Synthesis of N-heterocyclic compounds via ene-yne metathesis reactions

Available online at www.sciencedirect.com

Tetrahedron 64 (2008) 204e218

www.elsevier.com/locate/tet

Synthesis of N-heterocyclic compounds via eneeyne metathesis reactions

a,c

Elisabetta Groaz ^a, Donatella Banti ^a,b,, Michael North

*

^aDepartment of Chemistry, King’s College, Strand, London, WC2R 2LS, UK

^bSchool of Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston-upon-Thames, Surrey KT1 2EE, UK

^cSchool of Natural Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK

Received 4 July 2007; received in revised form 28 September 2007; accepted 18 October 2007

Available online 23 October 2007

Abstract

Propargylamino and allylamino derivatives of cyclohexene and norbornene were subjected to tandem metathesis reactions with ﬁrst and sec-

ond generation Grubbs’ catalysts 1 and 2. Results show that the method is compatible with suitably protected nitrogen-containing compounds.

Cyclohexenes gave intriguing results in terms of the possibility to perform ring rearrangement metathesis (RRM) reactions, showing a difference

with the analogous allyl and propargyl ether substrates.

Keywords: Nitrogen heterocycles; Ring closing; Enyne; Metathesis; Ruthenium

1. Introduction

1 and 2 for the synthesis of highly functionalized polycyclic

oxygenated heterocycles through cascade metathesis processes

or tandem metathesis/DielseAlder reactions of norbornene

derivatives,⁶our focus being the deﬁnition of scope and limi-

tations for Cross Enyne Metathesis (CEYM) and Ring Closing

Enyne Metathesis (RCEYM).

Recently, we have also reported similar chemistry with 4,5-

diallyloxy and -dipropargyloxy derivatives of cyclohexane and

cyclohexene. The major difference between the two substrate

classes being that the unstrained, disubstituted alkene unit

within the cyclohexene ring does not participate in these me-

tathesis cascades.⁷

Nitrogen-containing heterocycles are widely represented

amongst naturally occurring products and biologically active

molecules in the form of isolated or fused ring systems. There-

fore, it was of interest to demonstrate whether the substitution

of oxygen by a nitrogen atom at the propargylic positions

would also provide good candidates for domino processes upon

treatment with ruthenium initiators.

Metathesis reactions are a powerful tool in the hand of

organic chemists for the synthesis of CeC bonds. The range

of their application in synthetic chemistry has expanded rap-

idly in the last 15 years¹and enyne metatheses in particular

have become popular very recently.²These phenomena can be

attributed to growing efforts and research into new catalyst

design and applications. Amongst these, relatively stable and

user-friendly rutheniumecarbene catalysts have been widely

used.³First⁴and second⁵generation Grubbs’ catalysts 1 and

2 (Fig. 1) are probably the most general for synthetic purposes.

Our group has worked extensively on the use of both catalysts

PCy₃

N

Cl

N

Cl

Ru

Ph

PCy₃

Cl

Ph

PCy₃

1

2

Nevertheless, it is important to be aware of issues around

the presence of amino groups in metathesis reactions as it is

commonly accepted that amino groups can coordinate to the

transition metal and deactivate it. Successful methodologies

to react amine containing substrates in metathesis reactions

Figure 1. First, 1 and second, 2 generation Grubbs’ catalysts.

* Corresponding author. Tel.: þ44 208 547 7554; fax: þ44 208 547 7497.

E-mail address: d.banti@kingston.ac.uk (D. Banti).

doi:10.1016/j.tet.2007.10.076

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

205

with catalysts 1 and 2,⁸have mainly involved the use of

amines bearing strongly electron-withdrawing groups.⁹The

use of ammonium salts,¹⁰or the addition of Lewis acids to co-

ordinate to the amine,¹¹has also proved effective, though there

are examples in the literature that prove that these prerequi-

sites are not always essential.¹²

In this paper we describe the synthesis and metathesis of

the allylamino and propargylamino derivatives of norbornene

and cyclohexene¹³analogous to the allyl and propargyl ether

derivatives used previously.^6,7In the case of the cyclohexenes

we show that the cyclohexene unit of these compounds can

participate in metathesis cascade sequences, leading to 2,2⁰-

bis-(tetrahydropyridine) derivatives.¹⁴

conditions, which included the use of xylene and higher tem-

peratures (180 ^ꢀC),^15,16we chose to perform the reaction in the

absence of solvent. Under these conditions, conversion of 5 to

7 was quantitative and yields were consistently higher than

those reported in the literature.

Exhaustive base hydrolysis of 7 required a two steps proce-

dure.¹⁵Upon heating with aqueous KOH in reﬂuxing metha-

nol for 4 h, hydrolysis of DielseAlder adduct 7 progressed

only to removal of the acetyl groups. In order to fully unmask

the targeted diamine, a further treatment was needed. Thus, the

intermediate was heated with an alkaline aqueous solution in

a sealed tube at 155 ^ꢀC for 24 h. The free diamine thus gener-

ated was immediately converted to the dihydrochloride salt 8

for storage, by treatment with a 1 M solution of hydrogen

chloride in diethyl ether.

2. Results and discussion

The ﬁrst substrate to be tested for metathesis was the tetra-

propargylamine 9, obtained by reacting the bis-ammonium salt

8 with propargyl bromide in the presence of potassium carbon-

ate as a base (Scheme 2).¹⁷Product 9 could only be isolated in

a 28% yield due to its difﬁcult puriﬁcation by either chroma-

tography or distillation.

2.1. Norbornene derivatives

By analogy with previous studies on oxygen-containing de-

rivatives, it was decided to synthesize 2,3-diamino-endo,cis-

norborn-5-ene dihydrochloride as the ﬁrst substrate.

2,3-Diamino-endo,cis-norborn-5-ene dihydrochloride 8, was

obtained by a modiﬁed literature procedure using a DielseAlder

reaction between cyclopentadiene 6 and imidazolyl derivative 5

as the key step.¹⁵The overall strategy for preparing compound 8

is shown in Scheme 1.

NH₃⁺Cl^-K₂CO₃, CH₃CN

N

Δ reflux, 16h

NH₃⁺Cl^-

Br

8

9

O

Scheme 2.

Me

H

N

H

N

1. DIBALH, THF

0 °C, 2 h

O

N

(CH₃CO)₂O

Δ reflux, ¹

/₂h

Attempted metathesis reactions on compound 9 did not

give any results with catalyst 1 or 2 when using the standard

conditions of dry dichloromethane as solvent under an ethene

atmosphere, either at room temperature or reﬂux. Substrate 9

has two amino groups that could chelate the metal centre in

the catalyst deactivating it. In order to try to break a possible

chelate formation a Lewis acid (Ti(OⁱPr)₄) was added with cat-

alyst 1, but this strategy did not prove to be effective.

It was then decided to decrease the nucleophilicity of the

amino group by converting it into a sulfonamide. The decision

to use tosyl was due to a compromise between the desired steric

andelectronicproperties. Theformationofditosyldiamine10es-

sentiallyfollowed theliterature procedure for similartransforma-

tions (Scheme 3).¹⁸Thus, the addition of triethylamine followed

by p-toluenesulfonyl chloride in dichloromethane at room tem-

perature turned out to be optimal in terms of isolated yield.

O

2. MeOH aq.

Δ reflux, on

N

H

N

H

Me

O

3

4 (62%)

5 (68%)

O

Me

O

1. KOH aq./MeOH

NH₃⁺Cl^-

Δ reflux, 4 h

N

6

2. KOH aq./MeOH

155 °C, 24 h

3. HCl, Et₂O

N

140 °C

24 h

Me

O

8 (51%)

7 (100%)

Scheme 1.

Dienophile 5 was accessed in two steps via a modiﬁed lit-

erature procedure from commercially available hydantoin 3.¹⁶

Addition of diisobutylaluminium hydride (DIBALH) to com-

pound 3 was followed by hydrolysis with aqueous methanol.

The so-generated reduction product underwent elimination af-

ter overnight reﬂux affording 1,3-dihydro-imidazol-2-one 4 in

62% yield. The subsequent acetylation of compound 4 to bis-

amide 5 was easily achieved by reﬂuxing 1,3-dihydro-imid-

azol-2-one 4 for 30 min with an excess of acetic anhydride

and yielded 68% of the desired 1,3-diacetyl-1,3-dihydro-imid-

azol-2-one 5.

NH₃⁺Cl^-

NHTs

TsCl, Et₃N

CH₂Cl₂, 16 h

NHTs

10 (79%)

8

Scheme 3.

For the ﬁnal stage of the synthesis, compound 10 was

intended to be converted into the corresponding endo-bis-

propargylamino metathesis precursor 12 via nucleophilic sub-

stitution with propargyl bromide. However, under our standard

Compound 5 was then heated with an excess of freshly dis-

tilled cyclopentadiene 6 in a sealed tube at 140 ^ꢀC for 24 h to

provide DielseAlder adduct 7. Rather than using the reported

206

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

alkylation conditions (NaH in DMF, excess of propargyl bro-

mide, room temperature, 24 h) a mixture of mono-alkylated

product 11 and unreacted starting material 10 was obtained

along with the desired dialkylated product 12 (Scheme 4). At-

tempts to force the reaction to 100% conversion of the starting

material under different conditions such as higher tempera-

tures (50 ^ꢀC or reﬂuxing in DMF), longer reaction times (48,

72 and 96 h) and addition of sodium iodide were unsuccessful

as the ratio of bis to mono-alkylated products was never in-

rearrangement without further puriﬁcation. Curtius rearrange-

ment of the crude azide in toluene formed bis-isocyanate 15,

which was immediately hydrolysed to the dihydrochloride

salt of trans-diamine 16 in 95% yield. Standard tosylation

conditions were applied to 16 to give the bis-tosylated trans-

norbornene diamine 17 in high yield (85%) after work-up and

puriﬁcation by column chromatography (Scheme 6). We were

pleased to ﬁnd that bis-propargylation of 17 could be achieved

effortlessly under standard conditions. The crude compound

was puriﬁed by recrystallization from ethyl acetate/hexane,

thus providing the trans-diamine 18 in 72% yield.

1

creased from the initial 2:1 value, as revealed by H NMR

analysis of the crude mixture.

Ts

N

Ts

N

O

1) NaH, DMF

0 °C, 2 h

NHTs

NaN₃aq., 2 h

Cl

N₃

+

2) 0 °C→r.t.

NH

Ts

N

Ts

- 10 °C→ 0 °C

Br

dry THF

O

10

11

12

14 (98%)

13

Scheme 4.

PhMe

Δ reflux, ¹

/

₂h

Complete separation of compounds 11 and 12 by column

chromatography or recrystallization was not possible due to

their very similar retention times and solubilities in a wide

range of solvent mixtures. Moreover, reaction of a mixture

of compound 12 containing minor amounts of 11 as impurity

and with 5 mol % of catalyst 1 in dichloromethane at room

temperature under an ethene atmosphere was unsuccessful

since the ruthenium catalyst could not tolerate the presence

of mono-alkylated compound 11 even as a minor impurity.

As a consequence, the screening of other possible base/sol-

vent combinations that might affect the desired deprotonation

under sufﬁciently mild conditions was carried out. None of the

conditions examined were entirely satisfactory. Interestingly it

was found that the use of a stronger base, for instance potas-

sium hydride, avoided the formation of the mono-substituted

species 11; nevertheless only 43% of 10 was converted into

bis-propargylated diamine 12 after reﬂuxing for 3 days in

THF as proven by inspection of the ¹H NMR spectrum. Addi-

tion of catalytic amounts of 18-crown-6 was not advantageous

in encouraging the reaction to completion and the chromato-

graphic separation of the two compounds proved very difﬁcult.

The non-nucleophilic base potassium hexamethyldisilazide

(KHMDS), failed to give the desired deprotonation probably

due to steric factors. At this point it was decided to discontinue

this route to the bis-endo substituted compound 12.

Nevertheless, we were encouraged to continue our research

into amino substituted norbornene rings by a recent report on

the straightforward Ring Rearrangement Metathesis (RRM) of

a mono-endo-propargylamino norbornene.^9oAn opportunity to

test our protocol on N,N⁰-bis-amino substituted norbornenes

was available by using the analogous trans-substrates.

There was no precedent in the literature for the preparation

of trans-2,3-diamino-norborn-5-ene dihydrochloride 16. The

synthesis, illustrated in Scheme 5, started with the addition

of an aqueous solution of sodium azide to commercially avail-

able (þ/ꢁ)-trans-5-norbornene-2,3-dicarbonyl chloride 13 to

form the corresponding diacyl azide 14 in excellent yield

(98%). Compound 14 was then subjected to thermal

NH₃⁺Cl^-

N

C O

6N HCl

Δ reflux, 3 h

N

r.t., on

16 (95%)

15 (99%)

Scheme 5.

Ts

N

1) NaH, DMF

NH₃⁺Cl^-

NHTs

TsCl, Et₃N

CH₂Cl₂, 16 h

0 °C, 2 h

2) 0 °C → r.t.

Br

N

Ts

17 (85%)

18 (72%)

16

Scheme 6.

Three possible RRM products could be obtained by treating

substrate 18 with either catalyst 1 or 2 (Scheme 7). First, the

metathesis of 18 was attempted with 5 mol % of 1 in dry di-

chloromethane at room temperature. As expected, by working

under a nitrogen atmosphere and in the absence of an addi-

tional oleﬁn, no conversion was observed after 48 h.

Ts

N

Ts

N

Ts

1 or 2

N

Ts

+

Ts

N

Ts

N

Ts

18

19a

Scheme 7.

19b

19c

Therefore, the experiment was repeated in the presence

of an ethene atmosphere. Results are presented in Table 1.

Reaction with 5 mol % of 1 in dichloromethane at room tem-

perature in the presence of ethene resulted in complete con-

sumption of starting material over a period of 6 h (Table 1,

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

207

Table 1

Metathesis of diyne 18 with catalysts 1 and 2 in the presence of ethene

puriﬁed by Kugelrohr distillation prior to use in the subsequent

¨

chlorination reaction, which was carried out with thionyl chlo-

ride in CCl₄upon addition of a catalytic amount of DMF. The

so-formed acyl chloride 22 underwent a second Curtius rear-

rangement, followed by hydrolysis of bis-isocyanate 23 to

afford cis-diamine 24 in the form of a dihydrochloride salt.

Diamine 24 was thus prepared in a comparable yield to that

reported in the literature (53%).¹⁹

Entry

Cat (mol %)

Solvent

T (^ꢀC)

t (h)

Conv^a

19a (%)^b

1

2

3

4

a

1 (5)

CH₂Cl₂

Toluene

25

60

6

16

24

100

0

41

43

37

0

1 (5)þ2 (5)

2 (5)

Percentage conversion was estimated from the ¹H NMR spectrum of the

crude mixture.

b

This column reports the percentage yield calculated on the product recov-

ered after chromatographic puriﬁcation.

O

C

O

C

O

S

O

SiMe₃

Me₃SiN₃

O

Cl

O

dioxane

70-80 °C

CCl₄, cat. DMF

50 °C

entry 1). Inspection of the ¹H NMR spectrum of the crude res-

idue obtained after removal of all the volatiles and TLC anal-

ysis showed that the reaction yielded multiple products, the

identiﬁcation of which was complicated by the lack of symme-

try in compounds 18 and 19.

N

C O

N

C O

O

20

21 (92%)

22 (80%)

Me₃SiN₃

NH₃⁺Cl^-

N

C O

dioxane

HCl conc.

dioxane/acetone

35-40 °C

In attempts to purify the products by ﬂash chromatography,

different solvent mixtures were employed but none was partic-

ularly successful. However, using dichloromethane as eluent it

was possible to isolate the tricyclic compound 19a incorporat-

ing two azacyclohexene substructures in 41% yield. Evidence

of two additional products: cis- and trans-mono-cyclized com-

pounds 19b and 19c, was observed by NMR spectroscopy, but

they were only present in mixed fractions. Given the difﬁcul-

ties in obtaining analytically pure samples of these compounds

by conventional separation techniques; the impure samples

were submitted to GCeMS analysis, which showed the pres-

ence of the expected molecular ion peaks. The exact relative

ratio of the two mono-cyclized products could not be esta-

blished, however, a cis preference of ring closure (forming

19b) for the ring opened carbene could be postulated due to

the shape of the substrate.

r.t. → 70-80 °C

24 (53%)

23

Scheme 8.

Compound 24 was converted into the corresponding N,N⁰-

bis-tosylate 25 in 75% yield after puriﬁcation by ﬂash chroma-

tography (Scheme 9). This core structure was then used in

alkylation reactions for the synthesis of different substrates for

metathesis reactions. Once again, the ﬁrst substrate to be

tested for metathesis activity was a simple oleﬁnic substrate

26. N,N⁰-Bis-allylation of bis-tosyl cis-diamine 25 was carried

out with NaH as base in DMF as solvent following a general

literature procedure (Scheme 9).²⁰The reaction was quenched

with saturated aqueous NH₄Cl and after work-up readily

yielded substrate 26 in excellent yield (98%).

Longer reaction times did not produce a signiﬁcant change

in the chemoselectivity of the process and compound 19a was

still formed in 43% yield (Table 1, entry 2). An additional at-

tempt to drive the reaction towards the selective formation of

tricycle 19a was carried out by adding 5 mol % of 1 followed

by 5 mol % of 2. This approach, which was found to be useful

in previous examples,⁶in this case did not lead to any im-

provement in the yield of 19a (Table 1, entry 3). The use of

catalyst 2 alone in toluene at 60 ^ꢀC did not give any positive

results (Table 1, entry 4).

Ts

N

1) NaH, DMF

NH₃⁺Cl^-

NHTs

TsCl, Et₃N

0 °C, 2 h

2) 0 °C→ r.t.

Br

CH₂Cl_2,16 h

N

Ts

26 (98%)

24

25 (75%)

Scheme 9.

Substrate 26 was subjected to metathesis reaction in the

presence of either catalyst 1 or 2. The possible products that

could result follow the rationale previously illustrated for the

ether analogues⁷of 26 (Scheme 10). Reaction conditions and

results are presented in Table 2. As was the case for bis-allyl

ethers,⁷ring-closing metathesis at the exocyclic double bonds

was found to prevail over the alternative tandem ROM/RCM

route.

2.2. Cyclohexyl derivatives

2.2.1. Alkene metathesis

As mentioned in Section 1, cyclohexene derivatives bearing

analogous propargyl and allyl tosyldiamino groups were also

synthesized and tested for metathesis reactions with catalysts

1 and 2.

The synthesis of cis-1,2-diamino-cyclohex-4-ene dihydro-

chloride 24 (Scheme 8) has been previously reported.¹⁹Com-

mercially available 1,2,3,6-tetrahydrophthalic anhydride 20

was puriﬁed by heating under reﬂux for 3 h with acetic anhy-

dride and petroleum ether before being treated with trimethyl-

silylazide in dioxane. Trimethylsilyl ester product 21 was

Ts

N

Ts

N

1 or 2

+

N

Ts Ts

N

Ts

N

Ts

26

27

28

Scheme 10.

208

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

Table 2

Metathesis of diene 26 with catalysts 1 and 2

RCM metathesis leading to product 27 decreased relative to

the competing formation of bis-dihydropyrrolidine product

28 via the anticipated tandem ROM/RCM reaction. After con-

sumption of the starting diene 26 over a period of 20 h at room

temperature under nitrogen, the two products were formed in

an approximate ratio of 2.5:1 in favour of product 27 (Table

2, entry 3). Under an ethene atmosphere, complete consump-

tion of the starting material did not occur, but 27 and 28

were still formed with the same ratio in an overall 30% yield

(Table 2, entry 4).

Entry^a

Cat (mol %)

Atm

Yield^b(%)

27

28

26^c

1

2

3

4

a

1 (5)

2 (5)

N₂

100

83

0

17

0

H₂C]CH₂

N₂

H₂C]CH₂

71

21

29

9

70

All the reactions were carried out at 25 ^ꢀC in dry dichloromethane.

b

Yields were calculated on the product recovered after chromatographic

puriﬁcation.

c

Recovered starting material.

2.2.2. Enyne metathesis

In view of the successful metathesis of bis-allyl amine 26,

related enyne metatheses were investigated. Substrate 30,

having an allyl and a propargyl substituent was synthesized,

following the procedure shown in Scheme 11. The mono-

allylated precursor 29 was obtained by reacting diamine 25

with allylbromide under standard alkylation conditions. Com-

pound 29 was easily isolated by column chromatography from

a mixture of bis-alkylated product 26 (43%) and unreacted

ditosylamine 25 (3%). Compound 29 was then treated with

propargyl bromide to give the enyne metathesis precursor 30

in 78% yield after puriﬁcation by column chromatography.

When compound 30 was treated with catalyst 1, two differ-

ent products were obtained depending on the reaction condi-

tions (Scheme 12). The reaction was ﬁrst attempted using

standard reaction condition of 5 mol % catalyst 1, in dichloro-

methane at room temperature under a nitrogen atmosphere.

Product 32 was obtained in 32% yield along with 51% of re-

covered starting material 30. For subsequent reactions, the

amount of catalyst 1 was increased to 10 mol %. Results are

presented in Table 3. By carrying out the reaction in dichloro-

methane under an inert atmosphere using 10 mol % of catalyst

1 (Table 3, entries 1 and 2), the only isolable product after col-

umn chromatography was 6,8-fused bicyclic butadiene 32. In

analogous RCM of dienes, Mori et al. associated an accelerat-

ing effect on the rate of eight-membered ring formation via

ring-closing enyne metathesis to the steric bulk of the tosyl

When cis-N,N⁰-bis-allyl-N,N⁰-bis-( p-toluenesulfonyl)-1,2-

diamino-cyclohex-4-ene 26 was treated with 5 mol % of 1 in

dichloromethane at room temperature for 20 h under a nitrogen

atmosphere (Table 2, entry 1), intramolecular alkene metathe-

sis proceeded quantitatively leading exclusively to 6,8-fused

bicycle 27. Notably, no oligomerization was observed in the

metathesis of 26, in contrast to our results with structurally

similar compounds. Indeed under exactly the same experimen-

tal conditions, the reaction of 1,2-bis-allyloxy-cis-cyclohex-4-

ene⁷did not proceed to completion and products resulting

from oligomerization were also present. This could be related

to the presence of an element of constraint in the substrate rep-

resented by the tosyl groups on the nitrogens. It has been sug-

gested for similar substrates that pre-organized conformational

constraints facilitate RCM by enhancing the rates of the reac-

tion relative to the rates of competing intermolecular meta-

thesis leading to oligomers.²¹

Performing the reaction under an ethene atmosphere (Table

2, entry 2) did not prevent the RCM reaction from taking place

and product 27 could still be obtained in an appreciable yield

(83%). This is quite surprising considering that ethene is

released as a by-product upon ring-closing and that the oxo-

analogues did not react under the same conditions.⁷By con-

ducting the reaction in the presence of 2 (5 mol %) (Table 2,

entries 3 and 4) it was observed that the rates of alkene

Ts

N

Ts

NaH, DMF

N

NaH, DMF

0 °C, 2 h

NHTs

0 °C, 2 h

0 °C → r.t.

NH

Ts

N

Ts

NHTs

Br

29 (37%)

30 (78%)

25

Scheme 11.

Ts

N

Ts

N

Ts

N

1 10 mol%

CH₂Cl₂, 24 h

H₂C=CH₂

CH₂Cl₂, 24 h

N₂

N

Ts

N

Ts

N

Ts

31

30

32

Scheme 12.

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

209

Table 3

Metathesis of substrate 30 with 10 mol % catalyst 1

Entry^a

T (^ꢀC)

Atm

Yield^b(%)

Ts

N

Ts

N

Ts

30^c

1 or 2

32

31

+

N

Ts

N

Ts

1

2

3

4

a

25

35

25

35

N₂

44

56

0

26

13

d

H₂C]CH₂

68

79

0

33

34

Scheme 14.

35

All the reactions were carried out in dry dichloromethane using 10 mol %

of catalyst 1.

b

Yields were calculated on the product recovered after chromatographic

puriﬁcation.

c

Table 4

Metathesis of diyne 33 with 1 and 2 under an ethene atmosphere

Recovered starting material.

Entry^a

Cat (mol %)

Solvent

T (^ꢀC)

Yield^b(%)

group.^22,23It was therefore expected for 30 to display in-

creased metathesis reactivity compared to cis-O-enyne.⁷The

yields of these reactions were, however, uncharacteristically

moderate.

34

35

33^c

1

2

3

4

a

1 (5)

CH₂Cl₂

Toluene

25

50

60

10

16

17

22

53

63

44

59

37

20

39

18

1 (10)

2 (10)

In contrast with earlier results, we found that the reaction

also proceeded when performed under an ethene atmosphere,

though through a different pathway. Substrate 30 underwent

cross metathesis with ethene at the alkyne moiety, yielding

compound 31 as the sole reaction product in good yield after

puriﬁcation by column chromatography (Table 3, entries 3 and

4). This is in accordance with literature reports²⁴for enyne

cross metathesis under 1 atm of ethene using catalyst 1,

according to which the bulkiness of the substituent at the prop-

argylic position has a profound inﬂuence on the product yield

while at the same time oxygen functionalities impede enyne

metathesis by chelation. The structure of products 31 and 32

could be deduced from their spectroscopic data. In the case

of compound 32, the NOESY spectrum was particularly diag-

nostic as it demonstrated that the cyclohexene ring was still

intact.

The next substrate to be investigated was bis-propargyl-

amine 33, which was prepared by a standard procedure as

illustrated in Scheme 13. The metathesis reactivity of com-

pound 33 catalysed by complex 1 was investigated ﬁrst. As

previously observed for related compounds, changing the

steric and electronic requirement of the substituents on the

cyclohexene resulted in a dramatic change in reactivity. In-

deed, compound 33 did not behave similarly to the analogous

dipropargyl ether described in earlier papers.⁷Compound, 33

reacted readily with catalyst 1, giving monocross-metathesised

derivative 35 as the major product, together with smaller quan-

tities of bis-azacycle 34 (Scheme 14). In the light of this result,

it can be concluded that compound 33 is a useful probe of the

mechanistic diversity available by metathesis of differently

substituted cyclohexene derivatives.

All the reactions were carried out in dry dichloromethane using an ethene

atmosphere.

b

Yields were calculated on the product recovered after chromatographic

puriﬁcation.

c

Recovered starting material.

Several conditions for the metathesis of substrate 33 were

systematically examined. It was generally observed that no re-

action was observed under a nitrogen atmosphere with either

catalyst 1 or 2. Table 4 reports the results obtained with cata-

lysts 1 and 2 under an ethene atmosphere with different reac-

tion conditions.

It was observed that when the reaction was carried out at

room temperature, increasing the amount of catalyst from

5 mol % to 10 mol % increased the overall conversion of the

starting diyne into ring rearranged product 34 and cross meta-

thesis product 35 after overnight stirring, without signiﬁcantly

changing the ratio of products 35 and 34 (Table 4, entries 1

and 2). Based on literature precedent,²⁵the reaction was per-

formed at 50 ^ꢀC in a sealed system in order to increase the che-

moselectivity towards bis-aza-cycle 34. Although leading to

a lower overall conversion, the higher temperature produced

a decrease in the 35/34 ratio (2.5:1) (Table 4, entry 3). The

same effect was observed with the use of catalyst 2 in toluene

at 60 ^ꢀC (Table 4, entry 5). We were able to elucidate the struc-

ture of the products from this reaction only after detailed exam-

ination of 2D NMR experiments including HMQC, HMBC,

long-range ¹He¹H correlations and NOESY spectra. Although

Ring Rearrangement Metathesis (RRM) reaction of diyne 33

occurs slowly, and the major compound formed from the

metathesis of 33 is monocross-metathesised product 35, this

result is interesting as it proves that the metathesis catalysts

can react via ring opening for 1,2-disubstituted cyclohexenes.

Ts

N

1) NaH, DMF

NHTs

0 °C, 2 h

2) 0 °C → r.t.

Br

N

Ts

3. Conclusions

33 (96%)

25

In conclusion, attempts to extend the cascade enyne me-

tathesis process promoted by ruthenium based metathesis

Scheme 13.

210

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

initiators 1 and 2 to allyl- and propargyl-amino-substituted

norbornene and cyclohexene derivatives gave some intriguing

results, highlighting the different catalytic reactivities of the

two complexes.¹³The study also illustrated once again that

the usual generalization that complex 2 is more reactive than

complex 1 is not always valid.

This study also led to the discovery of an interesting dicho-

tomy occurring between the chemistry of oxygen and nitrogen-

containing systems. In addressing the possibility of applying

this chemistry to nitrogen-containing derivatives, it is clear

that the method is compatible with amino compounds if they

are suitably protected.

RRM pathway while the six-membered ring of cyclohexene

derivatives does not participate and they undergo mainly

RCM or RCEYM.⁷For the nitrogen-containing derivatives,

however, it is possible to obtain RRM products (that is, tandem

ROM/RCM) for both cyclohexene and norbornene substrates.

This evidences that for nitrogen-containing derivatives it is

possible to achieve enough stabilization by forming cyclic

products such as 19aec and bicyclic products such as 28 and

34 to drive the equilibrium towards the ring opening of either

a strained or an unstrained six-membered ring.

In the norbornene systems a trans-disposition of the precur-

sor does not prevent the reaction from taking place. With

regards to the cyclohexene derivatives, apart from its prepara-

tive utility, this study raises several mechanistically relevant

issues. A contrast in reactivity between ether and amino com-

pounds with metathesis catalysts has been suggested before

throughout the literature^24,26,27although an accurate rationale

for this occurrence was not provided.

It has been previously observed⁷that treatment of cis- and

trans-cyclohexene systems bearing O-propargylic side chains

with second generation Grubbs’ catalyst 2 in the presence of

ethene generates intermediates possessing the functionality

to undergo ring-closing dieneeyne metathesis, allowing un-

usual fused 6,8-bicyclic triene heterocycles to be formed

(the ﬁrst generation Grubbs’ catalyst 1 was found to be com-

pletely inactive in this reaction). The same reaction conditions,

in the presence of either catalyst 1 or 2 applied to the analo-

gous N-tosyl derivative 33 led to a monocross-metathesised

product as the major compound, but RRM (namely tandem

ROM/RCEYM) was also observed rather than ring closing at

the side chain.

It is possible to speculate that for amino derivatives, the re-

quired conformations for RRM might be more energetically

accessible than those of the related ether compounds. In this

context, it is possible to assume that a step in the catalytic cy-

cle serves as a kinetic barrier for formation of rearranged prod-

ucts and the presence of sterically demanding tosyl functions

at the nitrogen atoms in compound 33 could bias the equilib-

rium amongst the possible rotamers towards the production of

a rotamer, which is energetically and conformationally dis-

posed towards ROM/RCEYM.

A similar analysis can be carried out for diallyl substrate 26

giving the RRM (ROM/RCM) product 28 as a minor product

and in the presence of catalyst 2 only. The formation of RCM

product 27 as a major product shows that when an alternative

RCM path is available, the formation of metathesis products

seems to be kinetically governed, as the thermodynamically

favourable route is indeed less favoured. These are intriguing

results as no conditions were found under which the analogous

oxygenated cyclohexene compounds would undergo RRM

reactions.⁷

4. Experimental section

4.1. General

Dichloromethane was dried by distillation over calcium hy-

dride. Toluene was dried by distillation from metallic sodium

prior to use. All reactions were carried out under a nitrogen at-

mosphere. Chromatographic separations were performed using

silica gel 60 (230e400 mesh) supplied by Merck. Analytical

thin layer chromatography (TLC) was carried out on Merck

polyester backed sheets coated with silica gel 60 F254, using

short wavelength (254 nm) ultraviolet light, or basic potassium

permanganate (KMnO₄) stains to visualise components.

Melting points were determined on a Gallenkemp melting

point apparatus and are uncorrected. Infrared spectra were re-

corded on a PerkineElmer Paragon 1000 Fourier transform IR

spectrometer using sodium chloride plates. Characteristic ab-

sorptions are reported in wavenumbers (cm^ꢁ1) with the fol-

lowing abbreviations: strong (s), medium (m) or weak (w).

¹H and ¹³C NMR spectra were recorded using Bruker

Avance digital NMR spectrometers operating at 360, 400 or

500 MHz for protons and 90, 100 or 125 MHz for carbons.

All spectra were recorded at room temperature in CDCl₃(un-

less otherwise stated) and referenced to tetramethylsilane.

Chemical shifts are expressed in parts per million. Coupling

constants are given in Hertz. The multiplicity of signals is re-

ported as singlet (s), doublet (d), triplet (t), quartet (q), multi-

plet (m), broad (br) or a combination of any of these. The

proton or carbon attributed to the peak is sometime italicised

for clarity and a * or a ** indicates that assignment for the cor-

responding nuclei could be interchanged. Determination of

structures was achieved with the aid of DEPT spectra and

2D NMR techniques including COSY, long-range COSY,

NOESY, one-bond heteronuclear correlation and multiple bond

heteronuclear correlation as appropriate.

Low and high resolution mass spectra were recorded at the

EPSRC national service at the University of Wales, Swansea,

or on a Bruker Apex III FTMS or Jeol AX505W spectrometer

within the chemistry department at King’s College London.

The sample was ionized by electron ionization (EI), chemical

ionization (CI) or positive electrospray ionization (ESI). The

major fragment ions are reported and only the molecular

ions are assigned. GCeMS was performed on the Jeol

To summarise this parallel analysis of oxygen- and nitrogen-

containing analogues it is possible to say that for oxygen-

containing derivatives the presence of strain in the six-membered

ring of norbornene drives the metathesis reaction towards the

AX505W spectrometer using

(25 mꢂ0.25 mm) with helium as the carrier gas at 12 psi.

a 0.25 mm BP1 column

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

211

The temperature was held at 60 ^ꢀC for 2 min, and then in-

creased at 8 ^ꢀC/min to 280 ^ꢀC.

reﬂux for 4 h. The resulting slurry was ﬁltered and the solid

washed several times with water and dried in a vacuum oven

for 24 h at 60 ^ꢀC to provide crude product (1.62 g). The ﬁltrate

was partially concentrated (30 ml), extracted with chloroform

(3ꢂ20 ml), neutralized with 6 N HCl and extracted again with

chloroform (3ꢂ20 ml). The combined organic phases were

dried over anhydrous MgSO₄, ﬁltered and concentrated in va-

cuo to give additional crude product (2.30 g). The combined

crude material (3.92 g) was suspended in 50% aq KOH

(35 ml) and methanol (14 ml) and the mixture was then heated

in a pressure tube at 155 ^ꢀC for 24 h. After cooling to room

temperature, the reaction mixture was extracted with chloro-

form (6ꢂ20 ml). The combined organic phases were dried

over anhydrous MgSO₄, ﬁltered and concentrated under re-

duced pressure to give a brown oil. The oil was dissolved in

diethyl ether and ﬁltered to remove solid brown impurities.

The ﬁltrate was cooled to 0 ^ꢀC and treated with ethereal HCl

to provide the bis-ammonium chloride salt 8 (1.28 g,

6.53 mmol, 51%) as a pale brown solid. Mp>280 ^ꢀC dec

(lit.¹⁵275 ^ꢀC dec); ¹H NMR (d, DMSO): 8.33 (br s, 6H,

2ꢂNH^þ₃), 6.33 (s, 2H, CH]CH), 3.93 (br s, 2H, 2ꢂCHN),

3.15 (br s, 2H, CHC]), 1.55 (d, J 9.8 Hz, 1H, CH₂), 1.53

(d, J 9.8 Hz, 1H, CH₂).

All metathesis products were puriﬁed by ﬂash chromato-

graphy so that the concentration of residual ruthenium species

1

and/or phosphine was below the detection limits of H and

¹³C NMR spectroscopy.

4.2. 1,3-Dihydro-imidazol-2-one (4)¹⁶

Compound 4 was prepared by the following modiﬁcation of

a literature procedure. Hydantoin 3 (3.00 g, 30.0 mmol) was

suspended in dry tetrahydrofuran (30 ml) and cooled to 0 ^ꢀC

under a nitrogen atmosphere. DIBALH (53 ml, 1.5 M, 25%

in toluene) was added dropwise with stirring over a period

of 30 min and the solution was stirred for 2 h at 0 ^ꢀC. Aqueous

methanol (90%, 225 ml) was carefully added, then the solution

was heated at reﬂux overnight, ﬁltered and evaporated to dry-

ness to give 1,3-dihydro-imidazol-2-one 4 (1.56 g, 18.6 mmol,

62%) as a white solid. Mp 240e243 ^ꢀC (lit.²⁸250e251 ^ꢀC);

¹H NMR (d, DMSO): 9.70 (br s, 2H, 2ꢂNH), 6.24 (s, 2H,

2ꢂCH).

4.3. 1,3-Diacetyl-1,3-dihydro-imidazol-2-one (5)¹⁶

Compound 5 was prepared by the following modiﬁcation

of a literature procedure. 1,3-dihydro-imidazol-2-one¹⁶

4.6. N,N,N⁰,N⁰-Tetra-(prop-2-ynyl)-2,3-diamino-

endo,cis-norborn-5-ene (9)

4

(4.00 g, 47.6 mmol) was stirred with acetic anhydride

(30.1 g, 27.8 ml, 295.2 mmol) at reﬂux for 30 min. The reac-

tion was then cooled to room temperature and evaporated to

dryness to leave a yellow solid. The residue was recrystallized

from diethyl ether to give pure 1,3-diacetyl-1,3-dihydro-imi-

dazol-2-one 5 (5.44 g, 32.4 mmol, 68%) as a white solid.

To a solution of bis-ammonium chloride salt 8 (0.10 g,

0.51 mmol) in CH₃CN (2 ml) were added propargyl bromide

(0.38 g, 80% toluene soln, 2.54 mmol) and potassium carbon-

ate (0.70 g, 5.08 mmol). The mixture was heated to reﬂux for

16 h, then cooled to room temperature and evaporated to give

a brown oil (0.16 g), which was puriﬁed by column chroma-

tography to give product 9 (0.04 g; 28%) as an off white vis-

cous liquid. IR (n_max, cm^ꢁ1): 3299 (s), 3062 (w), 2966 (s),

1

Mp 103e105 ^ꢀC (lit.²⁸105e106 ^ꢀC); H NMR (d, DMSO):

7.15 (s, 2H, CH]CH), 2.53 (s, 6H, 2ꢂCH₃).

1

4.4. 2,3-Diacetyl-1,3,3a,4,7,7a-hexahydro-4,7-methano-

2H-benzimidazol-2-one (7)¹⁶

2872 (s), 2817 (s), 2361 (w), 2247 (w), 2120 (w); H NMR

(d, CDCl₃): 6.08 (t, J 1.7 Hz 2H, CH]CH), 3.65 (dd, J

16.7, 2.3 Hz, 4H, 4ꢂNCH₂), 3.59 (dd, J 16.7, 2.3 Hz, 4H,

4ꢂNCH₂), 3.29e3.28 (m, 2H, CHN), 3.07 (br s, 2H,

CHC]), 2.12 (t, J 2.3 Hz, 4H, 4ꢂ^CH), 1.39 (dt, J 8.9,

2.2 Hz, 1H, CH₂), 1.15e1.18 (m, 1H, CH₂); ¹³C NMR

(d,CDCl₃): 133.6 (C]C), 79.6 (C^), 71.3 (^CH), 63.0

(CHN), 45.9 (CH₂N), 44.6 (CHC]), 40.7 (CH₂); m/z (CI,

%): 277 (MH^þ, 100); found (ESI) 277.1713 (MH^þ),

C₁₉H₂₁N₂requires: 277.1704.

Compound 7 was prepared by the following modiﬁcation of

a literature procedure. 1,3-Diacetyl-1,3-dihydro-imidazol-2-

one¹⁶5 (1.00 g, 5.95 mmol) and an excess of freshly distilled

cyclopentadiene 6 (3.93 g, 4.90 ml, 59.5 mmol) were stirred in

a sealed tube at 140 ^ꢀC for 24 h. The mixture was then cooled

to room temperature and evaporated in vacuo. The residue was

puriﬁed by column chromatography (ﬁrst dichloromethane,

then diethyl ether) to give diacetyl adduct 7 (1.39 g,

5.94 mmol, 100%) as a white solid. Mp 120e123 ^ꢀC (lit.¹⁶

4.7. N,N⁰-Bis-( p-toluenesulfonyl)-2,3-diamino-endo,cis-

norborn-5-ene (10)

1

119e120 ^ꢀC); H NMR (d, CDCl₃): 5.96 (t, J 1.8 Hz, 2H,

CH]CH), 4.34 (t, J 1.6 Hz, 2H, 2ꢂCHN), 3.44 (t, J 1.6 Hz,

2H, 2ꢂCHCH]), 2.37 (s, 6H, 2ꢂCH₃), 1.61 (dt, J 9.8,

1.7 Hz, 1H, CH₂), 1.32 (d, J 9.7 Hz, 1H, CH₂).

To a suspension of 2,3-diamino-endo,cis-norborn-5-ene

dihydrochloride¹⁵8 (0.38 g, 1.90 mmol) in dry dichlorome-

thane (15 ml) was added freshly distilled triethylamine

(0.77 g, 1.06 ml, 7.61 mmol), followed by a solution of p-tol-

uenesulfonyl chloride (0.73 g, 3.81 mmol) in dry dichlorome-

thane (8 ml). The mixture was stirred for 16 h at room

temperature under a nitrogen atmosphere. The solution was

then acidiﬁed with 2 M aq HCl and extracted with

4.5. 2,3-Diamino-endo,cis-norborn-5-ene

dihydrochloride (8)¹⁵

A slurry of diacetyl adduct¹⁶7 (3.00 g, 12.8 mmol) in

methanol (10 ml) and 50% aq KOH (40 ml) was heated at

212

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

dichloromethane (3ꢂ10 ml). The combined organic phases

were dried over anhydrous MgSO₄, ﬁltered and evaporated

in vacuo. The residue was puriﬁed by column chromatography

(hexane/ethyl acetate 60:40) to leave the title compound 10

(0.65 g, 1.50 mmol, 79%) as a white solid. Mp 185e187 ^ꢀC;

IR (n_max, KBr): 3294 (s), 2977 (w), 1599 (m), 1497 (w),

4.10. trans-2,3-Diamino-norborn-5-ene dihydrochloride

(16)

A stirring solution of trans-norborn-5-ene-2,3-diisocyanate

15 (3.00 g, 17.0 mmol) in 6 N HCl (60 ml) was gently reﬂuxed

for 3 h. The reaction mixture was then allowed to cool to room

temperature overnight. The solvent was removed in vacuo by

azeotroping with ethanol to yield product 16 (3.31 g,

16.8 mmol, 99%) as a light brown solid. Mp>260 ^ꢀC dec;

1

1438 (s) and 1328 cm^ꢁ1(s); H NMR (d, CDCl₃): 7.68 (d, J

8.3 Hz, 4H, CH_Ar), 7.26 (d, J 8.0 Hz, 4H, CH_Ar), 6.04e6.03

(m, 2H, CH]CH), 4.73e4.67 (m, 2H, 2ꢂNH), 3.61e3.54

(m, 2H, 2ꢂCH), 2.69 (br s, 2H, 2ꢂCHC]), 2.37 (s, 6H,

2ꢂCH₃), 1.30 (dt, J 9.6, 2.0 Hz, 1H, CH₂), 1.03 (d, J

9.6 Hz, 1H, CH₂); ¹³C NMR (d, CDCl₃): 144.2 (C_Ar), 137.1

(C_Ar), 136.6 (CH]), 130.3 (CH_Ar), 127.6 (CH_Ar), 55.4

(CHN), 46.7 (CHC]), 44.9 (CH₂), 22.0 (CH₃); m/z (EI, %):

433 (MH^þ, 3), 366 (35), 277 (13), 211 (100); found (ESI)

455.1082 (MþNa^þ), C₂₁H₂₄N₂O₄S₂Na requires 455.1075.

IR (n_max, Nujol): 3470 (w), 2923 (s) and 1564 cm^ꢁ1(m); H

1

NMR (d, DMSO): 8.30 (br s, 6H, 2ꢂNH^þ₃), 6.42 (dd, J 5.5,

3.3 Hz, 1H, CH]), 6.19 (dd, J 5.7, 2.7 Hz, 1H, CH]), 3.59

(d, J 3.2 Hz, 1H, CHN), 3.09 (s, 1H, CHC]), 2.98 (s, 1H,

CHC]), 2.87 (br s, 1H, CHN), 2.02 (d, J 10.1 Hz, 1H,

CH₂), 1.59 (d, J 10.1 Hz, 1H, CH₂); ¹³C NMR (d, DMSO):

138.0 (CH]), 134.1 (CH]), 55.4 (CHN), 55.1 (CHN), 45.7

(CHC]), 44.8 (CH₂), 44.6 (CHC]); m/z (EI, %): 125

(MꢁHCl^þ₂, 100), 108 (39); found (ESI) 125.1080 (MH^þ),

C₇H₁₃N₂requires 125.1079.

4.8. trans-Norborn-5-ene-2,3-dicarbonyl azide (14)

A concentrated aqueous solution of sodium azide (7.42 g,

114.1 mmol) was added dropwise to a stirring solution

of trans-norborn-5-ene-2,3-dicarbonyl chloride 13 (5.00 g,

3.71 ml, 22.8 mmol) in dry THF (50 ml) under an argon atmo-

sphere at ꢁ10 ^ꢀC. The solution was allowed to warm slowly to

room temperature over 1 h and then left for a further hour at

room temperature. The solution was then diluted with water

(50 ml) and extracted with ethyl acetate (3ꢂ50 ml). The com-

bined organic phases were then washed with saturated aq

Na₂CO₃(2ꢂ50 ml), saturated aq NaCl (2ꢂ50 ml), dried over

anhydrous MgSO₄, ﬁltered and evaporated in vacuo to give

product 14 (4.39 g, 18.9 mmol, 98%) as a pale yellow oil. IR

(n_max, neat): 2988 (m), 2263 (m), 2142 (s) and 1701 cm^ꢁ1(s);

¹H NMR (d, CDCl₃): 6.23 (dd, J 5.6, 3.2 Hz, 1H, CH]), 6.07

(dd, J 5.6, 2.8 Hz, 1H, CH]), 3.35 (t, J 4.0 Hz, 1H, CHCO),

3.21 (br s, 1H, CHC]), 3.11 (br s, 1H, CHC]), 2.63 (dd, J

4.5, 1.6 Hz, 1H, CHCO), 1.53 (d, J 9.0 Hz, 1H, CH₂), 1.43

(dq, J 9.0, 1.7 Hz, 1H, CH₂); ¹³C NMR (d, CDCl₃): 181.3

(CO), 180.1 (CO), 138.1 (C]), 135.5 (C]), 50.7 (CHCO),

49.9 (CHCO), 48.5 (CHC]), 47.6 (CH₂), 46.5 (CHC]); m/z

(CI, %): 250 (MþNH^þ₄, 100).

4.11. trans-N,N⁰-Bis-( p-toluenesulfonyl)-2,3-diamino-

norborn-5-ene (17)

To a suspension of trans-2,3-diamino-norborn-5-ene dihy-

drochloride 16 (1.00 g, 5.08 mmol) in dry dichloromethane

(40 ml) was added freshly distilled triethylamine (2.05 g,

2.83 ml, 20.3 mmol), followed by a solution of p-toluenesul-

fonyl chloride (1.93 g, 10.1 mmol) in dry dichloromethane

(20 ml). The mixture was stirred for 16 h at room temperature

under a nitrogen atmosphere. The solution was then acidiﬁed

with 2 M aq HCl and extracted with dichloromethane

(3ꢂ15 ml). The combined organic phases were dried over an-

hydrous MgSO₄, ﬁltered and evaporated in vacuo. The residue

was puriﬁed by column chromatography (hexane/ethyl acetate

60:40) to leave the title compound 17 (1.87 g, 4.33 mmol,

85%) as a white solid. Mp 171e175 ^ꢀC; IR (n_max, CH₂Cl₂):

3522 (w), 3262 (s), 2980 (w), 1652 (w), 1597 (m), 1495

1

(w), 1436 (s) and 1327 cm^ꢁ1(s); H NMR (d, CDCl₃): 7.74

(d, J 8.3 Hz, 4H, CH_Ar), 7.34 (d, J 8.3 Hz, 2H, CH_Ar), 7.35

(d, J 8.3 Hz, 2H, CH_Ar), 6.18 (dd, J 5.7, 3.3 Hz, 1H, CH]),

6.03 (dd, J 5.7, 2.8 Hz, 1H, CH]), 4.88 (br s, 1H, NH),

4.39 (br s, 1H, NH), 3.32 (t, J 2.7 Hz, 1H, CHN), 2.89 (br s,

1H, CHC]), 2.75 (br s, 1H, CHC]), 2.64 (br s, 1H, CHN),

2.46 (s, 3H, CH₃), 2.45 (s, 3H, CH₃), 1.61 (s, 1H, CH₂),

1.62 (s, 1H, CH₂); ¹³C NMR (d, CDCl₃): 143.8 (C_Ar), 137.3

(CH]), 136.3 (C_Ar), 134.8 (CH]), 129.9 (CH_Ar), 129.8

(CH_Ar), 127.2 (CH_Ar), 127.1 (CH_Ar), 62.7 (CHN), 62.5

(CHN), 47.4 (CHC]), 45.3 (CHC]), 44.9 (CH₂), 21.5

(CH₃); m/z (EI, %): 433 (MH^þ, 4), 366 (33), 277 (14), 211

(100); found (ESI) 455.1072 (MþNa^þ), C₂₁H₂₄N₂O₄S₂Na re-

quires 455.1075.

4.9. trans-Norborn-5-ene-2,3-diisocyanate (15)

A stirring solution of trans-norborn-5-ene-2,3-dicarbonyl

azide 14 (4.30 g, 18.5 mmol) in dry toluene (40 ml) was

heated to gentle reﬂux (85e90 ^ꢀC). The reaction was followed

by IR spectroscopy (w2140e2260 cm^ꢁ1), and after 30 min

the solvent was removed in vacuo to yield product 15

(3.13 g, 17.8 mmol, 96%) as a pale golden oil. IR (n_max

,

neat): 2983 (m), 2253 (s) and 1685 cm^ꢁ1(m); H NMR (d,

CDCl₃): 6.27 (dd, J 5.7, 3.3 Hz, 1H, CH]), 6.21 (dd, J 5.8,

2.8 Hz, 1H, CH]), 3.61 (dd, J 3.5, 2.4 Hz, 1H, CHCO),

3.19 (s, 1H, CHCO), 3.00 (br s, 1H, CHC]), 2.86 (br s,

1H, CHC]), 1.73 (d, J 1.1 Hz, 1H, CH₂), 1.72 (d, J 1.3 Hz,

1H, CH₂); ¹³C NMR (d, CDCl₃): 135.8 (C]), 134.6 (C]),

121.6 (NCO), 61.9 (CHN), 50.1 (CHN), 46.9 (CHC), 42.3

(CH₂); m/z (EI, %): 176 (M^þ, 6), 147 (6), 134 (11), 120 (56).

1

4.12. trans-N,N⁰-Bis-(prop-2-ynyl)-N,N⁰-bis-( p-toluene-

sulfonyl)-2,3-diamino-norborn-5-ene (18)

To a stirring solution of trans-N,N⁰-bis-( p-toluenesulfo-

nyl)-2,3-diamino-norborn-5-ene 17 (1.00 g, 2.31 mmol) in

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

213

dimethylformamide (20 ml) at 0 ^ꢀC was slowly added sodium

hydride (0.28 g, 6.94 mmol, 60% in mineral oil). After stirring

for 1 h at 0 ^ꢀC, propargyl bromide (1.72 g, 1.3 ml, 11.6 mmol,

80% in toluene) was added and the reaction mixture was al-

lowed to warm to room temperature. The mixture was then

stirred overnight. To the reaction mixture was added saturated

aq NH₄Cl, and the aqueous layer was extracted with ethyl ac-

etate (4ꢂ15 ml). The combined organic phases were washed

with brine, dried over anhydrous MgSO₄, ﬁltered and evapo-

rated in vacuo to leave a yellow solid, which was recrystallized

from ethyl acetate/hexane to give product 18 (0.85 g,

1.67 mmol, 72%) as a white solid. Mp 138e140 ^ꢀC; IR

(n_max, CH₂Cl₂): 3274 (m), 2979 (w), 2120 (w), 1597 (m),

0.92e0.83 (m, 1H, CH₂); ¹³C NMR (d, CDCl₃): 143.3 (C_Ar),

143.1 (C_Ar), 137.9 (C_Ar), 137.3 (C_Ar), 136.6 (CH]CH₂),

135.7 (CH]CH₂), 135.2 (C]), 131.3 (CH]C), 130.5

(CH]C), 130.0 (C]), 129.5 (CH_Ar), 129.3 (CH_Ar), 127.9

(CH_Ar), 127.6 (CH_Ar), 112.8 (]CH₂), 112.1 (]CH₂), 62.3

(CHN), 55.5 (CHN), 48.1 (CH₂N), 38.9 (CH₂N), 37.4

(CHC]), 31.7 (CHC]), 31.6 (CH₂), 21.6 (CH₃), 21.5

(CH₃); m/z (ESI, %): 559 (MþNa^þ, 100), 537 (MH^þ, 8),

227 (6), 174 (100); found (ESI) 559.1691 (MþNa^þ),

C₂₉H₃₂N₂O₄S₂Na requires 559.1696.

4.14. Trimethylsilyl cis-2-isocyanatocyclohex-4-ene-1-

carboxylate (21)^19,29

1

1494 (w), 1438 (w) and 1335 cm^ꢁ1(s); H NMR (d, CDCl₃):

7.73 (d, J 8.1 Hz, 2H, CH_Ar), 7.67 (d, J 8.1 Hz, 2H, CH_Ar),

7.23 (d, J 6.0 Hz, 4H, CH_Ar), 6.16 (s, 2H, CH]CH), 4.25e

4.20 (m, 2H, CHN, CH₂N), 4.07 (dd, J 18.7, 1.8 Hz, 1H,

CH₂N), 3.82 (dd, J 19.0, 1.9 Hz, 1H, CH₂N), 3.71 (dd, J

18.7, 1.9 Hz, 1H, CH₂N), 3.60 (d, J 4.6 Hz, 1H, CHN), 2.81

(br s, 1H, CHC]), 2.41 (br s, 1H, CHC]), 2.36 (s, 6H,

CH₃), 2.08 (t, J 2.1 Hz, 1H, ^CH), 2.05 (t, J 2.2 Hz, 1H,

^CH), 1.75 (d, J 9.5 Hz, 1H, CH₂), 1.52 (d, J 8.9 Hz, 1H,

CH₂); ¹³C NMR (d, CDCl₃): 143.8 (C_Ar), 143.7 (C_Ar), 137.3

(CH]), 136.6 (C_Ar), 135.3 (CH]), 129.6 (CH_Ar), 129.5

(CH_Ar), 128.0 (CH_Ar), 127.8 (CH_Ar), 79.5 (C^), 79.0 (C^),

73.3 (^CH), 72.7 (^CH), 61.2 (CHN), 57.7 (CHN), 47.2

(CH₂), 45.3 (CHC]), 44.7 (CHC]), 33.7 (CH₂N), 33.3

(CH₂N), 21.6 (CH₃); m/z (CI, %): 526 (MþNH^þ₄, 30), 355

(12), 227 (6), 174 (100); found (ESI) 509.1565 (MH^þ),

C₂₇H₂₉N₂O₄S₂requires 509.1563.

Commercial 1,2,3,6-tetrahydrophthalic anhydride 20 (40.00 g,

263.2 mmol) was puriﬁed by being heated under reﬂux for

3 h with acetic anhydride (72.00 g, 66.5 ml, 705.3 mmol)

and light petroleum ether (210 ml). The mixture was allowed

to cool over 12 h. The white needles, which crystallized

were ﬁltered, washed with dry diethyl ether and dried, afford-

ing pure 1,2,3,6-tetrahydrophthalic anhydride 20 (28.94 g,

190.1 mmol). Mp 101e102 ^ꢀC (lit.²⁹101e102 ^ꢀC).

Freshly recrystallized 1,2,3,6-tetrahydrophthalic anhy-

dride²⁹20 (5.00 g, 32.9 mmol) was dissolved in dry dioxane

(30 ml) under an argon atmosphere. Trimethylsilyl azide

(5.31 g, 6.1 ml, 46.0 mmol) was then added slowly to the

solution at room temperature. The gently stirred solution

was immersed in an oil bath preheated to 70e80 ^ꢀC. A vigor-

ous reaction occurred and was controlled by occasional cool-

ing. After nitrogen evolution had subsided (30e45 min), the

reaction mixture was boiled for 30 min. The solution was

then cooled to 35e40 ^ꢀC and concentrated in vacuo (bath tem-

perature <35 ^ꢀC) to a slightly yellow oil, which was puriﬁed

by distillation under reduced pressure to yield trimethylsilyl

ester 21 (7.27 g, 30.4 mmol, 92%) as a colourless oil. IR

(n_max, neat): 3032 (w), 2946 (w), 2265 (m) and 1720 cm^ꢁ1

4.13. Racemic (4aS,5aR,9aR,9bR)-1,9-bis-(toluene-4-

sulfonyl)-3,7-divinyl-2,4a,5,5a,8,9,9a,9b-octahydro-1H-

cyclopenta[2,1-b;3,4-b⁰]dipyridine (19a)

Diyne 18 (0.100 g, 0.197 mmol) was dissolved in dry di-

chloromethane (17 ml) and ethene was passed through the

stirred solution for 20 min. A solution of ﬁrst generation

Grubbs’ catalyst 1 (0.008 g, 0.010 mmol, 5 mol %) in dry di-

chloromethane (3 ml) was then added and the reaction mixture

was stirred at room temperature for 20 h under an ethene at-

mosphere until all the starting material had been consumed.

The solvent was then removed in vacuo to leave a residue,

which was subjected to column chromatography (dichlorome-

thane/ethyl acetate 95:5) to give tricyclic product 19a

1

(s); H NMR (d, CDCl₃): 5.73e5.70 (m, 1H, CH]), 5.55e

5.52 (m, 1H, CH]), 4.22e4.21 (m, 1H, CHN), 2.61e2.57

(m, 1H, CHCO), 2.41e2.22 (m, 4H, 2ꢂCH₂), 0.25 (s, 9H,

3ꢂCH₃).

4.15. cis-2-Isocyanatocyclohex-4-ene-1-carbonyl

chloride (22)¹⁹

Trimethylsilyl ester^19,2921 (7.27 g, 30.4 mmol) was dis-

solved in carbon tetrachloride (15 ml). Dimethylformamide

(3 drops) was then added followed by freshly distilled thionyl

chloride (5.07 g, 3.1 ml, 42.6 mmol). The reaction mixture

was heated to 40e50 ^ꢀC in an oil bath. Gas evolution began

within 5e10 min. The temperature of the reaction mixture was

maintained at w50 ^ꢀC and the progress of the reaction was

followed by infrared spectroscopy. Upon disappearance of the

ester group absorption at 1720 cm^ꢁ1(30e45 min), the solu-

tion was cooled to room temperature and concentrated in

vacuo to leave a viscous yellow oil, which was distilled under

reduced pressure to afford the desired product 22 (4.52 g,

24.4 mmol, 80%) as a colourless oil. The compound was used

(0.045 g, 0.085 mmol, 43%) as a colourless oil. IR (n_max

CH₂Cl₂): 2980 (w), 1652 (w), 1596 (w), 1494 (w), 1436 (m)

,

1

and 1334 cm^ꢁ1(s); H NMR (d, CDCl₃): 7.86 (d, J 8.3 Hz,

2H, CH_Ar), 7.66 (d, J 8.2 Hz, 2H, CH_Ar), 7.24 (d, J 8.1 Hz,

2H, CH_Ar), 7.13 (d, J 8.1 Hz, 2H, CH_Ar), 6.13 (dd, J 17.8,

11.0 Hz, 1H, CH]CH₂), 5.96 (dd, J 17.8, 11.0 Hz, 1H,

CH]CH₂), 5.72 (s, 1H, CH]C), 5.22 (s, 1H, CH]C),

5.10e4.91 (m, 5H, 2ꢂ]CH₂, CHN), 4.34 (d, J 18.3 Hz,

1H, CH₂N), 4.15 (d, J 17.1 Hz, 1H, CH₂N), 3.84 (d, J

17.1 Hz, 1H, CH₂N), 3.57 (d, J 18.3 Hz, 1H, CH₂N), 3.13 (t,

J 11.2 Hz, 1H, CHN), 2.55e2.49 (m, 2H, CHCH]), 2.36

(s, 3H, CH₃), 2.31 (s, 3H, CH₃), 2.17e2.09 (m, 1H, CH₂),

214

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

immediately in the next reaction. IR (n_max, neat): 3032 (w),

1

4.18. cis-N,N⁰-Bis-allyl-N,N⁰-bis-( p-toluenesulfonyl)-1,2-

diamino-cyclohex-4-ene (26)

2945 (w), 2250 (m) and 1790 cm^ꢁ1(s); H NMR (d, CDCl₃):

5.82e5.79 (m, 1H, CH]), 5.69e5.66 (m, 1H, CH]), 4.47

(br s, 1H, CHN), 3.10 (ddd, J 10.6, 6.0, 2.0 Hz, 1H, CHCO),

2.64e2.41 (m, 4H, 2ꢂCH₂).

To a stirring solution of cis-N,N⁰-bis-( p-toluenesulfonyl)-

1,2-diamino-cyclohex-4-ene 25 (0.50 g, 1.19 mmol) in dime-

thylformamide (15 ml) at 0 ^ꢀC was slowly added sodium

hydride (0.14 g, 3.57 mmol, 60% in mineral oil). After stirring

for 2 h at 0 ^ꢀC, allyl bromide (0.72 g, 0.52 ml, 5.95 mmol)

was added and the reaction mixture was allowed to warm to

room temperature. The mixture was then stirred overnight.

To the reaction mixture was added saturated aq NH₄Cl, and

the aqueous layer was extracted with diethyl ether

(4ꢂ20 ml). The combined organic phases were washed with

brine, dried over anhydrous MgSO₄, ﬁltered and evaporated

in vacuo to leave a residue, which was puriﬁed by column

chromatography (dichloromethane/ethyl acetate 95:5) to give

the desired compound 26 (0.58 g, 1.16 mmol, 98%) as a white

solid. Mp 175e177 ^ꢀC; IR (n_max, CH₂Cl₂): 3076 (m), 3037

(m), 2977 (m), 2922 (s), 1639 (m), 1596 (s), 1495 (m), 1432

(s) and 1335 cm^ꢁ1(s); ¹H NMR (d, CDCl₃): 7.61 (d, J

8.2 Hz, 4H, CH_Ar), 7.22 (d, J 8.1 Hz, 4H, CH_Ar), 5.92 (ddt,

J 16.5, 10.3, 6.2 Hz, 2H, CH]CH₂), 5.51 (s, 2H, CH]CH),

5.06 (dd, J 17.3, 1.7 Hz, 2H, 2ꢂ]CH₂), 5.02 (dd, J 10.3,

1.0 Hz, 2H, 2ꢂ]CH₂), 4.04 (t, J 5.5 Hz, 2H, 2ꢂCHN), 3.95

(d, J 5.8 Hz, 4H, 2ꢂCH₂N), 2.37 (s, 6H, 2ꢂCH₃), 2.09 (dd,

4.16. cis-1,2-Diamino-cyclohex-4-ene dihydrochloride

(24)¹⁹

Acid chloride¹⁹22 (4.52 g, 24.4 mmol) was dissolved in

dry dioxane (14 ml) under an argon atmosphere. Trimethyl-

silyl azide (3.93 g, 4.5 ml, 34.1 mmol) was added dropwise

at room temperature to the stirring solution, which was subse-

quently heated to 70e80 ^ꢀC in an oil bath. Vigorous nitrogen

evolution began within 5e10 min and continued for 20e

30 min. The reaction was then cooled to 35e40 ^ꢀC and diluted

with acetone. Concentrated hydrochloric acid (7 ml) was

added cautiously through the top of the condenser. Stirring

was continued until CO₂formation ceased (w30 min). The

resulting precipitate was ﬁltered and washed with

acetone and diethyl ether, providing the bis-ammonium chlo-

ride salt 24 (2.40 g, 13.0 mmol, 53%) as a white powder.

1

Mp 285e290 ^ꢀC (lit.¹⁹255e265 ^ꢀC); H NMR (d, DMSO):

8.56 (br s, 6H, 2ꢂNH₃), 5.65 (s, 2H, CH]CH), 3.70 (br s,

2H, 2ꢂCH), 2.54e2.50 (m, 2H, CH₂), 2.29 (dd, J 17.2,

6.7 Hz, 2H, CH₂).

J

16.9, 5.1 Hz, 2H, 2ꢂCH₂C]), 1.8e1.9 (m, 2H,

2ꢂCH₂C]); ¹³C NMR (d, CDCl₃): 143.6 (C_Ar), 137.8

(C_Ar), 137.2 (CH]CH₂), 130.0 (CH_Ar), 128.0 (CH_Ar), 126.5

(CH]CH), 117.3 (]CH₂), 55.9 (CHN), 48.7 (NCH₂), 28.9

(eCHCH₂), 21.9 (CH₃); m/z (CI, %): 518 (MþNH^þ₄, 100),

345 (14), 283 (13), 191 (66), 174 (70); found (ESI)

501.1879 (MH^þ), C₂₆H₃₃N₂O₄S₂requires 501.1876.

4.17. cis-N,N⁰-Bis-( p-toluenesulfonyl)-1,2-diamino-

cyclohex-4-ene (25)

To a suspension of cis-1,2-diamino-cyclohex-4-ene dihy-

drochloride¹⁹24 (2.00 g, 10.8 mmol) in dry dichloromethane

(80 ml) was added freshly distilled triethylamine (4.38 g,

6.0 ml, 43.2 mmol), followed by a solution of p-toluenesul-

fonyl chloride (4.53 g, 23.8 mmol) in dry dichloromethane

(30 ml). The reaction mixture was stirred for 16 h at room

temperature under a nitrogen atmosphere. The solution was

then acidiﬁed with 2 M aq HCl and extracted with dichlorome-

thane (3ꢂ20 ml). The combined organic phases were dried

over anhydrous MgSO₄, ﬁltered and evaporated in vacuo.

The residue was puriﬁed by column chromatography (ﬁrst

hexane/ethyl acetate 60:40 and then dichloromethane/ethyl

acetate 90:10) to afford ditosylate 25 (3.38 g, 8.05 mmol,

75%) as a white solid. Mp 180e182 ^ꢀC; IR (n_max, CH₂Cl₂):

3271 (s), 3034 (w), 2923 (w), 1597 (m), 1437 (s) and

4.19. Metathesis products racemic (3Z,6aR,10aS )-

1,2,5,6,6a,7,10,10a-octahydro-1,6-ditosyl-

benzo[b][1,4]diazocine (27) and racemic (R)-1,2,3,6-

tetrahydro-2-((S )-1,2,3,6-tetrahydro-1-tosyl-

pyridin-2-yl)-1-tosylpyridine (28)

4.19.1. Procedure A

To a stirring solution of compound 26 (0.050 g, 0.100 mmol)

in dry dichloromethane (8 ml) was added a solution of ﬁrst

generation Grubbs’ catalyst 1 (0.004 g, 0.005 mmol, 5 mol %)

in dry dichloromethane (2 ml). The reaction mixture was

stirred for 20 h at room temperature under a nitrogen atmo-

sphere. After the solvent was removed in vacuo, the residue

was puriﬁed by column chromatography (dichloromethane/

ethyl acetate 96:4) to afford 6,8-fused bicyclic product 27

(0.047 g, 0.100 mmol, 100%) as a white solid.

1

1328 cm^ꢁ1(s); H NMR (d, CDCl₃): 7.71 (d, J 8.3 Hz, 4H,

CH_Ar), 7.33 (d, J 8.1 Hz, 4H, CH_Ar), 5.50 (s, 2H, CH]CH),

4.97 (d, J 9.1 Hz, 2H, 2ꢂNH), 3.30e3.56 (m, 2H, 2ꢂCHN),

2.47 (s, 6H, 2ꢂCH₃), 2.25 (dd, J 16.9, 4.8 Hz, 2H, 2ꢂCH₂),

1.84 (dd, J 17.3, 6.5 Hz, 2H, 2ꢂCH₂); ¹³C NMR (d,

CDCl₃): 144.1 (C_Ar), 137.9 (C_Ar), 130.2 (CH_Ar), 127.6

(CH_Ar), 124.7 (CH]CH), 51.3 (CHN), 31.0 (CH₂), 22.0

(CH₃); m/z (CI, %): 438 (MþNH^þ₄, 100), 353 (8), 267 (21);

found (ESI) 443.1072 (MþNa^þ), C₂₀H₂₄N₂O₄S₂Na requires

443.1070.

4.19.2. Procedure B

To

a stirring solution of compound 26 (0.060 g,

0.120 mmol) in dry dichloromethane (10 ml) was added a solu-

tion of second generation Grubbs’ catalyst 2 (0.005 g,

0.006 mmol, 5 mol %) in dry dichloromethane (2 ml). The re-

action mixture was stirred for 20 h at room temperature under

a nitrogen atmosphere. After the solvent was removed in

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

215

vacuo, the residue was subjected to column chromatography

(dichloromethane/ethyl acetate 98:2) to give RCM product

27 (0.040 g, 0.085 mmol, 71%) together with ROM/RCM

product 28 (0.016 g, 0.034 mmol, 29%) as white solids.

170e172 ^ꢀC; IR (n_max, CH₂Cl₂): 3268 (m), 3033 (w), 2923

(w), 1645 (w), 1597 (m), 1494 (w), 1436 (m), 1332 (s) and

1160 cm^ꢁ1(s); ¹H NMR (d, CDCl₃): 7.7e7.5 (m, 4H,

CH_Ar), 7.3e7.1 (m, 4H, CH_Ar), 5.71 (ddt, J 16.1, 10.3,

5.8 Hz, 1H, CH]CH₂), 5.52 (d, J 9.9 Hz, 1H, CH]CH),

5.36 (dd, J 10.1, 1.7 Hz, 1H, CH]CH ), 5.08 (dd, J 17.2,

1.3 Hz, 1H, ]CH₂), 5.01 (dd, J 10.2, 1.2 Hz, 1H, ]CH₂),

4.89 (d, J 8.8 Hz, 1H, NH), 4.01 (ddt, J 17.2, 5.8, 1.4 Hz,

1H, NCH₂), 3.85 (dd, J 17.1, 5.8 Hz, 1H, NCH₂), 3.82e3.79

(m, 1H, CHN), 3.41e3.35 (m, 1H, CHNH), 2.38 (s, 3H,

CH₃), 2.37 (s, 3H, CH₃), 2.16e2.01 (m, 3H, CH₂CHN), 1.65

(br d, J 16.7 Hz, 1H, CH₂CHN); ¹³C NMR (d, CDCl₃):

143.6 (C_Ar), 143.4 (C_Ar), 137.7 (C_Ar), 137.4 (C_Ar), 136.4

(CH]CH₂), 129.7 (CH_Ar), 127.3 (CH_Ar), 127.1 (CH_Ar),

126.0 (CH]CH), 123.7 (CH]CH), 116.7 (]CH₂), 54.5

(CHN), 51.2 (CHNH), 47.8 (CH₂NH), 32.2 (CH₂CH), 26.9

(CH₂CH), 21.6 (CH₃); m/z (CI, %): 478 (MþNH^þ₄, 100),

307 (34), 267 (11), 174 (41); found (ESI) 483.1376 (MþNa^þ),

C₂₃H₂₈N₂S₂O₄Na requires 483.1383.

4.19.3. Data for 27

Mp 166e169 ^ꢀC; IR (n_max, CH₂Cl₂): 3028 (w), 2920 (w),

1639 (w), 1597 (m), 1493 (w), 1334 (s) and 1157 cm^ꢁ1(s);

¹H NMR (d, CDCl₃): 7.56 (d, J 8.3 Hz, 4H, CH_Ar), 7.23 (d,

J 8.2 Hz, 4H, CH_Ar), 5.69 (t, J 3.3 Hz, 2H, 2ꢂ]CHCH₂N),

5.47 (s, 2H, 2ꢂ]CHCH₂CH), 4.30 (dd, J 16.7, 2.7 Hz, 2H,

2ꢂNCH₂), 4.15 (t, J 4.9 Hz, 2H, 2ꢂCHN), 3.91 (dd, J 17.3,

3.3 Hz, 2H, 2ꢂNCH₂), 2.43e2.34 (m, 2H, 2ꢂCH₂CHN),

2.37 (s, 6H, 2ꢂCH₃), 2.22 (dd, J 17.4, 5.7 Hz, 2H,

2ꢂCH₂CHN); ¹³C NMR (d, CDCl₃): 143.4 (C_Ar), 137.5

(C_Ar), 129.8 (CH_Ar), 128.7 (]CHCH₂N), 126.8 (CH_Ar),

125.2 (]CHCH₂CH), 53.9 (CHN), 43.5 (NCH₂), 30.2

(CH₂CH), 21.6 (CH₃); m/z (CI, %): 490 (MþNH^þ₄, 100),

317 (10), 255 (7), 163 (43); found (ESI) 490.1822 (MþNH^þ₄),

C₂₄H₃₂N₃O₄S₂requires 490.1829.

4.19.4. Data for 28

Mp 172e174 ^ꢀC; IR (n_max, CH₂Cl₂): 2921 (w), 1648 (w),

4.21. cis-N-Allyl-N⁰-prop-2-ynyl-N,N⁰-bis-( p-toluene-

sulfonyl)-1,2-diamino-cyclohex-4-ene (30)

1

1596 (w), 1496 (m), 1334 (s) and 1159 cm^ꢁ1(s); H NMR

(d, CDCl₃): 7.56 (d, J 8.2 Hz, 4H, CH_Ar), 7.23 (d, J 8.1 Hz,

4H, CH_Ar), 5.54e5.51 (m, 4H, 2ꢂCH]CH), 4.14e4.13 (m,

2H, 2ꢂCH₂N), 4.07 (br s, 2H, 2ꢂCHN), 3.58e3.57 (m, 1H,

CH₂N), 3.52e3.51 (m, 1H, CH₂N), 2.33 (s, 6H, 2ꢂCH₃),

2.18 (d, J 17.6 Hz, 2H, CHCH₂C]), 1.77 (d, J 16.8 Hz, 2H,

CHCH₂C]); ¹³C NMR (d, CDCl₃): 143.8 (C_Ar), 137.9

(C_Ar), 130.1 (CH_Ar), 127.2 (CH_Ar), 124.6 (CH]), 122.0

(CH]), 49.6 (CHN), 41.0 (CH₂N), 23.2 (CH₂CH), 22.0

(CH₃); m/z (CI, %): 490 (MþNH^þ₄, 100), 317 (10); found

(ESI) 495.1379 (MþNa^þ), C₂₄H₂₈N₂O₄S₂Na requires

495.1383.

To a stirring solution of cis-N-allyl-N,N⁰-bis-( p-toluenesul-

fonyl)-1,2-diamino-cyclohex-4-ene 29 (0.20 g, 0.44 mmol) in

dimethylformamide (8 ml) at 0 ^ꢀC was slowly added sodium

hydride (0.05 g, 1.30 mmol, 60% in mineral oil). After stirring

for 2 h at 0 ^ꢀC, propargyl bromide (0.13 g, 0.10 ml,

1.30 mmol) was added and the reaction mixture was allowed

to warm to room temperature. The mixture was then stirred

overnight. To the reaction mixture was added saturated aq

NH₄Cl, and the aqueous layer was extracted with diethyl ether

(4ꢂ10 ml). The combined organic phases were washed with

brine, dried over anhydrous MgSO₄, ﬁltered and evaporated

in vacuo to leave a residue, which was puriﬁed by column

chromatography (dichloromethane/ethyl acetate 95:5) to give

the desired compound 30 (0.17 g, 0.34 mmol, 78%) as a white

solid. Mp 162e164 ^ꢀC; IR (n_max, CH₂Cl₂): 3273 (m), 3032

(w), 2923 (m), 2118 (w), 1639 (m), 1598 (s), 1497 (m),

4.20. cis-N-Allyl-N,N⁰-bis-( p-toluenesulfonyl)-1,2-

diamino-cyclohex-4-ene (29)

To a stirring solution of cis-N,N⁰-bis-( p-toluenesulfonyl)-

1,2-diamino-cyclohex-4-ene 25 (0.60 g, 1.43 mmol) in dime-

thylformamide (15 ml) at 0 ^ꢀC was slowly added sodium

hydride (0.07 g, 1.71 mmol, 60% in mineral oil). After stirring

for 2 h at 0 ^ꢀC, allyl bromide (0.17 g, 0.12 ml, 1.43 mmol)

was added and the reaction mixture was allowed to warm to

room temperature. The mixture was then stirred overnight. To

the reaction mixture was added saturated aq NH₄Cl, and the

aqueous layer was extracted with diethyl ether (4ꢂ20 ml).

The combined organic phases were washed with brine,

dried over anhydrous MgSO₄, ﬁltered and evaporated in vacuo

to leave a crude product. The residue was subjected to col-

umn chromatography (hexane/dichloromethane/ethyl acetate

50:50:10) to give the title compound 29 (0.24 g, 0.53 mmol,

37%) as a white solid. cis-N,N⁰-Bis-allyl-N,N⁰-bis-( p-toluene-

sulfonyl)-1,2-diamino-cyclohex-4-ene 26 (0.30 g, 0.61 mmol,

43%) and cis-N,N⁰-bis-( p-toluenesulfonyl)-1,2-diamino-cyclo-

hex-4-ene 25 (0.02 g, 0.04 mmol, 3%) were also obtained. Mp

1

1432 (s), 1332 (s) and 1161 cm^ꢁ1(s); H NMR (d, CDCl₃):

7.69 (d, J 8.3, Hz, 2H, CH_Ar), 7.65 (d, J 8.2 Hz, 2H, CH_Ar),

7.21 (d,

J 8.4 Hz, 4H, CH_Ar), 6.00e5.89 (m, 1H,

CH]CH₂), 5.53 (s, 2H, CH]CH), 5.09 (dd, J 17.5, 1.8 Hz,

1H, ]CH₂), 5.05 (dd, J 10.4, 1.1 Hz, 1H, ]CH₂), 4.36 (dd,

J 18.9, 2.2 Hz, 1H, CH₂C^), 4.20e4.13 (m, 2H, CH₂C^,

CHN), 4.02e3.83 (m, 3H, CH₂C], CHN), 2.37 (s, 3H,

CH₃), 2.35 (s, 3H, CH₃), 2.23e2.16 (m, 3H, CH₂CHN), 2.11

(t, J 2.4 Hz, 1H, ^CH), 1.89 (br d, J 18.2 Hz, 1H, CH₂CHN);

¹³C NMR (d, CDCl₃): 143.4 (C_Ar), 143.3 (C_Ar), 137.1 (C_Ar),

136.6 (CH]CH₂), 129.6 (CH_Ar), 129.4 (CH_Ar), 127.7

(CH_Ar), 127.5 (CH_Ar), 126.0 (CH]CH), 125.8 (CH]CH),

117.2 (]CH₂), 80.5 (C^), 72.6 (^CH), 55.8 (CHN), 55.0

(CHN), 48.1 (NCH₂), 34.7 (CH₂C^), 28.5 (CH₂CH), 27.4

(CH₂CH), 21.6 (CH₃); m/z (CI, %): 516 (MþNH^þ₄, 100),

345 (10), 174 (32); found (ESI) 516.1982 (MþNH^þ₄),

C₂₆H₃₄N₃O₄S₂requires 516.1985.

216

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

4.22. Metathesis products racemic (1R,2S )-N¹-allyl-N²-

(2-methylenebut-3-enyl)-N¹,N²-ditosylcyclohex-4-ene-

1,2-diamine (31) and racemic (3Z,6aR,10aS )-

1,2,5,6,6a,7,10,10a-octahydro-1,6-ditosyl-3-

vinylbenzo[b][1,4]diazocine (32)

5.50e5.41 (m, 2H, CH]CH), 5.15 (d, J 17.3 Hz, 1H,

]CH₂), 5.01 (d, J 11.0 Hz, 1H, ]CH₂), 4.48e4.42 (m, 2H,

2ꢂNCH₂), 4.21e4.13 (m, 2H, 2ꢂNCH), 4.09e4.04 (m, 2H,

2ꢂNCH₂), 2.38 (s, 3H, CH₃), 2.38 (s, 3H, CH₃), 2.34e2.09

(m, 4H, 2ꢂCH₂); ¹³C NMR (d, CDCl₃): 143.6 (C_Ar)*, 143.4

(C_Ar)*, 139.7 (C])*, 138.4 (CH]CH₂), 137.5 (C_Ar), 137.3

(C_Ar), 129.9 (CH_Ar), 129.8 (CH_Ar), 128.2 (CH]C), 126.9

(CH_Ar), 126.8 (CH_Ar), 126.0 (CH]CH), 124.8 (CH]CH),

113.6 (]CH₂), 52.7 (CHN), 52.6 (CHN), 43.1 (NCH₂), 42.3

(NCH₂), 30.7 (CH₂CH), 30.6 (CH₂CH), 21.6 (CH₃); m/z

(CI, %): 516 (MþNH^þ₄, 86), 188 (79), 174 (100); found (ESI)

499.1720 (MH^þ), C₂₆H₃₁N₂O₄S₂requires 499.1720.

4.22.1. Procedure A

Compound 30 (0.050 g, 0.100 mmol) was dissolved in dry

dichloromethane (8 ml) and ethene was passed through the

stirred solution for 20 min. A solution of ﬁrst generation

Grubbs’ catalyst 1 (0.008 g, 0.010 mmol, 10 mol %) in dry di-

chloromethane (2 ml) was then added and the reaction mixture

was stirred at 35 ^ꢀC for 20 h under an ethene atmosphere. The

solvent was then removed in vacuo. The residue was subjected

to column chromatography (dichloromethane/ethyl acetate

98:2) to give product 31 as a colourless oil (0.042 g,

0.080 mmol, 79%). Data for 31. IR (n_max, CH₂Cl₂): 3268 (s),

3133 (m), 2923 (m), 1732 (s), 1645 (w), 1598 (m), 1494

(w), 1436 (m), 1336 (s) and 1160 cm^ꢁ1(s); ¹H NMR

(d, CDCl₃): 7.76 (d, J 8.2 Hz, 2H, CH_Ar), 7.33 (d J 8.1 Hz,

2H, CH_Ar), 7.29 (d, J 8.1 Hz, 2H, CH_Ar), 7.17 (d, J 8.1 Hz,

2H, CH_Ar), 6.35 (dd, J 17.9, 11.2 Hz, 1H, CeCH]CH₂),

5.92e5.85 (m, 1H, CH₂eCH]CH₂), 5.57e5.56 (m, 1H,

CH]CH), 5.42e5.41 (m, 1H, CH]CH ), 5.23 (s, 1H,

C]CH₂), 5.21 (d, J 18.0 Hz, 1H, CH]CH₂), 5.13 (s,

1H, C]CH₂), 5.05 (d, J 11.2 Hz, 1H, CH]CH₂), 4.9e5.0

(m, 2H, CH]CH₂), 4.63e4.58 (m, 1H, CH₂C]), 4.45e

4.40 (m, 1H, CH₂C]), 4.03e4.00 (m, 1H, CHN), 3.86e

3.84 (m, 1H, CHN), 3.70e3.63 (m, 2H, NCH₂), 2.42 (s, 3H,

CH₃), 2.35 (s, 3H, CH₃), 2.17e2.01 (m, 3H, CH₂CH), 1.23

(br d, 1H, CH₂CH); ¹³C NMR (d, CDCl₃): 143.4 (C])*,

143.3 (C_Ar)*, 143.0 (C_Ar)*, 137.1 (CH]), 136.6 (CH]),

129.6 (CH_Ar), 129.5 (CH_Ar), 127.9 (CH_Ar), 127.2 (CH_Ar),

125.2 (CH]CH), 117.2 (]CH₂), 116.4 (C]CH₂), 113.7

(]CH₂), 55.2 (CHN), 55.1 (CHN), 48.1 (NCH₂), 46.7

(NCH₂), 29.8 (CH₂CH), 27.9 (CH₂CH), 21.6 (CH₃), 21.5

(CH₃); m/z (CI, %): 544 (MþNH^þ₄, 72), 490 (100), 373 (29),

217 (45), 188 (25), 174 (84); found (ESI) 527.2026 (MH^þ),

C₂₈H₃₅N₂O₄S₂requires 527.2033.

4.23. cis-N,N⁰-Bis-(prop-2-ynyl)-N,N⁰-bis-( p-toluene-

sulfonyl)-1,2-diamino-cyclohex-4-ene (33)

To a stirring solution of cis-N,N⁰-bis-( p-toluenesulfonyl)-

1,2-diamino-cyclohex-4-ene 25 (0.50 g, 1.19 mmol) in dime-

thylformamide (15 ml) at 0 ^ꢀC was slowly added sodium

hydride (0.14 g, 3.57 mmol, 60% in mineral oil). After stirring

for 2 h at 0 ^ꢀC, propargyl bromide (0.89 g, 0.66 ml,

5.95 mmol, 80% in toluene) was added and the reaction mix-

ture was allowed to warm to room temperature. The mixture

was then stirred overnight. To the reaction mixture was added

saturated aq NH₄Cl, and the aqueous layer was extracted with

diethyl ether (4ꢂ10 ml). The combined organic phases were

washed with brine, dried over anhydrous MgSO₄, ﬁltered

and evaporated in vacuo to leave a residue, which was puriﬁed

by column chromatography (dichloromethane/ethyl acetate

95:5) to afford the desired product 33 (0.54 g, 1.14 mmol,

96%) as a pale yellow solid. Mp 168e172 ^ꢀC; IR (n_max

,

CH₂Cl₂): 3275 (s), 3032 (w), 2923 (m), 2118 (w), 1598 (s),

1

1497 (w), 1434 (m), 1347 (s) and 1161 cm^ꢁ1(s); H NMR

(d, CDCl₃): 7.73 (d, J 8.3 Hz, 4H, CH_Ar), 7.22 (d, J 8.1 Hz,

4H, CH_Ar), 5.57 (s, 2H, CH]CH), 4.25 (d, J 1.9 Hz, 4H,

2ꢂCH₂C^), 4.10e4.04 (m, 2H, CHN), 2.36 (s, 6H,

2ꢂCH₃), 2.22 (br s, 4H, 2ꢂCH₂CH), 2.17 (t, J 2.3 Hz, 2H,

^CH); ¹³C NMR (d, CDCl₃): 143.9 (C_Ar), 137.3 (C_Ar),

129.2 (CH_Ar), 128.1 (CH_Ar), 126.3 (CH]), 80.9 (C^), 73.2

(^CH), 55.7 (CHN), 35.0 (NCH₂), 28.2 (CH₂CH), 22.0

(CH₃); m/z (CI, %): 514 (MþNH^þ₄, 100), 341 (8), 174 (43);

found (ESI) 519.1386 (MþNa^þ), C₂₆H₂₈N₂O₄S₂Na requires

519.1383.

4.22.2. Procedure B

To a stirring solution of compound 30 (0.05 g, 0.100 mmol)

in dry dichloromethane (8 ml) was added a solution of ﬁrst

generation Grubbs’ catalyst

1

(0.008 g, 0.010 mmol,

10 mol %) in dry dichloromethane (2 ml). The reaction mix-

ture was stirred for 20 h at 35 ^ꢀC under a nitrogen atmosphere.

After the solvent was removed in vacuo, the residue was sub-

jected to column chromatography (dichloromethane/ethyl ace-

tate 98:2) to afford 6,8-fused bicyclic diene 32 (0.028 g,

0.056 mmol, 56%) as a white solid. Unreacted starting mate-

rial 30 (13%) was also recovered. Data for 32. Mp 165e

167 ^ꢀC; IR (n_max, CH₂Cl₂): 3032 (w), 2920 (w), 2849 (w),

1639 (w), 1596 (m), 1496 (w), 1432 (m), 1334 (s) and

4.24. Metathesis products racemic (R)-1,2,3,6-

tetrahydro-2-((S )-1,2,3,6-tetrahydro-1-tosyl-5-

vinylpyridine-2-yl)-1-tosyl-5-vinylpyridine (34) and

racemic (1R,2S )-N¹-(2-methylenebut-3-enyl)-N²-(prop-

2-ynyl)-N¹,N²-ditosylcyclohex-4-ene-1,2-diamine (35)

cis-N,N⁰-Bis-(prop-2-ynyl)-N,N⁰-bis-(p-toluenesulfonyl)-1,2-

diamino-cyclohex-4-ene 33 (0.100 g, 0.212 mmol) was dis-

solved in dry dichloromethane (16 ml) and ethene was passed

through the stirred solution for 20 min. A solution of ﬁrst gen-

eration Grubbs’ catalyst 1 (0.017 g, 0.021 mmol, 10 mol %) in

dry dichloromethane (5 ml) was then added and the reaction

mixture was stirred at room temperature for 20 h under an

1

1157 cm^ꢁ1(s); H NMR (d, CDCl₃): 7.57 (d, J 8.0 Hz, 2H,

CH_Ar), 7.55 (d, J 7.6 Hz, 2H, CH_Ar), 7.25 (d, J 8.0 Hz, 2H,

CH_Ar), 7.24 (d, J 8.0 Hz, 2H, CH_Ar), 6.19 (dd, J 17.7,

11.2 Hz, 1H, CH]CH₂), 5.74 (t, J 6.9 Hz, 1H, CH]C),

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

217

ethene atmosphere. The solvent was then removed in vacuo.

References and notes

The residue was subjected to column chromatography (di-

chloromethane/ethyl acetate 96:4) to give compound 34

(0.017 g, 0.032 mmol, 16%) as a white solid and compound

35 (0.067 g, 0.127 mmol, 63%) as a colourless oil. Unreacted

starting material 33 (21%) was also recovered.

1. For reviews of metathesis reactions using ruthenium based initiators see:

(a) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012e3043; (b) Trnka,

¨

T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18e29; (c) Blechert,

D. S.; Connon, S. J. Angew. Chem., Int. Ed. 2003, 42, 1900e1923; (d)

McReynolds, M. D.; Dougherty, J. M.; Hanson, P. R. Chem. Rev. 2004,

104, 2239e2258; (e) Grubbs, R. H. Tetrahedron 2004, 60, 7117e7140;

(f) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.

2005, 44, 4490e4527; (g) Wallace, D. J. Angew. Chem., Int. Ed. 2005,

44, 1912e1915; (h) Donohoe, T. J.; Orr, A. J. Angew. Chem., Int. Ed.

2006, 45, 2664e2670; (i) Grubbs, R. H. Angew. Chem., Int. Ed. 2006,

45, 3760e3765; (j) Arisawa, M.; Nishida, A.; Nakagawa, M. J. Organo-

met. Chem. 2006, 691, 5109e5121; (k) Colacino, E.; Martinez, J.;

Lamaty, F. Coord. Chem. Rev. 2007, 251, 726e764.

4.24.1. Data for 34

Mp>182 ^ꢀC dec; IR (n_max, CH₂Cl₂): 2923 (w), 2850 (w),

1652 (w), 1596 (w), 1496 (w), 1432 (m), 1344 (s) and

1

1159 cm^ꢁ1(s); H NMR (d, CDCl₃): 7.52 (d, J 8.3 Hz, 4H,

CH_Ar), 7.15 (d, J 8.0 Hz, 4H, CH_Ar), 6.16 (dd, J 17.9,

11.1 Hz, 2H, CH]CH₂), 5.48 (d, J 4.5 Hz, 2H, CH]C),

4.98 (d, J 18.6 Hz, 2H, ]CH₂), 4.94 (d, J 11.7 Hz, 2H,

]CH₂), 4.36 (d, J 18.3 Hz, 2H, 2ꢂNCH₂), 3.96 (dd, J 3.5,

1.5 Hz, 2H, 2ꢂCHN), 3.60 (d, J 18.3 Hz, 2H, 2ꢂNCH₂),

2.32 (s, 6H, 2ꢂCH₃), 2.26 (dd, J 18.4, 4.4 Hz, 2H,

2ꢂCH₂CH), 1.84 (d, J 18.3 Hz, 2H, 2ꢂCH₂CH); ¹³C NMR

(d, CDCl₃): 143.4 (C_Ar), 137.3 (C_Ar), 136.5 (CH]CH₂),

130.4 (C]), 129.7 (CH_Ar), 126.7 (CH_Ar), 125.4 (CH]C),

111.2 (CH₂]), 49.3 (CHN), 39.8 (CH₂N), 23.3 (CH₃), 21.5

(CH₂CH); m/z (CI, %): 542 (MþNH^þ₄, 89), 371 (26), 174

(100); found (ESI) 525.1883 (MH^þ), C₂₈H₃₃N₂O₄S₂requires

525.1876.

2. For recent reviews of enyne metathesis see: (a) Poulsen, C. S.; Madsen, R.

Synthesis 2003, 1e18; (b) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004,

104, 1317e1382; (c) Maifeld, S. V.; Lee, D. Chem.dEur. J. 2005, 11,

6118e6126; (d) Van de Weghe, P.; Bisseret, P.; Blanchard, N.; Eustache,

J. J. Organomet. Chem. 2006, 691, 5078e5108; (e) Diver, S. T. Coord.

Chem. Rev. 2007, 251, 671e701; (f) Mori, M. Adv. Synth. Catal. 2007,

349, 121e135; (g) Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev.

2007, 36, 55e66.

3. For selected examples see: (a) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H.

J. Am. Chem. Soc. 1997, 119, 3887e3897; (b) Robson, D. A.; Gibson,

V. C.; Davies, R. G.; North, M. Macromolecules 1999, 32, 6371e6373;

(c) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda,

A. H. J. Am. Chem. Soc. 1999, 121, 791e799; (d) Weskamp, T.; Kohl,

F. J.; Hieringer, W.; Gleich, D.; Herrmann, W. A. Angew. Chem., Int. Ed.

1999, 38, 2416e2419; (e) Lynn, D. M.; Mohr, B.; Grubbs, R. H.; Henling,

L. M.; Day, M. W. J. Am. Chem. Soc. 2000, 122, 6601e6609; (f) Furstner,

¨

4.24.2. Data for 35

A.; Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.;

Stelzer, F.; Thiel, O. R. Chem.dEur. J 2001, 7, 3236e3253; (g)

Castarlenas, R.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2003, 42, 4524e

4527.

IR (n_max, CH₂Cl₂): 3270 (s), 3131 (m), 2924 (m), 1734 (m),

1598 (s), 1493 (m), 1436 (m), 1336 (s) and 1160 cm^ꢁ1(s); ¹H

NMR (d, CDCl₃): 7.75 (d, J 8.3 Hz, 2H, CH_Ar), 7.43 (d, J

8.2 Hz, 2H, CH_Ar), 7.28 (d, J 8.0 Hz, 2H, CH_Ar), 7.16 (d, J

4. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118,

100e110.

8.0 Hz, 2H, CH_Ar), 6.34 (dd,

J 17.9, 11.2 Hz, 1H,

5. Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc.

2003, 125, 10103e10109.

CH]CH₂), 5.62e5.59 (m, 1H, CH]CH), 5.45e5.43 (m,

1H, CH]CH ), 5.22 (d, J 18.0 Hz, 1H, CH]CH₂), 5.19

(s, 1H, C]CH₂), 5.14 (s, 1H, C]CH₂), 5.03 (d, J 11.2 Hz,

1H, CH]CH₂), 4.60 (d, J 18.6 Hz, 1H, NCH₂C]), 4.40 (d,

J 18.8 Hz, 1H, NCH₂C]), 4.17e4.09 (m, 2H, CHN,

CH₂C^), 3.98e3.87 (m, 1H, CH₂C^), 3.87e3.84 (m, 1H,

CHN), 2.42 (s, 3H, CH₃), 2.34 (s, 3H, CH₃), 2.27 (br s, 2H,

CH₂CH), 2.13e2.07 (m, 1H, CH₂CH), 2.06 (t, J 2.4 Hz, 1H,

^CH), 1.59 (br d, 1H, CH₂CH); ¹³C NMR (d, CDCl₃):

143.6 (C_Ar)*, 143.4 (C])*, 143.1 (C_Ar)*, 138.2 (C_Ar)*,

136.9 (CH]CH₂), 136.5 (C_Ar)*, 129.5 (CH_Ar), 127.9

(CH_Ar), 127.5 (CH_Ar), 126.8 (CH]CH), 125.3 (CH]CH),

116.3 (C]CH₂), 114.1 (CH]CH₂), 80.0 (C^), 73.1

(^CH), 55.5 (CHN), 54.6 (CHN), 46.7 (NCH₂C]), 35.2

(NCH₂C^), 29.2 (CHN)**, 27.9 (^CH)**, 21.6 (CH₃),

21.5 (CH₃); m/z (CI, %): 542 (MþNH^þ₄, 49), 174 (100); found

(ESI) 547.1683 (MþNa^þ), C₂₈H₃₂N₂O₄S₂Na requires

547.1695.

6. (a) Banti, D.; North, M. Adv. Synth. Catal. 2002, 344, 694e704; (b) Banti,

D.; North, M. Tetrahedron Lett. 2002, 43, 1561e1564; (c) Banti, D.;

North, M. Tetrahedron Lett. 2003, 44, 8157e8160; (d) Banti, D.; Groaz,

E.; North, M. Tetrahedron 2004, 60, 8043e8052.

7. (a) Groaz, E.; Banti, D.; North, M. Adv. Synth. Catal. 2007, 349, 142e146;

(b) Groaz, E.; Banti, D.; North, M. Eur. J. Org. Chem. 2007, 22, 3727e3745.

8. For a review of the synthesis of nitrogen-containing heterocycles using

metathesis reactions see: Deiters, A.; Martin, S. F. Chem. Rev. 2004,

104, 2199e2238.

9. (a) Kinoshita, A.; Mori, M. Synlett 1994, 1020e1022; (b) Kinoshita, A.;

Sakakibara, N.; Mori, M. J. Am. Chem. Soc. 1997, 119, 12388e12389; (c)

Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P.

¨

J. Org. Chem. 2000, 65, 2204e2207; (d) Arisawa, M.; Kato, C.; Kaneko,

H.; Nishida, A.; Nakagawa, M. J. Chem. Soc., Perkin Trans. 1 2000,

1873e1876; (e) Kinderman, S. S.; van Maarseveen, J. H.; Schoemaker,

H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Org. Lett. 2001, 3, 2045e2048; (f)

Kitamura, T.; Mori, M. Org. Lett. 2001, 3, 1161e1163; (g) Sutton, A. E.;

Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002,

124, 13390e13391; (h) Yang, C.; Murray, W. V.; Wilson, L. J. Tetrahedron

Lett. 2003, 44, 1783e1786; (i) Terada, Y.; Arisawa, M.; Nishida, A. Angew.

Chem., Int. Ed. 2004, 43, 4063e4067; (j) Brouwer, A. J.; Liskamp, R. M. J.

J. Org. Chem. 2004, 69, 3662e3668;(k) Maechling,S.;Zaja, M.;Blechert, S.

Adv. Synth. Catal. 2005, 347, 1413e1422; (l) Holub, N.; Neidhofer, J.;

´

¨

Acknowledgements

Blechert, S. Org. Lett. 2005, 7, 1227e1229; (m) Dougherty, J. M.; Jimenez,

M.; Hanson, P. R. Tetrahedron 2005, 61, 6218e6230; (n) Grigg, R.; Martin,

W.; Morris, J.; Sridharan, V. Tetrahedron 2005, 61, 11380e11392; (o)

Maechling, S.; Norman, S. E.; McKendrick, J. E.; Basra, S.; Koppner, K.;

Blechert, S. Tetrahedron Lett. 2006, 47, 189e192.

The authors thank the EPSRC national mass spectrometry

service at the University of Wales, Swansea for recording

mass spectra.

218

E. Groaz et al. / Tetrahedron 64 (2008) 204e218

10. (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,

115, 9856e9857; (b) Furstner, A.; Grabowski, J.; Lehmann, C. W.

16. Whitney, R. A. Tetrahedron Lett. 1981, 22, 2063e2066.

17. Duckworth, D. M.; Lee-Wong, S.; Slawin, A. M. Z.; Smith, E. H.;

Williams, D. J. J. Chem. Soc., Perkin. Trans. 1 1996, 815e821.

18. Kinderman, S. S.; Wekking, M. M. T.; van Maarseveen, J. H.; Schoemaker,

H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 5519e5527.

19. Witiak, D. T.; Rotella, D. P.; Filppi, J. A.; Gallucci, J. J. Med. Chem. 1987,

30, 1327e1336.

¨

J. Org. Chem. 1999, 64, 8275e8280; (c) Furstner, A.; Grabowski, J.;

¨

Lehmann, C. W.; Kataoka, T.; Nagai, K. Chem. Biochem. 2001, 2, 60e68;

(d) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308e311;

¨

(e) Scheiper, B.; Glorius, F.; Leitner, A.; Furstner, A. Proc. Natl. Acad.

Sci. U.S.A. 2004, 101, 11960e11965; (f) Guidry, E. N.; Cantrill, S. J.;

Stoddart, J. F.; Grubbs, R. H. Org. Lett. 2005, 7, 2129e2132; (g) Gracias,

V.; Gasiecki, A. F.; Djuric, S. W. Tetrahedron Lett. 2005, 46, 9049e9052;

(h) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem., Int. Ed.

2006, 45, 5546e5549.

20. Kitamura, T.; Sato, Y.; Mori, M. Adv. Synth. Catal. 2002, 344, 678e693.

21. Miller, S. J.; Kim, S. H.; Chen, Z. R.; Grubbs, R. H. J. Am. Chem. Soc.

1995, 117, 2108e2109.

22. Mori, M.; Kitamura, T.; Sakakibara, N.; Sato, Y. Org. Lett. 2000, 2,

543e545.

23. Mori, M.; Kitamura, T.; Sato, Y. Synthesis 2001, 654e664.

24. Kinoshita, A.; Sakakibara, N.; Mori, M. Tetrahedron 1999, 55,

8155e8167.

11. (a) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871e874; (b)

€

Vedrenne, E.; Dupont, H.; Oualef, S.; Elkaım, L.; Grimaud, L. Synlett

2005, 670e672; (c) Bai, C.-X.; Lu, X.-B.; He, R.; Zhang, W.-Z.; Feng,

X.-J. Org. Biomol. Chem. 2005, 3, 4139e4142.

12. At the time of writing we found a useful yet unpublished review on amine

metathesis: Compain, P. Adv. Synth. Catal. 2007, 349, 1829e1846.

13. For preliminary results see: Groaz, E.; Banti, D.; North, M. Tetrahedron

Lett. 2007, 48, 1927e1930.

25. Ruckert, A.; Eisele, D.; Blechert, S. Tetrahedron Lett. 2001, 42,

5245e5247.

26. Randl, S.; Lucas, N.; Connon, S. J.; Blechert, S. Adv. Synth. Catal. 2002,

344, 631e633.

14. For reviews on the synthesis and biological applications of tetrahydro-

pyridines see: (a) Felpin, F. X.; Lebreton, J. Curr. Org. Synth. 2004, 1,

83e109; (b) Matyus, P.; Elias, O.; Tapolcsanyi, P.; Polonka-Balint, A.;

Halasz-Dajka, B. Synthesis 2006, 2625e2639.

27. Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996,

118, 6634e6640.

28. Hilbert, G. E. J. Am. Chem. Soc. 1932, 54, 3413e3417.

29. Booth, H.; Khedhair, K. A.; Alshirayda, H. A. R. Y. Tetrahedron 1988, 44,

1465e1475.

15. Eissenstat, M. A.; Weaver, J. D. J. Org. Chem. 1993, 58, 3387e3390.

Article Doi

Synthesis of N-heterocyclic compounds via ene-yne metathesis reactions

DOI: 10.1016/j.tet.2007.10.076

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2007.10.076

Full text of DOI:10.1016/j.tet.2007.10.076

Products guided by the article

R&D Labs maybe for 934389-54-5

Relevant to this article

Hot Product