Simple, chemoselective, and diastereoselective Reformatsky-type synthesis of α-bromo-α-fluoro-β-lactams

Article abstract of DOI:10.1016/j.tetlet.2010.02.023

The chemoselective and diastereoselective synthesis of syn-α-bromo-α-fluoro-β-lactams was achieved using the diethylzinc-mediated Reformatsky-type reaction of ethyl dibromofluoroacetate with imines. The reaction led to diastereomerically pure β-lactams in good to moderate yields (up to 78% yield) with only small amounts of aziridine derivatives. Noncyclized 3-amino-2-bromo-2-fluoro carboxylic esters, usual Reformatsky adducts, were not formed. In contrast, reactions carried out under typical Reformatsky conditions using zinc metal were poorly chemoselective, leading to mixtures of β-lactams and aziridine derivatives.

Full text of DOI:10.1016/j.tetlet.2010.02.023

Tetrahedron Letters 51 (2010) 2000–2003
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Simple, chemoselective, and diastereoselective Reformatsky-type synthesis
of a-bromo-a-fluoro-b-lactams
Atsushi Tarui a, Naoto Kawashima a, Kazuyuki Sato a, Masaaki Omote a, Yoshihisa Miwa b,
Hideki Minami b, Akira Ando a,
*
a Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
b Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1, Hirokoshingai, Kuré, Hiroshima 737-0112, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemoselective and diastereoselective synthesis of syn-a-bromo-a-fluoro-b-lactams was achieved
Received 2 December 2009
Revised 2 February 2010
Accepted 5 February 2010
Available online 10 February 2010
using the diethylzinc-mediated Reformatsky-type reaction of ethyl dibromofluoroacetate with imines.
The reaction led to diastereomerically pure b-lactams in good to moderate yields (up to 78% yield) with
only small amounts of aziridine derivatives. Noncyclized 3-amino-2-bromo-2-fluoro carboxylic esters,
usual Reformatsky adducts, were not formed. In contrast, reactions carried out under typical Reformatsky
conditions using zinc metal were poorly chemoselective, leading to mixtures of b-lactams and aziridine
derivatives.
Ó 2010 Elsevier Ltd. All rights reserved.
Organofluorine compounds are utilized in many fields, especially
in the medicinal field.1 For example, the interesting effects were
brought about by introducing a fluorine atom on a suitable position
of bioactive compounds.2 Therefore, many methods were developed
for the introduction of fluorine functional groups to molecules.
Among these methods, the Reformatsky reaction is a powerful
method for the synthesis of fluorine-containing b-lactams and b-
aminocarboxylic acids using fluorine-containing building blocks
like ethyl bromodifluoro-acetate.3 Frequently found in antibiotics
and enzyme inhibitors, b-lactam rings can be used as synthons
for the synthesis of b-amino acid derivatives via ring-opening reac-
tion.4 For example, Joyeau et al. reported that 3,3-difluorinated and
3-bromo-3-fluorinated b-lactams inhibited the human leukocyte
elastase.5
compounds.8 Iseki et al. also reported that the aldol reaction of
aldehydes with bromofluoroketene silyl acetals derived from 4
gave the corresponding syn- and anti-a-bromo-a-fluoro-b-
hydroxycarboxylates as a syn/anti mixture of 11/89.9
To expand our previous results,6 we examined the Reformatsky-
type reaction of 4, instead of 1, with imines (5) in order to form
a-bromo-a-fluoro-b-lactams (6) (Scheme 2). Herein we report
our interesting results regarding the Et2Zn-mediated chemo and
stereoselective Reformatsky-type reaction.
First, we attempted the reaction of 4 with benzylidene–benzyl-
amine (5a) in THF at À10 °C using the previous conditions.6c In the
presence of RhCl(PPh3)3, the reaction gave syn-b-lactam (6a) in 63%
yield as a single diastereomer, in which the relative configuration
between hydrogen and fluorine atoms was syn (Table 1, entry 1).
Recently, we reported that the Rh-catalyzed Reformatsky reac-
tion of bromodifluoroacetate (1) with imines (2) using Et2Zn instead
of Znmetalgavedifluoro-b-lactams(3) ingood yields.6 Furthermore,
we showed that the synthesis of 3 using a chiral ester 1 was stereo-
selective (Scheme 1).6b,c Conventional Reformatsky reaction condi-
tions require the activation of zinc metal by acid wash or by the
addition of an activating reagent such as TMSCl.3 Our method cir-
cumvented these problems by using commercially available Et2Zn.
Ishihara et al. reported that the reaction of ethyl dibromofluoro-
acetate (4) with carbonyl compounds using a Zn/Et2AlCl combina-
tion gave the Reformatsky 1,2-adducts in good to moderate yields,
but the products were obtained as a nonselective diastereomixture
R1
R1
O
RhCl(PPh3)3
Et2Zn
N
N
BrCF2CO2R
+
R2
R2
F
R3
1
R3
F
2
3
Scheme 1. Rhodium-catalyzed Reformatsky reaction of 1 with imines.
R1
R2
O
R1
RhCl(PPh3)3
Et2Zn
of
a-bromo-a
-fluoro-b-hydroxycarboxylates.7 Jubault and co-
N
N
Br2CFCO2Et
+
workers reported Et2Zn-promoted reactions of 4 with carbonyl
F
R2
4
H
Br
5
6
* Corresponding author. Tel.: +81 72 866 3140; fax: +81 72 866 3142.
E-mail address: aando@pharm.setsunan.ac.jp (A. Ando).
Scheme 2. The Reformatsky-type reaction of 4 with imines.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.023

A. Tarui et al. / Tetrahedron Letters 51 (2010) 2000–2003
2001
Table 1
Optimization of Et2Zn-mediated Reformatsky reaction
Bn
Bn
Bn
O
Bn
N
NH
O
Zn source
N
O
N
Br2CFCO2Et
+
+
+
F
Ph
OEt
OEt
Ph
solvent, -10 °C
Ph
H
4
Ph
Br
rac-6a
F
8a
Br
F
5a
rac-7a
Entry
Zn source
Solvent
Time (h)
Yield of 6aa (%)
dr of 6ab (syn:anti)
19F NMR yield of 7a (%)
Dr of 7ab (syn:anti)
Yield of 8aa (%)
c
1
2
3
4
5
6
7
8
9
RhCl(PPh3)3 with Et2Zn
THF
THF
THF
THF
1
2
1
24
1
2
1
18
26
63
44
71
100:0
100:0
100:0
—
100:0
100:0
100:0
—
15
35
10
—
2 :1
2 :1
1:1
—
0:1
0:1
0:1
—
N.D.
N.D.
N.D.
—
N.D.
N.D.
N.D.
—
Activated Zn dust
Et2Zn
Me2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
No reaction
76
74
Et2O
8
Hexane
Toluene
DMF
10
11
—
77
No reaction
No reaction
Et2Zn
DMPU
—
—
—
—
a
b
c
Isolated yields.
Determined by 19F NMR.
1 mol % Rh catalyst was used.
A diastereomixture of aza-Darzens-type by-products (7a) was also
detected in 15% yield using 19F NMR (dr syn/anti = 2/1).
and DMPU were ineffective, as no product was observed, and the
imine 5a was detected by TLC (entries 8 and 9).
Next, Reformatsky conditions were examined on the reaction
of 4 with 5a (entries 1–4). Under the standard Reformatsky con-
ditions using activated Zn, the yield of 7a increased while the
yield of 6a decreased, consistent with a decrease in chemoselec-
tivity (entry 2). Even when Et2Zn was used alone, without the Rh
catalyst, 6a was obtained in good yield (entry 3). In this case, a
small amount of the diastereomixture of 7a was also obtained.
The use of Me2Zn as an alkylzinc reagent was not effective at
all (entry 4). In all entries, 6a was obtained as a single diastereo-
mer and ethyl 3-benzylamino-2-bromo-2-fluoro-3-phenyl-propi-
onate (8a), the noncyclized Reformatsky adduct, was not
obtained.
Changing the solvent from THF to Et2O improved the yield to
76% and the highest chemoselectivity was achieved among these
results (entry 5). Less polar solvents such as hexane and toluene
showed similar yields and chemoselectivity as Et2O. With these
solvents, an aziridine by-product of anti configuration was formed
(entries 5–7). On the other hand, highly polar solvents such as DMF
In all cases, the formation of 6a was diastereoselective in this
Reformatsky-type reaction. The optimization of the reaction condi-
tions showed that the highest yield and chemoselectivity of 6a
were attained using Et2Zn as a promoter and Et2O as a solvent at
À10 °C, in the absence of Rh catalyst.10,11 The reaction of various
imines was examined under this optimized reaction condition
and the corresponding
a-bromo-a-fluoro-b-lactams (6) were ob-
tained in good yields with high diastereoselectivity (Table 2). The
aromatic aldimines were efficiently converted to the desired 6a–f
products. Imines bearing electron-donating or electron-withdraw-
ing groups on their aromatic ring substituents gave the products in
good yields, suggesting that their substituents did not affect the
yields and diastereoselectivity of 6. However, the aliphatic imine
5g, derived from cyclohexanecarbaldehyde and p-anisidine, gave
a mixture of products that were unstable on silica gel chromatog-
raphy and could not be isolated (entry 7). 19F and 1H NMR spec-
troscopy measurements suggested that these unstable products
might be lactam and aziridine.
Table 2
Scope and limitation of the optimized diethylzinc-mediated reaction
R1
R2
O
R1
N
Et2Zn
N
Br CFCO Et
+
2
2
F
Et2O, -10 °C
R2
H
4
Br
6a
5
Entry
5
Time (h)
Yield of 6b (%)
Dr of 6c (syn:anti)
R2
R1
1
2
3
4
Ph–
Ph–
Bn–
5a
1
1
1
1
1
2
76
72
78
74
77
70
—
100:0
100:0
100:0
100:0
100:0
100:0
—
PMB–
PMB–
PMB–
PMB–
PMB–
PMP–
5b
5c
5d
5e
5f
4-Cl–C6H4–
4-MeOCO–C6H4–
4-Me–CsH4–
4-MeO–C6H4–
Cyclohexyl
5
6
7d
5g
10 min
a
b
c
Racemic products were obtained.
Isolated yields.
Determined by 19F NMR.
d
The products 6g and 7g decomposed rapidly.

2002
A. Tarui et al. / Tetrahedron Letters 51 (2010) 2000–2003
We investigated the relative configuration of 6a by single-crys-
dance with the Zimmerman–Traxler transition-state model (TS
1–4). TS-1 and TS-2 easily lead to the desired syn-6a enantiomers
via addition and intramolecular cyclization. On the other hand, TS-
3 and TS-4, which lead to the anti-6a isomers, are difficult to be
formed due to the 1,3-diaxial repulsion between the bromine atom
and the N-benzyl group and between the phenyl and the ethoxy
groups. We believe that the difference between diastereoslectivi-
ties of our reaction of imines and Ishihara’s reaction of aldehydes
is attributed to the presence of the N-substituent. On the other
hand, 2-fluoroaziridine was generated from E-11 via TS-5 and TS-
6, in which there was no 1,3-diaxial interaction. In TS-5 and TS-
6, the nucleophilic nitrogen atom and bromine atom leaving
groups are located in an antiperiplanar position, allowing the
resulting adduct 12 to cyclize into anti-2-fluoroaziridine (7a). We
suggested that the highly diastereoselective formation of 6 was
explained by the predominant formation of Z-11 and the rigid
chair-like transition states (TS-1, -2). The study on the further
mechanistic details is in progress.
tal X-ray analysis and determined its H-F coupling constants using
1H and 19F NMR. X-ray analysis showed that the configuration of 6a
was syn, as shown in Figure 1.12 The H–F coupling constant of 6a
was found to be 10 Hz. This value was larger than that of another
diastereomer of 6a. The H–F coupling constant of another diaste-
reomer of 6a was 2.5 Hz13, which was obtained by the procedure
described as follows. The reaction of N-benzyldibromofluoroaceta-
mide (9) with benzaldehyde in the presence of Et2Zn and
RhCl(PPh3)3 gave the diastereomixture of N-benzyl-2-bromo-2-flu-
oro-3-hydroxy-propanamides (10a) in 86% yield (dr = 4/3). The
diastereoisomers were cyclized to b-lactam (6a) and its isomer un-
der Mitsunobu conditions in 57% yield (anti/syn = 7/1) (Scheme 3).
All diastereomixtures of 6 and isomers were synthesized using this
procedure and the diastereoratios were determined by 19F NMR.
Finally, a tentative reaction mechanism for the diastereoselec-
tive formation of 6a by the reaction of 4 with imine 5a is shown
in Figure 2. In this proposed mechanism, the reaction of 4 with
Et2Zn first gives Z-bromofluorozinc-enolates 11 predominantly, in
which coordination of bromine onto zinc allows plausibly the
formation of five-membered ring. This idea was supported by
DFT calculation of E- and Z-11. Namely, Z-11 is more stable than
E-11 for 5.25 kJ/mol (B88-PW91/6-31G). The stable Z-11 predomi-
nantly adds to imine to give chair-like transition states, in accor-
In conclusion, we described a simple and diastereoselective
Reformatsky-type reaction of ethyl dibromofluoroacetate with imi-
nes using commercially available Et2Zn to yield
a-bromo-a-fluoro-
b-lactams. The reaction was diastereoselective, and X-ray analysis
showed that these
configuration.
a-bromo-a-fluoro-b-lactams have a syn
Figure 1. Single-crystal X-ray structure of 6a.
PhCHO
RhCl(PPh3)3
Et2Zn
O
Bn
Ph
OH
F
O
DEAD
Ph3P
N
Bn
Br2CFCONHBn
Ph
N
H
F
9
Br
Br
diastereomixture of 10a
diastereomixture
of β-lactams
yield 86%
dr = 4:3
yield 57%
syn/anti = 7/1
Scheme 3. Synthesis of diastereomixture of b-lactams.

A. Tarui et al. / Tetrahedron Letters 51 (2010) 2000–2003
2003
First: Enolization of 4 promoting Et2Zn
Et
Et
Zn
Zn
O
O
F
Br2CFCO2Et
+
Et2Zn
+
EtBr
Br
EtO
4
EtO
Br
-11
F
E
Z
-11
Second: Addition of 11 to imine following to intramolecular cyclization
TS-1
Et
Br
N
F
O
Bn
Zn
syn-6a
Ph
(3 , 4
R S
)
H
OEt
TS-5
H
Bn
TS-2
OEt
Zn
Br
H
Bn
F
OEt
Zn
Ph
H
N
Et
Ph
syn-6a
(3 , 4
N
F
Ph
Et
F
OEt
anti-7a
O
Br
F
O
S
R
)
(2 , 3
S S
)
N
12
F
Bn
H
O
EtZn
Bn
H
Br
N
Bn
N
+
-11
Z
Bn
Br
N
+
E
-11
Ph
Et
TS-3
TS-4
Ph
TS-6
ZnEt
O
Et
5a
5a
Zn
N
O
Ph
Br
N
Bn
Ph
anti-6a
S
(3 , 4 )
H
Zn
Bn
OEt
anti-7a
R
(2 , 3 )
F
S
Br
R
Ph
OEt
H
H
OEt
O
12
Ph
OEt
Zn
N
Et
anti-6a
R
(3 , 4 )
H
F
O
R
Bn
Br
Figure 2. Proposed mechanism of the diastereoselective reactions.
8. (a) Zoute, L.; Dutheuil, G.; Qurion, J.-C.; Jubault, P.; Pannecoucke, X. Synthesis
2006, 20, 3409–3418; (b) Lemonnier, G.; Zoute, L.; Dupas, G.; Quirion, J.-C.;
Jubault, P. J. Org. Chem. 2009, 74, 4124–4131.
9. Iseki, K.; Kuroki, Y.; Kobayashi, Y. Tetrahedron 1999, 55, 2225–2236.
10. Preparation of
a-bromo-a-fluoro-b-lactam (6a): Ethyl dibromofluoroacetate (4;
Supplementary data
Supplementary data (experimental procedures and spectral
date of all new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.02.023.
0.41 mL, 3 mmol) was added to a solution of imine (5a; 0.19 mL, 1 mmol) in
Et2O (8 mL) at À10 °C. Then 1.0 M Et2Zn in hexane (3 mL, 3 mmol) was slowly
added to the mixture at À10 °C, and the resulting mixture was stirred at same
temperature for 1 h. The reaction was quenched with saturated aqueous
NaHCO3, and the mixture was filtered through Celite pad. The filtrate was
extracted with AcOEt, and then the extract was washed with brine and dried
over MgSO4. The solvent was removed in vacuo and the residue was purified by
column chromatography (SiO2, AcOEt/hexane = 1:9) to give the corresponding
References and notes
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a
-bromo-a-fluoro-b-lactam (6a, 254.5 mg, 76%).
11. Spectroscopic data of 5a: A colorless solid; mp 81.5–82.0 °C; 1H NMR (CDCl3,
400 MHz) d: 3.93 (1H, d, J = 14.9 Hz), 4.77 (1H, d, J = 10.3 Hz), 4.97 (1H, d,
J = 14.9 Hz), 7.13 (2H, m), 7.20 (2H, m), 7.32 (3H, m), 7.44 (3H, m); 13C NMR
(CDCl3, 100 MHz) d: 44.9, 69.4 (d, J = 25 Hz), 106.2 (d, J = 299 Hz), 127.8, 128.3,
128.5, 128.7, 129.0, 129.7, 132.2, 133.3, 161.0 (d, J = 26 Hz); 19F NMR (CDCl3,
600 MHz) d: À54.9 (1F, d, J = 10.3 Hz); MS m/z = 333 (M+); HRMS (pos-FAB,
Gly.) Calcd for C16H13BrFNO: 333.017 (M+), found: 334.024 (M++H); IR (KBr)
cmÀ1: 1787, 1204.
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These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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