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CN bond forming cross-coupling reactions:

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Cite this: DOI: 10.1039/c3cs60228a

an overview
Jitender Bariwalab and Erik Van der Eycken*a

Nitrogen containing compounds are of great importance because of their interesting and diverse
biological activities. The construction of the CN bond is of significant importance as it opens avenues
for the introduction of nitrogen in organic molecules. Despite significant advancements in this field, the
Received 2nd July 2013 construction of the CN bond is still a major challenge for organic chemists, due to the involvement of
DOI: 10.1039/c3cs60228a harsh reaction conditions or the use of expensive catalysts in many cases. Thus, it is a challenge to
develop alternative, milder and cheaper methodologies for the construction of CN bonds. Herein, we
www.rsc.org/csr have selected some prime literature reports that may serve this purpose.

Key learning points

(1) This review highlights significant advancements in the construction of CN bonds.
(2) New ligands are highlighted for CN bond forming cross-coupling reactions.
(3) Transition metal-catalyzed CN bond formation reactions.
(4) Metal free CN cross-coupling reactions.

Introduction like (hetero)aryl (pseudo)halides to react with amines.1 CN

bond formation employing mild and inexpensive reaction condi-
Heterocyclic compounds, especially nitrogen containing com- tions is still a challenging task.
pounds, are extremely important because of their abundance in Recently, some significant achievements have been made in
various natural products as well as in synthetic organic com- CN coupling reactions using metal complexes with new ligands
pounds that show interesting biological activities.1 The construc- under mild conditions in a cost effective manner. Although, there
tion of the CN bonds of aromatic compounds is particularly are a few excellent reviews highlighting inter alia CC and CN bond
important and proved to be challenging to medicinal chemists.2 formation,1,7,8 the progress made in the area of CN bond formation
The introduction of the amino group in a controlled manner has using (non)activated substrates has not been documented in a
been extensively investigated by chemists and was first reported single review so far. The present review aims to highlight recent
by Ullmann and Goldberg,3,4 more than a hundred years ago. advances in CN coupling strategies that have emerged within
They used stoichiometric amounts of copper salts to activate aryl recent years, covering the period starting from 2010.
(pseudo)halides to react with amine nucleophiles. However, the For a better understanding of the subject, we have divided this
generation of stoichiometric amounts of copper salts as waste review into the following sections, based on the type of transition
and harsh reaction conditions limit the synthetic utility of this metal used as the catalyst:
procedure. In the 1990s, Buchwald and Hartwig independently (1) Copper(Cu)-catalyzed CN bond formation
developed the Pd- and Cu-catalyzed N-arylation using suitable (2) Palladium(Pd)-catalyzed CN bond formation
diamine or phosphine ligands.5,6 The presently used strategies (3) Other transition metals used in CN bond formation
to construct the CN bond are presented in Fig. 1. The current (4) Metal-free CN bond formation
CN bond forming strategies employ pre-activated starting materials

a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
1. Copper(Cu)-catalyzed CN bond formation
University of Leuven (KU Leuven), Department of Chemistry, Celestijnenlaan 200F,
B-3001, Leuven, Belgium. E-mail: Erik.VanderEycken@chem.kuleuven.be
Copper was the first metal used by Ullmann and Goldberg for
b
Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga-142001, the construction of the CN bond.3,4 In recent years, consider-
Punjab, India able advancements have been achieved in CN bond formation

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Fig. 1 Currently available CN bond formation strategies.

using various copper salts. These reactions utilize a catalytic those with electron-donating groups. With benzoyl chlorides
amount of copper in the presence of various ligands. In this bearing a bulky group at the ortho-position the yields of
section, we have chosen some latest and interesting reports where 6H-isoindolo[2,1-a]indol-6-ones 1 are drastically decreased.
various copper salts were used for CN bond formation. Recently, a robust method for the coupling of a variety of
The synthesis of a series of 6H-isoindolo[2,1-a]indol-6-ones 1 furazanyl iodides with 1,2,4,5-tetrazines has been developed by
has been reported by Bao and co-workers9 via a one-pot sequential Sheremetev and co-workers10 (Scheme 2). This is the only report
coupling reaction (Scheme 1). The first step in this sequence is where electron-deficient nitrogen-rich heterocyclic iodides were
a Cu-catalyzed CN coupling cyclization which is followed by a coupled with electron-deficient nitrogen-rich heterocyclic amines.
Pd-catalyzed CH activation. They started the sequence by reacting Aminotetrazine 5 was allowed to react with substituted iodo-
ortho-gem-dibromovinyl anilines 2 and substituted benzoyl chloride furazans 6 in the presence of Cu(OAc)2 and 2-acetylcyclohexanone
3 in the presence of CuBr (10%), N,N-dimethyl ethylenediamine L1 as the supporting ligand, at 50 1C for 4 h, to get access to
(DMEDA) (20%) as a ligand, and K2CO3 (1.0 equiv.) in toluene at coupled secondary amines 7 in good yields. Various functional
120 1C, to obtain (2-bromo-1H-indol-1-yl)(phenyl)methanones 4 in groups on the furazanyl iodide part like nitro, azido, and azo
moderate to good yields. This step is followed by a Pd-catalyzed proved to be insensitive to the given reaction conditions. Moreover,
CH activation resulting in the formation of 6H-isoindolo[2,1-a]- both 3,6-disubstituted and annelated s-tetrazines react readily with
indol-6-ones 1. It has been observed that the aromatic ring of the iodofurazans to furnish the desired secondary amines. How-
ortho-gem-dibromovinyl anilines 2 bearing electron-withdrawing ever, coupling of 3,4-diiodofurazan (R = I) and 4-N-acetylfurazan
groups favours the formation of the indole ring, in contrast to (R = NHAc) failed to give the desired product.

Dr Jitender Bariwal is Assistant Prof. Erik Van der Eycken

Professor at the ISF College of received his PhD degree (1987)
Pharmacy, Moga, Punjab, India. in organic chemistry from the
He received his PhD-degree in University of Ghent, Belgium.
Pharmaceutical Sciences from From 1988 to 1992 he worked
Saurashtra University, Rajkot, as a scientific researcher at the
India, with Prof. Anamik Shah R&D-laboratories of AGFA-
and Prof. Kishor Jain. He has Gevaert, Mortsel, Belgium. Then
worked as a postdoctoral he moved back to the University
researcher with Prof. Erik Van of Ghent (19921997). In 1997 he
der Eycken from 2009 to 2010 was appointed at KU Leuven. He
where he was involved in the spent time as visiting scientist at
Jitender Bariwal total synthesis of naamine Erik Van der Eycken the University of Graz (2002,
alkaloids and intramolecular C. O. Kappe), at The Scripps
A3-coupling reactions. After completing his tenure at LOMAC, he Research Institute, La Jolla, USA (2003, K. B. Sharpless), and at
started his independent research career. He is focusing his research Uppsala University (2004, M. Larhed, A. Hallberg). The main focus
on organometallic chemistry and heterocyclic chemistry for various of his research is (microwave-assisted) organic synthesis.
biological targets.

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Scheme 1 Synthesis of 6H-isoindolo[2,1-a]indol-6-ones 1.

Scheme 2 Coupling reaction of furazanyl iodides with s-tetrazinylamines.

An unprecedented chemical reactivity of N-alkenyl amidines aromatic rings including bromophenyl, thienyl groups and
8 under Cu-catalyzed aerobic reaction conditions for the syn- alkyl substituents and gave good yield under these conditions.
thesis of bi- and tricyclic amidines 9 has been reported by Chiba However, the reaction of N-5-hexenyl amidine did not aord the
and co-workers11 (Scheme 3). The concerted [3+2]-annulation [3+2]-annulation product. The [3+2]-annulation reaction pro-
reaction proceeds through a putative nitrene species using CuI ceeds in a concerted manner as the reactions of both (E)- and
(10 mol%) as the catalyst and 2,2 0 -bipyridine L2 (10 mol%) as (Z)-N-5-phenyl-4-pentenyl derivatives provided a single diastereo-
an additive in DMF at 60 1C for 23 h under aerobic conditions mer with retention of the configuration of the alkenyl moiety.
as optimized reaction conditions. The [3+2]-annulation was However, the reaction of N-5,5-dimethyl-4-pentenyl amidine failed
well tolerated with a variety of N-alkenyl amidines as various to aord the product even by using a stoichiometric amount of

Scheme 3 Synthesis of bi- and tri-cyclic amidines 9.

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Scheme 4 Synthesis of 3-aminobenzofurans 12 and 3-aminoindoles 13.

CuI and 2,2 0 -bipyridine. In the case of N-allyl amidine, the

desired bicyclic aziridine was obtained in only 33% yield.
A Cu-catalyzed annulative amination of ortho-alkynylphenols
and -anilines 10 with ortho-benzoyl hydroxylamines 11 has been
reported by Hirano, Miura and co-workers12 for the synthesis of
3-aminobenzofurans 12 and 3-aminoindoles 13 respectively
(Scheme 4). The optimum conditions for this reaction utilize
Cu(OTf)2 as the copper source, Li or Na tertiary butoxide as base
and NMP as solvent to give the corresponding product at mild
reaction temperature. The alkyne terminus tolerates electron- Scheme 5 Synthesis of 2-quinolones 14.
donating as well as electron-withdrawing functional groups.
In general, electron-rich alkynes show higher reactivity, whereas
primary/secondary or tertiary alkyl groups are well tolerated The presence of substituents at both meta-positions of the
under these reaction conditions. Various hydroxylamines 11 aromatic fragment does not hamper the reaction. Interestingly,
including diethylamine, acyclic allyl- and benzylamines parti- in the case of unsymmetrical 3,3-diarylacrylamides (R1 a R2),
cipate smoothly in this annulative amination. Interestingly, high selectivity was observed where the aromatic ring trans to the
when this protocol was applied to N-mesyl-ortho-alkynylanilines amide group bears ortho-methyl, -chloro, or -bromo substituents.
(10, where Y = NMs) for the synthesis of the desired 3-amino- An unprecedented CuII-catalyzed aerobic oxidative synthesis
indoles 13, better yields were obtained when DMF was used as of 2,4,5-triaryl-1,2,3-triazoles 16 and 1,3,5-triaryl-1,2,4-triazoles
solvent. However, cyclohexyl- and tert-butyl substituted alkynyl- 17 has been reported by Punniyamurthy and co-workers14 from
anilines resulted in lower yields because of steric reasons. The bisarylhydrazones 18 as the common starting precursor via
introduction of electron-donating groups on the aniline 10 cascade CH functionalization/CC/NN/CN bond formation
increased the reactivity, whereas electron-withdrawing func- under mild reaction conditions (Scheme 6). The 1,2,3-triazole
tions decreased the yield. The present methodology lacks the 16 was accessed in high yield using the reaction of bisaryl-
generality for cyclic amines (piperidine, hydroxylmorpholine hydrazones 18 in the presence of 20 mol% Cu(OAc)2H2O in
and piperazines) in ortho-benzoyl hydroxylamines 11 as they toluene at 60 1C under air. Various bisarylhydrazones bearing
reacted only moderately. electron-withdrawing, electron-donating and unsubstituted
A new Cu-catalyzed approach for the construction of the arenes give the corresponding heterocycles in moderate to high
2-quinolones 14 has been developed by Cacchi and co-workers.13 yields. Arylhydrazones containing furanyl and thiophenyl moieties
This is based on an intra-molecular CH functionalization/CN also undergo cyclization providing the target heterocycles in
bond forming process (Scheme 5). The 2-quinolones 14 were moderate yields. These reaction conditions were also compatible
obtained in good yields when 3,3-diarylacrylamides 15 were for the synthesis of unsymmetrical 2,4,5-triaryl-1,2,3-triazoles.
treated with CuI (10 mol%), PPh3 (20 mol%) and KO-tBu in Furthermore, it has been found that bisarylhydrazone could
ortho-xylene at 100 1C for 5 to 24 h under aerobic conditions. readily undergo reaction with the organic base, 1,4-diazabicyclo-
In the case of symmetrical 3,3-diarylacrylamides (R1 = R2), [2.2.2]octane (DABCO) in dioxane at 60 1C to give an intermediate
moderate to high yields of the desired products were obtained that could further undergo reaction with Cu(OAc)2H2O at rt
which bear neutral, electron-rich, or moderately electron-poor to afford 1,3,5-triaryl-1,2,4-triazoles 17 in good yields. Bisaryl-
aromatic rings. However, strongly electron-withdrawing groups hydrazones bearing electron-withdrawing and electron-donating
did not afford 2-quinolones suggesting that the nucleophilicity substituents on the aryl ring afforded the 1,3,5-triaryl-1,2,4-
of the aromatic ring plays a key role in the cyclization event. triazoles 17 in good to high yields. The modified reaction

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Scheme 6 Synthesis of 2,4,5-triaryl-1,2,3-triazoles 16 and 1,3,5-triaryl-1,2,4-triazoles 17.

conditions could also be readily employed for the synthesis of for the synthesis of diverse ynimines in moderate to good yields.
unsymmetrical 1,3,5-triaryl-1,2,4-triazoles. A variety of aromatic and alkyl-substituted alkynes undergo
Recently, Yao, Ma and co-workers15 have reported 2-(2,6- this reaction smoothly. Terminal enynes were also found to be
dimethylphenylamino)-2-oxoacetic acid (DMPAO) L3 as a power- excellent substrates. However, the presence of a chelating group
ful and inexpensive ligand for the Cu-catalyzed aryl amination of such as a benzoate on the terminal enyne hampers the oxidative
aryl-halides 19 and amines 20 to give good to high yields of the cross-coupling reaction as all the starting material was recovered
corresponding N-arylated products 21 (Scheme 7). In the case in this case. The substitution pattern of the starting imine has a
of aliphatic acyclic secondary amines, both electron-rich and strong impact on the outcome of the reaction as ortho-substituted
electron-deficient aryl halides provided the corresponding diaryl imines yielded a single stereoisomer of ynimines, whereas
N-arylation products in good to excellent yields. However, ortho- meta-substituted diarylimines gave equimolar amounts of (E)- and
substituted aryl halides gave poor conversions due to steric (Z)-isomers of the corresponding ynimine.
hindrance. Electron-deficient aryl halides seemed to be more A convenient method for the synthesis of N,N-disubstituted
reactive than electron-rich yielding compound 21 in shorter hydrazines 26 has been reported by Ma and co-workers17 via a
reaction times. Aryl iodides showed higher reactivity than aryl CuI-catalyzed coupling reaction of aryl iodides 27 with N-acyl-
bromides. For primary amines and cyclic secondary amines, N 0 -substituted hydrazines 28. Using slightly modified conditions,
the use of 1 mol% of CuI and 2 mol% of DMPAO provided the coupling of aryl hydrazides 28 with 2-bromoarylcarbonyls 29
complete conversions for a wide range of aryl bromides. The could also be performed, providing access to 1-aryl-1H-indazoles
electronic nature of the amines as well as steric hindrance plays 30 (Scheme 9). For N,N-disubstituted hydrazines 26, the reac-
a critical role and has a pronounced influence on their reactivity. tion proceeded well under catalysis with CuI (10 mol%) and
Ecient syntheses of ynimines 22 have been reported by 4-hydroxy-L-proline (20 mol%) in DMSO at 60 1C. Various
Evano and co-workers16 via a Cu-mediated oxidative cross-coupling N-acyl-N0 -(un)substituted hydrazines 26 (R = Ph) bearing electron-
of imines 23 with terminal alkynes 24 (Scheme 8). The combi- donating as well as electron-withdrawing substituents at the meta-
nation of CuCl2 and pyridine in toluene significantly reduces or para-positions on either aryl ring proceeded smoothly. However,
the formation of GlaiserHay dimer 25 and gave ynimine 22 in ortho-substituted N-aryl hydrazides gave low yields, due to steric
good yields. These reaction conditions were found to be general hindrance. Various aryl iodides 27 bearing both electron-rich and

Scheme 7 Synthesis of N-arylated product 21.

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Scheme 8 Synthesis of ynimines 22.

Scheme 9 Synthesis of N,N-disubstituted hydrazines 26 and 1-aryl-1H-indazole 30.

electron-deficient substituents were found to be compatible, hydrazide gave low yield, indicating that the electronic nature of
providing the corresponding N,N-diaryl hydrazides in high aryl bromides has little influence on this protocol.
yields. Interestingly, ortho-substituted aryl iodides also gave Evano and co-workers18 have reported an ecient and
good yield indicating that the steric hindrance has little influ- general procedure for the cross-coupling of 1,1-dibromoalkenes
ence on the coupling reaction. Further, coupling of 2-bromoaryl- 31 and nitrogen (N), oxygen (O) and phosphonate (P) nucleo-
carbonyls 29 with N-aryl hydrazides gave coupled product 29a. philes (Scheme 10). The selective monocoupling was achieved
Subsequent deprotection provides access to 29b which upon with vinyl dibromides 31 and amides 32 using a catalytic
intramolecular condensation aorded 1-aryl-1H-indazoles 30 amount of CuI, N,N 0 -dimethylethylenediamine (DMEDA) and
under similar reaction conditions. Various N-aryl hydrazides potassium phosphate in 1,4-dioxane at 80 1C to give access
bearing either electron-donating or electron-withdrawing groups to bromoenamides 33 as 2 : 1 mixtures of stereoisomers, the
provide corresponding 1-aryl-1H-indazoles 30 in excellent yield (Z)-olefin being the major one. A variety of aryl- and alkyl-substituted
except for nitro-substituted products. Similarly, pyridine-embodied dibromides 31 yielded the corresponding 1-bromoenamides in

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Scheme 10 Reaction of 1,1-dibromoalkenes 31 to yield 1-bromoenamides 33, ynamides 35 and 36, conjugated N-heterocycles 38 and double cross-coupling
products 39.

good yields. Moreover, lactams and oxazolidinones perform of electron-withdrawing or -donating substituents on the
equally well, yielding the corresponding 1-bromoenamides with N-heterocyles had virtually no eect on the reaction. The
similar eciency. alkynylative cross-coupling, double cross-coupling products 39
In alkynylative cross-coupling reactions, 1,1-dibromoalkenes were obtained by reacting dibromide 31 with nitrogen nucleo-
31 were reacted with sulfonamides 34 using Cs2CO3 as base to phile 40 using K3PO4 as base in toluene. The reaction gave the
give access to the desired ynamides 35 as the sole products. A best yield with lactams, and with aryl- or alkenyl substituted
wide range of dibromides 31 and sulfonamides 34 gave good to dibromoalkenes. However, the use of other N-nucleophiles
high yields. The nature of the substituents on the sulfonamide such as sulfonamides or conjugated N-heterocycles did not give
had no eect on the yield of the product. However, the gem- the corresponding ketene acetals.
dibromo olefins substituted with an alkyl group reacted slowly, A Cu-catalyzed Petasis-type reaction of imines 41, acid
possibly due to a slower elimination step. The reactivity of chlorides 42, and organoboranes 43 has been developed by
pyrrolidinone, carbamates, and oxazolidinones 32 with various Arndtsen and co-workers19 to get access to a-substituted amides
dibromides 31 gave the corresponding ynamides 36 in good to 44 (Scheme 11). This reaction does not require the use of
excellent yields. Importantly, bulky substituents around the specifically substituted imines or organoboranes. A number
nitrogen had no eect on the cross-coupling reaction. of simple imines including N-benzyl, -aryl, and -alkyl imines, as
Further, p-excessive nitrogen nucleophiles 37 (electron rich well as imines derived from aryl- or heteroarylaldehydes gave
nitrogen) were reacted with vinyl dibromides 31 to give the good to high yield. Similarly, aryl-, alkyl- and heteroaryl-acid
corresponding conjugated N-heterocycles 38. The presence chlorides provide amides in good yield. In addition to simple

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Scheme 11 Synthesis of a-substituted amides 44.

phenylsubstituted borates, functionalized aryl-, heteroaryl, and Zou, Zhang and co-workers21 have developed a simple and
alkyl groups can be transferred to the imine in good yields. In ecient Cu-catalyzed method for the synthesis of indolo[1,2-c]-
addition, a,b-unsaturated imines can also be employed. quinazolines 47. In this protocol, readily available 2-(2-halo-
Recently, Liubchak, Tolmachev and co-workers20 have elaborated phenyl)-1H-indoles 48 and (aryl)methanamines 49 have been
a new synthetic approach for the construction of 4-substituted reacted using air as oxidant, Cu(OAc)2 as the catalyst without the
imidazo[4,5-c]pyrazoles 45 (Scheme 12). They have proposed use of any ligands to provide access to indolo[1,2-c]-quinazolines
the cyclization of N 0 -(4-halopyrazol-5-yl)amidines 46 under in moderate to good yield (Scheme 13). For substituted 2-(2-
Cu-catalyzed cross-coupling conditions using 0.05 mol% of halophenyl)-1H-indoles, the aryl iodides showed higher reactivity
CuI, 0.1 mol% of DMEDA, and an excess of K2CO3 under MW than the corresponding bromides. The electronic properties of
and conventional heating using DMF as solvent (Scheme 12). the substituents in the indole ring have a very limited influence
The nature of the solvent proves to be the most significant as in over the reactivity. Functional groups, including methyl, fluoride,
all cases as the use of DMSO or DMF instead of acetonitrile and chloride, are well tolerated in this domino transformation.
or toluene leads to a drastically increased yield of the target In the case of arylmethanamines, both electron-rich and electron-
product. Both, bromo and iodo derivatives undergo smoothly deficient arylmethanamines participate in the reaction smoothly
cross-coupling and provide high yields of the cyclized products. to aord the desired products. The naphthyl-substituted methan-
Pyrazoles bearing short alkyl groups like methyl at C-3 furnish amines and various heteroaromatic methanamines are compati-
high yields of the product. Similarly, pyrazoles bearing an alkyl ble with this domino reaction to give the desired products. It has
or aryl group at N-1 provide high yields. If the amidine nitrogen been observed that the reactivity of thiophen-2-yl methanamine
is substituted with a short alkyl chain or an aryl group bearing is better than furan-2-yl methanamine and pyridin-3-yl methan-
electron donating groups, high yields of the cyclized product amine in this protocol.
are obtained. When the carbon atom of the amidine is bearing Monguchi, Sajiki and co-workers22 have developed a new method
an alkyl or aryl group also high yields of the cyclized product are for the synthesis of primary arylamines 50 by the reductive cross-
furnished. Interestingly, cyclization reactions of N 0 -(4-bromo- coupling reaction between aryl halides 51 (chlorides, bromides,
pyrazolyl) and N 0 -(4-iodopyrazolyl) derivatives of N-aryl substi- and iodides) and azido compounds 52 (such as TMSN3, NaN3
tuted amidines gave the desired product under milder reaction and diphenylphosphoryl azide (DPPA)) in the presence of copper
conditions in high yields. reagents and 2-aminoethanol in DMA (Scheme 14). This one-pot

Scheme 12 Synthesis of 4-substituted imidazo[4,5-c]pyrazoles 45.

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Scheme 13 Synthesis of indolo[1,2-c]-quinazolines 47.

Scheme 14 Synthesis of primary arylamines 50.

reaction proceeds smoothly for the reduction of the azido reactions under mild conditions. A few years back, Buchwald
function and the cross-coupling with aryl halides without the and Hartwig independently developed Pd- and Cu-catalyzed
formation of the aryl azide as the intermediate. Aryl bromides N-arylation reactions with the help of the appropriate diamine
and iodides bearing an electron-withdrawing group, such as or phosphine ligands.5,6,2325
nitro, ester, phenyl, and chlorine functionalities, on the aromatic Triazole nucleosides are challenging substrates for metal-
nucleus, were eectively aminated. Aryl bromides and iodides catalyzed cross-coupling reactions due to the low reactivity of
possessing a methyl or methoxy group at the meta-position were the heterocyclic triazole ring, the multiple coordinating N and
better substrates compared to the ortho- or para-substituted aryl O-atoms and the labile glycosidic bond. A highly ecient mixed
bromides and iodides. This reaction proved applicable to fused ligand, Pd-catalytic system for the (aryl)amination of triazole
aromatic bromides, such as bromonaphthalenes, and 3-bromo- nucleoside analogues has been reported by Peng and co-workers.26
quinoline. However, highly electron-deficient compounds gave The coupling reaction was carried out by reacting 5-bromotriazole
the aminated product with low yields. In this reaction, organic ribonucleoside 53 with substituted anilines 54 using a combi-
azides such as DPPA and NaN3 may be employed instead of nation of two phosphor ligands, Synphos L4 and Xantphos L5
TMSN3 for the amination procedure. DPPA was found to be an (ratio 2 : 1) in toluene to get the target N-arylaminotriazole
eective amino source, compared to NaN3. However, a slight ribonucleosides 55 in excellent yields (Scheme 15). This cata-
change in reaction conditions, namely NaN3 together with CuF2, lytic system was found to be very ecient for arylamines bearing
gave access to the corresponding anilines in good to excellent either electron-donating or electron-withdrawing groups at
yields regardless of the type of substituents on the aromatic various positions. Interestingly, the CN coupling reaction
nucleus. proceeded very smoothly even with sterically hindered ortho-
Besides these reports, there is an outburst of communica- substituted arylamines and pyrenylamine. However, the use of
tions where Cu has been utilized in cross-coupling reactions, a single-ligand system consisting of either Synphos L4 or
particularly because of its low cost. However, Cu often requires Xantphos L5 results in very low yields of the N-arylaminotriazole
high reaction temperatures and high catalyst loadings. ribonucleoside. This catalytic system is also very efficient for
different nucleoside substrates. It is the first report on efficient
2. Palladium(Pd)-catalyzed CN bond formation arylamination of triazole nucleosides with different isomeric
structures and different sugar components. Importantly, much
Palladium is extensively used in CN bond forming reactions as less reactive purine nucleosides such as 6-chloropurine ribo-
well as in CH activation. In this section some prime reports are nucleoside, provided access to the corresponding products in
presented where palladium efficiently provides CN cross-coupling excellent yields.

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Scheme 15 Synthesis of N-arylaminotriazole ribonucleosides 55.

Scheme 16 Synthesis of N-phenylsulfinamides 58.

Recently, an ecient Pd-catalyzed CN cross-coupling reac- halides promotes the cross-coupling and results in higher
tion of sulfonamides 56 and aryl halides 57 has been elaborated product yields.
by Zeng and co-workers27 to give access to the N-phenylsulfin- An ecient method for the synthesis of indolines 59 from
amides 58 applying Pd2(dba)3 as the palladium source, 2-di-tert- picolinamide (PA)-protected b-arylethylamines 60 via Pd-catalyzed
butylphosphino-2 0 ,4 0 ,6 0 -triisopropyl-biphenyl (tBuXPhos) L6 as intramolecular amination of ortho-C(sp2)H bonds has been
the ligand, and NaOH as the base (Scheme 16). The reaction developed by Chen and co-workers28 (Scheme 17). This intra-
proceeds smoothly at 90 1C and affords N-phenyl-sulfinamides molecular amination was achieved in toluene using Pd(OAc)2
in low to excellent yields within 20 h. A small volume of degassed (2 mol%) at 60 1C for 24 h (general condition a) or with
water accelerates the reaction by dissolving the inorganic Pd(OAc)2 (0.5 mol%) at 80 1C for 24 h (general condition b)
base. Interestingly, the chirality of (R)- and (S)-sulfinamide under an inert atmosphere of argon to afford indoline 59 in
was preserved in the N-arylsulfinamides during the coupling. high yield. Molecular oxygen has an inhibitory effect on the
The presence of electron-withdrawing groups in the aryl cyclization reaction, particularly with lower catalyst loading or

Scheme 17 Synthesis of indolines 59.

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at lower reaction temperature. In general, electron-deficient Substrates like benzylamine, aliphatic primary amines, gave the
substrates were cyclized in excellent yields along with small amination product in very low yields. However, aromatic primary
amounts (o10%) of undesired acetoxylated products, whereas amines undergo this amination reaction with slight modifica-
substrates bearing electron-donating functional groups are tions in reaction conditions using K3PO4 as base and DME as
slightly less selective. In particular, substrates bearing electron- solvent at 45 1C for 24 h and gave high yields of the desired
donating groups para to the targeted CH bond, gave consider- product. ortho-Substituted anilines gave low yields due to steric
ably diminished yields of the cyclized product, with increased eects. Further, a variety of chloromethylnaphthalenes reacts
amounts of acetoxylated side products. Excellent regioselectivity well under these reaction conditions. A slightly modified protocol
at the least sterically hindered position was observed in sub- was applied to 9-chloromethylanthracene and various amines.
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strates bearing two nonequivalent ortho-CH bonds. In addition, The Pd-catalyzed amination reaction of 62 with various amines
common functional groups such as esters, acetyls, and TBS in DME using NaOtBu as base for 1236 h, results in the
protecting groups were well tolerated. production of the corresponding amination products 64. Cyclic
A general catalytic method for the conversion of chloromethyl- secondary amines exhibited higher reactivity than N-alkyl sub-
naphthalene 61 and chloromethylanthracene 62 to naphthyl- stituted anilines.
amines 63 and anthrylamines 64 respectively, has been developed A general Pd-catalyzed cross-coupling of alkyl cyanamides
by Bao and co-workers29 by reacting them with amines 65 66 with aryl/heteroaryl/vinyl halides/pseudohalides 67 has been
using Pd(PPh3)4 as the catalyst under mild reaction conditions developed by Louie and co-workers30 under mild conditions
(Scheme 18). This Pd-catalyzed amination of 1-chloromethyl- using Pd2dba3, Cs2CO3 and tBuXPhos L6 as ligand in tAmyl-OH
naphthalene with primary and secondary amines takes place at as solvent to give access to the cross-coupled product 68
the para position to aord 1-amino-4-methylnaphthalenes. (Scheme 19). The reactions proceed selectively in moderate to
The reaction of 61 with five- and six-membered cyclic amines excellent yields. The reaction is amenable to electron-donating
(pyrrolidine, piperidine, morpholine and thiomorpholine), non- and -withdrawing aryl halides as well as heteroaryl halides,
cyclic aromatic amines (N-methylaniline, 4-methyl-N-methyl- pseudohalides and vinyl halides. The order of reactivity of various
aniline, and 4-methoxy-N-methylaniline) proceeded smoothly and halides was found to be: aryl bromides > triflates > iodides.
gave access to the corresponding products in moderate yields. However, reactions of aryl chlorides led to catalyst poisoning.

Scheme 18 Synthesis of naphthylamines 63 and anthrylamines 64.

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Scheme 19 Cross-coupling of alkyl cyanamides 66 with aryl/heteroaryl/vinyl halides/pseudohalides 67.

For electron-rich aryl halides, product yields are generally low, benzamide 70, electron-donating groups as well as electron-
and require longer reaction times and higher catalyst loadings. withdrawing groups provide high yields of the arylation pro-
Bulky group bearing cyanamides lead to decreased yields of duct. The coupling reaction of tert-butyl carbamate and aryl
product 68. Heterocyclic halides lead to excellent yields of the bromide was found to happen/work quantitatively. The reaction
cross-coupled product. seems to be insensitive to electronic and steric eects of the
A coupling reaction between inactivated aryl halides 69 and functional groups on the aryl bromide. However, aryl chlorides
amides 70/tert-butyl carbamate 71 to give cross-coupled pro- bearing electron-withdrawing groups gave higher yields than
ducts 72 and 73 respectively, has been reported by Zhang and those with electron-donating groups, due to their higher
co-workers31 using bulky and electron-rich 2-dialkylphosphino- electrophilicity and the poor dissociation of chloride from the
2 0 -alkoxyl-1,1 0 -binaphthyl as ligand L7, where Pd(dba)2 was PdII-complex.
used as a precatalyst, Cs2CO3 as the base, and tBuOH as the A Pd-catalyzed reaction of vinyl iodides 74 and N-tosyl-
solvent (Scheme 20). Studies have revealed that bidentate hydrazones 75 has been developed through a carbenylative
phosphine and monodentate biarylphosphine ligands bearing amination reaction to generate pyrrolidine and piperidine ring
a substituent ortho to the phosphorus, can promote the cata- systems 76 by Van Vranken and co-workers32 (Scheme 21). It
lytic amidation of aryl halides through inhibition of the for- has been observed that large variations are allowed on the vinyl
mation of the k2-amidate complex by steric hindrance. A variety iodides. Sterically hindered amines such as the benzhydryls are
of primary amides, (aliphatic and aromatic) and lactams parti- tolerated on the nitrogen (at R1). Moreover, the reaction also
cipated in the coupling reactions to give good to excellent tolerates a methyl group at the site of alkylation (at R2). Interest-
yields. A number of functional groups, such as fluoro, methoxy, ingly, oxidatively labile amino protecting groups are also well
and heteroaromatic, were well tolerated on the amide 70 under tolerated. N-Tosylhydrazone substituted with an ortho-bromine,
these reaction conditions. In the case of substituents on the aords the product in high yield in a 5 : 1 ratio of (E) and (Z) isomers.

Scheme 20 Reaction of aryl halides 69 and amides 70/t-butyl carbamate 71.

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Scheme 21 Synthesis of pyrrolidine and piperidine ring systems 76.

Both electron-rich and electron-deficient groups are well tolerated An ecient Pd-catalyzed Multi Component Reaction (MCR)
on the N-tosylhydrazones. The low yield of the aryl carbonate is has been developed by Ruijter, Orru and co-workers34 for the
presumed probably due in part to its nucleophilic sensitivity. synthesis of 4-aminophthalazin-1(2H)-ones 80 by reacting ortho-
The reaction also works well with vinyl hydrazones. The appli- (pseudo)halobenzoates 81 and hydrazines 82 with isocyanide 83
cation of the ligand (S)-BINAP provided promising levels of followed by lactamization. The reactants were allowed to react
asymmetric induction but in low yields. in the presence of Pd(OAc)2 (2 mol%) and ligand L8 (XantPhos)
A general and ecient method for the coupling of (hetero)aryl (4 mol%) in DMSO (Scheme 23). For methyl ortho-halobenzoate,
nonaflates 77 and primary sulfonamides 78 to give access to bromides, iodides and triflates provided the product in excellent
various sulfonamides 79 in high yields has been reported by yields. However, chlorides proved to be less ecient coupling
Shekhar, Dunn and co-workers33 (Scheme 22). The reaction is partners. Both electron-donating and -withdrawing substituents
catalyzed by the Pd-complex of the readily available biaryl are well tolerated on the aryl bromide. The 4-aminophthalazin-
phosphine ligand, tBuXPhos L6 using K3PO4 in tert-amyl alcohol 1(2H)-ones 80 substituted at C5 and C6 as well as naphthalene-
as the optimal base-solvent combination. Although both electron- fused derivatives were obtained in excellent yields. The use of
poor and electron-rich nonaflates gave the coupled products in substituted hydrazines proved to drastically reduce the product
high yields, the reaction rate was highly dependent on the yields, as was observed with the use of phenylhydrazine. However,
electron-donating ability of the substituent. Bulky aryl nonaflates yields were improved by using an additional base such as iso-
dramatically reduces the product yield. Base-sensitive functional propylamine. Interestingly, a change in the electronic character of
groups are well tolerated. The reactions of heterocyclic aryl non- the aryl hydrazine has a pronounced eect as electron-poor
aflates provided the corresponding sulfonamides in high yields. phenylhydrazines gave low yields. The reaction is highly specific
The reaction of both electron-rich and electron-poor aromatic for tertiary alkyl isocyanides, as primary and secondary aliphatic
sulfonamides aorded the product in high yield. However, bulky or aromatic isocyanides did not gave the desired product.
sulfonamides required a higher temperature and higher catalyst Buchwald and co-workers35 have developed an ecient method
loading for full conversion. Interestingly, the challenging sub- for the synthesis of unsymmetrical ureas 84 via a Pd-catalyzed
strate combination of an electron-rich nonaflate and an electron- cross-coupling of aryl chlorides and triflates 85 with sodium
poor sulfonamide was accomplished in excellent yields under cyanates. The reaction proceeds nicely using Pd2(dba)3 as
slightly forcing conditions. The only limitation identified in this palladium source upon heating with ligand L9 at 110 1C for
methodology is the inability of 2,6-disubstituted aryl nonaflates 16 min in the presence of NEt3, and gave the desired biaryl
to eciently participate in the reaction. ureas in good to high yield (Scheme 24). The aryl isocyanates 86

Scheme 22 Synthesis of sulfonamides 79.

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Scheme 23 Synthesis of 4-aminophthalazin-1 (2H)-ones 80.

Scheme 24 Synthesis of unsymmetrical ureas 84.

are identified as intermediates and are subsequently in situ standard phosphine ligands, Me4-tBu-XPhos L10 and tBu-Brett-
converted into unsymmetrical N,N 0 -di- and N,N,N 0 -trisubstituted Phos L11, gave the desired product 90 in excellent yields
ureas upon addition of an amine nucleophile 87. A wide array (Scheme 25). A variety of 2-chloro-3-aminopyridines gave the
of electron-neutral, -deficient, and -rich aryl chlorides and aryl desired imidazo[4,5-b]pyridines in good to excellent yields.
triflates could be converted into unsymmetrical ureas in high Alkyl substitutions on the 2-chloro-3-aminopyridines were well
yield. Small ortho-substituents on the aryl chlorides were well- tolerated, and no b-hydride elimination was encountered in
tolerated. However, an ortho-methyl group resulted in a diminished this reaction. Excellent yields were obtained for both branched
yield of the aryl isocyanate. Electron deficient aryl chlorides and un-branched alkyl groups. However, substituted amides such
and triflates are superior coupling partners in the first step. as cyclohexanecarboxamide, coupled in 89% yield but failed to
Similarly, a variety of amine nucleophiles demonstrates that undergo the dehydrative cyclization, while cinnamamide gave a
both aliphatic and aromatic amines could be used to provide 3 : 1 mixture of uncyclized to cyclized products in 92% yield.
the desired products. A number of dierent heterocyclic com- Pyrazines react well under the standard reaction conditions to
ponents, such as quinoline, pyridine, thiazole, and N-methyl- give access to the desired imidazo[4,5-b]pyrazines in excellent
benzimidazole, could be successfully incorporated into the yield and the reactions commence up to 8-times faster as com-
urea motif by using the corresponding amines. Electron-rich pared to pyridines. In the case of C2 unsubstituted imidazo-
anilines are better nucleophiles and facilitate the second step [4,5-b]pyridines, C2 can be easily functionalized.
of the sequence. Competitive experiments using various aryl Wu and co-workers37 have developed a one-pot, Pd-catalyzed
halides suggests that transmetalation is the rate-limiting synthesis of 9-(pyridin-2-yl)-9H-carbazoles 91 by reacting N-phenyl-
step and the rate of PdNCO formation decreases in the order pyridin-2-amines 92 with potassium aryl-trifluoroborates 93
Cl > Br > I. through CH activation and Pd-catalyzed cross-coupling of the
Clark and co-workers36 have described a regioselective intermediate N-phenylpyridin-2-amines 94. For this reaction,
Pd-catalyzed coupling of protected 2-chloro-3-aminopyridines silver acetate and 1,4-dioxane proved to be the best oxidant and
88 with a primary amide 89, followed by in situ cyclization solvent respectively, whereas para-benzoquinone (BQ) and
and dehydration to provide access to imidazo[4,5-b]pyridines DMSO were used as co-oxidant and ligand respectively, at
90 in a one-pot method using potassium phosphate as base 140 1C for 48 h. The target product was obtained in good yield
and tert-butanol as solvent. Under optimized conditions, (Scheme 26). The use of various aryl boranes reveals that

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Scheme 25 Synthesis of imidazo[4,5-b]pyridines 90.

Scheme 26 Synthesis of 9-(pyridin-2-yl)-9H-carbazoles 91.

neutral or electron-withdrawing groups gave the products 94

and 91 in higher yields than those with an electron-donating
group. This reaction also showed good tolerance for halogenated
arylboranes, such as fluoro, chloro, and bromo substituents. It is
noteworthy that carbazole 91 was the major product in all cases
with excellent yields. Surprisingly, N-(4-methoxyphenyl)pyridine-
2-amine gave only trace amounts of product, probably due to
formation of a stable complex with the oxidant AgOAc. Steric
effects play a major role in the conversion of the bulky substrate
into the carbazole and result in extremely poor yields.
Based on the above discussions, it is evident that Pd is widely
used for CN bond formation, particularly due to its generality,
Scheme 27 Synthesis of N-arylated derivatives 97.
practicality and relatively low catalyst loading (0.55.0 mol%).
However, the high cost of Pd is a major drawback.
been isolated in high yields (Scheme 27). It has been observed
that electron donating or electron-withdrawing groups on the
3. Other transition metals used in CN bond iodobenzene and nitrogen nucleophile have no significant
formation effect on the yield of the CN cross-coupled product. However,
ortho-substituted aryl halides were found to be less reactive
In addition to Cu and Pd, various other transition metals have and gave low yields. This new catalytic system was found
been eciently utilized for the construction of the CN bond. to be ineffective for the coupling of heteroaryl halides with
Recently, a new and ecient method for CN bond for- nitrogen nucleophiles, even at elevated temperatures. In
mation through cross-coupling reaction of aryl halides (iodide this protocol, aryl bromides gave low yields compared to aryl
or bromide) 95 with aromatic/heteroaromatic amines 96 iodides, whereas aryl chlorides fail to give the corresponding
has been reported by Nageswar and co-workers,38 employing cross-coupling product. The heterogeneous catalyst La2O3 can
lanthanum(III) oxide (10 mol%), DMEDA (20 mol%) and KOH as be efficiently reused upto four cycles with negligible loss of
base in DMSO. The resulting N-arylated derivatives 97 have catalytic activity.

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Scheme 28 Synthesis of isoquinolones 100.

Very recently, an oxidative coupling approach to access did not aord the desired amides when functional groups such
nitrogen-containing heterocycles, in particular isoquinolones, as esters, nitro, and cyanide are present.
has been reported by Fagnou and co-workers.39 A benzhydroxa- A direct iron catalyzed N-alkylation of imidazoles with benzylic
mic acid 98 was allowed to react with a disubstituted alkyne 99 hydrocarbons has been elaborated by Qiu and co-workers.41
to yield isoquinolone 100 applying mild reaction conditions Benzimidazoles 104 and benzylic hydrocarbons 105 were
which are insensitive to air and moisture (Scheme 28). The reacted using FeCl2 (10 mol%) as the catalyst and di-tert-butyl
reaction proceeded smoothly using the (pentamethyl-cyclo- peroxide (DTBP) as the oxidant in chlorobenzene at 120 1C
pentadiene)rhodium dichloride dimer {[RhCp*Cl2]2} (2.5 mol%) for 24 h, to access substituted imidazoles 106 in high yields
as a catalyst and CsOAc (30 mol%) as base in methanol without (Scheme 30). Employing these optimized conditions, various
any external oxidant. A variety of substituted benzhydroxamic diarylmethanes bearing either electron-withdrawing or electron-
acids, regardless of their electron-donating or -withdrawing donating groups react well and gave access to the corre-
character, could be used. A meta-substituted benzohydroxamic sponding products in moderate to good yields. However, strong
acid provides exclusively the C-7 substituted regioisomer. Both electron-withdrawing groups gave considerably lower yields.
symmetrical and unsymmetrical alkynes are well tolerated as
coupling partners and the insertion of an arylalkyl disubsti-
tuted alkyne occurs regioselectively with the sp2 center to be
installed at the 3-position. Interestingly, the N-methoxy group
was found to be essential for the isoquinolone formation.
A highly ecient AlMe3-promoted reaction has been reported
by Li and co-workers40 for coupling of amines 101 and carboxylic
acids 102 to give the corresponding amides 103 (Scheme 29).
A wide range of amines including less nucleophilic or bulky
amines, unprotected secondary amino acids, and acids with poor
solubility, were coupled smoothly to give the desired products in
good to excellent yields. Primary and secondary aromatic and
aliphatic amines were also easily converted as well as aromatic,
heteroaromatic, and aliphatic acids. However, this method Scheme 30 Synthesis of substituted imidazoles 106.

Scheme 29 Synthesis of amides 103.

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Scheme 31 Synthesis of 1,4,5-trisubstituted-2-iminoimidazolines 107.

Direct N-alkylation of imidazoles with ethylbenzene or propyl- A facile nickel-catalyzed method for the amination of syntheti-
benzene were also possible but in low yields. The 2-substituted cally useful aryl sulfamates and carbamates has been developed by
imidazoles having either electron-withdrawing or electron-donating Garg and co-workers.43 This new approach employs NiCl2(DME)
groups display higher activities than benzoimidazole itself. as a bench-stable NiII-precatalyst, SIPrHCl L12 as ligand and
Recently, a short and ecient AgI-mediated synthesis of diverse Ph-B(pin) as reducing agent to give access to aminated product
1,4,5-trisubstituted-2-iminoimidazolines 107 from readily available 112 in good to excellent yields by reacting aryl sulfamates/
polysubstituted secondary propargylamines 108 and thioureas carbamates 113 with various amines 114 under mild reaction
109 has been described by Van der Eycken and co-workers42 conditions (Scheme 32). A large variety of aryl sulfamates and
(Scheme 31). The intermediate propargylguanidine 110 could carbamates gave good to high yields of aminated products.
be assembled from propargylamine 108 via a guanylation Fused arenes, ortho-substituted arenes, heterocycles such as indoles
procedure. The resulting propargylguanidines 110 underwent and pyridines were well tolerated. Various amines including cyclic
cyclization in the presence of AgNO3 or AgOTf to give the and acyclic secondary amines as well as anilines reacted success-
desired Boc-protected 2-iminoimidazolines 107 in quantitative fully providing high yields. Amines with appended heterocycles
yield within 20 min in MeCN (route a). Interestingly, guanyl- were also well tolerated. Other electrophilic substrates, like phenyl
ation of propargylamines with protected S-methylisothioureas tosylate, were most ecient whereas tert-butyl phenyl carbonate
111 in the presence of AgNO3 and Et3N in MeCN, gave the and phenyl pivalate gave low yields. Phenyl triflates were not
corresponding Boc- and Cbz-protected 2-iminoimidazolines in suitable for this reaction.
high yields in a single step within 520 minutes at rt (route b). Beside these reports, a literature survey reveals that other
Remarkably, sterically hindered propargylamines underwent transition metals have also been extensively used in CN bond
efficient cyclization. This new synthetic approach was applied forming reactions. The Rh catalyst works well even at low cata-
for the total synthesis of 1,4,5-trisubstituted 2-aminoimidazole lytic loadings under mild reaction conditions.39 Other catalysts
alkaloids of the naamine family. like Fe, Ag, Au and Al, require higher loadings, while Ni systems

Scheme 32 Amination reaction of aryl sulfamates and carbamates 113.

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are great but are not as active as the Pd catalyst, need higher 12 h to give the corresponding substituted diphenylamine 117
loadings, and are sensitive to oxygen. using 2,6-lutidine as the coupling reagent (Scheme 33). This
However, the use of other catalysts such as Ni, Fe, Ag, Au and novel cross-coupling reaction tolerates a variety of functional
Al has potential drawbacks. One of the examples discussed here groups on both counterparts. Noticeably, all primary alkyl
involves the lanthanide catalyst used by Nageswar.38 However, isocyanates gave slightly poorer yields than the corresponding
some serious doubts exist with regard to the actual nature of the secondary alkyl isocyanates due to their lower electron density.
catalyst.44 Similar doubts exist about an iron catalysed reaction,41 The strongly hindered tertiary isocyanate showed poorer reactivity
where the actual catalyst are Cu impurities in the iron source.44 toward the benzyne. The coupling reaction strongly depends on
Thus, impurities in the catalyst play a critical role, as e.g. Cu the electronic eects of the aliphatic and substituted aromatic
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impurities are capable of catalysing such cross-coupling reac- isocyanates. Importantly, in case the phenyl ring of 116 is
tions even at ppm levels. Moreover, careful attention to the substituted with an electron-withdrawing group, a significant
mechanistic aspects has to be given while using these metal reduction of the yield is observed due to the lower nucleophili-
catalysts in CN bond formation reactions. city of the resulting secondary amine. In this case the single
In addition, continuous-flow chemistry has proved to boost CN bond coupling product 118 was observed predominantly.
the CN cross-coupling itself. Various transition metal catalysts A metal-free oxidative coupling reaction of methyl ketones
are used for dierent catalytic reaction cycles, without purifica- 119 and primary/secondary amines 120 has been developed by
tion. This technique can be adapted to large reaction volumes Wan and co-workers,47 to give access to a-ketoamides 121 in
and has been proven as a new interesting tool for both synthetic moderate to excellent yields. The mild reaction conditions use
and process chemists. The application of microreactors provides iodine (50 mol%) in iPrOH at rt (Scheme 34). A variety of
several advantages over traditional batch reactors. For example, substituted aryl methyl ketones bearing electron-donating or
enhanced heat- and mass-transfer characteristics, safe handling electron-withdrawing substituents could be used. Oxidative
of exothermic, explosive or toxic reagents, excellent control over sensitive groups, such as alkenes and hydroxyl groups, are well
reaction times, protection of sensitive reactions from air and tolerated in this reaction. Gratifyingly, ketones with heteroaryl
moisture, high surface-to-volume ratio, the possibility of auto- substituents gave moderate to high product yields. Acyclic amines
mation and the ease of scale-up.45 worked well and gave the corresponding a-ketoamides in moderate
Interestingly, palladium-catalyzed CN bond forming cross- to excellent yields. The BocNH group is well maintained under
coupling reactions under flow conditions are performed in a these reaction conditions and the expected a-ketoamides are
biphasic solvent system of toluene and water to solubilize both obtained in satisfactory yields. Primary amines with a variety of
the organic and inorganic salts to prevent irreversible clogging of aromatic substituents (electron-rich, electron-poor, and hetero-
the microchannels. The development of more efficient catalyst aromatic), are well tolerated.
recycling systems and devices that can introduce and handle A three-component domino reaction has been developed by Tu,
slurries in microchannels are of utmost importance. Li and co-workers48 that provides access to multifunctionalized
fused pyrroles 122 and 123 with dierent substitution patterns
4. Metal-free CN bond formation (Scheme 35). This new synthetic strategy employs mild reaction
conditions to react arylglyoxal monohydrate 124, b-enaminones
CN bond formation without the use of any metal catalyst is of 125 and amine 126 in a one-pot fashion with excellent regio- and
particular interest. It is interesting to note that some protocols chemoselectivities. Enaminones bearing various functional groups
can efficiently promote CN bond formation even under mild such as ether and CCl (or Br) bonds are tolerated. 5,5-Unsubstituted
reaction conditions. In this section, we have selected some enaminones provide the corresponding amination products in
interesting reports. excellent yields. Various amine substrates 126 gave the corre-
A transition metal-free and low catalyst loading N-arylation sponding arylamino substituted fused pyrroles. Interestingly,
protocol, involving the coupling of isocyanates and benzynes N-carboxyethyl substituents in 125 afforded the allylic aminates
has been elaborated by Hsieh and co-workers.46 Substituted 122, whereas N-carboxymethyl counterparts gave N-arylation
ortho-(trimethylsilyl)phenyl triflate 115 was reacted with various product (multifunctionalized fused pyrroles 123) with different
isocyanates 116 using CsF as base in acetonitrile at 70 1C for substituted patterns under these reaction conditions.

Scheme 33 Coupling reaction of isocyanates 116 and benzynes 115.

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starting from N-acetylated aryloxy anilides 128 by transition

metal-free, base catalyzed cyclization in the presence of DMEDA
(10 mol%) and K2CO3 in toluene (Scheme 36). Various substrates
worked well with this catalytic system. However, the cyclization
of the corresponding bromo and triflyl (OTf) derivatives failed,
indicating that the iodo substituent is essential. Changing the
N-substituent from acetyl to benzoyl, methyl, tosyl, or benzyl,
resulted in lower yields or no reactivity at all. Various other
aryloxy acetanilides underwent smooth intramolecular N-arylation
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aording the corresponding phenoxazines 127 (or aza derivatives)

in good to excellent yields. The nature of the substituent on the
anilide part (as R1) had no eect on the course of the reaction.
However, halo-substituted (as R1) anilides gave the highest
yields. The substitution pattern on the iodo aryl part influences
the reaction as electron-donating groups provided slightly
Scheme 34 Synthesis of a-ketoamides 121.
better yields.
A one-pot cascade reaction of (hetero)aryl ketones 128 has
Recently, the synthesis of N-substituted phenoxazines 127 been developed by Liang and co-workers50 to give access to
and related aza-analogs has been reported by Bolm and Thome49 a-imidoketones 129 using N-bromosuccinimide (NBS) 130 that

Scheme 35 Synthesis of multifunctionalized fused pyrroles 122 and 123.

Scheme 36 Synthesis of N-substituted phenoxazines 127 and related aza-analogs.

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Scheme 37 Synthesis of a-imidoketones 129.

provides both the electrophilic bromine and the nucleophilic 4 I. Goldberg, Ber. Dtsch. Chem. Ges., 1906, 39, 16911692.
nitrogen. The diazabicyclo[5.4.1]undec-7-ene (DBU) works well 5 J. F. Hartwig, Acc. Chem. Res., 2008, 41, 15341544.
as base and as a nucleophilic promoter for the activation of NBS 6 D. S. Surry and S. L. Buchwald, Chem. Sci., 2011, 2,
(Scheme 37). Under the optimized conditions, (hetero)aryl 2750.
ketones 128 react with NBS in MeCN at rt. Various ketones react 7 (a) W. Shi, C. Liu and A. Lei, Chem. Soc. Rev., 2011, 40,
smoothly with NBS to give good to high yield of the product. 27612776; (b) N. Rodrguez and L. J. Goossen, Chem. Soc.
Methyl aryl ketones containing both electron-donating or electron- Rev., 2011, 40, 50305048.
withdrawing groups on the aryl ring undergo smooth transforma- 8 Y. Yamamoto, Heterocycles, 2012, 85, 799819.
tion. In addition, heteroaryl ketones, including furan, thiophene 9 H. He, S. Dong, Y. Chen, Y. Yang, Y. Le and W. Bao,
and pyridine were converted to the target products in high yields. Tetrahedron, 2012, 68, 31123116.
However, bulky alkyl substituents hindered the reaction as iso- 10 A. B. Sheremetev, N. V. Palysaeva, M. I. Struchkova, K. Yu.
butyrophenone and a-tetralone did not react. Other N-haloimides Suponitsky and M. Yu. Antipin, Eur. J. Org. Chem., 2012,
such as N-bromophthalimide (NBP) also aorded the desired 22662272.
products in high yields. However, N-bromosaccharin fails to give 11 Yi-F. Wang, X. Zhu and S. Chiba, J. Am. Chem. Soc., 2012,
the desired product under these conditions. 134, 36793682.
12 N. Matsuda, K. Hirano, T. Satoh and M. Miura, J. Org.
Chem., 2012, 77, 617625.
Conclusions and outlook
13 R. Berrino, S. Cacchi, G. Fabrizi and A. Goggiamani, J. Org.
In this tutorial review we have highlighted some recent advances Chem., 2012, 77, 25372542.
for the construction of the CN bond to give access to various 14 M. M. Guru and T. Punniyamurthy, J. Org. Chem., 2012, 77,
biologically important nitrogen containing organic compounds. 50635073.
Various copper salts are extensively used as a catalyst for these 15 Y. Zhang, X. Yang, Q. Yao and D. Ma, Org. Lett., 2012, 14,
reactions due to their high efficiency and low cost. Besides copper, 30563059.
palladium is the second most commonly used metal for CN 16 A. Laouiti, M. M. Rammah, M. B. Rammah, J. Marrot,
bond forming cross-coupling reactions along with some other F. Couty and G. Evano, Org. Lett., 2012, 14, 69.
metals such as rhodium, aluminium, nickel, silver etc. In addi- 17 X. Xiong, Y. Jiang and D. Ma, Org. Lett., 2012, 14, 25522555.
tion, there are some excellent reports where metal-free and mild 18 K. Jouvin, A. Coste, A. Bayle, F. Legrand, G. Karthikeyan,
conditions have been explored. Metal-free activation approaches K. Tadiparthi and G. Evano, Organometallics, 2012, 31,
have been successfully applied to various synthetic transforma- 79337947.
tions, opening new avenues as attractive alternatives for conven- 19 M. S. T. Morin, Y. Lu, D. A. Black and B. A. Arndtsen, J. Org.
tional cross-coupling reactions. Continuous-flow microreactors Chem., 2012, 77, 20132017.
have attracted a lot of interest from chemists because of their 20 K. Liubchak, A. Tolmachev and K. Nazarenko, J. Org. Chem.,
various advantages over the batch process in such metal-catalyzed 2012, 77, 33653372.
reactions, particularly their scalability. We hope that this review 21 P. Sang, Y. Xie, J. Zou and Y. Zhang, Org. Lett., 2012, 14,
will attract the synthetic community that focuses on CN cross- 38943897.
coupling reactions and will be observed as an anchor to help and 22 T. Maejima, Y. Shimoda, K. Nozaki, S. Mori, Y. Sawama,
develop focused research in this area. Y. Monguchi and H. Sajiki, Tetrahedron, 2012, 68, 17121722.
23 S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42,
References 54005449.
24 I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev.,
1 S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2004, 248, 23372364.
2011, 40, 50685083. 25 D. Ma and Q. Cai, Acc. Chem. Res., 2008, 41, 14501460.
2 R. Hili and A. K. Yudin, Nat. Chem. Biol., 2006, 2, 284287. 26 Y. Fan, Y. Xia, J. Tang, F. Ziarelli, F. Qu, P. Rocchi, J. L.
3 F. Ullmann, Ber. Dtsch. Chem. Ges., 1903, 36, 23822384. Iovanna and L. Peng, Chem.Eur. J., 2012, 18, 22212225.

Chem. Soc. Rev. This journal is c The Royal Society of Chemistry 2013
 View Article Online

Chem Soc Rev Tutorial Review

27 X. Sun, X. Tu, C. Dai, X. Zhang, B. Zhang and Q. Zeng, J. Org. 39 N. Guimond, C. Gouliaras and K. Fagnou, J. Am. Chem. Soc.,
Chem., 2012, 77, 44544459. 2010, 132, 69086909.
28 G. He, C. Lu, Y. Zhao, W. A. Nack and G. Chen, Org. Lett., 40 J. Li, K. Subramaniam, D. Smith, J. X. Qiao, J. J. Li, J. Qian-
2012, 14, 29442947. Cutrone, J. F. Kadow, G. D. Vite and B. Chen, Org. Lett.,
29 S. Zhang, Y. Wang, X. Feng and M. Bao, J. Am. Chem. Soc., 2012, 14, 214217.
2012, 134, 54925495. 41 Q. Xia, W. Chen and H. Qiu, J. Org. Chem., 2011, 76,
30 R. M. Stolley, W. Guo and J. Louie, Org. Lett., 2012, 14, 75777582.
322325. 42 D. S. Ermolatev, J. B. Bariwal, H. P. L. Steenackers, S. C. J.
31 F. Ma, X. Xie, L. Zhang, Z. Peng, L. Ding, L. Fu and Z. Zhang, De Keersmaecker and E. V. Van der Eycken, Angew. Chem.,
Published on 30 September 2013. Downloaded by University of Guelph on 30/09/2013 19:35:50.

J. Org. Chem., 2012, 77, 52795285. Int. Ed., 2010, 49, 94659468.
32 A. Khanna, C. Maung, K. R. Johnson, T. T. Luong and 43 L. Hie, S. D. Ramgren, T. Mesganaw and N. K. Garg,
D. L. Van Vranken, Org. Lett., 2012, 14, 32333235. Org. Lett., 2012, 14, 41824185.
33 S. Shekhar, T. B. Dunn, B. J. Kotecki, D. K. Montavon and 44 (a) B. P. Fors and S. L. Buchwald, Adv. Synth. Catal., 2010,
S. C. Cullen, J. Org. Chem., 2011, 76, 45524563. 352, 31193120; (b) S. L. Buchwal and C. Bolm, Angew.
34 T. Vlaar, E. Ruijter, A. Znabet, E. Janssen, F. J. J. de Kanter, Chem., Int. Ed., 2009, 48, 55865587.
B. U. W. Maes and R. V. A. Orru, Org. Lett., 2012, 13, 45 T. Noel and S. L. Buchwald, Chem. Soc. Rev., 2011, 40,
64966499. 50105029.
35 E. V. Vinogradova, B. P. Fors and S. L. Buchwald, J. Am. 46 Y.-H. Lee, Y.-C. Chen and J.-C. Hsieh, Eur. J. Org. Chem.,
Chem. Soc., 2012, 134, 1113211135. 2012, 247250.
36 A. J. Rosenberg, J. Zhao and D. A. Clark, Org. Lett., 2012, 14, 47 W. Wei, Y. Shao, H. Hu, F. Zhang, C. Zhang, Y. Xu and
17641767. X. Wan, J. Org. Chem., 2012, 77, 71577165.
37 J. Chu, P. Lin, Y. Lee, W. Shen and M. Wu, Chem.Eur. J., 48 B. Jiang, Y. Li, M. Tu, S. Wang, S. Tu and G. Li, J. Org. Chem.,
2011, 17, 1361313620. 2012, 77, 74977505.
38 S. N. Murthy, B. Madhav, V. P. Reddy and Y. V. D. Nageswar, 49 I. Thome and C. Bolm, Org. Lett., 2012, 14, 18921895.
Adv. Synth. Catal., 2010, 352, 32413245. 50 Y. Wei, S. Lin and F. Liang, Org. Lett., 2012, 14, 42024205.

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