Cycloaddition Reactions in Organic Synthesis

7.3 Nitrone and Nitronate Cycloadditions 271

Scheme 7.23

Scheme 7.24

but no switch of the mode of enantioselectivity was observed unlike the two cases mentioned above (Scheme 7.25). When magnesium sulfate was used instead of MS 4 Å in the nickel(II) complex-catalyzed reaction, equally excellent endo and enantioselectivities were achieved, indicating that MS 4 Å worked simply as a dehydrating agent in this case. This is very different from the case observed by Jørgensen’s group [28]. It is concluded on the basis of these results that the transition state structure having a trigonal bipyramid complex F (Scheme 7.7) is responsible for the high endo and enantioselectivities. In the presence of water, an octahedral transition state structure D (Scheme 7.7) may have been involved leading to poor selectivities due to ineffective chiral shielding and the diminished steric demand for the selective formation of the endo cycloadduct [57].

272 7 Aqua Complex Lewis Acid Catalysts for Asymmetric 3+2 Cycloaddition Reactions

Scheme 7.25

7.3.3

Nitronate Cycloadditions

Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct - elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74].

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-1,2-oxazine N-oxide, as fiveand six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-1-nitropropane and 4-iodo-1- nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-1,2-oxazino[2,3- b]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-1,2-oxazino[2,3-b]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions.

We are the first group to succeed with the highly enantioselective 1,3-dipolar cycloadditions of nitronates [75]. Thus, the reaction of 5,6-dihydro-4H-1,2-oxazine N- oxide as a cyclic nitronate to 3-acryloyl-2-oxazilidinone, at –40 C in dichloromethane in the presence of MS 4 Å and R,R-DBFOX/Ph·Ni(II) complexes, gave a diastereomeric mixture of perhydroisoxazolo[2,3-b][1,2]oxazines as the ring-fused isoxazolidines in high yields. The R,R-DBFOX/Ph aqua complex prepared from

7.3 Nitrone and Nitronate Cycloadditions 273

Scheme 7.26

Ni(ClO4)2·6H2O showed a little better enantioselectivity than the anhydrous complex. Although the uncatalyzed reaction was highly exo selective (cis/trans = 3 : 97), the catalyzed reactions were very poor in diastereoselectivity, a mixture of endo and exo cycloadducts being formed. We expected that this poor diastereoselectivity would not be a serious problem since the same enantioface should be involved at the 2-position of the diastereomeric cycloadducts (Scheme 7.27). The best enantioselectivity (cis: > 99% ee, trans: 94% ee) was observed when the reaction was catalyzed by R,R-DBFOX/Ph·Ni(SbF6)2 (50 mol%). With the decreased amount of catalyst (10 mol%) still a satisfactory level of enantioselectivity was observed for the cis cycloadduct (94% ee).

The parent five-membered nitronate having no substituent at the 3-position was too unstable to be isolated. However, 3-substituted derivatives were highly stabilized. Especially, the 3-ethyl derivatives having a terminal electron-withdrawing substituent are readily available by the dehydrochlorination of 3-chloro-1-nitropropane in the presence of electron-deficient alkenes. It was our delight that the reaction of 3-al- kyl-substituted five-membered nitronates was also successfully catalyzed by R,R- DBFOX/Ph·Ni(SbF6)2 complex to at room temperature. This reaction was highly endo-selective (cis/trans = 91 : 9) and enantioselective for the endo cycloadduct (92% ee).

On the basis of the assumed reaction mechanism, we expected that the same enantiofaces participated in the formation of two diastereomers of cycloadducts. If our expectation is correct, both diastereomers of the ring-fused cycloadduct should provide the same enantiomer upon the ring cleavage across the O(7)–N(8) bond. Accordingly, the diastereomer mixture was submitted to the acid-catalyzed transformation to 2-isoxazoline derivative. When the mixture was treated with trifluoroacetic acid and then with trifluoroacetic anhydride, the corresponding 2-oxazoline was produced through the ring opening of isoxazine ring of the ring-fused cycloadduct in high yield with an excellent enantioselectivity (85%, 97% ee). Thus, the catalyzed asymmetric 1,3-dipolar cycloaddition of cyclic nitronates was achieved for the first time. This reaction corresponds to an equivalent to the catalyzed asymmetric cycloadditions of a functionalized nitrile oxide.

274 7 Aqua Complex Lewis Acid Catalysts for Asymmetric 3+2 Cycloaddition Reactions

Scheme 7.27

7.3.4

Reactions of Monodentate Dipolarophiles

Monodentate dipolarophiles such as acrolein, methacrolein, and -bromoacrolein could be successfully utilized in the R,R-DBFOX/Ph-transition metal complex-cata- lyzed asymmetric nitrone cycloadditions [76]. The reactions of N-benzylideneani- line N-oxide with acrolein in the presence of the nickel(II) aqua complex R,R- DBFOX/Ph·Ni(ClO4)2·3H2O (10 mol%) and MS 4 Å produced a mixture of two regioisomers (5-formyl/4-formyl regioisomers: ca 3 : 1). However, enantioselectivities for the both regioisomers were excellent when the reaction was performed at –10 C (up to 98% ee, Scheme 7.28).

The nitrone cycloaddition reactions with methacrolein were exclusively regioselective when catalyzed by the R,R-DBFOX/Ph·Ni(ClO4)2·3H2O in the presence of MS 4 Å leading to the 5-formyl derivative with high enantioselectivities (up to 97% ee), while the reactions catalyzed by the R,R-DBFOX/Ph aqua zinc(II) complex were less selective to give a mixture of two regioisomeric cycloadducts. On the other hand, -

7.3 Nitrone and Nitronate Cycloadditions 275

Scheme 7.28

bromoacrolein was much more reactive than methacrolein and this dipolarophile produced the 4-formyl regioisomeric cycloadducts in an exclusive regioselective manner in the nitrone cycloadditions catalyzed by the R,R-DBFOX/Ph complexes. Especially, the aqua zinc(II) complex R,R-DBFOX/Ph·Zn(ClO4)2·3H2O was more effective than the anhydrous zinc(II) complex and the aqua nickel(II) complex, absolute diastereoand enantioselectivities being observed.

It was our great surprise that the R,R-DBFOX/Ph complex catalysts derived from Zn(ClO4)2·6H2O, Zn(OTf)2, and ZnI2 were found to be equally effective as shown with the following results: Zn(ClO4)2·6H2O (–40 C, 83% yield, ds > 99%, ee > 99%), Zn(OTf)2 (–40 C, 94% yield, ds > 99%, ee > 99%), and ZnI2 (rt, 72% yield, ds = 94%, ee = 95%) (Scheme 7.29). The perchlorate catalyst is cationic, while the iodide catalyst should be neutral since the zinc-iodine bond can not be readily cleaved under the reaction conditions. This indicates that the R,R-DBFOX/ Ph·ZnI2 catalyst should have only one vacant position for the coordination of dipolarophile and hence this catalyst belongs to a “pin hole type Lewis acid catalyst” like aluminum tris(2,6-diphenylphenoxide) (ATPh) [77]. If this is the case, the zinc iodide catalyst must have a relatively strong Lewis acidity since no aggregated form is structurally possible. We believe that the R,R-DBFOX/Ph-zinc(II) iodide complex catalyst has a high catalytic activity because of its monomeric form.

276 7 Aqua Complex Lewis Acid Catalysts for Asymmetric 3+2 Cycloaddition Reactions

Scheme 7.29

7.3.5

Transition Structures

Absolute configurations of the isoxazolidines obtained in the nitrone cycloaddition reactions described in Schemes 7.21 and 7.22 were determined to be 3S,4R,5S structure by comparison of the optical rotations as well as retention times in a chiral HPLC analysis with those of the authentic samples. Selection of the si face at C position of 3-crotonoyl-2-oxazolidinone in nitrone cycloadditions was the same as that observed in the Diels-Alder reactions of cyclopentadiene with 3-croto- noyl-2-oxazolidinone in the presence of the R,R-DBFOX/Ph·Ni(ClO4)2·3H2O complex (Scheme 7.7), and this indicates that the s-cis conformation of the dipolarophile has participated in the reaction.

Nitrones are a rather polarized 1,3-dipoles so that the transition structure of their cycloaddition reactions to alkenes activated by an electron-withdrawing substituent would involve some asynchronous nature with respect to the newly forming bonds, especially so in the Lewis acid-catalyzed reactions. Therefore, the transition structures for the catalyzed nitrone cycloaddition reactions were estimated on the basis of ab-initio calculations using the 3-21G* basis set. A model reaction includes the interaction between CH2=NH(O) and acrolein in the presence or absence of BH3 as an acid catalyst (Scheme 7.30). Both the catalyzed and uncatalyzed reactions have only one transition state in each case, indicating that the reactions are both concerted. However, the synchronous nature between the newly forming O1–C5 and C3–C4 bonds in the transition structure TS-J of the catalyzed reaction is rather different from that in the uncatalyzed reaction TS-K. For example, the bond lengths and bond orders in the uncatalyzed reaction are 1.93 Å and 0.37 for the O1–C5 bond and 2.47 Å and 0.19 for the C3–C4 bond, while those in

7.3 Nitrone and Nitronate Cycloadditions 277

the catalyzed reaction are 1.88 Å and 0.59 for the O1–C5 bond and 2.94 Å and 0.05 for the C3–C4 bond. Apparently, the asynchronism in the bond formation of O1–C5 precedes to that of C3–C4 in the transition state of the catalyzed reaction.

Scheme 7.30

The simple structure of R,R-DBFOX/Ph complex catalysts facilitates discussion of transition structures and proceeds insight into the role of MS 4 Å. On the basis of ab-initio molecular orbital calculations of a model nitrone cycloaddition, a variable temperature 1H NMR study of the substrate complex derived from DBFOX/Ph, Zn(ClO4)2, 3-acetyl-2-oxazolidinone, and the observed high catalytic activity, the nitrone cycloaddition in the presence of MS 4 Å is most likely to proceed through the transition structure TS-L with a trigonal bipyramid structure (Scheme 7.31). Face shielding by one of the 4-phenyl substituents (the top 4-phenyl) becomes very effective and the other 4-phenyl substituent (the bottom 4-phenyl) inhibits the exo approach of the nitrone. As a result, the reaction shows high endo- and enantioselectivities in the absence of water. In the reactions catalyzed by the aqua DBFOX complex in the absence of MS 4 Å, a water molecule coordinates on the nickel ion so that octahedral transition structure TS-M becomes predominant. The reaction site of the coordinated substrate in TS-M is more open for the approach of nitrone, and both the si and re faces (C ) allow the attack of nitrone, showing low enantioselectivity. In addition, the exo approach of nitrone leading to 3,4-cis isoxazolidines is not difficult, and poor endo selectivity results. Even when a trace of water is present, TS-L may participate predominantly to the reaction since the octahedral complex catalyst should be less reactive than the trigonal bipyramid complex catalyst based on the trans effect by the aqua ligand.

278 7 Aqua Complex Lewis Acid Catalysts for Asymmetric 3+2 Cycloaddition Reactions

Scheme 7.31

7.4

Diazo Cycloadditions

No single examples have been reported so far for the catalyzed asymmetric diazoalkane cycloadditions. Based on the kinetic data on the relative reaction rates observed by Huisgen in the competitive diazomethane cycloadditions between 1- alkene and acrylic ester (Scheme 7.32), it is found that diazomethane is most nucleophilic of all the 1,3-dipoles examined (kacrylate/k1-alkene = 250 000) [78]. Accordingly, the cycloadditions of diazoalkanes to electron-deficient alkenes must be most efficient when catalyzed by a Lewis acid catalyst. The author’s group has become aware of this possibility and started to study the catalyzed enantioselective diazoalkane cycloadditions of 3-(2-alkenoyl)-2-oxazolidinones.

Diazoalkane cycloadditions to alkenes produce 1-pyrazolines as the initial cycloadducts which are not so quite stable that these undergo spontaneous 1,3-proton

7.4 Diazo Cycloadditions 279

Scheme 7.32

migration leading to thermodynamically more stable 2-pyrazoline derivatives [79]. Usually a more acidic hydrogen moves and consequently the chirality at this position disappears. Carreira and co-workers have recently reported the diastereoselective diazoalkane cycloadditions of trimethylsilyldiazomethane to chiral alkenes [80]. Upon treatment with a protonic acid or acid chloride-silver triflate after the completion of reaction, the 1-pyrazolines as the initial cycloadducts underwent a regioselective protodesilylation or acyldesilylation of the 2,3-diazoallylsilane moiety masked in the resulting heterocycles to produce 2-pyrazolines (Scheme 7.33).

Scheme 7.33

7.4.1

Screening of Lewis Acid Catalysts

Accordingly, we examined the cycloaddition reactions using trimethylsilyldiazomethane and 3-crotonoyl-2-oxazolidinone in the presence of a wide variety of Lewis

280 7 Aqua Complex Lewis Acid Catalysts for Asymmetric 3+2 Cycloaddition Reactions

acid catalysts (25 mol%) in dichloromethane at room temperature [81]. Acetic anhydride was used for the electrophile to induce the regioselective desilylation. As shown in the table of Scheme 7.34, some Lewis acid catalysts showed significant rate acceleration, titanium and ytterbium salts being especially effective. Three kinds of 2-pyrazoline cycloadducts, Na, Nb, and Nc, were produced together with other products in some cases, and the product ratios depended upon the nature of Lewis acid catalysts employed. Types of products were presumably determined depending upon the difference of coordination types of the catalyst (Scheme 7.34).

Scheme 7.34

When the catalyst coordinates to the pyrazoline nitrogen and carbonyl oxygen at the step of 1-pyrazoline formation, desilylation or deprotonation takes place at the same position to give either Na or Nb, respectively. On the other hand, when the catalyst coordinates to the two carbonyl oxygens, the methine hydrogen derived from the acceptor molecule is deprotonated to give Nc. In the reaction using a Le-