Enantioselective iron/bisquinolyldiamine ligand‐catalyzed oxidative coupling reaction of 2‐naphthols

Article abstract of DOI:10.3390/molecules25040852

An iron‐catalyzed asymmetric oxidative homo‐coupling of 2‐naphthols for the synthesis of 1,1′‐Bi‐2‐naphthol (BINOL) derivatives is reported. The coupling reaction provides enantioenriched BINOLs in good yields (up to 99%) and moderate enantioselectivities (up to 81:19 er) using an iron‐complex generated in situ from Fe(ClO₄)2 and a bisquinolyldiamine ligand [(1R,2R)‐N¹,N²‐di(quinolin‐8‐yl)cyclohexane‐1,2‐diamine, L1]. A number of ligands (L2–L8) and the analogs of L1, with various substituents and chiral backbones, were synthesized and examined in the oxidative coupling reactions.

Full text of DOI:10.3390/molecules25040852

molecules
Article
Enantioselective Iron/Bisquinolyldiamine
Ligand-Catalyzed Oxidative Coupling Reaction
of 2-Naphthols
Lin-Yang Wu, Muhammad Usman and Wen-Bo Liu *
Sauvage Center for Molecular Sciences; Engineering Research Center of Organosilicon Compounds & Materials,
Ministry of Education; College of Chemistry and Molecular Sciences; Wuhan University, Wuhan 430072, Hubei,
China; 2016282030199@whu.edu.cn (L.-Y.W.); whitestar399@hotmail.com (M.U.)
* Correspondence: wenboliu@whu.edu.cn
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Hans-Joachim Knölker and Jean-Luc Renaud
Received: 15 January 2020; Accepted: 12 February 2020; Published: 14 February 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: An iron-catalyzed asymmetric oxidative homo-coupling of 2-naphthols for the synthesis of
1,10-Bi-2-naphthol (BINOL) derivatives is reported. The coupling reaction provides enantioenriched
BINOLs in good yields (up to 99%) and moderate enantioselectivities (up to 81:19 er) using an
iron-complex generated in situ from Fe(ClO4)2 and a bisquinolyldiamine ligand [(1R,2R)-N1,N2-
di(quinolin-8-yl)cyclohexane-1,2-diamine, L1]. A number of ligands (L2–L8) and the analogs of L1,
with various substituents and chiral backbones, were synthesized and examined in the oxidative
coupling reactions.
Keywords: iron catalysis; asymmetric catalysis; nitrogen ligand; oxidative coupling; BINOL synthesis
1. Introduction
Axially chiral compounds (atropisomers) have aroused much attention from organic chemists
due to their prevalence in natural products, bioactive molecules, functional materials, and their wide
applications in asymmetric transformations [
the asymmetric synthesis of axially chiral compounds, both employing transition-metal catalysts [
and organocatalysts [
]. In particular, 1,10-Bi-2-naphthol (BINOL) is one of the most useful structural
motifs and ligand substructures in asymmetric catalysis [ ]. Since the pioneering report by the
1]. Many elegant methods have been established for
2]
1
3–9
Noyori group utilizing enantioenriched BINOL as the ligand in asymmetric catalysis [10], numerous
BINOL-derived ligands/catalysts (i.e., BINAP [11], BINAM [12], chiral phosphoric acid [13], chiral
phosphoramidite [14], and BINSA [15]; Figure 1) have been designed and synthesized. The emergence
of such a library of ligands/catalysts has brought marvelous contributions to the synthetic community,
with tremendously efficient asymmetric transformations such as reductive coupling [16], allylation [17],
ene-type [18], and Aldol [19] reactions and axial chirality assembly [20].
In the past few decades, enormous efforts have been devoted to the enantioselective assembly
of BINOL scaffolds. Transition-metal-catalyzed asymmetric oxidative coupling of 2-naphthols have
shown its power in the synthesis of BINOLs (Figure 2a). Efficient vanadium-catalyzed [21] protocols
were reported by the Uang [22], Chen [23], Gong [24
Many research groups, including Nakajima, Kozlowski, and others, have successfully developed
a series of copper-catalyzed coupling reactions of 2-naphthols [30 44]. Recently, a notable work
–26], and Sasai [27–29] groups, independently.
–
by the Tu group [45] established a Cu/SPDO (spirocyclic pyrrolidine oxazoline) complex-catalyzed
cross-coupling reaction to synthesize 3,30-disubstituted BINOLs. Nevertheless, iron-catalyzed coupling
strategies in this area have not been explored so far. Only a handful of remarkable iron catalysts,
namely, an iron-salen complex reported by Katsuki and co-workers [46,47], a chiral diphosphine
Molecules 2020, 25, 852; doi:10.3390/molecules25040852
www.mdpi.com/journal/molecules

Molecules 2020, 25, 852
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oxide–iron(II) complex developed by the Ishihara group [48], and an iron-chiral phosphoric acid (CPA)
catalyst introduced by the Pappo group [49,50], have been disclosed to date (Figure 2a).
Figure 1. Representative 1,10-Bi-2-naphthol (BINOL)-derived ligands/catalysts.
Recently, we have developed an iron-catalyzed direct amination of aliphatic C-H bonds [51,52],
and it was interesting to find that the catalysts used were simply generated by in situ mixing of an iron
salt and an aminopyridine ligand. Inspired by these results, we envisaged that introducing a chiral
aminopyridine-type ligand might impart chirality to the products. Our attention was drawn to
N,N0-dimethyl-N,N0-bis(8-quinolyl)-cyclohexanediamine (BQCN), developed by the Che group
and successfully applied in iron-catalyzed asymmetric cis-dihydroxylation of alkenes [53] and,
most recently, in Friedel-Crafts reactions [54]. Since our previous studies revealed that free
secondary amine ligand presented a good reactivity [51], we were wondering whether the
N-unprotected bis(8-quinolyl)-cyclohexanediamine ligand (bisquinolyldiamine, L1), which is
synthesized straightforwardly from 8-haloquinoline and diamine, is capable of controlling the
selectivities in the iron-catalyzed oxidative coupling of 2-naphthols. Herein, we report the studies
toward the synthesis of the amino ligands and their applications in the synthesis of optically active
BINOL derivatives via an oxidative homo-coupling reaction of 2-naphthols under mild conditions
(Figure 2b).

Molecules 2020, 25, 852
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Figure 2. Transition metal-catalyzed coupling for the enantioselective synthesis of BINOLs. (
a) The
previous examples of homo- or cross-coupling of 2-naphthols. ( ) Our proposed asymmetric oxidative
b
homo-coupling of 2-naphthols using iron/bisquinolyldiamine catalyst.
2. Results and Discussion
2.1. Synthesis of Bisquinolyldiamine Ligands
The Buchwald-Hartwig C–N coupling reaction [55,56] was used for the synthesis of a variety of
bisquinolyldiamine ligands following the literature procedure [53]. As shown in Figure 3, with the
catalyst derived from 5 mol% Pd2(dba)3 and 10 mol% rac-BINAP, eight ligands were synthesized in
moderate to good yields. The chiral backbones of these ligands include (1R,2R)-cyclohexane-1,2-
diamine (L1), (R)-[1,10-binaphthalene]-2,20-diamine (L6), (12R)-9,10-dihydro-9,10-ethanoanthracene-
11,12-diamine (L7), and (1R,2R)-1,2-diphenylethane-1,2-diamine (L8). Ligands with a variety of
electronically differentiated substituents at the C6 position of the quinoline moiety (L2–L4) and an

Molecules 2020, 25, 852
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acridine-derived ligand (L5) were also prepared to probe the electronic and steric effects of the ligands
on the reaction.
Figure 3. Ligands synthesis.
2.2. Reaction Investigation
To test our hypothesis, we selected 2-naphthol (1a) as the model substrate for optimization of
reaction conditions (Table 1). All reactions were carried out with the catalyst generated in situ by
stirring Fe(ClO4)2 and L1 for 30 min before the addition of the substrate, and under atmospheric
dioxygen. Various solvents (methanol, dichloroethane, chloroform, toluene, and chlorobenzene) were
screened first (entries 1–5) and resulted in moderate conversions and enantioselectivities, except toluene
and methanol. The reaction in chlorobenzene gave a better balance between reactivity and selectivity
(53% conv. and 79:21 er, entry 5). The addition of 4Å MS led to a slightly higher enantioselectivity
with partial conversion in a much shorter◦reaction time (entries 5 vs. 6). We were delighted to find
◦
that increasing the temperature from 30 C to 50 C delivered 39% conversion with comparable
enantioselectivity (entry 7). Further increase in temperature (i.e., 70 ◦C and 90 ◦C) resulted in lower
enantioselectivities (entries 8 and 9). Then, the reaction with different iron salts were investigated,
including Fe(ClO4)3, Fe(OAc)2, Fe(OTf)2, Fe(acac)2, and FeCl2, but failed to provide better results
(entries 10–14). The ratio of iron precursor versus L1 was also examined (entries 14–19). Surprisingly,
increasing Fe(ClO4)2-loading from 5 mol% to 10 mol% improves the efficiency without affecting
the enantioselectivity and delivered the coupling product 2a in 84% isolated yield with 80:20 er
(entries 15 and 16). Although further increasing Fe(ClO4)2 to 12.5 mol% improved the yield, a slightly
diminished er was also observed (entry 17). Finally, reactions with the catalysts derived from the
diamine ligand (L2–L8) were inspected. Electron-withdrawing groups-substituted ligands (L2 and L3)
showed excellent reactivities but with low enantioselectivities (entries 20 and 21). In contrast, ligand
L4 with an electron-donating substituent delivered the product in reduced yield, albeit with good er
(entry 22). Upon further screening, the ligands (L5–L8) bearing different chiral backbones, lower yield,
and er were obtained with L5, while ligands L6–L8 failed to give any product (entries 23–26).

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Table 1. Conditions Screening a.
Ln
(y mol%)
conv. (%)
Entry
Fe (x mol%)
Additives Solvent
T ◦C
t/h
er (%) c
b
f
1
2
3
4
5
6
7
8
9
Fe(ClO4)2 (5.0)
Fe(ClO4)2 (5.0)
Fe(ClO4)2 (5.0)
Fe(ClO4)2 (5.0)
Fe(ClO4)2 (5.0)
Fe(ClO4)2 (5.0)
Fe(ClO4)2 (5.0)
Fe(ClO4)2 (5.0)
Fe(ClO4)2 (5.0)
Fe(ClO4)3 (5.0)
Fe(OAc)2 (5.0)
Fe(OTf)2 (5.0)
Fe(acac)2 (5.0)
FeCl2 (5.0)
Fe(ClO4)2 (7.5)
Fe(ClO4)2 (10.0)
Fe(ClO4)2 (12.5)
Fe(ClO4)2 (5.0)
Fe(ClO4)2 (10.0)
Fe(ClO4)2 (10.0)
Fe(ClO4)2 (10.0)
Fe(ClO4)2 (10.0)
Fe(ClO4)2 (10.0)
Fe(ClO4)2 (10.0)
Fe(ClO4)2 (10.0)
Fe(ClO4)2 (10.0)
L1(5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (5.0)
L1 (10.0)
L1 (10.0)
L2 (5.0)
L3 (5.0)
L4 (5.0)
L5 (5.0)
L6 (5.0)
L7 (5.0)
L8 (5.0)
-
-
-
-
MeOH
DCE
CHCl3
toluene
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
30
30
30
30
30
30
50
70
90
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
28.5
28.5
28.5
28.5
28.5
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
-
57 d
68 d
22 d
53 d
12 d
39 d
38 d
28 d
76
n.d.
73:27
77:23
80:20
79:21
80:20
78:22
73:27
70:30
76:24
-
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
a
f
16
19
23
20
n.d.
n.d.
n.d.
n.d.
f
f
f
78
77:23
80:20
72:28
77:23
77:23
70:30
60:40
78:22
55:45
88(84 e)
95
39
86
90
85
53 e
67 e
-
f
n.d.
n.d.
n.d.
f
-
-
f
b
All reactions carried out with 1a (0.5 mmol), MS 4Å (150 mg) in 5 mL solvent under O2 atmosphere (1 atm).
c
Conversions determined by GC using dodecane as an internal standard. Determined by HPLC (Chiralpak AS-H).
Determined by 1H-NMR analysis. Isolated yield. n.d.: not detected.
d
e
f
2.3. Substrates Scope
Next, we investigated the scope of the iron-catalyzed asymmetric oxidative coupling reaction, and
the results were summarized in Scheme 1. A variety of substituted 2-naphthols with electronic and steric
properties were examined. Substrate
OBn, o-tolyl, and Ph were successfully converted into the coupling products (2b
1
containing functionalities at the C3-position, including OMe,
2e) in 56–88% yields
–
with 56:44 to 81:19 er. The substrate bearing an electron-withdrawing Br substitution at the C3-position
was also converted into the corresponding product (2f) in 51% yield with 79:21 er. The electronic effects
of different functionalities are clearly demonstrated by the observation that electron-donating groups
delivered higher yield (e.g., C3-OMe 88%, 2b vs. C3-Br 51%, 2f). However, C3-substituted substrates
with carbonyl functionalities like CO2H, COPh, and CO2Bn failed to give any products (2g–2i). When
C6-Br-substituted 2-naphthol was applied, the desired product (2j) was obtained in 82% yield with
79:21 er. A C6-phenyl-substituted 2-naphthol also resulted in 64% yield and 74:26 er (2k). Moreover,
C7-substituted (BnO, nBuO, TBSO, and MeO) substrates were also effectively coupled and delivered
the corresponding products (2l–2o) in 65–99% yields, albeit with dramatically diminished er.

Molecules 2020, 25, 852
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R1
R
R2
R1
OH
R
Fe(ClO4)2 (10 mol%)
L1 (5 mol%)
R2
R2
OH
OH
PhCl, O2 (1 atm)
50 °C, MS 4Å, 5 – 18 h
R1
R
2
1
o-tolyl
OMe
OBn
Ph
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
o-tolyl
OMe
OBn
2c
68% yield; 80 : 20 er
Ph
2a
2b
2e
2d
84% yield; 80 : 20 er
88% yield; 81 : 19 er
66% yield; 56 : 44 er
72% yield; 77 : 23 er
Br
COOH
COPh
COOBn
Br
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Br
COOH
COPh
COOBn
Br
2f
51% yield; 66 : 34 er
Ph
2g
0% yield
2h
0% yield
2i
2j
82% yield; 79 : 21 er
0% yield
BnO
BnO
OH
OH
nBuO
nBuO
OH
OH
TBSO
TBSO
OH
OH
MeO
MeO
OH
OH
OH
OH
Ph
2l
2m
99% yield; 60 : 40 er
2n
76% yield; 68 : 32 er
2o
65% yield; 59 : 41 er
2k
64% yield; 74 : 26 er
71% yield; 58 : 42 er
a
Scheme 1. Substrates Scope a. Reactions conducted with Fe(ClO4)2 (10 mol%), L1 (5 mol%), substrate
1
(0.5 mmol), and 4Å MS (150 mg) in PhCl (5 mL) under oxygen atmosphere (1 atm) at 50 ◦C. Percentage
represented isolated yields. Er determined by HPLC.
3. Materials and Methods
3.1. General Information
Unless otherwise noted, all reagents were purchased commercially and used without further
purification. Petroleum ether (PE) (60–90 ◦C), ethyl acetate (EA), and dichloromethane (DCM) were
used for silica gel chromatography. MeCN, toluene, DMF, and THF were purchased commercially
or were dried by passage through an activated alumina column under argon [57]. PhCl, CHCl3,
1
MeOH, and acetone were freshly distilled after drying over CaH2. H-NMR spectra were recorded at
room temperature on a Bruker ADVANCE III 400 MHz spectrometer and were reported relative to
residual Chloroform-d (
Bruker ADVANCE III 400 MHz spectrometer (100 MHz) and were reported relative to Chloroform-d
77.16 ppm). 19F-NMR spectra were recorded on a Bruker ADVANCE III 400 MHz spectrometer
(376 MHz). Data for 1H-NMR were reported as chemical shift (
ppm) (multiplicity, coupling constant
δ 7.26 ppm) or DMSO-d6 (δ
2.50 ppm). 13C-NMR spectra were recorded on a
(δ
δ
(Hz), and integration) using standard abbreviations for multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, and m = multiplet. Data for 13C-NMR and 19F-NMR were reported in terms
of chemical shifts (δ ppm). High-resolution mass spectra (HRMS) were obtained by using a Bruker
Compact TOF mass spectrometer in electrospray ionization mode (ESI). Enantiomeric ratio (er) was
determined by an Agilent 1260 Series HPLC utilizing DAICEL Chiralpak (AD-H, AS-H, or IC) or
Chiralcel (OD-H) columns (4.6 mm
Elmer 343 polarimeter and were reported as: [
×
250 mmL). Optical rotations were measured with a Perkin
T (concentration in g/100 mL, solvent). The NMR
α
]
D
spectra of all new compounds and HPLC spectra of oxidative coupling products were provided in the
Supplementary Materials.

Molecules 2020, 25, 852
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3.2. Preparation of Ligands
General Procedure (Scheme 2): To an oven-dried Schlenk flask were added diamine
3
(1.0 equiv),
Pd2(dba)3 (5 mol%), rac-BINAP (10 mol%), NaOtBu (3.0 equiv), and toluene under Ar atmosphere.
Then 8-haloqunoline
4
(2.2 equiv) was added directly. The flask was sealed, and the reaction was stirred
. The mixture was cooled to room
at 85 ◦C until the complete consumption of the starting material
3
temperature, filtered through a silica plug, and the plug was washed with EA. The combined filtrates
were concentrated under reduced pressure, and the residue was purified by silica gel chromatography
to give the desired product Ln.
Scheme 2. Synthesis of Bisquinolyldiamine Ligands.
(1R,2R)-N1,N2-Di(quinolin-8-yl)cyclohexane-1,2-diamine (L1) [53]: Following the general procedure,
the reaction was carried out with (1R,2R)-cyclohexane-1,2-diamine 3a (0.36 g, 3.2 mmol, 1.0 equiv);
Pd2(dba)3 (0.15 g, 0.16 mmol, 5 mol%); rac-BINAP (0.20 g, 0.32 mmol, 10 mol%); NaOtBu (0.92 g,
9.6 mmol, 3.0 equiv); and 8-bromoqunoline 4a (1.46 g, 7.0 mmol, 2.2 equiv) in 30 mL of toluene. The
desired product was obtained (0.88 g, 75% yield) as a pale yellow solid after purification by silica gel
1
chromatography (PE/EA = 30/1 to 10/1). H-NMR (400 MHz, Chloroform-d)
δ 8.57 (dd, J = 4.2, 1.7 Hz,
2H), 7.98 (dd, J = 8.3, 1.7 Hz, 2H), 7.36 (td, J = 8.0, 0.9 Hz, 2H), 7.30–7.25 (m, 2H), 6.98 (dd, J = 8.2,
1.3 Hz, 2H), 6.84 (dd, J = 7.7, 1.1 Hz, 2H), 6.43 (brs, 2H), 3.86–3.67 (m, 2H), 2.49–2.31 (m, 2H), 1.86 (td, J
= 4.6, 4.1, 2.2 Hz, 2H), 1.67–1.48 (m, 4H).
(1R,2R)-N1,N2-Bis(6-fluoroquinolin-8-yl)cyclohexane-1,2-diamine (L2): Following the general procedure,
the reaction was carried out with (1R,2R)-cyclohexane-1,2-diamine 3a (81.6 mg, 0.7 mmol, 1.0 equiv);
Pd2(dba)3 (32.8 mg, 0.04 mmol, 5 mol%); rac-BINAP (45.1 mg, 0.07 mmol, 10 mol%); NaOtBu (206.9 mg,
2.2 mmol, 3.0 equiv); and 8-bromo-6-fluoroquinoline 4b (356.7 mg, 1.6 mmol, 2.2 equiv) in 2 mL of
toluene. The desired product was obtained (262.3 mg, 93% yield) as a pale yellow solid after purification
1
by silica gel chromatography (PE/EA = 5/1). H-NMR (400 MHz, Chloroform-d)
δ 8.49 (dd, J = 4.2,
1.5 Hz, 2H), 7.87 (dd, J = 8.3, 1.2 Hz, 2H), 7.34–7.21 (m, 2H), 6.68–6.49 (m, 4H), 6.46 (dd, J = 9.3, 2.5 Hz,
2H), 3.76–3.56 (m, 2H), 2.45–2.28 (m, 2H), 1.97–1.79 (m, 2H), 1.66–1.47 (m, 4H) (Figure S2); 13C-NMR
(100 MHz, Chloroform-d)
δ 162.4 (d, JC–F = 243.3 Hz), 146.3 (d, JC–F = 13.5 Hz), 145.6 (d, JC–F = 2.4 Hz),
135.6, 135.4 (d, JC–F = 5.8 Hz), 129.3 (d, JC–F = 12.8 Hz), 122.2, 96.1 (d, JC–F = 22.8 Hz), 95.1 (d, JC–F
=
30.6 Hz), 56.6, 31.7, 24.5 (Figure S3); 19F NMR (376 MHz, Chloroform-d)
δ
–110.9 (Figure S4); HRMS
(ESI+) calcd for C24H23F2N4 [M + H]+: 405.1885, found 405.1880; [α]2D4
=
−
315.6 (c = 0.2, CHCl3); M. p.
162–166 ◦C.
(1R,2R)-N1,N2-Bis(6-(trifluoromethyl)quinolin-8-yl)cyclohexane-1,2-diamine (L3): Following the general
procedure, the reaction was carried out with (1R,2R)-cyclohexane-1,2-diamine 3a (0.31 g, 2.7 mmol,
1.0 equiv); Pd2(dba)3 (0.13 g, 0.14 mmol, 5 mol%); rac-BINAP (0.17 g, 0.28 mmol, 10 mol%); NaOtBu
(0.79 g, 8.2 mmol, 3.0 equiv); and 8-bromo-6-trifluoromethylquinoline 4c (1.57 g, 5.7 mmol, 2.1 equiv)
in 25 mL of toluene. The desired product was obtained (1.04 g, 76% yield) as a yellow green solid
1
after purification by silica gel chromatography (PE/DCM = 10/1 to 5/1 to 1/1). H-NMR (400 MHz,
Chloroform-d)
δ 8.61 (dd, J = 4.2, 1.5 Hz, 2H), 7.95 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 8.2, 4.2 Hz, 2H),
7.14–7.03 (m, 2H), 6.95–6.83 (m, 2H), 6.55 (s, 2H), 3.87–3.62 (m, 2H), 2.45–2.24 (m, 2H), 2.03–1.85 (m,

Molecules 2020, 25, 852
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2H), 1.70–1.48 (m, 4H) (Figure S5); 13C-NMR (100 MHz, Chloroform-d)
δ
148.4, 144.9, 138.8, 136.9,
129.4 (q, JC–F = 31.7 Hz), 127.5, 124.5 (q, JC–F = 272.7 Hz), 122.3, 110.6 (q, JC–F = 4.7 Hz), 100.0, 57.3,
32.3, 24.8 (Figure S6); 19F NMR (376 MHz, Chloroform-d) –62.8 (Figure S7); HRMS (ESI+) calcd for
δ
C26H23F6N4 [M + H]+: 505.1821, found 505.1817; [α]D24 = −329.1 (c = 1.0, CHCl3); M. p. 120–124 ◦C.
(1R,2R)-N1,N2-Bis(6-(tert-butyl)quinolin-8-yl)cyclohexane-1,2-diamine (L4): Following the general
procedure, the reaction was carried out with (1R,2R)-cyclohexane-1,2-diamine 3a (0.68 g, 6.0 mmol,
1.0 equiv); Pd2(dba)3 (0.28 g, 0.3 mmol, 5 mol%); rac-BINAP (0.37 g, 0.6 mmol, 10 mol%); NaOtBu
(1.73 g, 18 mmol, 3.0 equiv); and 8-bromo-6-(tert-butyl)quinoline 4d (3.46 g, 13.1 mmol, 2.2 equiv) in 35
mL of toluene. The desired product was obtained (2.44 g, 85% yield) as a yellow solid after purification
1
by silica gel chromatography (PE/DCM = 10/1 to PE/EA = 5/1). H-NMR (400 MHz, Chloroform-d)
δ
8.55 (dd, J = 4.3, 1.7 Hz, 2H), 7.99 (d, J = 7.5 Hz, 2H), 7.31–7.25 (m, 2H), 7.02–6.89 (m, 4H), 3.87–3.81 (m,
2H), 2.38 (d, J = 12.2 Hz, 2H), 1.91–1.83 (m, 2H), 1.71–1.50 (m, 4H), 1.36 (s, 18H) (Figure S8); 13C-NMR
(100 MHz, Chloroform-d)
δ 150.6, 146.2, 143.5, 137.4, 136.0, 128.5, 121.3, 109.4, 104.3, 55.5, 35.2, 31.4,
30.7, 24.0 (Figure S9); HRMS (ESI+) calcd for C32H41N4 [M + H]+: 481.3326, found 481.3323; [α]D24
−39.2 (c = 1.0, CHCl3); M. p. 172–174 ◦C.
=
(1R,2R)-N1,N2-Di(acridin-4-yl)cyclohexane-1,2-diamine (L5): Following the general procedure, the reaction
was carried out with (1R,2R)-cyclohexane-1,2-diamine 3a (0.19 g, 1.6 mmol, 1.0 equiv); Pd2(dba)3 (0.08
g, 0.08 mmol, 5 mol%); rac-BINAP (0.10 g, 0.16 mmol, 10 mol%); NaOtBu (0.47 g, 4.9 mmol, 3.0 equiv);
and 4-iodoacridine 4e (1.07 g, 3.5 mmol, 2.2 equiv) in 30 mL of toluene. The desired product was
obtained (0.46 g, 61% yield) as a yellow solid after purification by silica gel chromatography (PE/DCM
= 2/1 to PE/DCM = 1/1 to DCM). 1H-NMR (400 MHz, DMSO-d6)
δ 8.78 (s, 2H), 8.01 (d, J = 8.3 Hz, 2H),
7.91 (d, J = 8.7 Hz, 2H), 7.67 (t, J = 8.0 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.43 (t, J = 7.9 Hz, 2H), 7.18
(d, J = 8.4 Hz, 2H), 6.97 (d, J = 7.5 Hz, 2H), 6.75 (d, J = 7.0 Hz, 2H), 3.98–3.90 (m, 2H), 2.37–2.30 (m,
2H), 1.86–1.80 (m, 2H), 1.62–1.55 (m, 4H) (Figure S10); 13C-NMR (100 MHz, Chloroform-d)
δ 146.5,
144.2, 140.7, 135.1, 129.7, 128.9, 127.8, 127.3, 127.2, 127.0, 125.5, 113.8, 103.1, 56.6, 31.6, 24.4 (Figure S11);
HRMS (ESI+) calcd for C32H29N4 [M + H]+: 469.2387, found 469.2371; [α]2D4
M. p. 198–202 ◦C.
= −678.0 (c = 0.5, CHCl3);
0
(R)-N2,N2 -Di(quinolin-8-yl)-[1,10-binaphthalene]-2,20-diamine (L6) [53]: Following the general procedure,
the reaction was carried out with (R)-[1,10-binaphthalene]-2,20-diamine 3b (141.9 mg, 0.5 mmol, 1.0
equiv); Pd2(dba)3 (23.2 mg, 0.025 mmol, 5 mol%); rac-BINAP (31.4 mg, 0.05 mmol, 10 mol%); NaOtBu
(148.2 mg, 1.5 mmol, 3.0 equiv); and 8-bromoqunoline 4a (224.0 mg, 1.1 mmol, 2.2 equiv) in 10 mL of
toluene. The desired product was obtained (196.6 mg, 73% yield) as a yellow solid after purification by
recrystallization from EA. 1H-NMR (400 MHz, Chloroform-d)
δ 8.42 (d, J = 3.0 Hz, 2H), 7.99–7.95 (m,
4H), 7.94–7.86 (m, 6H), 7.37 (dt, J = 8.0, 4.0 Hz, 2H), 7.30–7.19 (m, 8H), 6.94–6.89 (m, 4H).
(12R)-N11,N12-Di(quinolin-8-yl)-9,10-dihydro-9,10-ethanoanthracene-11,12-diamine (L7) [53]: Following
the general procedure, the reaction carried out with (12R)-9,10-dihydro-9,10-ethanoanthracene-
11,12-diamine 3c (20 mg, 0.08 mmol, 1.0 equiv); Pd2(dba)3 (5.3 mg, 5 mol%); rac-BINAP (6.2 mg,
10 mol%); NaOtBu (25.5 mg, 0.26 mmol, 3.0 equiv); and 8-bromoqunoline 4a (41.8 mg, 0.2 mmol,
2.2 equiv) in 1 mL of toluene. The desired product was obtained (33.4 mg, 85% yield) as a white solid
1
after purification by silica gel chromatography (PE/EA = 5/1). H-NMR (400 MHz, Chloroform-d)
δ
8.61 (dd, J = 4.1, 1.4 Hz, 2H), 8.06 (d, J = 4.0 Hz, 2H), 7.44 (d, J = 7.1 Hz, 2H), 7.40–7.13 (m, 10H), 7.06 (d,
J = 8.1 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.18 (s, 2H), 4.63 (s, 2H), 3.97 (s, 2H).
(1R,2R)-1,2-Diphenyl-N1,N2-di(quinolin-8-yl)ethane-1,2-diamine (L8) [58]: Following the general
procedure, the reaction was carried out with (1R,2R)-1,2-diphenylethane-1,2-diamine 3d (1.06 g,
5.0 mmol, 1.0 equiv); Pd2(dba)3 (0.23 g, 0.25 mmol, 5 mol%); rac-BINAP (0.33 g, 0.5 mmol, 10 mol%);
NaOtBu (1.47 g, 15 mmol, 3.0 equiv); and 8-bromoqunoline 4a (2.51 g, 12 mmol, 2.4 equiv) in 90 mL of

Molecules 2020, 25, 852
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toluene. The desired product was obtained (1.47 g, 63% yield) as a white solid after purification by
1
silica gel chromatography (PE/DCM = 30/1 to PE/EA = 5/1). H-NMR (400 MHz, Chloroform-d)
δ 8.67
(dd, J = 4.3, 1.6 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.36 (m, 4H), 7.28–7.09 (m, 12H), 7.03 (d, J = 8.0 Hz,
2H), 6.50 (d, J = 7.6 Hz, 2H), 5.01 (s, 2H).
3.3. Preparation of Substituted Quinolines
General procedure for synthesis of substituted 8-bromoquinoline (Scheme 3): to a 50 mL round
bottom flask was added 4-substituted 2-bromoaniline
, glycerol (17.0 equiv), m-nitrobenzenesulfonate
sodium (1.2 equiv), FeSO4
•
7H2O (0.05 equiv), and MsOH. The reaction mixture was heated at 125 ◦C
for 24 h. After cooling to room temperature, aqueous NaOH solution (2.5 M) was added to the reaction
mixture to adjust pH to 12. Then EtOH was added to form a black solution, which was extracted with
EA or DCM (3
×
100 mL). The combined organic phase was washed with H2O (100 mL), brine (100
mL), and dried with anhydrous Na2SO4. After removing the solvents, the residue was purified by
silica gel chromatography.
Scheme 3. Synthesis of Substituted Quinolines (Skraup Reaction).
8-Bromo-6-fluoroquinoline (4b) [59]: Following the general procedure, the reaction was carried out
with 2-bromo-4-fluoroaniline (1.57 g, 8.3 mmol, 1.0 equiv); glycerol (11 mL, 149.0 mmol, 18.0 equiv);
m-nitrobenzenesulfonate sodium (2.24 g, 10.0 mmol, 1.2 equiv); FeSO4 7H2O (0.12 g, 0.4 mmol, 0.05
•
equiv), and MsOH (11 mL). The desired product was obtained (0.86 g, 43% yield) as a pale yellow solid
1
after purification by silica gel chromatography (PE/EA = 10/1 to 5/1). H-NMR (400 MHz, Chloroform-d)
δ
9.02 (dd, J = 4.2, 1.2 Hz, 1H), 8.14 (dd, J = 8.3, 1.6 Hz, 1H), 7.90 (dd, J = 8.1, 2.7 Hz, 1H), 7.50 (ddd, J =
8.3, 4.2, 0.6 Hz, 1H), 7.46 (dd, J = 8.3, 2.7 Hz, 1H).
8-Bromo-6-(trifluoromethyl)quinoline (4c): Following the general procedure, the reaction was carried out
with 2-bromo-4-(trifluoromethyl)aniline (6.38 g, 26.6 mmol, 1.0 equiv); glycerol (20 mL, 271.5 mmol,
10.0 equiv); m-nitrobenzenesulfonate sodium (7.19 g, 32.0 mmol, 1.2 equiv); FeSO4 7H2O (0.37 g,
•
1.3 mmol, 0.05 equiv), and MsOH (35 mL). The desired product was obtained (1.57 g, 21% yield) as a
1
pale orange solid after purification by silica gel chromatography (PE/EA = 10/1 to 5/1). H-NMR (400
MHz, Chloroform-d)
1H), 8.16–8.10 (m, 1H), 7.60 (dd, J = 8.3, 4.2 Hz, 1H) (Figure S12); 13C-NMR (100 MHz, Chloroform-d)
153.4, 146.5, 137.7, 129.1(q, JC–F = 33.4 Hz), 129.0(q, JC–F = 3.1 Hz), 128.4, 126.3, 125.7 (q, JC–F = 4.3 Hz),
δ 9.16 (dd, J = 4.2, 1.7 Hz, 1H), 8.28 (dd, J = 8.3, 1.7 Hz, 1H), 8.24 (d, J = 1.9 Hz,
δ
123.2, 123.2(q, JC–F = 272.8 Hz) (Figure S13); 19F NMR (376 MHz, Chloroform-d)
δ –62.5 (Figure S14);
HRMS (ESI+) calcd for C10H6BrF3N [M + H]+: 275.9630, found 275.9620; M. p. 58–62 ◦C.
8-Bromo-6-(tert-butyl)quinoline (4d) [60]: Following the general procedure, the reaction was carried
out with 2-bromo-4-(tert-butyl)aniline (1.78 g, 7.8 mmol, 1.0 equiv); glycerol (10 mL, 135.7 mmol,
17.0 equiv); m-nitrobenzenesulfonate sodium (2.11 g, 9.4 mmol, 1.2 equiv); FeSO4 7H2O (0.11 g, 0.41
•
mmol, 0.05 equiv); and MsOH (10 mL). The desired product was obtained (1.73 g, 84% yield) as a
yellow solid after purification by silica gel chromatography (PE/EA = 20/1). 1H-NMR (400 MHz,
Chloroform-d)
δ 9.00 (dd, J = 4.2, 1.5 Hz, 1H), 8.18–8.12 (m, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.45 (dd, J =
8.2, 4.2 Hz, 1H), 1.42 (s, 9H).

Molecules 2020, 25, 852
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4-Iodoacridine [4e] (Scheme 4)
Scheme 4. Synthesis of 4-Iodoacridine.
To a 100 mL Schlenk flask were added TMP (1.14 g, 8.1 mmol, 1.5 equiv) and 20 mL of THF. The
solution was cooled to 0 ◦C, and nBuLi (2.4 M, 4 mL, 9.6 mmol, 1.7 equiv) was added dropwise by
syringe. Upon the completion of the addition, the mixture was stirred at 0 ◦C for another 30 min.
Then ZnCl2
TMEDA (0.68 g, 2.7 mmol, 0.5 equiv) was added at 0 ◦C, and the resultant mixture was
•
stirred for 20 min before acridine (0.98 g, 5.5 mmol, 1.0 equiv) was added. After the reaction was
warmed up to 25 ◦C, I2 (2.17 g, 8.5 mmol, 1.5 equiv) in THF (20 mL) was added dropwise. The reaction
mixture was stirred for 2 h and then quenched with saturated Na2S2O3 solution and extracted with EA
(
3 × 30 mL). The combined organic phase was washed with brine and dried over anhydrous Na2SO4.
The desired product was obtained (1.08 g, 64% yield) as a yellow solid after purification by silica gel
chromatography (PE/DCM = 20/1 to 5/1). H-NMR (400 MHz, Chloroform-d)
1
δ
8.72 (s, 1H), 8.46 (dd,
J = 7.1, 1.1 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.09–7.93 (m, 2H), 7.83 (ddd, J = 8.5, 6.6, 1.3 Hz, 1H),
7.63–7.52 (m, 1H), 7.31–7.19 (m, 1H) (Figure S15); 13C-NMR (100 MHz, Chloroform-d)
δ 149.8, 147.1,
141.0, 137.2, 130.9, 130.1, 129.4, 127.9, 127.2, 126.7, 126.63, 126.58, 104.0 (Figure S16); HRMS (ESI+) calcd
for C13H9IN [M + H]+: 305.9774, found 305.9763; M.p. 100–104 ◦C.
2-Methoxynaphthalene [61]: Following the reported procedure, the reaction was carried out with
2-naphthol (1.14 g, 10 mmol, 1.0 equiv); NaH (60% wt, 0.41 g, 17 mmol, 1.7 equiv); and MeI (1.76 g, 12
mmol, 1.2 equiv) in 10 mL of DMF. The desired product was obtained (1.28 g, 81% yield) as a white
solid after purification by silica gel chromatography (DCM). 1H-NMR (400 MHz, Chloroform-d)
δ 7.78
(dd, J = 11.5, 8.4 Hz, 3H), 7.47 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.36 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.22–7.13
(m, 2H), 3.94 (s, 3H).
2-Bromo-3-methoxynaphthalene [62]: Following the reported procedure, the reaction was carried out
n
with 2-methoxynaphthalene (0.79 g, 5.0 mmol, 1.0 equiv); BuLi solution (1.67 M in hexane, 3 mL,
5.3 mmol, 1.1 equiv); and 1,2-dibromoethane (1.30 g, 6.9 mmol, 1.3 equiv) in 10 mL of THF. The desired
product was obtained (0.87 g, 73% yield) as a white solid after recrystallization from hot hexane for 3
1
times. H-NMR (400 MHz, Chloroform-d)
δ
8.06 (s, 1H), 7.71 (dd, J = 13.0, 8.2 Hz, 2H), 7.51–7.42 (m,
1H), 7.40–7.32 (m, 1H), 7.16 (s, 1H), 4.01 (s, 3H).
3-Methoxynaphthalen-2-ol (1b) [63]: Following the reported procedure, the reaction was carried out with
naphthalene-2, 3-diol (1.60 g, 10 mmol, 1.0 equiv); K2CO3 (1.81 g, 13 mmol, 1.3 equiv); and MeI (1.73 g,
12 mmol, 1.2 equiv) in 10 mL of acetone. The desired product was obtained (0.57 g, 33% yield) as a
white solid after purification by silica gel chromatography (PE/EA = 50/1 to PE/EA = 20/1 to PE/EA =
1
10/1). H-NMR (400 MHz, Chloroform-d)
δ
8.06 (s, 1H), 7.71 (dd, J = 13.0, 8.2 Hz, 2H), 7.50–7.42 (m,
1H), 7.40–7.33 (m, 1H), 7.16 (s, 1H), 4.01 (s, 3H).
3-(Benzyloxy)naphthalen-2-ol (1c) [64]: Following the reported procedure, the reaction was carried out
with naphthalene-2, 3-diol (1.61 g, 10 mmol, 1.0 equiv); K2CO3 (1.82 g, 13 mmol, 1.3 equiv); and BnBr
(2.58 g, 15 mmol, 1.5 equiv) in 20 mL of DMF. The desired product was obtained (0.88 g, 35% yield) as a
1
yellow solid after purification by silica gel chromatography (PE/EA = 50/1 to 20/1 to 10/1). H-NMR
(400 MHz, Chloroform-d) δ 7.71–7.64 (m, 2H), 7.52–7.31 (m, 7H), 7.29 (s, 1H), 7.22 (s, 1H), 5.97 (s, 1H),
5.24 (s, 2H).

Molecules 2020, 25, 852
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General procedure (Scheme 5): To a Schlenk flask were added 2-bromo-3-methoxynaphthalene
(1.0 equiv), aryl boronic acid (2.2 equiv), K2CO3 (3.0 equiv), Pd(PPh3)4 (2.5 mol%), and degassed
EtOH/toluene/water (1/1/1) under Ar atmosphere. The mixture was heated at 90 ◦C until the completion
of the reaction. Then the mixture was cooled to room temperature, and DCM was added. The mixture
was washed with NaOH solution (20% wt), and the aqueous phase was extracted with DCM (2 × 20 mL).
The combined organic phase was washed with brine (20 mL) and dried over anhydrous MgSO4. After
removing the solvent, the residue was dissolved in anhydrous DCM. The solution was cooled to
78 ◦C,
−
and BBr3 (1 M in DCM, 5.0 equiv) was added slowly by syringe. Then the mixture was warmed up to
room temperature and stirred until the complete consumption of the starting material. The mixture
was poured into the ice water (50 mL) and extracted with DCM (3
phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. After removing the solvent,
the residue was purified by silica gel chromatography to give the desired product.
×
50 mL). The combined organic
Scheme 5. Synthesis of Substrates 1d–1e.
3-(o-Tolyl)naphthalen-2-ol (1d) [65]: Following the general procedure, the reaction was carried out
with 2-bromo-3-methoxynaphthalene (236.2 mg, 1.0 mmol, 1.0 equiv); o-tolylboronic acid (304.8 mg,
2.2 mmol, 2.2 equiv); K2CO3 (417.7 mg, 3.0 mmol, 3.0 equiv); and Pd(PPh3)4 (29.9 mg, 2.5 mol%) in
6 mL of degassed solvents. Then BBr3 (1 M in DCM, 5 mL, 5 mmol, 5.0 equiv) was used to remove the
methyl group. The desired product was obtained (185.1 mg, 79% yield overall) as a brown sticky liquid
1
after purification by silica gel chromatography (PE/DCM = 10/1). H-NMR (400 MHz, Chloroform-d)
δ
7.80–7.72 (m, 2H), 7.63 (s, 1H), 7.45 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.44–7.28 (m, 6H), 4.92 (s, 1H), 2.20
(s, 3H).
3-Phenylnaphthalen-2-ol (1e) [66]: Following the general procedure, the reaction was carried out with
2-bromo-3-methoxynaphthalene (0.71 g, 3.0 mmol, 1.0 equiv); phenylboronic acid (0.55 g, 4.5 mmol,
1.5 equiv); K2CO3 (1.90 g, 13.8 mmol, 4.5 equiv); and Pd(PPh3)4 (0.09 g, 2.5 mol%) in 30 mL of degassed
solvent. Then BBr3 (1 M in DCM, 15 mL, 15 mmol, 5.0 equiv) was used to remove the methyl group.
The desired product was obtained (0.63 g, 95% yield overall) as a pale brown solid after purification by
silica gel chromatography (DCM). 1H-NMR (400 MHz, Chloroform-d)
δ 7.81–7.76 (m, 1H), 7.74 (d, J =
7.2 Hz, 2H), 7.60–7.51 (m, 4H), 7.49–7.41 (m, 2H), 7.39–7.32 (m, 2H), 5.30 (s, 1H).
3-Bromonaphthalen-2-ol (1f) [67]: Following the general procedure, the reaction was carried out with
2-bromo-3-methoxynaphthalene (240.6 mg, 1.0 mmol, 1.0 equiv) and BBr3 (1 M in DCM, 5 mL, 5.0 mmol,
5.0 equiv). The desired product was obtained (226.0 mg, quantitative yield) as a white solid after
purification by silica gel chromatography (DCM). 1H-NMR (400 MHz, Chloroform-d)
δ 8.03 (s, 1H),
7.69 (ddt, J = 7.4, 2.2, 1.2 Hz, 2H), 7.45 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.39 (s, 1H), 7.35 (ddd, J = 8.2, 6.8,
1.2 Hz, 1H), 5.64 (s, 1H).
6-Phenylnaphthalen-2-ol (1k) [5]: Following the general procedure, the reaction was carried out with
6-bromonaphthalen-2-ol (1.12 g, 5.0 mmol, 1.0 equiv); phenylboronic acid (0.73 g, 6.0 mmol, 1.2 equiv);
K2CO3 (3.00 g, 21.8 mmol, 4.4 equiv); and Pd(PPh3)4 (0.15 g, 2.5 mol%) in 30 mL of degassed solvent.
The desired product was obtained (0.77 g, 70% yield) as a white solid after purification by silica gel
chromatography (DCM). 1H-NMR (400 MHz, Chloroform-d)
δ 7.98 (d, J = 1.7 Hz, 1H), 7.82 (d, J =

Molecules 2020, 25, 852
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8.8 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.71 (ddd, J = 8.2, 2.8, 1.5 Hz, 3H), 7.48 (dd, J = 8.5, 6.9 Hz, 2H),
7.41–7.33 (m, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.8, 2.5 Hz, 1H).
7-(Benzyloxy)naphthalen-2-ol (1l) [68]: Following the reported procedure, the reaction was carried out
with naphthalene-2,7-diol (1.60 g, 10 mmol, 1.0 equiv); K2CO3 (1.80 g, 13 mmol, 1.3 equiv), and BnBr
(2.65 g, 15 mmol, 1.5 equiv) in 20 mL of DMF. The desired product was obtained (0.75 g, 30% yield)
1
as a white solid after purification by silica gel chromatography (PE/EA = 5/1). H-NMR (400 MHz,
Chloroform-d) δ 7.71–7.63 (m, 2H), 7.52–7.45 (m, 2H), 7.45–7.38 (m, 2H), 7.38–7.31 (m, 1H), 7.15–7.06
(m, 2H), 7.04 (d, J = 2.5 Hz, 1H), 6.94 (dd, J = 8.8, 2.4 Hz, 1H), 5.16 (s, 2H).
7-Butoxynaphthalen-2-ol (1m) [69]: Following the reported procedure, the reaction was carried out with
naphthalene-2,7-diol (1.60 g, 10 mmol, 1.0 equiv); K2CO3 (1.80 g, 13 mmol, 1.3 equiv); and nBuI (2.26 g,
12 mmol, 1.2 equiv) in 20 mL of acetone. The desired product was obtained (0.32 g, 15% yield) as a
1
white solid after purification by silica gel chromatography (PE/DCM = 1/1 to PE/EA = 5/1). H-NMR
(400 MHz, Chloroform-d)
δ 7.65 (dd, J = 8.7, 2.5 Hz, 2H), 7.17–6.83 (m, 4H), 5.04 (s, 1H), 4.06 (t, J =
6.5 Hz, 2H), 1.83 (dq, J = 8.7, 6.6 Hz, 2H), 1.62–1.43 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H);
7-((tert-Butyldimethylsilyl)oxy)naphthalen-2-ol (1n) [70]: Following the reported procedure, the reaction
was carried out with naphthalene-2,7-diol (1.60 g, 10 mmol, 1.0 equiv); imidazole (0.68 g, 10 mmol,
1.0 equiv); and TBSCl (1.35 g, 9 mmol, 0.9 equiv) in 15 mL of DMF. The desired product was obtained
(0.75 g, 33% yield) as a yellow solid after purification by silica gel chromatography (PE/EA = 5/1).
1H-NMR (400 MHz, Chloroform-d)
δ 7.65 (t, J = 9.3 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 7.00 (d, J = 2.4 Hz,
1H), 6.93 (ddd, J = 11.0, 8.8, 2.4 Hz, 1H), 1.01 (s, 4H), 0.24 (s, 3H).
7-Methoxynaphthalen-2-ol (1o) [69]: Following the reported procedure, the reaction was carried out with
naphthalene-2,7-diol (1.61 g, 10 mmol, 1.0 equiv); K2CO3 (1.80 g, 13 mmol, 1.3 equiv); and MeI (1.75 g,
12 mmol, 1.2 equiv) in 20 mL of acetone. The desired product was obtained (0.53 g, 30% yield) as a
1
white solid after purification by silica gel chromatography (PE/DCM = 1/1 to PE/EA = 5/1). H-NMR
(400 MHz, Chloroform-d)
δ 7.66 (dd, J = 9.2, 3.6 Hz, 2H), 7.06 (d, J = 2.3 Hz, 1H), 7.01–6.97 (m, 2H), 6.94
(dd, J = 8.7, 2.4 Hz, 1H), 3.90 (s, 3H).
3.4. Iron-Catalyzed Asymmetric Oxidative Coupling Reaction of 2-Naphthols
(S)-[1,10-Binaphthalene]-2,20-diol (2a) [47]: Fe(ClO4)2 (12.7 mg, 10 mol%; NOTE: perchlorate salt is a
potential explosive [71] and should be handled with extreme caution) and L1 (9.2 mg, 5 mol%) were
dissolved in anhydrous PhCl (5 mL) in a 25 mL Schlenk tube, and the mixture was stirred at room
temperature for 30 min. Then, 2-naphthol (72.3 mg, 0.5 mmol, 1.0 equiv) and MS 4Å (152.7 mg)
were added. The reaction mixture was quickly evacuated and refilled with oxygen (1 atm), and this
◦
operation was repeated for three cycles. Then the mixture was stirred at 50 C under oxygen, as
monitored by TLC. The desired product was obtained (60.6 mg, 84% yield) as a pale yellow solid after
purification by silica gel chromatography (PE to PE/EA = 10/1 to 5/1). 80:20 er (HPLC: Chiralpak AS-H,
1
hexane/propan-2-ol = 90/10, 0.5 mL/min,
(400 MHz, Chloroform-d)
λ
= 230 nm, tR (min): major = 24.9, minor = 38.9). H-NMR
δ
7.99 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 7.9 Hz, 2H), 7.38 (td, J = 7.7, 1.6 Hz, 4H),
7.31 (ddd, J = 8.2, 6.9, 1.4 Hz, 2H), 7.19–7.12 (m, 2H), 5.04 (s, 2H).
(S)-3,30-Dimethoxy-[1,10-binaphthalene]-2,20-diol (2b) [30]: The reaction was conducted with Fe(ClO4)2
(12.7 mg, 10 mol%) and L1 (9.2 mg, 5 mol%); 3-methoxynaphthalen-2-ol (87.5 mg, 0.5 mmol, 1.0 equiv);
and MS 4Å (152.5 mg). The desired product was obtained (76.2 mg, 88% yield) as a white solid after
purification by silica gel chromatography (PE to PE/EA = 5/1). 81:19 er (HPLC: Chiralpak AS-H,
1
hexane/propan-2-ol = 50/50, 1.0 mL/min,
λ
= 230 nm, tR (min): major = 14.3, minor = 24.4). H-NMR

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(400 MHz, Chloroform-d)
δ
7.83–7.74 (m, 2H), 7.38–7.28 (m, 4H), 7.23–7.08 (m, 4H), 5.90 (s, 2H), 4.10 (s,
6H).
(S)-3,30-Bis(benzyloxy)-[1,10-binaphthalene]-2,20-diol (2c) [72]: The reaction was conducted with Fe(ClO4)2
(12.7 mg, 10 mol%) and L1 (9.2 mg, 5 mol%); 3-(benzyloxy)naphthalen-2-ol (125.2 mg, 0.5 mmol, 1.0
equiv); and MS 4Å (150.0 mg). The desired product was obtained (84.9 mg, 68% yield) as a white solid
after purification by silica gel chromatography (PE to PE/EA = 5/1). 80:20 er (HPLC: Chiralpak AS-H,
1
hexane/propan-2-ol = 85/15, 1.0 mL/min,
(400 MHz, Chloroform-d)
λ
= 254 nm, tR (min): major = 35.1, minor = 42.1). H-NMR
δ
7.77 (d, J = 8.1 Hz, 2H), 7.57–7.48 (m, 4H), 7.47–7.36 (m, 8H), 7.32 (dt, J =
8.1, 4.0 Hz, 2H), 7.17 (d, J = 3.9 Hz, 4H), 6.01 (s, 2H), 5.33 (s, 4H).
(S)-3,30-Di-o-tolyl-[1,10-binaphthalene]-2,20-diol (2d) [73]: The reaction was conducted with Fe(ClO4)2
(13.4 mg, 10 mol%) and L1 (9.4 mg, 5 mol%); 3-(o-tolyl)naphthalen-2-ol (116.0 mg, 0.5 mmol, 1.0 equiv);
and MS 4Å (155.6 mg). The desired product was obtained (84.2 mg, 72% yield) as a brown solid after
purification by silica gel chromatography (PE/DCM = 10/1 to 1/1 to PE/EA = 5/1). 77:23 er (HPLC:
Chiralpak AD-H, hexane/propan-2-ol = 70/30, 0.8 mL/min,
λ = 254 nm, tR (min): major = 19.8, minor =
1
6.4). H-NMR (400 MHz, Chloroform-d)
δ
7.94–7.86 (m, 2H), 7.86 (s, 2H), 7.46–7.25 (m, 14H), 5.15 (s,
2H), 2.27 (s, 6H).
(S)-3,30-Diphenyl-[1,10-binaphthalene]-2,20-diol (2e) [74]: The reaction was conducted with Fe(ClO4)2
(13.1 mg, 10 mol%) and L1 (9.0 mg, 5 mol%); 3-phenylnaphthalen-2-ol (111.6 mg, 0.5 mmol, 1.0 equiv);
and MS 4Å (158.0 mg). The desired product was obtained (72.2 mg, 66% yield) as a pale yellow
solid after purification by silica gel chromatography (PE/DCM = 1/1). 56:44 er (HPLC: Chiralpak IC,
1
hexane/propan-2-ol = 90/10, 0.8 mL/min,
(400 MHz, Chloroform-d)
λ
= 230 nm, tR (min): major = 6.6, minor = 10.1). H-NMR
δ
8.03 (s, 2H), 7.97–7.89 (m, 2H), 7.78–7.70 (m, 4H), 7.53–7.47 (m, 4H), 7.44–7.36
(m, 4H), 7.36–7.30 (m, 2H), 7.23 (dd, J = 8.3, 1.1 Hz, 2H), 5.38 (s, 2H).
(S)-3,30-Dibromo-[1,10-binaphthalene]-2,20-diol (2f) [75]: The reaction was conducted with Fe(ClO4)2
(12.7 mg, 10 mol%) and L1 (9.2 mg, 5 mol%); 3-bromonaphthalen-2-ol (111.5 mg, 0.5 mmol, 1.0 equiv);
and MS 4Å (150.4 mg). The desired product was obtained (56.2 mg, 51% yield) as a pale yellow solid
after purification by silica gel chromatography (PE to PE/EA = 10/1). 66:34 er (HPLC: Chiralpak IC,
1
hexane/propan-2-ol = 97/3, 1.0 mL/min,
(400 MHz, Chloroform-d)
λ
= 230 nm, tR (min): major = 12.2, minor = 14.3). H-NMR
δ
8.25 (d, J = 0.7 Hz, 2H), 7.86–7.77 (m, 2H), 7.39 (ddd, J = 8.2, 6.8, 1.3 Hz,
2H), 7.31 (ddd, J = 8.3, 6.8, 1.4 Hz, 2H), 7.10 (dq, J = 7.7, 0.7 Hz, 2H), 5.55 (s, 2H).
(S)-6,60-Dibromo-[1,10-binaphthalene]-2,20-diol (2j) [76]: The reaction was conducted with Fe(ClO4)2
(12.7 mg, 10 mol%) and L1 (9.2 mg, 5 mol%); 6-bromonaphthalen-2-ol (112.7 mg, 0.5 mmol, 1.0 equiv);
and MS 4Å (156.0 mg). The desired product was obtained (90.6 mg, 82% yield) as a pale yellow solid
after purification by silica gel chromatography (PE to PE/EA = 10/1 to 5/1). 79:21 er (HPLC: Chiralpak
AS-H, hexane/propan-2-ol = 90/10, 0.5 mL/min,
λ = 254 nm, tR (min): major = 27.8, minor = 38.9).
1H-NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 0.7 Hz, 2H), 7.85–7.78 (m, 2H), 7.39 (ddd, J = 8.2, 6.8,
1.3 Hz, 2H), 7.31 (ddd, J = 8.3, 6.8, 1.4 Hz, 2H), 7.10 (dq, J = 7.6, 0.7 Hz, 2H), 5.55 (s, 2H).
(S)-6,60-Diphenyl-[1,10-binaphthalene]-2,20-diol (2k) [23]: The reaction was conducted with Fe(ClO4)2
(12.7 mg, 10 mol%) and L1 (9.2 mg, 5 mol%); 6-phenylnaphthalen-2-ol (109.5 mg, 0.5 mmol, 1.0 equiv);
and MS 4Å (160.6 mg). The desired product was obtained (70.2 mg, 64% yield) as pale yellow solid
after purification by silica gel chromatography (PE to PE/EA = 10/1 to 5/1). 74:26 er (HPLC: Chiralpak
AS-H, hexane/propan-2-ol = 90/10, 0.8 mL/min,
1H-NMR (400 MHz, Chloroform-d)
8.03 (s, 2H), 7.96–7.90 (m, 2H), 7.77–7.71 (m, 4H), 7.53–7.46 (m,
4H), 7.45–7.36 (m, 4H), 7.35–7.29 (m, 2H), 7.23 (dd, J = 8.3, 1.1 Hz, 2H), 5.38 (s, 2H).
λ = 254 nm, tR (min): major = 13.1, minor = 10.2).
δ

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(S)-7,70-Bis(benzyloxy)-[1,10-binaphthalene]-2,20-diol (2l) [77]: The reaction was conducted with Fe(ClO4)2
(12.9 mg, 10 mol%) and L1 (9.0 mg, 5 mol%); 7-(benzyloxy)naphthalen-2-ol (125.4 mg, 0.5 mmol,
1.0 equiv); and MS 4Å (160.6 mg). The desired product was obtained (88.5 mg, 71% yield) as a pale
yellow solid after purification by silica gel chromatography (PE to PE/EA = 5/1). 58:42 er (HPLC:
Chiralcel OD-H, hexane/propan-2-ol = 85/15, 1.0 mL/min,
λ = 230 nm, tR (min): major = 14.8, minor =
1
26.7). H-NMR (400 MHz, Chloroform-d)
δ 7.89 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.9 Hz, 2H), 7.22 (dt, J =
6.1, 2.2 Hz, 8H), 7.16 (dd, J = 6.6, 3.1 Hz, 4H), 7.11 (dd, J = 8.9, 2.5 Hz, 2H), 6.49 (d, J = 2.4 Hz, 2H), 4.99
(s, 2H), 4.80 (d, J = 11.7 Hz, 2H), 4.74 (d, J = 11.7 Hz, 2H).
(S)-7,70-Dibutoxy-[1,10-binaphthalene]-2,20-diol (2m) [29]: The reaction was conducted with Fe(ClO4)2
(12.3 mg, 10 mol%) and L1 (9.0 mg, 5 mol%); 7-butoxynaphthalen-2-ol (108.5 mg, 0.5 mmol, 1.0 equiv);
and MS 4Å (150.0 mg). The desired product was obtained (106.5 mg, 99% yield) as a white solid after
purification by silica gel chromatography (PE/EA = 10/1 to 5/1). 60:40 er (HPLC: Chiralpak AD-H,
1
hexane/propan-2-ol = 90/10, 1.0 mL/min,
(400 MHz, Chloroform-d)
λ
= 254 nm, tR (min): major = 8.3, minor = 19.3). H-NMR
δ
7.84 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.9 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H),
7.03 (dd, J = 8.9, 2.4 Hz, 2H), 6.48 (d, J = 1.9 Hz, 2H), 5.08 (s, 2H), 3.71 (ddt, J = 27.6, 9.3, 6.5 Hz, 4H),
1.67–1.53 (m, 4H), 1.34 (tt, J = 16.4, 8.3 Hz, 4H), 0.86 (t, J = 7.4 Hz, 6H).
(S)-7,70-Bis((tert-butyldimethylsilyl)oxy)-[1,10-binaphthalene]-2,20-diol (2n): The reaction was conducted
with Fe(ClO4)2 (12.6 mg, 10 mol%) and L1 (9.8 mg, 5 mol%); 7-((tert-butyldimethylsilyl)oxy)
naphthalen-2-ol (138.2 mg, 0.5 mmol, 1.0 equiv); and MS 4Å (153.7 mg). The desired product
was obtained (103.8 mg, 76% yield) as a brown solid after purification by silica gel chromatography
(PE to PE/EA = 5/1). 68:32 er (HPLC: Chiralpak IC, hexane/propan-2-ol = 97/3, 1.0 mL/min,
λ = 254 nm,
1
tR (min): major = 6.0, minor = 8.5). H-NMR (400 MHz, Chloroform-d)
δ 7.86 (dd, J = 9.0, 0.7 Hz, 2H),
7.75 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.9 Hz, 2H), 6.95 (dd, J = 8.8, 2.4 Hz, 2H), 6.46 (d, J = 2.4 Hz, 2H),
5.07 (s, 2H), 0.83 (s, 18H), 0.03 (s, 6H),
0.06 (s, 6H) (Figure S17); 13C-NMR (100 MHz, Chloroform-d)
4.5 (Figure S18); HRMS
H]−: 545.2549, found 545.2578; [α]D24 = 56.6 (c = 1.0, CHCl3);
−
−
δ
155.3, 153.2, 134.9, 131.1, 129.9, 125.1, 119.9, 115.3, 111.7, 109.8, 25.8, 18.3,
−
(ESI−), m/z calc0d for C32H41O4Si2 [M
−
M.p. 118–122 ◦C.
(S)-7,70-Dimethoxy-[1,10-binaphthalene]-2,20-diol (2o) [78]: The reaction was conducted with Fe(ClO4)2
(12.4 mg, 10 mol%) and L1 (9.4 mg, 5 mol%); 7-methoxynaphthalen-2-ol (87.3 mg, 0.5 mmol, 1.0 equiv);
and MS 4Å (156.3 mg). The desired product was obtained (56.3 mg, 65% yield) as a white solid
after purification by silica gel chromatography (PE to PE/EA = 5/1). 59:41 er (HPLC: Chiralcel OD-H,
1
hexane/propan-2-ol = 85/15, 1.0 mL/min,
(400 MHz, Chloroform-d)
λ
= 230 nm, tR (min): major = 11.1, minor = 18.8). H-NMR
δ
7.88 (dd, J = 9.0, 0.7 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.8 Hz,
2H), 7.03 (dd, J = 8.9, 2.5 Hz, 2H), 6.48 (d, J = 2.5 Hz, 2H), 3.57 (s, 6H).
4. Conclusions
In summary, we have developed an iron/bisquinolyldiamine-catalyzed asymmetric oxidative
coupling of 2-naphthols. This method employs in situ-formed iron complexes from Fe(ClO4)2
and readily available ligand L1 and uses 1 atm oxygen as the oxidant. The atom economy of
this transformation, the easily available catalyst, and operationally simple procedure provide new
applications of asymmetric iron catalysis. Further studies on synthesizing a library of nitrogen ligands
and extending their applications are underway in our laboratory.
Supplementary Materials: The following are available online. NMR and HPLC spectra.
Author Contributions: L.-Y.W. performed the experiments; L.-Y.W., M.U., and W.-B.L. wrote the paper; and
W.-B.L. conceived and designed the experiments. All authors have read and agreed to the published version of
the manuscript.

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Funding: We thank the National Natural Science Foundation of China (21602160 and 21772148) and Wuhan
University for financial support.
Conflicts of Interest: The authors declare no conflicts of interest.
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