A Stereospecific Entry to Functionalized cis-1,2

Chapter 6

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A Stereospecific Entry to Functionalized cis-1,2-Difluoroalkenes Anilkumar Raghavanpillai1,2 and Donald J . Burton1,* 1

Department of Chemistry, The University of Iowa, Iowa City, IA 52242 Current Address: DuPont Central Research and Development, Experimental Station, Wilmington, DE 19880 2

The stereospecific preparation of various 1,2-difluoroalkenyl synthons and their utilization for the synthesis of the corresponding functionalized 1,2-difluoroalkenes is discussed. The focus of this review is on the recent developments in our laboratory on the stereospecific introduction of several cis1,2-difluoroalkenylorganometallic building blocks and their functionalization for the preparation of synthetically intricate cis-1,2-difluoroalkenes, such as cis-1,2-difluorostyrenes, cis-2iodo-1,2-difluorostyrenes, cis-2-alkylsubstituted-1,2-difluorostyrenes, cis-aryl substituted 2,3-difluoroacrylic esters, cis-2,3difluoro-4-oxo-substituted 2-butenoates, symmetrically and unsymmetrically substituted cis-1,2-difluorostilbenes, cis-1 -arylperfluoroalkenes and cis-1-iodoperfluoroalkenes. The terminology 'cis' or 'trans'-1,2-difluoro refers to fluorines on the same or opposite side of the double bond of the 1,2difluoroalkenyl species.

© 2007 American Chemical Society

In Current Fluoroorganic Chemistry; Soloshonok, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

83

84


Introduction 1,2-Difluoroalkenes are versatile organofluorine building blocks because of their wide range of applications in the area of fluoropolymers, liquid crystalline materials and biologically active agents (/, 2, 3, 4, 5, 6). Generally, the physical and biological properties of 1,2-difluoroalkenes largely depend on their geometry, and the development of the corresponding synthons via a cis or trans selective route would allow studies on the stereochemical, synthetic, kinetic, and biological aspects of compounds involving such building blocks. However, practical methods for the stereospecific introduction of the 1,2-difluoroalkenyl unit remains as a considerable synthetic challenge. Although several methodologies for the introduction of fraAW-l,2-difluoroethenyl synthons and substituted trans- 1,2-difluoroalkenes are well established, the corresponding sterospecific synthesis of cw-l,2-difluoroethenyl synthons and functionalized cis- 1,2-difluoroalkenes is still relatively underdeveloped. Herein we briefly review some of the approaches for the stereospecific preparation of several cis1,2-difluoroethenyl building blocks and their utilization for the synthesis of various substituted cis- 1,2-difluoroalkenes.

1,2-difluoroalkenyl synthons: A n overview A large number of methods have been developed for the preparation of 1,2difluoroalkenes which involve the utilization of Wittig type chemistry (7, 8, 9), addition-elimination reactions (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), dehydrohalogenation reactions (21, 22, 23, 24, 25, 26) and synthesis involving 1,2-difluoroalkenyl organometallic synthons (27, 28, 29, 30, 31). The classical route to RCF=CFX, where X = F, CI or R and R is alkyl or aryl, involves reactions of the corresponding fluoroalkenes [CF =CFX] with organolithium compounds R L i . For example, reaction of phenyllithium with a number of perfluoroalkenes produced 1-phenylsubstituted fluoroalkenes in 20-60% yields together with products resulting from the successive displacement of fluorines by phenyl groups (10). Reaction of substituted aryl Grignard reagents with perfluoroalkenes have been reported to produce corresponding aryl substituted 1,2-difluoroalkenes as a mixture of trans and cis isomers with trans isomer as the favored product. (12, 13). Dehydrohalogentaion reactions have been widely used for the synthesis of 1,2-difluoroalkenes from the corresponding suitable precursors. Leroy synthesized various 1,2-difluoroalkenes by the dehydrofluorination of the corresponding 1,2,2-trifluoro precursors using tB u O K base (21). In this report, the c/s-l,2-difluoroalkene was obtained as the sole product and the cw-selectivity was attributed to the increased stability of the cw-isomer compared to the trans one. Similar to Leroy's work, fluoroalkenes of F

2


85 the general formula c/s-RCF=CFCF (R = cyclopentyl, cyclohexyl) were stereospecifically synthesized recently by the dehydofluorination of the corresponding alkanes using f-BuOK base (24). Hiyama and co-workers synthesized c/s-2-alkylsubstituted-1 -bromo-1,2-difluoroalkenes (RCF=CFBr) stereospecifically by dehydrobromination of the corresponding brominated precursor (22). These workers have also developed synthetic methods for both cis and fraws-l-aryl-perfluoroalkenes where the trans- 1-arylperfluoroalkenes prepared by the dehydrohalogenation of the corresponding precursor using D B U upon photoisomerization produced pure c/s-l-and aryl-perfluoroalkenes (23). We have recently reported a similar method for the synthesis of 1-aryl perfluoroalkenes by dehydrofluorination of the corresponding precursor using lithium hexamethyldisilazide (25, 26). 1,3-Diearbonyl compounds have been shown to undergo reaction with nucleophilic fluorinating agents, such as D A S T or Deoxofluor to produce a mixture of cis and trans isomers (1:1) of 2,3difluoroeneones (32, 33).


3

The most important and widely used approach for the synthesis of 1,2difluoroalkenes is via the corresponding 1,2-difluoroalkenylorganometallic synthons. Tarrant and co-workers reported an exclusive formation of transperfluoropropenyllithium (fra/w-CF CF=CFLi) during the low temperature metallation of a 1:1 mixture of cis and trans-CF CF=CFH (34). They proposed that the cw-lithium reagent [cw-CF CF=CFLi] readily isomerized to the trans isomer during the metallation process. However, reinvestigation of this preparation in our laboratory did not detect any isomerization of the ds-lithium reagent, instead metallation of a mixture of 80:20 trans and c/s-CF CF=CFH, produced corresponding lithium reagents with the retention of stereochemical integrity of the starting alkenes (tran/cis 80:20) (35). Although the preparation and synthetic utility of 1,2-difluoroalkenyl synthons via the corresponding lithium reagent was largely exploited by Normant and co-workers, a significant disadvantage of this route was the highly unstable nature of the 1,2difluoroalkeneyllithium reagents at ambient temperatures (27, 36, 37, 38). It was also reported that the frafls-difluorovinyllithium reagents were more stable than their cis analogues (36, 39) Thus, the alkyl substituted transdifluoroethenyllithium reagent could be prepared at -30 °C in T H F and decomposed above -5 °C, whereas the corresponding c/s-difluorovinyllithium was prepared in a mixture of ether-THF at -110 °C, but decomposed when warmed to -80 °C (Scheme 1) (36). rra/25>l,2-difluoroalkenylmagnesium reagents are well known and were prepared from the readily available frarts-l^-difluoroalkenylhalides either by direct reaction with magnesium or exchange reaction with organomagnesium halides at a relatively higher temperature (-20 to 5 °C) (40, 41, 42). For example, *ra/w-perfluoroalkenylmagnesium halides were synthesized by the reaction with magnesium in T H F at rt and utilized for the reaction with a variety of 3

3

3

3


86 n-BuLi

n-C H 7

HCHO

THF, -30 °C

F

OH

n-BuLi E t 0 / THF -110°C Downloaded by NORTH CAROLINA STATE UNIV on September 27, 2012 | http://pubs.acs.org Publication Date: January 11, 2007 | doi: 10.1021/bk-2007-0949.ch006

2

-80 °C

Decomposition Products

Scheme 1. Preparation of alkyl substituted trans and cis-1,2difluoroalkenyllithium reagents at low temperature.

electrophiles to produce corresponding fra/w-perfluoroalkenylated products (Scheme 2) (40, 41, 42, 43, 44). rra«s-perfluoroalkenylmagnesium reagents also react with phosphrous (III) chlorides to produce the corresponding phosphonites which upon reaction with hexafluoroacetone produced the corresponding dioxaphospholanes (45, 46, 47, 48). Similarly, trans-1,2-difluoro-2-(pentafluorosulfanyl)ethenyl magnesium iodide [ ^ a ^ - S F C F = C F M g I ] [generated from frafls-l,2-difluoro-l-iodo-2(pentafluorosulfanyl)ethene] reacted with selected phosphorous (III) chlorides to produce the corresponding phosphorate derivatives which upon reaction with hexafluoroacetone produced the corresponding penatfluorosulfanyl dioxaphospholanes (Scheme 3) (48). Since the utility of 1,2-difluoroalkenyllithium reagents have been limited by their poor thermal stability, attention has been focused on the development of more stable 1,2-difluoroalkenyl synthons. Transmetallation of trans- 1,2difluoroalkenyllithium or magnesium reagent with an organotin halide like tributyltin chloride provides the more stable *ra/w-l,2-difluoroalkenyltin reagent. (44, 49). Under Barbier conditions, where the tributyltin halide was used in situ during the metallation process, the yield of fraAw-l,2-difluoroalkenyltin regent was significantly improved (Scheme 4). Normant and co-workers developed several 1,2-difluoroalkenylzinc reagents by trans-metallation of 1,2difluoroalkenyllithium or magnesium reagents with zinc halide at low temperature (Scheme 4) (50, 51, 52, 53, 54, 55, 56). The 1,2-difluoroalkenylzinc reagents could also be conveniently prepared by a zinc insertion reaction with 1,2-difluoroalkenyl halides at ambient temperature (Scheme 4) (31, 57, 58). The stereochemical integrity of the 1,2-difluroalkenyl halide was retained during the preparation of the zinc reagent thus providing the corresponding cis or trans- 1,2difluoroalkenyl zinc reagents from stereochemically pure cis or frafls-alkenyl iodides. The 1,2-difluoroalkenylzinc reagents synthesized by either route exhibited excellent thermal stability at room temperature (57). 5



87

Scheme 2. Preparation of trans-perfluoroalkenylmagnesium reagents and their reaction with various electrophiles.

C F F S

F

5

/

=

\

L

l . M g , E t

2

O , - 4 0 ° C

2.ClP(OEt) ,-80°C 2

¥

S

*

F

\

/

C F P(OEt)

2

3

C O C F

Et 0,rt 2

3

3

/ ^ W ^ ^ ^

/^O^™*

F E

Scheme 3. Synthesis of

3

t

0

OEt

C

p

trans-l,2-difluoro-2-(pentafluorosulfanyl)ethenyl phosphonites.


3

88

/

>==< \

R

F

F/

V Li


R

i

F

C

3

L

v /

F

P

"

t

/

2

R

n

C

T1HF.-30 HF 30°C C ZnCl

I ^ \

R

^

Z

R

n

C

e

f

J

5

°

ZnCl p

p

F C

F

3

>=\

F C

7

Z

I

M

F

Ref.57,58

3

Znl

H

F

/

\

Tnglyme,rt

p

/

F

F

2

Zn

\

H

"

T • i ZT* Tnglyme,rt

3

F

i

Z

Ref.44 ^

2

F C

H

/

THF/Et O,-110°C

/ = \

F

3

/

V

)=(

THF,Bu SnCl

I F

n

D M A c , rt 7

DMF,

-

rt

H F

Z n I

Znl

W

F

Scheme 4. Stereospecific preparation of 1,2-difluoroalkenyltin and zinc reagents

The 1,2-difluoroalkenylzinc reagents underwent palladium catalyzed crosscoupling reaction with aryl, or alkenyl iodides to produce the corresponding 1,2difluoroalkenes or dienes in good isolated yield (Scheme 5). Similar to the 1,2difluoroalkenylzinc reagents, 1,2-difluoroalkenylcadmium reagents were prepared either by transmetallation of the corresponding lithium reagent with cadmium halide or by cadmium insertion into the corresponding alkenyl bromides (27, 59). The stereochemistry of the alkenyl halide was retained during the cadmium insertion reaction. The 1,2-difluroalkenylcadmium reagents also showed impressive thermal stability and excellent reactivity towards various electrophiles {27, 59).


89


Ref. 50, 52

Ref.53

Ref. 56

Ref. 50, 52

Ref. 58

Scheme 5. Stereospecific synthesis of various 1,2-difluoroalkenes via the corresponding 1,2-difluoroalkenylzinc reagents.

Normant and co-workers also prepared several trans- 1,2-difluoroalkenes from trifluoroalkenyltrialkylsilane intermediates prepared by the metallation of the trifluoroalkenyl halides with an alkyllithium in presence of the trialkylsilylchloride (28, 54, 60, 61). Trans-(2-?\ky\ or 2-aryl)-l,2difluoroethenylsilanes were synthesized by addition-elimination reaction of the trifluoroethenylsilane with alkyl or aryl lithium reagents and the resulting lithium reagent was transformed to potential synthons for the introduction of trans-1,2disubstituted-1,2-difluoroalkenes (29, 30, 38, 54, 62, 63, 64). The synthetic potential of these silanes was further investigated in our laboratory and in a stereospecific transformation, trans-(2-&lkyl or 2-aryl)-l,2-difluoroethenylsilanes were converted to the trans-(2-&\kyl or 2-aryl)-l,2-difluoroethenyl stannanes as illustrated in Scheme 6. The trans-(2-dXky\ or 2-aryl)-l,2-difluoroethenyl


90


stannanes were then utilized for the palladium catalyzed cross-coupling reaction with aryl or alkenyl iodides to obtain the corresponding fran.s-l,2-disubstituted1,2-difluoroalkenes (65). Recent work in our laboratory has demonstrated that 1,2-difluoroalkenyl stannanes could be obtained in a stereospecific fashion via the correposnding thermally stable zinc or cadmium reagents (66, 67).

J F C=< \

l.RLi,R SiCl, — UEt 0,-78°C

2

2

X = Cl,Br

F

\ _ /

S

I

88%

R

KF/H Q

3

F C=< \ i R

-

2

F

\ _ /

H

THF

3

R = Et,PbMe

2

F

R'Li

3

\

/

S I R

3

) = ( / \

R

2

F

BuLi

\=y

E

R' = alkyl, aryl, R = Me, Et Fv SiR \—/

33

R»'

F

, ~ (Bu Sn) Q ^ m

c

3

2

KF, DMF

F SnBu \ — /

J3

R»

F

A

T

Arl Pd(0),CuI

F Ar \ — / v

R«

F

Scheme 6. Synthesis of trans-2-substituted-l,2-difluoroethenylsilanes and stannanes and their transformation to trans-1,2-disubstituted-1,2difluoroalkenes.

Trifluoroethenyltrialkylsilane upon reduction with UAIH4 produced a 95: 5 mixture of trans and c/s-l,2-difluoroethenyltrialkylsilanes, which were utilized for the introduction of various other useful 1,2-difluoroethenylsynthons (Scheme 7) (29, JO) For example, rra«s-(l,2-difluoro-2-iodoethenyl)triethylsilane was obtained in quantitative yield by the reaction of a 95: 5 mixture of trans and cis1,2-difluoroethenyltrialkylsilane with H - B u L i followed by treatment with iodine. The /m«5-(l,2-difluoro-2-iodoethenyl)triethylsilane was further transformed to 1,2-difluoroethenyl iodide which was used as a synthon for the generation of the fra«s-l,2-difluoroethenylzinc reagent. The fra«s-l,2-difluoroethenylzinc reagent upon palladium catalyzed cross-coupling reaction with aryl iodides produced the corresponding /ra«.s-l,2-difluorostyrenes (68).ln another transformation, fra«s-l,2-difluoroethenyltrialkylsilanes were converted to the trans- 1,2-difluoroethenyltributylstannane by the reaction with K F in the presence of the tributyltin chloride or tributyltin oxide (30).


91

\

Et;0,-78°C

X = CI, Br

\

88%

i

R

j

R = Et, PhMe

H

THF,0°C 87%

H

2

+H

F H SiR When R = Et trans/cis = 95 : 5

3


1. «-BuLi, -90 °C 2.1 ,91% 2

iRj

K

KF/K DMSO, 70%

I

F KF/I H

F

2

DMSO, rt

Bu SnCl KF, DMF, 80% 70 °C

F I W p / V F

i rj l.Zn

L

Z

F

v

n

, 2.ArI,Pd(0) SnBu

F

H

Ar W F

3

3

u

) \

H

F

Scheme 7. Synthesis of trans-1,2-difluoroethenyltrialkylsilanes and its utilization for the preparation of various 1,2-difluoroethenyl synthons. In addition to the above discussed 1,2-difluoroalkenylorganometallic synthons, several other useful 1,2-difluoroalkenyl organometallic or metalloid compounds have been reported, which involve 1,2-difluoroalkenyl mercury, copper, silver, germanium, boron, xenon compounds. The 1,2difluoroalkenylcopper reagents are prepared by transmetallation of the corresponding alkenyllithium with cuprous salts at very low temperature (27). A more convenient approach was developed in our laboratory where, the metathesis of the corresponding trans- 1,2-difluoroalkenylzinc or cadmium reagents with cuprous halides produced the corresponding copper reagent stereospecifically. The /raws-l^-difluoroalkenylcopper reagents exhibit excellent thermal stability and readily undergo fimctionalization reactions. Metathesis of the Jrojw-pentafluoropropenyl cadmium reagent with silver trifluoroacetate produced the corresponding silver reagent (27). The 1,2difluoroalkenylmercury organometallics have also been reported and were prepared by a Barbier reaction of the corresponding alkenyl bromide with magnesium in the presence of mercuric halides (27, 49). Brisdon and co-workers recently synthesized fra«s-l,2-difluoroalkenylgemanium compounds, where trifluoroethenyltriphenylgermamum (Ph GeCF=CF ), prepared by the metallation of HFC-134a with «-BuLi and triphenylgermanium bromide, upon reaction with L i A l H or a range of organolithium reagents (RLi, R = H , Me, nBu, /-Bu, Ph) produced the corresponding fro«s-l,2-difluoroethenylgennanes 3

2

4


92 (fraAw-Ph GeCF=CFR) (69). Frohn and co-workers recently reported the synthesis of 1,2-difluoroalkenylboron and xenon compounds (70, 71, 72). In their preparation, cis and fra/is-polyfluoroalk-l-enyltrifluoroborates were generated by the nucleophilic addition of corresponding cis or trans-RCF=CFLi to B ( O C H ) followed by hydrolysis and fluoride substitution with K [ H F ] in aqueous H F (Scheme 8) (70, 71). Photoisomerization of the mixture of cis and fraAW-polyfluoroalk-l-enyltrifluoroborates to the corresponding cis- borates was attempted, but was only moderately successful (73). The c/s-l,2-difluoroalk-leneylboranes upon reaction with X e F produced the corresponding c/s-1,2difluoroalk-l-eneylxenon (II) salts, whereas the corresponding trans-isomers under similar conditions failed to give the corresponding xenon salt (72). 3


3

3

2

2

RCF"CFLi

°

(

0

- J BF

M

*

W

^

™

*

)

«

,

K[RCF=CFBFj]

RCF=CFB=< ' \

SiEt

3

92%

Scheme 10. Transformation of cis-l,2-difluorO'l-trialkylsilylethenes difluorotriethylsilylethenyl stannane and cis-l,2-difluoro-2-iodo triethylsilylethenes

/ }=\

3

^

68%

\

SiEt 82%

to cis-1,2(bromo)-

\

SnBu

3

+

Et SiF

— ^ — 0°C-rt

(ref. 31)

3

W H

(ref30,76) \

6 3 / 0

Scheme 11. Transformation of cis-l,2-difluoro-l-trialkylsilylethenes difluoro-2-iodoethenes

to cis-1,2-


95


obtained after irradiation could be fractionally distilled to give the ds-isomer in >95% isomeric purity. When the ds-alkene was subjected to irradiation with PhSSPh, the cis/trans isomeric ratios obtained were identical to the isomer ratios obtained on irradiation of the fraws-isomer, suggesting that equilibrium had been attained. The capability to obtain the ds-isomer in high purity via distillation provided the opportunity to readily prepare ds-fiinctionalized 1,2difluorosubstituted alkenes. Typical examples are cited in Table 1.

R = n-Bu = f-Bu = =

80 98 85 91

5-Bu C

6

H

1 1

: : : :

Scheme 12. Synthesis of cis-2-alkylsubstituted-l

20 2 15 9 ,2-difluoroalkenes

Table 1. Stereospecific preparation of ds-l-alkyl-2-arylsubstituted-l,2difluoroalkenes \

F /

t-BuLi \

Bu SnCl -90 °C 3

Entry

\

/

Arl

/""SjnBu,

3

R

n-Bu s-Bu «-C H 6

2

6

2

6

4

6

]3

FF

\

Pd(PPh )

Ar 3-N0 C H 4-MeOC H42-N0 C H Configuration assigned on the basis of V ( = 10-15 Hz.

1 2 3 a

>

4

4

/

/ \ r

Yield (%)" 91 82 86

c£y)

Wesolowski (78) utilized this methodology to prepare the corresponding c/s-l,2-difluoro-2-iodo substituted alkenes, which on carboalkoxylation stereospecifically afforded the ds-3-alkyl-2,3-difluoroacrylates, as illustrated in Scheme 13.


96 R

v

z

1

F ^ F

R'OH,NR' 2

3


C

v

/ ° p

3

Cl Pd(PPh ) 70-105 °C


R

C O (80480 psi)

2 R

'

\

R = «-Bu, 82% = f-Bu,83%

2

cis-3-alkyl-2,3-difluoroacrylates

The above examples demonstrate the utility of the c/s-l,2-difluoroethenyltrialkylsilane to be converted into other useful cw-l,2-difluoroethenyl building blocks. The major obstacle at this junction of our research activities was the problem of scale-up of these procedures. The cost of Et SiCl or PhMe SiCl was a major problem for the large scale synthesis of the key intermediate, namely the 1,2-difluoroethenyltrialkylsilane, on a practical scale. Fortunately, a co-worker, Vinod Jairaj, in our laboratory provided an answer to this dilemma. He found that the readily available zinc reagent, [F C=CFZnBr], could be easily functionalized with chlorotrimethylsilane and catalytic Cu(I)Br to give (cleanly) l,l,2-trifluoro-2-trimethylsilylethene, as shown in Scheme 14 (79). 3

2

2

F C=CFBr

„

2

D M F

>

• F C=CFZnBr 2

r t

J ^ B ^ DMF,Cu(I)Br

p C=CFSiMe ^ 2

Scheme 14. Synthesis of l,l,2-trifluoro-2-trimethylsilylethene trifluoroethenylzinc reagent

3

via

This preparation has been routinely carried out on a 0.5 to 2.0 mol. scale in our laboratory. It is a cheaper, less hazardous method than the previously reported procedures (80, 81, 82). Subsequently, this synthon was employed in place of the Et Si-group noted above in our further development of new functionalized building blocks. In one of those transformations, the cis-1,2difluorotrimethylsilylethene was transformed to cis-1,2difluorotrimethylsilylethenyl stannane by an in situ metallation using 4-methoxyL T M P in the presence of Bu SnCl. Palladium catalyzed cross-coupling reaction of the c/s-l,2-difluorotrimethylsilylethenyl stannane with trifluoroethenyl iodide under Stille-Liebeskind conditions [Pd(0)/Cul] produced the cw-trimethylsilyl1,2,3,4-pentafluoro-1,3-butadiene. The c/s-trimethylsilyl-1,2,3,4-pentafluoro1,3-butadiene was further transformed to c/s-tributylstannyl-l,2,3,4-pentafluoro1,3-butadiene by the treatment with Bu SnOSnBu and catalytic K F (Scheme 15) in D M F (83). 3

3

3

3


97 F \

/

F

H

SiMe

F

F

Bu SnCl,-90°C THF-Ether.84%

3

F

3

F

3

F

c f 2 = c f i

Bu Sn

SiMe

3

Pd(PPh ) , C u l

3

3

1


/

Bu SnSiMe

3

W

W F C=FC 2

F V

4-MethoxyLTMP^

F

3

F

F H

3 rt 67%

3

SiMej

2

%

Bu SnOS„Bu

+

SiMe

5

F C=FC

4

F

'

2

C=FC

SnBu

Scheme 15. Synthesis of cis-trimethylsilyl-1,2,3,4-pentafluoro-l,3-butadiene and cis-tributylstannyl-1,2,3,4-pentafluoro-l ,3-butadiene.

3

and

Stereospecific synthesis of cis-1,2-difluorostyrenes, cis-1,2dijluoro-1-idodostyerenes and cis-12-difluorostilbenes t

The cis- 1,2-difluoroiodoethene synthon (cw-CHF=CFI) synthesized by the previously discussed methodology was used for a convenient preparation of cis1,2-difluorostyrenes. The cis- 1,2-difluoroiodoethene was transformed to cis- 1,2difluoroalkenylzinc reagent (ds-CHF=CFZnI) by a zinc insertion reaction. The zinc reagent, thus generated, was then utilized for the palladium catalyzed crosscoupling reaction with aryl iodides to obtain ds-l,2-difluorostyrenes (57, 84), as illustrated in Table 2. The cw-l,2-difluorostyrenes prepared by this methodology were then converted to c/s-l,2-difluoro-l-iodostyrenes via two approaches (Table 3). In Method A , metallation of the c/s-l,2-difluorostyrene with lithium tetramethylpiperidide (LTMP) at low temperature, followed by in situ trapping with Bu SnCl, stereospecifically afforded the corresponding cis-1,2difluoroethenylstannanes, which on reaction with iodine produced the cis-1,2difluoro-l-iodostyrenes. In Method B , rt-BuLi was utilized to metallate the cis1,2-difluorostyrene at low temperatures; quenching the corresponding ethenyllithium with iodine gave the cis- 1,2-difluoro-l-iodostyrenes (57). These results are summarized in Table 3. 3


98 Table 2. Stereospecific preparation of c/s-l,2-difluoroalkenylzinc reagent and ds-l,2-difluorostyrenes

F

/ H

F

W

F

_ Z n

\I

DMF*

F

W

ArI,Pd(PPh )

x / VZ n l

H

3

DMF

F 4

/ \

.

nT

F W

H

rt)1 3h

Ar


cis/trans = 95:5 Entry 1 2 3 4 5 6 7 8 9 10 11 0

Yield (%)"

Cis-1,2-difluorostyrenes 6

2

6

2

6

3

I4-QH4I2

6

6

4-CF C H4l 2-(CH ) CHC H I

3

6

2

2

4

2

6

3

6

3

2

3

5

3

6

3

65 85 66* 78 72 93 71 60 80 70 55

C H CF=CFH 4-CH OC H CF=CFH 4-N0 OC H4CF=CFH 2-N0 OC H4CF=CFH 4-CH OC6H4CF=CFH 4-Et0 CC6H4CF=CFH 4-CH C(0)C H4CF=CFH 3-CIC6H4CF=CFH 4-HFC=CFC H4CF=CFH 4-CF C H4CF=CFH 2-(CH ) CHC H CF=CFH

4-CH3OQH4I 4-N02C6H4I 2-N0 C H4l 4-CH3QH4I 4-Et0 CC6H4l 4-CH C(0)C H4l 3-CIQHJ

6

4

6

3

b

2

6

c

4

0

Isolated yield of ds-isomer. Isolated as 95:5 cis/trans mixture. Reaction conditions, 60 °C, 8 h.

These cw-l,2-difluorovinylstannanes/iodides can be subsequently employed in Pd(0) coupling reactions to prepare symmetrical or unsymmetrical cis-1,2difluorostilbenes; a class of compounds that has been relatively inaccessible by most current methodologies. A typical example is illustrated in Scheme 16 (85).

Sterospecific preparation of cis and trans-aryl substituted 2,3difluoroacrylic esters Aryl substituted 2,3-difluoroacrylic esters are interesting and useful synthons and several methods have been established for the synthesis of the trans-ester (50, 52, 78, 86). The first stereospecific preparation of the cissubstituted 2,2-difluoroacrylic esters was described earlier in this report via carboalkoxylation of the corresponding 1,2-difluoro-l-iodoalkenes (where R = alkyl). When R = aryl or substituted aryl, the carboalkoxylation also (78) worked well. However, a major limitation of this methodology was the requirement of pure alkyl or aryl substituted vinyl iodides, since each precursor


99 Table 3. Stereospecific preparation of cis-l,2-difluoro-l-idodostyerenes

A LTMP . BujSnCl \r -78 °C


Ar

D M F , rt SnBu

H h

n-BuLi ioo°c B Entry 1 2 3 4 5 6 7 8 9 10 a

3

\

Product 4-CH OC H CF=CFI 4-CH OC H CF=CFI C H CF=CFI 4-CH C H4CF=CFI 2-(CH ) CHC H CF=CFI 4-CF C H4CF=CFI 4-CF C H CF=CFI 4-Et0 CC H CF=CFI 4-Et0 CC H CF=CFI 3-ClC H CF=CFI 6

3

6

4

3

6

4

3

Method

6

3

3

2

6

4

6

3

6

4

2

6

4

2

6

4

6

4

F

F

Ar

I

-100 °C

i

A B B B B A B B A A

5

-H

Yield (%)" 87 85 83 65 54 92 81 39* 77 85 e

c

b

Isolated yield based on ArCF=CFH. LTMP was used instead n-BuLi. procedure; vinylstannane intermediate was treated directly with I .

c

One-pot

2

Scheme 16. Stereospecific synthesis of unsymmetrical cis-1,2-difluorostilbenes

needed to be prepared independently. To circumvent this problem, a more general approach to the aryl analogues was designed using a common synthon, where the introduction of the aryl group occurs in the final stage of the synthetic sequence. Thus, both the cis and fra«s-2,3-difluoro-3-stannylacrylate synthons



100 were developed. The fra«s-2,3-difluoro-3-stannylacrylic ester was readily prepared from the corresponding /ra«s-l,2-difluorotrialkylsilylethene via stereospecific stannyl/silyl exchange (30) (Scheme 17). Subsequent coupling with aryl iodides under Stille-Liebeskind conditions (Pd(0)/Cul) afforded the corresponding aryl substituted fra/w-2,3-difluoroacrylic esters (87). With this synthon a stereospecific synthesis of fluorinated dienes could also be achieved via coupling of the fraAw-2,3-difluoro-3-stannylacrylic ester synthons with ethenyl halides under Stille-Liebeskind conditions (87, 88) (Scheme 17). For example, reaction of ^«s-2,3-difluoro-3-(tributylstannyl)acylate with cis-liodostyrenes under Pd(PPh )4/CuI catalysis afforded the corresponding ethyl (2£,4Z)-2,3-difluoro-5-phenyl-2,4-pentadienoate in 80% yield (88). 3

E t

3

l.t-BuLi,-90°C 2.CO ,-90°C

S l F

f

2

Bu SnI 3

2

Z n , D M F rt

F

/===\ + Cu C0 Et

2

I


Cu(I)I

2

7

4

%

F

\

/

c / c O . E t

Scheme 19. Formation of cis-2,3-difluoroethenylcopper via tin/Cu(I) excahange as well as from cis-2,3-difluoroethenylzinc reagent

Table 6. Synthesis of 3,4-difluoro-6-substituted-2-pyrones

F

PdCl (PPh )

F

2

3

2

+ RC=CH I

C 0

2

Cu(I)I, E t N 3

H

R

C H C N , rt 3

Entry

R

1

C6H

O

Time

Isolated Yiled

24

62

24

59

24

64 69

(%) 2 3

5

«-C H„ 5

CGH5CH CH 2

2

4

P-CF3QH4

12

5

p-MeOC£U

16

71

24

43

6

general synthesis of this class of 2-pyrones. Table 6 summarizes some typical 2pyrones prepared by this one-pot methodology. A slight modification of the above route also provides a key entry to synthesize 3,4-difluoro-5-iodo-6-substituted-2-pyrones (90) via an electrocyclization reaction illustrated in Scheme 20. The iodo-substituted 2pyrones thus generated, readily undergo Negishi or Sonogashira coupling reactions to give the 5,6-disubstituted-3,4-difluoro-2-pyrones.


104 RC=CH F

F

PdCl (PPh ) 2

I^C0 Et

3

h

2

C0 Et 2

Cu(I)I,Et N C H C N , rt

2

cHoCl 2^2

3

2

3



3,4-difluoro-5-iodo-6-substituted-2-pyrones

"Bis "-cis-1,2-difluoroalkenyl synthons Most of the 1,2-difluorosynthons described above were "mono" synthons capable of a single coupling reaction. The first "bis"-synthon developed in our laboratory was rra«5-(l,2-ethenediyl)bis[tributylstannane] (97), which was prepared by the metallation of fra/w-l,2-difluorotributylstannane with L T M P followed by transmeallation with Bu SnCl (Scheme 21). The stable bis-stannane thus generated could be coupled with aryl iodides under Stille-Liebeskind conditions to afford a clean, efficient route to symmetrically substituted trans1,2-difluorostilbenes. 3

F

SiMe3

S

I

M

E

Bu SnOSnBu

3

3

F^SnBu

3

H F _ , 91 % trans p Q«chi ^\_/

l . L i T M P , THF,-90 °C ^

H

2. Bu SnCl

b

H

n

B

U

TBAF (cat), THF

F

3

/

Bu Sn 3

Decomposition of the intermediate lithium reagent

r

3

N ^

S

n

B

U

3

2ArI, Pd(PPh ) ,Cu(I)I 3

F

4

DMF/THF, rt or 60 °C

3

F

3

, T - T W O T U P onor l.LiTMP,THF,-90 C 2. Bu SnCl

3

p

F

v SnBu \==/

Bu Sn

3

SnBu

W

H F 97% trans after column chromatography F

3

3

F r

Ar

) = {

T

F

Ar = symmetrical aromatic groups, 51-89% Scheme 21. Synthesis of trans-(l,2-ethenediyl)bis[tributylstannane] symmetrically substituted trans-1,2-difluorostilbenes.


and

105


Other "bis" synthons under development in our laboratory are the cis and frafls-2-halo-l,2-difluoro-l-iodoalkenes (where X = Br, CI) (92).These synthons should be capable of sequential fimctionalization by metal-catalyzed coupling reactions and thus capable of the synthesis of both cis and trans - symmetrical or unsymmetrical fimctionalized derivatives (for eg. cis and trans 1,2difluorostilbenes) (Scheme 22).

Scheme 22. Cis and trans-2-halo-l,2-difluoro-l-iodoalkene, possible bissynthon for the sequential introduction of unsymmetrical aryl groups.

Stereospecific synthesis of cis-l-Arylperfluoroalkenes. The addition-elimination or dehydrohalogenetaion methods reported for the preparation of 1-arylperfluoroalkenes generally produce exclusively the transisomer or a mixture of isomers favoring trans as the major product (10, 11, 12, 13). The first synthesis of stereospecifically pure ds-l-arylperfluoropropenes were achieved in our laboratory via the Pd(0) coupling of cisperfluoropropenylzinc reagent (cw-CF CF=CFZnI) with aryl iodides. The cisperfluoralkenylzinc reagents were generated from ds-l-iodoperfluoroalkenes (R CF=CFI) ( R = C F , C F ) (57, 58) which in turn was prepared from cisR CF=FH. The c/s-R CF=FH was not readily available and was prepared by a stereospecific phosphodefluoridation of perfluoroalkenes (R CF=CF ,. R = C F C F - ) (8, 93, 94, 95) to obtain corresponding fra/w-R CF=FH, which was then isomerized using SbF to obtain desired ds-R CF=FH (93, 96). But this methodology for the preparation of ds-R CF=FH was not feasible for perfluoroalkenes with longer chains due to the formation of internal isomers in 3

F

F

F

3

2

5

F

F

2

5

2

F

5

F

F


F

3t

106 addition to the desired 1-hydroperfluoroalkene (97) Recent work of Frohn and co-workers demonstrated that metallation of C F i C F C H F under conditions similar to that of the metallation of HFC-134a at low temperature produced the corresponding perfluoroalkenyllithium (C Fi CF=CFLi) in a cw-selective fashion (>95%) (72, 98). This observation prompted us to investigate a similar process for the preparation of the corresponding cw-perfluoroalkenylzinc reagents (cw-R CF=CFZnCl) via our in situ metallation strategy developed for the generation of trifluoroalkenyl and halodifluoroalkenylzinc reagents (99, 100, 101, 102, 103, 104). The cw-perfluoroalkenylzinc reagents thus generated could be effectively used in a coupling reaction with aryl iodides to produce cis-\arylperfluoroalkenes. Thus, commercially available C F C F C H F was metallated using L D A in the presence of Z n C l at 15 °C, to produce the corresponding perfluoropropenylzinc reagent in 67% yield with selectivity in favor of the cisisomer [(cis/trans)-CF CF=CFZnCl = -82:18] (74). When the metallation was performed at -78 °C, an improved yield (81%) and selectivity [(cis/trans)CF CF=CFZnCl = -89:11] of the perfluoropropenylzinc reagent was observed (Scheme 23). The zinc reagent was then hydrolyzed using acetic acid to obtain corresponding 1-hydroperfluoropropene with similar selectivity [(cis/trans)C F C F = C F H = 87:13]. The perfluoropropenylzinc reagent underwent Pd(0) catalyzed cross-coupling reaction with aryl iodides to produce the corresponding 1-arylperfluoropropenes in excellent isolated yield (74). The preferred cisgeomerty of the zinc reagent was retained during the coupling process and no isomerization was observed. 6

6

3

2

2

3


F

3

2

2

2

3

3

3

LDA, ZnCl CF CF CH F 3

2

2

Arl, 65 °C

2

THF, -78 °C

Ar Pd(PPh ) F C Ar = various aryl groups 77-82% cis > 89% 81% cis/tans = 89:11 ZnCl

FC 3

3

4

3

Scheme 23. Synthesis of cis-perfluoropropenylzinc reagent and cis-1arylperfluoroprop-1 -enes

After the successful synthesis of the c/s-pentafluoropropenylzinc reagent and cw-l-arylperfluoroprop-l-enes, the in situ metallation of higher homologues of 77/,7//-perfmoroalkenes ( C F C F C H F , C F C F 2 C H F , C F C F C H F and C i F i C F C H F ) were performed and the results are summarized in Table 7 (74). It was observed that the size of the R group influenced the selectivity in the 4

0

2

2

9

2

2

5

U

2

6

1 3

2

2

F


2

107 elimination process; excellent c/s-selectivity, up to 99%, was observed for longer sized R groups ( C F , C F , C F , C F i ) . Due to the poor solubility of 1HJHperfluorododecane in THF, the metallation of C F i C F C H F was performed in a THF-diethyl ether solution at a higher temperature (-10 °C) to produce the perfluorododec-l-enylzinc reagent in 61% yield with a slightly diminished selectivity (-93% cis). Palladium catalyzed cross-coupling reaction of each of the perfluoroaleknylzinc reagents with a variety of aryl iodides were then performed to obtain the corresponding 1-arylperfluoroalkenes in excellent isolated yield with the retention of cw-stereochemistry (74). Representative examples for the coupling reaction of perfluoroalkenylzinc reagents with iodobenzene are summarized in Table 7. The excellent cw-selectivity observed during the metallation of R C F C H F could be due to the preferred syn-clinal conformation of R C F C H F over the less favored anti-periplanar conformation. The syn-clinal effect is attributed to the relatively large electron flow from the G C - H bond towards to the a * - F relative to the electron flow from a - bond to the o* _ bond in the anti-periplanar conformation (74, 105). F

2

5

4

9

5

n

6

3


1 0

F

F

2

2

2

2

2

2

2

C

C

c

F

F

Table 7. Synthesis of various c/s-perfluoroalkenyl zinc reagents and cis-\phenylperfluoroalkenes

R CF CH F F

2

LDA, ZnCl

C H I, 65 °C 6

2

THF, -78 °C

Entry

R

F

R'

CF C F C4F9 QF 3

2

5

n

CeF.3 C10F21

Pd(PPh )

ZnCl

F

3

4

R

K

/

Yield (%)" of R CF=CFZnCl

cis/trans ratio " R CF=CFZnCl

Yield (%) * of R CF=CFC H

80 76 75 83 79 61

89:11 94:6 96:4 99:1 98:2 93:7

80 89 81 89 81 78

F

1 2 3 4 5 6

5

2

F

l 9

" The Z/E ratio determined by F NMR (Vpp Isolated yield based on iodobenzene.

{trans)

F

= ~ 132 Hz, Vpp

6

(cis)

=

5

~


C H 6

5

cis/ trans ratio" 87:13 93:7 96:4 99:1 98:2 94:6 12 Hz). *

108

Stereospecific synthesis of cis-l-iodoperfluoroalkenes The cw-l-iodo-perfluoroalkenes are less conveniently available and difficult to synthesize, especially the higher homologues [the higher homologues other than R = CF , C F could not be prepared by the SbF catalyzed isomerization of trans-R CF=CFH (8, 93, 96, 97). Cw-perfluoroalkenylzinc reagents generated by the metallation of V//,///-perfluoroheptene and 7//,7//-perfluorooctene, upon iodinolysis, produced the corresponding 1-iodoperfluoroalkenes in good yield, with >98% cw-selectivity (Scheme 24) (74). F

3

2

5

5


F

LDA,ZnCl

F \s

2

R^CFoCHoF

•

THF,-78°C

F

F

Rp 5

•

ZnCl

x b

6

F

13


\

2

/ = \

R = n-C F 83%, 98% cis R = AI-C F , 79%, 99% cis F

I

/=%

R/

0°C

F / I

R = n-C ¥ 68%, 98% cis R = «-C F , 70%, 99% cis F

F

5

{

6

u

13

cis-l-iodo-perfluoroalkenes

Conclusion In summary, we have presented the synthesis of several 1,2-difluoroalkenyl synthons and their utilization for the stereospecific preparation of the corresponding 1,2-difluoroalkenes. By the utilization of a variety of cis- 1,2difluoroalkenyl organometallic synthons, it was demonstrated that several synthetically intricate cis- 1,2-difluoroalkenes such as cw-l,2-difluorostyrenes, cw-2-iodo-1,2-difluorostyrenes, cw-2-alkylsubstituted-1,2-difluorostyrenes, cisaryl substituted 2,3-difluoroacrylic esters, cw-2,3-difluoro-4-oxo-substituted 2butenoates, symmetrically and unsymmetrically substituted cis-1,2difluorostilbenes, cis-1 -arylperfluoroalkenes and cis-1 -iodoperfluoroalkenes could be readily prepared. C/s-2,3-difluoroacrylic acid synthons could be used as an efficient synthon for a one-pot synthesis of 5 (4, 5 di) substituted 2,3-difluoro2-pyrones.

References 1.

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109 2. 3.

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7. 8. 9. 10. 11. 12. 13. 14.

15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

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