New method for the synthesis of functionalized 1,3-bis-exocyclic dienes via a palladium-catalyzed reaction. Scope and synthetic applications

FEATURE ARTICLE

311

New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes via a

Palladium-Catalyzed Reaction. Scope and Synthetic Applications

New

M

ethod fo

h

r

the

S

ynthes

i

is of Fu

e

nctionalize

r

d

1,3-bi

r

s-Exoc

y

clic Dienes Lomberget, Didier Bouyssi, Geneviève Balme*

Laboratoire de Chimie Organique 1, associé au CNRS, Université Claude Bernard Lyon 1, CPE, 43 Bd du 11 Novembre 1918,

69622 Villeurbanne, France

Fax +33(4)72431214; E-mail: balme@univ-lyon1.fr

Received 26 April 2004; revised 21 May 2004

palladium species leads to the cyclization product and re-

Abstract: The palladium-catalyzed tandem cyclization–coupling

generates the catalyst.

reaction of conjugated enynes having a stabilizing carbon nucleo-

phile with aryl iodides and vinyl halides or triflates produced stereo-

defined, functionalized five- and six-membered 1,3-bis-exocyclic

dienes in moderate to good yields. These stereodefined dienes

proved to be versatile substrates for the preparation of various poly-

cyclic products through subsequent Diels–Alder, intramolecular

Friedel–Crafts or thermal electrocyclization reactions.

Through recent studies on these palladium-mediated cy-

clizations, we have developed efficient strategies for the

construction of various substituted hetero- and carbocy-

cles.³In line with this continuing interest, it was envi-

sioned that the application of the same concept to

conjugated enynes such as 1 or 2 would lead to the forma-

tion of stereodefined, functionalized 1,3-bis-exocyclic

dienes (Scheme 2). Such products would be useful build-

ing blocks for the formation of more complex ring sys-

tems since their dienic system offers opportunities for

subsequent Diels–Alder or electrocyclization reactions.⁴

1

Introduction

2

3

3.1

3.2

4

Formation of Cyclopentanic Derivatives

Formation of Cyclohexanic Derivatives

Synthesis of 1,3-Bis-Exocyclic Dienes

Synthesis of Conjugated Trienes

Synthetic Applications

4.1

4.2

4.3

Diels–Alder Reaction

Intramolecular Friedel–Crafts Reaction

Thermal Electrocyclization

4.3.1 Reaction on Conjugated Exocyclic Trienes

4.3.2 One-Pot Synthesis of Functionalized Cyclohexadienes

5

Conclusion

Key words: palladium, cyclization, enynes, exocyclic dienes, elec-

trocyclization

1

Introduction

In recent years, cascade palladium-catalyzed cyclizations

have emerged as efficient new synthetic routes for the sin- Scheme 1

gle-step elaboration of a wide range of complex systems

with high levels of regio- and stereocontrol. The scope

In this paper, we wish to report the scope and limitations

and limitations of such reactions has been the subject of

of the palladium-mediated tandem cyclization–coupling

reaction of functionalized enynes 1 and 2.⁵Furthermore,

the utility of the resulting stereodefined exocyclic dienes

for the preparation of complex polycyclic products will

also be presented.

recent reviews.¹

Current efforts in our group are focusing on the synthetic

potential of a new palladium-mediated cyclizations of un-

saturated substrates bearing a carbo or hetero (oxygen or

nitrogen) nucleophile (Scheme 1).²This cyclization pro-

ceeds in a completely trans manner since it involves an in-

tramolecular attack of the nucleophile onto the

unsaturated bond from the opposite side of the activating

s-unsaturated palladium species. The latter is, in most

cases, generated in situ from oxidative addition of the pal-

ladium(0) complex to an unsaturated halide or triflate. Fi-

nally, a reductive elimination from the resulting s-bonded

2

Formation of Cyclopentanic Derivatives

We first planned to extend this strategy to the formation

of cyclopentanic derivatives. However, a potential prob-

lem was anticipated in the cyclization of enynes of type 1.

We assumed that the strain generated by the presence of

the alkene moiety would make the 5-exo cyclization too

slow and lead to competitive side-reactions.

SYNTHESIS 2005, No. 2, pp 0311–0329

Advanced online publication: 21.10.2004

DOI: 10.1055/s-2004-834879; Art ID: Z07804SS

x

.

x

.2

0

4

In order to investigate the feasibility of the 5-exo ring clo-

sure, functionalized enynes 1a–c were prepared via the

four-step sequence outlined in Scheme 3 from the known

312

T. Lomberget et al.

FEATURE ARTICLE

3-bromo-3-buten-1-ol.⁶Thus, a Sonogashira coupling re-

action between this vinyl halide and trimethylsilylacety-

lene, followed by a deprotection of the silyl group under

basic conditions, afforded alcohol 3. Conversion of this

alcohol to the corresponding iodide followed by reaction

with the sodium salts of methyl cyanoacetate, dimethyl

malonate and malononitrile, gave the corresponding

enynes 1a–c (Scheme 3).

R¹

R²

n

R¹

R²

n

Ar

Z

Z'

Ar

Z'

n

R³

R⁴

n

R³

R⁴

The palladium-catalyzed cyclization of 1a with iodoben-

zene was first examined using the optimum reaction con-

ditions that recently gave good results in related

cyclization–coupling reactions.^3bThus, the preformed

enolate (1a and 1.2 equivalents of KH) and 0.2 equivalent

of 18-crown-6 were stirred in THF at 30 °C in the pres-

ence of 1.5 equivalents of iodobenzene and 5 mol% of

Z

∆

Z'

Z

Z'

1a-c : n = 1

2a-g : n = 2

Z, Z' = electron-withdrawing groups

Scheme 2

Biographical Sketches

Thierry Lomberget was born in cyclization reactions of conjugated working on the desymmetrization of

1973 in Bourg-en-Bresse, France. He enynes.

received his PhD from the University

arene chromium tricarbonyl com-

plexes. His main interests are in the

field of organometallic chemistry,

pericyclic reactions and asymmetric

synthesis.

He is currently a post-doctoral fellow

Claude Bernard of Lyon in 2002 un-

der the supervision of Dr. G. Balme

for research on palladium-catalyzed

at the University of Geneva in the re-

search group of Prof. E. P. Kündig,

Didier Bouyssi was born in Valence, cyclization processes. After a one- rent research interests cover the de-

France, in 1964 and studied chemis- year period as ‘ATER’ (Attaché velopment of synthetic organic

try at the University of Lyon where Temporaire d’Enseignement et de methods using transition metal com-

he obtained his PhD in 1992 under Recherche) in the same university, he plexes as catalytic reagents, multi-

the guidance of Prof. Jacques Goré was appointed by University of Lyon component reactions and the

and Dr. Geneviève Balme for re- as a ‘Maître de Conférences’ in the synthesis of natural or unnatural bio-

search on new palladium-mediated group of Geneviève Balme. His cur- active compounds.

Geneviève Balme was born in Saint her PhD degrees in the same Univer- main research interests focus on the

Symphorien s/s Coise, a small town sity (Doctorat de 3ième cycle, 1979: development of new synthetic meth-

situated in the hills about 30 km west supervisors Pr. Jacques Goré and Dr. ods using transition metal complex-

of Lyon. After a first academic posi- Max Malacria; Doctorat d’état, 1983: es, including palladium-catalyzed

tion as a primary school teacher (two supervisor Pr. Jacques Goré). In sequential reactions, multicompo-

years in France, three years in Island 1994, she was promoted to Directeur nent reactions, and their application

of Reunion) she studied chemistry at de Recherche at the Centre National to the synthesis of natural products

the University of Lyon and received de la Recherche Scientifique. Her and biologically active compounds.

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

FEATURE ARTICLE

New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes

313

ing decarboxylated product were observed. This tandem

reaction seems to be sensitive to the nature of the electro-

philic partner. To explain this difference of behavior, we

suggest that potassium iodide, liberated during the cy-

clization reaction involving iodobenzene, would be able

to effect a demethoxycarbonylation of the resulting steri-

cally hindered substrate 4a.¹⁰

Br

OH

a, b

c, d

Z

+

OH

TMS

Z'

3

1a Z = CN, Z' = CO₂Me

1b Z, Z' = CO₂Me

1c Z, Z' = CN

When the bulkier nucleophile 1b was subjected to the cy-

clization–coupling reaction with iodobenzene according

to the protocol developed for homolog 1a, the desired cy-

clized product 4b was isolated in moderate yield (30%)

along with traces of the monoester 5b (Table 1, entry 4).

This last result showed that the yield of this tandem reac-

tion is strongly influenced by the nature of the nucleo-

philic part of the starting material. The low yield observed

with the bulky nucleophile is presumably due to steric in-

teraction of the two adjacent methylene groups and the

geminal dimethyl esters in the rigid coplanar system 4b.

Scheme 3 a) Pd(PPh₃)₄(0.01 equiv), CuI (0.015 equiv), Et₃N, THF,

83%. b) K₂CO₃(0.15 equiv), MeOH, 81%. c) Imidazole, PPh₃, I₂,

Et₂O/CH₃CN, 78%. d) Methyl cyanoacetate, dimethylmalonate or

malononitrile, NaH, THF/DMF, 1a 62%, 1b 74% and 1c 59%.

Pd(0)(diphenylphosphinoethane).⁷The reaction required

six hours to reach completion and gave rise to two cy-

clized compounds: the expected product 4a and the dienic

substrate 5a, which results from a decarboxylative reac-

tion of 4a, in a 40% combined yield (26% and 14% isolat-

ed yield, respectively, after chromatography; Table 1,

entry 1). The use of PdCl₂(PPh₃)₂(reduced in situ by n-

BuLi as catalyst^8,9) in place of Pd(0)(dppe) improved

these results: the two cyclized products 4a and 5a were

obtained in a reasonable combined isolated yield of 58%

(Table 1, entry 2). The use of t-BuOK instead of KH did

not improve the yield. Interestingly, when the reaction

was performed with 1-cyclohexenyl triflate in place of io-

dobenzene, the stereodefined product 6a was isolated in

49% yield (Table 1, entry 3). No traces of the correspond-

To evaluate the effect of a more compact nucleophile, the

reaction was also carried out on the less sterically de-

manding nucleophile 1c that bears two cyano groups. Sur-

prisingly, this substrate gave a complex mixture of

unidentified products when subjected to the same reaction

conditions (Table 1, entry 5). This outcome is probably

due to the relative hardness of the anion a to the cyano

groups, compared to the one from substrate 1a, which

could favor side reactions.¹¹

Table 1 Access to 1,3-bis-Exocyclic Cyclopentadienes

Entry

1

Starting enyne

Iodide or triflate

Reaction time^aProducts (isolated yields)

1a

6 h

+

Z = CN

Z¢ = CO₂Me

Ph

I

NC

CO₂Me

CN

4a

(26%)^b

(39%)

5a

(14%)^b

(19%)

2

3

1a

"

4 h

3 h

TfO

NC

CO₂Me

6a^c(49%)

4

5

1b

3 h

+

Z = Z¢ = CO₂Me

Ph

CO₂Me

I

MeO₂C

CO₂Me

4b (30%)

complex degradation mixture

5b (4%)

1c

"

8 h^d

Z = Z¢ = CN

^aAll reactions were performed at 30 °C in THF with 1.2 equiv of KH, 0.2 equiv of 18-C-6 and 1.5 equiv of iodide or triflate, using 5 mol% of

PdCl₂(PPh₃)₂reduced by n-BuLi.

^b5 mol% Pd(0)(dppe) as catalyst.

^cNo decarboxylation product was detected.

^dThe same reaction carried out at 50 °C in NMP also gave a complex degradation mixture.

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

314

3

T. Lomberget et al.

FEATURE ARTICLE

screened (Table 2, entries 4–9). A significant improve-

ment in yield of the target compound was obtained by us-

Formation of Cyclohexanic Derivatives

On the basis of the above results, we reasoned that the ing KH since only a small amount of the competing

exocyclization reaction might be favored by using sub- product was formed (7b:8b = 19:1) (Table 2, entry 4). It is

strates with one more carbon in the side chain. However, noteworthy that a further recrystallization of this mixture

while the methodology for the preparation of cyclopen- gave pure dienic substrate 6b in 61% yield. With cesium

tane derivatives is well developed,¹²the construction of tert-butoxide,¹⁶a 1:2 mixture of compounds 7b:8b was

cyclohexane homologs has proven to be more difficult. isolated in 70% overall yield (Table 2, entry 6). By using

Several previous attempts¹³to obtain six-membered rings Cs₂CO₃, the selectivity of the reaction was completely re-

from alkynes were unsuccessful due to the strong tenden- versed as only the coupling product 8b was obtained in an

cy to give a direct coupling reaction of the alkyne with the excellent 87% yield (Table 2, entry 7). Then, we won-

aryl halide (Sonogashira coupling reaction).

dered if the use of CsOH·H₂O, which gave good results in

related cyclizations of unactivated alkynes having a cyano

electron-withdrawing group,¹⁷would be beneficial for our

system. Unfortunately, this base gave the coupling prod-

uct 8b in moderate yield in either THF or NMP (Table 2,

entries 8 and 9).

The required starting materials 2a–g were easily prepared

in good to moderate yields by conversion of the known¹⁴

4-methylenehex-5-yn-1-ol to the corresponding iodide

followed by reactions with the sodium salts of various ac-

tivated methylene compounds (Scheme 4).

Next, we attempted the cyclization of enyne 2c, which

bears two cyano groups. This was carried out under the

usual reaction conditions used for 2a. After 24 h at 30 °C,

the reaction provided exclusively the desired cyclized

product 7c which was, however, isolated in low

yield (27%) (Table 2, entry 10). Changing the solvent to

1-methyl-2-pyrrolidinone allowed the isolation of 7c in

53–57% yield with none of the side product 8c (Table 2,

entries 11 and 12). This is in marked contrast to the results

obtained with the lower homolog 1c leading to a complex

mixture of products as outlined in Table 1, entry 5.

Z'

a, b

OH

Z

Z = CN, Z' = CO₂Me

Z, Z' = CO₂Me

2a

2b

2c

2d

2e

2f

Z, Z' = CN

Z = CO₂Me, Z' = COMe

Z = CO₂Me, Z' = SO₂Ph

Z = CN, Z' = SO₂Ph

Z = CN, Z' = CO₂i-Pr

2g

Scheme 4 a) Imidazole, PPh₃, I₂, Et₂O/CH₃CN, 89%. b) ZCH₂Z¢,

NaH, THF/DMF, 2a 77%, 2b 81%, 2c 61%, 2d 72%, 2e 91%, 2f 76%

and 2g 53%.

Other enynes 2d–f were tested for this reaction but, in

these cases, we were not able to obtain the 1,3-bis-exocy-

clic dienes 7 selectively since various amounts of the di-

rect coupling products 8 were also detected (Table 2,

entries 13–20). It is important to note that the desired

dienes 7 were easily separated from the direct coupling

products by conventional flash chromatography. With

enyne 2d bearing a methyl acetoacetate as the nucleo-

phile, the major product of the reaction was the coupling

product 8d (Table 2, entry 13). Use of KH instead of t-

BuOK slightly increased the amount of the cyclized prod-

uct 7d (Table 2, entry 14) whereas a more polar solvent

like NMP gave exclusively the coupling product 8d with

an excellent 87% yield (Table 2, entry 15).¹⁸The same be-

havior was also observed with enynes 2e and 2f bearing a

sulfone group since the cyclization–direct coupling prod-

ucts 7e:8e ratio improved (from 1:1 to 1:1.7) by swapping

t-BuOK for KH (Table 2, entries 16 and 17).¹⁹Similarly,

when the polarity of the solvent increased (from THF to

NMP), the coupling products 8e and 8f were isolated in

excellent yields, 80 and 90% respectively, as the sole

products (Table 2, entries 18 and 20).

3.1

Synthesis of 1,3-Bis-Exocyclic Dienes

The initial studies were performed on enyne 2a. Thus,

treatment of 2a with KH in the presence of iodobenzene

under the optimal reaction conditions described above led,

after three hours at room temperature, to the exclusive for-

mation of the expected cyclized product 7a in 77% yield

(Scheme 5).¹⁵

Pd(0) 5 mol%

CO₂Me

PhI 1.5 equiv

KH 1.2 equiv

Ph

CN

18-C-6 0.2 equiv

2a

NC CO₂Me

THF, 30 °C, 3 h

7a

Pd(0): PdCl₂(PPh₃)₂/ n-BuLi

77%

Scheme 5

The palladium-mediated cyclization was then studied

with enyne 2b. Thus, treatment of 2b with t-BuOK under

the conditions described above resulted in the formation

of the desired cyclic compound 7b together with the linear

coupling product 8b in a ratio of approximately 5:1 and

76% combined yield (Table 2, entry 3). In order to mini-

mize the competitive coupling reaction, a range of bases

such as KH, KHMDS and cesium-derived bases were

As described previously for the lower homologs, the

scope of the reaction (cyclization versus direct coupling

reaction) is strongly dependent on the nature of the nu-

cleophilic part of enynes 2 and total selectivity for the cy-

clization process was only noted with enynes 2a and 2c.

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

FEATURE ARTICLE

New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes

315

Table 2 Effect of the Electron-Withdrawing Groups on the Cycliza-

tion–Direct Coupling Products Ratio of the Wacker-Type Reaction of

Conjugated Enynes 2

Table 2 Effect of the Electron-Withdrawing Groups on the Cycliza-

tion–Direct Coupling Products Ratio of the Wacker-Type Reaction of

Conjugated Enynes 2 (continued)

base 1.2 equiv

18-C-6 0.2 equiv

base 1.2 equiv

18-C-6 0.2 equiv

+

Pd(0) 5 mol%

Ph

Pd(0) 5 mol%

Ph

PhI 1.5 equiv

Z

Z'

Z

Z'

7

8

2

Entry Enyne Base

Conditions

Yield^a

7 (%)

Yield^a

8 (%)

Entry Enyne Base

Conditions

Yield^a

7 (%)

Yield^a

8 (%)

1

2

3

4

5

6

7

8

9

2a

t-BuOK

KH

THF, 30 °C,

4 h

73

–

19

20

2f

KH

THF, 50 °C,

7 h

39

–

13

THF, 30 °C,

3 h

77

–

t-BuOK

NMP, 50 °C,

3 h

90

76^b

^aIsolated products.

2b

t-BuOK

KH

THF, 30 °C,

6 h

7b:8b 83:17^d

^bOverall yield of cyclized and direct coupling products 7 and 8.

^cReaction was carried out without 18-C-6.

78^b

^dCalculated by ¹H NMR.

THF, 30 °C,

7 h

7b:8b 96:4^d,e

^e61% yield of analytically pure cyclized product 7b after recrystalli-

zation in CH₂Cl₂–MeOH (1:1, removal of 4% of 8b).

KHMDS

t-BuOCs^c

THF, 30 °C,

22 h

72 ^b

7b:8b 68:32

To explore the scope and generalization of this process,

enynes 2a and 2b were allowed to react with a variety of

aryl iodides possessing different functional groups, with

the reaction being performed under the optimal conditions

reported above. As summarized in Table 3, good yields of

dienic substrates were obtained with electron-rich aryl io-

dides (Table 3, entries 3, 8 and 9). The presence of an

electron-withdrawing group such as an ester group in the

para position on the aryl iodide slightly decreases the

yield of the corresponding dienic substrates (Table 3, en-

tries 4 and 6) while a relatively long reaction time is ob-

served when aryl iodide bearing a CF₃group in the meta

position was used as coupling partner (Table 3, entries 5

and 7). In these two last cases, undesired acyclic products

of type 8 are formed in approximately 15%. As shown in

entries 1, 2 and 10, the steric hindrance due to the presence

of an ortho substituent on the aryl iodide does not affect

the yields of the cyclized products. However, a slight de-

crease in the yield of the expected substrates, as well as

lower selectivity, are observed with aryl iodides that have

a protected benzylic alcohol in the ortho position

(Table 3, entries 11 and 12). This is possibly due to a

chelating effect of the ortho-substituents to the Pd(0) cat-

alyst, which could reduce the rate of the cyclization pro-

cess and then favor the competing direct coupling

reaction. As shown above, this cyclization–direct cou-

pling balance is also strongly dependent on the nature of

the nucleophilic part of enynes 2. With enyne 2b, which

bears two ester groups, various amounts of the corre-

sponding direct coupling products (5–15%) were ob-

THF, 30 °C,

22 h

70 ^b

7b:8b 35:65

c

Cs₂CO₃

THF, 30 °C,

7 h

–

87

CsOH·H₂O^cTHF, 30 °C,

7 h

47 ^b

7b:8b 7:93

CsOH·H₂O^cNMP, 50 °C, 3h

47

7b:8b 0:100

10

11

2c

t-BuOK

THF, 30 °C, 24h 27

–

NMP, 50 °C,

4 h

53

–

12

13

14

15

16

17

18

KH

NMP, 50 °C,

4 h

57

–

2d

t-BuOK

KH

THF, 30 °C,

27 h

14

52

44

87

THF, 50 °C,

21 h

23

t-BuOK

KH

NMP, 50 °C,

3 h

–

2e

THF, 50 °C,

7 h

70%^b

7e:8e 63:37^d

t-BuOK

THF, 50 °C,

5 h

27

30

NMP, 50 °C,

3 h

–

80

1

served by H NMR spectroscopic analysis of the crude

product.

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

316

T. Lomberget et al.

FEATURE ARTICLE

Table 3 Palladium-Catalyzed Cyclization Reaction of Enynes 2a and 2b with Substituted Aryl Iodides

Entry

1

Enyne

Aryl iodide

Reaction time

4 h

Exocyclic diene

Isolated yield (%)

52

Br

2a

Z = CN,

Z¢ = CO₂Me

I

NC CO₂Me

Br

10a

2

3

4

2a

9 h

4 h

9 h

68

75

66

MeO

I

NC CO₂Me

OMe

11a

OMe

I

NC CO₂Me

12a

CO₂Me

NC CO₂Me

13a

5

6

2a

18 h

6 h

46^a

CF₃

NC CO₂Me

14a

2b

67^b,d

CO₂Me

Z = Z¢ = CO₂Me

MeO₂C CO₂Me

13b

7

8

2b

30 h

3 h

52^b,e

CF₃

I

CF₃

MeO₂C CO₂Me

14b

83^b,c

OMe

I

MeO₂C CO₂Me

15b

9

10

11

2b

6 h

5 h

79^b,c

63^b,d

47^b,e

O

MeO₂C CO₂Me

16b

Me

I

MeO₂C CO₂Me

Me

17b

21 h

AcO

I

9a

MeO₂C CO₂Me

OAc

18b

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

FEATURE ARTICLE

New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes

317

Table 3 Palladium-Catalyzed Cyclization Reaction of Enynes 2a and 2b with Substituted Aryl Iodides (continued)

Entry

12

Enyne

Aryl iodide

Reaction time

8 h

Exocyclic diene

Isolated yield (%)

52^b,e

2b

THPO

I

MeO₂C CO₂Me

9b

OTHP

19b

^aDirect coupling product isolated in a 14% yield.

^bCyclization and direct coupling products were separated by flash chromatography. Cyclization:coupling products ratios were determined by

¹H NMR on the crude mixture.

^cCyclization:coupling products ratio = 95:5.

^dCyclization:coupling products ratio = 90:10.

^eCyclization:coupling products ratio = 85:15.

been reported.^4a–fMore seldom are the cases dealing with

3.2 Synthesis of Conjugated Trienes

their corresponding sterically hindered (Z)-isomers. We

An attractive application of this methodology is the effi-

therefore investigated the [4+2] cycloaddition reactions of

cient synthesis of conjugated trienes through a cycliza-

functionalized 1-benzylidene-2-methylene cyclohexanes

tion–coupling reaction involving vinylpalladium

7a–c.²²The use of very reactive dienophiles, like tetracy-

complexes as activating intermediates in place of the

anoethylene and N-phenyltriazolinedione, allowed the

arylpalladium ones. Indeed, such systems are able to un-

formation of the expected polycyclic structures 23 under

dergo an electrocyclic rearrangement to form cyclohexa-

atmospheric pressure, whereas hyperbaric conditions (16

dienes.²⁰To this end, we investigated the Wacker-type

kbar) were necessary to form the adducts with less reac-

cyclization reaction of enyne 2a with the commercial b-

tive dienophiles (Scheme 6).

bromostyrene (mixture of 85% trans and 15% cis iso-

mers). The reaction proceeded at 30 °C in THF in the

presence of KH as base, and led to the exclusive formation

of the expected product 20a as a single geometric isomer

E

∆

+

1 atm or

16 kbar

Ph

in 71% yield. Only the trans isomer was incorporated²¹

and the (E)-stereochemistry of the styrene fragment was

assigned by ¹H NMR spectral analysis (Table 4, entry 1).

The same conditions were successfully applied to enyne

2g, which has a bulky isopropyl group (Table 4, entry 2),

and to the reaction of 2a with 2-bromopropene (Table 4,

entry 4). The reaction was also conducted on enyne 2a

with a vinyl triflate such as 1-cyclohexenyltriflate, and the

conjugated triene 22a was then obtained with a very good

77% yield (Table 4, entry 5). With enyne 2c, which has

two cyano groups, the reaction must be carried out in a

more polar solvent (NMP) and the trienic substrate 20c

was isolated in 51% yield (Table 4, entry 3).

E'

Z

Z'

Z

Z'

Ph

23

53-100%

7a-c

E, E': electron with-

drawing groups

Z, Z' = CN, CO₂Me

Scheme 6

4.2

Intramolecular Friedel–Crafts Reaction

The stereodefined configuration of the benzylidene frag-

ment allowed a Lewis acid-mediated intramolecular

Friedel–Crafts alkylation of the exocyclic methylene sub-

stituent onto the vicinal aromatic ring. A wide range of

Lewis acids have been tested in this reaction and it was

found that a catalytic amount of Sc(OTf)₃allowed this re-

action to proceed.²³The method was applied to com-

pounds 7b, 15b, 16b and 17b, and was very efficient for

constructing the 4a-methyltetrahydrofluorene skeleton 24

that bears electron-donating substituents, an uncommon

structure present in some recently isolated natural

products²⁴(Scheme 7).

4

Synthetic Applications

With the desired stereodefined 1,3-bis-exocyclic dienes in

hand, we decided to explore their synthetic potential for

the preparation of diverse ring structures. In line with this,

their behavior in Diels–Alder reaction was first investigat-

ed. Other reactions exploiting this structural unit, such as

intramolecular Friedel–Crafts alkylations and thermal

electrocyclizations (with an exocyclic conjugated triene),

were also investigated.

4.3

Thermal Electrocyclization

4.3.1 Reaction on Conjugated Exocyclic Trienes

The electrocyclic ring closure of conjugated trienes²⁵was

first investigated in the cyclohexanic series by simple

heating of a solution of the substrates 20–22 in order to

obtain the functionalized cyclohexadienes 25–27

(Table 5). The thermal electrocyclization of 1,3,5-triene

4.1

Diels–Alder Reaction

Numerous Diels–Alder reactions involving (E)-1-ben-

zylidene or alkylidene 2-methylene cycloalkanes have

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

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T. Lomberget et al.

FEATURE ARTICLE

Table 4 Synthesis of Conjugated Trienes

R¹

R²

R¹

R²

CN

Pd(0),

X

Z

KH 1.2 equiv

THF, 30 °C

Z

CN

2

20-22

X = Br, OTf

Z = CN, CO₂Me, CO₂i-Pr

Entry

1

Enyne

Vinyl bromide or triflate

Reaction time

7 h

Conjugated triene

Isolated yield (%)

71

2a

Ph

Z = CN,

Z¢ = CO₂Me

Br

(2 equiv)^a

NC CO₂Me

20a

2

2g

5 h

70

Ph

Z = CN,

Z¢ = CO₂i-Pr

Br

(2 equiv)^a

NC CO₂i-Pr

20g

3

4

5

2c

8 h^b

5 h

51

66

77

Ph

Z = Z¢ = CN

Br

(2 equiv)^a

NC CN

20c

2a

Br

(3 equiv)

NC CO₂Me

21a

TfO

NC CO₂Me

(1.5 equiv)

22a

^aCommercial b-bromostyrene (mixture of 85% trans and 15% cis isomers); only the trans isomer was incorporated.

^bReaction was carried out in NMP, 50 °C.

(Z = CN and Z¢ = CO₂Me) and the cyclohexadiene 25a

was isolated as an inseparable 85:15 diastereomeric mix-

ture in 90% yield (Table 5, entry 2). Introduction of an

isopropyl group on the ester functionality did not modify

the diastereomeric excess, as 25g was obtained in quanti-

tative yield and in the same ratio (Table 5, entry 3). When

compared to the cyclization of substrates 20a,c,g, which

all have an aryl group appended to the incorporated dou-

ble bond, reactions of the corresponding alkyl-substituted

1,3,5-trienes 21a and 22a, took a shorter time to complete

(respectively 45 minutes and one hour) and gave tricyclic

compounds 26a and 27a, respectively, in quantitative

yield (Table 5, entries 4 and 5). It is noteworthy that the

electrocyclization of 21a can also be performed in reflux-

ing THF (seven hours) and the results are comparable to

those obtained in toluene (Table 5, entries 5 and 6).

Lewis acid

73-96%

R

MeO₂C CO₂Me

7b

24

15b, 16b, 17b

R = electron-

donating groups

Scheme 7

20c did not proceed in THF even after prolonged reflux

times. When the reaction was conducted in refluxing tol-

uene for five hours, the expected compound 25c was ob-

tained in good yield (90%) (Table 5, entry 1). These

conditions were also successful for the electrocyclization

of the trienic substrate 20a bearing two different groups

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

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New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes

319

Table 5 Thermal 6-p Electrocyclization of Conjugated Trienes

R¹

R²

R¹

R²

∆

Z

Z'

25-27

Z

Z'

20-22

Z, Z' = CN, CO₂Me, CO₂i-Pr

Entry

1

Conjugated triene

Conditions

Product

Yield^a(%)

90

Ph

toluene, reflux, 5 h

Ph

NC CN

20c

NC CN

25c

2

3

4

toluene, reflux, 5 h

toluene, reflux, 1 h

90^b

100^b

98^b

H

Ph

NC CO₂Me

20a

25a

Ph

NC CO₂i-Pr

20g

25g

NC CO₂Me

22a

27a

5

6

toluene, reflux, 45 min

THF, reflux, 7 h

99

100

NC CO₂Me

21a

26a

^aIsolated products.

^bDiastereomeric ratio 85:15.

4.3.2 One-Pot Synthesis of Functionalized Cyclohexa- (Table 6, entries 2 and 4). Under the same conditions as

dienes

used for the lower homolog, the tricyclic compound 27a

was obtained after 90 minutes reaction time in 68% yield,

starting from enyne 2a (Table 6, entry 3). This one-pot se-

quence was also carried out with vinyl bromides such as

commercial b-bromostyrene or 2-bromopropene. The cor-

responding cyclohexadienes 25a and 26a were obtained

in 60% and 61% yields, respectively (Table 6, entries 4

and 5). In this last example, the reaction was complete af-

ter heating for two hours in a sealed tube, while reaction

with b-bromostyrene required a longer reaction time (five

hours) to form the rearranged product 25a.

The one-pot transformation that avoids isolation of the

conjugated triene was also envisaged. Table 6 summariz-

es some of our results. We initially examined the reaction

of the potassium enolate of 1a with 1-cyclohexenyl tri-

flate, in refluxing toluene. Under these conditions, the tri-

cyclic compound 28a was obtained in 46% yield (Table 6,

entry 1). When the reaction was conducted with the vinyl

triflate derived from acetophenone, the cyclization–elec-

trocyclization sequence could be carried out in THF at

30 °C and cyclohexadiene 29a was then isolated in 51%

yield (Table 6, entry 2). Re-establishment of the conjuga-

tion between the aryl group and the double bonds could be

the driving force for the electrocyclization, and would fa-

vor this rearrangement at a lower temperature, compared

to the conditions required for another phenyl position

These experiments demonstrate that the one-pot reaction

that combines cyclization and in situ thermal electrocy-

clization is a very efficient and elegant method to synthe-

size functionalized cyclohexadienes, since three carbon–

carbon bonds and two rings are formed in one step. More-

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

320

T. Lomberget et al.

FEATURE ARTICLE

Table 6 One-Pot Synthesis of Functionalized Cyclohexadienes

R¹

n

R¹

R²

Pd(0),

X

NC

KH 1.2 equiv

toluene, reflux

n

R²

CO₂Me

NC

CO₂Me

25a, 26a, 27a,

28a, 29a

1a : n = 1

2a : n = 2

n

R¹

R²

NC

CO₂Me

Entry

1

Enyne

Halide or triflate, Reaction time

Product

Yield^a(%)

46^c

H

1a

TfO

(1.5 equiv) 1 h

NC

CO₂Me

28a

2

3

1a

2a

51

TfO

Ph

(1.5 equiv) 8 h^b

NC

CO₂Me

29a

68^c

H

TfO

(1.5 equiv) 1 h 30 min

NC CO₂Me

27a

4

5

2a

60^c

Ph

Br

(2 equiv)^d5 h

NC CO₂Me

25a

61

Br

(3 equiv)^e2 h

NC CO₂Me

26a

^aIsolated products.

^bReaction was carried out at 30 °C in THF.

^cDiastereomeric ratio 85:15.

^dCommercial b-bromostyrene (mixture of 85% trans and 15% cis isomers); only the trans isomer was incorporated.

^eReaction carried out in a sealed tube.

over, use of vinyl triflates widens the scope of this meth- Friedel–Crafts alkylations and thermal electrocycliza-

od, as a large number of these reagents can be prepared tions. In this last case, it was possible to develop a one-pot

from commercially available ketones.

reaction combining the tandem cyclization–coupling re-

action with a 6-p electrocyclization, providing functional-

ized cyclohexadienes in good yields.

5

Conclusion

All reactions were carried out under a positive pressure of nitrogen

and with oven-dried glassware. Petroleum ether (PE) refers to the

40–60 °C boiling point fraction. All the reaction solvents were dis-

tilled prior to use: over sodium/benzophenone for THF, over phos-

phorus pentaoxide for DMF and over calcium hydride for

acetonitrile, diethyl ether, dichloromethane, toluene, DMSO and t-

BuOH. HPLC grade triethylamine, methanol and NMP were used

In summary, we have developed an efficient method for

the preparation of stereodefined functionalized 1,3-bis

exocyclic dienes and conjugated trienes. These dienes can

be used as precursors to various polycyclic compounds

through subsequent Diels–Alder reactions, intramolecular

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

FEATURE ARTICLE

New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes

321

without distillation. n-Buli solutions in hexanes were titrated using

N-Benzylbenzamide.²⁶All reagents, except commercial products of

satisfactory quality were purified with literature procedures prior to

use. Potassium hydride (35% in mineral oil) was washed with anhy-

drous THF, dried and stored under nitrogen before use.

¹³C NMR (75 MHz, CDCl₃): d = 40.1, 60.5, 77.7, 83.4, 125.3,

127.2.

5-Iodo-3-methylenepent-1-yne

To a vigorously stirred solution of 3-methylene-pent-4-yn-1-ol

(1.57 g, 16.4 mmol) in a 3:1 mixture of Et₂O–CH₃CN (68 mL) was

added successively at 0 °C imidazole (3.34 g, 49.1 mmol), PPh₃

(6.44 g, 24.5 mmol) and iodine (6.23 g, 24.5 mmol). The resulting

mixture was stirred for 2 h at 0 °C and a further 1 h at r.t. Petroleum

ether was added to precipitate triphenylphosphine oxide and the so-

lution was then filtered onto a pad of silica gel (eluting with Et₂O).

The solvents were removed under reduced pressure and the crude

product was purified by flash chromatography (PE) to give the title

compound as a pale yellow liquid. Yield: 2.73 g (81%).

Thin layer chromatography (TLC) was carried out with Merck

60F254 silica gel plates (supported on aluminum); the revelation

was done by UV lamp (254 and 365 nm) and chemical staining

(acidic solution of p-anisaldehyde in ethanol). Preparative flash

chromatography was carried out under medium pressure using

Merck silica gel 60 Å (40–63 mm); volumetric composition of the

eluent is indicated in parentheses (PE = petroleum ether).

Infrared spectra were recorded on Perkin-Elmer 298 or Perkin-Elm-

er FT-IR PARAGON 500 spectrometers. NMR spectra were re-

corded at room temperature on Bruker AM 300, ALS 300, DRX 300

and Bruker AC 200 NMR instruments. Internal references are tet-

ramethylsilane (d = 0.0 ppm) or residual protons of deuterated sol-

vents (d = 7.26 ppm for ¹H NMR and d = 77.16 ppm for ¹³C NMR

for CDCl₃). Abbreviations s, d, t, q, quint, hept, m and br respective-

ly refer to singlet, doublet, triplet, quadruplet, quintuplet, heptuplet,

multiplet and broad. Low- and high-resolution mass spectroscopy

was recorded with ThermoQuest FINNIGAN MAT 95 XL appara-

tus operating at 70eV (for chemical ionizations, isobutane was

used). Melting points were measured on a BÜCHI B-540 apparatus

and are uncorrected. Elemental Analyses were performed by the

Service Central d’Analyses du CNRS, Solaize, France. 3-Bromo-

IR (neat): 3280, 2950, 1610, 1420, 1230, 1170, 910 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 2.71 (t, J = 7.3 Hz, 2 H), 2.93 (s,

1 H), 3.33 (t, J = 7.3 Hz, 2 H), 5.38 (d, J = 0.6 Hz, 1 H), 5.56 (d,

J = 0.6 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 3.0, 41.0, 78.3, 82.5, 125.0, 129.0.

2-Cyano-5-methylene-hept-6-ynoic Acid Methyl Ester (1a)

To a suspension of 60% NaH in mineral oil (232 mg, 5.8 mmol) in

THF (5 mL), was added dropwise at 0 °C methyl cyanoacetate (1.02

mL, 11.6 mmol). 5-Iodo-3-methylene-pent-1-yne (920 mg, 4.47

mmol) in DMF (5 mL) was added at r.t. and the resulting mixture

was stirred for 2 h. Et₂O (20 mL) and an aq 1 M solution of HCl (20

mL) were added, the organic phase was separated and the aqueous

phase was extracted with Et₂O (2 × 20 mL). Combined organic

phases were washed with brine, dried (MgSO₄) and concentrated in

vacuo. The crude product was purified by flash chromatography

(PE–Et₂O, 75:25) to give 1a as a colorless oil. Yield: 487 mg (62%).

but-3-en-1-ol⁶,

4-methylene-hex-5-yn-1-ol,¹⁴

t-BuOCs,¹⁶

Pd(PPh₃)₄,²⁷and iodides 9a and 9b from commercial 2-iodobenzyl

alcohol were prepared according to literature procedures.

3-Methylene-5-(trimethylsilanyl)pent-4-yn-1-ol

To a stirred solution of 3-bromobut-3-en-1-ol (2.26 g, 15 mmol) in

20 mL of THF was successively added Et₃N (2.72 mL, 19.5 mmol),

Pd(PPh₃)₄(173 mg, 0.15 mmol), CuI (43 mg, 0.23 mmol) and tri-

methylsilylacetylene (2.76 mL, 19.5 mmol). The resulting mixture

was stirred overnight at room temperature (16 h). The solution was

filtered through a pad of celite (eluting with Et₂O) and concentrated

in vacuo. The residue was dissolved in Et₂O, washed with saturated

NH₄Cl solution, dried (MgSO₄) and the solvents were removed un-

der reduced pressure. The crude product was purified by flash chro-

matography (PE–Et₂O, 60:40) to give the title compound as a

yellow oil. Yield: 2.06 g (82%).

IR (neat): 3285, 3011, 2956, 2251, 1752, 1612, 1437, 1399, 1265,

1216, 1178, 1156, 1059, 1010, 915, 653 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 2.08–2.25 (m, 2 H), 2.40 (m, 2 H),

2.94 (s, 1 H), 3.55 (dd, J = 8.9, 5.7 Hz, 1 H), 3.82 (s, 3 H), 5.42 (s,

1 H), 5.52 (s, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 28.0, 33.9, 36.3, 53.7, 78.5, 82.6,

116.2, 125.3, 127.7, 166.5.

Anal. Calcd for C₁₀H₁₁NO₂(177.20): C, 67.78; H, 6.26; N, 7.90.

Found: C, 67.44; H, 6.29; N, 7.93.

IR (neat): 3350, 2960, 2900, 2140, 1610, 1410, 1250, 1050, 950,

840, 760 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 0.18 (s, 9 H), 1.78 (t, J = 5.7 Hz,

1 H), 2.40 (t, J = 5.7 Hz, 2 H), 3.80 (m, 2 H), 5.34 (d, J = 1.5 Hz, 1

H), 5.48 (d, J = 1.5 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = –0.04, 40.3, 60.8, 94.9, 104.8,

124.6, 128.1.

2-(3-Methylenepent-4-ynyl)malonic Acid Dimethyl Ester (1b)

Following the same experimental procedure as for 1a, scale: NaH

60% in mineral oil (94 mg, 2.30 mmol), 5-iodo-3-methylenepent-1-

yne (400 mg, 1.94 mmol), dimethyl malonate (335 mL, 2.91 mmol),

1:1 mixture of THF–DMF (4 mL). The crude product was purified

by flash chromatography (PE–Et₂O, 75:25) to give 1b as a colorless

oil. Yield: 302 mg (74%).

IR (neat): 3280, 2950, 2250, 1730, 1610, 1450, 1150, 1100, 910

cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 2.10–2.23 (m, 4 H), 2.90 (s, 1 H),

3.40 (t, J = 7.2 Hz, 1 H), 3.73 (s, 6 H), 5.30 (s, 1 H), 5.44 (d, J = 0.8

Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 27.0, 34.5, 50.6, 52.7, 77.8, 83.3,

124.1, 129.0, 169.7.

3-Methylenepent-4-yn-1-ol (3)

To a solution of 3-methylene-5-(trimethylsilyl)pent-4-yn-1-ol (3.38

g, 20.1 mmol) in MeOH (40 mL) was added K₂CO₃(416 mg, 3

mmol). After 1 h at r.t., H₂O (10 mL) was added and the resulting

mixture was extracted with Et₂O (2 × 50 mL). The organic layer

was washed with brine, dried (MgSO₄) and concentrated in vacuo.

The crude product was purified by flash chromatography (PE–Et₂O,

50:50) to give the title compound as a yellow oil. Yield: 1.57 g

(81%).

(3-Methylenepent-4-ynyl)malononitrile (1c)

Following the same experimental procedure as for 1a, scale: NaH

60% in mineral oil (240 mg, 6 mmol), 5-iodo-3-methylenepent-1-

yne (824 mg, 4 mmol), malononitrile (396 mg, 6 mmol), 1:1 mix-

ture of THF–DMF (8 mL). The crude product was purified by flash

chromatography (PE–Et₂O, 80:20) to give 1c as a colorless oil.

Yield: 340 mg (59%).

IR (neat): 3350, 3290, 2960, 2880, 1610, 1420, 1250, 1050, 910,

840 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 2.37 (t, J = 6.1 Hz, 2 H), 2.44 (br

s, 1 H), 2.91 (s, 1 H), 3.75 (t, J = 6.1 Hz, 2 H), 5.36 (d, J = 0.9 Hz,

1 H), 5.48 (d, J = 0.9 Hz, 1 H).

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T. Lomberget et al.

FEATURE ARTICLE

IR (neat): 3280, 2910, 2250, 1610, 1440, 920 cm^–1.

mL). After purification (PE–Et₂O, 80:20), the cyclization product

6a was obtained as a colorless oil. Yield: 86 mg (49%).

¹H NMR (300 MHz, CDCl₃): d = 2.31 (dt, J = 7.1, 7.1 Hz, 2 H),

2.50 (t, J = 7.1 Hz, 2 H), 3.00 (s, 1 H), 3.76 (t, J = 7.1 Hz, 1 H),

5.49 (d, J = 0.4 Hz, 1 H), 5.59 (s, 1 H).

IR (neat): 3093, 2929, 2856, 2834, 2241, 1740, 1636, 1434, 1294,

1172, 1077, 994, 903, 791 cm^–1.

¹³C NMR (75 MHz, CDCl₃): d = 21.5, 29.1, 33.5, 79.3, 81.8, 112.4,

¹H NMR (300 MHz, CDCl₃): d = 1.62 (m, 4 H), 2.09 (m, 4 H), 2.23

(m, 1 H), 2.47–2.55 (m, 1 H), 2.59–2.77 (m, 2 H), 3.82 (s, 3 H), 5.17

(s, 1 H), 5.58 (s, 1 H), 5.85 (m, 1 H), 6.37 (s, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 22.0, 22.7, 25.5, 26.9, 32.9, 34.1,

53.1, 53.8, 112.8, 119.9, 129.3, 132.7, 133.7, 134.9, 142.7, 168.6.

126.3, 126.4.

Anal. Calcd for C₉H₈N₂(114.17): C, 74.98; H, 5.59; N, 19.43.

Found C, 74.43; H, 5.65; N, 18.92.

Palladium-Catalyzed Cyclization of Functionalized Enynes 1

and 2: General Procedure 1 (GP1)

CI-MS: m/z (%) = 314 [52, (M + C₄H₉)⁺], 258 (100, MH⁺), 231

(69).

To a suspension of a base (1.2 mmol) in 3 mL of THF was added

18-C-6 (53 mg, 0.2 mmol), enyne 1 or 2 (1 mmol) in 4 mL of THF,

and aryl or vinyl halide or triflate (1.5 to 3 mmol). This mixture was

stirred at r.t. for 15 min. In a separate flask, n-BuLi (2.6 M in hex-

anes) was added dropwise at r.t. to a suspension of PdCl₂(PPh₃)₂(35

mg, 0.05 mmol) in THF (3 mL) until the mixture becomes dark

green. After heating at reflux for 5 min, the mixture turned to a dark

red homogeneous solution and was added after cooling via a cannu-

la to the anion solution prepared above. The resulting mixture was

then stirred at 30 °C and monitored by TLC until completion. The

solution was then filtered through a short pad of silica gel (eluting

with Et₂O) and the solvents were removed under reduced pressure.

The resulting residue was purified by flash chromatography (PE–

Et₂O mixtures).

CI-HRMS calcd for C₁₆H₁₉NO₂: 258.1494 (MH⁺), found: 258.1490.

2-Benzyl-3-methylenecyclopent-1-enecarboxylic Acid Methyl

Ester (5b)

According to GP1, scale: KH (29 mg, 0.72 mmol), 18-C-6 (32 mg,

0.12 mmol), enyne 1b (126 mg, 0.60 mmol), iodobenzene (100 mL,

0.84 mmol), PdCl₂(PPh₃)₂(21 mg, 0.03 mmol), THF (6 mL). After

purification (PE–Et₂O, 80:20), two products were isolated: the less

polar fraction corresponds to the cyclization-decarboxylation prod-

uct 5b, which was obtained as a colorless oil. Yield: 6 mg (4%).

¹H NMR (300 MHz, CDCl₃): d = 2.62 (m, 2 H), 2.73 (m, 2 H), 3.77

(s, 3 H), 4.06 (s, 2 H), 5.09 (t, J = 2.4 Hz, 1 H), 5.21 (t, J = 2.4 Hz,

1 H), 7.24 (m, 5 H).

The more polar fraction is the cyclized product 4b, which was ob-

tained as a white solid. Yield: 53 mg (30%); mp 56–58 °C.

2-Benzyl-3-methylenecyclopent-1-enecarbonitrile (5a)

According to General Procedure 1 (GP1), scale: KH (38 mg, 0.95

mmol), 18-C-6 (42 mg, 0.16 mmol), enyne 1a (140 mg, 0.79 mmol),

iodobenzene (135 mL, 1.19 mmol), PdCl₂(PPh₃)₂(28 mg, 0.04

mmol), THF (8 mL). After purification (PE–Et₂O, 80:20), two prod-

ucts were isolated: the less polar fraction corresponds to the cycliza-

tion-decarboxylation product 5a, which was obtained as a pale

yellow oil. Yield: 29 mg (19%).

¹H NMR (CDCl₃): d = 2.69 (s, 4 H), 3.79 (s, 2 H), 5.10 (t, J = 1.5

Hz, 1 H), 5.19 (t, J = 1.5 Hz, 1 H), 7.22–7.32 (m, 5 H).

¹³C NMR (75 MHz, CDCl₃): d = 29.2, 31.6, 33.1, 109.6, 116.8,

126.8, 128.5, 128.7, 137.4, 137.6, 151.1, 158.3.

2-Benzylidene-3-methylenecyclopentane-1,1-dicarboxylic Acid

Dimethyl Ester (4b)

IR (KBr): 3043, 3010, 2953, 2847, 1734, 1600, 1575, 1494, 1435,

1263, 1154, 1110, 1068, 1029, 999, 897, 764, 699 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 2.38 (br t, J = 6.7 Hz, 2 H), 2.51

(m, 2 H), 3.78 (s, 6 H), 4.91 (s, 1 H), 5.08 (s, 1 H), 6.82 (s, 1 H), 7.22

(m, 1 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.40 (d, J = 7.6 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): d = 33.0, 33.3, 53.0, 65.5, 111.3,

127.3, 128,5, 128.5, 130.1, 137.4, 137.4, 144.6, 171.4.

EI-MS: m/z (%) = 286 (M⁺, 12), 227 (28), 226 (100), 211 (42), 194

(36), 183 (29), 167 (89), 165 (67), 152 (24).

EI-MS: m/z (%) = 195 (M⁺, 100), 194 (43), 180 (40), 167 (53), 153

(63), 142 (80), 141 (38), 115 (28), 91 (50), 89 (44), 77 (79), 61 (70),

51 (33), 43 (54).

EI-HRMS calcd for C₁₇H₁₈O₄: 286.1205, found 286.1205.

EI-HRMS calcd for C₁₄H₁₃N: 195.1048, found: 195.1044.

6-Iodo-3-methylene-hex-1-yne

The more polar fraction is the cyclized product 4a, which was ob-

tained as a pale yellow oil. Yield: 78 mg (39%).

Following the same experimental procedure as for 5-iodo-3-meth-

ylenepent-1-yne; scale: 4-methylenehex-5-yn-1-ol (2.00 g, 18.2

mmol), 3:1 mixture of Et₂O–CH₃CN (72 mL), imidazole (3.71 g,

54.5 mmol), PPh₃(7.15 g, 27.3 mmol) and iodine (6.92 g, 27.3

mmol). The crude product was purified by flash chromatography

(PE) to give the title compound as a pale yellow liquid. Yield: 3.57

g (89%).

(E)-2-Benzylidene-1-cyano-3-methylenecyclopentanecarboxyl-

ic Acid Methyl Ester (4a)

¹H NMR (300 MHz, CDCl₃): d = 2.29 (dt, J = 13.0, 8.5 Hz, 1 H),

2.54–2.73 (m, 2 H), 2.79–2.84 (m, 1 H), 3.87 (s, 3 H), 5.03 (s, 1 H),

5.25 (s, 1 H), 6.95 (s, 1 H), 7.24–7.36 (m, 3 H), 7.39–7.41 (d, J = 7.4

Hz, 2 H).

IR (neat): 3290, 3090, 2940, 2840, 1610, 1445, 1430, 1395, 1260,

1210, 1170, 1115, 910 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 2.05 (quint, J = 6.9 Hz, 2 H), 2.29

(t, J = 6.9 Hz, 2 H), 2.90 (s, 1 H), 3.20 (t, J = 6.9 Hz, 2 H), 5.39 (d,

J = 0.8 Hz, 1 H), 5.48 (s, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 5.9, 31.2, 37.4, 77.6, 83.4, 124.2,

128.6.).

¹³C NMR (50 MHz, CDCl₃): d = 33.0, 34.1, 53.1, 54.0, 113.0,

119.7, 128.0, 128.3, 128.6, 129.8, 135.7, 137.4, 142.0, 168.4.

EI-MS: m/z (%) = 253 (M⁺, 7), 194 (33), 167 (19), 165 (18), 142

(100).

EI-HRMS calcd for C₁₆H₁₅NO₂: 253.1103, found: 253.1107.

¹³C NMR (75 MHz, C₆D₆): d = 5.5, 31.5, 37.5, 78.1, 83.5, 123.8,

1-Cyano-2-cyclohex-1-enylmethylene-3-methylenecyclopen-

tanecarboxylic Acid Methyl Ester (6a)

According to GP1, scale: KH (27 mg, 0.82 mmol), 18-C-6 (36 mg,

0.14 mmol), enyne 1a (121 mg, 0.68 mmol), cyclohexenyl triflate

(236 mg, 1.02 mmol), PdCl₂(PPh₃)₂(24 mg, 0.03 mmol), THF (7

129.2.

EI-MS: m/z (%) = 220 (35, M⁺), 205 (17), 178 (11), 165 (13), 145

(14), 129 (30), 116 (18), 111 (26), 97 (40), 84 (64), 65 (100).

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

FEATURE ARTICLE

New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes

323

2-Cyano-6-methylene-oct-7-ynoic Acid Methyl Ester (2a)

Following the same experimental procedure as for 1a, scale: NaH

60% in mineral oil (312 mg, 7.8 mmol), 6-iodo-3-methylenehex-1-

yne (1.32 g, 6.0 mmol), methyl cyanoacetate (1.37 mL, 15.6 mmol),

1:1 mixture of THF–DMF (12 mL). The crude product was purified

by flash chromatography (PE–Et₂O, 75:25) to give 2a as a colorless

oil. Yield: 888 mg (77%).

J = 7.4 Hz, 2 H), 3.74 (s, 3 H), 5.31 (d, J = 1.1 Hz, 1 H), 5.43 (d,

J = 1.1 Hz, 1 H).

¹³C NMR (50 MHz, CDCl₃): d = 25.6, 27.3, 28.8, 36.5, 52.4, 59.4,

77.3, 83.7, 123.3, 129.9, 170.2, 202.9.

Anal. Calcd for C₁₂H₁₆O₃(208.25): C, 69.21; H, 7.74. Found: C,

68.86; H, 7.55.

IR (neat): 3280, 2940, 2860, 2240, 1745, 1610, 1435, 1255, 1205,

1065, 990, 910 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.76 (m, 2 H), 1.96 (m, 2 H), 2.23

(t, J = 7.3 Hz, 2 H), 2.91 (s, 1 H), 3.53 (t, J = 7.3 Hz, 2 H), 3.82 (s,

3 H), 5.33 (d, J = 1.1 Hz, 1 H), 5.46 (d, J = 1.1 Hz, 1 H).

¹³C NMR (50 MHz, CDCl₃): d = 25.0, 28.9, 35.9, 37.3, 53.5, 77.8,

83.3, 116.3, 123.8, 129.3, 166.5.

2-Benzenesulfonyl-6-methyleneoct-7-ynoic Acid Methyl Ester

(2e)

Following the same experimental procedure as for 1a, scale: NaH

60% in mineral oil (265 mg, 6.6 mmol), 6-iodo-3-methylenehex-1-

yne (1.32 g, 6.0 mmol), methyl phenylsulfonylacetate (1.414 g, 6.6

mmol), 1:1 mixture of THF–DMF (20 mL). The crude product was

purified by flash chromatography (PE–Et₂O, 60:40) to give 2e as a

very viscous colorless oil. Yield: 1.68 g (91%).

Anal. Calcd for C₁₁H₁₃NO₂(191.23): C, 69.09; H, 6.85; N, 7.32.

Found: C, 68.96; H, 6.84; N, 7.19.

IR (neat): 3270, 3060, 2945, 1860, 1740, 1610, 1585, 1480, 1445,

1325, 1310, 1195, 1145, 1085, 1020, 910, 845, 760, 720 cm^–1.

2-(4-Methylenehex-5-ynyl)malonic Acid Dimethyl Ester (2b)

Following the same experimental procedure as for 1a, scale: NaH

60% in mineral oil (288 mg, 7.2 mmol), 6-iodo-3-methylenehex-1-

yne (1.32 g, 6.0 mmol), dimethyl malonate (1.03 mL, 9.0 mmol),

1:1 mixture of THF–DMF (20 mL). The crude product was purified

by flash chromatography (PE–Et₂O, 75:25) to give 2b as a colorless

oil. Yield: 1.095 g (81%).

¹H NMR (300 MHz, CDCl₃): d = 1.56 (quint, J = 7.5 Hz, 2 H),

1.93–2.09 (m, 2 H), 2.16 (t, J = 7.5 Hz, 2 H), 2.86 (s, 1 H), 3.68 (s,

3 H), 3.96 (dd, J = 10.9, 4.2 Hz, 1 H), 5.27 (s, 1 H), 5.41 (s, 1 H),

7.58 (t, J = 7.4 Hz, 2 H), 7.70 (tt, J = 7.4, 2.1 Hz, 2 H), 7.87 (d,

J = 7.4 Hz, 2 H).

¹³C NMR (50 MHz, CDCl₃): d = 25.2, 26.0, 36.2, 53.0, 70.7, 77.6,

83.4, 123.7, 129.1, 129.3, 129.4, 134.4, 137.1, 166.3.

IR (neat): 3280, 2940, 2860, 1735, 1610, 1430, 1340, 1200, 1145,

1055, 1000, 905 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.57 (m, 2 H), 1.91 (m, 2 H), 2.19

(t, J = 7.4 Hz, 2 H), 2.87 (s, 1 H), 3.38 (t, J = 7.5 Hz, 1 H), 3.82 (s,

6 H), 5.31 (d, J = 1.1 Hz, 1 H), 5.42 (dd, J = 1.7, 1.1 Hz, 1 H).

¹³C NMR (50 MHz, CDCl₃): d = 25.5, 28.0, 36.4, 51.5, 52.5, 77.2,

83.7, 123.3, 129.9, 169.7.

Anal. Calcd for C₁₆H₁₈O₄S (306.38): C, 62.72; H, 5.92. Found: C,

62.62; H, 5.95.

2-Benzenesulfonyl-6-methyleneoct-7-ynenitrile (2f)

Following the same experimental procedure as for 1a, scale: NaH

60% in mineral oil (176 mg, 4.4 mmol), 6-iodo-3-methylenehex-1-

yne (880 mg, 4.0 mmol), phenylsulfonylacetonitrile (798 mg, 4.4

mmol), 1:1 mixture of THF–DMF (16 mL). The crude product was

purified by flash chromatography (PE–Et₂O, 60:40) to give 2f as a

white solid. Yield: 833 mg (76%); mp 53–55 °C.

Anal. Calcd for C₁₂H₁₆O₄(224.25): C, 64.27; H, 7.19. Found: C,

64.22; H, 7.22.

IR (KBr): 3280, 3090, 3060, 2920, 2860, 2240, 1610, 1580, 1450,

1395, 1325, 1310, 1180, 1150, 1080, 1045, 1000, 910, 850, 790,

780, 750, 680 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.69–1.80 (m, 1 H), 1.84–2.00 (m,

2 H), 2.16–2.28 (m, 3 H), 2.91 (s, 1 H), 3.94 (dd, J = 10.7, 4.4 Hz,

1 H), 5.33 (d, J = 1.1 Hz, 1 H), 5.46 (d, J = 1.1 Hz, 1 H), 7.65 (m, 2

H), 7.78 (tt, J = 7.4, 1.8 Hz, 1 H), 8.0 (m, 1 H), 8.03 (m, 1 H).

2-(4-Methylenehex-5-ynyl)malononitrile (2c)

Following the same experimental procedure as for 1a, scale: NaH

60% in mineral oil (360 mg, 9.0 mmol), 6-iodo-3-methylenehex-1-

yne (1.32 g, 6.0 mmol), malononitrile (595 mg, 9.0 mmol), 1:1 mix-

ture of THF–DMF (12 mL). The crude product was purified by flash

chromatography (PE–Et₂O, 75:25) to give 2c as a pale yellow oil.

Yield: 577 mg (61%).

IR (neat): 3280, 2910, 2880, 2250, 1610, 1445, 1310, 1265, 910

cm^–1.

¹³C NMR (50 MHz, CDCl₃): d = 24.9, 25.9, 35.9, 57.4, 78.1, 83.2,

113.9, 124.1, 128.9, 129.7, 129.7, 135.4, 135.6.

¹H NMR (300 MHz, CDCl₃): d = 1.90 (m, 2 H), 2.06 (m, 2 H), 2.29

(t, J = 7.0 Hz, 2 H), 2.95 (s, 1 H), 3.75 (t, J = 6.8 Hz, 1 H), 5.37 (s,

1 H), 5.50 (s, 1 H).

Anal. Calcd for C₁₅H₁₅NO₂S (273.35): C, 65.91; H, 5.53; N, 5.12.

Found: C, 66.08; H, 5.56; N, 5.15.

2-Cyano-6-methyleneoct-7-ynoic Acid Isopropyl Ester (2g)

Following the same experimental procedure as for 1a, scale: NaH

60% in mineral oil (208 mg, 5.2 mmol), 6-iodo-3-methylenehex-1-

yne (880 mg, 4.0 mmol), isopropyl cyanoacetate (1.32 g, 10.4

mmol), 1:1 mixture of THF–DMF (8 mL). The crude product was

purified by flash chromatography (PE–Et₂O, 80:20) to give 2g as a

colorless oil. Yield: 466 mg (53%).

¹³C NMR (50 MHz, CDCl₃): d = 22.6, 24.7, 29.8, 35.4, 78.3, 82.9,

112.6, 124.4, 128.7.

Anal. Calcd for C₁₀H₁₀N₂(158.20): C, 75.92; H, 6.37; N, 17.71.

Found: C, 76.04; H, 6.42; N, 17.58.

2-Acetyl-6-methyleneoct-7-ynoic Acid Methyl Ester (2d)

Following the same experimental procedure as for 1a, scale: NaH

60% in mineral oil (220 mg, 5.5 mmol), 6-iodo-3-methylenehex-1-

yne (1.1 g, 5.0 mmol), methyl acetylacetate (650 mL, 6.0 mmol), 1:1

mixture of THF–DMF (10 mL). The crude product was purified by

flash chromatography (PE–Et₂O, 75:25) to give 2d as a colorless

oil. Yield: 750 mg (72%).

IR (neat): 3280, 2980, 2930, 2860, 2220, 1735, 1610, 1455, 1375,

1355, 1265, 1205, 1145, 1100, 970, 905, 830 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.30 (d, J = 6.3 Hz, 6 H), 1.70–

1.81 (m, 2 H), 1.95 (m, 2 H), 2.24 (t, J = 7.0 Hz, 2 H), 2.91 (s, 1 H),

3.47 (t, J = 7.0 Hz, 1 H), 5.09 (hept, J = 6.3 Hz, 1 H), 5.33 (s, 1 H),

5.46 (s, 1 H).

IR (neat): 3270, 2930, 2860, 1740, 1715, 1610, 1435, 1355, 1200,

1145, 1050, 905 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.47–1.57 (m, 2 H), 1.82–1.90 (m,

2 H), 2.18 (t, J = 7.4 Hz, 2 H), 2.23 (s, 3 H), 2.88 (s, 1 H), 3.44 (t,

¹³C NMR (75 MHz, CDCl₃): d = 21.6, 24.9, 28.9, 35.9, 37.7, 70.9,

77.7, 83.3, 116.5, 123.6, 129.4, 165.5.

Synthesis 2005, No. 2, 311–329 © Thieme Stuttgart · New York

324

T. Lomberget et al.

FEATURE ARTICLE

EI-MS: m/z (%) = 219 (7, M⁺), 191 (19), 177 (30), 160 (37), 132

(67), 131 (74), 118 (44), 105 (39), 93 (44), 91 (80), 77 (36), 43

(100), 41 (29).

(E)-2-Benzylidene-3-methylenecyclohexane-1,1-dicarbonitrile

(7c)

According to GP1, scale: KH (39 mg, 0.97 mmol), 18-C-6 (43 mg,

0.16 mmol), enyne 2c (128 mg, 0.81 mmol), iodobenzene (135 mL,

1.21 mmol), PdCl₂(PPh₃)₂(28 mg, 0.04 mmol), NMP (8 mL) at

50 °C. After purification (PE–Et₂O, 80:20), the cyclization product

7c was obtained as a yellow solid. Yield: 108 mg (57%); mp 76–

78 °C.

(E)-2-Benzylidene-1-cyano-3-methylenecyclohexanecarboxylic

Acid Methyl Ester (7a)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), iodobenzene (170 mL, 1.5

mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10 mL). After pu-

rification (PE–Et₂O, 80:20), the cyclization product 7a was ob-

tained as a pale yellow solid. Yield: 206 mg (77%); mp 79–81 °C.

IR (KBr): 3080, 3020, 2960, 2920, 2850, 2230, 1635, 1570, 1490,

1445, 1345, 1170, 1055, 1000, 920, 845, 780, 695 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 2.03 (m, 2 H), 3.69 (m, 4 H), 4.98

(s, 1 H), 5.20 (d, J = 1.1 Hz, 1 H), 6.95 (s, 1 H), 7.26–7.38 (m, 5 H).

¹³C NMR (50 MHz, CDCl₃): d = 23.4, 35.1, 38.1, 42.0, 114.1,

119.6, 128.3, 128.4, 129.1, 129.1, 132.1, 134.6, 138.7.

IR (KBr): 3080, 3040, 3010, 2960, 2940, 2860, 2230, 1745, 1630,

1590, 1440, 1250, 1200, 1175, 1080, 1035, 1010, 975, 935, 900,

875, 860, 845, 780, 755, 735, 705 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.94 (m, 2 H), 2.17 (dt, J = 14.0,

6.5 Hz, 1 H), 2.43 (t, J = 6.5 Hz, 2 H), 2.60 (dt, J = 14.0, 5.5 Hz, 1

H), 3.85 (s, 3 H), 4.81 (d, J = 1.1 Hz, 1 H), 5.02 (d, J = 1.5 Hz, 1 H),

6.63 (s, 1 H), 7.18–7.30 (m, 3 H), 7.34 (m, 2 H).

Anal. Calcd for C₁₆H₁₄N₂(234.30): C, 82.02; H, 6.02; N, 11.96.

Found: C, 82.26; H, 6.03; N, 11.73.

(E)-1-Acetyl-2-benzylidene-3-methylenecyclohexanecarboxylic

Acid Methyl Ester (7d)

¹³C NMR (50 MHz, CDCl₃): d = 23.5, 35.4, 35.5, 53.2, 53.7, 117.4,

117.9, 127.4, 128.0, 128.1, 129.0, 135.7, 135.8, 141.1, 167.1.

According to GP1, scale: KH (41 mg, 1.02 mmol), 18-C-6 (45 mg,

0.17 mmol), enyne 2d (177 mg, 0.85 mmol), iodobenzene (145 mL,

1.28 mmol), PdCl₂(PPh₃)₂(30 mg, 0.04 mmol), THF (9 mL). After

purification (PE–Et₂O, 80:20), two products were isolated: the less

polar fraction corresponds to the cyclization product 7d, which was

obtained as a yellow oil. Yield: 56 mg (23%).

Anal. Calcd for C₁₇H₁₇NO₂(267.32): C, 76.38; H, 6.41; N, 5.24.

Found: C, 76.43; H, 6.50; N, 5.19.

(E)-2-Benzylidene-3-methylenecyclohexane-1,1-dicarboxylic

Acid Dimethyl Ester (7b)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2b (224 mg, 1.0 mmol), iodobenzene (170 mL,

1.5 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10 mL). After

purification (PE–Et₂O, 80:20), a mixture of cyclization product 7b

and coupling product 8b (96:4 respectively) was obtained as a pale

brown solid. Yield: 206 mg (78%). Additional recrystallization us-

ing a 1:1 mixture of CH₂Cl₂–MeOH afforded analytically pure cy-

clized product 7b as a colorless solid. Yield: 182 mg (61%); mp 91–

92 °C.

IR (neat): 3080, 3050, 3020, 2940, 2870, 1740, 1710, 1630, 1595,

1430, 1350, 1175, 1090, 905, 750 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.52–1.67 (m, 1 H), 1.71–1.82 (m,

1 H), 2.21 (m, 1 H), 2.35 (s, 3 H), 2.37–2.51 (m, 3 H), 3.78 (s, 3 H),

4.72 (d, J = 1.8 Hz, 1 H), 4.91 (s, 1 H), 6.22 (s, 1 H), 7.16–7.32 (m,

5 H).

¹³C NMR (50 MHz, CDCl₃): d = 24.0, 28.0, 32.3, 36.3, 52.5, 69.7,

116.5, 127.0, 128.0, 128.0, 128.9, 136.9, 140.4, 143.7, 171.8, 205.5.

IR (KBr): 3050, 3020, 2990, 2930, 2860, 1735, 1720, 1630, 1435,

1280, 1190, 1080, 990, 910, 840, 780, 640 cm^–1.

Anal. Calcd for C₁₈H₂₀O₃(284.35): C, 76.03; H, 7.09. Found: C,

75.69; H, 7.28.

¹H NMR (300 MHz, CDCl₃): d = 1.71 (m, 2 H), 2.40 (br t, J = 6.1

Hz, 4 H), 3.79 (s, 6 H), 4.76 (d, J = 2.2 Hz, 1 H), 5.02 (m, 1 H), 6.12

(s, 1 H), 7.13–7.26 (m, 3 H), 7.31 (m, 2 H).

The more polar fraction is the coupling product 8d, which was ob-

tained as an oil. Yield: 126 mg (44%).

¹³C NMR (50 MHz, CDCl₃): d = 24.3, 34.0, 36.3, 52.7, 65.0, 116.6,

2-Acetyl-6-methylene-8-phenyloct-7-ynoic Acid Methyl Ester

(8d)

126.7, 126.8, 127.9, 129.0, 137.0, 139.7, 143.1, 170.8.

IR (neat): 3080, 3050, 2930, 2850, 1740, 1715, 1640, 1605, 1490,

Anal. Calcd for C₁₈H₂₀O₄(300.35): C, 71.98; H, 6.71. Found: C,

71.93; H 6.65.

1435, 1355, 1240, 1200, 1145, 1060, 985, 900, 755, 690 cm^–1.

¹H NMR (300 MHz, CDCl₃) : 1.54–1.64 (m, 2 H), 1.80–1.95 (m, 2

H), 2.22 (s, 3 H), 2.27 (t, J = 7,3 Hz, 2 H), 3.47 (t, J = 7.3 Hz, 1 H),

3.72 (s, 3 H), 5.31 (d, J = 1.6 Hz, 1 H), 5.43 (d, J = 1.6 Hz, 1 H),

7.31 (m, 3 H); 7.43 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): 25.8, 27.4, 28.8, 36.8, 52.3, 59.5, 89.4,

89.6, 121,8, 123.2, 128.3, 128.3, 130.8, 131.6, 170.2, 203.0.

2-(4-Methylene-6-phenylhex-5-ynyl)malonic Acid Dimethyl Es-

ter (8b)

According to GP1, scale: Cs₂CO₃(170 mg, 0.53 mmol), enyne 2b

(112 mg, 0.5 mmol), iodobenzene (85 mL, 0.75 mmol),

PdCl₂(PPh₃)₂(18 mg, 0.025 mmol), THF (5 mL). After purification

(PE–Et₂O, 80:20), the coupling product 8b was obtained as a yellow

oil. Yield: 131 mg (87%).

(E)-1-Phenylsulfonyl-2-benzylidene-3-methylenecyclohexane-

carboxylic Acid Methyl Ester (7e)

IR (neat): 2940, 1735, 1610, 1490, 1435, 1340, 1215, 1055, 900,

755, 690 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.61–1.69 (m, 2 H), 1.97 (m, 2 H),

2.28 (t, J = 7.4 Hz, 2 H), 3.41 (t, J = 7.5 Hz, 1 H), 3.73 (s, 6 H), 5.31

(d, J = 1.5 Hz, 1 H), 5.43 (d, J = 1.8 Hz, 1 H), 7.31 (m, 3 H), 7.44

(m, 2 H).

According to GP1, scale: t-BuOK (135 mg, 1.2 mmol), 18-C-6 (53

mg, 0.2 mmol), enyne 2e (308 mg, 1.0 mmol), iodobenzene (170

mL, 1.5 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10 mL) at

50 °C. After purification (PE–Et₂O, 90:10), two products were iso-

lated: the less polar fraction corresponds to the cyclization product

7e, which was obtained as a solid. Yield: 105 mg (27%); mp 111–

113 °C.

¹³C NMR (50 MHz, CDCl₃): d = 25.8, 28.1, 36.7, 51.6, 52.5, 89.4,

89.5, 121.8, 123.2, 128.2, 128.3, 130.8, 131.6, 169.8.

IR (KBr): 3070, 3020, 2920, 2860, 2830, 1735, 1630, 1580, 1490,

1445, 1305, 1195, 1070, 1020, 970, 790, 690 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.77 (m, 1 H), 2.12 (m, 1 H), 2.51

(m, 4 H), 3.76 (s, 3 H), 4.70 (s, 1 H), 4.95 (d, J = 1.5 Hz, 1 H), 6.59

FEATURE ARTICLE

New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes

325

(s, 1 H), 7.13–7.25 (m, 5 H), 7.54 (t, J = 7.8 Hz, 2 H), 7.68 (t, J = 7.8

Hz, 1 H), 7.96 (d, J = 7.8 Hz, 2 H).

(E)-2-(2-Bromobenzylidene)-1-cyano-3-methylenecyclohexane-

carboxylic Acid Methyl Ester (10a)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), o-bromoiodobenzene

(190 mL, 1.5 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10

mL). After purification (PE–Et₂O, 80:20), the cyclization product

10a was obtained as a solid. Yield: 152 mg (52%); mp 106–107 °C.

¹³C NMR (50 MHz, CDCl₃): d = 21.2, 29.5, 33.2, 53.2, 79.3, 118.3,

127.3, 128.1, 128.2, 128.8, 131.4, 132.8, 133.9, 134.5, 136.7, 136.7,

141.1, 168.4.

CI-MS: m/z (%) = 383 (3, M⁺), 241 (100).

EI-MS: m/z (%) = 241 (87), 181 (100), 166 (25), 141 (6), 115 (6).

IR (KBr): 3014, 2955, 2879, 2242,1748, 1642, 1634, 1461, 1434,

1243, 1177, 1084, 1024, 1008, 938, 905, 869, 849, 742 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.93 (quint, J = 6.2 Hz, 2 H), 2.20

(m, 1 H), 2.38 (t, J = 6.2 Hz, 2 H), 2.60 (dt, J = 13.6, 5.5 Hz, 1 H),

3.88 (s, 3 H), 4.66 (s, 1 H), 4.93 (d, J = 1.5 Hz, 1 H), 6.70 (s, 1 H),

7.09 (m, 1 H), 7.19 (m, 2 H), 7.54 (d, J = 8.1 Hz, 1 H).

Anal. Calcd for C₂₂H₂₂O₄S (382.47): C, 69.09; H, 5.80. Found: C,

68.66; H, 5.69.

The more polar fraction is the coupling product 8e, which was ob-

tained as an oil. Yield: 115 mg (30%).

¹³C NMR (50 MHz, CDCl₃): d = 23.2, 35.1, 35.2, 52.6, 117.8,

117.9, 123.9, 126.9, 128.3, 128.9, 130.3, 132.4, 136.9, 137.3, 140.3,

167.1.

2-Phenylsulfonyl-6-methylene-8-phenyloct-7-ynoic Acid Meth-

yl Ester (8e)

IR (neat): 3060, 2950, 2860, 1740, 1610, 1585, 1490, 1445, 1325,

1310, 1270, 1200, 1150, 1085, 1025, 1000, 905, 845, 755, 725, 690,

665 cm^–1.

¹H NMR (300 MHz, CDCl₃): 1.63 (m, 2 H), 1.95–2.15 (m, 2 H),

2.25 (t, J = 7.1Hz, 2 H), 3.65 (s, 3 H), 3.99 (dd, J = 10.7–4.4 Hz, 1

H), 5.27 (d, J = 1.5 Hz, 1 H), 5.41 (d, J = 1.5 Hz, 1 H), 7.31 (m, 3

H), 7.42 (m, 2 H), 7.55 (t, J = 7.4 Hz, 2 H), 7.68 (t, J = 7.4 Hz, 1 H),

7.87 (d, J = 7.4 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): 25.4, 26.1, 36.5, 53.0, 70.7, 89.2, 89.8,

122.2, 123.0, 128.4, 128.4, 129.1, 129.3, 130.3, 131.6, 134.4, 137.2,

166.4.

Anal. Calcd for C₁₇H₁₆BrNO₂(346.22): C, 58.97; H, 4.66; N, 4.05.

Found: C, 59.29; H, 4.79; N, 4.08.

(E)-1-Cyano-2-(2-methoxybenzylidene)-3-methylenecyclohex-

anecarboxylic Acid Methyl Ester (11a)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), 2-iodoanisole (195 mL,

1.5 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10 mL). After

purification (PE–Et₂O, 80:20), the cyclization product 11a was ob-

tained as a solid. Yield: 200 mg (68%); mp 75–77 °C.

IR (KBr): 3060, 2950, 2920, 2840, 2230, 1750, 1630, 1575, 1485,

1465, 1440, 1290, 1245, 1200, 1160, 1115, 1090, 1045, 1025, 1010,

980, 940, 900, 850, 785, 730 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.92 (quint, J = 6.3 Hz, 2 H), 2.19

(m, 1 H), 2.41 (t, J = 6.3 Hz, 2 H), 2.56 (dt, J = 12.9, 5.9 Hz, 1 H),

3.82 (s, 3 H), 3.87 (s, 3 H), 4.74 (s, 1 H), 4.93 (s, 1 H), 6.70 (s, 1 H),

6.83 (m, 2 H), 7.22 (m, 2 H).

¹³C NMR (50 MHz, CDCl₃): d = 23.4, 35.3, 35.4, 53.2, 53.6, 55.4,

110.7, 116.6, 118.2, 120.0, 124.1, 125.0, 128.8, 129.8, 135.5, 141.4,

157.2, 167.5.

(E)-1-Phenylsulfonyl-2-benzylidene-3-methylenecyclohexane-

carbonitrile (7f)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2f (273 mg, 1.0 mmol), iodobenzene (170 mL, 1.5

mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10 mL) at 50 °C.

After purification (PE–Et₂O, 70:30), two products were isolated:

the less polar fraction corresponds to the cyclization product 7f,

which was obtained as a pale brown solid. Yield: 137 mg (39%); mp

104–106 °C.

IR (KBr): 3060, 3010, 2930, 2860, 1630, 1580, 1445, 1320, 1290,

1200, 1160, 1145, 1080, 915, 770, 730, 685, 610 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.89 (m, 1 H), 2.28–2.44 (m, 3 H),

2.61 (m, 1 H), 3.05 (m, 1 H), 4.91 (s, 1 H), 5.13 (s, 1 H), 6.28 (s, 1

H), 7.02 (d, J = 6.6 Hz, 2 H), 7.20 (m, 3 H), 7.66 (t, J = 7.8 Hz, 2

H), 7.82 (t, J = 7.4 Hz, 2 H), 8.02 (d, J = 7.8 Hz, 2 H).

¹³C NMR (50 MHz, CDCl₃): d = 21.5, 31.7, 34.0, 69.6, 117.8,

119.0, 127.9, 128.3, 128.6, 129.0, 130.3, 131.1, 133.8, 135.1, 135.3,

136.6, 138.5.

Anal. Calcd for C₁₈H₁₉NO₃(297.35): C, 72.71; H, 6.44; N, 4.71.

Found: C, 72.95; H, 6.50; N, 4.75.

(E)-1-Cyano-2-(4-methoxybenzylidene)-3-methylenecyclohex-

anecarboxylic Acid Methyl Ester (12a)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), 4-iodoanisole (351 mg,

1.5 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10 mL). After

purification (PE–Et₂O, 80:20), the cyclization product 12a was ob-

tained as a viscous oil. Yield: 224 mg (75%).

Anal. Calcd for C₂₁H₁₉NO₂S (349.45): C, 72.18; H, 5.48; N, 4.01.

Found: C, 72.27; H, 5.59; N, 4.06.

IR (neat): 3083, 2954, 2839, 2253, 1752, 1634, 1607, 1575, 1509,

1439, 1298, 1243, 1177, 1034, 912, 884, 826, 733 cm^–1.

The more polar fraction is the coupling product 8f which was ob-

¹H NMR (300 MHz, CDCl₃): d = 1.92 (m, 2 H), 2.14 (m, 2 H), 2.41

(t, J = 6.2 Hz, 2 H), 2.57 (td, J = 13.4, 5.5 Hz, 1 H), 3.78 (s, 3 H),

3.84 (s, 3 H), 4.85 (d, J = 1.9 Hz, 1 H), 5.05 (d, J = 1.7 Hz, 1 H),

6.54 (s, 1 H), 6.80 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): d = 23.6, 35.4, 35.5, 53.3, 53.7, 55.2,

113.5, 117.0, 118.1, 127.4, 128.1, 130.4, 133.9, 141.5, 159.0, 167.3.

tained as a viscous oil. Yield: 45 mg (13%).

2-Phenylsulfonyl-6-methylene-8-phenyloct-7-ynenitrile (8f)

IR (neat) : 3060, 2920, 2860, 2240, 1610, 1585, 1490, 1450, 1330,

1310, 1205, 1180, 1155, 1115, 1070, 1025, 1000, 905, 790, 755,

725, 690, 665 cm^–1.

¹H NMR (300 MHz, CDCl₃): 1.77–1.88 (m, 1 H), 1.92–2.05 (m, 2

H), 2.23–2.30 (m, 1 H), 2.33 (t, J = 7.0 Hz, 2 H), 3.97 (dd, J = 10.3,

4.4 Hz, 1 H), 5.33 (d, J = 1.5 Hz, 1 H), 5.47 (d, J = 1.5 Hz, 1 H),

7.32 (m, 3 H), 7.44 (m, 2 H), 7.62 (t, J = 8,0 Hz, 2 H), 7.76 (tt,

J = 7.4, 1.5 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 2 H).

4-{(E)-[2-Cyano-2-(methoxycarbonyl)-6-methylenecyclohexy-

lidene]methyl}benzoic Acid Methyl Ester (13a)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), 4-iodobenzoic methyl es-

ter (393 mg, 1.5 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10

mL). After purification (PE–Et₂O, 60:40), the cyclization product

13a was obtained as a solid. Yield: 216 mg (66%); mp 126–128 °C.

¹³C NMR (75 MHz, CDCl₃): 25.2, 26.0, 36.2, 57.4, 88.9, 90.2,

114.1, 122.6, 122.9, 128.4, 128.5, 129.6, 129.7, 129.9, 131.7, 135.3,

135.6.

326

T. Lomberget et al.

FEATURE ARTICLE

IR (KBr): 2950, 2930, 2840, 2240, 1760, 1720, 1635, 1605, 1440,

1405, 1310, 1280, 1250, 1180, 1110, 1040, 1015, 980, 950, 935,

905, 875, 850, 785, 750, 710, 690 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.94 (quint, J = 6.1 Hz, 2 H), 2.18

(m, 1 H), 2.37–2.51 (m, 2 H), 2.63 (dt, J = 13.6, 5.2 Hz, 1 H), 3.86

(s, 3 H), 3.91 (s, 3 H), 4.76 (s, 1 H), 5.02 (d, J = 1.5 Hz, 1 H), 6.67

(s, 1 H), 7.39 (d, J = 8.3 Hz, 2 H), 7.94 (d, J = 8.3 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): d = 23.8, 35.7, 35.8, 52.5, 53.5, 54.2,

118.1, 118.3, 127.6, 129.3, 129.3, 129.8, 138.3, 140.9, 141.1, 167.1,

167.2.

CI-HRMS calcd for C₂₁H₂₄O₆: 373.1651 (MH⁺), found 373.1652.

3-Methylene-2-{2-[(tetrahydropyran-2-yloxy)methyl]ben-

zylidene}cyclohexane-1,1-dicarboxylic Acid Dimethyl Ester

(19b)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2b (224 mg, 1.0 mmol), iodide 9b (477 mg, 1.5

mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10 mL). After pu-

rification (PE–Et₂O, 80:20), the cyclization product 19b was ob-

tained as a white solid. Yield: 216 mg (52%); mp 67–69 °C.

IR (KBr): 2949, 2869, 1744, 1727, 1636, 1446, 1436, 1268, 1245,

1120, 1059, 1028, 979, 902 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.56–1.85 (br m, 8 H), 2.35 (br t,

J = 6.1 Hz, 2 H), 2.40 (br t, J = 6.1 Hz, 2 H), 3.54 (m, 1 H), 3.77 (s,

6 H), 3.91 (m, 1 H), 4.49 (m, 2 H), 4.73 (m, 2 H), 4.78 (d, J = 1.9

Hz, 1 H), 6.32 (s, 1 H), 7.14–7.19 (m, 3 H), 7.37 (d, J = 6.4 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): d = 19.4, 24.0, 25.6, 30.6, 33.7, 36.2,

52.7, 62.0, 64.6, 67.3, 98.1, 116.6, 125.8, 126.9, 127.3, 128.4,

129.2, 136.2, 137.0, 140.2, 142.7, 170.9.

Anal. Calcd for C₁₉H₁₉NO₄(325.36): C, 70.14; H, 5.89; N, 4.31.

Found: C, 70.07; H, 5.92; N, 4.36.

(E)-1-Cyano-3-methylene-2-(3-trifluoromethylbenzylidene)cy-

clohexanecarboxylic Acid Methyl Ester (14a)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), m-trifluoromethyliodo-

benzene (220 mL, 1.5 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol),

THF (10 mL) at 50 °C. After purification (PE–Et₂O, 80:20), two

products were isolated: the less polar fraction corresponds to the cy-

clization product 14a which was obtained as a colorless oil. Yield:

153 mg (46%).

Anal. Calcd for C₂₄H₃₀O₆(414,49): C, 69.54; H, 7.30. Found: C,

69.63; H, 7.49.

IR (film): 3080, 2940, 2860, 2840, 2230, 1750, 1635, 1590, 1485,

1435, 1330, 1280, 1230, 1210, 1160, 1120, 1090, 1030, 985, 905,

875, 700 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.92 (quint, J = 5.9 Hz, 2 H), 2.17

(m, 1 H), 2.36–2.50 (m, 2 H), 2.60 (dt, J = 13.6, 5.2 Hz, 1 H), 3.85

(s, 3 H), 4.76 (d, J = 1.5 Hz, 1 H), 5.02 (dd, J = 1.5, 1.5 Hz, 1 H),

6.66 (s, 1 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.45 (d, J = 7.4 Hz, 1 H), 7.50

(d, J = 7.4 Hz, 1 H), 7.58 (s, 1 H).

(E)-1-Cyano-3-methylene-2-(3-phenylprop-2-enylidene)cyclo-

hexanecarboxylic Acid Methyl Ester (20a)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), b-bromostyrene (260 mL,

2.0 mmol, 85:15 trans:cis mixture), PdCl₂(PPh₃)₂(35 mg, 0.05

mmol), THF (10 mL). After purification (PE–Et₂O, 80:20), the cy-

clization product 20a was obtained as a pale yellow solid. Yield:

209 mg (71%); mp 73–75 °C.

IR (neat): 3070, 3020, 2950, 2930, 2860, 2840, 2230, 1750, 1625,

1590, 1490, 1440, 1250, 1190, 1160, 1075, 1035, 975, 910, 835,

745, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.90 (quint, J = 6.1 Hz, 2 H), 2.12

(dt, J = 12.8, 7.4 Hz, 1 H), 2.24–2.41 (m, 2 H), 2.56 (dt, J = 13.6,

5.0 Hz, 1 H), 3.85 (s, 3 H), 5.04 (s, 1 H), 5.30 (s, 1 H), 6.48 (d,

J = 10.7 Hz, 1 H), 6.74 (d, J = 15.5 Hz, 1 H), 7.12 (dd, J = 15.5,

10.7 Hz, 1 H), 7.32 (m, 5 H).

¹³C NMR (50 MHz, CDCl₃): d = 23.4, 35.4, 35.4, 53.0, 53.8, 117.7,

117.9, 124.0 (q, J = 272 Hz), 124.1 (q, J = 3.8 Hz), 125.8 (q, J = 3.8

Hz), 126.7, 128.6, 130.6 (q, J = 32.2 Hz), 132.2, 136.6, 137.8, 1408,

166.8.

Anal. Calcd for C₁₈H₁₆F₃NO₂(335.32): C, 64.47; H, 4.81; N, 4.18.

Found: C, 64.70; H, 4.84; N, 4.17.

The more polar fraction is the corresponding direct coupling prod-

uct, which was obtained as a colorless oil. Yield: 45 mg (13%).

¹³C NMR (75 MHz, CDCl₃): d = 23.1, 35.1, 35.3, 52.5, 53.7, 117.5,

118.1, 124.9, 126.7, 128.1, 128.7, 128.8, 135.0, 135.8, 137.1, 141.6,

167.3.

2-Cyano-6-methylene-8-(3-trifluoromethylphenyl)oct-7-ynoic

Acid Methyl Ester

¹H NMR (300 MHz, CDCl₃): 1.83 (m, 2 H), 2.01 (m, 2 H), 2.33 (t,

J = 7.0 Hz, 2 H), 3.57 (t, J = 6.8 Hz, 1 H), 3.81 (s, 3 H), 5.39 (dd,

J = 1.5, 1.5 Hz, 1 H), 5.51 (d, J = 1.5 Hz, 1 H), 7.44 (t, J = 7.4 Hz,

1 H), 7.56 (d, J = 7.5 Hz, 1 H), 7.62 (d, J = 7.4 Hz, 1 H), 7.71 (s, 1

H).

Anal. Calcd for C₁₉H₁₉NO₂(293.36): C, 77.79; H, 6.53; N, 4.77.

Found: C, 78.13; H, 6.46; N, 4.87.

(E)-1-Cyano-3-methylene-2-(3-phenylprop-2-enylidene)cyclo-

hexanecarboxylic Acid Isopropyl Ester (20g)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2g (221 mg, 1.0 mmol), b-bromostyrene (260 mL,

2.0 mmol, 85:15 trans:cis mixture), PdCl₂(PPh₃)₂(35 mg, 0.05

mmol), THF (10 mL). After purification (PE–Et₂O, 80:20), the cy-

clization product 20g was obtained as a pale yellow solid. Yield:

224 mg (70%); mp 69–71 °C.

2-(4-Acetoxymethylbenzylidene)-3-methylenecyclohexane-1,1-

dicarboxylic Acid Dimethyl Ester (18b)

According to GP1, scale: KH (34 mg, 0.84 mmol), 18-C-6 (37 mg,

0.14 mmol), enyne 2b (156 mg, 0.7 mmol), iodide 9a (290 mg, 1.05

mmol), PdCl₂(PPh₃)₂(25 mg, 0.035 mmol), THF (7 mL). After pu-

rification (PE–Et₂O, 60:40), the cyclization product 18b was ob-

tained as a solid. Yield: 123 mg (47%); mp 86–88 °C.

IR (KBr): 3040, 2980, 2927, 2870, 2247, 1750, 1738, 1634, 1592,

1447, 1386, 1231, 1181, 1107, 945, 885, 745, 639 cm^–1.

IR (KBr): 2954, 1745, 1722, 1648, 1450, 1435, 1384, 1251, 1193,

1082, 1030, 922, 758 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.70 (m, 2 H), 2.12 (s, 3 H), 2.35

(br t, J = 6.2 Hz, 2 H), 2.42 (br t, J = 6.1 Hz, 2 H), 3.78 (s, 6 H), 4.55

(d, J = 1.8 Hz, 1 H), 4.82 (s, 1 H), 5.11 (s, 2 H), 6.28 (s, 1 H), 7.22

(m, 3 H), 7.33 (m, 1 H).

¹H NMR (300 MHz, CDCl₃): d = 1.29 (d, J = 6.5 Hz, 3 H), 1.32 (d,

J = 6.5 Hz, 3 H), 1.88 (m, 2 H), 2.09 (m, 1 H), 2.25–2.41 (m, 4 H),

2.56 (dt, J = 13.2, 5.2 Hz, 1 H), 5.02 (s, 1 H), 5.11 (hept, J = 6.5 Hz,

1 H), 5.29 (s, 1 H), 6.53 (d, J = 10.7 Hz, 1 H), 6.73 (d, J = 15.8 Hz,

1 H), 7.13 (dd, J = 15.8, 10.7 Hz, 1 H), 7.32 (m, 1 H), 7.39 (t, J = 7.4

Hz, 2 H), 7.40 (m, 2 H).

¹³C NMR (75 MHz, CDCl₃): d = 21.1, 24.0, 33.7, 34.3, 36.2, 52.8,

64.8, 116.9, 125.2, 127.2, 128.2, 129.0, 129.6, 132.6, 133.2, 140.8,

142.6, 169.4, 170.9.

¹³C NMR (50 MHz, CDCl₃): d = 21.5, 21.6, 23.2, 35.1, 35.15, 52.5,

71.0, 117.3, 118.3, 125.0, 126.7, 128.0, 128.7, 128.7, 135.3, 135.5,

137.1, 141.8, 166.2.

FEATURE ARTICLE

New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes

327

Anal. Calcd for C₂₁H₂₃NO₂(321.41): C, 78.47; H, 7.21; N, 4.36.

Found: C, 78.15; H, 7.23; N, 4.31.

Thermal Electrocyclizations of Conjugated Trienes: General

Procedure 2 (GP2)

A solution of conjugated triene (0.4 mmol) in 4 mL toluene was

heated in a 10 mL round-bottomed flask fitted with a condenser un-

til all the starting material has disappeared (following the reaction

by TLC). After cooling, the solution was purified (without evapora-

tion of the toluene) by flash chromatography (PE–Et₂O mixtures).

(E)-3-Methylene-2-(3-phenylprop-2-enylidene)cyclohexane-

1,1-dicarbonitrile (20c)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2c (158 mg, 1.0 mmol), b-bromostyrene (260 mL,

2.0 mmol, 85:15 trans:cis mixture), PdCl₂(PPh₃)₂(35 mg, 0.05

mmol), NMP (10 mL) at 50 °C. After purification (PE–Et₂O,

80:20), the cyclization product 20c was obtained as a pale yellow

solid. Yield: 133 mg (51%); mp 90–92 °C.

6-Phenyl-3,4,5,6-tetrahydronaphthalene-1,1(2H)-dicarboni-

trile (25c)

According to General Procedure 2 (GP2), scale: triene 20c (100 mg,

0.384 mmol), toluene (4 mL). After purification (PE–Et₂O, 80:20),

product 25c was obtained as a pale yellow solid. Yield: 90 mg

(90%).

IR (KBr): 3020, 2940, 2920, 2860, 1630, 1570, 1490, 1450, 1435,

1330, 1180, 1100, 970, 910, 835, 750, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 2.01 (m, 2 H), 2.38 (m, 4 H), 5.20

(s, 1 H), 5.45 (d, J = 1.5 Hz, 1 H), 6.75 (d, J = 10.7 Hz, 1 H), 6.85

(d, J = 15.8 Hz, 1 H), 7.07 (dd, J = 15.8, 10.7 Hz, 1 H), 7.28–7.37

(m, 3 H), 7.42 (d, J = 7.7 Hz, 2 H).

¹³C NMR (50 MHz, CDCl₃): d = 23.1, 34.7, 37.7, 41.2, 114.2,

119.7, 123.7, 127.0, 128.6, 128.8, 129.5, 130.8, 136.5, 137.9,

139.3.

IR (KBr): 3020, 2920, 2860, 2820, 2240, 1600, 1490, 1450, 1420,

755, 700 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.86–1.98 (m, 2 H), 2.01–2.11 (m,

1 H), 2.23 (m, 1 H), 2.38–2.44 (m, 3 H), 2.51 (m, 1 H), 3.70 (m, 1

H), 6.01 (dd, J = 9.9, 3.7 Hz, 1 H), 6.24 (dd, J = 9.9, 2.2 Hz, 1 H),

7.25 (m, 3 H), 7.34 (m, 2 H).

¹³C NMR (50 MHz, CDCl₃): d = 18.6, 28.8, 33.5, 34.2, 37.9, 39.9,

115.5, 115.6, 118.8, 122.9, 126.9, 127.5, 128.8, 131.6, 136.9, 143.7.

Anal. Calcd for C₁₈H₁₆N₂(260.33): C, 83.04; H, 6.19; N, 10.76.

Found: C, 83.12; H, 6.10; N, 10.67.

Anal. Calcd for C₁₈H₁₆N₂(260.33): C, 83.04; H, 6.19; N, 10.76.

Found: C, 83.10; H, 6.23; N, 10.69.

(E)-1-Cyano-2-(2-methylprop-2-enylidene)-3-methylenecyclo-

hexanecarboxylic Acid Methyl Ester (21a)

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), 2-bromopropene (270

mL, 3 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10 mL). Af-

ter purification (PE–Et₂O, 80:20), the cyclization product 21a was

obtained as a white solid. Yield: 152 mg (66%); mp 35–37 °C.

1-Cyano-6-phenyl-1,2,3,4,5,6-hexahydronaphthalene-1-car-

boxylic Acid Methyl Ester (25a)

According to GP2, scale: triene 20a (200 mg, 0.68 mmol), toluene

(7 mL). After purification (PE–Et₂O, 70:30), product 25a (85:15

mixture of diastereomers) was obtained as a yellow solid. Yield:

179 mg (90%). Only the major diastereomer will be described.

IR (KBr): 3080, 2960, 2940, 2860, 2840, 2230, 1745, 1630, 1595,

1440, 1375, 1200, 1095, 1020, 930, 840, 750, 640 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.85 (s, 3 H), 1.88 (m, 2 H), 2.10

(m, 1 H), 2.31 (m, 2 H), 2.51 (m, 2 H), 3.82 (s, 3 H), 4.91 (d, J = 1.5

Hz, 1 H), 5.04 (m, 1 H), 5.06 (s, 1 H), 5.12 (s, 1 H), 6.21 (s, 1 H).

¹³C NMR (50 MHz, CDCl₃): d = 21.7, 23.5, 35.3, 35.4, 53.2, 53.6,

117.2, 118.1, 119.8, 130.4, 134.8, 140.7, 142.1, 167.3.

IR (KBr): 3020, 2950, 2910, 2890, 2850, 2230, 1740, 1650, 1600,

1490, 1450, 1425, 1275, 1250, 1210, 1185, 1115, 1090, 1070, 1005,

950, 920, 760, 725, 705, 700 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.79–2.05 (m, 3 H), 2.21–2.30 (m,

3 H), 2.33–2.44 (m, 2 H), 3.63–3.72 (m, 1 H), 3.85 (s, 3 H), 5.85

(dd, J = 10.2, 3.3 Hz, 1 H), 6.00 (dd, J = 9.7, 2.6 Hz, 1 H), 7.23–

7.36 (m, 5 H).

¹³C NMR (50 MHz, CDCl₃) : d = 18.9, 29.2, 32.5, 38.1, 40.3, 46.8,

53.8, 119.2, 121.4, 123.9, 126.7, 127.6, 128.7, 130.0, 135.9, 144.6,

169.3.

Anal. Calcd for C₁₄H₁₇NO₂(231.29): C, 72.70; H, 7.41; N, 6.06.

Found: C, 72.98; H, 7.50; N, 6.08.

(E)-1-Cyano-2-cyclohex-1-enylmethylene-3-methylenecyclo-

hexanecarboxylic Acid Methyl Ester (22a)

Anal. Calcd for C₁₉H₁₉NO₂(293.36): C, 77.79; H, 6.53; N, 4.77.

Found: C, 77.59; H, 6.67; N, 4.79.

According to GP1, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), cyclohexenyl triflate (345

mg, 1.5 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), THF (10 mL).

After purification (PE–Et₂O, 70:30), the cyclization product 22a

was obtained as a pale yellow solid. Yield: 208 mg (77%); mp 81–

82 °C.

1-Cyano-6-phenyl-1,2,3,4,5,6-hexahydronaphthalene-1-car-

boxylic Acid Isopropyl Ester (25g)

According to GP2, scale: triene 20g (100 mg, 0.31 mmol), toluene

(4 mL). After purification (PE–Et₂O, 70:30), product 25g (85:15

mixture of diastereomers) was obtained as a white solid. Yield: 99.5

mg (quantitative). Only the major diastereomer is described here.

¹H NMR (300 MHz, CDCl₃): d = 1.29 (d, J = 6.3 Hz, 3 H), 1.35 (d,

J = 6.3 Hz, 3 H), 1.78–2.05 (3H, M), 2.20–2.39 (m, 4 H), 3.66 (m,

1 H), 5.12 (hept, J = 6.3 Hz, 1 H), 5.85 (dd, J = 9.6, 3.0 Hz, 1 H),

6.02 (dd, J = 9.9, 2.6 Hz, 1 H), 7.22–7.36 (m, 5 H).

¹³C NMR (75 MHz, CDCl₃): d = 18.9, 21.5, 21.6, 29.2, 32.3, 38.2,

40.4, 47.0, 71.0, 119.3, 121.7, 124.0, 126.6, 127.6, 128.7, 129.8,

135.6, 144.7, 168.2.

IR (KBr): 3080, 2920, 2850, 2830, 2240, 1745, 1630, 1445, 1430,

1245, 1200, 1180, 1170, 1075, 1030, 1005, 935, 900, 880, 840, 740,

640 cm^–1.

¹H NMR (300 MHz, CDCl₃): d = 1.53 (m, 4 H), 1.81–2.17 (m, 7 H),

2.29 (t, J = 6.3 Hz, 2 H), 2.49 (ddd, J = 13.4, 6.8, 4.4 Hz, 1 H), 3.82

(s, 3 H), 4.88 (d, J = 2.2 Hz, 1 H), 5.10 (s, 1 H), 5.84 (br s, 1 H), 6.09

(s, 1 H).

¹³C NMR (50 MHz, CDCl₃): d = 22.0, 22.9, 23.6, 26.1, 28.2, 35.3,

35.5, 53.3, 53.5, 116.8, 118.4, 131.7, 133.0, 134.7, 142.6, 142.7,

167.6.

Anal. Calcd for C₂₁H₂₃NO₂(321.41): C, 78.47; H, 7.21; N, 4.36.

Found: C, 78.38; H, 7.34; N, 4.39.

Anal. Calcd for C₁₇H₂₁NO₂(271.35): C, 75.25; H, 7.80; N, 5.16.

Found: C, 75.50; H, 7.63; N, 5.18.

328

T. Lomberget et al.

FEATURE ARTICLE

1-Cyano-1,2,3,4,5,6,7,8,10,10a-decahydroanthracene-1-carbox-

ylic Acid Methyl Ester (27a)

According to GP2, scale: triene 22a (88 mg, 0.32 mmol), toluene (4

mL). After purification (PE–Et₂O, 70:30), product 27a (85:15 mix-

ture of diastereomers) was obtained as a white solid. Yield: 86.4 mg

(98%). Only the major diastereomer will be described.

¹H NMR (300 MHz, CDCl₃): 1.33–1.37 (m, 3 H), 1.75–1.89 (m, 4

H), 1.92–2.14 (m, 5 H), 2.18–2.25 (m, 2 H), 2.25–2.33 (m, 3 H),

3.82 (s, 3 H), 5.41 (s, 1 H, H₇, s).

¹³C NMR (50 MHz, CDCl₃): 18.9, 26.0, 27.1, 28.9, 32.6, 33.9, 35.8,

37.3, 35.3, 47.1, 53.6, 116.0, 119.6, 120.4, 133.0, 141.7, 169.6.

CI-HRMS calcd for C₁₆H₁₉NO₂: 258.1494 (MH⁺), found: 258.1494.

1-Cyano-6-phenyl-2,3,4,5-tetrahydro-1H-indene-1-carboxylic

Acid Methyl Ester (29a)

According to GP3, scale: KH (29 mg, 0.73 mmol), 18-C-6 (32 mg,

0.12 mmol), enyne 1a (107 mg, 0.60 mmol), 1-phenyl-vinyl triflate

(212 mg, 0.84 mmol), PdCl₂(PPh₃)₂(20 mg, 0.03 mmol) THF (7

mL). After purification (PE–Et₂O, 80:20), product 29a was ob-

tained as a pale solid. Yield: 86 mg (51%).

¹H NMR (300 MHz, CDCl₃): 2.48 (t, J = 9.5 Hz, 2 H), 2.57–2.86

(m, 6 H), 3.86 (s, 3 H), 6.40 (s, 1 H), 7.28 (m, 1 H), 7.37 (t, J = 7.4

Hz, 2 H), 7.48 (d, J = 7.4 Hz, 2 H).

¹³C NMR (50 MHz, CDCl₃): 24.9, 26.1, 33.9, 35.0, 53.6, 53.8,

115.7, 119.4, 125.3, 127.6, 128.5, 130.6, 137.9, 140.4, 142.6, 168.8.

Anal. Calcd for C₁₇H₂₁NO₂(271.35): C, 75.25; H, 7.80; N, 5.16.

Found: C, 75.49; H, 7.91; N, 5.29.

1-Cyano-7-methyl-1,2,3,4,5,6-hexahydronaphthalene-1-car-

boxylic Acid Methyl Ester (26a)

Anal. Calcd for C₁₈H₁₇NO₂(279.33): C, 77.40; H, 6.13; N, 5.01.

Found: C, 77.12; H, 6.21; N, 5.01.

According to GP2, scale: triene 21a (95 mg, 0.41 mmol), toluene (4

mL). After purification (PE–Et₂O, 60:40), product 26a was ob-

tained as a pale yellow solid. Yield: 93.9 mg (99%); 20 °C < mp <

30 °C.

1-Cyano-1,2,3,4,5,6,7,8,10,10a-decahydroanthracene-1-carbox-

ylic Acid Methyl Ester (27a)

According to GP3, scale: KH (48 mg, 1.2 mmol), 18-C-6 (53 mg,

0.2 mmol), enyne 2a (191 mg, 1.0 mmol), cyclohexenyl triflate (345

mg, 1.5 mmol), PdCl₂(PPh₃)₂(35 mg, 0.05 mmol), toluene (10 mL).

After purification (PE–Et₂O, 80:20), product 27a (85:15 mixture of

diastereomers) was obtained as a yellow solid. Yield: 184 mg

(68%).

IR (KBr): 3030, 3010, 2950, 2920, 2870, 2830, 2230, 1750, 1660,

1620, 1450, 1430, 1415, 1280, 1250, 1170, 1145, 1105, 1075, 1040,

1000, 960, 920, 835, 775, 720 cm^–1.

¹H NMR (300 MHz, CDCl₃): 1.77 (s, 3 H), 1.81–1.91 (m, 2 H),

2.09–2.23 (m, 8 H), 3.82 (s, 3 H), 5.50 (s, 1 H).

¹³C NMR (50 MHz, CDCl₃): 19.0, 23.1, 27.9, 29.0, 29.2, 32.6, 47.0,

53.6, 118.1, 119.6, 121.5, 132.9, 136.0, 169.6.

1-Cyano-6-phenyl-1,2,3,4,5,6-hexahydronaphthalene-1-car-

boxylic Acid Methyl Ester (25a)

According to GP3, scale: KH (55 mg, 1.37 mmol), 18-C-6 (61 mg,

0.23 mmol), enyne 2a (219 mg, 1.14 mmol), b-bromostyrene (295

mL, 2.3 mmol, 85:15 trans:cis mixture), PdCl₂(PPh₃)₂(40 mg, 0.057

mmol), toluene (11 mL). After purification (PE–Et₂O, 80:20), prod-

uct 25a (85:15 mixture of diastereomers) was obtained as a yellow

solid. Yield: 199 mg (60%).

Anal. Calcd for C₁₄H₁₇NO₂(231.29): C, 72.70; H, 7.41; N, 6.06.

Found: C, 72.65; H, 7.51; N, 6.06.

One-Pot Synthesis of Functionalized Cyclohexadienes: General

Procedure 3 (GP3)

To a suspension of KH (48 mg, 1.2 mmol) in 3 mL of anhyd toluene

was added 18-C-6 (53 mg, 0.2 mmol), enyne 1a or 2a (1 mmol) in

4 mL of toluene, and vinyl halide or triflate (1.5 to 3 mmol). This

mixture was stirred at r.t. for 15 min. In a separate flask, n-BuLi (2.6

M in hexanes) was added dropwise at r.t. to a suspension of

PdCl₂(PPh₃)₂(35 mg, 0.05 mmol) in 3 mL of toluene until the mix-

ture becomes dark green. After heating at reflux for 5 min, the mix-

ture turned to a red-orange solution and was added after cooling via

a cannula to the anion solution prepared above. The resulting mix-

ture was then stirred under reflux (110 °C) and monitored by TLC

until completion. The solution was then filtered through a short pad

of silica gel (eluting with Et₂O) and the solvents were removed un-

der reduced pressure. The resulting residue was purified by flash

chromatography (PE–Et₂O mixtures).

1-Cyano-7-methyl-1,2,3,4,5,6-hexahydronaphthalene-1-car-

boxylic Acid Methyl Ester (26a)

According to GP3, scale: KH (38 mg, 0.96 mmol), 18-C-6 (42 mg,

0.16 mmol), enyne 2a (153 mg, 0.8 mmol), 2-bromopropene (220

mL, 2.4 mmol), PdCl₂(PPh₃)₂(28 mg, 0.04 mmol), toluene (8 mL).

This reaction was carried out in a screw-cap sealed tube. After pu-

rification (PE–Et₂O, 60:40), product 26a (85:15 mixture of diaste-

reomers) was obtained as a yellow solid. Yield: 112 mg (61%).

Acknowledgment

T. L. thanks the Ministère de l’Education Nationale, de la Recher-

che et de la Technologie for a fellowship.

1-Cyano-2,3,4,4a,5,6,7,8-octahydro-1H-cyclopenta[b]naphtha-

lene-1-carboxylic acid Methyl Ester (28a)

References

According to General Procedure 3 (GP3), scale: KH (39 mg, 1.0

mmol), 18-C-6 (42 mg, 0.16 mmol), enyne 1a (142 mg, 0.8 mmol),

cyclohexenyl triflate (276 mg, 1.2 mmol), PdCl₂(PPh₃)₂(28 mg,

0.04 mmol), toluene (8 mL). After purification (PE–Et₂O, 80:20),

product 28a (85:15 mixture of diastereomers) was obtained as a vis-

cous oil. Yield: 94 mg (46%). Only the major diastereomer will be

described.

¹H NMR (300 MHz, CDCl₃): d = 1.25–1.43 (br m, 3 H), 1.59–1.72

(br m, 1 H), 1.77–1.80 (br m, 2 H), 1.95–2.09 (br m, 2 H), 2.32–2.36

(m, 1 H), 2.42–2.56 (br m, 5 H), 2.67–2.74 (m, 1 H), 3.81 (s, 3 H),

5.61 (s, 1 H).

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FEATURE ARTICLE

New Method for the Synthesis of Functionalized 1,3-Bis-Exocyclic Dienes

329

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Article Doi

New method for the synthesis of functionalized 1,3-bis-exocyclic dienes via a palladium-catalyzed reaction. Scope and synthetic applications

DOI: 10.1055/s-2004-834879

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