Cu(ii)-thiophene-2,5-bis(amino-alcohol) mediated asymmetric Aldol reaction and Domino Knoevenagel Michael cyclization : a new highly efficient Lewis acid catalyst
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Cu(ii)- hiophene-2,5-bis(amino-alcohol) media ed asymme ic Aldol eac ion and
Domino Knoe enagel Michael cycliza ion : a new highly e icien Lewis acid ca alys
© 2022 he Au ho s
Published e sion
Al-Majid, Abdullah Mohammed; Alamma i, Abdullah Saleh; Alshah ani, Saeed;
Haukka, Ma i; Islam, Mohammad Shahidul; Ba aka , Assem
Al-Majid, A. M., Alamma i, A. S., Alshah ani, S., Haukka, M., Islam, M. S., & Ba aka , A. (2022).
Cu(ii)- hiophene-2,5-bis(amino-alcohol) media ed asymme ic Aldol eac ion and Domino
Knoe enagel Michael cycliza ion : a new highly e icien Lewis acid ca alys . RSC Ad ances,
12(10), 6149-6165. h ps://doi.o g/10.1039/d2 a00674j
2022
Cu(II)- hiophene-2,5-bis(amino-alcohol) media ed
asymme ic Aldol eac ion and Domino
Knoe enagel Michael cycliza ion: a new highly
efficien Lewis acid ca alys †
Abdullah Mohammed Al-Majid,*
a
Abdullah Saleh Alamma i,
a
Saeed Alshah ani,
a
Ma i Haukka,
b
Mohammad Shahidul Islam *
a
and Assem Ba aka
a
The highly efficien Lewis acid-ca aly ic sys em Cu(II)- hiophene-2,5-bis(amino-alcohol) has been
de eloped o enan ioselec i e Aldol eac ion o isa in de i a i es wi h ke ones. The new ca aly ic sys em
also p o ed o be highly enan ioselec i e o he one po h ee-componen Domino Knoe enagel
Michael cycliza ion eac ion o subs i u ed isa in wi h malononi ile and e hylace oace a e. The chi al
ligand (2S,20S)-2,20-(( hiophene-2,5-diylbis(me hylene))bis(azanediyl))bis(3-phenylp opan-1-ol) (L1)in
combina ion wi h Cu(OAc)
2
$H
2
O employed as a new Lewis acid ca alys , u nished 3-subs i u ed-3-
hyd oxyindolin-2-ones de i a i es (3a–s) in good o excellen yields (81–99%) wi h high
enan ioselec i i ies (up o 96% ee) and spi o[4H-py an-3,3-oxindole] de i a i es (6a–l) in excellen yields
(89–99%) wi h high ee (up o 95%). These aldol p oduc s and spi o-oxindoles cons i u e a co e s uc u al
mo i in a la ge numbe o pha maceu ically ac i e molecules and na u al p oduc s.
In oduc ion
The chi al ligand–Lewis acid–me al ca alysed ca bon–ca bon
bond cons uc ion p ocess has become inc easingly in e es ing
o syn he ic chemis s as well as pha macis s, o ca ying ou
a ious c ucial o ganic ans o ma ions. In pa icula , chi al
e sions o hese ca aly ic p ocesses a e one o he p ominen
s a egies o access se e al enan iopu e bioac i e molecules.
1–5
Among hem, he asymme ic Aldol eac ion and Domino
Knoe enagel Michael cycliza ion eac ion a e he mos powe ul
and efficien app oaches o accessing a ious enan iome ically
en iched biomolecules.
6,7
The co e amewo k ‘3-alkyl-3-hyd oxyindolin-2-ones’is
p esen in a la ge numbe o na u al p oduc s
8–14
and d ug
molecules
15–19
such as ma emycins,
17
a undaphine,
20
donaxa -
idine,
21
pa a unamide,
22
,(R)-con olu amydines A, B and E,
23–27
us aminol,
28
diazonamides,
29–33
lep osin D,
34
30-
hyd oxyglucoisa isin,
35
CPC-1,
36
3-hyd oxy welwi indolinones
C,
37
TMC-95 (A–D),
38–40
celogen in K,
41
dioxib assinin
42
(Fig. 1).
The e o e, he de elopmen o efficien and p ac ical
me hods o syn hesize his kind o building block is o g ea
impo ance and is cu en ly an open a ea o esea ch in asym-
me ic ca alysis.
43–45
A ep esen a i e example has been de el-
oped ecen ly o asymme ic Aldol eac ion o ke ones wi h
Fig. 1 P ominen bioac i e compounds based 3-subs i u ed-3-
hyd oxy-2-oxindoles and spi o[4H-py an-3,30-oxindole] mo i s.
a
Depa men o Chemis y, College o Science, King Saud Uni e si y, P. O. Box 2455,
Riyadh 11451, Saudi A abia. E-mail: 436106737@s uden .ksu.edu.sa;
[email p o ec ed]; [email p o ec ed]du.sa; chemis y99y@gmail.
com; [email p o ec ed].sa; [email p o ec ed]; [email p o ec ed]; Fax: +966-
61-1467-5992
b
Depa men o Chemis y, Uni e si y o Jy ¨
askyl¨
a, P. O. Box 35, FI-40014 Jy ¨
askyl¨
a,
Finland. E-mail: ma i.o.haukka@jyu.
†Elec onic supplemen a y in o ma ion (ESI) a ailable. CCDC 2143162. Fo ESI
and c ys allog aphic da a in CIF o o he elec onic o ma see DOI:
10.1039/d2 a00674j
Ci e his: RSC Ad ., 2022, 12,6149
Recei ed 31s Janua y 2022
Accep ed 9 h Feb ua y 2022
DOI: 10.1039/d2 a00674j
sc.li/ sc-ad ances
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a ious isa ins which is one o he mos s aigh o wa d and
powe ul me hods in o de o achie e highly enan iopu e bio-
logically ac i e co e amewo k ‘3-alkyl-3-hyd oxyindolin-2-
ones’wi h new chi al s e eocen e s.
46–52
E e since, p oline
ca alysed c oss-Aldol eac ion o aldehydes and ke ones s
epo ed by Lis and Ba bas in 2000,
53
since hen, lo o chi al
amine ligands ha e been used as o gano-ca alys o he c oss-
Aldol asymme ic eac ion.
47,54
In 2005, o he s ime asym-
me ic Aldol eac ion o isa in wi h ace one was s de eloped
by Tomasini e al. employing dipep ide-based ligand as o ga-
noca alys .
55–59
Howe e , signican effo s ha e been made o
de eloping efficien asymme ic Aldol eac ions o isa ins wi h
ke ones mos ly using o ganoca alys s such as p oline,
60–62
p o-
linamides,
63–69
sulphonamides,
70–72
amines,
73,74
quinidine- hio-
u eas,
75–77
icinal amino-alcohol,
78
enzymes,
79
4-
hyd oxydia ylp olinol
80
and amino acid sal s.
81
The spi o-he e ocyclic oxindoles a e he eye-ca ching a ge s
o he syn he ic chemis and biologis because o hei biolog-
ical signicance o a wide- ange o syn he ic u ili y such as
alkaloids in e media es, d ug candida es and clinical pha ma-
ceu icals agen s.
82–89
In pa icula , ‘spi o[4H-py an-3,30-oxin-
dole]’moie y is he mos impo an he e ocyclic skele on ha
could be ound in spi ooxindoles amewo k complex mole-
cules o se e al alkaloids and d ug agen s.
82,83
O e he couple
yea s, sizable numbe o in es iga ion ha e been ca ied ou
success ully o he cons uc ion o spi o[4H-py an-3,30-oxin-
dole] amewo k as a co e skele on o spi ooxindole s uc-
u es.
90–92
Domino Knoe enagel Michael cycliza ion is one o he
highly success ul p ocedu es o he s e eoselec i e syn hesis o
spi ooxindole de i a i es de i ed spi o[4H-py an-3,30-oxindole]
moie y.
93,94
To cons uc his in e es ing scaffold, Yuan and co-
wo ke s in 2010 o he s ime, u ilized cup eine-(60-
hyd oxycinchonidine) as o ganoca alys o accessing chi al
spi o[4H-py an-3,30-oxindole] de i a i es om mul i compo-
nen eac ions o N-alkyla ed isa ins.
95
Recen ly, Nakano e al.
epo ed hyb id squa amide amino alcohol o gano-ca alyzed
asymme ic Domino Michael cycliza ion eac ions o oxoindo-
lines wi h cyclic 1,3-dike ones, affo ding chi al spi o-
conjuga ed oxindoles e he ing 2-aminopy ans he e ocyclic
ing sys ems wi h excellen yield and enan ioselec i i y.
96
In
2019, Swapna Konda and co-wo ke s syn hesized chi al spi o
[4H-py an-3,30-oxindole] de i a i es wi h good chemical yield
(up o 92%) and enan ioselec i i y (up o 87% ee) using
cinchona alkaloid hiou eas as an o ganoca alys s.
97
Howe e ,
ill da e e y limi ed effo s ha e been made o he cons uc ion
o s e eoselec i e spi o-he e ocyclic oxindole, eng aing 2-
amino-4H-py an-3-ca boni ile ing a he C
3
posi ion o oxin-
dole ia asymme ic Domino Michael cycliza ion eac ion.
Howe e , e y limi ed ndings ha e been epo ed o he
applica ion o Lewis acid ca alyzed asymme ic Aldol eac ion
98
o ke ones wi h isa in in o de o excess de i a i e o ‘3-alkyl-3-
hyd oxyindolin-2-ones’and asymme ic Domino Michael cycli-
za ion eac ion
99–101
o isa in wi h malononi ile and e hyl-
ace oace a e o u nish enan iopu e spi o[4H-py an-3,30-
oxindole] de i a i es. The e o e, u he in es iga ions a e
equi ed o p oduce bioac i e mo i like ‘3-alkyl-3-
hyd oxyindolin-2-ones’and spi o[4H-py an-3,30-oxindole] using
Lewis acid ca alys , ha emains a g ea challenge.
Recen ly, a se ies o new chi al bis(amino-alcohol) hiophene
ligands-Cu(OAc)
2
$H
2
O as a Lewis acid ca aly ic sys em ha e
been de eloped by ou g oup and hei ca aly ic applica ion was
success ully applied o enan ioselec i e Hen y eac ion o
affo d he co esponding chi al Hen y p oduc wi h sa is ac o y
yield and enan ioselec i i y.
5
On obse ing hei good ca aly ic
enan ioselec i e induc ion in he Hen y eac ion, we decided o
explo e he u ili y o hose chi al ligands o diffe en applica-
ions such as enan ioselec i e Aldol eac ion as well as Domino
Michael cycliza ion eac ion.
As pe he bes o ou knowledge, we a e epo ing o he
s ime chi al bis(amino-alcohol) hiophene ligand–Lewis acid
ca alysed enan ioselec i e Aldol eac ion o isa ins wi h
subs i u ed ace one o p oduce enan iopu e 3-subs i u ed-3-
hyd oxy-2-oxindoles de i a i es as well as Domino Michael
cycliza ion eac ion o isa ins wi h malononi ile and e hyl-
ace oace a e o affo d he chi al oxindoles spi o[4H-py an-3,30-
oxindole] used wi h 2-aminopy ans he e ocyclic ing sys ems.
Resul s and discussion
Ca aly ic asymme ic s udies o Aldol eac ion
The ollowing ligands as shown in Fig. 2 epo ed ecen ly by
ou esea ch g oup as an examples o C
2
-symme ic chi al
hiophene-2,5-bis(amino-alcohol) ligands (L1–L5) and success-
ully applied hem in ca aly ic asymme ic Hen y eac ion o
ni ome hane wi h subs i u ed aldehydes in excellen yield and
enan ioselec i i y (yield up o 99% and ee up o 95%).
5
(Fig. 2).
We u he decided o examine hei asymme ic ca aly ic effi-
ciency and he e o e enan ioselec i e Aldol eac ion o isa in
wi h subs i u ed ace one as well as h ee-componen chi al
Domino Michael cycliza ion eac ion o isa in wi h malononi-
ile and e hylace oace a e ha e been explo ed success ully.
Ini ially, Aldol eac ion o 5-b omoisa in (1a) wi h ace one
(2a) as model subs a e we e ca ied ou o accessing 3-
subs i u ed-3-hyd oxy-2-oxindoles de i a i es, using 20 mol%
chi al hiophene-2,5-bis(amino-alcohol) ligands (L1–L5)as
o ganoca alys s in e hanol (2 mL) a oom empe a u e ( )
unde ine a mosphe e o 24–48 h and we obse e ha , all he
ligands we e ound o be efficien o u nish aldol p oduc 3a
(89–99% yield) in excellen yield bu un o una ely ailed o
induce enan ioselec i i y (16–21% ee) effec i ely (Table 1).
Then he ca aly ic efficacy o hese ligands we e examined in
combina ion wi h me al sal like coppe ace a e monohyd a e
(Cu(OAc)
2
$H
2
O) gene a ed a me al complex in si u as a Lewis
Fig. 2 C
2
-symme ic chi al hiophene-2,5-bis(amino-alcohol) ligands
(L1–L5) used o Aldol eac ion and Domino Michael addi ion eac ion.
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acid ca aly ic sys em o asymme ic Aldol eac ion o 5-b o-
moisa in (1a) wi h ace one (2a, 50 eq.). Subsequen ly, he eac-
ion was pe o med in e hanol (2 mL) a 25 C unde ine
a mosphe e, using 10 mol% o ligands L1–L5 wi h 20 mol% o
Cu(OAc)
2
$H
2
O o 24 h and he co esponding ndings we e
documen ed in Table 2. Fo una ely, all he ligands (L1–L5)
we e ound o be capable o p oducing aldol p oduc 3a wi h
signican ly enhanced enan ioselec i i y (44–58% ee) (Table 2,
en ies 1–5) bu he chemical yields we e signican ly d opped
(44–60%). In e es ingly, ligand L1 and L4 bea ing benzyl and -
bu yl g oup espec i ely we e ound o be he mos effec i e
ligand in combina ion wi h Cu(OAc)
2
$H
2
O, u nishing highes
yield (60% and 58%) acco dingly. Howe e , highe enan iose-
lec i i y (58% ee) was obse ed in p esence o L1 as compa ed o
L4 (48% ee) (Table 2, en ies 1 and 4) and he e o e L1 has been
chosen o u he op imiza ion.
In o de o imp o e he yield and enan ioselec i i y, asym-
me ic Aldol eac ion o 5-b omoisa in (1a) wi h ace one (2a,50
eq.) was u he in es iga ed. The effec o diffe en me al sal s
such as Cu(OAc)
2
$H
2
O, Zn(OAc)
2
$2H
2
O, Zn(OT )
2
, Mg(OT )
2
,
E (OT )
3
and Yb(OT )
3
as a Lewis acid as well as a ious sol en s
sys em like E OH, CH
2
Cl
2
, dioxane and THF we e explo ed,
using 10 mol% o ligand L1 wi h 20 mol% me al sal s a o e
he pe iod o 24–72 h and he summe y o he esul s we e
shown in Table 3. I is e iden om he esul s ha , he ca aly ic
sys em o L1-Cu(OAc)
2
$H
2
O in sol en s like CH
2
Cl
2
and
dioxane, imp o ed enan iome ic excess (ee) (74% & 76%)
espec i ely as compa ed o e hanol (yield 60%, ee 58%) bu he
chemical yields we e s ill low (58% and 45%) (Table 3, en ies 1–
3). Howe e , in case o ca aly ic sys em L1-Cu(OAc)
2
$H
2
O
(10 : 20 mol%) in THF as sol en was ound o be he bes choice
as Lewis acid ca alys o he asymme ic Aldol eac ion o 5-
b omoisa in (1a) wi h ace one (2a, 50 eq.), u nishing he bes
yield and enan ioselec i i y (65% yield, 82% ee) (Table 3, en y
4). Ne e heless, L1-Zn(OAc)
2
$2H
2
O in THF p oduce 50% yield
wi h e y poo enan ioselec i i y (17% ee) in 72 h (Table 3, en y
4). Mo eo e , ligand L1 in combina ion wi h me al sal s like
Zn(OT )
2
, Mg(OT )
2
, E (OT )
3
and Yb(OT )
3
in THF we e ound o
be comple ely ineffec i e o he asymme ic Aldol eac ion
(Table 3, en ies 6–9). The poo efficiency o Zn
+2
complex as
compa ed o Cu
+2
complex could be a ibu ed o he highe
elec onega i i y [EN o (Cu
2+
)¼1.90 > EN o (Zn
2+
)¼1.65] and
g ea e cha ge o adius a io o Cu
+2
han Zn
+2
ion, hose a e
wo ac o s pe haps help Cu
2+
o o m co alen bond wi h O
and N a oms o ligand s onge han Zn
2+
du ing he complex
o ma ion.
F om hese se e al a emp s o achie e accep able yield and
high enan ioselec i i y, i can be concluded ha , L1-Cu(OAc)
2
-
$H
2
O (10 : 20 mol%) as Lewis acid ca alys , in THF a o 24 h
Table 1 Enan ioselec i i y Aldol eac ion o 5-b omoisa in (1a) wi h
ace one (2a) ca alyzed by o ganoca alys s L1–L5
En ies
a
Ligands Time (h) Yield
b
(%) ee
c
(%)
1L1 24 99 21
2L2 24 99 16
3L3 24 99 19
4L4 24 99 20
5L5 48 89 20
a
Reac ions we e pe o med on 0.2 mmol o isa in and 10.0 mmol o
ace one.
b
Isola ed yields ae column pu ica ion.
c
Enan iome ic
excess (ee) was de e mined by chi al HPLC using a Daicel Chi alpak
AD-H (25 cm 4.6 mm 5mm).
Table 2 Enan ioselec i i y Aldol eac ion o 5-b omoisa in (1a) wi h
ace one (2a) ca alyzed by ligand (L1–L5) in p esence o Cu(OAc)
2
$H
2
O
En ies
a
Ligands Time (h) Yield
b
(%) ee
c
(%)
1L1 24 60 58
2L2 24 44 47
3L3 24 48 45
4L4 24 58 48
5L5 24 45 44
a
Reac ions we e pe o med on 0.2 mmol o isa in and 10.0 mmol o
ace one.
b
Isola ed yields ae column pu ica ion.
c
Enan iome ic
excess (ee) was de e mined by chi al HPLC using a Daicel Chi alpak
AD-H (25 cm 4.6 mm 5mm).
Table 3 Enan ioselec i i y Aldol eac ion o 5-b omoisa in (1a) wi h
ace one (2a); sol en s and me al sal sc eening
En ies
a
Sol en s Me al sal s Time (h) Yield
b
(%) ee
c
(%)
1 E OH Cu(OAc)
2
$H
2
O24 60 58
2CH
2
Cl
2
Cu(OAc)
2
$H
2
O24 58 74
3 Dioxane Cu(OAc)
2
$H
2
O24 45 76
4THF Cu(OAc)
2
$H
2
O24 65 82
5 THF Zn(OT )
2
72 T ace —
6 THF Zn(OAc)
2
$2H
2
O72 50 17
7 THF Mg(OT )
2
72 ——
8 THF Yb(OT )
3
72 ——
9 THF E (OT )
3
72 ——
a
Reac ions we e pe o med on 0.2 mmol o isa in and 10.0 mmol o
ace one.
b
Isola ed yields ae column pu ica ion.
c
Enan iome ic
excess (ee) was de e mined by chi al HPLC using a Daicel Chi alpak
AD-H (25 cm 4.6 mm 5mm).
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able o affo d be e yield and enan ioselec i i y o he asym-
me ic Aldol eac ion o 5-b omoisa in (1a) wi h ace one (2a,50
eq.). Howe e , u he op imiza ions a e equi ed as he esul s
we e no up o he ma ks as a as yields and enan ioselec ios
a e conce ned. The e o e, o he c ucial pa ame e s such as
loading o ca alys , equi alen o ace one, ime a ia ion and
empe a u e con ol we e u he sc eened o ob ain he bes
op imized condi ion o he asymme ic Aldol eac ion.
To nd ou he bes op imized pa ame e s, ini ially Aldol
eac ion we e pe o med using 5 mol% and 15 mol% o ligand
L1 wi h 20 mol% o Cu(OAc)
2
$H
2
O in THF a o 24 h and i
can be seen om he esul s ha nei he he yields (52% & 68%)
no enan ioselec i i ies (74% & 70% ee) we e imp o ed (Table 4,
en ies 1 & 2). Then he loading o Cu(OAc)
2
$H
2
O as me al sal
we e inc eased om 20 o 30 and 40 mol%, keeping he o he
pa ame e s unchanged (10 mol% o ligand L1 in THF a o 24
h). We obse ed ha , bo h he co esponding yields (88% and
88%) as well as enan iome ic excess (96% & 86% ee) we e
imp o ed signican ly (Table 4, en ies 3 & 4), al hough
10 : 30 mol% a io o L1-Cu(OAc)
2
$H
2
O was ound o be he bes
choice o he asymme ic Aldol eac ion as i has u nished he
nal p oduc 3a in excellen yield and enan ioselec i i y (88%
yield, 96% ee) (Table 4, en y 3). Nex , may be he empe a u e
has an impac on ca aly ic efficiency o his new ca aly ic
sys em. The e o e, he eac ion was u he pe o med, using
10 : 30 mol% o L1-Cu(OAc)
2
$H
2
O in THF a o 24 h a lowe
empe a u e 10 C as well as 0 C, bu un o una ely esul s
indica ed ha , he yields (69% & 53%) and enan ioselec i i ies
(73%, 71% ee) bo h we e signican ly d opped (Table 4, en ies
5 & 6) al hough p olong eac ion ime (48 h) was gi en. We
u he in es iga ed he eac ion wi h diffe en mola a io o
ace one (10, 20, 40, 60 eq.) unde he bes op imum pa ame e s
and he ndings a e epo ed in Table 4 en ies 7–10, s ill 50 eq.
o ace one is he bes choice o ge be e yield and
enan ioselec i i y. F om he o e all in es iga ion, we came o
conclusion ha , 10 mol% o ligand L1 wi h 30 mol% o
Cu(OAc)
2
$H
2
O in THF a o 24 h p oduced bes esul as we
ob ained aldol p oduc in high yield (88%) and enan iose-
lec i i y (96%).
Ae es ablishing s anda d eac ion pa ame e s, we
ex ended he subs a e scope o he asymme ic Aldol eac ion
unde he op imized eac ion condi ion, using Lewis acid
ca alys L1-Cu(OAc)
2
$H
2
O (10 : 30 mol%) in THF a o 24 h. A
a ie y o subs i u ed isa in (1a–l) wi h se e al ace one de i a-
i es (2a–h) we e sc eened o he asymme ic Aldol eac ion
using op imized eac ion pa ame e and he co esponding
aldol chi al de i a i es o 3-hyd oxyindolin-2-one (3a–s) we e
ob ained in good o excellen yields (81–99%) wi h mode a e o
high enan iome ic excess (35–96% ee) and he esul s a e
summa ized in Table 5. Ou op imized ca aly ic sys em wo ked
efficien ly in case o isa in de i a i es bea ing elec on-dona ing
g oups (5-Me and N-Me) which affo ded aldol p oduc s 3h (99%
yield, 93% ee) and 3j (91% yield, 89% ee) espec i ely (Table 5,
en ies 8 & 10). Excep ionally, 5-b omoisa in affo ded bes
enan ioselec i i y (96% ee) and good yield (88%) (Table 5, en y
1). While, in case o isa in de i a i es con aining elec on-
wi hd awing g oups such as 5-Cl, N-benzyl and N-e hyl-
b omide, his ca aly ic sys em also wo ked ema kable well and
affo ded espec i e aldol p oduc s (3c,3k and 3l) wi h excellen
yields (99%, 91% and 98%) and e y good enan iome ic excess
(76%, 78% and 71% ee) (Table 5, en ies 3, 11 & 12). Howe e ,
his ca aly ic sys em u nished aldol p oduc s 3b,3e,3 and 3i
wi h e y good yields (99%, 99%, 88% and 97%) and mode a e
enan ioselec i i ies (62%, 55%, 44% and 53% ee) when isa in, 5-
me hoxy, 5-ni o and 5-uo o isa in we e used as nucleophilic
cen e o Aldol eac ion (Table 5, en ies 2, 5, 6 & 9). No ewo hy
o men ion ha , while using 6-chlo o and 5,7-dib omo isa in o
he Aldol eac ion, ou ca aly ic sys em pe o med unde
Table 4 Enan ioselec i e Aldol eac ion o 5-b omoisa in (1a) wi h ace one (2a); loading o ca alys and empe a u e con ol
#
a
L1/Cu(OAc)
2
$H
2
O
(mol%) Ace one (eq.) Time (h) Temp (
o
C) Yield
b
(%) ee
c
(%)
1 05/20 50 24 25 52 74
2 15/20 50 24 25 68 70
310/30 50 24 25 88 96
4 10/40 50 24 25 88 86
5 10/30 50 48 10 69 73
6 10/30 50 48 0 53 71
7 10/30 10 24 25 65 82
8 10/30 20 24 25 72 85
9 10/30 40 24 25 79 86
10 10/30 60 24 25 74 85
a
Reac ions we e pe o med on a 0.2 mmol o isa in and 10–60 eq. o ace one.
b
Isola ed yields ae column pu ica ion.
c
Enan iome ic excess (ee)
was de e mined by chi al HPLC using a Daicel Chi alpak AD-H (25 cm 4.6 mm 5mm).
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Table 5 L1-Cu(OAc)
2
$H
2
O ca alyzed asymme ic Aldol eac ion o subs i u ed isa in (1a–l) wi h ke one (2a–h) unde op imized eac ion
pa ame e s. P oposed ansi ion s a es o he final compound
En ies
a
R
1
R
2
R
3
(2a–g)3a–sTime [h] Yield
b
[%] ee
c
[%] Abs. con .
d
1 5-B H CH
3
3a 24 88 96 (S)
d67
2HHCH
3
3b 30 99 62 (S)
d67
3 5-Cl H CH
3
3c 30 99 76 (S)
d67
4 6-Cl H CH
3
3d 30 99 35 (S)
d
5 5-OMe H CH
3
3e 30 99 55 (S)
d67
6 5-NO
2
HCH
3
3 30 88 44 (S)
d67
7 5,7-B H CH
3
3g 30 90 36 (S)
d67,78
8 5-CH
3
HCH
3
3h 35 99 93 (S)
d67
9 5-F H CH
3
3i 35 97 53 (S)
d67
10 H CH
3
CH
3
3j 38 91 89 (S)
d67,78
11 H Bn CH
3
3k 38 98 78 (S)
d67
12 H C
2
H
4
–B CH
3
3l 35 99 71 (S)
d
13 5-B H Ph 3m 15 93 77 (S)
d
14 5-B H 2-NO
2
Ph 3n 15 96 70 (S)
d
15 5-B H 4-FPh 3o 15 93 81 (S)
d
16 5-B H 4-B Ph 3p 15 92 81 (S)
d
17 5-B H 4-NO
2
Ph 3q 15 88 54 (S)
d
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expec a ion in inducing chi ali y in he aldol p oduc s and
affo ded 3d and 3g wi h poo enan ioselec i i ies (35% & 36%
ee), howe e quan i a i e chemical yields we e ob ained (99% &
90%) (Table 5, en ies 4 & 7).
In iew o he abo e ndings, we u he in es iga ed he
efficiency o ou bes ca aly ic sys em L1-Cu(II) as a Lewis acid
ca alys unde he op imized eac ion pa ame e s. Subse-
quen ly, he asymme ic Aldol eac ion o 5-b omo isa in (1a)
wi h subs i u ed ace one (2b–e,2h) we e ca ied ou and he
co esponding aldol p oduc 3m–pand 3s we e ob ained in
excellen yields (93%, 96%, 93%, 92% and 99%) wi h e y good
enan iome ic excess (77%, 70%, 81%, 81% and 85% ee) (Table
5, en ies 13–16, 19). Howe e , aldol p oduc 3q and 3 we e
u nished in good yields (88% and 81%) wi h mode a e enan-
iome ic excess (54% and 50% ee) while using p-ni o and p-
hyd oxy ace ophenone (2 ,2g) as subs a e o he Aldol eac ion
unde op imized eac ion condi ions o 15 h and he ndings
a e epo ed in Table 5, en ies 13–19.
Table 5 (Con d. )
En ies
a
R
1
R
2
R
3
(2a–g)3a–sTime [h] Yield
b
[%] ee
c
[%] Abs. con .
d
18 5-B H 4-OHPh 3 15 81 50 (S)
d
19 5-B H Cyclohexanone 3s 35 99 85 (S,R)
d72
a
Reac ions we e pe o med on a 0.2 mmol o isa in and 10.0 mmol o ace one o cyclohexanone in 2 mL o THF.
b
Isola ed yields ae column
pu ica ion.
c
Enan iome ic excess (ee) was de e mined by chi al HPLC using a Daicel Chi alpak AD-H/OD-H column (25 cm 4.6 mm 5
mm).
d
Absolu e congu a ions we e de e mined by c ys al s uc u e and e en ion ime ma ched wi h he li e a u e.
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No ewo hy o men ion ha , he (S)-enan iome elu ed as e
han (R)-enan iome in he HPLC ch oma og am o aldol
p oduc 3a–c,3e–l, while o he N-subs i u ed aldol p oduc 3j,
3k and 3l, e e se ends we e ollowed, hose a e epo ed in
he li e a u e.
67,78
Fo aldol p oduc 3s, e en ion ime o syn-
majo /mino and an i-majo /mino we e well ma ched wi h
he da a a ailable in he li e a u e.
72
The e o e, all he aldol
p oduc s a e p edominan ly ound o be en iched wi h (S)-
enan iome as hei e en ion ime and op ical o a ions we e
absolu ely in ag eemen wi h he li e a u e da a.
67,78
The abso-
lu e congu a ion o compound 3 was u he unambiguously
con med by single-c ys al X- ay analysis (CCDC numbe -
2143162, see ESI†S-64). In case o aldol p oduc s 3m– he
absolu e congu a ions we e also assigned as (S)-enan iome ,
assuming ha he eac ion ook place by ollowing uni o m
mechanis ic pa hway (Fig. 3).
Ca aly ic asymme ic s udies o Domino Knoe enagel Michael
cycliza ion
To illus a e he gene ali y o ca aly ic asymme ic applica ion
o ou Lewis acid ca aly ic sys em (10 : 30 mol% o L1-Cu(II)in
THF a oom empe a u e o 5–15 h), we ex ended he eac ion
scope and he e o e ca aly ic asymme ic Domino Knoe enagel
Michael cycliza ion eac ions we e pe o med using he same
op imized pa ame e s and he summa y o he ndings a e
documen ed in Table 6. F om he esul s o Domino Knoe e-
nagel Michael eac ion, i can be clea ly obse ed ha he
subs i u ed isa ins (1a–l) eac ed e y well wi h malononi ile (4)
and e hylace oace a e (5) in o de o u nished ano he se o
biologically impo an oxindoles de i a i es (6a–l) in excellen
yields (89–99%) and mode a e o high enan iome ic excess (24–
95% ee), hose cons i u es o spi o[4H-py an-3,30-oxindole]
mo i used wi h 2-aminopy ans he e ocyclic ing. I can be
Fig. 3 P oposed mechanism o Lewis acid ca alysis o asymme ic Aldol condensa ion eac ion.
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no iced ha his ca aly ic sys em p oduced bes yields (98%,
93% & 97%) and enan iome ic excess (91%, 87% & 95% ee)
when 5-b omo, 5-me hoxy and 5-me hyl isa ins we e subse-
quen ly used as subs a e (Table 5, en ies 1, 5 & 8); while in case
o 5-ni o and N-benzyl isa ins, ou ca aly ic sys em L1-
Cu(OAc)
2
$H
2
O a e also ound o be qui e capable o inducing
p e y good chi ali y (80% & 81% ee) wi h high yields (89% &
98%) acco dingly (Table 6, en ies 6 & 11). In case o isa in and
i s de i a i es such as 5-Cl, 6-Cl, 5,7-dib omo, 5-F and N-Me
isa ins, he ca alys L1-Cu(OAc)
2
$H
2
O pe o med e y well in
e ms o chemical yields (92–99%) o p oduce co esponding
spi o[4H-py an-3,30-oxindole] de i a i es 6b–d,6g,6i and 6j
wi h mode a e enan ioselec i i ies (41.7%, 57.1%, 47%, 50%,
39%, 63% ee) (Table 6, en ies 2–4, 7, 9 & 10). Ne e heless, his
ca aly ic sys em pe o med poo ly in p omp ing chi al induc-
ion when N-e hylb omide isa in was used as subs a e pe haps
due o he s e ic hind ance caused by he wo long chain o N-
e hylb omide o subs a e (1l) and enol-es e (5) (Fig. 4) and he
a e o eac ion is compa a i ely high as i has aken 5 h only
(89% yield, 24% ee). Howe e chemical con e sion is e y good
(Table 6, en y 12). All he Domino Knoe enagel Michael p od-
uc s a e ound o be en iched wi h (S)-enan iome
p edominan ly.
(R)-enan iome elu ed as e han (S)-enan iome in he
HPLC ch oma og am o Domino Knoe enagel Michael cyclized
spi o-oxindole p oduc s 6a–c,6e,6h and 6i, while o he N-
subs i u ed spi o-oxindole 6j,6k and 6l, e e se ends we e
ollowed, hose a e well epo ed in he li e a u e.
97
All he spi o-
oxindole p oduc s a e p edominan ly ound o be en iched wi h
(S)-enan iome as hei e en ion ime and op ical o a ion we e
well in ag eemen wi h he li e a u e da a.
97
The absolu e
congu a ion o spi o-oxindole p oduc s 6d,6 and 6g we e
also assigned as (S)-enan iome as hei e en ion ime ollowed
he simila ends as o compound 6a–c, assuming ha he
eac ion ook place by ollowing uni o m mechanis ic pa hway
(Fig. 4).
Expe imen al
Gene al
All he chemicals (isa in, de i a i es o isa in, ace one, ace one
de i a i es, me al sal s) and sol en s we e pu chased om
Sigma-Ald ich and used as ecei ed. Thiophene-2,5-bis(b-
amino-alcohol) ligands (L1–L5) we e eshly syn hesized om
comme cially a ailable hiophene-2,5-dica baldehyde and
chi al b-amino alcohols in a well d ied ask unde a s a ic
p essu e o ni ogen. S anda d p ocedu es we e ollowed o
sol en s d ying be o e usage. Reac ions we e moni o ed by hin
laye ch oma og aphy using Me ck silica gel 60 Kieselgel F254
TLC (Me ck, Kenilwo h, NJ, USA) and column ch oma og aphy
was pe o med on silica gel 100–200 (40–63 mm, ASTM) om
Me ck using he p ope sol en s.
1
H and
13
C-NMR spec a we e
eco ded in CDCl
3
and DMSO-d
6
on a Jeol Spec ome e (Jeol,
Tokyo, Japan) (500 MHz). The chemical shis a e epo ed
in ppm. All he acemic p oduc s we e eshly p epa ed as pe
Table 6 L1-Cu(OAc)
2
$H
2
O ca alyzed asymme ic h ee componen s one po syn hesis o spi ooxindole using subs i u ed isa in (1a–l), malo-
noni ile (4) and e hylace oace a e (5) unde op imized eac ion pa ame e s
En y
a
R
1
R
2
6a–lTime [h] Yield
b
[%] ee
c
[%] Abs. con .
d
1 5-B H 6a 15 98 91 (S)
97
2H H 6b 13 99 42 (S)
97
3 5-Cl H 6c 89657(S)
97
4 6-Cl H 6d 15 92 47 (S)
5 5-OCH
3
H6e 15 93 87 (S)
97
6 5-NO
2
H6 15 89 80 (S)
7 5,7-B H 6g 15 96 50 (S)
8 5-CH
3
H6h 15 97 95 (S)
97
9 5-F H 6i 15 98 39 (S)
97
10 H CH
3
6j 15 99 63 (S)
97
11 H Bn 6k 15 98 81 (S)
95,97
12 H C
2
H
4
–B 6l 58924(S)
a
Reac ions we pe o med on a 0.2 mmol o isa in in 2 mL o THF.
b
Isola ed yields ae column pu ica ion.
c
Enan iome ic excess (ee) was
de e mined by chi al HPLC using a Daicel Chi alpak AD-H column (25 cm 4.6 mm 5mm).
d
Absolu e congu a ions we e de e mined by
c ys al s uc u e and e en ion ime ma ched wi h he li e a u e.
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CH
3
OH); [ e . 97 [a]
24
D
¼+20.4(c1.0, MeOH)];
1
H-NMR (500
MHz, DMSO-d
6
): d(ppm) ¼7.48–7.45 (m, 2H, A –H), 7.33–7.30
(m, 2H, A –H), 7.28 (s, 1H, A –H), 7.25 (s, 2H, NH
2
), 7.20 ( d, J¼
7.7, 1.3 Hz, 1H, A –H), 7.15 (dd, J¼7.4, 1.3 Hz, 1H, A –H), 7.00
( d, J¼7.5, 1.0 Hz, 1H, A –H), 6.86 (d, J¼7.7 Hz, 1H, A –H), 5.00
(d, J¼15.8 Hz, 1H, CH
2(a)
Bn), 4.78 (d, J¼15.8 Hz, 1H,
CH
2(b)
Bn), 3.78 (q, J¼7.1 Hz, 1H, CH
2
CH
3
), 3.52 (dd, J¼10.8,
7.1 Hz, 1H, CH
2
CH
3
), 2.34 (s, 3H, CH
3
), 0.58 ( , J¼7.1 Hz, 3H,
CH
2
CH
3
);
13
C-NMR (126 MHz, DMSO-d
6
): d(ppm) ¼177.20,
164.38, 159.19, 158.86, 142.77, 136.19, 133.65, 128.40, 127.55,
123.34, 122.73, 117.57, 108.91, 104.55, 60.11, 56.12, 48.52,
43.39, 18.65, 13.08. All he analy ical da a a e well in ag eemen
wi h he epo ed li e a u e.
97
E hyl-(S)-20-amino-1-(2-b omoe hyl)-30-cyano-60-me hyl-2-oxo-
spi o[indoline-3,40-py an]-50-ca boxyla e (6l). 1-(2-B omoe hyl)
isa in 1l (50.8 mg, 0.2 mmol), malononi ile 4(13.2 mg, 0.2
mmol) and e hylace oace a e 5 (26.0 mg, 0.2 mmol) we e eac ed
acco ding o he GP2 o yield p oduc 6l as whi e solid; m.p.:
148–150 C; isola ed yield (76.9 mg, 89%). Enan iome ic excess
(ee) was de e mined by chi al HPLC [Daicel Chi alpak AD-H
column], 85.0% n-hexane/i-P OH, 1.0 mL min
1
;
majo
¼
15.03 min;
mino
¼24.53 min; l¼254 nm; 23% ee; [a]
20
D
¼
+5.34(c0.10, CH
3
OH); IR (KB ): 3382, 2924, 2854, 2191, 1709,
1682, 1613, 1599, 1486, 1466, 1419, 1380, 1348, 1282, 1253,
1211, 1149, 1077, 756, 682 cm
1
;
1
H-NMR (500 MHz, DMSO-d
6
):
d(ppm) ¼7.29 ( d, J¼7.6, 1.3 Hz, 1H, A –H), 7.23 (s, 2H, NH
2
),
7.18–7.13 (m, 2H, A –H), 7.03 ( d, J¼7.5, 1.0 Hz, 1H, A –H), 4.16
(ddd, J¼14.2, 7.7, 6.5 Hz, 1H, CH
3
CH
2(a)
), 4.03 (ddd, J¼14.2,
7.7, 6.1 Hz, 1H, CH
3
CH
2(b)
), 3.82 (dq, J¼11.0, 7.1 Hz, 1H,
NCH
2(a)
), 3.72 (qd, J¼7.1, 4.6 Hz, 1H, NCH
2(b)
), 3.63–3.57 (m,
2H, CH
2
B ), 2.33 (s, 3H, CH
3
), 0.71 ( , J¼7.1 Hz, 3H, CH
2
CH
3
);
13
C-NMR (126 MHz, DMSO-d
6
): d(ppm) ¼177.03, 164.32,
158.99, 142.18, 133.54, 128.76, 123.41, 122.84, 117.14, 108.70,
104.36, 60.25, 56.08, 48.41, 41.57, 28.36, 18.67, 13.22.
Conclusions
In summa y, we ha e de eloped e y efficien enan ioselec i e
p ocess o he asymme ic Aldol eac ion o subs i u ed isa in
wi h se e al ace one de i a i es using L1-Cu(II) as a new Lewis
acid ca alys based on hiophene-2,5-bis(amino-alcohol)
amewo k. Ou Lewis acid ca aly ic sys em L1-Cu(II) ac s b il-
lian ly and u nished aldol p oduc s 3a–sin high yields and
selec i i y (up o 99% yield; up o 96% ee). This ca aly ic sys em
L1-Cu(OAc)
2
$H
2
O was u he u ilized o asymme ic Domino
Knoe enagel Michael cycliza ion eac ion o subs i u ed isa in
wi h malononi ile and e hylace oace a e and affo ded chi al
spi o[4H-py an-3,3-oxindole] de i a i es 6a–lwi h high yields
and mode a e o high enan ioselec i i ies (up o 99% yield; up
o 95% ee). Bo h he eac ions we e pe o med unde mild
eac ion condi ion a oom empe a u e.
Au ho con ibu ions
Concep ualiza ion, A. M. A.-M. and A. B.; supe ision, A. M. A.-
M., A. B. and M. S. I; me hodology, A. S. A., M. S. I. and A. M. A.-
M.; alida ion, M. S. I., A. S. A., S. A. and A. M. A.-M.; o mal
analysis, A. S. A.; M. S. I. and S. A.; in es iga ion, A. S. A.; M. S. I.
and S. A.; esou ces, A. M. A.-M. and A. B.; da a cu a ion, A. S.
A., M. S. I., and A. B.; w i ing—o iginal d ap epa a ion, M. S.
I., A. B. and A. S. A.; w i ing— e iew and edi ing, M. S. I., A. B.
and A. M. A.-M.; isualiza ion, A. B., M. S. I and S. A.; p ojec
adminis a ion, A. M. A.-M. and A. B.; unding acquisi ion, A. M.
A.-M. and A. B.; sowa e A. S. A., M. S. I., M. A. and A. B.; all
au ho s ha e ead and ag eed o he published e sion o he
manusc ip .
Conflic s o in e es
The e a e no conic s o decla e.
Acknowledgemen s
The au ho s would like o ex end hei since e app ecia ion o
he Resea che s Suppo ing P ojec (RSP2022R427), King Saud
Uni e si y, Riyadh, Saudi A abia.
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