Asymmetric α-hydroxy ketone synthesis by direct ketone oxidation using a bimetallic palladium(II) complex

Article abstract of DOI:10.1016/j.tetlet.2012.03.066

The oxidation of ketones by a chiral bimetallic palladium(II) complex in the presence of CuCl₂ in THF-water solvents gave an enantioselective synthesis of α-hydroxyketones in catalytic oxidation utilizing an atmosphere of oxygen. The ee's ranged from 61% to 92%. The reaction was accelerated by addition of strong acid that presumably increases the rate of enolization.

Full text of DOI:10.1016/j.tetlet.2012.03.066

Tetrahedron Letters 53 (2012) 2699–2701
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric
a-hydroxy ketone synthesis by direct ketone oxidation
using a bimetallic palladium(II) complex
Othman A. Hamed a, Arab El-Qisairi b, Hanan Qaseer b, Emad M. Hamed c, , Patrick M. Henry d,z
,
Daniel P. Becker d,
⇑
a Department of Chemistry, An-Njaha National University, PO Box 7, Nablus, Palestine
b Department of Chemistry, Mu’tah University, PO Box 7, Mu’tah-Karak, Jordan
c Department of Chemistry, University of Guelph, Ontario, Canada N1G 2W1
d Department of Chemistry, Loyola University Chicago, 6525 N. Sheridan Road, Chicago, IL 60626, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxidation of ketones by a chiral bimetallic palladium(II) complex in the presence of CuCl2 in THF–
water solvents gave an enantioselective synthesis of -hydroxyketones in catalytic oxidation utilizing
an atmosphere of oxygen. The ee’s ranged from 61% to 92%. The reaction was accelerated by addition
of strong acid that presumably increases the rate of enolization.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 22 January 2012
Revised 8 March 2012
Accepted 20 March 2012
Available online 25 March 2012
a
Keywords:
Asymmetric synthesis
a-Hydroxyketone
Palladium catalysis
Acyloin
Bimetallic palladium
Chiral
a
-hydroxy ketones (acyloins) are important intermedi-
reactions. We also previously showed that Pd(II) in the presence
of CO catalyzes the conversion of cyclic ketones into diesters,
proceeding via the enol isomer.12
ates for the asymmetric synthesis of natural products, fine chemi-
cals, and drugs.1 For that reason, their enantioselective synthesis is
of considerable interest and there have been a number of reports
We first observed a-hydroxy ketone formation in studies of the
with various approaches to chiral
a
-hydroxy ketones.2 One general
CuCl2 promoted chlorohydrin reaction catalyzed by the bimetallic
complex A shown in Scheme 1.13 Treatment of a terminal alkene
with bimetallic complex A in the presence of LiCl with CuCl2 as
re-oxidant produced the chiral chlorohydrin, along with some
approach involves the preparation of enolates or enol derivatives,3
while another method involves catalytic asymmetric oxidation of
(E)-enol phosphates by (salen) Mn(III) complexes.4 A recent ap-
proach to chiral
a-hydroxy ketones involves the reactions of tin
enolates with nitrosobenzene.5 Macmillan reported the direct
proline-catalyzed oxyamination of aldehydes.6
Bimetallic complex A
O2, LiCl, CuCl2
CH
H2C
The oxidation of carbonyl compounds by metal species is a well-
known and widely studied reaction.7 and many of these reactions
apparently proceed via oxidation of the enol tautomer. Thus, the
oxidation of ketones by the two electron oxidants, Hg(II), Tl(III),
and Mn(VII)8 as well as some one-electron oxidants such as Mn(III)9
and tris(1,10-phenanthroline) complexes of Fe(III) and Ru(III)10
were postulated to involve the enol isomer. It has been shown that
the Pd(II)-catalyzed carbonylation of ketones also proceeds via the
enol isomer,11 and the results indicated that the enol form of the
ketone has a long enough lifetime to undergo Pd(II)-catalyzed
CH2R
H2O-THF
O
O
OH
s
R
R
Cl
s
R
+
+
+
OH
L
L
Bimetallic complex A =
L-L = ( )-cyclohexane-
PdII
PdII
O
O
O
1,2-diamine
s = solvent
R1
R2
⇑
Corresponding author.
E-mail address: dbecke3@luc.edu (D.P. Becker).
Scheme 1. Alkene oxidation with bis-Pd(II) catalyst affording chlorohydrin plus
ketone and hydroxyketone by-products.
Present address.
Deceased: October 19, 2008.
z
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.066

2700
O. A. Hamed et al. / Tetrahedron Letters 53 (2012) 2699–2701
ketone and 2-hydroxy ketone as by-products. In a related study we
showed that oxidation of ketones with Pd(II) bimetallic complex A
as catalyst in the absence of LiCl and at lower concentration of
a modest ee of 68% for the (R)-enantiomer, while the same sub-
strate in the absence of acid (Run 3) was very slow in the conver-
sion (28% of SM consumed after 2 days) but the asymmetric
induction was higher (82%). Thus acid is beneficial for the forward
progress of the reaction, since acid catalyzes ketone enolization,
although higher acidity may ultimately compromise the ee of the
product. The conversions for all other reactions were much higher,
and workup was performed when >90% of the starting material
was consumed by GC. Run 4 with propiophenone included 2.0 M
of LiCl, in addition to cupric chloride, and resulted in a lower ee rel-
CuCl2 produces predominantly the racemic
The results together suggest the possibility of a new and direct
asymmetric synthesis of -hydroxyketones by incorporation of a
a
-hydroxy ketones.14
a
chiral ligand in the place of the achiral ligand cyclohexane-1,2-dia-
mine in the coordination sphere of bimetallic complex A. Herein
we report the success of this direct approach and describe a new
procedure for the direct asymmetric catalytic
ketones.
a-hydroxylation of
ative to Run 3. Butyrophone gave the corresponding (R)-
yketone in 71% ee, quite comparable to the 68% ee for the shorter
homolog of Run 2. Asymmetric -hydroxylation of the sterically
a-hydrox-
Chiral bimetallic catalyst B (Table 1) was chosen for this study
because of its ease of preparation and success in asymmetric
halohydrin formation. The complex was prepared by reacting tet-
rakis(acetonitrile) palladium(II) tetrafluoroborate complex with
1-phenylhexane-1,3,5-trione followed by (R)-BINAP.13 The result-
ing asymmetric Pd(II) complex B was then utilized in asymmetric
oxidation of various symmetrical and unsymmetrical ketones in
an aqueous solution of THF in the presence of cupric chloride, lith-
ium chloride, and a catalytic amount of trifluoroacetic acid.
The oxidation results are summarized in Table 1, and the abso-
a
larger 1,2-diphenylethanone afforded the (R)-enantiomer (Run 6),
and replacing (R)-BINAP with (S)-BINAP produced the opposite
enantiomer as expected, affording (S)-2-hydroxyketone (Run 7).
Employment of the more bulky 1-(3-chlorophenyl)-propan-1-one
gave (R)-a-hydroxyketone in 92% ee (Run 8), the highest observed
in this series. The similar substrate 1-(3,5-difluorophenyl)-2-
hydroxypropan-1-one gave the product with the (R)-configuration
also in a high ee of 90%. Employing 3,3,3-trifluoro-1-phenylpro-
pan-1-one afforded (R)-furoin, with the opposite configuration rel-
ative to the generally-observed configuration (fluorine reverses the
Cahn–Ingold–Prelog priorities), and the opposite configuration of
what is drawn for Table 1. Run 11 employing furyl furfuryl ketone
lute configurations of the resulting a-hydroxy ketones were deter-
mined based on the comparison of the sign of optical rotation with
literature values.15 We first examined the oxidation of the sym-
metrical cyclic ketone cyclohexanone (Run 1) which produced a
modest ee of 67% for the (R)-enantiomer, then proceeded with
unsymmetrical aralkyl ketones. Propiophenone (Run 2) also gave
gave
Mechanistically, we propose that the
initial enolization, which is accelerated by acid, giving rise to a
-bound enol palladium species. An equilibrating mixture of E
a-hydroxyketone in quite high ee.
a-hydroxylation involves
p
Table 1
Asymmetric synthesis of
a-hydroxyl ketones using chiral bimetallic palladium
and Z-enols should exist in solution, although the two stereoiso-
mers may have quite different binding constants to palladium. A
2,1-insertion involving a palladium-bound solvent water molecule
complex Ba
O
should install the
a-hydroxyl, and reductive elimination then af-
O
[Pd2(triketone)(L*-L*)]
R1
fords the product plus the reduced catalyst, which is reoxidized
by CuCl2, and the resulting CuCl is oxidized by oxygen to complete
the catalytic cycle. Running the reaction under an inert atmosphere
led to only slightly lower isolated yields of products and with no
impact on enantioselectivities, consistent with the presence of ex-
cess CuCl2.
*
R1
R2
CuCl2, O2
R2
OH
CF3CO2H, H2O, THF
1-11
L*-L* = (R)-BINAP
ee = 61-92%
Run
R1
R2
Yieldb (%)
eec (%)
R/S
The result of Run 4 that was conducted at high [Clꢀ] affording a
lower ee suggests that the mode of H2O addition may be different
from that of other runs. In this case of high [Clꢀ], the chloride ion
would replace the solvent in the coordination sphere of Pd(II) dis-
couraging syn hydroxypalladation (2,1-insertion) and giving rise to
1
2
CH2CH2CH2CH2
64
64
36
52
61
52
52
56
53
48
72
67
68
82
51
71
85
87
92
90
89
91
Rg
Rh
Rh
Rh
Ri
CH3
CH3
CH3
CH3CH2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3d
4e
5
6
Rj
7f
8
Ph
Sj
the possibility of nucleophilic attack of water on the
p-complex,
CH3
CH3
CF3
(3-Cl)Ph
3,5-di-F-Ph
Ph
Rk
Rl
leading to the opposite stereochemistry. Several earlier studies
showed that anti-hydroxypalladation predominates at a high con-
centration of LiCl.16
9
10
11
Rm
Rn
2-furyl
2-furyl
In summary, enantioselectivities of the catalytic alpha-hydrox-
ylation were at least 70% and reached a maximum of 92%. The E/Z
enol ratio would be expected to impact the enantioselectivity, but
as noted the two stereoisomers would have different binding
constants to the palladium catalyst, and different rates of attack
once bound. Further, the presence of excess chloride decreases
the enantioselectivities. With modest increases in enantioselectiv-
ities, which may be realized by varying chiral auxiliaries and reac-
tion conditions, this catalytic oxidation procedure should compete
with much more elaborate and involved procedures for preparing
a
All runs contain 0.08–0.2 mmol of catalyst in 20 mL 4:1 THF/H2O, 0.5 M in
CuCl2, with a catalytic amount of CF3CO2H. t = 25 °C.
b
Yields for isolated products after column chromatography. Absolute configu-
ration as drawn except for run 10.
c
ee’s were determined by 1H NMR utilizing Eu(hfc)3 chiral shift reagent.
No acid catalyst was used in this run.
d
e
Contains 2.0 M of LiCl in addition to CuCl2.
(S)-BINAP was used rather than (R)-BINAP.
f
For (R) ½a 2D0
ꢁ
= +26.20 (c = 1.35, CHCl3)15a; Run 1: ½a D20
ꢁ
= +14.0 (c = 2.0, CHCl3).
= +82.2 (c = 2.0, CHCl3)15c
;
g
For (R) ½a 2D0
ꢁ
= +81.0 (c = 1.5, CHCl3), ee = 96%15b; ½a D20
ꢁ
h
Run 2: ½a 2D0
ꢁ
= +60.3 (c = 2.0, CHCl3); Run 3: ½a D20
ꢁ
= +69.8 (c = 2.0, CHCl3); Run 4:
½
a 2D0
ꢁ = +46.2 (c = 2.0, CHCl3).
i
For (S) ½ ꢁ
a 2D0 = ꢀ30.8 (c = 2.24, CHCl3), ee = 95% in Davis,15d but for (S)
optically active
a-hydroxy ketones. Ongoing work is focused on
understanding the mechanism, improving the enantioselectivities,
and exploring other nucleophiles.
½
a 2D0
ꢁ
= +40.5 (c = 0.3, CHCl3) in Krawczyk15c; Run 5: ½a D20
ꢁ
= +23.7 (c = 2.0, CHCl3).
For (R) ½a 2D0
ꢁ
= ꢀ170.1 (c = 1.0, benzene)15b; ½a D20
ꢁ
= ꢀ230.5 (c = 1.0, benzene)15f
;
j
for (S) ½a 2D0
ꢁ
= +138.4 (c = 0.25, CHCl3)15c, ½a D20
ꢁ
= +114.9 (c = 1.5, acetone)15e; Run 6
= +141.8 (c = 0.2, CHCl3).
½
a 2D0
ꢁ
= ꢀ139.6 (c = 0.2, CHCl3); Run 7 ½a D20
ꢁ
Acknowledgments
For (R) ½a 2D0
ꢁ
= +64.2 (c = 1.2, CHCl3)15g; Run 8: ½a D20
ꢁ
= +66.5 (c = 2.0, CHCl3).
= +46.8 (c = 2.0, CHCl3).
= ꢀ7.8 (c = 0.2, CHCl3).
= +59.2 (c = 1.0, CHCl3).
k
l
For (R) ½a 2D0
ꢁ
= +50.0 (c = 1.0, CHCl3)15h; Run 9 ½a D20
ꢁ
For (S) ½a 2D0
ꢁ
= +8.6 (c = 0.2, CHCl3)15h; Run 10 ½a D20
ꢁ
m
n
American Chemical Society Petroleum Research Fund for
support of this research through ACS PFR #48511-AC1. NSF Grant
For (R) ½a 2D0
ꢁ
= +62.7 (c = 0.9, CHCl3)15h; Run 11 ½a D20
ꢁ

O. A. Hamed et al. / Tetrahedron Letters 53 (2012) 2699–2701
2701
3. Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919.
No. DBI-0216630 is gratefully acknowledged for the Varian INOVA-
300 NMR obtained through the NSF Major Instrumentation
Program.
4. (a) Marcune, B. F.; Karady, S.; Reider, P. J.; Miller, R. A.; Biba, M.; DiMichele, L.;
Reamer, R. A. J. Org. Chem. 2003, 68, 8088; (b) Krawczyk, N.; Koprowski, M.;
Skowron´ ska, A.; Łuczak, J. Tetrahedron: Asymmetry 2004, 15, 2599–2602.
5. Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038.
6. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003,
125, 10808–10809.
Supplementary data
7. (a) Rocek, J. In The Chemistry of the Carbonyl Group; Patai, S., Ed.; Wiley: New
York, 1966. Chapter 10; (b) De Klein, W. J. In Organic Synthesis by Oxidation with
Metal Compounds; Mijs, W. J., De Jonge, C. R. H. I., Eds.; Plenum Press: New York,
1986; p 261.
8. (a) Best, P. A.; Littler, J. S.; Waters, W. A. J. Chem. Soc. 1962, 822; (b) Littler, J. S. J.
Chem. Soc. 1962, 832; (c) Green, A. J.; Kemp, T. J.; Littler, J. S.; Waters, W. A. J.
Chem. Soc. 1964, 2722.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
03.066.
References and notes
9. (a) den Hertog, H. J., Jr.; Kooyman, E. C. J. Catal. 1966, 6, 357; (b) Heiba, E. I.;
Dessau, R. M. J. Am. Chem. Soc. 1971, 93, 524.
1. (a) Hanessian, S. Total Synthesis of Natural Products The Chrion Approach;
Permagon Press: New York, 1983. Chapter 2; (b) Oppolzer, W. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 876; (c) Girijavallabhan, V. M.; Ganguly, A. K.; Pinto, P. A.;
Sarre, O. Z. Bioorg. Med. Chem. Lett. 1991, 1, 349; (d) Whitesell, J. K.; Buchanan,
C. M. J. Org. Chem. 1986, 51, 5443; (e) Du Bois, J.; Tomooka, C. S.; Hong, J.;
Carreira, E. M. Acc. Chem. Res. 1997, 30, 364; (f) Tanaka, T.; Kawase, M.; Tani
Bioorg, S. J. Med. Chem. 2004, 12, 501–505.
2. (a) Davis, F. A.; Chen, B. C. In Houben-Weyl: Methods of Organic Chemistry;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, 1995; Vol. 21, p 4497; (b) Zhou, P.; Chen, B. C.; Davis, F. A. In
Asymmetric Oxidation Reactions; Katsuki, T., Ed.; Oxford University Press:
10. Ng, F. T. T.; Henry, P. M. Can. J. Chem. 1977, 55, 2900.
11. Hamed, O.; El-Qisairi, A.; Henry, P. M. J. Org. Chem. 2001, 66, 180.
12. Hamed, O.; El-Qisairi, A.; Henry, P. M. Tetrahedron Lett. 2000, 41, 3021.
13. (a) El-Qisiari, A. K.; Henry, P. M. J. Organomet. Chem. 2000, 603, 50; (b) El-
Qisiari, A. K.; Qaseer, H. A.; Henry, P. M. J. Organomet. Chem. 2002, 656, 167.
14. El-Qisairi, A. K.; Qaseer, H. A. J. Organomet. Chem. 2002, 659, 50.
15. (a) Jiao, P.; Kawasaki, M.; Yamamoto, H. Angew. Chem.,Int. Ed. 2009, 18(3333–
3336), pp. S3333/1-S3333/42.; (b) Demir, A. S.; Hamamci, H.; Tanyeli, C.;
Akhmedov, I. M.; Doganel, F. Tetrahedron: Asymmetry 1998, 10, 1673–1677; (c)
Krawczyk, E.; Koprowski, M.; Skowronska, A.; Luczak, J. Tetrahedron:
Asymmetry 2004, 17, 2599–2602; (d) Davis, F. A.; Weismiller, M. C.; Murphy,
C. K.; Reddy, R. T.; Chen, B. C. J. Org. Chem. 1992, 26, 7274–7285; (e) Davis, F. A.;
Sheppard, A. C.; Chen, B. C.; Haque, M. S. J. Am. Chem. Soc. 1990, 18, 6679–6690;
(f) Enders, D.; Bhushan, V. Tetrahedron Lett. 1988, 20, 2437–2440; (g) Lukas, R.
J.; Muresan, A. Z.; Damaj, M. I.; Blough, B. E.; Huang, X.; Navarro, H. A.;
Mascarella, S. W.; Eaton, J. B.; Marxer-Miller, S. K.; Carroll, F. I. J. Med. Chem.
2010, 12, 4731–4748; (h) Nestl, B. M.; Bodlenner, A.; Stuermer, R.; Hauer, B.;
Kroutil, W.; Faber, K. Tetrahedron: Asymmetry 2007, 12, 1465–1474.
16. Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1997, 62, 7082–7083.
Oxford, 2001; p 128; (c) Coppola, G. M.; Schuster, H. F.
a-Hydroxy Acids in
Enantioselective Synthesis; Wiley-VCH: Weinheim, 1997; (d) Hashiyama, T.;
Morikawa, K.; Sharpless, K. B. J. Org. Chem. 1992, 57, 5067; (e) Knight, R. L.;
Leeper, F. J. J. Chem. Soc. Perkin Trans.1 1998, 1891; (f) Enders, D.; Breuer, K.;
Teles, J. Helv. Chim. Acta 1996, 79, 1217; (g) Enders, D.; Breuer, K. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 2, pp 1093–1102; (h) Koike, T.; Murata, K.;
Ikariya, T. Org. Lett. 2000, 2, 3833; (i) Lee, J. C.; Jin, Y. S.; Choi, J. H. Chem.
Commun. 2001, 956.