Cinchona alkaloid derivatives catalyzed asymmetric aza-Friedel–crafts reaction of α-naphthols with aryl aldimines

Article abstract of DOI:10.1002/chir.22714

Cinchona alkaloid derivatives as organocatalysts were applied in the asymmetric aza-Friedel–Crafts reaction of α-naphthol with aryl aldimines. The desired chiral aminoarylnaphthols were obtained in 85% enantiomeric excess.

Full text of DOI:10.1002/chir.22714

Received: 25 February 2017
DOI: 10.1002/chir.22714
Revised: 3 April 2017
Accepted: 28 April 2017
R E G U L A R A R T I C L E
Cinchona alkaloid derivatives catalyzed asymmetric aza‐Friedel–
crafts reaction of α‐naphthols with aryl aldimines
Ya Wei Li1,2 | Li Ming Wang1 | Ying Jin1 | Sheng Chang1
1 Department of Pharmacy, Jilin Medical
Abstract
University, Jilin, China
Cinchona alkaloid derivatives as organocatalysts were applied in the asymmetric
aza‐Friedel–Crafts reaction of α‐naphthol with aryl aldimines. The desired chiral
aminoarylnaphthols were obtained in 85% enantiomeric excess.
2 Institute of Military Veterinary Sciences,
Academy of Military Medical Sciences,
Changchun, China
Correspondence
KEYWORDS
Ying Jin and Sheng Chang, Department of
Pharmacy, Jilin Medical University, Jilin
132013, China.
asymmetric, aza‐Friedel‐crafts reaction, cinchona alkaloid derivatives, α‐naphthol
Email: jinying2288@163.com;
jmu_changsheng@126.com
1 | INTRODUCTION
aminoarylnaphthols in good yields and enantioselectivities
(Scheme 1).
The Friedel–Crafts (F‐C) reaction is a highly effective
carbon–carbon bond‐forming method that involves the
reaction of aromatic compounds with aldehydes, ketones,
activated olefins, and imides,1-4 Naphthols are good F‐C
donors with a range of nitrogen‐contained electrophiles. The
resulting arylamine products could serve as biologically active
compounds, the skeleton structure of synthetic drugs, or chiral
ligands in asymmetric syntheses.5-7 Accordingly, the broad
utility of chiral aminoarylnaphthols has prompted considerable
interest to develop asymmetric methods for their preparation.
However, studies rarely focused on the organocatalytic asym-
metric aza‐Friedel–Crafts (aza‐F‐C) reaction of α‐naphthol.
In 1990, Erker and Van der Zeijden first reported the asymmet-
ric aza‐F‐C reaction of α‐naphthol with ethyl pyruvate by
using zirconium trichloride.8 Very recently, Kumari et al.
reported chiral dinuclear copper(II) complexes catalyzed
asymmetric aza‐F‐C alkylation of α‐naphthol and N‐tosyl
aldimine.9 In 2007, Chen and Chimini presented the first
organocatalytic asymmetric Michael‐type F‐C alkylation of
naphthols and nitroolefins promoted by bifunctional thio-
urea‐tertiary amine organocatalysts.10 In 2011, Wang and col-
leagues11 and Chauhan and colleagues12 disclosed the
organocatalytic enantioselective F‐C reaction of α‐naphthols
with N‐sulfonyl imines to afford a direct access to chiral
In this article we report the asymmetric aza‐F‐C reaction
of α‐naphthol with aryl aldimines using a series of cinchona
alkaloid derivatives 1a–h, which were derived by making
modifications to the 9‐OH, 6′‐OH, and terminal vinyl groups
of quinine and quinidine (Figure 1).
2 | MATERIALS AND METHODS
2.1 | Instruments and materials
The 1H NMR spectra were recorded on 500 MHz spectrom-
eters using CDCl3 as a solvent. The chemical shifts are
reported in ppm with the solvent signal used as a reference
(7.26 ppm). The splitting patterns of the signals are reported
as s singlet; d, doublet; t, triplet; q, quartet; dd, doublet of
doublets; m, multiplet; bs, broad signal. The 13C nuclear
magnetic resonance (NMR) spectra were recorded on 125
MHz instruments using CDCl3 as a solvent. The chemical
shifts are reported in ppm with the solvent signal used as a
reference (77.0 ppm). High‐resolution mass spectra (HRMS)
were measured on a mass spectrometer equipped with an
electrospray ionization (ESI) source in the positive‐ion mode.
The enantiomeric excess (ee) values of the products were
determined by Chiral HPLC using Daicel Chiralcel OD‐H
458
© 2017 Wiley Periodicals, Inc.
wileyonlinelibrary.com/journal/chir
Chirality. 2017;29:458–463.

LI ET AL.
459
3H), −0.32 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 156.9,
147.6, 146.3, 143.4, 139.6, 130.9, 126.8, 123.4, 118.6,
115.0, 106.6, 71.6, 59.9, 49.8, 49.5, 40.1, 27.8, 26.1(×3),
25.7, 19.2, 17.9, −4.6, −4.9. HRMS (ESI+): m/z calcd. For
C25H37N2O2Si [M + H]: 425.2624, found: 425.2629.
SCHEME 1 Enantioselective Friedel–crafts reactions of α‐naphthols
with aldimines
2.3 | General procedure for the asymmetric
aza‐Friedel–crafts reaction
and Chiralpak AD‐H columns. The melting points are uncor-
rected. The reactions were monitored by thin‐layer chroma-
tography (TLC). Purifications by column chromatography
were conducted over silica gel (200–300 mesh). The catalysts
1a–d, 1f–h were synthesized according to reported proce-
dures.13 The aromatic imines were prepared according to lit-
erature procedures.13-15 The catalyst 1e was synthesized as
follows.
To a solution of α‐naphthol (0.5 mmol) and imine (0.1 mmol)
in toluene (1 mL) was added catalyst (0.01 mmol) at 0 °C,
and the resulting mixture was stirred for 24 h at 0 °C. The
crude mixture was directly loaded onto a column packed
with silica gel using Hexane/EtOAc (12:1) to furnish
aminoarylnaphthols 3a–k.
2.3.1 | N‐((1‐Hydroxynaphthalen‐2‐yl)(phe-
nyl)methyl)‐4‐methyl benzenesulfonamide 3a
2.2 | Synthesis of catalyst 1e
To a solution of 1b (0.20 g, 0.62 mmol) in DMF (3 mL) were
added Et3N (0.45 mL, 0.31 mmol), DMAP (7.50 mg,
0.06 mol), and TBSCl (0.14 g, 0.93 mmol). The mixture
was allowed to stir for 6 h and worked up by adding toluene
and washing with water. The toluene was removed under
vacuum and the main oil was used in the next step reaction
without further purification.
The crude product was dissolved in methanol (2 mL); p‐
toluenesulfonic acid (0.21 g, 1.24 mmol) was then added.
The mixture was stirred for 3 h at room temperature (rt)
(monitored by TLC). Then the methanol was evaporated
under vacuum and the residue was purified by flash column
chromatography (dichloromethane/methanol 20:1) to yield
the product 1f (0.21 g, 80%) as a white solid. mp. 105–
106 °C. 1H NMR (500 MHz, CDCl3): δ 8.69 (d,
J = 4.5 Hz, 1H), 8.01 (d, J = 9.0 Hz, 2H), 7.50 (d,
J = 4.5 Hz, 1H), 7.32 (dd, J = 2.5, 9.0 Hz, 1H), 6.12–6.04
(m, 1H), 5.95 (s, 1H), 5.08 (d, J = 5.5 Hz, 1H), 5.06 (s,
1H), 3.49–3.43 (m, 1H), 3.06 (dd, J = 10.5, 12.5 Hz, 1H),
2.83–2.75 (m, 3H), 2.34–2.28 (m, 2H), 1.79 (s, 1H), 1.81–
1.23 (m, 3H), 1.08–1.06 (m, 1H), 0.94 (s, 9H), 0.13 (s,
1H NMR (500 MHz, CDCl3, δ): 8.08–8.06 (m, 1H), 7.76–
7.74 (m, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.51–7.48 (m, 2H),
7.31–7.25 (m, 4H), 7.23–7.20 (m, 2H), 6.99 (d, J = 8.0 Hz,
2H), 6.92 (d, J = 8.5 Hz, 1H), 6.75 (s, 1H), 5.93 (d,
J = 7.5 Hz, 1H), 5.37 (d, J = 7.0 Hz, 1H), 2.21 (s, 3H);
HPLC (Daicel Chiralpak AD‐H, Vhex: ViPrOH = 80:20,
1.0 mL/min, 235 nm), tR: 13.9 min (minor), 35.1 min
(major).
2.3.2 | N‐((1‐Hydroxynaphthalen‐2‐yl)(2‐
chlorophenyl)methyl)‐4‐
methylbenzenesulfonamide 3b
1H NMR (500 MHz, CDCl3, δ): 8.23–8.21(m, 1H), 7.74–7.71
(m, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.50–7.48 (m, 2H), 7.32–
7.28 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 7.21–7.16 (m, 2H),
7.04 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 8.5 Hz, 1H), 6.21 (d,
J = 8.5 Hz, 1H), 5.41 (d, J = 7.0 Hz, 1H), 2.27 (s, 3H); HPLC
(Daicel Chiralpak AD‐H, Vhex: ViPrOH = 90:10, 0.5 mL/min,
235 nm), tR: 95.4 min (minor), 101.3 min (major).
FIGURE 1 The structure of Cinchona
alkaloid catalysts 1a–h

460
LI ET AL.
2.3.3 | N‐((1‐Hydroxynaphthalen‐2‐yl)(2‐
bromophenyl)methyl)‐4‐
2.3.6 | N‐((1‐Hydroxynaphthalen‐2‐yl)(3‐
fluorophenyl)methyl)‐4‐
methylbenzenesulfonamide 3c
methylbenzenesulfonamide 3f
1H NMR (500 MHz, CDCl3, δ): 8.10–8.07 (m, 1H), 8.05 (s,
1H), 7.97–7.94 (m, 1H), 7.80–7.77 (m, 1H), 7.62 (d,
J = 8.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.55–7.51 (m,
2H), 7.48–7.42 (m, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.00 (d,
J = 8.0 Hz, 2H), 6.90 (d, J = 8.5 Hz, 1H), 6.28 (s, 1H),
6.03 (d, J = 8.5 Hz, 1H), 5.65 (d, J = 8.5 Hz, 1H), 2.20 (s,
3H); 13C NMR (125 MHz, CDCl3, δ):162.9, 149.5, 143.9,
141.6, 136.6, 130.2, 130.0, 129.5(×2), 128.0, 127.3(×2),
126.8, 125.9, 125.7, 125.0, 124.2, 120.9, 120.7, 119.5,
115.1, 113.9, 58.5, 21.3; HRMS (ESI, m/z): [M + Na]+ calcd
for C24H20FNNaO3S, 444.1046, found 444.1043; HPLC
(Daicel Chiralpak AD‐H, Vhex: ViPrOH = 80:20, 1.0 mL/
min, 235 nm), tR: 10.9 min (minor), 12.7 min (major).
1H NMR (500 MHz, CDCl3, δ): 8.26–8.23 (m, 1H), 7.74–
7.71 (m, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.50–7.46 (m, 3H),
7.34–7.30 (m, 2H), 7.25–7.20 (m, 2H), 7.12–7.09 (m, 1H),
7.05 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.21 (d,
J = 7.0 Hz, 1H), 5.38 (d, J = 7.0 Hz, 1H), 2.27 (s, 3H);
13C NMR (125 MHz, CDCl3, δ): 150.6, 143.8, 137.2,
135.5, 134.3, 133.3, 129.3 (×2), 129.2 (×2), 127.4, 127.3
(×2), 127.2, 126.7, 125.4, 125.3, 125.0, 123.2, 122.1,
120.1, 116.9, 57.9, 21.2; HRMS (ESI, m/z): [M + Na]+ calcd
for C24H20ClNNaO3S, 460.0750, found 460.0745; HPLC
(Daicel Chiralcel OD‐H, Vhex: ViPrOH = 95:5, 0.5 mL/min,
235 nm), tR: 142.6 min (minor), 160.6 min (major).
2.3.4 | N‐((1‐Hydroxynaphthalen‐2‐yl)(2‐
trifluoromethyphenyl) methyl)‐4‐
methylbenzenesulfonamide 3d
2.3.7 | N‐((1‐Hydroxynaphthalen‐2‐yl)(3‐
chlorophenyl)methyl)‐4‐
methylbenzenesulfonamide 3 g
1H NMR (500 MHz, CDCl3, δ): 8.23–8.21 (m, 1H), 7.72–
7.70 (m, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 9.0 Hz,
1H), 7.62–7.57 (m, 3H), 7.52–7.46 (m, 3H), 7.37 (t,
J = 8.0 Hz, 1H), 7.23–7.20 (m, 2H), 7.05 (d, J = 8.0 Hz,
2H), 6.65 (d, J = 8.5 Hz, 1H), 6.35 (d, J = 6.5 Hz, 1H),
5.25 (d, J = 6.5 Hz, 1H), 2.29 (s, 3H); 13C NMR (125 MHz,
CDCl3, δ): 149.9, 143.9, 136.8, 135.1, 134.1, 132.0, 129.5,
129.2 (×2), 127.9, 127.6, 127.4 (×2), 127.3, 126.8, 126.3,
126.2, 125.5, 125.2, 124.8, 122.0, 120.0, 118.1, 54.0, 21.3;
HRMS (ESI, m/z): [M + Na]+ calcd for C25H20F3NNaO3S,
494.1014, found 494.1011; HPLC (Daicel Chiralpak AD‐H,
Vhex: ViPrOH = 90:10, 0.5 mL/min, 235 nm), tR: 78.3 min
(minor), 93.6 min (major).
1H NMR (500 MHz, CDCl3, δ): 7.94 (d, J = 3.5 Hz, 1H),
7.93 (d, J = 6.0 Hz, 1H), 7.47–7.35 (m, 4H), 7.18 (d,
J = 8.0 Hz, 1H), 7.13–7.02 (m, 4H), 6.85 (d, J = 8.0 Hz,
2H), 6.78 (d, J = 8.5 Hz, 1H), 6.59 (s, 1H), 5.81(d,
J = 8.0 Hz, 1H), 5.60 (d, J = 8.5 Hz, 1H), 2.09 (s, 3H);
13C NMR (125 MHz, CDCl3, δ): 149.3, 143.6, 141.5,
136.2, 133.9, 131.0, 130.2, 129.8, 129.1 (×2), 127.8, 127.1
(×2), 126.6, 126.0, 125.9, 125.6, 124.9, 121.0, 120.9,
120.7, 119.3, 57.1, 21.2; HRMS (ESI, m/z): [M + Na]+ calcd
for C24H20ClNNaO3S, 460.0750, found 460.0755; HPLC
(Daicel Chiralpak AD‐H, Vhex: ViPrOH = 80:20, 1.0 mL/
min, 235 nm), tR: 11.2 min (minor), 14.8 min (major).
2.3.8 | N‐((1‐Hydroxynaphthalen‐2‐yl)(3‐
bromophenyl)methyl)‐4‐
2.3.5 | N‐((1‐Hydroxynaphthalen‐2‐yl)(2‐
methylphenyl)methyl)‐4‐
methylbenzenesulfonamide 3 h
methylbenzenesulfonamide 3e
1H NMR (500 MHz, CDCl3, δ): 8.03–8.01(m, 1H), 7.77–
7.75 (m, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.52–7.49 (m, 1H),
7.35 (d, J = 7.5 Hz, 1H), 7.31–7.28 (m, 2H), 7.15–7.12 (m,
2H), 6.99 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.5 Hz, 1H),
6.50 (s, 1H), 5.91 (d, J = 8.0 Hz, 1H), 5.47 (d, J = 8.0 Hz,
1H), 2.21 (s, 3H); 13C NMR (125 MHz, CDCl3, δ): 149.1,
143.7, 141.3, 136.0, 134.1, 130.7, 130.0, 129.9, 129.2 (×2),
127.6, 127.0 (×2), 126.6, 126.3, 125.7 (×2), 124.9, 122.6,
120.8, 120.7, 119.1, 57.7, 21.2; HRMS (ESI, m/z):
[M + Na]+ calcd for C24H20BrNNaO3S, 504.0245, found
1H NMR (500 MHz, CDCl3, δ): 8.23–8.20 (m, 1H), 7.72–
7.70 (m, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.50–7.47 (m, 2H),
7.23–7.20 (m, 4H), 7.17–6.99 (m, 2H), 6.74 (d, J = 8.5 Hz,
2H), 6.10 (d, J = 7.5 Hz, 1H), 5.17 (d, J = 7.5 Hz, 1H),
2.23 (s, 3H), 2.13 (s, 3H); 13C NMR (125 MHz, CDCl3, δ):
150.2, 143.6, 136.4, 135.9, 135.6, 130.8, 129.1, 127.7 (×2),
127.3, 127.2, 127.1, 127.0 (×2), 126.5, 126.4, 126.0, 125.4,
125.1, 121.9, 120.2, 118.3, 54.9, 21.2, 18.9; HRMS (ESI,
m/z): [M + Na]+ calcd for C25H23NNaO3S, 440.1296, found
440.1292; HPLC (Daicel Chiralpak AD‐H, Vhex
iPrOH = 80:20, 1.0 mL/min, 235 nm), tR: 13.6 min (minor),
15.1 min (major).
:
504.0248; HPLC (Daicel Chiralpak AD‐H, Vhex
iPrOH = 80:20, 1.0 mL/min, 235 nm), tR: 11.6 min (minor),
16.3 min (major).
:
V
V

LI ET AL.
461
2.3.9 | N‐((1‐Hydroxynaphthalen‐2‐yl)(3‐
methylphenyl)methyl)‐4‐
2.3.10 | N‐((1‐Hydroxynaphthalen‐2‐yl)(4‐
methylmethyl)‐4‐methyl benzenesulfonamide 3j
methylbenzenesulfonamide 3i
1H NMR (500 MHz, CDCl3, δ): 8.06–8.04 (m, 1H), 7.74–
7.72 (m, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.50–7.46 (m, 2H),
7.27 (d, J = 8.5 Hz, 1H), 7.10–7.05 (m, 4H), 6.98 (d,
J = 8.0 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.74 (s, 1H), 5.87
(d, J = 7.0 Hz, 1H), 5.28 (d, J = 7.0 Hz, 1H), 2.30 (s, 3H),
2.20 (s, 3H); 13C NMR (125 MHz, CDCl3, δ): 149.4, 143.5,
137.6, 136.1, 135.8, 134.0, 129.9, 129.3 (×2), 129.0, 127.4
(×2), 127.1, 126.8, 126.4, 126.0, 125.4, 125.2, 124.7,121.3,
120.4, 119.3, 58.6, 21.1, 20.8; HRMS (ESI, m/z): [M + Na]
1H NMR (500 MHz, CDCl3, δ): 8.23–8.21 (m, 1H), 7.72–
7.70 (m, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.60 (d,
J = 9.0 Hz, 1H), 7.62–7.57 (m, 3H), 7.52–7.46 (m, 3H),
7.37 (t, J = 8.0 Hz, 1H), 7.23–7.20 (m, 2H), 7.05 (d,
J = 8.0 Hz, 2H), 6.65 (d, J = 8.5 Hz, 1H), 6.35 (d,
J = 6.5 Hz, 1H), 5.25 (d, J = 6.5 Hz, 1H), 2.29 (s, 3H),
2.18 (s, 3H); 13C NMR (125 MHz, CDCl3, δ): 149.9,
143.9, 136.8, 135.1, 134.1, 132.0, 129.5, 129.2 (×2), 127.9,
127.4 (×2), 127.3, 126.8, 126.3, 126.2, 125.5, 125.2, 124.8,
122.0, 120.0, 118.1, 54.0, 21.3, 21.0; HRMS (ESI, m/z):
[M + Na]+ calcd for C25H23NNaO3S, 440.1296, found
+
calcd for C25H23NNaO3S, 440.1296, found 440.1295;
HPLC (Daicel Chiralpak AD‐H, Vhex: ViPrOH = 80:20,
1.0 mL/min, 235 nm), tR: 48.2 min (minor), 54.6 min (major).
440.1290; HPLC (Daicel Chiralpak AD‐H, Vhex
iPrOH = 80:20, 1.0 mL/min, 235 nm), tR: 16.2 min (minor),
20.2 min (major).
:
V
TABLE 1 Screening of reaction conditions for the asymmetric aza‐F‐C reactiona
Entry
1
Cat
1a
1b
1c
1d
1e
1f
Solvent
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DCM
CHCl3
Xylene
THF
T/ oC
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
0
Cat. Loading (mmol%)
Yield (%)b
78
Ee (%)c
14
Conf.d
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
R
S
2
76
‐44
70
3
89
R
S
4
88
‐67
‐67
‐34
‐32
20
5
85
S
6
75
S
7
1 g
1 h
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
81
S
8
79
R
R
R
R
—
—
R
R
R
R
R
R
9
84
59
10
11
12
13
14
15
16
17
18
19
0
83
60
0
75
61
0
—
—
—
—
CH3CN
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
0
0
87
80
0
70
75
0
20
20
10
10
88
72
−20
−20
−40
77
77
75
76
68
77
aAll of the reactions were performed with N‐Tosyl benzaldimine (0.10 mmol), α‐naphthol (0.50 mmol) in different solvent for 5 ~ 6 h.
bIsolated yield.
cDetermined by HPLC analysis (Chiralpak AD‐H)
dThe configuration was established by comparison with the optical rotation from the literature.11

462
LI ET AL.
as in catalyst 1e, the same enantioselectivity was observed
(entry 5).
2.3.11 | N‐((1‐Hydroxynaphthalen‐2‐yl)(4‐
nitrophenyl)methyl)‐4‐methyl
To optimize the enantioselectivity of the reaction, we
investigated different reaction variables, including the
solvent, catalyst loading, and temperature. The results
showed that the solvent significantly influenced the
enantioselectivity of the reaction. Toluene provided the
best yield and enantioselectivity (entry 14). No desired
product was observed when THF and CH3CN were used
as the reaction solvents. The screening of different amounts
of catalyst showed that a 10 mmol% loading was optimal
in terms of enantioselectivity. Attempts to reduce the
catalyst loading to 5 mmol% decreased the yield and
enantioselectivity (entry 15 vs. entry 14), whereas further
increasing the catalyst loading to 20 mmol% decreased the
ee value by 8% (entry 16 vs. entry 14). Temperature exerted
a moderate effect on the level of enantioselectivity. When
the reaction temperature was lowered from rt (25 °C) to
0 °C, the enantioselectivity increased obviously (entry 14
vs. entry 3). However, on further reducing the temperature
to −20 °C or −40 °C, no improvement was obtained in
the enantioselectivity but reduced the yields (entries 18, 19
vs. entry 14). On the basis of these experiments, the opti-
mized conditions were determined to be toluene as the sol-
vent with a 10 mmol% loading of catalyst 1c at 0 °C.
With the optimized conditions in hand, we evaluated the
scope and general applicability of this asymmetric aza‐F‐C
reaction using different aryl aldimines (Table 2). All
aldimines tested in the current study reacted smoothly to give
the corresponding products in good yields (75–88%) with
moderate to high enantioselectivities. As shown in Table 2,
benzenesulfonamide 3 k
1H NMR (500 MHz, CDCl3, δ): 8.10 (d, J = 9.0 Hz, 2H),
7.95–7.92 (m, 1H), 7.80–7.77 (m, 1H), 7.57 (d, J = 8.0 Hz,
2H), 7.55–7.51 (m, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.32 (d,
J = 8.5 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.88 (d,
J = 8.5 Hz, 1H), 6.21 (s, 1H), 6.01 (d, J = 8.5 Hz, 1H),
5.65 (d, J = 8.5 Hz, 1H), 2.20 (s, 3H). HPLC (Daicel
Chiralpak AD‐H, Vhex: ViPrOH = 90:10, 0.8 mL/min,
235 nm), tR: 44.4 min (minor), 72.8 min (major).
3 | RESULTS AND DISCUSSION
Catalysts 1a–h were applied in the asymmetric aza‐F‐C
reaction of α‐naphthol with aryl aldimines. The results
of these screening experiments are shown in Table 1.
All catalysts smoothly catalyzed the reaction to provide
the desired products in good yields (75–89%). The
quinine derivative catalyst 1c, which was derived from
1b following the introduction of a bulky TBDPS group
at the C9 position, produced an excellent yield with
the highest ee (70% ee, entry 3). Based on a comparison
of the optical rotation of the product material with
a value from the literature,11 the absolute configuration
of the major product was determined to be R. The
pseudoenantiomeric quinidine derivative catalyst 1d induced
the reaction to afford the S isomer with 67% ee (entry 4).
When the TBDPS group in 1d was changed to a TBS group,
TABLE 2 Asymmetric aza‐F‐C reaction of α‐nahthol with tosyl iminesa
Entry
Product
3a
R
Yield (%)b
ee (%)c
80
1
2
H
87
85
88
86
83
79
87
85
80
75
82
3b
2‐Cl
2‐Br
2‐CF3
2‐CH3
3‐F
3‐Cl
3‐Br
3‐CH3
4‐CH3
4‐NO2
76
3
3c
73
4
3d
85
5
3e
75
6
3f
56
7
3g
60
8
3h
65
9
3i
67
10
11
3j
73
3k
72
aAll of the reactions were performed with N‐Tosyl benzaldimine (0.10 mmol), α‐naphthol (0.50 mmol), and catalyst (0.01 mmol) in 1 mL toluene at 0 °C.
bIsolated yield.
cDetermined by HPLC analysis (Chiralpak AD‐H, Chiralcel OD‐H).

LI ET AL.
463
4. Bandini M, Melloni A, Tommasi S, Umani‐Ronchi A. A journey
across recent advances in catalytic and stereoselective alkylation of
indoles. Synlett. 2005;8:1199‐1222.
the reaction on ortho‐substituted substrates furnished the cor-
responding products with a high level of enantioselectivities
(73–85% ee, entries 2–5). The ortho‐trifluoromethyl aryl
aldimine 3d was employed in the reaction and yielded the
highest enantioselectivity (85% ee, entry 4). The correspond-
ing meta‐substituted substrates produced much lower levels
of enantioselectivities (56–67% ee, entries 6–9). Therefore,
the enantioselectivities were obviously affected by the type
and position of the substituents on the phenyl ring.
5. Shirakawa S, Berger R, Leighton JL. Enantioselective Friedel‐crafts
alkylations with benzoylhydrazones promoted by a simple strained
silacycle reagent. J Am Chem Soc. 2005;127:2858‐2859.
6. Kocovsky P, Vyskocil S, Smrcina M. Non‐symmetrically substituted
1,1′‐binaphthyls in enantioselective catalysis. Chem Rev.
2003;103:3213‐3246.
7. Rueping M, Nachtsheim BJ. A review of new developments in the
Friedel‐crafts alkylation — From green chemistry to asymmetric
catalysis. Beilstein J Org Chem. 2010;6:1007‐1013.
4 | CONCLUSION
8. Erker G, Van der Zeijden AAH. Enantioselective catalysis with a
new zirconium trichloride Lewis acid containing
a
“dibornacyclopentadienyl” ligand. Angew Chem Int Ed.
1990;29:512‐514.
In summary, a series of cinchona alkaloid derivatives were
synthesized and evaluated for their catalytic performance in
the asymmetric aza‐F‐C reaction of α‐naphthol with aryl
aldimines. The optimized conditions were confirmed to
include toluene as the solvent with a 10 mmol% loading of
quinine derivative catalyst 1c at 0 °C. We used our optimized
conditions to expand upon the substrate scope of this trans-
formation. Further investigations are currently under way in
our laboratory to clarify the exact catalytic mechanism and
the capacity of this methodology.
9. Kumari P, Jakhar A, Khan NH, et al. Recyclable chiral dinuclear
copper(II) complexes catalyzed asymmetric Friedel–crafts alkyl-
ation of 1‐naphthol using N‐tosyl aldimine. Catal Commun.
2015;69:138‐142.
10. Liu TY, Cui HL, Chai Q, et al. Organocatalytic asymmetric Friedel–
crafts alkylation/ cascade reactions of naphthols and nitroolefins.
Chem Commun. 2007;22:2228‐2230.
11. Liu GX, Zhang SL, Li H, Zhang TZ, Wang W. Organocatalytic
enantioselective Friedel‐crafts reactions of 1‐naphthols with
aldimines. Org Lett. 2011;13:828‐831.
12. Chauhan P, Chimni SS. Asymmetric organocatalytic aza‐Friedel‐
crafts reaction of naphthols with N‐sulfonyl imines. Eur J Org
Chem. 2011;2011:1636‐1640.
ACKNOWLEDGMENTS
Contract grant sponsor and grant number: National Natural
Science Foundation of China (21102055), the Natural
Science Foundation of Jilin province (201015237), Depart-
ment of Education of Jilin Province (JJKH20170409KJ),
the Science Technology Department of Jilin Province
(20140311110YY).
13. Zhang TY, He W, Zhao XY, Jin Y. Asymmetric oxaziridination
catalyzed by cinchona alkaloid derivatives containing sulfide.
Tetrahedron. 2013;69:7416‐7422.
14. Cheng L, Liu L, Jia H, Wang D, Chen YJ, Liu L. Enantioselective
organo‐catalytic anti‐Mannich‐type reaction of N‐unprotected 3‐
substituted 2‐oxindoles with aromatic N‐Ts‐aldimines. J Org Chem.
2009;74:4650‐4653.
REFERENCES
15. Jia Y‐X, Xie J‐H, Duan H‐F, Wang L‐X, Zhou Q‐L. Asymmetric
Friedel‐crafts addition of indoles to N‐sulfonyl aldimines: A simple
approach to optically active 3‐indolyl‐methanamine derivatives. Org
Lett. 2006;8:1621‐1624.
1. Poulsen TB, Jorgensen KA. Catalytic asymmetric Friedel‐crafts
alkylation reactions copper showed the way. Chem Rev.
2008;108:2903‐2915.
2. Szatmári I, Martinek TA, Lázár L, Fülöp F. Synthesis of 2,4‐Diaryl‐
3,4‐dihydru‐2H‐ naphth[2,1‐e] [1,3] oxazines and study of the
effects of the substituents on their ring‐chain tautomerism. Eur J
Org Chem. 2004;10:2231‐2238.
How to cite this article: Li YW, Wang LM, Jin Y,
Chang S. Cinchona alkaloid derivatives catalyzed
asymmetric aza‐Friedel–crafts reaction of α‐naphthols
with aryl aldimines. Chirality. 2017;29:458‐463.
https://doi.org/10.1002/chir.22714
3. Bandini M, Melloni A, Umani‐Ronchi A. New catalytic approaches
in the stereoselective Friedel‐crafts alkylation reaction. Angew Chem
Int Ed. 2004;43:550‐556.