Prabhath Et Al. - 2017 - Recent Advances in Cyanamide Chemistry Synthesis PDF

molecules
Review
Recent Advances in Cyanamide Chemistry: Synthesis
and Applications
M. R. Ranga Prabhath, Luke Williams, Shreesha V. Bhat and Pallavi Sharma *
School of Chemistry, Joseph Banks Laboratories, University of Lincoln, Lincoln LN6 7DL, UK;
ranga_prabhath@yahoo.com (M.R.R.P.); luwilliams@lincoln.ac.uk (L.W.); shreeshabhat@yahoo.co.in (S.V.B.)
* Correspondence: psharma@lincoln.ac.uk; Tel.: +44-015-2288-6885
Academic Editor: Margaret A. Brimble

Received: 9 March 2017; Accepted: 7 April 2017; Published: 12 April 2017
Abstract: The application of alkyl and aryl substituted cyanamides in synthetic chemistry has diversified
multi-fold in recent years. In this review, we discuss recent advances (since 2012) in the chemistry of
cyanamides and detail their application in cycloaddition chemistry, aminocyanation reactions, as well
as electrophilic cyanide-transfer agents and their unique radical and coordination chemistry.
Keywords: cyanamide; synthesis; aminocyanation; cycloaddition; electrophilic cyanation; radical

reaction; coordination chemistry
1. Introduction
Cyanamide enjoys a rich chemical history, which can be traced to its unique and chemically
promiscuous nitrogen-carbon-nitrogen (NCN) connectivity. The chemistry of the nitrile-substituted
amino-group of the ‘cyanamide-moiety’ is dominated by an unusual duality of a nucleophilic sp3 -amino
nitrogen and an electrophilic nitrile unit.
The reported use of unsubstituted cyanamide (NH2 CN) and metal cyanamides
(MNCN, where M = metal) date back as far as the late 19th century, where the likes of calcium
cyanamide (CaNCN) was used as a fertilizer, and later as source of ammonia and nitric acid,
which fueled the industrial production of metal cyanamides. In contrast, the reported use of the
corresponding substituted organic cyanamides (RNHCN or RR’NCN) gathered pace only in more
recent years.
The last decade has witnessed a significant increase in the use and application of substituted
cyanamides in synthetic chemistry, along with development of more sustainable and robust synthetic
routes to these important family of compounds.
A number of excellent review articles describing the chemistry of cyanamide have appeared in
the literature in recent years, and we encourage the readers to investigate these articles. Nekasarov
and co-workers [1] summarized the synthesis and reactions of mono and disubstituted cyanamides in
a seminal review article in 2004, whereas the literature from 2004 to 2012 was captured concisely by
Fensterbank and Lacôte et al [2]. Thus, in the present review, we limit our discussion to developments
appearing in the literature from 2012. The present review is by no means exhaustive and we apologize
to authors whose work has been omitted. The present article focuses on some leading topics in
cyanamide chemistry such as aminocyanation, electrophilic cyanation, selected cycloaddition reactions,
coordination chemistry and radical reactions, whereas more traditional chemistry has not been covered
here and we would like to direct the readers to appropriate primary literature.
2. Synthesis of Mono and Disubstituted Cyanamides

The direct alkylation of metal cyanamides such as calcium cyanamide is the most straightforward
approach to mono and disubstituted derivatives, and reports on these strategies have been previously
Molecules 2017, 22, 615; doi:10.3390/molecules22040615 www.mdpi.com/journal/molecules

Molecules 2017, 22, 615 2 of 27
Molecules 2017, 22, 615 2 of 27
2. Synthesis
Molecules of Mono and Disubstituted Cyanamides
2017, 22,
2. Synthesis of 615
Mono and Disubstituted Cyanamides 2 of 28
approach
covered to mono
[1–3]. and
Thisand disubstituted
section details more derivatives, and reports
recent approaches, on these strategies have
including been previously
approach to mono disubstituted derivatives, and reports on thesedevelopment
strategies have of been
new previously
reagents to
covered
access [1–3].
substituted This section
cyanamides. details more recent approaches, including development of new reagents
covered [1–3]. This section details more recent approaches, including development of new reagents
to access substituted cyanamides.
to access substituted cyanamides.
2.1. N-Cyanation of Secondary Amine
2.1. N-Cyanation of Secondary Amine
2.1. N-Cyanation of Secondary Amine +
2.1.1. Using Electrophilic Nitrile [CN] Reagents
2.1.1. Using Electrophilic Nitrile [CN]++ Reagents
2.1.1.The
Using Electrophiliccyanation
electrophilic Nitrile [CN] Reagents amines is the most prevalent method used to
of secondary
accessThedisubstituted
electrophilic cyanamides,
cyanation of secondary
with cyanogenamines bromide
is the most prevalent
(BrCN) being method used common
the most to access
The electrophilic cyanation of secondary amines is the most prevalent method used to access
disubstituted
reagent. Thoughcyanamides,
cheap and with cyanogen
effective, thebromide
toxicity(BrCN) being
associated the this
with mostreagent
common reagent.
has promptedThoughthe
disubstituted cyanamides, with cyanogen bromide (BrCN) being the most common reagent. Though
cheap and effective,
development of saferthe toxicityagents
cyanating associated
such with this reagent has prompted cyanobenzimidazole,
as 2-cyanopyridazin-3(2H)-one, the development of safer and
cheap and effective, the toxicity associated with this reagent has prompted the development of safer
cyanating agents such
1-cyanoimidazole as 2-cyanopyridazin-3(2H)-one, cyanobenzimidazole, and 1-cyanoimidazole [4–6].
[4–6].
cyanating agents such as 2-cyanopyridazin-3(2H)-one, cyanobenzimidazole, and 1-cyanoimidazole [4–6].
In 2014, Chen et et al.
al. used
usedaacombination
combinationofofhypochlorite
hypochloriteand andTMSCN
TMSCN forfor
the inin
the situ generation
situ generation of
In 2014, Chen et al. used a combination of hypochlorite and TMSCN for the in situ generation of
cyanogen
of cyanogen chloride
chloride (CNCl)
(CNCl)to accomplish
to accomplish the the
N-cyanation
N-cyanation of a of
variety of secondary
a variety of secondaryamines [7]. The
amines [7].
cyanogen chloride (CNCl) to accomplish the N-cyanation of a variety of secondary amines [7]. The
hypochlorite
The hypochlorite oxidizes
oxidizes the the
TMSCN TMSCN to to
release
releasethetheactive
activeCNCl
CNClreagent,
reagent, which
which then cyanates
then cyanates
hypochlorite oxidizes the TMSCN to release the active CNCl reagent, which then cyanates
nucleophilic amines. Both Both dialkyl
dialkyl and
and alkyl-aryl
alkyl-aryl amines
amines were
were readily cyanated
cyanated using this method,
nucleophilic amines. Both dialkyl and alkyl-aryl amines were readily cyanated using this method,
products in
offering the products in good
good toto excellent
excellent yields
yields (Scheme
(Scheme 1).1).
offering the products in good to excellent yields (Scheme 1).
Scheme 1. In situ generation of CNCl for cyanation.

Scheme 1. In situ generation of CNCl for cyanation.
Alcarazo and co-workers have developed the thiocyanoimidazolium salt 5 as an electrophilic

Alcarazo and
Alcarazo and co-workers
co-workers have
have developed
developed the thiocyanoimidazolium
thiocyanoimidazolium salt salt 55 as an electrophilic
cyanation reagent for secondary amines [8]. Halogenation of thiourea led to the hypervalent sulfur
cyanation reagent
cyanation reagent for secondary
secondary amines
amines [8]. Halogenation
Halogenation of of thiourea
thiourea led
led to the hypervalent sulfur
species 4, which upon treatment with TMSCN provided the active reagent 5. In the presence of an
species 4,
species which upon
4, which upontreatment
treatmentwith
withTMSCN
TMSCNprovided
providedthe theactive
active reagent
reagent 5. 5. In the
In the presence
presence of
of an
amine base such as diisopropylethylamine (DIPEA), the reagent 5 successfully transferred the active
an amine
amine basebase
suchsuch as diisopropylethylamine
as diisopropylethylamine (DIPEA),
(DIPEA), the reagent
the reagent 5 successfully
5 successfully transferred
transferred the
the active
[CN]++ to a number of alkyl and aryl sec-amines to give corresponding cyanamides in good yield
+ to a number
active
[CN] [CN]
to a number of alkylofand
alkyl
aryl aryl sec-amines
andsec-amines to givetocorresponding
give corresponding cyanamides
cyanamides in yield
in good good
(Scheme 2). The protocol was deemed to be operationally simple and wide in scope, however
yield (Scheme
(Scheme 2). protocol
2). The The protocol
was was deemed
deemed to be
to be operationally
operationally simple
simple andwide
and wideinin scope,
scope, however
precaution must be taken when handling the cyanating reagent 5; just like the isolobal hypervalent
precaution must be taken when handling the cyanating reagent 5; just like the isolobal hypervalent
iodine reagents, they show strong exothermic decomposition upon heating.
iodine reagents, they show strong exothermic decomposition upon heating.
Scheme 2. Thiocyanoimidazolium salts for electrophilic cyanation.

Scheme
Scheme 2.
2. Thiocyanoimidazolium
Thiocyanoimidazolium salts
salts for
for electrophilic
electrophilic cyanation.
cyanation.
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The Morrill group reported trichloroacetonitrile (6) as an effective cyanating reagent of sec-amines
following aThe Morrill
one-pot
Molecules 2017, group reported
protocol
22, 615 trichloroacetonitrile
[9]. Though not strictly (6) as an+effective
a [CN] transfercyanating
reagent,reagent of sec-amines
the two-step-single-pot
3 of 27
following a one-pot protocol [9]. Though not strictly a [CN] + transfer reagent, the two-step-single-pot
protocol involved formation of the amidine 7 (Scheme 3) via nucleophilic addition and its further
protocol involved formation of trichloroacetonitrile
the amidine t7 (Scheme (6) as3)
anvia nucleophilic
conversion The Morrill
into the group
nitrilereported
mediated by NaO Am base effective
(Scheme 3). Bothaddition
cyanating reagent
cyclic and
and its further
of sec-amines
acyclic dialkyl
conversion
following into theprotocol
a one-pot nitrile mediated
[9]. Though by not
NaO tAm base
strictly (Scheme
a [CN] 3).reagent,
+ transfer Both cyclic and acyclic dialkyl
the two-step-single-pot
cyanamides were obtained in good yields. The trichloroacetonitrile reagent 6 allowed the selective
cyanamides
protocol were obtained
involved formationinofgood yields. The
the amidine trichloroacetonitrile
7 (Scheme reagentaddition
3) via nucleophilic 6 allowed
andtheitsselective
further
cyanation of secondary
cyanation
conversion ofinto
secondaryamines
amines
the nitrile in in
mediatedthethepresence
presence
by NaOtAm of other
of base nucleophilic
other(Scheme
nucleophilic centers,
centers,
3). Both cyclic which
which
and is a significant
is a significant
acyclic dialkyl
benefitcyanamides
compared
benefit compared to other cyanating
to other cyanating
were obtained reagents.
reagents.
in good yields. The trichloroacetonitrile reagent 6 allowed the selective
cyanation of secondary amines in the presence of other nucleophilic centers, which is a significant
benefit compared to other cyanating reagents.
Scheme
Scheme 3.3.Trichloroacetonitrile
Trichloroacetonitrile for
forcyanation.
cyanation.
2.1.2. Under Copper CatalysisScheme 3. Trichloroacetonitrile for cyanation.

2.1.2. Under Copper Catalysis
Cheng et al. developed a transition metal catalyzed cyanation of sec-amines for N–CN bond
2.1.2. Under
Cheng et al. Copper
developedCatalysistransition metal catalyzed cyanation of sec-amines for N–CN bond
formation under oxidative a coupling conditions [10], using CuCN as the source of nitrile. When used
formation underetoxidative
in combination
Cheng with
al. coupling conditions
metal[10],
N,N,N’,N′-tetramethylethylenediamine
developed a transition usingcyanation
catalyzed CuCN
(TMEDA), asofthe source
which itselfof
sec-amines nitrile.
was
for When
proposed
N–CN bondto used
play the
formation dual
under role of a
oxidative 0
ligand 0 and
coupling a base in
conditions the catalytic
[10], using cycle,
CuCN molecular
as
in combination with N,N,N ,N -tetramethylethylenediamine (TMEDA), which itself was proposed the oxygen
source of (O )
nitrile.
2 and
When sodium
used
to playsulfate,
in the sec-amine
combination
the dual rolewith underwent andcyanation
a base ininthe thecatalytic
of aN,N,N’,N′-tetramethylethylenediamine
ligand presence of CuBrmolecular
(TMEDA),
cycle, 2 (Scheme
which4). Thewas
itself
oxygen CuCN was also
proposed
(O to
2 ) and sodium
shown
play thetodual
self-catalyze
role of athe cyanation
ligand and a reaction
base in when conducted
the catalytic in molecular
cycle, the absenceoxygen
of any additional copper
(O2) and sodium
sulfate, the sec-amine underwent cyanation in the presence of CuBr2 (Scheme 4). The CuCN was also
source. the
sulfate, Based on the underwent
sec-amine experimental evidence
cyanation in the
the authors
presenceproposed the catalytic
of CuBr2 (Scheme cycle
4). The CuCNillustrated
was alsoin
shown to self-catalyze the cyanation reaction when conducted in the absence of any additional copper
Schemeto4,self-catalyze
shown where a Cu(II) species is thought
the cyanation reaction to
whenparticipate in the
conducted catalytic
in the absencecycle.
of any additional copper
source. Based
source. on the
Based on theexperimental
experimentalevidence
evidence the authorsproposed
the authors proposed thethe catalytic
catalytic cyclecycle illustrated
illustrated in in
Scheme 4, where a Cu(II) species is thought to participate in the
Scheme 4, where a Cu(II) species is thought to participate in the catalytic cycle. catalytic cycle.
Scheme 4. Copper catalyzed cyanation of secondary amines.

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Continuing their efforts to provide a safer source of cyanide for N–CN bond formation under
copper Continuing
catalysis, the theirauthors
efforts to provide a safer
investigated the source
use ofofthe cyanide forinitiator
radical N–CN bond formation under
azobisisobutyronitrile
(12,copper catalysis,
Molecules
AIBN) 2017, 22,
[11]. the
In615theauthors
presence investigated
of CuI, in the use of the with
combination radical initiator azobisisobutyronitrile
molecular oxygen and K2 CO (12,
4 of,27
3 AIBN
AIBN) [11]. In the presence of CuI, in combination with molecular oxygen and K2CO3, AIBN efficiently
efficiently led to a variety of disubstituted cyanamides starting from both alkyl and aryl secondary
led to aContinuing
variety oftheir efforts to provide
disubstituted a saferstarting
cyanamides source of cyanide
from both for N–CN
alkyl andbond
aryl formation
secondaryunder
amines
amines (Scheme
copper 5). Based
catalysis, thetheiron their
authors experimental
investigated observations
the use of the the authorsazobisisobutyronitrile
proposed a radical pathway,
(Scheme 5). Based on experimental observations the radical
authorsinitiator
proposed a radical pathway, which (12,
whichAIBN)
incorporates
[11].the
In thethe generation
presence of of in
a nitrile radical from AIBN. Molecular andoxygen mediated oxidation
incorporates generation of CuI, combination
a nitrile radical from with molecular
AIBN. oxygenoxygen
Molecular K2CO 3, AIBN efficiently
mediated oxidation of
of Cu(I) to
led to Cu(II)
to Cu(II)
a variety leads to species 13 cyanamides
of to
disubstituted in the presence of the
starting from base.
bothThe generation of nitrile radical from
Cu(I) leads species 13 in the presence of the base. Thealkyl and arylofsecondary
generation amines
nitrile radical from
AIBN
AIBN assisted
(Scheme 5).by
assisted molecular
Based
by on their oxygen
molecular oxygeninsert
experimental into 13 to
into 13
observations
insert to give 14. A
the authors
give 14. Areductive
reductive aelimination
proposed elimination ofof
radical pathway,1414 provides
which
provides
thethe incorporates
final N-cyanated the generation
product 2 of a nitrile 5).
(Scheme radical from AIBN. Molecular oxygen mediated oxidation of
final N-cyanated product 2 (Scheme 5).
Cu(I) to Cu(II) leads to species 13 in the presence of the base. The generation of nitrile radical from
AIBN assisted by molecular oxygen insert into 13 to give 14. A reductive elimination of 14 provides
the final N-cyanated product 2 (Scheme 5).
Scheme5.5.AIBN
Scheme AIBNmediated
mediated cyanation
cyanation of
ofsecondary
secondaryamine.
amine.
Scheme 5. AIBN mediated cyanation of secondary amine.
2.2. Cyanamides from Amidoximes and Guanidoximes
2.2. Cyanamides from Amidoximes and Guanidoximes
2.2.Chauhan
Cyanamides
andfrom Amidoximes
co-workers and Guanidoximes
reported the synthesis of monosubstituted N-arylcyanamides via the
Chauhan and co-workers reported the synthesis of monosubstituted N-arylcyanamides via the
oxidation of the corresponding guanidoximes
Chauhan and co-workers reported the synthesisin an ionic liquid (SchemeN-arylcyanamides
of monosubstituted 6) [12], which is proposed
via the
oxidation of the corresponding guanidoximes in an ionic liquid (Scheme 6) [12], which is proposed
to mimic
oxidationtheof
natural enzymatic oxidation
the corresponding of oximes
guanidoximes in antoionic
nitriles. The
liquid imidazolium
(Scheme 6) [12], ionic
whichliquid was used
is proposed
to mimic the natural enzymatic oxidation of oximes to nitriles. The imidazolium ionic liquid was
as to
the reaction
mimic medium
the natural for theoxidation
enzymatic H2O2 mediated
of oximesoxidation
to nitriles.catalyzed by the ionic
The imidazolium water soluble
liquid was anionic
used
used as the
as the reaction
reactionmedium
iron(III)-porphyrins medium
[TAPSforforthe
theHH 22Omediated
2O
4Fe(III)Cl].
2 mediated oxidation
oxidation catalyzed
catalyzed by water
by the the water soluble
soluble anionic
anionic
iron(III)-porphyrins [TAPS
iron(III)-porphyrins [TAPS Fe(III)Cl].
4 4Fe(III)Cl].
Scheme 6. Cont.
Scheme 6. Cont.
Scheme 6. Cont.
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Molecules 2017, 22, 615 5 of 27
Scheme 6. Conversion of guanidoximes to monosubstituted cyanamide.

A peroxo-species like 21 was proposed as an intermediate, itself obtained upon nucleophilic
addition Aofperoxo-species
iron-peroxo 20 likeon21 the
was oxime
proposed double
as an bond. The peroxo-complex
intermediate, itself obtained upon 21 then undergoes
nucleophilic
A peroxo-species like 21 was proposed as an intermediate, itself obtained upon nucleophilic
cyclization
additionfollowed by selective
of iron-peroxo 20 on ring opening
the oxime doubleto give
bond.23, The
followed by the elimination
peroxo-complex of water and
21 then undergoes
addition of iron-peroxo 20 on the oxime double bond. The peroxo-complex 21 then undergoes
loss of NO to render
cyclization followed thebytarget cyanamide
selective ring opening18 (Scheme
to give 23,6).The generation
followed of cyanamide
by the elimination typeand
of water species
cyclization followed by selective ring opening to give 23, followed by the elimination of water and loss
loss
fromofthe of NO to render the target cyanamide 18 (Scheme 6).The generation
reaction of amidoxime with aryl-sulfonyl-chloride was first observed by Tiemann in 1891 [13].of cyanamide type species
NO to render the target cyanamide 18 (Scheme 6).The generation of cyanamide type species from the
fromseminal
In their the reaction of amidoxime
report, Tiemann with aryl-sulfonyl-chloride
detected a serieswas of first was first
diverse observed
mixture by Tiemannwhich
of products, in 1891 [13].
reaction of amidoxime with aryl-sulfonyl-chloride observed by Tiemann in 1891 [13]. In included
their
In their
cyanamide, seminal report,
carbodiimide, Tiemann
guanidine detected
and a series
benzimidazole, of diverse
among mixture
others.of products,
In 2014 which
Chien etincluded
al. revisited
seminal report, Tiemann detected a series of diverse mixture of products, which included cyanamide,
cyanamide,
this carbodiimide,
reaction and carbodiimide,
developed guanidine and benzimidazole, among others.formation
In 2014 Chien of et al. revisited
guanidine and conditions
benzimidazole, thatamong
led to the
others. selective
In 2014 Chien et al. revisitedmonosubstituted
this reaction
this reaction and developed conditions that led to the selective formation of monosubstituted
aryl-cyanamide
and developed from the corresponding
conditions that led to the aryl-amidoxime
selective formation [14].ofUpon treatment aryl-cyanamide
monosubstituted with p-TsCl in the
aryl-cyanamide from the corresponding aryl-amidoxime [14]. Upon treatment with p-TsCl in the
from of
presence theDIPEA
corresponding aryl-amidoxime
or pyridine, the amidoximes[14]. Upon weretreatment
converted withtop-TsCl in the presence
cyanamides in good ofto
DIPEA
excellent
presence of DIPEA or pyridine, the amidoximes were converted to cyanamides in good to excellent
or
yields pyridine,
(Scheme the amidoximes
7). The authors were
observed converted to cyanamides in good to excellent yields (Scheme 7).
yields (Scheme 7). The authors observedthat that the
the reaction
reaction of ofthe
theamidoxime
amidoxime 25 25
withwith p-TsCl,
p-TsCl, and and
the the
The authors
subsequent observed
product that the reaction
distribution, was of the amidoxime 25 with p-TsCl, andsubstrates.
the subsequent product
subsequent product distribution, wasdependent
dependent on the electronics
on the electronics ofof
thethesubstrates. It wasIt was observed
observed
distribution, was dependent on the electronics of the substrates. It was observed that cyanamide
that cyanamide products were predominantly formed with electron rich
that cyanamide products were predominantly formed with electron rich aryl substrates. The authors aryl substrates. The authors
products were predominantly formed with electron rich aryl substrates. The authors further observed
further observed
further observed thatthat
thetherate
rateofofthe thekey
key rearrangement
rearrangement step stepdepends
dependsonon thethe crucial
crucial N–ON–O bondbond
that the rate of the key rearrangement step depends on the crucial N–O bond cleavage and reports
cleavage
cleavage and reports o-NsCl as a better leaving group for challenging substrates
and reports o-NsCl as a better leaving group for challenging substrates (electron-deficient (electron-deficient
o-NsCl as a better leaving group for challenging substrates (electron-deficient aryl- and alkyl-substrates)
aryl-
aryl-atand and alkyl-substrates)
alkyl-substrates) at atelevated
elevatedreaction
reaction temperatures. AAvariety of of
aryl, alkyl and andvinyl
elevated reaction temperatures. A variety of aryl,temperatures. variety
alkyl and vinyl cyanamides canaryl, alkyl
be accessed undervinyl
cyanamides
cyanamides can be accessed under these
can be accessed under these conditions. conditions.
these conditions.
Scheme 7. Amidoximes to substituted cyanamides.

Scheme
Scheme7.7.Amidoximes
Amidoximes to substitutedcyanamides.
to substituted cyanamides.
2.3. Cyanamides from Isoselenocyanates
2.3. Cyanamides fromfrom
2.3. Cyanamides Isoselenocyanates
The dehydration Isoselenocyanates
of urea or desulfurization of thiourea are both well-established methods that
are
Theused
The to access cyanamides
dehydration
dehydration or[2].
of urea
of urea orSimilarly, cyanamides
desulfurization
desulfurization of of can also
thiourea
thiourea beboth
areare prepared by the deselenization
bothwell-established
well-established methods
methods of that
selenourea.
that to In
areaccess 2015, Xie
used cyanamidesand co-workers,
to access cyanamides described a one-pot
[2]. cyanamides hypervalent
Similarly, cyanamides iodine-mediated
can also be deselenization
are used [2]. Similarly, can also be prepared by prepared by the of
the deselenization
of aryl-isoselenocyanates
deselenization of [15], using
selenourea. In the recyclable
2015, Xie andionic liquid supported
co-workers, described1-(4-diacetoxyiodobenzyl)-
a one-pot hypervalent
selenourea. In 2015, Xie and co-workers, described a one-pot hypervalent iodine-mediated deselenization
3-methylimidazolium
iodine-mediated tetrafluoroborate
deselenization ([dibmim]+[BF4]–), [15],
of aryl-isoselenocyanates whichusing
gavethea variety of ionic
recyclable cyanamides
liquid
of aryl-isoselenocyanates
(Scheme 8). [15], using the recyclable ionic liquid supported 1-(4-diacetoxyiodobenzyl)-
supported 1-(4-diacetoxyiodobenzyl)-3-methylimidazolium tetrafluoroborate ([dibmim]+ [BF ]– ),
4
3-methylimidazolium tetrafluoroborate ([dibmim]+[BF4]–), which gave a variety of cyanamides
which gave a variety of cyanamides (Scheme 8).
(Scheme 8).
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Molecules 2017, 22, 615 6 of 27
Scheme 8. Isoselenocyanates
Scheme 8. Isoselenocyanates to
to aryl-cyanamide.
aryl-cyanamide.
Scheme 8. Isoselenocyanates to aryl-cyanamide.
During the syntheses of 5-alkylselanyl-1-aryl-1H-tetrazoles from aryl-isoselenocyanates, the
During the syntheses of 5-alkylselanyl-1-aryl-1H-tetrazoles
During 5-alkylselanyl-1-aryl-1H-tetrazoles from aryl-isoselenocyanates,
aryl-isoselenocyanates, the
serendipitous synthesis of N-alkyl-N-aryl-cyanamides was observed by Roh and co-workers [16].
serendipitous synthesis
serendipitous synthesis of N-alkyl-N-aryl-cyanamideswas
of N-alkyl-N-aryl-cyanamides was observed
observed by by Roh
Roh andand co-workers
co-workers [16].
[16].
The disubstituted cyanamide 30 was formed as predominant product when aryl-isoslelenocyanate
The disubstituted
disubstituted cyanamide
cyanamide 30 was formed as predominant product when aryl-isoslelenocyanate
28 was treated with azide followed by an alkyl-halide (Scheme 9). Mechanistically the loss of
28 was treated with azide
azide followed
followed by by an
an alkyl-halide
alkyl-halide (Scheme
(Scheme 9). Mechanistically the
9). Mechanistically the loss
loss of
elemental selenium and dinitrogen (N2) from the intermediate tetrazole 32 led to the anionic species 33,
elemental selenium
elemental seleniumand
anddinitrogen
dinitrogen(N(N ) from
2)2from the
the intermediate
intermediate tetrazole
tetrazole ledled
32 32 to the
to the anionic
anionic species
species 33,
which upon alkylation provided the disubstituted cyanamides (Scheme 9).
33, which upon alkylation provided the disubstituted cyanamides
which upon alkylation provided the disubstituted cyanamides (Scheme 9). (Scheme 9).
Scheme 9. Synthesis of disubstituted cyanamide by the cycloaddition of azide with isoselenocyanate.

Scheme
Scheme 9.
9. Synthesis
Synthesis of
of disubstituted
disubstituted cyanamide
cyanamide by
by the
the cycloaddition
cycloaddition of azide with isoselenocyanate.
3. Synthetic Applications of Substituted Cyanamides
3.
3. Synthetic
Synthetic Applications
Applications of of Substituted
Substituted Cyanamides
Cyanamides
3.1. Cycloaddition Reactions
3.1. Cycloaddition
Cycloaddition Reactions
Reactions
The carbon-nitrogen triple bond of cyanamides readily undergo [3 + 2] and [2 + 2 + 2] cycloadditions
The carbon-nitrogen triple bond of cyanamides readilyreadily
undergoundergo
[3 + 2] and [2++2]
2 +and
2] cycloadditions
whenThe carbon-nitrogen
exposed triple
to suitable reacting bond of cyanamides
partners, which ultimately lead to the [3
formation of [2
five+ and
2 + six
2]
when exposed when
cycloadditions to suitable reacting
exposed to partners,
suitable which
reacting ultimately
partners, lead
which to the formation
ultimately lead to of formation
the five and six of
membered ring heterocycles, respectively.
membered
five and sixring heterocycles,
membered respectively.respectively.
ring heterocycles,
3.1.1. [3 + 2] Cycloaddition
3.1.1. [3
[3 ++2]
2]Cycloaddition
Cycloaddition
Cyanamides participate as dipolarophiles in [3 + 2] cycloaddition reactions with dipoles to offer
Cyanamides participate
Cyanamides participateasasdipolarophiles
dipolarophiles inin
[3 [3
+ 2]+cycloaddition
2] cycloaddition reactions
reactions withwith dipoles
dipoles to
to offer
cycloadducts; e.g., the reaction with azide dipoles offer 4-aminotetrazole adducts [2]. Recently,
offer cycloadducts;
cycloadducts; e.g., reaction
e.g., the the reaction
withwith azide
azide dipoles
dipoles offer4-aminotetrazole
offer 4-aminotetrazoleadducts
adducts[2].
[2]. Recently,
Recently,
cyanamides have been shown to participate in reactions with alkynes and other dipoles to offer a
cyanamides have
cyanamides havebeen
beenshown
showntotoparticipate
participateininreactions
reactionswith
withalkynes
alkynesand
andother
otherdipoles
dipolestoto offer
offer a
variety of heterocyclic products.
a variety of heterocyclic products.
variety of heterocyclic products.
Kukushkhin et al. applied a gold catalyzed heterocyclization of alkynes with substituted
cyanamides in the presence of the oxygen donor 2-picoline oxide (35), to give 2-amino-1,3-oxazoles
cyanamides in the presence of the oxygen donor 2-picoline oxide (35), to give 2-amino-1,3-oxazoles
36 (Scheme 10) [17]. A variety of terminal alkynes 34 in the presence of Ph3PAuNTf2 and 2-picoline
36 (Scheme 10) [17]. A variety of terminal alkynes 34 in the presence of Ph3PAuNTf2 and 2-picoline
Molecules 2017, 22, 615 7 of 28

Molecules 2017, 22, 615 7 of 27
cyanamides in 615
Molecules 2017, 22, the presence of the oxygen donor 2-picoline oxide (35), to give 2-amino-1,3-oxazoles
7 of 27
36 (Scheme
oxide 10) [17]. A variety
in chlorobenzene, underwentof terminal alkynes
cyclization in the presence of Phto
34dimethylcyanamide
with 3 PAuNTf 2 and
offer the 2-picoline 2-
5-substitued
oxide in chlorobenzene,
chlorobenzene, underwent
underwent cyclization
cyclization with
with dimethylcyanamide
dimethylcyanamide to to offer
offer the
the
amino-1,3-oxazoles 36. The reaction was proposed to proceed through a β-gold(I)-vinyloxypyridinium 5-substitued
5-substitued 2-
2-amino-1,3-oxazoles
amino-1,3-oxazoles
intermediate 37, which 36. The
36.isThe reaction
reaction
trapped was
bywas proposed
the proposed
cyanamide to proceed
to nitrile.
proceed through a β-gold(I)-vinyloxypyridinium
a β-gold(I)-vinyloxypyridinium
intermediate 37, which
intermediate 37, which isistrapped
trappedby bythe
thecyanamide
cyanamidenitrile.
nitrile.
Scheme 10.10.
Scheme
Scheme 2-Amino-1,3-oxazoles
10. 2-Amino-1,3-oxazolessynthesis
2-Amino-1,3-oxazoles synthesis via
synthesis cycloaddition ofalkynes
cycloaddition of
via cycloaddition of alkynesand
alkynes andcyanamides.
and cyanamides.
cyanamides.
AAA cycloaddition protocolfor

cycloaddition for the synthesis
synthesis of 1,2,4-oxadiazoles 39 was developed utilizing
cycloadditionprotocol
protocol for the
the synthesis of 1,2,4-oxadiazoles39
1,2,4-oxadiazoles 39was
wasdeveloped
developedutilizing
utilizing
cyanamides
cyanamides as core building block by Goldberg and co-workers [18]. A zinc-chloride catalyzed
cyanamidesasas core buildingblock
core building blockbyby Goldberg
Goldberg and co-workers
and co-workers [18]. A[18]. A zinc-chloride
zinc-chloride catalyzed catalyzed
reverse
reverse
reverse nucleophilicaddition
additionofofN-Boc-hydroxylamine
N-Boc-hydroxylamine (38) to the cyanamide-nitrile, followed byby
nucleophilic addition of N-Boc-hydroxylamine (38) to the cyanamide-nitrile, followed byfollowed
nucleophilic (38) to the cyanamide-nitrile, acylation,
acylation,
acylation, deprotectionand
deprotection andring-closure,
ring-closure,mediated
mediated by
by TFAA
TFAA and
andtoTFA,
TFA, lead
leadto
tothe
thefinal cyclized
final cyclized1,2,4-
1,2,4-
deprotection and ring-closure, mediated by TFAA and TFA, lead the final cyclized 1,2,4-oxadiazole
oxadiazole
oxadiazole targets
targets 3939 (Scheme
(Scheme 11).
11).
targets 39 (Scheme 11).
Scheme 11. 1,2,4-Oxadiazoles synthesis from cyanamides.

Scheme
Scheme11.
11.1,2,4-Oxadiazoles
1,2,4-Oxadiazoles synthesis fromcyanamides.
synthesis from cyanamides.
Recently, we (Sharma and co-workers) investigated the in situ trapping of a cyanamide anion 44
Recently,
with we (Sharma
1,3-dipoles nitrileand co-workers) investigated the in situ
richtrapping of a cyanamide
a formal anion + 2]44
Recently, welike
(Sharma oxide 43 for the syntheses
and co-workers) of nitrogen
investigated the in situ heterocycles
trapping of avia
cyanamide [3
anion
with 1,3-dipoles
cycloaddition
44
like nitrile
[19]. Using
with 1,3-dipoles
oxide 43
TBAFoxide
like nitrile
for the
as a reagent syntheses
43 for the
of
forsynthesesnitrogen
both the detosylationrich
of nitrogen rich
heterocycles via
of N-tosyl-cyanamide a formal
heterocycles via aand
[3 + 2]
the
formal
cycloaddition
[3 [19]. Using
dehydrochlorination
+ 2] cycloaddition TBAF
[19]. asTBAF
of chlorooxime,
Using a reagent
allowed forthe
both
as a reagent theboth
formation
for detosylation
of
theboth of N-tosyl-cyanamide
complimentary
detosylation and the
reactive species
of N-tosyl-cyanamide
dehydrochlorination
in one pot. The of chlorooxime,
nucleophilic addition allowed
of the the formation
cyanamide anion oftoboth
the complimentary
nitrile-oxide
and the dehydrochlorination of chlorooxime, allowed the formation of both complimentary reactive reactive
followed by species
5-exo-
dig
one cyclization
in species
pot.inThe gave
pot. Thethenucleophilic
one nucleophilic oxadiazol-5-imine
of the product
additionaddition cyanamide 41 in excellent
anion
of the cyanamide to theyields
anion the(Scheme
nitrile-oxide
to 12). These
followed
nitrile-oxide by
followed novel
5-exo-
by
heterocycles,
dig5-exo-dig
cyclization which
gave theare useful but somewhat
oxadiazol-5-imine productunder-represented
41 in excellent in pharmaceutical
yields (Scheme
cyclization gave the oxadiazol-5-imine product 41 in excellent yields (Scheme 12). These novel drugs,
12). These were
novel
further converted
heterocycles,
heterocycles, whichto
which are
arethe biologically
useful
useful but
but relevant
somewhat
somewhat oxadiazol-5-ones
under-represented
under-represented in42 upon acidic hydrolysis.
in pharmaceutical
pharmaceutical drugs, were Further
drugs,
furtherwere
investigation
further convertedinto tothe
the reactions of
biologicallycyanamide
relevant anion led to the
oxadiazol-5-ones syntheses
42 upon of other
acidic
converted to the biologically relevant oxadiazol-5-ones 42 upon acidic hydrolysis. Further investigationnovel heterocycles
hydrolysis. Further
under
into thetrapping
investigation intoconditions
reactions the
of cyanamidewithof
reactions dipoles
anion ledlike
cyanamide nitrile
to theanion imine.
led toofthe
syntheses syntheses
other of other novel
novel heterocycles under heterocycles
trapping
under trapping
conditions conditions
with with
dipoles like dipoles
nitrile like nitrile imine.
imine.
Molecules 2017, 22, 615 8 of 28
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Molecules 2017, 22, 615 8 of 27
Scheme 12. 1,2,4-oxadizole-5-imines synthesis from cyanamides.

3.1.2. [2 + 2 + 2] Cycloaddition
The metal-catalyzed [2 + 2 + 2] cyclotrimerization of substituted cyanamides to triazine products
The
aremetal-catalyzed [2 + 2that
well studied reactions + 2] cyclotrimerization
have of substituted
been previously reviewed cyanamides
[2]. In contrast, to triazine products
the co-cyclization of
are wellthestudied
nitrile moiety of cyanamides
reactions that have with dialkyne
been or alkenyl-nitrile
previously reviewedsystem[2]. Inoffers a routethe
contrast, to functionally
co-cyclization of
diverse
the nitrile six membered
moiety heterocyclic
of cyanamides withsystems suchor
dialkyne as 2-aminopyridine and aminopyrimidine
alkenyl-nitrile system offers a route derivatives.
to functionally
diverse six membered heterocyclic systems such as 2-aminopyridine and aminopyrimidine derivatives.
Early reports routinely employed cobalt-based catalysts for such transformations [20,21]. In more
recent years nickel, iron and iridium-based catalysts have been applied for the co-cyclization of
cyanamides and alkynes [2
The metal-catalyzed to +render 2-aminopyridine with
2 + 2] cyclotrimerization excellentcyanamides
of substituted regiocontrol. to The Louie
triazine group
products
reported
are the use reactions
well studied of Ni(cod)that
2 in have
combination with IMes
been previously ligand as[2].
reviewed anIneffective
contrast,catalyst system for the
the co-cyclization of
reaction
the nitrileofmoiety
diyne with a variety of
of cyanamides dialkyl
with cyanamides
dialkyne to give N,N-disubstituted
or alkenyl-nitrile system offers a route 2-aminopyridines
to functionally
(Scheme
diverse six13a) [22].
membered heterocyclic systems such as 2-aminopyridine and aminopyrimidine derivatives.
Scheme 13. Metal catalyzed [2 + 2 + 2] cycloaddition reactions of cyanamides.
Early reports routinely employed cobalt-based catalysts for such transformations [20,21].
In more recent years nickel, iron and iridium-based catalysts have been applied for the co-cyclization
of cyanamides and alkynes to render 2-aminopyridine with excellent regiocontrol. The Louie group
reported the use of Ni(cod)2 in combination with IMes ligand as an effective catalyst system for the
reaction of diyne with a variety of dialkyl cyanamides to give N,N-disubstituted 2-aminopyridines
(Scheme 13a) [22].
Scheme 13.
Scheme 13. Metal
Metal catalyzed
catalyzed [2
[2 +
+ 22 ++ 2]
2] cycloaddition
cycloaddition reactions
reactions of
of cyanamides.
cyanamides.
Early reports routinely employed cobalt-based catalysts for such transformations [20,21].
In more recent years nickel, iron and iridium-based catalysts have been applied for the co-cyclization
of cyanamides and alkynes to render 2-aminopyridine with excellent regiocontrol. The Louie group
reported the use of Ni(cod)2 in combination with IMes ligand as an effective catalyst system for the
Molecules 2017, 22, 615 9 of 28
Later in 2012, the same group demonstrated the effectiveness of an iron based catalyst system
[FeCl2 /Zn/L1] for the cyclization reaction [23]. In such systems, the Fe(II) salt is reduced by Zn to
a low valent Fe catalyst species, followed by the slow addition of diyne (Scheme 13b). The authors also
report the successful intermolecular cyclization of terminal aryl acetylenes with cyanamides to offer
2-amino-4,6-aryl pyridines 51 (Scheme 13c) [24]. Further modification of the iron based catalyst system
was introduced by Wan et al., wherein FeI2 /dppp/Zn realizes the products in comparable yields and
regioselectivity but with the benefit of lower reaction temperatures and catalyst loadings [25].
The [2 + 2 + 2] co-cyclization utilizing cyanamide was further applied by Louie et al. to access
aminopyrimidines 53 [26]. The cyclization of alkenyl-nitrile 52 with cyanamide under FeI2 , iPrPDAI,
Zn dust in toluene gave access to the substituted pyrimidines (Scheme 13d).
Given the significance and prevalence of substituted aminopyridines in pharmaceutical drugs
and natural product cores, more flexible catalyst systems were developed to improve the yield and
selectivity. Takeuchi and co-workers found [Ir(cod)Cl]2 /BINAP as an efficient catalyst for the [2 + 2 + 2]
cycloaddition of α,ω-diynes 54 with cyanamide nitriles (Scheme 13e). The authors argue that the
presence of a phosphine-ligand-offered flexibility with respect to the catalytic activity, which could be
achieved by choosing the appropriate phosphine ligand [27].
3.2. N-CN Bond Cleavage

The cleavage of the N–CN bond of cyanamide offers: (i) an electrophilic cyanating agent;
(ii) amino-transfer group (aminating reagent); as well as (iii) the synchronized transfer of both amino
and nitrile-groups, could offer routes to difunctionalization of C–C multiple bond aminocyanation.
These reactions of cyanamides are accomplished under both metal catalysis and metal-free conditions,
offering highly functionalized substrates. The present section will detail recent pioneering work in
these subcategories.
3.2.1. Aminocyanation
Metal catalyzed aminocyanation involves the simultaneous installment of an amino and
nitrile-group on adjacent carbon atoms, commonly in unsaturated systems. Unlike its congeners,
oxycyanation, carbocyanation, thiocyanation etc., the field of aminocyanation is relatively unexplored.
The first example of aminocyanation via the cleavage of the N–CN bond by a cooperative
palladium/triorganoboron catalysis was reported by Nakao et al. in 2014 [28]. An intramolecular
insertion of N–CN into the double bond of N-cyano-N-[2-(2-methylallyl)aryl]acetamide 56 was
achieved under the catalytic system: CpPd(allyl), 4,5-bis-(diphenylphosphino)-9,9-dimethylxanthene
(xantphos), and BEt3. The 5-exo-trig products were obtained in good to excellent yield under elevated
temperature (Scheme 14). The same authors also investigated the enantioselective aminocyanation,
by replacing the xantphos ligand with an (R,R,R)-Ph-SKP ligand. A catalytic cycle was proposed,
wherein the boron Lewis acid coordinated to the N–CN group 58 undergo oxidative addition to
a Pd(0)−xantphos complex. Syn-aminopalladation of 59 in an exo-trig fashion followed by C−CN
bond-forming reductive elimination generates the boron-bound product (Scheme 14).
Chien and Co-workers synthesized a series of 1-sulfonyl-3-cyanoindole (62) products by CuI catalyzed
intramolecular aminocyanation of N-(2-ethynylphenyl)-N-sulfonyl-cyanamides 61 (Scheme 15) [29]. In the
presence of CuI and Na2 CO3 , both terminal ethynyl and TMS-ethynyl-N-tosylcyanamide-substituted
aryl-derivatives underwent intramolecular aminocyanation across the C–C triple bond leading to the
3-cyanoindole skeleton. Based on the experimental results with internal alkynes, it was postulated that the
reaction proceeds via the formation of a key Cu-acetylide intermediate.
Molecules 2017, 22, 615 10 of 28
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Molecules 2017, 22, 615 10 of 27
Scheme 14.
Scheme 14. Palladium/triorganoboron
Palladium/triorganoboron cooperative
cooperative catalysis
catalysis for
for aminocyanation.
aminocyanation.
Scheme 14. Palladium/triorganoboron cooperative catalysis for aminocyanation.
Scheme 15. Copper catalyzed intramolecular aminocyanation.

A metal free intramolecular aminocyanation was achieved under Lewis acid catalysis by Douglas
et al. A
which
metalproceeds via cleavageaminocyanation
free intramolecular of the N–CN bond wasofachieved
cyanamide [30].
under The coordination
Lewis acid catalysisofbythe Lewis
Douglas
acid A metalwith
catalyst freethe
intramolecular
sulfonyl-group aminocyanation
lead to the was achieved
weakening of the key under
N–CN Lewis
bond, acid
thereby catalysis
inducing by
et al. which proceeds via cleavage of the N–CN bond of cyanamide [30]. The coordination of the Lewis
Douglas
bond et al.
cleavage. which
Hence, proceeds via cleavage
starting with alead
varietyof the N–CN bond
of N-tosylcyanamides of cyanamide
63,N–CN [30].
the indoline The coordination of
acid catalyst with the sulfonyl-group to the weakening of the key bond, products 64 were
thereby inducing
the Lewis
obtained acid
in goodcatalyst with the
yieldsstarting sulfonyl-group
when treated lead
with equivalent to the weakening
quantity of B(C of the key
F5)3indoline N–CN
. The authors bond, thereby
proposed a
bond cleavage. Hence, with a variety of N-tosylcyanamides 63, 6the products 64 were
inducing bond
mechanism cleavage.
consistent Hence,
with starting with
nucleophilic attack a variety
of the of N-tosylcyanamides
alkene on the nitrile 63, the
center, indoline
which is products
supported
obtained in good yields when treated with equivalent quantity of B(C6F5)3. The authors proposed a
64 were
by obtaineddata
experimental in good yields 16).when treated with equivalent quantity oftheB(C 6 F5 )3 . The authors
mechanism consistent(Scheme A comparable
with nucleophilic attack of the yield was obtained
alkene when
on the nitrile center, reaction
which iswas carried
supported
proposed
out with a
20mechanism
mol % of consistent
Lewis acid,with nucleophilic
although attack
extended of the
reaction alkene
times on
werethe nitrile
required. center, which
Initially is
the
by experimental data (Scheme 16). A comparable yield was obtained when the reaction was carried
supported
reaction by experimental data (Scheme complex,
16). A comparable yield was obtained when the reaction was
out withwas 20 performed
mol % of Lewiswith a acid,
rhodiumalthough extended but further investigation
reaction times were indicated
required. that the N–CN
Initially the
carried
bond out with
activation 20
can mol
be % of Lewis
achieved acid,
without although
the extended
addition of anyreaction times
transition were
metal required.
catalysts. Initially the
reaction was performed with a rhodium complex, but further investigation indicated that the N–CN
reaction was performed with a rhodium complex, but further investigation indicated that the N–CN
bond activation can be achieved without the addition of any transition metal catalysts.
bond activation can be achieved without the addition of any transition metal catalysts.
Molecules 2017, 22, 615 11 of 28
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Molecules 2017, 22, 615 11 of 27
Molecules 2017, 22, 615 11 of 27
Scheme
Scheme 16. 16. Lewis
Lewis acid
acid activatedcleavage
activated cleavage of
of N–CN
N–CN bond
bondfor
forintramolecular
intramolecularaminocyanation.
aminocyanation.
Scheme 16. Lewis acid activated cleavage of N–CN bond for intramolecular aminocyanation.
Another example of a metal-free cleavage of the N–CN bond was described by Zeng et al. [31].
Another example
Scheme 16. of a metal-free
Lewis cleavage ofN–CN
the N–CN bond wasbond
described by Zengaminoet al. [31].
The Another
researchers
example of aacid
demonstrated activated
metal-free cleavage ofof
that aryne-insertion
cleavage bond for
the across
N–CN theintramolecular
bond N–CN aminocyanation.
was described to by
deliver
Zengtheet al. [31].
The benzonitriles
researchers (68)
demonstrated
could be achieved that aryne-insertion across the N–CN bond to deliver the amino
The researchers demonstrated that by in situ generation
aryne-insertion of arynes
across the N–CN69 and an anionic
bond species
to deliver the44amino
from
Another
benzonitriles (68)example
could
the mono-substituted of
be a metal-free
achieved bycleavage
in situ of the N–CN
generation bond
of was
arynes described
69 and by
an Zeng et
anionic al. [31].
species
via a 44
benzonitriles (68) couldcyanamide.
be achievedBoth by in ofsitu
the generation
reactive species were69generated
of arynes simultaneously
and an anionic species 44 from
fromtheThe researchers
themono-substituteddemonstrated
mono-substituted cyanamide. that aryne-insertion
Both of the across
reactive the
speciesN–CN bond to deliver the amino
fluoride ion source (CsF). The aryne
cyanamide. underwent
Both of the nucleophilic
reactive species werewere
addition togenerated simultaneously
give simultaneously
generated the phenyl-anion a via
via70,
benzonitriles
a fluoride ion (68) could
source (CsF). beTheachieved
aryne by in situ generation
underwent of arynes
nucleophilic 69 and an
addition to anionic
give species
the 44 from
phenyl-anion
fluoride ion source (CsF). The aryne underwent nucleophilic addition to give the phenyl-anion 70, 70,
which on cyclization gave the highly strained four-membered intermediate 71. Ring opening of the
the mono-substituted
intermediate 71 andgave cyanamide.
protonation Both
led of the
tostrained
the reactive
final species were
aminocyanated generated
product (Scheme simultaneously
17). via a
which on cyclization
which on cyclization gavethe thehighly
highly strained four-membered
four-membered intermediate
intermediate 71.71. Ring
Ring opening
opening of the
of the
fluoride ion source (CsF). The aryne underwent nucleophilic addition to give the phenyl-anion 70,
intermediate
intermediate71 and
71 andprotonation
protonationled ledtotothe
thefinal
final aminocyanated product(Scheme
aminocyanated product (Scheme 17).
17).
which on cyclization gave the highly strained four-membered intermediate 71. Ring opening of the
intermediate 71 and protonation led to the final aminocyanated product (Scheme 17).
Scheme 17. Aminocyanation of arynes.

3.2.2. Aminating Agent Scheme 17. Aminocyanation of arynes.
3.2.2.In
Aminating Agentand co-workers reported the amination of 2-halobenzothiazole and benzoxazole
2014 Nageswar
3.2.2.3.2.2.
Aminating Agent
Aminating Agent
derivatives
In 2014on reaction
Nageswar withco-workers
and dialkyl cyanamides
reported under Ru/C catalysis
the amination (Scheme 18). Theand
of 2-halobenzothiazole reaction utilizes
benzoxazole
In 2014
cyanamides
derivativesNageswar
as
onNageswar
In 2014 and
aminating co-workers
agent
reaction with with reported
the
dialkyl cyanamides
and co-workers the
concomitantamination
reported under loss of of 2-halobenzothiazole
nitrile
Ru/C catalysis
the amination group [32].
(Scheme 18). The
of 2-halobenzothiazole and and benzoxazole
reaction utilizes
benzoxazole
derivatives
cyanamideson on
derivatives reaction
reactionwith
as aminatingwith dialkyl
dialkyl
agent with cyanamides
cyanamides under
under
the concomitant loss Ru/C
Ru/C catalysis
catalysis
of nitrile (Scheme
group (Scheme 18). The
18). The reaction
[32]. reaction
utilizes
utilizes cyanamides
cyanamides as aminating
as aminating agent agent with
with the the concomitant
concomitant loss group
loss of nitrile of nitrile
[32].group [32].
Scheme 18. Cyanamide as aminating agent.

Scheme 18. Cyanamide as aminating agent.
Scheme18.
Scheme 18.Cyanamide
Cyanamide as
asaminating
aminatingagent.
agent.
Molecules 2017, 22, 615 12 of 28
Molecules 2017, 22, 615 12 of 27

3.2.3. Electrophilic Cyanation
3.2.3. Electrophilic Cyanation
N-Sulfonyl cyanamides viz N-cyano-N-tosyl-sulfonamide (74, NCTS), also known as
N-Sulfonyl cyanamides viz N-cyano-N-tosyl-sulfonamide
N-cyano-N-phenyl-p-methylbenzene-sulfonamide (74, NCTS),
[33], are popular also known
cyanamide as N-cyano-
derivatives with
N-phenyl-p-methylbenzene-sulfonamide [33], are popular cyanamide derivatives with significant
significant applications in synthetic chemistry. The reactivity and stereoelectronic properties of the
applications in synthetic chemistry. The reactivity and stereoelectronic properties of the sulfonyl
sulfonyl group have been exploited to orchestrate diverse reactions of cyanamides; e.g., Lewis acid
group have been exploited to orchestrate diverse reactions of cyanamides; e.g., Lewis acid assisted
assisted aminocyanation [30], generation of cyanamide anion by action of a nucleophilic fluoride
aminocyanation [30], generation of cyanamide anion by action of a nucleophilic fluoride ion [19],
ion [19], electrophilic cyanation by reaction with Grignard reagents [34] as well as for heterocyclic
electrophilic cyanation by reaction with Grignard reagents [34] as well as for heterocyclic ring
ring construction [35,36]. Since the re-introduction of NCTS by Beller et al. in 2011 as an efficient
construction [35,36]. Since the re-introduction of NCTS by Beller et al. in 2011 as an efficient electrophilic
electrophilic cyanation source of aryl- and alkenyl-substrates under rhodium catalysis [37], there has
cyanation source of aryl- and alkenyl-substrates under rhodium catalysis [37], there has been a
been a growing interest in developing new catalytic metal systems for such reactions [38,39].
growing interest in developing new catalytic metal systems for such reactions [38,39].
Wang and co-workers reported the first example of rhodium-catalyzed intramolecular C–H
Wang and co-workers reported the first example of rhodium-catalyzed intramolecular C–H
cyanation
cyanationinin2013
2013[40].
[40]. The
The intramolecular C–H cyanation
intramolecular C–H cyanation ofof an
an appropriately
appropriatelydecorated
decoratedstyrene
styrene
substrate (75) was achieved via a rhodium(I)-catalyzed N–CN cleavage (Scheme 19a). Good
substrate (75) was achieved via a rhodium(I)-catalyzed N–CN cleavage (Scheme 19a). Good substrate substrate
tolerance
tolerancewaswasshown
shown for
for different
different substituents attached on
substituents attached on the
the arene
arenering
ringand
andstyrene
styreneα-position.
α-position.
Alkyl-substituents
Alkyl-substituentsin inthe
the olefinic
olefinic α-position of the
α-position of the styrene
styrene has
has led
ledto
toacrylonitriles
acrylonitrilesiningood
goodyields,
yields,
whereas
whereas corresponding arene substitution on the olefinic α-position, resulted in moderate yields ofof
corresponding arene substitution on the olefinic α-position, resulted in moderate yields
the
thecyanated
cyanatedproducts.
products. The
The reaction
reaction establishes the importance
establishes the importanceof ofα-substitution
α-substitutionininstyrene
styrenefor
forthe
the
cyanation
cyanationtotobebefeasible.
feasible.
Scheme19.
Scheme 19. Rhodium-catalyzed
Rhodium-catalyzed electrophilic
electrophilic cyanation
cyanationwith
withNCTS.
NCTS.
Fu and co-workers reported the syntheses of aromatic nitriles 78 under Rh-catalyzed directed
Fu and co-workers
C−H cyanation reported
using NCTS the syntheses
as the cyanating of aromatic
agent nitriles
(Scheme 19b)78 under
[41]. TheRh-catalyzed
cyanation was directed
first
−H cyanation
Cdeveloped using NCTS as the cyanating agent (Scheme 19b) [41]. The cyanation
for acetophenone O-methyl oxime substrates (77) and eventually extended to different was first
developed for acetophenone O-methyl oxime substrates (77) and eventually extended
directing groups such as pyridines, pyrazoles, dihydroimidazoles and dihydrooxazoles, which all to different
directing
resulted groups such as
in moderate to pyridines,
good yieldspyrazoles, dihydroimidazoles
of the nitrile and dihydrooxazoles,
products. The reaction which aall
was found to tolerate
resulted
variety of synthetically demanding functional groups (e.g., unprotected phenol, Ar-I, epoxide),awhich
in moderate to good yields of the nitrile products. The reaction was found to tolerate variety
ofproved
synthetically demanding functional groups (e.g., unprotected
to be challenging with other transition metal catalysts such as Pd.phenol, Ar-I, epoxide), which proved
to be challenging
A series of with other
reports on transition metal
the chelation catalysts
assisted C–H such as Pd. for cyanation under Rh-catalysis
activation
A NCTS
with series of reports
have sinceon the chelation
appeared. assistedetC–H
Anbarasan activationthe
al. described forcyanation
cyanationof under
phenylRh-catalysis
pyridineswith
79
NCTS
with have since
[RhCp*Cl 2]2appeared.
catalyst inAnbarasan
the presence et al. described
of AgSbF the cyanation
6 (Scheme 19c) [42].ofThis
phenyl pyridines
method 79 with
allowed the
synthesis of various aryl nitrile derivatives in good to excellent yields, while reducing the catalytic
loading to 1 mol %.
Molecules 2017, 22, 615 13 of 28
[RhCp*Cl2 ]2 catalyst in the presence of AgSbF6 (Scheme 19c) [42]. This method allowed the synthesis
of various aryl nitrile derivatives in good to excellent yields, while reducing the catalytic loading
to 1 mol %.
The H.-Y. Ding group on the other hand employed the chelation-assisted ortho-cyanation on
arylphosphate substrates 81 under rhodium catalysis (Scheme 19d) [43]. The protocol delivered
complete ortho-selectivity, thereby hindering the formation of biscyanated aryl-phosphonate byproducts.
Zhu and co-workers applied the rhodium based catalytic protocol for C–H cyanation of symmetric
azobenzenes (83) at the ortho-position (Scheme 19e) [44]. The protocol was more effective for the
cyanation of aromatic azo-compounds having electron donating groups than those with electron
withdrawing groups.
Chelation assisted C–H functionalization was extended to the indole and indoline scaffolds.
Indole and indolines are ubiquitous structural motifs found in natural products and find application
in pharmaceuticals, agrochemicals and dyes. The introduction of cyano groups to these structural
motifs provides a means of decorating the indole and indoline rings. In particular, selective C-2
cyanation of indoles and C-7 cyanation of indolines have received much attention. In 2015, Kim et al.
Molecules 2017, 22, 615 13 of 27
reported site selective, directing group-assisted C−H cyanation of indolines and indoles at the
C-7 and C-2 positions respectively, via rhodium-catalyzed reaction with NCTS (Scheme 20a) [45].
The H.-Y. Ding group on the other hand employed the chelation-assisted ortho-cyanation on
The results indicated
arylphosphate substrates N-carbonyl
that81 or carbamoyl-directing
under rhodium catalysis (Scheme 19d)groups actprotocol
[43]. The very effectively in the C-7
delivered complete
cyanation (compounds
ortho-selectivity, to 86), whereas
thereby85hindering C-2, C-3
the formation or C-4 substituted
of biscyanated N-pivaloyl-indolines
aryl-phosphonate byproducts. deliver
the C-7Zhucyanated products only in moderate to good yields. A similar protocol was
and co-workers applied the rhodium based catalytic protocol for C–H cyanation of symmetric used in the
synthesis of C2-cyanated
azobenzenes (83) at the indoles 88, utilizing
ortho-position a removable
(Scheme pyrimidyl-directing
19e) [44]. The protocol was more group to achieve
effective for thethe
desired product
cyanation in excellent
of aromatic yields. Extending
azo-compounds their
having work, donating
electron Kim et al.groups
reported thethose
than C-7 cyanation of C-2
with electron
substituted
withdrawing indoles
groups.93 and 94 (Scheme 20c) [46].
Scheme20.
Scheme 20.Rhodium
Rhodiumcatalyzed
catalyzed electrophilic
electrophilic cyanation
cyanationwith
withNCTS.
NCTS.
Chelation assisted C–H functionalization was extended to the indole and indoline scaffolds.
Indole and indolines are ubiquitous structural motifs found in natural products and find application
in pharmaceuticals, agrochemicals and dyes. The introduction of cyano groups to these structural
motifs provides a means of decorating the indole and indoline rings. In particular, selective C-2
cyanation of indoles and C-7 cyanation of indolines have received much attention. In 2015, Kim et al.
reported site selective, directing group-assisted C−H cyanation of indolines and indoles at the C-7
Molecules 2017, 22, 615 14 of 28
Molecules 2017, 22, 615 14 of 27

Appearing at a similar time as Kim’s report, a publication by the Anbarasan group described
the electrophilic
2-cyanoindolesC-2 and selective cyanation
pyrrole products wereof indoles
obtained in and pyrolesof(Scheme
the presence low catalyst20b) [47]. The
loadings cyanation
(1–3 mol %)
process was assisted
and additives. by a removable directing group such as N-pyridyl, N-quinolyl and N-pyrimidyl.
The 2-cyanoindoles
Concurrentlyand to thepyrrole productsstudy
C–H cyanation wereofobtained
indoles and in the presence
pyrroles, of lowand
Anbarasan catalyst loadings
co-workers
(1–3also
mol reported
%) and additives.
the C–H cyanation of acrylonitriles/vinyl-nitriles (95) with NCTS via rhodium(III)
Concurrently
catalysis (Scheme to 20d).
the C–H cyanation
In this study2 of
case, Cu(OAc) wasindoles
used asand pyrroles,[48].
an additive Anbarasan
The new and co-workers
method toleratesalso
a variety
reported the of
C–Hfunctional
cyanation groups, thereby allowing the synthesis
of acrylonitriles/vinyl-nitriles of diverse
(95) with NCTS substituted acrylonitriles
via rhodium(III) 96.
catalysis
Rhodium catalyzed C–H cyanation of substituted vinyl amides 97 with
(Scheme 20d). In this case, Cu(OAc)2 was used as an additive [48]. The new method tolerates a variety NCTS to access alkenyl-
nitriles (98)
of functional was accomplished
groups, thereby allowing by Futhe et synthesis
al. (Scheme of 20e) [49].substituted
diverse This methodology exhibited
acrylonitriles 96. good
functional group tolerance and both acrylamides and ketoximes
Rhodium catalyzed C–H cyanation of substituted vinyl amides 97 with NCTS to accesscould be used as directing groups.
Expanding the scope of the rhodium catalyzed C−H cyanation with NCTS, Yi and co-workers
alkenyl-nitriles (98) was accomplished by Fu et al. (Scheme 20e) [49]. This methodology exhibited good
reported the C−H cyanation of a wide range of ortho-substituted N-methoxybenzamides 99 (Scheme 20f).
functional group tolerance and both acrylamides and ketoximes could be used as directing groups.
The reactions showed good substrate and functional group tolerance [50]. The new protocol delivers
Expanding the scope of the rhodium catalyzed C−H cyanation with NCTS, Yi and co-workers
products with good regioselectivity and under mild reaction conditions.
the C−
reportedRecently H etcyanation
Sun al. reportedof theasynthesis
wide range of ortho-substituted102
of 2-(alkylamino)benzonitriles N-methoxybenzamides
via a rhodium catalyzed 99
(Scheme 20f). The reactions showed good substrate and functional
aryl C−H cyanation and denitrosation of N-nitrosoarylamines 101 with NCTS (Scheme group tolerance [50].
20g) [51]. TheThenewnew
protocol delivers
reaction productsgood
demonstrated withtolerance
good regioselectivity
to a wide range andof under mild reaction
substituents conditions.
on the aryl-ring and amino-
Recently
group, whileSun et al. reported
delivering the synthesis
the corresponding productsof 2-(alkylamino)benzonitriles
in moderate to good yields. 102 via a rhodium
catalyzed aryl C−toHrhodium,
In addition cyanation cobalt anddenitrosation
and ruthenium catalysts have also been developed
of N-nitrosoarylamines 101 aswith
efficient
NCTS
transition metal catalysts for the electrophilic cyanation of C–H bond by NCTS.
(Scheme 20g) [51]. The new reaction demonstrated good tolerance to a wide range of substituents on the
aryl-ringTheandfirst example of while
amino-group, a cobalt-catalyzed
delivering the cyanation of C–H bonds
corresponding products withinNCTS was reported
moderate to good by yields.
Ackermann and Li in 2014 (Scheme 21a) [52]. The reaction was found
In addition to rhodium, cobalt and ruthenium catalysts have also been developed as efficientto be dependent on the co-
catalyst AgSbF6 and carboxylate additives. Mechanistic studies indicate that in situ generation of the
transition metal catalysts for the electrophilic cyanation of C–H bond by NCTS.
highly active cationic cobalt(III) acetate is vital for site-selective ortho-cyanation. The methodology is
The first example of a cobalt-catalyzed cyanation of C–H bonds with NCTS was reported by
also applicable to removable directing groups such as pyridyl, pyrimidyl and pyrazole.
Ackermann and Li in 2014 (Scheme 21a) [52]. The reaction was found to be dependent on the co-catalyst
In 2014 Glorius and co-workers reported the C–H cyanation of heteroaryls (ortho-cyanation),
AgSbF 6 and(C-2
indoles carboxylate
cyanation), additives.
and olefins Mechanistic
under cobalt studies
catalysisindicate
(Scheme that
21b)in [53].
situ The
generation
method of the highly
exhibited
active cationic cobalt(III) acetate is vital for site-selective ortho-cyanation.
good functional group tolerance and high efficacy when used in combination with different directingThe methodology is also
applicable
groups to removable
(pyridyl, directing
pyrimidyl groups such as pyridyl, pyrimidyl and pyrazole.
and pyrazole).
Scheme 21. Cobalt catalyzed electrophilic cyanation with NCTS.

Scheme 21. Cobalt catalyzed electrophilic cyanation with NCTS.
Recently the Gosmini’s group reported the C–H cyanation of aryl-zinc compounds catalyzed by
In 2014 [54].
cobalt(II) Glorius and co-workers
The study was inspiredreported the of
by utilization C–Hmildcyanation of heteroaryls
reaction conditions (ortho-cyanation),
and one-pot synthesis
indoles (C-2 cyanation),
of aryl-zinc derivativesandfromolefins underand
aryl-halides cobalt catalysis
subsequent (Schemeusing
cyanation 21b)the
[53].
sameThe methodcatalyst
cobalt(II) exhibited
good(Scheme 21c).group
functional In contrast to previous
tolerance reports,
and high Gosmini’s
efficacy when protocol uses low valent
used in combination cobalt(II)
with catalysts.
different directing
However, in this case, a catalytic
groups (pyridyl, pyrimidyl and pyrazole). amount of zinc dust was used to release the reactive cobalt species
in the cyanation
Recently step. Despite
the Gosmini’s the high
group tolerance
reported the level,
C–H the authors of
cyanation report that the
aryl-zinc protocol is ineffective
compounds catalyzed by
in the [54].
cobalt(II) presence
The of a strong
study waschelating
inspired group (ketone or
by utilization of nitrile) on the aryl-zinc
mild reaction species.
conditions and one-pot synthesis
of aryl-zinc derivatives from aryl-halides and subsequent cyanation using the same cobalt(II) catalyst
Molecules 2017, 22, 615 15 of 28
(Scheme 21c). In contrast to previous reports, Gosmini’s protocol uses low valent cobalt(II) catalysts.
However, in this case, a catalytic amount of zinc dust was used to release the reactive cobalt species in
the cyanation step. Despite the high tolerance level, the authors report that the protocol is ineffective
in the presence of a strong chelating group (ketone or nitrile) on the aryl-zinc species.
Molecules 2017,
Recently 22, 615 et al. described the first cobalt(III) catalyzed C–C bond cleavage of15secondary
Morandi of 27
and tertiary alcohols and subsequent electrophilic cyanation by NCTS (Scheme 21d) [55]. In this
Recently
Molecules 2017, 22,Morandi
615 et al. described the first cobalt(III) catalyzed C–C bond cleavage of secondary 15 of 27
protocol,
anddirecting groups and
tertiary alcohols suchsubsequent
as pyridylelectrophilic
are important to bothby
cyanation facilitate the β-carbon
NCTS (Scheme elimination
21d) [55]. In this and
stabilize the cobalt-aryl intermediate + trapping.
Recently
protocol, Morandi
directing et al.such
groups asagainst
described
pyridyl proto-demetallation
the first
are cobalt(III) to both prior
important catalyzed C–C to electrophile/[CN]
bond
facilitate thecleavage
β-carbonofelimination
secondary
and tertiary
Mechanistic studies
stabilize alcohols
the andthat
indicate subsequent
cobalt-aryl electrophilic
the cyanation
intermediate cyanation by NCTS
takesproto-demetallation
against place directly from (Scheme
the to
prior 21d) [55].intermediate
cobalt-aryl In this+
electrophile/[CN]
protocol,
rather trapping.
than prior directing
Mechanistic groups
protonation suchindicate
studies
followedas pyridyl
bythat
C–Hare important
cyanationtotakes
theactivation. bothplace
facilitate the β-carbon
directly from the elimination
cobalt-aryl
andAckermann
stabilize rather
intermediate
The the group
cobalt-aryl
haveintermediate
than prior protonation
also explored against
the proto-demetallation
followed by C–H activation.
applicability prior to electrophile/[CN]
of ruthenium(II)
+
catalysts for C–H
trapping.Ackermann
Mechanisticgroupstudies indicate that the thecyanation takes place directly from the cobalt-aryl
cyanation Thewith NCTS (Scheme have
22a) also explored
[56]. Ackermann applicability
explored the of ruthenium(II)
feasibility ofcatalysts for C–H
a ruthenium catalyst
intermediate
cyanation withrather
NCTS than prior protonation
(Scheme followed by
22a) [56]. Ackermann C–H activation.
explored the feasibility of a ruthenium catalyst
with weakly coordinating amide groups for chelation assisted directed C–H cyanation of arenes and
with The Ackermann
weakly group
coordinating havegroups
amide also explored the applicability
for chelation of ruthenium(II)
assisted directed C–H cyanation catalysts for C–H
of arenes and
heteroarenes.
cyanationThe
heteroarenes.with protocol
TheNCTS proved
(Scheme
protocol proved
toto
22a) be effective,
[56]. Ackermann
be effective,
demonstrating
explored thegood
demonstrating
good substrate
feasibility of ascope
substrate
scope
ruthenium and tolerance
catalyst
and tolerance
to a wide
with
to range
weakly
a wide of
range functional
coordinating groups.
amide
of functional groups for chelation assisted directed C–H cyanation of arenes and
groups.
heteroarenes. The protocol proved to be effective, demonstrating good substrate scope and tolerance
to a wide range of functional groups.
Scheme 22. Ruthenium catalyzed electrophilic cyanation with NCTS.

Scheme 22. Ruthenium catalyzed electrophilic cyanation with NCTS.
Deb et al. demonstrated ruthenium(II)
Scheme 22. Ruthenium catalyzed
catalyzed ortho-aryl
electrophilic C–H with
cyanation cyanation
NCTS.of azoindoles with
Deb
NCTS et (Scheme 22b) [57]. ruthenium(II) catalyzed ortho-aryl C–H cyanation of azoindoles with
al. demonstrated
NCTS (Scheme Deb
A et22b)
al. mechanism
general demonstrated
[57]. canruthenium(II) catalyzed
be proposed for ortho-aryl
the metal C–H
catalyzed cyanation
reactions: of azoindoles
Initial with
C–H metalation
NCTS
is (Scheme
followed by 22b)coordination
the [57]. and migratory insertion of NCTS. Finally, β-elimination and proto-
A general mechanism can be proposed for the metal catalyzed reactions: Initial C–H metalation
A general results
demetallation mechanismin thecan be proposed for
corresponding the metal
product and catalyzed reactions: InitialM(II/III)
the regenerated C–H metalation
is followed by the coordination and migratory insertion of NCTS. cationic catalyst
Finally, β-elimination and
is followed
(Scheme 23).by the coordination and migratory insertion of NCTS. Finally, β-elimination and proto-
proto-demetallation resultsininthe
demetallation results thecorresponding
corresponding product
product andand
thethe regenerated
regenerated cationic
cationic M(II/III)
M(II/III) catalyst
catalyst
(Scheme 23).
(Scheme 23).
Scheme 23. General catalytic cycle for metal catalyzed [Ru, Rh, Co] C–H activation and cyanation.
Molecules 2017, 22, 615 16 of 28
In 2014 Buchwald and Yang reported the copper catalyzed ortho C−H cyanation of vinylarenes
(121) with NCTS (Scheme 24a) [58]. Inspired by using π-directing groups instead of strong σ-directing
groups, the team developed the reaction with vinyl-arenes. Here, the C–C double bond acts as both
a reaction site, which undergoes simultaneous borylation, and as a directing group. The proposed
mechanism involves transmetallation of the phosphine-ligated copper catalyst with the diboron
reagent, which then undergoes subsequent borocupration to form the benzyl-copper intermediate
131. Electrophilic ortho-cyanation takes place on the benzyl-copper intermediate with NCTS to give
the dearomatized cyanation product 132, which transforms to the aromatized product 122 via rapid
H-transfer (Scheme 25). The mechanism was further explored by Yang and Liu. Diverse vinyl
naphthylenes bearing both electron donating and withdrawing groups undergo this site-selective
transformation in good yield. The resulting borylated compounds can be diversified effectively into
other useful
Molecules complex
2017, 22, 615 molecules. 16 of 27
Scheme 24. Copper-catalyzed

Scheme 24. Copper-catalyzed electrophilic cyanation with
electrophilic cyanation with NCTS.
NCTS.
Exploring the simultaneous

In 2014 Buchwald ortho-cyanation
and Yang reported the copperandcatalyzed
hydroboration of styrene
ortho C−H cyanation derivatives with
of vinylarenes
NCTS/(BPin)
(121) with NCTS system, Montgomery et al. disclosed the use of N-heterocyclic carbene
2 (Scheme 24a) [58]. Inspired by using π-directing groups instead of strong σ-directing (NHC)-ligated
Cu-catalysts
groups, the team(Scheme 24b) [59].
developed the The protocol
reaction withrequired mild reaction
vinyl-arenes. Here, theconditions
C–C double andbond
was acts
compatible
as both
with a broad range of substituted styrenes, resulting in selective ortho-cyanation
a reaction site, which undergoes simultaneous borylation, and as a directing group. The proposed on the least substituted
ortho-position.
mechanism involves Polycyclic substrates with
transmetallation of extended conjugation gave
the phosphine-ligated the catalyst
copper cyanation on the
with the adjacent
diboron
ring structure. The resulting products were further derivatized to indanone
reagent, which then undergoes subsequent borocupration to form the benzyl-copper intermediate derivatives via a novel
131.
AgNO /Selectfluor-mediated
Electrophilic
3 radical cyclization. This two-step protocol provides
ortho-cyanation takes place on the benzyl-copper intermediate with NCTS to give the an efficient method
for cyclopentannulation
dearomatized cyanationofproduct
styrenes. 132, which transforms to the aromatized product 122 via rapid
H-transfer (Scheme 25). The mechanism was copper-NHC
The group also reported an unprecedented further exploredbasedby catalyst
Yang system
and Liu. forDiverse
the cyanation
vinyl
and diborylation of terminal allenes 125 with
naphthylenes bearing both electron donating and withdrawing NCTS/(BPin) 2 (Scheme 24c). The protocol exhibited
groups undergo this site-selective
exceptional
transformation chemo-, region-
in good and
yield. Thediastereoslectivity,
resulting borylated while being compatible
compounds with trifunctionalization
can be diversified eﬀectively into
of a variety of terminal allenes
other useful complex molecules. [60].
More recently,
Exploring Yang applied ortho-cyanation
the simultaneous NCTS for cyanation of 1-allyl-2-vinylnaphthalenes
and hydroboration of styrene derivatives127 under
with
copper catalysis (Scheme 24d) [61]. Similar to previous work, this reaction
NCTS/(BPin)2 system, Montgomery et al. disclosed the use of N-heterocyclic carbene (NHC)-ligated cascade was initiated
by a copper catalyzed
Cu-catalysts (Scheme electrophilic
24b) [59]. The dearomatization
protocol required process.
mild The resulting
reaction dearomatized
conditions and wasintermediate
compatible
undergoes a regio and stereospecific 1,3-transposition of an allyl-fragment
with a broad range of substituted styrenes, resulting in selective ortho-cyanation via a rearomatizing
on the Copeleast
rearrangement to give the final compound 128. This method also demonstrated
substituted ortho-position. Polycyclic substrates with extended conjugation gave the cyanation on the promising results
against
adjacenta ring
widestructure.
range of substrates
The resultingdiffering
productsat the naphthyl
were furthermoiety and the
derivatized to migrating allyl fragment.
indanone derivatives via
Cyanation
a novel of arene diazonium salts
AgNO3/Selectfluor-mediated are known
radical to beThis
cyclization. challenging
two-stepdue to homo-coupling
protocol at high
provides an efficient
temperatures and ready decomposition.
method for cyclopentannulation Lee et al. reported a palladium based electrophilic cyanation
of styrenes.
protocol for synthetically challenging arenediazonium
The group also reported an unprecedented copper-NHC tetrafluoroborates
based catalyst andsystem
aryl halides
for thewith NCTS
cyanation
and diborylation of terminal allenes 125 with NCTS/(BPin)2 (Scheme 24c). The protocol exhibited
exceptional chemo-, region- and diastereoslectivity, while being compatible with trifunctionalization
of a variety of terminal allenes [60].
More recently, Yang applied NCTS for cyanation of 1-allyl-2-vinylnaphthalenes 127 under copper
catalysis (Scheme 24d) [61]. Similar to previous work, this reaction cascade was initiated by a copper
Molecules 2017, 22, 615 17 of 28
under mild reaction conditions [62]. The authors emphasized the importance of using a polar solvent
(e.g., EtOH) for the reaction, presumably due to its involvement in the reduction of Pd(II) to Pd(0)
together2017,
Molecules with22,the
615generation of CH3 COOH (Scheme 26). 17 of 27
Molecules 2017, 22, 615 17 of 27
Scheme 25. Copper catalytic cycle for C–H cyanation.

Scheme 25. Copper
Scheme 25. Copper catalytic
catalytic cycle
cycle for
for C–H
C–H cyanation.
cyanation.
Scheme 26. Palladium-catalyzed electrophilic cyanation with NCTS.

While NCTS is the reagent of choice for many transition metal catalyzed cyanation protocols,
While NCTS is the reagent of choice for many transition metal catalyzed cyanation protocols,
efforts haveNCTS
While also been directed
is the reagenttowards the for
of choice development of transition-metal-free
many transition conditions.protocols,
metal catalyzed cyanation An early
efforts have also been directed towards the development of transition-metal-free conditions. An early
example
efforts of NCTS
have also for cyanation
been directed under metal-free
towards the conditions
development of was reported by the groups
transition-metal-free of Beller
conditions. and
An early
example of NCTS for cyanation under metal-free conditions was reported by the groups of Beller and
Wang
example [4,63]. Beller
of NCTS and colleagues employed NCTS in the direct cyanation of aryl and heteroaryl-
Wang [4,63]. Bellerfor
andcyanation under
colleagues metal-free
employed NCTS conditions was cyanation
in the direct reported by of the
arylgroups of Beller
and heteroaryl-
halides
and via in[4,63].
Wang situ generated Grignard
Beller and reagents,
colleagues to synthesize
employed NCTSa diverse
in thearray of benzonitrile
direct cyanation ofderivatives.
aryl and
halides via in situ generated Grignard reagents, to synthesize a diverse array of benzonitrile derivatives.
Meanwhile the
heteroaryl-halides Wang group
via in demonstrated
situ generated the
Grignard applicability of NCTS
reagents, to synthesize for the site-selective
a diverse cyanation
array of benzonitrile
Meanwhile the Wang group demonstrated the applicability of NCTS for the site-selective cyanation
of indoles and pyrroles under Lewis acid catalysis.
of indoles and pyrroles under Lewis acid catalysis.
In 2016 Minakata et al. reported the cyanation of boron enolates 141 with NCTS [64]. Inspired
by synthesizing β-ketonitriles 142, which are important building blocks in the synthesis of different
heterocycles (pyrazoles, pyrimidines, thiophenes), Minakata planned to intercept the electrophilic
nitrile (NCTS) with an enolate. Boron enolates were derived from either the ketone 137 or the
α,β-unsaturated ketone 138 and the resulting enolate 141 was reacted with NCTS under milder reaction
Molecules 2017, 22, 615 18 of 28
derivatives. Meanwhile the Wang group demonstrated the applicability of NCTS for the site-selective
cyanation of indoles and pyrroles under Lewis acid catalysis.
α,β-unsaturated ketone 138 and the resulting enolate 141 was reacted with NCTS under milder
Molecules 2017, 22, 615 18 of 27
reaction conditions. Even though the mechanistic aspect of the reaction is yet not fully resolved,
the pathway
is believed toisbebelieved
initiatedtoby
bethe
initiated by the
activation activation
of NCTS of NCTS via to
via coordination coordination to theboron
the Lewis acidic Lewiscenter.
acidic
boron center. This coordination is also assumed to enhance the nucleophilicity of the boron-enolate,
This coordination is also assumed to enhance the nucleophilicity of the boron-enolate, promoting the
promoting
cyanation. A the cyanation.
diverse rangeAofdiverse range of
β-ketonitriles synthesizedwere
β-ketonitriles
were synthesized
through through
this protocol this protocol
exhibiting ample
exhibiting ample scope for
scope for substrates (Scheme 27).substrates (Scheme 27).
Scheme 27.
Scheme 27. Metal free cyanation
Metal free cyanation of
of boronenolates.
boronenolates.
3.3. Cyanamides
3.3. Cyanamides in
in Radical
Radical Reactions
Reactions
Cyanamide-based radical
Cyanamide-based radical cascade
cascade reactions
reactions are emerging as
are emerging as an
an important
important tooltool to
to access
access
nitrogen-containing polycyclic frameworks. These compounds are key intermediates
nitrogen-containing polycyclic frameworks. These compounds are key intermediates in heterocyclic in heterocyclic
natural products.
natural products. TheTheradical cascade
radical cascadereactions allow
reactions rapid
allow access
rapid to complex
access to complexcores,cores,
initiated with
initiated
simple starting materials, while maintaining not only atom- and step-economy, but
with simple starting materials, while maintaining not only atom- and step-economy, but also highalso high stereo-
selectivity. The seminal
stereo-selectivity. work in
The seminal this in
work area
thiswas reported
area by Fensterbank
was reported et al [65,66].
by Fensterbank et al [65,66].
Extending their previously reported radical cascade reactions of N-acyl-cyanamides to generate
guanidine derivatives, Fensterbank et al. achieved the syntheses of two natural products;
deoxyvasicinone (143) and mackinazolinone (144). The group also synthesized two guanidine
analogues, α-methyldeoxyvasicinone (145) and α,α’-dimethyldeoxyvasicinone (146) [67]. The 5,6,6-and
6,6,6-tricyclic guanidine derivatives were successfully synthesized in good yields by reacting
N-acylcyanamide with Bu3 SnH and AIBN in benzene under reflux conditions (Scheme 28). This protocol
was not only effective with the previously reported aminyl- and vinyl-radicals, but also compatible with
alkyl-radicals. Alkyl substituted N-acylcyanamides were cyclized in both 5- and 6-exo-dig pathways,
although the 6-exo-dig cyclization was comparatively slower. Attempts to achieve tin-free reaction
conditions with (TMS)3 SiH resulted in substantially lower yields. The mechanism of the reaction was
postulated to proceed with the formation of an alkyl radical via the abstraction of phenyl-selenide
by a tributyltin-radical. The resulting alkyl-radical undergoes 5- or 6-exo-dig cyclization, forming the
amide-iminyl-radical, which itself undergoes a final rearomatization–cyclization through β-hydrogen
abstraction by AIBN (Scheme 29).
Scheme 28. Radical reaction of N-acyl-cyanamides for the synthesis of guanidine based natural products.

3.3. Cyanamides in Radical Reactions
Cyanamide-based radical cascade reactions are emerging as an important tool to access
nitrogen-containing polycyclic frameworks. These compounds are key intermediates in heterocyclic
natural products. The radical cascade reactions allow rapid access to complex cores, initiated with
simple starting
Molecules materials, while maintaining not only atom- and step-economy, but also high stereo-
2017, 22, 615 19 of 28
selectivity. The seminal work in this area was reported by Fensterbank et al [65,66].
Molecules 2017, 22, 615 19 of 27
was not only effective with the previously reported aminyl- and vinyl-radicals, but also compatible
with alkyl-radicals. Alkyl substituted N-acylcyanamides were cyclized in both 5- and 6-exo-dig
pathways, although the 6-exo-dig cyclization was comparatively slower. Attempts to achieve tin-free
reaction conditions with (TMS)3SiH resulted in substantially lower yields. The mechanism of the
reaction was postulated to proceed with the formation of an alkyl radical via the abstraction of
phenyl-selenide by a tributyltin-radical. The resulting alkyl-radical undergoes 5- or 6-exo-dig
cyclization, forming the amide-iminyl-radical, which itself undergoes a final rearomatization–cyclization
Scheme
Scheme 28.
28. Radical reaction
reaction of
of N-acyl-cyanamides
Radical abstraction N-acyl-cyanamides for the
the synthesis
for29). of guanidine
synthesis of guanidine based
based natural
natural products.
products.
through β-hydrogen by AIBN (Scheme
guanidine derivatives, Fensterbank et al. achieved the syntheses of two natural products;
deoxyvasicinone (143) and mackinazolinone (144). The group also synthesized two guanidine
analogues, α-methyldeoxyvasicinone (145) and α,α’-dimethyldeoxyvasicinone (146) [67]. The 5,6,6-
and 6,6,6-tricyclic guanidine derivatives were successfully synthesized in good yields by reacting
N-acylcyanamide with Bu3SnH and AIBN in benzene under reflux conditions (Scheme 28). This protocol
Scheme 29. Proposed mechanism for the radical cascade involving N-acyl-cyanamide to generate
Scheme 29. Proposed mechanism for the radical cascade involving N-acyl-cyanamide to generate
guanidine derivatives.
guanidine derivatives.
Cui and co-workers applied a radical cascade cyclization protocol to construct dihydroisoquinolinone
Cui and co-workers
and 4-quinazolinone applied
cores 152 and a methodology
153. The radical cascade
involvedcyclization protocolphosphorylation/
a silver(I) mediated to construct
dihydroisoquinolinone and 4-quinazolinone cores 152 and 153. The
cyclization radical cascade of N-acyl-cyanamide alkenes [68]. A wide range of phosphorous methodology involved
a silver(I) mediated phosphorylation/cyclization radical cascade of N-acyl-cyanamide
quinazolinone derivatives were achieved in good yields by reacting N-acyl-cyanamide alkenes [68]. alkenes 151
A wide range of phosphorous quinazolinone derivatives were achieved in good yields
(1 equiv.) and diphenylphosphine oxide (154, 2 equiv.) in the presence of AgNO3 (1 equiv.) in CH3CN. by reacting
N-acyl-cyanamide
Following alkenes 151
this protocol, the (1para-substituted
equiv.) and diphenylphosphine oxide (154, delivered
N-acylcyanamidebutenes 2 equiv.) inphosphorous
the presence
of AgNO3 (1 equiv.)
4-quinolinones in CH3 CN. to
in moderate Following thisyields,
excellent protocol, the para-substituted
while exhibiting a broad N-acylcyanamidebutenes
functional group
compatibility (Scheme 30). When meta-substituted cyanamides were subjected to theexhibiting
delivered phosphorous 4-quinolinones in moderate to excellent yields, while reaction, a amixture
broad
functional group compatibility (Scheme 30). When meta-substituted cyanamides were
of regioisomeric phosphorous 4-quinolinones resulted. The protocol was also amenable for heterocyclic subjected to
the reaction,
moieties sucha mixture
as indoles of regioisomeric
and pyrazoles. phosphorous 4-quinolinones
Di-substituted alkenes were resulted. The protocol
more effective was also
compared to
amenable for heterocyclic moieties such as indoles and pyrazoles. Di-substituted alkenes
mono-substituted alkenes, which can be attributed to the stabilization of the in situ generated alkyl- were more
effectiveintermediate.
radical compared to mono-substituted alkenes, which can be attributed to the stabilization of the in
situ generated alkyl-radical
Interestingly, the reactionintermediate.
of unactivated cyclic internal alkenes resulted in a range of spirocyclic
compounds. Dihydroquinolinones were obtained in moderate to good yields when N-acylcyanamide-
propenes was subjected to cyclization protocol. The feasibility of both phosphonates and phosphine
oxides substrates were investigated with positive outcomes. The phosphonate addition was
particularly attractive as it gave access to the phosphonic acid derivatives. The authors reported that
the addition of a radical scavenger resulted in the quenching of the reaction, which is indicative of a
Molecules 2017, 22, 615 20 of 28
Molecules 2017, 22, 615 20 of 27
Molecules 2017, 22, 615 20 of 27
Scheme 30. Phosphorylation/cyclization radical cascade of N-acyl cyanamide alkenes.

Goswami et al. disclosed a metal and base free protocol for chemo-selective generation of primary
Interestingly, the reaction
amines via ipso-amination of unactivated
of substituted boronic cyclic internal
acids using alkenes
cyanamide resulted
radicals in a range of
as the aminating
agentcompounds.
spirocyclic [69]. They envisaged that radical transfer were
Dihydroquinolinones to the aryl cyanamides
obtained occurred via
in moderate to succinimidyl-
good yields when
radicals, which itself was
N-acylcyanamide-propenes generated
was subjectedin situ by the actionprotocol.
to cyclization of a hypervalent iodine derivatives
The feasibility of both such as
phosphonates
phenyliodine-bis(trifluoroacetate) (PIFA) (Scheme 31).
and phosphine oxides substrates were investigated with positive outcomes. The phosphonate
Subsequently the cyanamide-radicals reacted with boronic acid derivatives via the nitrile nitrogen
additionatom
wastoparticularly
give the primaryattractive as it gave
amine products. Theaccess
protocolto the
was phosphonic
highly effectiveacid
withderivatives.
both aliphaticThe
andauthors
reported that the
aromatic addition
boronic acids of
andacould
radical scavenger
tolerate a varietyresulted in the
of functional quenching
groups. of theofreaction,
The likelihood a radical which
pathway
is indicative of was confirmed
a radical by the addition
pathway of radical scavengers
being involved. to the reaction
The reaction medium.
is initiated with the formation of
a diphenyl-phosphine-oxide-radical
Goswami et al. disclosed a metal andand
155 baseits subsequent
free protocol for trapping by the
chemo-selective olefin toofform
generation the alkyl
primary
radicalamines via ipso-amination
156. This of substitutedcascade
undergoes a subsequent boronicreaction
acids using
withcyanamide radicalsnitrile
the cyanamide as theto
aminating
offer the final
agent
cyclized [69]. They
product 153 envisaged
(Scheme 30). that radical transfer to the aryl cyanamides occurred via succinimidyl-
radicals, which itself was generated
Goswami et al. disclosed a metal in situ
andbybase
the action of a hypervalent
free protocol iodine derivativesgeneration
for chemo-selective such as of
phenyliodine-bis(trifluoroacetate) (PIFA) (Scheme 31).
primary amines via ipso-amination of substituted boronic acids using cyanamide radicals as the
aminating
atom toagent
give [69].
the Theyamine
primary envisaged that
products. Theradical transfer to the aryl with
cyanamides occurred
and via
Scheme 31. Synthesis of primary amines byprotocol was
reaction of highly effective
cyanamide-radical bothacids.
with boronic aliphatic
succinimidyl-radicals,
aromatic boronic acids which itself tolerate
and could was generated
a variety ofinfunctional
situ by groups.
the action of a hypervalent
The likelihood of a radicaliodine
derivatives
pathway such
wasasconfirmed
phenyliodine-bis(trifluoroacetate)
3.4. Coordination Chemistry
by of Cyanamides
the (PIFA) (Scheme
addition of radical scavengers 31). medium.
to the reaction
The organometallic complexes of cyanamide find application in materials sciences and more
recently in the biological sciences [70,71]. Substituted cyanamides offer multiple coordination sites:
(i) end on σ-bonding via the nitrile nitrogen (ii) side on π-bond via the nitrile group (iii) via the amine
nitrogen and (iv) via the aromatic π-system in the aryl-substituted cyanamides. The coordination
mode and strength of cyanamide bonding depends hugely on their steric and electronic properties;
i.e., the number and kind of N-substitution; for example the monoalkyl- and dialkylcyanamides have
increased electron density on the NCN system, whereas the aryl-substituted cyanamides offer
Scheme 31. Synthesis of primary amines by reaction of cyanamide-radical with boronic acids.
extended
Scheme 31. π-conjugation
Synthesis ofinto the aromatic
primary amines ring. This provides
by reaction an energetically
of cyanamide-radical favourable
with means
boronic acids.
through which a metal ion can couple into a conjugated organic π-system.
3.4. Coordination Chemistry of Cyanamides
In addition, the mono-substituted cyanamides, such as phenylcyanamide (PhNHCN) are known
The organometallic
to participate complexes
as coordinating ligandsofincyanamide find as
neutral as well application in materials
anionic cyanamido formsciences
([PNCN]and more
−) [72].
atom to
recently in the biological sciences [70,71]. Substituted cyanamides offer multiple coordination sites: and
give the primary amine products. The protocol was highly effective with both aliphatic
aromatic boronic
(i) end acids and
on σ-bonding could
via the tolerate
nitrile nitrogena variety of π-bond
(ii) side on functional groups.
via the The likelihood
nitrile group of a radical
(iii) via the amine
pathway was confirmed
nitrogen and (iv) viabythethe addition
aromatic of radical
π-system in thescavengers to thecyanamides.
aryl-substituted reaction medium.
The coordination
3.4. Coordination
i.e., the numberChemistry
and kind ofof
Cyanamides
N-substitution; for example the monoalkyl- and dialkylcyanamides have
increased electron density on the NCN system, whereas the aryl-substituted cyanamides offer
The organometallic complexes of cyanamide find application in materials sciences and more
extended π-conjugation into the aromatic ring. This provides an energetically favourable means
recently in thewhich
through biological
a metalsciences [70,71].
ion can couple intoSubstituted
a conjugatedcyanamides offer multiple coordination sites:
organic π-system.
In addition, the mono-substituted cyanamides, such as phenylcyanamide (PhNHCN) are known
to participate as coordinating ligands in neutral as well as anionic cyanamido form ([PNCN]−) [72].
Molecules 2017, 22, 615 21 of 28
(i) end on σ-bonding via the nitrile nitrogen (ii) side on π-bond via the nitrile group (iii) via the amine
nitrogen and (iv) via the aromatic π-system in the aryl-substituted cyanamides. The coordination
i.e., the number and kind of N-substitution; for example the monoalkyl- and dialkylcyanamides have
increased electron density on the NCN system, whereas the aryl-substituted cyanamides offer extended
π-conjugation into the aromatic ring. This provides an energetically favourable means through which
Molecules 2017, 22, 615 21 of 27
a metal ion can couple into a conjugated organic π-system.
In addition, the mono-substituted
The coordination chemistry of cyanamides,
alkylcyanamide, such as phenylcyanamide
arylcyanamide (PhNHCN)
and dicyanamides has are
beenknown
to participate as coordinating ligands in neutral as well as anionic cyanamido form ([PNCN] − ) [72].
previously covered in a number of excellent reviews [73,74]. The present section will provide an
The coordination
overview chemistry
on the application of alkylcyanamide,
of substituted cyanamide in arylcyanamide and dicyanamides
coordination chemistry has been
via a few selected
representative
previously covered examples from theof
in a number recent literature.
excellent A more
reviews detailedThe
[73,74]. discussion
presentis beyond
sectionthe scope
will provide
of this article.
an overview on the application of substituted cyanamide in coordination chemistry via a few selected
representative examples from the recent literature. A more detailed discussion is beyond the scope of
3.4.1. Dialkyl-Cyanamide Complexes
this article.
Albertin et al. initiated a program to study the behavior of amino substituted nitriles, such as
3.4.1.cyanamides
Dialkyl-Cyanamide Complexesand their coordination chemistry with metals like iron, ruthenium
and cyanaoguanidines,
and osmium [75,76]. The bivalent metallic bis-cyanamide complex of iron 161 was obtained by mixing
Albertin et al. initiated a program to study the behavior of amino substituted nitriles, such as
FeCl2 with P(OEt)3 and then treating with dialkyl-cyanamide followed by addition of an excess of
cyanamides and cyanaoguanidines,
NaBPh4 (Scheme and their
32A). The corresponding coordination
osmium chemistry withcomplexes
and ruthenium-derived metals like iron,
162a andruthenium
162b
and osmium [75,76]. The bivalent metallic bis-cyanamide complex of iron 161 was
were obtained by treating the corresponding metal hydride (MH2L4) with one equivalent of HOTf obtained by or
mixing
FeClMeOTf
2 with P(OEt)
followed 3 and then treating
by addition withofdialkyl-cyanamide
of excess followed
dialkylcyanamide (Scheme by addition
32B). The authorsof an excess of
further
NaBPh 4 (Scheme
studied the 32A).
reaction The
of corresponding
these complexes osmium
with and ruthenium-derived
nucleophilic hydrazine. The complexes
reactions, in 162a
each and
case, 162b
wereproduced
obtainedaby solid product
treating characterized
the as hydrazinecarboximidamide
corresponding metal hydride (MH2 L4 )complex
with one 164. The reaction
equivalent ofwas
HOTf or
MeOTf proposed
followed to by
proceed via of
addition theexcess
displacement of a cyanamide
of dialkylcyanamide ligand 32B).
(Scheme with The
hydrazine
authors followed
further by
studied
intramolecular nucleophilic attack on the neighboring nitrile carbon by the
the reaction of these complexes with nucleophilic hydrazine. The reactions, in each case, second amino group of
produced
hydrazine leading to the five membered azametallocycle (Scheme 32C).
a solid product characterized as hydrazinecarboximidamide complex 164. The reaction was proposed
In comparison the reaction of the iron triad with aliphatic amines like iPrNH2 and nPrNH2 led to the
to proceed via the displacement of a cyanamide ligand with hydrazine followed by intramolecular
mono-substituted mixed ligand product only with no observed nucleophilic attack on the cyanamide
nucleophilic
nitrile. Noattack
mixedon the neighboring
ligand nitrile carbon
product was observed by the second
upon reaction with theamino group ofaromatic
corresponding hydrazine leading
amine
to theand
five
NH membered
3. azametallocycle (Scheme 32C).
Scheme
Scheme 32.32.Reaction
Reactionof
of amines
amines with
withcyanamide
cyanamidemetal
metalcomplex.
complex.
Recently Bokach et al. reported the synthesis of two Co(II) (dimethylcyanamide) complexes
along with the structural details of their dihydrate complexes trans-[Co(H2O)4(NCNMe2)2]X2·2H2O [77].
A key feature of the X-ray crystal structure was the hydrogen bonding of the counter anion and the
ligated water of crystallization. They studied the effect of both chloride and bromide counter ions
Molecules 2017, 22, 615 22 of 28
In comparison the reaction of the iron triad with aliphatic amines like i PrNH2 and n PrNH2 led
to the mono-substituted mixed ligand product only with no observed nucleophilic attack on the
cyanamide nitrile. No mixed ligand product was observed upon reaction with the corresponding
aromatic amine and NH3 .
Recently Bokach et al. reported the synthesis of two Co(II) (dimethylcyanamide) complexes along
with the structural details of their dihydrate complexes trans-[Co(H2 O)4 (NCNMe2 )2 ]X2 ·2H2 O [77].
A key feature of the X-ray crystal structure was the hydrogen bonding of the counter anion and
the ligated water of crystallization. They studied the effect of both chloride and bromide counter
ions and associated water molecules on the 3D network of hydrogen bonding, and rationalized the
differences observed based on the electronic differences primarily between the counter ions in terms of
electrostatics but also depending on the metal center size and electronegativity.
3.4.2. Aryl Cyanamide Complexes

The electronic properties of substituted cyanamides are known to play a crucial role as a bridging
ligand for metal-metal coupling in dinuclear complexes, which directly affects their magnetic
properties [78]. In 2013 Crutchley et al. synthesized a series of nine mononuclear [Ru(Tp)(dppe)L]
complexes, (where L is a substituted phenylcyanamide ligand, Tp is hydrotris(pyrazol-1-yl)-borate, dppe
is 1,2-bis[(diphenyl-phosphino)ethane) and a dinuclear complex [{Ru(trpy)(bpy)}2 (µ-adpc)]2+ , (where
trpy is 2,20 :60 ,200 -terpyridine, and bpy is 2,20 -bipyridine and adpc2− is azo-4,40 -diphenylcyanamide),
of ruthenium with substituted phenylcyanamide ligands [79]. The crystal structure of [Ru(Tp)(dppe)
(Cl5 pcyd)] and [{Ru(Tp)(dppe)}2 (µ-adpc)] revealed that the cyanamide coordinates to the ruthenium(II)
through the terminal nitrogen. Significant conjugation between the cyanamide and phenyl ring was
predicted, given the planarity of the cyanamide group in the complex.
A mixed valence complex was observed for these complexes upon oxidation, which showed
strong π-interactions between Ru(III) and the cyanamide group, operating through the super exchange
mechanism. The authors also investigated the effect of disrupting the strong π-interactions through
a scorpionate ligand, which possesses strong π-donor properties via the anionic coordination mode
and weakens the inter-metal coupling. This allowed an overall charge reduction, whilst retaining the
properties of the original mixed-valence complex.
The Chiniforoshan group have been investigating coordination complexes of a range
of transition metal with cyanamide derivative ligands and their possible medicinal activity.
The group recently reported the synthesis and characterization of Ni(II) and Cd(II) complexes
with 4-nitrophenylcyanamido ligands [80,81]. More recently the group reported the synthesis and
biological activities of the polymeric coordination complexes of mercury(II), with the anions of
a number of arylcyanamides [82]. The complexes were obtained via deprotonation of the relevant
arylcyanamide with NaOH, followed by mixing the arylcyanamide anion with Hg(NO3 )2 ·H2 O in
acetone at reflux temperature.
The structural analysis of the solid products revealed that the cyanamide ligand is coordinated
through the amine nitrogen, which is relatively rare. The nitrile coordination mode was observed, but
was thermodynamically less favorable than the amine isomer. Analysis also revealed that the anion of
the acetone, the reaction solvent, was present as a bridging ligand connecting two mercury ions through
the carbon atom of one and carbonyl oxygen (C=O) atom of another acetone anion. Antimicrobial
assays indicated some inhibition to bacterial growth, but there was no overall improvement when
compared the free ligand itself (Figure 1).
The group also reported the synthesis of trimethyltin(IV) complexes with 4-nitrophenylcyanamide
and a biphenyl derivative of cyanamide ligand [83]. The complexes were obtained by mixing
the trialkyl-tin with the ligand in an alkali medium (NaOH), and irradiating the mixture under
high-intensity ultrasound. In these complexes the cyanamide coordinates to the metal through the
nitrile nitrogen; the biphenyl derivative was found to bridge between two trimethyltin metal centers
(Figure 2). All compounds showed some activity in the antimicrobial/antifungal assay, but did not
coordination complexes of mercury(II), with the anions of a number of arylcyanamides [82]. The
complexes were obtained via deprotonation of the relevant arylcyanamide with NaOH, followed by
mixing the arylcyanamide anion with Hg(NO3)2·H2O in acetone at reflux temperature.
The structural analysis of the solid products revealed that the cyanamide ligand is coordinated
through the amine nitrogen, which is relatively rare. The nitrile coordination mode was observed,
Molecules 2017, 22, 615 23 of 28
but was thermodynamically less favorable than the amine isomer. Analysis also revealed that the
anion of the acetone, the reaction solvent, was present as a bridging ligand connecting two mercury
exceed the efficacy
ions through of ciprofloxacin
the carbon atom of oneor fluconazole
and carbonyl foroxygen
antimicrobial
(C=O) or antifungal
atom of anotheractivity. However,
acetone anion.
the cytotoxic activity of these compounds were impressive against the HeLa cell line.
Antimicrobial assays indicated some inhibition to bacterial growth, but there was no overall Both complexes
had similar efficacy
improvement whenin causing cell
compared the death in theitself
free ligand MTT(Figure 1). this was comparable to cis-platin.
assay, and
Molecules 2017, 22, 615 23 of 27
nitrile nitrogen; the biphenyl derivative was found to bridge between two trimethyltin metal centers
(Figure 2). All compounds showed some activity in the antimicrobial/antifungal assay, but did not
exceed the efficacy of ciprofloxacin or fluconazole for antimicrobial or antifungal activity. However,
the cytotoxic activity of these compounds were impressive against the HeLa cell line. Both complexes
had similarFigure 1. Ain
efficacy schematic
causingrepresentation of Mercury
cell death in the basedand
MTT assay, polymeric coordination
coordination
this was comparablecomplex.
complex.
to cis-platin.
The group also reported the synthesis of trimethyltin(IV) complexes with 4-nitrophenylcyanamide
and a biphenyl derivative of cyanamide ligand [83]. The complexes were obtained by mixing the
trialkyl-tin with the ligand in an alkali medium (NaOH), and irradiating the mixture under
high-intensity ultrasound. In these complexes the cyanamide coordinates to the metal through the
Figure
Figure 2.
2. Structure
Structure of
of trimethyltin
trimethyltin derivatives.
derivatives.
Recently, Chiniforoshan et al. synthesized three mononuclear complexes of nickel(II) with 4-

Recently, Chiniforoshan et al. synthesized three mononuclear complexes of nickel(II) with
nitrophenyl-cyanamide and their antimicrobial and cytotoxic properties were investigated [71]. The
4-nitrophenyl-cyanamide and their antimicrobial and cytotoxic properties were investigated [71].
three complexes [Ni(HIm)4(4-NO2pcyd)2]·CH3OH, [Ni(bpy)2(4-NO2pcyd)2]·CH3CH2OH, and [Ni(phen)2
The three complexes [Ni(HIm) (4-NO2 pcyd)2 ]·CH3 OH, [Ni(bpy)2 (4-NO2 pcyd)2 ]·CH3 CH2 OH,
(4-NO2pcyd)2]·CH3OH were readily4 obtained by the reaction of 4-nitrophenylcyanamide ligand with
and [Ni(phen)2 (4-NO2 pcyd)2 ]·CH3 OH were readily obtained by the reaction of 4-nitrophenylcyanamide
Ni(OAc)2·4H2O in the presence of 1,10-phenanthroline (phen), 2,20-bipyridine (bpy), imidazole (HIm)
ligand with Ni(OAc)2 ·4H2 O in the presence of 1,10-phenanthroline (phen), 2,20-bipyridine (bpy),
respectively. X-ray crystallographic studies of the complexes 168 and 169 revealed that in each case,
imidazole (HIm) respectively. X-ray crystallographic studies of the complexes 168 and 169 revealed
the cyanamide ligand is coordinated via the terminal nitrile nitrogen rather than the sterically
that in each case, the cyanamide ligand is coordinated via the terminal nitrile nitrogen rather than the
hindered amine nitrogen (Figure 3). The observed bond angles and bond distances between the
sterically hindered amine nitrogen (Figure 3). The observed bond angles and bond distances between
metal-ligand and those of N–C–N of the cyanamide ligand suggested that the coordination mode of
the metal-ligand and those of N–C–N of the cyanamide ligand suggested that the coordination mode of
the cyanamide group to Ni(II) ion is approximately linear. This finding helps to confirm the extended
conjugation of the cyanamide π-electrons into the aromatic ring and thereby the ability of the Ni(II)
conjugation of the cyanamide π-electrons into the aromatic ring and thereby the ability of the Ni(II) to
to accept π-density into a filled dπ orbital. The authors further conducted biological studies and tested
accept π-density into a filled dπ orbital. The authors further conducted biological studies and tested the
the cytotoxicity and antimicrobial potential of these complexes.
cytotoxicity and antimicrobial potential of these complexes.
Efficacy was shown by all of the complexes against human lung adenocarcinoma (A549), prostate
(Du145), epithelial carcinoma (HeLa) and breast cancer (MCF-7) cell lines. When compared to
cis-platin, higher or equal efficacy was shown by all compounds against Du145 and HeLa cell
lines. This suggests that the compounds may be more effective against prostate and cervical cancers
respectively. The compounds also had some antibacterial and antifungal activities.
Figure 3. Representative drawing of nickel cyanamide complexes.
hindered amine nitrogen (Figure 3). The observed bond angles and bond distances between the
metal-ligand and those of N–C–N of the cyanamide ligand suggested that the coordination mode of
conjugation of the cyanamide π-electrons into the aromatic ring and thereby the ability of the Ni(II)
to accept2017,
Molecules π-density
22, 615 into a filled dπ orbital. The authors further conducted biological studies and 24
tested
of 28
the cytotoxicity and antimicrobial potential of these complexes.
Figure 3. Representative
Figure 3. Representative drawing of nickel
drawing of nickel cyanamide
cyanamide complexes.
complexes.
4. Conclusions
(Du145), epithelial carcinoma (HeLa) and breast cancer (MCF-7) cell lines. When compared to
Since higher
cis-platin, the early reported
or equal use of
efficacy wascyanamides,
shown by allthecompounds
applicationagainst
of thisDu145
uniqueandfunctional moiety
HeLa cell lines.
have diversified hugely, further enriching the field of amino-substituted nitrile chemistry.
This suggests that the compounds may be more effective against prostate and cervical cancers Here we
have presented
respectively. Thea compounds
selection of recent synthetic
also had methodologies
some antibacterial and developed to access this special group
antifungal activities.
of compounds, along with selected examples of the diverse synthetic applications. The number of
reports in the recent years on substituted cyanamide aptly demonstrate the interest that this moiety
has generated among synthetic chemists world-over. These new advances in cyanamide chemistry
will no doubt attract further studies, thereby widening the applications in the relatively unchartered
areas at the interface of chemistry, biology and material science.
Acknowledgments: We wish to thank University of Lincoln, UK for PhD funding to L.W and S.V.B. and EPSRC
(Grant No EP/N00969X/1) for financial support to M.R.R.P. and P.S. The authors would also like to thank
John E. Moses, La Trobe Institute for Molecular Science, Australia, for helpful discussion and constructive
feedback on our manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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Academic Editor: Margaret A. Brimble

Keywords: cyanamide; synthesis; aminocyanation; cycloaddition; electrophilic cyanation; radical

2. Synthesis of Mono and Disubstituted Cyanamides

Molecules 2017, 22, 615; doi:10.3390/molecules22040615 www.mdpi.com/journal/molecules

Scheme 1. In situ generation of CNCl for cyanation.

Alcarazo and co-workers have developed the thiocyanoimidazolium salt 5 as an electrophilic

Scheme 2. Thiocyanoimidazolium salts for electrophilic cyanation.

Molecules 2017, 22, 615 3 of 27

2.1.2. Under Copper CatalysisScheme 3. Trichloroacetonitrile for cyanation.

Scheme 4. Copper catalyzed cyanation of secondary amines.

Scheme 4. Copper catalyzed cyanation of secondary amines.

Molecules 2017, 22, 615 4 of 27

Molecules 2017, 22, 615 5 of 28

Scheme 6. Conversion of guanidoximes to monosubstituted cyanamide.

Scheme 6. Conversion of guanidoximes to monosubstituted cyanamide.

Scheme 7. Amidoximes to substituted cyanamides.

Scheme 9. Synthesis of disubstituted cyanamide by the cycloaddition of azide with isoselenocyanate.

Kukushkhin et al. applied a gold catalyzed heterocyclization of alkynes with substituted

AAA cycloaddition protocolfor

Scheme 11. 1,2,4-Oxadiazoles synthesis from cyanamides.

Molecules 2017, 22, 615 8 of 27

Scheme 12. 1,2,4-oxadizole-5-imines synthesis from cyanamides.

Scheme 13. Metal catalyzed [2 + 2 + 2] cycloaddition reactions of cyanamides.

3.2. N-CN Bond Cleavage

Molecules 2017, 22, 615 10 of 27

Scheme 15. Copper catalyzed intramolecular aminocyanation.

Molecules 2017, 22, 615 11 of 27

Molecules 2017, 22, 615 11 of 27

Scheme 17. Aminocyanation of arynes.

Scheme 18. Cyanamide as aminating agent.

Molecules 2017, 22, 615 12 of 27

Molecules 2017, 22, 615 14 of 27

Scheme 21. Cobalt catalyzed electrophilic cyanation with NCTS.

Scheme 22. Ruthenium catalyzed electrophilic cyanation with NCTS.

Scheme 24. Copper-catalyzed

Exploring the simultaneous

Scheme 25. Copper catalytic cycle for C–H cyanation.

Scheme 26. Palladium-catalyzed electrophilic cyanation with NCTS.

Extending their previously reported radical cascade reactions of N-acyl-cyanamides to generate

Molecules 2017, 22, 615 19 of 27

Molecules 2017, 22, 615 20 of 27

Scheme 30. Phosphorylation/cyclization radical cascade of N-acyl cyanamide alkenes.

3.4.2. Aryl Cyanamide Complexes

Molecules 2017, 22, 615 23 of 27

Recently, Chiniforoshan et al. synthesized three mononuclear complexes of nickel(II) with 4-

Figure 3. Representative drawing of nickel cyanamide complexes.

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