Friedel-Crafts alkylation with α-bromoarylacetates for the preparation of enantioenriched 2,2-diarylethanols

Article abstract of DOI:10.1039/c9ob00706g

Highly enantioenriched 2,2-diarylethanols can be efficiently synthesized through the Friedel-Crafts alkylation of (hetero)arenes with configurationally labile α-bromoarylacetates. The substitution of highly diastereoenriched α-bromoarylacetates occurs in the presence of AgOTf, and the subsequent reduction affords diverse 2,2-diarylethanols with high yields and enantioselectivities up to 99 : 1 er. In addition, the application of this asymmetric synthetic methodology to the preparation of highly enantioenriched dihydrobenzofuran and indoline derivatives is demonstrated.

Full text of DOI:10.1039/c9ob00706g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C9OB00706G
ARTICLE
Friedel-Crafts Alkylation with -Bromo Arylacetates for the
Preparation of Enantioenriched 2,2-Diarylethanols
Yongtae Kim,a Yun Soo Choi,a Su Kyung Hong,a and Yong Sun Park*a
Received 00th January 20xx,
Accepted 00th January 20xx
Highly enantioenriched 2,2-diarylethanols can be efficiently synthesized through the Friedel-Crafts alkylation of
(hetero)arenes with configurationally labile -bromo arylacetates. The substitution of highly diastereoenriched -bromo
arylacetates occurs in the presence of AgOTf, and the subsequent reduction affords diverse 2,2-diarylethanols with high
yields and enantioselectivities up to 99:1 er. In addition, the application of this asymmetric synthetic methodology to the
preparation of highly enantioenriched dihydrobenzofuran and indoline derivatives is demonstrated.
DOI: 10.1039/x0xx00000x
diastereoenriched
a solid with a diastereomeric ratio (dr) of >99:1 and efficiently
used for the asymmetric synthesis of -substituted arylacetates
under various reaction conditions. These results led us to
examine the possibility that -bromo arylacetate ( R)- might
be activated by Lewis acid and used as a chiral electrophile for
the Friedel-Crafts reaction of (hetero)arene (Ar’-H) as shown in
Figure 1. The stereoselective Friedel–Crafts reaction of
(hetero)arene with chiral alkyl halide is a powerful way to
introduce new chiral functionalities into the (hetero)arene.
-bromo arylacetate (R)-1 was obtained as
Introduction

Diarylmethine stereogenic centers are ubiquitous in many
important bioactive molecules,1 and the synthesis of optical
active gem-diarylalkyl derivatives has been investigated in
numerous studies.2 Asymmetric Friedel-Crafts alkylation has
recently been developed3 and provide a simple and attractive
method for the formation of optically active gem-diarylalkyl
derivatives from various electrophiles.4 Some particularly
effective examples have included the Friedel–Crafts alkylation
of (hetero)arenes with secondary alcohols,4a-c electron-


1
Given the ready availability of optically pure
-bromo
arylacetates by CIDR, this simple substitution could be rather
useful for the asymmetric synthesis of gem-diarylalkyl
deficient olefins,4d-g aldimines,4h-j and optically pure epoxides.4k-
o
Inspired by these works, we began to envision whether
-
derivatives using
a
wide variety of easily available
bromoacetates could be utilized as an electrophile in the
Friedel–Crafts alkylation of arenes. While many methods for
(hetero)arenes under mild conditions.
stereoselective substitution (SN2) of
diverse nucleophiles have been developed by the dynamic
resolution of configurationally labile -bromoacetates, the
-bromoacetates with

subject of stereoselective reactions with arene nucleophiles has
yet to be successfully explored.5,6,7 The Friedel–Crafts reaction
of arene nucleophiles with a secondary alkyl halide for
generating a tertiary carbon center remains an unusual
disconnection in asymmetric organic synthesis. In this paper, we
describe a novel method for the asymmetric synthesis of 2,2-
diarylethanols using the Friedel–Crafts alkylation of
Figure 1. The CIDR of
Friedel-Crafts alkylations
-bromo arylacetates and stereospecific
(hetero)arenes with highly diastereoenriched
-bromo
Results and discussion
In order to obtain highly diastereoenriched product from the
Friedel-Crafts alkylation described in Figure 1, it is important
that the substitution occurs fast with respect to the
arylacetates. The practical utility of this method is
demonstrated through the preparation of highly
enantioenriched dihydrobenzofuran and indoline derivatives.
We recently reported the N-benzoyl L-threonine isopropyl
ester-mediated crystallization induced dynamic resolution
epimerization, so that the epimerization of
arylacetate is minimized upon exposure to Lewis acid. We thus
chose 1,2,5-trimethylpyrrole as strong heteroarene
nucleophile for our initial experiment with -bromo
phenylacetate ( R)-1a. As shown in Table 1, entry 1, no
substitution of ( R)-1a with 1,2,5-trimethylpyrrole occurred
-bromo
(CIDR) of configurationally labile 
-bromo arylacetates.8 Highly
a



a.Department of Chemistry, Konkuk University, Seoul 05029, Korea
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
without Lewis acid catalyst. We next attempted the same
reaction in the presence of some selected Lewis acids. Using
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Journal Name
aluminum chloride (AlCl3), which is the most frequently used 99:1 dr with no loss of optical purity (entry 7).1V1ieIwnArotircdleeOrnlitnoe
Lewis acid in Friedel–Crafts reactions, the reaction in CHCl3 for clarify the information about the configurDaOtIi:o1n0a.1l0l3a9b/iCli9tOyBo0f0(706G
R)-
24 h gave with 56:44 dr and 30% conversion (entry 2) and the 1a in the presence of AgOTf, we carried out the reactions of
unreacted 1a was recovered with significant epimerization (ca. stepwise addition of AgOTf and the nucleophile as shown in
50:50 dr). Therefore, a mild activation of the C-Br bond of the entries 8 and 9, respectively. When ( R)-1a was treated with
-bromoacetate is required as the strongly acidic catalysts may AgOTf for 0.5 h or 1 h prior to the addition of 1,2,5-
promote the epimerization of R)-1a When milder trimethylpyrrole, the product was obtained with 80:20 dr and
conventional catalysts such as FeCl3 and SnCl4 were employed 63:37 dr, respectively. The results clearly indicate that ( R)-1a
in place of AlCl3, the reactions successfully produce with underwent an epimerization process in the presence of AgOTf

2


(

.
2

2
substantially higher drs of 75:25 and 98:2, respectively, albeit prior to the addition of the nucleophile. In addition, the
with low conversions of 44% and 58% after 24 h (entries 3 and nucleophilic substitutions of 1a of 52:48 and 75:25 drs produced
4, respectively). In order to promote the reactivity of (
R)-1a, it
2 with 51:49 and 75:25 dr values, respectively (entries 9 and 10,
is advisable to use a mild and strongly halophilic Lewis acid such respectively). The observed dependency of the product ratios
as silver salts to facilitate bromide abstraction and AgBr on the dr of 1a implies that no dynamic kinetic resolution of
precipitation.9 Using Ag2O as a Lewis acid produced the configurationally labile 1a is operating in the nucleophilic
substitution product
2 with 68% conversion and 95:5 dr (entry substitution.
5). Silver trifluoroacetate (AgO2CCF3) and silver triflate (AgOTf)
gave the substitution with high conversions and drs as shown in Table 2. Alkylations of selected (hetero)arenes with (
entries 6 and 7, respectively. AgOTf was found to be the most
R)-1a
.
efficient Lewis acid for catalyzing the stereoselective
substitution reaction of (
proceed to completion within 5 min. and ultimately produced
R)- of 99:1 dr with complete inversion of the
R)-1a with 1,2,5-trimethylpyrrole to
(

2
stereochemistry.10 None of other solvents explored gave better
selectivities than CHCl3 and the reactions in DMF and CH3CN are
very slow.
Time to
Entry Ar’-H
Conditionsa Product
Drc
Completionb
Table 1. Alkylation of 1,2,5-trimethylpyrrole with (R)-1a.
1
2
A
A
3
0.1 h
98:2
93:7
4
5
0.5 h
1 h
3
4
5
A
A
B
80:20
60:40
99:1
Entrya
Conditions
Conversionb Dr of 2b
6 (86:14) 3 h
1
no catalyst
-
-
4
5
0.1 h
2
AlCl3
30
44
58
68
99
99
99
99
99
99
56:44
75:25
98:2
95:5
97:3
99:1
80:20
63:37
51:49
75:25
3
FeCl3
6
B
0.5 h
98:2
4
SnCl4
5
Ag2O
7
8
B
C
6 (92:8) 2 h
6 (90:10) 24 h
77:23
86:14
6
AgO2CCF3
7
AgOTf
8
AgOTf (0.5 h); Nucc
AgOTf (1 h); Nucc
AgOTf with 1a of 52:48 dr
AgOTf with 1a of 75:25 dr
(a) Conditions A: The reactions were carried out with 5.0 equiv of arene
in CHCl3 (0.2 M) at room temp.; Conditions B: neat (20 equiv of arene)
at room temp.; Conditions C: neat at 0°C. (b) The time to completion
9
1
10
11
was determined by H NMR of the reaction mixture. (c) The dr values
1
were determined by H NMR of the reaction mixture and confirmed by
chiral HPLC analysis after the removal of auxiliary.
(a) All the reactions were carried out with 5.0 equiv of pyrrole and 1.0
equiv of Lewis acid in CHCl3 (0.2 M) at rt for 24 h. (b) The conversions
after 24 h and the dr values were determined by 1H NMR of the reaction
mixture. (c) Stepwise addition of AgOTf and nucleophile after the time
shown in parentheses.
In order to investigate the influence of nucleophilicity of
(hetero)arenes on stereoselectivity in the substitutions of (R)-
1a, a series of (hetero)arene nucleophiles with varying
nucleophilicities was selected and is presented in Table 2. The
four nucleophiles that are, less reactive than 1,2,5-
trimethylpyrrole, are selected to represent a range in reactivity
spanning from the most reactive, 1-methylindole, to the least
In the AgOTf-catalyzed nucleophilic substitution of (
with 1,2,5-trimethylpyrrole nucleophiles, the substitution rate
may be sufficiently fast relative to the epimerization of ( R)-1a
R)- of
R)-1a

,
thereby giving the highly diastereoenriched product (

2
2 | J. Name., 2012, 00, 1-3
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reactive, toluene.12 When (αR)-1a was treated with 1-
methylindole in CHCl3 (0.2 M) at room temp. in the presence of
AgOTf, the fast substitution successfully gave Friedel-Crafts
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DOI: 10.1039/C9OB00706G
alkylation product (αR)-
However, when 2,5-dimethylfuran was used as the nucleophile
in the presence of AgOTf, the substitution produced (αR)- with
93:7 dr (Table 1, entry 2). The markedly diminished dr of
indicates that the substitution with 2,5-dimethylfuran is not
sufficiently fast relative to the rate of epimerization of ( R)-1a
3 with 98:2 dr (Table 2, entry 1).
4
4

.
Additionally, in the slower substitution reaction with 1,3-
dimethoxybenzene (1 h for completion), the epimerization of
(R)-1a is more likely to proceed under acidic conditions, which
results in a much lower dr value of 80:20 (entry 3). As shown in
entry 4, the reaction with the least reactive toluene proceeded
most slowly (3 h for completion) and gave para-substituted
product with 60:40 dr along with ortho-substituted product
(86:14 regioisomeric ratio). Consistent with the previously
reported nucleophilicity scale,12 the competitive epimerization
gave an erosion of product dr values in every case of reduced
nucleophilicity (entries 2-4). In addition, when we carried out a
competition experiment to compare the rates of substitution of
2,5-dimethylfuran, 1,3-dimethoxybenzene and toluene, the
reaction gave a mixture of
4, 5, and 6 in a ratio of 9:5:1,
respectively. From these results, it can clearly be seen that the
stereoselectivity significantly depends on the reactivity of the
(hetero)arene nucleophiles.13
In order to increase the rate of substitution with respect to
the epimerization, we explored the utility of neat conditions
with excess amounts of nucleophile (20 equiv). As shown in
entries 5 and 6, the neat reactions of (αR)-1a with the
nucleophiles in the presence of AgOTf are completed faster
than the solution reaction shown in entries 2 and 3, respectively.
The reactions under neat conditions afforded (αR)-4 and (αR)-5
with substantially better drs of 99:1 and 98:2, respectively.
However, the reaction of the least reactive toluene produced
(αR)-
6 with a slightly improved dr of 77:23 under neat
conditions (entry 7). Lowering the reaction temperature to 0
°
C
produced (αR)-6 with 86:14 dr, while the reaction was very slow
(entry 8).
Chiral 2,2-diarylethanols are important intermediates in the
organic syntheses of many biologically active compounds.2
Highly enantioenriched 2,2-diarylethanols can be obtained
using the Friedel-Crafts alkylation method developed in Tables Scheme 1. Highly enantioenriched 2,2-diarylethanols
1 and 2 along with the following reduction to remove the chiral
auxiliary. In order to evaluate the scope of the reactions leading crude reaction mixture to the reduction condition afforded 2,2-
to highly enantioenriched diarylethanols, we examined the diarylethanols in comparable overall yields ranging from 43% to
Friedel-Crafts reactions of 1a-c with five selected heteroarenes 90%. The highly regioselective substitutions of (αR)-1a at the 3-
and five selected anisole derivatives and the results are position of 1,2,5-trimethylpyrrole, 3-position of 1-methylindole,
summarized in Scheme 1. The Friedel-Crafts reactions 3-position of 1,5-dimethylfuran, 2-position of 1-methylpyrrole
proceeded efficiently in the presence of AgOTf under neat and 3-position of indole and following reduction produced 2,2-
conditions using 10 equiv of (hetero)arene and the subsequent diarylethanols
7, 8, 9, 10 and 11, respectively with 99:1 er. In
reduction with LiAlH4 afforded 2,2-diarylethanols 20 with high addition, the highly regioselective Friedel-Crafts reactions of
7
-
enantioselectivities up to an enantiomeric ratio (er) of 99:1. We (αR)-1a with 1,3,5-trimethoxybenzene, 1,3-dimethoxybenzene,
investigated the feasibility of a procedure that avoids the 1,2-dimethoxybenzene, and 2-methylanisole under neat
purification of the acetate product and uses the crude material conditions using 10 equiv of (hetero)arene and the subsequent
in the subsequent reduction step. After the extractive workup reduction produced 2,2-diarylethanols 12
, 13, 14 and 15,
of the reaction mixture of Friedel-Crafts reaction, subjecting the respectively with >98:2 er. In the substitution with the most
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weakly nucleophilic anisole, the competitive epimerization gave and a regioisomeric para-substituted phenol as a minor product
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a slight reduction of enantioselectivity to afford 16 with 96:4 er. in a ratio of 2:1. When major product 24 DwOaIs: 1t0re.1a03te9/dCw9OitBh00D7E0A6DG
The same two-step reactions of p-bromophenylacetate 1b and and PPh3, 6-methoxy-3-phenyl-dihydrobenzofuran 30 was
p-chloro phenylacetate 1c with 1-methylindole and 1,2,5- produced in 61% yield with 99:1 er.
trimethylpyrrole afforded 2,2-diarylethanols 17-20 with 99:1 er
in overall yields of 88−53%.
We also attempted to synthesize 3-aryl substituted
indolines from N-protected aniline derivatives using similar
protocols. In the Friedel-Crafts reaction of N-acyl protected 3,5-
dimethoxyaniline with (αR)-1a, we observed that only ortho-C-
alkylation product was afforded successfully with 99:1 dr and
that no other regioisomer was detected. However, the
reduction of the substitution product initially proved to be
problematic. Using LiAlH4 in THF at room temperature provided
2,2-diarylethanol in low yields of 5-10%. The other procedures
including the use of DIBAL or LiBH4 did not proceed properly.
We found that the use of NaBH4 in methanol cleanly provided
2,2-diarylethanol in high yield, but with a somewhat reduced er
of 90:10 after the reduction. In order to circumvent the low
yield and low er of the 2,2-diarylethanol, we examined N-mesyl-
protected 3,5-dimethoxyaniline as a nucleophile under the
same conditions. Pleasingly, the substitution reactions of 1a and
1c with N-mesyl-3,5-dimethoxyaniline and the subsequent
reduction by LiAlH4 produced ortho-substituted anilines 25 and
26, respectively with a high er of 99:1. When they were treated
with DEAD and PPh3, 3-aryl substituted indolines 31 and 32
were successfully produced in yields of 52 and 58% with 97:3 er
and 98:2 er, respectively.
Experimental
General Methods: All reactions were performed in oven-dried
glassware under nitrogen atmosphere. All chemicals were obtained
from commercial sources and were used as received. Analytical thin
layer chromatography (TLC) was performed on silica gel plates with
QF-254 indicator and TLC visualization was carried out with UV-light.
Flash column chromatography was performed with 230–400 mesh
silica gel. 1H and 13C NMR spectra were acquired on Bruker (400 MHz
1H, 100.6 MHz 13C) or Jeol (500 MHz 1H, 125 MHz 13C) spectrometer
using chloroform-d (CDCl3) as the internal standard. Chemical shifts
(δ) are reported in ppm relative to chloroform-d (7.26 ppm 1H, 77.07
ppm 13C). Multiplicities are indicated by: s (singlet), d (doublet), t
(triplet), q (quartet) and br (broad). Coupling constants (J) are
reported in Hz. HRMS spectra were measured on a JEOL JMS-700 by
using FAB method.
Scheme
2. Preparation of highly enantioenriched 3-aryl
substituted 2,3-dihydrobenzofuran and indoline derivatives.
Furthermore, to extend the applicability of the present
methodology, we explored the asymmetric synthesis of 3-aryl
substituted dihydrobenzofuran and indoline derivatives, the
core structures present in
pharmaceuticals and natural products.14 Our approach to these
heterocycles is based on the Friedel-Crafts alkylation at the
a
number of important
ortho position of phenol or aniline derivatives with
-bromo
arylacetates 1a-c, followed by reduction and cyclodehydration
as shown in Scheme 2. With the 3,5-dimethoxyphenol
nucleophile, the C-alkylation at the ortho position to the
hydroxy group was maximized, and the following reduction
provided ortho-substituted phenol 21 with 97:3 er in 61%
General Procedure for the asymmetric preparation of 2,2-
diarylacetates 2-6 (conditions B): To a solution of L-threonine-
derived
-bromo ester 1a (1.0 equiv, >99:1 dr) at room
overall yield without any isomers derived from O-alkylation and temperature were added a nucleophile (20 equiv) and AgOTf
(1.0 equiv). After the mixture was stirred at rt for the specified
time (Table 2), the resulting mixture was washed with saturated
NaHCO3 solution, dried with anhydrous MgSO4, filtered,
para-C-alkylation. When the cyclodehydration of 21 proceeded
by means of an intramolecular Mitsunobu protocol (DEAD,
PPh3), 3-phenyl substituted dihydrobenzofuran 27 was
produced in 81% yield without racemization. The three-step
synthetic method was readily extended to p-bromo and p-
chloro substituted arylacetates 1b and 1c to give
dihydrobenzofurans 28 and 29, respectively with 97:3 er in
excellent yields. In addition, we observed that the substitution
of 1a with meta-methoxyphenol and following reduction
produced ortho-substituted phenol 24 in 45% yield with 99:1 er
concentrated and purified by column chromatography to afford
1
a diarylacetate (
2
-
6
). The dr of 2-6 was determined by the H
NMR integration of the hydrogens of the two diastereomers.
N-Benzoyl-O-[α-(1,2,5-trimethyl-1H-pyrrol-3-yl)phenylacetyl]-
L-threonine Isopropyl Ester (2) A yellow oil was obtained in 90%
yield with 99:1 dr from 1a. 1H NMR (CDCl3, 400 MHz) 7.66-7.20
(m, 10H), 6.55 (d, J = 9.2 Hz, 1H), 5.83 (s, 1H), 5.56-5.50 (m, 1H),
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4.96-4.87 (m, 2H), 4.85 (s, 1H), 3.29 (s, 3H), 2.11 (s, 3H), 2.07 (s, THF (0.5 M) was added the solution of LiAlH4 (1.0 M in THF, 3
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DOI: 10.1039/C9OB00706G
3H), 1.33 (d, J = 6.4 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.15 (d, J = equiv) at 0˚C, and the reaction mixture was stirred at room
6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 172.1, 169.2, 167.4, 139.8, temperature for 2 h. The reaction was quenched with saturated
133.8, 131.8, 128.6, 128.4, 128.3, 127.2, 127.1, 126.8, 124.9, NH4Cl solution and the aqueous layer was extracted with EtOAc.
114.6, 105.3, 71.1, 69.9, 56.2, 49.6, 30.2, 21.8, 21.5, 17.5, 12.5, The combined organic extracts were dried with anhydrous
10.2; HRMS: calcd. for C29H35N2O5 [M++1] 491.2546; found MgSO4, filtered and concentrated under reduced pressure.
491.2548.
Chromatographic separation on silica gel afforded a highly
enantioenriched a 2,2-diarylethanol ( 26). The ers of 26 were
N-Benzoyl-O-[α-(1-methyl-1H-indol-3-yl)phenylacetyl]-L-
7
-
7-
threonine Isopropyl Ester (3) A yellow oil was obtained in 92% determined by CSP-HPLC.
yield with 98:2 dr from 1a. 1H NMR (CDCl3, 400 MHz) 7.47-6.98 (R)-2-Phenyl-2-(1,2,5-trimethyl-1H-pyrrol-3-yl)ethanol (7)
(m, 15H), 6.54 (d, J = 9.2 Hz, 1H), 5.62-5.56 (m, 1H), 5.56 (s, 1H), yellow oil was obtained in 54% overall yield from 1a. The
4.98-4.91 (m, 2H), 3.67 (s, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.20 (d, J spectral data of were identical to those of the authentic
A
7
= 6.0 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) material reported previously.4n 1H NMR (CDCl3, 400 MHz) 7.27-
171.7, 169.3, 167.5, 138.4, 137.1, 133.6, 131.9, 128.6, 128.4, 7.09 (m, 5H), 5.81 (s, 1H), 4.06-4.03 (m, 1H), 3.97-3.92 (m, 2H),
128.0, 127.3, 127.2, 127.0, 122.0, 119.3, 111.7, 109.4, 71.7, 70.0, 3.33 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H), 1.72 (br, 1H); 13C NMR
56.1, 49.2, 32.8, 21.8, 21.6, 17.3; HRMS: calcd. for C31H33N2O5 (CDCl3, 100 MHz) 143.1, 128.5, 128.0, 127.5, 126.3, 125.2, 117.0,
[M++1] 513.2389; found 513.2389.
N-Benzoyl-O-[α-(2,5-dimethylfuran-3-yl)phenylacetyl]-L-
66.9, 45.9, 30.3, 12.6, 10.2; Chiral HPLC: >99:1 er, tR (R)-major
enantiomer, 29.9 min; tR (S)-minor enantiomer, 33.7 min;
threonine Isopropyl Ester (4) A yellow oil was obtained in 89% (Chiralcel OD column; 3% 2-propanol in hexane; 0.5 mL/min).
yield with 99:1 dr from 1a. 1H NMR (CDCl3, 400 MHz) 7.69-7.24 (R)-2-(1-Methyl-1H-indol-3-yl)-2-phenylethanol (8) A yellow oil
(m, 15H), 6.58 (d, J = 9.2 Hz, 1H), 6.01 (s, 1H), 5.57-5.51 (m, 1H), was obtained in 88% overall yield from 1a. The spectral data of
4.99-4.92 (m, 2H), 4.75 (s, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 1.33 (d,
8 were identical to those of the authentic material reported
J = 6.4 Hz, 3H), 1.24 (d, J = 6.0 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H); previously.15a,4n,4k 1H NMR (CDCl3, 400 MHz) 7.46-7.18 (m, 8H),
13C NMR (CDCl3, 100 MHz) 171.2, 169.2, 167.5, 149.8, 146.8, 7.05-7.02 (m, 1H), 6.94 (s, 1H), 4.48-4.45 (m, 1H), 4.23-4.11 (m,
138.4, 133.7, 131.9, 128.7, 128.0, 127.2, 127.1, 116.7, 106.9, 2H), 3.74 (s, 3H); 13C NMR (CDCl3, 100 MHz) 141.8, 137.2, 128.7,
71.7, 70.0, 56.0, 48.2, 21.8, 21.4, 17.3, 13.5, 11.6; HRMS: calcd. 128.3, 127.5, 126.7, 121.9, 119.5, 119.1, 114.4, 109.3, 66.5, 45.6,
for C28H32NO6 [M++1] 478.2230; found 478.2231.
32.8; [

]20 = +1.2° (c = 0.021, CHCl3); Chiral HPLC: 97:3 er, tR (R)-
D
N-Benzoyl-O-[α-(2,4-dimethoxylphenyl)phenylacetyl]-L-
major enantiomer, 36.4 min; tR (S)-minor enantiomer, 19.6 min;
threonine Isopropyl Ester (5) A yellow oil was obtained in 96% (Chiralcel OD column; 20% 2-propanol in hexane; 0.5 mL/min).
yield with 98:2 dr from 1a. 1H NMR (CDCl3, 500 MHz) 7.59-7.25 (R)-2-(2,5-Dimethylfuran-3-yl)-2-phenylethanol (9) A yellow oil
(m, 10H), 6.91 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 9.2 Hz, 1H), 6.45- was obtained in 64% overall yield from 1a. 1H NMR (CDCl3, 400
6.39 (m, 2H), 5.59-5.45 (m, 1H), 5.24 (s, 1H), 5.05-4.89 (m, 2H), MHz) 7.33-7.20 (m, 5H), 5.92 (s, 1H), 4.00-3.90 (m, 3H), 2.23 (s,
3.75 (s, 3H), 3.74 (s, 3H), 1.30 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.3 3H), 2.18 (s, 3H), 1.56 (br, 1H); 13C NMR (CDCl3, 100 MHz) 150.0,
Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H); 13C NMR (CDCl3, 125 MHz) 171.7, 147.0, 141.4, 128.7, 127.9, 126.7, 118.9, 105.5, 66.3, 44.6, 13.6,
169.3, 167.5, 160.3, 157.9, 137.9, 131.9, 129.8, 129.1, 128.7, 11.7; Chiral HPLC: 99:1 er, tR (R)-major enantiomer, 29.4 min; tR
128.6, 127.3, 127.2, 120.1, 104.1, 98.6, 71.4, 69.9, 56.2, 55.5, (S)-minor enantiomer, 39.8 min; (Chiralcel OJ-H column; 10% 2-
55.4, 50.9, 21.8, 21.7, 17.3; HRMS: calcd. for C30H34NO7 [M++1] propanol in hexane; 0.5 mL/min); HRMS: calcd. for C14H17O2 [M+
520.2335; found 520.2336.
+ 1] 217.1229; found 217.1228.
N-Benzoyl-O-[α-(4-methylphenyl)phenylacetyl]-L-threonine
(R)-2-Phenyl-2-(1-methyl-1H-pyrrol-2-yl)ethanol
(10)
A
Isopropyl Ester (6) A mixture of inseparable two regioisomers colorless oil was obtained in 87% overall yield from 1a. The
(90:10) was obtained in 85% yield from 1a. 1H NMR (CDCl3, 500 spectral data of 10 were identical to those of the authentic
MHz, major regioisomer) 7.68-7.11 (m, 14H), 6.55 (d, J = 9.2 Hz, material reported previously.15b,4n 1H NMR (CDCl3, 400 MHz)
1H), 5.61-5.59 (m, 1H), 4.98-4.89 (m, 3H), 2.31 (s, 3H), 1.35 (d, J 7.31-7.14 (m, 5H), 6.59-6.58 (m, 1H), 6.17-6.14 (m, 2H), 4.19-
= 6.3 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H); 13
C
4.15 (m, 1H), 4.11-4.06 (m, 1H), 3.97-3.91 (m, 1H), 3.32 (s, 3H),
NMR (CDCl3, 125 MHz) 171.4, 169.3, 167.6, 138.6, 137.1, 135.5, 1.85 (br, 1H); 13C NMR (CDCl3, 100 MHz) 140.2, 131.6, 128.8,
133.7, 131.9, 129.0, 129.4, 128.7, 128.6, 128.5, 128.0, 127.4, 128.3, 127.0, 122.5, 106.8, 105.5, 66.4, 46.5, 33.8; Chiral HPLC:
127.3, 71.7, 70.1, 57.0, 56.1, 21.8, 21.6, 21.2, 17.3; HRMS: calcd. 99:1 er, tR (R)-major enantiomer, 26.3 min; tR (S)-minor
for C29H32NO5 [M++1] 474.2280; found 474.2281.
General Procedure for the asymmetric preparation of 2,2- hexane; 0.5 mL/min).
diarylethanols 7-26: To a solution of L-threonine-derived (R)-2-(1H-indol-3-yl)-2-phenylethanol (11) A colorless oil was
enantiomer, 19.2 min; (Chiralcel OD column; 10% 2-propanol in
-
bromo ester 1a-c (1.0 equiv, >99:1 dr) at room temperature obtained in 43% overall yield from 1a. The spectral data of 11
were added a nucleophile (10 equiv) and AgOTf (1.0 equiv). (if were identical to those of the authentic material reported
needed for solubility reason, we used least possible amount of previously.15a,4n,4k 1H NMR (CDCl3, 500 MHz) 8.09 (br, 1H), 7.46-
solvent, CHCl3.) After the mixture was stirred at rt for 0.5 h, the 7.03 (m, 9H), 4.49 (t, J = 6.9 Hz, 1H), 4.25 (dd, J = 6.9 and 10.9
resulting mixture was washed with saturated NaHCO3 solution, Hz, 1H), 4.25 (dd, J = 7.2 and 10.9 Hz, 1H), 1.67 (br, 1H); 13C NMR
dried with anhydrous MgSO4, filtered, and concentrated. To a (CDCl3, 125 MHz) 141.7, 136.6, 128.7, 128.4, 127.1, 126.9, 122.4,
solution of 2,2-diarylacetate (crude material after work-up) in 122.0, 119.7, 119.5, 116.1, 111.3, 66.5, 45.7; Chiral HPLC: 99:1
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er, tR (R)-major enantiomer, 71.4 min; tR (S)-minor enantiomer, 7.02 (m, 8H), 6.93 (s, 1H), 4.43-4.40 (m, 1H), 4.19-V4ie.1w1Art(imcle,O2nHlin)e,
]20 = +10.3° (c = 0.010, CHCl3); (Chiralcel OD column; 3.76 (s, 3H), 1.61 (br, 1H); C NMR (CDCl3, 100 MHz) 141.0,
13
DOI: 10.1039/C9OB00706G
60.2 min; [

D
10% 2-propanol in hexane; 0.5 mL/min).
137.3, 131.7, 130.1, 127.2, 126.8, 122.0, 120.5, 119.3, 119.2,
(R)-2-(2,4,6-Trimethoxyphenyl)-2-phenylethanol
(12)
A
113.9, 109.4, 66.2, 45.0, 32.8; Chiral HPLC: 99:1 er, tR (R)-major
colorless oil was obtained in 63% overall yield from 1a. The enantiomer, 33.2 min; tR (S)-minor enantiomer, 20.3 min;
spectral data of 12 were identical to those of the authentic (Chiralcel OD column; 20% 2-propanol in hexane; 0.5 mL/min).
material reported previously.15c 1H NMR (CDCl3, 500 MHz) 7.29- (R)-2-(4-Bromophenyl)-2-(1,2,5-trimethyl-1H-pyrrol-3-
7.11 (m, 5H), 6.14 (s, 2H), 4.82-4.79 (m, 1H), 4.29-4.27 (m, 2H), yl)ethanol (18) A yellow oil was obtained in 53% overall yield
3.79 (s, 3H), 3.73 (s, 6H), 1.68 (br, 1H); 13C NMR (CDCl3, 125 MHz) from 1b. 1H NMR (CDCl3, 400 MHz) 7.39 (d, J = 8.4 Hz, 2H), 7.15
160.2, 159.6, 142.6, 128.1, 128.0, 125.8, 110.8, 91.5, 65.0, 55.8, (d, J = 8.4 Hz, 2H), 5.77 (s, 1H), 4.03-3.91 (m, 3H), 3.35 (s, 3H),
55.4, 43.4; [

]20 = +11.5° (c = 0.011, CHCl3); Chiral HPLC: 98:2 er, 2.19 (s, 3H), 2.09 (s, 3H), 1.62 (br, 1H); 13C NMR (CDCl3, 100 MHz)
D
tR (R)-major enantiomer, 30.7 min; tR (S)-minor enantiomer, 142.2, 131.5, 129.8, 127.7, 125.3, 120.0, 103.4, 66.6, 45.3, 30.2,
26.5 min; (Chiralcel OD column; 10% 2-propanol in hexane; 0.5 12.5, 10.2; Chiral HPLC: >99:1 er, tR (R)-major enantiomer, 36.1
mL/min).
min; tR (S)-minor enantiomer, 43.0 min; (Chiralcel OD column;
(R)-2-(2,4-Dimethoxyphenyl)-2-phenylethanol (13) A yellow oil 3% 2-propanol in hexane; 0.5 mL/min); HRMS: calcd. for
was obtained in 75% overall yield from 1a. 1H NMR (CDCl3, 500 C15H19BrNO [M++1] 308.0650; found 308.0653.
MHz) 7.30-7.17 (m, 5H), 7.08-7.06 (m, 1H), 6.47-6.45 (m, 2H), (R)-2-(4-Chlorophenyl)-2-(1-methyl-1H-indol-3-yl)ethanol (19)
4.59-4.56 (m, 1H), 4.15-4.08 (m, 2H), 3.75 (s, 6H), 1.66 (br, 1H); A colorless oil was obtained in 87% overall yield from 1c. The
13C NMR (CDCl3, 125 MHz) 159.7, 158.5, 141.8, 128.8, 128.5, spectral data of 19 were identical to those of the authentic
126.5, 122.3, 104.3, 99.0, 65.5, 55.6, 55.4, 46.1; Chiral HPLC: material reported previously.15d 1H NMR (CDCl3, 400 MHz) 7.40-
98:2 er, tR (R)-major enantiomer, 38.1 min; tR (S)-minor 7.01 (m, 8H), 6.92 (s, 1H), 4.43-4.39 (m, 1H), 4.17-4.08 (m, 2H),
enantiomer, 20.9 min; (Chiralcel OD column; 10% 2-propanol in 3.74 (s, 3H), 1.70 (br, 1H); 13C NMR (CDCl3, 100 MHz) 140.5,
hexane; 0.5 mL/min); HRMS: calcd. for C16H19O3 [M++1] 137.3, 132.4, 129.7, 128.7, 127.3, 126.7, 122.0, 119.4, 119.2,
259.1334; found 259.1333.
114.0, 109.4, 66.2, 45.0, 32.8; Chiral HPLC: 99:1 er, tR (R)-major
(R)-2-(3,4-Dimethoxyphenyl)-2-phenylethanol (14)
A
pale enantiomer, 61.9 min; tR (S)-minor enantiomer, 37.8 min;
1
yellow oil was obtained in 62% overall yield from 1a. H NMR (Chiralcel OD column; 10% 2-propanol in hexane; 0.5 mL/min).
(CDCl3, 500 MHz) 7.31-7.22 (m, 5H), 6.83-6.76 (m, 3H), 4.17-4.09 (R)-2-(4-Chlorophenyl)-2-(1,2,5-trimethyl-1H-pyrrol-3-
(m, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 1.63 (br, 1H); 13C NMR (CDCl3, yl)ethanol (20) A pale yellow oil was obtained in 68% overall
125 MHz) 149.2, 148.0, 141.7, 134.0, 128.8, 128.3, 126.9, 120.2, yield from 1c. 1H NMR (CDCl3, 400 MHz) 7.24-7.19 (m, 4H), 5.77
112.0, 111.4, 66.3, 56.0, 55.9, 53.3; Chiral HPLC: 99:1 er, tR (R)- (s, 1H), 4.04-3.90 (m, 3H), 3.34 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H),
major enantiomer, 57.9 min; tR (S)-minor enantiomer, 42.0 min; 1.71 (br, 1H); 13C NMR (CDCl3, 100 MHz) 141.7, 131.9, 129.4,
(Chiralcel OD column; 10% 2-propanol in hexane; 0.5 mL/min); 128.6, 127.7, 125.3, 116.5, 103.4, 66.7, 45.2, 30.2, 12.5, 10.2;
HRMS: calcd. for C16H19O3 [M++1] 259.1334; found 259.1334.
Chiral HPLC: >99:1 er, tR (R)-major enantiomer, 33.6 min; tR (S)-
(R)-2-(4-Methoxy-3-methylphenyl)-2-phenylethanol (15)
yellow oil was obtained in 50% overall yield from 1a. H NMR propanol in hexane; 0.5 mL/min); HRMS: calcd. for C15H19ClNO
(CDCl3, 500 MHz) 7.33-7.21 (m, 5H), 7.11-7.03 (m, 2H), 6.82-6.79 [M++1] 264.1155; found 264.1155.
A
minor enantiomer, 36.2 min; (Chiralcel OD column; 3% 2-
1
(m, 1H), 4.18-4.09 (m, 3H), 3.80 (s, 3H), 2.22 (s, 3H), 1.65 (br, (R)-2-(2-Hydroxy-4,6-dimethoxyphenyl)-2-phenylethanol (21)
1H); 13C NMR (CDCl3, 125 MHz) 158.1, 142.0, 133.1, 130.8, 128.8, A yellow oil was obtained in 61% overall yield from 1a. The
128.3, 126.8, 126.6, 126.5, 110.2, 66.4, 55.4, 53.0, 16.5; Chiral spectral data of 21 were identical to those of the authentic
HPLC: 99:1 er, tR (R)-major enantiomer, 104.2 min; tR (S)-minor material reported previously.15
enantiomer, 88.2 min; (Chiralcel OJ-H column; 5% 2-propanol in e 1H NMR (CDCl3, 400 MHz) 7.23-7.11 (m, 5H), 6.09 (d, J = 2.4 Hz,
hexane; 0.5 mL/min); HRMS: calcd. for C16H19O2 [M++1] 1H), 6.04 (d, J = 2.4 Hz, 1H), 4.80 (dd, J = 2.8 and 4.8 Hz, 1H),
243.1385; found 243.1383.
4.33 (dd, J = 5.2 and 11.2 Hz, 1H), 4.05 (dd, J = 2.8 and 10.8 Hz,
(R)-2-(4-Methoxyphenyl)-2-phenylethanol (16) A colorless oil 1H), 3.69 (s, 3H), 3.64 (s, 3H); 13C NMR (CDCl3, 100 MHz) 160.1,
was obtained in 90% overall yield from 1a. The spectral data of 159.1, 157.0, 140.8, 128.5, 128.1, 126.3, 109.2, 95.0, 91.4, 65.7,
16 were identical to those of the authentic material reported 55.9, 55.3, 41.7; Chiral HPLC: 97:3 er, tR (R)-major enantiomer,
previously.15c 1H NMR (CDCl3, 500 MHz) 7.32-7.17 (m, 7H), 6.86 38.1 min; tR (S)-minor enantiomer, 32.6 min; (Chiralcel OD
(d, J = 6.8 Hz, 2H), 4.16-4.12 (m, 3H), 3.78 (s, 3H), 1.51 (br, 1H); column; 10% 2-propanol in hexane; 0.5 mL/min).
13C NMR (CDCl3, 125 MHz) 158.5, 141.8, 133.5, 129.4, 128.8, (R)-2-(4-Chlorophenyl)-2-(2-hydroxy-4,6-
128.6, 128.5, 128.3, 126.8, 114.2, 66.3, 55.4, 52.9; Chiral HPLC: dimethoxyphenyl)ethanol (22) A brownish yellow oil was
96:4 er, tR (R)-major enantiomer, 86.5 min; tR (S)-minor obtained in 47% overall yield from 1b. 1H NMR (CDCl3, 400 MHz)
enantiomer, 83.2 min; (Chiralcel OJ-H column; 10% 2-propanol 7.23-7.17 (m, 4H), 6.10 (d, J = 2.4 Hz, 1H), 6.06 (d, J = 2.4 Hz, 1H),
in hexane; 0.5 mL/min).
4.80 (dd, J = 3.2 and 4.4 Hz, 1H), 4.38 (dd, J = 4.8 and 10.8 Hz,
(R)-2-(4-Bromophenyl)-2-(1-methyl-1H-indol-3-yl)ethanol (17) 1H), 4.10 (dd, J = 3.2 and 11.2 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H);
A colorless oil was obtained in 88% overall yield from 1b. The 13C NMR (CDCl3, 100 MHz)160.2, 158.9, 156.9, 139.2, 132.0,
spectral data of 17 were identical to those of the authentic 129.4, 128.5, 108.7, 95.0, 91.3, 65.6, 55.8, 55.3, 41.0; Chiral
material reported previously.15a 1H NMR (CDCl3, 400 MHz) 7.42- HPLC: 97:3 er, tR (R)-major enantiomer, 32.0 min; tR (S)-minor
6 | J. Name., 2012, 00, 1-3
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enantiomer, 29.3 min; (Chiralcel OD column; 10% 2-propanol in General procedure for the asymmetric preparation of
View Article Online
hexane; 0.5 mL/min); HRMS: calcd. for C16H18ClO4 [M++1] dihydrobenzofurans 27-30 and indolines 31-32: To a solution
DOI: 10.1039/C9OB00706G
309.0894; found 309.0893.
(R)-2-(4-Bromophenyl)-2-(2-hydroxy-4,6-
of 2,2-diarylethanol in CH3CN (0.5 M) was added PPh3 (2.5 equiv)
and DEAD (2.5 equiv) and the mixture was stirred at room
dimethoxyphenyl)ethanol (23) A brownish yellow oil was temperature for 2 h. After the solvent was removed in vacuo,
obtained in 50% overall yield from 1c. 1H NMR (CDCl3, 400 MHz) chromatographic separation of the crude mixture on silica gel
7.40 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.14 (m, 2H), 4.82 (EtOAc/hexanes solvents) afforded a cyclized protduct.
(br, 1H), 4.38 (dd, J = 5.2 and 10.8 Hz, 1H), 4.14 (dd, J = 2.8 and (R)-4,6-Dimethoxy-3-phenyl-2,3-dihydrobenzofuran (27)
A
10.4 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H); 13C NMR (CDCl3, 100 MHz) colorless oil was obtained in 81% overall yield from 21. The
160.1, 159.2, 156.6, 140.4, 131.3, 130.0, 120.0, 109.0, 95.1, 91.5, spectral data of 27 were identical to those of the authentic
65.2, 55.9, 55.3, 41.4; Chiral HPLC: 99:1 er, tR (R)-major material reported previously.4m 1H NMR (CDCl3, 400 MHz) 7.24-
enantiomer, 36.6 min; tR (S)-minor enantiomer, 33.6 min; 7.11 (m, 5H), 6.12 (d, J = 1.6 Hz, 1H), 5.98 (d, J = 2.0 Hz, 1H),
(Chiralcel OD column; 10% 2-propanol in hexane; 0.5 mL/min); 4.81-4.77 (m, 1H), 4.52 (dd, J = 4.0 and 8.8 Hz, 1H), 4.41 (dd, J =
HRMS: calcd. for C16H18BrO4 [M++1] 353.0388; found 353.0390. 4.4 and 8.4 Hz, 1H), 3.72 (s, 3H), 3.55 (s, 3H); 13C NMR (CDCl3,
(R)-2-(2-Hydroxy-4-methoxyphenyl)-2-phenylethanol (24)
A
100 MHz) 162.4, 162.3, 157.3, 143.8, 128.6, 127.3, 126.6, 109.6,
colorless oil was obtained in 45% overall yield from 1a. The 91.7, 88.5, 80.5, 55.6, 55.4, 46.1; Chiral HPLC: 97:3 er, tR (R)-
spectral data of 24 were identical to those of the authentic major enantiomer, 14.9 min; tR (S)-minor enantiomer, 11.8 min;
material reported previously.15e 1H NMR (CDCl3, 500 MHz) 7.72 (Chiralcel OD column; 10% 2-propanol in hexane; 0.5 mL/min).
(br, 1H), 7.39-7.18 (m, 3H), 6.95-6.83 (m, 1H), 6.47-6.38 (s, 2H), (R)-3-(4-Chlorophenyl)-4,6-dimethoxy-2,3-dihydrobenzofuran
4.41-4.33 (m, 1H), 4.22-4.11 (m, 2H), 3.71 (s, 3H), 2.87 (br, 1H); (28) A colorless oil was obtained in 83% overall yield from 22
.
13C NMR (CDCl3, 125 MHz) 159.7, 155.7, 140.7, 130.5, 128.8, 1H NMR (CDCl3, 400 MHz) 7.19 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4
128.4, 126.9, 120.9, 106.3, 102.9, 66.6, 55.4, 47.9; Chiral HPLC: Hz, 2H), 6.11 (d, J = 2.0 Hz, 1H), 5.98 (d, J = 2.0 Hz, 1H), 4.80-4.76
99:1 er, tR (R)-major enantiomer, 37.6 min; tR (S)-minor (m, 1H), 4.49 (dd, J = 4.4 and 9.2 Hz, 1H), 4.36 (dd, J = 4.4 and
enantiomer, 35.7 min; (Chiralcel OD column; 10% 2-propanol in 8.8 Hz, 1H), 3.72 (s, 3H), 3.57 (s, 3H); 13C NMR (CDCl3, 100 MHz)
hexane; 0.5 mL/min); HRMS: calcd. for C15H17O3 [M++1] 162.5, 162.3, 157.1, 142.3, 132.3, 128.6, 109.2, 91.7, 88.5, 80.2,
245.1178; found 245.1178.
55.5, 55.3, 45.4; Chiral HPLC: 97:3 er, tR (R)-major enantiomer,
(R)-2-(4-Hydroxy-2-methoxyphenyl)-2-phenylethanol
(24- 14.6 min; tR (S)-minor enantiomer, 11.2 min; (Chiralcel OD
minor) A colorless oil was obtained in 23% overall yield from 1a
.
column; 10% 2-propanol in hexane; 0.5 mL/min); HRMS: calcd.
1H NMR (CDCl3, 500 MHz) 7.31-7.18 (m, 5H), 6.99 (d, J = 8.6 Hz, for C16H16ClO3 [M++1] 291.0788; found 291.0786.
1H), 6.41 (d, J = 2.3 Hz, 1H), 6.35 (dd, J = 2.3 and 8.0 Hz, 1H), (R)-3-(4-Bromophenyl)-4,6-dimethoxy-2,3-dihydrobenzofuran
4.69 (br, 1H), 4.38 (t, J = 7.5 Hz, 1H), 4.10 (m, 2H), 3.76 (s, 3H), (29) A colorless oil was obtained in 87% overall yield from 23
1.54 (br, 1H); 13C NMR (CDCl3, 125 MHz) 158.6, 155.5, 141.7, 1H NMR (CDCl3, 400 MHz) 7.21 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 7.6
129.0, 128.6, 128.5, 126.5, 122.2, 107.0, 99.3, 65.5, 55.6, 46.0; Hz, 2H), 6.00 (s, 1H), 5.86 (s, 1H), 4.68-4.63 (m, 1H), 4.35 (dd, J
.
HRMS: calcd. for C15H17O3 [M++1] 245.1178; found 245.1179.
(R)-2-(2-Mesylamino-4,6-dimethoxyphenyl)-2-phenylethanol
= 4.0 and 9.2 Hz, 1H), 4.23 (dd, J = 4.4 and 8.8 Hz, 1H), 3.61 (s,
3H), 3.45 (s, 3H); 13C NMR (CDCl3, 100 MHz) 162.8, 162.3, 157.1,
1
(25) A yellow oil was obtained in 48% overall yield from 1a. H 142.8, 131.6, 129.1, 120.4, 109.8, 91.7, 88.6, 80.1, 55.6, 55.3,
NMR (CDCl3, 500 MHz) 8.82 (br, 1H), 7.34-7.15 (m, 5H), 6.87 (s, 45.5; Chiral HPLC: 97:3 er, tR (R)-major enantiomer, 16.1 min; tR
1H), 6.34 (s, 1H), 4.95-4.93 (m, 1H), 4.57-4.54 (m, 1H), 4.13-4.09 (S)-minor enantiomer, 11.9 min; (Chiralcel OD column; 10% 2-
(m, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 2.92 (br, 1H), 2.08 (s, 1H); 13
C
propanol in hexane; 0.5 mL/min C16H16BrO3 [M++1] 335.0283;
NMR (CDCl3, 125 MHz) 160.1, 159.0, 142.4, 138.2, 128.7, 128.0, found 335.0285.
126.3, 115.4, 98.4, 95.6, 64.8, 56.1, 55.5, 40.4, 38.4; Chiral HPLC: (R)-3-Phenyl-6-methoxy-2,3-dihydrobenzofuran
(30)
A
99:1 er, tR (R)-major enantiomer, 28.2 min; tR (S)-minor colorless oil was obtained in 61% overall yield from 24. 1H NMR
enantiomer, 39.3 min; (Chiralcel OD column; 10% 2-propanol in (CDCl3, 500 MHz) 7.31-7.19 (m, 5H), 6.89 (m, 1H), 6.47-6.40 (m,
hexane; 0.5 mL/min); HRMS: calcd. for C17H22NO5S [M++1] 2H), 4.93-4.90 (m, 1H), 4.68-4.62 (m, 1H), 4.44-4.40 (m, 1H),
352.1219; found 352.1218.
(R)-2-(4-Chlorophenyl)-2-(2-mesylamino-4,6-
3.78 (s, 3H); 13C NMR (CDCl3, 125 MHz) 161.6, 160.8, 143.3,
128.9, 127.8, 127.1, 125.4, 122.7, 106.6, 96.2, 80.2, 55.6, 48.0;
dimethoxyphenyl)ethanol (26) A yellow oil was obtained in 57% Chiral HPLC: 99:1 er, tR (R)-major enantiomer, 31.1 min; tR (S)-
1
overall yield from 1c. H NMR (CDCl3, 500 MHz) 7.25-7.22 (m, minor enantiomer, 48.3 min; (Chiralcel OJ-H column; 10% 2-
4H), 6.81 (d, J = 2.3 Hz, 1H), 6.33 (d, J = 2.9 Hz, 1H), 4.87 (br, 1H), propanol in hexane; 0.5 mL/min); HRMS: calcd. for C15H15O2
4.49-4.47 (m, 1H), 4.11-4.07 (m, 1H), 3.78 (s, 3H), 3.76 (s, 3H), [M++1] 227.1072; found 227.1072.
3.23 (br, 1H), 2.26 (s, 1H); 13C NMR (CDCl3, 125 MHz) 160.2, (R)-4,6-Dimethoxy-1-methanesulfonyl-3-phenylindoline (31)
A
159.0, 140.6, 138.0, 132.0, 129.4, 128.6, 115.1, 98.6, 95.7, 64.7, pale yellow sticky oil was obtained in 52% overall yield from 25
.
56.0, 55.5, 40.1, 38.8; Chiral HPLC: 99:1 er, tR (R)-major 1H NMR (CDCl3, 500 MHz) 7.39-7.09 (m, 5H), 6.75 (d, J = 1.7 Hz,
enantiomer, 82.1 min; tR (S)-minor enantiomer, 89.3 min; 1H), 6.17 (d, J = 2.3 Hz, 1H), 4.52-4.49 (m, 1H), 4.29-4.25 (m, 1H),
(Chiralcel OD column; 5% 2-propanol in hexane; 0.5 mL/min); 3.98-3.94 (m, 1H), 3.83 (s, 3H), 3.64 (s, 3H), 2.81 (s, 3H); 13C NMR
HRMS: calcd. for C17H21ClNO5S [M++1] 386.0829; found (CDCl3, 125 MHz) 162.4, 157.3, 144.1, 143.2, 128.7, 127.1, 126.9,
386.0826.
113.4, 94.7, 91.9, 60.1, 55.8, 55.5, 43.0, 34.9; Chiral HPLC: 97:3
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3
4
(a) M. M. Heravi, V. Zadsirjan, B. Masoumi, M. Heydari, J.
er, tR (R)-major enantiomer, 51.9 min; tR (S)-minor enantiomer,
31.4 min; (Chiralcel OD column; 10% 2-propanol in hexane; 0.5
mL/min); HRMS: calcd. for C17H20NO4S [M++1] 334.1113; found
334.1112.
View Article Online
Organomet. Chem., 2019, 879, 78. (DbO) IT: 1.0B.1.03P9o/Cu9lsOeBn0,0K70. 6AG.
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(R)-3-(4-Chlorophenyl)-4,6-dimethoxy-1-
methanesulfonylindoline (32) A yellow sticky oil was obtained
in 58% overall yield from 26. 1H NMR (CDCl3, 500 MHz) 7.23 (d,
J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 2.3 Hz, 1H),
6.16 (d, J = 1.8 Hz, 1H), 4.48-4.46 (m, 1H), 4.26-4.22 (m, 1H), 3.91
(dd, J = 3.5 and 10.4 Hz, 1H), 3.82 (s, 3H), 3.64 (s, 3H), 2.84 (s,
3H); 13C NMR (CDCl3, 125 MHz) 162.6, 157.2, 144.0, 141.7, 132.7,
128.8, 128.5, 113.0, 94.6, 91.9, 59.8, 55.8, 55.5, 42.5, 34.8;
Chiral HPLC: 93:7 er, tR (R)-major enantiomer, 48.6 min; tR (S)-
minor enantiomer, 28.6 min; (Chiralcel OD column; 10% 2-
propanol in hexane; 0.6 mL/min); HRMS: calcd. for C17H19ClNO4S
[M++1] 368,0723; found 368.0722.
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Conclusions
The simple procedure described in this paper provides a novel
protocol for the asymmetric Friedel-Crafts alkylations of diverse
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furan and anisole derivatives, by using
a new type of electrophiles. The direct C-H functionalization of
the (herero)arenes with highly diastereoenriched -bromo
-bromo arylacetates as

arylacetates is promoted in the presence of AgOTf, and
subsequent reduction can afford highly enantioenriched 2,2-
diarylethanols. Because highly diastereoenriched
-bromo
arylacetates are readily available, our approach could serve as a
new and very attractive tool in the asymmetric synthesis of
various diarylmethine containing natural products. The capacity
to introduce new chiral functionalities into the (hetero)arene
allows for a diverse range of synthetic elaboration. An example
of the synthetic utility of the methodology is demonstrated
through the asymmetric synthesis of diarylmethine containing
dihydrobenzofuran and indoline derivatives.
6
7
Examples for non-stereoselective Friedel-Crafts alkylation
with
-bromoacetates, see: (a) D. Ellis, Tetrahedron:
Asymmetry, 2001, 12, 1589. (b) C. P. Ashcroft, S. Challenger,
D. Clifford, A. M. Derrick, Y. Hajikarimian, K. Slucock, T. V. Silk,
N. M. Thomson, J. R. Williams, Organic Process Research &
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Sarwar, M. G. Chudzinski, M. S. Taylor, Tetrahedron, 2011, 67
7586.
,
Examples for stereoselective Friedel-Crafts reactions with
chiral cationic species, see: (a) F. Mühlthau, O. Schuster, T.
Bach, J. Am. Chem. Soc., 2005, 127, 9349. (b) J. Y. L. Chung, D.
Mancheno, P. G. Dormer, N. Variankaval, R. G. Ball, N. N. Tsou,
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Chem. Soc., 2016, 138, 2134. (d) R. R. Naredla, D. A. Klumpp,
Chem. Rev., 2013, 113, 6905.
Conflicts of interest
There are no conflicts to declare.
8
9
(a) K. J. Park, Y. Kim, M. Lee, Y. S. Park, Eur. J. Org. Chem., 2014,
1645. (b) Y. S. Choi, S. Park, Y. S. Park, Eur. J. Org. Chem., 2016,
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2008, 10, 969. (d) G. L. Hamilton, T. Kanai, F. D. Toste, J. Am.
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Acknowledgements
This work was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education (2017R1D1A1B03035502).
10 The absolute configuration of the products obtained by the
reaction of (αR)-1a with pyrroles, indoles and anisole
derivatives were assigned to be (R) by comparing the chiral
HPLC analysis and/or the optical rotation of previously
Notes and references
1
(a) D. Ameen, T. J. Snape, Med. Chem. Comm., 2013, 4, 893.
(b) H. Xu, M. Lv, X. Tian, Curr. Med. Chem., 2009, 16, 327. (c)
B. Malhotra, K. Gandelman, R. Sachse, N. Wood, M.C. Michel,
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reported 2,2-diarylethanols 7, 8, 10, . The
11, and 12 4k,4n,15c
complete inversion of stereochemistry indicates the
occurrence of SN2-type reaction.
11 When (αR)-1a of >99:1 dr was allowed to epimerize in the
presence of AgOTf (1.0 equiv) in CDCl3 (0.2M), (αR)-1a was
2
For recent overviews on asymmetric synthesis of gem-
diarylalkyl derivatives, see: (a) T. Jia, P. Cao, J. Liao, Chem. Sci.,
2018,
9, 546. (b) S. Mondal, D. Roy, G. Panda, ChemCatChem,
2018, 10, 1941.
8 | J. Name., 2012, 00, 1-3
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recovered with 98:2 dr after 0.1 h, 91:9 dr after 0.2 h, 84:16
dr after 0.5 h, 79:21 dr after 1 h, and 71:29 dr after 5 h.
View Article Online
DOI: 10.1039/C9OB00706G
12 Mayr’s nucleophilicity values (N)12a have been used as a
measure for the relative reactivity of the nucleophiles; 1,2,5-
trimethylpyrrole (8.69),12b 1-methylindole (5.75),12c 2-
methylfuran (3.61),12c 1,3-dimethoxybenzene (2.48),12d and
toluene (‒4.36).12e Although the nucleophilicity value of 2,5-
dimethylfuran is unknown, we hypothesized it would lie
between 3.7 and 4.7 based on the value of 2-methylfuran. (a)
H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66.
(b) T. A. Nigst, M. Westermaier, A. R. Ofial, H. Mayr, Eur. J. Org.
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13902.
13 The configurational stability of diarylacetates
2-6 was
examined by the treatment with AgOTf (1.0 equiv) and arene
(5.0 equiv) in CHCl3 (0.2 M) for 24 h. The substitution product
was quantitatively recovered and no epimerization was
detected by H-NMR in every reaction.
14 (a) C. Soldi, K. N. Lamb, R. A. Squitieri, M. Gonzꢀlez-Lꢁpez, M.
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Table of Contents: Graphic
Friedel-Crafts
Alkylation
Br
Br
Ar'
OH
Ar'-H +
Ar
Ar
CO2R*
CIDR
Ar
up to 99:1 er
20 examples
Ar'-H: pyrrole, indole, furan,
and anisole derivatives
Ar: Ph, p-Cl-Ph, p-Br-Ph
CO2R*
Highly enantioenriched 2,2-diarylethanols can be efficiently synthesized using AgOTf-promoted
Friedel-Crafts alkylation of (hetero)arenes with configurationally labile -bromo arylacetates.