Synthesis of α,α-difluoro-β-amino esters or gem-difluoro-β-lactams as potential metallocarboxypeptidase inhibitors

FULL PAPER

DOI: 10.1002/ejoc.200800363

Synthesis of α,α-Difluoro-β-amino Esters or gem-Difluoro-β-lactams as

Potential Metallocarboxypeptidase Inhibitors

Nicolas Boyer,^[a]Philippe Gloanec,^[b]Guillaume De Nanteuil,^[b]Philippe Jubault,*^[a]and

Jean-Charles Quirion*^[a]

Keywords: β-Lactams / Fluorinated building blocks / 3,3-Difluoroazetidin-2-ones / α,α-Difluoro-β-amino acids / Reformat-

sky reaction

The synthesis of gem-difluorinated β-lactams and gem-diflu-

orinated β-amino acids, each possessing a potential basic

functional group, from ethyl bromodifluoroacetate and either

imines (for β-lactams) or N-(α-aminoalkyl)benzotriazoles (for

β-amino esters) was investigated. A series of these com-

peptidase inhibitors. N-Alkylation and N-acylation of these

two versatile scaffolds were carried out, leading to the ex-

pected targets in moderate to good yields.

pounds were used for the design of novel metallocarboxy- Germany, 2008)

mers.^[6]In particular, β-amino acids are recognized as phar-

Introduction

macologically important compounds,^[7,8]since β-peptides

are able to adopt stable and well-organized conforma-

tions.^[9]Such building blocks provide useful scaffolds for the

design of functional mimics of natural proteinic structures.

Furthermore, β-peptides are stable to proteolytic degrada-

tion in vitro and in vivo,^[10]which represents an important

advantage over natural peptides and proteins. Moreover, β-

amino acids also play key roles in medicinal chemistry as,

for example, precursors of pharmacologically important β-

lactam antibiotics^[11]and components of biologically active

unnatural oligopeptides.^[12]

Introduction of fluorine atoms into bioorganic and bio-

active molecules often induces modifications of chemical,

physical, and biological properties and as a consequence

leads to the generation of novel and potent biological, phar-

macological, and chemotherapeutic agents.^[1–3]The strength

of the C–F bond (485.6 kJmol^–1) confers relative stability

against metabolic transformations.^[4]Furthermore, the

small nature of the steric perturbations produced in the

molecule, because of the relative homology of the

van der Waals radii of H (1.20 Å) and F (1.47 Å), usually

allows them to enter metabolic pathways similarly to the

corresponding non-fluorinated compounds. The replace-

ment of hydrogen by fluorine does alter the properties of

molecules, however, affecting the basicity or acidity of

neighboring groups, lipophilicity/hydrophobicity, hydrogen

bonding, dipole moment, and overall reactivity and sta-

bility. As a result, a large number of physiologically active

compounds and therapeutic agents containing strategically

located fluorine atoms are currently widely used or in devel-

opment.^[5]

Because of the exciting benefits of fluorine substitution

and the importance of amino acids in biochemical func-

tions, the area of fluorine-containing amino acids (FAAs)

is expanding rapidly, taking a major place in the family of

nonnatural amino acids.^[13]FAAs are known to show anti-

bacterial activity, to act as proteinase inhibitors, and to ex-

hibit promising properties as candidates for peptide modifi-

cation.^[14]Given the biomedicinal and synthetic potential

reported for β-amino acids, and the biological influence of

fluorine substitution in the β-position relative to the amino

group, it is not surprising that considerable efforts have

been devoted to the development of efficient syntheses of

gem-difluoromethylene compounds,^[15]and more specifi-

cally of α,α-difluoro-β-amino acids. Replacement of various

functional groups by a gem-difluoromethylene group has

generated potent transition-state-type inhibitors.^[16]Several

α,α-difluoro-β-amino acids^[17]or gem-difluorinated pep-

tides^[18]have been synthesized and tested as potent competi-

tive serine protease inhibitors or [¹⁸F]-radiolabeled

markers.^[19]The gem-difluoromethylene/methylene transpo-

sition in the “western” β-amino acid moiety of the naturally

In the past decade, increasing work has been devoted to

the study of nonnatural foldamers and sequence-specific

oligomers that mimic various aspects of the folding, organi-

zation, and function of polypeptides or biological poly-

[a] UMR CNRS 6014, Institut de Recherche en Chimie Organique

Fine, INSA et Université de Rouen,

1 rue Tesnière, 76131 Mont-Saint-Aignan Cedex, France

Fax: +33-2-35522959

E-mail: philippe.jubault@insa-rouen.fr

quirion@insa-rouen.fr.

[b] Division D of Medicinal Chemistry, Institut de Recherches

Servier,

11 rue des Moulineaux, 92150 Suresnes, France

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N. Boyer, P. Gloanec, G. De Nanteuil, P. Jubault, J.-C. Quirion

In the course of a medicinal chemistry program devoted

FULL PAPER

occurring antifungal cyclic tetrapeptide rhodopeptin results

in improved activity and novel physical properties to the synthesis of basic metallocarboxypeptidase inhibi-

(Scheme 1).^[20]Incorporation of fluorinated β-amino acids tors, we were interested in small and original molecules. In

in the side chain of analogues of Docetaxel (Taxotere^®) was this study we report the synthesis and functionalization of

investigated to improve the cytotoxicity of this chemo- α,α-difluoro-β-amino acid and 3,3-difluoroazetidin-2-one

therapy drug (Scheme 1).^[21]The introduction of a β-amino templates. Our strategy was based on the salt bridge interac-

acid bearing one or two fluorine atoms in its 2-position into tions between the C-terminal carboxylate of the substrate

a β-peptide chain induces an alteration of the neighboring and the basic residues of the active site of the carboxypepti-

electronic environment without incurring steric constraints. dase. 3,3-Difluoroazetidin-2-ones can be regarded as the

Such modifications improve stability against enzymatic de- masked forms of gem-difluoroacetyl functional groups, and

gradations and can beneficially influence the biological ac- have turned out to be prodrugs for the corresponding β-

tivity.^[22]

amino acids. Since a metalloprotease substrate requires a

zinc-binding group (ZBG) for coordination with the cata-

lytic zinc atom of the active site, it was decided to use the

neutral thiol moiety and the carboxylic acid function as

ZBG. We were therefore interested in molecules of small

size and high water solubility possessing a carboxylate or a

thiol as zinc-chelating group and a basic functional group.

β-Substituted α,α-difluoro-β-amino acids and 3,3-difluo-

roazetidin-2-ones are attractive scaffolds for the design of

novel metallocarboxypeptidase inhibitors (Scheme 3).

Scheme 1. Examples of introduction of β-amino acid moieties into

bioactive compounds.

The azetidin-2-one (β-lactam) skeleton has attracted sig-

nificant interest among synthetic and medicinal chemists,

mainly because it is the core of natural and nonnatural anti-

biotics. Great efforts have been dedicated to the synthesis

of new types of β-lactams to address the bacterial resistance

of some of these drugs.^[23]To tackle this growing problem,

the introduction of fluorine, in particular of the difluorome-

thylene moiety, into the azetidinone structure has been sug-

gested because of the unique changes produced in physio-

chemical, and consequently biological, behavior. 3,3-Di-

fluoroazetidin-2-ones have been already synthesized, and

some of them have demonstrated potential biological activi-

ties^[18a,24](Scheme 2) or have turned out to be versatile syn-

thetic intermediates and useful building blocks.^[25,26]The

growing interest in 3,3-difluoroazetidines^[27]is illustrated by

their potential therapeutic inhibitory activity towards di-

peptidyl peptidase-IV for the antihyperglycaemic treatment

of type 2 diabetes.^[28]

Scheme 3. Design of potent metallocarboxypeptidase inhibitors.

Several general methodologies for the syntheses of the

3,3-difluoroazetidin-2-one and α,α-difluoro-β-amino ester

skeletons have been developed. Among them, Reformatsky-

type reactions^[32]with ethyl halodifluoroacetate are usually

applied either with carbonyl compounds or with imines,

thus leading to β-hydroxy esters and β-amino ester/β-lac-

tam mixtures,^[33]respectively (Scheme 4). In the first case,

the pathways mainly involve either a two-step strategy with

conversion of the formed 2,2-difluoro-3-hydroxy esters into

the desired 2,2-difluoro-3-hydroxypropionamides^[21a,26,34]

or hydroxamates,^[18a]followed by internal N1–C4 cycliza-

tion or the replacement of a hydroxy group by different

nucleophiles^[21a,35]under Mitsunobu conditions. In the sec-

ond case, condensation of the appropriate Reformatsky rea-

gents derived from ethyl bromodifluoroacetate with ald-

imines or synthetic equivalents can lead, depending on the

Scheme 2. Examples of bioactive 3,3-difluoroazetidin-2-ones.

The importance and usefulness of β-lactams as versatile

synthetic intermediates has also been widely recognized

with the development of the “β-lactam synthon method”^[29]

for the preparation of various amino acids, peptides, pepti-

domimetics, human cytomegalovirus protease inhibitors

based on activated carbonyl groups,^[30]cholesterol absorp-

tion inhibitors,^[31]and other types of compounds of bio-

logical and medicinal interest.

Scheme 4. General strategies directed towards the production of

3,3-difluoroazetidin-2-ones and α,α-difluoro-β-amino esters

through Gilman–Speeter and Reformatsky reactions.

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Eur. J. Org. Chem. 2008, 4277–4295

α,α-Difluoro-β-amino Esters and gem-Difluoro-β-lactams

reaction conditions and/or the substitution of the substrate,

either to the β-amino ester or 3,3-difluoroazetidin-2-one de-

rivatives or to mixtures of these two products (these are

difficult to separate in most cases).^[18b,34c,36]The Gilman–

Speeter reaction, also called ester-imine condensation, has

emerged as a powerful approach for the synthesis of gem-

difluoro-β-amino carbonyl compounds, mainly in their

racemic forms, but also in the enantiomerically pure

series.^{[25b–25d,37]}

Scheme 5. (a) LiAlH₄, THF, room temp.; (b) CbzCl, Na₂CO₃,

CH₂Cl₂/H₂O, room temp.; (c) (COCl)₂, DMSO, DIEA, CH₂Cl₂,

–60 °C Ǟ room temp.

We recently disclosed the stereoselective and chemoselec-

tive preparation of 3,3-difluoroazetidin-2-ones and α,α-di-

fluoro-β-amino acids.^[38]The key transformation is the ad-

dition, with high levels of stereoselectivity (up to 98%), of

the organozinc reagent derived from ethyl bromodifluo-

roacetate to chiral 1,3-oxazolidines or aldimines derived

from aliphatic and aromatic aldehydes, and either (R)-phen-

ylglycinol or (R)-methoxyphenylglycinol.

To extend the usefulness of this type of reaction in the

synthesis of biologically active compounds, we now report

our results relating to the straightforward and chemoselec-

tive synthesis of β-lactams and β-amino esters derived from

several aldehydes bearing basic functional groups. We have

also investigated the introduction of thiol and carboxylate

zinc-binding groups in good to excellent yields by N-alky-

lation of β-lactams and N-acylation of β-amino esters.

Cbz-protected 4-(aminomethyl)benzaldehyde derivative

4c was prepared from 4-cyanobenzaldehyde (5) in a four-

step sequence as shown in Scheme 6. Formation of dioxol-

ane-type acetal 6 was followed by the reduction of the cy-

ano group.^[41]The primary amine 7 was converted into the

corresponding N-Cbz-protected amine and was then sub-

jected to mild acidic conditions to remove the acetal in 93%

yield.^[42]

Results and Discussion

Scheme 6. (a) Ethylene glycol, PTSA, toluene, reflux; (b) LiAlH₄,

THF, 0 °C Ǟ 65 °C; (c) CbzCl, Na₂CO₃, CH₂Cl₂/H₂O, room temp.;

To develop original compounds as novel metallocarboxy- (d) AcOH, H₂O, room temp.

peptidase inhibitors, we prepared a series of β-lactams and

β-amino esters substituted (R², Scheme 3) with protected or

unprotected basic groups [namely pyridin-3-yl, pyridin-4-

Synthesis of gem-Difluoro-β-lactams and -β-amino Esters

yl, piperidin-4-yl, and 4-(aminomethyl)benzyl groups]. Such

functional groups can be introduced by use of the corre-

sponding aldehydes.

Racemic N-deprotected 3,3-difluoroazetidin-2-ones can

be efficiently prepared in a three-step route based on Gil-

man–Speeter reactions between the Reformatsky reagent

derived from ethyl bromodifluoroacetate and the appropri-

ate aldimines (Scheme 7). (p-Methoxybenzyl)amine was

used, because the PMB protecting group can be easily re-

Preparation of Starting Aldehydes

The Cbz-protected piperidine-4-carbaldehyde 4b was moved under mild conditions. The imines were easily pre-

prepared by the synthetic route outlined in Scheme 5. Re- pared by condensation of the appropriate arene-, heterocy-

duction of commercially available methyl isonipecotate (1) cle-, and alkanecarbaldehydes 4a–e and (p-methoxybenzyl)-

with LiAlH₄in THF gave 2 in 90% yield.^[39]The protection amine in CH₂Cl₂in the presence of MgSO₄, and were iso-

of (piperidin-4-yl)methanol as its Cbz derivative followed lated quantitatively without further purification. Com-

by Swern oxidation afforded aldehyde 4b in 58% overall pounds 9a–e were treated with ethyl bromodifluoroacetate

yield.^[40]

(2 equiv.) in the presence of freshly activated Zn dust in

Scheme 7. Synthesis of 3,3-difluoroazetidin-2-ones. (a) MgSO₄, p-MeOC₆H₄CH₂NH₂, CH₂Cl₂, room temp.; (b) BrZnCF₂CO₂Et, THF,

reflux; (c) CAN, CH₃CN, H₂O, 0 °C.

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N. Boyer, P. Gloanec, G. De Nanteuil, P. Jubault, J.-C. Quirion

FULL PAPER

THF at reflux over 2 h, leading to the expected products sors in Katritzky’s methodology.^[45]To our delight, benzo-

in high yields. In situ activation of zinc, performed with triazole-mediated aminoalkylations provided protected α,α-

dibromoethane and chlorotrimethylsilane at room temp., difluorinated β-amino esters 14b–e in high yields through

and preparation of the organozinc reagent prior to the ad- Reformatsky reactions with ethyl bromofluoroacetate, acti-

dition of the aldimine led to higher yields under milder con- vated zinc, and trimethylsilyl chloride in THF at reflux.

ditions.^[43]The results are summarized in Table 1. The di-

We then turned our attention to the conversion of diben-

fluoroazetidin-2-ones 10 were the major or the only isolated zylated amines into primary amines by catalytic hydro-

products except in the case of 9c, in which a particular re- genolysis (Scheme 9). Selective removal of benzyl protecting

sult was observed (Table 1, Entry 3): a 1:1 β-lactam 10c/β- groups from 14b was achieved by a two-step route. Hydro-

amino ester 11c ratio was obtained in good overall yield. genolysis of the Cbz group followed by in situ Boc protec-

As previously described by our group,^[38b]the presence of a tion gave 14f in quantitative yield. Debenzylation of the ter-

primary carbamate greatly disfavored the cyclization step. tiary amine by hydrogenolysis in the presence of Pearlman’s

Pyridine derivatives 9d and 9e each gave 10% yields of α,α- catalyst in ethanol or in a mixture of ethanol and ethyl ace-

difluoro-β-amino esters 11d and 11e, which could not be tate was inefficient, and a complex mixture of products was

eliminated after purification on silica gel by flash obtained, due to transcarbamoylation. Other conditions

chromatography. Nevertheless, this noncyclized byproduct such as catalytic transfer hydrogenation with cyclohexene

was degraded during the oxidative debenzylation step. De- turned out to be inefficient in our case.^[46]Hydrogenolysis

protection was then carried out by a classical procedure of the two benzyl protecting groups was finally carried out

with 3 equiv. of ceric ammonium nitrate (CAN) in a mix- with the following combination: H₂(1 bar)/Pearlman’s cata-

ture of acetonitrile and water in a 9:1 ratio, leading to race- lyst/EtOH/MeOH/room temp. to afford the β-amino ester

mic azetidin-2-ones 12a–e in moderate to good yields.^[44]

15b in 17% yield.

Table 1. Preparation of azetidin-2-ones 10 and 12.

Entry

Starting

aldehyde

Yield 10 + 11

Ratio 10/11

Yield 12

[%]^[a]

[%]^[b]

[%]^[c]

1

2

3

4

5

4a

4b

4c

4d

4e

74

70

100:0

83^[d]

38

72

52:48^[e]

89:11^[g]

90:10^[g]

43

85^[f]

86^[f]

62^[h]

49^[h]

[a] Global isolated yield. [b] Ratios determined by ¹⁹F NMR spec-

troscopy. [c] Isolated yield from β-lactam 10. [d] See ref.^[38a]for full

characterization. [e] The two products can be separated on silica

gel. [f] See ref.^[37b]for full characterization of this product. [g] Not

separable by silica gel flash chromatography. [h] See ref.^[38b]for full

characterization.

As we were looking for an efficient and short way to

prepare β-amino ester derivatives in a selective manner, we

decided to investigate Katritzky’s procedure,^[36c]using the

ethyl bromodifluoroacetate zinc derivative and N-(α-amino-

alkyl)benzotriazoles for the preparation of α,α-difluoro-β-

amino esters.

Scheme 9. (a) H₂(1 bar), Boc₂O, Pd/C, EtOH, 40 °C; (b) H₂,

Pd(OH)₂/C, EtOH/MeOH, 40 °C; (c) H₂(1 bar), Pd/C, EtOH, Ac-

OEt, HCl/iPrOH (6 ), 40 °C; (d) Boc₂O (1 equiv.), Et₃N, CH₂Cl₂,

room temp.; (e) H₂(1 bar), Pd/C, EtOH, HCl/iPrOH (6 ), room

N-(α-Aminoalkyl)benzotriazoles 13 (Scheme 8), easily

prepared from dibenzylamine, benzotriazole, and aldehydes

4b–e, were used without purification as iminium salt precur- temp.

Scheme 8. Synthesis of β-branched ethyl 3-(dibenzylamino)-2,2-difluoropropanoates. (a) Bn₂NH, BtH, EtOH, 78 °C; (b) BrZnCF₂CO₂Et,

TMSCl, THF, 67 °C.

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Eur. J. Org. Chem. 2008, 4277–4295

α,α-Difluoro-β-amino Esters and gem-Difluoro-β-lactams

Removal of the benzyl functional groups in 14c was ylate moiety with bromoacetate esters (17a: R = methyl,

achieved by hydrogenolysis [Pearlman’s catalyst, H₂(1 bar), 17b: R = benzyl). The required side chain can be introduced

EtOH, AcOEt, HCl/iPrOH 6 , 40 °C] to afford diamine by base-mediated alkylation of the nitrogen atom in a 1-

16 as a monochloride salt (72%). Selective protection with unsubstituted 3,3-difluoroazetidin-2-one. To the best of our

Boc₂O (1 equiv.) was tentatively carried out in a conven- knowledge, only one example of such a strategy has been

tional manner but was not selective enough, so 15c (and its reported. De Kimpe^[57]described the synthesis of N-substi-

methyl analog 15cЈ obtained by transesterification of 15c tuted gem-difluorinated azetidinones under phase-transfer

during the purification process due the presence of meth- conditions.

anol in the eluent composition) was isolated in only 19%

The N-alkylation of model β-lactam 12a was therefore

yield. Cleavage of the benzyl groups in 14d and 14e was best carefully optimized by varying the electrophile, the base,

achieved by hydrogenolysis in the presence of Pd/C catalyst and experimental conditions (Scheme 10, Table 2). Exten-

under 1 bar of hydrogen in EtOH and HCl/iPrOH (6 ) to sive experimentation showed that numerous sets of condi-

afford 15d and 15e in excellent yields.

tions were either unsuccessful or gave inconsistent results.

Treatment with strong bases such as NaH or LDA proved

to be inefficient. Attempts with KOH in homogeneous or

heterogeneous systems induced complete β-lactam degrada-

N-Alkylation of gem-Difluorinated β-Lactams

N-Alkylation of β-lactams 12a–e, as required for the tion. Functionalization of 12a under the phase-transfer

preparation of potential metallocarboxypeptidase inhibi- conditions described by De Kimpe^[57]turned out to be inef-

tors, was then investigated. A review of the literature re- ficient in our case. Whereas Hünig’s base caused rapid de-

vealed that N-alkylation of N-unsubstituted β-lactams was gradation and triethylamine gave low levels of conversion,

not consistently efficient.^[47]Strong bases (such as NaH,^[48]treatment of β-lactam 12a with methyl or benzyl bromoace-

NaNH₂, tBuOK,^[49]nBuLi,^[50]or LiHMDS^[51]) have been tates, and tetramethylguanidine in the presence of TBAI

employed with basic scaffolds, but such basic conditions in- (tetrabutylammonium iodide) provided the N-substituted

duce either polymerization of azetidin-2-ones or epimeriz- azetidin-2-ones 18a and 18b in excellent yields (Table 2, En-

ation of chiral centers (especially at C-3). Alkylation under tries 5–6).

less basic conditions have been described either with or-

In order to introduce a sulfhydryl group as a Zn-chelat-

ganic non-nucleophilic bases such as Et₃N or DIEA or with ing function, we then applied these conditions to S-(3-bro-

inorganic bases (K₂CO₃in acetone,^[52]Cs₂CO₃in MeCN,^[53]mopropyl)thioacetate.^[58]Unfortunately, none of these ex-

CsF in DMF,^[54]Ag₂O in MeCN^[55]). These milder condi- perimental conditions allowed access to the corresponding

tions were compatible with various functionalities and pre- N-substituted β-lactam, due to the poor electrophilicity of

vented potential epimerization. However, only highly reac- this alkylating agent. We next examined deprotection of 18a

tive electrophiles gave satisfactory levels of conversion and and 18b in order to obtain functionalized N-substituted lac-

yields, probably because of the low nucleophilicity of the tams. Compound 18a was subjected to various sets of acidic

nitrogen atom. Good yields can be obtained by phase-trans- or basic conditions in order to carry out saponification. In

fer catalysis methodology (KOH/nBu₄NBr/THF) as de- most cases, we observed rapid degradation of the β-lactam

scribed by Reuschling et al.,^[56]despite the risks of side reac- skeleton. However, when benzyl ester 18b was subjected to

tions or nucleophilic opening of the β-lactam ring.

hydrogenolysis conditions (H₂, Pd/C), we were pleased to

In order to find the best conditions for alkylation, we observe the formation of 2-oxoazetidin-1-ylacetic acid 19 in

first turned our attention to the introduction of the carbox- 91% yield.

Scheme 10. Synthesis of N-substituted azetidin-2-ones.

Table 2. Optimization of the N-alkylation step.

Entry

Base [equiv.]

BrCH₂CO₂R [equiv.]

Solvent

Temperature

Time [h]

18, yield [%]

1

2^[b]

3

tBuOK (1.6)

KOH (2)

CsF (10)

17a (1.5)

17a (3)

17a (10)

17b (10)

THF

DMF

THF

0 °C Ǟ room temp.

room temp.

20

72

14

6

18a, 37^[a]

18a, 50^[c]

room temp.

18a, 10^[c]

4

Et₃N (1)

18a, 20^[c]

5^[b]

TMG^[d](2)

18a, quantitative

6^[b]

18

18b, 91^[a]

[a] Isolated yields. [b] Addition of 0.5 equiv. of TBAI. [c] Conversion determined by ¹⁹F NMR relative to 12a. [d] 1,1,3,3-Tetramethyl-

guanidine.

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FULL PAPER

This synthetic strategy was then applied to several highly e with benzyl bromoacetate 17b under previously optimized

functionalized 3,3-difluoroazetidin-2-ones (Scheme 11). conditions, to provide 20b–e in moderate to excellent yields

With this goal, we performed alkylation of β-lactams 12b– (Table 3).

In the case of pyridinyl derivatives (12d and 12e), 1 equiv.

of benzyl bromoacetate was used in order to minimize alky-

lation of the pyridine ring. Treatment of 20b and 20c with

hydrogen in the presence of Pd/C resulted in removal of the

N-Cbz protecting group and the labile benzyl ester to afford

amino acids 21b and 21c (Scheme 11). Unexpected partial

degradation occurred during hydrogenolysis of 20c, leading

to the cleavage of the N1–C4 bond of the β-lactam ring and

the isolation of the corresponding amido acid. Disappoint-

ingly, removal of the benzyl ester protecting groups from

compounds 20d and 20e with Pd/C hydrogenation systems

turned out to be ineffective, whereas higher pressures of hy-

drogen induced side reactions. To circumvent this problem,

we investigated the synthesis of tert-butyl esters that could

be used to facilitate deprotection of the carboxylate. Subse-

quent treatment of azetidin-2-ones 12d and 12e with tert-

butyl bromoacetate (17c) and TMG in MeCN afforded N-

alkylated products (22d and 22e) in 50% yield. Acidic de-

protection (50% TFA/CH₂Cl₂) of these compounds af-

forded the acids, which were purified by gel permeation

chromatography to recover β-lactams 21d and 21e in 44%

and 56% yields, respectively.

Scheme 11. (a) BrCH₂CO₂Bn, TMG, TBAI, MeCN, room temp.;

(b) H₂, Pd/C, EtOH, room temp.; (c) BrCH₂CO₂tBu, TMG, TBAI,

MeCN, room temp.; (d) TFA, CH₂Cl₂, 0 °C.

Table 3. Syntheses of functionalized 3,3-difluoroazetidinones.

Entry Substrate Alkylation agent [equiv.]

R

20 or 22,

21,

yield [%]^[a]yield[%]^[b]

1

2

3

4

5

6

12b

12c

12d

12e

12d

12e

17b (37)

17b (11)

17b (1.1)

17c (1.1)^[d]

Bn

20b, 30

20c, 95

20d, 29

20e, 50

21b, 50

21c, 25

n.r.^[c]

tBu 22d, 47

tBu 22e, 50

21d, 44^[e]

21e, 56^[e]

[a] Isolated yield. [b] Isolated yield after purification by gel permea-

tion chromatography. [c] No reaction under atmospheric pressure

of hydrogen, and higher pressure induced the slow formation of

unidentified compounds. [d] Use of NaI (1 equiv.) instead of TBAI.

[e] Partial degradation: formation of β-amino acids produced by

cleavage of the N–C(O) bond in the β-lactam intermediate by water

during purification.

N-Acylation of gem-Difluorinated β-Amino Acids

In an effort to synthesize novel potential metallocarboxy-

peptidase inhibitors, we decided to develop a family of

sulfhydryl acids containing basic groups. We envisioned the

preparation of these targets by N-acylation of the β-amino

Scheme 12. (a) DIEA, DMAP, CH₂Cl₂, room temp.; (b) 50% TFA, CH₂Cl₂, 0 °C; (c) NaOH, H₂O, MeOH, room temp.; (d) HCl_(g)

MeOH, room temp.; (e) Et₃N, DMAP, CH₂Cl₂, room temp.; (f) LiOH, H₂O, MeOH, THF, 0 °C.

,

4282

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Eur. J. Org. Chem. 2008, 4277–4295

α,α-Difluoro-β-amino Esters and gem-Difluoro-β-lactams

benzotriazole; CAN = ceric ammonium nitrate; Cbz = benzyloxy-

carbonyl; CH₂Cl₂= dichloromethane; CI = chemical ionization;

DIEA = N,N-diisopropylethylamine; DMAP = 4-(dimethylamino)-

pyridine; DMF = dimethyl formamide; DMSO = dimethyl sulfox-

ide; EI = electron impact ionization; ESI = electrospray ionization;

EtOAc = ethyl acetate; FAAs = fluorine-containing amino acids.

IR = infrared; LDA = lithium diisopropylamide; LiHMDS = lith-

ium hexamethyldisilazide; MeCN = acetonitrile; MeOH = meth-

anol; MS = mass spectrometry; NMR = nuclear magnetic reso-

nance; PMB = p-methoxybenzyl; PTSA = p-toluenesulfonic acid;

acids derived from α,α-difluorinated β-amino esters 15b–e,

since these molecules are highly useful synthetic intermedi-

ates for the insertion of zinc-binding groups. We were inter-

ested in the introduction of thiol and carboxylate function-

alities.

This strategy thus required the use of a highly reactive

electrophile in order to overcome the rather low reactivity

of the deactivated amine due to the inductive effect of the

neighboring CF₂moiety.

Keeping the aforementioned goals in mind, we decided TBAI = tetrabutylammonium iodide; TFA = trifluoroacetic acid;

THF = tetrahydrofuran; TLC = thin layer chromatography; TMG

= N,N,NЈ,NЈ-tetramethylguanidine; TMSCl = chlorotrimethylsil-

ane; ZBG = zinc-binding group; Zn* = activated zinc dust.

to use acyl chlorides bearing masked sulfhydryl or carbox-

ylic functions. Starting from mercaptoacetic acid, we there-

fore prepared (acetylsulfanyl)acetic acid (23; Scheme 12) by

acetylation with Ac₂O and Et₃N, followed by the action of General: Unless otherwise mentioned, all the reagents were pur-

chased from commercial sources and used as received. All glass-

ware was dried in an oven at 100 °C prior to use. THF was distilled

from sodium/benzophenone ketyl under nitrogen prior to use.

Dichloromethane (CH₂Cl₂) was distilled under nitrogen from P₂O₅

prior to use. DMSO and MeCN were distilled under nitrogen from

CaH₂, and DMF from BaO. NMR spectra were recorded with a

Bruker DXP 300 instrument. ¹H NMR chemical shifts

(300.13 MHz) are expressed in parts per million (ppm, δ) downfield

from tetramethylsilane (δ = 0 ppm) in CDCl₃. ¹³C NMR chemical

shifts (75.47 MHz) are expressed in parts per million downfield

oxalyl chloride in CH₂Cl₂at room temperature, in 43%

overall yield.^[59]Commercially available methyl malonyl

chloride (24) proved to be an excellent starting material for

the introduction of a carboxyl group.

The synthesis of the series of sulfhydryl acids 27 was car-

ried out by starting from the appropriately substituted gem-

difluorinated β-amino esters 15b–e (Scheme 12). Addition

of (acetylthio)acetyl chloride (23) in the presence of cata-

lytic DMAP gave the acylated compounds 25b–e in moder-

ate to good yields. The thioester 25b was then converted from CDCl₃as internal standard (δ = 77.16 ppm). ¹⁹F NMR chem-

ical shifts (282.40 MHz) are expressed in parts per million down-

field from CFCl₃as internal standard (δ = 0 ppm). Coupling con-

stants J are reported in Hertz. Abbreviations used for peak multi-

plicity are: br.: broad; s: singlet; d: doublet; t: triplet; q: quadruplet;

m: multiplet. Progress of the reactions was monitored by TLC on

Merck silica gel plates (thickness 0.2 mm with fluorescence indi-

cator 60F₂₅₀). Flash column chromatography purifications were

carried out on 40–63 mesh silica gel 60A by “flash” methodology.

Silica TLC plates were visualized under UV light, by use of a solu-

tion of phosphomolybdic acid in ethanol (10%) followed by heat-

ing, or by use of a solution of aqueous alkaline potassium perman-

ganate (1 ) and heating. Values of R_fwere measured after an elu-

tion of 6 cm. Infrared (IR) spectra were recorded with a Perkin–

Elmer 1420 instrument. Absorption bands are reported in cm^–1.

Elemental analyses were performed with a Carlo Erba 1106 instru-

ment. Melting points are uncorrected. Mass spectra were per-

formed with a Thermofinnigan Navigator 2.1 instrument for elec-

trospray or with a JEOL AX500 instrument (isobutane, 200 eV) for

CI. HRMS measurements were performed with a JEOL AX500

spectrometer.

into the thiol 27b by Boc deprotection with 50% TFA/

CH₂Cl₂followed by basic deprotection with aqueous

NaOH in 59% yield. Removal of the protecting groups of

25c and 25cЈ with methanolic HCl followed by treatment

with aqueous NaOH gave disulfide 27c in moderate yield.

In addition to rapid and unavoidable oxidation of thiol

functionality, the amide bond proved to be particularly

weak, and, as a consequence, the corresponding β-amino

acid was isolated in only 20% yield. Deprotection of 25e

with aqueous LiOH afforded 27e.

With an effective sequence to hand, a similar route was

used for diacid compounds 28d and 28e, but methyl malo-

nyl chloride (24) was used instead of 23. Treatment with

triethylamine in CH₂Cl₂resulted in acylation to give

diesters 26d and 26e in good yields, and these were then

hydrolyzed to diacids. Unfortunately, due to an arduous

purification, the yields of 28d and 28e were only 20%.

Conclusions

Starting Materials: All substrate imines were readily synthesized by

condensation of the appropriate aldehyde with (p-methoxybenzyl)-

amine according to the following procedure. Anhydrous MgSO₄

(2 g) and the appropriate aldehyde (1 equiv.) were added at ambient

temperature to a solution of the corresponding amine (10 mmol)

in CH₂Cl₂(10 mL). The mixture was stirred at room temperature

for 12 h. The solids were filtered by suction, and the filtrate was

washed with CH₂Cl₂(2ϫ20 mL). The corresponding imine was

recovered quantitatively after concentration under reduced pres-

sure, and was used without purification. Activated zinc was pre-

pared by stirring a quantity of zinc dust in dilute hydrochloric acid

for about 5 min. The zinc was then filtered off, washed neutral with

deionized water, with ethanol, with acetone, and with diethyl ether,

and dried at 100 °C under vacuum.^[32a]All N,N-disubstituted 1H-

benzotriazolylamines were synthesized according to the following

general procedure. Dibenzylamine (3.21 g, 30 mmol) and the ap-

propriate aldehyde (30 mmol, 1 equiv.) were successively added to

We succeeded in the synthesis of the target molecules dis-

playing specific features in the course of our medicinal pro-

gram devoted to the synthesis of basic metallocarbopeptid-

ase inhibitors. A general synthetic route, in the racemic

series, of various gem-difluoro-β-lactams and -β-amino es-

ters, possessing different basic groups, has been successfully

developed. N-Alkylation of gem-difluoro-β-lactams and N-

acylation of gem-difluoro-β-amino esters were carried out,

leading, in moderate to good yields, to the expected poten-

tial basic metallocarbopeptidase inhibitors.

Experimental Section

Abbreviations: AcOH = acetic acid; Boc = tert-butoxycarbonyl;

BopCl = bis(2-oxo-3-oxazolidinyl)phosphinic chloride; BtH = 1H-

Eur. J. Org. Chem. 2008, 4277–4295

www.eurjoc.org

4283

N. Boyer, P. Gloanec, G. De Nanteuil, P. Jubault, J.-C. Quirion

FULL PAPER

a solution of 1H-benzotriazole (3.57 g, 30 mmol, 1 equiv.) dissolved

in a minimum amount of ethanol (ca. 5 mL). The mixture was

heated at reflux for 4 h in the presence of dried molecular sieves

(3 Å, 1 g), and then stirred at room temp. for 12 h. After removal

of molecular sieves by suction filtration through a pad of Celite

and concentration of the filtrate under vacuum, the obtained solid

could be recrystallized from ethanol.

solvent was removed in vacuo, and the residual product was puri-

fied by chromatography on a silica gel column [cyclohexane/EtOAc

(9:1 to 6:4) as eluent] to give 4b as a colorless oil; yield 7.42 g

(72%); TLC: silica gel (cyclohexane/EtOAc, 6:4), R_f= 0.38. ¹H

NMR (CDCl₃, 300.3 MHz): δ = 9.64 (s, 1 H), 7.35–7.30 (m, 5 H),

3

2

5.10 (s, 2 H), 4.10–3.95 (m, 2 H), 3.00 (dt, J_H,H= 2.5, J_H,H

=

13 Hz, 2 H), 2.45–2.35 (m, 1 H), 1.95–1.85 (m, 2 H), 1.56 (ddd,

³J_H,H= 4, ³J_H,H= 11, ²J_H,H= 24 Hz, 2 H) ppm. ¹³C NMR (CDCl₃,

75.4 MHz): δ = 202.7, 128.5, 128.0, 127.9, 67.1, 47.7, 43.0,

(Piperidin-4-yl)methanol (2): A solution of methyl isonipecotate (1,

10 mL, 74 mmol) in anhydrous THF (80 mL) was slowly added un-

der argon to an ice-cooled suspension of LiAlH₄(3.5 g, 92.2 mmol,

1.25 equiv.) in anhydrous THF (250 mL). After the visible gas evol-

ution had ceased, the mixture was left standing at room temp. for

20 h. After treatment with water (4 mL), aqueous NaOH solution

(1 , 4 mL), and water (8 mL), and stirring with diethyl ether

(200 mL) for 30 min, the slurry was filtered and washed with di-

ethyl ether (2ϫ100 mL). The organic fraction was dried with

MgSO₄, and the solvents were removed under vacuum to afford

25.0 ppm. IR (KBr):

ν

=

1728, 1698, 1278, 1225 cm^–1.

˜

max

C₁₄H₁₇NO₃(247.30): calcd. C 68.00, H 6.93, N 5.66; found C

67.15, H 6.57, N 5.55.

4-(1,3-Dioxolan-2-yl)benzonitrile (6): 4-Cyanobenzaldehyde (5,

15 g, 114.4 mmol) was placed in a round flask together with ethyl-

eneglycol (11.5 mL, 206 mmol, 1.8 equiv.), dry toluene (300 mL),

and p-toluenesulfonic acid as catalyst (1.5 g, 8.7 mmol, 8% with

respect to 5). The solution was heated at reflux in a Dean–Stark

apparatus with water trap for 18 h. It was then neutralized with

the title compound as a colorless oil; yield 7.67 g (90%). ¹H NMR

3

(CDCl₃, 300.3 MHz): δ = 3.42 (d, J_H,H= 6 Hz, 2 H), 3.05 (dt, saturated aqueous NaHCO₃solution (100 mL), and the phases

2

3

2

³J_H,H= 3, J_H,H= 12 Hz, 2 H), 2.56 (td, J_H,H= 2.5, J_H,H

=

were separated. The aqueous layer was extracted with toluene

12 Hz, 2 H), 2.15 (br. s, 2 H), 1.75–1.65 (m, 2 H), 1.65–1.50 (m, 1 (3ϫ50 mL), and the combined organic layers were collected, dried

3

2

H), 1.10 (ddd, J_H,H= 4, J_H,H= 13, J_H,H= 25 Hz, 2 H) ppm.

¹³C NMR (CDCl₃, 75.4 MHz): δ = 68.3, 46.6, 39.4, 30.2 ppm. IR

with MgSO₄, and filtered. The toluene solution was concentrated

under reduced pressure, and the title compound 6 was obtained as

a pale yellow solid; yield 20.04 g (99%); m.p. 160 °C (dec.). ¹H

(KBr): ν

= 3368, 1634, 1039 cm^–1. MS (EI+): m/z (%) = 115.0

˜

max

[M]⁺. C₆H₁₃NO (115.18): calcd. C 62.57, H 11.38, N 12.16; found

NMR (CDCl₃, 300.3 MHz): δ = 7.63 (d, J_H,H= 8 Hz, 2 H), 7.54

3

C 62.09, H 11.44, N 12.28.

(d, J_H,H= 8 Hz, 2 H), 5.80 (s, 1 H), 4.10–3.95 (m, 4 H) ppm. ¹³C

NMR (CDCl₃, 75.4 MHz): δ = 142.9, 132.0, 127.0, 118.4, 112.7,

Benzyl 4-(Hydroxymethyl)piperidine-1-carboxylate (3): Amine 2

(7.67 mmol, 66.6 mmol) was dissolved in CH₂Cl₂(230 mL) at 0 °C.

A solution of Na₂CO₃(32 g, 302 mmol, 4.5 equiv.) in water

(230 mL) was added. Benzyloxycarbonyl chloride (10 mL,

72 mmol, 1.1 equiv.) was added dropwise. After the system had

been stirred at room temp. for 12 h, ice-cold water (200 mL) was

added, and the mixture was extracted with CH₂Cl₂(2ϫ100 mL).

The organic layers were combined, filtered, dried with MgSO₄, and

concentrated in vacuo to give the crude material. Silica gel flash

column chromatography [CH₂Cl₂/EtOAc (8:2 to 6:4) as eluent] gave

pure 3 as a colorless oil; yield 14.78 g (89%); TLC: silica gel (cyclo-

102.2, 65.3 ppm. IR (KBr): ν_max= 2230, 1085, 942 cm^–1. MS (EI+):

˜

m/z = 175 [M]^+·, 144, 130, 103, 73, 51. C₁₀H₉NO₂(175.19): calcd.

C 68.56, H 5.18, N 8.00; found C 68.08, H 4.88, N 7.59.

4-(1,3-Dioxolan-2-yl)benzylamine (7): A solution of nitrile 6 (10.6 g,

60.5 mmol) in anhydrous THF (40 mL) was added dropwise at 0 °C

to a suspension of LiAlH₄(5.1 g, 127.7 mmol, 2 equiv.) in anhy-

drous THF (200 mL). The reaction mixture was allowed to warm

to room temp., heated at reflux for 4 h, and stirred at room temp.

for 12 h. The mixture was then recooled in an ice bath, and diethyl

ether was added (200 mL). The mixture was then carefully

hexane/EtOAc, 7:3), R_f= 0.39. ¹H NMR (CDCl₃, 300.3 MHz): δ quenched with water (5 mL), aqueous NaOH solution (1 , 5 mL),

= 7.45–7.35 (m, 5 H), 5.19 (s, 2 H), 4.35–4.20 (m, 2 H), 3.55 (d,

and a second portion of water (10 mL). After 30 min, the white

suspension was filtered through a pad of Celite, and concentrated

³J_H,H= 6 Hz, 2 H), 2.90–2.80 (m, 2 H), 1.85–1.75 (m, 2 H), 1.75–

1.65 (m, 1 H), 1.30–1.15 (m, 2 H) ppm. ¹³C NMR (CDCl₃, in vacuo to give amine 7 as a yellow oil; yield 10.3 g (95%). ¹H

75.4 MHz): δ = 155.2, 136.7, 128.4, 127.9, 127.7, 67.3, 66.9, 43.8, NMR (CDCl₃, 300.3 MHz): δ = 7.42 (d, J_H,H= 8 Hz, 2 H), 7.30

3

38.6, 28.4 ppm. IR (KBr): ν

= 3432, 1697, 1439, 1247, 1215,

(d, ³J_H,H= 8 Hz, 2 H), 5.77 (s, 1 H), 4.10–4.05 (m, 2 H), 4.05–3.95

˜

max

1038 cm^–1. MS (EI+): m/z = 249 [M]^+·, 204, 158, 142, 91. (m, 2 H), 3.84 (s, 2 H), 1.58 (br. s, 2 H) ppm. ¹³C NMR (CDCl₃,

C₁₄H₁₉NO₃(249.31): calcd. C 67.45, H 7.68, N 5.62; found C

67.90, H 7.57, N 5.14.

75.4 MHz): δ = 144.3, 136.3, 127.0, 126.6, 103.6, 65.2, 46.2 ppm.

IR (KBr): ν_max= 3667, 1616, 1081, 943 cm^–1. C₁₀H₁₃NO₂(179.22):

˜

calcd. C 67.02, H 7.31, N 7.82; found C 66.84, H 7.71, N 7.59.

1-(Benzyloxycarbonyl)piperidine-4-carboxaldehyde (4b): A stirred

solution of freshly distilled DMSO (13.3 mL, 187.3 mmol,

4.5 equiv.) in anhydrous CH₂Cl₂(70 mL) was cooled to –78 °C. A

solution of oxalyl chloride (5.3 mL, 61.8 mmol, 1.5 equiv.) in dry

CH₂Cl₂(10 mL) was then added dropwise, and stirring was contin-

ued for 30 min. Next, a solution of alcohol 3 (10.4 g, 41.7 mmol)

in anhydrous CH₂Cl₂(150 mL) was added dropwise over 15 min,

and the resultant slurry was stirred at –78 °C for 30 min. N,N-Di-

isopropylethylamine (36.1 mL, 217.9 mmol, 5.25 equiv.) was added,

and the resultant slurry was stirred at –60 °C for an additional

30 min. The mixture was allowed to warm to room temp. overnight.

A solution of NaH₂PO₄(7.5 g, 64.1 mmol, 1.5 equiv.) in water

(100 mL) was added, and the mixture was extracted with CH₂Cl₂

(2ϫ200 mL). The organic phases were washed with aqueous HCl

(1 , 100 mL), saturated aqueous NaHCO₃solution (100 mL), and

brine (100 mL), and were then dried with anhydrous MgSO₄. The

Benzyl [4-(1,3-Dioxolan-2-yl)benzyl]carbamate (8): A solution of so-

dium carbonate (19.6 g, 185 mmol, 4 equiv.) in water (60 mL) was

added to a solution of amine 7 (8.14 g, 45.4 mmol) in CH₂Cl₂

(140 mL). Benzyl chloroformate (6.5 mL, 45.7 mmol, 1 equiv.) was

added dropwise at 0 °C and with stirring. After having been stirred

at room temp. for 12 h, the reaction mixture was extracted with

CH₂Cl₂(2ϫ150 mL). The combined organic layers were further

washed with water (100 mL), saturated aqueous NH₄Cl solution

(50 mL), and brine (50 mL), and dried with anhydrous MgSO₄.

After concentration, 8 was obtained as a pale yellow solid; yield

13.8 g (97%); m.p. 145 °C; TLC: silica gel (cyclohexane/EtOAc,

1

3

7:3), R_f= 0.25. H NMR (CDCl₃, 300.3 MHz): δ = 7.39 (d, J_H,H

3

= 14.5 Hz, 2 H), 7.35–7.30 (m, 5 H), 7.29 (d, J_H,H= 14.5 Hz, 2

3

H), 5.78 (s, 1 H), 5.11 (s, 3 H), 4.37 (d, J_H,H= 6 Hz, 2 H), 4.15–

3.95 (2ϫm, 4 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ = 156.4,

4284

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Eur. J. Org. Chem. 2008, 4277–4295

α,α-Difluoro-β-amino Esters and gem-Difluoro-β-lactams

139.4, 137.2, 136.4, 128.5, 128.1, 127.5, 126.7, 103.4, 66.9, 65.3,

β-amino ester 11c as a white solid; yield 0.89 g and 0.90 g (72%

global yield).

44.8 ppm. IR (KBr): ν_max= 3280, 1681, 1554, 1260, 1077, 941 cm^–1.

˜

C₁₈H₁₉NO₄(313.36): calcd. C 69.00, H 6.11, N 4.47; found C

69.14, H 6.29, N 4.41.

β-Lactam 10c: TLC: silica gel (cyclohexane/EtOAc, 7:3), R_f= 0.35.

¹H NMR (CDCl₃, 300.3 MHz): δ = 7.35–7.25 (m, 7 H), 7.17 (d,

3

³J_H,H= 8 Hz, 2 H), 7.00 (d, J_H,H= 8.5 Hz, 2 H), 6.81 (d, J_H,H

=

Benzyl (4-Formylbenzyl)carbamate (4c): A solution of acetal 8

(13.9 g, 43.9 mmol) in aqueous AcOH (50%, 140 mL) was stirred

at room temp. for 12 h. After concentration, flash column

chromatography [cyclohexane/EtOAc (9:1 to 6:4) as eluent] gave

aldehyde 4c as a colorless solid; yield 11.0 g (93%); m.p. 68 °C;

TLC: silica gel (cyclohexane/EtOAc, 7:3), R_f= 0.49. ¹H NMR

8.5 Hz, 2 H), 5.22 (br. s, 1 H), 5.13 (s, 2 H), 4.86 (d, ²J_H,H= 14 Hz,

3

1 H), 4.65 (dd, J_H,F= 1.5, J_H,F= 7 Hz, 1 H), 4.39 (m, 2 H), 3.79

(d, ²J_H,H= 14 Hz, 1 H), 3.77 (s, 3 H) ppm. ¹³C (CDCl₃, 75.4 MHz):

2

δ = 160.7 (t, J_C,F= 30.5 Hz), 159.6, 156.7, 140.5, 137.1, 136.4,

1

130.9, 129.5, 129.2, 128.5, 128.2, 128.1, 127.7, 120.4 (t, J_C,F

=

3

2

(CDCl₃, 300.3 MHz): δ = 9.97 (s, 1 H), 7.82 (d, J_H,H= 8 Hz, 2

292 Hz), 114.4, 67.4 (dd, J_C,F= 24, J_C,F= 26.5 Hz), 66.9, 55.3,

3

44.6, 43.6 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –114.8 (dd,

H), 7.42 (d, J_H,H= 8 Hz, 2 H), 7.35–7.30 (m, 5 H), 5.23 (br. s, 1

3

H), 5.13 (s, 2 H), 4.44 (d, J_H,H= 6 Hz, 2 H) ppm. ¹³C NMR

³J_F,H= 7.5, J_F,F= 223 Hz), –121.9 (d, J_F,F= 223 Hz) ppm. IR

2

(CDCl₃, 75.4 MHz): δ = 191.8, 156.4, 145.4, 136.2, 135.6, 130.1,

(KBr): ν

= 3340, 1787, 1718, 1612, 1514, 1302, 1249, 1201,

˜

max

1034 cm^–1. C₂₆H₂₄F₂N₂O₄(466.49): calcd. C 66.94, H 5.19, N 6.01;

128.6, 128.3, 128.2, 127.5, 67.1, 44.8 ppm. IR (KBr): ν

= 3304,

˜

max

1682, 1609, 1529, 1253, 1207, 1052 cm^–1. C₁₆H₁₅NO₃(269.30):

found C 66.88, H 5.45, N 5.91.

calcd. C 71.36, H 5.61, N 5.20; found C 71.09, H 5.72, N 5.14.

β-Amino Ester 11c: M.p. 106 °C; TLC: silica gel (cyclohexane/

EtOAc, 7:3), R_f= 0.45. H NMR (CDCl₃, 300.3 MHz): δ = 7.35–

General Procedure for 10b–e. Benzyl 4-[3,3-Difluoro-1-(4-meth-

oxybenzyl)-4-oxoazetidin-2-yl]piperidine-1-carboxylate (10b): A dry,

60-mL Schlenk tube was charged with a suspension of freshly acid-

washed zinc dust (4.75 g, 72.7 mmol, 6 equiv.) in anhydrous THF

(19 mL) under argon. Chlorotrimethylsilane (460 µL, 5 mol-%) and

1,2-dibromoethane (315 µL, 5 mol-%) were added to the suspen-

sion. The mixture was stirred at room temp. for 10 min. Controlled

1

3

7.25 (m, 9 H), 7.09 (d, J_H,H= 7 Hz, 2 H), 6.81 (d, J_H,H= 7 Hz,

3

2 H), 5.13 (br. s, 2 H), 4.40 (d, J_H,H= 6 Hz, 2 H), 4.25 (q, J_H,H

3

= 7 Hz, 2 H), 4.18 (dd, J_H,F= 6.5, J_H,F= 21 Hz, 1 H), 3.77 (s, 3

H), 3.69 (d, ²J_H,H= 13 Hz, 1 H), 3.42 (d, ²J_H,H= 13 Hz, 1 H), 2.07

(br. s, 1 H), 1.26 (t, J_H,H= 7 Hz, 3 H) ppm. ¹³C NMR (CDCl₃,

3

2

75.4 MHz): δ = 163.9 (dd, J_C,F= 30.5, J_C,F= 34 Hz), 158.8,

addition of

a solution of ethyl bromodifluoroacetate (5 g,

156.4, 139.0, 136.4, 133.4, 130.9, 129.5, 129.2, 128.5, 128.2, 128.1,

24.6 mmol, 2.05 equiv.) in anhydrous THF (5 mL) was performed

with a syringe. A temperature of ca. 50 °C was maintained during

the addition (self-heating). After the end of the addition, the reac-

tion mixture was stirred at room temp. for 10 min. A solution of

the corresponding imine 9b (12.1 mmol) in anhydrous THF (8 mL)

was added. The reaction mixture was then heated to reflux for 2 h.

The reaction mixture was cooled to room temp. and quenched by

addition of saturated aqueous NH₄Cl solution (10 mL). After fil-

tration, the aqueous layer was extracted with EtOAc (2ϫ100 mL).

The organic layers were combined, dried with MgSO₄, and concen-

trated under vacuum. The crude product was then purified by flash

chromatography on silica gel [cyclohexane/EtOAc (95:5 to 70:30)

as eluent] to afford β-lactam 10b as a yellow oil; yield 3.76 g (70%).

¹H NMR (CDCl₃, 300.3 MHz): δ = 7.35–7.30 (m, 5 H), 7.10 (d,

1

127.7, 115.1 (dd, J_C,F= 253.5, J_C,F= 257 Hz), 113.7, 66.9, 62.8,

62.5 (dd, ²J_C,F= 21, ²J_C,F= 27 Hz), 55.2, 49.9, 44.7, 13.9 ppm. ¹⁹

NMR (CDCl₃, 288.3 MHz): δ = –108.6 (dd, J_F,H= 7.5, J_F,F

F

=

3

2

3

2

257 Hz), –121.0 (dd, J_F,H= 21.5, J_F,F= 223 Hz) ppm. IR (KBr):

ν

= 3334 1769, 1703, 1612, 1303, 1250, 1210, 1072, 699 cm^–1.

˜

max

C₂₈H₃₀F₂N₂O₅(512.56): calcd. C 65.61, H 5.90, N 5.47; found C

65.13, H 5.55, N 5.38.

3,3-Difluoro-1-(4-methoxybenzyl)-4-phenylazetidin-2-one

(10a):

Preparation, description, and spectroscopic data for this compound

have already been reported in ref.^[38a]

3,3-Difluoro-1-(4-methoxybenzyl)-4-(pyridin-4-yl)azetidin-2-one

(10d) and Ethyl 2,2-Difluoro-3-[(4-methoxybenzyl)amino]-3-(pyridin-

4-yl)propanoate (11d): Preparation, description, and spectroscopic

data for these compounds have already been reported in ref.^[38b]

3

³J_H,H= 8.5 Hz, 2 H), 6.87 (d, J_H,H= 8.5 Hz, 2 H), 5.09 (s, 2 H),

4.88 (d, ²J_H,H= 15 Hz, 1 H), 4.30–4.05 (m, 2 H), 4.03 (dd, J = 2.5,

²J_H,H= 15 Hz, 1 H), 3.78 (s, 3 H), 3.55–3.45 (m, 1 H), 2.80–2.60

3,3-Difluoro-1-(4-methoxybenzyl)-4-(pyridin-3-yl)azetidin-2-one

(10e) and Ethyl 2,2-Difluoro-3-(4-methoxybenzylamino)-3-(pyridin-

3-yl)propanoate (11e): Preparation, description and spectroscopic

data of these compounds have already been reported in ref.^[38b]

(m, 2 H), 1.90–1.80 (m, 1 H), 1.70–1.60 (m, 2 H), 1.25–1.10 (m, 2

2

H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ = 161.4 (t, J_C,F

=

30.5 Hz), 159.6, 155.0, 136.5, 129.5, 128.5, 128.0, 127.9, 125.3,

1

2

120.8 (dd, J_C,F= 285.5, J_C,F= 291.5 Hz), 114.5, 68.1 (dd, J_C,F

= 22, J_C,F= 24 Hz), 67.1, 55.2, 45.7, 43.3, 36.0, 28.2 ppm. ¹⁹F

NMR (CDCl₃, 288.3 MHz): δ = –114.5 (d, J_F,F= 236.5 Hz),

2

General Procedure for 12b–e. rac-Benzyl 4-(3,3-Difluoro-4-oxo-

azetidin-2-yl)piperidine-1-carboxylate (12b): CAN (7 g, 12.7 mmol,

3.6 equiv.) was added in small portions at 0 °C to N-protected β-

lactam 10b (1.56 g, 3.5 mmol) in a mixture of CH₃CN/H₂O (9:1,

22 mL). After 20 min at 0 °C and 6 h at room temp., the mixture

was poured into water (100 mL). The aqueous layer was extracted

2

3

2

–123.6 (dd, J_F,H= 73, J_F,F= 236.5 Hz) ppm. IR (KBr): ν

=

˜

max

1787, 1698, 1514, 1434, 1301, 1249, 1225, 1061, 699 cm^–1.

C₂₄H₂₆F₂N₂O₄(444.48): calcd. C 64.85, H 5.90, N 6.30; found C

64.99, H 6.03, N 6.09.

Benzyl

benzyl}carbamate (10c) and Benzyl 4-{2-(Ethoxycarbonyl)-2,2-di-

fluoro-1-[(4-methoxybenzyl)amino]ethyl}benzylcarbamate (11c):

These compounds were prepared according to the above General

{4-[3,3-Difluoro-1-(4-methoxybenzyl)-4-oxoazetidin-2-yl]- with EtOAc (2ϫ100 mL). The combined organic layers were

washed with NaHCO₃(5%, 100 mL), Na₂SO₃(10%, 100 mL),

NaHCO₃(5%, 100 mL), and finally brine (50 mL). After concen-

tration and flash column chromatography [CH₂Cl₂/EtOAc (95:5 to

Procedure, from aldehyde 4c (1.37 g, 5.1 mmol), (p-methoxy- 80:20) as eluent] the desired racemic product 12b was obtained as

1

benzyl)amine (0.70 g, 5.1 mmol), activated zinc dust (2 g,

30.6 mmol), ethyl bromodifluoroacetate (2.12 g, 10.4 mmol), and

anhydrous acetonitrile (16 mL). The crude product was purified by

silica gel column chromatography [cyclohexane/EtOAc (85:15 to

70:30) as eluent] to give the β-lactam 10c as a colorless oil and the

an orange oil; yield 0.43 g (38%). H NMR (CDCl₃, 300.3 MHz):

δ = 7.40–7.30 (m, 5 H), 5.10 (s, 2 H), 5.02 (br. s, 1 H), 4.30–4.10

(m, 2 H), 3.62 (t, ³J_H,H= 9, ³J_H,F= 9 Hz, 1 H), 2.90–2.70 (m, 2 H),

1.70–1.50 (m, 3 H), 1.30–1.10 (m, 2 H) ppm. ¹³C NMR (CDCl₃,

2

75.4 MHz): δ = 161.1 (t, J_C,F= 31 Hz), 155.3, 136.4, 128.5, 128.1,

Eur. J. Org. Chem. 2008, 4277–4295

www.eurjoc.org

4285

N. Boyer, P. Gloanec, G. De Nanteuil, P. Jubault, J.-C. Quirion

FULL PAPER

1

127.9, 121.5 (dd, J_C,F= 287.5, J_C,F= 291 Hz), 67.4, 66.2 (dd,

4 mmol) and aldehyde 4b (1 g, 4.05 mmol, 1 equiv.) were success-

ively added to a solution of 1H-benzotriazole (0.48 g, 4 mmol,

1 equiv.) dissolved in dry ethanol (1 mL). The mixture was heated

at reflux for 4 h in the presence of dried molecular sieves (3 Å,

0.5 g) and was then stirred at room temp. for 12 h. After removal

of molecular sieves by suction filtration and concentration of the

filtrate under vacuum, the obtained solid could be recrystallized

from ethanol. Chlorotrimethylsilane (1.1 mL, 8.6 mmol, 2.2 equiv.)

was added to a suspension of activated zinc dust (0.79 g, 12 mmol,

3 equiv.) in anhydrous THF (10 mL), stirred in a dry Schlenk tube

under argon, followed 10 min later by ethyl bromodifluoroacetate

(1.83 g, 9 mmol, 2.2 equiv.). After 10 min, a solution of 13b

(4 mmol) in anhydrous THF (4 mL) was added dropwise. After 3 h

at 60 °C, the mixture was cooled, poured into saturated aqueous

NaHCO₃solution (20 mL), and then filtered through Celite. The

layers were separated, and the aqueous phase was extracted with

EtOAc (2ϫ60 mL). The organic layers were combined and washed

with brine (40 mL), and were then dried with MgSO₄. After fil-

tration and evaporation of the solvent, the crude product was chro-

matographed [cyclohexane/EtOAc (95:5 to 80:20) as eluent] to give

pure ester 14b as a yellow oil; yield 1.88 g (83%; 2 steps). ¹H NMR

(CDCl₃, 300.3 MHz): δ = 7.25–7.10 (m, 15 H), 4.96 (br. s, 2 H),

2

²J_C,F= 23, J_C,F= 24 Hz), 43.3 and 43.1, 35.9, 27.9 and 27.6 ppm.

¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –114.2 (d, J_F,F= 239 Hz),

2

3

2

–125.4 (dd, J_F,H= 40, J_F,F= 239 Hz) ppm.

rac-Benzyl

4-(3,3-Difluoro-4-oxoazetidin-2-yl)benzylcarbamate

(12c): This compound was prepared from 10c according to the

same procedure as employed for 12b, from β-lactam 10c (4.3 g,

9.2 mmol) and CAN (15.2 g, 27.7 mmol, 3 equiv.) in a mixture of

CH₃CN/H₂O (9:1, 170 mL). Chromatography [CH₂Cl₂/EtOAc

(95:5 to 85:15) as eluent] gave pure racemic 12c as a white solid;

yield 1.37 g (43%); TLC: silica gel (CH₂Cl₂/EtOAc, 9:1), R_f= 0.52.

¹H NMR (CD₃OD, 300.3 MHz): δ = 7.40–7.25 (m, 9 H), 5.10 (dd,

3

³J_H,F= 2.5, J_H,F= 7.5 Hz, 1 H), 5.09 (s, 2 H), 4.32 (s, 2 H) ppm.

¹³C NMR (CDCl₃, 75.4 MHz): δ = 163.4 (t, J_C,F= 30 Hz), 159.0,

2

141.8, 138.2, 133.0, 129.4, 129.0, 128.8, 128.6, 128.2, 122.8 (t, ¹J_C,F

2

= 292 Hz), 67.5, 65.5 (dd, J_C,F= 24, J_C,F= 26 Hz), 45.1 ppm.

¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –116.6 (dd, J_F,H= 7.5, J_F,F

3

2

= 222.5 Hz), –122.9 (d, J_F,F= 222.5 Hz) ppm.

rac-3,3-Difluoro-4-(pyridin-4-yl)azetidin-2-one (12d): This com-

pound was prepared from the mixture of 10d and 11d according to

the same procedure as employed for 12b, from β-lactam 10d (1.2 g,

3.95 mmol) and CAN (6.5 g, 11.85 mmol, 3 equiv.) in a mixture

of CH₃CN/H₂O (9:1, 55 mL). Chromatography [CH₂Cl₂/MeOH/

NH₄OH (95:5:0.5 to 80:20:2) as eluent] gave pure racemic 12d as a

pale beige solid; yield 0.45 g (62%); m.p. 160 °C (dec.); TLC: silica

3

2

4.11 (q, J_H,H= 7 Hz, 2 H), 4.10–3.90 (m, 2 H), 3.79 (d, J_H,H

=

2

13.5 Hz, 2 H), 3.72 (d, J_H,H= 13.5 Hz, 2 H), 3.25–3.05 (m, 1 H),

2.65–2.50 (m, 2 H), 1.95–1.85 (m, 1 H), 1.85–1.70 (m, 1 H), 1.50–

3

1.40 (m, 1 H), 1.17 (t, J_H,H= 7 Hz, 3 H), 1.10–1.00 (m, 1 H),

0.90–0.85 (m, 1 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ = 164.3

gel (CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1), R_f

=

0.44. ¹H NMR

2

(t, J_C,F= 32 Hz), 155.0, 139.0, 136.8, 129.4, 128.4, 128.2, 127.9,

(CDCl₃, 300.3 MHz): δ = 10.32 (t, J = 12.5 Hz, 1 H), 8.98 (d, ³J_H,H

1

2

127.8, 127.2, 119.0 (t, J_C,F= 260 Hz), 67.0, 62.9, 62.2 (t, J_C,F

=

3

= 6.5 Hz, 2 H), 8.01 (d, J_H,H= 6.5 Hz, 2 H), 5.69 (dd, J_H,F

=

20 Hz), 55.0, 44.2 and 43.8, 35.3, 30.4 and 28.8, 13.8 ppm. ¹⁹F

3

1.5, J_H,F= 7 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ =

3

2

NMR (CDCl₃, 288.3 MHz): δ = –102.1 (dd, J_F,H= 7.5, J_F,F

=

2

1

160.3 (t, J_C,F= 29.5 Hz), 151.0, 144.3, 124.9, 121.8 (t, J_C,F

=

3

2

259 Hz), –113.7 (dd, J_F,H= 24.5, J_F,F= 259 Hz) ppm. IR (KBr):

2

294.5 Hz), 62.5 (dd, J_C,F= 22.5, J_C,F= 26 Hz) ppm. ¹⁹F NMR

ν

˜

= 1787, 1698, 1514, 1434, 1249, 1225, 1061, 699 cm^–1.

(CDCl₃, 288.3 MHz): δ = –112.7 (ddd, ³J_F,H= 7, ⁴J_F,H= 13.5, ²J_F,F

max

C₃₂H₃₆F₂N₂O₄(550.65): calcd. C 69.80, H 6.59, N 5.09; found C

69.22, H 6.71, N 4.97.

4

2

= 219.5 Hz), –118.7 (dd, J_F,H= 11.5, J_F,F= 219.5 Hz) ppm. IR

(KBr): ν

= 3079, 1813, 1384, 718 cm^–1. MS (CI+): m/z = 185

˜

max

[M + H]⁺, 173, 159, 145, 93.

rac-Benzyl 4-[1-(Dibenzylamino)-2-(ethoxycarbonyl)-2,2-difluoroeth-

yl]benzylcarbamate (14c): The N,N-disubstituted 1H-benzotri-

azolylamine 13c was prepared according to the same procedure as

employed for 14b; dibenzylamine (5.13 g, 26 mmol) and aldehyde

4c (7 g, 26 mmol, 1 equiv.) were successively added to a solution of

1H-benzotriazole (3.1 g, 26 mmol, 1 equiv.) dissolved in dry etha-

nol (5 mL). The mixture was heated at reflux for 4 h in the presence

of dried molecular sieves (3 Å, 2 g), and was then stirred at room

temp. for 12 h. After removal of molecular sieves by suction fil-

tration and concentration of the filtrate under vacuum, the ob-

tained solid could be recrystallized from ethanol. Racemic β-amino

ester 14c was obtained from N,N-disubstituted 1H-benzotriazolyl-

amine 13c according to the procedure already described for the

conversion of 13b into 14b, with activated zinc dust (6.3 g,

96.4 mmol, 4 equiv.), chlorotrimethylsilane (3.7 mL, 28.9 mmol,

1.2 equiv.), and ethyl bromodifluoroacetate (10.7 g, 52.9 mmol,

2.2 equiv.) in anhydrous THF (95 mL). Chromatography [cyclohex-

ane/EtOAc (97:3 to 80:20) as eluent] gave pure ester 14c as a white

solid; yield 8.93 g (60%; 2 steps); TLC: silica gel (cyclohexane/

rac-3,3-Difluoro-4-(pyridin-3-yl)azetidin-2-one (12e): This com-

pound was prepared from the mixture of 10e and 11e according to

the same procedure as employed for 12b, from β-lactam 10e (12.6 g,

41.4 mmol) and CAN (68 g, 124 mmol, 3 equiv.) in a mixture of

CH₃CN/H₂O (9:1, 550 mL). Chromatography [CH₂Cl₂/MeOH/

NH₄OH (95:5:0.5 to 80:20:2) as eluent] gave pure racemic 12e as a

brown viscous oil; yield 3.74 g (49%); TLC: silica gel (CH₂Cl₂/

MeOH/NH₄OH, 95:5:0.5), R_f

=

0.25. ¹H NMR (CD₃OD,

3

300.3 MHz): δ = 8.70–8.65 (m, 2 H), 8.02 (d, J_H,H= 8 Hz, 1 H),

7.66 (dd, ³J_H,H= 5, ³J_H,H= 8 Hz, 1 H), 5.35 (dd, ³J_H,F= 2.5, ³J_H,F

1

= 7 Hz, 1 H) ppm. H NMR ([D₆]DMSO, 300.3 MHz): δ = 10.04

4

3

(t, J_H,F= 12 Hz, 1 H), 8.65–8.60 (m, 2 H), 7.86 (d, J_H,H= 8 Hz,

3

1 H), 7.53 (dd, J_H,H= 5, J_H,H= 8 Hz, 1 H), 5.42 (dd, J_H,F

=

2.5, J_H,F= 7 Hz, 1 H) ppm. ¹³C NMR (CD₃OD, 75.4 MHz): δ =

3

2

162.8 (t, J_C,F= 30 Hz), 150.1, 148.3, 138.1, 131.8, 125.8, 125.6 (t,

¹J_C,F= 294.5 Hz), 63.3 (dd, J_C,F= 23.5, J_C,F= 26.5 Hz) ppm.

2

¹⁹F NMR (CD₃OD, 288.3 MHz): δ = –116.4 (dd, ³J_F,H= 6.5, J_F,F

2

= 228 Hz), –122.5 (d, ²J_F,F= 228 Hz) ppm. ¹⁹F NMR ([D₆]DMSO,

1

EtOAc, 7:3), R_f= 0.58. H NMR (CDCl₃, 300.3 MHz): δ = 7.40–

3

4

2

288.3 MHz): δ = –114.2 (ddd, J_F,H= 7.5, J_F,H= 14, J_F,F

=

7.10 (m, 15 H), 5.13 (s, 3 H), 4.41 (d, ³J_H,H= 6 Hz, 2 H), 4.31 (dd,

3

4

2

223 Hz), –120.3 (ddd, J_F,H= 2, J_F,H= 12, J_F,F= 223 Hz) ppm.

3

³J_H,F= 8, J_H,F= 26 Hz, 1 H), 4.30 (q, J_H,H= 7 Hz, 1 H), 4.01

IR (KBr): ν_max= 3079, 1813, 1384, 718 cm^–1. MS (CI+): m/z = 185

˜

2

3

(d, J_H,H= 13.5 Hz, 2 H), 3.99 (q, J_H,H= 7 Hz, 1 H), 3.06 (d,

[M + H]⁺, 165, 142, 100, 91.

²J_H,H= 13.5 Hz, 2 H), 1.12 (t, J_H,H= 7 Hz, 3 H) ppm. ¹³C NMR

3

2

General Procedure for 14b–e. rac-Benzyl 4-[1-(Dibenzylamino)-2-

(ethoxycarbonyl)-2,2-difluoroethyl]piperidine-1-carboxylate (14b):

The N,N-disubstituted 1H-benzotriazolylamine 13b was prepared

according to the above General Procedure; dibenzylamine (0.79 g,

(CDCl₃, 75.4 MHz): δ = 163.9 (dd, J_C,F= 30, J_C,F= 34 Hz),

156.5, 139.0, 138.7, 136.4, 131.3, 129.1, 128.5, 128.3, 128.1, 127.3,

1

127.2, 117.1 (dd, J_C,F= 253, J_C,F= 259.5 Hz), 66.9, 63.3 (dd,

²J_C,F= 19.5, ²J_C,F= 28.5 Hz), 62.8, 54.9, 44.7, 13.6 ppm. ¹⁹F NMR

4286

www.eurjoc.org

Eur. J. Org. Chem. 2008, 4277–4295

α,α-Difluoro-β-amino Esters and gem-Difluoro-β-lactams

2

(CDCl₃, 288.3 MHz): δ = –102.0 (d, J_F,F= 262 Hz), –113.8 (d,

(dd, ³J_F,H= 25, ²J_F,F= 257 Hz) ppm. IR (KBr): ν_max= 1770, 1292,

˜

²J_F,F= 262 Hz) ppm.

1204, 1064, 700 cm^–1. C₂₄H₂₄F₂N₂O₂(410.47): calcd. C 70.23, H

5.89, N 6.82; found C 69.95, H 5.83, N 6.75.

rac-Ethyl 3-(Dibenzylamino)-2,2-difluoro-3-(pyridin-4-yl)propanoate

(14d): The N,N-disubstituted 1H-benzotriazolylamine 13d was pre-

pared according to the same procedure as employed for 14b; diben-

zylamine (8.37 g, 42.4 mmol) and pyridine-4-carbaldehyde (4d, 5 g,

46.7 mmol, 1.1 equiv.) were successively added to a solution of 1H-

benzotriazole (5.06 g, 42.5 mmol, 1 equiv.) dissolved in dry ethanol

(5 mL). The mixture was heated at reflux for 4 h in the presence of

dried molecular sieves (3 Å, 4 g), and was then stirred at room

temp. for 12 h. After removal of molecular sieves by suction fil-

tration and concentration of the filtrate under vacuum, the ob-

tained solid could be recrystallized from ethanol. Racemic β-amino

ester 14d was obtained from N,N-disubstituted 1H-benzotriazolyl-

amine 13d by the procedure already described for the conversion

of 13b to 14b, from iminium salt 13d (9 g, 22.2 mmol), activated

zinc dust (3 g, 45.9 mmol, 2 equiv.), chlorotrimethylsilane (3.5 mL,

27.4 mmol, 1.2 equiv.), and ethyl bromodifluoroacetate (6.75 g,

33.3 mmol, 1.5 equiv.) in anhydrous THF (7 mL). Chromatography

[cyclohexane/EtOAc (95:5 to 70:30) as eluent] gave pure ester 14d

as a pale yellow solid; yield 7.47 g (82%; 2 steps); m.p. 93 °C; TLC:

rac-tert-Butyl 4-[1-(Dibenzylamino)-2-(ethoxycarbonyl)-2,2-difluoro-

ethyl]piperidine-1-carboxylate (14f): A solution of racemic β-amino

ester 14b (10 g, 17.8 mmol) and Boc₂O (4.3 g, 19.7 mmol,

1.1 equiv.) in EtOH (80 mL) was added to a suspension of palla-

dium on charcoal 10% (1 g) in EtOH (10 mL). The mixture was

hydrogenated at atmospheric pressure and 40 °C until no starting

material could be observed by TLC (ca. 48 h), filtered through Ce-

lite, and concentrated. The crude oil was crystallized from diethyl

ether and, after filtration and drying, the pure β-amino ester 14f

was obtained as a white solid; yield 9.19 g (quant.); m.p. 124 °C;

TLC: silica gel (cyclohexane/EtOAc, 8:2), R_f= 0.55. ¹H NMR

(CDCl₃, 300.3 MHz): δ = 7.30–7.15 (m, 10 H), 4.25–4.05 (m, 2 H),

2

4.05–3.90 (m, 2 H), 3.80 (d, J_H,H= 12.5 Hz, 1 H), 3.73 (d, J_H,H

3

= 12.5 Hz, 1 H), 3.20 (td, J_H,H= 7.5, J_H,F= 7.5, J_H,F= 23 Hz,

1 H), 2.60–2.45 (m, 2 H), 2.00–1.85 (m, 1 H), 1.85–1.70 (m, 1 H),

3

1.50–1.40 (m, 1 H), 1.24 (t, J_H,H= 7 Hz, 3 H), 1.15–1.00 (m, 1

H), 1.00–0.85 (m, 1 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ =

2

164.4 (t, J_C,F= 32 Hz), 154.6, 139.0, 129.4, 128.2, 127.2, 119.0 (t,

1

¹J_C,F= 260 Hz), 79.4, 62.9, 62.3 (t, ²J_C,F= 20 Hz), 55.1, 43.8, 35.4,

30.5 and 28.9, 28.4, 13.8 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ

silica gel (cyclohexane/EtOAc, 7:3), R_f= 0.30. H NMR (CDCl₃,

3

300.3 MHz): δ = 8.69 (d, J_H,H= 6 Hz, 2 H), 7.35–7.20 (m, 12 H),

4.45–4.30 (m, 2 H), 4.04 (d, ²J_H,H= 13.5 Hz, 2 H), 3.10 (d, ²J_H,H

=

2

3

2

= –106.1 (d, J_F,F= 250 Hz), –107.2 (dd, J_F,H= 11.5, J_F,F

=

13.5 Hz, 2 H), 1.18 (t, ³J_H,H= 7 Hz, 3 H) ppm. ¹³C NMR (CDCl₃,

250 Hz) ppm. IR (KBr): ν_max= 1773, 1695, 1295, 1210, 1176, 1063,

˜

2

700 cm^–1.

75.4 MHz): δ = 163.3 (dd, J_C,F= 29.5, J_C,F= 34 Hz), 149.6,

139.5, 138.0, 129.1, 128.4, 127.5, 125.7, 116.6 (dd, ¹J_C,F= 255, ¹J_C,F

2

rac-tert-Butyl 4-[1-Amino-2,2-difluoro-2-(methoxycarbonyl)ethyl]-

piperidine-1-carboxylate (15b): A solution of dibenzylamine 14f

(7.15 g, 13.8 mmol) was added to a suspension of Pearlman’s cata-

lyst (palladium hydroxide 20% on activated charcoal, 0.5 g) in etha-

nol (80 mL). The reaction mixture was stirred at 40 °C under hy-

drogen (1 bar) for 48 h. The catalyst was filtered off and washed

with ethanol (2ϫ20 mL). The combined organic layers were con-

centrated, and the residue was chromatographed on silica gel [cy-

clohexane/EtOAc + 0.5% Et₃N (95:5 to 70:30) as eluent] to give

15b as a yellow oil; yield 0.76 g (17%). ¹H NMR (CDCl₃,

300.3 MHz): δ = 4.25–4.00 (m, 2 H), 3.87 (s, 3 H), 3.08 (ddd, ³J_H,H

= 261 Hz), 63.1, 62.7 (dd, J_C,F= 19.5, J_C,F= 28.5 Hz), 54.9,

13.6 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –102.1 (dd, ³J_F,H

=

7.5, ²J_F,F= 259 Hz), –113.7 (dd, ³J_F,H= 24.5, ²J_F,F= 259 Hz) ppm.

IR (KBr): ν_max= 1770, 1293, 1204, 1066, 700 cm^–1. C₂₄H₂₄F₂N₂O₂

˜

(410.47): calcd. C 70.23, H 5.89, N 6.82; found C 69.91, H 6.02, N

6.46.

rac-Ethyl 3-(Dibenzylamino)-2,2-difluoro-3-(pyridin-3-yl)propanoate

(15e): The N,N-disubstituted 1H-benzotriazolylamine 13e was pre-

pared according to the same procedure as employed for 14b; diben-

zylamine (16.74 g, 84.9 mmol) and pyridine-3-carbaldehyde (4e,

10 g, 93.4 mmol, 1.1 equiv.) were successively added to a solution

of 1H-benzotriazole (10.11 g, 84.9 mmol, 1 equiv.) dissolved in dry

ethanol (15 mL). The mixture was heated at reflux for 4 h in the

presence of dried molecular sieves (3 Å, 6 g), and then stirred at

room temp. for 12 h. After removal of molecular sieves by suction

filtration and concentration of the filtrate under vacuum, the ob-

tained solid could be recrystallized from ethanol. Racemic β-amino

ester 14e was obtained from N,N-disubstituted 1H-benzotriazolyl-

amine 13e according to the procedure already described for the

conversion of 13b into 14b, from iminium salt 13e (9 g, 22.2 mmol),

activated zinc dust (3 g, 45.9 mmol, 2 equiv.), chlorotrimethylsilane

(3.5 mL, 27.4 mmol, 1.2 equiv.), and ethyl bromodifluoroacetate

(6.75 g, 33.3 mmol, 1.5 equiv.) in anhydrous THF (7 mL).

3

= 4, J_H,F= 10.5, J_H,F= 18 Hz, 1 H), 2.75–2.55 (m, 2 H), 1.80–

1.65 (m, 1 H), 1.42 (s, 9 H), 1.60–1.20 (m, 4 H) ppm. ¹³C NMR

(CDCl₃, 75.4 MHz): δ = 164.7 (d, ²J_C,F= 32, ²J_C,F= 33 Hz), 154.6,

1

2

116.7 (t, J_C,F= 255 Hz), 79.4, 57.5 (t, J_C,F= 23 Hz), 53.3, 43.7,

36.5, 28.4, 29.4 and 26.4 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ

= –111.2 (dd, J = 115, ²J_F,F= 263 Hz), –117.0 (dd, ³J_F,H= 11, ²J_F,F

= 263 Hz) ppm.

rac-Ethyl 3-Amino-3-[4-(aminomethyl)phenyl]-2,2-difluoropropano-

ate Hydrochloride (16): A solution of N-protected β-amino ester

14c (10.94 g, 18.1 mmol) in EtOAc (30 mL) was added to a suspen-

sion of palladium on charcoal (10%, 0.5 g) in ethanol (30 mL),

followed by the addition of HCl (5 )/iPrOH (15 mL). The mixture

Chromatography [cyclohexane/EtOAc (9:1 to 7:3) as eluent] gave was hydrogenated at atmospheric pressure and 40 °C until no start-

pure ester 14e as a yellow oil; yield 7.35 g (81%); TLC: silica gel

ing material could be observed by TLC (ca. 3 d), filtered through

a pad of Celite, washed with ethanol (2ϫ25 mL), and concen-

trated. The hydrochloride salt of β-amino ester 16 was obtained as

(cyclohexane/EtOAc, 7:3), R_f

=

0.42. ¹H NMR (CDCl₃,

4

3

300.3 MHz): δ = 8.62 (dd, J_H,H= 1.5, J_H,H= 5 Hz, 1 H), 8.55

4

3

1

(d, J_H,H= 2 Hz, 1 H), 7.81 (dt, J_H,H= 1.5, J_H,H= 7.5 Hz, 1 H),

a hygroscopic white solid; yield 3.84 g (72%). H NMR (CD₃OD,

3

7.35 (dd, J_H,H= 5, J_H,H= 8 Hz, 1 H), 7.30–7.20 (m, 10 H), 4.37

300.3 MHz): δ = 7.60–7.40 (m, 4 H), 5.16 (dd, J_H,F= 7.5, J_H,F=

3

(dd, J_H,F= 8, J_H,F= 9 Hz, 1 H), 4.30 (q, J_H,H= 7 Hz, 2 H),

19 Hz, 1 H), 4.07 (q, J_H,H= 7 Hz, 2 H), 4.03 (s, 2 H), 1.04 (t,

2

4.00 (d, J_H,H= 13 Hz, 2 H), 3.03 (d, J_H,H= 13 Hz, 2 H), 1.26 (t, ³J_H,H= 7 Hz, 3 H) ppm. ¹³C NMR (CD₃OD, 75.4 MHz): δ = 161.8

³J_H,H= 7 Hz, 3 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ = 163.5

(t, J_C,F= 24 Hz), 137.4, 131.1, 130.9, 114.2 (t, J_C,F= 259 Hz),

2

1

2

(dd, J_C,F= 30, J_C,F= 34 Hz), 151.9, 150.0, 138.1, 137.9, 129.2,

65.3, 57.3 (dd, J_C,F= 22.5, J_C,F= 24.5 Hz), 43.7, 14.1 ppm. ¹⁹F

NMR (CD₃OD, 288.3 MHz): δ = –108.7 (dd, J_F,H= 6.5, J_F,F

260 Hz), –120.1 (dd, J_F,H= 18.5, J_F,F= 260 Hz) ppm. IR (KBr):

ν

˜

max

128.4, 127.5, 126.3, 123.4, 120.3 (t, ¹J_C,F= 290 Hz), 63.0, 61.6 (dd,

=

3

2

²J_C,F= 19.5, J_C,F= 29.5 Hz), 54.9, 13.7 ppm. ¹⁹F NMR (CDCl₃,

2

3

2

3

2

288.3 MHz): δ = –101.5 (dd, J_F,H= 7.5, J_F,F= 257 Hz), –113.6

= 3401, 1778, 1596–1519, 1315, 1200, 1128–1100, 1056 cm^–1.

Eur. J. Org. Chem. 2008, 4277–4295

www.eurjoc.org

4287

N. Boyer, P. Gloanec, G. De Nanteuil, P. Jubault, J.-C. Quirion

FULL PAPER

rac-Benzyl

4-[1-Amino-2-(ethoxycarbonyl)-2,2-difluoroethyl]ben-

(2.3 g, 6.3 mmol, 0.5 equiv.), and methyl bromoacetate (17a,

15 mL, 158 mmol, 12.5 equiv.) in anhydrous acetonitrile (17 mL)

was treated dropwise with 1,1,3,3-tetramethylguanidine (2.9 g,

25.1 mmol, 2 equiv.). The mixture was stirred at room temp. for

12 h. The solvent was evaporated to dryness, and the residue was

chromatographed on silica gel [cyclohexane/EtOAc (95:5 to 70:30)

as eluent] to give β-lactam 18a as an opalescent oil; yield 3.21 g

(quant.); TLC: silica gel (cyclohexane/EtOAc, 8:2), R_f= 0.35. ¹H

NMR (CDCl₃, 300.3 MHz): δ = 7.43 (m, 3 H), 7.28 (m, 2 H), 5.25

zylcarbamate (15c) and rac-Benzyl 4-[1-Amino-2,2-difluoro-2-(meth-

oxycarbonyl)ethyl]benzylcarbamate (15cЈ): A solution of amine hy-

drochloride 17 (4 g, 13.6 mmol), triethylamine (4.15 mL, 30 mmol,

2.2 equiv.), Boc₂O (2.97 g, 13.6 mmol, 1 equiv.), and DMAP as cat-

alyst (20 mg, 1 mol-%) was stirred at room temp. for 24 h. The mix-

ture was poured into saturated aqueous NH₄Cl solution (50 mL)

and extracted with CH₂Cl₂(2ϫ100 mL). The organic layer was

dried with MgSO₄and concentrated before purification by flash

chromatography on silica gel [CH₂Cl₂/MeOH (98:2 to 96:4) as elu-

3

(dd, J_H,F= 2.5, J_H,F= 7.5 Hz, 1 H), 4.49 (d, J_H,H= 18 Hz, 1

2

ent] to afford the mixture of β-amino esters 15c and 15cЈ as a pale

yellow oil; yield 0.91 g (19%). H NMR (CDCl₃, 300.3 MHz): δ = NMR (CDCl₃, 75.4 MHz): δ = 167.2, 161.2 (t, J_C,F= 31 Hz),

H), 3.73 (s, 3 H), 3.61 (dd, J = 2, J_H,H= 18 Hz, 1 H) ppm. ¹³C

1

2

3

7.35–7.15 (m, 8 H), 4.85 (br. s, 2 H), 4.43 (dd, J_H,F= 11.5, J_H,F

= 14.5 Hz, 2 H), 4.28 (d, ³J_H,H= 6 Hz, 4 H), 4.23 (q, ³J_H,H= 7 Hz,

2 H), 3.65 (s, 3 H), 1.76 (br. s, 2 H), 1.43 (br. s, 18 H), 1.22 (t, ³J_H,H

= 7 Hz, 3 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ = 165.0 (t,

¹J_C,F= 33 Hz), 155.9, 139.6, 135.2, 128.2, 127.6, 79.6, 62.9, 58.1 (t,

²J_C,F= 23.5 Hz), 53.3, 44.2, 28.5, 28.4, 13.9 ppm. ¹⁹F NMR

130.0, 129.6, 129.1, 128.0, 120.9 (t, ¹J_C,F= 291 Hz), 69.2 (dd, ²J_C,F

2

=

24, J_C,F

=

27 Hz), 52.7, 40.7 ppm. ¹⁹F NMR (CDCl₃,

3

2

288.3 MHz): δ = –116.9 (dd, J_F,H= 7.5, J_F,F= 225 Hz), –124.6

(d, ²J_F,F= 225 Hz) ppm. IR (KBr): ν_max= 1799, 1750, 1323, 1208,

˜

1131, 1068, 703 cm^–1. C₁₂H₁₁F₂NO₃(255.22): calcd. C 56.47, H

4.34, N 5.49; found C 56.46, H 4.75, N 5.21.

3

2

(CDCl₃, 288.3 MHz): δ = –114.4 (dd, J_F,H= 12, J_F,F= 261 Hz),

rac-Benzyl

2-(3,3-Difluoro-2-oxo-4-phenylazetidin-1-yl)acetate

–117.8 (dd, ³J_F,H= 16.5, ²J_F,F= 261 Hz) ppm (ethyl β-amino ester);

(18b): This compound was prepared from racemic β-lactam 12a

according to the procedure already described for the conversion of

12a into 18a, from azetidin-2-one 12a (2 g, 10.9 mmol), nBu₄NI

(2 g, 5.4 mmol, 0.5 equiv.), benzyl bromoacetate (17b, 17.35 mL,

109 mmol, 10 equiv.), and 1,1,3,3-tetramethylguanidine (2.5 g,

21.7 mmol, 2 equiv.) in anhydrous acetonitrile (10 mL).

Chromatography on silica gel [cyclohexane/EtOAc (10:0 to 8:2) as

eluent] gave β-lactam 18b as a colorless oil; yield 3.28 g (91%);

δ = –113.4 (dd, ³J_F,H= 11 Hz, J_F,F= 261 Hz), –117.3 (dd, J_F,H

=

2

3

16 Hz, ²J_F,F= 261 Hz) ppm (methyl β-amino ester). IR (KBr): ν

˜

max

= 3340, 1767, 1698, 1516, 1367, 1276, 1252, 1170, 1073, 758 cm^–1.

rac-Ethyl 3-Amino-2,2-difluoro-3-(pyridin-4-yl)propanoate Hydro-

chloride (15d): A solution of N-protected β-amino ester 14d (7.45 g,

18.1 mmol) in ethanol (30 mL) was added to a suspension of palla-

dium on charcoal (10%, 1 g) in ethanol (15 mL), followed by the

addition of HCl (5 )/iPrOH (15 mL). The mixture was hydroge-

nated at atmospheric pressure and 40 °C until no starting material

could be observed by TLC (ca. 3 d), filtered through a pad of Ce-

lite, washed with ethanol (2ϫ25 mL), and concentrated. The hy-

drochloride salt of β-amino ester 16d was obtained as a hygroscopic

white solid; yield 3.62 g (75%); m.p. 190 °C (dec.); TLC: silica gel

(CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1), R_f= 0.70. ¹H NMR ([D₆]-

DMSO, 300.3 MHz): δ = 8.91 (d, ³J_H,F= 6 Hz, 2 H), 7.97 (d, ³J_H,H

TLC: silica gel (cyclohexane/EtOAc, 8:2), R_f= 0.41. ¹H NMR

3

(CDCl₃, 300.3 MHz): δ = 7.40–7.15 (m, 10 H), 5.17 (dd, J_H,F

=

2.5, ³J_H,F= 7 Hz, 1 H), 5.11 (d, ²J_H,H= 12 Hz, 1 H), 5.05 (d, ²J_H,H

= 12 Hz, 1 H), 4.46 (d, ²J_H,H= 18 Hz, 1 H), 3.58 (d, ²J_H,H= 18 Hz,

1 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ = 166.8, 161.4 (t, ²J_C,F

= 31 Hz), 134.7, 130.2, 129.7, 129.3, 128.9, 128.8, 128.7, 128.2,

1

2

121.0 (dd, J_C,F= 289, J_C,F= 292 Hz), 69.4 (dd, J_C,F= 24.5,

²J_C,F= 27 Hz), 67.9, 41.1 (t, J = 30 Hz) ppm. ¹⁹F NMR (CDCl₃,

288.3 MHz): δ = –114.1 (d, J_F,F= 225.5 Hz), –121.8 (d, J_F,F

2

3

=

= 6 Hz, 2 H), 5.59 (dd, J_H,F= 11.5, J_H,F= 15 Hz, 1 H), 5.3–4.3

3

225.5 Hz) ppm. IR (KBr): ν

= 1798, 1747, 1323, 1201, 1067,

˜

max

(br. s, 3 H), 4.28 (q, J_H,H= 7 Hz, 2 H), 1.18 (t, J_H,H= 7 Hz, 3

701 cm^–1.

H) ppm. ¹³C NMR ([D₆]DMSO, 75.4 MHz): δ = 160.5 (t, J_C,F

=

2

1

30.5 Hz), 146.6, 143.3, 126.0, 112.5 (t, J_C,F= 258 Hz), 64.6, 54.3

rac-2-(3,3-Difluoro-2-oxo-4-phenylazetidin-1-yl)acetic Acid (19): β-

Lactam 18b (3.31 g, 10 mmol) was dissolved in ethanol (60 mL),

and palladium on charcoal (10%, 0.2 g) was added. The mixture

was first placed under nitrogen and subsequently under hydrogen

(hydrogen balloon, 1 bar). After the system had been stirred at

room temp. for 24 h, the hydrogen gas was removed with the aid

of a nitrogen flow. The catalyst was filtered off through a pad of

Celite and washed with ethanol (2ϫ20 mL). The solvent was evap-

orated in vacuo. The crude product was purified by steric exclusion

chromatography on a column of Biogel P2 (Bio-Rad) with MeCN/

H₂O/HCl (1 , 500:500:10) as the solvent. Fractions containing

only product were pooled, and the solvent was removed under vac-

uum. Lyophilization yielded the title compound 20 as a white solid;

(t, ²J_C,F= 24.5 Hz), 13.6 ppm. ¹⁹F NMR ([D₆]DMSO, 288.3 MHz):

δ = –109.5 (dd, ³J_F,H= 11, J_F,F= 259 Hz), –112.5 (dd, ³J_F,H= 15,

2

²J_F,F= 259 Hz) ppm. IR (KBr): ν

= 3399, 2790, 1778, 1640–

˜

max

1616–1529, 1318, 1223, 1071 cm^–1.

rac-Ethyl 3-Amino-2,2-difluoro-3-(pyridin-4-yl)propanoate Hydro-

chloride (15e): This compound was prepared from N,N-dibenzyl β-

amino ester 14e according to the same procedure as employed for

15d, from N-protected β-amino ester 14e (2.9 g, 7.05 mmol), palla-

dium on charcoal (10%, 0.17 g), HCl (5 )/iPrOH (3 mL) in etha-

nol (10 mL). The hydrochloride salt of β-amino ester 15e was ob-

tained as a white, viscous oil; yield 1.69 g (90%); TLC: silica gel

1

(CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1), R_f= 0.70. H NMR (CD₃OD,

300.3 MHz): δ = 9.14 (d, J_H,H= 6 Hz, 1 H), 9.08 (br. s, 1 H), 8.75

1

yield 3.28 g (91%); m.p. 162 °C. H NMR (CD₃OD, 300.3 MHz):

3

δ = 7.50–7.45 (m, 3 H), 7.40–7.35 (m, 2 H), 5.34 (dd, J_H,F= 2,

3

(m, 1 H), 8.21 (m, 1 H), 5.80 (dd, J_H,F= 8, J_H,F= 9 Hz, 1 H),

2

³J_H,F= 7.5 Hz, 1 H), 4.45 (d, J_H,H= 18 Hz, 1 H), 3.74 (dd, J =

3

4.42 (q, J_H,H= 7 Hz, 2 H), 1.34 (t, J_H,H= 7 Hz, 3 H) ppm. ¹³C

2

1, J_H,H= 18 Hz, 1 H) ppm. ¹³C (CD₃OD, 75.4 MHz): δ = 170.0,

2

NMR (CD₃OD, 75.4 MHz): δ = 165.0 (t, J_C,F= 30.5 Hz), 147.3,

2

1

162.8 (t, J_C,F= 31 Hz), 131.4, 130.9, 130.1, 129.2, 122.4 (t, J_C,F

1

146.1, 145.6, 130.3, 128.5, 113.5 (dd, J_C,F= 259.5, J_C,F

=

= 290 Hz), 70.5 (dd, J_C,F= 24, J_C,F= 27 Hz), 42.1 ppm. ¹⁹F

NMR (CD₃OD, 288.3 MHz): δ = –104.2 (dd, J_F,H= 7.5, J_F,F

225 Hz), –121.9 (d, J_F,F= 225 Hz) ppm. IR (KBr): ν

2

261.5 Hz), 65.9, 54.8 (t, J_C,F= 24.5 Hz), 14.0 ppm. ¹⁹F NMR

2

3

2

=

(CD₃OD, 288.3 MHz): δ = –110.4 (dd, ³J_F,H= 7.5, ²J_F,F= 275 Hz),

2

= 3044,

˜

3

2

max

–116.4 (dd, J_F,H= 16.5, J_F,F= 275 Hz) ppm. IR (KBr): ν

=

˜

max

1791, 1718, 1323, 1243, 701 cm^–1. MS (CI+): m/z = 242 [M + H]⁺,

198, 154, 140, 102, 93. HRMS (CI+): calcd. for C₁₁H₉F₂NO₃

242.0629; found 242.0626. C₁₁H₉F₂NO₃(241.20): calcd. C 54.78,

H 3.76, N 5.81; found C 54.82, H 3.58, N 5.78.

3401, 1769, 1668, 1318, 1210, 1072 cm^–1.

rac-Methyl

2-(3,3-Difluoro-2-oxo-4-phenylazetidin-1-yl)acetate

(18a): A solution of azetidin-2-one 12a (2.3 g, 12.6 mmol), nBu₄NI

4288

www.eurjoc.org

Eur. J. Org. Chem. 2008, 4277–4295

α,α-Difluoro-β-amino Esters and gem-Difluoro-β-lactams

Benzyl rac-4-{1-[(Benzyloxycarbonyl)methyl]-3,3-difluoro-4-oxo-

2

–120.6 (d, J_F,F= 225.5 Hz) ppm. MS (EI+): m/z = 332 [M]^+·, 281,

azetidin-2-yl}piperidine-1-carboxylate (20b): This compound was

prepared from racemic β-lactam 12a according to the procedure

already described for the conversion of 12a into 18b, from azetidin-

2-one 12b (0.56 g, 1.7 mmol), nBu₄NI (0.3 g, 0.8 mmol, 0.5 equiv.),

benzyl bromoacetate (17b, 10 mL, 63 mmol, 37 equiv.), and 1,1,3,3-

tetramethylguanidine (0.39 g, 3.4 mmol, 2 equiv.) in anhydrous ace-

tonitrile (10 mL). Chromatography on silica gel [cyclohexane/

EtOAc (95:5 to 80:20) as eluent] gave β-lactam 20b as an orange

oil; yield 0.24 g (30%); TLC: silica gel (cyclohexane/EtOAc, 8:2),

R_f= 0.40. ¹H NMR (CDCl₃, 300.3 MHz): δ = 7.40–7.25 (m, 10

H), 5.20 (d, ²J_H,H= 12 Hz, 1 H), 5.15 (d, ²J_H,H= 12 Hz, 1 H), 5.10

(s, 2 H), 4.43 (d, ²J_H,H= 18 Hz, 1 H), 4.30–4.05 (m, 2 H), 3.96 (dt,

232, 198, 169, 141, 91, 65.

rac-Benzyl 2-[3,3-Difluoro-2-oxo-4-(pyridin-3-yl)azetidin-1-yl]acet-

ate (20e): This compound was prepared from racemic β-lactam 12e

according to the procedure already described for the conversion of

12a into 18b, from azetidin-2-one 12e (0.5 g, 2.7 mmol), nBu₄NI

(0.5 g, 3.3 mmol, 1.2 equiv.), benzyl bromoacetate (17b, 0.68 g,

3.0 mmol, 1.1 equiv.), and 1,1,3,3-tetramethylguanidine (0.62 g,

5.4 mmol, 2 equiv.) in anhydrous acetonitrile (50 mL). Chromatog-

raphy on silica gel [CH₂Cl₂/MeOH/NH₄OH (99.5:0.5:0.05 to

98:2:0.2) as eluent] gave β-lactam 20e as a pale yellow oil; yield

0.45 g (50%); TLC: silica gel (CH₂Cl₂/MeOH/NH₄OH, 98:2:0.2),

R_f= 0.48. ¹H NMR (CDCl₃, 300.3 MHz): δ = 8.65 (d, J_H,H

=

3

³J_H,F= 2.5, J_H,H= J_H,F= 11 Hz, 1 H), 3.87 (d, J_H,H= 18 Hz,

1 H), 2.85–2.60 (m, 2 H), 2.00–1.85 (m, 1 H), 1.75–1.65 (m, 1 H),

1.60–1.45 (m, 1 H), 1.30–1.10 (m, 2 H) ppm. ¹³C NMR (CDCl₃,

75.4 MHz): δ = 166.6, 161.2 (t, ²J_C,F= 31 Hz), 155.0, 136.5, 134.5,

3

2

4

3

4 Hz, 1 H), 8.49 (s, 1 H), 7.61 (dd, J_H,H= 1, J_H,H= 8 Hz, 1 H),

3

7.4–7.2 (m, 6 H), 5.26 (dd, J_H,F= 2.5, J_H,F= 7 Hz, 1 H), 5.17

(d, ²J_H,H= 12 Hz, 1 H), 5.11 (d, ²J_H,H= 12 Hz, 1 H), 4.49 (d, ²J_H,H

= 18 Hz, 1 H), 3.63 (dd, J = 1.5, J_H,H= 18 Hz, 1 H) ppm. ¹³C

2

128.9, 128.7, 128.6, 128.5, 128.1, 127.9, 69.8 (dd, J_C,F= 22, J_C,F

2

NMR (CDCl₃, 75.4 MHz): δ = 166.3, 160.8 (t, J_C,F= 30.5 Hz),

= 25 Hz), 67.8, 67.2, 43.3, 43.2 and 43.1, 35.7, 28.1 and 27.6 ppm.

151.3, 149.6, 135.6, 134.3, 128.8, 128.7, 128.5, 124.6, 123.8, 120.8

3

2

¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –113.5 (dd, J_F,H= 8, J_F,F

=

1

2

(t, J_C,F= 292 Hz), 67.9, 67.0 (dd, J_C,F= 24, J_C,F= 27 Hz),

3

2

234 Hz), –114.5 (dd, J_F,H= 21, J_F,F= 234 Hz) ppm. IR (KBr):

41.1 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –113.8 (dd, ³J_F,H

=

ν

max

= 1798, 1747, 1323, 1201, 1067, 701 cm^–1.

˜

2

7.5, J_F,F= 226 Hz), –121.2 (d, J_F,F= 226 Hz) ppm. IR (KBr):

ν

= 1800, 1747, 1312, 1206, 1067, 699 cm^–1.

Benzyl rac-[2-(4-{[(Benzyloxycarbonyl)amino]methyl}phenyl)-3,3-di-

fluoro-4-oxoazetidin-1-yl]acetate (20c): This compound was pre-

pared from racemic β-lactam 12c according to the procedure al-

ready described for conversion of 12a into 18b, from azetidin-2-one

12c (1.28 g, 3.7 mmol), nBu₄NI (1.38 g, 3.7 mmol, 1 equiv.), benzyl

bromoacetate (17b, 9.2 g, 40 mmol, 10.8 equiv.), and 1,1,3,3-tet-

ramethylguanidine (0.84 g, 7.3 mmol, 2 equiv.) in anhydrous aceto-

nitrile (80 mL). Chromatography on silica gel [CH₂Cl₂/EtOAc

(100:0 to 98:2) as eluent] gave β-lactam 20c as a colorless oil; yield

˜

max

rac-tert-Butyl 2-[3,3-Difluoro-2-oxo-4-(pyridin-4-yl)azetidin-1-yl]-

acetate (22d): This compound was prepared from racemic β-lactam

12d according to the procedure already described for the conver-

sion of 12a into 18b, from azetidin-2-one 12d (1.9 g, 10.3 mmol),

NaI (1.8 g, 12 mmol, 1.15 equiv.), tert-butyl bromoacetate (17c, 2 g,

10.3 mmol, 1 equiv.), and 1,1,3,3-tetramethylguanidine (2.37 g,

20.6 mmol, 2 equiv.) in anhydrous acetonitrile (100 mL).

Chromatography on silica gel [CH₂Cl₂/MeOH/NH₄OH (99:1:0.1 to

98:2:0.2) as eluent] gave β-lactam 22d as a brown oil; yield 1.44 g

(47%).

1

1.74 g (95%); TLC: silica gel (CH₂Cl₂/EtOAc, 95:5), R_f= 0.75. H

NMR (CDCl₃, 300.3 MHz): δ = 7.40–7.25 (m, 12 H), 7.21 (d, ³J_H,H

3

= 8 Hz, 2 H), 5.21 (dd, J_H,F= 2.5, J_H,F= 7.5 Hz, 1 H), 5.17 (d,

²J_H,H= 12 Hz, 1 H), 5.12 (br. s, 3 H), 5.10 (d, J_H,H= 11.5 Hz, 1

2

rac-tert-Butyl 2-[3,3-Difluoro-2-oxo-4-(pyridin-3-yl)azetidin-1-yl]-

acetate (22e): This compound was prepared from racemic β-lactam

12e according to the procedure already described for the conversion

of 12a into 18b, from azetidin-2-one 12e (0.65 g, 3.5 mmol), NaI

(0.6 g, 4 mmol, 1.15 equiv.), tert-butyl bromoacetate (17c, 0.69 g,

3.5 mmol, 1 equiv.), and 1,1,3,3-tetramethylguanidine (0.81 g,

7 mmol, 2 equiv.) in anhydrous acetonitrile (50 mL). Chromatog-

raphy on silica gel [CH₂Cl₂/MeOH/NH₄OH (99.5:0.5:0.05 to

98:2:0.2) as eluent] gave β-lactam 22e as a pale yellow solid; yield

0.52 g (50%); m.p. 85 °C; TLC: silica gel (CH₂Cl₂/MeOH/NH₄OH,

95:5:0.5), R_f= 0.75. ¹H NMR (CDCl₃, 300.3 MHz): δ = 8.65 (d,

2

3

H), 4.50 (d, J_H,H= 18 Hz, 1 H), 4.38 (d, J_H,H= 6 Hz, 2 H), 3.61

(dd, J = 1.5, J_H,H= 18 Hz, 1 H) ppm. ¹³C NMR (CDCl₃,

2

75.4 MHz): δ = 166.5, 161.1 (t, ²J_C,F= 31 Hz), 156.4, 140.7, 136.2,

134.5, 128.8, 128.7, 128.5, 128.4, 128.2, 128.1, 128.0, 120.8 (t, ¹J_C,F

= 291 Hz), 68.9 (dd, ²J_C,F= 23.5, ²J_C,F= 26.5 Hz), 67.7, 66.9, 44.5,

40.9 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –114.1 (dd, ³J_F,H

=

2

7.5, J_F,F

=

225 Hz), –121.8 (d, J_F,F

=

225 Hz) ppm.

C₂₇H₂₄F₂N₂O₅(494.50): calcd. C 65.58, H 4.89, N 5.67; found C

65.97, H 5.06, N 5.57.

rac-Benzyl 2-[3,3-Difluoro-2-oxo-4-(pyridin-4-yl)azetidin-1-yl]acet-

ate (20d): This compound was prepared from racemic β-lactam 12d

according to the procedure already described for the conversion of

12a into 18b, from azetidin-2-one 12d (5.15 g, 28 mmol), nBu₄NI

(10.3 g, 29.7 mmol, 1 equiv.), benzyl bromoacetate (17b, 7 g,

30.6 mmol, 1.1 equiv.), and 1,1,3,3-tetramethylguanidine (6.4 g,

55.6 mmol, 2 equiv.) in anhydrous acetonitrile (150 mL).

Chromatography on silica gel [CH₂Cl₂/MeOH/NH₄OH (99.5:0.5:

0.05 to 98:2:0.2) as eluent] gave β-lactam 20d as a pale yellow oil;

yield 2.70 g (29%); TLC: silica gel (CH₂Cl₂/MeOH/NH₄OH,

97:3:0.3), R_f= 0.73. ¹H NMR (CDCl₃, 300.3 MHz): δ = 8.66 (d,

³J_H,H= 5 Hz, 1 H), 8.54 (s, 1 H), 7.63 (d, J_H,H= 8 Hz, 1 H), 7.36

3

(dd, J_H,H= 5, J_H,H= 8 Hz, 1 H), 5.25 (dd, J_H,F= 2.5, J_H,F

=

2

7 Hz, 1 H), 4.33 (d, J_H,H= 18 Hz, 1 H), 3.47 (dd, J = 1, J_H,H

18 Hz, 1 H), 1.39 (s, 9 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ

2

= 165.4, 160.8 (t, J_C,F= 31 Hz), 151.3, 149.6, 135.5, 125.9, 123.8,

1

2

120.8 (t, J_C,F= 291.5 Hz), 83.6, 66.9 (dd, J_C,F= 23.5, J_C,F

=

27 Hz), 41.8, 27.8 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –114.1

3

2

(dd, J_F,H= 7.5, J_F,F= 225.5 Hz), –121.3 (d, J_F,F= 225.5 Hz)

ppm. IR (KBr): ν

= 1797, 1733, 1416, 1374, 1315, 1248, 1166,

˜

max

1066, 720 cm^–1. C₁₄H₁₆F₂N₂O₃(298.29): calcd. C 56.37, H 5.41, N

9.39; found C 56.45, H 5.45, N 9.46.

3

³J_H,H= 6 Hz, 2 H), 7.40–7.25 (m, 5 H), 7.18 (d, J_H,H= 6 Hz, 2

H), 5.22 (dd, ³J_H,F= 2, ³J_H,F= 7 Hz, 1 H), 5.17 (d, ²J_H,H= 12 Hz, rac-2-[3,3-Difluoro-2-oxo-4-(piperidin-4-yl)azetidin-1-yl]acetic Acid

2

1 H), 5.11 (d, J_H,H= 12 Hz, 1 H), 4.54 (d, J_H,H= 18 Hz, 1 H), Hydrochloride (21b): β-Lactam 20b (0.23 g, 0.5 mmol) was dis-

3.67 (dd, J = 1.5, J_H,H= 18 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, solved in ethanol (5 mL), and Pd/C (10%, 50 mg) was added. The

2

75.4 MHz): δ = 166.3, 160.7 (t, ²J_C,F= 31 Hz), 150.6, 138.8, 134.3, mixture was first placed under nitrogen and subsequently under

1

128.9, 128.7, 128.5, 122.5, 120.7 (dd, J_C,F= 291, J_C,F= 293 Hz),

hydrogen (hydrogen balloon, 1 bar). After the mixture had been

stirred at room temp. for 24 h, the hydrogen gas was removed with

the aid of a nitrogen flow. The catalyst was filtered off through a

68.0 (dd, J_C,F= 23.5, J_C,F= 27 Hz), 67.9, 41.3 ppm. ¹⁹F NMR

2

(CDCl₃, 288.3 MHz): δ = –113.3 (dd, ³J_F,H= 7.5, ²J_F,F= 225.5 Hz),

Eur. J. Org. Chem. 2008, 4277–4295

www.eurjoc.org

4289

N. Boyer, P. Gloanec, G. De Nanteuil, P. Jubault, J.-C. Quirion

FULL PAPER

2

pad of Celite, and washed with ethanol (2ϫ10 mL). The solvent

was evaporated in vacuo. The crude product was purified by steric

exclusion chromatography on a column of Biogel P2 (Bio-Rad)

with MeCN/H₂O/HCl (1 , 100:100:2) as the solvent. Fractions

containing only product were pooled, and the solvent was removed

under vacuum. Lyophilization yielded the hydrochloride salt of the

title compound 21b as a pale yellow lyophilizate; yield: 70 mg

(50%). ¹H NMR (D₂O, 300.3 MHz): δ = 4.13 (dt, ³J_H,F= 2.5, ³J_H,F

18 Hz, 1 H), 4.32 (s, 2 H), 4.04 (d, J_H,H= 18 Hz, 1 H) ppm. ¹³C

2

NMR (CD₃OD, 75.4 MHz): δ = 169.8, 164.1 (t, J_C,F= 30.5 Hz),

1

2

152.4, 144.4, 127.4, 122.3 (t, J_C,F= 293 Hz), 68.9 (dd, J_C,F= 23,

²J_C,F= 27 Hz), 43.3 ppm. ¹⁹F NMR (CD₃OD, 288.3 MHz): δ =

3

2

–77.9 (CF₃), –115.6 (dd, J_F,H= 7.5, J_F,F= 224 Hz), –121.6 (d,

²J_F,F= 224 Hz) ppm. IR (KBr): ν

= 3422, 2350, 1801, 1730,

˜

max

1643, 1420, 1324, 1193, 720 cm^–1. MS (ESI+): m/z = 242.9 [M +

H]⁺.

2

= 9 Hz, 1 H), 4.06 (d, J_H,H= 17.5 Hz, 1 H), 3.82 (d, J_H,H

=

rac-3-[(Carboxymethyl)amino]-2,2-difluoro-3-(pyridin-4-yl)pro-

panoic Acid Hydrochloride: The trifluoroacetate form of the prod-

uct of nucleophilic ring-opening was obtained during the TFA de-

protection step of 22d, after isolation from the steric exclusion

chromatography as a white lyophilizate; yield 200 mg (11%). ¹H

17.5 Hz, 1 H), 3.45–3.35 (m, 2 H), 3.00–2.85 (m, 2 H), 2.30–2.10

(m, 1 H), 2.00–1.85 (m, 2 H), 1.65–1.45 (m, 2 H) ppm. ¹³C NMR

2

(D₂O, 75.4 MHz): δ = 174.0, 163.6 (t, J_C,F= 30.5 Hz), 120.5 (t,

¹J_C,F= 290 Hz), 70.5 (dd, J_C,F= 22, J_C,F= 24.5 Hz), 49.8, 44.2

2

and 44.1, 33.6, 25.5 and 24.6 ppm. ¹⁹F NMR (D₂O, 288.3 MHz):

3

NMR (D₂O, 300.3 MHz): δ = 8.89 (d, J_H,H= 6.5 Hz, 2 H), 8.19

3

2

δ = –115.2 (dd, J_F,H= 8.5, J_F,F= 232.5 Hz), –125.3 (d, J_F,F

=

3

(d, J_H,H= 6 Hz, 2 H), 5.32 (dd, J_H,F= 8.5, J_H,F= 15 Hz, 1 H),

232.5 Hz) ppm. MS (ESI–): m/z = 247.0 [M – H]^–, 183.0.

3.80 (s, 2 H) ppm. ¹³C NMR (D₂O, 75.4 MHz): δ = 170.3, 165.8

2

1

(t, J_C,F= 26 Hz), 149.8, 142.6, 128.4, 114.0 (t, J_C,F= 261 Hz),

rac-2-{2-[4-(Aminomethyl)phenyl]-3,3-difluoro-4-oxoazetidin-1-yl}-

acetic Acid Hydrochloride (21c): This compound was prepared from

racemic β-lactam 20c according to the procedure already described

for the conversion of 20b into 21b, from azetidin-2-one 20c (1.71 g,

3.4 mmol) and Pd/C (10%, 0.2 g) in methanol (60 mL). The crude

product was purified by steric exclusion chromatography on a

column of Biogel P2 (Bio-Rad) with MeCN/H₂O/HCl (1 ,

500:500:10) as the solvent. Fractions containing only product were

pooled, and the solvent was removed under vacuum. Lyophiliza-

tion yielded the hydrochloride salt of the title compound 21c as a

white lyophilizate; yield 0.26 g (25%). ¹H NMR (D₂O, 300.3 MHz):

62.6 (dd, J_C,F= 24, J_C,F= 26 Hz), 47.5 ppm. ¹⁹F NMR (D₂O,

2

3

2

288.3 MHz): δ = –77.9 (CF₃), –108.3 (dd, J_F,H= 8.5, J_F,F

=

254.5 Hz), –112.4 (dd, ³J_F,H= 15, ²J_F,F= 254.5 Hz) ppm. IR (KBr):

ν

˜

= 3412, 1740, 1644, 1510, 1407, 1295, 1243, 1194 cm^–1. MS

max

(ESI+): m/z = 260.9 [M + H]⁺.

rac-2-[3,3-Difluoro-2-oxo-4-(pyridin-3-yl)azetidin-1-yl]acetic Acid

Hydrochloride (21e): TFA (2.5 mL) was added to a solution of azet-

idin-2-one 22e (0.3 g, 1 mmol) in wet CH₂Cl₂(2.5 mL). The mix-

ture was stirred at 0 °C for 1 h. After concentration, the crude

product was purified by steric exclusion chromatography on a col-

umn of Biogel P2 (Bio-Rad) with MeCN/H₂O/HCl (1 , 200:200:4)

as the solvent. Fractions containing only product were pooled, and

the solvent was removed under vacuum. Lyophilization yielded the

hydrochloride salt of the title compound 21e as a pale yellow lyo-

philizate; yield 0.16 g (56%). ¹H NMR (D₂O, 300.3 MHz): δ = 8.97

3

δ = 7.65 (d, J_H,H= 8 Hz, 2 H), 7.61 (d, J_H,H= 8 Hz, 2 H), 5.58

3

2

(dd, J_H,F= 2, J_H,F= 7 Hz, 1 H), 4.58 (d, J_H,H= 18 Hz, 1 H),

4.32 (s, 2 H), 4.04 (d, J_H,H= 18 Hz, 1 H) ppm. ¹³C NMR (D₂O,

2

75.4 MHz): δ = 170.9, 163.4 (t, J_C,F= 31 Hz), 134.8, 130.8, 129.7,

1

2

129.4, 120.3 (t, J_C,F= 288 Hz), 69.4 (dd, J_C,F= 24, J_C,F

=

26.5 Hz), 43.0, 42.3 ppm. ¹⁹F NMR (D₂O, 288.3 MHz): δ = –115.8

3

2

(s, 1 H), 8.85 (d, J_H,H= 5.5 Hz, 1 H), 8.76 (d, J_H,H= 7.5 Hz, 1

3

2

(dd, J_F,H= 6.5, J_F,F= 225.5 Hz), –123.0 (d, J_F,F= 225.5 Hz)

3

H), 8.15 (t, J_H,H= 6.5 Hz, 1 H), 5.74 (dd, J_H,F= 2, J_H,F

=

ppm. IR (KBr): ν

= 3042, 1752, 1518, 1412, 1220 cm^–1. MS

˜

2

max

6.5 Hz, 1 H), 4.45 (d, J_H,H= 18.5 Hz, 1 H), 4.05 (d, J_H,H

(ESI+): m/z = 292.9 [M + Na]⁺, 270.9 [M + H]⁺, 254.0 [M + H –

18.5 Hz, 1 H) ppm. ¹³C NMR (D₂O, 75.4 MHz): δ = 170.5, 166.0

(t, ²J_C,F= 23.5 Hz), 147.4, 142.6, 141.9, 131.7, 128.0, 66.6 (dd, ²J_C,F

NH₃]⁺.

= 23.5, J_C,F= 27 Hz), 42.8 ppm. ¹⁹F NMR (D₂O, 288.3 MHz): δ

2

2-{3-[4-(Aminomethyl)phenyl]-2,2-difluoropropanamido}acetic Acid:

The hydrogenolysis deprotection step of 20c into 21c was ac-

companied by partial degradation. The corresponding hydrochlo-

ride salt was isolated from the steric exclusion chromatography as

a white lyophilizate; yield 105 mg (10 %). ¹H NMR (D₂O,

300.3 MHz): δ = 7.40–7.35 (m, 4 H), 4.14 (s, 2 H), 3.91 (s, 2 H),

3

2

= –115.2 (dd, J_F,H= 6.5, J_F,F= 226.5 Hz), –125.5 (d, J_F,F

=

226.5 Hz) ppm. IR (KBr): ν = 3412, 1802, 1736, 1637, 1400,

˜

max

1313, 1203 cm^–1. MS (ESI+): m/z = 242.9 [M + H]⁺.

rac-3-[(Carboxymethyl)amino]-2,2-difluoro-3-(pyridin-4-yl)propa-

noic Acid Hydrochloride: The hydrochloride form of the product of

nucleophilic ring-opening was obtained during the TFA deprotec-

tion step of 22e, after isolation from the steric exclusion chromatog-

3

3.43 (dt, J_H,H= 3, J_H,F= 16.5 Hz, 2 H) ppm. ¹³C NMR (D₂O,

2

75.4 MHz): δ = 172.6, 166.6 (t, J_C,F= 30 Hz), 132.6, 132.3, 131.5,

129.3, 117.4 (t, ¹J_C,F= 252 Hz), 43.0, 41.1, 40.2 (t, ²J_C,F= 24.5 Hz)

1

raphy as a pale yellow lyophilizate; yield 130 mg (44%). H NMR

ppm. ¹⁹F NMR (D₂O, 288.3 MHz): δ = –106.4 (t, J_F,F= 16.5 Hz)

2

3

(D₂O, 300.3 MHz): δ = 8.98 (s, 1 H), 8.92 (d, J_H,H= 6 Hz, 1 H),

3

ppm. IR (KBr): ν

= 3330, 2038, 1697, 1551, 1407, 1230, 902,

˜

max

8.76 (d, J_H,H= 8 Hz, 1 H), 8.18 (dd, J_H,H= 6, J_H,H= 8 Hz, 1

770 cm^–1. MS (ESI+): m/z = 294.9 [M + Na]⁺, 273.0 [M + H]⁺,

3

H), 5.36 (dd, J_H,F= 8, J_H,F= 16 Hz, 1 H), 3.84 (s, 2 H) ppm.

256.0 [M + H – NH₃]⁺.

¹³C NMR (D₂O, 75.4 MHz): δ = 169.9, 165.7 (t, J_C,F= 25 Hz),

2

1

147.8, 143.7, 142.8, 129.9, 128.5, 114.0 (t, J_C,F= 260 Hz), 60.8

rac-2-[3,3-Difluoro-2-oxo-4-(pyridin-4-yl)azetidin-1-yl]acetic Acid

Hydrochloride (21d): TFA (6 mL) was added to a solution of azeti-

din-2-one 22d (1.44 g, 4.85 mmol) in wet CH₂Cl₂(8 mL). The mix-

ture was stirred at 0 °C for 1 h. After concentration, the crude

product was purified by steric exclusion chromatography on a col-

umn of Biogel P2 (Bio-Rad) with MeCN/H₂O/HCl (1 ,

500:500:10) as the solvent. Fractions containing only product were

pooled, and the solvent was removed under vacuum. Lyophiliza-

tion yielded the trifluoroacetate salt of the title compound 21c as

(dd, J_C,F= 23.5, J_C,F= 26 Hz), 47.3 ppm. ¹⁹F NMR (D₂O,

2

3

2

288.3 MHz): δ = –108.3 (dd, J_F,H= 8.5, J_F,F= 256 Hz), –113.0

(dd, ³J_F,H= 16, ²J_F,F= 256 Hz) ppm. IR (KBr): ν_max= 3416, 1740,

˜

1637, 1406, 1297, 1196 cm^–1. MS (ESI+): m/z = 282.9 [M + Na]⁺,

260.9 [M + H]⁺. MS (ESI–): 258.7 [M – H]^–.

(Acetylsulfanyl)acetyl Chloride (23): Acetic anhydride (30 mL,

317 mmol, 1.1 equiv.) was added dropwise at 0 °C to a solution

of mercaptoacetic acid (20 mL, 287 mmol), triethylamine (80 mL,

569 mmol, 2 equiv.), and DMAP as catalyst (100 mg) in anhydrous

MeCN (200 mL). The mixture was stirred at room temp. for 18 h.

The reaction was quenched with water (20 mL). The solvent was

1

a pale yellow lyophilizate; yield 0.76 g (44%). H NMR (CD₃OD,

300.3 MHz): δ = 7.65 (d, ³J_H,H= 8 Hz, 2 H), 7.61 (d, ³J_H,H= 8 Hz,

3

2

2 H), 5.58 (dd, J_H,F= 2, J_H,F= 7 Hz, 1 H), 4.58 (d, J_H,H

=

4290

www.eurjoc.org

Eur. J. Org. Chem. 2008, 4277–4295

α,α-Difluoro-β-amino Esters and gem-Difluoro-β-lactams

3

evaporated to dryness, and the residue was taken up in CH₂Cl₂

(200 mL). The organic layer was washed with water (2ϫ100 mL),

and extracted with aqueous NaOH solution (1 , 100 mL). The

aqueous layer was washed with diethyl ether (100 mL), acidified to

pH = 1 by the addition of aqueous HCl solution (4 ), and ex-

tracted with EtOAc (3ϫ150 mL). The combined organic phases

were washed with brine (50 mL), dried with MgSO₄, filtered, and

concentrated. The residue was distilled under reduced pressure

(1 Torr), and the fraction boiling between 118 and 122 °C was col-

lected to afford pure (acetylsulfanyl)acetic acid as a pale yellow oil;

yield 25.03 g (65%). ¹H NMR (CDCl₃, 300.3 MHz): δ = 10.17 (br.

s, 1 H), 4.09 (s, 2 H), 2.38 (s, 3 H) ppm. ¹³C (CDCl₃, 75.4 MHz):

4.86 (br. s, 1 H), 4.28 (d, J_H,H= 6.5 Hz, 2 H), 4.23 (2ϫq, J_H,H

= 7 Hz, 2 H), 3.53 (m, 2 H), 2.41 (s, 3 H), 1.43 (s, 9 H), 1.25 (t,

³J_H,H= 7 Hz, 3 H) ppm. ¹³C (CDCl₃, 75.4 MHz): δ = 196.6, 167.9,

2

162.8 (t, J_C,F= 25 Hz), 155.9, 140.1, 131.5, 128.5, 127.7, 117.0 (t,

²J_C,F= 258 Hz), 79.6, 63.3, 55.0 (t, ²J_C,F= 24 Hz), 32.8, 30.2, 28.4,

13.8 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –111.8 (dd, ³J_F,H

=

2

3

2

9.5, J_F,F= 258 Hz), –115.6 (dd, J_F,H= 17, J_F,F= 258 Hz) ppm.

Methyl Ester 25cЈ: 49%. ¹H NMR (CDCl₃, 300.3 MHz): δ = 7.30–

3

7.15 (m, 5 H), 5.63 (td, J_H,F= 2.5, J_H,H= J_H,F= 9.5 Hz, 1 H),

3

4.86 (br. s, 1 H), 4.28 (d, J_H,H= 6.5 Hz, 2 H), 3.79 (s, 3 H), 3.53

(m, 2 H), 2.41 (s, 3 H), 1.43 (s, 9 H) ppm. ¹³C NMR (CDCl₃,

2

75.4 MHz): δ = 196.5, 167.8, 162.9 (t, J_C,F= 25 Hz), 155.9, 140.1,

δ = 193.9, 174.7, 31.3, 30.1 ppm. IR (KBr): ν_max= 3450, 1697 cm^–1.

2

˜

131.5, 128.5, 127.6, 117.0 (t, J_C,F= 258 Hz), 79.6, 55.0 (t, J_C,F

=

24 Hz), 53.6, 32.8, 30.2, 28.4, 13.8 ppm. ¹⁹F NMR (CDCl₃,

C₄H₆O₃S (134.15): calcd. C 35.81, H 4.51, S 23.90; found C 36.02,

H 4.99, S 23.59. Oxalyl chloride (7.5 mL, 88.4 mmol, 1.5 equiv.)

was added dropwise at 0 °C over 1 h to a solution of acid (8 g,

59.6 mmol) and DMF (0.6 mL, 7.7 mmol) in anhydrous CH₂Cl₂

(100 mL). The mixture was stirred at room temp. for 12 h, and the

solvents were evaporated to dryness. The crude oil was distilled at

7 mbar to give pure acyl chloride 23 as an orange oil; yield 6.10 g

(67%); b.p. 62 °C. ¹H NMR (CDCl₃, 300.3 MHz): δ = 4.15 (s, 2

H), 2.40 (s, 3 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ = 192.9,

169.6, 42.4, 30.4 ppm.

3

2

288.3 MHz): δ = –111.3 (dd, J_F,H= 8.5, J_F,F= 259 Hz), –115.2

(dd, J_F,H= 17, J_F,F= 259 Hz) ppm.

3

2

rac-Ethyl 3-{[(Acetylsulfanyl)acetyl]amino}-2,2-difluoro-3-(pyridin-

3-yl)propionate (25e): Racemic β-amino ester 25e was obtained

from β-amino ester 15e according to the procedure already de-

scribed for the conversion of 15b into 25b, from 15e (1 g,

3.75 mmol), DMAP (50 mg), triethylamine (1.8 mL, 12.8 mmol,

3.4 equiv.), and acyl chloride 23 (0.73 g, 4.8 mmol, 1.25 equiv.) in

anhydrous CH₂Cl₂(10 mL). The crude product was chromato-

graphed on silica gel [CH₂Cl₂/MeOH/NH₄OH (98:2:0.2 to 96:4:0.4)

as eluent] to afford 25e as a yellow solid; yield 0.90 g (69%); m.p.

117 °C; TLC: silica gel (CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1), R_f=

rac-tert-Butyl 4-[1-{[(Acetylsulfanyl)acetyl]amino}-2,2-difluoro-2-

(methoxycarbonyl)ethyl]piperidine-1-carboxylate (25b): A solution

of acyl chloride 23 (0.75 g, 4.9 mmol, 2.05 equiv.) in anhydrous

CH₂Cl₂(3 mL) was added under nitrogen to a solution of β-amino

ester 15b (0.79 g, 2.4 mmol) in anhydrous CH₂Cl₂(5 mL). N,N-

Diisopropylethylamine (0.87 mL, 5 mmol, 2.1 equiv.) was then

added dropwise to the solution at 0 °C, and the mixture was stirred

at room temp. for 12 h. The reaction was quenched by the addition

of saturated aqueous NaHCO₃solution (20 mL), and the reaction

mixture was extracted with CH₂Cl₂(2ϫ80 mL). The combined ex-

tracts were dried with anhydrous MgSO₄, and the solvent was evap-

orated to give a crude oily product. This was subjected to column

chromatography [CH₂Cl₂/EtOAc (90:10 to 75:25) as eluent] to af-

ford pure amide 25b as a yellow oil; yield 0.78 g (74%); TLC: silica

gel (CH₂Cl₂/EtOAc, 7:3), R_f= 0.78. ¹H NMR (CDCl₃,

1

3

0.43. H NMR (CDCl₃, 300.3 MHz): δ = 8.60 (d, J_H,H= 1.5 Hz,

1 H), 8.58 (d, J_H,H= 1.5 Hz, 1 H), 7.66 (d, J_H,H= 8 Hz, 1 H),

7.40 (br. d, J_H,H= 9.5 Hz, 1 H), 7.29 (dd, J_H,H= 5, J_H,H

7.5 Hz, 1 H), 5.70 (m, 1 H), 4.26 (dq, J = 1.5, J_H,H= 7 Hz, 2 H),

4

3

=

3

2

3.57 (d, J_H,H= 18 Hz, 1 H), 3.50 (d, J_H,H= 18 Hz, 1 H), 2.40 (s,

3 H), 1.27 (t, J_H,H= 7 Hz, 3 H) ppm. ¹³C NMR (CDCl₃,

3

2

75.4 MHz): δ = 196.7, 168.0, 162.2 (dd, J_C,F= 31, J_C,F

=

1

32.5 Hz), 150.3, 149.6, 135.8, 128.8, 123.5, 113.2 (t, J_C,F

2

257.5 Hz), 63.6, 53.2 (dd, J_C,F= 24, J_C,F= 27.5 Hz), 32.7, 30.2,

13.8 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –110.7 (dd, ³J_F,H

=

8.5, ²J_F,F= 261 Hz), –115.7 (dd, ³J_F,H= 18.5, ²J_F,F= 261 Hz) ppm.

rac-2,2-Difluoro-3-[(mercaptoacetyl)amino]-3-(piperidin-4-yl)-

propionic Acid (27b): TFA (10 mL) and water (1 mL) were added

to a solution of amide 25b (0.78 g, 2.4 mmol) in CH₂Cl₂(10 mL).

The mixture was stirred at 0 °C for 1 h. After concentration, the

crude product was dissolved in a mixture of MeOH/H₂O (1:3,

40 mL) and treated with aqueous NaOH solution (2 ) until pH =

9 was reached. The reaction mixture was stirred at 0 °C for 12 h.

Most of the solvents were evaporated, and the mixture was washed

with diethyl ether (30 mL) and acidified with aqueous HCl solution

(1 ) until pH = 1 was reached. The aqueous phase was washed

with diethyl ether (30 mL), and lyophilized. The crude product was

purified by steric exclusion chromatography on a column of

Biogel P2 (Bio-Rad) with MeCN/H₂O/HCl (1 , 500:500:10) as the

solvent. Fractions containing only product were pooled, and the

solvent was removed under vacuum. Lyophilization yielded the hy-

drochloride salt of the title compound 27b as a yellow lyophilizate;

yield 0.45 g (59%). ¹H NMR (D₂O, 300.3 MHz): δ = 4.46 (dt, ³J_H,F

3

300.3 MHz): δ = 6.59 (d, J_H,H= 10 Hz, 1 H), 4.55–4.40 (m, 1 H),

2

4.15–3.95 (m, 2 H), 3.77 (s, 3 H), 3.49 (d, J_H,H= 14.5 Hz, 1 H),

2

3.43 (d, J_H,H= 14.5 Hz, 1 H), 2.70–2.50 (m, 2 H), 1.95–1.80 (m,

1 H), 1.36 (s, 9 H), 1.7–1.2 (m, 4 H) ppm. ¹³C NMR (CDCl₃,

2

75.4 MHz): δ = 196.2, 168.5, 163.1 (dd, J_C,F= 31, J_C,F

=

1

2

33.5 Hz), 154.4, 114.5 (t, J_C,F= 257 Hz), 79.4, 53.9 (dd, J_C,F

2

22.5, J_C,F= 27 Hz), 53.5, 43.2, 35.3, 32.6, 30.0, 29.1, 28.2,

26.6 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –109.7 (dd, ³J_F,H

=

2

3

2

6, J_F,F= 265 Hz), –115.6 (dd, J_F,H= 18.5, J_F,F= 265 Hz) ppm.

rac-Ethyl 3-{[(Acetylsulfanyl)acetyl]amino}-3-(4-{[(tert-butoxycar-

bonyl)amino]methyl}phenyl)-2,2-difluoropropionate (25c) and rac-

Methyl 3-{[(Acetylsulfanyl)acetyl]amino}-3-(4-{[(tert-butoxycar-

bonyl)amino]methyl}phenyl)-2,2-difluoropropionate (25cЈ): Racemic

β-amino ester 25c and its methyl ester derivative 25cЈ were obtained

from β-amino ester 15c and its methyl ester derivative 15cЈ (mixture

of ethyl and methyl esters) according to the procedure already de-

scribed for the conversion of 15b into 25b, from 15c and 15cЈ

(0.91 g, 2.6 mmol), DMAP (50 mg), N,N-diisopropylethylamine

(0.5 mL, 2.9 mmol, 1.2 equiv.), and acyl chloride 23 (0.79 g,

5.1 mmol, 2 equiv.) in anhydrous CH₂Cl₂(13 mL). The crude prod-

uct was chromatographed on silica gel [CH₂Cl₂/EtOAc (95:5 to

90:10) as eluent] to afford 25c as a yellow oil; yield 0.42 g (34%).

3

= 5.5, J_H,H= J_H,F= 14.5 Hz, 1 H), 3.35–3.45 (m, 2 H), 3.26 (s,

2 H), 2.90–3.05 (m, 2 H), 2.05–2.20 (m, 1 H), 1.95–2.05 (m, 2 H),

1.45–1.65 (m, 2 H) ppm. ¹³C NMR (D₂O, 75.4 MHz): δ = 172.5,

2

1

2

166.0 (t, J_C,F= 28 Hz), 113.8 (t, J_C,F= 257 Hz), 52.3 (t, J_C,F

=

24.5 Hz), 41.5 and 41.4, 31.2, 25.0, 21.8 and 21.7 ppm. ¹⁹F NMR

(D₂O, 288.3 MHz): δ = –110.1 (dd, ³J_F,H= 14.5, ²J_F,F= 249.5 Hz),

3

2

–111.0 (dd, J_F,H= 14.5, J_F,F= 249.5 Hz) ppm. IR (KBr): ν

=

˜

max

Ethyl Ester 25c: 51%. ¹H NMR (CDCl₃, 300.3 MHz): δ = 7.30– 3390, 2496, 1756, 1666, 1545, 1422, 1202, 959, 682 cm^–1. MS

3

7.15 (m, 5 H), 5.58 (td, J_H,F= 2.5, J_H,H= J_H,F= 9.5 Hz, 1 H),

(ESI+): m/z = 304.9 [M + Na]⁺, 283.0 [M + H]⁺.

Eur. J. Org. Chem. 2008, 4277–4295

www.eurjoc.org

4291

N. Boyer, P. Gloanec, G. De Nanteuil, P. Jubault, J.-C. Quirion

FULL PAPER

3

2

rac-3-[4-(Aminomethyl)phenyl]-3-[({[({1-[4-(aminomethyl)phenyl]-2- = 11, J_H,F= 15.5 Hz, 1 H), 3.17 (d, J_H,H= 15 Hz, 1 H), 3.11 (d,

carboxy-2,2-difluoroethyl}carbamoyl)methyl]disulfanyl}acetyl)- ²J_H,H= 15 Hz, 1 H) ppm. ¹³C NMR (D₂O, 75.4 MHz): δ = 174.1,

2

amino]-2,2-difluoropropionic Acid (27c): Anhydrous HCl was

bubbled through a solution of the mixture of β-amino ester 25c

and its methyl ester derivative 25cЈ (0.42 g, 0.9 mmol) in anhydrous

MeOH for 10 min. The resulting solution was then stirred at room

temp. for 3 h and concentrated. The resulting yellow oil was dis-

solved in a mixture of MeOH/THF (1:1, 20 mL) and treated with

aqueous NaOH (2 ) solution until pH = 9 was reached. The reac-

tion mixture was stirred at room temp. for 12 h, poured into water

(30 mL), washed with diethyl ether (30 mL), and acidified with

aqueous HCl (1 ) until pH = 1 was reached. The aqueous phase

was washed with diethyl ether (30 mL), and lyophilized. The crude

product was purified by steric exclusion chromatography on a col-

umn of Biogel P2 (Bio-Rad) with MeCN/H₂O/HCl (1 ,

500:500:10) as the solvent. Fractions containing only product were

pooled, and the solvent was removed under vacuum. Lyophiliza-

tion yielded the hydrochloride salt of the title compound 27c as a

pale yellow lyophilizate; yield 0.10 g (36 %). ¹H NMR (D₂O,

300.3 MHz): δ (pair of diastereomers) = 7.45–7.35 (m, 8 H), 5.53

165.3 (dd, J_C,F= 26, J_C,F= 27 Hz), 147.0, 142.0, 141.2, 134.5,

1

2

127.9, 114.2 (dd, J_C,F= 256, J_C,F= 261 Hz), 53.4 (dd, J_C,F

=

2

25.5, J_C,F= 28 Hz), 27.2 ppm. ¹⁹F NMR (D₂O, 288.3 MHz): δ =

2

–111.4 (d, J_F,F= 256 Hz), –112.6 (d, J_F,F= 256 Hz) ppm. IR

(KBr): ν

= 3404, 2360, 1756, 1669, 1547, 1409, 1325, 1194,

˜

max

682 cm^–1. MS (ESI–): m/z = 275.0 [M – H]^–, 190.9, 117.0.

rac-Ethyl 2,2-Difluoro-3-[3-methoxy-3-oxopropanoyl)amino]-3-(pyr-

idin-4-yl)propanoate (26d): A solution of methyl malonyl chloride

(24, 0.7 mL, 6.05 mmol, 1.6 equiv.) in anhydrous CH₂Cl₂(3 mL)

was added under nitrogen to a solution of β-amino ester 15d (1 g,

3.75 mmol) in anhydrous CH₂Cl₂(12 mL). N,N-Diisopropylethyl-

amine (1.7 mL, 9.85 mmol, 2.6 equiv.) was then added dropwise to

the solution at 0 °C, and the mixture was stirred at room temp. for

12 h. The reaction was quenched by the addition of saturated aque-

ous NaHCO₃solution (20 mL), and the mixture was extracted with

CH₂Cl₂(2ϫ80 mL). The combined extracts were dried with anhy-

drous MgSO₄, and the solvent was evaporated to give a crude oily

product. This was subjected to column chromatography [CH₂Cl₂/

MeOH/NH₄OH (98:2:0.2 to 96:4:0.4) as eluent] to afford pure

amide 26d as a brown oil; yield 0.53 g (43 %); TLC: silica gel

(CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1), R_f= 0.49. ¹H NMR (CDCl₃,

3

(dd, J_H,F= 13, J_H,F= 15.5 Hz, 2 H), 4.08 (s, 2 H), 4.05 (s, 2 H),

2

3.34 (d, J_H,H= 14.5 Hz, 1 H), 3.31 (s, 2 H), 3.24 (d, J_H,H

=

14.5 Hz, 1 H) ppm. ¹³C NMR (D₂O, 75.4 MHz): δ (pair of dia-

stereomers) = 171.8, 167.4 (t, ²J_C,F= 28.5 Hz), 134.3, 133.8, 129.5,

3

300.3 MHz): δ = 8.61 (d, J_H,H= 6 Hz, 2 H), 8.54 (d, J_H,H

=

1

2

129.4, 115.2 (t, J_C,F= 257 Hz), 56.0 (t, J_C,F= 24.5 Hz), 42.9,

41.1 ppm. ¹⁹F NMR (D₂O, 288.3 MHz): δ (pair of diastereomers)

3

9.5 Hz, 1 H), 8.30 (d, J_H,H= 6 Hz, 2 H), 5.75 (dt, J_H,F= 9.5,

³J_H,F= 16 Hz, 1 H), 4.26 (q, ³J_H,H= 7 Hz, 2 H), 3.76 (s, 3 H), 3.42

3

2

3

= –111.6 (dd, J_F,H= 12.5, J_F,F= 250.5 Hz), –111.8 (dd, J_F,H

=

2

(d, J_H,H= 18.5 Hz, 1 H), 3.34 (d, J_H,H= 18.5 Hz, 1 H), 1.25 (t,

³J_H,H= 7 Hz, 3 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz): δ = 169.8,

2

3

2

13, J_F,F= 250.5 Hz), –114.3 (dd, J_F,H= 16, J_F,F= 250.5 Hz),

3

2

–114.5 (dd, J_F,H= 16, J_F,F= 250.5 Hz) ppm. IR (KBr): ν

=

˜

max

2

1

164.8, 162.2 (t, J_C,F= 31 Hz), 150.2, 141.8, 123.1, 113.1 (t, J_C,F

3500–3000, 1753, 1656, 1543, 1420, 1190, 971, 685 cm^–1. MS

(ESI+): m/z = 628.9 [M + Na]⁺, 607.0 [M + H]⁺, 589.8 [M + H –

NH₃]⁺.

2

= 258 Hz), 63.6, 54.2 (dd, J_C,F= 24.5, J_C.F= 26 Hz), 52.7, 40.0,

13.7 ppm. ¹⁹F NMR (CDCl₃, 288.3 MHz): δ = –110.7 (dd, ³J_F,H

=

2

3

2

8.5, J_F,F= 262 Hz), –114.5 (dd, J_F,H= 16, J_F,F= 262 Hz) ppm.

rac-3-Amino-3-[4-(aminomethyl)phenyl]-2,2-difluoropropanoic Acid

Hydrochloride: The hydrochloride form of the product of amide

bond cleavage was obtained during the NaOH deprotection step of

25c, after isolation by steric exclusion chromatography, as a white

rac-Ethyl 2,2-Difluoro-3-[3-methoxy-3-oxopropanoyl)amino]-3-(pyr-

idin-3-yl)propanoate (26e): Racemic β-amino ester 26e was obtained

from β-amino ester 15e according to the procedure already de-

scribed for the conversion of 15d into 26d, with β-amino ester 15e

(1.04 g, 3.9 mmol), methyl malonyl chloride (24, 0.7 mL,

6.05 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (1.7 mL,

9.85 mmol, 2.5 equiv.) in anhydrous CH₂Cl₂(10 mL). Chromatog-

raphy [CH₂Cl₂/MeOH/NH₄OH (99:1:0.1 to 96:4:0.4) as eluent]

gave pure amide 26e as a yellow oil; yield 0.72 g (56%). TLC: silica

1

lyophilizate; yield 50 mg (20%). H NMR (D₂O, 300.3 MHz): δ =

3

7.51 (s, 4 H), 5.05 (dd, J_H,F= 6, J_H,F= 9 Hz, 1 H), 4.19 (s, 2 H)

ppm. ¹H NMR ([D₆]DMSO, 300.3 MHz): δ = 9.43 (br. s, 1 H),

3

8.70 (br. s, 3 H), 7.57 (s, 4 H), 5.09 (dd, J_H,F= 10, J_H,F= 16 Hz,

1 H), 4.01 (s, 2 H) ppm. ¹³C NMR (D₂O, 75.4 MHz): δ = 166.5 (t,

²J_C,F= 26 Hz), 135.2, 130.0, 129.8, 129.4, 114.6 (dd, J_C,F= 257.5,

1

¹J_C,F= 261 Hz), 57.0 (dd, J_C,F= 22.5, J_C,F= 26 Hz), 42.9 ppm.

2

gel (CH₂Cl₂/MeOH/NH₄OH, 9:1:0.1), R_f= 0.5. H NMR (CDCl₃,

300.3 MHz): δ = 8.63 (d, ⁴J_H,H= 2 Hz, 1 H), 8.55 (dd, ⁴J_H,H= 1.5,

¹⁹F NMR (D₂O, 288.3 MHz): δ = –107.8 (dd, J_F,H= 5.5, J_F,F

=

3

2

3

³J_H,H= 5 Hz, 1 H), 8.50 (br. d, J_H,H= 10 Hz, 1 H), 7.72 (d, J_H,H

3

2

245 Hz), –117.4 (dd, J_F,H= 18.5, J_F,F= 245 Hz) ppm. IR (KBr):

3

= 3020, 2044, 1682, 1592, 1410, 1217, 817 cm^–1. MS (ESI+):

= 8 Hz, 1 H), 7.31 (dd, J_H,H= 5, J_H,H= 7.5 Hz, 1 H), 5.79 (dt,

ν

˜

max

³J_H,F= 10, J_H,F= 16 Hz, 1 H), 4.26 (q, J_H,H= 7 Hz, 2 H), 3.76

3

m/z = 253.0 [M + Na]⁺, 231.0 [M + H]⁺, 214.0 [M + H – NH₃]⁺.

2

(s, 3 H), 3.40 (d, J_H,H= 18 Hz, 1 H), 3.33 (d, J_H,H= 18 Hz, 1

rac-2,2-Difluoro-3-[(mercaptoacetyl)amino]-3-(pyridin-3-yl)propionic

Acid (27e): A solution of amide 25e (0.9 g, 2.6 mmol) in a mixture

of MeOH/THF/H₂O (1:1:1, 18 mL) was treated with an aqueous

LiOH solution (1 , 7 mL). The reaction mixture was stirred at

0 °C for 12 h. Most of the solvents were evaporated, and the mix-

ture was washed with diethyl ether (30 mL) and acidified with

aqueous HCl solution (1 ) until pH = 1 was reached. The aqueous

phase was washed with diethyl ether (30 mL) and lyophilized. The

crude product was purified by steric exclusion chromatography on

H), 1.26 (t, ³J_H,H= 7 Hz, 3 H) ppm. ¹³C NMR (CDCl₃, 75.4 MHz):

2

δ = 169.9, 164.6, 162.3 (dd, J_C,F= 31, J_C,F= 32.5 Hz), 150.3,

149.7, 135.8, 129.0, 123.6, 113.3 (t, ¹J_C,F= 257 Hz), 63.6, 53.1 (dd,

²J_C,F= 25, ²J_C,F= 27 Hz), 52.7, 40.0, 13.8 ppm. ¹⁹F NMR (CDCl₃,

3

2

288.3 MHz): δ = –110.7 (dd, J_F,H= 8.5, J_F,F= 262 Hz), –114.5

(dd, ³J_F,H= 16, ²J_F,F= 262 Hz) ppm. IR (KBr): ν_max= 3293, 1770,

˜

1748, 1671, 1550, 1330, 1292, 1203, 1133, 1073, 713 cm^–1.

rac-3-[(Carboxyacetyl)amino]-2,2-difluoro-3-(pyridin-4-yl)propanoic

a column of Biogel P2 (Bio-Rad) with MeCN/H₂O/HCl (1 , Acid (28d): A solution of amide 26d (0.54 g, 1.6 mmol) in a mixture

200:200:4) as the solvent. Fractions containing only product were

pooled, and the solvent was removed under vacuum. Lyophiliza-

tion yielded the hydrochloride salt of the title compound 27e as a

of MeOH/H₂O (1:1, 10 mL) was treated with aqueous NaOH solu-

tion (1 , 1.65 mL, 1 equiv.). The reaction mixture was stirred at

room temp. for 2 h. Most of the solvent was evaporated, and the

white lyophilizate; yield 0.16 g (20%). ¹H NMR (D₂O, 300.3 MHz): mixture was washed with diethyl ether (2ϫ30 mL) and acidified

3

δ = 8.82 (s, 1 H), 8.65 (d, J_H,H= 6 Hz, 1 H), 8.52 (d, J_H,H

=

with aqueous HCl solution (1 ) until pH = 1 was reached. The

aqueous phase was washed with diethyl ether (30 mL) and

8 Hz, 1 H), 7.95 (dd, ³J_H,H= 6, ³J_H,H= 8 Hz, 1 H), 5.70 (dd, ³J_H,F

4292

www.eurjoc.org

Eur. J. Org. Chem. 2008, 4277–4295

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kina, S. V. Galushko, A. E. Sorochinsky, V. P. Kukhar, M. V.

lyophilized. The crude product was purified by steric exclusion

chromatography on a column of Biogel P2 (Bio-Rad) with MeCN/

H₂O/HCl (1 , 200:200:4) as the solvent. Fractions containing only

product were pooled, and the solvent was removed under vacuum.

Lyophilization yielded the hydrochloride salt of the title compound

28d as a yellow lyophilizate; yield 93 mg (20%). ¹H NMR (D₂O,

3

300.3 MHz): δ = 8.78 (d, J_H,H= 6.5 Hz, 2 H), 8.10 (d, J_H,H

=

6.5 Hz, 2 H), 5.80 (t, ³J_H,F= 13 Hz, 1 H), 3.56 (d, ²J_H,H= 16.5 Hz,

2

1 H), 3.47 (d, J_H,H= 16.5 Hz, 1 H) ppm. ¹³C NMR (D₂O,

2

75.4 MHz): δ = 169.0, 166.3, 163.4 (t, J_C,F= 31 Hz), 154.9, 141.7,

1

2

127.1, 113.7 (t, J_C,F= 255.5 Hz), 56.0 (dd, J_C,F= 24, J_C,F

=

27.5 Hz), 42.0 ppm. ¹⁹F NMR (D₂O, 288.3 MHz): δ = –110.9 (dd,

³J_F,H= 13, J_F,F= 256 Hz), –111.8 (dd, ²J_F,F= 13, J_F,F= 256 Hz)

2

[6]

ppm. IR (KBr): ν

= 3404, 2360, 1756, 1669, 1547, 1409, 1325,

˜

max

1194, 682 cm^–1. MS (ESI+): m/z = 288.9 [M + H]⁺.

rac-3-[(Carboxyacetyl)amino]-2,2-difluoro-3-(pyridin-3-yl)propanoic

Acid (28e): Racemic β-amino acid 28e was obtained from β-amino

ester 26e according to the procedure already described for the con-

version of 26d into 28d, from β-amino ester 26e (0.65 g, 1.95 mmol)

and an aqueous LiOH solution (1 , 6 mL, 6 mmol, 3 equiv.) in a

mixture of MeOH/THF/H₂O (1:1:1, 18 mL). The crude product

was purified by steric exclusion chromatography on a column of

Biogel P2 (Bio-Rad) with MeCN/H₂O/HCl (1 , 200:200:4) as the

solvent. Fractions containing only product were pooled, and the

solvent was removed under vacuum. Lyophilization yielded the hy-

drochloride salt of the title compound 28e as a white lyophilizate;

yield 112 mg (20%). ¹H NMR (D₂O, 300.3 MHz): δ = 8.82 (s, 1

[7]

[8]

[9]

3

H), 8.75 (d, ³J_H,H= 6 Hz, 1 H), 8.62 (d, J_H,H= 8.5 Hz, 1 H), 8.06

[10]

3

(dd, J_H,H= 6, J_H,H= 8.5 Hz, 1 H), 5.79 (t, J_H,F= 13 Hz, 1 H),

3.50 (d, ²J_H,H= 16.5 Hz, 1 H), 3.41 (d, ²J_H,H= 16.5 Hz, 1 H) ppm.

¹H NMR ([D₆]DMSO, 300.3 MHz): δ = 9.39 (d, J_H,H= 9.5 Hz, 1

3

[11]

[12]

3

H), 8.86 (s, 1 H), 8.76 (d, J_H,H= 5 Hz, 1 H), 8.26 (d, J_H,H

=

8 Hz, 1 H), 7.78 (dd, ³J_H,H= 5, ³J_H,H= 8 Hz, 1 H), 5.84 (dt, J_H,H

3

2

= J_H,F= 10, J_H,F= 18 Hz, 1 H), 3.32 (d, J_H,H= 15.5 Hz, 1 H),

3.25 (d, J_H,H= 15.5 Hz, 1 H) ppm. ¹³C ([D₆]DMSO, 75.4 MHz):

2

δ = 169.0, 166.3, 163.4 (t, ²J_C,F= 31 Hz), 145.1, 144.5, 142.8, 132.9,

[13]

1

2

126.2, 113.7 (t, J_C,F= 255.5 Hz), 52.0 (dd, J_C,F= 24, J_C,F

=

27.5 Hz), 42.6 ppm. ¹⁹F NMR ([D₆]DMSO, 288.3 MHz): δ =

3

2

–109.8 (dd, J_F,H= 9.5, J_F,F= 254.5 Hz), –114.6 (dd, J_F,F= 19,

²J_F,F= 254.5 Hz) ppm. MS (ESI+): m/z = 310.9 [M + Na]⁺, 288.9

[M + H]⁺. C₁₁H₁₀F₂N₂O₅·HCl (324.67): C 40.69, H 3.42, N 8.63;

found C 40.64, H 3.37, N 8.66.

Acknowledgments

We gratefully acknowledge financial support (grant to N. B.) from

the Institut de Recherches SERVIER. We also warmly thank

Louise Chervel, Maryse Thiverny, Laëtitia Bailly and Elisabeth

Roger for their initial contribution to this work.

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Received: April 9, 2008

Published Online: July 10, 2008

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4295

Article Doi

Synthesis of α,α-difluoro-β-amino esters or gem-difluoro-β-lactams as potential metallocarboxypeptidase inhibitors

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