Perfluorinated Enolate Chemistry - American Chemical Society

Chapter 6

Perfluorinated Enolate Chemistry Selective Generation and Unique Reactivities of Ketone F-Enolates Cheng-Ping Qian and Takeshi Nakai

Downloaded by CORNELL UNIV on August 23, 2016 | http://pubs.acs.org Publication Date: February 22, 1991 | doi: 10.1021/bk-1991-0456.ch006

Department of Chemical Technology, Tokyo Institute of Technology, Meguro, Tokyo 152, Japan

A general, highly regio- and stereoselective method is developed to generate the metal F-enolates, CF3C(OM)=CFRf (Rf=F, CF3; M=Li, Na, K), from CF3CH(OH)CF2Rf. The F-enolates thus generated are shown to exhibit unique and wide spectra of reactivity toward a variety of reagents. Of particular interest is that the F-enolates show a rather unusual electrophilic behavior toward organometallic reagents, while the F-enolates still demonstrate the usual enolate reactivities including aldol reactivity. These reactivities of the F-enolates are well accommodated by their ab initio molecular orbital calculations. The unique spectrum of reactivity of β-hydro-and β-alkyl-F-enolates, CF3C(OLi)=CF-R (R=H, n-Bu), is also described. In sharp contrast to the prominent position of metal enolates in synthetic organic chemistry, the chemistry of perfluorinated enolates (F-enolates) remains relatively unexplored, mainly because of the lack of practical methods for their generation. Only a few examples of metal F-enolates have been recorded in the literature. (7, 2). We believe that perfluoro-enolate chemistry can play an equally important role in organofluorine synthesis (Figure 1). In this paper we wish to describe the recent advances in ketone F-enolate chemistry which have been made in our laboratory. Generation of F-Enolates Generation of Parent F-Enolate. Recently we have successfully developed a new, practical method for generating the parent ketone F-enolate 1 from commercially available hexafluoroisopropyl alcohol (ΗΠΡ) (5). The newlydeveloped method is quite simple (eq 1). Thus, the alcohol is treated with two equivalents of buthyllithium in THF around -40 °C for 2 h, or at 20 °C for 20 min to generate F-enolate 1 (M=Li) in essentially quantitative yield. Not unexpectedly, the lithium F-enolate is quite stable even at room temperature as determined by 19F NMR spectroscopy: 19F NMR (Et20, ex. CF3CO2H), δ -8.0 (d, d, J=9.4 and 22.6 Hz, CF3), +30.3 (br., d, J=88.4 Hz, F trans to CF3), and +41.3 (br., d, J=88.4 Hz, F cis to CF3).

0097-6156/91/0456-O082$06.00/0 © 1991 American Chemical Society

Welch; Selective Fluorination in Organic and Bioorganic Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1991.


6. QIAN AND NAKAI

83

Perfluorinated Enolate Chemistry

Generation of sodium (1, M=Na) and potassium F-enolates (1, M=K) is also feasible by successive treatment of ΗΠΡ with NaH (1 equiv) and Λ-BuLi (1 equiv) and with K H (1 equiv) and n-BuLi (1 equiv), respectively, under similar conditions. The Na- and K-enolates show different NMR spectrafromthat of the Li-enolate; the δ-values for the CF3 peak (Et20, ex. CF3CO2H) are -6.4 ppm for M=Na and -7.0 ppm for M=K. It should be noted that the K-enolate is relatively unstable and gradually decomposes at room temperature. Of special interest is the observation that the rate of F-enolate formation from the metal alkoxides significantly varies in the order: M=K>Na>Li. We found that the Fenolate yields (after benzoylation) of reactions of the alkoxides with n-BuLi conducted at- 70 °C for 4 h were 37% for M=Li, 81% for M=Na, and 91% for M=K. This order is somewhat surprising in view of the known order of the ionic character of the M--0 bonds, suggesting that the stronger coordination by F to M in the alkoxide (see Figure 2) makes the elimination faster. The role of the coordination by F to M is evidenced by the independentfindingthat the F-enolate formationfromthe potassium alkoxide is considerably suppressed by addition of 18-crown-6, which reduces the F--K coordination at least partially. For instance, the reaction of the alkoxide (M=K) with n-BuLi in the presence of 18-crown-6 (1.0 equiv) at -78 °C for 4 h was found to afford only 19% yield of the F-enolate compared with an 83% yield in the absence of the crown ether. Selective Generation of p-CFa-substituted F-enolates. We have also examined regio- and stereoselectivity in the dehydrofluorinative generation of Fenolates (4). Thus, the di(F-ethyl)carbinol 3a and F-methyl-F-ethylcarbinol 3b were prepared in ca.70% distilled yields by reduction of the corresponding F-ketone, obtainedfromRfC02Et and CF3CF2I according to the literature (5). The selectivities observed in the generation of F-enolate 4 from alcohol 3 are summarized in Table I (eq 2). For the lithium F-enolates (entries 1-5), only the (Z) isomers are formed in ether, whereas in THF the selectively decreases and in THF/HMPA it reverses to favor the (E) isomer. "Internal" enolate 4b are produced almost exclusively, irrespective of solvent and metal ion employed, except for the reaction with n-BuLi in ether, which gives appreciable "termini" enolate 5 (entry 3). Notably, (Z)-4b (M=K) is formed both regio- and stereospecifically in ether (entry 6). It should be noted here that the "Internal" enolate formation is favored both kinetically and thermodynamically. Under identical reaction conditions [n-BuLi (2.1 equiv), THF, -78 °C, 4 h], 100% of F-enolate is formed from (CF3CF )2CHOH but only 37%from(CF3) CHOH. The relative stability of the free enolates (gas phase) is (F)-CF C(0 )=CFCF (0) > (Z)-CF C(0 )=CFCF (5.6) > CF2=C(0 ) CF2CF3 (26.3 kcal/mol)fromthe ab initio calculations (yide infra). Control experiments, however, rule out any equilibrations under our reaction conditions, and therefore the observed isomer ratios in Table I are the kinetic product distributions. The increase in (Z)-stereoselectivity with decreasing solvent coordination to Li (HMPA>THF>ether) indicates that the stereoselectivity is controlled by the extent of internal F - L i coordination in the Li alkoxide intermediate. Thus, it appears likely that the HF elimination proceeds in a trans fashion exclusively through species A in ether, but partially through Β in THF and more so in THF/HMPA (Figure 3). Further noteworthy is that a similar (Z):(E) ratio (1:3) to that in entry 5 is observed in the F-enol ether formation from CF3CH(OMEM)CF2CF3 with LDA in THF, where F~Li coordination cannot be operative.

L1AIH4

2

2

3

3

3

3

Generation of Terminal F-Enolates. We have also developed an entirely different approach for the generation of "terminal" F-enolates without regiochemical ambiguity (6). For instance (eq 3), treatment of bromodifluoromethyl F-ketone 6


84

SELECTIVE FLUORINATION IN ORGANIC AND BIOORGANIC CHEMISTRY

F-Enolate

Enolate OM

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R-C=CH-R'

Organofluorine Synthesis

Organic synthesis OM

OM

H

5

CF -C=CF

C F 3- -CCH H- CF3 :

3

3

CF3-CH-CF3 (HFIP)

(1)

2

1

(M=Li, Na, K) Figure 1. F-Enolate vs. Enolate.

CF^-f-F H

? R -CH-CF CF H

f

2

3a,R=C F 3b,R=CF 2

3

3

— ^

MO W

F

F

MO

(Z)-4 Figure 2.

3

+ R

5

CF

+ /

F (E)-4

OM CF =Ô-CF CF 2

2

5 5

Structure of 2.


3

(2)

QIAN AND NAKAI


Table I. Regio- and Stereoselectivity of F-Enolate Formation Isomeric ratio" entry

alcohol

M*

solvent

Z-4

1

3a

Li

Et 0

100 :: 0

Li

THF

79 :: 21

74

Li

Et 0

88 :: 0 : 12

82

4

Li

THF

5

Li

THF/HMPA

6

Κ

Et 0

100 : 0 : 0

78

7

Κ

THF

65 :: 35 : 0

71

2 Downloaded by CORNELL UNIV on August 23, 2016 | http://pubs.acs.org Publication Date: February 22, 1991 | doi: 10.1021/bk-1991-0456.ch006

3

a

3b

2

2

yield, %

: E-4 : 5

81

68

87 : 13 : 0

2

C

b

68

40 : 60 : Q

d

Run at -70 °C for 4 h using 2.2 equiv of n-BuLi for 4(M=Li) or 1.2 equiv of KH

followed by 1.1 eq. of /i-BuLi for 4(M=K). Determined by F NMR after trapping b

1 9

with AcCl for 4a or with MEMC1 for 4b. The isomeric F-enol acetates and ethers 1 9

are clearly distinguishable by F NMR (ex. TFA), particularly by the multiplicity of the b-CF signals: d -11.5 (d, t, J=7.5 and 15.1 Hz) for Z-4a; d -7.7 (d, J=7.5 Hz) for 3

£-4a; d -11.6 (br. q, J=7.5 Hz) forZ-4b, d -8.6 (d, J=7.5 Hz) for£-4b; d +7.3 (s) for c

d

5. THF:HMPA=4:1 by volume. (Z)-4b:(E)-4b:5=38:58:4 from Me SiCl trapping 3

experiments.

A

Β

Figure 3. Chelation vs. Nonchelation.

: Fs-C-CF Br 2

2

6

^ C F5-C=CF 2

7

2

2 ) M e L j

- C Fs-*< OCOPh CF3-C=Ç-Bu CF 15(55%) 1

n

B u L i

3

Reactions of f-enolate 4b.


,

3


Table II. Electronic Properties of Free F-Enolates* charge (e) on C H (16)

0.44

-0.82 -0.63

-1.83

CF -C(0>CF (1)

0.11

0.18 -0.61

-3.45

10.03

0.21

-0.09 -0.53

-4.43

8.61

0.19

-0.13 -0.53

-4.45

8.52

3

2

3

2

(2)-CF -C(0>CFCF (4b) 3

3

(£)-4b Downloaded by CORNELL UNIV on August 23, 2016 | http://pubs.acs.org Publication Date: February 22, 1991 | doi: 10.1021/bk-1991-0456.ch006

HOMO (eV)

11.60

* Calculated at the optimized geometry obtained with a doublet-ζ basis set augmented by d functions on C and O. The basis set is from Dunning and Hay (Dunning, T. H; Hay, P. J. In Methods of Electronic Structure Theory, Schaefer, H. F. HI, Ed.; Plenum Press: New York, 1977; Chapter 1) and has the form (9,5,1/9,5/4) / [3.2.1/3.2/2] in the order CO/F/H.

MEMCI -20°C, 10 min

OLi

PhCHO

CF -C=CF-R

35°C, 1 h

3

11a, R=H 11b, R=n-Bu

OMEM CF -C=CF-R 3

R=H (51%);R=Bu(60%)

OH

OH

CF3-Ç-C -Cî-CFR-CH-CF3 3

R=H (100%); R=Bu (31%)

n-BuLi 20°C, 30 min

Figure 6.

OCOPh CF -6=C-fl èu R=H, Bu (0%) 3

Reactions of enolate 11a and l i b .

LUMO: 9.98 eV HOMO: -3.19 eV (2)-11a Figure 7.

Electronic properties of

(Z)-lla.


6. QIAN AND NAKAI


89


substituted (4b) are well accommodated by the ab initio calculations on thefreeFenolates, which have been done by Drs. Dixon and Smart (4). The calculated electronic properties of the F-enolates and the hydrocarbon reference enolate 16 are summarized in Table Π. The most revealing features are as follows, (a) The oxygen charge densities of the F-enolates and 16 are very similar, (b) The β-carbons of the F-enolates no longer have a large negative charge, (c) The HOMO and LOMO are both significantly lowered in 1 vs.16 and also in 4b vs. 1. The β-C electrophilic reactivity of the F-enolates is rationalized by their relatively low lying LUMOs combined with the small positive or slightly negative charge on the β-carbon atoms. The lower LUMO level of 4b relative to that of 1 nicely accounts for its enhanced C-electrophilicity, and its comparatively lower HOMO level is consistent with its poor reactivity in aldol reaction. Reactivities of β-Hydro- and β-Alkyl-Substituted F-Enolates. The following scheme (Figure 6) shows the unique reactivity patterns observed with the β-hydro-F-enolate 11a (R=H, M=Li) and the β-butyl-F-enolate l i b (R=n-Bu, M=Li) (7). Both 11a and l i b shows a slightly higher 0-nucleophilicity toward MEMC1 and equally high aldol reactivity, compared with the parent F-enolate (1). Interestingly, however, both 11a and l i b no longer show the electrophilic reactivity toward n-BuLi. Let's look at the calculated electronic properties of thefreeenolate (Z)-llb (7). As shown below (Figure 7), the β-carbon has a slightly larger negative charge, and the HOMO and LUMO levels are both slightly higher, compared with those of the parent F-enolate 1. The equally high aldol reactivity of 11a is rationalized by its comparably high lying HOMO, coupled with the large negative charge on the βcarbon. However, theriseof the LUMO level is apparently too small to account for its poor reactivity toward H - B U L L Thus, we must await the additional calculations on the lithum coordinated F-enolate 11a. In summary, we have developed facile and regio- and stereoseleactive procedures to generate various types of F-enolates whose reactivities markedly differfromthose of their hydrocarbon analogues but can be anticipated by ab initio molecular orbital calculations. This work convincingly reveals the interesting aspects of hitherto unexplored F-enolate chemistry, providing a new, basic technology for organofluorine synthesis. Further studies on the mechanism of Fenolate formation and synthetic utility are in progress. Finally, it should be noted that the ketone F-enolate chemistry described herein represents one extreme of enolate chemistry which we believe significantly promotes the understanding of the rich chemistry of partiallyfluorinatedketone enolates, a current subject of extensive investigations (8-11). Acknowledgments. We are grateful to Drs. David A. Dixon and Bruce E . Smart of Ε. I. du Pont de Nemours & Co. Inc. for their excellent calculations and stimulating discussions, and Dr. Masamichi Maruta of Central Grass Co. for his helpful discussions. This work is partially supported by a Grant-in-Aid for Scientific Researchfromthe Ministry of Education, Japan, the Chemical Materials Research & Development Fundation, Central Glass Co., and Du Pont, Japan, Ltd., which are gratefully acknowledged. We also thank Central Glass Co. and Asahi Glass Co. for the gift of HFIP and C2F5I, respectively. Literature Cited. (1) Bekker, R. Α.; Melikyan, G. G.; Daytkin, B. L.; Knanyants, I. L. Zh. Org. Khim. 1976, 12, 1379. (2) Farnharn, W. B.; Middleton, W. J.; Fultz, W. C.; Smart, Β. E. J. Am. Chem. Soc. 1986, 108, 3125.



90


(3) Qian, C. -P.; Nakai, T. Tetrahedron Lett. 1988, 29, 4119 (4) Qian, C. -P.; Nakai, T.; Dixon, D. Α.; Smart, Β. E. J. Am. Chem. Soc. 1990, 112, 4602. (5) Chen, L. S.; Chen, G. J.; Tamborski, C. J. Fluorine Chem. 1984, 26, 341. (6) Qian, C. -P.; Nakai, T. The 59th Annual Meeting of Chemical Society of Japan, Yokohama, 1990, Abstr. 4D125. (7) Qian, C. -P.; Maruta, M.; Nakai, T. The 56th Annual Meeting of Chemical Society of Japan, Tokyo, 1988, Abstr. 3XIA17. (8) Kuroboshi, M.; Okada, Y.; Ishihara, T.; Ando, T. Tetrahedron Lett. 1987, 28, 350. (9) Ishihara, T.; Yamaguchi, K.; Kuroboshi, M. Chem. Lett. 1989, 1191. (10) Whitten, J. P.; Barney, C. L.; Huber, E. W.; Bey, P.; McCarthy, J. R. TetrahedronLett.1989, 28, 3649. (11) Zeifman, Y. V.; Postovoi, S. Α.; Vol'pin, I. M.; German, L. S. Proceedings of the 6th Regular Meeting of Soviet-Japanese Fluorine Chemists, Novosibirsk, 1989, I-1, and references cited therein. RECEIVED October 19, 1990


Perfluorinated Enolate Chemistry - American Chemical Society

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