A two-step four-component queuing cascade involving a Heck coupling, π-allylpalladium trapping and Diels-Alder reaction

Tetrahedron 61 (2005) 11355–11373

A two-step four-component queuing cascade involving a Heck

coupling, p-allylpalladium trapping and Diels–Alder reaction^*

*

¨

Baris Yucel, Lars Arve and Armin de Meijere

¨ ¨ ¨ ¨

Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat Gottingen, Tammannstrasse 2, D-37077 Gottingen, Germany

Received 14 July 2005; revised 24 August 2005; accepted 2 September 2005

Available online 10 October 2005

Abstract—Palladium-catalyzed cross-coupling of bicyclopropylidene (1) with iodoethene (11) in the presence of a secondary amine

12 provides allylidenecyclopropanes 13 which undergo immediate Diels–Alder reactions upon addition of dienophiles 14–18 to provide

8-(1⁰-aminoethyl)-substituted spiro[2.5]oct-7-ene derivatives 23a–26a in 29–66% yield. The same one-pot, two-step queuing cascade can be

carried out with other iodoalkenes including cyclic ones and with cyclic dienophiles such as N-arylmaleinamides 19–22 and N-phenyl-

triazolinedione 37 to furnish highly substituted spiro[2.5]oct-4-enes and spirocyclopropanated heterobicycles 47a–49a, 41a–46a (17–50%).

Spirocyclopropanated heterobicycles such as 55, 56 (25 and 38% yield, respectively) can also be obtained by an inter-intra-intra-

intermolecular version of this queuing cascade involving 1-hydroxyethyl- and 1-aminoethyl-substituted iodoethenes 53, 54.

1. Introduction

(Scheme 1).⁷The combinatorial potential of this process has

been demonstrated with the automatized preparation of a

structurally diverse set of these multifunctional biaryl

mimics.⁸A related three-component sequence starts with

the same carbopalladation of the unusually reactive

double bond in bicyclopropylidene (1) and subsequent

One of the foremost aims in the development of modern

organic synthetic methods is an increase in efﬁciency,²as

expressed in the increase in molecular complexity in a

minimum number of procedural steps. Both multi-

component³and cascade (or domino) reactions⁴bring

about remarkable changes in molecular complexity. While

multicomponent reactions by deﬁnition constitute a sub-

group of cascade reactions,⁵not all cascade reactions do

necessarily involve more than one component. Thus,

multicomponent reactions in which one or more of the

reaction partners are involved in more than one step of the

overall transformation cascade, are particularly efﬁcient in

terms of increasing the molecular complexity.

In recent years, we have found several new examples of

such multicomponent molecular queuing cascades,⁶in

which palladium-catalyzed cross-couplings and the highly

reactive C₆-building block bicyclopropylidene (1) play

pivotal rules.⁶One of them is a cross-coupling between 1,

an aryl iodide 2 leading to an allylidenecyclopropane 7

which immediately reacts with a dienophile 4, present in the

mixture to yield a 4-arylspiro[2.5]oct-4-ene derivative 3

^*See Ref. 1.

Scheme 1. Two recently developed three-component reactions involving

bicyclopropylidene (1), an aryl iodide and a cyclopropylcarbinyl to

homoallylpalladium rearrangement. (A) Pd(OAc)₂, PPh₃, K₂CO₃,

Et₄NCl, MeCN, 80 8C, 48 h. (B) Pd(OAc)₂, TFP, K₂CO₃, Et₄NCl, NuH,

MeCN, 80 8C, 24 h.

Keywords: p-Allylpalladium species; Bicyclopropylidene; Cascade

reactions; Cycloadditions; Small rings; Spiro[2.5]octenes.

*

Corresponding author. Tel.: C49 551 393232; fax: C49 551 399475;

e-mail: ameijere@gudg.de

doi:10.1016/j.tet.2005.09.014

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11356

cyclopropylcarbinyl to homoallyl rearrangement of 5

affording the homoallylpalladium species 6, which rapidly

undergoes a b-hydride elimination to yield the diene 7.

In the absence of a dienophile 4 and favored by the presence

of tris(2-furyl)phosphine (TFP) instead of triphenylphos-

phine, 7 undergoes hydridopalladation with the reverse

regioselectivity to form the s-allylpalladium intermediate

10. Irrespective of the latter equilibrating with the

p-allylpalladium species 9,⁹it is trapped regioselectively

by an added nucleophile, for example, lithium acetate or

an amine, to furnish a 2-arylallyl derivative of type 8

(Scheme 1).¹⁰Since the cross coupling of 1 with an alkenyl

iodide in the presence of a dienophile leads to a transmissive

Diels–Alder adduct of an intermediately formed cross-

conjugated triene, we conceived the possibility of extending

the second reaction mode into an overall four-component

queuing cascade by coupling an alkenyl iodide with

bicyclopropylidene (1) in the presence of TFP. This would

yield, after trapping of the formed p-allylpalladium

intermediate with a nucleophile, a conjugated diene,

which would undergo a Diels–Alder reaction with an

added dienophile. This concept was tested, and here we

present our ﬁrst results.

2. Results and discussion

The palladium-catalyzed cross-coupling with rearrange-

ment and nucleophilic trapping cannot be carried out with

the dienophile being present from the beginning, since a

Michael addition of the nucleophile onto the dienophile

would compete with the desired reaction. Therefore,

bicyclopropylidene (1) and iodoethene (11) in the presence

of a secondary amine 12 in dimethylformamide were treated

with a typical palladium catalyst cocktail (e.g., Pd(OAc)₂,

TFP, NEt₃) at 80 8C for 2 h, then a dienophile like methyl

acrylate (14) was added, and the mixture was heated at

80 8C for 48 h (Scheme 2 and Table 1).

With morpholine (12a) as a secondary amine, well known to

be a good nucleophile,¹¹the yields in this one-pot, two-step

queuing cascade were generally good (37–66%), irrespec-

tive of the nature of the dienophile (Table 1). With

piperidine (12b), pyrrolidine (12c), N-benzylpiperazine

(12d), and N-tert-butoxycarbonylpiperazine (12e) in com-

bination with 1, 11 and the best yielding tert-butyl acrylate

(15), the cascade reaction gave the corresponding products

24b–e mostly in moderate yield (29–49%). In all cases, the

products from unsymmetrical dienophiles 14–16 were only

5-substituted spiro[2.5]oct-7-ene derivatives as assigned on

the basis of their NMR spectra. This is in agreement with the

previously observed regioselectivities in Diels–Alder

additions of acrylates to allylidenecyclopropanes.^6a,12

The reaction with dimethyl fumarate 17 and dimethyl

maleate 18 both gave mixtures of dimethyl cis- and trans-

spiro[2.5]octenedicarboxylates (cis- and trans-26a) in

slightly different ratios (Table 1), irrespective of the

conditions (A or B in Scheme 2) used. Control experiments

conﬁrmed that simple heating in dimethylformamide at

80 8C causes 18 to isomerize to 17, (50% conversion after

1.5 h, w98% conversion after 6 h), whereas heating of 18 in

Scheme 2. A new one-pot, two-step four-component queuing cascade

involving bicyclopropylidene (1), iodoethene (11), nucleophiles 12a–e and

dienophiles 14–18, 19–22. (A) Pd(OAc)₂, TFP, NEt₃, 2 h, 80 8C, DMF.

(B) Pd(OAc)₂, TFP, K₂CO₃, Et₄NCl, 2 h, 80 8C, MeCN. For further details

see Table 1.

Table 1. One-pot, two-step four-component queuing cascade involving bicyclopropylidene (1), iodoethene 11, nucleophiles 12a–e, dienophiles 14–18 and 19–

22 (see Scheme 2)

Nucleophile 12 NuH

Cond.

Dienophile

EWG¹

EWG²

EWG³

Product

Yield (%)^a

d.r.^b

a Morpholine

b Piperidine

c Pyrrolidine

d N-Bn-Piperazine

e N-Boc-piperazine

a Morpholine

B

A

B

A

B

A

14

15

16

17

18

17

15

19

20

21

22

CO₂Me

CO₂tBu

SO₂Ph

CO₂Me

H

CO₂Me

CO₂tBu

H

23a

24a

25a

cis/trans-26a

24b

24c

24d

24e

65

66

62

58

52

39

33

29

48

49

40

38

44

37

1.1:1

1.3:1

1.2:1

1.7:1

1.3:1

1:1

H

CO₂Me

H

CO₂Me

H

1:1

1.1:1

1:1

1.2:1

1.1:1

1.6:1

27a

28a

29a

30a

CF₃

H

CF₃

H

CF₃

^aIsolated yields are given.

^bDiastereomeric ratios were determined by integration of relevant ¹H NMR signals in the spectra of the crude products.

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11357

acetonitrile at 80 8C did not lead to any isomerization even

after 24 h.

then cyclize to furnish the cycloadduct of dimethyl maleate

(18). Since only two diastereomers were obtained from both

17 and 18, the stereocenter present in the diene 13a most

probably controls the approach of the dienophile 17 in such

a way as to only form the zwitterion trans-26a-zw as shown,

and this undergoes rotation only to cis-26a-zw or ring

closure to trans-26a.

Attention was then turned to the reaction of isolated diene

13a with dimethyl maleate (18) to explain the formation of

the trans-spirooctenedicarboxylate trans-26a along with

cis-26a under conditions B (i.e., in acetonitrile), since

isomerization of 18 to 17 during the course of the Heck

reaction is well known.¹³In other words, in the absence of

the catalyst ingredients, cis-26a would be expected as a

single product if the cycloaddition of dimethyl maleate (18)

to the 1,3-diene 13a occurred in a concerted mode.

Surprisingly, however, the reaction of a fourfold excess of

dimethyl maleate (18) with diene 13a in acetonitrile at 80 8C

after 24 h again gave virtually the same mixture of cis- and

trans-26a in a ratio of 1.4:1 in quantitave yield (based on the

diene 13a) along with a 3:1 mixture of 17 and 18.

The complexity of the product structure was further

increased by the use of heteroatom-containing dienophiles

19, 21 and 37 with various substituted vinyl iodides 31–36

(Scheme 4 and Table 2), which were prepared according to

published procedures.¹⁵In most of these cases, however, the

yields were only moderate and, in general, lower than with

iodoethene (11). In the reactions of a-iodostyrene (31)

(entries 1, 8 and 10 in Table 2) and 5-(1-iodovinyl)benzo-

[1,3]dioxole 32 (entry 2 in Table 2), more than one

equivalent of morpholine had to be added, and the reaction

mixture with the palladium catalyst had to be heated for

more than two hours to drive the ﬁrst section of the

sequential reaction to completion. Indeed, when the

reactions of iodoalkenes 31 and 32 were carried out with

sterically encumbered dienophiles such as tert-butyl

acrylate (15) (entries 1, 2 in Table 2), prolonged reaction

times and higher temperatures than 80 8C were necessary

for the Diels–Alder reaction in the second step to be

successful. For example, the reaction of a-iodostyrene (31)

with 1 and one equivalent of morpholine (12a) under the

usual conditions (80 8C, 2 h for the ﬁrst step and 80 8C, 48 h

for the second step) yielded the diene 51 (8%) and the

The reaction of 13a with a twofold excess of 18 was also

performed in deuterated acetonitrile and monitored by NMR

spectroscopy. After 1 h, some dimethyl fumarate (17) was

detectable, but none of the cycloadduct cis- or trans-26a

from the diene 13a. The concentration of 17 continued to

increase until the formation of cis- and trans-26a set in.

Thus, the second order rate of the cycloaddition of 17 to 13a

at the given temperature becomes comparable to that of the

ﬁrst order or pseudo-ﬁrst order rate of isomerization of 18 to

17 only when the concentration of 17 has reached a certain

level (almost one third of that of 18 after 7 h). It is well

known that dimethyl fumarate (17) is more reactive as a

dienophile than dimethyl maleate (18) by a factor of about

82.¹⁴Most probably, the diene 13a, which is a tertiary

amine, catalyzes the isomerization of 18 to 17. Indeed, in a

control experiment, N-allylmorpholine as a model for 13a

was shown to cause this isomerization.

Altogether these results imply that the cycloaddition of

dimethyl fumarate (17) to 13a must proceed in two steps

through the zwitterionic intermediate trans-26a-zw, just as

has been suggested for the reaction of (1⁰-arylallylidene)-

cyclopropanes with 17 and 18 (Scheme 3).^6aRather than

undergoing immediate cyclization, the initial zwitterion

trans-26a-zw by internal rotation can go to cis-26a-zw and

Scheme 4. One-pot, two-step four-component queuing cascade involving

bicyclopropylidene (1), iodoalkenes 11 and 31–36, morpholine 12a and

dienophiles 15, 19, 21, 37 and 38. (A) Pd(OAc)₂, TFP, NEt₃, 80 8C, DMF.

(B) Pd(OAc)₂, TFP, K₂CO₃, Et₄NCl, 80 8C, MeCN. EZCO₂tBu, For

details see Table 2.

Scheme 3. Rationalizing the formation of both diastereomeric cycloadducts

trans-26a and cis-26a from the allylidenecyclopropane 13a and dimethyl

fumarate (17). EZCO₂Me.

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B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11358

Table 2. One-pot, two-step four-component queuing cascade involving bicyclopropylidene (1), iodoalkenes 11 and 31–36, morpholine 12a and dienophiles 15,

19, 21, 37 and 38 (see Scheme 4)

Entry

Cond.

Time [h]

Alkenyl

Iodide

R¹

R²

Dienophile

Product

Yield (%)

d.r.

1

2

B^a,b

3

31

32

Ph

H

15

39a

40a

36

44

1.1:1

1.2:1

3

4

5

A

3

5

3

33

34

35

H

2-Thienyl

37

41a

42a

43a

26

33

17

1:1

4.6:1

—

A^c

B

–(CH₂)₄–

d

6

7

8

9

10

11

12

A

B

2

3

2

3

2

36

11

31

36

31

36

11

H

Ph

H

Ph

H

Ph

H

Ph

H

Ph

H

37

19

21

38

44a

45a

46a

47a

48a

49a

50a

35

50

35

42

40

37

30

1.4:1

d

—

2:1

B^b

A^e

A^b,f

A^e

B^f

d

1.18:1

2:1

d

—

^a100 8C, 65 h for the second step.

^b1.5 equiv of morpholine (12a) used in the ﬁrst step.

^c100 8C for the ﬁrst step.

^dOnly one diastereomer was isolated.

^e80 8C, 4 h for the second step.

80 8C, 48 h for the second step.

f

styryl[2.5]spirooctene derivative 52 (27%) along with the

expected product 39a (18%) (Scheme 4). Formation of

the by-products 51 and 52 could only be eliminated by

applying 1.5 equiv of 12a in the ﬁrst step and prolonged

heating (65 h) at elevated temperature (100 8C) for the

second step (entry 1 in Table 2). Interestingly, however, in

the case of (E)-1-iodo-2-phenylethene (36) (entries 6, 9 and

11 in Table 2) 2 h without using more than one equivalent of

morpholine were enough to complete the ﬁrst step of the

reaction.

moderate yields only (at best 25 and 38%, respectively)

(Scheme 5).¹⁷Although this is not a four-component

reaction, this inter-intra-intra-intermolecular queuing cas-

cade proceeds by the same number of individual steps and

with formation of the same number of carbon–carbon and

carbon-heteroatom bonds (altogether four) as the four-

component cascades discussed above.

Interestingly, the iodohomoallyl alcohol 53 gave the best

results under conditions B in acetonitrile with potassium

carbonate and the phase transfer agent (Et₄NCl), whereas

the N-tosylhomoallylamine 54 gave the best yield of 38%

under conditions A (Pd(OAc)₂, TFP, NEt₃, DMF, 80 8C,

3 h), and the product 56 was obtained as a single

diastereomer along with the tosylaminobutenylspiro[2.5]-

octenecarboxylate 57 resulting from b-hydride elimination

in the intermediate of type 6 and immediate Diels–Alder

addition of 15. The conﬁguration of 56 was also rigorously

proved by an X-ray crystal structure analysis (Fig. 2). All

Yet, even spirocyclopropanated heterooligocyclic systems

42a and 43a (entries 4 and 5 in Table 2) were accessible by

the use of iodocyclohexene 34 and N-benzyl-4-iodotetra-

hydropyridine 35, respectively. For the ﬁrst step of the

sequential reaction of iodocyclohexene (34), the mixture

had to be heated exceptionally long, that is, for 5 h at

100 8C, to reach the maximum yield, whereas the reactions

of other iodoalkenes gave lower yields when the tempera-

ture for the ﬁrst steps exceeded 80 8C. The conﬁguration of

the major diastereomer 42a was rigorously proved by an

X-ray crystal structure analysis (Fig. 1). A heterocyclic

substituent could also be attached to the spirooctene core as

in 41a by means of 2-(2-iodovinyl)thiophene 33 in the

cross-coupling step (entry 3 in Table 2).

Furthermore, heteroatoms could be incorporated in the

spirooctene moiety of the Diels–Alder products by employ-

ing the highly reactive dienophile N-phenyltriazolinedione

(PTAD) 37. Whereas with N-phenylmaleimide (19) the

cycloaddition could be completed at 80 8C in 4 h, the

reaction with 37 gave better yields when carried out at 20 8C

for prolonged times (up to 2 days).

Figure 1. Structure of compound 42a in the crystal.¹⁶C₂₄H₃₀N₄O₃

(422.52); crystal size 0.50!0.50!0.50 mm³, orthorhombic, aZ919.67

(18), bZ1352.8 (3), cZ1733.3 (4) pm, aZ908 bZ908, gZ908, VZ2.1565

(7) nm³; ZZ4, space group P2₁/2₁/2₁, TZ200 (2) K, rZ1.301 mg m^K3

,

absorption coefﬁcient Z0.087 mm^K1, F_oZ904, q range for data

collectionZ3.56–24.968, reﬂection collected Z2892, R_intZ2575[0.0374],

data/restraints/parametersZ2575/0/281, Goof on F²Z1.037, Final R

indices [IO2s(I)]ZR₁(0.0374), wR₂(0.0912), R indices (all data) ZR₁

(0.0400), wR₂(0.0943), Largest diff. peak and hole Z0.144 and

To extend the scope of this cascade reaction even further,

functionalized vinyl iodides 53 and 54 were employed to

provide, by intramolecular p-allylpalladium trapping in the

ﬁrst step after the cross-coupling and rearrangement,

spirocyclopropanated heterobicycles 55, 56, albeit in

K3

˚

K0.227 e A

.

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B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11359

Scheme 5. An inter-intra-intra-intermolecular queuing cascade involving bicyclopropylidene (1) a functionalized iodoalkene 53, 54, and a dienophile 15.

(A) Pd(OAc)₂, TFP, NEt₃, 80 8C, DMF. (B) Pd(OAc)₂, TFP, K₂CO₃, Et₄NCl, 80 8C, MeCN. EZCO₂tBu.

coupling constants, J, are given in Hertz. Multiplicities

were determined by DEPT (distortionless enhancement by

polarization transfer): CZprimary or tertiary (positive

DEPT signal), KZsecondary (negative DEPT Signal),

C_quatZquaternary carbon atoms] or APT (attached proton

test) measurements. HMQC (heteronuclear multiple quan-

tum coherence) spectra were also measured. IR spectra were

recorded on a Bruker IFS 66 spectrometer and measured as

KBr pellets or as oils between KBr plates. Low resolution

mass spectra (EI at 70 eV or DCI with NH₃) were obtained

on a Finnigan MAT 95 spectrometer. High resolution mass

spectra (HRMS) were obtained on a Finnigan MAT 95

spectrometer by preselected-ion peak matching at

Rz10,000 to be within G2 ppm of the exact masses.

Elemental analyses were carried out by the Mikro-

analytisches Laboratorium des Instituts fu¨r Organische

Figure 2. Structure of compound 56 in the crystal.¹⁶C₂₄H₃₃NO₄S (431.57);

crystal size 0.30!0.20!0.20 mm³, monoclinic, aZ1135.4(2), bZ

1289.1(3), cZ1632.3(3) pm, aZ908 bZ108.0(3)8, gZ908, VZ2.2723(8)

nm³; ZZ4, space group P2₁/c, TZ133(2) K, rZ1.262 mg m^K3, absorption

coefﬁcient Z0.172 mm^K1, F_oZ928, q range for data collectionZ1.89–

24.828, reﬂection collected Z33280, R_intZ3897[0.0774], data/restraints/

parametersZ3897/0/276, Goof on F²Z1.021, Final R indices [IO2s(I)]Z

R₁(0.0536), wR₂(0.1333), R indices (all data)ZR₁(0.0873), wR₂(0.1439),

und Biomolekulare Chemie der Universitat Gottingen.

Chromatographic separations were performed with Merck

Silica 60 (200–400 or 70–230 mesh). The dimensions of the

columns are given as ‘diameter!height of the silica gel

column’. TLC was performed with Macherey-Nagel TLC

Alugram^wSil G/UV 254 plates, detection was under UV

light at 254 nm and development with MOPS reagent (10%

molybdophosphoric acid in ethanol). Melting points were

obtained with a Bu¨chi apparatus according to Dr. Tottoli;

values are uncorrected. All reagents were used as purchased

from commercial suppliers without further puriﬁcation.

Acetonitrile was dried over P₂O₅, DMF and CH₂Cl₂were

distilled from CaH₂. Ether and THF were freshly distilled

from sodium/benzophenone ketyl. Solvents for column

chromotography, ethyl acetate and light petroleum were

distilled in a rotatory evaporator.

¨

K3

˚

Largest diff. peak and holeZ0.974 and K0.403 e A

.

attempts to suppress the formation of 57 by increasing the

reaction temperature or the time were unsuccessful.

3. Conclusion

In conclusion, another dimension of diversity has been

added to an already powerful combinatorial approach to

libraries of spiro[2.5]octene derivatives. The new one-pot,

two-step four-component queuing cascade leads to a

particularly rich pattern of substituents by variation of the

iodoalkenes, the nucleophiles and the dienophiles, exceed-

ing those of the previously described spirocyclopropanated

carbo- and heterocyclic skeletons.⁶This sequential trans-

formation may also open up new approaches to natural

products containing spiro[2.5]octane substructures.¹⁸

Starting materials: bicyclopropylidene (1),¹⁹iodoalkenes

11,²⁰31, 32, 34,^15a33,^15c35,²¹36,^15e,jand functionalized

iodoalkenes 53,^15b54,²²pyrrole-2,5-dione derivatives

19–22²³were prepared according to published procedures.

4.2. General procedure for the one-pot, two-step queuing

cascade involving bicyclopropylidene (1) an iodoalkene,

a secondary amine 12 and a dienophile under conditions

A (GP-A)

4. Experimental

4.1. General

Palladium acetate (22.4 mg, 100 mmol, 5 mol%) and tri-2-

furylphosphine (46.4 mg, 200 mmol, 10 mol%), were

suspended in anhydrous DMF (1 mL) in a screw-cap

pyrex bottle. Argon was bubbled through the mixture for

5 min, and then the respective amine (2.00 or 2.50 mmol),

NMR spectra were recorded with a Varian Mercury 200

(200 MHz for ¹H and 50.3 MHz for ¹³C), a Bruker AM 250

1

(250 MHz for H and 62.9 MHz for ¹³C NMR), a Varian

triethylamine

(202 mg,

2.00 mmol),

iodoalkene

UNITY-300 (300 MHz for ¹H and 75.5 MHz for ¹³C NMR)

or a Varian Inova 600 (600 MHz for H and 151 MHz for

(2.00 mmol) and bicyclopropylidene (1) (320 mg,

4.00 mmol) were added. After having stirred the mixture

for the given time at the stated temperature the bottle was

cooled to ambient temperature, the respective dienophile

1

¹³C NMR) instruments. Chemical shifts d are given in ppm

relative to residual peaks of deuterated solvents and

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B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11360

(4.00 mmol) was added, (N-phenyltriazolinedione was

added to the ice-cooled mixture), and then the mixture

was stirred for an additional time as stated at the given

temperature in a preheated oil bath. After cooling to room

temperature, the reaction mixture was taken up in 20 mL of

diethyl ether. The solution was washed with water (2!

20 mL). The aqueous phase was extracted with diethyl ether

(2!20 mL). The combined organic phases were dried

(MgSO₄). After removal of the solvent in a rotatory

evaporator, the residue was subjected to chromatography

on silica gel.

6.23 Hz, 3H, CH₃), 1.24 (ddd, JZ12.75, 2.72, 1.2 Hz, 1H,

4- or 6-H), 2.03 (ddd, JZ12.5, 12.5, 1.7 Hz, 1H, 4- or 6-H),

2.12 (q, JZ6.23 Hz, 1H, 1⁰-H), 2.29–2.45 (m, 6H,

CH₂NCH₂, 4- or 6-H), 2.67–2.80 (m, 1H, 5-H), 3.63–3.69

(m, 4H, CH₂OCH₂), 3.66 (s, 3H; OCH₃), 5.77 (dd, JZ4.4,

2.9 Hz, 1H, 7-H); ¹³C NMR (62.9 MHz, CDCl₃, DEPT):

dZ10.74 (K, cPr-C), 13.23 (K, cPr-C), 17.78 (C, CH₃),

19.47 (C_quat, cPr-C), 28.34 (K, C-4 or -6), 38.56 (K, C-4

or -6), 39.29 (C, C-5), 50.74 (K, CH₂NCH₂), 51.56 (C,

OCH₃), 59.17 (C, C-1⁰), 67.20 (K, CH₂OCH₂), 124.8 (C,

C-7), 140.73 (C_quat, C-8), 176.09 (C_quat, C]O); MS (70 eV,

EI), m/z (%): 279 (29) [M^C], 264 (100) [M^CKCH₃], 250

(11) [M^CKC₂H₅], 133 (21), 114 (86), 91 (24), 86 (12);

C₁₆H₂₅NO₃(279.38): calcd 279.1834 (correct HRMS);

elemental analysis calcd (%) for C₁₆H₂₅NO₃: C 68.79, H

9.02; found: C 68.63, H 9.10.

4.3. General procedure for the one-pot, two-step queuing

cascade involving bicyclopropylidene (1) an iodoalkene,

a secondary amine 12 and a dienophile under conditions

B (GP-B)

Minor diastereomer. R_fZ0.23 (light petroleum/ethyl acet-

ate, 3:1); IR (ﬁlm): n~Z3079, 2952, 2851, 2805, 1740, 1650,

A screw-cap Pyrex bottle was charged with anhydrous

acetonitrile (2 mL), K₂CO₃(556 mg, 4.00 mmol) and

Et₄NCl (332 mg, 2.00 mmol). Argon was bubbled through

the mixture for 5 min, Pd(OAc)₂(22.4 mg, 100 mmol,

5 mol%), and tri-2-furylphosphine (46.4 mg, 200 mmol,

10 mol%) were added, and the mixture was stirred once

more for an additional 5 min with argon bubbling through,

before the respective iodoalkene (2.00 mmol), the nucleo-

phile (2.00 or 2.50 mmol) and bicyclopropylidene (1)

(320 mg, 4.00 mmol) were added. The bottle was tightly

closed, and the mixture was stirred for the given period of

time at the stated temperature. After the bottle was cooled to

ambient temperature, the respective dienophile (4.00 mmol)

was added, (N-phenyltriazolinedione was added to the ice-

cooled mixture), and then the mixture was stirred for the

additional time at the given temperature in a preheated oil

bath. After cooling to room temperature, the reaction

mixture was taken up in 20 mL of diethyl ether. The

solution was washed with water (2!20 mL), the aqueous

phase was extracted with diethyl ether (2!20 mL), and the

combined organic phases were dried (MgSO₄). After

removal of the solvent in a rotatory evaporator, the residue

was subjected to chromatography on silica gel.

1457, 1257, 1194, 1172, 945, 861 cm^K^{1 1}H NMR

;

(250 MHz, CDCl₃): dZ0.35–0.51 (m, 2H, cPr-H), 0.59–

0.66 (m, 1H, cPr-H), 1.03 (d, JZ6.8 Hz, 3H, CH₃), 1.02–

1.14 (m, 1H, cPr-H), 1.48 (dd, JZ12.8, 3.1 Hz, 1H, 4- or

6-H), 1.90 (dd, JZ10.2, 13 Hz, 1H, 4- or 6-H), 2.20 (q, JZ

6.8 Hz, 1H, 1⁰-H), 2.32–2.48 (m, 6H, CH₂NCH₂, 4- or 6-H),

2.69–2.80 (m, 1H, 5-H), 3.63–3.71 (m, 4H, CH₂OCH₂),

3.66 (s, 3H, OCH₃), 5.71 (t, JZ3.8 Hz, 1H, 7-H); ¹³C NMR

(62.9 MHz, CDCl₃, DEPT): dZ11.75 (K, cPr-C), 12.39

(K, cPr-C), 16.99 (C, CH₃), 18.51 (C_quat, cPr-C), 27.80

(K, C-4 or -6), 38.16 (K, C-4 or -6), 38.72 (C, C-5), 50.38

(K, CH₂NCH₂), 51.42 (C, OCH₃), 58.51 (C, C-1⁰), 67.24

(K, CH₂OCH₂), 121.4 (C, C-7), 143.67 (C_quat, C-8),

175.84 (C_quat, C]O); MS (70 eV, EI), m/z (%): 279 (26)

[M^C], 264 (100) [M^CKCH₃], 250 (16) [M^CKC₂H₅], 133

(19), 114 (94), 91 (22), 86 (16); C₁₆H₂₅NO₃(279.38): calcd

279.1834 (correct HRMS).

4.3.2. tert-Butyl 8-(1-morpholin-4-ylethyl)spiro[2.5]oct-

7-ene-5-carboxylate (24a). According to GP-A, Pd(OAc)₂

(22.4 mg, 100 mmol), tri-2-furylphosphine (46.4 mg,

200 mmol), Et₃N (202 mg, 2.00 mmol), morpholine (12a,

174 mg, 2.00 mmol), iodoethene (11, 308 mg, 2.00 mmol)

and bicyclopropylidene (1, 320 mg, 4.00 mmol) were stirred

in anhydrous DMF (1 mL), at 80 8C for 2 h. After cooling

the mixture to room temperature, tert-butyl acrylate (15,

512 mg, 4.00 mmol) was added, and the mixture stirred at

80 8C for 48 h. After work-up and drying (MgSO₄), the

solvent was removed in a rotatory evaporator. The residue

was subjected to column chromatography on silica gel

(100 g, 3!30 cm, light petroleum/ethyl acetate 3:1) to yield

24a (426 mg, 66%, yellowish oil) as a mixture of two

diastereomers (ratio 1.3:1 according to NMR).

4.3.1. Methyl 8-(1-morpholin-4-ylethyl)spiro[2.5]oct-7-

ene-5-carboxylate (23a). According to GP-B, Pd(OAc)₂

(22.4 mg, 100 mmol), tri-2-furylphosphine (46.4 mg,

200 mmol), K₂CO₃(556 mg, 4.00 mmol), Et₄NCl (332 mg,

2.00 mmol), morpholine (12a, 174 mg, 2.00 mmol),

iodoethene (11, 308 mg, 2.00 mmol) and bicyclopropyl-

idene (1, 320 mg, 4.00 mmol) were stirred in anhydrous

MeCN (2 mL) at 80 8C for 2 h. After cooling the mixture to

room temperature methyl acrylate (14, 344 mg, 4.00 mmol)

was added, and then the mixture was heated again with

stirring at 80 8C for 48 h. After work-up and drying

(MgSO₄), the solvent was removed in a rotatory evaporator.

The residue was subjected to column chromatography on

silica gel (100 g, 3!30 cm, light petroleum/ethyl acetate,

3:1) to yield 23a (363 mg, 65%, yellowish oil) as a mixture

of two diastereomers (ratio 1.1:1 according to NMR).

Major diastereomer. R_fZ0.34 (light petroleum/ethyl acet-

ate, 3:1); IR (ﬁlm): n~Z3077, 2977, 2851, 2809, 2689, 1731,

1

1455, 1367, 1339, 1253, 1150, 1119, 942, 855 cm^K1; H

NMR (250 MHz, CDCl₃): dZ0.32–0.39 (m, 1H, cPr-H),

0.47–0.54 (m, 1H, cPr-H), 0.77–0.92 (m, 2H, cPr-H), 1.02

(d, JZ6.2 Hz, 3H, CH₃), 1.19 (ddd, JZ12.4, 2.7, 1.2 Hz,

1H, 4- or 6- H), 1.43 [s, 9H, C(CH₃)₃], 1.98 (t, JZ12.7 Hz,

1H, 4- or 6-H), 2.09 (q, JZ6.4 Hz, 1H, 1⁰-H), 2.27–2.42 (m,

6H, CH₂NCH₂, 4- or 6-H), 2.53–2.68 (m, 1H, 5-H), 3.65 (t,

JZ4.4 Hz, 4H, CH₂OCH₂), 5.76 (t, JZ3.6 Hz, 1H, 7-H);

Major diastereomer. R_fZ0.27 (light petroleum/ethyl acet-

ate, 3:1); IR (ﬁlm): n~Z3076, 2973, 2851, 2809, 1738, 1653,

1456, 1329, 1160, 1120, 911, 866 cm^K^{1 1}H NMR

;

(250 MHz, CDCl₃): dZ0.32–0.39 (m, 1H, cPr-H), 0.47–

0.54 (m, 1H, cPr-H), 0.77–0.95 (m, 2H, cPr-H), 1.02 (d, JZ

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11361

¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ10.75 (K,

cPr-C), 13.16 (K, cPr-C), 17.87 (C, CH₃), 19.45 (C_quat

(d, JZ6.3 Hz, 3H, CH₃), 1.38 (ddd, JZ12.4, 2.7, 1.2 Hz,

1H, 6- or 8-H), 2.04–2.17 (m, 2H, 1⁰-H, 6- or 8-H), 2.29–

2.41 (m, 6H, CH₂NCH₂, 6- or 8-H), 3.28–3.45 (m, 1H, 7-H),

3.65 (t, JZ4.56 Hz, 4H, CH₂OCH₂), 5.72 (t, JZ3.8 Hz, 1H,

5-H), 7.52–7.70 (m, 3H, Ph), 7.86–7.90 (m, 2H, Ph); ¹³C

NMR (62.9 MHz, CDCl₃, DEPT): dZ10.74 (K, cPr-C),

13.37 (K, cPr-C), 17.34 (C, CH₃), 19.49 (C_quat, cPr-C),

25.57 (K, C-6 or -8), 34.67 (K, C-6 or -8), 50.46 (K,

CH₂NCH₂), 59.00 (C, C-1⁰), 59.77 (C, C-7), 66.99 (K,

CH₂OCH₂), 118.60 (C, C-5), 128.71 (C, Ph-C), 128.99

(C, Ph-C), 133.56 (C, Ph-C), 137.02 (C_quat), 141.18

(C_quat); MS (70 eV, EI), m/z (%): 361 (11) [M^C], 346 (38)

[M^CKCH₃], 204 (35), 117 (28), 114 (100), 91 (33);

elemental analysis calcd (%) for C₂₀H₂₇NO₃S (361.5): C

66.45, H 7.53; found: C 66.24, H 7.61.

,

cPr-C), 28.00 [C, C(CH₃)₃], 28.53 (K, C-4 or -6), 38.51

(K, C-4 or -6), 40.32 (C, C-5), 50.75 (K, CH₂NCH₂),

59.11 (C, C-1⁰), 67.15 (K, CH₂OCH₂), 79.78 [C_quat

,

C(CH₃)₃], 120.7 (C, C-7), 140.64 (C_quat, C-8), 174.98

(C_quat, C]O); MS (70 eV, EI) m/z (%): 321 (46) [M^C], 306

(68) [M^CKCH₃], 250 (60) [M^CKC₂H₅], 133 (30), 114

(100), 100 (22), 86 (20); elemental analysis calcd (%) for

C₁₉H₃₁NO₃(321.5): C 70.99, H 9.72; found: C 70.78, H

9.52.

Minor diastereomer. R_fZ0.29 (light petroleum/ethyl acet-

ate, 3:1); IR (ﬁlm): n~Z3079, 2977, 2851, 2804, 2689, 1730,

1

1454, 1367, 1329, 1256, 1150, 1119, 945, 863 cm^K1; H

NMR (250 MHz, CDCl₃): dZ0.35–0.42 (m, 1H, cPr-H),

0.46–0.54 (m, 1H, cPr-H), 0.57–0.64 (m, 1H, cPr-H), 1.03

(d, JZ6.6 Hz, 3H, CH₃), 1.08–1.17 (m, 1H, cPr-H), 1.43 [s,

10H, C(CH₃)₃, 4- or 6-H*], 1.87 (t, JZ12.9 Hz, 1H, 4- or

6-H), 2.20 (q, JZ6.5 Hz, 1H, 1⁰-H), 2.31–2.42 (m, 6H,

CH₂NCH₂, 4- or 6-H), 2.57–2.68 (m, 1H, 5-H), 3.64 (t, JZ

4.6 Hz, 4H, CH₂OCH₂), 5.71 (t, JZ3.6 Hz, 1H, 7-H).

*The peak of this proton sits under the broad singlet of the

tert-butyl group, thus the spin coupling constant of this

proton could not be determined. This proton correlates

clearly with the carbon peak at 38.14 ppm in the HMQC

spectrum.¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ12.13

(K, cPr-C), 12.43 (K, cPr-C), 17.15 (C, CH₃), 18.63

(C_quat, cPr-C), 28.01 [C, C(CH₃)₃], 28.01 (K, C-4 or -6),

38.14 (K, C-4 or -6), 39.85 (C, C-5), 50.47 (K,

CH₂NCH₂), 58.58 (C, C-1⁰), 67.17 (K, CH₂OCH₂),

Minor diastereomer. R_fZ0.38 (light petroleum/ethyl acet-

ate, 1:1); IR (ﬁlm): n~Z3057, 2967, 2858, 2812, 1447, 1306

(S]O), 1273 (S]O), 1147 (S]O), 1114 (S]O), 944, 751,

725 cm^K1; ¹H NMR (250 MHz, CDCl₃): dZ0.24–0.38 (m,

1H, cPr-H), 0.45–0.55 (m, 2H, cPr-H), 0.92 (d, JZ6.6 Hz,

3H, CH₃), 1.17–1.23 (m, 1H, cPr-H), 1.33 (ddd, JZ12.7,

2.7, 1.4 Hz, 1H, 6- or 8-H), 2.04 (t, JZ12.1 Hz, 1H, 6- or

8-H), 2.16–2.45 (m, 7H, CH₂NCH₂, 1⁰-H, 6- or 8-H), 3.20–

3.36 (m, 1H, 7-H), 3.54 (t, JZ4.6 Hz, 4H, CH₂OCH₂),

5.72 (dd, JZ5.5, 4.9 Hz, 1H, 5-H), 7.44–7.63 (m, 3H, Ph),

7.77–7.82 (m, 2H, Ph); ¹³C NMR (62.9 MHz, CDCl₃,

DEPT): dZ11.83 (K, cPr-C), 13.85 (K, cPr-C), 16.31 (C,

CH₃), 19.06 (C_quat, cPr-C), 25.65 (K, C-6 or -8), 34.36 (K,

C-8 or -6), 50.19 (K, CH₂NCH₂), 58.56 (C, C-1⁰), 59.67

(C, C-7), 67.25 (K, CH₂OCH₂), 120.09 (C, C-5), 128.82

(C, Ph-C), 129.13 (C, Ph-C), 133.68 (C, Ph-C), 137.23

(C_quat), 141.61 (C_quat); MS (70 eV, EI), m/z (%): 361 (13)

[M^C], 346 (47) [M^CKCH₃], 204 (42), 117 (37), 114 (100),

91 (33) 77 (61); elemental analysis calcd (%) for C₂₀H₂₇NO₃S

(361.5): C 66.45, H 7.53; found: C 66.21, H 7.62.

79.88 [C_quat, C(CH₃)₃], 120.68 (C, C-7), 140.58 (C_quat

,

C-8), 174.81 (C_quat, C]O); MS (70 eV, EI), m/z (%): 321

(49) [M^C], 306 (94) [M^CKCH₃], 250 (80) [M^CKC₂H₅],

133 (30), 114 (100), 100 (26), 86 (22); elemental analysis

calcd (%) for C₁₉H₃₁NO₃: C 70.99, H 9.72; found: C 70.72,

H 9.98. C₁₉H₃₁NO₃(321.46): calcd 321.2304 (correct

HRMS).

4.3.4. 4,5-Dimethyl 8-(1-morpholin-4-ylethyl)spiro[2.5]

oct-7-ene-carboxylate (cis-/trans-26a). (a) According to

GP-B, Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), K₂CO₃(556 mg, 4.00 mmol), Et₄NCl

(332 mg, 2.00 mmol), morpholine (12a, 174 mg,

2.00 mmol), iodoethene (11, 308 mg, 2.00 mmol) and

bicyclopropylidene (1, 320 mg, 4.00 mmol) were stirred in

anhydrous MeCN (2 mL), at 80 8C for 2 h. After cooling the

mixture to room temperature, dimethyl fumarate (17,

576 mg, 4.00 mmol) was added, and then the mixture was

heated again with stirring at 80 8C for 48 h. After work-up

and drying over MgSO₄, the solvent was removed in a

rotatory evaporator. The residue was subjected to column

chromatography on silica gel (100 g, 3!30 cm, light

petroleum/ethyl acetate, 1:1) to yield cis-/trans-26a

(391.7 mg, 58%, yellowish oil) as a mixture of two

diastereomers (ratio 1.2:1 according to NMR).

4.3.3. 4-[1-(7-Benzenesulfonylspiro[2.5]oct-4-en-4-yl)-

ethyl]morpholine (25a). According to GP-B, Pd(OAc)₂

(22.4 mg, 100 mmol), tri-2-furylphosphine (46.4 mg,

200 mmol), K₂CO₃(556 mg, 4.00 mmol), Et₄NCl (332 mg,

2.00 mmol), morpholine (12a, 174 mg, 2.00 mmol),

iodoethene (11, 308 mg, 2.00 mmol) and bicyclopropyl-

idene (1, 320 mg, 4.00 mmol) were stirred in anhydrous

MeCN (2 mL) at 80 8C for 2 h. After cooling the mixture to

room temperature phenyl vinyl sulfone (16, 672 mg,

4.00 mmol) was added, and then the mixture was heated

again with stirring at 80 8C for 48 h. After work-up and

drying (MgSO₄), the solvent was removed in a rotatory

evaporator. The residue was subjected to column chroma-

tography on silica gel (100 g, 3!30 cm, light petroleum/

ethyl acetate, 1:1) to yield 25a (450 mg, 62%, yellowish oil)

as a mixture of two diastereomers (ratio 1.2:1 according to

NMR).

Major and minor diastereomers*. R_fZ0.27 (light petro-

leum/ethyl acetate, 3:1); IR (ﬁlm): n~Z3083, 2953, 2850,

2809, 2691, 1739, 1466, 1349, 1265, 1197, 1172, 1119,

Major diastereomer. R_fZ0.45 (light petroleum/ethyl acet-

ate, 1:1); IR (KBr): n~Z3064, 2972, 2955, 2856, 2814, 1448,

1311 (S]O), 1275 (S]O), 1152 (S]O), 1116 (S]O),

1

1021, 945, 918, 864 cm^K1; H NMR (250 MHz, CDCl₃):

dZ0.43–0.50 (m, 1H, cPr-H), 0.59–0.68 (m, 3H, cPr-H),

0.70–0.81 (m, 2H, cPr-H), 0.93–0.99 (m, 2H, cPr-H), 1.04

(d, JZ6.5 Hz, 3H, CH₃), 1.04 (d, JZ6.5 Hz, 3H, CH₃),

2.08 (q, JZ6.7 Hz, 1H, 1⁰-H), 2.19–2.52 (m, 13H, 2!

1

1023, 938, 861, 726 cm^K1; H NMR (250 MHz, CDCl₃):

dZ0.30–0.39 (m, 1H, cPr-H), 0.52–0.62 (m, 1H, cPr-H),

0.74–0.84 (m, 1H, cPr-H), 0.92–1.00 (m, 1H, cPr-H), 0.99

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11362

(CH₂NCH₂), 2!6-H, 1⁰-H), 2.58 (d, JZ4.3 Hz, 1H, 4-H),

2.82 (d, JZ7.3 Hz, 1H, 4-H), 3.12 (q, JZ7.0 Hz, 1H, 5-H),

3.21–3.26 (m, 1H, 5-H), 3.62–3.68 (m, 8H, 2!CH₂OCH₂),

3.65 (s, 3H, OCH₃), 3.67 (s, 9H, 3!OCH₃), 5.75 (q, JZ

3.5 Hz, 2H, 2!7-H); ¹³C NMR (75.5 MHz, CDCl₃, DEPT):

dZ9.77 (K, cPr-C), 9.86 (K, cPr-C), 10.65 (K, cPr-C),

11.61 (K, cPr-C), 16.95 (C, CH₃), 17.22 (C, CH₃), 18.61

(C_quat, cPr-C), 19.29 (C_quat, cPr-C), 24.51 (K, C-6), 26.51

(K, C-6), 40.56 (C, C-5), 41.33 (C, C-5), 49.77 (C, C-4),

50.52 (K, CH₂NCH₂), 50.66 (K, CH₂NCH₂), 50.77 (C,

C-4), 51.59 (C, 4!OCH₃), 58.93 (C, C-1⁰), 59.56 (C,

C-1⁰), 67.22 (K, 2!CH₂OCH₂), 120.04 (C, C-7), 121.09

(C, C-7), 138.76 (C_quat, C-8), 139.65 (C_quat, C-8), 173.11

(C_quat, C]O), 173.24 (C_quat, C]O), 174.04 (C_quat, C]O),

174.72 (C_quat, C]O); MS (70 eV, EI), m/z (%): 337 (10)

[M^C], 322 (47) [M^CKCH₃], 262 (5), 191 (11), 131 (24),

114 (100), 91 (24) 59 (26); elemental analysis calcd (%) for

C₁₈H₂₇NO₅(337.4): C 64.07, H 8.07; found: C 64.26, H

7.86. *Proton and carbon chemical shifts were given for

both diastereomers together because ¹H NMR and ¹³C NMR

spectra were not proper to classify all of the peaks for major

and minor diastereomers. IR, EI mass and elemental

analysis were carried out for the mixture of diastereomers.

(100), 84 (26); elemental analysis calcd (%) for C₂₀H₃₃NO₂

(319.5): C 75.19, H 10.41; found: C 74.97, H 10.66.

Diastereomer II. R_fZ0.18 (light petroleum/ethyl acetate 1:

1); IR (ﬁlm): n~Z3078, 2975, 2932, 2852, 2790, 2748, 1729,

1456, 1391, 1367, 1332, 1257, 1153, 1117, 933, 850 cm^K1

;

¹H NMR (250 MHz, CDCl₃): dZ0.27–0.34 (m, 1H, cPr-H),

0.40–0.48 (m, 1H, cPr-H), 0.51–0.58 (m, 1H, cPr-H), 0.98

(d, JZ6.7 Hz, 3H, CH₃), 1.09–1.19 (m, 1H, cPr-H), 1.29–

1.51 (m, 7H, 4- or 6-H, piperidine), 1.37 [s, 9H, C(CH₃)₃],

1.79–1.89 (m₀, 1H, 4- or 6-H), 2.18–2.40 (m, 7H, 4- or 6-H,

piperidine, 1 -H), 2.51–2.63 (m, 1H, 5-H), 5.68 (d, JZ

3.9 Hz, 1H, 7-H); ¹³C NMR (62.9 MHz, CDCl₃, DEPT):

dZ12.24 (K, cPr-C), 12.60 (K, cPr-C), 16.36 (C_quat

,

cPr-C), 18.76 (C, CH₃), 24.62 (K, piperidine), 26.12 (K,

piperidine), 27.94 [C, C(CH₃)₃], 28.09 (K, C-4 or -6),

38.25 (K, C-4 or -6), 39₀.92 (C, C-5), 50.75 (K,

piperidine), 58.76 (C, C-1 ), 79.68 [C_quat, C(CH₃)₃],

121.45 (C, C-7), 141.00 (C_quat, C-8), 174.87 (C_quat, C]

O); MS (70 eV, EI), m/z (%): 319 (18) [M^C], 304 (58)

[M^CKCH₃], 248 (60), 234 (12), 112 (100), 84 (26);

elemental analysis calcd (%) for C₂₀H₃₃NO₂(319.5): C

75.19, H 10.41; found: C 74.97, H 10.66.

(b) From the same quantities of reagents, but dimethyl

maleate (18) instead of dimethyl fumarate (17), compound

cis-/trans-26a (351 mg, 52%) was obtained as a mixture of

two diastereomers (ratio 1.7:1 according to NMR) accord-

ing to GP-B after column chromatography.

4.3.6. tert-Butyl 8-(1-pyrrolidin-4-ylethyl)spiro[2.5]oct-

7-ene-5-carboxylate (24c). According to GP-A, Pd(OAc)₂

(22.4 mg, 100 mmol), tri-2-furylphosphine (46.4 mg,

200 mmol), Et₃N (202 mg, 2.00 mmol), pyrrolidine (12c,

142 mg, 2.00 mmol), iodoethene (11, 308 mg, 2.00 mmol)

and bicyclopropylidene (1, 320 mg, 4.00 mmol) were stirred

in anhydrous DMF (1 mL), at 80 8C for 2 h. After cooling

the mixture to room temperature tert-butyl acrylate (15,

512 mg, 4.00 mmol) was added, and the mixture stirred at

80 8C for 48 h. After work-up and drying (MgSO₄), the

solvent was removed in a rotatory evaporator. The residue

was subjected to column chromatography on silica gel

(100 g, 3!30 cm, light petroleum/ethyl acetate/methanol

3:1:1) to yield 24c (176 mg, 29%, yellowish oil) as a

mixture of two diastereomers (ratio 1:1 according to NMR).

4.3.5. tert-Butyl 8-(1-piperidin-4-ylethyl)spiro[2.5]oct-7-

ene-5-carboxylate (24b). According to GP-A, Pd(OAc)₂

(22.4 mg, 100 mmol), tri-2-furylphosphine (46.4 mg,

200 mmol), Et₃N (202 mg, 2.00 mmol), piperidine (12b,

170.3 mg, 2.00 mmol), iodoethene (11, 308 mg, 2.00 mmol)

and bicyclopropylidene (1, 320 mg, 4.00 mmol) were stirred

in anhydrous DMF (1 mL), at 80 8C for 2 h. After cooling

the mixture to room temperature tert-butyl acrylate (15,

512 mg, 4.00 mmol) was added, and the mixture stirred at

80 8C for 48 h. After work-up and drying (MgSO₄), the

solvent was removed in a rotatory evaporator. The residue

was subjected to column chromatography on silica gel

(100 g, 3!30 cm, light petroleum/ethyl acetate 1:1) to yield

24b (209 mg, 33%, yellowish oil) as a mixture of two

diastereomers (ratio 1:1 according to NMR).

Diastereomer I. R_fZ0.33 (light petroleum/ethyl acetate/

methanol, 3:1:1); IR (ﬁlm): n~Z3075, 2971, 2932, 2875,

2776, 2712, 1728, 1478, 1457, 1256, 1152, 985, 850 cm^K1

;

¹H NMR (600 MHz, CDCl₃): dZ0.34–0.38 (m, 1H, cPr-H),

0.46–0.49 (m, 1H, cPr-H), 0.62–0.66 (m, 1H, cPr-H), 0.80–

0.84 (m, 1H, cPr-H), 1.07 (d, JZ6.2 Hz, 3H, CH₃), 1.14–

1.17 (m, 1H, 4- or 6-H), 1.39 [s, 9H, C(CH₃)₃], 1.66–1.71

(m, 4H, pyrrolidine), 1.81 (q, JZ6.11 Hz, 1H, 1⁰-H), 1.96

(td, JZ1.8, 12.5 Hz, 1H, 4- or 6-H), 2.21 (ddd, JZ17.5,

11.5, 2.5 Hz, 1H, 4- or 6-H), 2.33–2.38 (m, 3H, 4- or 6-H,

pyrrolidine), 2.42–2.44 (m, 2H, pyrrolidine), 2.55–2.60 (m,

1H, 5-H), 5.79 (dd, JZ2.4, 4.9 Hz, 1H, 7-H); ¹³C NMR

(62.9 MHz, CDCl₃, DEPT): dZ10.59 (K, cPr-C), 13.17

(K, cPr-C), 18.66 (C_quat, cPr-C), 22.72 (C, CH₃), 23.35

(K, pyrrolidine), 28.04 [C, C(CH₃)₃], 28.55 (K, C-4 or -6),

38.30 (K, C-4 or -6), 40.43 (C, C-5), 52.66 (K,

pyrrolidine), 59.31 (C, C-1⁰), 79.78 [C_quat, C(CH₃)₃],

119.74 (C, C-7), 142.42 (C_quat, C-8), 175.16 (C_quat, C]

O); MS (70 eV, EI), m/z (%): 305 (20) [M^C], 290 (56)

[M^CKCH₃], 234 (44), 220 (10), 98 (100), 70 (22);

elemental analysis calcd (%) for C₁₉H₃₁NO₂(305.5): C

74.71, H 10.23; found: C 74.41, H 10.01.

Diastereomer I. R_fZ0.28 (light petroleum/ethyl acetate, 1:

1); IR (ﬁlm): n~Z3075, 2975, 2932, 2852, 2793, 2747, 1729,

1456, 1391, 1367, 1320, 1255, 1153, 1060, 932, 851 cm^K1

;

¹H NMR (250 MHz, CDCl₃): dZ0.29–0.34 (m, 1H, cPr-H),

0.45–0.49 (m, 1H, cPr-H), 0.82–0.91 (m, 2H, cPr-H), 0.99

(d, JZ6.7 Hz, 3H, CH₃), 1.13–1.19 (m, 1H, 4- or 6-H),

1.36–1.51 (m, 6H, piperidine), 1.43 [s, 9H, C(CH₃)₃], 1.98

(t, JZ11.9 Hz, 1H, 4- or 6-H), 2.19–2.45 (m, 7H, 4- or 6-H,

piperidine, 1⁰-H), 2.58–2.71 (m, 1H, 5-H), 5.68–5.71 (m,

1H, 7-H); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ10.77

(K, cPr-C), 13.70 (K, cPr-C), 16.41 (C, CH₃), 19.91

(C_quat, cPr-C), 24.75 (K, piperidine), 26.19 (K, piperidine),

28.02 [C, C(CH₃)₃], 28.64 (K, C-4 or -6), 38.79 (K, C-4 or

-6), 40.41 (C, C-5), 50.91 (K, piperidine), 59.49 (C, C-1⁰),

79.71 [C_quat, C(CH₃)₃], 120.29 (C, C-7), 141.16 (C_quat

C-8), 175.21 (C_quat, C]O); MS (70 eV, EI), m/z (%): 319

,

(18) [M^C], 304 (58) [M^CKCH₃], 248 (60), 234 (12), 112

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11363

Diastereomer II. R_fZ0.25 (light petroleum/ethyl acetate/

methanol, 3:1:1); IR (ﬁlm): n~Z3078, 2971, 2875, 2776,

2710, 1728, 1478, 1457, 1391, 1367, 1256, 1054, 947,

850 cm^K1; ¹H NMR (250 MHz, CDCl₃): dZ0.36–0.42 (m,

1H, cPr-H), 0.44–0.51 (m, 1H, cPr-H), 0.55–0.61 (m, 1H,

cPr-H), 0.96–1.03 (m, 1H, cPr-H), 1.07 (d, JZ6.5 Hz, 3H,

CH₃), 1.40–1.47 (m, 1H, 4- or 6-H), 1.41 [s, 9H, C(CH₃)₃],

1.67–1.71 (m, 4H, pyrrolidine), 1.82–1.89 (m, 1⁰H, 4- or

6-H), 1.98 (q, JZ6.4 Hz, 1H, 1⁰-H), 2.27–2.34 (m, 2H, 4- or

6-H), 2.43–2.54 (m, 4H, pyrrolidine), 2.54–2.63 (m, 1H,

5-H), 5.79 (t, JZ4.0 Hz, 1H, 7-H); ¹³C NMR (62.9 MHz,

CDCl₃, DEPT): dZ12.11 (K, cPr-C), 12.27 (K, cPr-C),

18.42 (C_quat, cPr-C), 22.64 (C, CH₃), 23.33 (K, pyrro-

lidine), 28.03 [C, C(CH₃)₃], 38.07 (K, C-4 or -6), 39.88

(C, C-5), 52.67 (K, pyrrolidine), 58.19 (C, C-1⁰), 79.80

[C_quat, C(CH₃)₃], 120.97 (C, C-7), 142.54 (C_quat, C-8),

174.86 (C_quat, C]O); MS (70 eV, EI), m/z (%): 305 (4)

[M^C], 290 (24) [M^CKCH₃], 234 (28), 220 (12), 98 (100),

70 (35), 57 (30), 41 (18); elemental analysis calcd (%) for

C₁₉H₃₁NO₂(305.5): C 74.71, H 10.23; found: C 74.41, H

10.01.

Minor diastereomer. R_fZ0.55 (light petroleum/ethyl acet-

n~Z3063, 3026 2974, 2931, 2807, 1727,

ate 3:1); IR (ﬁlm):

1495, 1455, 1391, 1367, 1318, 1256, 1150, 1013, 906, 849,

825, 736 cm^K1; ¹H NMR (250 MHz, CDCl₃): dZ0.29–0.35

(m, 1H, cPr-H), 0.47–0.52 (m, 1H, cPr-H), 0.80–0.89 (m,

2H, cPr-H), 1.02 (d, JZ6.4 Hz, 3H, CH₃), 1.15–1.21 (m,

1H, 4- or 6-H), 1.43 [s, 9H, C(CH₃)₃], 1.98 (t, JZ12.30 Hz,

1H, 4- or 6-H), 2.17 (q, JZ6.42 Hz, 1H, 1⁰-H), 2.24–2.56

(m, 10H, piperazine, 4- or 6-H), 2.56–2.68 (m, 1H, 5-H),

3.48 (s, 2H, Bn), 5.73 (t, JZ3.8 Hz, 1H, 7-H); 7.21–7.30 (m,

5H, Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ10.79

(K, cPr-C), 13.38 (K, cPr-C), 17.71 (C, CH₃), 19.62

(C_quat, cPr-C), 28.05 [C, C(CH₃)₃], 28.59 (K, C-4 or -6),

38.68 (K, C-4 or -6), 40.41 (C, C-5), 49.₀99 (K,

piperazine), 53.43 (K, piperazine), 58.88 (C, C-1 ), 63.09

(K, Bn), 79.76 [C_quat, C(CH₃)₃], 120.48 (C, C-7), 126.88

(C, Ph-C), 128.09 (C, Ph-C), 129.18 (C, Ph-C), 138.22

(C_quat), 141.04 (C_quat), 175.09 (C_quat, C]O); MS (70 eV,

EI), m/z (%): 410 (36) [M^C], 395 (8) [M^CKCH₃], 337 (19),

203 (14), 175 (100), 91 (35); elemental analysis calcd (%)

for C₂₆H₃₈N₂O₂(410.6): C 76.06, H 9.33; found: C 75.81, H

9.14.

4.3.7. tert-Butyl 8-[1-(4-benzylpiperazin-1-yl)ethyl]

spiro[2.5]oct-7-ene-5-carboxylate (24d). According to

GP-B, Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), K₂CO₃(556 mg, 4.00 mmol), Et₄NCl

(332 mg, 2.00 mmol), N-benzylpiperazine (12d, 352.5 mg,

2.00 mmol), iodoethene (11, 308 mg, 2.00 mmol) and

bicyclopropylidene (1, 320 mg, 4.00 mmol) were stirred in

anhydrous MeCN (2 mL) at 80 8C for 2 h. After cooling the

mixture to room temperature tert-butyl acrylate (15,

512 mg, 4.00 mmol) was added, and then the mixture was

heated again with stirring at 80 8C for 48 h. After work-up

and drying (MgSO₄), the solvent was removed in a rotatory

evaporator. The residue was subjected to column chroma-

tography on silica gel (100 g, 3!30 cm, light petroleum/

ethyl acetate, 3:1) to yield 24d (395 mg, 48%, yellowish oil)

as a mixture of two diastereomers (ratio 1.1:1 according to

NMR).

4.3.8. tert-Butyl 4-[1-(7-tert-butoxycarbonylspiro[2.5]

oct-4-en-4-yl)ethyl]piperazinecarboxylate

(24e).

According to GP-B, Pd(OAc)₂(22.4 mg, 100 mmol),

tri-2-furylphosphine (46.4 mg, 200 mmol), K₂CO₃

(556 mg, 4.00 mmol), Et₄NCl (332 mg, 2.00 mmol), N-

Boc-piperazine (12e, 372 mg, 2.00 mmol), iodoethene (11,

308 mg, 2.00 mmol) and bicyclopropylidene (1, 320 mg,

4.00 mmol) were stirred in anhydrous MeCN (2 mL), at

80 8C for 2 h. After cooling the mixture to room

temperature, tert-butyl acrylate (15, 512 mg, 4.00 mmol)

was added, and then the mixture was heated again with

stirring at 80 8C for 48 h. After work-up and drying

(MgSO₄), the solvent was removed in a rotatory evaporator.

The residue was subjected to column chromatography on

silica gel (100 g, 3!30 cm, light petroleum/ethyl acetate,

3:1) to yield 24e (410.7 mg, 49%, yellowish oil) as a

mixture of two diastereomers (ratio 1:1 according to NMR).

Major diastereomer. R_fZ0.39 (light petroleum/ethyl acet-

ate 3:1); IR (ﬁlm): n~Z3063, 2975, 2932, 2808, 2689, 1727,

1495, 1391, 1367, 1330, 1258, 1153, 1013, 910, 849, 823,

734 cm^K1; ¹H NMR (250 MHz, CDCl₃): dZ0.33–0.40 (m,

1H, cPr-H), 0.45–0.52 (m, 1H, cPr-H), 0.56–0.64 (m, 1H,

cPr-H), 1.03 (d, JZ6.6 Hz, 3H, CH₃), 1.11–1.18 (m, 1H,

cPr-H), 1.36–1.43 (m, 1H, 4- or 6-H), 1.43 [s, 9H, C(CH₃)₃],

1.88 (t, JZ11.6 Hz, 1H, 4- or 6-H), 2.09 (q, JZ6.2 Hz, 1H,

1⁰-H), 2.31–2.42 (m, 10H, piperazine, 4- or 6-H), 2.56–2.67

(m, 1H, 5-H), 3.48 (s, 2H, Bn), 5.68 (t, JZ3.8 Hz, 1H, 7-H),

7.21–7.30 (m, 5H, Ph); ¹³C NMR (62.9 MHz, CDCl₃,

DEPT): dZ12.11 (K, cPr-C), 12.61 (K, cPr-C), 17.37

(C, CH₃), 18.73 (C_quat, cPr-C), 28.03 [C, C(CH₃)₃],

28.12 (K, C-4 or -6), 38.30 (K, C-4 or -6), 39.99

(C, C-5), 49.81 (K, piperazine), 53.51 (K, piperazine),

58.23 (C, C-1⁰), 63.10 (K, Bn), 79.77 [C_quat, C(CH₃)₃],

121.5 (C, C-7), 126.87 (C, Ph-C), 128.08 (C, Ph-C),

129.21 (C, Ph-C), 138.21 (C_quat), 141.16 (C_quat), 174.88

(C_quat, C]O); MS (70 eV, EI), m/z (%): 410 (26) [M^C], 395

(6) [M^CKCH₃], 203 (10), 175 (100), 91 (42); elemental

analysis calcd (%) for C₂₆H₃₈N₂O₂(410.6): C 76.06, H

9.33; found: C 75.81, H 9.14.

Diastereomer I. R_fZ0.54 (light petroleum/ethyl acetate 3:

1); IR (ﬁlm): n~Z3076, 2976, 2931, 2814, 1727, 1698, 1455,

1

1422, 1366, 1291, 1248, 1170, 1003, 923, 733 cm^K1; H

NMR (250 MHz, CDCl₃): dZ0.31–0.38 (m, 1H, cPr-H),

0.47–0.54 (m, 1H, cPr-H), 0.77–0.92 (m, 2H, cPr-H), 1.02

(d, JZ6.4 Hz, 3H, CH₃), 1.16–1.21 (m, 1H, 4- or 6-H), 1.43

[s, 9H, C(CH₃)₃], 1.44 [s, 9H, C(CH₃)₃], 1.98 (t, JZ

12.3 Hz, 1H, 4- or 6-H), 2.18 (q, JZ6.3 Hz, 1H, 1⁰-H),

2.25–2.38 (m, 6H; piperazine, 4- or 6-H), 2.57–2.69 (m, 1H,

5-H), 3.35 (t, JZ4.8 Hz, 4H, piperazine), 5.75 (dd, JZ2.7,

4.6 Hz, 1H, 7-H); ¹³C NMR (62.9 MHz, CDCl₃, DEPT):

dZ10.65 (K, cPr-C), 13.19 (K, cPr-C), 17.22 (C, CH₃),

19.46 (C_quat, cPr-C), 27.85 [C, C(CH₃)₃], 28.21 [C,

C(CH₃)₃], 28.39 (K, C-4 or -6), 38.41 (K, C-4 or -6),

40.13 (C, C-5), 43.19 (K, piperazine)*, 49.59 (K,

piperazine), 58.60 (C, C-1⁰), 79.08 [C_quat, C(CH₃)₃],

79.58 [C_quat, C(CH₃)₃], 120.63 (C, C-7), 140.59 (C_quat),

154.51 (C_quat, C]O). 174.79 (C_quat, C]O); *It appears as a

multiplet of low intensity. This carbon correlates clearly

with the triplet at 3.35 ppm in the HMQC spectrum. MS

(70 eV, EI), m/z (%): 420 (3) [M^C], 397 (8), 284 (17), 213

(52), 157 (100), 57 (48), 41 (14); elemental analysis calcd

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B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11364

(%) for C₂₄H₄₀N₂O₄(420.6): C 68.54, H 9.59; found: C

68.30, H 9.42.

(%): 366 (46) [M^C], 351 (93) [M^CKCH₃], 152 (6), 133 (8),

117 (18), 114 (100), 91 (16), 86 (27); elemental analysis

calcd (%) for C₂₂H₂₆N₂O₃(366.5): C 72.11, H 7.15; found:

C 71.96, H 7.02.

Diastereomer II. R_fZ0.48 (light petroleum/ethyl acetate 3:

1); IR (ﬁlm): n~Z3078, 2975, 2931, 2811, 2756, 1727, 1699,

1455, 1422, 1366, 1291, 1248, 1167, 1003, 923, 733 cm^K1

;

Diastereomer II. Mp 140 8C, R_fZ0.38 (light petroleum/

ethyl acetate 1:1); IR (KBr): n~Z3064, 2965, 2891, 2846,

2815, 1773, 1702, 1597, 1500, 1455, 1435, 1390, 1301,

¹H NMR (250 MHz, CDCl₃): dZ0.34–0.42 (m, 1H, cPr-H),

0.46–0.54 (m, 1H, cPr-H), 0.56–0.64 (m, 1H, cPr-H), 1.02

(d, JZ6.6 Hz, 3H, CH₃), 1.08–1.21 (m, 1H, cPr-H), 1.38–

1.44 (m, 1H, 4- or 6-H), 1.43 [s, 9H, C(CH₃)₃], 1.44 [s, 9H,

C(CH₃)₃], 1.88 (dd, JZ10.7, 12.8 Hz, 1H, 4- or 6-H), 2.22–

2.43 (m, 7H, piperazine, 4- or 6-H, 1⁰-H), 2.57–2.69 (m, 1H,

5-H), 3.35 (t, JZ4.9 Hz, 4H, piperazine), 5.68 (t, JZ3.8 Hz,

1H, 7-H); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ12.10

(K, cPr-C), 12.39 (K, cPr-C), 16.43 (C, CH₃), 18.51

(C_quat, cPr-C), 27.89 [C, C(CH₃)₃], 27.89 (K, C-4 or -6),

28.27 [C, C(CH₃)₃], 38.09 (K, C-4 or -6), 39.75 (C, C-5),

43.58 (K, piperazine)*, 49.32 (K, piperazine), 59.74 (C,

C-1⁰), 79.14 [C_quat, C(CH₃)₃], 79.69 [C_quat, C(CH₃)₃],

121.65 (C, C-7), 140.58 (C_quat), 154.61 (C_quat, C]O),

174.64 (C_quat, C]O). *It appears as a multiplet of low

intensity. This carbon correlates clearly with the triplet at

3.35 ppm in the HMQC spectrum. MS (70 eV, EI), m/z (%):

420 (13) [M^C], 405 (18) [M^CKCH₃], 293 (22), 279 (10),

213 (18), 157 (32), 133 (50), 57 (100), 41 (34); elemental

analysis calcd (%) for C₂₄H₄₀N₂O₄(420.6): C 68.54, H

9.59; found: C 68.30, H 9.42.

1

1189, 1172, 1115, 1040, 944, 923, 754 cm^K1; H NMR

(250 MHz, CDCl₃): dZ0.35–0.43 (m, 1H, cPr-H), 0.79–

0.87 (m, 1H, cPr-H), 0.98 (d, JZ6.7 Hz, 3H, CH₃), 1.06–1,

18 (m, 1H, cPr-H), 1.47–1.55 (m, 1H, cPr-H), 2.31–2.50 (m,

6H, CH₂NCH₂, 3a-H, 7-H), 2.80–2.92 (m, 2H, 1⁰-H, 7-H),

3.32–3.40 (m, 1H, 7a-H), 3.52–3.63 (m, 4H, CH₂OCH₂),

5.93 (br s, 1H, 6-H), 7.13–7.17 (m, 2H, Ph), 7.34–7.45 (m,

3H, Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ6.71 (K,

cPr-C), 11.87 (C, CH₃), 12.73 (K, cPr-C), 22.29 (C_quat

,

cPr-C), 24.56 (K, C-7), 41.60 (C, C-7a),₀49.16 (K,

CH₂NCH₂), 50.05 (C, C-3a), 60.80 (C, C-1 ), 67.28 (K,

CH₂OCH₂), 123.30 (C, C-6), 126.33 (C, Ph-C), 128.49

(C, Ph-C), 129.05 (C, Ph-C), 131.98 (C_quat), 143.59

(C_quat), 177.74 (C_quat, C]O), 178.96 (C_quat, C]O); MS

(70 eV, EI), m/z (%): 366 (25) [M^C], 351 (77) [M^CKCH₃],

133 (6), 114 (100), 86 (16); elemental analysis calcd (%) for

C₂₂H₂₆N₂O₃(366.5): C 72.11, H 7.15; found: C 71.96, H

7.02.

4.3.10. 5-[1⁰-(Morpholin-4⁰⁰-yl)ethyl]-2-(3⁰⁰⁰-triﬂuoro-

methyl)phenylspiro[cyclopropane-1⁰,4-(3a,4,7,7a-tetra-

hydroisoindole)]-1,3-dione (28a). According to GP-A,

Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), Et₃N (202 mg, 2.00 mmol), morpho-

line (12a, 174 mg, 2.00 mmol), iodoethene (11, 308 mg,

2.00 mmol) and bicyclopropylidene (1, 320 mg, 4.00 mmol)

were stirred in anhydrous DMF (1 mL) at 80 8C for 2 h.

After cooling the mixture to room temperature 1-(3⁰-

triﬂuoromethylphenyl)-2,5-dihydro-pyrrole-2,5-dione (20,

965 mg, 4.00 mmol) was added, and the mixture stirred at

80 8C for 4 h. After work-up and drying (MgSO₄), the

solvent was removed in a rotatory evaporator. The residue

was subjected to column chromatography on silica gel

(100 g, 3!30 cm, light petroleum/ethyl acetate, 2:3) to

yield 28a (327.4 mg, 38%, pale yellow solid) as a mixture of

two diastereomers (ratio 1.2:1 according to NMR).

4.3.9. 5-[1⁰-(Morpholin-4⁰⁰-yl)ethyl]-2-phenylspiro[cyclo-

propane-1⁰,4-(3a,4,7,7a-tetrahydroisoindole)]-1,3-dione

(27a). According to GP-A, Pd(OAc)₂(22.4 mg, 100 mmol),

tri-2-furylphosphine (46.4 mg, 200 mmol), Et₃N (202 mg,

2.00 mmol), morpholine (12a, 174 mg, 2.00 mmol),

iodoethene (11, 308 mg, 2.00 mmol) and bicyclopropyli-

dene (1, 320 mg, 4.00 mmol) were stirred in anhydrous

DMF (1 mL) at 80 8C for 2 h. After cooling the mixture to

room temperature, 1-phenyl-pyrrole-2,5-dione (19, 693 mg,

4.00 mmol) was added, and the mixture stirred at 80 8C for

4 h. After work-up and drying (MgSO₄), the solvent was

removed in a rotatory evaporator. The residue was subjected

to column chromatography on silica gel (100 g, 3!30 cm,

light petroleum/ethyl acetate, 1:1) to yield 27a (290 mg,

40%, yellow solid) as a mixture of two diastereomers (ratio

1:1 according to NMR).

Diastereomer I. Mp 127 8C, R_fZ0.42 (light petroleum/ethyl

acetate 1:1); IR (KBr): n~Z3087, 3022, 2955, 2906, 2847,

2809, 1708, 1595, 1494, 1456, 1435, 1368, 1298, 1183,

Major diastereomer. Mp 147 8C; R_fZ0.51 (light petroleum/

ethyl acetate, 2:3); IR (KBr): n~Z3067 (C–H), 1721 (C]O),

1705, 1616, 1526, 1415, 1340, 1223, 1163 (C–F), 1129,

1

1170, 1135, 1111, 855, 759 cm^K1; H NMR (250 MHz,

1110, 1071, 842, 824, 818 cm^K^{1 1}H NMR (250 MHz,

;

CDCl₃): dZ0.300.34 (m, 1H, cPr-H), 0.72–0.80 (m, 1H,

cPr-H), 1.58 (d, JZ6.7 Hz, 3H, CH₃), 1.20–1.26 (m, 1H,

cPr-H), 1.75–1.83 (m, 1H, cPr-H), 2.21–2.47 ₀(m, 6H,

CH₂NCH₂, 3a-H, 7-H), 2.65 (q, JZ6.7 Hz, 1H, 1 -H), 2.81

(ddd, JZ2.0, 7.2, 14.8 Hz, 1H, 7-H), 3.29–3.36 (m, 1H, 7a-

H), 3.50 (t, JZ4.6 Hz, 4H, CH₂OCH₂), 5.85 (dd, JZ2.9,

6.9 Hz, 1H, 6-H), 7.18–7.21 (m, 2H, Ph), 7.32–7.45 (m, 3H,

Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ7.65 (K,

CDCl₃): dZ0.30–0.44 (m, 1H, cPr-H), 0.74–0.89 (m, 1H,

cPr-H), 1.06 (d, JZ6.9 Hz, 3H, CH₃), 1.19–1.33 (m, 1H,

cPr-H), 1.82 (m_c, 1H, cPr-H), 2.19–2.39 (m, 4H,

CH₂NCH₂), 2.35 (d, JZ9.1 Hz, 1H, 3a-H), 2.45 (ddd, JZ

15.0, 6.6, 3.3 Hz, 1H, 7-H), 2.67 (q, ³JZ6.9 Hz, 1H, 1⁰-H),

2.84 (ddd, JZ15.0, 6.9, 1.8 Hz, 1H, 7-H), 3.33–3.45 (m, 1H,

7a-H), 3.45–3.59 (m, 4H, CH₂OCH₂), 5.86 (dd, JZ7.3,

3.3 Hz, 1H, 6-H), 7.40–7.75 (m, 4H, Ar-H); ¹³C NMR

(62.9 MHz, CDCl₃, DEPT): dZ7.73 (K, cPr-C), 13.3 (K,

cPr-C), 15.0 (C, CH₃), 20.6 (C_quat, C-4), 24.2 (K, C-7),

41.7 (C, C-7a), 50.3 (C, C-1⁰), 50.6 (K, CH₂NCH₂), 63.9

(C, C-3a), 67.0 (K, CH₂OCH₂), 123.0 (C, C-6), 123.5

cPr-C), 13.04 (K, cPr-C), 15.04 (C, CH₃), 20.05 (C_quat

,

cPr-C), 24.19 (K, C-7), 41.59 (C, C-3a), 50.19 (C, C-7a),

50.57 (K, CH₂NCH₂), 64.02 (C, C-1⁰), 66.96 (K,

CH₂OCH₂), 125.95 (C, Ph-C, C-6), 128.26 (C, Ph),

128.88 (C, Ph-C), 131.89 (C_quat), 144.11 (C_quat), 177.07

(C_quat, C]O), 178.88 (C_quat, C]O); MS (70 eV, EI), m/z

1

(C_quat, q, J(C,F)Z247 Hz, CF₃), 125.0 (C, C-5⁰⁰⁰), 125.5

(C, Ar-C), 125.9 (C, Ar-C), 129.2 (C, Ar-C), 131.4 (C_quat

,

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11365

2

q, J(C,F)Z33.3 Hz, C-3⁰⁰⁰), 132.4 (C_quat, Ar-C), 144.2

33.3 Hz, C-4⁰⁰⁰), 126.5 (C, 4!Ar-C), 127.8 (C_quat, q, ¹J(C,

F)Z272 Hz, CF₃), 135.0 (C_quat, Ar-C), 143.8 (C_quat, C-5),

177.8 (C_quat, C]O), 178.7 (C_quat, C]O); MS (70 eV), m/z

(%): 435/434 (10/42) [M^C], 420/419 (22/89) [M^CKCH₃],

117 (13), 114 (100), 91 (12), 86 (13) [morpholine^CKH];

HRMS (EI): calcd for C₂₃H₂₅F₃N₂O₃[M^C]: 434.1817,

correct HRMS.

(C_quat, C-5), 176.8 (C_quat, C]O), 178.5 (C_quat, C]O); MS

(70 eV), m/z (%): 434 (48) [M^C], 419 (100) [M^CKCH₃],

114 (100), 86 (14) [morpholine^CKH]; HRMS (EI): calcd

for C₂₃H₂₅F₃N₂O₃[M^C] 434.1817, correct HRMS.

Minor diastereomer. Mp 146 8C; R_fZ0.44 (light petroleum/

ethyl acetate, 2:3); IR (KBr): n~Z3068 (C–H), 1723 (C]O),

1702, 1618, 1529, 1413, 1342, 1225, 1164 (C–F), 1126,

Minor diastereomer. Mp 149 8C; R_fZ0.57 (light petroleum/

ethyl acetate 2:3); IR (KBr): n~Z2958, 2853, 2810, 1710

(C]O), 1702 (C]O), 1613, 1518, 1384 (CH₃), 1325, 1173

1113, 1074, 841, 823, 817 cm^K^{1 1}H NMR (250 MHz,

;

CDCl₃): dZ0.35 (m_c, 1H, cPr-H), 0.74–0.85 (m, 1H,

cPr-H), 1.05 (d, JZ6.7 Hz, 3H, CH₃), 1.18–1.31 (m, 1H,

3

1

(C–F), 1124, 1066, 1020, 845 cm^K1; H NMR (250 MHz,

cPr-H), 1.81 (m_c, 1H, cPr-H), 2.17–2.39 (m, 5H, CH₂NCH₂,

3a-H), 2.45 (ddd, JZ15.0, 6.6, 3.3 Hz, 1H, 7-H), 2.67 (q,

JZ6.90 Hz, 1H, 1⁰-H) 2.83 (ddd, JZ15.0, 6.9, 1.8 Hz, 1H,

7-H), 3.39 (m_c, 1H, 7a-H), 3.44–3.57 (m, 4H, CH₂OCH₂),

5.87 (dd, JZ7.3, 3.4 Hz, 1H, 6-H), 7.39–7.70 (m, 4H, Ar-

H); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ6.68 (K, cPr-

C), 11.8 (C, CH₃), 12.8 (K, cPr-C), 22.9 (C_quat, C-4), 24.5

(K, C-7), 41.6 (C, C-7a), 49.1 (K, CH₂NCH₂), 50.1 (C,

C-1⁰), 60.7 (C, C-3a), 67.3 (K, CH₂OCH₂), 123.2 (C,

C-6), 123.4 (C_quat, q, ¹J(C,F)Z245 Hz, CF₃), 125.1 (C, Ar-

CDCl₃): dZ0.36 (m_c, 1H, cPr-H), 0.80 (m_c, 1H, cPr-H),

1.06 (d, JZ6.7 Hz, 3H, CH₃), 1.19–1.31 (m, 1H, cPr-H),

1.85 (m_c, 1H, cPr-H), 2.19–2.40 (m, 4H, CH₂NCH₂), 2.36

(d, JZ9.2 Hz, 1H, 3a-H), 2.46 (ddd, JZ15.0, 6.6, 3.3 Hz,

1H, 7-H), 2.67 (q, JZ6.7 Hz, 1H, 1⁰-H), 2.84 (ddd, JZ15.0,

6.9, 1.8 Hz, 1H, 7-H), 3.39 (m_c, 1H, 7a-H), 3.52 (m_c, 4H,

CH₂OCH₂), 5.87 (dd, JZ7.4, 2.9 Hz, 1H, 6-H), 7.42 (d, JZ

8.5 Hz, 2H, Ar), 7.70 (d, JZ8.5 Hz, 2H, Ar); ¹³C NMR

(62.9 MHz, CDCl₃, DEPT): dZ7.72 (K, cPr-C), 13.3 (K,

cPr-C), 15.2 (C, CH₃), 20.6 (C_quat, C-4), 24.6 (K, C-7),

41.8 (C, C-7a), 50.4 (C, C-1⁰), 50.7 (K, CH₂NCH₂), 64.2

(C, C-3a), 67.0 (K, CH₂OCH₂), 126.1 (C, C-6), 126.1

C), 125.2 (C, Ar-C), 129.5 (C, Ar-C), 129.6 (C, Ar-C),

2

131.8 (C_quat, q, J(C,F)Z33.3 Hz, C-3⁰⁰⁰), 132.4 (C_quat

Ar-C), 143.7 (C_quat, C-5), 177.4 (C_quat, C]O), 178.6 (C_quat

,

2

(C_quat, q, J(C,F)Z33.3 Hz, C-4⁰⁰⁰), 126.2 (C, 4!Ar),

C]O); MS (70 eV), m/z (%): 434 (48) [M^C], 419 (100)

[M^CKCH₃], 114 (100), 86 (14) [morpholine^CKH]; HRMS

(EI): calcd for C₂₃H₂₅F₃N₂O₃[M^C]: 434.1817, correct

HRMS.

127.8 (C_quart, q, ¹J(C,F)Z272 Hz, CF₃), 135.0 (C_quat, Ar-C),

144.3 (C_quat, C-5), 176.8 (C_quat, C]O), 178.5 (C_quat, C]

O); MS (70 eV), m/z (%): 435/434 (10/42) [M^C], 420/419

(22/89) [M^CKCH₃], 117 (13), 114 (100), 91 (12), 86 (13)

[morpholine^CKH]; HRMS (EI): calcd for C₂₃H₂₅F₃N₂O₃

[M^C]: 434.1817, correct HRMS.

4.3.11. 5-[1⁰-(Morpholin-4⁰⁰-yl)ethyl]-2-(4⁰⁰⁰-triﬂuoro-

methyl)phenylspiro[cyclopropane-1⁰,4-(3a,4,7,7a-tetra-

hydroisoindole)]-1,3-dione (29a). According to GP-A,

Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), Et₃N (202 mg, 2.00 mmol), morpho-

line (12a, 174 mg, 2.00 mmol), iodoethene (11, 308 mg,

2.00 mmol) and bicyclopropylidene (1, 320 mg, 4.00 mmol)

were stirred in anhydrous DMF (1 mL) at 80 8C for 2 h.

After cooling the mixture to room temperature 1-(4⁰-

triﬂuoromethylphenyl)-2,5-dihydropyrrole-2,5-dione (21,

965 mg, 4.00 mmol) was added, and the mixture stirred at

80 8C for 4 h. After work-up and drying (MgSO₄), the

solvent was removed in a rotatory evaporator. The residue

was subjected to column chromatography on silica gel

(130 g, 3!40 cm, light petroleum/ethyl acetate 2:3) to yield

29a (384 mg, 44%, pink crystals) as a mixture of two

diastereomers (ratio 1.1:1, according to NMR).

4.3.12. 5-[1⁰-(Morpholin-4⁰⁰-yl)ethyl]-2-[bis-(3⁰⁰⁰,5⁰⁰⁰-tri-

ﬂuoromethyl)]phenylspiro[cyclopropane-1⁰,4-(3a,4,7,7a-

tetrahydroisoindole)]-1,3-dione (30a). According to

GP-A, Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), Et₃N (202 mg, 2.00 mmol), morpho-

line (12a, 174 mg, 2.00 mmol), iodoethene (11, 308 mg,

2.00 mmol) and bicyclopropylidene (1, 320 mg, 4.00 mmol)

were stirred in anhydrous DMF (1 mL) at 80 8C for 2 h.

After cooling the mixture to room temperature, 1-[3⁰,5⁰-

bis(triﬂuoromethyl)phenyl]-2,5-dihydropyrrole-2,5-dione

(22, 1236 mg, 4.00 mmol) was added, and the mixture

stirred at 80 8C for 4 h. After work-up and drying (MgSO₄),

the solvent was removed in a rotatory evaporator. The

residue was subjected to column chromatography on silica

gel (130 g, 3!40 cm, light petroleum/ethyl acetate, 2:3) to

yield 30a (376 mg, 37%, pale yellow crystals) as a mixture

of two diastereomers (ratio 1.6:1, according to NMR).

Major diastereomer. Mp 158 8C; R_fZ0.51 (light petroleum/

ethyl acetate, 2:3); IR (KBr): n~Z2966, 2852, 1714 (C]O),

1616, 1519, 1384 (CH₃), 1326, 1172 (C–F), 1115, 1067,

Major diastereomer. Mp 94 8C; R_fZ0.60 (light petroleum/

ethyl acetate, 2:3); IR (KBr): n~Z2962, 1791 (C]O), 1628,

cm^K^{1 1}H NMR (250 MHz, CDCl₃): dZ0.41 (m_c, 1H,

;

1

cPr-H), 0.79–0.90 (m, 1H, cPr-H), 0.97 (d, JZ6.8 Hz, 3H,

CH₃), 1.04–1.20 (m, 1H, cPr-H), 1.52 (m_c, 1H, cPr-H),

2.31–2.41 (m, 4H, CH₂NCH₂), 2.41–2.47 (m, 1H, 3a-H),

2.47–2.54 (m, 2H, 1⁰-H, 7-H), 2.86 (m_c, 1H, 7-H), 3.37 (m_c,

1H, 7a-H), 3.61 (m_c, 4H, CH₂OCH₂), 5.94 (d, JZ7.3,

3.1 Hz, 1H, 6-H), 7.36 (d, JZ8.5 Hz, 2H, Ar), 7.70 (d, JZ

8.5 Hz, 2H, Ar); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ

6.66 (K, cPr-C), 11.9 (C, CH₃), 12.8 (K, cPr-C), 22.8

(C_quat, C-4), 24.4 (K, C-7), 41.6 (C, C-7a), 49.1 (K,

CH₂NCH₂), 50.1 (C, C-1⁰), 60.7 (C, C-3a), 67.3 (K,

CH₂OCH₂), 123.2 (C, C-6), 126.1 (C_quat, q, ²J(C,F)Z

1472, 1395 (C–F), 1280, 1176 (C–F), 1137, 892 cm^K1; H

NMR (250 MHz, CDCl₃): dZ0.37 (m_c, 1H, cPr-H), 0.82

(m_c, 1H, cPr-H), 1.05 (d, JZ6.7 Hz, 3H, CH₃), 1.19–1.30

(m, 1H, cPr-H), 1.76–1.90 (m, 1H, cPr-H), 2.19–2.43 (m,

5H, 3a-H, CH₂NCH₂), 2.43–2.55 (m, 1H, 7-H), 2.66 (q,

³JZ6.7 Hz, 1H, 1⁰-H), 2.84 (ddd, JZ15.0, 7.8, 1.8 Hz, 1H,

7-H), 3.41 (m_c, 1H, 7a-H), 3.50 (m_c, 4H, CH₂OCH₂), 5.94

(dd, JZ7.3, 3.2 Hz, 1H, 6-H), 7.75 (s, 2H, Ar), 7.86 (s, 1H,

Ar); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ6.74 (K,

cPr-C), 11.8 (C, CH₃), 13.0 (K, cPr-C), 22.9 (C_quat, C-4),

24.5 (K, C-7), 41.7 (C, C-7a), 49.1 (K, CH₂NCH₂), 50.2

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11366

(C, C-1⁰), 60.7 (C, C-3a), 67.2 (K, CH₂OCH₂), 121.9 (C,

61.86 (C, C-1⁰), 67.00 (K, CH₂OCH₂), 79.98 [C_quat

,

1

Ar-C), 122.7 (C_quat, q, J(C,F)Z271 Hz, 2!CF₃), 123.2

C(CH₃)₃], 126.12 (C, Ph-C), 128.09 (C, Ph-C), 128.17 (C,

Ph-C), 135.69 (C_quat), 136.43 (C_quat), 144.11 (C_quat), 174.77

(C_quat, C]O); MS (70 eV, EI), m/z (%): 397 (30) [M^C], 382

(8) [M^CKCH₃], 254 (36), 209 (31), 114 (100), 100 (26), 57

(39); elemental analysis calcd (%) for C₂₅H₃₅NO₃(397.6):

C 75.53, H 8.87; found: C 75.59, H 8.64.

2

(C, C-6), 126.3 (C, 2!Ar-C), 132.4 (C_quat, q, J(C,F)Z

33.3 Hz, C-3⁰⁰⁰, C-5⁰⁰⁰), 133.4 (C_quat, Ar-C), 143.9 (C_quat

,

C-5), 177.0 (C_quat, C]O), 178.2 (C_quat, C]O); MS

(70 eV), m/z (%): 502 (27) [M^C], 488/487 (24/100)

[M^CKCH₃], 229 (13), 114 (48), 43 (35); HRMS (EI):

calcd for C₂₄H₂₄F₆N₂O₃[M^C]: 502.1691, correct HRMS.

Minor diastereomer. R_fZ0.44 (light petroleum/ethyl acet-

ate 10:1); IR (ﬁlm): n~Z3077, 2975, 2851, 2806, 1726, 1450,

Minor diastereomer. Mp 69 8C; R_fZ0.59 (light petroleum/

ethyl acetate, 2:3); IR (KBr): n~Z3105 (C–H), 2967, 1720

(C]O), 1627, 1472, 1396 (C–F), 1280, 1176 (C–F), 1135,

892 cm^K1; ¹H NMR (250 MHz, CDCl₃): dZ0.43 (m_c, 1H,

cPr-H), 0.77–0.93 (m, 1H, cPr-H), 0.96 (d, JZ6.8 Hz, 3H,

CH₃), 1.02–1.18 (m, 1H, cPr-H), 1.55 (m_c, 1H, cPr-H),

2.20–2.42 (m, 5H, 3a-H, CH₂NCH₂), 2.44–2.59 (m, 1H,

7-H), 2.80–2.94 (m, 2H, 1⁰-H, 7-H), 3.43 (m_c, 1H, 7a-H),

3.56–3.70 (m, 4H, CH₂OCH₂), 5.88 (dd, JZ7.1, 3.2 Hz, 1H,

6-H), 7.75 (br s, 1H, Ar), 7.80 (br s, 2H, Ar); ¹³C NMR

(62.9 MHz, CDCl₃, DEPT): dZ6.87 (K, cPr-C), 12.1 (C,

CH₃), 12.8 (K, cPr-C), 22.9 (C_quat, C-4), 24.5 (K, C-7),

41.8 (C, C-3a), 49.2 (K, CH₂NCH₂), 50.2 (C, C-1⁰), 60.9

(C, C-7a), 67.1 (K, CH₂OCH₂), 119.3 (C, Ar-C), 122.1

(C, C-6), 122.7 (C_quat, q, ¹J(C,F)Z273 Hz, 2!CF₃), 126.4

1

1367, 1265, 1151, 1122, 943, 864, 703 cm^K1; H NMR

(250 MHz, CDCl₃): dZ0.37–0.45 (m, 1H, cPr-H), 0.54–

0.62 (m, 1H, cPr-H), 1.00 (d, JZ7.1 Hz, 3H, CH₃), 1.02–

1.09 (m, 1H, cPr-H), 1.32 (dd, JZ12.7, 3.6 Hz, 1H, 4- or

6-H), 1.43 [s, 9H, C(CH₃)₃], 1.83–1.98 (m, 2H, 4- or 6-H,

cPr-H), 2.22 (br s, 4H, CH₂NCH₂), 1.83–1.98 (m, 2H, 4- or

6-H), 2.73–2.88 (m, 2H, 5-H, 1-H), 3.55 (t, JZ4.6 Hz, 4H,

CH₂OCH₂), 7.04 (d, JZ8.1 Hz, 2H, Ph), 7.18–7.33 (m, 3H,

Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ13.07 (K,

cPr-C), 14.13 (K, cPr-C), 18.78 (C_quat, cPr-C), 19.07 (C,

CH₃), 27.97 [C, C(CH₃)₃], 36.56 (K, C-4 or -6), 39.69 (K,

C-4 or -6), 40.56 (C, C-5), 51.55 (K, CH₂NCH₂), 61.11

(C, C-1⁰), 67.06 (K, CH₂OCH₂), 79.93 [C_quat, C(CH₃)₃],

125.91 (C, Ph-C), 127.98 (C, Ph-C), 128.17 (C, Ph-C),

2

(C, 2!Ar-C), 132.4 (C_quat, q, J(C,F)Z33.5 Hz, C-3⁰⁰⁰,

135.63 (C_quat), 136.66 (C_quat), 144.35 (C_quat), 174.65 (C_quat

,

C-5⁰⁰⁰), 133.3 (C_quat, Ar-C), 139.3 (C_quat, C-5), 177.0 (C_quat

,

C]O); MS (70 eV, EI), m/z (%): 397 (22) [M^C], 382 (8)

[M^CKCH₃], 254 (32), 209 (28), 114 (100), 100 (25), 57

(30); elemental analysis calcd (%) for C₂₅H₃₅NO₃(397.6):

C 75.53, H 8.87; found: C 75.57, H 8.56.

C]O), 178.1 (C_quat, C]O); MS (70 eV), m/z (%): 502 (27)

[M^C], 488/487 (24/100) [M^CKCH₃], 229 (13), 114 (48), 43

(35); HRMS (EI): calcd for C₂₄H₂₄F₆N₂O₃[M^C]: 502.1691,

correct HRMS).

(b) According to GP-A, Pd(OAc)₂(22.4 mg, 100 mmol), tri-

2-furylphosphine (46.4 mg, 200 mmol), Et₃N (202 mg,

2.00 mmol), morpholine (12a, 174 mg, 2.00 mmol),

(1-iodovinyl)benzene (31, 460 mg, 2.00 mmol) and bicyclo-

propylidene (1, 320 mg, 4.00 mmol) were stirred in

anhydrous DMF (1 mL) at 80 8C for 2 h. After cooling the

mixture to room temperature, tert-butyl acrylate (15,

512 mg, 4.00 mmol) was added, and the mixture stirred at

80 8C for 48 h. After work-up and drying (MgSO₄), the

solvent was removed in a rotatory evaporator. The residue

was subjected to column chromatography on silica gel

(100 g, 3!30 cm, light petroleum/ethyl acetate 10:1) to

yield 39a (142.5 mg, 18%, yellowish oil) as a mixture of

two diastereomers (ratio 1:1 according to NMR), 51

(45.6 mg, 8%, yellowish oil) and 52 (170 mg, 27%,

yellowish oil).

4.3.13. tert-Butyl 8-(1-morpholin-4-ylethyl)-7-phenyl-

spiro[2.5]oct-7-ene-5-carboxylate (39a). (a) According to

GP-B, Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), K₂CO₃(556 mg, 4.00 mmol),

Et₄NCl (332 mg, 2.00 mmol), morpholine (12a, 261 mg,

3.00 mmol), (1-iodovinyl)benzene (31, 460 mg, 2.00 mmol)

and bicyclopropylidene (1, 320 mg, 4.00 mmol) were stirred

in anhydrous MeCN (2 mL) at 80 8C for 3 h. After cooling

the mixture to room temperature, tert-butyl acrylate (15,

512 mg, 4.00 mmol) was added, and then the mixture was

heated again with stirring at 100 8C for 65 h. After work-up

and drying (MgSO₄), the solvent was removed in a rotatory

evaporator. The residue was subjected to column chroma-

tography on silica gel (100 g, 3!30 cm, light petroleum/

ethyl acetate, 10:1) to yield 39a (286 mg, 36%, yellowish

oil) as a mixture of two diastereomers (ratio 1.1:1 according

to NMR).

4.3.14. 4-(2-Cyclopropylidene-1-methyl-3-phenyl-but-3-

enyl)morpholine (51). R_fZ0.33 (light petroleum/ethyl

acetate, 10:1); IR (ﬁlm): n~Z3078, 3052, 2972, 2851,

2807, 1724, 1597, 1492, 1445, 1265, 1118, 1009, 942,

Major diastereomer. R_fZ0.48 (light petroleum/ethyl acet-

ate, 10:1); IR (ﬁlm): n~Z3003, 2980, 2951, 2853, 2803,

1

1723, 1450, 1263, 1149, 1113, 943, 849, 705 cm^K1; H

1

777, 701 cm^K1; H NMR (250 MHz, CDCl₃): dZ0.76 (t,

NMR (250 MHz, CDCl₃): dZ0.29–0.36 (m, 1H, cPr-H),

0.59–0.66 (m, 1H, cPr-H), 0.83–0.95 (m, 1H, cPr-H), 1.05–

1.13 (m, 1H, 4- or 6-H), 1.11 (d, JZ7.0 Hz, 3H, CH₃), 1.41

(s, 9H, C(CH₃)₃), 1.63–1.70 (m, 1H, cPr-H), 2.02–2.37 (m,

5H, CH₂NCH₂, 4- or 6-H), 2.37–2.59 (m, 2H, 4- or 6-H),

2.75–2.93 (m, 2H, 5-H, 1-H), 3.57 (t, JZ4.1 Hz, 4H,

CH₂OCH₂), 7.05 (d, JZ9.1 Hz, 2H, Ph), 7.19–7.34 (m, 3H,

Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ13.78 (K,

JZ7.8 Hz, 2H, cPr-H), 1.18 (t, JZ7.8 Hz, 2H, cPr-H), 1.28

(d, JZ7.1 Hz, 3H, CH₃), 2.38–2.55 (m, 4H, CH₂NCH₂),

3.39 (q, JZ6.7 Hz, 1H, 1-H), 3.65 (t, JZ4.7 Hz, 4H,

CH₂OCH₂), 5.25 (d, JZ1.9 Hz, 1H, vinyl), 5.60 (d, JZ

1.88 Hz, 1H, vinyl), 7.21–7.32 (m, 5H, Ph); ¹³C NMR

(62.9 MHz, CDCl₃, DEPT): dZ2.98 (K, cPr-C), 3.82 (K,

cPr-C), 14.70 (C, CH₃), 50.04 (K, CH₂NCH₂), 63.22 (C,

C-1), 67.34 (K, CH₂OCH₂), 114.04 (K, vinyl), 125.49

(C_quat), 126.66 (C, Ph-C), 127.56 (C, Ph-C), 127.80 (C,

Ph-C), 129.78 (C_quat), 142.56 (C_quat), 149.51 (C_quat); MS

cPr-C), 14.83 (K, cPr-C), 18.04 (C, CH₃), 19.14 (C_quat

,

cPr-C), 28.02 [C, C(CH₃)₃], 36.85 (K, C-4 or -6), 40.35

(K, C-4 or -6), 40.99 (C, C-5), 51.86 (K, CH₂NCH₂),

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11367

(70 eV, EI) m/z (%): 269 (18) [M^C], 268 (37), 183 (4)

[M^CKmorpholinyl], 114 (100).

131 (22), 114 (95), 100 (28), 57 (100), 41 (45); elemental

analysis calcd (%) for C₂₆H₃₅NO₅(441, 6): C 70.72, H 7.99;

found: C 70.55, H 7.72.

4.3.15. tert-Butyl 8-(1-phenylvinyl)spiro[2.5]oct-7-ene-5-

carboxylate (52). R_fZ0.76 (light petroleum/ethyl acetate,

10:1); IR (ﬁlm): n~Z3081, 2977, 2931, 1726, 1367, 1255,

Minor diastereomer. R_fZ0.39 (light petroleum/ethyl acet-

ate 4:1); IR (KBr): n~Z3077, 2975, 2852, 2805, 1725, 1505,

1485, 1433, 1367, 1239, 1150, 1121, 1039, 938, 810 cm^K1

;

1

1152, 903, 780 cm^K1; H NMR (250 MHz, CDCl₃): dZ

¹H NMR (250 MHz, CDCl₃): dZ0.36–0.44 (m, 1H, cPr-H),

0.53–0.61 (m, 1H, cPr-H), 0.77–0.90 (m, 1H, cPr-H), 0.99

(d, JZ6.9 Hz, 3H, CH₃), 1.30 (dd, JZ12.7, 3.6 Hz, 1H, 4-

or 6-H), 1.43 [s, 9H, C(CH₃)₃], 1.85–1.94 (m, 2H, cPr-H, 4-

or 6-H), 2.24 (br s, 4H, CH₂NCH₂), 2.35–2.58 (m, 2H, 4- or

6-H), 2.72–2.89 (m, 2H, 5-H, 1-H), 3.58 (t, JZ4.3 Hz, 4H,

CH₂OCH₂), 5.92–5.97 (m, 2H, OCH₂O), 6.48 (dd, JZ8.1,

1.0 Hz, 1H, Ph), 6.54 (d, JZ1.5 Hz, 1H, Ph), 6.76 (d, JZ

8.0 Hz, 1H, Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ

13.14 (K, cPr-C), 14.17 (K, cPr-C), 18.76 (C, CH₃), 19.03

(C_quat, cPr-C), 27.97 [C, C(CH₃)₃], 36.55 (K, C-4 or -6),

37.67 (K, C-4 or -6), 40.51 (C, C-5), 51.59 (K,

CH₂NCH₂), 61.18 (C, C-1), 67.12 (K, CH₂OCH₂), 79.98

[C_quat, C(CH₃)₃], 100.74 (K, OCH₂O), 107.98 (C, Ph-C),

108.80 (C, Ph-C), 121.14 (C, Ph-C), 136.07 (C_quat, 2!

Ph-C), 138.06 (C_quat, Ph-C), 145.62 (C_quat), 147.24 (C_quat),

174.67 (C_quat, C]O); MS (70 eV, EI), m/z (%): 441 (29)

[M^C], 426 (14) [M^CKCH₃], 298 (100), 253 (17), 131 (14),

114 (42), 100 (13), 57 (22), 41 (5); elemental analysis calcd

(%) for C₂₆H₃₅NO₅(441.6): C 70.72, H 7.99; found: C

70.55, H 7.72.

0.29–0.61 (m, 4H, cPr-H), 1.37 (dd, JZ2.9, 13.1 Hz, 1H, 4-

or 6-H), 1.46 [s, 9H, C(CH₃)₃], 2.09 (t, JZ12.2 Hz, 1H, 4-

or 6-H), 2.47 (dd, JZ3.7, 7.9 Hz, 2H, 4- or 6-H), 2.71–2.86

(m, 1H, 5-H), 4.94 (d, JZ1.8 Hz, 1H, vinyl), 5.42 (d, JZ

1.8 Hz, 1H, vinyl), 5.65 (t, JZ3.8 Hz, 1H, 7-H), 7.23–7.32

(m, 3H, Ph), 7.37–7.41 (m, 2H, Ph); ¹³C NMR (62.9 MHz,

CDCl₃, DEPT): dZ12.80 (K, cPr-C), 13.69 (K, cPr-C),

19.44 (C_quat, cPr-C), 28.07 [C, C(CH₃)₃], 28.47 (K, C-4 or

-6), 37.29 (K, C-4 or -6), 40.37 (C, C-5), 79.97 [C_quat

,

C(CH₃)₃], 114.22 (K, vinyl), 124.82 (C, C-7), 126.04 (C,

Ph-C), 127.48 (C, Ph-C), 128.22 (C, Ph-C), 140.16 (C_quat),

142.22 (C_quat), 147.56 (C_quat), 174.88 (C_quat, C]O); MS

(70 eV, EI) m/z (%): 310 (3) [M^C], 254 (60), 209 (41), 181

(30), 167 (39), 115 (19), 103 (32), 91 (46), 77 (27), 57 (100),

41 (52).

4.3.16. tert-Butyl 7-(benzo[1,3]dioxol-5-yl)-8-(1-morpho-

lin-4-ylethyl)spiro[2.5]oct-7-ene-5-carboxylate (40a).

According to GP-B, Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-

furylphosphine (46.4 mg, 200 mmol), K₂CO₃(556 mg,

4.00 mmol), Et₄NCl (332 mg, 2.00 mmol), morpholine

(12a, 261 mg, 3.00 mmol), 5-(1-iodovinyl)benzo[1,3]-

dioxole (32, 548.1 mg, 2.00 mmol) and bicyclopropylidene

(1, 320 mg, 4.00 mmol) were stirred in anhydrous MeCN

(2 mL), at 80 8C for 3 h. After cooling the mixture to room

temperature, tert-butyl acrylate (15, 512 mg, 4.00 mmol)

was added, and then the mixture was heated with stirring at

80 8C for an additional 48 h. After work-up and drying

(MgSO₄), the solvent was removed in a rotatory evaporator.

The residue was subjected to column chromatography on

silica gel (100 g, 3!30 cm, light petroleum/ethyl acetate,

4:1) to yield 40a (386 mg, 44%, yellowish oil) as a mixture

of two diastereomers (ratio 1.2:1 according to NMR).

4.3.17. 6⁰-(1-Morpholin-4-ylethyl)-2⁰-phenyl-8⁰-(thio-

phen-2-yl)spiro[cyclopropane-1,5⁰(8⁰H)-[1,2,4]triazolo-

[1,2-a]pyridazine]-1⁰,3⁰-dione (41a). According to GP-A,

Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), Et₃N (202 mg, 2.00 mmol), morpho-

line (12a, 174 mg, 2.00 mmol), 2-(2-iodovinyl)thiophene

(33, 472 mg, 2.00 mmol) and bicyclopropylidene (1,

320 mg, 4.00 mmol) were stirred in anhydrous DMF

(1 mL) at 80 8C for 3 h. N-Phenyltriazolinedione (37,

700 mg, 4.00 mmol) was added to the ice-cooled mixture,

and then it was stirred again at room temperature for 48 h.

After work-up and drying (MgSO₄), the solvent was

removed in a rotatory evaporator. The residue was subjected

to column chromatography on silica gel (100 g, 3!30 cm,

light petroleum/ethyl acetate, 3:1) to yield 41a (232 mg,

26%, colorless solid) as a mixture of two diastereomers

(ratio 1:1 according to NMR).

Major diastereomer. R_fZ0.44 (light petroleum/ethyl acet-

ate 4:1); IR (KBr): n~Z2976, 2952, 2806, 1726, 1606, 1485,

1452, 1433, 1367, 1266, 1238, 1211, 1152, 1121, 1039, 939,

1

810 cm^K1; H NMR (250 MHz, CDCl₃): dZ0.2–0.34 (m,

1H, cPr-H), 0.57–0.65 (m, 1H, cPr-H), 0.78–0.95 (m, 1H,

cPr-H), 1.05 (dd, JZ12.7, 3.3 Hz, 1H, 4- or 6-H), 1.11 (d,

JZ7.0 Hz, 3H, CH₃), 1.41 [s, 9H, C(CH₃)₃], 1.62–1.69 (m,

1H, cPr-H), 2.03 (td, JZ12.0, 2.0 Hz, 1H, 4- or 6-H), 2.22

(br s, 4H, CH₂NCH₂), 2.34–2.55 (m, 2H, 4- or 6-H), 2.77–

2.89 (m, 2H, 5-H, 1-H), 3.57 (br s, 4H, CH₂OCH₂), 5.94–

5.96 (m, 2H, OCH₂O), 6.47 (dd, JZ7.8, 1.7 Hz, 1H, Ph),

6.53 (d, JZ1.6 Hz, 1H, Ph), 6.76 (d, JZ7.6 Hz, 1H, Ph);

¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ13.69 (K,

Diastereomer I. Mp 160 8C, R_fZ0.15 (light petroleum/ethyl

acetate 3:1); IR (KBr): n~Z3102, 3088, 2963, 2859, 2815,

1769, 1715, 1502, 1409, 1310, 1165, 1116, 767, 731 cm^K1

;

¹H NMR (250 MHz, CDCl₃): dZ1.14–1.21 (m, 1H, cPr-H),

1.19 (d, JZ6.8 Hz, 3H, CH₃), 1.59–1.74 (m, 2H, cPr-H),

2.46–2.64 (m, 6H, cPr-H, CH₂NCH₂, 1-H), 3.70 (t, JZ

4.6 Hz, 4H, CH₂OCH₂), 5.88 (d, JZ5.2 Hz, 1H, 8⁰-H), 6.17

(d, JZ5.2 Hz, 1H, 7⁰-H), 6.99 (dd, JZ3.6, 5.1 Hz, 1H,

thiophene), 7.21 (d, JZ3.8 Hz, 1H, thiophene), 7.27–7.42

(m, 6H, Ph, thiophene); ¹³C NMR (62.9 MHz, CDCl₃,

DEPT): dZ10.36 (K, cPr-C), 11.32 (K, cPr-C), 16.08 (C,

CH₃), 41.85 (C_quat, cPr-C), 50.14 (K, CH₂NCH₂), 53.57

(K, C-8⁰), 57.28 (C, C-1), 67.07 (K, CH₂OCH₂), 121.17

(C, C-7⁰), 125.45 (C, Ph), 126.38 (C, thiophene), 126.93

(C, thiophene), 127.87 (C, Ph or thiophene), 128.01 (C,

Ph or thiophene), 128.87 (C, Ph), 130.76 (C_quat), 138.93

cPr-C), 14.78 (K, cPr-C), 17.96 (C, CH₃), 19.04 (C_quat

,

cPr-C), 27.93 [C, C(CH₃)₃], 36.81 (K, C-4 or -6), 40.18

(K, C-4 or -6), 40.84 (C, C-5), 51.80 (K, CH₂NCH₂),

61.77 (C, C-1), 66.89 (K, CH₂OCH₂), 79.86 [C_quat

C(CH₃)₃], 100.72 (K, OCH₂O), 108.05 (C, Ph-C),

108.59 (C, Ph-C), 120.94 (C, Ph-C), 135.79 (C_quat

,

Ph-C), 136.05 (C_quat, Ph-C), 137.70 (C_quat, Ph-C), 145.69

(C_quat), 147.27 (C_quat), 174.64 (C_quat, C]O); MS (70 eV,

EI), m/z (%): 441 (12) [M^C], 426 (5) [M^CKCH₃], 298 (56),

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11368

(C_quat), 139.48 (C_quat), 149.94 (C_quat, C]O), 152.08 (C_quat

,

58.66 (C, cychex), 66.79 (K, CH₂OCH₂), 125.46 (C,

Ph-C), 127.66 (C, Ph-C), 127.85 (C_quat), 128.62 (C, Ph-C),

131.36 (C_quat), 133.92 (C_quat), 149.51 (C_quat, C]O), 151.98

(C_quat, C]O); MS (70 eV, EI), m/z (%): 422 (54) [M^C], 393

(16), 337 (22), 336 (100), 217 (16), 114 (14), 100 (42);

elemental analysis calcd (%) for C₂₄H₃₀N₄O₃(422.5): C

68.22, H 7.16; found: C 67.91, H 7.07.

C]O); MS (70 eV, EI), m/z (%): 450 (27) [M^C], 364 (100)

[M^CKmorpholine], 348 (8), 173 (17), 114 (30), 100 (90);

elemental analysis calcd (%) for C₂₄H₂₆N₄O₃S (450.6): C

63.98, H 5.82, N 12.43; found: C 63.76, H 5.71, N 12.68.

Diastereomer II. Mp 122 8C, R_fZ0.15 (light petroleum/

ethyl acetate 3:1); IR (KBr): n~Z3108, 3062, 2963, 2858,

1

2796, 1775, 1714, 1502, 1411, 1112, 766, 713 cm^K1; H

Minor diastereomer. R_fZ0.108 (light petroleum/ethyl

acetate 3:1); IR (KBr): n~Z3071, 2932, 2853, 1772, 1714,

1546, 1504, 1413, 1295, 1264, 1130, 1117, 1029, 985,

766 cm^K1;¹H NMR (300 MHz, CDCl₃): dZ0.60–0.67 (m,

1H, cPr-H), 0.70–0.77 (m, 1H, cPr-H), 0.82–0.89 (m, 1H,

cPr-H), 0.99–1.06 (m, 1H, cPr-H), 1.13–1.29 (m, 1H,

cychex), 1.36 (d, JZ6.3 Hz, 3H, CH₃), 1.46 (td, JZ3.2,

12.0 Hz, 1H, cychex), 1.57 (tt, JZ3.5, 13.0 Hz, 1H,

cychex), 1.71 (td, JZ3.5, 13.7 Hz, 1H, cychex), 1.82–1.86

(m, 2H, cychex), 2.56 (t, JZ4.6 Hz, 4H, CH₂NCH₂), 2.98–

3.03 (m, 1H, cychex), 3.25 (d, JZ13.60 Hz, 1H, cychex),

3.58 (q, JZ3.9 Hz, 4H, CH₂OCH₂), 4.17 (dd, JZ4.1,

11.2 Hz, cychex), 4.67 (q, JZ6.3 Hz, 1H, 1-H), 7.29–7.34

(m, 1H, Ph), 7.46–7.51 (m, 4H, Ph); ¹³C NMR

(75.478 MHz, CDCl₃, DEPT): dZ11.25 (K, cPr-C),

13.51 (K, cPr-C), 19.87 (C, CH₃), 23.83 (K, cychex),

27.25 (K, cychex), 30.26 (K, cychex), 34.44 (K, cychex),

44.07 (C_quat, cPr-C), 49.66 (K, CH₂NCH₂), 51.37 (C, C-1),

58.39 (C, cychex), 67.30 (K, CH₂OCH₂), 125.37 (C,

Ph-C), 126.99 (C_quat), 127.80 (C, Ph-C), 128.95 (C, Ph-C),

131.33 (C_quat), 136.57 (C_quat), 149.67 (C_quat, C]O), 152.78

(C_quat, C]O); MS (70 eV, EI), m/z (%): 422 (79) [M^C], 407

(11) [M^CKCH₃], 336 (55), 261 (18), 247 (30), 246 (100),

232 (27), 218 (24), 178 (20), 119 (39), 91 (42), 77 (20), 41

(22) for C₂₄H₃₀N₄O₃(422.53); HRMS(EI):calcd 422.2318

(correct HRMS).

NMR (250 MHz, CDCl₃): dZ1.17–1.44 (m, 3H, cPr-H),

1.25 (d, JZ6.4 Hz, 3H, CH₃), 2.32 (q, JZ6.4 Hz, 1H, 1-H),

2.47 (br s, 4H, cPr-H, CH₂NCH₂), 2.81–2.90 (m, 1H, cPr-

H), 3.69 (t, JZ4.5 Hz, 4H, CH₂OCH₂), 5.89 (d, JZ5.0 Hz,

1H, 8⁰-H), 6.29 (d, JZ4.86 Hz, 1H, 7⁰-H), 6.98 (dd, JZ3.5,

5.1 Hz, 1H, thiophene), 7.19 (d, JZ3.4 Hz, 1H, thiophene),

7.27–7.42 (m, 6H, Ph, thiophene); ¹³C NMR (62.9 MHz,

CDCl₃, DEPT): dZ9.37 (K, cPr-C), 11.56 (K, cPr-C),

18.22 (C, CH₃), 41.92 (C_quat, cPr-C), 50.76 (K,

CH₂NCH₂), 53.19 (K, C-8⁰), 58.27 (C, C-1), 67.04 (K,

CH₂OCH₂), 120.19 (C, C-7⁰), 125.47 (C, Ph), 126.49 (C,

Ph or thiophene), 126.83 (C, thiophene), 127.76 (C,

thiophene), 128.06 (C, Ph or thiophene), 128.91 (C, Ph),

130.75 (C_quat), 138.75 (C_quat), 139.31 (C_quat), 150.45 (C_quat

,

C]O), 152.15 (C_quat, C]O); MS (70 eV, EI), m/z (%): 450

(9) [M^C], 363 (32) [M^CKmorpholine-H], 348 (4), [M^CK

morpholine–H–CH₃], 173 (11), 114 (36), 100 (100);

elemental analysis calcd (%) for C₂₄H₂₆N₄O₃S(450.6): C

63.98, H 5.82; found: C 63.90, H 6.06.

4.3.18. 6⁰-[1-Morpholin-4-ylethyl]-2⁰-phenylspiro[cyclo-

propane-1,5⁰(10a’H)-5⁰,7⁰,8⁰,9⁰,10⁰,10a⁰-hexahydro-[1,2,

4]triazolo[1,2-a]cinnoline]-1,3-dione (42a). According to

GP-A, Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), Et₃N (202 mg, 2.00 mmol), morpho-

line (12a, 174 mg, 2.00 mmol), 1-iodo-cyclohexene (34,

416 mg, 2.00 mmol) and bicyclopropylidene (1, 320 mg,

4.00 mmol) were stirred in anhydrous DMF (1 mL), at

100 8C for 5 h. N-Phenyltriazolinedione (37, 700 mg,

4.00 mmol) was added to the ice-cooled mixture, and then

it was stirred again at room temperature for 48 h. After

work-up and drying (MgSO₄), the solvent was removed in a

rotatory evaporator. The residue was subjected to column

chromatography on silica gel (100 g, 3!30 cm, light

petroleum/ethyl acetate, 3:1) to yield 42a (280 mg, 33%,

colorless solid) as a mixture of two diastereomers (ratio

4.6:1 according to NMR).

4.3.19. 6⁰-[1-Morpholin-4-ylethyl]-9⁰-(N)-benzyl-2⁰-

phenylspiro[cyclopropane-1,5⁰(10a’H)-5⁰,7⁰,8⁰,9⁰,10⁰,

10a⁰-hexahydro[1,2,4]triazolo[1,2-a]cinnoline]-1,3-dione

(43a). According to GP-B, Pd(OAc)₂(22.4 mg, 100 mmol),

tri-2-furylphosphine (46.4 mg, 200 mmol), K₂CO₃(556 mg,

4.00 mmol), Et₄NCl (332 mg, 2.00 mmol), morpholine

(12a, 174 mg, 2.00 mmol), 1-benzyl-4-iodo-1,2,3,6-tetra-

hydropyridine (35, 600 mg, 2.00 mmol) and bicyclopropyl-

idene (1, 320 mg, 4.00 mmol) were stirred in anhydrous

MeCN (2 mL), at 80 8C for 3 h. N-Phenyltriazolinedione

(37, 700 mg, 4.00 mmol) was added to the ice-cooled

mixture, and then it was stirred at room temperature for an

additional 48 h. After work-up and drying (MgSO₄), the

solvent was removed in a rotatory evaporator. The residue

was subjected to column chromatography on silica gel

(100 g, 3!30 cm, light petroleum/ethyl acetate, 3:1) to

yield 43a (180 mg, 17%, colorless oil), R_fZ0.17 (light

petroleum/ethyl acetate 3:1); IR (ﬁlm): n~Z3028, 2956,

2850, 2798, 1770, 1713, 1503, 1456, 1412, 1361, 1265,

Major diastereomer. Mp 151 8C, R_fZ0.446 (light petro-

leum/ethyl acetate, 3:1); IR (KBr): n~Z3033, 2961, 2926,

2856, 1762, 1709, 1504, 1459, 1415, 1301, 1270, 1128,

1

1117, 1069, 1033, 866, 765 cm^K1; H NMR (300 MHz,

C₂D₂Cl₄, 100 8C): dZ1.22–1.36 (m, 1H, cPr-H), 1.28 (d,

JZ6.8 Hz, 3H, CH₃), 1.37–1.48 (m, 1H, cPr-H), 1.51–1.67

(m, 1H, cychex), 1.75 (dt, JZ3.6, 13.1 Hz, 1H, cychex),

1.88–2.00 (m, 5H, cPr-H, cychex), 2.06–2.14 (m, 1H,

cPr-H), 2.47–2.54 (m, 1H, 1-H), 2.49 (t, JZ4.4 Hz, 4H,

CH₂NCH₂), 2.65–2.71 (m, 1H, cychex), 3.71 (t, JZ4.7 Hz,

4H, CH₂OCH₂), 3.77 (br s, 1H, cychex), 4.23 (dd, JZ4.2,

10.8 Hz, 1H, cychex), 7.35–7.52 (m, 5H, Ph); ¹³C NMR

(75.5 MHz, C₂D₂Cl₄, 100 8C, DEPT): dZ10.03 (K, cPr-C),

10.48 (K, cPr-C), 18.04 (C, CH₃), 24.28 (K, cychex),

26.80 (K, cychex), 29.91 (K, cychex), 31.99 (K, cychex),

40.88 (C_quat, cPr-C), 51.88 (K, CH₂NCH₂), 57.68 (C, C-1),

1120, 1071, 1029, 936, 863, 736, 739 cm^K^{1 1}H NMR

;

(300 MHz, C₂D₂Cl₄, 100 8C): dZ1.24–1.33 (m, 1H, cPr-H),

1.29 (d, JZ6.8 Hz, 3H, CH₃), 1.36–1.43 (m, 1H, cPr-H),

1.79–1.87 (m, 1H, cPr-H), 2.02–2.15 (m, 2H, tetrahydro-

pyridine), 2.24 (t, JZ10.3 Hz, 1H, tetrahydropyridine),

2.29–2.35 (m, 1H, cPr-H), 2.39–2.51 (m, 1H, 1-H), 2.47 (q,

JZ4.3 Hz, 4H, CH₂NCH₂), 2.94–2.99 (m, 1H, tetrahydro-

pyridine), 3.56–3.78 (AB system: d_AZ3.6, d_BZ3.8, J_ABZ

13.3 Hz, 2H, Bn), 3.56–3.78 (1H, tetrahydropyridine)*, 3.68

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11369

(t, JZ4.6 Hz, 4H, CH₂OCH₂), 3.98–4.02 (m, 1H, tetra-

hydropyridine), 4.47 (dd, JZ4.4, 9.9 Hz, 1H, tetrahydro-

pyridine), 7.28–7.48 (m, 10H, Ph); * The peak of this proton

sits under the peaks of the AB system, thus the spin

couplings of this proton could not be determined. This

proton correlates clearly with the carbon peak at 28.49 ppm

in the HMQC spectrum. ¹³C NMR (75.5 MHz, C₂D₂Cl₄,

100 8C, DEPT): dZ9.40 (K, cPr-C), 10.67 (K, cPr-C),

17.85 (C, CH₃), 28.49 (K, tetrahydropyridine), 40.74

(C_quat, cPr-C), 51.80 (K, CH₂NCH₂), 52.61 (K, tetrahy-

dropyridine), 57.06 (C, tetrahydropyridine), 57.32 (K,

tetrahydropyridine), 57.71 (C, C-1), 61.61 (K, Bn), 66.70

(K, CH₂OCH₂), 125.52 (C, Ph), 126.86 (C, Ph), 127.77

(C, Ph), 127.98 (C, Ph), 128.53 (C, Ph), 128.66 (C, Ph),

128.81 (C_quat), 130.99 (C_quat), 131.19 (C_quat), 137.72 (C_quat),

149.24 (C_quat, C]O), 152.27 (C_quat, C]O); MS (70 eV,

EI), m/z (%): 513 (34) [M^C], 427 (26) [M^CKmorpholinyl],

397 (9), 307 (6), 134 (46), 100 (46), 91 (100), 42 (14);

elemental analysis calcd (%) for C₃₀H₃₅N₅O₃(513.6): C

70.15, H 6.87; found: C 69.98, H 6.71.

NMR (250 MHz, CDCl₃): dZ1.24 (d, JZ6.3 Hz, 3H, CH₃),

1.31–1.39 (m, 2H, cPr-H), 1.43–1.51 (m, 1H, cPr-H), 2.36–

2.49 (m, 5H, CH₂NCH₂, 1-H), 2.74–2.82 (m, 1H, cPr-H),

3.69 (t, JZ4.4 Hz, 4H, CH₂OCH₂), 5.60 (d, JZ4.9 Hz, 1H,

8⁰-H), 6.15 (d, JZ5.0 Hz, 1H, 7⁰-H), 7.29–7.44 (m, 10H,

Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ9.61 (K,

cPr-C), 11.59 (K, cPr-C), 17.83 (C, CH₃), 41.97 (C_quat

,

cPr-C), 50.61 (K, CH₂NCH₂), 58.18 (C, C-1), 58.29 (K,

C-8⁰), 67.09 (K, CH₂OCH₂), 120.47 (C, C-7⁰), 125.43 (C,

Ph-C), 128.00 (C, Ph-C), 128.43 (C, Ph-C), 128.59 (C,

Ph-C), 128.72 (C, Ph-C), 128.89 (C, Ph-C), 130.81 (C_quat),

134.48 (C_quat), 138.44 (C_quat), 150.56 (C_quat, C]O), 151.60

(C_quat, C]O); MS (70 eV, EI), m/z (%): 444 (25) [M^C], 358

(80) [M^CKmorpholinyl], 357 (94), 167 (14), 119 (15), 114

(26), 100 (100), 91 (16); elemental analysis calcd (%) for

C₂₆H₂₈N₄O₃(444.5): C 70.25, H 6.35; found: C 70.43, H

6.07.

4.3.21. 6⁰-(1-Morpholin-4-ylethyl)-2⁰-phenylspiro[cyclo-

propane-1,5⁰(8⁰H)-[1,2,4]triazolo[1,2-a]pyridazine]-1⁰,

3⁰-dione (45a). According to GP-B, Pd(OAc)₂(22.4 mg,

100 mmol), tri-2-furylphosphine (46.4 mg, 200 mmol),

K₂CO₃(556 mg, 4.00 mmol), Et₄NCl (332 mg,

2.00 mmol), morpholine (12a, 174 mg, 2.00 mmol),

iodoethene (11, 308 mg, 2.00 mmol) and bicyclopropyl-

idene (1, 320 mg, 4.00 mmol) were stirred in anhydrous

MeCN (2 mL) at 80 8C for 2 h. N-Phenyltriazolinedione

(37, 700 mg, 4.00 mmol) was added to the ice-cooled

mixture, and then it was stirred at room temperature for an

additional 48 h. After work-up and drying (MgSO₄), the

solvent was removed in a rotatory evaporator. The residue

was subjected to column chromatography on silica gel

(100 g, 3!30 cm, CH₂Cl₂/ethyl acetate, 1:1) to yield 45a

(367.2 mg, 50%, colorless solid), mp 130 8C, R_fZ0.25

(CH₂Cl₂/ethyl acetate 1:1); IR (KBr): n~Z2962, 2953, 2852,

2813, 1771, 1709, 1699, 1504, 1421, 1313, 1268, 1142,

4.3.20. 6⁰-(1-Morpholin-4-ylethyl)-2⁰,8⁰-diphenylspiro-

[cyclopropane-1,5⁰(8⁰H)-[1,2,4]triazolo-[1,2-a]pyrida-

zine]-1⁰,3⁰-dione (44a). According to GP-A, Pd(OAc)₂

(22.4 mg, 100 mmol), tri-2-furylphosphine (46.4 mg,

200 mmol), Et₃N (202 mg, 2.00 mmol), morpholine (12a,

174 mg, 2.00 mmol), (E)-1-iodo-2-phenylethene (36,

460 mg, 2.00 mmol) and bicyclopropylidene (1, 320 mg,

4.00 mmol) were stirred in anhydrous DMF (1 mL), at 80 8C

for 2 h. N-phenyltriazolinedione (37, 700 mg, 4.00 mmol)

was added to the ice-cooled mixture and then it was stirred

at room temperature for an additional 48 h. After work-up

and drying (MgSO₄), the solvent was removed in a rotatory

evaporator. The residue was subjected to column chroma-

tography on silica gel (100 g, 3!30 cm, light petroleum/

ethyl acetate, 1:1) to yield 44a (310 mg, 35%, colorless

solid) as a mixture of two diastereomers (ratio 1.4:1

according to NMR).

1

1123, 916, 860, 767 cm^K1; H NMR (250 MHz, CDCl₃):

dZ1.17 (d, JZ6.5 Hz, 3H, CH₃), 1.18–1.26 (m, 1H, cPr-H),

1.34–1.43 (m, 1H, cPr-H), 1.69–1.78 (m, 1H, cPr-H), 2.31–

2.52 (m, 6H, cPr-H, CH₂NCH₂, 1-H), 3.68 (t, JZ4.6 Hz,

4H, CH₂OCH₂), 4.18–4.40 (m, 2H, 8⁰-H), 6.01 (t, JZ

6.6 Hz, 1H, 7⁰-H), 7.32–7.46 (m, 5H, Ph); ¹³C NMR

(62.9 MHz, CDCl₃, DEPT): dZ9.76 (K, cPr-C), 11.58 (K,

cPr-C), 15.91 (C, CH₃), 41.36 (C_quat, cPr-C), 44.28 (K,

C-8⁰), 49.94 (K, CH₂NCH₂) 58.20 (C, C-1), 66.93 (K,

CH₂OCH₂), 116.49 (C, C-7⁰), 125.29 (C, Ph), 127.92 (C,

Ph), 128.87 (C, Ph), 130.83 (C_quat), 138.72 (C_quat), 149.66

(C_quat, C]O), 152.62 (C_quat, C]O); MS (70 eV, EI), m/z

(%): 368 (20) [M^C], 281 (100) [M^CKmorpholine], 266 (6)

[M^CKmorpholine–CH₃], 178 (16), 114 (10), 100 (64);

elemental analysis calcd (%) for C₂₀H₂₄N₄O₃(368.4): C

65.20, H 6.57; found: C 64.90, H 6.25.

Major diastereomer. Mp 171 8C, R_fZ0.47 (light petroleum/

ethyl acetate 1:1); IR (KBr): n~Z3106, 3058, 3026, 2977,

2857, 2818, 1763, 1706, 1506, 1411, 1290, 1174, 1112,

1

768 cm^K1; H NMR (250 MHz, CDCl₃): dZ1.18 (d, JZ

6.7 Hz, 3H, CH₃), 1.21–1.31 (m, 1H, cPr-H), 1.55–1.65 (m,

1H, cPr-H), 1.90–2.00 (m, 1H, cPr-H), 2.32–2.65 (m, 6H,

cPr-H, CH₂NCH₂, 1-H), 3.66 (t, JZ4.6 Hz, 4H, CH₂OCH₂),

5.54 (d, JZ4.6 Hz, 1H, 8⁰-H), 5.99 (d, JZ4.7 Hz, 1H, 7⁰-H),

7.25–7.44 (m, 10H, Ph); ¹³C NMR (75.5 MHz, CDCl₃,

DEPT): dZ10.96 (K, cPr-C), 11.33 (K, cPr-C), 15.02 (C,

CH₃), 41.54 (C_quat, cPr-C), 49.86 (K, CH₂NCH₂), 57.92

(C, C-1), 58.98 (K, C-8⁰), 67.00 (K, CH₂OCH₂), 121.82

(C, C-7⁰), 125.39 (C, Ph-C), 127.90 (C, Ph-C), 127.98

(C, Ph-C), 128.57 (C, Ph-C), 128.64 (C, Ph-C), 128.82

(C, Ph-C), 130.85 (C_quat), 137.07 (C_quat), 137.80 (C_quat),

149.68 (C_quat, C]O), 151.83 (C_quat, C]O); MS (70 eV,

EI), m/z (%): 444 (11) [M^C], 358 (46) [M^CKmorpholinyl],

167 (12), 114 (26), 100 (100) 91 (14); elemental analysis

calcd (%) for C₂₆H₂₈N₄O₃(444.5): C 70.25, H 6.35; found:

C 70.54, H 6.26.

4.3.22. 6⁰-(1-Morpholin-4-ylethyl)-2⁰,7⁰-diphenylspiro-

[cyclopropane-1,5⁰(8⁰H)-[1,2,4]triazolo[1,2-a]pyrida-

zine]-1⁰,3⁰-dione (46a). According to GP-B, Pd(OAc)₂

(22.4 mg, 100 mmol), tri-2-furylphosphine (46.4 mg,

200 mmol), K₂CO₃(556 mg, 4.00 mmol), Et₄NCl (332 mg,

2.00 mmol), morpholine (12a, 261 mg, 3.00 mmol),

(1-iodovinyl)benzene (31, 460 mg, 2.00 mmol) and bicyclo-

propylidene (1, 320 mg, 4.00 mmol) were stirred in

anhydrous MeCN (2 mL) at 80 8C for 3 h. N-Phenyltriazo-

linedione (37, 700 mg, 4.00 mmol) was added to the

Minor diastereomer. Mp 170 8C, R_fZ0.47 (light petroleum/

ethyl acetate, 1:1); IR (KBr): n~Z3065, 2962, 2854, 2811,

1

1769, 1711, 1502, 1414, 1301, 1265, 1116, 765 cm^K1; H

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11370

ice-cooled mixture and then it was stirred at room

temperature for an additional 48 h. After work-up and

drying (MgSO₄), the solvent was removed in a rotatory

evaporator. The residue was subjected to column chroma-

tography on silica gel (100 g, 3!30 cm, light petroleum/

ethyl acetate, 3:1) to yield 46a (311 mg, 35%, colorless

solid), mp 70 8C, R_fZ0.30 (light petroleum/ethyl acetate

3:1); IR (KBr): n~Z3050, 2956, 2850, 2805, 1772, 1713,

CH₂NCH₂), 64.7 (C, C-3a), 67.3 (K, CH₂OCH₂), 126.2

(C, C-6), 126.5 (C, Ph-C), 126.9 (C, Ph-C), 128.2 (C,

Ph-C), 128.3 (C, Ph-C), 128.9 (C, Ph-C), 129.4 (C, Ph-C),

131.8 (C_quat), 139.7 (C_quat), 144.2 (C_quat), 175.3 (C_quat, C]

O), 176.9 (C_quat, C]O).

Minor diastereomer. ¹H NMR (250 MHz, CDCl₃): dZ

0.41–0.56 (m, 1H, cPr-H), 0.90–1.04 (m, 1H, cPr-H), 1.09

(d, JZ6.7 Hz, 3H, CH₃), 1.22–1.32 (m, 1H, cPr-H), 1.61–

1.71 (m, 1H, cPr-H), 2.29–2.51 (m, 4H, CH₂NCH₂), 2.45 (d,

JZ8.6 Hz, 1H, 3a-H), 2.78 (q, JZ6.7 Hz, 1H, 1⁰-H), 3.53–

3.70 (m, 5H, CH₂OCH₂, 7-H), 4.00–4.07 (m, 1H, 7a-H),

6.30 (d, JZ3.5 Hz, 1H, 6-H), 7.10–7.60 (m, 10H, Ph); ¹³C

NMR (62.9 MHz, CDCl₃, DEPT): dZ6.62 (K, cPr-C), 13.0

(K, cPr-C), 14.1 (C, CH₃), 21.5 (C_quat, C-4), 23.9 (C, C-7),

41.8 (C, C-7a), 48.2 (C, C-1⁰), 60.3 (K, CH₂NCH₂), 64.2

(C, C-3a), 67.0 (K, CH₂OCH₂), 126.0 (C, C-6), 126.5 (C,

Ph-C), 126.9 (C, Ph-C), 128.2 (C, Ph-C), 128.3 (C, Ph-C),

128.9(C, Ph-C),129.4(C, Ph-C),131.8(C_quat),139.5(C_quat),

143.7 (C_quat), 175.3 (C_quat, C]O), 176.4 (C_quat, C]O).

1

1598, 1503, 1407, 1265, 1143, 1119, 942, 863 cm^K1; H

NMR (250 MHz, CDCl₃): dZ1.25 (d, JZ7.0 Hz, 3H, CH₃),

1.29–1.37 (m, 1H, cPr-H), 1.53–1.62 (m, 1H, cPr-H), 2.14–

2.22 (m, 2H, cPr-H), 2.30 (br s, 4H, CH₂NCH₂), 3.08 (q, JZ

6.7 Hz, 1H, 1-H), 3.61 (t, JZ4.4 Hz, 4H, CH₂OCH₂), 4.50

(s, 2H, 8⁰-H), 7.10–7.14 (m, 2H, Ph), 7.33–7.42 (m, 4H, Ph),

7.45–7.50 (m, 4H, Ph); ¹³C NMR (75.5 MHz, CDCl₃,

DEPT): dZ11.77 (K, cPr-C), 13.69 (K, cPr-₀C), 17.51 (C,

CH₃), 38.24 (C_quat, cPr-C), 48.67 (K, C-8 ), 51.50 (K,

CH₂NCH₂), 59.79 (C, C-1), 66.77 (K, CH₂OCH₂), 125.33

(C, Ph-C), 127.63 (C, Ph-C), 127.89 (C, Ph-C), 128.56

(C, Ph-C), 128.88 (C, Ph-C), 131.22 (C_quat), 133.44

(C_quat), 136.70 (C_quat), 137.78 (C_quat), 150.39 (C_quat, C]O),

152.97 (C_quat, C]O); MS (70 eV, EI) m/z (%): 444 (22)

[M^C], 357 (52) [M^CKmorpholinyl], 254 (7), 167 (16), 114

(27), 100 (100); elemental analysis calcd (%) for

C₂₆H₂₈N₄O₃(444.5): C 70.25, H 6.35, N 12.60; found: C

69.98, H 6.52, N 12.42.

4.3.24. 5-(1⁰-(Morpholin-4⁰⁰-yl)ethyl)-2,6-diphenylspiro-

[cyclopropane-1⁰,4-(3a,4,7,7a-tetrahydroisoindole)]-1,3-

dione (48a). According to GP-A, Pd(OAc)₂(22.4 mg,

100 mmol), tri-2-furylphosphine (46.4 mg, 200 mmol), Et₃N

(202 mg, 2.00 mmol), morpholine (12a, 174 mg, 2.00 mmol),

(1-iodovinyl)benzene (31, 460 mg, 2.00 mmol) and bicyclo-

propylidene (1, 320 mg, 4.00 mmol) were stirred in

anhydrous DMF (1 mL) at 80 8C for 2 h. After cooling the

mixture to room temperature, 1-Phenyl-2,5-dihydropyrrole-

2,5-dione (19, 693 mg, 4.00 mmol) was added, and the

mixture stirred at 80 8C for 4 h. After work-up and drying

(MgSO₄), the solvent was removed in a rotatory evaporator.

The residue was subjected to column chromatography on

silica gel (100 g, 3!30 cm, light petroleum/ethyl acetate

3:1) to yield 48a (353 mg, 40%, colorless solid) as a mixture

of two diastereomers (ratio 1.18:1 according to NMR).

4.3.23. 5-(1⁰-(Morpholin-4⁰⁰-yl)ethyl)-2,7-diphenylspiro-

[cyclopropane-1⁰,4-(3a,4,7,7a-tetrahydroisoindole)]-1,3-

dione (47a). According to GP-A, Pd(OAc)₂(22.4 mg,

100 mmol), tri-2-furylphosphine (46.4 mg, 200 mmol), Et₃N

(202 mg, 2.00 mmol), morpholine (12a, 174 mg,

2.00 mmol), (E)-1-iodo-2-phenylethene (36, 460 mg,

2.00 mmol) and bicyclopropylidene (1, 320 mg,

4.00 mmol) were stirred in anhydrous DMF (1 mL) at

80 8C for 2 h. After cooling the mixture to room temperature

1-phenyl-2,5-dihydropyrrole-2,5-dione (19, 693 mg,

4.00 mmol) was added, and the mixture stirred at 80 8C

for 4 h. After work-up and drying (MgSO₄), the solvent was

removed in a rotatory evaporator. The residue was subjected

to column chromatography on silica gel (100 g, 3!30 cm,

light petroleum/ethyl acetate, 2:3) to yield 47a (370 mg,

42%, pale yellow solid) as a mixture of two diastereomers

(ratio 2:1 according to NMR). R_fZ0.51 (light petroleum/

ethyl acetate, 2:3); IR (KBr)*: n~Z3095 (C–H), 1723

(C]O), 1499, 1456, 1393, 1376 (CH₃), 1314, 1163, 1149,

1123, 1110, 1076, 1057, 1036, 838 cm^K1; MS (70 eV, EI)*,

m/z (%): 442 (14) [M^C], 427 (26) [M^CKCH₃], 173 (63), 88

(14) [morpholinyl^CCH], 70 (24), 61 (38), 43 (100); HRMS

(EI)*: calcd for C₂₈H₃₀N₂O₃(442.6): 442.2256, correct

HRMS. *IR, low and high resolution mass measurements

were carried out for the mixture of diastereomers.

Major diastereomer. Mp 165 8C, R_fZ0.18 (light petroleum/

ethyl acetate 3:1); IR (KBr): n~Z2969, 2847, 2802, 1777,

1

1713, 1597, 1493, 1388, 1185, 1115, 862 cm^K1; H NMR

(250 MHz, CDCl₃): dZ0.41–0.49 (m, 1H, cPr-H), 0.78–

0.86 (m, 1H, cPr-H), 1.15 (d, JZ6.8 Hz, 3H, CH₃), 1.21–

1.28 (m, 1H, cPr-H), 2.17 (br s, 4H, CH₂NCH₂), 2.31 (d, JZ

9.2 Hz, 1H, 3a-H), 2.41–2.49 (m, 1H, cPr-H), 2.95–2.98 (m,

2H, 7-H), 3.08 (q, JZ7.0 Hz, 1H, 1⁰-H), 3.42–3.49 (m, 1H,

7a-H), 3.55 (t, JZ4.45 Hz, 4H, CH₂OCH₂), 6.94–6.97 (m,

2H, Ph), 7.22–7.52 (m, 8H, Ph); ¹³C NMR (62.9 MHz,

CDCl₃, DEPT): dZ8.44 (K, cPr-C), 13.47 (K, cPr-C),

16.75 (C, CH₃), 21.33 (C_quat, cPr-C), 31.72 (K, C-7), 42.07

(C, C-7a), 51.11 (C, C-3a), 51.42 (K, CH₂NCH₂), 59.89

(C, C-1⁰), 67.01 (K, CH₂OCH₂), 126.11 (C, Ph), 126.66

(C, Ph), 127.58 (C, Ph), 128.26 (C, Ph), 128.43 (C, Ph),

129.15 (C, Ph), 131.99 (C_quat), 138.10 (C_quat), 139.28

Major diastereomer. ¹H NMR (250 MHz, CDCl₃): dZ

0.41–0.56 (m, 1H, cPr-H), 0.90–1.04 (m, 1H, cPr-H), 1.19

(d, JZ6.6 Hz, 3H, CH₃), 1.22–1.32 (m, 1H, cPr-H), 1.61–

1.71 (m, 1H, cPr-H), 2.29–2.51 (m, 4H, CH₂NCH₂), 2.46

(d, JZ8.6 Hz, 1H, 3a-H), 3.03 (q, JZ6.9 Hz, 1H, 1⁰-H),

3.53–3.70 (m, 5H, CH₂NCH₂, 7-H), 4.00–4.07 (m, 1H,

7a-H), 6.30 (d, JZ3.5 Hz, 1H, 6-H), 7.10–7.60 (m, 10H,

Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ7.56 (K,

cPr-C), 11.6 (C, CH₃), 13.7 (K, cPr-C), 21.5 (C_quat, C-4),

23.9 (C, C-7), 41.9 (C, C-7a), 50.6 (C, C-1⁰), 60.7 (K,

(C_quat), 141.69 (C_quat), 177.43 (C_quat, C]O), 178.44 (C_quat

,

C]O); MS (70 eV, EI), m/z (%): 442 (35) [M^C], 427 (33)

[M^CKCH₃], 355 (20) [M^CKmorpholinyl–H], 209 (14),

165 (15), 114 (100), 88 (10); elemental analysis calcd

(%) for C₂₈H₃₀N₂O₃(442.6): C 75.99, H 6.83; found: C

75.70, H 7.03.

Minor diastereomer. Mp 168 8C, R_fZ0.22 (light petroleum/

ethyl acetate 3:1); IR (KBr): n~Z3077, 3051, 2965, 2852,

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11371

2791, 1779, 1709, 1596, 1492, 1390, 1181, 1151, 1120,

143.9 (C_quat, C-5), 174.9 (C_quat, C]O), 176.4 (C_quat, C]O)

.

1

1113, 861 cm^K1; H NMR (300 MHz, CDCl₃): dZ0.41–

0.49 (m, 2H, cPr-H), 1.08 (d, JZ7.4 Hz, 3H, CH₃), 1.21–

1.29 (m, 1H, cPr-H), 1.61 (q, JZ7.1 Hz, 1H, cPr-H), 2.12

(br s, 4H, CH₂NCH₂), 2.53 (d, JZ9.2 Hz, 1H, 3a-H), 2.83–

2.99 (m, 2H, 7-H) 3.05 (q, JZ7.0 Hz, 1H, 1⁰-H), 3.28–3.46

(m, 5H, CH₂OCH₂, 7a-H), 7.05–7.07 (m, 2H, Ph), 7.24–

7.49 (m, 8H, Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ

9.28 (K, cPr-C), 12.94 (K, cPr-C), 17.53 (C, CH₃), 21.10

(C_quat, cPr-C), 32.11 (K, C-7), 42.40 (C, C-7a), 49.71 (C,

C-3a), 51.45 (K, CH₂NCH₂), 60.62 (C, C-1⁰), 66.84 (K,

CH₂OCH₂), 126.07 (C, Ph-C), 126.59 (C, Ph-C), 127.75

(C, Ph-C), 128.17 (C, Ph-C), 128.46 (C, Ph-C), 129.07

(C, Ph-C), 131.82 (C_quat), 138.98 (C_quat), 139.27 (C_quat),

141.98 (C_quat), 177.60 (C_quat, C]O), 178.57 (C_quat, C]O);

MS (70 eV, EI), m/z (%): 442 (34) [M^C], 427 (66) [M^CK

CH₃], 355 (30) [M^CKmorpholinyl–H], 208 (16), 165 (15),

114 (100), 88 (16); elemental analysis calcd (%) for

C₂₈H₃₀N₂O₃(442.6): C 75.99, H 6.83; found: C 75.70, H

6.90.

Minor diastereomer. ¹H NMR (250 MHz, CDCl₃): dZ

0.43–0.61 (m, 1H, cPr-H), 0.91–1.05 (m, 1H, cPr-H), 1.18

(d, JZ6.6 Hz, 3H, CH₃), 1.23–1.34 (m, 1H, cPr-H), 1.62–

1.75 (m, 1H, cPr-H), 2.25–2.56 (m, 5H, CH₂NCH₂, 3a-H),

2.79 (q, JZ6.6 Hz, 1H, 1⁰-H), 3.47–3.78 (m, 5H,

CH₂NCH₂, 7-H), 4.01–4.11 (m, 1H, 7a-H), 6.27–6.37 (m,

1H, 6-H), 7.24–7.49 (m, 7H, Ar), 7.67 (d, JZ8.4 Hz, 2H,

Ar); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ7.62 (K,

cPr-C), 13.7 (K, cPr-C), 16.0 (C, CH₃), 21.4 (C_quat, C-4),

41.6 (C, C-7a), 48.3 (C, C-7), 50.8 (C, C-1⁰), 60.3 (K,

CH₂NCH₂), 64.7 (C, C-3a), 67.0 (K, CH₂OCH₂), 125.9

(C, Ar-C), 126.0 (C, Ar-C), 127.1 (C, Ar-C), 127.5 (C_quat

,

1

q, J(C,F)Z273 Hz, CF₃), 128.2 (C, 3!Ar-C), 128.8 (C,

Ar-C), 129.3 (C, 2!Ar-C), 130.1 (C_quat, q, ²J(C,F)Z

33 Hz, C-4⁰⁰⁰), 134.7 (C_quat), 139.2 (C_quat), 144.3 (C_quat

C-5), 175.1 (C_quat, C]O), 175.9 (C_quat, C]O).

,

4.3.26. Dimethyl 8-(1-morpholin-4-ylethyl)spiro[2.5]

octa-4,7-diene-4,5-dicarboxylate (50a). According to

GP-B, Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), K₂CO₃(556 mg, 4.00 mmol), Et₄NCl

(332 mg, 2.00 mmol), morpholine (12a, 174 mg,

2.00 mmol), iodoethene (11, 308 mg, 2.00 mmol) and

bicyclopropylidene (1, 320 mg, 4.00 mmol) were stirred in

anhydrous MeCN (2 mL) at 80 8C for 2 h. After cooling the

mixture to room temperature dimethyl acetylenedicarb-

oxylate (38, 568 mg, 4.00 mmol) was added, and then the

mixture was heated again with stirring at 80 8C for 48 h.

After work-up and drying (MgSO₄), the solvent was

removed in a rotatory evaporator. The residue was subjected

to column chromatography on silica gel (100 g, 3!30 cm,

light petroleum/ethyl acetate, 1:1) to yield 50a (200 mg,

30%, yellowish oil). R_fZ0.5 (light petroleum/ethyl acetate,

1:1), IR (ﬁlm): n~Z3056, 2953, 2895, 2857, 2824, 1733,

1630, 1587, 1436, 1371, 1266, 1162, 1118, 1033, 737,

704 cm^K1; ¹H NMR (250 MHz, CDCl₃): dZ1.00–1.15 (m,

3H, cPr-H), 1.06 (d, JZ6.7 Hz, 3H, CH₃), 1.25–1.35 (m,

1H, cPr-H), 2.22 (q, JZ6.5 Hz, 1H, 1-H), 2.35–2.50 (m, 4H,

CH₂NCH₂), 3.15 (d, JZ3.6 Hz, 2H, 6-H), 3.65 (t, JZ

4.5 Hz, 4H, CH₂OCH₂), 3.72 (s, 3H, OCH₃), 3.78 (s, 3H,

OCH₃), 5.85 (t, JZ3.7 Hz, 1H, 7-H); ¹³C NMR (62.9 MHz,

CDCl₃, DEPT): dZ13.46 (K, cPr-C), 14.15 (K, cPr-C),

17.14 (C, CH₃), 22.21 (C_quat, cPr-C), 26.51 (K, C-6), 50.31

(K, CH₂NCH₂), 51.93 (C, OCH₃), 52.13 (C, OCH₃),

57.91 (C, C-1), 67.10 (K, CH₂OCH₂), 119.91 (C, C-7),

4.3.25. 5-[1⁰-(Morpholine-4⁰⁰-yl)ethyl]-2-(4⁰⁰⁰-triﬂuoro-

methylphenyl)spiro[cyclopropane-1⁰,4-(7-phenyl-3a,4,7,

7a-tetrahydroisoindole)]-1,3-dione (49a). According to

GP-A, Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-furylphosphine

(46.4 mg, 200 mmol), Et₃N (202 mg, 2.00 mmol), morpho-

line (12a, 174 mg, 2.00 mmol), (E)-1-iodo-2-phenylethene

(36) (460 mg, 2.00 mmol), and bicyclopropylidene (1,

320 mg, 4.00 mmol) were stirred in anhydrous DMF

(1 mL), at 80 8C for 2 h. After cooling the mixture to

room temperature 1-(4⁰-triﬂuoromethylphenyl)-2,5 dihydro-

pyrrole-2,5-dione (21, 964 mg, 4.00 mmol) was added, and

the mixture stirred at 80 8C for 4 h. After work-up and

drying over MgSO₄, the solvent was removed in a rotatory

evaporator. The residue was subjected to column chroma-

tography on silica gel (100 g, 3!30 cm, light petroleum/

ethyl acetate, 2:3) to yield 49a (380 mg, 37%, pink crystals)

as a mixture of two diastereomers (ratio 2:1 according to

NMR). R_fZ0.60 (light petroleum/ethyl acetate 2:3); IR

(KBr)*: n~Z2966, 2853 (C–H), 1717 (C]O), 1376 (CH₃),

1326 (C–F), 1170 (C–F), 1117 (C–F), 1068, 1021 cm^K1MS

(70 eV, EI)*, m/z (%): 511/510 (12/55) [M^C], 497/496 (26/

100) [M^CCH–CH₃], 114 (95), 86 (26) [morpholinyl–H], 56

(11), 43 (29), 42 (10), 41 (13); HRMS (EI)*: calcd for

C₂₉H₂₉F₃N₂O₃(510.6): 510.2130, correct HRMS. *IR, low

and high resolution mass spectrometric measurements were

carried out for the mixture of diastereomers.

Major diastereomer. ¹H NMR (250 MHz, CDCl₃): dZ

0.43–0.61 (m, 1H, cPr-H), 0.91–1.05 (m, 1H, cPr-H), 1.08

(d, JZ6.6 Hz, 3H, CH₃), 1.23–1.34 (m, 1H, cPr-H), 1.62–

1.75 (m, 1H, cPr-H), 2.25–2.56 (m, 5H, CH₂NCH₂, 3a-H),

3.02 (q, JZ6.6 Hz, 1H, 1⁰-H), 3.47–3.78 (m, 5H,

CH₂OCH₂, 7-H), 4.01–4.11 (m, 1H, 7a-H), 6.27–6.37 (m,

1H, 6-H), 7.24–7.49 (m, 7H, Ar-H), 7.67 (d, JZ8.4 Hz, 2H,

Ar); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ6.73 (K,

cPr-C), 11.7 (C, CH₃), 13.0 (K, cPr-C), 23.8 (C_quat, C-4),

41.9 (C, C-7a), 48.3 (C, C-7), 50.7 (C, C-1⁰), 60.7 (K,

CH₂NCH₂), 64.7 (C, C-3a), 67.2 (K, CH₂OCH₂), 126.0

(C, Ar-C), 126.1 (C, Ar-C), 126.3 (C, C-6), 127.1 (C, Ar-

124.75 (C_quat), 136.82 (C_quat), 146.69 (C_quat), 165.78 (C_quat

,

C]O), 168.46 (C_quat, C]O); MS (70 eV, EI), m/z (%): 335

(41) [M^C], 334 (100) [M^CKH], 320 (12), 276 (16), 216

(13), 189 (17), 157 (11), 114 (26), 100 (34); elemental

analysis calcd (%) for C₁₈H₂₅NO₅(335.4): C 64.46, H 7.51;

found: C 64.19, H 7.76.

4.3.27. 2-Methyl-8-tert-butoxycarbonylspiro[cyclo-

propane-1⁰,10-(3-oxabicyclo[4.4.0]dec-1(6)-ene)] (55).

According to GP-B, Pd(OAc)₂(22.4 mg, 100 mmol), tri-2-

furylphosphine (46.4 mg, 200 mmol), K₂CO₃(556 mg,

4.00 mmol), Et₄NCl (332 mg, 2.00 mmol), 3-iodobut-3-en-

1-ol (53, 396 mg, 2.00 mmol) and bicyclopropylidene (1,

320 mg, 4.00 mmol) were stirred in anhydrous MeCN

(4 mL) at 80 8C for 24 h. After cooling the mixture to

1

C), 127.5 (C_quat, q, J(C,F)Z273 Hz, CF₃), 128.2 (C, 3!

Ar-C), 128.8 (C, Ar-C), 129.3 (C, 2!Ar-C), 130.1 (C_quart

,

2

q, J(C,F)Z33 Hz, C-4⁰⁰⁰), 134.7 (C_quat), 139.4 (C_quat),

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11372

room temperature, tert-butyl acrylate (15, 512 mg,

4.00 mmol) was added, and then the mixture was heated

with stirring at 80 8C for an additional 48 h. After work-up

and drying (MgSO₄), the solvent was removed in a rotatory

evaporator. The residue was subjected to column chroma-

tography on silica gel (100 g, 3!30 cm, light petroleum/

ethyl acetate, 4:1) to yield 55 (140 mg, 25%, yellowish oil)

as a mixture of two diastereomers (ratio 1.3:1 according to

NMR).

(d, JZ8.3 Hz, 2H, Ph); ¹³C NMR (62.9 MHz, CDCl₃,

DEPT): dZ11.91 (K, cPr-C), 13.17 (K, cPr-C), 18.75

(C_quat, cPr-C), 20.21 (C, CH₃), 21.10 (C, CH₃), 28.01 [C,

C(CH₃)₃], 28.25 (K), 33.09 (K), 37.42 (K), 38.15 (K),

40.47 (C), 46.93 (C), 79.52 [C_quat, C(CH₃)₃], 125.59

(C_quat), 127.45 (C, Ph-C), 129.42 (C, Ph-C), 132.62

(C_quat), 139.07 (C_quat), 142.67 (C_quat), 174.13 (C_quat, C]O);

MS (70 eV, EI), m/z (%): 431 (4) [M^C], 416 (4) [M^CK

CH₃], 375 (6), 361 (17), 360 (100), 220 (26), 204 (10), 174

(18), 133 (11), 105 (15), 91 (66), 57 (52), 41 (24); elemental

analysis calcd (%) for C₂₄H₃₃NO₄S (431.6): C 66.79, H

7.71; found: C 66.68, H 7.50. 57: R_fZ0.31 (light petroleum/

ethyl acetate 4:1); IR (ﬁlm): n~Z3275 (N–H), 3080, 3003,

2976, 2924, 2872, 1728 (C]O), 1599, 1457, 1421, 1392,

Major and minor diastereomers*. R_fZ0.56 (light petro-

leum/ethyl acetate, 4:1); IR (ﬁlm): n~Z3081, 2977, 2932,

1726, 1452, 1392, 1367, 1318, 1259, 1153, 1107, 1036, 984,

850 cm^K1; ¹H NMR (250 MHz, CDCl₃): dZ0.34–0.72 (m,

6H, cPr-H), 0.76–0.89 (m, 2H, cPr-H), 1.11 (d, JZ6.5 Hz,

3H, CH₃), 1.15–1.23 (m, 2H), 1.28 (d, JZ6.4 Hz, 3H, CH₃),

1.44 [s, 18H, 2!C(CH₃)₃], 1.69–2.27 (m, 10H), 2.68–2.82

(m, 2H), 3.58–3.78 (m, 3H), 3.80–3.99 (m, 3H); ¹³C NMR

(62.9 MHz, CDCl₃, DEPT): dZ10.23 (K, cPr-C), 11.87

(K, cPr-C), 13.08 (K, cPr-C), 13.43 (K, cPr-C), 18.37

(C_quat, cPr-C), 19.03 (C_quat, cPr-C), 19.80 (C, CH₃), 20.58

(C, CH₃), 28.02 [C, 2!C(CH₃)₃], 29.09 (K), 30.08 (K),

32.69 (K), 33.54 (K), 38.06 (K), 39.32 (K), 40.13 (C),

40.43 (C), 57.45 (K), 54.49 (K), 66.13 (C), 68.77 (C),

79.99 [C_quat, 2!C(CH₃)₃], 124.40 (C_quat), 127.22 (C_quat),

132.29 (C_quat), 133.58 (C_quat), 174.68 (C_quat, C]O), 174.79

(C_quat, C]O); MS (DCI), m/z (%): 296 (100) [MCNH^C₄],

279 (2) [MCH^C], 240 (73), 232 (20); elemental analysis

calcd (%) for C₁₇H₂₆O₃(278.4): C 73.35, H 9.41; found: C

73.59, H 9.41. *Proton and carbon chemical shifts are given

1367, 1337, 1257, 1167, 1095, 985, 903, 847, 814, 667 cm^K1

;

¹H NMR (300 MHz, CDCl₃): dZ0.20–0.28 (m, 1H, cPr-H),

0.37–0.44 (m, 2H, cPr-H), 0.46–0.57 (m, 1H, cPr-H), 1.14–

1.20 (m, 1H), 1.35 [s, 9H, C(CH₃)₃], 1.80 (t, JZ12.1 Hz,

1H), 2.02–2.09 (m, 2H), 2.11–2.18 (m, 2H), 2.34 (s, 3H,

CH₃), 2.48–2.58 (m, 1H, 5-H), 2.77–2.99 (m, 2H), 4.27 (t,

JZ5.9 Hz, 1H), 4.53 (d, JZ2.7 Hz, 1H, vinyl), 4.66 (br s,

1H, vinyl), 5.00–5.03 (m, 1H, 7-H), 7.23 (d, JZ8.0 Hz, 2H,

Ph), 7.68 (d, JZ8.0 Hz, 2H, Ph); ¹³C NMR (62.9 MHz,

CDCl₃, DEPT): dZ11.71 (K, cPr-C), 13.12 (K, cPr-C),

18.43 (C_quat, cPr-C), 21.26 (C, CH₃), 27.81 (K)*, 27.81 [C

, C(CH₃)₃], 36.50 (K), 36.81 (K), 39.94 (C, C-5), 40.82

(K), 79.78 [C_quat, C(CH₃)₃], 115.14 (K, vinyl), 122.46 (C,

C-7), 126.91 (C, Ph-C), 129.44 (C, Ph-C), 136.56 (C_quat),

141.52 (C_quat), 143.08 (C_quat), 144.14 (C_quat), 174.50 (C_quat

,

1

C]O). *The peak of this carbon sits under the broad

singlet of the tert-butyl group. This carbon peak

correlates clearly with the multiplet between 2.11–

2.18 ppm in the HMQC spectrum. MS (ESI, MeOH) m/z

(%): 885 (100) [2MCNa]^C, 454 (63) [MCNa]^C; HRMS

(ESI) calcd for C₂₄H₃₃NO₄S [MCH]^C432.22031; found

432.22036

in one series for both diastereomers together because H

NMR and ¹³C NMR spectra were not appropriate to classify

all of the peaks for major and minor diastereomers. IR, DCI

mass and elemental analysis were carried out for the mixture

of diastereomers.

4.3.28. 2-Methyl-3-(toluene-4-sulfonyl)-8-tert-butoxy-

carbonylspiro[cyclopropane-1⁰,10-(3-azabicyclo[4.4.0]

dec-1(6)-ene)](56) and 2,2-dimethylpropionic acid 8-[1-

methylene-3-toluene-4-sulfonylamino)propyl]spiro[2.5]

oct-7-en-5-yl ester (57). According to GP-A, Pd(OAc)₂

(22.4 mg, 100 mmol), tri-2-furylphosphine (46.4 mg,

200 mmol), Et₃N (202 mg, 2.00 mmol), N-(3-iodobut-3-

enyl)-4-methylbenzenesulfonamide (54, 702.4 mg,

2.00 mmol) and bicyclopropylidene (1, 320 mg,

4.00 mmol) were stirred in anhydrous DMF (2 mL), at

80 8C for 3 h. After cooling the mixture to room temperature

tert-butyl acrylate (15, 512 mg, 4.00 mmol) was added, and

the mixture stirred at 80 8C for 48 h. After work-up and

drying (MgSO₄), the solvent was removed in a rotatory

evaporator. The residue was subjected to column chroma-

tography on silica gel (100 g, 3!30 cm, light petroleum/

ethyl acetate 4:1) to yield 56 (328 mg, 38%, colorless solid)

and 57 (311 mg, 36%, yellowish oil), 56: mp 110 8C, R_fZ

0.35 (light petroleum/ethyl acetate 4:1); IR (KBr): n~Z3097,

3072, 3002, 2978, 2909, 2869, 2829, 1716, 1597, 1448,

1433, 1372, 1367, 1338, 1263, 1158, 1089, 1033, 942, 815,

694 cm^K1; ¹H NMR (250 MHz, CDCl₃): dZ0.36–0.44 (m,

1H, cPr-H), 0.49–0.67 (m, 2H, cPr-H), 0.80–0.89 (m, 1H,

cPr-H), 1.05–1.11 (m, 1H), 1.18 (d, JZ6.5 Hz, 3H, CH₃),

1.42 [s, 9H, C(CH₃)₃], 1.63–1.98 (m, 4H), 2.03–2.18 (m,

1H), 2.41 (s, 1H, CH₃), 2.47–2.59 (m, 1H), 3.26–3.38 (m,

1H), 3.63–3.79 (m, 2H), 7.25 (d, JZ7.8 Hz, 2H, Ph), 7.65

4.3.29. 5-(1-Iodovinyl)benzo[1,3]dioxole (32). To an ice-

cold solution of 5-[(1-diethoxyphosphinyl)oxo-vinyl]-

benzo[1,3]dioxole* (2 g, 6.66 mmol) in anhydrous CH₂Cl₂

(20 mL) was added Me₃SiI (2.85 mL, 20.0 mmol) dropwise

with a syringe. After stirring 15 min at 0 8C, the reaction

mixture was quenched by addition of saturated NaHCO₃

(20 mL) and saturated Na₂SO₃(20 mL) solutions. The

organic layer was separated, and the aqueous layer was

extracted with CH₂Cl₂(2!10 mL). The combined organic

phases were dried (MgSO₄) and concentrated. The vinyl

iodide was puriﬁed by column chromatography using

n-pentane as an eluent. 36 was isolated as a very sensitive

pink oil (1.092 g, 60%) and immediately used after

isolation. *This precursor was prepared according to a

known procedure from the corresponding ketone and

directly used for the preparation of 32 without further

puriﬁcation.²⁴

¹H NMR (250 MHz, CDCl₃) dZ5.98 (s, 2H, OCH₂O), 6.35

(d, JZ1.4 Hz, 1H, vinyl), 6.71–6.75 (m, 1H, vinyl), 7.01–

7.05 (m, 3H, Ph); ¹³C NMR (62.9 MHz, CDCl₃, DEPT): dZ

101.36 (K), 106.68 (C_quat), 107.49 (C, Ph), 108.16 (C,

Ph-C), 122.13 (C, Ph-C), 126.13 (K), 135.84 (C_quat),

147.16 (C_quat), 147.93 (C_quat).

¨

B. Yucel et al. / Tetrahedron 61 (2005) 11355–11373

11373

¨

A. J. Org. Chem. 1983, 48, 1135–1137. (c) Ang, K. H.; Brase,

S.; Steinig, A. G.; Meyer, F. E.; Llebaria, A.; Voigt, K.; de

Meijere, A. Tetrahedron 1996, 52, 11503–11528.

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Article Doi

A two-step four-component queuing cascade involving a Heck coupling, π-allylpalladium trapping and Diels-Alder reaction

DOI: 10.1016/j.tet.2005.09.014

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