Catalytic Asymmetric Aziridination of Benzhydryl Imines and Diazoacetate Esters with BOROX Catalysts from 3,3′-Disubstituted VANOL Ligands

Article abstract of DOI:10.1055/s-0039-1690860

This work details the synthesis of 22 new chiral VANOL ligands that differ by the nature of the substituent in the 3- and 3′-positions of the ligand. These ligands were incorporated into boroxinate catalysts that were used to screen the catalytic asymmetric aziridination of benzhydryl imines with ethyl diazoacetate. Each catalyst was screened in the reaction of imines generated from benzaldehyde and cyclohexanecarboxaldehyde and some with 4-nitro- and 4-methoxybenzaldehyde. In addition, the first report of the effect of the ester substituent of the diazoacetate ester on the asymmetric induction in these aziridination reactions is presented. The first X-ray structure of a boroxinate catalyst generated from a VANOL-derived ligand is also reported.

Full text of DOI:10.1055/s-0039-1690860

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–S
paper
A
en
Y. Guan et al.
Paper
Synthesis
Catalytic Asymmetric Aziridination of Benzhydryl Imines and
Diazoacetate Esters with BOROX Catalysts from 3,3′-Disubstituted
VANOL Ligands
Yong Guan
R = aryl, alkyl
(S)-BOROX
Ph
Ph
Ph
H
Zhenjie Lu
O
catalyst
(5 mol%)
N
N
Ph
H
Xiaopeng Yin
OR2
OR2
+
R1
R1
N2
toluene
rt, 24 h
Aliakbar Mohammadlou
Richard J. Staples
William D. Wulff*
O
66 examples
25–92% yield
7–99% ee
R3 = aryl, heteroaryl
and alkyl
R7
R7
R
7 = aryl
[H-imine]
OPh
Department of Chemistry, Michigan State University,
East Lansing, MI 48824, USA
wulff@chemistry.msu.edu
O
O
B
R3
R3
O
O
R3
R3
OH
OH
B
O
B
OPh
R7 = aryl
R7
R7
R3 = aryl, heteroaryl
and alkyl
(S)-VANOL Derivatives
BOROX catalysts
Received: 30.12.2019
Accepted after revision: 25.02.2020
Published online: 24.03.2020
nate boron atoms and one four-coordinate boron.2 The an-
ionic charge on the boroxinate is countered with a proton-
ated imine.2 The catalyst functions by serving as a chiral an-
ionic platform for the binding of both the protonated imine
and the diazo compound by hydrogen bonds.4
DOI: 10.1055/s-0039-1690860; Art ID: ss-2019-m0715-op
Abstract This work details the synthesis of 22 new chiral VANOL li-
gands that differ by the nature of the substituent in the 3- and 3′-posi-
tions of the ligand. These ligands were incorporated into boroxinate
catalysts that were used to screen the catalytic asymmetric aziridina-
tion of benzhydryl imines with ethyl diazoacetate. Each catalyst was
screened in the reaction of imines generated from benzaldehyde and
cyclohexanecarboxaldehyde and some with 4-nitro- and 4-methoxy-
benzaldehyde. In addition, the first report of the effect of the ester sub-
stituent of the diazoacetate ester on the asymmetric induction in these
aziridination reactions is presented. The first X-ray structure of a borox-
inate catalyst generated from a VANOL-derived ligand is also reported.
The level of the enantio- and stereoselectivities is a
function of the nature of the non-activating group on the
imine nitrogen and on the nature of the ligand used to pre-
pare the BOROX catalyst.1d In addition to the VANOL and
VAPOL catalysts, we have prepared substituted VANOL li-
gands with substituents in all five open positions on the
naphthalene core of VANOL, as indicated in structure 4 in
Figure 1.5 We have explored the effect of various substitu-
ents in positions 4–8 of VANOL on the aziridination reac-
tion, but not variations in the 3-positions. It was found that
substituents in the 7- and 7′-positions were the most bene-
ficial to the asymmetric inductions in the aziridination re-
action. We then prepared 31 different 7,7′-substituted
VANOL ligands of the type 5 and found that a t-butyl group
was the optimal substituent for the aziridination reaction.5
Catalysts generated from VANOL and VAPOL will cata-
lyze the aziridination of the benzhydryl imine of benzalde-
hyde to give the aziridine 12a in 93 and 94% ee; however,
the reaction with the benzhydryl imine of cyclohexanecar-
boxaldehyde only gives the aziridine 12b in 81 and 82% ee
(Table 1, entries 1 and 2).1e Improved enantioselectivities
were found for the imine of cyclohexanecarboxaldehyde if
the N-protecting group was changed to MEDAM, which
gave the aziridine 13b in 91% ee for both the VANOL and
VAPOL BOROX catalysts (entries 6 and 7).1d At the same
time, the use of the MEDAM group increased the asymmet-
ric induction with the imine of benzaldehyde to 97 and
Keywords VANOL, asymmetric catalysis, aziridines, BOROX catalysts,
imines
The catalytic asymmetric aziridination of imines with
ethyl diazoacetate mediated by BOROX catalysts can give
very high asymmetric inductions, yields and diastereoselec-
tivities in the formation of cis-3-substituted aziridine-2-
carboxylates.1 The BOROX catalysts can be generated from
the vaulted biaryl ligands VANOL and VAPOL directly by
treatment with three equivalents of triphenylborate and
three equivalents of water and one equivalent of a base,
which, in the case of the aziridination reaction, is an imine,2
or an amine3 in a three-component reaction with an alde-
hyde. Alternatively, a pre-catalyst can be generated from
the ligand and B(OPh)3 and water as indicated in Scheme
1.1e,g In this case, the BOROX catalyst is generated when the
imine is added to the pre-catalyst. The core structure of the
BOROX catalyst is a boroxinate ring with two three-coordi-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Guan et al.
Paper
Synthesis
PG
N
(S)-BOROX
catalyst
or pre-catalyst
O
PG
H
N
H
OEt
OEt
+
R1
R1
N2
toluene
rt, 1–24 h
O
[H-imine]
OPh
B
O
B(OPh)3 (3 equiv)
H2O (3 equiv)
imine (1 equiv)
O
O
O
O
Ph
Ph
Ph
Ph
OH
OH
Ph
Ph
OH
OH
B
OR
solvent, rt, 15 min
B
OPh
VANOL/VAPOL BOROX
catalyst 3
(S)-VAPOL 1
(S)-VANOL 2
pre-catalyst
ligand
+
B(OPh)3
(4 equiv)
+
H2O
(1 equiv)
0.5 mm Hg
0.5 h
toluene,
85 °C, 1 h
(1 equiv)
Scheme 1 Catalytic asymmetric aziridination of imines with BOROX catalysts
>99% ee. The introduction of substituents in the 7- and 7′-
positions of the VANOL ligand also lead to enhanced asym-
metric inductions, with the di-t-butyl derivative 5a giving
98% ee for imine 8a and 94% ee for imine 8b (entry 3).5
The benzhydryl imines 8 are more attractive as sub-
strates for the aziridination reaction because benzhydryl
amine is commercially available whereas the amines for the
preparation of the MEDAM and BUDAM imines are not. The
subject of the present work was to explore ways to improve
the yields and asymmetric inductions in the aziridination of
benzhydryl imines with diazoacetates. This was done by ex-
ploring the effect of different diazoacetate esters 11 and by
preparing and evaluating a series of disubstituted VANOL li-
gands of the type 6 and 7 where the substituent in the 3-
and 3′-positions were varied with different aryl and alkyl
substituents (Figure 1).
A screen of the effectiveness of different diazoacetate
esters in the aziridination of the benzhydryl imine of benz-
aldehyde 8a was performed and the results are summarized
in Table 2. All of the diazo compounds presented in Table 2
were prepared from the tosylhydrazone of glyoxylic acid;
details are given in the Supporting Information. It was of in-
terest to observe that both the commercial and the freshly
prepared ethyl diazoacetate gave essentially identical re-
sults for the formation of the aziridine 12 (entries 2 and 3).
Surprisingly, there was not a great difference in either the
yield or asymmetric induction of these reactions for the
methyl, ethyl, isopropyl, tert-butyl or phenyl esters, with all
giving 84–89% yield and 91–93% ee in carbon tetrachloride
as solvent. Clearly, given the ease of access to ethyl diazo-
acetate from commercial sources, this was the diazo com-
pound of choice for the BOROX catalyst aziridination reac-
tion. The best solvent for the reaction with ethyl diazo-
acetate was carbon tetrachloride by a thin margin; however,
R6
R7
R7
R5
R7
R8
R4
R3
R3
OH
OH
OH
OH
Ph
Ph
OH
OH
Ph
Ph
OH
OH
Ph
Ph
R3
R3
OH
OH
R8
R4
R7
R7
R5
R7
R6
(S)-VANOL 2
(S)-VANOL 4
(S)-VANOL 5
(S)-VANOL 6
R3 - Ph
(S)-VANOL 7
R7 - H
MeO
OMe
MeO
OMe
BUDAM
MEDAM
benzhydryl
Figure 1 VANOL ligands and imine protecting groups
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

C
Y. Guan et al.
Paper
Synthesis
Table 1 Effects of Ligand and Imine Protecting Group on the Aziridination Reaction
(S)-BOROX
catalyst
(2–5 mol%)
PG
N
O
PG
N
H
OEt
+
OEt
toluene
rt, 1–24 h
R1
H
R1
12–14
N2
11b
O
8–10
(1.1 equiv)
a
b
R = Ph
R = C6H11
a
b
R = Ph
R = C6H11
Entry
PG
Imine
Ligand
Aziridine
a R1 = Ph
b R1 = C6H11
Ref.
Yield (%)
ee (%)
Yield (%)
ee (%)
1e
1e
5
1
2
3
4
5
6
7
8
9
benzhydryl
8
8
VAPOL 1
VANOL 2
12
12
12
12
12
13
13
14
14
82
87
82
89
85
98
94
98
97
94
93
73
79
88
78
83
98
95
89
87
81
82
94
85
93
91
91
89
84
benzhydryl
benzhydryl
benzhydryl
benzhydryl
MEDAM
8
7,7′-t-Bu2VANOL 5a
7,7′-Br2VANOL 5b
7,7′-(4-t-BuC6H4)2VANOL 5c
VAPOL 1
98
5
8
89
5
8
97
1d
1d
1f
1f
9
>99
97
MEDAM
9
VANOL 2
BUDAM
10
10
VAPOL 1
99
BUDAM
VANOL 2
98
for reasons of cost and safety, toluene was identified as the
solvent of choice. VAPOL gives a slightly better result than
VANOL in methylene chloride (entries 4 vs 5) and VAPOL
gives a slightly better induction in toluene than methylene
chloride (entry 4 vs 6).
in >99% ee by deracemization with a copper complex of (–)-
sparteine to give the (S)-enantiomer.7 We have previously
Table 2 Effects of the Diazoacetate Esters on the Azridination of Imine
8aa
The preparation of the 3,3-disubstituted VANOL deriva-
tives 6 follows from the procedure that we developed for
the synthesis of VANOL and is outlined in Table 3.6 The key
step is the reaction of phenylacetyl chloride 19 with aryl
acetylene 20 in the presence of isobutyric anhydride 21.
The reaction proceeds via a cycloaddition/electrocyclization
cascade (CAEC) that results in the formation of the 3-aryl
substituted naphthol 22. This reaction proceeds via the in-
termediacy of phenyl ketene, which undergoes a [2+2] cyc-
loaddition with the alkyne to give a cyclobutenone that
subsequently undergoes a 4e– electrocyclic ring-opening to
give a vinyl ketene that then undergoes an 6e– electrocy-
clization to the phenyl group to give naphthol 22 after tau-
tomerization. The purpose of the anhydride 21 is to trap the
naphthol 22 so that it does not react with phenyl ketene, a
process that dramatically reduces the yield. A hydrolysis
step is then necessary to liberate the naphthol 22 from its
ester with isobutyric acid. Moderate to good yields were
obtained with aryl acetylenes that bear electron-rich sub-
stituents including alkoxy groups as well as electron-poor
substituents in the form of halogens. Higher yields were ob-
served in the phenol coupling step in the preparation of 7,
which was carried out in air at 160 °C to give the racemic
ligands 6. Each of the optically pure ligands were obtained
Ph
Ph
Ph
(S)-BOROX
pre-catalyst
(10 mol%)
O
N
N
Ph
H
OR
+
OR
solvent
rt, 24 h
H
N2
O
8a
11
12
Entry
R
Diazo Ligand
Solvent Aziridine Yield (%)b ee (%)c
1
Me
11a
11b
11b
11b
11b
11b
11c
11d
11e
(S)-VAPOL
(S)-VAPOL
(S)-VAPOL
(S)-VAPOL
(S)-VANOL
(S)-VAPOL
(S)-VAPOL
(S)-VAPOL
(S)-VAPOL
CCl4
15
12
12
12
12
89
84
85
83
81
83
84
89
85
91
93
93
89
88
91
92
92
91
2
Et
CCl4
3d
4d
5d
6d
7
Et
CCl4
Et
CH2Cl2
CH2Cl2
Et
Et
toluene 12
i-Pr
CCl4
CCl4
CCl4
16
17
18
8
t-Bu
9
Ph
a Unless otherwise specified, all reactions were carried out at 0.5 M in imine
with catalyst (10 mol%) and 11 (1.1 equiv). The pre-catalyst was made as
indicated in Scheme 1 except that 3 equiv of B(OPh)3 was used and H2O was
not included.
b Yield of pure cis-aziridine isolated by silica gel chromatography.
c Determined by HPLC on pure cis-aziridine.
d Diazo compound purchased from Aldrich Chemical Co.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

D
Y. Guan et al.
Paper
Synthesis
Table 3 Preparation of 3,3-Disubstituted VANOL Ligands 6
CuCl
(1.7 equiv)
air
Ar
KOH
(4 equiv)
20 (1.3 equiv)
air
Ar
Ar
OH
OH
OH
OH
Ar
Ar
mineral oil
160 °C, 24 h
O
O
H2O
100 °C, 12 h
(–)-sparteine
(3.5 equiv)
MeOH/CH2Cl2
rt, 12 h
Ar
OH
Cl
O
O
19
22
21 (2 equiv)
190 °C, 48 h
(
)-6
(S)-6
Entry
Series
Ar
Yield (%)
ee (%) of (S)-6
22
(±)-6
(S)-6
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
4-FC6H4
53
45
61
66
41
61
56
37
57
79
59
40
76
62
60
53
45
59
64
74
91
32
17
55
47
73
40
>99
>99
>99
>99
>99
>99
>99
>99a
>99a
4-BrC6H4
4-PhC6H4
3,5-Me2C6H3
4-MeOC6H4
4-EtOC6H4
g
h
i
3,5-Me2-4-MeOC6H2
2-thienyl
3-thienyl
a Reaction carried out with (+)-sparteine to give (R)-6.
established that the (R)-enantiomer of 7,7-disubstituted
VANOL ligands can be prepared in good yield and in >99% ee
by deracemization with (+)-sparteine and it would be ex-
pected that (+)-sparteine would be equally effective for 3,3-
diaryl ligands of type 6.5
Given that the 7,7′-disubstituted VANOL ligands were
found to be clearly superior to VANOL as ligands in the
aziridination reaction, we prepared a number of VANOL li-
gands with substituents in the 7,7′-positions and substitut-
ed phenyl substituents in the 3- and 3′-positions. It was en-
visioned that the most expedient method for the synthesis
Table 4 Preparation of 3,3-Disubstituted VANOL Ligands 7
Br
Br
CuCl
(1.7 equiv)
air
Br
Ar
Br
KOH
20 (1.3 equiv)
(4 equiv)
air
Ar
Ar
OH
OH
OH
OH
Ar
Ar
H2O
100 °C, 12 h
(–)-sparteine
(3.5 equiv)
MeOH/CH2Cl2
rt, 12 h
O
O
mineral oil
165 °C, 24 h
Ar
OH
X
O
O
25
23 X = OH
24 X = Cl
21 (2 equiv)
190 °C, 48 h
a
Br
Br
(
)-7
(S)-7
Entry
Series
Ar
Yield (%)
ee (%) of (S)-7
25b
(±)-7
(S)-7
1
2
3
4
5
6
a
d
e
g
j
4-FC6H4
37
61
30
50
68
47
70
65
42c
40
62
87
75
69
74
80
>99
>99
>99
>99
>99
3,5-Me2C6H3
4-MeOC6H4
3,5-Me2-4-MeOC6H2
4-n-BuC6H4
d
k
3,4,5-(MeO)3C6H2
–
a SOCl2, 90 °C, 1 h.
b Yield from 23.
c Reaction at 175 °C.
d Not determined.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

E
Y. Guan et al.
Paper
Synthesis
Table 5 Preparation of 3,3′- and 7,7′-Substituted VANOL Ligands 7
t-Bu
Br
(HO)2B
t-Bu
26a (4 equiv)
OH
OH
Pd(PPh3)4 (10 mol%)
Ar
Ar
OH
OH
Ar
Ar
Na2CO3
benzene/EtOH, 90 °C
Br
(S)-7
(S)-7
t-Bu
Entry
Starting material
Ar
C6H5
Product
Yield (%)
1
2
3
4
5b
7j
7o
7p
7q
7r
41
50
48
26
4-n-BuC6H4
7d
7g
3,5-Me2C6H4
3,5-Me2-4-MeOC6H5
Br
Br
R
(HO)2B
R
26 (4 equiv)
Pd(PPh3)4
(10 mol%)
OMe
OMe
OH
OH
OH
OH
Ar
Ar
Ar
Ar
Ar
Ar
BBr3
NaH
MeI
Na2CO3
DME, 90 °C
88%
Br
Br
R
(S)-7
(S)-27
(S)-7
Entry
Starting material
Ar
R
Boronic acid
26b
Product
Yield (%) from (S)-27
1
2
7j
7j
4-n-BuC6H5
4-n-BuC6H5
C6H5
9-anthracenyl
7n
7s
74
53
26c
of these ligands would be to adopt the convergent synthesis
illustrated in Table 4. Each of the aryl substituents would be
first introduced with the CAEC cascade on various aryl acet-
ylenes along with a bromo substituent in the 7,7′-positions.
The bromo-substituent could then be used to introduce ad-
ditional groups. Comparing the same syntheses of ligands
of the type 6 (Table 3) with those of the same ligands that
have the 7,7′-dibromo substituents (Table 4, entries 1–4) it
can be seen that slightly lower yields are observed for the
CAEC cascade step as well as for the phenol coupling step.
However, the efficiency of the deracemization step is much
greater, giving yields that are approximately double for the
bromo series.
The preparation of the VANOL ligands 7n–s are outlined
in Table 5 and began with the corresponding optically pure
7,7′-dibromo-substituted VANOLs. The aryl groups at the 7-
and 7′-positions were all introduced by the Suzuki coupling
reaction with aryl boronic acids. Two strategies were
employed; one without the protection of the phenol units
(ligands 7o–r) and one with protection of the phenol units
(ligands 7n and 7s). It is our general observation that
although two additional steps were required when the phe-
nols were protected, the overall yields were higher.
The preparation of the VANOL derivatives 6m and 6n
with alkyl groups in the 3- and 3′-positions is outlined in
Scheme 2. The preparation of VANOL derivatives with
methyl and n-decyl groups in the 3- and 3′-positions have
been reported by the CAEC method.8 We have examined an
alternative method for the preparation of this class of
O
OH
KO-t-Bu
(1.2 equiv)
R
R
OH
OH
air
mineral oil
165 °C, 36 h
THF,
80 °C, 2 h
R
R
28m R = C6H11
28n R = n-Bu
29m R = C6H11 94%
29n R = n-Bu 94%
(
(
)-6m R = C6H11 51%
)-6n R = n-Bu 44%
CuCl
(1.7 equiv)
air
(R)-6m
(R)-6n
R = C6H11 70% (>99% ee)
OH
OH
R
R
R = n-Bu 19% (95% ee)
(+)-sparteine
(3.5 equiv)
MeOH/CH2Cl2
rt, 12 h
Scheme 2 Preparation of 3,3-disubstituted VANOL ligands 6m and 6n
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

F
Y. Guan et al.
Paper
Synthesis
VANOL ligands that begins with o-alkynyl acetophenones.
This method relies on the base-induced cyclization of o-
alkynyl acetophenones to give 3-substituted naphthols, as
developed by Makra and co-workers.9 Treatment of alkynyl
acetophenone 28m with potassium t-butoxide at 80 °C in
THF gave 3-cyclohexyl-1-naphthol 29m in 94% yield. Phe-
nol coupling of 29m in air at 165 °C gave the racemic 3,3′-
dicyclohexyl VANOL 6m in 51% yield. In a likewise manner,
the racemic 3,3′-di-n-butyl VANOL 6n was obtained in 94%
and 44% yields, respectively, for the two steps. Deracemiza-
tion with sparteine gave 3,3′-dicyclohexyl VANOL (S)-6m in
70% yield with >99% ee. Deracemization of (±)-6m gave
3,3′-di-n-butyl VANOL (S)-6n in ≥99% ee but the yield was
only 19%. The reason for this low yield is not yet clear.
The effects of variations of the substituents in the 3-
and 3′-positions of the VANOL ligands (R3 in 6, Figure 1) on
the aziridination of imines 8a and 8b were surveyed and
the results are presented in Table 6. The benzhydryl imine
of benzaldehyde 8a and of cyclohexanecarboxaldehyde 8b
were chosen as representative of aryl and aliphatic alde-
hydes. As controls, phenyl imine 8a gave the aziridine 12a
with 92% ee with the BOROX catalyst generated from the
VANOL ligand 2, and the cyclohexyl substituted imine 8b
gave aziridine 12b in 81% ee also with the unsubstituted
VANOL catalyst (Table 6, entry 1). Most of the substituted
VANOL ligands led to 2–4% higher asymmetric inductions
with the phenyl imine 8a, with the exception of the para-
cyano ligand 6l and the thiophene substituted ligands 6h
and 6i. The best asymmetric induction of 96% ee with the
phenyl imine 8a was observed with a catalyst generated
from ligand 6g that has 3,5-dimethyl-4-methoxyphenyl
substituents on the 3- and 3′-positions (entry 8). A precipi-
tous drop in induction was noted for the ligands 6m and 6n,
which have alkyl groups in the 3- and 3′-positions. At this
point we have not investigated the source of this dramatic
difference between aryl and alkyl groups in the 3- and 3′-
positions. In the case of the cyclohexyl substituted imine 8b
there was a significant increase in the asymmetric induc-
tion of 6–7% observed with ligands that had methyl groups
in the 3- and 5-positions of the aryl groups in the 3- and 3′-
positions (entries 6 and 8). While the source of the effect of
these methyl groups is not clear, it may be due to C–H  in-
teractions between the ligand and the protonated imine
substrate, as hinted by the X-ray structure of the BOROX
catalyst generated from ligand 6g binding with the proton-
ated imine 30a (Scheme 3 and Figure 2).
The results presented in Table 6 reveal the effect of the
substituents at the 3- and 3′-positions of VANOL on the
aziridination of the benzhydryl imine derived from benzal-
dehyde and, in Table 7, the synergistic effects of these li-
gands and the electronic nature of the imines are examined
in the aziridination reaction. Two imines were chosen that
Table 6 Aziridinations with BOROX Catalysts Prepared from Ligand 6a
Ph
R
Ph
Ph
(S)-BOROX
pre-catalyst
(5 mol%)
O
N
N
Ph
H
OEt
OEt
+
R
H
N2
toluene
rt, 24 h
O
8a R = Ph
8b R = C6H11
11b
(1.1 equiv)
12a R = Ph
12b R = C6H11
Entry
R3 in 6
Ligand
12a R1 = Ph
12b R1 = C6H11
Yield (%)b
ee (%)c
Yield (%)b
ee (%)c
81
1
2
C6H5
2
84
86
82
82
82
87
81
85
92
91
69
71
92
89
94
94
95
95
95
96
89
89
–11
7
77
4-NCC6H4
4-FC6H4
6l
3
6a
6b
6c
6d
6e
6g
6h
6i
84
80
82
84
80
79
83
83
78
82
82
88
80
87
77
79
4
4-BrC6H4
5
4-PhC6H4
3,5-Me2C6H4
4-MeOC6H4
3,5-Me2-4-MeOC6H3
2-thienyl
6
7
8
9
10
11
12
3-thienyl
cyclohexyl
n-Bu
6m
6n
a Unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 11b (1.2 equiv) at 25 °C for 24 h and went to 100%
completion with 5 mol% catalyst. The pre-catalyst was prepared as indicated in Scheme 1.
b Yield of cis-aziridine isolated by silica gel chromatography.
c Determined by HPLC on pure cis-aziridine.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

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Synthesis
BH3•SMe2 (4 equiv)
PhOH (3 equiv)
H2O (2 equiv)
MeO
MeO
0.2 mm Hg
85 °C, 45 min
OH
OH
pre-catalyst 6g
toluene, 85 °C, 1 h
OMe
(S)-6g
OMe
3
N
OPh
2
1
H
OMe
O
B
O
B
OPh
MeO
MeO
O
4
B
O
O
H
30a (1 equiv)
CH2Cl2/pentane
N
pre-catalyst 6g
H
OMe
31 (X-ray)
OMe
MeO
OMe
O
pre-catalyst 6g
H
N
(10 mol%)
+
OEt
N
toluene, rt
OEt
N2
O
H
OMe
11b
93% yield
99% ee
30a
32a
Scheme 3
had substantially different electronic characteristics, the
electron-rich imine 8d derived from para-methoxybenzal-
dehyde and the electron-poor imine 8c derived from para-
nitrobenzaldehyde. It was observed that the para-nitro sub-
stituted imine 8c did not show any significantly different
outcome in the aziridination when the ligand bearing the
para-bromophenyl group 6b or the 3,5-dimethylphenyl
group 6d was used to prepare the catalyst (Table 7, entries 2
and 3). The reaction of the imine of para-methoxybenzal-
dehyde 8d was observed to give a slight drop in the induc-
tion with ligand 6b with the para-bromophenyl group (en-
try 5) but an increase in the induction with the ligand 6d
with the 3,5-dimethylphenyl group (entry 6). Like the
imine of benzaldehyde 8a, the imine of para-methoxybenz-
aldehyde 8d gave the highest asymmetric induction
(96% ee) with ligand 6g, which has the 3,5-dimethyl-4-
methoxyphenyl substituent in the 3- and 3′-positions of
the VANOL ligand (entry 7).
The data presented in Table 8 show the interactive ef-
fects of substituents in both the 3- and 3′-positions and the
7- and 7′-positions of the VANOL ligand on the aziridination
reaction of the aryl and alkyl imines 8a and 8b, respectively
(7 in Figure 1). When the substituent in the R7 positions
was a bromide, the asymmetric induction was either un-
changed or slightly increased (0–3% ee) relative to the 7,7′-
unsubstituted ligand 6 (Table 6) for the imine of benzalde-
hyde 8a (entries 3–6), except when the R3 substituents
were phenyl, for which the induction drops by 3% (entry 1).
For the reactions of the cyclohexyl imine 8b, the inductions
increased by 4–7% ee for all of the different substituents at
the R3 positions when the R7 substituents were bromide
(entries 1, 3, 5 and 6) rather than hydrogen, except for li-
gand 7d, which had the R3 substituents as 3,5-dimethylphe-
nyl and for which the inductions drop by 2% (entry 4). The
effect of a para-tert-butylphenyl substituent at the 7- and
7′-positions significantly enhanced the asymmetric induc-
tions of the aziridination of both the phenyl and cyclohexyl
substituted imines 8a and 8b. Moreover, they enhanced the
inductions of the best substituents in the R3 positions. For
example, the ligand 7q, with the 3,5-dimethylphenyl
groups at position R3, gave a 5% increase (88 to 93%) in
asymmetric induction for the reaction of the cyclohexyl
imine 8b and a 3% increase (95 to 98%) for the phenyl imine
8a compared to when the para-tert-butylphenyl substitu-
ent was not present (Table 6, entry 6 vs. Table 8, entry 10).
A number of solid-state structures of the boroxinate cat-
alysts containing the VAPOL ligand had been previously re-
ported, which confirmed the presence of a boroxine ring in
the catalyst.2 In contrast, there are no solid-state structures
of a VANOL-boroxinate catalyst, although the structure is
supported by other spectroscopic data.4a It was noted that
the boroxinate catalyst formed from the VANOL ligand 6g
tended to crystallize within the NMR tube. We previously
found that the boroxinate catalyst generated from VAPOL
was particularly prone to crystallization when the catalyst
was formed with the MEDAM imine 30a. Therefore, in an
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

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Synthesis
Table 7 Effect of Ligand 6 on the Aziridination of Imines 8c and 8da
Ph
Ph
O
(S)-BOROX
catalyst
(10 mol%)
Ph
O
N
N
Ph
H
OEt
+
OEt
toluene
rt, 24 h
H
N2
R
R
11b
(1.1 equiv)
8c
8d
R = NO2
R = OMe
R = NO2
R = OMe
12c
12d
Entry
R
Imine
R3 in 6
Ligand
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
NO2
8c
8c
8c
8d
8d
8d
8d
8d
C6H5
2
86
86
85
61
68
54
62
58
89
89
88
87
85
92
96
88
NO2
4-BrC6H4
3,5-Me2C6H4
C6H5
6b
6d
2
NO2
OMe
OMe
OMe
OMe
OMe
4-BrC6H4
3,5-Me2C6H4
6b
6d
6g
4f
3,5-Me2-4-MeOC6H5
4-EtOC6H4
a Unless otherwise specified, all reactions were carried out in 0.5 M imine in toluene at r.t. for 24 h with 11b (1.1 equiv). Pre-catalyst prepared as indicated in
Scheme 1.
b Isolated yield after silica gel chromatography.
c Determined by HPLC on a Chiralcel OD-H column.
Table 8 Effect of 3,3′,7,7′-Tetrasubstituted VANOL Ligands on the Aziridination of 8a and 8ba
Ph
R1
Ph
Ph
(S)-BOROX
catalyst
(5 mol%)
O
N
H
+
N
Ph
OEt
OEt
N2
toluene
rt, 24 h
R1
H
O
R1 = Ph
R1 = C6H11
R1 = Ph
R1 = C6H11
11b
(1.1 equiv)
8a
8b
12a
12b
12a R1 = Ph
12b R1 = C6H11
Entry
R7 in 7
R3 in 7
Ligand
Yield (%)b
ee (%)c
Yield (%)b
ee (%)c
1
2
Br
C6H5
5b
7j
89
87
81
82
82
81
82
85
87
82
86
57
89
93
94
97
95
98
95
97
97
98
96
90
78
78
77
63
75
74
84
83
80
83
83
25d
85
85
84
86
85
87
91
93
90
93
92
64
Br
4-n-BuC6H4
4-FC6H4
3
Br
7a
7d
7e
7g
7n
7o
7p
7q
7r
4
Br
3,5-Me2C6H4
4-MeOC6H4
5
Br
6
Br
3,5-Me2-4-MeOC6H5
4-n-BuC6H4
7
Ph
8
4-t-BuC6H4
4-t-BuC6H4
4-t-BuC6H4
4-t-BuC6H4
9-anthracenyl
C6H5
9
4-n-BuC6H4
10
11
12
3,5-Me2C6H4
3,5-Me2-4-MeOC6H5
4-n-BuC6H4
7s
a Unless otherwise specified, all reactions were run at 0.5 M in imine in toluene on a 0.5 mmol scale with 11b (1.2 equiv) at r.t., for 24 h and went to 100%
completion with 5 mol% catalyst. The pre-catalyst was prepared as indicated in Scheme 1.
b Yield of isolated cis-aziridine by silica gel chromatography.
c Determined by HPLC on a Chiralcel OD-H column.
d Reaction time was 48 h.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

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Synthesis
Figure 2 X-ray crystal structure of BOROX-iminium complex 31
effort to obtain the first X-ray structure of a boroxinate cat-
alyst derived from a VANOL ligand, we prepared the precat-
alyst from the ligand (S)-6g as indicated in Scheme 3 and
then added 1 equivalent of the MEDAM imine 30a. The re-
sulting mixture was divided among several NMR tubes un-
der nitrogen with various mixtures of pentane and methy-
lene chloride. Yellow crystals grew in several of the NMR
tubes and were found to be of suitable quality for X-ray dif-
fraction analysis. Crystals of this complex could also be
grown from a solution prepared from B(OPh)3 instead of
BH3·SMe2 and phenol.2 To confirm that this VANOL borox-
inate was indeed capable of catalyzing the aziridination re-
action, we carried out the reaction of imine 30a with ethyl
diazoacetate 11b with 10 mol% precatalyst 6g and obtained
the aziridine 32a in 93% yield and 99% ee.
H- interaction (3.210 Å) between one of the arenes on the
diarylmethyl substituent on the nitrogen and a methyl
group on the aryl ring in the 3-position of the VANOL li-
gand. This type of interaction is not present in the VAPOL
structure.2
In conclusion, a series of 22 new VANOL derivatives
were prepared and examined as boroxinate catalysts in the
asymmetric aziridination of imines with diazoacetate es-
ters. Emphasis was placed on the preparation of ligands that
varied in the nature of the substituent in the 3- and 3′-posi-
tions since catalysts from these derivatives have not previ-
ously been reported. These ligands were prepared by the
cycloaddition/electrocyclic ring opening/electrocyclic ring
closing cascade (CAEC) and also by an intramolecular eno-
late/alkyne addition. The asymmetric induction in the aziri-
dination of catalysts generated from these 22 ligands were
all screened with imines prepared from both benzaldehyde
and cyclohexanecarboxaldehyde. The incorporation of a
number of different aryl groups in the 3- and 3′-positions of
the VANOL ligand led to catalysts that gave rise to aziridines
with slightly improved asymmetric inductions for both
imines when compared to the standard phenyl group in the
VANOL ligand itself. Exception was found with a 4-cyano-
phenyl group and 2- and 3-thiophene substituents. The in-
troduction of alkyl groups in the 3- and 3′-positions of VA-
NOL resulted in a catastrophic loss of asymmetric induction
in the aziridines. The combination of substituents in both
the 3,3′-position and the 7,7′-positions of the VANOL ligand,
in general, gave rise to slightly improved outcomes in the
aziridination of the imine of benzaldehyde in comparison
with those ligands only having substituents in the 3- and
3′-positions and this was especially true for the aziridina-
tions of the imine from cyclohexanecarboxaldehyde (with
phenyl substituents in the 7,7′-positions). In addition, the
The X-ray crystal structure of 31 (Figure 2) confirmed
that a boroxinate ring was also generated in the reaction of
a VANOL derivative with borane dimethyl sulfide complex,
phenol, water and an imine.
There are both similarities and differences in the borox-
inate structures of VANOL and VAPOL. As in VAPOL borox-
inate complexes, there are a number of noncovalent inter-
actions between the protonated imine substrate and the
anionic boroxinate core of VANOL.2 The strongest interac-
tion is undoubtedly the H-bond between the protonated
imine and O-2 of the boroxinate core (H–O 2.457 Å). In con-
trast to the VAPOL structure, the arene group on the imine
carbon does not have a - stacking interaction with the
naphthalene ring (phenanthrene in the case of VAPOL) of
the VANOL ligand 6g.
Instead, there is a C-H- interaction (2.800 Å) from the
edge of the phenyl ring on the imine carbon and the face of
the naphthalene ring. This twist in the orientation of the
imine in the binding pocket allows for the formation of a C-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

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Y. Guan et al.
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Synthesis
effect of the variation of the oxygen substituent on the ester
of the -diazoacetate ester was examined in the aziridina-
tion reaction and it was found that the yield and asymmet-
ric induction of the aziridines were essentially independent
of the nature of the oxygen substituent. Unlike VAPOL, the
boroxinate structure in a BOROX catalyst has not been pre-
viously confirmed with a VANOL ligand before by X-ray dif-
fraction but has been in the present work with a complex
from ligand 6g and the imine 30a. The noncovalent binding
of the protonated imine 30a substrate in the BOROX cata-
lyst 31 is similar to that of VAPOL in that the protonated
imine is H-bonded to the boroxinate core to O-2, but the
orientation of the imine is skewed to produce C–H interac-
tions with the aryl substituent in the 3- and 3′-positions of
the VANOL ligand. This was not observed in the VAPOL
structure, presumably because the VAPOL ligand had un-
substituted phenyl groups in the 3- and 3′-positions.
3-(4-Fluorophenyl)naphthalen-1-ol (22a)
The reaction of phenylacetyl chloride 19 (2.64 mL, 20.0 mmol), 1-
ethynyl-4-fluorobenzene 20a (2.40 g, 20.0 mmol) and (i-PrCO)2O (6.7
mL, 40 mmol) was performed according to Typical Procedure I. Purifi-
cation of the crude product by column chromatography on silica gel
(50 mm × 250 mm, CH2Cl2/hexanes 1:1 to 2:1 to 1:0) gave 22a.
Yield: 2.54 g (10.6 mmol, 53%); off-white solid; mp 96–97 °C; Rf = 0.30
(CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 5.30 (s, 1 H), 7.02 (d, J = 2.0 Hz, 1 H),
7.11–7.17 (m, 2 H), 7.45–7.53 (m, 2 H), 7.58 (s, 1 H), 7.59–7.64 (m,
2 H), 7.82–7.85 (m, 1 H), 8.14–8.17 (m, 1 H).
13C NMR (CDCl3, 125 MHz):  = 108.27, 115.61 (2JCF = 21 Hz), 118.64,
121.42, 123.47, 125.41, 127.02, 127.97, 128.83 (3JCF = 7.9 Hz), 134.94,
137.03 (4JCF = 3.3 Hz), 137.91, 151.76, 162.56 (1JCF = 245.4 Hz).
19F NMR (CDCl3, 283 MHz):  = –113.77.
IR (thin film): 3399br w, 1507s, 1401s, 1237s cm–1
HRMS (ESI+): m/z [M + H]+ calcd for C16H12FO: 239.0872; found:
239.0884.
.
3-(4-Bromophenyl)naphthalen-1-ol (22b)
Dichloromethane, acetonitrile and triethylamine were distilled from
calcium hydride under nitrogen. Toluene, THF, benzene and diethyl
ether were distilled from sodium under nitrogen. Hexanes and EtOAc
were ACS grade and used as purchased. Other reagents were used as
purchased from Aldrich or other commercial sources. Commercially
available benzhydrylamine and liquid aldehydes were distilled prior
to use. Alkynes were prepared according to the published proce-
dures.10–13 Ligand 5b and 7o were prepared according to the pub-
lished procedure.14
The reaction of phenylacetyl chloride 19 (2.64 mL, 20.0 mmol), 1-bro-
mo-4-ethynylbenzene 20b (3.62 g, 20.0 mmol) and (i-PrCO)2O (6.7
mL, 40 mmol) was performed according to Typical Procedure I. Purifi-
cation of the crude product by column chromatography on silica gel
(50 mm × 250 mm, CH2Cl2/hexanes 1:1 to 2:1 to 1:0) gave 22b.
Yield: 2.70 g (9.03 mmol, 45%); off-white solid; mp 168–169 °C; Rf =
0.31 (CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 5.36 (s, 1 H), 7.01 (d, J = 1.5 Hz, 1 H),
7.46–7.54 (m, 4 H), 7.55–7.59 (m, 2 H), 7.59 (s, 1 H), 7.82–7.85 (m,
1 H), 8.14–8.17 (m, 1 H).
13C NMR (CDCl3, 125 MHz):  = 107.97, 118.70, 121.46, 121.70,
123.68, 125.57, 127.09, 128.03, 128.85, 131.92, 134.92, 137.64,
139.83, 151.88.
Synthesis of 3-Aryl-1-naphthols (Table 3); Typical Procedure I
3-(3,5-Dimethylphenyl)naphthalen-1-ol (22d)
To a 250 mL flame-dried round-bottom flask was added phenylacetyl
chloride 19 (2.64 mL, 20.0 mmol), 1-ethynyl-3,5-dimethylbenzene
20d (2.60 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) under N2.
The mixture was stirred at 190 °C for 48 h with a gentle nitrogen flow
across the top of the condenser. The brown reaction mixture was
cooled to below 100 °C (ca. 60 °C, oil bath temperature) and a solution
of KOH (4.48 g, 80 mmol) in H2O (20 mL) was then added slowly. The
two-phase mixture was stirred at 100 °C overnight. The mixture was
cooled to r.t. and EtOAc (60 mL) was added and the mixture stirred for
10 min before the organic layer was separated. The aqueous layer was
extracted with EtOAc (2 × 30 mL) and the combined organic layer was
washed with brine (30 mL), dried over MgSO4, filtered through Celite
and concentrated to dryness. Purification of the crude product by col-
umn chromatography on silica gel (50 mm × 250 mm, CH2Cl2/hexanes
1:1 to 2:1 to 1:0) gave 22d.
IR (thin film): 3355br w, 1576s, 1493s, 1399s, 1265s cm–1
HRMS (ESI+): m/z [M + H]+ calcd for C16H1079BrO: 296.9915; found:
.
296.9906.
3-(4-Methoxyphenyl)naphthalen-1-ol (22e)
The reaction of phenylacetyl chloride 19 (2.64 mL, 20.0 mmol), 1-
ethynyl-4-methoxybenzene 20e (2.64 g, 20.0 mmol) and (i-PrCO)2O
(6.7 mL, 40 mmol) was performed according to Typical Procedure I.
Purification of the crude product by column chromatography on silica
gel (50 mm × 250 mm, CH2Cl2/hexanes 1:1 to 2:1 to 1:0) gave 22e.
Yield: 2.07 g (8.28 mmol, 41%); pale-brown solid; mp 151–152 °C; Rf =
0.19 (CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 3.85 (s, 3 H), 5.27 (s, 1 H), 6.99 (dd, J =
9.0, 2.0 Hz, 2 H), 7.05 (d, J = 1.0 Hz, 1 H), 7.43–7.51 (m, 2 H), 7.58–7.61
(m, 3 H), 7.82 (d, J = 7.5 Hz, 1 H), 8.12–8.15 (m, 1 H).
Yield: 3.26 g (13.1 mmol, 66%); yellow solid; mp 104–105 °C; Rf = 0.34
(CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 2.39 (s, 6 H), 5.26 (s, 1 H), 7.01 (s, 1 H),
7.07 (d, J = 1.5 Hz, 1 H), 7.29 (s, 2 H), 7.44–7.52 (m, 2 H), 7.83–7.85 (m,
1 H), 8.13–8.16 (m, 1 H).
13C NMR (CDCl3, 125 MHz):  = 55.39, 108.26, 114.30, 118.05, 121.40,
123.24, 125.05, 126.84, 127.88, 128.30, 133.43, 135.04, 138.51,
151.65, 159.29.
13C NMR (CDCl3, 125 MHz):  = 21.43, 108.59, 118.73, 121.42, 123.53,
125.19, 125.24, 126.81, 128.01, 129.13, 135.00, 138.34, 139.18,
140.92, 151.59.
IR (thin film): 3357br w, 1587s, 1456s, 1401s, 1250s, 1184s cm–1
HRMS (ESI–): m/z [M – H]– calcd for C17H13O2: 249.0916; found:
.
249.0921.
IR (thin film): 3430br s, 2919s, 1576s, 1456s, 1400s, 1271s cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C18H17O: 249.1279; found:
249.1268.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

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Synthesis
3-(4-Methoxy-3,5-dimethylphenyl)naphthalen-1-ol (22g)
Synthesis of 3-Aryl-7-bromo-1-naphthols (Table 4); Typical Proce-
dure II
The reaction of phenylacetyl chloride 19 (2.64 mL, 20.0 mmol), 5-
ethynyl-2-methoxy-1,3-dimethylbenzene 20g (3.20 g, 20.0 mmol)
and (i-PrCO)2O (6.7 mL, 40 mmol) was performed according to Typical
Procedure I. Purification of the crude product by column chromatog-
raphy on silica gel (50 mm × 250 mm, CH2Cl2/hexanes 1:1 to 2:1 to
1:0) gave 22g.
7-Bromo-3-(4-fluorophenyl)naphthalen-1-ol (25a)
A single-neck round-bottom flask equipped with a condenser was
charged with 4-bromo-phenylacetic acid 23 (4.30 g, 20.0 mmol), and
SOCl2 (5.3 mL, 73 mmol). The top of the condenser was vented to a
bubbler and then into a beaker filled with NaOH (sat. aq.) to trap acid-
ic gases. The mixture was heated to reflux for 1 h in a 90 °C oil bath,
and then all of the volatiles were carefully removed by swirling it un-
der high vacuum (1 mmHg) for 1 h with a second liquid N2 trap to
protect the pump. To the flask containing the acyl chloride 24
was added 1-ethynyl-4-fluorobenzene 20a (2.40 g, 20.0 mmol) and
(i-PrCO)2O (6.7 mL, 40 mmol) under N2. The mixture was stirred at
190 °C for 48 h with a gentle nitrogen flow across the top of the con-
denser. The brown reaction mixture was cooled to below 100 °C (ca.
60 °C, oil bath temperature) and a solution of KOH (4.48 g, 80 mmol)
in H2O (20 mL) was then added slowly. The two-phase mixture was
stirred at 100 °C overnight. The mixture was cooled to r.t., EtOAc (60
mL) was added and the mixture was stirred for 10 min before the
organic layer was separated. The aqueous layer was extracted with
EtOAc (2 × 30 mL) and the combined organic layer was washed with
brine (30 mL), dried over MgSO4, filtered through Celite and concen-
trated to dryness. Purification of the crude product by column chro-
matography on silica gel (50 mm × 250 mm, CH2Cl2/hexanes 1:1 to
2:1 to 1:0) gave 25a.
Yield: 3.10 g (11.1 mmol, 56%); light-yellow solid; mp 156–157 °C;
Rf = 0.19 (CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 2.36 (s, 6 H), 3.77 (s, 3 H), 5.33 (s, 1 H),
7.02 (d, J = 1.5 Hz, 1 H), 7.31 (s, 2 H), 7.43–7.51 (m, 2 H), 7.57 (s, 1 H),
7.82 (d, J = 7.5 Hz, 1 H), 8.13–8.15 (m, 1 H).
13C NMR (CDCl3, 125 MHz):  = 16.29, 59.84, 108.39, 118.32, 121.44,
123.38, 125.07, 126.79, 127.75, 127.91, 131.18, 134.96, 136.54,
138.68, 151.63, 156.57.
IR (thin film): 3359br s, 2942s, 1576s, 1489s, 1402s, 1230s,
1157s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C19H17O2: 277.1229; found:
277.1224.
3-(Thiophen-2-yl)naphthalen-1-ol (22h)
The reaction of phenylacetyl chloride 19 (3.72 mL, 28.1 mmol), 2-
ethynylthiophene 20h (3.04 g, 28.1 mmol) and (i-PrCO)2O (9.33 mL,
56.3 mmol) was performed according to Typical Procedure I. Purifica-
tion of the crude product by column chromatography on silica gel (50
mm × 250 mm, CH2Cl2/hexanes 1:2 to 1:1 to 1:0) gave 22h.
Yield: 2.33 g (7.35 mmol, 37%); off-white solid; mp 96–97 °C; Rf = 0.30
(CH2Cl2).
Yield: 1.66 g (7.35 mmol, 37%); brownish pink solid; mp 128–129 °C;
Rf = 0.35 (CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 5.27 (s, 1 H), 7.01 (d, J = 1.5 Hz, 1 H),
7.14 (t, J = 8.7 Hz, 2 H), 7.52 (s, 1 H), 7.53–7.62 (m, 3 H), 7.68 (d, J =
8.7 Hz, 1 H), 8.34 (d, J = 1.9 Hz, 1 H).
13C NMR (CDCl3, 125 MHz):  = 109.16, 115.81 (2JCF = 21.3 Hz), 118.47,
119.39, 124.29, 124.61, 128.81 (3JCF = 7.5 Hz), 129.53, 130.45, 133.34,
136.64 (4JCF = 3.8 Hz), 138.41, 150.93, 162.68 (1JCF = 246.3 Hz).
1H NMR (CDCl3, 500 MHz):  = 5.35 (s, 1 H), 7.07–7.11 (m, 2 H), 7.30
(dd, J = 5.0, 1.5 Hz, 1 H), 7.36 (dd, J = 3.5, 1.5 Hz, 1 H), 7.43–7.51 (m,
2 H), 7.67 (s, 1 H), 7.79–7.82 (m, 1 H), 8.11–8.14 (m, 1 H).
13C NMR (CDCl3, 125 MHz):  = 107.20, 117.36, 121.51, 123.42,
123.77, 125.02, 125.34, 127.14, 127.84, 128.06, 131.95, 134.91,
144.22, 151.69.
19F NMR (CDCl3, 283 Hz):  = –113.30.
IR (thin film): 3399br w, 1507s, 1401s, 1237s cm–1
.
IR (thin film): 3320br s, 1599s, 1401s, 1262s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C14H9OS: 225.0374; found:
225.0377.
7-Bromo-3-(3,5-dimethylphenyl)naphthalen-1-ol (25d)
The reaction of 4-bromo-phenylacetic acid 23 (4.30 g, 20.0 mmol),
SOCl2 (5.3 mL, 73 mmol), 1-ethynyl-3,5-dimethylbenzene 20d (2.60 g,
20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed accord-
ing to Typical Procedure II. Purification of the crude product by col-
umn chromatography on silica gel (50 mm × 250 mm, CH2Cl2/hexanes
1:1 to 2:1 to 1:0) gave 25d.
3-(Thiophen-3-yl)naphthalen-1-ol (22i)
The reaction of phenylacetyl chloride 19 (2.64 mL, 20.0 mmol), 3-
ethynylthiophene 20i (2.16 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40
mmol) was performed according to Typical Procedure I. Purification
of the crude product by column chromatography on silica gel (50 mm
× 250 mm, CH2Cl2/hexanes 1:2 to 1:1 to 1:0) gave 22i.
Yield: 3.96 g (12.1 mmol, 61%); off-white solid; mp 110–111 °C; Rf =
0.19 (2:1 CH2Cl2/hexanes).
Yield: 2.58 g (11.4 mmol, 57%); brownish pink solid; mp 119–120 °C;
Rf = 0.32 (CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 2.39 (s, 6 H), 5.22 (s, 1 H), 7.01 (s, 1 H),
7.07 (d, J = 1.5 Hz, 1 H), 7.26 (s, 2 H), 7.55 (dd, J = 9.0, 2.0 Hz, 1 H), 7.57
(s, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 8.33 (d, J = 2.0 Hz, 1 H).
13C NMR (CDCl3, 125 MHz):  = 21.40, 109.43, 118.53, 119.13, 124.25,
124.60, 125.16, 129.34, 129.55, 130.21, 133.35, 138.43, 139.67,
140.47, 150.72.
1H NMR (CDCl3, 500 MHz):  = 5.34 (s, 1 H), 7.06 (d, J = 1.5 Hz, 1 H),
7.40 (dd, J = 5.5, 3.0 Hz, 1 H), 7.45–7.51 (m, 4 H), 7.65 (s, 1 H), 7.82 (d,
J = 7.5 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H).
13C NMR (CDCl3, 125 MHz):  = 107.84, 117.90, 120.62, 121.43,
123.58, 125.22, 126.31, 126.38, 126.96, 127.88, 133.44, 134.99,
142.05, 151.66.
IR (thin film): 3509br m, 2918w, 1587s, 1474s, 1404s, 1267s cm–1
.
MS: m/z (%) = 328 (91, 81Br) [M]+, 326 (100, 79Br) [M]+, 202 (42), 163
(20).
IR (thin film): 3362br s, 1599s, 1507s, 1418s, 1275s cm–1
HRMS (ESI–): m/z [M – H]– calcd for C14H9OS: 225.0374; found:
.
Anal calcd for C18H15BrO: C, 66.07; H, 4.62. Found: C, 66.00; H, 4.42.
225.0382.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

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Y. Guan et al.
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Synthesis
7-Bromo-3-(4-methoxyphenyl)naphthalen-1-ol (25e)
13C NMR (CDCl3, 125 MHz):  = 13.94, 22.39, 33.58, 35.31, 109.28,
118.29, 119.10, 124.26, 124.57, 127.05, 128.98, 129.54, 130.23,
133.43, 137.78, 139.42, 142.63, 150.82.
The reaction of 4-bromo-phenylacetic acid 23 (4.30 g, 20.0 mmol),
SOCl2 (5.3 mL, 73 mmol), 1-ethynyl-4-methoxybenzene 20e (2.64 g,
20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed accord-
ing to Typical Procedure II. Purification of the crude product by col-
umn chromatography on silica gel (50 mm × 250 mm, CH2Cl2/hexanes
1:1 to 2:1 to 1:0) gave 25e.
IR (thin film): 3260br s, 2926s, 1589s, 1406s, 1254s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C20H1879BrO: 353.0541; found:
353.0539.
Yield: 1.98 g (6.0 mmol, 30%); off-white solid; mp 168–170 °C; Rf =
0.26 (CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 3.85 (s, 3 H), 5.24 (s, 1 H), 6.98–7.00
(m, 2 H), 7.53–7.55 (m, 2 H), 7.56–7.58 (m, 2 H), 7.67 (d, J = 9.0 Hz,
1 H), 8.32 (d, J = 2.0 Hz, 1 H).
7-Bromo-3-(3,4,5-trimethoxyphenyl)naphthalen-1-ol (25k)
The reaction of 4-bromophenylacetic acid 23 (4.30 g, 20.0 mmol),
SOCl2 (5.3 mL, 73 mmol), 5-ethynyl-1,2,3-trimethoxybenzene 20k
(3.84 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was performed
according to Typical Procedure II. Purification of the crude product
13C NMR (CDCl3, 125 MHz):  = 55.40, 109.13, 114.38, 117.87, 118.96,
124.24, 124.37, 128.27, 129.46, 130.25, 132.99, 133.45, 139.03,
150.82, 159.48.
by column chromatography on silica gel (50 mm
EtOAc/hexanes 1:4 to 1:2) gave 25k.
× 250 mm,
Yield: 3.69 g (9.49 mmol, 47%); yellow solid; mp 177–179 °C; Rf = 0.16
(1:2 EtOAc/hexanes).
IR (thin film): 3395br s, 1578s, 1507s, 1402s, 1240s, 1179s cm–1
;
1H NMR (CDCl3, 500 MHz):  = 3.90 (s, 6 H), 3.91 (s, 3 H), 5.74 (s, 1 H),
6.80 (s, 2 H), 6.99 (d, J = 1.0 Hz, 1 H), 7.50 (s, 1 H), 7.56 (dd, J = 8.5,
2.0 Hz, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 8.36 (d, J = 2.0 Hz, 1 H).
13C NMR (CDCl3, 125 MHz):  = 56.28, 61.03, 104.71, 109.39, 118.20,
119.26, 124.38, 124.76, 129.47, 130.36, 133.28, 136.73, 139.56,
151.03, 153.53.
MS: m/z (%) = 330 (89, 81Br) [M]+, 328 (100, 79Br) [M]+, 315 (29, 81Br),
313 (31, 79Br), 285 (14), 205 (15).
Anal calcd for C17H13BrO2: C, 62.03; H, 3.98. Found: C, 61.83; H, 3.92.
7-Bromo-3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol
(25g)
IR (thin film): 3413br m, 2938m, 1589s, 1503s, 1406s, 1240s,
The reaction of 4-bromo-phenylacetic acid 23 (4.30 g, 20.0 mmol),
SOCl2 (5.3 mL, 73 mmol), 5-ethynyl-2-methoxy-1,3-dimethylbenzene
20g (3.20 g, 20.0 mmol) and (i-PrCO)2O (6.7 mL, 40 mmol) was per-
formed according to Typical Procedure II. Purification of the crude
product by column chromatography on silica gel (50 mm × 250 mm,
CH2Cl2/hexanes 1:1 to 2:1 to 1:0) gave 25g.
1129s cm–1
.
MS: m/z (%) = 390 (14, 81Br) [M]+, 388 (13, 79Br) [M]+, 375 (7, 81Br), 373
(7, 79Br), 236 (4, 81Br), 234 (4, 79Br).
Anal calcd for C19H17BrO4: C, 58.63; H, 4.40. Found: C, 58.39; H, 4.19.
Yield: 3.56 g (10.0 mmol, 50%); off-white solid; mp 146–148 °C; Rf =
0.22 (CH2Cl2).
Oxidative Dimerization of 3-Aryl-1-naphthols and Their Deracem-
ization (Table 3 and Table 4): Typical Procedure III
1H NMR (CDCl3, 500 MHz):  = 2.35 (s, 6 H), 3.78 (s, 3 H), 5.46 (s, 1 H),
6.98 (d, J = 1.5 Hz, 1 H), 7.27 (s, 2 H), 7.51 (s, 1 H), 7.54 (dd, J = 8.5,
2.0 Hz, 1 H), 7.67 (d, J = 9.0 Hz, 1 H), 8.33 (d, J = 2.0 Hz, 1 H).
13C NMR (CDCl3, 125 MHz):  = 16.29, 59.84, 109.29, 118.15, 119.02,
124.28, 124.52, 127.72, 129.49, 130.21, 131.30, 133.38, 136.13,
139.22, 150.80, 156.79.
VANOL Derivative (S)-6a
Oxidative phenol-coupling: To a flame-dried, three-neck, round-bot-
tom flask equipped with a cooling condenser was added 3-(4-fluoro-
phenyl)naphthalen-1-ol 22a (952 mg, 4.00 mmol) and mineral oil (5
mL). Airflow was introduced from one side neck via a needle located
one inch above the mixture. The airflow rate was about one bubble
per second. The mixture was stirred at 165 °C for 24 h. Purification by
column chromatography on silica gel (35 mm × 200 mm, CH2Cl2/hex-
anes 2:3) gave racemic 6a as an off-white solid (752 mg, 1.58 mmol,
79% yield).
IR (thin film): 3341br s, 2928s, 1587s, 1485s, 1402s, 1227s,
1157s cm–1
.
MS: m/z (%) = 358 (77, 81Br) [M]+, 356 (80, 79Br) [M]+, 343 (50, 81Br),
341 (52, 79Br), 314 (4, 81Br), 312 (5, 79Br), 202 (28), 189 (49), 171 (34),
100 (100).
Deracemization: The original procedure7 involves sonification to pre-
sumably facilitate reaction. However, it was later found that the dera-
cemization of VAPOL gives the same result whether or not sonifica-
tion is employed. The following procedure follows the original report:
To a round-bottom flask was added (–)-sparteine (754 mg, 3.22
mmol), CuCl (155 mg, 1.57 mmol) and MeOH (25 mL) under an atmo-
sphere of air. The reaction mixture was sonicated in a water bath for
60 minutes with exposure to air. The flask was then sealed with a
septum and purged with argon, which was introduced by a needle
under the surface for 60 minutes. At the same time, to a flame-dried
round-bottom flask was added racemic 6a (155 mg, 1.57 mmol) and
CH2Cl2 (100 mL). The resulting solution was purged with argon for 60
minutes under the surface. The green Cu(II)-sparteine solution was
then transferred via cannula to the solution of racemic 6a under ar-
gon and then the combined mixture was sonicated for 15 minutes
and then allowed to stir at r.t. overnight with an argon balloon at-
tached to the flask, which was covered with aluminum foil. The reac-
tion was quenched by slow addition of sat. aq. NaHCO3 (12 mL), H2O
Anal calcd for C19H17BrO2: C, 63.88; H, 4.80. Found: C, 63.73; H, 4.72.
7-Bromo-3-(4-butylphenyl)naphthalen-1-ol (25j)
The reaction of 4-bromo-phenylacetic acid 23 (23.7 g, 110 mmol),
SOCl2 (29 mL, 398 mmol), 1-butyl-4-ethynylbenzene 20j (20 g, 127
mmol) and (i-PrCO)2O (37 mL, 223 mmol) was performed according
to Typical Procedure II. Purification of the crude product by column
chromatography on silica gel (50 mm × 250 mm, CH2Cl2/hexanes 1:3
to 1:2 to 1:1 to 2:1) gave 25j.
Yield: 26.5 g (74.6 mmol, 68%); light-brown solid; mp 106–109 °C;
Rf = 0.21 (2:1 CH2Cl2/hexanes).
1H NMR (CDCl3, 500 MHz):  = 0.94 (t, J = 7.5 Hz, 3 H), 1.34–1.43 (m,
2 H), 1.60–1.67 (m, 2 H), 2.65 (t, J = 7.5 Hz, 2 H), 5.25 (s, 1 H), 7.07 (d, J
= 1.5 Hz, 1 H), 7.25–7.28 (m, 2 H), 7.53–7.57 (m, 4 H), 7.69 (d, J =
8.5 Hz, 1 H), 8.33 (d, J = 2.0 Hz, 1 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

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Y. Guan et al.
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Synthesis
(40 mL) and most of the organic solvent was removed under reduced
pressure. The residue was then extracted with CH2Cl2 (3 × 30 mL). The
combined organic layer was dried over MgSO4, filtered through Celite
and concentrated to dryness. Purification of the crude product by col-
umn chromatography on silica gel (35 mm × 200 mm, CH2Cl2/hexanes
2:3) afforded (S)-6a.
Yield: 160 mg (0.32 mmol, 32%); light-yellow solid; mp 79–83 °C; Rf =
0.39 (2:1 CH2Cl2/hexanes); >99% ee (HPLC analysis; Chiralcel OD-H
column, 99:1 hexane/iPrOH at 254 nm, flow-rate: 0.7 mL/min): tR
10.14 [(R)-6d; minor], 16.96 [(S)-6d; major] min; []D = –233.9 (c
1.0, CH2Cl2) on >99% ee (S)-6d (HPLC).
=
20
1H NMR (CDCl3, 500 MHz):  =  1.99 (s, 12 H), 5.78 (s, 2 H), 6.33 (d, J =
1.0 Hz, 4 H), 6.70 (s, 2 H), 7.31 (s, 2 H), 7.50–7.55 (m, 4 H), 7.74–7.77
(m, 2 H), 8.31–8.34 (m, 2 H).
Yield: 281 mg (0.59 mmol, 64%); off-white solid; mp 107–112 °C; Rf =
0.33 (2:1 CH2Cl2/hexanes); >99% ee (HPLC analysis; Pirkle D-Phenyl-
glycine column; 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0
13C NMR (CDCl3, 125 MHz):  = 21.05, 113.06, 121.60, 122.64, 122.78,
125.46, 126.82, 127.32, 127.54, 128.19, 134.53, 136.58, 140.13,
141.00, 150.42.
20
mL/min): tR = 20.55 [(R)-6a, minor], 24.49 [(S)-6a, major] min; []D
–193.6 (c 1.0, CH2Cl2) on >99% ee (S)-6a (HPLC).
=
1H NMR (CDCl3, 500 MHz):  = 5.83 (s, 2 H), 6.57–6.61 (m, 4 H), 6.63–
6.68 (m, 4 H), 7.29 (s, 2 H), 7.54–7.60 (m, 4 H), 7.77–7.79 (m, 2 H),
8.33–8.35 (m, 2 H).
13C NMR (CDCl3, 125 MHz):  = 112.40, 114.40 (2JCF = 21.1 Hz), 122.05,
122.78, 122.93, 125.93, 127.69, 127.77, 130.43 (3JCF = 8.3 Hz), 134.59,
136.16 (4JCF = 3.3 Hz), 139.41, 150.42, 161.90 (1JCF = 244.9 Hz).
IR (thin film): 3513br s, 2921s, 1597s, 1497s, 1387s, 1277s cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C36H31O2: 495.2324; found:
495.2332.
VANOL Derivative (S)-6e
The synthesis of racemic 6e was performed according to Typical Pro-
cedure III, with 3-(4-methoxyphenyl)naphthalen-1-ol 22e (590 mg,
2.36 mmol). Purification by column chromatography on silica gel (30
mm × 250 mm, EtOAc/hexanes 1:20 to 1:10) gave racemic 6e as a yel-
low solid (362 mg, 0.73 mmol, 62% yield). After deracemization of
racemic 6e (299 mg, 0.60 mmol) with CuCl (101 mg, 1.02 mmol) and
(–)-sparteine (491 mg, 2.10 mmol), the crude product was purified by
column chromatography on silica gel (35 mm × 200 mm, CH2Cl2/
hexanes 4:1) to afford (S)-6e.
19F NMR (CDCl3, 283 Hz):  = –114.15.
IR (thin film): 3517br s, 3058s, 1512s, 1495s, 1385s, 1221s cm–1
HRMS (ESI+): m/z [M + H]+ calcd for C32H21F2O2: 475.1510; found:
475.1504.
.
VANOL Derivative (S)-6b
The synthesis of racemic 6b was performed according to Typical Pro-
cedure III with 3-(4-bromophenyl)naphthalen-1-ol 22b (1.20 g, 4.00
mmol). Purification by column chromatography on silica gel (35 mm
× 250 mm, CH2Cl2/hexanes 1:2 to 2:3) gave racemic 6b as an off-white
solid (699 mg, 1.17 mmol, 59% yield). After de-racemization of race-
mic 6b (596 mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and (–)-
sparteine (819 mg, 3.50 mmol), the crude product was purified by
column chromatography on silica gel (35 mm × 200 mm, CH2Cl2/
hexanes 1:2 to 2:3) to afford (S)-6b.
Yield: 50 mg (0.10 mmol, 17%); yellow solid; mp 212–215 °C; Rf = 0.42
(CH2Cl2); >99% ee (HPLC analysis; Chiralpak AS column, 90:10 hex-
ane/iPrOH at 254 nm, flow-rate: 0.5 mL/min): tR = 12.41 [(S)-6e; ma-
jor], 22.56 [(R)-6e; minor] min; []D20 = –242.3 (c 1.0, CH2Cl2) on >99%
ee (S)-6e (HPLC).
1H NMR (CDCl3, 500 MHz):  = 3.68 (s, 6 H), 5.78 (s, 2 H), 6.49–6.53
(m, 4 H), 6.59–6.63 (m, 4 H), 7.30 (s, 2 H), 7.50–7.57 (m, 4 H), 7.75–
7.78 (m, 2 H), 8.30–8.33 (m, 2 H).
Yield: 443 mg (0.74 mmol, 74%); off-white solid; mp 143–148 °C; Rf =
0.33 (2:1 CH2Cl2/hexanes); >99% ee (HPLC analysis; Chiralcel OD-H
column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 0.7 mL/min): tR
18.72 [(S)-6b; major], 21.78 [(R)-6b; minor] min; []D = –186.8 (c
1.0, CH2Cl2) on >99% ee (S)-6b (HPLC).
1H NMR (CDCl3, 500 MHz):  = 5.82 (s, 2 H), 6.48–6.51 (m, 4 H), 7.08–
7.11 (m, 4 H), 7.29 (s, 2 H), 7.55–7.61 (m, 4 H), 7.78–7.80 (m, 2 H),
8.32–8.35 (m, 2 H).
13C NMR (CDCl3, 125 MHz):  = 55.14, 112.92, 112.93, 121.78, 122.75,
122.78, 125.43, 127.42, 127.58, 129.94, 132.83, 134.62, 140.30,
150.27, 158.46.
=
20
IR (thin film): 3507br s, 2930s, 1514s, 1495s, 1383s, 1246s cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C34H27O4: 499.1909; found:
499.1902.
13C NMR (CDCl3, 125 MHz):  = 112.02, 121.11, 122.12, 122.80,
123.03, 126.11, 127.76, 127.89, 130.49, 130.65, 134.58, 139.06,
139.17, 150.48.
VANOL Derivative (S)-6g
The synthesis of racemic 6g was performed according to Typical Pro-
cedure III, with 3-(4-methoxy-3,5-dimethylphenyl)naphthalen-1-ol
22g (1.12 g, 4.00 mmol). Purification by column chromatography on
silica gel (35 mm × 250 mm, EtOAc/hexanes 1:20) gave racemic 6g as
a light-yellow solid (590 mg, 1.06 mmol, 53% yield). After deracemiza-
tion of racemic 6g (188 mg, 0.34 mmol) with CuCl (58 mg, 0.59
mmol) and (–)-sparteine (278 mg, 1.19 mmol), the crude product was
purified by column chromatography on silica gel (20 mm × 200 mm,
CH2Cl2/hexanes 4:1) to afford (S)-6g.
IR (thin film): 3505br s, 3052s, 1570s, 1489s, 1385s, 1221s cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C32H2179Br2O2: 594.9908; found:
594.9921.
VANOL Derivative (S)-6d
The synthesis of racemic 6d was performed according to Typical Pro-
cedure III with 3-(3,5-dimethylphenyl)naphthalen-1-ol 22d (992 mg,
4.00 mmol). Purification by column chromatography on silica gel (30
mm × 250 mm, CH2Cl2/hexanes 1:2) gave racemic 6d as a light-yellow
solid (754 mg, 1.52 mmol, 76% yield). After deracemization of racemic
6d (494 mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and (–)-
sparteine (819 mg, 3.50 mmol), the crude product was purified by
column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/
hexanes 1:2) to afford (S)-6d.
Yield: 88 mg (0.16 mmol, 47%); yellow solid; mp 207–210 °C; Rf = 0.32
(CH2Cl2); >99% ee (HPLC analysis; Chiralcel OD-H column, 99:1
hexane/iPrOH at 254 nm, flow-rate: 0.5 mL/min): tR = 24.40 [(R)-6g;
minor], 27.43 [(S)-6g; major] min; []D = –209.2 (c 1.0, CH2Cl2) on
>99% ee (S)-6g (HPLC).
1H NMR (CDCl3, 500 MHz):  = 1.94 (s, 12 H), 3.61 (s, 6 H), 5.78 (s,
2 H), 6.32 (s, 4 H), 7.29 (s, 2 H), 7.49–7.56 (m, 4 H), 7.74–7.77 (m, 2 H),
8.30–8.33 (m, 2 H).
20
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Y. Guan et al.
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Synthesis
13C NMR (CDCl3, 125 MHz):  = 15.85, 59.69, 113.05, 121.48, 122.62,
122.70, 125.46, 127.37, 127.51, 129.41, 129.44, 134.53, 135.73,
140.41, 150.38, 155.92.
VANOL Derivative (S)-7a
The synthesis of racemic 7a was performed according to Typical Pro-
cedure III, with 7-bromo-3-(4-fluorophenyl)naphthalen-1-ol 25a
(2.06 g, 6.50 mmol). After cooling to r.t., CH2Cl2 (30 mL) was added to
the flask and the mixture was stirred until all large chunks had been
broken up. The suspension was cooled in a freezer (–20 °C) and then
filtered through filter paper. The yellow powder was washed with
chilled CH2Cl2/hexanes and dried under vacuum to afford a yellow
solid (1.19 g). Purification of the product remaining in the mother
liquor by column chromatography on silica gel (30 mm × 250 mm,
CH2Cl2/hexanes 1:1) gave racemic 7a as a yellow solid (0.25 g). The to-
tal yield was 70% (1.44 g, 2.28 mmol). After deracemization of racemic
7a (632 mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and (–)-
sparteine (819 mg, 3.50 mmol), the crude product was purified
by column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/
hexanes 2:3) to afford (S)-7a.
IR (thin film): 3515br s, 2930s, 1570s, 1487s, 1387s, 1225s cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C36H29I2O4: 779.0155; found:
779.0159.
VANOL Derivative (R)-6h
The synthesis of racemic 6h was performed according to Typical Pro-
cedure III, with 3-(thiophen-2-yl)naphthalen-1-ol 22h (1.70 g, 7.50
mmol). Purification by column chromatography on silica gel (30 mm
× 250 mm, CH2Cl2/hexanes 2:3) gave racemic 6h as a yellow solid (757
mg, 1.68 mmol, 45% yield). After deracemization of racemic 6h (652
mg, 1.45 mmol) with CuCl (244 mg, 2.46 mmol) and (+)-sparteine
(1.19 g, 5.09 mmol), the crude product was purified by column chro-
matography on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 1:1) to
afford (R)-6h.
Yield: 560 mg (0.89 mmol, 87%); off-white solid; mp 152–158 °C; Rf =
0.24 (1:1 CH2Cl2/hexanes); >99% ee (HPLC analysis; Pirkle D-Phenyl-
glycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0
mL/min): tR = 29.55 [(R)-7a; minor], 35.61 [(S)-7a; major] min; []D
= –152.7 (c 1.0, CH2Cl2) on >99% ee (S)-7a (HPLC).
1H NMR (CDCl3, 500 MHz):  = 5.75 (s, 2 H), 6.54–6.56 (m, 4 H), 6.65–
6.69 (m, 4 H), 7.25 (s, 2 H), 7.64 (d, J = 1.0 Hz, 4 H), 8.50 (d, J = 1.0 Hz,
2 H).
13C NMR (CDCl3, 125 MHz):  = 113.26, 114.58 (2JCF = 21 Hz), 120.21,
121.99, 123.98, 125.31, 129.36, 130.34 (3JCF = 8.1 Hz), 131.35, 133.02,
135.64 (4JCF = 3.3 Hz), 139.79, 149.55, 162.06 (1JCF = 245.8 Hz).
19F NMR (CDCl3, 283 MHz):  = –113.46.
IR (thin film): 3517br s, 1512s, 1489s, 1375s, 1235s cm–1
MS: m/z (%) = 634 (5, 81Br81Br) [M]+, 632 (10, 81Br79Br) [M]+, 630 (7,
79Br79Br) [M]+, 425 (5), 317 (21, 81Br), 315 (17, 79Br), 289 (12, 81Br), 287
(13, 79Br), 227 (65), 212 (83), 196 (100), 159 (100).
Yield: 476 mg (1.06 mmol, 73%); off-white foamy solid; mp 157–
159 °C; Rf = 0.37 (2:1 CH2Cl2/hexanes); >99% ee (HPLC analysis; Pirkle
D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate:
1.0 mL/min): tR = 30.75 [(R)-6h; major], 34.92 [(S)-6h; minor] min;
[]D20 = +124.9 (c 1.0, CH2Cl2) on >99% ee (R)-6h (HPLC)
1H NMR (CDCl3, 500 MHz):  = 5.60 (s, 2 H), 6.68 (dd, J = 3.5, 1.0 Hz,
2 H), 6.73 (dd, J = 5.0, 1.0 Hz, 2 H), 7.50–7.54 (m, 2 H), 7.56–7.61 (m,
2 H), 7.76 (s, 2 H), 7.86 (d, J = 8.0 Hz, 2 H), 8.24–8.26 (m, 2 H).
20
13C NMR (CDCl3, 125 MHz):  = 111.44, 121.47, 122.94, 123.29,
125.91, 126.00, 126.04, 127.03, 127.74, 127.96, 133.07, 134.80,
141.52, 151.31.
.
IR (thin film): 3505br s, 1570s, 1491s, 1387s, 1210s cm–1
.
HRMS (ESI–): m/z [M – H]+ calcd for C28H17O2S2: 449.0670; found:
449.0660.
Anal calcd for C32H18Br2F2O2: C, 60.79; H, 2.87. Found: C, 60.99; H,
2.72.
VANOL Derivative (R)-6i
The synthesis of racemic 6i was performed according to Typical Pro-
cedure III, with 3-(thiophen-3-yl)naphthalen-1-ol 22i (904 mg, 4.00
mmol). Purification by column chromatography on silica gel (30 mm
× 250 mm, CH2Cl2/hexanes 1:1) gave racemic 6i as a light-yellow solid
(534 mg, 1.19 mmol, 59% yield). After deracemization of racemic 6i
(360 mg, 0.80 mmol) with CuCl (135 mg, 1.36 mmol) and (+)-
sparteine (655 mg, 2.80 mmol), the crude product was purified by
column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/hex-
anes 1:1) to afford (R)-6i.
VANOL Derivative (S)-7d
The synthesis of racemic 7d was performed according to Typical Pro-
cedure III, with 7-bromo-3-(3,5-dimethylphenyl)naphthalen-1-ol
25d (2.62 g, 8.01 mmol). Purification by column chromatography on
silica gel (30 mm × 250 mm, CH2Cl2/hexanes 1:3) gave racemic 7d as a
white solid (1.62 g, 2.48 mmol, 65% yield). After deracemization of
racemic 7d (652 mg, 1.00 mmol) with CuCl (168 mg, 1.70 mmol) and
(–)-sparteine (819 mg, 3.50 mmol), the crude product was purified by
column chromatography on silica gel (30 mm × 200 mm, CH2Cl2/
hexanes 1:3) to afford (S)-7d.
Yield: 144 mg (0.32 mmol, 40%); off-white solid; >99% ee (HPLC anal-
ysis; Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm,
flow-rate: 1.0 mL/min): tR = 25.76 [(R)-6i; major], 30.40 [(S)-6i;
minor] min; mp 188–189 °C; Rf = 0.18 (1:1 CH2Cl2/hexanes); []D
+155.1 (c 1.0, CH2Cl2) on >99% ee (R)-6i (HPLC).
1H NMR (CDCl3, 500 MHz):  = 5.68 (s, 2 H), 6.62–6.65 (m, 4 H), 6.96
(dd, J = 5.0, 3.5 Hz, 2 H), 7.50–7.59 (m, 6 H), 7.81–7.84 (m, 2 H), 8.26–
8.29 (m, 2 H).
13C NMR (CDCl3, 125 MHz):  = 112.45, 121.33, 122.69, 122.83,
123.07, 124.43, 125.71, 127.63, 127.67, 127.94, 134.68, 135.10,
140.46, 150.46.
IR (thin film): 3505br s, 1570s, 1495s, 1379s, 1265s cm–1
HRMS (ESI–): m/z [M – H]– calcd for C28H17O2S2: 449.0670; found:
20
Yield: 488 mg (0.75 mmol, 75%); off-white foamy solid; mp 130–
134 °C; Rf = 0.19 (1:2 CH2Cl2/hexanes); >99% ee (HPLC analysis; Pirkle
D-Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate:
1.0 mL/min): tR = 21.79 [(S)-7d; major], 24.01 [(R)-7d; minor] min;
[]D20 = –171.4 (c 1.0, CH2Cl2) on >99% ee (S)-7d (HPLC).
1H NMR (CDCl3, 500 MHz):  = 2.00 (s, 12 H), 5.70 (s, 2 H), 6.28 (s,
4 H), 6.72 (s, 2 H), 7.27 (d, J = 0.5 Hz, 2 H), 7.60–7.62 (m, 4 H), 8.48–
8.49 (m, 2 H).
=
13C NMR (CDCl3, 125 MHz):  = 21.09, 113.92, 119.66, 121.56, 123.82,
125.14, 126.68, 128.51, 129.24, 130.90, 132.95, 136.78, 139.60,
141.41, 149.50.
.
449.0685.
IR (thin film): 3517br s, 2919s, 1581s, 1487s, 1373s, 1279s cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

O
Y. Guan et al.
Paper
Synthesis
HRMS (ESI–): m/z [M – H]– calcd for C36H2779Br2O2: 649.0378; found:
649.0355.
mL) were added to the flask and the mixture was stirred until all large
chunks had been broken up. The suspension was cooled in a freezer
(–20 °C) and then filtered through filter paper. The yellow powder
was washed with chilled CH2Cl2/hexanes and dried under vacuum to
afford a yellow solid (2.42 g). Purification of the product remaining in
the mother liquor by column chromatography on silica gel (30 mm ×
250 mm, CH2Cl2/hexanes 1:2) gave racemic 7j as an off-white solid
(1.25 g). The total yield was 62% (3.67 g, 5.18 mmol). After deracem-
ization of racemic 7j (6.75 g, 9.54 mmol) with CuCl (1.61 g, 16.3
mmol) and (–)-sparteine (7.81 g, 33.4 mmol), the crude product was
purified by column chromatography on silica gel (50 mm × 250 mm,
CH2Cl2/hexanes 1:3) to afford (S)-7j.
VANOL Derivative (S)-7e
The synthesis of racemic 7e was performed according to Typical Pro-
cedure III, with 7-bromo-3-(4-methoxyphenyl)naphthalen-1-ol 25e
(1.58 g, 4.80 mmol) except that the temperature was 175 °C. Purifica-
tion by column chromatography on silica gel (30 mm × 250 mm,
CH2Cl2/hexanes 3:2) gave racemic 7e as a yellow solid (654 mg, 1.00
mmol, 42% yield). After deracemization of racemic 7e (548 mg, 0.84
mmol) with CuCl (141 mg, 1.42 mmol) and (–)-sparteine (684 mg,
2.92 mmol), the crude product was purified by column chromatogra-
phy on silica gel (30 mm × 200 mm, CH2Cl2/hexanes 3:2) to afford (S)-
7e.
Yield: 5.38 g (7.60 mmol, 80%); off-white foamy solid; mp 85–88 °C;
Rf = 0.19 (1:2 CH2Cl2/hexanes); >99% ee (HPLC analysis; Pirkle D-
Phenylglycine column, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0
Yield: 380 mg (0.58 mmol, 69%); light-yellow solid; mp 147–150 °C;
Rf = 0.24 (2:1 CH2Cl2/hexanes); >99% ee (HPLC analysis; Chiralcel
20
mL/min): tR = 23.71 [(S)-7j; major], 28.67 [(R)-7j; minor] min; []D
–187.5 (c 1.0, CH2Cl2) on >99% ee (S)-7j (HPLC).
=
OD-H column, 90:10 hexane/iPrOH at 254 nm, flow-rate: 0.5
1H NMR (CDCl3, 500 MHz):  = 0.88 (t, J = 7.5 Hz, 6 H), 1.25–1.30 (m,
4 H), 1.46–1.51 (m, 4 H), 2.46 (t, J = 7.5 Hz, 4 H), 5.68 (s, 2 H), 6.52 (dd,
J = 6.5, 2.0 Hz, 4 H), 6.76 (d, J = 8.0 Hz, 4 H), 7.29 (s, 2 H), 7.59–7.65 (m,
4 H), 8.46–8.48 (m, 2 H).
13C NMR (CDCl3, 125 MHz):  = 13.89, 22.20, 33.45, 35.12, 113.79,
119.66, 121.74, 123.92, 125.29, 127.64, 128.57, 129.32, 130.92,
133.07, 136.94, 141.11, 141.66, 149.39.
20
mL/min): tR = 4.68 [(R)-7e; minor], 6.65 [(S)-7e; major] min; []d
–182.6 (c 1.0, CH2Cl2) on >99% ee (S)-7e (HPLC).
=
1H NMR (CDCl3, 500 MHz):  = 3.68 (s, 6 H), 5.70 (s, 2 H), 6.51–6.52
(m, 4 H), 6.57–6.59 (m, 4 H), 7.25 (s, 2 H), 7.60–7.62 (m, 4 H), 8.46–
8.47 (m, 2 H).
13C NMR (CDCl3, 125 MHz):  = 55.17, 113.09, 113.81119.63, 121.71,
123.82, 125.28, 129.28, 129.85, 130.96, 132.26, 133.06, 140.70,
149.41, 158.74.
IR (thin film): 3519br s, 2928s, 2857s, 1561s, 1487s, 1375s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C40H3579Br2O2: 705.1004; found:
IR (thin film): 3503br s, 2930m, 1514s, 1487s, 1375s, 1248s cm–1
.
705.0973.
HRMS (ESI–): m/z [M – H]– calcd for C34H23O479Br2: 652.9963; found:
652.9937.
Susuki Coupling for the Synthesis of VANOL Derivatives (S)-7n to
(S)-7s (Table 5); Typical Procedure IV
VANOL Derivative (S)-7g
The synthesis of racemic 7g was performed according to Typical Pro-
cedure III, with 7-bromo-3-(4-methoxy-3,5-dimethylphenyl)naph-
thalen-1-ol 25g (2.50 g, 7.00 mmol). Purification by column chroma-
tography on silica gel (20 mm × 200 mm, CH2Cl2/hexanes 3:2) gave
racemic 7g as a light-yellow solid (990 mg, 1.39 mmol, 40% yield). Af-
ter deracemization of racemic 7g (712 mg, 1.00 mmol) with CuCl (168
mg, 1.70 mmol) and (–)-sparteine (819 mg, 3.50 mmol), the crude
product was purified by column chromatography on silica gel (30 mm
× 200 mm, CH2Cl2/hexanes 3:2) to afford (S)-7g.
VANOL Derivative (S)-7o
Benzene, EtOH and Na2CO3 (aq. 2 M) were purged (>10 min) with in-
ert gas (Ar or N2) prior to use. To a 25 mL round-bottom flask was
added (S)-5b (60 mg, 0.10 mmol), tetrakis(triphosphine)palladium
(12 mg, 0.010 mmol), benzene (1 mL) and Na2CO3 (aq. 2 M, 0.5 mL)
under argon. To the stirred mixture was added 4-tert-butylphenylbo-
ronic acid 26a (71 mg, 0.40 mmol) and EtOH (0.5 mL). The mixture
was stirred at 90 °C for 14 h with an argon balloon attached to the
condenser. After cooling to r.t., the mixture was partitioned between
EtOAc (10 mL) and brine (5 mL). The organic layer was separated,
dried over MgSO4, filtered through Celite and concentrated to dry-
ness. Purification of the crude product by column chromatography on
silica gel (20 mm × 250 mm, CH2Cl2/hexanes 1:2) gave (S)-7o.
Yield: 526 mg (0.74 mmol, 74%); light-yellow solid; mp 203–206 °C;
Rf = 0.33 (CH2Cl2); >99% ee (HPLC analysis; Pirkle D-Phenylglycine col-
umn, 98:2 hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min): tR
44.60 [(R)-7g; minor], 49.09 [(S)-7g; major] min; []D = –176.4 (c
1.0, CH2Cl2) on >99% ee (S)-7g (HPLC).
=
20
Yield: 29 mg (0.041 mmol, 41%); white solid; mp >300 °C; Rf = 0.21
(1:2 CH2Cl2/hexanes); []D20= +29.2 (c 1.0, CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 1.39 (s, 18 H), 5.89 (s, 2 H), 6.67 (dd, J =
8.5, 1.5 Hz, 4 H), 6.96–7.00 (m, 4 H), 7.06–7.10 (m, 2 H), 7.34 (d, J =
1.0 Hz, 2 H), 7.51–7.55 (m, 4 H), 7.73–7.76 (m, 4 H), 7.84 (d, J = 1.5 Hz,
4 H), 8.56 (d, J = 1.0 Hz, 2 H).
13C NMR (CDCl3, 125 MHz):  = 31.39, 34.60, 113.11, 120.45, 121.80,
123.24, 125.86, 126.64, 127.09, 127.11, 127.50, 128.21, 128.90,
133.66, 138.11, 138.31, 140.25, 140.58, 150.55, 150.61.
1H NMR (CDCl3, 500 MHz):  = 1.95 (s, 12 H), 3.61 (s, 6 H), 5.70 (s,
2 H), 6.28 (s, 4 H), 7.25 (d, J = 0.5 Hz, 2 H), 7.60–7.62 (m, 4 H), 8.47–
8.48 (m, 2 H).
13C NMR (CDCl3, 125 MHz):  = 15.89, 59.70, 113.93, 119.64, 121.43,
123.75, 125.12, 129.21, 129.29, 129.68, 130.94, 132.96, 135.20,
140.85, 149.48, 156.20.
IR (thin film): 3513br s, 2930s, 1577s, 1483s, 1375s, 1225s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C38H3179Br2O4: 709.0589; found:
709.0590.
IR (thin film): 3517br s, 2961s, 1559s, 1456s, 1387s, 1267s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C52H45O2: 701.3420; found:
701.3448.
VANOL Derivative (S)-7j
The synthesis of racemic 7j was performed according to Typical Pro-
cedure III, with 7-bromo-3-(4-butylphenyl)naphthalen-1-ol 25j (5.09
g, 14.3 mmol). After cooling to r.t., CH2Cl2 (30 mL) and hexanes (30
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

P
Y. Guan et al.
Paper
Synthesis
VANOL Derivative (S)-7p
13C NMR (CDCl3, 125 MHz):  = 15.89, 31.39, 34.59, 59.90, 113.44,
120.22, 121.26, 123.02, 125.85, 126.91, 127.03, 128.04, 129.42,
129.49, 133.60, 135.79, 137.96, 138.12, 140.34, 150.50, 150.64, 155.9.
The reaction of (S)-7j (284 mg, 0.40 mmol), tetrakis(triphos-
phine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2
M, 4 mL), 4-tert-butylphenylboronic acid (285 mg, 1.60 mmol) and
EtOH (2 mL) was performed according to Typical Procedure IV. Purifi-
cation of the crude product by column chromatography on silica gel
(30 mm × 200 mm, CH2Cl2/hexanes 2:5) gave (S)-7p.
IR (thin film): 3519br s, 2959s, 1559s, 1489s, 1389s, 1223s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C58H57O4: 817.4257; found:
817.4262.
Yield: 162 mg (0.199 mmol, 50%); off-white solid; mp >260 °C; Rf =
0.22 (1:2 CH2Cl2/hexanes); []D20 = –31.7 (c 1.0, CH2Cl2).
VANOL Derivative (S)-27
To a flame-dried 250 mL round-bottom flask was added (S)-7j (1.42 g,
2.00 mmol) and anhydrous THF (15 mL). The resulting mixture was
cooled to 0 °C and NaH (176 mg, 60% in mineral oil, 4.40 mmol) was
added. The mixture was stirred at 0 °C for 15 minutes and MeI (0.8
mL, 12.8 mmol) was added. The mixture was warmed to r.t. and
stirred for additional 24 h. NH4Cl (sat. aq. 4 mL) was added to the mix-
ture and the organic solvent was removed by rotary evaporation. The
residue was extracted with CH2Cl2 (3 × 5 mL). The combined organic
layer was washed with Na2S2O3 (sat. aq. 2 × 5 mL), brine (5 mL), and
dried over MgSO4, filtered through Celite and concentrated to dry-
ness. Purification of the crude product by column chromatography on
silica gel (20 mm × 320 mm, CH2Cl2/hexanes 1:4) gave (S)-27.
1H NMR (CDCl3, 500 MHz):  = 0.89 (t, J = 7.5 Hz, 6 H), 1.27–1.32 (m,
4 H), 1.39 (s, 18 H), 1.49–1.52 (m, 4 H), 2.47 (t, J = 7.5 Hz, 2 H), 5.84 (s,
2 H), 6.58 (dd, J = 6.5, 2.0 Hz, 4 H), 6.78 (d, J = 8.0 Hz, 4 H), 7.36 (d, J =
1.0 Hz, 2 H), 7.52 (dd, J = 6.5, 2.0 Hz, 4 H), 7.74 (dd, J = 6.5, 2.0 Hz, 4 H),
7.83–7.84 (m, 4 H), 8.54 (m, 2 H).
13C NMR (CDCl3, 125 MHz):  = 13.91, 22.24, 31.40, 33.52, 34.59,
35.15, 113.30, 120.48, 121.61, 123.18, 125.84, 126.98, 127.08, 127.57,
128.14, 128.69, 133.69, 137.53, 138.09, 138.18, 140.60, 141.26,
150.48, 150.49.
IR (thin film): 3499br s, 2957s, 1559s, 1456s, 1388s, 1267s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C60H61O2: 813.4672; found:
813.4709.
Yield: 1.30 g (1.76 mmol, 88%); white foamy solid; mp 75–77 °C; Rf =
0.29 (1:2 CH2Cl2/hexanes); []D20 = –85.4 (c 1.0, CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 0.91 (t, J = 7.5 Hz, 6 H), 1.28–1.33 (m,
4 H), 1.49–1.53 (m, 4 H), 2.45–2.49 (m, 4 H), 3.63 (s, 6 H), 6.63 (dd, J =
6.5, 2.0 Hz, 4 H), 6.74 (d, J = 8.0 Hz, 4 H), 7.50 (s, 2 H), 7.57 (dd, J = 8.5,
2.0 Hz, 2 H), 7.71 (d, J = 8.5 Hz, 2 H), 8.33 (d, J = 2.0 Hz, 2 H).
13C NMR (CDCl3, 125 MHz):  = 13.91, 22.24, 33.58, 35.10, 61.14,
120.02, 124.84, 125.25, 126.37, 127.64, 128.10, 128.72, 129.82,
129.90, 132.99, 137.66, 140.65, 141.17, 153.39.
VANOL Derivative (S)-7q
The reaction of (S)-7d (261 mg, 0.40 mmol), tetrakis(triphos-
phine)palladium (46 mg, 0.040 mmol), benzene (4 mL), Na2CO3 (aq. 2
M, 4 mL), 4-tert-butylphenylboronic acid (285 mg, 1.60 mmol) and
EtOH (2 mL) was performed according to Typical Procedure IV. Purifi-
cation of the crude product by column chromatography on silica gel
(30 mm × 200 mm, CH2Cl2/hexanes 2:5) gave (S)-7q.
IR (thin film): 2955s, 2928s, 2857s, 1561s, 1480s, 1352s, 1105s cm–1
.
Yield: 145 mg (0.191 mmol, 48%); off-white solid; mp 170–185 °C; Rf
= 0.19 (1:2 CH2Cl2/hexanes).
HRMS (ESI+): m/z [M + H]+ calcd for C42H4179Br2O2: 735.1473; found:
1H NMR (CDCl3, 500 MHz):  = 1.38 (s, 18 H), 2.01 (s, 12 H), 5.82 (s,
2 H), 6.36 (d, J = 0.5 Hz, 4 H), 6.71 (s, 2 H), 7.33 (d, J = 0.5 Hz, 2 H), 7.52
(dd, J = 6.5, 2.0 Hz, 4 H), 7.75 (dd, J = 7.0, 2.0 Hz, 4 H), 7.82–7.83 (m,
4 H), 8.55 (d, J = 0.5 Hz, 2 H).
735.1495.
VANOL Derivative (S)-7n
To a flame-dried 25 mL round-bottom flask were added (S)-27 (184
mg, 0.25 mmol), tetrakis(triphosphine)palladium (29 mg, 0.025
mmol) and DME (1.7 mL) under argon. To the stirred mixture were
added phenyboronic acid (107 mg, 0.88 mmol) and Na2CO3 (aq. 2 M,
0.7 mL). The mixture was stirred at 90 °C for 14 h with an argon bal-
loon attached. After cooling to r.t., the mixture was filtered through a
pad of Celite and washed with CH2Cl2. After removal of the solvent,
the residue was dissolved in CH2Cl2 (20 mL) and washed with NH4Cl
(sat. aq. 5 mL) and brine (5 mL). The organic layer was separated,
dried over MgSO4, filtered through Celite and concentrated to dry-
ness. The residue was purified by column chromatography (silica gel,
20 mm × 250 mm, CH2Cl2/hexanes 1:2). The purified and concentrat-
ed product was dissolved in CH2Cl2 (4 mL) and cooled to 0 °C, BBr3 (1
M in CH2Cl2, 1.5 mL, 1.5 mmol) was added dropwise to the mixture at
0 °C. The mixture was stirred at r.t. overnight with an argon balloon
attached to the flask. The mixture was then cooled to 0 °C and H2O (8
mL) was added dropwise. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined or-
ganic layer was dried over MgSO4, filtered through Celite and concen-
trated to dryness. Purification of the crude product by column chro-
matography on silica gel (20 mm × 260 mm, CH2Cl2/hexanes 1:2) gave
(S)-7n.
13C NMR (CDCl3, 125 MHz):  = 21.10, 31.39, 34.59, 113.41, 120.24,
121.36, 123.07, 125.84, 126.82, 126.86, 127.03, 128.06, 128.22,
133.58, 136.62, 137.95, 138.12, 140.17, 140.90, 150.49, 150.65.
IR (thin film): 3519br s, 2961s, 1597s, 1495s, 1387s, 1267s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C56H53O2: 757.4046; found:
757.4055.
VANOL Derivative (S)-7r
The reaction of (S)-7g (214 mg, 0.30 mmol), tetrakis(triphos-
phine)palladium (35 mg, 0.030 mmol), benzene (3 mL), Na2CO3 (aq. 2
M, 1.5 mL), 4-tert-butylphenylboronic acid (214 mg, 1.20 mmol) and
EtOH (1.5 mL) was performed according to Typical Procedure IV. Puri-
fication of the crude product by column chromatography on silica gel
(30 mm × 200 mm, CH2Cl2/hexanes 3:2) gave (S)-7r.
Yield: 63 mg (0.077 mmol, 26%); off-white solid; mp 172–178 °C; Rf =
0.40 (CH2Cl2); []D20 = –40.8 (c 1.0, CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 1.39 (s, 18 H), 1.96 (s, 12 H), 3.62 (s,
6 H), 5.84 (s, 2 H), 6.36 (s, 4 H), 7.32 (s, 2 H), 7.53 (dd, J = 6.5, 2.0 Hz,
4 H), 7.76 (dd, J = 6.5, 2.0 Hz, 4 H), 7.82–7.83 (m, 4 H), 8.55–8.56 (m,
2 H).
Yield: 130 mg (0.185 mmol, 74% isolated yield over two steps); light-
20
yellow solid; mp 225–226 °C; Rf = 0.26 (1:1, CH2Cl2/hexanes); []D
–86.8 (c 1.0, CH2Cl2).
=
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Y. Guan et al.
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Synthesis
1H NMR (CDCl3, 500 MHz):  = 0.89 (t, J = 7.5 Hz, 6 H), 1.27–1.32 (m,
4 H), 1.47–1.54 (m, 4 H), 2.47 (t, J = 7.5 Hz, 4 H), 5.84 (s, 2 H), 6.59 (d,
J = 8.0 Hz, 4 H), 6.78 (d, J = 8.0 Hz, 4 H), 7.36–7.40 (m, 4 H), 7.48–7.52
(m, 4 H), 7.78–7.88 (m, 8 H), 8.55 (d, J = 0.5 Hz, 2 H).
Cycloaromatization Promoted by Potassium t-Butoxide (Scheme
2); Typical Procedure V
3-Cyclohexyl-1-naphthol 29m
13C NMR (CDCl3, 125 MHz):  = 13.90, 22.23, 33.51, 35.15, 113.36,
120.75, 121.63, 123.15, 127.02, 127.41, 127.44, 127.59, 128.24,
128.69, 128.89, 133.81, 137.46, 138.25, 140.78, 141.10, 141.33,
150.53.
To an oven-dried 100 mL round-bottom flask was added KtOBu
(1.347 g, 12.00 mmol, 1.200 equiv) and THF (20 mL). o-(Cyclohexyl-
ethynyl)acetophenone 28m (2.264 g, 10.00 mmol) was added in one
portion at r.t. and the reaction mixture was heated to 80 °C under N2
atmosphere. After 2 h, the reaction mixture was acidified with 1 M
H2SO4 (50 mL) at 0 °C and then extracted with EtOAc (3 × 50 mL). The
combined organic layer was dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure. The residue was purified
by silica gel flash column chromatography (hexane/EtOAc 20:1 to
10:1) to obtain 29m.
IR (thin film): 3503br s, 2928s, 1559s, 1489s, 1387s, 1215s cm–1
.
HRMS (ESI–): m/z [M – H]– calcd for C52H45O2: 701.3420; found:
701.3411.
VANOL Derivative (S)-7s
To a flame-dried 25 mL round-bottom flask were added (S)-27 (184
mg, 0.25 mmol), tetrakis(triphosphine)palladium (29 mg, 0.025
mmol) and DME (1.7 mL) under argon. To the stirred mixture were
added anthracene-9-boronic acid (195 mg, 0.88 mmol) and Na2CO3
(aq. 2 M, 0.7 mL). The mixture was stirred at 90 °C for 14 h with an
argon balloon attached. After cooling to r.t., the mixture was filtered
through a pad of Celite and washed with CH2Cl2. After removal of the
solvent, the residue was dissolved in CH2Cl2 (20 mL) and washed with
NH4Cl (sat. aq. 5 mL) and brine (5 mL). The organic layer was separat-
ed, dried over MgSO4, filtered through Celite and concentrated to dry-
ness. The residue was purified by column chromatography (silica gel,
20 mm × 250 mm, CH2Cl2/hexanes 1:2). The purified and concentrat-
ed product was dissolved in CH2Cl2 (4 mL) and cooled to 0 °C, BBr3 (1
M in CH2Cl2, 1.5 mL, 1.5 mmol) was added dropwise to the mixture at
0 °C. The mixture was stirred at r.t. overnight with an argon balloon
attached to the flask. The mixture was then cooled to 0 °C and H2O (8
mL) was added dropwise. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined or-
ganic layer was dried over MgSO4, filtered through Celite and concen-
trated to dryness. Purification of the crude product by column chro-
matography on silica gel (20 mm × 260 mm, CH2Cl2/hexanes 1:2) gave
(S)-7s.
Yield: 2.124 g (9.380 mmol, 94%); white solid; mp 100–101 °C; Rf =
0.41 (hexanes/EtOAc 8:1).
1H NMR (500 MHz, CDCl3):  = 1.25–1.55 (m, 6 H), 1.76–2.00 (m, 5 H),
2.57 (tt, J = 11.5, 3.2 Hz, 1 H), 6.31 (s, 1 H), 6.69 (d, J = 1.4 Hz, 1 H),
7.28–7.38 (m, 1 H), 7.51 (dddd, J = 25.4, 8.1, 6.8, 1.3 Hz, 2 H), 7.78–
7.93 (m, 1 H), 8.27 (dd, J = 8.4, 1.3 Hz, 1 H).
13C NMR (126 MHz, CDCl3):  = 26.28, 27.01, 34.32, 44.74, 109.29,
117.62, 121.54, 123.29, 124.65, 126.52, 127.58, 135.03, 146.32,
151.14.
HRMS (ESI–): m/z [M – H]– calcd. for C16H17O: 225.1279; found:
225.1296.
3-Butyl-1-naphthol 29n
Naphthol 29n was prepared from o-(butylethynyl)acetophenone 28n
(2.003 g, 10.00 mmol) by Typical Procedure V. The crude product was
purified by column chromatography (silica gel, hexanes/EtOAc 40:1 to
9:1) to give 29n.
Yield: 1.889 g (9.430 mmol, 94%); yellow liquid; Rf = 0.45 (hexanes/
EtOAc 8:1).
1H NMR (500 MHz, CDCl3):  = 0.92 (td, J = 7.3, 1.1 Hz, 3 H), 1.37 (qd,
J = 7.5, 1.9 Hz, 2 H), 1.65 (tt, J = 9.0, 6.8 Hz, 2 H), 2.55–2.76 (m, 2 H),
5.14 (s, 1 H), 6.67 (d, J = 1.3 Hz, 1 H), 7.21 (d, J = 1.6 Hz, 1 H), 7.35–7.50
(m, 2 H), 7.72 (dt, J = 7.6, 1.4 Hz, 1 H), 8.02–8.13 (m, 1 H).
Yield: 120 mg (0.133 mmol, 53% isolated yield over two steps); light-
20
yellow solid; mp 170–172 °C; Rf = 0.15 (1:2 CH2Cl2/hexane); []D
=
–497.9 (c 1.0, CH2Cl2).
1H NMR (CDCl3, 500 MHz):  = 0.96 (t, J = 7.5 Hz, 6 H), 1.35–1.40 (m,
4 H), 1.56–1.62 (m, 4 H), 2.57 (t, J = 7.5 Hz, 4 H), 5.87 (s, 2 H), 6.69 (d,
J = 8.0 Hz, 4 H), 6.89 (d, J = 8.0 Hz, 4 H), 7.30–7.34 (m, 2 H), 7.40–7.50
(m, 8 H), 7.61 (dd, J = 8.5, 2.0 Hz, 2 H), 7.72 (d, J = 8.5 Hz, 2 H), 7.82 (d,
J = 8.5 Hz, 2 H), 7.98 (d, J = 8.5 Hz, 2 H), 8.04–8.09 (m, 4 H), 8.42 (d, J =
1.0 Hz, 2 H), 8.53 (s, 2 H).
13C NMR (126 MHz, CDCl3):  = 13.99, 22.37, 33.33, 35.81, 110.08,
119.23, 121.28, 122.77, 124.38, 126.42, 127.19, 134.82, 140.85,
151.10.
HRMS (ESI–): m/z [M – H]– calcd. for C14H15O: 199.1123; found:
199.1129.
13C NMR (CDCl3, 125 MHz):  = 13.97, 22.34, 33.63, 35.26, 113.59,
121.84, 122.91, 125.10, 125.14, 125.17, 125.44, 125.51, 126.76,
126.95, 127.64, 127.69, 128.35, 128.47, 128.82, 130.42, 130.53,
131.07, 131.45, 131.49, 133.94, 136.03, 136.94, 137.63, 141.11,
141.41, 150.54 (one sp2 C not located).
3,3′-Cy2VANOL (±)-6m
VANOL derivative (±)-6m was prepared from 3-cyclohexyl-1-naph-
thol 28m (6.64 mL, 29.3 mmol) by Typical Procedure III, with heating
at 165 °C for 36 h. The crude product was purified by column chroma-
tography (silica gel, CH2Cl2/hexanes: 1:3 to 1:1) to give (±)-6m.
IR (thin film): 3520br s, 3052m, 2928s, 1559s, 1456s, 1387s cm–1
.
Yield: 3.360 g (7.460 mmol, 51%); off-white solid; mp 196–198 °C;
Rf = 0.41 (hexanes/EtOAc 8:1).
HRMS (ESI–): m/z [M – H]– calcd for C68H53O2: 901.4046; found:
901.4084.
1H NMR (500 MHz, CDCl3):  = 0.74–1.38 (m, 8 H), 1.52–1.81 (m,
12 H), 2.20 (tt, J = 11.8, 3.3 Hz, 2 H), 5.19 (s, 2 H), 7.42–7.58 (m, 6 H),
7.83 (dt, J = 8.3, 0.8 Hz, 2 H), 8.22 (ddd, J = 8.3, 1.3, 0.6 Hz, 2 H).
13C NMR (126 MHz, CDCl3):  = 26.01, 26.78, 26.81, 33.71, 36.09,
41.42, 112.75, 117.92, 122.44, 122.70, 124.78, 127.11, 127.23, 134.96,
146.15, 149.80.
HRMS (ESI–): m/z [M – H]– calcd. for C32H33O2: 449.2481; found:
449.2519.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

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Y. Guan et al.
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Synthesis
3,3′-Bu2VANOL (±)-6n
Catalytic Asymmetric Aziridination of Benzhydryl Imines with
Ethyl Diazoacetate (Tables 6–8); Typical Procedure for the Prepara-
tion of Aziridine 12a Mediated by a Catalyst Prepared from Ligand
7q (Table 8, entry 10)5
VANOL derivative 6n was prepared from 3-butyl-1-naphthol 29n
(6.822 g, 34.10 mmol) by Typical Procedure III with heating at 165 °C
for 24 h. The crude product was purified by column chromatography
(silica gel, CH2Cl2/hexanes: 1:3 to 1:2) to give (±)-6n.
A 25 mL pear-shaped, single-necked Schlenk flask that had its 14/20
joint replaced with a threaded high vacuum Teflon valve was flame-
dried (with a stir bar in it) and cooled to r.t. under N2 and charged
with 7q (19.0 mg, 0.025 mmol) and triphenylborate (29 mg, 0.10
mmol). The mixture was dissolved in anhydrous toluene (1 mL). After
the addition of H2O (0.45 mL, 0.025 mmol), the Teflon valve was
closed and the flask was heated at 80 °C for 1 h. Toluene was carefully
removed by exposing to high vacuum (0.1 mmHg) by slight cracking
of the Teflon valve. After removal of the solvent, the Teflon valve was
completely opened and the flask was heated to 80 °C under high vac-
uum for 30 min. To the Schlenk flask containing the catalyst were
added imine 8a (136 mg, 0.50 mmol) and anhydrous toluene (1 mL).
The reaction mixture was stirred at r.t. for 5 minutes and then ethyl
diazoacetate (62 L, 0.6 mmol) was added via syringe. The Teflon
valve was closed and the reaction mixture was stirred at r.t. for 24 h.
The mixture was then diluted with hexanes (5 mL) and transferred to
a 25 mL round-bottom flask. Rotary evaporation of the solvent fol-
lowed by exposure to high vacuum (0.5 mmHg) for 30 minutes gave
the crude mixture as an off-white solid. The conversion was deter-
mined from the 1H NMR spectrum of the crude reaction mixture by
integration of the aziridine ring methine protons relative to either the
imine methine proton or the H on the imine carbon. The cis/trans ra-
tio was determined to be >100:1 from the 1H NMR spectrum of the
crude reaction mixture by integration of the ring methine protons for
each aziridine. The cis (J = 6–8 Hz) and the trans (J = 1–3 Hz) coupling
constants were used to differentiate the two isomers. The yields of
the acyclic enamine products were determined to be <1% from the 1H
NMR spectrum of the crude reaction mixture by integration of the N-
H proton of the enamine relative to the aziridine ring methine pro-
tons with the aid of the isolated yield of the cis-aziridine. The crude
product was purified by column chromatography on silica gel (35 mm
× 400 mm, EtOAc/hexanes 1:19) to afford 12a.
Yield: 3.360 g (7.550 mmol, 44%); yellow semisolid; Rf = 0.39 (hex-
anes/EtOAc 8:1).
1H NMR (500 MHz, CDCl3):  = 0.86 (t, J = 7.4 Hz, 6 H), 1.30 (qd, J = 7.3,
2.0 Hz, 4 H), 1.60 (p, J = 7.6 Hz, 4 H), 2.52 (qt, J = 14.8, 7.8 Hz, 4 H),
5.41 (s, 2 H), 7.52–7.59 (m, 4 H), 7.64 (ddd, J = 8.2, 6.8, 1.3 Hz, 2 H),
7.92 (d, J = 8.3 Hz, 2 H), 8.36 (d, J = 8.3 Hz, 2 H).
13C NMR (126 MHz, CDCl3):  = 13.97, 22.62, 32.22, 33.32, 113.42,
120.00, 122.73, 122.80, 124.95, 127.21, 127.29, 134.95, 140.41,
150.20.
HRMS (ESI–): m/z [M – H]– calcd. for C28H29O2: 397.2168; found:
397.2189.
Deracemization of 3,3′-DialkylVANOL Derivatives (Scheme 2); Typ-
ical Procedure VI
(R)-3,3′-Cy2VANOL (R)-6m
To a 100 mL round-bottom flask was added (+)-sparteine (0.81 mL,
3.5 mmol, 3.5 equiv), CuCl (168 g, 1.70 mmol) and MeOH (27 mL) un-
der an atmosphere of air. The reaction mixture was sonicated in a wa-
ter bath for 60 minutes with exposure to air. The flask was then sealed
with a septum and purged with argon, which was introduced by a
needle under the surface for 60 minutes. At the same time, to a 250
mL flame-dried round-bottom flask was added racemic 6m (451 mg,
1.00 mmol) and CH2Cl2 (54 mL). The resulting solution was purged
with argon for 60 minutes under the surface. The green Cu(II)-
sparteine solution was then transferred via cannula to the solution of
racemic 6m under argon and then the combined mixture was soni-
cated for 15 minutes and then allowed to stir at r.t. overnight with an
argon balloon attached to the flask, which was covered with alumi-
num foil. The reaction was quenched by slow addition of NaHCO3 (sat.
aq. 15 mL), H2O (40 mL) and most of the organic solvent was removed
under reduced pressure. The residue was then extracted with CH2Cl2
(30 mL). The combined organic layer was dried over anhydrous
Na2SO4, filtered through Celite and concentrated to dryness. Purifica-
tion of the crude product by column chromatography on silica gel
(CH2Cl2/hexanes 1:2) gave the product (R)-6m.
Yield: 146 mg (0.41 mmol, 82%); white solid; mp 126–127 °C; Rf =
0.13 (1:9 EtOAc/hexanes); 98% ee (HPLC; Chiralcel OD-H column, 222
nm, 90:10 hexane/iPrOH, flow rate: 0.7 mL/min): tR = 4.42 [(2S,3S)-
20
12a; minor], 8.17 [(2R,3R)-12a; major] min; []D = +36.2 (c 1.0,
CH2Cl2) on 98% ee (2R,3R)-12a.
1H NMR (CDCl3, 500 MHz):  = 0.96 (t, J = 7.0 Hz, 3 H), 2.65 (d, J =
7.0 Hz, 1 H), 3.19 (d, J = 7.0 Hz, 1 H), 3.93 (s, 1 H), 3.90–3.94 (m, 2 H),
7.14–7.20 (m, 2 H), 7.20–7.26 (m, 5 H), 7.30–7.34 (m, 2 H), 7.37–7.40
(m, 2 H), 7.46–7.49 (m, 2 H), 7.57–7.60 (m, 2 H).
13C NMR (CDCl3, 125 MHz):  = 13.93, 46.38, 48.03, 60.55, 77.71,
127.19, 127.21, 127.31, 127.40, 127.54, 127.75, 127.78, 128.48,
135.03, 142.38, 142.52, 167.72 (one sp2 C not located).
Yield: 315 mg (0.699 mmol, 70%); off-white foamy solid; mp 196–
198 °C; >99% ee (HPLC analysis; Pirkle D-Phenylglycine column, 98:2
hexane/iPrOH at 254 nm, flow-rate: 1.0 mL/min): tR = 8.69 [(R)-6m;
major], 10.36 [(S)-6m; minor] min.
3,3′-Bu2VANOL (R)-6n
IR (thin film): 3031w, 2982w, 1738s, 1456m, 1204s cm–1
.
Typical Procedure VI was followed with (±)-3,3′-n-Bu2VANOL 6n
(1.568 g, 3.930 mmol). Purification of the crude product by column
chromatography on silica gel (CH2Cl2/hexanes 1:2) gave the product
(R)-6n.
MS: m/z (%) = 357 (0.05) [M]+, 190 (46), 167 (100), 117 (61).
Procedure for Growing Crystals of the Boroxinate/Imine complex
31 (Scheme 3)
Yield: 293 mg (0.735 mmol, 19%); off-yellow foamy semi-solid; 95%
ee (HPLC analysis; Pirkle D-Phenylglycine column, 98:2 hexane/iPrOH
at 254 nm, flow-rate: 1.0 mL/min): tR = 8.73 [(R)-6n; major], 10.37
[(S)-6n; minor] min.
To a flame-dried 25 mL Schlenk flask flushed with argon was added
activated 4Å MS (bead) and 10 mL pentane at least 4 h prior to the
preparation of the catalyst. To a 25 mL flame-dried Schlenk flask
flushed with argon was added (S)-6g (28 mg, 0.05 mmol), BH3·SMe2
(100 L, 0.2 mmol) (2 M in toluene) and phenol (15 mg, 0.15 mmol),
followed by addition of distilled toluene (1.5 mL) and then H2O (1.8
L, 0.1 mmol). The flask was sealed, and then placed in an 85 °C oil
bath. After 1 hour, a vacuum (0.2 mmHg) was applied carefully for 45
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S

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Y. Guan et al.
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Synthesis
minutes while the flask was still heated at 85 °C. The prepared cata-
lyst was allowed to cool to r.t. under argon. At the same time, NMR
tubes (2 to 3 for parallel experiments) were taken from the oven and
immediately capped with either a plastic cap or a sealed cap depend-
ing on the type of the NMR tube. These NMR tubes were then con-
nected to vacuum, flame-dried and cooled under argon. To the
Schlenk flask containing the prepared catalyst flushed with argon was
then added N-MEDAM phenyl imine 30a (20 mg, 0.05 mmol), the Tef-
lon cap was switched with a medium-size rubber septum, followed
by the addition of distilled CH2Cl2 (1.5 mL) through the septum to give
a light-brown solution. To this solution was carefully added dried
pentane until a cloudy suspension appeared (ca. 4–6 mL), to which
was added CH2Cl2 again (0.2 mL). The solution was then transferred to
the prepared NMR tube by syringe (the smaller the diameter of the
needle, the better) in the amounts of 1.5 mL, 2 mL and full for the par-
allel experiments, the empty space in each NMR tube was then filled
with pentane to the top (Note: if a plastic cap was used for the NMR
tube, after transferring, the cap was replaced with a new one). The
NMR tubes were wrapped with parafilm and covered with aluminum
foil, then set for a week or longer to let the crystals grow. These crys-
tals could also be prepared from B(OPh)3 instead of BH3·SMe2 and
phenol. One of these crystals was submitted to X-ray analysis and the
result has been deposited with the Cambridge Crystallographic Data
Centre.
13C NMR (126 MHz, CDCl3):  = 168.06, 156.08, 155.92, 137.99,
137.83, 135.30, 130.65, 130.63, 127.87, 127.81, 127.75, 127.41,
127.25, 77.05, 60.55, 59.62, 59.56, 48.24, 46.28, 29.73, 16.29, 16.22,
14.06.
Funding Information
This work was supported by the National Institute of General Medical
Sciences (GM 094478).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690860.
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References
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this paper. The data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/get-
structures.
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Asymmetric Aziridination of Imine 30a with a Catalyst Prepared
from Ligand (S)-6g (Table 3)
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The reaction was performed in a flame-dried 25 mL Schlenk flask.
The flask was charged with (S)-6g (10 mol%, 0.025 mmol, 14 mg) fol-
lowed by addition of B(OPh)3 (40 mol%, 0.1 mmol, 29 mg) and H2O (10
mol%, 0.025 mmol, 0.45 L). The mixture was dissolved in toluene
(0.0125 M, 2 mL) and heated at 85 °C for 1 hour. The Teflon cap of the
Schlenk flask was opened carefully to remove the solvent, and high
vacuum (1 mmHg) was applied for 30 minutes at 85 °C. To the
Schlenk flask, MEDAM imine 30a (1.0 equiv 0.25 mmol, 97 mg) and
toluene (0.125 M, 2 mL) were added and the resulting mixture was
stirred at r.t. for 10 minutes. The reaction was carried out by addition
of ethyl diazoacetate (1.1 equiv 0.275 mmol, 34 L) and stirring at r.t.
for 24 h. The mixture was diluted with hexane (5 mL) and transferred
to a 50 mL round-bottom flask and the Schlenk flask was rinsed with
CH2Cl2 (6 mL). After the evaporation of the solvent an off-white solid
was obtained as the crude mixture of the reaction. The NMR yield and
conversion were determined based on the 1H NMR spectrum of the
crude reaction mixture by using triphenylmethane as the internal
standard. The conversion and the NMR yield were 99%. The crude
product was purified by using column chromatography on silica gel
with a 90:10 mixture of hexanes and EtOAc to give the pure product.
Yield: 93% isolated yield; off-white solid; 99% ee (HPLC; Chiralcel, OD-H
column, 226 nm 99:1 hexane/iPrOH, flow rate 0.7 mL/min): Rt = 6.47
(minor enantiomer), 9.67 (major enantiomer) min.
1H NMR (500 MHz, CDCl3):  = 7.39 (d, J = 7.4 Hz, 2 H), 7.27–7.16 (m,
5 H), 7.12 (s, 2 H), 3.94 (p, J = 6.5 Hz, 2 H), 3.69 (d, J = 8.3 Hz, 3 H), 3.64
(s, 3 H), 3.13 (d, J = 6.8 Hz, 1 H), 2.58 (d, J = 6.8 Hz, 1 H), 2.27 (s, 6 H),
2.21 (s, 6 H), 1.00 (t, J = 7.0 Hz, 3 H).
(13) Hsung, R. P.; Chidsey, C. E. D.; Sita, L. R. Organometallics 1995,
14, 4808.
(14) Guan, Y.; Ding, Z.; Wulff, W. D. Chem. Eur. J. 2013, 19, 15565.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–S