Alkyl Nitrites as Valuable Reagents in Organic ...

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Alkyl Nitrites as Valuable Reagents in Organic Synthesis Ferenc Csende* Taxus Research Laboratory, H-4080 Hajdúnánás, Bocskai u. 22., Hungary Abstract: Alkyl nitrites are inexpensive, mild, relatively stable and easy-to-handle alkyl esters of nitrous acid, that can be prepared simply and used in various synthetic reactions. Alkyl nitrites were discovered in the 19th century and were initially used as medical vasodilators. After several years it was observed, that alkyl nitrites are useful chemical reagents, especially as efficient NO source, consequently these were used for diazotization and as nitrating agent or oxidant. In this review several important and novel applications of alkyl nitrites in organic transformations are reported.

Keywords: Alkyl nitrites, alternative Sandmeyer reaction, arylation, nitration, oxidation, oximes. 1. INTRODUCTION Alkyl nitrites are relatively stable liquids with low or medium boiling points (17-105°C) and generally with favorable solubility. There are three main types of nitrites (Scheme 1), which are practically used in preparative chemistry. Thus, n-pentyl nitrite (n-amyl nitrite) 1a, the isopentyl nitrite 1b and the t-butyl nitrite (t-BuONO or TBN) 1c are used in most cases. Sometimes i-propyl- and ethyl nitrite are also used, although these compounds are rather volatile agents. Alkyl nitrites are commercially available, however these agents can be prepared from the corresponding alcohols and sodium nitrite in sulfuric acid solution or by other alternative procedures [1, 2]. Two interesting reviews described the synthesis and applications of alkyl nitrites previously, however one of them is relatively an early review [1] while the other one is a very short summary (spotlight) [2]. We aimed to search further alkyl nitrite-induced reactions and novel results are summarized and reported in this review. Alkyl nitrites are applicated in different organic synthetic operations, using in alternative Sandmeyer reactions in the presence of halogeno-methane (e.g. CHBr3, CHCl3, CCl4 and CH2I2) or copper(II) halides as copartners, instead of conventional aqueous NaNO2-acid systems. On the other hand one-step methods were developed for the preparation of aryl azides, for the fluorodediazoniation and the deamination of aryl amines in this way using alkyl nitrites. When alkyl nitrites are reacted with alkyl-ketones or cycloalkanones αoximinoketones are formed. By the arylation of olefinic compounds (styrene, acrylonitrile, acrylic acid and others) in the deamination of arylamines by alkyl nitrites and copper (II) halides were achieved conveniently and efficiently as a variation of the Meerwein arylation reaction. When benzene was used instead of olefinic derivatives, without copper salts, unsymmetrical biaryl compounds and phenylheteroaryls were obtained in the presence of alkyl nitrites. These *Address correspondence to this author at the Taxus Research Laboratory, H-4080 Hajdúnánás, Bocskai u. 22., Hungary; Tel: +36-52-351-480; E-mail: [email protected] 1570-193X/15 $58.00+.00

reactions generally based on the formation of aryl radicals from primary amines through azo- and diazo-derivatives. Direct nitration of arylboronic acids and chemoselective nitration of phenols with tert-butyl nitrite was also developed. Moreover, among others several oxidation reactions of alcohols, of 2-nitrotoluene, 2,6-disubstituted phenols and of 1,3-diketones with alkyl nitrites were described. Finally, numerous and special or unique reactions are reviewed in this article. 2. ALTERNATIVE SANDMEYER REACTIONS 2.1. Halogenation of Aryl Amines with Halomethanes Cadogan et al. investigated the formation of aryl bromides by the reaction of the corresponding amines 2 with pentyl nitrite in CHBr3 at 100°C for about 2 hours (Scheme 2) to obtain substituted aryl bromides 3 (X = Br) in good yields (39-73 %). Using CHCl3 in similar conditions the corresponding aryl chlorides 3 (X = Cl) were prepared only in poor yields (1-28%) and deaminated benzene derivatives (X = H) as side products in 17-42 % yields. The CCl4 in the presence of n-pentyl nitrite resulted in exclusively in aryl chlorides 3 (X = Cl), in 19-55 % yields [3]. Some heteroaryl amines, such as the 3-amino-pyridine were also successfully converted to haloheteroaryl derivatives in this way [3]. Several aryl amines 2 were reacted with isoamyl nitrite-CH2I2 system at 80°C (Scheme 3) to produce iodoaryls 5 in good or excellent yields. The authors presumed, that increasing steric hindrance at the reaction site decreases the yield of product and in a plausible mechanism diazoaminobenzene 4 forms from anilines 2 with isoamyl nitrite quickly. Diazoaminobenzene 4 is stable in CH2I2 at 80°C and addition of a second equivalent isoamyl nitrite to the mixture leads to the rapid formation of 5 iodobenzenes via phenyl radicals under N2 evolution [4]. Later Tanji et al. described the synthesis of 5-bromo- and 5-iodo-3H-1,2,3-triazolo[4,5-d]pyrimidines 7a,b from the corresponding 6 amino derivative (Scheme 4) with a mixture of isopentyl nitrite and CHBr3 or CH2I2 by heating at 85°C in fairly good yields (51-65%) [5]. © 2015 Bentham Science Publishers

1282

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 H3C

O

N

Ferenc Csende H3C

O

O CH3

1a

N

O

H3C H3C

1b

O CH3

N

O

1c

Scheme 1 . NH2 R3

X

CHBr3, or CHCl3 or CCl4 n-C5H11ONO, 100°C, 2h

R1

R3

R2 2

R1 R2 3 X = Br, Cl (10-73%)

R1 = H, NO2, CO2Et R2 = H, NO2, Br, R3 = H, Cl, Br, NO2, OMe

Scheme 2 . R3

R3 NH2 R2

CH2I2

N

i-C5H11ONO, 80°C

N

H N

I R2

R1 4

2

R1 5 (36-90%)

R1 = H, NO2, 2'-NH2Ph- R2 = H, NO2, OMe R3 = H, NO2,

Scheme 3 . N i-C5H11ONO,CHBr3 85°C, 30 min N

N

N N Ph

N 6

NH2

N

N N Ph

N

Br

7a (51%)

i-C5H11ONO, CH2I2 ,85°C, 1h N

N

N N Ph

N

I

7b (65%)

Scheme 4.

2.2. Halogenation of Aryl- and Heteroaryl Amines with Elementar Halogens Aprotic iodination of aniline with amyl nitrite and molecular iodine was studied in different molar rations. In case of equivalent amount of aniline, amyl nitrite and I2 in benzene, iodobenzene 5a was obtained in 50% yield with small amounts of biphenyl. The iododeamination reaction and side reactions, furthermore the variation of the relative amounts of starting compounds and the ratios of obtained products are summarized in Scheme 5. However, increasing addition of I2 resulted in a significant amount of pdiiodobenzene 5b (33-39%), biphenyl 8 formation did not become significant until less than equivalent amount of I 2 was present [6]. The direct reaction of the unprotected 2-amino-6-chloro8-aza-7-deazapurine with isoamyl nitrite, CuI, I2, and CH2I2 was failed, giving only decomposition products. On the other hand the modified reaction of the 4-methoxybenzyl derivative, using isoamyl nitrite in refluxing THF after 1 h

afforded a 62% yield of 4-chloro-6-iodo-1-(4methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine as a key intermediate for the desired cyano derivative [7]. An efficient method was developed for the safe and reliable iododeamination of aromatic and heteroaromatic amines (Scheme 6) with 1.5 equiv. of t-butyl nitrite in a continuous flow reactor. Treatment of anilines 2 with alkyl nitrites under anhydrous and neutral conditions are widely known to lead to the aryl radical upon by heating [3]. Several earlier mechanistic studies have shown that the reaction does not proceed via diazonium ion as in classical Sandmeyer protocols, but through the intermediate diazoaminobenzene 4 that leads to the aryl radical in all cases. The conditions were optimized, so when the reaction temperature was arisen from the room temperature to 60°C it resulted shorter reaction time (~ 1hour to 25 min). It is worth noting that in similar conditions heteroaryl amines gave the corresponding ioido derivatives 9-11 (Scheme 7) in good yields [8]. Earlier 4-amino-3-arylisothiazole-5-methyl esters 12 were halodeaminated with elementary I2 and Br2 efficiently, by heating in CHCl3 for 15-30 minutes in the presence of isopentyl nitrite (Scheme 8) [9]. Similarly, the amines in refluxing THF after 0.5-1.5 hours resulted in 14 deaminated derivatives in medium or good yields depending on substituents. 2.3. Other Halogenation Methods with Alkyl Nitrite Application of mixture of isoamyl nitrite and hydrogen halides (HBr, HCl) seemed to be a mild and efficient reagent for the electrophilic aromatic halogenation of substituted arenes and heteroarenes. For example, the bromination of the functionalized indolizinones 15 with isoamyl nitriteHBr system led to the corresponding mono halogenated

Alkyl Nitrites as Valuable Reagents in Organic Synthesis

NH2

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 129 3

n-C5H11ONO, I2 benzene, reflux, 2 h

I

I +

+ I

5a

2

8

5b

Equivalent of Reagents

Ratios of Products (%)

2

Amyl Nitrite

I2

5a

5b

8

Overall Yields (%)

1

2

1

1

89

10

1

56

2

2

1

0.5

86

11

3

47

3

1

1

0.5

78

21

1

60

4

1

3

0.5

85

13

2

77

5

1

1.2

1.5

57

39

4

63

6

1

1.2

1

64

33

3

60

7

1

1.2

0.5

82

16

2

60

8

1

1.2

0.25

77

2

21

41

Entry

Scheme 5. R4

R4

t-BuONO, I2 MeCN, 60°C, 25 min, 100 psi

NH2 R3

R3

R1 R2

R1 R2

R1 = H, Br, CN, CF3, t-Bu R2 = H, Cl, CN R3 = H, Br, CN, Me, OMe, Ac R4 = H, Br

2

I

5

(5-91%)

Scheme 6 . EtO2C

I

S I

N

I

N N

Ph 9 (83%)

N

Cl

11 (51%)

10 (79%)

Scheme 7. i-C5H11ONO, Br2 or I2, CHCl3, !, 15-30 min N

MeO2C

Ar

S X

Ar i-C5H11ONO, THF, ! , 30-90 min

S

N

MeO2C

NH2 12 Ar = Ph, 4-ClPh, 3-ClPh, 3-MeOPh, 3-F3CPh

13 (46-63%) X = Br, I Ar N

S MeO2C 14 (44-73%)

Scheme 8.

derivatives 16 (X = Br) almost quantitatively (Scheme 8), on the other hand mixture of isoamyl nitrite and 37% HCl showed reduced reactivity and resulted in chlorinated indolizinones 16 (X = Cl) in less yield. This halogenation

procedure was extended successfully to other ring systems, such as 1,3-benzodioxole, naphthalene and 8-hydroxyquinoline. However the acid sensitive 2-methylfuran was entirely decomposed, while quinoline did not react due to formation of inert hydrobromide salt (Scheme 9) [10]. Carbocyclic 2’-deoxyribonucleoside analogs were prepared by a facile coversion of hydroxy-lactone 17 with 2-amino-6chloropurine 18 in a multi-step synthesis. A novel heteroaryl amine-halogen exchange was developed using trimethylchlorosilane (TMCS) as chlorinating agent in the presence of isopentyl nitrite in DCM (Scheme 10) to give 20 chloro derivative [11]. 2.4. Halogenation of Aryl Amines with Copper (II) Halides The synthesis of aryl halides from arylamines by the conventional Sandmeyer reaction involves initial diazotization of amine followed by addition of the diazonium salt to the copper (I) halide in an aqueous solution with the corrresponding hydrogen halides (e.g. HCl, HBr) or in a subsequent displacement with other substituents (e.g. I-, CN, RS-, HO-). The classical Sandmeyer procedure is complicated due to several competing reactions. To minimize these side reactions and simplify the procedure Doyle et al. developed a modified and successful alkyl

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Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2

O

i-C5H11ONO, MeO2C 48% HBr, DCM, 20°C, 5h or 37% HCl, THF, 20°C, 15h-7 days

O

MeO2C

Ferenc Csende

N

X

N

CO2Me

CO2Me CO2Me R

CO2Me R

16 (X = Br 98 %) (X = Cl 60-74 %)

15 R = H, Et

Scheme 9. Cl

Cl H

OH

N

O

N H

O

N

N

+ N

NH2

18

17

N

N R

Me3SiCl, DCM, 0°C, i-C5H11ONO, 2h, 0°C to RT, 5h

N

N N

NH2

19 (48%)

Cl

R

AcO R=

H

N N

Cl

20 (61%)

H

Scheme 10. R3

R3 NH2

R2

t-BuONO, CuX2, MeCN 25-65°C, 10-30 min

R1

X R2

2 R1 = H, Me, Cl, CO2H, NO2 R2 = H, Me, OMe, F, Cl, Ac, NO2, CF3 R3 = H, Me, Cl

R1 3

X = Br, Cl (32-98 %)

Scheme 11.

nitrite-copper (II) halide deamination reaction of aryl amines, so they could get the expected aryl halides [12]. However, the use of nitrosyl complexes of anhydrous copper (II) halides (CuCl2-NO or CuBr2-NO) have recently been reported to direct conversion of aromatic amines into corresponding aryl halides at room temperature [13], Doyle’ method mentioned above is simpler and more successful in case of various substituents in practice. The typical procedure (Scheme 11) applies the amine, anhydrous copper (II) halide (CuCl2 or CuBr2) and t-butyl nitrite in anhydrous MeCN. At 65°C gas evolution (N2) is generally complete within 10 minutes, resulting in aryl halides (usually in good yields) and CuO and t-butyl alcohol, therefore this method is advantageous because of it can be used in larger scale and easier isolation of the product 3 [12]. An expeditious solvent-free methodology was described for conversion of aryl amines into chlorides and bromides via arenediazonium tosylate salt under grinding conditions using t-butyl nitrite and a catalytic amount of copper (II) halide in the presence of p-toluenesulfonic acid (PTSA), benzyltriethylammonium chloride (BTAC) or tetrabutylammonium bromide (TBAB). The transformation of various anilines with NaBr in the presence of catalytic amount of CuBr2, t-butyl nitrite, PTSA and a few drops of water gave aryl bromides in moderate yields (10-65%) after 15-20 min of grinding at room temperature. Limitation of the aniline substrate, that requires a strong electron-withdrawing group (e.g. NO2- or CN-). To eliminate this disadvantage tetrabutylammonium bromide (TBAB) was used as the bromide source in the absence of water, in case of electron-

donating substituent (-OMe) at different position, increased yields were observed. Similarly, aryl chlorides were prepared in good yields (44-87%) by treating anilines with benzyltriethylammonium chloride (BTAC) and catalytic amount of CuCl2 under the same conditions [14]. Heteroaryl amines such as the 6-phenylpyridazin-4amine 21 were also converted successfully to corresponding 22 chloro analogs, which have herbicidal activity, using the alternative Sandmeyer reaction (Scheme 12) with t-butyl nitrite [15]. An efficient and simple synthesis of 2,5-dihalothiazole-4carboxylates 24 was reported starting from the corresponding 23 amine via the one-step diazotization with isoamyl nitrite and halogenation (Scheme 13) with copper (II) halides or CH2I2 respectively. This procedure is very advantageous since, in the course of the conventional Sandmeyer reaction the intermediate diazonium salt could transform easily to unwanted reduced thiazole derivative [16]. Previous attemps to prepare the halogenated pentiptycene phenols 26 (R = OH, X = Cl, Br) were unsuccessful. These central-ring halogenated derivatives can be utilized as building blocks for preparing new pentiptycene-derived πconjugated systems. The one-pot preparation of halogenated phenols 26 is based on the method of Doyle et al. [12], where t-butyl nitrite is the diazotizing agent, CuCl2 or CuBr 2 is the source of halogens in MeCN as the solvent at 65°C (Scheme 14) resulting in halogenated derivatives in good yields [17].

Alkyl Nitrites as Valuable Reagents in Organic Synthesis

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 1315

NH2

Cl t-BuONO, CuCl2

N F3C

N

N F3C

21

N

22 (81%)

Scheme 12. NH2 N

S

i-C5H11ONO, CuY2, MeCN, 0°C, 2 h or i-C5H11ONO, CH2I2, THF

CO2Et

Y

23 Y = Cl, Br

X S

Y X = Cl, Br, I Y = Cl, Br

NH2 R

N

2

CO2Et 24 (50-77%)

t-BuONO, CuCN, N2, DMSO, 50-55°C, 3 h

CN R

R = 2-NO2, 3-NO2, 4-NO2, 2-CO2Me, 4-CO2Me, 2,6-di-i-Pr, 2,4,6-tri-Br, 2,3,4,5,6-penta-Cl,

27

(20-52%)

Scheme 13.

Scheme 15.

2.5. Direct Preparation of Nitriles from Aryl Amines

2.6. Fluoro Derivatives from Aryl Amines

A simple and rapid procedure was reported for the synthesis of aryl nitriles from several substituted aryl amines with CuCN-t-butyl nitrite system in DMSO in fair to moderate yields. The best choice of solvent was DMSO, because it has complexing properties and the copper salt is moderately soluble at about 50°C. Applying of a stoichiometric amount of CuCN, the reaction with alkyl nitrite (Scheme 15) proceeded promptly, resulting in the corresponding aryl nitrile 27 as main product, besides a few side products, such as arenes, sulfoxides and phenolic or nitro arene derivatives in different ratio and yields [18].

When in situ generated nitrosyl fluoride is produced in the presence of an aromatic amine, excess boron trifluoride, alkyl nitrite and arenediazonium tetrafluoroborate salts 32 are formed in high yield (Scheme 17). The diazotization reactions are performed under mild conditions using anhydrous DCM, Et2O or THF as solvents. The anhydrous tetrafluoroborate salts 32 precipitated from the reaction mixture as main product and were obtained after simple filtration. Usually, by the application of DCM as solvent, significant yield advantages were observed over other solvents [23].

The tricyclic 10,11-dihydro-5H-dibenz[b,f]azepine (iminodibenzyl) and its substituted derivatives are important pharmaceutical intermediates of several CNS drugs. There is only one patent for the direct conversion of the amino derivative 28, which applies the convetional Sandmeyer reaction obtaining the corresponding 3-chloro, and 3-bromoderivatives 29 in moderate yields and low purity [19]. Later our group developed a modified procedure of the Doyle’s method [12], by the optimization of conditions of the diazotization-halogenation reaction and further deamination reactions of key intermediate 28 was achieved using i-pentyl nitrite [20, 21]. In this manner iodo- and nitrile derivatives 29 (X = I, CN) were also prepared using CuI and CuCN in moderate yields (33-40%), furthermore when amine 28 was refluxed in benzene in the presence of alkyl nitrite, 5-acetyl3-phenyl-iminodibenzyl 30 was obtained. Finally, the reductive deamination of amine 28 resulted in 5-acetyliminodibenzyl 31 with DMF as hydrogen donor [22] in the presence of i-pentyl nitrite (Scheme 16).

NH2

HO

25

Scheme 14.

Application of SiF4 to deaminative fluorination of anilines as a fluorine source was also investigated. A diazotization of anilines proceeds under mild condition, in DCM at room temperature for 1-17 hours and the following fluoro-dediazoniation affords fluoroarenes (e.g. 4-fluorobenzenecarbonitrile and 4-fluorobenzoic acid methyl ester) at 130-140°C for 1h in good yields, but this method is limited by the toxicity of SiF4 [24]. Garel et al. extended Doyle’s procedure [23], which is a simple and safe route to the preparation of arenediazonium tetrafluoroborate salts 32. Thus several solvents were investigated for the diazotation reaction in similar conditions, however 1,2-dichlorobenzene was preferred as suitable solvent since its high boiling point (~180°), which is appropriate for the thermal decomposition of intermediate tetrafluoroborate salts to required aryl fluorides 33 (Scheme 18). In this way a convenient one-pot procedure was achieved for the fluoro-dediazoniation of anilines in neutral, organic medium [25].

t-BuONO, CuX2, MeCN, 65°C, 30 min

X = Cl, Br

X

HO

26 (85-89%) X = Cl, Br

6 Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 132

Ferenc Csende

i-C5H11ONO, CuX2 or CuX, MeCN, RT, 1h X = Cl, Br, I, CN

N Ac 29

X X = Cl, Br, I, CN (30-85 %)

i-C5H11ONO, PhH, reflux, 2 h N Ac

NH2

N Ac

i-C5H11ONO, DMF, RT, 2-3 h

28

Ph

30 (26 %)

N Ac 31

(64 %)

Scheme 16. t-BuONO, BF3·Et2O, DCM or Et2O or THF -15°C, 10-20 min

NH2 R3

R1

N2 BF4 R3

R2

R1 R2

2

32 (76-100%)

R1 = H, NO2, Me, Cl, CO2H R2 = H, NO2, Cl R3 = H, NO2, Me, OMe, Cl, Br, CO2H

Scheme 17. NH2 t-BuONO, BF3·Et2O, 1,2-ClPh, 20°C, then 90-120°C, 25-60 min R3

R1

R3

R2 2

F R1 R2

R1 = H, Cl, R2 = H, Me, CF3, Ac R3 = H, NO2, Br

33 (25-60%)

Scheme 18. R4

R4 NH2 R3

t-BuONO, NaN3, t-BuOH, RT, 1-7 h

R1 R2

N3 R3

R1 R2

34 (60-92%) 2 R1 = H, Me, Et, CO2Me R2 = H, Me, F, OMe, NO2 R3 = H, F, Br, i-Pr, OMe, NO2, Br R4 = H, Et, OMe

Scheme 19.

2.7. Preparation of Aryl Azides A number of (hetero)aryl azides 34 were prepared by the transformation of substituted aryl- and heteroaryl amines using t-butyl nitrite and moist NaN3 in t-BuOH (Scheme 19) usually after a short time at room temperature in good to excellent yields. It was observed that addition of small quantities of water increased the rate of the reaction considerably and the reaction was complete quickly. It is important to note that when isoamyl nitrite was used instead of t-butyl nitrite, the reaction was slow and the conversion

was lower [26]. An improved and efficient procedure for the synthesis of aromatic azides was developed using the t-butyl nitrite with a quite stable and safer azidotrimethylsilane (TMSN3) under similar mild reaction conditions (MeCN, 0°C to RT, 1h) in high or excellent yields (65-96%) [27, 28]. Alternative diazotization reactions of L-alanine- and Lphenylalanine ester salts were carried out in aprotic 1,2dimethoxyethane (DME) as solvent in the presence of NaN 3 using t-butyl nitrite, however instead of desired azide products, α-chloro derivatives were formed probably due to hydrochloride salt form of amino acid esters [29]. 2.8. Deamination of Aryl- and Heteroaryl Amines As it was previously mentioned, deamination of aryl amines occured by alkyl nitrites rapidly in DMF, resulting in the replacement of the primary amino group by hydrogen in moderate to high yields [20, 22]. In this way stirring a mixture of 4,6-dibromo-5-aminoisatin ketal 35 and t-butyl nitrite in DMF for 10 h at 60°C gave the corresponding deaminated derivative, then it was subjected directly to deprotection with aqueous oxalic acid to give dibromoisatin

Alkyl Nitrites as Valuable Reagents in Organic Synthesis

Br

O

H2N

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 133 7

Br

O

O

2. aq.(CO2H)2, 60°C, 12 h

N H

Br

O

1. t-BuONO, DMF, 60°C, 10 h

O

35

Br

N H 36 (24%)

Scheme 20. R

NH2

+

Entry

R

R

38 (29-48 %)

R = H, Me, Cl, Br, NO2

37

2

n-C5H11ONO, 110-120°C, 2 h

Ratio of 38 Isomers (~ ca.)

Overall Yield (%)

ortho

meta

para

1

Me

29

57

28

14

2

NO2

36

45

15

40

3

Cl

41

55

27.5

17.5

4

Br

48

48

34

18

Scheme 21. O t-BuONO, DMSO-H2O 25°C, 0.3-12 h

NH2

+

R

O

2

39

R = Me, OMe, Br, I, CN, NO2, CO2Me, 1-naphthyl

R

O

O 40 (42-77%)

Scheme 22.

36 (Scheme 20) as key convolutamydine A [30].

intermediate

of

alkaloid

When 5-amino-1-aryl-1H-pyrazole derivatives were stirred and refluxed for ~ 2h with t-butyl nitrite and dry THF a similar deamination reaction took place in good yields (6286%) [31]. 3. ARYLATION NITRITES

REACTIONS

WITH

ALKYL

3.1. Arylation with Aryl Amines Arylation of aromatic compounds is usually generated by free-radical methods and the required aryl radicals can be obtained from primary amines through diazotization. One of these processes is the Gomberg-Bachmann reaction, which is an aryl-aryl coupling reaction via formation of the diazonium salt. In this reaction the arene is coupled in a basic and aqueous medium with diazonium salt to the biaryl through an intermediate aryl radical, but yields are generally low and many side-reactions of diazonium salts occur. Therefore, a convenient and simple method was developed by Cadogan using pentyl nitrite with (hetero)aryl amines in refluxing benzene instead of the conventional diazotization procedure

[32]. The reaction of arylamines with amyl nitrite in aromatic solvents 37 gave moderate yields of 38 biaryl products (Scheme 21). Substituted anilines, such as toluidines or o-chloroaniline with benzene also gave the corresponding biaryl products 38 and for determination of optimum reaction conditions o-chloroaniline was used with a slight excess of amyl nitrite in high excess of benzene. Different isomers of biaryls were isolated in various ratio (Scheme 20), the isomer distributions showed ortho substitution mainly, while lower para and meta substitutions were detected. Similarly significant para orientation was observed in the presence of electron withdrawing group (e.g. nitro- or carboxyl group) [33]. Later we applied this arylation method in case of a 3-amino-10,11-dihydro-5H-[b,f]azepine derivative successfully, obtaining the corresponding phenyl substituted compound 30 in pure form but in low yield [20]. Recently, direct C-H arylation of quinones with aryl diazonium salt in strongly acidic conditions was described, moreover this method was improved by using of the t-butyl nitrite. This modified environment-friendly coupling procedure was carried out at room temperature in neutral aqueous medium (Scheme 22), resulting in 2-aryl-1,4-benzoquinones 40 in good yields [34].

8 Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 134

t-BuONO, BF3 OEt2 B(OH)2 nano-Pd(0), MeOH, 60°C, 5 h

NH2

+ R1

R2

2

Ferenc Csende

R1, R2 = H, Me, OMe, Cl, Br, CN, NO2, CO2Et

41

R2

R1

42

(18-95 %)

Scheme 23. NH2

+

H2C

R1

CH 43

2 R1 = H, Me, OMe, Cl, NO2, Ac

R2

R2

t-BuONO, CuX2, MeCN, 25°C, 10-30 min X = Cl, Br

R2 = CN, Ph, CO2Et, CONH2

R1

X 44 (32-93 %)

Scheme 24.

+ H2N

R

t-BuONO, stir bar, 60°C, 1 h

R n

45

2

R = Cl, Br, t-Bu, CO2Me, NO2

46 (22-34 %)

Scheme 25.

Biaryl derivatives 42 were also prepared by a magnetic Pd-nanoparticle catalyzed one-pot diazotization-crosscoupling reaction of substituted anilines and arylboronic acids 41 (Scheme 23). The reaction is not moisture- and airsensitive and the MeOH proved to be the best solvent. For the formation of arenediazonium salt an acidic reagent is essential, so beside of AcOH and PTSA (p-toluenesulfonic acid) BF3·OEt2 was also investigated as additive, and showed significant efficiency. Application of Fe3O4-supported catalysts are very useful and convenient in this crosscoupling reaction, thus a new Pd/ Fe3O4/sulfonated graphene (s-G) composite was used in the one-pot procedure. It was found that under optimal reaction conditions (60°C, 5 h) the Pd/Fe3O4/s-G catalyst could be easily recycled several times [35]. A modified Meerwein reaction was achieved by the addition of arylamine to an MeCN solution containing tbutyl nitrite, anhydrous Cu(II)halides, and an 43 activated olefinic substrate (Scheme 24), resulting in the vicinal αhalo-β-arylated product 44. Originally, the Meerwein reaction is a copper salt catalyzed addition of an aryl diazonium salt to an electron-poor alkene, which is a twostep procedure, conducted in buffered solutions within the pH range of 2-4 to minimize side reactions, moreover the products often lose a hydrogen halide during the reaction process. The reaction mechanism was defined as a radicalnucleophilic aromatic substitution. Relatively higher product yields were obtained conveniently by the direct one-step method, however using of the more reactive CuBr2 led to mixture of Sandmeyer and Meerwein side products that included e.g. aryl bromides [36]. A fundamentally new single-walled 45 and multiwalled carbon nanotube (SWNT and MWNT) sidewall functionalization technique has been developed using the alternative Sandmeyer diazotization-arylation procedure with

tert-butyl nitrite (Scheme 25) in a solvent-free condition, which greately shortens the reaction times. Using a series of 4-substituted anilines 2 and an alkyl nitrite, the aryl diazonium intermediates were generated in situ and permitted to react with the nanotubes. Rapid decomposition of intermediate diazonium species led to a highly reactive aryl radical which after attacking the carbon nanotube framework generates the 46 aryl-functionalized nanotubes [37, 38]. A microwave-induced preparation of multiple fuctionalized carbon nanotubes (SWNT) was reported after using a similar diazotization-arylation method. The arylation of the SWNT can be realized both in the first step or after the 1,3-dipolar cycloaddition of azomethine ylides. Therefore, SWNT or mono functionalized SWNT (f-SWNT) was dispersed in water with p-toluidine in a microwave glass vessel, then isoamyl nitrite was added to the mixture, and it was irradiated for 90 min at 80°C at different power (100W and 30W) in the reactor. For the thorough and comparative study of the double functionalization (f,f’) the order of the two different reactions (the 1,3-dipolar cycloaddition and the addition of in situ generated arene radical) was changed, however the obtained ff’- SWNTs had similar Raman spectra [39]. 3.2. Formation and Reactions of Benzyne It was found earlier that anthranilic acid 47 and its substituted forms are diazotized by alkyl nitrites in aprotic media (Scheme 26) to give benzenediazonium-2carboxylates 48, which undergo fragmentation to benzyne (1,2-dehydrobenzene) 50 with loss of CO2 and N2 at moderate temperatures [40]. However, this compound is extremely sensitive, unstable and reactive, therefore the in situ generated benzyne is trapped as a dienophile in a DielsAlder reaction.

Alkyl Nitrites as Valuable Reagents in Organic Synthesis

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2

O

9 135

O i-C5H11ONO, THF or OH MeCOMe or DCE

O

NH2

N

47

48

- CO2

N

N

49

N2

N

50

Scheme 26.

51 (59%) [41] O

53 (9%) [42]

O

50

O Ph

Ph

52 (75%) [41]

54 (~ 30%) [43]

Ph

Ph

Ph Ph Ph Ph 55 (93%) [44]

Scheme 27.

Several useful and excellent reviews were published recently, which collected and presented the reactivity and application of arynes, and among others reactions, benzyne 50 with dienes [41]. Some of these representative reactions are depicted in Scheme 27. When anthranilic acid 47 was reacted in acetone or THF in refluxing mixture of anthracene and amyl nitrite triptycene 51 was obtained, while similar reaction with furan resulted in 1,4-epoxy-1,4dihydronaphthalene 52 in good yields [42]. Benzyne and buta-1,3-diene, generated by the concurrent thermal decomposition of benzenediazonium-2-carboxylate 48 and 3-sulpholene respectively, was reacted at 100°C to give a very poor yield of 1,4-dihydronaphthalene 53 [43]. Starting from anthranilic acid 47 as an aryne intermediate benzyne was formed via elimination reactions, then dimerized to biphenylene 54 by heating, though the yields of 54 formation are generally low (21-30%). The explosive benzenediazonium-2-carboxylate 48 was added directly to hot DCE in a few minutes carefully, while the dimerization led to biphenylene 54 [44]. The polycyclic aromatic hydrocarbon 1,2,3,4-tetraphenylnaphthalene (55) was produced in almost quantitatively from in situ generated benzyne and tetraphenylcyclopentadienone by Diels-Alder cycloaddition via an unstable bicyclic product. Then, it spontaneously underwent a cheletropic pericyclic reaction and a new aromatic ring was formed by CO evolution [45]. A novel strategy for the C-C formation by the [2+2] cycloaddition is the reaction of diisopropoxy anthranilic acid

and isoamylnitrite in situ generated benzyne and the icosahedral metallofullere Sc3N@C80 at 60°C for 12 hours under Ar atmosphere to affording an isomeric mixture of cycloadducts in 29% yield. In the presence of air an unusual open-cage metallofullerene is formed also [46]. 4. NITROSATION REACTIONS 4.1. C-Nitrosation Processes For the nitrosation of aliphatic compounds electronwithdrawing groups have to be placed near the carbon atom to be nitrosated, moreover for preparative purposes this carbon hase to be a tertiary carbon atom, as the nitrosation of primary or secondary carbon atoms often leads to the production of the isomeric oximes. While nitrosobenzenes 56 appear in the solution as equilibrium of two forms, monomers 56 and diazene dioxide dimers 57 (Scheme 28), in solid-state most of them crystallizes predominantly in the form of dimers [47]. N

O

O

O N

N

2 R

R 56

Scheme 28.

R= H, 3-Cl, 4-Cl, 4-Br

R 57

136 10

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Ferenc Csende

The monomer, if contains α-hydrogen may undergo tautomerization to the corresponding oxime in solution (Scheme 29), which is essentially irreversible, since the oxime is generally much more stable than the nitroso compound [48]. R1 ! CH

salt of tetrahydroisoquinoline 65 afforded oxime 66 in high yield (Scheme 32). According to the proposed mechanism a strong electrophile ClNO agent was formed in situ, which then reacted with the free base (from the imine and enamine equilibrium) and the N-nitroso intermediate isomerized by HCl to oxime 66 [54, 55].

R1 N

N

R2

O

R2

R2 OH

R3

65

R3

. HCl

N

59 58 R1, R2= H, Me, Et,Cl-CH2-, cycloalkyl, Ph, naphthyl, pyrrolyl

R2

t-BuONO, CHCl3, 50°C, 1h

R1

N R1= H, Me, Ph R2, R3= H, Me

R1

Scheme 29.

Recently, an excellent and detailed review was puplished to represent several synthetic routes for the nitrosoalkanes and nitrosoarenes. Among others that article described many uses of alkyl nitrites for the C-nitroso derivatives [49], therefore only a few selected nitrosation examples are demonstrated below in this paper. Direct nitrosation of aromatic ring of 60 with alkyl nitrite (Scheme 30) afforded stable and a well-characterized C-nitroso compound 61 in good yield, without the N-nitrosated by-product [50].

PhHN

i-C5H11ONO, toluene, 23°C, 15h

Alkyl nitrites are succesfully used for the nitrosation of enolizable carbonyl compouns under both acidic and basic conditions. Treatment of m-cresol 67 with isoamyl nitrite in DMF in the presence of K2CO3 at 50°C afforded 2-methyl1,4-benzoquinone 1-monooxime 68 (Scheme 33), however the naphthalene analog of 67 resulted in low formation of nitrosated derivative [56].

60

i-C5H11ONO, DMF, K2CO3, 50°C, 1h

NHPh 61 (90 %)

Nitrosation of cycloalkanes 62 as a clean and convenient method was developed by treatment of 62 with t-butyl nitrite in the presence of N-hydroxyphthalimide (NHPI) catalyst in AcOH at 80°C. In this manner this reaction of cycloalkanes (cyclopentane as well as higher cycloalkanes) resulted in the desired C-nitroso derivatives 63 and oximes 64 in different ratio (Scheme 31). In case of cyclopentane and cyclohexane only C-nitroso derivatives 63 were obtained practically, while cyclooctane produced oxime 64 solely in 56% yield. Probably, that forming nitrosocyclooctane isomerized rapidly into more stable oxime. Nitrosocycloalkanes 63 can easily be converted into oximes in reaction with amines (e. g. Et3N) in EtOAc at 80°C quantitatively. Cycloalkanone oximes are valuable intermediates for lactams, such as laurolactam or ɛ-caprolactam via Beckmann rearrangement [51-53]. NOH

NO

( )n 62 n = 1-4, 8

+ ( )n ( )n 63 (0-51 %) 64 (2-56 %)

Scheme 31.

In most cases due to the above mentioned nitroso-oxime isomerization, the C-nitrosation reaction with alkyl nitrites mainly led to oxime derivatives under similar conditions. In this way the interaction of t-butyl nitrite and hydrochloride

Me

Me 67

Scheme 30.

t-BuONO, cat. NHPI, AcOH, 80°C, 2h, Ar

O

OH NO

PhHN

NHPh

NOH 66 (62-82%)

Scheme 32.

NHPh

NHPh

. HCl

N

OH 68 (71%)

Scheme 33.

Several new ninhydrid analog 1,2-indanediones were developed and evaluated as visulaizing reagents for amino acid components of latent fingerprints. For the intermediate 1,2-indanedione-2-oxime, 1-indanone was treated with nbutyl nitrite at room temperature and the reaction was completed after 10-30 min to give oxime in 80-90% yield [57]. From ketones α,α’-dianions were obtained using strong bases (KH and n-BuLi), and nitrosation of dianions produced two regioisomers of oximes with t-butyl nitrite in Et2O, in different ratio [58]. The same reaction of 2-butanone was also performed in alcohols using base (alkali metal alkoxides) catalysts and the nitrosation mechanisms were investigated [59]. Similarly, in the presence of strong base (EtONa) 2-acetylnaphthalene was reacted with i-amyl nitrite stirring for 40 hours at room temperature to produce 2naphthylglyoxalaldoxime in 20% yield [60]. Nitrosation of camphor with i-amyl nitrite using t-BuOK as base in THF resulted in the corresponding α-oximino ketone in high yields and in most cases the anti isomer was formed almost exclusively [61]. Various α,β-unsaturated carbonyl compounds (esters, ketones, nitriles and amides) 69 were efficiently converted in one-step procedure (Scheme 34) to the α-hydroxyimino carbonyl derivatives 70 on treatment with butyl nitrite and phenylsilane in the presence of a catalytic amount of N,N'bis(2-ethoxycarbonyl-3-oxobutylidene)ethylenediaminatocobalt(II) complex (Co(eobe)) under mild conditions [62].

Alkyl Nitrites as Valuable Reagents in Organic Synthesis

cat. Co(eobe), t-BuONO, PhSiH3,THF, RT,19-48 h

R1

R1

R1= H, Me, n-Pr, CO2Et R2= OEt, OBun, OBut, OBn, Et, Ph Me

N

R

Me

NO

74 (~ 46 %)

Scheme 36.

CO2Et N

i-C3H7ONO, CHCl3, reflux, 3h

Scheme 34.

The α-oximation of ketones proceeded successfully on treatment with a combination of trimethylsilyl chloride (TMSCl) and i-amyl nitrite either neat or in DCM solution at -20°C within a short time (0.5-3.5h) [63]. The reaction of iamyl nitrite with (Z)-2-(phenanthridin-6(5H)-ylidene)-1arylylethanones 71 resulted α-oximino derivatives 72 (Scheme 35) in good to excellent yields in DMF under ultrasound irradiation. Presence of 100 mol % anhydrous Na2SO4 as dehydration agent increased yields moderately, moreover unlike conventional methods, the sonochemical procedure accelerated the reaction [64]. 4.2. Preparation of N-Nitroso Derivatives

N

NH

NO 76 (50 %)

75

Scheme 37. Me

Me S Me

S N H

n-BuONO, hexane, AcOH, 0°C-RT, overnight

Thialdine 77 (trimethyldihydrodithiazine), that occurs in the aroma of cooked meat and is a component of several foods and flavors, it might form a stable N-nitroso derivative under cooking. The classical nitrosation procedure for 78 (with NaNO2 and acid) was failed, however Keefer et al. reported an effective and simple method for preparing bulk quantities of N-nitrosothialdine 78 (Scheme 38) using nbutyl nitrite and AcOH in hexane [67]. A simple nitrosation process for the N-nitrosoazetidine 76 was achieved by refluxing a mixture of azetidine 75 and i-propyl nitrite (Scheme 37), followed fractional distillation afforded pure nitrosamine 76 in fairly good yield [66].

Me

Me

N

78

Me O (38 %)

N-Nitrosated N-phenylalanine esters 80 were obtained almost quantitatively from the corresponding amino ester 79 with ethyl nitrite (Scheme 39) standing at room temperature in the dark. After further reduction the N-nitroso-derivative 80 (when R = Me) was useful intermediate for the synthesis of N-substituted indole and tetahydrocarbazole via Fischer cyclization [68]. EtONO, THF-EtOH, RT, 12h

Me N H

CO2R

NO 80 98-99%

79 R = Me, Et

Scheme 39.

Analogously, 4-hydroxy-L-proline, a cylic α-amino acid which is essential component of collagen was transformed into N-nitroso-derivative by butyl nitrite in acidic medium at 25°C for 7 days in high yield (82%). The structure of the nitrosated product was established by X-ray crystallography, its geometry optimization was carried out in gas phase and in solution using ab initio and conformational calculations. The most stable conformer of 4-hydroxy-1-nitroso-L-proline was observed in an aqueous solution [69].

O N

H

H

R

Me N

CO2R

N

71

S

N

77

i-C5H11ONO, DMF, US ))), Na2SO4, 25-35°C, 10-35 min

O

S

Scheme 38.

Practically, the reaction of nitrite and nitrogen oxides readily forms N-nitroso compounds (nitrosamines) by interaction with secondary and tertiary amines or amides. The main types of N-nitroso derivatives include dialkyl-, cyclic-, aromatic nitrosamines, alkylnitrosourea and -amide derivatives. These compounds have broad biological activity in animal experiments and are highly potent group of carcinogens. Previously, Giumanini et al. prepared the unsymmetrical N-nitroso-N-methylaniline 74 from N,Ndimethylaniline or N-methylaniline 73 alternatively, heating with amyl nitrite (Scheme 36) and the conformation of this compound was studied using the low resolution microwave spectroscopy [65].

Scheme 35.

N

137 11

C5H11ONO, 100°C or reflux, 2-3h

73 R = H, Me

O Co

EtO2C

N

COR2 70 (70-98 %)

Me O

Co(eobe) =

Me

NOH

COR2 69

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2

R= H, 4-Me, 4-OMe, 2-OMe, 4-F, 2-F, 4-Cl, 4-NO2, 3-NO2

O

N

72 (73-95 %)

R

12 138

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Ferenc Csende

Several novel S-nitrosated cysteine and glutathionecontaining dipeptide or tripeptide derivatives were synthesized, their effects on vasorelaxation and inhibition of platelet aggregation were examined. Thus, S-nitrosation procedure of N-acetyl-D-β,β-dimethylcysteinyl glycine esters 83 was achieved with t-butyl nitrite in DCM (Scheme 41). In solid state, novel S-nitrosated dipeptides were found to be stable at 0°C for 12 months, and possibly longer. The vasorelaxant potencies of prepared S-nitrosated dipeptide esters 84 were significantly greater than that of S-nitroso-Nacetyl-D-β,β-dimethylcysteine (D-isomer of SNAP) in rat, although the antiaggregatory and antithrombotic activities between SNAP(D) and the S-nitrosated dipeptide esters 84 were not different on human platelets [75].

4.3. Preparation of S-Nitroso Derivatives S-Nitrosothiols (thionitrites) have increasing significance nowadays in biochemistry, because they provide donors for nitrosonium ion (NO+) and nitric oxide (NO) by decompositions, some organic nitroso derivatives serve as signaling molecules in living systems, especially related to vasodilation. Furthermore S-nitrosated proteins serve to transmit NO bioactivity and to regulate protein function through mechanisms analogous to phosphorylation [70]. The synthesis and stability of some S-nitroso derivatives was studied and described expansively. For the preparation of water soluble S-nitroso derivatives from cysteamine or mercaptoethanols, equimolar or a slight excess of t-butyl nitrite was reacted in aqueous solution. Compounds prepared have different stabilities (t1/2 5 min - 44h) and spontaneously decompose in water even in neutral medium at 37°C [71]. Similarly, cysteine reacted quite rapidly with various alkyl nitrites in water at 25°C in the pH range 6-13 to afford the somewhat unstable S-nitrosocysteine [72]. The S-nitrosothiol 82 was prepared via direct S-nitrosation of the hydrochloride of L-cysteine ethyl ester 81 with ethyl nitrite in MeOH solution at ~ 0°C (Scheme 40). Compound 82 is relatively stable in crystal form and it can be neutralized in aqueous solution to the free base, which is a lipophilic compound that was taken up by human neutrophils. Application of Snitroso-L-cysteine ethyl ester salt 82 will be advantageous when intracellular reactions of trans-S-nitrosation will be studied [73]. The X-ray crystal structure of S-nitrosocysteine derivative 82 was also determined and two rotamers established respect to N-C-C-S moiety in ratio 7:3 (syn:anti), furthermore the C-S-N=O group was in the syn form for both rotamer [74]. CO2Et

HS

EtONO, MeOH, 0-4°C, 15 min

NH2 . HCl

5.1. Nitration of Aromatic Compounds Recently, Townsend et al. have found that polyhalogenated benzimidazole ribonucleosides are potent and selective inhibitors of human cytomegalovirus (HCMV) replication. In the course of nonaqueous diazotization of 2amino-5,6-disubstituted benzimidazole riboside using a tertiary alkyl nitrite unexpected results were obtained. When 1-(β-D-ribofuranosyl)- benzimidazol-2-one 88 was treated with 10 equiv. of t-butyl nitrite in diiodomethane at 110°C, a

NH2 . HCl

N

81

5. DIRECT NITRATION REACTION OF ALKYL NITRITES

CO2Et

S O

A stable S-nitrosothiol 87 bearing trityl-type steric protection group was synthesized and its molecular structure was established by X-ray crystallography. The novel aliphatic type of bowl-shaped molecule, which is a triarylmethyl derivative, where the aryl groups (Ar) are mterphenyl moieties and it would form a dendrimer-like structure. It was transformed from the corresponding tertiary alcohol 85 via thiolation to 86. Treatment of thiol 86 with tbutyl nitrite in CDCl3 resulted in crude S-nitrosothiol quantitatively (Scheme 42), which afforded purified Snitrosothiol 87 in 72% yield after recrystallization from hexane [76].

82

Scheme 40.

O Me

Me

SH

ON Me H N

N H

t-BuONO, DCM, RT, 1h

O O

R

O

Me

Me

O 83

N H

S

Me H N

O

O 84 ~ quant.

R = Me, Et, i-Pr, n-Pr, n-Bu, t-Bu

Scheme 41. OH

Lawesson's r., toluene, reflux

Ar Ar

Ar

SH Ar

Ar Ar

Ar = Me Me

Ar Ar 87 (72 %)

Me

Me

SNO Ar

86 (82 %)

85

Scheme 42.

t-BuONO, CDCl3, RT, 1h

O

R

Alkyl Nitrites as Valuable Reagents in Organic Synthesis

Cl

H N

Cl

N

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 139 13

O O

AcO AcO

NO2

t-BuONO, CH2I2, 110°C, 2h, N2

Cl

H N

Cl

N

O O

AcO OAc

AcO

88

OAc 89 (86 %)

Scheme 43.

R

R

90

OH

OH

OH t-BuONO, THF, RT, 10 min-12h, air

R

NO2

R

+ if R = H 92

NO2

R = H, OMe, t-Bu

91

(72-85 %)

Scheme 44. OH

OH O O

HO2C

H N

NO2

H N

NHBoc

NHBoc O

O

93

OH 94 (50 %)

OBn

Scheme 45.

complete conversion to 4-nitro derivative 89 was observed within 2 h (Scheme 43) without the detection of any other intermediates, product 89 was isolated from this reaction in 86% yield after recrystallization [77]. The t-butyl nitrite was also used as nitrating agent for chemo- and regioselective nitration of phenols 90, tyrosine and its oligopeptide derivatives. This method is compatible with solid supported synthesis of mono-nitrated tyrosinecontaining peptides, because the nitration is realized in aprotic media. This procedure was effective at converting electron-rich compounds into C-nitro derivatives in a variety of steric contexts after optimization of solvent. When both ortho and para positions are available, a mixture of mononitrated regioisomers was obtained (R = H) in good yield (82%) and in ratio 37/45 (91/ 92). As it was expected, ortho- and para-substituted phenols exclusively provided the corresponding para- and ortho-nitro derivatives, respectively (Scheme 44). Extending the method to protected tyrosine-containing dipeptide 93 and oligopeptides, having a free aromatic hydroxyl group chemoselective nitration was observed (Scheme 45) under same conditions on the polymersupported substrates. The proposed mechanism for the nitration with alkyl nitrite via formation of phenoxyl radicals was also described [78].

Several para-substituted nitrobenzenes 96 and 1- or 2nitronaphthalenes were prepared by direct nitration of arylboronic acids 95 with t-butyl nitrite in moderate to good yields in one-step procedure (Scheme 46). In the comparison of effects of solvents on experimental nitration of phenylboronic acid 95 (R = H) the best result was accomplished in dioxane (87%). Use of polar solvents (DME, MeCN) resulted in decreased yields (36-52%), while the non-polar heptane led to slight yield (22%). Notably, in alcoholic solvents (EtOH, n-BuOH) transformation was not observed. Beside simplicity the advantage of this method is the catalyst-free procedure [79]. B(OH)2

NO2

t-BuONO, dioxane, 80°C, 16 h, air R

R 95 R = H, Me, OMe, F, Br, Ph, OPh, CHO

96 (45-87 %)

Scheme 46.

A novel method for the efficient and chemoselective conversion of aromatic sulfonamides into their mono-nitro derivatives 98 was described using alkyl nitrite. Tosylamines 97 were dissolved in MeCN and treated t-butyl nitrite at moderate temperature (Scheme 47) to obtaine 98. This type

14 140

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Ferenc Csende

of nitration permits the presence of a wide variety of parasubstituents. The tosyl group is useful as a protecting group for amines, since the resulting sulfonamide is extremely stable, however it can be deprotected later. Preliminary results suggested that reaction occured via a radical based mechanism [80]. NHTs

t-BuONO, MeCN, 45°C, 6 h

NHTs NO2

R

R 97

R = H, Me, OMe, Cl, CN, CF3, NO2, CO2Et

98

(20-95 %)

Scheme 47.

5.2. Nitration of Alkenes with Alkyl Nitrites Nitroolefins are an outstanding class of synthetic intermediates for both synthetic chemistry and pharmaceutical developments. Maiti and co-workers reported a metal-free nitration of various olefins (styrenes 99a, heteroaryl- and aliphatic alkenes 99b) in a stereoselective way with t-butyl nitrite and 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) system in the presence of air. This newly performed method is operationally simple, functional group tolerant, high yielding, and scalable. To achieve the best condition by further optimization of the amount of reagents, temperature, concentration, and reaction time it was found that 2 equiv of nitrite and 0.2-0.4 equiv of TEMPO in 1,4-dioxane at 90°C (Scheme 48) could provide the optimal yield of the desired nitro product 100 with complete E-selectivity. The electronic properties of substituents had no effect on the yields of the products. Olefins attached to electron-rich benzothiophenes

R 99a R = H, Me, OMe, F, Cl, Br, CN, CN, ClCH2-

and benzofurans were also nitrated in excellent yields (7187%) and selectivities, moreover, even the electron-deficient vinyl pyridines underwent successful nitration efficiently too. Similarly, the simple unsubstituted 1-octene or substituted terminal olefins having distant bromo and ester functions as well as vinyl cyclohexane afforded the 100 expected nitro products [81]. A similar metal-free decarboxylative nitration protocol was performed as an alternative route for the preparation of the nitroolefins 100 from α,β-unsaturated carboxylic acids 101 using t-butyl nitrite and TEMPO. The α,β-unsaturated carboxylic acids possessing β-aryl (phenyl-, naphthyl- or thienyl-) substituents gave (E)-nitroolefins exclusively under mild conditions (Scheme 49). The conditions (solvent, reaction time and temperature or use of additive) were carefully optimized. A radical based pathway has been proposed for this decarboxylative nitration reaction [82]. Rajanna et al. tested and compared various methods for this transformation to β-nitrostyrenes, such as the conventional nitration, sonication and microwave irradiation procedures. β-nitrostyrenes were obtained in good yields from substituted cinnamic acids with t-butyl nitrite under classical conditions. However, ultrasonic and microwaveassisted reactions reduced the reaction times significantly and increased the yields from good to excellent [83]. Another excellent method was developed using a combination of t-butyl nitrite and molecular oxygen for the oxidative nitration of activated alkenes 102 to give β-nitro alcohols 103 (Scheme 50). The procedure provided a practically more favourable method for the synthesis of nitro compounds 103 due to the mild reaction conditions, the use of inexpensive reagents and a simple experimental process.

t-BuONO, TEMPO, dioxane, 90°C,12 h, air

NO2

R 100

R

(46-89 %) E-isomer R = aryl, heteroaryl, alkyl, cycloalkyl

99b R = heteroaryl, alkyl, cycloalkyl

Scheme 48. CO2H R

t-BuONO, TEMPO, MeCN, 50°C,12 h

NO2 R

101 R = 2-Me, 4-Me, 2-OMe, 4-OMe, 3,4-diOMe, 3,4,5-triOMe, 4-F, 4-Cl, 4-Br, 4-CN, 3-NO2,

(34-87 %)

100

Scheme 49. R1 CH2 R2 102

Scheme 50.

HO

t-BuONO, hexane-H2O, air, RT, 1-17 h

R1 = H, Me R2 = H, OMe, Br, NO2,

R1 NO2

R2 103

(20-74 %)

Alkyl Nitrites as Valuable Reagents in Organic Synthesis

Me

Me

H2C

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 14115

t-BuONO, DMSO, O2 (1atm), RT, 5-19 h

R1

O

Me

R1

O2N

R2

OH

R2 105 (15-54 %) (dr 50:50-75:25)

104 R1 = H, Me R2 = H, Me, CN, OBn, CO2Me

Scheme 51.

In some cases nitrate derivatives were also isolated as byproducts in negligible quantity depending on the R2 substituent, however by changing the aromatic ring to alkyl substituent the major product was the nitrate derivative in DCM [84]. In continuation and extension of a previous work, treatment of alkenes 104 with 5 equivalents of t-butyl nitrite in DMSO under O2 atmosphere at room temperature afforded nitromethyl-substituted γ-lactols 105 in various yields (Scheme 51). The diastereomeric ratios (dr) were approximately estimated by 1H-NMR analysis. This novel multifunctionalization reaction involving direct sp3 C-H oxidation of aliphatic alkenes and present reaction proceeded through a sequence of radical processes including oxynitration via a 1,5-hydrogen shift [85]. In the presence of water this aerobic radical reaction produced 4-hydroxy-5nitropentyl nitrate or 4-hydroxy-3-nitropentyl nitrate derivatives instead of nitrated lactol products [86]. CH3

CHO i-PrONO, MeONa, O2N pentane, 25-40°C

O2N

106

107 (24 %)

Scheme 52.

6. ALKYL REACTIONS

NITRITE-PROMOTED

OXIDATION

6.1. Oxidation of Alkane and Alkene The original Lapworth's procedure is modified for direct conversion of 2-nitrotoluene 106 to 2-nitrobenzaldehyde 107 was described and compared with other methods. The alternative route used i-propyl nitrite as oxidant agent in the

R2 R1

presence of MeONa in pentane (Scheme 52) and after purification the procedure gave 2-nitrobenzaldehyde 107 in 24% yield. The presented simple method is useful in an industrial scale [87]. The green method for aerobic oxidative cleavage of C = C double bonds was developed using a t-butyl nitrite, O2 and compressed CO2 system (Scheme 53) under metal-free conditions to give the corresponding carbonyl compounds 109 from styrenes 108. An alkoxyl radical and NO, arised from tbutyl nitrite, could serve as initiator for cleavage of benzylic C=C bonds. The para-substituted styrene gave better results than styrene, whereas ortho- or meta-substituted styrene showed slightly lower activity. The oxidation is selective, overoxidation to acid and oligomerization were not observed or only in a negligible amount [88]. 6.2. Oxidation of Alcohols and Phenols The efficient oxidation of primary and secondary benzylic alcohols 110 to aldehydes and ketones 111 was achieved by using t-butyl nitrite (Scheme 54) as a stoichiometric oxidant in toluene at 120°C. The reaction presumably proceeded by a nitrosyl exchange and a subsequent thermal decomposition of benzylic nitrites. This method was environmentally benign since it did not require heavy metal based reagents or additional catalysts. Furthermore, almost pure products were obtained by a simple evaporation work-up in good to excellent yields and heteroaromatic substrates were also suitable for the reaction [89]. Application of TEMPO as catalyst for the t-butyl nitrite-promoted aerobic oxidation of alcohols, accelerated this process and increased the yields significantly. Furthermore lower reaction temperature (80°C) was required under 0.2MPa of O2 in DCE. Formation of aromatic carboxylic acids (e.g. benzoic acid) by-products were not observed [90]. CHO

t-BuONO, O2(1MPa), CO2(13MPa), 80°C,12-24h

R1

108 R1 = H, 2-Me, 3-Me, 4-Me ,4-Cl R2 = H, CH2OH, CO2Me

109 (11-80 %)

Scheme 53. OH

O R2

t-BuONO, toluene or DME,100-120°C, 8-20h

R1

R1 110

Scheme 54.

R2

R1 = H, Me, OMe, t-Bu, CF3, Cl R2 = H, Me, Et, Pr, Ph

111 (71-99 %)

16 142 Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2

Ferenc Csende

R2

112

R1

R1

OH R1

i-C5H11ONO, DCM, RT, 24h or reflux, 2-15h

O

O R2

R2

R1, R2 = Me, OMe, t-Bu, Ph, Cl

113

(10-65 %)

Scheme 55. O

O

O Ph

R

t-BuONO, cat. FeCl3, 30°C, 12 h

R = H, 2-Me, 3-Me, 4-Me, 4-OMe, 4-F, 4-Cl, 4-Br, 4-I

114

Ph R

O 115 (70-83 %)

Scheme 56. O

O CO2H NH2

n-BuONO, THF, reflux, 16 h, +

47

O NH2 A

Ph +

O

Ph

N H

B

H - PhOH

O

N H 116 (47 %)

Scheme 57.

Oxidation of 2,6-disubstituted phenols 112 with isoamyl nitrite gave the corresponding 4,4’-diphenoquinones 113 (Scheme 55) after 18-24 h at ambient temperature in DCM. When sterically hindering groups, such as tert-butyl or deactivating substituents (R1 or R2 = Cl) occupied the ortho positions, the yields were lower, moreover the higher oxidation potential of 2,6-dichlorophenol completely inhibited its oxidation to diphenoquinone. In the proposed mechanism phenoxy radicals arise by the alkyl nitrite and the free para positions allow dimerization to biphenol, then subsequent oxidation, lead to 4,4’-diphenoquinone [91]. The selective C-C bond cleavage of 1,3-diketones 114 affords the 1,2-diketones 115 in high yields under mild reaction conditions in air by the use of FeCl3 as catalyst and t-butyl nitrite as oxidant without using any solvent (Scheme 56). A high variety of 1,3-diketones were examined and it was found that reaction of unsymmetrical 1,3-diketones was highly selective. Naphthyl-substituted and mono- or diheteroaryl 1,3-diketones also readily transformed into valuable symmetric and unsymmetric 1,2-diketones under similar conditions in good yields (45-84%). According to a plausible mechanism firstly, the radical reaction of 1,3diketones 114 in the presence of alkyl nitrite produced a diketone oxime at the active methylene carbon. The oxime intermediate gave the triketone, which the subsequent (or simultaneous) FeCl3-mediated liberation of CO and cleavage of C-C bond resulted in the 1,2-diketone [92].

7. SYNTHESIS OF HETEROCYCLES WITH AKYL NITRITES 7.1. Preparation of One Nitrogen-containing Heterocycles As we mentioned above (section 3.2.) the reaction of anthranilic acid 47 with alkyl nitrite affords an unstable and highly reactive benzyne (aryne) intermediate via diazotization process. Thus a mixture of anthranilic acid 47 and n-butyl nitrite was refluxed in THF (Scheme 57) and after workup pure acridone 116 was obtained in 47% yield. The acridone formation required 3 equialents of anthranilic acid, due to in situ generation of co-partner benzyne. Presumably, the phenyl anthranilate A intermediate formed first, which with a further molecule benzyne resulted in Nphenyl derivative B and by intramolecular free-radical cyclization led to acridone 116, while splitting off a molecule phenol under reflux [93]. 7.2. Synthesis of Heterocycles with Two or Three Nitrogen Atoms Condensation of the appropriate 2-nitrobenzaldehydes 107 with 2-methyl- and 2-ethylfurans in dioxane in the presence of HClO4, followed by reduction gave 2aminophenyldifurylmethanes 117. These aryl amines were diazotized with isoamyl nitrite and Me3SiCl in MeCN and cinnoline derivatives 118 were isolated (Scheme 58) from

Alkyl Nitrites as Valuable Reagents in Organic Synthesis

R1

NO2

R1

R1

CHO

R1

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 143 17

NH2 O

107 R1= H, OMe, OCH2O, OCH2CH2O

R2

i-C5H11ONO, MeCN, Me3SiCl, 0°C, 15 min,

R1

N

N

R2

O

R1

O

O

R2 117 R = Me, Et 2

R2

118 (76-89 %)

Scheme 58. 1. t-BuONO, TMSN3, MeCN, 2. Cu+,H2O, RT, overnight or MW, 80°C, 10 min. + HC R2

NH2 R1

N N

R1 R1 = H, I, CN, NO2 R2 = C5H11, C6H13, CH3CO, CO2Et, Ph, 3-thienyl, 1-cyclohexenyl

119

N R2

120 (80-96 %)

Scheme 59.

N

O ( )n

O R1

O

R2

N H NH2 121

N

R1 R1 = 5-Cl, 6-Cl, 5,8-diCl, 6-Br, 6-NO2, 8-Me R2 = 1-naphthylmethyl, allyl, cyclobutyl, cyclohexylmethyl n = 0, 1, 3

R2

( )n

O

t-BuONO, AcOH /NMP, 25°C, 16 h

N

N 122

N (80-95 %)

Scheme 60.

the reaction mixture in high yields. Regards to the formation of cinnoline ring, the diazonium intermediate (cyclized by intramolecular electrophilic) was supposed to attack at the furan ring with its subsequent cleavage [94]. The azide-alkyne Huisgen 1,3-dipolar cycloaddition gave 1,2,3-triazoles 120, however the regioselectivity of the reaction depended on electronic and steric effects. Unfortunately, the thermal 1,3-dipolar cycloaddition of alkynes to azides requires elevated temperatures and often produces mixtures of the two regioisomers when using asymmetric alkynes. A copper(I)-catalyzed variant of azidealkyne cycloaddition, can be conducted under aqueous conditions, even at room temperature, to afford 1,4regioisomers of 1,2,3-triazoles as sole products. The practical and efficient one-pot azidation of anilines 119 with combination of t-butyl nitrite and TMSN3 was a useful tool for the click-chemistry. After complete azide formation, in the presence of in situ generated Cu(I) catalyst (from aqueous solution of CuSO4 and sodium ascorbate) was added to the corresponding terminal acetylene (Scheme 59), and reacted at room temperature overnight or heated in the microwave at 80°C for a few minutes to give 1,2,3-triazoles 120. Reaction times were dramatically reduced and product yields greatly increased using microwave radiation [95].

The 1,2,3-benzotriazin-4-ones display several pharmaceutically remarkable activities such as sedative, diuretic, anesthetic and antiarthritic effects. Hereby the improvement of the solid-phase synthesis of substituted derivatives is important method for drug development. The classical ring closure route starting from 2-aminobenzamides by diazotization in a NaNO2-acid system was difficult or unsuccessful, therefore a combination of t-butyl nitrite/AcOH was examined in the presence of N-methylpyrrolidone (NMP) (Scheme 60). This procedure proved to be an appropriate method to accomplish various substituted 1,2,3-benzotriazin4-ones. After treating resins with 95% aqueous THF, benzotriazinones were obtained successfully with a variety of substituents in high purity and good yields [96]. 7.3. Preparation of Isoxazoles and 1,2-benzisoxazoles A simple and efficient two-step procedure was developed to prepare 5-substituted isoxazoles from tertiary cyclopropanols 123. By treating with an excess of amyl nitrite at room temperature cyclopropanols, are smoothly converted into dimeric β-nitrosoketones (Scheme 61), and by subsequent heating the methanolic solutions of the latter under reflux affords 5-substituted isoxazoles in good yields. Keeping the mixture of substituted cyclopropanol, amyl

18 144

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Ferenc Csende

nitrite, and small amount of benzene at room temperature for two to three days yielded dimeric β-nitrosoketones 124 almost quantitatively. After the removal of volatile reactants under reduced pressure crystalline compounds 124 were isolated as mixtures of Z and E isomers. The conversion of β-nitrosoketones 124 into isoxazoles 125 proceeded via the intermediate formation of 5-substituted-5-hydroxy-Δ2isoxazoline [97]. OH

O

n-C5H11ONO, PhH, RT, 48-78 h

R

R

A novel synthesis of 3-substituted benzisothiazoles 129 was reported starting from easily available o-mercaptoacylphenones 128 treating with i-pentyl nitrite in THF (Scheme 63) then addition to EtPPh2. The key cyclization step was a mild S-nitrosation that was followed by intramolecular azaWittig reaction leading to the formation of the benzisothiazole ring. Organophosphines reacted with S-nitrosothiols to form azaylide intermediates and these reactive intermediates could undergo intramolecular reactions with different electrophiles attached on the phosphine substrates. Different alkyl nitrites were evaluated but ethyl nitrite did not lead to any detectable benzisothiazole formation, while tbutyl nitrite provided the desired product in a moderate yield (33%). i-Pentyl nitrite proved to be the best reagent, which afforded benzisothiazole 129 in good yield (70%). Numerous solvents and phosphine reagents were also examined (e.g. THF, dioxane, DMF, DCM, benzene), however the THF and EtPPh2 were found as the best suitable agents for this reaction. Although PPh3 showed good reactivity in this process, other phosphine reagents (PBu3, P(OEt)3) were ineffective or moderately effective [99].

O

N

N

O

R

O

123 R = n-hexyl, n-octyl, Ph, 9-decenyl, 2,2-diethoxyethyl

124 (62-90 %) MeOH, reflux, 10-72 h

N

R

O

125 (67-92 %)

Scheme 61.

O

Several 1,2-benzisoxazole derivatives show different potent pharmacological properties. A simple and efficient one-pot protocol for the preparation of these compounds was described, which based on an improved 1,3-dipolar cycloaddition of nitrile oxides and benzyne. Key steps to the procedure are the in situ generation of the reactive nitrile oxide and benzyne simultaneously by alkyl nitrite from anthranilic acid 47 and hydroximoyl chlorides 126 as precursors. This approach to 1,2-benzisoxazoles 127 was accelerated by using microwave irradiation or heating in a sealed tube, which led to improved yields compared to previous methods (Scheme 62). Practically, the mixture of arylhydroximoyl chloride 126, anthranilic acid 47 (2.0 equiv.) and K2CO3 was reacted in MeCN followed by the addition of t-butyl nitrite (2.0 equiv.), then it was heated in a microwave reactor at 120°C. Purification of the reaction mixture using flash column chromatography gave 3-phenyland 3-naphthyl-1,2-benzisoxazoles 127 in good to excellent yields [98]. NH2

HO

+ CO2H

N

Cl

R

1. i-C5H11ONO, THF, 0°C, 5 min. 2. EtPPh2MeCN, 0°C to RT, 1h

R = Me, n-Bu, s-Bu, Ph, 2-MePh, 4-MePh, 2-MeOPh, 4-MeOPh

126

8. MISCELLANEOUS REACTIONS The stereospecific and convenient deamination of substituted aziridines 130 to the corresponding alkenes 131 was achieved by application of n-butyl nitrite (Scheme 64) and addition of a small amount of Et3N in mild conditions. Presumably, after N-nitrosation a deamination process took place by spliting off the gaseous N2O from the N-nitroso intermediate spontaneously, leading to the substituted alkenes 131 in good to quantitative yields [100].

t-BuONO, K2CO3, MeCN, MW, 120°C, 10 min.

O N

R

R = 2,6-diMe, 2-Et, 4-i-Pr, 4-Ph, 2-MeO, 4-MeO, 4-NO2, 2-NO2

(39-96 %)

127

Scheme 62. R1 R2

R3 N H

R4

n-BuONO, Et3N THF, RT

R1 R2

130 R1, = H, Ph R2 = H, Me R3 = n-C5H11, n-C6H13, Ph, Bn, R4 = H, Me, Et, Ph,

Scheme 64.

129 (37-85 %)

Scheme 63.

R

47

N S

SH 128

R

R3 N

R4

-N2O

R1

R3

R2

R4

NO 131

(58-100 %)

Alkyl Nitrites as Valuable Reagents in Organic Synthesis

Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2 145 19 145

When α-amino acid esters 132 dissolved in CHCl3 or benzene and were refluxed with isoamyl nitrite in the presence of a small amount of acid, α-diazo ester 133 were obtained (Scheme 65) in fairly good yields. It was necessary to purify the products by chromatography on alumina to remove slight amounts of α-hydroxy acids as by-products. In this way a high variety esters of amino acids (e.g. alanine, valine, leucine, phenylalanine, tyrosine or tryptophan) were converted to diazo-derivatives. Several organic acids were tried out, the AcOH or benzoic acid gave the best results, while using stronger acids such as CF3 CO2H or HCl were less effective. The CHCl3 and benzene were found to be the most suitable solvent, unlike using EtOH, Et2O or DMF, which decreased the yields dramatically. The application of this method for the synthesis of α-diazoamide or diazopeptide derivatives was unsuccessful in most cases [101]. O R1

OR2

Me

R1

Me

OR2

Me

O

O

Me

O

O Me

2

Arylboronic acids and arylboronates have found common applications in transition-metal-catalyzed C-C bond forming reactions, as represented in the Suzuki-Miyaura crosscoupling reaction. The standard procedure for the conversion of arylamines to arylboronic acids or boronates requires two steps, namely a Sandmeyer reaction to convert the amino group into a halogen group, followed by the use of Grignard reagent or a Pd-catalyzed borylation. A novel and special method replaces the aromatic amino group with a boron group under Sandmeyer reaction conditions directly. Thus, when a solution of substituted anilines 2, bis(pinacolato)diboron (B2pin2) 134 and t-butyl nitrite in MeCN was

i-C5H11ONO, THF, 0°C, 5-10 min.

N

R2

R1

Scheme 67.

n(

)

n-C5H11ONO, AcOH/HCl (3:1), -10°C

139 n = 1-4, 8

Cl

O n(

NO

)

140

Cl

n(

N

)

( )n

N O Cl 141 (75-85 %)

levulinic acid, HCl, 75°C, 4-6.5 h n(

)

O

Cl 142 (75-89 %)

Scheme 68.

135

Me

(22-93 %)

When different alkyl- or aryl thioacids were treated with alkyl nitrites or HCl/NaNO2 in organic solutions at room temperature or 0°C the corresponding S-nitrosothioacids were formed. Although the S-nitrosothioacids prepared were unstable on the course of studies, it was practically necessary to trap S-nitrosothioacids in situ with some nucleophiles. Amines proved to be excellent substrates, and the formation of amide from thioacids via S-nitrosothioacids intermediate was realized in a very successful and rapid route. The coupling reaction between thioacid and amines was carried

R1 = t-Bu, Bn, CH2CO2Me, 138 (77-100 %) R2 = H, Bn or R1,R2= -(CH2)4-

137

O

Scheme 66.

O

136

Me

B R

O H

Me O

R = H, 2-Me, 4-Me, 4-OMe, 2-Ac, 4-Ac, 2-NO2, 3-NO2, 4-NO2, 4-F, 4-Cl, 4-Br, 2-CN, 4-CN, 4-AcNH, 3-CF3, 4-CF3

Scheme 65.

+ R1 N R2

Me

Me

133 (26-86 %)

SH

Me

134 t-BuONO, BPO, MeCN, RT or 60°C, 1-2h

NH2

R

N2 R1, = Me, i-Pr, i-Bu, Ph, Bn, BOM R2 = Me, Et, n-Bu, Bn, 4-NO2Ph

Me B B

O

i-C5H11ONO, AcOH, CHCl3, reflux, 15-60 min

NH2 132

heated at 60°C for 1 h, phenylboronates 135 were obtained in medium yields (Scheme 66). Using benzoyl peroxide (BPO) as an additive, the reaction could be carried out at room temperature with improved yields, although the reaction time was extended from 1 to 2 hours. Furthermore the reaction was marginally affected by solvents and the ratio of reaction component too. The reaction occurred smoothly with meta- and para-substituted arylamines, while reactions with ortho-substituted arylamines gave lower yields or in the case of o-nitroaniline only trace amounts of the product. However substrates with electron-withdrawing groups at the para and meta positions exhibited good reactivity [102].

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Mini-Reviews in Organic Chemistry, 2015, Vol. 12, No. 2

out with amyl nitrite in THF at 0°C (Scheme 67). Other solvents (DCM, DMF, MeCN) were also observed as suitable conditions for this reaction. Amidation of Nprotected α-aminothioacids also resulted in the corresponding aliphatic amide in similarly good yields (7189%) [103]. An excellent development of a simple method for the preparation of α-chloroketones 142 starting from alkenes 139 according to the green chemistry principle of solvent-free reaction was reported recently. The procedure involved addition of NOCl (generated in situ by the reaction of AcOH/HCl (3:1) with amyl nitrite) to cycloalkenes 139 resulting in vic-chloronitroso compounds 140, which after spontaneous transformation were isolated as dimers 141 (Scheme 68). The latter is a three-step domino reaction, in which the first is the dissociation of dimer to monomer 140, the second is the tautomerisation of the nitroso function to oxime followed by deoximation in the third step by heating for 4-6 h to get finally the desired α-chloroketone 142 in good yield. The isolation of monomer vic-chloronitroso cycloalkanes 140 and oxime intermediates would be difficult and there is unnecessary [104]. The gem-chloronitroso and vic-chloronitroso compounds were also prepared from ketoximes and olefins by reacting with NOCl generated in situ from chlorotrimethylsilane (TMSCl) and isoamyl nitrite. Cetyltrimethylammonium hypochlorite (CTAHC) oxidized gem-chloronitroso and vicchloronitroso compounds to the corresponding chloronitro derivatives. While gem-chloronitro derivatives were obtained in good yields, the vic-chloronitro derivatives were formed in moderate yields, because of the propensity of the vicchloronitroso group to tautomerize into α-chlorooxime [105].

Ferenc Csende [8]

[9] [10] [11]

[12]

[13] [14]

[15] [16] [17] [18] [19] [20]

CONFLICT OF INTEREST The author confirms that this article content has no conflict of interest.

[21]

ACKNOWLEDGEMENTS The author would like to thank Gergely Csende and Dr. Tibor Tímár for their careful revision of manuscript and their useful remarks.

[22]

[23]

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Revised: May 28, 2014

Accepted: November 10, 2014