Synthesis of Various Heterocycles Having a Dienamide Moiety by Ring-Closing Metathesis of Ene-ynamides

SYNTHESIS

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paper

A

en

H. Wakamatsu et al.

Paper

Synthesis

Synthesis of Various Heterocycles Having a Dienamide Moiety by

Ring-Closing Metathesis of Ene-ynamides

Hideaki Wakamatsu*^a

Yoshimi Sasaki^a

Masatoshi Kawahata^b,c

Kentaro Yamaguchi^b

Yuichi Yoshimura*^a

6- to 8-membered

heterocycles

MesN

Cl

NMes

Cl

Ru

n

Ph

R¹

PCy₃

X

N

R¹

N

m

RCM of ene-ynamides

up to 99% yield

m

Ts

^aFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical

University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

hiwaka@tohoku-mpu.ac.jp

azepine, azocine,

isoquinoline, quinoline,

benzoazepine,

benzodiazepine,

benzodiazocine derivatives

yoshimura@tohoku-mpu.ac.jp

^bKagawa School of Pharmaceutical Sciences, Tokushima Bunri University,

1314-1 Shido, Sanuki, Kagawa 769-2193, Japan

^cLaboratory of Pharmaceutical Sciences and Education, Showa Pharma-

ceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo

194-8543, Japan

Received: 23.03.2018

Accepted after revision: 23.04.2018

Published online: 30.05.2018

Several kinds of transition-metal-catalyzed reactions of

ynamides, including [2+2+1] cycloaddition,^8gPauson–

Khand reaction,^8hcycloisomerization,⁸ⁱtriazole synthesis,^8j

[4+2] cycloaddition,^8k[2+2] cycloaddition,^8land Sonogashi-

ra cross-coupling,^8m,nhave been reported in recent years.⁸

We have studied RCM of ene-ynamides, which can be ap-

plied for the synthesis of pyrrolizidine and piperidine de-

rivatives. Furthermore, the diene derivative, which was ob-

tained by RCM of ene-ynamide, can afford indole and quin-

oline derivatives by Diels–Alder reaction (Scheme 1).⁹

DOI: 10.1055/s-0037-1609857; Art ID: ss-2018-f0202-op

Abstract Ring-closing metathesis (RCM) of ynamides, having alkene

substituents of various lengths on the side chain, was demonstrated us-

ing the second-generation Grubbs catalyst. When the reaction of ene-

ynamides was carried out in the presence of 5 mol% of the catalyst,

RCM proceeded smoothly to give quinoline or isoquinoline derivatives

having a dienamide unit in good yields. Furthermore, RCM of ene-

ynamides, having one more carbon on the side chain, proceeded

smoothly to provide seven-membered heterocycles having a dienamide

component. Similarly, eight-membered heterocycles, diazocine and

benzodiazocine, were also synthesized by RCM of ene-ynamides in good

yields.

L

Cl

Ru

R²

Ph

1

Cl

n

R²

PCy₃

R¹

Key words ruthenium carbene complex, ynamide, ring-closing me-

tathesis, heterocycles, medium-sized ring

N

R¹

N

RCM of ene-ynamide

Ts

n = 0: pyrrolidine

n = 1: piperidine

Carbon–carbon double bonds have been shown to be

useful building blocks in synthetic organic chemistry.¹Ole-

fin metathesis, which is catalyzed by transition metal com-

plexes, is one of the most powerful tools for the construc-

tion of the C=C bonds.²Ring-closing metathesis (RCM) is

used as a key reaction for the synthesis of various natural

products, and is the essential method for the construction

of the carbon framework at this moment. Likewise, ring-

closing enyne metathesis (RCEYM) has attracted much in-

terest because various cyclic products having a conjugated

diene moiety can be obtained in a single step.³The distinc-

tive reactivity of ynamides, which have an electron-defi-

cient π-orbital and higher stability relative to ynamines, is

attractive for organic chemists.⁴As useful synthetic meth-

ods for the preparation of ynamides have already been re-

ported by Kitamura,⁵Brückner^4i,6and Hsung,⁷a variety of

ynamides can be synthesized at present.

R³(R⁴)

n

R⁴(R³)

R²

1a: L = PCy₃

R³

R⁴

NMes

Diels–Alder reaction

1b: L =

N

R¹

Ts

indole, quinoline

Scheme 1 Synthesis of pyrrolidine and piperidine derivatives using

RCM of ene-ynamide

On the basis of the above discussion, we decided to ex-

plore the further expansion of the RCM of ene-ynamides.

Herein, we wish to report the synthesis of various hetero-

cyclic compounds having a dienamide moiety, especially to

establish the efficient synthesis of seven- and eight-mem-

bered heterocycles.¹⁰Ene-ynamide derivatives were pre-

pared by the several synthetic methods, as shown in

Schemes 2 through 5.

B

H. Wakamatsu et al.

Paper

Synthesis

Tosyl amides 2–4, which were synthesized by the litera-

ture procedure,^11–13were treated with butyllithium, fol-

lowed by treatment with formylbenzotriazole, to provide

N-formyl derivatives 5–7. The ynamide unit was construct-

ed by the modified Corey–Fuchs alkyne synthesis^6,14to ob-

tain ene-ynamides 11–13. Ene-ynamide 12c, having a phe-

nyl group on the alkyne, was obtained from compound 9 by

Negishi coupling (Scheme 2).¹⁵

Allyl tosyl amide 19, whose synthesis was reported by

Stetter,¹⁷was reacted with butyllithium and iodonium salt

20 to provide 21d in 61% yield. Ene-ynamide 21a was ob-

tained from 21d by the removal of the TMS group on the

alkyne. The synthesis of ene-ynamide 21b and 21c from

21a was accomplished by lithiation on the terminal alkyne

or Sonogashira cross-coupling¹⁸(Scheme 4).

Ts

NH₂

N

1) TsCl, Py, 79%

n

2) NaH, DMF

1) BuLi, THF, –78 °C

CHO

NHTs

then allyl bromide, 94%

19

18

N

2)

NHTs

m

N

m

Ts

N

Ts

N

5: m = 0, n = 1 (77%)

6: m = 1, n = 0 (80%)

7: m = 1, n = 1 (99%)

2: m = 0, n = 1

3: m = 1, n = 0

4: m = 1, n = 1

CHO

TBAF

THF

1) BuLi, THF

TMS

Ph

2)

N

n

TMS

I

Ts

Cl

OTf

CCl₄, PPh₃

THF, 60 °C

1) BuLi, THF, –78 °C

21d (61%)

20

N

2) NH₄Cl or ClCO₂Et

m

Ts

N

Ts

N

1) BuLi, THF, –78 °C

2) ClCO₂Et

8: m = 0, n = 1 (81%)

9: m = 1, n = 0 (89%)

CO₂Et

N

10: m = 1, n = 1 (95%)

Ts

21a (92%)

21b (72%)

11a: m = 0, n = 1, R = H (85%)

11b: m = 0, n = 1, R = CO₂Et (76%)

R

n

Ts

N

12a: m = 1, n = 0, R = H (84%)

12b: m = 1, n = 0, R = CO₂Et (77%)

13a: m = 1, n = 1, R = H (88%)

13b: m = 1, n = 1, R = CO₂Et (79%)

PhI, Pd(PPh₃)₄, CuI

Et₃N, THF

N

21a

Ph

m

Ts

N

Ts

Ph

21c (98%)

Scheme 4 Preparation of substrate for the synthesis of benzodiazepine

derivatives

1) BuLi, THF, –78 °C, 1 h

2) ZnBr₂

9

NTs

3) PhI, Pd₂(dba)₃·CHCl₃

PPh₃, rt, 21 h

12c (56%)

Alcohols 24 and 25 were prepared from 22¹⁹by the easy

exchange of its protecting group. Mitsunobu reaction of N-

tosylformamide 14 and alcohol 23–25, followed by treat-

ment with carbon tetrachloride and triphenylphosphine,

provided dichloroolefins 26–28, which were treated with

butyllithium and ammonium chloride or ethyl chlorocar-

bonate to obtain ene-ynamides 29–31 in good yields

(Scheme 5).

Scheme 2 Preparation of substrate for the synthesis of quinoline, iso-

quinoline, and benzazepine derivatives

Mitsunobu reaction¹⁶of 14 and 15, followed by dichloro-

olefination, provided 16, which could be converted into 17

in good yield by treatment with butyllithium (Scheme 3).

The synthetic route for the preparation of compounds

46 and 47 is shown in Scheme 5. N-Boc-protected tosyl-

amide derivative 36 was obtained through a stepwise Mit-

sunobu reaction of propanediol derivative 33 with allyl to-

syl amide 32 and N-Boc tosylamide 35, in good yield. On the

other hand, the synthesis of an another N-Boc tosylamide

derivative 39 having a phenyl group on the alkyl chain was

accomplished by Mitsunobu reaction of 38, which was syn-

thesized by a literature procedure.²⁰N-Boc deprotection of

the compounds 36 and 39 by treatment with trifluoroacetic

acid afforded tosylamide derivatives 40 and 41, which upon

formylation, dichloroolefination, and alkynylation provided

ene-ynamides 46a, 46b, and 47a, 47b, respectively. TMS-

protected ene-ynamide 47c, on the other hand, was ob-

tained by the reaction of tosylamide 41 with butyllithium

and iodonium salt 20.

HO

15

H

CHO

CCl₄, PPh₃

THF

N

Ts

DEAD, PPh₃, THF

Cl

N

14

Ts

Cl

16 (56%)

1) BuLi, THF, –78 °C

2) NH₄Cl or ClCO₂Et

R

N

Ts

17a: R = H (85%)

17b: R = CO₂Et (71%)

Scheme 3 Preparation of substrate for the synthesis of azepine deriva-

tive

C

H. Wakamatsu et al.

Paper

Synthesis

The synthesis of quinoline derivative 48 is shown in Ta-

ble 1. The reaction of 11a in the presence of 5 mol% of the

second-generation Grubbs catalyst 1b in toluene at 80 °C

for 0.5 hour under ethylene atmosphere furnished quino-

line derivative 48a in 93% yield (Table 1, entry 1). The reac-

tion of ene-ynamide having an ethoxycarbonyl group on

the alkyne did not give good results (entry 2). However, this

problem was solved by replacing ethylene by argon, leading

to the formation of the cyclized product 48b in 79% yield

(entry 3).

Next, Diels–Alder reaction of 48a with dimethyl acety-

lenedicarboxylate (DMAD) was examined. It was found that

the construction of acridine skeleton was possible, and

compound 49 was obtained in 45% yield (Scheme 6).

R²

Cl

R¹

H

CHO

DEAD, PPh₃

THF

CCl₄, PPh₃

THF, 60 °C

1) BuLi, THF

2) R²X

+

N

PO

Cl

Ts

NTs

14

22: P = TBDMS, R¹= CH₂OH

23: P = H, R¹= H

26: R¹= H (48%)

27: R¹= CH₂OBn (44%)

28: R¹= -CH₂OCMe₂OCH₂- (47%)

29a: R¹= H, R²= H (84%)

29b: R¹= H, R²= CO₂Et (79%)

30a: R¹= CH₂OBn, R²= H (88%)

30b: R¹= CH₂OBn, R²= CO₂Et (68%)

31a: R¹= -CH₂OCMe₂OCH₂-,

R²= H (85%)

24: P = H, R¹= CH₂OBn

25: P = H, R¹= -CH₂OCMe₂OCH₂-

31b: R¹= -CH₂OCMe₂OCH₂-,

R²= CO₂Et (95%)

H

Boc

N

Ts

35

1) DEAD, PPh₃, THF, 64%

2) TBAF, THF, 99%

H

+

HO

OTBDMS

N

TsN

Boc

NTs

TsN

Ts

DEAD, PPh₃

THF

OH

32

33

36 (quant.)

34

H

Boc

N

NH₂

Ts

35

1) TsCl, Py, CH₂Cl₂, 98%

TsN

Boc

NTs

CO₂Me

OH

DEAD, PPh₃

THF

2) NaH, DMF

then allyl bromide, 99%

37

38

3) LiAlH₄, THF, 96%

39 (84%)

TFA

TsN

1) BuLi, THF, –78 °C

TsN

Boc

NTs

H

TsN

R

CHO

NTs

N

CH₂Cl₂

2)

NTs

N

R

CHO

36: R = -CH₂CH₂-

39: R =

40: R = -CH₂CH₂- (quant)

42: R = -CH₂CH₂- (92%)

43: R = (83%)

R²

41: R =

(quant)

Cl

CCl₄, PPh₃

THF

1) BuLi, THF, –78 °C

2) NH₄Cl or ClCO₂Et

TsN

Cl

TsN

NTs

R

44: R = -CH₂CH₂- (97%)

45: R = (98%)

46a: R = -CH₂CH₂-, R²= H (76%)

46b: R = -CH₂CH₂-, R²= CO₂Et (81%)

TMS

47a: R =

47b: R =

, R²= H (78%)

TsN

NTs

1) BuLi, THF, –78 °C

2)

41

, R²= CO₂Et (83%)

Ph

TMS

I

OTf

20

47c (73%)

Scheme 5 Preparation of substrate for the synthesis of azocine derivatives

D

H. Wakamatsu et al.

Paper

Synthesis

Table 1 Construction of Quinoline Ring

yield. However, the double bond of 51 was isomerized to a

conjugated position, which was different from the expected

position. On the other hand, tricyclic compound 52 was ob-

tained without isomerization of the double bond when the

metathesis reaction of 12a was carried out under identical

conditions, followed by the treatment with DMAD under

argon atmosphere (Scheme 7).²¹It is not clear at this stage

why the double bond of 52 is not isomerized to a conjugat-

ed position. If the lone pair of nitrogen or π electrons is as-

sociated to ruthenium center, the double bond isomeriza-

tion is suppressed.

R

5 mol% 1b

N

toluene, 80 °C

Ts

R

11a: R = H

11b: R = CO₂Et

48a: R = H

48b: R = CO₂Et

Entry

Substrate

Atmosphere

Time (h)

48

Yield (%)

1

2

3

11a

11b

CH₂=CH₂

Ar

0.5

12

1

48a

48b

93

49^a

79

CO₂Me

^aStarting material 11b was recovered in 11% yield.

MeO₂C

DMAD, toluene

80 °C, 21 h

NTs

CO₂Me

NTs

CO₂Me

DMAD, toluene

50a

51 (50%)

N

80 °C, 12 h

45%

Ts

N

Ts

CO₂Me

48a

49

1) 5 mol% 1b, toluene

MeO₂C

CH₂=CH₂, 80 °C, 0.5 h

Scheme 6 Synthesis of acridine derivative by Diels–Alder reaction of

cyclic dienamides

NTs

2) DMAD, Ar, 80 °C, 12 h

NTs

52 (46%)

12a

The synthesis of isoquinoline derivatives was examined

as further application of the construction of 6+6 ring sys-

tem. The reaction of ene-ynamide 12a with 5 mol% of cata-

lyst 1b under an identical reaction conditions proceeded

smoothly to furnish the cyclized product 50a in 70% yield,

in only 30 minutes (Table 2, entry 1). Substituted alkynes

can be used in this isoquinoline synthesis, in contrast to the

quinolone synthesis. The cyclized product 50b was ob-

tained in 78% yield, when the ethoxycarbonyl group was

substituted on the alkyne (entry 2). Although a slightly lon-

ger reaction time was required in the case of the phenyl-

substituted alkyne, the resulting isoquinoline derivative

50c was obtained in almost identical yield (entry 3).

Scheme 7 Synthesis of phenanthridine derivatives

The construction of a benzazepine ring was examined

next. When a toluene solution of 13a was stirred with 10

mol% of the catalysts 1b at 80 °C for 1.5 hours under an eth-

ylene atmosphere, the cyclized product 53a was obtained in

22% yield (Table 3, entry 1). A corresponding reaction car-

ried out under an argon atmosphere led to an improved

yield of 53a at 49% (entry 2). RCM of 13b, which was pre-

pared by the introduction of an ethoxycarbonyl group on

the alkyne, was attempted next. When the reaction of 13b

was carried out in a manner similar as that used for the

synthesis of 53a, benzazepine derivative 53b was obtained

in 69% yield (entry 3). This yield could be enhanced to 84%

Table 2 Construction of Isoquinoline Ring

R

Table 3 Construction of Benzazepine Ring

5 mol% 1b

R

toluene, 80 °C

NTs

R

1b

CH₂= CH₂

toluene, 80 °C

12a: R = H

12b: R = CO₂Et

12c: R = Ph

50a: R = H

50b: R = CO₂Et

50c: R = Ph

R

N

Ts

13a: R = H

13b: R = CO₂Et

53a: R = H

53b: R = CO₂Et

Entry

Substrate

Time (h)

50

Yield (%)

Entry Substrate Atmosphere

1b

(mol%)

Time

(h)

53

Yield

(%)^a

1

2

3

12a

12b

12c

0.5

1

50a

50b

50c

70

78

77

1

2

3

4

13a

13b

CH₂=CH₂

Ar

10

5

1.5

53a

22

49

69

84

1.5

0.5

3.5

0.5

53a

53b

CH₂=CH₂

Ar

10

5

When a toluene solution of 50a and DMAD was stirred

at 80 °C for 21 hours, the Diels–Alder reaction proceeded

smoothly to provide phenanthridine derivative 51 in 50%

^aIsolated yield.

E

H. Wakamatsu et al.

Paper

Synthesis

by performing the reaction under an argon atmosphere

(entry 4).

Subsequently, the synthesis of 1,5-benzodiazepine de-

rivatives was also examined. When a solution of 21a in

toluene was exposed to a catalytic amount of 1b at 80 °C for

1 hour, the starting material 21a was not consumed, and an

inseparable complex mixture consisting of 21a, cyclized

product 56a, an intermolecular metathesis product with

ethylene, and undefined products was obtained (Table 5,

entry 1). Replacement of the solvent and a longer reaction

time gave a similar result (entry 2). The reaction of the

TMS-substituted ene-ynamide 21d did not proceed and the

starting material was recovered (entry 3). Surprisingly,

when 21b was used as the substrate instead of 21a, benzo-

diazepine 56b was obtained in quantitative yield (entry 4).

Reduction of the catalyst amount did not affect the yield of

56b (entry 5). The RCM also proceeded smoothly in CH₂Cl₂

as the solvent, although a longer reaction time was required

(entry 6). An excellent yield of 56b was also observed when

the reaction was carried out under an argon atmosphere

(entry 7). Likewise, when the phenyl-substituted ene-

ynamide 21c was used as the substrate, benzodiazepine 56c

was obtained in quantitative yield (entry 8).

Furthermore, the synthesis of 54 was examined with

the aim of constructing the dibenzoazepine skeleton

(Scheme 8). Tricyclic heterocycle 54 was obtained in 36%

yield when 13a was exposed to a catalytic amount of 1b in

toluene at 80 °C for 0.5 hour under argon atmosphere, fol-

lowed by treatment with DMAD at the same temperature.

MeO₂C

CO₂Me

1) 5 mol% 1b

toluene, Ar

80 °C, 0.5 h

N

2) DMAD, 80 °C

N

Ts

29 h

Ts

13a

36%

54

Scheme 8 Synthesis of dibenzoazepine derivative

Next, RCM of linear α,ω-ene-ynamides was examined.

When the reaction of 17a was carried out in the presence of

the catalyst 1b in toluene at 80 °C for 1 hour, starting mate-

rial 17a was recovered in 53% yield (Table 4, entry 1). Re-

placement of toluene by CH₂Cl₂led to a better result, and

55a was obtained in 36% yield after heating for 15 hours, to-

gether with 38% of 17a (entry 2). A similar result was

achieved when the reaction was conducted under an argon

atmosphere or upon prolonging the reaction time (entries 3

and 4). In the case of 17b, a substrate having an ethoxycar-

bonyl group on the alkyne, the yield of the cyclized product

55b was only 5% when the reaction was carried out in tolu-

ene with heating (entry 5). However, a higher yield of 55b

was obtained when the reaction was carried out in CH₂Cl₂

(entry 6).

Table 5 Construction of Benzodiazepine Ring

Ts

N

Ts

N

10 mol% 1b

R

solvent, temp, time

CH₂= CH₂

N

Ts

R

21a: R = H

21b: R = CO₂Et

21c: R = Ph

56a: R = H

56b: R = CO₂Et

56c: R = Ph

21d: R = TMS

56d: R = TMS

Entry Substrate Solvent

Temp (°C) Time (h) 56

Yield (%)^a

Table 4 Construction of Azepine Ring

1

21a

21d

21b

21c

toluene

CH₂=CH₂

toluene

CH₂Cl₂

80

1

28

5

–

R

2

reflux

80

–

10 mol% 1b

b

3

–

CH₂Cl₂, reflux, time

R

NTs

4

80

0.5

15

56b

56c

99

97

95

97

NTs

5^c

6

80

17a: R = H

17b: R = CO₂Et

55a: R = H

55b: R = CO₂Et

reflux

80

7^d

8

CH₂Cl₂

20

1

Entry Sub-

Atmosphere Time

(h)

55

Yield

(%)^a

17

Recovery

strate

of 17 (%)^a

toluene

^aIsolated yield.

1^b

2

17a

17b

CH₂=CH₂

Ar

1

–

17a

53

38

33

31

74

–

^bRecovered 21d: 87%.

^cCatalyst 1b used: 5 mol%.

15

26

48

3

55a

36

37

33

5

17a

17b

^dReaction was carried out under an argon atmosphere.

3

55a

55b

4

Ar

Encouraged by the successful construction of the six-

membered rings and a seven-membered ring, we became

interested in the synthesis of eight-membered heterocycles.

Initially, various linear ene-ynamides were examined for

the synthesis of azocine derivative 57. However, the desired

cyclized product 57 was not obtained in any case, and the

5^b

6

CH₂=CH₂

1.5

74^c

^aYields were determined by ¹H NMR spectroscopy using (E)-stilbene as an

internal standard.

^bReaction was carried out in the presence of 5 mol% 1b in toluene at 80 °C.

^cIsolated yield.

F

H. Wakamatsu et al.

Paper

Synthesis

only a trace amount of alkene dimer, formed by the inter-

molecular reaction of the ene-ynamides was observed in

NMR experiment (Scheme 9).

try 2). Then, a solution of 47b in CH₂Cl₂was heated in the

presence of 1b for 21 hours, and the reaction was

monitered by TLC (entry 3). A new spot appeared on the

TLC plate, suggesting the formation of 59b. However, it was

difficult to deduce the correct structure of 59b due to the

broad peaks in its ¹H NMR spectrum. This was probably due

to the rapid interconversion of several stable confomers un-

der the influence of the benzene ring, at room temperature.

R¹

R²

1b

R¹

CH₂Cl₂or toluene

NTs

1

R¹= H or CO₂Et

29: R²= H

57

The peaks were clearly separated when the H NMR spec-

trum was recorded at low temperature of –50 °C (Figure 1).

We have reported that the dimeric compound was ob-

tained, because the largest m/z value of FAB-MS spectra was

observed at 1133 (M⁺+ H).¹⁰However, the structure of the

metathesis product was conclusively established by X-ray

crystallography (Figure 2), and it was found that the desired

eight-membered ring 59b was obtained in 14% yield.

30: R²= CH₂OBn

31: R²= -CH₂OCMe₂OCH₂-

Scheme 9 Construction of azocine ring

Furthermore, RCM of linear ene-ynamide 46, which

contains two tosylamide groups in the chain, was exam-

ined. When a CH₂Cl₂solution of 46a was heated for 21

hours in the presence of 10 mol% of 1b, starting material

46a was recovered in 33% yield (Table 6, entry 1). The intro-

duction of an ethoxycarbonyl group on the alkyne promot-

ed the formation of an eight-membered ring, and diazocine

58b was obtained in 15% yield (entry 2). Improved yield was

achieved when the reaction was performed under an argon

atmosphere (entry 3). Higher recovery of starting material

46b was observed when toluene was used as the solvent

(entry 4). However, an encouraging result was observed in

the construction of an eight-membered ring, and 58b was

obtained in 78% yield when the reaction was conducted

under high-dilution conditions (entry 5).

Table 7 Construction of Benzodiazocine Ring

R

10 mol% 1b

TsN

R

TsN

CH₂Cl₂, reflux, time

NTs

47a: R = H

59a: R = H

47b: R = CO₂Et

47c: R = Ph

59b: R = CO₂Et

59c: R = Ph

Entry Substrate Atmosphere Time 59

Yield

47

Recovery

(h)

(%)^a

of 47 (%)^a

1

47a

47b

47c

CH₂=CH₂

Ar

21

0.5

–

47a

58

53

63

44

86

–

Table 6 Construction of Diazocine Ring

2^b

3

–

47a

47b

–

21

6

59b

–

14

52

–

R

10 mol% 1b

4

TsN

R

TsN

5^b

6^b

7^b

8

CH₂=CH₂

Ar

CH₂Cl₂, reflux, time

NTs

2

59b

–

77

–

46a: R = H

46b: R = CO₂Et

58a: R = H

58b: R = CO₂Et

Ar

17

6

47c

83

99

Ar

–

^aIsolated yield.

Entry Substrate Atmosphere Time 58

Yield 46

Recovery

(%)^a

of 46 (%)^a

^bReactions were carried out in the presence of 5 mol% 1b in toluene at

(h)

80 °C.

1

46a

46b

CH₂=CH₂

Ar

21

6

–

46a

46b

–

33

49

25

68

–

2

58b

15

33

–

An argon atmosphere was effective for the cyclization of

47b, and the yield of 59b was increased to 52% (Table 7, en-

try 4). Appropriate combination of the solvent and the at-

mosphere was important for the formation of 59b. Upon

changing the solvent to toluene from CH₂Cl₂, high recovery

of 47b was observed under an ethylene atmosphere (entry

5) and a higher yield of 59b was observed under an argon

atmosphere (entry 6). Unfortunately, in the case of the phe-

nyl-substituted ene-ynamide 47c, the formation of the

eight-membered heterocycle 59c was not observed, and the

starting material was recovered in high yield (entries 7, 8).

3

4^b

5^c

CH₂=CH₂

Ar

24

78^d

^aYields were determined by ¹H NMR spectrum using (E)-stilbene as an

internal standard.

^bReaction was carried out in the presence of 5 mol% 1b in toluene at 80 °C.

^cReaction was carried out under low concentration (0.002 M).

^dIsolated yield.

Next, the synthesis of benzodiazocine was examined.

The reaction of 47a with the catalyst 1b did not proceed,

and starting material was recovered (Table 7, entry 1);

shortening of the reaction time did not affect the result (en-

G

H. Wakamatsu et al.

Paper

Synthesis

Table 8 Temperature Effect for the Construction of Eight-Membered

Ring

CO₂Et

TsN

CO₂Et

5 mol% 1b

TsN

NTs

Ar, toluene,

temp, time

59b

47b

Entry

Temp (°C)

Time (h)

Yield of 59b (%)^aRecovery of 47b (%)^a

1

2

3

80

50

r.t.

2

10

42

77

57

45

–

4

16

^aIsolated yield.

Figure 1 ¹H NMR spectrum of 59b

1 reacts with the alkene part of A (cycle b, ene-then-yne

pathway). The carbene part of complex V then reacts with

the alkyne part of V intramolecularly to provide ruthenacy-

clobutene VI, which converts into complex VII. If the carbe-

ne part of VII reacts with A intermolecularly, the desired

product B would be obtained together with V. Two intrigu-

ing results were observed in the construction of the seven-

and eight-membered ring:

1) The desired product was obtained in high yield when

substituents were present on the terminal alkyne, while

the yield of the cyclized product was decreased in the case

of unsubstituted ene-ynamides.

2) The reaction proceeded under an argon atmosphere

to provide the cyclized product in a yield similar to that ob-

tained under an ethylene atmosphere.

The reactivity of the ruthenium complex with the C≡C

bond should increase because of the higher electron densi-

ty of ynamides. As a result, the yne-then-ene mechanism

would predominate (cycle a). On the other hand, it is

thought that the reaction of the ruthenium complex and

the double bond have an advantage when a substituent ex-

ists on the terminal alkyne. The ruthenium carbene should

react with the double bond instead of the triple bond, by

the introduction of the ethoxycarbonyl group on the

alkyne. These effects, which decrease the electron density

of ynamides, would favor the predominance of the ene-

then-yne mechanism (cycle b).

Taking into consideration the ring-closure factor, it is

proposed that the rate of ring closure for medium-sized

rings is lower than that for five- or six-membered rings. If

the conversion rate from III to IV decreases, complex III

would react with the substrate or the other alkene species

to provide a variety of alkene compounds. On the other

hand, if the conversion rate from V to VI decreases, complex

V would react intermolecularly with the alkene part of an

another substrate to form the alkene dimer. In addition,

complex V would react only with ethylene in the case of the

reaction of 47b under ethylene atmosphere.

Figure 2 X-ray crystal structure of 59b

Furthermore, the effect of temperature on the construc-

tion of the eight-membered-ring compounds was exam-

ined (Table 8). A lower reaction rate was observed with the

decreasing reaction temperature, and 59b was obtained in

45% yield at room temperature with the recovery of the

starting material 47b in 16% yield (entry 3).

It is thought that this reaction progresses via one of the

two pathways described in Scheme 10. In the yne-then-ene

pathway (cycle a), the carbene complex 1 first reacts with

substrate A or ethylene to provide ruthenium carbene com-

plex I, which is the active species for the metathesis reac-

tion. Carbene complex I then reacts with the alkyne part of

A to provide ruthenacyclobutene II, which is converted to

complex III. If the ruthenium carbene part of III reacts with

the alkene part intramolecularly, ruthenacyclobutane IV

would be obtained, which then converts to product B, re-

generating ruthenium carbene complex I. On the other

hand, ruthenium carbene V is thought to be formed, when

H

H. Wakamatsu et al.

Paper

Synthesis

L

Cl

R¹

Ru

Ph

Cl

PCy₃

1

R¹

N

R

N

R

R²

R¹

B

A

Ru

R²

Ru

L

N

R

R¹

Cl

N

R

R²

N

R

Ru

Cl

Ph

R²

A

PCy₃

VI

II

1

Ru

R¹

Ru

N

R

R²

R¹

I

cycle b

cycle a

Ru

N

V

N

R²

R¹

R

Ph

A

R²

or

R¹

Ru

N

R

III

R²

VII

R¹

Ph

or

N

R

R²

A''

Ru

A'

R¹

N

or

CH₂

R

R²

CH₂

Ph

R¹

N

R

IV

Ph

R¹

R²

N

R²

R

R²

R

B

A

B

Scheme 10 Proposed reaction mechanism

It is more than evident from the current study that the

reaction can proceed by both mechanisms, depending on

the substituent on the terminal alkyne, although a recent

study strongly supports the predominance of the initial cy-

clometalation on an alkene over an alkyne.²²It is presumed

that the reaction progresses via cycle b in the substrate

with the ethoxycarbonyl group on the alkyne. In other

words, the construction of medium-sized rings, which is a

challenging task in organic chemistry, is achieved by the

modification of the substrates suitable for cycle b.

In conclusion, the synthesis of various heterocycles hav-

ing a dienamide unit was attempted by RCM of ene-

ynamides. The reaction proceeded smoothly to provide the

products in high yields in the synthesis of quinoline and

isoquinoline derivatives, and the argon atmosphere was ac-

ceptable for the synthesis of quinoline derivatives. The in-

troduction of an ethoxycarbonyl group on the terminal

alkyne of the ene-ynamide was conducive for the construc-

tion of the seven-membered ring, although the synthesis of

benzodiazepine derivatives from non-substituted ene-

ynamides was difficult. Further, the presence of an ethoxy-

carbonyl group on the terminal alkyne of the ene-ynamides

and an argon atmosphere under the given reaction condi-

tions were necessary for the formation of the eight-mem-

bered ring. In particular, an eight-membered ring could be

constructed under these reaction conditions; thus, this

method would serve as a useful strategy for the construc-

tion of eight-membered rings, which is a challenging task in

organic chemistry.

The metathesis reactions were carried out under an atmosphere of

ethylene (1 atm) or an argon atmosphere (1 atm). All other manipula-

tions were carried out under an atmosphere of argon, unless other-

wise mentioned. Ru complexes were purchased from Aldrich Chemi-

cal Company. All other solvents and reagents were purified when

necessary using standard procedure. Column chromatography was

performed on silica gel 60 N (spherical, neutral, 40–60 μm, Kanto

Chemical Co.). IR spectra were recorded on PerkinElmer FT-IR 1725X

1

spectrophotometer. H and ¹³C NMR spectra were recorded on a Jeol

JNM-EX400 (¹H: 400 MHz, ¹³C: 100 MHz) spectrometer. Chemical

shift values were reported in ppm (δ) downfield from TMS as an in-

ternal standard, or residual solvent peak [¹H NMR, CHCl₃(7.24): ¹³C

NMR, CHCl₃(77.0)]. Coupling constants (J) are reported in hertz (Hz).

EI mass spectra were recorded on a Jeol JMN-DX 303/JMA-DA 5000

mass spectrometer.

N-(2-Allylphenyl)-N-formyl-p-toluenesulfonamide (5)

To a solution of 2 (1.37 g, 4.77 mmol) in THF (25 mL) was added BuLi

(3.6 mL, 5.72 mmol, 1.58 M hexane solution) slowly at –78 °C, and

stirred at the same temperature for 1 h. To the resulting mixture was

added 1-formylbenzotriazole (1.40 g, 9.53 mmol), and warmed to

–30 °C for 1 h. Sat. aq NH₄Cl was added, and the aqueous phase was

extracted with EtOAc. The combined organic phases were washed

with brine, and dried (MgSO₄). The volatiles were removed under re-

duced pressure, and the residue was purified by column chromatog-

raphy on silica gel (hexane/Et₂O 3:1) to provide 5 (1.15 g, 77%) as a

colorless oil.

IR (neat): 1715 (s), 1597 (m), 1361 (s), 1172 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 9.29 (br, 1 H), 7.61 (d, J = 8.2 Hz, 2 H),

7.40–7.29 (m, 4 H), 7.16 (dt, J = 1.5, 7.7 Hz, 1 H), 6.66 (d, J = 7.7 Hz, 1

H), 5.68 (dddd, J = 6.3, 7.3, 10.1, 16.9 Hz, 1 H), 5.08–5.00 (m, 2 H), 3.19

(dd, J = 7.3, 15.9 Hz, 1 H), 2.99 (dd, J = 6.3, 15.9 Hz, 1 H), 2.47 (s, 3 H).

I

H. Wakamatsu et al.

Paper

Synthesis

¹³C NMR (100 MHz, CDCl₃): δ = 161.1, 145.8, 140.4, 135.3, 134.5,

¹³C NMR (100 MHz, CDCl₃): δ = 144.7, 140.7, 135.6, 135.2, 134.4,

130.4, 130.2, 130.1, 130.1, 129.9, 128.2, 127.1, 117.2, 35.1, 21.7.

130.0, 129.7, 129.7, 129.0, 127.8, 126.4, 125.9, 116.9, 112.8, 35.4, 21.5.

MS (EI): m/z = 315 (M⁺), 287, 160, 132, 117, 91.

MS(EI): m/z = 381 (M⁺), 285, 226, 191, 150, 130, 115, 91.

HRMS (EI): m/z calcd for

C

₁₇H₁₇NO₃S (M⁺): 315.0929; found:

HRMS (EI): m/z calcd for C₁₈H₁₇³⁵Cl₂NO₂S (M⁺): 381.0357; found:

315.0926.

381.0360.

N-Formyl-N-(2-vinylbenzyl)-p-toluenesulfonamide (6)

N-(2,2-Dichlorovinyl)-N-(2-vinylbenzyl)-p-toluenesulfonamide

(9)

According to the procedure for the synthesis of 5, a solution of 3 (1.76

g, 6.12 mmol), BuLi (4.7 mL, 7.35 mmol, 1.58 M hexane solution) and

1-formylbenzotriazole (1.80 g, 12.25 mmol) in THF (30 mL) was

stirred at 0 °C for 1 h to afford 6 (1.54 g, 80%) after purification by col-

umn chromatography on silica gel (hexane/EtOAc 5:1) as a colorless

oil.

According to the procedure for the synthesis of 8, a solution of 6 (1.42

g, 4.50 mmol), PPh₃(2.95 g, 11.26 mmol) and CCl₄(3.6 mL, 36.92

mmol) in THF (45 mL) was stirred at 60 °C for 12 h to afford 9 (1.53 g,

89%) as a pale yellow solid after purification by column chromatogra-

phy on silica gel (hexane/EtOAc 10:1); mp 93 °C.

IR (neat): 1699 (s), 1597 (m), 1361 (s), 1166 (s) cm^–1

.

IR (KBr): 1596 (w), 1356 (m), 1164 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 9.21 (s, 1 H), 7.40 (d, J = 8.2 Hz, 2 H),

7.26–7.09 (m, 6 H), 6.85 (dd, J = 11.1, 17.4 Hz, 1 H), 5.36 (dd, J = 1.5,

17.4 Hz, 1 H), 5.25 (dd, J = 1.5, 11.1 Hz, 1 H), 4.87 (s, 2 H), 2.37 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 161.3, 144.9, 137.1, 135.2, 133.9,

131.0, 129.7, 128.9, 128.0, 127.7, 127.1, 126.2, 117.1, 42.9, 21.5.

¹H NMR (400 MHz, CDCl₃): δ = 7.73 (d, J = 8.2 Hz, 2 H), 7.48 (d, J = 7.7

Hz, 1 H), 7.35 (d, J = 8.2 Hz, 2 H), 7.29 (dd, J = 7.2, 7.7 Hz, 1 H), 7.21

(dd, J = 7.2, 7.7 Hz, 1 H), 7.17 (d, J = 7.7 Hz, 1 H), 7.07 (dd, J = 11.1, 17.4

Hz, 1 H), 6.04 (s, 1 H), 5.63 (dd, J = 1.5, 17.4 Hz, 1 H), 5.35 (dd, J = 1.5,

11.1 Hz, 1 H), 4.53 (s, 2 H), 2.46 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.3, 137.7, 135.0, 133.7, 131.4,

130.0, 129.9, 128.6, 128.0, 127.7, 127.5, 126.2, 124.5, 116.9, 50.8, 21.6.

MS (EI): m/z = 315 (M⁺), 160, 133, 115, 91.

HRMS (EI): m/z calcd for

C

₁₇H₁₇NO₃S (M⁺): 315.0929; found:

MS (EI): m/z = 381 (M⁺), 285, 226, 117, 91.

HRMS (EI): m/z calcd for C₁₈H₁₇N³⁵Cl₂O₂S (M⁺): 381.0357; found:

315.0922.

381.0385.

N-(2-Allylbenzyl)-N-formyl-p-toluenesulfonamide (7)

According to the procedure for the synthesis of 5, a solution of 4 (2.95

g, 9.78 mmol), BuLi (7.4 mL, 11.74 mmol, 1.58 M hexane solution)

and 1-formylbenzotriazole (2.88 g, 19.57 mmol) in THF (50 mL) was

stirred at 0 °C for 40 min to afford 7 (3.18 g, 99%) after purification by

column chromatography on silica gel (hexane/Et₂O 2:1) as a colorless

oil.

N-(2-Allyl-benzyl)-N-(2,2-dichloro-vinyl)-p-toluenesulfonamide

(10)

According to the procedure for the synthesis of 8, a solution of 7 (2.65

g, 8.05 mmol), PPh₃(5.28 g, 20.13 mmol) and CCl₄(6.4 mL, 66.02

mmol) in THF (40 mL) was stirred at 60 °C for 9 h to afford 10 (3.03 g,

95%) as a white solid after purification by column chromatography on

silica gel (hexane/Et₂O 2:1); mp 72–73 °C.

IR (neat): 1699 (s), 1597 (m), 1361 (s), 1166 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 9.24 (s, 1 H), 7.50 (d, J = 8.2 Hz, 2 H),

7.20 (d, J = 8.2 Hz, 2 H), 7.14 (d, J = 7.7 Hz, 1 H), 7.06–6.99 (m, 3 H),

5.86 (ddt, J = 10.3, 16.9, 6.0 Hz, 1 H), 5.05 (dd, J = 1.5, 10.3 Hz, 1 H),

4.88 (dd, J = 1.5, 16.9 Hz, 1 H), 4.77 (s, 2 H), 3.35 (d, J = 6.0 Hz, 2 H),

2.29 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 161.0, 144.8, 136.9, 135.9, 134.7,

132.0, 129.5, 129.2, 127.3, 127.2, 126.8, 126.1, 115.7, 42.2, 36.4, 21.0.

IR (KBr): 1598 (w), 1356 (m), 1165 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.73 (d, J = 8.2 Hz, 2 H), 7.36 (d, J = 8.2

Hz, 2 H), 7.27–7.15 (m, 4 H), 6.05 (s, 1 H), 5.94 (ddt, J = 10.1, 16.9, 6.3

Hz, 1 H), 5.08 (ddt, J = 1.9, 10.1, 1.5 Hz, 1 H), 4.97 (ddt, J = 1.9, 16.9, 1.5

Hz, 1 H), 4.46 (s, 2 H), 3.50 (dt, J = 6.3, 1.5 Hz, 2 H), 2.47 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.3, 138.6, 136.5, 134.7, 132.4,

130.0, 129.9, 129.8, 128.4, 127.7, 127.4, 126.3, 124.7, 116.0, 50.8, 36.4,

21.5.

MS (EI): m/z = 329 (M⁺), 174, 130, 115, 91.

HRMS (EI): m/z calcd for

C

₁₈H₁₉NO₃S (M⁺): 329.1086; found:

MS (EI): m/z = 395 (M⁺), 299, 155, 131, 105, 91.

HRMS (EI): m/z calcd for C₁₉H₁₉³⁵Cl₂NO₂S (M⁺): 395.0514; found:

329.1082.

395.0492.

N-(2-Allylphenyl)-N-(2,2-dichlorovinyl)-p-toluenesulfonamide (8)

To a solution of 5 (1.15 g, 3.65 mmol) and PPh₃(2.39 g, 9.12 mmol) in

THF (24 mL) was added CCl₄(2.9 mL, 29.90 mmol) in THF (12 mL, to-

tal 0.1 M) at 60 °C over 3 h, and stirred at the same temperature for 1

h. After cooling the reaction mixture to r.t., sat. aq NaHCO₃was added,

and the aqueous phase was extracted with EtOAc. The combined or-

ganic phases were washed with brine, and dried (MgSO₄). The vola-

tiles were removed under reduced pressure, and the residue was puri-

fied by column chromatography on silica gel (hexane/EtOAc 10:1) to

provide 8 (1.12 g, 81%) as a pale red oil.

N-(2-Allylphenyl)-N-ethynyl-p-toluenesulfonamide (11a)

To a solution of 8 (228.1 mg, 0.60 mmol) in THF (10 mL) was added

BuLi (0.85 mL, 1.31 mmol, 1.55 M hexane solution) at –78 °C, and

stirred at the same temperature for 0.5 h. Sat. aq NH₄Cl was added,

and the aqueous phase was extracted with EtOAc. The combined or-

ganic phases were washed with brine, and dried (MgSO₄). The vola-

tiles were removed under reduced pressure, and the residue was puri-

fied by column chromatography on silica gel (hexane/EtOAc 10:1) to

provide 11a (157.5 mg, 85%) as a white solid; mp 87–88 °C.

IR (neat): 1598 (w), 1367 (s), 1170 (s) cm^–1

.

IR (KBr): 2131 (m), 1597 (w), 1369 (s), 1168 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 8.3 Hz, 2 H), 7.33–7.28 (m, 4

H), 7.10 (s, 1 H), 7.08 (m, 1 H), 6.71 (d, J = 7.8 Hz, 1 H), 5.83 (m, 1 H),

5.15–5.10 (m, 2 H), 3.35 (d, J = 4.9 Hz, 2 H), 2.46 (s, 3 H).

J

H. Wakamatsu et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃): δ = 7.71 (d, J = 8.2 Hz, 2 H), 7.36 (d, J = 8.2

Hz, 2 H), 7.32–7.29 (m, 2 H), 7.12 (m, 1 H), 6.82 (d, J = 7.7 Hz, 1 H),

5.91 (ddt, J = 10.6, 16.9, 6.8 Hz, 1 H), 5.15–5.09 (m, 2 H), 3.49 (br, 2 H),

2.76 (s, 1 H), 2.47 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 145.1, 139.6, 136.4, 135.6, 133.6,

130.4, 129.5, 129.5, 128.2, 127.6, 127.0, 116.7, 76.9, 57.7, 35.2, 21.5.

was stirred at –50 °C for 0.5 h to afford 12b (240.7 mg, 77%) as a pale

yellow oil after purification by column chromatography on silica gel

(hexane/benzene 2:3).

IR (neat): 2219 (s), 1702 (s), 1375 (m), 1172 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 8.7 Hz, 2 H), 7.47 (d, J = 7.2

Hz, 1 H), 7.34–7.29 (m, 3 H), 7.24–7.21 (m, 2 H), 6.94 (dd, J = 10.9,

17.2 Hz, 1 H), 5.59 (dd, J = 1.2, 17.2 Hz, 1 H), 5.33 (dd, J = 1.2, 10.9 Hz,

1 H), 4.67 (s, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 2.46 (s, 3 H), 1.25 (t, J = 7.2

Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.8, 145.4, 137.7, 133.9, 133.2,

130.3, 130.3, 129.9, 129.1, 127.8, 127.8, 126.3, 117.6, 82.5, 68.1, 61.4,

52.7, 21.6, 14.0.

MS (EI): m/z = 311 (M⁺), 263, 246, 156, 128, 91.

HRMS (EI): m/z calcd for

C

₁₈H₁₇NO₂S (M⁺): 311.0980; found:

311.0979.

Ethyl [(2-Allylphenyl)-(p-toluenesulfonyl)amino]propynoate

(11b)

MS (EI): m/z = 383 (M⁺), 228, 182, 154, 129, 117, 91.

To a solution of 8 (0.33 g, 0.86 mmol) in THF (17 mL) was added BuLi

(1.2 mL, 1.90 mmol, 1.58 M hexane solution) at –78 °C, and stirred at

the same temperature for 0.5 h. To the resulting mixture was added

ethyl chlorocarbonate (0.17 mL, 1.73 mmol) and warmed to –50 °C

over 0.5 h. Sat. aq NH₄Cl was added, and the aqueous phase was ex-

tracted with EtOAc. The combined organic phases were washed with

brine and dried (MgSO₄). The volatiles were removed under reduced

pressure, and the residue was purified by column chromatography on

silica gel (hexane/EtOAc 10:1) to provide 11b (0.25 g, 76%) as a pale

yellow oil.

HRMS (EI): m/z calcd for

C

₂₁H₂₁NO₄S (M⁺): 383.1191; found:

383.1194.

N-Phenylethynyl-N-(2-vinylbenzyl)-p-toluenesulfonamide (12c)

To a solution of 9 (239.0 mg, 0.63 mmol) in THF (8 mL) was added

BuLi (0.87 mL, 1.38 mmol, 1.58 M hexane solution) at –78 °C, and

stirred at the same temperature for 0.5 h. To the resulting mixture

was added ZnBr₂(168.9 mg, 0.75 mmol) in THF (2 mL), and stirred at

r.t. for 0.5 h to provide the crude alkynylzinc solution. This alkynylz-

inc solution was transferred with THF (3 mL) to the alkylpalladium

complex in THF solution (5 mL), which was prepared from PhI (0.08

mL, 0.75 mmol), Pd₂(dba)₃·CHCl₃(32.4 mg, 31.26 μmol) and PPh₃

(32.8 mg, 0.13 mmol). The resulting mixture was stirred at r.t. for 21

h. After the volatiles were removed under reduced pressure, brine was

added and the aqueous phase was extracted with EtOAc. The com-

bined organic phases were washed with brine, and dried (MgSO₄).

The volatiles were removed under reduced pressure, and the residue

was purified by column chromatography on silica gel (hexane/EtOAc

10:1) to provide 12c (134.9 mg, 56%) as a pale yellow oil.

IR (neat): 2220 (s), 1706 (s), 1597 (w), 1375 (s), 1177 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 8.2 Hz, 2 H), 7.40–7.30 (m, 4

H), 7.16 (ddd, J = 1.9, 6.8, 8.2 Hz, 1 H), 6.83 (dd, J = 1.0, 7.7 Hz, 1 H),

5.87 (ddt, J = 10.6, 17.4, 6.8 Hz, 1 H), 5.14–5.07 (m, 2 H), 4.22 (q, J = 7.3

Hz, 2 H), 3.40 (br, 2 H), 2.49 (s, 3 H), 1.30 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.9, 145.9, 139.4, 135.3, 135.2,

133.2, 130.6, 130.1, 129.9, 128.4, 127.8, 127.2, 117.1, 82.6, 65.9, 61.4,

35.1, 21.6, 14.0.

MS (EI): m/z = 383 (M⁺), 338, 319, 290, 272, 244, 228, 154, 128, 115,

91.

IR (neat): 2238 (s), 1598 (m), 1366 (s), 1170 (s) cm^–1

.

HRMS (EI): m/z calcd for

C

₂₁H₂₁NO₄S (M⁺): 383.1191; found:

¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 7.7

Hz, 1 H), 7.38–7.27 (m, 5 H), 7.25–7.14 (m, 5 H), 7.07 (dd, J = 11.1,

17.4 Hz, 1 H), 5.65 (dd, J = 1.0, 17.4 Hz, 1 H), 5.33 (dd, J = 1.0, 11.1 Hz,

1 H), 4.61 (s, 2 H), 2.46 (s, 3 H).

383.1185.

N-Ethynyl-N-(2-vinylbenzyl)-p-toluenesulfonamide (12a)

According to the procedure for the synthesis of 11a, a solution of 9

(305.9 mg, 0.80 mmol) and BuLi (1.1 mL, 1.76 mmol, 1.58 M hexane

solution) in THF (16 mL) was stirred at –78 °C for 1 h to afford 12a

(209.6 mg, 84%) as a white solid after purification by column chroma-

tography on silica gel (hexane/EtOAc 10:1); mp 88–89 °C.

¹³C NMR (100 MHz, CDCl₃): δ = 144.7, 137.8, 134.0, 133.4, 130.8,

130.7, 129.7, 128.8, 128.0, 127.7, 127.6, 127.4, 126.8, 126.0, 122.7,

117.0, 82.4, 71.5, 52.8, 21.6.

MS (EI): m/z = 387 (M⁺), 248, 232, 217, 155, 117, 91.

C

₂₄H₂₁NO₂S (M⁺): 387.1293; found:

IR (KBr): 2141 (m), 1596 (w), 1360 (s), 1174 (s) cm^–1

.

HRMS (EI): m/z calcd for

387.1291.

¹H NMR (400 MHz, CDCl₃): δ = 7.79 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 7.7

Hz, 1 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.29 (ddd, J = 1.9, 7.3, 7.7 Hz, 1 H),

7.24–7.17 (m, 2 H), 7.01 (dd, J = 11.1, 17.4 Hz, 1 H), 5.62 (dd, J = 1.5,

17.4 Hz, 1 H), 5.32 (dd, J = 1.5, 11.1 Hz, 1 H), 4.52 (s, 2 H), 2.59 (s, 1 H),

2.45 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.8, 137.5, 133.9, 133.3, 130.5,

130.3, 129.7, 128.7, 127.6, 127.5, 125.9, 117.0, 75.8, 59.8, 52.4, 21.5.

N-(2-Allylbenzyl)-N-ethynyl-p-toluenesulfonamide (13a)

According to the procedure for the synthesis of 11a, a solution of 10

(182.5 mg, 0.46 mmol) and BuLi (0.64 mL, 1.01 mmol, 1.58 M hexane

solution) in THF (9 mL) was stirred at –78 °C for 1 h to afford 13a

(131.5 mg, 88%) as a pale yellow oil after purification by column chro-

matography on silica gel (hexane/EtOAc 10:1).

MS (EI): m/z = 310 (M⁺– 1), 156, 129, 117, 91.

IR (neat): 2132 (w), 1597 (w), 1369 (m), 1173 (s) cm^–1

.

HRMS (EI): m/z calcd for

C

₁₈H₁₇NO₂S (M⁺): 311.0980; found:

¹H NMR (400 MHz, CDCl₃): δ = 7.80 (d, J = 8.2 Hz, 2 H), 7.36 (d, J = 8.2

Hz, 2 H), 7.30–7.14 (m, 4 H), 5.93 (ddt, J = 10.1, 16.9, 6.0 Hz, 1 H), 5.06

(dd, J = 1.5, 10.1 Hz, 1 H), 4.96 (dd, J = 1.5, 16.9 Hz, 1 H), 4.47 (s, 2 H),

3.45 (d, J = 6.0 Hz, 2 H), 2.60 (s, 1 H), 2.47 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.8, 138.7, 136.4, 133.9, 131.7,

130.3, 129.9, 129.7, 128.7, 127.6, 126.3, 116.0, 76.0, 59.7, 52.4, 36.5,

21.5.

311.0992.

Ethyl [(p-Toluenesulfonyl)-(2-vinylbenzyl)amino]propynoate

(12b)

According to the procedure for the synthesis of 11b, a solution of 9

(313.3 mg, 0.82 mmol), BuLi (1.2 mL, 1.97 mmol, 1.58 M hexane solu-

tion), and ethyl chlorocarbonate (0.16 mL, 1.64 mmol) in THF (16 mL)

K

H. Wakamatsu et al.

Paper

Synthesis

MS (EI): m/z = 324 (M⁺– 1), 260, 170, 143, 131, 117, 91.

¹H NMR (400 MHz, CDCl₃): δ = 7.80 (d, J = 8.2 Hz, 2 H), 7.35 (d, J = 8.2

Hz, 2 H), 5.75 (ddt, J = 10.1, 16.9, 6.3 Hz, 1 H), 5.02–4.93 (m, 2 H), 3.31

(t, J = 7.3 Hz, 2 H), 2.73 (s, 1 H), 2.45 (s, 3 H), 2.05 (dt, J = 6.3, 7.3 Hz, 2

H), 1.66 (tt, J = 7.3, 7.7 Hz, 2 H), 1.41 (tt, J = 7.3, 7.7 Hz, 2 H).

HRMS (EI): m/z calcd for

C

₁₉H₁₉NO₂S (M⁺): 325.1136; found:

325.1143.

¹³C NMR (100 MHz, CDCl₃): δ = 144.6, 138.0, 134.4, 129.7, 127.5,

114.8, 75.9, 59.0, 50.8, 32.9, 26.9, 25.2, 21.5.

MS (EI): m/z = 276 (M⁺– 1), 212, 155, 122, 91.

Ethyl [(2-Allylbenzyl)-(p-toluenesulfonyl)amino]propynoate (13b)

According to the procedure for the synthesis of 11b, a solution of 10

(179.5 mg, 0.45 mmol), BuLi (0.69 mL, 1.09 mmol, 1.58 M hexane

solution), and ethyl chlorocarbonate (0.09 mL, 0.91 mmol) in THF (9

mL) was stirred at –10 °C for 2 h to afford 13b (142.7 mg, 79%) as a

pale yellow oil after purification by column chromatography on silica

gel (hexane/EtOAc 10:1).

HRMS (EI): m/z calcd for

C

₁₅H₁₉O₂NS (M⁺): 277.1136; found:

277.1122.

Ethyl [Hex-5-enyl-(p-toluenesulfonyl)amino]propynoate (17b)

IR (neat): 2218 (s), 1705 (s), 1597 (w), 1375 (s), 1172 (s) cm^–1

.

According to the procedure for the synthesis of 11b, a solution of 16

(313.0 mg, 0.90 mmol), BuLi (1.3 mL, 2.16 mmol, 1.63 M hexane solu-

tion), and ethyl chlorocarbonate (0.17 mL, 1.80 mmol) in THF (18 mL)

was stirred at –20 °C for 1.5 h to afford 17b (223.3 mg, 71%) as a color-

less oil after purification by column chromatography on silica gel

(hexane/Et₂O 3:1).

¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.2

Hz, 2 H), 7.28 (dt, J = 1.9, 7.2 Hz, 1 H), 7.25–7.14 (m, 3 H), 5.91 (ddt,

J = 10.1, 16.9, 5.8 Hz, 1 H), 5.06 (dd, J = 1.5, 10.1 Hz, 1 H), 4.94 (dd,

J = 1.5, 16.9 Hz, 1 H), 4.60 (s, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 3.41 (d,

J = 5.8 Hz, 2 H), 2.46 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 21.6, 36.6, 52.5, 61.4, 68.0, 82.6,

116.2, 126.6, 127.8, 129.0, 129.9, 130.1, 130.2, 131.1, 133.9, 136.3,

138.6, 145.5, 153.9.

IR (neat): 2219 (s), 1705 (s), 1597 (w), 1376 (s), 1174 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.82 (d, J = 8.2 Hz, 2 H), 7.38 (d, J = 8.2

Hz, 2 H), 5.73 (ddt, J = 10.1, 16.9, 6.3 Hz, 1 H), 5.02–4.93 (m, 2 H), 4.23

(q, J = 7.2 Hz, 2 H), 3.42 (t, J = 7.3 Hz, 2 H), 2.46 (s, 3 H), 2.08–2.01 (m,

2 H), 1.72–1.63 (m, 2 H), 1.42–1.33 (m, 2 H), 1.31 (t, J = 7.2 Hz, 3 H).

MS (EI): m/z = 398 (M⁺+ 1), 242, 196, 155, 131, 117, 91.

HRMS (EI): m/z calcd for

C

₂₂H₂₃NO₄S (M⁺): 397.1348; found:

397.1344.

¹³C NMR (100 MHz, CDCl₃): δ = 154.2, 145.4, 137.8, 134.2, 130.0,

127.7, 115.1, 82.4, 67.7, 61.5, 51.2, 32.9, 27.3, 25.2, 21.7, 14.1.

MS (EI): m/z = 348 (M⁺– 1), 304, 194, 166, 148, 91.

N-(2,2-Dichlorovinyl)-N-hex-5-enyl-p-toluenesulfonamide (16)

To a solution of 14 (2.99 g, 15.00 mmol), 15 (2.5 mL, 20.41 mmol), and

PPh₃(5.51 g, 21.01 mmol) in THF (30 mL) was added DEAD (8.9 mL,

19.51 mmol) at 0 °C, and the mixture was stirred at r.t. for 4 h. The

volatiles were removed under reduced pressure, and the residue

passed through a short column of silica gel (eluent: hexane/EtOAc

5:1) to provide the crude alkylated formyltosylamide. To a solution of

this crude product and PPh₃(9.84 g, 37.50 mmol) in THF (30 mL) was

added CCl₄(12 mL, 123.00 mmol) in THF (10 mL) at 60 °C over 3 h,

and the resulting mixture was stirred at the same temperature for 12

h. Sat. aq NaHCO₃was added after cooling to r.t., and the aqueous

phase was extracted with Et₂O. The combined organic phases were

washed with brine, and dried (MgSO₄). The volatiles were removed

under reduced pressure, and the residue was purified by column

chromatography on silica gel (hexane/EtOAc 10:1) to provide 16 (2.91

g, 56%) as a white solid; mp 90 °C.

HRMS (EI): m/z calcd for

349.1339.

C

₁₈H₂₃O₄NS (M⁺): 349.1348; found:

N-[2-(N-Allyl-N-p-toluenesulfonylamino)phenyl]-N-ethynyl-p-

toluenesulfonamide (21a)

To a solution of 21d (243.1 mg, 0.44 mmol) in THF (4 mL) was added

TBAF (1.3 mL, 1.32 mmol, 1 M THF solution) at 0 °C, and stirred at the

same temperature for 5 min. Sat. aq NH₄Cl was added, and the aque-

ous phase was extracted with EtOAc. The combined organic phases

were washed with brine and dried (MgSO₄). The volatiles were re-

moved under reduced pressure, and the residue was purified by col-

umn chromatography on silica gel (hexane/EtOAc 2:1) to provide 21a

(194.1 mg, 92%) as a white solid; mp 146 °C.

IR (KBr): 2130 (w), 1596 (m), 1372 (m), 1165 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 8.2 Hz, 2 H), 7.84 (d, J = 7.7

Hz, 2 H), 7.41–7.25 (m, 6 H), 7.20 (dd, J = 1.5, 7.7 Hz, 1 H), 6.99 (dd,

J = 1.5, 7.7 Hz, 1 H), 5.95 (ddt, J = 10.1, 16.9, 6.8 Hz, 1 H), 5.09–5.02 (m,

2 H), 4.22 (d, J = 6.8 Hz, 2 H), 2.72 (s, 1 H), 2.49 (s, 3 H), 2.45 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 145.3, 143.8, 138.3, 137.6, 136.1,

133.5, 133.2, 131.4, 129.8, 129.6, 129.5, 129.1, 129.0, 128.7, 128.5,

119.3, 77.2, 58.1, 54.4, 21.8, 21.6.

IR (KBr): 1599 (w), 1356 (s), 1165 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.69 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2

Hz, 2 H), 6.28 (s, 1 H), 5.76 (ddt, J = 10.2, 16.9, 6.8 Hz, 1 H), 5.02–4.94

(m, 2 H), 3.33 (t, J = 7.2 Hz, 2 H), 2.44 (s, 3 H), 2.05 (dt, J = 6.8, 7.2 Hz, 2

H), 1.56–1.48 (m, 2 H), 1.42–1.36 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.1, 138.1, 135.5, 129.8, 127.2,

124.9, 124.3, 114.9, 48.9, 33.1, 27.8, 25.7, 21.6.

MS (EI): m/z = 480 (M⁺), 325, 262, 171, 139, 91.

MS (EI): m/z = 347 (M⁺), 264, 251, 192, 155, 91.

HRMS (EI): m/z calcd for C₁₅H₁₉³⁵Cl₂NO₂S (M⁺): 347.0514; found:

HRMS (EI): m/z calcd for

C

₂₅H₂₄N₂O₄S₂(M⁺): 480.1177; found:

480.1180.

347.0522.

Ethyl {[2-(Allyl-p-toluenesulfonylamino)phenyl]-p-toluenesulfo-

nylamino}propynoate (21b)

N-Ethynyl-N-hex-5-enyl-p-toluenesulfonamide (17a)

According to the procedure for the synthesis of 11a, a solution of 16

(206.2 mg, 0.59 mmol) and BuLi (0.82 mL, 1.30 mmol, 1.58 M hexane

solution) in THF (10 mL) was stirred at –78 °C for 1 h to afford 17a

(140.0 mg, 85%) as a white solid after purification by column chroma-

tography on silica gel (hexane/EtOAc 10:1); mp 43 °C.

To a solution of 21a (305.9 mg, 0.64 mmol) in THF (13 mL) was added

BuLi (0.42 mL, 0.70 mmol, 1.65 M hexane solution) at –78 °C, and

stirred at the same temperature for 0.5 h. To the resulting mixture

was added ethyl chlorocarbonate (0.07 mL, 0.76 mmol), and warmed

to –15 °C for 1.5 h. Sat. aq NH₄Cl solution was added, and the aqueous

phase was extracted with EtOAc. The combined organic phases were

IR (KBr): 2133 (m), 1598 (w), 1359 (s), 1169 (s) cm^–1

.

L

H. Wakamatsu et al.

Paper

Synthesis

washed with brine and dried (MgSO₄). The volatiles were removed

under reduced pressure, and the residue was purified by column

chromatography on silica gel (hexane/Et₂O Ac 2:1) to provide 21b

(252.2 mg, 72%) as a white solid; mp 48 °C.

MS (EI): m/z = 552 (M⁺), 537, 397, 241, 169, 91.

HRMS (EI): m/z calcd for C₂₈H₃₂N₂O₄S₂Si (M⁺): 552.1573; found:

552.1567.

IR (KBr): 2221 (s), 1706 (s), 1597 (w), 1374 (m), 1176 (s) cm^–1

.

N-(2,2-Dichlorovinyl)-N-hept-6-enyl-p-toluenesulfonamide (26)

¹H NMR (400 MHz, CDCl₃): δ = 7.90 (d, J = 8.7 Hz, 2 H), 7.74 (d, J = 8.2

Hz, 2 H), 7.41 (d, J = 8.7 Hz, 2 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.39–7.28 (m,

2 H), 7.13 (dd, J = 1.5, 7.7 Hz, 1 H), 7.05 (dd, J = 1.9, 7.7 Hz, 1 H), 5.93

(ddt, J = 9.7, 16.9, 7.2 Hz, 1 H), 5.09–5.02 (m, 2 H), 4.21–4.15 (m, 4 H),

2.49 (s, 3 H), 2.44 (s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.9, 146.0, 143.9, 137.8, 136.6,

135.6, 133.0, 132.9, 131.3, 130.0, 129.8, 129.5, 129.2, 129.2, 128.6,

128.6, 119.6, 83.1, 66.5, 61.5, 54.6, 21.8, 21.6, 14.1.

To a solution of 14 (3.00 g, 15.06 mmol), 23 (2.7 mL, 20.33 mmol), and

PPh₃(5.53 g, 21.08 mmol) in THF (30 mL) was added DEAD (8.9 mL,

19.58 mmol) at 0 °C, and the mixture was stirred at r.t. for 4 h. The

volatiles were removed under reduced pressure, and the residue was

passed through a short column of silica gel (eluent: hexane/EtOAc

5:1) to provide the crude alkylated formyltosylamide. To a solution of

this crude product and PPh₃(9.87 g, 37.64 mmol) in THF (30 mL) was

added CCl₄(12 mL, 123.48 mmol) in THF (10 mL) at 60 °C for 3 h, and

the resulting mixture was stirred at the same temperature for 7 h. Sat.

aq NaHCO₃was added after cooling to r.t., and the aqueous phase was

extracted with Et₂O. The combined organic phases were washed with

brine and dried (MgSO₄). The volatiles were removed under reduced

pressure, and the residue was purified by column chromatography on

silica gel (hexane/Et₂O 10:1) to provide 26 (2.59 g, 48%) as a white

solid; mp 69 °C.

MS (EI): m/z = 552 (M⁺), 507, 397, 334, 259, 243, 169, 139, 91.

HRMS(EI): m/z calcd for

C

₂₈H₂₈N₂O₆S₂(M⁺): 552.1389; found:

552.1385.

N-[2-(N-Allyl-N-p-toluenesulfonylamino)phenyl]-N-(2-phenyl-

ethynyl)-p-toluenesulfonamide (21c)

IR (KBr): 1599 (w), 1354 (s), 1165 (s) cm^–1

.

To a mixture of Pd(PPh₃)₄(13.4 mg, 11.59 μmol), CuI (2.2 mg, 11.59

μmol), and PhI (0.05 mL, 0.46 mmol) in Et₃N (2 mL) and benzene (1

mL) was added 21a (111.4 mg, 0.23 mmol) at r.t., and the mixture was

stirred at the same temperature for 48 h. The volatiles were removed

under reduced pressure, and the residue was purified by column

chromatography on silica gel (hexane/EtOAc, 2:1) to provide 21c

(126.4 mg, 98%) as a white solid; mp 53 °C.

¹H NMR (400 MHz, CDCl₃): δ = 7.69 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 8.5

Hz, 2 H), 6.27 (s, 1 H), 5.78 (ddt, J = 10.1, 16.9, 6.8 Hz, 1 H), 5.02–4.92

(m, 2 H), 3.31 (t, J = 7.5 Hz, 2 H), 2.44 (s, 3 H), 2.03 (dt, J = 6.8, 7.2 Hz, 2

H), 1.56–1.47 (m, 2 H), 1.42–1.26 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.1, 138.6, 135.5, 129.8, 127.2,

124.9, 124.3, 114.6, 49.0, 33.5, 28.3, 28.2, 26.0, 21.6.

IR (KBr): 2241 (w), 1597 (w), 1356 (m), 1168 (s) cm^–1

.

MS (EI): m/z = 361 (M⁺), 278, 265, 206, 155, 91.

HRMS (EI): m/z calcd for C₁₆H₂₁³⁵Cl₂NO₂S (M⁺): 361.0607; found:

¹H NMR (400 MHz, CDCl₃): δ = 7.92–7.86 (m, 4 H), 7.41–7.24 (m, 12

H), 7.05 (d, J = 8.3 Hz, 1 H), 5.97 (ddt, J = 9.8, 16.6, 6.8 Hz, 1 H), 5.10–

5.02 (m, 2 H), 4.27 (d, J = 6.8 Hz, 2 H), 2.49 (s, 3 H), 2.38 (s, 3 H).

361.0667.

¹³C NMR (100 MHz, CDCl₃): δ = 145.2, 143.7, 138.1, 138.0, 136.5,

133.8, 133.3, 131.9, 131.4, 129.6, 129.6, 129.5, 129.1, 128.9, 128.7,

128.6, 128.2, 127.8, 122.7, 119.4, 83.8, 69.8, 54.4, 21.7, 21.6.

N-[4,4-Bis(benzyloxymethyl)hept-6-enyl]-N-(2,2-dichlorovinyl)-p-

toluenesulfonamide (27)

According to the procedure for the synthesis of 26, a solution of 14

(0.799 g, 4.01 mmol), 24 (1.09 g, 3.09 mmol), PPh₃(1.01 g, 3.86

mmol), and DEAD (1.7 mL, 3.70 mmol) in THF (6 mL) was stirred at r.t.

for 1 h and then a solution of the crude product obtained, an addi-

tional amount of PPh₃(2.02 g, 7.72 mmol), and CCl₄(2.4 mL, 25.31

mmol) in THF (9 mL) were stirred at 60 °C for 24 h to afford 27 (811.2

mg, 44%) as a colorless oil after purification by column chromatogra-

phy on silica gel (hexane/EtOAc 10:1).

MS (EI): m/z = 556 (M⁺), 456, 417, 401, 301, 245, 139, 119, 91.

HRMS (EI): m/z calcd for

C

₃₁H₂₈O₄N₂S₂(M⁺): 556.1490; found:

556.1497.

N-[2-(N-Allyl-N-p-toluenesulfonylamino)phenyl]-N-(2-trimethyl-

silyl)ethynyl-p-toluenesulfonamide (21d)

To a solution of 19 (811.2 mg, 1.78 mmol) in THF (27 mL) was added

BuLi (1.3 mL, 1.95 mmol, 1.55 M hexane solution) at –78 °C, and

stirred at the same temperature for 1 h. To the resulting mixture was

added phenyl(trimethylsilylethynyl)iodonium triflate (960.0 mg, 2.13

mmol). The mixture was warmed to r.t. over 1 h, and stirred at the

same temperature for 18 h. Sat. aq NH₄Cl was added, and the aqueous

phase was extracted with EtOAc. The combined organic phases were

washed with brine and dried (MgSO₄). The volatiles were removed

under reduced pressure, and the residue was purified by column

chromatography on silica gel (hexane/EtOAc 2:1) to provide 21d

(595.4 mg, 61%) as a white solid; mp 35–36 °C.

IR (neat): 1639 (w), 1598 (w), 1360 (s), 1167 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.66 (d, J = 8.7 Hz, 2 H), 7.36–7.25 (m,

12 H), 6.29 (s, 1 H), 5.77–5.65 (m, 1 H), 5.04–4.98 (m, 2 H), 4.45 (s, 4

H), 3.30–3.23 (m, 6 H), 2.42 (s, 3 H), 2.07 (d, J = 7.7 Hz, 2 H), 1.54–1.44

(m, 2 H), 1.28–1.22 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.9, 138.6, 135.3, 133.9, 129.7,

128.1, 128.1, 127.2, 127.0, 124.8, 123.0, 117.5, 73.0, 72.4, 49.5, 41.2,

36.4, 28.9, 22.0, 21.4.

MS (EI): m/z = 601 (M⁺), 510, 446, 355, 340, 249, 155, 91.

IR (KBr): 2165 (m), 1597 (w), 1359 (m), 1173 (s) cm^–1

.

HRMS (EI): m/z calcd for C₃₂H₃₇³⁵Cl₂NO₄S (M⁺): 601.1820; found:

601.1814.

¹H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 8.3 Hz, 2 H), 7.83 (d, J = 8.3

Hz, 2 H), 7.39–7.24 (m, 7 H), 7.01 (dd, J = 1.0, 7.3 Hz, 1 H), 5.93 (ddt,

J = 9.8, 16.6, 6.8 Hz, 1 H), 5.05–4.99 (m, 2 H), 4.17 (d, J = 6.8 Hz, 2 H),

2.49 (s, 3 H), 2.45 (s, 3 H), 0.12 (s, 9 H).

N-[3-(5-Allyl-2,2-dimethyl[1,3]dioxan-5-yl)-propyl]-N-(2,2-di-

chlorovinyl)-p-toluenesulfonamide (28)

¹³C NMR (100 MHz, CDCl₃): δ = 145.1, 143.7, 137.9, 137.4, 136.4,

133.6, 133.2, 131.7, 129.5, 129.4, 129.4, 129.1, 129.0, 128.9, 128.4,

119.4, 95.9, 72.6, 54.1, 21.7, 21.6, –0.1.

According to the procedure for the synthesis of 26, a solution of 14

(784.3 mg, 3.94 mmol), 25 (703.0 mg, 3.28 mmol), PPh₃(1.205 g, 4.59

mmol), and DEAD (1.9 mL, 4.26 mmol) in THF (15 mL) was stirred at

M

H. Wakamatsu et al.

Paper

Synthesis

r.t. for 4 h and then a solution of the crude product obtained, an addi-

tional amount of PPh₃(2.15 g, 8.20 mmol), and CCl₄(2.6 mL, 26.90

mmol) in THF (15 mL) were stirred at 60 °C for 17 h to afford 28

(707.1 mg, 47%) as a white solid after purification by column chroma-

tography on silica gel (hexane/EtOAc 5:1); 54 °C.

solution) in THF (10 mL) was stirred at –78 °C for 10 min to afford 30a

(237.3 mg, 88%) as a pale yellow oil after purification by column chro-

matography on silica gel (hexane/EtOAc 10:1).

IR (neat): 2135 (m), 1639 (w), 1597 (w), 1367 (s), 1169 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.77 (d, J = 8.2 Hz, 2 H), 7.35–7.25 (m,

12 H), 5.71 (m, 1 H), 5.04–4.97 (m, 2 H), 4.44 (s, 4 H), 3.28–3.21 (m, 6

H), 2.68 (s, 1 H), 2.42 (s, 3 H), 2.06 (d, J = 7.7 Hz, 2 H), 1.68–1.58 (m, 2

H), 1.30–1.23 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.5, 138.6, 134.4, 133.9, 129.6,

128.1, 127.4, 127.2, 127.2, 117.6, 75.9, 73.0, 72.4, 59.0, 51.7, 41.3,

36.3, 28.5, 21.4, 21.4.

IR (KBr): 1598 (w), 1354 (s), 1167 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2

Hz, 2 H), 6.31 (s, 1 H), 5.70 (ddt, J = 10.1, 17.9, 7.2 Hz, 1 H), 5.12–5.05

(m, 2 H), 3.56 (d, J = 11.6 Hz, 2 H), 3.50 (d, J = 11.6 Hz, 2 H), 3.31 (t,

J = 7.2 Hz, 2 H), 2.44 (s, 3 H), 2.11 (d, J = 7.2 Hz, 2 H), 1.53–1.43 (m, 2

H), 1.40 (s, 3 H), 1.39 (s, 3 H), 1.34–1.28 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.2, 135.5, 133.0, 129.9, 127.3,

124.8, 123.9, 118.4, 98.1, 67.5, 49.6, 36.6, 35.0, 29.2, 23.9, 23.6, 21.9,

21.6.

MS (EI): m/z = 530 (M⁺– 1), 440, 376, 270, 91.

HRMS (EI): m/z calcd for

C

₃₂H₃₇O₄NS (M⁺): 531.2443; found:

531.2467.

MS (EI): m/z = 461 (M⁺), 446, 306, 277, 248, 155, 91.

HRMS (EI): m/z calcd for C₂₁H₂₉³⁵Cl₂NO₄S (M⁺): 461.1194; found:

461.1175.

Ethyl {[4,4-Bis(benzyloxymethyl)hept-6-enyl](p-toluenesulfo-

nyl)amino}propynoate (30b)

According to the procedure for the synthesis of 11b, a solution of 27

(444.4 mg, 0.74 mmol), BuLi (1.0 mL, 1.62 mmol, 1.63 M hexane solu-

tion), and ethyl chlorocarbonate (0.08 mL, 0.88 mmol) in THF (15 mL)

was stirred at –30 °C for 1 h to afford 30b (302.7 mg, 68%) as a pale

yellow oil after purification by column chromatography on silica gel

(hexane/EtOAc 5:1).

N-Ethynyl-N-hept-6-enyl-p-toluenesulfonamide (29a)

According to the procedure for the synthesis of 11a, a solution of 26

(235.7 mg, 0.65 mmol) and BuLi (0.88 mL, 1.43 mmol, 1.63 M hexane

solution) in THF (13 mL) was stirred at –78 °C for 20 min to afford 29a

(158.8 mg, 84%) as a pale yellow oil after purification by column chro-

matography on silica gel (hexane/EtOAc 10:1).

IR (neat): 2218 (s), 1704 (s), 1598 (w), 1376 (s), 1174 (s) cm^–1

.

IR (neat): 2133 (m), 1597 (w), 1366 (s), 1169 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 8.7 Hz, 2 H), 7.35–7.25 (m,

12 H), 5.68 (m, 1 H), 5.04–4.97 (m, 2 H), 4.44 (s, 4 H), 4.19 (q, J = 7.3

Hz, 2 H), 3.35 (t, J = 7.3 Hz, 2 H), 3.25 (s, 2 H), 3.24 (s, 2 H), 2.43 (s, 3

H), 2.05 (d, J = 6.8 Hz, 2 H), 1.68–1.59 (m, 2 H), 1.27 (t, J = 7.3 Hz, 3 H),

1.26–1.20 (m, 2 H).

¹H NMR (400 MHz, CDCl₃): δ = 7.80 (d, J = 8.2 Hz, 2 H), 7.35 (d, J = 8.2

Hz, 2 H), 5.78 (ddt, J = 10.1, 16.9, 6.8 Hz, 1 H), 5.02–4.91 (m, 2 H), 3.29

(t, J = 7.3 Hz, 2 H), 2.73 (s, 1 H), 2.45 (s, 3 H), 2.02 (dt, J = 6.8, 7.2 Hz, 2

H), 1.69–1.60 (m, 2 H), 1.42–1.27 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.6, 138.5, 134.5, 129.7, 127.5,

114.5, 75.9, 59.0, 51.0, 33.4, 28.2, 27.4, 25.5, 21.6.

MS (EI): m/z = 290 (M⁺– 1), 227, 155, 136, 91.

¹³C NMR (100 MHz, CDCl₃): δ = 153.9, 145.2, 138.5, 134.0, 133.7,

129.8, 128.1, 127.5, 127.2, 127.2, 117.6, 82.3, 73.0, 72.2, 67.7, 61.3,

51.9, 41.2, 36.3, 28.5, 21.7, 21.5, 14.0.

MS (EI): m/z = 603 (M⁺), 448, 342, 155, 91.

HRMS (EI): m/z calcd for C

₃₅H₄₁NO₆S (M⁺): 603.2655; found:

HRMS (EI): m/z calcd for

C

₁₆H₂₁NO₂S (M⁺): 291.1293; found:

291.1298.

603.2673.

Ethyl [Hept-6-enyl-(p-toluenesulfonyl)amino]propynoate (29b)

N-[3-(5-Allyl-2,2-dimethyl[1,3]dioxan-5-yl)propyl]-N-ethynyl-p-

toluenesulfonamide (31a)

According to the procedure for the synthesis of 11b, a solution of 26

(287.3 mg, 0.79 mmol), BuLi (1.1 mL, 1.74 mmol, 1.63 M hexane solu-

tion), and ethyl chlorocarbonate (0.11 mL, 1.19 mmol) in THF (16 mL)

was stirred at –30 °C for 1 h to afford 29b (228.6 mg, 79%) as a pale

yellow oil after purification by column chromatography on silica gel

(hexane/EtOAc 10:1).

According to the procedure for the synthesis of 11a, a solution of 28

(225.5 mg, 0.49 mmol) and BuLi (0.69 mL, 1.07 mmol, 1.55 M hexane

solution) in THF (10 mL) was stirred at –78 °C for 0.5 h to afford 31a

(161.8 mg, 85%) as a pale yellow oil after purification by column chro-

matography on silica gel (hexane/EtOAc 3:1).

IR (neat): 2218 (s), 1705 (s), 1597 (w), 1376 (s), 1174 (s) cm^–1

.

IR (neat): 2134 (m), 1597 (w), 1372(s), 1170 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.82 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.2

Hz, 2 H), 5.76 (ddt, J = 10.1, 16.9, 6.8 Hz, 1 H), 5.02–4.91 (m, 2 H), 4.23

(q, J = 7.2 Hz, 2 H), 3.41 (t, J = 7.3 Hz, 2 H), 2.46 (s, 3 H), 2.05–1.98 (m,

2 H), 1.71–1.62 (m, 2 H), 1.31 (t, J = 7.2 Hz, 3 H), 1.42–1.24 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 154.0, 145.4, 138.3, 134.1, 129.9,

127.5, 114.5, 82.3, 67.6, 61.4, 51.2, 33.3, 28.0, 27.6, 25.3, 21.5, 14.0.

¹H NMR (400 MHz, CDCl₃): δ = 7.80 (d, J = 8.2 Hz, 2 H), 7.35 (d, J = 8.2

Hz, 2 H), 5.70 (ddt, J = 11.6, 16.9, 7.7 Hz, 1 H), 5.11–5.05 (m, 2 H), 3.55

(d, J = 11.6 Hz, 2 H), 3.50 (d, J = 11.6 Hz, 2 H), 3.29 (t, J = 7.0 Hz, 2 H),

2.75 (s, 1 H), 2.45 (s, 3 H), 2.12 (d, J = 7.7 Hz, 2 H), 1.66–1.54 (m, 2 H),

1.40 (s, 3 H), 1.38 (s, 3 H), 1.33–1.25 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.8, 134.5, 132.9, 129.8, 127.6,

118.4, 98.1, 75.8, 67.4, 59.3, 51.6, 36.4, 35.0, 28.9, 24.1, 23.4, 21.6,

21.1.

MS (EI): m/z = 363 (M⁺), 318, 208, 162, 155, 91.

HRMS (EI): m/z calcd for

C

₁₉H₂₅NO₄S (M⁺): 363.1504; found:

363.1489.

MS (EI): m/z = 390 (M⁺– 1), 376, 304, 236, 178, 91.

HRMS (EI): m/z calcd for

391.1815.

C

₂₁H₂₉NO₄S (M⁺): 391.1817; found:

N-[4,4-Bis(benzyloxymethyl)hept-6-enyl]-N-ethynyl-p-toluene-

sulfonamide (30a)

According to the procedure for the synthesis of 11a, a solution of 27

(305.5 mg, 0.51 mmol) and BuLi (0.68 mL, 1.12 mmol, 1.63 M hexane

N

H. Wakamatsu et al.

Paper

Synthesis

Ethyl {[3-(5-Allyl-2,2-dimethyl[1,3]dioxan-5-yl)propyl]-(p-tolue-

nesulfonyl)amino}propynoate (31b)

N-[3-(N-Allyl-N-p-toluenesulfonyl)aminopropyl]-N-tert-butoxy-

carbonyl-p-toluenesulfonamide (36)

According to the procedure for the synthesis of 11b, a solution of 28

(212.8 mg, 0.46 mmol), BuLi (0.65 mL, 1.01 mmol, 1.55 M hexane

solution), and ethyl chlorocarbonate (0.05 mL, 0.55 mmol) in THF (9

mL) was stirred at –30 °C for 1 h to afford 31b (203.3 mg, 95%) as a

pale yellow oil after purification by column chromatography on silica

gel (hexane/EtOAc 3:1).

To a solution of 34 (304.5 mg, 1.13 mmol), 35 (337.4 mg, 1.24 mmol),

and PPh₃(370.6 mg, 1.41 mmol) in THF (6 mL) was added DEAD (0.62

mL, 1.36 mmol) at 0 °C, and the mixture was stirred at r.t. for 20 min.

The volatiles were removed under reduced pressure, and the residue

was purified by column chromatography on silica gel (hexane/EtOAc

3:1) to provide 36 (590.9 mg, quant) as a colorless oil.

IR (neat): 2218 (s), 1705 (s), 1598 (w), 1374 (s), 1175 (s) cm^–1

.

IR (neat): 1728 (s), 1644 (w), 1598 (m), 1350 (s), 1157 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.82 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.2

Hz, 2 H), 5.67 (m, 1 H), 5.12–5.05 (m, 2 H), 4.22 (q, J = 7.2 Hz, 2 H),

3.55 (d, J = 11.6 Hz, 2 H), 3.48 (d, J = 11.6 Hz, 2 H), 3.40 (t, J = 7.0 Hz, 2

H), 2.46 (s, 3 H), 2.10 (d, J = 7.3 Hz, 2 H), 1.68–1.59 (m, 2 H), 1.39 (s, 3

H), 1.38 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.30–1.24 (m, 2 H).

¹H NMR (400 MHz, CDCl₃): δ = 7.77 (d, J = 8.2 Hz, 2 H), 7.70 (d, J = 8.2

Hz, 2 H), 7.33–7.28 (m, 4 H), 5.63 (ddt, J = 10.1, 16.9, 6.3 Hz, 1 H), 5.20

(d, J = 16.9 Hz, 1 H), 5.15 (d, J = 10.1 Hz, 1 H), 3.85 (d, J = 6.3 Hz, 2 H),

3.83 (t, J = 7.2 Hz, 2 H), 3.22 (t, J = 7.2 Hz, 2 H), 2.44 (s, 3 H), 2.42 (s, 3

H), 2.05–1.96 (m, 2 H), 1.34 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 154.1, 145.6, 134.2, 132.7, 130.1,

127.8, 118.5, 98.1, 82.1, 67.9, 67.4, 61.6, 51.8, 36.5, 35.0, 28.8, 23.8,

23.7, 21.7, 21.5, 14.2.

¹³C NMR (100 MHz, CDCl₃): δ = 150.7, 144.1, 143.2, 137.1, 136.7,

132.7, 129.6, 129.2, 127.6, 127.0, 119.2, 84.2, 50.4, 44.8, 44.6, 28.6,

27.7, 21.5, 21.4.

MS (EI): m/z = 462 (M⁺– 1), 448, 308, 250, 220, 155, 91.

MS (EI): m/z = 522 (M⁺), 465, 449, 421, 267, 224, 155, 91.

HRMS (EI): m/z calcd for

C

₂₄H₃₃NO₆S (M⁺): 463.2029; found:

HRMS (EI): m/z calcd for C

₂₅H₃₄N₂O₆S₂(M⁺): 522.1858; found:

463.2026.

522.1843.

N-Allyl-N-(3-hydroxypropyl)-p-toluenesulfonamide (34)

N-[2-(N-Allyl-N-p-toluenesulfonyl)aminobenzyl]-N-tert-butoxy-

carbonyl-p-toluenesulfonamide (39)

To a solution of 32 (1.81 g, 8.57 mmol), 33 (1.63 g, 8.57 mmol), and

PPh₃(2.81 g, 10.71 mmol) in THF (20 mL) was added DEAD (4.7 mL,

10.29 mmol) at 0 °C, and the mixture was stirred at r.t. for 2 h. The

volatiles were removed under reduced pressure, and the residue was

purified by column chromatography on silica gel (hexane/EtOAc 5:1)

to provide N-allyl-N-[3-(tert-butyldimethylsilanyloxy)propyl]-p-tol-

uenesulfonamide (2.10 g, 64%) as a pale yellow oil.

To a solution of 38 (2.97 g, 9.36 mmol), 35 (2.79 g, 10.29 mmol), and

PPh₃(3.07 mg, 11.70 mmol) in THF (50 mL) was added DEAD (5.1 mL,

11.23 mmol) at 0 °C, and the mixture was stirred at r.t. for 0.5 h. The

volatiles were removed under reduced pressure, and the residue was

purified by column chromatography on silica gel (hexane/EtOAc 4:1)

to provide 39 (4.50 g, 84%) as a white solid; mp 65 °C.

IR (neat): 1644 (w), 1599 (m), 1345 (s), 1162 (s) cm^–1

.

IR (KBr): 1732 (s), 1598 (w), 1354 (s), 1167 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.70 (d, J = 8.3 Hz, 2 H), 7.29 (d, J = 8.3

Hz, 2 H), 5.65 (ddt, J = 10.2, 16.6, 6.3 Hz, 1 H), 5.20–5.10 (m, 2 H), 3.81

(d, J = 6.3 Hz, 2 H), 3.58 (dd, J = 5.9, 6.3 Hz, 2 H), 3.23–3.18 (m, 2 H),

2.42 (s, 3 H), 1.76–1.68 (m, 2 H), 0.87 (s, 9 H), 0.02 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 142.9, 136.9, 133.1, 129.4, 127.0,

118.5, 60.1, 50.7, 44.4, 31.4, 25.7, 21.3, 18.0, –5.6.

¹H NMR (400 MHz, CDCl₃): δ = 7.80 (d, J = 8.2 Hz, 2 H), 7.56 (d, J = 8.2

Hz, 2 H), 7.40 (d, J = 7.2 Hz, 1 H), 7.34–7.28 (m, 5 H), 7.10 (ddd, J = 1.0,

7.2, 7.7 Hz, 1 H), 6.49 (dd, J = 1.0, 7.2 Hz, 1 H), 5.87 (m, 1 H), 5.42 (d,

J = 17.6 Hz, 1 H), 5.26 (d, J = 17.6 Hz, 1 H), 5.07–5.01 (m, 2 H), 4.43 (dd,

J = 5.8, 14.0 Hz, 1 H), 3.91 (dd, J = 7.7, 14.0 Hz, 1 H), 2.46 (s, 6 H), 1.35

(s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 151.1, 144.2, 143.7, 139.5, 137.1,

136.6, 135.1, 132.4, 129.5, 129.2, 128.7, 128.2, 128.1, 127.8, 127.0,

126.9, 119.6, 84.3, 54.9, 47.9, 27.8, 21.6, 21.6.

MS (EI): m/z = 382 (M⁺– 1), 368, 326, 228, 91.

HRMS (EI): m/z calcd for C₁₉H₃₃NO₃SSi (M⁺): 383.1950; found:

383.1946.

MS (EI): m/z = 570 (M⁺), 497, 415, 315, 144, 91.

To a solution of the above coupling product (665.1 mg, 1.73 mmol) in

THF (3.5 mL) was added TBAF (5.2 mL, 5.20 mmol, 1 M THF solution)

at 0 °C, and the resulting mixture was stirred at r.t. for 40 min. Sat. aq

NH₄Cl was added, and the aqueous phase was extracted with EtOAc.

The combined organic phases were washed with brine and dried

(MgSO₄). The volatiles were removed under reduced pressure, and the

residue was purified by column chromatography on silica gel (hex-

ane/EtOAc 1:1) to provide 34 (463.5 mg, 99%) as a colorless oil.

HRMS (EI): m/z calcd for

570.1854.

C

₂₉H₃₄N₂O₆S₂(M⁺): 570.1858; found:

N-Allyl-N-[3-(N-p-toluenesulfonyl)aminopropyl]-p-toluenesul-

fonamide (40)

To a solution of 36 (590.9 mg, 1.13 mmol) in CH₂Cl₂(5 mL) was added

TFA (1 mL) at 0 °C, and the mixture was stirred at r.t. for 1 h. The vola-

tiles were removed under reduced pressure, and the residue was puri-

fied by column chromatography on silica gel (hexane/EtOAc 2:1) to

provide 40 (477.7 mg, quant) as a colorless oil.

IR (neat): 3534 (m), 1644 (w), 1598 (m), 1337 (s), 1159 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.70 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.2

Hz, 2 H), 5.62 (ddt, J = 10.1, 16.4, 6.3 Hz, 1 H), 5.20–5.11 (m, 2 H), 3.82

(d, J = 6.3 Hz, 2 H), 3.74 (dd, J = 5.3, 5.8 Hz, 2 H), 3.25 (dd, J = 6.3, 6.8

Hz, 2 H), 2.44 (s, 3 H), 2.35 (br, 1 H), 1.76–1.69 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.2, 136.3, 132.8, 129.6, 126.8,

118.8, 58.6, 50.8, 43.9, 30.6, 21.3.

IR (neat): 3283 (m), 1644 (w), 1598 (m), 1331 (s), 1159 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, J = 8.2 Hz, 2 H), 7.67 (d, J = 8.2

Hz, 2 H), 7.34–7.29 (m, 4 H), 5.53 (ddt, J = 10.1, 16.9, 6.8 Hz, 1 H), 5.21

(t, J = 6.8 Hz, 1 H), 5.16–5.08 (m, 2 H), 3.73 (d, J = 6.8 Hz, 2 H), 3.15 (t,

J = 6.3 Hz, 2 H), 3.04 (ddd, J = 5.3, 6.8, 6.8 Hz, 2 H), 2.44 (s, 3 H), 2.43 (s,

3 H), 1.76–1.68 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.2, 142.9, 136.7, 135.9, 132.4,

129.5, 129.4, 126.7, 126.6, 118.9, 50.7, 44.2, 39.6, 27.8, 21.1, 21.1.

MS (EI): m/z = 269 (M⁺), 224 155, 114, 91.

HRMS (EI): m/z calcd for

C

₁₃H₁₉NO₃S (M⁺): 269.1086; found:

269.1104.

O

H. Wakamatsu et al.

Paper

Synthesis

MS (EI): m/z = 422 (M⁺), 267, 224, 155, 91.

IR (KBr): 1702 (s), 1598 (w), 1349 (s), 1166 (s) cm^–1

.

HRMS (EI): m/z calcd for

422.1316.

C

₂₀H₂₆N₂O₄S₂(M⁺): 422.1334; found:

¹H NMR (400 MHz, CDCl₃): δ = 9.24 (s, 1 H), 7.77 (d, J = 8.2 Hz, 2 H),

7.50 (d, J = 8.2 Hz, 2 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.28 (d, J = 8.2 Hz, 2

H), 7.17–7.26 (m, 2 H), 7.05 (ddd, J = 1.9, 6.8, 8.2 Hz, 1 H), 6.41 (d,

J = 7.7 Hz, 1 H), 5.85 (dddd, J = 6.3, 7.7, 10.2, 16.9 Hz, 1 H), 5.02–5.10

(m, 2 H), 5.00 (d, J = 16.9 Hz, 1 H), 4.93 (d, J = 16.9 Hz, 1 H), 4.45 (dd,

J = 6.3, 14.0 Hz, 1 H), 3.83 (dd, J = 7.7, 14.0 Hz, 1 H), 2.46 (s, 3 H), 2.45

(s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 161.5, 145.6, 143.9, 137.0, 136.9,

134.8, 134.4, 132.3, 130.3, 129.4, 128.5, 128.2, 127.5, 127.4, 127.3,

127.2, 119.7, 54.8, 42.6, 21.6, 21.6.

N-Allyl-N-[2-(N-p-toluenesulfonyl)aminomethylphenyl]-p-tolue-

nesulfonamide (41)

To a solution of 39 (4.43 g, 7.76 mmol) in CH₂Cl₂(40 mL) was added

TFA (8 mL) at 0 °C, and the mixture was stirred at r.t. for 1 h. The vola-

tiles were removed under reduced pressure, and the residue was puri-

fied by column chromatography on silica gel (hexane/EtOAc 2:1) to

provide 41 (3.65 g, quant) as a white solid; mp 121 °C.

MS (EI): m/z = 498 (M⁺), 343, 315, 159, 144, 91.

IR (KBr): 1597 (w), 1344 (s), 1160 (s) cm^–1

.

HRMS (EI): m/z calcd for

498.1273.

C

₂₅H₂₆N₂O₅S₂(M⁺): 498.1283; found:

¹H NMR (400 MHz, CDCl₃): δ = 7.83 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 7.7

Hz, 1 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.35 (d, J = 8.7 Hz, 2 H), 7.31–7.25 (m,

3 H), 7.09 (dt, J = 1.0, 7.7 Hz, 1 H), 6.35 (d, J = 7.7 Hz, 1 H), 5.63 (dd,

J = 3.9, 8.7 Hz, 1 H), 5.50 (dddd, J = 5.8, 8.2, 10.2, 16.9 Hz, 1 H), 4.95 (d,

J = 10.2 Hz, 1 H), 4.88 (d, J = 16.9 Hz, 1 H), 4.39 (dd, J = 5.8, 14.0 Hz, 1

H), 4.23–4.15 (m, 2 H), 3.58 (dd, J = 8.2, 14.0 Hz, 1 H), 2.46 (s, 3 H),

2.45 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.1, 143.2, 138.1, 137.5, 137.0,

134.3, 131.7, 131.6, 129.7, 129.6, 129.0, 128.4, 128.1, 127.4, 127.2,

120.1, 55.0, 43.0, 21.6, 21.5.

N-[3-(N-Allyl-N-p-toluenesulfonyl)aminopropyl]-N-(2,2-dichloro-

ethenyl)-p-toluenesulfonamide (44)

According to the procedure for the synthesis of 8, a solution of 42

(2.01 g, 4.45 mmol), PPh₃(2.92 g, 11.13 mmol), and CCl₄(3.5 mL,

36.51 mmol) in THF (15 mL) was stirred at 60 °C for 4.5 h to afford 44

(2.24 g, 97%) as a colorless oil after purification by silica gel column

chromatography (hexane/EtOAc 3:1).

MS (EI): m/z = 470 (M⁺), 315, 144, 91.

IR (neat): 1598 (m), 1345 (s), 1165 (s) cm^–1

.

HRMS (EI): m/z calcd for

470.1329.

C

₂₄H₂₆N₂O₄S₂(M⁺): 470.1334; found:

¹H NMR (400 MHz, CDCl₃): δ = 7.70–7.65 (m, 2 H), 7.36–7.29 (m, 4 H),

6.20 (s, 1 H), 5.60 (ddt, J = 10.1, 16.9, 6.8 Hz, 1 H), 5.22–5.13 (m, 2 H),

3.79 (d, J = 6.8 Hz, 2 H), 3.33 (t, J = 7.3 Hz, 2 H), 3.15 (t, J = 7.2 Hz, 2 H),

2.45 (s, 3 H), 2.43 (s, 3 H), 1.85–1.76 (m, 2 H).

N-[3-(N-Allyl-N-p-toluenesulfonyl)aminopropyl]-N-formyl-p-tol-

¹³C NMR (100 MHz, CDCl₃): δ = 144.0, 143.0, 136.1, 134.4, 132.7,

129.6, 129.4, 126.9, 126.7, 124.8, 124.5, 118.7, 50.8, 46.6, 44.7, 27.0,

21.1, 21.1.

MS (EI): m/z = 516 (M⁺), 481, 393, 361, 224, 155, 91.

HRMS (EI): m/z calcd for C₂₂H₂₆³⁵Cl₂N₂O₄S₂(M⁺): 516.0711; found:

uenesulfonamide (42)

According to the procedure for the synthesis of 5, a solution of 40

(2.04 g, 4.84 mmol), BuLi (3.6 mL, 5.80 mmol, 1.63 M hexane solu-

tion), and 1-formylbenzotriazole (1.42 g, 9.67 mmol) in THF (25 mL)

was stirred at –50 °C for 0.5 h to afford 42 (2.01 g, 92%) as a colorless

oil after purification by column chromatography on silica gel (hex-

ane/EtOAc 3:1).

516.0704.

IR (neat): 1699 (s), 1643 (w), 1597 (m), 1357 (s), 1165 (s) cm^–1

.

N-[2-(N-Allyl-N-p-toluenesulfonyl)aminobenzyl]-N-(2,2-dichlor-

ovinyl)-p-toluenesulfonamide (45)

¹H NMR (400 MHz, CDCl₃): δ = 9.07 (s, 1 H), 7.75 (d, J = 8.2 Hz, 2 H),

7.66 (d, J = 8.2 Hz, 2 H), 7.38 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 8.2 Hz, 2

H), 5.55 (ddt, J = 10.1, 16.9, 6.8 Hz, 1 H), 5.19–5.09 (m, 2 H), 3.79 (d,

J = 6.8 Hz, 2 H), 3.49–3.43 (m, 2 H), 3.13 (t, J = 6.8 Hz, 2 H), 2.45 (s, 3

H), 2.41 (s, 3 H), 1.85–1.75 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 161.1, 145.5, 143.3, 136.5, 134.5,

132.5, 130.3, 129.6, 127.3, 127.0, 119.3, 50.3, 44.5, 40.2, 26.5, 21.5,

21.4.

According to the procedure for the synthesis of 8, a solution of 43

(2.93 g, 5.88 mmol), PPh₃(3.85 g, 14.69 mmol), and CCl₄(4.6 mL,

48.19 mmol) in THF (20 mL) was stirred at 60 °C for 4 h to afford 45

(3.27 g, 98%) as a white solid after purification by column chromatog-

raphy on silica gel (hexane/EtOAc 4:1); mp 137 °C.

IR (KBr): 1736 (w), 1598 (m), 1351 (s), 1166 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.72–7.78 (m, 3 H), 7.46 (d, J = 8.2 Hz, 2

H), 7.38 (d, J = 8.2 Hz, 2 H), 7.33 (ddd, J = 1.0, 7.2, 7.7 Hz, 1 H), 7.27 (d,

J = 8.2 Hz, 2 H), 7.10 (ddd, J = 1.4, 7.7, 7.7 Hz, 1 H), 6.40 (dd, J = 1.0, 8.2

Hz, 1 H), 6.22 (s, 1 H), 5.63 (dddd, J = 5.8, 7.7, 10.1, 16.9 Hz, 1 H), 5.03

(dd, J = 1.5, 10.1 Hz, 1 H), 4.96 (dd, J = 1.5, 16.9 Hz, 1 H), 4.82 (d,

J = 16.4 Hz, 1 H), 4.70 (d, J = 16.4 Hz, 1 H), 4.41 (dd, J = 5.8, 13.5 Hz, 1

H), 3.69 (dd, J = 7.7, 13.5 Hz, 1 H), 2.48 (s, 3 H), 2.45 (s, 3 H).

MS (EI): m/z = 450 (M⁺), 295, 224, 155, 91.

HRMS (EI): m/z calcd for

C

₂₁H₂₆N₂O₅S₂(M⁺): 450.1283; found:

450.1287.

N-[2-(N-Allyl-N-p-toluenesulfonyl)aminobenzyl]-N-formyl-p-tol-

uenesulfonamide (43)

¹³C NMR (100 MHz, CDCl₃): δ = 144.3, 143.9, 138.0, 137.0, 135.3,

134.4, 131.7, 130.0, 129.5, 129.5, 128.6, 128.1, 127.7, 127.4, 127.1,

126.5, 125.7, 120.1, 54.8, 49.5, 21.6, 21.6.

MS (EI): m/z = 564 (M⁺), 529, 441, 409, 300, 144, 91.

HRMS (EI): m/z calcd for C₂₆H₂₆³⁵Cl₂N₂O₄S₂(M⁺): 564.0711; found:

According to the procedure for the synthesis of 5, a solution of 41

(3.55 g, 7.65 mmol), BuLi (5.8 mL, 9.05 mmol, 1.55 M hexane solu-

tion), and 1-formylbenzotriazole (2.22 g, 15.09 mmol) in THF (40 mL)

was stirred at –30 °C for 1 h to afford 43 (3.12 g, 83%) as a white solid

after purification by column chromatography on silica gel (hex-

ane/EtOAc 4:1); mp 63 °C.

564.0712.

P

H. Wakamatsu et al.

Paper

Synthesis

N-[3-(N-Allyl-N-p-toluenesulfonyl)aminopropyl]-N-ethynyl-p-tol-

uenesulfonamide (46a)

¹³C NMR (100 MHz, CDCl₃): δ = 144.9, 143.9, 137.1, 137.0, 134.6,

134.5, 131.9, 129.9, 129.5, 129.1, 128.7, 128.1, 127.9, 127.8, 127.5,

119.9, 60.4, 58.8, 54.8, 51.5, 21.7, 21.6.

According to the procedure for the synthesis of 11a, a solution of 44

(269.6 mg, 0.52 mmol) and BuLi (0.70 mL, 1.15 mmol, 1.63 M hexane

solution) in THF (10 mL) was stirred at –78 °C for 10 min to afford 46a

(176.2 mg, 76%) as a colorless oil after purification by column chro-

matography on silica gel (hexane/EtOAc 3:1).

MS (EI): m/z = 494 (M⁺), 339, 183, 144, 91.

HRMS (EI): m/z calcd for

C

₂₆H₂₆N₂O₄S₂(M⁺): 494.1334; found:

494.1321.

IR (neat): 2134 (m), 1644 (w), 1598 (m), 1364 (s), 1167 (s) cm^–1

.

Ethyl {[2-(Allyl-p-toluenesulfonylamino)benzyl](p-toluenesulfo-

¹H NMR (400 MHz, CDCl₃): δ = 7.79 (d, J = 8.2 Hz, 2 H), 7.68 (d, J = 8.2

Hz, 2 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 5.60 (ddt,

J = 10.1, 16.4, 6.3 Hz, 1 H), 5.22–5.12 (m, 2 H), 3.77 (d, J = 6.3 Hz, 2 H),

3.32 (dd, J = 6.8, 7.3 Hz, 2 H), 3.14 (dd, J = 6.8, 7.7 Hz, 2 H), 2.73 (s, 1

H), 2.46 (s, 3 H), 2.43 (s, 3 H), 1.99–1.91 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.8, 143.2, 136.2, 133.8, 132.5,

129.7, 129.6, 127.4, 126.9, 119.2, 75.4, 59.3, 51.0, 48.7, 44.5, 26.6,

21.4, 21.3.

nyl)amino}propynoate (47b)

According to the procedure for the synthesis of 11b, a solution of 45

(382.3 mg, 0.68 mmol), BuLi (0.96 mL, 1.49 mmol, 1.55 M hexane

solution), and ethyl chlorocarbonate (0.08 mL, 0.81 mmol) in THF (10

mL) was stirred at –30 °C for 1 h to afford 47b (318.8 mg, 83%) as a

pale yellow oil after purification by column chromatography on silica

gel (hexane/EtOAc 3:1).

IR (neat): 2220 (s), 1706 (s), 1598 (m), 1348 (s), 1172 (s) cm^–1

.

MS (EI): m/z = 445 (M⁺– 1), 381, 317, 291, 224, 155, 135, 91.

¹H NMR (400 MHz, CDCl₃): δ = 7.86 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 8.2

Hz, 1 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.40 (d, J = 7.7 Hz, 2 H), 7.34–7.26 (m,

3 H), 7.13 (dt, J = 1.5, 7.7 Hz, 1 H), 6.45 (dd, J = 1.0, 8.2 Hz, 1 H), 5.73

(dddd, J = 5.8, 7.7, 10.2, 16.9 Hz, 1 H), 5.09–4.96 (m, 3 H), 4.81 (d,

J = 15.9 Hz, 1 H), 4.41 (dd, J = 5.8, 13.5 Hz, 1 H), 4.16 (q, J = 7.2 Hz, 2

H), 3.76 (dd, J = 7.7, 13.5 Hz, 1 H), 2.49 (s, 3 H), 2.45 (s, 3 H), 1.25 (t,

J = 7.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.9, 145.6, 144.0, 137.2, 136.4,

134.4, 134.1, 131.7, 130.2, 129.5, 129.0, 128.8, 128.2, 128.1, 127.9,

127.5, 120.4, 83.1, 67.3, 61.4, 54.7, 51.5, 21.7, 21.6, 14.1.

HRMS (EI): m/z calcd for

C

₂₂H₂₆N₂O₄S₂(M⁺): 446.1334; found:

446.1353.

Ethyl {[3-(Allyl-p-toluenesulfonylamino)propyl]-(p-toluenesulfo-

nyl)amino}propynoate (46b)

According to the procedure for the synthesis of 11b, a solution of 44

(508.8 mg, 0.98 mmol), BuLi (1.3 mL, 2.16 mmol, 1.63 M hexane solu-

tion), and ethyl chlorocarbonate (0.11 mL, 1.18 mmol) in THF (20 mL)

was stirred at –20 °C for 2 h to afford 46b (415.2 mg, 81%) as a pale

yellow oil after purification by column chromatography on silica gel

(hexane/EtOAc 2:1).

MS (EI): m/z = 566 (M⁺), 521, 411, 365, 255, 144, 91.

HRMS (EI): m/z calcd for

C

₂₉H₃₀N₂O₆S₂(M⁺): 566.1545; found:

IR (neat): 2219 (s), 1705 (s), 1598 (w), 1372 (s), 1174 (s) cm^–1

.

566.1533.

¹H NMR (400 MHz, CDCl₃): δ = 7.81 (d, J = 8.2 Hz, 2 H), 7.67 (d, J = 8.2

Hz, 2 H), 7.38 (d, J = 7.7 Hz, 2 H), 7.31 (d, J = 7.7 Hz, 2 H), 5.60 (ddt,

J = 9.7, 16.4, 6.7 Hz, 1 H), 5.22–5.12 (m, 2 H), 4.23 (q, J = 7.3 Hz, 2 H),

3.76 (d, J = 6.7 Hz, 2 H), 3.45 (dd, J = 6.8, 7.7 Hz, 2 H), 3.13 (dd, J = 6.8,

7.3 Hz, 2 H), 2.47 (s, 3 H), 2.43 (s, 3 H), 2.00–1.91 (m, 2 H), 1.31 (t,

J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.8, 145.6, 143.4, 136.2, 133.7,

132.6, 130.1, 129.7, 127.6, 127.0, 119.4, 81.8, 67.7, 61.5, 51.2, 49.0,

44.5, 26.9, 21.6, 21.4, 14.0.

N-[2-(N-Allyl-N-p-toluenesulfonyl)aminobenzyl]-N-(2-trimethyl-

silylethynyl)-p-toluenesulfonamide (47c)

According to the procedure for the synthesis of 21d, a solution of 41

(511.7 mg, 1.09 mmol), BuLi (0.80 mL, 1.20 mmol, 1.55 M hexane

solution), and phenyl(trimethylsilylethynyl)iodonium triflate (587.5

mg, 1.30 mmol) in toluene (10 mL) was stirred at r.t. for 18 h to afford

47c (452.1 mg, 73%) as a pale brownish solid after purification by col-

umn chromatography on silica gel (hexane/EtOAc 3:1); mp 105 °C.

IR (KBr): 2173 (s), 1647 (w), 1597 (m), 1368 (s), 1165 (s) cm^–1

.

MS (EI): m/z = 518 (M⁺), 473, 454, 363, 339, 317, 299, 267, 252, 224,

¹H NMR (400 MHz, CDCl₃): δ = 7.81 (d, J = 8.2 Hz, 2 H), 7.60 (dd,

J = 1.0, 7.7 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.2 Hz, 2 H),

7.32–7.26 (m, 3 H), 7.12 (dt, J = 1.0, 7.7 Hz, 1 H), 6.46 (dd, J = 1.0, 8.2

Hz, 1 H), 5.70 (m, 1 H), 5.01–4.95 (m, 2 H), 4.87 (d, J = 15.7 Hz, 1 H),

4.65 (d, J = 15.7 Hz, 1 H), 4.35 (dd, J = 5.8, 14.0 Hz, 1 H), 3.82 (dd,

J = 7.7, 14.0 Hz, 1 H), 2.48 (s, 3 H), 2.45 (s, 3 H), 0.08 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.7, 143.8, 137.2, 137.1, 134.7,

134.4, 132.1, 129.7, 129.5, 129.5, 128.6, 128.1, 127.9, 127.8, 127.6,

119.7, 96.1, 72.8, 54.8, 51.8, 21.7, 21.6, –0.0.

207, 155.

HRMS (EI): m/z calcd for

518.1538.

C

₂₅H₃₀N₂O₆S₂(M⁺): 518.1545; found:

N-[2-(N-Allyl-N-p-toluenesulfonyl)aminobenzyl]-N-ethynyl-p-tol-

uenesulfonamide (47a)

According to the procedure for the synthesis of 11a, a solution of 45

(303.8 mg, 0.54 mmol) and BuLi (0.76 mL, 1.18 mmol, 1.55 M hexane

solution) in THF (10 mL) was stirred at –78 °C for 0.5 h to afford 47a

(208.4 mg, 78%) as a pale yellow oil after purification by column chro-

matography on silica gel (hexane/EtOAc 3:1).

MS (EI): m/z = 566 (M⁺), 551, 411, 255, 144, 91.

HRMS (EI): m/z calcd for C₂₉H₃₄N₂O₄S₂Si₂(M⁺): 566.1729; found:

IR (neat): 2136 (s), 1645 (w), 1597 (s), 1348 (s), 1171 (s) cm^–1

.

566.1717.

¹H NMR (400 MHz, CDCl₃): δ = 7.84 (d, J = 8.7 Hz, 2 H), 7.62 (d, J = 6.8

Hz, 1 H), 7.48 (d, J = 8.2 Hz, 2 H), 7.39 (d, J = 8.2 Hz, 2 H), 7.34–7.26 (m,

3 H), 7.12 (dt, J = 1.5, 7.7 Hz, 1 H), 6.46 (dd, J = 1.0, 8.2 Hz, 1 H), 5.71

(dddd, J = 5.8, 7.7, 10.6, 16.4 Hz, 1 H), 5.01–4.94 (m, 2 H), 4.86 (d,

J = 15.9 Hz, 1 H), 4.72 (d, J = 15.9 Hz, 1 H), 4.38 (dd, J = 5.8, 14.0 Hz, 1

H), 3.77 (dd, J = 7.7, 14.0 Hz, 1 H), 2.63 (s, 1 H), 2.49 (s, 3 H), 2.45 (s, 3

H).

Metathesis Reaction of 11a; 1-(p-Toluenesulfonyl)-2-vinyl-1,4-di-

hydroquinoline (48a); Typical Procedure (Table 1, entry 1)

To a solution of the ruthenium carbene complex 1b (17.2 mg, 20.22

μmol, 5 mol%) in toluene (15 mL) was added 11a (125.9 mg, 0.40

mmol) in toluene (5 mL) at 0 °C, and the solution was stirred at 80 °C

for 0.5 h under an ethylene atmosphere. A few drops of ethyl vinyl

Q

H. Wakamatsu et al.

Paper

Synthesis

ether was added to the mixture, and the volatiles were removed un-

der reduced pressure. The residue was purified by column chroma-

tography on silica gel (hexane/EtOAc 10:1) to afford 48a (116.8 mg,

93%) as a pale yellow oil.

2-(p-Toluenesulfonyl)-3-vinyl-1,2-dihydroisoquinoline (50a)

According to the typical procedure for the metathesis reaction of 11a,

a solution of 12a (48.9 mg, 0.16 mmol) and 1b (6.7 mg, 7.85 μmol) in

toluene (8.0 mL) was stirred at 80 °C for 0.5 h under an ethylene at-

mosphere to afford 50a (34.4 mg, 70%) as a pale yellow oil after purifi-

cation by column chromatography on silica gel (hexane/EtOAc 10:1).

IR (neat): 1597 (w), 1354 (s), 1172 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.74 (dd, J = 1.0, 8.2 Hz, 1 H), 7.30 (ddd,

J = 1.0, 7.3, 8.2 Hz, 1 H), 7.25 (d, J = 8.2 Hz, 2 H), 7.18 (ddd, J = 1.0, 7.3,

7.7 Hz, 1 H), 7.10 (d, J = 8.2 Hz, 2 H), 6.87 (dd, J = 1.0, 7.7 Hz, 1 H), 6.46

(dd, J = 10.6, 17.4 Hz, 1 H), 5.91 (t, J = 4.8 Hz, 1 H), 5.78 (d, J = 17.4 Hz,

1 H), 5.26 (d, J = 10.6 Hz, 1 H), 2.38 (s, 3 H), 2.43–2.02 (br, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 144.0, 140.1, 137.5, 134.7, 133.8,

133.8, 129.2, 128.0, 127.8, 127.2, 126.9, 126.6, 123.2, 115.5, 27.6, 21.6.

IR (neat): 1598 (w), 1349 (s), 1164 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.30 (d, J = 8.2 Hz, 2 H), 7.04 (ddd,

J = 1.0, 7.0, 7.2 Hz, 1 H), 6.99–6.92 (m, 2 H), 6.83 (d, J = 8.2 Hz, 2 H),

6.68 (d, J = 7.2 Hz, 1 H), 6.54 (dd, J = 11.1, 17.4 Hz, 1 H), 6.44 (s, 1 H),

5.84 (d, J = 17.4 Hz, 1 H), 5.37 (d, J = 11.1 Hz, 1 H), 4.75 (s, 2 H), 2.18 (s,

3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.1, 138.4, 134.3, 133.9, 131.1,

MS (EI): m/z = 311 (M⁺), 156, 128.

130.0, 128.3, 127.8, 127.5, 127.2, 125.2, 124.9, 120.4, 117.3, 50.4, 21.2.

MS (EI): m/z = 311 (M⁺), 156, 128.

HRMS (EI): m/z calcd for

311.0981.

C

₁₈H₁₇NO₂S (M⁺): 311.0980; found:

HRMS (EI): m/z calcd for

C

₁₈H₁₇NO₂S (M⁺): 311.0980; found:

Ethyl 2-[1-(p-Toluenesulfonyl)-1,4-dihydroquinolin-2-yl]acrylate

311.0979.

(48b)

According to the typical procedure for the metathesis reaction of 11a,

a solution of 11b (40.3 mg, 0.11 mmol) and 1b (4.5 mg, 5.25 μmol) in

toluene (5.5 mL) was stirred at 80 °C for 1 h under an argon atmo-

sphere to afford 48b (31.8 mg, 79%) as a pale yellow oil after purifica-

tion by column chromatography on silica gel (hexane/EtOAc 10:1).

Ethyl 2-[2-(p-Toluenesulfonyl)-1,2-dihydroisoquinolin-3-yl]acry-

late (50b)

According to the typical procedure for the metathesis reaction of 11a,

a solution of 12b (45.4 mg, 0.12 mmol) and 1b (5.0 mg, 5.92 μmol) in

toluene (6.0 mL) was stirred at 80 °C for 1 h under an ethylene atmo-

sphere to afford 50b (35.2 mg, 78%) as a pale yellow oil after purifica-

tion by column chromatography on silica gel (benzene/EtOAc 30:1).

IR (neat): 1719 (s), 1597 (w), 1351 (m), 1170 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.74 (d, J = 7.7 Hz, 1 H), 7.34–7.28 (m, 3

H), 7.19 (dd, J = 7.2, 7.7 Hz, 1 H), 7.14 (d, J = 7.7 Hz, 2 H), 6.89 (d, J = 7.3

Hz, 1 H), 6.31 (s, 1 H), 6.12 (s, 1 H), 6.11 (t, J = 4.8 Hz, 1 H), 4.29 (q,

J = 7.3 Hz, 2 H), 2.39 (s, 3 H), 2.29 (br, 2 H), 1.34 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.7, 144.1, 138.5, 137.3, 136.7,

134.1, 133.9, 129.2, 127.9, 127.4, 127.2, 127.0, 126.7, 125.9, 125.4,

61.0, 27.7, 21.6, 14.2.

IR (neat): 1721 (s), 1352 (s), 1165 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.33 (d, J = 8.5 Hz, 2 H), 7.09 (dd,

J = 7.2, 7.7 Hz, 1 H), 7.03–6.98 (m, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 6.76

(d, J = 7.7 Hz, 1 H), 6.58 (s, 1 H), 6.34 (d, J = 1.0 Hz, 1 H), 6.08 (d, J = 1.0

Hz, 1 H), 4.85 (s, 2 H), 4.32 (q, J = 7.2 Hz, 2 H), 2.19 (s, 3 H), 1.37 (t,

J = 7.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.6, 143.1, 138.9, 135.5, 134.6,

130.7, 130.0, 128.4, 128.2, 127.3, 127.3, 127.0, 125.2, 125.1, 122.9,

61.1, 50.1, 21.3, 14.1.

MS (EI): m/z = 383 (M⁺), 338, 318, 228, 182, 154, 128, 91.

HRMS (EI): m/z calcd for

C

₂₁H₂₁NO₄S (M⁺): 383.1191; found:

383.1194.

MS (EI): m/z = 383 (M⁺), 228, 182, 154, 128.

Dimethyl 10-(p-Toluenesulfonyl)-3,9,9a,10-tetrahydroacridine-

HRMS (EI): m/z calcd for C

₂₁H₂₁NO₄S (M⁺): 383.1191; found:

1,2-dicarboxylate (49)

383.1194.

To a solution of 48a (30.6 mg, 0.10 mmol) in toluene (5 mL) was add-

ed DMAD (0.06 mL, 0.49 mmol), and the solution was stirred at 80 °C

for 12 h. The volatiles were removed under reduced pressure, and the

residue was purified by column chromatography on silica gel (hex-

ane/EtOAc 2:1) to provide 49 (19.9 mg, 45%) as a pale yellow oil.

3-(1-Phenylvinyl)-2-(p-toluenesulfonyl)-1,2-dihydroisoquinoline

(50c)

According to the typical procedure for the metathesis reaction of 11a,

a solution of 12c (40.2 mg, 0.10 mmol) and 1b (4.4 mg, 5.19 μmol) in

toluene (5.0 mL) was stirred at 80 °C for 1.5 h under an ethylene at-

mosphere to afford 50c (30.8 mg, 77%) as a pale yellow oil after purifi-

cation by column chromatography on silica gel (hexane/EtOAc 10:1).

IR (neat): 1728 (s), 1361 (m), 1171 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.87 (d, J = 8.3 Hz, 1 H), 7.45 (d, J = 8.3

Hz, 2 H), 7.27–7.18 (m, 3 H), 7.10 (dd, J = 7.3, 7.8 Hz, 1 H), 6.96 (d,

J = 7.8 Hz, 1 H), 6.17 (m, 1 H), 3.79 (s, 3 H), 3.75 (s, 3 H), 3.32–3.15 (m,

2 H), 2.80 (dd, J = 5.9, 15.6 Hz, 1 H), 2.67 (m, 1 H), 2.39 (s, 3 H), 2.37

(m, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 167.5, 167.0, 144.2, 137.0, 136.7,

135.4, 132.2, 129.8, 129.6, 129.0, 127.6, 127.6, 127.0, 125.4, 124.9,

121.4, 52.4, 52.3, 33.6, 33.1, 28.2, 21.5.

IR (neat): 1598 (w), 1354 (s), 1166 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.47–7.28 (m, 7 H), 7.07 (ddd, J = 1.0,

7.3, 7.8 Hz, 1 H), 7.02–6.95 (m, 2 H), 6.89 (d, J = 8.3 Hz, 2 H), 6.73 (d,

J = 7.3 Hz, 1 H), 6.41 (s, 1 H), 5.75 (d, J = 1.0 Hz, 1 H), 5.47 (d, J = 1.0 Hz,

1 H), 4.80 (s, 2 H), 2.21 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.1, 143.1, 140.0, 140.0, 135.3,

131.2, 130.3, 128.4, 128.2, 128.1, 128.0, 127.8, 127.5, 127.3, 125.2,

125.1, 122.6, 117.5, 50.5, 21.3.

MS (EI): m/z = 453 (M⁺), 422, 389, 330, 266, 238, 194, 179.

HRMS (EI): m/z calcd for

C

₂₄H₂₃NO₆S (M⁺): 453.1246; found:

MS (EI): m/z = 387 (M⁺), 230, 217, 202, 154, 117, 91.

453.1263.

HRMS (EI): m/z calcd for

C

₂₄H₂₁NO₂S (M⁺): 387.1293; found:

387.1293.

R

H. Wakamatsu et al.

Paper

Synthesis

Dimethyl 5-(p-Toluenesulfonyl)-3,4,5,6-tetrahydrophenanthri-

MS (EI): m/z = 325 (M⁺), 260, 170, 117, 91.

dine-1,2-dicarboxylate (51)

HRMS (EI): m/z calcd for

C

₁₉H₁₉NO₂S (M⁺): 325.1136; found:

To a solution of 50a (48.2 mg, 0.15 mmol) in toluene (3 mL) was add-

ed DMAD (0.06 mL, 0.46 mmol) at r.t., and the mixture was stirred at

80 °C for 21 h. The volatiles were removed under reduced pressure,

and the residue was purified by column chromatography on silica gel

(hexane/EtOAc, 2:1) to provide 51 (34.8 mg, 50%) as a pale yellow oil.

325.1121.

Ethyl 2-[2-(p-Toluenesulfonyl)-2,5-dihydro-1H-benzo[c]azepin-3-

yl]acrylate (53b)

According to the typical procedure for the metathesis reaction of 11a,

a solution of 13b (35.7 mg, 0.09 mmol) and 1b (3.8 mg, 4.49 μmol) in

toluene (4.5 mL) was stirred at 80 °C for 0.5 h under an argon atmo-

sphere to afford 53b (29.9 mg, 84%) as a pale yellow oil after purifica-

tion by column chromatography on silica gel (hexane/EtOAc 3:1).

IR (neat): 1732 (s), 1354 (m), 1165 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.29 (d, J = 8.4 Hz, 2 H), 7.07 (ddd,

J = 1.0, 6.8, 7.3 Hz, 1 H), 7.02–6.97 (m, 2 H), 6.88 (d, J = 8.4 Hz, 2 H),

6.81 (d, J = 7.3 Hz, 1 H), 4.72 (s, 2 H), 3.80 (s, 3 H), 3.66 (s, 3 H), 3.00 (t,

J = 8.9 Hz, 2 H), 2.61 (t, J = 8.9 Hz, 2 H), 2.22 (s, 3 H).

IR (neat): 1722 (s), 1599 (w), 1349 (s), 1162 (s) cm^–1

.

¹³C NMR (100 MHz, CDCl₃): δ = 168.3, 166.7, 143.7, 142.0, 136.8,

135.1, 130.2, 129.5, 128.8, 127.4, 127.4, 126.7, 126.6, 125.6, 123.4,

122.1, 52.3, 52.3, 50.8, 27.0, 23.9, 21.3.

¹H NMR (400 MHz, CDCl₃): δ = 7.28 (d, J = 7.7 Hz, 1 H), 7.11 (d, J = 7.7

Hz, 2 H), 7.20–7.09 (m, 2 H), 6.95 (d, J = 7.7 Hz, 2 H), 6.80 (d, J = 7.2 Hz,

1 H), 6.12 (d, J = 1.4 Hz, 1 H), 5.69 (d, J = 1.4 Hz, 1 H), 5.63 (t, J = 5.3 Hz,

1 H), 4.95 (s, 2H), 4.22 (q, J = 7.2 Hz, 2 H), 3.48 (d, J = 5.3 Hz, 2 H), 2.30

(s, 3 H), 1.33 (t, J = 7.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.7, 142.5, 141.4, 138.4, 136.5,

136.1, 135.9, 129.4, 129.2, 128.7, 127.6, 127.2, 126.5, 125.9, 124.4,

60.9, 54.4, 34.7, 21.4, 14.1.

MS (EI): m/z = 453 (M⁺), 422, 298, 266, 238, 180.

HRMS (EI): m/z calcd for

C

₂₄H₂₃NO₆S (M⁺): 453.1246; found:

453.1244.

Dimethyl 5-(p-Toluenesulfonyl)-3,5,6,10b-tetrahydrophenanthri-

dine-1,2-dicarboxylate (52)

MS (EI): m/z = 397 (M⁺), 352, 242, 196, 168, 117, 91.

C

₂₂H₂₃NO₄S (M⁺): 397.1348; found:

According to the typical procedure for the metathesis reaction of 11a,

a solution of 12a (43.5 mg, 0.14 mmol) and 1b (5.9 mg, 6.98 μmol) in

toluene (7.0 mL) was stirred at 80 °C for 0.5 h under an ethylene at-

mosphere. After cooling to r.t., DMAD (0.09 mL, 0.70 mmol) was add-

ed and the mixture was stirred at 80 °C for 12 h under an argon atmo-

sphere. The volatiles were removed under reduced pressure, and the

residue was purified by column chromatography on silica gel (hex-

ane/EtOAc 2:1) to provide 52 (29.1 mg, 46%) as a pale yellow oil.

HRMS (EI): m/z calcd for

397.1364.

Dimethyl 5-(p-Toluenesulfonyl)-5,6,11,11a-tetrahydro-3H-diben-

zo[b,e]azepine-1,2-dicarboxylate (54)

According to the typical procedure for the metathesis reaction of 11a,

a solution of 13a (33.4 mg, 0.10 mmol) and 1b (4.4 mg, 5.13 μmol) in

toluene (5.1 mL) was stirred at 80 °C for 0.5 h under an argon atmo-

sphere. After cooling to r.t., DMAD (0.04 mL, 0.31 mmol) was added

and the mixture was stirred at 80 °C for 29 h under an argon atmo-

sphere. The volatiles were removed under reduced pressure, and the

residue was purified by column chromatography on silica gel (hex-

ane/EtOAc 2:1) to provide 54 (17.1 mg, 36%) as a pale yellow oil.

IR (neat): 1732 (s), 1354 (m), 1168 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.71 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.2

Hz, 2 H), 7.24–7.21 (m, 3 H), 6.93 (m, 1 H), 5.93 (t, J = 3.6 Hz, 1 H), 4.89

(d, J = 13.8 Hz, 1 H), 4.34 (d, J = 13.8 Hz, 1 H), 3.86 (s, 3 H), 3.77 (t,

J = 6.3 Hz, 1 H), 3.69 (s, 3 H), 3.22–3.16 (m, 2 H), 2.42 (s, 3 H).

IR (neat): 1732 (s), 1339 (m), 1160 (s) cm^–1

.

¹³C NMR (100 MHz, CDCl₃): δ = 168.8, 166.6, 144.2, 138.9, 138.6,

134.8, 132.1, 131.6, 129.8, 128.3, 127.7, 127.4, 126.9, 126.9, 123.3,

110.7, 52.5, 52.4, 49.5, 39.2, 29.5, 21.6.

¹H NMR (400 MHz, CDCl₃): δ = 7.38 (d, J = 8.2 Hz, 2 H), 7.32 (m, 1 H),

7.24–7.18 (m, 2 H), 7.09 (d, J = 8.2 Hz, 2 H), 7.00 (m, 1 H), 5.85 (dd,

J = 3.4, 3.9 Hz, 1 H), 5.00 (d, J = 15.2 Hz, 1 H), 4.36 (d, J = 15.2 Hz, 1 H),

3.79 (s, 3 H), 3.77 (s, 3 H), 3.18–3.00 (m, 2 H), 2.92–2.83 (m, 2 H), 2.70

(dd, J = 9.2, 15.0 Hz, 1 H), 2.35 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 167.6, 167.4, 143.2, 139.0, 137.0,

136.6, 136.6, 136.2, 130.9, 129.5, 129.3, 129.3, 128.3, 127.3, 126.9,

124.4, 53.9, 52.4, 52.3, 39.7, 39.5, 28.4, 21.4.

MS (EI): m/z = 453 (M⁺), 422, 389, 330, 298, 266, 238, 180.

HRMS (EI): m/z calcd for

C

₂₄H₂₃NO₆S (M⁺): 453.1246; found:

453.1244.

2-(p-Toluenesulfonyl)-3-vinyl-2,5-dihydro-1H-benzo[c]azepine

(53a)

MS (EI): m/z = 467 (M⁺), 436, 403, 371, 344, 280, 252, 213, 104.

According to the typical procedure for the metathesis reaction of 11a,

a solution of 13a (33.4 mg, 0.10 mmol) and 1b (4.4 mg, 5.13 μmol) in

toluene (5.1 mL) was stirred at 80 °C for 0.5 h under an argon atmo-

sphere to afford 53a (16.2 mg, 49%) as a pale yellow oil after purifica-

tion by column chromatography on silica gel (hexane/EtOAc 10:1).

HRMS (EI): m/z calcd for

C

₂₅H₂₅NO₆S (M⁺): 467.1403; found:

467.1378.

1-(p-Toluenesulfonyl)-7-vinyl-2,3,4,5-tetrahydro-1H-azepine

(55a)

IR (neat): 1597 (w), 1338 (s), 1159 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.27 (d, J = 8.2 Hz, 2 H), 7.19–7.11 (m, 2

H), 7.06 (ddd, J = 1.9, 7.3, 7.3 Hz, 1 H), 6.97 (d, J = 8.2 Hz, 2 H), 6.73 (d,

J = 7.7 Hz, 1 H), 6.38 (dd, J = 10.6, 16.9 Hz, 1 H), 5.77 (t, J = 5.8 Hz, 1 H),

5.43 (d, J = 16.9 Hz, 1 H), 5.13 (d, J = 10.6 Hz, 1 H), 4.81 (s, 2 H), 3.30 (d,

J = 5.8 Hz, 2 H), 2.30 (s, 3 H).

According to the typical procedure for the metathesis reaction of 11a,

a solution of 17a (20.7 mg, 0.07 mmol) and 1b (6.3 mg, 7.46 μmol) in

CH₂Cl₂(4.0 mL) was stirred at reflux for 26 h under an argon atmo-

sphere to afford 55a (7.7 mg, 37%) as a pale yellow oil together with

17a (6.8 mg, 33%).

IR (neat): 1599 (w), 1343 (s), 1158 (s) cm^–1

.

¹³C NMR (100 MHz, CDCl₃): δ = 142.6, 141.1, 137.0, 135.3, 135.2,

129.8, 129.6, 129.0, 128.8, 127.4, 127.3, 126.3, 125.0, 115.1, 53.5, 33.9,

21.4.

S

H. Wakamatsu et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, J = 8.2 Hz, 2 H), 7.27 (d, J = 8.2

Hz, 2 H), 6.25 (dd, J = 10.6, 17.2 Hz, 1 H), 5.94 (dd, J = 6.8, 7.3 Hz, 1 H),

5.29 (d, J = 17.2 Hz, 1 H), 5.05 (d, J = 10.6 Hz, 1 H), 3.49 (br, 2 H), 2.42

(s, 3 H), 1.90–1.84 (m, 2 H), 1.73–1.66 (m, 2 H), 1.36–1.29 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 143.1, 142.4, 139.1, 134.6, 131.9,

129.4, 127.5, 114.6, 49.1, 29.2, 26.0, 23.6, 21.5.

IR (neat): 1597 (m), 1356 (s), 1166 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 8.7 Hz, 2 H), 7.61–7.56 (m, 3

H), 7.38–7.32 (m, 3 H), 7.18 (d, J = 8.2 Hz, 2 H), 7.28–7.17 (m, 6 H),

7.10 (dd, J = 1.5, 7.7 Hz, 1 H), 5.39 (s, 1 H), 5.32 (dd, J = 3.4, 3.9 Hz, 1

H), 5.28 (s, 1 H), 4.54 (dd, J = 3.9, 18.4 Hz, 1 H), 3.79 (dd, J = 3.4, 18.4

Hz, 1 H), 2.44 (s, 3 H), 2.40 (s, 3 H).

MS (EI): m/z = 277 (M⁺), 212, 155, 122, 91.

¹³C NMR (100 MHz, CDCl₃): δ = 147.8, 144.2, 143.6, 140.4, 139.2,

138.7, 138.7, 137.3, 136.1, 129.7, 129.6, 129.3, 129.2, 128.6, 128.3,

128.2, 128.0, 127.9, 127.2, 126.5, 122.0, 116.4, 48.8, 21.6, 21.5.

HRMS (EI): m/z calcd for

C

₁₅H₁₉NO₂S (M⁺): 277.1136; found:

277.1134.

MS (EI): m/z = 556 (M⁺), 401, 301, 245, 145, 119, 91.

C

₃₁H₂₈N₂O₄S₂(M⁺): 556.1490; found:

Ethyl 2-[1-(p-Toluenesulfonyl)-4,5,6,7-tetrahydro-1H-azepin-2-

HRMS (EI): m/z calcd for

yl]acrylinoate (55b)

556.1481.

According to the typical procedure for the metathesis reaction of 11a,

a solution of 17b (21.2 mg, 0.06 mmol) and 1b (5.2 mg, 6.07 μmol) in

CH₂Cl₂(3.0 mL) was stirred at reflux for 1.5 h under an ethylene atmo-

sphere to afford 55b (15.6 mg, 74%) as a pale yellow oil after purifica-

tion by column chromatography on silica gel (hexane/Et₂O 3:2).

Ethyl 2-[1,5-Bis(toluene-4-sulfonyl)-1,4,5,6,7,8-hexahydro[1,5]di-

azocin-2-yl]acrylate (58b)

According to the typical procedure for the metathesis reaction of 11a,

a solution of 46b (34.4 mg, 0.07 mmol) and 1b (5.6 mg, 6.63 μmol) in

CH₂Cl₂(33 mL) was stirred at reflux for 24 h under an argon atmo-

sphere to afford 58b (26.8 mg, 78%) as a pale yellow oil after purifica-

tion by column chromatography on silica gel (hexane/EtOAc 3:2).

IR (neat): 1715 (s), 1599 (w), 1344 (s), 1161 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.65 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 8.2

Hz, 2 H), 6.14 (d, J = 1.7 Hz, 1 H), 5.87 (t, J = 6.8 Hz, 1 H), 5.86 (d, J = 1.7

Hz, 1 H), 3.92 (q, J = 7.3 Hz, 2 H), 3.69–3.63 (m, 2 H), 2.40 (s, 3 H),

2.11–2.04 (m, 2 H), 1.88–1.81 (m, 2 H), 1.50–1.42 (m, 2 H), 1.16 (t,

J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.7, 142.8, 139.8, 139.5, 138.4,

131.4, 129.3, 128.0, 127.2, 60.7, 50.7, 30.5, 27.0, 23.4, 21.5, 14.0.

IR (neat): 1717 (s), 1598 (w), 1343 (s), 1161 (s) cm^–1

.

¹H NMR (400 MHz, CDCl₃): δ = 7.65 (d, J = 8.2 Hz, 2 H), 7.58 (d, J = 8.2

Hz, 2 H), 7.31 (d, J = 7.7 Hz, 2 H), 7.23 (d, J = 7.7 Hz, 2 H), 6.18 (t, J = 8.2

Hz, 1 H), 6.16 (s, 1 H), 5.81 (s, 1 H), 3.90 (q, J = 7.3 Hz, 2 H), 3.85 (d,

J = 8.2 Hz, 2 H), 3.63 (t, J = 5.3 Hz, 2 H), 3.47–3.41 (m, 2 H), 2.44 (s, 3

H), 2.40 (s, 3 H), 1.93–1.86 (m, 2 H), 1.15 (t, J = 7.3 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.0, 143.4, 143.4, 139.3, 137.8,

136.7, 136.2, 131.0, 130.5, 129.8, 129.4, 127.4, 127.0, 60.9, 51.8, 48.5,

44.1, 27.9, 21.5, 21.5, 13.9.

MS (EI): m/z = 349 (M⁺), 304, 194, 166, 148, 120, 91.

HRMS (EI): m/z calcd for

C

₁₈H₂₃NO₄S (M⁺): 349.1348; found:

349.1339.

MS (EI): m/z = 518 (M⁺), 473, 397, 363, 335, 317, 267, 238, 207, 180,

155, 134, 91.

Ethyl 2-[1,5-Bis-(p-toluenesulfonyl)-4,5-dihydro-1H-ben-

zo[b][1,4]diazepin-2-yl]acrylate (56b)

HRMS (EI): m/z calcd for

C

₂₅H₃₀N₂O₆S₂(M⁺): 518.1545; found:

According to the typical procedure for the metathesis reaction of 11a,

a solution of 21b (33.3 mg, 0.06 mmol) and 1b (5.1 mg, 6.03 μmol) in

toluene (3.0 mL) was stirred at 80 °C for 0.5 h under an ethylene at-

mosphere to afford 56b (33.2 mg, 99%) as a white solid after the puri-

fication by column chromatography on silica gel (hexane/EtOAc 2:1);

mp 187–188 °C.

518.1538.

Supporting Information

Supporting information for this article is available online at

IR (KBr): 1720 (m), 1598 (w), 1355 (s), 1164 (s) cm^–1

.

https://doi.org/10.1055/s-0037-1609857.

S

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¹H NMR (400 MHz, CDCl₃): δ = 7.87 (d, J = 8.2 Hz, 2 H), 7.72 (d, J = 8.2

Hz, 2 H), 7.46 (m, 1 H), 7.36–7.26 (m, 7 H), 6.25 (s, 1 H), 5.88 (s, 1 H),

5.30 (dd, J = 2.9, 3.9 Hz, 1 H), 4.57 (dd, J = 3.9, 18.4 Hz, 1 H), 4.15–4.06

(m, 2 H), 3.73 (dd, J = 2.9, 18.4 Hz, 1 H), 2.44 (s, 3 H), 2.42 (s, 3 H), 1.24

(t, J = 7.2 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.1, 144.0, 143.7, 140.3, 139.4,

137.8, 137.0, 136.9, 136.3, 130.4, 129.9, 129.5, 129.1, 128.4, 128.3,

128.1, 127.5, 125.7, 121.4, 61.0, 49.1, 21.6, 21.6, 14.1.

References

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(b) Muniz, K.; Hövelmann, C. H.; Streuff, J.; Campos-Gomez, E.

Pure Appl. Chem. 2008, 80, 1089. (c) Geurts, K.; Fletcher, S. P.;

van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L. Pure Appl. Chem.

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MS (EI): m/z = 552 (M⁺), 507, 397, 242, 169, 139, 91.

HRMS (EI): m/z calcd for

C

₂₈H₂₈N₂O₆S₂(M⁺): 552.1389; found:

552.1399.

4-(1-Phenylvinyl)-1,5-bis-(p-toluenesulfonyl)-2,5-dihydro-1H-

benzo[b][1,4]diazepine (56c)

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1

–

V3o.

l

Grubbs, R. H., Ed.; Wiley-VCH:

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V

o.

l

According to the typical procedure for the metathesis reaction of 11a,

a solution of 21c (41.9 mg, 0.08 mmol) and 1b (6.4 mg, 7.53 μmol) in

toluene (3.8 mL) was stirred at 80 °C for 1 h under an ethylene atmo-

sphere to afford 56c (40.7 mg, 97%) as a pale yellow oil after purifica-

tion by column chromatography on silica gel (hexane/EtOAc 2:1).

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general reviews, see: (c) Montgomery, T. P.; Ahmed, T. S.;

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Article Doi

Synthesis of Various Heterocycles Having a Dienamide Moiety by Ring-Closing Metathesis of Ene-ynamides

DOI: 10.1055/s-0037-1609857

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Full text of DOI:10.1055/s-0037-1609857

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