41 Nitro, Nitroso, Azo, Azoxy, and Diazonium Compounds; Azides, Triazenes, and Tetrazenes
Banert, K., Science of Synthesis, (2010) 41, 1.
This volume covers the synthesis of compounds containing a nitrogen functionality bonded to sp3-hybridized carbon atoms, as shown in Table 1. However, only in the cases of nitroalkanes, nitrosoalkanes, azides, and N,N-dihaloamines are the substituents R1 and R2 strictly limited to alkyl groups. Aliphatic diazonium compounds are divided into the subclasses of short-lived alkanediazonium compounds (Section 41.7.1) and the less labile alkenediazonium compounds (Section 41.7.2). Section 41.5 includes 1,2-dialkyldiazene 1-oxides and azoxy compounds carrying a vinyl group at one of the two different nitrogen atoms. In the cases of azo compounds (Section 41.6) and tetrazenes (Section 41.10), derivatives bearing aryl, vinyl, or acyl substituents at the nitrogen functionality are described along with such compounds having only alkyl groups. A few examples of rare tetraz-2-enes with lower symmetry than that shown in Table 1 are summarized in Section 41.10.2.1.5. The section on alkyltriazenes (Section 41.9) also includes derivatives with aryl or acyl groups at the nitrogen atom, while N-nitroamines bearing aryl or vinyl groups in addition to alkyl groups are discussed in Section 41.3. In the case of both of these nitrogen functionalities, hydrogen at the sp3-hybridized nitrogen (R2 = H) is also possible. This is in contrast to N-nitrosoamines (Section 41.4), which are exclusively derived from secondary dialkyl- or alkyl(aryl)amines, or the corresponding acyl derivatives. N-Nitrosoamines originating from primary amines (R2 = H) are unstable and lead to diazonium compounds (see Section 41.7).
Table 1 Classes of Compounds Covered in Volume 41
a This section also includes N,N-dialkoxyamines [nitroso acetals, R1N(OR2)2; see Section 41.2.1.11].
b A few examples of rare tetraz-1-enes are also described (see Section 41.10.1).
N-Nitrosoamines are well known to be highly toxic and carcinogenic agents. However, some other compounds bearing other nitrogen functionalities, for example aliphatic azo or azoxy compounds, are also powerful carcinogens. Before handling such substances, the safety advice at the beginning of the corresponding sections and the corresponding references should be noted. The same holds true for the explosive properties of several product classes discussed here. Whereas azides and diazonium compounds with a high proportion of nitrogen are known to be highly energetic materials, and several nitroalkanes and N-nitroamines are utilized as commercial explosives, similar properties of other product classes, such as azo compounds, alkyltriazenes, alkyltetrazenes, and N,N-dihaloamines, should also be taken into consideration. Synthesis, handling, and reactions of nitrosoalkanes are inseparably linked with the special behavior of these compounds (Section 41.2), which are often in equilibrium with their dimers, the azo dioxides (1,2-diazene 1,2-dioxides). Furthermore, the less stable nitrosoalkanes bearing at least one α-hydrogen atom are able to equilibrate with tautomeric oximes (isonitroso compounds), which are thermodynamically more stable in most cases. Not only azo dioxides, but also aliphatic azo and azoxy compounds (Sections 41.6 and 41.5, respectively) can form E- and Z-configured stereoisomers of different stability. Thus, the configuration of these diastereomers is important for the synthesis and subsequent reactions of the corresponding substances.
The representatives of the product classes described in this volume are useful intermediates in organic synthesis and have found a variety of applications. In the case of nitrosoalkanes (Section 41.2.2, including nitroso acetals), alkenediazonium compounds (Section 41.7.2.2), azidoalkanes (Section 41.8.2), alkyltriazenes (Section 41.9.2), and N,N-dihaloamines (Sections 41.11.1, 41.11.2, 41.11.3, 41.11.4, 41.11.5, 41.11.6, and 41.11.7), applications in organic synthesis are summarized in special subsections. Moreover, a very great number of reactions starting with the compounds shown in Table 1 are described in other volumes of Science of Synthesis because these reactions serve as methods to prepare a variety of other functional groups. In several cases, however, representatives of one of the product classes described in Sections 41.1–41.11 are transformed into compounds that belong to a different product class within Volume 41. Thus, the methods of synthesis of the products shown in Table 2 are, simultaneously, applications of the corresponding starting materials in organic synthesis.
Table 2 Transformations of Representatives of a Product Class Leading to Compounds of Another Product Class of Volume 41
| Starting Material | Product | Method | Section(s) |
|---|---|---|---|
| nitroalkanes (Section 41.1 | nitrosoalkanes | reduction | 41.2.1.5 |
| [2,3]-sigmatropic rearrangement | 41.2.1.7 | ||
| nitrosoalkanes (Section 41.2 | nitroalkanes | oxidation | 41.1.1.2.10–41.1.1.2.18,41.2.2.1 |
| azoxy compounds | treatment with N,N-dihaloamines | 41.2.2.4.2, 41.5.1.2.2 | |
| treatment with azides | 41.2.2.4.2 | ||
| reduction of dimers | 41.5.1.1.4 | ||
| condensation with hydroxylamines | 41.5.1.2.1 | ||
| azo compounds | condensation with amine derivatives | 41.2.2.4.3, 41.6.1.2 | |
| N-nitrosoamines (Section 41.4 | N-nitroamines | exchange | 41.3.4.1.5 |
| diazonium compounds | cleavage | 41.7.1.1.1, 41.7.1.1.3 | |
| alkyltetrazenes | reductive dimerization | 41.10.2.1.2 | |
| aliphatic azoxy compounds (Section 41.5 | azo compounds | reduction | 41.6.2.3 |
| azo compounds (Section 41.6 | nitroalkanes | treatment with nitrogen dioxide | 41.1.1.1.32 |
| azoxy compounds | oxidation | 41.5.1.1.1 | |
| diazonium compounds | cleavage | 41.7.2.1.4.4 | |
| aliphatic diazonium compounds (Section 41.7 | azo compounds | treatment with arenes | 41.7.1 |
| alkyltriazenes | treatment with amines | 41.7.1 | |
| azidoalkanes (Section 41.8 | nitroalkanes | oxidation | 41.1.1.2.6, 41.1.1.2.7 |
| treatment with nitroalkyl anions | 41.1.1.5.7 | ||
| alkyltriazenes | treatment with organometallic reagents | 41.9.1.1 | |
| alkyltriazenes (Section 41.9 | diazonium compounds | acid-induced cleavage | 41.7.1.1.2, 41.7.2.1.4.3 |
| N,N-dihaloamines (Section 41.11 | N-nitroamines | substitution | 41.3.1.1.4 |
Synthetic methods are not restricted to the transformation of functional groups. Formation of new C—C bonds and thus construction of molecules with extended scaffolds are also important. In some cases, introduction of a novel functionality and generation of new C—C bonds are performed in one step.
The acidity of primary and secondary nitroalkanes of type 1 facilitates deprotonation to give the anion 2, which can be treated with carbon electrophiles 3 to yield the product 4 with formation of a new C—C bond (Scheme 1). Thus, alkylation of 2 using haloalkanes 3 (R3 = alkyl) or similar compounds is possible (see Sections 41.1.1.5.1–41.1.1.5.8 and 41.1.1.5.11), and acylation of 2 utilizing acid halides 3 (R3 = acyl) or other carboxylic and carbonic acid derivatives is also successful (see Section 41.1.1.5.14). Moreover, vinylation (Section 41.1.1.5.9) and arylation (Section 41.1.1.5.10) of 2 have also been reported. Treatment of anions 2 with aldehydes or ketones 5 is called the Henry reaction, and leads to β-nitro alcohols 6 (Section 41.1.1.5.12). Michael addition of 2 at the electron-deficient alkenes 7 gives rise to the products 8. If the electron-withdrawing group is itself a nitro group (EWG = NO2), product 8 includes this unit twice (see Sections 41.1.1.5.66–41.1.1.5.68). It should be noted that the Michael additions of 2 to unsaturated carbonyl compounds or nitriles are not described in this volume, but are discussed with the synthesis of ketones, esters, and nitriles in other volumes of Science of Synthesis {see, for example, Vol. 19 [Three Carbon—Heteroatom Bonds: Nitriles, Isocyanides, and Derivatives (Section 19.5.14.8.4)]}. Alkylations analogous to the reaction of nitro anion 2 with electrophiles 3 (R3 = alkyl) to give products 4 have been reported for the anions derived from nitrosoalkanes (Section 41.2.1.9) and N-nitrosoamines (Section 41.4.1.2.1). Furthermore, N-nitrosoamines deprotonated at the α-position can undergo nucleophilic addition at aldehydes or ketones similar to the Henry reaction (see Section 41.4.1.2.1).
Scheme 1 Formation of C—C Bonds in the Synthesis of Products with a Nitro Group Bound to an sp3-Hybridized Carbon
A variety of CH-acidic compounds of type 10, but also organometallic compounds or other carbon nucleophiles, react with nitroalkenes 9 to afford the Michael products 11 or similar products (see Sections 41.1.1.5.46–41.1.1.5.80). The electron-deficient nature of nitroalkenes enables several cycloaddition reactions (Sections 41.1.1.5.82–41.1.1.5.84). For example, Diels–Alder reaction of 9 and the diene 12 leads to the [4 + 2] cycloadduct 13 (Scheme 2).
The transformation of the nitroalkene 14 to the bicyclic N,N-dialkoxyamine (nitroso acetal) 18 includes the formation of two new C—C bonds (Section 41.2.1.11). Thus, nitroalkene 14 and the electron-rich alkene 15 undergo a [4 + 2]-cycloaddition reaction with inverse electron demand, and the resulting intermediate 16 is combined with the electron-poor reaction partner 17 by 1,3-dipolar cycloaddition (Scheme 3).
Scheme 2 C—C Bond-Forming Reactions of Nitroalkenes
Substitution of the halogen in α-halonitroalkanes by carbon nucleophiles such as CH-acidic compounds of type 10 or organometallic compounds is strongly influenced by the nitro group (see Sections 41.1.1.5.17–41.1.1.5.34). However, formation of new C—C bonds is certainly not restricted to nitro compounds. For example, the chlorine atom of 2-chloroalkenediazonium compounds can be substituted by electron-rich arenes (Section 41.7.2.1.6). Deprotonation of the hydrazones 19 leads to the anionic species 20, which yield the azo compounds 22 by C-alkylation or C-acylation using the electrophilic halides 21, whereas treatment with the acceptor-substituted alkenes 23 furnishes the Michael products 24 (Section 41.6.2.5). Carboazidations typically proceed via a radical mechanism starting with an α-functionalized acetic acid ester 25 and a radical initiator (Scheme 3). The terminal alkene 26 and an arenesulfonyl azide as the azide source are necessary to get the product 27 (Section 41.8.1.10.4). Radical processes are also involved in the formation of C—C bonds and the generation of a new nitrogen functionality during photochemical transformation of unsaturated alkyl nitrites into hydroxy-substituted nitrosoalkanes (41.2.1.6).
Scheme 3 Formation of C—C Bonds in the Synthesis of Aliphatic Azo Compounds and Azides
Several of the reactions shown in Schemes 1–3 can be performed enantioselectively. When the Henry reaction of 2 and 5 is conducted in the presence of an enantiopure organocatalyst, the product 6 is isolated with high diastereoselectivity and enantioselectivity (Section 41.1.1.5.12). The same is true for the Michael addition of 10 or other carbon nucleophiles, such as silyl enol ethers or organometallic compounds, at the nitroalkene 9 (Sections 41.1.1.5.49, 41.1.1.5.50, 41.1.1.5.56, 41.1.1.5.57, 41.1.1.5.62, and 41.1.1.5.75.3; for enantioselectivity alone, see Sections 41.1.1.5.54, 41.1.1.5.55, and 41.1.1.5.77.141.1.1.5.77.1). Enantioselective hydrogenation of nitroalkenes 9 has also been reported (Sections 41.1.1.5.44 and 41.1.1.5.45).
The synthesis of enantiopure azidoalkanes often starts with enantiopure halides, esters, or alcohols utilizing the clean inversion (SN2) of the nucleophilic substitution (Sections 41.8.1.4.2, 41.8.1.6.2) and the Mitsunobu reaction (Section 41.8.1.6.2). The same is true for azides prepared by ring opening of optically active β-lactones (Section 41.8.1.5.2) or epoxides and aziridines (Section 41.8.1.8). In the case of meso-epoxides 28 and meso-aziridines 30, desymmetrization and formation of the products 29 and 31, respectively, can be performed with good enantioselectivity when the ring cleavage is performed in the presence of enantiopure Lewis acids, as shown in Scheme 4 (see Section 41.8.1.8.2). Kinetic resolution of a racemic epoxide by asymmetric ring opening using azidotrimethylsilane and an enantiopure catalyst has also been reported (Section 41.8.1.8.2). Electrophilic azidation of amides 32, bearing the Evans auxiliary, successfully gives the azidoalkanes 33 with good to excellent diastereoselectivity (Section 41.8.1.9). Hydroazidation of the electron-deficient alkenes 34 leads enantioselectively to the product 35 if an appropriate catalyst is utilized (Section 41.8.1.10.1). Finally, diastereoselective bromoazidation is also possible when the substituent R2 is an enantiopure amine or sultam auxiliary. Thus, the addition product 36 is available, and on careful hydrolysis affords the carboxylic acid 37 without epimerization (Section 41.8.1.10.5).
Scheme 4 Asymmetric Synthesis of Enantiopure Azidoalkanes
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