Copper- and borinic acid-catalyzed propargylic etherification of propargylic carbonates with benzyl alcohols

Article abstract of DOI:10.1246/cl.180123

Propargylic substitution reactions have offered useful synthetic methods because further transformations based onthe alkyne moiety in the propargylic substituted products are readily achieved to construct more complex organic compounds. A large number of studies have been devoted to enantioselective propargylic substitution reactions with a variety of nucleophiles. However, successful examples of the use of alcohols as nucleophiles have been quite limited until now. To achieve utilization of aliphatic alcohols, herein we report the use of combined catalysis of a copper-pybox complex and a borinic acid. In this catalytic system, aliphatic alcohols such as benzyl alcohol derivatives were successfully applied to afford the corresponding propargylic etherified products in good yields with high enantioselectivities.

Full text of DOI:10.1246/cl.180123

Advance Publication Cover Page
Copper- and Borinic Acid-Catalyzed Propargylic Etherification of Propargylic Carbonates
with Benzyl Alcohols
Kohei Tsuchida, Masahiro Yuki, Kazunari Nakajima, and Yoshiaki Nishibayashi*
Advance Publication on the web March 2, 2018
doi:10.1246/cl.180123
©
2018 The Chemical Society of Japan
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1
Copper- and Borinic Acid-Catalyzed Propargylic Etherification of Propargylic Carbonates
with Benzyl Alcohols
Kohei Tsuchida, Masahiro Yuki, Kazunari Nakajima and Yoshiaki Nishibayashi*
Department of Systems Innovation, School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
E-mail: ynishiba@sys.t.u-tokyo.ac.jp
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Propargylic substitution reactions have offered useful
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acid-catalyzed reaction system is available toward the use of
monodentate alcohols such as benzyl alcohols (Scheme 1b).
Herein, we report preliminary results.
synthetic methods because further transformations based on
the alkyne moiety in the propargylic substituted products
was readily achieved to construct more complex organic
compounds. A large number of works have been devoted
to enantioselective propargylic substitution reactions with a
variety of nucleophiles. However, successful examples of
the use of alcohols as nucleophiles have been quite limited
until now. To achieve utilization of aliphatic alcohols,
herein we report the use of combined catalysis of a copper-
pybox complex and a borinic acid. In this catalytic system,
aliphatic alcohols such as benzyl alcohol derivatives were
successfully applied to afford the corresponding propargylic
etherified products in good yields with high
enantioselectivities.
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Keywords: Propargylic etherification, Copper catalyst,
Borinic acid
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Enantioselective substitution reactions at carbon
centers adjacent to an alkyne moiety, that is, propargylic
substitution reactions have attracted outstanding interest in
organic chemistry because of the high utility for subsequent
1
transformations of the alkyne moiety. In 2008, van
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3,4
Maarseveen and co-workers and our group independently
reported copper-catalyzed enantioselective propargylic
substitution reactions of propargylic alcohol derivatives.
After these reports, the copper-catalyzed reaction systems
have been extensively studied to allow the use of various
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Scheme 1. Enantioselective propargylic etherification with
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,6
nucleophiles for the last decade.
57
aromatic and aliphatic alcohols.
Despite the eager studies by several groups,
enantioselective propargylic substitution reactions with
alcohols as nucleophiles have not been achieved until
recently. Our group reported the first successful example of
the enantioselective propargylic etherification with the use
58
The initial investigation on the reaction conditions was
59 carried out with tert-butyl 1-phenyl-2-propyn-1-yl carbonate
60 (1a) and benzyl alcohol (2a) as typical substrates (Table 1).
61 At first, the reaction using the copper-pybox complex as a
62 sole catalyst was tested under the conditions similar to our
3
d
of copper-pybox system (Scheme 1a). However, the
applicable alcohols were limited to phenol derivatives,
otherwise an excess amount of simple alcohols (methanol
and ethanol) as solvents is necessary to promote catalytic
reactions.
3
d
63 previous work (Table 1, Entry 1). In this case, no
64 etherification product (3a) was observed. Next, we
65 investigated the combination of the copper-pybox complex
66 with a boron compound. The reaction of 1a with 2a was
To improve the utility of aliphatic alcohols, we focused
on combination of copper and boron catalysts. Recently,
boron compounds have been successfully employed to
67 carried
out
in
the
presence
of
copper(I)
68 trifluoromethanesulfonate benzene complex (5 mol% based
69 on Cu atom), (S)-Ph-pybox ligand L1 (10 mol%), 3,5-
8
7
activate alcohols as nucleophiles by formation of boronate.
70 bis(trifluoromethyl)phenylboronic acid (B1) (5 mol%), and
71 Hünig's base (30 mol%) (Table 1, Entry 2). Fortunately, the
72 desired propargylic ether 3a was obtained in 68% yield with
73 89% ee (R). Encouraged by this result, we tested other
74 boron compounds. Among the tested boron compounds:
75 boronic acids (Table 1, Entries 3-5), bis(neopentyl
76 glycolato)diboron (Table 1, Entry 6), dichlorophenylborane
77 (Table 1, Entry 7), borinic acids (Table 1, Entries 8-10), and
78 a fused triphenyl borane derivative (Table 1, Entry 11),
79 some boronic and borinic acids were revealed to be
This activation mode was expected to be useful to promote
the propargylic substitution reactions with aliphatic alcohols.
Meanwhile, during our investigation of the present work,
Niu and coworkers independently reported the copper- and
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borinic acid-catalyzed propargylic etherification reactions.
In this reaction system, however, available alcohols have
been limited to diols and polyols, which may coordinate the
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d
boron center in a bidentate fashion. Complementary to our
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and Niu’s works, we have found the copper- and borinic

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effective; the highest enantioselectivity was observed when
using the dibenzo-1,4-oxaborine-derived borinic acid B2
(Table 1, Entry 9). Then, we examined the choice of the
pybox ligand. The use of (S)-Me-pybox ligand (L2) which
was the optimized ligand in our previous work gave 3a in
good yield but with slightly lower enantioselectivity (Table
1, Entry 12). On the other hand, the diPh-pybox L3
exhibited poor reactivity (Table 1, Entry 13). We also
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Table 2. Reactions of propargylic carbonates (1) with aliphatic
alcohols (2).
1
9
CuOTfꞏ1/2C H (5 mol%)
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6
L1 (10 mol%)
B2 (5 mol%)
Pr NEt (30 mol%)
2
3
d
Ar1
i
Ar1
Ar2
+
HO
Ar2
OBoc
O
CH Cl
–10 °C, 48 h
2
2
3
1
2, 2 equiv
yield, ee
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1
0
1
Table 1. Reactions of tert-butyl 1-phenyl-2-propyn-1-yl
carbonate (1a) with benzyl alcohol (2a).
MeO
Me
O
Ph
O
Ph
3b, 75% yield, 95%ee
3c, 95% yield, 91%ee
F
Me
O
Ph
O
Ph
3d, 75% yield, 97%ee
3e, 50% yield, 95%ee
Cl
Br
O
Ph
O
Ph
3f, 84% yield, 98%ee
3g, 45% yield, 96%ee
Ph
OMe
Ph
Me
O
O
3
h, 45% yield, 96%ee
3i, 84% yield, 96%ee
Ph
Cl
Ph
F
O
O
3j, 65% yield, 96%ee
3k, 74% yield, 96%ee
Ph Br
Ph
O
O
Ph
3l, 60% yield, 97%ee
3m, 67% yield, 74%ee
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0
1
a
All reactions of propargylic carbonate 1 (0.200 mmol) with aliphatic
alcohol (0.400 mmol) were carried out in the presence of
CuOTfꞏ1/2C (0.010 mmol), L1 (0.020 mmol), B2 (0.010 mmol),
2
2
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2
6
H
6
i
b
and Pr NEt (0.067 mmol) in CH Cl (2.0 mL) at –10 ºC for 48 h.
Isolted yield. Determined by chiral HPLC analysis.
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2
c
examined chiral diphosphine ligand L4, which effectively
3a,b
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3
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worked in propargylic amination, but no 3a was observed
(Table 1, Entry 14). Finally, lowering the reaction
temperature to –10 ºC successfully produced 3a in
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a
31 satisfactory yield with the highest enantioselectivity (92%
All reactions of 1a (0.200 mmol) with 2a (0.400 mmol) were carried
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2
yield, 97% ee) (Table 1, Entry 15).
out in the presence of CuOTfꞏ1/2C
mmol), a boron compound (0.010 mmol), and Pr
CH Cl (2.0 mL) at the indicated conditions.
Determined by chiral HPLC analysis.
6 6
H (0.010 mmol), a ligand (0.020
i
2
NEt (0.067 mmol) in
With the optimized reaction conditions in hand, the
b
c
2
2
Isolted yield.
34 reactions of various propargylic carbonates were examined
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(Table 2). Propargylic carbonates bearing electron donating

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and withdrawing substituents at the para-position of the
benzene ring in 1 were successfully transformed into the
corresponding propargylic etherified products (3b, 3c, and
3e-g) in moderate to high yields with an excellent
enantioselectivity. Introduction of a methyl group at the
meta-position, which might change the steric environment
around the chiral center, also produced the desired product
(3d) with a similar enantioselectivity.
Next, the use of benzyl alcohol derivatives was
investigated. Benzyl alcohol derivatives with methoxy,
methyl, fluoro, chloro, and bromo substituents at the para-
position of the benzene ring in 3 (3h-l) were available in this
reaction system. An aliphatic alcohol with a longer alkyl
chain, 2-phenylethanol, was transformed into 3m in good
yield but with a slightly lower enantioselectivity (74% ee).
The absolute stereoconfiguration of the propargylic
etherification product 3a was confirmed by comparison with
the separately prepared (R)-3a from commercially available
(R)-1-phenyl-2-propyn-1-ol. Treatment of the (R)-1-phenyl-
2-propyn-1-ol with sodium hydride and benzyl bromide
afforded (R)-3a without loss of the optical purity (Scheme
2). By comparison of the HPLC analyses, we confirmed the
(R)-isomer of 3a was the major product under the present
copper-pybox- and borinic acid-catalysis.
40 from [Cu
41 CuOTfꞏ1/2C
42 allenylidene ligand is a key step, although the alcohol is
2
(L1)
2
][OTf]
2
,9 which is generated in situ from
6
H
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and 1 equiv of L1, from Si face of the
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d
1
0
43 presumably activated by forming boronate complex in the
44 present reaction system (Scheme 3). Similar pathways have
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45 been proposed by other research groups.
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In summary, we have developed a copper- and borinic
47 acid-catalyzed reaction system that furnishes propargylic
48 etherification products with aliphatic alcohols as
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49 nucleophiles
in
good
yields
with
excellent
50 enantioselectivities. We also revealed the monodentate
51 alcohols were effectively activated by the borinic acid
52 catalyst probably due to formation of the boronate complex
53 in a similar manner to diols and polyols. We believe that the
54 present findings may be further applicable in a variety of
55 reaction systems.
56
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58 Supporting
Information
is
available
on
59 http://dx.doi.org/10.1246/cl.******.
6
0 References and Notes
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Scheme 2. Preparation of propargylic ether 3a with
unambiguous stereoconfiguration.
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Scheme 3. Plausible enantio-induction step.
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The (R)-selective product formation by using (S)-
pybox ligands as the chiral source is same to the previous
propargylic etherification with aromatic alcohols and diols,
indicating a similar transition state on the enantio-induction
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3
d,3e
100
step to the previous work.
At present, we consider the
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02
03
present etherification proceeds via a similar pathway to our
previous work, where nucleophilic attack of an alcohol
toward a dimetallic copper-allenylidene complex derived 104

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6
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1
1
1
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1
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1
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