Gas-F ee Amino- and Alkoxyca bonyla ion o A yl Iodides
in a Bioinspi ed Deep Eu ec ic Sol en wi h Mo(CO)6as a
Sa e CO Sou ce
F ancesco Messa,[a] And ea Nicola Papa ella,[b] Dominik Veselý,[c] Joze K ajčo ič,[c]
Pa ide Papadia,[a] Se ena Pe one,*[a] and An onio Salomone*[d]
The Pd-ca alyzed amino- and alkoxyca bonyla ion o a yl
iodides has been exploi ed, o he i s ime, in a bioinspi ed
Deep Eu ec ic Sol en and unde gas- ee condi ions, by using
Mo(CO)6as he CO sou ce. The me hod allows o he
p epa a ion o ca boxylic amides and es e s in high yields (up
o 99%), sho eac ion ime (2 h) and unde mild eac ion
condi ions (80°C), wi h a low ca alys loading (2.5 mol%).
No ewo hy, in he case o N-hexylbenzamide, i has been
demons a ed ha bo h he ca alys and DES can be used o
ou consecu i e uns, wi h a mode a e dec ease o ca aly ic
e iciency. The me hodology has been also applied o he
p epa a ion o an Ac i e Pha maceu ical Ing edien used o he
ea men o human scabies and lice.
In oduc ion
The Pd-ca alyzed ca bonyla ion o o ganic halides is one o he
mos powe ul s a egies o he di ec inco po a ion o a
ca bonyl moie y in o an o ganic compound.[1–4] The ca bon-
yla ion eac ion is a mul icomponen p ocess which allows he
di ec syn hesis o a a ie y o impo an ca bonyl compounds,
including ca boxylic acids, es e s, amides, and ke ones. I is also
commonly used in he p oduc ion o he e ocyclic
compounds.[5–7] Following i s ini ial epo by R.F. Heck in
1974,[8] his me hodology has gained signi ican in e es and
a en ion in ecen yea s, no jus in academic esea ch bu also
in indus y, whe e i has become a c ucial ool o he
p oduc ion o ine chemicals and pha maceu ical ing edien s;
he e o e, i s e ec i eness and e sa ili y ha e made i a
ele an me hod o indus ial applica ions.[9] I is impo an o
ecognize ha ca aly ic ca bonyla ions o e bo h aluable
syn he ic applica ions and p omo e sus ainable p ac ices. By
allowing o he combina ion o an elec ophile, ca bon
monoxide, and a nucleophile in a single syn he ic s ep, ca aly ic
ca bonyla ions minimize was e gene a ion and elimina e he
need o in e media e isola ion. Addi ionally, his p ocess max-
imizes he a om economy, in line wi h he p inciples o g een
chemis y.[10,11]
His o ically, ca bonyla ion eac ions we e conduc ed unde
high p essu e o oxic ca bon monoxide, hus equi ing
specialized labo a o y equipmen such as s eel au ocla es.
Recognizing he po en ial dange s associa ed wi h his ap-
p oach, al e na i e me hods ha e been de eloped o eplace
gaseous CO wi h i s p ecu so s o sou ces. This has led o a
sa e and mo e accessible implemen a ion o hese eac ions in
a a ie y o expe imen al p o ocols: o mic acid,[12] alkyl- and
a yl o ma es,[13] N- o mylsaccha in,[14] chlo o o m,[15] acyl
chlo ides,[16] ca bon dioxide,[17] silaneca boxylic acid[18] and me al
ca bonyls[19–21] ha e been success ully employed as syn he ic
equi alen s o gaseous CO. Among me al ca bonyls, he
po en ial o molybdenum hexaca bonyl o acili a e ca bon-
yla ion eac ions has ecen ly a ac ed signi ican conside a ion
due o i s abili y o p o ide a sa e, p ac ical, and a manageable
solid sou ce o ca bon monoxide.[22] Mo(CO)6can elease CO
ei he h ough he mic ea men ,[23] o ligand exchange wi h
se e al Lewis bases such as DBU,[24] pipe idine,[25] o MeCN.[26]
In an e o o iden i y en i onmen ally iendly and sa e
eplacemen s o con en ional Pd-ca alyzed ca bonyla ion p o-
cedu es elying on gaseous CO, a ema kable esea ch s udy
has been conduc ed ha exploi s he u ili y o Mo(CO)6as
ca bon monoxide sou ce.[22]
Rega ding he mos no ably and sus ainable ca bonyla ion
me hods o gene al applicabili y, in 2014, he g oup o Lam and
Lo desc ibed a e sa ile mic owa e-assis ed ca bonyla ion o
[a] D . F. Messa, D . P. Papadia, D . S. Pe one
Dipa imen o di Scienze e Tecnologie
Biologiche ed Ambien ali, Uni e si à del Salen o
P o .le Lecce-Mon e oni, I-73100 Lecce (I aly)
E-mail: [email p o ec ed]
[b] D . A. N. Papa ella
Dipa imen o di Fa macia-Scienze del Fa maco
Uni e si à degli S udi di Ba i “Aldo Mo o”
Conso zio C.I.N.M.P.I.S., Via O abona, 4
I-70125 Ba i (I aly)
[c] D . D. Veselý, P o . J. K ajčo ič
B no Uni e si y o Technology, Facul y o Chemis y
Pu kyňo a 464/118, 612 00, B no (Czech Republic)
[d] P o . A. Salomone
Dipa imen o di Chimica
Uni e si à degli S udi di Ba i “Aldo Mo o”
Conso zio C.I.N.M.P.I.S., Via O abona, 4
I-70125 Ba i (I aly)
E-mail: [email p o ec ed]
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a yl b omides and iodides wi h alcohols o amines, in wa e o
unde nea condi ions. The p ocess led o he syn hesis o es e s
and amides hanks o he syne gy be ween Mo(CO)6, as CO
sou ce, and a luo ina ed oxime-based palladacycle, as he
ca alys . The ca aly ic sys em also showed an excellen ecycla-
bili y (Scheme 1a).[27]
In 2020, Bolm, He nandez and co-wo ke s epo ed a e y
as mechanochemical ca bonyla ion o a yl iodides unde he
ca alysis o a palladium-phosphine complex. The me hod
a o ded ca boxylic es e s and amides in mode a e o excellen
yields. The p essu e was moni o ed in eal- ime and he esul s
indica ed ha he ans e o he CO ligand om Mo(CO)6 o he
ac i e ca aly ic Pd-species occu ed apidly and wi hou signi i-
can elease o CO gas (Scheme 1b).[28]
A deep s udy, conduc ed in 2020 by Baye and colleagues,
showed a new me hod o pe o ming a Pd-ca alyzed ca bon-
yla ion o a yl b omides using enewable sol en s as eac ion
media, such as limonene, dime hylca bona e, and α-pinene.
This ou e, in ol ing he use o 9-me hyl-9H- luo ene-9-ca bonyl
chlo ide (COgen) as he sou ce o ca bon monoxide, was ca ied
ou unde mild eac ion condi ions (80°C), and esul ed in
mode a e o excellen yields o a oma ic amides, and es e s.
The me hodology equi ed a wo-chambe eac o , wi h one
chambe dedica ed o he elease o CO om COgen, which
was un in a pe oleum-de i ed sol en (1,4-dioxane),
Scheme 1c.[29]
In ligh o he la es indings, i is essen ial o encou age he
de elopmen o inno a i e echniques o he ca bonyla ion o
o ganic compounds ha elimina e he need o haza dous CO
gas. These me hods should p io i ize sa e y, a o dabili y, and
a om economy, while main aining high p ocess e iciency.
Ou ecen esea ch e o s ha e been dedica ed o he
ad ancemen o sus ainable syn he ic me hodologies using wo
dis inc app oaches; he i s one in ol es he use o mul iple
bond- o ming s a egies,[30–33] while he second app oach
ocuses on he eplacemen o oxic and ola ile o ganic
sol en s, de i ed om pe oleum, wi h Deep Eu ec ic Sol en s
(DESs).[34–40] These eu ec ic mix u es ep esen a p omising new
class o en i onmen ally iendly pola sol en s, o en de i ed
om bio- enewable sou ces, and wi h a ious applica ions in
sus ainable chemis y.[41]
Resul s and Discussion
Ou esea ch g oup p e iously epo ed he i s aminoca bony-
la ion o a yl iodides wi h p essu ized gaseous CO in cholinium
chlo ide-based DESs.[42] Mo eo e , we ha e ecen ly desc ibed
he i s alkoxyca bonyla ion o iodo a enes in me h-
yl iphenylphosphonium b omide/e hylene glycol (EG) eu ec ic
mix u e, which led o an easy p epa a ion o e hylene glycol
es e s, by using molybdenum hexaca bonyl as he CO sou ce
(Scheme 1d).[43]
As a na u al e olu ion o hese s udies, o imp o e bo h he
sus ainabili y and he gene al applicabili y o he ca bonyla ion
me hodology in eu ec ic mix u es, he ein we epo a no el
gas- ee alkoxy- and aminoca bonyla ion p ocess. Compa ed o
ou ecen wo k,[43] his me hod allows an e icien syn hesis o
bo h ca boxylic es e s and amides, by employing he na u e-
inspi ed, sus ainable, and easy o ecycle cholinium chlo ide
(ChCl)/u ea DES (Scheme 1e).
This gas- ee eac ion, ca alyzed by Pd(OAc)2, is pe o med
in he bioinspi ed ChCl/u ea (1:2) eu ec ic mix u e, a a low
empe a u e (80°C) and exploi s he powe o Mo(CO)6as a sa e
sou ce o CO (Scheme 1e).
Ou in es iga ion s a ed by pe o ming he ca bonyla i e
coupling be ween iodobenzene 1a and pipe idine 2 a, in ChCl/
u ea (1:2) as he g een eac ion medium, o ob ain N-
benzoylpipe idine 3aa. The ca aly ic sys em was composed by
Pd(OAc)2(5.0 mol%) and MePPh2(20 mol%), whe eas he
p esence o 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.5 mmol)
ensu ed he CO elease om Mo(CO)6; in hese expe imen al
condi ions, he a ge amide 3aa o med, a e 2 hou s, in
mode a e yield (60%, Table 1, en y 1). The eac ion wi hou
DBU (Table 1, en y 2) did no a o d he a ge p oduc 3aa,
al hough in he p esence o an excess o bo h MePh2P
(1.0 mmol) and pipe idine 2a (3.0 mmol), hus e idencing he
impo ance o a s ong Lewis base o he CO elease om Mo
complex.
When he ca alys loading was educed o 2.5 mol%, a
dec ease o 3aa yield was obse ed (52%, Table 1, en y 3).
In e es ingly, in he absence o he phosphine ligand, he amide
o ma ion inc eased up o 60%, al hough he Pd-loading
Scheme 1. Sus ainable Pd-ca alyzed ca bonyla ions in g een sol en s, o
nea condi ions, wi h al e na i e sou ces o ca bon monoxide.
Resea ch A icle
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emained unchanged (2.5 mol%) (Table 1, en y 4). By hal ing
he olume o DES o 1 mL (Table 1, en y 5) and he amoun o
Mo(CO)6 o 0.25 mmol (Table 1, en y 6), he p ocess eached a
sa is ying e iciency, p oducing he a ge amide in 84% yield,
in a eac ion ime o only 2 hou s and a 80°C.
The use o di e en sou ces o Pd (i.e., PdCl2and Pd/C)
sugges ed he peculia ca aly ic ac i i y o he Pd(OAc)2in he
eu ec ic mix u e; in ac , only aces o he p oduc 3aa we e
de ec ed in he c ude mix u e (Table 1, en ies 7–8).
Wi h he aim o educe he ca alys loading (1.0 mol%,
Table 1, en y 9) o o eplace DBU wi h g eene al e na i es
(i.e., NaOAc, KOH, K2CO3, Table 1, en ies 10–12), unsa is ac o y
ou comes esul ed, a o ding he expec ed amide 3aa in a 37–
50% yield.
The use o a non-p o ic e he eal sol en , such as he
biomass- de i ed CPME, was also in es iga ed bu wi h a lowe
esul (Table 1, en y 13): only 64% o he s a ing iodide 1a
was con e ed, a e 2 hou s a 80°C, p o iding he a ge
p oduc 3aa in 46% yield. Mo eo e , EI-MS and 1H-NMR
analyses o he c ude eac ion mix u e e ealed he p esence o
a by-p oduc (17% yield), p obably de i ing om he double
ca bonyla ion eac ion o s a ing iodide 1a; he by-p oduc
was iden i ied as he 1-phenyl-2-(pipe idin-1-yl)e hane-1,2-
dione and quan i ied by in e nal s anda d echnique (17%
yield).
Fu he mo e, he op imized p o ocol (Table 1, en y 6) was
applied o ca bonyla i e coupling be ween b omobenzene and
pipe idine, bu un o una ely he expec ed amide 3aa was no
o med. E en by inc easing he eac ion empe a u e o 100°C
and doubling he eac ion ime (4 h), only aces o he a ge
p oduc we e de ec ed in he c ude eac ion mix u e.
Amides a e widely sp ead in na u e and echnology.
Polypep ides and many syn he ic polyamides like he plas ics
Nylons, A amid, Twa on, and Ke la a e polyme s whose
monome s a e connec ed by amidic bonds.[44] Mo eo e , i is
wo hwhile o no e ha he amide sca old cons i u es one o
he mos aluable pha macopho es in medicinal chemis y
esea ch. Pa ace amol, penicillin, o examples, a e well known
d ugs including amide moie y in hei s uc u e.[45,46]
Once he op imal eac ion condi ions we e ound (Table 1,
en y 6), by a ying he a yl iodide and amine componen s, he
scope o his no el aminoca bonyla ion p o ocol in a g een
eu ec ic mix u e was p obed. The esul s a e summa ized in
Scheme 2.
Mos no ably, we we e pleased o ind ha , besides he
ca bonyla ion eac ion wi h pipe idine (2 a) as nucleophile,
a ious amines, bo h alipha ic and a oma ic, we e smoo hly
coupled wi h iodobenzene 1 a, a o ding he co esponding
amides 3aa–3a in mode a e o excellen yields (61-99%).
Pa icula ly, he simple long-chain p ima y n-hexylamine 2b
was p o ed o be a sui able subs a e o ou ca bonyla i e
p o ocol, ob aining he amide 3ab in quan i a i e yield. When
p ima y alipha ic N-nucleophiles, such as he 2-amino-2-me h-
ylp opan-1-ol 2c and cyclohexanamine 2d, we e employed, he
aminoca bonyla ion p ocess led o he desi ed amides 3ac–3ad
in mode a e yield (61–69%). This p o ocol wo ked e icien ly
also wi h he benzylamine 2 e and he aniline de i a i e 2 ,
gi ing he p oduc s 3ae and 3a in 95% and 91% yield,
espec i ely. The p esence o elec on-wi hd awing (Cl) o
elec on-dona ing (OMe) g oups on he phenyl moie y o he
a yl iodide does no a ec he end o he p ocess, bo h wi h
p ima y and seconda y alipha ic amines, leading o he desi ed
amide de i a i es 3ba,3bd and 3ca in 76–86% yields. Mo e-
o e , also he s e ically hinde ed 1-iodonaph halene 1 d can be
success ully applied o ou ca bonyla i e me hod, achie ing
3da in a 77% yield.
In o de o p o e he unc ional g oup ole abili y o he
me hod, he ca bonyla i e p o ocol was applied o 4’-iodoace-
ophenone 1e, bea ing a eac i e unc ionali y, ob aining he
co esponding amides 3ee in 86% yield. Also he use o an
he e oa yl subs a e such as he 3-iodopy idine 1 , led o he
nico inamide de i a i e 3 e in a sa is ac o y 75% yield.
The e o e, encou aged by he excellen esul s ob ained
wi h hese gas- ee aminoca bonyla ion eac ions, we p o-
ceeded o use he same ca aly ic sys em o he alkoxyca bony-
la ion o a yl halides, in ChCl/u ea (1:2) g een medium, o
a o d es e s.
Es e s a e widesp ead in na u e, as well as widely employed
bo h o indus ial and medical applica ions.[47] Se e al million
ons o polyes e s (i.e., polye hylene e eph hala e, ac yla e
es e s, cellulose ace a e) a e p oduced indus ially e e y yea [47]
and hey ep esen he la ges classes o syn he ic lub ican s on
he comme cial ma ke .[48] Mo eo e , because o hei pleasan
a oma, hey a e commonly used as ag ances.
Table 1. Sc eening o he eac ion condi ions o he aminoca bonyla ion
o iodobenzene 1a wi h pipe idine 2a and Mo(CO)6, in ChCl/u ea (1:2)
DES.[a]
en y Base Ligand Pd-Ca . [mol%] 3aa Yield [%][b]
1 DBU MePh2P Pd(OAc)2(5) 60
2[c] – MePh2P Pd(OAc)2(5) 0
3 DBU MePh2P Pd(OAc)2(2.5) 52
4 DBU – Pd(OAc)2(2.5) 60
5[d] DBU – Pd(OAc)2(2.5) 78
6[d,e] DBU – Pd(OAc)2(2.5) 84
7[d] DBU – PdCl2(2.5) 12
8[d] DBU – Pd/C (2.5) 3
9[d] DBU – Pd(OAc)2(1.0) 43
10[d] NaOAc – Pd(OAc)2(2.5) 46
11[d] KOH – Pd(OAc)2(2.5) 50
12[d] K2CO3– Pd(OAc)2(2.5) 37
13[ ] DBU – Pd(OAc)2(2.5) 46
[a] Reac ion condi ions: iodobenzene 1 a (0.5 mmol), pipe idine 2a
(1.5 mmol) Mo(CO)6(0.5 mmol), Pd-ca (2.5–5 mol%), base (1.5 mmol),
MePh2P ligand (20 mol%), ChCl/u ea (1/2 mol/mol, 2 mL), a 80°C o
2 hou s. (ChCl=Cholinium Chlo ide) [b] Calcula ed ia 1H NMR analysis o
he c ude eac ion mix u e using he in e nal s anda d echnique (NMR
in e nal s anda d: dime hyl sul one). [c] Reac ion pe o med wi h 1.0 mmol
o MePh2P and 3.0 mmol o 2 a. [d] Reac ion pe o med in 1 mL o DES.
[e] Reac ion pe o med wi h 0.25 mmol o Mo(CO)6. [ ] Reac ion pe o med
in CPME (1.0 mL). Beside he expec ed amide 3 aa, also 1-phenyl-2-
(pipe idin-1-yl)e hane-1,2-dione was de ec ed and quan i ied (17% yield)
by 1H NMR and EI-MS analyses on he c ude eac ion mix u e.
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In a model eac ion, iodobenzene 1a was ea ed wi h
benzyl alcohol 4a, in he p esence o Pd(OAc)2, Mo(CO)6and
DBU as he base. A e 2 hou s a 80°C, he expec ed benzyl
benzoa e 5aa o med in only 22% (Table 2, en y 1). E en by
doubling he Pd loading, he yield o he desi ed es e emained
unchanged (22%, Table 2, en y 2).
No ably, we ound ha he p esence o a phosphine ligand
in he mix u e was a key ac o in his alkoxyca bonyla ion
p ocess: he expe imen al esul s desc ibed in en ies 3–4
p o ided e idence ha he addi ion o Ph3P o MePh2P as
ca alys ligands signi ican ly imp o ed he es e o ma ion,
esul ing in a 5aa yield o 65% and 67%, espec i ely.
The inc ease in he alcohol 4 a concen a ion esul ed in an
enhancemen o he 5aa yield (79%, Table 2, en y 5), hus
sugges ing ha a compe i ion be ween he hyd oxyla ed DES
componen (cholinium chlo ide) and he nucleophile is ope -
a i e in ou ca bonyla i e coupling. Wi h he aim o educe he
amoun o noble me al in ol ed in he p ocess, we lowe ed he
DES olume (1 mL, Table 2, en y 6) and ound ha wi h only
2.5 mol% loading o ca alys and 10 mol% o MePh2P, he es e
5aa o med in sa is ac o y yield (70%). The ca aly ic ac i i y o a
p e o med PdII-phosphine complex was also es ed (Table 2,
en y 7), bu wi h less sa is ac o y esul s, as he benzyl
benzoa e 5aa was ob ained in 55% yield.
The bes expe imen al condi ions o his gas- ee alkox-
yca bonyla ion o 1a in he ChCl/u ea (1:2) medium, wi h
Mo(CO)6and Pd(OAc)2, we e inally gi en by hose ones
epo ed in Table 2, en y 8 (86% o 5 aa yield).
Scheme 2. Scope o Pd-Ca alyzed ca bonyla i e coupling be ween a oma ic iodides 1 a– and amines 2a– in ChCl/u ea (1:2) as g een medium and Mo(CO)6
as a sa e CO sou ce. Reac ion condi ions: a yl iodide (0.5 mmol), amine (1.5 mmol), Pd(OAc)2(2.5 mol%), Mo(CO)6(0.25 mmol), DBU (1.5 mmol), ChCl/u ea (1/
2 mol/mol, 1.0 mL), 80°C, 2 h. Isola ed yields a e epo ed.
Table 2. Sc eening o he eac ion condi ions o he alkoxyca bonyla ion
o iodobenzene 1a wi h benzyl alchohol 4 a and Mo(CO)6in ChCl/u ea
(1:2) DES.[a]
en y 4a
(mmol)
Pd-ligand Pd-Ca .
[mol%]
5aa Yield
[%][b]
1 1.5 – Pd(OAc)2(2.5) 22
2 1.5 – Pd(OAc)2(5) 22
3 1.5 Ph3P Pd(OAc)2(5) 65
4 1.5 MePh2P Pd(OAc)2(5) 67
5 3 MePh2P Pd(OAc)2(5) 79
6[c,d] 1.5 MePh2P Pd(OAc)2(2.5) 70
7[d] 1.5 – Pd(PPh3)2Cl2(2.5) 55
8[c,d] 3 MePh2P Pd(OAc)2(2.5) 86
[a] Reac ion condi ions: iodobenzene 1a (0.5 mmol), benzyl achohol 4a
(1.5 mmol), Pd-ca (2.5–5 mol%), Mo(CO)6(0.5 mmol), DBU (1.5 mmol),
MePh2P (0–20 mol%), ChCl/u ea (1/2 mol/mol, 2.0 mL). [b] Calcula ed ia
1H NMR analysis o he c ude eac ion mix u e using he in e nal s anda d
echnique (NMR in e nal s anda d: dime hyl sul one). [c] Reac ion pe -
o med wi h 10 mol% o MePh2P. [d] Reac ion pe o med in 1.0 mL o DES.
Resea ch A icle
doi.o g/10.1002/ejoc.202300309
Eu . J. O g. Chem. 2023,26, e202300309 (4 o 8) © 2023 The Au ho s. Eu opean Jou nal o O ganic Chemis y published by Wiley-VCH GmbH
Wiley VCH Mi woch, 14.06.2023
2324 / 304059 [S. 60/64] 1
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Any a emp o eplace DBU wi h a g eene base, o o
educe he ca alys loading, esul ed de imen al o he 5aa
yield (see ESI, Table S1).
I is impo an o no e ha , among he syn he ized es e s,
benzyl benzoa e 5aa ep esen s a aluable o ganic p oduc .
Fi s s udied medically in 1918,[49] i is lis ed in he Wo ld Heal h
O ganiza ion’s Lis o Essen ial Medicines[50] o he ea men o
human scabies and lice.[51]
Wi h he aim o explo e he applicabili y o he p esen
me hod, we also pe o med he syn hesis o API 5aa on a g am
scale. Unde he bes condi ions shown in Table 2 (en y 8), and
s a ing om 1.0 g ams o iodobenzene 1a, we we e pleased o
ind ha , despi e scaling up he eac ion by a ac o o 10, he
yield o benzyl benzoa e emained almos unchanged, a o ding
he benzoa e 5aa in 82% yield.
Unde he op imal condi ions (Table 2, en y 8), di e en
a yl iodides and alcohols we e es ed o showcase he subs a e
scope o his no el alkoxyca bonyla ion me hodology, employ-
ing Mo(CO)6as a sa e CO su oga e and he sus ainable eu ec ic
mix u e ChCl/u ea (1:2) as he sol en . A i s , di e en p ima y
and seconda y alipha ic alcohols we e selec ed as O-nucleo-
philic pa ne s in he ca bonyla ion p ocess. As shown in
Scheme 3, in he eac ion wi h iodobenzene 1a, 3,3-dime h-
ylbu an-1-ol 4b was con enien ly ans o med o he co e-
sponding es e 5ab, ob ained in good yield (83%). Also he
p ima y alcohol 4c eac ed well wi h 1a, gi ing he a ge es e
5ac in high yield (92%)
Compa ed o p ima y alcohols, he seconda y cyclohexanol
4d was p o en o be less e icien in he alkoxyca bonyla ion
p ocess, achie ing he es e 5ad in a 68% yield. Howe e , wi h
he use o o he seconda y alcohols, such as he hinde ed 9H-
luo en-9-ol 4e and (+)-bo neol 4 , he p o ocol wo ked
smoo hly, a o ding he co esponding es e s 5ae-5a in
excellen yields (88-97%). Mo eo e , he diol EG (4g) was
employed in he alkoxy ca bonyla ion o he halide 1a, albei
he desi ed EG-de i a i e 5ag o med in mode a e yield (70%).
In his case aces o he dies e p oduc we e de ec ed in he
mix u e (by GC-MS).
The p esence o elec on-wi hd awing (e.g. Cl) o elec on-
dona ing (e.g. Me- and MeO-) subs i uen s on he a yl iodide,
did no in luence signi ica i ely he e iciency o he p ocess,
esul ing in he syn hesis o he es e s 5bc–5cc and 5gc in high
yields (90–99%).
F om good o mode a e es e yields (81–71%) we e also
achie ed wi h he employmen o he iodide 1e deco a ed wi h
a eac i e unc ionali y and wi h he he e oa yl iodide 1 .
Addi ionally, a b ie in es iga ion was pe o med o es i
ou me hod could allow he ecycling o bo h ca alys and DES.
The Pd-ca alysed aminoca bonyla ion o iodobenzene 1a
wi h n-hexylamine 2b in ChCl/u ea (1:2) was chosen as he
model eac ion, since i p o ided almos quan i a i e yield o
he co esponding amide 3ab (Scheme 2). A e he i s
ca bonyla ion un, he c ude mix u e was ex ac ed wi h he
biomass-de i ed sol en 2-MeTHF,[52] a o ding he p oduc 3ab
Scheme 3. Scope o Pd-Ca alyzed ca bonyla i e coupling be ween a oma ic iodides 1 a–c,e–gand alcohols 4a–gin ChCl/u ea (1:2) as g een medium and
Mo(CO)6as a sa e CO sou ce. Reac ion condi ions: a yl iodide (0.5 mmol), alcohol (3.0 mmol), Pd(OAc)2(2.5 mol%), MePh2P (10 mol%), Mo(CO)6(0.5 mmol),
DBU (1.5 mmol), ChCl/u ea (1/2 mol/mol, 1.0 mL), 80°C, 2 h. Isola ed yields a e epo ed.
Resea ch A icle
doi.o g/10.1002/ejoc.202300309
Eu . J. O g. Chem. 2023,26, e202300309 (5 o 8) © 2023 The Au ho s. Eu opean Jou nal o O ganic Chemis y published by Wiley-VCH GmbH
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in a >98% yield (Figu e 1, numbe o cycles=0), lea ing he
ac i e ca alys species in he eu ec ic mix u e. The DES phase
was hen d ied unde acuum un il a cons an weigh .
Upon he simple addi ion o he new, esh eagen s [1 a,
2b, Mo(CO)6and DBU), he ca alys and eac ion medium could
be easily e-used o addi ional eac ion cycles. As shown in
Figu e 1, he ca alys emained ac i e o o e 4 uns.
Pa icula ly, i s ac i i y emained almos una ec ed in he
i s ecycle (98% o 3ab yield) and unde wen a g adual
deac i a ion du ing he second and he hi d ecycles, wi h
80% and 73% o 3 ab yield, espec i ely. The ecycling
e iciency su e ed a consis en dec ease om he ou h
ecycle, wi h a d op down in he chemical yield o he a ge
p oduc up o 12%.
The d op in he eac ion e iciency obse ed du ing he
ecycling p ocedu e could be explained as ollows. The ans-
o ma ion o Mo(CO)6and Pd(OAc)2du ing he ca aly ic cycle
could p oduce ino ganic solids, which accumula e in he
eac ion mix u e o e consecu i e uns, hus hinde ing he
s i ing and consequen ly dec easing he e iciency o he
p ocess. Addi ionally, du ing he successi e ca bonyla ion
eac ions, p o ona ed DBU (DBU-H+) accumula es in he DES
phase. This was con i med h ough a ca e ul cha ac e iza ion,
by 1H- and 13C-NMR, o he DES a e pe o ming he model
eac ion (see Suppo ing In o ma ion o mo e de ails).
Al hough lipophilic molecules, like he ca bonyla ion p od-
uc s, can be ex ac ed wi h 2Me-THF du ing he wo kup
p ocedu e, he ammonium ca ion DBU-H+s o es in he DES
phase, hus educing he medium basici y, known o be a
c ucial key ac o in aminoca bonyla ion p ocesses.
The possibili y ha a change in DES composi ion could be
esponsible o he dec ease in ecycling e iciency has also
been conside ed. Howe e , a quan i a i e 13C-NMR analysis on
he ChCl/u ea eu ec ic mix u e, a e unning a model eac ion,
showed ha he DES composi ion emained unchanged and
uled ou his hypo hesis (see Suppo ing In o ma ion o
u he de ails).
To gain a quan i a i e unde s anding o he en i onmen al
impac o ou ca bonyla i e coupling in DES, o he ca bon-
yla i e syn hesis o N-hexyl benzamide 3ab om iodobenzene
1a and N-hexylamine 2b, we calcula ed wo g een me ics,
namely EcoScale and E- ac o . Such pa ame e s we e hen
compa ed wi h he co esponding ones ela ed o he amino-
ca bonyla ions epo ed in Scheme 1. Based on he g een
me ic analysis, we de e mined ha ou me hodology exhibi ed
a compa able en i onmen al impac (EcoScale=44.5) o he
p ocedu e epo ed by Bolm (EcoScale=47), which was he
mos sus ainable among he compa ed me hods, as indica ed
by he EcoScale. Howe e , in e ms o he E-Fac o , ou p o ocol,
wi h a alue o 45.5, signi ican ly ou pe o med all o he s,
making i he mos a o able op ion (see Suppo ing In o ma-
ions o u he de ails).
Finally, wi h he aim o unde s and he ole o DES in his
eac ion, we endea o ed o conduc he ca bonyla ion eac ion
using a mix u e o he biomass-de i ed CPME, as a sus ainable
sol en , and ei he choline chlo ide o u ea as addi i es (20 w %
espec wi h CPME). Reg e ably, bo h choline chlo ide and u ea
exhibi ed minimal solubili y in his e he eal sol en , signi ican ly
hampe ing he ou come o ou expe imen al e o s. As a esul ,
he wo model ca bonyla i e eac ions, pe o med be ween
iodobenzene and pipe idine, yielded he amide 3aa in a simila
yield o 40–43%, i compa ed wi h he same eac ion pe o med
in pu e CPME. Based on li e a u e epo s, we suppose ha he
ole o DES componen s is s ic ly ela ed o he ionic cha ac e
o cholinium chlo ide; an aspec ha po en ially enables he
o ma ion o anionic Pd-species, which a e conside ed o ac as
he au hen ic ca alys s in c oss-coupling eac ions.[53]
Conclusion
To summa ize, we ha e de eloped a no el gas- ee ca bon-
yla ion p ocess o gene al applicabili y which aims a a mo e
sus ainable syn hesis o a oma ic es e s and amides, by using
Mo(CO)6as a sa e sou ce o ca bon monoxide in ChCl/u ea
(1:2), an en i onmen ally esponsible and bioinspi ed deep
eu ec ic sol en . This p ocess o e s a ious bene i s in compa -
ison o o he app oaches. These include he use o mild eac ion
condi ions (80°C), sho eac ion ime (2 h), low ca alys loading
(2.5 mol%), no equi emen o specialized lab equipmen , and
he possibili y o use bo h ca alys and DES o a leas 4
consecu i e uns, wi h only a modes dec ease in he ca aly ic
sys em‘s pe o mance. The p o ocol enables he syn hesis o
aluable es e s and amides in up o 99% yield, including a
pha macologically ele an molecule such as he benzyl
benzoa e 5aa, also syn hesized on a g am scale. Ou u u e
s udies will ocus on explo ing how he DES componen s could
acili a e ca bonyla ion eac ions, he eby b oadening he ange
o subs a es ha could be employed and ex ending he
esea ch o he use o non-noble me al ca alys s.
Expe imen al Sec ion
Syn hesis o amides 3aa–3 e by he aminoca bonyla ion eac ion
o a yl iodides in ChCl/u ea eu ec ic mix u e: In a 10 mL ound
bo om lask, a yl iodide (1a– , 0.5 mmol), Mo(CO)6(66.0 mg,
0.25 mmol), amine (2 a– , 1.5 mmol) DBU (228.3 mg, 224.0 μL,
1.5 mmol), Pd(OAc)2( ime ic, FW=673.46, 2.5 mol%, 0.0125 mmol,
8.4 mg) and ChCl/u ea (1:2) DES (1.0 mL) we e sequen ially added.
Figu e 1. Recycling o Pd(OAc)2and ChCl/u ea (1:2) in he ca bonyla i e
syn hesis o N-hexyl benzamide 3ab om iodobenzene 1a and N-hexyl-
amine 2b.
Resea ch A icle
doi.o g/10.1002/ejoc.202300309
Eu . J. O g. Chem. 2023,26, e202300309 (6 o 8) © 2023 The Au ho s. Eu opean Jou nal o O ganic Chemis y published by Wiley-VCH GmbH
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The eac ion was s i ed o 2 hou s a 80°C. A e his ime, he
eac ion mix u e was cooled o oom empe a u e and wa e
(2.5 mL) and HCl solu ion (10% / ) up o pH=2 we e sequen ially
added. The mix u e was hen ex ac ed wi h AcOE (5 mL×3) and
he euni ed o ganic phases we e washed wi h b ine, d ied o e
anhyd ous Na2SO4, il e ed h ough a celi e pad and e apo a ed
unde educed p essu e. The c ude was pu i ied by lash column
ch oma og aphy on silica gel (using as eluen pe oleum e he /
AcOE 70/30 o pe oleum e he /AcOE 50/50), ob aining he
desi ed amides 3aa–3 e as pu e compounds.
Syn hesis o es e s 5aa–5 c by he alkoxyca bonyla ion eac ion
o a yl iodides in ChCl/u ea eu ec ic mix u e: In a 10 mL ound
bo om lask, a yl iodide (1a–c,e–g, 0.5 mmol), Mo(CO)6(132.0 mg,
0.5 mmol), alcohol (4 a–g, 3.0 mmol) DBU (228.3 mg, 224.0 μL,
1.5 mmol), Pd(OAc)2( ime ic, FW=673.46, 2.5 mol%, 0.0125 mmol,
8.4 mg), MePh2P (10.0 mol%, 0.05 mmol, 10.0 mg, 9.3 μL) and ChCl/
u ea (1:2) DES (1.0 mL) we e sequen ially added. The eac ion was
s i ed o 2 hou s a 80°C. A e his ime, he eac ion mix u e was
cooled o oom empe a u e and wa e (2.5 mL) and HCl solu ion
(10% / ) up o pH=2 we e sequen ially added. The mix u e was
hen ex ac ed wi h AcOE (5 mL×3) and he euni ed o ganic
phases we e washed wi h b ine, d ied o e anhyd ous Na2SO4,
il e ed h ough a celi e pad and e apo a ed unde educed
p essu e. The c ude was pu i ied by lash column ch oma og aphy
on silica gel (using as eluen pe oleum e he /AcOE 98/2 o
pe oleum e he /AcOE 70/30), ob aining he desi ed es e s 5aa–
5 c as pu e compounds.
Suppo ing In o ma ion
Addi ional e e ences ci ed wi hin he Suppo ing In o ma ion.
[54-74]
Acknowledgemen s
S.P. acknowledges Regione Puglia o unding Resea ch o
Inno a ion (REFIN)” – P ojec “Sin esi a basso impa o ambien ale
di molecole a macologicamen e a i e in sol en i eu e ici di
o igine na u ale”, p ojec no. D2464488, in he amewo k o POR
PUGLIA FESR-FSE 2014/2020 p ojec s. D.V. acknowledges he
p ojec No. FCHS-23-8208 “New ad anced ma e ials and ma e ial
echnologies o con empo a y social needs”.
Con lic o In e es s
The au ho s decla e no con lic o in e es .
Da a A ailabili y S a emen
The da a ha suppo he indings o his s udy a e a ailable
om he co esponding au ho upon easonable eques .
Keywo ds: alkoxyca bonyla ion ·aminoca bonyla ion ·Pd-
ca alysis ·deep eu ec ic sol en ·molybdenum hexaca bonyl
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