Halogenation of 4-phenyl-3-(phenylsulfonyl)-2-azetidinones with N-halosuccinimides. Kinetic vs thermodynamic control

Full text of DOI:10.1021/jo000273c

J . Org. Chem. 2000, 65, 7203-7207
7203
Ch a r t 1
Ha logen a tion of
4-P h en yl-3-(p h en ylsu lfon yl)-2-a zetid in on es
w ith N-Ha losu ccin im id es. Kin etic vs
Th er m od yn a m ic Con tr ol
Patricia M. Freihammer and Michael R. Detty*
Departments of Chemistry and Medicinal Chemistry, State
University of New York at Buffalo, Buffalo, New York 14260
mdetty@acsu.buffalo.edu
Received February 26, 2000
Sch em e 1
The development of synthetic routes to monocyclic
2-azetidinones (â-lactams) was stimulated by the anti-
bacterial activity of monobactams and norcardicins.1
Although interest in 2-azetidinones as antibiotics has
waned, 2-azetidinones have served as important inter-
mediates in many other applications. Monocyclic 2-aze-
tidinones have been used as precursors to â-amino
alcohols and â-amino acids, useful building blocks for
peptides containing nonprotein amino acids.2-4 2-Azeti-
dinones have served as precursors to γ-lactones via N-
to O-acyl migration as demonstrated in the total synthe-
sis of the macrolide antitumor antibiotic Lankacidin C.5
Certain 2-azetidinones have also displayed potent cho-
lesterol absorption inhibitory activity.6
streochemistry have been prepared from the addition of
organometallic agents to 4-phenylazetidine-2,3-diones 3.8
We have recently described the synthesis of trans-3-
(arylsulfonyl)-4-phenylazetidinones 4 from the [3 + 1]
addition of ammonia or primary amines to 2-(arylsulfo-
nyl)cinnamic acid derivatives9 as well as an enantiose-
lective route to the same molecules.10 Oxidation of
compounds 4 to the equivalent oxidation state of dione 3
might provide useful precursors to novel side chains.
Herein, we describe the halogenation of C3 in compounds
4 with N-halosuccinimides, which proceeds with surpris-
ingly high diastereoselectivity in several cases.
Interest in the chemistry of 2-azetidinones increased
with the use of 3-hydroxy-4-phenyl-2-azetidinones 1
(Chart 1) as alternatives to N-benzoyl-(2R,3S)-3-phenyli-
soserine (2) for adding the side chain in the semisynthesis
of paclitaxel.7 These azetidinones have been prepared by
an ester enolate-imine condensation (a [2 + 2] cycload-
dition) to yield the correct stereochemistry in greater
than 96% ee. Other azetidinones with the correct alcohol
(1) Du¨rckheimer, W.; Blumbach, J .; Lattrell, R.; Scheinemann, K.
H. Angew. Chem., Int. Ed. Engl. 1985, 24, 180-202.
(2) (a) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita,
M.; Abe, R. J . Org. Chem. 1991, 56, 1681-1683. (b) Ojima, I.; Komata,
T.; Qui, X. J . Am. Chem. Soc. 1990, 112, 770. (c) Ojima, I.; Pei, Y.
Tetrahedron Lett. 1990, 31, 977.
(3) (a) Palomo, C.; Aizpurua, J . M.; Ganboa, I. In Enantioselective
Synthesis of â-Amino Acids; J uaristi, E., Ed.; Wiley-VCH: New York,
1997; pp 279-357. (b) J ung, M. J . In Chemistry and Biochemistry of
Amino Acids; Barrett, G. C., Ed.; Chapman and Hall: New York, 1985;
p 227.
(4) (a) Palomo, C.; Aizpurua, J . M.; Cuevas, C. J . Chem. Soc., Chem.
Commun. 1994, 1957-1958. (b) Palomo, C.; Aizpurua, J . M.; Galarza,
R.; Mielgo, A. J . Chem. Soc., Chem. Commun. 1996, 633-634.
(5) Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J . Am. Chem.
Soc. 1995, 117, 8258-8270.
(6) (a) McKittrick, B. A.; Ma, K.; Huie, K.; Yumibe, N.; Davis, H.,
J r.; Clader, J . W.; Czarniecki, M.; McPhail, A. T.; J . Med. Chem. 1998,
41, 752-759. (b) Burnett, D. A.; Caplen, M. A.; Davis, H. R., J r.;
Burrier, R. E.; Clader, J . W. J . Med. Chem. 1994, 37, 1733-1736. (c)
McKittrick, B. A.; Ma, K.; Dugar, S.; Clader, J . W.; Davis, H., J r.;
Czarniecki, M.; McPhail, A. T. Bioorg. Med. Chem. Lett. 1996, 6, 1947-
1950.
(7) (a) Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; J ayasinghe, L. R.
J . Org. Chem. 1991, 56, 1681-1683. (b) Holton, R. A.; Somoza, C.; Kim,
H.-B.; Liang, F.; Beidiger, R. J .; Boatman, P. D.; Shindo, M.; Smith,
C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.;
Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J . H. J . Am. Chem. Soc.
1994, 116, 1597-1600. (c) Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y.
H.; Duclos, O.; Kuduk, S. Tetrahedron Lett. 1996, 34, 4149-4152. (d)
Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.;
Brigaud, T. Tetrahedron. 1992, 48, 6985-7012. (e) Dasgupta, D.; Park,
H.; Harriman, G. C. B.; Georg, G. I.; Himes, R. H. J . Med. Chem. 1994,
37, 2976-2980. (f) Georg, G. I.; Cheruvallath, Z. S.; Himes, R. H.;
Mejillanao, M. R.; Burke, C. T. J . Med. Chem. 1992, 35, 4230-4237.
(g) Ojima, I.; Zucco, M.; Duclos, O.; Kuduk, S. D.; Sun, C. M.; Park, Y.
H. Bioorg. Med. Chem. Lett. 1993, 3, 2479-2482.
Resu lts a n d Discu ssion
P r ep a r a tion of tr a n s-3-(P h en ylsu lfon yl)-4-p h en -
yl-2-a zet id in on e. Z-3-Phenyl-2-(phenylthio)propenoic
acid (5) was prepared by the addition of thiophenol to
ethyl phenylpropiolate followed by saponification of the
resulting ethyl Z-3-phenyl-2-(phenylthio)propenoate.9 Oxi-
dation of 5 with hydrogen peroxide in acetic acid11 gave
Z-3-phenyl-2-(phenylsulfonyl)propenoic acid (6) in 65%
isolated yield following recrystallization from EtOAc
(Scheme 1). Compound 6 had previously been prepared
in two steps involving the isolation of the sulfoxide
intermediate.9 Compound 6 was converted to the acid
chloride 7 with oxalyl chloride in anhydrous chloroform
in the presence of 0.1 mol % DMF. The addition of
ammonia to 7 gave amide 8 in 16% isolated yield and
(8) Kant, J .; Schwartz, W. S.; Fairchild, C.; Gao, Q.; Huang, S.; Long,
B. H.; Kadow, J . F.; Langley, D. R.; Farina, V.; Vyas, D. Tetrahedron
Lett. 1996, 37, 6495-6498.
(9) Zhou, F.; Rosen, J .; Zebrowski-Young, J . M.; Freihammer, P. M.;
Detty, M. R.; Lachicotte, R. J . J . Org. Chem. 1998, 63, 5403-5412.
(10) Zhou, F.; Detty, M. R.; Lachicotte, R. J . Tetrahedron Lett. 1999,
40, 585-588.
(11) Paquette, L. A. and Carr, R. V. C. Org. Synth. 1986, 64, 157-
163.
10.1021/jo000273c CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/21/2000

7204 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
Sch em e 2
Ha logen a t ion of Azet id in on es 11 a n d 12 w it h
N-Ha losu ccin im id es. The addition of N-bromosuccin-
imide to 1-benzoylazetidinone 12 in the presence of
NaHCO3 gave two products in a 78:22 ratio that were
separable via chromatography on silica gel (Scheme 3).
The two products were isomeric based on NMR and mass
spectral data as well as on the elemental analyses for
the individual compounds. The spectral and analytical
data were consistent with the two diastereomers of 13,
which we designate as trans-13 and cis-13 in reference
to the orientation of the phenyl substituent on C4 relative
to the halogen substituent on C3. The major component
was unambiguously assigned the trans-stereochemistry
(trans-13) by X-ray crystallography. The protons at C4
appeared at distinctly different chemical shifts in the 1H
NMR spectra for the trans- and cis-stereoisomers, which
allowed the assignment of stereochemistry in the other
halogenation products. The C4 proton appeared at δ 5.92
for trans-13 and at δ 6.23 for cis-13.
Sch em e 3
Chlorination of 12 with N-chlorosuccinimide gave an
inseparable 67:33 mixture of monochloro products 14
with chemical shifts for the C4 proton of δ 5.78 for the
major product and δ 6.32 for the minor product. Iodina-
tion of 12 with N-iodosuccinimide gave monoiodo product
1
15 as a single stereoisomer (>98% by H NMR) with a
trans-3-(phenylsulfonyl)-4-phenyl-2-azetidinone (9) in 80%
isolated yield.
chemical shift of δ 5.93 for the proton at C4. By analogy
to diastereomers 13, the major component is assigned the
trans-stereochemistry (trans-14 and trans-15, respec-
tively), and the minor component is assigned the cis-
stereochemistry (cis-14) based on the chemical shifts of
the C4 protons.
P r otection of th e Azetid in on e Nitr ogen . The pro-
ton on C3 of azetidinone 9 should be relatively acidic due
to the electron-withdrawing nature of both the carbonyl
and the phenylsulfonyl groups. Oxidation of 9 with
positive halogen sources such as the N-halosuccinimides
should be possible in the presence of a base to assist in
deprotonation. The free amine proton of 9 may be
oxidized as well in the presence of N-halosuccinimides,
which necessitated protection of the azetidinone nitrogen.
Surprisingly, our initial attempts to protect the azeti-
dinone nitrogen with the tert-butoxycarbonyl (t-Boc)
protecting group under standard conditions failed to give
the desired azetidinone.12 Azetidinone 9 was treated with
1 equiv of triethylamine (TEA), 1 equiv of N,N-(dimethy-
lamino)pyridine (DMAP), and 2 equiv of di-tert-butyl
dicarbonate in CH2Cl2 to give tert-butyl ester 10 in 93%
isolated yield. As shown in Scheme 2, the desired product
11 most likely is formed, but ring-opening promoted by
the second equivalent of base would relieve the strain of
the four-membered ring. The subsequent loss of isocy-
anate would lead to the observed product.
Halogenation of the t-Boc-protected azetidinone 11
gave similar products, but with even greater diastereo-
selectivity for the trans-halogenated products than was
observed with azetidinone 12. The addition of N-chloro-
succinimide to 11 gave a 91:9 mixture of the two,
monochloro diastereomers 16 with chemical shifts for the
C4 proton of δ 5.45 for the major product and δ 6.02 for
the minor product. Bromination of 11 with N-bromosuc-
cinimide and iodination with N-iodosuccinimide gave only
one detectable diastereomer in each case (>98% diaste-
1
reoselectivity by H NMR) with chemical shifts for the
C4 proton of δ 5.90 for the monobromo product 17 and δ
5.62 for the monoiodo product 18. By analogy to the
stereochemical assignments for 13-15, the major com-
ponents of the 16-18 mixtures were assigned the trans-
stereochemistry based on the upfield chemical shift of the
protons at C4.
Kin etic vs Th er m od yn a m ic Con tr ol in th e Ha lo-
gen a tion s. The major product in each of the halogena-
tion reactions of 11 and 12 with N-halosuccinimides has
the bulky C4 phenyl and C3 phenylsulfonyl substituents
cis to one another. One might expect a trans-orientation
of these two groups and a cis-orientation of the C4 phenyl
and C3 halogen to have smaller steric interactions overall
and to be favored energetically. Simple MM2 calculations
on both diastereomers of 13-18 favor the cis-orientation
of halogen and phenyl relative to the trans-diastereomer
by 0.35-1.1 kcal mol-1. The high diastereoselectivities
observed for all three halogenations of 11 and for iodi-
nation of 12 were somewhat surprising.
We observed that heating the 3-halo azetidinones in
DMSO gave equilibration of cis- and trans-diastereomers.
Heating a DMSO solution of either the pure trans-
diastereomer of 13 or the pure cis-diastereomer of 13 at
80 °C for 15 h gave a 17:83 mixture of trans-13 to cis-13
at equilibrium, which indicates that the cis-diastereomer
The N-protected azetidinone 11 could be isolated using
1 equiv each of base and di-tert-butyl dicarbonate in CH2-
Cl2 to minimize the formation of 10. Potassium carbonate
was sluggish as a base giving a 13% isolated yield of 11
following 17 h at reflux, while either DMAP or TEA gave
11 in 66% isolated yield. The best results were obtained
using 1 equiv of pyridine as base, which gave 11 in 93%
isolated yield (Scheme 3).
Protection of the azetidinone nitrogen of 9 with the
N-benzoyl group using benzoyl chloride in CH2Cl2 was
also dependent upon the base employed. The use of one
equiv of TEA gave azetidinone 12 in 46% isolated yield.
The use of one equiv of DMAP gave 12 in 27% isolated
yield. Again, the use of pyridine as a base gave the best
results for the formation of 12, which was isolated in 73%
yield (Scheme 3).
(12) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48,
2424-2426.

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7205
Sch em e 4
were not characterized. Compound 19 was obtained in
50% isolated yield by the reaction of either diastereomer
of 13 with silver nitrate in DMF at 80 °C.
The structure of 19, which was isolated as an oil,
followed from its spectral data. The IR spectrum of 19
indicated a carbonyl band at 1637 cm-1 as did the 13C
NMR spectrum with a peak at δ 166.7, which are
consistent with the amide functional group. The 12
carbon signals in the aromatic region of the 13C NMR
spectrum are consistent with the three phenyl groups
with two aliphatic carbons at δ 60.55 and 50.23. The
F igu r e 1. Favored approach for kinetic control of azetidinone
halogenation.
1
aliphatic region of the H NMR spectrum displayed an
Sch em e 5
ABX pattern with signals centered at δ 3.53, 3.88, and
5.46 while the amide N-H was buried under the aro-
matic protons. The mass spectrum gave a parent ion
consistent with the C21H19NO3S molecular formula of 19.
Compound 19 is formally a reduction product of 13
under oxidative conditions. We assume that the 50%
maximum yield is consistent with half of the reactant
being oxidized to products unkown while half of the
reactant is reduced to 19 in the process.
is favored by approximately 0.9 kcal mol-1. It follows that
the initial bromination proceeds under kinetic control to
give the 78:22 mixture of trans- to cis-13.
As shown in Figure 1, deprotonation of azetidinone 11
or 12 would lead to an sp2-hybridized, delocalized car-
banion. The phenyl substituent would block approach of
the electrophile on the same face of the azetidinone, and
the trans-orientation of halogen and phenyl would result
as the kinetic product.
Su m m a r y a n d Con clu sion s
N-Benzoyl-protected azetidinone 11 and t-Boc-protect-
ed azetidinone 12 are readily halogenated by N-halosuc-
cinimides in CH3CN in the presence of NaHCO3 to give
3-halo-3-(phenylsulfonyl)-4-phenylazetidinones 13-18 in
64-84% isolated yield. The major products in the halo-
genation reactions have the C4 phenyl substituent and
the C3 halogen substituents trans to one another. Heat-
ing the trans-diastereomers in DMSO at 80 °C leads to
isomerization to the more stable cis-diastereomer, which
indicates that halogenation proceeds under kinetic con-
trol. The isomerization is accelerated in the presence of
silver(I) salts, but a new ring-opened product 19 is formed
in the process.
The bromides 17 derived from the t-Boc-protected
azetidinone 12 were more sluggish to equilibrate in
DMSO at 80 °C. However, a new singlet at δ 6.21 slowly
grew over 40 h at 80 °C (a 45:55 mixture of trans- to cis-
17 at this point, but decomposition products were also
beginning to appear). The chlorides 14 and 16 were even
slower to equilibrate in DMSO at 80 °C while decomposi-
tion of iodides 15 and 18 was competitive with the
equilibration of diastereomers. At higher temperatures
in DMSO, all of the halides 13-18 gave decomposition
products.
Red u ctive Rin g-Op en in g P r od u cts u n d er Oxid a -
tive Con d ition s. We sought to accelerate the equilibra-
tion of the diastereomers through the addition of silver(I)
salts such as silver tetrafluoroborate and silver nitrate.
The addition of the silver(I) salt to DMSO solutions of
13 not only accelerated the equilibration of diastereo-
mers, but also gave a new product that was identified
as the 1-amino-2-(phenylsulfonyl)ethane derivative 19
(Scheme 5). Compound 19 was isolated in 40-45% yield
under a variety of reaction conditions including silver
tetrafluoroborate or silver nitrate in the presence of
DMSO, triphenylphosphine oxide, or pyridine N-oxide (all
compounds that transfer oxygen via nucleophilic addi-
tion). In addition to 19, TLC analysis of the product
mixture was indicative of myriad other products that
The azetidinones 11 and 12 remain intact during the
halogenation process. We are currently investigating
reactions of 11-18 that lead to the formation of diones
3 in our quest for novel side-chain precursors for pacli-
taxel.
Exp er im en ta l Section
Gen er a l Meth od s. Solvents and reagents were used as
received from Sigma-Aldrich Chemical Co (St. Louis, MO) unless
otherwise noted. Concentration in vacuo was performed on a
Bu¨chi rotary evaporator. Elemental analyses were conducted by
Atlantic Microanalytical, Inc. Z-3-Phenyl-2-(phenylthio)prope-
noic acid (5) was prepared as reported in ref 9.
P r ep a r a tion of Z-3-P h en yl-2-(p h en ylsu lfon yl)p r op en oic
Acid (6). Acid 59 (5.00 g, 21.2 mmol) was dissolved in glacial
acetic acid (25 mL) with mild heating. Hydrogen peroxide (8.27
mL of a 30% solution, 73 mmol) was added via syringe. The
reaction was heated to reflux with stirring for 2 h. A color change
from deep yellow to pale yellow was noted. The reaction mixture

7206 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
was diluted with ether, washed with water, dried over MgSO4,
and concentrated. Crystallization from EtOAc gave 3.99 g (65%)
of 6 as a white crystalline solid, mp 70-73 °C; 1H NMR (CDCl3)
δ 7.95 (s, 1 H), 7.93 (m, 2 H), 7.49 (m, 5 H), 7.34 (m, 3 H); 13C
NMR (CDCl3) δ 165.6, 145.0, 140.4, 135.0, 134.2, 132.1, 131.9,
Meth od C. Azetidinone 9 (0.100 g, 0.350 mmol) was dissolved
in dry CH2Cl2 (5 mL). N,N-(Dimethylamino)pyridine (0.0425 g,
0.350 mmol) and di-tert-butyl dicarbonate (0.0915 g, 0.417 mmol)
were added successively. The reaction mixture was stirred for 1
h at ambient temperature and was then concentrated. The
residue was purified by chromatography on SiO2 eluted with 10%
EtOAc-hexanes followed by recrystallization from EtOAc-
hexanes to give 0.09 g (66%) of 11 as a white powder, mp 150-
152 °C.
130.7, 129.6, 129.4, 129.1; IR (KBr) 3000 (br), 1727, 1615 cm-1
;
FAB MS, m/z 289 (C15,H12O4S + H+), 244 (M - CO2), 102 (base
peak, HCCPh+). Anal. Calcd for C15H12O4S: C, 62.48; H, 4.20.
Found: C. 62.59; H, 4.26.
P r ep a r a tion of Z-3-P h en yl-2-(p h en ylsu lfon yl)p r op en oyl
Ch lor id e (7). Acid 3 (1.00 g, 3.49 mmol) was dissolved in
anhydrous CHCl3 (10 mL). Oxalyl chloride (10 mL) was added
followed by the addition of 10 µL of N,N-dimethylformamide.
The resulting solution was heated at reflux for 4 h. The reaction
mixture was concentrated in vacuo and was used without further
purification. For 7: 1H NMR (CDCl3) δ 8.30 (s, 1 H), 7.85 (m,
2 H), 7.65 (m, 1 H), 7.55 (m, 2 H), 7.45-7.30 (m, 5 H).
Ad d ition of Am m on ia to 7. Propenoyl chloride 7 (1.07 g,
3.49 mmol) was dissolved in dry CH2Cl2 (35 mL) in a flask
equipped with a gas condenser containing a dry ice-acetone
cooling bath. Approximately 0.50 g (≈30.0 mmol) of ammonia
was condensed into the reaction mixture. The resulting solution
was stirred at ambient temperature for 0.5 h. Ammonia was
allowed to evaporate, and the reaction mixture was concentrated.
The products were separated by chromatography on SiO2 eluted
with 20% EtOAc-CH2Cl2 to give 0.14 g (14%) of propenamide 8
(mp 177-178 °C from CH3CN) and 0.80 g (80%) of trans-
azetidinone 9 (mp 167-168 °C from CH3CN).
F or Z-3-p h en yl-2-(p h en ylsu lfon yl)p r op en oyl a m id e
(8): 1H NMR (CDCl3) δ 7.93 (m, 2 H), 7.86 (s, 1 H), 7.45-7.65
(m, 5 H), 7.39 (m, 3 H), 6.42 (br s, 1 H), 5.70 (br s, 1 H); IR
(CDCl3) 1687, 1620 cm-1; FAB MS, m/z 288 (C15H13O3SN + H+).
Anal. Calcd for C15H13O3SN: C, 62.70; H, 4.56; N, 4.87. Found:
C, 62.76; H, 4.61; N, 4.83.
F or tr a n s-4-p h en yl-3(p h en ylsu lfon yl)a zetid in -2-on e (9):
1H NMR (CDCl3) δ 8.03 (d, 2 H), 7.70 (m, 1 H), 7.59 (m, 2 H),
7.36 (m, 5 H), 6.32 (br s, 1 H), 5.26 (d, 1 H, J ) 2 Hz), 4.38 (d,
1 H, J ) 2 Hz); 13C NMR (CDCl3) δ 159.3, 138.3, 137.2, 135.2,
130.0,129.7, 129.6, 129.5, 126.3, 79.4, 53.4; IR (KBr) 2983, 1791
cm-1; FAB MS, m/z 288 (C15H13O3SN + H+). Anal. Calcd for
C15H13O3SN: C, 62.70; H, 4.56; N, 4.87. Found: C, 62.25; H,
4.60; N, 4.83.
P r ep a r a tion of ter t-Bu tyl Z-3-p h en yl-2-(p h en ylsu lfon yl)-
p r op en oa te (10). Azetidinone 9 (0.500 g, 1.75 mmol) was
dissolved in dry CH2Cl2 (3.5 mL). Triethylamine (0.24 mL, 1.75
mmol), N,N-(dimethylamino)pyridine (0.214 g, 1.75 mmol), and
di-tert-butyl dicarbonate (0.764 g, 3.50 mmol) were added. The
solution was stirred under argon at ambient temperature for 2
h and then concentrated in vacuo. The product was isolated by
chromatography on SiO2 eluted with 10% hexanes-CH2Cl2.
Crystallization from CH2Cl2 gave 0.56 g (93%) of 10 as a white
crystalline solid, mp 96-97 °C: 1H NMR (CDCl3) δ 7.94 (d, 2
H), 7.87 (s, 1 H), 7.63 (t, 1 H), 7.54 (t, 2 H), 7.47 (d, 2 H), 7.38 (q,
3 H), 1.35 (s, 9 H); 13C NMR (CDCl3) δ 162.1, 142.3, 140.2, 136.1,
133.6, 131.9, 131.3, 130.0, 129.1, 128.8, 128.5, 84.2, 27.6; IR
(KBr) 3068, 2982, 1718, 1618, 1142, 1032 cm-1; EIMS m/z 344
(C19H20O4S). Anal. Calcd for C19H20O4S: C, 66.25; H, 5.85.
Found: C, 66.39; H, 5.92.
P r ep a r a tion of tr a n s-N-(ter t-Bu toxyca r bon yl)-4-p h en yl-
3-(p h en ylsu lfon yl)-2-a zetid in on e (11). Meth od A. Azetidi-
none 9 (0.100 g, 0.350 mmol) was dissolved in dry CH2Cl2 (5
mL). Potassium carbonate (0.100 g) and di-tert-butyl dicarbonate
(0.153 g, 0.700 mmol were added successively. The reaction
mixture was allowed to stir for 17 h under argon at ambient
temperature. Potassium carbonate was removed by filtration,
and the filtrate was concentrated. The residue was purified by
chromatography on SiO2 eluted with 10% EtOAc-hexanes
followed by recrystallization from EtOAc-hexanes to give 0.14
g (13%) of 11 as a white powder, mp 151-152 °C.
Meth od D. Azetidinone 9 (0.810 g, 2.82 mmol) was dissolved
in dry CH2Cl2 (15 mL). Pyridine (0.229 mL, 2.82 mmol) and di-
tert-butyl dicarbonate (0.744 g, 3.40 mmol) were added succes-
sively. The reaction mixture was allowed to stir for 22 h at
ambient temperature and then concentrated. The residue was
purified by chromatography on by chromatography on SiO2
eluted with 20% EtOAc-hexanes. The product was recrystallized
from EtOAc-hexanes to give 1.01 g (93%) of 11 as a white
powder, mp 150-152 °C: 1H NMR (CDCl3) δ 7.98 (d, 2 H), 7.71
(t, 1 H), 7.59 (t, 2 H), 7.33 (d, 5 H), 5.44 (s, 1 H), 4.38 (s, 1 H),
1.38 (s, 9 H); 13C NMR (CDCl3) δ 156.2, 146.8, 137.6, 135.4, 135.1,
129.8, 129.5, 129.4, 129.2, 126.0, 84.9, 77.7, 56.1, 27.9; IR (KBr)
3060, 2985, 1806, 1723, 1450, 1339, 1027, 1153 cm-1; EI MS,
m/z 244 (C14H12O2S+, M - CO2 - HNCO - C4H8). Anal. Calcd
for C20H21O5NS: C, 61.99; H, 5.46; N, 3.62. Found: C, 61.94; H,
5.53; N, 3.54.
P r ep a r a tion of tr a n s-N-Ben zoyl-4-p h en yl-3-(p h en ylsu l-
fon yl)-2-a zetid in on e (12). Meth od A. Azetidinone 9 (0.200 g,
0.777 mmol) was dissolved in dry CH2Cl2. TEA (0.078 g, 0.78
mmol) and benzoyl chloride (0.108 mL, 0.933 mmol) were added
successively. The reaction mixture was allowed to stir for 28 h
under argon at ambient temperature. The reaction mixture was
diluted with water and extracted with CH2Cl2. The organic
layers were combined, washed with brine, dried over MgSO4,
and concentrated. The residue was purified by chromatography
on SiO2 eluted with CH2Cl2 followed by recrystallization
from EtOAc to give 0.14 g (46%) of 12 as a white solid, mp 149-
150 °C
Meth od B. Azetidinone 9 (0.110 g, 0.386 mmol) was dissolved
in dry CH2Cl2 (5 mL). N,N-(Dimethylamino)pyridine (0.0417 g,
0.386 mmol) and benzoyl chloride (0.0538 mL, 0.463 mmol) were
added successively. The reaction mixture was allowed to stir for
4 h under argon at ambient temperature. The reaction mixture
was diluted with water and extracted with CH2Cl2. The organic
layers were combined, washed with brine, dried over MgSO4,
and concentrated. The residue was purified by chromatography
on SiO2 eluted with CH2Cl2 followed by recrystallization from
EtOAc to give 0.40 g (27%) of 12 as a white, flakey solid, mp
149-150 °C.
Meth od C. Azetidinone 9 (1.10 g, 3.86 mmol) was dissolved
in dry CH2Cl2 (25 mL). Pyridine (0.305 g, 3.86 mmol) and benzoyl
chloride (0.538 mL, 4.63 mmol) were added successively. The
reaction mixture was allowed to stir for 4 h under argon at
ambient temperature. The reaction mixture was diluted with
water and extracted with CH2Cl2. The organic layers were
combined, washed with brine, dried over MgSO4, and concen-
trated. The residue was purified by chromatography on SiO2
eluted with CH2Cl2 followed by recrystallization from EtOAc to
give 1.10 g (73%) of 12 as a white, flakey solid, mp 149-150 °C;
1H NMR (CDCl3) δ 7.99 (t, 4 H), 7.75 (t, 1 H), 7.65 (q, 3 H), 7.48
(t, 2 H), 7.36 (s, 5 H), 5.8 (d, 1 H, J ) 3.3), 4.52 (d, 1 H, J ) 3.6);
13C NMR (CDCl3) δ 165.9, 155.8, 135.7, 135.1, 134.9, 133.9,
130.9, 129.9, 129.2, 129.1, 128.9, 128.4, 125.7, 75.6, 54.3; IR
(KBr) 1816, 1685, 1448, 1294, 1156 cm-1; EI MS m/z 250
(C16H12O2N+, M - C6H5SO2). Anal. Calcd for C22H17O4NS: C,
67.50; H, 4.38; N, 3.58; S, 8.19. Found: C, 67.58; H, 4.31; N,
3.58; S, 8.10.
P r ep a r a tion of 1-Ben zoyl-3-br om o-4-p h en yl-3-(p h en yl-
su lfon yl)a zetid in -2-on es (13). Azetidinone 12 (0.500 g, 1.28
mmol) was dissolved in CH3CN (8.0 mL). N-Bromosuccinimide
(0.273 g, 1.53 mmol) was added followed by saturated NaHCO3
solution (2.0 mL). The reaction mixture was stirred at 40 °C for
5 h. Water was added, and the resulting mixture was extracted
with CH2Cl2. The combined organic extracts were dried over
MgSO4 and concentrated. The residue was purified by chroma-
tography on SiO2 eluted with 50% CH2Cl2-hexanes to give 0.300
g (50%) of a white crystalline solid identified as the trans-isomer
Meth od B. Azetidinone 9 (0.100 g, 0.350 mmol) was dissolved
in dry CH2Cl2 (5 mL). Triethylamine (0.0488 mL, 0.350 mmol)
and di-tert-butyl dicarbonate (0.153 g, 0.700 mmol) were added
successively. The reaction mixture was stirred for 49.5 h under
argon at ambient temperature. The reaction mixture was
concentrated. The residue was purified by chromatography on
SiO2 eluted with 10% EtOAc-hexanes followed by recrystalli-
zation from EtOAc-hexanes to give 0.090 g (66%) of 11 as a
white powder, mp 151-152 °C.

Notes
J . Org. Chem., Vol. 65, No. 21, 2000 7207
(trans-13) and 0.0843 g (14%) of a white powder identified as
the cis-isomer (cis-13) following recrystallization from EtOAc-
hexanes.
(0.200 g, 0.516 mmol) was dissolved in CH3CN (2.0 mL) and
N-bromosuccinimide (0.101 g, 0.568 mmol) was added followed
by saturated NaHCO3 (0.50 mL). The reaction mixture was
stirred at 40 °C for 3 h and then was diluted with water. The
products were extracted with CH2Cl2. The combined organic
extracts were dried over MgSO4 and concentrated. The 1H NMR
spectrum of the crude product mixture was indicative of >98%
of a single diastereomer of 17. The residue was purified by
chromatography on SiO2 eluted with 70% CH2Cl2-hexanes to
give 0.194 g (81%) of 17 as a white powder following recrystal-
lization from EtOAc-hexanes: mp 148-149 °C; 1H NMR
(CDCl3) δ 8.03 (s, 2 H), 7.74 (t, 1 H), 7.60 (t, 2 H), 7.40 (d, 3 H),
7.26 (s, 2 H), 5.90 (s, 1 H), 1.43 (s, 9 H); 13C NMR (CDCl3) δ
156.4, 147.6, 135.5, 134.2, 132.7, 131.1, 129.5, 129.1, 128.6, 127.1,
1
For trans-13: mp 198 °C (dec); H NMR (CDCl3) δ 8.13 (d, 2
H), 7.70 (m, 5 H), 7.56 (t, 2 H), 7.42 (m, 6 H), 5.92 (s, 1 H); 13C
NMR (CDCl3) δ 165.2, 156.8, 135.9, 135.0, 134.6, 130.7, 130.4,
129.7, 129.1, 128.8, 128.4, 128.2, 72.4, 69.0; IR (KBr) 3063, 2361,
1805, 1685, 1294, 1155, 726 cm-1; FAB(+) MS m/z 470
(C22H16O479BrNS + H+). Anal. Calcd for C22H16O4BrNS: C,
56.18; H, 3.43; Br, 16.99; N, 2.98; S, 6.82. Found: C, 56.30; H,
3.44; Br, 17.11, N, 3.01; S, 6.72.
1
For cis-13: mp 167-168 °C; H NMR (CDCl3) δ 8.02 (t × d,
4 H), 7.76-7.49 (m, 6 H), 7.38 (m, 3 H), 7.26 (m, 2 H), 6.23 (s, 1
H); 13C NMR (CDCl3) δ 165.2, 156.4, 135.5, 134.3, 134.1, 132.7,
131.1, 130.7, 130.6, 130.1, 129.5, 129.1, 128.8, 128.5, 126.9, 59.2;
IR (KBr) 3066, 2960, 1797, 1683, 1260, 1149, 711 cm-1; FAB
MS m/z 470 (C22H16O479BrNS + H+). Anal. Calcd for C22H16O4-
BrNS: C, 56.18; H, 3.43; Br, 16.99; N, 2.98; S, 6.82. Found: C,
56.03; H, 3.34; Br, 17.10, N, 2.91; S, 6.72.
85.4, 78.6, 60.8, 27.8; IR (KBr) 3068, 2974, 2363, 1820, 1736,
79
1326, 1326, 1155, 559 cm-1; FAB(+) MS m/z 466 (C20H20O5
-
BrNS + H+). Anal. Calcd for C20H20O5BrNS: C, 51.51; H, 4.32;
Br, 17.14; N, 3.00; S, 6.88. Found: C, 51.62; H, 4.39; Br, 17.22;
N, 2.92; S, 6.76.
P r ep a r a tion of 1-Ben zoyl-3-ch lor o-4-p h en yl-3-(p h en yl-
su lfon yl)a zetid in -2-on e (14). Azetidinone 12 (0.250 g, 0.638
mmol) was dissolved in CH3CN (2.5 mL) and N-chlorosuccin-
imide (0.111 g, 0.830 mmol) was added in one portion followed
by saturated NaHCO3 (0.62 mL). The reaction mixture was
stirred at 40 °C for 3 h. Water was added, and the products were
extracted with CH2Cl2. The combined organic extracts were dried
over MgSO4 and concentrated. The residue was purified by
chromatography on SiO2 eluted with CH2Cl2 to give 0.187 g
(69%) of 14 as an inseparable mixture of the two isomers in a
67:33 ratio by 1H NMR. For trans-14 (major component): 1H
NMR (CDCl3) δ 8.14 (d, 2 H), 7.74-7.26 (m, 13 H), 6.32, (s, 1
H). For cis-14: 1H NMR (CDCl3) δ 8.03 (q, 2 H), 7.74-7.26 (m,
13 H), 5.78 (s, 1 H). For the mixture: IR (KBr) 3064, 2960, 2359,
1811, 1683, 1294, 1157, 688 cm-1; FAB(+) MS m/z 426 (C22H16O4-
ClNS+H+). Anal. (of the mixture) Calcd for C22H16O4ClNS: C,
62.05; H, 3.79; N, 3.29. Found: C, 61.89; H, 3.94; N, 3.16.
P r ep a r a tion of 1-Ben zoyl-3-iod o-4-p h en yl-3-(p h en ylsu l-
fon yl)a zetid in -2-on e (15). Azetidinone 12 (0.200 g, 0.511
mmol) was dissolved in CH3CN (2.0 mL), and N-iodosuccinimide
(0.149 g, 0.664 mmol) was added in one portion followed by
saturated NaHCO3 (0.50 mL). The reaction was stirred at 40
°C for 3 h. The reaction was diluted with water (20 mL) and
extracted with CH2Cl2 (30 mL × 2). The combined organic
extracts were dried over MgSO4 and concentrated. The 1H NMR
spectrum of the crude reaction mixture showed >98% of a single
stereoisomer of 15 with perhaps a trace of the second diastere-
omer at δ 6.22. The residue was purified by chromatography on
SiO2 eluted with CH2Cl2 to give 0.215 g (71%) of trans-15 as a
white powder following recrystallization from EtOAc-hexanes:
mp 156-157 °C; 1H NMR (CDCl3) δ 8.03 (t, 4 H), 7.74-7.51 (m,
7 H), 7.43 (d, 3 H), 7.25 (s, 1 H), 5.93 (s, 1 H); 13C NMR (CDCl3)
δ 165.2, 157.6, 135.4, 135.3, 134.4, 134.2, 131.2, 130.7, 130.1,
129.5, 129.0, 128.7, 128.5, 126.4, 61.8, 58.9; IR (KBr) 3062, 2361,
1796, 1691, 1290, 1152, 561 cm-1; FAB(+) MS m/z 518 (C22H16O4-
INS + H+). Anal. Calcd for C22H16O4INS: C, 51.08; H, 3.12; N,
2.71. Found: C, 50.86; H, 3.16; N, 2.57.
P r ep a r a tion of 1-(ter t-Bu toxyca r bon yl)-3-iod o-4-p h en yl-
3-(p h en ylsu lfon yl)a zetid in -2-on e (18). Azetidnone 11 (0.150
g, 0.387 mmol) was dissolved in CH3CN (2.0 mL), and N-
iodosuccinimide (0.113 g, 0.503 mmol) was added in one portion
followed by saturated NaHCO3 (0.50 mL). The reaction was
stirred at 40 °C for 3 h and was then diluted with water. The
products were extracted with CH2Cl2. The combined organic
extracts were dried over MgSO4 and concentrated. The 1H NMR
spectrum of the crude product mixture was indicative of >98%
of a single diastereomer of 18. The residue was purified by
chromatography on SiO2 eluted with 70% CH2Cl2-hexanes to
give 0.165 g (84%) of 18 as a white powder following recrystal-
lization from EtOAc-hexanes: mp 129-131 °C; 1H NMR
(CDCl3) δ 8.04 (dxd, 2 H), 7.72 (txd, 1 H), 7.60 (t, 2 H), 7.41 (d,
3 H), 7.20 (d of d, 2 H), 5.62 (s, 1 H), 1.42 (s, 9 H); 13C NMR
(CDCl3) δ 157.5, 146.6, 135.3, 135.2, 134.5, 131.1, 129.5, 128.9,
128.5, 126.6, 85.2, 62.9, 60.5, 27.7; IR (KBr) 3067, 2984, 2363,
1814, 1736, 1324, 1153, 544 cm-1; FAB(+) MS m/z 514 (C20H20O5-
INS+H+). Anal. Calcd for C20H20O5INS: C, 46.80; H, 3.93; N,
2.73. Found: C, 46.73; H, 4.01; N, 2.67.
Isom er iza tion of 13. A 50-mg sample of either trans-13 or
cis-13 was dissolved in 3 mL of dry DMSO, and the resulting
solution was heated at 80 °C in a constant temperature oil bath
for 15 h. The reaction mixture was diluted with water, and the
products were extracted with ether. The combined ether extracts
were washed with several portions of brine, dried over Na2SO4,
and concentrated to give 45 mg (90% recovery) of trans- and cis-
13. The ratio of diastereomers was determined from the 1H NMR
spectrum of the crude product mixture.
Rea ction of 13 w ith Silver Nitr a te in DMF . P r ep a r a tion
of N-Ben zoyl-1-p h en yl-2-(p h en ylsu lfon yl)eth yla m in e (19).
A mixture of silver nitrate (0.170 g, 1.00 mmol) and cis- or trans-
13 (0.235 g, 0.500 mmol) in 10 mL of DMF was stirred for 4 h
at 80 °C. The reaction mixture was poured into water, and the
products were extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over Na2SO4, and
concentrated. The residue was purified via chromatography on
SiO2 eluted with CH2Cl2-hexanes (1:1) to give 0.092 mg (50%)
of 19 as a colorless oil: 1H NMR (CDCl3) δ 7.81 (t × d, 4 H),
7.59 (t, 1 H), 7.52-7.40 (m, 6 H), 7.24 (s, 5 H), 5.49-5.44 (m, 1
H), 3.83 (d × d, 1 H, J ) 14.4), 3.58 (d × d, 1 H, J ) 15 Hz), 13C
NMR (CD2Cl2) δ 166.70, 139.74, 134.38, 134.26, 132.42, 132.16,
129.80, 129.22, 128.98, 128.37, 128.31, 127.44, 126.65, 60.55,
P r ep a r a tion of 1-(ter t-Bu toxyca r bon yl)-3-ch lor o-4-p h en -
yl-3-(p h en ylsu lfon yl)a zetid in -2-on es (16). Azetidinone 11
(0.250 g, 0.645 mmol) was dissolved in CH3CN (2.5 mL) and
N-chlorosuccinimide (0.112 g, 0.839 mmol) was added in one
portion followed by saturated NaHCO3 (0.62 mL). The reaction
was stirred at 40 °C for 4 h. The reaction was diluted with water
and extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4 and concentrated. The 1H NMR spectrum of
the crude product mixture was indicative of a 91:9 mixture of
the two diastereomers of 16 based on the C4 singlets at δ 5.45
for the major comonent and δ 6.05 for the minor component.
The residue was purified by chromatography on SiO2 eluted with
CH2Cl2 to give 0.187 g (69%) of 16 as a white powder: mp 133-
50.23, IR (KBr) 3257, 3063, 2934, 1637, 1535, 1300, 1143 cm-1
;
FAB(+)MS m/z 366 (C21H19NO3S + H+). Anal. Calcd for C21H19
-
NO3S: C, 69.02; H, 5.24; 3.83. Found: C, 68.74; H, 5.23; N, 3.80.
Su p p or tin g In for m a tion Ava ila ble: ORTEP plot, ex-
perimental procedure, crystal data and structure refinement,
atomic coordinates and equivalent isotropic displacement
parameters, bond lengths and angles, anisotropic displacement
parameters, and hydrogen coordinates and isotropic displace-
ment parameters for trans-13 and Cartesian coordinates and
computed total energies for the MM2 calculations on cis- and
trans-13-18. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
134 °C; H NMR (CDCl3) δ 7.74 (d, 2 H), 7.44 (m, 8 H), 5.45 (s,
1 H), 1.42 (s, 9 H); 13C NMR (CDCl3) δ 156.7, 146.5, 135.0, 130.6,
129.7, 129.2, 129.0, 128.8, 128.4, 128.1, 85.5, 70.4, 27.7; IR (KBr)
3084, 2978, 2338, 1820, 1735, 1326, 1159, 774 cm-1; FAB(+) MS
m/z 422 (C20H20O5ClNS + H+), 424.2. Anal. Calcd for C20H20O5-
ClNS: C, 56.94; H, 4.78; N, 3.32. Found: C, 56.82; H, 4.86; N,
3.27.
P r epar ation of 1-(ter t-Bu toxycar bon yl)-3-br om o-4-ph en -
yl-3-(p h en ylsu lfon yl)a zet id in -2-on e (17). Azetidinone 11
J O000273C