Current Fluoroorganic Chemistry - American Chemical Society

Chapter 2

Downloaded by STANFORD UNIV GREEN LIBR on September 27, 2012 | http://pubs.acs.org Publication Date: January 11, 2007 | doi: 10.1021/bk-2007-0949.ch002

Syntheses of Organofluorine Derivatives by a New Radical Process Samir Z . Zard

Laboratoire de Synthèse Organique Associéau CNRS, Ecole Polytechnique, 91128 Palaiseau, France

New routes to organofluorine derivatives based on the powerful xanthate radical transfer technology are described. A special emphasis is placed on the synthesis of trifluoromethyl -substituted structures, including trifluoromethylketones and fluorinated aromatic and heteroaromatic substances of interest to the pharmaceutical and agrochemical industries.

Introduction The enormous importance of organofluorine derivatives for the pharmaceutical and agrochemical industries and for material sciences has generated a steep demand for cheap, efficient, andflexiblemethods for the introduction offluorineorfluorinatedgroups into various families of compounds (1). Countless, and in many cases ingenious, approaches have been devised to cover the needs of academic and industrial chemists interested in organofluorine derivatives. Nevertheless, there is still a niche for new reactions allowing the direct introduction offluorinatedgroups into the substrate or the synthesis of fluorinated building-blocks that can then be incorporated in a given synthetic scheme. We have developed in recent years a new radical chemistry of xanthates 1 and related derivatives of general formula Z-C(=S)S-R which allows the generation and capture of various types of radicals (2). We thus found that © 2007 American Chemical Society

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

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26


xanthates are capable of undergoing additions to various olefins by way of the simplified radical chain mechanism outlined in Scheme 1. The overall result is the addition of the elements of the xanthate across the olefinic bond to give adduct 4. As the examples in the following pages will show, it turns out that this process is also a uniquely powerful tool for the synthesis of numerous fluorinated synthons and building blocks, many of which would not be easily accessible otherwise.

-

Ionic manifold

S

Scheme L Simplified mechanism for the degenerative xanthate transfer.

The subtleties of the mechanistic manifold will not be discussed in detail, but three general properties are especially important: (a) The reaction of radical R» with its xanthate precursor (path A ) is degenerate and does not consume the radical. This effective absence of competition forces the radical into reacting with the olefinic trap either in an intra- or intermolecular mode (path B). This translates into a unique ability to accomplish intermolecular additions to un-activated olefins and sets this method apart from essentially all other radical processes. (b) The adduct is itself a xanthate. This allows the implementation of another radical sequence (which can in turn lead to yet another xanthate), or the xanthate group can be used as an entry into the extremely rich "ionic" chemistry of sulfur. Hence, a large array of synthetic transformations can now be used to introduce further diversity and complexity into the structure. (c) It is important, for the chain process to be efficient, to select the reacting partners in such a way that the adduct radical 2 is less stable than the initial radical R% in order to favour the fragmentation of intermediate 3 in the desired direction. This consideration is crucial, especially when intermolecular additions are concerned, as it provides a handle for stopping at the mono-adduct in



27 preference to telomerisation. It is nevertheless possible, when the adduct radical 2 has a low oxidation potential and therefore easily oxidised into the corresponding cation, to use the peroxide both as an initiator and an oxidant (path C). Oxidising the radical opens a passageway from a radical to a polar reaction manifold and expands considerably the synthetic scope. This aspect will have its importance in the context of a tin-free reductive removal of the xanthate group and in cyclisations involving aromatic rings (vide infra). The utility of this process is that it allows the inter- or intra-molecular creation of C—C bonds, even in the case of non-activated alkenes. As far as fluorinated groups are concerned, they can be present in the olefin, in the xanthate, or in both. The convergent synthesis of a di-fluoro nucleoside analogue 9 detailed in Scheme 2 illustrates the case where the fluorine atoms adorn the olefinic partner (3). The efficient radical addition is followed by aminolysis of the adduct xanthate 6, ring-closure to thiolactone 7, and mild reduction to give a thiolactol intermediate. Finally, acetylation provides a substrate, 8, capable of undergoing a Vorbruggen type introduction of the thymine base.

CH2CMe3

,PO(OEt)

Q

E

1)H NCH CH NH ethanol, 20°C

T

2

2

2

2

0

2

JL* * E t o

2)CF CO H,60°C

(EtO) OP.

3

0

f

~ ? F4-^

2

s

2

EtO

Lauroyl peroxide (0.2eq.) cyclohexane, A

O 5

6, 60%

7, 86%

OneoPn

1)NaBH ethanol, 4i

M

\f E t

°

e

3

V o

OEtL/-H

- 1 8 ° C , 10 days

OSiMe

/ N H

F

V

N^OSiMe SnCI CH A C H CN, CN, A

2)Ac 0, Et N, DMAP, CH CI 50°C 2

F

OAc

3

2

2

3

EtcOOEt

H

4

9,80%

33

8,68%

Scheme 2. Synthesis of a nucleoside analogue.

Alternatively, the fluorinated group can be attached to the xanthate. A number of reagents can thus be readily prepared and used to access to a large array of fluorinated synthons. For instance, starting from the hemiacetal of trifluoroacetaldehyde, crystalline xanthate 10 can be prepared on a multigram scale. Its addition to variously substituted olefins proceeds efficiently and cleanly to afford a multitude of structures possessing a geminally disposed trifluoromethyl and amido groups (4). The examples pictured in Scheme 3 underscore the remarkable compatibility of this synthetic method with a broad diversity of functional groups present on the olefinic partner. The specific



28 reactivity of the various substituents can be harnessed to further increase the complexity, for example by inducing ring-closures to form nitrogen or sulfur heterocycles. Furthermore, the presence of the xanthate group in the addition products can be exploited in countless ways. In some cases, another radical addition can be accomplished, as shown by the transformation on the right in Scheme 4 leading to compound 11, where almost every carbon is fiinctionalised. Densely functionalised, complex fluorinated structures can thus be swiftly assembled (4). Addition to vinyl acetate provides an adduct containing a masked aldehyde function, since the xanthate is now geminal to the acetoxy group. Heating this adduct with methanol and acid gives crystalline acetal 12, a compound bearing both a protected amine and a masked aldehyde; it constitutes thus a very interesting synthon for the synthesis of trifluoromethylated heterocycles. The third example in Scheme 4 concerns the addition to N-vinyl pyrrolidone, which gives a product that can be thermolysed into enamide 13 in essentially quantitative yield (4).

Scheme 3. Examples of xanthate transfer radical additions.


29


Enamides such as 13 are useful precursors for the synthesis of trifluoroalanine, trifluoroanalinal, and trifluoroalaninol, through ozonolysis of the olefinic bond followed by an appropriate oxidative or reductive work up of the ozonolysis medium. One synthetic application is depicted at the bottom of Scheme 4, where in situ condensation of the aldehyde with acetylacetone leads to trifluoromethylated pyrrole 14 through the classical Knorr condensation (5).

CF ^NHCOCH 3

SCSOEt CF

NHAc

3

—'

\

ft

0 ,

}

= 0

(peroxide)

L^SCSOEt

X

o

3

87% PhCI reflux

CF

3

SiMe

3

NHAc

s

CF

3

NHAc L^OMe OMe

13,100%

12, 72%

0

1)0 CH CI .-78 C ' 2) PPh 3

2

2

3

o CH3CONH

CF ' 3

o /-Me

X X piperidine, TFA, EtOH, reflux

CF ^ ^Me ^ 3

N

Scheme 4. Further transformations of the adducts.

It is interesting to note that in the absence of a trap, xanthate 15, the benzoyl analogue of 10, reacts with a stoichiometric quantity of lauroyl peroxide to give homodimer 16, as 1:1 mixture of the meso and d,l diastereomers (Scheme 5). The benzoyl analogue was used to simplify isolation (4). The formation of dimers by coupling of radicals is not surprising when dealing with radical intermediates; what is astonishing is the remarkably high yield of the homodimer, since one would have expected a complex mixture arising from


30


anarchic and statistical recombinations of the various radicals in the medium. The mechanistic implications of this observation are exceedingly important and reveal some subtle aspects of the process (6), but these will not be discussed here. Suffice it to say that this approach represents a unique, practical route to protected 2,3-diamino-l,l,l,4,4,4-hexafluorobutane, a hitherto unknown family of fluorinated vicinal diamines of potential use for the synthesis of unusual ligands for transition metal chemistry or for the construction of fluorinated nitrogen heterocycles.

„ CF ^ NHCOPh k

3

SCSOEt 15

Lauroyl peroxide (stoichiometric) Chlorobenzene reflux

CF ^NHC0Ph T CF NHCOPh 3

C F ^ NHCOPh 3

16,79%

3

Scheme 5. Formation of homodimers. Other useful xanthates can be obtained from the hemiacetal of trifluoroacetaldehyde. The acetoxy and chloro derivatives were prepared in a similar manner to the amide analogue 10 and found to react in the same way with a variety of olefinic traps, as indicated by the examples collected in Scheme 6 (6). Again, notice the richness and density of the functional groups.

74%

Scheme 6. Synthesis and addition of xanthates derived from trifluoroacetaldehyde hemiacetal.



31 It is possible to use the chemistry of xanthate to access trifluomethyl ketones by a radical pathway. The precursor is easily made by reacting a xanthate salt with commercially available l-bromo-3,3,3-trifluoropropan-2-one (7). The Oneopentyl xanthate was used in this case to increase lipophilicity and limit complications due to the reversible formation of the hydrate. Again, numerous olefins can be used as traps, and trifluoromethyl ketones that would otherwise be very difficult to obtain can be made in essentially one step. As far as we are aware, this is the only instance that trifluoroacetyl radicals have been applied in synthesis. The examples in Scheme 7 are representative of the tremendous potential of this approach. The first example corresponds to the synthesis of a masked aminoacid, whereas the second is a protected (Phth = phthalimido) amino ketone which should close to a trifluoromethyl piperidine derivative upon deprotection of the amino group.

Scheme 7. Synthesis of trifluoromethyl ketones. A simple trifluoromethyl group can be introduced via the corresponding xanthate. Such xanthates, however, and not surprisingly, cannot be made by a simple nucleophilic substitution on a trifluoromethyl halide, as in the case of the previous derivatives. A n indirect route via the decarbonylation of the 5trifluoroacyl xanthate 17 was devised to overcome this problem (8). A "heavier" xanthate was employed to aid in handling the intermediates and to avoid having to manipulate a potentially volatile reagent. Xanthate 18 turns out to be a highly effective agent for the introduction of the trifluoromethyl group, as shown by the example displayed in Scheme 8. The olefinic partner can be varied in the same way as in the preceding schemes. A large variety of trifluoromethylated building


32


blocks thus become accessible, starting from cheap, readily available starting materials. The xanthate group in the product provides an entry into the exceptionally rich chemistry of sulfur and a plethora of subsequent transformations can be envisaged following the radical addition step. Nevertheless, reductive removal of the xanthate group is often also a desired transformation. Many traditional reagents (tributylstannane, Raney nickel, nickel boride) are capable of accomplishing this task cleanly. However, these reagents are not very convenient for large scale use because of toxicity, cost, or problems with purification.

s

(CFaCOfcO

O

(Lauroyl peroxide) CH CN, reflux

S

NaS

O

3

,Ph

CF

CH CN 3

:

17

-CO, S CF

:

OAc" 84%

3

(Lauroyl peroxide) DCF, reflux

^CF

C F S. X , O 0

18,

^

3

.Ph .

40% P

h

^

0

\ ^ C F

3

Scheme 8. Generation and capture of trifluoromethyl radicals. We found that a simple, yet highly efficient reductive method existed, which took advantage of the electrophilic character of a radical centre adjacent to inductively acting (- I) electron withdrawing groups, and especially fluorine atoms. Reduction of compound 21, obtained by radical addition of acetonitrile derived xanthate 19 to heptadecafluorodecene, is a case in point (9). The xanthate is simply dissolved in refluxing cyclohexane and treated with a small amount of lauroyl peroxide. A chain reaction sets in, whereby the cyclohexane acts as the hydrogen atom source, as outlined in Scheme 9. Intermediate radical 22 is highly electrophilic in character, because of the powerful electron withdrawing effect exerted by the nearby fluorine atoms, yet unstabilised. It therefore rapidly abstracts a hydrogen atom from the solvent to give a cyclohexyl radical to propagate the chain. The importance of the fluorine atoms can be visualised, by comparing in a competition experiment, the behaviour of adduct 21 with that of the non-fluorinated analogue 20. The latter is hardly affected under these conditions and recovered mostly intact. In order to be able to reduce ordinary secondary xanthates that are not substituted by reactivity enhancing electron-withdrawing groups, it is necessary to use a better hydrogen atom donor than cyclohexane. A convenient candidate turns out to be 2-propanol (10). Its hydrogen atom donor ability is much greater



33 than cyclohexane, but this is counterbalanced by the fact that the resulting ketyl radical is too stabilised and therefore incapable of propagating the chain. This radical can, however, be oxidised by electron transfer to the peroxide into the corresponding cation, which then sheds a proton to give a molecule of acetone. The peroxide acts therefore as an initiator and as a stoichiometric oxidant. The first application pictured in Scheme 10 illustrates the synthesis of a differentially protected 1,4-butanediamine (4). The second transformation concerns the appending of a trifluoroacetonyl group on native pleuromutilin, a terpene antimicrobial (11). This transformation is remarkable in that there is no need to protect any of the functional groups present in the substrate. It is perhaps worth stressing that a traditional approach to all these products would certainly be lengthy and tedious. S

19

S

Scheme 9. Reductions using cyclohexane. The fact that the peroxide can be used both as an initiator and as an oxidant opens numerous opportunities for the synthesis of fluorinated aromatic derivatives. These are highly valuable precursors for pharmaceuticals and agrochemicals, as well for material sciences. The underlying principle of this approach is to exploit the relatively long life of the intermediate radicals generated from the xanthate to force cyclisation on an aromatic or heteroaromatic ring and to use the peroxide to oxidise the adduct radical (a cyclohexadienyl radical in the case of benzene type aromatics) into the cation, which then rapidly aromatises by loss of a proton. The fluorine-bearing motif can be part of the aromatic structure or incorporated into the xanthate. A n enormous advantage of this strategy is the fact that strongly electron withdrawing substituents such as trifluoromethyl groups, which severely retard Friedel-Crafts



34 and other mechanistically related electrophilic substitutions commonly used in the synthesis of aromatic derivatives, do not generally affect much the radical cyclisation step. This expands considerably the range of substrates can thus be used in this approach, as illustrated by the examples discussed in the following paragraphs. The synthesis of naphthalenes displayed in Scheme 11 relies on the intermolecular addition of a /?-fluorophenacyl radical to vinyl pivalate, followed by ring closure onto the aromatic ring to give tetralone 23 (12). Both of these radical steps are very easy to execute using the xanthate technology but would be almost impossible to accomplish as efficiently with any of the other radical methods currently available.

s AcHN N is

L J

-x^v. N is

7

0

/

V

E t s o

-

_ z f ^

B

-

%

Scheme 14. An alternative synthesis of trifluoromethyl ketones.

Acknowledgements: I wish to express my heartfelt thanks to my collaborators, whose names appear in references and whose dedication and skills made this work possible. I also wish to gratefully acknowledge generous financial support from Ecole Polytechnique, the CNRS, Rhodia, Sanofi-Aventis, CONACyT (Mexico), and the Ministerio de Educacion, Cultura y Deporte (Spain).

References 1.

(a) Shimizu, M .; Hiyama, T. Angew. Chem. Int. Ed. Engl. 2005, 44, 214231. (b) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell Publishing: Oxford, 2004. (c) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004. (d) Topics in Current Chemistry Organofluorine Chemistry: Techniques and Synthons; Chambers, R. D., Ed.; Springer: Berlin, 1997, Volume 193. (e) Biomedical Frontiers of



38 Fluorine Chemistry; Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds.; American Chemical Society: Washington, D.C., 1996. (f) Fluoroorganic Chemistry: Synthetic Challenges and Biomedical Rewards; Resnati, G.; Soloshonok, V . A . , Eds. Tetrahedron Symposium-in-Print No. 58; Tetrahedron 1996, 52, 1-330. (g) Fluorine-Containing Amino Acids; Kukhar, V . P.; Soloshonok, V . A . , Eds.; Wiley: Chichester, 1994. (h) Organofluorine in Medicinal Chemistry and Biochemical Applications; Filler, R.; Kobayashi, Y.; Yagupolski, L . M., Eds.; Elsevier: Amsterdam, 1993. 2. Zard, S. Z. Angew. Chem. Int. Ed. Engl. 1997, 36, 672-685. (b) QuicletSire, B . ; Zard, S. Z. Phosphorus, Sulfur, and Silicon 1999, 153-154, 137154. (c) Zard, S. Z . in Radicals in Organic Synthesis; P. Renaud, P.; M . P. Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 90-108. 3. Boivin, J.; Ramos, L.; Zard, S. Z. Tetrahedron Lett. 1998, 39, 6877-6880. 4. Gagosz, F.; Zard, S. Z. Org. Lett. 2003, 5, 2655-2657. 5. Tournier, L. PhD Thesis; Ecole Polytechnique: Palaiseau, 2005. 6. Tounier, L.; Zard, S. Z . Tetrahedron Lett. 2005, 46, 455-459. 7. Denieul, M.-P.; Quiclet-Sire, B . ; Zard, S. Z. Chem. Commun. 1996, 25112512. 8. Bertrand, F.; Pevere, V . ; Quiclet-Sire, B . ; Zard, S. Z . Org. Lett. 2001, 3, 1069-1071. 9. Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 1996, 118, 9190-9191. 10. Liard, A . ; Quiclet-Sire, B . ; Zard, S. Z. Tetrahedron Lett. 1996, 37, 58775880. 11. Bacqué, E.; Pautrat, F.; Zard, S. Z. Chem. Commun. 2002, 2312-2313. 12. Cordero-Vargas, A.; Pérez-Martin, I . ; Quiclet-Sire, B . ; Zard, S. Z. Org. Biomol. Chem. 2004, 2, 3018-3025. 13. Binot, G.; Zard, S. Z. Tetrahedron Lett. 2005, 46, 7503-7506. 14. Quiclet-Sire, B.; Zard, S. Z. Chem. Commun. 2002, 2306-2307 15. Sortais, B. PhD Thesis; Univeristé Paris-Sud: Orsay: 2002. 16. Bertrand, F.; Leguyader, F.; Liguori, L.; Ouvry, G.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. C. R. Acad. Sci. Paris 2001, II4, 547-555.


Current Fluoroorganic Chemistry - American Chemical Society

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