The chemistry of diazo compounds has a long history, including the frequent application of these reactants in organic synthesis, for example, as carbene and carbenoid precursors. Diazo compounds can be easily prepared by convenient procedures and possess various reactivity, depending on the structure. The main achievements in chemistry of diazo compounds have been reviewed in detail.1 10

This review is dedicated to carbenoid reactions at С–Н bonds as key steps in the total synthesis of some natural compounds and their synthetic analogs, characterized by a broad range of biological activity. However, this review is not meant to be comprehensive and can provide only a general view of the synthetic potential of such reactions.

The unusual reaction of carbene insertion at hydrocarbon C–H bonds was discovered a half-century ago and attracted considerable interest due to its potential for building new С–С bonds.11 The insertion of diazo compounds at the C–H bond in the synthesis of heterocyclic compounds was developed by Davies,12 , 13 Doyle,14 , 15 Du Bois,16 Taber,17 , 18 and others. Such C–H insertion reactions are the key steps in many syntheses of heterocyclic systems, analogs of natural compounds.19

Intramolecular insertion reactions at C–H bonds have the highest synthetic importance, while only a few cases are known for intermolecular reactions of this type.20 , 21 The theoretical aspects, mechanism, catalysts, chemo-, regio-, diastereo-, and enantioselectivity of intra- and intermolecular insertion reactions of diazo compounds at С–Н bonds have been reviewed.3

Synthesis of nitrogen-containing heterocycles

The intramolecular insertion of diazocarbonyl compounds in C–H bonds is mostly used in the synthesis of fivemembered nitrogen-containing heterocycles.16 The pyrrolidine moiety is found as a structural or substructural unit in many biologically active alkaloids.

A convenient method for the synthesis of highly functionalized pyrrolidine derivatives, which can be used as intermediates for obtaining more complex synthetic targets, has been proposed based on intramolecular C–H bond insertion of diazoamides and pyrrolidine diazo derivatives. It was shown that the protective group at nitrogen atom must be unreactive towards metallocarbenoids, while also promoting intramolecular insertion at C–H bonds, forming nitrogen-containing heterocyclic compounds.22 , 23 For example, (+)-α-allokainic acid (4) was obtained from the key diazoamide 1, which was synthesized from serine.24 The intramolecular insertion at C–H bond (Scheme 1) occurred highly regio- and diastereoselectively with the formation of functionally substituted pyrrolidinone 2, subsequently transformed to the ester 3 and then to (+)-α-allokainic acid (4).

Scheme 1
scheme 1

Later it was shown that sterically crowded protecting groups at the nitrogen atom, for example, bis(trimethylsilyl) methyl (BTMSM) group and the electronwithdrawing pivaloxyl group hinder the alternative insertion at the C–H bond and the starting diazo ketone 5 is smoothly cyclized to the pyrrolidinone 6 (Scheme 2) with high regio-, chemo-, and diastereoselectivity (the isomer ratio was 21:1). Subsequent oxidative cleavage of the aromatic ring, followed by reduction of the amide and methylenation of ketone led to the formation of (±)-α-allokainic acid (4).25

Scheme 2
scheme 2

Intramolecular insertion at the C–H bond in α-phenylsulfonyl-α-diazoamides 7 (Scheme 3)26 obtained from amino acids was studied as a potential route for the synthesis of functionally substituted tetrahydropyrrolo[1,2-c]-oxazolones 8, structural fragments of biologically active compounds, such as lactacystin and pramanicin 9, an antibiotic that is highly effective against the infectious agents of meningitis. It has been proposed26 that the presence of a bulky substituent (i-Pr, Ph, Bn, CH2CO2Me) at position 4 of 1,3-oxazoline fragment in diazoamides of type 7 and the electronic effect of substituent at the nitrogen atom facilitate this reaction and provide for the high trans selectivity. The intramolecular cyclization products were obtained in quantitative yields.

Scheme 3
scheme 3

Based on the intramolecular C–H bond insertion reaction catalyzed by chiral rhodium carboxylates, a method was developed for the preparation of β-lactam 11 – a precursor to 1β-methylcarbapenem (13), a long-acting β-lactam antibiotic (Scheme 4).27 The starting compound was diazoamide 10. The use of Rh2(OAc)4 as catalyst led to the formation of diastereomers 11 and 12 in a sufficiently good yield (75%) in 25:75 ratio. However, the relative yield of the target isomer 11 was low. The diastereoselectivity of the reaction could be substantially increased by using dirhodium tetrakis(N-phthaloyl-(S)-phenylalaninate) (Rh2((S)-PTPA)4). The change of catalyst allowed to obtain the target 3-oxa-1-azabicyclo[4.2.0]octane 11 in 47% yield, followed by standard transformations of functional groups in β-lactam 11 leading to 1β-methylcarbapenem (13).

Scheme 4
scheme 4

The synthesis of (R)-(−)-rolipram (16), a highly potent and selective phosphodiesterase type IV inhibitor, was accomplished by using α-carbomethoxy- and phenylsulfonyl- substituted diazoamides of type 14 in the presence of rhodium-containing catalysts. The key stage in asymmetric synthesis of (R)-(−)-rolipram (16) was the dediazotization of diazoamide 14 in the presence of chiral Rh(II) carboxylates (Scheme 5).28 It was established that the use of dirhodium tetrakis(N-phthaloyl-(S)-tert-leucinate) (Rh2((S)-PTTL)4) resulted in cyclization that produced the respective γ-lactams 15, while the formation of regioisomeric β-lactams was never observed. The subsequent decarboxylation and deprotection led to (R)-(−)-rolipram (16) in up to 75% total yield.

Scheme 5
scheme 5

The Geissman–Waiss lactone 18 is a key intermediate in the synthesis of necine bases, which are a part of pyrrolizidine alkaloids. Both (−)- and (+)-enantiomers of lactone 18 were synthesized29 , 30 by C–H bond insertion reaction from the readily available (R)- or (S)-(3-pyrrolidinyl) diazoacetates 17 (Scheme 6).

Scheme 6
scheme 6

In the case of diazoacetate (R)-17, it was established that dirhodium tetrakis[methyl (4R)-1-(3-phenylpropanoyl)- 2-imidazolidinone-4-carboxylate] (Rh2((4R)-MPPIM)4) is the most effective catalyst, since it provided the highest yield of the bicyclic lactone (−)-18, and the C–H bond insertion reaction occurred with a high regio- and diastereoselectivity. Remarkably, the C–H bond insertion reaction led to the lactone (−)-18 independently of the catalyst used (Rh2((4R)-MPPIM)4 or Rh2((4S)-MPPIM)4). However, the use of Rh2((4S)-MPPIM)4 gave significantly lower yields of the target lactone due to the formation of dimer 19. The lactone (−)-18 was easily transformed into the target product, the necine base (−)-turneforcidine (22) (Scheme 6).

Tri- and tetracyclic derivatives of pyrrolo[1,2-a]quinolones 23 (Scheme 7) show activity against both Gram-positive and Gram-negative bacteria. Similar structures were obtained by intramolecular insertion of diazo compound 24 into an aromatic С–Н bond.31 The C–H bond insertion reactions catalyzed by Rh2(OAc)4 produced acceptable yields of tricyclic products 25 only in the case of diazoamides 24 containing N-aryl substituents.31

Scheme 7
scheme 7

It has been demonstrated31 that the regioselectivity of C–H bond insertion reaction in the case of diazoamides 26 depends on the nature of aryl substituent at the С-4 atom of the pyrrolidinone fragment. Thus, when R = Ph, the product 27 was isolated in 67% yield, while in the case when R = 2-thienyl, compound 28 was isolated in 68% yield (Scheme 8).

Scheme 8
scheme 8

Synthesis of oxygen-containing heterocycles

γ-Butyrolactone and tetrahydrofuran are some of the most common oxygen-containing heterocyclic fragments in natural compounds, such as nucleosides, (neo)lignans, carbohydrates, as well as in synthetic intermediates.

The diazoacetates 29 and 31 (Scheme 9), containing a 1,3-dioxane substituent, could be easily converted in two steps to the enantiomeric pairs of D- and L-2-deoxyribo- 1,4-lactones, as well as D- and L-2-deoxyxylo-1,4-lactones 30, 32.32 , 33 High diastereo- and enantioselectivity of C–H bond insertion reaction was achieved by using dirhodium(II) carboxamides, such as Rh2((4R)/(4S)-MEOX)4 and Rh2((4R)/(4S)-MEPY)4 (MEOX = tetrakis[methyl 2-oxooxazolidine- 4-(R/S)-carboxylate], MEPY = tetrakis[methyl 2-oxapyrrolidine- 4(R/S)-carboxylate]). In general, it was shown that catalysts with ligands in (R)-configuration gave D-lactones, while catalysts with ligands in (S)-configuration gave L-lactones. We should note that the insertion of metallocarbene occurred at the equatorial C–H bond in the case of dioxane 29, and preferentially at the axial C–H bond in the case of dioxane 31.

Scheme 9
scheme 9

The C–H bond insertion of diazocarbonyl compounds containing a carbohydrate fragment is a convenient method for obtaining such compounds as C-branched carbohydrates, valuable agents for chemotherapy.34 , 35 For example, α-substituted γ-butyrolactones, derivatives of nucleosides, are of interest as intermediates for the synthesis of more complex C-branched nucleosides. The synthetic method for these compounds involves a regioselective, Rh2(OAc)4-catalyzed intramolecular C–H bond insertion of diazoester 33 (Scheme 10), and leads to the formation of bicyclic lactones 34 in high yields and selectivity for the exo isomer.34

Scheme 10
scheme 10

Biologically active furofuran lignans, such as epimagnolin А (37), feature a cis-fused 3,7-dioxabicyclo-[3.3.0]octane fragment, where the aryl substituent at the C-2 atom is in endo position, and at the C-6 atom – in exo position. A single-stage approach to the construction of furofuran skeleton has been proposed,36 based on intramolecular C–H bond insertion of α-diazo-γ-butyrolactone 35 in the presence of Rh2(OAc)4 (Scheme 11). The reaction occurs at the activated benzylic C–H bond and leads to the formation of bicyclic lactone 36, having the necessary configuration at positions 2 and 6. The subsequent reduction of lactone ring to tetrahydrofuran completed the synthesis of epimagnolin А (37).

Scheme 11
scheme 11

Chiral γ-butyrolactone derivatives have found use as intermediates in the synthesis of natural products and their analogs,37 , 38 for example, in the synthesis of (+)-imperanene (40).37 The key γ-lactone 39 with (S)-configuration was obtained with a high yield and enantio-selectivity (ee 93%) from the diazo compound 38 by using Rh2((4S)-MPPIM)4 catalyst (Scheme 12). We should note that performing the reaction in the presence of (R)-catalyst led to formation of (R)-enantiomer. At the same time, other Rh(II) carboxamides Rh2((4S)-MEOX)4 and Rh2((4S)-IBAZ)4 (IBAZ = tetrakis[isobutyl 2-oxaazetidine-4(S)-carboxylate]) showed low catalytic activity and enantioselectivity. The γ-lactone 39 was further converted to (+)-imperanene (40) according to standard methods.

Scheme 12
scheme 12

This method was used for the synthesis of (R)-baclofen (43), a GABAB agonist.38 The key step was C–H bond insertion of diazoacetate 41 in the presence of Rh2((4R)-MPPIM)4 (Scheme 13). The (R)-isomer of γ-lactone 42 was obtained with high yield (81%) and enantioselectivity (ee 95%). The subsequent esterification, amination, and hydrolysis of lactone 42 led to the formation of amino acid (R)-baclofen (43).

Scheme 13
scheme 13

The intramolecular С–Н insertion reactions of aryldiazoacetate ester group have found applications in the synthesis of β-lactones – important organic intermediates and structural fragments of natural compounds and pharmaceuticals. It has been shown39 that the yield of obtained β-lactones can be significantly increased by introducing an ortho substituent at the aryl group of aryldiazoacetate, enabling intramolecular insertion reactions even at relatively unreactive С–Н bonds (Scheme 14). Another effective catalyst proposed for the transformation of (ortho-bromoaryl)diazoacetate 44 to β-lactone 45 is dirhodium tetrakis(N-tetrachlorophthaloyl-(S)-tert-leucinate) (Rh2((S)-TCPTTL)4), which allows to perform C–H bond insertion reactions in high yields and with good stereo and enantioselectivity.

Scheme 14
scheme 14

Many biologically active compounds, such as neolignans and spermine alkaloids, contain 2,3-dihydrobenzofuran moieties. Stereoselective synthesis of dihydrobenzofuran derivatives40 , 41 was achieved by using asymmetric intramolecular C–H bond insertion of 2-alkoxy-α-diazophenylacetates 46 in the presence of catalysts Rh2((S)-DOSP)4 and Rh2((S)-biTISP)4 40 (DOSP = tetrakis-((S)-N-(dodecylbenzenesulfonyl)prolinate, biTISP = bi[N-2,4,6-triisopropylphenylsulfonyl]prolinate) (Scheme 15). When using Rh2((S)-DOSP)4, the insertion of carbenoid at the methine C–H bond was highly effective, with 98% yield and 94% enantiometric excess (ee) of benzofuran 47. The insertion at the methylene C–H bond (at R1 = H) occurred quite effectively, giving excess of cis isomer, but the enantioselectivity of the reaction was not high. The use of Rh2((S)-biTISP)4 did not improve the stereoselectivity of this reaction.

Scheme 15
scheme 15

Based on the example of 2-alkoxy-α-diazophenylacetate 49 42, the effect of alkoxy substituents (Scheme 16) on the С–Н bond insertion reaction was studied in the presence of chiral Rh(II) carboxylates. It was shown that the presence of a phenoxy group at the α-position had an activating effect on the C–H bond, ensuring the high enantioselectivity of this reaction. High enantio and cis stereoselectivity in this reaction was achieved with Rh(II) carboxylates containing bridging ligands, such as Rh2((S)-PTTL)4. The reaction with this catalyst occurred under complete stereocontrol: the methyl esters of cis-2-aryl-2,3-dihydrobenzofuran- 3-carboxylic acid (50) were obtained in up to 86% yields and with ее up to 94%.42

Scheme 16
scheme 16

The same approach was used for the synthesis of spermine alkaloid (−)-ephedradine А (54) (Scheme 17), containing a trisubstituted dihydrobenzofuran fragment.41 , 43

Scheme 17
scheme 17

We should note that the application of optically active rhodium catalysts did not ensure the necessary trans configuration of substituents in dihydrobenzofuran fragment.40 , 42 A method of synthesis was therefore proposed, including double asymmetric induction, where chiral centers are present both in the diazoester and the catalyst. The introduction of methyl (R)-lactate or pyrrolidinyl-(R)-lactamide fragments into the molecular structure of diazo ester 52 (Scheme 17) enabled a complete stereocontrol during the synthesis of (−)-ephedradine А (54).43

The synthesis of 2,8-dioxobicyclo[3.2.1]octane 56, which is a structural fragment of the therapeutically important zaragozic acid (58) (Scheme 18), was based on a regioselective intramolecular C–H bond insertion of 2-diazoacetyl-1,3-dioxane 55, catalyzed by dirhodium(II) carboxylates.44 , 45 The reaction of diazo ketone 55 containing gem-dialkyl groups at the C-5 atom, catalyzed by Rh2(OAc)4, led to the expected C–H bond insertion product – compound 56, and a small amount of the methylidene derivative 57. The use of Rh2(Cap)4 as a less electrophilic catalyst had practically no effect on the yield or product ratio. At the same time, the introduction of substituents at positions 4 and 6 of the dioxane ring in diazo ester 55 resulted in selective formation of 2,8-dioxabicyclo[3.2.1]octanone 56. Even though the yield of compound 56 was only moderate, the method was applied to the synthesis of alkoxy-substituted diazo ketone 59, where the target furodioxane 60 was obtained in 48% yield (Scheme 19). The bicyclic compound 60 was further transformed to dihydroxylated compound 61 by the transformation of the tetrahydrofuranone fragment into the О-sililated enole, followed by hydroboration and oxidation.44

Scheme 18
scheme 18

Scheme 19
scheme 19

An analogous approach was used for the synthesis of (±)-7-episordidin and (±)-sordidin (65) (Scheme 20).45 It was noted by the authors that the presence of an equatorial ethyl substituent in the starting diazo ketone 62, unlike in the diazo ketone 55 (Scheme 18), had a substantial effect on the reaction (Scheme 20). The reaction catalyzed by Rh2(OAc)4 produced a significant amount of methylidene derivative 64 along with the target product 63, in a ratio 63 : 64 = 2:1. The application of chiral catalysts was not effective: compound 63 was obtained in low yield and with poor enantioselectivity. Copper-based catalysts, such as Cu(acac)2, were not suitable either, because under these conditions the major product was compound 64. The bicyclic ketone 63 was readily transformed in three steps to (±)-7-episordinin (65).

Scheme 20
scheme 20

2,5-Disubstituted 3(2Н)-furanones serve as intermediates in the synthesis of β-hydroxycarboxylic acids and can be easily obtained from α'-alkoxy-α-diazo ketones.46 , 47 The intramolecular reaction of diazo ketone 66 catalyzed by Rh2(OAc)4 at room temperature (Scheme 21) gave the furanone 67 in 30% yield and 1.4:1 ratio of cis and trans isomers.

Scheme 21
scheme 21

Changing the catalyst to Rh2(Oct)4 under the same conditions gave a slightly better yield of compound 67 (39%), but performing the reaction in refluxing benzene allowed to obtain 75% yield of the lactone 67 as cis isomer, which was converted in several steps to the β-hydroxy acid 69.46

The C–H bond insertion reaction was successfully applied to the synthesis of (−)-serotobenine (72), a tetracyclic alkaloid isolated from the seeds of safflower (Carthamus tinctorius), with the molecular structure featuring indole, dihydrobenzofuran, and eight-membered lactam rings. The total synthesis consists of 20 steps. The key diazo ester 70 was obtained in a Leimgruber–Batcho reaction from 3-methyl-4-nitrophenol. The reaction of compound 70 catalyzed by Rh2((S)-DOSP)4 in the presence of piperidinyl mandelate led to the dihydrofuroindole 71 in 92% yield (Scheme 22). The further route of synthesis, including macrolactamization, provided (−)-serotobenine (72).48

Scheme 22
scheme 22

One of the steps in the synthesis of (+)-lithospermic acid (75), of medicinal importance for the treatment of cardiovascular diseases, several types of hepatites, and chronic kidney disease, was an intramolecular asymmetric insertion at the benzylic C–H bond of diazo ester 73. The reaction was catalyzed by Rh2((S)-DOSP)4 and gave the trans isomer of dihydrobenzofuran 74 as the major product in 85% yield with 8:1 ratio of diastereomers (Scheme 23). The starting diazo ester 73 was obtained in several steps from О-eugenol.49 , 50

Scheme 23
scheme 23

The crucial step determining the enantioselectivity in the synthesis of maoecrystal V (78), a molecule, based on caran structure and found in Isodon plants, and used in the treatment of viral respiratory and gastrointestinal infections, is the construction of dihydrobenzofuran fragment in an intramolecular C–H bond insertion reaction catalyzed by rhodium salts.51 The diazo ester 76 was obtained from sesamol in several steps (Scheme 24).

Scheme 24
scheme 24

Syringolides 81 are a family of specific non-protein mediators of hypersensitive responses in plants used for active defense mechanisms, causing cell death in infected areas. Such structures can be obtained in several steps from spirolactones 80. The latter were synthesized by Rh2(OAc)4- catalyzed intramolecular C–H bond insertion of β-diazo esters 79, obtained by acylation of primary alcohols with the respective β-ketoacids, followed by diazo transfer reaction. The authors studied the influence of aryl, vinyl, and β-carbonyl substituents on the course of this reaction (Scheme 25).52 , 53 Thus, the highest yields (63–85%) were obtained by using aryldiazoacetates 79 (R = 3- and 4-MeОС6Н4, R1 = H).

Scheme 25
scheme 25

This review summarized the literature data about the broad possibilities for using diazo compounds in organic synthesis. The application of highly effective rhodiumbased catalysts, including chiral complexes, has enabled a selective synthesis of heterocyclic systems ranging from basic to highly complex, including analogs of natural compounds with various types of biological activity.