Interaction of dihydropyridines and nucleophiles with carbene complexes of chromium: Diastereo- and enantioselective synthesis of polycyclic butenolides

FULL PAPER

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of

Chromium: Diastereo- and Enantioselective Synthesis of Polycyclic Butenolides

[a]

´

Henri Rudler,* Andree Parlier, Victor Certal, Gabriel Lastennet, Max Audouin,

and Jacqueline Vaissermann^[a]

Keywords: Chromium / Carbenes / Dihydropyridines / Nucleophiles / Butenolides

The interaction of N-methyldihydropyridine with carbene

complexes of chromium promotes their spontaneous homo-

logation upon addition of a hydride to the carbene carbon

and an insertion of CO. This is followed in the case of com-

plexes tethered to a triple bond by cascade insertions of the

formation was first extended to dihydronicotinamides, to

chiral dihydropyridines such as dihydronicotines which led

to the butenolides in an enantioselective way, and to other

sources of hydrides. Second, a series of nucleophiles such as

alkoxides, alkyllithium and alkylmagnesium compounds led

triple bond and of a CO ligand giving finally butenolides. also to polycyclic, substituted butenolides. Moreover, the fi-

The scope of the reaction has been established with its lim-

itations, together with the stereochemical outcome, which is

discussed. [5.5], [5.6], [5.7] bicyclic and tricyclic systems have

been synthesised together with chiral butenolides starting

from chiral carbene complexes. Most of the new structures

have been assessed by X-ray crystallography. This trans-

nal lactone enolates could be trapped with oxygen and gave

unsaturated lactonols. The key point in all of these reactions

is the formation of tetrahedral intermediates upon interaction

of the nucleophiles with the carbene carbon.

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

Germany, 2004)

Introduction

Fischer alkoxycarbene complexes^[1,2]owe their import-

ance and success among the organic chemistry community

to three reasons: they are easily prepared and obtained as

fairly stable complexes,^[3]and, in contrast to most other me-

tal complexes, can suffer important modifications of the or-

ganic carbene moiety, going from the α-alkylation^[4]to the

metathesis of tethered olefinic groups.^[5]They have thus

been used as building blocks for the synthesis of a tremen-

dous number of elaborate organic compounds.^[6]Many of

their reactions are similar to those of carbonyl compounds

yet their reactivity is much higher.^[7]This is especially strik-

ing in their behaviour towards nucleophiles and is directly

linked to the presence of the metal with its carbonyl groups.

One of the earliest transformations of alkoxy carbene com-

plexes 1 was the substitution reaction of the alkoxy group

by various nucleophiles — a reaction that leads to the new

carbene complexes 3 (Scheme 1).

Scheme 1

tetrahedral intermediates.^[8]In contrast to the interaction

products of esters with nucleophiles,^[9]complexes such as 2

could be isolated and characterised in a few instances. How-

ever, these elusive addition products, which are in fact nega-

tively charged, often highly functionalised alkylmetal

compounds,

have not been employed for further

carbonϪcarbon bond formations.^[10]

General Features

However, most reported studies have been confined to

the preparation of new carbene complexes, or a detailed

study of the mechanism of these transformations, which

were assumed to occur by a stepwise mechanism involving

Access to complexes of the type [(CO)₅MR]^Ϫ(M ϭ Cr,

Mo, W) has been achieved by Ruff,^[11]Ellis^[12]and Casey^[13]

starting either from [M₂(CO)₁₀]^2Ϫand alkyl halides or from

[M(CO)₅Br]^Ϫand alkyllithium compounds. However, only

a limited number of them (R ϭ Me, Ph, CH₂Ph, CH₂CN)

have been isolated, most of the other derivatives undergoing

fast thermal decomposition. More recently, the interaction

of KHCr(CO)₅with methyl acrylate has been shown to

lead to a (β-methoxycarbonyl)(pentacarbonyl)chromate.^[14]

Interestingly, a few such complexes have also been syn-

[a]

Laboratoire de Chimie Organique, UMR CNRS 7611,

´

Universite P. M. Curie, T 44Ϫ45,

4 place Jussieu case 181, 75252 Paris Cedex 05, France

Fax: (internat.) ϩ33-1-44275504

E-mail: rudler@ccr.jussieu.fr

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

Eur. J. Org. Chem. 2400, 2471Ϫ2502

DOI: 10.1002/ejoc.200400036

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2471

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

thesised from simple carbene complexes. The pioneering reaction (e.g. 11a Ǟ 14 via 12) and then to new carbene

work in this area was carried out by Casey and co-workers complexes 15.^[22d]

who successfully characterised complexes 5, 6, and 8, orig-

inating, for 5, from the interaction of 4a with a complex

hydride,^[15]for 6, from the interaction of 4a with methyllith-

ium,^[16]and for 8, from the interaction of 7 with butyllith-

ium.^[17]In these complexes the negative charge is delocal-

ised over the [M(CO)₅] fragment^[18](Scheme 2).

Scheme 4

This result is fundamental since it demonstrates that even

in the absence of added external carbon monoxide an inser-

tion can take place, at the expense of the starting material,

giving coordinatively saturated complexes (11a Ǟ 15).

However, no general high yielding approach to such com-

plexes starting from carbene complexes^[23,24]existed until

1992 when we disclosed the first biomimetic reduction of

alkoxycarbene complexes of tungsten and chromium with

Scheme 2

dihydropyridines.^[25]

Biomimetic Reduction of Carbene Complexes with

Dihydropyridines

Since alkylmetal compounds in general are known to un-

dergo carbon monoxide insertions,^[19]such transformations

have also been attempted. Thus, Casey found that even low

pressures of CO induce an almost quantitative formation of

(acyl)metal complexes (9 Ǟ 10),^[20]the rate of the insertion

being highly dependent on the nature of the R group, with

no reaction at all for R ϭ Bn (Scheme 3). Such insertions

were also induced by triphenylphosphane.

Two points guided our approach: the analogy which had

been established between carbene complexes and carbonyl

compounds^[6,7]and the known biological and biomimetic

reductions of carbonyl compounds by dihydronicotina-

mides.^[26]We found indeed that simple dihydropyridines

transferred a hydride to the carbene carbon almost quanti-

tatively,^[27]but that the intermediate alkylmetal compounds

16 underwent a spontaneous transformation into pyridin-

ium ylide complexes 18 via unstable alkylidene complexes

17 (Scheme 5).

Scheme 3

That the ligands in these negatively charged alkyl- and

acylmetal complexes are even more labile than in carbene

complexes^[13]has been firmly established by Cooper,^[21]

since scrambling of the carbonyl groups of the acyl ligand

and the additional CO ligands of the metal was observed

in the presence of labelled CO. However, the most import-

ant and early observation, as far as our investigations are

concerned, came from the group of E. O. Fischer,^[22aϪ22c]

who demonstrated that the interaction of alkoxycarbene

tungsten and chromium complexes with sodium alkoxides

Scheme 5

We discovered, however, that this reduction evolved in a

not only led to new carbene complexes upon exchange of quite different direction when N-methyldihydropyridine

the alkoxy groups (e.g. 11a Ǟ 13; Scheme 4) but also, al- (19) was used instead: it led to the fairly stable complexes

though to only a small extent, to unexpected acylmetal 20.^[28]This result prompted us to examine the behaviour

complexes 14 as the result of a carbon monoxide insertion of these ’’ate’’ complexes towards conjugated ketones. The

2472

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

interaction of 20 with cyclopentenone did not, however,

lead to 22, the possible 1,4-addition product, but to 23 due

to the formation of 21 and its addition to the double bond

of the ketone^[29](Scheme 6).

Scheme 8

Due to our experience in the thermal rearrangement of

alkynyl(amino)carbene complexes of the type 30, which led

to the lactams 33 via the nitrogen ylide complexes 32

(Scheme 9),^[31]we focused our attention on the behaviour of

complexes of the type 34 towards N-methyldihydropyridine.

Scheme 6

Along the same lines, complex 24, containing a tethered

double bond, led to the substituted cyclopentanone 28

upon reduction with N-methyldihydropyridine, a reaction

reminiscent of those observed for alkylcarbonylferrates^[30]

(Scheme 7).

Scheme 9

Such complexes might indeed lead to transients such as

oxycarbene species 35, similar to 30, upon successive re-

duction of the carbene function and insertion of CO, and

then undergo transformations akin to those of 30; this was

indeed the case (Scheme 10).

Scheme 7

To summarise, we had established that the alkoxycarbene

complexes 1 of tungsten and chromium could be trans-

formed in a single step into elaborate 21, which can also be

described as carbene complexes 29 bearing an exceptional

electron-rich substituent. The transformation of 1 into 29

Scheme 10

Thus, complex 37, when mixed with an excess of N-

can thus be viewed as a spontaneous homologation of the methyldihydropyridine (19, mixture of two isomers) led to

carbene complex 1 induced by a hydride (Scheme 8). a mixture of two isomeric butenolides 38 and 39 (73%; de

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2473

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

80%) (Scheme 11). The structure of the less abundant, crys- to the organic HalbanϪWhite rearrangement of cross-con-

talline compound 39 was firmly established by X-ray crys- jugated ketenes, which also leads to butenolides.^[34]

tallography.^[28]

Scheme 11

These compounds are the result of the reduction of the

carbene function of 37 (C⁷-H), the insertion of a first car-

bonyl group, (C^7aϪO¹), the insertion of the triple bond (six-

membered ring), and the insertion of a second carbonyl

group (C²ϪO). The key point of this transformation is the Scheme 13

efficient transfer of a hydride to the carbene carbon. The

steps leading to 42 (described as a ketene complex or a di-

carbonyl metal complex) are classical routes in organomet-

The behaviour of complexes of the type 30 and 35 is

allic chemistry.^[32]The formation of the subsequent lactone therefore the same. However, whereas the former leads to

enolate 43, which at first sight seems less obvious, can be lactams at rather elevated temperatures (refluxing toluene),

explained as for the transformation of 31 into 32 the transformation of the latter into butenolides takes place

(Scheme 9).

spontaneously at low temperature (Ϫ10 °C to room tem-

Interaction of the negatively charged oxygen with the perature). An interesting structural feature of these new lac-

central carbon of the ketene might lead to the lactone enol- tones is the location of the carbonyl groups originating

ate 43 (Scheme 12, 42 Ǟ 43). Alternatively, the oxygen in from the starting (hexacarbonyl)chromium: they are con-

41 might interact with a coordinated carbonyl group and tiguous and respectively linked by a carbonϪcarbon, a

give, after reductive elimination of the metal, the same enol- carbonϪoxygen and an oxygenϪcarbon bond.^[35,36]Thus,

ate complex 43 and finally lead, upon protonation, to the alkylcarbonyl complexes obtained from easy to synthesise

observed lactones. Rearrangements of dicarbonyl-metal carbene complexes allow the elaboration of polycyclic lac-

complexes of the general structure 44, similar to 42, had tones in a single step without the need for external CO. This

already been observed and described in many instances for contrasts sharply with earlier assumptions.^[12]Butenolides

Fe, Rh, Pd, Ni, Co, Mn, Mo and W complexes.^[32]They of this type, bearing extra functional groups, are well-

lead to unsaturated lactones 47 or lactone complexes 46 known among natural products and exhibit, for some of

(Scheme 13).^[32d,33]This rearrangement can also be related them, important biological properties.^[32]

Scheme 12

2474

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

The purpose of this paper is linked to our general interest

in the synthesis of such compounds in a diastereo- and en-

antioselective way,^[38]which led us to examine carefully the

possibility and limits of this new approach by structurally

modifying the starting carbene complexes and the dihydro-

pyridines and to show how this chemistry could be ex-

tended to nucleophiles different from hydrides.

Scheme 15

Table 1. Reduction of complexes 48aϪf with N-methyldihydropyri-

dine 19

Results and Discussion

Entry Complex OR¹

R²R³R⁴n Yield [%] de [%] Products

Synthesis of the Carbene Complexes

A retrosynthetic picture indicates which modifications

can easily be carried out: a major structural feature is the

location of the triple bond-containing fragment. It can

either be bound directly to the carbon or to the oxygen

atoms of the carbene ligand (X ϭ CHR or X ϭ O). Other

modifications concern the nature of the substituents of the

carbene carbon (R¹), of the triple bond (R²), and of the

alkyl chain bearing the triple bond and finally of the oxygen

atom (Scheme 14).

1

2

3

4

5

6

7

37

OEt

H

H Ph 1 63

80

60

40

22

33

0

38, 39

48e

48f

48d

48c

48a

48b

OCH₂cPr H H Ph 1 62

50e, 51e

50f, 51f

50d, 51d

50c, 51c

50a, 51a

50b, 51b

OBn

OEt

H H Ph 1 32

Bn H Ph 1 65

Me H Ph 1 70

H

Ph Ph 1 42

H Et 0 58

The following comments can, however, be addressed.

First, the nature of the substituent on the oxygen of the

carbene complex does not modify the stereochemical out-

come of the reaction: only a drop in the yield of the reaction

is observed in going from ethyl to benzyl (Entries 1Ϫ3).

Whereas the introduction of substituents on the alkyl chain

had no influence on the yield of the reaction (Entries 4Ϫ6),

a change in the trans/cis ratios appeared however. This was

especially important in the case of an α-substituent (Entries

4 and 5 vs. Entry 1). Indeed, complex 48d led to a mixture

of butenolides 50d and 51d in which the major isomer has

a cis geometry. However, complex 48c led again to a mix-

ture of two isomers 50c and 51c in about a 1:1 ratio, the

trans isomer (J_{H7,H7a ϭ}8.2 Hz) being slightly more abun-

dant than the cis isomer (J_H7,H7aϭ 3.4 Hz). In the trans

compound 50c, the ethoxy and the methyl groups are equa-

torial and the protons H^7a, H⁷, and H⁶are axial. An NOE

enhancement (5.3%) is indeed observed for H^7aand H⁶

upon irradiation of H⁷. In the cis isomer, the ethoxy group

is axial whereas the methyl group is equatorial. Again,

NOE enhancements are observed as indicated in

Scheme 16.

Scheme 14

Two main methods have been used for the synthesis of

the different complexes.^[3,39]The direct Fischer method in-

volving the interaction of a suitable alkyllithium derivative

with (hexacarbonyl)chromium led to complexes 37 and

48a,b. Complex 37 was then modified by α-alkylation^[4,40]

to give 48c,d. For complexes bearing alkoxy groups differ-

ent from ethoxy and methoxy, the reaction of a suitable

alcohol with a carbonylchromium acylate salt gave com-

plexes 49aϪl. Finally, combination of the two methods led

to two alkynyl(alkoxy)carbene complexes 48e,f bearing dif-

ferent alkoxy groups. The preparation of the various com-

plexes together with their physical data can be found in the

Exp. Sect.

N-Methyldihydropyridine-Induced Transformations of

Complexes 48a؊f into the Butenolides 50a؊f and 51a؊f ؊

Scope of the Reaction and Influence of the Nature of the

Substituents on the Carbene Complexes

Scheme 16

All of the reactions were performed according to the pro-

cedure used for the transformation of complex 37 into the

Introduction of a phenyl group β to the carbene carbon

butenolides 38 and 39 (Scheme 15). Table 1 confirms that (Entry 6, complex 48a) led to a similar result, the most

the transformation is of a general scope, which led in each abundant compound being also the trans isomer 50a, (J ϭ

case to a mixture of isomers, the trans isomers being the 8.1 Hz). The configurations of the various substituents were

major products.

also assessed by NOE experiments (Scheme 17).

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2475

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

Scheme 19

Scheme 17

One of the most striking results is the stereochemical out-

come of these reactions: as can be seen in Table 2, all but

one transformation took place in a diastereospecific way,

with the yields of the lactones ranging from 30 to 74%. The

Modification of the Length of the Alkyl Chain

Up to now we have described the synthesis of [5.6]-fused

systems. A [5.5]-fused bicyclic lactone could also be syn-

thesised from the appropriate carbene complex 48b, which

led to a 1:1 mixture of two isomeric lactones 50b and 51b

in a 58% overall yield. Besides these two expected com-

pounds, the (ethoxy)propylidenecyclopentanone 52 was ob-

tained in 11% yield (Scheme 18). The formation of such a

ketone, lacking an inserted CO group with respect to the

butenolides 50b and 51b, had already been observed in the

case of the reduction of similar tungsten carbene com-

plexes.^[28,35]

structures of these new butenolides were assessed both by

¹H NMR spectroscopy — the 8.8 Hz coupling constant in-

dicating a trans relationship between H⁷and H^7a— and by

X-ray crystallography. Neither the introduction of different

substituents on the carbene carbon, nor the modification of

the substituents on the triple bond had any influence on the

isomers’ distribution. The only exception which has to be

noticed arose in the case of complex 49c, which led, besides

the trans isomer 53c (57% yield), to a small percentage of

the cis isomer 54c (7%).

An interesting modification of the carbene complexes

was achieved by the introduction of substituents on the

alkyl chain. This allowed the synthesis of enantiomerically

pure substituted butenolides (Entry 7), of polysubstituted

butenolides (Entries 8Ϫ10), and ultimately, of tricyclic but-

enolides (Entries 11 and 12, Table 2). In the first example

(Entry 7, complex 49g), a phenyl group is present α to the

triple bond. This chiral complex was obtained upon interac-

tion of the corresponding chiral alcohol derived from op-

tically pure styrene oxide and lithium phenylacetylide^[41]

with the appropriate chromium complex. Upon reaction of

complex 49g with N-methyldihydropyridine (19), two iso-

meric butenolides were isolated in 58% yield. The main iso-

Scheme 18

Interaction of Complexes 49a؊l with N-Methyldihydro-

pyridines: Diastereospecific Formation of Butenolides 53a؊l

20

mer (49%), isolated as a solid [m.p. 97 °C, [α]_Dϭ ϩ171]

shows the typical doublet at δ ϭ 4.96 ppm for the proton at

Since access to ω-acetylenic alcohols is very easy, a large the ring junction. The coupling constant with the adjacent

variety of complexes such as 49aϪl (Table 2) could be syn- proton (9.0 Hz), is in agreement with a trans configuration

thesised. Their reaction with the dihydropyridine 19 led to as in 53g. This was confirmed by an X-ray crystallo-

the butenolides 53aϪl (Scheme 19).

graphic analysis.

Table 2. Reduction of complexes 49aϪl with N-methyldihydropyridine (19)

Entry

Complex

R¹

R³

R⁴

R⁵

Yield [%]

de [%]

Products

1

2

3

4

5

6

7

8

9

49a

49b

49c

49d

49e

49f

49g

49h

49i

Ph

H

Ph

H

Ph*

Me

H

Me

46

47

64

63

38

48

58

53

30

39

74

53

100

80

53a

Me

cPr

Ph

Me

cPr

Ph

53b

53c, 54c

53d

53e

53f

53g, 55g

53h

53i

53j

100

Ph

Me

cPr

Ph

10

11

12

49j

49k

49l

ϪCH₂Ϫ(CH₂)₂ϪCH₂Ϫ

53k

53l

cPr

2476

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

The second isomer, 55g, isolated as a solid [m.p. 174 °C,

[α]_D²⁰ϭ ϩ91] corresponded also, according to its ¹H NMR

spectrum, to a trans isomer (J_H7,H7aϭ 9.4 Hz). Since the

butenolides 53g and 55g are isomers, then H⁴and H^7amust

be in a cis relationship. Moreover, since the absolute con-

figuration of carbon C-4 is known (R), then the absolute

configurations of the stereogenic centres of the second but-

enolide 55g are as indicated in Scheme 20.

Scheme 21

Finally, attempts were made to prepare [7.5] bicyclic lac-

tones although the formation of a seven-membered ring

system seemed to be less obvious.^[43]For that purpose, the

two complexes 56a and 56b were synthesised. Both were

submitted to the reduction reaction and led, surprisingly, to

the expected butenolides (Scheme 22). However, whereas

56a gave 57a and 58a in a satisfactory 52% yield (de ϭ

37%), only a low 8% yield of 57b was observed from 56b.

The two isomers originating from 56a were separated by

chromatography. A trans configuration of H⁸and H^8a(J ϭ

8.6 Hz) could be assigned to the main isomer 57a (m.p. 73

°C) and finally confirmed by X-ray crystallography (molec-

ular projection shown in Figure 2).

Scheme 20

Starting from complexes 49hϪj containing a disubsti-

tuted alkyl chain, a single trans butenolide was isolated each

time (Entries 8Ϫ10). Thus, butenolides containing four ster-

eogenic centres could be synthesised very efficiently. As an

example, the reduction of complex 49h led to the crystalline

butenolide 53h. Its structure was confirmed both by NMR

and by X-ray crystallography.

Easy access to an acetylenic alcohol derived from cyclo-

hexene oxide^[41]prompted us to synthesise complexes of the

type 49k,l (Entries 11 and 12). They led again to single iso-

mers upon reduction with dihydropyridine. Thus, in the

case of complex 49k, the butenolide 53k was isolated as a

solid (m.p. 184 °C). Its structure was again determined by

X-ray crystallography, the molecular projection appearing

in Figure 1. This confirmed the trans configuration of H^3a

and H⁴, and of H^5aand H^9a, and the cis relationship be-

tween H^3aand H^9a, and between H⁴and H^5a. Surprisingly,

only one enantiomer of 53k appears in the lattice, a spon-

taneous separation of the two enantiomers of 53k having

taken place upon recrystallisation (Scheme 21).^[42]

Scheme 22

Figure 2. X-ray structure of the butenolide 57a (CAMERON view),

atoms drawn at 50% probability

Influence of the Nature of the Solvent

A point which might be of importance in a reaction in-

volving coordinatively unsaturated species, and during

which a triple bond must enter in the coordination sphere

of the metal, is the nature of the solvent. We found that

most solvents, with the exclusion of alcohols, were suitable

for the synthesis of the butenolides. Whereas no straightfor-

Figure 1. X-ray structure of the butenolide 53k (CAMERON view),

atoms drawn at 50% probability

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2477

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

ward difference was observed in going from dichlorometh-

ane (the most usual solvent) to acetonitrile, via DMF and

THF, in the case of phenyl-substituted carbene complexes,

a significant variation of the de’s appeared in the case of

methyl-substituted carbene complex 49e.

Table 4. Reduction of complexes 37, 48a and 48d with the dihydro-

pyridines 19 and 59

Entry Complex Dihydropyridine Products de [%] Yield [%]

1

2

3

4

5

6

37

19

59

19

59

19

59

38, 39

50a, 51a 34

50a, 51a

50d, 51d 40

50d, 51d 12

80

60

63

43

42

65

45

37

48a

48d

Table 3. Influence of the solvent in the reduction of complexes 49d

and 49e

0

Entry

Complex

Solvent

Yield [%]

de [%]

Products

1

2

3

4

5

6

7

49d

49e

49d

49e

49d

CH₂Cl₂

THF

MeCN

DMF

63

38

30

56

42

0

100

60

100

82

53d

53e

53d

53e

53d

Ϫ

When complex 37 was treated with the dihydropyridine

59 at room temperature, a mixture of the expected butenol-

ides 38 and 39 was obtained: only a slight decrease in the

overall yield was observed (43 vs. 63% in the case of 19;

Scheme 23, Table 4). However, the diastereoselectivity was

lower (de, 60% vs. 80%). A similar trend was observed in

the case of substituted carbene complexes 48a,d.

100

Ϫ

MeOH

Behaviour of Dihydropyridines Different from N-Methyldi-

We then turned to the dihydronicotinamide 60. To our

delight it also induced the formation of the butenolides: 53a

was obtained in 37% yield from complex 49a as a single

isomer (Scheme 24).

hydropyridine

The dihydropyridines involved in both biological and bi-

omimetic reductions are far more complex than N-methyl-

dihydropyridines. We thus considered the possibility of

using first simple dihydronicotinamides closer to the struc-

ture of the prosthetic group of NADH, and then chiral di-

hydropyridines, to see whether they would also reduce car-

bene complexes, possibly in an enantioselective way.

Reduction of Carbene Complexes with N-Benzyldihydro-

pyridine (59) and N,N-Diethyl-N-methyl-1,4-dihydro-

nicotinamide (60)

Scheme 24

N-benzyldihydropyridine (59) and N-methyl-N,N-diethyl-

1,4-dihydronicotinamide (60) were prepared according to a

literature procedure.^[44]

Enantioselective Reduction of Alkoxycarbene Complexes:

Formation of Chiral Butenolides

The biomimetic reduction of carbonyl compounds by di-

hydronicotinamides has been the subject of intense investi-

gations both from a mechanistic and preparative point of

view;^[45]ee’s of almost 100% were finally achieved by the

use of elaborate chiral dihydronicotinamides.^[46Ϫ48]The en-

antioselective synthesis of butenolides from carbene com-

plexes and chiral dihydropyridines thus appeared feasible

since in both cases the first step is the transfer of a hydride

to an sp²carbon.

Three series of chiral dihydropyridines were tested: di-

hydronicotinamides 61Ϫ63 bearing the stereogenic centre

on the nitrogen of the amide function,^{[46aϪ46i,49]}dihydro-

pyridines 64Ϫ68 bearing the stereogenic centre on the nitro-

gen of the pyridine,^[50aϪ50e]and dihydropyridines 71 and 73

having a stereogenic centre on a substituent of the pyri-

dine ring.

Scheme 23

2478

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

the case of 61 and 62 (Entry 1, Table 5), and as a mixture

of isomers in the case of complex 49e and the dihydronic-

otinamide 63 (Entry 3). The enantiomeric excesses deter-

mined by chiral GC were low, yet significant (ee ϭ 20%)

in the case of complex 49d (Entry 2, R¹ϭ Ph) and the

dihydronicotinamide 61.

Changing the solvent had an important impact on the

ee’s although the yields and the de’s remained almost un-

changed, dichloromethane appearing as the most suitable

solvent (ee ϭ 20% vs. 1% in acetonitrile)

In the case of 64 and 65 (Entries 4, 5, 6), the reduction-

insertions took place again with high diastereoselectivities

(100%) but with low enantioselectivities, ranging from 0 to

27%. Similar results (de’s, 100%, ee’s, 8Ϫ18%) were ob-

served with dihydropyridines 66, 67 and 68 (Entries 7 and

8) bearing one or two extra heteroatoms in their structure.

Moreover, the ee’s were again solvent dependent, the best

results being observed in the case of the less-polar solvents

(ee ϭ 26% for pentane and 3% for acetonitrile). However,

neither the yields nor the de’s and ee’s of the reactions were

dependent on the dihydropyridine/complex ratio.

Behaviour of Chiral Dihydronicotinamides 61؊68:

Enantioselective Synthesis of Butenolides 53d,e upon

Reduction of Carbene Complexes 49d,f

Stereogenic Center on a Substituent of the Pyridine Ring:

Synthesis of Dihydronicotines 71 and 73 and their

Interaction with Carbene Complexes

Among the complexes that were submitted to the re-

duction with the three dihydronicotinamides 61, 62 and 63,

we chose 49d,e for sake of simplicity since N-methyldi-

hydropyridine (19) reduced them stereoselectively to a sin-

gle butenolide (Scheme 25).

The most reliable and general reductants of alkoxycar-

bene complexes of chromium and tungsten appeared to be

the simplest derivatives of pyridine — dihydropyridine and

N-methyldihydropyridine.^[28,35]We reasoned that chiral di-

hydropyridines bearing a stereogenic centre on a substituent

of the pyridine nucleus might also be good candidates for

these reactions. Among the substituted pyridines, nicotine

69, a cheap, abundant yet toxic substituted pyridine which

has attracted much attention due to its pharmacological

properties, but not as a chiral ligand (or precursor), em-

erged as the most promising.^[51]Indeed, we demonstrated

that nicotine could be reduced, like pyridine, to a mixture of

the three possible dihydronicotines. Moreover, this mixture

reduced carbene complexes 4a,b to give the expected nicoti-

Scheme 25

Their interaction with the dihydronicotinamides 61, 62 nium ylide complexes in high yield.^[28]Although the syn-

and 63 led to the expected butenolides as single isomers, in thesis of N-methyl-1,2-dihydronicotine from the known N-

Table 5. Reduction of complexes 49dϪf with chiral dihydropyridines 61Ϫ68

Entry

Complex

Yield [%]

de [%]

ee [%]

Products

Yield [%]

de [%]

ee [%]

with 61

55

30

with 63

15

with 62

Ϫ

13

1

2

49e

49d

100

1

20

53e

53d

Ϫ

100

Ϫ

2

3

49e

49

11

Ϫ

with 64

62

60

58

with 66

25

with 65

67

72

60

with 67

68

4

5

6

49e

49d

49f

100

1.2

4.3

1.8

53e

53d

53f

100

11.5

27

1

7

8

49d

49e

100

11

8

53d

53e

100

18

with 68

50

Ϫ

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2479

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

methylnicotinium iodide^[52]failed, the reduction of the

known^[53]N-benzylnicotinium bromide (70) with sodium

dithionite led to N-benzyl-1,4-dihydronicotine (71,

Scheme 26).

Scheme 28

Scheme 26

In all the cases examined the de’s were again 100%, with

the ee’s being dependent on the nature of the substituents

on the carbene carbon; the cyclopropyl group appearing as

the less enantiodifferentiating group. It is, however, notice-

able that the nature of the substituents on the triple bond

has no effect. Two other parameters were examined in the

case of complex 49e in order to try to improve the yields

and the ee’s: the nature of the solvent and the dihydronic-

otine/carbene complex ratio in dichloromethane. However,

neither of these parameters had any influence on the out-

come of the reaction.

N-Methyl-1,2-dihydronicotine (73) was, however, ob-

tained by the method developed by Fowler for the synthesis

of N-methyl-1,2-dihydropyridine.^[54]Thus, sodium borohyd-

ride reduction of nicotine (69) in ethanol (instead of meth-

anol) in the presence of methyl chloroformate, at low tem-

perature, led to the protected dihydronicotine 72, which was

reduced with LiAlH₄to afford pure 73 in 90% yield

(Scheme 27).

Behaviour of Carbene Complexes towards Other Nucleo-

philes: A General Access to Substituted Butenolides

The reaction of nucleophiles, for example alkoxides or

amines, with alkoxycarbene complexes, giving new carbene

complexes upon exchange of the alkoxy group, strongly im-

plicated the existence of a symmetric tetrahedral intermedi-

ate^[56]similar to those known for organic carbonyl com-

pounds (Scheme 1). Therefore such intermediates for Nu ϭ

H^Ϫ, OR^Ϫ, Me^Ϫor Ph^Ϫmight also be trapped intramolecu-

larly by alkynes and lead to substituted butenolides. The

following results confirmed this assumption.^[57]

Scheme 27

The interaction of N-benzyl-1,4-dihydronicotine (71)

with complex 49e led to a disappointing result: although a

51% yield of the expected butenolide 53e was observed, the

enantioselectivity was insignificant (ee, 4%).^[55]Much better

Reaction of Complex 49a with KHB(OiPr)₃: Formation of

Butenolide 53a

Casey has described the formation of the tungsten com-

results were, however, observed in the case of N-methyl-1,2- plex 5 upon interaction of KHB(OiPr)₃with complex 4a

dihydronicotine (73). Its interaction with complex 49e gave after cation exchange^[15](Scheme 2). We demonstrated that

the butenolide 53e as a single isomer in 20% yield with a the reaction of 4b with KHB(OiPr)₃followed by cation ex-

very encouraging ee of 55%. Although the chemical yields change with N-methylpyridinium iodide (74) led to complex

with the other complexes were in general higher, the enanti- 75, identical in all respect to the complex obtained upon

omeric excesses were unfortunately much lower, ranging reduction of 4b with N-methyldihydropyridine 19

from 12.5 to 37% (Scheme 28, Table 6).

(Scheme 29).

Table 6. Reduction of complexes 49aϪf with the dihydronicotine 73

Entry

Complex

R¹

R²

Product

Yield [%]

de [%]

ee [%]

[α]²_D⁰(CHCl₃)

1

2

3

4

5

6

49e

49b

49d

49a

49f

49c

Me

Ph

cPr

H

Ph

H

Ph

H

Ph

53e

53b

53d

53a

53f

53c

20

10

63

38

32

43

100

55

37

33

30

14

12.5

35.9, c ϭ 2.3

Ϫ30.4, c ϭ 2.0

44.3, c ϭ 2.3

54.0, c ϭ 2.0

9.3, c ϭ 2.1

5.5, c ϭ 2.1

2480

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

amounts of this compound (13 and 22%, respec-

tively).^[23f,58,59]

Reaction of Alkoxides with Carbene Complexes:

Introduction of Alkoxy Groups into the Butenolides

As already mentioned in the introduction, the interaction

of alcohols with alkoxycarbene complexes of chromium in

the presence of sodium alkoxide was the first direct indi-

cation of the possible exchange of alkoxy groups in carbene

complexes via a tetrahedral intermediate.^[3aϪ3c]Moreover,

this reaction brought to the fore an important ’’side reac-

tion’’ — the easy insertion of CO into this tetrahedral inter-

mediate and thus its possible use to synthesise butenolides

bearing an alkoxy group on the former carbene carbon in-

stead of a hydride. We therefore carried out three types of

reactions which were supposed to give the same tetrahedral

complex 81 bearing two alkoxy groups as the intermediate.

Such a complex might form upon interaction of 49a with

MeONa (route a), upon interaction of 11b with sodium

phenylbutynolate (route b), or upon interaction of 49a with

sodium phenylbutynolate (route c). This latter would rule

out the formation of a non-productive carbene complex

(route d) (Scheme 31).

Scheme 29

Similarly, reaction of KHB(OiPr)₃with complex 4b fol-

lowed by the addition of cyclopentenone led to the 1,4-ad-

dition product 23 (Scheme 6). This result was a good indi-

cation that the cascade insertions might also be induced

by hydrides not originating from dihydropyridines. Indeed,

when 49a was reduced with KHB(OiPr)₃, the expected but-

enolide 53a was isolated in a 21% yield together with a 32%

mixture of two isomeric (benzylidene)phenyltetrahydrofur-

ans 79 and 80 (Scheme 30).

Scheme 30

The formation of the latter can be explained by a hydride

transfer to the carbene carbon, followed by a direct inser-

tion of the triple bond into the chromate 76 to give 79 and

80 via 77 and 78.

Scheme 31

The addition of a 30% solution of MeONa in MeOH to

a THF solution of 49a, at 0 °C, followed by stirring at room

Remarks on the Behaviour of Other Inorganic Hydrides

Following this result, we carried out a series of reactions temperature for 15 h led indeed to two butenolides, 82

between 49e and different inorganic hydrides. Whereas Li- (22%) and 83 (8%), (Scheme 32) which were fully character-

AlH₄, LiAlH(tBuO)₃and 9-BBN did not lead to 53e, both ised by NMR spectroscopy and, for 83, by X-ray crystal-

NaBH₄and the complex 9-BBN/nicotine gave substantial lography.

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2481

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

tively. The NMR spectra of 85 confirmed the presence of

the unsaturated lactone, but also of three phenyl groups, a

carbonϪcarbon triple bond with signals at δ ϭ 86.9 and

81.6 ppm, and a signal at δ ϭ 100.1 ppm for the carbon

bearing the two oxygen atoms originating from butynol, the

angular proton displaying a singlet at δ ϭ 4.7 ppm.

Reaction of Complexes 49a and 49h with Alkyllithium and

Magnesium Derivatives: Formation of Alkyl-Substituted

Butenolides

Casey, Fischer, and our group have studied the interac-

tion of aryl- and alkyllithium derivatives with phenyl-sub-

stituted alkoxycarbene complexes en route to non-het-

eroatom-stabilized carbene (alkylidene) complexes^[15c,16,59]

via tetrahedral intermediates 2 (Scheme 1, Nu^Ϫϭ Ph, Me).

Attempts were thus made to carry out similar addition reac-

tions on the more elaborate carbene complexes 49a and 49h

in order to trap the triple bond-containing alkylmetallates

intramolecularly. However, the interaction of complex 49a

with PhLi, at Ϫ40 °C, followed by stirring at room tempera-

ture, did not lead to the expected butenolide. When the

same reaction was carried out with MeLi, the red colour

of the starting complex faded rapidly. After 15 h at room

temperature, two new products were isolated in 66% yield

(Scheme 33).

Scheme 32

The NMR spectra of 82 display the expected signals for

such a butenolide, with the methoxy group giving a signal

at δ ϭ 2.96 ppm in the H NMR spectrum, and, in the ¹³C

1

NMR spectrum, signals at δ ϭ 172.5 ppm (CO) and at δ ϭ

101 ppm, characteristic of C-7, the former carbene carbon

now bearing two oxygen atoms. Moreover, the hydrogen

H^7a, at the ring junction, appears now as a singlet. The

second product 83 could be the result of the elimination of

methanol from 82 but probably originates directly from the

intermediate lactone chromium enolate (vide infra).

Similarly, complex 11b gave the ethoxy-substituted buten-

olide 84 in 25% yield in the presence of sodium butynolate,

according to route b (Scheme 31). Most characteristic are

the signals in the NMR spectra at δ ϭ 172.6 ppm, and the

multiplets at δ ϭ 3.28Ϫ3.06 ppm for the two diastereotopic

hydrogens of the ethoxy group. Its structure was confirmed

by an X-ray struture analysis (Figure 3). The second prod-

uct of the reaction was again the conjugated butenolide 83

(25%).

Scheme 33

According to their elemental analysis, and mass and

NMR spectra, these compounds were indeed the expected

butenolides 86a and 87a, formed as a 40:60 cis/trans mix-

ture of isomers. Both the angular protons and the methyl

groups appear as singlets at δ ϭ 4.96 and 5.08 ppm and at

δ ϭ 1.40 and 1.81 ppm, respectively. The structure, and thus

the stereochemistry of the major isomer 86a — a trans

orientation of the methyl group with respect to the angular

hydrogen — were confirmed by an X-ray analysis.

Attempts to improve the yield of this transformation led,

however, to erratic results: besides the butenolides 86a, vari-

able amounts of a second product 88 were obtained

(Scheme 34).

Figure 3. X-ray structure of the butenolide 84 (CAMERON view),

atoms are drawn at 50% probability

Finally, sodium phenylbutynolate reacted with complex

49a, according to route c, to give two products, the expected

butenolide 85 with two incorporated phenylbutynol units,

and the elimination product 83, in 9 and 29% yield, respec- Scheme 34

2482  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

According to its spectroscopic data, this product was also

These results urged us to extend the reaction first to sev-

a butenolide [δ(CO) ϭ 170 ppm] containing a methyl group eral organolithium and organomagnesium derivatives

[singlet, δ(CH₃) ϭ 1.6 ppm]. Moreover, the signal corre- (Scheme 36): butyllithium, (trimethylsilyl)methyllithium,

sponding to C-7a moved from δ ϭ 85.2 to 102.1 ppm, con- ethyllithium and methylmagnesium bromide led to the ex-

firming the introduction of an extra oxygen atom on this pected substituted butenolides (Table 7).

carbon. That the oxygen belongs to an alcohol is consistent

with the presence of a broad singlet at δ ϭ 3.2 ppm. All the

data were thus consistent with the formation of a lactonol

due to the presence of oxygen. The structure of this new

type of product was finally assessed by an X-ray diffraction

study which confirmed the presence of a tertiary alcohol at

the ring junction, cis with respect to the phenyl group. Thus

the efficiency and the reproducibility of the reaction relied

on how carefully oxygen was removed from the reaction

Scheme 36

medium. This was confirmed in the following way: when

the reaction was carried out as above, then the temperature

of the solution raised to 0 °C, and oxygen added, 88 was

obtained as a single product in 14.5% yield (Scheme 34).

Similar results were observed in the case of complex 49h

Table 7. Reaction of complex 49a with various alkyllithium and

magnesium derivatives

which led, depending on the reaction conditions, to up to

four products, the two expected butenolides 89 and 90, and

two unsaturated lactonols 91 and 92 (Scheme 35).

Entry

Nucleophile

Yield [%]

Products

de [%]

1

2

3

4

5

MeLi

EtLi

BuLi

Me₃SiCH₂Li

MeMgBr

66

25

43

34

30

86a, 87a

86b, 87b

86c, 87c

86d, 87d

86a, 87a

20

Ͼ 90

46

Scheme 35

Their spectroscopic data are in full agreement with the

proposed structures and confirmed by an X-ray structure

of 91 (Figure 4).

Figure 4. X-ray structure of the butenolide 91 (CAMERON view),

atoms are drawn at 50% probability

Scheme 37

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2483

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

Peculiar results (not indicated in Table 7) were, however,

observed in the case of ethyllithium and ethylmagnesium

bromide. Whereas ethyllithium, on its own, gave the ex-

pected butenolides 86b and 87b, both reagents led to 53a,

the butenolide obtained previously upon reduction of the

carbene function of 49a. Moreover, when two equivalents

of ethylmagnesium bromide were used, the course of the

reaction was again different: besides small amounts (4%) of

the lactonol 93, a second unexpected butenolide 94 was also

detected. Its physical data are in agreement with the intro-

duction of two ethyl groups, one, as expected, on C-7, and

the second one at the ring junction (Scheme 37). The origin

of this product has not yet been established.

Calcium cyanide has been shown by Fischer to lead to

the nitrile complex 100a (2.5%)^[60]via complex 99, upon

interaction with complex 11a. We confirmed this result by

using the more soluble tetramethylammonium cyanide:

complex 11b led indeed to ethoxy(phenyl)acetonitrile in

19% yield (Scheme 40).

Finally, a triple bond could also be introduced into the

carbene complexes by means of an alkynyllithium deriva-

tive; phenylbutynyllithium reacted with complex 95 to give

a modest yield of the butenolide 96 (16%), one of the ex-

pected products of this reaction (Scheme 38).

Scheme 40

When the reaction was carried out in the presence of

cyclopentenone, the 1,4-addition product 101 was obtained

in 47% yield as a mixture of two isomers (Scheme 40). Fi-

nally complex 49a, under the same conditions, led also to

an addition/protonation product 98b (Nu ϭ CN) in 23%

yield (Scheme 39).

Scheme 38

Peculiar Behaviour of Sodium Phenylthiolate and

Tetramethylammonium Cyanide

Thiols react with alkoxycarbene complexes to give alkyl-

and arylthiocarbene complexes via tetrahedral intermedi-

ates.^[4]These fleeting intermediates might thus also be

trapped as such or as the CO insertion products by a suit-

able triple bond. We therefore reacted complex 49a with

sodium phenylthiolate at Ϫ40 °C, in THF, then, after heat-

ing to room temperature, at reflux of the solvent for 12 h.

Work up, followed by silica gel chromatography, gave, how-

ever, 98a in 46% yield; this product results from the ad-

dition of the thiolate to 49a followed by the protonation of

the resulting chromate 97a. Neither of the expected inser-

tions — CO and/or the triple bond — took place. A similar

behaviour was observed with cyanide anions (Scheme 39).

Remarks on the Stereochemical Outcome of the Insertion

Reactions

Achiral Dihydropyridines and Nucleophiles

One of the remarkable points of these transformations,

other than the large variety of butenolides which can be

synthesised, is their stereochemical aspects. Indeed, high

diastereoselectivities are very often observed, especially

when the alkynyl group was directly bound to the oxygen

atom of the carbene function. How can this result be ex-

plained? A first general remark: due to the presence of a

five-membered unsaturated lactone, the hydrogen atom at

the ring junction, adjacent to the stereogenic centres, is al-

ways axial, whereas the adjacent substituent of the former

carbene carbon can either be axial or equatorial.

In the postulated mechanism, two fundamental steps

must be considered. In the first one, the carbene function

is reduced by the hydride originating from a dihydropyri-

dine or undergoes the addition of a nucleophile. In the most

simple cases, the two faces of the carbene function are en-

antiotopic since no stereogenic centre is included in the sub-

stituents of the carbene function (Scheme 41).^[61]The last

step is the protonation of an η⁵-bonded lactone, one limit-

ing form of the chromium enolate. Here, the two faces of

the enolate are diastereotopic, thus two isomers can form.

Scheme 39

2484

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

However, the addition of nucleophiles bulkier than a hy-

dride modified the stereochemical outcome: indeed, for

Nu ϭ methyl, two isomers were obtained. In the major

product, as shown by X-ray diffraction studies, the phenyl

group is still in an equatorial position. Nevertheless, 40%

of a product in which this group is in an axial position are

formed. For the butyl and trimethylsilylmethyl groups, the

reaction is again highly selective. Nevertheless, small

amounts (Ͻ 10%) of the second isomer could be detected

1

by H NMR spectroscopy, giving a singlet for the proton

at the ring junction at about 5 ppm, downfield from the

signal of the corresponding proton in the major isomer. We

thus tentatively assigned a stereochemistry for these two

compounds in which the introduced alkyl groups are axial.

Thus, in all the cases examined, the phenyl group is equa-

torial in the major isomer.

Scheme 41

For Y ϭ OR, X ϭ CHR, other factors have to be con-

sidered: First, the anomeric effect and the oxygen-oxygen

repulsion, which both favour the axial orientation of OR,^[64]

and second, steric hindrance between an axial Y group and

the bulky ligands of the metal could also be critical and

must be taken into account. It is thus not surprising to ob-

serve a balanced formation of the two isomers in this latter

case, although according to the thermodynamics, the more

stable product of the reaction has a trans diaxial geometry.

Let’s first consider the case of the more simple carbene

complexes in which no substituent is present on the alkyl

chain. The transfer of a hydride to the carbene carbon will

lead to an alkylchromate as a single isomer. This is followed

by the insertion of a CO ligand with the critical step, as

far as the stereochemistry is concerned, probably being a

concerted coordination of the triple bond. In the transition

state, the pre-formed cycle B of the butenolide most prob-

ably adopts a chair conformation in which Y, the former

substituent of the carbene function, could either be equa-

torial or axial. For Y ϭ alkyl, aryl and X ϭ O, one can

assume that, as in six-membered ketones of similar struc-

tures,^[62]the more favoured stereochemistry of Y is the

equatorial one, especially in the case of a phenyl group

(Scheme 42). Thus, for X ϭ O, only one isomer in which

the two hydrogen atoms H-7 and H-7a are trans diaxial

should form, which is indeed observed. Moreover, accord-

ing to calculations, this compound is the thermo-

dynamically more stable isomer (∆H_Fϭ Ϫ42.68 kcal·mol^Ϫ1

vs. ∆H_Fϭ Ϫ40.30 kcal·mol^Ϫ1for the trans and the cis iso-

mer, respectively).^[63]In the case of a methyl group, it is

likely that the energy difference between the two possible

conformers is lower and that weak interactions with the sol-

vent can change the stereochemical outcome of the reac-

tion. This is also observed (vide supra).

(∆H_Fϭ Ϫ90.21 kcal·mol^Ϫ1vs. ∆H_Fϭ Ϫ88.40 kcal·mol^Ϫ1

)

In the case of alkoxides, it is interesting to note that, ac-

cording to the X-ray structure, the ethoxy group in com-

pound 84 (Scheme 32, Figure 3) is in an axial position. This

stereochemistry corresponds to that of the more stable

product: due to the presence in the six-membered ring of

an oxygen atom on the carbon bearing the alkoxy group,

these two groups will be antiperiplanar as a result of the

anomeric effect.^[64]

For carbene complexes bearing a substituent on the alkyl

chain, for example a benzyl group as in complex 48d, a

diastereoselectivity can already be expected in the first step,

the reduction step. We can reason as for linear substituted

carbonyl compounds: a FelkinϪAnh model^[65]might ac-

count for the formation of a major compound in which the

benzyl substituent and the alkoxy group are erythro. Indeed,

if the more bulky group, the benzyl of the alkyl chain, is

antiperiplanar to the nucleophile, and the chain gauche

with respect to the metal (Scheme 43), then the ethoxy and

the benzyl groups in the resulting alkylmetalate will be syn

in the major product, and thus the butenolide having an

axially oriented ethoxy group and an equatorially oriented

benzyl group will be the more abundant. Such an effect has

already been observed by Cutler during the stepwise con-

version of CO into poly(alkoxylethylene) acyl complexes.^[66]

For less-crowded substituents such as methyl groups, the

distribution can again be reversed: since the chain can now

be considered as the more crowded substituent, then the

trans isomer will be the more abundant product, in agree-

ment with the thermodynamic data (∆H_Fϭ Ϫ96.62

kcal·mol^Ϫ1vs. ∆H_Fϭ Ϫ93.91 kcal·mol^Ϫ1). Finally, for the

[5.5]-fused system, and in agreement with calculations

Scheme 42

(∆H_F

ϭ

Ϫ114.30 kcal·mol^Ϫ1vs. ∆H_F

ϭ

Ϫ113.44

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2485

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

kcal·mol^Ϫ1), an equimolar amount of each isomer is formed

during the insertion reaction, the enolate being almost

planar and the protonation occurring with equal prob-

ability on the two sides of this intermediate.

Scheme 43

The possibility for dihydronicotine to be coordinated to

the carbene complex as a bidentate ligand prior to the hy-

dride migration might thus be at the origin of the better

enantioselection. According to calculations on the dihydro-

nicotine 73,^[67]a preferential conformation exists in which

the dihydropyridine and the pyrrolidine rings are almost

perpendicular, as in nicotine.^[68]A heteroatom substituent

on the dihydropyridine might organize the transition state

through coordination of the nitrogen atom of the pyrroli-

dine to the positive terminus of the carbene complex — the

oxygen atom — as depicted in Figure 5. Moreover, a tight

interaction between the pyridine ring, due to a developing

positive charge on the nitrogen atom, and the negative ter-

minus of the carbene, and thus with the substituents of the

carbene carbon, can occur. It thus seems clear that the ee’s

should be dependent on the nature of these substituents

(vide supra).

Compound 63, which is a dihydronicotinamide, appears

in the third rank (ee 20%). Here the stereogenic centre is

four atoms away from the carbon which bears the hydride.

It might be compared to 64, the efficiency of which is much

lower (ee 1.4%). How can a more efficient interaction occur

in this case? 63 contains a secondary amide with a rather

acidic hydrogen atom. Thus a hydrogen bond between a

carbonyl group of the complex and the hydrogen of the am-

ide might form, which again might favour one transition

state over the other. Such interactions have already been

observed in the case of (arenetricarbonyl)chromium com-

plexes and amides.^[69]

Chiral Dihydropyridines

Two important results have been observed: both dihydro-

nicotinamides and dihydropyridines reduce carbene com-

plexes and promote the cascade insertion reactions, al-

though the yields are better in the case of simple dihydro-

pyridines (75 vs. 37%). Moreover, both types of chiral ana-

logues of NADH lead enantioselectively to butenolides.

According to Scheme 41, a chiral hydride-transfer reagent

should indeed be able to distinguish between the two faces

of the carbene complex, as is the case for a ketone.^[61]Two

diastereomeric transition states might therefore form upon

interaction of the chiral dihydropyridines with the carbene

complexes, possibly giving rise to two enantiomers at differ-

ent rates (stability control mechanism). There is, however,

an important difference between carbene complexes and ke-

tones which renders the discussion even more complicated:

the alkoxycarbene complexes can exist as two different con-

formers around the oxygen atom at low temperature, their

relative amounts depending on the nature of the substitu-

ents (Figure 5). According to the results gathered here, the

following comments can tentatively be addressed. The best

ee’s are achieved by the use of 1,2-dihydropyridines 65 and

73. In both cases, the hydrides which can be transferred are

on a carbon that is one atom away from the stereogenic

centre — a carbon atom in 65 and a nitrogen atom in 73 —

the difference between the two dihydropyridines being the

presence of a second potential binding site in 73, the nitro-

gen atom of the pyrrolidine substituent.

To sum up, a transition state such as that depicted in

Figure 5 would also be akin to the ternary ketone-dihydro-

pyridine-Mg^2ϩcomplexes which have been proposed in the

enantioselective reductions of ketones with analogues of

NADH.^[48]This reinforces the deep analogy which exists

between carbene complexes and carbonyl compounds. Al-

though no exceptional ee’s were observed up to now, the

results are interesting and encouraging when compared to

the efforts which have been devoted to the biomimetic en-

antioselective reduction of carbonyl compounds.^[45,46]

A

way to perhaps improve the efficiency of the reducing di-

hydropyridines would be to either constrain the bicyclic sys-

tem of nicotine or to add substituents on the pyrrolidine

ring. Indeed, analogues of nicotine in which the rotation of

the pyrrolidine ring is inhibited have been synthesised and

Figure 5. Transition-state model for the interaction of N-methyldi-

hydronicotine with a carbene complex

2486

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

Scheme 44

are indeed much better haptens than nicotine for biological alkynes into aminocarbene complexes of chromium, be-

systems.^[70]Other approaches to enantioselectivity would be haved similarly and led to aminolactones upon oxidation

to use chirally modified complex hydrides of the type with molecular oxygen.^[73a,73c]

KHB(OR*)₃as reducing agents or to carry out the reaction

with other nucleophiles in conjunction with chiral additives.

Work in this direction is underway.

Behaviour of Sodium Thiophenolate and Ammonium

Cyanide

In most of the intermediates obtained upon interaction

of a nucleophile with the carbene complexes the metal bears

a benzylic group. It is known that benzylic groups are not

very prone to migrate to a coordinated carbon monoxide

ligand to give an acylmetal derivative.^[13,74]However, due to

the presence of electron-rich substituents, such as alkoxy

groups, the reaction takes place, although the presence of a

nitrile, an electron-withdrawing group, inhibits the ’’inser-

tion’’ of CO completely. Such a behaviour is also known

from the literature: methoxycarbonyl substituents on an

alkylmetal derivative inhibit the formation of metalacyl

complexes.^[74]The case of sodium thiophenolate is however

less clear: since the electronegativities of sulfur and carbon

are about the same, the alkylchromium intermediate should

also insert a CO group and lead to a butenolide.That ne-

ither the CO nor the triple bond insertions were observed

might be indicative of a direct interaction of the introduced

functions(CN or SPh) with the metal.

Behaviour of Other Nucleophiles

We have clearly demonstrated that the addition of vari-

ous nucleophiles to alkoxycarbene complexes of chromium

is the key to the success of their general transformation into

differently substituted butenolides. Crucial in this regard is

the fact that no undesired interaction of the nucleophile

with the various intermediates took place. A few points

warrant a special comment: the behaviour of ethylmag-

nesium and -lithium derivatives, the formation of the un-

saturated lactonols, and finally indications as to the limits

of the method.

The formation of products due to a ’’reduction’’ of the

starting carbene complexes upon their interaction either

with ethylmagnesium or ethyllithium derivatives reflects

again their analogy with carbonyl compounds as it is

known that hindered carbonyl compounds can react with

metal alkyl derivatives upon transfer of a hydride originat-

ing from the alkyl group, rather than of an alkyl group.^[71]

The formation of lactonols along with the butenolides

can easily be understood: The last step of the multiple inser-

tion reactions is the protonation of a lactone enolate, one

limiting form of which is a 2-oxyfuran. This may combine

Conclusion

In this paper we have demonstrated that a reaction which

with triplet oxygen to afford a hydroperoxide which, in the was interesting from a mechanistic point of view — the bi-

presence of low-valent chromium species, will collapse into omimetic reduction of carbene complexes with dihydropyri-

the lactonol and oxidized chromium. Conversely, direct in- dines — could be applied to the synthesis of highly func-

teraction of oxygen with the metal of the final chromium tionalised unsaturated lactones by the use of various nucle-

enolate, a strong nucleophile, might lead to the same lac- ophiles ranging from hydrides originating from dihydro-

tonol upon insertion of oxygen into the chromiumϪcarbon pyridines to alkyllithium derivatives and alkoxides. The

bond (Scheme 44),^[72a,72b]a radicalar pathway cannot, how- analogy with biomimetic reactions allowed us to carry out

ever, be excluded.^[72c]

the transformation in an enantioselective way with moder-

Nitrogen ylide complexes which are in fact ’’internal’’ ate, yet encouraging, success thanks to a new, efficient chiral

tetraalkylammonium chromates, formed upon insertion of reducing agent, N-methyldihydronicotine. The step which

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2487

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

bonyl)chromium (4.40 g, 20.00 mmol) and triethyloxonium tetra-

fluoroborate (4.20 g, 22.00 mmol). After chromatography on silica

gel an orange oil identified as complex 48b was obtained (3.50 g,

10.60 mmol, 53.0%). ¹H NMR (200 MHz, CDCl₃): δ ϭ 5.11 (q,

J ϭ 7.0 Hz, 2 H, H⁸), 3.50 (t, J ϭ 6.0 Hz, 2 H, H²), 2.30 (t, J ϭ

6.0 Hz, 2 H, H³), 2.11 (q, J ϭ 8.0 Hz, 2 H, H⁶), 1.64 (t, J ϭ 7.0 Hz,

3 H, H⁹), 1.07 (t, J ϭ 8.0 Hz, 3 H, H⁷) ppm. C₁₄H₁₄CrO₆(330.3):

calcd. C 50.90, H 4.24; found C 50.97, H 4.50.

triggers the rearrangement of these complexes is the trans-

fer of a nucleophile to the carbene carbon giving a high

energy electron-overloaded species which spontaneously

leads to a new acyl complex. This new synthetic strategy

led to the formation of six new bonds, up to four

carbonϪcarbon bonds and two carbonϪoxygen bonds, in

a one-pot reaction involving alkoxycarbene complexes teth-

ered to alkynes and various nucleophiles.

Experimental Section

General: Note that the experimental details for the preparation of

some complexes can be found in the Supporting Information; for

Supp. Inf. see also the footnote on the first page of this article.

Complexes 37 and 48a,b

Carbene Complex 48c

General Procedure: tert-Butyllithium (2.1 equiv. of a 1.7  hexane

solution) was added with a syringe over a period of 10 min to a

solution of the corresponding iodide (1.0 equiv.) under argon at

Ϫ78 °C in diethyl ether (7 mL/mmol of iodide) and pentane

(10 mL/mmol of iodide). This solution was stirred at Ϫ78 °C for a

period of 15 min and then transferred by cannula to a suspension

of (hexacarbonyl)chromium [or (hexacarbonyl)tungsten; 1.0 equiv.]

in diethyl ether (15 mL/mmol) at Ϫ78 °C. This mixture was

warmed to room temperature and was stirred for 2.5 h. The solvent

was removed on a rotary evaporator and the reaction mixture was

cooled to 0 °C. Water (15 mL/mmol), petroleum ether (boiling frac-

tion 40Ϫ65 °C, 15 mL/mmol), and then triethyloxonium tetra-

fluoroborate (1.1 equiv.) were added. The reaction mixture was

warmed to room temperature and was extracted with petroleum

ether. The organic layer was washed with sodium hydrogencarbon-

ate solution, water, brine and dried with sodium sulfate. The sol-

vent was removed on a rotary evaporator and final purification was

achieved by chromatography on silica gel using pure petroleum

ether as eluent.

General Procedure: These compounds were prepared by catalytic

phase-transfer alkylation of complex 37 with alkyl bromides or iod-

ides. A mixture of the carbene complex (n mmol) and tetrabutylam-

monium bromide (0.1  mmol) in dichloromethane (15 n mL) was

treated with 50% aqueous NaOH and the halide (2Ϫ5  mmol).

The mixture was stirred at room temperature under argon until the

starting material had been consumed. The reaction mixture was

diluted with water, extracted with dichloromethane, dried, and con-

centrated under reduced pressure. The pure product was isolated

by chromatography on silica gel by elution with petroleum ether.

Complex 48c: The general procedure was followed using carbene

complex 37 (4.24 g, 10.82 mmol), and methyl iodide (3.18 mL,

51 mmol), as starting material. After chromatography on silica gel

a deep reed oil identified as complex 48c was obtained (2.83 g,

1

6.97 mmol, 64.4%). H NMR (200 MHz, CDCl₃): δ ϭ 7.40Ϫ7.24

(m, 5 H, arom. H), 5.08 (q, J ϭ 7.0 Hz, 2 H, H⁸), 4.17 (m, 1 H,

H²), 2.41 (m, 2 H, H⁴), 1.88 (m, 1 H, H³), 1.60 (t, J ϭ 7.0 Hz, 3

H, H⁹), 1.46 (m, 1 H, H³), 1.06 (d, J ϭ 6.6 Hz, 3 H, H⁷) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ ϭ 363.3 (C¹), 223.1 (trans CO), 216.4

(cis CO), 131.6Ϫ127.8 (arom. HC), 123.81 (qC), 89.1, 81.5 (C⁵or

C⁶), 78.1 (C⁸), 64.5 (C²), 31.9 (C⁴), 17.6 (C³), 16.1 (C⁷), 14.9 (C⁹)

ppm. HRMS (EI^ϩ), calcd. for C₂₀H₁₈CrO₆: 406.0508; found

406.0486.

Complex 48a: The general procedure was followed using (5-iodo-4-

phenylpent-1-yn-1-yl)benzene (4.83 g; 13.96 mmol), tert-butyllith-

ium (17.2 mL, 29.3 mmol), (hexacarbonyl)chromium (3.07 g,

13.95 mmol) and triethyloxonium tetrafluoroborate (2.92 g,

15.33 mmol). After chromatography on silica gel a reddish oil

identified as complex 48a was obtained (2.28 g, 4.87 mmol, 34.9%).

¹H NMR (200 MHz, CDCl₃): δ ϭ 7.38Ϫ7.18 (m, 10 H, arom. H),

4.92 (q, J ϭ 7.0 Hz, 2 H, H⁷), 3.96 (d, J ϭ 7.3 Hz, 2 H, H²), 3.44

(m, 1 H, H³), 2.66 (m, 2 H, H⁴), 1.40 (t, J ϭ 7.0 Hz, 3 H, H⁸) ppm.

¹³C NMR (100 MHz, CDCl₃): δ ϭ 357.5 (C¹), 223.2 (trans CO),

216.4 (cis CO), 142.9 (qC), 131.7 (qC), 128.6Ϫ127.3 (arom. HC),

123.6 (qC), 87.6, 83.1 (C⁵or C⁶), 78.2 (C³), 67.8 (C⁸), 42.3 (C²),

27.2 (C⁴), 14.8 (C⁹) ppm. HRMS [M

C₂₅H₂₄CrNO₆: 486.1069; found 486.1071.

ϩ NH₄] calcd. for

Salts A, B and C

Salt A: Methyllithium (15.05 mL, 1.33 , 20 mmol) was added to

a suspension of [Cr(CO)₆] (4.4 g, 20 mmol) in Et₂O (95 mL). After

10 minutes at room temperature, the solvent was evaporated in va-

cuo. Addition of water (100 mL) followed by filtration through ce-

lite and treatment with a saturated solution of tetramethylam-

monium bromide (6.16 g, 40 mmol) in water (10 mL) led to im-

mediate formation of the ammonium salt. Dissolution in CH₂Cl₂

and addition of pentane gave the salt A as a yellow solid (5.19 g,

16.80 mmol, 84.0%).

Complex 48b: The general procedure was followed using 1-iodohex-

3-yne (4.16 g, 20.00 mmol), tert-butyllithium (24.7 mL), (hexacar-

2488

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

(dt J ϭ 6.9Ϫ7.9 Hz, 2 H,, H³), 1.43 (m, 1 H, H⁸), 0.79Ϫ0.47 (m, 4

H, H⁹and H¹⁰) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 358.4 (C¹),

223.1 (trans CO), 216.5 (cis CO), 131.6Ϫ127.9 (arom. HC), 123.7

(qC), 88.8Ϫ81.8 (C⁵or C⁶), 86.9 (C⁷), 66.1 (C²), 25.2 (C⁴), 19.0

(C³), 10.3 (C⁸), 3.7 (C⁹and C¹⁰) ppm. HRMS [M ϩ NH₄] calcd.

for C₂₁H₂₂CrNO₆(436.4): 436.0852; found 43.0851.

Salt B: Phenyllithium (30.5 mL, 0.65 , 20 mmol) was added to a

suspension of [Cr(CO)₆] (4.4 g, 20 mmol) in Et₂O (95 mL). After 10

minutes at room temperature, the solvent was evaporated in vacuo.

Addition of water (100 mL) followed by filtration through celite

and treatment with a saturated solution of tetramethylammonium

bromide (6.16 g, 40 mmol) in water (10 mL) led to the formation

of the ammonium salt. The salt B was extracted with CH₂Cl₂and

dried with sodium sulfate. The solvent was removed on a rotary

evaporator to give a red solid (6.83 g, 18.40 mmol, 92.0%).

Complex 48f: tert-Butyllithium (24.7 mL, 42.00 mmol, 1.7 ) was

added with a syringe over a period of 10 min to a solution of (5-

iodopent-1-ynyl)benzene (5.40 g, 20 mmol) under argon at Ϫ78 °C

in diethyl ether (140 mL) and pentane (200 mL). This solution was

stirred at Ϫ78 °C for a period of 15 min and then transferred by

cannula to a suspension of (hexacarbonyl)chromium (4.40 g,

20 mmol) in diethyl ether (300 mL) at Ϫ78 °C. This mixture was

warmed to room temperature and was stirred for 2.5 h. The solvent

was removed on a rotary evaporator, water was added (100 mL)

and the resultant solution was filtered through celite and added to

a solution of tetramethylammonium bromide (6.16 g, 40 mmol) in

water (10 mL). The reaction mixture was extracted with CH₂Cl₂(3

ϫ 100 mL) and dried with sodium sulfate. The solvent was removed

on a rotary evaporator giving the ammonium salt as a brownish

oil (5.16 g, 11.82 mmol, 59.1%). The triflate derived from benzylic

alcohol (1.18 g, 4.92 mmol) was added to a solution of this salt

(1.80 g, 4.12 mmol) in CH₂Cl₂(100 mL) at Ϫ20 °C and the reaction

mixture was stirred for two hours before being allowed to reach

room temperature. After column chromatography, the complex 48f

was obtained as a yellow solid (800 mg, 1.76 mmol, 42.8%), m.p.

35 °C. ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.50Ϫ7.28 (m, 10 H,

arom. H), 6.06 (s, 2 H, H⁷), 3.61 (t, J ϭ 7.0 Hz, 2 H, H²), 2.45 (t,

J ϭ 7.0 Hz, 2 H, H⁴), 1.77 (qn, J ϭ 7.0 Hz, 2 H, H³) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ ϭ 360.2 (C¹), 223.1 (trans CO), 216.4

(cis CO), 131.6 (qC), 129.4Ϫ128.4 (arom. HC), 123.7 (qC), 88.7,

81.9 (C⁵or C⁶), 83.7 (C⁷), 62.3 (C²), 25.3 (C⁴), 19.1 (C³) ppm.

C₂₄H₁₈CrO₆(454.4): calcd. C 63.44, H 3.99; found C 63.34, H 4.39.

Salt C: A solution of tBuLi (24.7 mL, 1.7 ) in hexane was added

slowly to a solution of bromocyclopropane (2.42 g, 20 mmol) in

Et₂O (100 mL) at Ϫ78 °C. After 10 minutes at Ϫ78 °C, the resulting

mixture was transferred to a flask containing a suspension of

[Cr(CO)₆] (4.4 g, 20 mmol) in Et₂O (200 mL) at Ϫ78 °C. After two

hours at room temperature, the solvent was evaporated in vacuo.

The crude product was dissolved in water (100 mL), filtered

through celite and treated with a saturated aqueous solution of

tetramethylammonium bromide (8.00 g/10 mL) to cause formation

of a yellow precipitate. This material was dissolved in CH₂Cl₂and

crystallisation was induced by addition of pentane. Salt C was ob-

tained as a yellow solid in 70.0% yield (4.69 g, 14.00 mmol).

Carbene Complexes 48e,f

Complex 48e: Pivaloyl chloride (2.48 mL, 13.38 mmol) was added

with a syringe to a solution of salt A (4.13 g, 13.38 mmol) in

CH₂Cl₂(25 mL) at Ϫ40 °C. The reaction mixture was stirred at

Ϫ40 °C for one hour, then a solution of cyclopropylmethanol

(963 mg, 13.38 mmol) in CH₂Cl₂(5 mL) was added. The reaction

mixture was stirred for 2 h at this temperature before being allowed

to reach room temperature. The resulting orange solution was eva-

porated to dryness and the crude product was purified by flash

chromatography using PE as eluent giving a carbene complex as a

orange oil (2.60 g, 8.96 mmol, 67%). nButyllithium (5.38 mL,

8.62 mmol) was added to a solution of this complex (2.50 g,

8.62 mmol) in THF (100 mL) at Ϫ78 °C. After 10 minutes, a solu-

Carbene Complexes 49g,h

tion of the triflate derived from 4-phenylbut-3-yn-1-ol (2.86 g, General Procedure 1: The pentacarbonyl[(tetramethylammonio)car-

10.29 mmol) in THF (15 mL) was added and the reaction was bene]chromium salt (A, B or C; 1.0 molar equivalent) was dissolved

warmed to Ϫ20 °C and stirred for two hours at this temperature. in CH₂Cl₂(20 mL/mmol) under argon. The flask was covered with

Column chromatography on silica gel gave the complex 48e as a aluminium foil, cooled to Ϫ20 °C and acetyl chloride (1.1 mol

1

red oil (620 mg, 1.44 mmol, 16.7%). H NMR (200 MHz, CDCl₃): equivalent) was added dropwise over 5 min with a syringe to give

δ ϭ 7.39Ϫ7.25 (m, 5 H, arom. H), 4.84 (d, J ϭ 7.3 Hz, 2 H, H⁷), a red solution. After the addition, the mixture was warmed to Ϫ10

3.51 (t, J ϭ 7.9 Hz, 2 H, H²), 2.45 (t, J ϭ 6.9 Hz, 2 H, H⁴), 1.80

°C and stirred for 10 min. The alkynol (1.0 mol equivalent) was

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2489

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

added as a solution in CH₂Cl₂(1 mL/mmol) and the solution was pyridine (3 mol equiv.) in CH₂Cl₂(0.5 mL/mmol of amine) was

FULL PAPER

stirred at room temperature for 30 min. The mixture was concen-

trated under reduced pressure and the residue was purified by flash

chromatography to give the carbene complex.

added dropwise from an addition funnel to a solution of the car-

bene complex (1 mol equiv.) in CH₂Cl₂(25 mL/mmol of carbene)

at Ϫ10 °C, under argon. After 15 min, the ice bath was removed

and the mixture stirred at room temperature for 24 h. The solution

slowly turned dark red. The solvent was evaporated under vacuum

and the residue was purified by chromatography on silica gel with

mixture of PE/Et₂O as eluent.

General Procedure 2: A solution of pentacarbonyl[(tetramethylam-

monio)carbene]chromium salt (A, B or C; 1 mmol) dissolved in

CH₂Cl₂(15 mL/mmol) in an oven-dried flask was put under argon

and cooled to Ϫ40 °C with an acetone/dry ice bath. Pivaloyl chlo-

ride (1.1 mol equivalent) was added to the red solution with a syr-

inge. The reaction mixture was stirred at Ϫ40 °C for one hour and

the solution changed slowly to deep-red/brown. Then, a solution

of alcohol (1.1 mol equivalent) in CH₂Cl₂(5 mL/mmol) was added.

The reaction was stirred for about 3 h at this temperature before

being allowed to reach room temperature. The resulting red solu-

tion was evaporated and the crude product was purified by flash

chromatography using mixtures of PE/CH₂Cl₂as eluent giving,

after evaporation of the solvents, the pure carbene complex.

With Complex 48e. 7-Cyclopropylmethoxy-3-phenyl-5,6,7,7a-tetra-

hydro-4H-benzofuran-2-one (50e and 51e): The general procedure

was followed using carbene complex 48e (600 mg, 1.43 mmol). Elu-

tion with PE/Et₂O (60:40) gave the butenolide. 50e: (202 mg,

1

0.71 mmol, 49.7%). H NMR (400 MHz, CDCl₃): δ ϭ 7.50Ϫ7.33

(m, 5 H, arom. H), 4.73 (d, J ϭ 8.7 Hz, 1 H, H^7a), 3.66 (dd, J ϭ

7.1Ϫ10.2 Hz, 1 H, H⁸), 3.51 (dd, J ϭ 7.1Ϫ10.2 Hz, 1 H, H^8Ј), 3.26

(ddd, J ϭ 4.6, 8.7, 13.2 Hz, 1 H, H⁷), 3.04 (m, 1 H, H⁴), 2.26 (ddd,

J ϭ 6.1, 13.7, 13.7 Hz, 1 H, H^4Ј), 2.17 (m, 1 H, H⁶), 2.01 (m, 1 H,

H⁵), 1.60 (m, 1 H, H^6Ј), 1.31 (m, 1 H, H^5Ј), 1.10 (m, 1 H, H⁹),

0.59Ϫ0.21 (m, 4 H, H¹⁰, H¹¹) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ ϭ 172.7 (C²), 160.9 (C^3a), 129.7 (Cq), 129.0Ϫ128.5 (arom. HC),

125.0 (qC), 85.7 (C^7a), 82.8 (C⁷), 75.9 (C⁸), 30.0 (C⁶), 26.3 (C⁴), 23.7

(C⁵), 11.0 (C⁹), 3.2 (C¹⁰and C¹¹) ppm. C₁₈H₂₀O₃(284.4): calcd. C

76.03, H 7.09; found C 76.05, H 7.19. 51e: (51 mg, 0.18 mmol,

12.4%). ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.49Ϫ7.29 (m, 5 H,

arom. H), 4.79 (d, J ϭ 3.6 Hz, 1 H, H^7a), 4.15 (m, 1 H, H⁷), 3.40

(m, 2 H, H⁸), 3.08 (m, 1 H, H⁴), 2.28 (m, 1 H, H^4Ј), 2.01 (m, 1 H,

H⁶), 1.73 (m, 2 H, H⁵), 1.59 (m, 1 H, H^6Ј), 0.94 (m, 1 H, H⁹),

0.46Ϫ0.14 (m, 4 H, H¹⁰, H¹¹) ppm.

Complex 49g: Salt B (1.52 g, 4.11 mmol), pivaloyl chloride (556 µL,

4.52 mmol) and (R)-2,4-diphenylbut-3-yn-1-ol (1.00 g, 4.52 mmol)

were combined following the general procedure 2. Complex 49g

was obtained as a deep-red oil (932 mg, 1.86 mmol, 45.2%). ¹H

NMR (200 MHz, CDCl₃): δ ϭ 7.49Ϫ7.11 (m, 15 H, arom. H), 4.98

(br. s, 1 H, H³), 4.58 (br. s, 1 H, H⁴) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ ϭ 350.0 (C¹), 224.5 (trans CO), 216.0 (cis CO), 153.1

(qC), 136.7 (qC), 131.8Ϫ128.3 (arom. HC), 122.7 (qC), 86.7, 85.4

(C⁵or C⁶), 82.9 (C³), 39.3 (C⁴) ppm. HRMS calcd. for

C₂₈H₁₈CrO₆: 502.0509; found 502.0499.

Complex 49h: Salt

B (3.20 g, 8.62 mmol), pivaloyl chloride

(1.06 mL, 8.62 mmol) and 3-methyl-5-phenylpent-4-yn-2-ol (1.00 g,

5.75 mmol) were combined following the general procedure 2.

Complex 49h was obtained as a red solid (1.85 g, 4.08 mmol,

71.0%). ¹H NMR (200 MHz, CDCl₃): δ ϭ 7.40Ϫ7.25 (m, 10 H,

arom. H), 5.28 (m, 1 H, H³), 3.14 (m, 1 H, H⁴), 1.60 (d, J ϭ 5.9 Hz,

3 H, H⁷), 1.40 (d, J ϭ 6.9 Hz, 3 H, H⁸) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ ϭ 348.7 (C¹), 224.6 (trans CO), 216.2 (cis CO),

131.7Ϫ122.1 (arom. HC and qC), 89.7 (C³), 89.2, 83.6 (C⁵or C⁶),

33.2 (C⁴), 19.1 (C⁷), 17.0 (C⁸) ppm. C₂₄H₁₈CrO₆(454.4): calcd. C

63.44, H 3.99; found C 62.95, H 4.48.

With Complex 48f. 7-Benzyloxy-3-phenyl-5,6,7,7a-tetrahydro-4H-

benzofuran-2-one (50f and 51f): The general procedure was followed

using carbene complex 48f (780 mg, 1.72 mmol). The butenolide

was obtained as two isomers: Elution with PE/Et₂O (60:40) gave

the trans isomer 50f. 50f: White solid (105 mg, 0.33 mmol, 19.2%),

m.p. 76 °C. ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.59Ϫ7.18 (m, 10

H, arom. H), 4.98 (d, J ϭ 11.8 Hz, 1 H, H⁸), 4.86 (d, J ϭ 8.4 Hz,

1 H, H^7a), 4.76 (d, J ϭ 11.8 Hz, 1 H, H^8Ј), 3.41 (ddd, J ϭ 4.6, 8.4,

15.3 Hz, 1 H, H⁷), 3.06 (dd, J ϭ 1.8Ϫ14.3 Hz, 1 H, H⁴), 2.30 (dt,

J ϭ 7.5, 14.3 Hz, 1 H, H⁴), 2.22 (m, 1 H, H⁶), 2.03 (m, 1 H, H⁵),

1.65 (m, 1 H, H^6Ј), 1.36 (m, 1 H, H^5Ј) ppm. ¹³C NMR (100 MHz,

CDCl₃):

δ ϭ

172.6 (C²), 160.8 (C^3a), 138.0Ϫ128.9 (qC),

128.6Ϫ128.4 (arom. HC), 127.8 (qC), 85.7 (C^7a), 82.2 (C⁷), 72.4

(C⁸), 29.8 (C⁶), 26.1 (C⁴), 23.5 (C⁵) ppm. C₂₁H₂₀O₃(320.4): calcd.

C 78.73, H 6.29; found C 79.20, H 6.54. Further elution with PE/

Et₂O (70:30) gave the cis isomer 51f. 51f: (70 mg, 0.22 mmol,

12.8%). ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.53Ϫ7.28 (m, 10 H,

arom. H), 4.88 (d, J ϭ 3.5 Hz, 1 H, H^7a), 4.77 (d, J ϭ 12.2 Hz, 1

H, H⁸), 4.77 (d, J ϭ 12.2 Hz, 1 H, H^8Ј), 4.28 (m, 1 H, H⁷), 3.11

(m, 1 H, H⁴), 2.36 (m, 1 H, H^4Ј), 2.10 (m, 1 H, H⁶), 1.79 (m, 2 H,

H⁵and H^5Ј), 1.63 (m, 1 H, H^6Ј) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 173.2 (C²), 161.0 (C^3a), 138.7 (qC), 129.3 (qC),

128.9Ϫ127.7 (arom. HC), 125.4 (qC), 82.1 (C^7a), 75.6 (C⁷), 73.3

(C⁸), 28.3 (C⁶), 26.9 (C⁴), 20.8 (C⁵) ppm.

Reaction of N-Methyldihydropyridine with Carbene Complexes

48a؊c, 48e,f, 49c,d and 49g,h

General Procedure: N-Methyldihydropyridine (19)^[54]was prepared

following the literature procedure. A solution of N-methyldihydro-

2490

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

173.0 (C²), 159.6 (C^3a), 143.7 (qC), 129.9 (qC), 128.9Ϫ127.0 (arom.

HC), 125.7 (qC), 81.4 (C^7a), 75.3 (C⁷), 67.3 (C⁸), 38.4 (C⁵), 35.9

(C⁶), 34.3 (C⁴), 15.7 (C⁹) ppm. HRMS [M ϩ 1] calcd. for C₂₂H₂₃O₃

(335.4): 335.1647; found 335.1652.

With Complex 48c. 7-Ethoxy-6-methyl-3-phenyl-5,6,7,7a-tetra-

hydro-4H-furan-2-one (50c and 51c): The general procedure was fol-

lowed using carbene complex 48c (2.03 g, 5.00 mmol). Elution with

PE/Et₂O (70:30) gave the butenolide as a 4:3 mixture of two iso-

mers (952 mg, 3.50 mmol 70.0%). 50c: White solid, m.p. 58 °C,

534 mg, 1.96 mmol, 39.3%: ¹H NMR (400 MHz, CDCl₃): δ ϭ

7.49Ϫ7.24 (m, 5 H, arom. H), 4.74 (d, J ϭ 8.2 Hz, 1 H, H^7a), 4.06

(dq, J ϭ 7.0, 9.2 Hz, 1 H, H⁹), 3.60 (dq, J ϭ 7.0, 9.2 Hz, 1 H, H⁹),

2.98 (ddd, J ϭ 1.8, 4.1, 14.1 Hz, 1 H, H⁴), 2.81 (dd, J ϭ 8.2,

10.2 Hz, 1 H, H⁷), 2.32 (dt, J ϭ 5.9, 14.1 Hz, 1 H, H⁴), 1.56 (m, 1

H, H⁵), 1.75 (m, 1 H, H⁶), 1.24 (t, J ϭ 7.0 Hz, 3 H, H¹⁰), 1.09 (m,

1 H, H⁵), 1.08 (d, J ϭ 6.6 Hz, 3 H, H⁸) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 172.6 (C²), 161.2 (C^3a), 129.6 (qC), 128.8Ϫ128.2

(arom. HC), 124.45 (qC), 87.8 (C⁷), 85.9 (C^7a), 68.0 (C⁹), 36.0 (C⁶),

32.4 (C⁵), 25.7 (C⁴), 17.4 (C⁸), 15.5 (C¹⁰). 51c: 418 mg, 1.54 mmol,

30.7%. ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.49Ϫ7.24 (m, 5 H,

arom. H), 4.82 (d, J ϭ 3.4 Hz, 1 H, H^7a), 3.82 (br. s, 1 H, H⁷), 3.72

(m, dq, J ϭ 7.0, 9.4 Hz, 1 H, H⁹), 3.57 (dq, J ϭ 7.0, 9.4 Hz, 1 H,

H⁹), 3.01 (m, 1 H, H⁴), 2.30 (m, 1 H, H⁴), 1.80 (m, 1 H, H⁶), 1.58

(m, 2 H, H⁵), 1.13 (t, J ϭ 9.0 Hz, 3 H, H¹⁰), 1.08 (d, J ϭ 6.3 Hz,

3 H, H⁸) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 173.0 (C²), 160.7

(C^3a), 130.3 (qC), 129.0Ϫ128.3 (arom. HC), 125.5 (qC), 82.7 (C^7a),

80.7 (C⁷), 69.6 (C⁹), 34.2 (C⁶), 26.4 (C⁵), 25.9 (C⁴), 17.6 (C⁸), 15.7

(C¹⁰) ppm. HRMS calcd. for C₁₇H₂₁O₃: 273.1491; found 273.1495.

With Complex 48b. 6-Ethoxy-3-ethyl-4,5,6,6a-tetrahydrocyclopenta-

[b]furan-2-one (50b, 51b) and 2-Ethoxy-5-propylidenecyclopentanone

(52): The general procedure was followed using carbene complex

48b (2.50 g, 7.58 mmol). Elution with PE/Et₂O (90:10) gave the

cyclopentanone 52 as an oil (142 mg, 0.85 mmol, 11.1%). ¹H NMR

(400 MHz, CDCl₃): δ ϭ 6.65 (m, 1 H, H⁶), 3.91 (t, J ϭ 8.0 Hz, 1

H, H⁵), 3.83 (m, 1 H, H⁹), 3.63 (m, 1 H, H⁹), 2.65 (m, 1 H, H³),

2.34 (m, 2 H, H³and H⁴), 2.17 (m, 2 H, H⁷), 1.77 (m, 1 H, H⁴),

1.25 (t, J ϭ 8.0 Hz, 3 H, H¹⁰), 1.05 (t, J ϭ 8.0 Hz, 3 H, H⁸) ppm.

¹³C NMR (100 MHz, CDCl₃): δ ϭ 203.7 (C¹), 140.1 (C⁶), 133.7

(C²), 81.6 (C⁵), 65.8 (C⁹), 27.2 (C⁴), 22.8 (C⁷), 22.4 (C³), 15.4 (C¹⁰),

12.9 (C⁸) ppm. HRMS calcd. for C₁₀H₁₇O₂: 169.1229; found

169.1230. The butenolide was obtained as two isomers in 1:1 ratio

(863 mg, 4.40 mmol, 58.1%). Elution with PE/Et₂O (85:15) gave

1

50b (trans) as a yellow oil. H NMR (200 MHz, CDCl₃): δ ϭ 4.66

(d, J ϭ 8.0 Hz, 1 H, H^6a), 3.77 (m, 1 H, H⁹), 3.56 (m, 2 H, H⁶and

H⁹), 2.75Ϫ2.00 (m, 6 H, H⁴, H⁵and H⁷), 1.20 (t, J ϭ 7.0 Hz, 3 H,

H¹⁰), 1.06 (t, J ϭ 7.4 Hz, 3 H, H⁸) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 176.0 (C²), 164.7 (C^3a), 127.8 (C³), 88.4 (C^6a), 80.7

(C⁶), 66.2 (C⁹), 31.3 (C⁵), 20.9 (C⁴), 18.1 (C⁷), 15.6 (C¹⁰), 12.6 (C⁸)

ppm. Further elution with PE/Et₂O (80:20) gave 51b (cis) as a yel-

1

low oil. H NMR (200 MHz, CDCl₃): δ ϭ 4.89 (br. s, 1 H, H^6a),

3.95 (m, 1 H, H⁶), 3.57 (m, 2 H, H⁹), 2.62Ϫ2.14 (m, 6 H, H⁴, H⁵

and H⁷), 1.18 (t, J ϭ 7.4 Hz, 3 H, H¹⁰), 1.05 (t, J ϭ 7.0 Hz, 3 H,

H⁸) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 177.1 (C²), 166.5

(C^3a), 133.9 (C³), 86.0 (C^6a), 75.5 (C⁶), 67.1 (C⁹), 32.7 (C⁵), 20.4

(C⁴), 18.4 (C⁷), 15.8 (C¹⁰), 12.6 (C⁸) ppm. HRMS calcd. for

C₁₁H₁₇O₃: 197.1178; found 197.1181.

With Complex 48a. 7-Ethoxy-3,5-diphenyl-5,6,7,7a-tetrahydro-4H-

benzofuran-2-one (50a and 51a): The general procedure was fol-

lowed using carbene complex 48a (1.15 g, 2.46 mmol). The butenol-

ide was obtained as two isomers: Elution with PE/Et₂O (70:30)

gave the trans isomer 50a as white solid (227 mg, 0.68 mmol,

1

27.6%) m.p. 120 °C. H NMR (400 MHz, CDCl₃): δ ϭ 7.42Ϫ7.14

(m, 10 H, arom. H), 4.79 (d, J ϭ 8.1 Hz, 1 H, H^7a), 3.83 (dq, J ϭ

6.9, 9.1 Hz, 1 H, H⁸), 3.62 (dq, J ϭ 6.9, 9.1 Hz, 1 H, H⁸), 3.35

(ddd, J ϭ 4.0Ϫ8.1Ϫ12.7 Hz, 1 H, H⁷), 3.15 (m, 1 H, H⁴), 2.65 (m,

1 H, H⁵), 2.45 (m, 1 H, H⁴), 2.28 (m, 1 H, H⁶), 1.82 (m, 1 H, H⁶),

1.18 (t, J ϭ 6.9 Hz, 3 H, H⁹) ppm. ¹³C NMR (100 MHz, CDCl₃):

With Complex 49c: 7-Cyclopropyl-3-phenyl-4,5,7,7a-tetrahydro-

δ ϭ 172.5 (C²), 159.5 (C^3a), 142.7 (qC), 129.2 (qC), 129.0Ϫ127.0 furo[2,3-c]pyran-2-one (53c and 54c): The general procedure was fol-

(arom. HC), 126.4 (qC), 85.3 (C^7a), 81.8 (C⁷), 66.3 (C⁸), 41.9 (C⁵), lowed using carbene complex 49c (1.32 g, 3.38 mmol). The butenol-

37.3 (C⁶), 34.1 (C⁴), 15.7 (C⁹) ppm. HRMS [M ϩ 1] calcd. for ide was obtained as two isomers: Elution with PE/Et₂O (70:30)

C₂₂H₂₃O₃: 335.1647; found 335.1652. Further elution with PE/

gave 53c the trans isomer as white solid (521 mg, 1.95 mmol,

57.6%), m.p. 89 °C. H NMR (400 MHz, CDCl₃): δ ϭ 7.51Ϫ7.35

1

Et₂O (60:40) gave the cis isomer 51a as a white solid (118 mg,

1

0.35 mmol, 14.4%). m.p. 92 °C. H NMR (400 MHz, CDCl₃): δ ϭ (m, 5 H, arom. H), 4.66 (d, J ϭ 8.7 Hz, 1 H, H^7a), 4.20 (dd, J ϭ

7.45Ϫ7.18 (m, 10 H, arom. H), 4.89 (d, J ϭ 4.0 Hz, 1 H, H^7a), 4.15 6.6, 11.5 Hz, 1 H, H⁵), 3.28 (ddd, J ϭ 2.0, 11.5, 11.5 Hz, 1 H, H^5Ј),

(m, 1 H, H⁷), 3.58 (m, 2 H, H⁸), 3.19 (m, 1 H, H⁴), 3.10 (m, 1 H, 3.02 (dd, J ϭ 2.0, 13.5 Hz, 1 H, H⁴), 2.78 (ddd, J ϭ 6.6, 11.5,

H⁵), 2.48 (m, 1 H, H^4Ј), 2.17 (m, 1 H, H⁶), 1.84 (m, 1 H, H^6Ј), 1.09 13.5 Hz, 1 H, H^4Ј), 2.63 (dd, J ϭ 7.5, 8.7 Hz, 1 H, H⁷), 1.21 (m, 1

(t, J ϭ 7.0 Hz, 3 H, H⁹) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ

H, H⁸), 0.72Ϫ0.40 (m, 4 H, H⁹and H¹⁰) ppm. ¹³C NMR

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2491

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

(100 MHz, CDCl₃): δ ϭ 171.2 (C²), 159.9 (C^3a), 133.0 (qC), CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.56Ϫ6.80 (m, 15 H,

129.4Ϫ128.7 (arom. HC), 124.0 (qC), 86.7 (C⁷), 80.9 (C^7a), 67.4 arom. H), 4.84 (d, J ϭ 9.4 Hz, 1 H, H^7a), 4.39 (d, J ϭ 9.4 Hz, 1

(C⁵), 29.3 (C⁴), 14.2 (C⁸), 2.2Ϫ2.0 (C⁹or C¹⁰) ppm. HRMS [M ϩ H, H⁷), 4.33 (dd, J ϭ 6.4, 11.0 Hz, 1 H, H⁵), 4.22 (dd, J ϭ 6.4,

1] calcd. for C₁₆H₁₇O₃: 257.1178; found 257.1182. Further elution

11.0 Hz, 1 H, H⁴), 3.69 (dd, J ϭ 11.0, 11.0 Hz, 1 H, H⁵) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ ϭ 172.8 (C²), 160.0 (C^3a), 138.1 (qC),

with PE/Et₂O (80:20) gave the cis isomer 54c. 54c: (31 mg,

0.21 mmol, 6.1%). ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.53Ϫ7.25 134.0 (qC), 129.7Ϫ126.6 (arom. HC), 122.2 (qC), 84.3 (C⁷), 81.7

(m, 5 H, arom. H), 5.09 (d, J ϭ 7.1 Hz, 1 H, H^7a), 3.94 (dd, J ϭ (C^7a), 74.3 (C⁵), 48.2 (C⁴) ppm. HRMS [M ϩ 1] calcd. for

7.6,11.7 Hz, 1 H, H⁵), 3.77 (ddd, J ϭ 2.8, 11.7, 11.7 Hz, 1 H, H^5Ј),

3.62 (dd, J ϭ 7.1, 9.7 Hz, 1 H, H⁷), 3.04 (dd, J ϭ 2.8, 13.5 Hz, 1

H, H⁴), 2.81 (m, 1 H, H^4Ј), 1.18 (m, 1 H, H⁸), 0.80Ϫ0.28 (m, 4 H,

H⁹and H¹⁰) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 175.5 (C²),

157.8 (C^3a), 136.7 (qC), 129.4Ϫ128.7 (arom. HC), 125.3 (qC), 82.7

(C⁷), 78.1 (C^7a), 59.5 (C⁵), 28.9 (C⁴), 14.3 (C⁸), 6.0, 5.6 (C⁹or

C¹⁰) ppm.

C₂₅H₂₁O₃: 369.1491; found 369.1485.

With Complex 49h. 4,5-Dimethyl-3,7-diphenyl-4,5,7,7a-tetrahydro-

furo[2,3-c]pyran-2-one (53h): The general procedure was followed

using carbene complex 49h (830 mg, 1.83 mmol). Elution with PE/

Et₂O (60:40) gave the butenolide 53h as a white solid (310 mg,

0.97 mmol, 52.9%). m.p. 168 °C. ¹H NMR (400 MHz, CDCl₃): δ ϭ

7.51Ϫ7.25 (m, 10 H, arom. H), 4.68 (d, J ϭ 9.2 Hz, 1 H, H^7a), 4.23

(d, J ϭ 9.2 Hz, 1 H, H⁷), 3.41 (dq, J ϭ 6.1, 9.7 Hz, 1 H, H⁵), 2.64

(dq, J ϭ 6.8, 9.7 Hz, 1 H, H⁴), 1.41 (d, J ϭ 6.1 Hz, 3 H, H⁹), 0.90

(d, J ϭ 6.8 Hz, 3 H, H⁸) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ

173.1 (C²), 163.1 (C^3a), 138.2 (qC), 130.7 (qC), 130.2Ϫ126.7 (arom.

HC), 126.0 (qC), 83.9 (C⁷), 82.0 (C^7a), 80.7 (C⁵), 42.8 (C⁴), 19.5

(C⁹), 14.1 (C⁸) ppm. C₂₁H₂₀O₃(320.4): calcd. C 78.73, H 6.29;

found C 78.57, H 6.45.

With Complex 49d. 7-Phenyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-

one (53d): The general procedure was followed using carbene com-

plex 49d (940 mg, 2.68 mmol). Elution with PE/Et₂O (80:20) gave

the butenolide 53d as white solid (365 mg, 1.69 mmol, 63.1%), m.p.

48 °C. ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.48Ϫ7.25 (m, 5 H, arom.

H), 5.93 (s, 1 H, H³), 4.66 (d, J ϭ 8.7 Hz, 1 H, H^7a), 4.42 (ddd,

J ϭ 6.5, 11.1, 11.1 Hz, 1 H, H⁵), 4.05 (d, J ϭ 8.7 Hz, 1 H, H⁷),

3.51 (ddd, J ϭ 2.7, 11.1, 11.1 Hz, 1 H, H^5Ј), 2.86 (dd, J ϭ 2.7,

13.7 Hz, 1 H, H⁴), 2.77 (ddd, J ϭ 6.5, 11.1, 13.7 Hz, 1 H, H^4Ј)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 169.7 (C²), 167.6 (C^3a),

137.8 (qC), 128.7Ϫ128.3 (arom. HC), 126.5 (qC), 113.6 (C³), 85.3

(C⁷), 82.9 (C^7a), 68.1 (C⁵), 30.4 (C⁴) ppm. HRMS [M ϩ 1] calcd.

for C₁₃H₁₃O₃: 217.0865; found 217.0869.

Reaction of N-Benzyldihydropyridine 59 with Complexes 37, 48a

and 48d

1,4-N-Benzyldihydropyridine 59 was synthesised following the lit-

erature procedure.^[44]

With Complex 49g. (4R,7R,7aS)-3,4,7-Triphenyl-4,5,7,7a-tetra-

hydrofuro[2,3-c]pyran-2-one (53g) and (4R,7S,7aR)-3,4,7-Triphenyl-

4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (55g): The general pro-

cedure was followed using carbene complex 49g (820 mg,

1.63 mmol). The butenolide was obtained as two isomers: Elution

with PE/Et₂O (80:20) gave the trans-trans isomer 53g. 53g: Fluor-

escent solid (293 mg, 0.80 mmol, 48.9%), m.p. 97 °C. [α]²_D⁰ϭ 171.43

(c ϭ 2.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.58Ϫ7.25

(m, 15 H, arom. H), 4.96 (d, J ϭ 9.0 Hz, 1 H, H^7a), 4.70 (d, J ϭ

11.7 Hz, 1 H, H⁵), 4.46 (d, J ϭ 3.1 Hz, 1 H, H⁴), 4.26 (d, J ϭ

General Procedure: A solution of N-benzyldihydropyridine (3 mol

equiv.) in CH₂Cl₂(0.5 mL/mmol of amine) was added dropwise

from an addition funnel to a solution of the carbene complex (1

mol equiv.) in CH₂Cl₂(25 mL/mmol of carbene) at Ϫ10 °C, under

argon. After 15 min the ice bath was removed and the mixture

stirred at room temperature for 24 h. The solution slowly turned

dark red. The solvent was evaporated under vacuum and the resi-

due was purified by chromatography on silica gel with mixtures of

PE/Et₂O as eluent.

7

5

9.0 Hz, 1 H, H ), 3.87 (dd, J ϭ 3.1, 11.7 Hz, 1 H, H ) ppm. ¹³C

´

NMR (100 MHz, CDCl₃): δ ϭ 172.2 (C²), 161.2 (C^3a), 139.2 (qC), With Complex 37. 7-Ethoxy-3-phenyl-3,6,7,7a-tetrahydro-4H-benzo-

138.3 (qC), 132.5Ϫ129.0 (arom. HC), 126.9 (qC), 126.2 (qC), 86.0 furan-2-one (38 and 39): The general procedure was followed using

(C⁷), 80.1 (C^7a), 72.7 (C⁵), 44.5 (C⁴) ppm. C₂₅H₂₀O₃(368.4): calcd. carbene complex 7 (1.74 g, 4.44 mmol). Elution with PE/Et₂O

C 81.50, H 5.47; found C 81.33, H 5.36. Further elution with PE/

(20:80) gave the butenolide as two isomers in 43.0% overall yield:

Et₂O (70:30) gave the trans-cis isomer 55g. 55g: Yellow solid trans isomer 38 (394 mg, 1.53 mmol, 34.4%), cis isomer 39 (98 mg,

(515 mg, 0.14 mmol, 8.60%), m.p. 174 °C, [α]²_D⁰ϭ 90.93 (c ϭ 2.0, 0.38 mmol, 8.6%), de ϭ 60%.

2492

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

With Complex 48d. 6-Benzyl-7-ethoxy-3-phenyl-5,6,7,7a-tetrahydro-

of carbene) at Ϫ40 °C, under argon. After 20 min the ice bath was

4H-benzofuran-2-one (50d and 51d): The general procedure was fol-

removed and the mixture stirred at room temperature for 24 h. The

lowed using carbene complex 48d (1.50 g, 3.11 mmol). Elution with solution slowly turned dark red. The solvent was evaporated under

PE/Et₂O (30:70) gave the butenolide as two isomers in 45.0% over-

all yield: trans isomer 50d (205 mg, 0.59 mmol, 21.0%), cis isomer

51d (283 mg, 0.81 mmol, 24.0%), de ϭ 16%.

vacuum and the corresponding butenolides were obtained after sil-

ica gel chromatography using mixtures of PE/Et₂O as eluent.

With Dihydropyridine 64: The general procedure was followed using

complex 49d (410 mg, 1.17 mmol). Elution with PE/Et₂O (80:20)

gave the butenolide 53d (151 mg, 0.70 mmol, 59.7%, de ϭ 100%,

ee ϭ 4.3%).

With Complex 48a. 7-Ethoxy-3,5-diphenyl-5,6,7,7a-tetrahydro-4H-

benzofuran-2-one (50a and 51a): The general procedure was fol-

lowed using carbene complex 48a (1.05 g, 2.24 mmol). Elution with

PE/Et₂O (30:70) gave the butenolide as two isomers in 42.0% global

yield: trans isomer 50a (157 mg, 0.47 mmol, 21.0%), cis isomer 51a

(157 mg, 0.47 mmol, 21.0%), de ϭ 0%.

The general procedure was followed using complex 49e (746 mg,

2.57 mmol). Elution with PE/Et₂O (80:20) gave the butenolide 53e

(247 mg, 1.60 mmol, 62.5%, de ϭ 100%, ee ϭ 1.2%).

The general procedure was followed using complex 49f (1.00 g,

3.18 mmol). Elution with PE/Et₂O (80:20) gave the butenolide 53f

(332 mg, 1.84 mmol, 58.0%, de ϭ 100%, ee ϭ 1.8%).

Reaction of N,N-Diethyl-N-(methyl)dihydronicotinamide 60 with

Complex 49a

Dihydronicotinamide 60^[44]was prepared following the literature

procedure. A solution of nicotinamide 60 (3 mol equiv.) was added

dropwise with a syringe to a solution of carbene complex 49a

(360 mg, 0.84 mmol) in CH₂Cl₂(20 mL) at Ϫ10 °C, under argon.

After 20 min the ice bath was removed and the mixture stirred at

room temperature for 24 h. The solvent was evaporated under vac-

uum and the butenolide 53a was obtained after silica gel chroma-

tography as a white solid (91 mg, 0.31 mmol, 37.0%, de ϭ 100%).

With Dihydropyridine 65: The general procedure was followed using

complex 49d (380 mg, 1.08 mmol). Elution with PE/Et₂O (80:20)

gave the butenolide 53d (167 mg, 0.77 mmol, 71.6%, de ϭ 100%,

ee ϭ 27%).

The general procedure was followed using complex 49e (480 mg,

1.67 mmol). Elution with PE/Et₂O (80:20) gave the butenolide 53e

(171 mg, 1.11 mmol, 66.7%, de ϭ 100%, ee ϭ 11.5%).

The general procedure was followed using complex 49f (500 mg,

1.59 mmol). Elution with PE/Et₂O (80:20) gave the butenolide 53f

(172 mg, 0.95 mmol, 60.0%, de ϭ 100%, ee ϭ 1%).

Reaction of the Chiral Nicotinamides 61, 62, and 63

Dihydronicotinamides 61,^[46a]62,^[46i]63,^[49a,49b]were prepared fol-

lowing the literature procedures

With Dihydropyridine 66: The general procedure was followed using

complex 49d (396 mg, 1.13 mmol). Elution with PE/Et₂O (80:20)

gave the butenolide 53d (165 mg, 0.76 mmol, 67.5.%, de ϭ 100%,

ee ϭ 18.0%).

General Procedure: A solution of the appropriate nicotinamide

(3 mol equiv.) was added dropwise with a syringe to a solution of

carbene complexes 49e or 49d (1 mol equiv.) in CH₂Cl₂(25 mL/

mmol of carbene) at Ϫ40 °C, under argon. After 20 min the ice

bath was removed and the mixture stirred at room temperature for

24 h. The solution slowly turned dark red. The solvent was evapo-

rated under vacuum and the butenolides 53d and 53e were obtained

after silica gel chromatography using mixtures of PE/Et₂O as elu-

ent.

With Dihydropyridine 67: The general procedure was followed using

complex 49d (600 mg, 1.71 mmol). Elution with PE/Et₂O (80:20)

gave the butenolide 53d (94 mg, 0.43 mmol, 25.3%, de ϭ 100%,

ee ϭ 11.0%).

With Dihydropyridine 68: The general procedure was followed using

complex 49e (443 mg, 1.54 mmol). Elution with PE/Et₂O (70:30)

gave the butenolide 53e (118 mg, 0.77 mmol, 50.0%, de ϭ 100%,

ee ϭ 7.6%).

With Nicotinamide 61: The general procedure was followed using

complex 49d (350 mg, 1.00 mmol). Elution with PE/Et₂O (80:20)

gave the butenolide 53d (65 mg, 0.30 mmol, 30.1%, de ϭ 100%,

ee ϭ 20%).

Synthesis of N-Benzyldihydronicotine (71): N-benzylnicotinium bro-

mide (70)^[53]was prepared following the literature procedure. An

aqueous solution (25 mL) of N-benzylnicotinium bromide (70, 5 g,

15 mmol) was added from a dropping funnel to a suspension of

sodium dithionite (15.66 g, 99 mmol) and potassium carbonate

(12.43 g, 90 mmol) in toluene (80 mL) and water (90 mL). The re-

sulting mixture was refluxed for 12 min. The organic phase was

separated, washed with sodium hydrogencarbonate solution and

water, and dried with sodium sulfate. After removal of the solvent,

the N-benzyl-1,4-dihydronicotine (71) was obtained as a yellow oil

in 24% yield (1.04 g, 4.1 mmol). ¹H NMR (200 MHz, CDCl₃): δ ϭ

7.33Ϫ7.14 (m, 5 H, arom. H), 5.8 (m, 2 H, H⁶, H²), 4.46 (m, 1 H,

H⁵), 4.16 (s, 2 H, Bn CH₂), 3.46 (m, 1 H, H^2Ј), 3.05 (m, 2 H, H^5Ј),

2.88 (m, 2 H, H⁴), 2.40Ϫ1.50 (m, 7 H, H⁴Ј, H^3Ј, Me^1Ј) ppm.

The general procedure was followed using complex 49e (734 mg,

2.55 mmol). Elution with PE/Et₂O (70:30) gave the butenolide 53e

(216 mg, 1.40 mmol, 55.0%, de ϭ 100%, ee ϭ 1%).

With Nicotinamide 62: The general procedure was followed using

complex 49d (402 mg, 1.15 mmol). Elution with PE/Et₂O (80:20)

gave the butenolide 53d (32 mg, 0.15 mmol, 13.1%, de ϭ 100%,

ee ϭ 2%).

With Nicotinamide 63: The general procedure was followed using

complex 49e (402 mg, 1.15 mmol). Elution with PE/Et₂O (70:30)

gave the butenolide 53e (20 mg, 0.13 mmol, 15.0%, de ϭ 49%,

ee ϭ 11%).

Reactivion with the Chiral N-Alkyldihydropyridines 64, 65, 66, 67,

and 68

Dihydropyridines 64,^[50a]65,^[50b]66,^[50c]67,^[50b]and 68^[50a]were pre-

pared following the literature procedures.

General Procedure: A solution of the appropriate N-alkyldihydrop-

yridine (3 mol equiv.) was added dropwise with a syringe to a solu-

tion of carbene complexes (1 mol equiv.) in CH₂Cl₂(25 mL/mmol

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2493

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

Synthesis of N-Methyldihydronicotine (73)

Reaction of N-Benzyldihydronicotine (71) with Complex 49e. 7-

Methyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (53e): A solution

Formation of Methyl 3-(1-Methylpyrrolidin-2-yl)-2H-pyridine-1-car-

boxylate (72): A solution of methyl chloroformate (3.80 mL,

49.40 mmol) in Et₂O (16 mL) was added to a mixture of (S)-(Ϫ)-

nicotine (69, 8.00 g, 49.40 mmol) and sodium borohydride (1.88 g,

49.40 mmol) in absolute ethanol (60 mL) at Ϫ78 °C. The tempera-

ture was not allowed to exceed Ϫ70 °C. The reaction mixture was

warmed to Ϫ40 °C and stirred for an additional 1.5 h, then poured

into ice water before being extracted three times with Et₂O

(200 mL). The organic layers were combined, washed with brine

and finally dried with sodium sulfate. The crude oil was purified

by flash chromatography on silica gel using a mixture of PE/EtOAc

(65:35) as eluent. After solvent removal compound 72 was obtained

as a yellow oil in 76% yield (8.36 g, 37.64 mmol).

of N-benzyldihydronicotine (71, 720 mg, 3 mmol) in CH₂Cl₂

(4 mL) was added dropwise from a syringe to a solution of carbene

complex 49e (576 mg, 2 mmol) in CH₂Cl₂(40 mL) at Ϫ40 °C, un-

der argon. After 20 min the ice bath was removed and the mixture

stirred at room temperature for 24 h. The solvent was evaporated

and, after silica gel chromatography, the butenolide 53e was ob-

tained as a colourless oil (157 mg, 1.02 mmol, 51.1%, ee ϭ 4.3%).

Reaction of N-Methyldihydronicotine (73) with Complexes 49a؊f

General Procedure: A solution of N-methyldihydronicotine (73, 3

mol equiv.) was added dropwise from a syringe to a solution of the

appropriate carbene complex (1 mol equiv.) in CH₂Cl₂(25 mL/

mmol of carbene) at Ϫ40 °C, under argon. After 20 min the ice

bath was removed and the mixture stirred at room temperature for

24 h. The solution slowly turned dark red. The solvent was evapo-

rated under vacuum and the expected butenolide was obtained

after silica gel chromatography using mixtures of PE/Et₂O as elu-

ent.

Reaction of Complex 4b with KHB(OiPr)₃and 1-Methylpyridinium

Iodide 74. Complex 75: At 0 °C, 4 mL of potassium triisopropox-

yborohydride solution (0.83  in THF) was added to a solution of

the carbene complex 4b (1.00 g, 2.67 mmol) in 30 mL of THF. The

reaction turned immediately from red to yellow and, after five mi-

nutes, 2 mL of a 10% sodium hydroxide solution in water was ad-

ded in order to destroy the unreacted hydride. Then 1-methylpyridi-

nium iodide (1.18 g, 5.34 mmol) was added leading to the forma-

tion of the tungstenate complex 75 as a red oil (1.31 g, 2.38 mmol,

Mixture of two rotamers A and B (50:50). ¹H NMR (200 MHz,

CDCl₃): δ ϭ 6.73 (d, J ϭ 7.6 Hz, 0.5 H, H^6A), 6.60 (d, J ϭ 7.6 Hz,

0.5 H, H^6B), 5.78 (d, J ϭ 6.0 Hz, 1 H, H⁴), 5.17 (m, 1 H, H⁵), 4.32

(m, 1 H, H²), 4.13 (m, 1 H, H²), 3.76 (s, 3 H, OMe), 3.06 (m, 1 H,

H^5Ј), 2.59 (m, 1 H, H^2Ј), 2.17 (s, 3 H, NMe), 2.16Ϫ2.01 (m, 2 H,

H^2Јand H^5Ј), 1.89Ϫ1.27 (m, 4 H, H^3Јand H^4Ј) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ ϭ 154.8Ϫ153.8 (CϭO), 132.6Ϫ131.3 (qC),

125.6Ϫ124.6 (C⁶), 119.2Ϫ118.2 (C⁴), 105.3Ϫ105.1 (C⁵), 71.2Ϫ70.8

(C^2Ј), 56.8 (C^5Ј), 53.1 (OMe), 40.5 (NMe), 29.8Ϫ29.4 (C^3Ј), 22.7

(C^4Ј) ppm. C₁₂H₁₈N₂O₂(222.3): calcd. C 64.84, H 8.16, N 8.16;

found C 64.67, H 8.35, N 12.57. [α]²_D⁰ϭ Ϫ83.3 (c ϭ 2.33, CHCl₃).

1

89.0%). H NMR (CDCl₃, 400 MHz): δ ϭ 9.12 (d, J ϭ 6.0 Hz, 2

H, H_opy.), 8.72 (t, J ϭ 7.0 Hz, 1 H, H_ppy.), 8.27 (m, 2 H, H_mpy.),

8.00Ϫ7.01 (m, 5 H, arom. H), 5.05 (s, 1 H, H¹), 4.65 (s, 3 H, H⁴),

3.42 (m, 1 H, H²), 3.06 (m, 1 H, H²Ј), 1.15 (t, J ϭ 7.0 Hz, 3 H,

H³) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ ϭ 205.1 (trans CO),

192.4 (cis CO), 146.5Ϫ120.3 (arom. HC and qC), 97.4 (C¹), 67.2

(C²), 49.7 (C⁴), 16.6 (C³) ppm.

Reduction of 72. 1-Methyl-3-(1-methylpyrrolidin-2-yl)-1,2-dihydro-

pyridine (73): An Et₂O solution (25 mL) of methyl 3-(1-methylpyr-

rolidin-2-yl)-2H-pyridine-1-carboxylate (8.35 g, 37.60 mmol) was

added to a suspension of lithium aluminium hydride (2.44 g, 1.7

equiv.) in Et₂O (120 mL) at 0 °C. After the addition the mixture

was refluxed for 24 h. A 10% solution of sodium hydroxide (50 mL)

was added slowly at 0 °C. The mixture was extracted three times

with Et₂O (250 mL), washed with water and brine, and then dried

with sodium sulfate. After removal of the solvent, the N-methyl-

1,2-dihydropyridine 73 was obtained as a yellow oil in 90% yield

Reaction of Complex 4b with N-Methyldihydropyridine (19). Com-

plex 75: A solution of N-methyldihydropyridine (19, 650 mg,

6.80 mmol) in Et₂O (20 mL) was added to a solution of complex

4b (1.00 g, 2.30 mmol) in CH₂Cl₂(10 mL) at Ϫ78 °C. The solution

immediately turned dark red. After warming at 0 °C, the solvent

was evaporated under vacuum to give the tungstenate complex 75

(1.09 g, 1.98 mmol, 86.0% yield).

1

(6.02 g, 33.82 mmol). H NMR (200 MHz, CDCl₃): δ ϭ 5.93 (dd,

J ϭ 0.7, 7.0 Hz, 1 H, H⁶), 5.77 (d, J ϭ 5.5 Hz, 1 H, H⁴), 4.68 (dd,

J ϭ 5.5, 7.0 Hz, 1 H, H⁵), 3.66 (s, 2 H, H²), 3.05 (m, 2 H, H^5Ј),

2.63 (s, 3 H, NMe), 2.58 (m, 1 H, H^2Ј), 2.17Ϫ2.0 (m, 5 H, H^3Јand

NMe), 1.77 (m, 2 H, H^4Ј) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ

138.5 (C⁶), 124.3 (qC), 121.6 (C⁴), 95.2 (C⁵), 72.0 (C^2Ј), 56.9 (C^5Ј),

49.2 (C²), 42.5 (NMe), 40.6 (NMe), 29.0 (C^3Ј), 22.6 (C^4Ј) ppm.

[α]²_D⁰ϭ Ϫ92.6 (c ϭ 2.42, CHCl₃).

Reaction of Complex 49a with KHB(OiPr)₃. 3-Benzylidene-2-phe-

nyltetrahydrofuran (79, 80), 3,7-Diphenyl-4,5,7,7a-tetrahydro-

furo[2,3-c]pyran-2-one (53a) and 4-Phenylbut-3-yn-1-ol: At Ϫ10 °C,

845 µL of potassium triisopropoxyborohydride solution (0.83  in

THF) was added to a solution of the carbene complex 49a (300 mg,

0.70 mmol) in 15 mL of THF. After 10 minutes at 0 °C the reaction

was warmed to room temperature and then stirred for 15 h. After

cooling to 0 °C the unreacted hydride was destroyed by addition

of ice and then the THF was removed on a rotary evaporator. After

extraction with CH₂Cl₂(3 ϫ 10 mL) the combined extracts were

2494

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

washed with water and brine and dried with anhydrous Na₂SO₄.

Chromatography on silica gel with mixtures of PE/Et₂O as eluent

first gave 3-benzylidene-2-phenyltetrahydrofuran 79 and 80 as a

(3.00 mL; 1.50 mmol, 0.5 ) in THF (3 mL) at Ϫ20 °C. The yellow

solution turned red immediately. The mixture was allowed to reach

room temperature and stirred for 24 h. The expected butenolide

clear oil (50 mg, 0.21 mmol, 30.2%) as a mixture of two isomers in 53e was obtained after silica gel chromatography as a mixture of

a 6:4 ratio: one isomer: ¹H NMR (400 MHz, CDCl₃): δ ϭ two isomers in 6:4 ratio in 12.8% yield (29 mg, 0.19 mmol).

7.28Ϫ6.99 (m, 10 H, arom. H), 6.60 (d, J ϭ 1.5 Hz, 1 H, H⁶), 5.68

(s, 1 H, H²), 3.83 (t, J ϭ 6.8 Hz, 2 H, H⁵), 2.95Ϫ2.76 (m, 2 H, H⁴)

Reaction of Complex 49a with Sodium Methoxide. 3,7-Diphenyl-4,5-

ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 142.4 (C³), 140.1 (qC),

dihydrofuro[2,3-c]pyran-2-one (83) and 7-Methoxy-3,7-diphenyl-

137.1 (qC), 128.9Ϫ127.0 (arom. HC), 124.1 (C⁶), 80.8 (C²), 65.5

4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (82): At 0 °C, 66 µL of a

(C⁵), 35.9 (C⁴) ppm. HMRS [M ϩ 1] calcd. for C₁₇H₁₇O 237.1279;

30% MeO^ϪNa^ϩ/MeOH solution was added with a syringe to a

1

found 237.1273. Other isomer: H NMR (400 MHz, CDCl₃): δ ϭ

solution of carbene complex 49a (153 mg; 0.36 mmol) in 15 mL of

7.34Ϫ6.99 (m, 10 H, arom. H), 6.02 (d, J ϭ 2.3 Hz, 1 H, H⁶), 5.68

THF. The solution turned from red to yellow. The resulting mixture

(d, J ϭ 1.5 Hz, 1 H, H²), 4.23 (m, 1 H, H⁵), 3.87 (m, 1 H, H⁵),

was stirred for 10 minutes at 0 °C and then warmed to room tem-

2.96Ϫ2.92 (m, 2 H, H⁴) ppm. ¹³C NMR(100 MHz, CDCl₃): δ ϭ

perature and stirred for 15 h. Removal of the solvent left a brown-

144.7 (C³), 141.9 (qC), 137.9 (qC), 128.8Ϫ127.1 (arom. HC), 123.2

ish residue that was purified by silica gel chromatography with vari-

(C⁶), 85.3 (C²), 68.4 (C⁵), 32.2 (C⁴) ppm.

ous mixtures of PE/Et₂O as eluent. Two butenolides 83 and 82 were

obtained. 83: (8 mg, 0.03 mmol, 7.7%), white solid, m.p. 119 °C.

Further elution gave the butenolide 53a in 20.9% yield as a single

¹H NMR (400 MHz, CDCl₃): δ ϭ 8.05Ϫ7.34 (m, 10 H, arom. H),

trans isomer. Finally, the alcohol 4-phenylbut-3-yn-1-ol was ob-

4.42 (t, J ϭ 6.3 Hz, 2 H, H⁵), 3.19 (t, J ϭ 6.3 Hz, 2 H, H⁴) ppm.

tained as a colourless oil (33 mg, 0.22 mmol, 32.1%).

¹³C NMR (100 MHz, CDCl₃): δ ϭ 169.0 (C²), 143.4 (C^7a), 141.5

(qC), 135.2 (C⁷), 130.9Ϫ127.9 (arom. HC and qC), 116.6 (C³), 67.1

(C⁵), 24.7 (C⁴) ppm. HMRS [M ϩ 1] calcd. for C₁₉H₁₅O₃291.1021;

found 291.1013. 82: (25 mg, 0.08 mmol, 21.6%). ¹H NMR

(400 MHz, CDCl₃): δ ϭ 7.71Ϫ7.37 (m, 10 H, arom. H), 4.88 (s, 1

H, H^7a), 4.11 (dd, J ϭ 6.6, 7.4 Hz, 1 H, H⁵), 3.76 (dd, J ϭ 3.4,

11.7 Hz, 1 H, H⁵), 3.13Ϫ2.78 (m, 2 H, H⁴), 2.96 (s, 3 H, H⁸) ppm.

¹³C NMR (100 MHz, CDCl₃): δ ϭ 172.5 (C²), 156.3 (C^3a), 137.5

(C³), 130.8Ϫ125.0 (arom. CH and qC), 101.1 (C⁷), 82.8 (C^7a), 59.8

(C⁵), 49.8 (C⁸), 28.3 (C⁴) ppm.

Reaction of Carbene Complex 49e with NaBH₄. 7-Methyl-4,5,7,7a-

tetrahydrofuro[2,3-c]pyran-2-one( 53e): Sodium borohydride (7 mg;

0.25 equiv.) was added in portions to a solution of carbene complex

49e (199 mg; 0.69 mmol) in THF (10 mL) at Ϫ20 °C. The reaction

mixture was slowly warmed to room temperature and stirred for

12 h. The starting material was completely reduced after 5 minutes

(TLC monitoring). Addition of 2 mL of water followed by extrac-

tion with CH₂Cl₂(3 ϫ 15 mL), followed by drying over anhydrous

sodium sulfate and evaporation of the solvents gave a brown resi-

due. Silica gel chromatography gave the butenolide as a yellow oil

and as two isomers in 7:3 ratio in 22.4% global yield (23.8 mg,

0.15 mmol). trans Isomer 49e: ¹H NMR (400 MHz, CDCl₃): δ ϭ

5.81 (s, 1 H, H³), 4.30 (d, J ϭ 8.6 Hz, 1 H, H^7a), 4.21 (dd, J ϭ

6.7Ϫ11.3 Hz, 1 H, H⁵), 3.31 (ddd, J ϭ 2.6, 11.3, 11.3 Hz, 1 H, H^5Ј),

3.11 (dq, J ϭ 6.1, 8.6 Hz, 1 H, H⁷), 2.78 (dd, J ϭ 2.9, 13.6 Hz, 1

H, H⁴), 2.65 (m, 1 H, H^4Ј) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ ϭ 169.9 (C²), 168.0 (C^3a), 112.7 (C³), 83.2 (C⁷), 80.1 (C^7a), 67.6

(C⁵), 30.2 (C⁴), 19.3 (C⁸) ppm. C₈H₁₀O₃(154.2): calcd. C 62.33, H

1

6.54; found C 62.42, H 6.56. cis Isomer 53eЈ: H NMR (200 MHz,

CDCl₃): δ ϭ 5.85 (s, 1 H, H³), 4.96 (d, J ϭ 7.1 Hz, 1 H, H^7a), 4.66

(m, 1 H, H⁵), 3.88 (m, 1 H, H^5Ј), 3.55 (dt, J ϭ 3.6, 9.3 Hz, 1 H,

H⁴), 2.80Ϫ2.50 (m, 2 H, H⁴and H⁷), 1.00 (d, J ϭ 6.4 Hz, 3 H, C⁸)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 173.1 (C²), 168.1 (C^3a),

114.1 (C³), 79.3 (C⁷), 72.8 (C^7a), 58.9 (C⁵), 29.7 (C⁴), 19.9 (C⁸) ppm.

Reaction of Complex 11b with Sodium Phenylbutynolate. 3,7-Di-

phenyl-4,5-dihydrofuro[2,3-c]pyran-2-one (83) and 7-Ethoxy-3,7-di-

phenyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (84): A solution of

4-phenylbut-3-yn-1-ol (255 mg, 1.75 mmol, 1.1 equiv.) in THF

(10 mL) was added to a suspension of NaH (210 mg, 60% oil,

5.25 mmol, 3.3 equiv.) in THF (15 mL) and the mixture was stirred

at room temperature for 1 h. The resulting solution was transferred

with a cannula to a solution of carbene complex 11b (518 mg,

1.59 mmol, 1 equiv.) in THF (15 mL) at Ϫ40 °C. The mixture was

stirred for 20 minutes at this temperature then warmed to room

temperature and stirred for 15 h. Removal of the solvent left a

brownish residue that was purified by silica gel chromatography. 83

(116 mg, 0.397 mmol, 25%) and 84 (134 mg, 0.397 mmol, 25%)

were obtained. 84 as a white solid, m.p. 150 °C. ¹H NMR

(200 MHz, CDCl₃): δ ϭ 7.72Ϫ7.36 (m, 10 H, arom. H), 4.66 (s, 1

H, H^7a), 4.11 (dd, J ϭ 5.5, 11.7 Hz, 1 H, H⁵), 3.78 (dd, J ϭ 2.9,

11.8 Hz, 1 H, H⁵), 3.28Ϫ3.06 (m, 3 H, H⁴and H⁸), 2.81 (m, 1 H,

H⁴), 1.06 (t, 3 H, H⁹) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 172.6

(C²), 156.3 (C^3a), 138.6 (C³), 129.7Ϫ125.5 (arom. HC and

Reaction of Carbene Complex 49e with KHB(OiPr)₃. 7-Methyl-

4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (53e): At Ϫ10 °C,

1.46 mL of potassium triisopropoxyborohydride solution (0.83  in

THF) was added to a solution of the carbene complex 49e (349 mg,

1.21 mmol) in 15 mL of THF. After 10 minutes at 0 °C the reaction

was warmed to room temperature and then stirred for 15 h. After

cooling to 0 °C, the unreacted hydride was destroyed by addition

of ice and then THF was removed on a rotary evaporator. After

extraction with CH₂Cl₂(3 ϫ 10 mL) the combined extracts were

washed with water and brine and dried with anhydrous Na₂SO₄.

Chromatography on silica gel gave the butenolide 53e as a mixture

of two isomers (trans/cis: 90:10) in 12.5% yield (23 mg, 0.15 mmol).

Reaction of Carbene Complex 49e with 9-BBN and (S)-(؊) Nicotine.

7-Methyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one 53e: A solution qC), 100.8 (C⁷), 82.8 (C^7a), 59.7 (C⁵), 57.6 (C⁸), 28.3 (C⁴), 14.7 (C⁹)

of complex 49e (425 mg, 1.47 mmol) in THF (5 mL) was added to ppm. HMRS [M ϩ 1] calcd. for C₂₁H₂₁O₄337.1440; found

a mixture of (S)-(Ϫ)nicotine 69 (243 mg, 1.5 mmol) and 9-BBN 337.1437.

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2495

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

5.08 (s, 1 H, H^7a), 4.00 (ddd, J ϭ 2.5, 6.2, 11.7 Hz, 1 H, H⁵), 3.64

(ddd, J ϭ 5.5, 9.7, 11.7 Hz, 1 H, H⁵), 2.98Ϫ2.88 (m, 2 H, H⁴), 1.81

(s, 3 H, H⁸). ¹³C NMR (50 MHz, CDCl₃): δ ϭ 172.4 (C²), 158.3

(C^3a), 139.6 (qC), 129.3Ϫ124.8 (arom. HC and qC), 85.1 (C^7a), 80.7

(C⁷), 60.8 (C⁵), 32.6 (C⁸), 28.1 (C⁴) ppm. C₂₀H₁₈O₃(306.4): calcd.

C 78.41, H 5.92; found C 78.51, H 6.05.

Reaction of Complex 49a with Sodium Phenylbutynolate. 3,7-Di-

phenyl-7-(4-phenylbut-3-ynyloxy)-4,5,7,7a-tetrahydrofuro[2,3-c]-

pyran-2-one (85): A solution of 4-phenylbut-3-yn-1-ol (188 mg,

1.29 mmol, 1.1 equiv.) in THF (10 mL) was added to a suspension

of NaH (154 mg, 60% oil, 3.9 mmol, 3.3 equiv.) in THF (15 mL)

and the mixture was stirred for 1 hour at room temperature. The

resulting solution was transferred with a cannula to a solution of

carbene complex 49a (500 mg, 1.17 mmol, 1 equiv.) in THF

(15 mL) at Ϫ40 °C. The mixture was stirred for 20 minutes at this

temperature then warmed to room temperature and stirred for 15

h. Removal of the solvent left a brownish residue that was purified

by silica gel chromatography. Two butenolides were obtained: 83

(100 mg, 0.345 mmol, 29%) and 85 (44 mg, 0.101 mmol, 9%) as a

white solid, m.p. 142 °C. ¹H NMR (400 MHz, CDCl₃): δ ϭ

7.7Ϫ7.1 (m, 15 H, arom. H), 4.7 (s, 1 H, H^7a), 4.1 (m, 2 H, H⁵),

3.4 (ddd, J ϭ 6, 9, 9 Hz, 1 H, H^1Ј), 3.2 (dq, J ϭ 5, 6.5, 9 Hz, 1 H,

H^1Ј), 3.0 (dd, J ϭ 2.8, 13.5 Hz, 1 H, H⁴), 2.8 (ddd, J ϭ 7.5, 11.5,

13.5 Hz, 1 H, H⁴), 2.6 (m, 1 H, H^2Ј) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 172.7 (C²), 156.2 (C^3a), 138 (Cq), 131.5Ϫ123.4 (arom.

and qC), 100.6 (C⁷), 86.9 (C^3Ј), 82.7 (C^7a), 81.6 (C^4Ј), 60.3 (C^1Ј),

60.0 (C⁵), 28.3 (C⁴), 20.4 (C^2Ј) ppm. C₂₉H₂₅O₄(437.5): calcd. C

79.8, H 5.54; found C79.4, H 5.73.

Reaction of MeLi with Carbene Complex 49a. 7-Methyl-3,7-di-

phenyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (86a) and 7a-

Hydroxy-7-methyl-3,7-diphenyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-

2-one (88): Methyllithium (1.6 , 1.23 mL, 1.97 mmol, 1.05 equiv.)

was added with a syringe to a solution of carbene complex 49a

(800 mg, 1.87 mmol) in THF (30 mL) at Ϫ40 °C, under an argon.

After 30 minutes the ice bath was removed and the mixture was

stirred at room temperature for 24 h. The solvent was evaporated

under vacuum and the residue was purified by chromatography on

silica gel with mixture of EP/Et₂O as eluent. The butenolide 86a

(107 mg, 0.35 mmol, 19%), then 88 (120 mg, 0.37 mmol, 20%) as a

white solid, m.p. 119 °C. ¹H NMR (400 MHz, CDCl₃): δ ϭ

7.8Ϫ7.4 (m, 10 H, arom. H), 4.2 (ddd, J ϭ 11.3, 6.5, 1.8 Hz, 1 H,

H⁵), 3.9 (dt, J ϭ 11.3, 4 Hz, 1 H, H^5Ј), 3.2 (s, 1 H, OH), 3.1Ϫ3 (m,

2 H, H⁴), 1.6 (s, 3 H, Me) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ

170.2 (C²), 155.8 (C^3a), 139.5 (qC), 128.9Ϫ126.6 (arom. HC and

qC), 102.1 (C^7a), 82.7 (C⁷), 60.6 (C⁵), 26.9 (C⁴), 19.8 (Me) ppm.

HRMS [M ϩ 1] calcd. for C₂₀H₁₉O₄: 323.1283, found 323.1279.

Reaction of MeLi with Carbene Complex 49a. 7-Methyl-3,7-di-

phenyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (86a, 87a): Meth-

yllithium (520 µL, 1.6 , 0.82 mmol) was added with a syringe to

a solution of carbene complex 49a (350 mg, 0.82 mmol) in THF

(20 mL) at Ϫ40 °C and the resulting mixture was stirred for 30

minutes at this temperature before being allowed to reach room

temperature. After 12 h, the solution was hydrolysed with aqueous

10% HCl and then extracted three times with CH₂Cl₂. The organic

layers were combined, washed with brine and finally dried with

sodium sulfate. The residue was purified by thin layer chromatogra-

phy (elution with 10% EtOAc/cyclohexane) and the butenolide was

obtained as two isomers (de ϭ 22%). 86a (100 mg, 0.33 mmol,

40.2%) as a white solid, m.p. 132 °C. ¹H NMR (400 MHz, CDCl₃):

δ ϭ 7.74Ϫ7.35 (m, 10 H, arom. H), 4.96 (s, 1 H, H^7a), 4.21 (dd,

J ϭ 7.6, 11.7 Hz, 1 H, H⁵), 3.82 (dd, J ϭ 3.5, 11.7 Hz, 1 H, H⁵),

Reaction of MeLi with Carbene Complex 49a under O₂. 7a-

Hydroxy-7-methyl-3,7-diphenyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-

2-one (88): Methyllithium (l.4 mL, 1.6 , 2.24 mmol) was added

with a syringe to a solution of carbene complex 49a (804 mg,

1.89 mmol) in THF (30 mL) cooled to Ϫ40 °C and the resulting

mixture was stirred for 30 minutes at this temperature before being

allowed to reach room temperature. The flask was purged with O₂

and the solution stirred for 12 h. Silica gel was introduced and the

solvent was evaporated under reduced pressure. The residue was

purified by chromatography (elution EP/Et₂O). The lactonol 88

(89 mg, 0.28 mmol, 14.5%) was obtained.

Reaction of MeLi with Carbene Complex 49h. 4,5,7-Trimethyl-3,7-

3.12 (dd, J ϭ 3.5, 14.2 Hz, 1 H, H⁴), 2.87 (ddd, J ϭ 7.6, 11.7, diphenyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (89, 90). 7a-

14.2 Hz, 1 H, H⁴), 1.40 (s, 3 H, H⁸) ppm. ¹³C NMR (100 MHz, Hydroxy-4,5,7-trimethyl-3,7-diphenyl-4,5,7,7a-tetrahydrofuro[2,3-c]-

CDCl₃): δ ϭ 172.4 (C²), 158.2 (C^3a), 145.5 (qC), 129.4Ϫ124.9 pyran-2-one (91, 92): Methyllithium (1.4 mL, 1.6 , 2.22 mmol) was

(arom. HC and qC), 83.2 (C^7a), 80.5 (C⁷), 60.1 (C⁵), 28.7 (C⁴), 17.5

added with a syringe to a solution of carbene complex 49h (839 mg,

(C⁸) ppm. C₂₀H₁₈O₃: calcd. C 78.41, H 5.92; found C 78.44, H 1.82 mmol) in THF (30 mL) at Ϫ40 °C. After 30 minutes the ice

5.89. 87a (65 mg, 0.21 mmol, 25.6%) as a white solid, m.p. 119 °C.

¹H NMR (400 MHz, CDCl₃): δ ϭ 7.72Ϫ7.23 (m, 10 H, arom. H),

bath was removed and the mixture stirred at room temperature.

After 24 h, silica gel was added to the flask and the solvent was

2496

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

evaporated under reduced pressure. The residue was purified by

chromatography (elution EP/Et₂O) and the butenolide was ob-

1 H, H^8Ј), 1.02 (m, 3 H, H⁹, H^9Ј, H¹⁰), 0.78 (m, 1 H, H^10Ј), 0.67 (t,

J ϭ 7.5 Hz, 3 H, CH₃) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ

tained as two isomers (de ϭ 8%). 89 (136 mg, 0.41 mmol, 22%) as 172.5 (C²), 158.2 (C^3a), 143.7 (qC), 129.5Ϫ125.2 (arom. HC and

a white solid, m.p. 168 °C. ¹H NMR (400 MHz, CDCl₃): δ ϭ qC), 84.1 (C^7a), 82.3 (C⁷), 58.8 (C⁵), 28.7 (C⁴), 27.1 (C⁸), 23.3 (C¹⁰),

7.6Ϫ7.2 (m, 10 H, arom. H), 5.3 (d, J ϭ 1.3 Hz, 1 H, H^7a), 3.5 (dq, 22.8 (C⁹), 14.1 (CH₃) ppm. HRMS [M ϩ 1] calcd. for C₂₃H₂₅O₃:

J ϭ 6, 9.6 Hz, 1 H, H⁵), 3.1 (dq, J ϭ 7, 9.6 Hz, 1 H, H⁴), 1.4 (d,

J ϭ 6 Hz, 3 H, Me⁵), 1.3 (s, J ϭ 6 Hz, 3 H, Me⁷), 1.1 (d, J ϭ 7 Hz,

3 H, Me⁴) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 173.4 (C²),

164.8 (C^3a), 146.4 (qC), 133.9Ϫ124.7 (arom. HC and qC), 82.0

(C^7a), 81.5 (C⁷), 73.1 (C⁵), 40.6 (C⁴), 25.6 (Me⁷), 19.4 (Me⁵), 15.7

(Me⁴) ppm. HRMS [M ϩ 1] calcd. for C₂₂H₂₃O₃: 335.1647,

found 335.1643.

349.1804, found 349.1801.

90: (159 mg, 0.48 mmol, 26%) as a white solid, m.p. 146 °C. ¹H

NMR (400 MHz, CDCl₃): δ ϭ 7.7Ϫ7.3 (m, 10 H, arom. H), 4.8 (s,

1 H, H^7a), 3.6 (dq, J ϭ 9.4, 5.8 Hz, 1 H, H⁵), 2.5 (dq, J ϭ 9.4,

6.8 Hz, 1 H, H⁴), 1.42 (s, 3 H, Me⁷), 1.40 (d, J ϭ 5.8 Hz, 3 H,

Me⁵), 0.90 (d, J ϭ 6.8 Hz, 3 H, Me⁴) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ ϭ 173.6 (C²), 161.7 (C^3a), 145.5 (qC), 130.2Ϫ125.0

(arom. HC and qC), 84.0 (C^7a), 79.7 (C⁷), 72.6 (C⁵), 42.5 (C⁴),

19.8 (Me⁵), 17.9 (Me⁷) 14.1 (Me⁴) ppm. Further elution furnished

lactonol as two isomers (de ϭ 20%). 91: (24 mg, 0.068 mmol, 3.7%)

Reaction of (Trimethylsilylmethyl)lithium with Carbene Complex

49a.

3,7-Diphenyl-7-trimethylsilylmethyl-4,5,7,7a-tetrahydrofuro-

[2,3-c]pyran-2-one (86d, 87d): Butyllithium (2.34µL, 1 , 4.4 mmol)

was added with a syringe to a solution of carbene complex 49a

(500 mg, 1.17 mmol) in THF (30 mL) at Ϫ40 °C. After 30 min the

ice bath was removed and the mixture stirred at room temperature

for 24 h. The solution was hydrolysed with aqueous 10% HCl and

extracted three times with CH₂Cl₂. The organic layers were com-

bined, washed with brine and finally dried with sodium sulfate. The

solvent was evaporated under vacuum and the residue was purified

by chromatography on silica gel with mixture of EP/Et₂O as eluent.

The butenolide was obtained as a mixture of isomers 86d and 87d

(de Ͼ 90%). 86d trans isomer (151 mg, 0.4 mmol, 34%), as a yellow

solid, m.p. 97 °C. ¹H NMR (400 MHz, CDCl₃): δ ϭ 7.70Ϫ7.29 (m,

10 H, arom. H), 4.69 (s, 1 H, H^7a), 4.14 (dd, J ϭ 7.0, 11.7 Hz, 1

H, H⁵), 3.68 (dt, J ϭ 3.0, 11.7 Hz, 1 H, H^5Ј), 3.06 (dd, J ϭ 3.0,

13.5 Hz, 1 H, H⁴) 2.80 (ddd, J ϭ 7.0, 11.7, 13.5 Hz, 1 H, H^4Ј), 1.27

(d, J ϭ 16 Hz, 1 H, H⁸), 1.1 (d, J ϭ 16 Hz, 1 H, H^8Ј), Ϫ0.3 (s, 9

H, 3 CH₃) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 172.6 (C²), 157.9

(C^3a), 145.2 (qC), 129.6Ϫ125.1 (arom. HC and qC), 84.7 (C^7a), 83.1

(C⁷), 60.1 (C⁵), 28.7 (C⁴), 16.5 (C⁸), Ϫ0.34 (3 CH₃) ppm. HRMS

[M ϩ 1] calcd. for C₂₃H₂₇O₃Si: 379.1716, found 379.1718.

1

as a white solid, m.p. 140 °C. H NMR (400 MHz, CDCl₃): δ ϭ

7.7Ϫ7.3 (m, 10 H, arom. H), 4.1 (dq, J ϭ 9.5, 6 Hz, 1 H, H⁵), 3.4

(s, 1 H, OH), 3.0 (dq, J ϭ 9.5, 7 Hz, 1 H, H⁴) 1.46 (s, 3 H, Me⁷),

1.42 (d, J ϭ 6 Hz, 3 H, Me⁵), 1.2 (d, J ϭ 7 Hz, 3 H, Me⁴) ppm.

¹³C NMR (50 MHz, CDCl₃): δ ϭ 170.8 (C²), 161.0 (C^3a), 140.0

(qC), 129.5Ϫ125.6 (arom. HC and qC), 103.0 (C^7a), 84.6 (C⁷), 72.5

(C⁵), 40.1 (C⁴), 27.9 (Me⁷), 19.5 (Me⁵), 16.2 (Me⁴) ppm. 92: (16 mg,

0.046 mmol, 2.5%) as an oil. ¹H NMR (400 MHz, CDCl₃): δ ϭ

7.8Ϫ7.3 (m, 10 H, arom. H), 3.8 (dq, J ϭ 9.5, 6 Hz, 1 H, H⁵), 3.2

(s, 1 H, OH), 2.8 (dq, J ϭ 9.5, 7 Hz, 1 H, H⁴) 1.6 (s, 3 H, Me⁷),

1.43 (d, J ϭ 6 Hz, 3 H, Me⁵), 0.90 (d, J ϭ 7 Hz, 3 H, Me⁴) ppm.

¹³C NMR (50 MHz, CDCl₃): δ ϭ 171.3 (C²), 159.8 (C^3a), 139.6

(qC), 130.1Ϫ126.7 (arom. HC and qC), 102.8 (C^7a), 82.0 (C⁷), 73.1

(C⁵), 40.3 (C⁴), 20.4 (Me⁷), 19.7 (Me⁵) 13.8 (Me⁴) ppm.

Reaction of BuLi with Carbene Complex 49a. 7-Butyl-3,7-diphenyl-

4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (86c, 87c): Butyllithium

(470 µL, 2.5 , 1.17 mmol) was added with a syringe to a solution

of carbene complex 49a (500 mg, 1.17 mmol) in THF (30 mL) co-

oled to Ϫ40 °C and the resulting mixture was stirred for 30 minutes

at this temperature before being allowed to reach room tempera-

ture. After 24 h, the solution was hydrolysed with aqueous 10%

HCl and then extracted three times with CH₂Cl₂. The organic lay-

ers were combined, washed with brine and finally dried with so-

dium sulfate. The solvent was evaporated under reduced pressure

and the residue was purified by chromatography (elution EP/Et₂O).

The butenolide was obtained as two isomers 86c and 87c (de Ͼ

90%). 86c trans isomer, viscous oil (173 mg, 0.5 mmol, 43%). ¹H

NMR (400 MHz, CDCl₃): δ ϭ 7.61Ϫ7.16 (m, 10 H, arom. H), 4.73

(s, 1 H, H^7a), 4.08 (dd, J ϭ 7.6, 11.7 Hz, 1 H, H⁵), 3.54 (dt, J ϭ

Reaction of Ethyllithium with Carbene Complex 49a. 7-Ethyl-3,7-

diphenyl-4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (86b, 87b) and

53a: Ethyllithium (282 µL, 0.5 , 2.8 mmol, 2 equiv.) was added

with a syringe to a solution of carbene complex 49a (600 mg,

1.4 mmol) in THF (25 mL) at Ϫ40 °C, under argon. After 30 min

3.0, 11.7 Hz, 1 H, H^5Ј), 3.01 (dd, J ϭ 3.0, 14.2 Hz, 1 H, H⁴), 2.76 the ice bath was removed and the mixture stirred at room tempera-

(ddd, J ϭ 7.6, 11.7, 14.2 Hz, 1 H, H^4Ј), 1.72 (m, 1 H, H⁸), 1.6 (m,

ture for 24 h. The solvent was evaporated under vacuum and the

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2497

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

residue was purified by chromatography on silica gel with mixtures

Formation of Butenolides 93. 7-Ethyl-7a-hydroxy-3,7-diphenyl-

of EP/Et₂O as eluent. Two butenolides 86b and 87b (de Ͼ90%) 4,5,7,7a-tetrahydrofuro[2,3-c]pyran-2-one (93) and 53a: The general

were obtained. 86b (113 mg, 0.35 mmol, 25%) as a white solid, m.p.

127 °C. ¹H NMR (200 MHz, CDCl₃): δ ϭ 7.7Ϫ7.3 (m, 10 H, arom.

procedure was followed using carbene 49a (300 mg, 0.704 mmol)

and 1.2 equivalents of ethylmagnesium bromide (0.845 mmol, 282

H), 4.8 (s, 1 H, H^7a), 4.15 (ddd, J ϭ 0.9, 6.5, 11.5 Hz, 1 H, H⁵), µL). Butenolide 53a was obtained (5 mg, 0.017 mmol, 2%) then 93

3.6 (dt, J ϭ 3, 11.5 Hz, 1 H, H⁵), 3.1 (dd, J ϭ 3, 14 Hz, 1 H, H⁴),

(21 mg, 0.062 mmol, 9%) as a white solid, m.p. 138 °C. H NMR

1

2.85 (m, 1 H, H⁴), 1.8 (m, 2 H, H⁸), 0.6 (t, J ϭ 7 Hz, 3 H,H⁹ppm. (200 MHz, CDCl₃): δ : 7.5Ϫ7.2 (m, 10 H, arom. H), 4.2 (ddd, J ϭ

¹³C NMR (50 MHz, CDCl₃): δ ϭ 172.5 (C²), 158.2 (C^3a), 143.3 0.7, 3.2, 4 Hz, 1 H, H⁵), 3.7 (dt, J ϭ 2, 5 Hz, 1 H, H⁵), 3.2 (s, 1 H,

(qC), 129.5Ϫ124.4 (arom. HC and qC), 84 (C^7a), 82.5 (C⁷), 59.7 OH), 3 (m, 2 H, H⁴), 2 (m, 1 H, H⁸), 1.9 (m, 1 H, H⁸), 0.5 (t, J ϭ

(C⁵), 28.7 (C⁴), 20.3 (C⁸), 5.5 (C⁹) ppm. HRMS [M ϩ 1] calcd. for 3.5 Hz, 3 H, H⁹) ppm. ¹³C NMR (50 MHz, CDCl₃): δ ϭ 170.2

C₂₁H₂₁O₃: 321.1491; found 321.1486. And 53a (40 mg,

0.14 mmol, 10%).

(C²), 156.2 (C^3a), 137.3 (qC), 128.9Ϫ126.8 (arom. HC and qC),

102.2 (C^7a), 85.3 (C⁷), 60.1 (C⁵), 26.8 (C⁴), 22.5 (C⁸), 6.1 (C⁹) ppm.

HRMS [M ϩ 1] calcd. for C₂₁H₂₁O₄: 337.1440; found 337.1442.

Reaction of Phenylpentynyllithium with Carbene Complex 95. 3-Phe-

nyl-7-(o-tolyl)-5,6-dihydro-4H-benzofuran-2-one (96): At Ϫ78 °C,

2.6 mL of tert-butyllithium solution (1.6 , 4.4 mmol, 3 equiv.) was

added to a solution of (5-iodo-pent-1-ynyl) benzene (600 mg, 2.2

mmol, 1.5 equiv.) in pentane (19 mL) and diethyl ether (10 mL).

The mixture was stirred for 15 min and was then transferred with

a cannula into a solution of carbene complex (500 mg, 1.47 mmol)

in diethyl ether (20 mL) at Ϫ78 °C. The mixture first became clear

red then gradually deep purple. After 1Ϫ2 h, the mixture was al-

lowed to reach room temperature and stirred for 12 h. After hy-

drolysis and extraction with dichloromethane, the residue was puri-

fied by thin layer chromatography (elution with 10% EtOAc/cyclo-

hexane): the UV fluorescent stripe under the unreactive carbene

complex furnished 96 (70 mg, 0.231 mmol, 16%) as an oil. ¹H

NMR (200 MHz, CDCl₃): δ ϭ 7.69Ϫ7.20 (m, 10 H, arom. H), 2.93

(t, J ϭ 6 Hz, 2 H, H⁴or H⁶), 2.61 (t, J ϭ 6 Hz, 2 H, H⁴or H⁶), 2.23

(s, 3 H, CH₃), 1.97 (qt, J ϭ 6 Hz, 2 H, H⁵) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ ϭ 169.3 (C²), 148.0 (C^7a), 145.1 (qC),

136.4Ϫ125.7 (arom. HC and qC), 124.5 (C³), 121.2 (C⁷), 30.6 (C⁴),

24.6 (C⁶), 23.4 (C⁵), 20.3 (CH₃) ppm. HRMS [M ϩ 1] calcd. for

C₂₁H₁₉O₂: 303.1385, found 303.1384.

Formation of Butenolides 93 and 7,7a-Diethyl-3,7-diphenyl-4,5,7,7a-

tetrahydrofuro[2,3-c]pyran-2-one (94): The general procedure was

followed using carbene 49a (655 mg, 1.54 mmol) and two equiva-

lents of ethylmagnesium bromide (3.08 mmol, 1.03 mL). Butenol-

1

ide 94 (79 mg, 0.23 mmol, 15%) was obtained as an oil. H NMR

(400 MHz, CDCl₃): δ ϭ 7.5Ϫ7.2 (m, 10 H, arom. H), 4.5 (q, J ϭ

8 Hz, 1 H, H⁵), 4.1 (dt, J ϭ 3, 11 Hz, 1 H, H⁵), 2.9 (m, 1 H, H⁴),

2.4 (ddd, J ϭ 3, 8, 12.4 Hz, 1 H, H⁴), 2.2 (m, 1 H, H⁸or H¹⁰), 2.1

(m, 1 H, H⁸or H¹⁰), 1.4 (m, 1 H, H⁸or H¹⁰), 1.2 (m, 1 H, H⁸or

H¹⁰), 1.0 (t, J ϭ 7.5 Hz, 3 H, H⁹or H¹¹), 0.4 (t, J ϭ 7.5 Hz, 3 H,

H⁹or H¹¹) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 177.6 (C²),

155.2 (C^3a), 139.3 (qC), 130.0Ϫ125.5 (arom. HC and qC), 113.9

(C^7a), 90.3 (C⁷), 64.5 (C⁵), 33.0 (C⁴), 29.7 (C¹⁰) 19.7 (C⁸), 11.5 (C¹¹),

7.4 (C⁹) ppm. HRMS [M ϩ 1] calcd. for C₂₃H₂₅O₃: 349.1804;

found 349.1800. Then 93 (23 mg, 0.07 mmol, 5%).

Reaction of Methylmagnesium Bromide with Complex 49a: Methyl-

magnesium bromide (3  in diethyl ether, 2.8 mmol, 950 µL) was

added with a syringe to a solution of carbene complex 49a (600 mg,

1.4 mmol) in THF (25 mL) at Ϫ40 °C, under argon. After 20 min

the ice bath was removed and the mixture stirred at room tempera-

ture for 24 h. The solution was hydrolysed with a saturated solution

of NH₄Cl and extracted three times with CH₂Cl₂. The organic lay-

ers were combined, washed with brine and finally dried with so-

dium sulfate. The solvent was evaporated under vacuum and the

Reaction of Ethylmagnesium Bromide with Carbene Complex 49a

General Procedure: Ethylmagnesium bromide (3  in diethyl ether,

x mol equiv.) was added with a syringe to a solution of carbene

complex 49a (1 mol equiv.) in THF (25 mL/mmol) at Ϫ40 °C, un-

der argon. After 20 min the ice bath was removed and the mixture

stirred at room temperature for 24 h. The solution was hydrolysed

with a saturated solution of NH₄Cl and extracted three times with

CH₂Cl₂. The organic layers were combined, washed with brine and residue was purified by chromatography on silica gel with mixture

finally dried with sodium sulfate. The solvent was evaporated under

vacuum and the residue was purified by chromatography on silica

gel with mixture of EP/Et₂O as eluent.

of EP/Et₂O as eluent and the butenolide was obtained as two iso-

mers (de ϭ 46%) 86a (93 mg, 0.3 mmol, 22%) and 87a (33 mg,

0.10 mmol, 8%).

2498

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Interaction of Dihydropyridines and Nucleophiles with Carbene Complexes of Chromium

FULL PAPER

Reaction of Sodium Phenylthiolate with Complex 49a. Formation of

98a: Thiophenol (0.2 mL, 2 equiv.) was added with a syringe to a

suspension of sodium hydride (80 mg, 60% oil, 1.64 mmol, 2 equiv.)

in THF (25 mL), and the mixture was stirred at room temperature

during 15 min. A solution of carbene complex 49a (350 mg,

0.82 mmol) in THF (5 mL) was added with a cannula to the re-

sulting mixture at Ϫ40 °C, which was stirred for 30 min at this

temperature and then allowed to reach room temperature. After

one hour, the mixture was heated to reflux and stirred at this tem-

perature for 12 h. After hydrolysis and extraction with dichloro-

methane, the residue was purified by thin layer chromatography

(elution with 5% EtOAc/cyclohexane). The first stripe at the top of

the plate gave PhSSPh (168 mg, 0.77 mmol). The second one fur-

nished 98a as an oil (129 mg, 0.37 mmol, 46%). ¹H NMR

(200 MHz, CDCl₃): δ ϭ 7.53Ϫ7.12 (m, 15 H, arom. H), 5.89 (s, 1

H, H^2Ј), 4.01 (q, J ϭ 7, 8.8 Hz, 1 H, H¹), 3.73 (q, J ϭ 7, 8.8 Hz, 1

H, H¹), 2.76 (t, J ϭ 7 Hz, 2 H, H²) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ ϭ 139.1Ϫ126.4 (arom.), 89.5 (C^2Ј), 86.7Ϫ83.57 (C³, C⁴),

67.0 (C¹), 20.7 (C²) ppm. HRMS [M ϩ 1] calcd. for C₂₃H₂₁OS:

345.1313, found 345.1309.

Reaction of Tetramethylammonium Cyanide with Complex 49a.

Phenyl(4-phenylbut-3-ynyloxy)acetonitrile (98b):

Tetramethylam-

monium cyanide (128 mg, 0.82 mmol) was added at 0 °C to a solu-

tion of carbene complex 49a (350 mg, 0.82 mmol) in anhydrous

CH₂Cl₂(10 mL). The solution turned from red to yellow. After 15

min the solution was allowed to reach room temperature and

stirred for 24 h. Water was then added. After extraction three times

with CH₂Cl₂, the organic layers were combined, washed with brine

and finally dried with sodium sulfate. The solvent was evaporated

under reduced pressure and the residue purified by chromatography

(elution EP/Et₂O). 98b was obtained as an oil (50 mg, 0.19 mmol,

23%). IR: ν˜ ϭ 1947 (CN) cm^Ϫ1. ¹H NMR (200 MHz, CDCl₃): δ ϭ

7.53Ϫ7.29 (m, 10 H, arom. H), 5.40 (s, 1 H, H^2Ј), 3.85 (m, 2 H,

H¹), 2.77 (t, J ϭ 6.5 Hz, 2 H, H²) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ ϭ 133.2Ϫ123.3 (arom.), 117.1 (CN), 85.7 (C⁴), 82.1 (C³),

70.9 (C^2Ј), 67.9 (C¹), 20.7 (C²) ppm. HRMS [M ϩ 1] calcd. for

C₁₈H₁₆NO: 262.1232, found 262.1230.

Reaction of Tetramethylammonium Cyanide with Carbene Complex

11b. Ethoxy(phenyl)acetonitrile (100): Tetramethylammonium cyan-

ide (156 mg, 1 mmol) was added at room temperature to a solution

of carbene complex 11b (326 mg, 1 mmol) in THF (20 mL). The

red solution became slowly greenish. After 12 h the solution was

hydrolysed with aqueous NH₄Cl then extracted three times with

CH₂Cl₂. The organic layers were combined, washed with brine and

finally dried with sodium sulfate. The solvent was evaporated under

reduced pressure and the residue purified by chromatography (elu-

tion EP/EtOAc). The first product eluted was ethyl benzoate

(66 mg, 0.44 mmol, 44%). Further elution furnished 100b as an oil

(31 mg, 0.19 mmol, 19%).

CCDC-227184 (for 53g), -227185 (for 53h), -161753 (for 53k),

-227186 (for 57a), -227187 (for 83), -227188 (for 84), -184028 (for

86a), -227189 (for 88) and -227190 (for 91) contain the supplemen-

tary crystallographic data for this paper. These data can be ob-

tained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html

[or from the Cambridge Crystallographic Data Centre, 12 Union

Road, Cambridge CB2 1EZ, UK; Fax: ϩ44-1223-336033; E-mail:

deposit@ccdc.cam.ac.uk].

Reaction of Tetramethylammonium Cyanide with Carbene Complex

Supporting Information Available (see also the footnote on the first

11b and 2-Cyclopentenone. Ethoxy(3-oxocyclopentyl)(phenyl)aceto- page of this article): Experimental details describing the synthesis of

nitrile (101). Tetramethylammonium cyanide (312 mg, 2 mmol) was the carbene complexes and their transformation into butenolides.

added at room temperature to a solution of carbene complex 11b

(652 mg, 2 mmol) and 2-cyclopentenone (300 µL, 4 equiv.) in THF

(50 mL) and the resulting mixture was refluxed for 12 h. The solu- Acknowledgments

tion was hydrolysed with aqueous NH₄Cl then extracted three

This work was supported by CNRS and Ministry of Education and

times with CH₂Cl₂. The organic layers were combined, washed with

brine and finally dried with sodium sulfate. The solvent was evapo-

Research (PhD grant to V. C.). Dr. Louis Hamon, Laboratoire de

`

´

Synthese Asymmetrique, UPMC, is acknowledged for carrying

rated under reduced pressure and the residue purified by chroma-

tography (elution EP/EtOAc). Compound 101 was obtained as a

colourless liquid, a mixture of diastereoisomers (de ϭ 30%)

(228 mg, 0.94 mmol, 47%). ¹H NMR (400 MHz, CDCl₃): δ ϭ

7.48Ϫ7.37 (m, 5 H, arom. H), 3.61 (m, 1 H, H⁷), 3.32 (m, 1 H,

H^7Ј), 2.72 (m, 1 H, H³), 2.50Ϫ1.73 (m, 6 H, H⁵, H⁴, H²) 1.22 and

1.20 (t, 3 H, H⁸) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 216.3

and 215.8 (C¹), 136.2 (qC), 129.4Ϫ125.7 (arom. HC), 117.6 (CN),

84.4 and 83.7 (C⁶), 62.8 (C⁷), 48.5 (C³), 40.9 and 40.6.38.2 and

38.1, 24.7 (C⁵,C²and C⁴), 14.9 (C⁸) ppm. HRMS (EI^ϩ), calcd. for

C₁₅H₁₈NO₂: 244.1338; found 244.1315.

out calculations.

[1]

E. O. Fischer, A. Massböl, Angew. Chem. 1964, 76, 645; Angew.

Chem. Int. Ed. Engl. 1964, 76, 580.

[2]

E. O. Fischer, A. Massböl, Chem. Ber. 1967, 100, 2445.

[3] [3a]

E. O. Fischer, U. Schubert, W. Kleine, H. Fischer, Inorg.

[3b]

Synth. 1979, 19, 164Ϫ172.

U. Klabunde, E. O. Fischer, J.

[3c]

Am. Chem. Soc. 1967, 89, 7141Ϫ7142.

E. O. Fischer, M.

Leupold, Chem. Ber. 1972, 105, 599Ϫ608.

[4] [4a]

E. O. Fischer, M. Leupold, C. G. Kreiter, J. Müller, Chem.

[4b]

Ber. 1972, 105, 150Ϫ162.

C. P. Casey, R. A. Boggs, R. L.

Eur. J. Org. Chem. 2004, 2471Ϫ2502

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2499

H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J. Vaissermann

FULL PAPER

[4c]

[15] [15a]

Anderson, J. Am. Chem. Soc. 1972, 94, 8947.

C. P. Casey,

C. P. Casey, S. W. Polichnowski, J. Am. Chem. Soc. 1977,

[15b]

R. A. Boggs, D. F. Marten, J. C. Calabrese, J. Chem. Soc.,

99, 6097Ϫ6099.

C. P. Casey, S. W. Polichnowski, H. E.

[4d]

Chem. Commun. 1973, 243.

C. T. Lam, C. V. Senoff, J. E.

Tuinstra, L. D. Albin, J. C. Calabrese, Inorg. Chem. 1978, 17,

[15c]

H. Ward, J. Organomet. Chem. 1974, 70, 273Ϫ281.

3045.

C. P. Casey, S. W. Polichnowski, H. E. Tuinstra, A.

[5] [5a]

J. Shusterman, R. J. Jones, J. Am. Chem. Soc. 1979, 101,

C. Alvarez-Toledano, A. Parlier, H. Rudler, J. C. Daran, Y.

Jeannin, J. Chem. Soc., Chem. Commun. 1984, 576. ^[5b]C. Alva-

7282Ϫ7292.

[16]

[17]

[18]

[19]

C. P. Casey, L. D. Albin, T. J. Burkhardt, J. Am. Chem. Soc.

1977, 99, 5833Ϫ5834.

C. P. Casey, R. L. Anderson, J. Am. Chem. Soc. 1974, 96,

1230Ϫ1231.

P. Veya, C. Floriani, A. Chiesi-Villa, C. Rizzoli, Organometall-

ics 1994, 13, 214Ϫ223.

rez, A. Pacreau, A. Parlier, H. Rudler, J. C. Daran, Organomet-

[5c]

allics 1987, 6, 1057.

J. A. Gladysz, E. B. Bauer, Handbook

of Metathesis (Ed.: B. Grubbs),Wiley-VCH, Weinheim, 2003.

K. H. Dötz, H. Fischer, P. Hofmann, F. R. Kreissl, U. Schub-

[6]

ert, K. Weiss, Transition Metal Carbene complexes; Wiley-

[6b]

VCH, Weinheim, 1983.

P. J. Harrington, Transition Metals

in Total Synthesis; John Wiley & Sons, New York, 1990, p. 364.

For the formation and chemistry of acyl complexes see, for

[6c]

[19a]

W. D. Wulff, Comprehensive Organic Synthesis (Eds.: B. K.

example:

S. Murai, K. Iwamoto, in Modern Carbonyl

M. Trost, I. Fleming), Pergamon; Oxford, UK, 1991, vol. 4,

Chemistry (Ed.: J. Otera), Wiley-VCH: Weinheim, Germany,

pp. 1065Ϫ1113. ^[6d]M. P. Doyle, Comprehensive Organometallic

2000; p. 131. ^[19b]J. A. M. Andersen, J. R. Ross, Adv. Or-

[19c]

Chemistry II (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson),

ganomet. Chem. 1995, 37, 169Ϫ218.

J. P. Collman, Acc.

[6e]

Chem. Res. 1975, 8, 342. ^[19d]E. J. Corey, L. S. Hegedus, J. Am.

Pergamon: Oxford, UK, 1995, vol. 12, pp. 387Ϫ420.

W. D.

[19e]

Wulff, Comprehensive Organometallic Chemistry II (Eds.: E. W.

Abel, F. G. A. Stone, G. Wilkinson), Pergamon: Oxford, UK,

Chem. Soc. 1969, 91, 4926.

Org. Chem. 1985, 50, 4955.

L. S. Hegedus, R. J. Perry, J.

[6f]

[20]

1995, vol. 12, pp. 469Ϫ547.

L. S. Hegedus, Comprehensive

C. P. Casey, M. C. Cesa, Organometallics 1982, 1, 87Ϫ94.

[21] [21a]

Organometallic Chemistry II (Eds.: E. W. Abel, F. G. A. Stone,

G. Wilkinson), Pergamon: Oxford, UK, 1995, vol. 12, pp.

549Ϫ576. ^[6g]L. S. Hegedus, Transition Metals in the Synthesis

of Complex Organic Molecules, 2nd ed.; University Science

J. M. Maher, R. P. Beatty, N. J. Cooper, Organometallics

1982, 1, 215Ϫ217. For related discussions on CO lability in

negatively charged complexes see: ^[21b]A. Kovacs, G. Frenking,

[21c]

Organometallics 2001, 20, 2510Ϫ2524.

S. A. Macgregor,

Books: Sausolito, C. A, 1999, 28, 187. ^[6h]K. H. Dötz, P. Tom-

D. MacQueen, Inorg. Chem. 1999, 38, 4868Ϫ4876.

E. O. Fischer, Angew. Chem. 1974, 86, 651.

Fischer, U. Schubert, W. Kalbfus, C. G. Kreiter, Z. Anorg. Allg.

U. Schubert, E. O. Fischer,

Justus Liebigs Ann. Chem. 1975, 393Ϫ400.

[6i]

schat, Chem. Soc. Rev. 1999, 28, 187.

Chem. 1990, 14, 143.

K. H. Dötz, New J.

W. D. Wulff, Comprehensive Organic

Synthesis (Eds.: B. K. M. Trost, I. Fleming), Pergamon; Ox-

W. D. Wulff, Advances in Metal-

Organic Chemistry (Ed.: L.S. Liebeskind), JAI Press Inc.;

[22] [22a]

[22b]

E. O

[6j]

[22c]

Chem. 1975, 416, 135Ϫ141.

[6k]

ford, UK, 1990, vol. 5.

[22d]

For a recent

description and uses of chromium acyl complexes obtained

upon radical reductions of carbene complexes see: K. Fuchibe,

N. Iwasawa, Chem. Eur. J. 2003, 9, 905Ϫ914.

[6l]

Greenwich, Conn. 1989; vol. 1.

Advances in Metal Carbene

Chemistry (Ed.: U. Schubert), Kluwer: Hingham, MA, 1989.

^[6m]H. Rudler, M. Audouin, E. Chelain, B. Denise, R. Gou-

mont, A. Massoud, A. Parlier, A. Pacreau, M. Rudler, R. Yef-

sah, C. Alvarez, F. Delgado-Reyes, Chem. Soc. Rev. 1991, 501.

[23]

For the reduction of Fischer carbene complexes with cleavage

of the carbonϪmetal bond, see: ^[23a]A. Connor, P. D. Rose, R.

[23b]

M. Turner, J. Org. Chem. 1973, 55, 111Ϫ119.

C. P. Casey,

[6n]

K. H. Dötz, H. C. Jahr, Carbene Chemistry (Ed.: G. Ber-

[23c]

S. M. Neumann, J. Am. Chem. Soc. 1977, 99, 1651.

E.

trand), Marcel Dekker: Switzerland, 2002. ^[6o]A. de Meijere, H.

Nakamura, K. Tanaka, S. Aoki, J. Am. Chem. Soc. 1992, 114,

Schirmer, M. Duetsch, Angew. Chem. Int. Ed. 2000, 39,

[23d]

9715Ϫ9716.

C. Baldoli, P. Del Buttero, E. Licandro, S.

[6p]

3964Ϫ4002.

R. Aumann, H. Nienaber, Adv. Organomet.

Maiorana, A. Papagni, A. Zanotti-Gerosa, Synlett 1994,

[6q]

Chem. 1997, 41, 163Ϫ242.

J. Barluenga, Pure Appl. Chem.

M. A. Sierra, Chem. Rev. 2000, 100,

J. W. Herndon, Tetrahedron 2000, 56,

J. W. Herndon, Coord. Chem. Rev. 2000,

[23e]

677Ϫ678.

S. H. Goh, R. L. Huang, S. H. Ong, H. Sieh, J.

[6r]

1999, 71, 1385Ϫ1391.

[23f]

Chem. Soc., C 1971, 2282Ϫ2284.

J. Mancheno, P. Ramirez, C. Pinar, M. A. Sierra, Tetrahedron

M. Gomez-Gallego, M.

[6s]

3591Ϫ3637.

4847Ϫ5037.

[6t]

2000, 4893Ϫ4905.

206Ϫ207, 237Ϫ262.

[24]

For the reduction of other carbene complexes without cleavage

[7]

R. Hoffmann, Angew. Chem. 1982, 94, 725; Angew. Chem. Int.

[24a]

of the carbonϪmetal bond, see:

M. L. H. Green, L. C.

Ed. Engl. 1982, 21, 711Ϫ724.

Mitchard, M. G. Sandwick, J. Chem. Soc., (A) 1971, 794Ϫ797.

[8] [8a]

[8b]

^[24b]A. Davison, D. L. Reger, J. Am. Chem. Soc. 1972, 94, 9237.

C. F. Bernasconi, Chem. Soc. Rev. 1997, 26, 299.

C.

F. Bernasconi, M. L. Ragains, J. Am. Chem. Soc. 2001, 123,

[24c]

C. C. Tso, A. R. Cutler, J. Am. Chem. Soc. 1987, 109,

[8c]

11890Ϫ11898.

C. F. Bernasconi, V. Ruddat, J. Am. Chem.

5844Ϫ5845.

[8d]

Soc. 2002, 124, 14968Ϫ14976.

C. F. Bernasconi, S. Bhatta-

charya, Organometallics 2003, 22, 426Ϫ433 and references

[25]

F. Cohen, R. Goumont, H. Rudler, J. C. Daran, R. A. Toscano,

J. Organomet. Chem. 1992, 431, C6ϪC7.

cited therein.

[26] [26a]

K. P. Nambiar, D. M. Stauffer, P. A. Kolodziej, S. A.

See for example: ^[9a]C. D. Ritchie, J. Am. Chem. Soc. 1975, 97,

1170Ϫ1179. J. F. Marlier, Acc. Chem. Res. 2001, 283Ϫ290.

M. Topf, P. Varnai, W. G. Richards, J. Am. Chem. Soc. 2002,

124, 14780Ϫ14788.

See, however, the more recent addition of alkynyllithiums to

[9]

Benner, J. Am. Chem. Soc. 1983, 105, 5886. ^[26b]D. L. Comins,

S. O’Connor, Adv. Heterocycl. Chem. 1988, 27, 223.

[9b]

[26c]

P. D.

Boyer, The Enzymes, 3rd ed., Academic Press, New York, 1975,

vol. 11 and 1976, vol. 13. ^[26d]H. Dugas, Bioorganic Chemistry.

A Chemical Approach to Enzyme Action, 2nd ed.; Springer-Ver-

lag, N.Y. 1988, p. 187 and 489. ^[26e]R. Lavilla, J. Chem. Soc.,

Perkin Trans. 1. 2002, 1141Ϫ1156.

[10]

[10a]

carbene complexes:

N. Iwasawa, K. Maeyama, M. Saitou,

[10b]

J. Am. Chem. Soc. 1997, 119, 1486.

J. Barluenga, A. A.

Trabanco, J. Florez, S. Garcia-Granda, M. A. Llorca, J. Am.

Chem. Soc. 1998, 120, 12129Ϫ12130.

[27] [27a]

H. Rudler, R. Goumont, M. Audouin, A. Parlier, B. Mar-

tin-Vaca, T. Durand-Reville, J. Vaissermann, J. Am. Chem. Soc.

1996, 118, 12045. ^[27b]H. Rudler, B. Martin-Vaca, M. Nicolas,

M. Audouin, J. Vaissermann, Organometallics 1998, 17, 361.

[11] [11a]

W. J. Schlientz, J. K. Ruff, J. Organomet. Chem. 1971, 33,

[11b]

C64.

W. J. Schlientz, J. K. Ruff, J. Chem. Soc., (A) 1971,

[27c]

1139.

H. Rudler, A. Parlier, Trends in Organometallic Chemistry,

[12]

[13]

1999, vol. 3, 112Ϫ164. ^[27d]B. Martin-Vaca, H. Rudler, M. Au-

douin, M. Nicolas, B. Vissiere, T. Durand-Reville, J. Or-

J. E. Ellis, G. P. Hagen, Inorg. Chem. 1977, 16, 1357Ϫ1360.

C. P. Casey, S.W. Polichnowski, J. Am. Chem. Soc. 1978, 100,

7565Ϫ7578.

B. Andrieu, J. J. Brunet, O. Diallo, B. Donnadieu, J. Lienafa,

E. Roblou, J. Organomet. Chem. 2002, 643Ϫ644, 27Ϫ31.

`

´

[27e]

ganomet. Chem. 1998, 567, 119Ϫ126.

B. Martin-Vaca, T.

[14]

´

Durand-Reville, M. Audouin, H. Rudler, Synthesis 1998, 10,

[27f]

´

H. Rudler, T. Durand-Reville, J. Organomet. Chem.

1534.

2500

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 2471Ϫ2502

Article Doi

Interaction of dihydropyridines and nucleophiles with carbene complexes of chromium: Diastereo- and enantioselective synthesis of polycyclic butenolides

DOI: 10.1002/ejoc.200400036

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200400036

Full text of DOI:10.1002/ejoc.200400036

Products guided by the article

R&D Labs maybe for 128037-78-5

Relevant to this article

Hot Product