The simple and selective synthesis of 3-amino-2,2-difluorocarboxylic esters and difluoro-β-lactams using ethyl bromodifluoroacetate in the presence of rhodium catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.09.031

Treatment of imines (5) with ethyl bromodifluoroacetate (1) and Et ₂Zn in the presence of RhCl(PPh₃)₃ in anhydrous medium gave difluoro-β-lactams (7) in good to excellent yields, while 3-amino-2,2-difluorocarboxylic esters (6) were obtained in good yields by adding MgSO₄·7H₂O to the reaction medium.

Full text of DOI:10.1016/j.tetlet.2005.09.031

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7679–7681
The simple and selective synthesis of
3-amino-2,2-difluorocarboxylic esters and difluoro-b-lactams
using ethyl bromodifluoroacetate in the presence of rhodium catalyst
Kazuyuki Sato, Atsushi Tarui, Seiji Matsuda, Masaaki Omote, Akira Ando*
and Itsumaro Kumadaki*
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
Received 17 August 2005; revised 29 August 2005; accepted 8 September 2005
Available online 22 September 2005
Abstract—Treatment of imines (5) with ethyl bromodifluoroacetate (1) and Et2Zn in the presence of RhCl(PPh3)3 in anhydrous
medium gave difluoro-b-lactams (7) in good to excellent yields, while 3-amino-2,2-difluorocarboxylic esters (6) were obtained in
good yields by adding MgSO4Æ7H2O to the reaction medium.
Ó 2005 Elsevier Ltd. All rights reserved.
The b-lactam antibiotics including penicillins and ceph-
alosporins have been used widely in the clinical field.
Their biological activity is recognized as inhibition of
the enzyme synthesizing bacteriaꢀs cell walls.1 b-Lactam
ring is known as an important component to exhibit the
antibiotic effect. Furthermore, b-lactams are one of the
most important synthetic intermediate for the b-amino
acid derivatives. Although both b-lactam and b-amino
acid derivatives can be easily synthesized using Refor-
matsky-type reaction2 or aldol-type reaction3 of imines,
the selective synthesis of these compounds is difficult.
unsaturated ketones (2) in the presence of Et2Zn and
RhCl(PPh3)3 to give the novel products (3), where the
CF2COOEt group was introduced to the a-position of
a,b-unsaturated ketones, or the Reformatsky-type 1,2-
addition product (4) in good yields selectively by choos-
ing the solvents (Scheme 1).7
In order to extend our previous results, we attempted to
examine the reaction of imines with 1 and Et2Zn in the
presence of RhCl(PPh3)3. Honda et al. reported that the
reaction of BrCH2COOEt and imines (5) with Et2Zn in
the presence of RhCl(PPh3)3 gave the b-lactams and 3-
aminocarboxylic esters depending on the solvents and
temperature.8 Generally, the Reformatsky reaction
using halodifluoroacetate and imines with Zn powder
gave the difluoro-b-lactams (7).9 So we expected that 6
and 7 could be synthesized selectively by the examina-
tion of reaction conditions.
On the other hand, rhodium mediated organic reaction
is one of the most useful carbon–carbon bond formation
procedures. This can be used for carbonylation, hydro-
genation, and methathesis.4 The rhodium-catalyzed
1,4-addition reaction of organoboronic acids, organo-
stannanes, or organosilanes to a,b-unsaturated carbonyl
compounds has also been reported.5
Herein, we would like to report a simple and selective
synthesis of 3-amino-2,2-difluorocarboxylic esters (6)
and difluoro-b-lactams (7) (Scheme 2).
Recently, we reported the novel trifluoromethylation at
the a-position of a,b-unsaturated ketones using CF3I,
Et2Zn, and RhCl(PPh3)3.6 Furthermore, we reported
that ethyl bromodifluoroacetate (1) reacted with a,b-
RhCl(PPh3)3
O
Et2Zn
R
R'
THF
O
3
CF2COOEt
BrCF2COOEt
+
RhCl(PPh3)3
Et2Zn
R
R'
Keywords: Fluorine; Rhodium catalyst; Imine; b-Lactam; Amino acid.
1
HO CF2COOEt
R'
2
*
Corresponding authors. Tel.: +81 72 866 3141; fax: +81 72 850 7020
(A.A.); tel.: +81 72 866 3140; fax: +81 72 850 7020 (I.K.); e-mail
addresses: aando@pharm.setsunan.ac.jp; kumadaki@pharm.setsunan.
ac.jp
CH3CN
R
4
Scheme 1. Reaction of 1 with 2 in the presence of RhCl(PPh3)3.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.031

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K. Sato et al. / Tetrahedron Letters 46 (2005) 7679–7681
R3
N
It is interesting to note that Honda and colleague ob-
R3
R1
R3
R2
O
RhCl(PPh3)3
NH
tained the b-lactams and amino esters by changing the
solvent.8 On the other hand, we only obtained the corre-
sponding difluoro-b-lactams (7), even if a variety of sol-
vents were examined. We thought that the fluorine
group might play an important role to form 7. However,
recently, Fujii and co-workers reported the reaction of 1
with an imine (5) to give 3-amino-2,2-difluorocarboxylic
ester (6) in a moderate yield on the way to the peptide
isostere.10 We were interested in their results, since, we
obtained 7 but not 6 in most cases. Therefore, we read
their experimental part carefully, and found they formed
the imine in the presence of molecular sieves and used
them without isolation. We assumed that H2O on the
molecular sieves was essential for the formation of 6,
though they did not mention this fact. To confirm our
assumption, we examined the reaction of 5b in the pres-
ence or absence of traces of H2O. The results are shown
in Table 3.
N
BrCF COOEt
+
2
+
R1
F
Et2Zn
0˚C
R1
1
CF2COOEt
R2
R2
F
5
6
7
Scheme 2. Reaction of 1 with 5 in the presence of RhCl(PPh3)3.
The effect of solvents and amounts of Rh catalyst, 1 and
Et2Zn are summarized in Table 1. Based on our previ-
ous result,7 we examined the reaction of 1 and N-benzyl-
ideneaniline (5a) in CH3CN, but neither 6 nor 7 was
hardly obtained. Using THF as the solvent, 7 was ob-
tained in a good yield, although 6 was hardly obtained
as shown in entry 2. A long reaction time was needed
in the absence of Rh catalyst (entry 1). From the exam-
ination of several conditions, we found that entry 6 is
the best condition to obtain the difluoro-b-lactams (7).
Based on the above result, we applied the reaction to
other various imines (Table 2). As shown in entries 1–
9, the aromatic aldimines (5a–f) gave the corresponding
difluoro-b-lactams (7) in good to excellent yield,
although the p-nitrophenyl and the aliphatic aldimines
(5g–i) gave poor results. The substituents on the nitro-
gen atom hardly affected the reaction as shown in entries
1, 2, 10, and 11. The difluoro-b-lactams (7) were also ob-
tained in poor to moderate yields using ketimines (5l,m)
as shown in entries 12 and 13.
As shown in Table 3, when pure 5b was used in this reac-
tion, 7b was the primary product (entry 1). Now, we
paid attention to the fact that Fujiiꢀs group used the
imine without isolation. We used MgSO4 in the place
of molecular sieves. Thus, we formed 5b from benzalde-
hyde and benzylamine in the presence of MgSO4 in situ,
followed by the reaction with 1 in the presence of Et2Zn
and RhCl(PPh3)3, and obtained 6b as a major product
Table 1. Examination of the reaction conditions
Entry
RhCl(PPh3)3 (mol %)
Solvent
Temperature (°C)
1 and Et2Zn (equiv)
Time (h)
Yield of 7 (%)
1
2
3
4
5
6
7
8
None
1
5
10
1
1
THF
THF
THF
THF
0
0
0
0
0
0
0
0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
7
3
3
1
2
2
22
23
60
62
48
22
48
67
Trace
49
Et2O
CH2Cl2
DMF
Toluene
1
1
Table 2. Reaction of 1 with various imines
R3
N
O
R3
RhCl(PPh3)3
N
BrCF2COOEt
+
R1
Et2Zn
THF / 0˚C
R1
R2
F
7a-m
1
R2
F
5a-m
Entry
Compound 5
Time (h)
Yield of 7 (%)
R1
R2
R3
1
2
3
4
5
6
7
8
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
tBu
Bn
Bn
a
b
c
d
e
f
2
1
6
1
1
67
83
93
80
82
80
Trace
35
NR
62
86
4-MeO–Ph
4-iPr–Ph
4-Cl–Ph
4-MeOOC–Ph
4-NO2–Ph
C6H11
tBu
Ph
Ph
Ph
Ph
1
7
g
h
i
18
17
2
21
2
9
10
11
12
13
j
k
l
44
8a
m
46
a The reaction was refluxed.

K. Sato et al. / Tetrahedron Letters 46 (2005) 7679–7681
Table 3. Examination of the selective synthesis of 6 and 7
7681
Entry
5b
Additive (equiv)
Time (h)
Yield of 6b (%)
Yield of 7b (%)
1a
2
3
4
5
6
7
Isolated
Synthesized by MgSO4
Synthesized and then removed of MgSO4
Isolated
Isolated
Isolated
Isolated
None
None
None
MgSO4 (2)
BnNH2 (0.1)
H2O (1)
1
3
1
1
1
2
1
Trace
46
4
5
3
83
8
59
64
80
16
Trace
48
65
MgSO4Æ7H2O (1)
a The entry 1 of Table 3 is the same result with the entry 2 of Table 2.
Bn
R
O
Bn
R
Bn
H
NH
CF2COOEt
RhCl(PPh3)3
N
N
References and notes
BrCF2COOEt
+
+
CH2Cl2, Et2Zn
F
1
R
H
H
F
MgSO4 7H2O
7
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5423.
5b,c,e
6b = 65%
6c = 59%
6e = 60%
0˚C
(traces from
5b,c,e)
Scheme 3. Reaction of 1 with 5 in the presence of RhCl(PPh3)3 and
MgSO4Æ7H2O.
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(entry 2). These results supported our assumption that
H2O played an important role for the selective forma-
tion of 6 and 7. By the examination of several reaction
conditions, the addition of equimolar amount of
MgSO4Æ7H2O was found to lead to the best formation
of 6. The application to other substrates (5c,e) also gave
the similar results in moderate to good yields (Scheme
3).
In conclusion, we could obtain difluoro-b-lactams (7) in
good to excellent yields using rhodium-catalyzed Refor-
matsky-type reaction. Moreover, we could obtain 3-ami-
no-2,2-difluorocarboxylic esters (6) in good yields by
adding MgSO4Æ7H2O to the reaction medium. This is
the first report for the selective synthesis of 6 and 7 with-
out the troublesome handling. In addition, compounds 6
and 7 are fluorine analogs of b-amino acid derivatives
and are very important compounds in pharmacology.
We provided a new procedure to synthesize each by add-
ing MgSO4Æ7H2O or not. There are no reports up to now
that difluoro-b-lactams and 3-amino-2,2-difluorocarb-
oxylic esters were selectively synthesized only from the
addition of an additive. We believe that this reaction
could be widely used in various fields.
Supplementary data
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.09.031.
10. Otaka, A.; Watanabe, J.; Yukimasa, A.; Sasaki, Y.;
Watanabe, H.; Kinoshita, T.; Oishi, S.; Tamamura, H.;
Fujii, N. J. Org. Chem. 2004, 69, 1634–1645.