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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.
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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
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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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