Diastereoselective synthesis of trans-trifluoromethyl-β-lactams and α-alkyl-β-trifluoromethyl-β-amino esters

Article abstract of DOI:10.1016/j.tet.2011.03.001

The diastereoselective synthesis of β-lactams was examined from N-tosyl-1-chloro-2,2,2-trifluoroethylamine 3 and various nonactivated aliphatic acid chlorides in the presence of a Br?nsted base. The mild reaction conditions allowed to get trifluoromethyl-

Full text of DOI:10.1016/j.tet.2011.03.001

Tetrahedron 67 (2011) 3254e3259
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Diastereoselective synthesis of trans-trifluoromethyl-
b-lactams
and
a
-alkyl-
b
-trifluoromethyl-b-amino esters
, ,
y
b
c,
Vitaliy Petrik a , Gerd-Volker Roschenthaler , Dominique Cahard
*
*
€
a Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Str. 1, 02094 Kyiv, Ukraine
b School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany
c
ꢀ
ꢁ
UMR 6014 CNRSdC.O.B.R.A., Universite et INSA de Rouen, 1 rue Tesniere, 76130 Mont Saint Aignan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereoselective synthesis of b-lactams was examined from N-tosyl-1-chloro-2,2,2-trifluoroethyl-
Received 3 November 2010
Received in revised form 22 February 2011
Accepted 1 March 2011
amine 3 and various nonactivated aliphatic acid chlorides in the presence of a Brønsted base. The mild
reaction conditions allowed to get trifluoromethyl- -lactams in good yields with high trans-diastereo
selectivity. In addition, we also demonstrated that ring-opening of -lactams easily provided -alkyl-
-trifluoromethyl- -amino esters.
b
b
a
Available online 5 March 2011
b
b
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
while substituting a methyl group with a trifluoromethyl group in-
creases the lipophilicity. Moreover, due to its high electronegativity,
the trifluoromethyl group strongly impacts the neighboring func-
tionalities within the molecule.17 All these parameters contribute to
improve the pharmacokinetic properties of trifluoromethylated
molecules that often possess a better therapeutic profile. Conse-
Azetidin-2-ones, which are called
b-lactams, are part of the
structure of several antibiotic families, principally the penicillins,
cephalosporins, carbapenems, and the monobactam.1,2 They bi-
ologically act by irreversible acylation of the nucleophilic serine
residue at the active site of key enzymes involved in bacterial
quently, the effective synthesis of stereoselectively defined b-lac-
cell-wall synthesis. More recently, synthetic
b
-lactams have found
tams featuring a trifluoromethyl group became a desirable goal
applications as inhibitors of other serine proteases, particularly
human cytomegalovirus (HCMV) serine protease,3e5 elastases,6,7
thrombin,8 tryptase,9,10 and chimase.11 The stereochemistry of
for organic and medicinal chemists.18e20 Intensive research has
generated several methods of synthesizing the
b-lactam scaffold.
b-Lactams are commonly constructed through the Staudinger re-
b
-lactams is very important for their biological activities. For in-
action (keteneeimine cycloaddition, pathway A)21e24 or by ester
enolateeimine cyclocondensation (pathway B), two mechanistically
distinct approaches (Fig. 1).25e31 A less frequently proposed mech-
anism involves the direct acylation by an acid chloride at the nitro-
gen atom of an imine followed by a favored [4-exo-tet] cyclization
process (pathway C). This pathway becomes probably operative
whenthe acidchloride is mixed withtheiminebefore theaddition of
the base.32e34
stance, the penicillin and cephalosporin antibiotics possess a cis-
lactam unit, whereas thienamycin, that is, a naturally-occurring
carbapenem antibiotic and most of the synthetic inhibitors of other
serine proteases have a trans-
activity of these antibiotics is often hampered by the development
of resistance due to the ability of bacteria to produce -lactamases
that hydrolyze the -lactam ring thus inactivating the antibi-
otics.12,13 It is suggested in the literature that introducing an elec-
b
-
b-lactam moiety. The bactericidal
b
b
ꢀ
ꢀ
More than 10 year ago Begue co-workers published the first
synthesis of a cis-trifluoromethylated
-lactam involving a [2þ2]
keteneeimine cycloaddition and methyl syn-3-trifluoromethyl-
isoserinate after opening of the
-lactam cycle.18,19 Unfortunately,
this approach cannot be applied to nonactivated acid chlorides, only
-benzyloxyacetyl chloride reacted with trifluoromethylated imines.
tron-withdrawing fluorinated substituent on the
b
-lactam ring
b
would have a good effect on antibacterial activity.14e16 Indeed, the
introduction of fluorine atom(s) into a bioactive compound causes
minimal steric interaction but it substantially modifies its physico-
chemical properties. The higher strength of the CeF bond com-
pared to CeH bond avoids undesired metabolic transformations
b
a
As part of our continuing efforts on the development of methods for
preparing new trifluoromethylated compounds, we became in-
terested in solving this problem and we now propose the synthesis of
new trifluoromethylated
b-lactams. In view of the three main
* Corresponding authors. E-mail addresses: vitpetrik@yahoo.com (V. Petrik),
pathways to the -lactam scaffold, which require the same imine as
b
dominique.cahard@univ-rouen.fr (D. Cahard).
y
common substrate and three different reaction partners, we
surmised that chemical diversity could be provided using a simple
Present address: ChemTaurus GmbH, Leobener Str., NW2 Block C, 28359
Bremen, Germany.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.001

V. Petrik et al. / Tetrahedron 67 (2011) 3254e3259
3255
Fig. 1. Synthetic pathways to the b-lactam scaffold.
a
-chloroamine, instead of the imine, to react with an acid chloride.
3 were obtained. The chloroamine 337 was readily generated but 3
is moisture sensitive and can be easily hydrolyzed to the starting
hemiaminal 2. As a consequence, 3 was obtained after evaporation
of the crude mixture, characterized by 1H and 19F NMR and im-
mediately used in the next reaction step. Preferentially, the one-pot
process from hemiaminal 2 to b-lactams (vide infra) was achieved
in order to minimize the hydrolysis of 3.
We initially employed 3-methylbutanoyl chloride 4d and N-(1-
chloro-2,2,2-trifluoroethyl)-4-methylbenzenesulfonamide 3 to set
up suitable reaction conditions for the diastereoselective formation
This is one advantage when considering the very moisture sensitive
nature of highly reactive trifluoromethylated imines featuring
an electron-withdrawing group (i.e., N-tosyltrifluoroacetaldehyde
imine) asmentioned by Kumadaki and co-workers35 We chose the N-
tosyl-1-chloro-2,2,2-trifluoroethylamine 3 (see Scheme 2) as the
trifluoromethylated reactant and various aliphatic acid chlorides for
the highly diastereoselective synthesis of trans-trifluoromethylated-
b-lactams and their ring opening reaction leading to
a-alkyl-b-tri-
fluoromethyl- -amino esters.
b
of b-lactam 5d. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and ter-
tiary amines were employed as bases. Base (3 equiv) was required
for the overall process to take place. We reduced the amount of base
to 2 equiv but the reaction was much slower and the conversion
was not complete. The use of dimethylethylamine as the base gave
the best results, whereas other bases resulted in a loss of diastereo
selection and a strong reduction in yield (Table 1).
2. Results and discussion
Trifluoroacetaldehyde (fluoral) or its hemiacetals are readily avail-
able starting materials and suitable for the construction of sophisti-
cated trifluoromethylated molecules.36 Fluoral hemiacetals are known
to react with amines under acidic conditions for generating hemi-
aminals.16,35 We modified the conditions reported by Kumadaki from
two commercially available fluoral hemiacetals 1a and 1b and tosyl-
amine in the presence of a Lewis acid, TiCl4 as dehydrating reagent.35
The reaction was performed at room temperature for 24 h providing
N-(1-hydroxy-2,2,2-trifluoroethyl)-4-methylbenzenesulfonamide 2 in
65% yield from 1a but only in 25% yield from the ethyl hemiacetal 1b.
In this latter case 2 was accompanied by N-(1-ethoxy-2,2,2-tri-
fluoroethyl)-4-methylbenzenesulfonamide 20 as the major product
isolated in 75% yield (Scheme 1).
The diastereomeric ratios trans/cis 5d were determined by 19F
NMR on the crude reaction mixtures. Two signals (doublets) for CF3
group of the diastereomeric
b-lactams were recorded at ꢁ74 and
ꢁ69 ppm with relative integration values as shown in Table 1. By 1H
NMR, we also found signals for two diastereomers. The relative trans
configuration was assigned on the basis of the JH3-H4 coupling
constant values: the JH3-H4 coupling constant of 6 Hz indicates the cis
relative configuration, whereas JH3-H4 coupling constant of 2 Hz
indicates the trans relative configuration as mentioned in the litera-
Scheme 1. Preparation of hemiaminal 2.
ture.38,39 Additionally, the
b-lactam trans-5d was characterized by
single-crystal X-ray crystallography, which clearly shows the trans
relationship between the CF3 and the i-propyl groups.40 Previous
syntheses of 3-substituted-4-trifluoromethyl-b-lactams were ach-
ieved through a Staudinger keteneeimine cycloaddition from a tri-
fluoromethylaldimine and benzyloxyacetyl chloride in the presence
Scheme 2. Preparation of chloroamine 3.
of Et3N. Under these conditions, the cis-
exclusively obtained sometimes accompanied by 5e8% of the trans-
-lactams.19 Because these studies were focussed on the access to
syn-3-CF3-isoserinates, used for instance as side-chain of Docetaxel,
other 3-substituted-4-trifluoromethyl- -lactams with alkyl group at
C3 were not reported; consequently, all the -lactams synthesized in
b-lactams are almost
Next, the hemiaminal 2 smoothly reacted with SOCl2 either in
CH2Cl2 or without solvent at 40 ꢀC to give the N-(1-chloro-2,2,2-
b
trifluoroethyl)-4-methylbenzenesulfonamide
3 in quantitative
b
yield (Scheme 2). Quite interestingly, chlorination of 2 with PCl5
furnished a complex mixture and with oxalyl chloride only traces of
b

3256
V. Petrik et al. / Tetrahedron 67 (2011) 3254e3259
Table 1
applied to a series of nonactivated aliphatic acid chlorides 4aeg
(Table 2). Whatever the size of the R group, the reaction provided
the -lactams in very similar yields with high diastereoselectivity,
Synthesis of b-lactams 5d: study of reaction parameters
b
greater than 94:6. However, an improved yield was obtained from
3-phenylpropanoyl chloride 4g. Although, the diastereomeric ratio
was high with R¼Me and Et, the diastereoselectivity is almost total
with bulkier R groups (Pr, i-Pr, Bu, t-Bu, CH2Ph). It is worth noting
that diastereomeric mixtures could be purified by careful silica gel
column chromatography to afford each diastereomers in analyti-
Entry
Base
Yield [%]a
Dr (trans/cis)b
1
2
3
4
5
DBU
Et(i-Pr)2N
Et3N
Bu3N
Me2EtN
0
<5
54
50
69
d
d
cally pure form. All these b-lactams are new compounds that were
fully characterized (see Experimental section).
80:20
75:25
98:2
a
Isolated yields of pure products obtained by flash column chromatography.
b
Diastereomeric ratio determined by 19F NMR on the crude reaction mixture
Table 2
Synthesis of b-lactams 5aeg from various acyl chlorides
after work-up.
this work are new compounds. Alternatively, the lithium ester eno-
lateeimine cyclocondensation developed by Ojima and co-workers
also gave cis-
cis- -lactams was rationalized by the selective generation of the E-
lithium enolate and a ZimmermaneTraxler transition state.41 How-
ever, Guanti and co-workers obtained exclusively a trans- -lactam by
b-lactams in most cases. The exclusive formation of the
b
Entry
Acyl chloride, R
b
-lactamb
Yield [%]a
Dr (trans/cis)b
b
1
2
3
4
5
6
7
4a, Me
4b, Et
4c, Pr
4d, i-Pr
4e, Bu
4f, t-Bu
4g, CH2Ph
5a
5b
5c
5d
5e
5f
68
67
64
69
66
63
80
94:6
97:3
99:1
98:2
96:4
99:1
99:1
cyclocondensation of N-(2,2,2-trifluoroethylidene)-4-methoxyani-
line with the lithium enolate of N,N-dibenzyl ethylglycinate. In this
case, the Z-enolate is favored leading to the trans-
recently, 3-substituted-4-trifluoromethyl- -lactams were synthe-
-trifluoromethyl imine yet
b
-lactam.16 More
b
sized by Reformatsky reaction with
a
5g
without discussion on the cis/trans ratios.42
a
Isolated yields of pure products obtained by flash column chromatography.
b
Diastereomeric ratio determined by 19F NMR on the crude reaction mixture
In our case study, the precise mechanism and the origin of the
excellent diastereoselection are not clear. From a mechanistic point
of view, we believe that in our experimental conditions with
addition of the acid chloride to the chloroamine 3 when no base is
present, a chemical outcome similar to pathway C (see Fig. 1) is
reasonable. Indeed, although poorly nucleophilic, the chloroamine
3 could react directly with the acid chloride to form the corre-
sponding adduct.43 Attempts to isolate the adduct were un-
successful. A reversible equilibrium between the two reactants and
the adduct is likely to happen and displacement of this equilibrium
takes place by addition of the base. Then, addition of the tertiary
amine causes abstraction of a proton leading to the enolate, which
could cyclize via an intramolecular SN2 reaction. Nevertheless,
a standard Staudinger reaction through formation of ketene
(pathway A, Fig. 1) or a reaction proceeding through an in-
termediate zwitterionic ketene enolate that reacts with the elec-
trophilic imine (pathway B, Fig. 1) cannot be completely excluded.
The high diastereomeric ratios in favor of the trans-substituted
lactams is likely to be obtained from reaction instead of epimeri-
after work-up.
Trifluoromethylated
synthesis of fluorinated
optimized conditions for the synthesis of trans-
if necessary through additional epimerisation step to pure trans-
lactams, we decided to focus our efforts in the opening of the
-lactam cycle. The azide-catalyzed methanolysis is a well estab-
b
-lactams are useful building blocks for the
-amino acid derivatives. Thus, having
-lactams 5aeg,
b
b
b
-
b
lished methodology for this purpose. Indeed, the ring opening by
methanol was performed in DMF at room temperature providing
a
-alkyl-
b
-trifluoromethyl-
b
-amino esters (2S
*
, 3R )-6aeg in good
*
to high yields as single diastereomers (Table 3).46
Table 3
Ring opening of b-lactams: synthesis of a-alkyl-b-trifluoromethyl-b-amino esters
6aeg
zation. Indeed, the diastereomeric ratio of
b-lactams 5d was
determined by 19F NMR during the reaction in the presence of
triethylamine at various temperatures ꢁ78 ꢀC, ꢁ20 ꢀC, and 25 ꢀC
and gave the same mixture 20:80 of cis-b-lactam and trans-b-
Entry
b
-lactam, R
Ester
Yield [%]a
lactam 5d. Concomitantly, the epimerization of the two di-
astereomeric -lactams by the tertiary amine could convert the
original diastereomeric mixture of lactams to a thermodynamic
equilibrium in which the trans- -lactam could be even more
favored. To examine the possibility of C3-epimerization for cis-
lactam to trans- -lactam 5d, we placed a mixture 20:80 of cis-
-lactam and trans- -lactam 5d under basic conditions with the aid
of Et3N as isomerization reagent in CH2Cl2. After stirring the mix-
ture at room temperature for 15 h, the pure diastereoisomer trans-
5d was quantitatively obtained. A similar complete isomerization
1
2
3
4
5
6
7
5a, Me
5b, Et
5c, Pr
5d, i-Pr
5e, Bu
5f, t-Bu
5g, CH2Ph
6a
6b
6c
6d
6e
6f
82
79
97
73
99
82
86
b
b
b
-
b
6g
b
b
a
Isolated yields of pure products obtained by flash column chromatography.
3. Conclusion
ꢀ
ꢀ
was described by Begue and co-workers with t-BuOK in acetoni-
trile44 while Vaccaro and co-workers reported t-BuOK epimeriza-
tion in THF leading to a 1:4 (cis/trans) mixture of
Having established suitable reaction conditions for the synthesis
-lactam 5d with high diastereoselectivity, the methodology was
We have achieved a convenient highly diastereoselective one-
b
-lactams.45
pot synthesis of trifluoromethylated trans-
chloro-2,2,2-trifluoroethyl)-4-methylbenzenesulfonamide
various nonactivated aliphatic acid chlorides. The originality of this
b
-lactams using N-(1-
3
and
of
b

V. Petrik et al. / Tetrahedron 67 (2011) 3254e3259
3257
cyclocondensation reaction is the use of the chloroamine 3 as
reactant. The methodology is simple and provides rapid access to
(d, Jd¼10 Hz, 1H, NH), 7.36 (d, Jd¼8 Hz, 2H, AB-pattern), 7.81 (d,
Jd¼8 Hz, 2H, AB-pattern); 13C NMR (CDCl3):
22.1, 66.2 (q, Jq¼39 Hz,
d
unprecedented 3-alkyl-4-trifluoromethyl-
trans diastereoselectivity. We also obtained
methyl- -amino esters by simple ring opening reaction of the
-lactams.47,48 The present synthetic methodology could find im-
portant applications; in particular for the construction of different
types of -peptides and potential biologically active compounds.
b
-lactams with excellent
CeCF3), 121.6 (q, JCeF¼280 Hz, CF3), 127.9, 130.5, 136.3, 145.6; 19F
a
-alkyl- -trifluoro-
b
NMR (CDCl3):
36%), 155 (TolSO2þ, 100%).
d
ꢁ78.3 (d, Jd¼3.8 Hz CF3); MS (CI) m/z: 251 (MþꢁHCl,
b
b
4.3. General procedure for the synthesis of N-tosyl-
3-substituted-4-trifluoromethyl-azetidin-2-ones 5
b
Further studies concerning the mechanism of the reaction, the
deprotection of the tosyl group, the synthesis of amino acids and
dipeptides, as well as the development of enantioselective ap-
4.3.1. trans-1-Tosyl-3-methyl-4-(trifluoromethyl)azetidin-2-one
5a. In an oven-dried, two-neck, 50 ml, round-bottom flask equip-
ped with magnetic stirring bar, a reflux condenser, and an argon
inlet were placed 2 (1 g, 3.72 mmol) and SOCl2 (5 ml) in DCM (5 ml).
The reaction mixture was stirred for 2 h at 40 ꢀC. Solvent and excess
of SOCl2 were removed in vacuum. The residue was dried for 3 h
and was dissolved in DCM (8 ml). To the formed solution of 3 was
added propionyl chloride 4a (0.41 g, 0.38 ml, 4.43 mmol) in DCM
(1 ml). The solution was cooled to ꢁ78 ꢀC and Me2EtN (0.81 g,
1.2 ml, 11 mmol) was added. After the mixture was stirred at ꢁ78 ꢀC
for 2 h and then was stirred overnight (the temperature sponta-
neously was warmed to room temperature). The reaction was
complete as monitored by 19F NMR. The solvent was removed in
vacuum and residue was treated with EtOAc. The precipitate was
filtered, the mother solution was concentrated in vacuum. The
crude product was purified by crystallization in cold ethanol (or
column chromatography on SiO2 with hexane/EtOAc¼9/1) to give
5a (0.78 g) as white solid: yield 68%; mp 136e138 ꢀC; 1H NMR
proaches to chiral nonracemic
b-lactams are under investigation in
our laboratories.22,30,49,50
4. Experimental
4.1. General
Allreactionswere carried outunderanatmosphereofdrynitrogen
or argon. Solvents were dried according to standard procedures and
distilledpriortouse.The1H,13C,and19FNMR spectrawere recorded at
200.1, 50.3, and 188.3 MHz, respectively, using CDCl3 and CD3CN as
solvents. The chemical shifts are reported in parts per million relative
to CHCl3 (
the central CDCl3 resonance (
d
¼7.25 ppm) and CH3CN (
d
¼1.94 ppm) for 1H NMR and to
d
77.0) for 13C NMR. Hexafluorobenzene
(C6F6) served as internal standard (dF¼ꢁ162.9 ppm) for 19F NMR.
Coupling constants (J) are reported in Hertz. Melting points were
uncorrected. Flash chromatographies were performed on silica gel
(230e400 mesh). Mass spectrometry data are reported in the form of
m/z (intensity relative to base peak¼100).
(CDCl3):
d
1.41 (d, Jd¼8 Hz, 3H, CH3), 2.48 (s, 3H, CH3), 3.35 (qd,
Jd¼2 Hz, Jq¼8 Hz, 1H, CH), 4.15 (dq, Jd¼2 Hz, Jq¼4 Hz 1H, CH), 7.39
(d, Jd¼8 Hz, 2H, AB-pattern), 7.89 (d, Jd¼8 Hz, 2H, AB-pattern); 13
C
NMR (CDCl3):
d
12.69, 22.16, 47.98, 59.5 (q, Jq¼36 Hz, CeCF3), 123
4.2. Synthetic procedure for compounds 2 and 3
(q, JCeF¼279 Hz, CF3), 128.08, 130.52, 135.22, 146.36, 165.29; 19F
NMR (CDCl3):
d
ꢁ74.53 (d, Jd¼3.8 Hz CF3); MS (ESI, m/z): 330.2
4.2.1. N-(1-Hydroxy-2,2,2-trifluoroethyl)-4-methylbenzenesul-
(MþþNa), 696.2; MS (CI, m/z): 307 (Mþ, 7%), 232 (31%), 197 (36%),
fonamide 2. To
a
stirred suspension of p-toluenesulfonamide
155 (TolSO2þ
, 92%), 91 (Tolþ, 100%); HRMS-EI, m/z calcd for
(10 g, 58 mmol) and trifluoroacetaldehyde methyl hemiacetal 1a
(7.6 g, 58 mmol) in 100 ml of dry DCM was added TiCl4 (44.32 g,
232 mmol) at room temperature. The light yellow solution was
stirred for 20 h at room temperature. The reaction was quenched by
the addition of water (50 ml). The titanium hydroxide was filtered
through Celite and the organic phase was separated. The aqueous
phase was extracted with DCM (3ꢂ20 ml). The combined organic
phases were dried over sodium sulfate, filtered, and concentrated
under vacuum. The crude product was triturated with a small
quantity of DCM. The solid was filtered and dried under vacuum to
afford 8.16 g of 2. The mother solution was concentrated under
vacuum and purified by column chromatography with 2:1 hexane/
ethyl acetate mixture as the eluent to give 2.04 g of the title com-
pound. Total amount of 2 was 10.2 g (65%): white solid; mp
C12H12F3NO3S, 307.04900; found, 307.04884.
4.3.2. trans-1-Tosyl-3-ethyl-4-(trifluoromethyl)azetidin-2-one
5b. Yield 67%; mp 80e82 ꢀC; 1H NMR (CDCl3):
d
1.0 (t, Jt¼8 Hz, 3H,
CH3), 1.8 (m, 2H, CH2), 2.47 (s, 3H, CH3), 3.25 (td, Jt¼8 Hz, Jd¼2 Hz,
1H, CH), 4.20 (dq, Jd¼2 Hz, Jq¼4 Hz 1H, CH), 7.38 (d, Jd¼8 Hz, 2H, AB-
pattern), 7.88 (d, Jd¼8 Hz, 2H, AB-pattern); 13C NMR (CDCl3):
d
11.02, 21.25, 22.15, 54.41, 57.78 (q, Jq¼36 Hz, CeCF3), 123.54
(q, JCeF¼279 Hz, CF3), 128.08, 130.5, 135.35, 146.31, 164.81; 19F NMR
(CDCl3):
d
ꢁ74.33 (d, Jd¼3.8 Hz CF3); MS (EI, m/z): 321 (Mþ, 3%),
301 (19%), 232 (30%), 197 (32%), 155 (TolSO2þ
, 100%), 91 (Tolþ,
92%); HRMS-EI, m/z calcd for C13H14F3NO3S, 321.06465; found,
321.06483.
155e156 ꢀC; 1H NMR (CD3CN):
d
2.42 (s, 3H, CH3), 4.98 (d, J¼6 Hz,1H,
4.3.3. trans-1-Tosyl-3-propyl-4-(trifluoromethyl)azetidin-2-one
OH), 5.26 (m,1H, CH), 6.82 (d, Jd¼10 Hz,1H, NH), 7.39 (d, Jd¼8 Hz, 2H,
5c. Yield 64%; mp 61e63 ꢀC; 1H NMR (CDCl3):
d
0.95 (t, Jt¼8 Hz, 3H,
AB-pattern), 7.76 (d, Jd¼8 Hz, 2H, AB-pattern); 13C NMR (CD3CN):
CH3), 1.44 (m, 2H, CH2), 1.76 (m, 2H, CH2), 2.48 (s, 3H, CH3), 3.30 (td,
Jt¼8 Hz, Jd¼2 Hz,1H, CH), 4.21 (dq, Jd¼2 Hz, Jq¼4 Hz 1H, CH), 7.38 (d,
Jd¼8 Hz, 2H, AB-pattern), 7.89 (d, Jd¼8 Hz, 2H, AB-pattern); 13C
d
21.0, 75.5 (q, Jq¼36 Hz, CeCF3), 117.8, 123.0 (q, JCeF¼282 Hz, CF3),
127.2,130.1,138.8,144.5;19FNMR(CD3CN):
d
ꢁ80.8(d, Jd¼3.8HzCF3);
MS (EI) m/z: 269 (Mþ, 5%), 200 (15%),171 (25%),155 (TolSO2, 55%), 91
(Tol, 100%); HRMS-EI, m/z calcd for C9H10F3NO3S, 269.03335; found,
269.03344.
NMR (CDCl3):
d
13.87, 20.05, 22.12, 29.85, 52.92, 58.16 (q, Jq¼36 Hz,
CeCF3), 123.0 (q, JCeF¼279 Hz, CF3), 128.05, 130.49, 135.32, 146.32,
164.98; 19F NMR (CDCl3):
d
ꢁ74.33 (d, Jd¼3.8 Hz CF3); MS (EI, m/z):
336 (MþþH, 10%), 232 (27%), 198 (34%), 155 (TolSO2
þ, 100%), 91
4.2.2. N-(1-Chloro-2,2,2-trifluoroethyl)-4-methylbenzenesulfonamide
3. To a stirred suspension of N-(1-hydroxy-2,2,2-trifluoroethyl)-4-
methylbenzenesulfonamide 2 (1 g, 3.72 mmol) in 5 ml of dry DCM
was added SOCl2 (5 ml) at room temperature. The reaction mixture
was stirred for 2 h at 40 ꢀC. Solvent and excess of SOCl2 were
removed under vacuum. The residue was dried for 3 h to afford 3
(quantitative yield) as colorless solid: moisture sensitive; 1H NMR
(Tolþ, 82%); MS (CI, m/z): 688 (2MþþNH4, 5%), 353 (MþþNH4,
100%).
4.3.4. trans-1-Tosyl-3-isopropyl-4-(trifluoromethyl)azetidin-2-one
5d. Yield 69%; mp 66e68 ꢀC; 1H NMR (CDCl3):
d
0.98 (d, Jd¼8 Hz,
3H, CH3), 1.4 (d, Jd¼8 Hz, 2H, CH2), 2.11 (septet, J¼8 Hz, 1H, CH), 2.46
(s, 3H, CH3), 3.10 (dd, J1¼8 Hz, J2¼2 Hz, 1H, CH), 4.25 (dq, Jd¼2 Hz,
Jq¼4 Hz 1H, CH), 7.38 (d, Jd¼8 Hz, 2H, AB-pattern), 7.89 (d, Jd¼8 Hz,
(CDCl3):
d
2.46 (s, 3H, CH3), 5.85 (dq, Jd¼10 Hz, Jq¼4 Hz, 1H, CH), 6.16

3258
V. Petrik et al. / Tetrahedron 67 (2011) 3254e3259
2H, AB-pattern); 13C NMR (CDCl3):
d
19.85, 19.9, 22.15, 27.98, 56.7
J¼6.8 Hz, J¼2.9 Hz,1H, CH), 3.71 (s, 3H, OCH3), 4.09 (m,1H, CH), 6.35
(d, J¼9.3 Hz, 1H, NH), 7.29 (d, J¼8.3 Hz, 2H), 7.75 (d, J¼8.3 Hz, 2H);
(q, Jq¼36 Hz, CeCF3), 59.51, 123.6 (q, JCeF¼279 Hz, CF3), 128.08,
130.47, 135.46, 146.28, 164.43; 19F NMR (CDCl3):
d
ꢁ74.06 (d,
13C NMR (CDCl3):
d
15.60, 21.86, 37.25, 52.85, 57.84 (q, JCeF¼31.2 Hz,
Jd¼3.7 Hz CF3); MS (EI, m/z): 335 (Mþ, 5%), 198 (28%), 155 (TolSO2
þ
,
CeCF3), 124.60 (q, JCeF¼282.8 Hz, CF3), 127.29, 130.00, 138.50,
79%), 118 (37%), 91 (Tolþ, 100%).
144.14, 174.71; 19F NMR (CDCl3):
EI, m/z calcd for C13H16F3NO4S, 339.07521; found, 339.07526.
d
ꢁ74.54 (d, J¼6.9 Hz, CF3); HRMS-
4.3.5. trans-1-Tosyl-3-butyl-4-(trifluoromethyl)azetidin-2-one
5e. Yield 66%; mp 60e62 ꢀC; 1H NMR (CDCl3):
d
0.89 (t, Jt¼6 Hz, 3H,
4.4.3. Methyl 4,4,4-trifluoro-2-ethyl-3-(4-methylphenylsulfonamido)
CH3), 1.32 (m, 4H, 2CH2), 1.75 (m, 2H, CH2), 2.47 (s, 3H, CH3), 3.29
(td, Jt¼6 Hz, Jd¼2 Hz, 1H, CH), 4.19 (dq, Jd¼2 Hz, Jq¼4 Hz 1H, CH),
7.38 (d, Jd¼8 Hz, 2H, AB-pattern), 7.89 (d, Jd¼8 Hz, 2H, AB-pattern);
butanoate 6b. Yield 79%; mp 65e67 ꢀC; 1H NMR (CDCl3):
d 0.93 (t,
J¼7.3 Hz, 3H, CH3), 1.68 (m, 2H, CH2), 2.39 (s, 3H, CH3), 2.71 (m, 1H,
CH), 3.68 (s, 3H, OCH3), 4.1 (m, 1H, CH), 6.42 (d, J¼8.8 Hz, 1H, NH),
7.27 (d, J¼7.9 Hz, 2H), 7.74 (d, J¼7.9 Hz, 2H); 13C NMR (CDCl3):
13C NMR (CDCl3):
d 14.03, 22.12, 22.55, 27.52, 28.65, 53.11, 58.1 (q,
Jq¼36 Hz, CeCF3), 123.54 (q, JCeF¼279 Hz, CF3), 128.06, 130.5,
d
11.84, 21.86, 23.88, 43.93, 52.73, 56.25 (q, JCeF¼31.3 Hz, CeCF3),
135.33, 146.32, 165.02; 19F NMR (CDCl3):
d
ꢁ74.32 (d, Jd¼3.7 Hz
124.21 (q, JCeF¼283.2 Hz, CF3), 127.27, 129.93, 138.60, 144.07, 174.70;
CF3); MS (EI, m/z): 350 (MþþH, 9%), 329 (MþꢁHF, 74%), 198 (43%),
19F NMR (CDCl3):
d
ꢁ74.84 (d, J¼8.6 Hz, CF3); HRMS-EI, m/z calcd for
155 (TolSO2
þ
, 100%), 91 (Tolþ, 91%).
C14H18F3NO4S, 353.09086; found, 353.09034.
4.3.6. trans-1-Tosyl-3-tert-butyl-4-(trifluoromethyl)azetidin-2-one
5f. Yield 63%; mp 107e109 ꢀC; 1H NMR (CDCl3):
1.0 (s, 3H, 3CH3),
4.4.4. Methyl 4,4,4-trifluoro-2-propyl-3-(4-methylphenyl-
sulfonamido) butanoate 6c. Yield 97%; mp 70e71 ꢀC; 1H NMR
d
2.47 (s, 3H, CH3), 3.11 (d, Jd¼2 Hz,1H, CH), 4.28 (dq, Jd¼2 Hz, Jq¼4 Hz
(CDCl3):
d
0.82 (t, J¼7.3 Hz, 3H, CH3), 1.1e1.6 (m, 4H, CH2CH2), 2.38
1H, CH), 7.38 (d, Jd¼8 Hz, 2H, AB-pattern), 7.90 (d, Jd¼8 Hz, 2H, AB-
(s, 3H, CH3), 2.80 (m, 1H, CH), 3.66 (s, 3H, OCH3), 4.10 (m, 1H, CH),
6.45 (d, J¼8.8 Hz, 1H, NH), 7.26 (d, J¼8.3 Hz, 2H), 7.73 (d, J¼8.3 Hz,
pattern); 13C NMR (CDCl3):
d
22.12, 27.04, 32.31, 55.6 (q, Jq¼36 Hz,
CeCF3), 63.36, 123.7 (q, JCeF¼279 Hz, CF3), 128.11, 130.45, 135.55,
2H); 13C NMR (CDCl3):
d 13.80, 20.47, 21.80, 32.44, 42.00, 52.71,
146.29,164.19; 19F NMR (CDCl3):
d
ꢁ73.84 (d, Jd¼3.7 Hz CF3); MS (EI,
56.50 (q, JCeF¼31.3 Hz, CeCF3), 124.24 (q, JCeF¼282.8 Hz, CF3),
m/z): 350 (MþþH, 14%), 232 (30%), 198 (32%), 155 (TolSO2
þ, 100%),
127.29, 129.96, 138.62, 144.09, 174.78; 19F NMR (CDCl3):
d
ꢁ74.94
152 (82%), 91 (Tolþ, 86%); MS (CI, positive, m/z): 367 (MþþNH4,
100%), 350 (MþþH, 1%); MS (CI, negative, m/z): 348 (MþꢁH, 7%),
321 (4%), 194 (100%).
(d, J¼8.6 Hz, CF3); HRMS-EI, m/z calcd for C15H20F3NO4S, 367.10651;
found, 367.10670.
4.4.5. Methyl 4,4,4-trifluoro-2-butyl-3-(4-methylphenylsulfonamido)
4.3.7. trans-1-Tosyl-3-benzyl-4-(trifluoromethyl)azetidin-2-one
butanoate 6e. Yield 99%; mp 77e79 ꢀC; 1H NMR (CDCl3):
d 0.83
5g. Yield 80%; mp 138e140 ꢀC; 1H NMR (CDCl3):
d
2.47 (s, 3H, CH3),
(t, J¼6.8 Hz, 3H, CH3), 1.1e1.6 (m, 6H, (CH2)3), 2.38 (s, 3H, CH3), 2.76
(m, 1H, CH), 3.67 (s, 3H, OCH3), 4.11 (m, 1H, CH), 6.44 (d, J¼8.8 Hz,
1H, NH), 7.26 (d, J¼8.3 Hz, 2H), 7.74 (d, J¼8.3 Hz, 2H); 13C NMR
3.05 (dd, J1¼2 Hz, J2¼6 Hz, 2H, CH2), 3.61 (td, Jt¼6 Hz, Jd¼2 Hz, 1H,
CH), 4.19 (dq, Jd¼2 Hz, Jq¼4 Hz 1H, CH), 7.14 (m, 2H, HAr), 7.31 (m,
5H, HAr), 7.78 (d, Jd¼8 Hz, 2H, AB-pattern); 13C NMR (CDCl3):
(CDCl3):
d 14.03, 21.81, 22.51, 29.31, 30.18, 42.24, 52.73, 56.52 (q,
d
22.15, 33.19, 53.98, 56.94 (q, Jq¼36 Hz, CeCF3), 123.5 (q,
JCeF¼31.0 Hz, CeCF3), 124.31 (q, JCeF¼283.2 Hz, CF3), 127.29, 129.96,
JCeF¼279 Hz, CF3), 127.96, 128.04, 129.39, 129.47, 130.52, 135.18,
135.27,146.24,164.30; 19F NMR (CDCl3):
ꢁ74.09 (d, Jd¼3.8 Hz CF3);
MS (EI, m/z): 383 (Mþ, 27%), 228 (16%), 198 (17%), 186 (89%), 155
(TolSO2
, 60%), 117 (38%), 91 (Tolþ, 100%); HRMS-EI, m/z calcd for
138.63, 144.09, 174.81; 19F NMR (CDCl3):
HRMS-EI, m/z calcd for C16H22F3NO4S, 381.12216; found, 381.12196.
d
ꢁ75.63 (d, J¼8.6 Hz, CF3);
d
þ
4.4.6. Methyl 4,4,4-trifluoro-2-tert-butyl-3-(4-methylphenyl-
sulfonamido) butanoate 6f. Yield 82%; mp 96e98 ꢀC; 1H NMR
C18H16F3NO3S, 383.08030; found, 383.07976.
(CDCl3): d 1.17 (s, 9H, (CH3)3), 2.42 (s, 3H, CH3), 2.61 (m,1H, CH), 3.73
4.4. General procedure for the opening of
cycle by sodium azide
b
-lactam
(s, 3H, OCH3), 4.48 (m, 1H, CH), 6.76 (d, J¼6.9 Hz, 1H, NH), 7.28
(d, J¼7.3 Hz, 2H), 7.74 (d, J¼7.3 Hz, 2H); 13C NMR (CDCl3):
d 21.91,
28.66, 34.20, 50.33, 52.48, 54.09 (q, JCeF¼30.4 Hz, CeCF3), 124.27 (q,
4.4.1. Methyl 4,4,4-trifluoro-2-isopropyl-3-(4-methylphenyl-
sulfonamido) butanoate 6d. To a solution of 5d (0.2 g, 0.596 mmol)
in MeOH (3 ml) and DMF (1 ml) was added sodium azide (0.08 g,
1.23 mmol). The reaction mixture was stirred at room temperature
for 12 h. The solution was poured into water (10 ml) and extracted
with EtOAc (2ꢂ15 ml). The organic phases were combined, dried
with Na2SO4, and concentrated. Chromatography (hexane/EtOAc 3/
1) gave 0.16 g (73%) of 6d as white solid: mp 109e110 ꢀC; 1H NMR
JCeF¼283.8 Hz, CF3), 127.09, 129.75, 139.26, 143.69, 173.96; 19F NMR
(CDCl3):
d
ꢁ75.38 (d, J¼6.9 Hz, CF3); HRMS-EI, m/z calcd for
C16H22F3NO4S, 381.12216; found, 381.12364.
4.4.7. Methyl 4,4,4-trifluoro-2-benzyl-3-(4-methylphenyl-
sulfonamido) butanoate 6g. Yield 86%; mp 107e110 ꢀC; 1H NMR
(CDCl3):
d 2.47 (s, 3H, CH3), 2.9e3.2 (m, 3H, CHCH2), 3.57 (s, 3H,
OCH3), 4.1e4.3 (m, 1H, CH), 6.52 (d, J¼6.9 Hz, 1H, NH), 7.1e7.4 (m,
(CDCl3):
d
0.94 (d, J¼6 Hz, 3H, CH3), 1.1 (d, J¼6 Hz, 3H, CH3), 2.09 (m,
7H), 7.78 (d, J¼8.3 Hz, 2H); 13C NMR (CDCl3):
d 21.94, 36.48, 44.51,
52.79, 56.25 (q, JCeF¼31.3 Hz, CeCF3),124.59 (q, JCeF¼283.6 Hz, CF3),
1H, CH), 2.43 (s, 3H, CH3), 2.47 (dd, J¼2.4 Hz, J¼10.3 Hz, 1H, CH),
3.72 (s, 3H, OCH3), 4.34 (m, 1H, CH), 6.44 (d, J¼8 Hz, 1H, NH), 7.3 (d,
127.36, 127.68, 129.17, 129.40, 130.02, 136.93, 138.61, 144.19, 174.05;
J¼8 Hz, 2H), 7.76 (d, J¼8 Hz, 2H); 13C NMR (CDCl3):
d
20.54, 20.88,
19F NMR (CDCl3):
C19H20F3NO4S, 415.10651; found, 415.10700.
d
ꢁ71.08 (d, J¼6.9 Hz, CF3); HRMS-EI, m/z calcd for
21.86, 28.35, 49.38, 52.56, 54.72 (q, JCeF¼31.2 Hz, CeCF3), 124.86 (q,
JCeF¼283 Hz, CF3), 127.23, 129.89, 138.73, 143.99, 174.75; 19F NMR
(CDCl3):
d
ꢁ75.58 (d, J¼7.5 Hz, CF3); MS (EI, m/z): 367 (Mþ,16%), 336
(10%), 298 (21%), 270 (7%), 266 (10%), 224 (7%), 212 (17%), 171 (14%),
Acknowledgements
164 (38%), 155 (TolSO2þ
, 62%), 138 (12%), 115 (78%), 91 (Tolþ, 100%);
HRMS-EI, m/z calcd for C15H20F3NO4S, 367.10651; found, 367.10719.
Dr. V.P. is grateful to Deutsche Forschungsgemeinschaft (DFG)
for generous support, DFG Grant (RO 362/36-1). We also thank Dr.
Alexander Chernega (Institute of Organic Chemistry, National
Academy of Sciences of Ukraine, Murmanska str. 5, 02094 Kyiv,
4.4.2. Methyl 4,4,4-trifluoro-2-methyl-3-(4-methylphenyl-
sulfonamido) butanoate 6a. Yield 82%; mp 83e84 ꢀC; 1H NMR
(CDCl3):
d
1.30 (d, J¼7.3 Hz, 3H, CH3), 2.43 (s, 3H, CH3), 2.97 (qd,
Ukraine) for recording the X-ray crystal structure of b-lactam 5d.

V. Petrik et al. / Tetrahedron 67 (2011) 3254e3259
3259
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