Biomimetic hydrogenation: A reusable NADH co-enzyme model for hydrogenation of α,β-epoxy ketones and 1,2-diketones

Article abstract of DOI:10.1016/j.tetlet.2013.05.047

A biomimetic method has been developed to transform α,β-epoxy ketones or 1,2-diketones into corresponding β-hydroxy ketones or α-hydroxy ketones using a catalytic amount of BNAH or BNA ⁺Br^-. The regeneration of BNAH or BNA⁺Br ^- is achieved by a mixture of HCOOH/Et₃N. A radical mechanism is proposed to explain these observations.

Full text of DOI:10.1016/j.tetlet.2013.05.047

Tetrahedron Letters 54 (2013) 3877–3881
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Biomimetic hydrogenation: a reusable NADH co-enzyme model for
hydrogenation of a,b-epoxy ketones and 1,2-diketones
Qiang Huang a, Ji-Wei Wu a, Hua-Jian Xu a,b,
⇑
a School of Chemical Engineering, School of Medical Engineering, Hefei University of Technology, Hefei 230009, PR China
b Key Laboratory of Advanced Functional Materials and Devices, Hefei 230009, Anhui Province, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 February 2013
Revised 6 May 2013
Accepted 13 May 2013
Available online 18 May 2013
A biomimetic method has been developed to transform
a,b-epoxy ketones or 1,2-diketones into
corresponding b-hydroxy ketones or
a
-hydroxy ketones using a catalytic amount of BNAH or BNA+Brꢀ.
The regeneration of BNAH or BNA+Brꢀ is achieved by a mixture of HCOOH/Et3N. A radical mechanism
is proposed to explain these observations.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Biomimetic hydrogenation
a,b-Epoxy ketones
1,2-Diketones
NADH coenzyme model
NAD(P)+/NAD(P)H coenzyme couple plays an important role in
the redox reaction of biological system (Scheme 1).1 It is of great
significance to simulate the function of the co-enzyme couple
and apply them to synthetic organic chemistry. However, a great
difficulty of this biocatalytic reduction is the use of a stoichiome-
tric amount of the expensive NADH co-enzyme. In order to solve
this problem, on one hand, great efforts have been made to turn
NAD+ into NADH,2 generally mediated by enzyme or metallic
complexes.3,4 On the other hand, NAD(P)H models have become
the focus of biomimetic chemistry over the past few decades. As
the simplest NAD(P)H models,5 Hantzsch ester and 1-benzyl-1,4-
dihydronicotinamide (BNAH) are widely exploited. However, a
stoichiometric amount of the NADH model compound needs to
be used in most of these procedures.6,7 It remains a challenge to
achieve these reactions with a catalytic amount of NAD+/NADH
model (Scheme 2).8,9
mixture of HCOOH/Et3N, especially in the absence of any metallic
catalyst or enzyme.
The initial experiment was focused on whether the
a,b-epoxy
ketone (1a) could be converted to b-hydroxy ketone (2a) by formic
acid and triethylamine in the presence of a NAD+ model.11 When
we tested the effect of irradiation with a 450 W high-pressure mer-
cury lamp (k > 300 nm),9,12 2a was obtained. Next, different sol-
vents were employed as shown in Table 1. It was necessary for
the reaction to proceed smoothly in a mixed organic/water solvent
to compromise the solubility of both the substrate and the ionic
catalyst. AcOEt/H2O (1:1) gave comparatively good isolated yields,
while water or acetonitrile/water (1:1) gave moderate conversion
and low yield (Table 1, entries 1 and 2). Thus AcOEt/H2O (1:1)
was used in the following experiments.
Previous studies showed that HCOOH/Et3N plays an important
role in the hydrogenation reaction.13 We wondered whether or
not the pH value has an influence on the reaction. Different propor-
tions of formic acid and triethylamine were tested. It seems that a
trace amount of product could be obtained in the acidic conditions
while the conversion and the yield are greatly increased in the
basic conditions (entry 4). When the amount of formic acid and tri-
ethylamine was approximately increased to 5 equiv and 6.3 equiv,
a good yield was obtained within a short time (entry 5). However,
use of more formic acid and triethylamine does not enhance the
yield (entry 8). Use of more triethylamine appears to accelerate
the conversion of the substrate (entries 5–7). In addition, some
other amines can also work, such as diethylamine and N,N-diiso-
propylethylamine (entries 9 and 10).
Herein, we would report the hydrogenation of
ketones and 1,2-diketones to form b-hydroxy ketones and
a
,b-epoxy
-hy-
a
droxy ketones in good to excellent yields mediated by a catalytic
amount of BNA+/BNAH. In 1977, Ohnishi and Tanimoto, reported
that BNA+ could be converted to BNAH by a mixture of HCOOH/
Et3N in acetonitrile at room temperature,10 but no corresponding
following application was reported. It would be of great interest
to accomplish the catalytic function of BNA+, mediated by a
⇑
Corresponding author at: School of Chemical Engineering, School of Medical
Engineering, Hefei University of Technology, Hefei 230009, PR China. Tel.: +86 551
62904353; fax: +86 551 62904405.
E-mail address: hjxu@hfut.edu.cn (H.-J. Xu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.047

3878
Q. Huang et al. / Tetrahedron Letters 54 (2013) 3877–3881
H
H
CONH2
Regeneration
Reduction
N
O
P
O
O
O
O
O
Substrates
Products
NAD(P)H
Biosynthesis
NAD(P)+
OH OH
NH2
N
O
N
E1
E2
Hydrogen
Resource
N
O
N
P
O
OH OR
NADH: R=H
NADPH: R=PO3
2-
Scheme 1. NAD(P)H-mediated reduction reaction (E1: regeneration enzyme; E2: production enzyme).
H
H
CONH2
Regeneration
Reduction
N
O
P
O
O
O
O
O
NAD(P)H
Model
Substrates
Products
OH OH
NH2
N
O
Biomimetic approach
N
Hydrogen
Resource
N
O
N
NAD(P)+
Model
P
O
OH OR
NADH: R=H
NADPH: R=PO3
2-
Scheme 2. Biomimetic hydrogenation process.
Table 1
Optimization of the conditions of hydrogenation of
a
,b-epoxy ketones to b-hydroxy ketonesa
O
BNA+Br-, solvent
O
OH
Ph
Ph
Ph
Ph
HCOOH, Et3N, Ar, hv, rt
O
1a
2a
Entry
HCOOH (equiv)
Et3N (equiv)
Solvent (v/v = mL:mL)
Catalyst (%)
Time (h)
Conversion (%)
Isolated yield (%)
1
2
3
4
5
6
7
8
5
5
5
4
5
5
5
10
5
5
6.3
7.5
6.3
5
6.3
5.5
10
H2O
20
10
10
10
10
10
10
10
10
10
10
10
—
16
30
16
30
16
16
14
16
28
28
16
24
20
16
16
80
76
98
97
95
85
95
98
90
45
33
68
47
78
73
51
69
70b
54c
CH3CN/H2O = 2:2
Et2O/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
EtOAc/H2O = 2:2
11
9
6.3
6.3
6.3
6.3
6.3
6.3
6.3
10
11
12
13
14
15
88
d
5
5
5
5
<10
<10
24
100
88
—
e
—
7f
20
5
88
60
5
a
b
c
d
e
f
Reactions under Ar and irradiation with a 450 W high-pressure mercury lamp (k > 300 nm).
Triethylamine is substituted by diethylamine.
Triethylamine is substituted by N,N-diisopropylethylamine.
At 70 °C without h
At room temperature without h
‘––’Means no catalyst was added.
m
. ‘—’Means no product observed.
m
. ‘—’Means no product observed.

Q. Huang et al. / Tetrahedron Letters 54 (2013) 3877–3881
3879
Table 2
Substrate scope of a
,b-epoxy ketonesa,b
O
BNA+Br- (20 mol %)
OH
R2
O
EtOAc:H2O (1:1)
R1
R2
R1
O
HCOOH, Et3N, Ar, hv, rt
1a-1s
2a-2s
O
OH
O
OH
O
OH
O
2a, 88% (16 h)
OH
2b, 85% (55 h)
OH
2c, 81% (27 h)
OH
O
O
O
F
Cl
Br
2d, 78% (18 h)
OH
2e, 74% (34 h)
OH
2f, 71% (58 h)
OH
O
O
O
O
O
2g, 73% (60 h)
OH
2h, 75% (60 h)
OH
2i, 70% (30 h)
OH
O
O
O
Cl
S
2j, 83% (37 h)
2k, 73% (30 h)
2l, 80% (30 h)
O
OH Cl
O
OH Br
O
OH OCH3
2m
2n
2o
, 91% (16 h)
, 87% (20 h)
, 76% (57 h)
OH
O
O
OH
O
OH
OCH3
Br
Cl
2p, 70% (50 h)
2q, 78% (30 h)
2r, 71% (35 h)
O
OH
CH3
2s
, 78% (38 h)
a
1 (0.4 mmol), BNA+ (0.08 mmol), HCOOH (5 equiv), Et3N (6.3 equiv) were stirred in 4 mL EtOAc/H2O (1:1) at room temperature under Ar and irradiation with a 450 W
high-pressure mercury lamp (k >300 nm).
b
Isolated yields.
Other experimental conditions were also investigated. When
the reaction was carried out at room temperature or heated at
70 °C without irradiation, no product was observed (entries 11
and 12). A high temperature led to the destruction of the catalyst
in the presence of formic acid and triethylamine.14 When the reac-
tion was proceeded in the absence of BNA+Brꢀ, both the conversion
and the yield were poor (entry 13).15 However, when the amount
of BNA+Brꢀ was decreased to 5 mol %, a moderate yield (60%)
was obtained (entry 15). When the amount of BNA+Brꢀ was
increased to 20 mol %, a complete conversion and an excellent
isolated yield (88%) were obtained (entry 14).
irradiation using 20 mol % of BNA+Brꢀ as shown in Table 2. Good to
excellent yields (70–91%) were obtained in the presence of elec-
tron-donating groups or electron-withdrawing groups. Substitu-
tion at the ortho, para, or meta positions can all be well tolerated
(2k–2s). When the R1 is substituted by the 2-furyl group or the
2-thienyl group, the reaction can also proceed smoothly (2i and
2j). The reaction times varied with different substituents. When
R1 was substituted with electron-donating groups, the reaction
times would be long (2b, 2h). When R1 was substituted with halo-
gen-containing phenyl groups, the reaction times increased with
weakening ability of electron-drawing (2d–2f). When R2 is substi-
tuted with 2-halogen phenyl groups, the reaction can proceed well
within a short time (2m, 2n). In addition, when R1 is substituted by
With the optimized conditions in hand, we explored the scope
of this reaction. Various a,b-epoxy ketones were investigated with

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Q. Huang et al. / Tetrahedron Letters 54 (2013) 3877–3881
O-
Ph
8
Ph
R1
O
O-
O
7
O-
R2
O
Ph
Ph
Ph
BNAH
Ph
O
O
O
O-
6
O
10
R1
R2
R2
R1
9
BNA
5
O
BNAH
O
Ph
O
O-
Ph
12
O-
O
3
R1
R2
Ph
Ph
BNAH
R2
11
O
O
H2O
BNA
R1
OH
O
O
1
O
OH
R2
Ph
Ph
R1
HCOOH, Et3N
OH
2
4
Scheme 3. A proposed mechanism for the reactions.
a,b-epoxy ketone (1a) was under the air instead of argon, both
the conversion and the yield were poor, which was consistent with
Table 3
the phenomenon of the former work about the hydrogenation of
Catalytic hydrogenation of 1,2-diketones mediated by BNA+Br
a
,b-epoxy ketones.9,12b In addition, a catalytic amount of BNAH
BNA+Br- (20 mol%)
HCOOH, Et3N
could also reduce a
,b-epoxy ketone as efficiently as BNA+Brꢀ, indi-
OH
O
O
R2
R2
OH
4'
cating a turnover of the redox couple.9
R2
R1
R1
R1
Based on the above results and relevant literatures,12b,16 a rad-
ical mechanism is proposed for this reaction, as shown in Scheme 3.
First, BNA+ is transformed into 1-benzyl-1,4-dihydronicotinamide
(BNAH) in the presence of a mixture of HCOOH/Et3N.9,10,14,17 Sec-
ond, an electron from BNAH is given to 1 (or 3) to form an anionic
radical 5 (or 6) and BNAH+Å. Third, a carbon–oxygen bond cleavage
occurs to convert 5 (or 6) into 7 (or 8). Then, a proton is transferred
from BNAH+Å to 7 (or 8) followed by an enol/keto tautomerization
to form 9 (or 10) and BNAÅ. Next, 9 (or 10) accepts an electron
transferred from BNAÅ to turn into 11 (or 12) while the BNA+ is
regenerated. At last, the reaction is completed with the protonation
of 11 (or 12) by water.
EtOAc (2 mL) / H2O (2 mL)
Ar, hv, rt
O
O
3
4
Entry
R1
R2
Products
Yielda (%) (ratiob 4/40)
1
2
3
C6H5
C6H5
C6H5
C6H5 3a
4-FC6H4 3b
4-MeOC6H4 3c
4a
4b/4b0
4c/4c0
85
62 (1.1:1)
74 (6.3:1)
a
Isolated yields.
The ratio of 4/40 was determined by 1H NMR spectrum.
b
In conclusion, an efficient method has been developed to
the tert-butyl or the methyl group, unfortunately, no detectable
product was observed. This probably was due to that the aliphatic
anionic radical 5 would be quite unstable if R1 was substituted by
aliphatic groups. So 1 can hardly be converted to 5 and the reaction
can hardly proceed (see Scheme 3).
transform
a,b-epoxy ketones or benzil into corresponding
b-hydroxy ketones or benzoin using a BNAH (or BNA+Brꢀ) as a
catalyst. As far as we know, this is the first time to achieve the
hydrogenation catalyzed by an NAD+/NADH co-enzyme model
employing the mixture of HCOOH/Et3N in the absence of any
metal complex or enzyme. More applications of this protocol
are under exploration.
Further investigations were carried out on the feasibility of
other type of substrates. To our surprise, benzil (3a) could be con-
verted to benzoin (4a) with the above reaction condition, as shown
in Table 3.8d However, it was difficult to convert benzil completely
to benzoin. When the reaction time was extended to 66 h, a good
yield (85%) was obtained using formic acid and triethylamine cat-
alyzed by BNA+Brꢀ (20 mol %) in the solvent of EtOAc/H2O (1:1)
(Table 3, entry 1). Next, we tested the selectivity of substituted
benzil under this catalytic system. When we employed 3c as the
substrate, we found that the carbonyl groups next to the phenyl
rings without electron-donating groups tended to be reduced eas-
ier (Table 3, entry 3). However, when one of the phenyl rings of
benzil was substituted with the 4-fluoro phenyl group, the selec-
tivity would be not obvious (Table 3, entry 2).
Acknowledgments
We gratefully acknowledge financial support from the
National Natural Science Foundation of China (Nos. 21272050,
21072040, 21071040) and the Program for New Century Excellent
Talents in University of the Chinese Ministry of Education (NCET-
11-0627).
Supplementary data
In order to study the possible mechanism of the reactions, more
experiments were performed. When the reaction of reducing
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.047.

Q. Huang et al. / Tetrahedron Letters 54 (2013) 3877–3881
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