Ci a ion: He e o, M.T.; Díaz de
Sa alde, J.; Conde, N.; He án, A.;
U goi ia, G.; SanMa in, R.
Me al-Ca alyzed Cascade Reac ions
be ween Alkynoic Acids and
Dinucleophiles: A Re iew. Ca alys s
2023,13, 495. h ps://doi.o g/
10.3390/ca al13030495
Academic Edi o s: Vic o io Cadie no
and Ra aella Mancuso
Recei ed: 30 Janua y 2023
Re ised: 25 Feb ua y 2023
Accep ed: 25 Feb ua y 2023
Published: 28 Feb ua y 2023
Copy igh : © 2023 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
ca alys s
Re iew
Me al-Ca alyzed Cascade Reac ions be ween Alkynoic Acids
and Dinucleophiles: A Re iew
Ma ía Te esa He e o, Jokin Díaz de Sa alde, Ne ea Conde, Ai o He án, Ga azi U goi ia and Raul SanMa in *
Depa men o O ganic and Ino ganic Chemis y, Facul y o Science and Technology, Uni e si y o he Basque
Coun y (UPV/EHU), Sa iena Auzoa, z/g, 48940 Leioa, Spain
*Co espondence: [email p o ec ed]
Abs ac :
Cascade eac ions p o ide a s aigh o wa d access o many aluable compounds and
educe conside ably he numbe o s eps o a syn he ic sequence. Among he domino and mul i-
componen p ocesses ha in ol e alkynes, he cascade eac ion be ween alkynoic acids and C-, N-,
O- and S-aminonucleophiles s ands ou as a pa icula ly powe ul ool o he one-po cons uc ion
o lib a ies o ni ogen-con aining he e ocyclic compounds wi h sca old di e si y and molecula
complexi y. This eac ion, based on an ini ial me al-ca alyzed cycloisome iza ion ha gene a es an
alkylidene lac one in e media e, was o iginally ca alyzed by gold(I) ca alys s, along wi h sil e sal s
o B öns ed acid addi i es, bu o he al e na i e me al ca alys s ha e eme ged in he las decade as
well as di e en eac ion media. This e iew examines he exis ing li e a u e on he opic o me al-
ca alyzed cascade eac ions o ace ylenic acids and dinucleophiles and discusses aspec s conce ning
subs a e/ca alys a io o e e y ca alys sys em, na u e o he aminonucleophile in ol ed and
subs a e scope. In addi ion, al e na i e sol en s a e also conside ed, and an insigh in o he pa hway
o he eac ion and possible in e media es is also p o ided.
Keywo ds: cascade eac ions; domino p ocesses; me al ca alys s; cycloisome iza ion
1. In oduc ion
In con as wi h classical s epwise syn hesis o o ganic compounds, cascade-based
s a egies p o ide a much as e , and in many cases, mo e e icien app oach o an inc eas-
ingly la ge numbe o complex s uc u es [
1
–
4
]. In ac , e ms such as a om-economy
and g een chemis y a e o en associa ed wi h me al-ca alyzed cascade eac ions [
5
,
6
]. The
las decades ha e wi nessed signi ican ad ances in he ields o me al-ca alyzed hyd o-
unc ionaliza ion o alkynes [
7
–
13
], and, mo e speci ically, o cascade eac ions in ol ing
alkyne hyd o unc ionaliza ion s eps [
14
–
19
]. The in amolecula e sion o such cascade
eac ions, o en based on he p esence o sui ably loca ed ca bo- and he e onucleophiles
in he s a ing ma e ials, has been also desc ibed [
16
,
18
,
19
]. In his ega d,
π
-coo dina ion
o he C-C iple bond o a ca bophilic ansi ion me al ca alys can p omo e an ini ial
cycloisome iza ion p ocess ha becomes he key s ep o a cascade app oach o ela i ely
complex amewo ks. Among a numbe o subs a es bea ing alkyne and nucleophilic
moie ies (o-,
γ
-, o
δ
-alkynyl N-a ylni ones, amines, ca boxamides, alkenes, a enes and
he e oa enes, in e alia) [
20
–
25
], alkynoic acids s and ou o hei syn he ic po en ial, since
cycloisome iza ion o hese ace ylenic de i a i es gene a es alkylidene lac ones, which a e
p one o unde go nucleophilic a ack (Scheme 1) [26–30].
In many cases, as a esul o he abo e cascade eac ions s a ing om alkynoic
acids, analogs and isos e es o a numbe o pha macologically ele an compounds ha e
been s aigh o wa dly p epa ed. Among o he s, e ahyd o-
γ
-ca bolines (e.g., Ge o o-
line,Tubas a in A and Dimebon), iden i ied as po en immunosupp essan s and neu o-
p o ec i e agen s [
31
–
38
]; ac inophenan h olines [
39
] and quinazoline alkaloids such as
Ca alys s 2023,13, 495. h ps://doi.o g/10.3390/ca al13030495 h ps://www.mdpi.com/jou nal/ca alys s
Ca alys s 2023,13, 495 2 o 20
Vasicine (peganine), Mackinazolinone,Ba acyclin and T yp an h in ha exhibi an icance , an i-
in lamma o y, an ip o ozoal, an ialle gic, an ioxidan and an imic obial ac i i ies [
40
–
47
]
(Figu e 1).
Ca alys s 2023, 13, x 2 o 22
OH
O
OONu
Nu'
O
NuH
Nu'H
()
n
[M] ()
n
R
R
()
n
Scheme 1. An o e all pic u e o me al-ca alyzed cascade eac ion o ace ylenic acids and dinucleo-
philes.
In many cases, as a esul o he abo e cascade eac ions s a ing om alkynoic acids,
analogs and isos e es o a numbe o pha macologically ele an compounds ha e been
s aigh o wa dly p epa ed. Among o he s, e ahyd o-γ-ca bolines (e.g., Ge o oline, Tu-
bas a in A and Dimebon), iden i ied as po en immunosupp essan s and neu op o ec i e
agen s [31–38]; ac inophenan h olines [39] and quinazoline alkaloids such as Vasicine
(peganine), Mackinazolinone, Ba acyclin and T yp an h in ha exhibi an icance , an i-in-
lamma o y, an ip o ozoal, an ialle gic, an ioxidan and an imic obial ac i i ies [40–47]
(Figu e 1).
Figu e 1. S uc u e o se e al e ahyd o-γ-ca bolines, ac inophenan h olines and quinazoline alka-
loids.
The syn hesis o he la e s uc u es has been limi ed o sequences in ol ing wo o
mo e s eps, al hough, ecen ly, mo e e icien s a egies o en based on mul iple conden-
sa ions ha e been epo ed [45]. In his espec , he wo k o Sondhi and Rani on he sol-
en less condensa ion o dica boxylic acids wi h diamines unde mic owa e i adia ion
[48], he one-po oxida i e condensa ion o an h anilamides wi h 3,3-dihyd o-2H-py one
ollowed by in amolecula Mi sunobu coupling, as epo ed by Kim and Cheon [49], he
annula ion/anodic oxida ion o 2-aminobenzamides and aldehydes desc ibed by Cao e
al. [50], he educ i e condensa ion o o-ni obenzaldehydes wi h amines using i on pen-
aca bonyl as educ an ollowed by oxida ion, ecen ly disclosed by he g oup o Chuso
[51], and he eac ion o e -bu yl 2-aminobenzylca bama e and acid anhyd ides o
Scheme 1.
An o e all pic u e o me al-ca alyzed cascade eac ion o ace ylenic acids and dinucleophiles.
Ca alys s 2023, 13, x 2 o 22
OH
O
OONu
Nu'
O
NuH
Nu'H
()
n
[M] ()
n
R
R
()
n
Scheme 1. An o e all pic u e o me al-ca alyzed cascade eac ion o ace ylenic acids and dinucleo-
philes.
In many cases, as a esul o he abo e cascade eac ions s a ing om alkynoic acids,
analogs and isos e es o a numbe o pha macologically ele an compounds ha e been
s aigh o wa dly p epa ed. Among o he s, e ahyd o-γ-ca bolines (e.g., Ge o oline, Tu-
bas a in A and Dimebon), iden i ied as po en immunosupp essan s and neu op o ec i e
agen s [31–38]; ac inophenan h olines [39] and quinazoline alkaloids such as Vasicine
(peganine), Mackinazolinone, Ba acyclin and T yp an h in ha exhibi an icance , an i-in-
lamma o y, an ip o ozoal, an ialle gic, an ioxidan and an imic obial ac i i ies [40–47]
(Figu e 1).
Figu e 1. S uc u e o se e al e ahyd o-γ-ca bolines, ac inophenan h olines and quinazoline alka-
loids.
The syn hesis o he la e s uc u es has been limi ed o sequences in ol ing wo o
mo e s eps, al hough, ecen ly, mo e e icien s a egies o en based on mul iple conden-
sa ions ha e been epo ed [45]. In his espec , he wo k o Sondhi and Rani on he sol-
en less condensa ion o dica boxylic acids wi h diamines unde mic owa e i adia ion
[48], he one-po oxida i e condensa ion o an h anilamides wi h 3,3-dihyd o-2H-py one
ollowed by in amolecula Mi sunobu coupling, as epo ed by Kim and Cheon [49], he
annula ion/anodic oxida ion o 2-aminobenzamides and aldehydes desc ibed by Cao e
al. [50], he educ i e condensa ion o o-ni obenzaldehydes wi h amines using i on pen-
aca bonyl as educ an ollowed by oxida ion, ecen ly disclosed by he g oup o Chuso
[51], and he eac ion o e -bu yl 2-aminobenzylca bama e and acid anhyd ides o
Figu e 1.
S uc u e o se e al e ahyd o-
γ
-ca bolines, ac inophenan h olines and quinazoline alkaloids.
The syn hesis o he la e s uc u es has been limi ed o sequences in ol ing wo o
mo e s eps, al hough, ecen ly, mo e e icien s a egies o en based on mul iple condensa-
ions ha e been epo ed [
45
]. In his espec , he wo k o Sondhi and Rani on he sol en less
condensa ion o dica boxylic acids wi h diamines unde mic owa e i adia ion [
48
], he
one-po oxida i e condensa ion o an h anilamides wi h 3,3-dihyd o-2H-py one ollowed
by in amolecula Mi sunobu coupling, as epo ed by Kim and Cheon [
49
], he annula-
ion/anodic oxida ion o 2-aminobenzamides and aldehydes desc ibed by Cao e al. [
50
],
he educ i e condensa ion o o-ni obenzaldehydes wi h amines using i on pen aca bonyl
as educ an ollowed by oxida ion, ecen ly disclosed by he g oup o Chuso [
51
], and
he eac ion o e -bu yl 2-aminobenzylca bama e and acid anhyd ides o gene a e he
co esponding imides, which a e subsequen ly cyclized unde acidic condi ions [
52
] should
be men ioned (Scheme 2).
In o de o co e he li e a u e on cascade eac ions be ween alkynoic acids and
dinucleophiles, his e iew is o ganized acco ding o he me al ca alys used o p omo e he
a o emen ioned cycloisome iza ion and u he eac ion wi h he dinucleophile species. In
addi ion o he eac ion scope, special emphasis will be gi en o he subs a e: ca alys a io
and eac ion media, and in some cases, he mechanis ic p oposals o such ans o ma ions
will be desc ibed, along wi h se e al expe imen s pe o med o shed ligh o he ole o he
me al ca alys and o he addi i es employed.
Ca alys s 2023,13, 495 3 o 20
Ca alys s 2023, 13, x 3 o 22
gene a e he co esponding imides, which a e subsequen ly cyclized unde acidic condi-
ions [52] should be men ioned (Scheme 2).
Scheme 2. Al e na i e s a egies o he syn hesis o i- and e acyclic quinazoline and quinazoli-
none de i a i es. Sondhi, 2010: [48]; A anasye , 2020: [51]; Cao, 2018: [50]; Kshi saga , 2009: [52].
In o de o co e he li e a u e on cascade eac ions be ween alkynoic acids and di-
nucleophiles, his e iew is o ganized acco ding o he me al ca alys used o p omo e he
a o emen ioned cycloisome iza ion and u he eac ion wi h he dinucleophile species.
In addi ion o he eac ion scope, special emphasis will be gi en o he subs a e:ca alys
a io and eac ion media, and in some cases, he mechanis ic p oposals o such ans o -
ma ions will be desc ibed, along wi h se e al expe imen s pe o med o shed ligh o he
ole o he me al ca alys and o he addi i es employed.
2. Au Ca alys s
2.1. In oduc ion
Al hough some i alling candida es ha e appea ed along he way, gold-based ca a-
lys s ha e domina ed he ield om he e y beginning. In addi ion o a ela i ely low
ca alys amoun , gold ca alys s allow o he use o mos aminonucleophiles explo ed so
Scheme 2.
Al e na i e s a egies o he syn hesis o i- and e acyclic quinazoline and quinazolinone
de i a i es. Sondhi, 2010: [48]; A anasye , 2020: [51]; Cao, 2018: [50]; Kshi saga , 2009: [52].
2. Au Ca alys s
2.1. In oduc ion
Al hough some i alling candida es ha e appea ed along he way, gold-based ca alys s
ha e domina ed he ield om he e y beginning. In addi ion o a ela i ely low ca alys
amoun , gold ca alys s allow o he use o mos aminonucleophiles explo ed so a . Indeed,
his ample scope combined wi h a high e iciency ha e made gold he me al o choice
o such ans o ma ions o a long ime. In mos cases, gold(I) ca alys s we e enough o
p omo e he eac ions, al hough occasionally combina ion wi h sil e sal s o B öns ed
acids ha e led o op imized condi ions.
2.2. Ini ial Repo s
In 2007, Dixon and col. p esen ed a pionee ing wo k on he Au(I)-ca alyzed cascade
eac ion o alkynoic and 2-p opa gyloxye hanoic acids wi h 1-(2-aminoe hyl)py ole and
3-(2-aminoe hyl)indole ( yp amine) in oluene o xylene [
53
]. Good o excellen yields we e
achie ed in his AuPPh
3
Cl/AgOT -ca alyzed eac ion, and he au ho s p o ed no only he
Ca alys s 2023,13, 495 4 o 20
pa icipa ion o he alkynyl g oup as a masked ke one moie y eleased a e nucleophilic
a ack a he ini ially o med exocyclic alkylidene lac one bu also ha a Lewis acid-assis ed
B øns ed acid ca alysis is esponsible o he o ma ion o he N-acyliminium in e media e,
which is he hi d s age o he cycliza ion cascade (Scheme 3).
Ca alys s 2023, 13, x 4 o 22
a . Indeed, his ample scope combined wi h a high e iciency ha e made gold he me al
o choice o such ans o ma ions o a long ime. In mos cases, gold(I) ca alys s we e
enough o p omo e he eac ions, al hough occasionally combina ion wi h sil e sal s o
B öns ed acids ha e led o op imized condi ions.
2.2. Ini ial Repo s
In 2007, Dixon and col. p esen ed a pionee ing wo k on he Au(I)-ca alyzed cascade
eac ion o alkynoic and 2-p opa gyloxye hanoic acids wi h 1-(2-aminoe hyl)py ole and
3-(2-aminoe hyl)indole ( yp amine) in oluene o xylene [53]. Good o excellen yields
we e achie ed in his AuPPh3Cl/AgOT -ca alyzed eac ion, and he au ho s p o ed no
only he pa icipa ion o he alkynyl g oup as a masked ke one moie y eleased a e nu-
cleophilic a ack a he ini ially o med exocyclic alkylidene lac one bu also ha a Lewis
acid-assis ed B øns ed acid ca alysis is esponsible o he o ma ion o he N-acyliminium
in e media e, which is he hi d s age o he cycliza ion cascade (Scheme 3).
Scheme 3. Scope o he Au(I)-Ca alyzed Cascade and mechanis ic p oposal.
In his ega d, N-(2-(1H-py ol-1-yl)e hyl)-4-oxopen anamide, p oposed as he ke-
oamide in e media e a e he ing-opening o he ini ial alkylidene lac one wi h 1-(2-
aminoe hyl)py ole, was syn hesized and subjec ed o se e al eac ion condi ions. Al -
hough boiling in oluene o 4 days esul ed in no con e sion, when a ca aly ic amoun o
i lic acid was added, he eac ion p o ided a ge 10b-me hyl-1,5,6,10b- e ahyd odipy -
olo[1,2-a:2′,1′-c]py azin-3 (2H)-one. The esul s om hese and o he expe imen s wi h
he same subs a e in he p esence o he 2-die hylamino-1,3-dime hyl-pe hyd o-1,3,2-di-
azaphospho ine (BEMP) base and he abo e gold ca alys led he au ho s o pos ula e ha
a Lewis acid-assis ed B øns ed acid ca alysis p o ides he ac i a ion equi ed o he sec-
ond s age o he cascade. 4-Hexynoic acid was also eac ed wi h yp amine and p o ided
he co esponding he e ocycle, al hough as a mix u e o egioisome s. The same g oup
published an enan ioselec i e app oach o he p oduc s de i ed om yp amine by using
p e o med enol lac ones and (R)-BINOL phospho ic acid de i a i es as chi al B öns ed
acid ca alys s. A numbe o 5-monosubs i u ed and 4,5-disubs i u ed u an-2(3H)-ones
Scheme 3. Scope o he Au(I)-Ca alyzed Cascade and mechanis ic p oposal.
In his ega d, N-(2-(1H-py ol-1-yl)e hyl)-4-oxopen anamide, p oposed as he ke oamide
in e media ea e he ing-openingo he ini ialalkylidene lac onewi h1-(2-aminoe hyl)py ole,
was syn hesized and subjec ed o se e al eac ion condi ions. Al hough boiling in oluene o
4 days esul ed in no con e sion, when a ca aly ic amoun o i lic acid was added, he eac ion
p o ided a ge 10b-me hyl-1,5,6,10b- e ahyd odipy olo[1,2-a:2
0
,1
0
-c]py azin-3 (2H)-one. The
esul s om hese and o he expe imen s wi h he same subs a e in he p esence o he
2-die hylamino-1,3-dime hyl-pe hyd o-1,3,2-diazaphospho ine (BEMP) base and he abo e
gold ca alys led he au ho s o pos ula e ha a Lewis acid-assis ed B øns ed acid ca alysis
p o ides he ac i a ion equi ed o he second s age o he cascade. 4-Hexynoic acid was
also eac ed wi h yp amine and p o ided he co esponding he e ocycle, al hough as a
mix u e o egioisome s. The same g oup published an enan ioselec i e app oach o he
p oduc s de i ed om yp amine by using p e o med enol lac ones and (R)-BINOL phos-
pho ic acid de i a i es as chi al B öns ed acid ca alys s. A numbe o 5-monosubs i u ed
and 4,5-disubs i u ed u an-2(3H)-ones and 6-me hyl-3,4-dihyd o-2H-py an-2-one we e
eac ed wi h se e al yp amine de i a i es in he p esence o 3,3
0
-bis( iphenylsilyl)-(R)-
BINOL phospho ic acid o p o ide he co esponding indolizino[8,7-b]indol-3-ones [54].
2.3. Au-Ca alyzed Reac ion be ween Alkynoic Acids and C-, O- and N-Aminonucleophiles; Fu he
Ad ances in he Field
A la ge a ie y o py olo- and py ido[2,1-b]benzo[d][1,3]oxazin-1-ones
1
we e syn he-
sized by Liu and col. om o-aminobenzyl alcohols and 4-pen ynoic- and 5-hexynoic acids
in he p esence o a 2 mol% o [Au{P( -Bu)
2
(o-biphenyl)}{CH
3
CN}]SbF
6
. Te ahyd o u an
Ca alys s 2023,13, 495 5 o 20
(THF) was he sol en o choice when dealing wi h mos o he 4-pen ynoic acid de i a i es,
while oluene was employed o eac ions wi h 5-hexynoic acid. Rega ding he eac ion
mechanism, he au ho s p oposed ha , a e he ini ial cycloisome iza ion s ep, nucleophilic
a ack by he amino g oup gene a es a ke oamide in e media e
A
ha , upon in amolecula
condensa ion and he o ma ion o he co esponding N-acyliminium ion
B
, unde goes
nucleophilic a ack by he ca binol moie y, hus p o iding i- and e acycles
1
wi h good
yields [55] (Scheme 4).
Ca alys s 2023, 13, x 5 o 22
and 6-me hyl-3,4-dihyd o-2H-py an-2-one we e eac ed wi h se e al yp amine de i a-
i es in he p esence o 3,3′-bis( iphenylsilyl)-(R)-BINOL phospho ic acid o p o ide he
co esponding indolizino[8,7-b]indol-3-ones [54].
2.3. Au-Ca alyzed Reac ion be ween Alkynoic Acids and C-, O- and N-Aminonucleophiles;
Fu he Ad ances in he Field
A la ge a ie y o py olo- and py ido[2,1-b]benzo[d][1,3]oxazin-1-ones 1 we e syn-
hesized by Liu and col. om o-aminobenzyl alcohols and 4-pen ynoic- and 5-hexynoic
acids in he p esence o a 2 mol% o [Au{P( -Bu)2(o-biphenyl)}{CH3CN}]SbF6. Te ahyd o-
u an (THF) was he sol en o choice when dealing wi h mos o he 4-pen ynoic acid
de i a i es, while oluene was employed o eac ions wi h 5-hexynoic acid. Rega ding
he eac ion mechanism, he au ho s p oposed ha , a e he ini ial cycloisome iza ion
s ep, nucleophilic a ack by he amino g oup gene a es a ke oamide in e media e A ha ,
upon in amolecula condensa ion and he o ma ion o he co esponding N-acylimin-
ium ion B, unde goes nucleophilic a ack by he ca binol moie y, hus p o iding i- and
e acycles 1 wi h good yields [55] (Scheme 4).
OH
R5
NH2
R2
R3
()
n
R1
COOH
O
R5
N
R2
R3
O
R1
()
n
(2 mol%)
THF o PhMe,
120 ºC, 12_24h, A
O
N
O
R1
()
n
O
N
O
O
O
n= 0, 1; R1=H,Hex
R3= H, Cl; R4=H,Me
R2=H,Me,F,Cl,B ,I,Ph
23 examples (53_98%)
R4
R4R5=H,Me
n= 0, 1; R1=H,Hex
3examples(78
_96%)
69%
O O
R1
Au(I)
NH2
OH
R
NH
OH
R
O
R1
O
OH
N
()
n
()
n
O
( )
n
Au(I)
A
B
1
Ph
P( Bu)2
Au
NSbF6
Scheme 4. Di ec app oach o benzo[e]indolo[1,2-a]py olo[2,1-c][1,4]diazepine-3,9-diones and
benzo[e]indolo[1,2-a]py ido[2,1-c][1,4]diazepine-3,9-diones.
Almos simul aneously, his g oup epo ed he use o o-aminobenzoic acids and o-
aminobenzamides as dinucleophiles o gene a e py olo/py ido[2,1-a][1,3]benzoxazi-
nones and py olo/py ido [2,1-a]quinazolinones 2. A e a sc eening o di e en Au(III)
and Au(I) sou ces, he same ca alys sys em was employed, al hough, his ime, in 1,2-
dichlo oe hane (DCE) was he sol en . I was con i med no only ha he eac ion sys em
was no sensi i e o ai and mois u e a low ca alys loadings (1.5 mol%) bu also ha no
sil e sal o B öns ed acid (AgSbF6 o CF3COOH, espec i ely) was equi ed o ob ain
op imal esul s o sho e eac ion imes. A simila mechanism was p oposed o his
ans o ma ion ha ook place a he same empe a u e (120 °C, Scheme 5) [56].
Scheme 4.
Di ec app oach o benzo[e]indolo[1,2-a]py olo[2,1-c][1,4]diazepine-3,9-diones and
benzo[e]indolo[1,2-a]py ido[2,1-c][1,4]diazepine-3,9-diones.
Almos simul aneously, his g oup epo ed he use o o-aminobenzoic acids and
o-aminobenzamides
as dinucleophiles o gene a e py olo/py ido[2,1-a][1,3]benzoxazinones
and py olo/py ido [2,1-a]quinazolinones
2
. A e a sc eening o di e en Au(III) and Au(I)
sou ces, he same ca alys sys em was employed, al hough, his ime, in 1,2-dichlo oe hane
(DCE) was he sol en . I was con i med no only ha he eac ion sys em was no sensi i e
o ai and mois u e a low ca alys loadings (1.5 mol%) bu also ha no sil e sal o
B öns ed acid (AgSbF
6
o CF
3
COOH, espec i ely) was equi ed o ob ain op imal esul s
o sho e eac ion imes. A simila mechanism was p oposed o his ans o ma ion ha
ook place a he same empe a u e (120 ◦C, Scheme 5) [56].
In 2011, ano he ype o dinucleophiles, (2-aminophenyl)(1H-indol-1-yl)me hanone
de i a i es
3
, was eac ed wi h pen ynoic, hexynoic and 2-p opa gyloxye hanoic acids.
In his case, [Au{P( -Bu)
2
(o-biphenyl)}{CH
3
CN}]SbF
6
was combined wi h AgSbF
6
o
op imal esul s in oluene as a sol en , hus ob aining benzo[e]indolo[1,2-a]py olo[2,1-
c][1,4]diazepine-3,9-diones and benzo[e]indolo[1,2-a]py ido[2,1-c][1,4]diazepine-3,9-diones
4
wi h good yields. In o de o p o e he p oposed mechanism, he au ho s eac ed al a-
angelica lac one
5
(5-me hyl-2(3H)- u anone) wi h dinucleophile
3
unde he op imized e-
ac ion condi ions, and he co esponding benzo[e]indolo[1,2-a]py olo[2,1-c][1,4]diazepine-
3,9-dione 4a was ob ained in 90% yield [57] (Scheme 6).
Ca alys s 2023,13, 495 6 o 20
Ca alys s 2023, 13, x 6 o 22
Scheme 5. An h anilic acids and o-aminobenzamides as dinucleophiles o he gold-ca alyzed cas-
cade eac ion wi h alkynoic acids.
In 2011, ano he ype o dinucleophiles, (2-aminophenyl)(1H-indol-1-yl)me hanone
de i a i es 3, was eac ed wi h pen ynoic, hexynoic and 2-p opa gyloxye hanoic acids. In
his case, [Au{P( -Bu)2(o-biphenyl)}{CH3CN}]SbF6 was combined wi h AgSbF6 o op imal
esul s in oluene as a sol en , hus ob aining benzo[e]indolo[1,2-a]py olo[2,1-c][1,4]diaz-
epine-3,9-diones and benzo[e]indolo[1,2-a]py ido[2,1-c][1,4]diazepine-3,9-diones 4 wi h
good yields. In o de o p o e he p oposed mechanism, he au ho s eac ed al a-angelica
lac one 5 (5-me hyl-2(3H)- u anone) wi h dinucleophile 3 unde he op imized eac ion
condi ions, and he co esponding benzo[e]indolo[1,2-a]py olo[2,1-c][1,4]diazepine-3,9-
dione 4a was ob ained in 90% yield [57] (Scheme 6).
Con empo aneously, Pa il and col. epo ed he cascade eac ion o alkynoic acids
wi h phenylenediamines o o-aminobenzylamines in he p esence o 1 mol% o
Ph3PAuOT ca alys . Conside ing he subs i u ion a he a oma ic ing o hese nucleo-
philes, he excellen egioselec i i y obse ed o he 37 i- and e acycles ob ained was
a ibu ed o he di e ence in nucleophilici y be ween amino g oups. When α- o α,α′-
subs i u ed pen ynoic acids we e employed, he co esponding dihyd obenzimidazoles 6
and e ahyd oquinazolines 7 we e ob ained wi h good o excellen dias e eome ic a ios
(Figu e 2), which was con i med by NOE s udies. In addi ion, he au ho s p o ided an
al e na i e p ocedu e based on mic owa e i adia ion in he same sol en (1,2-dichlo o-
e hane), hus enhancing he eac ion a e in compa ison wi h con en ional hea ing (30 min
s. 24 h). Finally, se e al mechanis ic s udies we e conduc ed in o de o shed ligh no
only on he ole o he Au(I) ca alys and he possible pa icipa ion o B öns ed acid T OH
bu also on he eason o he dias e eoselec i i y obse ed [58].
Scheme 5.
An h anilic acids and o-aminobenzamides as dinucleophiles o he gold-ca alyzed cascade
eac ion wi h alkynoic acids.
Ca alys s 2023, 13, x 7 o 22
Scheme 6. Cascade eac ion wi h aminophenyl)(1H-indol-1-yl)me hanone de i a i es.
Figu e 2. Dias e eoselec i i y obse ed in he cascade eac ions wi h phenylenediamines o o-ami-
nobenzylamines epo ed by Pa il and col.
Scheme 6. Cascade eac ion wi h aminophenyl)(1H-indol-1-yl)me hanone de i a i es.
Con empo aneously, Pa il and col. epo ed he cascade eac ion o alkynoic acids
wi h phenylenediamines o o-aminobenzylamines in he p esence o 1 mol% o Ph
3
PAuOT
ca alys . Conside ing he subs i u ion a he a oma ic ing o hese nucleophiles, he ex-
cellen egioselec i i y obse ed o he 37 i- and e acycles ob ained was a ibu ed
o he di e ence in nucleophilici y be ween amino g oups. When
α
- o
α
,
α0
-subs i u ed
pen ynoic acids we e employed, he co esponding dihyd obenzimidazoles
6
and e ahy-
Ca alys s 2023,13, 495 7 o 20
d oquinazolines
7
we e ob ained wi h good o excellen dias e eome ic a ios (Figu e 2),
which was con i med by NOE s udies. In addi ion, he au ho s p o ided an al e na i e
p ocedu e based on mic owa e i adia ion in he same sol en (1,2-dichlo oe hane), hus
enhancing he eac ion a e in compa ison wi h con en ional hea ing (30 min s. 24 h).
Finally, se e al mechanis ic s udies we e conduc ed in o de o shed ligh no only on he
ole o he Au(I) ca alys and he possible pa icipa ion o B öns ed acid T OH bu also on
he eason o he dias e eoselec i i y obse ed [58].
Ca alys s 2023, 13, x 7 o 22
Scheme 6. Cascade eac ion wi h aminophenyl)(1H-indol-1-yl)me hanone de i a i es.
Figu e 2. Dias e eoselec i i y obse ed in he cascade eac ions wi h phenylenediamines o o-ami-
nobenzylamines epo ed by Pa il and col.
Figu e 2.
Dias e eoselec i i y obse ed in he cascade eac ions wi h phenylenediamines o
o-aminobenzylamines epo ed by Pa il and col.
In 2013, he same g oup expanded d ama ically he scope and syn he ic po en ial o
his cascade eac ion by eac ing equimolecula amoun s o 30 di e en dinucleophiles
(sca old-building agen s) and 8 alkynoic acids in dichlo oe hane a 100
◦
C o 24–36 h in he
p esence o he same Au(I) ca alys (Ph
3
PAuOT , 5 mol%). As a esul o his combina ion,
a lib a y o 61 polycyclic s uc u es (Figu e 3) we e eadily p epa ed. Indeed, his eac ion
was used as a basis o a ca aly ic b anching cascade ha gene a es a la ge sca old di e si y,
and he e o e implemen ed as a powe ul s a egy o di e si y-o ien ed syn hesis. I
should be also poin ed ou ha mos eac ions ook place wi h good yields and comple e
chemo- and egioselec i i y [59].
In 2012, Liu’s g oup epo ed a mo e sus ainable eac ion media o he cascade be ween
4-pen ynoic acid and 2-(1H-indol-1-yl)e han-1-amine de i a i es. The eac ion was ca ied ou
in wa e using 10 mol% o chlo o[(1,1
0
-bi-phenyl-2-yl)di e -bu ylphosphine]gold(I) ca alys
a 150
◦
C unde mic owa e i adia ion, p o iding se e al e ahyd opy olopy azino[1,2-
a]indolones wi h good yields (88–97%). Howe e , when
α
-subs i u ed pen ynoic acids
o 5-hexynoic acid o 3-(1H-indol-1-yl)p opan-1-amine we e employed as subs a es o
when elec on-wi hd awing g oups we e p esen in he 2-(1H-indol-1-yl)e han-1-amine
dinucleophile, a one-po wo-s ep p ocedu e was equi ed o p epa e a ge e acycles in
Ca alys s 2023,13, 495 8 o 20
good yields. Thus, a e eac ing in he p esence o he abo e Au(I) ca alys , i luo oace ic
acid (1 equi .) was added and mic owa e hea ing con inued o a u he 30 min [60].
Ca alys s 2023, 13, x 9 o 22
N
H
N
R
R
O
R= H, _(CH2)4_
N
H
NO
N
H
N
OR
R
R= H, _(CH2)5-
N
H
N
O
R3
R2
R1
R1=H,Me
R2=R
3=H,_(_CH=CH_)2
N
N
O
()
n
n= 1, 2
N
H
RNO
()
n
n= 1, 2
R= H, B
N
N
R2
R3R3
R1
O
R1=H,CF
3
R2=H; R3=H,_(CH2)4_
R2=R
3=(
_CH=CH_)2
N
R1
NO
R2R3
R1=H,Me
R2=R
3=H, (_CH=CH_)2
N
R
O
O
O
R= H, Me
NN
H
R
O
R= H,
Me
N
H
N
R
O
R= H, Me
NNO
NNO
R1
R2
R1=R
2=H,_(_CH=CH_)2
NNO
O
O
N
R
O
R= H, OMe
N
NH
R
O
S
N
RR
O
R= H, Me R= H, _(CH2)4_
O
N
R
O
R= H, Me
O
N
O
N
N
O
N
N
R
O
N
R= H, Me
N
R
()
n
O
O
n= 0, 1
R= H, n-Hep
N
NH
O
R1
R2
R1
R2
R1=R
2=H,_(_CH=CH_)2
S
N
R
O
R= H, n-Hep
S
N
O
R1R1
R2
R1=H,_(CH2)4_
NNO
R1R2R3
R4
R1=R
2=H,Me
R3=R
4=H,
_(_CH=CH_)2
N
N
R1
R2
O
R1=R
2=H,_(_CH=CH_)2
NNO
R1
R2
R1=R
2=H,_(_CH=CH_)2
N
N
N
O
R
R= H, Me
N
N
N
O
R
R= H, Me
N
N
NN
N
OR
R
R= H, _(CH2)4_
Figu e 3. Lib a y o compounds p epa ed by a elay ca aly ic b anching cascade om alkynoic acids
and dinucleophiles. No e: The moie ies de i ed om alkynoic acids and dinucleophiles a e depic ed
espec i ely in ed and blue in he inal p oduc s.
Figu e 3.
Lib a y o compounds p epa ed by a elay ca aly ic b anching cascade om alkynoic acids
and dinucleophiles. No e: The moie ies de i ed om alkynoic acids and dinucleophiles a e depic ed
espec i ely in ed and blue in he inal p oduc s.
Ca alys s 2023,13, 495 9 o 20
The same g oup epo ed he p epa a ion o 31 benzo[4,5]imidazo[1,2-c]py olo[1,2-
a]quinazolinones
8
by eac ing 2-(1H-benzo[d]imidazol-2-yl)anilines wi h 4-pen ynoic acids
in he p esence o 10 mol% o [Au{P( -Bu)
2
(o-biphenyl)}{CH
3
CN}]SbF
6
and 20 mol% o
AgBF
4
in oluene a 120–130
◦
C. These op imized condi ions we e de e mined by es ing
a numbe o Au(I) and Ag ca alys s, including AuCl(PPh
3
), AgSbF
6
, and AgBF
4
, among
o he s. Possible addi i e e ec s om he combina ion o coca alys s (AgSbF
6
, AgBF
4
,
AgO
2
CCF
3
, AgOT , and i luo oace ic acid) we e also examined. The au ho s s udied he
in luence o he subs i uen s a bo h he benzoimidazole and aniline moie ies in he eac ion
ou come. In his ega d, hey obse ed ha he p esence o elec on-dona ing subs i uen s
such as me hyl o me hoxy a he aniline moie y, and specially a he o ho-posi ion (R
4
subs i uen , Scheme 7) caused a subs an ial dec ease in he eac ion yield. A simila e ec
ela ed o he p esence o me hyl o chlo o g oups a he benzimidazole moie y o he
2-(1H-benzo[d]imidazol-2-yl)aniline eagen was also obse ed (R
2
and R
3
subs i uen s). A
dec eased yield could be a ibu ed o a possible s e ic hind ance when using
α
-subs i u ed
3-e hynylnonanoic acid was also accoun ed o . When he op imized p o ocol was applied
o 5-hexynoic acid, he co esponding benzo[4,5]imidazo[1,2-c]py ido[1,2-a]quinazolin-
6-ones
9
we e ob ained, albei in lowe yields han hose om 4-pen ynoic acid, e en a
sligh ly highe empe a u es (130
◦
C). The same dec easing e ec s ela ed o he p esence
o R
2
-R
3
subs i uen s a he benzimidazole moie y, and R
4
-R
6
a he aniline agmen o he
2-(1H-benzo[d]imidazol-2-yl)aniline N-aminonucleophile we e no iced, wi h 5-hexynoic
acid as he coun e pa [61] (Scheme 7).
Ca alys s 2023, 13, x 10 o 22
Scheme 7. Cascade eac ion wi h 2-(1H-benzo[d]imidazol-2-yl)aniline de i a i es.
Some yea s la e , in 2019, his g oup desc ibed he i s use o 1,3-unsubs i u ed 2-
(1H-indol-2-yl)e hanamines as aminonucleophiles. Taking Au(PPh3)Cl as ca alys and an
ex ensi e numbe o dinucleophiles, hey ca ied ou he cons uc ion o a lib a y o in-
dole/py ole/ hiophene/benzene/naph halene/py idine-based ni ogen-con aining he e -
ocyclic compounds wi h sca old di e si y (mo e han 78 examples we e p epa ed). How-
e e , in many cases, i was necessa y o pe o m a one-o wo-s ep p ocedu e which in-
ol ed he addi ion o i lu oace ic acid and hea ing in he second s ep (1. Au(PPh3)Cl (5
mol%), DCE, 120–140 °C, 20–24 h; 2. CF3COOH (1 equi .), 120–140 °C, 20–24 h). Se e al
addi ional expe imen s (Scheme 8) showed no only he pa icipa ion enol lac one in e -
media es bu also ha he gold ca alys is esponsible o he o ma ion o enol lac one
in e media e and o he iminium ion o ma ion. In addi ion, a 90% yield was ob ained
om he eac ion be ween 2-(1H-indol-2-yl)e hanamine and 4-pen ynoic acid on a g am
scale. A simple ca bonyl g oup educ ion wi h LiAlH4-AlCl3 o some he compounds o
he abo e lib a y p o ided se e al α1A-ad enocep o an agonis s. In addi ion, a e a pha -
macological sc eening o he compounds di ec ly accessed h ough he cascade eac ion,
he au ho s epo ed he an ip oli e a i e ac i i ies agains human cance cell lines o wo
compounds, a e ahyd opy olo[1,2-a]quinazoline-1,5-dione and a e ahyd oin-
dolo[3′,2′:3,4]py ido[2,1-a]isoquinolin-6(5H)-one [62].
Following hei esea ch on such cascade eac ions in wa e [60], Liu and Zhao’s
g oup also disclosed a mo e e icien me hod based on he same Au(I) ca alys (1 mol%)
and B ons ed acid o eac ions pe o med in wa e as he only sol en . Mo e han 70 com-
pounds we e p epa ed unde hese condi ions, wi h yields anging 18–96%. As in p e i-
ous cases, depending on he subs a es in ol ed, an Au(I)-ca alyzed genuine cascade o a
one-po wo-s ep andem eac ion was equi ed o access a ge compounds. The au ho s
also conduc ed deu e a ion and 18O labeling expe imen s o mechanis ic pu poses, and
some o he ob ained e a- and pen acycles we e de i a ized by educing he amide ca -
bonyl g oup wi h LiAlH4/AlCl3 [63].
Scheme 7. Cascade eac ion wi h 2-(1H-benzo[d]imidazol-2-yl)aniline de i a i es.
Some yea s la e , in 2019, his g oup desc ibed he i s use o 1,3-unsubs i u ed 2-
(1H-indol-2-yl)e hanamines as aminonucleophiles. Taking Au(PPh
3
)Cl as ca alys and
an ex ensi e numbe o dinucleophiles, hey ca ied ou he cons uc ion o a lib a y
o indole/py ole/ hiophene/benzene/naph halene/py idine-based ni ogen-con aining
he e ocyclic compounds wi h sca old di e si y (mo e han 78 examples we e p epa ed).
Howe e , in many cases, i was necessa y o pe o m a one-o wo-s ep p ocedu e which
in ol ed he addi ion o i lu oace ic acid and hea ing in he second s ep (1. Au(PPh
3
)Cl
(5 mol%), DCE, 120–140
◦
C, 20–24 h; 2. CF
3
COOH (1 equi .), 120–140
◦
C, 20–24 h). Se e al
addi ional expe imen s (Scheme 8) showed no only he pa icipa ion enol lac one in e -
media es bu also ha he gold ca alys is esponsible o he o ma ion o enol lac one
in e media e and o he iminium ion o ma ion. In addi ion, a 90% yield was ob ained om
he eac ion be ween 2-(1H-indol-2-yl)e hanamine and 4-pen ynoic acid on a g am scale. A
simple ca bonyl g oup educ ion wi h LiAlH
4
-AlCl
3
o some he compounds o he abo e
lib a y p o ided se e al
α1A
-ad enocep o an agonis s. In addi ion, a e a pha macologi-
cal sc eening o he compounds di ec ly accessed h ough he cascade eac ion, he au ho s
epo ed he an ip oli e a i e ac i i ies agains human cance cell lines o wo compounds,
Ca alys s 2023,13, 495 16 o 20
In o de o de e mine he ole o he ca alys s in his cascade eac ion, he au ho s ca -
ied ou a se ies o expe imen s. 5-Me hylenedihyd o u an-2(3H)-one was easily p epa ed
by eac ing 4-pen ynoic acid wi h he abo e NNC complex (10
−2
mol%) and ie hylamine
(2 mol%) in dichlo ome hane a oom empe a u e and hen ea ed wi h an h anilic acid un-
de he op imized eac ion condi ions o p o ide a ge benzo[d]py olo[2,1-b][1,3]oxazine-
1,5(2H)-dione
18
in 90% yield. The kine ic plo o he con e sion o an h anilic acid s.
ime showed nei he sigmoidal shape no induc ion ime, and when he eac ion was
pe o med in he p esence o se e al poisoning agen s (me cu y d op es , ca bon disul-
ide and poly inylpy idine, among o he s), no inhibi ion was obse ed, hus sugges ing
he pa icipa ion o uly homogeneous ca aly ic species in he eac ion. The absence o
palladium nanopa icles, as de e mined by TEM-EDX analysis o he eac ion mix u e,
p o ided addi ional p oo o con i m he hypo hesis o homogeneous ca alysis. Mo eo e ,
some key in e media es we e de ec ed by UPLC-MS o he eac ion mix u e. Acco d-
ingly, a mo e nuanced mechanism desc ibing he ole o he me al species and ansien
in e media es de ec ed by UPLC-ESI was also p oposed [
79
] (Figu e 4). These esul s
a e in acco dance wi h se e al examples o bime allic co-ca alysis, including he a o e-
men ioned epo s on he gold-sil e co-ca alyzed cascade eac ions (Sec ions 2.2 and 2.3,
Schemes 3,6and 7) [53,57,61]
and o he accoun s on me al-me al syne gis ic e ec s and
me al–ligand coope a ion [80–82].
Ca alys s 2023, 13, x 17 o 22
an h anilic acid s. ime showed nei he sigmoidal shape no induc ion ime, and when
he eac ion was pe o med in he p esence o se e al poisoning agen s (me cu y d op
es , ca bon disul ide and poly inylpy idine, among o he s), no inhibi ion was obse ed,
hus sugges ing he pa icipa ion o uly homogeneous ca aly ic species in he eac ion.
The absence o palladium nanopa icles, as de e mined by TEM-EDX analysis o he eac-
ion mix u e, p o ided addi ional p oo o con i m he hypo hesis o homogeneous ca al-
ysis. Mo eo e , some key in e media es we e de ec ed by UPLC-MS o he eac ion mix-
u e. Acco dingly, a mo e nuanced mechanism desc ibing he ole o he me al species
and ansien in e media es de ec ed by UPLC-ESI was also p oposed [79] (Figu e 4).
These esul s a e in acco dance wi h se e al examples o bime allic co-ca alysis, including
he a o emen ioned epo s on he gold-sil e co-ca alyzed cascade eac ions (Sec ions 2.2
and 2.3, Schemes 3, 6 and 7) [53,57,61] and o he accoun s on me al-me al syne gis ic e -
ec s and me al–ligand coope a ion [80–82].
Figu e 4. P oposed ca aly ic pa hway o he cascade eac ion pe o med in he p esence o a palla-
dium pince complex and i on(II) b omide.
7. Conclusions and Ou look
In he p esence o se e al dinucleophiles, a ca bophilic me al-ca alyzed in amolecu-
la hyd oca boxyla ion o alkynoic acids igge s a cascade eac ion ha gene a es ela-
i ely complex polycyclic s uc u es. The inc easing numbe o ace ylenic acids and dinu-
cleophiles (C-, N-, O- and S-aminonucleophiles) ha can se e as subs a es ha e g ea ly
ex ended he scope o his mul i-s ep p ocess so ha a la ge lib a y o aluable ni ogen-
con aining he e ocyclic compounds can be easily p epa ed om comme cially o eadily
a ailable subs a es o eagen s. Rega ding he ca alys equi ed o hese ans o ma ions,
al hough gold(I) complexes ei he alone o along wi h Ag(I) sal s o B öns ed acid ( i lu o-
ace ic acid) ha e domina ed he ield and demons a ed a supe io pe o mance and sub-
s a e scope, o he compe i o s based on coppe (II) sal s in ionic liquids, u henium ca -
benes, palladium(II) complexes and i on sal s ha e appea ed in ecen yea s. These al e na-
i e candida es show an excellen ca alys p o ile, bu , wi h he excep ion o u henium ca -
benes, hey appea o be unable o p omo e he eac ion wi h C-aminonucleophiles, hus
limi ing he eac ion scope o N-, O- o S-aminonucleophiles. I is ce ainly di icul o com-
pa e all hese ca aly ic p o iles i , in addi ion o he subs a e scope, e iciency and economic
alue a e also conside ed. Indeed, ypical ca alys loading anges om 1 o 20 mol% o Au,
Figu e 4.
P oposed ca aly ic pa hway o he cascade eac ion pe o med in he p esence o a
palladium pince complex and i on(II) b omide.
7. Conclusions and Ou look
In he p esence o se e al dinucleophiles, a ca bophilic me al-ca alyzed in amolecula
hyd oca boxyla ion o alkynoic acids igge s a cascade eac ion ha gene a es ela i ely
complex polycyclic s uc u es. The inc easing numbe o ace ylenic acids and dinucle-
ophiles (C-, N-, O- and S-aminonucleophiles) ha can se e as subs a es ha e g ea ly
ex ended he scope o his mul i-s ep p ocess so ha a la ge lib a y o aluable ni ogen-
con aining he e ocyclic compounds can be easily p epa ed om comme cially o eadily
a ailable subs a es o eagen s. Rega ding he ca alys equi ed o hese ans o ma ions,
al hough gold(I) complexes ei he alone o along wi h Ag(I) sal s o B öns ed acid ( i-
lu oace ic acid) ha e domina ed he ield and demons a ed a supe io pe o mance and
subs a e scope, o he compe i o s based on coppe (II) sal s in ionic liquids, u henium
ca benes, palladium(II) complexes and i on sal s ha e appea ed in ecen yea s. These al e -
Ca alys s 2023,13, 495 17 o 20
na i e candida es show an excellen ca alys p o ile, bu , wi h he excep ion o u henium
ca benes, hey appea o be unable o p omo e he eac ion wi h C-aminonucleophiles, hus
limi ing he eac ion scope o N-, O- o S-aminonucleophiles. I is ce ainly di icul o com-
pa e all hese ca aly ic p o iles i , in addi ion o he subs a e scope, e iciency and economic
alue a e also conside ed. Indeed, ypical ca alys loading anges om 1 o 20 mol% o
Au, Ag, Cu, Ru and Fe ca alys s, al hough he use o a PCN palladium complex along wi h
FeB
2
allowed a much highe subs a e/ca alys a io (10,000:1). I on, an abundan and less
oxic i s ow ansi ion me al, can also ca alyze he eac ion al hough wi h he subs a e
limi a ions no ed abo e. The high economic alue o Au, Ag, Ru and Pd p ecious me al
ca alys s canno be unde es ima ed, al hough his issue should be examined in iew o
he amoun o ca alys equi ed (e.g., he economic cos o 20 mol% o a sil e ca alys is
much highe han ha o a 10
−2
mol% o a palladium complex). As o eac ion media,
oluene is by a he sol en o choice in many o he ans o ma ions desc ibed, e en i
g eene al e na i es such as wa e , ionic liquids and sol en less eac ions ha e been de-
sc ibed. Con en ional hea ing is almos ubiqui ous in all he epo s, al hough mic owa e
i adia ion has been also epo ed. Exhaus i e mechanis ic s udies ca ied ou o many
o he ca alys sys ems epo ed ha e led o he iden i ica ion o se e al in e media es o
he eac ion ( he alkylidene lac one gene a ed om he ini ial cycloisome iza ion s ep, he
ke oamide p oduced as a esul o he subsequen aminolysis and he N-acyliminium ion
p io o he a ack by he second nucleophilic g oup o he aminonucleophile). In addi ion,
such expe imen s ha e aided o de ine he ole o he ca alys and he addi i es employed.
In mos cases, me al ca alys is essen ial o he ini ial in amolecula alkyne hyd oca boxy-
la ion (some imes helped by subs oichiome ic amoun s o a base-like ie hylamine o
py idine) and p o ides, alone o wi h he help o ce ain sil e o B öns ed acid addi i es,
he ac i a ion equi ed o he second s age o he cascade.
We o esee he de elopmen o new ca alys sys ems o his syn he ically powe ul
eac ion in he coming yea s. Such u u e ca alys s will p obably o e come he desc ibed
limi a ions and will p o ide mo e sus ainable p o ocols o a cascade eac ion ha o e s
s aigh o wa d access o a whole a ay o polyhe e ocyclic compounds, some o hem
showing ema kable biological ac i i y.
Au ho Con ibu ions:
Co-au ho s G.U., J.D.d.S., N.C. and A.H. con ibu ed o sea ching and col-
la ing o he ele an li e a u e and he p oo eading o he documen . Co-au ho M.T.H. and
co esponding au ho R.S. w o e he body o he a icle. All au ho s ha e ead and ag eed o he
published e sion o he manusc ip .
Funding:
This esea ch was unded by he Basque Go e nmen (IT1583-22) and he Spanish Minis y
o Economy and Compe i i eness (CTQ2017-86630-P).
Acknowledgmen s:
Technical and human suppo p o ided by SGIke o UPV/EHU a e g a e-
ully acknowledged.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
Re e ences
1.
Nicolaou, K.C.; Chen, J.S. The a o o al syn hesis h ough cascade eac ions. Chem. Soc. Re .
2009
,38, 2993–3009. [C ossRe ]
[PubMed]
2.
Nicolaou, K.C.; Edmonds, D.J.; Bulge , P.G. Cascade Reac ions in To al Syn hesis. Angew. Chem. In . Ed.
2006
,45, 7134–7186.
[C ossRe ] [PubMed]
3.
Hwang, E.T.; Lee, S. Mul ienzyma ic Cascade Reac ions ia Enzyme Complex by Immobiliza ion. ACS Ca al.
2019
,9, 4402–4425.
[C ossRe ]
4.
Xu, Z.-J.; Liu, X.-Y.; Zhu, M.-Z.; Xu, Y.-L.; Yu, Y.; Xu, H.-R.; Cheng, A.-X.; Lou, H.-X. Pho o edox-Ca alyzed Cascade Reac ions
In ol ing A yl Radical: To al Syn hesis o (±)-No ascy onone A and (±)-Eudesmol. O g. Le . 2021,23, 9073–9077. [C ossRe ]
5.
Hinkle, R.J.; Lewis, S.E. A om Economical, One-Po , Th ee-Reac ion Cascade o No el T icyclic 2,4-Dihyd o-1H-benzo[ ]isoch omenes.
O g. Le . 2013,15, 4070–4073. [C ossRe ]
6.
Buñuel, E.; Cá denas, D.J. Towa ds Use ul Bo ona es h ough A om-Economical Ca alyzed Cascade Reac ions. Chem. Eu . J.
2018
,
24, 11239–11244. [C ossRe ]
Ca alys s 2023,13, 495 18 o 20
7.
Pa il, N.T.; Ka he, R.D.; Shinde, V.S. T ansi ion me al-ca alyzed addi ion o C-, N- and O-nucleophiles o unac i a ed C-C
mul iple bonds. Te ahed on 2012,68, 8079–8146. [C ossRe ]
8. Suess, A.M.; Lalic, G. Coppe -Ca alyzed Hyd o unc ionaliza ion o Alkynes. Synle 2016,27, 1165–1174. [C ossRe ]
9.
Shibuya, M.; Okamo o, M.; Fuji a, S.; Abe, M.; Yamamo o, Y. Bo on-Ca alyzed Double Hyd o unc ionaliza ion Reac ions o
Unac i a ed Alkynes. ACS Ca al. 2018,8, 4189–4193. [C ossRe ]
10.
Cadie no, V. Me al-Ca alyzed Hyd o unc ionaliza ion Reac ions o Haloalkynes. Eu . J. Ino g. Chem.
2020
,2020, 886–898.
[C ossRe ]
11.
Cheng, Z.; Guo, J.; Lu, Z. Recen ad ances in me al-ca alysed asymme ic sequen ial double hyd o unc ionaliza ion o alkynes.
Chem. Commun. 2020,56, 2229–2239. [C ossRe ]
12.
Ga cía-Fe nández, P.D.; Iglesias-Sigüenza, J.; Ri e o-Je ez, P.S.; Díez, E.; Gómez-Bengoa, E.; Fe nández, R.; Lassale a, J.M.
Au(I)-Ca alyzed Hyd oalkynyla ion o Haloalkynes. J. Am. Chem. Soc. 2020,142, 16082–16089. [C ossRe ] [PubMed]
13.
Chapple, D.E.; Ho e , M.A.; Boyle, P.D.; Blacquie e, J.M. Alkyne Hyd o unc ionaliza ion Mechanism Including an O -Cycle
Alkoxyca bene Deac i a ion Complex. O ganome allics 2022,41, 1532–1542. [C ossRe ]
14.
Fang, G.; Bi, X. Sil e -ca alysed eac ions o alkynes: Recen ad ances. Chem. Soc. Re .
2015
,44, 8124–8173. [C ossRe ] [PubMed]
15.
Gao, D.-W.; Gao, Y.; Shao, H.; Qiao, T.-Z.; Wang, X.; Sanchez, B.B.; Chen, J.S.; Liu, P.; Engle, K.M. Cascade CuH-ca alysed
con e sion o alkynes in o enan ioen iched 1,1-disubs i u ed p oduc s. Na . Ca al. 2020,3, 23–29. [C ossRe ] [PubMed]
16.
Co pas, J.; Mauleón, P.; Gómez A ayás, R.; Ca e e o, J.C. T ansi ion-Me al-Ca alyzed Func ionaliza ion o Alkynes wi h
O ganobo on Reagen s: New T ends, Mechanis ic Insigh s, and Applica ions. ACS Ca al. 2021,11, 7513–7551. [C ossRe ]
17.
Jin, S.; Liu, K.; Wang, S.; Song, Q. Enan ioselec i e Cobal -Ca alyzed Cascade Hyd osilyla ion and Hyd obo a ion o Alkynes o
Access Enan ioen iched 1,1-Silylbo yl Alkanes. J. Am. Chem. Soc. 2021,143, 13124–13134. [C ossRe ]
18.
Liao, X.; Zhou, F.; Bin, Z.; Yang, Y.; You, J. Palladium-Ca alyzed Cascade Dea oma i e Spi ocycliza ion and C
−
H Annula ion o
A oma ic Halides wi h Alkynes. O g. Le . 2021,23, 5203–5207. [C ossRe ]
19.
Zhang, W.-Z.; Yang, M.-W.; Yang, X.T.; Shi, L.-L.; Wang, H.-B.; Lu, X.-B. Double ca boxyla ion o o-alkynyl ace ophenone wi h
ca bon dioxide. O g. Chem. F on . 2016,3, 217–221. [C ossRe ]
20.
Du, Y.-L.; Zhu, Y.-F.; Han, Z.-Y. Pd(II)-Ca alyzed Cycloisome iza ion/Dipola Cycloaddi ion Cascade o N-A ylni one Alkynes
wi h Ole ins. J. O g. Chem. 2015,80, 7732–7738. [C ossRe ]
21.
Hi ano, K.; Inaba, Y.; Wa anabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Gold-Ca alyzed In amolecula Alkyne Cycloisome iza ion
Cascade: Di ec Syn hesis o A yl-Annula ed[a]ca bazoles om Aniline-Subs i u ed Die hynyla enes. Ad . Syn h. Ca al.
2010
,
352, 368–372. [C ossRe ]
22.
S o ch, J.; Be na d, M.; Sýko a, J.; Ka ban, J.; ˇ
Ce mák, J. In amolecula Cascade Hyd oa yla ion/Cycloisome iza ion S a egy o
he Syn hesis o Polycyclic A oma ic and He e oa oma ic Sys ems. Eu . J. O g. Chem. 2013,2013, 260–263. [C ossRe ]
23.
Ál a ez-Pé ez, M.; F u os, M.; Viso, A.; Fe nández de la P adilla, R.; de la To e, M.C.; Sie a, M.A.; Go ni zka, H.; Hemme , C.
Gold(I)-Ca alyzed Cycloisome iza ion–Dime iza ion Cascade o Benzene-Te he ed 1,6-Enynes. J. O g. Chem.
2017
,82, 7546–7554.
[C ossRe ]
24.
Alonso-Ma añón, L.; Sa andeses, L.A.; Ma ínez, M.M.; Pé ez Ses elo, J. Syn hesis o used ch omenes by indium(III)-ca alyzed
cascade hyd oa yla ion/cycloisome iza ion eac ions o polyyne- ype a yl p opa gyl e he s. O g. Chem. F on .
2018
,5, 2308–2312.
[C ossRe ]
25.
Millán, R.E.; Rod íguez, J.; Sa andeses, L.A.; Gómez-Bengoa, E.; Pé ez Ses elo, J. Indium(III)-Ca alyzed S e eoselec i e Syn hesis o
T icyclic F amewo ks by Cascade Cycloisome iza ion Reac ions o A yl 1,5-Enynes. J. O g. Chem.
2021
,86, 9515–9529. [C ossRe ]
[PubMed]
26.
Nagendi an, A.; Ve ho, O.; Halle , C.; Johns on, E.V.; Bäck all, J.-E. Cycloisome iza ion o Ace ylenic Acids o
γ
-Alkylidene
Lac ones using a Palladium(II) Ca alys Suppo ed on Amino-Func ionalized Siliceous Mesocellula Foam. J. O g. Chem.
2014
,
79, 1399–1405. [C ossRe ]
27.
Ke, D.; Espinosa, N.A.; Ladei a, S.M.; Mono , J.; Ma in-Vaca, B.; Bou issou, D. E icien Syn hesis o Unsa u a ed d- and
e-Lac ones/Lac ams by Ca aly ic Cycloisome iza ion: When P Ou pe o ms Pd. Ad . Syn h. Ca al.
2016
,358, 2324–2331.
[C ossRe ]
28.
F ancos, J.; Cadie no, V. Me al-Ca alyzed In a- and In e molecula Addi ion o Ca boxylic Acids o Alkynes in Aqueous Media:
A Re iew. Ca alys s 2017,7, 328. [C ossRe ]
29.
Saa ed a, B.; Pé ez, J.M.; Rod íguez-Ál a ez, M.J.; Ga cía-Ál a ez, J.; Ramón, D.J. Imp egna ed palladium on magne i e as a
wa e compa ible ca alys o he cycloisome iza ion o alkynoic acid de i a i es. G een Chem. 2018,20, 2151–2157. [C ossRe ]
30.
Tian, G.; Song, L.; Li, Z.; Robeyns, K.; Mee el , L.V.; Van de Eycken, E.V. A Gold(I)-Ca alyzed Hyd oamina ion/Cycloisome iza ion
Cascade: Concise Syn hesis o (±)-seco-An o ine and (±)-Sep icine. O g. Le . 2020,22, 8441–8445. [C ossRe ]
31.
Sk o so a, V.I.; Bachu in, S.O.; Us yugo , A.A.; Kukha sky, M.S.; Deikin, A.V.; Buchman, V.L.; Ninkina, N.N. Gamma-Ca bolines
De i a i es As P omising Agen s o he De elopmen o Pa hogenic The apy o P o einopa hy. Ac a Na .
2018
,10, 59–62.
[C ossRe ]
32.
Xu, S.-M.; Wei, L.; Shen, C.; Xiao, L.; Tao, H.-Y.; Wang, C.-J. S e eodi e gen assembly o e ahyd o-
γ
- ca bolines ia syne gis ic
ca aly ic asymme ic cascade eac ion. Na . Commun. 2019,10, 5553. [C ossRe ] [PubMed]
33.
Dai, J.; Dan, W.; Zhang, Y.; Wang, J. Recen de elopmen s on syn hesis and biological ac i i ies o
γ
-ca boline. Eu . J. Med. Chem.
2018,157, 447–461. [C ossRe ]
Ca alys s 2023,13, 495 19 o 20
34.
O o, R.; Penzis, R.; Gaube, F.; Winckle , T.; Appen o h, D.; Fleck, C.; T änkle, C.; Lehmann, J.; Enzenspe ge , C. Be a and gamma
ca boline de i a i es as po en ial an i-Alzheime agen s: A compa ison. Eu . J. Med. Chem.
2014
,87, 63–70. [C ossRe ] [PubMed]
35.
Doody, R.S.; Ga ilo a, S.I.; Sano, M.; Thomas, R.G.; Aisen, P.S.; Bachu in, S.O.; Seely, L.; Hung, D. E ec o dimebon on cogni ion,
ac i i ies o daily li ing, beha iou , and global unc ion in pa ien s wi h mild- o-mode a e alzheime ’s disease: A andomised,
double-blind, placebo-con olled s udy. Lance 2008,372, 207–215. [C ossRe ]
36.
Kalin, J.H.; Bu le , K.V.; Akimo a, T.; Hancock, W.W.; Kozikowski, A.P. Second-gene a ion his one deace ylase 6 inhibi o s
enhance he immunosupp essi e e ec s o Foxp3+ T- egula o y cells. J. Med. Chem. 2012,55, 639–651. [C ossRe ]
37.
Bu le , K.V.; Kalin, J.; B ochie , C.; Vis oli, G.; Langley, B.; Kozikowski, A.P. Ra ional design and simple chemis y yield a supe io ,
neu op o ec i e HDAC6 inhibi o , ubas a in A. J. Am. Chem. Soc. 2010,132, 10842–10846. [C ossRe ]
38.
Wang, S.; Wang, Y.; Liu, W.; Liu, N.; Zhang, Y.; Dong, G.; Liu, Y.; Li, Z.; He, X.; Miao, Z.; e al. No el ca boline de i a i es as po en
an i ungal lead compounds: Design, syn hesis, and biological e alua ion. ACS Med. Chem. Le . 2014,5, 506–511. [C ossRe ]
39.
Nam, S.-J.; Kau man, C.A.; Jensen, P.R.; Moo e, C.E.; Rheingold, A.L.; Fenical, W. Ac inobenzoquinoline and ac inophenan h o-
lines A-C, unp eceden ed alkaloids om a ma ine Ac inobac e ium. O g. Le . 2015,17, 3240–3243. [C ossRe ]
40.
Kau , R.; Manjal, S.K.; Rawal, R.K.; Kuma , K. Recen syn he ic and medicinal pe spec i es o yp an h in. Bioo g. Med. Chem.
2017,25, 4533–4552. [C ossRe ]
41.
Zeng, Q.; Luo, C.; Cho, J.; Lai, D.; Shen, X.; Zhang, X.; Zhou, W. T yp an h in exe s an i-b eas cance e ec s bo h
in i o
and
in i o h ough modula ing he in lamma o y umo mic oen i onmen . Ac a Pha m. 2021,71, 245–266. [C ossRe ]
42.
Jahng, Y. P og ess in he s udies on yp an h in, an alkaloid o his o y. A ch. Pha m. Res.
2013
,36, 517–535. [C ossRe ] [PubMed]
43.
Moloudiza ga i, M.; Mikaili, P.; Aghajanshake i, S.; Asgha i, M.H.; Shayegh, J. Pha macological and he apeu ic e ec s o
Peganum ha mala and i s main alkaloids. Pha macogn. Re . 2013,7, 199–212. [C ossRe ] [PubMed]
44.
Nepali, K.; Sha ma, S.; Ojha, R.; Dha , K.L. Vasicine and s uc u ally ela ed quinazolines. Med. Chem. Res.
2013
,22, 1–15.
[C ossRe ]
45.
Shakhidoya o , K.M.; Elmu ado , B.Z. T icyclic Quinazoline Alkaloids: Isola ion, Syn hesis, Chemical Modi ica ion, and Biological
Ac i i y. Chem. Na . Compd. 2014,50, 781–800. [C ossRe ]
46.
Nepali, K.; Ojha, R.; Singh, A.; Budhi aja, A.; Bedi PM, S.; Dha , K.L. Design, syn hesis and e alua ion o a ylidene py olo and
py ido used quinazolones as an imic obial agen s. Le . D ug Des. Disco . 2013,10, 522–528. [C ossRe ]
47.
Kshi saga , U.A. Recen de elopmen s in he chemis y o quinazolinone alkaloids. O g. Biomol. Chem.
2015
,13, 9336–9352.
[C ossRe ]
48.
Sondhi, S.M.; Rani, R. Mic owa e-media ed one s ep syn hesis o i- and e acyclic he e ocyclic molecules. G een Chem. Le . Re .
2010,3, 115–120. [C ossRe ]
49.
Kim, Y.; Cheon, C.-H. Syn hesis o quinazolinones om an h anilamides and aldehydes ia me al- ee ae obic oxida ion in DMSO.
Te ahed on Le . 2014,55, 2340–2344. [C ossRe ]
50.
Cao, L.; Huo, H.; Zeng, H.; Yu, Y.; Lu, D.; Gong, Y. One-Po Syn hesis o Quinazolin-4(3H)-ones h ough Anodic Oxida ion and
he Rela ed Mechanis ic S udies. Ad . Syn h. Ca al. 2018,360, 4764–4773. [C ossRe ]
51.
A anasye , O.I.; Podyache a, E.; Rudenko, A.; Tsyganko , A.A.; Maka o a, M.; Chuso , D. Redox Condensa ions o o-
Ni obenzaldehydes wi h Amines unde Mild Condi ions: To al Syn hesis o he Vasicinone Family. J. O g. Chem.
2020
,
85, 9347–9360. [C ossRe ] [PubMed]
52.
Kshi saga , U.A.; A gade, N.P. Facile app oach o di e se ange o 1,3-diaza-he e ocycles: Angula /linea selec i i y pa adigm
and a ema kable in amolecula me hyl mig a ion. Te ahed on 2009,65, 5244–5250. [C ossRe ]
53.
Yang, T.; Campbell, L.; Dixon, D.J. A Au(I)-Ca alyzed N-Acyl Iminium Ion. Cycliza ion Cascade. J. Am. Chem. Soc.
2007
,
129, 12070–12071. [C ossRe ] [PubMed]
54.
Mu a o e, M.E.; Holloway, C.A.; Pilling, A.W.; S o e , R.I.; T e i , G.; Dixon, D.J. Enan ioselec i e B øns ed Acid-Ca alyzed
N-Acyliminium Cycliza ion Cascades. J. Am. Chem. Soc. 2009,131, 10796–10797. [C ossRe ]
55.
Zhou, Y.; Zhai, Y.; Ji, X.; Liu, G.; Feng, E.; Ye, D.; Zhao, L.; Jiang, H.; Liu, H. Gold(I)-Ca alyzed One-Po Tandem Cou-
pling/Cycliza ion: An E icien Syn hesis o Py olo-/Py ido[2,1-b]benzo[d][1,3]oxazin-1-ones. Ad . Syn h. Ca al.
2010
,
352, 373–378. [C ossRe ]
56.
Feng, E.; Zhou, Y.; Zhang, D.; Zhang, L.; Sun, H.; Jiang, H.; Liu, H. Gold(I)-Ca alyzed Tandem T ans o ma ion: A Simple
App oach o he Syn hesis o Py olo/Py ido[2,1-a][1,3]benzoxazinones and Py olo/Py ido[2,1-a]quinazolinones. J. O g. Chem.
2010,75, 3274–3282. [C ossRe ]
57.
Zhou, Y.; Li, J.; Ji, X.; Zhou, W.; Zhang, X.; Qian, W.; Jiang, H.; Liu, H. Sil e - and Gold-Media ed Domino T ans o ma ion: A
S a egy o Syn hesizing Benzo[e]indolo[1,2-a]py olo/py ido[2,1-c][1,4]diazepine-3,9-diones. J. O g. Chem.
2011
,76, 1239–1249.
[C ossRe ]
58.
Pa il, N.T.; Mu yala, A.K.; Lakshmi, P.G.V.; Gajula, B.; S idha , B.; Po i eddyga i, G.R.; Rao, T.P. Au(I)-Ca alyzed Cascade
Reac ion In ol ing Fo mal Double Hyd oamina ion o Alkynes Bea ing Te he ed Ca boxylic G oups: An Easy Access o Fused
Dihyd obenzimidazoles and Te ahyd oquinazolines. J. O g. Chem. 2010,75, 5963–5975. [C ossRe ]
59.
Pa il, N.T.; Shinde, V.S.; S idha , B. Relay Ca aly ic B anching Cascade: A Technique o Access Di e se Molecula Sca olds.
Angew. Chem. In . Ed. 2013,52, 2251–2255. [C ossRe ]
60.
Feng, E.; Zhou, Y.; Zhao, F.; Chen, X.; Zhang, L.; Jiang, H.; Liu, H. Gold-ca alyzed andem eac ion in wa e : An e icien and
con enien syn- hesis o used polycyclic indoles. G een Chem. 2012,14, 1888–1895. [C ossRe ]
Ca alys s 2023,13, 495 20 o 20
61.
Ji, X.; Zhou, Y.; Wang, L.; Zhao, L.; Jiang, H.; Liu, H. Au(I)/Ag(I)-ca alyzed cascade app oach o he syn hesis o
benzo[4,5]imidazo[1,2-c]py olo[1,2-a]quinazolinones. J. O g. Chem. 2013,78, 4312–4318. [C ossRe ]
62.
Qiao, J.; Jia, X.; Li, P.; Liu, X.; Zhao, J.; Zhou, Y.; Wang, J.; Liu, H.; Zhao, F. Gold-ca alyzed Rapid Cons uc ion o Ni ogen-
con aining He e -ocyclic Compound Lib a y wi h Sca old Di e si y and Molecula Complexi y. Ad . Syn h. Ca al.
2019
,
361, 1419–1440. [C ossRe ]
63.
Jia, X.; Li, P.; Liu, X.; Lin, J.; Chu, Y.; Yu, J.; Wang, J.; Liu, H.; Zhao, F. G een and Facile Assembly o Di e se Fused N-He e ocycles
Using Gold-Ca alyzed Cascade Reac ions in Wa e . Molecules 2019,24, 988. [C ossRe ] [PubMed]
64.
Naidu, S.; Reddy, S.R. Coppe -ca alyzed andem eac ion in ionic liquid: An e icien eusable ca alys and sol en media o he
syn hesis o used poly he e o cyclic compounds. RSC Ad . 2016,6, 62742–62746. [C ossRe ]
65.
Naidu, S.; Reddy, S.R. A G een and Recyclable Coppe and Ionic Liquid Ca aly ic Sys em o he Cons uc ion o Polyhe e ocyclic
Compounds ia One-po Tandem Coupling Reac ion. Chemis ySelec 2017,2, 1196–1201. [C ossRe ]
66.
Alcaide, B.; Almend os, P. Non-Me a he ic Beha io Pa e ns o G ubbs’ Ca bene. Chem. Eu . J.
2003
,6, 1258–1262. [C ossRe ]
[PubMed]
67.
Alcaide, B.; Almend os, P.; Luna, A. G ubbs’ Ru henium-Ca benes Beyond he Me a hesis Reac ion: Less Con en ional Non-
Me a he ic U ili y. Chem. Re . 2009,109, 3817–3858. [C ossRe ] [PubMed]
68.
Takagi, R.; Yamamo o, K.; Hi aga, Y.; Kojima, S.; Abe, M. A no el non-me a he ic beha io o G ubbs ca alys : Ru henium-
media ed in amolecula [3 + 2] cycloaddi ion o bis-1,3-dienes. J. O ganome . Chem. 2013,723, 171–175. [C ossRe ]
69.
KeiIio, K.; Sachimo i, S.; Wa anabe, T.; Fuwa, H. Ru henium-Ca alyzed In amolecula Double Hyd oalkoxyla ion o In e nal
Alkynes. O g. Le . 2018,20, 7851–7855. [C ossRe ]
70.
Fuwa, H.; Sasaki, M. Exploi ing Ru henium Ca bene-Ca alyzed Reac ions in To al Syn hesis o Ma ine Oxacyclic Na u al P oduc s.
Bull. Chem. Soc. Jpn. 2016,89, 1403–1415. [C ossRe ]
71.
Ka abulu , S.; Öz ü k, B.Ö.; ˙
Imamo˘glu, Y. Ru-media ed selec i e addi ion eac ions o ca boxylic acids o in e nal and e minal
alkynes. J. O ganome . Chem. 2010,695, 2161–2166. [C ossRe ]
72.
Öz ü k, B.Ö.; Gü cü, D.; ¸Sehi o˘glu, S.K. Ca boxylic acid addi ion o e minal alkynes u ilizing ammonium agged Ho eyda-
G ubbs ca alys suppo ed on magne ically sepa able co e/shell silica: A highly eusable and ai compa ible ca aly ic sys em.
J. O ganome . Chem. 2019,883, 11–16. [C ossRe ]
73.
Melis, K.; Ops al, T.; Ve poo , F. Selec i e Dime isa ion and Addi ion o Ca boxylic Acids o Te minal Alkynes, Ca alysed
by The molysed G ubbs’ Ca alys : A No el Syn hesis o Enynes and Vinyl Es e s. Eu . J. O g. Chem.
2002
,2002, 3779–3784.
[C ossRe ]
74.
Zheng, Y.; Liu, J.; Lei, X. Ru-Ca alyzed cascade eac ion o
α
,
ω
-alkynoic acids and a yle hylamines owa ds he syn hesis o
a yl- used he e o-cycles. O g. Chem. F on . 2020,7, 660–665. [C ossRe ]
75.
He e o, M.T.; Diaz de Sa alde, J.; SanMa in, R.; B a o, L.; Dominguez, E. Cesium Ca bona e-P omo ed Hyd oamida ion o
Alkynes: En-amides, Indoles and he E ec o I on(III) Chlo ide. Ad . Syn h. Ca al. 2012,354, 3054–3064. [C ossRe ]
76.
Díaz de Sa alde, J.; He e o, M.T.; SanMa in, R.; Domínguez, E. P ocedimien o Pa a la P epa ación de Polihe e ociclos
Ni ogenados Ca alizado po Compues os de Hie o. ES2549705, 30 Oc obe 2015.
77.
Diaz de Sa alde, J.; As obie a, E.; Se illa ARincón, Y.; He e o, M.T.; U goi ia, G.; SanMa in, R. I on-ca alyzed cascade syn hesis
o ni ogen polycycles om alkynoic acids and unc ionalized amines. En i on. Chem. Le . 2022,20, 3421–3427. [C ossRe ]
78.
Conde, N.; SanMa in, R.; He e o, M.T.; Domínguez, E. Palladium NNC Pince Complex as an E icien Ca alys o he
Cycloisome iza ion o Alkynoic Acids. Ad . Syn h. Ca al. 2016,358, 3283–3292. [C ossRe ]
79.
Conde, N.; He e o, M.T.; U goi ia, G.; SanMa in, R. Palladium-Ca alyzed Domino Cycloisome iza ion/Double Condensa ion o
Ace ylenic Acids wi h Dinucleophiles. Ca alys s 2022,12, 127. [C ossRe ]
80.
Yao, B.; Jaccoud, C.; Wang, Q.; Zhu, J. Syne gis ic E ec o Palladium and Coppe Ca alys s: Ca aly ic Cycliza i e Dime iza ion o
o ho-(1-Alkynyl)benzamides Leading o Axially Chi al 1,3-Bu adienes. Chem. Eu . J. 2012,7, 5864–5868. [C ossRe ]
81.
Neb a, N.; Mono , J.; Shaw, R.; Ma in-Vaca, B.; Bou issou, D. Me al
−
Ligand Coope a ion in he Cycloisome iza ion o Alkynoic
Acids wi h Indenediide Palladium Pince Complexes. ACS Ca al. 2013,3, 2930–2934. [C ossRe ]
82.
Zheng, L.-L.; Bo Yin, B.; Tian, X.-C.; Yuan, M.-Y.; Li, X.-H.; Gao, F. Pd/Cu bime allic co-ca alyzed di ec 2-a yla ion o benzoxazole
wi h a yl chlo ide. Te ahed on Le . 2019,60, 151316. [C ossRe ]
Disclaime /Publishe ’s No e:
The s a emen s, opinions and da a con ained in all publica ions a e solely hose o he indi idual
au ho (s) and con ibu o (s) and no o MDPI and/o he edi o (s). MDPI and/o he edi o (s) disclaim esponsibili y o any inju y o
people o p ope y esul ing om any ideas, me hods, ins uc ions o p oduc s e e ed o in he con en .
