Improved Synthetic Utility of a Sluggish Electrophile: Reaction of Chlorosulfonyl Isocyanate with Unreactive and Reactive Alkenes

Article abstract of DOI:10.1055/s-0034-1380553

Chlorosulfonyl isocyanate (CSI) is a sluggish electrophile in reactions with electron-deficient alkenes or with many monofluoroalkenes. The efficiency of these reactions is improved at temperatures between 15 and 25C because, at these temperatures, CSI an

Full text of DOI:10.1055/s-0034-1380553

SYNTHESIS
0
0
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1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1944–1950
paper
1944
D. F. Shellhamer et al.
Paper
Synthesis
Improved Synthetic Utility of a Sluggish Electrophile: Reaction of
Chlorosulfonyl Isocyanate with Unreactive and Reactive Alkenes
Dale F. Shellhamer*
Kelsey L. Alexander
Summer A. Bunting
Sarah L. Elwin
O
bimolecular
the unimolecular reaction of
CSI to give N-chlorosulfonyl-b-
lactams is more efficient than
the bimolecular reaction carried
out above 25 °C
X
SO2Cl
Christine J. Licata
Jacob C. Milligan
Ryan D. Robinson
Danielle E. Shipowick
Lincoln B. Smith
Marc C. Perry
complex
or
unimolecular
+ ClSO2N=C=O
(CSI)
SET
intermediate
X
X = H or
F
Department of Chemistry, Point Loma Nazarene University,
3900 Lomaland Drive, San Diego, CA 92106-2899, USA
dshellha@pointloma.edu
Received: 16.02.2015
Accepted after revision: 19.03.2015
Published online: 22.04.2015
We recently reported that reactions of CSI below room
temperature show nonlinear Arrhenius relationships in
which the rate of the reaction increases as a result of a pre-
equilibrium (Schemes 1 and 2).5a Cooling the reaction mix-
ture to below room temperature drives the equilibrium to-
ward a complex or a single-electron transfer (SET) interme-
diate that increases the reaction rate, as shown by the
nonlinear Arrhenius plots.5a,6 Our kinetic studies also
showed that monofluoroalkenes with an ionization poten-
tial (IP) of more than 8.9 eV react by a concerted pathway
(Scheme 1),5a whereas alkenes with IP values of less than
8.5 eV react by the SET pathway (Scheme 2).5a,6
DOI: 10.1055/s-0034-1380553; Art ID: ss-2015-m1497-op
Abstract Chlorosulfonyl isocyanate (CSI) is a sluggish electrophile in
reactions with electron-deficient alkenes or with many monofluoro-
alkenes. The efficiency of these reactions is improved at temperatures
between –15 and 25 °C because, at these temperatures, CSI and the
alkene are in equilibrium with an intermediate. A unimolecular reaction
of the intermediate at a temperature between –15 and 25 °C is more
efficient than the bimolecular reaction of the dissociated reagents
above room temperature. This finding provides a method for improving
the reactions of CSI with unreactive alkenes.
Key words electrophilic additions, alkenes, amides, radical cations,
complexes, cycloadditions
We used these findings to improve the synthetic utility
of reactions of CSI with a wide range of reactive and unre-
active alkenes in several solvents. Previously reported
yields of N-chlorosulfonyl β-lactam products from CSI and
electron-deficient hydrocarbon alkenes or unreactive
monofluoroalkenes were poor.1e,f,5b An improved synthesis
of N-chlorosulfonyl β-lactams and N-chlorosulfonyl β-fluo-
rolactams is desirable because the corresponding reduced
β-lactams have a wide range of potential uses.1e,f,2c,3a–e,4a–k
The alkenes that we investigated in this study are listed
in Table 1. The results listed in Table 1 for 4-chlorostyrene
(1) represent a thorough study of the reactions of CSI (Table
1, entries 1–21). After entry 22, Table 1 lists only the opti-
mal reaction conditions along with a few selected reactions
for alkenes 2 through 13. For these alkenes, more-detailed
sets of data for their reactions with CSI (like those given in
Chlorosulfonyl isocyanate (ClSO2NCO; CSI) is a highly
versatile and reactive isocyanate,1 but it is unreactive with
electron-deficient alkenes. CSI reacts with alkenes to give
N-chlorosulfonyl β-lactams that can be readily reduced to
the corresponding β-lactams (azetidin-2-ones).2,3 This reac-
tion sequence provides a synthetic route to a wide range of
products, including β-lactam antibiotics,4a–e potential cho-
lesterol-lowering drugs,4f and various derivatives from ring-
opening chlorosulfonyl reactions,1e,f,2c,3b–d,4g,h from nitrogen
alkylations of the reduced azetidin-2-ones,3e from oxygen
alkylations to give imino ethers,3c,4i from free-radical ring-
opening reactions,4j and from allylations of the N-chlorosul-
fonyl β-lactams.4k
R
R
R
alkenes with IP values > 8.9 eV
F
N
C O
F
+
N
fast
slow step, unimolecular
but second-order
ClO2S
F
ClO2S
O
CSI
complex
( CSI )
E- and Z-alkenes are stereospecific
Scheme 1 Concerted pathway for the reaction of chlorosulfonyl isocyanate with alkenes
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1944–1950

1945
D. F. Shellhamer et al.
Paper
Synthesis
R
X
R
R
monofluoroalkenes with
IP < 8.5 eV when X = F
X
R
X
X
+
CSI
N
C O
or
fast
N
C O
N=C=O
hydrocarbon alkenes when
X = H, alkyl, aryl
SO2
Cl
ClO2S
O2S
Cl
R = alkyl, aryl
X = F, H
complex
SET intermediate
O
slow step
R
N
X
unimolecular but
second-order
SO2Cl
Scheme 2 Proposed single-electron-transfer stepwise pathway for the reaction of chlorosulfonyl isocyanate with alkenes
Table 1, entries 1–21, for alkene 1) are available in the Sup-
porting Information. In Table 1,Tmax is the low temperature
that gives the best product yield for analytical reactions run
in an NMR tube. Preparative reactions run at the Tmax tem-
perature were conducted on a 6 mmol scale and are shown
in bold face in Table 1.
times. These reactions show a linear Arrhenius behavior
above room temperature5a or below –15 °C. Between room
temperature and –15 °C, the equilibrium is shifting toward
the complex or SET intermediate, which reacts in a more ef-
ficient manner than do the dissociated reagents (Scheme
2).5a,6
Microwave initiation of the reaction of CSI with 4-chlo-
rostyrene (1) or other unreactive electron-deficient alkenes
has not been productive because the polar N-chlorosulfonyl
β-lactam products decompose at temperatures above
60 °C.6 Graf reported that 4-chlorostyrene (1) reacts poorly,
but gave no details.1e,f We previously reported the reaction
of 4-chlorostyrene (1) with CSI in dichloromethane at 55 °C
and isolated the N-chlorosulfonyl β-lactam product in 40%
yield.5a On the basis of our kinetic study,5a we reduced the
temperature for this reaction, and we found that the yield
of the product from 1 and CSI was maximal (97% isolated) at
10 °C (Tmax) (Table 1, entry 14). Toluene appears to be a
good solvent, because Fülöp and co-workers reported that
CSI reacts with 1 in toluene at room temperature to give a
58% yield of the lactam (entry 2).3d Increasing the tempera-
ture to 50 °C in toluene improved the yield and decreased
the reaction time (entry 1). For this reaction, a higher tem-
perature improved the outcome because the product from
CSI and alkene 1 is more stable than most other N-chloro-
sulfonyl β-lactam products. However, reducing the tem-
perature to 15 °C in toluene-d8 gave an 80% yield (entry 3),
comparable to that obtained at 50 °C (entry 1). At room
temperature, the reaction of CSI with 1 in nitromethane, a
more-polar solvent, also gave the lactam product, but it re-
arranged and decomposed in nitromethane at 25 °C (entry
17). At 10 or 0 °C in nitromethane, the N-chlorosulfonyl β-
lactam product was stable during the short reaction time
required for completion of the reaction (entries 18 and 19).
Decreasing the temperature to 0 °C or less in toluene (en-
tries 5 and 6), chloroform (entries 10 and 11), dichloro-
methane (entries 15 and 16), or nitromethane (entry 21)
resulted in lower product yields and/or longer reaction
Graf reported that p-nitrostyrene (2) and 2,6-dichloro-
styrene (3) barely reacted with CSI, however, he did not re-
port the yields of these reactions.1e,f In nitromethane as sol-
vent, 2 and 3 gave moderate to low product yields at 50–
55 °C (Table 1, entries 22 and 23). The reactions of CSI with
2 or 3 did not show improved results below room tempera-
ture. Alkenes that are unreactive because of the presence of
strongly electron-withdrawing substituents, such as sty-
renes 2 and 3, require the polar solvent nitromethane to
give products. These results suggest that very strongly elec-
tron-deficient styrenes may not function as electron donors
to give SET intermediates, as shown in Scheme 2, because
their ionization potentials (IPs) and oxidation potentials are
too high for the transfer of an electron to CSI. 4-Chlorosty-
rene (1) has a calculated IP of 8.47 eV,7b and it reacts with
CSI by the SET pathway.5a Monofluoroalkenes with IP values
greater than 8.9 eV react through a concerted pathway.5a
Styrenes 2 and 3 have calculated IP values of 10.0 eV7a and
10.5 eV,7c respectively, suggesting that they might react by a
concerted pathway because they cannot function as elec-
tron donors to CSI. Styrenes 2 and 3 might be the first hy-
drocarbon alkenes to show a reaction by a concerted path-
way, and they were the least reactive alkenes from which
we were able to obtain N-chlorosulfonyl β-lactam products
with CSI in the current study.
The more-reactive styrene (4) and CSI gave the best re-
sults at 0 °C in nitromethane as solvent (Table 1, entry 24).
Kinetic data show that, in dichloromethane, styrene reacts
7.8 times faster at 0.5 °C than it does at 25 °C;5a,6 those data
were confirmed by our measured reaction times for com-
pletion of the reaction (see Supporting Information). The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1944–1950

1946
D. F. Shellhamer et al.
Paper
Synthesis
Table 1 Synthetic Utility of Reactions of CSI at Lower Temperatures
R2
O
R1
R2
X
R1
R3
hydrocarbon alkenes: X = H
monofluoroalkenes: X = F
+
CSI
N
R3
SO2Cl
X
Entry
Alkene
Solvent
Temp (°C)
Time
2.5 h
Yielda (%)
Ref.
1
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
toluene-d8
toluene
toluene-d8
toluene
toluene-d8
toluene-d8
CDCl3
50
85
58
80
70c
75
3d
2
25
24 h
16 h
16 h
22 h
24 h
4 h
3
15b
15b
0
4
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-chlorostyrene (1)
4-nitrostyrene (2)
2,6-dichlorostyrene (3)
styrene (4)
5
d
6
–15
50
–
7
30
8
CDCl3
25
5 h
55
9
CDCl3
10
7 h
50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
CDCl3
0
–10b
7 h
45
CDCl3
1 d
75
CD2Cl2
50
1 h
30
CH2Cl2
25b
10b
0
4 h
95c
97c
50
CH2Cl2
7 h
CD2Cl2
3 h
CD2Cl2
–10
25
30 h
5 min
5 min
5 min
10 min
5 min
24 h
1 week
20 min
2.5 h
30 h
5 h
75
5a
CD3NO2
CD3NO2
CD3NO2
MeNO2
CD3NO2
CD3NO2
CD3NO2
CD3NO2
CD3NO2
toluene-d8
CH2Cl2
36e
80f
80f
80c,f
10
0b
0b
5a
5a
f,g
–15
55
–
25h
50
0b
10b
30
90
trans-β-methylstyrene (5)
trans-β-methylstyrene 5
trans-β-methylstyrene 5
cis-stilbene (6)
95
25
90
85c
25
10b
CD3NO2
toluene-d8
CDCl3
30 d
30 d
41 d
14 d
2 d
80 (cis/trans = 1:1)
cis-stilbene (6)
25
60 (cis/trans = 2:1)
cis-stilbene (6)
25
60 (cis/trans = 1:1)
hex-1-ene (7)
CH2Cl2
10b
25b
–10b
0b
10b
–20
25
99c
50e
91c
87c
95i
95j
80e,i
80i
trans-hex-3-ene (8)
2-methylbut-2-ene (9)
CD3NO2
toluene
CH2Cl2
1 h
methylenecyclohexane (10)
α-fluorostyrene (11)
30 min
2 h
toluene
toluene
CH2Cl2
5b
α-fluorostyrene (11)
13 h
4 h
α-fluoro-4-methylstyrene (12)
2-fluorodec-1-ene (13)
2-fluorodec-1-ene (13)
MeNO2
toluene
15b
3 h
–10
8 d
80i
a Yield by 1H NMR with toluene as internal standard (unless otherwise stated).
b Tmax (The temperature that gave the best yield in the shortest reaction time).
c Isolated yield (6.0 mmol scale).
d Only 40% of the alkene reacted.
e The yield was low because the product rearranged and decomposed under these conditions.
f CDCl3 was added at the completion of the reaction to dissolve the N-chlorosulfonyl β-lactam product.
g Only 20% of the alkene reacted.
h The N-chlorosulfonyl β-lactam carbonyl group was observed at 1820 cm–1. On reduction of the crude reaction mixture with NaHSO3/NaHCO3, the carbonyl
group of the reduced β-lactam appeared at 1764 cm–1
.
i Yield by 19F NMR with o- or p-fluoroanisole as internal standard.
j Isolated yield on a 1.0 mmol scale.
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D. F. Shellhamer et al.
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Synthesis
efficiency of this reaction is maximized when the preequi-
librium is shifted toward the SET intermediate at 0 °C in ni-
tromethane (Scheme 2).
Monofluoroalkenes 11, 12, and 13 were chosen for this
study because 12 reacts with CSI by the SET process, like
most hydrocarbon alkenes, whereas 11 and 13 react by a
concerted pathway.5a [2,2,6,6-Tetramethylpiperidin-1-
yl)oxyl (TEMPO) inhibits the reaction of CSI with 12, but
does not inhibit the concerted reactions of 11 or 13.]5a
Monofluoroalkene 12 is more electron-rich than 11, but it
reacts 0.5 times more slowly than 11 because these two
monofluoroalkenes react by different pathways.5a The
change in mechanism for the reaction of CSI with monoflu-
oroalkenes occurs between calculated vertical IPs of 8.5 and
8.9 eV.5a Alkene 12 has an IP of 8.46 eV and reacts by the
SET pathway (Scheme 2). α-Fluorostyrene (11), which has a
higher IP of 8.88 eV, is the most electron-rich and reactive
monofluoroalkene that reacts by the concerted pathway
(Scheme 1).5a Of the alkenes that were studied, monofluo-
roalkene 13 is the most electron-deficient and least reactive
alkene that reacts with CSI by a concerted mechanism, and
it has an IP of 9.60 eV.5a
Other kinetic data8 show that styrene (4) reacts 12.5
times faster than the more-electron-rich trans-β-methyl-
styrene (5); this was confirmed by the results shown in Ta-
ble 1 (entries 24 and 25). The slower reactions rate of CSI
with trans-β-methylstyrene (5) compared with styrene (4)
is due to an in-plane stepwise transition state that is sensi-
tive to steric effects from the vinyl methyl group on 5.5b We
found that the best yield of N-chlorosulfonyl β-lactam prod-
uct from 5 in the shortest reaction time was obtained in ni-
tromethane at 10 °C (entry 25). Toluene and dichlorometh-
ane as solvents also provide good results at 25 °C (entries
26 and 27). When the reduced reactivity of an alkene with
CSI is caused by steric effects, less-polar solvents generally
give good yields without the decomposition that sometimes
accompanies reactions of CSI in nitromethane. The synthet-
ic utility of reactions of 5 is degraded below 10 °C in nitro-
methane and below 25 °C in less-polar solvents.
The reaction of α-fluorostyrene (11) with CSI in di-
chloromethane gave the N-chlorosulfonyl β-fluorolactam
product in 65% yield.5b The optimal conditions for the reac-
tion of 11 with CSI were found to be 10 °C in toluene; these
gave a 95% yield of the N-chlorosulfonyl β-fluorolactam
product (Table 1, entry 35). Lowering the temperature to
below 10 °C with 11 decreased the yield (see Supporting In-
formation). At –20 °C, however, the yield from the reaction
of CSI with 11 returned to 95% (entry 36). The reaction of
CSI with 11 in toluene at the higher temperature of 10 °C is
more efficient, in that the reaction time is shorter (entries
35 and 36). 4-Methyl-α-fluorostyrene (12) reacts by the
stepwise pathway,5a and the best results were obtained at
25 °C in dichloromethane (entry 37). 2-Fluorodec-1-ene
(13) reacts about 100 times more slowly than styrene, but it
reacts slightly faster than dec-1-ene.5a,8 Conditions for the
reaction of 13 were optimal at 15 °C in nitromethane (entry
38). Presumably, the concentration of the complex in
Scheme 1 is maximized for CSI and 13 at 15 °C in nitro-
methane and at –10 °C in toluene (entry 39).
CSI is even less reactive with cis-stilbene (6) than with
trans-β-methylstyrene (5) (Table 1, entries 25 and 28). Ste-
ric factors in the stepwise transition state again contribute
to the reduced rate of the reaction of CSI with cis-stilbene
(6). Reactions of CSI with stilbenes are stereoselective,9
whereas reactions with cis- or trans-β-methylstyrenes and
cis- or trans-hex-3-enes are stereospecific.10 The best yield
of the N-chlorosulfonyl β-lactam product from the reaction
of CSI with cis-stilbene (6) was obtained in nitromethane at
10 °C (entry 28). The reaction of cis-stilbene (6) with CSI
also gave good yields at 25 °C in toluene (entry 29) or chlo-
roform (entry 30), but the product yields were lower in
less-polar solvents than they were in nitromethane at 10 °C.
Styrene (4) reacts about 103 times faster with CSI than
does the monosubstituted alkene hex-1-ene (7) or the
disubstituted alkene trans-hex-3-ene (8).8 The optimal con-
ditions for the reaction of CSI with hex-1-ene (7) involved a
temperature of 10 °C in dichloromethane; in this case the
yield was quantitative (Table 1, entry 31). Steric effects in
the reaction of CSI with trans-hex-3-ene (8) rendered reac-
tions in toluene or dichloromethane impracticable. The re-
action in nitromethane at room temperature was faster, but
the yield suffered as a result of decomposition of the prod-
uct (entry 32). The overall best yield (74%) for the reaction
of CSI with 8 is that reported by Moriconi and co-workers,
who used diethyl ether as the solvent.2c
From the kinetic data5a,8 and our time-to-completion
study, the order of reactivity for SET reaction of CSI with
alkenes is: 9 ≈ 10 > 4 ≈ 12 > 5 > 6 > 7 ≈ 8 > 1. The least reac-
tive alkenes in the SET pathway are 4-chlorostyrene (1), cis-
stilbene (6), and the hydrocarbon alkenes 7 and 8. Hydro-
carbon alkenes 1, 6, 7, and 8 are not as electron-deficient as
2 or 3, and they show an improved performance at lower
temperatures, indicating a shift in the equilibrium to the
complex or SET intermediate. Hydrocarbon alkenes 5, 6, and
8, which react slowly with CSI as a result of steric interac-
tions, perform best in nitromethane as solvent, but they
also react well in less-polar solvents. Steric effects are less
noticeable in alkenes such as 9 and 10 because these are
more reactive than alkenes 7 and 8. The N-chlorosulfonyl β-
fluorolactam from α-fluorostyrene 11 can be isolated at
2-Methylbut-2-ene (9) is 25 times more reactive with
CSI than is styrene (4).8 Rates of reactions of CSI with meth-
ylenecyclohexane (10) were comparable those with 2-
methylbut-2-ene (9) (Table 1, entries 33 and 34). These
more reactive alkenes show improved product yields at
lower temperatures, indicating that the preequilibrium is
shifted toward the SET intermediate. Reaction yields for
both 9 and 10 were maximal in toluene as solvent at –10 °C
and +10 °C, respectively (entries 33 and 34).
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D. F. Shellhamer et al.
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Synthesis
low temperature,5b but the the corresponding product from
12 decomposes at or above room temperature (see Sup-
porting Information).
as internal standard. In their IR spectra, all products showed a peak
between1810 and 1830 cm–1 corresponding to a carbonyl group; this
is definitive for the corresponding N-chlorosulfonyl β-lactams. Pre-
parative reactions were performed on a 6.0 mmol scale in 6.0 mL of
solvent. The progress of the preparative reactions was monitored by
following the disappearance of the IR carbonyl frequency of CSI at
This study has shown how recent observations of non-
linear Arrhenius behavior for the [2+2] cycloaddition of CSI
with alkenes below room temperature can be used to im-
prove the outcomes of reactions. Between room tempera-
ture and –15 °C, the rates increase because the preequilibri-
um shifts toward a complex or SET intermediate that reacts
more efficiently. Furthermore, the N-chlorosulfonyl β-lact-
am products are less susceptible to rearrangement and de-
composition when the reactions are carried out below
room temperature. Above room temperature in nitrometh-
ane, decomposition can occur with many N-chlorosulfonyl
β-lactam products, and isomerization is more prevalent at
elevated temperatures for the N-chlorosulfonyl cis-β-lactam
product from cis-stilbene. In their reactions with CSI, unre-
active alkenes such as 2, 3, and 13 give the best results in
the polar solvent nitromethane. Reactions of CSI with sty-
renes such as 2 and 3 do not benefit from lower tempera-
tures because their preequilibrium does not shift suffi-
ciently between 0 and –15 °C or because these alkenes are
not sufficiently electron-rich to form a complex or SET in-
termediate. The styrenes 2 and 3 may be too electron-defi-
cient to serve as electron donors to CSI, which is required
for the formation of the SET intermediate. It is possible that
styrenes 2 and 3 are the first hydrocarbon alkenes to be
identified as reacting with CSI by a concerted process
(Scheme 1) that is similar to that followed by monofluoro-
alkenes with IP values equal to or higher than that of α-fluo-
rostyrene 11.5a
~2230 cm–1
.
4-Phenylazetidin-2-one
Competing polymerization of styrene (4) during its reaction with CSI
made crystallization of the corresponding N-chlorosulfonyl β-lactam
difficult. Consequently, the crude N-chlorosulfonyl β-lactam was re-
duced2a with NaHSO3 to give 4-phenylazetidin-2-one, which was eas-
ier to crystallize. Freshly distilled styrene (1.04 g, 1.14 mL, 10.0
mmol) was dissolved in anhyd toluene (1.0 mL), and the stirred solu-
tion was cooled to 15 °C. CSI (1.41 g, 0.870 mL, 11.0 mmol) was added
dropwise. After 15 min at 15 °C, the mixture was slowly added to ice-
cold 2% aq NaHCO3. The organic layer was separated and the aqueous
layer was extracted with Et2O (3 × 25 mL). The organic layers were
combined, dried (Na2SO4), and concentrated under vacuum to give
the crude product as a clear oil (IR: 1817 cm–1). The crude product
was dissolved in Et2O (2 mL) and the soln was added dropwise to a
vigorously stirred solution of NaHSO3 (40 mg) and NaHCO3 (360 mg)
in H2O (2 mL). The mixture was stirred for 15 min at r.t., the organic
layer was separated, and the aqueous layer was extracted with Et2O
(3 × 25 mL). The organic layers were combined and dried (Na2SO4),
and then the Et2O was evaporated until the solution became cloudy.
Crystallization gave white crystals; yield: 700 mg (4.8 mmol, 48%);
mp 104–105 °C (Lit.12 104–105 °C).
IR (ATR): 1757 cm–1
.
The high-field NMR data agreed with those reported in the litera-
ture.12
2-Oxo-1-azaspiro[3.5]nonane-1-sulfonyl Chloride: Typical Prepar-
ative-Scale Procedure
A round-bottom flask equipped with a drying tube and magnetic stir-
rer bar was charged with methylenecyclohexane (10; 576 mg 6.00
mmol) and anhyd CH2Cl2 (6.0 mL) at 0 °C. CSI (863 mg, 535 μL, 6.10
mmol) was added dropwise. After 30 min at 0 °C, ice-water (25 mL)
was added and the organic layer was separated. The aqueous layer
was extracted with CH2Cl2 (2 × 5 mL), and the organic extracts were
combined, washed with 2% aq NaHCO3 (2 × 10 mL), and dried
(Na2SO4). The solvent was removed under vacuum and the product
was purified by column chromatography (silica gel, hexanes–EtOAc)
to give white crystals; yield: 1.240 g (87%); mp 87.5–89.0 °C (Lit.2b
88–89 °C).
The monofluoroalkenes used in this study were synthesized by the
reported procedures.11 Hydrocarbon alkenes and CSI were obtained
from commercial sources. Solvents were dried over molecular sieves.
Characterization data for all products in this study have been previ-
ously reported. 1H NMR data were recorded by using a Varian Mercury
spectrometer at 500 or 400 MHz in CDCl3 as solvent with TMS as in-
ternal standard. High-field 1H and 13C NMR data for the N-chlorosulfo-
nyl β-lactam products from alkenes 1,5a 11,5b and 135b were identical
to those that we previously reported. High-field NMR data for the
other products for which only low-field data or no published NMR
data were available are reported below. IR spectra were recorded on a
Thermo Electron (Nicolet) 4700 FT-IR spectrometer with an ATR at-
tachment.
IR (ATR): 1810 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.02 (s, 2 H), 2.24 (m, 2 H), 2.01 (m, 4
H), 1.73 (m, 1 H), 1.27 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 161.6, 70.9, 48.8, 34.4, 24.3, 23.9.
Kinetic Studies with NMR Monitoring
A dry NMR tube was charged with the appropriate solvent (0.5 mL),
alkene (0.50 mmol), and toluene or PhCl (0.10 mmol) as internal stan-
dard. The initial NMR spectrum (t = 0) was recorded, and the alkene
and internal standard peaks were integrated. CSI (92 mg, 56 μL, 0.65
mmol) was added at the appropriate temperature (Table 1), and the
progress of the reaction of CSI with alkenes 1–10 was monitored by
1H NMR. The progress of the reaction of the monofluoroalkenes 11,
12, and 13 was similarly monitored by 19F NMR with 4-fluoroanisole
2-(4-Nitrophenyl)-4-oxoazetidine-1-sulfonyl Chloride
Prepared by the typical procedure from 4-chlorostyrene (2) (solvent:
CD3NO2; reaction time: 24 h; temp: 55 °C) as a light-yellow oil; yield:
435 mg (1.50 mmol, 25%).
IR (ATR): 1817 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 168.4, 140.2, 128.9, 128.2, 125.7, 50.4,
47.9.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1944–1950

1949
D. F. Shellhamer et al.
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Synthesis
2-(2,6-Dichlorophenyl)-4-oxoazetidine-1-sulfonyl Chloride
1H NMR (500 MHz, CDCl3): δ = [3.98 and 3.97 (t, J = 7.5 Hz, 1 H], 3.10
(m, 1 H), 2.16–2.24 (m, 1 H), 1.76–1.95 (m, 3 H), 1.10 (t, J = 7.5 Hz, 3
H), 1.05 (t, J = 7.5 Hz, 3 H).
Prepared by the typical procedure from 2,6-dichlorostyrene (3) (sol-
vent: CD3NO2; reaction time: 7 d; temp: 50 °C) as white crystals;
yield: 565 mg (1.79 mmol, 30%); mp 107–108 °C.
13C NMR (125 MHz, CDCl3): δ = 164.9, 64.5, 57.5, 25.5, 21.4, 11.2, 9.1.
IR (ATR): 1824 cm–1
.
2,2,3-Trimethyl-4-oxoazetidine-1-sulfonyl Chloride
13C NMR (125 MHz, CDCl3): δ = 160.6, 131.3, 130.7, 129.2, 127.5, 54.2,
Prepared by the typical procedure from 2-methylbut-2-ene (9) (sol-
vent: toluene; reaction time: 1 h; temp: –10 °C) as waxy crystals;
yield: 1.15 g (5.46 mmol, 91%); mp 44–45 °C (Lit.2c 44–45 °C).
44.0.
2-Methyl-4-oxo-2-phenylazetidine-1-sulfonyl Chloride
IR (ATR): 1809 cm–1
.
Prepared by the typical procedure from trans-β-methylstyrene (5)
(solvent: CD3NO2; reaction time: 2.5 h; temp: 10 °C) as white crystals;
yield: 1.46 g (5.70 mmol, 95%); mp 44–45 °C (Lit.2c 44–45 °C).
IR (ATR): 1817 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.42 (m, 5 H), 4.85 and 4.84 (s, 1 H),
3.48 and 3.47 (q, J = 7.5 Hz, 1 H), 1.49 (d, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.8, 134.5, 129.7, 129.2, 126.6, 66.9,
1H NMR (400, MHz, CDCl3): δ (two isomers syn and anti to the chloro-
sulfonyl group) = [3.29 and 3.25 (q, J = 7.6 Hz, 1 H)], [1.76 and 1.75 (s,
3 H)], [1.65 and 1.64 (s, 3 H)]; [1.32 and 1.31 (d, J = 7.6 Hz, 3 H)].
.
13C NMR (100 MHz, CDCl3): δ = 165.3, 69.8, 55.7, 26.4, 20.5, 8.9.
Attempts to isolate the N-chlorosulfonyl β-lactam product from 4-
methyl-α-fluorostyrene (12) were unsuccessful because the product
decomposed (see Supporting Information).
55.8, 12.2.
2-Oxo-3,4-diphenylazetidine-1-sulfonyl Chloride
Acknowledgment
Prepared by the typical procedure from cis-stilbene (6) (solvent:
CD3NO2; reaction time: 30 d; temp 10 °C) as a red oil; yield: 145 mg
(4.87 mmol 80%).
Support for this work was provided by the National Science Founda-
tion (NSF-RUI Grant No. CHE-0640547) and the Research Associates
of Point Loma Nazarene University, our science alumni support
group. We wish to thank Dr. Rouffet for helpful suggestions and guid-
ance during this study. We also acknowledge our use of the 400 and
500 MHz NMR spectrometers at the University of San Diego, obtained
by support from the National Science Foundation (NSF-MRI Grant No.
CHE-0417731).
cis-Isomer
IR (ATR): 1811 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 5.20 (d, J = 7.5 Hz, 1 H), 5.72 (d, J = 7.5
Hz, 1 H), 7.06–7.18 (m, 10 H).
13C NMR (125 MHz, CDCl3): δ = 163.3, 131.5, 129.3, 128.9, 128.6,
128.4, 128.3, 128.2, 127.3, 64.6, 62.1.
Supporting Information
2-Butyl-4-oxoazetidine-1-sulfonyl Chloride
Prepared by the typical procedure from hex-1-ene (7) (solvent:
CH2Cl2; reaction time: 14 d; temp: 10 °C) as a clear oil; yield: 1.34 g
(5.94 mmol, 99%).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380553.
S
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p
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IR (ATR): 1814 cm–1
.
1H NMR (500, MHz, CDCl3) : δ = 4.34 (m, 1 H), 3.39 (dd, J = 17.5 and
7.0 Hz, 1 H), 2.98 (dd, J = 17.5 and 4.0 Hz, 1 H), 2.18 (m, 1 H), 1.78 (m,
1 H), 1.39 (m, 4 H), 0.94 (t, J = 7.0 Hz, 3 H).
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2-Butyl-4-oxoazetidine-1-sulfonyl chloride was reduced with
NaHSO3/NaHCO3 as described above for 4-phenylazetidin-2-one.
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1944–1950