Application of ruthenium complexes of triazole-containing tridentate ligands to asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1021/ol302354z

The synthesis of a series of tridentate ligands based on a homochiral 1,2-diamine structure attached to a triazole group and their subsequent applications to the asymmetric transfer hydrogenation of ketones are described. In the best cases, alcohols of up to 93% ee were obtained. Although base is not required, the use of Ru₃(CO)₁₂ as metal source is essential, indicating a unique mechanism for the formation of the active catalyst.

Full text of DOI:10.1021/ol302354z

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5230–5233
Application of Ruthenium Complexes
of Triazole-Containing Tridentate Ligands
to Asymmetric Transfer Hydrogenation
of Ketones
Tarn C. Johnson, William G. Totty, and Martin Wills*
Department of Chemistry, The University of Warwick, Coventry CV4 7AL,
United Kingdom
m.wills@warwick.ac.uk
Received August 23, 2012
ABSTRACT
The synthesis of a series of tridentate ligands based on a homochiral 1,2-diamine structure attached to a triazole group and their subsequent
applications to the asymmetric transfer hydrogenation of ketones are described. In the best cases, alcohols of up to 93% ee were obtained. Although
base is not required, the use of Ru3(CO)12 as metal source is essential, indicating a unique mechanism for the formation of the active catalyst.
The development of improved catalysts for the asym-
metric reduction of ketones represents a continuing
challenge to synthetic chemists.1 During the course of
an ongoing project directed at the development of new
catalysts for asymmetric transfer hydrogenation (ATH)
of ketones and imines,2ꢀ4 we elected to study the use of
ligands containing triazole donor groups.5 Several exam-
ples of tridentate ligands have been reported for ATH
reactions,4 some of which contain a triazole donor group,
such as 14a and 24b (Scheme 1). Closely related ligand 3 was
(1) (a) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300–
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r
10.1021/ol302354z
Published on Web 10/01/2012
2012 American Chemical Society

not as effective. A complex of ligand 2 also reduced
tetralone in 94% ee and 4-chromanone in >99% ee,
although the reduction of ortho-methoxyacetophenone
gave a product of just 34% ee.4b
related ligands,4 Cu(I)-catalyzed azideꢀalkyne cycloaddi-
tion (CuAAC) was found to be an effective method for the
creation of the required heterocyclic groups.9
The enantioselective reduction by ATH of ortho-
substituted products of ketone reduction is generally
considered to be more challenging than that of related
meta- and para-substituted substrates.2 Most established
systems commonly reduce such substrates in lower ee
values than the analogous meta- or para-substituted
substrates.
Scheme 1. Asymmetric Transfer Hydrogenation of Ketones
Ligands 8 and 9 were prepared using the two alkylation
products (1110 and 12) of Boc-protected cyclohexyl-1,2-
diamine 10 isolated from the first step of the sequence
(Scheme 2). Reaction of 1,2-diphenyl-1,2-diaminoethane
with propargyl bromide could be partially controlled to
give the N,N0-dialkylated (38%) or the N-monoalkylated
(52%) products. Subsequent [3 þ 2]-cycloaddition of
these intermediates with benzylazide furnished ligands 13
and 14, respectively. Nonprotected derivative 15 was also
prepared.
Using Ligands Containing a Triazole Group4a,b
We therefore chose to investigate a ligand structure and
metal combination sharply different than those previously
reported, in the expectation that these might provide an
opportunity to develop catalysts for the asymmetric re-
duction of a wider range of substrates (Figure 1).
Scheme 2. Synthesis of Ligands 8 and 9
Figure 1. Triazole-containing ligands used in ketone ATH.
In initial studies, we examined a series of ligands
which contain one or two triazole groups, some of which
could potentially act as either tri-4 or tetradentate6 li-
gands. Ligand 4 was prepared via asymmetric reduction
of R-amino ketone 5 to alcohol 6 in 90% ee using the
tethered catalyst 7.7,8 Following the precedent set by
Initial tests focused on the use of a range of metals with
ligand 8, which was closest in structure to those previously
reported. Of these, only Ru3(CO)12 gave a product of
any significant ee. However, this represented a promising
result, using a metal source not commonly employed in
ATH reactions (Table 1). The use of the other ligands
(6) (a) Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15,
1087–1089. (b) Sues, P. E.; Lough, A. J.; Morris, R. H. Organometallics
2011, 30, 4418–4431. (c) Sonnenberg, J. F.; Coombs, N.; Dube, P. A.;
Morris, R. H. J. Am. Chem. Soc. 2012, 134, 5893–5899. (d) Lagaditis,
P. O.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2011, 133, 9662–
9665. (e) Morris, R. H. Chem. Soc. Rev. 2009, 8, 2282–2291.
(9) (a) Finn, M. G.; Fokin, V. V. In Catalysis without Precious
Metals; Bullock, R. M., Ed.; Wiley-VCH: Weinheim, Germany, 2010;
Chapter 10. (b) Wang, B.-G.; Zou, M.-H.; Li, W.-Z.; Chai, X.-Y.; Yu,
S.-C.; Wu, Q.-Y. Dier Junyi Daxue Xuebao 2010, 31, 1114–1119. (c) Mindt,
T. L.; Schweinsberg, C.; Brans, L.; Hagenbach, A.; Abram, U.;
(7) (a) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am.
Chem. Soc. 2005, 127, 7318–7319. (b) Cheung, F. K.; Lin, C.; Minissi, F.;
ꢀ
Lorente Criville, A.; Graham, M. A.; Fox, D. J.; Wills, M. Org. Lett.
ꢀ
2007, 9, 4659–4662. (c) Cheung, F. K.; Clarke, A. J.; Glarkson, G. J.;
Fox, D. J.; Graham, M. A.; Lin, C.; Lorente Criville, A.; Wills, M.
Dalton Trans. 2010, 39, 1395–1402. (d) Soni, R.; Collinson, J.-M.;
Clarkson, G. C.; Wills, M. Org. Lett. 2011, 13, 4304–4307.
(8) The reduction of the analogous substrate to 5 but with Ph in place
of TBS groups gave an alcohol of 97% ee.
Tourwee, D.; Garcia-Garayoa, E.; Schibli, R. ChemMedChem 2009, 4,
ꢀ
529–539. (d) de la Fuente, V.; Marcos, R.; Cambreiro, X. C.; Castillon,
S.; Claver, C.; Pericas, M. A. Adv. Synth. Catal. 2011, 353, 3255–3261.
(10) (a) Takasu, K.; Azuma, T.; Takemoto, Y. Tetrahedron Lett.
2010, 51, 2737–2740. (b) Takasu, K.; Azuma, T.; Erkhtaivan, I.;
Takemoto, Y. Molecules 2010, 15, 8327–8348.
Org. Lett., Vol. 14, No. 20, 2012
5231

diamine-based ligands 16 and 17; a product was formed
in 92% ee and almost quantitative conversion using 17.
Table 1. ATH of Acetophenone Using Ligands 4, 8, 9 and 13a
temp
t
conv ee
entry ligand
metal/(mol %)
(°C) (h) (%)
%
R/S
1
2
8
8
RuCl3 3H2O (1)
80
24
24
24
24
24
6
0
53
74
80
0
3
Having identified 17 as an optimal ligand, the reduction
of a further series of substrates was completed (Table 3).
An electron-withdrawing trifluoromethyl group in the
para position of the substrate had little effect on the reac-
tion, with essentially quantitative conversion and 91% ee
after 16 h. An electron-donating para-methoxy group re-
quired a longer reaction time of 65 h to reach 91%
conversion. A methoxy group in the ortho or meta posi-
tions did not impact the reactivity; in both cases, the
reaction was complete after 16 h. It is noteworthy that a
series of ortho-substituted acetophenones could be reduced
in good enantioselectivity without significant reduction of
the ee, which stands in contrast to the usual behavior of
challenging ortho-substituted substrates in ATH reactions,
as discussed earlier.2
[Ru(benzene)Cl2] (0.5) 80
0
0
3
8
[RhCp*)Cl2] (0.5)
[RhCp*)Cl2] (0.5)
Fex(CO)yb (1)
80
28
80
80
80
80
80
80
80
80
60
80
4
8
67
R
5
8
6
8
Ru3(CO)12 (1)
48
48
88
18
70
16
99
63
98
80
81
78
18
44
2
R
R
R
R
S
R
S
R
R
7
8
Ru3(CO)12 (0.66)
Ru3(CO)12 (0.33)
Ru3(CO)12 (1)
6
8
8
6
9
4
24
48
24
24
24
24
10
11
12
13
14
9
Ru3(CO)12 (0.33)
Ru3(CO)12 (0.33)
Ru3(CO)12 (0.33)
Ru3(CO)12 0.33)
Ru3(CO)12 (0.33)c
10
13
8
69
76
79
8
a [Acetophenone] = 0.1 M. b x,y = 1,5; 2,9; 3,12. c No KOH.
did not give an improved result with this combination of
reagents.
Table 2. ATH of Acetophenone Using Ligands 8 and 14ꢀ17a
entry
ligand
conv (%)
ee %
R/S
Changing the metal to ligand ratio resulted in improved
conversions; a ratio of 1:1 proved to be optimal, and the
initial selection of a 3:1 metal to ligand ratio was based on a
related system where a cluster complex was proposed to be
the active catalyst.11
1
2
3
4
5
8
14
15
16
17
98
97
12
94
97
78
76
3
R
R
R
R
R
80
92
Lowering the temperature to 60 °C resulted in lower
conversion and eventually to the loss of all catalytic
activity. Most interestingly, control experiments showed
thata base was not required for reduction totake place. No
reaction occurred when a 5:2 formic acid/triethylamine
(FA/TEA) mixture was used as the solvent and hydrogen
donor.
With these promising results in hand, further tests
were carried out under the revised conditions (Table 2)
with 14 and the deprotected 15. In addition, the N-tosy-
lated ligands 16 and 17 were prepared using a CuAAC
cycloaddition of the propargylic intermediates 18 and 19,
respectively (Table 2).
a [Acetophenone] = 0.1 M.
A bulky bromine substituent in the ortho position,
however, resulted in a longer reaction time and reduced
enantioselectivity. Substitution in the R-position is not
tolerated, with propiophenone being reduced in just 4%
conversion and R-chloroacetophenone resisting any reduc-
tion, even after long reaction times. This may indicate a
very well-defined binding pocket in the active catalyst.
Cyclohexyl methyl ketone was reduced in 93% conversion
but required 88 h, and the enantioselectivity was low. An
attempted reduction of alkyne-containing PhCCCOMe
failed to give any reduction product.
To gather information about the mechanism of the
reaction, ligands 20ꢀ23 were prepared. Compound 21 is
a known compound,2 and 20 was prepared by an analo-
gous reductive amination procedure. Ligand 22 was pre-
pared via reductive methylation10 of 19 using methanal
Ligand 14 was similar in reactivity to 8. Removal of
the Boc group from 8, however, resulted in almost total
loss of activity. The best results were provided by the
(11) Zhang, H.; Yang, C.-B.; Li, Y.-Y.; Donga, Z.-R.; Gao, J.-X.;
Nakamura, H.; Murata, K.; Ikariya, T. Chem. Commun. 2003, 142–143.
5232
Org. Lett., Vol. 14, No. 20, 2012

Table 3. Reduction of a Range of Ketones Using 17a
Scheme 3. Proposed Mechanism of Catalysis by 17/Ru3(CO)12
entry
Ar
R
t (h)
conv (%)
ee %
R/S
1
2
4-CF3C6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
2-FC6H4
Me
Me
Me
Me
Me
Me
Me
Me
16
65
16
16
16
16
65
44
88
20
44
88
99
91
97
98
99
96
99
89
27
96
52
93
91
89
93
85
83
84
77
87
79
91
67
13
R
R
R
R
R
R
R
R
R
R
R
R
3
4
5
6
2-ClC6H4
7
2-BrC6H4
8
2-MeC6H4
tetralone
9
10
11
12
4-chromanone
2-pyridyl
Me
Me
cyclohexyl
a [Ketone] = 0.1 M.
hydrogen atoms to substrate to give 28. Reaction of 28
withi-PrOH maythenregenerate27tocompletea catalytic
cycle. The mechanism of transfer of hydrogen from 27 to
a ketone may be analogous to the known “bifunctional”
catalysis mechanism exhibited by related Ru(II)/TsDPEN
ATH catalysts.12
Heating 17 and Ru3(CO)12 at 80 °C in toluene for 5h
resulted in formation of a complex which contained two
signals at ca. ꢀ16 and ꢀ17 ppm in the 300 MHz 1H NMR
spectrum (CDCl3), that is, indicative of the formation of a
RuꢀH species. These signals may be due to formation of
hydride species in the proposed mechanism.
and sodium cyanoborohydride to give 24, followed by a
CuAAC reaction with benzylazide to form the required
ligand 22. Methylation of 19 using MeI and K2CO3, in
contrast, furnished 25, which was subsequently converted
to 23.
In conclusion, tridentate diaminotriazoles in conjunc-
tion with Ru3(CO)12 in 2-propanol formed effective cata-
lysts for ATH reactions of ketones. Thereductions proceed
without the need for base, and enantioselectivities of up to
93% were obtained. Notably, a range of ortho-substituted
acetophenones could be reduced in up to 99% conversion
and 85% ee.
Acknowledgment. We thank the EPSRC for funding
T.C.J. via the SUPERGEN XIV programme “Delivery of
Sustainable Hydrogen” for funding (to T.C.J.).
The reduction of acetophenone with benzyl-substituted
diamines (R,R)-20 and (R,R)-21 gave only trace conver-
sions of acetophenone to 1-phenylethanol, indicating that
the triazole may be bound to the metal center in the active
catalyst. A similar observation was made when 22 and 23
were applied to the ATH of acetophenone; <5% reduc-
tion was observed in either case, which indicates that the
presence of both NH groups is essential for formation of a
competent catalyst.
The ligands may form an active catalyst through an
initial reaction with fragmentation of Ru3(CO)12 to form a
bidentate complex via loss of CO to give 26, followed by
insertion of ruthenium into the NꢀH(Ts) bond to form
ruthenium hydride 27 (Scheme 3) which transfers two
Supporting Information Available. Experimental pro-
cedures, NMR spectra, and chiral GC data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(12) (a) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem.
2001, 66, 7931–7944. (b) Yamakawa, M.; Yamada, I.; Noyori, R.
Angew. Chem., Int. Ed. 2001, 40, 2818–2821. (c) Casey, C. P.; Johnson,
J. B. J. Org. Chem. 2003, 68, 1998–2001. (d) Brandt, P.; Roth, P.;
Andersson, P. G. J. Org. Chem. 2004, 69, 4885–4890.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
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