Reactive Intermediate Chemistry

R'' = Me or Ph.

Figure 13.32. Photolysis of N-aminopyridinium ions.

trapping agents (such as electron-rich aromatic compounds) have overlapping absorption bands. However many biochemically relevant nitrenium ions are in fact singlet, aromatic substituted species and the important DNA damaging reactions occur in aqueous media.

Photolysis of N-aminopyridinium ions (53) also can be used to create nitrenium ions.110,111,138–147 In this reaction, photolysis and N N bond heterolysis generates

a neutral pyridine fragment (54) and the corresponding nitrenium ion (Fig. 13.32). This route is, in principle, capable of producing any primary or secondary nitrenium ion depending on the substitution in the precursor. Salts 53 typically exhibit long wavelength charge-transfer absorption bands in the near-UV or low wavelength visible region of the spectrum. For example, 1-(N,N-diphenylamino)pyridinium ion has an absorption maximum at 380 nm.145 High wavelength absorption bands allow for the selective photolysis of the precursor in the presence of traps, such as arenes, which might otherwise compete for the light.

The principal disadvantage to the aminopyridinium ion route is the accessibility of the precursors. None are available commercially, and most require multistep syntheses giving relatively low yields. Another potential pitfall is the formation of the pyridine byproduct (54). Pyridines can function as nucleophiles, attacking the nitrenium ion and creating complex mixtures. Finally, pyridinium ions are electron deficient and can serve as good ground-state electron acceptors. Many of the stable products generated from nitrenium ion reactions are amines and are relatively easy to oxidize. Thus, a potential problem is secondary reaction, whereby primary photoproducts are oxidized by the precursor.

Davidse et al.148 described the photolysis of N-chloroamine and hydroxylamine esters (55) to form nitrenium ions by heterolysis (Fig. 13.33). As noted above, these reactants also yield nitrenium ions through thermal chemistry, albeit more slowly.

R1 = Aryl, R2 = H or CH2-aryl, R3 = Ac

Figure 13.33. Arylnitrenium ions through photoheterolysis.

618 NITRENIUM IONS

Photolysis in polar media (e.g., H2O–MeCN mixtures) results in the same products observed from thermal generation. In addition, however, the parent amine, which is not observed in the thermal reactions, is formed photochemically. This finding suggests that there may be a competition between heterolysis and homolysis in the photochemical reaction. It has also been suggested that the amine might result from formation of the triplet nitrenium ion. In any case this competing process along with the instability of the precursors has limited interest in this photochemical route.

3.3. Electrochemical Methods

Nitrenium ions can be generated from the electrochemical oxidation of amines (Figs. 13.34 and 13.35). Rieker et al.149–152 used a similar procedure to generate

40-dimethylamino-4-(2,6-di-tert-butyl)biphenylylnitrenium ion 58 from precursor 57. Both this nitrenium ion and its corresponding dication 59 are sufficiently stable to be characterized by NMR and UV–vis spectroscopy.

The only nitrenium ions that have been directly characterized by electrochemical generation are those that are kinetically stabilized by resonance and steric hindrance. The main limitation to the electrochemical method appears to be competing

polymerization processes (Fig. 13.7). It is known that electrolysis of aniline and its simple derivatives provides poly(aniline).27,29,153 The polymerization mechanism is

controversial, but the more recent experiments point to the coupling of amine cation radicals. Others have suggested that the elongation step occurs via addition of a nitrenium ion to an unconverted amine. In any case, the use of the electrochemical method for detailed study of nitrenium ions obviously requires that the competing polymerization process be suppressed.

Figure 13.34. Nitrenium ions from electrochemical oxidation of benzidine derivatives.

Figure 13.35. Nitrenium ions through b-decay of tritiated amines.

Nefedov et al.154 reported the generation and study of nitrenium ions by a novel method: radiochemical decay (Fig. 13.35). Tritium is known to decay by b-particle emission, whereby a neutron is converted into a proton, and has the effect of converting the tritium into 3He. Thus a tritium-substituted amine (60), upon radiolytic decay, is converted into a nitrenium ion–He complex (61). It is assumed that the helium atom is weakly bound and dissociates. These workers used this method to generate phenylnitrenium ion in benzene and toluene. One interesting property of this route to nitrenium ions is that it is possible to generate a truly ‘‘free’’ nitrenium ion. The b-particle byproduct is ejected with sufficient energy that it can be presumed not to interact with the nitrenium ion. On the other hand, this nuclear decay has a half-life of 12.2 years. Thus, high conversion of the starting material over practical time scales is not possible. For example, the study of phenylnitrenium ion in benzene required a reaction time of several months.

4. REACTIONS OF NITRENIUM IONS

There have been numerous specific reactions attributed to nitrenium ions over the years. Space constraints prohibit an exhaustive catalogue, so that the reactions described below should be understood to be typical examples that highlight important trends, rather than a comprehensive listing. In particular, we emphasize reactions where the involvement of the nitrenium ion has been well established or at least widely acknowledged. As noted above, there are numerous reactions of electrophilic nitrogen species in which the involvement of a nitrenium ion is possible but where the data are insufficient to permit any firm conclusion. Interested readers are encouraged to consult the Additional Reading section for further examples.

4.1. Singlet-State Rearrangement and Elimination Reactions

By analogy to carbenium ions, it can be expected that alkylnitrenium ions will experience 1,2-alkyl and hydride shifts. These would presumably be orbital symmetry allowed reactions that convert the nitrenium ion into a more stable iminium ion. This idea is supported by several theoretical studies suggesting that simple

Bz = benzoyl

Figure 13.36. 1,2-Alkyl shift of an alkylarylnitrenium ion.

65

Figure 13.37. A 1,2-hydride shift in a N-methyl-N-arylnitrenium ion.

singlet alkylnitrenium ions should rearrange or eliminate, in some cases with no detectable barrier.66,73,155

The observation of apparent 1,2-alkyl and hydride shift products was the basis of much discussion of alkylnitrenium ion chemistry several decades ago. In fact, several reactions (e.g., Fig. 13.12) reported by Gassman and others, were ascribed to nitrenium ions. Unfortunately, it is in practice very difficult to determine whether such products resulted from reaction of a free nitrenium ion or whether they occurred concertedly with the dissociation of the leaving group.

The situation is different for alkylarylnitrenium ions. Haley first demonstrated that a N-1-adamantyl-N-(2-benzoylphenyl) nitrenium ion 62 (Fig. 13.36) could be generated by photolysis of an anthranilium ion.112 In this case, rearrangement of the adamantyl ring, to give products from hydrolysis of 63, competes with addition reactions, giving 64. Similar experiments carried out on N-tert-butyl-N-arylni-

trenium ions also showed that the 1,2-shift of a methyl group competes with additions of nucleophiles to the aryl ring.117,156,157 In the latter cases, the formation

of the alkylarylnitrenium ion was verified by LFP.

Hydride shifts are more difficult to ascertain. This process gives a N-protonated iminium ion, which is the conjugate acid of an imine. The latter could also result when proton transfer occurs from the alkylnitrenium ion to a base. Chiapperino and Falvey143 examined the reactions of N-methyl-N-phenylnitrenium ion 65 (Fig. 13.37) in the presence and absence of chloride. It was found the yield of aniline (resulting from hydrolysis of the product iminium ion) was unaffected by added base. This finding ruled out a deprotonation process and led to the conclusion that a 1,2-hydride shift had occurred. Cramer et al.76 modeled this process using ab initio methods.

Diarylnitrenium ions have not been studied in detail, but work on Ph2Nþ (66, Fig. 13.38) shows that, in the absence of nucleophiles, the primary decay pathway

Figure 13.38. Cyclization of a diarylnitrenium ion.

is a cyclization reaction to form carbazole 68.144,145 This apparently proceeds via a Nazarov-like cyclization to give the carbozole tautomer 67. The latter undergoes a hydrogen shift and deprotonation to give the observed product. Typically, the isolated yields of carbazole are low because it reacts with nitrenium ion at the diffusion limited rate giving a poorly defined set of oxidized oligomeric products. Maximal yields of carbazole are obtained only when the reaction is carried out under highly dilute conditions.144

4.2. Singlet-State Reactions with n Nucleophiles

The only well-characterized addition of an n nucleophile to a nonaromatic nitre-

nium ion is the reaction of singlet NHþ2 with water or methanol to provide, respectively, NH2OH and NH2OMe (Fig. 13.39).158

In many studies, singlet arylnitrenium ions 69 have been generated in aqueous solutions. The primary decay route under such conditions is addition of water (or

alcohols) to the para (70) and ortho positions (71) of the aromatic ring (Fig. 13.40).39,44,78,89,159–161 Addition of water or hydroxide to the nitrenium center

has not been observed. This reaction pathway is very general and most n-type nucleophiles (N3 , halides, alcohols, amines) show analogous behavior. Mixtures of ortho and para adducts are seen with the more reactive nucleophiles which exhibit less selectivity, whereas less reactive nucleophiles show a preference for para addition.

There are some minor discrepancies in the experimental literature regarding the regiochemistry of this addition. Some workers report a firm preference for para addition, even in situations where the para position is substituted.160 Other studies of similar, but not identical nitrenium ions, show ortho products as the major adducts.162 It is likely that many of these differences can be traced to the reversibility of the addition process. For example, the initial adduct formed from water addition to arylnitreniums is an oxonium ion (72 or 73), a species that can also

Figure 13.39. Addition of water and alcohols to the singlet parent nitrenium ion.

Figure 13.40. Addition of nucleophiles to the ring carbons of arylnitrenium ions.

Figure 13.41. Addition of alcohols and water to arylnitrenium ions.

serve as a good leaving group (Fig. 13.41). Thus in some cases, especially under conditions where the concentration of base is low, the isolated adducts might reflect a thermodymic rather than a kinetic preference.

These addition reactions require formation of an imino-cyclohexadiene intermediate (Fig. 13.41). In cases where the ipso substituent is a proton, tautomerization to form the substituted aniline derivative is fast, and such intermediates have not been isolated. On the other hand, in situations where the nucleophile adds to a substituted ring position, the intermediate can undergo further secondary reactions. For example Novak et al.160 showed that the 4-biphenylylnitrenium ion reacts with water forming the imine cyclohexadiene intermediate 74, which in turn experiences an acid-catalyzed phenyl shift reaction to 76 via 75 (Fig. 13.42).

In cases where the substituent is a halide, the initial adduct is particularly reactive. For example, trapping of N-(4-chlorophenyl)-N-methylnitrenium ion 77 with methanol gives a variety of products (79–81).163 These result from various homolytic and heterolytic fragmentations of the intermediate 78. (Fig. 13.43).

With Br 164 and other reducing nucleophiles such as thiols,165 there is a competing inner-sphere reduction pathway that competes with adduct formation (Fig. 13.44). The initial step, as outlined in Figure 13.43, involves addition of the nucleophile to the ring to give 82. However, instead of rearranging, an additional Br combines with the original Br to form Br2 and the conjugate base of the parent amine 83. Thus the net effect of this process is a reduction of the nitrenium ion.

Figure 13.42. Addition followed by a 1,2-phenyl shift.

Figure 13.43. Addition and secondary reactions of N-methyl-N-(4-chlorophenyl)nitrenium ion.

Figure 13.44. Bromide reduction of arylnitrenium ions.

In some cases, the initial adduct can combine with an additional nucleophile to give a diadduct. This process is particularly likely when the driving force for aromatization of the monoadduct is weak or absent. For example, Novak has shown that heteroarylnitrenium ion 85 is trapped at first by water and then by an additional nucleophile to give the diadduct 87 (Fig. 13.45).166 Likewise, Bose et al.167 reported the dihydroxylation of the nitrenium ion 88 derived from stilbene

Figure 13.45. Addition of two nucleophiles to a heteroarylnitrenium ion.

624 NITRENIUM IONS

Figure 13.46. Sequential addition of water to a 4-stilbenylnitrenium ion.

(Fig. 13.46). The initial addition to the b-alkenyl carbon gives a imine quinone methide 89. The latter rearomatizes upon addition of another water molecule to give dihydroxyl adduct 90.

4.3. Singlet-State Reactions with p Nucleophiles

The addition of nitrenium ions to p nucleophiles (arenes and alkenes) has attracted attention as a potentially useful synthetic transformation. Takeuchi et al.140–142 and Srivastava et al.158 showed that the parent nitrenium ion is capable of adding to simple aromatics such as benzene, toluene and anisole (91) to give aniline derivatives (92a–c, Fig. 13.47). Unfortunately, these reactions give a distribution of regioisomers as well as products derived from competing hydride and/or hydrogen atom transfer.

Arylnitrenium ions are likewise capable of adding to p nucleophiles. With substituted aromatics (e.g., toluene) there exists the possibility of three reactive sites on the nitrenium ion (the nitrogen, orthoand para-ring positions), along with up to three possible sites on the arene (ortho, para, and meta in the case of a monosubstituted trap). Thus in a typical case there is the possibility of nine distinct regioisomers. Obviously, any synthetic utility of such chemistry relies on the ability of

the reagents to react in a selective manner.

An example of this is illustrated by a recent study of Takeuchi et al.,83,87 summarized in Figure 13.48. The phenylnitrenium ion was generated, in the presence of anisole, from N-hydroxylaniline using triflouroacetic acid and polyphosphoric acid.

Figure 13.47. Electrophilic addition of NHþ2 to arenes.

NHPh

NHPh

NHPh

OMe

NHPh

OMe

OMe

OMe

Figure 13.48. Addition of phenylnitrenium ion to anisole.

In general, six of the nine potential isomers are found in significant yields. There is a slight preference for coupling between the nitrenium ion’s nitrogen and the para position on anisole to give 93, followed by 94, then 95 and 96.

In a recent study by McIlroy and Falvey168 on N,N-diphenylnitrenium ion [generated by photolysis of the corresponding N-amino(2,4,6-trimethylpyridinium) ion], it was shown that Ph2Nþ is trapped by 1,3,5-trimethoxybenzene (97) to give adducts dominated by coupling to the 4-position on the nitrenium ion 99, along with nearly equal amounts of the N (98) and ortho adducts (100) (see Fig. 13.49). Apparently the additional aryl ring suppresses reaction at N and, to some extent, at the ortho positions through steric hindrance. Obviously, further development of this synthetic strategy will require more selective reactions.

Chiapperino et al.162 examined the behavior of N-methyl-N-4-biphenylylnitre- nium ion 101 (R ¼ Me) with a series of arenes. In most cases, the reactions gave predominantly ortho adduct along with significant amounts of the reduction

Ar = 2-(1,3,5-trimethoxyphenyl)

Figure 13.49. Addition of N,N-diphenylnitrenium ion to 1,3,5-trimethoxybenzene.

Figure 13.50. Addition–migration of N,N-dimethylaniline to 4-biphenylylnitrenium ion.

product, N-methyl-N-4-biphenylyamine. In some cases, N adducts were detected, but they were minor products, if they were formed at all. In this study, no adducts derived from para addition were found. It was argued that the initial adduct resulting from para addition suffered a relatively slow homolytic dissociation to give the N-methyl-N-(4-biphenylyl)aminyl radical. The latter abstracted an additional hydrogen atom to provide the reduction product.

Novak et al.169 examined the addition of N,N-dimethylaniline to 4-biphenylyni- trenium ion (101, R ¼ H) and found significant yields of meta adduct 103. This product was attributed to an initial addition coupling the para position of the nitrenium ion to the para position of the aniline to give 102, followed by an acidcatalyzed 1,2-migration of the trap to the meta position (Fig. 13.50). In this case, the solvent was water. In the previous case, the solvent was acetonitrile. Presumably, the difference in the fate of the initial para adduct is governed by the solvent. The 1,2-shift requires a general base, which is abundant in the buffered aqueous solutions used by Novak et al.169 The homolytic dissociation is more probable in aprotic media such as MeCN.

More promising from a synthetic point of view are the reactions of nitrenium ions that are covalently linked to aromatic substrates. The constraints provided by the linker generally reduce or eliminate the problem of forming multiple regioisomers. Wardrop et al.25,26 applied the cyclization of acylalkoxynitrenium ions (e.g., 104) and report good yields of spiro-N-alkoxypyrolidone derivatives (e.g., 105), which are intermediates in the synthesis of several natural products, such as TAN1251A (Fig. 13.51).

Figure 13.51. Cyclization of a N-acyl-N-alkoxynitrenium ion in the synthesis of TAN1251A.