Copper-catalyzed formal transfer hydrogenation/deuteration of aryl alkynes

Article abstract of DOI:10.1021/acs.orglett.0c03632

A copper-catalyzed reduction of alkynes to alkanes and deuterated alkanes is described under transfer hydrogenation and transfer deuteration conditions. Commercially available alcohols and silanes are used interchangeably with their deuterated analogues as the hydrogen or deuterium sources. Transfer deuteration of terminal and internal aryl alkynes occurs with high levels of deuterium incorporation. Alkyne-containing complex natural product analogues undergo transfer hydrogenation and transfer deuteration selectively, in high yield. Mechanistic experiments support the reaction occurring through a cis-alkene intermediate and demonstrate the possibility for a regioselective alkyne transfer hydrodeuteration reaction.

Full text of DOI:10.1021/acs.orglett.0c03632

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Letter
Copper-Catalyzed Formal Transfer Hydrogenation/Deuteration of
Aryl Alkynes
Samantha E. Sloane, Albert Reyes, Zoua Pa Vang, Lingzi Li, Kiera T. Behlow, and Joseph R. Clark*
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ABSTRACT: A copper-catalyzed reduction of alkynes to alkanes and
deuterated alkanes is described under transfer hydrogenation and
transfer deuteration conditions. Commercially available alcohols and
silanes are used interchangeably with their deuterated analogues as the
hydrogen or deuterium sources. Transfer deuteration of terminal and
internal aryl alkynes occurs with high levels of deuterium
incorporation. Alkyne-containing complex natural product analogues
undergo transfer hydrogenation and transfer deuteration selectively, in
high yield. Mechanistic experiments support the reaction occurring
through a cis-alkene intermediate and demonstrate the possibility for a
regioselective alkyne transfer hydrodeuteration reaction.
he reduction of an alkyne to an alkane is a fundamental
reaction in organic chemistry commonly accomplished
small molecules under relatively mild conditions. Strategies for
the synthesis of highly deuterated small molecules are often
limited by low reaction selectivity or lengthy synthetic
sequences. Recently, two techniques have been developed to
selectively reduce a 1,1-disubstituted aryl alkene functionality
to a deuterated alkane, under transfer hydrodeuteration
conditions.10 Because of the relatively mild conditions a
transfer hydrogenation approach offers in the reduction of π-
bonds, we began to explore a catalytic transfer hydrogenation
and transfer deuteration for the reduction and reductive
deuteration of alkynes.
It is well-established that Cu−H is capable of reducing an
alkyne to an alkene.11 Lalic and co-workers elegantly
demonstrated a cis-selective transformation that occurs in
high yield (Scheme 1a).11b Importantly, most Cu−H catalysts
are not sufficiently reactive to fully reduce an alkyne to an
alkane. To the best of our knowledge, there are no copper-
catalyzed transfer deuteration reactions for the reductive
deuteration of an alkyne to a deuterated alkane. Recently, a
precious metal-catalyzed transfer deuteration was demonstra-
ted for the reduction of an alkyne to an alkane.4a Although
several transfer hydrogenation examples were reported, the Ir-
catalyzed transfer deuteration scope was limited to only
diphenylacetylene (see Scheme 1b).
T
using a heterogeneous catalyst and hydrogen gas.1 Transfer
hydrogenation represents an alternative approach to reduce an
alkyne, obviating the use of flammable hydrogen gas.2 This not
only avoids potential hazards involved with handling H2, but
also offers the opportunity for improving reaction selectivity.1b
Transition-metal-catalyzed transfer hydrogenation has been
extensively studied for the reduction of polarized π-
functionality,2,3 but remains less frequently explored for the
reduction of alkynes to alkanes.4 Furthermore, adaptation of
transfer hydrogenation protocols to perform the selective
installation of four deuterium atoms can pose significant
challenges.
Recently, there has been a resurgence of interest in new
method development focused on the installation of deuterium
into small molecules.5 Deuterated organic molecules are
extensively used in chemical research. Small molecules with
at least three or four deuterium atoms can serve as valuable
standards for high-resolution mass spectrometry in analytical
and bioanalytical chemistry.5a,6 From an organometallic and
synthetic organic chemistry context, deuterium-labeled com-
pounds are used to elucidate reaction mechanisms and perform
kinetic isotope effect measurements.7 In drug discovery,
deuterium labeling of metabolically labile sites in drug
molecules is performed to alter the drug’s absorption,
distribution, metabolism, and excretion (ADME) properties.8
The success of this approach came to fruition in 2017, when
deutetrabenazine became the first FDA-approved deuterated
drug.9
Received: October 31, 2020
We are particularly interested in developing new alkyne
reduction methods that can be easily manipulated to catalyze
the selective installation of at least four deuterium atoms into
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A

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a
Scheme 1. Transfer Hydrogenation and Transfer
Deuteration of Alkynes
Table 1. Reaction Optimization
Based on previous alkene and alkyne hydroamination work,
we hypothesized that a highly reactive Cu−H species would
promote the reduction of an alkyne to an alkane (Scheme
1c).12 We considered dimethoxy(methyl)silane (DMMS) and
ethanol or isopropanol to be logical choices as hydrogen
donors for the desired transfer hydrogenation reactions. We
also hypothesized that these reagents could be readily
manipulated for use in the corresponding transfer deuteration
reaction. Reaction development commenced by screening
commercial copper sources and commercial phosphine-based
ligands known to promote Cu−H formation when combined
in situ with Si−H.11a
Commercially available 2-ethynyl-6-methoxynaphthalene 1
was used as the aryl acetylene for reaction optimization. We
found that triphenylphosphine and achiral bidentate phosphine
ligands were ineffective to provide the desired transfer
hydrogenation alkane product (see Table 1, entries 1−5).
We were hesitant to use chiral bidentate phosphine ligands to
perform an achiral process, but given the precedent for these
ligand types to support highly reactive Cu−H species, we
opted to screen BINAP and SEGPHOS type ligands (Table 1,
entries 6−8). We found that commercially available (R)-
DTBM-SEGPHOS was the most effective ligand for the Cu−
H-catalyzed reduction (Table 1, entry 8). Reducing the catalyst
loading to 1 mol % led to a slight reduction in yield (Table 1,
entry 9). The use of 2 mol % of catalyst was optimal and led to
a high product yield (91% isolated yield; see Table 1, entry
10). It is noteworthy that (R)-DTBM-SEGPHOS and (S)-
DTBM-SEGPHOS can be used interchangeably in this
reaction, and no alkane product is formed in the absence of
Cu(OAc)2 or phosphine ligand (Table 1, entries 11 and 12).
Gratifyingly, other silane reagents such as poly-
(methylhydrosiloxane) (PMHS) and diethoxy(methyl)silane
(DEMS) were successfully employed in the transfer hydro-
genation reaction (Table 1, entries 13 and 14). We chose to
use DMMS, because it is easily removed by evaporation from
crude reaction mixtures and can be readily converted to the
Si−D for transfer deuteration (vide infra).
a
b
Reactions were conducted using 0.2 mmol of substrate. Cu(OAc)2
c
was used in the reactions as a 0.2 M solution in THF. Yield was
determined by 1H NMR analysis of the crude reaction mixture, using
1,3,5-trimethylbenzene as an internal standard. dYield determined
after purification by flash column chromatography. ePoly-
(methylhydrosiloxane) (5 equiv) was used instead of dimethoxy-
f
(methyl)silane. Diethoxy(methyl)silane (5 equiv) was used instead
of dimethoxy(methyl)silane.
source.4a,11k,13 During our evaluation of the reaction scope, we
noticed that increasing the equivalents of alcohol (up to 5
equiv) resulted in full conversion of less-reactive substrates.
Hydrocarbons such as ethylbenzene, 2-ethylnaphthalene, 2-
ethyl-9H-fluorene, and 4-ethyl-1,1′-biphenyl were prepared
from the reduction of their respective alkynes in good yield
(4a−4d, 66%−79% yield). Substituting aryl acetylenes with
electron-donating phenoxy and methoxy groups was beneficial
for conversion and led to enhanced yields (4e−4f, 57%−84%
yield). We attempted a gram-scale reduction on the
optimization substrate, 2-ethynyl-6-methoxynaphthalene, and
isolated 2b in 95% yield. A chemoselective alkyne reduction
occurred in the presence of a benzyl ether under the mild
transfer hydrogenation conditions, using ethanol instead of 2-
propanol (4g, 65% yield). Importantly, no benzyl deprotection
product was observed as previously reported under heteroge-
neous metal-catalyzed hydrogenation with H2.14 We also found
that a methyl ester para to the alkyne was beneficial for
conversion to product (4h, 72% yield). No ester reduction
We evaluated the substrate scope for this transformation
using commercially available Cu(OAc)2, DTBM-SEGPHOS,
DMMS, and ethanol or isopropanol (see Scheme 2). Examples
using ethanol for transfer hydrogenation are scarce, and we
were pleased that this inexpensive feedstock is a viable proton
1
product was seen in the crude H NMR or after purification.
B
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material under the standard transfer hydrogenation conditions.
Importantly, the alkyne was completely reduced, resulting in
full conversion to alkane. A similar result was obtained when δ-
tocopherol analogue 4s was isolated in 62% yield from the
corresponding alkyne analogue.
Scheme 2. Transfer Hydrogenation Substrate Scope
To achieve our goal of selectively installing four deuterium
atoms across an alkyne, we hypothesized that using ethanol−
OD or 2-propanol−OD and Si−D would permit deuterium
installation in a mild manner. Inspired by previously reported
work,17 we were able to develop a scalable and reliable
protocol to make the Si−D on a 94 mmol scale (eq 1):For
deuterated small molecules to be used as internal standards for
quantitative bioanalytical liquid chromatography/mass spec-
trometry assays, it is typical that at least three to four
deuterium atoms are contained in the molecule to allow for
sufficient separation of peaks in the mass spectrum.6b,18 For
terminal alkynes, we proceeded to exchange the acetylenic
hydrogen atom for a deuterium atom prior to transfer
deuteration.19 This permitted the synthesis of substrates with
five deuterium atoms.
Our investigation into the transfer deuteration of aryl
alkynes began with a para-substituted aryl acetylene (6a, 73%
yield) (Scheme 3). It is noteworthy that efficient transfer
deuteration occurs with electron-withdrawing and electron-
donating para-substitution. Polyaromatic compounds such as
2-ethynylnaphthalene and 2-ethynyl-6-methoxynaphthalene,
Scheme 3. Transfer Deuteration Substrate Scope
a
Yield determined by 1H NMR analysis using 1,3,5-trimethylbenzene
b
c
as an internal standard. 2.4−2.6 equiv of EtOH used. Reaction
d
e
performed at 40 °C. Reaction performed at 23 °C. 5 mol %
Cu(OAc)2 and 5.5 mol % DTBM-SEGPHOS were used.
Because of their prevalence in bioactive molecules, nitrogen-
containing compounds and heterocycles were examined under
the transfer hydrogenation protocol.15 An electron-with-
drawing para-benzenesulfonamide was beneficial for reactivity
(4i, 79%). Even nitro-groups, which are known to be reduced
under heterogeneous reaction conditions, remained intact
under the homogeneous transfer hydrogenation conditions (4j,
65% yield).4c,16 Heterocycle-containing aryl acetylenes, such as
a tosyl-protected indole and a benzothiophene, were efficiently
reduced as well (4k−4l, 60%−72% yield).
Internal alkynes proved to be more-challenging substrates,
because of the increased steric bulk surrounding the alkyne.
Nonetheless, we found that 3-phenyl-2-propyn-1-ol reduced to
3-phenyl-1-propanol in moderate yield (4m, 57% yield), along
with naphthyl and biaryl alkynes (4n-4o, 70%−75% yield).
Further elucidation of the internal alkyne substrate scope
revealed that alkynes substituted with electron-deficient aryl
rings could also be reduced in good yield (4p−4q, 57%−61%
yield).
We explored the capacity for the Cu−H catalyst to reduce
alkyne-containing complex natural product analogues to their
corresponding alkanes. Estrone analogue 4r was isolated in
78% yield after reacting the corresponding alkyne starting
a
1
2
Deuterium incorporation measured by H NMR and/or H NMR.
b
c
2-propanol-d8 used and found to be equally effective as i-PrOD. 5
d
mol % Cu(OAc)2 and 5.5 mol % DTBM SEGPHOS used. Reaction
run for 38 h.
C
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along with a biphenyl-substituted alkyne were reductively
deuterated in high yields (6b−6d, 69%−81% yield). A benzyl
group was found to be stable under the transfer deuteration
conditions (6e, 76% yield), as no alcohol product was detected
in the crude reaction mixture. Nitrogen-containing substrates,
such as an aryl sulfonamide or indole-substituted alkyne,
afforded the corresponding d5-alkane in good yields (6f−6g,
78%−88% yield). Internal aryl alkynes were also reductively
deuterated in high yields, resulting in the synthesis of small
molecules containing four deuterium atoms (6h−6j, 69%−
87% yield). Importantly, the copper-catalyzed transfer
deuteration was effective for deuterating an alkyne-containing
natural product. Deuterated estrone analogue 6k was isolated
in 74% yield from the corresponding alkyne starting material.
This represents a mild procedure to make a highly deuterated
natural product that is suitable as an analytical standard for
mass spectrometry.
Table 2. Reaction Analysis
a
a
a
entry
reaction time
Z-7 (%)
E-7 (%)
8
(%)
6
1
2
3
4
5
6
15 min
30 min
45 min
90 min
180 min
9 h
74
48
40
17
7
0
2
5
7
5
0
25
36
54
61
79
Mechanistically, under transfer hydrogenation conditions,
we hypothesized that the formation of a Cu−H bond in the
presence of dimethoxy(methyl)silane, followed by insertion of
Cu−H bonds across an alkyne, would lead to alkenyl Cu
species i (see Scheme 4). Protodecupration of i with
0
a
Yields of each product were determined by 1H NMR of the
combined products after purification.
into alkene ii to form alkyl copper intermediate iii is reversible
(Scheme 4).
Scheme 4. Postulated Reaction Mechanism
To further probe the mechanism of the transfer hydro-
genation, we performed the reaction under transfer hydro-
deuteration conditions. We exchanged the alcohol reagent for
ethanol−OD and made no changes to the silane. The reaction
was only moderately regioselective (78% D inc. at C3, 18% D
inc. at C2), and isotopically labeled alkane 9a was isolated in
69% yield (see Scheme 5). Switching to ethanol and
(MeO)2MeSi−D led to a flip in regioselectivity (9b, 58%
yield, 30% D inc. at C3, 57% D inc. at C2).
Scheme 5. Regioselective Transfer Hydrodeuteration*
isopropanol would extrude alkene ii. Regeneration of the
Cu−H and addition across alkene ii to form alkyl Cu iii,
followed by protodecupration of iii, would provide the desired
alkane. Simply replacing the Si−H with Si−D and the alcohol
with alcohol−OD permits the reaction to operate under
transfer deuteration conditions.
*
All reactions performed with Cu(OAc)2 (5 mol %), (R)-DTBM-
To test our hypothesis of the intermediacy of cis-alkene ii
(Scheme 4), we evaluated the reduction of 5h over several
time periods. Consistent with the postulated mechanism,
alkene Z-7 appeared in the reaction mixture after 15 min (see
Table 2, entry 1). The appearance of E-7 after 30 min (Table
2, entry 2) suggested that Cu−H insertion into alkene ii to
form alkyl copper intermediate iii is reversible. After 180 min,
the reaction was almost finished (Table 2, entry 5), and it
reached completion after 9 h (8, 79% yield; Table 2, entry 6).
We also subjected E-7 to the standard transfer hydrogenation
conditions and isolated alkane 8 in 83% yield after 23 h.20
Importantly, trace amounts of Z-7 was observed in the crude
1H NMR after 1 h. These data further support that E-7 is a
viable and reactive alkene for the second transfer hydro-
genation step in the proposed mechanism and Cu−H insertion
SEGPHOS (5.5 mol %), THF (0.2 M, based on alkyne substrate), 60
°C. All yields are isolated and %D inc. was determined using 1H NMR
2
a
b
and/or H NMR. 5 equiv (MeO)2MeSi-H, 5 equiv EtOD, 24 h. 5
equiv (MeO)2MeSi-D, 5 equiv EtOH, 24 h. 9b was isolated as a
mixture with alkene (23% yield) present due to incomplete
c
conversion. See the Supporting Information for details. 5 equiv
(MeO)2MeSi-H, 5 equiv 2-propanol-d8, 21 h. d5 equiv (MeO)2MeSi-
D, 5 equiv i-PrOH, 21 h.
To avoid any potential regioselectivity bias that could occur
from proximal heteroatom functionality, similar transfer
hydrodeuteration experiments were also performed with alkyne
10. The reaction was slightly more regioselective, leading to
selectively deuterated alkane 11a (85% yield, 79% D inc. at C1,
7% D inc. at C2) and alkane 11b (79% yield, 23% D inc. at C1,
D
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68% D inc. at C2). Mild to good regioselectivity was observed
in all four transfer hydrodeuteration experiments, and this
supports a regioselective Cu−H/Cu−D addition across the
alkyne and/or alkene. Ongoing investigations in our laboratory
are focused on enhancing the regioselectivity of this transfer
hydrodeuteration reaction.
In summary, we have developed a Cu−H-catalyzed transfer
hydrogenation and transfer deuteration to reduce aryl alkynes
to their corresponding alkanes and deuterated alkanes. The
relatively mild transfer hydrogenation/deuteration permits the
selective reduction of aryl alkynes that contain functionality
commonly reduced under heterogeneous metal-catalyzed
reductions. The reaction is scalable and due to the modularity
of the reaction, a transfer deuteration is possible by simply
changing the Si−H and alcohol to Si−D and alcohol−OD.
This permitted facile access to aryl alkanes containing up to 5
deuterium atoms. The copper-catalyzed transfer hydrogenation
and transfer deuteration protocols were successfully applied to
aryl alkyne containing complex natural product analogs. As a
result, we anticipate this method could be useful to synthesize
highly deuterated analogs of drug molecules for ADME studies.
summer research fellowship and 2020 Eugene Kroeff summer
research fellowship.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank Isabella Alansari (Marquette University) for
making several alkyne substrates. We also thank Nicole Colon
■
́
Rosa (University of Puerto Rico, Cayey) and Emanuel Rivera
Torres (University of Puerto Rico, Cayey) for preliminary
studies.
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ASSOCIATED CONTENT
* Supporting Information
■
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General information; procedures for transfer hydro-
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materials; 1H NMR, 2H NMR (for selected com-
pounds), 19F NMR, and 13C NMR spectra; and
HRMS and IR data of all newly characterized products
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AUTHOR INFORMATION
Corresponding Author
■
Joseph R. Clark − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United
States; orcid.org/0000-0002-3081-5732;
Email: joseph.r.clark@marquette.edu
Authors
Samantha E. Sloane − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United
States
Albert Reyes − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United
States
Zoua Pa Vang − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United
States
Lingzi Li − Department of Chemistry, Marquette University,
Milwaukee, Wisconsin 53233-1881, United States
Kiera T. Behlow − Department of Chemistry, Marquette
University, Milwaukee, Wisconsin 53233-1881, United
States
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Complete contact information is available at:
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Funding
Generous financial support for this work was provided by
Marquette University. A.R. is grateful for a 2019 Todd Wehr
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https://dx.doi.org/10.1021/acs.orglett.0c03632
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