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Exploi ing he Chi al Ligands o Bis(imidazolinyl)- and Bis(oxazolinyl) hiophenes :
Syn hesis and Applica ion in Cu-Ca alyzed F iedel–C a s Asymme ic Alkyla ion
© 2021 by he au ho s. Licensee MDPI, Basel, Swi ze land
Published e sion
Islam, Mohammad Shahidul; Alamma i, Abdullah Saleh; Ba aka , Assem;
Alshah ani, Saeed; Haukka, Ma i; Al-Majid, Abdullah Mohammed
Islam, M. S., Alamma i, A. S., Ba aka , A., Alshah ani, S., Haukka, M., & Al-Majid, A. M. (2021).
Exploi ing he Chi al Ligands o Bis(imidazolinyl)- and Bis(oxazolinyl) hiophenes : Syn hesis and
Applica ion in Cu-Ca alyzed F iedel–C a s Asymme ic Alkyla ion. Molecules, 26(23), A icle
7408. h ps://doi.o g/10.3390/molecules26237408
2021
molecules
A icle
Exploi ing he Chi al Ligands o Bis(imidazolinyl)- and
Bis(oxazolinyl) hiophenes—Syn hesis and Applica ion in
Cu-Ca alyzed F iedel–C a s Asymme ic Alkyla ion
Mohammad Shahidul Islam 1,* , Abdullah Saleh Alamma i 1, Assem Ba aka 1, Saeed Alshah ani 1,
Ma i Haukka 2and Abdullah Mohammed Al-Majid 1,*


Ci a ion: Islam, M.S.; Alamma i,
A.S.; Ba aka , A.; Alshah ani, S.;
Haukka, M.; Al-Majid, A.M.
Exploi ing he Chi al Ligands o
Bis(imidazolinyl)- and
Bis(oxazolinyl) hiophenes—Syn hesis
and Applica ion in Cu-Ca alyzed
F iedel–C a s Asymme ic
Alkyla ion. Molecules 2021,26, 7408.
h ps://doi.o g/10.3390/
molecules26237408
Academic Edi o : Alexande
Vik o o ich Akseno
Recei ed: 2 No embe 2021
Accep ed: 3 Decembe 2021
Published: 6 Decembe 2021
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
published maps and ins i u ional a il-
ia ions.
Copy igh : © 2021 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/).
1Depa men o Chemis y, College o Science, King Saud Uni e si y, P.O. Box 2455,
Riyadh 11451, Saudi A abia; [email p o ec ed] o [email p o ec ed] (A.S.A.);
[email p o ec ed] (A.B.); [email p o ec ed] o [email p o ec ed] (S.A.)
2Depa men o Chemis y, Uni e si y o Jy äskylä, P.O. Box 35, FI-40014 Jy äskylä, Finland;
[email p o ec ed] (M.H.)
*Co espondence: [email p o ec ed] (M.S.I.); [email p o ec ed] (A.M.A-M.)
Abs ac :
Fi e new C
2
-symme ic chi al ligands o 2,5-bis(imidazolinyl) hiophene (
L1–L3
) and 2,5-
bis(oxazolinyl) hiophene (
L4
and
L5
) we e syn hesized om hiophene-2,5-dica boxylic acid (
1
)
wi h enan iopu e amino alcohols (
4a
–
c
) in excellen op ical pu i y and chemical yield. The u il-
i y o hese new chi al ligands o F iedel–C a s asymme ic alkyla ion was explo ed. Subse-
quen ly, he op imized iden a e ligand
L5
and Cu(OT )
2
ca alys (15 mol%) in oluene o 48 h
p omo ed F iedel–C a s asymme ic alkyla ion in mode a e o good yields (up o 76%) and wi h
good enan ioselec i i y (up o 81% ee). The bis(oxazolinyl) hiophene ligands we e mo e po en han
bis(imidazolinyl) hiophene analogues o he asymme ic induc ion o he F iedel–C a s asymme -
ic alkyla ion.
Keywo ds:
bis-oxazoline; bis-imidazoline; hiophene; indoles;
β
-ni oole ins; asymme ic ca alysis;
F iedel−C a s alkyla ion
1. In oduc ion
Me al-ca alyzed asymme ic ans o ma ion has become one o he mos desi able
s a egies in ad anced syn he ic chemis y o access a a ie y o enan iopu e o ganic
molecules [
1
–
8
]. The op ically ac i e sys em can be achie ed by means o a ious me hod-
ologies, such as chi al ligands assis ed o ganoca alysis [
9
–
11
] and enzyme-ca alyzed
asymme ic con e sion [
12
–
14
]. In addi ion, mo e ad anced and e ined app oaches
ha e been in oduced e ec i ely, such as s e eo-con e gen [
15
–
17
] and s e eo-di e gen
syn hesis [18–21] in o de o acqui e innume able chi al amewo ks.
Chi al ligand–Lewis acid me al complex-ca alyzed asymme ic F iedel–C a s alky-
la ion eac ions play a pi o al ole in syn he ic o ganic chemis y o he cons uc ion
o new C–C bonds [
22
–
26
]. Du ing he pas ew yea s, se e al chi al bidenda e ligands
ha e been de eloped and used in he Lewis acid me al-ca alyzed asymme ic F iedel–
C a s alkyla ion eac ion o indole wi h a ious subs a es, including
α
,
β
-unsa u a ed-R-
ke oes e s (R = alkyl, a yl) [
27
,
28
], R-hyd oxy enones (R = alkyl, a yl) [
29
,
30
], alkylidene
malona es [
31
–
33
], acyl phosphona es [
34
,
35
], acyl he e ocyclic compounds [
36
–
38
], N-
sul onyl aldimines ca alyzed by Schi base complexes o Cu(II)-chi al amino alcohol [
39
],
α
- i luo ome hyla ed
β
-ni os y enes ca alyzed by chi al BINOL me al phospha e [
40
],
ni oole ins ca alyzed by oxazoline-imidazoline-Zn(II) [
41
], bis(oxazolinyl)-Cu(II) [
42
] and
2,5-bis(oxazolinyl) hiophenes-Cu(II) complexes [
43
]. Ve y ecen ly, Tanaka e al. ha e docu-
men ed homochi al me al–o ganic amewo k-ca alyzed enan ioselec i e F iedel–C a s
alkyla ion o N,N-dialkylanilines wi h ans-
β
-ni os y ene [
44
]. Tha being said, e y ew
Molecules 2021,26, 7408. h ps://doi.o g/10.3390/molecules26237408 h ps://www.mdpi.com/jou nal/molecules
Molecules 2021,26, 7408 2 o 22
examples o chi al me al–box-bis(oxazoline)/bis(imidazoline) complex-ca alyzed enan ios-
elec i e F iedel–C a s alkyla ion o indole wi h ni oole ins ha e been documen ed o
da e [41,45–47].
In ecen yea s, he applica ion o ni oole ins as elec ophiles has also been gaining
no able in e es among pha macis s due o he ac i a ion unc ionali y o he ni o g oups,
which acili a e easy con e sion o o he use ul unc ional g oups o achie e nume ous eye-
ca ching chemical en i ies [
48
,
49
]. Fu he mo e, op ically ac i e F iedel–C a s-alkyla ed
p oduc o indole wi h ni oole ins can also se e as an an eceden o he p epa a ion o
a ious d ug molecules such as physos igmine [
50
,
51
], which ac s as a clinically ac i e
an icholine gic d ug [
52
], Recen ly, some examples o ni oalkenes ha e also been epo ed
as Michael accep o s in me al-ca alyzed asymme ic eac ion due o he p esence o s ong
elec on-wi hd awing ni o-g oups [
48
,
53
,
54
] e.g., hodium-ca alyzed addi ions o bo onic
acids o ni oalkenes [
55
], coppe -ca alyzed dialkylzinc addi ions o ni oalkenes [
56
,
57
],
conjuga ed educ ions o ni oalkenes [
58
] and he o gano-ca alyzed addi ions o 1,3-
dica bonyl compounds o ni oalkenes [59,60].
Mo eo e , o da e, mos o he esea ch wo k has been done wi h he main am-
ily o chi al ligands p edominan ly belonging o di-phosphine, diamine, di-ol, e c., i.e.,
phospho ous-, ni ogen- and oxygen-con aining subs a e. Ve y li le esea ch has been
done in he ecen pas on de eloping chi al ligands based on sul u -con aining compounds.
The e o e, esea che s a e highly in e es ed in de eloping new chi al ligands based on a
sul u -con aining moie y due o hei high coo dina ion abili y o he mos o he ansi ion
me als [
61
]. The sul u a om is also conside ed as a so a om ha can bind s ongly o
so me als, in pa icula coppe me al Cu(II). In addi ion, sul u -con aining ligands a e
poo
π
-accep o s and poo
σ
-dono s as compa ed o phosphine ligands, esul ing in s ong
me al–sul u bond s eng h. Howe e , sul u -con aining ligand p ecu so s a e easily a ail-
able, ha ing ex a ad an ages such as easy s o age due o hei highe ole ance o ai as
compa ed o phosphine-con aining ligands, which makes hem highly s able [61].
Recen ly, chi al ligand–Lewis acid-ca alyzed asymme ic induc ion o indole wi h
p ochi al
β
-ni oole in has become one o he mos signi ican and success ul pa hways
o accessing highly unc ionalized op ically pu e building blocks. Ou esea ch g oup
has epo ed a new ca aly ic sys em based on he Cu(II) me al/chi al hiophene-2,5-bis(
β
-
amino alcohol) ligands o an asymme ic Hen y eac ion o ni ome hane wi h a oma ic
aldehyde wi h excellen ee (up o 94.6%) and chemical yield (up o 99%) [
62
]. In con-
inua ion o ou esea ch p og am, he e o e, he design and syn hesis o no el chi al
2,5-bis(imidazolinyl) hiophene and 2,5-bis(oxazolinyl) hiophene box- ype ligands and hei
applica ions in a ious asymme ic ca alyses emains a ema kable and in e es ing esea ch
opic o o ganic chemis s. Howe e , chi al ligands based on 2,5-bis(imidazolinyl) hiophene
and 2,5-bis(oxazolinyl) hiophene amewo k could also be ad an ageous o se e al asym-
me ic ans o ma ions o he han F iedel–C a s alkyla ion eac ions, such as asymme ic
Hen y eac ions [
63
,
64
], Diels–Alde eac ions [
65
,
66
], enan ioselec i e addi ions o di-
e hylzinc o acyclic enones [
67
–
69
], asymme ic allylic subs i u ions [
70
,
71
] and asymme ic
cyclop opana ion [
72
,
73
] eac ions, e c. Keeping in mind he wide ange o chi al applica-
ions o 2,5-bis(imidazolinyl) hiophene and 2,5-bis(oxazolinyl) hiophene box- ype ligands
and he di e se unc ionali y o ni oole ins, we ha e decided o ocus on his pa icula
esea ch ield.
In his esea ch a icle, we epo he syn hesis o no el chi al ligands hiophene-
2,5-2,5-bis(imidazolinyl) hiophene (
L1–L3
) and hiophene-2,5-bis(oxazolinyl) hiophene (
L4
and
L5
) and hei applica ions in Lewis acid me al-ca alyzed asymme ic F iedel–C a s
alkyla ions o indole wi h elec on-de icien p ochi al β-ni oole ins.
Figu e 1shows some o he p e iously epo ed po en ligand s uc u es used o asym-
me ic F iedel–C a s alkyla ion eac ions o indole wi h β-ni os y enes [41,42,62,74–78].
Molecules 2021,26, 7408 3 o 22
Figu e 1. P e iously epo ed po en ligand s uc u es o asymme ic FC eac ion.
2. Resul s and Discussion
2.1. Syn hesis o chi al 2,5-bis(imidazolinyl) hiophene (L1–L3) and 2,5-bis(oxazolinyl) hiophene
(L4 and L5)
Two se o C
2
-symme ic 2,5-bis(imidazolinyl) hiophene (
L1–L3)
and 2,5-bis(oxazolinyl)
hiophene (
L4
and
L5
) ligands, based on hiophene amewo k, we e syn hesized om
eadily a ailable and cheap hiophene-2,5-dica boxlyic acid (
1
) and chi al amino alcohols
(
3a
–
c
) using well-known p ocedu es epo ed in he li e a u e [
79
] in i e s eps, as shown
in Scheme 1. A he e y ou se , hiophene-2,5-dica boxlyic acid (
1
) was ea ed wi h
hionylchlo ide (SOCl
2
) in he p esence o a ca aly ic amoun o N,N-dime hyl o mamide
(DMF 2-3 d ops) unde e lux o 24 h, leading o he o ma ion o acid chlo ide (
2
) in
quan i a i e yields (c ude), which was hen allowed o eac wi h h ee di e en amino
alcohols (
3a
–
c
) in he p esence o excess ie hylamine (TEA) in dichlo ome hane (CH
2
Cl
2
)
o p oduce hiophene-2,5-dica boxamide alcohol de i a i es
(4a
–
c)
wi h o e all excellen
isola ed yield (75–97%). Thiophene-2,5-dica boxamide alcohol (
4a)
was hen e luxed in
hionylchlo ide (SOCl
2
) o 24 h o a o d c ude hiophene-2,5-dica boxamide dichlo ide
(
5a
), which se ed as an in e media e o he syn hesis o ou a ge ligands
L1–L3
, while
hiophene-2,5-dica boxamide alcohol (
4b
–
c
) was chosen as he p ecu so o he syn hesis
o ligands L4 and L5 (Figu e 2).
Ligands (
L1–L3)
we e syn hesized using he in e media e hiophene-2,5-dica boxamide
dichlo ide
5a
(2.92 mmol) by he eac ion o h ee di e en a oma ic amines
6a
–
c
(2.5 mmol)
(aniline
6a
,p-chlo oaniline
6b
,p- oludine
6c
) in he p esence o excessi e ie hylamine
(12 eq.) o o m a co esponding hiophene-2,5-dica boxamide in e media e (
7a
–
c
), which
unde wen a ing closu e eac ion upon ea men wi h 15% aqueous sodium hyd oxide
(NaOH) solu ion o o m c ude hiophene-2,5-bis(imidazolinyl) hiophene ligands (
L1–
L3
)
.
Then, he ligands we e u he pu i ied by column ch oma og aphy by elu ing wi h
E OAc/pe oleum e he /E
3
N ( : : = 75:24:1) o a o d pu e ligands
L1–L3
(Scheme 1).
The isola ed yields o he ligands we e ound o be in he ange o 35–40%.
Unde ine condi ion, ligands (
L4 and L5),
we e p epa ed om hiophene-2,5-dica b
oxamide alcohol (
4b and 4c)
by ing closu e eac ion upon being ea ed wi h osylcho ide
(1.25 eq.) and ie hylamine (4.0 eq.) in he p esence o a ca aly ic amoun o DMAP (ca .
0.1eq.) in dichlo ome hane (CH
2
Cl
2
) a e 48 h o s i ing a oom empe a u e. The ligands
we e hen pu i ied by column ch oma og aphy, using 95% CH
2
Cl
2
/CH
3
OH as an eluen o
a o d pu e ligands
L4
and
L5
(Scheme 1) wi h 60% and 55% isola ed yield, espec i ely. The
o ma ions o he compound hiophene-2,5-dica boxamide alcohol (
3a)
and all he ligands
(L1–L5) we e con i med and cha ac e ized by NMR and mass spec oscopy analysis.
Molecules 2021,26, 7408 4 o 22
Scheme 1.
2,5-bis(imidazolinyl) hiophene (
L1
–
L3
) and 2,5-bis(oxazolinyl) hiophene (
L4
and
L5
).
Reac ion condi ions:
(I) SOCl
2
(8 mL/g), ca . DMF, 24 h, e lux; (II) i. CH
2
Cl
2
, TEA (5 eq.),
−
10
◦
C; ii. Amino alcohol (
3a
–
c
) (2.1 eq.); (III)
4a
,
SOCl
2
(8.8 mL/g), e luxed, 24 h; (IV) i.
5a
, E
2
O, TEA (12.0 eq.), 0
◦
C; ii. 2.5 eq. R
1
NH
2
(
6a
–
c
), 0
◦
C, hen . ., 12 h; (V)
NaOH (15% aq. soln., 15 mL/g), . , 24 h; (VI)
4b
–
4c
, Tosylchlo ide (1.25 eq.), DMAP (ca . 0.1 eq.), TEA (4.0 eq.), CH
2
Cl
2
, . ,
48 h, N2.
Figu e 2.
C
2
-symme ic 2,5-bis(imidazolinyl) hiophene (
L1–L3
) and ligands 2,5-bis(oxazolinyl) hiophene (
L4 and L5
) es ed
o he F iedel–C a s alkyla ion eac ion o indoles wi h ans-β-ni os y ene de i a i es.
2.2. Applica ion o Chi al Ligand (L1–L5)
2.2.1. Ca aly ic asymme ic F iedel–C a s Alkyla ion o Indoles wi h T ans-
β
-ni os y ene
De i a i es; Op imiza ion o Va ious Reac ion Pa ame e s
As soon as we had in ou hand op ically pu e ligands
L1–L5
, we decided o ca y ou
he ca aly ic ac i i y in an asymme ic F iedel–C a s alkyla ion eac ion be ween indoles
8a
–
d
and ni os y ene de i a i es
9a
–
h
. Indole (
8a
) and p- luo oni os y ene (
9a
) ha e
been chosen as a model subs a e o he eac ion pa ame e s op imiza ion. In o de o
iden i y he bes ligands o he asymme ic ca alysis, ini ially, he F iedel–C a s alkyla ion
eac ion o indole (
8a
) and p- luo oni os y ene (
9a
) was pe o med wi h he sc eened chi al
bis(imidazoline) and bis(oxazoline) ligands
L1–L5 (
15 mol%) and Cu(OT )
2
(15 mol%) as
me al sou ces in oluene a oom empe a u e o 48 h, and he subsequen indings a e
documen ed in Table 1. I is e iden om he esul s summa ized in Table 1, en ies 1–5, ha
he hiophene-2,5-bis(oxazoline) ligand
L5
pe o med e y well unde he abo e-men ioned
eac ion condi ions and a o ded F iedel–C a s alkyla ion adduc
10a
a 66% chemical
yield wi h 75% enan iome ic excess (ee) (Table 1; en y 5), while ligand
L4
yielded 70%
chemical yield wi h 45% ee (Table 1; en y 4). Al hough he ligands
L1–L3
u nished be e

Molecules 2021,26, 7408 5 o 22
chemical yields (78, 75 and 70%, espec i ely), only ace enan iome ic excess (ee) (3–5%)
was achie ed (Table 1, en ies 1-3). In o de o imp o e he chemical yield, he eac ion
was epea ed wi h ligand
L5
, and eac ion ime was ex ended up o 72 h, bu no signi ican
changes we e obse ed (Table 1; en y 6). Aiming o imp o e he chemical yield as well as
enan ioselec i i y ou pu o he eac ion, a se o ials was conduc ed by a ia ion o he
loading o ca alys
L5
:Cu(OT )
2
a 5, 10 and 20 mol%. The esul s showed ha ega dless o
he % ca alys loading, he chemical yield was lowe (20%, 46% and 65%, espec i ely) and
did no esul in any signi ican changes o he enan ioselec i i y (65%, 71% and 74% ee)
(Table 1, en ies 7–9). The in luences o he sol en e ec s we e also s udied; F iedel–C a s
alkyla ion eac ions o indole (
8a
) and p- luo oni os y ene (
9a
) we e also pe o med using a
ligand–me al a io o 15 mol% o
L5
:Cu(OT )
2
a oom empe a u e in se e al sol en s, such
as e ahyd o u an, me hanol, ace oni ile, dichlo ome hane, n-hexane and e hylace a e,
wi hin a ious ime ames (84–96 h) (Table 1, en ies 10–15), whe e dichlo ome hane was
ound o be he bes sol en o chemical yield imp o emen bu wi h no enan ioselec i i y
(Table 1; en y 13), whe eas no p oduc o ma ion ook place in n-hexane and e hylace a e
(Table 1, en ies 14 and 15), al hough in THF, mode a e yield (48%) and enan ioselec i i y
(55%) we e obse ed (Table 1; en y 10). F om he abo e p elimina y indings, i is ob ious
ha a 15 mol% ligand–me al a io [15 mol%
L5
:Cu(OT )
2
] in oluene a oom empe a u e
in 48 h was he op imum se o eac ion condi ions o a o d he inal C–C bond o ma ion
adduc . In e es ingly, i is clea om he p elimina y esul s ha oxazolinyl-based ligands
a e mo e po en han imidazolinyl-based ones; mo e in e es ingly, he subs i u ion a
he oxazolinyl moie y showed o also be c i ical o he asymme ic induc ion. Fu he
in es iga ion o be e unde s anding is highly ecommended.
Table 1.
F iedel–C a s alkyla ion eac ion o indole (
8a
) wi h p- luo oni os y ene (
9a
) as model subs a e; eac ion
op imiza ion (ligands, sol en s and ime).
Molecules 2021, 26, x FOR PEER REVIEW 6 o 23
In e es ingly, i is clea om he p elimina y esul s ha oxazolinyl-based ligands a e
mo e po en han imidazolinyl-based ones; mo e in e es ingly, he subs i u ion a he
oxazolinyl moie y showed o also be c i ical o he asymme ic induc ion. Fu he
in es iga ion o be e unde s anding is highly ecommended.
Table 1. F iedel–C a s alkyla ion eac ion o indole (8a) wi h p- luo oni os y ene (9a) as model
subs a e; eac ion op imiza ion (ligands, sol en s and ime).
En y [a]
Ligands
L:Cu(OT )2 [1:1]
Sol en s
Time [h]
Yield (%) [b]
ee (%) [c,d]
1.
L1
15 mol%
Toluene
48
78
5
2.
L2
15 mol%
Toluene
48
75
3
3.
L3
15 mol%
Toluene
48
77
3
4.
L4
15 mol%
Toluene
48
70
45
5.
L5
15 mol%
Toluene
48
66
75
6.
L5
15 mol%
Toluene
72
68
74
7.
L5
5 mol%
Toluene
48
20
65
8.
L5
10 mol%
Toluene
48
46
71
9.
L5
20 mol%
Toluene
48
65
74
10.
L5
15 mol%
THF
48
55
50
11.
L5
15 mol%
MeOH
72
30
5
12.
L5
15 mol%
ACN
96
10
4
13.
L5
15 mol%
DCM
72
80
0
14.
L5
15 mol%
Hexane
72
-
-
15.
L5
15 mol%
EA
96
aces
-
[a] All he eac ions we e conduc ed on a 0.2 mmol scale; [b] isola ed yields a e column pu i ica ion;
[c] he enan iome ic excess (ee) was measu ed by chi al HPLC using a Daicel OD-H column (25 cm ×
4.6 mm × 5 μm); [d] he absolu e con igu a ion was assigned as (S) compa ing he e en ion ime and
sign o op ical o a ion epo ed in he li e a u e [74].
Nex , ano he wo ac o s we e also in es iga ed, namely me al sal s and empe a u e
e ec s. The e o e, a F iedel–C a s alkyla ion o indole (8a) wi h p- luo oni os y ene (9a)
was ca ied ou using 15 mol% o ligand L5 wi h he combina ion o se e al me al i la es,
such as Zn(OT )2, Mg(OT )2, E (OT )2 and Yb(OT )2, and me al chlo ides such as FeCl3 and
PdCl2, in oluene a 25 °C, and he esul s a e summa ized in Table 2. I was obse ed om
he me al sc eening ha Zn(OT )2, FeCl3 and PdCl2 yielded p oduc 10a wi h excellen o
good chemical yields (97%, 80% and 70%, espec i ely), while he enan ioselec i i y
emains negligible (Table 2, en ies 1, 5 and 6). Two a emp s we e ca ied ou a low (0
°C) and high (70 °C) empe a u e o 92 h and 24 h, espec i ely, and hence o h, 42% and
70% chemical yields wi h 76% and 65% enan ioselec i i y we e obse ed (Table 2, en ies
7 and 8). The esul s showed no signi ican changes o ei he he chemical yield o he
enan ioselec i i y (Table 2, en y 8). F om he o e all indings, a ca alys gene a ed in si u
om ligand L5 and Lewis acid Cu(OT )2 in oluene was ound o be he op imum eac ion
condi ion o he asymme ic F iedel–C a s alkyla ion o indole (8a) and p-
luo oni os y ene (9a).
Table 2. F iedel–C a s a yla ion o indole (8a) wi h p- luo oni os y ene (9a) as model subs a e
eac ion op imiza ion ( empe a u e and me als sal s).
En y [a] Ligands L:Cu(OT )2[1:1] Sol en s Time [h] Yield (%) [b] ee (%) [c,d]
1. L1 15 mol% Toluene 48 78 5
2. L2 15 mol% Toluene 48 75 3
3. L3 15 mol% Toluene 48 77 3
4. L4 15 mol% Toluene 48 70 45
5. L5/, 15 mol% Toluene 48 66 75
6. L5 15 mol% Toluene 72 68 74
7. L5 5 mol% Toluene 48 20 65
8. L5 10 mol% Toluene 48 46 71
9. L5 20 mol% Toluene 48 65 74
10. L5 15 mol% THF 48 55 50
11. L5 15 mol% MeOH 72 30 5
12. L5 15 mol% ACN 96 10 4
13. L5 15 mol% DCM 72 80 0
14. L5 15 mol% Hexane 72 - -
15. L5 15 mol% EA 96 aces -
[a]
All he eac ions we e conduc ed on a 0.2 mmol scale;
[b]
isola ed yields a e column pu i ica ion;
[c]
he enan iome ic excess (ee) was
measu ed by chi al HPLC using a Daicel OD-H column (25 cm
×
4.6 mm
×
5
µ
m);
[d]
he absolu e con igu a ion was assigned as (S)
compa ing he e en ion ime and sign o op ical o a ion epo ed in he li e a u e [74].
Nex , ano he wo ac o s we e also in es iga ed, namely me al sal s and empe a u e
e ec s. The e o e, a F iedel–C a s alkyla ion o indole (
8a
) wi h p- luo oni os y ene
(
9a
) was ca ied ou using 15 mol% o ligand
L5
wi h he combina ion o se e al me al
i la es, such as Zn(OT )
2
, Mg(OT )
2,
E (OT )
2
and Yb(OT )
2
, and me al chlo ides such
Molecules 2021,26, 7408 6 o 22
as FeCl
3
and PdCl
2
, in oluene a 25
◦
C, and he esul s a e summa ized in Table 2. I
was obse ed om he me al sc eening ha Zn(OT )
2
, FeCl
3
and PdCl
2
yielded p oduc
10a
wi h excellen o good chemical yields (97%, 80% and 70%, espec i ely), while he
enan ioselec i i y emains negligible (Table 2, en ies 1, 5 and 6). Two a emp s we e
ca ied ou a low (0
◦
C) and high (70
◦
C) empe a u e o 92 h and 24 h, espec i ely,
and hence o h, 42% and 70% chemical yields wi h 76% and 65% enan ioselec i i y we e
obse ed (Table 2, en ies 7 and 8). The esul s showed no signi ican changes o ei he
he chemical yield o he enan ioselec i i y (Table 2, en y 8). F om he o e all indings, a
ca alys gene a ed in si u om ligand
L5
and Lewis acid Cu(OT )
2
in oluene was ound o
be he op imum eac ion condi ion o he asymme ic F iedel–C a s alkyla ion o indole
(8a) and p- luo oni os y ene (9a).
Table 2.
F iedel–C a s a yla ion o indole (
8a
) wi h p- luo oni os y ene (9
a
) as model subs a e eac ion op imiza ion
( empe a u e and me als sal s).
En y [a] Me als Sal s (15 mol%) Time [h] Temp [◦C] Yield (%) [b] ee (%) [c,d]
1. Zn(OT )248 25 97 10
2. Mg(OT )272 25 - -
3. E (OT )272 25 40 2
4. Yb(OT )272 25 47 0
5. FeCl324 25 80 2
6. PdCl224 25 70 0
7. Cu(OT )292 0 42 76
8. Cu(OT )224 70 66 65
[a]
All he eac ions we e conduc ed on a 0.2 mmol scale;
[b]
isola ed yields a e column pu i ica ion;
[c]
he enan iome ic excess (ee) was
measu ed by chi al HPLC using a Daicel OD-H column (25 cm
×
4.6 mm
×
5
µ
m);
[d]
he absolu e con igu a ion was assigned as (S)
compa ing he e en ion ime and sign o op ical o a ion epo ed in he li e a u e [74].
2.2.2. Subs a e Scope
To illus a e he gene ali y, 20 examples o asymme ic F iedel–C a s alkyla ion
eac ions ha e been ca ied ou using indoles
8a
–
d
wi h a ious ni oole ins (
9a
–
h
) unde
he op imized eac ion condi ions, i.e., 15 mol%
L5
:Cu(OT )
2
in oluene a 25
◦
C o 48 h,
and he esul s a e shown in Table 3. A e he obse ing he esul s, i seems ha subs a es
9a
–
h
eac ed wi h indole
8a
mode a ely and yielded chi al p oduc s
10a
–
in he ange o
40–67% yields wi h 64–80% enan ioselec i i y. Subs a es
9a
,
9b
,
9d
,
9e and 9h
pe o med
ai ly well, yielding co esponding FC p oduc s
10a
,
10b
,
10d, 10e
and
10h
wi h 67, 64, 66,
58 and 60% yields and good enan iome ic excess (ee) a 74, 80, 69, 70 and 64% ee, espec i ely
(Table 3, en ies 1, 2, 4, 5 and 8). While subs a es
9c, 9
and
9g
u nished he co esponding
F iedel–C a s alkyla ed p oduc s
10c, 10
and
10g
wi h poo chemical yields (40, 48 and
52%, espec i ely) because o he s e ic hind ance o he subs a e, he enan ioselec i i y
emained good (75, 71 and 71%, espec i ely) (Table 3, en ies 3, 6 and 7). When subs a e
9a
–
h
was allowed o eac wi h 5-b omoindole
(8b)
unde he op imized condi ions, poo
yields we e obse ed (
10i
–
p,
35–55%) wi h good enan ioselec i i y (60–81% ee) (Table 3,
en ies 9–16). A F iedel–C a s eac ion o 5- luo o indole wi h
β
-ni os y ene
9g
u nished a
mode a e yield (57%) wi h good enan ioselec i i y (66% ee) as compa ed o he eac ion wi h
he mo e hinde ed
9h,
which p oduced poo yield (45%) as well as poo enan ioselec i i y
(21% ee) (Table 3, en ies 17 and 18)
.
We u he pe o med he F iedel–C a s eac ion
wi h N-e hyl-p o ec ed indole and
β
-ni os y ene
9a
and
9d
, which p oduced good yields
(73 and 76%) wi h poo enan iome ic excess (35 and 27%) (Table 3, en ies 19 and 20).
Molecules 2021,26, 7408 7 o 22
In e es ingly, when he asymme ic F iedel–C a s alkyla ion o indole
8a
wi h ni os y ene
9a
was pe o med a a la ge scale (10- old), bo h he yield (76%) and enan ioselec i i y
(77% ee) we e imp o ed (Table 3, en y 1).
Table 3.
Subs a e scope by eac ion o indole de i a i es (
8a
–
d
) wi h subs i u ed ni os y ene (
9a
–
h
) unde op imized
eac ion condi ion.
En y [a] R1(9a–h) R2R310a–i Yields (%) [b] ee (%) [c] R/S Re .
1. 4-F-C6H4H H 10a 67 76[LS] 74 77[LS] (S)[d] [74]
2. 3-B -C6H4H H 10b 64 80 (S)[d] [74,76]
3. 4-CF3-C6H4H H 10c 40 75 (S)[d] [75]
4. 4-CH3O-C6H4H H 10d 66 69 (S)[d] [74]
5. 2-NO2-C6H4H H 10e 58 70 (R)[d] [80]
6. 2,4-Cl2-C6H3H H 10 48 71 (R)[d] [74]
7. 2- hienyl H H 10g 52 71 (S)[e] [42]
8. 2,6-Cl2-C6H3H H 10h 60 64 (R)[e] [41]
9. 4-F-C6H4B H 10i 55 77 (S)[e]
10. 3-B -C6H4B H 10j 46 81 (S)[e]
11. 4-CF3-C6H4B H 10k 35 79 (S)[e]
12. 4-CH3O-C6H4B H 10l 39 63 (S)[d] [81]
13. 2-NO2-C6H4B H 10m 42 78 (R)[e]
14. 2,4-Cl2-C6H3B H 10n 37 75 (R)[e]
15. 2- hienyl B H 10o 47 72 (S)[e] [42]
16. 2,6-Cl2-C6H3B H 10p 52 60 (R)[e]
17. 2- hienyl F H 10q 57 66 (S)[e]
18. 2,6-Cl2-C6H3F H 10 45 21 (R)[e]
19. 4-F-C6H4H E 10s 73 35 (S)[e]
20. 4-CH3O-C6H4H E 10 76 27 (S)[e] [82]
[a]
All he eac ions we e conduc ed on a 0.2 mmol scale;
[b]
isola ed yields a e column pu i ica ion;
[c]
he ee alues we e de e mined
by chi al HPLC using a Daicel OD-H column (25 cm
×
4.6 mm
×
5
µ
m) [
74
];
[d]
he absolu e con igu a ion was de e mined as (S) o (R)
compa ing hei e en ion ime and sign o op ical o a ion epo ed in he li e a u e;
[e]
he absolu e con igu a ion was assigned as (S) o (R)
assuming uni o m eac ion mechanism and compa ing wi h e en ion ime and sign o op ical o a ion;
[LS]
la ge-scale eac ion yield and
enan iome ic excess (ee).
Finally, o examine ano he ni os y ene sys em o he F iedel–C a s a yla ion, wo
ni os y ene (
9i
and
9j
)-based indole sca old we e syn hesized and cha ac e ized. The
syn hesized indole-based ni os y enes
9i
and
9j
we e used as subs a es o he asymme ic
F iedel–C a s a yla ion using ou op imized me hod, bu hey un o una ely did no
succeed in a o ding he inal desi ed chi al FC p oduc s
10u
and
10
, as shown in
Scheme 2
.
The equisi e inal compounds ei he did no occu o decomposed.
In Figu e 3, he p oposed cycle o he ca aly ic mechanism has been shown, whe e in
he in e media es (
II
) and (
III
), i has been clea ly shown ha he addi ion o an incoming
nucleophilic g oup om he Si ace is mo e a o able han he Re ace since he la e is a
mo e s e ically hinde ed ace as compa ed o o me .
Molecules 2021,26, 7408 8 o 22
Scheme 2.
F iedel–C a s a yla ion o indole (
8b
) wi h ni os y ene-based indole sca old (
9i
and
9j
).
Figu e 3.
P oposed mechanism:
L5
:Cu(OT )
2
-ca alyzed F iedel–C a alkyla ion o indole wi h
β
-ni oole in ca aly ic cycle.
In case o F iedel–C a p oduc wi h indole, he e en ion ime o he Senan iome
was ound o be lesse han he Renan iome in he chi al HPLC analysis using Daicel
OD-H chi al column and n-hexane/iso-p opanol sys em in he epo ed li e a u e, while
o FC p oduc s wi h 5-b omoindole i was ound o be ice e sa. The e o e, he absolu e
con igu a ion o he syn hesized chi al FC p oduc s
10a
–
d, 10g, 10i
–
l, 10o, 10q, 10s and
Molecules 2021,26, 7408 15 o 22
40.7; LC/MS (ESI): ound 363.02 [M+H]
+
, C
16
H
12
B FN
2
O
2
equi es 362.01; anal. calcd. o
C16H12B FN2O2: C, 52.91; H, 3.33; N, 7.71; ound: C, 53.01; H, 3.39; N, 7.65.
3.7.10. (S)-5-B omo-3-(1-(3-b omophenyl)-2-ni oe hyl)-1H-indole (10j)
5-b omoindole
8b
(39 mg, 0.2 mmol) and 3-b omoni os y ene
9b
(46 mg, 0.2 mmol)
we e eac ed acco ding o he
GP4
o yield p oduc
10h
as yellow oil (isola ed yield 39 mg,
46%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel OD-H column)
(80% n-hexane/i-P OH, 1.0 mL/min;
mino
= 21.41 min;
majo
= 34.37 min;
λ
= 254 nm);
79.5% ee;
[α]20
D=−
45.13
o
(c0.053, CH
3
OH); IR (KB ): 3401, 1538, 1378, 1009, 814, 745, 589,
535, 421 cm
-1
;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.24 (s, 1H, N
H
), 7.52 (d, J= 1.9 Hz,
1H, A –
H
), 7.42–7.37 (m, 2H, A –
H
), 7.28–7.22 (m, 2H, A –
H
), 7.21–7.16 (m, 2H, A –
H
),
7.03 (dd, J= 2.6, 0.9 Hz, 1H, A –
H
), 5.07 ( , J= 8.0 Hz, 1H, C
H
), 4.97 (dd, J= 12.7, 8.0 Hz,
1H, C
H2(a)
), 4.86 (dd, J= 12.7, 8.0 Hz, 1H, C
H2(b)
);
13
C-NMR (126 MHz, CDCl
3
):
δ
(ppm)
= 141.2, 135.2, 131.1, 130.8, 130.7, 127.8, 126.5, 126.0, 123.2, 122.9, 121.3, 113.5, 113.3, 113.1,
79.2, 41.0; LC/MS (ESI): ound 423.01 [M+H]
+
, C
16
H
12
B
2
N
2
O
2
equi es 421.93; anal. calcd.
o C16H12B 2N2O2: C, 45.31; H, 2.85; N, 6.61; ound: C, 45.23; H, 2.96; N, 6.52.
3.7.11. (S)-5-B omo-3-(2-ni o-1-(4-( i luo ome hyl)phenyl)e hyl)-1H-indole (10k)
5-b omoindole
8b
(39 mg, 0.2 mmol) and 4- i luo ome hyni os y ene
9c
(44 mg,
0.2 mmol) we e eac ed acco ding o he
GP4
o yield p oduc
10i
as colo less oil (isola ed
yield 29 mg, 35%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel
OD-H column) (75% n-hexane/i-P OH, 1.0 mL/min;
mino
= 11.80 min;
majo
= 19.82 min;
λ
= 254 nm); 78.43% ee;
[α]20
D=−
29.51
o
(c0.056, CH
3
OH); IR (KB ): 3418, 1537, 1371,
1247, 1103, 715, 519 cm
-1
;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.22 (s, 1H, N
H
), 7.60 (d,
J= 8.1 Hz
, 2H, A –
H
), 7.53 (d, J= 1.8 Hz, 1H, A –
H
), 7.44 (d, J= 8.1 Hz, 2H, A –
H
), 7.30
(dd, J= 8.7, 1.9 Hz, 1H, A –
H
), 7.25 (d, J= 8.7 Hz, 1H, A –
H
), 7.07 (d, J= 2.6 Hz, 1H, A –
H
),
5.20 ( , J= 8.0 Hz, 1H, C
H
), 5.04 (dd, J= 12.8, 7.6 Hz, 1H, C
H2(a)
), 4.94 (dd, J= 12.8, 8.4 Hz,
1H, C
H2(b)
);
13
C-NMR (126 MHz, CDCl
3
):
δ
(ppm) = 142.9, 135.2, 128.2, 127.7, 126.3, 126.23,
126.20, 126.1, 122.9, 121.4, 113.7, 113.3, 113.2, 79.0, 41.1; LC/MS (ESI): ound 423.01 [M+H]
+
,
C
17
H
12
B F
3
N
2
O
2
equi es 421.93; anal. calcd. o C
17
H
12
B F
3
N
2
O
2
: C, 49.42; H, 2.93; N,
6.78; ound: C, 49.61; H, 3.07; N, 6.69.
3.7.12. (S)-5-B omo-3-(1-(4-me hoxyphenyl)-2-ni oe hyl)-1H-indole (10l)
5-b omoindole
8b
(39 mg, 0.2 mmol) and 4-me hoxyni os y ene
9d
(36 mg, 0.2 mmol)
we e eac ed acco ding o he
GP4
o yield p oduc
10j
as whi e solid (isola ed yield 29 mg,
39%), m.p. 145–146
◦
C; Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel
OD-H column) (75% n-hexane/i-P OH, 1.0 mL/min;
mino
= 17.33 min;
majo
= 20.21 min;
λ
= 254 nm; 62.6% ee;
[α]20
D=−
29.43
o
(c0.053, CH
3
OH);
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.13 (s, 1H, N
H
), 7.53 (d, J= 1.9 Hz, 1H, A –
H
), 7.26 (d, J= 3.4 Hz, 1H, A –
H
),
7.23–7.18 (m, 3H, A –
H
), 7.06 (dd, J= 2.6, 0.9 Hz, 1H, A —
H
), 6.89–6.83 (m, 2H, A –
H
),
5.07 ( , J= 8.0 Hz, 1H, C
H
), 4.99 (dd, J= 12.3, 8.0 Hz, 1H, C
H2(a)
), 4.87 (dd, J= 12.3, 8.0 Hz,
1H, C
H2(b)
), 3.78 (s, 3H, C
H3
);
13
C-NMR (126 MHz, CDCl
3
):
δ
(ppm) = 159.2, 135.3, 130.8,
128.9, 128.0, 125.8, 122.7, 121.7, 114.6, 114.5, 113.4, 112.9, 79.7, 55.4, 40.7. All he analy ical
da a a e in acco dance wi h he epo ed li e a u e [81].
3.7.13. (R)-5-B omo-3-(2-ni o-1-(2-ni ophenyl)e hyl)-1H-indole (10m)
5-b omoindole
8b
(39 mg, 0.2 mmol) and 2-ni oni os y ene
9e
(39 mg, 0.2 mmol)
we e eac ed acco ding o he
GP4
o yield p oduc
10k
as yellow oil (isola ed yield 33 mg,
42%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel OD-H column)
(75% n-hexane/i-P OH, 1.0 mL/min;
mino
= 25.65 min;
majo
= 28.75 min;
λ
= 254 nm);
77.69% ee;
[α]20
D= +
21.38
o
(c0.07, CH
3
OH); IR (KB ): 3419, 1548, 1513, 1339, 723, 431
cm
-1
;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.32 (s, 1H, N
H
), 7.92 (dd, J= 8.1, 1.4 Hz, 1H,
A –
H
), 7.55–7.49 (m, 1H, A –
H
), 7.46–7.38 (m, 3H, A –
H
), 7.27–7.23 (m, 1H, A –
H
), 7.20 (d,
J= 8.6 Hz,
1H, A –
H
), 7.13 (d, J= 2.6 Hz, 1H, A –
H
), 5.83 ( , J= 7.7 Hz, 1H, C
H
), 5.10 (dd,

Molecules 2021,26, 7408 16 o 22
J= 13.3, 7.0 Hz, 1H, C
H2(a)
), 5.03 (dd, J= 13.3, 8.4 Hz, 1H, C
H2(b)
);
13
C-NMR (126 MHz,
CDCl
3
):
δ
(ppm) = 149.6, 135.2, 133.5, 133.4, 129.9, 129.0, 127.7, 126.1, 125.5, 123.5, 121.3,
113.6, 113.1, 112.3, 78.1, 36.4; LC/MS (ESI): ound 390.02 [M+H]
+
, C
16
H
12
B N
3
O
4
equi es
389.00; anal. calcd. o C
16
H
12
B N
3
O
4
: C, 49.25; H, 3.10; N, 10.77; ound: C, 49.33; H, 3.17;
N, 10.84.
3.7.14. (R)-5-B omo-3-(1-(2,4-dichlo ophenyl)-2-ni oe hyl)-1H-indole (10n)
5-b omoindole
8b
(39 mg, 0.2 mmol) and 2,4-dichlo oni oni os y ene
9
(44 mg,
0.2 mmol) we e eac ed acco ding o he
GP4
o yield p oduc
10l
as b own oil (isola ed
yield 31 mg, 37%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel
OD-H column) (75% n-hexane/i-P OH, 1.0 mL/min;
mino
= 9.90 min;
majo
= 20.31 min;
λ
= 254 nm); 74.6% ee;
[α]20
D=−
22.88
o
(c0.056, CH
3
OH); IR (KB ): 3417, 1542, 1456, 1348,
1098, 809, 742, 587 cm
−1
;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.26 (s, 1H, N
H
), 7.48 (dd,
J= 18.0
, 2.0 Hz, 2H, A –
H
), 7.28–7.24 (m, 1H, A –
H
), 7.21 (dd, J= 8.6, 1.0 Hz, 1H, A –
H
),
7.14 (dd, J= 8.4, 2.1 Hz, 1H, A –
H
), 7.10 (dd, J= 2.6, 1.1 Hz, 1H, A –
H
), 7.07 (dd, J= 8.4,
1.1 Hz, 1H, A –
H
), 5.59 ( , J= 7.9 Hz, 1H, C
H
), 4.92 (d, J= 1.9 Hz, 1H, C
H2(a)
), 4.91 (d,
J= 1.1 Hz
, 1H, C
H2(b)
);
13
C-NMR (126 MHz, CDCl
3
):
δ
(ppm) = 135.2, 134.8, 134.6, 134.4,
130.2, 129.8, 127.8, 126.1, 123.3, 121.4, 113.6, 113.1, 112.5, 77.4, 37.5; LC/MS (ESI): ound
413.01 [M+H]
+
, C
16
H
11
B Cl
2
N
2
O
2
equi es 411.94; anal. calcd. o C
16
H
11
B Cl
2
N
2
O
2
: C,
46.41; H, 2.68; N, 6.77; ound: C, 46.27; H, 2.57; N, 6.79.
3.7.15. (S)-5-B omo-3-(2-ni o-1-( hiophen-2-yl)e hyl)-1H-indole (10o)
5-b omoindole
8b
(39 mg, 0.2 mmol) and (E)-2-(2-ni o inyl) hiophene
9g
(31 mg,
0.2 mmol) we e eac ed acco ding o he
GP4
o yield p oduc
10m
as b own oil (isola ed
yield 33 mg, 47%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel
OD-H column) (75% n-hexane/i-P OH, 1.0 mL/min;
mino
= 12.18 min;
majo = 20.57 min
;
λ= 254 nm
); 72.0% ee;
[α]20
D=−
6.87
o
(c0.081, CH
3
OH);
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.50 (s, 1H, N
H
), 7.62 (d, J= 2.0 Hz, 1H, A –
H
), 7.27 (dd, J= 8.7, 1.9 Hz, 1H, A –
H
), 7.22–7.18 (m, 2H, A –
H
), 7.10 (d, J= 2.6 Hz, 1H, A –
H
), 6.97–6.92 (m, 2H, A –
H
), 5.38 ( ,
J= 7.9 Hz,
1H, C
H
), 5.03–4.93 (m, 2H, C
H2
);
13
C-NMR (126 MHz, CDCl
3
):
δ(ppm) = 142.57
,
135.16, 127.56, 127.18, 125.72, 125.46, 125.20, 123.31, 121.41, 113.62, 113.39, 113.16, 79.95,
36.80. All he analy ical da a a e in acco dance wi h he epo ed li e a u e [42].
3.7.16. (R)-5-B omo-3-(1-(2,6-dichlo ophenyl)-2-ni oe hyl)-1H-indole (10p)
5-B omoindole
8b
(39 mg, 0.2 mmol) and 2,6-dichlo oni oni os y ene
9h
(44 mg,
0.2 mmol) we e eac ed acco ding o he
GP4
o yield p oduc
10p
as b own oil (isola ed
yield 43 mg, 52%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel
OD-H column) (75% n-hexane/i-P OH, 1.0 mL/min;
mino
= 10.29 min;
majo
= 11.29 min;
λ
= 254 nm); 60.1% ee;
[α]20
D= +
32.64
o
(c0.034, CH
3
OH); IR (KB ): 3415, 1549, 1463, 1356,
1109, 822, 734, 605, 541, 424 cm
−1
;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.85 (s, 1H, N
H
),
7.50 (s, 1H, A –
H
), 7.32 (s, 1H, A –
H
), 7.26 (s, 1H, A –
H
), 7.22–7.19 (m, 2H, A –
H
), 7.18–7.13
(m, 2H, A –
H
), 6.12 ( d, J= 7.7, 1.2 Hz, 1H, C
H
), 5.39 (dd, J= 12.9, 7.7 Hz, 1H, C
H2(a)
),
5.29 (dd, J= 12.9, 7.8 Hz, 1H, C
H2(b)
);
13
C-NMR (126 MHz, CDCl
3
):
δ(ppm) = 134.86
,
133.93, 130.06129.64, 128.19, 125.38, 124.10, 121.60, 114.17, 113.25, 112.94, 111.02, 76.27, 37.77;
LC/MS (ESI): ound 412.98 [M+H]
+
, C
16
H
11
B Cl
2
N
2
O
2
equi es 411.94; Anal. calcd. o
C16H11B Cl2N2O2: C, 46.41; H, 2.68; N, 6.77; Found: C, 46.36; H, 2.74; N, 6.63.
3.7.17. (S)-5-Fluo o-3-(2-ni o-1-( hiophen-2-yl)e hyl)-1H-indole(10q)
5-Fluo oindole
8c
(27 mg, 0.2 mmol) and (E)-2-(2-ni o inyl) hiophene
9g
(31 mg,
0.2 mmol) we e eac ed acco ding o he
GP4
o yield p oduc
10o
as b own oil (isola ed
yield 33 mg, 57%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel
OD-H column) (75% n-hexane/i-P OH, 1.0 mL/min;
mino
= 11.81 min;
majo = 13.42 min;
λ= 254 nm
); 66.0% ee;
[α]20
D= +
36.97
o
(c0.035, CH
3
OH); IR (KB ): 3417, 1547, 1469, 1343,
1205, 827, 731, 541 cm
-1
;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.18 (s, 1H, N
H
), 7.40 (dd,
Molecules 2021,26, 7408 17 o 22
J= 8.7
, 5.2 Hz, 1H, A –
H
), 7.21 (dd, J= 5.1, 1.3 Hz, 1H, A –
H
), 7.13–7.08 (m, 1H, A –
H
),
7.04 (dd, J= 9.4, 2.3 Hz, 1H, A –
H
), 7.00–6.92 (m, 2H, A –
H
), 6.87 ( d, J= 9.2, 2.3 Hz,
1H, A –
H
), 5.43 ( , J= 7.9 Hz, 1H, C
H
), 5.05–4.96 (m, 2H, C
H2
);
13
C-NMR (126 MHz,
CDCl
3
):
δ(ppm) = 161.31
and 159.41 (C
1
-F, J
C-F
= 239.40 Hz), 142.84, 136.59, 136.49, 127.15,
125.46, 125.18, 122.48, 122.28 and 122.25 (C
4
-F, J
C-F
= 3.53 Hz), 119.84 and 119.76 (C
3
-F,
JC-F = 10.04 Hz
), 114.35, 109.22 and 109.02 (C
2
-F, J
C-F
= 23.94 Hz), 80.09, 36.99; LC/MS (ESI):
ound 291.10 [M+H]
+
, C
14
H
11
FN
2
O
2
S equi es 290.05; Anal. calcd. o C
14
H
11
FN
2
O
2
S: C,
57.92; H, 3.82; N, 9.65; Found: C, 58.11; H, 3.93; N, 9.52.
3.7.18. (R)-3-(1-(2,6-Dichlo ophenyl)-2-ni oe hyl)-1H-indole (10 )
5-Fluo oindole
8c
(27 mg, 0.2 mmol) and 2,6-dichlo oni oni os y ene
9h
(44 mg,
0.2 mmol) we e eac ed acco ding o he
GP4
o yield p oduc
10
as b own oil (isola ed
yield 32 mg, 45%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel
OD-H column) (75% n-hexane/i-P OH, 1.0 mL/min;
mino
= 7.99 min;
majo
= 10.29 min;
λ= 254 nm)
; 24.3% ee;
[α]20
D= +
65.97 (c0.029, CH
3
OH); IR (KB ): 3418, 1551, 1472, 1371,
1101, 819, 735 cm
−1
;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.20 (s, 1H, N
H
), 7.43–7.22 (m,
3H, A –
H
), 7.18–7.12 (m, 2H, A –
H
), 7.02 (dd, J= 9.4, 2.3 Hz, 1H, A –
H
), 6.81 (ddd, J= 9.5,
8.8, 2.3 Hz, 1H, A –
H
), 6.17 ( d, J= 7.6, 1.2 Hz, 1H, C
H
), 5.42 (dd, J= 12.8, 7.6 Hz, 1H, C
H2(a)
),
5.31 (dd, J= 12.9, 7.7 Hz, 1H, C
H2(b)
);
13
C-NMR (126 MHz, CDCl
3
):
δ(ppm) = 161.13
and
159.23 (C
1
-F, J
C-F
= 239.14 Hz), 136.22 and 136.12
(C5-F, JC-F = 10.34 Hz)
, 134.11, 129.61,
123.04, 122.94 and 122.91 (C
4
-F, J
C-F
= 3.65 Hz), 119.87 and 119.79 (C
3
-F,
JC-F = 10.21 Hz
),
111.85, 109.05 and 108.86 (C
6
-F, J
C-F
= 24.57 Hz), 97.85 and 97.64 (C
2
-F,
JC-F = 25.96 Hz)
,
76.39, 37.92; LC/MS (ESI): ound 353.10 [M+H]
+
, C
16
H
11
Cl
2
FN
2
O
2
equi es 352.01; anal.
calcd. o C16H11Cl2FN2O2: C, 54.41; H, 3.14; N, 7.93; ound: C, 54.58; H, 3.08; N, 8.03.
3.7.19. (S)-1-E hyl-3-(1-(4- luo ophenyl)-2-ni oe hyl)-1H-indole (10s)
1-E hyl-1H-indole
8d
(29 mg, 0.2 mmol) and 4- lo oni os y ene
9a
(34 mg, 0.2 mmol)
we e eac ed acco ding o he
GP4
o yield p oduc
10s
as yellow oil (isola ed yield 46 mg,
73%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel OD-H column)
(70% n-hexane/i-P OH, 1.0 mL/min;
mino
= 16.38 min;
majo
= 34.92 min;
λ
= 254 nm);
35.2% ee;
[α]20
D= +
44.27
o
(c0.022, CH
3
OH); IR (KB ): 3418, 1557, 1349, 1174, 739, 573 cm
-1
;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 7.42 (d, J= 7.9 Hz, 1H, A –
H
), 7.36–7.29 (m, 3H,
A –
H
), 7.25–7.21 (m, 1H, A –
H
), 7.08 (ddd, J= 8.0, 7.0, 1.0 Hz, 1H, A –
H
), 7.02 ( ,
J= 8.6 Hz
,
2H, A –
H
), 6.92 (d, J= 0.9 Hz, 1H, A –
H
), 5.18 (dd, J= 8.7, 7.4 Hz, 1H, C
H
), 5.06 (dd,
J= 12.5
, 7.2 Hz, 1H, C
H2(a)
), 4.91 (dd, J= 12.5, 8.9 Hz, 1H, C
H2(b)
), 4.14 (q,
J= 7.3 Hz
, 2H,
C
H2
), 1.45 ( , J= 7.3 Hz, 3H, C
H3
);
13
C-NMR (126 MHz, CDCl
3
):
δ
(ppm) = 163.17 and 161.21
(C
1
-F, J
C-F
= 246.71 Hz), 136.50, 135.28 and 135.26 (C
4
-F, J
C-F
= 3.15 Hz), 129.52, 129.46 (C
3
-F,
J
C-F
= 8.06 Hz), 126.66, 124.56, 122.34, 119.62, 119.14, 116.02, 115.85 (C
2
-F,
JC-F = 21.55 Hz
),
112.81, 109.79, 79.73, 41.19, 41.06, 15.55; LC/MS (ESI): ound 313.10 [M+H]
+
, C
18
H
17
FN
2
O
2
equi es 312.13; anal. calcd. o C
18
H
17
FN
2
O
2
: C, 69.22; H, 5.49; N, 8.97; ound: C, 69.34; H,
5.43; N, 8.85.
3.7.20. (S)-1-E hyl-3-(1-(4-me hoxyphenyl)-2-ni oe hyl)-1H-indole (10 )
1-E hyl-1H-indole
8d
(29 mg, 0.2 mmol) and 4-me hoxyni os y ene
9d
(36 mg, 0.2 mmol)
we e eac ed acco ding o he
GP4
o yield p oduc
10
as yellow oil (isola ed yield 49 mg,
76%). Enan iome ic excess (ee) was de e mined by chi al HPLC (Chi acel OD-H column)
(70% n-hexane/i-P OH, 1.0 mL/min;
mino
= 20.94 min;
majo = 35.44 min
;
λ= 254 nm
);
26.74% ee;
[α]20
D= +
20.60
o
(c0.024, CH
3
OH); IR (KB ): 3417, 152, 1337, 1171, 741, 534 cm
−1
;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 7.44 (d, J= 8.0 Hz, 1H, A –
H
), 7.32 (d, J= 8.3 Hz, 1H,
A –
H
), 7.27–7.24 (m, 2H, A –
H
), 7.21 ( , J= 7.0 Hz, 1H, A –
H
), 7.06 ( , J= 7.5 Hz, 1H, A –
H
),
6.90 (s, 1H, A –
H
), 6.85 (d, J= 8.7 Hz, 2H, A –
H
), 5.13 ( , J= 8.0 Hz, 1H, C
H
), 5.03 (dd,
J= 12.3
, 7.3 Hz, 1H, C
H2(a)
), 4.89 (dd, J= 12.4, 8.8 Hz, 1H, C
H2(b)
), 4.12 (q, J= 7.3 Hz, 2H,
C
H2
), 3.77 (s, 3H, C
H3
), 1.43 ( , J= 7.3 Hz, 3H, C
H3
);
13
C-NMR (126 MHz, CDCl
3
):
δ
(ppm)
= 158.99, 136.49, 131.51, 128.94, 126.82, 124.62, 122.18, 119.48, 119.28, 114.38, 113.33, 109.70,
Molecules 2021,26, 7408 18 o 22
55.37, 41.14, 41.06, 15.55; LC/MS (ESI): ound 325.20 [M+H]
+
, C
19
H
20
N
2
O
3
equi es 324.15;
anal. calcd. o C19H20N2O3: C, 70.35; H, 6.21; N, 8.64; ound: C, 70.19; H, 6.13; N, 8.54.
4. La ge-Scale Syn hesis o (S)-3-(1-(4-Fluo ophenyl)-2-ni oe hyl)-1H-indole (10a)
An o en-d ied 50-mL ound bo om lask equipped wi h a condense unde ni ogen
a mosphe e was cha ged wi h ligand
L5
(100 mg, 0.3 mmol, 15% mol), Cu(OT )
2
(110 mg,
0.3 mmol, 15 mol %) and d y oluene (20 mL). The mix u e was hen s i ed a e lux o 2 h.
A e cooling o oom empe a u e, 4- lo oni os y ene (
9a)
(334 mg, 2.0 mmol) and 4A
◦
molecula sie es we e added. Then, he mix u e was s i ed o ano he 30 min, ollowed
by he addi ion o indole
8a
(234 mg, 2.0 mmol). The eac ion was hen le s i ing o
48 h a oom empe a u e. The sol en was emo ed unde educed p essu e, and he
c ude p oduc was isola ed by lash column ch oma og aphy on silica gel, elu ing wi h
e hylace a e/n-hexane (2:8, / ) o a o d a pu e F iedel–C a s p oduc (
10a
) isola ed
yield o 76% (432 mg) wi h 77.2% enan iome ic excess (ee). Enan iome ic excess (ee) was
de e mined by chi al HPLC (Chi acel OD-H column) (70% n-hexane/i-P OH, 1.0 mL/min;
majo
= 25.09 min;
mino
= 30.30 min;
λ
= 254 nm); 77.2% ee;
1
H-NMR (500 MHz, CDCl
3
):
δ
(ppm) = 8.13 (s, 1H, N
H
), 7.47–7.40 (m, 1H, A –
H
), 7.35 (s, 1H, A –
H
), 7.32–7.28 (m,
2H, A –
H
), 7.23 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H, A –
H
), 7.11 (ddd, J= 8.1, 6.9, 1.0 Hz, 1H,
A –
H
), 7.04–6.96 (m, 3H, A –
H
), 5.19 ( , J= 8.0 Hz, 1H, C
H
), 5.05 (dd, J= 12.5, 7.5 Hz, 1H,
C
H2(a)
), 4.90 (dd, J= 12.5, 8.6 Hz, 1H, C
H2(b)
);
13
C-NMR (126 MHz, CDCl
3
):
δ
(ppm) = 163.1
and 161.18 (C
1
-F, J
C-F
= 246.58 Hz), 136.6, 135.07 and 135.04 (C
4
-F, J
C-F
= 3.15 Hz), 129.50
and 129.44 (C
3
-F, J
C-F
= 7.94 Hz), 126.0, 122.9, 121.6, 120.1, 118.9, 115.99 and 115.82 (C
2
-F,
JC-F = 21.67 Hz), 114.2, 111.6, 79.6, 41.0.
5. Conclusions
In summa y, we ha e syn hesized new C
2
-symme ic 2,5-bis(oxazolinyl) hiophene and
2,5-bis(imidazolinyl) hiophene ligands based on hiophene sys ems and success ully es ed
hem in asymme ic F iedel–C a s alkyla ion eac ions o indole wi h ans
β
-ni oole ins.
Ou newly de eloped ca aly ic sys em (15 mol% o
L5
:Cu(OT )
2
in oluene a 25
◦
C) was
ound o be applicable in inducing chi ali y in o ni oalkyla ed indoles wi h low o good
yields (35–76%) and low o good enan ioselec i i y (21–81%) a oom empe a u e. On
he basis o he sc eening pe o med, his me hodology could be an al e na i e ool o
asymme ic F iedel–C a s eac ions using his ca aly ic sys em. The ad an age o his
ca aly ic sys em is ha i is easy o p epa e he chi al ligands om he widely accessible
hiophene p ecu so , and he eac ion can also be pe o med a oom empe a u e as
compa ed o o he ca aly ic sys em ca ied ou a lowe empe a u es. The e is an ongoing
esea ch p ojec o explo e mo e u ili ies o hese new chi al hiophene ligands and hei
applica ions in asymme ic ans o ma ion, and i s ou come will be communica ed soon
in u u e.
Supplemen a y Ma e ials:
Page
S4–S35
:
1
H-NMR and
13
C-NMR o compounds
4a–c
,
L1–L5
and
10a– and chi al HPLC analysis o compound 10a- .
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., S.A. and M.H.; 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., A.B. and M.H.; w i ing—o iginal d a p 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., A.M.A.-M. and M.H.; isualiza ion, A.B.,
M.S.I., S.A. and M.H.; p ojec adminis a ion, A.M.A.-M. and A.B.; unding acquisi ion, A.M.A.-M.
and A.B.; so wa e, A.S.A., M.S.I., A.B. and M.H. All au ho s ha e ead and ag eed o he published
e sion o he manusc ip .
Funding:
Resea che s Suppo ing P ojec numbe (RSP-2021/64), King Saud Uni e si y, Riyadh,
Saudi A abia.
Ins i u ional Re iew Boa d S a emen : No applicable.
Molecules 2021,26, 7408 19 o 22
In o med Consen S a emen : No applicable.
Da a A ailabili y S a emen :
The da a p esen ed in his s udy a e a ailable in Supplemen a y
Ma e ials.
Acknowledgmen 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 (RSP-2021/64), King Saud Uni e si y, Riyadh, Saudi A abia.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
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