Synthesis of α-alkenyl-α-amino esters via addition of potassium Alkenyltrifluoroborate salts to imine in the presence of Yb(OTf)3

Article abstract of DOI:10.1016/j.tetlet.2013.08.133

A simple protocol which led to an effective construction of α-alkenyl-α-amino esters was achieved under mild conditions. This transformation proceeded by Yb-catalyzed addition of alkenyltrifluoroborates across the imine double bond. A variety of functional groups could be applicable to both partners.

Full text of DOI:10.1016/j.tetlet.2013.08.133

Tetrahedron Letters 54 (2013) 6204–6207
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of
a-alkenyl-a-amino esters via addition of potassium
Alkenyltrifluoroborate salts to imine in the presence of Yb(OTf)3
a
a
b
b
Hélio A. Stefani a, , Amna N. Khan , Flávia Manarin , Pedro H. Vendramini , Marcos N. Eberlin
⇑
a Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil
b Instituto de Química, Universidade Estadual de Campinas, Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple protocol which led to an effective construction of
a
-alkenyl-
a
-amino esters was achieved under
Received 7 August 2013
Revised 26 August 2013
Accepted 30 August 2013
Available online 7 September 2013
mild conditions. This transformation proceeded by Yb-catalyzed addition of alkenyltrifluoroborates
across the imine double bond. A variety of functional groups could be applicable to both partners.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Vinyltrifluoroborate
Amino acid
Addition reaction
Lewis acid
Ytterbium
Introduction
In a previous attempt, a rhodium catalyst along with the ligand
upon heating resulted in the formation of
a-branched allylic
b,
c
-Unsaturated
a
-amino acid derivatives, a unique class of
amines.3a,b Herein, we would like to present a very simple reaction
protocol which has not only eliminated the use of an expensive
metal catalyst, but also eradicated the role of any ligand.3a Further-
more, our reaction proceeds under mild conditions for which the
aid from a base, co-solvent, or heat is not required. Thus, it is worth
studying ytterbium-catalyzed nucleophilic addition of potassium
organotrifluoroborate to carbon heteroatom multiple bonds.
non-proteogenic amino acids, are the main structural motifs pres-
ent in the realm of many biologically active natural compounds as
well as pharmaceuticals.1 The biological properties of certain ami-
no acids and their derivatives are greatly affected by the presence
of unsaturation in the side chain, which not only alters the meta-
bolic activities of certain microorganisms, thus imparting potential
therapeutic advantages, but also plays an important role in chem-
ical transformation as well as chemical stapling.2
Results and discussion
In the past decade, a great number of methods have been devel-
oped to access these valuable compounds.1a In contrast, from a
We initiated our studies using PMP-protected
a-imino esters,
synthetic standpoint, b,c-alkenyl-a-amino acid derivatives are still
along with trans-styryltrifluoroborate, as they could be readily syn-
thesized and are more stable than their corresponding imines. Fur-
thermore, deprotection of the resulting products could be achieved
under mild conditions using cerium ammonium nitrate (CAN).6 In
the absence of any catalyst, the reaction of potassium trans-styryl-
challenging to make up. To date, only a few precedents are avail-
able.3 However, to the best of our knowledge, approaches toward
an important synthon for
acid derivatives, that explore the addition of potassium alkenyltri-
a-amino acids, b,c-unsaturated a-amino
fluoroborate salts to a-imino esters catalyzed by ytterbium triflate
trifluoroborate with an
a-imino ester did not deliver the desired
are hitherto unprecedented.4
product in reasonable yield (Table 1, entry1).
Potassium organotrifluoroborate salts have ousted their corre-
sponding boronic acids because these air- and moisture-stable
monomeric trifluoroborates can be easily prepared, have tremen-
dous oxidative and thermal stability, and predictable reactivity
patterns which ameliorates the yield of the desired products.5
Then, we envisioned that the addition of potassium alkenyltri-
fluoroborate to
a-imino esters using an appropriate metal activator
should readily provide the
a
-alkenyl -amino acid derivative
a
(Table 1). By taking advantage of the numerous synthetic applica-
tions of Lewis acids, the robustness of this method was explored.
We found that 10 mol % loading of Lewis acids, such as Sc(OTf)3,
Cu(OTf)2, Inbr3, MnCl2, or AgOTf furnished the corresponding
⇑
Corresponding author. Tel.: +55 11 3091 3654; fax: +55 11 3815 4418.
E-mail address: hstefani@usp.br (H.A. Stefani).
a
-alkenyl-a-amino acid derivatives in CH3NO2 at ambient
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.133

H. A. Stefani et al. / Tetrahedron Letters 54 (2013) 6204–6207
6205
Table 1
Table 2
Screening of Lewis acids for the addition of alkenyltrifluoroborate to
a
-imino esters
Addition of various alkenyltrifluoroborates to PMP-protected
a
-imino esters
OMe
OMe
OMe
Ph
OMe
R
Lewis acid (10mol%)
Solvent, N2, rt, 2h
Yb(OTf)3 (10 mol%)
N
HN
HN
N
+
+
EtO
EtO
EtO
EtO
BF3K
BF3K
CH2Cl2, N2, rt, 2h
R
H
H
Ph
O
O
O
O
3a-k
2
1
Entry
Catalyst
—
Sc(OTf)3
Cu(OTf)2
InBr3
Base
Yield (%)
1
2
3
4
5
6
7
8
9
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH2Cl2
Dioxane
THF
<10
42
42
41
18
43
66
70
43
50
54
40
#
1
Alkenyltrifluoroborate
Product
Yield (%)
70
OMe
OMe
OMe
OMe
HN
MnCl2
AgOTf
EtO
BF3K
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
O
10
11
12
HN
2
3
4
43
54
21
CH3CN
MeOH
EtO
BF3K
O
HN
temperature in a period of 2 h, in 18–66% yield. Among them,
Yb(OTf)3 was found to be the most effective catalyst (Table 1, entry
7).
BF3K
EtO
O
In continued pursuit of our goal to find the optimal reaction
conditions, the screening of commonly used solvents with Yb(OTf)3
revealed the suitability of this reaction with dichloromethane
(Table 1, entry 8), which provided the best results in terms of yield.
After having optimized the reaction conditions in hand,7 the
general utility and scope of the reaction was explored. As summa-
rized in Table 2, a variety of alkenyltrifluoroborates were success-
BF3
K
HN
EtO
O
BF3K
OMe
OMe
fully reacted with different
a
-imino esters, under same reaction
5
82
HN
EtO
conditions to afford the corresponding products with moderate
to good yields.
O
To verify the reactivity of different a-amino esters on the addi-
tion reaction of alkenylltrifluoroborate salts, a variety of imines
(Table 3) were randomly chosen to prepare the corresponding ami-
no esters under described reaction conditions.7 In general, the
addition reactions of alkenyltrifluoroborates with respect to the
BF3K
6
7
72
HN
EtO
EtO
O
coupling partner highlighted that
tron-donating group on the aromatic ring afforded the best results
in terms of yield (Table 3, entries 1, 3 and 4), while -imino esters
a-imino esters with an elec-
OMe
BF3K
a
HN
0
with an electron-withdrawing substituent proved to be less reac-
tive and resulted in low isolated yield (Table 3, entry 2).
Real-time infrared techniques8–10 were used to delve deeper
into the reaction and provide a useful reaction outcome; the reac-
tion between potassium trans-styryltrifluoroborate salts and ethyl
2-(4-methoxyphenylimino)acetate was chosen for this investiga-
tion. It was found that, after the addition of trans-styryltrifluorob-
orate, the characteristic band of imine at 1595 cmÀ1 slowly
disappeared (see Supplementary data), indicating that the reaction
had progressed to completion.
O
bond, forming intermediate(II). Finally, intermediate(II) is proton-
ated by aqueous work-up, leading to the alkenyl amine and regen-
erating the active Yb(III) triflate.
An interesting aspect of the use of rare earth metal triflates12 is
that the catalyst can be recovered from the reaction medium and
recycled. This prompted us to evaluate the possibility of reusing
Yb(OTf)3 in our reactions. We were able to re-isolate the catalyst
from the reaction medium by filtration, sequential washing with
dichloromethane, and drying at 70 °C for 2 h. This process was re-
peated twice, affording the desired product in 82% (first run), 77%
(second run), and 65% (third run) yield, as shown in Figure 2.
Initial mechanistic studies were undertaken to elucidate the
details of the Yb(OTf)3-mediated activation of
a-imino esters.
Matteson11 and Kim demonstrated that Lewis acid activated
alkenyltrifluoroborates to intermediate dihaloboranes, which is
the active species in the reaction. In this way, a possible mecha-
nism for this Yb(III)-catalyzed alkenylation is proposed in Figure 1.
In the first step, the electrophilic alkenyldifluoroborane gener-
ated in situ by the reaction between the corresponding alkenyltri-
fluoroborate salt 2 and the Lewis acid11 forms a nitrogen-boron
Conclusion
In conclusion, a particularly efficient and operationally trouble-
complex(I) with the
a
-imino ester. This complexation facilitates
free Lewis acid catalyzed
a-imino ester C-alkenylation has been
the migration of the alkenyl group from the boron to the C@N
established. This method is worth considering as an unsaturation

6206
H. A. Stefani et al. / Tetrahedron Letters 54 (2013) 6204–6207
Table 3
Addition of alkenyltrifluoroborates to various with a-imino esters
R
HN
R2
R
H
R2
R3
R1
N
Yb(OTf)3 (10 mol%)
CH2Cl2, rt, N2 ,2h
EtO
+
R3
EtO
BF3K
R1
O
O
1
2
3h-k
Entry
1
Alkenyltrifluoroborate
Imino ester
Product
Yield (%)
80
BF3K
OMe
NO2
Cl
OMe
NO2
Cl
N
N
N
N
HN
EtO
EtO
EtO
EtO
EtO
EtO
EtO
EtO
O
O
O
O
O
BF3K
BF3K
BF3K
2
3
4
HN
13
84
90
O
HN
O
I
I
HN
O
O
O
Ph
HN
N
O
NH
Yb(OTf)3 (10 mol%)
CH2Cl2, r.t.
R
+
EtO
EtO
O
BF3K
Yb(OTf)3
R
O
O
BF3K
3e
NR1
F
R
+
B
EtO
3
F
F
O
F
B
F
R
F
N
R1
R1
B
N
2
1
O
O
R
TfO
TfO
TfO
TfO
Yb
F
O
Yb
F
O
(I)
(II)
0
50
100
yield (%)
Figure 2. Recyclability of the catalyst.
Figure 1. Proposed mechanism for the addition reaction of alkenyltrifluoroborates
to -imino esters.
a
Supplementary data
since the product offers a versatile scaffold for further useful
derivatization. It also provides the additional advantage of catalyst
recovery.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
08.133.
Acknowledgments
References and notes
The authors gratefully acknowledge financial support by the
São Paulo Research Foundation (FAPESP—grant 2012/00424-2,
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