Development of radical addition-cyclization-elimination reaction of oxime ether and its application to formal synthesis of (±)-martinelline

Tetrahedron 63 (2007) 10092–10117

Development of radical addition–cyclization–elimination

reaction of oxime ether and its application to

formal synthesis of ( )-martinelline

Okiko Miyata, Atsushi Shirai, Shintaro Yoshino, Toshiki Nakabayashi, Yoshifumi Takeda,

*

Toshiko Kiguchi, Daisuke Fukumoto, Masafumi Ueda and Takeaki Naito

Kobe Pharmaceutical University, 4-19-1, Motoyamakita, Higashinada, Kobe 658-8558, Japan

Received 19 June 2007; revised 4 July 2007; accepted 4 July 2007

Available online 10 July 2007

Abstract—Radical addition–cyclization–elimination (RACE) reaction of oxime ether carrying unsaturated ester provides a novel method for

the construction of pyrroloquinoline. Treatment of oxime ethers with Bu₃SnH and AIBN gave N-norpyrroloquinoline as a major product,

which was also obtained by the radical reaction of the corresponding hydrazone and imine. The radical reaction of aldehyde and ketone car-

rying unsaturated ester proceeded stereoselectively to give cis-furoquinolines and cis-hydroxyesters. The RACE reactions by using each of

Bu₃SnNMe₂, Bu₃SnD, and/or D₂O were also examined in order to propose a reaction pathway to N-norpyrroloquinoline. Furthermore, the

synthetic utility of RACE reaction is demonstrated by preparation of a key intermediate for the synthesis of (ꢀ)-martinelline.

1. Introduction

become the synthetic targets of many organic and medicinal

chemists.⁶As a part of our program directed toward the de-

velopment of efﬁcient radical reactions, we report here in

detail radical addition–cyclization reaction of imine and

ketone derivatives 1 carrying an unsaturated ester, nitrile,

and amide. This method is suitable for the preparation of

pyrroloquinolines 2a,b (X: NH, Z: C]O), furoquinolines

2c,d (X: O, Z: C]O), and substituted quinolines 3. Further-

more, we applied this domino type of radical reaction to the

synthesis of key intermediate 4 of (ꢀ)-martinelline (5a)

(Scheme 1).^5c

Free-radical cyclization reactions are recognized as having

a powerful effect on carbon–carbon bond forming reactions,

including the construction of mono- and polycyclic com-

pounds.¹These processes usually occur with regio- and

stereoselective control and can be modulated to form differ-

ent-sized rings. They have been applied to the synthesis of

a number of natural products, including terpenoids, steroids,

lignans, and b-lactams.¹We have recently developed efﬁ-

cient radical addition–cyclization reaction based on sul-

fanyl²and alkyl³radicals for the preparation of various

types of carbocycles and heterocycles. We found also the

efﬁcient synthesis of substituted pyrrolidine and piperidine

derivatives using stannyl^4,5c,dradical addition–cyclization

of the oxime ethers connected with either carbonyl or a,b-

unsaturated carbonyl group. In order to develop new method

for constructing the quinoline ring, we investigated stannyl

radical addition–cyclization of oxime ethers connected

with a,b-unsaturated ester.

2. Results and discussion

2.1. Preparation and radical addition–cyclization–

elimination reaction of oxime ethers carrying an

unsaturated ester, amide, and nitrile

We ﬁrst investigated the radical reaction of oxime ethers.

The requisite substrates 1a–g for the radical reactions were

prepared as follows. The oxidation of benzyl alcohol 6, pre-

pared from commercially available methyl anthranilate by

the reported procedure,⁷with MnO₂followed by the treat-

ment of the resulting aldehyde with benzyloxyamine hydro-

chloride in the presence of sodium acetate gave oxime ether

7a, which was then N-alkylated with ethyl 4-bromocrotonate

to afford the ester 1a. Similarly, the corresponding tert-butyl

ester 1b, amide 1c, and nitrile 1d were prepared from 6. The

O-methyloxime ether 1e was prepared from 6 via 7b

The quinoline moiety is present as a substructure in a broad

range of both natural and unnatural biologically active com-

pounds, most notably within antimalarial agents.⁶Due to

such biological importance, quinoline derivatives have

Keywords: Radical reaction; Martinelline; Pyrroloquinoline; Oxime ether;

a,b-unsaturated ester.

* Corresponding author. Tel.: +81 78 441 7554; fax: +81 78 441 7556;

e-mail: taknaito@kobepharma-u.ac.jp

doi:10.1016/j.tet.2007.07.007

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10093

X

Z

R

Y

X

Y

R

Bu₃SnH

AIBN

R

+

N

Ts

3

Ts

1

2

X=NOR¹Y=CO₂R²

R=H, Me

NNPh₂

NBn

O

CONR₂

CN

H

N

H₂N

Martinelline 5a: R =

NH

Martinellic acid 5b: R = H

N

H

CbzN

N

MeO₂C

8

RO₂C

H

N

H

N

OH

N

H

N

4

H

NH

4

Scheme 1.

O

NOR

Me

NHTs

(Scheme 2, Table 1). The ketoxime ethers 1f and 1g were

also prepared from acetophenone 8 according to similar pro-

cedure (Scheme 3). The geometrical ratios of aldoxime

ethers 1a–g were determined by the ¹H NMR spectra.

1) TsCl

Me

2) RONH₂·HCl

NH₂

8

7c: R = Bn, 79% (E only)

(E only)

7d: R = Me, 69%

OH

NOR

K₂CO₃

Br

CO₂Et

RON

1) MnO₂

acetone

2) RONH₂·HCl

AcONa

NHTs

CO₂Et

7a: R = Bn, 70% (E only)

7b: R = Me, 48% (E/Z = 4)

6

Me

N

K₂CO₃

EWG

Ts

Br

1f: R = Bn, (oxime ether: E only)

(alkene: E only)

1g: R = Me, (oxime ether: E only)

(alkene: E only)

acetone

RON

EWG

Scheme 3.

N

Ts

1a-e

with a low stereoselectivity but they were isolated; cis-iso-

mer 9a was also isolated. Surprisingly, a major product of

the reaction was an unexpected tricyclic pyrroloquinoline

Scheme 2.

Table 1. Preparation of oxime ethers 1a–e

Entry Substrate EWG Product Yield (%)

1a-e

Bu₃SnH C₆H₆

1

2

3

4

5

7a

7b

(E)-CO₂Et

1a

1b

81 (oxime ether: E only;

alkene: E only)

89 (oxime ether: E only;

alkene: E only)

99 (oxime ether: E only;

alkene: E only)

AIBN

reflux

t

(E)-CO₂Bu

O

RO

(E)-CONHBn 1c

NH EWG

HN

(E/Z)-CN

1d

1e

73 (oxime ether: E only;

alkene: E/Z¼1)

N

(E)-CO₂Et

81 (oxime ether: E only;

alkene: E only)

Ts

2a

3a-e

+

O

NH₂EWG

RON

We then investigated the radical reaction of aldoxime ethers

1a–e and found an interesting radical addition–cyclization–

elimination (RACE) reaction (Scheme 4, Table 2).

According to our procedure developed in the radical addi-

tion–cyclization of oxime ethers, the treatment of O-benzyl-

oxime ether 1a bearing an ethoxycarbonyl group with

Bu₃SnH and AIBN in reﬂuxing benzene gave three types

of products 2a, 3a, 9a, and benzyl alcohol (11) (entry 1).

Mixtures of two stereoisomers 2a and 3a were formed

N

Ts

10a-d

Ts

9a, e

+

BnOH

11

Scheme 4.

10094

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

Table 2. Radical reaction of aldoxime ethers 1a–e

Entry

Substrate

R

EWG

Yield (%) (cis/trans)

2a

3a–e

9a,e

10b–d

11

1

2

1a

1e

1b

1c

(Z)-1d

(E)-1d

Bn

Me

Bn

(E)-CO₂Et

(E)-CO₂-Bu

(E)-CONHBn

(Z)-CN

(E)-CN

46 (1/1.3)

56 (1/1.1)

14 (1/0)

—

13 (1/1.3)

15 (1/1.1)

29 (1/1)

—

24 (3/1)

14 (5/1)

7 (1/0)

2 (1/0)

—

33

—

14

—

t

3

38 (1/3.5)

26 (1/1.3)

14 (1/1)

14 (0/1)

4^a

5

6

—

a

Compound 7a was obtained in 8% yield in addition to 10c.

1f, g

Bu₃SnH C₆H₆

2a, which does not carry the benzyloxy group in the mole-

cule. The fact that the benzyl alcohol (11) was isolated in

this radical reaction suggests that the benzyloxy group on

oxime ether moiety was eliminated as benzyl alcohol in

the transformation of 1a to 2a.

AIBN

reflux

O

OR

CO₂Et

HN

Me

On the other hand, expected bicyclic tetrahydroquinoline 3a

and N-benzyloxypyrroloquinoline 9a were obtained as mi-

nor products. The cis-benzyloxyamino ester 3a was treated

with TsOH in MeOH at room temperature to give cis-lactam

9a. However, the trans-isomer 3a did not cyclize to trans-9a

under the same reaction conditions.

Me

H

N

Ts

3f, g

Ts

2b

+

O

7c, d

Similarly, O-methyloxime ether 1e gave 2a, 3e, and 9e under

the same reaction conditions (entry 2). The yield of 2a was

improved by the use of methyloxime ether 1e rather than

benzyloxime ether 1a. The radical reaction of oxime ether

1b bearing the tert-butoxycarbonyl group gave 4-aminoqui-

noline 10b as a major product in addition to 2a, 3b, and ben-

zyl alcohol (11) (entry 3). The N-norpyrroloquinoline 2a was

obtained in low yield but with cis-selectivity. The cis-amino

ester 10b was converted into cis-N-norpyrroloquinoline 2a

in reﬂuxing benzene while trans-isomer 2a was not obtained

from trans-10b in reﬂuxing benzene. Similarly, amide 1c

gave 4-aminoquinoline 10c but the desired product 2a was

not obtained (entry 4).

RON

Me

+

H

NOBn

Me

N

Ts

CO₂Et

9f, g

N

Ts

Z-1f

Scheme 5.

compounds 3d and 10d in low yields. (d) The sterically hin-

dered ketoxime ethers 1f,g cyclized but gave products 2b

and 9f,g in low yield because the existence of a methyl group

would interfere cyclization. Thus, we have now established

novel RACE reaction of oxime ethers to form tricyclic

pyrroloquinolines in only one procedure.

In the case of nitrile 1d, readily separable E- and Z-1d were

also subjected to the radical reaction to form bicyclic tetra-

hydroquinolines 3d and 10d in low yields accompanied

with no formation of pyrroloquinoline 2a (entries 5 and 6).

Considering the foregoing results, we propose a plausible

reaction pathway roughly as depicted in Scheme 6. Tributyl-

stannyl radical generated from Bu₃SnH and AIBN would

add to either oxime ether or ester to give the respective inter-

mediary radical A or B, which cyclizes to give the amino es-

ter 3a carrying tetrahydroquinoline core. The conversion of

3a into debenzyloxylated N-norpyrroloquinoline 2a would

proceed via three possible reaction pathways. The cycliza-

tion of 3a followed by debenzyloxylation of the resulting

N-benzyloxypyrroloquinoline 9a would afford the desired

pyrroloquinoline 2a. As second route, the cyclization and

debenzyloxylation would occur at the same time to afford

For the systematic study on our RACE, we next examined

the radical reaction of ketoxime ethers 1f,g (Scheme 5, Table

3). However, tricyclic products 2b and 9f,g were obtained

only in low yield in addition to tosylamides 7c,d, which

would be formed by the elimination reaction of the alkyl

group as the almost same paper reported by Bertrand.⁸

The radical reaction of oxime ethers 1 carrying unsaturated

ester, amide, and nitrile can be summarized as follows. (a) In

the case of oxime ethers 1a and 1e, the N-norpyrroloquino-

line 2a was obtained as a major product. (b) The oxime ether

1b carrying tert-butyl ester gave amino ester 10b with no

benzyloxy group as a major product and two other products

2a and 3b as minor products, respectively. In this case, the

formation of pyrrolidinone ring would be difﬁcult due to

the existence of a sterically bulky tert-butyl group. Similar

trend of the difﬁcult formation of pyrrolidinone ring was ob-

served in the radical reaction of amide 1c. (c) The radical re-

action of nitrile 1d proceeded inefﬁciently to form bicyclic

Table 3. Radical reaction of ketoxime ethers 1f,g

Substrate

R

Yield (%)

2b 3f,g

(cis/trans) (cis/trans)

7c,d

9f,g

(cis/trans)

(Z)-1f

1f

1g

Bn 4 (1/1)

Me 5 (1/1)

—

5 (1/1)

21 (7c)

20 (7d)

—

2

—

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10095

Sn

H

O

BnO

N

CO₂Et

BnOH

HN

BnON

N

Ts

A

9a

2a

Sn

BnOH

Sn

H

O

OEt

BnOHN

CO₂Et

H

NH₂CO₂Et

BnON

N

Ts

BnOH

1a

B

3a

10a

Radical Addition

Cyclization

''RACE reaction''

Elimination

Sn = SnBu₃

Scheme 6.

Table 4. Radical reaction of 1a in the presence of additive

Entry Conditions Yield (%)

3a

2a. Finally, the initial debenzyloxylation and subsequent

cyclization would give 2a. Thus, the radical reaction from

1a to 2a involves three types of reactions, which are

addition, cyclization, and elimination. We designated this

domino type of radical addition–cyclization–elimination

reaction as ‘RACE’ reaction.

2a

9a 10a

(trans)

(cis/trans) (cis/trans)

1

2

C₆H₆

46 (1/1.3) 13 (1/1.3)

38 (1/1.3) 21 (1/1.5) 12

7

—

EtOH (5 equiv)

C₆H₆

BnOH (2.5 equiv)

C₆H₆

TFA (1.2 equiv)

C₆H₆

p-TsOH (1.2 equiv)

C₆H₆

In order to disclose RACE reaction pathway, we next exam-

ined the additive effect in this reaction (Scheme 7, Table 4).

At ﬁrst, we investigated RACE reaction of oxime ether 1a in

the presence of either EtOH or BnOH, which are formed in

situ in this radical reaction (entries 2 and 3). As the result, the

yield of amino ester 3a increased while the yield of

N-norpyrroloquinoline 2a decreased. The presence of

BnOH resulted in the formation of trans-debenzyloxylated

amino ester 10a, which was converted into trans-pyrroloqui-

noline 2a in reﬂuxing benzene. We next examined the inﬂu-

ence of Brønsted and Lewis acids, which would form

a possible complex with nitrogen atom on oxime ether to af-

fect addition reaction of tributylstannyl radical at ﬁrst step

(entries 4–6). Employment of TFA, p-TsOH, and SnCl₄as

an acid decreased the yield of 2a. The presence of molecular

sieves to remove moisture did not inﬂuence the yield of tri-

cyclic compound 2a (entry 7).

3

4

5

6

7

21 (1.7/1) 24 (1/1.1)

33 (1/1.4) 14 (1/1.3)

33 (1.1/1) 19 (1/1.3)

1

3

5

4

5

9

—

30 (1/1.2)

45 (1/1.1)

7 (1/1)

SnCl₄(1.2 equiv)

C₆H₆

MS (powder)

8 (1/1.3)

deuterated 3a-D, in which deuterium was incorporated into

1⁰-position in cis- and trans-3a-D with low deuterium in-

corporation (19–34%). On the other hand, the deuterium

incorporation at the 3-position in compounds of cis- and

trans-2a-D was not detected (entry 2). Insufﬁcient incorpo-

ration of deuterium in the compound 3a-D under the condi-

tions shown in entry 2 would be probably explained by the

formation of BnOH and EtOH in the reaction mixture. As

expected, the radical reaction of 1a with Bu₃SnH in the pres-

ence of D₂O resulted in high deuterium incorporation

(82–83%) of 3a-D (entry 3). These deuterium experiments

Bu₃SnH

AIBN

1a

2a + 3a + 9a + trans-10a

conditions

reflux

O

HN

Scheme 7.

D

conditions

3

1a

In order to clarify the reaction pathway of radical addition

reaction in ﬁrst step, we investigated RACE reaction using

either Bu₃SnD or D₂O (Scheme 8, Table 5). The RACE

reaction of oxime ether 1a with Bu₃SnD/AIBN afforded

deuterated 2a-D and 3a-D, the latter of which was hardly

deuterated (entry 1). ¹H NMR spectra of cis- and trans-2a-

D showed that deuterium was incorporated in 69–76% at

the 3-position. On the other hand, the deuterium was incor-

porated only in 1-3% into 1⁰-position of cis- and trans-3a-D.

The radical reaction of 1a with Bu₃SnH followed by treat-

ment of the resulting reaction mixture with D₂O gave

C₆H₆

reflux

N

Ts

2a-D

BnO

NH CO₂Et

D

1'

N

Ts

3a-D

Scheme 8.

10096

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

Table 5. Radical reaction of 1a with the deuterated reagents

Entry Conditions

Deuterium incorporation (%)^a

2a-D 3a-D

trans trans

Table 7. Reaction of 9a with dimethylaminotributyltin

Entry Bu₃SnNMe₂Conditions

(equiv)

Yield (%)

cis-2a

9a

cis

(1) Bu₃SnD/AIBN; (2) H₂O 69

cis

1

0

Bu₃SnH (2 equiv),

AIBN (0.2 equiv), C₆H₆,

reﬂux

No reaction,

SM was

recovered

33

1

2

3

76

0

3

19

82

1

34

83

(1) Bu₃SnH/AIBN; (2) D₂O

Bu₃SnH/AIBN/D₂O

0

2

3

4.3

Neat, 110 ^ꢁC

60

—

Bu₃SnH (2 equiv), AIBN

(0.2 equiv), C₆H₆, reﬂux

83

Calculated by ¹H NMR.

a

be expected to generate in situ by the reaction of 3a and 9a

with Bu₃SnNMe₂. The reaction of cis-3a with a large

amount of Bu₃SnNMe₂proceeded in reﬂuxing benzene to

give the desired debenzyloxylated N-norpyrroloquinoline

2a in low yield (entry 2, Table 6). The same reaction with

1 equiv of Bu₃SnNMe₂did not give 2a. When the reaction

was carried out under the neat reaction conditions, the de-

sired product 2a was obtained in 34% yield in addition to

pyrroloquinoline 9a (28%) and amide 12 (16%) (entry 3).

Similarly, trans-3a gave 2a in 27% yield under the same

neat conditions (entry 6). Reaction of cis- and trans-amino

esters 3a with Bu₃SnNMe₂proceeded inefﬁciently under

RACE reaction conditions (entries 4 and 7).

suggest that the major reaction pathways to either pyrrolo-

quinoline 2a or amino ester 3a are possibly not the same.

For establishment of the reaction pathway of the debenzyl-

oxylation step, we then attempted conversion of the bicyclic

amino ester 3a and tricyclic N-benzyloxypyrroloquinoline

9a into the N-norpyrroloquinoline 2a (Schemes 9 and 10,

Tables 6 and 7). However, reaction of 3a and 9a under the

same radical reaction conditions did not give the desired pyr-

roloquinoline 2a but recovered 3a and 9a, respectively (en-

tries 1 and 5 in Table 6; entry 1 in Table 7). Therefore, we

propose aminostannanes C and D instead of 3a and 9a as

a possible intermediate for debenzyloxylation. According

to the reported procedure,⁹aminostannanes C and D would

We next examined the conversion of 9a into 2a in the pres-

ence of Bu₃SnNMe₂and obtained 2a in 33% yield with

recovering 60% of 9a (entry 2, Table 7). Furthermore, 9a

was treated with Bu₃SnNMe₂under RACE reaction condi-

tions (Bu₃SnH/AIBN in reﬂuxing benzene) to give the de-

sired 2a in good yield (entry 3). As mentioned above, we

found that the debenzyloxylated N-norpyrroloquinoline 2a

is formed from 3a and 9a via aminostannanes C and D in

RACE reaction.

3a

Bu₃SnNMe₂

conditions

2a + 9a

SnBu₃

BnO

BnON

CO₂Et

NH CONMe₂

N

Ts

Under the debenzyloxylation conditions (Bu₃SnNMe₂,

Bu₃SnH, AIBN), amino ester cis-3a gave N-norpyrroloqui-

noline 2a not in good yield (only 16%) but N-benzyloxylac-

tam 9a gave the corresponding 2a in good yield (83%). This

result strongly suggests not only that the reaction pathway

from 9a to 2a would be different from that from 3a to 2a

but also that conversion of 9a into 2a would proceed via rad-

ical process.

C

12

Scheme 9.

Bu₃Sn

BnON

O

Bu₃SnNMe₂

conditions

9a

We propose possible reaction pathway for RACE reaction

(Scheme 11). It is known that O-coordinated Ph₃SnH would

more readily undergo H-atom abstraction than uncoordi-

nated Ph₃SnH^10aand that O-coordinated stannyl radicals

would exist for a longer lifetime in solution compared

with their uncoordinated radicals.¹⁰Therefore, Bu₃SnH

would moderately coordinate to the ester and/or oxime ether

N

Ts

D

cis-2a

Scheme 10.

Table 6. Reaction of 3a with dimethylaminotributyltin

Entry

Substrate 3a

Bu₃SnNMe₂(equiv)

Conditions

Yield (%)

2a

9a

12

1

2

3

4

5

6

7

cis

trans

0

19

8

4

0

Bu₃SnH (2 equiv), AIBN (0.2 equiv), C₆H₆, reﬂux

C₆H₆, reﬂux

No reaction, SM was recovered

2

34

16

7

28

—

16

65

Neat, 110 ^ꢁC

Bu₃SnH (2 equiv), AIBN (0.2 equiv), C₆H₆, reﬂux

Neat, 110 ^ꢁC

No reaction, SM was recovered

4.7

4

27

—

50

74

Bu₃SnH (2 equiv), AIBN (0.2 equiv), C₆H₆, reﬂux

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10097

1a

Sn = SnBu₃

Bu₃SnH

2a

AIBN

C₆H₆

reflux

Me

H₂O

OSn

(R = C Me

CN

)

AIBN

R

Δ

H

Sn

NH₂CO₂Et

N

Sn

O

OEt

H

OEt

H

BnON

N

Ts

K

N

10a

N

Ts

Sn

E

H

Sn

path a

path b

Sn

+

O

OEt

path a

BnO

OEt

N

BnON

H

D

H

N

Ts

F

G

I

J

path b

Sn

H

O

Sn

O

OEt

BnO

OEt

BnON

NH

3a

9a

EtOH

BnOH

H₂O

N

Ts

L

M

Scheme 11.

group in the substrate 1a on RACE reaction to form the in-

termediate E. This hypothesis is supported by the improved

yield (69%) of N-norpyrroloquinoline 2a in RACE reaction

of 1a with Ph₃SnH, which is well known for more acidic than

Bu₃SnH. Then, the reaction of E with AIBN generated the

coordinated stannyl radical F, which would be converted

into 2a, 3a, and 9a via two possible reaction pathways, paths

a and b. The addition of stannyl radical F to the oxime ether

part forms more stable (a-stannylamino)benzyl radical G

(path a), which cyclizes to a,b-unsaturated ester to form

the a-ethoxycarbonylmethyl radical H. The radical H is

trapped by Bu₃SnH to afford the intermediate I. The removal

of the benzyloxy group in intermediate I followed by the cy-

clization of the resulting amino ester 10a gives N-norpyrro-

loquinoline 2a. As an alternative route, the intermediate I

could be converted into 2a via ﬁrst cyclization followed by

second removal of the benzyloxy group. The attack of stan-

nyl radical at the lactam carbonyl group in J followed by the

cleavage of N–O bond gives the stannyl enolate K, which

would be converted into 2a by work-up procedure with

water. On the other hand, concomitant formation of the ben-

zyloxyamino ester 3a and cis-N-benzyloxypyrroloquinoline

9a would be explained through path b based on the experi-

mental results using either Bu₃SnD or D₂O. The addition

of stannyl radical in F to a,b-unsaturated ester followed by

the cyclization of the resulting radical L gives the stannyl

enolate M, which is converted into 3a by protonation with

either BnOH and EtOH existed in the reaction mixture or

water during work-up procedure. cis-3a is partially con-

verted into cis-9a under the radical reaction conditions.

2.2. Preparation and radical reaction of unsaturated

esters carrying the cyano, hydrazono, imino, and

carbonyl groups

To survey the scope and limitations of our radical addition–

cyclization method, we investigated RACE reaction of a,b-

unsaturated esters 1h–l carrying cyano, hydrazono, imino,

and carbonyl groups. The requisite substrates 1h–l for the

radical reaction were prepared according to almost same

procedure given for the preparation of oxime ethers 1a–g.

We then investigated the radical reaction of 1h–j. Under

the standard radical conditions, nitrile 1h gave unfortunately

sulfonamide 7e¹¹in 59% yield as in the case of the reactions

of ketoxime ethers 1f,g (Scheme 12).

N

CO₂Et

Bu₃SnH

AIBN

C₆H₆

reflux

NHTs

N

Ts

1h

7e

59%

Scheme 12.

In the case of hydrazone 1i, the radical addition–cyclization

reaction proceeded smoothly to form N-norpyrroloquinoline

2a (24%), bicyclic hydrazine 3i (34%), and diphenylamine

14 (29%) with a small amount of tricyclic N-diphenylamino-

pyrroloquinoline 9i. The fact that major product is not

N-norpyrroloquinoline 2a but bicyclic hydrazine 3i is

10098

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

contrast with the result found in RACE of oxime ether 1a. It

is shown that the cleavage of N–N bond in hydrazines is pos-

sible but not so easy compared with that of N–O bond in al-

koxyamines (Scheme 13).

the formation of trans-pyrroloquinoline 2a was not observed

because the cyclization of trans-amino ester 10a would be

more difﬁcult than that of the corresponding cis-stereoiso-

mer 10a. Furthermore, the radical N was reduced by Bu₃SnH

to give the benzylamino ester 3j, which was also formed by

the addition of stannyl radical to oxime ether followed by

cyclization.

Ph₂NN

N

CO₂Et

1j

Sn = SnBu₃

Ts

1i

Bu₃SnH

AIBN

Bu₃SnH

AIBN

C₆H₆

reflux

C₆H₆

reflux

Ph₂NHN

N

CO₂Et

2a

H

Sn

O

24%

OEt

N

Ph

(cis/trans = 1/ 1.7)

1) Bu₃SnH

2) H₂O

+

3j

Ts

O

3i

N

Ph₂NN

Ts

34%

(cis/trans = 5/ 1)

N

+

N

Ph₂NH

14

Ts

H₂O

cis-9i

3%

cis-10a

15

29%

H₂O

Scheme 13.

The radical reaction of imine 1j gave cis-N-norpyrroloquino-

line 2a, bicyclic trans-amino ester 10a, bicyclic imine 15,

and interestingly trans-benzylamino ester 3j (Scheme 14).

The cis-imine 15 was converted into cis-N-norpyrroloquino-

line 2a via cis-amino ester 10a on standing at room temper-

ature. On the other hand, trans-imine 15 gave not only the

trans-pyrroloquinoline 2a but also the trans-amino ester 10a.

trans-10a

cis-2a

Scheme 15.

The radical reactions of aldehyde 1k and ketone 1l carrying

unsaturated ester proceeded smoothly to give cis-furoquino-

lines 2c,d as a major product, in addition to trans-furoquino-

lines 2c,d and cis-hydroxy ester 3k,l the latter of which were

treated with TsOH at 60 ^ꢁC to give cis-2c,d (Scheme 16,

Ph

N

CO₂Et

BnN

CO₂Et

Bu₃SnH

AIBN

O

CO₂Et

C₆H₆

reflux

N

Ts

R

15

18%

(cis /trans = 1.5/1)

1j

N

Ts

1k: R = H

1l: R = Me

BnHN

CO₂Et

Bu₃SnH

AIBN

C₆H₆

reflux

N

Ts

trans-3j

4%

O

cis-2a

20%

O

R

trans-10a

17%

N

Ts

cis-2c, d

Ts

trans-2c, d

Scheme 14.

+

From the above result, we propose the reaction pathway of

radical reaction of imine 1j (Scheme 15). The benzylic hy-

drogen atom in intermediary aminyl radical N, formed by

the addition of stannyl radical to the unsaturated ester and

subsequent cyclization, was abstracted to give the imine

15. During work-up procedure, cis-imine 15 was subjected

to hydrolysis to form cis-amino ester 10a, which was easily

converted into cis-pyrroloquinoline 2a. On the other hand,

CO₂Et

OH

R

p-TsOH

C₆H₆

60°C

for 3k : 91%

for 3l : 53%

N

Ts

3k, l

Scheme 16.

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

Table 8. Radical reaction of carbonyl compounds 1k,l

10099

H

Sn

O

Entry

Substrate

R

Yield (%)

trans-2c,d

OEt

O

cis-2c,d

3k,l

1

2

1k

1l

H

Me

59

52

3

6

29

24

N

Ts

O

Sn = SnBu₃

Table 8). Thus, radical reactions of carbonyl compounds 1k,l

proceeded with high cis-stereoselectivity.

Figure 1.

In order to clarify cis-stereoselectivity in this reaction, we

examined the radical reaction using either Bu₃SnD or

D₂O. The reaction of carbonyl compounds 1k,l with

Bu₃SnD/AIBN afforded deuterated cis-2c,d-D, trans-2c,d-

D, and 3k,l-D as shown in Scheme 17 and Table 9. On the

other hand, when the radical reaction of 1k,l with Bu₃SnH

was carried out in the presence of D₂O, deuterium was not

incorporated into any products, cis-2c,d, trans-2c,d, and

3k,l.

(a) Nitrile 1h underwent fragmentation without cyclization.

(b) RACE reaction of hydrazone 1i proceeded almost similar

to that of oxime ether. (c) The imine 1j was subjected to rad-

ical addition–cyclization–oxidation even under reductive

conditions to give imine 15, which was converted into pyrro-

loquinoline 2a by hydrolysis followed by cyclization. (d)

The radical reaction of carbonyl compounds 1k,l gave the

cis-furoquinoline and cis-hydroxy ester with high cis-stereo-

selectivity.

1k: R = H

1l: R = Me

2.3. A formal synthesis of ( )-martinelline

Bu₃SnD C₆H₆

With cis-pyrroloquinoline 2a in hand, we next investigated

the synthetic potentiality of our RACE methodology by

converting 2a into a key intermediate 4 for the synthesis of

(ꢀ)-martinelline (5a) (Scheme 1). Martinelline and martinel-

lic acid were isolated from an organic extract of the Marti-

nella iquitosensis root in 1995.¹²These compounds show

antibiotic activity against Gram-positive and Gram-negative

bacteria and afﬁnity for several G-protein receptors, and are

the ﬁrst non-peptide bradykinin receptor antagonist reported

to date. The pyrrolo[3,2-c]quinoline ring system of the mar-

tinellines core has not been reported previously in any natural

product. Their biological activity and unique structure have

made them the subject of intense synthetic interest.^5,13,14

AIBN

reflux

O

R

D

N

Ts

cis-2c, d-D

Ts

trans-2c, l-D

+

R

CO₂Et

D

OH

N

Ts

Our synthetic strategy includes two crucial radical reactions:

(1) an above-mentioned RACE reaction for the construction

of pyrroloquinoline ring (1a/2a); (2) C–C bond formation

through a 1,5-hydrogen atom translocation for the stereo-

selective introduction of the side chain into the C(4)-position

of pyrroloquinoline (16/17) (Scheme 18).

3k, l-D

Scheme 17.

This results show that the addition of stannyl radical takes

place on aldehyde and ketone to give cis-2c,d, trans-2c,d,

and 3k,l, all of which are formed through the same route.

Thus, we propose a possible intermediate O in which

Bu₃SnH would coordinate to both the ester and formyl

groups (Fig. 1). The furoquinoline 2c is obtained by the for-

mation of lactone ring under the reaction conditions. The

fact that high cis-selectivity was observed in radical reaction

of 1k,l is explained by stronger coordination of stannane

with oxygen than that with nitrogen (see Scheme 11). The

radical reactions of nitrile 1h, hydrazone 1i, imine 1j, and

carbonyl compounds 1k,l can be summarized as follows.

We examined the introduction of a carbonyl group into the

C(8)-position and a C₃unit into the C(4)-position of cis-2a

possessing requisite stereostructure for the synthesis of mar-

tinelline (Scheme 19). Reduction of cis-2a with BH₃$Me₂S

followed by work-up with 6 M HCl to cleave the B–N bond

of the resulting intermediate gave the corresponding amine,

which without puriﬁcation was then acetylated with AcCl in

the presence of Et₃N to give amide 18 in 94% yield (two

steps from cis-2). According to the known procedure, we in-

vestigated the Friedel–Crafts reaction of 18. When 18 was

treated with AcCl (3 equiv) and AlCl₃(6 equiv) in reﬂuxing

1,2-dichloroethane, we obtained fortunately the 1,5,8-triace-

tyl compound 19 in which the tosyl group was converted into

the easily removable acetyl group.¹⁵Treatment of 19 with

10% aqueous NaOH in MeOH at room temperature caused

selective deacetylation at the vinylogous imide system to

give the 1,8-diacetyl compound 20 in 47% yield (two steps

from 18).

Table 9. Radical reaction of carbonyl compounds 1k,l using Bu₃SnD

Substrate

Deuterium incorporation (%)^a

cis-2c,d-D

trans-2c,d-D

3k,l-D

1k

1l

95

70

56

100

66

80

Calculated by ¹H NMR.

a

10100

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

R²

Ac

X

C-C bond

radical

formation via

1,5-hydrogen

atom translocation

BnON

N

CO₂Et

addition-

cyclization-

elimination

N

R¹

Ac

8

4

N

CO₂Me

Ts

1a

R³

Bz

17

2a : X = O, R¹= R²= H, R³= Ts

16 : X = H₂, R¹= R²= Ac, R³= 2-bromobenzoyl

Scheme 18.

Ac

N

R¹

N

X

a, b

e

cis-2a

O

N

R²

25a: X = Br

25b: X = I

18: R¹= H, R²= Ts

19: R¹= Ac, R²= Ac

20: R¹= Ac, R²= H

c

Bu₃SnH

conditions

d

CO₂Me

16

f

N

Ac

N

CO₂Me

Bz

N

O

R³

Ac

+

CO₂Me

26

+

N

27

N

Bz

O

17: R³= Ac

g, h

N

21: R³= CO₂Me

22

Bz

28

i

R⁴

N

Scheme 20.

MeO₂C

k

4

N

CO₂Me

26 (22%), the tetracyclic product 27^18a,b(47%), and the re-

duced product 28^18a,c(26%) (entry 1). In order to improve

yield of the desired product 26, Williams procedure¹⁷was

then applied. When a solution of Bu₃SnH and AIBN in ben-

zene was slowly added by using a syringe pump to a solution

of 25a and methyl acrylate in reﬂuxing benzene, the yield of

desired compound 26 improved to 34% (entry 2). Under the

same reaction conditions, the yield of 26 increased further by

using 10 equiv of methyl acrylate (entry 3). The radical reac-

tion of 25a using Et₃B as a radical initiator gave 26 but only

in 20% yield with recovering substrate 25a (entry 4). Same

type of radical reaction of 25b carrying O-iodobenzoyl

group gave similar results (entries 5 and 6).

Bz

23: R⁴= H

j

24: R⁴= Cbz

Scheme 19. Reagents: (a) BH₃$Me₂S, THF, reﬂux; (b) AcCl, Et₃N, CH₂Cl₂,

0 ^ꢁC; (c) AcCl, AlCl₃, ClCH₂CH₂Cl, reﬂux; (d) 10% NaOH, MeOH, rt; (e)

2-bromobenzoyl chloride, Et₃N, CH₂Cl₂, rt; (f) methyl acrylate, Bu₃SnH,

AIBN, benzene, reﬂux; (g) Br₂, 2.5% NaOH, 0 ^ꢁC; (h) concd H₂SO₄,

MeOH, reﬂux; (i) Et₃O$BF₄, NaHCO₃, rt, then satd NaHCO₃, rt; (j) CbzCl,

Et₃N, CH₂Cl₂, 0 ^ꢁC; (k) LiBH₄, MeOH/THF, rt.

Snieckus¹⁶and Williams¹⁷have reported a diastereoselective

carbon–carbon bond formation of an a-carbon adjacent to

a nitrogen via a 1,5-hydrogen atom translocation and subse-

quent Michael-type of radical addition to methyl acrylate.

This method would allow the introduction of the C₃unit

side chain into the C(4)-position adjacent to nitrogen from

the less hindered convex face to afford the desired product.

Based on these preliminary results, we next investigated the

radical reaction of 16 with methyl acrylate (Scheme 19).

Amine 20 was acylated with 2-bromobenzoyl chloride in

the presence of Et₃N to give the radical precursor 16 in

91% yield. When a solution of Bu₃SnH and AIBN in ben-

zene was slowly added by using a syringe pump to a solution

of 16 and methyl acrylate in reﬂuxing benzene, the desired

compound 17 was formed as a single diastereomer in 43%

yield along with the pentacyclic product 22 (19%). The con-

version of the C(8)-acetyl group into the methoxycarbonyl

group in 17 was achieved by the conventional procedure

via haloform reaction. Treatment of 17 with Br₂in 2.5%

aqueous NaOH followed by esteriﬁcation of the resulting

carboxylic acid gave the ester 21 in 76% yield.

As a preliminary experiment for introduction of side chain

into C(4)-position, we investigated the radical reaction of

N-(2-halogenobenzoyl)tetrahydroquinolines 25a,b prepared

by acylation of tetrahydroquinoline with either o-bromoben-

zoylchlorideoro-iodobenzoyl chloride (Scheme 20, Table 10).

According to a procedure reported by Snieckus,¹⁶methyl

acrylate, Bu₃SnH, and AIBN were added to the solution of

25a in toluene and then the reaction mixture was heated at

110 ^ꢁC to give three products, which are the desired product

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

Table 10. 1,5-Hydrogen transfer reaction of 25a,b

10101

Entry

Substrate

Conditions, initiator (equiv)

Methyl acrylate (equiv)

Time (h)

Products (% yield)

26

27

28

1

25a

25b

AIBN (0.12), toluene, reﬂux

AIBN (0.1), benzene, reﬂux

Et₃B (7.0), toluene, rt

AIBN (0.1), benzene, reﬂux

Et₃B (3.5), toluene, rt

5

3

10

5

10

13.5

6

3

13

5

4

22

34

41

20

36

47

46

47

21

60

52

26

—

8

—

Trace

9

2^a

3^a

4^b

5^a

6

a

The reaction was carried out by using a syringe pump.

Starting material was recovered (<59%).

b

In order to convert 21 into the known intermediate 4 for mar-

tinelline synthesis, we investigated the conversion of the

functional groups. Treatment of 21 with Et₃O$BF₄followed

by hydrolysis of the resulting unstable imidate with saturated

aqueous NaHCO₃afforded amine 23 in 42% yield along

with starting material 21 (19%). Amine 23 was reacted

with CbzCl in the presence of Et₃N to give the protected

compound 24 in 84% yield. Finally, the regioselective reduc-

tion of the isolated ester moiety in 24 with LiBH₄in a mix-

ture of 1/10 MeOH/THF at room temperature gave the

desired alcohol 4 in 58% yield, which is a key intermediate

for the synthesis of martinelline. The spectra of 4 were

superimposable with those provided by Professor Ma.^13d

MnO₂(22 g, 0.25 mol) under a nitrogen atmosphere at

room temperature. After being stirred for 1.5 h, the reaction

mixture was ﬁltrated through a pad of Celite and the ﬁltrate

was concentrated at reduced pressure to give the crude alde-

hyde. To a solution of the crude aldehyde in CH₂Cl₂/MeOH

(1:1) (80 mL) were added NaOAc (500 mg, 6.2 mmol) and

BnONH₂$HCl (1.0 g, 6.2 mmol) under a nitrogen atmo-

sphere at room temperature. After being stirred for 1.5 h,

the reaction mixture was diluted with saturated aqueous

NaHCO₃and extracted with CH₂Cl₂. The organic phase

was washed with brine, dried over MgSO₄, and concentrated

at reduced pressure. The residue was puriﬁed by recrystalli-

zation from EtOH to afford 7a (1.92 g, 70%) as colorless

crystals. Mp 138–140 ^ꢁC (EtOH). IR n_maxcm^ꢂ1: 3154

1

(NH). H NMR (300 MHz) d: 8.07 (1H, s), 7.62 (1H, br d,

3. Conclusion

J¼8 Hz), 7.34–7.54 (8H, m), 7.23 (1H, br t, J¼8 Hz), 7.05–

7.14 (3H, m), 6.99 (1H, br t, J¼7.5 Hz), 5.23 (2H, s), 2.32

(3H, s). ¹³C NMR (75 MHz) d: 151.3, 143.6, 136.9, 136.8,

136.4, 132.1, 130.5, 129.4, 129.0, 128.7, 128.3, 127.2,

123.1, 118.8, 118.3, 76.9, 21.4. HRMS (EI) m/z: Calcd for

C₂₁H₂₀N₂O₃S (M⁺) 380.1194. Found: 380.1200. Anal.

Calcd for C₂₁H₂₀N₂O₃S$1/5H₂O: C, 65.67; H, 5.35; N,

7.29. Found: C, 65.65; H, 5.12; N, 7.22.

We have developed an unprecedented example of the stannyl

radical addition–cyclization–elimination (RACE) reaction

of oxime ethers carrying unsaturated ester for constructing

the pyrroloquinoline in one procedure. Additionally, the

RACE reaction was applied to other imine derivatives and

carbonyl compounds to afford various types of heterocycles

such as substituted tetrahydroquinolines and furoquinolines.

4.1.2. N-[2-[(1E/Z)-(Methoxyimino)methyl]phenyl]-4-

methylbenzenesulfonamide (7b). According to the proce-

dure described in the preparation of 7a, oxidation of 6

(2 g, 7.2 mmol) with MnO₂(22 g, 250 mmol) gave crude

aldehyde. Condensation of crude aldehyde with

MeONH₂$HCl (0.52 g, 6.2 mmol) gave 7b (873.1 mg

48%) as colorless crystals and a 4:1 mixture of E- and Z-iso-

mers. Mp 127–131 ^ꢁC (EtOH). IR n_max(KBr) cm^ꢂ1: 3439

Furthermore, we have succeeded in a formal synthesis of

martinelline via the route involving two radical reactions.

4. Experimental

4.1. General

1

(NH), 1340, 1121 (NSO₂). H NMR (200 MHz) d: 10.33

1

Melting points are uncorrected. H and ¹³C NMR spectra

(1H, br s), 7.99 (4/5H, s), 7.95–6.91 (8H+1/5H, m), 4.03

(12/5H, s), 3.84 (3/5H, s), 2.45 (3/5H, s), 2.33 (12/5H, s).

¹³C NMR (50 MHz) d: 150.7, 143.7, 136.6, 136.5, 132.0,

130.4, 129.6, 129.4, 127.1, 123.3, 119.0, 118.8, 62.6, 21.4.

HRMS m/z: Calcd for C₁₅H₁₆N₂O₃S (M⁺) 304.0881. Found:

304.0872. Anal. Calcd for C₁₅H₁₆N₂O₃S: C, 58.94; H, 5.52;

N, 8.87. Found: C, 58.99; H, 5.22; N, 8.63.

were recorded at 200, 300, or 500 MHz and at 50, 75, or

125 MHz for solution in deuteriochloroform (with tetrame-

thylsilane as an internal reference), respectively. IR spectra

were recorded using FTIR apparatus for solutions in chloro-

form except for KBr pellet. Mass spectra were obtained by

EI method. Flash column chromatography (FCC) was

preformed using E. Merck Kieselgel 60 (230–400 mesh).

Medium-pressure column chromatography (MCC) was per-

4.2. General procedure for preparation of oxime ethers

1a–e [Table 1]

€

formed using Lober Große B (E. Merck 310-25, Lichroprep

Si60). Preparative TLC (PTLC) separations were carried out

on precoated silica gel plates (E. Merck 60F₂₅₄).

To a solution of 7a or 7b in acetone (0.05–0.1 mmol/mL)

were added ethyl 4-bromocrotonate, tert-butyl 4-bromocrot-

onate,²⁰(2E)-4-bromo-N-(phenylmethyl)-2-butenamide,¹⁹

or (E/Z)-4-bromocrotononitrile²¹(1–1.5 equiv), and K₂CO₃

(2-5 equiv) under a nitrogen atmosphere at room tempera-

ture. After disappearance of the starting material (TLC

4.1.1. 4-Methyl-N-[[2-[(1E)-(phenylmethoxy)imino]-

methyl]phenyl]benzenesulfonamide (7a). To a solution

of N-[2-(hydroxymethyl)phenyl]-4-methylbenzenesulfona-

mide (6)⁷(2 g, 7.2 mmol) in CH₂Cl₂(150 mL) was added

10102

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

monitoring), the reaction mixture was diluted with saturated

aqueous NaHCO₃and extracted with Et₂O. The organic

phase was washed with brine, dried over MgSO₄, and con-

centrated at reduced pressure. The residue was puriﬁed by

FCC.

HRMS m/z: Calcd for C₂₅H₂₄N₃O₃S (M+H⁺) 446.1537.

Found: 446.1549.

4.2.5. (2Z)-4-[[(4-Methylphenyl)sulfonyl][2-[(1E)-[(phe-

nylmethoxy)imino]methyl]phenyl]amino]-2-buteneni-

trile ((Z)-1d) [entry 4]. Colorless crystals. Mp 126–128 ^ꢁC

(EtOH). IR n_maxcm^ꢂ1: 2225 (CN), 1358, 1166 (NSO₂). ¹H

NMR (200 MHz) d: 8.51 (1H, s), 7.94 (1H, dd, J¼8, 2 Hz),

7.56–7.20 (11H, m), 6.63 (1H, dd, J¼8, 2 Hz), 6.45 (1H, br

dt, J¼11, 7 Hz), 5.26 (1H, dt, J¼11, 1 Hz), 5.21 (2H, s), 4.63

(1H, br dd, J¼15, 5 Hz), 4.16 (1H, br dd, J¼15, 8 Hz), 2.44

(3H, s). ¹³C NMR (75 MHz) d: 147.6, 145.8, 144.5, 137.29,

137.26, 133.9, 133.2, 130.3, 129.7, 129.0, 128.33, 128.29,

128.0, 127.9, 127.8, 127.1, 114.4, 102.7, 76.4, 51.7, 21.5.

HRMS m/z: Calcd for C₂₅H₂₄N₃O₃S (M+H⁺) 446.1537.

Found: 446.1549. Anal. Calcd for C₂₅H₂₃N₃O₃S: C, 67.39;

H, 5.20; N, 9.43. Found: C, 67.38; H, 5.18; N, 9.49.

4.2.1. Ethyl-(2E)-4-[[(4-methylphenyl)sulfonyl][2-[(phe-

nylmethoxy)imino]methyl]phenyl]amino-2-butenoate

(1a) [entry 1]. Colorless crystals. Mp 61–62 ^ꢁC (AcOEt). IR

n_maxcm^ꢂ1: 1717 (CO₂Et). ¹H NMR (300 MHz) d: 8.34 (1H,

s), 7.92 (1H, dd, J¼8, 2 Hz), 7.53 (2H, br d, J¼8 Hz), 7.20–

7.44 (9H, m), 6.75 (1H, dt, J¼15.5, 7 Hz), 6.73 (1H, dd,

J¼7.5, 1 Hz), 5.77 (1H, br d, J¼15.5 Hz), 5.19 (2H, s),

4.13 (2H, q, J¼7 Hz), 4.00–4.40 (2H, m), 2.42 (3H, s),

1.24 (3H, t, J¼7 Hz). ¹³C NMR (75 MHz) d: 165.2, 145.6,

144.1, 140.9, 137.41, 137.35, 135.0, 132.9, 130.0, 129.6,

128.9, 128.8, 128.3, 128.2, 127.9, 127.2, 124.8, 76.4, 60.5,

52.8, 21.5, 14.1. HRMS (EI) m/z: Calcd for C₂₇H₂₈N₂O₅S

(M⁺) 492.1717. Found: 492.1716. Anal. Calcd for

C₂₇H₂₈N₂O₅S: C, 65.83; H, 5.73; N, 5.69. Found: C,

65.75; H, 5.67; N, 5.68.

4.2.6. Ethyl-(2E)-4-[[2-[(1E)-(methoxyimino)methyl]-

phenyl][(4-methylphenyl)sulfonyl]amino]-2-butenoate

(1e) [entry 5]. Colorless crystals. Mp 149–151 ^ꢁC (EtOH).

1

IR n_maxcm^ꢂ1: 1717 (COO), 1355, 1164 (NSO₂). H NMR

4.2.2. 1,1-Dimethylethyl-(2E)-4-[[(4-methylphenyl)sul-

fonyl][2-[(1E)-[(phenylmethoxy)imino]methyl]phenyl]a-

mino]-2-butenoate (1b) [entry 2]. Colorless crystals. Mp

109–110 ^ꢁC (EtOH). IR n_maxcm^ꢂ1: 1709 (COO), 1357,

(300 MHz) d: 8.28 (1H, s), 7.93 (1H, dd, J¼8, 1.5 Hz),

7.53 (2H, br d, J¼6 Hz), 7.35–7.22 (4H, m), 6.76 (1H, dt, J¼

16, 7 Hz), 6.72 (1H, br d, J¼8 Hz), 5.80 (1H, dt, J¼16,

1 Hz), 4.34 (2H, m), 4.13 (2H, q, J¼7 Hz), 3.96 (3H, s), 2.45

(3H, s), 1.25 (3H, t, J¼7 Hz). ¹³C NMR (50 MHz) d: 165.2,

145.2, 144.1, 140.8, 137.3, 134.8, 133.0, 130.0, 129.6,

128.74, 128.65, 127.8, 127.0, 124.8, 61.9, 60.4, 52.8, 21.4,

14.0. HRMS m/z: Calcd for C₂₁H₂₄N₂O₅S (M⁺) 416.1404.

Found: 416.1399. Anal. Calcd for C₂₁H₂₄N₂O₅S: C, 60.56;

H, 5.81; N, 6.73. Found: C, 60.56; H, 5.81; N, 6.71.

1

1163 (NSO₂). H NMR (200 MHz) d: 8.34 (1H, s), 7.93

(1H, dd, J¼7, 2 Hz), 7.56–7.20 (11H, m), 6.72 (1H, dd,

J¼7, 2 Hz), 6.63 (1H, dt, J¼16, 7 Hz), 5.69 (1H, br d,

J¼16 Hz), 5.19 (2H, s), 4.22 (2H, m), 2.42 (3H, s), 1.42

(9H, s). ¹³C NMR (50 MHz) d: 165.4, 146.8, 144.2, 140.9,

137.5, 134.8, 133.0, 130.2, 129.7, 128.9, 128.8, 127.9,

127.0, 124.8, 60.6, 52.8, 21.5, 14.0. HRMS m/z: Calcd for

C₂₉H₃₃N₂O₅S (M+H⁺) 521.2108. Found: 521.2100. Anal.

Calcd for C₂₉H₃₂N₂O₅S: C, 66.90; H, 6.20; N, 5.38. Found:

C, 66.80; H, 6.22; N, 5.35.

4.2.7. 4-Methyl-N-[2-[1-(1E)-[(phenylmethoxy)imino]-

ethyl]phenyl]benzenesulfonamide (7c). To a solution of N-

(2-acetylphenyl)-4-methylbenzenesulfonamide²²(500 mg,

1.7 mmol) in EtOH/CH₂Cl₂(1:1) (10 mL) was added

BnONH₂$HCl (340 mg, 2.2 mmol) under a nitrogen atmo-

sphere. After being stirred and heated at reﬂux for 8 h,

BnONH₂$HCl (95 mg, 0.86 mmol) was added two for times

every 10 h. The reaction mixture was diluted with water and

extracted with CHCl₃. The organic phase was washed with

brine, dried over MgSO₄, and concentrated at reduced pres-

sure. The residue was puriﬁed by recrystallization from

EtOH to afford 7c (506.4 mg, 79%) as colorless crystals.

Mp 129–131 ^ꢁC (EtOH). IR n_maxcm^ꢂ1: 3031 (NH), 1339,

4.2.3. (2E)-4-[[(4-Methylphenyl)sulfonyl][2-[(phenylme-

thoxy)imino]methyl]phenyl]amino-N-(phenylmethyl)-2-

butanamide (1c) [entry 3]. Colorless crystals. Mp

129–133 ^ꢁC (AcOEt). IR n_maxcm^ꢂ1: 3440 (NH), 1680

1

(CON). H NMR (300 MHz) d: 8.40 (1H, s), 7.90 (1H, d,

J¼7.5 Hz), 7.53 (1H, d, J¼7 Hz), 7.20–7.40 (15H, m),

6.72 (1H, d, J¼7.5 Hz), 6.63 (1H, dt, J¼15.5, 6 Hz), 5.83

(1H, d, J¼15.5 Hz), 5.69 (1H, br s), 5.14 (2H, s), 4.43

(2H, d, J¼5.5 Hz), 4.24 (2H, br s), 2.42 (3H, s). ¹³C NMR

(75 MHz) d: 164.4, 146.1, 144.1, 137.9, 137.6, 137.4,

136.8, 135.2, 133.0, 130.1, 129.7, 129.0, 128.9, 128.7,

128.4, 128.3, 127.9, 127.8, 127.6, 127.4, 127.2, 52.8, 43.6,

21.6. HRMS m/z: Calcd for C₃₂H₃₁N₃O₄S (M) 553.2034.

Found: 553.2041. Anal. Calcd for C₃₂H₃₁N₃O₄S$1/2H₂O:

C, 68.31; H, 5.73; N, 7.47. Found: C, 68.48; H, 5.65; N, 7.40.

1

1161 (NSO₂). H NMR (200 MHz) d: 10.66 (1H, br s),

7.64–7.01 (13H, m), 5.26 (2H, s), 2.32 (3H, s), 2.07 (3H,

s). ¹³C NMR (50 MHz) d: 156.5, 143.2, 137.1, 136.2,

135.7, 129.5, 129.2, 128.6, 128.4, 128.1, 127.0, 124.6, 123.9,

123.7, 121.0, 76.6, 21.2, 13.2. HRMS m/z: Calcd for

C₂₂H₂₂N₂O₃S (M⁺) 394.1340. Found: 394.1359. Anal.

Calcd for C₂₂H₂₂N₂O₃S: C, 66.98; H, 5.62; N, 7.10. Found:

C, 66.99; H, 5.62; N, 7.16.

4.2.4. (2E)-4-[[(4-Methylphenyl)sulfonyl][2-[(1E)-[(phe-

nylmethoxy)imino]methyl]phenyl]amino]-2-buteneni-

trile ((E)-1d) [entry 4]. A colorless oil. IR n_maxcm^ꢂ1: 2231

(CN), 1358, 1165 (NSO₂). ¹H NMR (200 MHz) d: 8.28 (1H,

s), 7.90 (1H, dd, J¼8, 2 Hz), 7.53–7.22 (11H, m), 6.71 (1H,

dd, J¼8, 2 Hz), 6.54 (1H, dt, J¼16, 7 Hz), 5.33 (1H, dt,

J¼16, 2 Hz), 5.19 (2H, s), 4.20 (2H, br d, J¼7 Hz,), 2.42

(3H, s). ¹³C NMR (75 MHz) d: 148.0, 145.4, 144.4, 137.2,

137.0, 134.6, 132.8, 130.2, 129.7, 129.1, 128.8, 128.4,

128.3, 127.9, 127.8, 127.5, 116.0, 103.4, 76.5, 53.1, 21.5.

4.2.8. N-[2-[1-(1E)-(Methoxyimino)ethyl]phenyl]-

4-methylbenzenesulfonamide (7d). To a solution of N-

(2-acetylphenyl)-4-methylbenzenesulfonamide²²(500 mg,

1.7 mmol) in EtOH (9 mL) were added MeONH₂$HCl

(289 mg, 3.5 mmol) and pyridine (0.28 mL, 3.5 mmol) un-

der a nitrogen atmosphere. After being stirred and heated

at reﬂux for 15 h, the reaction mixture was diluted with water

and extracted with CHCl₃. The organic phase was washed

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10103

with brine, dried over MgSO₄, and concentrated at reduced

pressure. The residue was puriﬁed by recrystallization

from EtOH to afford 7d (382.1 mg, 69%) as pale yellow

crystals. Mp 136–138 ^ꢁC (EtOH). IR n_maxcm^ꢂ1: 3030 (NH),

1339, 1162 (NSO₂). ¹H NMR (300 MHz) d: 10.74 (1H, br s),

7.66–7.04 (8H, m), 4.07 (3H, s), 2.35 (3H, s), 2.01 (3H, s).

¹³C NMR (50 MHz) d: 155.8, 143.4, 136.2, 135.6, 129.5,

129.2, 128.3, 126.9, 124.3, 124.0, 121.6, 62.3, 21.2, 12.9.

HRMS m/z: Calcd for C₁₆H₁₈N₂O₃S (M⁺) 318.1037. Found:

318.1044. Anal. Calcd for C₁₆H₁₈N₂O₃S: C, 60.36; H, 5.70;

N, 8.80. Found: C, 60.32; H, 5.68; N, 8.79.

cis-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sulfonyl]-

2H-pyrrolo[3,2-c]quinolin-2-one (cis-2a). Colorless crys-

tals. IR n_maxcm^ꢂ1: 3433 (NH), 1701 (NCO), 1354, 1166

1

(NSO₂). H NMR (500 MHz) d: 7.71 (1H, dd, J¼8, 1 Hz),

7.52 (2H, br d, J¼8 Hz), 7.31 (1H, td, J¼7.5, 1 Hz), 7.28–

7.16 (4H, m), 6.60 (1H, br s), 4.37 (1H, d, J¼6.5 Hz), 4.20

(1H, dd, J¼14, 5 Hz), 3.15 (1H, dd, J¼14, 12 Hz), 2.62

(1H, dd, J¼17.5, 9 Hz), 2.54 (1H, m), 2.40 (3H, s), 2.02 (1H,

dd, J¼17.5, 2 Hz). ¹³C NMR (75 MHz) d: 175.5, 144.0,

137.0, 136.4, 129.8, 128.8, 128.6, 128.2, 126.9, 126.0,

124.9, 52.0, 47.4, 34.5, 31.8, 21.5. HRMS m/z: Calcd for

C₁₈H₁₈N₂O₅S (M⁺) 342.1037. Found: 342.1042. Anal.

Calcd for C₁₈H₁₈N₂O₅S$1/10H₂O: C, 62.81; H, 5.33; N,

8.14. Found: C, 62.58; H, 5.05; N, 7.84.

4.2.9. Ethyl-(2E)-4-[[(4-Methylphenyl)sulfonyl][2-[1-

(1E)-[(phenylmethoxy)imino]ethyl]phenyl]amino]-2-

butenoate (1f). According to the procedure described in the

preparation of 1a–e, alkylation of 7c (114 mg, 0.28 mmol)

with ethyl 4-bromocrotonate (0.038 mL, 0.28 mmol) in the

presence of K₂CO₃(153 mg, 1.1 mmol) gave 1f (135 mg,

96%) as colorless crystals. Mp 103–105 ^ꢁC (EtOH). IR

trans-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sulfo-

nyl]-2H-pyrrolo[3,2-c]quinolin-2-one (trans-2a). Colorless

crystals. IR n_maxcm^ꢂ1: 3429 (NH), 1727 (NCO), 1356,

1

1168 (NSO₂). H NMR (500 MHz) d: 7.82 (1H, dd, J¼8,

1

n_maxcm^ꢂ1: 1716 (COO), 1369, 1161 (NSO₂). H NMR

0.5 Hz), 7.46–7.40 (3H, m), 7.35–7.30 (1H, br t, J¼8 Hz),

7.21–7.17 (3H, m), 6.99 (1H, br d, J¼7.5 Hz), 3.99 (1H,

dd, J¼11, 6 Hz), 3.58 (1H, br t, J¼11 Hz), 3.23 (1H, d,

J¼10.5 Hz), 2.55 (1H, dd, J¼15.5, 6.5 Hz), 2.39 (3H, s),

2.20 (1H, dd, J¼15.5, 12.5 Hz), 2.10 (1H, m). ¹³C NMR

(75 MHz) d: 178.1, 144.0, 135.2, 133.8, 133.5, 129.8,

128.0, 126.8, 126.6, 125.6, 121.1, 56.6, 49.4, 42.8, 36.2,

21.6. HRMS m/z: Calcd for C₁₈H₁₈N₂O₅S (M⁺) 342.1037.

Found: 342.1047. Anal. Calcd for C₁₈H₁₈N₂O₅S$EtOH: C,

61.79; H, 6.26; N, 7.14. Found: C, 61.99; H, 5.96; N, 7.10.

(200 MHz) d: 7.56–7.17 (12H, m), 6.85 (1H, br d,

J¼7 Hz), 6.79 (1H, dt, J¼16, 7 Hz), 5.68 (1H, dd, J¼16,

1 Hz), 5.19 (2H, s), 4.16–4.05 (4H, m), 2.40 (3H, s), 2.18

(3H, s), 1.22 (3H, t, J¼7 Hz). ¹³C NMR (75 MHz) d: 165.2,

155.1, 143.4, 142.0, 138.9, 138.1, 136.34, 136.30, 129.8,

129.6, 129.3, 128.7, 128.4, 128.1, 127.6, 127.5, 127.3, 123.8,

75.5, 60.0, 53.1, 21.2, 16.1, 13.9. HRMS m/z: Calcd for

C₂₈H₃₁N₂O₅S (M+H⁺) 507.1952. Found: 507.1929. Anal.

Calcd for C₂₈H₃₀N₂O₅S: C, 66.38; H, 5.97; N, 5.53. Found:

C, 66.11; H, 5.91; N, 5.51.

Ethyl cis-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulfonyl]-

4-[(phenylmethoxy)amino]quinoline-3-acetate (cis-3a). A

pale yellow oil. IR n_maxcm^ꢂ1: 1728 (CO₂Et), 1353, 1166

4.2.10. Ethyl-(2E)-4-[[(4-methylphenyl)sulfonyl][2-[1-

(1E)-(methoxyimino)ethyl]phenyl]amino]-2-butenoate

(1g). According to the procedure described in the prepara-

tion of 1a–e, alkylation of 7d (223 mg, 0.70 mmol) with

ethyl 4-bromocrotonate (0.097 mL, 0.70 mmol) in the pres-

ence of K₂CO₃(388 mg, 2.8 mmol) gave 1g (301 mg, 99%)

as a pale yellow oil. IR n_maxcm^ꢂ1: 1717 (COO), 1351, 1162

(NSO₂). ¹H NMR (200 MHz) d: 7.57 (2H, d, J¼8 Hz), 7.38–

7.20 (5H, m), 6.92 (1H, dt, J¼16, 7 Hz), 6.86 (1H, d,

J¼8 Hz), 5.80 (1H, dd, J¼16, 1 Hz), 4.35 (2H, dd, J¼7,

1 Hz), 4.13 (2H, q, J¼7 Hz), 3.96 (3H, s), 2.42 (3H, s),

2.16 (3H, s), 1.24 (3H, t, J¼7 Hz). ¹³C NMR (50 MHz) d:

165.4, 155.0, 143.6, 142.1, 139.0, 136.7, 136.2, 129.8,

129.6, 129.4, 128.8, 128.6, 127.7, 123.9, 61.5, 60.2, 53.4,

21.3, 15.8, 14.0. HRMS m/z: Calcd for C₂₂H₂₇N₂O₅S

(M+H⁺) 431.1639. Found: 431.1633.

1

(NSO₂). H NMR (500 MHz) d: 7.90 (1H, br dd, J¼8.5,

1 Hz), 7.55 (2H, br d, J¼8 Hz), 7.32–7.15 (9H, m), 7.05

(1H, br t, J¼7.5, 1 Hz), 5.14 (1H, br d, J¼3 Hz), 4.49 and

4.39 (2H, ABq, J¼12 Hz), 4.19–4.08 (3H, m), 3.93 (1H,

br s), 3.53 (1H, dd, J¼13, 12 Hz), 2.60 (1H, dd, J¼15.5,

6.5 Hz), 2.34 (3H, s), 2.29 (1H, m), 1.25 (3H, t, J¼

7.5 Hz). ¹³C NMR (75 MHz) d: 171.7, 143.7, 137.0, 136.5,

135.7, 130.0, 129.55, 129.46, 128.5, 128.3, 127.8, 127.5,

127.1, 124.2, 122.4, 75.7, 60.5, 58.5, 46.9, 34.2, 33.1, 25.0,

23.2, 21.4, 14.1. HRMS m/z: Calcd for C₂₇H₃₀N₂O₅S (M⁺)

494.1874. Found: 494.1881.

Ethyl trans-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulfo-

nyl]-4-[(phenylmethoxy)amino]quinoline-3-acetate (trans-

3a). A pale yellow oil. IR n_maxcm^ꢂ1: 1728 (CO₂Et), 1351,

1165 (NSO₂). H NMR (500 MHz) d: 7.70–7.65 (3H, m),

1

4.2.10.1. Radical reaction of oxime ether 1a [Table 2,

entry 1]. To a boiling solution of 1a (296 mg, 0.60 mmol)

in benzene (15 mL) was added a solution of Bu₃SnH

(0.32 mL, 1.2 mmol) and AIBN (20 mg, 0.12 mmol) in ben-

zene (15 mL) by syringe pump under a nitrogen atmosphere.

After being stirred at reﬂux for 10 h, a solution of Bu₃SnH

(0.32 mL, 1.2 mmol) and AIBN (20 mg, 0.12 mmol) in ben-

zene (2 mL) was added by syringe pump. After being stirred

at reﬂux for 17 h, the reaction mixture was extracted with

hexane/MeCN. The MeCN phase was concentrated at re-

duced pressure. The residue was puriﬁed by MCC (hex-

ane/AcOEt 3:1) to afford cis-2a (41 mg, 20%), trans-2a

(53 mg, 26%), cis-3a (17 mg, 6%), trans-3a (22 mg, 7%),

9a (18 mg, 7%), and benzyl alcohol (11) (21.6 mg, 33%).

Benzyl alcohol was identical with authentic sample.

7.36–7.16 (9H, m), 7.02 (1H, td, J¼7.5, 1.5 Hz), 5.24 (1H,

br s), 4.57 and 4.48 (2H, ABq, J¼11.5 Hz), 4.20–4.13

(2H, m), 3.97–3.90 (2H, m), 3.77 (1H, br d, J¼4.5 Hz),

2.61 (1H, m), 2.36 (3H, s), 2.31–2.28 (2H, m), 1.27 (3H, t,

J¼7.5 Hz). ¹³C NMR (75 MHz) d: 171.7, 143.6, 137.5,

137.3, 136.8, 130.6, 129.5, 128.4, 128.2, 127.8, 127.0, 124.6,

123.7, 121.0, 76.6, 60.9, 60.5, 46.7, 34.9, 31.0, 21.4, 14.0.

HRMS m/z: Calcd for C₂₇H₃₀N₂O₅S (M⁺) 494.1874. Found:

494.1892.

cis-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sulfonyl]-

1-(phenylmethoxy)-2H-pyrrolo[3,2-c]quinolin-2-one (9a).

Colorless crystals. IR n_maxcm^ꢂ1: 1713 (NCO), 1358, 1166

1

(NSO₂). H NMR (300 MHz) d: 7.78 (1H, br d, J¼8 Hz),

10104

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

7.67–7.45 (3H, m), 7.38 (1H, br t, J¼8 Hz), 7.32–7.18 (8H,

m), 4.36 (1H, d, J¼7 Hz), 4.85 and 4.25 (2H, ABq,

J¼9.5 Hz), 4.11 (1H, dd, J¼14, 4.5 Hz), 3.33 (1H, dd,

J¼14, 10.5 Hz), 2.56 (1H, dd, J¼17, 9 Hz), 2.39 (3H, s),

2.32 (1H, m), 2.15 (1H, dd, J¼17.5, 1.5 Hz). ¹³C NMR

(75 MHz) d: 169.7, 144.1, 137.1, 136.8, 134.1, 131.8,

129.8, 129.6, 129.2, 128.7, 128.3, 126.9, 124.9, 124.4,

123.6, 77.8, 55.7, 47.8, 31.1, 26.6, 21.4. HRMS m/z: Calcd

for C₂₅H₂₄N₂O₄S (M⁺) 448.1455. Found: 448.1466.

m/z: Calcd for C₂₁H₂₆N₂O₅S (M⁺) 418.1561. Found:

418.1563.

cis-1,3,3a,4,5,9b-Hexahydro-1-(methoxyamino)-5-[(4-meth-

ylphenyl)sulfonyl]-2H-pyrrolo[3,2-c]quinolin-2-one (9e).

Colorless crystals. Mp 169–170 ^ꢁC (Et₂O). IR n_maxcm^ꢂ1

:

1

1719 (g-lactam), 1358, 1165 (NSO₂). H NMR (500 MHz)

d: 7.78 (1H, dd, J¼8, 1 Hz), 7.55–7.51 (3H, m), 7.39–7.36

(1H, m), 7.26–7.21 (4H, m), 4.39 (1H, d, J¼7 Hz), 4.14

(1H, dd, J¼14, 5 Hz), 3.43 (3H, s), 3.38 (1H, dd, J¼14,

11 Hz), 2.55 (1H, dd, J¼17.5, 9.5 Hz), 2.40 (3H, s), 2.38–

2.36 (1H, m), 2.13 (1H, dd, J¼17.5, 1.5 Hz). ¹³C NMR

(125 MHz) d: 169.9, 144.2, 137.0, 136.9, 131.3, 129.9,

129.3, 127.0, 125.3, 124.7, 124.0, 63.8, 55.3, 47.8,

31.2, 26.4, 21.6. HRMS m/z: Calcd for C₁₉H₂₀N₂O₄S

(M⁺) 372.1142. Found: 372.1142. Anal. Calcd for

C₁₉H₂₀N₂O₄S$1/4 H₂O: C, 60.54; H, 5.48; N, 7.43. Found:

C, 60.59; H, 5.34; N, 7.44.

4.2.10.2. Conversion of 3a into 9a. To a solution of cis-

3a/trans-3a (1:1, 76 mg, 0.155 mmol) in MeOH (1 mL) was

added p-TsOH (29.3 mg, 0.155 mmol) under a nitrogen at-

mosphere at room temperature. After being stirred at room

temperature for 4 h, the reaction mixture was diluted with

saturated aqueous NaHCO₃and was extracted with Et₂O.

The organic phase was washed with brine, dried over

MgSO₄, and concentrated at reduced pressure. The residue

was puriﬁed by PTLC (hexane/AcOEt 1:1) to afford cis-9a

(22 mg, 32%) and to recover trans-3a (30 mg, 37%).

4.2.11.1. Radical reaction of oxime ether 1b [Table 2,

entry 3]. To a boiling solution of 1b (165 mg, 0.31 mmol)

in benzene (2 mL) was added a solution of Bu₃SnH

(0.17 mL, 0.62 mmol) and AIBN (10 mg, 0.062 mmol) in

benzene (2.5 mL) by syringe pump under a nitrogen atmo-

sphere. After being stirred at reﬂux for 4 h, a solution of

Bu₃SnH (0.17 mL, 0.62 mmol) and AIBN (10 mg,

0.062 mmol) in benzene (2 mL) was added by syringe

pump. After being stirred at reﬂux for 3 h, the reaction mix-

turewas extracted with hexane/MeCN. The MeCN phasewas

concentrated at reduced pressure. The residuewas puriﬁed by

MCC (hexane/AcOEt 3:1) to afford cis-2a (15 mg, 14%),

cis-3b (24 mg, 14.5%), trans-3b (24 mg, 14.5%), cis-10b

(11 mg, 8%), trans-10b (38 mg, 30%), and benzyl alcohol

(11). Benzyl alcohol was identical with authentic sample.

4.2.11. Radical reaction of oxime ether 1e [Table 2, entry

2]. To a boiling solution of 1e (250 mg, 0.60 mmol) in ben-

zene (4.5 mL) was added a solution of Bu₃SnH (0.32 mL,

1.2 mmol) and AIBN (20 mg, 0.12 mmol) in benzene

(4.5 mL) by syringe pump under a nitrogen atmosphere.

After being stirred at reﬂux for 3 h, a solution of Bu₃SnH

(0.32 mL, 1.2 mmol) and AIBN (20 mg, 0.12 mmol) in ben-

zene (2 mL) was added by syringe pump. After being stirred

at reﬂux for 4 h, the reaction mixture was extracted with

hexane/MeCN. The MeCN phase was concentrated at

reduced pressure. The residue was puriﬁed by MCC (hex-

ane/AcOEt 3:1) to afford cis-2a (54 mg, 26%), trans-2a

(62 mg, 30%), cis-3e (17 mg, 7%), trans-3e (22 mg, 8%),

and 9e (5.1 mg, 2%).

1,1-Dimethylethyl cis-1,2,3,4-tetrahydro-1-[(4-methylphe-

nyl)sulfonyl]-4-[(phenylmethoxy)amino]quinoline-3-ace-

tate (cis-3b). A pale yellow oil. IR n_maxcm^ꢂ1: 3566 (NH),

Ethyl cis-1,2,3,4-tetrahydro-4-(methoxyamino)-1-[(4-methyl-

phenyl)sulfonyl]quinoline-3-acetate (cis-3e). A pale yellow

oil. IR n_maxcm^ꢂ1: 3566 (NH), 1728 (COO), 1352, 1166

(NSO₂). ¹H NMR (500 MHz) d: 7.90 (1H, dd, J¼7.5,

1 Hz), 7.74–7.69 (1H, m), 7.57–7.16 (5H, m), 7.08 (1H, td,

J¼7.5, 1 Hz), 5.06 (1H, br s), 4.17 (2H, br q, J¼7 Hz),

4.12 (1H, dd, J¼12.5, 4 Hz), 3.88 (1H, br d, J¼4 Hz), 3.49

(1H, dd, J¼12.5, 11.5 Hz), 3.29 (3H, s), 2.57 (1H, dd,

J¼16, 7 Hz), 2.36 (3H, s), 3.12 (1H, dd, J¼16, 7 Hz),

2.29–2.23 (1H, m), 1.28 (3H, t, J¼7 Hz). ¹³C NMR

(125 MHz) d: 171.7, 143.8, 136.6, 135.8, 129.9, 129.5,

128.6, 127.7, 127.2, 124.4, 122.7, 61.2, 60.5, 58.5, 46.9,

34.3, 33.1, 21.5, 14.2. HRMS m/z: Calcd for C₂₁H₂₆N₂O₅S

(M⁺) 418.1561. Found: 418.1565.

1

1722 (COO), 1352, 1165 (NSO₂). H NMR (200 MHz) d:

7.89 (1H, br d, J¼8 Hz), 7.55 (2H, br d, J¼8 Hz), 7.35–

7.01 (10H, m), 5.22 (1H, br s), 4.48 and 4.35 (2H, ABq,

J¼11.5 Hz), 4.11 (1H, dd, J¼13, 3.5 Hz), 3.88 (1H, br d,

J¼3 Hz), 3.53 (1H, br t, J¼11 Hz), 2.52 (1H, dd, J¼18,

10 Hz), 2.33 (3H, s), 2.38–2.20 (2H, m), 2.22 (2H, br d,

J¼7 Hz), 1.45 (9H, s). ¹³C NMR (50 MHz) d: 171.1, 143.7,

137.2, 136.7, 135.9, 130.2, 129.5, 128.5, 128.4, 127.9, 127.8,

127.2, 124.2, 122.5, 80.8, 75.9, 58.6, 47.1, 35.6, 33.6, 28.1,

21.5. HRMS m/z: Calcd for C₂₉H₃₄N₂O₅S (M⁺) 522.2186.

Found: 522.2180.

1,1-Dimethylethyl trans-1,2,3,4-tetrahydro-1-[(4-methyl-

phenyl)sulfonyl]-4-[(phenylmethoxy)amino]quinoline-3-ac-

etate (trans-3b). A pale yellow oil. IR n_maxcm^ꢂ1: 3548

(NH), 1721 (COO), 1352, 1164 (NSO₂). ¹H NMR

(200 MHz) d: 7.67 (2H, br d, J¼8 Hz), 7.35–6.97 (11H,

m), 7.28–7.19 (4H, m), 7.06 (1H, td, J¼7.5, 1 Hz), 5.28 (1H,

br s), 4.59 and 4.50 (2H, ABq, J¼12 Hz), 3.95 (2H, d,

J¼5 Hz), 3.78 (1H, br d, J¼3.5 Hz), 2.63–2.61 (1H, m),

2.36 (3H, s), 1.47 (9H, s). ¹³C NMR (50 MHz) d: 171.1,

143.7, 137.6, 137.5, 137.0, 130.8, 129.7, 128.5, 128.4, 127.9,

127.1, 124.5, 123.7, 120.9, 80.8, 76.8, 61.1, 46.7, 36.2, 31.6,

28.1, 21.5. HRMS m/z: Calcd for C₂₉H₃₄N₂O₅S (M⁺)

522.2186. Found: 522.2179.

Ethyl

methylphenyl)sulfonyl]quinoline-3-acetate (trans-3e).

trans-1,2,3,4-tetrahydro-4-(methoxyamino)-1-[(4-

A

pale yellow oil. IR n_max(neat) cm^ꢂ1: 3262 (NH), 1736

(COO), 1341, 1160 (NSO₂). H NMR (500 MHz) d: 7.71

1

(1H, dd, J¼7.5, 1 Hz), 7.67–7.65 (2H, m), 7.28–7.19 (4H,

m), 7.06 (1H, td, J¼7.5, 1 Hz), 5.29 (1H, br s), 4.21–4.13

(2H, m), 4.07 (1H, dd, J¼12.5, 4 Hz), 3.90 (1H, dd,

J¼12.5, 6.5 Hz), 3.74 (1H, br d, J¼4 Hz), 3.36 (3H, s),

2.61–2.57 (1H, m), 2.38 (3H, s), 2.35–2.28 (2H, m), 1.28

(3H, t, J¼7 Hz). ¹³C NMR (125 MHz) d: 171.8, 143.7,

137.4, 136.9, 130.3, 129.6, 128.5, 127.2, 125.3, 124.1,

121.7, 62.5, 61.0, 60.7, 47.2, 35.2, 31.2, 21.5, 14.2. HRMS

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10105

1,1-Dimethylethyl

methylphenyl)sulfonyl]quinoline-3-acetate (cis-10b).

cis-4-amino-1,2,3,4-tetrahydro-1-[(4-

A

2.30–2.39 (1H, m), 2.33 (3H, s), 2.20–2.28 (1H, m), 2.14 (1H,

dd, J¼14, 6 Hz). ¹³C NMR (125 MHz) d: 170.7, 143.9, 138.2,

135.9, 135.3, 132.8, 129.7, 129.0, 128.8, 128.0, 127.8, 127.6,

127.1, 124.5, 122.7 49.4, 46.1, 43.7, 36.1, 35.0, 21.5. HRMS

m/z: Calcd for C₂₉H₃₄N₂O₅S (M⁺) 522.2186. Found:

522.2180.

pale yellow oil. IR n_maxcm^ꢂ1: 3423, 3385 (NH), 1721

(COO), 1355, 1166 (NSO₂). H NMR (500 MHz) d: 7.87

1

(1H, br d, J¼8.5 Hz), 7.56 (2H, br d, J¼8.5 Hz), 7.25–

7.17 (4H, m), 7.08 (1H, br t, J¼7.5 Hz), 4.07 (1H, dd,

J¼13, 4 Hz), 3.76 (1H, br d, J¼3.5 Hz), 3.45 (1H, dd,

J¼13, 11.5 Hz), 2.33 (1H, dd, J¼15, 7.5 Hz), 2.36 (3H, s,

2.20 (1H, dd, J¼15, 7 Hz), 2.16–2.13 (1H, m), 1.49 (9H,

s). ¹³C NMR (125 MHz) d: 171.2, 143.8, 136.0, 135.6,

129.6, 128.0, 127.3, 127.2, 124.5, 122.8, 81.0, 49.6, 45.7,

35.3, 34.9, 28.1, 21.5. HRMS m/z: Calcd for C₂₂H₂₈N₂O₄S

(M⁺) 416.1768. Found: 416.1746.

trans-1,2,3,4-Tetrahydro-1-[(4-methylphenyl)sulfonyl]-4-

[(phenylmethoxy)amino]-N-(phenylmethyl)quinoline-3-acet-

amide (trans-10c). A pale yellow oil. IR n_maxcm^ꢂ1: 3296

1

(NH), 1652 (CON). H NMR (500 MHz) d: 7.62 (3H, d,

J¼8.5 Hz), 7.30–7.36 (2H, m), 7.21–7.30 (6H, m), 7.17

(1H, td, J¼7.5, 1.5 Hz), 7.07 (1H, td, J¼7.5, 1.5 Hz),

6.34 (1H, br s), 4.46 (1H, dd, J¼15, 6 Hz), 4.40 (1H, dd,

J¼15, 5.5 Hz), 4.02 (1H, dd, J¼13, 3.5 Hz), 3.76 (1H,

dd, J¼13, 7 Hz), 3.57 (1H, d, J¼5.5 Hz), 2.37 (3H, s),

2.26 (2H, dd, J¼ 9, 7 Hz), 2.16–2.22 (1H, m). ¹³C NMR

(125 MHz) d: 170.8, 143.8, 138.2, 136.9, 136.0, 131.7,

129.7, 129.1, 128.7, 127.8, 127.7, 127.5, 127.0, 124.5,

122.0, 52.4, 47.6, 43.7, 37.9, 37.6, 21.5. HRMS m/z: Calcd

for C₂₅H₂₇N₃O₃S (M⁺) 449.1772. Found: 449.1780.

1,1-Dimethylethyl trans-4-amino-1,2,3,4-tetrahydro-1-[(4-

methylphenyl)sulfonyl]quinoline-3-acetate (trans-10b). A

pale yellow oil. IR n_max(neat) cm^ꢂ1: 3392, 3319 (NH),

1

1723 (COO), 1351, 1164 (NSO₂). H NMR (500 MHz) d:

7.71 (1H, dd, J¼8.5, 1 Hz), 7.60 (2H, br d, J¼8.5 Hz),

7.32–7.19 (4H, m), 7.10 (1H, td, J¼7, 1 Hz), 4.14 (1H, dd,

J¼13, 4 Hz), 3.61 (1H, dd, J¼13, 8.5 Hz), 3.45 (1H, br d,

J¼7 Hz), 2.41–2.35 (4H, m), 2.37 (3H, s), 2.17 (1H, dd, J¼

16, 8 Hz), 2.01–2.00 (1H, m), 1.48 (9H, s). ¹³C NMR

(125 MHz) d: 171.2, 143.7, 136.7, 136.1, 132.6, 129.6,

128.6, 127.6, 127.2, 124.8, 122.8, 80.9, 52.5, 48.3, 37.7,

37.1, 28.1, 21.5. HRMS m/z: Calcd for C₂₂H₂₈N₂O₄S (M⁺)

416.1768. Found: 416.1788.

4.2.13. Radical reaction of oxime ether (Z)-1d [Table 2,

entry 5]. To a boiling solution of (Z)-1d (148 mg,

0.33 mmol) in benzene (2.5 mL) was added a solution

of Bu₃SnH (0.18 mL, 0.66 mmol) and AIBN (11 mg,

0.066 mmol) in benzene (2.5 mL) by syringe pump under

a nitrogen atmosphere. After being stirred at reﬂux for 2 h,

a solution of Bu₃SnH (0.18 mL, 0.66 mmol) and AIBN

(11 mg, 0.066 mmol) in benzene (2 mL) was added by sy-

ringe pump. After being stirred at reﬂux for 3 h, the reaction

mixture was extracted with hexane/MeCN. The MeCN phase

was concentrated at reduced pressure. The residue was puri-

ﬁed by MCC (hexane/AcOEt 3:1) to afford cis-3d (26.4 mg,

18%), trans-3d (8.7 mg, 6%), cis-10d (8.1 mg, 7%), and

trans-10d (8.1 mg, 7%).

4.2.11.2. Conversion of cis-10b into cis-2a. After a boil-

ing solution of cis-10b (3.3 mg, 0.008 mmol) in benzene

(2 mL) was stirred under a nitrogen atmosphere for 9 h,

the reaction mixture was concentrated at reduced pressure.

The residue was puriﬁed by PTLC (AcOEt) to afford cis-

2a (1.7 mg, 63%).

4.2.11.3. Attempted conversion of trans-10b into trans-

2a. According to the procedure described in the conversion

of cis-10b into cis-2a, reaction of trans-10b (33 mg,

0.079 mmol) recovered trans-10b (28 mg, 84%).

cis-1,2,3,4-Tetrahydro-1-[(4-methylphenyl)sulfonyl]-4-[(phe-

nylmethoxy)amino]quinoline-3-acetonitrile (cis-3d). A pale

yellow oil. IR n_maxcm^ꢂ1: 3156 (NH), 2254 (CN), 1381,

1168 (NSO₂). ¹H NMR (200 MHz) d: 7.93 (1H, br d,

J¼8 Hz), 7.53 (2H, br d, J¼8 Hz), 7.36–7.01 (10H, m),

5.02 (1H, br s), 4.58 and 4.48 (2H, ABq, J¼11.5 Hz), 4.16

(1H, dd, J¼11.5, 4 Hz), 3.94 (1H, br d, J¼4 Hz), 3.52

(1H, br t, J¼11.5 Hz), 2.53 (1H, dd, J¼16.5, 7.5 Hz), 2.37

(3H, s), 2.30 (1H, dd, J¼16.5, 7.5 Hz), 2.00–1.92 (1H, m).

¹³C NMR (75 MHz) d: 144.1, 137.3, 137.0, 136.5, 130.5,

129.8, 128.9, 128.7, 128.5, 128.2, 127.0, 124.4, 123.6,

121.5, 117.7, 76.7, 60.1, 46.3, 32.0, 21.5, 18.7. HRMS m/z:

Calcd for C₂₅H₂₅N₃O₃S (M⁺) 447.1615. Found: 447.1621.

4.2.12. Radical reaction of oxime ether 1c [Table 2, entry

4]. To a boiling solution of 1c (199.8 mg, 0.36 mmol) in ben-

zene (2 mL) was added slowly a solution of Bu₃SnH

(0.19 mL, 0.72 mmol) and AIBN (11.8 mg, 0.072 mmol)

in benzene (2 mL) under a nitrogen atmosphere. After being

stirred at reﬂux for 2 h, a solution of Bu₃SnH (0.19 mL,

0.72 mmol) and AIBN (11.8 mg, 0.072 mmol) in benzene

(2 mL) was added slowly. After being stirred at reﬂux for

3 h, the reaction mixture was extracted with hexane/

MeCN. The MeCN phase was concentrated at reduced pres-

sure. The residue was puriﬁed by PTLC (hexane/AcOEt 1:1)

to afford cis-10c (18 mg, 11%), trans-10c (23 mg, 14.5%),

and 7a (11 mg, 8%).

trans-1,2,3,4-Tetrahydro-1-[(4-methylphenyl)sulfonyl]-4-

[(phenylmethoxy)amino)]quinoline-3-acetonitrile (trans-3d).

A pale yellow oil. IR n_maxcm^ꢂ1: 3526 (NH), 2254 (CN),

1381, 1168 (NSO₂). ¹H NMR (200 MHz) d: 7.66 (2H, br d,

J¼8 Hz), 7.50–7.10 (11H, m), 5.81 (1H, d), 4.77 and 4.71

(2H, ABq, J¼8 Hz), 4.38 (1H, dd, J¼13.5, 2.5 Hz), 3.60

(1H, br d, J¼2.5 Hz), 3.23 (1H, dd, J¼15, 13.5 Hz), 2.46–

2.32 (2H, m), 2.41 (3H, s), 2.19 (1H, dd, J¼13, 4 Hz). ¹³C

NMR (75 MHz) d: 143.6, 138.8, 138.7, 137.0, 136.6,

129.8, 128.7, 128.55, 128.52, 128.2, 127.1, 126.1, 119.1,

117.7, 76.8, 64.5, 51.1, 35.2, 29.9, 21.5. HRMS m/z: Calcd

for C₂₅H₂₅N₃O₃S (M⁺) 447.1615. Found: 447.1600.

cis-1,2,3,4-Tetrahydro-1-[(4-methylphenyl)sulfonyl]-4-[(phe-

nylmethoxy)amino]-N-(phenylmethyl)quinoline-3-acetamide

(cis-10c). A pale yellow oil. IR n_maxcm^ꢂ1: 3230 (NH), 1652

1

(CON). H NMR (500 MHz) d: 7.81 (1H, d, J¼8 Hz), 7.53

(2H, d, J¼8.5 Hz), 7.30–7.34 (2H, m), 7.24–7.28 (3H, m),

7.16–7.20 (3H, m), 7.10 (1H, dd, J¼75, 1.5 Hz), 7.04 (1H,

td, J¼7.5, 1 Hz), 6.16 (1H, br s), 4.43 (1H, dd, J¼15,

5.5 Hz), 4.40 (1H, dd, J¼15, 5.5 Hz), 4.00 (1H, dd, J¼13,

3.5 Hz), 3.70 (1H, d, J¼4 Hz), 3.42 (1H, dd, J¼13, 10.5 Hz),

10106

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

cis-4-Amino-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulfo-

nyl]quinoline-3-acetonitrile (cis-10d). A pale yellow oil. IR

n_maxcm^ꢂ1: 3505, 3385 (NH), 2253 (CN), 1354, 1165

9b-Me (d 1.07). ¹³C NMR (125 MHz) d: 174.3, 144.1,

137.2, 135.4, 133.6, 129.8, 128.2, 127.2, 126.7, 126.6,

125.6, 57.5, 48.3, 38.9, 33.6, 29.9, 21.5. HRMS m/z: Calcd

for C₁₉H₂₀N₂O₃S (M⁺) 356.1194. Found: 356.1191.

1

(NSO₂). H NMR (200 MHz) d: 7.72–7.12 (8H, m), 4.18

(1H, dd, J¼13.5, 4 Hz), 3.68 (1H, dd, J¼13.5, 9 Hz), 3.59

(1H, br d, J¼8 Hz), 2.51 (2H, br d, J¼6 Hz), 2.40 (3H, s),

1.90–1.70 (1H, m). ¹³C NMR (125 MHz) d: 161.3, 144.2,

137.6, 136.1, 132.2, 131.7, 130.3, 129.8, 129.2, 127.9,

127.2, 117.0, 57.2, 56.7, 29.8, 23.1, 21.6. HRMS m/z: Calcd

for C₁₈H₁₉N₃O₂S (M⁺) 341.1196. Found: 341.1175.

trans-1,3,3a,4,5,9b-Hexahydro-9b-methyl-5-[(4-methylphe-

nyl)sulfonyl]-2H-pyrrolo[3,2-c]quinolin-2-one (trans-2b).

A colorless solid. IR n_maxcm^ꢂ1: 3419 (NH), 1696 (g-lac-

tam), 1356, 1168 (NSO₂). ¹H NMR (500 MHz) d: 7.94

(1H, br d, J¼8 Hz), 7.63 (2H, br d, J¼8 Hz), 7.28–7.24

(3H, m), 7.09 (1H, br t, J¼8 Hz), 6.96 (1H, br d, J¼8 Hz),

6.75 (1H, br s), 4.07 (1H, dd, J¼13, 5 Hz), 3.60 (1H, dd,

J¼13, 10.5 Hz), 2.46–2.30 (3H, m), 2.38 (3H, s), 0.76

(3H, s). NOESY: NOE was observed between 4-Hax (d

3.60) and 9b-Me (d 0.76). ¹³C NMR (125 MHz) d: 176.8,

144.2, 135.6, 135.6, 134.1, 129.8, 128.0, 127.0, 124.0,

123.3, 121.2, 58.7, 46.4, 42.1, 32.6, 29.7, 21.6. HRMS m/z:

Calcd for C₁₉H₂₀N₂O₃S (M⁺) 356.1194. Found: 356.1200.

trans-4-Amino-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulf-

onyl]quinoline-3-acetonitrile (trans-10d). A pale yellow oil.

IR n_maxcm^ꢂ1: 3388, 3324 (NH), 2250 (CN), 1355, 1167

1

(NSO₂). H NMR (200 MHz) d: 7.91–7.22 (8H, m), 4.34

(1H, dd, J¼14.5, 3 Hz), 4.10–3.92 (1H, m), 3.84 (1H, dd,

J¼14.5, 11 Hz), 2.73 (2H, dd, J¼6, 4 Hz), 2.40 (3H, s),

1.70–1.50 (1H, m). ¹³C NMR (50 MHz) d: 144.2, 136.4,

135.6, 132.1, 129.8, 128.3, 128.0, 127.1, 125.3, 123.3,

117.7, 51.6, 47.8, 37.6, 21.5, 19.0. HRMS m/z: Calcd for

C₁₈H₁₉N₃O₂S (M⁺) 341.1197. Found: 341.1219.

Ethyl-(2Z)-4-[[(4-methylphenyl)sulfonyl][2-[1-(1E)-[(phe-

nylmethoxy)imino]ethyl]phenyl]amino]-2-butenoate (Z-1f).

A colorless oil. IR n_maxcm^ꢂ1: 1709 (COO), 1352, 1191

1

4.2.14. Radical reaction of oxime ether (E)-1d [Table 2,

entry 6]. To a boiling solution of (E)-1d (103 mg,

0.23 mmol) in benzene (2 mL) was added a solution of

Bu₃SnH (0.12 mL, 0.46 mmol) and AIBN (7.6 mg,

0.046 mmol) in benzene (2 mL) by syringe pump under a ni-

trogen atmosphere. After being stirred at reﬂux for 3 h, a so-

lution of Bu₃SnH (0.12 mL, 0.46 mmol) and AIBN (7.6 mg,

0.046 mmol) in benzene (2 mL) was added by syringe pump.

After being stirred at reﬂux for 3 h, the reaction mixture was

extracted with hexane/MeCN. The MeCN phase was con-

centrated at reduced pressure. The residue was puriﬁed by

MCC (hexane/AcOEt 3:1) to afford cis-3d (12.2 mg,

11.5%), trans-3d (2.2 mg, 2.5%), and trans-10d (8.4 mg,

14%).

(NSO₂). H NMR (300 MHz) d: 7.55 (2H, br d, J¼8 Hz),

7.44–7.17 (10H, m), 6.72 (1H, br d, J¼8 Hz), 6.41 (1H, dt,

J¼11.5, 6 Hz), 5.60 (1H, dd, J¼11.5, 2.5 Hz), 5.22 (2H, s,

4.72 (2H, very br), 4.09 (2H, q, J¼7 Hz), 2.43 (3H, s),

2.32 (3H, s), 1.23 (3H, t, J¼7 Hz). ¹³C NMR (75 MHz) d:

165.9, 155.8, 145.7, 143.6, 139.5, 138.3, 137.7, 135.3, 129.9,

129.5, 129.0, 128.5, 128.4, 128.2, 127.7, 127.6, 127.3, 120.6,

75.8, 60.1, 51.2, 21.5, 16.7, 14.2. HRMS m/z: Calcd for

C₂₈H₃₀N₂O₅S (M⁺) 506.1874. Found: 506.1888.

4.2.16. Radical reaction of ketoxime ether 1g [Table 3]. To

a boiling solution of 1g (219 mg, 0.51 mmol) in benzene

(3.6 mL) was added a solution of Bu₃SnH (0.27 mL,

1.02 mmol) and AIBN (17 mg, 0.10 mmol) in benzene

(4 mL) by syringe pump under a nitrogen atmosphere. After

being stirred at reﬂux for 2 h, a solution of Bu₃SnH (0.27 mL,

1.02 mmol) and AIBN (17 mg, 0.10 mmol) in benzene

(2 mL) was added by syringe pump. After being stirred at re-

ﬂux for 7 h, the reaction mixture was extracted with hexane/

MeCN. The MeCN phase was concentrated at reduced pres-

sure. The residue was puriﬁed by MCC (hexane/AcOEt 5:1)

to afford cis-2b (5.2 mg, 3%), trans-2b (4.4 mg, 2%), cis-3g

(5.7 mg, 2.7%), trans-3g (5.0 mg, 2.4%) and 9g (3.9 mg,

2%), 7d (31.6 mg, 20%), and 1g (75 mg, 34%).

4.2.15. Radical reaction of ketoxime ether 1f [Table 3]. To

a boiling solution of 1f (208 mg, 0.53 mmol) in benzene

(4 mL) was added a solution of Bu₃SnH (0.28 mL,

1.06 mmol) and AIBN (17 mg, 0.11 mmol) in benzene

(4 mL) by syringe pump under a nitrogen atmosphere. After

being stirred at reﬂux for 3 h, a solution of Bu₃SnH

(0.28 mL, 1.06 mmol) and AIBN (17 mg, 0.11 mmol) in

benzene (2 mL) was added by syringe pump. After being

stirred at reﬂux for 7 h, a solution of Bu₃SnH (0.28 mL,

1.06 mmol) and AIBN (17 mg, 0.11 mmol) in benzene

(2 mL) was added by syringe pump. After being stirred at re-

ﬂux for 3 h, the reaction mixture was extracted with hexane/

MeCN. The MeCN phase was concentrated at reduced pres-

sure. The residue was puriﬁed by MCC (hexane/AcOEt 5:1)

to afford cis-2b (4.2 mg, 2%), trans-2b (4.2 mg, 2%), Z-1f

(4.1 mg, 2%), 7c (44.8 mg, 21%), and 1f (78.6 mg, 36%).

Ethyl cis-1,2,3,4-tetrahydro-4-(methoxyamino)-4-methyl-1-

[(4-methylphenyl)sulfonyl]quinoline-3-acetate (cis-3g). A

colorless oil. IR n_maxcm^ꢂ1: 3615 (NH), 1724 (COO), 1352,

1164 (NSO₂). ¹H NMR (500 MHz) d: 7.86 (1H, br d,

J¼8 Hz), 7.52 (2H, br d, J¼8 Hz), 7.47 (1H, br d, J¼8 Hz),

7.28–7.17 (4H, m), 5.60 (1H, br s), 4.22 (2H, q, J¼7.5 Hz),

4.19 (1H, dd, J¼13.5, 4 Hz), 3.57 (1H, dd, J¼13.5,

11 Hz), 3.21 (3H, s), 2.58 (1H, br d, J¼15.5 Hz), 2.35 (3H,

s), 2.29 (1H, dd, J¼15.5, 10 Hz), 2.17–2.11 (1H, m), 1.33

(3H, t, J¼7.5 Hz), 0.83 (3H, s). NOESY: NOE was observed

between 2-Heq (d 4.19) and 4-Me (d 0.83), and 2-Hax (d

3.57) and 1⁰-H (d 2.29), 3-H (d 2.17–2.11) and 4-Me (d

0.83). ¹³C NMR (125 MHz) d: 172.6, 143.5, 136.8, 129.8,

129.4, 127.6, 127.5, 127.4, 125.2, 124.4, 121.3, 61.9, 60.8,

48.6, 32.5, 29.7, 25.2, 22.7, 21.5, 14.3. HRMS m/z: Calcd

for C₂₂H₂₈N₂O₅S (M⁺) 432.1718. Found: 432.1742.

cis-1,3,3a,4,5,9b-Hexahydro-9b-methyl-5-[(4-methylphe-

nyl)sulfonyl]-2H-pyrrolo[3,2-c]quinolin-2-one (cis-2b). A

colorless solid. IR n_maxcm^ꢂ1: 3436 (NH), 1697 (g-lactam),

1354, 1166 (NSO₂). ¹H NMR (500 MHz) d: 7.72 (1H, br d,

J¼8 Hz), 7.52 (2H, br d, J¼8 Hz), 7.31–7.22 (5H, m), 6.54

(1H, br s), 4.20 (1H, dd, J¼14, 5 Hz), 3.15 (1H, dd, J¼14,

13 Hz), 2.67 (1H, dd, J¼17.5, 8.5 Hz), 2.39 (3H, s), 2.32–

2.30 (1H, m), 1.96 (1H, br d, J¼17.5 Hz), 1.07 (3H, s). NO-

ESY: NOE was observed between 3a-H (d 2.32–2.30) and

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10107

Ethyl trans-1,2,3,4-tetrahydro-4-(methoxyamino)-4-methyl-

1-[(4-methylphenyl)sulfonyl]quinoline-3-acetate (trans-3g).

A colorless oil. IR n_max(neat) cm^ꢂ1: 3615 (NH), 1728

4.2.18. Attempted conversion of trans-10a into trans-2a.

According to the procedure described in the conversion of

cis-10b into cis-2a, reaction of trans-10a (3.5 mg,

0.009 mmol) gave trans-2a (1.3 mg, 42%).

1

(COO), 1352, 1165 (NSO₂). H NMR (500 MHz) d: 7.93

(1H, br d, J¼8 Hz), 7.58 (2H, br d, J¼8 Hz), 7.35 (1H, br

d, J¼8 Hz), 7.24–7.12 (4H, m), 5.51 (1H, br s), 4.42 (1H,

dd, J¼13.5, 3.5 Hz), 4.27–4.19 (2H, m), 3.41 (1H, dd,

J¼13.5, 11 Hz), 3.09 (3H, s), 2.63 (1H, dd, J¼15.5,

3.5 Hz), 2.58–2.52 (1H, m), 2.34 (3H, s), 2.03 (1H, dd,

J¼15.5, 11 Hz), 1.33 (3H, t, J¼7 Hz), 1.01 (3H, s). NOESY:

NOE was observed between 1⁰-H (d 2.03) and 4-Me (d 1.01),

and 1⁰-H (d 2.03) and 2-Hax (d 3.41), and 2-Hax (d 3.41) and

4-Me (d 1.01). ¹³C NMR (125 MHz) d: 172.3, 143.4, 136.9,

129.4, 127.60, 127.56, 126.5, 124.9, 123.7, 121.3, 62.7,

60.8, 47.5, 32.6, 32.5, 29.7, 21.9, 21.5, 14.3. HRMS m/z:

Calcd for C₂₂H₂₈N₂O₅S (M⁺) 432.1718. Found: 432.1715.

4.2.19. Radical reaction of 1a in the presence of Bu₃SnD

[Table 5, entry 1]. To a boiling solution of 1a (200 mg,

0.41 mmol) in benzene (2.0 mL) was added slowly a solution

of Bu₃SnD (0.22 mL, 0.82 mmol) and AIBN (13.5 mg,

0.082 mmol) in benzene (2.1 mL) under an Ar atmosphere.

After being stirred at reﬂux for 2 h, a solution of Bu₃SnD

(0.22 mL, 0.82 mmol) and AIBN (13.5 mg, 0.082 mmol)

in benzene (2.1 mL) was added slowly. After being stirred

at reﬂux for 4 h, the reaction mixture was extracted with

hexane/MeCN. The MeCN phase was concentrated at re-

duced pressure. The residue was puriﬁed by ﬂash column

chromatography (hexane/AcOEt 2:1) to afford cis-2a-D

(D: 69%) (42 mg, 29%), trans-2a-D (D: 76%) (55 mg,

39%), cis-3a-D (D: 3%) (13 mg, 6%) and trans-3a-D (D:

1%) (18 mg, 9%).

cis-1,3,3a,4,5,9b-Hexahydro-1-(methoxyamino)-9b-methyl-

5-[(4-methylphenyl)sulfonyl]-2H-pyrrolo[3,2-c]quinolin-2-

one (9g). Colorless solid. IR n_maxcm^ꢂ1: 1711 (g-lactam),

1

1359, 1165 (NSO₂). H NMR (500 MHz) d: 7.78 (1H, dd,

J¼8, 1.5 Hz), 7.70 (1H, dd, J¼8, 1.5 Hz), 7.46 (2H, br d,

J¼8 Hz), 7.37 (1H, br t, J¼8 Hz), 7.27 (1H, br t, J¼8 Hz),

7.22 (2H, br d, J¼8 Hz), 4.19 (1H, dd, J¼14, 4.5 Hz), 3.46

(3H, s), 3.28 (1H, dd, J¼14, 12.5 Hz), 2.52 (1H, dd,

J¼17.5, 8.5 Hz), 2.39 (3H, s), 2.10–2.05 (1H, m), 1.98

(1H, br d, J¼17.5 Hz), 1.12 (3H, s). NOESY: NOE was ob-

served between 3a-H (d 2.10–2.05) and 9b-Me (d 1.12). ¹³C

NMR (125 MHz) d: 168.8, 144.2, 136.9, 135.7, 129.9, 129.8,

128.8, 128.6, 127.2, 126.0, 125.3, 64.2, 59.8, 48.1, 33.4,

29.6, 23.9, 21.5. HRMS m/z: Calcd for C₂₀H₂₂N₂O₄S (M⁺)

386.1299. Found: 386.1324.

cis-3-d-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sul-

fonyl]-2H-pyrrolo[3,2-c]quinolin-2-one (cis-2a-D). Color-

less crystals. IR n_maxcm^ꢂ1: 3432 (NH), 1705 (g-lactam),

1

1354, 1166 (NSO₂). H NMR (500 MHz) d: 7.69 (1H, d,

J¼8.5 Hz), 7.50 (2H, br d, J¼8.5 Hz), 7.29 (1H, td, J¼8,

1.5 Hz), 7.18–7.22 (3H, m), 7.14 (1H, br d, J¼8 Hz), 6.44

(1H, br s), 4.34 (1H, d, J¼7 Hz), 4.17 (1H, dd, J¼14,

5 Hz), 3.13 (1H, dd, J¼14, 12.5 Hz), 2.57 (1/3H, d, J¼

8.5 Hz), 2.50–2.55 (1H, m), 2.38 (3H, s), 1.98 (2/3H, d,

J¼1.5 Hz). HRMS m/z: Calcd for C₁₈H₁₇DN₂O₃S (M⁺)

343.1100. Found: 343.1116. Incorporation of D was 69%

from the NMR spectrum.

4.2.17. General procedure for radical reaction of 1a

in the presence of additive [Table 4]. To a boiling solu-

tion of a mixture of 1a (200 mg, 0.4 mmol) and additive

(1.2–5.0 equiv) in solvent (2.7 mL) was added a solution

of Bu₃SnH (0.21 mL, 0.8 mmol) and AIBN (13 mg,

0.08 mmol) in solvent (3 mL) by syringe pump under a nitro-

gen atmosphere. After being stirred at reﬂux for 2 h, a solu-

tion of Bu₃SnH (0.21 mL, 0.8 mmol) and AIBN (13 mg,

0.08 mmol) in solvent (2 mL) was added by syringe pump.

After being stirred at reﬂux for 3 h, the reaction mixture

was extracted with hexane/MeCN. The MeCN phase was

concentrated at reduced pressure. The residue was puriﬁed

by MCC (hexane/AcOEt 3:1) to afford cis-2a, trans-2a,

cis-3a, trans-3a, 9a, and trans-10a in yield shown in Table 4.

trans-3-d-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sul-

fonyl]-2H-pyrrolo[3,2-c]quinolin-2-one (trans-2a-D). Col-

orless crystals. IR n_maxcm^ꢂ1: 3429 (NH), 1705 (g-lactam),

1

1356, 1167 (NSO₂). H NMR (500 MHz) d: 7.80 (1H, dd,

J¼8, 1 Hz), 7.39 (2H, br d, J¼8.5 Hz), 7.37 (1H, br s),

7.30 (1H, br t, J¼8 Hz), 7.17 (3H, br d, J¼8 Hz), 6.96

(1H, d, J¼7.5 Hz), 3.96 (1H, dd, J¼11.5, 4.5 Hz), 3.55

(1H, t, J¼12 Hz), 3.21 (1H, d, J¼10 Hz), 2.50 (1/5H, br d,

J¼7.5 Hz), 2.36 (3H, s), 2.16 (4/5H, br d, J¼12.5 Hz),

2.04–2.14 (1H, m). HRMS m/z: Calcd for C₁₈H₁₇DN₂O₃S

(M⁺) 343.1100. Found: 343.1103. Incorporation of D was

76% from the NMR spectrum.

4.2.20. Radical reaction of 1a in the presence of D₂O

[Table 5, entry 2]. To a boiling solution of 1a (200 mg,

0.41 mmol) in benzene (2 mL) was added slowly a solu-

tion of Bu₃SnH (0.22 mL, 0.82 mmol) and AIBN

(13.5 mg, 0.082 mmol) in benzene (2 mL) under a nitro-

gen atmosphere. After being stirred at reﬂux for 2 h, a

solution of Bu₃SnH (0.22 mL, 0.82 mmol) and AIBN

(13.5 mg, 0.082 mmol) in benzene (2 mL) was added

slowly. After being stirred at reﬂux for 3 h, D₂O (1 mL)

was added to it. After being stirred for 1 h, the reaction

mixture was extracted with hexane/MeCN. The MeCN

phase was concentrated at reduced pressure. The residue

was puriﬁed by FCC (hexane/AcOEt 2:1) to afford cis-2a

(23 mg, 16%), trans-2a (50.3 mg, 36%), cis-3a-D (D:

19%) (18.7 mg, 9%), and trans-3a-D (D: 34%) (27.9 mg,

14%).

Ethyl trans-4-amino-1,2,3,4-tetrahydro-1-[(4-methylphe-

nyl)sulfonyl]quinoline-3-acetate (trans-10a). A pale brown

oil. IR n_max(neat) cm^ꢂ1: 3384, 3313 (NH), 1732 (COO),

1

1352, 1166 (NSO₂). H NMR (500 MHz) d: 7.71 (1H, br

d, J¼8 Hz), 7.60 (2H, br d, J¼8 Hz), 7.32 (1H, br d,

J¼8 Hz), 7.24–7.19 (3H, m), 7.11 (1H, br t, J¼7.5 Hz),

4.19–4.13 (3H, m), 3.63 (1H, dd, J¼13, 9 Hz), 3.51 (1H,

d, J¼7 Hz), 2.48 (1H, dd, J¼16, 5.5 Hz), 2.38 (3H, s),

2.27 (1H, dd, J¼16, 8 Hz), 2.10–2.04 (1H, m), 1.28 (3H, t,

J¼7 Hz). NOESY: NOE was observed between 2-Hax (d

3.63) and 4-H (d 3.51), and 1⁰-H (d 2.27) and 4-H (d 3.51).

¹³C NMR (125 MHz) d: 172.0, 143.8, 136.7, 136.1, 132.0,

129.7, 128.7, 127.9, 127.2, 124.9, 122.9, 60.8, 52.3, 48.3,

37.1, 35.9, 21.5, 14.2. HRMS m/z: Calcd for C₂₀H₂₄N₂O₄S

(M⁺) 388.1455. Found: 388.1457.

10108

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

4.2.21. Radical reaction of 1a in the presence of D₂O [Ta-

ble 5, entry 3]. To a boiling solution of 1a (185.2 mg,

0.38 mmol) in a mixture of benzene (2 mL) and D₂O

(1.0 mL) was added slowly a solution of Bu₃SnH

(0.20 mL, 0.76 mmol) and AIBN (12.5 mg, 0.076 mmol)

in benzene (1.8 mL) under an Ar atmosphere. After being

stirred at reﬂux for 2 h, a solution of Bu₃SnH (0.20 mL,

0.76 mmol) and AIBN (12.5 mg, 0.076 mmol) in benzene

(1.8 mL) was added slowly. After being stirred for 2 h, the

reaction mixture was extracted with hexane/MeCN. The

MeCN phase was concentrated at reduced pressure. The res-

idue was puriﬁed by FCC (hexane/AcOEt 2:1) to afford cis-

2a-D (D: 2%) (16.7 mg, 13%), trans-2a-D (D: 0%) (5.3 mg,

4%), cis-3a-D (D: 82%) (18.4 mg, 10%), and trans-3a-D (D:

83%) (22.4 mg, 12%).

cis-1,2,3,4-Tetrahydro-N,N-dimethyl-1-[(4-methylphenyl)-

sulfonyl]-4-[(phenylmethoxy)amino]quinoline-3-acetamide

(cis-12). A colorless oil. IR n_maxcm^ꢂ1: 3665 (NH), 1640

1

(CON), 1352, 1165 (NSO₂). H NMR (500 MHz) d: 7.87

(1H, br d, J¼8 Hz), 7.58 (2H, br d, J¼8 Hz), 7.35–7.16 (9H,

m), 7.05 (1H, br t, J¼8 Hz), 4.47 and 4.44 (2H, ABq, J¼

12.5 Hz), 4.10 (1H, dd, J¼13, 3.5 Hz), 4.03 (1H, d, J¼

3.5 Hz), 3.58 (1H, br t, J¼13 Hz), 2.92 and 2.88 (each 3H,

s), 2.58 (1H, dd, J¼16, 7.5 Hz), 2.48–2.46 (1H, m), 2.34

(3H, s), 2.29 (1H, dd, J¼16, 6.5 Hz). ¹³C NMR (50 MHz)

d: 170.7, 143.7, 137.3, 136.6, 135.9, 130.2, 129.5, 128.4,

128.3, 128.2, 128.1, 127.8, 127.2, 124.1, 122.2, 75.8, 58.5,

47.6, 37.1, 35.4, 33.4, 32.8, 21.5. HRMS m/z: Calcd for

C₂₇H₃₁N₃O₄S (M⁺) 493.2034. Found: 493.2031.

4.2.24. [Table 6, entry 4]. To a boiling solution of cis-3a

(59 mg, 0.12 mmol) in benzene (1 mL) was added a solution

of Bu₃SnH (0.063 mL, 0.24 mmol), AIBN (3.8 mg,

0.024 mmol), and Bu₃SnNMe₂(79 mg, 0.24 mmol) in ben-

zene (1 mL) by syringe pump under a nitrogen atmosphere.

After being stirred at reﬂux for 4 h, Bu₃SnNMe₂(79 mg,

0.24 mmol) was added. After being stirred at reﬂux for

5 h, the reaction mixture was extracted with hexane/

MeCN. The MeCN phase was concentrated at reduced pres-

sure. The residue was puriﬁed by PTLC (AcOEt) to afford

cis-2a (6.4 mg, 16%) and cis-12 (38 mg, 65%).

A mixture of ethyl cis-1,2,3,4-tetrahydro-1-[(4-methylphe-

nyl)sulfonyl]-4-[(phenylmethoxy)amino]quinoline-3-(1-d)-

acetate (cis-3a-D). A pale yellow oil. IR n_maxcm^ꢂ1: 3526

(NH), 1732 (COO), 1354, 1168 (NSO₂). ¹H NMR

(500 MHz) d: 7.89 (1H, d, J¼8.5 Hz), 7.54 (2H, d, J¼

8.5 Hz), 7.14–7.34 (9H, m), 7.05 (1H, t, J¼7.5, 1 Hz), 4.38

and 4.49 (2H, ABq, J¼11.5 Hz), 4.10–4.18 (3H, m), 3.92

(1H, d, J¼3.5 Hz), 3.53 (1H, t, J¼12 Hz), 2.58 (3/5H, d,

J¼7.5 Hz), 2.37 (1/2H, d, J¼12 Hz), 2.34 (3H, s), 2.26–

2.32 (1H, m), 1.25 (3H, t, J¼7 Hz). HRMS m/z: Calcd for

C₂₇H₂₉DN₂O₅S (M⁺) 495.1937. Found: 495.1914. Incorpo-

ration of D was 82% from the NMR spectrum.

4.2.25. Conversion of trans-3a into trans-2a in the pres-

ence of Bu₃SnNMe₂[Table 6, entry 6]. According to the

procedure described in the conversion of cis-3a into cis-2a

in the presence of Bu₃SnNMe₂(Table 6, entry 3), reaction

of trans-3a (50 mg, 0.10 mmol) with Bu₃SnNMe₂

(132 mg, 0.48 mmol) gave trans-2a (9.3 mg, 27%) and

trans-12 (25 mg, 50%).

Ethyl trans-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulfo-

nyl]-4-[(phenylmethoxy)amino]quinoline-3-(1-d)-acetate

(trans-3a-D). A pale yellow oil. IR n_maxcm^ꢂ1: 3565 (NH),

1

1728 (COO), 1351, 1165 (NSO₂). H NMR (500 MHz) d:

7.69 (1H, d, J¼8.5 Hz), 7.66 (2H, d, J¼9 Hz), 7.14–7.36

(9H, m), 7.01 (1H, td, J¼8, 1 Hz), 5.24 (1H, br s), 4.50

and 4.56 (2H, ABq, J¼7 Hz), 4.12–4.20 (2H, m), 3.90–

3.96 (2H, m), 3.78 (1H, br s), 2.58–2.64 (1H, m), 2.36

(3H, s), 2.24–2.32 (12/10H, m), 1.27 (3H, t, J¼7.5 Hz).

HRMS m/z: Calcd for C₂₇H₂₉DN₂O₅S (M⁺) 495.1937.

Found: 495.1937. Incorporation of D was 83% from the

NMR spectrum.

trans-Tetrahydro-N,N-dimethyl-1-[(4-methylphenyl)sulfonyl]-

4-[(phenylmethoxy)amino]quinoline-3-acetamide (trans-12).

A colorless oil. IR n_maxcm^ꢂ1: 3671 (NH), 1639 (CON),

1

1350, 1164 (NSO₂). H NMR (500 MHz) d: 7.70 (2H, br

d, J¼8 Hz), 7.64 (1H, br d, J¼8 Hz), 7.35–7.23 (8H, m),

7.18 (1H, br t, J¼8 Hz), 7.01 (1H, br t, J¼8 Hz), 4.60 and

4.51 (2H, ABq, J¼12 Hz), 4.05 (1H, dd, J¼13, 4.5 Hz),

3.89 (1H, dd, J¼13, 3.5 Hz), 3.84 (1H, d, J¼2.5 Hz), 2.96

and 2.88 (each 3H, s), 2.92–2.85 (1H, m), 2.38 (1H, dd,

J¼16, 9 Hz), 2.37 (3H, s), 2.18 (1H, dd, J¼16, 5.5 Hz). NO-

ESY: NOE was observed between 1⁰-H (d 2.38) and 2-Heq (d

4.05), and 1⁰-H (d 2.18) and 4-H (d 3.84), and 4-H (d 3.84)

and 2-Heq (d 4.05). ¹³C NMR (50 MHz) d: 170.7, 143.6,

137.6, 137.2, 131.1, 129.7, 128.50, 128.45, 128.3, 127.8,

127.0, 124.5, 123.5, 120.5, 76.8, 61.1, 46.8, 37.2, 35.5,

33.3, 31.3, 21.5. HRMS m/z: Calcd for C₂₇H₃₁N₃O₄S (M⁺)

493.2033. Found: 493.2042.

4.2.22. Conversion of cis-3a into cis-2a in the presence of

Bu₃SnNMe₂[Table 6, entry 2]. To a boiling solution of cis-

3a (50 mg, 0.1 mmol) in benzene (3 mL) was added

Bu₃SnNMe₂(28 mg, 0.1 mmol) under a nitrogen atmo-

sphere. After being stirred at reﬂux for 2 h, Bu₃SnNMe₂

(155 mg, 0.6 mmol) was added three times for every 2 h. Af-

ter being stirred at reﬂux for 6 h, the reaction mixture was

concentrated at reduced pressure. The residue was puriﬁed

by FCC (hexane/AcOEt 10:1) to afford cis-2a (1.0 mg,

2%) and 9a (3.1 mg, 7%).

4.2.23. [Table 6, entry 3]. To a solution of cis-3a (28 mg,

0.056 mmol) was added Bu₃SnNMe₂(21 mg, 0.075 mmol)

under a nitrogen atmosphere at 110 ^ꢁC. After being stirred

at 110 ^ꢁC for 3 h, Bu₃SnNMe₂(52 mg, 0.19 mmol) was

added two times for every 1 h. After being stirred at

110 ^ꢁC for 3 h, the reaction mixture was extracted with

hexane/MeCN. The MeCN phase was concentrated at re-

duced pressure. The residue was puriﬁed by PTLC (AcOEt)

to afford cis-2a (6.5 mg, 34%), 9a (7.1 mg, 28%), and cis-12

(4.5 mg, 16%).

4.2.26. [Table 6, entry 7]. According to the procedure de-

scribed in the conversion of cis-3a into cis-2a in the presence

of Bu₃SnNMe₂(Table 6, entry 4), reaction of trans-3a

(50 mg, 0.10 mmol) with Bu₃SnH (0.052 mL, 0.19 mmol)

and Bu₃SnNMe₂(128 mg, 0.38 mmol) in benzene (1 mL)

in the presence of AIBN (3.1 mg, 0.019 mmol) gave trans-

12 (35 mg, 74%) as a colorless oil.

4.2.27. Conversion of 9a into cis-2a in the presence of

Bu₃SnNMe₂[Table 7, entry 2]. According to the procedure

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10109

described in the conversion of cis-3a into cis-2a in the pres-

ence of Bu₃SnNMe₂(Table 6, entry 3), reaction of 9a

(50 mg, 0.11 mmol) with Bu₃SnNMe₂(132 mg, 0.48 mmol)

gave cis-2a (12 mg, 33%) and 9a (30 mg, 60%).

d: 165.2, 143.6, 143.2, 141.1, 136.6, 136.4, 135.2, 132.0,

129.6, 129.5, 128.6, 128.3, 128.2, 127.6, 126.1, 124.6,

124.2, 122.3, 60.3, 52.6, 21.4, 14.0. HRMS m/z: Calcd for

C₃₂H₃₁N₃O₄S (M⁺) 553.2033. Found: 553.2031.

4.2.28. [Table 7, entry 3]. According to the procedure de-

scribed in the conversion of cis-3a into cis-2a in the presence

of Bu₃SnNMe₂(Table 6, entry 4), reaction of 9a (50 mg,

0.11 mmol) with Bu₃SnH (0.059 mL, 0.22 mmol) and

Bu₃SnNMe₂(42 mg, 0.15 mmol) in benzene (1 mL) in the

presence of AIBN (3.6 mg, 0.022 mmol) gave cis-2a

(32 mg, 83%).

4.3.3. Ethyl-(2E)-4-[[(4-methylphenyl)sulfonyl][2-[(1E)-

(phenylmethyl)imino]phenyl]amino]-2-butenoate (1j).

To a solution of 6 (100 mg, 0.33 mmol) in CH₂Cl₂

(11 mL) was added MnO₂(995 mg, 11 mmol) under nitro-

gen atmosphere at room temperature. After being stirred at

room temperature for 2 h, the reaction mixture was ﬁltered

through a pad of Celite and the ﬁltrate was concentrated at

reduced pressure to give the crude aldehyde as a colorless

solid. ¹H NMR spectrum of the residue proved the formation

of desired aldehyde, which without further puriﬁcation was

subjected to the following reaction. To a solution of the

crude aldehyde in CH₂Cl₂(2 mL) were added BnNH₂

(0.039 mL, 0.36 mmol) and Al₂O₃(100 mg, 0.98 mmol) un-

der a nitrogen atmosphere at room temperature. After being

stirred at room temperature for 1.5 h, the reaction mixture

was ﬁltered, diluted with water, and extracted with CHCl₃.

The organic phase was washed with brine, dried over

MgSO₄, and concentrated at reduced pressure. The residue

was puriﬁed by recrystallization from EtOH to afford corre-

sponding imine (88 mg 70%) as yellow crystals and a 2:1

mixture of E- and Z-isomers. Mp 116–119 ^ꢁC (EtOH). IR

n_maxcm^ꢂ1: 3690 (NH), 1383, 1169 (NSO₂). ¹H NMR

(200 MHz) d: 8.33 (2/3H, s), 8.22 (1/3H, d, J¼8, 2 Hz),

7.95 (1/3H, s), 7.71–6.96 (12H+2/3H, m), 4.81 (4/3H, s),

4.39 (2/3H, s), 2.40 and 2.30 (each 3H, s). ¹³C NMR

(50 MHz) d: 165.2, 144.5, 141.1, 140.7, 134.6, 133.9,

133.4, 131.1, 129.8, 128.9, 127.8, 124.8, 115.9, 114.4,

60.5, 51.9, 21.5, 14.0. HRMS m/z: Calcd for C₂₁H₂₀N₂O₂S

(M⁺) 364.1244. Found: 364.1254. Anal. Calcd for

C₂₁H₂₀N₂O₂S$1/5 EtOH: C, 68.78; H, 5.72; N, 7.50. Found:

C, 68.61; H, 5.52; N, 7.40. According to the procedure given

for alkylation of 7a,b, reaction of imine (1.1 g, 2.9 mmol)

with ethyl 4-bromocrotonate (0.40 mL, 2.9 mmol) in the

presence of K₂CO₃(1.6 g, 12 mmol) gave 1j (1.1 g, 80%)

as a pale yellow oil. IR n_maxcm^ꢂ1: 1717 (COO), 1355,

4.3. Radical reaction of oxime ether 1a in the presence of

Ph₃SnH

According to the procedure given for radical reaction of 1a

in the presence of Bu₃SnH, reaction of 1a (529 mg,

1.08 mmol) with Ph₃SnH (1.25 g, 4.3 mmol) in the presence

of AIBN (70.5 mg, 0.43 mmol) gave cis-2a (126 mg, 34%)

and trans-2a (127 mg, 35%).

4.3.1. Ethyl-(2E)-4-[(2-cyanophenyl)[(4-methylphenyl)-

sulfonyl]amino]-2-butenoate (1h). According to the

procedure given for alkylation of 7a,b, reaction of N-[2-

cyanophenyl]-4-methyl-benzenesulfonamide (7e)¹¹(2 g,

7.34 mmol) with ethyl 4-bromocrotonate (1.2 mL,

8.8 mmol) in the presence of K₂CO₃(4.6 g, 33 mmol) gave

1h (2.25 g, 80%) as colorless crystals. Mp 81–83 ^ꢁC

(EtOH/hexane). IR n_maxcm^ꢂ1: 2234 (CN), 1716 (COO),

1360, 1165 (NSO₂). ¹H NMR (200 MHz) d: 7.66–7.26 (8H,

m), 6.82 (1H, dt, J¼16, 6 Hz), 5.90 (1H, br d, J¼16 Hz),

4.41 (2H, br d, J¼6 Hz), 4.15 (2H, q, J¼7 Hz), 2.45 (3H,

s), 1.25 (3H, t, J¼7 Hz). ¹³C NMR (75 MHz) d: 165.3,

144.6, 141.2, 140.8, 137.3, 134.0, 133.5, 131.4, 129.9,

129.0, 127.9, 124.9, 116.0, 114.4, 60.6, 51.9, 21.6, 14.1.

HRMS m/z: Calcd for C₂₀H₂₀N₂O₄S (M⁺) 384.1142. Found:

384.1136. Anal. Calcd for C₂₀H₂₀N₂O₄S: C, 62.48; H, 5.24;

N, 7.29. Found: C, 62.45; H, 5.29; N, 7.28.

1

4.3.2. Ethyl-(2E)-4-[[(4-methylphenyl)sulfonyl][2-[(1E)-

(diphenylhydrazono)methyl]phenyl]amino]-2-butenoate

(1i). According to the procedure described in the preparation

of 7a,b, oxidation of 6 (300 mg, 1.08 mmol) with MnO₂

(3.3 g, 38 mmol) gave crude aldehyde. Condensation of

crude aldehyde with Ph₂NNH₂$HCl (240 mg, 1.09 mmol)

gave the corresponding hydrazone (288 mg 65%) as pale yel-

1164 (NSO₂). H NMR (200 MHz) d: 8.64 (1H, s), 8.16

(1H, dd, J¼7, 2 Hz), 7.54–7.24 (11H, m), 6.80 (1H, dt,

J¼16, 7 Hz), 6.72 (1H, dd, J¼7, 2 Hz), 5.81 (1H, br d,

J¼16 Hz), 4.77 (2 h, s), 4.42 (2H, m), 4.11 (2H, q, J¼

7 Hz), 2.39 (3H, s), 1.21 (3H, t, J¼7 Hz). ¹³C NMR

(50 MHz) d: 165.0, 158.3, 144.0, 138.9, 138.6, 135.9,

134.6, 130.8, 129.54, 129.47, 128.6, 128.2, 128.0, 127.8,

127.6, 126.7, 124.6, 65.0, 60.3, 52.8, 21.3, 13.9. HRMS m/z:

Calcd for C₂₇H₂₈N₂O₄S (M⁺) 476.1768. Found: 476.1777.

low crystals. Mp 197–198 ^ꢁC (EtOH). IR n_max(KBr) cm^ꢂ1

:

1

3467 (NH), 1343, 1159 (NSO₂). H NMR (300 MHz) d:

8.25 (1H, dd, J¼8, 2 Hz), 7.63–6.87 (18H, m), 2.44 (3H, s).

¹³C NMR (50 MHz) d: 144.6, 142.9, 137.5, 136.1, 132.2,

131.9, 131.2, 130.2, 129.4, 128.4, 127.8, 126.2, 124.4, 122.2,

21.5. HRMS m/z: Calcd for C₂₆H₂₃N₃O₂S (M⁺) 441.1510.

Found: 441.1521. According to the procedure given for al-

kylation of 7a,b, reaction of hydrazone (200 mg, 0.45 mmol)

with ethyl 4-bromocrotonate (0.06 mL, 0.45 mmol) in the

presence of K₂CO₃(250 mg, 1.80 mmol) gave 1i (192 mg,

77%) as a pale yellow oil. IR n_maxcm^ꢂ1: 1718 (COO),

4.3.4. Ethyl-(2E)-4-[[2-(hydroxymethyl)phenyl][(4-meth-

ylphenyl)sulfonyl]amino]-2-butenoate. According to the

procedure given for alkylation of 7a,b, reaction of 6

(200 mg, 0.72 mmol) with ethyl 4-bromocrotonate

(0.12 mL, 0.86 mmol) in the presence of K₂CO₃(398 mg,

2.9 mmol) gave the corresponding butenoate (153 mg,

55%) as colorless crystals. Mp 124–125 ^ꢁC (Et₂O/CHCl₃).

IR n_maxcm^ꢂ1: 3522 (OH), 1717 (COO), 1343, 1162

1

1352, 1163 (NSO₂). H NMR (300 MHz) d: 8.20 (1H, dd,

(NSO₂). H NMR (200 MHz) d: 7.63–7.11 (7H, m), 6.76

J¼8, 1.5 Hz), 7.48–7.11 (17H, m), 6.68 (1H, dd, J¼8,

1.5 Hz), 6.55 (1H, dt, J¼16, 7 Hz), 5.67 (1H, br d, J¼

16 Hz), 4.20 (1H, m), 4.13 (2H, q, J¼7 Hz), 3.88 (1H, m),

2.41 (3H, s), 1.23 (3H, t, J¼7 Hz). ¹³C NMR (50 MHz)

(1H, dt, J¼16, 6 Hz), 6.48 (1H, dd, J¼8, 1 Hz), 5.76 (1H,

dt, J¼16, 2 Hz), 4.91 (1H, br s), 4.55 (2H, br s), 4.13 (2H, q,

J¼7 Hz), 4.01 (1H, very br), 3.02 (1H, br t, J¼6 Hz), 2.46

(3H, s), 1.24 (3H, t, J¼7 Hz). ¹³C NMR (50 MHz)

10110

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

d: 165.3, 144.2, 142.0, 140.8, 136.8, 134.4, 131.0, 129.6,

129.2, 128.4, 128.0, 127.4, 124.8, 60.9, 60.5, 53.0, 21.5,

14.0. HRMS m/z: Calcd for C₂₀H₂₃NO₅S (M⁺) 389.1295.

Found: 389.1289. Anal. Calcd for C₂₀H₂₃NO₅S$1/15CHCl₃:

C, 60.64; H, 5.85; N, 3.52. Found: C, 60.62; H, 5.60; N, 3.47.

7.30–7.26 (5H, m, J¼8.5 Hz), 7.17–7.14 (2H, m), 7.06–

7.02 (6H, m), 6.91 (1H, td, J¼8.5, 1 Hz), 6.79 (1H, dd,

J¼7.5, 1 Hz), 4.31 (1H, dd, J¼12, 3 Hz), 4.08 (2H, m),

4.04 (1H, dd, J¼12, 3 Hz), 3.72 (1H, br s), 2.84–2.81

(1H, m), 2.40 (3H, s), 2.37 (1H, dd, J¼16, 7 Hz), 2.29

(1H, br s), 2.07 (1H, dd, J¼16, 7 Hz), 1.18 (3H, t,

J¼7 Hz). NOESY: NOE was observed between 1⁰-H (d

2.07) and 4-H (d 3.72), and 1⁰-H (d 2.37) and 2-H (d

4.31). ¹³C NMR (125 MHz) d: 171.9, 148.4, 143.8, 137.4,

137.2, 130.8, 129.8, 129.3, 129.3, 128.8, 127.0, 123.6,

123.3, 123.1, 121.0, 119.7, 60.6, 57.4, 46.1, 34.3, 30.5,

21.6, 14.8. HRMS m/z: Calcd for C₃₂H₃₃N₃O₄S (M⁺)

555.2190. Found: 555.2188.

4.3.5. Radical reaction of nitrile 1h [Scheme 12]. To a boil-

ing solution of 1h (200 mg, 0.52 mmol) in benzene (3.7 mL)

was added a solution of Bu₃SnH (0.28 mL, 1.0 mmol) and

AIBN (17.1 mg, 0.104 mmol) in benzene (3.7 mL) by sy-

ringe pump under a nitrogen atmosphere. After being stirred

at reﬂux for 3 h, a solution of Bu₃SnH (0.28 mL, 1.04 mmol)

and AIBN (17 mg, 0.10 mmol) in benzene (2 mL) was added

by syringe pump. After being stirred at reﬂux for 5 h, the

reaction mixture was extracted with hexane/MeCN. The

MeCN phase was concentrated at reduced pressure. The

residue was puriﬁed by MCC (hexane/AcOEt 3:1) to afford

7e (83.5 mg, 59%).

cis-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sulfonyl]-

1-(diphenylamino)-2H-pyrrolo[3,2-c]quinolin-2-one (cis-

9i). Pale yellow crystals. Mp 230–231 ^ꢁC (CHCl₃/hexane).

1

IR n_maxcm^ꢂ1: 1716 (g-lactam), 1360, 1166 (NSO₂). H

NMR (500 MHz) d: 7.75 (1H, br d, J¼8.5 Hz), 7.53 (2H,

br d, J¼8.5 Hz), 7.31–7.20 (6H, m), 7.09 (1H, dd, J¼8.5,

1.5 Hz), 7.03–6.94 (5H, m), 6.82 (1H, br t, J¼8.5 Hz),

6.51 (2H, br d, J¼8.5 Hz), 4.69 (1H, d, J¼7.5 Hz), 4.11

(1H, dd, J¼14, 4.5 Hz), 3.49 (1H, dd, J¼14, 10.5 Hz),

2.72 (1H, dd, J¼17.5, 8.5 Hz), 2.55–2.51 (1H, m), 2.38

(3H, s), 2.26 (1H, dd, J¼17.5, 2 Hz). ¹³C NMR (125 MHz)

d: 171.3, 145.0, 144.2, 143.2, 137.3, 136.8, 132.3, 129.9,

129.6, 129.3, 128.8, 127.0, 125.2, 124.1, 123.4, 123.3,

122.7, 120.2, 118.6, 54.3, 47.7, 31.9, 28.1, 21.6. HRMS m/

z: Calcd for C₃₀H₂₇N₃O₃S (M⁺) 509.1771. Found:

509.1767. Anal. Calcd for C₃₀H₂₇N₃O₃S$1/6 CHCl₃: C,

68.43; H, 5.17; N, 7.94. Found: C, 68.52; H, 5.35; N, 8.01.

4.3.6. Radical reaction of hydrazone 1i [Scheme 13]. To

a boiling solution of 1i (200 mg, 0.36 mmol) in benzene

(2.5 mL) was added a solution of Bu₃SnH (0.19 mL,

0.72 mmol) and AIBN (12 mg, 0.072 mmol) in benzene

(2.5 mL)bysyringepumpundera nitrogen atmosphere. After

being stirred at reﬂux for 4 h, a solution of Bu₃SnH (0.19 mL,

0.72 mmol) and AIBN (12 mg, 0.072 mmol) in benzene

(2 mL) was added by syringe pump. After being stirred at re-

ﬂux for 8 h, a solution of AIBN (11.8 mg, 0.072 mmol) in

benzene (2 mL) was added by syringe pump. After being

stirred at reﬂux for 1 h, the reaction mixture was extracted

with hexane/MeCN. The MeCN phase was concentrated at

reduced pressure. The residue was puriﬁed by MCC (hex-

ane/AcOEt 3:1) to afford cis-2a (11 mg, 9%), trans-2a

(19 mg, 15%), cis-3i (57 mg, 28%), trans-3i (11 mg, 6%),

cis-9i (6.2 mg, 3%), and diphenylamine (14) (17 mg, 29%).

Diphenylamine was identical with authentic sample.

4.3.7. Radical reaction of imine 1j [Scheme 14]. To a boil-

ing solution of 1j (250 mg, 0.51 mmol) in benzene (4 mL)

was added a solution of Bu₃SnH (0.27 mL, 1.0 mmol) and

AIBN (17 mg, 0.10 mmol) in benzene (3.6 mL) by syringe

pump under nitrogen atmosphere. After being stirred at re-

ﬂux for 1 h, a solution of Bu₃SnH (0.27 mL, 1.02 mmol)

and AIBN (16.7 mg, 0.102 mmol) in benzene (2 mL) was

added by syringe pump. After being stirred at reﬂux for

2 h, the reaction mixture was extracted with hexane/

MeCN. The MeCN phase was concentrated at reduced pres-

sure. The residue was puriﬁed by MCC (hexane/AcOEt 3:1)

to afford cis-15 (32 mg, 11%), trans-15 (21 mg, 7%), trans-

3j (9.4 mg, 4%), trans-10a (43 mg, 17%), and cis-2a

(34 mg, 20%).

Ethyl cis-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulfonyl]-

4-(2,2-diphenylhydrazino)quinoline-3-acetate (cis-3i). Pale

yellow crystals. Mp 139–140 ^ꢁC (hexane/Et₂O). IR n_max

1

cm^ꢂ1: 3571 (NH), 1725 (COO), 1353, 1167 (NSO₂). H

NMR (500 MHz) d: 7.94 (1H, br d, J¼8.5 Hz), 7.58 (2H,

br d, J¼8.5 Hz), 7.30 (4H, br t, J¼8.5 Hz), 7.21–7.17 (3H,

m), 7.07 (2H, br t, J¼7.5 Hz), 7.00 (4H, br d, J¼8.5 Hz),

6.89 (1H, td, J¼8.5, 1 Hz), 6.44 (1H, dd, J¼7.5, 1 Hz),

4.19 (1H, ddd, J¼12, 4, 1 Hz), 4.14–4.07 (2H, m), 4.06

(1H, br s), 3.80 (1H, t, J¼12 Hz), 3.17 (1H, br s), 2.62

(1H, dd, J¼16, 7 Hz), 2.31 (3H, s), 2.27 (1H, dd, J¼16,

7 Hz), 2.24–2.20 (1H, m), 1.19 (3H, t, J¼7.5 Hz). NOESY:

NOE was observed between 1⁰-H (d 2.27) and 2-Hax (d

3.80), and 3-H (d 2.24–2.20) and 4-H (d 4.06). ¹³C NMR

(125 MHz) d: 172.1, 148.9, 143.9, 136.8, 135.8, 129.61,

129.60, 129.33, 129.29, 128.6, 128.2, 127.3, 124.2, 123.5,

122.4, 121.5, 60.5, 55.3, 46.7, 33.77, 33.76, 21.5, 14.8.

HRMS m/z: Calcd for C₃₂H₃₃N₃O₄S (M⁺) 555.2190. Found:

555.2187. Anal. Calcd for C₃₂H₃₃N₃O₄S$1/3Et₂O: C, 68.98;

H, 6.31; N, 7.24. Found: C, 68.80; H, 6.03; N, 7.36.

Ethyl cis-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulfonyl]-

4-[(phenylmethylene)amino]quinoline-3-acetate (cis-15).

A Colorless solid. IR n_maxcm^ꢂ1: 1727 (COO), 1352, 1166

1

(NSO₂). H NMR (200 MHz) d: 8.16 (1H, s), 7.98 (1H, br

d, J¼8.5 Hz), 7.63–7.56 (4H, m), 7.45–6.93 (8H, m), 4.26–

4.20 (2H, m), 4.13 (2H, q, J¼7 Hz), 3.78 (1H, dd, J¼13,

11 Hz), 2.50–2.17 (3H, m), 2.30 (3H, s), 1.23 (3H, t,

J¼7 Hz). ¹³C NMR (75 MHz) d: 171.7, 160.8, 143.6, 136.2,

136.1, 135.7, 131.0, 129.9, 129.5, 128.5, 128.40, 128.36,

127.3, 124.1, 122.3, 67.9, 60.6, 47.0, 34.3, 34.1, 21.5, 14.2.

HRMS m/z: Calcd for C₂₇H₂₈N₂O₄S (M⁺) 476.1768. Found:

476.1762.

Ethyl trans-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulfo-

nyl]-4-(2,2-diphenylhydrazino)quinoline-3-acetate (trans-

3i). A pale yellow oil. IR n_maxcm^ꢂ1: 3681 (NH), 1727

(COO), 1351, 1165 (NSO₂). ¹H NMR (500 MHz) d:

7.76 (2H, br d, J¼8.5 Hz), 7.68 (1H, dd, J¼8.5, 1 Hz),

Ethyl trans-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulfonyl]-

4-[(phenylmethylene)amino]quinoline-3-acetate (trans-15).

A Colorless solid. IR n_maxcm^ꢂ1: 1728 (COO), 1351, 1165

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10111

(NSO₂). ¹H NMR (200 MHz) d: 8.16 (1H, s), 7.84 (1H, br d,

J¼8.5 Hz), 7.68–7.59 (4H, m), 7.45–6.91 (8H, m), 4.29 (1H,

dd, J¼13, 4 Hz), 4.10 (2H, m), 3.97 (1H, br d, J¼7 Hz), 3.76

(1H, dd, J¼13, 8 Hz), 2.57–2.43 (1H, m), 2.41–2.17 (2H,

m), 2.37 (3H, s), 1.23 (3H, t, J¼7 Hz). ¹³C NMR (75 MHz)

d: 171.4, 162.1, 143.7, 136.4, 136.1, 135.6, 131.1, 129.6,

129.0, 128.5, 128.4, 128.0, 127.2, 124.3, 122.5, 70.4, 60.6,

48.2, 35.41, 35.35, 21.5, 14.1. HRMS m/z: Calcd for

C₂₇H₂₈N₂O₄S (M⁺) 476.1768. Found: 476.1741.

0.14 mmol) in benzene (5 mL) by syringe pump under a

nitrogen atmosphere. After being stirred at reﬂux for 3 h,

a solution of Bu₃SnH (0.38 mL, 1.4 mmol) and AIBN

(23 mg, 0.14 mmol) in benzene (2 mL) was added by sy-

ringe pump. After being stirred at reﬂux for 2 h, the reaction

mixture was extracted with hexane/MeCN. The MeCN

phase was concentrated at reduced pressure. The residue

was puriﬁed by MCC (hexane/AcOEt 1:1) to afford cis-2c

(130 mg, 59%), trans-2c (6 mg, 3%), and 3k (72 mg, 29%).

Ethyl trans-1,2,3,4-tetrahydro-1-[(4-methylphenyl)sulfo-

nyl]-4-[(phenylmethyl)amino]quinoline-3-acetate (trans-

3j). Pale yellow crystals. Mp 83–85 ^ꢁC (EtOH/hexane). IR

n_max(KBr) cm^ꢂ1: 3339 (NH), 1724 (COO), 1336, 1158

(NSO₂). H NMR (500 MHz) d: 7.79 (1H, br d, J¼8 Hz),

cis-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sulfonyl]-

2H-furo[3,2-c]quinolin-2-one (cis-2c). Colorless crystals.

Mp 158–159 ^ꢁC (EtOH). IR n_max(KBr) cm^ꢂ1: 1780 (g-lac-

tone), 1348, 1167 (NSO₂). ¹H NMR (500 MHz) d: 7.70 (1H,

br d, J¼8 Hz), 7.55 (2H, br d, J¼8 Hz), 7.44 (1H, br d,

J¼8 Hz), 7.37 (1H, br t, J¼8 Hz), 7.27–7.24 (3H, m), 5.09

(1H, d, J¼6.5 Hz), 4.27 (1H, dd, J¼14, 5 Hz), 3.09 (1H,

dd, J¼14, 12.5 Hz), 2.84 (1H, dd, J¼18, 8.5 Hz), 2.67–

2.64 (1H, m), 2.41 (3H, s), 2.28 (1H, dd, J¼18, 2 Hz). ¹³C

NMR (125 MHz) d: 174.5, 144.3, 136.9, 136.7, 131.0,

130.0, 129.8, 127.0, 125.9, 125.3, 124.4, 75.2, 46.5, 32.9,

32.8, 21.6. HRMS m/z: Calcd for C₁₈H₁₇NO₄S (M⁺)

343.0877. Found: 343.0889. Anal. Calcd for C₁₈H₁₇NO₄S:

C, 62.96; H, 4.99; N, 4.08. Found: C, 62.69; H, 5.00; N, 4.03.

1

7.64 (2H, br d, J¼8 Hz), 7.31–7.15 (9H, m), 7.07 (1H, td,

J¼8, 1 Hz), 4.18–4.13 (3H, m), 3.78 (1H, dd, J¼13, 7 Hz),

3.50 (1H, br d, J¼5.5 Hz), 3.40 and 3.24 (2H, ABq, J¼

13 Hz), 2.51–2.49 (1H, m), 2.33 (1H, dd, J¼16.5, 6.5 Hz),

2.24 (3H, s), 2.25 (1H, dd, J¼16.5, 7.5 Hz), 1.27 (3H, t,

J¼7 Hz). NOESY: NOE was observed between 1⁰-H (d

2.33) and 4-H (d 3.50), and 3-H (d 2.51–2.49) and OCH₂Ph

(d 3.40 and 3.24). ¹³C NMR (125 MHz) d: 172.1, 143.8,

140.1, 137.0, 136.6, 129.62, 129.57, 129.0, 128.4, 128.0,

127.2, 127.0, 124.4, 122.4, 60.7, 58.1, 49.4, 35.5, 32.2, 21.4,

14.2. HRMS m/z: Calcd for C₂₇H₃₀N₂O₄S (M⁺) 478.1925.

Found: 478.1907. Anal. Calcd for C₂₇H₃₀N₂O₄S$1/3 EtOH:

C, 67.27; H, 6.53; N, 5.67. Found: C, 67.05; H, 6.41; N, 5.53.

trans-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sulfonyl]-

2H-furo[3,2-c]quinolin-2-one (trans-2c). Colorless solid. IR

n_maxcm^ꢂ1: 1797 (g-lactone), 1354, 1168 (NSO₂). ¹H NMR

(500 MHz) d: 7.83 (1H, br d, J¼8 Hz), 7.41–7.35 (3H, m),

7.25–7.20 (4H, m), 4.07 (1H, dd, J¼11.5, 6 Hz), 3.85 (1H,

d, J¼11 Hz), 3.54 (1H, br t, J¼11.5 Hz), 2.75 (1H, dd,

J¼16, 6.5 Hz), 2.40 (3H, s), 2.36 (1H, dd, J¼16, 13 Hz),

2.29–2.24 (1H, m). ¹³C NMR (125 MHz) d: 174.3, 144.4,

134.7, 133.4, 131.5, 129.9, 128.6, 126.8, 126.3, 125.8,

121.4, 78.1, 48.3, 42.7, 34.5, 21.6. HRMS m/z: Calcd for

C₁₈H₁₇NO₄S (M⁺) 343.0877. Found: 343.0880.

4.4. Ethyl-(2E)-4-[[2-(acetylphenyl)][(4-methylphenyl)-

sulfonyl]amino]-2-butenoate (1l)

According to the procedure given for alkylation of 7a,b,

reaction of N-(2-acetylphenyl)-4-methyl-benzenesulfon-

amide²²(500 mg, 1.7 mmol) with ethyl 4-bromocrotonate

(0.29 mL, 2.1 mmol) in the presence of K₂CO₃(956 mg,

6.9 mmol) gave 1l (675.1 mg, 97%) as colorless crystals.

Mp 88–91 ^ꢁC (EtOH). IR n_max(neat) cm^ꢂ1: 1717 (COO),

Ethyl cis-1,2,3,4-tetrahydro-4-hydroxy-1-[(4-methylphenyl)-

sulfonyl]quinoline-3-acetate (3k). A colorless oil. IR n_max

(neat) cm^ꢂ1: 3507 (OH), 1732 (COO), 1349, 1164 (NSO₂).

¹H NMR (500 MHz) d: 7.75 (1H, br d, J¼8 Hz), 7.60 (2H,

br d, J¼8 Hz), 7.39 (1H, br d, J¼8 Hz), 7.27–7.22 (3H,

m), 7.13 (1H, td, J¼8, 1 Hz), 4.23 (1H, br d, J¼7.5 Hz),

4.17 (2H, q, J¼7 Hz), 4.09 (1H, dd, J¼13, 4 Hz), 3.65

(1H, dd, J¼13, 8.5 Hz), 2.44 (1H, dd, J¼16, 6.5 Hz), 2.38

(3H, s), 2.32 (1H, dd, J¼16, 6.5 Hz), 2.24–2.20 (1H, m),

1.28 (3H, t, J¼7 Hz). ¹³C NMR (125 MHz) d: 172.2,

143.9, 136.3, 135.8, 130.3, 129.7, 128.6, 128.3, 127.1,

124.7, 122.3, 70.3, 60.9, 47.9, 36.9, 35.1, 21.5, 14.2.

HRMS m/z: Calcd for C₂₀H₂₃NO₅S (M⁺) 389.1296. Found:

389.1317.

1

1699 (CO), 1350, 1164 (NSO₂). H NMR (200 MHz) d:

7.63 (1H, dd, J¼7, 2 Hz), 7.47–7.23 (6H, m), 6.95 (1H, dt,

J¼16, 7 Hz), 6.79 (1H, dd, J¼7, 2 Hz), 5.88 (1H, dt, J¼16,

1 Hz), 4.41 (2H, br d, J¼7 Hz), 4.14 (2H, q, J¼7 Hz), 2.56

(3H, s), 2.42 (3H, s), 1.26 (3H, t, J¼7 Hz). ¹³C NMR

(50 MHz) d: 201.1, 165.5, 143.9, 141.6, 141.2, 136.1,

135.2, 131.4, 129.5, 129.4, 129.2, 128.5, 127.8, 124.6, 60.5,

52.8, 29.9, 21.5, 14.1. HRMS m/z: Calcd for C₂₁H₂₃NO₅S

(M⁺) 401.1295. Found: 401.1302. Anal. Calcd for

C₂₁H₂₃NO₅S: C, 62.82; H, 5.77; N, 3.49. Found: C, 62.80;

H, 5.78; N, 3.47.

4.4.1. Radical reaction of aldehyde 1k [Table 8, entry 1].

To a solution of ethyl-(2E)-4-[[2-(hydroxymethyl)phenyl]-

[(4-methylphenyl)sulfonyl]amino]-2-butenoate (250 mg,

0.64 mmol) in CH₂Cl₂(28 mL) was added MnO₂(1.9 g,

22 mmol) under a nitrogen atmosphere at room temperature.

After being stirred at room temperature for 2 h, the reaction

mixture was ﬁltered through a pad of Celite and the ﬁltrate

was concentrated at reduced pressure to give the crude alde-

hyde 1k as a colorless solid. ¹H NMR spectrum of the resi-

due proved the formation of desired aldehyde, which without

further puriﬁcation was subjected to the following reaction.

To a boiling solution of 1k in benzene (5 mL) was added a so-

lution of Bu₃SnH (0.38 mL, 1.4 mmol) and AIBN (23 mg,

4.4.2. Radical reaction of ketone 1l [Table 8, entry 2]. To

a boiling solution of 1l (224 mg, 0.56 mmol) in benzene

(4 mL) was added a solution of Bu₃SnH (0.30 mL,

1.1 mmol) and AIBN (18 mg, 0.12 mmol) in benzene

(4 mL) by syringe pump under a nitrogen atmosphere. After

being stirred at reﬂux for 2 h, a solution of Bu₃SnH

(0.30 mL, 1.1 mmol) and AIBN (18 mg, 0.12 mmol) in ben-

zene (2 mL) was added by syringe pump. After being stirred

at reﬂux for 3 h, the reaction mixture was extracted with hex-

ane/MeCN. The MeCN phase was concentrated at reduced

pressure. The residue was puriﬁed by MCC (hexane/AcOEt

10112

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

3:1) to afford cis-2d (105 mg, 52%), trans-2d (12 mg, 6%),

and 3l (55 mg, 24%).

(21 mg, 0.088 mmol) with p-TsOH$H₂O (17 mg,

0.088 mmol) gave cis-2d (17 mg, 53%).

cis-1,3,3a,4,5,9b-Hexahydro-9b-methyl-5-[(4-methylphenyl)-

sulfonyl]-2H-furo[3,2-c]quinolin-2-one (cis-2d). Colorless

crystals. Mp 172–175 ^ꢁC (EtOH). IR n_maxcm^ꢂ1: 1773 (g-

4.4.5. Radical reaction of aldehyde 1k in the presence of

Bu₃SnD [Table 9]. To a solution of ethyl-(2E)-4-[[2-

(hydroxymethyl)phenyl][(4-methylphenyl)sulfonyl]amino]-

2-butenoate (125 mg, 0.319 mmol) in CH₂Cl₂(14 mL) was

added MnO₂(964 mg, 11 mmol) under a nitrogen atmo-

sphere at room temperature. After being stirred at room tem-

perature for 2 h, the reaction mixture was ﬁltered through

a pad of Celite and the ﬁltrate was concentrated at reduced

pressure to give the crude aldehyde 1k as a colorless solid.

¹H NMR spectrum of the residue proved the formation of

desired aldehyde, which without further puriﬁcation was

subjected to the following reaction. To a boiling solution

of crude aldehyde 1k in benzene (2 mL) was added a solution

of Bu₃SnD (0.17 mL, 0.64 mmol) and AIBN (10 mg,

0.064 mmol) in benzene (2.5 mL) by syringe pump under

a nitrogen atmosphere. After being stirred at reﬂux for 2 h,

a solution of Bu₃SnD (0.17 mL, 0.64 mmol) and AIBN

(10 mg, 0.064 mmol) in benzene (2 mL) was added by

syringe pump. After being stirred at reﬂux for 1 h, the reac-

tion mixture was extracted with hexane/MeCN. The MeCN

phase was concentrated at reduced pressure. The residue was

puriﬁed by MCC (hexane/AcOEt 3:1) to afford cis-2c-D (D:

95%) (35 mg, 31%), trans-2c-D (D: 56%) (2.5 mg, 2%), and

3k-D (D: 66%) (24 mg, 19%).

1

lactone), 1358, 1166 (NSO₂). H NMR (500 MHz) d: 7.68

(1H, dd, J¼8, 1 Hz), 7.55 (2H, br d, J¼8 Hz), 7.49 (1H,

dd, J¼8, 1.5 Hz), 7.35 (1H, ddd, J¼8, 7, 1.5 Hz), 7.29–

7.24 (3H, m), 4.25 (1H, dd, J¼14, 5 Hz), 3.13 (1H, dd,

J¼14, 12 Hz), 2.88 (1H, dd, J¼18, 9 Hz), 2.54–2.48 (1H,

m), 2.40 (3H, s), 2.25 (1H, dd, J¼18, 2 Hz), 1.21 (3H, s).

NOESY: NOE was observed between 3a-H (d 2.54–2.48)

and 9b-Me (d 1.21). ¹³C NMR (125 MHz) d: 174.0, 144.3,

137.1, 135.6, 131.0, 129.9, 129.2, 128.6, 127.2, 126.5,

124.9, 82.0, 47.8, 32.9, 32.3, 28.5, 21.5. HRMS m/z: Calcd

for C₁₉H₁₉NO₄S (M⁺) 357.1033. Found: 357.1035. Anal.

Calcd for C₁₉H₁₉NO₄S: C, 63.85; H, 5.36; N, 3.92. Found:

C, 63.71; H, 5.38; N, 3.88.

trans-1,3,3a,4,5,9b-Hexahydro-9b-methyl-5-[(4-methylphe-

nyl)sulfonyl]-2H-furo[3,2-c]quinolin-2-one (trans-2d). A co-

lorless oil. IR n_maxcm^ꢂ1: 1784 (g-lactone), 1358, 1169

1

(NSO₂). H NMR (500 MHz) d: 7.97 (1H, br d, J¼8 Hz),

7.59 (2H, br d, J¼8 Hz), 7.32–7.23 (4H, m), 7.12 (1H, br

t, J¼8 Hz), 4.13 (1H, dd, J¼11, 5 Hz), 3.54 (1H, br dd,

J¼13, 11 Hz), 2.65–2.61 (1H, m), 2.55–2.49 (2H, m), 2.38

(3H, s), 0.80 (3H, s). NOESY: NOE was observed between

4-Hax (d 3.54) and 9b-Me (d 0.80). ¹³C NMR (125 MHz)

d: 174.1, 144.4, 135.1, 134.3, 133.6, 129.8, 128.5, 127.0,

124.3, 123.3, 121.6, 81.9, 46.1, 42.6, 31.3, 21.5, 19.5.

HRMS m/z: Calcd for C₁₉H₁₉NO₄S (M⁺) 357.1033. Found:

357.1029.

cis-3-d-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sul-

fonyl]-2H-furo[3,2-c]quinolin-2-one (cis-2c-D). Colorless

crystals. IR n_max(KBr) cm^ꢂ1: 1780 (g-lactone), 1358, 1165

1

(NSO₂). H NMR (300 MHz) d: 7.70 (1H, br d, J¼8 Hz),

7.54 (2H, br d, J¼8 Hz), 7.44 (1H, br d, J¼8 Hz), 7.44–

7.34 (2H, m), 7.27–7.22 (3H, m), 5.08 (1H, d, J¼6.5 Hz),

4.27 (1H, dd, J¼14, 5 Hz), 3.09 (1H, dd, J¼14, 12.5 Hz),

2.82 (2/5H, d, J¼8.5 Hz), 2.67–2.59 (1H, m), 2.41 (3H, s),

2.28 (3/5H, br s). ¹³C NMR (50 MHz) d: 174.5, 144.3,

136.8, 136.7, 130.9, 130.0, 129.7, 126.9, 125.8, 125.2,

124.3, 75.1, 46.5, 33.2, 32.7, 21.5. HRMS m/z: Calcd for

C₁₈H₁₆DNO₄S (M⁺) 344.0940. Found: 344.0942. Incorpora-

tion of D was 95% from the NMR spectrum.

Ethyl cis-1,2,3,4-tetrahydro-4-hydroxy-4-methyl-1-[(4-meth-

ylphenyl)sulfonyl]quinoline-3-acetate (3l). Colorless crys-

tals. Mp 120–121 ^ꢁC (EtOH). IR n_maxcm^ꢂ1: 3579 (OH),

1

1727 (COO), 1353, 1167 (NSO₂). H NMR (500 MHz) d:

7.86 (1H, dd, J¼8, 1.5 Hz), 7.56 (2H, br d, J¼8 Hz), 7.51

(1H, dd, J¼8, 1.5 Hz), 7.25–7.19 (3H, m), 7.11 (1H, td,

J¼8, 1.5 Hz), 4.21 (1H, dd, J¼13, 4.5 Hz), 4.17 (2H, q,

J¼7 Hz), 3.33 (1H, dd, J¼13, 11.5 Hz), 2.67 (1H, dd,

J¼16, 5 Hz), 2.36 (3H, s), 2.34–2.30 (1H, m), 2.15 (1H,

dd, J¼16, 8.5 Hz), 1.28 (3H, t, J¼7 Hz), 1.01 (3H, s). ¹³C

NMR (125 MHz) d: 172.2, 144.0, 136.4, 135.6, 134.7,

129.6, 128.1, 127.2, 125.5, 124.5, 122.0, 71.1, 61.0, 48.4,

40.6, 32.5, 23.8, 21.5, 14.2. HRMS m/z: Calcd for

C₂₁H₂₅NO₅S (M⁺) 403.1452. Found: 403.1433. Anal. Calcd

for C₂₁H₂₅NO₅S: C, 62.51; H, 6.25; N, 3.47. Found: C,

62.56; H, 6.16; N, 3.41.

trans-3-d-1,3,3a,4,5,9b-Hexahydro-5-[(4-methylphenyl)sul-

fonyl]-2H-furo[3,2-c]quinolin-2-one (trans-2c-D). Color-

less solid. IR n_maxcm^ꢂ1: 1789 (g-lactone), 1358, 1168

1

(NSO₂). H NMR (200 MHz) d: 7.84 (1H, br d, J¼8 Hz),

7.42–7.23 (7H, m), 4.08 (1H, dd, J¼11.5, 6 Hz), 3.86

(1H, d, J¼11 Hz), 3.54 (1H, br t, J¼11.5 Hz), 2.75 (2/

5H, m), 2.40 (3H, s), 2.34–2.17 (1H+3/5H, m). HRMS

m/z: Calcd for C₁₈H₁₆DNO₄S (M⁺) 344.0940. Found:

344.0935. Incorporation of D was 56% from the NMR

spectrum.

4.4.3. Conversion of 3k into cis-2c [Scheme 16]. To a solu-

tion of 3k (21 mg, 0.052 mmol) in benzene (1 mL) was

added p-TsOH$H₂O (10 mg, 0.052 mmol) under a nitrogen

atmosphere. After being stirred at 60 ^ꢁC for 1 h, the reaction

mixture was diluted with saturated aqueous NaHCO₃and ex-

tracted with Et₂O. The organic phase was washed with brine,

dried over MgSO₄, and concentrated under reduced pres-

sure. The residue was puriﬁed by PTLC (hexane/AcOEt

2:1) to afford cis-2c (16 mg, 91%).

Ethyl cis-1,2,3,4-tetrahydro-4-hydroxy-1-[(4-methylphenyl)-

sulfonyl]quinoline-3-(1-d)-acetate (3k-D). A colorless oil.

IR n_max(neat) cm^ꢂ1: 3509 (OH), 1731 (COO), 1340, 1165

1

(NSO₂). H NMR (200 MHz) d: 7.74 (1H, br d, J¼8 Hz),

7.60 (2H, br d, J¼8 Hz), 7.41–7.08 (5H, m), 4.24–4.05

(4H, m), 3.64 (1H, dd, J¼13, 8.5 Hz), 2.45–2.19 (1H+1H,

m), 2.38 (3H, s), 1.28 (3H, t, J¼7 Hz). ¹³C NMR

(75 MHz) d: 172.2, 143.9, 136.3, 135.8, 130.2, 129.7,

128.5, 128.4, 127.0, 124.6, 122.1, 70.2, 60.9, 47.8, 36.9,

35.0, 21.5, 14.1. HRMS m/z: Calcd for C₂₀H₂₂DNO₅S

4.4.4. Conversion of 3l into cis-2d [Scheme 16]. According

to the procedure given for cyclization of 3k, reaction of 3l

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10113

(M⁺) 390.1358. Found: 390.1361. Incorporation of D was

66% from the NMR spectrum.

(190 mL) was added slowly BH₃$Me₂S (2.0 M in THF,

9.5 mL, 19 mmol) under a nitrogen atmosphere at room tem-

perature. After being stirred at reﬂux for 9 h, 6 M aqueous

HCl at 0 ^ꢁC was added and the reaction mixture was stirred

at room temperature for 14 h. The reaction mixture was ba-

siﬁed with 10% aqueous NaOH at 0 ^ꢁC and concentrated at

reduced pressure. The residue was extracted with CHCl₃.

The organic phase was washed with brine, dried over

Na₂SO₄, and concentrated at reduced pressure. To a solution

of the residue and Et₃N (0.79 mL, 5.7 mmol) in CH₂Cl₂

(25 mL) was added AcCl (0.33 mL, 4.56 mmol) at 0 ^ꢁC. Af-

ter being stirred at reﬂux for 9 h, the reaction mixture was di-

luted with 10% aqueous HCl at 0 ^ꢁC and extracted with

CHCl₃. The organic phase was washed with brine, dried

over MgSO₄, and concentrated at reduced pressure. The res-

idue was puriﬁed by MCC (AcOEt) to afford 18 (1.34 g,

94%) as colorless crystals. Mp 144–146 ^ꢁC (EtOH). IR

4.4.6. Radical reaction of ketone 1l in the presence of

Bu₃SnD [Table 9]. To a boiling solution of 1l (218.0 mg,

0.54 mmol) in benzene (3.6 mL) was added a solution

of Bu₃SnD (0.29 mL, 1.1 mmol) and AIBN (17.7 mg,

0.11 mmol) in benzene (4 mL) by syringe pump under a ni-

trogen atmosphere. After being stirred at reﬂux for 2 h, a so-

lution of Bu₃SnD (0.29 mL, 1.1 mmol) and AIBN (17.7 mg,

0.11 mmol) in benzene (2 mL) was added by syringe pump.

After being stirred at reﬂux for 3 h, the reaction mixture was

extracted with hexane/MeCN. The MeCN phase was con-

centrated at reduced pressure. The residue was puriﬁed by

MCC (hexane/AcOEt 5:1) to afford cis-2d-D (D: 70%)

(76 mg, 39%), trans-2d-D (D: 100%) (26 mg, 14%), and

3l-D (D: 80%) (56 mg, 26%).

n_maxcm^ꢂ1

:

1635, 1416 (NCO, NSOO). ¹H NMR

cis-3-d-1,3,3a,4,5,9b-Hexahydro-9b-methyl-5-[(4-methylphe-

nyl)sulfonyl]-2H-furo[3,2-c]quinolin-2-one (cis-2d-D). Col-

orless crystals. IR n_maxcm^ꢂ1: 1769 (g-lactone), 1351, 1168

(300 MHz) d: 7.02–7.62 (16/2H, m), 4.87 (1/2H, d,

J¼8 Hz), 4.53 (1/2H, dd, J¼15.5, 9 Hz), 3.67 (1/2H, dd,

J¼14, 6.5 Hz), 3.29–3.59 (5/2H, m), 3.26 (1/2H, d, J¼

8 Hz), 3.01 (1/2H, dd, J¼14.5, 7 Hz), 2.84–2.93 (1/2H,

m), 2.58–2.72 (1/2H, m), 2.38 (6/2H, s), 2.08 (3/2H, s),

1.79–2.05 (2/2H, m), 1.70 (3/2H, s), 1.21–1.36 (1/2H, m).

¹³C NMR (300 MHz) d: 170.4, 169.7, 144.1, 144.0, 137.6,

137.4, 136.5, 136.4, 132.4, 130.4, 130.05, 129.98, 129.73,

128.5, 127.8, 127.6, 127.3, 126.9, 126.7, 125.5, 125.2,

122.8, 56.7, 53.3, 48.1, 47.7, 46.7, 45.1, 41.7, 37.5, 29.8,

28.8, 22.6, 21.7, 21.6, 21.5. HRMS m/z: Calcd for

C₂₀H₂₂N₂O₃S (M⁺) 370.1350. Found: 370.1349. Anal.

Calcd for C₂₀H₂₂N₂O₃S: C, 64.84; H, 5.99; N, 7.56. Found:

C, 64.88; H, 6.03; N, 7.53.

1

(NSO₂). H NMR (300 MHz) d: 7.68 (1H, dd, J¼8, 1 Hz),

7.54 (2H, br d, J¼8 Hz), 7.48 (1H, dd, J¼8, 1.5 Hz), 7.34

(1H, ddd, J¼8, 7, 1.5 Hz), 7.29–7.23 (3H, m), 4.25 (1H,

dd, J¼14, 5 Hz), 3.13 (1H, dd, J¼14, 12 Hz), 2.95–2.83

(2/5H, m), 2.55–2.48 (1H, m), 2.39 (3H, s), 2.28–2.21 (3/

5H, m), 1.20 (3H, s). ¹³C NMR (50 MHz) d: 174.0, 144.2,

137.0, 135.5, 130.9, 129.8, 129.1, 128.5, 127.1, 126.4,

124.8, 81.9, 47.7, 39.0, 32.2, 28.4, 21.4. HRMS m/z: Calcd

for C₁₉H₁₈DNO₄S (M⁺) 358.1096. Found: 358.1110. Incor-

poration of D was 70% from the NMR spectrum.

trans-3-d-1,3,3a,4,5,9b-Hexahydro-9b-methyl-5-[(4-methyl-

phenyl)sulfonyl]-2H-furo[3,2-c]quinolin-2-one (trans-2d-

D). A colorless oil. IR n_max(neat) cm^ꢂ1: 1791 (g-lactone),

4.4.8. cis-1,8-Diacetyl-2,3,3a,4,5,9b-hexahydro-1H-pyr-

rolo[3,2-c]quinoline (20). To a solution of AlCl₃(400 mg,

3 mmol) and AcCl (0.11 mL, 1.5 mmol) in Cl(CH₂)₂Cl

(2 mL) was added slowly a solution of 18 (185 mg,

0.5 mmol) in Cl(CH₂)₂Cl (2 mL) at room temperature. After

being stirred at reﬂux for 2.5 h, the reaction mixture was

added to ice-water and extracted with CHCl₃. The organic

phase was washed with saturated aqueous NaHCO₃, water

and brine, dried over Na₂SO₄, and concentrated at reduced

pressure. To a solution of the crude acetamide 19 in

MeOH (15 mL) was added 10% aqueous NaOH (1.5 mL)

under a nitrogen atmosphere at room temperature. After

being stirred at reﬂux for 9 h, the reaction mixture was

extracted with CHCl₃. The organic phase was washed with

brine, dried over Na₂SO₄, and concentrated at reduced pres-

sure. The residue was puriﬁed by MCC (CHCl₃/MeOH 20:1)

1

1355, 1169 (NSO₂). H NMR (300 MHz) d: 7.97 (1H, br

d, J¼8 Hz), 7.59 (2H, br d, J¼8 Hz), 7.33–7.23 (4H, m),

7.12 (1H, br t, J¼8 Hz), 4.13 (1H, dd, J¼11, 5 Hz), 3.61–

3.47 (1H, m), 2.64–2.43 (2H, m), 2.38 (3H, s), 0.80 (3H,

s). ¹³C NMR (75 MHz) d: 174.1, 144.4, 135.1, 134.3,

133.6, 129.8, 128.5, 127.0, 124.3, 123.2, 121.6, 81.9, 46.1,

42.5, 31.0, 21.5, 19.4. HRMS m/z: Calcd for C₁₉H₁₈DNO₄S

(M⁺) 358.1096. Found: 358.1102. Incorporation of D was

100% from the NMR spectrum.

Ethyl cis-1,2,3,4-tetrahydro-4-hydroxy-4-methyl-1-[(4-meth-

ylphenyl)sulfonyl]quinoline-3-(1-d)-acetate (3l-D). Color-

less crystals. IR n_maxcm^ꢂ1: 3579 (OH), 1727 (COO),

1

1353, 1167 (NSO₂). H NMR (300 MHz) d: 7.85 (1H, dd,

J¼8, 1.5 Hz), 7.56 (2H, br d, J¼8 Hz), 7.50 (1H, dd, J¼8,

1.5 Hz), 7.27–7.19 (3H, m), 7.10 (1H, td, J¼8, 1.5 Hz),

4.23–4.07 (3H, m), 3.32 (1H, dd, J¼13, 11.5 Hz), 2.67

(3/5H, dd, m), 2.36 (3H, s), 2.39–2.28 (1H, m), 2.18–2.10

(2/5H, m), 2.00 (1H, br s), 1.27 (3H, t, J¼7 Hz), 1.00 (3H,

s). ¹³C NMR (75 MHz) d: 172.5, 144.0, 136.3, 135.6,

134.7, 129.6, 128.1, 127.2, 125.5, 124.5, 122.0, 71.0, 61.0,

48.4, 40.5, 32.5, 23.7, 21.5, 14.1. HRMS m/z: Calcd for

C₂₁H₂₄DNO₅S (M⁺) 404.1515. Found: 404.1522. Incorpora-

tion of D was 80% from the NMR spectrum.

to afford 20 (61.2 mg, 47%) as colorless oil. IR n_maxcm^ꢂ1

:

1

3020, 1628 (NH, NCO, CO). H NMR (300 MHz) d: 8.23

(1H, dd, J¼2, 1 Hz), 7.68 (1H, dd, J¼8.5, 2 Hz), 6.47 (1H,

br d, J¼8.5 Hz), 5.51 (1H, d, J¼7.5 Hz), 4.43 (1H, very

br), 3.52–3.59 (3H, m), 3.27 (1H, dd, J¼12.5, 3 Hz), 2.47

(3H, s), 2.46–2.59 (1H, m), 2.14 (3H, s), 1.92–2.27 (2H,

m). ¹³C NMR (200 MHz) d: 196.8, 170.9, 147.9, 133.3,

128.3, 127.5, 120.0, 113.9, 54.0, 46.6, 41.0, 36.1, 26.6,

26.0, 22.5. HRMS m/z: Calcd for C₁₅H₁₈N₂O₂(M⁺)

258.1367. Found: 258.1374.

4.4.7. cis-1-[2,3,3a,4,5,9b-Hexahydro-5-[(4-methylphe-

nyl)sulfonyl]-1H-pyrrolo[3,2-c]quinolin-1-yl]ethanone

(18). To a solution of cis-2a (1.3 g, 3.8 mmol) in THF

4.4.9. cis-1,8-Diacetyl-5-(2-bromobenzoyl)-2,3,3a,4,5,9b-

hexahydro-1H-pyrrolo[3,2-c]quinoline (16). To a solution

of 20 (156 mg, 0.61 mmol) and Et₃N (0.13 mL, 0.91 mmol)

10114

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

in CH₂Cl₂(14 mL) was added o-bromobenzoyl chloride

(0.09 mL, 0.67 mmol) under nitrogen atmosphere at 0 ^ꢁC.

After being stirred at room temperature for 22.5 h, the reac-

tion mixture was diluted with 10% aqueous HCl and ex-

tracted with CHCl₃. The organic phase was washed with

saturated aqueous NaHCO₃and brine, dried over MgSO₄,

and concentrated at reduced pressure. The residue was puri-

ﬁed by MCC (CHCl₃/MeOH 20:1) to afford 16 (243 mg,

91%) as colorless crystals. Mp 165–167 ^ꢁC (AcOEt). IR

C₂₂H₂₀N₂O₃(M⁺) 360.1473. Found: 360.1484. Anal. Calcd

for C₂₂H₂₀N₂O₃$3/2H₂O: C, 68.20; H, 5.20; N, 7.23. Found:

C, 68.32; H, 5.31; N, 7.20.

4.4.11. (3aR,4R,9bR)-rel-1-Acetyl-5-benzoyl-2,3,3a,4,5,-

9b-hexahydro-4-(3-methoxy-3-oxopropyl)-1H-pyrrolo-

[3,2-c]quinoline-8-carboxylic acid methyl ester (21). To

a mixture of 2.5% NaOH (2 mL) and Br₂(20 mg) was added

a solution of 17 (19.8 mg, 0.044 mmol) in MeOH (1.5 mL)

under a nitrogen atmosphere at 0 ^ꢁC. After being stirred at

room temperature for 0.5 h, 10% Na₂S₂O₃was added. After

being stirred at room temperature for 5 min, the reaction

mixture was acidiﬁed with 10% HCl. The complex mixture

was extracted with CHCl₃, washed with brine, dried over

MgSO₄, and concentrated at reduced pressure. To a solution

of the residue in MeOH (5 mL) was added H₂SO₄(20 mg) at

0 ^ꢁC. After being stirred under a nitrogen atmosphere at re-

ﬂux for 4 h, the reaction mixture was poured into saturated

aqueous NaHCO₃at 0 ^ꢁC and extracted with CHCl₃. The or-

ganic phase was washed with brine, dried over MgSO₄, and

concentrated at reduced pressure. The residue was puriﬁed

by PTLC (AcOEt) to afford 21 (15.6 mg, 76%) as colorless

oil. IR n_maxcm^ꢂ1: 1722, 1640 (COO, CNO). ¹H NMR

(300 MHz) d: 8.57 (1H, s), 7.56 (1H, br d, J¼8.5 Hz),

7.24–7.42 (5H, m), 6.50 (1H, d, J¼8.5 Hz), 5.55 (1H, d,

J¼8 Hz), 4.92–5.02 (1H, m), 3.86 (3H, s), 3.66 (3H, s),

3.58–3.70 (1H, m), 2.66–2.74 (1H, m), 2.44–2.55 (1H, m),

2.25–2.38 (2H, m), 2.08–2.22 (1H, m), 2.14 (3H, s), 1.82–

1.96 (1H, m), 1.56–1.76 (2H, m). ¹³C NMR (300 MHz) d:

173.0, 170.8, 172.2, 166.4, 140.4, 134.8, 133.7, 131.1,

129.5, 128.7, 128.4, 127.1, 125.8, 55.5, 54.9, 52.2, 51.8,

47.2, 43.4, 30.5, 30.1, 27.9, 23.0. HRMS m/z: Calcd for

C₂₆H₂₈N₂O₆(M⁺) 464.1946. Found: 464.1947.

1

n_maxcm^ꢂ1: 1646, 1682 (NCO, CO). H NMR (300 MHz)

d: 8.33 (1H, br s), 7.58–7.60 (2H, m), 5.53 (1H, br s),

3.59–3.63 (3H, m), 2.97 (1H, br s), 2.56 (3H, s), 2.19 (3H,

s), 2.10–2.24 (1H, br s), 1.99–2.04 (2H, br s). ¹³C NMR

(200 MHz) d: 197.2, 171.0, 170.1, 141.4, 137.4, 134.3,

133.3, 131.1, 128.7, 127.8, 127.0, 125.0, 123.7, 119.8,

55.5, 47.1, 45.3, 41.1, 37.9, 26.5, 22.7, 22.4. HRMS m/z:

Calcd for C₂₂H₂₁BrN₂O₃(M⁺) 440.0734. Found:

440.0738. Anal. Calcd for C₂₂H₂₁BrN₂O₃: C, 59.87; H,

4.80; N, 6.35. Found: C, 59.58; H, 4.64; N, 6.50.

4.4.10. C–C bond formation of 16 via 1,5-hydrogen atom

translocation reaction. To a boiling solution of 16 (200 mg,

0.4545 mmol) and methyl acrylate (0.82 mL, 9.09 mmol) in

benzene (33 mL) was added slowly a solution of Bu₃SnH

(0.25 mL, 0.909 mmol) and AIBN (7.5 mg, 0.045 mmol)

in benzene (33 mL) by syringe pump for 4 h under a nitrogen

atmosphere. Then, a solution of AIBN (7.5 mg, 0.045 mmol)

in benzene (2 mL) was added. After being stirred for 4 h at

reﬂux, the reaction mixture was concentrated at reduced

pressure. To the residue were added Et₂O (10 mL) and

DBU (0.15 mL). The complex mixture was ﬁltered through

SiO₂column chromatography and the ﬁltrate was concen-

trated at reduced pressure. The residue was puriﬁed by ﬂash

column chromatography (AcOEt) to afford 17 (88.6 mg,

43%) and 22 (31.1 mg, 19%).

4.4.12. (3aR,4R,9bR)-rel-5-Benzoyl-2,3,3a,4,5,9b-hexa-

hydro-4-(3-methoxy-3-oxopropyl)-1H-pyrrolo[3,2-c]-

quinoline-8-carboxylic acid methyl ester (23). To a

mixture of 21 (24.1 mg, 0.052 mmol) and NaHCO₃

(52.3 mg, 0.623 mmol) in CH₂Cl₂(1.4 mL) was added

Et₃O$BF₄(1.0 M in CH₂Cl₂, 0.31 mL, 0.31 mmol) under an

Ar atmosphere at room temperature. After being stirred at

room temperature for 50 h, saturated aqueous NaHCO₃was

added. After being stirred at room temperature for 15 min,

the reaction mixture was extracted with CHCl₃, washed

with brine, dried over Na₂SO₄, and concentrated at reduced

pressure. The residue was puriﬁed by PTLC (CHCl₃/MeOH

20:1)toafford23(9.2 mg,42%)and21(4.6 mg,19%). Color-

4-(1,8-Diacetyl-5-benzoyl-2,3,3a,4,5,9b-hexahydro-1H-pyr-

rolo[3,2-c]quinoline)propanate (17). Colorless oil. IR n_max

cm^ꢂ1: 1732, 1679, 1643 (NCO, NCO, COO, CO). ¹H

NMR (300 MHz) d: 8.61 (1H, s), 7.50 (1H, d, J¼8.5 Hz),

7.26–7.43 (5H, m), 6.52 (1H, d, J¼8.5 Hz), 5.55 (1H, d,

J¼8 Hz), 4.96–4.68 (1H, m), 3.66 (3H, s), 3.58–3.66 (1H,

m), 2.71–2.74 (1H, m), 2.55 (3H, s), 2.45–2.55 (1H, m),

2.17–2.37 (2H, m), 2.16 (3H, s), 1.72–1.96 (4H, m). ¹³C

NMR (200 MHz) d: 197.3, 173.0, 171.1, 170.4, 140.3,

134.9, 134.0, 133.5, 131.2, 129.3, 128.8, 128.5, 126.9,

125.9, 55.3, 54.7, 51.8, 47.2, 43.0, 30.6, 29.6, 27.6, 26.5,

23.0. HRMS m/z: Calcd for C₂₆H₂₈N₂O₅(M⁺) 448.1996.

Found: 448.1996.

1

less oil. IR n_maxcm^ꢂ1: 1721, 1646 (COO, CNO). H NMR

(300 MHz) d: 8.03 (1H, s), 7.45–7.56 (3H, m), 7.23–7.41

(3H, m), 6.48 (1H, br d, J¼11 Hz), 4.94–5.03 (1H, m), 4.49

(1H, br d, J¼7.5 Hz), 3.85 (3H, s), 3.64 (3H, s), 3.10–3.19

(1H, m), 2.90–3.03 (1H, m), 2.70–2.80 (1H, m), 2.40–2.53

(1H, m), 2.13–2.35 (2H, m), 1.24–2.05 (3H, s). ¹³C NMR

(300 MHz) d: 173.2, 170.7, 166.2, 141.5, 135.0, 131.3,

131.0, 129.0, 128.7, 128.3, 126.9, 126.2, 56.0, 52.1, 51.7,

45.9, 44.1, 31.6, 30.6, 27.6. HRMS m/z: Calcd for

C₂₄H₂₆N₂O₅(M⁺) 422.1840. Found: 422.1843.

cis-1,7-Diacetyl-2,3,3a,4,5,5a-hexahydro-1,5-diazo-benzo-

[de]cyclopenta[b]anthracen-10-one (22). Colorless crys-

tals. Mp 267–268 ^ꢁC (CHCl₃/hexane). IR n_maxcm^ꢂ1

:

1

1731, 1643 (NCO, CO). H NMR (300 MHz) d: 8.84 (1H,

d, J¼1.5 Hz), 8.56 (1H, s), 8.52 (1H, d, J¼8 Hz), 8.40

(1H, d, J¼8 Hz), 7.82 (1H, t, J¼7.5 Hz), 7.64 (1H, t,

J¼7.5 Hz), 5.79 (1H, d, J¼7.5 Hz), 5.21 (1H, dd, J¼15,

2.5 Hz), 3.77 (1H, dd, J¼15, 3.5 Hz), 3.48–3.66 (2H, m),

2.82–2.94 (1H, m), 2.65 (3H, s), 2.18 (3H, s), 2.10–2.21

(1H, m), 1.84–1.95 (1H, m). ¹³C NMR (200 MHz) d:

197.2, 171.1, 161.8, 136.3, 133.4, 133.1, 131.9, 131.7,

128.7, 128.6, 125.3, 125.1, 122.4, 122.3, 118.8, 54.4, 46.8,

40.4, 34.5, 26.7, 26.5, 22.4. HRMS m/z: Calcd for

4.4.13. (3aR,4R,9bR)-rel-5-Benzoyl-2,3,3a,4,5,9b-hexa-

hydro-4-(3-methoxy-3-oxopropyl)-1H-pyrrolo[3,2-c]qu-

inoline-8-carboxylic acid, 8-methyl 1-(phenylmethyl)-

ester (24). To a solution of 23 (25.1 mg, 0.059 mmol) in

CH₂Cl₂(7 mL) were added Et₃N (0.01 mL, 0.072 mmol)

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10115

and CbzCl (0.01 mL, 0.070 mmol) under an Ar atmosphere

at 0 ^ꢁC. After being stirred at room temperature for 0.5 h, the

reaction mixture was acidiﬁed with 10% HCl and extracted

with CHCl₃. The organic phase was washed with saturated

aqueous NaHCO₃and brine, dried over MgSO₄, and concen-

trated at reduced pressure. The residue was puriﬁed by PTLC

(hexane/AcOEt 1:1) to afford 24 (27.8 mg, 84%) as colorless

4.4.16. 1,2,3,4-Tetrahydro-1-(2-iodobenzoyl)quinoline

(25b). According to the procedure described in the prepara-

tion of 25a, benzoylation of tetrahydroquinoline (400 mg,

3 mmol) with o-iodobenzoyl chloride (879 mg, 3.3 mmol)

gave 25b (1.09 g, 95%) as colorless crystals. Mp 124–

1

126 ^ꢁC (AcOEt). IR n_maxcm^ꢂ1: 1635 (NCO). H NMR

(300 MHz) d: 8.12 (1/2H, very br), 7.75 (2/2H, very br),

6.90–7.50 (11/2H, very br), 6.74 (1/2H, very br), 6.46

(1/2H, very br), 3.99 (2/2H, very br), 3.46 (2/2H, very br),

2.86 (4/2H, very br), 2.01 (4/2H, very br). ¹³C NMR

(200 MHz) d: 169.6, 142.8, 139.4, 130.2, 128.5, 125.8,

125.0, 124.7, 47.3, 43.7, 27.2. HRMS m/z: Calcd for

C₁₆H₁₄INO (M⁺) 363.0126. Found: 363.0127. Anal. Calcd

for C₁₆H₁₄INO: C, 52.91; H, 3.89; N, 3.86. Found: C,

52.84; H, 3.78; N, 3.87.

1

oil. IR n_maxcm^ꢂ1: 1699, 1651 (COO, CNOO, CNO). H

NMR (300 MHz) d: 8.50–8.10 (1H, very br), 7.49 (1H, br

d, J¼6.6 Hz), 7.12–7.34 (10H, m), 6.41 (1H, br d, J¼

8.5 Hz), 5.08–5.22 (3H, m), 4.83–4.92 (1H, m), 3.78 (3H,

s), 3.58 (3H, s), 2.64–2.71 (1H, m), 2.37–2.48 (1H, m),

2.14–2.27 (2H, m), 1.94–2.08 (1H, m), 1.38–1.70 (2H, m),

1.12–1.30 (2H, m). ¹³C NMR (300 MHz) d: 175.3, 173.4,

170.6, 166.6, 156.2, 141.0, 136.7, 135.2, 133.3, 131.3, 130.1,

129.2, 129.1, 128.8, 128.7, 128.4, 127.2, 126.2, 67.7,

56.3, 56.0, 52.4, 52.0, 46.5, 45.1, 30.9, 30.2, 28.4. HRMS

m/z: Calcd for C₃₂H₃₂N₂O₇(M⁺) 556.2207. Found:

556.2198.

4.5. General procedure for C–C bond formation via 1,5-

hydrogen atom translocation reaction

4.5.1. In the presence of AIBN as a radical initiator [Ta-

ble 10, entry 3]. To a boiling solution of 25a (158 mg,

0.5 mmol) and methyl acrylate (0.45 mL, 5.0 mmol) in ben-

zene (25 mL) was added slowly a solution of Bu₃SnH

(0.269 mL, 1.0 mmol) and AIBN (8.2 mg, 0.05 mmol) in

benzene (25 mL) by syringe pump for 3 h under a nitrogen

atmosphere. After being stirred at reﬂux for 3 h, the reaction

mixture was concentrated at reduced pressure. To the residue

were added Et₂O (10 mL) and DBU (0.15 mL). The complex

mixture was ﬁltered through SiO₂column chromatography

and the ﬁltrate was concentrated at reduced pressure. The

residue was puriﬁed by ﬂash column chromatography

(AcOEt/hexane 1:8/1:5/1:3) to afford methyl 1-benzoyl-

2-(1,2,3,4-tetrahydroquinoline)propanoate 26 (66.1 mg,

41%), 27^18a,b(55.6 mg, 47%), and 28^18a,c(9.5 mg, 8%).

4.4.14. (3aR,4R,9bR)-rel-2,3,3a,4,5,9b-Hexahydro-4-(3-

hydroxypropyl)-1H-pyrrolo[3,2-c]quinoline-1,8-dicarb-

oxylic acid, 8-methyl 1-(phenylmethyl)ester (4). To a

solution of 24 (2.7 mg, 4.9 mmol) in THF (1 mL) were added

LiBH₄(0.5 mg, 0.023 mmol) and MeOH (0.1 mL) under

a nitrogen atmosphere at room temperature. After being

stirred at room temperature for 0.5 h, the reaction mixture

was acidiﬁed with 1 M aqueous HCl at 0 ^ꢁC and extracted

with CHCl₃. The organic phase was washed with brine, dried

over MgSO₄, and concentrated at reduced pressure. The res-

idue was puriﬁed by PTLC (AcOEt) to afford 4 (1.2 mg,

58%) as colorless oil. The compound 4 was identical with

the Ma’s authentic sample upon comparison of their spectral

data.^13dIR n_maxcm^ꢂ1: 3365 (NH, OH), 1699 (COO, CNO).

¹H NMR (300 MHz) d: 8.06–8.17 (1H, very br), 7.64 (1H, br

d, J¼8.5 Hz), 7.16–7.48 (5H, m), 6.38 (1H, d, J¼8.5 Hz),

5.08–5.50 (3H, m), 5.00 (1H, very br), 3.75 (3H, s), 3.62–

3.78 (2H, m), 3.46 (2H, very br), 3.33–3.36 (2H, m), 2.28–

2.36 (1H, m), 1.88–1.96 (2H, m), 1.34–1.64 (2H, m).

HRMS m/z: Calcd for C₂₄H₂₈N₂O₅(M⁺) 424.1997. Found:

424.1991.

4.5.2. In the presence of Et₃B as a radical initiator [Table

10, entry 6]. To a solution of 25b (120 mg, 0.33 mmol),

methyl acrylate (0.3 mL, 3.3 mmol), and Bu₃SnH

(0.18 mL, 0.66 mmol) in toluene (12 mL) was added Et₃B

(1.0 M in Hexane, 0.82 mL, 0.82 mmol) under a nitrogen

atmosphere at room temperature. After being stirred for

4 h at room temperature, the reaction mixture was concen-

trated at reduced pressure. To the residue were added Et₂O

(6.6 mL) and DBU (0.1 mL). The complex mixture was ﬁl-

tered through SiO₂column chromatography and the ﬁltrate

was concentrated at reduced pressure. The residue was puri-

ﬁed by ﬂash column chromatography (AcOEt/hexane 1:8/

1:5/1:3) to afford methyl 1-benzoyl-2-(1,2,3,4-tetrahydro-

quinoline)propanoate 26 (38.4 mg, 36%), 27^18a,b(40.7 mg,

52%), and 28^18a,c(7.5 mg, 9%).

4.4.15. 1-(2-Bromobenzoyl)-1,2,3,4-tetrahydroquinoline

(25a). To a solution of tetrahydroquinoline (1.33 g,

10 mmol) and Et₃N (2.09 mL, 15 mmol) in CH₂Cl₂(20 mL)

was added slowly o-bromobenzoyl chloride (1.44 mL,

11 mmol) at 0 ^ꢁC. After being stirred at room temperature

for 1 h, the reaction mixture was diluted with 10% aqueous

HCl and extracted with CH₂Cl₂. The organic phase was

washed with saturated aqueous NaHCO₃, water and brine,

dried over MgSO₄, and concentrated at reduced pressure.

The residue was puriﬁed by recrystallization from AcOEt

to afford 25a (1.98 g, 63%) as colorless crystals. Mp 124–

Methyl 1-benzoyl-2-(1,2,3,4-tetrahydroquinoline)propano-

ate (26). Colorless crystals. Mp 107–109 ^ꢁC (EtOH). IR

1

126 ^ꢁC (AcOEt). IR n_maxcm^ꢂ1: 1637 (NCO). H NMR

n_maxcm^ꢂ1: 1732, 1635 (COO, CO). H NMR (300 MHz)

(300 MHz) d: 8.13 (1/2H, very br), 7.06 (1/2H, very br),

7.14–7.40 (11/2H, very br), 6.98 (1/2H, very br), 6.75 (1/

2H, very br), 6.49 (1/2H, very br), 4.09 (2/2H, very br),

3.94 (2/2H, very br), 2.86 (4/2H, very br), 2.04 (4/2H, very

br). ¹³C NMR (200 MHz) d: 168.2, 138.8, 132.9, 130.3,

129.7, 128.3, 127.3, 125.7, 125.0, 124.5, 45.4, 43.3, 27.1.

HRMS m/z: Calcd for C₁₆H₁₄BrNO (M⁺) 315.0259. Found:

315.0268. Anal. Calcd for C₁₆H₁₄BrNO: C, 60.78; H, 4.46;

N, 4.43. Found: C, 60.72; H, 4.37; N, 4.51.

d: 7.13–7.33 (6H, m), 7.00 (1H, td, J¼7.5, 1 Hz), 6.83 (1H,

br t, J¼7.5 Hz), 6.51 (1H, d, J¼7.5 Hz), 4.90 (1H, quint,

J¼6.5 Hz), 3.66 (3H, s), 2.80 (2H, t, J¼6.5 Hz), 2.33–2.55

(3H, m), 1.63–1.95 (3H, m). ¹³C NMR (300 MHz) d:

173.6, 170.0, 137.9, 136.3, 132.4, 129.9, 128.5, 127.9, 126.8,

126.0, 125.2, 51.8, 51.6, 30.8, 29.8, 28.7, 25.0. HRMS m/z:

Calcd for C₂₀H₂₁NO₃(M⁺) 323.1520. Found: 323.1514.

Anal. Calcd for C₂₀H₂₁NO₃: C, 74.28; H, 6.55; N, 4.33.

Found: C, 74.43; H, 6.67; N, 4.28.

10116

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

5. Formal total synthesis of martinelline and martinellic acid, see:

Acknowledgements

(a) Hadden, M.; Nieuwenhuyzen, M.; Potts, D.; Stevenson,

P. J.; Thompson, N.; Walker, D. A. Tetrahedron 2006, 62,

3977–3984; (b) He, Y.; Mahmud, H.; Moningka, R.; Lovely,

C. J.; Dias, H. V. R. Tetrahedron 2006, 62, 8755–8769; (c)

Takeda, Y.; Nakabayashi, T.; Shirai, A.; Fukumoto, D.;

Kiguchi, T.; Naito, T. Tetrahedron Lett. 2004, 45, 3481–3484;

(d) Miyata, O.; Shirai, A.; Yoshino, S.; Takeda, Y.; Sugiura,

M.; Naito, T. Synlett 2006, 893–896; (e) Hadden, M.;

Nieuwenhuyzen, M.; Osborne, D.; Stevenson, P. J.;

Thompson, N. Tetrahedron Lett. 2001, 42, 6417–6419; (f)

He, Y.; Moningka, R.; Mahmud, H.; Lovely, C. J.

Tetrahedron Lett. 2005, 46, 1251–1254.

We are grateful to acknowledge the research Grants-in-Aid

for Scientiﬁc Research (B) (to T.N.) and (C) (to O.M.)

from the Japan Society for the Promotion of Science

(JSPS) and Scientiﬁc Research on Priority Areas (A) (to

T.N.) from the Ministry of Education, Culture, Sports, and

Technology.

References and notes

1. (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;

Wiley-VCH: Weinheim, 2001; Vols. 1 and 2; (b) Tietze, L. F.;

Brasche, G.; Gericke, K. M. Domino Reactions in Organic

Synthesis; Tietze, L. F., Brasche, G., Gericke, K. M., Eds.;

Wiley-VCH: Weinheim, 2006; pp 219–279.

6. Balasubramanian, M.; Keay, J. G. Comprehensive Heterocyclic

Chemistry; Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;

Pergamon: London, 1996; Vol. 5, Chapter 5.06, pp 245–

300.

7. (a) Hewson, A. T.; Hughes, K.; Richardson, S. K.; Sharpe,

D. A.; Wadsworth, A. H. J. Chem. Soc., Perkin Trans. 1

1991, 1565–1569; (b) Hechavarria Fonseca, M.; Eibler, E.;

Zabel, M.; Konig, B. Tetrahedron: Asymmetry 2003, 14,

1989–1994.

8. (a) Bertrand, M. P.; Escoubet, S.; Gastaldi, S.; Timokhin, V. I.

Chem. Commun. 2002, 216–217; (b) Escoubet, S.; Gastaldi, S.;

Timokhin, V. I.; Bertrand, M. P.; Siri, D. J. Am. Chem. Soc.

2004, 126, 12343–12352.

9. Jones, K.; Lappert, M. F. J. Chem. Soc. 1965, 1944–1951.

10. (a) Dimopoulos, P.; Athlan, A.; Manaviazar, S.; George, J.;

Walters, M.; Lazarides, L.; Aliev, A. E.; Hale, K. J. Org.

Lett. 2005, 7, 5369–5372; (b) Nativi, C.; Taddei, M. J. Org.

Chem. 1988, 53, 820–826.

11. Corsaro, A.; Chiacchio, U.; Caramella, P.; Purrello, G.

J. Heterocycl. Chem. 1984, 21, 949–952.

12. Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard,

A. M.; Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.;

Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc. 1995,

117, 6682–6685.

13. Total synthesis of martinelline and martinellic acid, see: (a)

Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3,

4217–4220; (b) Powell, D. A.; Batey, R. A. Org. Lett. 2002,

4, 2913–2916; (c) Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org.

Lett. 2001, 3, 2189–2191; (d) Xia, C.; Heng, L.; Ma, D.

Tetrahedron Lett. 2002, 43, 9405–9409; (e) Ma, D.; Xia, C.;

Jiang, J.; Zhang, J.; Tang, W. J. Org. Chem. 2003, 68, 442–

451; (f) Ikeda, S.; Shibuya, M.; Iwabuchi, Y. Chem.

Commun. 2007, 504–506; (g) Badarinarayana, V.; Lovely,

C. J. Tetrahedron Lett. 2007, 48, 2607–2610.

14. Synthesis of the pyrroloquinoline core, see: (a) Gurjar, M. K.;

Pal, S.; Rama Rao, A. V. Heterocycles 1997, 45, 231–234; (b)

Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287–8294; (c)

Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough,

A. J. Chem. Commun. 1999, 651–652; (d) Hadden, M.;

Stevenson, P. J. Tetrahedron Lett. 1999, 40, 1215–1218; (e)

Lovely, C. J.; Mahmud, H. Tetrahedron Lett. 1999, 40, 2079–

2082; (f) Snider, B. B.; Ahn, Y.; Foxman, B. M. Tetrahedron

2. (a) Naito, T.; Honda, Y.; Miyata, O.; Ninomiya, I. J. Chem.

1 1995, 19–26; (b) Miyata, O.;

Soc., Perkin Trans.

Nishiguchi, A.; Ninomiya, I.; Naito, T.; Aoe, K.; Okamura,

K. Tetrahedron Lett. 1996, 37, 229–232; (c) Miyata, O.;

Nishiguchi, A.; Ninomiya, I.; Naito, T.; Aoe, K.; Okamura,

K. Chem. Pharm. Bull. 1996, 44, 1285–1287; (d) Naito, T.;

Honda, Y.; Bhavakul, V.; Yamaguchi, S.; Fujiwara, A.;

Miyata, O.; Ninomiya, I. Chem. Pharm. Bull. 1997, 45,

1932–1939; (e) Miyata, O.; Nishiguchi, A.; Ninomiya, I.;

Aoe, K.; Okamura, K.; Naito, T. J. Org. Chem. 2000, 65,

6922–6931; (f) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito,

T. Tetrahedron 2000, 56, 6199–6207; (g) Miyata, O.;

Nakajima, E.; Naito, T. Chem. Pharm. Bull. 2001, 49, 213–

224; (h) Miyata, O.; Naito, T. C. R. Acad. Sci. Paris Chim.

2001, 4, 401–421; (i) Miyata, O.; Muroya, K.; Kobayashi, T.;

Yamanaka, R.; Kajisa, S.; Koide, J.; Naito, T. Tetrahedron

2002, 58, 4459–4479.

3. (a) Miyabe, H.; Fujii, K.; Goto, T.; Naito, T. Org. Lett. 2000, 2,

4071–4074; (b) Miyabe, H.; Fujii, K.; Tanaka, H.; Naito, T.

Chem. Commun. 2001, 831–832; (c) Miyabe, H.; Tanaka, H.;

Naito, T. Tetrahedron Lett. 1999, 40, 8387–8390; (d) Miyabe,

H.; Ueda, M.; Fujii, K.; Nishimura, A.; Naito, T. J. Org.

Chem. 2003, 68, 5618–5626; (e) Ueda, M.; Miyabe, H.;

Nishimura, A.; Miyata, O.; Naito, T. Org. Lett. 2003, 5,

3835–3838; (f) Miyabe, H.; Tanaka, H.; Naito, T. Chem.

Pharm. Bull. 2004, 52, 842–847.

4. (a) Naito, T.; Nakagawa, K.; Nakamura, T.; Kasei, A.;

Ninomiya, I.; Kiguchi, T. J. Org. Chem. 1999, 64, 2003–

2009; (b) Naito, T.; Tajiri, K.; Harimoto, T.; Ninomiya, I.;

Kiguchi, T. Tetrahedron Lett. 1994, 35, 2205–2206; (c)

Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.;

Naito, T. J. Org. Chem. 1998, 63, 4397–4407; (d) Miyabe,

H.; Torieda, M.; Ninomiya, I.; Kiguchi, T.; Naito, T. Synlett

1997, 580–582; (e) Naito, T.; Torieda, M.; Tajiri, K.;

Ninomiya, I.; Kiguchi, T. Chem. Pharm. Bull. 1996, 44, 624–

626; (f) Naito, T.; Fukumoto, D.; Takebayashi, K.; Kiguchi,

T. Heterocycles 1999, 51, 489–492; (g) Miyabe, H.;

Kanehira, S.; Kume, K.; Kandori, H.; Naito, T. Tetrahedron

1998, 54, 5883–5892; (h) Kiguchi, T.; Ozaki, M.; Naito, T.

Heterocycles 1999, 51, 2711–2722; (i) Kiguchi, T.; Tajiri, K.;

Ninomiya, I.; Naito, T. Tetrahedron 2000, 56, 5819–5833; (j)

Naito, T.; Nair, J. S.; Nishiki, A.; Yamashita, K.; Kiguchi, T.

Heterocycles 2000, 53, 2611–2615; (k) Miyabe, H.; Tanaka,

H.; Naito, T. Chem. Pharm. Bull. 2004, 52, 74–78; (l)

Miyabe, H.; Nishiki, A.; Naito, T. Chem. Pharm. Bull. 2003,

51, 100–103.

ꢀ

Lett. 1999, 40, 3339–3342; (g) Frank, K. E.; Aube, J. J. Org.

Chem. 2000, 65, 655–666; (h) Nieman, J. A.; Ennis, M. D.

Org. Lett. 2000, 2, 1395–1397; (i) Nyerges, M.; Fejes, I.;

Toke, L. Tetrahedron Lett. 2000, 41, 7951–7954; (j) Snider,

B. B.; O’Hare, S. M. Tetrahedron Lett. 2001, 42, 2455–2458;

(k) Mahmud, H.; Lovely, C. J.; Dias, H. V. R. Tetrahedron

2001, 57, 4095–4105; (l) Hadden, M.; Nieuwenhuyzen, M.;

Potts, D.; Stevenson, P. J.; Thompson, N. Tetrahedron 2001,

O. Miyata et al. / Tetrahedron 63 (2007) 10092–10117

10117

57, 5615–5624; (m) Batey, R. A.; Powell, D. A. Chem.

Commun. 2001, 2362–2363; (n) Hamada, Y.; Kunimune, I.;

Hara, O. Heterocycles 2002, 56, 97–100; (o) He, Y.;

Mahmud, H.; Wayland, B. R.; Dias, H. V. R.; Lovely, C. J.

Tetrahedron Lett. 2002, 43, 1171–1174; (p) Malassene, R.;

Sanchez-Bajo, L.; Toupet, L.; Hurvois, J.-P.; Moinet, C.

Synlett 2002, 1500–1504; (q) Nyerges, M.; Fejes, I.; Toke, L.

Synthesis 2002, 1823–1828; (r) Hara, O.; Sugimoto, K.;

Makino, K.; Hamada, Y. Synlett 2004, 1625–1627; (s) Hara,

O.; Sugimoto, K.; Makino, K.; Hamada, Y. Tetrahedron

2004, 60, 9381–9390; (t) Yadav, J. S.; Subba, R. B. V.;

Sunitha, V.; Srinivasa, R. K.; Ramakrishna, K. V. S.

Tetrahedron Lett. 2004, 45, 7947–7950; (u) Nyerges, M.

Heterocycles 2004, 63, 1685–1712; (v) Shaw, J. T.; Masse,

C. E.; Ng, P. Y. Org. Lett. 2006, 8, 3999–4002.

17. Williams, L.; Booth, S. E.; Undheim, K. Tetrahedron 1994, 50,

13697–13708.

18. (a) Nagarajan, K.; Nair, M. D.; Pillai, P. M. Tetrahedron 1967,

23, 1683–1690; (b) Harayama, T.; Sato, T.; Hori, A.; Abe, H.;

Takeuchi, Y. Heterocycles 2005, 66, 527–530; (c) Crabb, T. A.;

Soilleux, S. L. J. Chem. Soc., Perkin Trans. 1 1985, 1381–1385.

19. (a) Kunz, H.; Dombo, B. Angew. Chem., Int. Ed. Engl. 1988,

27, 711–713; (b) Elliott, M.; Farnham, A. W.; Janes, N. F.;

Johnson, D. M.; Pulman, D. A. Pestic. Sci. 1987, 18, 229–238.

20. (a) Orsini, F.; Pelizzoni, F.; Ricca, G. Synth. Commun. 1982,

12, 1147–1154; (b) Salamonczyk, G. M.; Han, K.; Guo, Z.;

Sih, C. J. J. Org. Chem. 1996, 61, 6893–6900.

21. (a) Kirsop, P.; Storey, J. M. D.; Harrison, W. T. A. Acta

Crystallogr. 2004, 9, 1636–1638; (b) Sarrazin, L.; Mauze, B.

Synth. Commun. 1996, 3179–3191; (c) Bailey, W. J.; Bello, J.

J. Org. Chem. 1955, 20, 525–529.

22. (a) Carril, M.; SanMartin, R.; Dominguez, E.; Tellitu, I.

Tetrahedron 2006, 63, 690–702; (b) Carril, M.; SanMartin,

R.; Churruca, F.; Tellitu, I.; Dominguez, E. Org. Lett. 2005,

7, 4787–4789.

15. (a) Astill, B. D.; Boekelheide, V. J. Am. Chem. Soc. 1955, 77,

4079–4084; (b) Jiang, Y.; Ma, D. Tetrahedron Lett. 2002, 43,

7013–7015.

16. Beaulieu, F.; Arora, J.; Veith, U.; Taylor, N. J.; Chapell, B. J.;

Snieckus, V. J. Am. Chem. Soc. 1996, 118, 8727–8728.

Article Doi

Development of radical addition-cyclization-elimination reaction of oxime ether and its application to formal synthesis of (±)-martinelline

DOI: 10.1016/j.tet.2007.07.007

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2007.07.007

Full text of DOI:10.1016/j.tet.2007.07.007

Products guided by the article

R&D Labs maybe for 953054-20-1

Relevant to this article

Hot Product