Biomimetic reductive amination of perfluoroalkylcarboxylic acids to α,α-dihydroperfluoroalkylamines

Article abstract of DOI:10.1016/S0040-4039(02)01104-8

The first general method for the reducing reagent-free, biomimetic transformation of perfluorocarboxylic acids to the α,α-dihydroperfluoroalkyl amines is reported. High chemical yields and simplicity of the experimental procedure render this method immediately useful and synthetically superior to the conventional approaches relying on application of reducing reagents.

Full text of DOI:10.1016/S0040-4039(02)01104-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5449–5452
Biomimetic reductive amination of perfluoroalkylcarboxylic acids
to a,a-dihydroperfluoroalkylamines
Vadim A. Soloshonok,a,* Hironari Ohkuraa and Kenji Uneyamab
aDepartment of Chemistry and Biochemistry, University of Oklahoma, 620 Parrington Oval, Room 208, Norman,
OK 73019-3051, USA
bDepartment of Applied Chemistry, Faculty of Engineering, Okayama University, Okayama 700, Japan
Received 20 March 2002; revised 5 June 2002; accepted 6 June 2002
Abstract—The first general method for the reducing reagent-free, biomimetic transformation of perfluorocarboxylic acids to the
a,a-dihydroperfluoroalkyl amines is reported. High chemical yields and simplicity of the experimental procedure render this
method immediately useful and synthetically superior to the conventional approaches relying on application of reducing reagents.
© 2002 Elsevier Science Ltd. All rights reserved.
An amino group is one of a few truly fundamental
functionalites of organic molecules and is critically
involved in basic biological processes. Therefore, the
development of novel and practical methodologies to
prepare amino-compounds continues to be a topic of
paramount importance in organic chemistry. One of the
traditional approaches to create an amino group is a
reductive amination of the corresponding carbonyl-
compounds with application of external reducing
reagents.1 For quite some time, we have been interested
in a conceptually different approach to reductive ami-
nation of carbonyl-compounds, based on an
intramolecular reduction–oxidation process via a base-
catalyzed [1,3]-proton shift in the azaallylic system of
azomethines (imines) (Scheme 1). This approach, mim-
icking the biological transamination,2 i.e. the enzyme-
catalyzed interconversion of a-amino and a-keto
carboxylic acids,3 represents the most ideal solution to
the reductive amination of carbonyl compounds
(Scheme 1) and cannot be rivaled for the synthetic
efficiency by the purely chemical methods using reduc-
ing reagents.1 We were first to discover the synthetic
potential of this reducing reagent-free biomimetic
transamination process, referred to as a base-catalyzed
[1,3]-proton shift reaction (PSR), for efficient prepara-
tion of fluorine-containing amino compounds of a wide
range of potential synthetic, and biological applica-
tions.4 Previously we reported practical approaches for
biomimetic transamination, via PSR, of fluorine-con-
taining aldehydes and ketones,5 a- and b-keto car-
boxylic acids6 to the corresponding fluorinated amines
and amino acids. As an extension of our PSR method-
ology,7 we report here our successful preliminary results
on a reducing reagent-free, biomimetic reductive amina-
tion of perfluoroalkylcarboxylic acids to a,a-
dihydroperfluoroalkylamines.
H
R
R
R'
R
R
R'
+
H2N
Ph
Ph
N
N
Ph
base
R'
O
The major difference between the transamination of a
single carbonyl function, which is the case in the
reported5–7 transamination of aldehydes, ketones or
keto-acids, and a carboxylic group, is a necessity to
conduct two consecutive PSRs via formation of the
corresponding intermediate aldehyde 4 or its derivative
3 (Scheme 2). Moreover, the carboxylic group should
be transformed to a derivative of type 1, 2 to mimic the
single carbonyl function, since the presence of acidic
NH or OH groups might interfere with a successful
outcome of PSR.5–7 To avoid an undesirable isolation
(and purification) of the intermediate aldehyde 4, one
[1,3]-PSR
R'
+
H
O
Ph
NH2
Scheme 1.
Keywords: biomimetic reactions; reduction; amination; fluorine and
compounds; amines.
* Corresponding author. E-mail: vadim@ou.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01104-8

5450
V. A. Soloshonok et al. / Tetrahedron Letters 43 (2002) 5449–5452
OH
X
X
Ph
R
O
R
O
R
X
N
1
2
[1,3]-PSR
base
Ph
Ph
Ph
H
R
O
R
R
N
R
R
N
5
X
R
N
3
4
base
Ph
[1,3]-PSR
base
Ph
Ph
H
H
H
N
N
6
X
R
N
H
O
R
NH2
8
7
Scheme 2.
could envision transformation of the derivative 3 to
Schiff base 5. This process, occurring without any
change in the carbon atoms’ oxidation state, would
afford the product 5 capable of undergoing the PSR
giving rise to the derivative 6 subsequent hydrolysis
(two steps) of which could lead to the target amino-
compound 8 (Scheme 2). Analysis of the relevant litera-
ture has revealed that the desired type of
transformation, the isomerization of 3 to 5, could be
observed when the substituent X is chlorine,8 phospho-
rus- [-P(O)(OAlk)2; -PPh2; -P(O)Ph2]9 or sulfur-contain-
ing [-S-Aryl; -SP(S)(OEt)2; -SP(S)Ph2]10 groups. This
transformation was shown to take place at high temper-
atures (usually >100°C), giving rise to a mixture of
products of type 3 and 5 as a function of their thermo-
dynamic stability. In particular, Tanaka and co-
workers8e–f reported that the isomerization of N-ben-
zyl-2,2,2-trifluoroacetimidoyl chloride (11a) (Scheme 3)
to N-(2,2,2-trifluoroethyl)benzimidoyl chloride (14a)
could be achieved with low-to-moderate chemical yields
(49–78%) by heating (reflux) of the former in toluene
solution. While this type of transformation, as believed
to proceed through the corresponding nitrile ylides, has
found some limited (low chemical yields and stereose-
lectivity) synthetic applications for preparing various
heterocyclic compounds via [3+2]-cycloadditions,8a,8e–f
it was never recognized and realized, whatsoever, as an
important step in the direct preparation, designed by
us, of the amino compounds 16 starting from the
carboxylic acids 9 (Scheme 3). The synthetic problems,
usually associated with preparation of the derivatives of
type 3 and their transformation to compounds 5
(Scheme 2) are: (a) reversibility and therefore incom-
plete transformation of 3 to 5; (b) harsh reaction condi-
tions (high temperature: usually >100°C), and (c)
unsatisfactory chemical yields (up to 80%).8–10 These
discouraging literature data, in particular, the unsatis-
factory chemical yields, seemed to plague our goal of
developing
a synthetically practical and efficient
method for direct transformation of fluorinated car-
boxylic acids 9 to the corresponding amines 16. How-
ever, we reasoned that studying in detail each of the
seven reactions, according to Scheme 3, would put us in
position to face up to the challenge. First, we prepared
N-benzylamide 10a and, using the literature
procedures8e–f,11 converted it, in a moderate yield (up to
75%), to the imidoyl chloride 11a. Treatment of com-
pound 11a with triethylamine (TEA) at room tempera-
ture brought about smooth and complete [1,3]-proton
shift transfer giving rise to the Schiff base 12a.12
According to the literature data,8e–f further transforma-
tion of 12a to 13a and 14a requires relatively harsh
reaction conditions, as for instance prolonged heating
of 12a in a boiling toluene, thus suggesting that the
chlorine transfer might be a rate-limiting step in our
design.13 Therefore, we concentrated our efforts on
finding a way to facilitate this critical transformation.
Drawing inspiration from the results reported by
Onus’ko and co-workers on [1,3]-phosphorotropic
shifts,9 we found that addition of catalytic amounts of
PPh3/TEA to a solution of 11a in chloroform substan-
tially accelerates its transformation to the imidoyl chlo-
ride 14a, through the intermediate products 12a and
13a. Thus, in the presence of PPh3/TEA the desired
isomerization of 11a to the imidoyl chloride 14a was
observed even at room temperature albeit with low
reaction rate, requiring about 3 days for the comple-
tion. At elevated temperature (boiling chloroform) the
PPh3/TEA-catalyzed isomerization was found to pro-
ceed with substantially higher rate (less than 1 h),
affording clean and quantitative transformation of 11a
Rf
O
Rf
Cl
Rf
Cl
Rf
O
i or ii
iv
iii
N
Ph
N
Ph
N
Ph
OH
9a-c
H
10a-c
11a-c
12a-c
vii
Rf
Rf
Rf
Rf
vi
v
HCl NH2
N
Ph
N
Ph
N
Ph
H
O
Cl
Cl
16a-c
15a-c
14a-c
13a-c
Rf = CF3 (a); C2F5 (b); C3F9 (c)
Scheme 3. (i) (CF3CO)2 (instead of 9a), BnNH2, CHCl3, 0°C;
(ii) Ph3P (1.6 equiv.)/CCl4 (1.07 equiv.), BnNH2 (2 equiv.),
CHCl3, reflux, 40 min; (iii) Ph3P (1.6 equiv.)/CCl4 (1.07
equiv.), CHCl3 reflux, 40 min; (iv) Ph3P/TEA (cat.), CHCl3,
reflux, 40 min; (v) TEA (3 equiv.)/H2O (2 equiv.), CHCl3
reflux, overnight; (vi) MeOH/HCl (conc.) 2/1 v, reflux, 24 h;
(vii) BnNH2 (1 equiv.), Ph3P (4 equiv.)/CCl4 (4 equiv.), TEA
(1.5 equiv.), CHCl3 reflux, 40 min, then (v) and (vi).

V. A. Soloshonok et al. / Tetrahedron Letters 43 (2002) 5449–5452
5451
to 14a. The catalytic role of PPh3/TEA could be ratio-
nalized assuming that TEA facilitates the [1,3]-proton
shifts (from 11a to 12a and from 13a to 14a), while
PPh3 might accelerate the chlorine transfer (from 12a to
13a) through intermediate formation of the correspond-
ing phosphonium salt.9 The imidoyl chloride 14a was
subjected first to TEA-catalyzed hydrolysis to furnish
amid 15a which then was hydrolyzed using MeOH/HCl
to afford the target hydrochloride 16a.
reaction conditions is accompanied by partial dehy-
drofluorinaton of the perfluoroalkyl moieties, pre-
sumably on the stage of 12b,c to 14b,c isomerizations.
These results demonstrated that while the reaction con-
ditions for the perfluoroalkyl substrates are still in need
of some improvement, the developed method could be
generally applied for direct transformation of
perfluorocarboxylic acids to the corresponding amines.
In summary, the first general method for the reducing
reagent-free, biomimetic transformation of perfluoro-
carboxylic acids to the a,a-dihydroperfluoroalkyl
amines is reported. High chemical yields and simplicity
of the experimental procedure render this method
immediately useful and synthetically superior to the
conventional approaches relying on application of
reducing reagents. Currently we are working on further
improvement and generalization of the method to
embrace partially fluorinated and fluoroaromatic
compounds.
Having thus developed the stepwise procedure, we next
concentrated our efforts on a preparatively useful one-
pot protocol. Since PPh3/TEA was found to accelerate
the most crucial step, the chlorine transfer from 12a to
13a, we decided to use PPh3/CCl4 as a reagent which
was demonstrated to be useful for preparation of car-
boxamides from carboxylic acids and primary amines14
and for preparation of the corresponding imidoyl chlo-
rides from N-mono-substituted carboxamides.11 More-
over, one of us has previously reported successful
application of PPh3/CCl4 for the direct transformation
of perfluoroalkylcarboxylic acids to the corresponding
N-(alkyl)-, -(aryl)imidoyl chlorides.15 However, critical
examination of the reported chemical yields of the
products using these methods suggested incomplete
transformation (on average 85% or less) of the starting
compounds or formation of some byproducts. There-
fore we assumed that while the original
procedures11,14,15 are highly synthetically valuable for
one- or two-reaction transformations, the direct appli-
cation of these methods for the one-pot seven-reactions
process designed by us (Scheme 3) would not be suc-
cessful. Thus, we decided to study each of the chlorina-
tion steps (9a to 10a and 10a to 11a) in every detail to
find the conditions allowing for quantitative prepara-
tion of compounds 10a and 11a. After the series of
experiments varying the ratios of the starting com-
pounds we finally determined that the reagent PPh3/
CCl4 must be used in a ratio 1.30/1.07, respectively, to
achieve complete transformation of the acid 9a and
benzylamine to the amid 10a. The same excess of
PPh3/CCl4 (1.30/1.07) was found to be effective for
quantitative preparation of 11a from 10a, followed
PPh3/TEA-catalyzed isomerization of 11a to 14a. With
these results in hand we conducted direct preparation
of amine 16a starting with trifluoroacetic acid (9a).
One-pot preparation of 14a from 9a, followed by two
hydrolyses afforded the target amine 16a in 94% iso-
lated yield.16 Taking into account that the whole proce-
dure involves seven reactions, the obtained yield of 16a
was truly remarkable. This procedure was successfully
applied on 10 g scale demonstrating its preparative
value and reliability. Inspired by these results we
attempted to use this procedure for preparing fluori-
nated amines 16b,c starting with perfluoropropionic
(9b) and -buturic (9c) acids, respectively. Under the
same one-pot conditions developed for transformation
of 9a to 16a, the perfluorocarboxylic acids 9b,c were
smoothly converted to the target amines 16b,c, albeit
with noticeably lower chemical yields (up to 70%).
Based on some preliminary data, we can assume that in
sharp contrast to the transformation of 9a to 16a,
preparation of 16b,c from 9b,c, under the standard
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V. A. Soloshonok et al. / Tetrahedron Letters 43 (2002) 5449–5452
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(19.704 mmol) in CHCl3 (4 mL) at 0°C and under air
atmosphere TEA (7.389 mmol), fluoroalkylcarboxylic
acid 9a–c (4.926 mmol), benzylamine (4.926 mmol) and
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mixture was stirred for 10 min. After that, the mixture
was stirred for 40 min at 80°C. The resultant mixture was
evaporated and treated with AcOH (10 mL) and hexane
(30 mL). The AcOH phase was separated and washed
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washed with NaHCO3 and evaporated. The residue
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and stirred at 80°C for 12 h. The resultant mixture was
evaporated and treated with conc. hydrochloric acid (5
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