Lithium malonate enolates as precursors for radical reactions - Convenient induction of radical cyclizations with either radical or cationic termination

FULL PAPER

Lithium Malonate Enolates as Precursors for Radical Reactions ؊ Convenient

Induction of Radical Cyclizations with either Radical or Cationic Termination

Ullrich Jahn,*^[a]Philip Hartmann,^[a]Ina Dix,^[a]and Peter G. Jones^[b]

Dedicated to Professor Dr. Henning Hopf on the occasion of his 60th birthday

Keywords: Carbocations / Electron transfer / Enolates / Oxygenation / Radicals

Lithium malonate enolates 4 or 13 are oxidized to the corres- duced by CuCl₂(2) was also efficient. At least for alkyl rad-

ponding radicals by ferrocenium hexafluorophosphate (1) or

CuCl₂(2). Trapping by TEMPO (5) to produce 6, dimerization

icals, however, ligand transfer is the exclusive stabilization

pathway, giving access to chloroalkylcyclopentane derivat-

to 7, or radical 5-exo cyclizations are possible subsequent re- ives 21. Radical scavenging studies revealed that malonyl

action steps following radical generation. The structure of the

radical cyclization acceptor determines the outcome of the

radical trapping is slow, so that 5-exo cyclizations occurred.

The cyclized radicals couple with TEMPO (5) to afford oxy-

overall reaction sequence. Tertiary benzylic, alkyl, and α-al- genated cyclopentane derivatives 31, depending on the rate

koxy radicals are oxidized by 1. The carbenium ions are sta-

bilized by nucleophilic trapping or deprotonation to give

compounds 14 and 18. Secondary alkyl and vinyl radicals are

not oxidized and, in the absence of trapping reagents, form

radical-derived products. Radical 5-exo cyclization of 13 in-

of radical SET oxidation. The reaction behavior of com-

pounds 14, 22, 23, and 31 was investigated. Mechanistic

issues are discussed and implications for synthetic planning

are given.

Introduction

heterointermediate reaction sequences may be planned

either as overall oxidative processes or as overall reductive

ones. The prerequisite for these sequences is the incorpora-

tion of selective electron transfer steps that induce the

changes in the oxidation states.

Sequential reactions are of rapidly growing importance

in organic chemistry. Such reaction sequences allow time-

and resource-efficient access to complex target structures

from simple precursors.^[1]Most of the strategies so far ap-

plied consist of domino processes, in which one interme-

diate type (anions or radicals or cations or carbenes) or per-

icyclic processes are involved [Equation (1)]. However, the

success of the overall one-pot process will critically depend

on the characteristic reactivity of the chosen intermediates.

(2)

For reductive heterointermediate reaction sequences,

SmI₂has proven a valuable reagent.^[3]Oxidative heteroin-

termediate reaction sequences according to Equation (2), in

contrast, are much less well developed, but oxidative radical

(1)

reaction sequences of neutral carbonyl compounds em-

ploying Mn(OAc)₃

[4]

or ceric ammonium nitrate (CAN)^[5]

Consequently, reaction sequences in which multiple inter-

mediates of different oxidation states may be selectively gen-

erated and allowed to react are potentially much more at-

tractive [Equation (2)].^[2]This process amplifies the applic-

ability of these intermediates and opens up complementary

reaction channels in reaction sequences. Moreover, such

are well established. A different picture emerges if car-

banions, radicals, and carbenium ions are considered as in-

termediates in reaction sequences. In simple systems, enol-

ate oxidation^[6]followed by dimerization or oxygenation has

been accomplished by use of reagents such as Cu^{II [7]}or

Fe^IIIsalts,^[8]I₂,^[9]TiCl₄,^[10]or anodic oxidation.^[11]

Other synthetic applications of α-carbonyl radicals gener-

Institut für Organische Chemie, Technische Universität ated by SET oxidation of enolates are rather rare. Schäfer

[a]

Braunschweig,

and co-workers have studied anodic enolate oxidation/rad-

Hagenring 30, 38106 Braunschweig, Germany

ical addition/SET oxidation/lactonization.^[12]Kende dem-

Fax: (internat.) ϩ 49-(0)531/391-5388

E-mail: u.jahn@tu-bs.de

onstrated that equilibrium-generated β-diketone enolates

may undergo SET oxidation by K₃[Fe(CN)₆], followed by

radical cyclization onto phenolates ultimately to form spi-

ro[4,5]nonadienones.^[13]This method, however, is limited to

β-diketones as radical precursors; even malonates do not

react under these conditions.

[b]

Institut für Anorganische Chemie, Technische Universität

Braunschweig,

Hagenring 30, 38106 Braunschweig, Germany

Fax: (internat.) ϩ 49-(0)531/391-5387

E-mail: jones@xray36.anchem.nat.tu-bs.de

Supporting information for this article is available on the

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

Eur. J. Org. Chem. 2001, 3333Ϫ3355

WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001

1434Ϫ193X/01/0917Ϫ3333 $ 17.50ϩ.50/0

3333

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

giving G, or by another radical Y^·(Scheme 1). In this fun-

damental study, we chose malonates as starting materials,

since they form robust enolates and they are not prochiral,

thus avoiding the complicating problem of diastereomer

formation during radical cyclization.^[16]Malonate enolate

SET oxidation is most conveniently induced by ferrocenium

hexafluorophosphate^[17](1) and anhydrous CuCl₂(2). An

important issue is the termination of the cyclization reac-

tion. Depending on the alkene cyclization acceptor and the

oxidant, several functionalized structures can be obtained,

mainly in good yield and with high chemoselectivity. The

results of this study provide means for the generalization of

oxidative reaction sequences incorporating anions, radicals,

and cations in a predictable fashion. We also show that 1

is a conveniently accessible and recyclable SET oxidant for

enolates and radicals, thus adding an environmental ad-

vantage to these cyclization reactions.

Scheme 1

Results and Discussion

On the basis of these results, reaction sequences accord-

ing to Equation (2) should be feasible. The advantages of

employing anionic intermediates C as precursors for radical

reactions are clear (Scheme 1). The anionic precursor C is

simply generated by deprotonation of A. In contrast, tradi-

tional Bu₃SnH-mediated radical chain reactions require

precursors B that often actually originate from functionaliz-

ation of A or C. Slow radical reaction steps D Ǟ E, which

may not propagate chain reactions, especially at low tem-

perature, are not a particular concern in processes starting

from C. Finally, in contrast to radical chain reactions, re-

moval of the ultimate radicals E can be achieved either by

trapping with external reagents Y to form F or by further

SET oxidation to produce a carbenium ion G, which may

react with nucleophiles to give H. Opportunities for the syn-

thesis of diversely functionalized products are hence much

broader than those offered by tin hydride reactions.

Initial Studies ؊ SET Oxidation/Radical Trapping of

Lithium Methylmalonate Enolate 4

To test the efficiency of the enolate Ǟ malonyl radical

SET oxidation, diethyl methylmalonate (3) was chosen as a

model substrate. Deprotonation of 3 by LDA in DME^[18]

at Ϫ78 °C gave enolate 4. Two series of experiments were

performed with 4, to evaluate whether radical generation

occurs and whether the oxidant undergoes ligand transfer

sufficiently slowly to allow radical reactions (Scheme 2).

The most important potential advantage, however, is that

anionic reactions can be combined with radical and cationic

reactions, thus amplifying the applicability of interme-

diates.^[14]Nevertheless, such reaction sequences require SET

oxidation steps C Ǟ D and E Ǟ G, and so there is a need

to devise reagents that promote these steps efficiently and

predictably. An important prerequisite is that they should

not interfere with the intermediates generated during the

reaction sequence unless this is desired. No known oxidant

fulfills these requirements perfectly. In anodic radical gen-

eration, high radical concentrations near the electrode

sometimes produce unwanted side reactions such as dimer-

ization or overoxidation. PET conditions often produce low

yields of the desired products. Problems associated with

chemical oxidation may include dependence on the reaction

Scheme 2

In the first series, SET oxidation of 4 was performed with

conditions and, more seriously, ligand transfer from the ox- various oxidants at 0 °C in the presence of free radical

idant to radicals.

TEMPO (5) (Table 1). In a control experiment (Entry 1), it

Here we report the results of investigations aimed at the was established that 5 did not itself act as an oxidant.^[19]

development of techniques for the use of enolates C as pre- Oxidants 1 and 2 induced SET oxidation/oxygenation of 4,

cursors for radical 5-exo cyclizations.^[15]SET oxidation of efficiently providing piperidinyloxymethylmalonate 6a as a

C gives α-carbonyl radicals D, which cyclize. The final rad- colorless, crystalline solid, in 86% and 88% yields, respect-

icals E may be trapped either by further SET oxidation, ively (Entries 2 and 3). Other common oxidants such as

3334

Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

Table 1. Evaluation of SET oxidants for oxidative radical genera-

tion from methylmalonate enolates

Entry

Oxidant^[a]

3 [%]^[b]

6 [%]

7 [%]

8 [%]

1

2

3

4

5

6

7

8

5

95

Ϫ

80

72

Ϫ

8

92

84

35

50

Ϫ

21

74

Ϫ

10

Ϫ

26

Ϫ

7

1

a 86

a 88

Ϫ

b 3

Ϫ

2

FeCl₃

K₃[Fe(CN)₆]

1

2

Scheme 3

FeCl₃

9

10

11

K₃[Fe(CN)₆]

Fe(phen)₃(PF₆)₃

(p-BrC₆H₄)₃N·PF₆

1-pentenes 10aϪf,^[21,22]using NaH as the base in the pres-

ence of NaI (Scheme 3).

Ϫ

^[a]The oxidant was added portionwise as a solid to a [50 m] enol-

Oxidative Cyclizations of 5,5-Disubstituted 4-Pentenyl-

malonate Enolates

[b]

ate solution at 0 °C in DME until consumption ceased. Ϫ

All

yields are isolated yields.

The enolates used in this study were obtained by depro-

tonation of malonate 12a with various lithium bases such as

LDA, LiHMDS, or nBuLi, at Ϫ78 °C for 30 min. Oxidative

cyclizations of 13a were generally performed in [50 m]

DME solution at 0 °C, by portionwise addition of the oxid-

ants 1 or 2 until no more oxidant was consumed (Scheme 4,

Table 2). For 1, this could be monitored very easily by the

disappearance of the blue color of the oxidant; the addition

was complete when the blue-green color of the reaction

mixture persisted for 30 min. For 2, visual change was not

a good indicator; reactions were complete when excess

brown 2 remained suspended for a period of 1 h.

anhydrous FeCl₃or K₃[Fe(CN)₆] did not oxidize 4 (Entries

4 and 5).

To assess the degree of involvement of ligand-derived

products, enolate oxidation was conducted in the absence

of efficient radical scavenger 5. Oxidant 1 produced a separ-

able mixture of the symmetrical and the unsymmetrical

dimers 7 and 8, in 21% and 26% yields, respectively (Entry

6), with 3% of ferrocenylmalonate 6b also being isolated.

In contrast, oxidation of 4 with CuCl₂(2) gave only the

symmetrical dimer 7, in 74% yield, and 8% of 3 (Entry 7).

Enolate oxidation/dimerization experiments with FeCl₃and

K₃[Fe(CN)₆] paralleled those performed in the presence of

TEMPO. Enolate oxidation failed to occur with either re-

agent, use of LDA or nBuLi as the base for deprotonation

of 3 notwithstanding (Entries 8 and 9). Application of even

stronger SET oxidants was not useful; Schmittel’s

[20]

Fe(phen)₃(PF₆)₃

was consumed quickly, but only 10%

and 7% of dimers 7 and 8 were isolated, along with 35% of

recovered 3 (Entry 10). Tris(p-bromophenyl)aminium hexa-

fluorophosphate also reacted quickly, but only 50% of 3

was recovered, accompanied by tarry products (Entry 11).

Significantly, ferrocene 9 was recovered almost quantitat-

ively (by simple column chromatography, as the least polar

component) from all oxidative reactions induced by 1 (Ent-

ries 2 and 6); it may be recycled to 1 in high yield by use of

H₂SO₄(Exp. Sect.).

Scheme 4

Table 2. Oxidative cyclizations of malonate enolates 13a

Entry Base

Oxidant 12a [%] 14a [%] 15 [%] 16 [%] 17 [%]

2-(4-Pentenyl)malonate Enolates 13 as Radical 5-exo

Cyclization Precursors

1

2

3

4

5

6

7

8

LDA^[a]

1

Ϫ

64

57

54

trace

69

62

31

32

12

6

Ϫ

11

Ϫ

4

LiHMDS^[b]

BuLi^[c]

NaH^[d]

LDA

1

The results of the malonate enolate oxidation suggested

only compounds 1 and 2 as suitable SET oxidants. If a rad-

ical 5-exo cyclization occurs as desired after malonyl radical

generation, then the structure of the cyclized radical should

have a profound influence on product formation, since it

may either be trapped at the radical stage, or be further

oxidized to a carbenium ion. To investigate these pathways,

we therefore used several 5-substituted 4-pentenylmalonates

12, which could be prepared in good yields by alkylation of

1

13

60

Ϫ

20

58

50

Ϫ

1

2

BuLi^[c]

NaH^[d]

BuLi^[c]

2^[e]

2

Ϫ

[f]

^[a]1.3 equiv. Ϫ ^[b]1.13 equiv. Ϫ ^[c]1.0 equiv. Ϫ ^[d]1.5 equiv., depro-

tonation and attempted oxidation at 0 °C. Ϫ ^[e]In addition, 7% of a

compound corresponding to 2-chloro-2-(5,5-diphenyl-4-pentenyl)-

malonate was detected in the reaction mixture, but could not be

[f]

diethyl malonate 11 with 4-pentenyl tosylates or 5-bromo- obtained pure. Ϫ Fe(phen)₃(PF₆)₃as oxidant.

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3335

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

Oxidative cyclization of 13a generated with 1.3 equiv. of

LDA and induced by 1 provided the bicyclic lactone 14a as

single diastereomer in 64% yield, accompanied by 12% of

the acyclic ethylmalonate 15 (Entry 1). Increasing the

amount of LDA had no influence on the reaction outcome.

Deprotonation with LiHMDS or BuLi and oxidative cyc-

lization under identical conditions proceeded similarly, also

giving 14a and 15 (Entries 2 and 3). At Ϫ25 °C, the reac-

tions were considerably slower, resulting in only a 26% yield

of 14a after 5 h. The sodium enolate generated from 12a

and NaH at 0 °C, however, was not oxidized by compound

1, with 60% of 12a being recovered unchanged (Entry 4).

Addition of CuCl₂(2) to enolate 13a generated with LDA

provided 69% of 14a and 11% of 2-diphenylmethylenecyclo-

pentanedicarboxylate 16, while no malonate 15 was formed

(Entry 5). The enolate generated with BuLi similarly pro-

vided 62% of 14a, 4% of alcohol 17, and 7% of a 2-chloro-

malonate (Entry 6). Oxidative cyclization of the sodium en-

olate was also inefficient with CuCl₂(Entry 7), affording

only 31% of 14a and 58% of recovered 12a. In a final ex-

periment, oxidative cyclization of BuLi-generated 13a in the

presence of 2.5 equiv. Fe(phen)₃(PF₆)₃gave only 32% of

14a, with 50% of 12a being recovered (Entry 8).

Figure 1. X-ray crystal structure analysis of lactone 14a

The constitution of the bicyclic lactone 14a was unam-

biguously proven by X-ray crystal structure analysis (Fig-

ure 1). The ring junction stereochemistry is clearly shown

to be cis. The ethoxycarbonyl group and the phenyl ring on

the β-face of the butyrolactone ring are disposed in

pseudoaxial manner. The butyrolactone ring adopts an en-

velope conformation (mean deviation from planarity for

C6ϪO1ϪC7ϪC1 ϭ 0.7 pm, with C5 38.4 pm out of the

envelope plane). The conformation of the cyclopentane

fragment is a half chair, with C2 situated 32.8 pm above the

plane defined by C1ϪC5ϪC4, and C3 located 34.2 pm be-

low it. The distance between the ethoxycarbonyl group and

the phenyl ring is shown to be relatively short, amounting

to 368.7 pm for the closest contact. The crystal packing

shows weak nonclassical hydrogen bonds O2···H10BϪC10

Scheme 5

and O3···H19ϪC19, with interatomic distances and angles situated close to the shielding region of the phenyl ring (cf.

of 256 pm/349.9(3) pm/161.6° and 273 pm/365.4(3) pm/ 368.7 pm in the solid state, vide supra). The bridgehead

165.9°, respectively. This results in a chain arrangement of hydrogen, on the other hand, is shifted downfield to δ ϭ

14a parallel to the y axis.

4.03, due to its location in the deshielding zone of the

The structure of 14a in solution should be similar. In phenyl ring.

comparison to other derivatives, the ethoxy group suffers a

strong high-field shift in the H NMR spectrum, since it is was studied with 12b (Scheme 5, Table 3). Deprotonation

The reactivity of 1 and 2 towards tertiary alkyl radicals

1

Table 3. Products obtained from oxidative cyclization of malonate 12b

Entry

Base

Oxidant

14b [%]

18b/19b [%] (ratio)

20b [%]

21b [%]

1

2

3

4

5

6

7

LiHMDS^[a]

LiHMDS^[b]

LiHMDS^[c]

LDA^[d]

1

2

52

36

34

38

36

30

Ϫ

32 (4.3:1)

47 (4.2:1)

30 (3.3:1)

34 (4.3:1)

20 (19:1)

37 (17.5:1)

4 (1:1)

7

5

6

10

7

Ϫ

12

Ϫ

67

LDA^[e]

LDA^[f]

10

Ϫ

LDA^[g]

[b]

[c]

[d]

[e]

^[a]1.75 equiv. Ϫ 2.5 equiv. Ϫ 1.5 equiv. and 5 equiv. of 1,4-cyclohexadiene. Ϫ 1.5 equiv. Ϫ 1.3 equiv. and 2 equiv. of anhydrous

[f]

[g]

ZnCl₂. Ϫ 1.3 equiv., addition of 10 equiv. of TMEDA prior to addition of 1. Ϫ 1.3 equiv., 4% of 12b recovered.

3336 Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

with 1.75 equiv. of LiHMDS and oxidative cyclization af-

forded bicyclic lactone 14b as the major product, in 52%

yield. In addition, an inseparable mixture of a 4.3:1 ratio of

cyclopentane-1,1-dicarboxylates 18b and 19b was formed in

32% yield, and the cyclized ferrocene adduct 20b was isol-

ated in 7% yield. The overall cyclization yield was therefore

high, but diversification had occurred. When the amount of

LiHMDS was increased to 2.5 equiv., decreasing quantities

of lactone 14b and increasing amounts of 18b/19b were ob-

served (Entry 2). To gain information on the relative rates

of oxidation and intermolecular hydrogen abstraction, the

oxidative cyclization was performed in the presence of 5

equiv. of 1,4-cyclohexadiene (Entry 3). Significantly, besides

a decreased overall cyclization yield, the 18b/19b ratio de-

creased to 3.3:1; however, the bicyclic lactone still domin-

ated, with a yield of 34%. Use of the stronger base LDA

for deprotonation resulted in a reduction of the yield of 14b

to 38%, with 34% of 18b/19b and 10% of 20b being formed

(Entry 4). LiϪZn transmetalation complicated the reaction

mixture even more (Entry 5). In addition to the products

previously obtained, chloride 21b was formed in 12% yield.

Addition of tertiary amine TMEDA to 13b prior to oxidat-

ive cyclization markedly improved the 18/19 ratio, while 14b

was formed in a similar 30% yield (Entry 6). When CuCl₂

(2) was used as the oxidant, the cyclization result changed

dramatically. Chloride 21b was now by far the major prod-

uct, while only 4% of a 1:1 mixture of 18b/19b was formed.

The formation of lactone 14b was inhibited completely un-

der the reaction conditions (Entry 7).

Figure 2. X-ray crystal structure analysis of cyclopentylferrocene

20b

The structure of the lactone 14b was assigned by NMR.

The constitution of the ferrocene adduct 20b was also estab-

lished by crystal structure analysis (Figure 2). The structure

clearly shows the half-chair cyclopentane ring system, with

the ferrocene moiety attached to the exocyclic carbon atom

C-6. The bulky ferrocenylisopropyl group is disposed in a

pseudoequatorial fashion. The steric crowding around this

Scheme 6

Table 4. Product distribution of enolate oxidation/cyclization of 12c

group is clearly evident in the deviation of the C6ϪC5ϪC1 Entry Base

bond angle, which is widened to 121.8(2)°, while the

Oxidant 12c [%] 22 [%] 23 [%] 24 [%] 25 [%]

1

2

3

4

5

LDA^[a]

1

2

Ϫ

10

25

14

78

16

43

32

10

Ϫ

24

Ϫ

4

35

Ϫ

C5ϪC1ϪC2 bond angle is compressed to 101.9(2)°. Non-

classical hydrogen bonds are also present in 20b. Contacts

of 270 pm/362.5(3) pm/155.2° were found for

O1···H3AϪC3, together with values of 250 pm/338.5(3)

pm/154.5° for O3···H10ϪC10, producing a chain arrange-

ment parallel to the z axis.

LDA^[b]

LDA^[c]

LDA^[d]

LDA^[e]

Ϫ

22

Ϫ

^[a]1.4 equiv. Ϫ ^[b]1.1 equiv. and 7.7 equiv. of LiBr, 12 min reaction

[c]

[d]

[e]

time. Ϫ 1.3 equiv. Ϫ

1.3 equiv. in [50 m] THF.

1.3 equiv., cyclization at Ϫ70 °C. Ϫ

Oxidative Cyclizations of 5-Monosubstituted 4-Pentenyl-

malonate Enolates

matic effect, resulting in the exclusive production of the ra-

Cyclization of enolate 13c with an enol ether acceptor ther unstable aldehyde 22 in good yield (Entry 2). Use of

(Scheme 6, Table 4) produced after 60 min a partially separ- CuCl₂(2) as the oxidant induced the formation of 22, 23,

able 1.4:1 mixture of cyclized aldehyde 22 and dimethyl ace- and 24 in 16%, 24% and 22% yields, respectively (Entry 3).

tal 23, contaminated with a small quantity of n-butyl acetal When the same oxidative cyclization was conducted at Ϫ70

24. Surprisingly, mixed dimer 25 was formed in appreciable °C, only 22 was formed in 43% yield, with no formation of

yield (Entry 1). Shortening of the reaction time to 12 min 23 and 24 being observed at all (Entry 4). A change in solv-

and use of HMPA as an additive had no significant influ- ent to THF, with oxidative cyclization mediated by CuCl₂,

ence on the cyclization outcome, while application of an gave 22 as the exclusive product in 32% yield even at 0 °C,

excess of 2 equiv. of LDA reduced the overall yield. Addi- but significant quantities of 12c were always recovered

tion of 7.7 equiv. of lithium bromide, however, had a dra- (Entry 5). The seemingly not very useful mixtures of 22؊24

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3337

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

(Entries 1 and 3) can, however, easily be converted into ate 21d in 21% yield and with high diastereoselectivity, in

single products (vide infra).

addition to 14d and 26d (Entry 6).

Oxidative cyclization of the 5-phenyl-4-pentenylmalonate

The constitution of the dimers 26d was established by CI

enolate (Z)-13d generated with LDA gave 15% of bicyclic mass spectrometry, which showed [M ϩ H]^ϩϭ 607 as the

lactone 14d (dr 8:1)^[23]and 30% of 26d, as an inseparable base peak. Both dimers must be symmetrical, since only

1:1 mixture of meso and d/l dimers (Scheme 7, Table 5, half signal sets were observed in their H and ¹³C NMR

1

Entry 1). A reduction in the concentration and addition of spectra. In both isomers, the H⁶moieties appeared as doub-

HMPA resulted in a significant increase in the overall yield lets in the ¹H NMR spectra. More significantly, HMBC

of both compounds; however, the 14d/26d ratio remained spectra revealed a clear two bond cross peak from C6 to

almost constant (Entry 2). The analogous cyclization of H⁶Ј for both isomers, strengthening the dimer structure as-

(E)-13e afforded only 6% of lactone 14d, but 45% of dimers signment.

26d (Entry 3). Here, use of LiHMDS as the base was gener-

As a representative 5-alkyl-substituted 4-pentenylmalon-

ally not as effective as LDA and resulted in significantly ate, the cyclization behavior of (E)-4-hexenylmalonate 12f

reduced yields of 14d and 26d (Entries 4 and 5 vs. Entry 2). was studied (Scheme 8, Table 6). Deprotonation of 12f and

Inverse slow addition of the enolate solution to a suspen- oxidation with 1 gave an inseparable mixture of the cyclo-

sion of 1 did not change the reaction outcome significantly. pentanes 18f and 19f, in a 1:1 ratio. In addition, the ferro-

Use of CuCl₂(2) as the oxidant induced the oxidative cyc- cene adduct 20f and a diastereomeric mixture of dimers 26f

lization of (Z)-12d, but chlorine transfer occurred to a signi- were isolated in 18% and 34% yield (Entry 1). When CuCl₂

ficant extent, giving (chlorobenzyl)cyclopentanedicarboxyl- was used as oxidant, the reaction outcome changed com-

Scheme 7

Scheme 8

Table 5. Results of oxidative cyclizations of 12d and 12e

Entry

12

Base

Oxidant

14d [%] (dr)

26d [%] (dr)

21d [%] (dr)

1

2

3

4

5

6

(Z)-12d

(E)-12e

(Z)-12d

(E)-12e

(Z)-12d

LDA^[a]

1

2

15 (8:1)

28 (10:1)

6 (7:1)

4 (7:1)

7 (8:1)

30 (1:1)

48 (1:1)

45 (1:1)

28 (1:1)

24 (1:1)

47 (1:1)

Ϫ

LDA^[b]

LDA^[c]

LiHMDS^[d]

LDA^[e]

Ϫ

15 (9:1)

21 (12:1)

[a]

[b]

[c]

[d]

[e]

1.5 equiv. Ϫ 1.75 equiv. and 7 equiv. of HMPA. Ϫ 1.75 equiv. Ϫ 2.5 equiv. Ϫ 1.3 equiv.

Table 6. Oxidative radical cyclization/radical self-termination of malonate enolate 13f

Entry

Base

Oxidant

18f/19f [%]

20f [%]

26f [%]

21f [%] (dr)

27f [%]

1

2

LiHMDS^[a]

LDA^[c]

1

2

42 (1:1)

Ϫ

18

Ϫ

34^[b]

Ϫ

71 (3:1)

Ϫ

4

[a]

[b]

[c]

1.9 equiv. Ϫ Diastereomers not assigned. Ϫ 1.3 equiv., 12% of 12f recovered.

3338

Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

pletely. Only the acyclic and cyclic chlorides 27f and 21f Oxidative Cyclizations of 4-Pentenylmalonates 12 in the

were formed, in 4% and 71% yields, respectively (Entry 2).

Presence of Free Radical TEMPO (5)

In order to prove that radical intermediates are involved,

we studied trapping by stable free radical TEMPO (5). This

Oxidative Cyclization of 4-Pentynylmalonate Enolate 13g

Cyclizations onto alkynes are valuable reactions as they approach produces oxygenated products, and these may be

generate methylenecyclopentanes, which can undergo a further functionalized to produce valuable synthetic build-

variety of further transformations. Oxidative cyclization of ing blocks. This may be especially important as it avoids

malonate 13g (prepared in 61% yield by alkylation of di- the unsatisfactory formation of radical-radical reaction

ethyl malonate with 4-pentynyl tosylate) in DME afforded products such as dimers and disproportionation products.

2-methylenecyclopentane-1,1-dicarboxylate 28 as the major

Since we knew that the enolate did not react with

product in 57% yield (Scheme 9). In addition, 22% of TEMPO (vide supra), enolates 13 were generated in the

acyclic malonate dimer 29 and 9% of ferrocene adduct 20g usual fashion, followed by sequential addition of a small

were isolated. To test whether ferrocene 9 or 1 was the ac- excess of 5 and the oxidant (Table 7). Oxidative cyclization

tual reagent involved in the formation of 20g, the reaction of enolate 13a gave 47% of unstable 2-(2,2,6,6-tetramethyl-

was performed in the presence of 2 equiv. of 9. The 28/29/ piperidin-1-yloxy)malonate 32a and 25% of bicyclic lactone

20g ratio was, however, not changed in this experiment. Use 14a (Entry 1). With LiHMDS as the base, the yield of the

of THF as a solvent produced 56% of 28, while the acyclic TEMPO trapping product was somewhat lower

amounts of 29 and 20g decreased in favor of the tetrahy- (33%), while the amount of 14a remained the same. Surpris-

drofuran adduct 30. Use of benzene as the solvent resulted ingly, malonate 12b exclusively provided the cyclic trapping

in sharp decreases in the yields of all products, probably product 31b in 87% yield (Entry 2), with essentially the

because of the lesser solubility of 1 and precipitation of same result being obtained when 2 was used as the oxidant

forming LiPF₆.

(Entry 3). The cyclization of 13c was again characterized

by competing pathways. The cyclized mixed piperidinyloxy

acetal 31c was the major product, in 46% yield as a 2:1

diastereomeric mixture, accompanied by 15% of the acyclic

trapping product 32c. In addition, products 22؊25, previ-

ously obtained in the cyclization experiments in the absence

of TEMPO, were isolated in low yields (Entry 4, cf.

Table 4). The concentration of TEMPO had only a minor

influence on the product ratio (Entry 5). In contrast, the

TEMPO trapping of (E)-13d proved to be highly efficient.

The cyclized product 31d was isolated as a single diastere-

omer in 72% yield, accompanied by 7% of 32d (Entry 6).

The configuration of 31d was established by X-ray crystal

structure analysis (Figure 3). The cyclopentane ring adopts

an envelope conformation (mean deviation from planarity

for C2ϪO1ϪC5ϪC4 ϭ 3.8 pm, with C5 lying 64.6 pm out

of the envelope plane). The phenyl ring is located on the

same face as the ring hydrogen atom at C-5 and is oriented

almost parallel to the cis-ester functionality. The distance

Scheme 9

Table 7. Oxidative radical cyclization/TEMPO trapping of malonate enolates 13

Entry

12

Base

Oxidant

31 [%] (dr)

32 [%]

Other products [%]

1

2

3

4

5

6

7

8

9

a

b

c

d

f

LDA^[a]

1

2

1

Ϫ

87

47

Ϫ

traces

15

14a (25)

LiHMDS^[b]

LDA^[c]

Ϫ

LDA^[d]

46 (2:1)^[e]

37 (1:1)

72 (100:0)

50 (1.8:1)

41 (2:1)

Ϫ

22 (10), 23 (4), 25 (14)

22 (8), 23 (8), 25 (28)

Ϫ

LDA^[f]

LiHMDS^[g]

LiHMDS^[h]

LiHMDS^[k]

LDA^[l]

7

17^[i]

42

f

g

98

[a]

[b]

[c]

[d]

[e]

[f]

[g]

1.75 equiv. Ϫ 1.75 equiv. Ϫ 1.3 equiv. Ϫ 1.4 equiv. Ϫ Diastereomers not assigned. Ϫ 1.4 equiv. and 2.0 equiv. of 5. Ϫ

[h]

[i]

1.75 equiv. and 2.0 equiv. of 5. Ϫ

tartronate derivative 32fЈ (Exp. Sect.). Ϫ 1.0 equiv. and 2.0 equiv. of 5, 6% of 12f recovered. Ϫ 1.5 equiv.

1.0 equiv. and 1.0 equiv. of 5. Ϫ Because of its limited stability, 32f was characterized as its

[k] [l]

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3339

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

Figure 3. X-ray crystal structure analysis of diethyl 2-[(2,2,6,6-

tetramethylpiperidin-1-yloxy)benzyl]cyclopentane-1,1-

dicarboxylate (31d)

between the ethoxycarbonyl group and the phenyl ring

amounts to 363.5 (3) pm for the closest contact between

C8···C27. The bulky piperidine ring occupies the free space,

directed away from the cyclopentane ring to minimize inter-

actions with the ester groups and the cyclopentane ring.

Nonetheless, a remarkably close contact between the C20

methyl group and C22 or C23 of the phenyl ring was still

found [320.7(3) pm and 332.6(3) pm, respectively]. Nonclas-

sical hydrogen bonds are also present in 31d. A contact of

260 pm/354.0(3) pm/159.0° was found for O1···H4BϪC4

and one of 246 pm/338.0(3) pm/162.6° for O3···H10ϪC10.

These contacts assemble a chain parallel to [011].

Scheme 10

lonate enolate 13g exclusively afforded the acyclic trapping

product 32g in 98% yield (Entry 9).

Selected Transformations of the Oxidative Cyclization

Products

The solution structure of compound 31d seems to be sim-

ilar. One of the methyl groups of the piperidine ring is

shifted upfield to δ ϭ Ϫ0.09 and the cis-OCH₂ester frag-

ment experiences a shift to δ ϭ 3.44/3.70, with double

quadruplet multiplicity. This indicates that these groups are

Further investigations were undertaken in order to dem-

onstrate the synthetic value of the cyclization products

(Scheme 11). Most importantly, the cyclic TEMPO trap-

ping products 31 represent piperidinyl-protected alcohols.

1

located in the shielding zone of the phenyl ring. In the H

and ¹³C NMR spectra at room temperature, the signals of

the methyl groups and the carbon atoms of the piperidine

ring are broadened considerably. To assign the carbon

atoms, we conducted variable temperature measurements.

On warming 31d to 100 °C, in C₂D₂Cl₄solution in an

NMR tube, a new set of minor resonances appeared. These

were assigned to the diastereomeric TEMPO adduct 31dЈ,

and represented a final ratio of 2:1 (Scheme 10).^[24]This

limited configurational stability would need to be taken into

account should thermal reactions with these compounds

be planned.

Under these reaction conditions, malonate 12f provided

a mixture of cyclic and unstable acyclic trapping products

31f and 32f. The cyclic trapping product 31f proved to be a

2:1 diastereomeric mixture, the product ratio being depend-

ent on the amount of TEMPO added. With 1 equiv. of 5, a

3:1 ratio of 31f/32f was produced in 67% yield (Entry 7). On

the other hand, addition of 2 equiv. of 5 prior to oxidative

cyclization resulted in 1:1 mixture of 31f/32f (Entry 8).

However, this seemingly not very useful mixture converts

completely into the cyclized product after 7 d in CDCl₃or

DME/Et₂O, the cyclization stereoselectivity being un-

changed in the process. In the freezer in the dark, this reac-

tion did not take place. SET oxidation of the 4-pentynylma- Scheme 11

3340

Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

To deprotect the synthetically important alcohol func- generated from NaH were not efficiently oxidized either by

tionality, we cleaved the NϪO bond under reductive condi- 1 or by 2 (Table 2, Entries 4 and 7). Radical 5-exo cycliza-

tions with Zn/AcOH. Under these conditions, spontaneous tions of malonyl radicals 34aϪf occurred as desired to give

lactonization occurred, to give the bicyclic lactones 14b, cyclized radicals 35aϪf. At this juncture a diversification

14dЈ, and 14f in good yields. The integrity of the stereocen- point was reached, with the final product distribution larg-

ters was not compromised under the reaction conditions. ely being determined by radical structure and reagents.

Thus, oxidative cyclization/TEMPO trapping to give 31, fol- Radicals 35a and 35c were exclusively oxidized to carben-

lowed by reductive lactonization to give 14, represents a ium ions 36a and 36c, which were stabilized by nucleophilic

complementary pathway to the double oxidative cyclization trapping to give 14a/15 (path A) or products 23 and 25

12 Ǟ 14 for those compounds that do not undergo radical (path B). Tertiary alkyl radicals, as exemplified by 35b, pref-

oxidation. Furthermore, the stereochemistry of the lactone erentially underwent SET oxidation by 1 to give 36b, but

is reversed, since direct lactonization and TEMPO trapping formation of some disproportionation product 19b was also

occur from opposite faces of prochiral carbenium ion or detected. For 36b, nucleophilic lactonization to 14b was still

radical intermediates (vide infra).

preferred (path A), but deprotonation to 18b provided ser-

Bicyclic lactones 14a, and 14b underwent clean Krapcho ious competition (path C). A similar situation was found

dealkoxycarbonylation^[25]to give bicyclic lactones 33a and for 36c, with which dealkylation by base or halides to alde-

33b in 64% and 40% yields. The low yield of 33b is due to hyde 22 was predominant. Secondary benzyl and alkyl rad-

the high volatility of this compound.

icals 35d and 35f were not oxidized efficiently and provided

Another issue was the product diversity obtained in some typical radical disproportionation and/or dimerization

runs of the cyclization of enol ether 12c. The aldehyde/ace- products 18f, 19f, 26d, and 26f (path D). Finally, cyclization

tal mixture 22؊24 can be converted either into the aldehyde of the 4-pentynylmalonyl radical 34g (not shown) resulted

22 or into the dimethyl acetal 23, by acidic hydrolysis or in a vinyl radical 35g, which was stabilized by hydrogen

acetalization using trimethyl orthoformate/pTsOH.

abstraction from the solvent and addition to 1 to give 28

(Scheme 9). Furthermore, the cyclization to the destabilized

vinyl radical 35g seemed to be reversible, as indicated by

the formation of acyclic dimer 29 in this case.^[26]The forma-

tion of ferrocene adducts 20b, 20f, and 20g occurred as a

minor but constant reaction channel (path E). It must be

ascribed to a radical coupling, albeit not very efficient, of

the ferrocenium ion with the cyclized radical.^[27]This is sup-

ported by the fact that deliberate addition of excess ferro-

Mechanistic Interpretation of the Oxidative Cyclizations

All the results can be interpreted according to Scheme 12.

Lithium malonate enolates 13 were oxidized efficiently by 1

or 2 regardless of their method of generation. The SET ox-

idant and its reduced form did not interfere with reactions

of the malonyl radicals 34. In contrast, sodium enolates

Scheme 12

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3341

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

cene prior to oxidative cyclization of 13g had no influence steps. Thus, if SET oxidation is expected to be slow, the

on the product distribution. relative rates of enolate oxidation by 1 have to be taken

When 2 was used as the SET oxidant, chlorine transfer into account. Fortunately, malonates are on the slow end

occurred. This was found to be less pronounced for benzylic of enolate SET oxidation. Other enolate types are oxidized

radicals 35a and 35d and α-methoxy radical 35c, for which by 1 appreciably more rapidly, even at lower temper-

SET oxidation to carbenium ions 36a, 36c, and 36d and atures.^[16]

then to 14 or 22, 23, and 24 still dominated. For alkyl rad-

icals 35b and 35f, chlorine transfer was very efficient, giving 2.) Radical Oxidation

21b and 21f almost exclusively and in high yields.

The mechanistic picture is further substantiated by the

Radical oxidation is an important issue in these cycliza-

cyclization experiments in the presence of TEMPO (5). Sur- tions, since valuable information on the design of tandem

prisingly, radical coupling with the malonyl radicals 34aϪf processes can be obtained from these experiments. Radical

was slower or only as fast as radical 5-exo cyclization. It oxidation by ferrocenium hexafluorophosphate 1 very reli-

was therefore possible to use TEMPO to trap both radical ably reflects the known oxidation potentials of radicals.^[30]

species 34 and 35 involved in the radical cyclization, permit- The 1,1-diphenylethyl radical (E_1/2ϭ ϩ0.23 V vs. SCE)^[30a]

ting remote oxygenation after cyclization to give 31bϪf in in 35a is oxidized very rapidly, exclusively producing car-

moderate to high yields. Furthermore, it was also disco- bocation-derived products (Table 2). Radical oxidation of

vered that the malonyl radical-derived TEMPO adducts 32 35a is much faster even than TEMPO trapping (k ϭ

were prone to homolysis/cyclization in solution under or- 4.6ϫ10⁷



^Ϫ1s^Ϫ1),^[31]as no cyclized 31a was detected

dinary lab. light, providing 31. This represents an interest- (Table 7, Entry 1). Thus, 35a must be oxidized by 1 with a

ing application of the persistent radical effect.^[28]

Factors Influencing the Reaction Course

1.) Enolate Oxidation

rate constant k_oxϾ 10⁸^Ϫ1s^Ϫ1. Competitive trapping of

radical 35c by 5 vs. SET oxidation by 1 gave a ratio of 31c/

(22 ϩ 23 ϩ 25) of 1.6:1, indicating a rate constant of at

least 10⁷^Ϫ1s^Ϫ1for SET oxidation of 35c to 36c (Table 7,

Entries 4 and 5). Tertiary alkyl radical 35b was oxidized

more slowly, giving rise to some tertiary radical dispropor-

It can clearly be seen that the outcome of the reactions tionation (Table 3). The ratio of products 14b ϩ 18bЈ

is critically dependent on the oxidant. Weak or moderate (18bЈ ϭ 18b Ϫ 19b),^[32]derived from carbenium ion 36b, to

SET oxidants such as 1 or 2 are best suited for performing radical-derived products (2 ϫ 19b ϩ 20b) ranges from 2.5:1

malonate enolate SET oxidation. Stronger oxidants do not to 7.3:1. Polar additives influence this ratio. TMEDA or

oxidize malonate enolates 4 to radicals efficiently (Table 1). ZnCl₂significantly lessened the amount of reduced product

Even 1 and 2 show subtle differences in their reactivities, 19b (Table 3, Entries 5 and 6). Some rough information

however. While 1 oxidizes enolates 4 (E ϭ ϩ0.03 V vs. about the rate of tertiary radical oxidation by 1 is provided

ferrocene in DMSO)^[29]or 13aϪg only at temperatures of 0 by the competitive trapping experiments with TEMPO and

°C and above, the slightly stronger CuCl₂(2) performs well 1,4-cyclohexadiene. Radical oxidation cannot compete with

even at Ϫ70 °C (Table 4, Entry 4). The rate of enolate ox- TEMPO trapping (k_tBuϭ 7ϫ10⁸^Ϫ1s^Ϫ1),^[31]but is signific-

idation is important, however, since slow enolate oxidation antly faster than hydrogen abstraction from cyclohexadiene

may result in unwanted enolate anion/carbenium ion side (k ϭ 9.4ϫ10³^Ϫ1s^Ϫ1for the tert-butyl radical at 27 °C)^[33]

reactions in these reaction sequences. This is manifested in (Table 3, Entry 3). On the basis of these results, the rate for

the induction by 1 of malonate enolate oxidation/cycliza- SET oxidation can be roughly estimated as in the range of

tion/radical oxidation of 13a and 13c (Table 2, Entries 1 and 10⁴Ϫ10⁵^Ϫ1s^Ϫ1. Thus, radical oxidation may interfere with

2; Table 4, Entries 1 and 3). Compounds 15 or 25 can only subsequent intended radical cyclizations, especially if these

arise if oxidation of the enolate is the rate-determining step are slow.

of the sequence. Apparently 5-exo cyclization of 34a and Benzylic radical 35d (E_1/2ϭ ϩ0.37 V vs. SCE)^[30]undergoes

34c Ϫ and especially SET oxidation of the cyclized radicals oxidation only very sluggishly, to give lactone 14d. Dimeriz-

35a and 35c Ϫ are very fast, producing carbenium ions 36a ation resulting in 26d is much faster. Secondary alkyl rad-

and 36c while 13a and 13c are still present in the reaction icals and vinylic radicals are not oxidized at all by 1. The

mixture. This is further supported by the cyclization experi- last three results are significant, since further radical reac-

ments in the presence of TEMPO (5). While some malonyl tion steps can thus be envisaged as following the initial rad-

radical derived TEMPO adduct 32a was formed, no cy- ical cyclization in domino processes without interference of

clized 31a was detectable. TEMPO trapping of 35a cannot competitive radical oxidation.

compete at all with radical oxidation to give carbenium ion CuCl₂(2) showed much more highly differentiated behavior

36a (vide infra), whereas trapping of the α-methoxyalkyl towards radicals. The products derived from enolate 13a in-

radical 35c by 5 was competitive with SET oxidation by 1. dicate that SET oxidation followed by lactonization to 14a

However, products 15 and 25 were not formed in oxidative may occur as the major pathway. The formation of 2-(di-

cyclizations of 13a and 13c induced by 2 (Table 2 and 4, phenylmethylene)cyclopentane-1,1-dicarboxylate 16 and al-

Entries 5Ϫ7 and 3Ϫ5). This indicates that SET oxidation cohol 17, however, can be attributed to chlorine transfer

of 35a and 35c by 2 is faster than the following sequence followed by facile β-elimination of HCl or hydrolysis from

3342

Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

activated diphenylmethyl chloride. Since 16 was never ob-

served in oxidative reactions involving 1, direct depro-

tonation of the carbenium ion 36a seems to be an unlikely

pathway to 16, as the reaction conditions are identical ex-

cept for the oxidant. Chlorine transfer to 35 becomes more

competitive in the case of benzyl radical 35d, in which the

benzylic chloride 21d was isolated in 21% yield (Table 5,

Entry 6). The reaction is not clean, since dimerization,

chlorine transfer, and radical oxidation/lactonization occur

at the same time. For secondary and tertiary alkyl radicals

35b and 35f, on the other hand, chlorine transfer is the

dominant pathway, producing chlorides 21b and 21f in

good yields (Table 3 and 6, Entries 7 and 2). Chlorine trans-

fer from CuCl₂onto alkyl radicals is known to be a very

facile process, with rate constants of k ϭ 1Ϫ5ϫ10⁸

Scheme 13

interact with the neighboring ester functions. Instead, equi-

librium with the oxonium ion 37c, derived from the DME

solvent, seems to dominate. This complex most probably

fragments to afford dimethyl acetal 23 (Table 4, Entries 1

and 3). This stabilization pathway is further supported by

the fact that acetal 23 was not observed when the reaction

was performed in THF under otherwise identical condi-

tions. In addition, when a good nucleophile (Br^Ϫor Cl^Ϫ)

was present, direct demethylation of 36c to aldehyde 22 was

favored over reaction with the solvent (Table 4, Entries 2

and 4). Since compounds 22 and 23 are interconvertible

(Scheme 11), conversion into either single product 22 or 23

can be achieved. Future work must clearly be directed to

the development of conditions under which more selective

carbenium ion stabilization can be achieved.



^Ϫ1s^{Ϫ1 [34]}

. This argument is further substantiated by the

oxidative cyclization of 13b induced by 1 in the presence of

ZnCl₂. Here, 21b was formed in only 12% yield under other-

wise identical conditions (Table 3, Entry 5). This product

should rather result from nucleophilic trapping of the car-

benium ion 36b. Thus, CuCl₂(2) is able to induce oxidative

radical cyclizations starting from enolates. This reagent ox-

idizes only the most stabilized radicals to carbenium ions.

For most radicals, however, chlorine transfer interferes. For

alkyl radicals, this is the dominant pathway, due to its high

reaction rates, and may debar subsequent radical reaction

steps.

Comparison with Other Oxidative Cyclization Methods

There are several similar known oxidative cyclization

methods starting from carbonyl compounds, with induction

by Mn(OAc)₃, CAN, K₃[Fe(CN)₆], Fe(ClO₄)₃,^[23]or

Ti(OiPr)₄/amine/I₂.^[35]The critical question is how the pre-

sented method compares. All the previous methods are lim-

ited to easily enolizable carbonyl compounds. Most other

substrates, such as simple esters, nitriles, or ketones, vari-

ously require harshly acidic conditions for oxidation, cyclize

sluggishly, or do not react at all. In contrast, the method

presented effectively overcomes these limitations, since the

carbonyl compound is irreversibly transformed into its enol

form under very mild conditions. Although we employed

only malonates in this ‘‘proof of principle’’ study, the scope

of oxidants 1 or 2 is much broader, as we have observed

that all carbonyl structure types^[14,16]can be applied suc-

cessfully in related reactions.

3.) Stereoselectivity of the Cyclizations

High diastereoselectivity was observed in the radical cyc-

lization/trapping sequences involving malonate enolate 13d.

In radical 35d, the phenyl group is oriented away from the

cyclopentane ring, as shown in Scheme . Trapping can oc-

cur from one freely exposed face of the radical, while the

other face is completely shielded by the two ethyl ester func-

tions in the 1-position. Thus, the TEMPO adduct 31d and

the chlorine transfer product 21d were formed with high

diastereoselectivities. The same preferred conformation may

be attributed to the related carbenium ion 36d, which af-

fords lactone 14d. However, intramolecular nucleophilic

trapping by the cis-oriented carbonyl oxygen atom of

course occurs from the opposite face. A similar, although

much less marked, conformational preference can be de-

rived by analogy for radical 35f.

4.) Carbenium Ion Stabilization

For phenyl-substituted carbenium ions 36a and 36d, in-

tramolecular lactonization is the only pathway observed. A

similar situation is found in the tert-butyl analogue carben-

ium ion 36b, which produces lactone 14b. However, depro-

tonation becomes a more serious competitor, due to the un-

Scheme 14

Another important aspect of oxidative radical cycliza-

avoidable basic reaction conditions. Attempts to direct the tions is their termination. Lactonization to compounds of

deprotonation/lactonization ratio in one direction or other type 14, products of radical oxidation, is common for

by application of external bases or higher lithium amide Mn(OAc)₃- or CAN-mediated reactions, as also observed

concentration have so far met with only limited success with 1. However, ligand transfer can constitute serious com-

(Table 3). In contrast, no lactonization was observed for 36c petition, resulting in reduced yields of the desired products.

(Scheme 14). This less congested carbenium ion does not Therefore, in Mn(OAc)₃-mediated reactions, Cu(OAc)₂of-

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3343

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

wise noted, with Bruker DRX 400 or AC 200 spectrometers at 400

or 200, and 100 or 50 MHz, respectively. Connectivity was deter-

mined by ¹H-¹H COSY experiments. Ϫ ¹³C NMR assignments

were obtained from DEPT experiments. Ϫ EI mass spectra were

recorded with Finnigan MAT 8430 and MAT 8400 spectrometers

at 70 eV. Ϫ Combustion analyses were performed at the Microana-

lytical Laboratories of the Technical University of Braunschweig.

ten needs to be added in order to obtain alkenes by way of

copper hydride elimination. In contrast, in our cyclizations

employing 1 as SET oxidant, ligand transfer in the form of

ferrocene alkylation plays only a minor role, while CuCl₂

(2) is complementary in its reactivity, giving exclusive ligand

transfer for alkyl radicals. This opens up diverse func-

tionalization opportunities for the cyclized radicals. Last

but not least, oxidant 1 is efficiently recyclable, while all the

other methods, save for a few Mn(OAc)₃-mediated electro-

chemical reactions,^[36]do not allow oxidant recycling.

Ferrocenium Hexafluorophosphate (1): Ferrocene (5.58 g,

30.0 mmol) was added to concentrated H₂SO₄(10 mL) and the

mixture was stirred for 45 min. The blue-black reaction mixture

was slowly added to a solution of tBuOH (5.00 g) in H₂O (170

mL), stirred for 15 min, and filtered. At 0 °C, KPF₆(11.00 g,

60.0 mmol), dissolved in H₂O (235 mL), was added to the filtrate

and the mixture was stirred for 60 min at 0 °C. The blue precipitate

was filtered, washed twice with 40 mL ice-cold H₂O, 50 mL EtOH,

and ether until the ether remained colorless. Drying for 12 h in

vacuum yielded 8.46 g (85%) 1 as a blue powder. Ferrocene (9),

collected from the oxidative cyclizations, was recrystallized from

MeOH or n-hexane. Reoxidation as described above gave 1.

Conclusion

We have shown that radical reactions can conveniently be

induced from lithium malonate enolate starting materials.

SET oxidation by recyclable ferrocenium hexafluorophos-

phate (1) or CuCl₂(2) gave malonyl radicals amenable to

typical radical reactions such as dimerization, oxygenation

by TEMPO (5), or radical 5-exo cyclizations. The stabiliza-

tion of the cyclized radicals depends on the radical structure

and the oxidant used, but is now predictable. Tertiary

benzyl, alkyl, and α-alkoxy radicals are oxidized by 1 to

afford carbenium ions, which is followed by lactonization

or deprotonation. Secondary alkyl and benzyl radicals are

not oxidized by 1 and give radical self-termination prod-

ucts. However, selective radical trapping by TEMPO (5)

provided oxygenated cyclopentane derivatives in good

yields. The same radical generation is possible with CuCl₂

(2). However, ligand transfer to the cyclized radicals is a

competing or even exclusive stabilization pathway. Kinetic

information was derived from the results obtained, and im-

plications for synthetic planning using the accessible inter-

mediates obtainable using oxidants 1 or 2 have been out-

lined. A major implication of the methodology presented is

that radical reactions can in principle be predictably com-

bined with anionic reactions or transformations involving

carbocations in sequential processes. Future work must cle-

arly be directed towards verification of these implications

and development of more selective carbenium ion stabiliza-

tion methods to provide higher yields and selectivities.

These issues are actively under investigation.

Diethyl 2-Methyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)malonate

(6a): Compound 3 (261 mg, 1.50 mmol) was added, at Ϫ78 °C un-

der N₂, to a solution of LDA (1.95 mmol, 1.3 equiv.; prepared from

274 µL of iPr₂NH and 1.22 mL of BuLi [1.6  in hexane]) in 30

mL of dry DME. The solution was stirred between Ϫ78 and Ϫ60

°C for 30 min. At 0 °C, compound 5 (328 mg, 2.10 mmol) was ad-

ded, and the red solution was stirred for 5 min. Solid 1 or 2 was

added in portions at 0 °C. The mixture was stirred at 0 °C for

2 h, quenched with four drops of a saturated NH₄Cl solution, and

allowed to warm to room temperature. The reaction mixture was

diluted with 20 mL ether and filtered through a pad of silica gel.

The solvent was evaporated and the inhomogeneous residue was

preadsorbed on silica gel. Crude flash chromatography (50:1 gradi-

ent to 1:1) gave Ͼ 90% of 9, followed by product 6a, which was

further purified by flash chromatography and recrystallization from

pentane [R_f(10:1) ϭ 0.39] as a colorless solid, 425 mg (86%) and

Ϫ1

˜

435 mg (88%), m.p. 76Ϫ77 °C. Ϫ IR (KBr): ν ϭ 2971 cm (m),

1760 (s, CO₂), 1737 (s, CO₂), 1267 (s), 1219 (s), 1126 (s), 1110 (s).

Ϫ ¹H NMR (200 MHz): δ ϭ 0.94 (s, 6 H, NCCH₃), 1.15Ϫ1.48 (m,

6 H, CH₂CH₂CH₂), 1.19 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.34 (s,

6 H, NCCH₃), 1.64 (s, 3 H, OCCH₃), 4.14 (q, J ϭ 7.1 Hz, 4 H,

OCH₂). Ϫ ¹³C NMR (50 MHz): δ ϭ 14.0 (q, OCH₂CH₃), 16.9 (t,

NCCH₂CH₂), 17.8 (q, OCCH₃), 20.5 (q, NCCH₃), 32.9 (q,

NCCH₃), 40.7 (t, NCCH₂), 60.2 (s, NCCH₃), 61.4 (t, OCH₂), 85.4

(s, NOC), 170.2 (s, CO₂). Ϫ MS; m/z (%) ϭ 314 (10), 156 (100)

[TEMPO], 123 (30), 81 (12), 58 (17), 55(15). Ϫ C₁₇H₃₁NO₅(329.2):

calcd. C 61.96, H 9.49, N 4.25; found C 61.85, H 9.47, N 4.29.

Experimental Section

Oxidative Dimerization of Malonate 3 with 1: Compound 3

(261 mg, 1.50 mmol) was added, at Ϫ78 °C under N₂, to a solution

of LDA (1.95 mmol; prepared from 274 µL of iPr₂NH and 1.22

mL of BuLi [1.6  in hexane]) in 30 mL of dry DME. The solution

was stirred between Ϫ78 and Ϫ60 °C for 30 min. Solid 1 was added

General Remarks: All reactions were conducted in flame-dried

glassware under nitrogen. THF, DME, HMPA, DMSO, diisoprop-

ylamine, and hexamethyldisilazane were dried using standard

methods. The esters 3 and 11 were distilled prior to use. CuCl₂, in portions at 0 °C until a blue-green color persisted in the reaction

LiCl, LiBr, and ZnCl₂were dried in vacuum (160 °C, 0.8 mbar) for mixture for 30 min. The mixture was stirred at 0 °C for 2 h,

3 to 8 h. POLYGRAM SIL G/UV₂₅₄TLC plates (MachereyϪ quenched with four drops of a saturated NH₄Cl solution, and al-

Nagel) were used for monitoring reactions. Ϫ Chromatographic

separations were performed on silica gel 60 (Fluka, 230Ϫ400 mesh)

with n-hexane/ethyl acetate as eluent in the ratios given. Ϫ Melting

lowed to warm to room temperature. The reaction mixture was

diluted with 30 mL of ether and filtered through a pad of silica gel.

The solvent was evaporated and the inhomogeneous residue was

points are uncorrected. Ϫ IR spectra were taken with a Nicolet preadsorbed on silica gel. Crude flash chromatography (50:1 gradi-

DX-320 FT-IR spectrometer. Ϫ UV/Vis spectra were measured in ent to 1:1) gave Ͼ 90% of 9, followed by 6b, 7, and 8. The individual

CH₃CN, with a HewlettϪPackard 8452 diode array spectrometer. compounds were further purified by flash chromatography as indic-

Ϫ ¹H and ¹³C NMR spectra were recorded in CDCl₃, unless other-

ated in the characterization section.

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3344

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

Diethyl 2-Ferrocenyl-2-methylmalonate (6b): Flash chromatography

1.91 (m, 4 H, CH₂CH₂CH₂), 3.28 (t, J ϭ 7.6 Hz, 1 H, CHCO₂),

(50:1) gave 16 mg (3%) of 6b [R_f(5:1) ϭ 0.48] as an orange oil. Ϫ 4.15 (q, J ϭ 7.1 Hz, 4 H, OCH₂), 5.05 (t, J ϭ 7.1 Hz, 1 H, ϭCH).

Ϫ1

˜

IR (film): ν ϭ 3463 cm (w), 2983 (m), 1733 (s, CO₂), 1268 (s),

Ϫ

¹³C NMR (50 MHz): δ ϭ 14.0 (q, OCH₂CH₃), 17.6 (q, (Z)-ϭ

1248 (s), 1221 (s), 1204 (m), 1106 (s). Ϫ ¹H NMR (200 MHz): δ ϭ CCH₃), 25.6 (q, (E)-ϭCCH₃), 27.4 (t), 27.5 (t), 28.3 (t), 51.9 (d,

1.22 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.71 (s, 3 H, CCH₃), 4.06 (s, CHCO₂), 61.1 (t, OCH₂), 123.7 (d, ϭCH), 131.9 (s, ϭC), 169.4 (s,

5 H, Cp), 4.12 (d, J ϭ 1.9 Hz, 2 H, CHϭCH), 4.16 (q, J ϭ 7.1 Hz,

CO₂). Ϫ MS; m/z (%) ϭ 256 (17) [M^ϩ], 211 (22) [M^ϩϪ OEt], 173

4 H, OCH₂), 4.20 (d, J ϭ 1.7 Hz, 2 H, CHϭCH). Ϫ ¹³C NMR (23), 160 (30) [EtO₂CCHϭC(OH)OEt^ϩ], 137 (25) [M^ϩϪ CO₂Et

(50 MHz): δ ϭ 14.1 (q, OCH₂CH₃), 21.5 (q, CCH₃), 54.2 (s, Ϫ EtOH], 136 (60) [M^ϩϪ CO Ϫ 2 EtOH], 109 (23) [M^ϩϪ CO Ϫ

CCH₃), 61.4 (t, OCH₂), 67.5 (d, Cp), 68.0 (d, Cp), 68.8 (d, Cp), EtOH Ϫ CO₂Et], 95 (26), 82 (100), 69 (26), 67 (41), 55 (21). Ϫ

86.2 (s, (ipso-Cp)C), 170.9 (s, CO₂). Ϫ MS; m/z (%) ϭ 358 (100) HRMS: C₁₄H₂₄O₄: calcd. 256.1675; found 256.1667 Ϯ 3 ppm. Ϫ

[M^ϩ], 286 (49), 285 (44), 257 (24), 219 (18), 213 (18), 91 (45). Ϫ

HRMS: C₁₈H₂₂FeO₄: calcd. 358.0867; found 358.0860 Ϯ 2 ppm.

C₁₄H₂₄O₄(256.2): calcd. C 65.60, H 9.44; found C 65.59, H 9.48.

Diethyl 2-(5-Methoxypent-4-enyl)malonate (12c): Flash chromato-

graphy (25:1 gradient to 10:1) gave 1.83 g (71%) of a 6:1 (E)/(Z)

mixture of 12c [R_f(10:1) ϭ 0.49] as a colorless oil. Ϫ IR (film):

ν˜ ϭ 2938 cm^Ϫ1(m), 1750 (s, CO₂), 1732 (s, CO₂), 1702 (m), 1210

Tetraethyl Butane-2,2,3,3-tetracarboxylate (7): Flash chromato-

graphy (40:1) gave 109 mg (21%) or 384 mg (74%) of 7 [R_f(10:1) ϭ

0.38] as a colorless oil. Ϫ IR (film): ν˜ ϭ 2952 cm^Ϫ1(m), 1767 (m,

1

(m), 1151 (m). Ϫ (E)-12c: H NMR (200 MHz): δ ϭ 1.23 (t, J ϭ

1

CO₂), 1748 (s, CO₂), 1459 (m), 1241 (s), 1162 (m), 1058 (m). Ϫ H

7.1 Hz, 6 H, OCH₂CH₃), 1.35 (m, 2 H), 1.88 (m, 4 H), 3.27 (t, J ϭ

7.5 Hz, 1 H, CHCO₂), 3.46 (s, 3 H, OCH₃), 4.15 (q, J ϭ 7.1 Hz, 4

H, OCH₂), 4.64 (dt, J ϭ 12.6, 7.3 Hz, 1 H, ϭCHCH₂), 6.25 (d,

J ϭ 12.6 Hz, 1 H, ϭCHO). Ϫ ¹³C NMR (50 MHz): δ ϭ 14.0 (q,

OCH₂CH₃), 27.3 (t), 28.0 (t), 28.4 (t), 51.9 (d, CHCO₂), 55.8 (q,

OCH₃), 61.2 (t, OCH₂), 102.0 (d, ϭCHCH₂), 147.4 (d, ϭCHO),

NMR (200 MHz): δ ϭ 1.27 (t, J ϭ 7.1 Hz, 12 H, OCH₂CH₃), 1.89

(s, 6 H, CCH₃), 4.25 (q, J ϭ 7.1 Hz, 8 H, OCH₂). Ϫ ¹³C NMR

(50 MHz): δ ϭ 13.7 (q, OCH₂CH₃), 25.5 (q, CCH₃), 62.8 (t,

OCH₂), 66.0 (s, CCH₃), 167.1 (s, CO₂). Ϫ MS; m/z (%) ϭ 346 (1)

[M^ϩ], 301 (74) [M^ϩϪ OEt], 255 (53) [M^ϩϪ OEt Ϫ EtOH], 200

(25) [M^ϩϪ 2 CO₂Et], 181 (21), 174 (100) [CH₃CH(CO₂Et)₂], 173

(74) [CH₃C(CO₂Et)₂], 171 (25) [M^ϩϪ OEt Ϫ 2 CO₂Et], 160 (42),

128 (21), 127 (52) [M^ϩϪ 3 CO₂Et]. Ϫ C₁₆H₂₆O₈(346.2): calcd. C

55.48, H 7.57; found C 55.34, H 7.63.

1

169.5 (s, CO₂). Ϫ (Z)-12c: H NMR (200 MHz): δ ϭ 1.23 (t, J ϭ

7.1 Hz, 6 H, OCH₂CH₃), 1.35 (m, 2 H), 1.88 (m, 4 H), 3.30 (t, J ϭ

7.5 Hz, 1 H, CHCO₂), 3.53 (s, 3 H, OCH₃), 4.15 (q, J ϭ 7.1 Hz, 4

H, OCH₂), 4.26 (m, 1 H, ϭCHCH₂), 5.84 (d, J ϭ 6.2 Hz, 1 H, ϭ

CHO). Ϫ ¹³C NMR (50 MHz): δ ϭ 14.0 (q, OCH₂CH₃), 23.2 (t),

27.3 (t), 28.1 (t), 51.8 (d, CHCO₂), 55.8 (q, OCH₃), 61.1 (t, OCH₂),

Tetraethyl Butane-1,1,3,3-tetracarboxylate (8): Flash chromato-

graphy (40:1) gave 135 mg (26%) of 8 [R_f(10:1) ϭ 0.34] as a color-

Ϫ1

˜

less oil. Ϫ IR (film): ν ϭ 2985 cm (m), 1733 (s, CO₂), 1299 (s), 105.7 (d, ϭCHCH₂), 146.6 (d, ϭCHO), 169.5 (s, CO₂). Ϫ MS;

1250 (m), 1176 (m), 1153 (m), 1111 (m), 1024 (m). Ϫ ¹H NMR m/z (%) ϭ 258 (2) [M^ϩ], 226 (26), 167 (46) [M^ϩϪ EtOH Ϫ OEt],

(200 MHz): δ ϭ 1.21 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.23 (t, J ϭ

152 (28), 138 (40), 97 (28), 84 (100), 71 (66). Ϫ C₁₃H₂₂O₅(258.3):

7.1 Hz, 6 H, OCH₂CH₃), 1.37 (s, 3 H, CCH₃), 2.50 (d, J ϭ 6.0 Hz, calcd. C 60.45, H 8.58; found C 60.40, H 8.59.

2 H, CHCH₂), 3.49 (t, J ϭ 6.0 Hz, 1H, CH), 4.13 (q, J ϭ 7.0 Hz,

Diethyl (Z)/(E)-2-(5-Phenylpent-4-enyl)malonate (12d/12e): Flash

chromatography (25:1 gradient to 10:1) gave 2.28 g (75%) of a mix-

4 H, OCH₂), 4.15 (q, J ϭ 7.1 Hz, 4 H, OCH₂). Ϫ ¹³C NMR

(50 MHz): δ ϭ 13.78 (q, OCH₂CH₃), 13.84 (q, OCH₂CH₃), 20.2

(q, CCH₃), 33.8 (t, CHCH₂), 48.4 (d, CH₂CH), 52.6 (s, CCH₃),

61.3 (t, OCH₂), 61.5 (t, OCH₂), 169.1 (s, CO₂), 171.3 (s, CO₂). Ϫ

MS; m/z (%) ϭ 346 (1) [M^ϩ], 301 (95) [M^ϩϪ OEt], 255 (52) [M^ϩ

Ϫ OEt Ϫ EtOH], 227 (20) [M^ϩϪ EtOH Ϫ CO₂Et], 200 (25) [M^ϩ

ture of 12d and 12e (10:1) [R_f(10:1) ϭ 0.48] as a colorless oil. Ϫ

Ϫ1

˜

IR (film): ν ϭ 2983 cm (m), 1750 (s, CO₂), 1733 (s, CO₂), 1236

(m), 1213 (m), 1179 (m), 1147 (m). Ϫ UV: λ_max(lg ε) ϭ 202 nm

(4.38), 216 (3.99), 244 (4.76), 260 (3.89), 268 (3.32), 270 (3.14), 274

1

(2.91). Ϫ (Z)-12d: H NMR (200 MHz): δ ϭ 1.20 (t, J ϭ 7.1 Hz,

Ϫ

2

CO₂Et], 174 (100) [CH₃CH(CO₂Et)₂], 173 (73)

6 H, OCH₂CH₃), 1.44 (tt, J ϭ 7.7, 7.5 Hz, 2 H, ϭCHCH₂CH₂),

1.89 (dt, J ϭ 8.2, 7.5 Hz, 2 H, CH₂CHCO₂), 2.31 (ddt, J ϭ 7.4,

7.3, 1.4 Hz, 2 H, ϭCHCH₂), 3.26 (t, J ϭ 7.5 Hz, 1 H, CHCO₂),

4.12 (q, J ϭ 7.1 Hz, 4 H, OCH₂), 5.57 (dt, J ϭ 11.6, 7.2 Hz, 1 H, ϭ

CHCH₂), 6.38 (d, J ϭ 11.6 Hz, 1 H, CHPh), 7.21 (m, 5 H, Ph). Ϫ

¹³C NMR (50 MHz): δ ϭ 14.0 (q, OCH₂CH₃), 27.6 (t), 28.1 (t),

28.3 (t), 51.8 (d, CHCO₂), 61.2 (t, OCH₂), 126.5 (d, ϭCHCH₂),

128.1 (d, Ph), 128.7 (d, Ph), 129.5 (d, Ph), 131.8 (d, ϭCHPh), 137.5

[CH₃C(CO₂Et)₂], 171 (25) [M^ϩϪ OEt Ϫ 2 CO₂Et], 160 (35), 155

(35) [M^ϩϪ OEt Ϫ 2 CO₂Et], 128 (22), 127 (63) [M^ϩϪ 3 CO₂Et].

Ϫ C₁₆H₂₆O₈(346.2): calcd. C 55.48, H 7.57; found C 55.48, H 7.72.

Diethyl 2-(4-Pentenyl)malonates 12. ؊ General Procedure: Com-

pound 11 (3.20 g, 20.0 mmol) was added at 0 °C under N₂to a

suspension of NaH (80% in mineral oil, 450 mg, 15.0 mmol) in a

dry 100:10 mL THF/DMF mixture and the mixture was stirred for

30 min. The tosylates or bromides 10aϪg (10.0 mmol) and anhyd-

rous NaI (600 mg, 4.0 mmol) were added at room temperature. The

mixture was heated to reflux until reaction was complete by TLC

(12Ϫ60 h). The mixture was quenched with a saturated NH₄Cl so-

lution. The aqueous layer was extracted three times with ether. The

combined organic layers were dried with Na₂SO₄and the solvent

was evaporated. Excess 11 was distilled off at 50 °C and 0.8 mbar.

Purification of the residue by flash chromatography (25:1 gradient

to 5:1) yielded malonates 12aϪg.

1

(s, Ph), 169.3 (s, CO₂). Ϫ (E)-12e: H NMR (200 MHz): δ ϭ 0.92

(t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.44 (tt, J ϭ 7.8, 7.6 Hz, 2 H, ϭ

CHCH₂CH₂), 2.01 (dt, J ϭ 7.6, 7.5 Hz, 2 H, CH₂CHCO₂), 2.03

(dt, J ϭ 7.7, 6.8 Hz, 2 H, ϭCHCH₂), 3.36 (t, J ϭ 7.5 Hz, 1 H,

CHCO₂), 3.95 (q, J ϭ 7.1 Hz, 4 H, OCH₂), 6.00 (dt, J ϭ 15.8,

6.8 Hz, 1 H, ϭCHCH₂), 6.27 (d, J ϭ 15.8 Hz, 1 H, CHPh),

7.00Ϫ7.25 (m, 5 H, Ph). Ϫ ¹³C NMR (50 MHz): δ ϭ 14.0 (q,

OCH₂CH₃), 27.0 (t), 28.3 (t), 32.5 (t), 51.8 (d, CHCO₂), 61.2 (t,

OCH₂), 125.9 (d, ϭCHCH₂), 126.9 (d, Ph), 128.4 (d, Ph), 129.8 (d,

Ph), 130.5 (d, ϭCHPh), 137.5 (s, Ph), 169.3 (s, CO₂). Ϫ MS; m/z

(%) ϭ 304 (53) [M^ϩ], 259 (16) [M^ϩϪ OEt], 185 (40) [M^ϩϪ CO₂Et

Diethyl 2-(5-Methylhex-4-enyl)malonate (12b): Flash chromato-

graphy (25:1 gradient to 10:1) gave 1.72 g (67%) of 12b [R_f(5:1) ϭ Ϫ EtOH], 184 (70) [M^ϩϪ CO Ϫ 2 EtOH], 173 (46), 160 (20)

Ϫ1

˜

0.72] as a colorless oil. Ϫ IR (film): ν ϭ 2982 cm (m), 1752 (s,

[EtO₂CCHϭC(OH)OEt^ϩ], 130 (100), 129 (71), 128 (33), 117 (53),

CO₂), 1735 (s, CO₂), 1448 (w), 1243 (w), 1146 (m). Ϫ ¹H NMR 115 (62), 91 (41). Ϫ HRMS: C₁₈H₂₄O₄: calcd. 304.1675; found

(200 MHz): δ ϭ 1.23 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.35 (m, 2 304.1667 Ϯ 2 ppm. Ϫ C₁₈H₂₄O₄(304.4): calcd. C 71.03, H 7.95;

H, ϭCHCH₂CH₂), 1.55 (s, 3 H, ϭCCH₃), 1.64 (s, 3 H, ϭCCH₃),

found C 70.80, H 8.17.

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3345

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

Diethyl (E)-2-(Hex-4-enyl)malonate (12f): Flash chromatography

Transmetalation and Oxidative Cyclization of Diethyl 2-(5-Methyl-

(25:1 gradient to 10:1) gave 2.08 g (86%) of 12f [R_f(10:1) ϭ 0.46] hex-4-enyl)malonate (12b): Compound 12b (256 mg, 1.00 mmol)

Ϫ1

˜

was added at Ϫ78 °C under N₂

as a colorless oil. Ϫ IR (film): ν ϭ 2938 cm (m), 1752 (s, CO₂),

to a solution of LDA (1.30 mmol;

1734 (s, CO₂), 1448 (m), 1370 (m), 1264 (m), 1239 (m), 1153 (s). Ϫ

prepared from 185 µL of iPr₂NH and 810 µL of BuLi [1.6  in

¹H NMR (200 MHz): δ ϭ 1.23 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), hexane]) in 6 mL of dry DME and the resulting solution was stirred

1.34 (tt, J ϭ 7.7, 7.6 Hz, 2 H, ϭCHCH₂CH₂), 1.59 (d, J ϭ 4.5 Hz, between Ϫ78 and 0 °C for 30 min. This solution was transferred by

3 H, ϭCHCH₃), 1.84 (q, J ϭ 7.6 Hz, 2 H, CH₂CHCO₂), 1.97 (q, syringe to a suspension of anhydrous ZnCl₂(273 mg, 2.00 mmol) in

J ϭ 7.0 Hz, 2 H, ϭCHCH₂), 3.27 (t, J ϭ 7.5 Hz, 1 H, CHCO₂),

14 mL of dry DME and stirred for 40 min at room temperature.

4.15 (q, J ϭ 7.1 Hz, 4 H, OCH₂), 5.37 (m, 2 H, CHϭCH). Ϫ ¹³C Addition of 1 and workup were conducted according to the gen-

NMR (50 MHz): δ ϭ 14.0 (q, OCH₂CH₃), 17.7 (q, ϭCHCH₃), 27.1 eral procedure.

(t), 28.1 (t), 32.0 (t), 51.9 (d, CHCO₂), 61.1 (t, OCH₂), 125.3 (d, ϭ

Ethyl

3-Oxo-1,1-diphenyltetrahydrocyclopenta[c]furan-3a-carb-

CHCH₂), 130.4 (d, ϭCHCH₃), 169.4 (s, CO₂). Ϫ MS; m/z (%) ϭ

242 (2) [M^ϩ], 173 (100), 160 (50) [EtO₂CCHϭC(OH)OEt^ϩ], 150

(66), 122 (96), 95 (32), 68 (60). Ϫ C₁₃H₂₂O₄(242.3): calcd. C 64.44,

H 9.15; found C 64.43, H 9.19.

oxylate (14a): Recrystallization from pentane gave 14a [R_f(2:1) ϭ

0.71] as colorless blocks; m.p. 88 °C (for yields, see Table 2). Ϫ IR

(KBr): ν ϭ 1764 cm (s, CO₂), 1725 (s, CO₂), 762 (s, Ph), 702 (s).

Ϫ UV: λ_max(lg ε) ϭ 194 nm (4.67), 204 (4.43), 222 (3.94), 260

Ϫ1

˜

Diethyl 2-(Pent-4-ynyl)malonate (12g): Flash chromatography (25:1 (2.12). Ϫ ¹H NMR (400 MHz): δ ϭ 0.78 (t, J ϭ 7.2 Hz, 3 H,

gradient to 10:1) gave 1.38 g (61%) of 12g [R_f(5:1) ϭ 0.44] as a

OCH₂CH₃), 1.30 (m, 1 H, CHCH₂), 1.73 (m, 3 H, CHCH₂CH₂),

colorless oil. Ϫ IR (film): ν ϭ 3289 (w, ϵCϪH), 2940 (w), 2119 2.34 (m, 2 H, CH₂CCO₂), 3.47 (dq, J ϭ 10.7, 7.2 Hz, 1 H, OCH₂),

(w), 1750 (s), 1732 (s), 1151 (m). Ϫ ¹H NMR (200 MHz): δ ϭ 1.23

3.76 (dq, J ϭ 10.7, 7.2 Hz, 1 H, OCH₂), 4.03 (t, J ϭ 8.4 Hz, 1 H,

(t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.57 (m, 2 H), 1.94 (t, J ϭ 2.8 Hz, CH₂CH), 7.17Ϫ7.32 (m, 6 H, Ph), 7.40 (m, 2 H, Ph), 7.55 (m, 2

1 H, ϵCH), 1.99 (m, 2 H), 2.19 (dt, J ϭ 7.0, 2.6 Hz, 2 H, ϵCCH₂),

H, Ph). Ϫ ¹³C NMR (100 MHz): δ ϭ 13.3 (q, OCH₂CH₃), 26.2 (t),

3.31 (t, J ϭ 7.5 Hz, 1 H, CH₂CH), 4.16 (q, J ϭ 7.1 Hz, 4 H, OCH₂). 31.1 (t), 36.5 (t), 55.9 (d, CHCH₂), 61.8 (t, OCH₂), 63.2 (s, CCO₂),

¹³C NMR (50 MHz): δ ϭ 14.0 (q, OCH₂CH₃), 18.1 (t, ϵCCH₂), 89.7 (s, CPh₂), 124.7 (d, Ph), 125.5 (d, Ph), 127.3 (d, Ph), 127.7 (d,

26.1 (t), 27.7 (t), 51.5 (d, CH₂CH), 61.3 (t, OCH₂), 68.8 (d, ϵCH), Ph), 128.3 (d, Ph), 128.4 (d, Ph), 141.4 (s, Ph), 143.4 (s, Ph), 170.9

83.4 (s, ϵC), 169.2 (s, CO₂). Ϫ MS; m/z (%) ϭ 226 (Ͻ 1) [M^ϩ], (s, CO₂CH₂), 175.2 (s, CO₂CPh₂). Ϫ MS; m/z (%) ϭ 350 (46) [M^ϩ],

˜

Ϫ

197 (7) [M^ϩϪ Et], 181 (5) [M^ϩϪ OEt], 160 (100) [EtO₂CCHϭ

183 (100) [Ph₂COH^ϩ], 140 (42) [M^ϩϪ Ph₂CO Ϫ CO], 105 (41). Ϫ

C(OH)OEt^ϩ], 153 (30) [M^ϩϪ CO₂Et], 152 (34) [M^ϩϪ OEt Ϫ Et], C₂₂H₂₂O₄(350.4): calcd. C 75.41, H 6.33; found C 75.09, H 6.38.

134 (18) [M^ϩϪ 2 EtOH], 133 (29), 125 (53), 107 (50) [M^ϩϪ CO₂Et

Diethyl 2-(5,5-Diphenylpent-4-enyl)-2-ethylmalonate (15): Flash

Ϫ EtOH], 81 (45), 80 (22), 79 (97), 78 (20), 77 (26), 55 (40). Ϫ

C₁₂H₁₈O₄(226.3): calcd. C 63.70, H 8.02; found C 63.78, H 8.20.

chromatography (50:1) gave 42 mg (12%) or 21 mg (6%) of 15 [R_f

Ϫ1

˜

(5:1) ϭ 0.56] as a colorless oil. Ϫ IR (film): ν ϭ 2977 cm (m),

Oxidative Cyclization of Malonates 12aϪg with 1. ؊ General Pro-

cedure: Compounds 12aϪg (1.00 mmol) were added at Ϫ78 °C un-

der N₂to a solution of the lithium amide or nBuLi in 20 mL dry (3.69), 274 (3.34), 282 (3.04). Ϫ H NMR (200 MHz): δ ϭ 0.72 (t,

1731 (s, CO₂), 1445 (m), 1028 (m), 702 (m). Ϫ UV: λ_max(lg ε) ϭ

194 nm (4.64), 212 (4.23), 218 (4.08), 226 (3.95), 252 (3.85), 264

1

DME (for the amount of base, see Table 2Ϫ6). The solution was

stirred between Ϫ78 and Ϫ60 °C for 30 min. Solid 1 was added in 1.22 (m, 2 H, ϭCHCH₂CH₂), 1.78 (m, 2 H, CCH₂CH₂), 1.84 (q,

portions at 0 °C until a blue-green color persisted in the reaction J ϭ 7.5 Hz, 2 H, CCH₂CH₃), 2.04 (q, J ϭ 7.4 Hz, 2 H, ϭCHCH₂),

J ϭ 7.5 Hz, 3 H, CCH₂CH₃), 1.13 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃),

mixture for 30 min. The mixture was stirred at 0 °C for 2 h unless 4.08 (q, J ϭ 7.1 Hz, 4 H, OCH₂), 5.97 (t, J ϭ 7.4 Hz, 1 H, ϭCH),

otherwise noted. The mixture was quenched with four drops of a

saturated NH₄Cl solution and allowed to warm to room temper-

7.06Ϫ7.33 (m, 10 H, Ph). Ϫ ¹³C NMR (50 MHz): δ ϭ 8.4 (q,

CCH₂CH₃), 14.1 (q, OCH₂CH₃), 24.4 (t, CH₂CH₃), 25.2 (t,

ature. The reaction mixture was diluted with 20 mL of ether and CH₂CH₂C), 29.9 (t), 31.3 (t), 57.9 (s, CCH₂), 60.9 (t, OCH₂), 126.8

filtered through a pad of silica gel. The solvent was evaporated and (d, Ph), 126.9 (d, Ph), 127.2 (d, Ph), 128.0 (d, Ph), 128.1 (d, Ph),

the inhomogeneous residue was preadsorbed on silica gel. Crude

flash chromatography (50:1 gradient to 1:1) gave Ͼ 90% of 9 fol-

lowed by the products shown in Table 2Ϫ6. The individual com-

129.1 (d, ϭCH), 129.8 (d, Ph), 140.1 (s), 142.1 (s), 142.6 (s), 171.7

(s, CO₂). Ϫ MS; m/z (%) ϭ 408 (58) [M^ϩ], 362 (42) [M^ϩϪ EtOH],

289 (30), 288 (80), 206 (100), 205 (23), 191 (24), 188 (24), 178 (20),

pounds were further purified by flash chromatography as indicated 115 (27), 91 (27). Ϫ HRMS: C₂₆H₃₂O₄: calcd. 408.2301; found

in the characterization section.

408.2292 Ϯ 2 ppm. Ϫ C₂₆H₃₂O₄(408.2): calcd. C 76.44, H 7.90;

found C 76.27, H 7.90.

Oxidative Cyclization of Malonates 12aϪf with CuCl₂(2). ؊ Gen-

eral Procedure: Compounds 12aϪf (1.00 mmol) were added at Ϫ78 Diethyl 2-(Diphenylmethylene)cyclopentane-1,1-dicarboxylate (16):

°C under N₂to a solution of the lithium amide in 20 mL of dry Flash chromatography (50:1) gave 42 mg (11%) of 16 [R_f(5:1) ϭ

DME (for the amount of base, see Table 2Ϫ6). The solution was 0.47] as a colorless oil. Ϫ IR (film): ν ϭ 2981 cm (m), 1732 (s,

stirred between Ϫ78 and Ϫ60 °C for 30 min. Solid 2 was added in CO₂), 1264 (m), 1175 (m), 703 (m). Ϫ UV: λ_max(lg ε) ϭ 196 nm

Ϫ1

˜

portions at 0 °C until a brown-green color persisted in the reaction (4.54), 202 (4.51), 206 (4.46), 220 (4.10), 238 (4.01), 258 (3.82), 272

mixture and a brown suspension of excess CuCl₂was observed for

30 min. The mixture was stirred at 0 °C for 2 h unless otherwise

(3.36). Ϫ ¹H NMR (200 MHz): δ ϭ 1.09 (t, J ϭ 7.1 Hz, 6 H,

OCH₂CH₃), 1.60 (tt, J ϭ 7.4, 7.0 Hz, 2 H, CCH₂CH₂), 2.41 (t, J ϭ

noted. The mixture was quenched with four drops of a saturated 7.4 Hz, 2 H, CCH₂), 2.43 (t, J ϭ 6.9 Hz, 2 H, CCH₂), 3.69 (dq,

NH₄Cl solution and allowed to warm to room temperature. The

reaction mixture was diluted with 20 mL of ether and filtered

J ϭ 10.7, 7.1 Hz, 2 H, OCH₂), 3.88 (dq, J ϭ 10.7, 7.1 Hz, 2 H,

OCH₂), 7.09Ϫ7.36 (m, 10 H, Ph). Ϫ ¹³C NMR (100 MHz): δ ϭ

through a pad of silica gel, and the solvent was evaporated. Crude 13.8 (q, OCH₂CH₃), 23.1 (t), 32.7 (t), 40.0 (t), 61.3 (t, OCH₂), 65.0

flash chromatography of the residue (50:1 gradient to 1:1) gave the (s, CCO₂), 126.4 (d, Ph), 126.6 (d, Ph), 127.5 (d, Ph), 128.1 (d, Ph),

products shown in Table 2Ϫ6. The individual compounds were fur-

ther purified by flash chromatography as indicated in the character-

ization section.

128.3 (d, Ph), 129.2 (d, Ph), 138.96 (s), 139.02 (s), 141.0 (s), 144.1

(s), 169.4 (s, CO₂), 171.0 (s, CO₂). Ϫ MS; m/z (%) ϭ 378 (32) [M^ϩ],

260 (33) [M^ϩϪ OEt Ϫ CO₂Et], 259 (42) [M^ϩϪ EtOH Ϫ CO₂Et],

3346

Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

232 (33) [M^ϩϪ 2 CO₂Et], 231 (100) [M^ϩϪ EtOH Ϫ CO Ϫ

CHCH₃), 1.74 (m, 1 H), 1.84 (m, 2 H), 1.98 (m, 1 H), 2.58 (m, 1

CO₂Et], 216 (33), 215 (40), 203 (31), 202 (42), 184 (20), 165 (26). H), 3.30 (m, 1 H), 4.08 (q, J ϭ 7.1 Hz, 1 H, OCH₂), 4.19 (q, J ϭ

Ϫ HRMS: C₂₄H₂₆O₄: calcd. 378.1831; found 378.1823 Ϯ 2 ppm.

7.1 Hz, 1 H, OCH₂). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.9 (q,

OCH₂CH₃), 14.0 (q, OCH₂CH₃), 20.9 (q, CHCH₃), 22.8 (t), 22.9

(q, CHCH₃), 28.7 (t), 29.5 (d, CHCH₃), 36.6 (t), 53.4 (d, CHCH₂),

60.9 (t, OCH₂), 61.1 (t, OCH₂), 64.0 (s, CCO₂), 170.9 (s, CO₂),

172.8 (s, CO₂). Ϫ HRMS: C₁₄H₂₄O₄: calcd. 256.1675; found

256.1674 Ϯ 2 ppm.

Diethyl 2-(Diphenylhydroxymethyl)cyclopentane-1,1-dicarboxylate

(17): Flash chromatography (50:1) gave 16 mg (4%) of 17 as a col-

orless oil [R_f(5:1) ϭ 0.52]. Ϫ IR (film): ν˜ ϭ 3459 cm^Ϫ1(w, OH),

2978 (m), 1730 (s, CO₂), 1242 (s), 1177 (m), 1086 (m), 702 (m). Ϫ

UV: λ_max(lg ε) ϭ 198 nm (4.58), 218 (4.14), 224 (4.06), 230 (3.95),

252 (3.87), 276 (3.23). Ϫ ¹H NMR (200 MHz): δ ϭ 0.89 (t, J ϭ Diethyl

7.2 Hz, 3 H, OCH₂CH₃), 1.18 (m, 1 H), 1.24 (t, J ϭ 7.1 Hz, 3 H, (20b): Flash chromatography (50:1) and recrystallization from

2-(2-Ferrocenylprop-2-yl)cyclopentane-1,1-dicarboxylate

OCH₂CH₃), 1.44 (m, 1 H), 1.82 (m, 2 H), 2.24 (dt, J ϭ 12.7, 5.7 Hz,

pentane gave 20b [R_f(10:1) ϭ 0.38] as a yellow solid; m.p. 67Ϫ70

1 H), 2.45 (dd, J ϭ 12.2, 5.2 Hz, 1 H), 2.69 (dq, J ϭ 10.8, 7.1 Hz, °C (for yields, see Table 3). Ϫ IR (KBr): ν˜ ϭ 2979 cm^Ϫ1(m), 1743

1 H, OCH₂), 3.54 (dq, J ϭ 10.8, 7.1 Hz, 1 H, OCH₂), 4.15 (q, J ϭ (m, CO₂), 1716 (s, CO₂), 1257 (s), 1182 (m). Ϫ UV: λ_max(lg ε) ϭ

7.1 Hz, 2 H, OCH₂), 4.47 (t, J ϭ 8.0 Hz, 1 H, CHCH₂), 4.72 (s, 1 204 nm (4.63), 232 (3.75), 246 (3.60), 266 (3.37), 284 (2.94), 294

H, OH), 7.00Ϫ7.72 (m, 10 H, Ph). Ϫ ¹³C NMR (50 MHz): δ ϭ (2.44), 440 (2.12), 458 (2.13). Ϫ H NMR (200 MHz): δ ϭ 1.13 (s,

1

13.3 (q, OCH₂CH₃), 14.0 (q, OCH₂CH₃), 24.4 (t), 27.8 (t), 39.0 (t), 3 H, CCH₃), 1.20 (t, J ϭ 6.8 Hz, 3 H, OCH₂CH₃), 1.24 (t, J ϭ

51.8 (d, CH₂CH), 61.7 (t, OCH₂), 62.0 (t, OCH₂), 64.3 (s, CCH₂), 6.8 Hz, 3 H, OCH₂CH₃), 1.40 (s, 3 H, CCH₃), 1.31Ϫ1.88 (m, 5 H),

79.4 (s, COH), 125.2 (d, Ph), 125.8 (d, Ph), 126.0 (d, Ph), 126.4 (d,

2.35 (m, 1 H), 2.66 (dd, J ϭ 10.0, 7.1 Hz, 1 H, CHCH₂), 3.95Ϫ4.26

Ph), 127.85 (d, Ph), 127.93 (d, Ph), 147.0 (s, Ph), 147.1 (s, Ph), (m, 8 H, OCH₂, CpC), 4.12 (s, 5 H, Cp). Ϫ ¹³C NMR (50 MHz):

172.3 (s, CO₂), 174.9 (s, CO₂). Ϫ MS; m/z (%) ϭ 396 (1) [M^ϩ], 379

δ ϭ 13.8 (q, OCH₂CH₃), 14.0 (q, OCH₂CH₃), 21.8 (q, CCH₃), 22.6

(8) [M^ϩϪ OH], 260 (10) [M^ϩϪ OH Ϫ OEt Ϫ CO₂Et], 232 (9) [M^ϩ(t), 27.7 (q, CCH₃), 27.8 (t), 35.6 (s, CCH₃), 38.5 (t), 57.8 (d,

Ϫ OH Ϫ CO₂Et Ϫ EtOH Ϫ CO], 214 (21), 183 (52) [Ph₂COH], 182 CHCH₂), 60.8 (t, OCH₂), 60.9 (t, OCH₂), 61.5 (s, CCH₂), 66.4 (d,

(51), 168 (22), 105 (100), 77 (46) [Ph].

Cp), 66.6 (d, Cp), 67.2 (d, Cp), 67.5 (d, Cp), 68.7 (d, Cp), 102.9 (s,

(ipso-Cp)C), 172.0 (s, CO₂), 173.1 (s, CO₂). Ϫ MS; m/z (%) ϭ 440

(100) [M^ϩ], 227 (56) [M^ϩϪ 2 CO₂Et Ϫ Cp). Ϫ HRMS:

C₂₄H₃₂FeO₄: calcd. 440.1650; found 440.1650 Ϯ 3 ppm.

Ethyl

1,1-Dimethyl-3-oxo-tetrahydrocyclopenta[c]furan-3a-carb-

oxylate (14b): Flash chromatography (30:1) gave 14b [R_f(2:1) ϭ

0.61] as a colorless oil (for yields, see Table 3). Ϫ IR (film): ν˜ ϭ

2981 cm^Ϫ1(m), 1769 (s, CO₂), 1735 (s, CO₂), 1272 (s), 1257 (s), Diethyl 2-(2-Chloroprop-2-yl)cyclopentane-1,1-dicarboxylate (21b):

1

1180 (s), 1162 (s), 1105 (s). Ϫ H NMR (400 MHz): δ ϭ 1.27 (t, Flash chromatography (40:1) gave 35 mg (12%) or 195 mg (67%) of

J ϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.36 (s, 3 H, CCH₃), 1.45 (s, 3 H, 21b [R_f(10:1) ϭ 0.45] as a colorless solid; m.p. 32Ϫ33 °C. Ϫ IR

Ϫ1

˜

CCH₃), 1.54 (m, 1 H, CHCH₂CH₂), 1.80 (m, 3 H, CHCH₂CH₂), (KBr): ν ϭ 2984 cm (m), 1728 (s, CO₂), 1263 (s), 1181 (m). Ϫ

2.25 (m, 2 H, CH₂CCO₂), 2.83 (t, J ϭ 5.4 Hz, 1 H, CH), 4.20 (q, ¹H NMR (200 MHz): δ ϭ 1.21 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃),

J ϭ 7.0 Hz, 2 H, OCH₂). Ϫ ¹³C NMR (100 MHz): δ ϭ 13.9 (q,

1.24 (t, J ϭ 7.2 Hz, 3 H, OCH₂CH₃), 1.57Ϫ1.90 (m, 3 H), 1.61 (s,

OCH₂CH₃), 24.2 (q, CCH₃), 26.7 (t), 30.0 (t), 30.3 (q, CCH₃), 36.6 3 H, CCH₃), 1.70 (s, 3 H, CCH₃), 2.02 (m, 2 H, CH₂CH), 2.55 (m,

(t), 54.5 (d, CH), 62.0 (t, OCH₂), 64.0 (s, CCO₂), 84.8 (s, C(CH₃)₂], 1 H), 2.96 (dd, J ϭ 10.0, 8.4 Hz, 1 H, CHCH₂), 4.05 (dq, J ϭ 10.8,

171.2 (s, CO₂), 175.4 (s, CO₂). Ϫ MS; m/z (%) ϭ 211 (48) [M^ϩ

Ϫ

7.1 Hz, 1 H, OCH₂), 4.10 (dq, J ϭ 10.8, 7.1 Hz, 1 H, OCH₂), 4.18

CH₃], 182 (74), 140 (48), 137 (68), 135 (40), 109 (100), 95 (43), 67 (dq, J ϭ 10.8, 7.2 Hz, 2 H, OCH₂). Ϫ ¹³C NMR (50 MHz): δ ϭ

(59). Ϫ C₁₂H₁₈O₄(226.1): calcd. C 63.70, H 8.02; found C 63.84, 13.6 (q, OCH₂CH₃), 14.0 (q, OCH₂CH₃), 22.0 (t), 28.1 (t), 31.2 (q,

H 8.00.

CH₃), 35.0 (q, CH₃), 38.3 (t), 57.3 (d, CH), 61.2 (t, OCH₂), 61.3 (t,

OCH₂), 72.2 (s, CCl), 170.8 (s, CO₂), 172.8 (s, CO₂). Ϫ MS; m/z

(%) ϭ 292/290 (0.2/0.4) [M^ϩ], 254 (20) [M^ϩϪ HCl], 213 (34), 181

(57) [M^ϩϪ HCl Ϫ CO₂Et], 180 (100) [M^ϩϪHCl Ϫ EtOH Ϫ CO],

163 (23) [M^ϩϪ HCl Ϫ OEt Ϫ EtOH], 135 (65), 134 (45), 107 (36).

Ϫ C₁₄H₂₃ClO₄(290.8): calcd. C 57.83, H 7.97, Cl 12.19; found C

57.72, H 8.11, Cl 12.15.

Diethyl 2-Isopropenylcyclopentane-1,1-dicarboxylate (18b): Flash

chromatography (50:1) gave 18b/19b [R_f(10:1) ϭ 0.61] as an insep-

arable mixture (for yields, see Table 3). Ϫ IR (film): ν ϭ 2980 cm

(m), 1729 (s, CO₂), 1448 (w), 1261 (s), 1211 (m), 1176 (m), 1158

(m), 1031 (w). Ϫ H NMR (400 MHz): δ ϭ 1.16 (t, J ϭ 7.1 Hz, 3

H, OCH₂CH₃), 1.21 (t, J ϭ 7.0 Hz, 3 H, OCH₂CH₃), 1.52 (m, 1

Ϫ1

˜

1

H, CHCH₂CH₂), 1.72 (s, 3 H, ϭCCH₃), 1.74 (m, 1 H, CHCH₂), Oxidative Cyclization of Malonate 12c with 1: Compound 12c

1.84 (m, 2 H, CHCH₂CH₂), 1.98 (ddd, J ϭ 14.1, 8.4, 3.1 Hz, 1 H, (258 mg, 1.00 mmol) was added at Ϫ78 °C under N₂to a mixture

CH₂CH₂C), 2.58 (ddd, J ϭ 13.8, 9.6, 8.1 Hz, 1 H, CH₂CH₂C), 3.30 of anhydrous LiBr (670 mg, 7.70 mmol) and LDA (1.10 mmol; pre-

(dd, J ϭ 9.5, 7.9 Hz, 1 H, CH), 4.06 (q, J ϭ 7.1 Hz, 2 H, OCH₂), pared from 155 µL of iPr₂NH and 690 µL of BuLi [1.6  in hex-

4.12 (q, J ϭ 7.1 Hz, 2 H, OCH₂), 4.73 (d, J ϭ 1.0 Hz, 1 H, ϭCH₂),

4.74 (d, J ϭ 1.4 Hz, 1 H, ϭCH₂). Ϫ ¹³C NMR (100 MHz): δ ϭ and Ϫ60 °C for 30 min. Solid 1 (1.39 g, 4.20 mmol) was added in

13.9 (q, OCH₂CH₃), 14.0 (q, OCH₂CH₃), 23.2 (q, CCH₃), 23.4 (t), four portions at 0 °C. After 5 min, the resulting blue-green color

ane]) in 20 mL of dry DME. The mixture was stirred between Ϫ78

30.8 (t), 35.2 (t), 51.7 (d, CH), 60.9 (t, OCH₂), 61.1 (t, OCH₂), 64.0 of the reaction mixture changed to brown. The mixture was stirred

(s, CCH₂), 112.2 (t, ϭCH₂), 145.2 (s, ϭC), 170.9 (s, CO₂), 172.8 (s, at 0 °C for 12 min. The mixture was quenched with six drops of a

CO₂). Ϫ MS; m/z (%) ϭ 254 (22) [M^ϩ], 180 (100) [M^ϩϪ CO Ϫ 2  HCl solution and stirred for 7 min while warming to room

EtOH], 163 (26), 135 (55) [M^ϩϪ CO₂Et Ϫ EtOH], 107 (32) [M^ϩtemperature. The reaction mixture was diluted with 20 mL of ether

Ϫ 2 CO₂Et]. Ϫ HRMS: C₁₄H₂₂O₄: calcd. 254.1518; found 254.1518 and filtered through a pad of silica gel. The solvent was evaporated

Ϯ 2 ppm.

and the inhomogeneous residue was preadsorbed on silica gel.

Flash chromatography (50:1 gradient to 1:1) gave 189 mg (78%)

of 22.

Diethyl 2-Isopropylcyclopentane-1,1-dicarboxylate (19b):

NMR (400 MHz): δ ϭ 0.81 (d, J ϭ 6.6 Hz, 3 H, CHCH₃), 0.89 (d,

Ϫ

¹H

J ϭ 6.6 Hz, 3 H, CHCH₃), 1.16 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃), Diethyl 2-Formylcyclopentane-1,1-dicarboxylate (22): Flash chro-

1.21 (t, J ϭ 7.0 Hz, 3 H, OCH₂CH₃), 1.42 (m, 1 H), 1.71 (m, 1 H, matography (40:1) gave 22 [R_f(5:1) ϭ 0.35] as a colorless oil (for

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3347

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

yields, see Table 4). Ϫ IR (film): ν˜ ϭ 2983 cm^Ϫ1(m), 2901 (w, CCH₂), 47.8 (d, CH₂CH), 53.4 (q, OCH₃), 61.1 (t, OCH₂CH₃),

FULL PAPER

CHO), 2880 (w, CHO), 1735 (s, CHO), 1714 (s, CO₂), 1263 (s),

1213 (m). Ϫ H NMR (200 MHz): δ ϭ 1.11 (t, J ϭ 7.1 Hz, 3 H,

61.2 (t, OCH₂CH₃), 62.2 (s, CH₂C), 67.5 (t, OCH₂CH₂), 103.6 (d,

CHCHO), 170.8 (s, CO₂), 172.3 (s, CO₂). Ϫ MS; m/z (%) ϭ 299

1

OCH₂CH₃), 1.15 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.63 (m, 2 H), (20) [M^ϩϪ OMe], 257 (51) [M^ϩϪ OBu], 197 (38) [M^ϩϪ OMe

1.88 (m, 2 H), 2.17 (m, 2 H), 3.13 (dt, J ϭ 8.3, 0.9 Hz, 1 H, Ϫ OBu Ϫ Et], 183 (46), 169 (22), 123 (50), 117 (82), 61 (100). Ϫ

CHCHO), 4.06 (q, J ϭ 7.1 Hz, 2 H, OCH₂), 4.122 (q, J ϭ 7.1 Hz, MS (NH₃, CI, pos.): m/z (%) ϭ 348 (6) [M^ϩϩ NH₄], 299 (100)

1 H, OCH₂), 4.125 (q, J ϭ 7.1 Hz, 1 H, OCH₂), 9.65 (d, J ϭ 0.9 Hz,

1 H, CHO). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.9 (q, OCH₂CH₃), 14.0

(q, OCH₂CH₃), 22.6 (t), 25.1 (t), 34.6 (t), 57.5 (d, CHCH₂), 61.8

(t, OCH₂), 61.9 (t, OCH₂), 62.5 (s, CCO₂), 170.0 (s, CO₂), 171.0 (s,

CO₂), 200.0 (d, CHO). Ϫ MS; m/z (%) ϭ 240 (10), 213 (20) [M^ϩ

Ϫ CHO], 197 (12) [M^ϩϪ OEt], 169 (35) [M^ϩϪ CO₂Et], 168 (48)

[M^ϩϪ EtOH Ϫ CO], 141 (40), 140 (100) [M^ϩϪ CO₂Et Ϫ CHO],

139 (22) [M^ϩϪ CO Ϫ EtOH Ϫ CHO], 123 (20) [M^ϩϪ EtOH Ϫ

CO₂Et], 113 (43), 112 (48), 111 (29), 95 (72) [M^ϩϪ CO₂Et Ϫ EtOH

Ϫ CO], 67 (78).

[M^ϩϪ OMe], 276 (18), 257 (66) [M^ϩϪ OBu].

Diethyl 2-[2,2-Bis(ethoxycarbonyl)-1,7-dimethoxyhept-6-enyl]cyclo-

pentane-1,1-dicarboxylate (25): Flash chromatography (35:1) gave

90 mg (35%) of a 21:5:4:1 diastereomeric mixture of syn/anti-(E)/

˜

(Z)-25/25Ј [R_f(5:1) ϭ 0.24] as a colorless oil. Ϫ IR (film): ν ϭ

1

2940 cm^Ϫ1(w), 1731 (s, CO₂), 1255 (m), 1213 (w). Ϫ 25: H NMR

(400 MHz): δ ϭ 1.12 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.14 (t, J ϭ

7.1 Hz, 6 H, OCH₂CH₃), 1.17Ϫ1.39 (m, 4 H), 1.42Ϫ1.95 (m, 7 H),

2.25 (m, 1 H), 2.72 (dt, J ϭ 8.2, 2.9 Hz, 1 H, CCHCHCH₂), 3.11

(s, 3 H, CHOCH₃), 3.34 (s, 3 H, ϭCHOCH₃), 3.92Ϫ4.15 (m, 8 H,

Diethyl 2-(Dimethoxymethyl)cyclopentane-1,1-dicarboxylate (23): OCH₂), 4.18 (m, 1 H, CCHOCH₃), 4.55 (m, 1 H, (Z)-ϭCHCH₂),

Flash chromatography (10:1) gave 29 mg (10%) or 69 mg (24%) of

23 [R_f(5:1) ϭ 0.35] as a colorless oil. Ϫ IR (film): ν˜ ϭ 2941 cm^Ϫ1

(m), 1731 (s, CO₂), 1729 (s, CO₂), 1447 (m), 1261 (s), 1094 (s), 1073

4.62 (dt, J ϭ 12.7, 7.3 Hz, 1 H, (E)-ϭCHCH₂), 5.72 (d, J ϭ 6.2 Hz,

1 H, (Z)-ϭCHOCH₃), 6.14 (d, J ϭ 12.6 Hz, 1 H, (E)-ϭCHOCH₃).

Ϫ

¹³C NMR (100 MHz): δ ϭ 13.90 (q, OCH₂CH₃), 13.92 (q,

(s), 1061 (s). Ϫ ¹H NMR (200 MHz): δ ϭ 1.19 (t, J ϭ 7.1 Hz, 3 OCH₂CH₃), 13.96 (q, OCH₂CH₃), 13.98 (q, OCH₂CH₃), 23.2 (t),

H, OCH₂CH₃), 1.20 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.45 (m, 1

H), 1.73 (m, 3 H), 2.04 (m, 1 H), 2.34 (m, 1 H), 2.98 (m, 1 H, 55.8 (q, OCH₃), 59.2 (q, OCH₃), 60.8 (t, OCH₂), 60.9 (t, OCH₂),

CH₂CH), 3.23 (s, 3 H, OCH₃), 3.25 (s, 3 H, OCH₃), 4.00 (dq, J ϭ 61.1 (t, OCH₂), 61.8 (s, CCH₂), 63.6 (s, CCH₂), 80.9 (d,

10.8, 7.1 Hz, 1 H, OCH₂), 4.08 (dq, J ϭ 10.8, 7.1 Hz, 1 H, OCH₂), CCHOCH₃), 102.2 (d, (E)-ϭCHCH₂), 106.0 (d, (Z)-ϭCHCH₂),

4.16 (dq, J ϭ 10.8, 7.1 Hz, 1 H, OCH₂), 4.19 (dq, J ϭ 10.8, 7.1 Hz, 147.2 (d, (Z)-ϭCHOCH₃), 147.3 (d, (E)-ϭCHOCH₃), 170.2 (s,

24.0 (t), 25.8 (t), 28.0 (t), 33.0 (t), 34.7 (t), 47.0 (d, CCHCHCH₂),

1

1 H, OCH₂), 4.35 (d, J ϭ 6.7 Hz, 1 H, CHOCH₃). Ϫ ¹³C NMR CO₂), 171.15 (s, CO₂), 171.17 (s, CO₂), 172.4 (s, CO₂). Ϫ 25Ј: H

(50 MHz): δ ϭ 13.9 (q, OCH₂CH₃), 22.9 (t), 25.8 (t), 34.6 (t), 47.7 NMR (400 MHz): δ ϭ 1.12 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.14

(d, CH₂CH), 52.9 (q, OCH₃), 54.5 (q, OCH₃), 61.0 (t, OCH₂), 61.2 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.17Ϫ1.39 (m, 4 H), 1.42Ϫ1.95

(t, OCH₂), 62.0 (s, CCO₂), 104.5 (d, CHOCH₃), 170.9 (s, CO₂), (m, 7 H), 2.25 (m, 1 H), 2.72 (m, 1 H, CCHCHCH₂), 3.15 (s, 3 H,

172.4 (s, CO₂). Ϫ MS; m/z (%) ϭ 288 (3) [M^ϩ], 257 (20) [M^ϩ

Ϫ

CHOCH₃), 3.41 (s, 3 H, ϭCHOCH₃), 3.92Ϫ4.15 (m, 8 H, OCH₂),

OMe], 243 (10) [M^ϩϪ OEt], 183 (34) [M^ϩϪ CO Ϫ EtOH Ϫ 4.18 (m, 1 H, CCHOCH₃), 4.62 (dt, J ϭ 12.7, 7.3 Hz, 1 H, (E)-ϭ

OMe], 123 (27) [M^ϩϪ EtOH Ϫ CO Ϫ 2 OMe Ϫ Et], 75 (100). Ϫ

C₁₄H₂₄O₆(288.2): calcd. C 58.32, H 8.39; found C 58.35, H 8.66.

CHCH₂), 4.62 (m, 1 H, (Z)-ϭCHCH₂), 5.72 (d, J ϭ 6.2 Hz, 1 H,

(Z)-ϭCHOCH₃), 6.14 (d, J ϭ 12.6 Hz, 1 H, (E)-ϭCHOCH₃). Ϫ

¹³C NMR (50 MHz): δ ϭ 13.93 (q, OCH₂CH₃), 13.96 (q,

OCH₂CH₃), 13.98 (q, OCH₂CH₃), 14.1 (q, OCH₂CH₃), 22.1 (t),

24.0 (t), 26.4 (t), 28.3 (t), 32.7 (t), 35.8 (t), 52.3 (d, CCHCHCH₂),

56.7 (q, OCH₃), 59.3 (q, OCH₃), 60.8 (t, OCH₂), 60.9 (t, OCH₂),

61.1 (t, OCH₂), 61.8 (s, CCH₂), 62.9 (s, CCH₂), 85.4 (d,

CCHOCH₃), 102.4 (d, (E)-ϭCHCH₂), 106.0 (d, (Z)-ϭCHCH₂),

147.2 (d, (Z)-ϭCHOCH₃), 147.3 (d, (E)-ϭCHOCH₃), 170.0 (s,

CO₂), 171.16 (s, CO₂), 172.0 (s, CO₂). Ϫ MS (NH₃, CI, pos.): m/z

(%) ϭ 532 (13) [M^ϩϩ NH₄], 434 (65), 402 (28), 297 (29), 295 (28),

276 (28), 257 (100) [M^ϩ/2]. Ϫ C₂₆H₄₂O₁₀(514.6): calcd. C 60.68,

H 8.23; found C 60.76, H 8.15.

Diethyl

2-(Butoxymethoxymethyl)cyclopentane-1,1-dicarboxylate

(24): Flash chromatography (35:1) gave 13 mg (4%) or 73 mg (22%)

of a 1:1 diastereomeric mixture of 24/24Ј [R_f(5:1) ϭ 0.43] as a

Ϫ1

˜

colorless oil. Ϫ IR (film): ν ϭ 2961 cm (m), 1732 (s, CO₂), 1261

(m), 1097 (m), 1073 (m), 1046 (m). Ϫ 24: ¹H NMR (400 MHz):

δ ϭ 0.84 (t, J ϭ 7.3 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t, J ϭ 7.0 Hz,

3 H, OCH₂CH₃), 1.19 (t, J ϭ 7.0 Hz, 3 H, OCH₂CH₃), 1.29 (m, 2

H, CH₂CH₂CH₃), 1.44 (m, 4 H, CCH₂CH₂, CH₂CH₂CH₃),

1.61Ϫ1.83 (m, 2 H, CHCH₂), 1.95 (m, 1 H, CCH₂CH₂), 2.32 (m,

1 H, CCH₂CH₂), 2.91 (dt, J ϭ 8.1, 5.6 Hz, 1 H, CH₂CH), 3.22 (s,

3 H, OCH₃), 3.32 (m, 1 H, OCH₂CH₂), 3.55 (m, 1 H, OCH₂CH₂),

4.00 (m, 2 H, OCH₂CH₃), 4.15 (m, 2 H, OCH₂CH₃), 4.46 (d, J ϭ

Ethyl 3-Oxo-1-phenyltetrahydrocyclopenta[c]furan-3a-carboxylate

5.5 Hz, 1 H, CHOCH₃). Ϫ ¹³C NMR (100 MHz): δ ϭ 13.8 (q, (14d): Flash chromatography (35:1) gave a diastereomeric mixture

CH₂CH₂CH₃), 13.9 (q, OCH₂CH₃), 19.2 (t, CH₂CH₂CH₃), 22.8 (t, of 14d/14dЈ [R_f(5:1) ϭ 0.49] as a colorless oil (for yields, see

CHCH₂CH₂), 25.1 (t, CHCH₂), 31.8 (t, OCH₂CH₂), 35.3 (t, Table 5). Ϫ IR (film): ν˜

؍

2969 cm^Ϫ1(m), 1779 (s, CO₂), 1741 (s,

CCH₂), 48.4 (d, CH₂CH), 54.0 (q, OCH₃), 60.8 (t, OCH₂CH₃),

CO₂), 1453 (w), 1251 (s), 1147 (m), 729 (w), 701 (w). Ϫ 14d: UV:

61.2 (t, OCH₂CH₃), 61.8 (s, CH₂C), 65.3 (t, OCH₂CH₂), 103.6 (d, λ_max(lg ε) ϭ 192 nm (4.47), 198 (4.24), 206 (4.02), 210 (3.92), 222

CHCHO), 170.7 (s, CO₂), 172.4 (s, CO₂). Ϫ 24Ј: ¹H NMR (3.54). Ϫ ¹H NMR (200 MHz): δ ϭ 1.15 (t, J ϭ 7.1 Hz, 3 H,

(400 MHz): δ ϭ 0.84 (t, J ϭ 7.3 Hz, 3 H, CH₂CH₂CH₃), 1.18 (t, OCH₂CH₃), 1.55Ϫ1.77 (m, 2 H), 1.80Ϫ2.04 (m, 2 H), 2.16Ϫ2.46

J ϭ 7.0 Hz, 3 H, OCH₂CH₃), 1.20 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃),

1.29 (m, H, CH₂CH₂CH₃), 1.44 (m,

H, CCH₂CH₂, 5.00 (d, J ϭ 4.6 Hz, 1 H, CHPh), 7.34 (m, 5 H, Ph). Ϫ ¹³C NMR

CH₂CH₂CH₃), 1.61Ϫ1.83 (m, 3 H, CHCH₂CH₂), 2.06 (m, 1 H, (50 MHz): δ ϭ 13.8 (q, OCH₂CH₃), 25.5 (t), 33.8 (t), 35.0 (t), 54.4

CCH₂CH₂), 2.32 (m, 1 H, CCH₂CH₂), 3.01 (q, J ϭ 7.3 Hz, 1 H, (d, CH₂CH), 62.1 (t, OCH₂), 62.3 (s, CCH₂), 85.1 (d, OCHPh),

(m, 2 H), 3.08 (m, 1 H, CH₂CH), 4.12 (q, J ϭ 7.1 Hz, 2 H, OCH₂),

2

3

CH₂CH), 3.22 (s, 3 H, OCH₃), 3.41 (m, 1 H, OCH₂CH₂), 3.48 (m, 125.4 (d, Ph), 128.4 (d, Ph), 128.7 (d, Ph), 139.9 (s, Ph), 170.6 (s,

1

1 H, OCH₂CH₂), 4.15 (m, 4 H, OCH₂CH₃), 4.39 (d, J ϭ 7.2 Hz, 1 CO₂), 176.2 (s, CO₂). Ϫ 14dЈ: H NMR (200 MHz): δ ϭ 1.20 (m,

H, CHOCH₃).

Ϫ δ ϭ 13.8 (q, 1 H), 1.28 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.35Ϫ1.71 (m, 3 H),

¹³C NMR (100 MHz):

CH₂CH₂CH₃), 13.9 (q, OCH₂CH₃), 19.3 (t, CH₂CH₂CH₃), 22.7 (t, 2.35 (m, 3 H), 3.26 (m, 1 H, CH₂CH), 4.24 (q, J ϭ 7.1 Hz, 2 H,

CHCH₂CH₂), 26.2 (t, CHCH₂), 31.8 (t, OCH₂CH₂), 35.2 (t, OCH₂), 5.80 (d, J ϭ 6.5 Hz, 1 H, CHPh), 7.34 (m, 5 H, Ph). Ϫ

3348

Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

¹³C NMR (50 MHz): δ ϭ 14.1 (q, OCH₂CH₃), 25.9 (t), 28.5 (t), (36/100) [M^ϩϪ 2 EtOH Ϫ CO], 183 (70) [M^ϩϪ Cl Ϫ 2 EtOH Ϫ

34.5 (t), 51.4 (d, CH₂CH), 62.2 (t, OCH₂), 63.8 (s, CCH₂), 81.4 (d, CO], 173 (45), 155 [M^ϩϪ Cl Ϫ 2 EtOH Ϫ 2 CO], 129 (49), 128

CHPh), 124.9 (d, Ph), 127.9 (d, Ph), 128.5 (d, Ph), 136.5 (s, Ph), (25), 127 (42), 125 (45), 115 (25), 91 (35). Ϫ HRMS: C₁₈H₂₃ClO₄:

169.7 (s, CO₂), 175.9 (s, CO₂). Ϫ MS; m/z (%) ϭ 274 (46) [M^ϩ],

246 (30), 207 (23), 200 (27) [M^ϩϪ OEt Ϫ Et], 184 (21) [M^ϩϪ 2

OEt], 167 (28), 165 (26), 161 (22), 141 (67), 140 (100), 129 (22), 115

(38), 112 (42), 111 (30), 105 (38), 77 (36), 67 (46), 57 (30), 55 (29),

43 (69), 41 (58). Ϫ C₁₆H₁₈O₄(274.3): calcd. C 70.06, H 6.61; found

C 69.92, H 6.54.

calcd. 338.1285; found 338.1280 Ϯ 2 ppm.

Diethyl 2-Vinylcyclopentane-1,1-dicarboxylate (18f): Flash chroma-

tography (50:1) gave 101 mg (42%) of 18f/19f [R_f(10:1) ϭ 0.42] as

Ϫ1

˜

an inseparable mixture. Ϫ IR (film): ν

؍

2982 cm (m), 1729 (s,

CO₂), 1263 (m), 1223 (w), 1183 (m), 1098 (w). Ϫ ¹H NMR

(200 MHz): δ ϭ 1.22 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.25 (t, J ϭ

7.1 Hz, 3 H, OCH₂CH₃), 1.65 (m, 2 H), 1.70Ϫ2.15 (m, 3 H), 2.46

(m, 1 H), 3.50 (m, 1 H, ϭCHCH), 4.08 (dq, J ϭ 10.7, 7.1 Hz, 1 H,

OCH₂), 4.16 (dq, J ϭ 10.8, 7.1 Hz, 2 H, OCH₂), 4.24 (dq, J ϭ

10.7, 7.1 Hz, 1 H, OCH₂), 4.98 (dd, J ϭ 10.3, 1.9 Hz, 1 H, ϭCH₂),

5.13 (dd, J ϭ 17.2, 1.9 Hz, 1 H, ϭCH₂), 5.81 (ddd, J ϭ 17.2, 10.2,

7.9 Hz, 1 H, ϭCH). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.9 (q,

OCH₂CH₃), 22.8 (t), 30.7 (t), 34.4 (t), 47.9 (d, ϭCHCH), 60.7 (t,

OCH₂), 61.0 (t, OCH₂), 64.0 (s, CCO₂), 115.6 (t, ϭCH₂), 137.7

(d, ϭCH), 171.5 (s, CO₂), 172.6 (s, CO₂). Ϫ MS; m/z (%) ϭ 240

(11) [M^ϩ], 195 (10) [M^ϩϪ OEt], 167 (20) [M^ϩϪ CO₂Et], 166 (100)

[M^ϩϪ EtOH Ϫ CO], 138 (25), 149 (17) [M^ϩϪ OEt Ϫ EtOH],

138 (22) [M^ϩϪ CO₂Et Ϫ Et], 120 (18), 93 (28). Ϫ HRMS:

C₁₃H₂₀O₄: calcd. 240.1362; found 240.1356 Ϯ 3 ppm.

α,αЈ-Bis[2,2-bis(ethoxycarbonyl)cyclopentyl]bibenzyl (26d): Flash

chromatography (30:1) and crystallization from pentane gave 26d

[R_f(5:1) ϭ 0.43] as a 1:1 mixture of meso and d/l dimers as colorless

crystals; m.p. 82 °C (for yields, see Table 5). Ϫ IR (KBr): ν˜ ϭ 2988

cm^Ϫ1(m), 1740 (m, CO₂), 1720 (s, CO₂), 1455 (m), 1255 (s), 1103

(m), 703 (m). Ϫ UV: λ_max(lg ε) ϭ 192 nm (4.75), 208 (4.36), 216

1

(4.19), 230 (3.39), 232 (3.19), 262 (2.77). Ϫ H NMR (400 MHz):

δ ϭ 0.88 (t, J ϭ 6.8 Hz, 6 H, OCH₂CH₃), 0.89 (t, J ϭ 7.1 Hz, 6

H, OCH₂CH₃), 0.90 (t, J ϭ 6.9 Hz, 6 H, OCH₂CH₃), 0.93 (t, J ϭ

7.1 Hz, 6 H, OCH₂CH₃), 1.52 (m, 2 H, CH₂CH₂CH₂), 1.63 (m, 2

H, CH₂CH₂CH₂*), 1.75 (m, 6 H, CH₂CH₂CH₂, CH₂CH₂CH₂*,

CH₂CH), 1.93 (dt, J ϭ 10.5, 9.1 Hz, 2 H, CH₂CH*), 2.16 (m, 2 H,

CCH₂*), 2.28 (m, 6 H, CCH₂*, CCH₂), 2.56 (m, 4 H, CH₂CH*,

CH₂CH), 3.03 (m, 2 H, CHCH₂), 3.16 (m, 2 H, CHCH₂*), 3.26

(dq, J ϭ 10.7, 7.1 Hz, 2 H, OCH₂), 3.40 (dq, J ϭ 10.7, 7.1 Hz, 2

H, OCH₂), 3.47 (dq, J ϭ 10.7, 7.0 Hz, 2 H, OCH₂), 3.51 (dq, J ϭ

10.9, 7.1 Hz, 2 H, OCH₂), 3.54 (d, J ϭ 11.5 Hz, 2 H, CHPh*), 3.60

(d, J ϭ 11.4 Hz, 2 H, CHPh), 3.68 (dq, J ϭ 10.8, 7.2 Hz, 2 H,

OCH₂), 3.74 (dq, J ϭ 10.8, 7.2 Hz, 2 H, OCH₂), 3.75 (dq, J ϭ

10.8, 7.1 Hz, 2 H, OCH₂), 3.81 (dq, J ϭ 10.8, 7.1 Hz, 2 H, OCH₂),

6.55Ϫ7.35 (m, 20 H, Ph^#, Ph*^#). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.5

(q, OCH₂CH₃), 13.6 (q, OCH₂CH₃), 22.8 (t, CHCH₂CH₂*), 23.1

(t, CHCH₂CH₂), 31.6 (t, CHCH₂*), 33.1 (t, CHCH₂), 38.1 (t,

CH₂C*), 38.8 (t, CH₂C), 47.3 (d, CHCH₂), 48.9 (d, CHCH₂*), 49.4

(d, CHPh), 52.4 (d, CHPh*), 60.4 (t, OCH₂), 60.9 (t, OCH₂), 63.0

(s, CCH₂), 63.6 (s, CCH₂*), 126.0 (d, Ph^#), 126.1 (d, Ph^#), 126.7

(d, Ph^#), 131.2 (d, Ph^#), 138.2 (s, Ph), 140.5 (s, Ph*), 171.1 (s, CO₂),

171.3 (s, CO₂), 172.47 (s, CO₂), 172.53 (s, CO₂). Ϫ MS; m/z (%) ϭ

303 (100) [M^ϩ/2], 229 (43), 155 (20). Ϫ MS (NH₃, CI, pos.): m/z

(%) ϭ 624 (3) [M^ϩϩ NH₄], 607 (100) [M^ϩϩ H], 535 (7), 322 (22),

305 (34), 303 (42) [M^ϩ/2], 298 (40), 229 (8), 158 (8), 74 (6). Ϫ

C₃₆H₄₆O₈(606.8): calcd. C 71.26, H 7.64; found C 71.08, H 7.69.

Ϫ Resonances marked with an asterisk * can be assigned to one

diastereomer on the basis of C,H correlation and HMBC spectra;

#: broadened signals.

Diethyl 2-Ethylcyclopentane-1,1-dicarboxylate (19f): Ϫ ¹H NMR

(200 MHz): δ ϭ 0.89 (t, J ϭ 6.9 Hz, 3 H, CHCH₂CH₃), 1.00 (m,

1 H), 1.21 (t, J ϭ 7.0 Hz, 6 H, OCH₂CH₃), 1.58 (m, 2 H),

1.72Ϫ2.11 (m, 3 H), 2.39 (m, 2 H), 3.19 (quint, J ϭ 7.8 Hz, 1 H,

CH), 4.12 (m, 4 H, OCH₂). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.0 (q,

CHCH₂CH₃), 14.0 (q, OCH₂CH₃), 22.9 (t), 24.2 (t), 30.3 (t), 33.8

(t), 49.7 (d, CH), 60.8 (t, OCH₂), 63.4 (s, CCH₂), 170.6 (s, CO₂),

172.0 (s, CO₂). Ϫ MS; m/z (%) ϭ 197 (25) [M^ϩϪ OEt], 173 (100),

127 (43), 95 (71).

Diethyl 2-(1-Ferrocenylethyl)cyclopentane-1,1-dicarboxylate (20f):

Flash chromatography (50:1) gave 77 mg (18%) of 20f as a 1.8:1

diastereomeric mixture [R_f(10:1) ϭ 0.39] as a yellow solid; m.p.

Ϫ1

˜

71Ϫ75 °C. Ϫ IR (KBr): ν ϭ 2971 cm (m), 1724 (s, CO₂), 1182

(m). Ϫ UV: λ_max(lg ε) ϭ 204 nm (4.59), 232 (3.70), 242 (3.58), 256

(3.46), 268 (3.29), 412 (2.13), 440 (2.11). Ϫ H NMR (400 MHz):

1

δ ϭ 1.07 (d, J ϭ 7.0 Hz, 3 H, CHCH₃), 1.17 (t, J ϭ 6.9 Hz, 3 H,

OCH₂CH₃*), 1.18 (t, J ϭ 7.0 Hz, 3 H, OCH₂CH₃), 1.29 (t, J ϭ

7.1 Hz, 3 H, OCH₂CH₃*), 1.30 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃),

1.39 (d, J ϭ 6.8 Hz, 3 H, CHCH₃*), 1.47 (m, 4 H), 1.67 (m, 3 H),

1.90 (m, 2 H), 2.31 (m, 5 H), 2.69 (ddd, J ϭ 9.8, 7.4, 3.7 Hz, 1 H,

CHCH₂), 2.98 (dq, J ϭ 7.0, 3.4 Hz, 1 H, CHCH₃), 3.99Ϫ4.28 (m,

16 H, OCH₂, OCH₂*, CpC, CpC*), 4.06 (s, 5 H, Cp*), 4.07 (s, 5

H, Cp). Ϫ ¹³C NMR (100 MHz): δ ϭ 13.9 (q, OCH₂CH₃*), 14.1

(q, OCH₂CH₃), 15.8 (q, CHCH₃), 20.4 (q, CHCH₃*), 22.1 (t*),

22.3 (t), 25.7 (t), 31.1 (t*), 32.4 (d, CHCH₃), 35.22 (t), 35.24 (d,

CHCH₃*), 37.1 (t*), 53.1 (d, CHCH₂), 54.9 (d, CHCH₂*), 60.8 (t,

OCH₂*), 60.99 (t, OCH₂), 61.05 (t, OCH₂), 62.8 (s, CCH₂*), 63.0

(s, CCH₂), 65.5 (d, Cp*), 66.07 (d, Cp), 66.14 (d, Cp*), 66.6 (d,

Cp), 66.9 (d, Cp), 67.0 (d, Cp*), 67.94 (d, Cp), 68.35 (d, Cp*), 68.41

(d, Cp), 69.14 (d, Cp*), 95.2 (s, (ipso-Cp)C*), 96.1 (s, (ipso-Cp)C),

171.3 (s, CO₂*), 171.5 (s, CO₂), 172.5 (s, CO₂), 173.2 (s, CO₂*).

Ϫ MS; m/z (%) ϭ 426 (20) [M^ϩ], 213 (44), 121 (20). Ϫ HRMS:

C₂₃H₃₀FeO₄: calcd. 426.1494; found 426.1490 Ϯ 3 ppm. Ϫ Reson-

ances marked with an asterisk * correspond to the minor diastereo-

mer.

Diethyl

2-(Chlorophenylmethyl)cyclopentane-1,1-dicarboxylate

(21d): Flash chromatography (50:1) gave 71 mg (21%) of 21d [R_f

Ϫ1

˜

(5:1) ϭ 0.50] as a colorless oil. Ϫ IR (film): ν ϭ 2981 cm (m),

1779 (m), 1727 (s, CO₂), 1263 (s), 1209 (m), 1179 (m), 1151 (m),

1096 (m), 700 (m). Ϫ UV: λ_max(lg ε) ϭ 194 nm (4.59), 210 (3.98),

216 (3.90), 220 (3.85), 230 (3.51), 236 (3.26), 248 (2.90), 268 (2.77),

1

282 (2.62). Ϫ H NMR (400 MHz): δ ϭ 1.13 (t, J ϭ 7.1 Hz, 3 H,

OCH₂CH₃), 1.22 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.53 (m, 1 H),

1.82 (m, 1 H), 1.97 (m, 3 H), 2.50 (m, 1 H), 3.14 (dt, J ϭ 9.1,

5.0 Hz, 1 H, CHCHPh), 3.95 (m, 2 H, OCH₂), 4.06 (m, 1 H,

OCH₂), 4.19 (dq, J ϭ 10.8, 7.1 Hz, 1 H, OCH₂), 5.56 (d, J ϭ

4.9 Hz, 1 H, CHPh), 7.20Ϫ7.43 (m, 5 H, Ph). Ϫ ¹³C NMR

(100 MHz): δ ϭ 13.8 (q, 2 OCH₂CH₃), 22.1 (t), 26.8 (t), 35.8 (t),

53.8 (d, CHCHPh), 61.4 (t, OCH₂), 61.6 (t, OCH₂), 62.3 (s, CH₂C),

64.3 (d, CHPh), 127.5 (d, Ph), 127.8 (d, Ph), 128.1 (d, Ph), 141.5

2,3-Bis[2,2-bis(ethoxycarbonyl)cyclopentyl]butane (26f): Flash chro-

(s, Ph), 170.4 (s, CO₂), 172.1 (s, CO₂). Ϫ MS; m/z (%) ϭ 340/338 matography (40:1) gave 82 mg (34%) of 26f [R_f(5:1) ϭ 0.51] as a

(25/74) [M^ϩ], 303 (19) [M^ϩϪ Cl], 294/292 (29/82) [M^ϩϪ EtOH], 6.7:6.5:4.7:3:1.7 diastereomeric mixture. Ϫ IR (film): ν˜ ϭ 2979

257 (11) [M^ϩϪ Cl Ϫ OEt], 229 (35) [M^ϩϪ Cl Ϫ CO₂Et], 220/218 cm^Ϫ1(m), 1728 (s, CO₂), 1257 (s), 1218 (m), 1178 (m), 1163 (m),

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3349

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

1

1038 (m). Ϫ H NMR (400 MHz): δ ϭ 0.60 (d, J ϭ 6.5 Hz, 3 H,

17.8 (q, CHCH₃), 23.8 (t), 31.9 (t), 36.9 (t), 62.8 (t, OCH₂), 71.0

CHCH₃*), 0.64 (d, J ϭ 7.0 Hz, 3 H, CHCH₃^#), 0.67 (d, J ϭ 7.1 Hz, (s, CCl), 125.8 (d, ϭCHCH₃) 130.1 (d, ϭCHCH₂), 166.8 (s, CO₂).

3 H, CHCH₃^#), 0.71 (d, J ϭ 6.4 Hz, 6 H, CHCH₃^ϩ), 0.77 (d, J ϭ

Diethyl 2-Methylenecyclopentane-1,1-dicarboxylate (28): Flash

$

6.7 Hz, 3 H, CHCH₃*), 0.80 (d, J ϭ 6.4 Hz, 3 H, CHCH₃), 0.82

chromatography (50:1) gave 129 mg (57%) or 127 mg (56%) of 28

$

§

(d, J ϭ 6.4 Hz, 3 H, CHCH₃), 0.90 (d, J ϭ 6.9 Hz, 6 H, CHCH₃),

1.22 (m, 62 H, CH₂, OCH₂CH₃), 1.30Ϫ2.10 (m, 64 H), 2.37 (m, 9

H, CH₂, CHCH₂), 2.54 (m, 2 H, CHCH₂), 2.74 (m, 1 H, CHCH₂),

2.81 (m, 1 H, CHCH₂), 2.91 (m, 1 H, CHCH₂), 4.00Ϫ4.21 (m, 32

H, OCH₂). Ϫ ¹³C NMR (100 MHz): δ ϭ 10.5 (q, CHCH₃^#), 11.6

Ϫ1

˜

[R_f(10:1) ϭ 0.50] as a colorless oil. Ϫ IR (film): ν ϭ 2983 cm

(m), 1731 (s, CO₂), 1267 (s), 1247 (s), 1214 (m), 1146 (m). Ϫ ¹H

NMR (200 MHz): δ ϭ 1.18 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.66

(quint, J ϭ 7.0 Hz, 2 H, CCH₂CH₂), 2.27 (t, J ϭ 6.9 Hz, 2 H,

CH₂CCO₂), 2.38 (dt, J ϭ 7.2, 2.1 Hz, 2 H, ϭCCH₂), 4.12 (q, J ϭ

7.1 Hz, 4 H, OCH₂), 5.18 (t, J ϭ 1.9 Hz, 1 H, ϭCH₂), 5.24 (t, J ϭ

2.2 Hz, 1 H, ϭCH₂). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.9 (q,

OCH₂CH₃), 24.0 (t), 33.7 (t), 36.1 (t), 61.3 (t, OCH₂), 63.5 (s,

CCO₂), 111.7 (t, ϭCH₂), 148.2 (s, ϭC), 170.5 (s, CO₂). Ϫ MS; m/

$

(q, CHCH₃*), 12.8 (q, CHCH₃*), 12.9 (q, CHCH₃), 13.6 (q,

CHCH₃^ϩ), 13.87 (q, OCH₂CH₃), 13.94 (q, OCH₂CH₃), 13.99 (q,

OCH₂CH₃), 14.03 (q, OCH₂CH₃), 14.1 (q, OCH₂CH₃), 14.3 (q,

CHCH₃), 15.3 (q, CHCH₃^#), 16.9 (q, CHCH₃), 22.3 (t), 22.6 (t),

22.7 (t), 22.9 (t), 23.0 (t), 23.2 (t), 23.8 (t), 25.5 (t), 25.6 (t), 27.5

(t), 29.3 (t), 29.8 (t), 30.2 (t, 2 CH₂), 30.8 (t), 33.6 (d, CHCH₃^#),

34.8 (d, CHCH₃^#), 34.9 (t), 35.2 (t), 36.1 (t), 36.6 (d, CHCH₃*),

37.1 (d, CHCH₃*), 37.2 (d, CHCH₃^ϩ), 37.3 (t), 37.66 (t), 37.73 (t),

$

§

z (%) ϭ 226 (28) [M^ϩ], 181 (18) [M^ϩϪ OEt], 180 (24) [M^ϩ

Ϫ

EtOH], 154 (20), 153 (92) [M^ϩϪ CO₂Et], 152 (100) [M^ϩϪ EtOH

Ϫ CO], 126 (20), 125 (76), 108 (30) [M^ϩϪ CO₂Et Ϫ OEt], 107

(22) [M^ϩϪ CO₂Et Ϫ EtOH], 81 (38), 79 (44). Ϫ HRMS:

C₁₂H₁₈O₄: calcd. 226.1205; found 226.1199 Ϯ 2 ppm. Ϫ C₁₂H₁₈O₄

(226.1): calcd. C 63.70, H 8.02; found C 63.64, H 8.34.

$

§

$

37.8 (t), 39.2 (d, CHCH₃), 40.1 (d, CHCH₃), 42.7 (d, CHCH₃),

44.0 (d), 47.0 (d), 48.0 (d), 51.0 (d), 51.3 (d), 51.47 (d), 51.49 (d),

51.6 (d), 60.6 (t, OCH₂), 60.7 (t, OCH₂), 60.78 (t, OCH₂), 60.81 (t,

OCH₂), 60.86 (t, OCH₂), 60.94 (t, OCH₂), 61.0 (t, OCH₂), 62.6 (s,

CCH₂), 62.67 (s, CCH₂), 62.72 (s, CCH₂), 63.15 (s, CCH₂), 63.18

(s, CCH₂), 63.5 (s, CCH₂), 64.2 (s, CCH₂), 171.5 (s, CO₂), 171.6 (s,

CO₂), 171.8 (s, CO₂), 171.9 (s, CO₂), 172.0 (s, CO₂), 172.66 (s, CO₂),

172.71 (s, CO₂), 172.75 (s, CO₂), 172.81 (s, CO₂), 173.3 (s, CO₂),

173.4 (s, CO₂), 173.5 (s, CO₂). Ϫ MS; m/z (%) ϭ 482 (3) [M^ϩ],

241 (100), 167 (52). Ϫ HRMS: C₂₆H₄₂O₈: calcd. 482.2880; found

482.2870 Ϯ 3 ppm. Ϫ Resonances marked with $, #, §, *, ϩ corre-

spond to different diastereomers.

Diethyl

2-(Ferrocenylmethylene)cyclopentane-1,1-dicarboxylate

(20g): Flash chromatography (50:1) gave 37 mg (9%) of 20g [R_f

Ϫ1

˜

(10:1) ϭ 0.45] as a yellow oil. Ϫ IR (film): ν ϭ 2981 cm (m),

1729 (s), 1301 (m), 1260 (s), 1245 (s), 1219 (m), 1150 (m), 1105 (m),

1097 (m), 1029 (m). Ϫ UV: λ_max(lg ε) ϭ 194 nm (4.42), 202 (4.39),

230 (4.25), 284 (4.03), 304 (3.31), 312 (3.00), 452 (2.58). Ϫ ¹H NMR

(200 MHz): δ ϭ 1.25 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.80 (tt, J ϭ

7.0, 6.9 Hz, 2 H, ϭCCH₂CH₂), 2.30 (t, J ϭ 6.9 Hz, 2 H, CCH₂),

2.51 (dt, J ϭ 7.2, 2.5 Hz, 2 H, CCH₂), 4.09 (s, 5 H, Cp), 4.20 (m,

8 H, OCH₂, CpC), 4.32 (t, J ϭ 1.8 Hz, 1 H, ϭCH). Ϫ ¹³C NMR

(50 MHz): δ ϭ 14.1 (q, OCH₂CH₃), 24.6 (t), 31.8 (t), 36.0 (t), 61.4

(t, OCH₂), 65.1 (s, ϭCC), 68.7 (d, Cp), 69.0 (d, Cp), 82.2 (s, (ipso-

Cp)C), 124.7 (d, ϭCH), 136.7 (s, ϭC), 171.0 (s, CO₂). Ϫ MS; m/z

(%) ϭ 410 (16) [M^ϩ], 337 (2) [M^ϩϪ CO₂Et], 240 (12), 167 (21),

166 (100), 149 (16), 138 (21), 121 (17), 120 (19), 93 (27). Ϫ HRMS:

Diethyl

2-(1-Chloroethyl)cyclopentane-1,1-dicarboxylate

Flash chromatography (50:1) gave 196 mg (71%) of 21f as a 3:1

diastereomeric mixture [R_f(10:1) ϭ 0.40] and as a colorless oil. Ϫ

IR (film): ν ϭ 2983 (w), 1730 (s, CO₂), 1263 (m), 1211 (w). Ϫ H

(21f):

1

˜

NMR (200 MHz): δ ϭ 1.20 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃*), 1.21

(t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.24 (t, J ϭ 7.1 Hz, 3 H,

OCH₂CH₃), 1.41 (d, J ϭ 6.6 Hz, 3 H, CHCH₃*), 1.51 (d, J ϭ

6.7 Hz, 3 H, CHCH₃), 1.60 (m, 1 H, 1H*), 1.76Ϫ2.04 (m, 4 H, 4

H*), 2.35 (m, 1 H*), 2.47 (m, 1 H), 2.90 (ddd, J ϭ 9.7, 7.8, 3.9 Hz,

1 H, CHCHCl), 2.93 (m, 1 H, CHCHCl*), 4.08 (dq, J ϭ 10.8,

7.1 Hz, 1 H, OCH₂), 4.08 (m, 1 H, OCH₂), 4.11 (dq, J ϭ 10.8,

7.1 Hz, 1 H, OCH₂), 4.13 (q, J ϭ 7.1 Hz, 2 H, OCH₂*), 4.21 (dq,

J ϭ 10.8, 7.1 Hz, 1 H, OCH₂), 4.24 (m, 2 H, OCH₂*), 4.44 (dq,

J ϭ 6.7, 6.6 Hz, 1 H, CHCl*), 4.48 (dq, J ϭ 6.7, 3.9 Hz, 1 H,

CHCl). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.83 (q, OCH₂CH₃*), 13.86

(q, OCH₂CH₃), 13.93 (q, OCH₂CH₃), 13.98 (q, OCH₂CH₃*), 22.60

(t*), 22.62 (t), 23.5 (q, CHCH₃*), 25.3 (q, CHCH₃), 26.6 (t), 28.3

(t*), 35.6 (t), 36.6 (t*), 52.4 (d, CHCH₂), 55.1 (d, CHCH₂*), 57.8

(d, CHCl*), 59.4 (d, CHCl), 61.2 (t, OCH₂*), 61.37 (t, OCH₂*),

61.45 (t, OCH₂), 61.5 (t, OCH₂), 62.3 (s, CCO₂), 62.4 (s, CCO₂*),

170.2 (s, CO₂), 170.7 (s, CO₂*), 172.1 (s, CO₂*), 172.4 (s, CO₂). Ϫ

MS; m/z (%) ϭ 278/276 (1/3) [M^ϩ], 241 (33) [M^ϩϪ Cl], 235 (37),

231 (29), 230 (29), 195 (26) [M^ϩϪ Cl Ϫ OEt], 184 (21), 173 (75),

167 (100) [M^ϩϪ Cl Ϫ EtOH Ϫ CO], 166 (66), 149 (23), 139 (34),

127 (42), 121 (27), 95 (58), 93 (60), 67 (36). Ϫ C₁₃H₂₁ClO₄(276.8):

calcd. C 56.42, H 7.65; found 56.14, H 7.91. Ϫ Resonances marked

with an asterisk * correspond to the minor diastereomer.

C₂₂H₂₆FeO₄: calcd. 410.1180; found 410.1172

Ϯ 3 ppm. Ϫ

C₂₂H₂₆FeO₄(410.1): calcd. C 64.40, H 6.39; found C 64.18, H 6.46.

Tetraethyl Dodeca-1,11-diyne-6,6,7,7-tetracarboxylate (29): Flash

chromatography (15:1) gave 50 mg (22%) or 34 mg (15%) of 29 [R_f

Ϫ1

˜

(1:1) ϭ 0.59] as a colorless oil. Ϫ IR (film): ν ϭ 3282 cm (w,

ϵCH), 2984 (w), 2118 (w, CϵC), 1731 (s, CO₂), 1258 (s), 1218 (s),

1

1182 (m). Ϫ H NMR (200 MHz): δ ϭ 1.24 (t, J ϭ 7.1 Hz, 12 H,

OCH₂CH₃), 1.58 (m, 4 H), 1.92 (t, J ϭ 2.6 Hz, 2 H, ϵCH), 2.13

(m, 4 H, CH₂CCO₂) 2.17 (dt, J ϭ 7.1, 2.6 Hz, 4 H, ϵCCH₂), 4.15

(q, J ϭ 7.1 Hz, 4 H, OCH₂), 4.17 (q, J ϭ 7.1 Hz, 4 H, OCH₂). Ϫ

¹³C NMR (50 MHz): δ ϭ 13.8 (q, OCH₂CH₃), 18.9 (t), 24.7 (t),

30.5 (t), 61.4 (t, OCH₂), 62.7 (s, CCO₂), 68.5 (d, CϵCH), 83.7 (s,

ϵC), 169.4 (s, CO₂). Ϫ MS; m/z (%) ϭ 405 (49) [M^ϩϪ OEt], 311

(20), 265 (20), 225 (100) [M^ϩ/2], 179 (56) [M^ϩ/2 Ϫ EtOH], 178 (26),

153 (28), 152 (58) [M^ϩ/2 Ϫ CO₂Et], 125 (20), 93 (22), 91 (28), 79

(24), 77 (20), 59 (37), 43 (24). Ϫ C₂₄H₃₄O₈(450.2): calcd. C 63.98,

H 7.61; found C 63.78, H 7.81.

Diethyl 2-Pent-4-ynyl-2-(tetrahydrofuran-2-yl)malonate (30): Flash

chromatography (30:1) gave 44 mg (15%) of 30 [R_f(5:1) ϭ 0.32] as

a colorless oil. Ϫ IR (film): ν˜ ϭ 3282 cm^Ϫ1(m, ϵCH), 2981 (m),

1

2118 (w, CϵC), 1729 (s, CO₂), 1260 (s), 1180 (m), 1069 (m). Ϫ H

Diethyl 2-Chloro-2-(hex-4-enyl)malonate (27f): Flash chromato-

graphy (50:1) gave 11 mg (4%) of 27f [R_f(10:1) ϭ 0.38] as a color-

NMR (200 MHz): δ ϭ 1.23 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.26

(t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃), 1.40Ϫ1.59 (m, 2 H), 1.76 (m, 2

less oil. Ϫ ¹H NMR (200 MHz): δ ϭ 1.26 (t, J ϭ 7.1 Hz, 6 H, H), 1.88 (t, J ϭ 2.6 Hz, 1 H, ϵCH), 2.00 (m, 4 H), 2.14 (dt, J ϭ

OCH₂CH₃), 1.60 (d, J ϭ 4.8 Hz, 3 H, ϭCHCH₃), 1.50 (m, 2 H), 7.4, 2.4 Hz, 2 H, ϵCCH₂), 3.70 (m, 2 H, OCH₂CH₂), 4.14 (q, J ϭ

1.95 (m, 2 H), 2.19 (m, 2 H), 4.23 (q, J ϭ 7.1 Hz, 4 H, OCH₂), 7.1 Hz, 4 H, OCH₂CH₃), 4.29 (t, J ϭ 7.4 Hz, 1 H, OCHCH₂). Ϫ

5.36 (m, 2 H). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.9 (q, OCH₂CH₃), ¹³C NMR (100 MHz): δ ϭ 14.0 (q, OCH₂CH₃), 18.9 (t), 24.0 (t),

3350

Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

25.8 (t), 27.8 (t), 32.0 (t), 61.06 (t, OCH₂), 61.09 (t, OCH₂), 61.15 Diethyl 2-[Methoxy(2,2,6,6-tetramethylpiperidin-1-yloxy)methyl]-

(s, CCH), 68.53 (t, OCH₂CH₂), 68.54 (s, ϵC), 80.3 (d, OCHCH₂), cyclopentane-1,1-dicarboxylate (31c): Flash chromatography (50:1)

83.8 (d, ϵCH), 169.9 (s, CO₂), 170.2 (s, CO₂). Ϫ MS; m/z (%) ϭ

gave 190 mg (46%) or 153 mg (37%) of 31c as a 2:1 diastereomeric

251 (5) [M^ϩϪ OEt], 229 (8) [M^ϩϪ CH₂CH₂CH₂CϵCH], 223 (35) mixture [R_f(10:1) ϭ 0.38] as colorless crystals; m.p. 41Ϫ42 °C. Ϫ

[M^ϩϪ CO₂Et], 222 (42) [M^ϩϪ EtOH Ϫ CO], 183 (24) [M^ϩ

Ϫ

IR (KBr): ν ϭ 2982 cm^Ϫ1(m), 1745 (m, CO₂), 1727 (s, CO₂), 1363

˜

CH₂CH₂CH₂CϵCH Ϫ EtOH], 169 (100), 149 (22), 141 (22), 123 (m), 1270 (m), 1259 (m). Ϫ ¹H NMR (200 MHz): δ ϭ 1.01 (s, 6 H,

(47), 95 (41), 71 (42).

NCCH₃, NCCH₃*), 1.05 (s, 3 H, NCCH₃*), 1.07 (s, 3 H, NCCH₃),

1.171 (s, 6 H, NCCH₃, NCCH₃*), 1.174 (s, 6 H, NCCH₃, NCCH₃*),

1.21 (t, J ϭ 7.0 Hz, 3 H, OCH₂CH₃), 1.22 (t, J ϭ 7.1 Hz, 6 H,

OCH₂CH₃, OCH₂CH₃*), 1.24 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃*),

1.35Ϫ1.70 (m, 8 H, 8 H*), 1.75Ϫ2.20 (m, 3 H, 3 H*), 2.38 (m, 1

H, 1 H*), 2.68 (m, 1 H, CH₂CH*), 2.89 (dt, J ϭ 8.2, 2.1 Hz, 1 H,

CH₂CH), 3.47 (s, 3 H, OCH₃), 3.50 (s, 3 H, OCH₃*), 4.14 (q, J ϭ

7.1 Hz, 2 H, OCH₂*), 4.16 (q, J ϭ 7.2 Hz, 6 H, OCH₂, OCH₂*),

4.95 (d, J ϭ 2.2 Hz, 1 H, OCH), 5.08 (d, J ϭ 8.0 Hz, OCH*). Ϫ

¹³C NMR (50 MHz): δ ϭ 13.9 (q, OCH₂CH₃, OCH₂CH₃*), 14.0

(q, OCH₂CH₃, OCH₂CH₃*), 17.3 (t, CCH₂CH₂, CCH₂CH₂*), 19.9

(q, NCCH₃), 20.0 (q, NCCH₃*), 20.5 (q, NCCH₃, NCCH₃*), 22.0

(t*), 22.5 (t), 24.2 (t), 26.8 (t*), 32.3 (q, NCCH₃), 32.5 (q, NCCH₃*),

33.9 (q, NCCH₃), 34.2 (q, NCCH₃*), 34.7 (t), 35.8 (t*), 40.2 (t,

Treatment of Malonates 12aϪg with TEMPO (5). ؊ General Pro-

cedure: Compounds 12aϪg (1.00 mmol) were added at Ϫ78 °C un-

der N₂to a solution of the lithium amide in 20 mL of dry DME

(for the amount of base, see Table 7). The solution was stirred be-

tween Ϫ78 and Ϫ60 °C for 30 min. At 0 °C, compound 5 (172 mg,

1.10 mmol) was added and the red solution was stirred for 5 min.

Solid 1 or 2 was added in portions at 0 °C. The mixture was stirred

at 0 °C for 2 h, quenched with four drops of a saturated NH₄Cl

solution, and allowed to warm to room temperature. The reaction

mixture was diluted with 20 mL of ether and filtered through a pad

of silica gel. The solvent was evaporated and the inhomogeneous

residue was preadsorbed on silica gel. Flash chromatography (50:1

gradient to 1:1) gave the products shown in Table 7, followed by

unchanged 5.

CCH₂CH₂CH₂C),

40.3 (t,

CCH₂CH₂CH₂C), 40.5

(t,

CCH₂CH₂CH₂C*), 49.2 (d, CH₂CH), 52.6 (d, CH₂CH*), 59.1 (s,

NCCH₃*), 59.4 (s, NCCH₃), 60.2 (q, OCH₃), 60.3 (q, OCH₃*), 60.6

(s, NCCH₃), 60.8 (t, OCH₂, OCH₂*), 61.0 (t, OCH₂), 61.1 (t,

OCH₂*), 62.1 (s, CCO₂*), 62.4 (s, CCO₂), 106.5 (d, CHO*), 107.6

(d, CHO), 171.0 (s, CO₂*), 171.1 (s, CO₂), 172.3 (s, CO₂), 172.5 (s,

CO₂*). Ϫ MS; m/z (%) ϭ 257 (100) [M^ϩϪ TEMPO], 197 (41), 183

(96) [M^ϩϪ TEMPO Ϫ EtOH Ϫ CO], 142 (44), 140 (27), 123 (38).

Ϫ C₂₂H₃₉NO₆(413.5): calcd. C 63.90, H 9.51, N 3.39; found C

63.91, H 9.85, N 3.16. Ϫ Resonances marked with an asterisk *

correspond to the minor diastereomer.

Diethyl 2-(5,5-Diphenylpent-4-enyl)-2-(2,2,6,6-tetramethyl-

piperidin-1-yloxy)malonate (32a): Flash chromatography (50:1) gave

252 mg (47%) of 32a [R_f(5:1) ϭ 0.64] as a colorless oil. Ϫ IR (film):

ν˜ ϭ 2978 cm^Ϫ1(m), 1738 (s, CO₂), 1446 (m), 1364 (m), 1259 (m),

1179 (m). Ϫ UV: λ_max(lg ε) ϭ 194 nm (4.62), 218 (4.17), 250 (4.06),

1

276 (3.45), 284 (3.14). Ϫ H NMR (200 MHz): δ ϭ 1.06 (s, 6 H,

NCCH₃), 1.16 (s, 6 H, NCCH₃), 1.24 (t, J ϭ 7.1 Hz, 6 H,

OCH₂CH₃), 1.40 (m, 8 H), 2.12 (m, 4 H), 4.17 (q, J ϭ 7.2 Hz, 4

H, OCH₂), 6.06 (t, J ϭ 7.4 Hz, 1 H, ϭCH), 7.12Ϫ7.79 (m, 10

H, Ph). Ϫ ¹³C NMR (50 MHz): δ ϭ 14.1 (q, OCH₂CH₃), 17.0 (t,

NCCH₂CH₂), 20.9 (q, NCCH₃), 24.7 (t, ϭCHCH₂CH₂), 30.0 (t, ϭ

CHCH₂), 33.4 (q, NCCH₃), 34.0 (t, CH₂CCO₂), 41.2 (t,

NCCH₂CH₂), 60.9 (s, NCCH₃), 61.1 (t, OCH₂), 88.9 (s, CCO₂),

126.78 (d, Ph), 126.85 (d, Ph), 127.2 (d, Ph), 128.0 (d, Ph), 128.2

(d, Ph), 129.5 (d, ϭCH), 129.9 (d, Ph), 140.3 (s), 142.1 (s), 142.7

(s), 169.4 (s, CO₂). Ϫ MS; m/z (%) ϭ 379 (76) [M^ϩϪ TEMPO],

302 (85), 289 (48), 273 (100), 260 (91), 232 (41), 193 (27), 183 (54),

167 (45), 142 (52), 105 (98), 77 (37), 69 (46), 55 (36).

Diethyl 2-[Phenyl(2,2,6,6-tetramethylpiperidin-1-yloxy)methyl]-

cyclopentane-1,1-dicarboxylate (31d): Flash chromatography (50:1)

gave 331 mg (72%) of 31d [R_f(5:1) ϭ 0.66] as colorless crystals;

Ϫ1

˜

m.p. 85Ϫ87 °C. Ϫ IR (KBr): ν ϭ 2974 cm (m), 1731 (s, CO₂),

1456 (m), 1259 (s), 1196 (s), 703 (m). Ϫ UV: λ_max(lg ε) ϭ 192 nm

(4.60), 200 (4.18), 204 (4.04), 210 (3.98), 214 (3.92), 216 (3.88), 224

(3.49), 228 (3.27), 236 (3.09). Ϫ ¹H NMR (400 MHz, C₂D₂Cl₄):

δ ϭ Ϫ0.09 (br. s, 3 H, NCCH₃), 0.88 (s, 3 H, NCCH₃), 0.95 (t, J ϭ

7.1 Hz, 3 H, OCH₂CH₃), 1.02 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃),

1.11 (s, 3 H, NCCH₃), 1.35 (s, 3 H, NCCH₃), 1.28Ϫ1.55 (m, 8 H),

1.80 (m, 1 H), 2.10 (m, 1 H), 2.19Ϫ2.36 (m, 2 H), 3.37 (m, 2 H,

CHCHPh, OCH₂), 3.69 (m, 1 H, OCH₂), 3.76 (m, 2 H, OCH₂),

4.94 (d, J ϭ 10.4 Hz, 1 H, CHCHPh), 7.16Ϫ7.33 (m, 5 H, Ph). Ϫ

¹³C NMR (100 MHz, C₂D₂Cl₄): δ ϭ 13.6 (q, OCH₂CH₃), 13.9 (q,

OCH₂CH₃), 17.0 (t, NCCH₂CH₂), 20.3 (q, NCCH₃^#), 22.7 (t,

CHCH₂CH₂), 29.8 (t, CHCH₂), 32.6 (q, NCCH₃^#), 34.0 (q,

NCCH₃^#), 37.0 (t, CH₂CCO₂), 40.6 (t, NCCH₂CH₂CH₂C^#), 49.7

(d, CHCH₂), 58.7 (s, NCCH₃^#), 60.7 (t, OCH₂), 61.0 (t, OCH₂),

62.9 (s, CCO₂), 83.5 (d, CHPh), 126.4 (d, Ph), 127.4 (d, Ph), 129.6

(d, Ph), 139.3 (s, Ph), 170.6 (s, CO₂), 172.2 (s, CO₂). Ϫ MS; m/z

(%) ϭ 303 (100), 229 (97), 155 (51). Ϫ C₂₇H₄₁NO₅(459.6): calcd.

C 70.54, H 9.00, N 3.05; found C 71.03, H 9.25, N 2.94. Ϫ Reson-

ances marked with # are broad and of very low intensity at room

temperature.

Diethyl 2-[2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)prop-2-yl]cyclop-

entane-1,1-dicarboxylate (31b): Flash chromatography (50:1) gave

358 mg (87%) of 31b [R_f(10:1) ϭ 0.48] as a colorless oil. Ϫ IR

(film): ν˜ ϭ 2977 cm^Ϫ1(m), 2935 (m), 1728 (s, CO₂), 1255 (s). Ϫ ¹H

NMR (200 MHz): δ ϭ 1.00 (s, 3 H, NCCH₃), 1.06 (s, 3 H,

NCCH₃), 1.10 (s, 3 H, NCCH₃), 1.13 (s, 3 H, NCCH₃), 1.17 (t,

J ϭ 7.3 Hz, 3 H, OCH₂CH₃), 1.18 (t, J ϭ 7.2 Hz, 3 H, OCH₂CH₃),

1.27 (m, 6 H, CCH₂CH₂CH₂C), 1.27 (s, 3 H, CHCCH₃), 1.40 (s, 3

H, CHCCH₃), 1.73 (m, 3 H), 2.05 (m, 2 H), 2.40 (m, 1 H), 3.42

(dd, J ϭ 8.4, 8.0 Hz, 1 H, CH), 3.96 (dq, J ϭ 10.8, 7.1 Hz, 1 H,

OCH₂), 4.10 (m, 2 H, OCH₂), 4.22 (dq, J ϭ 10.8, 7.2 Hz, 1 H,

OCH₂). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.7 (q, OCH₂CH₃), 14.0

(q, OCH₂CH₃), 17.1 (t, NCCH₂CH₂), 20.6 (q, NCCH₃), 21.1 (q,

NCCH₃), 22.4 (t, CHCH₂CH₂), 23.2 (q, CHCCH₃), 25.2 (q,

CHCCH₃), 27.4 (t, CHCH₂), 34.9 (q, NCCH₃), 35.4 (q, NCCH₃),

37.3 (t, CH₂CCO₂), 41.1 (t, NCCH₂CH₂CH₂C), 55.9 (d, CH), 59.3

(s, NCCH₃), 60.84 (s, NCCH₃), 60.86 (t, OCH₂), 61.0 (t, OCH₂), Isomerization of 31d to 31dЈ: During a high-temperature NMR ex-

62.7 (s, CCO₂), 80.9 (s, CON), 171.7 (s, CO₂), 173.0 (s, CO₂). Ϫ

periment (25Ϫ100 °C) to assign the broad resonances at room tem-

perature, we observed the formation of diastereomer 31dЈ. The final

31d/31dЈ ratio was 2:1. A diastereomeric mixture of 31d/31dЈ (dr ϭ

MS; m/z (%) ϭ 255 (83) [M^ϩϪ TEMPO], 181 (100) [M^ϩ

Ϫ

TEMPO Ϫ EtOH Ϫ CO], 163 (38), 142 (61), 135 (65) [M^ϩ

Ϫ

TEMPO Ϫ 2 EtOH Ϫ CO], 134 (30), 107 (28). Ϫ C₂₃H₄₁NO₅9:1) in C₂D₂Cl₄isomerized to a 1:1 diastereomeric mixture on

(411.6): calcd. C 67.12, H 10.04, N 3.40; found C 66.81, H 10.09,

N 3.31.

exposure to daylight in an NMR tube for 9 d and temporary heat-

ing to 100 °C. Isomerization was monitored by NMR spectroscopy.

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3351

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

1

Compound 31dЈ: H NMR (400 MHz, C₂D₂Cl₄): δ ϭ 0.48 (br. s, 3 66.25, H 9.99, N 3.40. Ϫ Resonances marked with an asterisk *

H, NCCH₃), 0.88 (s, 3 H, NCCH₃), 1.11 (s, 3 H, NCCH₃), 1.15 (t, correspond to minor diastereomer.

J ϭ 7.0 Hz, 3 H, OCH₂CH₃), 1.23 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃),

Diethyl 2-(Hex-4-enyl)-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-

1.28Ϫ1.55 (m, 8 H), 1.35 (s, 3 H, NCCH₃), 1.80 (m, 1 H), 1.82 (m,

malonate (32f): ؊ ¹H NMR (200 MHz): δ ϭ 1.08 (s, 6 H, NCCH₃),

1 H), 2.19Ϫ2.36 (m, 2 H), 3.37 (m, 1 H, CHCHPh), 3.69Ϫ3.83 (m,

1.16 (s, 6 H, NCCH₃), 1.25 (t, J ϭ 6.9 Hz, 6 H, OCH₂CH₃),

2 H, OCH₂), 3.84 (m, 1 H, OCH₂), 4.14 (m, 1 H, OCH₂), 5.11 (d,

1.34Ϫ1.42 (m, 8 H), 1.59 (d, J ϭ 3.2 Hz, 3 H, CHCH₃), 1.95 (m,

J ϭ 5.9 Hz, 1 H, CHCHPh), 7.16Ϫ7.33 (m, 5 H, Ph). Ϫ ¹³C NMR

2 H), 2.14 (m, 2 H), 4.17 (q, J ϭ 7.2 Hz, 4 H, OCH₂), 5.36 (m, 2

(100 MHz, C₂D₂Cl₄):

δ ϭ 13.5 (q, OCH₂CH₃), 13.8 (q,

H, CHϭCH). Ϫ ¹³C NMR (50 MHz): δ ϭ 14.2 (q, OCH₂CH₃),

17.1 (t, NCCH₂CH₂), 18.0 (q, CHCH₃), 21.0 (q, NCCH₃), 24.2 (t,

CHCH₂CH₂), 32.8 (t, CHCH₂), 33.4 (q, NCCH₃), 34.1 (t,

CH₂CCO₂), 41.3 (t, NCCH₂CH₂CH₂C), 60.9 (s, NCCH₃), 61.1 (t,

OCH₂), 89.0 (s, CCO₂), 125.3 (d, ϭCH), 131.0 (d, ϭCH), 169.5

(s, CO₂).

OCH₂CH₃), 17.0 (t, NCCH₂CH₂), 20.3 (q, NCCH₃^#), 21.3 (t,

CHCH₂CH₂), 25.7 (t, CHCH₂), 32.6 (q, NCCH₃^#), 34.0 (q,

NCCH₃^#), 35.0 (t, CH₂CCO₂), 40.6 (t, NCCH₂CH₂CH₂C^#), 48.4

(d, CHCH₂), 58.7 (s, NCCH₃^#), 60.8 (t, OCH₂), 61.1 (t, OCH₂),

62.3 (s, CCO₂), 84.6 (d, CHPh), 126.9 (d, Ph), 127.0 (d, Ph), 131.4

(d, Ph), 140.0 (s, Ph), 170.6 (s, CO₂), 172.0 (s, CO₂). Ϫ Resonances

marked with # are broad and of very low intensity at room temper-

ature.

Diethyl

2-(Pent-4-ynyl)-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-

malonate (32g): Flash chromatography (50:1) gave 374 mg (98%) of

32g [R_f(10:1) ϭ 0.37] as a colorless oil. Ϫ IR (film): ν˜ ϭ 3289

cm^Ϫ1(w, ϵCH), 2936 (m), 2119 (w, CϵC), 1740 (s, CO₂), 1366

(m), 1302 (w), 1263 (s), 1217 (m), 1180 (m), 1086 (m). Ϫ ¹H NMR

(200 MHz): δ ϭ 0.88 (s, 6 H, NCCH₃), 0.95 (s, 6 H, NCCH₃), 1.05

(t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.15Ϫ1.43 (m, 8 H), 1.71 (t, J ϭ

2.5 Hz, 1 H, ϵCH), 1.97 (dt, J ϭ 6.9, 2.4 Hz, 2 H, ϵCCH₂), 2.07

(m, 2 H), 3.97 (q, J ϭ 7.1 Hz, 4 H, OCH₂). Ϫ ¹³C NMR (50 MHz):

δ ϭ 14.0 (q, OCH₂CH₃), 16.9 (t, NCCH₂CH₂), 18.7 (t), 20.8 (q,

NCCH₃), 23.5 (t), 33.3 (q, NCCH₃), 33.6 (t), 41.1 (t, NCCH₂), 60.8

(s, NCCH₂), 61.0 (t, OCH₂), 68.6 (d, ϵCH), 83.8 (s, ϵC), 88.6 (s,

CH₂CO), 169.1 (s, CO₂). Ϫ MS; m/z (%) ϭ 381 (Ͻ1) [M^ϩ], 156

(100) [TEMPO], 140 (16), 123 (19) [M^ϩϪ TEMPO Ϫ CO₂Et Ϫ

Et], 79 (18), 69 (18), 55 (21). Ϫ C₂₁H₃₅NO₅(381.5): calcd. C 66.11,

H 9.25, N 3.67; found C 65.91, H 9.50, N 3.29.

Cyclization of the Mixture 31f/32f. ؊ a) A solution of a 2.2:1 mix-

ture of 32f/31f (130 mg, 0.33 mmol) in 1 mL of CDCl₃was stored

at room temperature in daylight in an NMR tube for 7 d, mon-

itoring by NMR spectroscopy. The solvent was removed in va-

cuum. Flash chromatography (50:1 gradient to 30:1) of the crude

product gave 120 mg (92%) of 31f. Ϫ b) The crude orange reaction

solution of 31f/32f in 20 mL of DME/ether (1:1), obtained from

cyclization according to the general procedure after filtration

through a pad of silica gel, was stirred at room temperature under

ordinary lab light for 7 d. The solvent was removed in vacuum and

the residue was preadsorbed on silica gel. Flash chromatography

50:1 gradient to 15:1) gave 92% ferrocene and a total yield of

231 mg (58%) of 31f, based on 12f.

Deprotection of 31b, 31d, 31f, and 32f. ؊ General Procedure: Zn

dust (850 mg, 13.00 mmol) was added at 50 °C to solutions of 31b,

31d, 31f, and 32f (1.00 mmol) in 2 mL/1 mL/1 mL of AcOH/H₂O/

THF. The mixture was stirred at 50 °C for 3 h. After cooling to

room temperature, the mixture was diluted with ether and filtered

through a pad of silica gel. The filtrate was neutralized with satur-

ated NaHCO₃solution and washed twice with water. The solvent

was removed in vacuum, and the crude products 14b, 14dЈ, 14f, and

32fЈ were purified by flash chromatography (50:1 gradient to 15:1).

Diethyl 2-[1-(2,2,6,6-Tetramethylpiperidin-1-yloxy)ethyl]-

cyclopentane-1,1-dicarboxylate (31f): Flash chromatography (50:1)

gave 199 mg (50%) or 163 mg (41%) of 31f as a 2:1 diastereomeric

mixture and 32f [R_f(10:1) ϭ 0.39] as a colorless oil. Ϫ IR (film):

1

ν˜ ϭ 2938 cm^Ϫ1(m), 2935 (m), 1739 (s, CO₂), 1219 (s). Ϫ H NMR

(400 MHz): δ ϭ 1.00 (s, 6 H, NCCH₃, NCCH₃*), 1.04 (s, 6 H,

NCCH₃, NCCH₃*), 1.05 (s, 6 H, NCCH₃, NCCH₃*), 1.08 (s, 6 H,

NCCH₃, NCCH₃*), 1.11 (m, 3 H, CHCH₃*), 1.20 (t, J ϭ 7.0 Hz,

6 H, OCH₂CH₃), 1.21 (t, J ϭ 7.0 Hz, 6 H, OCH₂CH₃*), 1.24 (d,

J ϭ 5.7 Hz, 3 H, CHCH₃), 1.32 (m, 12 H, NCCH₂CH₂CH₂,

NCCH₂CH₂CH₂*), 1.52 (m, 2 H, CHCH₂CH₂, CHCH₂CH₂*),

Ethyl 1-Methyl-3-oxotetrahydrocyclopenta[c]furan-3a-carboxylate

(14f): Flash chromatography (20:1) gave 178 mg (84%) of 14f [R_f

(5:1) ϭ 0.37] as a 2:1 diastereomeric mixture and as a colorless oil.

1.80 (m,

CHCH₂CH₂CH₂, CHCH₂CH₂CH₂*), 2.38 (dt, J ϭ 13.7, 7.6 Hz, 1

H, CH₂CH₂CCH*), 2.51 (dt, 13.1, 8.3 Hz, H,

4 H, CHCH₂CH₂, CHCH₂CH₂*), 2.07 (m, 4 H,

Ϫ IR (film): ν ϭ 2981 cm^Ϫ1(m), 1771 (s, CO₂), 1739 (s, CO₂), 1255

˜

(s). Ϫ ¹H NMR (200 MHz): δ ϭ 1.21 (t, J ϭ 7.1 Hz, 3 H,

OCH₂CH₃), 1.22 (t, J ϭ 7.1 Hz, 3 H, OCH₂CH₃*), 1.32 (d, J ϭ

6.6 Hz, 3 H, CHCH₃), 1.39 (d, J ϭ 6.4 Hz, 3 H, CHCH₃*),

1.47Ϫ2.01 (m, 4 H, 4 H*), 2.06Ϫ2.24 (m, 1 H, 1 H*), 2.25Ϫ2.41

(m, 1 H, 1 H*), 2.68 (m, 1 H, CHCH₂*), 2.87 (dt, J ϭ 7.3, 6.3 Hz,

1 H, CHCH₂), 4.15 (q, J ϭ 7.3 Hz, 2 H, OCH₂), 4.16 (q, J ϭ

7.2 Hz, 2 H, OCH₂*), 4.22 (m, 1 H, CHCH₃*), 4.81 (dq, J ϭ 6.5,

6.4 Hz, 1 H, CHCH₃). Ϫ ¹³C NMR (50 MHz): δ ϭ 13.9 (q,

OCH₂CH₃*), 14.0 (q, OCH₂CH₃), 16.0 (q, CHCH₃), 21.9 (q,

CHCH₃*), 25.6 (t*), 26.3 (t), 27.1 (t), 33.9 (t*), 34.1 (t), 35.1 (t*),

50.8 (d, CHCH₂), 52.3 (d, CHCH₂*), 61.9 (t, OCH₂, OCH₂*), 62.7

(s, CCH₂*), 63.8 (s, CCH₂), 77.0 (d, CHCH₃), 82.4 (d, CHCH₃*),

170.0 (s, CO₂), 170.4 (s, CO₂*), 176.0 (s, CO₂*), 176.1 (s, CO₂). Ϫ

J

ϭ

1

CH₂CH₂CCH), 2.63 (dt, J ϭ 8.0, 5.7 Hz, 1 H, CHCH₂), 2.84 (dt,

J ϭ 7.7, 7.0 Hz, 1 H, CHCH₂*), 4.08 (dq, J ϭ 7.4, 6.1 Hz, 1 H,

CHCH₃), 4.12 (q, J ϭ 7.2 Hz, 4 H, OCH₂, OCH₂*), 4.14 (q, J ϭ

7.2 Hz, 4 H, OCH₂, OCH₂*), 4.17 (m, 1 H, CHCH₃*). Ϫ ¹³C NMR

(100 MHz): δ ϭ 13.92 (q, OCH₂CH₃, OCH₂CH₃*), 13.94 (q,

OCH₂CH₃, OCH₂CH₃*), 16.9 (t, CCH₂CH₂CH₂C*), 17.3 (t,

CCH₂CH₂CH₂C), 17.4 (q, CHCH₃*), 18.4 (q, CHCH₃), 20.6 (q,

NCCH₃, NCCH₃*), 20.7 (q, NCCH₃, NCCH₃*), 22.4 (t,

CHCH₂CH₂), 22.6 (t, CHCH₂CH₂*), 26.8 (t, CHCH₂), 26.9 (t,

CHCH₂*), 33.97 (q, NCCH₃, NCCH₃*), 34.03 (q, NCCH₃,

NCCH₃*), 35.6 (t, CH₂CCO₂), 36.7 (t, CH₂CCO₂*), 40.3 (t,

NCCH₂CH₂CH₂, NCCH₂CH₂CH₂*), 40.7 (t, NCCH₂CH₂CH₂,

NCCH₂CH₂CH₂*), 51.7 (d, CHCH₂*), 51.9 (d, CHCH₂), 58.7 (s,

NCCH₃, NCCH₃*), 60.5 (s, NCCH₃, NCCH₃*), 60.9 (t, OCH₂,

OCH₂*), 61.1 (t, OCH₂, OCH₂*), 62.1 (s, CCO₂*), 63.4 (s, CCO₂),

77.6 (d, CHCH₃*), 77.8 (d, CHCH₃), 170.8 (s, CO₂), 171.0 (s,

CO₂*), 172.5 (s, CO₂*), 172.8 (s, CO₂). Ϫ MS (NH₃, CI, pos.):

MS; m/z (%) ϭ 211 (10), 168 (63), 140 (58), 139 (40) [M^ϩ

Ϫ

CO₂Et], 123 (28), 122 (34), 111 (21), 95 (100), 94 (26), 93 (33), 67

(55), 43 (26). Ϫ C₁₁H₁₆O₄(212.2): calcd. C 62.25, H 7.60; found C

62.30, H 7.95. Ϫ Resonances marked with an asterisk * correspond

to minor diastereomer.

m/z (%) ϭ 398 (100) [M^ϩϩ H], 241 (10) [M^ϩϪ TEMPO], 167 (4). Diethyl 2-Hex-4-enyltartronate (32fЈ): Flash chromatography (50:1

Ϫ C₂₂H₃₉NO₅(397.6): calcd. C 66.47, H 9.89, N 3.52; found C gradient to 15:1) gave 209 mg (81%) of 32fЈ [R_f(3:1) ϭ 0.42] as a

3352

Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

Table 8. Crystal data, data collection, and refinement parameters for 14a, 20b, and 31d

Compound

14a

20b

31d

Empirical formula

M_r

C₂₂H₂₂O₄

350.40

colorless tablet

0.84ϫ0.46ϫ0.15

monoclinic

P2₁/c

C₂₄H₃₂FeO₄

440.35

colorless prism

0.60ϫ0.60ϫ0.30

monoclinic

P2₁/c

C₂₇H₄₁NO₅

459.61

orange prism

0.60ϫ0.45ϫ0.27

triclinic

¯

P1

Crystal habit

Crystal size [mm]

Crystal system

Space group

Cell constants:

a [pm]

b [pm]

c [pm]

α [°]

β [°]

1424.5(3)

1026.9(2)

1209.4(3)

90

99.29(2)

90

1.7459

4

1.333

1491.8(3)

1784.3(4)

814.6(3)

90

96.87(2)

90

2.1528

4

1.359

0.728

0.751Ϫ0.768

936

1077.6(4)

1098.7(5)

1125.3(5)

99.85(3)

98.33(3)

99.53(3)

1.2738

2

γ [°]

V [nm³]

Z

D_x[Mg m^Ϫ3

]

1.198

0.081

µ [mm^Ϫ1

]

0.091

Transmissions

F(000)

T [°C]

744

Ϫ130

50

500

Ϫ130

50

Ϫ130

5

2θ_max

No. of reflections:

measured

unique

6278

3083

0.034

236

0.112

0.044

1.03

6855

3866

0.026

266

0.074

0.030

1.03

4730

4484

0.015

304

0.108

0.043

1.05

R_int

Parameters

wR(F², all refl.)

R [F, Ͼ 4σ(F)]

S

3

˚

max. ∆ρ [e A ]

0.30

0.26

0.23

colorless oil. Ϫ IR (film): ν˜ ϭ 3499 cm^Ϫ1(w, OH), 2977 (m), 2935 UV: λ_max(lg ε) ϭ 192 nm (4.67), 202 (4.47), 204 (4.40), 216 (4.00),

(m), 1731 (s, CO₂), 1259 (s), 1188 (m), 1145 (w). Ϫ ¹H NMR 220 (3.96), 234 (3.36), 240 (2.76), 260 (2.67). Ϫ ¹H NMR

(200 MHz): δ ϭ 1.20 (t, J ϭ 7.1 Hz, 6 H, OCH₂CH₃), 1.34 (tt, J ϭ (200 MHz): δϭ 1.17 (m, 1 H), 1.61 (m, 3 H), 2.03 (m, 2 H), 3.00

7.4, 7.0 Hz, 2 H, ϭCHCH₂CH₂), 1.59 (d, J ϭ 4.3 Hz, 3 H, ϭ

(ddd, J ϭ 8.3, 8.0, 3.5 Hz, 1 H, CHCPh), 3.58 (m, 1 H, CHCO₂),

CHCH₃), 1.93 (m, 4 H, CH₂CH₂CH₂), 3.70 (s, 1 H, OH), 4.18 (q, 7.13Ϫ7.52 (m, 10 H, Ph). Ϫ ¹³C NMR (50 MHz): δ ϭ 25.6 (t),

J ϭ 7.1 Hz, 4 H, OCH₂), 5.34 (m, 2 H, CHϭCH). Ϫ ¹³C NMR 28.5 (t), 29.6 (t), 46.6 (d), 50.5 (d), 89.8 (s, CPh), 125.1 (d, Ph),

(50 MHz): δ ϭ 13.9 (q, OCH₂CH₃), 17.8 (q, ϭCHCH₃), 23.0 (t), 125.5 (d, Ph), 127.2 (d, Ph), 127.8 (d, Ph), 128.2 (d, Ph), 128.6 (d,

26.5 (t*), 32.1 (t), 34.0 (t), 34.1 (t*), 62.3 (t, OCH₂), 78.9 (s, COH), Ph), 142.1 (s, Ph), 144.1 (s, Ph), 179.7 (s, CO₂). Ϫ MS; m/z (%) ϭ

124.4 (d, ϭCHCH₂*), 125.3 (d, ϭCHCH₂), 129.7 (d, ϭCHCH₃*), 278 (20) [M^ϩ], 183 (100), 105 (58). Ϫ HRMS: C₁₉H₁₈O₂: calcd.

130.5 (d, ϭCHCH₃), 169.4 (s, CO₂). Ϫ MS; m/z (%) ϭ 258 (10) 278.1307; found 278.1300 Ϯ 3 ppm.

[M^ϩ], 212 (22) [M^ϩϪ EtOH], 194 (43) [M^ϩϪ EtOH Ϫ CO], 185

(21) [M^ϩϪ CO₂Et], 184 (46) [M^ϩϪ EtOH Ϫ CO], 176 (100), 166

(44), 165 (37), 139 (52), 128 (23), 111 (37), 93 (24), 83 (31), 69 (20),

68 (88), 55 (47). Ϫ C₁₃H₂₂O₅(258.3): calcd. C 60.45, H 8.58; found

C 60.32, H 8.95. Ϫ Resonances marked with an asterisk * corre-

spond to minor (Z)isomer.

3,3-Dimethylhexahydrocyclopenta[c]furan-1-one (33b): Flash chro-

matography (18:1) gave 16 mg (40%) of 33b [R_f(5:1) ϭ 0.36] as a

volatile liquid. Ϫ ¹H NMR (200 MHz): δ ϭ 1.33 (s, 3 H, CH₃),

1.35 (s, 3 H, CH₃), 1.60 (m, 4 H), 1.94 (m, 2 H), 2.46 (m, 1 H),

3.15 (m, 1 H). Ϫ ¹³C NMR (50 MHz): δ ϭ 23.7 (q, CH₃), 26.4 (t),

28.5 (t), 29.2 (t), 30.0 (q, CH₃), 46.5 (d), 50.2 (d), 84.3 (s, CCH₃),

180.2 (s, CO₂). Ϫ MS; m/z (%) ϭ 155 (2) [M^ϩϩ H], 154 (0.4)

[M^ϩ], 139 (98), 110 (38), 95 (66), 67 (100), 59 (58), 43 (82).

Deethoxycarbonylation of Lactones 14a and 14b: Mixtures of 14a

or 14b (0.25 mmol) and anhydrous LiCl (21 mg, 0.50 mmol) in H₂O

(4 µL, 0.22 mmol) and dry DMSO (0.8 mL) were heated to 195 °C

under N₂for 3 h. The brown mixtures were diluted with 10 mL of

ether and filtered through pads of silica gel. The filtrates were

washed twice with saturated Na₂CO₃solution and dried with

Na₂SO₄. After evaporation of the solvent in vacuum, purification

by flash chromatography (18:1) gave 10 mg (11%) of 14a and 45 mg

(64%) of 33a, or 16 mg (40%) of 33b.

Acetalization of Diethyl 2-Formylcyclopentane-1,1-dicarboxylate

(22): A solution of aldehyde 22 (140 mg, 0.58 mmol) and pTsOH

(25 mg, 0.15 mmol) in HC(OMe)₃(2 mL) and methanol (5 mL)

was stirred at room temperature for 24 h. After neutralization with

79 mg solid Na₂CO₃and stirring for 30 min, the solvent was re-

moved in vacuum. The residue was dissolved in 15 mL ether and

filtered through a pad of silica gel. Removal of the ether in vacuum

gave 117 mg (70%) of pure acetal 23.

3,3-Diphenylhexahydrocyclopenta[c]furan-1-one (33a): Flash chro-

matography (18:1) gave 45 mg (64%) of 33a [R_f(5:1) ϭ 0.39] as a

colorless solid; m.p. 96Ϫ98 °C. Ϫ IR (KBr): ν˜ ϭ 1770 cm^Ϫ1(s,

X-ray Crystallographic Studies of 14a, 20b, and 31d:^[37]A summary

CO₂), 1447 (m), 1202 (m), 1159 (m), 964 (m), 758 (m), 699 (m). Ϫ of the crystal data, data collection, and refinement parameters is

Eur. J. Org. Chem. 2001, 3333Ϫ3355 3353

U. Jahn, P. Hartmann, I. Dix, P. G. Jones

FULL PAPER

[10] [10a]

N. Kise, T. Ueda, K. Kumada, Y. Terao, N. Ueda, J. Org.

given in Table 8. A cut tablet (14a) or a cut prism (20b and 31d)

was mounted on a glass fiber in inert oil and transferred to the

cold gas stream of a Stoe STADI-4 diffractometer fitted with a

Siemens LT-2 low temperature attachment. The data were meas-

ured by ω/θ scans using graphite-monochromated Mo-K_αradiation

(λ ϭ 71.073 pm). An absorption correction using a semiempirical

method (ψ scans) was applied for 20b. All unique data were used

for calculations.^[38]Each structure was solved by direct methods

and refined anisotropically by full-matrix least squares on F². Hy-

drogen atoms (except rigid methyl groups) were refined with a rid-

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Acknowledgments

This strategy should not be limited to malonate enolates, since

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Jahn, J. Org. Chem. 1998, 63, 7130Ϫ7131. Ϫ

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U. Jahn, P.

We thank the Fonds der Chemischen Industrie, the DFG, and the

Dr. Otto Röhm Gedächtnisstiftung for generous financial support

of this work. Prof. Dr. H. Hopf’s encouragement and generous sup-

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Eur. J. Org. Chem. 2001, 3333Ϫ3355

Lithium Malonate Enolates as Precursors for Radical Reactions

FULL PAPER

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Received September 21, 2000

[O00489]

Eur. J. Org. Chem. 2001, 3333Ϫ3355

3355

Article Doi

Lithium malonate enolates as precursors for radical reactions - Convenient induction of radical cyclizations with either radical or cationic termination

DOI: 10.1002/1099-0690(200109)2001:17<3333::AID-EJOC3333>3.0.CO;2-A

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