Ruthenium-catalysed transfer hydrogenation reactions with dimethylamine borane

Article abstract of DOI:10.1016/j.tetlet.2011.10.039

Dimethylamine-borane adduct has been used as the hydrogen source for the reduction of carbonyl compounds, imines, oximes, nitriles, nitroarenes and alkenes using [Ru(p-cymene)Cl₂]₂ as the catalyst.

Full text of DOI:10.1016/j.tetlet.2011.10.039

Tetrahedron Letters 52 (2011) 6652–6654
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ruthenium-catalysed transfer hydrogenation reactions with
dimethylamine borane
⇑
⇑
Tracy D. Nixon, Michael K. Whittlesey , Jonathan M. J. Williams
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 15 October 2011
Dimethylamine–borane adduct has been used as the hydrogen source for the reduction of carbonyl com-
pounds, imines, oximes, nitriles, nitroarenes and alkenes using [Ru(p-cymene)Cl2]2 as the catalyst.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ruthenium
Catalysis
Reduction
Amine–boranes
Hydrogen transfer
Metal-catalysed transfer hydrogenation reactions provide a
widely-used alternative to direct hydrogenation reactions.1 The
reduction of carbonyl compounds into alcohols by metal-catalysed
transfer hydrogenation has received the most attention, where
2-propanol is often used as both the solvent and the hydrogen do-
nor.2 An excess of 2-propanol is usually required in order to drive
the equilibrium towards alcohol formation. Alternative hydrogen
donors which do not need to be used in excess include formic acid
and its derivatives3 and less commonly, Hantzsch esters4 and 1,4-
butanediol.5
There has been considerable interest in the use of amine
–borane adducts (R2NHꢀBH3) as storage materials for hydrogen.6
The majority of research has focussed on the metal-catalysed re-
lease of hydrogen from amine–borane adducts7 and this area has
recently been reviewed.8 The use of amine–borane adducts in
transfer hydrogenation reactions has been limited, with Manners
and co-workers reporting the use of rhodium colloids for the cata-
lytic reduction of cyclic alkenes with Me2NHꢀBH3.9 Recently, they
have also shown that heterogeneous rhodium catalysts can be used
to reduce a range of functional groups.10 Rhenium complexes11
have been used to catalyse the reduction of alkenes with
Me2NHꢀBH3 and there is a report on the use of pyrrolidine
–borane in the ruthenium-catalysed reduction of a limited range
of ketones and imines.12
and oxidation15 processes. In this Letter, we report the use of the
commercially-available ruthenium complex [Ru(p-cymene)Cl2]2
as the catalyst for the transfer hydrogenation of carbonyl com-
pounds, imines, oximes, nitriles, nitroarenes and alkenes using
Me2NHꢀBH3 as the hydrogen donor.
In order to identify an appropriate catalyst for transfer hydroge-
nation using Me2NHꢀBH3, we chose the reduction of acetophenone
(1) to the corresponding alcohol 2 as a model reaction (Scheme 1).
Various ruthenium complexes were screened for activity in this
reaction and the conversions obtained with each catalyst at room
temperature and at 70 °C are shown in Table 1.
All of the ruthenium complexes showed catalytic activity for the
reduction of acetophenone (1) using Me2NHꢀBH3 as the source of
hydrogen. Both Ru(PPh3)3(CO)H2 and [Ru(p-cymene)Cl2]2 led to
complete conversion into product after 24 h at 70 °C, but given
the relative costs of the two complexes, we selected [Ru(p-cymene)
Cl2]2 as the catalyst for the transfer hydrogenation of a range of
ketones.
Initially, we chose to investigate the reduction of carbonyl com-
pounds which was successful for a range of ketones and for an
aldehyde (Table 2). The corresponding alcohols were isolated in
good to excellent yield. Esters and amides were inert under the
same reaction conditions. When the reduction of acetophenone
We have recently been exploring the use of ruthenium com-
plexes as catalysts for hydrogen transfer reactions with a range
of applications including the use of alcohols as alkylating agents
using borrowing hydrogen methodology13 as well as reduction14
O
OH
Ru catalyst (5 mol% in Ru)
Ph
Me
Me2NH·BH3 (1 equiv.)
THF, r.t. or 70 °C, 24 h
Ph
Me
1
2
⇑
Corresponding authors.
E-mail address: j.m.j.williams@bath.ac.uk (Jonathan M. J. Williams).
Scheme 1. Model reaction for transfer hydrogenation using Me2NHꢀBH3.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.039

T. D. Nixon et al. / Tetrahedron Letters 52 (2011) 6652–6654
6653
Table 1
Catalyst A (0.1 mol%)
KOtBu (2 mol%)
O
OH
Ruthenium catalysts for the reduction of ketone 1
Ru Catalyst
Conversion at r.t.a (%)
Conversion at 70 °Ca (%)
Ph
Ph
Me
Ph
Me
Me2NH·BH3 (1 equiv.)
Ru(PPh3)3Cl2
45
90
5
26
82
54
100
82
99
100
THF, 21°C, 24 h
100% conversion
76% ee
Ru(PPh3)3(CO)H2
CpRu(PPh3)2Cl
[Ru(cod)Cl2]n
Catalyst A (0.1 mol%)
KOtBu (2 mol%)
O
O
OH
[Ru(p-cymene)Cl2]2
a
Conversion was determined by analysis of the 1H NMR spectra.
Me2NH·BH3 (1 equiv.)
Ph
100% conversion
73% ee
THF, 21 °C, 24 h
Table 2
Catalyst B (0.1 mol%)
KOtBu (2 mol%)
Reduction of ketones and aldehydes to alcohols
OH
O
OH
[Ru(p-cymene)Cl2]2 (2.5 mol%)
1-Naphth
Me
1-Naphth
Me
100% conversion
80% ee
Me2NH·BH3 (1 equiv.)
THF, 21 °C, 24 h
R
R'
R
R'
Me2NH·BH3 (2 equiv.)
70 °C, 24 h
3
4
Entry
1
Alcohol product 4
Yielda (%)
Catalyst A = [(R)-xylylBINAP][(R,R)-DPEN]RuCl2
Catalyst B = [(R)-BINAP][(R,R)-DPEN]RuCl2
OH
X = H
X = F
96
93
96
88
X = F3C
X = H3C
CH3
Scheme 2. Asymmetric reduction of ketones.
X
OH
Table 3
Reduction of imines to amines
2
77
H
N
[Ru(p-cymene)Cl2]2 (2.5 mol%)
R
R
N
R'
R'
OH
Me2NH·BH3 (1.5 equiv.)
70 °C, 24 h
3
4
85
94
5
6
Ph
Yielda (%)
OH
Entry
1
Amine product 6
PhO
H
57
74
Ph
N
Ph
OH
H
N
5
6
100b
90
p-MeC6H4
2
CH3
-ClC H
p
6
4
O
H
N
p-MeOC6H4
3
4
58b
49
Ph
OH
Ph
H
N
a
Isolated yield after purification by column chromatography.
Conversion determined by analysis of the 1H NMR spectrum. The product
decomposed during column chromatography.
p-MeC6H4
p-MeOC6H4
p-MeOC6H4
b
O
N
H
5
50
O
was performed for 2 h, a conversion of 80% was achieved. The reac-
tion was also performed in the presence of mercury and a 71% con-
version was achieved under otherwise identical conditions. This
suggests that the reaction operates principally through a homoge-
neous pathway.
a
Isolated yield after purification by column chromatography.
The starting imine was p-MeOC6H4CH@CHCH@NPh; 2.5 equiv of Me2NHꢀBH3
b
were used.
In the case of the reduction of 4-trifluoromethylacetophenone,
this reaction was repeated by heating in THF-d8 for 1.5 h at
70 °C. The 11B NMR spectrum revealed the complete consumption
of Me2NHꢀBH3 along with the appearance of new signals attributed
to [H2B-NH2]2 and (Me2N)2BH.
amines (Table 3, entries 1, 4 and 5) and from anilines (Table 3, en-
tries 2 and 3). In the case of entry 3, the substrate used was an a,b-
unsaturated imine which underwent reduction of the alkene and
the imine when sufficient Me2NHꢀBH3 was present. Only trace
amounts of the product were formed in the absence of the catalyst.
Under transfer hydrogenation conditions with 2-propanol,
ruthenium catalysts usually rearrange oximes into amides and no
reduction is observed.17 However, we found that aromatic oximes
were reduced to secondary amines using Me2NHꢀBH3 as the hydro-
gen donor (Scheme 3). We speculate that initial reduction of the
oxime affords a primary amine. The primary amine and oxime
are then in equilibrium with hydroxylamine and imine. Favourable
reduction of the imine leads to formation of the secondary amine.
When the same reaction conditions were applied to an aliphatic
oxime, PhCH2CH2CH@NOH, reduction was not observed, and the
isolated product was the corresponding nitrile.18 In the absence
of catalyst, starting material was recovered unchanged.
In all cases, there was at least some background uncatalyzed
reaction, and in order to demonstrate clearly that the ruthenium
played an active part in catalysis, we chose to examine an asym-
metric version of these ketone reductions. Using only 0.1 mol % of
the commercially available complexes [(R)-BINAP][(R,R)-DPEN]-
RuCl2 or [(R)-xylylBINAP][(R,R)-DPEN]RuCl2,16 prochiral ketones
were reduced with reasonable levels of enantiocontrol demonstrat-
ing the involvement of the catalyst in the reduction (Scheme 2).
The same reaction conditions were also used successfully for
the reduction of imines to amines (Table 3). After 24 h at 70 °C,
all of the starting materials had been consumed, although the iso-
lated yields were rather modest, presumably due to the loss of
material during work-up and isolation. The reduction reactions
were found to be successful for imines derived from primary
We examined the reduction of a small set of nitriles 9 which
were cleanly converted into the corresponding primary amines

6654
T. D. Nixon et al. / Tetrahedron Letters 52 (2011) 6652–6654
OH
H
Ph
[Ru(p-cymene)Cl2]2 (2.5 mol%)
Ph
Ph
N
CH3
Me2NH·BH3 (1 equiv.)
THF, 70 °C, 24 h
[Ru(p-cymene)Cl2]2(2.5 mol%)
Ph
NH
2
Me2NH·BH3 (1 equiv.)
THF, 70 °C, 24 h
84% isolated yield
Scheme 6. Alkene reduction by transfer hydrogenation.
X
X
7
8
X
Isolated yield
H
Acknowledgment
43%
48%
89%
Me
OMe
We thank the EPSRC for funding.
Scheme 3. Oxime reduction by transfer hydrogenation.
Supplementary data
CN
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.039.
[Ru(p-cymene)Cl2]2 (2.5 mol%)
NH3Cl
Me2NH·BH3 (3 equiv.)
X
X
THF, 70 °C, 24 h
9
10
References and notes
then HCl/Et2O
X
Isolated yield
1. de Vries, J. G., Elsevier, C. J., Eds.Handbook of Homogeneous Hydrogenation;
Wiley-VCH: Weinheim, 2007; 1–3,.
2. (a) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045; (b) Gladiali,
S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226.
3. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 2521.
4. (a) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4, 3955; (b) Shen,
X.-X.; Liu, Q.; Xing, R.-G.; Zhou, B. Catal. Lett. 2008, 126, 361.
63%
98%
80%
H
Me
MeO
Scheme 4. Nitrile reduction by transfer hydrogenation.
5. (a) Maytum, H. C.; Tavassoli, B.; Williams, J. M. J. Org. Lett. 2007, 9, 4387; (b)
Maytum, H. C.; Francos, J.; Whatrup, D. J.; Williams, J. M. J. Chem. Asian J. 2010,
5, 538.
6. Hamilton, C. W.; Baker, R. T.; Staubitz, A.; Manners, I. Chem. Soc. Rev. 2009, 38,
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7. For recent examples, see: (a) Chaplin, A. B.; Weller, A. S. Angew. Chem., Int. Ed.
2010, 49, 581; (b) Tang, C. Y.; Thompson, A. L.; Aldridge, S. Angew. Chem., Int. Ed.
2010, 49, 921; (c) Sloan, M. E.; Staubitz, A.; Clark, T. J.; Russell, C. A.; Lloyd-
Jones, G. C.; Manners, I. J. Am. Chem. Soc. 2010, 132, 3831; (d) Vogt, M.; de Bruin,
B.; Berke, H.; Trincado, M.; Grützmacher, H. Chem. Sci. 2011, 2, 723; (e) Stevens,
C. J.; Dallanegra, R.; Chaplin, A. B.; Weller, A. S.; Macgregor, S. A.; Ward, B.;
McKay, D.; Alcaraz, G.; Sabo-Etienne, S. Chem. Eur. J. 2011, 17, 3011; (f)
Chapman, A. M.; Haddow, M. F.; Wass, D. F. J. Am. Chem. Soc. 2011, 133, 8826;
(g) Ledger, A. E. W.; Ellul, C. E.; Mahon, M. F.; Williams, J. M. J.; Whittlesey, M. K.
Chem. Eur. J. 2011, 17, 8704.
8. (a) Clark, T. J.; Lee, K.; Manners, I. Chem. Eur. J. 2006, 12, 8634; (b) Staubitz, A.;
Robertson, A. P. M.; Sloan, M. E.; Manners, I. Chem. Rev. 2010, 110, 4023.
9. (a) Jaska, C. A.; Manners, I. J. Am. Chem. Soc. 2004, 126, 2698; (b) Jaska, C. A.;
Manners, I. J. Am. Chem. Soc. 2004, 126, 9776.
10. Sloan, M. E.; Staubitz, A.; Lee, K.; Manners, I. Eur. J. Org. Chem. 2011, 672.
11. (a) Jiang, Y.; Berke, H. Chem. Commun. 2007, 3571; (b) Jiang, Y.; Blacque, O.;
Fox, T.; Frech, C. M.; Berke, H. Organometallics 2009, 28, 5493.
12. Blaquiere, N.; Diallo-Garcia, S.; Gorelsky, S. I.; Black, D. A.; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 14304.
13. (a) Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.; Shermer, D. J.; Whittlesey, M. K.;
Williams, J. M. J.; Edney, D. D. Chem. Commun. 2004, 90; (b) Slatford, P. A.;
Whittlesey, M. K.; Williams, J. M. J. Tetrahedron Lett. 2006, 47, 6787; (c) Burling,
S.; Paine, B. M.; Nama, D.; Brown, V. S.; Mahon, M. F.; Prior, T. J.; Pregosin, P. S.;
Whittlesey, M. K.; Williams, J. M. J. J. Am. Chem. Soc. 2007, 129, 1987; (d) Hamid,
M. H. S. A.; Williams, J. M. J. Chem. Commun. 2007, 725; (e) Hamid, M. H. S. A.;
Williams, J. M. J. Tetrahedron Lett. 2007, 48, 8263; (f) Nixon, T. D.; Whittlesey,
M. K.; Williams, J. M. J. Dalton Trans. 2009, 753; (g) Hamid, M. H. S. A.; Allen, C.
L.; Lamb, G. W.; Maxwell, A. C.; Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J.
J. Am. Chem. Soc. 2009, 131, 1766.
when treated with three equivalents of Me2NHꢀBH3 and [Ru(p-
cymene)Cl2]2 (Scheme 4). No reaction was observed in the absence
of catalyst. We found that it was experimentally more straightfor-
ward to isolate the products as the hydrochloride salts 10. The ni-
trile group is inert to ruthenium-catalysed transfer hydrogenation
when an alcohol is present as the hydrogen donor.19
There have been relatively few reports of the reduction of the
nitro group by transfer hydrogenation.20 We found that the use
of Me2NHꢀBH3 with [Ru(p-cymene)Cl2]2 was also effective for the
reduction of nitroarenes 11 and 13 with no debromination ob-
served in the latter case. The aniline products 12 and 14 were iso-
lated in moderate yield (Scheme 5).
Given the ability of the Me2NHꢀBH3/[Ru(p-cymene)Cl2]2 catalyst
system to reduce so many functional groups and the fact that the
alkene group of an unsaturated imine was reduced, we examined
the reactivity of 1,1-diphenylethene and again this was reduced
under the standard conditions to give the corresponding alkane
(Scheme 6). The ruthenium-catalysed reduction of alkenes with
NaBH4 in the presence of water has been reported.21
In summary, the reduction of a range of organic substrates has
been achieved by transfer hydrogenation from Me2NHꢀBH3 using a
simple ruthenium catalyst. In comparison with the use of alcohols
as hydrogen donors, Me2NHꢀBH3 acts irreversibly and expands the
range of functional groups which are amenable to reduction.
14. Burling, S.; Whittlesey, M. K.; Williams, J. M. J. Adv. Synth. Catal. 2005, 347, 591.
15. Owston, N. A.; Nixon, T. D.; Parker, A. J.; Whittlesey, M. K.; Williams, J. M. J.
Synthesis 2009, 1578.
NO2
Me
NH2
[Ru(p-cymene)Cl2]2 (2.5 mol%)
16. Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40. BINAP = 2,20-
Me
bis[di(phenyl)phosphino]-1,10-binaphthyl;
xylylBINAP = 2,20-bis[di(3,5-
Me2NH·BH3 (4 equiv.)
THF, 70 °C, 24 h
xylyl)phosphino]-1,10-binaphthyl; DPEN = 1,2-diphenylethylenediamine..
17. (a) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007, 9, 73; (b)
Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007, 9, 3599; (c)
Gnanamgari, D.; Crabtree, R. H. Organometallics 2009, 28, 922; (d) Hull, J. F.;
Hilton, S. T.; Crabtree, R. H. Inorg. Chim. Acta 2010, 343, 1243.
11
12
50% isolated yield
Me
NO2
Br
Me
NH2
[Ru(p-cymene)Cl2]2 (2.5 mol%)
18. The ruthenium-catalysed conversion of oxime ethers into nitriles has been
reported, see: Anand, N.; Owston, N. A.; Parker, A. J.; Slatford, P. A.; Williams, J.
M. J. Tetrahedron Lett. 2007, 48, 7761.
19. Black, P. J.; Edwards, M. G.; Williams, J. M. J. Eur. J. Org. Chem. 2006, 4, 4367.
20. Alper, H.; Amaratunga, S. Tetrahedron Lett. 1980, 21, 2603.
21. Adair, G. R. A.; Kapoor, K. K.; Scolan, A. L. B.; Williams, J. M. J. Tetrahedron Lett.
2006, 47, 8943.
Br
Me2NH·BH3 (4 equiv.)
THF, 70 °C, 24 h
13
14
82% isolated yield
Scheme 5. Nitroarene reduction by transfer hydrogenation.