Controlled Radical Polymerization - American Chemical Society

Chapter 4

Cascade Radical Reactions in Organic Synthesis: An Overview Dennis P. Curran

Downloaded by UNIV OF TEXAS EL PASO on November 7, 2014 | http://pubs.acs.org Publication Date: January 8, 1998 | doi: 10.1021/bk-1998-0685.ch004

Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260

Abstract: This lecture w i l l provide an overview of the past decade of developments of cascade radical reactions i n organic synthesis that is targeted towards a polymer audience. M a n y of the principles in play in today's small molecule cascades emerged from polymer chemistry and were modified accordingly. Indeed, the lecture might instead be titled " H o w to Start a Radical Polymerization and Then Stop It Before It Really Gets Going". The similarities between polymer chemistry and small molecule synthesis w i l l be apparent. The key difference is that the goal of a radical polymerization is to get every radical to do the same thing while the goal of a cascade radical reaction is to get every radical to do a different thing. Prototypical sequences of inter- and intramolecular radical reactions w i l l be discussed along with the methods that are used to conduct them. I.

Introduction

Cascade reactions are now commonly used by synthetic organic chemists to fashion complex molecules from simpler precursors i n the fastest and most efficient way possible. Cascade radical reactions (sometimes called sequential or tandem radical reactions) are an important subclass that has played a central role i n the growth i n popularity of cascade reactions. The key features that impact on the design of cascade radical reactions are now relatively well understood, and it has become possible to design and execute an astounding assortment of useful reactions. This lecture w i l l provide an overview of the criteria for planning tandem radical reactions and show how these criteria are applied to the design and execution of large, important classes of cascade radical reactions. Given the increasing popularity of the field, comprehensive coverage is not possible. Instead, work from our laboratory w i l l be used to highlight key lessons that have been learned over the past fifteen years or so. There is no recent comprehensive review of this fast moving field, but older overviews and more recent treatments of some aspects of the field are available. The introduction of radical reactions to the synthetic repertoire has provided significant new options that both supplement and complement synthetic methods based on ionic and pericyclic reactions.^ Radical-based methods to form carbon-carbon bonds have been especially useful because they occur under such mild conditions that high selectivity is often possible. Tributyltin hydride and tris(trimethylsilyl)silicon hydride are the most popular reagents that are currently available for mediating radical reactions, but a new fluorous tin hydride is now providing new options as well (see 1

2

4

62

© 1998 American Chemical Society

In Controlled Radical Polymerization; Matyjaszewski, K.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

63

5

Figure l ) . Although reactions based on tin hydride remain the most popular for synthetic applications, there are a number of other fundamentally different strategies that offer unique advantages for synthetic applications. One of the most useful of these is the atom transfer method, summarized in Figure 2 . 3

6

Figure 1.

Radical Reactions with Tributyltin Hydride Bu SnH 3

R—X

• R—H -or(C F CH CH )3SnH (TMS) SiH 6

13

2

2


3

Figure 2. A Typical Atom Transfer Cyclization

In a very real sense, even the simplest radical reactions such as reductions o f halides by tin hydrides are sequential reactions because they occur in multi-step chains. However, for synthetic purposes, radical reactions are generally only considered sequential i f more than one bond forming or breaking process occurs between generation of the initial radical and removal of the final radical. Thus, the atom transfer cyclization shown in Figure 2 is not a tandem radical reaction; only one bond is formed between radical generation and trapping. Radical reactions are ideal for sequencing for a very simple reason: the product of every radical-molecule reaction is a radical. ' This, the generation of a radical from an initial precursors by the tin hydride method, the atom transfer method, or any other method can set off a cascade of events. Controlling the cascade is the key to developing a successful tandem radical reaction. Each individual radical must react selectively, which is a special challenge because radicals are transient. This generally means that cascades cannot be conducted "one step at a time" by sequential addition o f reagents. Instead, once started, they go from beginning to end. A whole collection of different radicals is present i n the same reaction medium and exposed to the same reaction conditions at the same time. A s the sequence becomes more and more complex, it becomes more and more difficult to control the selectivities of the individual intermediate radicals. Perhaps the most important step in a radical cascade from a selectivity standpoint is the last one. It is this step which draws the line between a cascade to make a small molecule in general steps and a polymerization o f many steps. E v e n i f a l l the intermediate radicals react as planned to complete a cascade, the product is still not formed until the last radical in the cascade is removed to provide a closed shell product. W h e n chain chemistry is used, this radical is removed by the chain transfer reaction. Controlling the chain transfer step is a crucial design element in any tandem reaction; ideally, only the last radical i n the cascade should suffer chain transfer. Reaching this ideal situation can be more or less difficult depending on the types of radical reactions in the sequence and the method by which they are conducted. 7


64


II.

Sequences of Intramolecular Reactions

A m o n g the easiest kinds o f radical sequences to conduct are those that contain only intramolecular reactions. In these kinds of sequences, the selectivities of the radicals are determined by the structures of the substrates. In general, each individual radical only has one reaction of reasonable rate that is can be expected to undergo. The large body of knowledge about rate constants of radical reactions and the many examples o f i n d i v i d u a l intramolecular reactions serve as guides for planning successful intramolecular sequences. In general, the last radical in a sequence is not given a good intermolecular option, and therefore it suffers chain transfer by default. The only requirement is that this chain transfer must be faster than radical-radical or r a d i c a l solvent reactions. G i v e n this, the sequence w i l l succeed provided that the slowest reaction along the way is still faster than chain transfer. In short, the requirements for designing sequences of intramolecular reactions are not that much more stringent than those for conducting a single intramolecular reaction. In both cases, selectivity is imposed by intramolecularity. The three most popular types of intramolecular radical reactions are cyclization, ring opening (the reverse of cyclization) and 1,5-hydrogen transfer. These reactions are often combined under the tin hydride method, although many of the other methods can and have been used to conduct sequences containing only intramolecular reactions. Prototypical examples of three representative sequences selected from among many are shown i n Figure 3. Figure 3a shows now classic examples of tandem cyclizations to form vicinal carbon-carbon double bonds. This is by far the most popular kind o f tandem radical reaction, and many imaginative double, triple, and even tetracyclizations have been executed. In these types of tandem cyclizations, the number of new C - C bonds formed equals the number of steps between radical generation and chain transfer. 8

Figure 3 a . Early Tandem

+ methyl epimer

Cyclizations

silphiperfolene

9

Figure 3b shows an example of a so-called Dowd-Beckwith ring expansion that is capped off with another c y c l i z a t i o n . A sequence o f cyclization-fragmentationcyclization occurs between radical generation and chain transfer. In one sense, this type of sequence is less powerful than straight tandem cyclization: only one net C - C bond is 10


65

gained i n this process (the other is "lost" i n the fragmentation). However, as the example i n Figure 3b clearly shows, the complexity of a tandem process cannot be measured simply by the number of bonds gained. Sequences of radical reactions can also involve radical translocations. In these reactions, the first-formed radical is "translocated" from a site where it is easy to generate to one where is not, and a reaction or series of reactions then f o l l o w s . The most popular types of radical translocations are hydrogen transfers, and these allow the indirect use of a C - H bond as a radical precursor. A n example is shown in Figure 3c. 11

Figure 3b.

A Cyclization-Fragmentation-Cyclization

Sequence


Br

Figure 3c.

A Radical Translocation-Cyclization

Sequence


66


III.

Radical Annulations

Sequences that combine inter- and intramolecular reactions become more difficult to conduct. In general, it is easier to conduct the intramolecular reaction first (because it is fast and can handily beat out a competing bimolecular reaction), and there are many examples of sequences of cyclization-addition. It is also relatively easy to conduct reactions in the reverse order (addition-cyclization) when radicals are added to dienes and related molecules. The most interesting type of sequence i n the "inter/intra" class is a "radical annulation" because a new ring is formed from two acyclic precursors by a sequence of addition (brings the two pieces together) and cyclization (forms the ring). In this sequence, both pieces are integrated into the new ring. This is in contrast to the above sequences, where all of the atoms of the ring are present in the cyclization component, and the addition component is tacked on before or after cyclization. A radical annulation also presents a unique selectivity problem: it is especially difficult to differentiate the initial radical from the final radical. T i n hydride is a relatively poor reagent for differentiating many kinds of radicals, and therefore the tin hydride method is not the most popular method for conducting radical annulations. Instead, these reactions are conducted either by atom transfer methods or by unimolecular chain transfer methods (see below). The iodine atom transfer method is especially useful. Almost all exothermic iodine atom transfer reaction are very fast, so the timing of iodine transfer can be controlled by the design of the intermediate radicals. In general, atom transfer can be timed to stop a sequence (and, because this is a chain transfer step, start the next one) whenever an intermediate radical is formed that: 1) is less stable than the starting radical, and 2) has no rapid unimolecular option. Several representative examples are shown i n Figure 4a. In each case, the iodides were removed in the end by tin hydride. However, the annulations cannot be conducted with tin hydride directly. ^ Figure 4 a . Atom Transfer Annulations

1) 0

3

2) D B U

The malononitrile class of reactions is especially interesting because the radical annulation can be followed by a nitrile transfer reaction, as shown by the examples in Figure 4 b . T w o simple molecules come together to selectively form complex, substituted rings in one operation by a sequence of addition-cyclization (to the alkene)cyclization (to the nitrile) and fragmentation. 1 3


67

Figure 4b.

Addition-Cyclization-Cyclization-Fragmentation


+ isomers

75% NC

7

Alkenes serve as natural reagent equivalents for the "two atom" components of "n + 2 " radical annulations. But by using carbon monoxide, isonitriles or a few other reagents, it is possible to conduct "n + 1" radical annulations. ^ For example, the sequence of addition-cyclization-cyclization shown in Figure 5 is a powerful way to make cyclopenta-fused q u i n o l i n e s , as has been shown by a recent synthesis of camptothecin and more than two dozen members of the camptothecin family of antitumor agents. 2

14

15

Figure 5 a .

An

Addition-Cyclization-Cyclization


68

Figure 5b.

Application to Camptothecin ο

ο


hv Me3SnSnMe3

,0 OH

Ο

Camptothecin 45-63%

IV.

Sequences of I n t e r m o d u l a r Reactions Only

Sequences of intramolecular reactions are the most difficult to conduct because they come dangerously close to polymerizations. It is possible to use alternating electronic requirements to control selectivity in a double addition. For example, i f a nucleophilic radical is generated in the presence of both an electron rich and an electron poor alkene, it w i l l add to the electron poor alkene first. The resulting electrophilic radical w i l l add to the electron rich alkene, so that the order of the double addition is controlled. But there now is a major problem because the last radical is also nucleophilic, and appears destined to repeat the fate of the first radical. The result is a well known alternating copolymerization. H o w can a chain transfer reaction rescue the double addition sequence from polymerization? The general solution to this fundamental selectivity problem is simple—the chain transfer reaction should be rendered unimolecular. Indeed, this is the logical reversal of the popular synthetic mode of operation, which involves conducting intramolecular radical additions (radical cyclizations) by using bimolecular chain transfer reactions. The same kinds of selectivity benefits can be gained by using unimolecular chain transfer reactions ( U M C T ) to conduct intermolecular radical addition reactions or other types of radical sequences. Previous work has focused on using allyl stannanes and related molecules as U M C T reagents. But hydrogen transfer is the most popular chain transfer reaction, so we have been developing silicon hydrides as U M C T reagents. Normal silicon hydrides have C - H bonds that are too strong to function as hydrogen donors i n bimolecular reactions with radicals; however, intramolecular hydrogen transfer reactions w i l l still occur. Thus, the problem of competing bimolecular reactions is solved by choosing a chain transfer reaction that w i l l only work intramolecularly; chain transfer cannot occur until the radical with the U M C T option is produced. A n example of a U M C T reagent that has been synthesized and used i n Giese reactions is shown in Figure 6 . These reactions give high yields without the usual requirements for excess alkene (only 1 equiv is used) or high dilution (0.5-1.0 M are the typical reaction conditions). B y using (TMS)4Si as an initiator, tin-free reactions can be conducted. Beyond these practical improvements, the U M C T method can be used to 16

17

1 6


69

selectively conduct bimolecular reactions that would be considered impossible by standard methods. This is illustrated by the last example in Figure 6. In this case, both the initial radical and the adduct radical are tertiary ester-substituted radicals, and they could never undergo competing bimolecular reactions (addition/hydrogen transfer) at different rates—selectively is impossible and ratios of adducts (reduced, mono, d i , tri, etc.) w o u l d be statistical. However, by using U M C T methods, control is straightforward because only the adduct radical can undergo intermolecular hydrogen transfer.


Figure 6.

Examples of Giese Reactions Conducted by the U M C T Method C0 Me

C0 Me

2

2

10% (Bu Sn) 3

SiPho

2

•

-or-

10% (TMS) Si 'BuOH, 2% H 0 80°C, 12h 0.5M 4

2

1 equiv

1 equiv

1y

OH

I

SiPh

2

-80% isolated yield

75% - 85% isolated yields for other Γ - and 2°-radicals

e

V.

1

u i v

1 equiv

69%

Conclusions and Outlook

Over the past 15 years, many of the basic concepts of how to plan and conduct tandem radical reactions have been laid out. But the types of transformations that can be conducted by radical reactions continues to expand rapidly, and imaginative new combinations of reactions continue to be introduced regularly. Thus, the prospects for research in this area continue to be very bright. Acknowledgments I express my sincere gratitude to all the present and former coworkers in my group who have worked i n the "tandem radical" area. M a n y of their names are listed i n the references. I also thank the National Institutes of Health and the National Science Foundation for sustained funding of our program.


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2.

3.

4. 5. 6. 7. 8.

9. 10. 11.

a) Wender, P. A. Chem. Rev. 1996, 96, 1. b) Ho, T.-L. Tandem Organic Reactions; Wiley-Interscience: NY, 1992, pp 398. c) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. Eng. 1993, 32, 131. a) Bertrand, M. P. Org. Prep. Procedure Int. 1994, 26, 257. b) Bunce, R. A. Tetrahedron 1995, 51, 13103. c) Little, R. D. Chem. Rev. 1996, 96, 93. d) Malacria, M . Chem. Rev. 1996, 96, 289. e) Molander, G. Α.; Harris, C. R. Chem. Rev. 1996, 96, 307. f) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195. g) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177. h) Snider, Β. B. Chem. Rev. 1996, 96, 339. i) Tietze, L. F. Chem. Rev. 1996, 96, 115. j) Wang, Κ. K. Chem. Rev. 1996, 96, 207. k) Koert, U. Angew. Chem. Int. Ed. 1996, 35, 405. a) Giese, B. "Radicals in Organic Synthesis", Pergamon: Oxford, 1986. b) Motherwell, W. B.; Crich, D. "Free Radical Chain Reactions in Organic Synthesis", Academic Press: London, 1991. c) Curran, D. P. "The Design and Application of Free Radical Chain Reactions in Organic Synthesis." Synthesis 1988, 417-439 and 489-513. d) Curran, D. P. "Radical Addition Reactions", In Comp. Org. Syn. Β. M . Trost and I. Fleming, Ed.; Pergamon: Oxford, 1991; Vol. 4; pp 715-778. e) Curran, D. P. "Radical Cyclizations and Sequential Radical Reactions", In Ibid. Vol. 4; pp 779-832. Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188. a) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118, 2531. b) Studer, Α.; Hadida, S.; Ferritto, R.; Kim, S. Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823. Curran, D. P. In Free Radicals in Synthesis and Biology, 1989; Vol. Nato Asi Ser., Ser. C, 260; pp 27. Curran, D. P. Synlett 1991, 63. a) Curran, D. P.; Kuo, S. C. J. Am. Chem. Soc. 1986, 108, 1106. b) Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943. c) Curran, D. P.; Chen, M.-H. Tetrahedron Lett 1985, 26, 4991. d) Curran, D. P.; Chen, M.-H.; Leszczweski, D.; Elliott, R. L.; Rakiewicz, D. M . J. Org. Chem. 1986, 51, 1612. e) Curran, D. P.; Kuo, S. C. Tetrahedron 1987, 43, 5653. f) Fevig, T. L.; Elliott, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988, 110, 5064. g) Curran, D. P. In Adv. Free Radical Chem.; D. D. Tanner, Ed.; JAI, Greewich, CN: 1990; Vol. 1; pp 121. h) Curran, D. P.; Wang, S. Tetrahedron 1993, 49, 755. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091. Dr. M. Yu and Mr. D. Christen, unpublished observations. a) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem. Soc. 1988, 110, 5900. b) Snieckus, V.; Cuevas, J. C.; Sloan, C. P.; Liu, H.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 896. c) Curran, D. P.; Abraham, A. C.; Liu, H. T. J Org Chem 1991, 56, 4335. d) Curran, D. P.; Kim, D.; Ziegler, C. Tetrahedron 1991, 47, 6189. e) Curran, D. P.; Yu, H. S. Synthesis 1992, 123. f) Curran, D. P.; Somayajula, Κ. V.; Yu, H. S. Tetrahedron Lett. 1992, 33, 2295. g) Curran, D. P.; Abraham, A. C. Tetrahedron 1993, 49, 4821. h) Curran, D. P.; Demello, N. C. J. Chem. Soc., Chem. Commun. 1993, 1314. i) Curran, D. P.; Shen, W. J. Am. Chem. Soc. 1993, 115, 6051. j) Curran, D. P.; Liu, H. T. J. Chem. Soc., Perkin Trans. 1 1994, 1377. k) Curran, D. P.; Yu, H. S.; Liu, H. T. Tetrahedron 1994, 50, 7343. l) Yamazaki, N.; Eichenberger, E.; Curran, D. P. Tetrahedron Lett. 1994, 35, 6623. m) Curran, D. P.; Xu, J. Y. J. Am. Chem. Soc. 1996, 118, 3142.


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Controlled Radical Polymerization - American Chemical Society

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