Reduction of activated carbonyl groups by alkyl phosphines: Formation of α-hydroxy esters and ketones

Article abstract of DOI:10.1039/b516467b

Reduction of activated carbonyl groups such as α-keto esters, benzils, 1,2-cyclohexanedione, and α-ketophosphonates by alkyl phosphines afforded the corresponding α-hydroxy esters or ketones in good to excellent yields in THF at room temperature. The mechanism of the proton transfer and intramolecular hydrolysis has been studied on the basis of deuterium and ¹⁸O labeling experiments. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b516467b

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Reduction of activated carbonyl groups by alkyl phosphines: formation
of a-hydroxy esters and ketones{
Wen Zhang and Min Shi*
Received (in Cambridge, UK) 21st November 2005, Accepted 19th January 2006
First published as an Advance Article on the web 1st February 2006
DOI: 10.1039/b516467b
result was obtained by using PMe3 as the reductant for 2 h in
THF.
Reduction of activated carbonyl groups such as a-keto esters,
benzils, 1,2-cyclohexanedione, and a-ketophosphonates by
alkyl phosphines afforded the corresponding a-hydroxy esters
or ketones in good to excellent yields in THF at room
temperature. The mechanism of the proton transfer and
intramolecular hydrolysis has been studied on the basis of
deuterium and 18O labeling experiments.
Using these optimized conditions, we next examined the
reactions of a variety of a-keto esters with PMe3 or PPh2Me.
The results are summarized in Table 2. Aryl group substituted
a-keto esters produced the corresponding reduction products 2 in
good yields (Table 1, entries 1–6). The electron-donating substrate
1g, which was reduced to 2g in low yield by biocatalysis,9 was
obtained reduced in 71% yield using this reduction method
(Table 2, entry 6). For substrates having two substituents on the
benzene ring such as (3,5-dimethylphenyl)-oxo-acetic acid ethyl
ester (1h), the reaction proceeded smoothly under identical
reactions to give the corresponding product 2h in 71% yield
(Table 2, entry 7). Alkyl group substituted a-keto esters 1i–k
afforded products 2i–k in excellent yields (Table 2, entries 8–10).
Furthermore, the reduction of benzils (3a–d) to benzoins (4a–d/
4a0–d0) proceeded smoothly under the standard conditions to give
the corresponding reduced products in high yields and various
moderate selectivities (Table 3, entries 1–4). In addition, for 1,2-
cyclohexanedione 3e, the corresponding reduced product 4e was
obtained in 80% yield (Table 3, entry 5).
a-Hydroxy esters are important synthetic intermediates, especially
in the field of bioactive molecule synthesis, that can be obtained
through transition metal catalyzed hydrogenation,1 bioreduction
with baker’s yeast reductase or Escherichia coli cells,2 and chemical
reduction by b-chlorodiisopinocampheylborane,3 titanium(II) por-
phyrin complexes4 or sodium dithionite.5 While phosphines are
widely used as Lewis bases or ligands in organic chemistry,6 to our
knowledge, the Staudinger reaction was the early report on the
reduction of azides to amines by Ph3P/H2O,7 no report regarding
their use as reductants accompanied with a proton movement has
been published. Herein, we report the reduction of activated
carbonyl groups in a-keto esters, benzils, 1,2-cyclohexanedione
and a-ketophosphonates by alkyl phosphines, such as trimethyl-
phosphine or diphenylmethylphosphine, under mild conditions
to form the corresponding a-hydroxy esters, ketones and
phosphonates.
Table 1 Reduction of methyl phenylglyoxylate 1a by various
phosphines in a variety of solventsa
An initial examination was carried out by the reaction of methyl
phenylglyoxylate (1a) (1.0 equiv.) with trimethylphosphine8
(PMe3) (1.0 equiv.) in THF at room temperature. We found that
reduction took place to give the corresponding hydroxy–phenyl–
acetic acid methyl ester (2a) in 75% yield within 2 h (Table 1,
entry 1) and using 0.5 equiv. of PMe3, resulted in 2a being
obtained in only 39% yield under identical conditions (Table 1,
entry 2). Molecular sieves did not affect the reduction, (Table 1,
entry 3) and using PPh2Me, PPhMe2, or PBu3 as reductants
prolonged the required reaction times (Table 1, entries 4–6). Both
PPh3 and P(OEt)3 showed no reaction (Table 1, entries 7 and 8).
These results suggest that aliphatic substituents of the phosphine
are necessary for reduction to occur. Solvent effects were also
examined for reactions PPh2Me and PPhMe2 (Table 1, entries 9–
16). For example, we observed that 2a was obtained in 70% yield
with 1.0 equiv. of PPh2Me in methanol after 48 h. Overall, the best
Entry
PR3
Solvent
Time/h
2a (%)b
1
PMe3
PMe3
PMe3
PPh2Me
PPhMe2
PBu3
THF
THF
THF
THF
THF
THF
THF
THF
PhCH3
Et2O
CH3CN
MeOH
1,4-dioxane
—
2
2
2
75
39
72
60
54
24
N.R.
N.R.
40
46
24
48
54
trace
70
36
2c
3d
4
48
48
48
72
72
48
48
48
48
48
72
48
48
5
6
7e
8e
9
PPh3
P(OEt)3
PPhMe2
PPhMe2
PPhMe2
PPhMe2
PPhMe2
PPhMe2
PPh2Me
PPh2Me
10
11
12
13
14
15
16
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai, 200032, China. E-mail: Mshi@pub.sioc.ac.cn;
Fax: 86-21-64166128
MeOH
1,4-dioxane
Methyl phenylglyoxylate (0.3 mmol), phosphine (0.3 mmol) and
{ Electronic supplementary information (ESI) available: 13C and 1H
NMR spectroscopic data for compounds 2a–2k, 4a–4e, 6, 8 and 10 and
deuterium and 18O labeling experiments, spectroscopic trace study for the
reaction system. See DOI: 10.1039/b516467b
b
solvent (0.3 mL, 1.0 M) were used. Isolated yields. 50 mol% of
c
d
trimethyl phosphine was used. Molecular sieves 4A were used.
No reaction occurred.
e
1218 | Chem. Commun., 2006, 1218–1220
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Table 2 Reduction of a-keto esters with trimethylphosphine or
diphenylmethylphosphine in THF at room temperaturea
Table 3 Reduction of benzils and 1,2-cyclohexanedione with tri-
methylphosphine
Entry R1
R2
Products Yield (%)a(ratio 4/49)b
Entry
1
1
Phosphine (PR03) Time/h
2
(%)b
1
2
3
4
5
a
C6H5 C6H5 3a
C6H5 4-FC6H4 3b
C6H5 4-MeOC6H4 3c 4c/4c9
C6H5 CH3 3d
–C4H8– 3e
4a
4b/4b9
84
PMe3
PPh2Mec
2
48
2b 81
2b 69
85 (1.2/1)
93 (5.5/1)
73 (1.4/1)
80
4d/4d9
4e
2
3
4
PMe3
PPh2Mec
2
48
2c 81
2a 80d
Isolated yields. The ratio of 4/49 was determined by 1H NMR
b
spectrum.
PMe3
PMe3
2
2
2d 85
2e 81
5
PMe3
2
2f 85
6
7
PMe3
PMe3
2
2
2g 71
2h 71
Scheme 1 Reduction of functionalized ketones with trimethylphosphine.
phosphorus atom through formation of the phosphine oxide
during work-up. Other control experiments were carried out by
adding one equivalent of D2O (D content = 99.8%) and H218O
(18O content = 94.1%) into the PPh2Me/THF reduction system,
respectively. We found that in the presence of H218O, 2a was
formed in 35% isolated yield along with 85% of P(18O)Ph2CH3, in
which 18O content is 25%, as determined by EI-MS. In the
presence of D2O, 2a-d(O) was formed in 31% yield (D content >
99%), along with P(O)Ph2CH2D in 82% isolated yield (D content
33%), as determined by 1H NMR analysis.13 Therefore, the
observed 18O and D contents are consistent with the formation of
2a. The excess formation of the corresponding phosphine oxide is
most likely due to the oxidation by the ambient oxygen during
8
PMe3
PMe3
PMe3
2
2
2
2i 80
2j 96
9
10
a
2k 97e
1 (0.3 mmol), phosphine (0.3 mmol) in THF (0.3 mL) were stirred
b
at room temperature. Isolated yields. MeOH was used as solvent.
c
d
e
The product was 2a. GLC yield.
On the other hand, the reduction of a-ketophosphonates 5 and
7 and diethyl ketomalonate 9 also proceeded smoothly to give the
corresponding reduced products 6, 8, and 10, respectively, in good
yields (Scheme 1). It should be noted that the alkene group in 7
remained unchanged under these reduction conditions.
In order to identify the proton source in these reactions, the
reduction of 1a with trimethylphosphine-D,9 prepared from
reaction of CD3MgI with tri-o-tolyl phosphite,10 was carried out
under the standard conditions and the product of 2a-D(C) was
produced in 70% isolated yield with 80% D incorporation at the C1
position (Scheme 2).11 A primary isotope effect was of kH/kD
#
5.5 was observed.12 This result suggests that only one proton is
directly transferred from trimethylphosphine to product 2a, and an
additional equivalent of water is required for the release of the
Scheme 2 Isotope labeling experiments.
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Chem. Commun., 2006, 1218–1220 | 1219

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350–353; (c) I. E. Maxwell, P. van den Brink, R. S. Downing,
A. H. Sijpkes, S. Gomez and T. Maschmeyer, Top. Catal., 2003, 24,
125–135; (d) S. Rodriguez, M. Kayser and J. D. Stewart, Org. Lett.,
1999, 1, 1153–1155; (e) I. A. Kaluzna, T. Matsuda, A. K. Sewell and
J. D. Stewart, J. Am. Chem. Soc., 2004, 126, 12827–12832; (f)
I. A. Kaluzna, B. D. Feske, W. Wittayanan, I. Ghiviriga and
J. D. Stewart, J. Org. Chem., 2005, 70, 342–345; (g) N. Kanomata
and T. Nakata, J. Am. Chem. Soc., 2000, 122, 4563–4568; (h)
N. Kanomata and T. Nakata, Angew. Chem., Int. Ed. Engl., 1997, 36,
1207–1211.
Scheme 3 A possible reaction mechanism.
3 (a) P. V. Ramachandran, S. Pitre and H. C. Brown, J. Org. Chem.,
2002, 67, 5315–5319; (b) H. C. Brown, J. Chandrasekharan and
P. V. Ramachandran, J. Am. Chem. Soc., 1988, 110, 1539–1546; (c) For
a review on DIP-Chloride, see: P. V. Ramachandran and H. C. Brown,
in Reductions in Organic Chemistry, ed. A. A. Abdel-Magid, ACS
Symposium Series No. 641, American Chemical Society, Washington,
DC, 1996, Chapter 5.
4 (a) G. Du, G. A. Mirafzal and L. K. Woo, Organometallics, 2004, 23,
4230–4235; (b) X. Wang and L. K. Woo, J. Org. Chem., 1998, 63,
356–360; (c) J. L. Thorman, V. G. Young, Jr., P. D. W. Boyd, I. A. Guzei
and L. K. Woo, Inorg. Chem., 2001, 40, 499–506; (d) L. K. Woo,
J. A. Hays, V. G. Young, Jr., C. L. Day, C. Caron, F. D’Souza and
K. M. Kadish, Inorg. Chem., 1993, 32, 4186–4192; (e) X. Wang,
S. D. Gray, J. Chen and L. K. Woo, Inorg. Chem., 1998, 37, 5–9.
5 (a) S. M. Heilmann, J. K. Rasmussen and H. K. Smith, II, J. Org.
Chem., 1983, 48, 987–992; (b) T. van Es and O. G. Backeberg, J. Chem.
Soc., 1963, 1371–1377; (c) E. Grandmougin, J. Prakt. Chem., 1907, 76,
124–142.
work-up (see Figures SI-8 to SI-19 in the Supporting
Information{).14
The proposed mechanism based on the observed results of this
interesting reaction is outlined in Scheme 3. Initially, coordination
of two oxygen atoms in 1a to the phosphorus atom of
diphenylmethylphosphine takes place to give intermediate A
according to the literature.15 The intramolecular proton transfer
from the methyl group of the phosphine to the corresponding
activated carbonyl group produces intermediate B, which subse-
quently undergoes O–P bond cleavage by ambient moisture or
during work-up to generate 2a and the corresponding phosphine
oxide. It should be noted that activated (by carbonyl or
phosphoryl groups) carbonyl groups are essential for this
reduction because no reaction occurred using phenylethanone or
b-keto esters as the substrate under the standard conditions.
In summary, we have presented the reduction of a-keto esters,
benzils, 1,2-cyclohexanedione and a-ketophosphonates by alkyl
phosphines (trimethylphosphine and diphenylmethylphosphine) in
THF or methanol at room temperature. This reaction system has
wide application on reduction of substituted aryl phenylglyoxyl-
ates. On the basis of the deuterium and 18O labeling experiments,
we found that this reaction proceeds through a proton transfer
from the alkyl phosphine and cleavage by H2O during work-up.
Efforts are in progress to further confirm mechanistic details of
this reaction and to understand its scope and limitations.{
We thank the State Key Project of Basic Research (Project 973)
(No. G2000048007), Shanghai Municipal Committee of Science
(04JC14083) and Technology, and the National Natural Science
Foundation of China (20472096, 203900502, and 20272069) for
financial support.
6 For a brief summary, see: J.-P. Majoral, in New Aspects in Phosphorus
Chemistry, I to IV, Springer, Berlin, Germany, 1986.
7 H. Staudinger and J. Meyer, Helv. Chim. Acta, 1919, 2, 635–646; Some
selected references on application for Staudinger reaction, see: (a)
E. C. Lee, B. L. Hodous, E. Bergin, C. Shih and G. C. Fu, J. Am. Chem.
Soc., 2005, 127, 11586–11587; (b) Y. Liang, L. Jiao, S. Zhang and J. Xu,
J. Org. Chem., 2005, 70, 334–337; (c) J. Li, H.-N. Chen, H. Chang,
J. Wang and C.-W. T. Chang, Org. Lett., 2005, 7, 3061–3064; (d)
P. T. Nyffeler, C.-H. Liang, K. M. Koeller and C.-H. Wong, J. Am.
Chem. Soc., 2002, 124, 10773–10778.
8 Trimethylphosphine as a THF solution (1.0 M) is commercially
available.
9 J. Gu, Z. Li and G. Lin, Tetrahedron, 1993, 49, 5805–5816.
10 R. T. Li, S. T. Nguyen, R. H. Grubbs and J. W. Ziller, J. Am. Chem.
Soc., 1994, 116, 10032–10040; CD3MgI was prepared from CD3I (D
content > 90%) with magnesium.
11 The D content of 2a–d(C) was determined by 1H NMR spectrum
(Please see the Supporting Information).
12 The equations of the initial stage within 40 minutes were Y = 6.2X +
68.37 for the P(CH3)3 system and Y = 1.125X + 40.50 for the P(CD3)3
system (Please see the Supporting Information).
13 The comparable reaction was carried out under identical conditions by
adding one equivalent of unlabeled H2O. We found that 2a was
obtained in 48% yield along with 52% of the starting materials 1a and
81% yield of the corresponding P(O)Ph2Me.
Notes and references
14 PPh2Me is very air sensitive in ambient atmosphere and can easily be
oxidized to P(O)Ph2Me during flash column chromatography.
15 (a) Y. Ogata and M. Yamashita, Tetrahedron, 1971, 27, 2725–2735; (b)
Y. Ogata and M. Yamashita, J. Am. Chem. Soc., 1970, 92, 4670–4674;
(c) F. Ramirez, S. B. Bhatia and C. P. Smith, Tetrahedron, 1967, 23,
2067–2080.
1 (a) R. A. Sheldon, in Chirotechnology, Marcel Dekker, New York, 1993;
(b) D. Sterk, M. S. Stephan and B. Mohar, Tetrahedron Lett., 2004, 45,
535–537; (c) P. Gamez, F. Fache and M. Lemaire, Tetrahedron:
Asymmetry, 1995, 6, 705–718.
2 Selected references: (a) D. C. Demirjian, P. C. Shah and F. Moris-Varas,
Top. Curr. Chem., 1999, 200, 1–29; (b) S. M. Senkan, Nature, 1998, 394,
1220 | Chem. Commun., 2006, 1218–1220
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