Conversion of α,β-unsaturated ketones into α-hydroxy ketones using an Mn(III) catalyst, phenylsilane and dioxygen: Acceleration of conjugate hydride reduction by dioxygen

Article abstract of DOI:10.1016/S0040-4039(00)01727-5

Treatment of a variety of α,β-unsaturated ketones with Mn(dpm)₃ (3 mol%)/PhSiH₃ (1.3 equiv.)/isopropyl alcohol/O₂, followed by reductive work-up with P(OEt)₃ resulted in the formation of α-hydroxy-ketones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01727-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9725–9730
Conversion of a,b-unsaturated ketones into a-hydroxy
ketones using an MnIII catalyst, phenylsilane and dioxygen:
acceleration of conjugate hydride reduction by dioxygen
Philip Magnus,* Andrew H. Payne, Michael J. Waring, David A. Scott and Vince Lynch†
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Received 7 August 2000; revised 25 September 2000; accepted 28 September 2000
Abstract
Treatment of a variety of a,b-unsaturated ketones with Mn(dpm)3 (3 mol%)/PhSiH3 (1.3 equiv.)/
isopropyl alcohol/O2, followed by reductive work-up with P(OEt)3 resulted in the formation of a-hydroxy-
ketones. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: a-hydroxyketone; manganese(III); phenylsilane; dioxygen.
Recently, we required a reaction that was capable of converting an a,b-unsaturated ester into
an a-hydroxy ester, preferably in a single step.1 In 1990 Isayama and Mukaiyama et al. reported
a single step method for accomplishing the above.2 They treated a number of simple a,b-unsat-
urated esters with a catalytic amount of bis(dipivaloylmethanato) manganese(II) [abbreviated to
Mn(dpm)2]/PhSiH3/O2 in isopropyl alcohol at 0°C, and obtained (after work-up with aqueous
Na2S2O3) the saturated a-hydroxyester in excellent yield. In this letter we report applications of
this reaction to a number of a,b-unsaturated ketones, and show that the so-called manganese(II)
catalyst is in fact a manganese(III) adduct. Furthermore, we have found that the hydridic
character of the putative reagent HMn(dpm)2 is substantially increased in the presence of
dioxygen and produces a new hydridic reagent that is capable of reducing b,b-disubstituted
enones.
The synthesis of acetylacetonatomanganese(II) complexes in air is known to be somewhat
ligand dependent and can give rise to the tris(acetylacetonato)manganese(III) adducts.3 Conse-
quently, when we prepared what is described as the Mn(dpm)2 complex4 we obtained an olive
green–brown solid more reminiscent of a Mn(III) complex.5 X-Ray quality crystals of the
complex were grown in isopropyl alcohol and revealed that the structure is an octahedral
complex Mn(dpm)3, Fig. 1, similar to Mn(acac)3.6
* Corresponding author.
†
Author for inquiries concerning the X-ray data.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01727-5

9726
Figure 1. Chem 3D representation of Mn(dpm)3 from X-ray coordinates
Treatment of the a,b-unsaturated ketones listed in Table 1 with Mn(dpm)3 (3 mol%)/PhSiH3/
isopropyl alcohol at 0–25°C under an oxygen balloon resulted in conjugate reduction,7 followed
by oxidation at the a-position to initially produce a mixture of a-hydroperoxyketone and
a-hydroxyketone. Addition of P(OEt)3 at the end of the reaction reduces the intermediate
a-hydroperoxide to give the a-hydroxyketone.8
The examples listed in Table 1 illustrate that the reaction proceeds in average (50%, entry 6)
to excellent (>95%, entries 8 and 9) yields. A particularly useful transformation is the direct
one-step conversion of 16-dehydroprogesterone 3 into 17a-hydroxyprogesterone 4 (85%, entry
2). This important transformation has been the subject of a number of patents17 and papers,18
and the method described above is superior to current methods since the non-basic conditions
avoid the formation of 17-keto derivatives,19 and the ring D-homo rearrangement.20
Treatment of b-ionone 9 under the standard reaction conditions surprisingly gave 10
(structure by X-ray). The bulk of the remaining mass balance was 9, and efforts to drive the
reaction to completion resulted in the formation of uncharacterized by-products. None of the
1,4-reduction product was observed.
Deuterium labeling studies in the absence of oxygen indicated that the conjugate hydride
addition step is irreversible.21 Furthermore, b,b-disubstituted enones are not reduced to their
saturated derivatives in the absence of oxygen. For example, exposure of mesityl oxide 21 to
Mn(dpm)3/PhSiH3/i-PrOH in the absence of oxygen did not produce any reaction, whereas the
same conditions in the presence of oxygen gave 22. Likewise 23 was inert to reduction until
oxygen was introduced, and this resulted in the formation of 24 and 24a (64%, 4:1), Scheme 1.
Treatment of b-ionone 9 with Mn(dpm)3/PhSiH3/i-PrOH gave 25 (25%, large amounts of 9),
whereas, the same reaction in the presence of oxygen gave 10.
We have also observed that the way in which the reaction flask is washed influences the
product distribution. For example, treatment of 13 in a flask washed with acetone (dried) under
the standard conditions gave 14 (20%) and substantial amounts of 2-nonanone (60%). Whereas,
treatment of 13, as before, but in a flask washed with Alconox® (pH 9) followed by acetone,

9727
gave 14 (70%) and only traces of 2-nonanone (<5%). It appears that the protic surface of the
flask is capable of converting 26 (Scheme 2) into the saturated derivative competitively with
a-hydroperoxide 28 formation.
Table 1
Entry Substrate
Conditions
Product
Yield
1
Mn(dpm)3 (3 mol%), PhSiH3 (2 equiv.),
i-PrOH (0.2 M conc of 1), O2
78%
Me
OH
Me
O
O
Me
1
Me
29
Me
2
1. Mn(dpm)3 (3 mol%), PhSiH3 (1.3
equiv.), i-PrOH/DCE, O2. 2. P(OEt)3
(1.1 equiv.)
Me
85%
O
O
OH
H
H
H
H
H
H
410
O
O
3
3
4
5
As above
As above
As above
59%
87%
51%
Me
OH
Me
O
O
Me
Me
611
5
Me
Me
OH
Me
Me
O
O
O
Me
O
Me
Me
Me
OH
812
O
7
O
Me
Me
H
Me
Me
Me
Me
O
Me
1013
Me
9
O
6
As above
As above
50%
HO
Ph
Ph
11
1214
O
O
7
8
73%
Me
Me
Me
Me
4
4
13
OH
1415
Me
Me
1. Mn(dpm)3 (3 mol%), PhSiH3 (1.3
equiv.), i-PrOH/DCM (1:4), O2. 2. P(OEt)3
(1.1 equiv.)
\95%
O
O
HO
O
O
OTr
OTr
15
16

9728
Table 1 (Continued)
Entry Substrate
Conditions
As above
Product
Yield
OTBS
OTBS
9
B95%
Me
Me
O
O
O
Me
HO
Me
Me
O
OTr
OTr
17
18
O
O
10
As above
70%
HO
Me
19
2016
Me
Me
Me
OH
Mn(dpm)3
Mn(dpm)3
No reaction
PhSiH3/CH2Cl2/i-PrOH
PhSiH3/CH2Cl2/i-PrOH
Me
O
O
Me
Me
O2
21
22
OH
OH
As above
As above
CO2Et
No reaction
Me
+
CO2Et
CO2Et
23
24
24a
O
Me
O
Me
O
H
OH
Me
Me As above
As above
Me
Me
Me
Me
Me
Me
Me
25
9
10
Scheme 1.
Treatment of a dark olive–green solution of Mn(dpm)3 in dichloromethane with stoichio-
metric amounts of PhSiH3 (2152 cm−1) produced no change (IR), but addition of isopropyl
alcohol to the solution rapidly (<1 min) produced a pale yellow solution that exhibited an IR
absorption at 2168 cm−1. This is consistent with the formation of HMn(dpm)2.21
Attempts to discover the fate of phenylsilane, the hydride source, indicated that formation of
phenylisopropyl(oxy)silane was inconclusive. Under the reaction conditions (and work-up)
phenylisopropyl(oxy)silane would have been converted into diphenyldisiloxane,22 which was
detected (1H NMR, authentic sample), but in relatively small amounts.
To explain these observations, especially the acceleration of conjugate reduction when oxygen
is present, appears to require two distinct reducing agents. The HMn(dpm)2 reagent reacts with
enones to produce 26, which is protonated to give the saturated ketone, Scheme 2. This reagent
does not reduce b,b-disubstituted enones. If HMn(dpm)2 (pale yellow–green) is exposed to
oxygen it immediately turns dark green–brown (under vacuum the pale yellow green color

9729
O
H
H
O
O
O
O
O
O
PhSiH3/CH2Cl2
PhSi OPri
+
+
Hdpm
Mn
O
Mn
No reaction until
i-PrOH is added
H
O
O
[HMn(dpm)2]
No 3O2
(PhSiH2)2O
[Mn(dpm)3]
3O2
O
H
i-PrOH
O
O
O
O
O
Mn(dpm)2
Mn
O
O
26
O
O
O
Mn(dpm)2
O
O
[HMnO2(dpm)2]
27
HOO
O
HO
P(OEt)3
+
O
28
29
Scheme 2.
returns), and this reagent does reduce b,b-disubstituted enones (Scheme 1 and entry 5, Table 1).
We suggest that the new manganese adduct formed in the presence of oxygen is
HMnO2(dpm)2,23 which reduces enones to the manganeseperoxyenolate 27, and subsequently
produces 28 and 29.24 Over a period of about 5 h at room temperature the peroxy-hydride
HMnO2(dpm)2 loses both reducing and oxidizing capability. Efforts to characterize
HMnO2(dpm)2 by X-ray crystallography are currently in progress.
It should be noted that Lippard has characterized the ‘bright yellow’ adduct
[Mn4(OEt)4(EtOH)2(dpm)4] and other similar Mn(II) adducts as alkoxide cubes with a Mn4O4
cubic core.25 We have prepared [Mn4(OEt)4(EtOH)2(dpm)4] according to the Lippard procedure,
and when a yellow ethanol solution of the complex (cat) is treated with PhSiH3 (1.3 equiv.)/O2/
4-oxoisophorone, the solution becomes olive green–brown and 4-oxoisophorone 7 (entry 4) is
converted into 8 (56%).26
Acknowledgements
The National Institutes of Health (GM 32718), The Robert A. Welch Foundation, Merck
Research Laboratories and Novartis are thanked for their support of this research. Dr. Richard
A. Jones is thanked for many helpful comments concerning the chemistry of manganese.
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