SYNTHESIS OF HETEROCYCLES BY INTRAMOLECULAR

CYCLIZATION OF ORGANIC AZIDES.

By Sergio Cenini, Fabio Ragaini, Emma Gallo, Alessandro Caselli.*

Dipartimento di Chimica Inorganica, Metallorganica e Analitica “Lamberto Malatesta”, Università

degli Studi di Milano, ISTM – CNR, via Venezian 21, 20133 Milano, Italy.

Corresponding author: Alessandro Caselli

Add/ Affiliation: Dipartimento di Chimica Inorganica, Metallorganica e Analitica “Lamberto

Malatesta”, Università degli Studi di Milano, ISTM – CNR, via Venezian 21, 20133 Milano, Italy.

Fax: (+39) 02 5031 4405

Tel: (+39) 02 5031 4372

Email: alessandro.caselli@unimi.it

Abstract

A review of synthetic methodologies reported in the last five years that yield N-heterocyclic

products by intramolecular cyclization of organic azides with a particular emphasis on

transformations catalyzed by metal complexes is presented. These reactions have been classified

according to the ring size of the formed heterocycle.

Keywords: Amination reactions; Heterocycles; Homogeneous catalysis; Intramolecular

cyclisations; Organic azides; Transition metal complexes.

2

Contents

1. Introduction

2. Five membered rings

2.1. Pyrroles and dihydropyrroles

2.2. Indoles and Carbazoles

2.3. Benzimidazoles

2.4. Miscellaneous

3. Six membered rings

4. Seven membered rings

5. Conclusions

Acknowledgments

References

1. Introduction

Metal mediated synthetic routes that transform hydrocarbon substrates into nitrogen-containing

products are the focus of continuing investigation in contemporary chemistry [1-3]. It is estimated

that over 90% of pharmaceutical have at least one nitrogen atom in their structure and about one

reaction out of seven in the pharmaceutical industry involves the formation of a carbon-nitrogen

bond [4]. Nitrogen heterocycles (aza-heterocycles) in particular occur in a wide variety of natural

and biologically active compounds. Efficient methods for the synthesis of nitrogen-containing

heterocycles are thus of fundamental importance and represent a major challenge in synthetic

chemistry. In this context, synthetic routes involving nitrene formation plays a significant role. Due

to their high reactivity, nitrenes are highly suitable for ring closing reactions. Ten years ago, the

3

field of the intramolecular annulations reaction of nitrene intermediates to yield heterocycles has

been covered in an excellent review by Söderberg [5]. Since then a considerable number of

publications have appeared on the subject, especially in the field of organometallic catalysis.

Among the generally employed nitrene generation methods, the thermal, photochemical or metal-

catalyzed activation of azides present several advantages and recently we [6, 7] and others [8] have

published reviews on this subject.

Organic azides are reactive molecules, which can be represented by the resonance structures

(A) and (B) (Figure 1).

RN N

RN N NN

A B

Figure 1. Resonance formulas for RN3.

These molecules are characterized by the lability of the N -N bond. Organic azides have been

long known as versatile and valuable intermediates in the construction of cyclic nitrogen-containing

compounds. Over the last thirty years several synthetic efforts have been devoted to the study of the

radical reactions of organic azides and their potential applications to organic synthesis [9]. In spite

of the fear of organic azides, arising from their potential explosive properties, in most recent years

the number of articles on those compounds has continued to increase tremendously.

In this review, which is not meant to be a comprehensive overview, we will discuss a selection

of papers appeared in the literature after 2005, concerning the intramolecular cyclization of organic

azides to yield heterocycles. For papers appeared on the subject before, readers are referred to the

excellent review of Bräse and co-authors [10]. The smallest of the aza-heterocycles, the aziridine,

will not be included in the present article since the chemistry of this ring has been extensively

covered elsewhere [11-14]. Compared to other nitrogen heterocycles the chemistry of azetidines is

much less developed because of their limited availability. However, synthetic routes to these

4

strained heterocycles have been recently reviewed [15]. Moreover, the emerging field of copper

catalyzed 1,3 dipolar cycloaddition reaction between azide and alkyne (Huisgen reaction) has been

covered by several reviews and will not be included [16-20]. In the following, we will consider the

intramolecular reactions of organic azides with particular emphasis on transition metal complex

catalyzed transformations, and the discussion will be divided in sections according to the size and

type of the formed N-heterocycle.

2. Five membered rings

Five membered rings containing one or more nitrogen atoms are often encountered in naturally

occurring molecules of high interest and many papers have extensively been described in the

literature over the last decades. In recent years, there has been a growing interest in the application

of azides for their synthesis. Common examples of reaction in which azides lead to the synthesis of

heterocycles where a single nitrogen atom is retained are reductive cyclization [21], Staudinger

reaction [22], Curtius rearrangement [23], Schmidt rearrangement [24], radical cyclization [25], and

nitrene insertion [26]. In the following sections we will present synthetic methods yielding five

membered ring N-heterocyclic compounds by intramolecular cyclization of organic azides. The

products will be classified by ring size.

2.1. Pyrroles and dihydropyrroles

Pyrrole derivatives are important not only in the synthesis of drugs, pigments and

pharmaceuticals, but also for the development of organic functional materials [27]. Substituted

pyrroles are an important class of compounds displaying remarkable pharmacological properties

such as antibacterial, antiviral, anti-inflammatory, antitumoral, and antioxidant activities [28].

Consequently, a wide range of procedures have been developed for the construction of the pyrrolic

ring [29]. Among them, the Paal-Knorr reaction [30] remains one of the most employed methods

5

for the synthesis of pyrroles, wherein 1,4-dicarbonyl precursors are converted to pyrroles by the

reaction with primary amines or ammonia in the presence of various promoting agents [31].

Despite the readily availability of dienyl azides, obtained by base catalyzed condensation

reaction of aldehydes with azidoacetates, their thermolysis reaction has seldom been employed for

the construction of pyrroles. In 2007, Driver and coworkers reported the synthesis of a range of 2,5-

disubstituted and 2,4,5-trisubstituted pyrroles from dienyl azides using catalytic quantities (5%) of

Lewis acids at room temperature (Scheme 1) [32].

N

H

R2

COOR3R1

R1COOR3

R2 N3

ZnI2 (5 mol %)

CH2Cl2, 25 °C

1 2

Scheme 1. Pyrrole formation catalyzed by ZnI2.

Although zinc(II) salts act as Lewis acids in a diverse range of reactions, they have seldom

been used to catalyze the azide decomposition. Interestingly, the authors reported that zinc iodide is

one of the most efficient catalyst in the construction of pyrroles starting from dienyl azides; the only

other catalyst that displayed similar activities were copper(II) triflate and Rh2(O2CC3F7)4. It should

be pointed out that only rhodium(II) perfluorobutyrate was efficient, instead, in the construction of

indoles from azidoacrylates, as previously reported by the same group (see later) [33]. Diminished

yields were observed when other Lewis acids were used, including mercury(II) triflate, gold(I)

triflate, rhodium(II, III) caprolactamate. Brønsted acid such as triflic acid seems to be not suitable

for pyrrole formation, since only decomposition products were observed. The best solvent for the

reaction was methylene chloride, while lower reactivity was observed with ethereal or aromatic

solvents. When the efficiency of the catalyst was compared by monitoring the conversion after 3 h

of reaction, both ZnI2 and Cu(OTf)2 were found to be more reactive than rhodium salts. The

reaction tolerated both electron-rich and electron poor aryl substituents (R1), even if the conditions

6

needed for the reaction to proceed when increasing the electron deficiency of the aryl substituent

became more forcing. In these last cases Rh2(O2CC3F7)4 was a superior catalyst. For electron poor

aryl substituents such as furan and thiophene, the reaction progress was very modest even when

increasing the catalyst loading and the reaction temperature. Interestingly, the reaction scope could

be extended also to dienyl azides containing alkyl substituents at the - or -position to yield 2,4,5

trisubstituted pyrroles (Scheme 1). Different carbonyl substituents were also examined, and if

increased steric hindrance of the ester did not influence the efficiency of the reaction, a keto group

required more forcing conditions.

On the basis of the observed reactivity trends, the authors proposed that the reaction follows a

Schmidt-like mechanism [34] initiated by a coordination of the Lewis acid to the azide (with the

help of the ester). The product would derive from the Zwitterionic intermediate 3a (Scheme 2),

without the formation of a nitrenoid intermediate. Alternatively, the coordination of zinc iodide to

the carbonyl increases the electrophilicity of the pendant olefin. Intramolecular attack of the azide

would form 3b. Loss of nitrogen, followed by tautomerization, would generate pyrroles 2.

NPh

MeO

O

N2

ZnI

I

ZnI2

NPh

OMe

N2

OZnI

I

N

OMe

OZnI

I

PhH

N2

NO

PhH

MeO

ZnI

I

11

2 2

3a 3b

N2

+ N2

Scheme 2. Proposed mechanism for pyrrole formation.

7

More recently a contribute from the university of Hong Kong, by Lin, Jia and coworkers,

revealed that commercially available RuCl3·nH2O [35] is also an effective catalyst in the pyrrole

formation starting from aromatic substituted dienyl azides [36]. In this case the reaction needed

higher temperatures (85 °C) with 3 mol% catalyst loading. As the authors of the paper pointed out,

commercially available ruthenium(III) chloride is not a single compound and it is a mixture mainly

of Ru(IV) complexes. The role played by those salts in different oxidation states in promoting the

amination reactions is however to be considered marginal, since none of the Ru(II) and Ru(IV)

complexes tested in the work gave satisfactory yields. In this case the solvent of choice for the

reaction was dimethoxyethane (DME). A series of pyrroles could be prepared with this

methodology and in refluxing DME the reaction is generally complete within 1.5 h. Also in this

case, both electron donating and electron withdrawing aryl substituents were tolerated (Scheme 3).

N

H

COOEtArAr

COOEt

N3DME, reflux

4

RuCl3 nH2O

Scheme 3. RuCl3·nH2O catalyzed pyrrole synthesis.

From a mechanistic point of view, in this case the authors proposed a two-step process

involving formal electrocyclization initiated by a ruthenium-imido (or nitrene) complex. This

proposal was well supported by a computational study, but since this study was performed in the

case of the synthesis of carbazole, the discussion of the mechanism will be presented later [36].

During our ongoing studies on aryl azide activation catalyzed by cobalt- [37-39] and

ruthenium-[40-44] porphyrin complexes, we have recently reported the Ru(CO)(porphyrin)

complexes catalyzed aziridination of conjugated dienes by aryl azides [45]. This reaction allowed us

to synthesize N-aryl-2-vinyl aziridines, a class of very reactive organic building blocks thanks to the

simultaneous presence of both an aziridine ring and a double bond that easily induce ring-opening

[46, 47] or ring expansion [48] reactions. Several hydrocarbons and azides were tested and we

8

showed that our protocol can provide N-aryl-2-vinyl aziridines with excellent chemoselectivities.

The crucial step in handling these products is their purification procedure. A lowering of the yields

can be observed during the chromatographic process even when using deactivated silica. We turned

the great instability of N-aryl-2-vinyl aziridines into an advantage promoting their isomerization to

form new N-heterocyclic compounds (Scheme 4) [49].

NR1

R2R3

R4

R

6

8

7

9

N3

R

+

NH

R1

R2

R3

R

R4

N

R4R1

R2R3

R

N

R

R3R2

R4R1

N

R3R2

R4R1

[Ru] = Ru(TPP)CO

1

2

34

5

R1

R2R3

R4

ox.

C3-N1

cleavage

C2-C3

C3-N1

R

cleavage

cleavage

[Ru]

-N2

5

Scheme 4. Synthesis of N-heterocycles by sigmatropic rearrangements of N-aryl-2-vinyl aziridines

(TPP = dianion of tetraphenylporphyrin).

Several dienes and arylazides were used to form N-aryl-2-vinyl aziridines that were

transformed without isolation into different N-heterocycles by adding small quantity of silica to the

reaction mixture or by increasing the temperature. In the case of terminal dienes, while the Lewis

acid catalysis increased the yield in benzoazepines 6 (see later), the high temperature mediated

rearrangement of 5 afforded the 2,5-dihydropyrroles 8 as the major product. On the other hand, if

the olefin is an internal diene, the reaction yielded 2,3-dihydropyrroles 7.

9

2,5-Dihydropyrroles 8 are obtained the by the cleavage of the C3-N1 bond (Scheme 5, path a),

while 2,3-dihydropyrroles 7 are formed by a C2-C3 bond cleavage (Scheme 5, path b).

N

R2 R1

R3R4

R5

R6

N

R2 R1

R3R4

R5

R6

R

R

N

R

R6

R4R3

R5R2

R1N

R

R4R3

R5R2

N

R6 R5

R2

R1

R3R4

R

benzenereflux

1,3 sigmatropic shift

1,3 sigmatropic shiftbenzene

reflux

ox.

if R1=R2=R5=R6=H

R3=R4=OCH3

path b

path a

F 7

98

Scheme 5. Proposed reaction pathways for the formation of N-heterocyclic compounds.

Spontaneous oxidation to pyrrole 9 was observed in the case of the reaction of 2,3-dimethoxy-

butadiene and p-nitrophenyl azide. In this case it was impossible to recover the N-aryl-2-vinyl

aziridine in a pure form and this can be explained by the presence of the electrodonating methoxy

groups. To predict the chemoselectivity of the rearrangement to N-heterocyclic compounds on the

basis of electronic and steric characteristics of the substituents and to gain insight into the

mechanism, we carried out theoretical calculations using density functional theory methods. The

results achieved indicate that the chemoselectivity of the reaction strongly depends both on steric

properties of the starting diene and on the experimental conditions employed for the rearrangement.

The effect of the former could be nicely rationalized by theoretical calculations at the DFT level on

the rearrangements of the intermediately formed N-aryl-2-vinyl aziridines. Calculations identified

the key role of the effects of the substituents on the relative stabilities of the starting N-aryl-2-vinyl

10

aziridines conformations allowing us to give a rationale of the experimentally observed

chemoselectivity of the rearrangement to N-heterocyclic compounds.

Employing a different synthetic approach, Dembinsky and coauthors recently reported the

synthesis of 2,5-di- and 2,3,5-trisubstituted pyrroles starting from homopropargyl azides (Scheme

6) [50]. Yields of pyrroles range from 41% to 91%, and the reaction needs high temperatures to

proceed. The best results are obtained under microwave conditions. The added value of the work is

that the best catalyst for the reaction is the commercially available, inexpensive zinc chloride

etherate. This reagent is easy to handle and offers the advantage to be soluble in commonly

employed organic solvent. In this case, the solvent of choice was 1,2-dichloroethane and the authors

proved that a 90% yield in pyrrole could be obtained also under conventional heating, although after

longer reaction times (16 h vs. 1 h). To ensure safe operations at the high temperatures that can be

reached inside a microwave reactor, the authors studied the thermal stability of a representative

homopropargyl azide recording a DSC trace (DSC = differential scanning calorimetry). From the

data collected it was clear that practical operations can be carried out at 135 °C. Homopropargyl

azides can be conveniently synthesized starting from alkynols and the substituents used in this work

include alkyl (propyl, butyl), cycloalkyl (cyclopropyl, fused cyclohexyl), and aryl (phenyl, p-tolyl,

and p-halophenyl).

N

H

R''

12

R

R'

OH

R''1) MsCl

2) NaN3 or (PhO)2P(O)N3

R

R'

N3

R''

ZnCl2

(CH2Cl)2

W or

R

R'

Scheme 6. Synthesis of pyrroles 12 (Ms = mesyl).

11

Other zinc containing compounds were tested in the work. Surprisingly good conversions and

yields in pyrroles were observed also with solid anhydrous ZnCl2 and ZnBr2 subjected to

microwave conditions. This can be explained on the basis of the high temperatures employed that

favor the partial dissolution of the salts in the reaction medium. With ZnI2, the authors observed

complete conversion of the starting azide, but significant amounts of by-products were formed. The

cyclization reaction of aryl substituted homopropargyl azides always gave better yields than the

corresponding cyclization of alkyl substituted ones.

Lower temperatures for the cyclization step are required when the catalyst for the same reaction

is based on the more precious gold/silver complexes employed by Toste and coauthors [51]. In this

case homopropargyl azides were cyclized to pyrroles in moderate to good yields using a 2.5 mol%

(dppm)Au2Cl2/5 mol% AgSbF6 mixture in dichloromethane. The reaction conditions are milder and

a complete conversion of the starting azide is observed in 20-40 min at lower temperatures (35 °C).

The gold/silver-catalyzed formation of pyrroles is believed to proceed by an intramolecular,

stepwise mechanism as shown in Scheme 7.

NH

R

N

RH

LAu

N3

R

N

R

N2

LAu

N

LAu R

N2

N

LAu R

N2

13

H

H

H

Scheme 7. Proposed mechanism for the gold catalyzed synthesis of pyrroles.

12

In a related work published in 2006, Matsumoto demonstrated that an efficient catalyst for the

same reaction is platinum tetrachloride, PtCl4 (5 mol%) in the presence of 20 mol% of 2,6-di-tert-

butyl-4-methylpyridine as the base [52]. The base is necessary to avoid the decomposition of the -

electron rich pyrrole under even weakly acidic conditions. These reaction conditions can be applied

to the preparation of functionalized pyrrole derivatives, with a wide tolerance for functional groups.

Moreover, for phenyl-substituted pyrroles the synthesis can be carried out under aerobic conditions.

A trisubstituted pyrrole has been isolated from the reaction of -azido acetophenone with

methyl acetoacetate under a hydrogen pressure using 10% Pd/C, but in this case it is reasonable to

assume that the formation of the N-heterocycle involves a vinyloguos carbamate as intermediate

[53].

2.2. Indoles and carbazoles

The indole nucleus is present in a large number of compounds of biological and/or

pharmaceutical interest. Because of this, chemical methods for its synthesis have been developed

for more than a hundred years [54]. The overwhelming majority of the reported synthetic strategies

require the availability of a nitrogen-functionalized arene (e.g., an arylamine or a nitroarene) also

having a suitable functional group in the ortho position with respect to the nitrogen substituent [55,

56]. We have recently reported that a palladium catalyst is very efficient for the intermolecular

condensation of nitro arenes and alkynes to afford indoles [57, 58]. Several functional groups on the

nitro arene are tolerated, except for bromide and activated chloride.

In recent years, Hajos et al. have worked out a valuable procedure combining the Suzuky-

Miyaura cross-coupling reaction [59] with thermally induced intramolecular nitrene insertion of the

formed o-azidophenyl substituted azine or diazine. This approach, which allowed the synthesis of

different indoles and pyridazine derivatives of biological importance, has been recently reviewed by

the same group in this journal [60]. Although nitrenes can be formed from azides by thermolysis,

the high temperatures required to promote this reaction cause safety concerns, which diminish the

13

usefulness of this method. The nitrenoid formation catalyzed by metal complexes is highly

appealing. In this field, rhodium(II)-mediated C-H bond amination from azidoacrylates reported by

Driver et al. represents a significant improvement (Scheme 8) [33].

CO2Me

N3

RRh2(O2CC3F7)4

-N2

CO2Me

N

R

[Rh]

R

NH

CO2Me

14 15

Scheme 8. Synthesis of indoles 15.

Dirhodium(II) carboxylates were the only metal complexes active for this cyclization reaction,

amongst those tested (Ag, Cu, Co and Fe complexes as well as other Lewis acids). The activity of

the rhodium catalyst is dependent upon the electronic nature of its ligands: the more electron

deficient carboxylates, such as perfluorobutyrates, gave the best yields. Not surprisingly,

Rh2(OAc)4, which is less soluble, gave only modest yields. Optimization of reaction conditions

revealed that toluene was superior to chlorinated solvents in this case. The optimal temperature to

run the reaction with a 3 mol% catalyst loading was found to be between 40 and 60 °C. Again, the

reaction tolerated both electron-donating and electron-withdrawing aryl substituents, but only 2-

indole carboxylate esters 15 could be synthesized according this methodology. In fact, the

cyclization step required an -azidomethylacetate (14). Based on the mechanism proposed for the

rhodium(II) C-H bond functionalization by -diazo esters [61, 62], initial coordination of the

dirhodium carboxylate with the -nitrogen of the azide to yield the intermediate azido adduct 16,

was suggested to be the first interaction with the catalyst. The rate determining step would be the

nitrogen loss to form the imido-complex. Isotope effects suggested that the following catalytic step

is a stepwise electrophilic aromatic substitution via arenium ion 17 (Scheme 9).

14

CO2Me

N3

R

Rh2(O2CC3F7)4

N2

CO2Me

N

R

[Rh]

R

NH

CO2Me

R

N

CO2Me

[Rh]

CO2Me

N

R

[Rh]

N

N

14

1617

15

H

Scheme 9. Proposed mechanism.

The cyclization of aryl azides 18, which can be formed by Suzuky-Miyaura cross-coupling of

commercially available 2-bromoanilines followed by diazo transfer, allowed the group of Driver to

obtain a wider range of differently 2-substituted indoles [63]. In contrast with the previously

reported aryl C-N bond formation starting from azido acrylates, in this case the indole synthesis

proceeds through the formation of a vinyl C-N bond (Scheme 10).

NH

R5

18 19

N3

H

R5

metal salt

PhMe

R1

R2

R3

R4

R1

R2

R3R4

Scheme 10. Synthesis of indoles 19 (metal salts = rhodium (II) carboxylate or lactamate

complexes).

Contrary to what previously observed by the same group in the case of azido acrylates, the

indole formation from o-vinylaryl azides 18 was efficiently mediated also by rhodium(II) octanoate,

although in this case the solvent of choice was 1,2-dichloroethane. The addition of molecular sieves

15

allowed for a 2 mol% catalyst loading. The nature of the R5 substituent is very important for the

efficiency of the C-H amination reaction. While the modulation of the electronic properties in the

case of aryl substituents had little impact on the reaction yield, changing to alkyl group reduced

both conversion and yield.

Again a stepwise mechanism, where indole formation occurs with C-N bond formation

preceding N-H bond formation, was proposed as the most likely.

More recently, the same group reported the extension of this methodology to the synthesis of

carbazoles [64]. The required biaryl azides 20 were readily obtained again by Suzuky-Miyaura

cross-coupling of commercially available 2-bromoanilines followed by diazo transfer. Carbazoles

21 were obtained by employing the same cyclization reaction used for indole synthesis by using

rhodium(II) perfluorobutyrate at 60 °C in toluene or rhodium(II) octanoate at the same temperature

but in 1,2-dichloroethane (Scheme 11). As in the previous case, the addition of crushed 4Å

molecular sieves was required to achieve reproducible yields.

20

N3

H PhMe

R1

R2

R3

R4

R5

R1

NH

R2 R3

R4

R5

Rh2(O2CC3F7)4

21

Scheme 11. Synthesis of carbazoles 21.

In this case the reaction occurs with activation of an arylic C-H bond. The electronic properties

of the aryl ring bearing the azide do not significantly affect the reaction rate and both electron-

donating and electron-withdrawing groups are well tolerated. On the other hand, the steric and

electronic properties of the substituents R2-R

5 (Scheme 11) strongly influence the carbazole

formation. In general the reaction was more efficient when the C-H bond of an electron poor aryl

16

ring was to be activated. Moreover a good control on regioselectivity was allowed when the

substituent R5 was electron-withdrawing.

The synthetic results suggested that the reactivity of rhodium arylnitrenoid might be more

similar to the chemistry of an arylnitrenium ion. In a very elegant full paper, Driver et al. reported

the results of a mechanistic study on triaryl azides that led to the conclusion that electronic donation

by the biaryl -system accelerates the formation of rhodium nitrenoid and that C-N bond formation

occurs through a 4 -electron-5-atom electrocyclization [65]. In agreement with this proposal,

substrates that lack a contiguous -system are unreactive. Evidence that the C-H(D) bond cleavage

does not occur in the product-determining step of the catalytic cycle was clearly shown by the lack

of a primary intermolecular kinetic isotope effect. A series of differently substituted arenes were

tested as substrates and the product ratios obtained were correlated with the Hammett equation

generating V-shaped plots, suggesting that a different mechanism is operating for electron-deficient

substrates. For these last systems, definitive mechanistic conclusion were prevented from the

limited data collected.

Commercially available RuCl3·nH2O, efficiently used by Lin, Gia and co-workers as catalyst in

the pyrrole formation starting from aromatic substituted dienyl azides (vide supra), is also a good

catalyst instead of the more expensive rhodium for the cyclization of azido aryl acrylates 22 and o-

phenylaryl azides 24 (Schema 12) [36].

17

R1

N3

CO2Et

NH

R1

CO2Et

N3

R2 R3

NH

R2 R3

24

22 23

25

RuCl3 nH2O

RuCl3 nH2O

Scheme 12. Synthesis of indoles 23 and carbazoles 25.

Ruthenium nitrene complexes have been often proposed to be involved in C-H amination

reactions, and in some cases they have been isolated. For instance, we have recently reported the

synthesis and characterization of a ruthenium bis-imido porphyrin complex, Ru(TPP)(NAr)2 (Ar =

3,5-(CF3)2C6H3), that is an active intermediate in C–H nitrene transfer reactions [40]. However, the

starting active compounds commonly employed in the literature are well defined ruthenium

complexes with ligands such as porphyrines, corroles, cyclopentadienyl, phosphines or Schiff bases.

These ligands can help both in the stabilization of high oxidation states of the metal and in the

solubilization of the active species. Surprisingly, the readily available and relatively cheap

ruthenium(III) chloride, which is poorly soluble and has an ill defined chemical composition, was

found to be an excellent catalyst for the intramolecular arylic C-H activation by azides. This finding

opens the possibility for further studies in this direction. Conversely, both well defined

ruthenium(II) complexes, such as CpRuCl(PPh3)2, Cp*RuCl(PPh3)2, Cp*RuCl(COD),

RuCl2(PPh3)3, and RuCl2(DMSO)4, and ruthenium(IV) species such as RuO2 and (NH4)2RuCl6 are

ineffective in promoting this reaction. The best solvent for the reaction was found to be DME, but

other polar solvents such as THF and dioxane were also effective, while non polar solvents do not

work, probably due to the very poor solubility of RuCl3·nH2O in these media.

18

Among other metal salts such as IrCl3, PdCl2, Cu(OTf)2, ZnI2, and ZnBr2, only RhCl3 was

found to be catalytically active for the transformation.

The authors, based on the commonly accepted mechanism for ruthenium mediated activation of

organic azides, proposed that the initial step for the reaction is the formation of a ruthenium imido

(or nitrene) complex B via an initial azido-ruthenium adduct A (Scheme 13) [36].

N3 24

[Ru]N

NN

[Ru]H

N

H

[Ru]N[Ru]

H

NH

N2

N [Ru]

H

N [Ru]

H

A

B

C

D

25

TSBD

Scheme 13. Proposed mechanism for the ruthenium catalyzed electrocyclization.

The ruthenium imido can lead to carbazole formation through two possible mechanisms: a one

step-concerted insertion of nitrene via transition state TSBD or a two-step process to give an

intermediate C followed by a 1,2 proton shift. The proposed catalytic cycle was supported by DFT

calculations, assuming RuCl3(DME) as reasonable active species, assumption that is well supported

by the experimental results (very poor reactivity was observed with ruthenium(II) or ruthenium(IV)

19

metal sources). Calculations showed that the two step mechanism is more likely, with a reaction

barrier of 16.8 kcal/mol and supported a formal Ru(III)/Ru(V) catalytic cycle. This mechanism is

also in agreement with all the experimental evidences presented by the authors.

Functionalization of aryl or vinyl C-H bond, although still a challenge for a synthetic chemist,

is not any more a curiosity in recent literature. On the other hand, C-H activation of aliphatic carbon

is much rarer [1, 66-68]. An iridium(I) complex, [Ir(cod)(OMe)]2, was recently found to be an

active catalyst for the intramolecular homobenzylic C-H bond amination of o-homobenzyl

substituted aryl azides 26 to produce indolines (Scheme 14) [69].

NH

Ar

26 28

N3

H

Ar [(cod)Ir(OMe)]2

PhH

R R

27

NH

ArR

[Ir]

Scheme 14. Synthesis of indolines 28

The identity of the iridium(I) complex was of fundamental importance and only

[Ir(cod)(OMe)]2 catalyzed the transformation at room temperature to yield the desired indolines 28

as major products. The presence of an electron-withdrawing group on the aryl moiety was

beneficial to the indoline selectivity, whilst the electronic properties of the homobenzylic group did

not show a great influence on the reaction outcome. In contrast to what reported by the same group

for arylic or vinylic C-H activation, rhodium catalysts were ineffective in the present case; on the

other hand, the iridium-catalyzed cyclization was not effective with all azido acrylates tested. The

scope of the iridium-catalyzed cyclization is limited to the amination of secondary benzylic C-H

bonds, and no reaction is observed with non benzylic or tertiary benzylic C-H bonds. Aryl C-H

bonds could also be activated and [Ir(cod)(OMe)]2 converted vinyl aryl azides and biaryl azides to

indoles and carbazoles in yields comparable to those observed in the presence of Rh2(O2CC3F7)4.

20

Experimental results showed that a benzylic C-H activation/nucleophilic addition mechanism

does not account for the N-heterocycle formation. The faster rate of indolines formation for electron

deficient aryl azide, and the presence of aniline as decomposition product, commonly encountered

in the case of nitrenoid species, prompted the authors to suggest the formation of an electrophilic

iridium nitrenoid, that could be responsible for the benzylic C-H activation through a concerted or a

radical mechanism.

2.3. Benzimidazoles

Benzimidazoles also are heterocyclic compounds of high importance, due to their wide

application as drugs [70], and their use as molecular precursors for the development of ligands [71],

dyes [72], and polymers [73].

As a natural development of the cyclization reaction of o-vinylaryl azides 18 mediated by

rhodium(II) complexes, Driver et al. studied also the benzimidazole formation after replacing the -

carbon in 18 with a nitrogen atom (Scheme 15) [74].

NH2

NH

N

Ar

30

N3

RArCHO

MgSO4

N

N3

RAr

H

FeBr2

4 Å MS

R

29

Scheme 15. Synthesis of benzimidazoles 30

In this case rhodium catalysis proved to be ineffective, but instead a Lewis acid activation of

imine 29 resulted in a facilitated benzimidazole formation. Aluminium chloride and ferric bromide

were found to be good catalysts, although the best yields in benzimidazole were obtained with

FeBr2 in the presence of molecular sieves and in methylene chloride at 40 °C. 2-Azidoaryl imines

29 are not sufficiently stable and their purification is hampered by their instability towards silica.

Thus the authors studied a two-step procedure, without the purification of the intermediately formed

imine. Higher yield of benzimidazole 30 were obtained with more electron deficient aryl aldehydes

21

while the presence of two electron withdrawing substituents on the aryl azide ring disabled the

cyclization step. Lewis acids tolerate well even coordinating cyano groups, which instead are

harmful for rhodium. On the other hand, the reaction mediated by ferrous chloride lacks of

stereospecificity.

On a completely different approach, benzimidazoles can be synthesized in a one-pot procedure

as recently reported by Wang et al. taking advantage of copper(I) catalyzed click-chemistry of p-

tolylsulfonyl azide (Scheme 16) [75]. Thus, the copper catalyzed reaction of aryl acetylene with p-

tolyl-sulfonyl azide and o-aminoaniline in the presence of triethylamine proceeded via a ketenimine

intermediate to afford acetimid amido derivatives. The benzimidazoles 31 were obtained after

reflux of these last products in 2% H2SO4 by intramolecular nucleophilic addition and subsequent

elimination.

NH2

NH

N

Ar

31

NH2

R

+ TsN3

1) CuI, Et3N

2) H2SO4

R

Ar

+

Scheme 16. Synthesis of benzimidazoles 31.

2.4. Miscellaneous

The first example of a metal catalyzed intramolecular amination of an olefin by an azido group

was the reaction of 2-alkenyloxycarbonyl azides, which in the presence of TMSCl and FeCl2 as

catalyst, afforded the corresponding 4-(chloromethyl)oxazolidinone (60-80% yield) presumably

through a stepwise single electron transfer pathway. A prevalence of the trans-diasteroisomer was

always observed [76, 77]. The procedure, summarized in Scheme 17, led to the iron(II) chloride

catalyzed intramolecular chloroamination yielding to oxazolidinones 32 and lactams 33 in moderate

to good yields [78].

22

32a

TMSClO O

N3HN

O

OCl

FeCl2

O O

N3

Ph

32b

HN

O

OPhTMSCl

FeCl2

Cl

O

N3 TMSCl

FeCl2

33

HN

O

Cl

Scheme 17. Synthesis of oxazolidinones 32 and lactams 33.

It could be proven that aziridines are not involved as intermediates. The authors proposed

instead that the reactions proceed via an N-centered radical. The synthesis of lactams 33 is

hampered by the great instability of the required acyl azides that undergoes a Curtius rearrangement

at temperatures slightly above 0 °C.

More recently Rovis et al. during a synthetic study aimed at the synthesis of 1,2-amino

alcohols, considered the use of trimethylsilyl azide (TMSN3) as nucleophiles to convert an epoxy

aldehyde into a -hydroxyacyl azide. Thermal Curtius rearrangement of the latter followed by

treatment with in situ generated hydrazoic acid by using equimolar ratios of TMSN3 and EtOH led

to the formation in moderate to good yields of several oxazolidinone derivatives [79].

As a part of their ongoing efforts to exploit the cobalt(II) porphyrin catalyzed activation of

azides for nitrene transfer reactions, Zhang and coworkers have reported the intramolecular C-H

amination of arylsulfonyl azides to yield benzosultams (Scheme 18) [80].

23

R6

R5

R4

R3

S

O O

N3

H

R2

R1

R6

R5

R4

R3

S

O O

NH

R2R1

Co(porphyrin)

-N2

Scheme 18. Synthesis of benzosultams 34.

Commercially available Co(TPP) (TPP = dianion of tetraphenylporphyrin) was found to be a

competent catalyst under mild conditions in chlorobenzene. Benzosultams were obtained by nitrene

insertion in benzylic tertiary, secondary and primary C-H bond, following the order 3° > 2° > 1°.

The competitive insertion into a non-benzylic C-H bond to yield a six membered heterocycle was

observed only when secondary benzylic and non benzylic C-H bond were contemporarily present in

the molecule. Formation of the five membered ring was favored at elevated temperatures,

suggesting the higher thermodynamic stability of the five membered ring structure.

3. Six membered rings

Six membered rings containing one or more nitrogen atoms occur in numerous natural

products, especially in alkaloids [81]. Many papers describing new routes for their synthesis have

appeared in the literature in the last few years, but only few reports have been published where

intramolecular cyclization reactions of organic azides were employed, if we exclude numerous

synthetic reports where N-heterocycles were obtained from three component reactions of organic

azides with terminal alkynes and a number of nucleophiles. In all cases in which the latter strategy

was used, the opening of the initially formed triazole ring (click-chemistry) accompanied by N2 loss

accounts for the formation of the heterocycle and, as already stated in the introduction, this

chemistry is not included in the present review.

Among the isoquinoline alkaloids, over 80 types of benzo[c]phenanthridine alkaloids have been

characterized [82]. The isoquinoline ring system is also an important building block in a number of

24

pharmacologically important compounds [83], and it has been used as ligand for transition metal

catalysis [84]. Its iridium complexes has proven to be efficient as light emitting diodes (OLEDs)

[85]. It is not surprising that a variety of methods for the preparation of this ring system have been

reported, allowing for a fine tuning of the biological or physical properties of the final product [86].

Many of the reported methods suffer of considerable drawbacks such as the use of strong acids

and/or elevated temperatures. On the other hand Brønsted or Lewis acid catalyzed syntheses of

substituted isoquinolines from arylacetylene derivatives have proven to be very efficient. In this

field many contributions are due to the group of Yamamoto at the Tohoku University, who first

reported the synthesis of highly substituted 4-iodoisoquinoline derivatives 38 from 2-alkynylaryl

azides 35 (Scheme 19) [87].

XR3

I+

35

R2

R1

N3

XR3

R1

N

R2I

NN

XR3

R1

N

I

R2

N2+

H

XR3

R1

N

I

R2

NN

NR3

R2

R1

TfOH

36 3738

39

-H+

-N2

Scheme 19. Synthesis of isoquinolines 38.

Optimal reaction conditions were obtained in dichloromethane as solvent, room temperature

and five equivalents of iodine as the source of iodinium ion as electrophile. This way, iodine is

incorporated in the final product at C4, allowing for further functionalization of the molecule. The

choice of the base was found to be dependent from the substrate and while for primary azides the

best results were obtained with K3PO4, in the case of secondary azides the base had to be changed

to NaHCO3. The reaction is not affected by different substituents R1 in the position with respect

to the azide and good yields were obtained both for electron-rich and electron-poor benzene rings

25

[88]. On the other hand, the substituent on the triple bond terminus (R2) plays a relevant role and

optimal yields were obtained for electron-rich aryl substituents. When R2 is an alkyl group different

iodine source have to be used, and among these the Barluenga reagent (Py2IBF4) under acidic

conditions gave the higher yields. Terminal acetylenes did not give the desired isoquinoline, but a

bis-iodine product derived from the addition of I2 across the triple bond.

All experimental data collected are in accord with the mechanism shown in Scheme 19. The

first step is the alkyne activation by electrophilic attack of I+ to give a cyclic iodinium ion (36); the

azide will act as a nucleophile, with ring closure on carbon 2’ of the alkyne to yield intermediate 37,

which then releases N2 and H+ to form isoquinoline 38. This proposal is reminiscent of the

intramolecular, stepwise mechanism proposed for the pyrrole formation in the gold/silver catalyzed

homopropargyl azides cyclization [51].

To prove the applicability of this new synthetic methodology, the authors reported the total

synthesis of norchelerythrine 40, which exhibits potent antitumor and antiviral activities (Scheme

20) [88].

N3

O

OTBDMSO

MeO

OMe

MeO

OMe

O

O

TBDMSO

N

I

I2

MeO

OMe

O

O

N

I

MeO

OMe

O

O

N

norchelerythrine40

Scheme 20. Synthesis of norchelerythrine 40.

26

Isoquinolines can be formed by cyclization of the starting 2-alkynylaryl azides 35 also in the

presence of substoichiometric amount of AuCl3/AgSbF6 in THF and in pressure vials at 100 °C

[89]. In this case the reaction is less sensible with respect to the R2 substituent at the alkyne

terminus and good yields are obtained even in the case of alkyl substituents such as butyl. For

secondary azides instead lower yields were always observed. Again, the proposed mechanism

involves the activation of the triple bond by the gold catalyst that enhances the electrophilicity of

the alkyne that undergoes nucleophilic attack from the azide. When protic acids (TfOH) or other

Lewis acids are used (In(II) and Cu(II) triflates), instead, the cyclization of 35 afforded the Huisgen

1,3-dipolar cycloaddition derived triazoles 39. In fact, there are two possible pathways for the attack

of the nucleophilic N3 group to the alkyne: (i) attack of a nitrogen atom to an electron deficient

carbon of the alkyne; (ii) a [3 +2] cycloaddition between N3 and the alkyne to yield the triazole.

Using DFT calculations, Yamamoto was able to demonstrate that looking at the binding energies of

realistic catalysts (not naked cations), gold compounds can be considered the most promising

activators of the triple bond [90].

Cyclisation permitting to form the isoquinoline ring is favored by non-symmetrical geometries

of the iodinium ion 36, as shown by calculations. Non-symmetrical or slightly non-symmetrical

geometries are adopted also by the adducts with PyI+, AuCl3 and Au(PMe3)

+. On the other hand the

Brønsted acid adducts adopt “symmetrical” geometries which favor the triazole formation.

The fact that a traditional electrophile such as H+ might play a relevant role in electrophilic

mediated cyclization reactions of alkynes has been clearly demonstrated in the silver catalyzed

formation of isoquinolines 38 from 2-alkynylaryl azides 35 [91]. The reaction of 1-(azidomethyl)-2-

phenyl)benzene run with 20 mol% of AgSF6 in DCE at 80 °C gave the isoquinoline in 34% yield,

that can be improved to 65% when 2 equivalents of TFA (trifluoroacetic acid) were added.

Changing the temperature to 90 °C in the same solvent caused a drop in the final isoquinoline

amount, which was formed along with the triazole. Even with the AgSbF6/TFA system electron-rich

27

aromatic rings as R2 substituents at the alkyne terminus gave higher yields, and the reaction

tolerates a range of functional groups.

Isoquinolones 41 can be obtained with high regioselectivity from the palladium on

carbon/copper catalyzed C-C coupling of 2-iodobenzoyl azide with acetylenes, followed by

intramolecular acetylenic Schmidt reaction (Scheme 21) [92].

I

CON3NH

O

R

R

+[Pd]

41

Scheme 21. Synthesis of 1(2H)-isoquinolones 41.

The best catalyst was found to be Pd/C-PPh3 in ethanol. The presence of CuI was needed for

the reaction to proceed. It is reasonable to assume that palladium is a good catalyst for this raction

since, due to the presence of the acyl group, extrusion of nitrogen is easier for acyl azides than for

the related 2-alkynilbenzyl azides. A variety of alkynes were tested and yield ranged from moderate

to good.

It is worth to note that Lewis acids such as FeCl3 in combination with NaI can reduce azides to

yield amines in good yields and with excellent selectivities [93]. During the course of their studies

Kamal and coauthors reported the synthesis of quinazolinones by a tandem azido

reduction/cyclization process by using substoichiometric quantities of Al(OTf)3 or Gd(OTf)3 in the

presence of 3 equivalents of NaI (Scheme 22) [94].

N3

R

N

O

O

n

N

N

O

nRM(OTf)3, NaI

n = 1-3 n = 1-3

42

Scheme 22. Synthesis of fused quinazolinones 42.

28

Zhang and co-authors have recently reported a Co(II)-porphyrin based catalytic system for the

intramolecular amination of phosphoryl azides [95]. A wide range of cyclophosphoramidates have

been synthesized in high yields under mild conditions. The system is effective for the amination of

tertiary, secondary and also primary C-H bonds. When benzylic C-H bonds are present, six-

membered rings, 43 are formed preferentially, but in their absence, seven-membered rings, 44 can

be formed by activation of a non-benzylic C-H bond (Scheme 23).

O

R2 R1

Co(II)(porphyrin)

-N2

R R

OCo(II)(porphyrin)

-N2

RNH

P

PO OR3

N3

CH2

NH

PO

R2R1

O

OR3

R2 R1

O

H

R2

R1

R

P

O OR3

N3

CH3

43

44

O

OR3

Scheme 23. Synthesis of cyclophosphoramidates 43 and 44.

4. Seven membered rings

The chemistry and biological activity of seven membered N-heterocyclic compounds continues

to attract significant attention [96]. In a closely related approach to the one reported for the

isoquinolone skeleton, very recently Heo and coworkers reported a new methodology for the

synthesis of dibenzo[c,e]azepin-5-ones bearing an amide moiety [97]. This methodology employs a

Suzuki-Miyaura coupling process between 2-bromobenzyl azides and 2-

(methoxycarbonyl)phenylboronic acid to yield the biaryl esters 45 (Scheme 24).

29

Br

R1

R2

N3

B(OH)2

COOMe

+Pd(OAc)2

KF

R1

R2

N3

COOMe

45

i) PPh3ii) NaOMe/MeOH

R1

R2

NH

O

46

orH2 (1 atm)Pd/C (10%)

Scheme 24. Synthesis of dibenzo[c,e]azepin-5-ones 46.

In this case however, the cyclization step to form dibenzo[c,e]azepin-5-ones 46, does not occur

through nucleophilic addition by the proximal nitrogen of the azide, but it is necessary to reduce the

azide to the amine. This step can be done either by using Pd/C catalyzed hydrogenation processes or

by the classical Staudinger reaction.

As already pointed out, the reduction of the azide can be conveniently carried out with the

metal triflate/NaI combination. Using this approach the intramolecular cyclization of 1-(2-

azidoaroyl)prolinals 47 afforded imine derivatives of pyrrolo[2.1-c][1,4]benzodiazepine 48 in good

yields (Scheme 25) [94].

N3

R

N

O

RM(OTf)3, NaI

48

N

N

O

CHO

R1

H

R1

47

Scheme 25. Synthesis of pyrrolo[2.1-c][1,4]benzodiazepine 48.

Intramolecular azide cycloaddition to give 4,5-dihydrotriazoles, which usually shows low

stability, followed by in situ thermal decomposition to yield 4,5-dihydro-1,4-benzodiazepin-3-ones

has been also recently reported [98].

30

As we already pointed out in section 2.1, the Lewis acid catalyzed [3,3] aza-Claisen

rearrangement of N-vinyl aziridines allowed us to synthesize 2,5-dihydro-1H-benzo[b]azepines in

yield up to 65% [49]. Collected data indicated that this sigmatropic rearrangement would involve

the attack of the vinyl group to the aryl ring with a concomitant C–N bond cleavage of the aziridine

moiety leading to an imine intermediate I. The following aromatization with a concomitant proton

shift from the aryl moiety to the nitrogen and a double bond shift from the imine to the aryl ring

would yield the final benzazepine product B (Scheme 26).

NR2

R1

R3

R4

R5

R

R6NR2

R1

R3

R4

R5

R

R6

H

TSa

TSb

NH

R2

R1

R3

R4 R5

R

R6

B

NR2

R1

R3

R4R5

R

R6

H

I

NR2

R1

R3

R4R5

R

R6

H

Scheme 26. Proposed mechanism for the aza-[3,3]-Claisen rearrangement of N-aryl-2-vinyl

aziridines to benzoazepines B.

5. Conclusions.

The synthesis of N-heterocycles of different ring size continues to interest the scientific

community ad newer and greener processes are needed. Among these processes the use of transition

31

metal catalyzed organic azide transformations surely deserves a close inspection. Although one of

the main safety concern about the industrial use of azide is the toxicity and detonation potential of

hydrazoic acid that can be released [99], the stability of this reactive molecules is dramatically

increased when the number of carbon atoms in the organic azide exceed the number of nitrogen

atoms. Their use is associated with a high synthetic versatility that allows for the generation of the

very reactive nitrene unit, “RN”, with the eco-friendly nitrogen being the only side product. The use

of metal-catalysis avoids the need of drastic reaction conditions required by the thermal activation

of the azide. Moreover, thermal and photochemical activation usually result with a poor selectivity

of the reaction. The use of transition metal catalysis can lead to the activation of C-H bonds that

react with high regio- and chemoselectivity, as shown by many of the papers reviewed. However,

while there are several reported examples of intramolecular activation of aryl or vinyl C-H bond by

organic azides, the functionalization of non-activated C-H bond still represents a challenge to

modern synthetic chemists.

Acknowledgements.

We thank MIUR (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale, (PRIN

2007HMTJWP_004) for financial support.

32

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