
Table 2 Raney Cobalt Reduction of Pyridyl Oximes
Entry
Starting material
Product
Yield
80%
NOH
CH3
NH2
CH3
1
F
N
F
N
N
N
2a
3a
NH2
CH3
NOH
CH3
N
N
N
N
2
3
45%a
85%
2b
2c
3b
3c
NOH
NH2
CH3
CH3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 201–204

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K. D. Baucom et al.
Letter
Synlett
Table 2 (continued)
Entry
Starting material
Product
Yield
86%
NH2
NOH
N
N
CH3
CH3
4
5
6
7
CH3
CH3
3d
3e
3f
2d
2e
2f
NOH
NH2
N
N
N
CH3
CH3
CH3
N
N
CH3
CH3
CH3
98%
95%
90%
NH2
NH2
NH2
NOH
NOH
NOH
N
N
N
3g
2g
CH3
CH3
8
25%a
85%
80%
88%
N
N
2h
3h
NOH
CH3
NH2
CH3
9
H3C
N
H3C
N
2i
3i
NOH
CH3
NH2
CH3
10
11
Cl
2j
N
Cl
3j
N
NOH
NH2
Cl
2k
N
Cl
3k
N
NH2
NOH
12
13
<10%a
40%a
N
N
2l
3l
N
N
NH2
NOH
2m
3m
a A 100% conversion of starting material was observed. Mass balance was conversion to the corresponding dimeric secondary amine (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 201–204

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K. D. Baucom et al.
Letter
Synlett
NOH
NH2
(2) (a) Abiraj, K.; Gowda, D. C. Synth. Commun. 2004, 34, 599.
(b) McEachern, E. J.; Yang, W.; Chen, G.; Skerlj, R. T.; Bridger, G. J.
Synth. Commun. 2003, 33, 3497. (c) Cai, Z.; Liu, G.; Jiao, G.;
Senanayake, C. H.; Tang, W. Synthesis 2013, 45, 3355. (d) Chu, Y.;
Shan, Z.; Liu, D.; Sun, N. J. Org. Chem. 2006, 71, 3998. (e) Baruah,
B.; Dutta, M. P.; Boruah, A.; Prajapari, D.; Sandhu, J. S. Synlett
1999, 409. (f) Itsuno, S.; Sakurai, Y.; Ito, K. Synthesis 1988, 995.
(g) Abele, S.; Breitenmoser, R. A.; Fink, T. Org. Process Res. Dev.
2012, 2008.
Raney Co
N
H
+
N
N
THF–MeOH
H2 (60 psi)
50 °C, 12 h
2l
3l
4
N
N
<10%
assay yield
90%
assay yield
Scheme 3 Raney cobalt reduction of aldoximes
(3) (a) Cwiek, R.; Niedziejko, P.; Kaluza, Z. J. Org. Chem. 2014, 79,
1222. (b) Bourrain, S.; Showell, G. A. Synthesis 1994, 505.
(c) Spreitzer, H.; Buchbauer, G.; Pueringer, C. Tetrahedron 1989,
45, 6999. (d) Burkhard, J. A.; Wuitschik, G.; Plancher, J. M.;
Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2013, 15, 4312.
(4) Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M.
J. Org. Chem. 2002, 8685.
(5) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J. Org. Chem. 1996, 3849. (b) Bharracharyya, S.;
Miriyala, B.; Williamson, J. S. Tetrahedron 2004, 1463.
(c) Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. J. Org.
Chem. 1990, 2552.
Direct reduction of nitriles with this catalyst system was
also examined. Subjecting nitriles to the reaction condi-
tions developed herein leads to the formation of dimeric
amines as the major reaction products (Scheme 4). This
presumably occurs via similar mechanism and intermedi-
ates as the previously reported results from the reduction
of aldoximes.
CN
Raney Co
N
H
R
R
R
THF–MeOH
H2(60 psi)
60 °C
(6) (a) Shan, Z.; Chu, Y.; Liu, D.; Sun, N. J. Org. Chem. 2006, 3998.
(b) Burkhardt, E. R.; Coleridge, B. M. Tetrahedron Lett. 2008,
5152.
major product
(7) (a) Adkins, H.; Winans, C. F. J. Am. Chem. Soc. 1933, 2051.
(b) Iffland, D. C.; Yen, T. F. J. Am. Chem. Soc. 1954, 76, 4180.
(c) Ran, L.; Liang, H.; Guan, Z. Chin. J. Org. Chem. 2013, 33, 66.
(8) (a) Banwell, M. G.; Jones, M. T.; Reekie, T. A.; Schwartz, B. D.;
Tan, S. H.; White, L. V. Org. Biomol. Chem. 2014, 12, 7433.
(b) Gebauer-Henke, E.; Leitner, W.; Prokofieva, A.; Vogt, H.;
Müller, T. E. Catal. Sci. Technol. 2012, 2, 2539.
(9) General Oxime Procedure: Ketone (76 mmol), hydroxylamine
hydrochloride (83 mmol), NaOAc (83 mmol) and EtOH (140 mL)
were combined and heated to reflux for 3 h. White solid
(oxime) was observed to precipitate from the solution during
this time. The mixture was then cooled, deionized H2O (140 mL)
was added, and the mixture was then stirred for 10 min. The
solids were isolated by filtration, washed with H2O (140 mL)
and dried at r.t. under nitrogen flow on the filter.
Scheme 4 Raney cobalt reduction of aromatic nitriles
In summary, we have developed a convenient procedure
to access heterocyclic primary amines via hydrogenation of
the corresponding oxime using Raney cobalt 2724 as the
catalyst.9 This is the first such study of amine synthesis
from oximes utilizing this catalyst. The reaction conditions
are mild and can tolerate the presence of reductively labile
halogen functionality and strongly coordinating heterocy-
cles. Furthermore, the products are readily separated from
the catalyst by simple filtration and can be purified by chro-
matography or salt formation.
General Reduction Procedure: To a mixture of oxime (0.86
mmol) and Raney Co 2724 (200 mg, slurry in H2O) were added
THF (1.5 mL) and MeOH (1.5 mL). The reaction mixture was
purged with nitrogen twice then pressurized to 60 psi H2 at 50
°C. The reaction was deemed complete when H2 consumption
ceased, typically after 2–10 h. Upon completion, the reaction
was filtered through a pad of celite and washed with MeOH. The
filtrate was then concentrated under reduced pressure, and
purified by flash chromatography (CH2Cl2–MeOH, 95:5) to
furnish the title compound. Alternatively, the product was con-
veniently isolated in high purity as the HCl salt. After filtering
off the catalyst, the filtrate solvent was changed to MTBE (1.5
mL) and HCl (0.95 mmol, 1 M in Et2O) was added dropwise to
crystallize the salt. The resulting HCl amine salt was then iso-
lated by filtration and washed with MTBE.
Acknowledgment
We thank Dr. Matthew M. Bio and Dr. Shawn D. Walker (Amgen) for
their review of the manuscript and helpful discussions.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379538.
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References and Notes
(1) (a) Nugent, T. C.; El-Shazley, M. Adv. Synth. Catal. 2010, 352, 753.
(b) LaRock, R. C. Comprehensive Organic Transformations, A
Guide to Functional Group Preparations; Wiley: New York, 1999,
2nd ed.
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