Stereoselective Suzuki coupling reaction of an α-bromo-α-fluoro-β-lactam

Article abstract of DOI:10.1055/s-0034-1379637

A new strategy has been developed for the synthesis of α-aryl-α-fluoro-β-lactams via the Suzuki cross-coupling of α-bromo-α-fluoro-β-lactam with a range of different aryl-(9-BBN) reagents. This method provides facile access to multisubstituted α-fluoro-β-lactams in a diastereoselective manner. The synthetic utility of α-bromo-α-fluoro-β-lactam has been demonstrated by the arylation of α-bromo-α-fluoro-β-lactam.

Full text of DOI:10.1055/s-0034-1379637

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 55–58
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Stereoselective Suzuki Coupling Reaction of an α-Bromo-α-fluoro-
β-lactam
Atsushi Tarui
NiBr2⋅diglyme (20 mol%)
Bn
O
t-Bu
t-Bu
Bn
O
Erina Miyata
Ayumi Tanaka
Kazuyuki Sato
Masaaki Omote
Akira Ando*
ligand (22 mol%)
N
N
+
Ar-(9-BBN)
F
Ar
Br
t-BuOLi (2.4 equiv)
i-BuOH (2.4 equiv)
2 (2.5 equiv)
Ph
Ph
F
N
ligand
N
(3S,4R)/(3R,4S)
(3S,4R)/(3R,4S)
up to 87% yield
diastereoselective
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1,
Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
aando@pharm.setsunan.ac.jp
tarui-a@pharm.setsunan.ac.jp
Received: 22.09.2014
Accepted after revision: 09.11.2014
Published online: 28.11.2014
tion of the parent molecule, the use of fluorine-containing
building blocks represents one of the most efficient and
practical methods for the site-selective introduction of a
fluorine substituent. β-Lactams are a well-known structur-
al class of bioactive compounds, including antibiotics and
hypercholesterol-lowering agents.3 The incorporation of a
fluorine atom into a β-lactam ring can be beneficial in
terms of the enhancing the electrophilicity of the parent
compound, which can have a dramatic effect on the poten-
cy and drug metabolism and pharmacokinetics (DMPK)
properties of the compound.4 Furthermore, fluorinated β-
lactams have been used as building blocks for the construc-
tion of fluorine-containing β-amino acid units,5 which
could be used to prevent epimerization at the α position of
the β-amino acid backbone. We recently reported the syn-
thesis of several non-chiral and chiral fluorinated β-lact-
ams,6,7 and have also demonstrated the utility of α-bromo-
α-fluoro-β-lactam (1) using a nickel-catalyzed cross-cou-
pling reaction and lithiation chemistry to provide access to
multisubstituted α-fluoro-β-lactams (Equation 1).8 Al-
though our reported Kumada coupling reaction was useful
for the arylation of 1,8a the reaction did not afford any of the
ortho-substituted arylated products. The nickel-catalyzed
Negishi and Suzuki coupling reactions of fluorinated halo
substrates have been reported by Fu et al.9 and Gandelman
et al.10 to provide the corresponding arylated α-fluoro car-
bonyl compounds and secondary alkyl fluorides, respec-
tively. Fu et al. also reported a similar reaction for the nickel-
catalyzed Suzuki arylation of alkyl halide using aryl-(9-BBN)
reagents.11 To the best of our knowledge, however, there
have been no reports in the literature concerning the direct
functionalization of fluoro-β-lactams, except those of our
own group and Welch’s group.12 To develop a new approach
for the construction of multisubstituted α-fluoro-β-lact-
ams, we investigated the cross-coupling reactions of 1. In
this study, we describe the Suzuki cross-coupling reaction
of 1 with aryl-(9-BBN) reagents, which allowed for the syn-
thesis of multisubstituted α-fluoro-β-lactams with high dia-
stereoselectivity (Scheme 1). In a further demonstration of
DOI: 10.1055/s-0034-1379637; Art ID: st-2014-u0786-c
Abstract A new strategy has been developed for the synthesis of
α-aryl-α-fluoro-β-lactams via the Suzuki cross-coupling of α-bromo-
α-fluoro-β-lactam with a range of different aryl-(9-BBN) reagents. This
method provides facile access to multisubstituted α-fluoro-β-lactams in
a diastereoselective manner. The synthetic utility of α-bromo-α-fluoro-
β-lactam has been demonstrated by the arylation of α-bromo-α-fluoro-
β-lactam.
Key words fluorine, β-lactam, cross-coupling, nickel, 9-BBN
Organofluorine compounds are becoming increasingly
popular with a growing number of applications in a variety
of fields, including medicine, agrochemicals and materials
science.1 The introduction of a fluorine substituent can
have a dramatic effect on the dipole moment of the parent
compound and enhance its electrophilicity, which can be
an attractive property in the drug discovery and medicinal
chemistry investigations.2
In terms of potential strategies for the introduction of
fluorine, site-selective approaches involving the fluorina-
tion of a target molecule are particularly desirable, because
they can potentially allow for the late-state introduction of
fluorine substituents. Compared with the direct fluorina-
R2
R1
O
R2
R1
O
1) n-BuLi
N
N
2) electrophile
Br
F
R3
F
1
1
NiCl2⋅DME
Ph-Box
ArMgBr
R2
R1
O
R2
O
N
N
Br
F
R1
F
Ar
Equation 1 Synthesis of multisubstituted α-fluoro-β-lactam
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 55–58

56
A. Tarui et al.
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Ni catalyst
ligand
base
vestigated, including sodium and potassium salts, but these
salts gave none of the desired coupling product (Table 1, en-
tries 2 and 3).
R2
R1
O
R2
O
N
N
+
Ar-(9-BBN)
F
Ar
Br
R1
F
Ph
Ph
1
2
3
N
N
Scheme 1 Suzuki coupling reaction of an α-bromo-α-fluoro-β-lactam
with an aryl-(9-BBN) reagent
N
N
N
N
L1
L2
L3
t-Bu
t-Bu
the synthetic utility of this strategy, we have also complet-
ed the synthesis of the highly enantiomerically enriched α-
arylated product 3 starting from chiral 1.
N
N
N
N
Several reaction conditions were initially investigated
for the Suzuki coupling reaction of the model substrate 1-
benzyl-3-bromo-3-fluoro-4-phenylazetidin-2-one (1a) with
phenyl-(9-BBN) (2a). When 1a was reacted with 2a using
tert-BuOLi as a base, NiCl2·DME as a catalyst and bipyridine
(L1; Figure 1) as a ligand, the desired arylated product (3a)
was formed diastereoselectively, albeit in a low yield (Table
1, entry 1).13 Several other tert-butoxides salts were also in-
L4
Figure 1 Ligand structures
L5
The poor results obtained with these salts were at-
tributed to the poor solubility profiles of sodium and potas-
sium tert-butoxides in organic solvents. Interestingly, the
use of NiBr2·diglyme instead of NiCl2·DME led to a slight in-
crease in the yield (Table 1, entry 4). Several other bipyridyl
ligands were also screened in the reaction, but resulted in
Table 1 Screening of Reaction Conditions
Ni catalyst (10 mol%)
ligand (11 mol%)
Bn
O
Bn
Ph
O
N
N
Ph-(9-BBN)
2a
(2.5 equiv)
+
Br
F
Ph
base (2.4 equiv)
i-BuOH (2.4 equiv)
Ph
F
(3S,4R)-/(3R,4S)-1a
(3S,4R)-/(3R,4S)-3a
Entry
Ni catalyst
Ligand Base
Nucleophile
Solvent
Temp (°C)
Time (h)
Yield of 3a
(%)a
1
NiCl2·DME
L1
L1
L1
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5d
L5d
L5
L5
t-BuOLi
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
Ph-(9-BBN)
PhB(OH)2
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
i-Pr2O
40
40
40
40
40
40
40
40
40
40
40
40
40
reflux
18
18
18
18
18
18
18
18
18
18
18
18
18
1
34b
0b
0b
36
0
2
NiCl2·DME
t-BuONa
t-BuOK
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOK
Cs2CO3
3
NiCl2·DME
4
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglymec
NiBr2·diglymec
NiBr2·diglyme
NiBr2·diglyme
5
6
10
14
66
58
52
26
23
82
87
0
7
8
9
10
11
12
13
14
15
16
dioxane
THF
toluene
benzene
benzene
i-Pr2O–i-BuOH (9:1)
r.t.
20
18
PhBF3K
benzene
reflux
0
a Isolated yield.
b 19F NMR yield.
c Amount of Ni catalyst used was 20 mol%.
d Amount of ligand was used was 22 mol%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 55–58

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Bn
Ph
O
Bn
N
O
ing material being recovered in both cases (Table 1, entries
15 and 16). It is noteworthy that the coupling product 3a
was obtained as a single diastereomer in all cases.14 With
the optimized conditions in hand, we proceeded to evaluate
the scope of the Suzuki coupling reaction of 1a with a vari-
ety of aryl-(9-BBN) reagents, which gave the corresponding
multisubstituted fluoro-β-lactams in good yields (Scheme
2). Thus, para- and meta-substituted aryl-(9-BBN) reagents
performed well in the cross-coupling reaction to give the
desired α-arylated products in good yields with high levels
of diastereoselectivity. Notably, both electron-rich and elec-
tron-poor nucleophiles performed well as the coupling
partners (e.g., 2b–h). The ortho-substituted aryl-(9-BBN)
reagents performed especially well in the reaction, with the
desired products 3i and 3j being formed in good yields. Fur-
thermore, the heterocyclic aryl-(9-BBN) reagent 2k reacted
successfully under the optimized conditions to give the cor-
responding product 3k in moderate yield. In contrast, alkyl-
(9-BBN) and alkenyl-(9-BBN) reagents were found to be un-
suitable coupling partners for the reaction.
NiBr2⋅diglyme (20 mol%)
L5 (22 mol%)
N
+
Ar-(9-BBN)
F
Ar
Br
2
t-BuOLi (2.4 equiv)
i-BuOH (2.4 equiv)
benzene, reflux
Ph
F
(2.5 equiv)
(3S,4R)-/(3R,4S)-1a
(3S,4R)-/(3R,4S)-3
Bn
Ph
O
Bn
O
Bn
O
N
N
N
F
F
F
Ph
Ph
3a
87% yield, 1 h
3b
77% yield, 1 h
3c
83% yield, 3 h
OMe
Me
Bn
O
Bn
O
Bn
O
N
N
N
F
F
F
Ph
Ph
Ph
Me
3f
78% yield, 1 h
3d
69% yield, 20 h
3e
77% yield, 1 h
Cl
F
The α-aryl-α-fluoro-β-lactams 3 described in the cur-
rent study were all prepared as racemic mixtures. To ex-
pand the scope of this chemistry, we also investigated the
asymmetric synthesis of these multisubstituted α-fluoro-β-
lactams using chiral 1a with phenyl-(9-BBN) (Scheme 3).
Pleasingly, the Suzuki coupling reaction of chiral 1a in the
3S,4R-configuration (92% ee) provided the enantiomerically
enriched product 3a in a diastereoselective manner without
any decrease in its enantiopurity (63% yield, 92% ee).
Bn
O
Bn
O
Bn
O
N
N
N
F
F
F
Me
Ph
Ph
Ph
OMe
F
3g
3h
3i
49% yield, 1 h
64% yield, 1 h
76% yield, 4 h
Bn
O
Bn
N
O
N
NiBr2⋅diglyme (20 mol%)
F
Bn
O
F
Bn
O
OMe
Ph
Ph
L5 (22 mol%)
N
N
+ Ph-(9-BBN)
O
O
F
Ph
Br
t-BuOLi (2.4 equiv)
i-BuOH (2.4 equiv)
benzene, reflux
2a
Ph
Ph
F
(2.5 equiv)
3j
85% yield, 1 h
3k
50% yield, 1 h
(3S,4R)-3a
(3S,4R)-1a
92% ee
63% yield, 92% ee
Scheme 2 Scope and limitations of this Suzuki coupling reaction
Scheme 3 Synthesis of enantioenriched 3a15
the recovery of 1a and low yields of the desired product (Ta-
ble 1, entries 4–7). Pleasingly, the use of 4,4′-di-tert-butyl-
2,2′-bipyridine (L5; Figure 1) as a ligand in this Suzuki cou-
pling reaction led to the highest yield of 3a, with all of the
starting material 1a being consumed (Table 1, entry 8). Fur-
ther attempts to optimize the reaction conditions, includ-
ing changing the solvent, led to much lower yields of the
product especially, when the reaction was carried out in
THF or toluene (Table 1, entries 9–12). Increasing the
amount of catalyst and ligand added to the reaction led to
an increase in the yield of 3a (Table 1, entry 13). A further
improvement in the product yield was also observed when
the reaction was conducted under reflux conditions, which
also led to a significant reduction in the reaction time (Ta-
ble 1, entry 14). Several other boron reagents were also in-
vestigated in this coupling reaction, but these reagents
failed to provide any of the desired products, with the start-
In summary, we have developed a new reaction for
highly diastereoselective construction of α-arylated α-fluo-
ro-β-lactams via the nickel-catalyzed Suzuki coupling reac-
tion of α-bromo-α-fluoro-β-lactam with aryl-(9-BBN) re-
agents. The chiral coupling product was also obtained dia-
stereoselectively without any reduction in its enantiopurity
when the reaction was conducted with enantioenriched
α-bromo-α-fluoro-β-lactam. Additional investigations to-
wards the synthesis of multisubstituted α-fluoro-β-lactams
are currently underway in our laboratory.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379637.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
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58
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References and Notes
(12) (a) Welch, J. T.; Araki, K.; Kawecki, R.; Wichtowski, J. A. J. Org.
Chem. 1993, 58, 2454. (b) Kawecki, R.; Welch, J. T. Tetrahedron
Lett. 1993, 34, 3087.
(1) (a) Jeschke, P. ChemBioChem 2004, 5, 570. (b) Müller, K.; Faeh,
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Chem. Commun. 2008, 5686. (d) O’Hagan, D. J. Fluorine Chem.
2010, 131, 1071.
(2) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
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(b) Kværnø, L.; Werder, M.; Hauser, H.; Carreira, E. M. J. Med.
Chem. 2005, 48, 6035.
(13) Typical Experimental Procedure for the Ni-Catalyzed Suzuki
Coupling Reaction of α-Bromo-α-fluoro-β-lactam: 4,4′-Di-
tert-butylbipyridine (29.5 mg, 0.11 mmol) and NiBr2·diglyme
(35 mg, 0.10 mmol) were added to a flask equipped with a mag-
netic stirrer bar. To the flask was added anhyd benzene (7.5 mL)
and the resulting mixture was stirred vigorously for 2 h (a light-
green slurry formed). The solution of the activated Ph-(9-BBN)
solution (1.25 mmol) was added to the slurry, and the whole
mixture was stirred for 20 min at same temperature. Then, 1
(0.5 mmol) was added to the slurry and the resulting mixture
was stirred for 1 h under reflux. The reaction was quenched by
brine and the mixture was extracted with EtOAc, and then the
extract was dried over MgSO4. The solvent was removed in
vacuo and the residue was purified by silica gel column chroma-
tography (hexane–EtOAc) to give the desired product 3.
(4) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(5) (a) Uoto, K.; Ohsuki, S.; Takenoshita, H.; Ishiyama, T.; Iimura, S.;
Hirota, Y.; Mitsui, I.; Terasawa, H.; Soga, T. Chem. Pharm. Bull.
1997, 45, 1793. (b) Li, X.-G.; Lähitie, M.; Kanerva, L. T. Tetrahe-
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Wu, J.; Yu, J.; Zhang, J.; Li, H.; Qian, X. Tetrahedron Lett. 2009, 50,
1982.
(6) (a) Sato, K.; Tarui, A.; Matsuda, S.; Omote, M.; Ando, A.;
Kumadaki, I. Tetrahedron Lett. 2005, 46, 7679. (b) Tarui, A.;
Kawashima, N.; Sato, K.; Omote, M.; Miwa, Y.; Minami, H.;
Ando, A. Tetrahedron Lett. 2010, 51, 2000.
(7) (a) Tarui, A.; Nishimura, H.; Ikebata, T.; Tahira, A.; Sato, K.;
Omote, M.; Minami, H.; Miwa, Y.; Ando, A. Org. Lett. 2014, 16,
2080. (b) Tarui, A.; Ikebata, T.; Sato, K.; Omote, M.; Ando, A. Org.
Biomol. Chem. 2014, 12, 6484.
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Y.; Ando, A. Tetrahedron 2013, 69, 1559. (b) Tarui, A.;
Kawashima, N.; Kawakita, T.; Sato, K.; Omote, M.; Ando, A.
J. Org. Chem. 2013, 78, 7903.
(3S,4R/3R,4S)-1-Benzyl-3-fluoro-3,4-diphenylazetidin-2-one
(3a): colorless solid (145 mg, 87%); mp 78.0–79.0 °C (uncor-
rected). 1H NMR (400 MHz, CDCl3): δ = 3.98 (dd, J = 14.8, 2.4 Hz,
1 H), 4.66 (d, J = 3.5 Hz, 1 H), 5.03 (d, J = 14.8 Hz, 1 H), 7.16–7.18
(m, 2 H), 7.29–7.33 (m, 5 H), 7.38 (m, 5 H), 7.42–7.44 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 44.4 (d, J = 2 Hz), 68.6 (d, J = 25
Hz), 102.2 (d, J = 225 Hz), 125.2 (d, J = 7 Hz), 128.0, 128.2 (d, J = 2
Hz), 128.5, 128.6, 128.7, 128.8, 129.0, 129.2 (d, J = 2 Hz), 132.1,
134.2 (d, J = 24 Hz), 134.4, 164.8 (d, J = 25 Hz). 19F NMR (84 MHz,
CDCl3): δ = –102.5 (s, 1 F). MS: m/z = 331 [M+]. HRMS (EI): m/z
[M+] calcd for C22H18FNO: 331.1372; found: 331.1378.
(14) See supporting information for the determination of the relative
configuration and the diastereoselective formation of coupling
products.
(9) Liang, Y.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 5520.
(10) Jiang, X.; Sakthivel, S.; Kulbitski, K.; Nisnevich, G.; Gandelman,
M. J. Am. Chem. Soc. 2014, 136, 9548.
(11) (a) Lundin, P. M.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 11027.
(b) Wilsily, A.; Tramutola, F.; Owston, N. A.; Fu, G. C. J. Am. Chem.
Soc. 2012, 134, 5794. (c) Zultanski, S. L.; Fu, G. C. J. Am. Chem.
Soc. 2013, 135, 624.
(15) The ee value was determined to be 92% by HPLC analysis [Daicel
CHIRALPAK AD-H, hexane–EtOH = 98:2, flow rate = 2.0 mL/min,
λ = 254 nm, tR (major) = 10.0 min and tR (minor) = 8.9 min].
25
[α]D +63.4 (c = 1.05, CHCl3). See the Supporting Information
for enantiopurity of 3a.
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