Halogen-metal exchange reactions of bromoaryl-substituted β-lactams

Article abstract of DOI:10.1016/j.tetlet.2013.07.007

β-Lactams are quite susceptible to ring opening when exposed to nucleophilic reagents. The robustness of a variety of bromo- and iodoarenes containing electrophilic functional groups toward alkyllithium reagents during the halogen-lithium exchange process

Full text of DOI:10.1016/j.tetlet.2013.07.007

Tetrahedron Letters 54 (2013) 4934–4936
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Halogen–metal exchange reactions of bromoaryl-substituted
b-lactams
⇑
Maryll Geherty, James Melnyk, Keith Chomsky, David A. Hunt
Department of Chemistry, The College of New Jersey, 2000 Pennington Road, Ewing, NJ 08628, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
b-Lactams are quite susceptible to ring opening when exposed to nucleophilic reagents. The robustness of
a variety of bromo- and iodoarenes containing electrophilic functional groups toward alkyllithium
reagents during the halogen–lithium exchange process was first described by Parham, Bradsher, and
co-workers. These observations led us to consider the behavior of bromoaryl-substituted b-lactams when
treated with n-butyllithium at À100 °C in tetrahydrofuran. The work discussed herein describes success-
ful halogen–metal exchange reactions on haloarene-substituted b-lactams thereby permitting a method
for aromatic ring elaborations in the presence of the highly electrophilic b-lactam ring.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 7 June 2013
Revised 24 June 2013
Accepted 1 July 2013
Available online 6 July 2013
Keywords:
Aryl-substituted b-lactams
Bromine–lithium exchange
Halogen–metal exchange
Functionalized aryllithiums
Introduction
normal conditions, would be of possible value toward the design
of new b-lactam derivatives, thereby serving as a tool in designing
In the 1970s, Parham and Bradsher demonstrated that halogen–
metal exchange reactions were possible on aryl bromides to form
aryl compounds bearing electrophilic groups (Scheme 1).1 These
reactions were conducted at low temperatures (typically
À100 °C) using either n-butyllithium or t-butyllithium as the ex-
change reagent. These studies established a new reaction para-
digm: halogen–lithium exchange reactions can occur at low
temperatures chemoselectively with little to no formation of un-
wanted side products resulting from reaction of the electrophilic
groups contained in the molecule with the alkylithium reagents.
Typically, these side reactions are observed at higher temperatures.
To the best of our knowledge, such reactions in the presence of
the b-lactam electrophilic moiety have yet to be investigated. As
previously indicated, these systems are of interest due to their
inherent biological activity with possible uses as anti-fungal agents
or b-lactamase inhibitors.2,3 While biological activity stems from
the very reactive four-membered b-lactam ring due to strain, the
same strain is also responsible for the reactivity of the system as
an electrophilic moiety (Scheme 2–penicillin reactivity).4 Nucleo-
philes, particularly oxygen nucleophiles, can attack the carbonyl
carbon5 leading to ring opening and a concomitant loss of biologi-
cal activity. The ability to perform chemical transformations on an
assembled b-lactam system, especially through the use of organo-
metallic reagents which function as potent nucleophiles under
b-lactam compounds as novel pharmaceutical agents (Scheme 2).
Results and discussion
Compounds containing the basic structure illustrated below (4)
are known to possess biological activity against some strains
of bacteria as well as fungi and constitute a new generation of
b-lactams.6 In addition, closely related analogs have proven effec-
tive as cholesterol absorption inhibitors.7 The preparation of
bromoaryl b-lactams within this series serves as a starting point
for the study described herein and involves a straightforward
8,9
two-step process as shown in Scheme 3.
While bromine substitution can occur at any position in either
aromatic ring, for the purpose of this study we prepared deriva-
tives containing bromine at the ortho- or meta-positions relative
to the point of attachment to the b-lactam due to ready availability
of the requisite starting materials (1, 2).
Halogen–lithium exchange was conducted at À100 °C in tetra-
hydrofuran using n-butyllithium as the organometallic exchange
reagent (Scheme 4). In order to determine whether the exchange
reaction occurred, the reaction mixture was quenched with various
electrophiles at low temperatures (H2O, CH3I, benzaldehyde, and
CO2/H3O+). Analysis of the reaction mixtures confirmed that inter-
mediates (5) did indeed form in the presence of the reactive
b-lactam ring, thereby proving that the b-lactam is indeed robust
enough to withstand the reaction conditions. The structures of
the elaborated b-lactams were confirmed by 1H NMR, 13C NMR,
IR, and GC/Mass spectra. (See Table 1)
⇑
Corresponding author.
E-mail address: hunt@tcnj.edu (D.A. Hunt).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.007

M. Geherty et al. / Tetrahedron Letters 54 (2013) 4934–4936
4935
(CH2)nX
Br
(CH2)nX
(CH2)nX
E+
n-C4H9Li
THF/-100 °C
warm to 25 °C
Li
E
n = 0-4
X = Br, Cl, CN, CO2H, CO2R
Scheme 1.
O
O
H
N
R'O
H
H
N
O
H
N
H
H
N
H
N
H
H
S
CH3
CH3
S
CH3
CH3
S
R
CH3
CH3
R
R
HN
OR'
O
H
O
O
CO2H
CO2H
CO2H
R'-OH
R'-O-H
Scheme 2.
X2
X2
X1
X1
NH2
X2
X1
CO2Et
Y1
Y2
Δ
+
N
-H2O
N
O
Y1
CHO
Y1
Y2
Y2
3a: X1=Br; X2=Y1=Y2=H
4a: X1=Br; X2=Y1=Y2=H
1a: X1=Br; X2=H
1b: X2=Br; X1=H
2a: Y1=H; Y2=H
2b: Y1=Br; Y2=H
3b
4b
: X2=Br; X1=Y1=Y2=H
: X2=Br; X1=Y1=Y2=H
3c: Y1=Br; X1=X2=Y2=H
3d: Y2=Br; X1=X2=Y1=H
4c: Y1=Br; X1=X2=Y2=H
4d: Y2=Br; X1=X2=Y1=H
1c
2c
: Y2=Br; Y1=H
: X1=H; X2=H
Scheme 3.
X2
X2
X2
X1
X1
X1
E+
n-BuLi
N
N
N
O
THF/-78 °C
O
O
Y1
Y2
Y1
Y1
Y2
Y2
4a: X1=Br; X2=Y1=Y2=H
5a: X1=Li; X2=Y1=Y2=H
6a: X1=E; X2=Y1=Y2=H
4b
: X2=Br; X1=Y1=Y2=H
5b
: X2=Li; X1=Y1=Y2=H
6b
: X2=E; X1=Y1=Y2=H
4c: Y1=Br; X1=X2=Y2=H
4d: Y2=Br; X1=X2=Y1=H
5c: Y1=Li; X1=X2=Y2=H
5d: Y2=Li; X1=X2=Y1=H
6c: Y1=E; X1=X2=Y2=H
6d: Y2=E X1=X2=Y1=H
Scheme 4.
The reaction of the bromoaryl b-lactams 4 in which a halogen–
metal exchange occurred at low temperatures to generate the reac-
tive intermediates 5 proved successful. The aryllithium which
formed was quenched with various electrophiles (including H2O,
CH3I, PhCHO, and CO2/H3O+) to afford the elaborated intermediates
in moderate to low yield with no products resulting from ring
opening of the highly reactive b-lactam ring observed.10
While these results indicate that halogen–metal exchange can
indeed occur at low temperatures without opening the b-lactam
ring system, efforts directed toward better understanding the reg-
ioselectivity effects of ring position (i.e., 4a vs 4b) with regard to
the efficiency of the exchange reaction remain to be studied. In
addition, further optimization work is necessary in order to fully
ascertain the potential of this method.

4936
M. Geherty et al. / Tetrahedron Letters 54 (2013) 4934–4936
formation. The resulting solution was then permitted to cool and was
Table 1
concentrated in vacuo to afford an oil which was purified by distillation in
vacuo to afford the product as a viscous yellow oil (29.59 g, bp 116 °C/0.7 Torr)
which solidified on standing, mp 43–44.5 °C (lit mp 45 °C. 1H NMR (CDCl3): d
6.73–7.80 (m, 9, ArH); 8.04 (s, 1, azomethine CH); IR (film) 1625 cmÀ1. Anal.
Calcd for C13H10BrN; C, 60.00; H, 3.85; Br, 30.77; N, 5.38. Found: C, 59.80; H,
3.68; Br, 30.42; N, 5.18.
Entry
Compound
E+
X/Y
% Yield (isolated)
1
2
3
4
5
6
7
8
9
6c
6c
6c
6a
6c
6b
6a
6d
6a
H2O
CH3I
PhCHO
H2O
C2H5I
H2O
CH3I
CH3I
CO2/HCl
H
62
66
9
46
62
69
50
47
67
CH3
CH(Ph)OH
H
C2H5
H
CH3
CH3
CO2H
9. General procedure for the preparation of bromoaryl b-lactams 4: Preparation of 1-
(2-bromophenyl)-3,3-dimethyl-4-phenylazetidin-2-one (4c): diisopropyl-
amine (809 mg, 8 mmol) in dry THF (15 ml) was placed in an oven-dried
100 mL 3-neck round bottomed flask equipped with
a low temperature
thermocouple, pressure-equalizing addition funnel, and nitrogen inlet. Under
nitrogen, the flask and its contents were cooled to À78 °C at which point n-
butyllithium (5 mL of 1.6 M in hexanes; 8 mmol) was added dropwise. After
the resulting mixture was stirred at À78 °C under nitrogen for 20 min, ethyl
isobutyrate (928 mg; 8 mmol) in THF (10 mL) was added dropwise. Stirring at
À78 °C continued for an additional 20 min at which point the desired Schiff
base (2.07 g; 8 mmol) was added dropwise at such a rate so as to maintain the
temperature below À70 °C. The resulting solution was allowed to stir for 1 h at
À78 °C, and then allowed to warm to room temperature and stir overnight
under nitrogen. The reaction mixture was poured into water (100 mL), and the
mixture was washed with EtOAc (2 Â 75 mL). The organics were dried
(MgSO4), filtered, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel eluting with a mixture of hexanes/ethyl
acetate. 1-(2-Bromophenyl)-3,3-dimethyl-4-phenylazetidin-2-one (4c) was
isolated as pale yellow needles (2.27 g, 91%), mp 58–62 °C; 1H NMR (CDCl3)
1.42 (s, 6H, CH3), 5.30 (s, 1H, azetidinone ring CH); 6.92 (t, 1H, ArH), 7.05–7.26
(m, 6H, ArH), 7.40 (d, 1H, ArH), 7.55 (d, 1H, ArH); 13C NMR (CDCl3) d 18.39,
23.04, 55.90, 69.78, 116.54, 126.38, 126.89, 127.62, 128.11, 128.21, 128.69,
Acknowledgments:
We wish to thank The College of New Jersey and Bristol Myers
Squibb for their generous support of this work.
References and notes
1. Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 10, 300–305.
2. Lewis, R. The Rise of Antibiotic-Resistant Infections. http://dwb4.unl.edu/chem/
chem869k/chem869klinks/www.fda.gov/fdac/features/795_antibio.html;
[accessed May 21, 2013].
3. http://www.cdc.gov/drugresistance/; [accessed May 21, 2013].
4. Patrick, G. L. Introduction to Medicinal Chemistry, 3rd ed.; Oxford Press: Oxford,
2005. Chapter 16.
5. For heteronucleophiles see: (a) Mukerjee, A. K.; Singh, A. K. Synthesis 1975,
547–589; (b) Mukerjee, A. K.; Singh, A. K. Tetrahedron 1978, 34, 1731–1767;
(c) Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose, A. K. Heterocycles 1988, 27,
1755–1802; For carbon nucleophiles see (d) Spero, D. M.; Kapadia, S.; Vittorio,
F. Tetrahedron Lett. 1995, 36, 4543–4546; (e) Palomo, C.; Aizpurua, J. M.; Garcia,
J. M.; Iturburu, M.; Odriozola, J. M. J. Org. Chem. 1994, 54, 5184–5188; (f) Kano,
S.; Ebata, T.; Shibuya, S. Chem. Pharm. Bull. 1979, 27, 2450–2455; (g)
Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F. Tetrahedron: Asymmetry
1999, 10, 4841–4849; (h) Panaiotova, B.; Pencheva, B. A.; Spasov, A. W. Doklady
Bolgarskoi Akademii Nauk 1972, 25, 787–790.
6. For example, see Vildan, G.; Yildirir, S.; Ozcelik, B.; Abbasoglu, U. Farmaco 2000,
55, 147–150.
7. Vaccaro, W.; Sher, R.; Davis, H. R. Bioorg. Med. Chem. Lett. 1998, 8, 319; (b) Repa,
J. J.; Dretschy, S. D.; Turley, S. D. J. Lipid Res. 2002, 43, 1864–1874. and
references cited therein.
8. General procedure for preparation of Schiff bases 3: Preparation of N-benzylidine-
o-bromoaniline (3c). o-Bromoaniline (25.00 g; 0.145 mol) and benzaldehyde
(15.41 g; 0.145 mol) were dissolved in toluene (500 mL) and placed in a round
bottomed flask equipped with a Dean–Stark trap and reflux condenser and
allowed to reflux until all of the water was removed through azeotrope
134.25, 134.86, 136.42, 172.45; IR (nujol) 1756 cmÀ1
17H16BrNO; C, 61.83; H, 4.88; Br, 24.20; N, 4.24. Found: C, 61.63; H, 4.56;
Br, 24.31; N, 4.37.
. Anal. Calcd for
C
10. General procedure for halogen–metal exchange of bromoaryl b-lactams 4:
Preparation of 3,3-dimethyl-1,4-diphenylazetidin-2-one (6b: X@Y@H):
bromoaryl b-lactam (4; 200 mg; 0.61 mmol) in dry THF was cooled to
À100 °C under nitrogen. n-Butyllithium (1.2 equiv of
a 1.6 M solution in
hexanes) was added at such a rate so as to maintain the temperature below
À90 °C. The resulting mixture was allowed to stir for 1 h at ca. À100 °C and was
then quenched with 1.5 equiv of the electrophile. The low temperature was
maintained for another hour and then the mixture was allowed to slowly
warm to room temperature. The reaction mixture was poured into water
(100 mL), and the resulting mixture was washed with EtOAc (2 Â 75 mL). The
organics were dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel eluting with a mixture of
hexanes/ethyl acetate. 3,3-Dimethyl-1,4-diphenylazetidin-2-one (7b: X@Y@H)
was isolated as a white amorphous solid (103 mg, 69%), mp 146–47.5 °C (lit11
mp 147.5–48.5 °C); 1H NMR (CDCl3) d 1.43 (s, 3H, CH3), 1.46 (s, 3H, CH3), 5.30
(s, 1H, azetidinone ring CH), 6.93–7.58 (m, 10H, ArH); 13C NMR (CDCl3) d 18.08,
22.95, 55.54, 66.59, 117.39, 123.80, 126.69, 128.15, 128.81, 129.15, 135.65,
137.99, 170.05; IR (nujol) 1733 cmÀ1
.
11. Gluchowski, C.; Cooper, L.; Bergbreuter, D. E.; Newcomb, M. J. Org. Chem. 1980,
45, 3413–3416.