Lanthanide replacement in organic synthesis: Luche-type reduction of α,β-unsaturated ketones in the presence of calcium triflate

Article abstract of DOI:10.1039/c2gc35619h

Development of a calcium-mediated regioselective 1,2-reduction of challenging α,β-unsaturated ketones, such as 2-cyclopententone, is reported. The corresponding allylic alcohols are obtained in very good regioselectivities using Ca(OTf)₂ and NaBH₄. Furthermore, we have shown that our method can stereoselectively reduce aziridinyl ketones.

Full text of DOI:10.1039/c2gc35619h

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Volume 14 | Number 8 | August 2012 | Pages 2073–2354
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Fuchter et al.
Lanthanide replacement in organic synthesis: Luche-type reduction of
α,β-unsaturated ketones in the presence of calcium triflate
1463-9262(2012)14:8;1-N

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COMMUNICATION
Lanthanide replacement in organic synthesis: Luche-type reduction of
α,β-unsaturated ketones in the presence of calcium triflate†
Nina V. Forkel,a David A. Hendersonb and Matthew J. Fuchter*a
Received 21st April 2012, Accepted 21st May 2012
DOI: 10.1039/c2gc35619h
to the lanthanide metals.3 This fact is slowly beginning to be
Development of
a calcium-mediated regioselective 1,2-
appreciated in the field of organic synthesis.4 Elegant studies by
Hill, Barrett and co-workers have demonstrated bulky calcium
amides as catalysts for hydroamination5 and hydrophosphination
of olefins,6 as well as in the Tischenko reaction.7 Blechert and
co-workers have also studied related calcium catalysts in hydroa-
mination chemistry.8 Harder and co-workers have demonstrated
calcium catalysis in hydroboration, hydrosilylation, and hydro-
genation reactions.9 There have also been reports on calcium-cat-
alysed Friedel–Crafts alkylation and hydroarylation,10 as well as
the use of efficient chiral calcium complexes for asymmetric
reactions.11
reduction of challenging α,β-unsaturated ketones, such as
2-cyclopententone, is reported. The corresponding allylic
alcohols are obtained in very good regioselectivities using
Ca(OTf)2 and NaBH4. Furthermore, we have shown that our
method can stereoselectively reduce aziridinyl ketones.
Introduction
The privileged position of trivalent lanthanide salts (along with
the chemically similar rare earth elements Sc and Y) in selective
organic synthesis is secured due to their applicability to a
number of processes, including oxidation, reduction and C–C
bond forming reactions.1 Despite this, there are several draw-
backs to their wider use, particularly in the synthesis of pharma-
ceuticals, which likely limits their use in pharmaceutical
industry. In the first instance, many of the lanthanide and other
rare earth elements are prohibitively expensive, especially for
large-scale and stoichiometric reactions. Also, while generally
the lanthanide salts are considered non-toxic, this is primarily
due to their inability to cross cell membranes, and they are there-
fore not absorbed if orally ingested. If administered intrave-
nously however, they are significantly toxic, gaining access to
intracellular calcium channels.2 Lack of information regarding
the Life Cycle Analysis of these reagents makes comparison to
conventional alternatives in the chemical industries difficult. It is
likely however, that their main limitations stem from the lack of
industrial experience in their utilisation, combined with their
reduced availability and increased purchase and cost. In addition,
since they contain rare metals, the production of these reagents
may itself be a polluting or hazardous process.
The selective reduction of α,β-unsaturated carbonyls with
sodium borohydride in the presence of cerium(III) chloride in
methanol, known as the Luche reduction, is a common and
simple method to synthesise allylic alcohols.12 We decided to
investigate whether calcium salts would be a suitable replace-
ment for cerium(III) chloride in this selective reduction. While
many of the calcium-mediated processes highlighted above rely
on calcium complexes that are highly air and moisture sensitive,
we selected to use only salts bearing hard conjugate bases, such
−
as OTf, to afford water-stable complexes, a function of the pKa
value of the ligand.13 A preliminary report on the use of calcium
chloride in this chemistry appeared in 1991.14 However, the
selectivity of 1,2-reduction versus the competing 1,4-reduction
was limited, especially for challenging substrates such as
2-cyclopentenone 1, which is known to undergo 1,4-reduction
more readily than 1,2-reduction. We envisaged that suitable
tuning of the calcium salt employed and the reaction conditions
should give access to a calcium-based protocol which rivals the
classical Luche process.
Results and discussion
The alkaline earth metals Mg, Ca, Sr and Ba are widely abun-
dant, cheap and largely environmentally benign. It is well estab-
lished that the reactivity and coordination behaviour of the
heavier alkaline earth metals, especially Ca, is somewhat similar
Our initial studies began with the optimisation of the reaction
conditions for the model reaction shown in Table 1. We found
that with stoichiometric amounts of sodium borohydride and
calcium chloride in MeOH at rt, reduction of enone 1 afforded
unsaturated alcohol 2 and saturated alcohol 3 as an approxi-
mately 50 : 50 mixture (entry 1, Table 1), while no calcium addi-
tive gave total selectivity for saturated alcohol 3 (entry 3,
Table 1, for complete initial screen table see ESI†). Encouraged
by this, we performed a full reaction parameter screen for
calcium chloride varying the reaction conditions. Key to our
aDepartment of Chemistry, Imperial College London, London SW7 2AZ,
UK. E-mail: m.fuchter@imperial.ac.uk; Fax: (+44) (0)20-7594-5805;
Tel: (+44) (0)20-7594-5815
bChemical Research and Development, Pfizer Ltd., Sandwich CT13 9NJ,
UK
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc35619h
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 2129–2132 | 2129

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Table 1 Reaction parameter screen with 2-cyclopentenone as model
Table 2 Calcium salt screen under optimised conditionsa
substratea
Selectivityb
Selectivityb
Entry
Calcium salt
2
3
Entry
Lewis acid
Conditions
2
3
1
2
3
4
5
6
7
8
CaF2
CaBr2 hydrate
CaCl2
CaI2 hydrate
Ca(BF4)2
Ca(OCl4)2 hydrate
Ca(OMe)2
Ca(OTf)2
0
100
21
13
64
74
9
79
87
36
26
91
18
92
48
73
21
18
17
92
83
91
1b
2
3
4
5
6
7
8
9
10
11
12
13
14c
15c
CaCl2
CeCl3·7H2O
—
NaBH4, rt, MeOH
NaBH4, rt, MeOH
NaBH4, rt, MeOH
NaBH4, rt, EtOH
NaBH4, rt, iPrOH
NaBH4, rt, THF
NaBH4, rt, H2O
NaBH4, 0 °C, MeOH
LiBH4, rt, MeOH
LiBH4, rt, MeOH
LiBH4, rt, MeOH
NBu4BH4, rt, MeOH
Ca(BH4)2, rt, THF/H2O
NaBH4, rt, dioxane/MeOH
NaBH4, rt, MeOH/THF
48
97
0
52
3
100
60
74
73
85
75
65
0
100
61
53
21
13
CaCl2
CaCl2
CaCl2
CaCl2
CaCl2
CaCl2
CeCl3·7H2O
—
CaCl2
CaCl2
CaCl2
CaCl2
40
26
27
15
25
35
100
0
39
47
79
87
82
8
9
Ca(OTs)2
52
27
79
82
83
8
10
11
12
13
14
15
16
Ca(OPhCl)2
Ca(OMs)2
Ca(OiPr)2
Ca(OC6H4OMe)2
Ca(SO3C8F17 2
Ca(NTf2)2
Ca(NTf2)2 NBu4PF6
)
17
9
a General screening conditions: 0.8 mmol of 1 and 0.8 mmol calcium
salt dissolved in MeOH (0.8 mL) and added to a suspension of
3.2 mmol sodium borohydride in THF (9.6 mL). b Selectivity was
determined by GC.
a General screening conditions: 0.8 mmol of 1, 0.8 mmol Lewis acid and
0.8 mmol borohydride in 0.5 M solution of solvent at rt for 20 min
unless otherwise stated. b Ratio and selectivity determined by GC (see
ESI†). c 4.0 Equivalents of sodium borohydride.
moderate selectivity for 1,2-reduction, however, in the presence
of calcium triflate, we obtained almost complete selectivity for
the majority of substrates. The selectivity for six-membered
rings was better than that for five- and seven-membered rings
(Table 3, entries 1, 2, and 3). Importantly, our conditions were
comparable, or in some cases better (Table 3, entry 9) than the
Luche conditions. While selectivity was uniformly high, certain
substrates (Table 3, entries 11 and 13) only gave moderate yield.
In general, we found this was due to a competing elimination
reaction of the resultant allylic alcohol.15
Delighted by the broad applicability of our method, we were
keen to further its potential applications outside selective 1,2-
reduction chemistry. Previously, it has been shown that calcium
chloride can mediate the stereoselective reduction of α,β-epoxy
ketones, with the epoxide functioning as a stereodirecting
group.16 To the best of our knowledge, an analogous study with
α,β-aziridinyl ketones has not been carried out.17 We have there-
fore completed preliminary studies, which show that stereo-
selective reduction of α,β-aziridinyl ketones under our developed
conditions is indeed possible and the product is isolated in high
diastereoselectivity (Scheme 1).
success was the discovery of a reaction solvent system (THF–
MeOH, 12 : 1) which gave high selectivity (87 : 13, 2 : 3) with a
stoichiometric amount of calcium chloride and four equivalents
of sodium borohydride (entry 15, Table 1).
With optimised reaction conditions in hand, a broad calcium
salt screen was performed to investigate the influence of different
calcium salts on the selectivity of the reduction. Using the same
conditions as shown in Table 1, entry 13, we found calcium
salts basing sulfonate counterions, e.g. calcium triflate and
Ca(SO3C8F17)2 (Table 2, entries 8 and 14) to increase the selecti-
vity of the reaction (2 : 3 was increased up to 92 : 8). Calcium
salts with poor solubility in MeOH, such as calcium methoxide,
calcium i-propoxide, and calcium p-methoxyphenolate showed
less selectivity for the desired product 2 (Table 2, entries 7, 12,
and 13).
In light of the exciting results obtained with calcium triflate, a
commercial available calcium salt, we further investigated the
ratios of THF and MeOH used in the reaction. It was found,
however, that our original conditions (THF–MeOH, 12 : 1)
proved to be optimum (see ESI†). The optimised conditions
therefore involved adding a methanolic solution of the starting
material and one equivalent of calcium triflate to a suspension of
four equivalents of sodium borohydride in THF to give an
overall ratio of THF–MeOH of 12 : 1.
Conclusions
In conclusion, we have developed a new method to reduce
α,β-unsaturated carbonyls selectively with sodium borohydride
in the presence of calcium triflate. Even challenging substrates,
such as 2-cyclopentenone, were reduced to the corresponding
allylic alcohols with very good selectivity. Furthermore, this
reaction method is suitable for the stereoselective reduction of
α,β-aziridinyl ketones.
Our developed conditions for the 1,2-reduction was applied to
a broad range of substrates, comparing our chemistry to the
Luche protocol, and also to the selectivity obtained when solely
using sodium borohydride in the absence of an additive
(Table 3). The sodium borohydride reduction of β-substituted
cyclic α,β-unsaturated ketones without any additive showed
2130 | Green Chem., 2012, 14, 2129–2132
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Table 3 Substrate scope of reaction conditions
Selectivity 2, 5a–n: 3, 6a–na
Entry
1
Substrate
Ca(OTf)2
92 : 8
CeCl3
No LAc
0 : 100
Yieldb,d (%)
75
97 : 3
2
3
4
99 : 1
87 : 13
97 : 3
99 : 1
50 : 50e
75 : 25
80 : 20
96
89 : 11
97 : 3
77
96h
5
98 : 2
99 : 1
67 : 33f
69
6
7
100 : 0
99 : 1
100 : 0
99 : 1
99 : 1
99
70 : 30e
52i
8
9
99 : 1
99 : 1
99 : 1
38 : 62g
99 : 1
78
93
87 : 13
10
11
99 : 1
99 : 1
100 : 0
100 : 0
94 : 6
92 : 8
61
44
12
13
100 : 0
99 : 1
100 : 0
99 : 1
88 : 12
87 : 13
72h
52h
14
100 : 0
100 : 0
90 : 10
79
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Table 3 (Contd.)
Selectivity 2, 5a–n: 3, 6a–na
Entry
15
Substrate
Ca(OTf)2
99 : 1
CeCl3
99 : 1
No LAc
90 : 10
Yieldb,d (%)
86h
a Selectivity was determined by GC. b Isolated yield. c No additive was added [NaBH4 (1.0 equiv.), MeOH, rt]. d General reaction conditions: 3 mmol
of enone and 3 mmol of calcium triflate dissolved in MeOH (3 mL) was added to 12 mmol sodium borohydride in THF (36 mL). e Published results:
see ref. 12b. f Published results: see ref. 14. g Published results: see ref. 12a. h Diastereoselectivities for the following products (determined by 1H
NMR): 5c (d.r. = 95 : 5), 5k (d.r. = 100 : 0), 5l (d.r. = 91 : 9), 5n (d.r. = 93 : 7). i d.r. could not be determined.
6 M. R. Crimmin, A. G. M. Barrett, M. S. Hill, P. B. Hitchcock and
P. A. Procopiou, Organometallics, 2007, 26, 2953; M. R. Crimmin,
M. Arrowsmith, A. G. M. Barrett, I. J. Casely, M. S. Hill and
P. A. Procopiou, J. Am. Chem. Soc., 2009, 131, 9670.
7 M. R. Crimmin, A. G. M. Barrtett, M. S. Hill and P. A. Procopiou, Org.
Lett., 2007, 9, 331.
8 S. Datta, P. W. Roesky and S. Blechert, Organometallics, 2007, 26, 4392;
S. Datta, M. T. Gamer and P. W. Roesky, Organometallics, 2008, 27,
Scheme 1 Asymmetric reduction of α,β-aziridinyl ketones. aDeter-
mined by 1H NMR.
1207.
Experimental
9 S. Harder and J. Spielmann, J. Organomet. Chem., 2012, 698, 7; F. Buch,
J. Brettar and S. Harder, Angew. Chem., Int. Ed., 2006, 45, 2741;
J. Spielmann, F. Buch and S. Harder, Angew. Chem., Int. Ed., 2008, 47,
9434.
General procedure to determine the substrate scope
To a suspension of NaBH4 (12.0 mmol) in THF (36 mL) was
added in one portion Ca(OTf)2 (3.0 mmol) and enone
(3.0 mmol) in MeOH (3 mL). The reaction mixture was stirred
for 30 min at rt until TLC indicated consumption of the starting
material. The reaction mixture was quenched with H2O (15 mL)
and the aqueous phase was extracted with Et2O (3 × 20 mL).
The combined organic layers were washed with brine, dried over
MgSO4 and the solvent was evaporated under reduced pressure.
The crude material was purified by flash chromatography on
silica to isolate the desired product.
10 V. J. Meyer and M. Niggemann, Eur. J. Org. Chem., 2011, 3671;
M. Niggemann and M. J. Meel, Angew. Chem., Int. Ed., 2010, 49, 3684;
M. Niggemann and N. Bisek, Chem.–Eur. J., 2010, 16, 11246;
S. Haubenreisser and M. Niggemann, Adv. Synth. Catal., 2011, 353, 469.
11 Selective examples of asymmetric reactions with alkaline earth metal
complexes: S. Kobayashi, T. Tsubogo, S. Saito and Y. Yamashita, Org.
Lett., 2008, 10, 807; T. Tsubogo, S. Saito, K. Seki, Y. Yamashita and
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Acknowledgements
We thank Imperial College London, EPRSC and Pfizer Ltd. for
their financial support.
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15 The elimination product of 4j was identified as (E)-(3-chloroprop-1-ene-
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2132 | Green Chem., 2012, 14, 2129–2132
This journal is © The Royal Society of Chemistry 2012