Synthetic Methods for the Preparation of Ring-Fluorinated

Chapter 14

Synthetic Methods for the Preparation of Ring-Fluorinated Heterocycles via Intramolecular Vinylic Substitution of gem-Difluoroalkenes

Downloaded by COLUMBIA UNIV on June 28, 2013 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch014

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

Ring-fluorinated heterocyclic compounds attract widespread attention as important components of agrochemicals, pharmaceuticals, and materials. To provide a general access to these compounds, a new methodology for the construction of ring-fluorinated heterocycles has been developed based on an intramolecular ring closure of 2,2-difluorovinylic compounds via an SNV (addition-elimination) process. In this chapter, the synthesis of five- and six-membered ring -fluorinated heterocycles including one or two oxygen, sulfur, or nitrogen atoms will be covered.

Introduction Selectively fluorinated heterocyclic compounds are widely used as important components in the pharmaceutical, agrochemical, and dyestuffs industries and also in material science (i). They have attracted much attention in terms of biological activities and other properties, which are often dramatically enhanced or altered by the introduction of fluorine onto the original molecules. Although introduction of fluorine into heterocyclic compounds can 262

© 2005 American Chemical Society

In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

263


be achieved by employing classical Balz-Sehiemann (fluorodediazotization) and Halex (halogen exchange) fluorinations, electrochemical fluorination, and fluorinating reagents (2), there still remain problems in the regioseleetivity of fluorination, the requirement of multistep procedures, and the difficulty in handling the fluorinating reagents. Especially for ring-fluorinated heterocyclic compounds, so far only a limited number of methods have been reported for their synthesis in spite of their substantial potential as components (J) and intermediates (4). The introduction of fluorine atoms onto heterocyclic ring carbons is known to be more difficult than the introduction of fluorine onto the carbons of fused benzene rings. Consequently, a general method for the synthesis of selectively ring-fluorinated heterocycles is a highly desirable goal.

Synthetic Strategy for Ring-Fluorinated Heterocycles ge/w-Difluoroalkenes possess remarkable reactivity toward nucleophilic substitution of their vinylic fluorines via addition-elimination processes (SNV process) (J). The orientation of attack is strictly governed so that the fluorines are placed at the position β to the electron-rich carbon in the transition state in order to avoid electron-pair repulsion. This reactivity is due to (i) the electrophilic activation of the C-C double bond by the two fluorine atoms, (ii) the stabilization of the intermediary carbanion by the β-anion stabilizing effect offluorine,and (iii) the leaving group ability of the fluoride ion (Scheme 1). Nucleophilic Substitution of Vinylic Fluorine: SNV Process

*\

β"

Nu-

- F -

KC=C;Ô-

V

ellmlnatlon

addition

Nu'

R

2

Scheme 1 These unique properties of ge/w-difluoroalkenes can be utilized to give access to ring-fluorinated heterocycles simply by conducting this substitution in an intramolecular fashion (Scheme 2). Depending on the nucleophilic Y - Z moiety, 0, S, iV-containing heterocyclic systems with a five, six, or largermembered ring can be made. In β,β-difluorostyrene derivatives as an example, nucleophiles with a Y - Z single bond (sp nucleophiles) afford dihydroheteroarenes, and this ring formation could be followed by aromatization via elimination or oxidation, leading to heteroaromatic systems. On the other hand, nucleophiles with a Y - Z double bond (sp nucleophiles) would give rise to the direct construction of heteroaromatic rings. Thus, this strategy should 3

2


264 provide a potent methodology for the synthesis of diverse ring-fluorinated heterocycles. In this chapter we describe our investigations on the "intramolecular substitution" concept for the synthesis of ring-fluorinated heterocycles starting from gem-difluoroalkenes. Other methods involving the vinylic fluorine substitution process provide ring-fluorinated quinolines (6), quinoxaline derivatives (7), pyrans (8% pyrazoles (P), and furan derivatives (10).


Intramolecular SNV Process R

R F

~ v

,!

νΚ·· ····>

Ίζλ>

Scheme 2

Preparation of g*?/M-Difluoroalkenes Bearing a Nucleophile orfAo-Functionalized gem-difluorostyrenes are the substrates for the construction of benzene-ring-fused heterocyclic systems. They are readily obtained from 2,2,2-trifluoroethyl /?-toluenesulfonate by using the two methods that we have previously established as depicted in Scheme 3 (11,12). Each method consists of the following two processes, which can be conducted in a one-pot operation: (i) the in situ generation of ge/w-difluorovinylboranes or zirconocene and (ii) their palladium-catalyzed cross-coupling reaction with aryl iodides bearing an orfAo-functional group such as N H , OMe, CHO, CH OH, CH OMs, or CN. Moreover, further transformations provide other substrates with an appropriate ortAo-functionality. The substrates for heterocycles without fused benzene rings can also be prepared by these two sequences. A similar cross-coupling reaction with vinylic halides affords ge/w-difluoro-1,3-dienes, which undergo regioselective hydroboration to afford homoallylic alcohols (12). Their Mitsunobu reaction or the substitution of their tosylates affords ge/w-difluoroalkenes bearing a functional group at the homoallylic position. 2

2


2

265

o-YZC H l

1)2"BuU

e

CF CH OTs 3

4

CF =C:

2

2

3

CH =C(R')lorBr 2

FC 2

BRo

2) BR /THF

Cul cat, Pd° /THF-HMPA t

YZ

Cul, cat. Pd° /THF-HMPA

R

1) 9-BBN /THF

n

2 BuU /THF

I

F C* Y ' C

OF}

2) aq. H 0 aq. NaOH


2

r>Ts CF =CC

2

YZ

o-YZC H l

"Cp^r"

e

2

H

R

2

C F 2 = C C

/THF

ZiCp X 2

4

F*C Znl , cat. Pd° 2

90%

2*

I|

YZ"

Scheme 3

Syntheses of 6-Membered Ring-Fluorinated Heterocycles 3

Cyclization of β,β-Difluorostyrenes Bearing an sp Heteroatom Nucleophile

3-Fluorinated Isochromenes, Isothiochromenes, andIsoquinoline Derivativ gem-Difluorostyrenes 1 and 3 were designed as substrates for the intramolecular substitution of sp oxygen and sulfiir nucleophiles, so that 6membered rings would be formed. Treatment of 1 or 3 with a base such as NaH or NaOMe generated the corresponding alkoxides or thiolates, which in turn readily underwent the expected cyclization (Scheme 4) (13). Thus, 3-fluoroisochromenes 2 and -thioisochromenes 4 were obtained in high to excellent yield (14). 3

F

2

C ^ Y %

ΗΟ^Λ^

NaH(2eq)

,

rt,2h/DMF

R = n-Bu: 84% 2 1

F

z

^

C

AcS J l ^ l N

sec-Bu: 77%

NaOMe (2 eq) rt,0.3h/DMF

•ύο

— το R = n-Bu; 94% 4 sec-Bu: 90%

Scheme 4


266 3


Similarly, the reaction of the substrates bearing an sp nitrogen nucleophile was successfully carried out. On treatment of styrene 5 with NaH, intramolecular cyclization readily proceeded to afford 3-fluoro-l,2dihydroisoquinolines 6. Employing 2 equiv of base successively promoted elimination of a aulfinic acid after the cyclization, leading to 3fluoroisoquinolines 7 in excellent yield (Scheme 5) (15,16).

R = n-Bu: 95%

7

sec-Bu: 90%

Scheme 5

3

Cyclization of β,β-Difluorostyrenes Bearing an sp Carbon Nucleophile 3-Fluorinated Quinolines For the construction of a quinoline framework, carbon nucleophiles should be employed instead of die nitrogen nucleophiles in the above isoquinoline synthesis. Thus, difluorostyrenes 8 were designed to bear a cyanomethylamino group as a precursor for a formal sp carbon nucleophile. In the reaction of 8, aromatization of the cyciized products is effected by elimination of (i) HCN or (ii) HX (X: a leaving group on the nitrogen) (Scheme 6). 3

"Bu

85%

Scheme 6


10

267

When styrènes 8 (Χ = H) were treated with NaH (R Φ Η) or lithium 2,2,6,6tetramethylpiperidide (LiTMP) (R = H), the intramolecular substitution of the in situ generated carbanions successfully proceeded, followed by elimination of HCN to give the desired fluoroquinolines 9 in high yield. In contrast, treatment of 8 (X = Ts) with 2 equiv of K C 0 promoted cyclization, and successive elimination of sulfinic acid afforded 2-cyano-3-fluoroquinoline 10. Its cyano group can be easily converted into carboxy, aminomethyl, and amino groups by die usual procedures (17,18).


2

3

Scheme 7 The reaction of 8 requires (i) a strong base (NaH or LiTMP) for the generation of the carbanions and (ii) a stoichiometric amount of K C N for the preparation of 8 from the corresponding o-aminostyrenes. These drawbacks are overcome by a benzoin-type condensation of imines as shown in Scheme 7. Addition of CN" to imines 11 followed by proton transfer provided the desired carbon nucleophiles. The generated carbanions were smoothly trapped by the intramolecular difluoroalkene moiety, and loss of HCN gave 3-fluoroquinolines 12. Moreover, this process proceeds under K C N catalysis in the presence of K C 0 , which represents a quite rare example of benzoin-type condensation of imines, C-C bond formation at the imino carbon with electrophiles (19). 2

3

2

Cyclization of β,β-Difluorostyrenes Bearing an sp Nitrogen Nucleophile 3-Fluorinated Isoquinoline Derivatives and Cinnolines In the reactions mentioned so far, aromatization was effected by elimination after cyclization. For the direct construction of aromatic rings, a similar replacement of the vinylic fluorine was attempted with sp nitrogen nucleophiles: oxime and imine nitrogens (-N=CH-). Since suitable starting materials, o-difluorovinyl-substituted benzaldehydes 13 were not stable enough, 2


268 the combined process of difluorostyrene synthesis and their cyclization was examined. When the crude products of the coupling reaction were treated with NH OAc or NH OH, the expected dehydration and successive cyclization were readily induced (Scheme 8). 3-Fluorinated isoquinolines 14 or their TV-oxides 15 were obtained in good yield based on o-iodobenzaldehyde (16,20). 4

2

1 ) "BuLi (2.1 eq) 2) R B(1.1eq) 3

CF CH OTs 3

F C

2

2

3) cat. Pd° Cul (1 eq) o-IC H CHO (0.9 eq) rt, 15min /THF-HMPA (4:1)


e

4

13

NH OAc(5eq) rt, 1 h /DMF-H O(10:1)

Y=H

4

R = η-Bu: 70%

2

or

sec-Bu:

00

14

71%

F

NH 0H»HCI(1.2eq) Et N (2.2 eq) rt, 12 h/DMF 2

3

Y = OH

R = n-Bu: 83% sec-Bu:

15

69%

Scheme 8 2

As a further example of sp nitrogen as a nucleophile, diimides (-N=N-) have been employed. Aminostyrene 16 was treated with isoamyl nitrite (/AmONO) for diazotization, and then reduced with benzenethiol. The expected intramolecular substitution of the diimide nitrogen smoothly proceeded to give 3-fluorocinnolines 17 (Scheme 9) (20,21). CF CQs>H (2 eq) 'AmONO (2 eq) 3

F C*

PhSH (3 eq)

2

0 °C, 0.5 h /CH CN 3

0°C,0.5h Ν R = f?-Bu: 88%

16

sec-Bu:

17

87%

Scheme 9 Another method for the generation of intramolecular sp nitrogen nucleophiles is the addition of external nucleophiles to C - N multiple bonds such as that of the cyano group. Thus in situ generated nucleophiles are expected to promote similar cyclizations to afford ring-fluorinated isoquinolines, which would allow introduction of a substituent on the C-l ring carbon (Scheme 10). Since there are two reaction sites to be attacked by nucleophiles in 18, the external nucleophiles must exclusively react with the cyano group without affecting the difluoromethylene moiety.


269 It was found that the addition of organolithiums in Et 0 or toluene regioselectively occurred to the cyano group of styrene 18. The generated iminometals promoted cyclization to afford isoquinolines 19 in high yield. This sequence provides a facile access to 1,4-disubstituted 3-fluoroisoquinolines (16,22). 2

R

1

R H*U(1.2eq)

1

R

1

- F~

F C' 2


-78 "C,1h / EtgO or Toluene

R

R

2

18

1

2

2

R = n-Bu,R =n-Bu: 86% Ph: 85% R = sec-Bu, R = n-Bu: 82% 1

19

2

Scheme 10 2

Cyclization of β,β-Difluorostyrenes Bearing an sp Carbon Nucleophile 3-Fluorinated Quinolines In the construction of the isoquinoline framework, the cyano group has proved to be a powerful precursor of sp nitrogen nucleophiles. By means of a similar tactics, quinoline synthesis is effected by changing the order of carbon and nitrogen in die ortho substituent of the substrates. The reaction of oisocyano-substituted styrenes 20 with external nucleophiles proceeds in a similar manner via the corresponding sp carbon nucleophiles to provide 3fluoroquinolines in an appropriate solvent system (Scheme 11). When isocyanide 20 was treated with Grignard reagent in toluene, addition selectively occurred to die isocyano carbon. Then, HMPA was added to raise the reactivity of the intermediary carbanion, which led to 2,4-disubstituted 3-fluoroquinolines 21 (18,22). This reaction allows the introduction of a substituent at the 2 position of the quinoline ring with nucleophiles. 2

2

R

1

R

tfMgBr or tfLi

(1.2 ^JK^P

20

eq)

F

2

C

R

1

* V i

rt, 15 min /Toluene

1

e

O C-*rt, 2 h /Toluene-HMPA (5:1) 2

R ^ N

R = η-Bu, R = π-Bu (MgBr): 69% f-Bu (Li, Toluene): 78% R = sec-Bu, R = π-Bu (MgBr): 62% 1

1

21

2

Scheme 11 The introduction of a C-2 substituent on the quinoline ring has been achieved not only with nucleophiles but also electrophiles (Scheme 12). Oneelectron reduction of the isocyano group of 20 with tributylstannyllithium


270


generates the radical anion, which in turn undergoes cyclization. The cyclized intermediates, 2-quinolyl radicals are reduced further to 2-quinolyl anions, which are trapped by electrophiles to allow introduction of hydroxymethyl, acyl, and iodo groups. The introduction of aryl groups is also effected by palladiumcatalyzed cross-coupling reaction via the transmetalation to zinc (23).

E* =

PhCHO(2.1)

tfsPhCHCOH):

PhCONMe (2.1) p - M e O C H l (0.8)* 6

78%

22

PhCO: 79%

2

4

p - M e O C H : 87% 6

4

t ZnCI , cat. Pd°, -78 °C ·*> rt, 3.5 h. 2

Scheme 12 By the two complementary methods (Schemes 11, 12), a variety of substituents can be introduced at the 2-position of 3-fluoroquinolines with either nucleophiles or electrophiles.

Syntheses of 5-Membered Ring-Fluorinated Heterocycles As shown above, the syntheses of 6-membered ring-fluorinated heterocycles have successfully been accomplished on the basis of the "intramolecular substitution" concept starting from gem-difluoroalkenes. According to the Baldwin's rules (24), this type of cyclization is classified as a 6-endo-trig ring closure, which is favored following these rules. On the other hand, for the construction of 5-membered rings by this methodology, the disfavored 5-endo-trig ring closure has to be effected. The unique properties of 1,1 -difluoro-1 -alkenes, however, were expected to make a nucleophilic approach to 5-endo-trig cyclization feasible. Specifically, we thought that (i) the highly polarized difluorovinylidene double bond ( C NMR: ca. 150 ppm and 90 ppm for CF =C) would allow initial ring formation by electrostatic attraction between the CF carbon and the internal nucieophile and (ii) the successive elimination of fluoride ion could suppress the reverse ring opening, thus functioning as a "lock" (Scheme 13). 13

2

2


271

Nucleophilic "Anti-Baldwin" Cycllzatlons

Scheme 13

3


Cyclization of β,β-Difluorostyrenes Bearing an sp Heteroatom Nucleophile 2-Fluorinated Benzofurans, Benzothiophenes, Indoles The reaction of an oxygen nucleophile was first attempted. When hydroxystyrene 23 was treated with NaH, the normally "disfavored" 5*endo-trig cyclization was successfully achieved to afford 2-fluorobenzo[i]furan 24 in high yield. The corresponding thiolate also undergoes the cyclization to provide 2fluorobenzo[6]thiophene 26 (Scheme 14) (12,25-27).

n-Bu: 84% (80 °C, sec-Bu: 8 1 % ( 8 0 ° C ,

27

R=

7 h)

28

5h)

H:73%(70°C,23h)

Scheme 14 Moreover, this type of cyclization can be applied to intramolecular nitrogen nucleophiles. On treatment of amidostyrenes 27 with NaH, the 5-endo-trig cyclizations again successfully occurred to afford 2-fluoroindoles 28 in high yield (Scheme 14) (12,25,28).


272 3

Cyclization of gew-Difluorobutenes Bearing an sp Heteroatom Nucleophile 2-Fluorinated Dihydrofurans, Dihydrothiophenes, Pyrrolines The scope of this nucleophilic 5-endo-trig cyclization has been broaden by the reaction of difluoroalkenes 29, 31, 33, where the nucleophilic functional groups are linked by two sp carbons to the olefin moieties (12,29). The 5-endotrig closures are successfully promoted by the intramolecular oxygen, sulfur, and nitrogen nucleophiles, leading to the desired ring-fluorinated dihydrofuran 30 (30), dihydrothiophene 32 (57), and pyrroline 34 (32,33) (Scheme 15). These results rule out the possibility of a 6jt-electrocyclization mechanism. Downloaded by COLUMBIA UNIV on June 28, 2013 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch014

3

R

R

F C*^Y

Me

N a H ( 1 2 e q )

F C*

2

Me

Me

2

J

e

90 C , 7 h / DMF

r -QT

-F-

29

R = CH CH(CH )Ph: 67% 30 2

3

R Me

NaH (11 eq)

R

Me

FC

F*U

Me

2

90 · 0 , 4 h / DMF

HS' R = (CH ) Ph: 76% 32

31

2

R

3

R Me

R

•'

1

FiC

ι

- F~

e

90 C,4d/DMF

TsHN

Me

NaH (1.1 eq)

TsN

33

ν

Ts R = CH CH(CH )Ph: 80% 34 2

3

Scheme 15 The favored nature of the 5-endo-trig cyclization in gem-difluoroalkene substrates was demonstrated by conducting a competitive reaction as shown in Scheme 16. The reaction proceeded not in a 5-exo-trig fashion but in a normally disfavored 5-endo-trig fashion, affording 2-fluoropyrroline 36 exclusively (12). £F Ν Ts

2

Ό

"5-exo-trig"

*

Synthetic Methods for the Preparation of Ring-Fluorinated

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