Selective ruthenium-catalyzed transfer hydrogenations of nitriles to amines with 2-butanol

Article abstract of DOI:10.1002/chem.201204633

Transfer your hydrogen: Fast and general transfer hydrogenation of nitriles to form primary amines is possible with a homogeneous Ru/1,4- bis(diphenylphosphino)butane (DPPB) catalyst (see scheme). The use of 2-butanol as the hydrogen-transfer reagent is essential for the selective reduction of aromatic, heteroaromatic, and aliphatic nitriles with this system. Copyright

Full text of DOI:10.1002/chem.201204633

COMMUNICATION
DOI: 10.1002/chem.201204633
Selective Ruthenium-Catalyzed Transfer Hydrogenations of Nitriles to
Amines with 2-Butanol
Svenja Werkmeister, Christoph Bornschein, Kathrin Junge, and Matthias Beller*[a]
Due to their importance in pharmaceuticals, agrochemi-
cals, as organic building blocks, and as intermediates for the
materials sciences, as well as in biological processes, amines
are of significant interest in academic and industrial re-
search.[1] The most general and often benign processes for
the production of amines rely on catalytic reductions. Com-
pared with selective reductions of nitroarenes and aliphatic
imines, as well as reductive amination of carbonyl com-
pounds, investigations of the catalytic hydrogenation of aro-
matic and especially aliphatic nitriles with organometallic
complexes are much less common to date.[2–4] Even fewer
studies of the related transfer hydrogenation (TH) of nitriles
have been reported in recent decades. However, the use of
transfer hydrogenation reagents does not require the han-
dling of molecular hydrogen and therefore, advantageously,
no high-pressure equipment is needed. Typically, in the
more common catalytic transfer hydrogenation of carbonyl
compounds, mixtures of formic acid and amines or formate
salts, as well as alcohols (typically isopropanol) in combina-
tion with a base are used as suitable hydrogen sources.[5]
The first examples of transfer hydrogenation of nitriles
were reported by Brown et al.[6] as early as 1982. In this
work, ammonium formate was used with a heterogeneous
palladium catalyst for the TH of aromatic nitriles. With one
notable exception (2,4-dimethylbenzonitrile was converted
to 2,4-dimethylbenzylamine) all of the nitriles studied were
the reducing agent. Despite these advances, the need for a
more general catalytic TH of nitriles remains.
In Scheme 1, the different reaction pathways for the hy-
drogenation/TH of nitriles are shown. Often, the formation
of secondary amines is observed as an unwanted side re-
AHCTUNGTREGaNNNU ction. Applying alcohols as hydrogen transfer reagents
opens the possibility of subsequent reductive amination.
Scheme 1. Reaction pathways for the hydrogenation/TH of nitriles and
possible side reactions.
reductively deaminated to give the corresponding sub
ACHTUNGTNERsNUNG ti-
ACHTUNGTRENNUNGtuted toluenes. More recently, other heterogeneous catalyst
systems for this transformation were developed by Gowda
et al.[7] in 2002 and most recently by Qian et al. in 2012.[8]
With respect to homogeneous catalysts, it is interesting to
note that Yamagishi et al.[9] and Albrecht et al.,[10] published
ruthenium-based catalyst systems for the hydrogenation of
benzonitrile to benzylamine with ammonium formate or iso-
propanol. Unfortunately, most of the reactions proceeded in
only low to moderate yields. In addition, it is noteworthy
that in 2011 Williams and co-workers[11] reported the Ru-cat-
alyzed reduction of nitriles with dimethylamino borane as
Based on our long-standing interest in transfer hydro
ACHTUNGTRENNUNGgen-
ACHTUNGTRENNUNGaAHCTUNGTRENNNUG
tion[12] and the catalytic reduction of nitriles,[2h,j,l] as well as
the general importance of this methodology, we recently set
up a project to develop the selective TH of nitriles to form
primary amines. Therefore, herein, we present a ruthenium-
catalyzed transfer hydrogenation of nitriles to form primary
amines with broad substrate scope by applying
2-butanol as a selective reducing agent in the presence of
sodium hydroxide.
For our initial studies, we used the benchmark reaction of
benzonitrile to benzyl amine to investigate the influence of
several catalysts, ligands, and reaction parameters by using
isopropanol/KOtBu (Table 1) as the hydrogen transfer
agent. We observed neither N-benzylidene-1-phenylmethan-
amine A nor dibenzylamine B as side products. Instead, the
benzyl amine formed initially reacted further with the re-
sulting ketone (acetone) to form the N-monoalkylated sec-
ondary amine D.
[a] S. Werkmeister, C. Bornschein, Dr. K. Junge, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204633.
Chem. Eur. J. 2013, 19, 4437 – 4440
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4437

Table 1. Variation of catalyst precursors and ligands.[a]
Nevertheless, the combination of 3 with different diphos-
phine ligands, that is, 1,2-bis(diphenylphosphino)ethane
(DPPE), 1,3-bis(diphenylphosphino)propane (DPPP), 1,4-
bis(diphenylphosphino)butane (DPPB), 1,5-bis(diphenyl-
phosphino)pentane
(DPPPE),
and
1,1’-bis(diphenyl-
AHCTUNGTREGpNNUN hosphino)ferrocene (DPPF) (Table 1, entries 5–8, 10), dis-
Entry
Ru precursor
Ligand
Yield
[%][b]
played high product yields between 64 and 78%. Conspicu-
ously, diphosphine ligands bearing an even number of C
atoms between the coordinating phosphorous atoms, except
DPPH (DPPH=1,6-bis(diphenylphosphino)hexane), caused
higher yields than chelating ligands bridged with an odd
number of C atoms.
1
2
3
[RuCl
E
–
–
–
68
9
5
[{Ru
[{Ru
ACHTUNGTRENNUNG
A
4
–
11
Next, with the best catalyst system ([{Ru(p-cyACTHUNTRGNEUNGmene)Cl2}2]/
DPPB) in hand, we focused on the role of different bases.
As shown in Table 2, there is no clear relationship between
5
6
7
8
9
[{Ru
[{Ru
[{Ru
[{Ru
[{Ru
N
72
59
Table 2. Variation of bases.[a]
78
64
<3
Entry
Base
Alcohol
t
Yield
[%][c]
10
11
12
[{Ru
[{Ru
[{Ru
G
76
74
6
AHCTUNGTERG[NNUN min]
1
2
3
4
5
6
NaOH
KOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
2-BuOH
2-BuOH
2-BuOH
10
10
10
10
10
10
10
10
20
59
–
–
47
78
64
79
75
93
Na2CO3
K2CO3
KOtBu
Cs2CO3
KOtBu
NaOH
NaOH
7[b]
8[b]
9[b]
13
14
[{Ru
[{Ru
63
44
[a] Reaction conditions: benzonitrile (0.5 mmol), [{RuACHTUNTRGNEUNG(p-cymene)2Cl2}2]
(1 mol%), DPPB (2 mol%), base (10 mol%), isopropanol (5 mL),
1208C. [b] 2-Butanol (5 mL) instead of isopropanol. [c] Yield determined
by GC analysis with hexadecane as the internal standard.
base strength and product yield. The reaction did not work
in the presence of potassium hydroxide or sodium carbonate
(10 mol%; Table 2, entries 2 and 3); however, sodium hy-
droxide, potassium tert-butoxylate and caesium carbonate
resulted in the desired product in good yields between 59
and 78% (Table 2, entries 1, 5, and 6).
15
[{Ru
(p-cymene)2Cl2}2]
5
[a] Reaction conditions: benzonitrile (0.5 mmol), Ru precursor
(1 mol%), ligand (2 mol%), KOtBu (10 mol%), isopropanol (5 mL),
10 min, 1208C. [b] Yield determined by GC analysis with hexadecane as
the internal standard.
To avoid the unwanted N-monoalkylation reaction, alco-
hols other than isopropanol were tested as transfer hydro-
As shown in Table 1, various defined ruthenium precata-
lysts gave highly active catalyst systems (reaction time:
10 min). For example, the commercially available complex
ACHTUNGTRNEgUNGN enAHCTUNRTGENNUNGaACHTUGTNRENNtGU ion reagents (Scheme 2). Gratifyingly, 2-butanol
showed nearly the same product yield, without forming any
side products. This is probably due to the increased steric
bulk, which should suppress the subsequent reductive ami-
nation process.
For final optimization of the reaction conditions, a small
selection of ligands and bases were tested again with the im-
proved hydrogen-transfer reagent (Table 2). Sodium hydrox-
ide seems to result in nearly the same yield of 2a as potassi-
um tert-butoxylate, but full conversion appeared to require a
longer reaction time (Table 2, entry 8). As a consequence,
we doubled the reaction time to 20 min and found an excel-
lent product yield of 93% (Table 2, entry 9).
[RuCl
(Table 1, entry 1). However, in the presence of [{Ru-
(cod)Cl2}n] (cod=1,5-cyclooctadiene), [{RuCl2A(benzene)2}2]
2ACHTUNGTRENNUNG(PPh3)3] led to a good yield (68%) of benzyl amine
A
U
and tetrachlorobis(2,7-dimethyl-2,6-octadienylene)dirutheni-
um, the desired product benzyl amine was obtained in only
5 to 11% yields (Table 1, entries 2–4). In addition, applying
[{RuACHTUNGTRENNUNG(p-cymene)Cl2}2] (3) in combination with different li-
gands furnished the desired product in varying yields be-
tween <3 and 78% (Table 1, entries 5–15). Without any
ligand present, no conversion of benzonitrile was observed.
4438
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 4437 – 4440

Transfer Hydrogenation of Nitriles
COMMUNICATION
Table 3. Substrate scope.[a]
Entry
Substrate
t
Yield
[%][b]
AHCTUNGTERG[NNUN min]
1
2
2a
2b
20
20
93
65
Scheme 2. Transfer hydrogenation with various alcohols as hydrogen-
transfer reagents.
To demonstrate the applicability of the new catalytic
method developed herein, the reduction of various ortho-,
meta-, and para-substituted aromatic nitriles in the presence
3
4
5
6
7
8
9
2c
2d
2e
2 f
2g
2h
2i
20
20
20
20
20
20
20
80
of [{RuACHTUNGTRENNUNG(p-cymene)Cl2}2] (1 mol%), DPPB (2 mol%), and
85
sodium hydroxide (10 mol%) in 2-butanol (5 mL) was per-
formed. Both electron-donating and electron-withdrawing
groups, including disubstituted substrates, gave the corre-
sponding benzyl amines in up to 93% yields (Table 3, en-
tries 3–7 and 9–11). A more challenging heteroaromatic sub-
strate could be converted into the primary amine in moder-
ate yield (68%) after 35 min (Table 3, entry 12). The reduc-
tion of 1-naphthonitrile gave the respective product with a
low yield of 34% (Table 3, entry 13). Furthermore, applying
alkyl nitriles resulted in moderate to good product yields be-
tween 42 and 84% (Table 3, entries 14 and 15).
73 (70)
83
93 (81)
84
In summary, we have shown that a commercially available
catalyst system consisting of [{RuACTHUNTRGNE(NUG p-cymene)Cl2}2]/DPPB
allows for rapid transfer hydrogenation of aromatic and ali-
phatic nitriles. Unwanted reductive amination reactions
could be avoided by application of 2-butanol as the hydro-
gen-transfer reagent. This protocol is the most general trans-
fer hydrogenation methodology demonstrated to date.
79
10
2j
20
82
Experimental Section
11
12
2k
2l
20
35
75 (67)
68
General procedure for the catalytic transfer hydrogenation of nitriles: A
vial (12 mL) capped with
mene)2Cl2}2] (0.005 mmol) and DPPB (0.01 mmol) under an argon at
ACHTUNGTRENNUNGsphere. Afterwards, a magnetic stirring bar and dry isopropanol or 2-bu-
a
septum was charged with [{Ru(p-cy-
N
ACHTUNGTRENNUNG
tanol (5 mL) were added. The solution was stirred for 5 min at room tem-
perature before NaOH (0.05 mmol) was added and the mixture was stir-
red for another 5 min. Then, the nitrile (0.5 mmol) was added and placed
on a preheated alloy plate with wells at 1208C for 10, 20, or 35 min.
After the reaction was finished, hexadecane was added as a standard and
the yield was determined by GC.
13
2m
20
34
14
15
2n
2o
20
20
84
42
For isolation as the HCl salt: HCl solution (1m, 1 mL) was added to the
solution. Afterwards, the solvent was removed under vacuum and the
HCl salt remained. After washing the salt with ethyl acetate, the product
was analyzed by NMR spectroscopy, GCMS, and HRMS.
[a] Reaction conditions: benzonitrile (0.5 mmol), [{RuACHTUNTRGNEUNG(p-cymene)2Cl2}2]
(1 mol%), DPPB (2 mol%), KOtBu (10 mol%), 2-butanol (5 mL),
20 min, 1208C. [b] Yield determined by GC analysis with hexadecane as
the internal standard; yield of the isolated HCl salt in parentheses.
Acknowledgements
This research has been funded by the State of Mecklenburg–Western
Pomerania, the BMBF, and the DFG (Leibniz Prize). We thank Dr.
Haijun Jiao for scientific discussions. We are also thankful to Dr. W. Bau-
Chem. Eur. J. 2013, 19, 4437 – 4440
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4439

M. Beller et al.
mann, Dr. C. Fischer, S. Buchholz, S. Schareina, and A. Koch (all at the
LIKAT) for their excellent technical and analytical support.
C. L. Liotta, C. A. Eckert, Ind. Eng. Chem. Res. 2004, 43, 7907–
7911.
[4] For an Ir-catalyzed hydrogenation, see: C. S. Chin, B. Lee, Catal.
Lett. 1992, 14, 135–140.
[5] For selected reviews on transfer hydrogenations, see: a) R. W. John-
stone, A. H. Wilbyian, I. D. Entwistle, Chem. Rev. 1985, 85, 129–
170; b) G. Zassinovich, G. Mestroni, S. Gladiali, Chem. Rev. 1992,
92, 1051–1069; c) H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H.
Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103–151; d) K. Ev-
eraere, A. Mortreux, J.-F. Carpentier, Adv. Synth. Catal. 2003, 345,
67–77; e) S. E. Clapham, A. Hadzovich, R. H. Morris, Coord. Chem.
Rev. 2004, 248, 2201–2237; f) S. Gladiali, E. Alberico, Chem. Soc.
Rev. 2006, 35, 226–236; g) J. S. M. Samec, J.-E. Bꢁckvall, P.-G. An-
dersson, P. Brandt, Chem. Soc. Rev. 2006, 35, 237.
[6] A. J. Foubister, G. R. Brown, Synthesis 1982, 1036–1037.
[7] S. Gowda, D. C. Gowda, Tetrahedron 2002, 58, 2211–2213.
[8] X. Chen, S. Zhou, C. Qian, Arkivoc 2012, viii, 128–136.
[9] E. Mizushima, M. Yamaguchi, T. Yamagishi, J. Mol. Catal. A: Chem.
1999, 148, 69–75.
Keywords: amines
ruthenium · transfer hydrogenation
·
nitriles
·
phosphane ligands
·
[1] For selected reviews and highlights, see: a) T. E. Mꢀller, M. Beller,
Chem. Rev. 1998, 98, 675–703; b) M. J. Palmer, M. Wills, Tetrahe-
dron: Asymmetry 1999, 10, 2045–2061; c) J. Seayad, A. Tillack,
C. G. Hartung, M. Beller, Adv. Synth. Catal. 2002, 344, 795–813;
d) F. Pohlki, S. Doye, Chem. Soc. Rev. 2003, 32, 104–114; e) W.
Tang, X. Zhang, Chem. Rev. 2003, 103, 3029; f) H.-U. Blaser, F.
Spindler in Handbook of Homogeneous Hydrogenation, Vol. 3
(Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH, Weinheim, 2007,
pp. 1193; g) R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36, 1407–
1420; h) T. E. Mꢀller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada,
Chem. Soc. Rev. 2008, 37, 3795–3892; i) T. C. Nugent, M. EI-Shazly,
Adv. Synth. Catal. 2010, 352, 753–819; j) M. Rueping, E. Sugiono,
F. R. Schoepke, Synlett 2010, 852–865.
[2] For ruthenium-catalyzed hydrogenations with molecular hydrogen,
see: a) R. A. Grey, G. P. Pez, A. Wallo, J. Am. Chem. Soc. 1981, 103,
7536–7545; b) T. Suarez, B. Fontal, J. Mol. Catal. 1988, 45, 335–344;
c) A. M. Joshi, K. S. MacFarlane, B. R. James, P. Frediani in Progress
in Catalysis (Eds.: K. J. Smith, E. C. Sanford), Elsevier, New York,
1992, pp. 143–146; d) A. M. Joshi, K. S. MacFarlane, B. R. James, P.
Frediani, Chemical Industries, Vol. 53, Catalysis of Organic Re-
[10] S. Horn, C. Gandolfi, M. Albrecht, Eur. J. Inorg. Chem. 2011, 2863–
2868.
[11] T. D. Nixon, M. K. Whittlesey, J. M. J. Williams, Tetrahedron Lett.
2011, 52, 6652–6654.
[12] a) S. Enthaler, R. Jackstell, A. Zapf, B. Hagemann, G. Erre, K.
Junge, M. Beller, J. Organomet. Chem. 2006, 691, 4652–4659; b) S.
Enthaler, G. Erre, M. K. Tse, K. Junge, M. Beller, Tetrahedron Lett.
2006, 47, 8095–8099; c) S. Enthaler, B. Hagemann, G. Erre, K.
Junge, M. Beller, Adv. Synth. Catal. 2007, 349, 853–860; d) S. En-
thaler, B. Spilker, G. Erre, M. K. Tse, K. Junge, M. Beller, Tetrahe-
dron 2008, 64, 3867–3876; e) S. Zhou, S. Fleischer, K. Junge, S. Das,
D. Addis, M. Beller, Angew. Chem. 2010, 122, 8298–8302; Angew.
Chem. Int. Ed. 2010, 49, 8121–8125; f) R. V. Jagadeesh, G. Wienhçf-
er, F. A. Westerhaus, A.-E. Surkus, M.-M. Pohl, H. Junge, K. Junge,
M. Beller, Chem. Eur. J. 2011, 17, 14375–14379; g) I. Sorribes, G.
Wienhçfer, C. Vicent, K. Junge, R. Llusar, M. Beller, Angew. Chem.
2012, 124, 7914–7918; Angew. Chem. Int. Ed. 2012, 51, 7794–7798;
h) G. Wienhçfer, F. A. Westerhaus, R. V. Jagadeesh, K. Junge, H.
Junge, M. Beller, Chem. Commun. 2012, 48, 4827–4829.
ACHTUNGTRENNUNGactions, Dekker, New York, 1992, 143–146; e) B. Fontal, M. Reyes,
T. Suꢃrez, F. Bellandi, N. Ruiz, J. Mol. Catal. A: Chem. 1999, 149,
87–97; f) C. Bianchini, V. Dal Santo, A. Meli, W. Oberhauser, R.
Psaro, F. Vizza, Organometallics 2000, 19, 2433–2444; g) T. Li, I.
Bergner, F. N. Haque, M. Zimmer-De Iuliis, D. Song, R. Morris, Or-
ganometallics 2007, 26, 5940–5949; h) S. Enthaler, K. Junge, D.
Addis, G. Erre, M. Beller, ChemSusChem 2008, 1, 1006–1010; i) S.
Enthaler, D. Addis, K. Junge, G. Erre, M. Beller, Chem. Eur. J.
2008, 14, 9491–9494; j) D. Addis, S. Enthaler, K. Junge, B. Wendt,
M. Beller, Tetrahedron Lett. 2009, 50, 3654–3656; k) R. Reguillo, M.
Grellier, N. Vautravers, L. Vendier, S. Sabo-Etienne, J. Am. Chem.
Soc. 2010, 132, 7854–7855; l) C. Gunanathan, M. Hçlscher, W. Leit-
ner, Eur. J. Inorg. Chem. 2011, 3381–3386.
[3] For Rh-catalyzed hydrogenations, see: a) T. Yoshida, T. Okano, S.
Otsuka, J. Chem. Soc. Chem. Commun. 1979, 870–871; b) X. Xie,
Received: December 30, 2012
Published online: February 28, 2013
4440
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 4437 – 4440