Synthesis of N-Protected 3,3-Difluoroazetidin-2-ones

Article abstract of DOI:10.1055/s-2003-42415

Representative N-protected 3,3-difluoroazetidin-2-ones 3 were obtained, either in one step by cycloaddition of zinc enolate 1 derived from ethyl bromodifluoroacetate onto N,N′,N″-trisubstituted hexahydro-1,3,5-triazines 2 (Schiff base trimer) in the case of 3a [N-(p-methoxybenzyl) derivative], or in two steps consisting of a Reformatsky-type reaction for the preparation of N-substituted 3-amino-2,2-difluoropropanotes 8 followed by N1-C2 cyclization under basic conditions in the cases of 3b (N-anisyl derivative) and 3c (N-benzhydryl derivative).

Full text of DOI:10.1055/s-2003-42415

PAPER
2483
Synthesis of N-Protected 3,3-Difluoroazetidin-2-ones
Synthesis of
N
i
-Protec
m
ted 3,3-Difluoroaze
o
tidin-2-onesn Lacroix, Arnaud Cheguillaume, Stéphane Gérard, Jacqueline Marchand-Brynaert*
Unité de Chimie Organique et Médicinale, Université catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur 1, 1348 Louvain-la-
Neuve, Belgium
Fax +32(10)474168; E-mail: Marchand@chim.ucl.ac.be
Received 21 July 2003
In the course of a medicinal chemistry program aimed at
Abstract: Representative N-protected 3,3-difluoroazetidin-2-ones
the discovery of new serine protease inhibitors, we needed
3 were obtained, either in one step by cycloaddition of zinc enolate
an easy and secure access towards N-protected 3,3-diflu-
1 derived from ethyl bromodifluoroacetate onto N,N ,N -trisubsti-
tuted hexahydro-1,3,5-triazines 2 (Schiff base trimer) in the case of
oroazetidin-2-ones (Scheme 1, R2 = H). Thus, we investi-
3a [N-(p-methoxybenzyl) derivative], or in two steps consisting of gated first the usual cycloaddition method of enolate 1
a Reformatsky-type reaction for the preparation of N-substituted 3-
amino-2,2-difluoropropanotes 8 followed by N1–C2 cyclization
under basic conditions in the cases of 3b (N-anisyl derivative) and
the Reformatsky reaction of ethyl bromodifluoroacetate
3c (N-benzhydryl derivative).
onto appropriate Schiff bases. Since disappointing results
were collected, we turned to a two-step approach based on
with N-substituted 1H-benzotriazolyl-1-methylamine,15
followed by N1–C2 cyclization in the presence of an or-
ganomagnesium reagent. In this paper, we describe a
Key words: fluoroazetidinone, Reformatsky-type reaction, cy-
cloaddition, cyclization
practical synthesis of 3,3-difluoroazetidin-2-one bearing
representative N-protecting groups.16,17
3,3-Difluoroazetidin-2-one derivatives (Scheme 1) have
Schiff bases derived from formaldehyde cannot be isolat-
been prepared either as enzyme inhibitors, or as synthetic
ed as such, but as cyclic trimers, i.e. N,N ,N -trisubstituted
intermediates for modified peptides.1–3 Generally, the
compounds were equipped with substituents in positions
hexahydro-1,3,5-triazines, which are in equilibrium with
the corresponding monomers in solution. Compounds
N1 and C4, and resulted from the cycloaddition of difluo-
2a,18 2b,19 and 2c20 were thus prepared and engaged in cy-
roenolate 1 with Schiff bases (Method A),4–6 or oxazol-
cloaddition reactions with enolate 1 formed by treatment
idines (Method B).7 The N1–C4 cyclization of 3-hydroxy-
of ethyl bromodifluoroacetate with zinc dust. NMR anal-
2,2-difluoropropionamide derivatives under Mitsunobu
ysis of the crude reaction mixtures revealed the presence
conditions (Method C) was also described.8–11
of at least four products: the expected azetidinones 3, eth-
yl difluoroacetate (4), and two 6-membered heterocycles
resulting from 2:1 (5) and 1:2 (6) condensations, respec-
tively (Scheme 2).
Scheme 1
The related C4 unsubstituted azetidinones (Scheme 1,
R2 = H) are scarcely described in the previous litera-
12–14
ture;
only one method of synthesis of 3,3-difluoro-
Scheme 2
azetidin-2-one derivatives has been reported by
Wakselman et al., based on the N1–C4 cyclization of N-
aryl-3-bromo-2,2-difluoropropionamides under strongly
basic conditions. The precursor of the required anilides
was ethyl 3-bromo-2,2-difluoropropanoate obtained by
fluorination of ethyl bromopyruvate with sulfur tetrafluo-
ride in an autoclave.12
The H,F coupling constant values in H and 19F NMR
spectra are typical features that allow to differentiate the
cycloadducts: 3JH-F was 6 Hz for the four-membered het-
erocycle 3 and 12 Hz for the six-membered heterocycles
5 and 6. The reduction product 4 was characterized by a
2JH-F value of 53 Hz.
1
In all cases, azetidinones 3 were the minor products, and
the chromatographic purifications were arduous. Pure N-
p-methoxybenzyl-3,3-difluoroazetidin-2-one (3a) could
be recovered in 25% yield, but N-anisyl (3b) and N-ben-
SYNTHESIS 2003, No. 16, pp 2483–2486
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42415; Art ID: P06503SS.pdf
© Georg Thieme Verlag Stuttgart · New York
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S. Lacroix et al.
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zhydryl (3c) derivatives could not be satisfactorily puri- of reaction in THF of spectroscopic grade and a tempera-
fied. Changing the experimental conditions (ratio of ture comprised between 25 °C and 50 °C. By this way, ad-
reagents, temperature, zinc activation) did not allow an ducts 8b and 8c were obtained in about 90% yield but not
improvement in the yield of azetidinones 3.
compound 8a because reagent 7a decomposed under heat-
ing and no clean reaction occurred at lower temperatures.
Since we recently developed a practical synthesis of , -
difluoro- -alanine,15 we tried to apply the cyclization
methods described in the literature to this precursor for the
1
In H NMR, the NCH2CF2 methylene of 8 gave a triplet
with a 3JH-F coupling constant value of 13 Hz.
preparation of azetidin-2-one from -alanine.21 Formation Intermediates 8b,c were further cyclized by treatment
of the lactam bond by treatment with triphenylphosphine with tert-butylmagnesium chloride in anhydrous ether at
and 2,2 -dithiopyridine21 (Mukaiyama’s reagent) failed. 0 °C (Scheme 3, equation 2). A total amount of two equiv-
Similarly, no cyclization product could be identified in the alents of base was used, added in two fractions. Pure aze-
crude reaction mixtures following treatment of , -diflu- tidinones 3b,c were recovered in moderate yields after
oro- -alanine with 2-chloro-N-methylpyridinium iodide22 column chromatography on silica gel. Compounds 3b,c
3
or with N-tert-butyl-2-benzothiazolylsulfenamide.23 Fur- were characterized by a JH-F coupling constant value of
thermore, attempts to cyclize ethyl , -difluoro- - 6.3 Hz; a similar value was previously observed for azeti-
alaninate15 via N-silylation followed by treatment with an dinone 3a synthesized according to Scheme 2.
organomagnesium reagent24 were unsuccessful.
Thus representative N-protected 3,3-difluoroazetidin-2-
Clearly, N-substituted , -difluoro- -alanine precursors ones 3 were obtained in one step by cycloaddition of zinc
should be better candidates for N1–C2 cyclization. There- enolate 1 onto Schiff base trimer 2 for N-(p-methoxyben-
fore, we prepared N-protected ethyl , -difluoro- -alani- zyl) derivative 3a, and in two steps by N1–C2 cyclization
nates 8 according to the Reformatsky-type strategy of a -amino acid precursor 8 resulting from addition of
outlined in Scheme 3 (i).
enolate 1 onto 1H-benzotriazolyl-1-methylamine deriva-
tive 7, in the cases of N-anisyl (3b) and N-benzhydryl (3c)
derivatives. This method could be readily applied for the
synthesis of N-aryl-3,3-difluoroazetidin-2-ones which is
of interest as suicide inhibitors of serine proteases.14 Com-
pounds 3a–c tested against porcine pancreatic elastase
(PPE)27 were found to be inactive.
Melting points were determined with an electrothermal microscope
and are uncorrected. IR spectra were taken with a Bio-Rad FTS 135
1
instrument and calibrated with polystyrene. The H, 13C and 19F
NMR spectra were recorded on Varian Gemini 300 (300 MHz for
1H, 50 MHz for 13C, and 282 MHz for 19F). References for the NMR
spectra were TMS for 1H NMR, CDCl3 for 13C NMR and CFCl3 for
19F NMR. Mass spectra were obtained on a Finnigan-MAT TSQ-70
instrument at 70 eV (chemical ionization mode). Microanalyses
were performed at the Christopher Ingold Laboratories, University
College, London, UK. HRMS were recorded at the University of
Mons, Belgium (Prof. R. Flammang).
Scheme 3
The required N-protected 1H-benzotriazolyl-1-methy-
lamine reagents 7 were prepared following a known
procedure15,25 from benzotriazole, formaldehyde and the
corresponding amines, namely p-methoxybenzylamine
(for 7a), p-anisyl (for 7b) and benzhydrylamine (for 7c).
TLC was carried out on silica gel 60 plates F254 (Merck, 0.1 mm
thickness); visualization was effected with UV light. Column chro-
matography (under medium pressure) was carried out with Merck
The crude compounds 7 were recovered in nearly quanti- silica gel 60 of 230–240 mesh ASTM.
tative yields. However, under recrystallization conditions
Reformatsky-Type Reaction for the Preparation of 3 and 8;
(hot methanol), 7a was unstable and slowly transformed
into benzotriazole and 2a. On the other hand, 7b (now
commercially available reagent) and 7c were stable and
could be stored in the solid state. Reagents 7 behave as
masked iminium salts, susceptible to be quenched by or-
ganometallic compounds.26 Thus, reaction of 7 with zinc
enolate 1 derived from ethyl bromodifluoroacetate fur-
nished N-substituted ethyl 3-amino-2,2-difluoropro-
panoates 8. Several reaction parameters have been
changed in view to improve the yields of product 8; in our
hands, the best conditions of this Reformatsky-type cou-
pling were as follows: two equivalents of zinc activated
with one equivalent of trimethylsilyl chloride, three hours
General Procedure
Trimethylsilyl chloride (1 equiv) was added under stirring to a sus-
pension of zinc powder (2 equiv) in THF (1 mL/100 mg Zn). After
10 min, ethyl bromodifluoroacetate (1 equiv) was added dropwise
under cooling with an ice bath. After 25 min, a solution of com-
pound 2 or 7 (1 equiv) in THF (3 mL/mmol) was added at r.t. The
mixture was then stirred during 3 h (at r.t. or at 50 °C, see particular
cases below). The mixture was quenched by addition of aq
NaHCO3. After filtration on Celite, the aqueous phase was extracted
with EtOAc (2 ×). The organic phases were combined, washed with
brine, dried (MgSO4) and evaporated under vacuum. The residue
was dissolved in Et2O and the eventual precipitate was filtered off.
The crude adduct could be purified by column chromatography on
silica gel.
Synthesis 2003, No. 16, 2483–2486 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Protected 3,3-Difluoroazetidin-2-ones
2485
1-(4 -Methoxybenzyl)-3,3-difluoroazetidin-2-one (3a)
Azetidinone 3a was obtained from the trimer of N-(4 -methoxyben-
zyl)imine (2a; 500 mg, 3.4 mmol, 1 equiv) and zinc enolate 1 pre-
pared according to the general procedure. The mixture was stirred
for 3 h at 25 °C. Pure 3a (193 mg, 25%) was recovered by column
chromatography (silica gel; hexane–CH2Cl2, 7:3; Rf 0.26) as a pale
orange oil.
Anal. Calcd for C18H19F2NO: C, 67.69; H, 5.99; N, 4.38. Found: C,
67.37; H, 5.94; N, 4.23.
Cyclization of 8 to Azetidinones 3; General Procedure
In a dried glassware and under argon, tert-butylmagnesium chloride
(2 M solution in anhyd Et2O, 1.3 equiv) was added at 0 °C under
stirring to a solution of compound 8 (1 equiv) in anhyd Et2O (4.8
mL, [8] = 0.25 M). After 1 h, a second portion of tert-butylmagne-
sium chloride (2 M solution in Et2O, 0.7 equiv) was added and the
mixture was brought to 20 °C. After completion of the reaction (19F
NMR, ca. 2 h), the mixture was treated with sat. aq NH4Cl (very
slow addition!) and the aqueous phase was extracted with CH2Cl2
(2 ×). The organic phases were combined, dried (MgSO4) and evap-
orated under vacuum. The solid obtained was then purified by col-
umn chromatography on silica gel.
IR (film): 1776 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): = 7.17 (d, 2 Harom, J = 8.8 Hz), 6.90
(d, 2 Harom, J = 8.8 Hz), 4.45 (s, 2 H, NCH2PhOMe), 3.81 (s, 3 H,
PhOCH3), 3.55 (t, 2 H, 3JH-F = 5.9 Hz, CH2CF2).
2
13C NMR (CDCl3, 50 MHz):
= 160.3 (t, JC-F = 30.5 Hz,
CF2C=O), 159.7, 129.5, 125.4 (t, 1JC-F = 245 Hz, CF2), 114.5, 113.8,
2
55.1 (s, PhOCH3), 53.8 (t, JC-F = 26.1 Hz, CH2CF2), 45.2 (s,
NCH2PhOMe).
19F NMR (CDCl3, 282 MHz): = –116.3 (t, 3JH-F = 6.3 Hz).
3,3-Difluoro-1-(4 -methoxyphenyl)azetidin-2-one (3b)
Starting from 8b (300 mg, 1.2 mmol, 1 equiv), 140 mg (45%) of 3b
were obtained as a white solid after chromatography (silica gel, hex-
ane–EtOAc, 8:2, Rf 0.4); mp 88–90 °C.
MS (CI/CH4-N2O): m/z (%) = 228 ([M + H]+, 24), 121
([CH2PhOMe]+, 100).
IR (KBr): 1763 cm–1 (C=O).
HRMS: m/z calcd for C11H11F2O2N: 228.0836; found: 228.0483.
1H NMR (CDCl3, 300 MHz): = 7.3 (d, 2 Harom, J = 9 Hz), 6.92 (d,
Ethyl 2,2-Difluoro-3-[(4 -methoxyphenyl)amino]propanoate
(8b)
2 Harom, J = 9 Hz), 4.01(q, 2 H, 3JH-F = 6.3 Hz, CH2CF2), 3.82 (s, 3
H, PhOCH3).
Ester 8b was obtained from 7b (5 g, 20 mmol, 1 equiv) and zinc
enolate 1 prepared according to the general procedure. The mixture
was stirred for 3 h at 50 °C. Work-up furnished 8b (4.58 g, 89%) as
a colorless oil which can be further used without purification. An
analytical sample was obtained by column chromatography (silica
gel, hexane–EtOAc, 8:2; Rf 0.44).
2
13C NMR (CDCl3, 50 MHz):
= 157.3 (t, JC-F = 30.8 Hz,
CF2C=O), 155.8, 129.9, 119.4 (t, 1JC-F = 235 Hz, CF2), 118.5, 114.6,
55.5 (s, PhOCH3), 54.4 (t, 2JC-F = 18 Hz, CH2CF2).
19F NMR (CDCl3, 282 MHz): = –115.1 (t, 3JH-F = 6.3 Hz).
MS (CI/CH4-N2O): m/z (%) = 213.8 ([M + H]+, 100).
IR (film): 1784 cm–1 (C=O).
HRMS: m/z calcd for C10H10F2NO2: 214.0683; found: 214.0679.
1H NMR (CDCl3, 300 MHz): = 6.75 (d, 2 Harom, J = 8.7 Hz), 6.63
Anal. Calcd for C10H9F2NO2: C, 56.34; H, 4.25; N, 6.57. Found: C,
56.06; H, 4.22; N, 6.34.
3
(d, 2 Harom, J = 8.7 Hz), 4.23 (q, J = 7.2 Hz, 2 H, OCH2), 3.73 (t,
3JH-F = 12.6 Hz, 2 H, CH2CF2), 3.72 (s, 3 H, PhOCH3), 1.26 (t,
3J = 7.2 Hz, 3 H, CH2CH3).
1-Benzhydryl-3,3-difluoroazetidin-2-one (3c)
Starting from 8c (4 g, 0.013 mol, 1 equiv), 2.311g (65%) of 3c was
obtained as a white solid after chromatography (silica gel, hexane–
EtOAc, 99:1, then 95:5) and recrystallization from propan-2-ol; mp
92–93 °C.
2
13C NMR (CDCl3, 50 MHz):
= 163.5 (t, JC-F = 31.8 Hz,
CF2C=O), 153.1, 140.6, 115.0, 114.8, 114.5 (t, 1JC-F = 251 Hz, CF2),
62.9 (s, OCH2) 55.7 (s, PhOCH3), 48.5 (t, 2JC-F = 27.4 Hz, CH2CF2),
15.2 (s, CH2CH3).
19F NMR (CDCl3, 282 MHz): = –110.9 (t, 3JH-F = 12.6 Hz).
MS (CI/CH4-N2O): m/z (%) = 260 ([M + H]+, 100), 259 ([M]+, 51).
HRMS: m/z calcd for C12H15F2O3N: 259.1016; found: 259.1020.
IR (KBr): 1784 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): = 7.15–7.39 (m, 10 Harom.), 6.26 (s,
1 H, Ph2CH), 3.64 (t, 2 H, 3JH-F = 6.3 Hz, CH2CF2).
13C NMR (CDCl3, 50 MHz):
= 160.3 (t, JC-F = 30.7 Hz,
2
1
Ethyl 3-(Benzhydrylamino)-2,2-difluoropropanoate (8c)
Ester 8c was obtained from 7c (6 g, 19 mmol, 1 equiv) and zinc eno-
late 1 prepared according to the general procedure. The mixture was
stirred for 3 h at 25 °C. Work-up furnished 8c (5.02 g, 86%) as a col-
orless oil which can be further used without purification. An analy-
tical sample was obtained by column chromatography (silica gel,
hexane–EtOAc, 9:1; Rf 0.61).
CF2C=O), 137.0, 128.9, 128.3, 127.9, 119.9 (t, JC-F = 284.5 Hz,
CF2), 59.5 (s, Ph2CH), 53.7 (t, 2JC-F = 26.4 Hz, CH2CF2).
19F NMR (CDCl3, 282 MHz): = –116.07 (t, J3H-F = 6.3 Hz).
MS (CI/CH4-N2O): m/z (%) = 274.0 ([M + H]+, 14), 166.9
([Ph2CH]+, 100).
HRMS: m/z calcd for C16H14F2NO: 274.1045; found: 214.1043.
IR (film): 1771 cm–1 (C=O).
Anal. Calcd for C16H13F2NO: C, 70.32; H, 4.79; N, 5.12. Found: C,
70.07; H, 4.91; N, 5.15.
1H NMR (CDCl3, 300 MHz): = 7.22–7.37 (m, 10 Harom), 4.89 (s,
3
1 H, Ph2CH), 4.34 (q, 2 H, J = 7.2 Hz, OCH2CH3) 3.18 (t, 2 H,
3JH-F = 13.2 Hz, CH2CF2) 1.35 (t, 3 H, 3J = 7.2 Hz, OCH2CH3).
13C NMR (CDCl3, 50 MHz): = 163.6 (t, 2JC-F = 32 Hz, CF2C=O),
Benzotriazole Derivatives 7; General Procedure
The appropriate amine (1 equiv) and formaldehyde (37% aq solu-
tion, 1.2 equiv) were successively added to a solution of benzotria-
zole (1 equiv) dissolved in a minimum amount of MeOH. The
mixture was then stirred at r.t. until a precipitate appeared. After
evaporation under vacuum, the solid obtained was recrystallized
from MeOH.
1
142.5, 128.5, 127.3, 127.2, 115.2 (t, JC-F = 251 Hz, CF2), 64.5 (s,
2
Ph2CH), 62.7 (s, OCH2), 49.7 (t, JC-F = 26 Hz, CH2CF2), 13.9 (s,
CH3).
19F NMR (CDCl3, 282 MHz): = –110.0 (t, 3JH-F = 13.2 Hz).
MS (CI/CH4-N2O): m/z (%) = 319.2 ([M]+, 3), 318.2 ([M – H]+, 15),
167.2 ([M – NHCH2CF2CO2Et]+, 100), 152.2 ([M – Ph2CH]+, 11).
N-(4 -Methoxybenzyl)-1H-benzotriazolyl-1-methylamine (7a)
This compound was unstable and characterized only by 1H NMR of
the crude mixture.
HRMS: m/z calcd for C18H19F2NO: 319.1361; found: 319.1383.
Synthesis 2003, No. 16, 2483–2486 © Thieme Stuttgart · New York

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S. Lacroix et al.
PAPER
1H NMR (CDCl3, 300 MHz): = 8.1–7.3 (m, 8 Harom), 6.9 (d, J = 9
Hz, 2 H, CH2), 5.68 (s, 2 H, CH2PhOMe), 3.81 (s, 3 H, OCH3).
(7) Marcotte, S.; Pannecoucke, X.; Feasson, C.; Quirion, J. C. J.
Org. Chem. 1999, 64, 8461.
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J. Med. Chem. 1987, 30, 1837.
N-(Benzhydryl)-1H-benzotriazolyl-1-methylamine (7c)
Starting from diphenylmethanamine (8.87 mL, 0.047 mol), 13.38 g
(97%) of 7c was obtained as a white solid; mp 101–103 °C.
1H NMR (CDCl3, 300 MHz): = 7.43–7.02 (m, 14 Harom), 5.50 (s,
2 H, CH2), 4.65 (s, 1 H, CHPh2), 2.96 (br s, 1H, NH).
13C NMR (CDCl3, 50 MHz): = 145.7, 141.9, 133.1, 128.6, 128.5,
127.4, 127.3, 127.2, 123.8, 119.8, 118.2, 109.3, 62.9, 59.8.
MS (CI/CH4-N2O): m/z (%) = 362.4 ([Ph2CHCH2NHCHPh2]+, 31),
196.0 ([CH2=NCHPh2]+, 35), 167.0 ([Ph2CH]+, 100), 119.9 ([1H-
benzotriazole]+).
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Acknowledgment
This work was supported by FNRS, FRIA and the Walloon Govern-
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FNRS and the fellowship to S.L. is granted by FRIA.
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Synthesis 2003, No. 16, 2483–2486 © Thieme Stuttgart · New York