Catalytic hydrogenation of α,β-epoxy ketones to form β-hydroxy ketones mediated by an NADH coenzyme model

Article abstract of DOI:10.1021/ol0610892

The hydrogenation of α,β-epoxy ketones can be mediated by a catalytic amount of BNAH or BNA⁺Br^- to form corresponding β-hydroxy ketones in high yield. Na₂S₂O₄ is used as the reducing agent to convert

Full text of DOI:10.1021/ol0610892

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3449-3451
Catalytic Hydrogenation of
r,â-Epoxy
Ketones to Form -Hydroxy Ketones
â
Mediated by an NADH Coenzyme Model
|
Hua-Jian Xu,† You-Cheng Liu,*,†,‡ Yao Fu,† and Yun-Dong Wu*,§,
Department of Chemistry, UniVersity of Science and Technology of China, Hefei,
230026, China, College of Chemistry, Lanzhou UniVersity, Lanzhou, 730000, China,
Department of Chemistry, The Hong Kong UniVersity of Science & Technology, Clear
Water Bay, Kowloon, Hong Kong, China, and College of Chemistry, Peking
UniVersity, Beijing, China
ycliu@ustc.edu.cn; chydwu@ust.hk
Received May 4, 2006
ABSTRACT
+
-
The hydrogenation of
r,â-epoxy ketones can be mediated by a catalytic amount of BNAH or BNA Br to form corresponding â-hydroxy
+
-
ketones in high yield. Na2S2O4 is used as the reducing agent to convert BNA Br to BNAH. A radical mechanism has been proposed to
understand many observations of this catalytic reaction.
The NAD+/NADH coenzyme couple-mediated hydrogena-
tion reactions (Scheme 1) are ubiquitous in biological
systems.1 There is a great interest in utilizing the coenzyme
couple in organic synthesis. Hantzsch ester and 1-benzyl-
1,4-dihydronicotinamide (BNAH) are common models of
NADH.2 These models are known to reduce aldehydes,
ketones, and activated olefins.3-5 Recently, Hantzsch ester,
accompanied with some small-molecule organocatalysts, was
used in hydrogenation of R,â-unsaturated aldehydes,6 imi-
nes,7 and R,â-epoxy ketones.8 These reactions are of great
importance in organic synthesis and are attracting increasing
attention.9 However, these procedures all require the use of
a stoichiometric amount of the NADH model compound. It
would be desirable to carry out the reactions using a catalytic
Scheme 1
† University of Science and Technology of China.
‡ Lanzhou University.
§ Hong Kong University of Science and Technology.
| Peking University.
(1) Westheimer, F. H. In Pyridine Nucleotide Coenzyme, Part A; Dolphin,
D., Poulson, R., Avramovic, O., Eds.; Wiley-Interscience: New York, 1988;
p 253.
(2) (a) Murakami, Y.; Kikuchi, J.-I.; Hisaeda, Y.; Hayashida, O. Chem.
ReV. 1996, 96, 721-758. (b) Stout, D. M.; Meyers, A. I. Chem. ReV. 1982,
82, 223-243.
10.1021/ol0610892 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/07/2006

amount of NADH models.10 Very recently, Imada et al.
reported a hydrogenation of olefins catalyzed by Flavin,
another redox coenzyme.11 In this communication, we wish
to report on our preliminary results using a catalytic amount
(1-5 mol %) of BNA+Br- or BNAH to mediate the
hydrogenation of R,â-epoxy ketones to form â-hydroxy
ketones in excellent yields.
Initial experiments were concentrated on the selection of
the solvent and other conditions for the hydrogenation of
1a in Table 1. As shown, several solvents were employed.
A mixed organic/water solvent is necessary for the reaction
because of the presence of both neutral aromatic and ionic
species. Water or ethanol/water (1:1) gave very poor conver-
sion (Table 1, entries 1 and 2). However, both MeCN/H2O
(1:1) and AcOEt/H2O (1:1) gave complete conversion and
high isolated yields.12 The latter solvent condition was chosen
for further studies in consideration of the environmental
cause.
Table 1. Optimization of Solvent and Other Conditions
BNA+Br- time conversion isolated
entry
solvents
(mol %)
(h)
(%)
yield (%)
1
2
3
4
5
6
7
8
9
H2O
5
5
5
5
5
5
5
1
40
40
48
26
48
26
2
<10
<10
60
100
60
100
100
100
90
2
2
EtOH/H2O (1:1)a
MeCN/H2O (1:9)
MeCN/H2O (1:1)
AcOEt/H2O (1:9)
AcOEt/H2O (1:1)
AcOEt/H2O (1:1) (hυ)b
AcOEt/H2O (1:1) (hυ)b
AcOEt/H2O (1:1) (hυ)b
40
91
35
93
91
90
60
16
40
0.2
a Volume ratio. b Irradiation with a 450 W high-pressure mercury lamp
Other reaction conditions were also studied. When the
reaction temperature was raised from room temperature to
60 °C, the reaction time could be reduced to about 2 h.
(λ > 300 nm).
However, the yield of 2a was drastically decreased to about
30% due to increased formation of byproducts. We then
tested the effect of irradiation with a high-pressure mercury
lamp and found that the reaction was significantly acceler-
ated. The reaction completed in 2 h, and 2a was formed in
about 91% yield (Table 1, entry 7). When BNA+Br- was
reduced to 1 mol %, the reaction time had to be increased
to about 16 h, again with about 90% isolated yield (entry
8). When BNA+Br- was further reduced to 0.2 mol %,
however, only 60% of 2a was isolated after 40 h (entry 9).
(3) (a) Fukuzumi, S.; Ish-ikama, M.; Tanaka, T. Tetrahedron 1984, 42,
1021-1034. (b) Gelbard, G.; Lin, J.; Roques, N. J. Org. Chem. 1992, 57,
1789-1793. (c) Kanomata, N.; Suzuki, M.; Yoshida, M.; Nakata, T. Angew.
Chem., Int. Ed. 1998, 37, 1410-1412. (d) Mikata, Y.; Hayashi, K.;
Mizukami, K.; Matsumoto, S.; Yano, S.; Yamazaki, N.; Ohno, A.
Tetrahedron Lett. 2000, 41, 1035-1038.
(4) (a) Dekoning, A. J.; Albertsjansen, H. J.; Boersma, J.; Vanderkerk,
G. J. M. Recl. TraV. Chim. Pays-Bas 1980, 99, 316-321. (b) Tanner, D.
D.; Singh, H. K.; Kharrat, A.; Stein, A. R. J. Org. Chem. 1987, 52, 2142-
2146. (c) Tanner, D. D.; Stein, A. R. J. Org. Chem. 1988, 53, 1642-1646.
(d) Fukuzumi, S.; Mochizuki, S.; Tanaka, T. J. Am. Chem. Soc. 1989, 111,
1497-1499. (e) Beijer, N. A.; Vekemans, J. A. J. M.; Buck, H. Recl. TraV.
Chim. Pays-Bas 1990, 109, 434-436.
A series of 16 R,â-epoxy ketones were then investigated
with and without irradiation using 5 mol % of BNA+Br-.
In all cases where R1 was an aromatic ring, complete
conversion and high yields (90-94%) were obtained as
shown in Table 2 (1a-o). The yield is somewhat reduced
when R1 is a methyl group (1p, 80%). Irradiation signifi-
cantly reduces the reaction time but only has a minor effect
on the yield. These results indicate a general feasibility of
the reaction.
(5) (a) Norcross, B. E.; Klinedinst, P. E.; Westheimer, F. H. J. Am. Chem.
Soc. 1962, 84, 797-802. (b) Wallenfels, K.; Ertel, W.; Friedrich, K. Liebigs
Ann. Chem. 1973, 1663-1674. (c) Zhu, X. Q.; Liu, Y. C. J. Org. Chem.
1998, 63, 2786-2787. (d) Li, J.; Liu, Y. C.; Deng, J. G. Tetrahedron:
Asymmetry 1999, 10, 4343-4347. (e) Li, J.; Liu, Y. C.; Deng, J. G.; Li, X.
Z.; Cui, X.; Li, Z. Tetrahedron: Asymmetry 2000, 11, 2677-2682. (f) Lee,
H. W.; Kim, B. Y.; Ahn, J. B.; Son, H. J.; Lee, J. W.; Ahn, S. K.; Hong,
C. I. Heterocycles 2002, 57, 2163-2173. (g) Torchy, S.; Cordonnier, G.;
Barbry, D.; Eynde, J. J. V. Molecules 2002, 7, 528-533. (h) Zhang, Z.;
Gao, J.; Xia, J.-J.; Wang, G.-W. Org. Biomol. Chem. 2005, 3, 1617-1619.
(6) (a) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem.,
Int. Ed. 2004, 43, 6660-6662. (b) Yang, J. W.; Hechavarria Fonseca, M.
T.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2005, 44, 108-110. (c)
Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 32-33. (d) Liu, Z.; Han, B.; Liu, Q.; Zhang, W.; Yang, L.; Liu, Z. L.;
Yu, W. Synlett 2005, 1579-1580. (e) Liu, Z.; Liu, Q.; Zhang, W.; Mu, R.;
Yang, L.; Liu, Z. L.; Yu, W. Synthesis 2006, 771-774.
(7) (a) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed.
2005, 44, 7424-7427. (b) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann,
T.; Bolte, M. Org. Lett. 2005, 7, 3781-3783. (c) Rueping, M.; Azap, C.;
Sugiono, E.; Theissmann, T. Synlett 2005, 2367-2369. (d) Storer, R. I.;
Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
84-86.
(8) Zhang, J.; Jin, M. Z.; Zhang, W.; Yang, L.; Liu, Z. L. Tetrahedron
Lett. 2002, 43, 9687-9689.
(9) Adolfsson, H. Angew. Chem., Int. Ed. 2005, 44, 3340-3342.
(10) Imada, Y.; Iida, H.; Naota, T. J. Am. Chem. Soc. 2005, 127, 14544-
14545.
All above reactions were conducted under argon. No
reaction was observed (starting material was recovered) in
an oxygen-saturated solution regardless of whether the
reaction was under irradiation. Both BNA+Br- and BNAH
work equally well, indicating a fast turnover of the redox
couple. On the basis of these observations and by reference
to the literature,8,13 we propose a radical mechanism for the
reaction, as shown in Scheme 2.14
In the present reaction, BNA+ is first transformed into
1-benzyl-1,4-dihydronicotinamide (BNAH) by the reducing
agent Na2S2O4.14 BNAH gives an electron to the R,â-epoxy
ketone to form an anionic radical 3 and BNAH+•. A radical
ring-opening reaction regioselectively converts 3 into 4.15
(11) Fish et al. reported the regeneration of NADH models using the
strategy of regioselective reduction of NAD+ models with the [Cp*Rh-
(bpy)H]+ transition-metal catalyst: Lo, H. C.; Buriez, O.; Kerr, J. B.; Fish,
R. H. Angew. Chem., Int. Ed. 1999, 38, 1429-1432.
(12) It appears that the mixed solvent increases the reactivity of BNAH
with an R,â-epoxy ketone considerably because in CH3CN solvent BNAH
and a Hantzsch ester do not react with an R,â-epoxy ketone even under
elevated temperatures (also see ref 8). It is possible that a better solubility
for the Na2SO4/Na2CO3/BNA+Br- system in a mixed solvent also contrib-
utes to the increased reaction rate.
(13) For a recent review on the mechanisms of NAD+/NADH-mediated
hydrogenations, see: Gebicki, J.; Marcinek, A.; Zieloka, J. Acc. Chem. Res.
2004, 37, 379-386.
(14) Caughey, W. S.; Schellenberg, K. A. J. Org. Chem. 1966, 31, 1978-
1982.
3450
Org. Lett., Vol. 8, No. 16, 2006

Scheme 2. Proposed Mechanism for the Hydrogenation of
R,â-Epoxy Ketones to â-Hydroxy Ketones Mediated by
BNA+Br-
Table 2. Hydrogenation of R,â-Epoxy Ketones to â-Hydroxy
Ketones
isolated yield (%)
a
b
substrate
R1
R2
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
2-MeO-C6H4
2-Cl-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a (93)
2b (91)
2c (90)
2d (94)
2e (91)
2f (92)
2g (90)
2h (90)
2i (94)
2j (93)
2k (93)
2l (92)
2m (91)
2n (91)
2o (90)
2p (80)
2a (91)
2b (90)
2c (90)
2d (92)
2e (89)
2f (90)
2g (88)
2h (87)
2i (92)
2j (92)
2k (91)
2l (93)
2m (93)
2n (90)
2o (88)
2p (72)
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-Br-C6H4
4-Cl-C6H4
2-furyl
2-thienyl
2-naphthyl
4-biphenyl
Me
a With room light, 24-28 h, 100% conversion. b With a 450 W mercury
lamp, 2-3 h, 100% conversion.
into substituted pyridine, which cannot be converted back
into Hantzsch ester under the present reaction conditions.
However, we have found that N-methylated Hantzsch ester,
which is analogues to BNAH, can mediate the current
reaction as efficiently as BNAH.
A proton transfer from BNAH+• to 4 followed by an enol/
keto tautomerization results in the formation of 5 and BNA•.
An electron transfer from BNA• to 5 results in the formation
of 6 and the regeneration of BNA+. The reaction is completed
with the protonation of 6 by water.16
This mechanism explains why the presence of O2 sup-
presses the reaction because O2 is a radical trapper and it
prevents the electron transfer from BNAH to 1 to generate
3 and BNAH+•. It is in accord with the observed specific
CR-O bond cleavage. The mechanism also accommodates
the observed rate acceleration by irradiation. Because we
used a Pyrex flask (λ > 300 nm) for the photoirradiation
experiment, the compound that absorbs light is presumed to
be BNAH (λmax ) 380 nm).
In summary, we have found an efficient catalytic version
of hydrogenation of R,â-epoxy ketones to form correspond-
ing â-hydroxy ketones using a BNAH (BNA+Br-) catalyst.
To the best of our knowledge, this is the first example of
catalytic hydrogenation mediated by an NAD+/NADH
coenzyme model. We are currently exploring the application
of the strategy in other reactions.
Acknowledgment. We are grateful to the National Nature
Science Foundation of China (Grant No. 20072036, 20225312)
and the Specialized Research Fund for the Doctoral Program
of Higher Education of China for their support.
We find that Hantzsch ester cannot be used for the catalytic
reaction. After the first cycle, Hantzsch ester is converted
Supporting Information Available: Characterization
data (IR, NMR, MS) for all the prepared â-hydroxy ketones.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Because the ketyl anion radical 3 has a resonance form with a radical
on oxygen and an anion on carbon, it is also possible that 3 undergoes an
anion-induced ring opening to give 4 with an enol radical and an oxygen
anion. This process is probably less preferred because the enolate form of
4 as shown in Scheme 2 is likely more stable.
(16) The reaction solution actually becomes slightly less basic because
the conversion of BNA+Br- to BNAH by Na2S2O4 generates acid.
OL0610892
Org. Lett., Vol. 8, No. 16, 2006
3451