Halodiazirines as Valuable Reagents for the Synthesis of Halocyclo­propanes

This short review is dedicated to Prof. Alain Krief on the occasion of his 80^th birthday.

Abstract

Halodiazirines have emerged as very useful reagents in photochemically or thermally mediated cyclopropanation reactions with alkenes. This short review highlights the synthetic applications of these reagents as precursors of halocarbenes in transformations with various alkenes.

1 Introduction

2 Cyclopropanation of Aryl Halodiazirines

3 Tandem Reactions Using Aryl Halodiazirines

4 Cyclopropanation of Alkyl- and Benzyl-halodiazirines

5 Cyclopropanation of Other Halodiazirines

6 Reactions of Halodiazirines with Alkynes

7 Conclusion and Outlook

Introduction

Diazirines are well-known carbene precursors and versatile reagents in organic synthesis.[1] Halodiazirines have been used as promising precursors of halocarbenes. In particular, halodiazirines have emerged as ideal substrates for spectroscopic and mechanistic studies of carbenes.[1] [2] [3] For the sake of space limits, this short review will mainly highlight synthetic transformations of halodiazirines with alkenes. The synthesis of halodiazirines was reported for the first time by Graham in 1965.[4] The one-pot oxidation of amidine salts into halodiazirines was reported using bleach. In this reaction, an amidine salt is reacted with NaOCl or NaOBr to give chloro- or bromodiazirines, where R is an alkyl or alkoxy, and X is either Cl or Br, with the yields of the oxidation step being typically around 20–60% (Scheme [1], eq 1). Amidines are prepared from the corresponding amidates, which are themselves made from nitriles. Therefore, the availability of the reactants makes halodiazirines an attractive potential halocarbene source. Trichloroamidines can be readily prepared from amidine hydrochlorides via chloroamidines by sequential chlorination with sodium hypochlorite and tert-butyl hypochlorite. Subsequent treatment with LiBr afforded mixtures of the corresponding bromo- and chlorodiazirines (Scheme [1], eq 2).[5] In addition, carboalkoxy-N,N,N′-trichloroformamidines were reductively dechlorinated into carboalkoxyhalodiazirines with LiBr (Scheme [1], eq 3).[6] [7]

Cyclopropanation of Aryl Halodiazirines

In 1981, Padwa et al. reported the reaction of chlorophenyldiazirine with trans-β-methylstyrene under thermal conditions followed by dehydrohalogenation to produce aryl-substituted cyclopropenes (Scheme [2]).[8] Chlorophenyldiazirine easily generates chlorophenylcarbene, which was reacted with various olefins to afford halocyclopropanes. These halocyclopropanes were then treated with potassium tert-butoxide to afford good yields of the corresponding cyclopropenes. Access to a carboxylic acid substituted cyclopropene was disclosed by Schmitz et al.[9] The reaction of chlorophenyldiazirine with methyl 3,3-dimethylacrylate at 95 °C gave a cis/trans mixture of a chlorocyclopropanecarboxylate in 70% yield (Scheme [2]). Subsequent base-mediated elimination and saponification by KOH in toluene afforded 3,3-dimethyl-2-phenyl-cyclopropenecarboxylic acid in 50% yield.

The reaction of chlorophenyldiazirine was investigated with various electron-rich alkenes used in excess, including enol ethers, under thermal conditions (Scheme [3]).[10] Doyle et al. found that α,β-unsaturated esters and nitriles reacted with chlorophenyldiazirine with a similar reactivity towards chlorophenylcarbene. This method was highlighted as an efficient route toward various chlorocyclopropanes.

Alternative methods as practical techniques for producing arylchlorocarbenes, such as the use of ultrasound or photolysis, have been reported (Scheme [4]).[11] The in situ generated carbenes were reacted with electron-poor unsaturated substrates. The yields of cyclopropanes from the ultrasonic studies are comparable to those from photolysis.

In 1994, Bonneau et al. reported the synthesis of chlorocyclopropanes from the reactions of various arylchlorodiazirines with allyl bromide (Scheme [5]).[12] An azine was also formed as a by-product when p-chlorophenylchlorodiazirine was used.[12] It was suggested by the authors that the cycloaddition of the corresponding carbene with allyl bromide is a slow reaction. In the case of p-nitrophenylchlorocarbene, a small amount of insertion product was also afforded in addition to the cyclopropanes. The formation of this side product was rationalized by the attack of the carbene on the bromine atom to generate a brominium ylide followed by an intramolecular allylic rearrangement.[12]

The reaction of C₆₀ with an equimolar amount of chlorophenyldiazirine in refluxing toluene afforded a C₆₀-chlorophenylcarbene 1:1 adduct (Scheme [6]).[13] The [6,6] adduct to C₆₀ was shown to possess the cyclopropane structure and was obtained in a moderate yield. Whereas diazirines can react with fullerenes via carbene precursors and/or diazoalkanes to afford the corresponding [6,6] and [5,6] adducts,[14] [15] the formation of the latter was seen to be negligible in the reaction with chlorophenyldiazirine, suggesting that its thermolysis yielded only a carbene as the intermediate.

The thermal and photochemical reactions of p-nitrophenylbromo- and p-nitrophenylchlorodiazirines with cis-butene afforded the corresponding cis-di-Me cyclopropanes in good yields (Scheme [7]).[16] Interestingly, the trans-di-Me cyclopropanes were isolated as side products (2–15% yields) when the reaction was run under photochemical conditions.

The decomposition of phenylchlorodiazirine in the presence of diethyl fumarate and diethyl maleate provided results of special significance (Scheme [8]).[17] [18] Only the trans diastereoisomer of the cyclopropane was obtained using diethyl fumarate. However, under the same conditions, the reaction of diethyl maleate led to the formation of three cyclopropane products, two of which preserved the cis geometry of the reactant alkene and one of which was a trans stereoisomer. This rearrangement involved the existence of a reaction intermediate with sufficient lifetime to allow bond rotation to occur. It was noted that no isomerization of diethyl maleate into diethyl fumarate occurred under the conditions. Indeed, control experiments established that isomerization did not occur in the absence of the diazirine under either the photochemical conditions employed for diazirine decomposition or even after heating in carbon tetrachloride under reflux for 3 days.

Fluorophenyldiazirines were obtained from the corresponding bromodiazirines by halide exchange using nBu₄NF.[19] They were photolyzed (λ > 300 nm) in the presence of 10-fold excesses of various alkenes, i.e., tetramethylethylene, trimethylethylene, isobutene, cis-2-butene, and trans-2-butene, and afforded the fluorocyclopropanes in yields ranging from 42% to 76% (Scheme [9]).[19] [20]

Arylchlorocarbenes with enhanced electrophilicity were also studied by Moss et al. (Scheme [10]).[21] [22] 3,5-Dinitrophenylchlorodiazirine was reacted with tetramethylethylene at 350 nm in pentane and afforded the corresponding cyclopropane in 70% yield. Moreover, pentafluorophenylhalodiazirines were appropriate reagents in the reaction with trans-2-butene. Interestingly, fluorocyclopropanes were prepared in good yields using this method.

Furthermore, the thermolysis of aryl halodiazirines was investigated in the presence of 1-cyclohexene-1-isocyanate by Rigby (Scheme [11]).[23]

Tandem Reactions Using Aryl Halodiazirines

The reaction of 3-chloro-3-phenyldiazirine with coumarin was initially studied in the context of the reactions of aryl halodiazirines with α,β-unsaturated carbonyl compounds. The isolated product was a bicyclic cyclopropane obtained as a mixture of endo and exo isomers in an overall yield of 70% (Scheme [12]).[24] In 1990, the same authors reported the successful cyclopropanation of benzofuran with the same 3-chloro-3-phenyldiazirine. Under these conditions, a cyclopropane product was obtained in 57% yield. Subsequently, this product was heated in water and afforded an intermediate benzopyrylium ion, which was further transformed into a bis(acetal) dimer in 79% yield.[25]

The intramolecular addition of unsaturated alkoxycarbenes to produce fused cyclopropanes in high yield and dia­stereoselectivity was reported in 1993 by the Vasella group (Scheme [13]).[26] The halodiazirine was treated with o-hydro­xycinnamate to give an alkoxydiazirine, as a thermally labile intermediate, evolving to a cyclopropa[b]benzofuran through intramolecular cycloaddition.

Dherange et al. reported that chlorodiazirine reagents enable a versatile novel ring expansion reaction with pyrrole and indole substrates (Scheme [14]).[27] The classic haloform-based process from the Ciamician–Dennstedt rearrangement can be modified to directly lead to 3-(hetero)arylpyridines and quinolines. Ring expansion of fused indoles provides access to quinolinophanes, which would otherwise be difficult to prepare.

Cyclopropanation of Alkyl- and Benzyl-halodiazirines

The reaction of chloromethyldiazirine was investigated by Moss et al. with various simple alkenes under photochemical conditions (Scheme [15]).[28] Stereospecificity and stereoselectivity aspects were studied, with the cyclopropanes usually being obtained in low yields.

In 1984, Tomioka et al. reported the addition of an alkene to a photolytically generated benzylchlorocarbene (Scheme [16]).[29] Irradiation of 3-benzyl-3-chlorodiazirines in cyclohexane was carried out with a high-pressure Hg lamp at 10 °C until all the diazirine had decomposed. Cyclopropanes were isolated together with E- and Z-4-methyl-2-pentene. Laser flash photolysis of 3-chloro-3-α,α-dichlorobenzyldiazirine generated α,α-dichlorobenzylchlorocarbene, which reacted with tetramethylethylene to afford a cyclopropane in a moderate yield.[30]

Cyclopropanation of Other Halodiazirines

Chloro-3-phenoxydiazirine was reacted with various alkenes to produce the corresponding cyclopropanes in low to moderate yields (Scheme [17]).[31] The PhOCCl carbene seemed to have an ambiphilic reactivity pattern similar to that of MeOCCl, but different from the electrophilic reactivity patterns of CCl₂ and MeCCl.

Fluorophenoxydiazirine was thermolyzed in an excess of degassed tetramethylethylene at 150 °C to give 35% of 1-fluoro-1-phenoxy-2,2,3,3-tetramethylcyclopropane (Scheme [18]).[20]

Thermolysis of carboalkoxychloro- and carboalkoxybromo-diazirines in tetramethylethylene afforded the corresponding cyclopropane carboxylates with high yields ranging from 89% to 96% (Scheme [19]).[6]

On pyrolysis, various halodiazirines generate the intermediate cyanofluoro-, fluoromethoxy-, and fluorodifluoramino-carbenes and react with tetrafluoroethylene to afford the corresponding cyclopropanes in low to moderate yields (Scheme [20]).[32]

Reactions of Halodiazirines with Alkynes

Phenylchlorocarbene, either generated through thermal or photochemical decomposition of phenylchlorodiazirine, can be trapped by substituted acetylenes to give cyclopropenyl compounds (Scheme [21]).[33] The [2 + 1] cycloaddition of phenylchlorocarbenes with alkynes was studied. Padwa disclosed the reaction of chlorophenyldiazirine with diphenylacetylene. The triphenylcyclopropenyl chloride was obtained and its structure confirmed after conversion into the corresponding ethyl ether by heating it in ethanol. When reacted with phenylacetylene, chlorophenyldiazirine was converted into bis-Δ′-l,2-diphenylcyclopropenylether by heating the obtained product in aqueous ethanol.

In 1987, the reactions of (phenylethynyl)naphthalene derivatives with chlorophenyldiazirine were disclosed by Komatsu.[34] When (phenylethynyl)naphthalene (Scheme [22], eq 1) or 1,5-bis(phenylethynyl)naphthalene (Scheme [22], eq 2) were reacted with chlorophenyldiazirine, the carbene adducts were isolated as fairly stable covalent chlorides. However, when 1,8-bis(phenylethynyl)naphthalene was heated with two equivalents of phenylchlorodiazirine in benzene, the reaction did not stop at the stage of formation of the monocyclopropene adduct but proceeded further toward the formation of a spirocyclopropene with a yield of 87%, together with a trace of a bis-carbene adduct (1.5%) (Scheme [22], eq 3).

Conclusion and Outlook

The chemistry of halodiazirine compounds continues to be a fascinating part of organic synthesis. Halodiazirines appear to be very useful in cyclopropanation reactions mediated either photochemically or thermally. Various highly valuable building blocks containing halogens have been obtained. Halocyclopropanes prepared in situ have also been used in the synthesis of heterocycles. Halodiazirines constitute attractive alternatives to diazo compounds for affording halocarbenes in situ. Therefore, a wider variety of halocyclopropane-containing molecules can be accessed. Whereas halodiazirines were often used in cyclopropanation reactions, telescoped synthetically useful transformations have been disclosed. These results suggest that synthetic transformations of halodiazirines can now be actively extended to other types of reaction. This family of compounds is definitively very promising in synthesis. The current activity in this field will develop even more and considerably enrich the chemist’s toolbox in carbene chemistry.

Conflict of Interest

The authors declare no conflict of interest.

• References

• 1 Moss RA. Acc. Chem. Res. 2006; 39: 267
  CrossrefPubMedSearch in Google Scholar
• 2 Moss RA, Tian J, Chu G, Sauers RR, Krogh-Jespersen K. Pure Appl. Chem. 2007; 79: 993
  CrossrefSearch in Google Scholar
• 3 Creary X. Acc. Chem. Res. 1992; 25: 31
  CrossrefSearch in Google Scholar
• 4 Graham WH. J. Am. Chem. Soc. 1965; 87: 4396
  CrossrefSearch in Google Scholar
• 5 Martinu T, Dailey WP. J. Org. Chem. 2006; 71: 5012
  CrossrefPubMedSearch in Google Scholar
• 6 Martinu T, Dailey WP. J. Org. Chem. 2004; 69: 7359
  CrossrefPubMedSearch in Google Scholar
• 7 Martinu T, Boehm S, Hanzlova E. Eur. J. Org. Chem. 2011; 6254
  Crossref
• 8 Padwa A, Pulwer MJ, Blacklock TJ. Org. Synth. 1981; 60: 53
  CrossrefSearch in Google Scholar
• 9 Schmitz E, Sonnenschein H, Kuban RJ. Tetrahedron Lett. 1985; 26: 4911
  CrossrefSearch in Google Scholar
• 10 Doyle MP, Terpstra JW, Winter CH. Tetrahedron Lett. 1984; 25: 901
  CrossrefSearch in Google Scholar
• 11 Bertram AK, Liu MT. H. J. Chem. Soc., Chem. Commun. 1993; 467
  Crossref
• 12 Bonneau R, Grobys M, Liu MT. H, Himori M, Fukushima K, Ibata T. Res. Chem. Intermed. 1994; 20: 141
  CrossrefSearch in Google Scholar
• 13 Komatsu K, Kagayama A, Murata Y, Sugita N, Kobayashi K, Nagase S, Wan TS. M. Chem. Lett. 1993; 2163
  Crossref
• 14 Kooistra FB, Leuning TM, Maroto Martinez E, Hummelen JC. Chem. Commun. 2010; 46: 2097
  CrossrefPubMedSearch in Google Scholar
• 15 Liu MT. H, Choe Y.-K, Kimura M, Kobayashi K, Nagase S, Wakahara T, Niino Y, Ishitsuka MO, Maeda Y, Akasaka T. J. Org. Chem. 2003; 68: 7471
  CrossrefPubMedSearch in Google Scholar
• 16 Moss RA, Lu Z, Sauers RR. Tetrahedron Lett. 2010; 51: 5940
  CrossrefSearch in Google Scholar
• 17 Doyle MP, Loh KL, Nishioka LI, McVickar MB, Liu MT. H. Tetrahedron Lett. 1986; 27: 4395
  CrossrefSearch in Google Scholar
• 18 Soundararajan N, Platz MS, Jackson JE, Doyle MP, Oon SM, Liu MT. H, Anand SM. J. Am. Chem. Soc. 1988; 110: 7143
  CrossrefSearch in Google Scholar
• 19 Moss RA, Lawrynowicz W. J. Org. Chem. 1984; 49: 3828
  CrossrefSearch in Google Scholar
• 20 Cox DP, Moss RA, Terpinski J. J. Am. Chem. Soc. 1983; 105: 6513
  CrossrefSearch in Google Scholar
• 21 Moss RA, Shen Y.-M, Wang L, Krogh-Jespersen K. Org. Lett. 2011; 13: 4752
  CrossrefPubMedSearch in Google Scholar
• 22 Wang L, Krogh-Jespersen K, Moss RA. J. Org. Chem. 2015; 80: 7590
  CrossrefPubMedSearch in Google Scholar
• 23 Rigby JH, Aasmul M. Heterocycles 2004; 62: 143
  CrossrefSearch in Google Scholar
• 24 Schmitz E, Sonnenschein H. Z. Chem. 1987; 27: 171
  CrossrefSearch in Google Scholar
• 25 Sonnenschein H, Schmitz E, Pritzkow W. Liebigs Ann. Chem. 1990; 277
  Crossref
• 26 Li C, Vasella A. Helv. Chim. Acta 1993; 76: 197
  CrossrefSearch in Google Scholar
• 27 Dherange BD, Kelly PQ, Liles JP, Sigman MS, Levin MD. J. Am. Chem. Soc. 2021; 143: 11337
  CrossrefPubMedSearch in Google Scholar
• 28 Moss RA, Mamantov A. J. Am. Chem. Soc. 1970; 92: 6951
  CrossrefSearch in Google Scholar
• 29 Tomioka H, Hayashi N, Izawa Y, Liu MT. H. J. Chem. Soc., Chem. Commun. 1984; 476
  Crossref
• 30 Liu MT. H, Bonneau R. J. Org. Chem. 1992; 57: 2483
  CrossrefSearch in Google Scholar
• 31 Moss RA, Perez LA, Wlostowska J, Guo W, Krogh-Jespersen K. J. Org. Chem. 1982; 47: 4177
  CrossrefSearch in Google Scholar
• 32 Mitsch RA, Neuvar EW, Koshar RJ, Dybvig DH. J. Heterocycl. Chem. 1965; 2: 371
  CrossrefSearch in Google Scholar
• 33 Padwa A, Eastman D. J. Org. Chem. 1969; 34: 2728
  CrossrefSearch in Google Scholar
• 34 Komatsu K, Arai M, Hattori Y, Fukuyama K, Katsube Y, Okamoto K. J. Org. Chem. 1987; 52: 2183
  CrossrefSearch in Google Scholar

Corresponding Author

Publication History

Received: 06 October 2022

Accepted after revision: 17 October 2022

Accepted Manuscript online:
17 October 2022

Article published online:
16 November 2022

© 2022. Thieme. All rights reserved

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• References

• 1 Moss RA. Acc. Chem. Res. 2006; 39: 267
  CrossrefPubMedSearch in Google Scholar
• 2 Moss RA, Tian J, Chu G, Sauers RR, Krogh-Jespersen K. Pure Appl. Chem. 2007; 79: 993
  CrossrefSearch in Google Scholar
• 3 Creary X. Acc. Chem. Res. 1992; 25: 31
  CrossrefSearch in Google Scholar
• 4 Graham WH. J. Am. Chem. Soc. 1965; 87: 4396
  CrossrefSearch in Google Scholar
• 5 Martinu T, Dailey WP. J. Org. Chem. 2006; 71: 5012
  CrossrefPubMedSearch in Google Scholar
• 6 Martinu T, Dailey WP. J. Org. Chem. 2004; 69: 7359
  CrossrefPubMedSearch in Google Scholar
• 7 Martinu T, Boehm S, Hanzlova E. Eur. J. Org. Chem. 2011; 6254
  Crossref
• 8 Padwa A, Pulwer MJ, Blacklock TJ. Org. Synth. 1981; 60: 53
  CrossrefSearch in Google Scholar
• 9 Schmitz E, Sonnenschein H, Kuban RJ. Tetrahedron Lett. 1985; 26: 4911
  CrossrefSearch in Google Scholar
• 10 Doyle MP, Terpstra JW, Winter CH. Tetrahedron Lett. 1984; 25: 901
  CrossrefSearch in Google Scholar
• 11 Bertram AK, Liu MT. H. J. Chem. Soc., Chem. Commun. 1993; 467
  Crossref
• 12 Bonneau R, Grobys M, Liu MT. H, Himori M, Fukushima K, Ibata T. Res. Chem. Intermed. 1994; 20: 141
  CrossrefSearch in Google Scholar
• 13 Komatsu K, Kagayama A, Murata Y, Sugita N, Kobayashi K, Nagase S, Wan TS. M. Chem. Lett. 1993; 2163
  Crossref
• 14 Kooistra FB, Leuning TM, Maroto Martinez E, Hummelen JC. Chem. Commun. 2010; 46: 2097
  CrossrefPubMedSearch in Google Scholar
• 15 Liu MT. H, Choe Y.-K, Kimura M, Kobayashi K, Nagase S, Wakahara T, Niino Y, Ishitsuka MO, Maeda Y, Akasaka T. J. Org. Chem. 2003; 68: 7471
  CrossrefPubMedSearch in Google Scholar
• 16 Moss RA, Lu Z, Sauers RR. Tetrahedron Lett. 2010; 51: 5940
  CrossrefSearch in Google Scholar
• 17 Doyle MP, Loh KL, Nishioka LI, McVickar MB, Liu MT. H. Tetrahedron Lett. 1986; 27: 4395
  CrossrefSearch in Google Scholar
• 18 Soundararajan N, Platz MS, Jackson JE, Doyle MP, Oon SM, Liu MT. H, Anand SM. J. Am. Chem. Soc. 1988; 110: 7143
  CrossrefSearch in Google Scholar
• 19 Moss RA, Lawrynowicz W. J. Org. Chem. 1984; 49: 3828
  CrossrefSearch in Google Scholar
• 20 Cox DP, Moss RA, Terpinski J. J. Am. Chem. Soc. 1983; 105: 6513
  CrossrefSearch in Google Scholar
• 21 Moss RA, Shen Y.-M, Wang L, Krogh-Jespersen K. Org. Lett. 2011; 13: 4752
  CrossrefPubMedSearch in Google Scholar
• 22 Wang L, Krogh-Jespersen K, Moss RA. J. Org. Chem. 2015; 80: 7590
  CrossrefPubMedSearch in Google Scholar
• 23 Rigby JH, Aasmul M. Heterocycles 2004; 62: 143
  CrossrefSearch in Google Scholar
• 24 Schmitz E, Sonnenschein H. Z. Chem. 1987; 27: 171
  CrossrefSearch in Google Scholar
• 25 Sonnenschein H, Schmitz E, Pritzkow W. Liebigs Ann. Chem. 1990; 277
  Crossref
• 26 Li C, Vasella A. Helv. Chim. Acta 1993; 76: 197
  CrossrefSearch in Google Scholar
• 27 Dherange BD, Kelly PQ, Liles JP, Sigman MS, Levin MD. J. Am. Chem. Soc. 2021; 143: 11337
  CrossrefPubMedSearch in Google Scholar
• 28 Moss RA, Mamantov A. J. Am. Chem. Soc. 1970; 92: 6951
  CrossrefSearch in Google Scholar
• 29 Tomioka H, Hayashi N, Izawa Y, Liu MT. H. J. Chem. Soc., Chem. Commun. 1984; 476
  Crossref
• 30 Liu MT. H, Bonneau R. J. Org. Chem. 1992; 57: 2483
  CrossrefSearch in Google Scholar
• 31 Moss RA, Perez LA, Wlostowska J, Guo W, Krogh-Jespersen K. J. Org. Chem. 1982; 47: 4177
  CrossrefSearch in Google Scholar
• 32 Mitsch RA, Neuvar EW, Koshar RJ, Dybvig DH. J. Heterocycl. Chem. 1965; 2: 371
  CrossrefSearch in Google Scholar
• 33 Padwa A, Eastman D. J. Org. Chem. 1969; 34: 2728
  CrossrefSearch in Google Scholar
• 34 Komatsu K, Arai M, Hattori Y, Fukuyama K, Katsube Y, Okamoto K. J. Org. Chem. 1987; 52: 2183
  CrossrefSearch in Google Scholar