The nucleophilic 5-endo-trig cyclization of 1,1-difluoro-1-alkenes: Ring-fluorinated hetero- and carbocycle synthesis and remarkable effect of the vinylic fluorines on the disfavored process

FEATURE ARTICLE

1917

The Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes:

Ring-Fluorinated Hetero- and Carbocycle Synthesis and Remarkable Effect

of the Vinylic Fluorines on the Disfavored Process

N

ucleophi

u

lic

5

-endo-tr

n

ig-Cyclizatio

j

n of 1,

i

1

-

Difluoro-1-

I

alkeneschikawa,* Yukinori Wada, Masaki Fujiwara, Kotaro Sakoda

Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Fax +81(3)58414345; E-mail: junji@chem.s.u-tokyo.ac.jp

Received 21 May 2002; revised 12 June 2002

ing effect of fluorine, and (iii) the leaving-group ability of

Abstract: The disfavored 5-endo-trig cyclizations have been ac-

the fluoride ion (Scheme 1). Thus, the attack of nucleo-

complished for 1,1-difluoro-1-alkenes with nitrogen, oxygen, sul-

philes is strictly regulated to occur at the difluoromethyl-

fur, and carbon nucleophiles by taking advantage of the properties

ene carbon, so that the fluorines are placed at the position

to the electron-rich carbon in the transition state to avoid

electron-pair repulsion.

of fluorine. , -Difluorostyrenes bearing tosylamido, hydroxy, or

methylsulfinyl group at the o-position undergo intramolecular nu-

cleophilic substitution with a loss of the vinylic fluorine, leading to

2-fluorinated indole, benzo[b]furan, and benzo[b]thiophene in

high yields. 1,1-Difluoro-1-butenes bearing homoallylic tosyl-

amido, hydroxy, mercapto, or iodomethyl group also successfully

cyclize via a 5-endo-trig process with the in situ generated intramo-

lecular nucleophiles to afford 2-fluoro-2-pyrroline, 5-fluoro-2,3-di-

hydrofuran, 5-fluoro-2,3-dihydrothiophene, and 1-fluorocyclo-

pentene. The two vinylic fluorines proved to be essential and play a

critical role in these ‘anti-Baldwin’ cyclizations.

R¹

R²

R¹

R²

Nu^–

– F ^–

F

Nu

F

–

^δ+C

C

Nu

C

C C

δ–

β

R²addition

elimination

F

Scheme 1 Nucleophilic substitution of vinylic fluorines.

Key words: cyclizations, fluorine, alkenes, heterocycles, carbo-

cycles

Taking advantage of this reactivity, we have already re-

ported regioselective syntheses of 3- and 5-fluoropyra-

zoles by the reactions of 2,2-difluorovinyl ketones with

hydrazines as external nucleophiles through a two-site re-

action, the substitution–cyclodehydration sequence.^8,9

Our interest in further applications of difluoroalkene

chemistry to ring constructions led us to explore an in-

tramolecular version of the substitution. This method pro-

vides an efficient access to ring-fluorinated hetero- and

carbocyclic compounds, whose synthetic methods are

quite limited in spite of their potential uses as components

of agrochemicals, pharmaceuticals, and dyestuffs.¹⁰

Introduction

The 5-endo-trig cyclization has long been considered, ac-

cording to Baldwin’s rules, to be a disfavored process for

the construction of five-membered rings, due to severe

distortions in the reaction geometry.¹As examples of this

disfavored cyclization, nucleophile-driven, electrophile-

driven, and radical-initiated ring closures have been re-

ported. The electrophile-driven cyclizations are initiated

by the coordination of a double bond in the substrate to an

external electrophile such as I₂, PhSeCl, or metal salts,²al-

though this type of cyclization does not seem likely to be

an exception to Baldwin’s rules.^1cExamples of efficient

radical-initiated cyclizations have been recently devised

to synthesize heterocyclic compounds including -lac-

tams.³In contrast to the above-mentioned two types of 5-

endo-trig cyclization, the corresponding nucleophile-

driven ring closure has been rarely observed in synthetic

chemistry (vide infra).^4–6

Moreover, we expected that the unique properties of 1,1-

difluoro-1-alkenes could make a nucleophilic approach to

5-endo-trig cyclization feasible. Specifically, we thought

that (i) the highly polarized difluorovinylidene double

bond (¹³C NMR: ca. 150 ppm and 90 ppm for CF₂=C)

would allow initial ring formation by electrostatic attrac-

tion between the CF₂carbon and the internal nucleophile

and (ii) the successive elimination of fluoride ion could

suppress the reverse ring opening, thus functioning as a

‘lock’ (Scheme 2). On the basis of these considerations,

we have investigated the nucleophilic 5-endo-trig cycliza-

tions of 1,1-difluoro-1-alkenes as a solution to conducting

ring closures disfavored according to Baldwin’s rules,

and the preliminary results have been briefly reported.⁵

In this paper, full accounts of these five-membered ring

closures are reported with the study to elucidate the effect

of fluorine on the ‘anti-Baldwin’ cyclization.¹¹

1,1-Difluoro-1-alkenes are susceptible to nucleophilic

substitution of the vinylic fluorines via an addition–elim-

ination process,⁷in which the fluorine can affect reactivity

by: (i) the electrophilic activation of the carbon-carbon

double bond by the two fluorine atoms, (ii) the stabiliza-

tion of the intermediary carbanion by the -anion stabiliz-

Synthesis 2002, No. 13, Print: 20 09 2002.

Art Id.1437-210X,E;2002,0,13,1917,1936,ftx,en;F04302SS.pdf.

ISSN 0039-7881

1918

J. Ichikawa et al.

FEATURE ARTICLE

R

C

Results and Discussion

R

δ–

– F ^–

δ+

F₂C

F

–

Preparation of Functionalized 1,1-Difluoro-1-

alkenes

F

–

Y

As substrates for the 5-endo-trig cyclizations, (i) , -di-

fluorostyrene and (ii) 1,1-difluoro-1-butene derivatives

were designed with a nucleophilic nitrogen, oxygen, sul-

fur, or carbon atom at the ortho or homoallylic position

suitable for substitution in a 5-endo-trig fashion.

Scheme 2 Nucleophilic 5-endo-trig cyclization of 1,1-difluoro-1-

alkenes.

Biographical Sketches

Junji Ichikawa was born in Japan, he moved to the in 1994, and the Daiichi

Tokyo, Japan in 1958. He Department of Applied Pharmaceutical Award in

received his BSc in 1981 Chemistry, Kyushu Institute Synthetic Organic Chemis-

and PhD in 1986 from the of Technology as Lecturer try, Japan in 1996 from the

University of Tokyo under in 1991 and was promoted Society of Synthetic Organ-

the supervision of Professor to Associate Professor in ic Chemistry, Japan. His re-

Teruaki Mukaiyama. He 1993. In 1999, he was ap- search interests lie in the

joined the Institute of Ad- pointed Associate Professor area of synthetic methodol-

vanced Material Study, Ky- in the Graduate School of ogy, specifically the devel-

ushu University as Assistant Science at the University of opment of novel reactions

Professor in 1985. From Tokyo. He received a Nip- based on the properties of

1989 to 1990, he worked pon Kasei Chemical Award metals and fluorine. Special

as a postdoctoral research in Synthetic Organic Chem- attention is given to a new

associate at Harvard Uni- istry, Japan in 1991, function of fluorine as a ver-

versity with Professor E. J. Progress Award in Synthet- satile synthetic tool.

Corey. After returning to ic Organic Chemistry, Japan

Yukinori Wada was born ceived his BEng in 1996 and he joined Ube Laboratory

in Kurume, Japan in 1972. PhD in 2001 under the guid- of Ube Industries, Ltd. He

He studied chemistry at the ance of Dr. Junji Ichikawa. currently works at the

Department of Applied After studying as a research Pharmaceutical Research

Chemistry, Kyushu Institute student at the University of Department, Ube Industries,

of Technology, where he re- Tokyo from 1999 to 2001, Ltd.

Masaki Fujiwara was born in 1995 and PhD in 2000 un- of Central Glass Co., Ltd.

in Hiroshima, Japan in der the guidance of Dr. Junji He currently works as a

1972. He studied chemistry Ichikawa. After studying as visiting postdoctoral re-

at the Department of Ap- a research student at the search associate at the State

plied Chemistry, Kyushu University of Tokyo from University of New York at

Institute of Technology, 1999 to 2000, he joined the Stony Brook with Professor

where he received his BEng Chemical Research Center Iwao Ojima.

Kotaro Sakoda was born in the University of Tokyo and PhD student at the same

Urawa, Japan in 1977. He received his BSc in 2001. University under the guid-

was trained as a chemist at He is currently working as a ance of Dr. Junji Ichikawa.

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes

1919

The difluorostyrenes were easily prepared as outlined in prepared from 2,2,2-trifluoroethyl p-toluenesulfonate (1)

Scheme 3 by using two kinds of one-pot sequences that and vinyl halides according to our method.^12,15The elec-

we have previously established for a wide range of 1,1-di- tron-rich, non-fluorinated double bond in 8 was expected

fluoro-1-alkenes.^12–14The coupling reactions of 2,2-di- to be more reactive toward borane reagents. Treatment of

fluorovinylboranes 2 [generated in situ from 2,2,2- difluorodienes 8 with 9-borabicyclo[3.3.1]nonane (9-

trifluoroethyl p-toluenesulfonate (1)] or 2,2-difluorovi- BBN) under reflux in THF promoted hydroboration selec-

nylzirconocene 7 [generated in situ from 2,2-difluorovi- tively at the fluorine-free double bond to generate difluo-

nyl p-toluenesulfonate (6)] with N-butylmagnesio-o- rohomoallylboranes. Subsequent treatment with alkaline

iodoaniline or o-iodoaniline, respectively, were effected aqueous hydrogen peroxide gave difluorohomoallyl alco-

in the presence of copper(I) iodide or zinc(II) iodide and a hols 9a–c, precursors of 5-fluorinated 2,3-dihydrofurans,

palladium catalyst. The o-amino- , -difluorostyrene de- in good yields.

rivatives 3a–f, which would act as precursors of 2-fluoro-

indoles, were obtained in good yields. o-Hydroxy- , -

difluorostyrene 4b, a precursor of 2-fluorobenzo[b]furan,

The corresponding nitrogen-containing substrates as pre-

cursors of 2-fluorinated 2-pyrrolines were prepared from

9 as shown in Scheme 4. N-Difluorohomoallyl-p-toluene-

was similarly prepared by the coupling of 2 with o-io-

sulfonamide 10b was derived from 9a by Mitsunobu reac-

doanisole, followed by demethylation with tribromobo-

tion with BocNHTs followed by deprotection of the Boc

rane. For generation of the thiolate moiety, methyl

group.¹⁶The Gabriel synthesis starting from 9c gave

sulfinyl group was selected as an ortho substituent of dif-

amine 10c.¹⁷N-Butyl and N-phenyldifluorohomoally-

luorostyrene. Sulfoxide 5b, a precursor of 2-fluoroben-

lamines 10d,e were prepared from 9c via its tosylate 9d by

zo[b]thiophene, was prepared from 3a via diazotization

substitution with excess butylamine and aniline, respec-

tively. Difluorohomoallyl hydrosulfide 11b, a precursor

of 5-fluorinated 2,3-dihydrothiophene, was similarly ob-

and introduction of a methylthio group, which was oxi-

dized to give the target molecule.

tained from 9d by the introduction of the acetylthio group,

followed by transesterification by treatment with potassi-

R

i, ii

iii

um carbonate in methanol (Scheme 4).

CF₃CH₂OTs

F₂C

CF₂

C

BR₂

Y

2

1

R¹

3–5

R²

i, ii

R²

F₂C

3a Y = NH₂, R = Bu (77%)

F₂C

iv

v

3b Y = NHTs, R = Bu (94%)

3c Y = NH₂, R = sec-Bu (72%)

3d Y = NHTs, R = sec-Bu (93%)

HO

Y

8

9a–c

9d, 10, 11

vi

vii

ix

4a Y = OMe, R = Bu (46%)

4b Y = OH, R = Bu (95%)

R¹= CH₂CH(Me)Ph, R²= Me (58%)

9a

iii

iv

10a Y = NTsBoc, R¹= CH₂CH(Me)Ph, R²= Me (86%)

10b Y = NHTs, R¹= CH₂CH(Me)Ph, R²= Me (91%)

9b R¹= Bu, R²= CH₂Ph (76%)

5a Y = SMe, R = Bu (58%)

viii

5b Y = S(O)Me, R = Bu (83%)

H

9c R¹= (CH₂)₃Ph, R²= Me (72%)

v

OTs

H

x

xi

vi

Y = NH_2,R¹= (CH₂)₃Ph, R²= Me (82%)

vii

ix

10c

F₂C

CF₂

C

CF₂

C

Y = OTs, R¹= (CH₂)₃Ph, R²= Me (80%)

H

ZrCp₂X

9d

Y

viii

xi

Y = NHBu, R¹= (CH₂)₃Ph, R²= Me (65%)

6 (91%)

7

10d

3

x

Y = NHPh, R¹= (CH₂)₃Ph, R²= Me (84%)

3e Y = NH₂

10e

iv

11a Y = SAc, R¹= (CH₂)₃Ph, R²= Me (90%)

11b Y = SH, R¹= (CH₂)₃Ph, R²= Me (95%)

3f Y = NHTs (40% from 6)

Scheme 3 Preparation of , -difluorostyrenes 3–5

Reagents and conditions: i, BuLi (2.1 equiv), THF, –78 °C, 0.5 h; ii,

BR₃(1.1 equiv), THF, –78 °C, 1 h then r.t., 3 h; iii, ArI (0.9 equiv),

CuI (1.0 equiv), Pd₂(dba)₃CHCl₃(0.02 equiv), PPh₃(3a: 0.08 equiv;

3c,4a: 0.16 equiv), THF–HMPA (4:1), r.t., 1 h; iv, TsCl (1.1 equiv),

Pyridine, 0 °C to r.t., 11 h; v, BBr₃(1.1 equiv), CH₂Cl₂, –15 °C to r.t.,

2 h; vi, CF₃CO₂H (2 equiv), i-AmONO (2 equiv), CH₃CN, 0 °C, 0.5

h; vii, aq NaSMe (3 equiv), CH₃CN, 0 °C to r.t., 1.5 h; viii, aq TiCl₃

(2 equiv), aq H₂O₂(3 equiv), MeOH–H₂O, r.t., 2 h; ix, BuLi (2.1

equiv), THF, –78 °C, 0.5 h; x, ‘Cp₂Zr’ (2 equiv), THF, –78 °C to r.t.,

3 h; xi, ArI (1.1 equiv), ZnI₂(1.1 equiv), Pd₂(dba)₃CHCl₃(0.02

equiv), PPh₃(0.16 equiv), THF, reflux, 2 h.

Scheme 4 Preparation of 1,1-difluoro-1-butenes 9–11

Reagents and conditions: i, 9-BBN (9a,c: 1.1 equiv; 9b: 1.4 equiv),

THF, reflux, 6–7 h; ii, aq H₂O₂, aq NaOH, 0 °C, 2 h; iii, BocNHTs (1

equiv), PPh₃(1 equiv), EtO₂CN=NCO₂Et (1 equiv), THF, r.t., 2 h; iv,

CF₃CO₂H (15 equiv), CH₂Cl₂, r.t., 2 h; v, phthalimide (1 equiv), PPh₃

(1 equiv), EtO₂CN=NCO₂Et (1 equiv), THF, r.t.,

2 h; vi,

NH₂NH₂H₂O (2 equiv), EtOH, reflux, 2 h; vii, TsCl (1 equiv), Pyri-

dine, r.t., 8 h; viii, BuNH₂(26 equiv), reflux, 6 h; ix, PhNH₂(26

equiv), reflux, 6 h; x, AcSNa (1 equiv), DMF, 70 °C, 3 h; xi, K₂CO₃

(1 equiv), MeOH, 0 °C, 1 h.

Difluoroalkene substrates bearing a carbon nucleophile,

1,1-difluoro-5-iodo-1-pentenes 13, were easily prepared

as outlined in Scheme 5 by using our one-pot se-

quence.^12,132,2-Difluorovinylboranes 2 were prepared in

To introduce a functional group at the homoallylic posi-

tion of difluorobutene, we tried the regioselective hydro-

boration of the non-fluorinated double bond in 1,1-

difluoro-1,3-butadienes 8 (Scheme 4), which were readily

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

1920

J. Ichikawa et al.

FEATURE ARTICLE

situ from 1 and trialkylboranes (generated by hydrobora-

tion of MOM ethers of allyl and methallyl alcohols). The

palladium-catalyzed coupling reactions of 2 with aryl io-

dides were successively conducted in the presence of cop-

per(I) iodide, followed by deprotection of the MOM

group to afford 12a–e. Thus alcohols 12a–e were trans-

formed into the desired iodides 13a–e via their mesylates.

CO₂Me

i

ii

F₂C

CF₃

BnO

18 (54%)

Y

19 Y = OH (67%)

iii

iv

20 Y = NTsBoc (77%)

17 Y = NHTs (97%)

Scheme 7 Preparation of 3,3-difluoroacrylate 17

Reagents and conditions: i, BnOCH₂Cu (1 equiv), TMSCl (2.5

equiv), THF, –78 °C to r.t., 6 h; ii, BCl₃(1.1 equiv), CH₂Cl₂, –78 °C

i, ii

R'

CF₃CH₂OTs

CF₂

C

BR'₂

to 0 °C,

5 h; iii, BocNHTs (1 equiv), PPh₃(1 equiv),

2 R' = -CH₂CHRCH₂OMOM

1

EtO₂CN=NCO₂Et (1 equiv), THF, r.t., 10 h; iv, CF₃CO₂H (3 equiv),

CH₂Cl₂, r.t., 7 h.

Ar

v, vi

iii, iv

F₂C

5-endo-trig Cyclization of Functionalized 1,1-Difluo-

ro-1-alkenes

I

HO

R

12a (43%)

12b (54%)

12c (47%)

12d (75%)

12e (58%)

13a (83%)

13b (77%)

13c (72%)

13d (68%)

13e (90%)

Ar = Ph, R = H

Cyclization of o-amino- , -difluorostyrene 3a by treat-

ment with 1.2 equivalents of BuLi did not proceed. To al-

ter the reactivity of the N-nucleophile, 3a was transformed

to the corresponding acetamide and p-toluenesulfonamide

3b.^2a,21Although treatment of the acetamide with 1.2

equivalents of sodium hydride in DMF resulted in a com-

plex mixture of products, the same conditions successful-

ly promoted the ‘disfavored’ 5-endo-trig-cyclization of

Ar = C₆H₄-p-CF₃, R = H

Ar = C₆H₄-p-MeO, R = H

Ar = Ph, R = Me

Ar = C₆H₄-p-MeO, R = Me

Scheme 5 Preparation of 1,1-difluoro-5-iodo-1-pentenes 13

Reagents and conditions: i, BuLi (2.1 equiv), THF, –78 °C, 0.5 h; ii,

BR ₃(12a,b,d: 1.0 equiv; 12c,e: 1.1 equiv), THF, –78 °C, 1 h then re-

flux, 1 h; iii, ArI (0.8 equiv), CuI (1.0 equiv), Pd₂(dba)₃CHCl₃(0.02 sulfonamide 3b to afford 2-fluoroindole 21a in 84% yield

(Scheme 8).²²Successful ring closure did not require the

use of high-dilution conditions, and proceeded smoothly

even in the case of difluorostyrenes 3d and 3f bearing a

secondary alkyl group or a hydrogen atom at the -posi-

tion. Similarly, this type of cyclization was satisfactorily

achieved with an intramolecular oxygen nucleophile.

When hydroxystyrene 4b was treated under similar condi-

tions, the 5-endo-trig cyclization of the corresponding

alkoxide occurred leading to 2-fluorobenzo[b]furan 22 in

equiv), PPh₃(12a,b,d: 0.08 equiv; 12c,e: 0.16 equiv), THF–HMPA

(4:1), r.t., 1 h; iv, aq HCl, THF, r.t., 1 h; v, MsCl (1.5 equiv), Et₃N (1.5

equiv), CH₂Cl₂, 0 °C to r.t., 4 h; vi, NaI (10 equiv), acetone, reflux, 5

h.

-Monofluorinated o-hydroxystyrenes 16 were prepared

as shown in Scheme 6. Both E- and Z-isomers of 15 were

obtained in a ratio of 53:47 by the reduction of OH-pro-

tected hydroxystyrene 14 with sodium bis(2-methoxy-

ethoxy)aluminum hydride (Red-Al).¹⁸After separation by

80% yield (Scheme 8).²³

chromatography, they were deprotected to give 16E and

16Z (Scheme 6).

R

i

F₂C

TsHN

Bu

F

i

iii

N

Ts

F₂C

F CY

F CH

3b

3d

3f

21a R = n-Bu (84%)

21b R = sec-Bu (81%)

21c R = H (73%)

HO

MOMO

HO

4b

14 Y = F (92%)

16E (86%)

16Z (84%)

ii

15 Y = H (88%, E/Z = 53/47)

Bu

Scheme 6 Preparation of -fluorostyrenes 16

ii

Reagents and conditions: i, NaH (1.1 equiv), MOMCl (3 equiv), THF,

–78 °C, 5 h; ii, Red-Al (2.8 equiv), toluene, 0 °C to reflux, 3 h; iii,

concd HCl, THF, 0 °C, 2.5 h.

F₂C

F

O

HO

22 (80%)

4b

3,3-Difluoroacrylate 17 was prepared as depicted in

Scheme 7. The S_N2 reaction of methyl 2-(trifluorometh-

yl)acrylate¹⁹with (benzyloxymethyl)copper²⁰[generated

in situ from (benzyloxymethyl)tributyltin] proceeded with

a loss of a fluoride ion to afford , -difluoro- , -unsatur-

ated ester 18. Subsequent deprotection of the benzyl

group followed by the introduction of N-functional group

via Mitsunobu reaction with BocNHTs yielded 20, which

after deprotection gave the desired substrate 17.¹⁶

Scheme

zo[b]furan 22

8

Synthesis of 2-fluoroindoles 21 and 2-fluoroben-

Reagents and conditions: i, NaH (1.2 equiv), DMF, 3b: 80 °C, 7 h;

3d: 80 °C, 5 h; 3f: 70 °C, 23 h, [3] = 0.2 M; ii, NaH (1.2 equiv), DMF,

60 °C, 2 h, [4b] = 0.1 M.

As a further example of this cyclization, we next tried the

intramolecular substitution utilizing a sulfur nucleophile,

which is favored by Baldwin’s rules since second-row el-

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes

1921

ements are allowed to obtain the appropriate conforma- tion, the intramolecular substitution of sulfur nucleophiles

tion in the 5-endo-trig process.^1bThe Pummerer (which is allowed for normally disfavored 5-endo-trig

rearrangement of , -difluoro-o-methysulfinylstyrene 5b process by Baldwin’s rules) was also examined.^1bThe re-

followed by transesterification brought about the cycliza- action of 11b under the above mentioned conditions pro-

tion via intermediary hemiacetal trifluoroacetate 23 (not vided 5-fluorinated dihydrothiophene 27 in 76% yield.²⁸

isolated) by loss of formaldehyde. Namely, successive In addition, treatment of thioacetic S-acid ester 11a with

treatment of 5b with (i) trifluoroacetic anhydride and tri- sodium methoxide directly gave the cyclization product

ethylamine in dichloromethane and (ii) potassium carbon- 27 via in situ generated thiolate.

ate in methanol provided 2-fluorobenzo[b]thiophene 24 in

82% yield (Scheme 9).²⁴

R¹

R²

i

F₂C

Bu

ZS

Bu

F

O

i

ii

HO

F₂C

F

25a R¹= CH₂CH(Me)Ph, R²= Me (67%)

25b R¹= Bu, R²= CH₂Ph (62%)

9a

9b

S

Me(O)S

5b

24 (82%)

23 Z = CH₂OCOCF₃

CH₂CH(Me)Ph

Me

PhCH(Me)CH₂

Me

Scheme 9 Synthesis of 2-fluorobenzo[b]thiophene 24

Reagents and conditions: i, (CF₃CO)₂O (3 equiv), Et₃N (3 equiv),

CH₂Cl₂, 0 °C, 0.5 h; ii, K₂CO₃(6 equiv), MeOH, 0 °C to reflux, 3 h.

ii

F₂C

F

N

TsHN

Ts

10b

26 (80%)

In the above-mentioned ring-forming reaction, the sub-

strates contain a benzene ring as an sp²-carbon linker be-

tween the nucleophilic functional group and the

difluoroalkene part, which could allow a 6 -electrocy-

clization process to work. In order to rule out the possibil-

ity of the electrocyclization mechanism²⁵and to broaden

the scope of this nucleophilic 5-endo-trig cyclization, we

investigated the reaction of 1,1-difluoro-1-butenes 9–11

bearing an N-, O-, or S-functional group linked by two sp³

carbons to the vinylic carbon. Thus, the reaction would af-

ford ring-fluorinated five-membered heterocycles, such

as pyrroline, dihydrofuran, and dihydrothiophene.

(CH₂)₃Ph

Ph(CH₂)₃

Me

iii or iv

Me

F₂C

F

S

YS

11b Y = H

11a Y = Ac

27 (76% from 11b)

(69% from 11a)

Scheme 10 Synthesis of 5-fluoro-2,3-dihydrofurans 25, 2-fluoro-

pyrroline 26, and 5-fluoro-2,3-dihydrothiophene 27

Reagents and conditions: i, NaH (1.2 equiv), DMF, 90 °C, 25a: 7 h;

25b: 11 h; ii, NaH (1.1 equiv), DMF, 90 °C, 4 d; iii, 11b: NaH (1.1

equiv), DMF, 90 °C, 4 h; iv, 11a: NaOMe (1 equiv), DMF, 90 °C, 8 h.

The cyclization of homoallyl alcohols 9a,b was attempted

by treatment with 1.2 equivalents of sodium hydride in

several solvents. While the use of N,N -dimethylpropyl-

eneurea (DMPU) or 1-methyl-2-pyrrolidinone (NMP)

gave no cyclized products, dimethyl sulfoxide (DMSO),

N,N-dimethylacetamide (DMA), or DMF successfully

promoted the 5-endo-trig cyclization to afford 5-fluoro-

2,3-dihydrofurans 25a,b in good yields (Scheme 10).²⁶

Potassium hydride was less effective than sodium hy-

dride, and high-dilution conditions ([9a] = 0.03 M) raised

the yield by 10% compared to the case of [9a] = 0.2 M.

These results demonstrate that the cyclization proceeds

not via the 6 -electrocyclization process²⁵but via the

intramolecular addition–elimination process and that

normally ‘disfavored’ 5-endo-trig ring closures are suc-

cessfully achieved in the reaction of 1,1-difluoro-1-alk-

enes bearing a nucleophilic heteroatom linked by two sp³-

carbons to the vinylic carbon as well as two sp²-carbons.

Thus, 4,4-difluorohomoallylic amine, alcohol, and thiol

derivatives open a new route for the synthesis of selective-

ly ring-fluorinated heterocyclic compounds.

Furthermore, we examined the 5-endo-trig cyclization of

the substrates with a N-nucleophile under similar condi-

tions, and found that the course of reaction depended on

the substituents on the nitrogen.²¹Whereas N-unsubstitut-

ed and N-butylhomoallylamines 10c,d did not cyclize, N-

phenylated substrate 10e afforded 4-methyl-1-phenyl-3-

(3-phenylpropyl)-2-pyrrolidone in 62% yield via hydroly-

sis of the C–F bond in the expected 2-fluoropyrroline.

p-Toluenesulfonamide 10b underwent the desired ring

closure to give 2-fluorinated pyrroline 26 in 80% yield

(Scheme 10).²⁷A similar preference for the tosylamido

group was observed in the cyclization of o-substituted

, -difluorostyrenes 3, which leads to 2-fluoroindoles 21

as mentioned above. As a further example of the cycliza-

Including our examples mentioned above,^5a-bmost nu-

cleophilic 5-endo-trig ring closures that have been report-

ed are effected by heteronucleophiles.^4a–c,6Although

carbocyclizations have great potential as effective car-

bon-carbon bond-forming reactions,²⁹they are most-

ly limited to a few examples of 5-endo trig addition of

stabilized carbanions (anions to carbonyl or cyano

groups) to electrophilic double bonds such as (1) alkenes

activated by sulfonyl, cyano, nitro, or carbonyl

groups,^4c–e(2) imines,^4f,gand also to (3) -allylpalladium

system.^4hOne exception, to our knowledge, is the cycliza-

tion of 2-(3-bromopropyl)-2-cyclohexenone via alkyl an-

ion generated by electrochemical reduction. This

cyclization is remarkably facilitated in microemulsions.⁴ⁱ

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

1922

J. Ichikawa et al.

FEATURE ARTICLE

We therefore turned our attention to the 5-endo-trig cy- nucleophiles but also by sp³-carbon nucleophiles, to

clization of 1,1-difluoro-1-alkenes with a non-stabilized which much less contribution has been made in spite of

sp³-carbon nucleophile to broaden the application of this their potential utility. By addition of this carbocyclization,

cyclization. For the generation of sp³-carbanions, metal- the scope of the intramolecular substitution of 1,1-difluo-

halogen exchange was adopted. Thus, the ring-forming ro-1-alkenes has been expanded in terms of five-mem-

reaction of 1,1-difluoro-1-alkenes bearing an iodine bered ring formation.

substituent was examined as a new synthetic method for

1-fluorocyclopentenes,^5cwhich is currently limited to a

Effect of Fluorine Substituents on 5-endo-trig

difluorination–dehydrofluorination sequence starting

Cyclization

from cyclic ketones.³⁰

In order to confirm the effect of fluorine on the reactivity

in the 5-endo-trig cyclization, we conducted similar reac-

tions of -monofluoro-, , -dichloro-, and , -dibromo-

Following the reported procedure for lithium-halogen ex-

change of primary alkyl iodides,³¹1,1-difluoro-5-iodo-4-

methyl-2-phenyl-1-pentene 13d was treated with 2.2

o-hydroxystyrenes 16, 29, and 30. The results are summa-

equivalents of tert-butyllithium in diethyl ether–hexane at

rized in Table 1.

–78 °C. The reaction was quenched at –78 °C to give the

cyclized product, 1-fluorocyclopentene 28d in 28% yield

along with 28% yield of the reduced product, 1,1-difluo-

ro-4-methyl-2-phenyl-1-pentene, whose formation con-

Table 1 Effect of Vinylic Fluorine on 5-endo-trig Cyclization

Bu

firmed the generation of the carbanion. The cyclization

NaH (1.2 equiv)

DMF

XCY

was effectively promoted by allowing the reaction mix-

ture to stand at room temperature for 1 h, improving the

yield of 28d up to 69%. When 1,1-difluoro-2-phenyl-1-

hexene was treated with 1.1 equivalents of butyllithium as

an external nucleophile under the same reaction condi-

tions, the intermolecular substitution of the butyl group

for the vinylic fluorine occurred to give the E/Z mixture

(E/Z = 70:30) of products in 69% yield. In the case of the

reaction of 13d in diethyl ether, direct replacement of the

fluorine by tert-butyllithium took place as a side reaction

in 10% yield.

Y

O

HO

4b, 16, 29, 30

22, 31, 32

Entry

X

F

Y

F

H

Substrate Conditions

Product Yield (%)

1

2

3

4

5

4b

60 °C, 2 h

80 °C, 43 h

60 °C, 8 h

60 °C, 5 h

22

31

–

80

17

19

16E

16Z

a

Cl Cl 29

Br Br 30

–

Cyclizations of several other 1,1-difluoro-5-iodo-1-

pentenes 13 were examined under the conditions opti-

mized above, and their results are shown in Scheme 11.

Concerning para-substituents on the 2-phenyl group,

electron-withdrawing and electron-donating groups had

little effect on the cyclization. 1,1-Difluoro-2-(3-iodopro-

pyl)-4-phenyl-1-pentene, a substrate without an aryl

group on the vinylic carbon, underwent no cyclization on

treatment with 2.2 equivalents of tert-butyllithium under

the same reaction conditions as those for 13, which shows

a sharp contrast to the cyclizations of 4,4-difluorohomoal-

lylic amine, alcohol, and thiol derivatives (Scheme 10).

32

15

^aStarting material 29 (80%) was recovered.

The reactions of the both E and Z isomers, 16E and Z,

with sodium hydride required harsher conditions

(Table 1, Entries 2 and 3) than that of 4b (Entry 1), lead-

ing to low yields of the cyclized product (no more than 20

%). These observations revealed that two vinylic fluorines

are essential to activate the substrate sufficiently for the

nucleophilic 5-endo-trig cyclization. Dichloro and dibro-

mo counterparts 29 and 30 (prepared via dihalomethyl-

enation of the corresponding OH-protected ketone

according to reported methods³²) gave poor results, even

though chlorine and bromine have better leaving-group

ability compared to fluorine (Entries 4 and 5). These re-

sults suggest that the crucial step is the cyclization (addi-

tion), not the elimination. Thus, the major distinction of

the 1,1-difluoro-1-alkenes appears to be the remarkable

polarization of the double bond, which is caused by the re-

pulsive interaction between the lone pairs of fluorine and

the -electrons. Such repulsion is much stronger for fluo-

rine than for other halogens, due to the 2p-orbital occu-

5-endo-trig Cyclizations of 1,1-difluoro-1-alkenes are

successfully achieved not only by intramolecular hetero-

Ar

i

F₂C

F

R

I

R

28a Ar = Ph, R = H (76%)

13a–e

28b Ar = C₆H₄-p-CF₃, R = H (65%)

28c Ar = C₆H₄-p-MeO, R = H (74%)

28d Ar = Ph, R = Me (69%)

28e Ar = C₆H₄-p-MeO, R = Me (69%)

pancy of both the lone pairs and

-electrons.

Consequently, the two vinylic fluorine substituents have

proven to be essential and play a critical role in promoting

the 5-endo-trig cyclization of 1,1-difluoro-1-alkenes.

Scheme 11 Synthesis of 1-fluorocyclopentenes 28

Reagents and conditions: i, t-BuLi (2.2 equiv), Et₂O–hexane (1:4), –

78 °C, 0.5 h then r.t., 1 h, [13] = 0.04 M.

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes

1923

♦ Difluorinated substrate

CF₂

O

CO₂Me

"5-exo-trig"

"5-endo-trig"

OMe

O

F

NaH (1.1 eq)

100 °C, 15 min

DMF

N

TsHN

CF₂

Ts

35 (62%)

19

♦ Fluorine-free substrate^1a

CH₂

CO₂Me

O

"5-endo-trig"

"5-exo-trig"

MeO₂C

OMe

O

MeO₂C

N

H

N

H₂N

CH₂

33

H

34

Scheme 12 Competitive cyclization: 5-endo-trig vs 5-exo-trig.

The favored nature of 5-endo-trig cyclization in 1,1-diflu- has been revealed that the two vinylic fluorine substitu-

oro-1-alkenes could be demonstrated by the competitive ents are essential and play a critical role in such 5-endo-

reaction between 5-endo-trig and 5-exo-trig processes. trig-cyclization.

Baldwin reported the cyclization of dimethyl 4-methyl-

The intramolecular cyclizations of 1,1-difluoro-1-alkenes

selectively afforded ring-fluorinated cyclic compounds,

for which only a limited number of synthetic methods

eneglutamate 33, showing how difficult 5-endo-trig cy-

clizations are.^1aIn this substrate, although there are two

competitive reaction sites to be attacked by the intramo-

have been reported. Thus, the present methodology pro-

lecular nitrogen in a 5-endo-trig fashion (Michael addi-

vides a solution to the synthetic problem of fluorinated

hetero- and carbocycles. The synthesized compounds may

be widely used as important components in the pharma-

ceutical, agrochemical, and dyestuffs industries. Further-

more, the ‘anti-Baldwin’ results indicate that some of the

unique reactivities of 1,1-difluoro-1-alkenes are derived

tion) and a 5-exo-trig fashion (transacylation), the

reaction afforded only the 5-exo-trig product 34

(Scheme 12). For comparison, we selected the difluorinat-

ed analog, , -difluoro- , -unsaturated ester 19 bearing a

2-(p-toluenesulfonamido)ethyl group, as a substrate.

On treatment of 19 with sodium hydride in DMF, the 5- from the properties of fluorine, which sheds light on a new

endo-trig cyclization occurred exclusively to give the 2- function of fluorine in synthetic chemistry.

fluorinated pyrroline derivative 35 in 62% yield as shown

in Scheme 12. The 5-exo-trig product was not detected in

NMR spectra were obtained on a JEOL JNM-A-500, JNM-AL-270,

19

the reaction mixture by F NMR measurement. This re-

sult shows a striking contrast to the reaction of 33, clearly

indicating the effect of fluorines on the course of cycliza-

tion.

or a Bruker DRX-500 spectrometer. Chemical shift values were

given in ppm relative to internal SiMe₄(for ¹H and ¹³C NMR: -val-

ue) or C₆F₆(for ¹⁹F NMR: _F-value). IR spectra were recorded on a

Horiba FT-300S or a JEOL JIR-WINSPEC50 spectrometer. Mass

spectra were taken with a JEOL JMS-DX-300 or a JEOL JMS-SX-

102A spectrometer under electron impact (EI) unless otherwise

noted. Elemental analyses were performed with a YANAKO MT-3

CHN Corder apparatus. THF was distilled from sodium diphe-

nylketyl prior to use. Methanol was distilled from magnesium meth-

oxide and stored over molecular sieves 3Å. DMF was dried over

P₂O₅, then distilled under reduced pressure from CaH₂and stored

over molecular sieves 4Å. Commercial NaH was used without fur-

ther purification. NaOMe was prepared from sodium and excess

MeOH, and then dried under vacuum at 100 °C. 2,2,2-Trifluoro-

ethyl p-toluenesulfonate (1) was purchased from Aldrich and re-

crystallized from hexane–Et₂O. 1,1-Difluoro-1,3-butadienes 8 were

prepared according to the literature.¹⁵

Conclusion

The ring-fluorinated 5-membered hetero- and carbocycles

such as indole, benzo[b]furan, benzo[b]thiophene, 2-pyr-

roline, 2,3-dihydrofuran, 2,3-dihydrothiophene, and cy-

clopentene have been successfully constructed via

intramolecular substitution of the vinylic fluorine in 1,1-

difluoro-1-alkenes bearing a nucleophilic moiety. This

type of reaction is classified as a 5-endo-trig ring closure,

a disfavored process in Baldwin’s rules, and has only rare-

ly been observed in synthetic chemistry. The nucleophilic

5-endo-trig cyclizations have been achieved by taking ad-

vantage of the exceptional properties of fluorine. In addi-

tion, by conducting the cyclization of -monofluoro-, , -

dichloro-, and , -dibromostyrenes and the competitive

reaction between 5-endo-trig and 5-exo-trig processes, it

o-(1-Butyl-2,2-difluorovinyl)aniline (3a)

BuLi (1.6 mL, 1.6 M in hexane, 2.5 mmol) was added to a solution

of 2,2,2-trifluoroethyl p-toluenesulfonate (1, 307 mg, 1.2 mmol) in

THF (10 mL) at –78 °C over 10 min under nitrogen. The reaction

mixture was stirred for 20 min at –78 °C, and then Bu₃B (1.3 mL,

1.0 M in THF, 1.3 mmol) was added at –78 °C. After stirring for 1

h, the reaction mixture was warmed to r.t. and stirred for an addi-

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

1924

J. Ichikawa et al.

FEATURE ARTICLE

tional 3 h. The solution was treated with HMPA (3 mL), PPh₃(25

mg, 0.10 mmol), and Pd₂(dba)₃CHCl₃, (25 mg, 0.024 mmol) and

stirred for 15 min. To the solution was added the magnesium salt

[generated from o-iodoaniline (238 mg, 1.1 mmol) and dibutylmag-

nesium (2.5 mL, 0.44 M in Et₂O, 1.1 mmol) in THF (3 mL) at 0 °C

for 30 min] and CuI (230 mg, 1.2 mmol). After the mixture had been

stirred for 1 h at r.t., the reaction was quenched with phosphate buff-

er (pH 7). The mixture was filtered through Celite, and then organic

materials were extracted with EtOAc (3 15 mL). The combined

extracts were washed with brine (10 mL) and dried over Na₂SO₄.

After removal of the solvent under reduced pressure, the residue

was purified by column chromatography on silica gel (hexane–

EtOAc 10:1) to give 3a (176 mg, 77%) as a yellow liquid.

IR (neat): 3390, 2960, 1730, 1615, 1495, 1455, 1300, 1215, 935,

750 cm^–1.

¹H NMR [500 MHz, (CD₃)₂SO, 100 °C]: = 0.99 (3 H, t, J = 7.3

Hz), 1.03–1.15 (3 H, m), 1.31–1.45 (1 H, m), 1.54–1.66 (1 H, m),

2.44–2.58 (1 H, m), 4.58 (2 H, br s), 6.62 (1 H, ddd, J = 7.4, 7.4, 1.4

Hz), 6.79 (1 H, d, J = 7.4 Hz), 6.92 (1 H, d, J = 7.4 Hz), 7.07 (1 H,

ddd, J = 7.4, 7.4, 1.4 Hz).

¹³C NMR [126 MHz, (CD₃)₂SO, 100 °C]: = 10.1, 17.2, 26.9, 34.5,

92.4 (dd, J_CF= 16, 16 Hz), 114.5, 115.4, 116.1, 127.8, 129.6, 145.8,

151.7 (dd, J_CF= 291, 285 Hz).

¹⁹F NMR (254 MHz, (CD₃)₂SO, 100 °C): = 71.2 (1 F, d, J_FF= 49

Hz), 74.1 (1 F, d, J_FF= 49 Hz).

IR (neat): 3475, 3375, 2960, 2930, 2860, 1740, 1620, 1495, 1230

cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.87 (3 H, t, J = 7.1 Hz), 1.30–

1.35 (4 H, m), 2.29 (2 H, tt, J = 7.0 Hz, J_HF= 2.3 Hz), 3.66 (2 H, br

s), 6.70–6.77 (2 H, m), 7.00 (1 H, dd, J = 7.6, 1.5 Hz), 7.12 (1 H,

ddd, J = 7.6, 7.6, 1.5 Hz).

MS (70 eV): m/z (%) = 211 (M⁺, 100), 182 (57), 162 (82).

HRMS: m/z calcd for C₁₂H₁₅NF₂(M⁺): 211.1173; found: 211.1184.

o -(1-sec-Butyl-2,2-difluorovinyl)-p-toluenesulfonanilide (3d)

Compound 3d was prepared by the method described for 3b using

TsCl (265 mg, 1.4 mmol), pyridine (5 mL), and 3c (196 mg, 0.93

mmol). Purification by PTLC on silica gel (hexane–EtOAc 5:1)

gave 3d (315 mg, 93%) as a pale yellow solid.

¹³C NMR (126 MHz, CDCl₃): = 13.8, 22.4, 27.7, 29.8 (dd,

J_CF= 3, 3 Hz), 89.1 (dd, J_CF= 22, 17 Hz), 115.6, 118.4, 119.0 (d,

IR (neat): 3280, 2966, 2933, 1732, 1495, 1400, 1338, 1244, 1163,

665 cm^–1.

J

_CF= 3 Hz), 128.9, 130.6, (d, J_CF= 2 Hz), 144.3, 152.8 (dd,

J_CF= 290, 288 Hz).

¹H NMR [500 MHz, (CD₃)₂SO, 80 °C]: = 0.93 (3 H, t, J = 7.1

Hz), 1.06 (3 H, d, J = 7.1 Hz), 1.24–1.37 (1 H, m), 1.57 (1 H, dqd,

J = 13.8, 7.1, 7.1 Hz), 2.30–2.43 (1 H, m), 2.41 (3 H, s), 7.11–7.16

(2 H, m), 7.22–7.27 (2 H, m), 7.41 (2 H, d, J = 8.1 Hz), 7.80 (2 H,

d, J = 8.1 Hz), 9.28 (1 H, br s).

¹³C NMR [126 MHz, (CD₃)₂SO, 80 °C]: = 11.2, 17.1, 20.4, 27.0,

34.8, 92.7 (dd, J_CF= 19, 15 Hz), 121.6, 124.0, 126.3, 126.5, 128.0,

129.1, 130.9, 135.9, 137.9, 142.7, 152.2 (dd, J_CF= 290, 284 Hz).

¹⁹F NMR [254 MHz, (CD₃)₂SO, 80 °C]: = 73.6 (1 F, d, J_FF= 46

Hz), 76.9 (1 F, d, J_FF= 46 Hz).

MS (70 eV): m/z = 365 (M⁺), 210, 136.

¹⁹F NMR (470 MHz, CDCl₃): = 72.7 (1 F, d, J_FF= 43 Hz), 68.7 (1

F, d, J_FF= 43 Hz).

MS (70 eV): m/z (%) = 211 (M⁺, 100), 168 (59), 148 (43).

Anal. Calcd for C₁₂H₁₅NF₂: C, 68.23; H, 7.16; N, 6.63. Found: C,

68.14; H, 7.07, N; 6.52.

o -(1-Butyl-2,2-difluorovinyl)-p-toluenesulfonanilide (3b)

TsCl (518 mg, 2.7 mmol) was added to a solution of 3a (382 mg, 1.8

mmol) in pyridine (6 mL) at 0 °C. The reaction mixture was stirred

for 11 h at r.t., and the reaction was quenched with phosphate buffer

(pH 7). Organic materials was extracted with EtOAc (3 20 mL).

The combined extracts were washed with aq HCl (10 mL) and dried

over Na₂SO₄. After removal of the solvent under reduced pressure,

the residue was purified by preparative thin layer chromatography

(PTLC) on silica gel (hexane–EtOAc, 5:1) to give 3b (620 mg,

94%) as an orange solid.

Anal. Calcd for C₁₉H₂₁NO₂SF₂: C, 62.45; H, 5.79; N, 3.83. Found:

C, 62.38; H, 5.89; N, 3.90.

o-(1-Butyl-2,2-difluorovinyl)anisole (4a)

BuLi (0.79 mL, 1.6 M in hexane, 1.3 mmol) was added to a solution

of 1 (155 mg, 0.61 mmol) in THF (3 mL) at –78 °C over 10 min un-

der nitrogen. The reaction mixture was stirred for 20 min at –78 °C,

and then Bu₃B (0.67 mL, 1.0 M in THF, 0.67 mmol) was added at

–78 °C. After being stirred for 1 h, the reaction mixture was warmed

to r.t. and stirred for an additional 3 h. The solution was treated with

HMPA (1 mL), PPh₃(25 mg, 0.098 mmol), and Pd₂(dba)₃CHCl₃

(13 mg, 0.012 mmol) and stirred for 15 min. To the solution was

added o-iodoanisole (129 mg, 0.55 mmol) and CuI (116 mg, 0.61

mmol). After the mixture was stirred for 16 h at r.t., the reaction was

quenched with phosphate buffer (pH 7). The mixture was filtered

through Celite, and then organic materials were extracted with

EtOAc (3 10 mL). The combined extracts were washed with brine

(10 mL) and dried over Na₂SO₄. After removal of the solvent under

reduced pressure, the residue was purified by PTLC on silica gel

(hexane–EtOAc, 50:1) to give 4a (58 mg, 46%) as a colorless liquid.

IR (neat): 3274, 2958, 1741, 1494, 1402, 1340, 1245, 1168, 1093,

916, 665, 566 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.79 (3 H, t, J = 7.3 Hz), 1.06–

1.22 (4 H, m), 1.99 (2 H, br s), 2.35 (3 H, s), 6.85 (1 H, s), 7.02 (1

H, dd, J = 7.4, 1.7 Hz), 7.05 (1 H, ddd, J = 7.4, 7.4, 1.0 Hz), 7.19–

7.27 (3 H, m), 7.63 (1 H, d, J = 7.9 Hz), 7.73 (2 H, d, J = 8.2 Hz).

¹³C NMR (126 MHz, CDCl₃): = 13.5, 21.4, 22.2, 28.0, 29.3, 87.9

(dd, J_CF= 23, 17 Hz), 119.6, 124.2, 127.1, 129.0, 129.6, 130.7,

135.0, 136.4, 144.0, 152.9 (dd, J_CF= 292, 288 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 71.8 (1 F, d, J_FF= 39 Hz), 74.9 (1

F, d, J_FF= 39 Hz).

MS (70 eV): m/z (%) = 365 (M⁺, 3), 210 (100), 148 (86).

HRMS: m/z calcd for C₁₉H₂₁NO₂F₂S (M⁺): 365.1261; found:

365.1221.

IR (neat): 2960, 2930, 1740, 1490, 1460, 1270, 1245, 1230, 1025,

750 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.85 (3 H, t, J = 7.2 Hz), 1.21–

1.34 (4 H, m), 2.30–2.35 (2 H, m), 3.80 (3 H, s), 6.89 (1 H, d, J = 7.6

Hz), 6.93 (1 H, ddd, J = 7.6, 7.6, 0.9 Hz), 7.12 (1 H, dd, J = 7.6, 1.6

Hz), 7.27 (1 H, ddd, J = 7.6, 7.6, 1.6 Hz).

¹³C NMR (126 MHz, CDCl₃): = 13.8, 22.2, 27.5, 29.7 (d, J_CF= 2

Hz), 55.4, 89.4 (dd, J_CF= 23, 16 Hz), 111.0, 120.4, 123.0 (dd,

J_CF= 3, 3 Hz) 129.0, 131.1 (d, J_CF= 2 Hz), 153.0 (dd, J_CF= 286,

286 Hz), 157.4 (d, J_CF= 2 Hz).

o-(1-sec-Butyl-2,2-difluorovinyl)aniline (3c)

Compound 3c was prepared by the method described for 3a using

BuLi (3.7 mL, 1.6 M in hexane, 6.0 mmol), 1 (719 mg, 2.8 mmol),

THF (14 mL), s-Bu₃B (3.1 mL, 1.0 M in THF, 3.1 mmol), HMPA

(4 mL), PPh₃(119 mg, 0.45 mmol), Pd₂(dba)₃CHCl₃(59 mg, 0.057

mmol), o-iodoaniline (558 mg, 2.6 mmol), dibutylmagnesium (2.6

mL, 1.0 M in Et₂O, 2.6 mmol), THF (2 mL), and CuI (593 mg, 2.8

mmol). Purification by column chromatography on silica gel (hex-

ane–EtOAc, 30:1) gave 3c (395 mg, 72%) as a pale yellow liquid.

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes

1925

¹⁹F NMR (470 MHz, CDCl₃): = 67.1 (1 F, dd, J_FF= 46 Hz, J_FH= 3

Hz), 70.9 (1 F, d, J_FF= 46 Hz).

pressure, the residue was purified by PTLC on silica gel (hexane–

EtOAc, 1:2) to give 5b (83 mg, 83%) as a colorless liquid.

MS (20 eV): m/z (%) = 226 (M⁺, 73), 215 (58), 149 (100).

HRMS: m/z calcd for C₁₃H₁₆OF₂(M⁺): 226.1169; found: 226.1171.

IR (neat): 2958, 2931, 1739, 1467, 1234, 1122, 1072, 1043, 968,

769 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.85–0.90 (3 H, m), 1.27–1.39 (4

H, m), 2.28–2.40 (2 H, m), 2.67 (3 H, s), 7.21 (1 H, dd, J = 7.6, 1.3

Hz), 7.51 (1 H, ddd, J = 7.6, 7.6, 1.3 Hz), 7.60 (1 H, ddd, J = 7.6,

7.6, 1.3 Hz), 8.10 (1 H, dd, J = 7.6, 1.3 Hz).

o-(1-Butyl-2,2-difluorovinyl)phenol (4b)

BBr₃(0.85 mL, 1.0 M in CH₂Cl₂, 0.85 mmol) was added to a solu-

tion of 4a (175 mg, 0.77 mmol) in CH₂Cl₂(5 mL) at –15 °C. The

reaction mixture was stirred for 2 h at r.t. The reaction was

quenched with phosphate buffer (pH 7), and then organic materials

were extracted with CH₂Cl₂(3 10 mL). The combined extracts

were washed with brine (10 mL) and dried over Na₂SO₄. After re-

moval of the solvent under reduced pressure, the residue was puri-

fied by PTLC on silica gel (hexane–EtOAc 10:1) to give 4b (156

mg, 95%) as a colorless liquid.

¹³C NMR (126 MHz, CDCl₃): = 13.7, 22.3, 28.7, 29.5 (dd,

J_CF= 3, 3 Hz), 43.5 (d, J_CF= 2 Hz), 89.9 (dd, J_CF= 24, 16 Hz),

123.9, 129.7, 130.5 (d, J_CF= 3 Hz), 131.0 (d, J_CF= 4 Hz), 131.2,

145.0 (d, J_CF= 2 Hz), 152.0 (dd, J_CF= 291, 286 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 70.4 (1 F, d, J_FF= 42 Hz), 74.1 (1

F, br d).

MS (70 eV): m/z (%) = 258 (M⁺, 46), 241 (23), 215 (100).

IR (neat): 3430, 2950, 2930, 2860, 1740, 1450, 1130, 965, 755 cm^–1.

HRMS: m/z calcd for C₁₃H₁₆OF₂S (M⁺): 258.0890; found:

258.0876.

¹H NMR (500 MHz, CDCl₃): = 0.87 (3 H, t, J = 7.2 Hz), 1.25–

1.36 (4 H, m), 2.33 (2 H, tt, J = 7.2 Hz, J_HF= 2.2 Hz), 4.88 (1 H, s),

6.88–6.96 (2 H, m), 7.03–7.12 (1 H, m), 7.19–7.26 (1 H, m).

¹³C NMR (126 MHz, CDCl₃): = 13.7, 22.2, 28.0, 29.7 (dd,

J_CF= 3, 3 Hz), 87.7 (dd, J_CF= 23, 16 Hz), 115.6, 115.9 (d, J_CF= 6

Hz) 120.7, 129.4, 129.7, 130.5, 153.2 (dd, J_CF= 307, 280 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 70.3 (1 F, dt, J_FF= 41 Hz, J_FH= 3

Hz), 73.8 (1 F, d, J_FF= 41 Hz).

MS (70 eV): m/z (%) = 212 (M⁺, 34), 192 (33), 107 (74).

2,2-Difluorovinyl p-Toluenesulfonate (6)

BuLi (39 mL, 1.6 M in hexane, 63 mmol) was added to a solution

of 1 (7.62 g, 30 mmol) in THF (150 mL) at –78 °C over 10 min un-

der nitrogen. The reaction mixture was stirred for 20 min at –78 °C,

and then the reaction was quenched with H₂O–THF (1:1, 100 mL).

Organic materials were extracted with EtOAc (3 80 mL), the com-

bined extracts were washed with brine (80 mL) and dried over

MgSO₄. After removal of the solvent under reduced pressure, the

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

ane–EtOAc, 10:1) to give 6 (6.40 g, 91%) as a colorless liquid.

HRMS: m/z calcd for C₁₂H₁₄OF₂(M⁺): 212.1013; found: 212.1008.

o-(1-Butyl-2,2-difluorovinyl)phenyl Methyl Sulfide (5a)

CF₃CO₂H (0.049 mL, 0.64 mmol) and isopentyl nitrite (0.085 mL,

0.64 mmol) were added to a solution of 3a (67 mg, 0.32 mmol) in

CH₃CN (3 mL) at 0 °C. The reaction mixture was stirred for 30 min.

The solution was treated with NaSMe (449 mg, 15% in H₂O, 0.96

mmol) and stirred for 1.5 h at 0 °C. The reaction was quenched with

phosphate buffer (pH 7), and then organic materials were extracted

with EtOAc (3 10 mL). The combined extracts were washed with

brine (10 mL) and dried over Na₂SO₄. After removal of the solvent

under reduced pressure, the residue was purified by PTLC on silica

gel (hexane–EtOAc, 10:1) to give 5a (45 mg, 58%) as a colorless

liquid.

IR (neat): 1759, 1383, 1344, 1248, 1178, 1119, 1090, 928, 748, 665

cm^–1.

¹H NMR (500 MHz, CDCl₃): = 2.47 (3 H, s), 6.08 (1 H, dd,

J_HF= 14.5, 3.8 Hz), 7.39 (2 H, br d, J = 8.3 Hz), 7.82 (2 H, br d,

J = 8.3 Hz).

¹³C NMR (126 MHz, CDCl₃): = 21.6, 100.8 (dd, J_CF= 60, 15 Hz),

128.3, 130.0, 131.1, 1401, 156.9 (dd, J_CF= 293, 283 Hz).

¹⁹F NMR (470 MHz, CDCl₃): _F= 52.9 (1 F, dd, J_FF= 51 Hz,

J_FH= 4 Hz), 71.5 (1 F, dd, J_FF= 51 Hz, J_FH= 14 Hz).

Anal. Calcd for C₉H₈O₃F₂S: C, 46.15; H, 3.44. Found: C, 46.17; H,

3.58.

IR (neat): 2958, 2927, 1741, 1467, 1436, 1259, 1232, 1122, 971,

746 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.87 (3 H, t, J = 6.9 Hz), 1.27–

1.36 (4 H, m), 2.28–2.36 (2 H, m),2.43 (3 H, s), 7.09 (1 H, dd,

J = 7.2, 1.8 Hz), 7.12 (1 H, ddd, J = 7.2, 7.2, 1.1 Hz), 7.21 (1 H, d,

J = 7.2 Hz), 7.29 (1 H, ddd, J = 7.2, 7.2, 1.8 Hz).

¹³C NMR (126 MHz, CDCl₃): = 13.8, 15.5, 22.4, 27.9, 29.6 (dd,

J_CF= 3, 3 Hz), 91.0 (dd, J_CF= 23, 16 Hz), 124.5, 125.1, 128.5, 130.3

(d, J_CF= 3 Hz) 132.4 (d, J_CF= 5 Hz), 138.8, 153.0 (dd, J_CF= 288,

287 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 68.0 (1 F, ddd, J_FF= 43 Hz,

J_FH= 3, 3 Hz), 72.8 (1 F, ddd, J_FF= 43, J_FH= 2, 2 Hz).

o -(2,2-Difluorovinyl)-p-toluenesulfonanilide (3f)

BuLi (23 mL, 1.6 M in hexane, 36 mmol) was added to a solution

of zirconocene dichloride (5.25 g, 18 mmol) in THF (100 mL) at

–78 °C under nitrogen, and the resulting mixture was stirred at the

same temperature for 1 h. To the reaction mixture was added a sol-

ution of 6 (2.10 g, 9.0 mmol) in THF (5 mL) at –78 °C. After stirring

for 5 min, the mixture was warmed to r.t. and stirred for an addition-

al 3 h. PPh₃(376 mg, 1.4 mmol) and Pd₂(dba)₃CHCl₃(186 mg, 0.18

mmol) were added at 0 °C, and the mixture was stirred for 10 min.

To the resulting solution were successively added o-iodoaniline

(2.16 g, 9.9 mmol) and ZnI₂(6.87 g, 22 mmol). The mixture was fil-

tered through Celite and organic materials were extracted with Et₂O

(3 50 mL). After removal of the solvent under reduced pressure,

the residue was treated with TsCl (1.88 g, 9.9 mmol) in pyridine (3

mL) at 0 °C. The reaction mixture was stirred for 12 h at r.t. The re-

action was quenched with phosphate buffer (pH 7), and organic ma-

terials were extracted with EtOAc (3 50 mL). The combined

extracts were washed with aq HCl (50 mL) and dried over Na₂SO₄.

After removal of the solvent under reduced pressure, the residue

was purified by column chromatography on silica gel (hexane–

EtOAc 2:1) to give 3f (1.11 g, 40%) as an orange solid.

MS (70 eV): m/z (%) = 242 (M⁺, 68), 165 (100), 134 (74).

HRMS: m/z calcd for C₁₃H₁₆F₂S (M⁺): 242.0941; found: 242.0916.

o-(1-Butyl-2,2-difluorovinyl)phenyl Methyl Sulfoxide (5b)

TiCl₃(602 mg, 20% in H₂O, 0.78 mmol) was added to a solution of

5a (94 mg, 0.39 mmol) in MeOH–H₂O (6:1, 8 mL) at 0 °C. The sol-

ution was treated with H₂O₂(133 mg, 30% in H₂O, 1.2 mmol) and

stirred for 2 h at r.t. The reaction was quenched with phosphate buff-

er (pH 7), and then organic materials were extracted with CH₂Cl₂(3

10 mL). The combined extracts were washed with brine (10 mL)

and dried over Na₂SO₄. After removal of the solvent under reduced

IR (neat): 3266, 1727, 1490, 1400, 1334, 1222, 1160, 1091, 815,

673, 566, 549 cm^–1.

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

1926

J. Ichikawa et al.

FEATURE ARTICLE

¹H NMR (500 MHz, CDCl₃): = 2.40 (3 H, s), 5.21 (1 H, dd,

_HF= 25.2, 3.2 Hz), 6.67 (1 H, s), 7.17–7.26 (5 H, m), 7.33–7.37 (1

H, m), 7.61 (2 H, d, J = 8.2 Hz).

¹³C NMR (126 MHz, CDCl₃): = 13.7, 22.5, 25.7 (d, J_CF= 3 Hz),

30.5, 35.9, 43.5, 64.0, 89.3 (dd, J_CF= 17, 13 Hz), 126.2, 128.3,

128.8, 139.6, 154.3 (dd, J_CF= 287, 287 Hz).

J

¹³C NMR (126 MHz, CDCl₃): = 21.5, 108.9 (d, J_CF= 16 Hz),

126.2, 127.0, 127.3, 128.2, 129.2, 129.2, 130.0, 133.4 (d, J_CF= 3

Hz), 136.2, 144.1, 156.5 (dd, J_CF= 298, 290 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 70.4 (1 F, d, J_FF= 54 Hz), 70.8 (1

F, d, J_FF= 54 Hz).

MS (70 eV): m/z (%) = 254 (M⁺, 10), 234 (32), 203, (66), 91 (100).

HRMS: m/z calcd for C₁₅H₂₀OF₂(M⁺): 254.1482; found: 254.1495.

¹⁹F NMR (470 MHz, CDCl₃): = 79.0 (1 F, ddd, J_FF= 25 Hz,

J_FH= 25, 2 Hz), 80.6 (1 F, dd, J_FF= 25 Hz, J_FH= 4 Hz).

MS (70 eV): m/z (%) = 309 (M⁺), 155, 154, 127.

HRMS: m/z calcd for C₁₅H₁₃NO₂F₂S (M⁺): 309.0635; found:

4,4-Difluoro-2-methyl-3-(3-phenylpropyl)but-3-ene-1-ol (9c)

Compound 9c was prepared by the method described for 9a using

THF (20 mL), 9-BBN (16.0 mL, 0.5 M in THF, 7.9 mmol) and 1,1-

difluoro-3-methyl-2-(3-phenylpropyl)-1,3-butadiene (8c, 1.60 g,

7.2 mmol), NaOH (9.6 mL, 3 M in H₂O, 29 mmol), and H₂O₂(9.6

mL, 30% in H₂O, 96 mmol). Hydroboration was carried out under

reflux for 6 h. Purification by column chromatography on silica gel

(hexane–EtOAc 4:1) gave 9c (1.25 g, 72%) as a colorless liquid.

309.0643.

4,4-Difluoro-3-(2-phenylpropyl)-2-methyl-but-3-ene-1-ol (9a)

9-BBN (0.8 mL, 0.5 M in THF, 0.40 mmol) was added to a solution

of 1,1-difluoro-3-methyl-2-(2-phenylpropyl)-1,3-butadiene (8a, 80

mg, 0.36 mmol) in THF (2 mL) under nitrogen. The reaction mix-

ture was heated under reflux for 5 h and then cooled to 0 °C. To the

resulting solution were added successively, NaOH (0.10 mL, 3 M in

H₂O, 0.30 mmol) and H₂O₂(0.10 mL, 30% in H₂O, 1.0 mmol). The

mixture was stirred for 2 h, then quenched with phosphate buffer

(pH 7). Organic materials were extracted with EtOAc (3 10 mL).

The combined extracts were washed with brine (10 mL), and then

dried over Na₂SO₄. After removal of the solvent under reduced

pressure, the residue was purified by PTLC on silica gel (hexane–

EtOAc 2:1) to give 9a (1:1 diastereomeric mixture, 50 mg, 58%) as

a colorless liquid.

IR (neat): 3350, 2939, 1739, 1605, 1497, 1454, 1214, 1032, 748,

700 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.01 (3 H, d, J = 7.3 Hz), 1.69–

1.79 (3 H, m), 1.93–2.00 (2 H, m), 2.49 (1 H, tq, J = 7.6, 7.3 Hz),

2.61 (2 H, d, J = 7.6 Hz), 3.48 (2 H, d, J = 7.6 Hz), 7.16 (2H, d,

J = 7.6 Hz), 7.17 (1 H, t, J = 7.3 Hz), 7.27 (2 H, dd, J = 7.6, 7.3 Hz).

¹³C NMR (126 MHz, CDCl₃): = 15.0 (dd, J_CF= 3, 2 Hz), 24.8 (d,

J_CF= 3 Hz), 30.4 (dd J_CF= 3, 2 Hz), 35.3 (d, J_CF= 2 Hz), 35.7, 65.4

(dd, J_CF= 3, 3 Hz), 90.5 (dd, J_CF= 16, 15 Hz), 125.8, 128.3, 128.3,

141.8, 154.0 (dd, J_CF= 287, 286 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 69.2 (1 F, d, J_FF= 55 Hz), 70.1 (1

F, d, J_FF= 55 Hz) ppm.

MS (70 eV): m/z (%) = 240 (M⁺, 7), 220 (77), 189 (100).

HRMS: m/z calcd for C₁₄H₁₈OF₂(M⁺): 240.1325; found: 240.1363.

IR (neat): 3340, 2966, 1735, 1602, 1494, 1452, 1376, 1224, 1033,

979, 763, 700 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.98 (1.5 H, d, J = 7.3 Hz), 1.00

(1.5 H, d, J = 6.7 Hz), 1.00–1.80 (1 H, br m), 1.27 (1.5 H, d, J = 7.3

Hz), 1.28 (1.5 H, d, J = 7.3 Hz), 2.10–2.30 (2 H, m), 2.39 (0.5 H, dd,

J = 13.0, 6.7 Hz), 2.41 (0.5 H, dd, J = 13.0, 7.3 Hz), 2.91 (1 H, tq,

J = 7.3, 7.3 Hz), 3.37 (0.5 H, d, J = 7.9 Hz), 3.39 (0.5 H, d, J = 7.9

Hz), 3.51 (0.5 H, d, J = 7.3 Hz), 3.52 (0.5 H, d, J = 7.9 Hz), 7.20–

7.24 (3 H, m), 7.30 (1 H, t, J = 7.3 Hz), 7.31 (1 H, t, J = 7.3 Hz).

¹³C NMR (126 MHz, CDCl₃): = 15.0, 15.0, 21.4, 21.6, 34.8, 34.9,

35.8, 35.8, 38.3 (dd, J_CF= 3, 2 Hz), 38.6 (dd, J_CF= 3, 2 Hz), 65.4

(dd, J_CF= 3, 3 Hz), 65.5 (dd, J_CF= 3, 3 Hz), 89.3 (dd, J_CF= 14, 14

Hz), 89.3 (dd, J_CF= 14, 14 Hz), 126.3, 126.4, 126.9, 126.9, 128.4,

128.4, 146.3, 146.4, 154.4 (dd, J_CF= 288, 287 Hz), 154.4 (dd,

J_CF= 288, 286 Hz).

N-tert-Butoxycarbonyl-N-[4,4-difluoro-2-methyl-3-(2-phenyl-

propyl)but-3-enyl]-p-toluenesulfonamide (10a)

To a solution of 9a (132 mg, 0.55 mmol) in THF (5 mL) was added

PPh₃(144 mg, 0.55 mmol), N-tert-butoxycarbonyl-p-toluene-

sulfonamide (149 mg, 0.55 mmol), and DEAD (239 mg, 40% in tol-

uene, 0.55 mmol) at r.t. under nitrogen. After the reaction mixture

was stirred for 2 h at r.t., phosphate buffer (pH 7) was added to

quench the reaction. Organic materials were extracted with EtOAc

(3 10 mL). The combined extracts were washed with brine (10

mL), and then dried over Na₂SO₄. After removal of the solvent un-

der reduced pressure, the residue was purified by PTLC on silica gel

(hexane–EtOAc 7:1) to give 10a (1:1 diastereomeric mixture, 233

mg, 86%) as a pale yellow liquid.

¹⁹F NMR (470 MHz, CDCl₃): _F= 70.7 (0.5 F, d, J_FF= 53 Hz), 70.8

(0.5 F, d, J_FF= 53 Hz), 71.8 (0.5 F, d, J_FF= 53 Hz), 72.5 (0.5 F, d,

J_FF= 53 Hz).

MS (70 eV): m/z (%) = 240 (M⁺, 3), 220 (100).

HRMS: m/z calcd for C₁₄H₁₈OF₂(M⁺): 240.1326; found: 240.1328.

IR (neat): 2974, 1732, 1599, 1495, 1358, 1255, 1157, 1090, 849,

700 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.01 (1.5 H, d, J = 7.1 Hz), 1.09

(1.5H, d, J = 7.3 Hz), 1.28 (1.5 H, d, J = 7.0 Hz), 1.31 (4.5 H, s),

1.32 (1.5 H, d, J = 7.0 Hz), 1.33 (4.5 H, s), 2.22–2.32 (2 H, m), 2.43

(1.5 H, s), 2.43 (1.5 H, s), 2.69 (0.5 H, qtd, J = 7.3, 7.3 Hz, J_HF= 2.4

Hz), 2.80 (0.5 H, tq, J = 7.0, 7.0 Hz), 2.94 (1 H, tq, J = 7.3, 7.3 Hz),

3.73 (0.5 H, d, J = 7.0 Hz), 3.74 (0.5 H, d, J = 8.5 Hz), 3.80 (1 H, d,

J = 7.6 Hz), 7.17–7.33 (7 H, m), 7.73 (1 H, d, J = 8.5 Hz), 7.75 (1

H, d, J = 8.5 Hz).

¹³C NMR (126 MHz, CDCl₃): = 15 5, 15.7, 21.5, 21.6, 27.7, 27.7,

33.3, 33.7, 35.0, 35.0, 35.8, 35.8, 38.4, 38.4, 50.2, 50.4, 84.2, 84.2,

89.4 (dd, J_CF= 15, 15 Hz), 89.8 (dd, J_CF= 15, 15 Hz), 126.2, 126.2,

126.9, 127.1, 127.8, 127.8, 128.3, 128.3, 129.2, 129.2, 137.3, 137.3,

144.1, 144.1, 146.3, 146.6, 151.0, 151.0, 154.6 (dd, J_CF= 289, 289

Hz), 154.6 (dd, J_CF= 286, 286 Hz).

2-Benzyl-3-butyl-4,4-difluorobut-3-en-1-ol (9b)

Compound 9b was prepared by the method described for 9a using

THF (3 mL), 9-BBN (2.5 mL, 0.5 M in THF, 1.3 mmol), 3-benzyl-

2-butyl-1,1-difluoro-1,3-butadiene (8b, 200 mg, 0.90 mmol),

NaOH (1.8 mL, 3 M in H₂O, 5.4 mmol), and H₂O₂(1.8 mL, 30% in

H₂O, 18 mmol). Hydroboration was carried out under reflux for 7 h.

Purification by PTLC on silica gel (hexane–EtOAc 3:1) gave 9b

(172 mg, 76%) as a colorless liquid.

IR (neat): 3336, 2956, 1740, 1605, 1497, 1456, 1250, 1219, 1032,

700 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.85 (3 H, t, J = 7.0 Hz), 1.18–

1.25 (4 H, m), 1.53 (1 H, s), 1.79–1.85 (2 H, m), 2.70–2.74 (2 H, m),

2.83 (1 H, dd, J = 17.1, 10.4 Hz), 3.63 (2 H, d, J = 6.1 Hz), 7.15 (2

H, d, J = 7.3 Hz), 7.19 (1 H, t, J = 7.3 Hz), 7.27 (2 H, dd, J = 7.6,

7.0 Hz).

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes

1927

¹⁹F NMR (470 MHz, CDCl₃): = 72.1 (0.5 F, d, J_FF= 52 Hz), 72.2

(0.5 F, d, J_FF= 52 Hz), 72.3 (0.5 F, d, J_FF= 52 Hz), 72.8 (0.5 F, d,

HRMS: m/z calcd for C₂₁H₂₄O₃F₂S (M⁺): 394.1414; found:

394.1401.

J_FF= 52 Hz).

S-4,4-Difluoro-2-methyl-3-(3-phenylpropyl)but-3-enyl Thio-

acetate (11a)

MS (70 eV): m/z = 493 (M⁺).

To a solution of thioacetic S-acid (90 mg, 1.2 mmol) in DMF (5 mL)

was added NaH (47 mg, 60% dispersion in mineral oil, 1.2 mmol)

at 0 °C under nitrogen. The mixture was stirred for 30 min, a solu-

tion of 9d (358 mg, 0.91 mmol) in THF (2 mL) was added and heat-

ed at 70 °C for 3 h, then quenched with phosphate buffer (pH 7).

Organic materials were extracted with EtOAc (3 10 mL). The

combined extracts were washed with H₂O, and then dried over

Na₂SO₄. After removal of the solvent under reduced pressure, the

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

ane–EtOAc, 50:1) to give 11a (243 mg, 90%) as a colorless liquid.

N-[4,4-Difluoro-2-methyl-3-(2-phenylpropyl)but-3-enyl]-p-tol-

uenesulfonamide (10b)

Trifluoroacetic acid (0.47 mL, 6.0 mmol) was added to a solution of

10a (200 mg, 0.40 mmol) in CH₂Cl₂(2.5 mL) at r.t. After the reac-

tion mixture was stirred for 1.5 h at r.t., aq NaHCO₃(10 mL) was

added to quench the reaction. Organic materials were extracted with

CH₂Cl₂(3 10 mL). The combined extracts were washed with H₂O,

and then dried over Na₂SO₄. After removal of the solvent under re-

duced pressure, the residue was purified by PTLC on silica gel (hex-

ane–EtOAc, 4:1) to give 10b (a 1:1 diastereomeric mixture, 143 mg,

91%) as a colorless liquid.

IR (neat): 2935, 1740, 1695, 1605, 1497, 1454, 1354, 1213, 1136,

957 cm^–1.

IR (neat): 3282, 2966, 1735, 1600, 1494, 1452, 1326, 1160, 1093,

815, 701 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.11 (3 H, d, J = 7.0 Hz), 1.74 (2

H, tt, J = 7.8, 7.8 Hz), 1.90–2.02 (2 H, m), 2.31 (3 H, s), 2.48 (1 H,

ddq, J = 7.5, 7.5, 7.5 Hz), 2.62 (2 H, dd, J = 8.5, 7.0 Hz), 2.86 (1 H,

dd, J = 13.4, 8.2 Hz), 2.96 (1 H, dd, J = 13.4, 7.3 Hz), 7.15–7.20 (3

H, m), 7.28 (2 H, dd, J = 7.6, 7.6 Hz).

¹³C NMR (126 MHz, CDCl₃): = 18.4, 24.9 (d, J_CF= 4 Hz), 30.3,

30.6, 32.9, 33.8, 35.7, 91.8 (dd, J_CF= 17, 14 Hz), 125.8, 128.3,

128.3, 141.8, 153.9 (dd, J_CF= 288, 286 Hz), 195.5.

¹H NMR (500 MHz, CDCl₃): = 0.90 (1.5 H, d, J = 6.7 Hz), 0.96

(1.5 H, d, J = 7.0 Hz), 1.21 (1.5 H, d, J = 6.7 Hz), 1.22 (1.5 H, d,

J = 7.0 Hz), 2.01–2.19 (2 H, m), 2.26–2.34 (1 H, m), 2.41 (1.5 H, s),

2.42 (1.5 H, s), 2.67–2.93 (3 H, m), 4.44 (0.5 H, br d, J = 5.6 Hz),

4.62 (0.5 H, br d, J = 6.1 Hz), 7.11–7.32 (7 H, m), 7.68 (1 H, d,

J = 8.2 Hz), 7.32 (1 H, d, J = 8.2 Hz).

¹³C NMR (126 MHz, CDCl₃): = 16.1, 16.3, 21.5, 21.5, 21.7, 21.7,

33.6, 33.7, 34.7 (d, J_CF= 3 Hz), 34.9, 38.2, 38.5, 46.5, 46.7, 89.3

(dd, J_CF= 14, 4 Hz), 89.4 (dd, J_CF= 13, 5 Hz), 126.3, 126.4, 126.9,

126.9, 127.0, 127.0, 128.4, 128.5, 129.6, 129.7, 136.9, 137.0, 143.3,

143.4, 146.0, 146.1, 154.3 (dd, J_CF= 288, 288 Hz), 154.3 (dd,

¹⁹F NMR (470 MHz, CDCl₃): _F= 69.7 (1 F, d, J_FF= 54 Hz), 70.4

(1 F, d, J_FF= 54 Hz).

4,4-Difluoro-2-methyl-3-(3-phenylpropyl)but-3-ene-1-thiol

(11b)

J_CF= 288, 288 Hz).

K₂CO₃(46 mg, 0.34 mmol) was added to a solution of 11a (91 mg,

0.31 mmol) in MeOH (2 mL) at 0 °C. After the reaction mixture was

stirred for 1 h, phosphate buffer (pH 7) was added to quench the re-

action. Organic materials were extracted with EtOAc (3 10 mL).

The combined extracts were washed with brine (10 mL), and then

dried over Na₂SO₄. After removal of the solvent under reduced

pressure, the residue was purified by PTLC on silica gel (hexane–

EtOAc, 50:1) to give 11b (75 mg, 95%) as a colorless liquid.

¹⁹F NMR (470 MHz, CDCl₃): = 71.8 (0.5 F, d, J_FF= 52 Hz), 72.0

(0.5 F, d, J_FF= 52 Hz), 72.5 (0.5 F, d, J_FF= 52 Hz), 73.1 (0.5 F, d,

J_FF= 52 Hz).

MS (70 eV): m/z (%) 393 (M⁺, 2), 105 (98), 155 (99), 184 (100).

HRMS: m/z calcd for C₂₁H₂₅NO₂F₂S (M⁺): 393.1574; found:

393.1581.

4,4-Difluoro-2-methyl-3-(3-phenylpropyl)but-3-enyl p-Tolu-

enesulfonate (9d)

IR (neat): 2935, 2573, 1740, 1605, 1495, 1454, 1252, 1213, 1092,

980 cm^–1.

TsCl (286 mg, 1.5 mmol) was added to a solution of 9c (300 mg, 1.3

mmol) in pyridine (3 mL) at r.t. After the reaction mixture was

stirred for 8 h, phosphate buffer (pH 7) was added to quench the re-

action. Organic materials were extracted with EtOAc (3 10 mL).

The combined extracts were washed with brine (10 mL), and then

dried over Na₂SO₄. After removal of the solvent under reduced

pressure, the residue was purified by column chromatography on

silica gel (hexane–EtOAc 10:1) to give 9d (422 mg, 80%) as a col-

orless liquid.

¹H NMR (500 MHz, CDCl₃): = 1.01 (3 H, d, J = 7.0 Hz), 1.33 (1

H, t, J = 8.1 Hz), 1.68–1.82 (2 H, m), 1.89–2.02 (2 H, m), 2.38–2.59

(3 H, m), 2.62 (2 H, t, J = 7.8 Hz), 7.18 (2 H, d, J = 7.6 Hz), 7.18 (1

H, t, J = 7.6 Hz), 7.28 (2 H, dd, J = 7.6, 7.6 Hz).

¹³C NMR (126 MHz, CDCl₃): = 18.1 (dd, J_CF= 3, 2 Hz), 24.8 (d,

J_CF= 3 Hz), 29.3 (dd J_CF= 3, 2 Hz), 30.5 (d, J_CF= 3 Hz), 35.7, 36.7

(d, J_CF= 3 Hz), 91.6 (dd, J_CF= 16, 14 Hz), 125.9, 128.3, 128.3,

141.8, 153.9 (dd, J_CF= 287, 287 Hz).

IR (neat): 2935, 1741, 1599, 1497, 1362, 1176, 970, 835, 700, 667

cm^–1.

¹⁹F NMR (470 MHz, CDCl₃): = 69.7 (1 F, d, J_FF= 54 Hz), 70.0 (1

F, d, J_FF= 54 Hz).

¹H NMR (500 MHz, CDCl₃): = 1.02 (3 H, d, J = 7.0 Hz), 1.61–

1.69 (2 H, m), 1.85–1.91 (2 H, m), 2.44 (3 H, s), 2.56 (2 H, t, J = 7.6

Hz), 2.61 (1 H, tq, J = 7.3, 7.0 Hz), 3.90 (2 H, d, J = 7.3 Hz), 7.14

(2 H, d, J = 7.3 Hz), 7.19 (1 H, t, J = 7.3 Hz), 7.28 (2 H, dd, J = 7.3,

7.3 Hz), 7.32 (2 H, d, J = 8.4 Hz), 7.75 (2 H, d, J = 8.4 Hz).

MS (70 eV): m/z (%) = 256 (M⁺, 12), 189 (51), 165 (44), 91 (100).

HRMS: m/z calcd for C₁₄H₁₈OF₂S (M⁺): 256.1097; found 256.1094.

5,5-Difluoro-4-phenylpent-4-en-1-ol (12a)

BuLi (67 mL, 1.6 M in hexane, 109 mmol) was added to a solution

of 1 (13 g, 52 mmol) in THF (270 mL) at –78 °C over 10 min under

argon, and the reaction mixture was stirred for 20 min at –78 °C.

Tris[3-(methoxymethoxy)propyl]borane [Borane–THF complex

(57 mL, 1.0 M in THF, 57 mmol) was added to a solution of allyl

methoxymethyl ether (16 g, 156 mmol) in THF (69 ml) at 0 °C, and

the mixture was stirred for 3 h at r.t.] was then added at –78 °C. Af-

ter being stirred for 1 h, the reaction mixture was heated to reflux

for an additional 1 h. After being cooled to r.t., the solution was

¹³C NMR (126 MHz, CDCl₃): = 15.0, 21.6, 25.1, 30.0, 32.4 (d,

J_CF= 2 Hz), 35.5, 71.8 (dd, J_CF= 3, 3 Hz), 89.5 (dd J_CF= 17,4 Hz),

125.9, 127.8, 128.2, 128.3, 129.8, 132.9, 141.6, 144.8, 153.9 (dd,

J_CF= 288, 287 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 70.9 (1 F, d, J_FF= 53 Hz), 71.0 (1

F, d, J_FF= 53 Hz).

MS (70 eV): m/z = 394 (M⁺).

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

1928

J. Ichikawa et al.

FEATURE ARTICLE

treated with HMPA (108 mL), PPh₃(1.1 g, 4.2 mmol), and

Pd₂(dba)₃CHCl₃(1.2 g, 1.0 mmol) and was stirred for 15 min. To

the resulting solution was added iodobenzene (8.5 g, 42 mmol) and

CuI (9.9 g, 52 mmol). After the mixture was stirred for 1 h at r.t., the

reaction was quenched with phosphate buffer (pH 7). The mixture

was filtered through Celite, and the organic materials were extract-

ed with EtOAc (3 100 mL). The combined extracts were washed

with brine (100 mL) and dried over Na₂SO₄. After removal of the

solvent under reduced pressure, the residue was purified by column

chromatography on silica gel (hexane–EtOAc, 20:1) to give a crude

product (9.0 g) as a yellow liquid. HCl (98 mL, 12 M in H₂O, 1.2

mol) was added to a solution of the crude product (9.0 g) in THF (74

mL) at r.t. under air. The reaction mixture was stirred for 1 h at r.t.,

the reaction was quenched with phosphate buffer (pH 7). Organic

materials were extracted with EtOAc (3 50 mL). The combined

extracts were washed with brine (50 mL) and dried over Na₂SO₄.

After removal of the solvent under reduced pressure, the residue

was purified by column chromatography on silica gel (hexane–

EtOAc, 3:1) to give 12a (3.6 g, 43%) as a colorless liquid.

mmol), allyl methoxymethyl ether (367 mg, 3.6 mmol), THF (1.5

mL), HMPA (3 mL), PPh₃(46 mg, 0.17 mmol), Pd₂(dba)₃CHCl₃

(23 mg, 0.022 mmol), p-iodoanisole (204 mg, 0.87 mmol) ), and

CuI (207 mg, 1.1 mmol). Purification by PTLC on silica gel (hex-

ane–EtOAc, 5:1) gave a crude product (170 mg) as a yellow liquid.

Treatment of the product with HCl (1.0 mL, 12 M in H₂O, 12 mmol)

and THF (1 mL) and purification by PTLC on silica gel (hexane–

EtOAc, 1:1) gave 12c (86 mg, 47%) as a colorless liquid.

IR (neat): 3359, 2945, 1732, 1610, 1514, 1444, 1253, 1180, 1034,

873 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.61 (2 H, tt, J = 7.0, 7.0 Hz), 1.64

(1 H, br s), 2.45 (2 H, tdd, J = 7.0 Hz, J_HF= 2.4, 2.4 Hz), 3.59 (2 H,

t, J = 7.0 Hz), 3.79 (3 H, s), 6.88 (2 H, d, J = 8.7 Hz), 7.23 (2H, d,

J = 8.7 Hz).

¹³C NMR (125 MHz, CDCl₃): = 24.0, 30.7, 55.2, 61.9, 91.3 (dd,

J_CF= 22, 14 Hz), 114.0, 125.7, 129.3 (dd, J_CF= 3, 3 Hz), 153.5 (dd,

J_CF= 289, 286 Hz), 158.8.

¹⁹F NMR (254 MHz, CDCl₃): = 69.3 (1 F, dt, J_FF= 53 Hz, J_FH= 2

Hz), 69.6 (1 F, d, J_FF= 53 Hz).

HRMS: m/z calcd for C₁₂H₁₄O₂F₂(M⁺): 228.0962, found: 228.0954.

IR (neat): 3352, 2935, 2873, 1732, 1446, 1232, 1124, 1061, 947,

762, 698 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.35 (1 H, br s), 1.63 (2 H, tt,

J = 6.9, 6.9 Hz), 2.51 (2 H, tt, J = 6.9 Hz, J_HF= 2.4 Hz), 3.62 (2 H,

t, J = 6.9 Hz), 7.27 (1 H, t, J = 7.3 Hz), 7.31 (2 H, d, J = 7.3 Hz),

7.35 (2 H, dd, J = 7.3, 7.3 Hz).

5,5-Difluoro-2-methyl-4-phenyl-4-pent-4-en-1-ol (12d)

Compound 12d was prepared by the method described for 12a us-

ing BuLi (1.2 mL, 1.6 M in hexane, 2.1 mmol), 1 (254 mg, 1.0

mmol), THF (5 mL), borane–THF complex (1.0 mL, 1.0 M in THF,

1.0 mmol), methoxymethyl 2-methyl-2-propenyl ether (348 mg, 3.0

mmol), THF (1.5 ml), HMPA (2.5 mL), PPh₃(21 mg, 0.080 mmol),

Pd₂(dba)₃CHCl₃(21 mg, 0.020 mmol), iodobenzene(163 mg, 0.80

mmol), and CuI (190 mg, 1.0 mmol). Purification by PTLC on silica

gel (hexane–EtOAc, 5:1) gave a crude product (131 mg) as a yellow

liquid. Treatment of the product with HCl (1.3 mL, 12 M in H₂O, 16

mmol) and THF (1 mL) and purification by PTLC on silica gel (hex-

ane–EtOAc, 2:1) gave 12d (127 mg, 75%) as a colorless liquid.

¹³C NMR (125 MHz, CDCl₃): = 24.0, 30.7, 62.0, 91.9 (dd,

J_CF= 35, 14 Hz), 127.3, 128.2 (dd, J_CF= 3, 3 Hz), 128.5, 133.5 (dd,

J_CF= 3, 3 Hz), 153.6 (dd, J_CF= 290, 287 Hz).

¹⁹F NMR (254 MHz, CDCl₃): = 70.3 (1 F, dt, J_FF= 43 Hz, J_FH= 2

Hz), 70.4 (1 F, dt, J_FF= 43 Hz, J_FH= 2 Hz).

Anal. Calcd for C₁₁H₁₂OF₂: C, 66.66; H, 6.10. Found: C, 66.48; H,

6.11.

5,5-Difluoro-4-(p-trifluoromethylphenyl)pent-4-en-1-ol (12b)

Compound 12b was prepared by the method described for 12a us-

ing BuLi (6.9 mL, 1.6 M in hexane, 11 mmol), 1 (1.3 g, 5.3 mmol),

THF (27 mL), borane–THF complex (5.8 mL, 1.0 M in THF, 5.8

mmol), allyl methoxymethyl ether (609 mg, 16 mmol), THF (7 ml),

HMPA (11 mL), PPh₃(110 mg, 0.42 mmol), Pd₂(dba)₃CHCl₃(121

mg, 0.21 mmol), p-iodotrifluoromethylbenzene (1.0 g, 3.7 mmol),

and CuI (1.0 g, 5.3 mmol). Purification by column chromatography

on silica gel (hexane–EtOAc 5:1) gave a crude product (1.2 g) as a

yellow liquid. Treatment of the product with HCl (10 mL, 12 M in

H₂O, 0.12 mol) and THF (8 mL) and purification by PTLC on silica

gel (hexane–EtOAc, 2:1) gave 12b (534 mg, 54%) as a colorless liq-

uid.

IR (neat): 3348, 2958, 2873, 1732, 1446, 1234, 1038, 771, 725, 698

cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.89 (3 H, d, J = 6.8 Hz), 1.51 (1

H, br s), 1.58–1.69 (1 H, m), 2.24 (1 H, dddd, J = 14.3, 8.5 Hz,

J_HF= 2.8, 2.8 Hz), 2.54 (1 H, dddd, J = 14.3, 6.0 Hz, J_HF= 2.9, 2.9

Hz), 3.41 (1 H, dd, J = 10.6, 5.9 Hz), 3.45 (1 H, dd, J = 10.6, 5.9

Hz), 7.26 (1 H, tt, J = 7.1, 1.9 Hz), 7.31 (2 H, d, J = 7.1 Hz), 7.34

(2 H, t, J = 7.1 Hz).

¹³C NMR (125 MHz, CDCl₃): = 16.0, 31.1, 34.1, 67.4, 91.0 (dd,

J_CF= 20, 16 Hz), 127.3, 128.3 (dd, J_CF= 3, 3 Hz), 128.5, 133.7,

154.0 (dd, J_CF= 288, 288 Hz).

¹⁹F NMR (254 MHz, CDCl₃): = 70.5 (s).

HRMS: m/z calcd for C₁₂H₁₄OF₂(M⁺): 212.1013; found: 212.1010.

IR (neat): 3446, 2955, 1728, 1618, 1358, 1329, 1244, 1174, 1128,

1068, 947, 847, 528 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.57 (1 H, br s), 1.59–1.66 (2 H,

m), 2.51-2.57 (2 H, m), 3.64 (2 H, dt, J = 5.3, 5.3 Hz), 7.45 (2 H, d,

J = 7.8 Hz), 7.61 (2 H, d, J = 7.8 Hz).

5,5-Difluoro-4-(p-methoxyphenyl)-2-methylpent-4-en-1-ol

(12e)

Compound 12e was prepared by the method described for 12a using

BuLi (1.4 mL, 1.6 M in hexane, 2.1 mmol), 1 (254 mg, 1.0 mmol),

THF (5 mL), borane–THF complex (1.1 mL, 1.0 M in THF, 1.1

mmol), methoxymethyl 2-methyl-2-propenyl ether (383 mg, 3.3

mmol), THF (1.5 ml), HMPA (2.5 mL), PPh₃(42 mg, 0.16 mmol),

Pd₂(dba)₃CHCl₃(21 mg, 0.020 mmol), p-iodoanisole (187 mg,

0.80 mmol), and CuI (190 mg, 1.0 mmol). Purification by PTLC on

silica gel (hexane–EtOAc, 5:1) gave a crude product (190 mg) as a

yellow liquid. Treatment of the product with HCl (1.2 mL, 12 M in

H₂O, 14 mmol) and THF (1 mL) and purification by PTLC on silica

gel (hexane–EtOAc, 1:1) gave 12e (113 mg, 58%) as a colorless liq-

uid.

¹³C NMR (125 MHz, CDCl₃): = 23.8, 30.6, 61.8, 91.4 (dd,

J_CF= 23, 13 Hz), 124.0 (q, J_CF= 272 Hz), 125.5 (q, J_CF= 4 Hz),

128.5 (dd, J_CF= 3, 3 Hz), 129.5 (q, J_CF= 33 Hz), 137.4, 153.9 (dd,

J_CF= 292, 289 Hz).

¹⁹F NMR (254 MHz, CDCl₃): = 72.3 (1 F, d, J_FF= 39 Hz), 72.6 (1

F, dt, J_FF= 39 Hz, J_FH= 3 Hz), 99.0 (3 F, s).

HRMS: m/z calcd for C₁₂H₁₁OF₅(M⁺): 266.0730; found: 266.0706.

5,5-Difluoro-4-(p-methoxyphenyl)pent-4-en-1-ol (12c)

Compound 12c was prepared by the method described for 12a using

BuLi (1.5 mL, 1.6 M in hexane, 2.3 mmol), 1 (277 mg, 1.1 mmol),

THF (5 mL), borane–THF complex (1.2 mL, 1.0 M in THF, 1.2

IR (neat): 3346, 2958, 1732, 1610, 1514, 1462, 1292, 1248, 1180,

1105, 1036, 964, 833 cm^–1.

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes

1929

¹H NMR (500 MHz, CDCl₃): = 0.89 (3 H, d, J = 6.8 Hz), 1.48 (1

H, br s), 1.59–1.70 (1 H, m), 2.21 (1 H, dddd, J = 14.3, 8.9 Hz,

J

_CF= 3, 3 Hz), 129.6 (q, J_CF= 32 Hz), 136.9, 154.1 (dd. J_CF= 291,

288 Hz).

J

_HF= 2.2, 1.2 Hz), 2.50 (1 H, dddd, J = 14.3, 6.1 Hz, J_HF= 3.0, 3.0

¹⁹F NMR (254 MHz, CDCl₃): = 73.1 (1 F, d, J_FF= 32 Hz), 73.7 (1

F, dt, J_FF= 32 Hz, J_FH= 2 Hz), 99.1 (3 F, s).

HRMS: m/z calcd for C₁₂H₁₀F₅I (M⁺): 375.9747; found: 375.9773.

Hz), 3.43 (1 H, dd, J = 10.6, 5.9 Hz), 3.45 (1 H, dd, J = 10.6, 6.0

Hz), 3.80 (3 H, s), 6.88 (2 H, ddd, J = 8.5 Hz, J_HF= 2.6, 2.6 Hz),

7.24 (2H, d, J = 8.5 Hz).

¹³C NMR (125 MHz, CDCl₃): = 16.1, 31.2, 34.1, 55.2, 67.4, 90.4

(dd, J_CF= 20, 15 Hz), 114.0, 125.8, 129.3 (dd, J_CF= 3, 3 Hz), 153.9

(dd, J_CF= 288, 287 Hz), 158.7.

¹⁹F NMR (254 MHz, CDCl₃): = 69.6 (1 F, d, J_FF= 47 Hz), 69.6 (1

F, d, J_FF= 47 Hz).

1,1-Difluoro-5-iodo-2-(p-methoxyphenyl)pent-1-ene (13c)

Compound 13c was prepared by the method described for 13a using

Et₃N (115mg, 1.1 mmol), MsCl (118 mg, 1.1 mmol), 12c (173 mg,

0.76 mmol), and CH₂Cl₂(6 mL). Purification by PTLC on silica gel

(hexane–EtOAc, 1:1) gave a crude product (197 mg) as a colorless

liquid. Treatment of the product with NaI (1.2 g, 7.8 mmol) in ace-

tone (12 mL) and purification by PTLC on silica gel (hexane–

EtOAc, 3:1) gave 13c (185 mg, 72%) as a colorless liquid.

HRMS: m/z calcd for C₁₃H₁₆O₂F₂(M⁺): 242.1118; found: 242.1117.

1,1-Difluoro-5-iodo-2-phenylpent-1-ene (13a)

Et₃N (2.6 g, 26 mmol) and MsCl (2.7 g, 26 mmol) were added to a

solution of 12a (3.4 g, 17 mmol) in CH₂Cl₂(130 mL) at 0 °C under

argon. The reaction mixture was stirred for 6 h at r.t., and the reac-

tion was quenched with phosphate buffer (pH 7). Organic materials

were extracted with Et₂O (3 40 mL). The combined extracts were

washed with brine (30 mL) and dried over Na₂SO₄. After removal

of the solvent under reduced pressure, the residue was purified by

column chromatography on silica gel (hexane–EtOAc, 2:1) to give

a crude product (4.9 g) as a colorless liquid. NaI (26 g, 176 mmol)

was added to a solution of the product (4.9 g) in acetone (192 mL)

at r.t. under air. The reaction mixture was heated under reflux for 5

h, and the reaction was quenched with phosphate buffer (pH 7). Or-

ganic materials were extracted with Et₂O (3 50 mL). The com-

bined extracts were washed with saturated aq Na₂S₂O₃(30 mL),

brine (30 mL), and dried over Na₂SO₄. After removal of the solvent

under reduced pressure, the residue was purified by column chro-

matography on silica gel (hexane–EtOAc, 20:1) followed by bulb-

to-bulb distillation (bp 85–95 °C/0.44 mmHg) in the dark to give

13a (4.4 g, 83%) as a colorless liquid.

IR (neat): 2958, 2837, 1732, 1610, 1516, 1290, 1250, 1180, 1103,

1036, 831 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.88 (2 H, tt, J = 7.2, 7.2 Hz), 2.49

(2 H, tt, J = 7.2 Hz, J_HF= 2.1 Hz), 3.13 (2 H, t, J = 7.2 Hz), 3.81 (3

H, s), 6.90 (2 H, d, J = 8.4 Hz), 7.22 (2 H, d, J = 8.4 Hz).

¹³C NMR (125 MHz, CDCl₃): = 5.1, 28.6, 31.5, 55.3, 90.5 (dd,

J_CF= 20, 15 Hz), 114.1, 125.2, 129.3 (dd, J_CF= 3, 3 Hz), 153.7 (dd.

J_CF= 289, 286 Hz), 158.9.

¹⁹F NMR (254 MHz, CDCl₃): = 70.2 (1 F, br d, J_FF= 44 Hz), 70.3

(1 F, dt, J_FF= 44 Hz, J_FH= 3 Hz).

Anal. Calcd for C₁₂H₁₃OF₂I: C, 42.63; H, 3.88. Found: C, 42.53; H,

3.90.

1,1-Difluoro-5-iodo-4-methyl-2-phenylpent-1-ene (13d)

Compound 13d was prepared by the method described for 13a us-

ing Et₃N (1.9 g, 19 mmol), MsCl (2.0 g, 19 mmol), 12d (2.7 g, 13

mmol), and CH₂Cl₂(95 mL). Purification by column chromatogra-

phy on silica gel (hexane–EtOAc, 4:1) gave a crude product (3.3 g)

as a colorless liquid. Treatment of the product with NaI (17 g, 110

mmol) in acetone (125 mL) and purification by column chromatog-

raphy on silica gel (hexane–EtOAc, 20:1) followed by distillation

(bp 115-120 °C/9.0 mmHg) gave 13d (2.9 g, 68%) as a colorless

liquid.

IR (neat): 3059, 2958, 1734, 1498, 1446, 1306, 1236, 1141, 1007,

912, 768, 696 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.87 (2 H, tt, J = 7.1, 7.1 Hz),

2.49–2.54 (2 H, m), 3.12 (2 H, t, J = 7.1 Hz), 7.27 (1 H, t, J = 7.5

Hz), 7.29 (2 H, d, J = 7.5 Hz), 7.35 (2H, dd, J = 7.5, 7.5 Hz).

¹³C NMR (125 MHz, CDCl₃): = 5.0, 28.5, 31.5, 91.0 (dd, J_CF= 21,

15 Hz), 127.5, 128.2 (dd, J_CF= 3, 3 Hz), 128.5, 133.1, 153.8 (dd.

IR (neat): 2964, 1730, 1498, 1446, 1379, 1244, 962, 769, 725, 696

cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.97 (3 H, d, J = 6.6 Hz), 1.45–

1.56 (1 H, m), 2.31 (1 H, dddd, J = 14.4, 8.0 Hz, J_HF= 2.4, 1.1 Hz),

2.54 (1 H, dddd, J = 14.4, 6.3 Hz, J_HF= 3.1, 3.1 Hz), 3.11 (1 H, dd,

J = 9.8, 5.8 Hz), 3.16 (1 H, dd, J = 9.8, 5.2 Hz), 7.28 (1 H, t, J = 7.7

Hz), 7.30 (2 H, d, J = 7.7 Hz), 7.36 (2 H, dd, J = 7.7, 7.7 Hz).

J

_CF= 291, 288 Hz).

¹⁹F NMR (254 MHz, CDCl₃): = 71.2 (1 F, d, J_FF= 43 Hz), 71.3 (1

F, d, J_FF= 43 Hz).

Anal. Calcd for C₁₁H₁₁F₂I: C, 42.88; H, 3.60. Found: C, 42.61; H,

3.54.

¹³C NMR (125 MHz, CDCl₃): = 15.7, 20.1, 33.1, 34.4, 90.7 (dd,

J_CF= 21, 14 Hz), 127.5, 128.3 (dd, J_CF= 3, 3 Hz), 128.6, 133.2 (dd,

1,1-Difluoro-5-iodo-2-(p-trifluoromethylphenyl)pent-1-ene

(13b)

J_CF= 4, 4 Hz), 154.0 (dd, J_CF= 291, 288 Hz).

¹⁹F NMR (254 MHz, CDCl₃): = 71.1 (1 F, d, J_FF= 40 Hz), 71.6 (1

F, d, J_FF= 40 Hz).

HRMS: m/z calcd for C₁₂H₁₃F₂I (M⁺): 322.0030; found: 322.0059.

Compound 13b was prepared by the method described for 13a us-

ing Et₃N (187 mg, 1.8 mmol), MsCl (194 mg, 1.8 mmol), 12b (330

mg, 1.2 mmol), and CH₂Cl₂(9 mL). Purification by PTLC on silica

gel (hexane–EtOAc, 2:1) gave a crude product (387 mg) as a color-

less liquid. Treatment of the product with NaI (1.67 g, 11 mmol) in

acetone (17 mL) and purification by PTLC on silica gel (hexane)

gave 13b (360 mg, 77%) as a colorless liquid.

1,1-Difluoro-5-iodo-2-(p-methoxyphenyl)-4-methylpent-1-ene

(13e)

Compound 13e was prepared by the method described for 13a using

Et₃N (58 mg, 0.57 mmol), MsCl (60 mg, 0.57 mmol), 12e (93 mg,

0.38 mmol), and CH₂Cl₂(3 mL). Purification by PTLC on silica gel

(hexane–EtOAc, 1:1) gave a crude product (131 mg) as a colorless

liquid. Treatment of the product with NaI (572 mg, 3.8 mmol) in ac-

etone (3 mL) and purification by PTLC on silica gel (hexane–

EtOAc, 3:1) gave 13e (120 mg, 90%) as a colorless liquid.

IR (neat): 2960, 1923, 1726, 1618, 1410, 1327, 1246, 1169, 1128,

1070, 845 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.87 (2 H, tt, J = 7.2, 7.2 Hz), 2.56

(2 H, tt, J = 7.2 Hz, J_HF= 2.3 Hz), 3.14 (2 H, t, J = 7.2 Hz), 7.44 (2

H, d, J = 8.2 Hz), 7.63 (2 H, d, J = 8.2 Hz).

¹³C NMR (125 MHz, CDCl₃): = 4.7, 28.3, 31.4, 90.5 (dd, J_CF= 22,

13 Hz), 124.0 (q, J_CF= 270 Hz), 125.5 (q, J_CF= 4 Hz), 128.5 (dd,

IR (neat): 2954, 2833, 1425, 1284, 1234, 951, 744, 723, 579 cm^–1.

Synthesis 2002, No. 13, 1917–1936 ISSN 0039-7881 © Thieme Stuttgart · New York

1930

J. Ichikawa et al.

FEATURE ARTICLE

¹H NMR (500 MHz, CDCl₃): = 0.97 (3 H, d, J = 6.5 Hz), 1.47–

1.55 (1H, m), 2.28 (1 H, br dd, J = 14.3, 8.0 Hz), 2.50 (1 H, dddd,

J = 14.3, 5.9 Hz, J_HF= 2.9, 2.9 Hz), 3.11 (1 H, dd, J = 9.8, 5.8 Hz),

3.15 (1 H, dd, J = 9.8, 5.2 Hz), 3.81 (3 H, s), 6.89 (2 H, d, J = 8.7

Hz), 7.23 (2 H, d, J = 8.7 Hz).

Hz), 126.4 (d, J_CF= 10 Hz), 128.8, 130.9 (d, J_CF= 2 Hz), 146.1 (d,

J_CF= 260 Hz), 155.4 (d, J_CF= 3 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 31.4 (1 F, dt, J_FH= 86, 3 Hz).

HRMS: m/z calcd for C₁₄H₁₉O₂F (M⁺): 238.1370; found: 238.1377.

¹³C NMR (125 MHz, CDCl₃): = 15.8, 20.1, 33.1, 34.5, 55.3, 90.1

(dd, J_CF= 22, 14 Hz), 114.1, 125.2, 129.4, 154.0 (dd, J_CF= 287, 287

Hz), 158.9.

¹⁹F NMR (254 MHz, CDCl₃): = 70.3 (1 F, d, J_FF= 44 Hz), 70.7 (1

F, d, J_FF= 44 Hz).

15Z

IR (neat): 2931, 1675, 1490, 1450, 1240, 1197, 1155, 1081, 1004,

754 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.85 (3 H, t, J = 7.2 Hz), 1.32–

1.35 (4 H, m), 2.22–2.30 (2 H, m), 3.47 (3 H, s), 5.17 (2 H, s), 6.60

(1 H, dt, J_HF= 86.7, J = 1.2 Hz), 7.00 (1 H, dd, J = 7.3, 7.3 Hz),

7.11–7.16 (2H, m), 7.22–7.27 (1 H, m).

Anal. Calcd for C₁₃H₁₅F₂I: C, 44.34; H, 4.29. Found: C, 44.37; H,

4.32.

¹³C NMR (126 MHz, CDCl₃): = 13.8, 22.2, 29.9 (d, J_CF= 3 Hz),

30.4 (d, J_CF= 5 Hz), 56.0, 94.5, 114.7, 121.0 (d, J_CF= 4 Hz), 121.6,

125.2 (d, J_CF= 2 Hz), 128.7, 130.7 (d, J_CF= 2 Hz), 143.7 (d,

o-(1-Butyl-2,2-difluorovinyl)phenoxymethyl Methyl Ether (14)

To a suspension of NaH (134 mg, 60% dispersion in mineral oil, 3.4

mmol) in THF (12 mL) was added 4b (648 mg, 3.1 mmol) at –78 °C

under nitrogen. After stirring for 10 min, chloromethyl methyl ether

(0.69 mL, 9.2 mmol) was added to the solution at –78 °C, and the

mixture was stirred for 5 h. The reaction was quenched with phos-

phate buffer (pH 7), and organic materials were extracted with

EtOAc (3 20 mL). The combined extracts were washed with brine

(20 mL) and dried over Na₂SO₄. After removal of the solvent under

reduced pressure, the residue was purified by column chromatogra-

phy on silica gel (hexane–EtOAc, 20:1) to give 14 (716 mg, 92%)

as a colorless liquid.

J_CF= 257 Hz), 154.5.

¹⁹F NMR (470 MHz, CDCl₃): = 31.1 (1 F, dt, J_FH= 86, 3 Hz).

MS (20 eV): m/z (%) = 238 (M⁺, 25), 174 (74), 132 (100).

HRMS: m/z calcd for C₁₄H₁₉O₂F (M⁺): 238.1370; found: 238.1370.

o-(1-Butyl-2-fluorovinyl)phenol (16E)

To a solution of 15E (168 mg, 0.70 mmol) in THF (7 mL) was add-

ed concd HCl (3.5 mL) at 0 °C. The reaction mixture was stirred for

2.5 h at 0 °C, and then phosphate buffer (pH 7) was added to quench

the reaction. Organic materials were extracted with EtOAc (3 10

mL). The combined extracts were washed with brine (10 mL) and

dried over Na₂SO₄. After removal of the solvent under reduced

pressure, the residue was purified by PTLC on silica gel (hexane–

EtOAc, 1:1) to give 16E (117 mg, 86%) as a colorless liquid.

IR (neat): 2958, 1745, 1492, 1454, 1228, 1197, 1155, 1079, 1004,

754 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.85 (3 H, t, J = 7.2 Hz), 1.22–

1.36 (4 H, m), 2.30–2.38 (2 H, m), 3.46 (3 H, s), 5.18 (2 H, s), 7.00

(1 H, ddd, J = 7.4, 7.4, 1.1 Hz), 7.10–7.16 (2 H, m), 7.25 (1 H, ddd,

J = 7.4, 7.4, 1.8 Hz).

IR (neat): 3529, 2958, 2931, 2861, 1488, 1450, 1284, 1211, 1178,

1110, 754 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.87 (3 H, t, J = 7.2 Hz), 1.28–

¹³C NMR (126 MHz, CDCl₃): = 13.8, 22.1, 27.7, 29.6 (dd,

J_CF= 3, 3 Hz), 56.0, 89.1 (dd, J_CF= 24, 16 Hz), 94.3, 114.4, 121.5,

123.5, 129.0, 131.0 (d, J_CF= 2 Hz), 153.0 (dd, J_CF= 286, 286 Hz),

155.0.

1.36 (4 H, m), 2.43–2.50 (2 H, m), 5.14 (1 H, s), 6.65 (1 H, d,

J_HF= 85.1 Hz), 6.80–6.93 (2 H, m), 6.90–7.10 (1 H, m), 7.18–7.23

¹⁹F NMR (470 MHz, CDCl₃): = 67.2 (1 F, dt, J_FF= 46 Hz, J_FH= 3

Hz), 71.3 (1 F, d, J_FF= 46 Hz).

MS (20 eV): m/z = 256 (M⁺), 193, 150.

(1 H, m).

¹³C NMR (126 MHz, CDCl₃): = 13.8, 22.5, 27.7 (d, J_CF= 2 Hz),

30.0 (d, J_CF= 2 Hz), 115.5, 120.5, 120.9 (d, J_CF= 8 Hz), 122.5 (d,

J_CF= 9 Hz), 129.2, 130.4 (d, J_CF= 3 Hz), 146.9 (d, J_CF= 264 Hz),

HRMS: m/z calcd for C₁₄H₁₈O₂F₂(M⁺): 256.1275; found: 256.1275.

153.4 (d, J_CF= 2 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 35.6 (1 F, dt, J_FH= 85, 3 Hz).

MS (20 eV): m/z (%) = 194 (M⁺; 51), 145 (40), 131 (100).

HRMS: m/z calcd for C₁₂H₁₅OF (M⁺): 194.1108; found: 194.1108.

o-(1-Butyl-2-fluorovinyl)phenoxymethyl Methyl Ether (15)

Red-Al (0.34 mL, 3.4 M in toluene, 1.2 mmol) was added to a solu-

tion of 14 (107 mg, 0.42 mmol) in toluene (1.5 mL) at 0 °C under

nitrogen. After the reaction mixture was heated to reflux for 3 h,

phosphate buffer (pH 7) was added to quench the reaction. Organic

materials were extracted with EtOAc (3 10 mL). The combined

extracts were washed with brine (10 mL) and dried over Na₂SO₄.

After removal of the solvent under reduced pressure, the residue

was purified by column chromatography on silica gel (hexane–

EtOAc, 20:1) to give 15E (47 mg, 47%) and 15Z (41 mg, 41%) as

colorless liquids.

o-(1-Butyl-2-fluorovinyl)phenol (16Z)

Compound 16Z was prepared by the method described for 16E us-

ing concd HCl (3.3 mL), THF (6.5 mL), and 15Z (155mg, 0.652

mmol). Purification by PTLC on silica gel (hexane–EtOAc, 5:1)

gave 16Z (106 mg, 84%) as a colorless liquid.

IR (neat): 3554, 3450, 2931, 1488, 1450, 1234, 1180, 1114, 1085,

752 cm^–1.

15E

¹H NMR (500 MHz, CDCl₃): = 0.86 (3 H, t, J = 7.0 Hz), 1.25–

1.34 (4 H, m), 2.23–2.29 (2 H, m), 5.01 (1 H, d, J_HF= 3.1 Hz), 6.73

(1 H, dt, J_HF= 85.5, J = 1.2 Hz), 6.92–6.96 (2 H, m), 7.70–7.11 (1

H, m), 7.19–7.24 (1 H, m).

IR (neat): 2956, 1488, 1228, 1195, 1155, 1114, 1101, 1079, 1004,

754 cm^–1.

MS (20 eV): m/z (%) = 238 (M⁺, 27), 174 (90), 132 (100).

¹³C NMR (126 MHz, CDCl₃): = 13.8, 22.2, 30.0 (d, J_CF= 2 Hz),

30.9 (d, J_CF= 5 Hz), 115.9, 119.4 (d, J_CF= 3 Hz), 120.6, 121.5,

128.8, 129.3, 144.3 (d, J_CF= 259 Hz), 152.7.

¹⁹F NMR (470 MHz, CDCl₃): = 35.0 (1 F, dtd, J_FH= 85, 6, 3 Hz).

MS (20 eV): m/z (%) = 194 (M⁺, 58), 152 (29), 131 (100).

HRMS: m/z calcd for C₁₂H₁₅OF (M⁺): 194.1108; found: 194.1108.

¹H NMR (500 MHz, CDCl₃): = 0.85 (3 H, t, J = 6.9 Hz), 1.24–

1.34 (4 H, m), 2.50–2.57 (2 H, m), 3.45 (3 H, s), 5.18 (2 H, s), 6.60

(1 H, d, J_HF= 86.7 Hz), 6.96 (1 H, dd, J = 7.4, 7.4 Hz), 7.10 (2 H,

d, J = 7.4 Hz), 7.22–7.27 (1 H, m).

¹³C NMR (126 MHz, CDCl₃): = 13.8, 22.4, 26.7 (d, J_CF= 3 Hz),

29.6 (d, J_CF= 2 Hz), 56.1, 94.4, 114.5, 121.6, 123.3 (d, J_CF= 10

FEATURE ARTICLE

Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes

1931

Methyl 2-(2-benzyloxyethyl)-3,3-difluoroacrylate (18)

¹H NMR (500 MHz, CDCl₃): = 1.36 (9 H, s), 2.43 (3 H, s), 2.68

(2 H, tdd, J = 6.4 Hz, J_HF= 2.1, 2.1 Hz), 3.82 (3 H,s), 4.00 (2 H, t,

J = 6.4 Hz), 7.30 (2 H, d, J = 8.1 Hz), 7.77 (2 H, d, J = 8.1 Hz).

¹³C NMR (126 MHz, CDCl₃): = 21.6, 25.2, 25.8, 45.4 (dd,

J_CF= 2, 2 Hz), 52.2, 84.3, 85.8 (dd, J_CF= 23, 7 Hz), 127.9, 129.2,

137.2, 144.2, 150.7, 160.7 (dd, J_CF= 311, 297 Hz), 164.8 (dd,

A solution of (benzyloxymethyl)tributylstannane (3.5 g, 8.6 mmol)

in THF (34 mL) was treated with BuLi (5.9 mL, 1.5 M in hexane,

9.1 mmol) at –78 °C under nitrogen. The reaction mixture was

transferred via a cooled cannula to a solution of CuBr (CH₃)₂S com-

plex (1.9 g, 9.1 mmol) in i-Pr₂S (7.5 mL) and THF (9 mL) [which

had been treated with isopropyl magnesium chloride (two drops, 2.0

M in THF) followed by stirring at –78 °C for 15 min] at –78 °C. To

the solution was added (CH₃)₃SiCl (2.7 mL, 22 mmol) and methyl

2-(trifluoromethyl)acrylate (1.5 g, 9.5 mmol). The reaction mixture

was stirred for 5 min at –78 °C and then at r.t. for an additional 6 h.

The reaction was quenched with phosphate buffer (pH 7), and or-

ganic materials were extracted with EtOAc (3 50 mL). The com-

bined extracts were washed with brine (30 mL) and dried over

Na₂SO₄. After removal of the solvent under reduced pressure, the

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

ane–EtOAc, 5:1) to give 18 (1.2 g, 54%) as a colorless liquid.

J_CF= 13, 7 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 89.8 (1 F, dt, J_FF= 8 Hz, J_FH= 3

Hz), 95.6 (1 F, d, J_FF= 8 Hz).

MS (70 eV) = m/z (%) 421 ([M + 2 H]⁺, 1), 363 (61), 184 (96), 155

(98), 57 (100).

HRMS: m/z calcd for C₁₈H₂₅NO₆F₂S ([M + 2 H]⁺): 421.1370;

found: 421.1342.

Methyl 3,3-Difluoro-2-(2-p-toluenesulfonamidoethyl)acrylate

(17)

IR (neat): 2954, 2863, 1749, 1718, 1438, 1349, 1270, 1157, 1112,

1027 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 2.56 (2 H, tdd, J = 6.6, J_HF= 2.2,

2.2 Hz), 3.56 (2 H, t, J = 6.6 Hz), 3.76 (3 H, s), 4.50 (2 H, s), 7.26–

7.60 (5 H, m).

¹³C NMR (126 MHz, CDCl₃): = 25.2, 52.1, 68.0 (dd, J_CF= 3 Hz),

72.8, 85.8 (dd, J_CF= 24, 7 Hz), 127.5, 127.6, 128.4, 138.2, 160.4

(dd, J_CF= 310, 296 Hz), 165.2 (dd, J_CF= 13, 7 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 89.1 (1 F, dt, J_FF= 6 Hz, J_FH= 3

Hz), 94.2 (1 F, d, J_FF= 6 Hz).

To a solution of 20 (421 mg, 1.0 mmol) in CH₂Cl₂(8 mL) was added

trifluoroacetic acid (0.23 mL, 3.0 mmol) at r.t. The reaction mixture

was stirred for 7 h at r.t., and then aq NaHCO₃was added to quench

the reaction. Organic materials were extracted with CH₂Cl₂(3 15

mL), and the combined extracts were washed with brine (15 mL)

and dried over Na₂SO₄. After removal of the solvent under reduced

pressure, the residue was purified by PTLC on silica gel (hexane–

EtOAc, 3:1) to give 17 (310 mg, 97%) as a pale yellow liquid.

IR (neat): 3293, 2956, 1718, 1438, 1328, 1218, 1159, 1093, 815,

663, 551 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 2.40 (2 H, tdd, J = 6.5 Hz,

J_HF= 2.1, 2.1 Hz), 2.42 (3 H, s), 3.09 (2 H, td, J = 6.5, 6.5 Hz), 3.75

(3 H, s), 5.09 (1 H, t, J = 6.5 Hz), 7.30 (2 H, d, J = 8.1 Hz), 7.73 (2

H, d, J = 8.1 Hz).

MS (20 eV): m/z (%) = 256 (M⁺, 21), 107 (89), 91 (100).

HRMS: m/z calcd for C₁₃H₁₄O₃F₂(M⁺): 256.0911; found: 256.0863.

Methyl 2-(2-hydroxyethyl)-3,3-difluoroacrylate (19)

¹³C NMR (126 MHz, CDCl₃): = 21.4, 25.2, 41.1, 52.3, 85.6 (dd,

J_CF= 23, 7 Hz), 127.0, 129.6, 137.0, 143.4, 160.4 (dd, J_CF= 312,

297 Hz), 165.1 (dd, J_CF= 13, 8 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 90.5 (1 F, dt, J_FF= 9 Hz, J_FH= 3

Hz), 96.2 (1 F, d, J_FF= 9 Hz).

HRMS–FAB: m/z calcd for C₁₃H₁₆O₄NF₂S ([M+H]⁺): 320.0768;

found: 320.0775.

BCl₃(2.0 mL, 1.0 M in CH₂Cl₂, 2.0 mmol) was added to a solution

of 18 (493 mg, 1.9 mmol) in CH₂Cl₂(12 mL) at –78 °C. The reac-

tion mixture was warmed to 0 °C and stirred for 5 h. The reaction

was quenched with phosphate buffer (pH 7). Organic materials

were extracted with CH₂Cl₂(3 30 mL). The combined extracts

were washed with brine (20 mL) and dried over Na₂SO₄. After re-

moval of the solvent under reduced pressure, the residue was puri-

fied by PTLC on silica gel (hexane–EtOAc, 5:1) to give 19 (213 mg,

67%) as a colorless liquid.

3-Butyl-2-fluoro-1-tosylindole (21a)

To a suspension of NaH (31 mg, 62% dispersion in mineral oil, 0.79

mmol) in DMF (0.5 mL) was added 3b (232 mg, 0.63 mmol) in

DMF (2.5 mL) at r.t. under nitrogen. The reaction mixture was

stirred at 80 °C for 7 h, and then phosphate buffer (pH 7) was added

to quench the reaction. Organic materials were extracted with

EtOAc (3 10 mL), and the combined extracts were washed with

brine (10 mL) and dried over Na₂SO₄. After removal of the solvent

under reduced pressure, the residue was purified by PTLC on silica

gel (hexane–EtOAc, 5:1) to give 21a (184 mg, 84%) as an orange

liquid.

IR (neat): 3511, 2958, 1774, 1720, 1440, 1351, 1272, 1178, 1095,

1024 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 2.50 (2 H, tdd, J = 6.3, J_HF= 2.2,

2.2 Hz), 2.55 (1 H, br s), 3.71 (2 H, t, J = 6.3 Hz), 3.80 (3 H, s).

¹³C NMR (126 MHz, CDCl₃): = 27.9, 52.2, 60.8 (dd, J_CF= 3 Hz),

85.7 (dd, J_CF= 24, 7 Hz), 160.4 (dd, J_CF= 310, 296 Hz), 165.7 (dd,

J_CF= 13, 7 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 89.4 (1 F, dt, J_FF= 6, J_FH= 3 Hz),

94.9 (1 F, d, J_FF= 6 Hz).

IR (neat): 2960, 2930, 2860, 1660, 1455, 1395, 1190, 1180, 745,

690, 665 cm^–1.

MS (70 eV): m/z = 167 ([M+H]⁺), 149 ([M–OH]⁺), 136, 105.

Methyl 2-(N-tert-Butoxycarbonyl-p-toluenesulfonamidoethyl)-

3,3-difluoroacrylate (20)

¹H NMR (500 MHz, CDCl₃): = 0.86 (3 H, t, J = 7.4 Hz), 1.21 (2

H, tq, J = 7.4, 7.4 Hz), 1.53 (2 H, tt, J = 7.4, 7.4 Hz), 2.34 (3 H, s),

2.52 (2 H, td, J = 7.4 Hz, J_HF= 0.8 Hz), 7.20 (2 H, d, J = 8.4 Hz),

7.23 (1 H, ddd, J = 7.7, 7.7, 1.2 Hz), 7.28 (1 H, ddd, J = 7.7, 7.7, 1.2

Hz), 7.33 (1 H, dd, J = 7.7, 1.2 Hz), 7.73 (2 H, d, J = 8.4 Hz), 8.08

(1 H, d, J = 7.7 Hz).

¹³C NMR (126 MHz, CDCl₃): = 13.6, 21.3 (d, J_CF= 3 Hz), 21.5,

22.1, 30.5, 99.7 (d, J_CF= 11 Hz), 114.4, 118.9 (d, J_CF= 7 Hz),

124.0, 124.0 (d, J_CF= 4 Hz), 126.8, 128.1 (d, J_CF= 6 Hz), 129.8,

130.6, 134.7, 145.2, 147.4 (d, J_CF= 276 Hz).

To a solution of N-tert-butoxycarbonyl-N-p-toluenesulfonamide

(348 mg, 1.3 mmol) in THF (15 mL) was added PPh₃(336 mg, 1.3

mmol), 19 (213 mg, 1.3 mmol), and DEAD (223 mg, 1.3 mmol) in

THF (2 mL) at r.t. under nitrogen. The reaction mixture was stirred

for 10 h and concentrated under reduced pressure. The residue was

purified by column chromatography on silica gel (hexane–EtOAc,

5:1) to give 20 (415 mg, 77%) as a colorless liquid.

IR (neat): 2981, 1720, 1438, 1355, 1286, 1155, 1087, 1051, 673,

595 cm^–1.

¹⁹F NMR (470 MHz, CDCl₃): = 29.1 (s).

1932

J. Ichikawa et al.

FEATURE ARTICLE

MS (20 eV): m/z (%) = 345 (M⁺; 100), 190 (68), 148 (92).

J = 7.4 Hz, J_HF= 1.0 Hz), 7.19–7.25 (2 H, m), 7.32–7.36 (1 H, m),

7.40–7.45 (1 H, m).

HRMS calcd for C₁₉H₂₀NO₂FS (M⁺): 345.1199; found: 345.1188.

¹³C NMR (126 MHz, CDCl₃): = 13.8, 21.0 (d, J_CF= 3 Hz), 22.4,

30.7 (d, J_CF= 2 Hz), 90.6 (d, J_CF= 12 Hz), 110.8, 119.2 (d, J_CF= 6

Hz), 123.1 (d, J_CF= 4 Hz), 123.2, 129.3 (d, J_CF= 3 Hz), 147.1,

157.1 (d, J_CF= 278 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 42.0 (s).

MS (20 eV): m/z (%) = 192 (M⁺, 43), 149 (100).

HRMS: m/z calcd for C₁₂H₁₃OF (M⁺): 192.0950; found: 192.0918.

Anal. Calcd for C₁₉H₂₀NO₂FS: C, 66.07; H, 5.84; N, 4.05. Found:

C, 65.97; H, 5.90; N, 4.10.

3-sec-Butyl-2-fluoro-1-tosylindole (21b)

Compound 21b was prepared by the method described for 21a us-

ing NaH (17 mg, 60% dispersion in mineral oil, 0.43 mmol) in DMF

(1 mL), and 3d (131 mg, 0.36 mmol) in DMF (1 mL). The reaction

was carried out at 80 °C for 5 h. Purification by PTLC on silica gel

(hexane–EtOAc, 5:1) gave 21b (100 mg, 81%) as an orange liquid.

3-Butyl-2-fluorobenzo[b]thiophene (24)

IR (neat): 2970, 2930, 1740, 1650, 1600, 1450, 1395, 1245, 1180,

1090, 745 cm^–1.

¹H NMR (400 MHz, CDCl₃): = 0.70 (3 H, t, J = 7.1 Hz), 1.26 (3

H, dd, J = 7.1, J_HF= 0.7 Hz), 1.55–1.73 (2 H, m), 2.33 (3 H, s), 2.77

(1 H, ddq, J = 7.1, 7.1, 7.1 Hz), 7.17–7.30 (4 H, m), 7.39 (1 H, dd,

J = 7.7, 1.0 Hz), 7.72 (2 H, d, J = 8.2 Hz), 8.06–8.11 (1 H, m).

¹³C NMR (101 MHz, CDCl₃): = 12.1, 19.4 (d, J_CF= 2 Hz), 21.6,

28.6 (d, J_CF= 2 Hz), 30.8 (d, J_CF= 3 Hz), 103.9 (d, J_CF= 9 Hz),

114.6, 119.5 (d, J_CF= 7 Hz), 123.9, 123.9, 126.8, 127.6 (d, J_CF= 5

Hz), 129.8, 130.7 (d, J_CF= 1 Hz), 134.6, 145.3, 147.1 (d, J_CF= 277z

Hz).

To a solution of 5b (93 mg, 0.36 mmol) in CH₂Cl₂(3 mL) was add-

ed trifluoroacetic anhydride (0.15 mL, 1.1 mmol) and Et₃N (0.15

mL, 1.1 mmol) at 0 °C under nitrogen. After the reaction mixture

was stirred for 0.5 h, the volatile components were removed by

evaporation, and the remaining residue was dissolved in MeOH (3

mL). The resulting solution was treated with K₂CO₃(300 mg, 2.2

mmol) at 0 °C and stirred at r.t. for 1 h, and then heated under reflux

for an additional 2 h. Phosphate buffer (pH 7) was added to quench

the reaction, and organic materials were extracted with EtOAc (3

10 mL). The combined extracts were washed with brine (10 mL)

and dried over Na₂SO₄. After removal of the solvent under reduced

pressure, the residue was purified by PTLC on silica gel (hexane–

EtOAc, 50:1) to give 24 (62 mg, 82%) as a colorless liquid.

¹⁹F NMR (376 MHz, CDCl₃): = 31.2 (s).

Anal. Calcd for C₁₉H₂₀O₂SNF: C, 66.07; H, 5.84; N, 4.05. Found:

C, 66.22; H, 5.94; N, 4.03.

IR (neat): 2960, 2930, 2860, 1610, 1460, 1435, 1265, 1190, 1065,

755, 730 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.94 (3 H, t, J = 7.5 Hz), 1.39 (2

H, tq, J = 7.5, 7.5 Hz), 1.64 (2 H, tt, J = 7.5, 7.5 Hz), 2.75 (2 H, td,

J = 7.5 Hz, J_HF= 1.3 Hz), 7.28 (1 H, ddd, J = 7.7, 7.7, 1.4 Hz), 7.35

(1 H, ddd, J = 7.7, 7.7, 0.9 Hz), 7.58 (1 H, d, J = 7.7 Hz), 7.64 (1 H,

d, J = 7.7 Hz).

¹³C NMR (126 MHz, CDCl₃): = 13.8, 22.5, 23.6, 31.0 (d, J_CF= 2

Hz), 115.5 (d, J_CF= 10 Hz), 121.5 (d, J_CF= 6 Hz), 122.6, 124.0 (d,

J_CF= 4 Hz), 124.6, 131.3 (d, J_CF= 2 Hz), 136.8 (d, J_CF= 6 Hz),

159.2 (d, J_CF= 289 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 29.1 (s).

MS (20 eV): m/z (%) = 208 (M⁺, 50), 165 (100).

HRMS: m/z calcd for C₁₂H₁₃FS (M⁺): 208.0722; found: 208.0694.

2-Fluoro-1-tosylindole (21c)

Compound 21c was prepared by the method described for 21a using

NaH (16 mg, 60% dispersion in mineral oil, 0.41 mmol) in DMF

(0.5 mL), and 3f (105 mg, 0.34 mmol) in DMF (1.5 mL). The reac-

tion was carried out at 70 °C for 23 h. Purification by PTLC on sil-

ica gel (hexane–EtOAc, 3:1) gave 21c (72 mg, 73%) as a colorless

liquid.

IR (neat): 2950, 2930, 1625, 1450, 1385, 1245, 1175, 1090, 745,

690 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 2.34 (3 H, s), 5.91 (1 H, d,

J_HF= 3.4 Hz), 7.20–7.24 (3 H, m), 7.29 (1 H, ddd, J = 8.4, 7.3, 1.2

Hz), 7.36 (1 H, d, J = 7.9 Hz), 7.78 (2 H, d, J = 8.2 Hz), 8.09 (1 H,

d, J = 8.4 Hz).

Anal. Calcd for C₁₂H₁₃FS: C, 69.20; H, 6.29. Found: C, 68.94; H,

6.33.

¹³C NMR (126 MHz, CDCl₃): = 21.6, 86.7 (d, J_CF= 12 Hz),

114.1, 120.7 (d, J_CF= 6 Hz), 124.1 (d, J_CF= 4 Hz), 124.2, 126.6 (d,

J

Hz).

_CF= 5 Hz), 126.9, 130.0, 130.8, 134.9, 145.6, 150.8 (d, J_CF= 279

5-Fluoro-3-methyl-4-(2-phenylpropyl)-2,3-dihydrofuran (25a)

NaH (12 mg, 60% dispersion in mineral oil, 0.30 mmol) was added

to a solution of 9a (60 mg, 0.25 mmol) in DMF (8 mL) under nitro-

gen. After the reaction mixture was stirred at 90 °C for 7 h, phos-

phate buffer (pH 7) was added to quench the reaction. Organic

materials were extracted with EtOAc (3 10 mL). The combined

extracts were washed with H₂O and then dried over Na₂SO₄. After

removal of the solvent under reduced pressure, the residue was pu-

rified by PTLC on silica gel (hexane–EtOAc, 10:1) to give 25a (a

1:1 diastereomeric mixture, 37 mg, 67%) as a colorless liquid.

¹⁹F NMR (470 MHz, CDCl₃): = 35.7 (d, J_FH= 3 Hz).

MS (70 eV): m/z (%) = 289 (M⁺, 23), 155 (50), 134 (80), 91 (100).

HRMS m/z calcd for C₁₅H₁₂NO₂FS (M⁺): 289.0574; found:

289.0565.

3-Butyl-2-fluorobenzo[b]furan (22)

To a solution of 4b (94 mg, 0.44 mmol) in DMF (4 mL) was added

NaH (21 mg, 62% dispersion in mineral oil, 0.53 mmol) at 0 °C un-

der nitrogen. The reaction mixture was stirred at 60 °C for 2 h, and

then phosphate buffer (pH 7) was added to quench the reaction. Or-

ganic materials were extracted with EtOAc (3 10 mL). The com-

bined extracts were washed with brine (10 mL) and dried over

Na₂SO₄. After removal of the solvent under reduced pressure, the

residue was purified by PTLC on silica gel (hexane–EtOAc, 30:1)

to give 22 (68 mg, 80%) as a colorless liquid.

IR (neat): 2962, 1740, 1603, 1495, 1452, 1383, 1252, 1120, 957,

762 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.05 (1.5 H, dd, J = 7.6 Hz,

J_HF= 1.2 Hz), 1.06 (1.5 H, dd, J = 7.6 Hz, J_HF= 1.2 Hz), 1.27 (1.5

H, d, J = 7.0 Hz), 1.31 (1.5 H, d, J = 7.0 Hz), 2.18 (0.5 H, dd,

J = 15.2, 7.6 Hz), 2.19 (0.5 H, dd, J = 15.2, 7.6 Hz), 2.35 (0.5 H, dd,

J = 15.2, 8.2 Hz), 2.39 (0.5 H, dd, J = 15.2, 9.1 Hz), 2.77–2.85 (1 H,

m), 2.85–2.94 (1 H, m), 3.82 (0.5 H, dd, J = 8.6, 7.0 Hz), 3.87 (0.5

H, dd, J = 8.6, 7.0 Hz), 4.35 (0.5 H, dd, J = 8.9, 8.6 Hz), 4.43 (0.5

H, dd, J = 9.1, 8.6 Hz), 7.20–7.28 (3 H, m), 7.31 (1 H, t, J = 7.6 Hz),

7.33 (1 H, t, J = 7.6 Hz).

IR (neat): 2960, 2940, 2860, 1675, 1455, 1380, 1295, 1260, 1185,

1140, 740 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.94 (3 H, t, J = 7.4 Hz), 1.39 (2

H, tq, J = 7.4, 7.4 Hz), 1.66 (2 H, tt, J = 7.4, 7.4 Hz), 2.57 (2 H, td,

FEATURE ARTICLE

Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes

1933

¹³C NMR (126 MHz, CDCl₃): = 18.5 (d, J_CF= 2 Hz), 18.6, 21.2,

22.0, 30.7 (d, J_CF= 3 Hz), 30.8 (d, J_CF= 2 Hz), 36.2 (d, J_CF= 3 Hz),

36.9 (d, J_CF= 4 Hz), 38.3 (d, J_CF= 2 Hz), 38.4 (d, J_CF= 2 Hz), 74.5

(d, J_CF= 3 Hz), 74.6 (d, J_CF= 3 Hz), 82.0 (d, J_CF= 13 Hz), 82.4 (d,

5-Fluoro-3-methyl-4-(3-phenylpropyl)-2,3-dihydrothiophene

(27)

From 11b: Compound 27 was prepared by the method described for

25a using NaH (6.9 mg, 60% dispersion in mineral oil, 0.17 mmol)

and 11b (40 mg, 0.16 mmol) in DMF (4.5 mL). The reaction was

carried out at 90 °C for 4 h. Purification by PTLC on silica gel (hex-

ane–EtOAc, 50:1) gave 27 (28 mg, 76%) as a colorless liquid.

J_CF= 15 Hz), 126.0, 126.1, 126.8, 126.8, 128.2, 128.3, 146.5, 147.3,

156.7 (d, J_CF= 271 Hz), 156.8 (d, J_CF= 270 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 42.1 (0.5 F, s), 42.5 (0.5 F, s).

MS (70 eV): m/z (%) = 220 (M⁺; 80), 115 (100).

HRMS: m/z calcd for C₁₄H₁₇OF (M⁺): 220.1263; found: 220.1257.

From 11a: Compound 27 was prepared by the method described for

25a using NaOMe (7.5 mg, 0.14 mmol) instead of NaH and 11a (40

mg, 0.13 mmol) in DMF (4 mL). The reaction was carried out at

90 °C for 8 h. Purification by PTLC on silica gel (hexane–EtOAc,

50:1) gave 27 (22 mg, 69%) as a colorless liquid.

3-Benzyl-4-butyl-5-fluoro-2,3-dihydrofuran (25b)

Compound 9b was prepared by the method described for 25a using

NaH (9.6 mg, 60% dispersion in mineral oil, 0.24 mmol) and 9b (51

mg, 0.20 mmol) in DMF (10 mL). The reaction was carried out at

90 °C for 11 h. Purification by PTLC on silica gel (hexane–EtOAc,

10:1) gave 25b (29 mg, 62%) as a colorless liquid.

IR (neat): 2929, 1672, 1603, 1497, 1452, 1188, 1153, 1030, 746,

700 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.10 (3 H, dd, J = 6.7 Hz,

J_HF= 1.2 Hz), 1.61–1.80 (2 H, m), 1.91–1.99 (1 H, m), 2.29 (1 H,

ddd, J = 15.2, 8.2, 7.0 Hz), 2.56–2.67 (2 H, m), 2.85 (1 H, ddd,

J = 10.7, 6.4 Hz, J_HF= 1.8 Hz), 2.89–2.98 (1 H, m), 3.42 (1 H, ddd,

J = 10.7, 7.9, J_HF= 1.2 Hz), 7.17 (2 H, d, J = 7.9 Hz), 7.18 (1 H, t,

J = 7.2 Hz), 7.28 (2 H, dd, J = 7.9, 7.2 Hz).

¹³C NMR (126 MHz, CDCl₃): = 17.7, 24.4, 29.2, 35.5, 37.9, 39.4

(d, J_CF= 4 Hz), 113.4 (d, J_CF= 8 Hz), 125.7, 128.3, 128.4, 142.1,

151.1 (d, J_CF= 290 Hz).

IR (neat): 2929, 1736, 1454, 1377, 1246, 1165, 1126, 1030, 731,

700 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.91 (3 H, t, J = 7.2 Hz), 1.22–

1.50 (4 H, m), 1.85–2.00 (1 H, m), 2.14 (1 H, dt, J = 15.3, 7.6 Hz),

2.51 (1 H, dd, J = 13.7, 10.1 Hz), 2.99 (1 H, dd, J = 13.7, 4.6 Hz),

3.21 (1 H, dddd, J = 10.1, 9.2, 5.6, 4.6 Hz), 4.05 (1 H, dd, J = 9.2,

5.6 Hz), 4.22 (1 H, dd, J = 9.2, 9.2 Hz), 7.15 (2 H, d, J = 7.6 Hz),

7.21 (1 H, t, J = 7.6 Hz), 7.29 (2 H, dd, J = 7.6, 7.6 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 35.7 (br s).

¹³C NMR (126 MHz, CDCl₃): = 13.8, 21.8 (d, J_CF= 2 Hz), 22.3,

29.9, 39.4, 43.5 (d, J_CF= 2 Hz), 72.1 (d, J_CF= 3 Hz), 82.5 (d,

MS (70 eV): m/z (%) = 236 (M⁺, 100), 161 (38), 84 (71).

HRMS: m/z calcd for C₁₄H₁₇FS (M⁺): 236.1035; found: 236.1039.

J_CF= 14 Hz), 126.3, 128.5, 128.8, 139.2, 156.4 (d, J_CF= 271 Hz).

¹⁹F NMR (470 MHz, CDCl₃): = 42.4 (s).

1-Fluoro-2-phenyl-1-cyclopentene (28a)

t-BuLi (0.79 mL, 1.4 M in pentane, 1.1 mmol) was added to a

solution of 13a (153 mg, 0.52 mmol) in Et₂O–hexane (1:4, 14 mL)

at –78 °C over 10 min under argon. The reaction mixture was stirred

for 30 min at –78 °C, then warmed to r.t. After stirred for 1 h, the

reaction was quenched with phosphate buffer (pH 7). Organic ma-

terials were extracted with Et₂O (3 10 mL), and the combined ex-

tracts were washed with brine (10 mL) and dried over Na₂SO₄. After

removal of the solvent under reduced pressure, the residue was pu-

rified by PTLC on silica gel (pentane) to give 28a (64 mg, 76%) as

a white solid.

MS (70 eV): m/z (%) = 234 (M⁺), 143 (100).

HRMS: m/z calcd for C₁₅H₁₉OF (M⁺): 234.1420; found: 234.1429.

2-Fluoro-4-methyl-3-(2-phenylpropyl)-1-tosyl-2-pyrroline (26)

Compound 26 was prepared by the method described for 25a using

NaH (5.6 mg, 60% dispersion in mineral oil, 0.14 mmol) and 10b

(50 mg, 0.13 mmol) in DMF (6.5 mL). The reaction was carried out

at 90 °C for 4 d. Purification by PTLC on silica gel (hexane–EtOAc,

7:1) gave 26 (1:1 diastereomeric mixture, 38 mg, 80%) as a color-

less liquid.

IR (KBr): 2960, 2854, 1678, 1496, 1354, 1198, 1063, 945, 762, 692

cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.98 (2 H, tt, J = 7.5, 7.5 Hz),

2.63–2.72 (4 H, m), 7.20 (1 H, t, J = 7.7 Hz), 7.33 (2 H, dd, J = 7.7,

7.7 Hz), 7.49 (2 H, d, J = 7.7 Hz).

IR (neat): 2962, 1738, 1603, 1495, 1377, 1174, 1092, 908, 814, 733

cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.66 (1.5 H, d, J = 7.3 Hz), 0.68

(1.5 H, d, J = 7.3 Hz), 1.07 (1.5 H, d, J = 6.7 Hz), 1.15 (1.5 H, d,

J = 6.7 Hz), 2.01 (0.5 H, ddd, J = 14.3, 6.4, 1.8 Hz), 2.09 (0.5 H,

ddd, J = 14.3, 6.4, 1.8 Hz), 2.14–2.23 (0.5 H, m), 2.23–2.40 (1.5 H,

m), 2.45 (1.5 H, s), 2.46 (1.5 H, s), 2.62 (0.5 H, tq, J = 7.3, 7.3 Hz),

2.79 (0.5 H, tq, J = 6.7, 6.7 Hz), 3.21 (0.5 H, ddd, J = 11.3, 5.8, 1.5

Hz), 3.17 (0.5 H, ddd, J = 11.3, 6.1, 1.2 Hz), 3.67 (0.5 H, dd,

J = 11.0, 9.8 Hz), 3.77 (0.5 H, dd, J = 11.0, 9.8 Hz), 7.00–7.07, (2

H, m), 7.12–7.30, (4 H, m), 7.34 (1 H, d, J = 8.2 Hz), 7.63 (1 H, d,

J = 8.2 Hz), 7.71 (1 H, d, J = 8.2 Hz).

¹³C NMR (125 MHz, CDCl₃): =18.1 (d, J_CF= 10 Hz), 29.7 (d,

J_CF= 8 Hz), 30.8 (d, J_CF= 21 Hz), 113.1 (d, J_CF= 4 Hz), 126.6,

126.6, 128.2, 133.8 (d, J_CF= 5 Hz), 157.8 (d, J_CF= 284 Hz).

¹⁹F NMR (254 MHz, CDCl₃): = 45.0 (s).

Anal. Calcd for C₁₁H₁₁F: C, 81.45; H, 6.84. Found: C, 81.15; H,

6.85.

¹³C NMR (126 MHz, CDCl₃): = 18.7, 18.7, 21.2, 21.6, 21.6, 21.9,

31.4, 31.7, 32.4 (d, J_CF= 3 Hz), 33.1, 38.0, 38.1, 54.4, 54.5, 101.6,

102.4, 126.2, 126.3, 126.6, 126.6, 127.9, 128.0, 128.3, 128.4, 129.7,

129.8, 132.5, 132.6, 144.2, 144.4, 145.7, 146.5, 147.1 (d, J_CF= 318

Hz), 147.2, (d, J_CF= 318 Hz).

1-Fluoro-2-(p-trifluoromethylphenyl)cyclo-1-pentene (28b)

Compound 28b was prepared by the method described for 28a us-

ing t-BuLi (0.77 mL, 1.5 M in pentane, 1.1 mmol), 13b (193 mg,

0.51 mmol), and Et₂O–hexane (1:4, 14 mL). Purification by PTLC

on silica gel (pentane) gave 28b (79 mg, 65%) as a white solid.

¹⁹F NMR (470 MHz, CDCl₃): = 36.2 (0.5 F, s), 36.6 (0.5 F, s).

MS (70 eV): m/z (%) = 373 (M⁺, 7), 268 (56), 117 (100).

HRMS: m/z calcd for C₂₁H₂₄NO₂FS (M⁺): 373.1512; found:

373.1506.

IR (KBr): 2927, 2862, 1676, 1618, 1329, 1167, 1120, 1066, 841,

607 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 2.03 (2H, tt, J = 7.3, 7.3 Hz),

2.67–2.74 (4H, m), 7.58 (4H, s).

¹³C NMR (125 MHz, CDCl₃): = 18.1 (d, J_CF= 10 Hz), 29.6 (d,

J_CF= 7 Hz), 30.9 (d, J_CF= 21 Hz), 112.4 (d, J_CF= 3 Hz), 124.3 (q,

1934

J. Ichikawa et al.

FEATURE ARTICLE

J_CF= 204 Hz), 125.2 (q, J_CF= 4 Hz), 126.7 (d, J_CF= 7 Hz), 128.3 (q,

_CF= 32 Hz), 137.3 (d, J_CF= 270 Hz), 159.7 (d, J_CF= 287 Hz).

¹⁹F NMR (254 MHz, CDCl₃): = 48.5 (1 F, s), 99.3 (3 F, s).

3-Butylbenzo[b]furan (31)

J

From 16E: Compound 31 was prepared by the method described for

22 using NaH (29 mg, 60% dispersion in mineral oil, 0.72 mmol)

and 16E (117 mg, 0.60 mmol) in DMF (6 mL). The reaction mixture

was stirred at 80 °C for 43 h. Purification by PTLC on silica gel

(hexane–EtOAc, 5:1) gave 31 (18 mg, 17%) as a colorless liquid.

Anal. Calcd for C₁₂H₁₀F₄: C, 62.61; H, 4.38. Found: C, 62.75; H,

4.56.

From 16Z: Compound 31 was prepared by the method described for

22 using NaH (22 mg, 60% dispersion in mineral oil, 0.55 mmol)

and 16Z (90 mg, 0.46 mmol) in DMF (5 mL). The reaction mixture

was stirred at 80 °C for 43 h. Purification by PTLC on silica gel

(hexane–EtOAc, 5:1) gave 31 (15 mg, 19%) as a colorless liquid.

1-Fluoro-2-(p-methoxyphenyl)cyclo-1-pentene (28c)

Compound 28c was prepared by the method described for 28a using

t-BuLi (0.75 mL, 1.4 M in pentane, 1.1 mmol), 13c (165 mg, 0.49

mmol), and Et₂O–hexane (1:4, 14 mL). Purification by PTLC on sil-

ica gel (hexane–Et₂O, 3:1) gave 28c (70 mg, 0.36 mmol 74%) as a

white solid.

IR (neat): 2958, 2929, 2858, 1452, 1278, 1186, 1089, 1008, 856,

744 cm^–1.

IR (KBr): 2954, 2854, 1685, 1608, 1512, 1254, 1182, 1029, 835

cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.97 (2 H, tt, J = 7.5, 7.5 Hz),

2.63–2.67 (4 H, m), 3.80 (3 H, s), 6.88 (2 H, br d, J = 9.4 Hz), 7.44

(2 H, br d, J = 9.4 Hz).

¹³C NMR (125 MHz, CDCl₃): = 18.1 (d, J_CF= 10 Hz), 29.8 (d,

J_CF= 8 Hz), 30.7 (d, J_CF= 21 Hz), 55.2, 112.5 (d, J_CF= 4 Hz),

113.7, 126.6 (d, J_CF= 5 Hz), 127.8 (d, J_CF= 7 Hz), 156.2 (d,

J_CF= 281 Hz), 158.1.

¹H NMR (500 MHz, CDCl₃): = 0.95 (3 H, t, J = 7.5 Hz), 1.42 (2

H, tq, J = 7.5, 7.5 Hz), 1.69 (2 H, tt, J = 7.5, 7.5 Hz), 2.67 (2 H, td,

J = 7.5, 0.9 Hz), 7.22 (1 H, ddd, J = 7.6, 7.6, 1.2 Hz), 7.28 (1 H, ddd,

J = 7.6, 7.6, 1.2 Hz), 7.39 (1 H, s), 7.45 (1 H, d, J = 7.6 Hz), 7.55 (1

H, dd, J = 7.6, 1.2 Hz).

¹³C NMR (126 MHz, CDCl₃): = 13.9, 22.5, 23.2, 31.2, 111.4,

119.6, 120.7, 122.1, 124.0, 128.4, 141.0, 155.4.

MS (70 eV): m/z (%) = 174 (M⁺, 32), 131 (100), 103 (12).

¹⁹F NMR (254 MHz, CDCl₃): = 42.2 (s).

HRMS: m/z calcd for C₁₂H₁₄O (M⁺): 174.1045; found: 174.1059.

Anal. Calcd for C₁₂H₁₃OF: C, 74.98; H, 6.82. Found: C, 75.03; H,

6.94.

2-Bromo-3-butylbenzo[b]furan (32)

Compound 32 was prepared by the method described for 21a using

NaH (18 mg, 62% dispersion in mineral oil, 0.45 mmol) in DMF

(3.5 mL) and 30 (126 mg, 0.38 mmol). The reaction was carried out

at 60 °C for 5 h. Purification by PTLC on silica gel (hexane–EtOAc,

30:1) gave 32 (14 mg, 15%) as a colorless liquid.

1-Fluoro-4-methyl-2-phenylcyclo-1-pentene (28d)

Compound 28d was prepared by the method described for 28a us-

ing t-BuLi (1.5 mL, 1.4 M in pentane, 2.2 mmol), 13d (325 mg, 1.0

mmol), and Et₂O–hexane (1:4, 28 mL). Purification by PTLC on sil-

ica gel (pentane) gave 28d (123 mg, 69%) as a colorless liquid.

IR (neat): 2956, 2929, 2858, 1581, 1448, 1265, 1224, 1130, 1103,

1083, 875, 744 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 0.94 (3 H, t, J = 7.5Hz), 1.39 (2

H, tq, J = 7.5, 7.5 Hz), 1.65 (2 H, tt, J = 7.5, 7.5 Hz), 2.64 (2 H, t,

J = 7.5 Hz), 7.20–7.26 (2 H, m), 7.41 (1 H, dd J = 7.2, 2.0 Hz),

7.46–7.50 (1 H, m).

¹³C NMR (126 MHz, CDCl₃): = 13.9, 22.4, 23.8, 30.9, 110.9,

118.9, 119.6, 122.8, 124.0, 126.2, 128.8, 155.2.

MS (70 eV): m/z (%) = 252 (M⁺, 82), 209 (98), 131 (100), 102 (67).

HRMS: m/z calcd for C₁₂H₁₃OBr (M⁺): 252.0150; found: 252.0125.

IR (neat): 2956, 2848, 1678, 1496, 1446, 1352, 1200, 762, 692 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.15 (3 H, dd, J = 7.0 Hz, J_HF= 1.1

Hz), 2.24–2.32 (2 H, m), 2.45 (1 H, ddddqd, J = 7.0, 7.0, 7.0, 7.0,

7.0 Hz, J_HF= 1.1 Hz), 2.78–2.89 (2 H, m), 7.19 (1 H, t, J = 7.8 Hz),

7.32 (2 H, dd, J = 7.8, 7.8 Hz), 7.48 (2 H, dt, J = 7.8, 1.0 Hz).

¹³C NMR (125 MHz, CDCl₃): = 22.2, 27.0 (d, J_CF= 9 Hz), 38.1

(d, J_CF= 7 Hz), 39.0 (d, J_CF= 9 Hz), 112.4 (d, J_CF= 3 Hz), 126.5,

126.6 (d, J_CF= 7 Hz), 128.2, 133.9 (d, J_CF= 5 Hz), 156.3 (d,

J_CF= 284 Hz).

¹⁹F NMR (254 MHz, CDCl₃): = 46.1 (s).

2-Fluoro-3-methoxycarbonyl-1-tosyl-2-pyrroline (35)

Anal. Calcd for C₁₂H₁₃F: C, 81.78; H, 7.44. Found: C, 81.77; H,

7.66.

Compound 35 was prepared by the method described for 21a using

NaH (6.1 mg, 60% dispersion in mineral oil, 0.15 mmol) in DMF (1

mL) and 19 (44 mg, 0.14 mmol) in DMF (1 mL). The reaction was

carried out at 100 °C for 15 min. Purification by PTLC on silica gel

(hexane–EtOAc, 1:1) gave 35 (25 mg, 62%) as a colorless liquid.

1-Fluoro-4-methyl-2-(p-methoxyphenyl)-cyclo-1-pentene (28e)

Compound 28e was prepared by the method described for 28a using

t-BuLi (0.60 mL, 1.4 M in pentane, 0.86 mmol), 13e (138 mg, 0.39

mmol), and Et₂O–hexane (1:4, 11 mL). Purification by PTLC on sil-

ica gel (hexane–EtOAc, 3:1) gave 28e (56 mg, 69%) as a colorless

liquid.

IR (neat): 1703, 1674, 1441, 1394, 1367, 1277, 1171, 1144, 1099,

577 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 2.46 (3 H, s), 2.62 (2 H, ddd,

J = 9.0, 9.0 Hz, J_HF= 4.8 Hz), 3.70 (3 H, s), 3.78 (2 H, ddd, J = 9.0,

9.0 Hz, J_HF= 0.8 Hz), 7.38 (2 H, d, J = 8.2 Hz), 7.78 (2 H, d, J = 8.2

Hz).

IR (neat): 2956, 2837, 1682, 1610, 1514, 1292, 1252, 1180, 1038,

831 cm^–1.

¹H NMR (500 MHz, CDCl₃): = 1.15 (3 H, d, J = 6.9 Hz), 2.21–

2.31 (2 H, m), 2.44 (1 H, ddddq, J = 6.9, 6.9, 6.9, 6.9, 6.9 Hz), 2.78–

2.87 (2 H, m), 3.80 (3 H, s), 6.87 (2 H, d, J = 8.8 Hz), 7.42 (2 H, d,

J = 8.8 Hz).

¹³C NMR (126 MHz, CDCl₃): = 21.6, 22.9, 46.4, 51.4, 88.7 (d,

J_CF= 5 Hz), 127.6, 130.2, 133.6, 145.4, 156.2 (d, J_CF= 296 Hz),

163.5 (d, J_CF= 6 Hz).

¹³C NMR (125 MHz, CDCl₃): = 22.2, 27.0 (d, J_CF= 9 Hz), 38.3

(d, J_CF= 7 Hz), 38.9 (d, J_CF= 19 Hz), 55.2, 111.8 (d, J_CF= 3 Hz),

113.7, 126.7 (d, J_CF= 5 Hz), 127.8 (d, J_CF= 7 Hz), 154.8 (d,

J_CF= 282 Hz), 158.2.

¹⁹F NMR (470 MHz, CDCl₃): = 61.8 (dd, J_FH= 4.7, 4.7 Hz).

MS (70 eV): m/z (%) = 299 (M⁺, 48), 155 (77), 91 (100).

HRMS: m/z calcd for C₁₃H₁₄NO₄FS (M⁺): 299.0627; found:

299.0627.

¹⁹F NMR (254 MHz, CDCl₃): = 43.3 (s).

HRMS: m/z calcd for C₁₃H₁₅OF (M⁺): 206.1107; found: 206.1117.

FEATURE ARTICLE

Acknowledgement

Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes

1935

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We gratefully acknowledge the financial support for this research

by Central Glass Co., Ltd. We also thank F-Tech, Inc. for a ge-

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FEATURE ARTICLE

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Article Doi

The nucleophilic 5-endo-trig cyclization of 1,1-difluoro-1-alkenes: Ring-fluorinated hetero- and carbocycle synthesis and remarkable effect of the vinylic fluorines on the disfavored process

DOI: 10.1055/s-2002-33912

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