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10.1002/adsc.201901420
Advanced Synthesis & Catalysis
With these limitations in mind, and taking into
account the industrial importance of enantiopure
BINOLs and their derivatives, we considered
alternative processes that could operate under mild
reaction conditions with high turnover frequencies,
with the ultimate goal of developing a continuous flow
process for the preparation of enantiomerically pure
BINOL (Scheme 1c).[7]
propargyloxy group at the beginning of the sequence.
Thus, 2-chloro-6-methoxybenzothiazole (1) was
demethylated with BBr3 and alkylated without
isolation with propargyl bromide (2) to afford 2-
chloro-6-propynyloxybenzo[d]thiazole (3) in 93%
yield. Then, following a modification of a literature
procedure,[17] neat 3 was heated in a pressure tube (135
ºC, 24 h) with a stoichiometric amount of (S)-2-amino-
2-phenylethanol and Hunig's base (2 eq.) followed by
in situ cyclization to afford 8-propynyloxy-BTM (4) in
58% yield (3 steps). Immobilization of 4 onto
azidomethyl polystyrene, prepared from commercial
Merrifield resin, was achieved by a Cu-catalyzed
azide−alkyne cycloaddition reaction. The nitrogen
content of the resulting polymer, determined by
elemental analysis, was used to calculate the
functionalization[18] of 5d (0.37 mmol g−1), and this
value was used to determine the catalyst loading in all
subsequent KRs.
Chiral isothioureas, first reported by Birman in 2006,[8]
have become useful catalysts for the acylative KR of
alcohols[9] and carboxylic acids[10] and, quite recently,
for the desymmetrization of axially chiral diols.[11]
Benzotetramisole (BTM), the archetypical example of
chiral isothioureas, is among the most readily available
and effective nonenzymatic enantioselective acylation
catalysts[12] reported to date.[8, 13] In 2016, we reported
the preparation of a polystyrene-supported BTM
analogue which was successfully used in the domino
Michael addition/cyclization reaction with excellent
yields and very high enantioselectivities, [14] and later
applied to asymmetric [4+2] and [8+2] annulation
reactions.[15] More recently, in a joint effort of our
laboratories, new polystyrene-supported isothiourea
catalysts, based on the homogeneous catalysts BTM
and HyperBTM, have been prepared and used for the
acylative KR of secondary[16a] and secondary and
tertiary heterocyclic alcohols[16b] in batch and in
continuous flow. However, there are currently no
examples where BTM catalysts have been applied for
the acylative KR of 1,1’-bi-2-naphthol (BINOL). We
report herein the application of second generation
immobilized BTM in the acylative KR of BINOLs
with high selectivity in batch and continuous flow, and
we show that the flow procedure can be operated at the
100 mmol scale (32.8 g) without any decrease in the
performance of the catalyst.
NH2
OH
N
S
1) BBr3 (1.8 eq), CH2Cl2, 0 ºC, 5h
N
S
1) DIPEA (2 eq), 135 ºC, 24 h
Cl
Cl
2) K2CO3 (5.0 eq), propargyl
bromide (2, 2.0 eq), acetone,
reflux, 16h
O
2) MsCl (1.2 eq), Et3N (2 eq),
CH2Cl2, 0 oC to rt, 4 h.
3) MeOH (2.0 eq), Et3N (3.0 eq),
CH2Cl2, reflux, overnight.
O
1
3
N3
N
S
CuI (5 mol%),
DIPEA (3.5 eq)
N
N
N
O
N
N
1:1 DMF/THF
40 ºC, 48 h
S
O
N
4
5d
Scheme 2. Synthesis of the second-generation polystyrene-
supported BTM catalyst (5d).
Our initial studies focused on the KR of parent
BINOL 6a with anhydrides, using 5 mol % of BTM 5c
as the catalyst (Scheme 3). Unfortunately, the
reactions were poorly selective, mixtures of binol with
its monoacylated and bisacylated products being
always obtained. Moreover, the reproducibility of
these experiments was rather poor.
Results and Discussion
We decided to evaluate isothioureas 5a-d as
catalysts for this study. The selection includes
monomers 5b-c as well as the first and second
generation PS-immobilized BTM-type catalysts 5a[14]
and 5d,[16b] and is guided by previous results in the KR
of axially chiral diols with homogeneous isothioureas
(Figure 1).[11]
N
N
R
S
5c (5 mol%)
OH
OH
OH
OH
OH
O
O
O
O
R
DIPEA (0.7 eq), CH2Cl2, rt
R
O
O
O
O
7 (0.6 eq)
R
O
R
8a
9a
rac-6a
6a
R = Me, iPr, tBu, Ph
N
N
N
Scheme 3. Acylative KR of rac-BINOL (6a).
O
N
S
N
S
N
S
N
S
N
N
N
N
O
In light of these results, we modified our strategy to
the acylative KR of monoacylated BINOLs (Table 1).
We first used isobutyric anhydride as an acyl donor
(0.6 equiv) for the KR of a series of monoacylated
BINOLs in CH2Cl2 at room temperature. As shown in
entry 1, the KR of monoacetyl BINOL with isobutyric
anhydride took place with a selectivity factor s = 14 at
58% conversion. The use of larger acyl groups on the
monoacylated BINOL substrate, such as isobutyryl,
pivaloyl or benzoyl, gave much lower selectivities
N
N
N
5a
5b
5c
5d
Figure 1. Catalysts used in this study.
For the preparation of 5d (Scheme 2) we used a
slight modification of the reported procedure that
simplifies the installment of the propargyl anchor by
performing the replacement of the methoxy by a
2
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