Copper-Catalyzed Propargylic Reduction with Diisobutylaluminum Hydride

Article abstract of DOI:10.1021/acs.orglett.8b02413

A mild and efficient method for the synthesis of allenes through selective copper-catalyzed hydride addition to propargylic chlorides using commercially available diisobutylaluminum hydride has been developed. This transformation, which is promoted by a readily accessible N-heterocyclic carbene-copper complex, provides a wide range of new and versatile functionalized allenes in good to excellent yields with high regio- A nd stereoselectivities.

Full text of DOI:10.1021/acs.orglett.8b02413

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Propargylic Reduction with Diisobutylaluminum
Hydride
Yuna Kim, Hanseul Lee, Sunga Park, and Yunmi Lee*
Department of Chemistry, Kwangwoon University, Seoul 01897, Republic of Korea
S
* Supporting Information
ABSTRACT: A mild and efficient method for the synthesis of
allenes through selective copper-catalyzed hydride addition to
propargylic chlorides using commercially available diisobutyla-
luminum hydride has been developed. This transformation,
which is promoted by a readily accessible N-heterocyclic
carbene−copper complex, provides a wide range of new and
versatile functionalized allenes in good to excellent yields with
high regio- and stereoselectivities.
llenes are important structural motifs present in natural
products, pharmaceuticals, and molecular materials,1 and
high regio- and diastereoselectivity. The same researchers
applied this methodology to the synthesis of functionalized
allenes through NHC-Cu-catalyzed hydride addition to
internal propargylic carbonates with PMHS under similar
reaction conditions.4b In the same year, Ito, Sawamura and co-
workers demonstrated that a catalytic system comprising
copper acetate and the Xantphos ligand also worked well for
the SN2′ reduction of propargylic carbonates with hydrosilanes,
affording di- and trisubstituted allenes, including enantiomeri-
cally enriched allenes.4a These CuH-catalyzed propargylic
reduction reactions for allene synthesis are highly regio- and
stereoselective and tolerant to various functional groups and
proceed under mild reaction conditions. Despite these
advances, only three examples of CuH-catalyzed propargylic
reduction for synthesizing mainly di- and trisubstituted allenes
have been reported, and only hydrosilanes, especially PMHS,
have been used as the hydride nucleophile source. Due to the
significance and synthetic utilities of functionalized allenes, the
development of practical and efficient approaches is still
required.
While silanes and boranes are the most commonly used
hydride sources in CuH catalysis, the application of aluminum
hydride in this field has been rarely studied.3d Although a few
examples of copper-free propargylic reduction using lithium
aluminum hydride or diisobutylaluminum hydride (DIBAL-H)
have been reported, there are challenging issues to be solved
for the further synthetic applications of these reactions: limited
substrate scope, high reaction temperature, and low to
moderate yields.11 In this study, we demonstrate the
applicability of DIBAL-H as a new alternative hydride
nucleophile for CuH catalysis. The selective hydride addition
of DIBAL-H to propargylic chlorides in the presence of 1−5
mol % of an NHC-Cu catalyst proceeds under mild and simple
reaction conditions to provide a broad range of new versatile
A
they serve as valuable intermediates in a variety of organic
transformations.2 Therefore, numerous synthetic method-
ologies for allenes have been studied.3 Among the routes for
the synthesis of allenes, copper-catalyzed selective SN2′
reduction of a propargylic electrophile with a hydride source
is one of the most attractive because of the use of low-cost and
easy-to-handle copper catalysts, the use of readily available and
convenient hydride nucleophiles such as silanes, and the use of
easily prepared propargylic substrates.4
Copper hydride (CuH)-catalyzed reactions have emerged as
an important tool for the formation of carbon−hydrogen
bonds. Since Brunner and co-workers developed the first
example of using a CuH catalyst for the reduction of
acetophenone with silanes,5 copper hydrides have been utilized
in numerous catalytic transformations including selective 1,2-
reduction, 1,4-reduction, SN2′ reduction, and hydrogenation.6,7
In particular, a wide range of alkene and alkyne hydro-
functionalization reactions proceed via the generation of alkyl-
or alkenylcopper intermediates derived from the insertion of
CuH species into multiple C−C bonds, followed by the
reaction of the organocopper intermediates with various
electrophiles. These reactions play a crucial role in forming
C−H, C−C, C−N, C−Si, and C−B bonds.8 Stryker,
Brummond and co-workers attempted copper-mediated
regioselective hydride addition to terminal propargylic acetate
moieties using stoichiometric Stryker’s reagent ([(Ph3P)-
CuH]6),9 which affored the 1,1′-disubstituted allenes.10
These results show that the use of copper hydride as a
reducing agent in the propargylic reduction reaction could be a
new approach for the synthesis of allenes. A catalytic version of
the propargylic reduction was first achieved by Krause and co-
workers.4c They reported that N-heterocyclic carbene (NHC)-
based copper complexes generated in situ from a mixture of an
imidazolium salt, CuCl, and NaOt-Bu catalyzed the SN2′
reduction of propargylic oxiranes with polymethylhydro-
siloxane (PMHS) to provide various α-hydroxyallenes in
Received: July 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02413
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
mono- and disubstituted allenes, including chiral allenes, in
good to excellent yields with high regio- and stereoselectivities.
We began our investigation by examining the ability of
NHC-copper catalysts to promote the regioselective SN2′
reduction of propargylic chloride 1a using inexpensive and
commercially available diisobutylaluminum hydride as a
hydride nucleophile, as shown in Table 1. When chloride 1a
followed by reductive elimination, to give the allene
product.4b,13 Phosphine ligands such as dppbz and DPEphos
were not effective (entries 4−5). Various NHC ligands were
tested, but inferior results in terms of efficiency and selectivities
were observed (entries 6−10). Notably, reactions with
sterically demanding isopropyl-substituted NHC-CuCl cata-
lysts generate side product 4 derived from the overreduction of
allene 2a (entries 6−7). Therefore, SIMesCuCl was selected as
the optimal catalyst for the selective and efficient synthesis of
allene 2a. As shown in entry 12 of Table 1, even if 1 mol % of
Cu catalyst was used, the hydride addition to 1a effectively
proceeded to complete conversion, affording the desired allene
2a in 92% yield.
Table 1. Optimization of the Cu-Catalyzed Propargylic
a
Reduction of 1a
After the optimized reaction conditions were established, the
substrate scope of the Cu-catalyzed SN2′ reduction of terminal
propargylic chlorides was investigated. All transformations
were carried out in the presence of 1−3 mol % SIMesCuCl
catalyst at ambient temperature, affording a variety of terminal
allenes with high regioselectivity and efficiency, as shown in
Scheme 1. The copper-catalyzed hydride addition of DIBAL-H
mol % of
Cu
equiv of
conv
b
yield (%) of
b
entry Cu complex
DIBAL-H
(%)
2a:3:4
1
2
3
4
5
SIMes-CuCl
no Cu
CuCl
dppbz + CuCl
DPEphos +
CuCl
5
0
5
5
5
1.2
1.2
1.2
1.2
1.2
88
<2
30
33
55
83:5:<2
<2
15:15:<2
8:25:<2
25:23:<2
Scheme 1. Cu-Catalyzed SN2′ Reduction with Various
a b
,
Propargylic Chlorides
6
7
8
9
IPr-CuCl
5
5
5
5
5
1.2
1.2
1.2
1.2
1.2
74
60
77
83
62
58:<2:14
40:<2:19
51:26:<2
26:22:<2
28:23:<2
SIPr-CuCl
IMes-CuCl
ICy-CuCl
Benz-ICy-
CuCl
10
11
12
SIMes-CuCl
SIMes-CuCl
5
1
1.5
1.5
96
>98
83:5:3
92:3:5
c
a
Reactions were performed on a 0.30 mmol scale of 1a in THF (0.2
M) under N2. Dppbz = 1,2-bis(diphenylphosphino)benzene,
b
DPEphos = bis[(2-diphenylphosphino)phenyl] ether. Determined
by 1H NMR or GC analysis using 1,3,5-trimethoxybenzene as an
c
internal standard. Reaction time was 3 h.
was treated with 1.2 equiv of DIBAL-H in the presence of 5
mol % SIMesCuCl (Figure 1), the desired terminal allene 2a
a
Reaction conditions: propargylic chloride 1 (0.30 mmol), DIBAL-H
(0.45 mmol), SIMesCuCl (1−3 mol %), THF (0.2 M) under N2. In
b
all cases, >95:<5 regioselectivity. Yields of the isolated products.
Figure 1. Various NHC-CuCl studied for propargylic reduction
reactions.
to phenethyl-substituted propargylic chlorides 1a−1d bearing
a chloro, bromo, or methoxy moiety on the meta-position of
the phenyl group proceeded to complete conversion within 3 h
to provide the desired allenes 2a−2d in excellent yields (82−
93%). However, compared to the reactions with 1a−1d, the
reaction of substrate 1e substituted with a chloro group on the
ortho-position of the phenyl group was less efficient (50% yield
of 2e) owing to steric hindrance. Functional groups such as an
ether or chloro moiety on the propargylic substrates were well
tolerated in the Cu-catalyzed reductions, affording the
corresponding allenes 2f−2j in 74−93% yields. In addition,
various alkyl-substituted allenes 2k−2m bearing an n-hexyl or
sterically demanding cyclohexyl unit were efficiently synthe-
sized in 73−86% yields. Unfortunately, these catalytic SN2′
reduction conditions were not effective in the reaction of an
aryl-substituted propargylic chloride. When (3-chloroprop-1-
was obtained in 83% yield with 94:6 regioselectivity (entry 1).
In contrast, there was no transformation of 1a without using a
Cu catalyst (entry 2). As the result in entry 3 describes, CuCl
itself did not efficiently or selectively catalyze the SN2′
reduction of 1a (15% of 2a, 1:1 = 2a:3), indicating that the
NHC ligand may play an important role in stabilizing the
copper hydride species4 and controlling regioselectivity. Based
on these results, we postulated that the copper hydride species
complexed with an NHC ligand12 might be generated from the
transmetalation of SIMesCuCl with DIBAL-H. Similar to the
mechanism of Cu-catalyzed propargylic reductions suggested
by Krause and co-workers, the in situ generated CuH species
presumably undergo SN2′ substitution with the propargylic
chloride via the formation of a copper(III) intermediate,
B
DOI: 10.1021/acs.orglett.8b02413
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yn-1-yl)benzene was employed with DIBAL-H in the presence
of 5 mol % of SIMesCuCl, the phenyl-substituted allene
product was obtained in <20% yield along with a mixture of
byproducts.
Scheme 3. Synthesis of Chiral Allenes
Next, we turned our attention to investigating the generality
of this catalytic propargylic reduction. As illustrated in Scheme
2, a wide range of internal propargylic chlorides could be
Scheme 2. Cu-Catalyzed Propargylic Reduction with
a b
,
Disubstituted Propargylic Chlorides
of enantiomerically enriched propargylic chlorides proceeds to
provide axially chiral allenes. When propargylic chlorides 7a
and 7b substituted with a chiral 2,2-dimethyl-1,3-dioxolane
group were treated with DIBAL-H, Cu-catalyzed anti-SN2′
substitution occurred to afford the corresponding chiral allenes
8a and 8b14 with the same diastereomeric ratios (dr) of
>98:<2 and 5:1, respectively, as the starting materials. In
addition, the central chirality of optically pure (S)-chloride 9
was transferred to the axial chirality of allene 10,15 showing
anti-SN2′ stereoselectivity with a >98:<2 enantiomeric ratio
(er).4
In conclusion, we have described the use of DIBAL-H as a
hydride nucleophile in highly regio- and stereoselective Cu-
catalyzed SN2′ reductions of propargylic chlorides to synthesize
a wide range of new and versatile functionalized allenes in
good to excellent yields. The reaction was promoted by an
NHC ligand and proceeded with complete chirality transfer to
provide optically active allenes. The importance and
practicality of this current methodology are highlighted by
the high efficiency and stereoselectivity, the simple and mild
reaction conditions, the broad substrate scope, the synthetic
potential of the functionalized allenes, and the new possibility
of readily available and inexpensive DIBAL-H as a substitute
for hydrosilanes, which have been the main hydride source
used for CuH catalysis. Further study will focus on applying
aluminum hydrides to other types of CuH catalysis.
a
Reaction conditions: propargylic chloride 5 (0.30 mmol), DIBAL-H
(0.45 mmol), SIMesCuCl (5 mol %), THF (0.2 M) under N2. In all
b
cases, >95:<5 regioselectivity. Yields of the isolated products.
c
Reaction time was 12 h.
utilized in the NHC-Cu-catalyzed hydride addition of DIBAL-
H, providing various new functionalized allenes in good to
excellent yields with excellent regioselectivity. Substrates 5a−
5g substituted with phenethyl and various alkyl functionalities,
such as methyl, propyl, butyl, isobutyl, benzyl, phenethyl, and
phenylpropyl groups, were successfully converted to the
corresponding internal allenes 6a−6g in 72−94% yields. It
was found that the reductions of internal propargylic chlorides
5d−5f with a sterically demanding isobutyl or benzyl
substituent required longer reaction times (12 h vs 3 h) for
improved yields. The catalytic hydride addition was compatible
with functional groups such as silyl ethers, benzyl ethers, or
alkenes. New and versatile internal allenes 6h−6l including a
silyl or benzyl ether group, which could be synthetically
valuable intermediates for further transformations, were
obtained in 70−97% yields. The alkene substituent present
in substrates 5m−5n was not reduced by DIBAL-H under the
catalytic reaction conditions, affording alkene-substituted
allenes 6m−6n in 51−84% yields. These results demonstrate
that the current methodology is a highly efficient and selective
route to prepare a broad range of functionalized allenes.
The findings shown in Scheme 3 reveal that, under the
present copper catalytic conditions, complete chirality transfer
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02413.
Experimental details, characterization data, and NMR
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ymlee@kw.ac.kr.
ORCID
Yunmi Lee: 0000-0003-1315-4001
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.8b02413
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) (NRF-2017R1A2B4008310). This work was also
partially supported by the Research Grant of Kwangwoon
University in 2018. The authors thank the Korea Basic Science
Institute for technical assistance with mass spectrometry.
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DOI: 10.1021/acs.orglett.8b02413
Org. Lett. XXXX, XXX, XXX−XXX