Synthesis of substituted 3-arylpiperidines and 3-arylpyrrolidines by radical 1,4 and 1,2-aryl migrations

Tetrahedron 63 (2007) 7187–7212

Synthesis of substituted 3-arylpiperidines and 3-arylpyrrolidines

by radical 1,4 and 1,2-aryl migrations

*

ꢀ

Alexandru Gheorghe, Beatrice Quiclet-Sire, Xavier Vila and Samir Z. Zard

´

Laboratoire de Syntheꢁse Organique associe au C. N. R. S., Departement de Chimie, Ecole Polytechnique, F-91128 Palaiseau, France

´

Received 26 February 2007; revised 25 April 2007; accepted 26 April 2007

Available online 3 May 2007

This paper is dedicated with respect to the memory of our friend, Dr Jean-Pierre Finet

Abstract—A route to 3-arylpiperidines and 3-arylpyrrolidines involving radical 1,4- and 1,2-aryl migrations has been explored. For the piper-

idines, the ﬁrst route requires a xanthate addition to an N-allylarylsulfonamide, followed by acetylation and treatment with lauroyl peroxide to

give the corresponding 1,4-aryl transfer product. This compound can be converted into the desired piperidine derivative following acidic

hydrolysis. For the second approach to piperidines, addition of an a-keto xanthate to oleﬁns of type 14 causes 1,2-aryl migration leading to

an a,b-unsaturated ester, which can be converted into a piperidine by the action of ammonia or a primary amine and sodium cyanoborohydride.

Substituted 3-arylpyrrolidines can be obtained by simply starting with an a-amido substituted xanthate.

1. Introduction

corticotropin-releasing factor (a peptide playing an impor-

tant role in response to stress),³inhibitors of steroid 5a-re-

ductase (potential therapeutic agents for the treatment of

benign prostatic hyperplasia and some prostatic cancers),⁴

or ligands for the s-1 receptor, which modulates the synthesis

and release of certain neurotransmitters, displays opioid an-

algesia, and is related to neuroprotective and anti-amnesic

activity.⁵

Aryl-substituted heterocycles, particularly arylpiperidines

and arylpyrrolidines, have attracted the attention of medici-

nal chemists since the early 1980s because of their varied

pharmacological activities, especially those related to the

central nervous system. In the case of 3-arylpiperidines,

a wide range of biological properties have been uncovered,

perhaps the most important targeting is the dopaminergic

neurotransmission. The main drug affecting this system is

preclamol (Fig. 1), a selective D2 autoreceptor agonist, of

which many analogues have been prepared in the search of

new drug candidates against diseases such as psychosis,

Parkinson’s disease, drug addiction or depression.¹Some

members of this family are antagonists of neurokinin recep-

tors (responsible for neurological inﬂammation, pain trans-

mission and broncho constriction),²antagonists of the

Substituted arylpyrrolidines are also important structures.

They are sometimes part of the framework of diverse alka-

loid families, or subunits in compounds with interesting an-

tidepressant, antinociceptive and anticonvulsant activities.⁶

Epibatidine (Fig. 1), a bicyclic 3-arylpyrrolidine alkaloid

isolated from the skin of a poison frog, has proved to be

a powerful non-opioid analgesic, with 200–500 times the po-

tency of morphine, and one of the most powerful nicotinic

agonists ever found.⁷

Despite their interesting and promising properties, only a few

synthetic routes to 3-arylpiperidines have been described so

far. The majority relies on pyridine-aryl cross-couplings

mediated by transition metals,⁸and especially the Suzuki re-

action,⁹or Heck cross-couplings with cyclic oleﬁns, e.g., tet-

rahydropyridines,¹⁰as shown in Scheme 1. The substituted

pyridine or tetrahydropyridine thus formed is then reduced

to the corresponding piperidine. These methods are limited

to molecules possessing functional groups compatible with

Grignard reagents or palladium catalysts and reductive con-

ditions, and are often constrained by a lack of starting mate-

rials with suitably diverse substituents.¹¹

Cl

N

OH

N

Epibatidine

Preclamol

H

Figure 1.

* Corresponding author. Tel.: +33 169334872; fax: +33 169333851; e-mail:

zard@poly.polytechnique.fr

doi:10.1016/j.tet.2007.04.091

7188

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

indeed took place, but the yield of the adducts was rather

Br

modest. Later, we found that the radical addition onto non-

acetylated arylsulfonamides 1 resulted in much higher yields

of the corresponding adducts 6, in the 70–90% range in most

of the cases (Scheme 4). A polarity mismatch between the

radical derived from the xanthate and oleﬁns 2a,b could be

the cause for the somewhat sluggish reaction and modest

yields.

N

H

Heck coupling

B(OH)₂

MgBr

Br

N

O

S

O

S

O

Nickel complex

induced coupling

AcCl

DMAP

DLP, DCE, rt

Suzuki coupling

N

H

N

R

SCSOEt

Ac

Scheme 1.

X

3

X

2a, X = 4-Me, 60%

2b, X = 4-OMe, 84%

1a, X = 4-CH₃

1b, X = 4-OCH₃

2. Results and discussion

3a, R = COCH₃

3b, R = COPh

3c, R = CO₂Me

3d, R = CN

O

S

O

In continuation of a previous work involving a radical syn-

thesis of 2-aryl¹²and 4-arylpiperidines,¹³we describe

a new, straightforward synthesis of 6-substituted 3-arylpi-

peridines and their corresponding pyridines and piperidones

obtained via a key step involving a radical 1,4-aryl transfer,

as well as the synthesis of 2,6-disubstituted 3-arylpiperidines

and 2,5-disubstituted 3-arylpyrrolidines via a radical se-

quence involving a neophyl rearrangement. The preliminary

results of this study were recently disclosed in a communica-

tion.¹⁴We now give a full account of our work, aiming at ex-

ploring the scope of this new method, and its extension to the

synthesis of ﬂuorinated arylpiperidines and pyrrolidines.

R

N

SCSOEt

Ac

X

4a, X = 4-Me, R = COCH₃, 34%

4b, X = 4-Me, R = COPh, 42%

4c, X = 4-Me, R = CO₂Me, 28%

4d, X = 4-OMe, R = CN, 58%

Scheme 3.

From that point onwards, as shown in Scheme 4, the radical

addition was carried out using non-acetylated oleﬁns, and

acetylation of the nitrogen was performed on the adducts

in the next step using acetyl chloride or acetic anhydride.

The acetylation is needed to allow the ultimate formation

of a reactive amidyl radical capable of abstracting a hydrogen

from the solvent (see Scheme 5). In the absence of an acetyl

or equivalent group, an unreactive aminyl radical would be

formed causing the sequence to fail.

The envisaged retrosynthetic pathway is depicted in

Scheme 2 and is based on the rich radical chemistry of xan-

thates.¹⁵As outlined in Scheme 2, the desired piperidines I

would be constructed by reduction of imines II, which in turn

would be prepared by acid-mediated internal condensation

of amidoketones III. The latter would be derived by a radical

1,4-aryl transfer of sulfonamides IV, obtained by a radical

addition of xanthates VI onto conveniently substituted

N-allylsulfonamides V.

The radical addition was successful with a broad variety of

xanthates, including alkyl, aryl, esters, heterocyclic xan-

thates, as summarised in Scheme 4. The acetylated sulfon-

amides

4 were converted into b-arylacetamides 5,

X

precursors of the desired 3-arylpiperidines, by a radical

1,4-aryl transfer promoted by lauroyl peroxide.

O

R

Since the discovery of the aryl migration almost a century

ago,¹⁶many examples have appeared in the literature. The

most extensively investigated is the 1,2-aryl migration (neo-

phyl rearrangement),¹⁷but 1,4- and 1,5-aryl migrations have

also been observed and studied.¹⁸Aryl migrations can take

place between two carbon atoms, but also between a carbon

and a heteroatom, or between two heteroatoms. In our case,

the aryl transfer would be between the sulfur of the sulfon-

amide and a carbon. In this type of rearrangement, ﬁrst de-

scribed by Speckamp in 1972,¹⁹it is possible to transfer

both electron-rich and electron-poor arenes. In the examples

reported, the yields are sometimes low because of premature

reduction prior to migration and/or competing ortho-cyclisa-

tion to the aromatic ring.²⁰

HN

Ac

N

H

R

N

III

I

II

O

SCSOEt

S

O

R

N

H

V

HN

S

X

O

X

+

O

VI

SCSOEt

IV

R

Scheme 2.

Oleﬁns 1 were easily made in good yield using the Schotten–

Baumann procedure from substituted arenesulfonyl chlo-

rides and allylamine (Scheme 3). They were further

acetylated on the nitrogen using acetyl chloride into N-acetyl

sulfonamides 2, which were then subjected to the radical

addition of xanthates 3a–d. The expected xanthate transfer

The proposed mechanism for our sequence is displayed in

Scheme 5. Treatment of sulfonamide 4 with lauroyl peroxide

(DLP) generates radical I, which adds to the aryl ring in a

5-exo fashion leading to radical II. Fragmentation of the latter

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7189

O

S

O

S

O

S

O

R

DLP, DCE, rt

3

AcCl or Ac₂O

N

H

SCSOEt

Ac

H

X

6

4

1c, X = 4-F

O

S

O

1d, X = 4-Cl

1e, X = 2-Cl

1f, X = 4-Br

1g, X = 4-I

O

Ph

O

S

O

EtO₂C

N

R

R'

N

H

Ph

SCSOEt

N

Me

SCSOEt

O

S

O

Me

1h, X = 4-CF₃

1i, X = 4-CN

1j, X = 4-t-Bu

1k, X = 4-OCF₃

6c, R' = OMe, R = H 85%

4c, R' = OMe, R = Ac 97%

6f, R' = CH₂Ph, R = H 70%

4f, R' = CH₂Ph, R = Ac 94%

6h, R' = OMe, R = H 93%

4h, R' = OMe, R = Ac 77%

N

6e 97%

SCSOEt

O

S

O

OAc

EtO₂C

Me

R

N

Ph

6g, R = H 83%

4g, R = Ac 49%

SCSOEt

O

Ac

SCSOEt

R

4e 72%

R'

O

S

O

S

N

O

S

OEt

SCSOEt

OPh

N

3e, R = Ph, R' = CO₂Et

3f, R = CH₂Ph, R' = H

3h, R = Cyclopropyl, R' = H

3j, R = CO₂Et, R' = H

3k, R = CO₂Ph, R' = H

3l, R = CH₂CO₂Et, R' = H

3n, R = 1-piperidyl, R' = H

3p, R = 2-thienyl, R' = H

3q, R = CO₂t-Bu, R' = H

3r, R = Cyclohexyl, R' = H

N

O

R

SCSOEt

MeO

Cl

R

F

CF₃O

R

6j, R = H 93%

4j, R = Ac 87%

6k, R = H 42%

6i, R = H 94%

4i, R = Ac 98%

4k, R = Ac 84%

EtO₂C

O

S

N

O

R

O

S

O

N

S

O

N

SCSOEt

Cl

R

Br

R

6l, R = H 76%

4l, R = Ac 75%

6m, R = H 92%

4m, R = Ac 89%

6n, R = H 66%

O

S

O

MeO₂C OMe

OMe

SCSOEt

4n, R = Ac 91%

N

H

O

I

S

O

S

O

Ot-Bu

O

6o, R = H 95%

4o, R = Ac 91%

S

N

O

R

S

N

O

R

N

SCSOEt

CF₃

NC

R

t-Bu

6p, R = H 49%

4p, R = Ac 86%

6q, R = H 81%

4q, R = Ac 93%

6r, R = H 80%

4r, R = Ac 93%

Scheme 4.

furnishes sulfonyl radical III and regenerates the aromaticity

of the aryl ring. Even though isopropanol is capable of hydro-

gen atom transfer to radical I, thus prematurely reducing it

and stopping the desired transformation, this process is rela-

tively slow and does not compete efﬁciently with the ipso

substitution. From radical III, two different paths can lead

to the ﬁnal product 5. In path A, extrusion of sulfur dioxide

gives a highly reactive electrophilic amidyl radical IV, which

is rapidly reduced by the isopropanol. Hence the need for the

acetylation step: in the absence of the acetyl group, the se-

quence would have furnished a much less reactive aminyl

radical. The ketyl radical, arising from the isopropanol, is

oxidised into acetone by the peroxide, which must therefore

be used in stoichiometric amounts. In path B, hydrogen ab-

straction takes place at the level of radical III. Such amido-

sulfonyl radicals are electrophilic and loss of sulfur dioxide

may be too slow to compete with the hydrogen abstraction.²¹

Either or both pathways may be operating but this has no con-

sequence as far as the preparative aspects are concerned.

a solution of xanthate 4a (Table 1, entry 1) in toluene was

added 15% DLP every 90 min, until disappearance of the

starting material. The transfer product 5a was obtained in

a 22% yield, much lower than the yield (66%) observed

when the reaction was carried out in i-PrOH. Another assay

using isopropyl acetate as a solvent instead of isopropanol in

the case of compound 4c again showed the superiority of the

latter (38% vs 71% yield, respectively; entries 3 and 4).

For some derivatives, the same conditions using isopropanol

were not so effective. For instance, compound 4m, submit-

ted to the same reaction conditions, produced rearranged

amide in only 25% yield (entry 5). By diluting the reaction

medium 10-fold and increasing the amount of DLP to ensure

complete consumption of the starting material, the yield of

amide 5m could be increased to 50% yield (entry 6).

Similarly, applying the standard transfer conditions to com-

pound 4j resulted in a 34% yield of migration product 5j (en-

try 7). Using a greater excess of DLP improved the yield to

45% (entry 8). Other solvents (entries 9–12) such as cyclo-

hexane, sec-butanol or isopropyl ether were either less effec-

tive or failed completely. The best results were obtained

We ﬁrst tried to establish the best conditions to carry out the

radical transfer, and also to ascertain that isopropanol was

indeed the best hydrogen atom donating solvent. Thus to

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A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

O

side reaction is a 5-exo-ring closure onto the double bond by

the intermediate amidyl radical leading to an unreactive ter-

tiary benzylic radical.

O

S

O

R

O

S

O

DLP

R

N

Ac

R

Ac SCSOEt

Ac

O

I

CN

Ac

OAc

Ph

X

N

H

X

Ac

4

N

H

R

O

N

H

Ac

O

Ac

N

S

CO₂Et

S

O

OMe

O

X

Me

O

5e 29%

5d 77%

Me

III

II

X

O

Path A

5a, R = CH₃66%

5b, R = Ph 53%

5c, R = OMe 71%

O

R

O

Ac

OH

Ac

-SO₂

N

H

N

O

Path B

5f, R = CH₂Ph 60%

5h, R = Cyclopropyl 54%

OH

O

5i 60%

IV

X

N

O

S

CF₃O

N

Ac

N

OH

N

R

O

HO

Ph

Ac

H

N

H

OEt

V

O

OH

-SO₂

5g 64%

Ac

X

N

H

R

Me

O

5j 69%

O

Ac

OMe

5

N

X

O

CO₂Et

H

PhO

Scheme 5.

Ac

N

H

N

H

Cl

5l 60%

Cl

using a 1:1 mixture of 1,2-dichloroethane and isopropanol

and a higher dilution (entries 13 and 14). These last condi-

tions were used in cases were isopropanol alone was not

sufﬁciently effective.

5m 72%

5k 47%

F

OMe

O

N

Ac

N

H

OMe

CO₂Me

N

H

The best results for the radical aryl migration are summar-

ised in Scheme 6. As shown, the nature of substituent X

on the aromatic ring does not seem to affect greatly the

course of the reaction. The yields were similar for both series

of electron donating and electron withdrawing substituents.

As for the R motif on the xanthate, many groups appear to be

tolerated: ketones, esters, lactones, nitriles or amides. In the

case of compounds 5b (R]PhCO–) and 5p (R]2-thiophe-

nylCO–) the yields (53% and 33%, respectively) were low-

ered by the competing ortho-cyclisation onto the aromatic

ring to form a tetralone. In compound 5e, the presence of

a double bond appears to be a source of complications and

the yield was consequently rather poor (29%). One possible

O

5o 60%

5n 70%

I

t-BuO

Br

Ac

N

H

O

Ac

S

N

H

N

H

O

CN

5q 81%

CF₃

t-Bu

5p 33%

5r 70%

Scheme 6.

Table 1. Conditions used to optimise the aryl transfer

Entry

Substrate 4

Solvent

Concentration (M)

DLP (equiv)

Product (yield)

1

2

3

4

5

6

7

8

4a

4c

4m

4j

Toluene

i-PrOH

Isopropyl acetate

i-PrOH

Cyclohexane

i-PrOH/cyclohexane 1:1

s-BuOH

0.25

0.025

0.25

0.03

0.02

1.00

1.50

1.05

1.35

1.20

2.20

1.20

2.70

0.70

1.25

1.50

2.00

5a (22%)

5a (66%)

5c (38%)

5c (71%)

5m (25%), 4m (30%)

5m (50%)

5j (34%)

5j (45%)

9

5j (27%), 4j (22%)

5j (32%), 4j (20%)

5j (0%)

5j (43%), 4j (34%)

5j (60%)

10

11

12

13

14

4j

i-Pr₂O

i-PrOH/DCE 1:1

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7191

Table 2. Inﬂuence of the protecting group (PG)

O

X

AcHN

R

6

PG

4

Transfer product (yield)

6c

6j

Ac

4c

5c (71%)

Conc. HCl

reflux

CO₂Me

t-Boc

COCF₃

4c2

4c3

4j2

5c2 (34%), reduced 4c2 (36%)

5c3 (37%), reduced 4c3 (43%)

5j2 (40%), 6j (15%), reduced 6j (11%)

O

N

H

X

9c, X = Me, 88%

9n, X = Br, 37%

5c, X = Me, R = OMe

5n, X = Br, R = piperidyl

We also examined the aryl migration in the case of sulfon-

amides 4 with other acyl groups besides acetyl, but the

results were less satisfactory. For reasons that are not yet

clear, the acetyl initially chosen proved to be the best group.

With carbamoyl groups, such as tert-butoxycarbonyl and

methoxycarbonyl, or triﬂuoroacetyl, signiﬁcant amounts of

reduced starting material were observed (Table 2).

O

Me

1) Conc. HCl,

dioxane, reflux

2) 10% Pd -C,

xylene, reflux

AcHN

Ph

N

Me

5b

10, 83% (2 steps)

OMe

I

AcHN

OMe

CO₂Me

Once the transfer products were in hand, hydrolysis of the

acetamide was carried out under acidic conditions. This in-

duced concomitant cyclisation to the imine or to the lactam,

depending on whether a ketone or an ester was present. Thus,

as shown in Scheme 7, treatment of amides 5 with concen-

trated HCl in dioxane at reﬂux temperature afforded the in-

termediate imines 7, which were generally not puriﬁed but

reduced with NaBH₃CN to afford the desired amines in

good yield and as single diastereoisomers. In the case of

amide 5q, the acid treatment also resulted in the hydrolysis

of the nitrile group to the corresponding carboxylic acid.

The last reduction step was therefore performed with

LiAlH₄, in order to reduce the carboxylic acid to the alcohol

and make the puriﬁcation easier.

MeO₂C

p-TsOH

DCM, rt

N

Ac

I

5o

11, 89%

Scheme 8.

We were also interested in applying the same approach to

access ﬂuorinated piperidines, as the introduction of ﬂuori-

nated groups in organic compounds is well known to modify

signiﬁcantly the chemical, physical and, most importantly,

the biological properties, largely as a result of the strong

electronegativity of the ﬂuorine atom and the enhanced

lipophilic character of ﬂuorine containing derivatives.²²

The introduction of ﬂuorinated motifs into heterocyclic

structures is seldom straightforward and relies generally

on two strategies, namely the direct ﬂuorination of an exist-

ing heterocyclic ring²³or the construction of the hetero-

cyclic ring using ﬂuorinated synthons.^24,25

NHAc

O

X

R

Conc. HCl

dioxane, reflux

5

R

N

7

X

5b, X = 4-Me, R = Ph

5f, X = 4-Me, R = Bn

Reduction

Syntheses of triﬂuoromethyl piperidines, for instance, are

scarce in the literature due to the difﬁculty of introducing

the triﬂuoromethyl group.²⁶By using xanthate 3s, derived

from commercially available 3-bromo-1,1,1-triﬂuoroace-

tone, it should be possible to introduce a triﬂuoromethyl

group into the ﬁnal piperidine structure as indicated in

Scheme 9. Radical addition of xanthate 3s to sulfonamide

1d afforded indeed the corresponding adduct 6s in good

yield. However, attempts to protect the sulfonamide failed,

due to the competing enol acetate formation. Even lowering

the amount of acetyl chloride to 1 equiv resulted in mixtures

of mono- and diacetylated products along with starting ma-

terial. Having encountered the previous example (Scheme 6,

compound 5e) where the radical transfer of a diacetylated

product proceeded in low yield, we considered protecting

the carbonyl group prior to acetylation of the sulfonamide

nitrogen. Initial attempts to form the acetal failed, so the car-

bonyl was eventually protected as O-methyloxime 6t. Acet-

ylation of this compound was accomplished in good yield,

but then the radical transfer proceeded in only a moderate

yield of 42%. Finally, cyclisation under strong acidic condi-

tions followed by imine reduction yielded the desired 2-tri-

ﬂuoromethyl-5-arylpiperidine in good yield.

5p, X = 4-CF₃, R = 2-thiophenyl

5q, X = 4-CN, R = t-Bu

X

5r, X = 4-t-Bu, R = cyclohexyl

8b, X = 4-Me, R = Ph, 89%

R

N

H

8f, X = 4-Me, R = Bn, 85%

8p, X = 4-CF₃, R = 2-thiophenyl, 64%

8q, X = 4-CH₂OH, R = t-Bu, 66%

8r, X = 4-t-Bu, R = cyclohexyl, 77%

8

Scheme 7.

Depending on the nature of the R substituent, it is possible to

obtain other piperidine derivatives. As depicted in Scheme 8,

acid hydrolysis of amide-ester 5c yielded lactam 9 in good

yield and cyclisation of double amide 5n afforded piperi-

done 9n in moderate yield. Pyridines can also be obtained

if, in the last step, the imine is subjected to oxidising condi-

tions. In that case, amide 5b was cleaved by acid hydrolysis,

and the intermediate imine 7b was heated with palladium in

xylene at reﬂux under air to furnish pyridine 10 in good

yield. Acid hydrolysis of dimethyl acetal 5o and acid-

mediated cyclisation yielded N-acyl piperidine 11, which

possesses a different substitution pattern and can be viewed

as a nicotinic acid derivative. The presence of the double

bond and the iodine atom allows numerous further transfor-

mations.

Our methodology could in principle be adapted to the syn-

thesis of preclamol (Fig. 1), starting from the appropriate

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A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

O

S

O

S

O

S

O

CO₂Et

1d

3j

N

H

N

H

N

H

CF₃

SCSOEt

O

F₃C

DLP, DCE

SCSOEt

DLP, DCE

reflux

SCSOEt

Cl

3s

OCH₃

6u, 80%

1l

6s 78%

O

S

O

NH₂OCH₃·HCl,

pyridine, EtOH

CO₂Et

SCSOEt

N

CH₃CH₂COCl

DMAP

AcCl, DMAP

DCM

4u, 94%

N-OMe

OCH₃

O

S

O

F₃C

OAc

DCE:iPrOH

reflux

DLP

S

N

CF₃

O

SCSOEt

H

SCSOEt

Ac

Cl

CO₂Et

Cl

OH

N

H

6t 74%

4s 49%

N

preclamol

5u, 38%

DLP

AcCl, DMAP

DCM

H₃CO

O

DCE: i-PrOH

MeO

S

N

OAc

CF₃

N-OMe

CF₃

O

S

Ac

EtO₂C

12, 8%

N

H

N

O

Ac

SCSOEt

Scheme 10.

Cl

4t 94%

5s 19%

Cl

S

DLP

DCE:i-PrOH

RS

OEt

DLP

R

N-OMe

CF₃

R

II

Cl

Ac

N

SO₂Me

HCl/H₂O

dioxane

MeO₂S

H

I

F₃C

N

R

– SO₂

5t 42%

Cl

7t 45%

Me

MeSO₂

+

Cl

NaBH₃CN, MeOH

IV

III

SO₂Me

Scheme 11.

F₃C

N

H

8t 68%

extrudes sulfur dioxide to give a methyl radical, an entity

that is sufﬁciently reactive to propagate the chain. The neo-

phyl 1,2-aryl shift is a relatively slow process and has there-

fore found only rare applications in organic synthesis.²⁸The

decisive advantage of the xanthate transfer process is that the

intermediate radicals have comparatively long lifetimes,

because the exchange of a xanthate group is a reversible

process. Thus, even though radical II can (and does) react

with the various xanthates in the medium, it is only irrevers-

ibly consumed through the neophyl shift, which now has

ample time to take place. The now efﬁcient aryl shift can

be applied to the synthesis of nitrogenated heterocycles pro-

vided there is a correct functionalisation in both the R and

the alkenyl extremities of compound IV in order to effect

ring closure.

Scheme 9.

meta-substituted aromatic ring (Scheme 10). Thus, addition

of xanthate 3j to sulfonamide 1l afforded adduct 6u

smoothly. Protection with propionyl chloride (preclamol

features an N-propyl substituent) was conducted in good

yield. Surprisingly, the radical migration occurred in low

yield and the product of ortho-cyclisation, which had not

been observed before when the aromatic ring was substituted

in the ortho- or para-position, was produced concomitantly.

In principle, compound 5u could be converted into precla-

mol by reduction of the amide and ester groups and ring clo-

sure through a Mitsunobu-type reaction, but this has not yet

been accomplished.

In parallel to these studies, we examined another equally

powerful route to 3-aryl piperidine derivatives hinging on

a 1,2-aryl migration, which we recently described.²⁷As out-

lined in Scheme 11, radical addition of a xanthate onto an

alkene such as I leads directly to the a,b-unsaturated ester

by means of a 1,2-aryl shift, which is made irreversible by

the b-elimination of a methylsulfonyl radical. The latter

The retrosynthetic analysis for the formation of aryl-

substituted heterocycles, including ﬁve-membered hetero-

cycles, depending on the nature of the starting xanthate, is

displayed in Scheme 12. The radical addition to oleﬁn IV

leads to a,b-unsaturated esters II and VI, which can undergo

classical conjugate addition, through reaction with a suitable

amine in the ﬁrst case and by basic treatment in the second,

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7193

SCSOEt

O

to furnish the desired heterocycles. Indeed, this approach af-

fords heterocycles substituted not only in position 3, but also

in the 2,6 positions in the case of piperidines and in the 2,5

positions in the case of pyrrolidines.²⁹

CF₃

14a

DLP, DCE

reflux

O

CO₂Et

SCSOEt

OMe

MeO

3t

15 (60%)

III

R

O

Ar

NaBH₃CN

RNH₂

AcOH / EtOH

reflux

O

N

H

R

SO₂Me

CO₂Et

Ar

CF₃

CO₂Et

I

II

IV

Ar

SCSOEt

N

O

CO₂Et

R

NH

MeO

R

MeO

NH

Z

R

N

H

R

NH

Z

CO₂Et

18a,b 72% (α:β 1:5)

16a,b; R = H, 71% (α:β 1:5)

17; R = cyclopropyl, 86% (β isomer only)

V

VI

VII

Scheme 12.

Scheme 14.

Our synthetic approach requires oleﬁns of structure 14.

These were very easily prepared by conjugate addition of

vinylmagnesium cuprate onto a,b-unsaturated esters 13

(Scheme 13), themselves readily accessible by a Knoevena-

gel condensation between ethyl methanesulfonylacetate and

the corresponding arenecarboxaldehyde. For the synthesis of

3-aryl-2,6-disubstituted piperidines, reaction between xan-

thate 3t and oleﬁn 14a in the presence of DLP in reﬂuxing

DCE resulted in the obtention of ketone 15 in 60% yield

(Scheme 14). Upon treatment with different amines and

sodium cyanoborohydride, this compound furnished the

desired heterocycles in good yield and as a mixture of diaste-

reomers in some cases. With ethylenediamine, bicyclo deriv-

ative 18 was obtained in good yield and as a mixture of two

diastereomers. The use of cyanoborohydride is to reduce the

intermediate enamine, but this operation can be omitted if

more oxidised (ultimately pyridines) derivatives are desired.

Thus, modiﬁcation of the xanthate, the oleﬁn and the amine

components can lead expeditiously to a vast number of aryl-

substituted piperidines and related derivatives that would be

otherwise laborious to obtain.

42% and could be performed with each diastereoisomer

separately, thus allowing the determination of the relative

conﬁguration of each of the precursors 19a and 19b. Interest-

ingly, pyrrolidines 21a,b may be viewed as open-chain ana-

logues of epibatidine and underscore the possibility of

introducing heteroaromatic rings through the neophylic rear-

rangement in addition to a triﬂuoromethyl group initially

present in xanthate 3s.³⁰In the case of oleﬁn 14c, the radical

addition with xanthate 3s proceeded in slightly lower yield

(43%) and the esters 20 were obtained as a 1.2:1 mixture

of two diastereomers, which could also be separated by col-

umn chromatography. Again the t-BuOK mediated cyclisa-

tion afforded the desired pyrrolidines 22a,b as a 1:1.3

mixture of two diastereomers in 48% yield, which in this

case could not be separated. Nevertheless, from 2D NMR

and NOESY experiments, the relative conﬁguration of

both diastereomers could be easily deduced. We noted

when the cyclisation was attempted with each diastereomer

20 separately, that a mixture of both diastereoisomers 22 was

formed in each case, indicating that during the course of the

cyclisation, epimerisation at the carbon g- to the ester group

had occurred. This was conﬁrmed by the detection of small

amounts of b,g-unsaturated acid 23, which can only arise

from the extended enolate of the unsaturated ester group.

Reaction of oleﬁn 14b with xanthate 3s furnished adducts

19a,b as a separable 1.3:1 mixture of diastereoisomers in

57% yield (Scheme 15). The ring closure was induced

with tert-butoxide in THF to give pyrrolidines 21a,b in

Ar

The literature routes to 3-arylpiperidines have been brieﬂy

discussed in Section 1. As for substituted 3-arylpyrrolidines,

their synthesis has hitherto relied mostly on 1,3-dipolar cy-

cloadditions between azomethine ylides and monosubsti-

tuted oleﬁns conjugated to an aromatic ring.³¹Other

strategies exploiting intramolecular cyclisations have also

been reported.³²The present two radical based approaches

to highly substituted 3-arylpiperidines and 3-arylpyrrol-

idines complement previous routes. They are ﬂexible,

employ cheap and readily available starting materials, and

bring to the fore the synthetic potential of the radical 1,4-

and 1,2-aryl migrations. New scaffolds containing pharma-

cologically interesting structural motifs and functional

groups that allow robotised construction of diverse libraries

can be rapidly assembled in a highly convergent manner.

Ar

MeSO₂

EtO₂C

MgCl

CuI

THF

ArCHO

toluene

reflux

CO₂Et

SO₂Me

13

CO₂Et

SO₂Me

14

14a, Ar = 4-CF₃C₆H₄- 72%

14b, Ar = 2-ClC₅H₃N- 76%

14c, Ar = 2,6-Cl₂C₆H₃- 94%

13a

94%

F₃C

13b

89%

60%

Cl

N

Cl

13c

Scheme 13.

7194

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

Ar

3.1.1.1. N-Allyl-4-methoxybenzenesulfonamide 1b.

Puriﬁed by crystallisation (EtOH), white solid, 73%; n_max

SCSOEt

NHAc

/

14b/14c

DLP, DCE

reflux

CO₂Et

cm^ꢀ13394, 3276 (NH), 3079 (Ar), 2839 (]CH₂), 1598

(C]C), 1498 (NH), 1335, 1258, 1159 (SO₂); d_H3.57–3.60

(m, 2H, CH₂N), 3.88 (s, 3H, OCH₃), 4.65 (br s, 1H, NH),

5.09–5.20 (dd, 2H, ]CH₂), 5.69–5.76 (m, 1H, CH]),

7.81–7.83 (m, 5H, ArH); d_C45.9 (CH₂N), 55.7 (OCH₃),

117.9 (]CH₂), 114.3 (CH Ar), 129.2 (CH Ar), 129.4 (CH

Ar), 131.5 (CH Ar), 133.0 (C Ar), 134.9 (CH]), 136.8 (C

Ar); m/z 228 (MH⁺), 245 (M+NH₄⁺).

F₃C

NHAc

F₃C

3s

19a,b 57% (1.3:1),

Ar=2-chloropyrid-5-yl-

20a,b 52%(0.85:1),

Ar=2,6-Cl₂C₆H₃-

t-BuOK

THF

Cl

N

F₃C

N

CO₂Et

Cl

N

Ac

3.1.1.2. N-Allyl-2-chlorobenzenesulfonamide 1e. Puri-

ﬁed by ﬂash column chromatography (petrol/EtOAc 9:1),

white solid, 55%; mp 67–70 ^ꢁC; n_max/cm^ꢀ13392, 1572

(NH), 1352, 1172 (SO₂); d_H3.58 (t, J¼6 Hz, 2H, H-1⁰),

5.07 (d, J¼10.4 Hz, 1H, H-3⁰), 5.10 (br s, 1H, NH), 5.16

(d, J¼16.8 Hz, 1H, H-3⁰), 5.69 (ddt, J¼6, 10.4, 16.8 Hz,

1H, H-2⁰), 7.41 (ddd, J¼2.5, 5.7, 7.9 Hz, 1H, ArH), 7.45–

7.55 (m, 2H, ArH), 8.08 (d, J¼7.2 Hz, 1H, ArH); d_C45.9

(C-1⁰), 118.0 (C-3⁰), 127.2 (CH Ar), 131.26 (CH Ar),

131.33 (CH Ar), 131.5 (CH Ar), 132.5 (C-2), 133.7 (CH

Ar), 137.4 (C-ipso), m/z 232 (MH⁺), 249 (M+NH₄⁺).

21a,b 42%

(α:β 1:1.5)

Cl

CO₂Et

CO₂H

F₃C

Ac

F₃C

NHAc

22a,b 48%

(α:β 1:1.3)

23

Scheme 15.

3. Experimental

3.1. General conditions

3.1.1.3. N-Allyl-4-triﬂuoromethylbenzenesulfonamide

1h. Puriﬁed by ﬂash column chromatography (petrol/EtOAc

9:1), white solid, 73%; mp 100–102 ^ꢁC; n_max/cm^ꢀ13399

(NH), 1323, 1174 (SO₂); d_H3.65 (d, J¼5.6 Hz, 2H, H-1⁰),

4.68 (br s, 1H, NH), 5.13 (dd, J¼0.8, 10.4 Hz, 1H, H-3⁰),

5.18 (dd, J¼0.8, 16.8 Hz, 1H, H-3⁰), 5.72 (ddt, J¼6, 10.4,

16.8 Hz, 1H, H-2⁰), 7.80 (d, J¼8.4 Hz, 2H, ArH), 8.02 (d,

J¼8 Hz, 2H, ArH); d_C45.6 (C-1⁰), 117.9 (C-3⁰), 123.1 (q,

J¼271.4 Hz, CF₃), 126.2 (C-m), 127.6 (C-o), 132.4 (C-2⁰),

134.2 (q, J¼32.5 Hz, C-p), 143.5 (C-ipso); m/z 266

(MH⁺), 283 (M+NH⁺₄).

All reactions were carried out under an inert atmosphere.

Commercial reagents were used as received without further

puriﬁcation. All products were puriﬁed by using silica gel

(SDS, Silice 60 ACC 40–63 mm) or by crystallisation. Ana-

lytical TLC was carried out on Merck silica gel plates using

short wave (254 nm) UV light, 1% aqueous KMnO₄solution

to visualise components. NMR spectra were recorded in

CDCl₃using a Bruker AMX400 operating at 400 MHz for

¹H and 100 MHz for ¹³C. The chemical shifts are expressed

in parts per million (ppm) referenced to residual chloroform.

¹H NMR data are reported as follows: d, chemical shift; mul-

tiplicity (recorded as s, singlet; br s, broad singlet; d, doublet;

t, triplet; q, quadruplet; qt, quintuplet; ht, heptuplet; dd, dou-

ble doublet; ddd, double double doublet; dddd, double dou-

ble double doublet; dt, double triplet; ddt, double double

triplet; dq, double quadruplet; tt, triple triplet; td, triple dou-

blet; tdd, triple double doublet; m, multiplet), coupling con-

stants (J are given in hertz, Hz) and integration. Infrared

absorption spectra were recorded as a solution in CCl₄

with a Perkin–Elmer 1600 Fourier Transform Spectropho-

tometer. Mass spectra were recorded with an HP 5989B

mass spectrometer via direct introduction for chemical pos-

itive ionisation (CI) using ammonia as the reagent gas. Melt-

ing points were determined by Reichert microscope

apparatus and were uncorrected. HRMS were performed

on JEOL JMS-GcMate II, GC–MS system spectrometer. Mi-

croanalyses were performed by the Service de Microana-

lyse, Institut de Chimie des Substantces Naturelles, CNRS,

F-91198, Gif-sur-Yvette.

3.1.1.4. N-Allyl-4-cyanobenzenesulfonamide 1i. Puri-

ﬁed by ﬂash column chromatography (petrol/EtOAc 7:3),

white solid, 93%; mp 80–81 ^ꢁC; n_max/cm^ꢀ13400, 3263

(NH), 2233 (CN), 1350, 1165 (SO₂); d_H3.65 (t, J¼5.4 Hz,

2H, H-1⁰), 4.93 (t, J¼5.4 Hz, 2H, NH), 5.11 (d,

J¼10.4 Hz, 1H, H-3⁰), 5.16 (d, J¼17.2 Hz, 1H, H-3⁰), 5.69

(ddt, J¼5.6, 11.2, 16.8 Hz, 1H, H-2⁰), 7.82 (d, J¼8.4 Hz,

2H, ArH), 7.99 (d, J¼8.4 Hz, 2H, 2H, ArH); d_C45.7 (C-

1⁰), 116.4 (C-p), 117.2 (CN), 118.2 (C-3⁰), 127.6 (CH Ar),

132.4 (C-2⁰), 132.9 (CH Ar), 144.5 (C-ipso); m/z 223

(MH⁺), 240 (M+NH⁺₄).

3.1.1.5. N-Allyl-4-tert-butylbenzenesulfonamide 1j.

Puriﬁed by ﬂash column chromatography (petrol/EtOAc

7:3), white solid, 85%; mp 65–68 ^ꢁC; n_max/cm^ꢀ13395, 3276,

1596 (NH), 1343, 1167 (SO₂); d_H1.34 (s, 9H, CH₃), 3.59 (t,

J¼5.6 Hz, 2H, H-1⁰), 4.75 (t, J¼5.8 Hz, 1H, NH), 5.09 (d,

J¼10.4 Hz, 1H, H-3⁰), 5.17 (d, J¼17.2 Hz, 1H, H-3⁰),

5.67–5.80 (m, 1H, H-2⁰), 7.52 (d, J¼8 Hz, 2H, ArH), 7.79

(d, J¼8 Hz, 2H, ArH); d_C31.1 (CH₃), 35.1 (C), 45.7 (C-1),

117.6 (C-3⁰), 126.0 (CH Ar), 126.9 (CH Ar), 133.1 (C-2),

136.9 (C-ipso), 156.4 (C-p); m/z 254 (MH⁺), 271 (M+NH₄⁺).

3.1.1. General procedure for the synthesis of N-allylbenz-

enesulfonamides 1. To a solution of NaOH (1.2 equiv) in

water (0.5 mL/mmol allylamine) and Et₂O (0.5 mL/mmol

allylamine) were added allylamine (1 equiv) and the arene-

sulfonyl chloride (1.1 equiv) at room temperature. After

5 h, the reaction mixture was extracted with CH₂Cl₂. The or-

ganic extracts were dried and evaporated, and the residue

was puriﬁed by the corresponding method.

3.1.1.6.

N-Allyl-4-triﬂuoromethoxybenzenesulfon-

amide 1k. Puriﬁed by crystallisation (petrol/EtOAc), white

crystals, 94%; mp 73–74 ^ꢁC; d_C3.64 (t, J¼6 Hz, 2H,

H-1⁰), 4.67 (br s, 1H, NH), 5.16 (dd, J¼13.5, 21.4 Hz, 2H,

H-3⁰), 5.73 (m, 1H, H-2⁰), 7.36 (d, J¼8.6 Hz, 2H, ArH),

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7195

7.93 (d, J¼8.6 Hz, 2H, ArH); d_C45.8 (C-1⁰), 118.0 (C-3⁰),

120.3 (q, J¼259 Hz, OCF₃), 138.4 (C Ar), 152.2 (C Ar),

121.1, 129.4, 132.7 (2CH Ar and C-2⁰); m/z 282 (MH⁺),

299 (M+NH⁺₄); Elem. Anal. Calcd for C₁₀H₁₀F₃NO₃S: C,

42.70; H, 3.58; found: C, 42.85; H, 3.67.

A mixture of the intermediate bromide and potassium

O-ethyl xanthate (15.6 g, 97.2 mmol) in acetone (375 mL)

was stirred at room temperature for 4 h. The reaction mixture

was then concentrated, the residue taken up in Et₂O and ﬁl-

trated through CeliteÔ. The solvent was evaporated, and

the residue was puriﬁed by ﬂash column chromatography

(petroleum ether/AcOEt 9:1), and the desired xanthate was

obtained as a brown solid (16.9 g, 89%, two steps); mp 55–

57 ^ꢁC, n_max/cm^ꢀ11730 (CO), 1224 (COS), 1052 (CS); d_H

1.39 (t, J¼7.2 Hz, 3H, CH₃), 3.90 (s, 2H, CH₂), 4.00 (s,

2H, CH₂), 4.60 (q, J¼7.2 Hz, 2H, OCH₂), 7.20–7.40 (m,

5H, ArH); d_C13.6 (CH₃), 44.8 (CH₂), 44.9 (CH₂), 70.8

(OCH₂), 127.2, 128.7, 129.5 (CH Ar), 133.2 (C-ipso),

200.6 (CO), 213.0 (CS); m/z 255 (MH⁺), 272 (M+NH₄⁺).

3.1.1.7. N-Allyl-3-methoxybenzenesulfonamide 1l. Pu-

riﬁed by ﬂash column chromatography (petrol/EtOAc 8:2),

transparent oil, 100%; n_max/cm^ꢀ13278 (NH), 1599 (NH),

1321 (SO₂), 1161 (SO₂); d_H3.55 (tt, J¼1.6, 6 Hz, 2H,

NCH₂), 3.81 (s, 3H, OCH₃), 5.04 (ddd, J¼1.2, 2.4, 10 Hz,

1H, CH]), 5.14 (ddd, J¼1.6, 2.8, 17.2 Hz, 1H, CH]),

5.27 (t, J¼6.2 Hz, 1H, NH), 5.68 (ddt, J¼6, 10, 17.2 Hz,

1H, CH]), 7.07 (ddd, J¼1.2, 2.4, 8.8 Hz, 1H, CH Ar),

7.35–7.40 (m, 2H, ArH), 7.42 (dt, J¼1.2, 8 Hz, 1H, ArH);

d_C45.6 (NCH₂), 55.5 (OCH₃), 111.6 (CH Ar), 117.4

(CH₂]), 119.0 (CH Ar), 119.1 (CH Ar), 130.0 (CH Ar),

132.8 (CH]), 140.8 (C Ar), 159.8 (C Ar); m/z 228

(MH⁺), 245 (M+NH⁺₄).

3.1.2.4. Dithiocarbonic acid O-ethyl ester S-phenoxy-

carbonylmethyl ester 3k. To a chilled (0 ^ꢁC) solution of

phenol (5.0 g, 53.1 mmol) and triethylamine (7.46 mL,

53.1 mmol) in Et₂O (53 mL) was added chloroacetyl chlo-

ride (4.23 mL, 53.1 mmol) and stirred at room temperature

for 1 h. After that time, Et₂O (100 mL) was added and the

reaction mixture was washed successively with 1 M HCl,

aqueous saturated NaHCO₃solution and aqueous saturated

NaCl solution. The organic layer was dried and evaporated,

and the residue was puriﬁed by ﬂash column chromato-

graphy (petroleum ether/AcOEt 9:1), and phenyl chloroace-

tate was obtained as white crystals (6.57 g, 73%).

3.1.2. General procedure for the synthesis of sulfon-

amides 2. To a solution of benzenesulfonamide 1 (1 equiv)

in toluene (2 mL/mmol) was added AcCl (15 equiv) and

heated to reﬂux temperature for 2 days. After that time,

the reaction mixture was ﬁltered and the residue was puriﬁed

by the method indicated.

3.1.2.1.

N-Acetyl-N-allyl-4-methylbenzenesulfon-

amide 2a. Puriﬁed by crystallisation (EtOH), white solid,

60%; n_max/cm^ꢀ13086, 2985, 1704 (CO), 1592 (C]C),

1367, 1172 (SO₂); d_H2.34 (s, 3H, CH₃), 2.46 (s, 3H, CH₃

Ar), 4.47 (d, J¼5.2 Hz, 2H, CH₂N), 5.27 (m, 2H, ]CH₂),

5.84–5.94 (m, 1H, CH]), 7.34 (d, J¼8 Hz, 2H, CH Ar),

7.82 (d, J¼8 Hz, 2H, CH Ar); d_C21.3 (CH₃acetyl), 24.4

(CH₃Ar), 48.5 (CH₂N), 117.9 (]CH₂), 127.6 (CH Ar),

127.7 (CH Ar), 129.4 (CH Ar), 130.0 (C Ar), 131.2 (CH

Ar), 132.8 (C Ar), 134.9 (CH]), 170.6 (CO); m/z 254

(MH⁺), 271 (M+NH⁺₄).

Phenyl chloroacetate (6.57 g, 38.5 mmol) was dissolved in

acetone (193 mL), potassium O-ethyl xanthate (8.03 g,

50.1 mmol) was added, and stirred at room temperature for

1 h. After that time, the reaction mixture was concentrated,

the residue taken up in Et₂O and ﬁltrated through CeliteÔ.

The solvent was evaporated, and the residue was puriﬁed

by ﬂash column chromatography (petroleum ether/AcOEt

7:3), and it was obtained the desired xanthate as a dark yel-

low oil (9.55 g, 97%); n_max/cm^ꢀ11759 (CO), 1212 (COS),

1066 (CS); d_H1.46 (t, J¼7 Hz, 3H, CH₃), 4.15 (s, 2H,

CH₂), 4.70 (q, J¼7.1 Hz, 2H, OCH₂), 7.14 (d, J¼8.4 Hz,

2H, ArH), 7.26 (t, J¼6.8 Hz, 1H, ArH), 7.40 (t, J¼7.8 Hz,

2H, ArH); d_C13.7 (CH₃), 37.9 (CH₂), 70.8 (OCH₂), 121.2,

126.1, 129.5 (C-o, C-m, C-p), 150.6 (C-ipso), 166.5 (CO),

212.3 (CS); m/z 257 (MH⁺), 274 (M+NH₄⁺).

3.1.2.2.

N-Acetyl-N-allyl-4-methoxybenzenesulfon-

amide 2b. Puriﬁed by crystallisation (EtOH), white solid,

84%; n_max/cm^ꢀ13083, 2840, 1703 (CO), 1596 (C]C), 1360

(SO₂), 1311, 1267, 1163, 1091 (SO₂); d_H2.30 (s, 3H, CH₃),

3.90 (s, 3H, OCH₃), 4.47 (d, J¼5.2 Hz, 2H, CH₂N), 5.24–

5.31 (m, 2H, ]CH₂), 5.85–5.95 (m, 1H, CH]), 7.34 (d, 2H,

J¼8 Hz, CH Ar), 7.82 (d, 2H, J¼8 Hz, CH Ar); d_C24.4

(CH₃), 48.5 (CH₂N), 55.6 (OCH₃), 114.3 (2CH Ar), 118.2

(]CH₂), 130.4 (2CH Ar), 131.0 (C Ar), 132.8 (CH]),

163.8 (C Ar), 170.6 (CO); m/z 270 (MH⁺), 287 (M+NH₄⁺).

3.1.2.5. Dithiocarbonic acid O-ethyl ester S-(2-oxo-2-

piperidin-1-yl-ethyl)ester 3n. To a suspension of K₂CO₃

(55.8 g, 404 mmol) and chloroacetyl chloride (8.1 mL,

101 mmol) in THF (116 mL) was added dropwise a solution

of piperidine (10 mL, 101 mmol) in THF (232 mL), and the

resulting mixture was stirred at room temperature for 16 h.

The reaction mixture was then ﬁltered and concentrated.

The residue was puriﬁed by ﬂash column chromatography

(petroleum ether/AcOEt 7:3), and the desired chloroacetyl-

piperidine was obtained as a yellow oil (13.1 g, 80%).

3.1.2.3. Dithiocarbonic acid O-ethyl ester S-(2-oxo-3-

phenylpropyl)ester 3f. To a solution of phenylacetone

(10 mL, 74.8 mmol) in glacial AcOH (25 mL) were added

concentrated HBr (12.5 mL) and a solution of Br₂(8.5 mL,

165 mmol) in glacial AcOH (41 mL), and the resulting mix-

ture was stirred at room temperature for 6 h. Acetone

(132 mL) was then added, and stirring continued for a further

18 h. The reaction mixture was then concentrated and ex-

tracted with CH₂Cl₂. The organic extracts were dried and

concentrated. The residue was puriﬁed by ﬂash column chro-

matography (petroleum ether/AcOEt 95:5), which afforded

1-bromo-3-phenylacetone as a dark yellow oil, as well as

other minor isomers due to non-regioselective bromination.

To a solution of chloroacetylpiperidine (13.1 g, 81.1 mmol)

in acetone (81 mL) at 0 ^ꢁC was added dropwise a suspension

of potassium O-ethyl xanthate (14.3 g, 89.2 mmol) in ace-

tone (357 mL), and the resulting mixture was stirred at

room temperature for 3 h. The reaction mixturewas then con-

centrated, the residue taken up in Et₂O and ﬁltered through

CeliteÔ. The solvent was evaporated, and the residue

was puriﬁed by ﬂash column chromatography (petroleum

7196

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

ether/AcOEt 7:3) and the desired xanthate was obtained as a

yellow oil (16 g, 80%); n_max/cm^ꢀ11651 (CO), 1220 (COS),

1054 (CS); d_H1.41 (t, J¼7.2 Hz, 3H, CH₃), 1.50–1.70 (m,

6H), 3.48 (t, J¼5.2 Hz, 2H, CH₂N), 3.56 (t, J¼5.2 Hz, 2H,

CH₂N), 4.11 (s, 2H, CH₂CO), 4.64 (q, J¼7.2 Hz, 2H,

OCH₂); d_C13.7 (CH₃), 24.3, 25.4, 26.5 (CH₂ring), 39.6

(CH₂CO), 43.4 (CH₂N), 47.3 (CH₂N), 70.4 (OCH₂), 164.7

(CO), 213.9 (CS); m/z 248 (MH⁺), 265 (M+NH₄⁺).

hydrate, which was not further puriﬁed (yellow oil,

6.77 g); n_max/cm^ꢀ13586 (OH), 1720 (CO), 1050 (CS); d_H

1.42 (t, J¼7 Hz, 3H, CH₃), 1.47 (t, J¼7 Hz, 3H, CH₃),

3.74 (s, 2H, 2OH), 3.94 (s, 2H, CH₂S), 4.31 (s, 2H, CH₂S),

4.64 (q, J¼7.2 Hz, 2H, OCH₂), 4.71 (q, J¼7.2 Hz, 2H,

OCH₂); m/z 233 (MH⁺).

3.1.3. General procedure for the synthesis of radical pre-

cursors 4. For compounds 4c, 4e, 4h and 4i: To a solution of

sulfonamide 6 (1 equiv) in pyridine (53 equiv) was added

acetic anhydride (17 equiv), and the reaction mixture stirred

until complete consumption of the starting material. The

mixture was then evaporated, and CH₂Cl₂was added. The

organic phase was washed with 1 M aqueous HCl, saturated

aqueous NaHCO₃solution, brine, dried and evaporated. The

residue was puriﬁed by ﬂash column chromatography.

3.1.2.6. Dithiocarbonic acid O-ethyl S-(2-cyclohexyl-2-

oxoethyl)ester 3r. To a solution of cyclohexane carboxylic

acid (2.45 g, 19.1 mmol) in THF (143 mL) at 0 ^ꢁC was added

MeLi (48 mL, 1.6 M solution in cyclohexane, 76.3 mmol)

and the reaction mixture stirred at that temperature for 2 h.

TMSCl (48.5 mL, 382 mmol) was then added, and the ice

bath was removed. 1 M aqueous HCl (7.5 mL) was then

added, and the reaction mixture was stirred for 30 min. The

two layers were then separated, and the aqueous phase was

further extracted with Et₂O. The organic extracts were dried

and evaporated. The residue was puriﬁed by ﬂash column

chromatography (petroleum ether/AcOEt 9:1), and acetyl-

cyclohexane was obtained as a yellow oil (1.20 g, 50%).

For compounds 4f, 4j, 4k, 4l, 4m, 4n, 4o, 4p, 4q, 4r, 4s and

4t: To a solution of sulfonamide 6 (1 equiv) in CH₂Cl₂

(2 mL/mmol) was added DMAP (4 equiv), and the solution

was cooled to 0 ^ꢁC. Acetyl chloride was then added drop-

wise (3 equiv), and the resulting mixture was stirred at

room temperature for 2 h. CH₂Cl₂was then added, and the

organic phase was washed with 1 M aqueous HCl, saturated

aqueous NaHCO₃solution, brine, dried and evaporated. The

residue was puriﬁed by ﬂash column chromatography.

Acetylcyclohexane (1.2 g, 9.52 mmol) was dissolved in

MeOH (7.5 mL), cooled to 0 ^ꢁC, and a single portion Br₂

(0.5 mL) added, and the resulting mixture stirred at a temper-

ature below 15 ^ꢁC for 3 h. Water (8 mL) was then added and

stirring continued for a further 15 h at room temperature.

The reaction mixture was then extracted with AcOEt, and

the organic extracts were dried and evaporated. The residue

was puriﬁed by ﬂash column chromatography (petroleum

ether/AcOEt 9:1), and the desired bromoacetylcyclohexane

was obtained as a yellow oil (1.35 g, 70%).

For compound 4c2: To a solution of sulfonamide 6c

(1 equiv) in CH₂Cl₂(2 mL/mmol) were added DMAP

(2.1 equiv) and methyl chloroformate (2 equiv). The reac-

tion mixture was stirred at room temperature for 12 h, and

after that time it was worked up as in the last procedure.

For compound 4c3: To a solution of sulfonamide 6c

(1 equiv) in CH₂Cl₂(2 mL/mmol) were added triethyl-

amine (1 equiv), di-tert-butyl dicarbonate (2 equiv) and

DMAP (1 equiv), and the reaction mixture was stirred at

room temperature for 7 h. After that time, the reaction mix-

ture was worked up as in the last procedure.

To a solution of bromoacetylcyclohexane (1.35 g, 6.59 g) in

acetone (33 mL) was added potassium O-ethyl xanthate

(1.37 g, 8.56 g), and the mixture was stirred at room temper-

ature for 1.5 h. The reaction mixture was then concentrated,

the residue taken up in Et₂O, and ﬁltered through CeliteÔ.

The solvent was evaporated, and the residue was puriﬁed

by ﬂash column chromatography (petroleum ether/AcOEt

97:3), and the desired xanthate was obtained as a yellow

semi-solid (1.03 g, 64%); n_max/cm^ꢀ11713 (CO), 1224

(COS), 1052 (CS); d_H1.25–1.50 (m, 5H), 1.40 (t, J¼

7.2 Hz, 3H, CH₃), 1.67 (d, J¼11.2 Hz, 3H, CH₃), 1.79 (d,

J¼12.4 Hz, 2H), 1.90 (d, J¼12.8 Hz, 2H), 2.59 (tt, J¼3.3,

10.9 Hz, 1H, H-1 cyclohexyl), 4.07 (s, 2H, CH₂S), 4.62

(q, J¼7.1 Hz, 2H, OCH₂); d_C13.7 (CH₃), 25.5 (C-4 cyclo-

hexyl), 25.7 (C-3 and C-5 cyclohexyl), 28.5 (C-2 and C-6 cy-

clohexyl), 44.5 (CH₂S), 49.8 (C-1 cyclohexyl), 70.6 (OCH₂),

205.7 (CO), 213.5 (CS); m/z 247 (MH⁺), 264 (M+NH₄⁺).

For compound 4j2: To a solution of sulfonamide 6e (1 equiv)

in CH₂Cl₂(2 mL/mmol) cooled at 0 ^ꢁC were added DMAP

(4 equiv) and triﬂuoroacetic anhydride (3 equiv), and stirred

at room temperature for 2 h. After that time, it was worked

up as in the last procedure.

Note: compounds 4a–d were prepared by radical reaction

between an oleﬁn 2 and a corresponding xanthate 3, follow-

ing the general methodology reported for compounds 6.

3.1.3.1. Dithiocarbonic acid O-ethyl ester S-[1-(N-acet-

yl-4-toluenesulfonylaminomethyl)-4-oxopentyl]ester 4a.

Prepared from 2a and 3a, puriﬁed by ﬂash column chroma-

tography (petrol/EtOAc gradient from 8:2 to 1:9), yellow oil,

34%; n_max/cm^ꢀ12925, 1719 (CO), 1495, 1366 (SO₂), 1226

(O–CS), 1169 (SO₂), 1048 (C]S); d_H1.46 (t, J¼8 Hz,

3H, CH₃xanthate), 1.80–1.90 (m, 1H, CH), 2.10–2.16 (m,

1H, CH), 2.17 (s, 3H, CH₃CO), 2.36 (s, 3H, CH₃acetyl),

2.46 (s, 3H, CH₃Ar), 2.58–2.78 (m, 2H, CH₂CO), 4.10–

4.18 (m, 1H, CHS), 4.13–4.14 (m, 2H, CH₂N), 4.66 (q,

J¼8 Hz, 2H, OCH₂), 7.36 (d, J¼8 Hz, 2H, CH Ar), 7.77

(d, J¼8 Hz, 2H, CH Ar); d_C13.8 (CH₃xanthate), 21.6

(CH₃CO), 21.8 (CH₂), 25.2 (CH₃acetyl), 30.1 (CH₃Ar),

3.1.2.7. Dithiocarbonic acid O-ethyl ester S-(2-oxo-

3,3,3-triﬂuoropropyl)ester 3s. To a chilled (0 ^ꢁC) solution

of 1-bromo-3,3,3-triﬂuoroacetone (5.0 g, 26.2 mmol) in ace-

tone (52 mL) was added a suspension of potassium O-ethyl

xanthate (5.04 g, 31.4 mmol) in acetone (126 mL), and

stirred at room temperature for 2 h. After that time, water

(100 mL) was added, and the acetone was evaporated. The

reaction mixture was extracted with a mixture of 7:3 petro-

leum ether/Et₂O, and the organic extracts were dried and

evaporated. The residue consisted in a ca. 1:1 mixture (esti-

1

mated by H NMR) of xanthate 3s and its corresponding

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7197

40.6 (CH₂CO), 49.0 (CH₂N), 49.6 (CHS), 70.5 (OCH₂),

127.6 (CH Ar), 127.7 (CH Ar), 130.1 (CH Ar), 136.2 (CH

Ar), 136.6 (C Ar), 145.3 (C Ar), 170.6 (CO), 207.4 (CO

ketone), 212.9 (CS); m/z 432 (MH⁺), 449 (M+NH₄⁺).

chromatography (petrol/EtOAc 78:22), yellow oil, 72%;

n_max/cm^ꢀ11772 (CO OAc), 1740 (CO ethyl ester), 1710

(CO amide), 1367, 1170 (SO₂), 1235 (CSO), 1048 (CS);

d_H0.98 (t, J¼7.2 Hz, CH₃ethyl ester), 1.45 (m, 3H,

J¼6.8 Hz, 3H, CH₃xanthate), 2.22 (s, 3H, CH₃acetoxy),

2.37 (s, 3H, CH₃NAc), 2.46 (s, 3H, CH₃tolyl), 2.88–2.92

(m, 2H, CH₂), 3.98–4.05 (m, 2H, OCH₂ester), 4.20 (d,

J¼8 Hz, 2H, NCH₂), 4.37–4.45 (m, 1H, CHS), 4.64 (q,

J¼6.8 Hz, 2H, OCH₂xanthate), 7.32–7.79 (m, 9H, ArH);

d_C13.7 (CH₃xanthate), 13.8 (CH₃ethyl ester), 21.1 (CH₃

OAc), 21.8 (CH₃tolyl), 25.1 (CH₃NAc), 30.7 (C-3⁰), 48.8

(C-1⁰and C-2⁰), 61.1 (OCH₂ethyl ester), 70.3 (OCH₂xan-

thate), 120.9 (C-4⁰), 127.7–130.1 (9CH Ar), 135.4 (C Ar),

136.3 (C Ar), 145.2 (C-ipso tolyl), 155.4 (C-5⁰), 167.4 (CO

acetoxy), 168.1 (CO ethyl ester), 170.6 (CO amide), 212.7

(CS); m/z 608 (MH⁺), 623 (M+NH₄⁺).

3.1.3.2. Dithiocarbonic acid O-ethyl ester S-[1-(N-acet-

yl-4-toluenesulfonylaminomethyl)-4-oxo-4-phenylbutyl]-

ester 4b. Prepared from 2a and 3b, puriﬁed by ﬂash column

chromatography (petrol/EtOAc gradient from 10:0 to 7:3),

pale yellow oil, 42%; n_max/cm^ꢀ12926, 1706 (CO), 1691

(CO), 1494, 1448, 1367 (SO2), 1224 (OC–S), 1160 (SO2),

1048 (C]S); d_H1.43 (t, J¼8 Hz, 3H, CH₃xanthate),

1.98–2.03 (m, 1H, CH), 2.27–2.34 (m, 1H, CH), 2.36 (s,

3H, CH₃acetyl), 2.46 (s, 3H, CH₃Ar), 3.18–3.30 (m, 2H,

CH₂CO), 4.15–4.23 (m, 2H, NCH₂), 4.24–4.33 (m, 1H,

CHS), 4.64 (q, J¼8 Hz, 2H, OCH₂), 7.35–7.58 (m, 5H,

ArH), 7.79 (d, J¼8 Hz, 2H, CH Ar), 7.88 (d, J¼8 Hz, 2H,

CH Ar); d_C13.8 (CH₃xanthate), 21.7 (CH₃acetyl), 25.2

(CH₂), 25.7 (CH₃Ar), 35.7 (CH₂CO), 49.1 (NCH₂), 49.7

(CHS), 70.5 (OCH₂), 127.5–133.2 (9CH Ar), 136.6 (C

Ar), 136.7 (C Ar), 145.2 (C Ar), 170.6 (CO), 198.8 (CO),

212.8 (CS); m/z 494 (MH⁺), 511 (M+NH₄⁺).

3.1.3.6. N-Acetyl-N-[2-ethoxythiocarbonylsulfanyl-5-

oxo-6-phenylhexenyl]-4-toluenesulfonamide 4f. Puriﬁed

by ﬂash column chromatography (petrol/EtOAc 7:3), brown

oil, 94%; n_max/cm^ꢀ11759 (CO), 1710 (CO), 1367, 1170

(SO₂), 1224 (COS), 1049 (CS); d_H1.42 (t, J¼7.1 Hz, 3H,

CH₃xanthate), 1.75–1.90 (m, 1H, CH), 2.05–2.15 (m, 1H,

CH), 2.33 (s, 3H, CH₃acetyl), 2.44 (s, 3H, CH₃tolyl),

2.60–2.75 (m, 2H, CH₂CO), 3.70 (s, 2H, CH₂Ph), 4.00–

4.30 (m, 3H, NCH₂and CHS), 4.63 (q, J¼7.1 Hz, 2H,

OCH₂), 7.20 (d, J¼7.1 Hz, 2H, ArH), 7.75 (dd, J¼2.8,

8.1 Hz, 2H, ArH); d_C13.7 (CH₃xanthate), 21.6 (CH₃tolyl),

25.0 (CH₃acetyl), 25.1 (CH₂), 38.9 (CH₂CO), 48.9 (NCH₂),

49.4 (CHS), 50.1 (CH₂Ph), 70.3 (OCH₂), 127.4, 128.7,

129.4, 130.0 (CH Ar), 134.0 (C-ipso phenyl), 136.6 (C-p

tolyl), 145.1 (C-ipso tolyl), 170.4 (CO acetyl), 206.8 (C-

5⁰), 212.7 (CS); m/z 509 (MH⁺), 525 (M+NH⁺₄).

3.1.3.3. Methyl 5-(N-acetyl-4-toluenesulfonylamino)-

4-ethoxythiocarbonylsulfanyl pentanoate 4c. Prepared

from 2a and 3c, puriﬁed by ﬂash column chromatography

(petrol/EtOAc gradient from 10:0 to 7:3), yellow oil; 28%,

if prepared from 6c, 95%; n_max/cm^ꢀ12986, 2951, 1741

(C]O), 1707 (NC]O), 1436, 1366 (SO₂), 1227 (OCS),

1169 (SO₂), 1111, 1051 (C]S); d_H1.45 (t, J¼8 Hz, CH₃

xanthate), 1.85–1.95 (m, 1H, CH), 2.13–2.19 (m, 1H, CH),

2.35 (s, 3H, CH₃CO), 2.46 (s, 3H, CH₃Ar), 2.51–2.59 (m,

2H, CH₂CO), 3.68 (s, 3H, OCH₃), 4.10–4.15 (m, 2H,

CH₂N), 4.18–4.23 (m, 1H, CHS), 4.65 (q, J¼8 Hz, 2H,

OCH₂), 7.36 (d, J¼8 Hz, 2H, CH Ar), 7.74 (d, J¼8 Hz,

2H, CH Ar); d_C13.8 (CH₃xanthate), 21.7 (CH₃acetyl),

25.2 (CH₂), 26.6 (CH₃Ar), 31.4 (CH₂CO), 49.06 (OCH₃),

49.1 (CH₂N), 49.5 (CHS), 70.5 (OCH₂), 126.3 (CH Ar),

127.6 (CH Ar), 130.2 (CH Ar), 130.3 (CH Ar), 136.6 (C

Ar), 145.3 (C Ar), 170.2 (CO), 174.0 (CO ester), 212.8

(CS); m/z 448 (MH⁺), 465 (M+NH₄⁺).

3.1.3.7. N-Acetyl-N-[2-ethoxythiocarbonylsulfanyl-4-

(2-benzyl-1H-tetrazole-5-yl)butyl]-4-toluenesulfonamide

4g. Puriﬁed by ﬂash column chromatography (petrol/EtOAc

6:4), yellow oil, 49%; n_max/cm^ꢀ11707 (CO), 1366 and 1168

(SO₂), 1228 (COS), 1051 (CS); d_H1.37 (t, J¼6.8 Hz, 3H),

1.95–2.02 (m, 1H, CH), 2.24–2.30 (m, 1H, CH), 2.33 (s,

3H, CH₃acetyl), 2.45 (s, 3H, CH₃tolyl), 2.85–2.90 (m,

2H, CH₂CO), 4.07–4.15 (m, 2H, NCH₂), 4.22–4.25 (m,

1H, CHS), 4.62 (s, 2H, CH₂benzyl), 7.21–7.75 (m, 9H,

CH Ar); d_C13.8 (CH₃xanthate), 20.5 (CH₃tolyl), 20.7

(CH₂CO), 24.9 (CH₃acetyl), 28.0 (CH₂), 48.4 (NCH₂),

49.2 (CHS), 50.1 (CH₂benzyl), 70.5 (OCH₂), 126.9–130.0

(9CH Ar), 133.3 (C-ipso phenyl), 136.1 (C-p tolyl), 145.3

(C-ipso tolyl), 154.0 (C-5⁰⁰), 170.4 (CO acetyl), 212.1

(CS); m/z 548 (MH⁺).

3.1.3.4. O-ethyl ester S-[1-(N-acetyl-4-methoxybenz-

enesulfonylaminomethyl)-3-cyanopropyl]dithiocarbonate

4d. Prepared from 2b and 3d, puriﬁcation by ﬂash column

chromatography (petrol/EtOAc gradient from 10:0 to 7:3),

58%, yellow oil; n_max/cm^ꢀ12963, 2942, 2841, 2249 (CN),

1705 (NC]O), 1596, 1498, 1366 (SO₂), 1310, 1263 (O–

CS), 1230, 1182, 1163 (SO₂), 1111, 1051 (C]S); d_H1.46

(t, J¼8 Hz, 3H, CH₃xanthate), 1.95–2.03 (m, 1H, CH),

2.17–2.25 (m, 1H, CH), 2.37 (s, 3H, CH₃acetyl), 2.50–

2.68 (m, 2H, CH₂CN), 3.90 (s, 3H, OCH₃), 4.11–4.15 (m,

2H, CH₂N), 4.17–4.27 (m, 1H, CHS), 4.66 (q, J¼8 Hz,

OCH₂), 7.02 (d, J¼8 Hz, CH Ar), 7.81 (d, J¼8 Hz, CH

Ar); d_C13.8 (CH₃xanthate), 15.1 (CH₂), 25.1 (CH₃acetyl),

27.6 (CH₂CN), 48.5 (CHS), 48.8 (CH₂N), 55.9 (OCH₃), 70.9

(OCH₂), 114.8 (2CH Ar), 119.0 (CN), 129.8 (2CH Ar),

130.5 (C Ar), 164.1 (C Ar), 170.6 (CO), 211.5 (CS); m/z

431 (MH⁺), 448 (M+NH⁺₄).

3.1.3.8. O-Ethyl-S-[1-(N-acetyl-4-toluenesulfonylami-

nomethyl)-4-cyclopropyl-4-oxo-butyl]dithiocarbonate

4h. Isolated as an oil, 77%; n_max/cm^ꢀ11705 (CO, CON),

1366, 1169 (NSO₂), 1224, 1050 (C]S, SC–O); d_H0.89–

0.84 (m, 2H, CH₂), 1.04–1.0 (m, 2H, CH₂), 1.45 (t, 3H,

J¼7.1 Hz, CH₃xanthate), 1.95–1.81 (m, 2H, CH, CHCO),

2.20–2.11 (m, 1H, CH), 2.35 (s, 3H, CH₃CO), 2.45 (s, 3H,

CH₃Ar), 2.87–2.71 (m, 2H, CH₂CO), 4.21–4.06 (m, 3H,

CHS and NCH₂), 4.66 (qd, 2H, J¼7.2 Hz, OCH₂), 7.34 (d,

2H, J¼8 Hz, CH Ar), 7.75 (d, 2H, J¼8 Hz, CH Ar); d_C

10.9 (2CH₂), 13.8 (CH₃xanthate), 20.6 (CHCO), 21.7

(CH₃Ar), 25.1 (CH₃CO), 25.4 (CH₂), 40.3 (CH₂CO), 49.1

(CH₂N), 49.7 (CHS), 70.4 (OCH₂), 127.5 (CH Ar), 130.1

3.1.3.5. N-Acetyl-N-(5-acetoxy-4-ethoxycarbonyl-2-

ethoxythiocarbonylsulfanyl-5-phenylpentene-4-enyl)-4-

toluenensulfonamide 4e. Puriﬁed by ﬂash column

7198

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

(CH Ar), 136.6 (C Ar), 145.2 (C Ar), 170.6 (CON), 209.5

(CO), 212.9 (CS); m/z 458 (MH⁺), 475 (M+NH₄⁺).

1711 (CO), 1368 (SO₂), 1228 (OC–S), 1171, 1052 (C]S);

d_H1.32 (t, J¼7.2 Hz, 3H, CH₃ester), 1.43 (t, J¼7.2 Hz,

3H, CH₃xanthate), 1.88–1.94 (m, 1H, CH), 2.13–2.21 (m,

1H, CH), 2.36 (s, 3H, CH₃acetyl), 2.36 (s, 2H, COCH₂CO),

2.87–2.97 (m, 2H, CH₂CO), 4.11–4.12 (m, 2H, NCH₂),

4.12–4.13 (m, 1H, CHS), 4.27 (q, J¼7.2 Hz, 2H, OCH₂

ester), 4.63 (q, J¼7.2 Hz, 2H, OCH₂xanthate), 7.52 (d,

J¼8 Hz, 2H, CH Ar), 7.85 (d, J¼8 Hz, 2H, CH Ar); d_C

13.7 (CH₃xanthate), 14.2 (CH₃ester), 25.0 (CH₂), 26.7

(CH₃acetyl), 35.4 (CH₂CO), 49.3 (COCH₂CO), 49.6

(NCH₂), 54.9 (CHS), 61.6 (OCH₂ester), 70.5 (OCH₂xan-

thate), 129.2 (2CH Ar), 129.6 (2CH Ar), 139.5 (C Ar),

145.3 (C Ar), 170.2 (CO amide), 174.8 (CO ester), 201.9

(CO ketone), 211.8 (C]S); m/z 524 (MH⁺), 541 (M+NH₄⁺).

3.1.3.9. O-Ethyl-S-[1-(N-acetyl-4-triﬂuoromethoxy-

benzenesulfonylaminomethyl)-4-oxo-4-(2-oxooxazolidin-

3-yl)butyl]dithiocarbonate 4i. Isolated as a foam, 98%;

n_max/cm^ꢀ11791 (OCON), 1708 (NCO), 1384, 1167

(NSO₂), 1215 (C]S), 1048 (COS); d_H8.0 (d, 2H,

J¼8 Hz, CH Ar), 7.36 (d, 2H, J¼8 Hz, CH Ar), 4.64 (q,

2H, J¼7.2 Hz, OCH₂), 4.42 (t, 2H, J¼8 Hz, CH₂), 4.22

(m, 1H, CHS), 4.16 (br s+br d, 2H, CH₂), 4.03 (t, 2H,

J¼8 Hz, CH₂), 3.15 (m, 2H, CH₂N), 2.38 (s, 3H, CH₃CO),

2.33–2.22 (m, 1H, CH), 2.01–1.94 (m, 1H, CH), 1.44 (t,

3H, J¼7.2 Hz, CH₃xanthate); d_C13.8 (CH₃xanthate),

25.1 (CH₃CO), 26.0 (CH₂), 32.3 (CH₂CO), 42.6 (CH₂N),

49.3 (CH₂N), 49.4 (CHS), 62.3 (CH₂OCO), 70.7 (OCH₂),

120.9 (Ar), 130.3 (Ar), 137.5 (Ar), 153.0 (Ar), 153.6 (CO),

170.4 (CO), 172.2 (CO), 212.7 (CS); m/z 590 (M+NH⁺₄).

3.1.3.13. N-Acetyl-N-[2-ethoxythiocarbonylsulfanyl-

3-(oxol-2-one-3-yl)propyl]-2-chlorobenzenesulfonamide

4m. (Two diastereomers, D1 and D2) puriﬁed by ﬂash col-

umn chromatography (petrol/EtOAc 1:1), yellow oil, 89%;

n_max/cm^ꢀ11780 (CO ester), 1709 (CO amide), 1368, 1168

(SO₂), 1227 (COS), 1045 (CS); d_H1.42 (t, J¼3.6 Hz, 3H,

CH₃), 1.45 (t, J¼3.6 Hz, 3H, CH₃), 1.80–1.92 (m, 2H, CH

D1 and CH D2), 1.94–2.17 (m, 2H, H-4⁰⁰ring D1 and

H-4⁰⁰ring D2), 2.19–2.39 (m, 2H, CH D1 and CH D2),

2.25 (s, 3H, CH₃), 2.28 (s, 3H, CH₃), 2.48 (dddd, J¼2, 6.4,

8.6, 14.8 Hz, 1H, H-4⁰⁰ring D1), 2.56 (dddd, J¼2, 6.4, 8.4,

14.8 Hz, 1H, H-4⁰⁰ring D2), 2.75–2.91 (m, 2H, H-3⁰⁰ring

D1 and H-3⁰⁰ring D2), 4.14–4.27 (m, 6H, NCH₂D1,

NCH₂D2, H-5⁰⁰ring D1 and H-5⁰⁰ring D2), 4.32–4.46 (m,

4H, CHS D1, CHS D2, H-5⁰⁰ring D1 and H-5⁰⁰ring D2),

4.59–4.73 (m, 4H, OCH₂D1 and D2), 7.44–7.62 (m, 6H,

CH Ar), 8.19 (d, J¼8 Hz, 2H, CH Ar); d_C13.7 (CH₃),

24.7 (CH₃Ac D2), 24.8 (CH₃Ac D1), 29.1 (C-4⁰⁰ring

D1), 29.4 (C-4⁰⁰ring D2), 31.9 (CH₂D1), 32.8 (CH₂D2),

37.2 (C-3⁰⁰ring D2), 37.4 (C-3⁰⁰ring D1), 48.1 (CHS D2),

48.6 (CHS D1), 49.4 (NCH₂D2), 50.4 (NCH₂D1), 66.4

(C-5⁰⁰ring D1), 66.5 (C-5⁰⁰ring D2), 70.4 (OCH₂D2),

70.7 (OCH₂D1), 127.3 (CH Ar), 131.8 (C Ar D2), 131.9

(C Ar D1), 132.1 (CH Ar D2), 132.2 (CH Ar D1), 132.36

(CH Ar D1), 132.41 (CH Ar D2), 134.8 (CH Ar D2),

134.9 (CH Ar D1), 136.7 (C Ar D1), 136.9 (C Ar D2),

169.8 (CO acetyl D1), 169.9 (CO acetyl D2), 178.38 (CO),

178.41 (CO), 212.4 (CS D2), 212.6 (CS D1), m/z 480

(MH⁺), 497 (M+NH⁺₄).

3.1.3.10. Ethyl 5-(N-acetyl-4-methoxybenzenesulfon-

ylamino)-4-ethoxythiocarbonylsulfanyl pentanoate 4j.

Puriﬁed by ﬂash column chromatography (petrol/CH₂Cl₂/

Et₂O 8:1:1), yellow oil, 87%; n_max/cm^ꢀ12981, 2941, 2839,

1736 (OC]O), 1705 (NC]O), 1597, 1498, 1367 (SO₂),

1229 (OC–S), 1163, 1049 (C]S); d_H1.26 (t, J¼7.6 Hz,

3H, CH₃ester), 1.44 (t, J¼6.8 Hz, 3H, CH₃xanthate),

1.87–1.94 (m, 1H, CH), 2.15–2.20 (m, 1H, CHS), 2.35 (s,

3H, CH₃acetyl), 2.44–2.57 (m, 2H, CH₂CO), 3.88 (s, 3H,

OCH₃), 4.13 (q, J¼7.6 Hz, 2H, OCH₂ester), 4.16–4.19

(m, 2H, NCH₂), 4.20–4.22 (m, 1H, CHS), 4.65 (q,

J¼6.8 Hz, 2H, OCH₂xanthate), 6.99 (d, J¼8.8 Hz, 2H,

CH Ar), 7.81 (d, J¼8.8 Hz, 2H, CH Ar); d_C13.8 (CH₃xan-

thate), 14.2 (CH₃ester), 25.1 (CH₃acetyl), 26.6 (CH₂), 31.6

(CH₂CO), 49.0 (CHS), 49.5 (NCH₂), 55.9 (OCH₃), 60.8

(OCH₂ester), 70.5 (OCH₂xanthate), 114.6 (2CH Ar),

129.9 (2CH Ar), 130.9 (C Ar), 163.9 (C Ar), 170.6 (CO

amide), 172.7 (CO ester), 212.8 (C]S); m/z 462 (MH⁺),

479 (M+NH⁺₄).

3.1.3.11. N-Acetyl-N-[2-ethoxythiocarbonylsulfanyl-

4-phenoxycarbonylbutyl]-4-ﬂuorobenzenesulfonamide

4k. Puriﬁed by ﬂash column chromatography (petrol/EtOAc

3:1), yellow oil, 84%; n_max/cm^ꢀ11761 (CO ester), 1710 (CO

amide); d_H1.43 (t, J¼7.1 Hz, 3H, CH₃), 1.95–2.07 (m, 1H,

CH), 2.20–2.35 (m, 1H, CH), 2.35 (s, 3H, CH₃acetyl), 2.70–

2.90 (m, 2H, CH₂CO), 4.16 (d, J¼7.3 Hz, NCH₂), 4.25–4.35

(m, 1H, CHS), 4.65 (q, J¼7.1 Hz, 2H, OCH₂), 7.09 (d,

J¼7.6 Hz, 2H, H-o phenyl), 7.15–7.30 (m, 3H, H-m ﬂuoro-

phenyl and H-p phenyl), 7.37 (t, J¼7.8 Hz, 2H, H-m phenyl),

7.93 (dd, J¼4.8, 8.8 Hz, 2H, H-o ﬂuorophenyl); d_C13.7

(CH₃xanthate), 25.0 (CH₃acetyl), 26.5 (CH₂), 31.4

(CH₂CO), 49.2 (NCH₂), 49.5 (CHS), 70.5 (OCH₂), 116.6

(d, J¼22.7 Hz, C-m ﬂuorophenyl), 121.5 (C-o phenyl),

125.8 (C-p phenyl), 129.3 (C-m phenyl), 130.6 (d,

J¼9.5 Hz, C-o ﬂuorophenyl), 135.3 (d, J¼3.1 Hz, C-ipso

ﬂuorophenyl), 150.6 (C-ipso phenyl), 165.6 (d, J¼128 Hz,

C-p ﬂuorophenyl), 170.2 (CO), 171.0 (CO), 212.3 (CS);

m/z 514 (MH⁺), 531 (M+NH⁺₄).

3.1.3.14. N-Acetyl-N-[2-ethoxythiocarbonylsulfanyl-

5-oxo-5-(piperidine-1-yl)pentenyl]-4-bromobenzenesul-

fonamide 4n. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc 1:1), yellow oil, 91%; n_max/cm^ꢀ11710

(CO), 1645 (CO), 1367, 1170 (SO₂), 1224 (COS), 1054

(CS); d_H1.42 (t, J¼7 Hz, 3H, CH₃), 1.45–1.65 (m, 6H),

1.80–1.95 (m, 1H, CH), 2.15–2.25 (m, 1H, CH), 2.33 (s,

3H, CH₃acetyl), 2.42–2.58 (m, 2H, CH₂CO), 3.36 (br s,

2H, H-2⁰⁰or H-6⁰⁰piperidine), 3.52 (ddd, J¼5.2, 13.2,

24 Hz, 2H, H-2⁰⁰or H-6⁰⁰piperidine), 4.05–4.25 (m, 3H,

CHS and NCH₂), 4.62 (q, J¼7 Hz, 2H, OCH₂), 7.66 (d,

J¼8.4 Hz, 2H, ArH), 7.78 (d, J¼8.4 Hz, 2H, ArH); d_C

13.7 (CH₃), 24.5 (CH₂piperidine), 25.0 (CH₃acetyl),

25.5, 26.4 (CH₂piperidine), 27.0 (CH₂), 30.2 (CH₂CO),

42.8 (C-2⁰⁰or C-6⁰⁰piperidine), 46.5 (C-2⁰⁰or C-6⁰⁰), 49.3

(NCH₂), 50.1 (CHS), 70.4 (OCH₂), 129.0 (C-p), 129.3

(CH Ar), 132.5 (CH Ar), 138.5 (C-ipso), 169.6 (CO),

170.3 (CO acetyl), 212.8 (CS); m/z 566 (MH⁺).

3.1.3.12. Ethyl 7-(N-acetyl-4-chlorobenzenesulfonyl-

amino)-6-ethoxythiocarbonylsulfanyl-3-oxoheptanoate

4l. Puriﬁed by ﬂash column chromatography (petrol/EtOAc

gradient from 10:0 to 8:2), yellow oil, 75%; n_max/cm^ꢀ12983,

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7199

3.1.3.15. O-Ethyl S-[1-(N-acetyl-4-iodobenzenesul-

fonylaminomethyl)-5,5-dimethoxy-4-oxopentyl]dithio-

carbonate 4o. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc 7:3), yellow oil, 91%; n_max/cm^ꢀ11739

(CO), 1711 (NCO), 1367, 1170 (SO₂), 1226 (CS), 1055

(COS); d_H1.43 (td, 3H, J¼7.2 Hz, OCH₃), 1.81–1.88 and

2.02–2.17 (2m, 2H, CH₂), 2.34 and 2.35 (2s, 3H, CH₃),

2.92 (m, 0.5H, CH), 3.07 (m, 0.5H, CH), 3.32, 3.36, 3.37

(s, br s, s, 6H, 2OCH₃), 3.71 and 3.73 (2s, 3H, CO₂CH₃),

4.15–4.03 (m, 2.5H, CHS, CH₂N), 4.18–4.25 (m, 0.5H,

CHS), 4.52 (t, 1H, J¼7 Hz, CHOCH₃), 4.63 (dq, 2H,

J¼7.2 Hz, OCH₂), 7.60 and 7.61 (2d, 2H, J¼8.4 Hz, ArH),

7.89 and 7.90 (2d, 2H, J¼8.4 Hz, ArH); d_C13.8 (CH₃xan-

thate), 25.1 (CH₃acetyl), 28.5 and 30.3 (CH₂), 46.6, 47.1,

48.1, 48.6 (CH), 48.9, 49.8 (CH₂N), 52.3, 53.4, 54.2, 54.9

(OCH₃), 70.5, 70.6 (OCH₂), 101.8 (CI), 104.3, 105.0

(CHOCH₃), 129.1, 138.6 (CH Ar), 170.4, 172.3, 172.5

(CO), 212.4 (CS).

CH cyclohexyl), 1.70–1.85 (m, 5H, CH and 4CH cyclohex-

yl), 2.05–2.15 (m, 1H, CH), 2.25–2.40 (m, 1H, H-1 cyclo-

hexyl), 2.35 (s, 3H, CH₃acetyl), 2.55–2.75 (m, 2H,

CH₂CO), 4.02–4.20 (m, 3H, CH₂N and CHS), 4.58–4.70

(m, 2H, OCH₂xanthate), 7.54 (d, J¼8.4 Hz, 2H, ArH),

7.78 (d, J¼8.4 Hz, 2H, ArH); d_C13.7 (CH₃xanthate), 25.0

(CH₂), 25.1 (CH₃acetyl), 25.62, 25.64, 25.8, 28.46, 28.52

t

(CH₂cyclohexyl), 31.0 (CH₃^tBu), 35.3 (C Bu), 37.5

(CH₂CO), 49.0 (CH₂N), 49.6 (CHS), 50.9 (C-1 cyclohexyl),

70.3 (OCH₂xanthate), 126.4 (CH Ar), 127.3 (CH Ar), 136.5

(C Ar), 158.0 (C Ar), 170.3 (CO acetyl), 212.5 and 212.8

(CO and CS); m/z 542 (MH⁺), 559 (MNH₄⁺).

3.1.3.19. Methyl 4-ethoxythiocarbonylsulfanyl-5-(N-

methoxycarbonyl-4-toluenesulfonylamino)pentanoate

4c2. Puriﬁed by ﬂash column chromatography (petrol/

CH₂Cl₂/Et₂O 6:2:2), pale yellow oil, 93%; n_max/cm^ꢀ1

2982, 2933, 1742 (CO), 1367, 1173 (SO₂), 1223 (OCS),

1051 (C]S); d_H1.43 (t, J¼6.8 Hz, 3H, CH₃xanthate),

1.84–1.98 (m, 1H, CH), 2.16–2.28 (m, 1H, CH), 2.44 (s,

3H, CH₃Ar), 2.47–2.67 (m, 2H, CH₂CO), 3.69 (OCH₃),

3.72 (s, 3H, OCH₃), 4.06–4.15 (m, 2H, NCH₂), 4.19–4.25

(m, 1H, CHS), 4.64 (q, J¼6.8 Hz, 2H, OCH₂), 7.30 (d,

J¼7.2 Hz, 2H, CH Ar), 7.86 (d, J¼7.2 Hz, 2H, CH Ar); d_C

13.9 (CH₃xanthate), 21.8 (CH₃Ar), 26.7 (CH₂), 31.3

(CH₂CO), 49.5 (NCH₂), 49.8 (OCH₃), 51.9 (CHS), 54.1

(OCH₃), 70.5 (OCH₂), 128.8 (CH Ar), 129.5 (CH Ar),

136.1 (C Ar), 144.9 (C Ar), 153.0 (CO), 173.1 (CO), 212.7

(CS); m/z 464 (MH⁺), 481 (M+NH₄⁺).

3.1.3.16.

O-Ethyl-S-[1-(N-acetyl-4-triﬂuoromethyl-

benzenesulfonylaminomethyl)-4-oxo-4-thiophen-2-yl-

butyl]dithiocarbonate 4p. Puriﬁed by ﬂash column

chromatography (petrol/EtOAc 7:3), yellow oil, 86%;

n_max/cm^ꢀ11712 (CO), 1669 (CO), 1368, 1173 (SO₂), 1226

(COS), 1063 (CS); d_H1.40 (t, J¼7 Hz, 3H, CH₃), 1.92–

2.05 (m, 1H, CH), 2.30–2.42 (m, 1H, CH), 2.38 (s, 3H,

CH₃acetyl), 3.16 (t, J¼7 Hz, 2H, CH₂CO), 4.18 (d,

J¼6.8 Hz, 2H, NCH), 4.22–4.31 (m, 1H, CHS), 4.52–4.66

(m, 2H, OCH₂), 7.13 (t, J¼4.0 Hz, 1H, H-4 thiophene),

7.64 (d, J¼4.8 Hz, 1H, CH thiophene), 7.73 (d, J¼3.2 Hz,

1H, CH thiophene), 7.81 (d, J¼8.4 Hz, 2H, H-m), 8.07 (d,

J¼8.4 Hz, 2H, H-o); d_C13.7 (CH₃xanthate), 25.0 (CH₃

acetyl), 25.8 (CH₂), 36.0 (CH₂CO), 49.5 (NCH₂), 49.7

(CHS), 70.6 (OCH₂), 122.9 (q, J¼271.4 Hz, CF₃), 126.4

(q, J¼3.6 Hz, C-m), 128.1 (C-4 thiophene), 128.4 (C-o),

132.0 (CH thiophene), 133.8 (CH thiophene), 135.4 (q,

J¼33.2 Hz, C-p), 142.8 (C-ipso), 143.8 (C-ipso), 170.3

(CO acetyl), 191.6 (CO), 212.4 (CS); m/z 554 (MH⁺), 571

(M+NH⁺₄).

3.1.3.20. Methyl 4-ethoxythiocarbonylsulfanyl-5-(N-

tert-butoxycarbonyl-4-toluenesulfonylamino)pentanoate

4c3. Puriﬁed by ﬂash column chromatography (petrol/

EtOAc gradient from 10:0 to 8:2), pale yellow oil, 93%;

n_max/cm^ꢀ12982, 2933, 1738 (CO), 1369, 1171 (SO₂),

1222 (OCS), 1048 (C]S); d_H1.35 (s, 9H, 3CH₃), 1.44 (t,

J¼6.8 Hz, 3H, CH₃xanthate), 1.84–1.98 (m, 1H, CH),

2.16–2.28 (m, 1H, CH), 2.43 (s, 3H, CH₃Ar), 2.47–2.67

(m, 2H, CH₂CO), 3.68 (s, 3H, OCH₃), 4.06–4.15 (m, 2H,

NCH₂), 4.19–4.25 (m, 1H, CHS), 4.64 (q, J¼6.8 Hz, 2H,

OCH₂), 7.30 (d, J¼7.2 Hz, 2H, CH Ar), 7.70 (d,

J¼7.2 Hz, 2H, CH Ar); d_C13.8 (CH₃xanthate), 21.7 (CH₃

Ar), 26.9 (CH₂), 27.9 (3CH₃), 31.3 (CH₂CO), 49.1

(NCH₂), 50.1 (OCH₃), 51.8 (CHS), 70.4 (OCH₂), 85.0 (C),

128.2 (CH Ar), 129.3 (CH Ar), 137.1 (C Ar), 144.4 (C

Ar), 151.0 (CO), 173.2 (CO), 212.8 (CS); m/z 506 (MH⁺),

523 (M+NH⁺₄).

3.1.3.17. O-Ethyl-S-[1-(N-acetyl-4-cyanobenzenesul-

fonylaminomethyl)-5,5-dimethyl-4-oxohexyl]dithiocar-

bonate 4q. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc 3:1), yellow oil, 93%; n_max/cm^ꢀ11709

(CO); d_H1.12 (s, 9H, CH₃), 1.42 (t, J¼7.2 Hz, 3H, CH₃xan-

thate), 1.70–1.82 (m, 1H, CH), 2.07–2.20 (m, 1H, CH), 2.35

(s, 3H, CH₃acetyl), 2.60–2.80 (m, 2H, CH₂CO), 4.05–4.20

(m, 3H, CH₂N and CHS), 4.61 (q, J¼7.2 Hz, 2H, OCH₂),

7.83 (d, J¼8.8 Hz, 2H, ArH), 8.07 (d, J¼8.4 Hz, 2H,

ArH); d_C13.7 (CH₃xanthate), 24.9 (CH₃acetyl), 25.1

3.1.3.21. Ethyl 4-ethoxythiocarbonylsulfanyl 5-(N-

triﬂuoroacetyl-4-methoxybenzenesulfonylamino)penta-

noate 4j2. Puriﬁed by ﬂash column chromatography (petrol/

EtOAc 8:2), yellow oil, 66%; d_H1.26 (t, J¼7 Hz, 3H, CH₃

ester), 1.43 (t, J¼7.2 Hz, 3H, CH₃xanthate), 1.80–1.92

(m, 1H, CH), 2.08–2.20 (m, 1H, CH), 2.40–2.60 (m, 2H,

CH₂CO), 3.89 (s, 3H, OCH₃), 4.10–4.35 (m, 5H, OCH₂es-

ter, CHS and NCH₂), 4.64 (q, J¼7.2 Hz, 2H, OCH₂xan-

thate), 6.99 (d, J¼8.8 Hz, 2H, ArH), 7.97 (d, J¼8.8 Hz,

2H, ArH); m/z 436 (MꢀCOCF₃), 454 (MꢀCOCF₃+NH⁺₄).

3.1.3.22. N-Acetyl-N-[5⁰-acetoxy-2⁰-ethoxythiocarbon-

ylsulfanyl-6,6,6-triﬂuorohex-4-en-1-yl]-4-chlorobenzene-

sulfonamide 4s. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc 8:2), yellow oil, 49%; n_max/cm^ꢀ11784

t

(CH₂), 26.5 (CH₃^tBu), 33.3 (CH₂CO), 44.1 (C Bu), 49.7

(CHS), 49.8 (CH₂N), 70.6 (OCH₂), 116.9 and 117.4 (C Ar

and CN), 128.7 (CH Ar), 132.8 (CH Ar), 143.4 (C Ar),

170.3 (CO acetyl), 212.6 and 214.5 (CO and CS); m/z 485

(MH⁺), 502 (MNH⁺₄).

3.1.3.18. O-Ethyl-S-[1-(N-acetyl-4-tert-butylbenzene-

sulfonylaminomethyl)-4-cyclohexyl-4-oxobutyl]dithio-

carbonate 4r. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc 8:2), yellow oil, 93%; n_max/cm^ꢀ11709

(CO), 1366, 1172 (SO₂), 1227, 1113 (COS), 1049 (CS); d_H

1.10–1.40 (m, 5H, CH ring), 1.34 (s, 9H, CH₃^tBu), 1.43

(t, J¼6.8 Hz, 3H, CH₃xanthate), 1.65 (d, J¼13.2 Hz, 1H,

7200

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

(CO), 1710 (CO), 1368, 1171 (SO₂), 1228 (COS), 1052

(CS); d_H1.44 (t, J¼7 Hz, 3H, CH₃), 2.27 (s, 3H, CH₃

AcO), 2.35 (s, 3H, CH₃NAc), 2.39–2.49 (m, 1H, CH),

2.53–2.62 (m, 1H, CH), 4.07 (d, J¼3.2 Hz, 1H, NCH),

4.09 (d, J¼2 Hz, 1H, NCH), 4.15–4.25 (m, 1H, CHS),

4.65 (q, J¼7.2 Hz, 2H, OCH₂), 6.22 (t, J¼7.4 Hz, 1H,

CH]), 7.52 (d, J¼8.8 Hz, 2H, CH Ar), 7.82 (d, J¼8.8 Hz,

2H, CH Ar); d_C13.4 (CH₃xanthate), 19.8 (CH₃AcO),

24.6 (CH₃AcN), 27.6 (CH₂), 47.9 (CHS), 70.4 (OCH₂),

119.3 (q, J¼271.1 Hz, CF₃), 121.6 (q, J¼13.2 Hz, CH]),

128.8, 128.9, 129.4 and 129.5 (CH Ar), 136.4 (q,

J¼36.3 Hz, C]), 137.2 (C Ar), 140.4 (C Ar), 166.9 (CO),

169.9 (CO), 211.5 (CS); m/z 547 (MH⁺), 564 (M+NH₄⁺).

3.1.4.2. N-(5-Oxo-5-phenyl-2-p-tolylpentyl)acetamide

5b. Puriﬁed by ﬂash column chromatography (petrol/EtOAc

1:9), yellow oil, 53% (method A, 2 equiv DLP); n_max/cm^ꢀ1

3453, 1549 (NH), 1706 (CO), 1691 (NCO); d_H1.90 (s, 3H,

CH₃acetyl), 1.92–2.00 (m, 1H, CH), 2.10–2.18 (m, 1H,

CH), 2.34 (s, 3H, CH₃tolyl), 2.81–2.88 (m, 2H, CH₂CO),

2.90–2.98 (m, 1H, NCH), 3.24–3.30 (m, 1H, NCH), 3.68–

3.76 (m, 1H, CHAr), 5.51 (br s, 1H, NH), 7.09 (d, J¼8 Hz,

2H, ArH), 7.15 (d, J¼8 Hz, 2H, ArH), 7.40–7.55 (m, 5H,

ArH); d_C23.3 (CH₃acetyl), 27.9 (CH₂), 30.0 (CH₃tolyl),

36.2 (CH₂CO), 44.6 (CHAr), 45.2 (NCH₂), 127.7–133.1

(CH Ar), 136.7 (C Ar), 136.8 (C Ar), 138.8 (C Ar), 170.2

(NCO), 200.2 (CO); m/z 310 (MH⁺).

3.1.3.23. O-Ethyl-S-[1-(N-acetyl-4-chlorobenzenesul-

fonylaminomethyl)-5,5,5-triﬂuoro-4-methoxyiminopent-

yl]dithiocarbonate 4t (two diastereomers). Puriﬁed by

ﬂash column chromatography (petrol/EtOAc 8:2), yellow

oil, 94%; n_max/cm^ꢀ11710 (CO), 1369 (SO₂), 1226 (O–

CS), 1171 (SO₂), 1053 (C]S); d_H1.435 and 1.442 (2t,

J¼7.2 Hz each, 3H, CH₃xanthate), 1.78–2.15 (m, 2H,

CH₂), 2.345–2.350 (2s, 3H, CH₃acetyl), 2.48–2.72 (m,

2H, CH₂C]N), 3.96–3.99 (2s, 3H, OCH₃), 4.07–4.15 (m,

2H, NCH₂), 4.18–4.26 (m, 1H, CHS), 4.60–4.68 (m, 2H,

OCH₂), 7.49–7.55 (m, 2H, CH Ar), 7.80–7.86 (m, 2H, CH

Ar); d_C13.7 (CH₃xanthate), 22.3 (CH₂), 25.1 (CH₃acetyl),

27.1 (CH₂C]N), 48.9 and 49.0 (NCH₂), 49.0 and 49.8

(CHS), 63.3 (OCH₃), 70.5 (OCH₂), 120.7 (q, J¼272.5 Hz,

CF₃), 129.0 and 129.1 (2CH Ar), 129.65 and 129.70 (2CH

Ar), 137.7 and 137.8 (C Ar), 140.70 and 140.74 (C Ar),

145.0 (q, J¼29.2 Hz, C]N), 147.8 (q, J¼31.7 Hz, C]N),

170.2 (CO), 212.3 and 212.4 (CS); m/z 535 (MH⁺), 552

(M+NH⁺₄).

3.1.4.3. Methyl 5-acetylamino-4-p-tolylpentanoate 5c.

Puriﬁed by ﬂash column chromatography (petrol/EtOAc

3:7), yellow oil, 71% (method A, 1.35 equiv DLP); n_max

/

cm^ꢀ13451, 3350, 1436 (NH), 1739 (CO ester), 1685 (CO

amide), 1513 (OMe); d_H1.88 (s, 3H, CH₃acetyl), 2.02–

2.04 (m, 1H, CH), 2.16–2.20 (m, 1H, CH), 2.33 (s, 3H,

CH₃tolyl), 2.69–2.77 (m, 1H, CHN), 3.16–3.24 (m, 1H,

CHN), 3.61 (s, 3H, OCH₃), 3.66–3.71 (m, 1H, CHAr),

5.44 (br s, 1H, NH), 7.05 (d, J¼8.4 Hz, 2H, ArH), 7.14 (d,

J¼7.6 Hz, 2H, ArH); d_C23.3 (CH₃acetyl), 28.8 (CH₂),

30.0 (CH₃tolyl), 36.2 (CH₂CO), 44.6 (CHAr), 45.2

(CH₂N), 52.0 (OCH₃), 127.7, 129.7, 129.9 (4CH Ar),

136.8 and 138.3 (C-ipso and C-p), 170.2 (CO amide),

174.0 (CO ester), m/z 264 (MH⁺), 281 (M+NH₄⁺).

3.1.4.4. N-[4-Cyano-2-(4-methoxyphenyl)butyl]acet-

amide 5d. Puriﬁed by ﬂash column chromatography (pet-

rol/EtOAc gradient from 9:1 to 3:7), yellow oil, 77%

(method A, 1.2 equiv DLP); n_max/cm^ꢀ13453 (NH), 2932,

2836, 2249 (CN), 1686, 1512 (NC]O), 1463 (NH), 1251,

1178, 1040; d_H1.77–1.80 (m, 1H, CH), 1.90 (s, 3H, CH₃ace-

tyl), 2.06–2.10 (m, 1H, CH), 2.11–2.15 (m, 1H, CHCN),

2.23–2.29 (m, 1H, CHCN), 2.83–2.87 (m, 1H, CHN),

3.19–3.26 (m, 1H, CHN), 3.65–3.72 (m, 1H, CHAr), 3.90

(s, 3H, OCH₃), 5.52 (br s, 1H, NH), 6.90 (d, J¼8 Hz, 2H,

CH Ar), 7.10 (d, J¼8 Hz, 2H, CH Ar); d_C15.2 (CH₂),

23.3 (CH₃acetyl), 29.3 (CH₂CN), 44.1 (NCH₂), 44.6

(CHAr), 55.4 (OCH₃), 114.7 (2CH Ar), 119.0 (CN), 128.7

(2CH Ar), 131.8 (C Ar), 159.1 (C Ar), 170.6 (CO); m/z

247 (MH⁺), 264 (M+NH⁺₄).

3.1.4. General procedure for the synthesis of the transfer

products 5. Method A: to a solution of acetylsulfonamide 4

(1 equiv) in isopropanol (4 mL/mmol) at reﬂux temperature

was added DLP (15% molar) every 1.5 h, until the disap-

pearance of starting material. The reaction mixture was

then evaporated, and the residue was puriﬁed by ﬂash col-

umn chromatography.

Method B: to a solution of acetylsulfonamide 4 (1 equiv) in

a mixture of 1,2-dichloroethane/isopropanol 1:1 (0.02 M) at

reﬂux temperature was added DLP (0.5 equiv) every hour,

until 2 equiv have been added. The reaction mixture was

then evaporated, and the residue was puriﬁed by column

chromatography.

3.1.4.5. Ethyl 3-acetoxy-2-(3-acetylamino-2-phenyl-

propyl)-3-phenyl acrylate 5e. Puriﬁed by ﬂash column

chromatography (petrol/CH₂Cl₂/Et₂O 55:22:22), yellow

oil, 29% (method A, 1.65 equiv DLP); n_max/cm^ꢀ13069,

2982, 1769 (OAc), 1712 (NC]O); d_H1.34 (t, J¼7.2 Hz,

CH₃ester), 1.85 (s, 3H, NCOCH₃), 2.38 (s, 3H, OCOCH₃),

2.41 (s, 3H, CH₃Ar), 2.85–3.05 (m, 2H, NCH₂), 3.42–3.49

(m, 1H, CHAr), 3.86–4.10 (m, 2H, CH₂), 4.21–4.32 (m, 2H,

OCH₂ester), 7.28–7.78 (m, 9H, CH Ar); d_C14.4 (CH₃ester),

21.0 (OCOCH₃), 21.7 (CH₃Ar), 24.1 (NCOCH₃), 26.4

(CH₂), 37.5 (CHAr), 50.1 (NCH₂), 61.0 (OCH₂ester),

114.6 (]C–CO), 123.7–130.9 (9CH Ar), 136.7 (C Ar),

137.9 (C Ar), 144.9 (C Ar), 150.3 (O–C]), 165.4 (CO),

168.8 (CO), 170.1 (CO); m/z 424 (MH⁺), 441 (M+NH₄⁺).

3.1.4.1. N-(5-Oxo-2-p-tolylhexyl)acetamide 5a. Puri-

ﬁed by ﬂash column chromatography (petrol/EtOAc gradi-

ent from 7:3 to 1:9), yellow oil, 66% (method A, 1.5 equiv

DLP); n_max/cm^ꢀ13453 (NH), 2925, 1718 (C]O), 1683

(NC]O), 1512 (NH), 1363, 1261, 1160; d_H1.75–1.82 (m,

1H, CH), 1.75–2.05 (m, 1H, CH), 1.88 (s, 3H, CH₃), 2.05

(s, 3H, CH₃acetyl), 2.28–2.31 (m, 2H, CH₂CO), 2.34 (s,

3H, CH₃Ar), 2.65–2.75 (m, 1H, NCH), 3.17–3.23 (m, 1H,

NCH), 3.64–3.68 (m, 1H, CHAr), 5.46 (br s, 1H, NH),

7.04 (d, J¼8 Hz, 2H, CH Ar), 7.14 (d, J¼8 Hz, 2H, CH

Ar); d_C21.1 (CH₃), 23.3 (CH₃acetyl), 27.2 (CH₂), 30.0

(CH₃Ar), 41.2 (CH₂CO), 44.4 (CHAr), 45.0 (NCH₂),

127.6 (2CH Ar), 129.6 (2CH Ar), 136.7 (C Ar), 143.5 (C

Ar), 170.1 (CO amide), 208.7 (CO ketone); m/z 248 (MH⁺).

3.1.4.6. N-(5-Oxo-6-phenyl-2-p-tolylhexyl)acetamide

5f. Puriﬁed by ﬂash column chromatography (petrol/EtOAc

3:7), yellow oil, 60% (method B); n_max/cm^ꢀ13451 (NH),

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7201

1714 (CO ketone), 1684 (CO amide); d_H1.70–1.80 (m, 1H,

CH), 1.87 (s, 3H, CH₃acetyl), 1.95–2.05 (m, 1H, CH), 2.35

(s, 3H, CH₃tolyl), 2.25–2.45 (m, 2H, CH₂CO), 2.65–2.75

(m, 1H, CHAr), 3.18 (ddd, J¼4.7, 8.5, 13.3 Hz, 1H,

CH₂N), 3.59 (s, 2H, CH₂Ph), 3.55–3.66 (m, 1H, CH₂N),

5.64 (br s, 1H, NH), 6.97 (d, J¼7.9 Hz, 2H, ArH), 7.05–

7.20 (m, 4H, ArH), 7.20–7.40 (m, 3H, ArH); d_C20.9 (CH₃

tolyl), 23.0 (CH₃acetyl), 27.1 (CH₂), 39.3 (CH₂CO), 44.2

(CHAr), 44.8 (CH₂N), 49.9 (CH₂Ph), 126.8, 127.5, 128.5,

129.2, 129.4 (CH Ar), 133.9 (C Ar), 136.4 (C Ar), 138.4 (C

Ar), 170.0 (CO amide), 207.9 (CO); m/z 324 (MH⁺), 341

(M+NH⁺₄); Elem. Anal. Calcd for C₂₁H₂₅NO₂$1/2H₂O: C,

75.87; H, 7.88; N, 4.21; found: C, 75.39; H, 7.84; N, 4.07.

(petrol/EtOAc gradient from 9:1 to 3:7), yellow oil, 69%

(method A, 1.6 equiv DLP); n_max/cm^ꢀ13451 (NH), 2933,

1735 (C]O), 1685 (NC]O), 1513, 1251 (OMe); d_H1.21

(t, J¼7.6 Hz, 3H, CH₃ester), 1.79–1.85 and 1.99–2.06

(2m, 2H, CH₂), 1.88 (s, 3H, CH₃acetyl), 2.14–2.17 (m,

2H, CH₂CO), 2.71–2.74 and 3.64–3.71 (m, 2H, NCH₂),

3.15–3.22 (m, 1H, CHAr), 3.80 (s, 3H, OCH₃), 4.06 (q,

J¼7.6 Hz, 2H, OCH₂ester), 6.87 (d, J¼8.8 Hz, 2H, CH

Ar), 7.08 (d, J¼8.8 Hz, 2H, CH Ar); d_C14.2 (CH₃ester),

23.3 (CH₃acetyl), 28.9 (CH₂), 32.0 (COCH₂), 44.0

(NCH₂), 44.2 (CHAr), 55.3 (OCH₃), 60.4 (OCH₂), 114.3

(2CH Ar), 128.8 (2CH Ar), 133.3 (C Ar), 158.6 (C Ar),

170.1 (NC]O), 173.5 (OC]O); m/z 294 (MH⁺).

3.1.4.7. N-[4-(1-Benzyl-1H-tetrazol-5-yl)-2-p-tolylbut-

yl]acetamide 5g. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc gradient from 9:1 to 3:7), yellow oil, 64%

(method A, 1.5 equiv DLP), n_max/cm^ꢀ13049, 2926, 1680

(C]O), 1442, 1422 (NH), 1267; d_H1.85–1.93 and 2.24–

2.30 (m, 2H, CH₂), 1.90 (s, 3H, CH₃acetyl), 2.35 (s, 3H,

CH₃Ar), 2.53–2.58 (m, 2H, CCH₂), 2.78–2.82 and 3.47–

3.62 (m, 2H, NCH₂), 3.20–3.26 (m, 1H, CHAr), 5.32 (s,

2H, NCH₂Ph), 5.78 (br s, 1H, NH), 6.97–7.32 (m, 9H, CH

Ar); d_C20.9 (CH₃Ar), 21.0 (CCH₂), 23.1 (CH₃acetyl),

30.2 (CH₂), 44.2 (NCH₂), 44.6 (CHAr), 50.5 (NCH₂Ph),

127.3–129.6 (9CH Ar), 133.0 (C Ar), 136.8 (C Ar), 137.7

(C Ar), 154.6 (C]N), 170.2 (NC]O); m/z 363 (MH⁺).

3.1.4.11. N-[2-(4-Fluorophenyl)-4-phenoxycarbonyl-

butyl]acetamide 5k. Puriﬁed by ﬂash column chromato-

graphy (petrol/EtOAc 3:7), yellow oil, 47% (method B);

n_max/cm^ꢀ13456 (NH), 1761 (CO ester), 1686 (CO); d_H

1.87 (s, 3H, CH₃acetyl), 1.80–2.00 (m, 1H, CH), 2.05–

2.15 (m, 1H, CH), 2.42 (t, J¼7.6 Hz, 2H, CH₂CO), 2.82–

2.95 (m, 1H, CHAr), 3.25 (ddd, J¼5.1, 8.6, 13.5 Hz, 1H,

CHN), 3.66 (td, J¼6.5, 13.2 Hz, 1H, CHN), 6.97–7.08 (m,

4H, H-m ﬂuorophenyl and H-o phenyl), 7.12–7.24 (m, 3H,

H-p phenyl and H-o ﬂuorophenyl), 7.35 (t, J¼8 Hz, 2H,

H-m phenyl); d_C23.1 (CH₃), 28.5 (CH₂), 31.9 (CH₂CO),

44.3 (CHAr), 44.9 (CH₂N), 115.8 (d, J¼21.1 Hz, C-m ﬂuo-

rophenyl), 121.4 (C-o phenyl), 125.8 (C-p phenyl), 129.2 (d,

J¼7.8 Hz, C-o ﬂuorophenyl), 129.3 (C-m phenyl), 137.0 (d,

J¼3.1 Hz, C-ipso ﬂuorophenyl), 150.5 (C-ipso phenyl),

161.9 (d, J¼243.9 Hz, C-p ﬂuorophenyl), 170.1 and 171.7

(CO amide and ester); m/z 330 (MH⁺), 347 (M+NH₄⁺);

Elem. Anal. Calcd for C₁₉H₂₀FNO₃$1/2H₂O: C, 67.44; H,

6.26; N, 4.14; found: C, 67.66; H, 6.41; N, 4.19.

3.1.4.8. N-(5-Cyclopropyl-5-oxo-2-p-tolylpentyl)acet-

amide 5h. Isolated as a white solid, 54% (method A); mp

(petrol/Et₂O): 101–102 ^ꢁC; n_max/cm^ꢀ13255 (NH), 1698,

1632 (CO); d_H0.84–0.76 (m, 2H, CH₂), 0.98–0.90 (m, 2H,

CH₂), 1.84–1.75 (m, 2H, CH, CHCO), 1.88 (s, 3H, CH₃ace-

tyl), 2.06–1.97 (m, 1H, CH), 2.34 (s, 3H, CH₃Ar), 2.44 (m,

2H, CH₂CO), 2.73 (m, 1H, CHAr), 3.21 (ddd, 1H, J¼4.8,

10.4, 13.2 Hz, CHN), 3.64 (m, 1H, CHN), 5.58 (m, 1H,

NH), 7.05 (d, J¼8 Hz, 2H, ArH), 7.14 (d, J¼8 Hz, 2H,

ArH); d_C10.7 (2CH₂), 20.5 and 21.0 (CH₃CO, CHCO),

23.2 (CH₃Ar), 27.5 (CH₂), 40.9 (CH₂CO), 44.5 (CHAr),

45.1 (CH₂N), 127.7 (CH Ar), 129.6 (CH Ar), 138.6 (C

Ar), 138.8 (C Ar), 170.1 (NHCO), 210.6 (CO); Elem.

Anal. Calcd for C₁₇H₂₃NO₂$0.25H₂O: C, 73.53; H, 8.53;

found: C, 73.52; H, 8.45.

3.1.4.12. Ethyl 7-acetylamino-6-(4-chlorophenyl)-3-

oxoheptanoate 5l. Puriﬁed by ﬂash column chromato-

graphy (petrol/EtOAc gradient from 9:1 to 7:3), yellow oil,

60% (method A, 1.5 equiv DLP); n_max/cm^ꢀ13455 (NH),

2981, 2929, 1743, 1709 (CO), 1687 (NC]O), 1507, 1171;

d_H1.40 (t, J¼6.8 Hz, 3H, CH₃ester), 1.82–1.92 (m, 1H,

CH), 2.05 (s, 3H, CH₃acetyl), 2.07–2.16 (m, 1H, CH),

2.36–2.49 (m, 2H, CH₂CO), 3.20 (t, J¼6.4 Hz, NCH₂),

3.80–3.84 (m, 1H, CHAr), 3.87 (s, 2H, COCH₂CO), 4.59

(q, J¼6.8 Hz, OCH₂ester), 5.09 (br s, 1H, NH), 6.97 (d,

J¼8.8 Hz, 2H, CH Ar), 7.78 (d, J¼8.8 Hz, 2H, CH Ar); d_C

14.2 (CH₃ester), 23.3 (CH₃acetyl), 29.6 (CH₂), 35.6

(COCH₂), 44.5 (NCH₂), 44.6 (CHAr), 44.8 (COCH₂CO),

60.9 (OCH₂ester), 129.1 (2CH Ar), 129.2 (2CH Ar),

133.0 (C Ar), 140.3 (C Ar), 170.1 (NC]O), 195.5

(OC]O), 198.6 (C]O); m/z 339 (MH⁺), 352 (M+NH₄⁺).

3.1.4.9.

N-[5-Oxo-5-(2-oxooxazolidin-3-yl)-2-(4-tri-

ﬂuoromethoxyphenyl)pentyl]acetamide 5i. Isolated as

white crystals, 60% (method A); mp (petrol/Et₂O): 135–

136 ^ꢁC; n_max/cm^ꢀ11791 (OCON), 1708 (NCO), 1384,

1167 (NSO₂), 1215 (C]S), 1048 (COS); d_H1.91 (s, 3H,

CH₃CO), 2.0–1.93 (m, 1H, CH), 2.14–2.05 (m, 1H, CH),

2.82 (m, 2H, CH₂CO), 2.92 (m, 1H, CH), 3.29 (ddd, 1H, J¼

5.2, 8.3, 13.5 Hz, CHN), 3.65 (td, 1H, J¼6.6, 13.4 Hz, CHN),

3.95 (m, 2H, CH₂), 4.39 (t, J¼8 Hz, 2H, CH₂), 5.67 (m, 1H,

NH), 7.19 (d, J¼8.4 Hz, 2H, ArH), 7.24 (d, J¼8.4 Hz, 2H,

ArH); d_C23.3 (CH₃CO), 28.1 (CH₂), 32.9 (CH₂CO), 42.5

(CH₂N), 44.5 (CH), 44.8 (CH₂N), 62.1 (CH₂OCO), 120.5

(q, J¼256 Hz, OCF₃), 121.3 (Ar), 129.2 (Ar), 140.4 (Ar),

148.2 (Ar), 153.5 (CO), 170.2 (CO), 172.8 (CO); m/z 389

(MH⁺), 405 (M+NH⁺₄); Elem. Anal. Calcd for

C₁₇H₁₉F₃N₂O₅: C, 52.58; H, 4.93; found: C, 52.91; H, 5.02.

3.1.4.13. N-[2-(2-Chlorophenyl)-3-(2-oxotetrahydro-

furan-3-yl)propyl]acetamide 5m. Two diastereomers, D1

and D2, puriﬁed by ﬂash column chromatography (petrol/

EtOAc 3:7), white foam, 72% (method B); n_max/cm^ꢀ1

1780 (CO ester), 1686 (CO amide); d_H1.62–1.85 (m, 3H,

CH D1, CH D2, CH ring D2), 1.90–1.91 (2s, 6H, CH₃ace-

tyl), 1.90–2.05 (m, 1H, CH ring D1), 2.12–2.25 (m, 2H, CH

ring D1, CHCO D2), 2.27–2.41 (m, 3H, CH ring D1, CH D1,

CH D2), 2.52–2.62 (m, 1H, CH ring D1), 3.20–3.40 (m, 2H,

CHN D1, CHN D2), 3.57–3.84 (m, 4H, CHN D1, CHN D2,

CHAr D1, CHAr D2), 4.09 (ddd, J¼6.4, 10.1, 19.4 Hz, 2H,

CHO), 4.27 (dt, J¼1.6, 8.9 Hz, 1H, CHO), 4.34 (dt, J¼2,

3.1.4.10. Ethyl 5-acetylamino-4-(4-methoxyphenyl)-

pentanoate 5j. Puriﬁed by ﬂash column chromatography

7202

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

8.8 Hz, 1H, CHO), 5.39 and 5.44 (2 br s, 2H, NH), 7.15–7.45

(m, 8H, ArH); d_C23.0 (CH₃), 28.8 (CH₂ring D2), 29.3 (CH₂

ring D1), 33.3 (CH₂D1), 33.8 (CH₂D2), 37.1 (CH₂ring D1),

37.7 (CH₂ring D2), 38.7 (CHAr D1), 39.6 (CHAr D2), 43.3

(CH₂N D2), 44.8 (CH₂N D1), 66.5 (CHO D1 and D2), 127.3,

127.7, 127.8, 128.2, 128.3, 129.7, 129.8 (CH Ar), 134.4,

134.8, 138.1, 139.3 (C-ipso and CCl), 170.35 and 170.42

(NCO D1 and D2), 179.3 (CO D1 and D2); m/z 296

(MH⁺), 313 (M+NH⁺₄).

3.1.4.17. N-[2-(4-Cyanophenyl)-6,6-dimethyl-5-oxo-

heptyl]acetamide 5q. Puriﬁed by ﬂash column chromato-

graphy (petrol/EtOAc 3:7), transparent oil, 81% (method

B); n_max/cm^ꢀ13458 (NH), 2231 (CN), 1705 (CO ketone),

1687 (CO amide); d_H1.07 (s, 9H, CH₃^tBu), 1.74–1.87 (m,

1H, CH), 1.92 (s, 3H, CH₃acetyl), 1.98–2.10 (m, 1H, CH),

2.34 (ddd, J¼5.5, 7.9, 18 Hz, 1H, CHCO), 2.44 (td, J¼7.6,

17.8 Hz, 1H, CHCO), 2.92 (t, J¼14.6 Hz, 1H, CHAr), 3.31

(ddd, J¼5.6, 8.1, 13.6 Hz, 1H, NCH), 3.60 (td, J¼6.5,

13.2 Hz, 1H, NCH), 5.73 (br s, 1H, NH), 7.32 (d,

J¼8.4 Hz, 2H, ArH), 7.65 (d, J¼8 Hz, 2H, ArH); d_C23.1

(CH₃acetyl), 26.3 (CH₃^tBu), 26.9 (CH₂), 33.6 (CH₂CO),

3.1.4.14. N-[2-(4-Bromophenyl)-5-oxo-5-piperidin-1-

yl-pentyl]acetamide 5n. Puriﬁed by ﬂash column chroma-

tography (EtOAc/MeOH 95:5), white foam, 70% (method

B); n_max/cm^ꢀ13465 (NH), 1683 (CO), 1641 (CO); d_H

1.40–1.60 (m, 6H), 1.72–1.82 (m, 1H, CH), 1.87 (s, 3H,

CH₃acetyl), 2.00–2.22 (m, 3H, CH and CH₂CO), 2.74–

2.84 (m, 1H, CHAr), 3.14–3.28 (m, 3H, NCH₂piperidine

and NCH), 3.40–3.58 (m, 3H, NCH₂piperidine and NCH),

5.99 (br s, 1H, NH), 7.03 (d, J¼8.4 Hz, 2H, ArH), 7.41 (d,

J¼8 Hz, 2H, ArH); d_C23.1 (CH₃), 24.4, 25.5 and 26.3

(3CH₂piperidine), 28.6 (CH₂), 30.3 (CH₂CO), 42.7 (NCH₂

piperidine), 44.4 (CHAr), 44.8 (NCH₂), 46.4 (NCH₂piperi-

dine), 120.6 (C Ar), 129.4 (CH Ar), 131.8 (CH Ar), 141.3 (C

Ar), 170.2 (CO), 170.5 (CO amide); m/z 380 (MH⁺); Elem.

Anal. Calcd for C₁₈H₂₅BrN₂O₂$1/2H₂O: C, 55.39; H, 6.71;

N, 7.18; found: C, 54.99; H, 6.53; N, 6.91.

t

44.0 (C Bu), 44.7 (NCH), 45.1 (CHAr), 110.8 and 118.6

(C Ar and CN), 128.6 (CH Ar), 132.5 (CH Ar), 148.0 (C

Ar), 170.1 (CO acetyl), 215.3 (CO); m/z 301 (MH⁺), 318

(M+NH⁺₄); Elem. Anal. Calcd for C₁₈H₂₄N₂O₂$1/2H₂O: C,

69.87; H, 8.14; N, 9.05; found: C, 69.81; H, 8.13; N, 8.99.

3.1.4.18. N-[2-(4-tert-Butylphenyl)-5-cyclohexyl-5-oxo-

pentyl]acetamide 5r. Puriﬁed by ﬂash column chromato-

graphy (EtOAc), white foam, 70% (method B); n_max/cm^ꢀ1

3453 (NH), 1708 (CO ketone), 1684 (CO amide); d_H1.00–

1.40 (m, 5H), 1.31 (s, 9H, CH₃^tBu), 1.55–1.85 (m, 7H),

1.88 (s, 3H, CH₃acetyl), 1.90–2.05 (m, 1H, CH), 2.15–

2.45 (m, 3H, H-1 cyclohexyl and CH₂CO), 2.71 (t,

J¼14.6 Hz, 1H, CHAr), 3.21 (ddd, J¼4.8, 8.2, 13.1 Hz,

1H, CHN), 3.61 (td, J¼6.6, 13.3 Hz, 1H, CHN), 5.79 (br s,

1H, NH), 7.06 (d, J¼8.2 Hz, 2H, ArH), 7.32 (d, J¼8.3 Hz,

2H, ArH); d_C23.1 (CH₃acetyl), 25.4, 25.5, 25.6 (CH₂cyclo-

hexyl), 26.9 (CH₂), 28.2, 28.4 (CH₂cyclohexyl), 31.2 (CH₃

3.1.4.15. Methyl 5-acetylamino-2-dimethoxymethyl-4-

(4-iodophenyl)pentanoate 5o. Puriﬁed by ﬂash column

chromatography (EtOAc), white foam, 60% (method A);

n_max/cm^ꢀ13453 (NH), 1739 (CO), 1687 (NCO); d_H1.84

(s, 1H, CH₃acetyl), 1.85 (s, 2H, CH₃acetyl), 1.78–2.07

(m, 2H, CH₂), 2.61–2.84 and 2.40–2.46 (2m, 2H), 3.22

and 3.14 (2s, 6H, 2 OCH₃), 3.16–3.26 (m, 1H, NCH), 3.28

and 3.29 (2s, 2H, CO₂CH₃), 3.40 (s, 1H, CO₂CH₃), 3.54–

3.66 (m, 1H, CHAr), 3.68 (s, 2H, CO₂CH₃), 4.39 (d,

0.33H, J¼7.6 Hz, CHOCH₃), 4.43 (d, 0.67H, J¼7.6 Hz,

CHOCH₃), 5.43 (m, 1H, NH), 6.90 (d, 2H, J¼8.3 Hz,

ArH), 7.64 (d, 2H, J¼8.4 Hz, ArH); d_C23.3 (CH₃CO).

31.4, 31.7 (CH₂), 43.3, 43.9 (CH), 44.6, 45.1 (CH₂N),

46.6, 47.6 (CH), 52.6, 53.6, 54.5, 54.7 (OCH₃), 92.4, 92.6

(CI), 104.4, 104.9 (CHOCH₃), 130.0, 130.2, 137.8, 137.9,

141.4, 140.9 (CH Ar), 170.1 (CO amide), 173.0 (CO ester),

m/z 418 (MH⁺ꢀMeOH), 450 (MH⁺), 467 (M+NH⁺₄); Elem.

Anal. Calcd for C₁₇H₂₄INO₅: C, 45.45; H, 5.38; found: C,

45.89; H, 5.58.

^tBu), 34.3 (C Bu), 38.0 (CH₂CO), 44.3 (CHAr), 44.9

t

(CH₂N), 50.6 (C-1 cyclohexyl), 125.4 (CH Ar), 127.2 (CH

Ar), 138.6 (C Ar), 149.5 (C Ar), 170.0 (CO acetyl), 213.7

(CO); m/z 358 (MH⁺).

3.1.4.19. Methyl 5-methoxycarbonylamino-4-p-tolyl-

pentanoate 5c2. Puriﬁed by ﬂash column chromatography

(petrol/CH₂Cl₂/Et₂O gradient from 10:0:0 to 60:20:20), yel-

low oil, 34% (method A, 1.65 equiv DLP); n_max/cm^ꢀ13456

(NH), 3021, 2951, 2927, 1741 (CO), 1467, 1369; d_H1.81–

1.98 (m, 1H, CH), 2.02–2.07 (m, 1H, CH), 2.17–2.77

(CH₂CO), 2.33 (s, 3H, CH₃Ar), 2.71–2.77 (m, 1H, CHN),

3.19–3.25 (m, 1H, CHAr), 3.52–3.58 (m, 1H, CHN), 3.62

(s, 3H, OCH₃), 3.62 (s, 3H, OCH₃), 4.60 (br s, 1H, NH),

7.02 (d, J¼7.2 Hz, 2H, CH Ar), 7.14 (d, J¼7.2 Hz, 2H,

CH Ar); d_C21.1 (CH₃Ar), 28.4 (CH₂), 31.7 (CH₂CO),

45.1 (OCH₃), 46.4 (NCH₂), 51.6 (OCH₃), 52.2 (CHAr),

127.5 (CH Ar), 129.4 (CH Ar), 136.6 (C Ar), 138.0 (C

Ar), 156.8 (CO), 173.6 (CO); m/z 280 (MH⁺), 297 (M+NH₄⁺).

3.1.4.16. N-[5-Oxo-5-thiophen-2-yl-2-(4-triﬂuorometh-

ylphenyl)pentyl]acetamide 5p. Puriﬁed by ﬂash column

chromatography (EtOAc), yellow oil, 33% (method B);

n_max/cm^ꢀ13458 (NH), 1685 (CO); d_H1.90 (s, 3H, CH₃ace-

tyl), 1.92–2.03 (m, 1H, CH), 2.15–2.27 (m, 1H, CH), 2.70–

2.87 (m, 1H, CH₂CO), 2.93–3.03 (m, 1H, CHAr), 3.32 (ddd,

J¼5.4, 8.2, 13.6 Hz, 1H, NCH), 3.65 (qt, J¼6.7 Hz, 1H,

NCH), 5.63 (br s, 1H, NH), 7.07 (dd, J¼4, 4.8 Hz, 1H,

H-4 thiophene), 7.31 (d, J¼8 Hz, 2H, H-o), 7.54–7.64 (m,

4H, H-m and 2CH thiophene); d_C23.1 (CH₃acetyl), 27.7

(CH₂), 36.5 (CH₂CO), 44.8 (NCH), 44.9 (CHAr), 124.1 (q,

J¼270.4 Hz, CF₃), 125.8 (q, J¼3.65 Hz, C-m), 128.1 (C-4

thiophene), 128.2 (C-o), 129.4 (q, J¼32.2 Hz, C-p), 131.9

and 133.7 (C-3 and C-5 thiophene), 143.9 (C-ipso), 146.1

(C-ipso), 170.2 (CO acetyl), 192.4 (CO); m/z 370 (MH⁺),

387 (M+NH⁺₄).

3.1.4.20. Methyl 5-tert-butoxycarbonylamino-4-p-tol-

ylpentanoate 5c3. Puriﬁed by ﬂash column chromatography

(petrol/CH₂Cl₂/Et₂O gradient from 10:0:0 to 50:30:20), yel-

low oil, 37% (method A, 1.50 equiv DLP); n_max/cm^ꢀ13456

(NH), 2980, 2928, 1739 (CO), 1718 (NCO); d_H1.40 (s, 9H,

3CH₃), 1.78–1.88 (m, 1H, CH), 1.97–2.07 (m, 1H, CH),

2.16–2.20 (m, 2H, CH₂CO), 2.33 (s, 3H, CH₃Ar), 2.68–

2.76 (m, 1H, NCH), 3.14–3.20 (m, 1H, CHAr), 3.43–3.51

(m, 1H, NCH), 3.61 (s, 3H, OCH₃), 4.44 (br s, 1H, NH),

7.05 (d, J¼7.2 Hz, 2H, ArH), 7.14 (d, J¼7.2 Hz, 2H,

ArH); d_C21.1 (CH₃Ar), 28.5 (3CH₃), 28.6 (CH₂), 31.9

(CH₂CO), 45.1 (CHAr), 46.2 (NCH₂), 51.6 (OCH₃), 76.8

(C), 127.8 (CH Ar), 129.6 (CH Ar), 136.6 (C Ar), 138.4

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7203

(C Ar), 150.4 (NCO), 173.9 (CO); m/z 322 (MH⁺), 339

308 (MH⁺), 325 (M+NH₄⁺); HRMS calcd for C₁₇H₂₅NO₄,

307.1784; found, 307.1784.

(M+NH⁺₄).

3.1.4.21. Ethyl 4-(4-methoxyphenyl)-5-triﬂuoroacetyl-

aminopentanoate 5j2. Puriﬁed by ﬂash column chromato-

graphy (petrol/EtOAc 7:3), yellow oil, 40% (method A);

d_H1.21 (t, J¼7.2 Hz, 3H, CH₃), 1.78–1.82 (m, 1H, CH),

1.95–2.08 (m, 1H, CH), 2.18 (t, J¼7.6 Hz, 2H, CH₂CO),

2.75–2.85 (m, 1H, NCH), 3.32 (ddd, J¼4.8, 8.4, 13.2 Hz,

1H, CHAr), 3.70 (qt, J¼6.8 Hz, 1H, NCH), 3.79 (s, 3H,

OCH₃), 4.07 (q, J¼7.2 Hz, 2H, OCH₂), 6.38 (br s, 1H,

NH), 6.87 (d, J¼8.4 Hz, 2H, ArH), 7.07 (d, J¼8.4 Hz, 2H,

ArH); m/z 348 (MH⁺), 365 (M+NH₄⁺).

3.1.5. General procedure for the synthesis of addition

products 6. To a solution of xanthate 3 (1.5 equiv) in 1,2-di-

chloroethane (1 mL/mmol) was added sulfonamide 1

(1 equiv), and the mixture was heated at reﬂux temperature.

DLP (5% molar) was then added every 1.5 h until almost

complete consumption of the starting material. Then the re-

action mixture was evaporated, and the residue was puriﬁed

by ﬂash column chromatography.

3.1.5.1. Methyl 4-ethoxythiocarbonylsulfanyl-5-(4-

toluenesulfonylamino)pentanoate 6c. Puriﬁed by ﬂash

chromatography (petrol/AcOEt 6:4), yellow oil, 85%;

n_max/cm^ꢀ11741 (CO), 1598 (NH), 1495, 1437, 1337,

1163 (SO₂), 1222 (COS), 1052 (CS); d_H1.41 (t, J¼8 Hz,

3H, CH₃), 1.85–1.95 (m, 1H, CH), 2.13–2.19 (m, 1H,

CH), 2.44 (s, 3H, CH₃tolyl), 2.46–2.50 (m, 2H, CH₂CO),

3.21–3.24 (m, 2H, CH₂N), 3.68 (s, 3H, OCH₃), 3.81–3.85

(m, 1H, CHS), 4.60 (q, J¼7.2 Hz, 2H, OCH₂), 7.30 (d,

J¼8 Hz, 2H, CH Ar), 7.71 (d, J¼8 Hz, 2H, CH Ar); d_C

13.8 (CH₃), 21.7 (CH₃tolyl), 26.2 (CH₂), 31.1 (CH₂CO),

44.6 (OCH₃), 46.3 (CH₂N), 50.1 (CHS), 70.6 (OCH₂),

127.2, 127.5, 129.9, 131.2 (CH Ar), 136.7 (C-p), 143.7

(C-ipso), 176.0 (CO), 212.6 (CS); m/z 406 (MH⁺), 423

(MNH⁺₄).

3.1.4.22.

5-Acetylamino-4-(4-chlorophenyl)-1-tri-

ﬂuoromethylpent-1-enyl acetate 5s. Puriﬁed by ﬂash col-

umn chromatography (EtOAc), yellow oil, 19% (method

B); n_max/cm^ꢀ13451 (NH), 1786 (CO), 1686 (CO); d_H1.89

(s, 3H, CH₃), 2.27 (s, 3H, CH₃), 2.20–2.32 (m, 1H, CH),

2.38 (dddd, J¼1.5, 6.8, 8.3, 15.1 Hz, 1H, CH), 2.97 (qt,

J¼7.4 Hz, 1H, CHAr), 3.32 (ddd, J¼5.6, 7.7, 13.5 Hz, 1H,

NCH), 3.50 (td, J¼6.8, 13.7 Hz, 1H, NCH), 5.67 (br s, 1H,

NH), 5.92 (dd, J¼6.8, 7.9 Hz, 1H, CH]), 7.11 (d,

J¼8.4 Hz, 2H, ArH), 7.31 (d, J¼8.4 Hz, 2H, ArH); d_C

20.2 (CH₃), 23.1 (CH₃), 29.8 (CH₂), 43.6 (CHAr), 44.7

(NCH₂), 119.5 (q, J¼271 Hz, CF₃), 128.8 (CH Ar), 129.1

(CH Ar), 133.1 (C Ar), 123.5 (q, J¼3.4 Hz, CH]), 135.5

(q, J¼36.5 Hz, C]), 139.5 (C Ar), 167.6 (CO), 170.1

(CO); m/z 363 (MH⁺), 380 (M+NH₄⁺).

3.1.5.2. Ethyl 2-benzoyl-4-ethoxythiocarbonylsul-

fanyl-5-(4-toluenesulfonylamino)pentanoate 6e. Puriﬁed

by ﬂash column chromatography (petrol/EtOAc gradient

from 10:0 to 7:3), 97%, yellow oil; n_max/cm^ꢀ13284 (NH),

3065, 2983, 2938, 1741 (OC]O), 1689 (C]O), 1598,

1342 (SO₂), 1237 (OC–S), 1164, 1052 (C]S); d_H(2 diaste-

reomers) 1.11–1.18 (m, 3H, CH₃ester), 1.27–1.30 and 1.37–

1.41 (2m, 3H, CH₃xanthate), 2.05–2.19 (m, 1H, CH), 2.40

and 2.41 (2s, 3H, CH₃Ar), 2.42–2.58 (m, 1H, CH), 3.20–

3.27 (m, 2H, CH₂N), 3.73–3.81 and 3.89–3.97 (2m, 1H,

CHS), 4.12–4.17 (m, 2H, OCH₂ester), 4.38–4.51 (m, 1H,

CHCO), 4.56–4.61 (m, 2H, OCH₂xanthate), 4.89–4.93

(m, 1H, NH), 7.27–7.28 (m, 2H, CH Ar), 7.44–7.50 (m,

2H, CH Ar), 7.57–7.62 (m, 1H, CH Ar), 7.72 (t, J¼8 Hz,

2H, CH Ar), 7.96 (t, J¼8 Hz, 2H, CH Ar); d_C13.6 (CH₃xan-

thate), 14.3 (CH₃ester), 21.6 (CH₃Ar), 30.3 (CH₂), 46.7

(CH₂N), 49.2 (CHS), 51.2 (CHCO), 61.9 (OCH₂ester),

70.7 (OCH₂xanthate), 127.3–133.9 (9CH Ar), 136.1 (C

Ar), 136.4 (C Ar), 143.7 (C Ar), 169.3 (CO), 194.7 (CO

ketone), 212.7 (CS); m/z 524 (MH⁺), 541 (M+NH₄⁺).

3.1.4.23.

N-[2-(4-Chlorophenyl)-6,6,6-triﬂuoro-5-

methoxyiminohexyl]acetamide 5t. Puriﬁed by ﬂash column

chromatography (petrol/EtOAc 1:1), transparent oil, 42%

(method B); n_max/cm^ꢀ13456 (NH), 1689 (CO, C]N); d_H

1.69–2.08 (m, 2H, CH₂), 1.88 (s, 3H, CH₃), 2.15 (ddd,

J¼5, 11.4, 13.2 Hz, 1H, CHC]N), 2.32 (ddd, J¼5, 11.2,

13.2 Hz, 1H, CHC]N), 2.72–2.84 (m, 1H, CHAr), 3.11

(ddd, J¼5.2, 9.2, 13.6 Hz, 1H, NCH), 3.70 (ddd, J¼5.6,

7.2, 13.6 Hz, 1H, NCH), 3.95 (s, 3H, OCH₃), 5.27 (br s,

1H, NH), 7.11 (d, J¼8.4 Hz, 2H, CH Ar), 7.33 (d,

J¼8.4 Hz, 2H, CH Ar); d_C22.6 (CH₂), 23.2 (CH₃acetyl),

28.8 (CH₂C]N), 44.9 (NCH₂), 45.2 (CHAr), 63.1

(OCH₃), 120.7 (q, J¼272.3 Hz, CF₃), 129.0 (CH Ar),

129.3 (CH Ar), 133.0 (C Ar), 139.7 (C Ar), 148.5 (q,

J¼31.4 Hz, C]N), 170.0 (CO); m/z 351 (MH⁺), 367

(M+NH⁺₄); HRMS calcd for C₁₅H₁₈F₃ClN₂O₂, 350.1009;

found, 350.1013.

3.1.4.24. N-[4-Ethoxycarbonyl-2-(3-methoxyphenyl)-

butyl]propionamide 5u. Puriﬁed by ﬂash column chroma-

tography (petrol/EtOAc 1:1), yellow oil, 38% (method B);

n_max/cm^ꢀ13451 (NH), 1735 (CO ester), 1684 (CO amide);

d_H1.07 (t, J¼7.6 Hz, 3H, CH₃), 1.22 (t, J¼7.2 Hz, 3H,

CH₃ester), 1.80–2.30 (m, 6H), 2.72–2.81 (m, 1H, CHAr),

3.21 (ddd, J¼4.4, 8.8, 13.2 Hz, 1H, NCH), 3.71 (qt, J¼

6.6 Hz, 1H, NCH), 3.80 (s, 3H, OCH₃), 4.07 (q, J¼7.2 Hz,

2H, OCH₂), 5.31 (br s, 1H, NH), 6.70 (t, J¼2 Hz, 1H, CH

Ar), 6.75 (d, J¼8 Hz, 1H, CH Ar), 6.79 (dd, J¼2, 8 Hz,

1H, CH Ar), 7.25 (t, J¼8 Hz, 1H, CH Ar); d_C9.8 (CH₃),

14.1 (CH₃ester), 28.5 (CH₂), 29.6 (CH₂), 31.9 (CH₂), 44.6

(NCH₂), 45.0 (CH Ar), 55.1 (OCH₃), 60.2 (OCH₂), 112.0

(CH Ar), 113.6 (CH Ar), 120.0 (CH Ar), 129.7 (CH Ar),

143.1 (C Ar), 159.8 (C Ar), 173.3 (CO), 173.9 (CO); m/z

3.1.5.3. O-Ethyl-S-[4-oxo-5-phenyl-1-(4-toluenesulfo-

nylaminomethyl)pentyl]dithiocarbonate 6f. Puriﬁed by

ﬂash chromatography (petrol/EtOAc 8:2), yellow oil, 70%;

n_max/cm^ꢀ13250 (NH), 1715 (CO), 1343, 1165 (SO₂), 1222

(COS), 1052 (CS); d_H1.39 (t, J¼7.2 Hz, 3H, CH₃), 1.78

(ddd, J¼6.8, 8.8, 21.6 Hz, 1H, CH), 2.06 (ddd, J¼7.2,

12.2, 14.4 Hz, 1H, CH), 2.42 (s, 3H, CH₃tolyl), 2.61 (t,

J¼7 Hz, 2H, CH₂CO), 3.15 (t, J¼6.2 Hz, 2H, CH₂N), 3.67

(s, 2H, CH₂Ph), 3.66–3.78 (m, 1H, CHS), 4.52–4.66 (m,

2H, OCH₂), 5.14 (t, J¼6.4 Hz, 1H, NH), 7.17 (d,

J¼6.8 Hz, 2H, ArH), 7.23–7.34 (m, 5H, ArH), 7.73 (d,

J¼8.4 Hz, 2H, ArH); d_C13.6 (CH₃), 21.5 (CH₃tolyl), 24.6

(CH₂), 38.6 (CH₂CO), 46.2 (CH₂N), 49.8 (CHS), 50.0

(CH₂Ph), 70.3 (OCH₂), 127.0, 128.7, 129.3, 129.7 (CH

7204

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

Ar), 133.8 (C Ar), 136.8 (C Ar), 143.5 (C Ar), 207.1 (CO),

212.5 (CS); m/z 466 (MH⁺), 483 (MNH₄⁺).

(d, J¼8.8 Hz, 2H, CH Ar); d_C13.8 (CH₃xanthate), 14.2

(CH₃ester), 26.1 (CH₂), 31.3 (CH₂CO), 46.2 (NCH₂), 50.0

(CHS), 55.7 (OCH₃), 60.8 (OCH₂ester), 70.5 (OCH₂xan-

thate), 114.4 (2CH Ar), 129.3 (2CH Ar), 131.3 (C Ar), 163

(C Ar), 172.8 (CO), 212.6 (CS); m/z 436 (MH⁺), 453

(M+NH⁺₄).

3.1.5.4. O-Ethyl-S-[3-(1-benzyl-1H-tetrazol-5-yl)-1-(4-

toluenesulfonylaminomethyl)propyl]dithiocarbonate 6g.

Puriﬁed by ﬂash column chromatography (petrol/EtOAc

9:1 to 6:4), 83%, yellow oil; n_max/cm^ꢀ13279 (NH), 2926,

1597, 1366, 1168 (SO₂), 1228 (OCS), 1051 (C]S); d_H

1.37 (t, J¼6.8 Hz, CH₃xanthate), 1.95–2.02 and 2.24–2.30

(m, 2H, CH₂), 2.42 (s, 3H, CH₃Ar), 2.85–2.90 (m, 2H,

CCH₂), 3.14–3.21 (m, 2H, NCH₂), 3.83–3.87 (m, 1H,

CHS), 4.54–4.60 (m, 2H, OCH₂xanthate), 5.07–5.10 (m,

1H, NH), 5.51 (d, J¼4 Hz, 2H, CH₂Ph), 7.19–7.72 (m, 9H,

CH Ar); d_C13.8 (CH₃xanthate), 20.8 (CH₃Ar), 28.0

(CH₂), 46.1 (NCH₂), 49.7 (CHS), 51.0 (CH₂Ph), 70.8

(OCH₂xanthate), 120.6 (C Ar), 127.1 (2CH Ar), 127.8

(2CH Ar), 129.1 (CH Ar), 129.4 (2CH Ar), 130.0 (2CH

Ar), 133.3 (C Ar), 143.9 (C Ar), 153.6 (C]N), 212.1

(C]S); m/z 247 (100), 383 (82).

3.1.5.8. N-(2-Ethoxythiocarbonylsulfanyl-4-phenoxy-

carbonylbutyl)-4-ﬂuorobenzenesulfonamide 6k. Puriﬁed

by ﬂash column chromatography (petrol/EtOAc 8:2), yellow

oil, 42%; n_max/cm^ꢀ13284 (NH), 1761 (CO), 1342, 1168

(SO₂), 1225 (CSO), 1052 (CS); d_H1.41 (t, J¼7 Hz, 3H,

CH₃), 1.90–2.05 (m, 1H, CH), 2.18–2.30 (m, 1H, CH),

2.69 (dd, J¼7.2, 16.8 Hz, 1H, CHCO), 2.76 (dd, J¼6.6,

17 Hz, 1H, CHCO), 3.29 (br s, 2H, NCH₂), 3.85–3.95 (m,

1H, CHS), 4.63 (q, J¼7 Hz, 2H, OCH₂), 5.10 (br s, 1H,

NH), 7.07 (d, J¼8.4 Hz, 2H, H-o phenoxy), 7.17 (t,

J¼8.4 Hz, 2H, H-m ﬂuorophenyl), 7.24 (t, J¼7 Hz, 1H,

H-p phenoxy), 7.38 (t, J¼7.8 Hz, 2H, H-m phenoxy), 7.87

(d, J¼5.2 Hz, 1H, H-o ﬂuorophenyl), 7.89 (d, J¼5.2 Hz,

1H, H-o ﬂuorophenyl); d_C13.7 (CH₃), 26.1 (CH₂), 31.3

(CH₂CO), 46.4 (NCH₂), 50.1 (CHS), 70.6 (OCH₂), 116.4

(d, J¼22.6 Hz, C-m ﬂuorophenyl), 121.4 (C-o phenoxy),

125.9 (C-p phenoxy), 129.4 (C-m phenoxy), 129.8 (d,

J¼9.3 Hz, C-o ﬂuorophenyl), 136.0 (d, J¼3.1 Hz, C-ipso

ﬂuorophenyl), 150.5 (C-ipso phenoxy), 165.1 (d,

J¼253.3 Hz, C-p ﬂuorophenyl), 171.2 (CO), 212.5 (CS);

m/z 472 (MH⁺), 489 (M+NH⁺₄).

3.1.5.5. O-Ethyl-S-[4-cyclopropyl-4-oxo-1-(4-toluene-

sulfonylaminomethyl)butyl]dithiocarbonate 6h. Isolated

as an oil, 93%; n_max/cm^ꢀ11702 (CO), 1343, 1164 (NSO₂),

1221, 1052 (C]S, SC–O); d_H0.84–0.89 (m, 2H, CH₂),

0.97–1.01 (m, 2H, CH₂), 1.43 (t, 3H, CH₃CH₂O), 1.80–

1.90 (m, 2H, CH, CHCO), 2.02–2.10 (m, 1H, CH), 2.45 (s,

3H, CH₃Ph), 2.73 (m, 2H, CH₂CO), 3.18 (m, 2H, CH₂N),

3.78 (m, 1H, CHS), 4.63 (q, J¼7.2 Hz, 2H, OCH₂), 5.06

(t, J¼6 Hz, 1H, NH), 7.33 (d, J¼8 Hz, 2H, CH Ar), 7.74

(d, J¼8 Hz, 2H, CH Ar); d_C11.1 (2CH₂), 13.7 (CH₃xan-

thate), 20.6 and 21.6 (CH₃and CHCO), 24.7 (CH₂), 40.0

(CH₂), 46.2 (CH₂), 50.0 (CHS), 70.4 (OCH₂), 127.1 (CH

Ar), 129.8 (CH Ar), 136.9 (C Ar), 143.5 (C Ar), 209.9

(CO), 212.7 (CS), m/z 416 (MH⁺), 433 (M+NH₄⁺).

3.1.5.9. Ethyl 7-(4-chlorobenzenesulfonylamino)-6-

ethoxythiocarbonylsulfanyl-3-oxoheptanoate 6l. Puri-

ﬁcation by ﬂash column chromatography (petrol/EtOAc

gradient from 10:0 to 8:2), 76%, yellow crystals; n_max

/

cm^ꢀ13294 (NH), 2983, 2929, 1740 (OC]O), 1720

(C]O), 1652, 1588, 1477, 1410, 1347 (SO₂), 1224 (OC–

S), 1167, 1052 (C]S); d_H1.26 (t, J¼7.2 Hz, 3H, CH₃ester),

1.40 (t, J¼7.2 Hz, 3H, CH₃xanthate), 1.78–1.88 (m, 1H,

CH), 2.07–2.17 (m, 1H, CH), 2.72 (q, J¼7.2 Hz, 2H,

CH₂CO), 3.23 (t, J¼6 Hz, 2H, CH₂N), 3.44 (s, 2H,

COCH₂CO), 3.75–3.83 (m, 1H, CHS), 4.20 (q, J¼7.2 Hz,

2H, OCH₂ester), 4.60 (q, J¼7.2 Hz, 2H, OCH₂xanthate),

5.28 (t, J¼6 Hz, 1H, NH), 7.49 (d, J¼8 Hz, 2H, CH Ar),

7.80 (d, J¼8 Hz, 2H, CH Ar); d_C13.8 (CH₃xanthate),

14.2 (CH₃ester), 24.4 (CH₂), 39.8 (CH₂CO), 46.4

(COCH₂CO), 49.3 (CH₂N), 49.9 (CHS), 61.6 (OCH₂ester),

70.7 (OCH₂xanthate), 128.6 (2CH Ar), 129.5 (2CH Ar),

138.4 (C Ar), 139.3 (C Ar), 167.1 (CO ester), 201.9 (CO

ketone), 212.6 (CS), m/z 482 (MH⁺), 499 (M+NH₄⁺).

3.1.5.6. O-Ethyl-S-[4-oxo-4-(2-oxooxazolidin-3-yl)-1-

(4-triﬂuoromethoxybenzene-sulfonylaminomethyl)butyl]-

dithiocarbonate 6i. Isolated as an oil, 94%; n_max/cm^ꢀ11792

(OCON), 1707 (NCO), 1386, 1164 (NSO₂), 1216 (C]S),

1051 (COS); d_H1.39 (t, 3H, J¼7.2 Hz, CH₃xanthate),

1.92 (m, 1H, CH), 2.18 (m, 1H, CH), 3.04 (m, 2H, CH₂),

3.29 (t, 2H, J¼6.4 Hz, CH₂), 3.83 (m, 1H, CHS), 4.01 (t,

2H, J¼8 Hz, CH₂), 4.43 (t, 2H, J¼8 Hz, CH₂), 4.60 (qd,

2H, J¼7.2 Hz, OCH₂), 5.41 (t, 1H, J¼6 Hz, NH), 7.34 (d,

J¼8 Hz, 2H, ArH), 7.93 (d, J¼8 Hz, 2H, ArH); d_C13.8

(CH₃xanthate), 25.6 (CH₂), 32.3 (CH₂CO), 42.6 (NCH₂),

46.2 (NCH₂), 49.8 (CHS), 62.4 (OCH₂), 70.7 (OCH₂xan-

thate), 121.1 (Ar), 129.4 (Ar), 138.4 (Ar), 152.2 (Ar),

153.5 (CO), 172.3, 212.7 (CS); m/z 531 (MH⁺), 548

(M+NH⁺₄).

3.1.5.10.

O-Ethyl-S-[2-(2-chlorobenzenesulfonyl-

amino)-1-(2-oxotetrahydrofuran-3-ylmethyl)ethyl]dithio-

carbonate 6m. Two diastereomers, D1 and D2, puriﬁed by

ﬂash chromatography (petrol/EtOAc 8:2), yellow oil, 92%;

n_max/cm^ꢀ13392, 1572 (NH), 1352, 1172 (SO₂); d_H1.39

and 1.41 (2t, J¼6.4 Hz, 6H, CH₃), 1.78 (ddd, J¼7, 8.4,

15 Hz, 1H, CH D2), 1.87–2.07 (m, 3H, CH D1, CH ring

D1 and CH ring D2), 2.16 (ddd, J¼4.3, 10.5, 14.7 Hz, 1H,

CH D1), 2.27 (dt, J¼6.9, 14.8 Hz, 1H, CH D2), 2.36–2.50

(m, 2H, CH ring D1 and CH ring D2), 2.70 (ddd, J¼7,

10.8, 14.8 Hz, 1H, CHCO D2), 2.78 (ddd, J¼4.4, 9.8,

19.4 Hz, 1H, CHCO D1), 3.16–3.36 (m, 4H, CH₂N), 3.92

(td, J¼5.6, 10.8 Hz, 1H, CHS D1), 4.08 (dt, J¼5.8,

15.2 Hz, 1H, CHS D2), 4.18 (dd, J¼9.2, 16.4 Hz, 2H,

3.1.5.7. Ethyl 4-ethoxythiocarbonylsulfanyl-5-(4-

methoxybenzenesulfonylamino)pentanoate 6j. Puriﬁcation

by ﬂash column chromatography (petrol/EtOAc 10:0 to

8:2), 93%, yellow oil; n_max/cm^ꢀ13275 (NH), 2983, 2939,

2839, 1736 (OC]O), 1652, 1598, 1477, 1348 (SO₂), 1223

(OC–S), 1160, 1052 (C]S); d_H1.26 (t, J¼7.6 Hz, 3H, CH₃

ester), 1.40 (t, J¼6.8 Hz, 3H, CH₃xanthate), 1.81–1.89 (m,

1H, CH), 2.05–2.14 (m, 1H, CH), 2.38–2.46 (m, 2H,

CH₂CO), 3.21 (t, J¼6 Hz, 2H, NCH₂), 3.79–3.83 (m, 1H,

CHS), 3.87 (s, 3H, OCH₃), 4.13 (q, J¼7.6 Hz, 2H, OCH₂es-

ter), 4.60 (q, J¼6.8 Hz, 2H, OCH₂xanthate), 5.08 (t,

J¼7.2 Hz, 1H, NH), 6.98 (d, J¼8.8 Hz, 2H, CH Ar), 7.79

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7205

CHO ring D1 and CHO ring D2), 4.36 (dd, J¼7.8, 15.8 Hz,

1H, CHO ring D1 and CHO ring D2), 4.57–4.65 (m, 4H,

OCH₂), 5.52 (t, J¼7.2 Hz, 1H, NH), 5.56 (t, J¼6.8 Hz,

1H, NH), 7.40–7.45 (m, 2H, ArH), 7.50–7.55 (m, 4H,

ArH), 8.08 (t, J¼7.6 Hz, 2H, ArH); d_C13.7 (CH₃), 29.2

(CH₂ring D1), 29.4 (CH₂ring D2), 31.5 (CH₂D1), 32.2

(CH₂D2), 36.96 (CHCO D1), 37.00 (CHCO D2), 46.4

(CH₂N D2), 46.7 (CH₂N D1), 48.8 (CHS D2), 49.0 (CHS

D1), 66.45 (CH₂O ring D2), 66.51 (CH₂O ring D1), 70.5

(OCH₂D2), 70.7 (OCH₂D1), 127.3 (CH Ar), 131.1 (CH

Ar D2), 131.3 (CH Ar D1), 131.39 (CCl D1), 131.42

(CCl D2), 131.6 (CH Ar D1), 131.7 (CH Ar D2), 133.8

(CH Ar D2), 133.9 (CH Ar D1), 136.9 (C-ipso D1), 137.0

(C-ipso D2), 178.4 (CO D2), 178.5 (CO D1), 211.9 (CS

D2), 212.2 (CS D1); m/z 438 (MH⁺), 455 (MNH₄⁺).

OCH₂), 5.47 (t, J¼6.4 Hz, 1H, NH), 7.12 (dd, J¼4,

4.8 Hz, 1H, H-4 thiophene), 7.64 (dd, J¼1, 5 Hz, 1H, CH

thiophene), 7.70 (dd, J¼1, 5 Hz, 1H, CH thiophene), 7.77

(d, J¼8.4 Hz, 2H, ArH), 8.00 (d, J¼8 Hz, 2H, ArH); d_C

13.6 (CH₃), 25.1 (CH₂), 35.9 (CH₂CO), 46.4 (CH₂N), 50.0

(CHS), 70.5 (OCH₂), 123.2 (q, J¼271.1 Hz, CF₃), 126.3

(q, J¼3.7 Hz, C-m), 127.6 (C-o), 128.2 (C-4 thiophene),

132.2 (CH thiophene), 134.0 (CH thiophene), 134.4 (q,

J¼32.9 Hz, C-p), 143.56 (C-ipso), 143.61 (C-ipso), 191.8

(CO), 212.4 (CS); m/z 512 (MH⁺), 529 (M+NH₄⁺).

3.1.5.14. Dithiocarbonic acid O-ethyl ester S-[1-(4-

cyanobenzenesulfonylaminomethyl)-5,5-dimethyl-4-oxo-

hexyl]ester 6q. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc 8:2), yellow oil, 81%; n_max/cm^ꢀ13225

(NH), 2234 (CN), 1705 (CO), 1352, 1166 (SO₂), 1225

(COS), 1052 (CS); d_H1.10 (s, 9H, CH₃^tBu), 1.40 (t,

J¼7 Hz, 3H, CH₃), 1.69–1.81 (m, 1H, CH), 2.00–2.10 (m,

1H, CH), 2.55–2.72 (m, 2H, CH₂CO), 3.23 (dd, J¼6.4,

13.2 Hz, 1H, CHN), 3.29 (dd, J¼6, 13.2 Hz, 1H, CHN),

3.63–3.76 (m, 1H, CHS), 4.53–4.66 (m, 2H, OCH₂), 5.46

(t, J¼6 Hz, 1H, NH), 7.81 (d, J¼8 Hz, 2H, H-m), 7.99 (d,

J¼8 Hz, 2H, H-o); d_C13.7 (CH₃), 24.5 (CH₂), 26.4 (CH₃

3.1.5.11. O-Ethyl-S-[1-(4-bromobenzenesulfonylami-

nomethyl)-4-oxo-4-piperidin-1-ylbutyl]dithiocarbonate

6n. Puriﬁed by ﬂash column chromatography (petrol/EtOAc

1.1), yellow oil, 66%; n_max/cm^ꢀ13197, 1576 (NH), 1632

(CO), 1347, 1168 (SO₂), 1221 (COS), 1054 (CS); d_H1.40

(t, J¼7.2 Hz, 3H, CH₃), 1.45–1.65 (m, 6H, CH₂piperidine),

1.80–1.96 (m, 1H, CH), 2.07–2.19 (m, 1H, CH), 2.32–2.48

(m, 2H, CH₂CO), 3.13 (dt, J¼6.7, 13.4 Hz, 1H, CHN),

3.26 (ddd, J¼5.6, 6.4, 13.2 Hz, 1H, CHN), 3.34 (t,

J¼5.4 Hz, 2H, 2CH piperidine), 3.50 (t, J¼5.6 Hz, 2H,

2CH piperidine), 3.74–3.83 (m, 1H, CHS), 4.53–4.66 (m,

2H, OCH₂), 6.13 (t, J¼6.2 Hz, 1H, NH), 7.62 (d,

J¼8.8 Hz, 2H, ArH), 7.74 (d, J¼8.4 Hz, 2H, ArH); d_C

13.7 (CH₃), 24.4 (CH₂piperidine), 25.5 (CH₂piperidine),

25.7 (CH₂), 26.3 (CH₂piperidine), 29.6 (CH₂CO), 43.0

(NCH₂piperidine), 46.0 (NCH₂), 46.5 (NCH₂piperidine),

49.9 (CHS), 70.4 (OCH₂), 127.3 (C Ar), 128.7 (CH Ar),

132.2 (CH Ar), 139.3 (C Ar), 169.9 (CO), 212.7 (CS); m/z

525 (MH⁺).

t

^tBu), 33.3 (CH₂CO), 44.1 (C Bu), 46.6 (CH₂N), 50.1

(CHS), 70.6 (OCH₂), 116.4 (C-p), 117.3 (CN), 127.7

(C-o), 132.9 (C-m), 144.4 (C-ipso), 212.8 and 215.2 (CO

and CS); m/z 443 (MH⁺), 460 (M+NH₄⁺).

3.1.5.15. O-Ethyl-S-[1-(4-tert-butylbenzenesulfonyl-

aminomethyl)-4-cyclohexyl-4-oxobutyl]dithiocarbonate

6r. Puriﬁed by ﬂash column chromatography (petrol/EtOAc

8:2), yellow oil, 80%; n_max/cm^ꢀ13274, 1596 (NH), 1710

(CO), 1342, 1167 (SO₂), 1221, 1113 (COS), 1053 (CS); d_H

1.10–1.30 (m, 5H, CH cyclohexyl), 1.32 (s, 9H, CH₃^tBu),

1.37 (t, J¼7 Hz, 3H, CH₃), 1.63 (d, J¼10.4 Hz, 1H, CH

cyclohexyl), 1.67–1.75 (m, 5H, 4CH cyclohexyl and CH),

1.98–2.12 (m, 1H, CH), 2.22–2.35 (m, 1H, H-1 cyclohexyl),

2.56 (t, J¼6.8 Hz, 2H, CH₂CO), 3.15 (dd, J¼6.8, 13.6 Hz,

1H, CHN), 3.71 (dd, J¼6.2, 13.4 Hz, 1H, CHN), 3.70–3.80

(m, 1H, CHS), 4.58 (q, J¼6.3 Hz, 2H, OCH₂), 5.29 (t,

J¼6.2 Hz, 1H, NH), 7.49 (d, J¼8 Hz, 2H, ArH), 7.76 (d,

J¼8 Hz, 2H, ArH); d_C13.6 (CH₃), 24.5 (CH₂cyclohexyl),

25.5 (CH₂), 25.7 (CH₂cyclohexyl), 28.4 (CH₂cyclohexyl),

3.1.5.12. Dithiocarbonic acid O-ethyl ester S-[1-(4-

iodobenzenesulfonylaminomethyl)-5,5-dimethoxy-4-oxo-

pentyl]ester 6o (two diastereomers). Puriﬁcation by ﬂash

column chromatography (petrol/EtOAc 8:2), yellow oil,

95%; n_max/cm^ꢀ13279 (NH), 1740 (CO), 1316, 1166

(SO₂), 1221 (COS), 1054 (CS); d_H1.40 (t, 3H, J¼7.1 Hz,

OCH₃), 1.75–1.86 (m, 1H, CH), 2.00–2.13 (m, 1H, CH),

2.83–2.88 (m, 0.5H, CHCO), 2.93–2.98 (m, 0.5H, CHCO),

3.23–3.37 (m+s, 8H, CH₂N, 2OCH₃), 3.64–3.88 (m+s, 4H,

CH, CO₂CH₃), 4.49–4.52 (m, 1H, CHS), 4.58–4.65 (m,

2H, OCH₂), 5.09 (m, 1H, NH), 7.57 (d, 2H, J¼7.7 Hz,

ArH), 7.87 (d, 2H, J¼8.3 Hz, ArH); d_C13.8 (CH₃) 28.4

and 28.9 (CH₂), 45.8 (CH₂N), 46.5, 46.7 (CH), 47.2

(CH₂N), 48.9 and 49.1 (CHCO), 52.3, 53.9, 54.1, 54.9 and

55.0 (OCH₃), 70.6 and 70.7 (OCH₂), 100.2 (CI), 104.5 and

104.8 (CHOCH₃), 128.6 and 138.5 (CH Ar), 172.5 and

172.6 (CO), 212.8 (CS); m/z 609 (M+NH⁺₄).

31.0 (CH₃Bu), 35.0 (C ^tBu), 37.1 (CH₂CO), 46.3 (CH₂N),

t

50.0 (CHS), 50.7 (C-1 cyclohexyl), 70.2 (OCH₂), 126.0

(CH Ar), 126.8 (CH Ar), 136.8 (C Ar), 156.4 (C Ar), 212.6

and 212.9 (CO and CS); m/z 500 (MH⁺), 517 (MNH₄⁺).

3.1.5.16. O-Ethyl-S-[1-(4-chlorobenzenesulfonylami-

nomethyl)-4-oxo-5,5,5-triﬂuoropentyl]dithiocarbonate

6s. Puriﬁed by ﬂash column chromatography (petrol/EtOAc

7:3), yellow oil, 78%; n_max/cm^ꢀ13432 (NH), 1766 (CO),

1313 (SO₂), 1225 (O–C), 1167 (SO₂), 1052 (CS); d_H1.39

(t, J¼7 Hz, 3H, CH₃xanthate), 1.82–1.94 (m, 1H, CH),

2.22 (dtd, J¼4.8, 7.2, 14.8 Hz, 1H, CH), 2.88 (td, J¼3.2,

7.2 Hz, 2H, CH₂CO), 3.25 (t, J¼6.4 Hz, 2H, NCH₂), 3.80

(td, J¼6, 10.4 Hz, 1H, CHS), 4.54–4.63 (m, 2H, OCH₂),

5.41 (t, J¼6.6 Hz, 1H, NH), 7.48 (d, J¼8.4 Hz, 2H, ArH),

7.79 (d, J¼8.4 Hz, 2H, ArH); d_C13.6 (CH₃), 23.6 (CH₂),

33.5 (CH₂CO), 46.4 (NCH₂), 49.6 (CHS), 70.8 (OCH₂),

115.3 (q, J¼290 Hz, CF₃), 128.5 (CH Ar), 129.5 (CH Ar),

138.1 (C Ar), 139.4 (C Ar), 190.5 (q, J¼35.4 Hz, CO),

212.0 (CS); m/z 447 (MH⁺).

3.1.5.13. Dithiocarbonic acid O-ethyl ester S-[4-oxo-4-

thiophen-2-yl-1-(4-triﬂuoromethylbenzenesulfonylamino-

methyl)butyl]ester 6p. Puriﬁed by ﬂash column

chromatography (petrol/EtOAc 7:3), yellow oil, 49%;

n_max/cm^ꢀ13283, 1517 (NH), 1668 (CO), 1322, 1173

(SO₂), 1226 (COS), 1063 (CS); d_H1.37 (t, J¼7.2 Hz, 3H,

CH₃), 1.94–2.04 (m, 1H, CH), 2.22–2.32 (m, 1H, CH),

3.07 (t, J¼6.8 Hz, 2H, CH₂CO), 3.31 (td, J¼2.1, 6.4 Hz,

2H, CH₂N), 3.82–3.90 (m, 1H, CHS), 4.50–4.63 (m, 2H,

7206

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

3.1.5.17. O-Ethyl-S-[1-(4-chlorobenzenesulfonylami-

3.1.7.1. (2SR,5SR)-2-Phenyl-5-p-tolylpiperidine 8b.

Puriﬁed by ﬂash column chromatography (EtOAc), white

solid, 89%; mp 119–121 ^ꢁC; n_max/cm^ꢀ13050 (NH); d_H

1.68–1.87 (m, 2H, H-4_axand H-3_ax), 1.96–2.15 (m, 2H,

H-4_eqand H-3_eq), 2.38 (s, 3H, CH₃), 2.85 (tt, J¼3.2,

11.2 Hz, 1H, H-5_ax), 2.91 (t, J¼11.2 Hz, 1H, H-6_ax), 3.35 (d,

J¼9.6 Hz, 1H, H-2_ax), 3.73 (dd, J¼2.4, 10.8 Hz, 1H, H-6_eq),

7.18 (d, J¼8 Hz, 2H), 7.22 (d, J¼8 Hz, 2H), 7.31 (d,

J¼7.2 Hz, 1H), 7.38 (t, J¼7.6 Hz, 2H), 7.45 (d, J¼7.2 Hz,

2H); d_C21.0 (CH₃), 32.5 and 35.0 (C-3 and C-4), 42.7

(C-5), 54.7 (C-6), 61.8 (C-2), 126.6, 127.0, 127.1, 128.4,

129.1 (CH Ar), 135.8, 141.5, 145.0 (C Ar); m/z 252 (MH⁺).

nomethyl)-4-methoxyimino-5,5,5-triﬂuoropentyl]dithio-

carbonate 6t. Two isomers, puriﬁed by ﬂash column

chromatography (petrol/EtOAc 9:1), yellow oil, 74%;

n_max/cm^ꢀ13276 (NH), 1719 (C]N), 1343 and 1166

(SO₂), 1222 (O–CS), 1052 (C]S); d_H1.38 (t, J¼7 Hz,

3H, CH₃), 1.70–1.85 (m, 1H, CH), 1.93–2.08 (m, 1H, CH),

2.38–2.60 (m, 2H, CH₂CO), 3.19–3.30 (m, 2H, NCH₂),

3.67–3.82 (m, 1H, CHS), 3.93–3.96 (2s, 3H, OCH₃), 4.53–

4.63 (m, 2H, OCH₂), 7.47 (d, J¼8.4 Hz, 2H, CH Ar), 7.78

(d, J¼8.4 Hz, 2H, CH Ar); d_C13.7 (CH₃xanthate), 22.1

(CH₂), 26.8 and 27.2 (CH₂C]N), 46.1 and 46.4 (NCH₂),

49.8 and 50.4 (CHS), 63.4 (OCH₃), 70.6 (OCH₂), 120.6 (q,

J¼272.4 Hz, CF₃), 117.9 (q, J¼270 Hz, CF₃), 128.5 (CH

Ar), 129.5 (CH Ar), 138.3 (C Ar), 139.3 (C Ar), 144.9 (q,

J¼29.3 Hz, C]N), 147.6 (q, J¼32.0 Hz, C]N), 212.3

(CS); m/z 493 (MH⁺), 510 (M+NH₄⁺).

3.1.7.2. (2SR,5SR)-2-Benzyl-5-p-tolylpiperidine 8f.

Puriﬁed by ﬂash column chromatography (petrol/EtOAc 1:1),

off-white solid, 85%; mp 118–119 ^ꢁC; n_max/cm^ꢀ13100

(NH); d_H1.60 (ddd, J¼2.6, 12.4, 24.6 Hz, 1H, H-4_ax), 1.75

(dt, J¼2.7, 13.9 Hz, 1H, H-3_ax), 1.92–2.06 (m, 2H, H-4_eq

and H-3_ax), 2.29 (s, 3H, CH₃), 2.88 (dd, J¼10.7, 15.0 Hz,

1H, CHPh), 2.92 (t, J¼12.6 Hz, 1H, H-6_ax), 3.09 (tt,

J¼3.3, 12.3 Hz, 1H, H-5_ax), 3.17–3.26 (m, 2H, CHAr and

H-2), 3.45 (dd, J¼1.8, 12.4 Hz, 1H, H-6_eq), 7.05 (d,

J¼8.3 Hz, 2H, ArH), 7.09 (d, J¼8.2 Hz, 2H, ArH), 7.20–

7.33 (m, 5H, ArH); d_C21.0 (CH₃), 28.2 (C-3), 30.0 (C-4),

39.1 (C-5), 39.7 (CH₂Ph), 50.6 (C-6), 58.7 (C-2), 126.8,

127.4, 129.0, 129.4, 129.6 (CH Ar), 134.9, 137.0, 137.3

(C Ar); m/z 266 (MH⁺).

3.1.5.18. Ethyl 4-ethoxythiocarbonylsulfanyl-5-(3-

methoxybenzenesulfonylamino)pentanoate 6u. Puriﬁed by

ﬂash column chromatography (petrol/EtOAc 8:2), yellow

oil, 80%; n_max/cm^ꢀ13282 (NH), 1736 (CO), 1345 (SO₂),

1222 (O–CS), 1161 (SO₂), 1051 (C]S); d_H1.22 (t,

J¼7.2 Hz, 3H, CH₃ester), 1.37 (t, J¼7.2 Hz, 3H, CH₃xan-

thate), 1.79–1.91 (m, 1H, CH), 2.05–2.15 (m, 1H, CH),

2.32–2.49 (m, 2H, CH₂CO), 3.22 (t, J¼6.4 Hz, 2H, NCH₂),

3.75–3.85 (m, 1H, CHS), 3.83 (s, 3H, OCH₃), 4.088 and

4.094 (2q, J¼7.2 Hz each, 2H, OCH₂ester), 4.52–4.62 (m,

2H, OCH₂xanthate), 5.27 (t, J¼6.4 Hz, 1H, NH), 7.07

(ddd, J¼1.6, 2.8, 7.4 Hz, 1H, ArH), 7.34–7.43 (m, 3H,

ArH); d_C13.6 (CH₃xanthate), 14.1 (CH₃ester), 26.0 (CH₂),

31.1 (CH₂CO), 46.2 (NCH₂), 49.9 (CHS), 55.6 (OCH₃),

60.6 (OCH₂ester), 70.4 (OCH₂xanthate), 111.5 (CH Ar),

119.07 (CH Ar), 119.14 (CH Ar), 130.1 (CH Ar), 140.8 (C

Ar), 159.9 (C Ar), 172.6 (CO ester), 212.4 (CS); m/z 436

(MH⁺), 454 (M+NH⁺₄).

3.1.7.3. (2SR,5SR)-2-(Thiophen-2-yl)-5-(4-triﬂuoro-

phenyl)piperidine 8p. Puriﬁed by ﬂash column chromato-

graphy (petrol/EtOAc 3:7), yellow solid, 64%; mp

103–105 ^ꢁC; n_max/cm^ꢀ13073 (NH); d_H1.78 (m, 2H, H-4_ax

and H-3_ax), 1.92 (br s, 1H, NH), 2.07–2.18 (m, 2H, H-4_eq

and H-3_eq), 2.89 (dd, J¼10.6, 17 Hz, 2H, H-2_axand H-6_ax),

3.31 (dd, J¼11, 17.4 Hz, 1H, H-5_ax), 4.04 (dd, J¼2.4,

10 Hz, 1H, H-6_eq), 6.96–7.02 (dd, J¼0.9, 5.2 Hz, 1H,

ArH), 7.36 (d, J¼8.1 Hz, 2H, ArH), 7.57 (d, J¼8.1 Hz,

2H, ArH); d_C31.9 and 35.7 (C-3 and C-4), 43.1 (C-5),

54.0 (C-6), 56.8 (C-2), 123.0, 123.8, 125.4, 126.4, 127.5

(CH Ar), 148.3 (C Ar), 148.6 (C Ar); m/z 311 (MH⁺);

Elem. Anal. Calcd for C₁₆H₁₆F₃NS: C, 61.72; H, 5.18;

found: C, 61.41; H, 5.11.

3.1.6. General procedure for the synthesis of imines 7.

Method A: To a solution of acetamide 5 (1 equiv) in dioxane

(0.4 mL/mmol) was added concentrated HCl (4 mL/mmol),

and the mixture was heated at reﬂux temperature for 1.5

days. The reaction mixture was then evaporated, the residue

dissolved in CH₂Cl₂, and washed with saturated aqueous

NaHCO₃solution. The organic phase was dried and concen-

trated, andtheiminewasobtainedwithoutfurtherpuriﬁcation.

3.1.7.4. (2SR,5SR)-2-(tert-Butyl)-5-(4-hydroxymethyl-

phenyl)piperidine 8q. Puriﬁed by ﬂash column chromato-

graphy (CH₂Cl₂/MeOH 95:5), white solid, 66%; mp

107–109 ^ꢁC; n_max/cm^ꢀ13617 (NH, OH); d_H0.93 (s, 9H, 3

CH₃), 1.29 (ddd, J¼3.6, 12.8, 24.4 Hz, 1H, H-3_ax), 1.56

(ddd, J¼3.6, 12.6, 24.2 Hz, 1H, H-4_ax), 1.82 (ddd, J¼3,

5.8, 12.6 Hz, 1H, H-3_eq), 1.99 (dt, J¼2.4, 13.6 Hz, 1H,

H-4_eq), 2.22 (dd, J¼2.4, 11.2 Hz, 1H, H-2_ax), 2.55–2.65

(m, 2H, H-6_axand H-5_ax), 3.12 (dd, J¼2, 8 Hz, 1H,

H-6_eq), 4.62 (s, 2H, OCH₂), 7.16 (d, J¼8 Hz, 2H, ArH),

7.28 (d, J¼8 Hz, 2H, ArH); d_C26.6 (3CH₃), 26.9 (C-3),

32.4 (C-4), 33.2 (C), 43.3 (C-5), 54.6 (C-6), 64.8 (OCH₂),

66.1 (C-2), 127.1 (CH Ar), 127.2 (CH Ar), 139.1 (C Ar),

144.0 (C Ar); m/z 248 (MH⁺); HRMS calcd for

C₁₆H₂₅NO, 247.1936; found, 247.1941.

Method B: To a solution of acetamide 5 (1 equiv) in dioxane

(0.4 mL/mmol) was added concentrated HCl (4 mL/mmol),

and the mixture was heated at reﬂux temperature for 1.5

days. The reaction mixture was then evaporated, and the im-

ine was obtained as the hydrochloride, which was used in the

next reaction without further puriﬁcation.

3.1.7. General procedure for the synthesis of piperidines

8. To a solution of imine 7 (1 equiv) in methanol (8 mL/

mmol) at 0 ^ꢁC were added NaBH₃CN (2.5 equiv) and

a few drops of glacial AcOH, and the resulting mixture

was stirred at room temperature for 3 h. After that time,

the reaction mixture was concentrated, CH₂Cl₂was added,

and the organic phase washed with saturated aqueous

NaHCO₃solution. The organic phase was dried and concen-

trated, and the residue was puriﬁed by ﬂash column chroma-

tography.

3.1.7.5. (2SR,5SR)-5-(4-tert-Butylphenyl)-2-cyclohex-

ylpiperidine 8r. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc 3:7), white solid, 77%; mp 201–204 ^ꢁC;

n_max/cm^ꢀ13100 (NH); d_H1.00–1.40 (m, 5H), 1.29 (s, 9H,

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7207

CH₃), 1.55–1.75 (m, 6H, H-4_ax, H-3_ax, H-1 cyclohexyl and

3CH cyclohexyl), 1.78–1.85 (m, 2H, CH₂cyclohexyl),

2.00–2.15 (m, 2H, H-4_eqand H-3_eq), 2.82–2.91 (m, 1H, H-

2_ax), 2.97 (t, J¼12.5 Hz, 1H, H-6_ax), 3.07–3.21 (m, 1H, H-

5_ax), 3.54 (dd, J¼1.2, 10.8 Hz, 1H, H-6_eq), 7.15 (d,

J¼8.3 Hz, 2H, ArH), 7.33 (d, J¼8.3 Hz, 2H, ArH); d_C

25.65, 25.7, 25.8, 26.0, 28.2 (CH₂), 29.1 and 30.1 (C-3 and

n_max/cm^ꢀ12925, 2855, 1594, 1472, 1446; d_H2.43 (s, 3H,

CH₃), 7.30–7.55 (m, 7H, CH Ar), 7.80 (d, J¼8.4 Hz, 1H,

H-3), 7.94 (dd, J¼1.4, 8.4 Hz, 1H, H-4), 8.03 (dd, J¼2.2,

8.2 Hz, 2H, CH Ar), 8.92 (d, J¼1.4 Hz, 1H, H-6); d_C21.2

(CH₃), 120.3 (C-3), 126.77 (CH Ar), 126.80 (CH Ar),

128.8 (CH Ar), 128.9 (CH Ar), 129.8 (CH Ar), 134.7

(C-5), 134.81 (C Ar), 134.84 (C-4), 138.0 (C Ar), 139.0

(C Ar), 147.9 (C-6), 155.8 (C-2); m/z 246 (MH⁺).

t

C-4), 31.3 (CH₃^tBu), 34.4 (C Bu), 39.0 (C-5), 40.1 (C-1

cyclohexyl), 51.0 (C-6), 62.4 (C-2), 125.7 (CH Ar), 126.7

(CH Ar), 137.1 (C Ar), 150.4 (C Ar); m/z 299 (MH⁺);

HRMS calcd for C₂₁H₂₃N, 299.2613; found, 299.2613.

3.1.10. Ethyl 1-acetyl-5-(4-iodophenyl)-1,4,5,6-tetrahy-

dropyridine-3-carboxylate 11. To a solution of acetamide

5o (96 mg, 0.21 mmol) in CH₂Cl₂(2 mL) was added p-

TsOH$H₂O (45 mg, 0.24 mmol) and heated at reﬂux tem-

perature for 4.5 h. After that time, the reaction mixture

was cooled and washed with saturated aqueous NaHCO₃so-

lution and brine. The organic phase was dried and concen-

trated, and the residue was puriﬁed by ﬂash column

chromatography (petroleum ether/AcOEt 1:1). The desired

piperidine was obtained as a white solid (72 mg, 89%); mp

111–113 ^ꢁC; n_max/cm^ꢀ11694 (CO), 1627 (CO); d_H2.32 (s,

3H, CH₃acetyl), 2.38 (ddd, J¼1.6, 14.8, 17.2 Hz, 1H,

H-4_ax), 2.74 (dd, J¼3.6, 17.2 Hz, 1H, H-4_eq), 2.87 (tt, J¼

4, 10.8 Hz, 1H, H-5), 3.10 (t, J¼12 Hz, 1H, H-6_ax), 3.75

(s, 3H, OCH₃), 4.39 (d, J¼12.4 Hz, 1H, H-6_eq), 6.96 (d,

J¼8.4 Hz, 2H, ArH), 7.64 (d, J¼8.4 Hz, 2H, ArH), 7.88

(br s, 1H, H-2); d_C21.6 (CH₃acetyl), 28.5 (C-4), 36.7

(C-5), 45.3 (C-6), 51.7 (OCH₃), 92.4 (C), 109.1 (C), 129.0

(CH Ar), 135.4 (C-2), 137.7 (CH Ar), 141.1 (C-ipso),

167.2 (CO), 169.1 (CO); HRMS calcd for C₁₅H₁₆INO₃,

385.0175; found, 385.0175.

3.1.7.6. (2SR,5SR)-5-(4-Chlorophenyl)-2-triﬂuorometh-

ylpiperidine 8t. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc 95:5), white solid, 68%; mp 71–74 ^ꢁC; n_max

/

cm^ꢀ13351 (NH); d_H1.54–1.70 (m, 2H, H-3 and H-4),

1.94 (br s, 1H, NH), 1.99–2.12 (m, 2H, H-3 and H-4),

2.64–2.76 (m, 2H, H-5 and H-6), 3.13–3.31 (m, 2H, H-2

and H-6), 7.13 (d, J¼8.4 Hz, 2H, ArH), 7.28 (d, J¼8.8 Hz,

2H, ArH); d_C25.1 (CH₂), 30.3 (CH₂), 42.3 (C-5), 52.8

(C-6), 57.8 (q, J¼28.7 Hz, C-2), 125.7 (q, J¼277.4 Hz,

CF₃), 128.3 (CH Ar), 128.7 (CH Ar), 132.4 (C Ar), 141.8

(C Ar); m/z 264 (MH⁺), 281 (M+NH⁺₄); HRMS calcd for

C₁₂H₁₃F₃ClN, 263.0689; found, 263.0694.

3.1.8. General procedure for the synthesis of piperidones

9. A solution of acetamide 5 (1 equiv) in concentrated HCl

(5 mL/mmol) was heated at reﬂux temperature for 4 h. The

reaction mixture was then concentrated, and the residue

was puriﬁed by ﬂash column chromatography.

3.1.8.1. 5-p-Tolylpiperidin-2-one 9c. Puriﬁed by ﬂash

column chromatography (EtOAc), white solid, 88%; mp

95–97 ^ꢁC; n_max/cm^ꢀ13451, 3305, 1496 (NH), 1685 (CO);

d_H2.02–2.08 (m, 2H, H-4), 2.34 (s, 3H, CH₃), 2.49–2.56

(m, 2H, H-3), 2.99–3.05 (m, 1H, H-5), 3.32–3.38 (m, 1H,

H-6_ax), 3.46–3.50 (m, 1H, H-6_eq), 6.33 (br s, 1H, H-1),

7.13–7.14 (m, 4H, ArH); d_C21.1 (CH₃), 27.9 (C-3), 31.4

(C-4), 39.2 (C-5), 48.8 (C-6), 126.9 (CH Ar), 129.5 (CH

Ar), 136.8 (C Ar), 138.8 (C Ar), 172.2 (C-2); m/z 190

(MH⁺), 207 (MNH⁺₄).

3.1.11. Ethyl 3-(7-methoxy-1,1-dioxo-2-propionyl-

1,2,3,4-tetrahydro-1l⁶-benzo[e][1,2]thiazin-4-yl)-propi-

onate 12. Puriﬁed by ﬂash column chromatography (petrol/

EtOAc 9:1), yellow oil, 8%; n_max/cm^ꢀ11736 (CO ester),

1708 (CO amide), 1348 (SO₂), 1162 (SO₂), 898 (S–N); d_H

1.21 (t, J¼7.4 Hz, 3H, CH₃), 1.26 (t, J¼7.2 Hz, 3H, CH₃

ester), 1.65–1.75 (m, 1H, CH), 1.90–2.00 (m, 1H, CH),

2.30–2.48 (m, 1H, CHCO ester), 2.53–2.68 (m, 1H, CHCO

ester), 2.91 (dq, J¼7.4, 17.8 Hz, 1H, CHCO amide), 3.05

(dq, J¼7.2, 17.6 Hz, 1H, CHCO amide), 3.18–3.25 (m,

1H, CHAr), 3.79 (dd, J¼3.4, 15.2 Hz, 1H, NCH), 3.87 (s,

3H, OCH₃), 4.08–4.18 (m, 2H, OCH₂), 4.94 (dd, J¼2.8,

14.8 Hz, 1H, NCH), 7.03 (d, J¼8.4 Hz, 1H, CH Ar), 7.42

(t, J¼8.4 Hz, 1H, CH Ar), 7.48 (d, J¼8.4 Hz, 1H, CH Ar);

d_C9.0 (CH₃), 14.2 (CH₃ester), 26.2 (CH₂), 31.2 (CH₂CO

amide), 31.9 (CH₂CO ester), 32.5 (CHAr), 44.1 (NCH₂),

55.9 (OCH₃), 60.3 (OCH₂), 113.9 (CH Ar), 115.7 (CH

Ar), 128.5 (C Ar), 128.9 (CH Ar), 138.1 (C Ar), 156.1 (C

Ar), 173.0 (CO), 173.1 (CO); m/z 370 (MH⁺), 387 (M+NH₄⁺).

3.1.8.2. 5-p-Bromophenylpiperidin-2-one 9n. Puriﬁed

by ﬂash column chromatography (CH₂Cl₂/MeOH 95:5),

white solid, 37%; mp 189–190 ^ꢁC; n_max/cm^ꢀ13400 (NH),

1675 (CO); d_H1.95–2.15 (m, 2H, H-4), 2.42–2.58 (m, 2H,

H-3), 2.97–3.07 (m, 1H, H-5), 3.33 (t, J¼11.4 Hz, 1H,

H-6_ax), 3.44–3.52 (m, 1H, H-6_eq), 6.50 (br s, 1H, NH),

7.13 (d, J¼8 Hz, 2H, ArH), 7.46 (d, J¼8 Hz, 2H, ArH); d_C

27.5 (C-4), 30.9 (C-3), 38.8 (C-5), 48.1 (C-6), 120.7 (C

Ar), 128.6 (CH Ar), 131.7 (CH Ar), 140.6 (C Ar), 172.1

(C-2); m/z 254 (MH⁺), 271 (M+NH⁺₄); HRMS calcd for

C₁₁H₁₂BrNO, 253.0102; found, 253.0103.

3.1.12. General procedure for the synthesis of a,b-unsat-

urated esters 13. To a solution of ethyl methanesulfonyl-

acetate (1 equiv) and the corresponding substituted

benzenecarbaldehyde (1 equiv) in toluene (0.66 mL/mmol)

was added some drops of AcOH and piperidine and the

mixture was heated to reﬂux in a Dean–Stark apparatus.

After the total consumption of the starting materials, the re-

action mixture was concentrated, and the residue was puri-

ﬁed by ﬂash column chromatography.

3.1.9. General procedure for the synthesis of pyridines

10. To a solution of imine 7 (1 equiv) in xylenes (25 mL/

mmol) was added 10% Pd/C (1 equiv in weight) and heated

at reﬂux temperature for 2.5 h. The reaction mixture was

then ﬁltered over CeliteÔ and concentrated. The residue

was puriﬁed by the appropriate method.

3.1.9.1. 2-Phenyl-5-p-tolylpyridine 10. Puriﬁed by re-

crystallisation (EtOH), yellow solid, 83%; mp 141–143 ^ꢁC;

3.1.12.1. Ethyl 3-(2,6-dichlorophenyl)-2-methane-

sulfonyl acrylate 13c. Puriﬁed by ﬂash column

7208

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

chromatography (petrol/EtOAc 9:1), two diastereomers

major and minor 9:1, orange semi-solid, 60%; n_max/cm^ꢀ1

1729 (CO), 1331 (SO₂), 1152 (SO₂); diastereomer major

d_H0.99 (t, J¼7.2 Hz, 3H, CH₃), 3.34 (s, 3H, CH₃), 4.14

(q, J¼7.2 Hz, 2H, OCH₂), 7.20–7.40 (m, 3H, ArH), 8.05

(s, 1H, CH]); d_C13.3 (CH₃), 43.5 (SCH₃), 62.3 (OCH₂),

127.9 (CH Ar), 130.6 (CH Ar), 131.1 (C), 133.2 (C), 139.0

(C), 143.6 (CH]), 161.1 (CO); diastereomer minor d_H

1.42 (t, J¼7 Hz, 3H, CH₃), 3.25 (s, 3H, CH₃), 4.41 (q,

J¼7.2 Hz, 2H, OCH₂), 7.20–7.40 (m, 3H, ArH), 8.08 (s,

1H, CH]); d_C14.0 (CH₃), 42.5 (SCH₃), 62.9 (OCH₂),

127.4 (CH Ar), 130.1 (CH Ar), 131.1 (C), 132.2 (C), 137.1

(C), 145.3 (C]), 161.5 (CO); m/z 323 (MH⁺), 340

(M+NH⁺₄).

7.12 (t, J¼8 Hz, 1H, CH Ar), 7.25 (d, J¼8 Hz, 1H, CH Ar),

7.33 (d, J¼8 Hz, 1H, CH Ar); d_C13.8 (CH₃), 39.1 (SCH₃),

44.9 (CHAr), 62.4 (OCH₂), 69.2 (CHS), 120.1 (CH₂]),

129.0 (CH Ar), 129.2 (CH Ar), 129.9 (CH Ar), 132.6

(CH]), 134.7 (C Ar), 135.4 (C Ar), 165.5 (CO); diastereo-

mer B: d_H0.91 (t, J¼7.2 Hz, 3H, CH₃), 3.08 (s, 3H, SCH₃),

3.88 (dq, J¼7.2, 10.8 Hz, 1H, OCH), 3.90 (dq, J¼7.2,

10.8 Hz, 1H, OCH), 5.02 (d, J¼11.6 Hz, CHS), 5.18 (dd,

J¼8, 10.8 Hz, 1H, CHAr), 5.21 (d, J¼10.4 Hz, 1H, CH]),

5.30 (d, J¼16.8 Hz, 1H, CH]), 6.50 (ddd, J¼8, 10,

17.2 Hz, 1H, CH]), 7.10 (t, J¼8 Hz, 1H, CH Ar), 7.22 (d,

J¼8 Hz, 1H, CH Ar), 7.33 (dd, J¼1.2, 8 Hz, 1H, CH Ar);

d_C13.3 (CH₃), 39.7 (SCH₃), 44.3 (CHAr), 62.1 (OCH₂),

70.6 (CHS), 119.5 (CH₂]), 128.7 (CH Ar), 129.2 (CH

Ar), 129.8 (CH Ar), 133.0 (CH]), 134.3 (C Ar), 135.9 (C

Ar), 164.5 (CO); m/z 351 (MH⁺), 368 (M+NH₄⁺).

3.1.13. General procedure for the synthesis of g,d-unsat-

urated esters 14. To a solution of vinylmagnesium chloride

(or bromide, 2.4 equiv) in THF (2 mL/mmol) at ꢀ78 ^ꢁC was

added CuI (1.2 equiv), and the temperature was raised to

ꢀ40 ^ꢁC for 10 min. After that time, the reaction mixture

was cooled down to ꢀ78 ^ꢁC and a solution of sulfone 13

(1 equiv) in THF (2 mL/mmol) was added dropwise. After

1 h, the reaction mixture was quenched by addition of aque-

ous saturated NH₄Cl solution, and it was extracted with

EtOAc. The organic extracts were dried and concentrated,

and the residue was puriﬁed by ﬂash column chromato-

graphy.

3.1.14. General procedure for the 1,2-aryl transfer prod-

ucts 15/19/20. A solution of sulfone 14 (1.5 equiv) and the

corresponding xanthate 3 (1 equiv) in DCE (4 mL/mmol)

heated at reﬂux temperature was added DLP (0.15 equiv)

every 1.5 h, until the disappearance of the xanthate. Then

the reaction mixture was concentrated and the residue was

puriﬁed by ﬂash column chromatography.

3.1.15. General procedure for the synthesis of amines 16/

17/18. To a solution of ketone 15 (1 equiv) in absolute EtOH

˚

(2.5 mL/mmol) were added 4 A molecular sieves, the corre-

3.1.13.1. Ethyl 3-(2-chloropyrid-5-yl)-2-methanesulfo-

nylpent-4-enoate 14b. Puriﬁed by ﬂash column chromato-

graphy (petrol/EtOAc 7:3), two diastereomers A and B 1:1,

pale yellow oil, 76%; n_max/cm^ꢀ11737 (CO); d_H0.96 (t,

J¼7.2 Hz, 1.5H, CH₃diast. A), 1.23 (t, J¼7.2 Hz, 1.5H,

CH₃diast. B), 2.98 (s, 1.5H, CH₃diast. B), 3.15 (s, 1.5H, CH₃

diast. A), 3.98 (dq, J¼1.6, 7.2 Hz, 1H, OCH₂diast. A), 4.21

(q, J¼7.2 Hz, 1H, OCH₂diast. B), 4.40 (d, J¼8.8 Hz, 0.5H,

CHS diast. B), 4.47 (d, J¼11.2 Hz, 0.5H, CHS diast. A), 4.62

(t, J¼8.8 Hz, 0.5H, CHAr diast. B), 4.64 (t, J¼11.2 Hz, 0.5H,

CHAr diast. A), 5.24 (d, J¼10 Hz, 0.5H, CH]diast. A), 5.27

(d, J¼5.2 Hz, 0.5H, CH]diast. A), 5.29 (d, J¼11.2 Hz,

0.5H, CH]diast. B), 5.33 (d, J¼10.8 Hz, 0.5H, CH]diast.

B), 6.00–6.20 (m, 1H, CH]), 7.15–7.25 (m, 1H, ArH), 7.61

(dd, J¼2, 7.6 Hz, 0.5H, ArH diast. A), 7.68 (dd, J¼2, 7.6 Hz,

0.5H, ArH diast. B), 8.27 (dd, J¼1.6, 4.8 Hz, 0.5H, ArH

diast. A), 8.29 (dd, J¼1.6, 4.8 Hz, 0.5H, ArH diast. B); d_C

13.5 (CH₃diast. A), 13.8 (CH₃diast. B), 40.2 (CH₃SO₂diast.

B), 40.4 (CH₃SO₂diast. A), 45.1 (CHAr), 62.5 (OCH₂diast.

A), 62.6 (OCH₂diast. B), 70.9 (CHS diast. B), 72.3 (CHS

diast. A), 119.7 (CH₂]diast. A), 120.5 (CH₂]diast. B),

122.7 (CH Ar), 132.6 (C Ar diast. B), 133.0 (CH]diast.

B), 133.2 (C Ar diast. A), 134.1 (CH]diast. A), 137.9 (CH

Ar diast. A), 138.8 (CH Ar diast. B), 148.5 (CH Ar), 150.0

(C Ar diast. B), 150.3 (C Ar diast. A), 164.5 (CO diast. A),

165.0 (CO diast. B); m/z 318 (MH⁺); HRMS calcd for

C₁₃H₁₆ClNO₄S, 317.0489; found, 317.0492.

sponding amine (as its acetate salt, 10 equiv), NaBH₃CN

(1.1 equiv) and the resulting mixture was heated at reﬂux

temperature for 7 h. The reaction mixture was then concen-

trated, dissolved in CH₂Cl₂and washed with saturated aque-

ous NaHCO₃solution. The organic layer was dried and

evaporated, and the residue was puriﬁed by ﬂash column

chromatography.

3.1.15.1. Ethyl (2SR,3SR,6SR)-[6-(4-methoxyphenyl)-

3-(4-triﬂuoromethylphenyl)piperidin-2-yl]acetate 16a.

Puriﬁed by ﬂash column chromatography (petrol/EtOAc

8:2), yellow solid, 60%; mp 80–83 ^ꢁC, n_max/cm^ꢀ11731

(CO); d_H1.16 (t, J¼7.2 Hz, 3H, CH₃), 1.55–1.75 (m, 2H,

H-5_axand H-4_ax), 1.91 (dd, J¼2.2, 12.2 Hz, 1H, H-5_eq),

2.03 (dd, J¼2.8, 12.8 Hz, 1H, H-4_eq), 2.23 (dd, J¼3.2,

16.8 Hz, 1H, CHCO), 2.30 (dd, J¼8.8, 16.8 Hz, 1H,

CHCO), 2.62 (td, J¼3.6, 11.6 Hz, 1H, H-3_ax), 3.39 (td,

J¼2.7, 10 Hz, 1H, H-2_ax), 3.59 (br s, 1H, NH), 3.80 (s,

3H, OCH₃), 3.86 (dd, J¼1.6, 10.8 Hz, 1H, H-6_ax), 3.95–

4.05 (m, 2H, OCH₂), 6.89 (d, J¼8.4 Hz, 2H, ArH methoxy-

phenyl), 7.35 (d, J¼8.4 Hz, 4H, 2ArH methoxyphenyl and 2

ArH triﬂuoromethylphenyl), 7.58 (d, J¼8 Hz, 2H, ArH tri-

ﬂuoromethylphenyl); d_C14.0 (CH₃), 34.0 (C-4), 34.2 (C-

5), 38.6 (CH₂CO), 48.3 (C-3), 55.2 (OCH₃), 58.4 (C-2),

60.4 (OCH₂), 61.0 (C-6), 113.8 (CH Ar methoxyphenyl),

124.2 (q, J¼270 Hz, CF₃), 125.5 (q, J¼2.7 Hz, C-m triﬂuoro-

methylphenyl), 127.8 (CH Ar methoxyphenyl), 128.2 (C-o

triﬂuoromethylphenyl), 129.0 (q, J¼32.1 Hz, C-p triﬂuoro-

methylphenyl), 136.6 (C Ar), 147.6 (C Ar), 158.8 (C Ar),

172.3 (CO); m/z 422 (MH⁺); Elem. Anal. Calcd for

C₂₃H₂₆F₃NO₃: C, 65.55; H, 6.22; found: C, 65.39; H, 6.52.

3.1.13.2. Ethyl 3-(2,6-dichlorophenyl)-2-methanesul-

fonylpent-4-enoate 14c. Puriﬁed by ﬂash column chromato-

graphy (petrol/EtOAc 8:2), two diastereomers A and B 1:1,

yellow oil, 94%; n_max/cm^ꢀ11736 (CO), 1328 (SO₂); diaste-

reomer A: d_H1.28 (t, J¼7 Hz, 3H, CH₃), 2.89 (s, 3H, CH₃),

4.25 (q, J¼7.2 Hz, 2H, OCH₂), 5.00–5.25 (m, 4H, CH₂],

CHS, CHAr), 6.14 (ddd, J¼8.4, 9.6, 17.2 Hz, 1H, CH]),

3.1.15.2. Ethyl (2SR,3SR,6RS)-[6-(4-methoxyphenyl)-

3-(4-triﬂuoromethylphenyl)piperidin-2-yl]acetate 16b.

Puriﬁed by ﬂash column chromatography (petrol/EtOAc

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7209

1:1), yellow solid, 11%; mp 85–86 ^ꢁC; n_max/cm^ꢀ11729

(CO); d_H1.24 (t, J¼7.2 Hz, 3H, CH₃), 1.67–1.76 (m, 1H,

H-4_ax), 1.81 (ddd, J¼4, 9, 18 Hz, 1H, H-4_eq), 2.00 (tt,

J¼4.2, 12.5 Hz, 1H, H-5_ax), 2.26 (dd, J¼3.8, 15.8 Hz, 1H,

CHCO), 2.32 (dd, J¼9, 16.2 Hz, 1H, CHCO), 2.20–2.35

(m, 1H, H-5_eq), 2.50 (br s, 1H, NH), 2.60 (td, J¼4, 9.6 Hz,

1H, H-3_ax), 3.47 (t, J¼4, 8.8 Hz, 1H, H-2_ax), 4.05–4.15

(br s, 1H, H-6_eq), 6.95 (d, J¼8.4 Hz, 2H, ArH methoxy-

phenyl), 7.28 (d, J¼8 Hz, 2H, H-o triﬂuoromethylphenyl),

7.46 (d, J¼8.4 Hz, 2H, ArH methoxyphenyl), 7.50 (d,

J¼8 Hz, 2H, H-m triﬂuoromethylphenyl); d_C14.2 (CH₃),

28.4 (C-4), 29.2 (C-5), 39.0 (CH₂CO), 48.2 (C-3), 51.9

(C-2), 53.3 (C-6), 55.3 (OCH₃), 60.5 (OCH₂), 114.0 (CH

Ar methoxyphenyl), 124.2 (q, J¼270 Hz, CF₃), 125.4 (q,

J¼3.7 Hz, C-m triﬂuorophenyl), 127.9 (CH Ar methoxy-

phenyl), 128.2 (C-o triﬂuoromethylphenyl), 128.8 (q, J¼

32.4 Hz, C-p triﬂuorophenyl), 134.5 (C Ar), 148.2 (C Ar),

158.2 (C Ar), 172.4 (CO); m/z 423 (MH⁺); Elem. Anal.

Calcd for C₂₃H₂₆F₃NO₃$3/4H₂O: C, 63.51; H, 6.37; N,

3.22; found: C, 63.41; H, 6.18; N, 2.81.

7.57 (d, J¼8.4 Hz, 2H, H-m triﬂuoromethylphenyl); d_C

34.0 and 35.6 (C-8 and C-9), 42.3 (C-1 and C-5), 49.5

(C-10), 55.2 (OCH₃), 56.2 (C-4), 63.4 (C-7), 68.5 (C-11),

114.0 (CH Ar methoxyphenyl), 124.1 (q, J¼271 Hz, CF₃),

125.8 (C-m triﬂuoromethylphenyl), 128.1 (CH Ar methoxy-

phenyl and C-o triﬂuoromethylphenyl), 128.8 (q, J¼32 Hz,

C-p triﬂuoromethylphenyl), 136.8 (C Ar), 148.2 (C Ar),

158.6 (C Ar), 176.6 (C-2); m/z 419 (MH⁺); HRMS calcd

for C₂₃H₂₅F₃N₂O₂, 418.1868; found, 418.1871.

3.1.15.5. (1SR,7RS,10SR)-7-(4-Methoxyphenyl)-10-(4-

triﬂuoromethylphenyl)octahydropyrido[1,2-d][1,4]di-

azepin-2-one 18b. Puriﬁed by ﬂash column chromato-

graphy (EtOAc/MeOH 99:1), white foam, 16%; n_max/cm^ꢀ1

3429 (NH), 1676 (CO); d_H1.64–1.77 (m, 2H, H-10), 1.78–

1.87 (m, 1H, H-9_ax), 1.98 (dt, J¼4.1, 10.6 Hz, 1H, H-9_eq),

2.25 (d, J¼14.8 Hz, H-6), 2.72–2.84 (m, 1H, H-3), 2.84

(dd, J¼9.6, 14.8 Hz, H-2), 2.97 (q, J¼4.8 Hz, H-8), 3.10

(dd, J¼5.6, 14.8 Hz, 1H, H-2), 3.38 (dd, J¼9.8, 13 Hz,

1H, H-6), 3.59 (ddd, J¼4.8, 9.6, 14.8 Hz, 1H, H-3), 3.77–

3.83 (m, 1H, H-7), 3.81 (s, 3H, OCH₃), 4.08 (dd, J¼4,

8 Hz, 1H, H-11_eq), 6.28 (br s, 1H, NH), 6.88 (d, J¼8.4 Hz,

2H, ArH methoxyphenyl), 7.27 (d, J¼8.4 Hz, 2H, ArH

methoxyphenyl), 7.57 (dd, J¼8.4 Hz, 2H, ArH triﬂuorome-

thylphenyl), 7.61 (d, J¼8.4 Hz, 2H, ArH triﬂuoromethyl-

phenyl); d_C27.4 and 28.6 (C-9 and C-10), 38.7 (C-6), 39.4

(C-2), 44.3 (C-8), 52.9 (C-3), 55.2 (OCH₃), 56.0 and 59.1

(C-11 and C-7), 114.0 (CH Ar methoxyphenyl), 125.1 (C-

m triﬂuoromethylphenyl), 128.5 (CH Ar methoxyphenyl),

128.6 (C-o triﬂuoromethylphenyl), 134.6 (C Ar), 148.6 (C

Ar), 158.6 (C Ar), 177.0 (C-5); m/z 419 (MH⁺).

3.1.15.3. Ethyl (2SR,3SR,6SR)-[1-cyclopropyl-6-(4-

methoxyphenyl)-3-(4-triﬂuoromethylphenyl)piperidin-

2-yl]acetate 17. Puriﬁed by ﬂash column chromatography

(petrol/EtOAc 9:1), yellow solid, 86%; mp 78–80 ^ꢁC; n_max

/

cm^ꢀ11737 (CO); d_H0.02 (q, J¼3.2 Hz, 2H, CH₂cyclo-

propyl), 0.13 (qt, J¼3.4 Hz, 2H, CH₂cyclopropyl), 1.11 (t,

J¼7.2 Hz, 3H, CH₃), 1.82 (ht, J¼3.6 Hz, 1H, CH cyclo-

propyl), 1.87 (ddd, J¼2.8, 5.6, 12.4 Hz, 1H, H-5_ax), 1.94–

2.06 (m, 2H, H-4), 2.02 (dd, J¼5.2, 14.8 Hz, 1H, CHCO),

2.07–2.18 (m, 1H, H-5_eq), 2.77 (dd, J¼8.4, 14.8 Hz,

CHCO), 3.38–3.44 (m, 1H, H-3_ax), 3.81 (s, 3H, OCH₃),

3.85 (q, J¼6.8 Hz, 2H, OCH₂), 3.86–3.92 (m, 1H, H-2_ax),

3.93–3.97 (m, 1H, H-6_ax), 6.84 (d, J¼8.4 Hz, 2H, ArH me-

thoxyphenyl), 7.24 (d, J¼8.4 Hz, 2H, ArH methoxyphenyl),

7.38 (d, J¼8 Hz, 2H, ArH triﬂuoromethylphenyl), 7.58 (d,

J¼8.4 Hz, 2H, ArH triﬂuoromethylphenyl); d_C7.4 and 8.9

(CH₂cyclopropyl), 14.0 (CH₃), 23.9 (C-4), 29.7 (CH₂CO),

29.9 (C-5), 32.7 (CH isopropyl), 42.5 (C-3), 55.2 (OCH₃),

59.4 (C-2), 60.2 (OCH₂), 62.4 (C-6), 113.1 (CH Ar methox-

yphenyl), 124.2 (q, J¼270 Hz, CF₃), 125.2 (q, J¼3.7 Hz,

C-m triﬂuoromethylphenyl), 128.0 (C-o triﬂuoromethyl-

phenyl), 128.6 (q, J¼32.2 Hz, C-p triﬂuoromethylphenyl),

129.8 (CH Ar methoxyphenyl), 134.8 (C Ar), 146.8 (C

Ar), 158.6 (C Ar), 172.6 (CO); m/z 462 (MH⁺); Elem.

Anal. Calcd for C₂₆H₃₀F₃NO₃: C, 67.66; H, 6.55; N, 3.03;

found: C, 67.59; H, 6.59; N, 2.88.

3.1.15.6. Ethyl (4RS,6SR)-(E)-6-acetylamino-4-(2-

chloropyrid-5-yl)-7,7,7-triﬂuorohept-2-enoate 19a. Puri-

ﬁed by ﬂash column chromatography (petrol/EtOAc 1:1),

white solid, 32%; mp 107–113 ^ꢁC; n_max/cm^ꢀ13441 (NH),

1711 (CO), 1656 (CO amide); d_H1.30 (t, J¼7.2 Hz, 3H,

CH₃), 1.89 (ddd, J¼3.5, 11.3, 14.5 Hz, 1H, CH), 2.07 (s,

3H, CH₃acetyl), 2.25 (ddd, J¼2.8, 10.4, 14.4 Hz, 1H,

CH), 3.96–4.04 (m, 1H, CHAr), 4.21 (q, J¼7.2 Hz, 2H,

OCH₂), 4.60–4.80 (m, 1H, CHCF₃), 5.49 (d, J¼9.2 Hz,

1H, NH), 5.99 (dd, J¼1.2, 15.6 Hz, 1H, ]CHCO), 6.96

(dd, J¼8, 15.6 Hz, 1H, ]CH), 7.28 (dd, J¼4.4, 7.6 Hz,

1H, ArH), 7.62 (dd, J¼1.8, 7.8 Hz, 1H, ArH), 8.33 (dd,

J¼1.8, 4.4 Hz, 1H, ArH); d_C14.0 (CH₃), 22.7 (CH₃acetyl),

32.8 (CH₂), 39.8 (CH Ar), 48.6 (q, J¼30.7 Hz, CHCF₃), 60.7

(OCH₂), 123.1 (CH Ar), 124.6 (]CHCO), 124.8 (q,

J¼279.8 Hz, CF₃), 135.4 (C Ar), 137.2 (CH Ar), 144.9

(]CH), 148.2 (CH Ar), 150.4 (C Ar), 165.8 (CO amide),

170.4 (CO ester); m/z 379 (MH⁺), 396 (M+NH₄⁺); HRMS

calcd for C₁₆H₁₈F₃ClN₂O₃, 378.0958; found, 378.0967.

3.1.15.4. (1SR,7SR,10SR)-7-(4-Methoxyphenyl)-10-(4-

triﬂuoromethylphenyl)octahydropyrido[1,2-d][1,4]di-

azepin-2-one 18a. Puriﬁed by ﬂash column chromato-

graphy (EtOAc), white solid, 56%; mp 220–222 ^ꢁC; n_max

/

cm^ꢀ11679; d_H1.60 (ddd, J¼3.3, 12.3, 24.3 Hz, 1H, H-9_ax),

1.72 (ddd, J¼2.8, 13, 24.2 Hz, 1H, H-8_ax), 1.79 (tdd, J¼3.2,

6.4, 13.2 Hz, 1H, H-8_eq), 1.87 (ddd, J¼3.2, 6, 12.8 Hz, 1H,

H-9_eq), 2.07 (dd, J¼9.6, 13.6 Hz, 1H, H-5), 2.30 (d,

J¼14.4 Hz, 1H, H-1), 2.62 (dd, J¼8.4, 14 Hz, 1H, H-1),

2.65–2.78 (m, 2H, H-10 and H-11), 2.93 (qt, J¼7.1 Hz,

1H, H-4), 3.03 (dd, J¼6.2, 13.4 Hz, 1H, H-5), 3.23 (dd,

J¼3, 11 Hz, 1H, H-7), 3.27 (dd, J¼4, 9.6 Hz, 1H, H-4),

6.80 (br s, 1H, H-3), 6.87 (d, J¼8.8 Hz, 2H, CH Ar methox-

yphenyl), 7.26 (d, J¼8.4 Hz, 2H, H-o triﬂuoromethyl-

phenyl), 7.32 (d, J¼8 Hz, 2H, CH Ar methoxyphenyl),

3.1.15.7. Ethyl (4RS,6RS)-(E)-6-acetylamino-4-(2-

chloropyrid-5-yl)-7,7,7-triﬂuorohept-2-enoate 19b. Puri-

ﬁed by ﬂash column chromatography (petrol/EtOAc 4:6),

white solid, 25%; mp 115 ^ꢁC; n_max/cm^ꢀ13441 (NH), 1709

(CO); d_H1.28 (t, J¼7.2 Hz, 3H, CH₃), 2.00 (s, 3H, CH₃ace-

tyl), 2.01–2.12 (m, 1H, CH), 2.39 (ddd, J¼3.6, 9.2, 14.4 Hz,

1H, CH), 4.10–4.25 (m, 1H, CHAr), 4.18 (q, J¼7.2 Hz, 2H,

OCH₂), 4.45–4.55 (m, 1H, CHCF₃), 5.45 (d, J¼10 Hz, 1H,

NH), 5.83 (dd, J¼1.2, 15.6 Hz, 1H, ]CHCO), 6.98 (dd,

J¼7.2, 15.6 Hz, 1H, ]CH), 7.30 (dd, J¼4.4, 7.6 Hz, 1H,

CH Ar), 7.55 (dd, J¼1.6, 7.6 Hz, 1H, CH Ar), 8.35 (dd,

7210

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

J¼2, 4.8 Hz, 1H, CH Ar); d_C14.1 (CH₃), 22.6 (CH₃acetyl),

31.3 (CH₂), 40.2 (CHAr), 48.4 (q, J¼30.6 Hz, CHCF₃), 60.6

(OCH₂), 122.5 (]CHCO), 123.2 (CH Ar), 124.8 (q,

J¼279.8 Hz, CF₃), 133.7 (C Ar), 137.1 (CH Ar), 147.0

(]CH), 148.5 (CH Ar), 151.2 (C Ar), 165.9 (CO amide),

170.3 (CO ester); m/z 379 (MH⁺), 396 (M+NH₄⁺); HRMS

calcd for C₁₆H₁₈F₃ClN₂O₃, 378.0958; found, 378.0946.

1H, CHCF₃), 5.07 (brm, 1H, NCH), 7.28 (dd, J¼4.8,

7.6 Hz, 1H, CHAr), 7.67 (dd, J¼1.8, 7.6 Hz, 1H, CH Ar),

8.33 (dd, J¼1.8, 7.6 Hz, 1H, CH Ar); d_C13.9 (CH₃), 22.6

(CH₃acetyl), 26.4 (CH₂), 36.1 (CH₂CO), 43.6 (CHAr),

55.7 (q, J¼26.4 Hz, CHCF₃), 57.7 (NCH), 60.9 (OCH₂),

122.5 (CH Ar), 125.1 (q, J¼279.4 Hz, CF₃), 129.9 (C Ar),

136.9 (CH Ar), 148.7 (CH Ar), 152.6 (C Ar), 169.4 (CO),

171.6 (CO); m/z 379 (MH⁺), 396 (M+NH₄⁺); HRMS calcd

for C₁₆H₁₈F₃ClN₂O₃, 378.0958; found, 378.0950.

3.1.15.8. Ethyl (E)-6-acetylamino-4-(2,6-dichloro-

phenyl)-7,7,7-triﬂuorohept-2-enoate 20a. Puriﬁed by ﬂash

column chromatography (petrol/EtOAc 8:2), white solid,

24%; mp 120 ^ꢁC; n_max/cm^ꢀ13443 (NH), 1714 (CO ester),

1651 (CO amide); d_H1.28 (t, J¼7 Hz, 3H, CH₃), 1.94 (s,

3H, CH₃acetyl), 2.00 (ddd, J¼4.8, 11.6, 14.4 Hz, 1H,

CH), 2.73 (ddd, J¼2.4, 8.8, 14.4 Hz, 1H, CH), 4.18 (q,

J¼7.2 Hz, 2H, OCH₂), 4.48–4.56 (m, 1H, CH), 4.65–4.78

(m, 1H, CH), 5.38 (br s, 1H, NH), 5.86 (dd, J¼1.4,

15.8 Hz, 1H, CH]), 7.15 (t, J¼8 Hz, 1H, CH Ar), 7.23

(dd, J¼6.8, 16 Hz, 1H, CH]), 7.28–7.36 (m, 2H, CH Ar);

d_C14.0 (CH₃), 22.5 (CH₃acetyl), 31.0 (CH₂), 40.0

(CHAr), 49.2 (q, J¼30.5 Hz, CHCF₃), 60.5 (OCH₂), 123.4

(CH]), 124.7 (q, J¼279.7 Hz, CF₃), 128.6 (CH Ar),

128.9 (CH Ar), 129.9 (CH Ar), 134.9 (C Ar), 135.4 (C

Ar), 136.5 (C Ar), 145.4 (CH]), 166.1 (CO), 170.4 (CO);

m/z 412 (MH⁺), 429 (M+NH⁺₄); HRMS calcd for

C₁₇H₁₈F₃Cl₂NO₃, 411.0616; found, 411.0633.

3.1.16.2. (2SR,3SR,5SR)-N-Acetyl-3-(2-chloropyrid-5-

yl)-2-ethoxycarbonylmethyl-5-triﬂuoromethylpyrrolidine

21b. Puriﬁed by ﬂash column chromatography (petrol/

EtOAc 4:6), white foam, 25%; n_max/cm^ꢀ11736 (CO ester),

1675 (CO amide); d_H1.02 (br m, 3H, CH₃), 2.20 (br m, 4H,

CH₃acetyl and CH), 2.46 (br m, 1H, CHCO), 2.62 (br m, 1H,

CH), 3.13 (br m, 1H, CHCO), 3.88 (br m, 3H, OCH₂and

CHAr), 4.49 (br m, 1H, CHCF₃), 4.75 (br m, 1H, NCH),

7.25 (dd, J¼4.8, 7.6 Hz, 1H, CH Ar), 7.66 (br m, 1H, CH

Ar), 8.29 (d, J¼3.2 Hz, 1H, CH Ar); d_C13.8 (CH₃), 22.4

(CH₃acetyl), 33.9 (CH₂), 39.7 (CH₂CO), 45.4 (CHAr),

59.9 (q, J¼31.4 Hz, CHCF₃), 60.58 (OCH₂), 60.62 (NCH),

123.0 (CH Ar), 125.0 (q, J¼280.6 Hz, CF₃), 134.9 (C Ar),

136.9 (CH Ar), 148.3 (CH Ar), 151.0 (C Ar), 170.2 (CO),

170.6 (CO); m/z 379 (MH⁺), 396 (M+NH₄⁺); HRMS calcd

for C₁₆H₁₈F₃ClN₂O₃, 378.0958; found, 378.0958.

3.1.15.9. Ethyl (E)-6-acetylamino-4-(2,6-dichloro-

phenyl)-7,7,7-triﬂuorohept-2-enoate 20b. Puriﬁed by ﬂash

column chromatography (petrol/EtOAc 7:3), white solid,

28%; mp 184–186 ^ꢁC; n_max/cm^ꢀ13444 (NH), 1714 (CO

ester), 1651 (CO amide); d_H1.26 (t, J¼7.2 Hz, 3H, CH₃),

1.94 (s, 3H, CH₃acetyl), 2.06 (ddd, J¼4.5, 12.8, 14 Hz,

1H, CH), 2.93 (ddd, J¼2.8, 10.8, 14 Hz, 1H, CH), 4.17 (q,

J¼7.2 Hz, 3H, OCH₂and CHCF₃), 4.60–4.68 (m, 1H,

CHAr), 5.75 (dd, J¼1.6, 15.6 Hz, 1H, CH]), 6.78 (d,

J¼9.2 Hz, 1H, NH), 7.15 (t, J¼8 Hz, 1H, CH Ar), 7.16

(dd, J¼6, 16 Hz, 1H, CH]), 7.26–7.33 (m, 2H, CH Ar);

d_C14.1 (CH₃), 22.8 (CH₃acetyl), 29.2 (CH₂), 39.8 (CH

Ar), 48.5 (q, J¼30.5 Hz, CHCF₃), 60.6 (OCH₂), 122.1

(CH]), 124.9 (q, J¼280.1 Hz, CF₃), 128.9 (CH Ar),

129.4 (CH Ar), 130.3 (CH Ar), 133.8 (C Ar), 134.9 (C

Ar), 136.4 (C Ar), 146.6 (CH]), 166.3 (CO), 170.2 (CO);

m/z 412 (MH⁺), 429 (M+NH⁺₄); HRMS calcd for

C₁₇H₁₈F₃Cl₂NO₃, 411.0616; found, 411.0616.

3.1.16.3.

(2SR,3SR,5RS)-N-Acetyl-3-(2,6-dichloro-

phenyl)-2-ethoxycarbonylmethyl-5-triﬂuoromethyl-

pyrrolidine 22a and (2SR,3SR,5SR)-N-acetyl-3-(2,

6-dichlorophenyl)-2-ethoxycarbonylmethyl-5-triﬂuorome-

thylpyrrolidine 22b. Puriﬁed by ﬂash column chromato-

graphy (petrol/EtOAc 7:3), white solid, 48%; mp 85 ^ꢁC;

n_max/cm^ꢀ11737 (CO ester), 1675 (CO amide); d_H0.98 (t,

J¼7 Hz, 3H, CH₃22a), 1.07 (t, J¼7 Hz, 3H, CH₃22b),

2.22 (s, 6H, 2CH₃acetyl), 2.36 (dd, J¼9.4, 13.4 Hz, 2H,

CH 22b and CH 22a), 2.47 (dd, J¼10, 15.6 Hz, 1H,

CHCO 22b), 2.55–2.66 (m, 1H, CH₂22a), 2.75–2.92 (m,

3H, CH₂22b and CH₂CO 22a), 3.18 (dd, J¼3.6, 16 Hz, 1H,

CHCO 22b), 3.75–4.05 (m, 4H, 2OCH₂), 4.30–4.46 (m, 2H,

2CHAr), 4.56 (qt, J¼8 Hz, 1H, CHCF₃22b), 4.88 (br m,

1H, NCH 22a), 5.17 (br m, 1H, NCH 22b), 5.20–5.30 (m,

1H, CHCF₃22a), 7.10–7.18 (m, 2H, ArH), 7.28–7.36

(m, 4H, ArH); d_C13.7 (CH₃ester), 21.5 (CH₃acetyl 22a),

22.3 (CH₃acetyl 22b), 29.3 (C-3 22a), 30.3 (C-3 22b),

40.2 (CH₂CO 22b), 42.3 (CH₂CO 22a), 44.9 (C-4 22b),

47.2 (C-4 22a), 57.7 (q, J¼32.1 Hz, C-2 22a), 58.9 (C-5

22b), 60.2 (q, J¼31.3 Hz, C-2 22b), 60.3 (C-5 22a), 60.4

(OCH₂22b), 60.9 (OCH₂22a), 128.5 (CH Ar), 128.7 (CH

Ar), 128.8 (CH Ar), 130.3 (CH Ar), 134.3 (C Ar), 135.8 (C

Ar), 136.15 (C Ar), 136.23 (C Ar), 169.8 (CO), 169.9 (CO),

170.3 (CO), 170.6 (CO); m/z 412 (MH⁺); HRMS calcd for

C₁₇H₁₈F₃Cl₂NO₃, 411.0616; found, 411.0625.

3.1.16. General procedure for the synthesis of pyrroli-

dines 21/22. To a solution of amidoester 19/20 (1 equiv) in

THF (4 mL/mmol) cooled at 0 ^ꢁC was added t-BuOK

(0.8 equiv) and stirred at that temperature for 1 h. After

that time, the reaction mixture was concentrated, and the res-

idue dissolved in EtOAc and washed with brine. The organic

layer was dried and concentrated, and the residue was puri-

ﬁed by ﬂash column chromatography.

References and notes

3.1.16.1. (2SR,3SR,5RS)-N-Acetyl-3-(2-chloropyrid-5-

yl)-2-ethoxycarbonylmethyl-5-triﬂuoromethylpyrrolidine

21a. Puriﬁed by ﬂash column chromatography (petrol/

EtOAc 1:1), white foam, 17%; n_max/cm^ꢀ11738 (CO ester),

1686 (CO amide); d_H1.08 (t, J¼7.2 Hz, 3H, CH₃), 2.19

(dd, J¼8.4, 16 Hz, 1H, CHCO), 2.28 (s, 3H, CH₃acetyl),

2.43 (dd, J¼6, 16 Hz, 1H, CHCO), 2.44–2.60 (m, 2H,

CH₂), 3.68–3.88 (m, 3H, OCH₂and CHAr), 4.93 (brm,

€

1. (a) Wikstrom, H.; Sanchez, D.; Lidberg, P.; Hacksell, U.;

Arvidsson, L.-E.; Johansson, A. M.; Thorberg, S.-O.;

Nilsson, J. L. G.; Svensson, K.; Hjorth, S.; Clark, D.;

Carlsson, A. J. Med. Chem. 1984, 27, 1030; (b) Liljefors, T.;

€

Wikstrom, H. J. Med. Chem. 1986, 29, 1896; (c) Liljefors, T.;

Bøgesø, K. P.; Hyttel, J.; Wikstrom, H.; Svensson, K.;

€

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

7211

Carlsson, A. J. Med. Chem. 1990, 33, 1015; Sonesson, C.; Lin,

C.-H.; Hansson, L.; Waters, N.; Svensson, K.; Carlsson, A.;

Smith, M. W.; Wikstrom, H. J. Med. Chem. 1984, 37, 2735;

(d) Hansson, L. O.; Waters, N.; Holm, S.; Sonesson, C.

J. Med. Chem. 1995, 38, 3121; (e) Cervetto, L.; Demontis,

G. C.; Giannaccini, G.; Longoni, B.; Macchia, B.; Macchia,

M.; Martinelli, A.; Orlandini, E. J. Med. Chem. 1998, 41,

4933; (f) Macchia, M.; Cervetto, L.; Demontis, G. C.;

Longoni, B.; Minutolo, F.; Orlandini, E.; Ortore, G.; Papi, C.;

Sbrana, A.; Macchia, B. J. Med. Chem. 2003, 46, 161.

2. (a) Giardina, G. A. M.; Grugni, M.; Rigolio, R.; Vassallo, M.;

Erhard, K.; Farina, C. Bioorg. Med. Chem. Lett. 1996, 6,

2307; (b) Vaz, R. J.; Maynard, G. D.; Kudlacz, E. M.;

Bratton, L. D.; Kane, J. M.; Shatzer, S. A.; Knippenberg,

R. W. Bioorg. Med. Chem. Lett. 1997, 7, 2825; (c) Harrison,

T.; Korsgaard, M. P. G.; Swain, C. J.; Cascieri, M. A.;

Sadowski, S.; Seabrook, G. R. Bioorg. Med. Chem. Lett.

1998, 8, 1343; (d) Kubota, H.; Okamoto, Y.; Fujii, M.; Ikeda,

K.; Takeuchi, M.; Shibanuma, T.; Isomura, Y. Bioorg. Med.

Chem. Lett. 1998, 8, 1541; (e) Carnell, A. J.; Escudero

Hernandez, M. L.; Pettman, A.; Bickley, J. F. Tetrahedron

Lett. 2000, 41, 6929; (f) Allan, G.; Carnell, A. J.; Escudero

Hernandez, M. L.; Pettman, A. Tetrahedron 2001, 57, 8193;

(g) MacKenzie, A. R.; Marchington, A. P.; Middleton, D. S.;

Newman, V.; Jones, B. C. J. Med. Chem. 2002, 45, 5365; (h)

MacKenzie, A. R.; Marchington, A. P.; Middleton, D. S.;

Newman, S. D.; Selway, C. N.; Terrett, N. K. Bioorg. Med.

Chem. Lett. 2003, 13, 2211.

8. (a) Hacksell, U.; Arvidsson, L.-E.; Svensson, U.; Nilsson,

J. L. G. J. Med. Chem. 1981, 24, 1475; (b) Tagat, J. R.;

McCombie, S. W.; Barton, B. E.; Jackson, J.; Shortall, J.

Bioorg. Med. Chem. Lett. 1995, 5, 2143.

9. (a) Thompson, W. J.; Gaudino, J. J. Org. Chem. 1984, 49, 5237;

Ali, N. M.; McKillop, A.; Mitchell, M. B.; Rebelo, R. A.;

Wallbank, P. J. Tetrahedron 1992, 48, 8117; (b) Tagata, T.;

Nishida, M. J. Org. Chem. 2003, 68, 9412; (c) Ciofﬁ, C. L.;

Spencer, W. T.; Richards, J. J.; Herr, R. J. J. Org. Chem.

2004, 69, 2210.

10. (a) Nilsson, K.; Hallberg, A. J. Org. Chem. 1992, 57, 4015; (b)

€

Buchner, I. K.; Metz, P. Tetrahedron Lett. 2001, 42, 5381; (c)

Carpes, M. J. S.; Correia, C. R. D. Tetrahedron Lett. 2002,

43, 741.

11. For other syntheses of 3-arylpiperidines, see inter alia: (a)

Iorio, M. A. J. Med. Chem. 1978, 21, 812; (b) Wong, Y.-S.;

ꢀ

Marazano, C.; Gnecco, D.; Genisson, Y.; Chiaroni, A.; Das,

B. C. J. Org. Chem. 1997, 62, 729; (c) Lindemann, U.; Reck,

G.; Wulff-Molder, D.; Wessig, P. Tetrahedron 1998, 54,

2529; (d) Klumpp, D. A.; Garza, M.; Jones, A.; Mendoza, S.

J. Org. Chem. 1999, 64, 6702; (e) Wu, X.; Dubois, K.;

Rogiers, J.; Toppet, S.; Compernolle, F.; Hoornaert, G. J.

Tetrahedron 2000, 56, 3043; (f) Klumpp, D. A.; Beauchamp,

P. S.; Sanchez, G. V., Jr.; Aguirre, S.; de Leon, S.

Tetrahedron Lett. 2001, 42, 5821; (g) Johnson, T. A.; Curtis,

M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 1004; (h) Liu,

D.-G.; Gao, Y.; Wang, X.; Kelley, J. A.; Burke, T. R., Jr.

ꢀ

J. Org. Chem. 2002, 67, 1448; (i) Amat, M.; Canto, M.; Llor,

N.; Escolano, C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org.

3. (a) Kumagai, T.; Okubo, T.; Kataoka-Okubo, H.; Chaki, S.;

Okuyama, S.; Nakazato, A. Bioorg. Med. Chem. 2001, 9,

1349; (b) Kumagai, T.; Okubo, T.; Kataoka-Okubo, H.;

Chaki, S.; Okuyama, S.; Nakazato, A. Bioorg. Med. Chem.

2001, 9, 1357.

ꢀ

Chem. 2002, 67, 5343; (j) Amat, M.; Canto, M.; Llor, N.;

Ponzo, V.; Perez, M.; Bosch, J. Angew. Chem., Int. Ed. 2002,

ꢀ

41, 335; Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett.

2004, 6, 345; (k) de Filippis, A.; Gomez Pardo, D.; Cossy, J.

Tetrahedron 2004, 60, 9757; (l) Takemiya, A.; Hartwig, J. F.

J. Am. Chem. Soc. 2006, 128, 6042.

4. Abell, A. D.; Prince, M. J.; McNulty, A. M.; Neubauer, B. L.

Bioorg. Med. Chem. Lett. 2000, 10, 1909.

5. Ablordeppey, S. Y.; Fischer, J. B.; Law, H.; Glennon, R. A.

Bioorg. Med. Chem. 2002, 10, 2759.

12. Boivin, J.; Pothier, J.; Zard, S. Z. Tetrahedron Lett. 1999, 40,

3701.

6. (a) Keely, S. L., Jr.; Martinez, A. J.; Tahk, F. C. Tetrahedron

1970, 26, 4729; (b) Langlois, M.; Guillonneau, C.; Meingan,

J.; Maillard, J. Tetrahedron 1971, 27, 5641; (c) Zelle, R. E.;

Hancock, A. A.; Buckner, S. A.; Basha, F. Z.; Tietje, K.;

DeBernardis, J. F.; Meyer, M. D. Bioorg. Med. Chem. Lett.

13. Vila, X.; Zard, S. Z. Heterocycles 2006, 70, 45.

14. Gheorghe, A.; Quiclet-Sire, B.; Vila, X.; Zard, S. Z. Org. Lett.

2005, 7, 1653.

15. (a) Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672; (b)

Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur Silicon

Relat. Elem. 1999, 137; (c) Zard, S. Z. Radicals in Organic

Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:

Weinheim, 2001; Vol. 1, pp 90–106; (d) Quiclet-Sire, B.;

Zard, S. Z. Chem.—Eur. J. 2006, 12, 6002; (e) Quiclet-Sire,

B.; Zard, S. Z. Top. Curr. Chem. 2006, 264, 201; (f) Zard,

S. Z. Org. Biomol. Chem. 2007, 5, 205.

€

1994, 4, 1319; (d) Sonesson, C.; Wikstrom, H.; Smith,

M. W.; Svensson, K.; Carlsson, A.; Waters, N. Bioorg. Med.

Chem. Lett. 1997, 7, 241; (e) Ahn, K. H.; Lee, S. J.; Lee,

C.-H.; Hong, C. Y.; Park, T. K. Bioorg. Med. Chem. Lett. 1999,

9, 1379; (f) Collina, S.; Azzolina, O.; Vercesi, D.; Sbacchi, M.;

Scheideler, M. A.; Barbieri, A.; Lanza, E.; Ghislandi, V.

Bioorg. Med. Chem. Lett. 2000, 10, 1925; (g) Collina, S.;

Azzolina, O.; Vercesi, D.; Brusotti, G.; Rossi, D.; Barbieri,

A.; Lanza, E.; Mennuni, L.; Alcaro, S.; Battaglia, D.; Linati,

L.; Ghislandi, V. Farmaco 2003, 58, 939; (h) Obniska, J.;

Zagorska, A. Farmaco 2003, 58, 1227; (i) Collina, S.; Rossi,

D.; Loddo, G.; Barbieri, A.; Lanza, E.; Linati, L.; Alcaro, S.;

Gallelli, A.; Azzolina, O. Bioorg. Med. Chem. 2005, 13, 3117.

7. (a) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh,

H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992,

114, 3475; (b) Zhang, C.; Gyermek, L.; Trudell, M. L.

Tetrahedron Lett. 1997, 38, 5619; (c) Che, C.; Petit, G.;

Kotzyba-Hibert, F.; Bertrand, S.; Bertrand, D.; Grutter, T.;

Goeldner, M. Bioorg. Med. Chem. Lett. 2003, 13, 1001; (d)

Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe, H.; Takemoto, Y.

Tetrahedron 2006, 62, 365.

16. Wieland, H. Chem. Ber. 1911, 44, 2550.

17. Urry, W. H.; Kharasch, M. S. J. Am. Chem. Soc. 1944, 66, 1438.

18. For a review on radical aryl migrations, see: (a) Studer, A.;

Bossart, M. Tetrahedron 2001, 57, 9649; (b) Studer, A.;

Bossart, M. Radicals in Organic Synthesis; Renaud, P., Sibi,

M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 62–76.

19. Loven, R.; Speckamp, W. N. Tetrahedron Lett. 1972, 13, 1567.

€

20. See, inter alia: (a) Kohler, J. J.; Speckamp, W. N. Tetrahedron

Lett. 1977, 18, 631; (b) Kohler, J. J.; Speckamp, W. N.

€

Tetrahedron Lett. 1977, 18, 635; (c) Speckamp, W. N.;

€

Kohler, H. J.; Speckamp, W. N. J. Chem. Soc., Chem.

Kohler, J. J. J. Chem. Soc., Chem. Commun. 1978, 166; (d)

€

Commun. 1980, 142; (e) Clive, D. L. J.; Boivin, T. L. B.

J. Org. Chem. 1989, 54, 1997; (f) Motherwell, W. B.;

Pennell, A. M. K. J. Chem. Soc., Chem. Commun. 1991, 877;

7212

A. Gheorghe et al. / Tetrahedron 63 (2007) 7187–7212

(g) Caddick, S.; Aboutayab, K.; West, R. Synlett 1993, 231; (h)

2003, 68, 8932; (g) Bariau, A.; Roblin, J.-P.; Troin, Y.;

Canet, J.-L. Synlett 2005, 1731; (h) Magueur, G.; Legros, J.;

ꢀ

Meyer, F.; Ourevitch, M.; Crousse, B.; Bonnet-Delpon, D.

Eur. J. Org. Chem. 2005, 1258.

da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F.

Tetrahedron Lett. 1997, 38, 137; (i) da Mata, M. L. E. N.;

Motherwell, W. B.; Ujjaainwalla, F. Tetrahedron Lett. 1997,

38, 141; (j) Studer, A.; Bossart, M. Chem. Commun. 1998,

2127; (k) Aldabbagh, F.; Bowman, W. R. Tetrahedron 1999,

55, 4109; (l) Caddick, S.; Shering, C. L.; Wadman, S. N.

Tetrahedron 2000, 56, 465.

27. Ouvry, G.; Zard, S. Z. Synlett 2003, 1627.

28. (a) Abeywickrema, A. N.; Beckwith, A. L. J.; Gerba, S. J. Org.

Chem. 1987, 52, 4072; (b) Parker, T. L.; Spero, D. M.;

Irman, K. Tetrahedron Lett. 1986, 27, 2833; (c) McNab, H.

J. Chem. Soc., Chem. Commun. 1990, 543; (d) Ishibashi, H.;

Kobayashi, T.; Nakashima, S.; Tamura, O. J. Org. Chem.

2000, 65, 9022; (e) Ishibashi, H.; Ohata, K.; Niihara, M.;

Sato, T.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 2000, 547.

29. For the synthesis of substituted pyrrolidines and piperidines,

21. (a) Moutrille, C.; Zard, S. Z. Chem. Commun. 2004, 1848; (b)

ˆ

Montermini, F.; Lacote, E.; Malacria, M. Org. Lett. 2004, 6,

921.

22. (a) Organoﬂuorine Compounds in Medicinal Chemistry and

Biochemical Applications; Filler, R., Kobayashi, Y.,

Yagupolskii, L., Eds.; Elsevier: Amsterdam, 1993; (b)

Organoﬂuorine Chemistry: Principles and Commercial

Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.;

Plenum: New York, NY, 1994.

ꢁ

see: (a) Pichon, M.; Figadere, B. Tetrahedron: Asymmetry

1996, 7, 927; (b) Bailey, P. D.; Millwood, P. A.; Smith, P. D.

Chem. Commun. 1998, 633.

30. For syntheses and pharmacological evaluation of open epibati-

dine analogues, see: (a) Xu, R.; Bai, D.; Chu, G.; Tao, J.; Zhu,

X. Bioorg. Med. Chem. Lett. 1996, 6, 279; (b) Bai, D.; Xu, R.;

Chu, G.; Zhu, X. J. Org. Chem. 1996, 61, 4600; Only 2 synthe-

ses of 3-aryl-5-triﬂuoromethylpyrrolidines have been reported:

(c) Tanaka, K.; Nagatani, S.; Ohsuga, M.; Mitsuhashi, K. Bull.

Chem. Soc. Jpn. 1994, 67, 589; (d) Zanatta, N.; Rosa, L. S.;

Cortelini, M. F. M.; Beux, S.; Santos, A. P. D.; Bonacorso,

H. G.; Martins, M. A. P. Synthesis 2002, 2404.

23. (a) Kobayashi, Y.; Yamamoto, K.; Asai, T.; Nakano, M.;

Kumadaki, I. J. Chem. Soc., Perkin Trans. 1 1980, 2755; (b)

ꢀ

Girard, Y.; Atkinson, J. G. P.; Belanger, C.; Fuentes, J. J.;

Rokach, J.; Rooney, C. S. J. Org. Chem. 1983, 48, 3220; (c)

McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48,

6555; (d) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432.

24. (a) Boivin, J.; El Kaim, L.; Zard, S. Z. Tetrahedron 1995, 51,

ꢀ

2585; (b) Bonnet-Delpon, D.; Begue, J.-P.; Lequeux, T.;

Ourevitch, M. Tetrahedron 1996, 52, 59; (c) Nenajdenko,

V. G.; Sanin, A. V.; Balenkova, E. S. Molecules 1997, 2, 186;

(d) Zhu, S.; Qin, C.; Xu, G.; Chu, Q.; Huang, Q. J. Fluorine

Chem. 1999, 99, 141; (e) Kruchok, I. S.; Gerus, I. I.; Kukhar,

V. P. Tetrahedron 2000, 56, 6533; (f) Nenejdenko, V. G.;

Statsuk, A. V.; Balenkova, E. S. Tetrahedron 2000, 56, 6549;

(g) Coles, S. J.; Mellor, J. M.; El-Sagheer, A. H.; Salem,

E. E. M.; Metwally, R. N. Tetrahedron 2000, 56, 10057; (h)

Krasovsky, A. L.; Nenajdenko, V. G.; Balenkova, E. S.

Tetrahedron 2001, 57, 201.

31. (a) Johnson, G.; Drummond, J. T.; Boxer, P. A.; Bruns, R. F.

J. Med. Chem. 1992, 35, 233; (b) Laborde, E. Tetrahedron

ꢀ

Lett. 1992, 33, 6607; (c) Begue, J.-P.; Bonnet-Delpon, D.;

Lequeux, T. Tetrahedron Lett. 1993, 34, 3279; (d) Ma, Z.;

Wang, S.; Cooper, C. S.; Fung, A. K. L.; Lynch, J. K.;

Plagge, F.; Chu, D. T. W. Tetrahedron: Asymmetry 1997, 8,

€

883; (e) Karlsson, S.; Han, F.; Hogberg, H.-E.; Caldirola, P.

Tetrahedron: Asymmetry 1999, 10, 2605; (f) Karlsson, S.;

€

Hogberg, H.-E. Tetrahedron: Asymmetry 2001, 12, 1977; (g)

ꢀ

Viranyi, A.; Nyerges, M.; Blasko, G.; TTke, L. Synthesis

2003, 2655; (h) Belyk, K. M.; Beguin, C. D.; Palucki, M.;

Grinberg, N.; DaSilva, J.; Askin, D.; Yasuda, N. Tetrahedron

Lett. 2004, 45, 3265.

25. For the synthesis of ﬂuorinated heterocycles, see: (a) Zhu,

S.-Z.; Quin, C.-Y.; Wang, Y.-L.; Chu, Q.-L. J. Fluorine

Chem. 1999, 99, 183; (b) Chi, K.-W.; Furin, G. G.; Gatilov,

Y. V.; Bagryanskay, I. Y.; Zhuzhgov, E. L. J. Fluorine Chem.

2000, 103, 105; (c) Andrew, R. J.; Mellor, J. M.; Reid, G.

Tetrahedron 2000, 56, 7255; (d) Andrew, R. J.; Mellor, J. M.

Tetrahedron 2000, 56, 7267; (e) Song, L.-P.; Chu, Q.-L.;

Zhu, S.-Z. J. Fluorine Chem. 2001, 107, 107.

32. (a) Keely, S. L., Jr.; Tahk, F. C. J. Am. Chem. Soc. 1968, 90,

5584; (b) De Smaele, D.; De Kimpe, N. J. Chem. Soc.,

Chem. Commun. 1995, 2029; (c) Denmark, S. E.; Marcin,

L. R. J. Org. Chem. 1995, 60, 3221; (d) Sonesson, C.;

Larhed, M.; Nyqvist, C.; Hallberg, A. J. Org. Chem. 1996,

61, 4756; (e) Langlois, N.; Dahuron, N.; Wang, H.-S.

Tetrahedron 1996, 48, 15117; (f) Anada, M.; Hashimoto,

S.-I. Tetrahedron Lett. 1998, 39, 79; (g) Wee, A. G. H.; Liu,

B.; McLeod, D. D. J. Org. Chem. 1998, 63, 4218; (h) Anada,

M.; Mita, O.; Watanabe, H.; Kitagani, S.; Hashimoto, S.

Synlett 1999, 1775; (i) Oda, K.; Meyers, A. I. Tetrahedron

Lett. 2000, 41, 8193; (j) Chung, J. Y. L.; Cvetovich, R.;

Amato, J.; McWilliams, J. C.; Reamer, R.; DiMichele, L.

J. Org. Chem. 2005, 70, 3592.

26. For some triﬂuoromethylpiperidine syntheses, see: (a) Okano,

T.; Sakaida, T.; Eguchi, S. J. Org. Chem. 1996, 61, 8826; (b)

McAtee, J. J.; Schinazi, R. F.; Liotta, D. C. J. Org. Chem.

ꢀ

1998, 63, 2161; (c) Crousse, B.; Begue, J.-P.; Bonnet-

Delpon, D. Tetrahedron Lett. 1998, 39, 5765; (d) Jiang, J.;

DeVita, R. J.; Doss, G. A.; Goulet, M. T.; Wyvratt, M. J.

ꢀ

J. Am. Chem. Soc. 1999, 121, 593; (e) Crousse, B.; Begue,

J.-P.; Bonnet-Delpon, D. J. Org. Chem. 2000, 65, 5009; (f)

Gille, S.; Ferry, A.; Billard, T.; Langlois, B. R. J. Org. Chem.

Article Doi

Synthesis of substituted 3-arylpiperidines and 3-arylpyrrolidines by radical 1,4 and 1,2-aryl migrations

DOI: 10.1016/j.tet.2007.04.091

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