First example of continuous-flow reaction conditions for biomimetic reductive amination of fluorine-containing carbonyl compounds

Article abstract of DOI:10.1016/j.jfluchem.2008.05.019

This study presents the first example of continuous-flow reaction conditions for biomimetic reductive amination of fluorinated carbonyl compounds using silica-adsorbed DBU as catalyst for on-column process. This new on-column process features operationall

Full text of DOI:10.1016/j.jfluchem.2008.05.019

Journal of Fluorine Chemistry 129 (2008) 785–787
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
First example of continuous-flow reaction conditions for biomimetic
reductive amination of fluorine-containing carbonyl compounds
a
Vadim A. Soloshonok a,b, , Taizo Ono
*
a National Institute of Advanced Industrial Science and Technology (AIST), 2266 Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Aichi 463-8560, Japan
b Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States
A R T I C L E I N F O
A B S T R A C T
Article history:
This study presents the first example of continuous-flow reaction conditions for biomimetic reductive
amination of fluorinated carbonyl compounds using silica-adsorbed DBU as catalyst for on-column
process. This new on-column process features operationally convenient conditions, higher chemical
yields and purity of products as compared with traditional in-flask reactions. Furthermore the removal of
base-catalyst is not an issue in this process at all, as the catalyst (DBU) remains on the column in the
‘‘reaction zone’’, the feature which makes the overall process substantially more efficient and
Received 2 May 2008
Received in revised form 24 May 2008
Accepted 29 May 2008
Available online 5 June 2008
Keywords:
inexpensive, in particular, for large-scale synthesis of the target
a-perfluoroalkyl amines.
1,3-Proton shift reaction
On-column reactions
ß 2008 Elsevier B.V. All rights reserved.
Continuous-flow reactions biomimetic
reductive amination
Fluorinated amino compounds
Biological transamination [1] (BTA) is among the most
fundamental biological processes, providing a unique chemical
solution to the reduction–oxidation processes that all living forms
have adopted through the process of evolution. In particular, one of
the most important biological transformations using BTA is the
The first synthetic application of this biomimetic approach was
reported by Corey’s group who used the base-catalyzed imine–
imine isomerization to achieve oxidative deamination, a key
reaction step in several total syntheses of natural products [5a].
Other groups [5b–i] have developed even more efficient reagents
and conditions for generalized transformations of amines to the
corresponding carbonyl compounds.
On the other hand, the opposite transformation, reductive
amination of carbonyl compounds, was found to be more difficult
to realize, producing only a limited number of successful examples
[6]. In sharp contrast to the not-so-successful application of the
biomimetic approach for reductive amination of conventional
carbonyl compounds, it was found that imines 9 (Scheme 2),
interconversion of
a-keto and a-amino acids, catalyzed by
pyridoxamine/pyridoxal-dependent enzymes [2]. Numerous
investigations of the native [3] BTA and its various chemical
models [4] have contributed to a reasonably detailed under-
standing of the corresponding mechanism including a rationale for
the observed stereochemistry. Thus, in a simplified form, the
mechanism of BTA involves a base-catalyzed 1,3-proton shift
across the azaallyllic system of imine 3 resulting in a transposition
of the imine-functionality and a formation of the isomeric imine 4
(Scheme 1).
derived from
(aldehydes [7], ketones [7], including
a
-trifluoromethyl-containing carbonyl compounds 8
-keto acids [8] and -keto
a
b
As one can envision, this biological reduction–oxidation process
via a base-catalyzed 1,3-proton shift could find a synthetic
application for biomimetic oxidative deamination/reductive ami-
nation reactions, starting, in general, with amine 1 and ketone/
aldehyde 2, and ketone/aldehyde 5 and amine 6, respectively.
acids [9]) and benzylamine (7) readily undergo virtually irrever-
sible isomerization to imines 10 under the action of regular organic
bases (TEA, DBU, DBN, and guanidine). Easy hydrolysis (acid-
catalyzed) of compounds 10 afforded various fluorinated amines
12 and benzaldehyde (11). This biomimetic method is general,
affordable and truly practical for large-scale preparations of
various fluorinated amines [10],
a- and b-amino acids. An
asymmetric version of this process, using chiral derivatives of
benzylamine, has also been developed [11].
However, in spite of the high synthetic value of this biomimetic
reductive amination for the preparation of fluorinated amines and
amino acids, its application with major advantages over the
* Corresponding author at: National Institute of Advanced Industrial Science and
Technology (AIST), 2266 Anagahora, Shimoshidami, Moriyama-ku, Nagoya, Aichi
463-8560, Japan.
E-mail address: vadim@ou.edu (V.A. Soloshonok).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.05.019

786
V.A. Soloshonok, T. Ono / Journal of Fluorine Chemistry 129 (2008) 785–787
Scheme 1. General mechanism for biomimetic oxidative deamination/reductive animation.
Scheme 2. Biomimetic transamination of fluorinated carbonyl compounds.
conventional reduction amination methods, the intramolecular
reduction–oxidation processes, has never been evaluated. Thus, we
have envisioned that since this biomimetic process do not require
13a–f to products 14a–f was found to depend heavily on
concentration of 13a–f, amount of DBU and rate of the elution.
Preliminary optimization of these parameters indicated that for a
given amount of the catalyst (see above) the imine concentration of
10 mol% and the elution rate about 1 drop/s from the column tip
provide for complete isomerization of starting imines 13a–f to
products 14a–f. The structure and purity of the products 14a–f,
conveniently collected from the column’s tip, were determined by
NMR.
the use of external reducing reagents,
a conceptually new
continuous-flow reductive amination process can be developed.
Here we report the first example of continuous-flow reaction
conditions for biomimetic reductive amination of fluorinated
carbonyl compounds using silica-adsorbed DBU as catalyst for on-
column process.
To demonstrate the proof of principle for the continuous-flow
reaction using the principle of biomimetic transamination, we
designed an extremely simple apparatus shown in Scheme 3. Thus,
the usual glass column was filled about 1/2 with a regular silica gel
(hexanes). Next, a calculated amount of DBU [12,13] (0.25 wt% of
the whole amount of silica gel) in a solution of dichloromethane
was charged carefully onto the top and allowed to percolate down
to the surface. Then an additional amount (1/4 of the whole
amount) of silica gel was charged carefully onto the column.
According to our experimental data, the DBU penetrates into the
silica gel to occupy about 1/4 of the whole silica gel column
volume. Thus prepared column consists of three functional parts:
protection zone (to prevent the direct contact of the starting
materials with DBU) (about 1/4 of the volume), reaction zone (1/4)
and purification zone (1/2). Fluorine-containing imines 13a–f,
prepared by standard procedures [7k] were charged onto the
column using a mixture of hexanes/acetonitrile (4/1) as a solvent.
As one can expect, the rate of the isomerization of starting imines
The experimental data collected in Table 1 on the isomerization
of series of aldimines 13a–e and ketimine 13f to the target
products 14a–f clearly demonstrate for the superior efficiency of
the continuous-flow reaction conditions (on-column) as compared
with the conventional (in-flask) procedure. Thus in all cases
studied the products 14a–f were obtained in higher chemical
yields and purity [7k] allowing for their further synthetic
transformations (hydrolysis) without any purification. The dur-
ability of the catalyst used in this continuous-flow reaction
procedure is currently under investigation. However, we can
report at least a successful preparation 2Kg+ of product 14a using
only 10 g of the on-column catalyst.
Generalization of this novel continuous-flow reaction proce-
dure for various different types of starting compounds and
catalysts, large-scale preparations and its application for asym-
metric transformations are currently under investigation.
In summary, the first example of
a conceptually new
continuous-flow reaction procedure for biomimetic transamina-
tion of fluorinated carbonyl compounds has been developed. As
follows from the results obtained, the new procedure might be
substantially more efficient, practical and operationally conveni-
ent as compared with the currently used conventional methods.
We believe that this new dimension in the biomimetic transami-
nation will further increase its synthetic efficiency leading to the
development of ultimately practical, environmentally benign and
metal-free reductive amination for the preparation of fluorinated
amino compounds.
Table 1
Continuous-flow base-catalyzed isomerization of 13a–f to 14a–f
13
R
RF
Yield of 14 (%) [7k]
a
b
c
d
e
f
H
H
H
H
H
Ph
CF3
>98 (87)
95 (86)
96 (89)
92 (89)
95 (90)
>98 (93)
C3F7
C4F9
H(CF2)4
H(CF2)6
CF3
Scheme 3.

V.A. Soloshonok, T. Ono / Journal of Fluorine Chemistry 129 (2008) 785–787
787
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