Highly Regioselective and E/ Z-Selective Hydroalkylation of Ynone, Ynoate, and Ynamide via Photoredox Mediated Ni/Ir Dual Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b02017

Exclusively α- and highly E/Z-selective hydroalkylation of ynone, ynoate, and ynamide was achieved via photoredox mediated Ni/Ir dual catalysis with high atom and step economy, producing trisubstituted enones, which are versatile synthetic building blocks. The developed reaction selectively delivered the α/Z isomer, which is complementary to the previously reported β-alkylation processes. The trisubstituted enones could be transformed to more valuable compounds via post-functionalization.

Full text of DOI:10.1021/acs.orglett.8b02017

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Highly Regioselective and E/Z‑Selective Hydroalkylation of Ynone,
Ynoate, and Ynamide via Photoredox Mediated Ni/Ir Dual Catalysis
Su Yong Go, Geun Seok Lee, and Soon Hyeok Hong*
Department of Chemistry, College of Natural Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic
of Korea
*
S Supporting Information
ABSTRACT: Exclusively α- and highly E/Z-selective hydroalkylation of
ynone, ynoate, and ynamide was achieved via photoredox mediated Ni/Ir
dual catalysis with high atom and step economy, producing trisubstituted
enones, which are versatile synthetic building blocks. The developed reaction
selectively delivered the α/Z isomer, which is complementary to the
previously reported β-alkylation processes. The trisubstituted enones could
be transformed to more valuable compounds via post-functionalization.
risubstituted enones are versatile synthetic building
blocks for the preparation of natural products and
Scheme 1. Synthesis of Trisubstituted Enones through
Hydroalkylation of Activated Alkynes with C(sp )−H
Bonds
3
T
biologically active compounds. A variety of methods such as
1
2
3,4
aldol reactions, olefination, cross-coupling, Heck reac-
5
6
tions, C−H activation, and the addition of organometallic
reagents have been developed to synthesize trisubstituted
7
enones. However, these approaches are less efficient in the
aspects of atom and step economy.
The direct, regioselective addition of C−H bonds across
activated alkynes can serve as a highly atom- and step-
economical reaction to yield multisubstituted olefinic struc-
tures. In 2014, Kang et al. developed the Co-catalyzed β-
8
alkylation of terminal alkynes with THF. In the case of
activated internal alkynes, the reaction resulted in the
formation of α-alkylated products. Hilt and co-workers
reported a Zn-mediated α-selective addition of THF across
9
the activated alkynes. Second, to avoid the use of a
stoichiometric amount of additives as employed in the
previously reported C−H additions to alkynes, the recent
photoredox-mediated Ni catalytic method, which enables the
generation of catalytically active alkyl radicals without external
aryl-propiolates. However, both these reactions suffered from
low E/Z selectivity and limited substrate scope, as only
terminal alkynes or propiolate derivatives could be applied.
Wang et al. reported a visible-light-promoted β-selective
10
alkenylation of THF with propiolate derivatives. However,
this method was also unable to overcome the low E/Z
selectivity and limited substrate scope, as only propiolate
derivatives could be employed. Wu and co-workers recently
demonstrated the highly regioselective and E/Z-selective
hydroalkylation of nonactivated alkynes with ethers via a
11,12
radical sources, was adopted.
By implementing these
3
strategies, a silyl-group-assisted C(sp )−H bond addition
reaction across activated alkynes was achieved via visible-
light-mediated Ni/Ir dual catalysis to afford trisubstituted
enones with exclusive α- and high E/Z-selectivity. This
methodology is complementary to the traditional and
1
1
metallaphotoredox strategy. However, for an activated
alkyne, ethyl 3-phenylpropiolate (one example), their method
failed to control the regioselectivity and produced α- and β-
alkylated mixtures (1:1.5). Therefore, it is still challenging to
generate highly α- and E/Z-selective trisubstituted enones by
the direct addition of C−H bonds to activated alkynes
10
previously reported β-alkylation processes.
The initial investigations were performed with the reaction
of ynones 1 with THF (Table 1). Various silyl groups in
compound 1 were evaluated to find the best silyl directing
group inducing the desired selectivity. Silyl groups such as
trimethylsilyl (TMS) and dimethylphenylsilyl (DMPS) groups
generated various unidentified products (entries 1 and 4).
Slightly more stable silyl groups such as tert-butyldimethylsilyl
(
Scheme 1).
To achieve a highly α- and E/Z-selective, atom-economical
C−H addition, two fundamental strategies were devised. First,
a silyl group, which can provide steric and electronic effects to
control the reaction selectivity with extensive opportunities for
post-functionalization, was introduced as a directing group into
Received: June 28, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02017
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of THF Alkenylation
Scheme 2. Scope of Ynone, Ynoate, and Ynamide
b
yield (%) (2:2′),
c
entry
R
deviation
(Z/E of 2)
1
2
3
4
5
TMS
TBDMS none
TES
DMPS
TIPS
none
complex mixture
52 (−), (1.6:1)
48 (−), (3:1)
none
none
none
complex mixture
d
83 (78 ) (only 2),
(
>20:1)
6
7
8
9
TIPS
TIPS
TIPS
TIPS
TIPS
NiBr ·glyme instead of NiCl ·
18 (only 2),
2
2
glyme
(>20:1)
NiBr ·glyme + LiCl (1 equiv)
41 (only 2),
(>20:1)
0
2
instead of NiCl ·glyme
2
Ni(acac) or Ni(cod) instead of
2
2
NiCl ·glyme
2
no cooling (60 °C) instead of
3 °C
18 (only 2),
(>20:1)
0
2
1
0
without NiCl or dtbbpy or [Ir] or
2
light
a
1
(0.06 mmol), NiCl ·glyme (20 mol %), dtbbpy (30 mol %),
2
Ir[dF(CF )ppy] (dtbbpy)PF (2 mol %), and THF (6.0 mL)
irradiated with a 34 W blue LED. NMR yields calculated using
3
2
6
b
c
2
,4,6-triiodophenol as the internal standard. Selectivity ratios were
a
1
d
1 (0.06 mmol), NiCl ·glyme (20 mol %), dtbbpy (30 mol %),
2
determined by the crude H NMR spectra. Isolated yield.
Ir[dF(CF )ppy] (dtbbpy)PF (2 mol %), and THF (6.0 mL)
3
2
6
irradiated with a 34 W blue LED. Z/E = >20:1, unless otherwise
b
noted. Isolated yields of the Z isomer. Z/E = 10:1.
(
TBDMS) and triethylsilyl (TES) groups exhibited better
yields and selectivities (entries 2 and 3). Use of the
triisopropylsilyl (TIPS) group resulted in the highest yield
facile with an electron-rich aromatic ynone (2f), while
electron-poor aromatic ynones resulted in poor yields. The
yield of benzyl ynone (2g) was increased by 30% compared to
the phenyl analogue. To our delight, a ynoate (2h), which can
serve as a good precursor for various trisubstituted enones
(Scheme 4), was highly reactive (98%). The reaction also
proceeded well with other functional groups such as bulkier
ynoates and an ynamide (2i−2l).
(
83%) with remarkable selectivities (entry 5). In particular, the
Z-selective, α-addition product was favored over the generally
favored E-isomer. Compound 2 was characterized by nuclear
Overhauser effect (NOE) experiments (Figures S1−S5).
Substituting TIPS with other alkyl or aryl groups resulted in
either poor selectivity or low yield (Table S1). For example, in
the case of linear alkyl groups, a mixture of all four isomers was
obtained (entry 2, Table S1). Replacing TIPS with aryl groups
or less sterically hindered alkyl groups resulted in poor yields
with low selectivity (Table S1). It was reasoned that the
bulkier TIPS group could make the reaction more sensitive to
the steric environment, providing enough stability to generate
Next, different C−H coupling partners were investigated. In
addition to THF, other cyclic and acyclic ethers, and even an
amide, performed well under the modified reaction conditions.
The use of cosolvent (benzene) with a decreased amount of
C−H coupling partners (20 equiv) was necessary, due to the
solubility issue of the catalyst mixture (Scheme 3). In the cases
of 2o and 2q, the yields were improved by increasing the
reaction temperature (50 °C). For 1,3-dioxolane, lower
efficiency as compared to the reaction with THF was observed,
likely owing to the decomposition of the product (2p).
13
the desired products. The role of chloride was essential, as
replacement of NiCl with other Ni(II) or Ni(0) precatalysts
2
resulted in significantly lower yields (entries 6 and 8). The
addition of LiCl to NiBr ·glyme improved the reactivity,
2
confirming the critical role of the chloride ligand (entries 7).
Conducting the reaction without a cooling fan (about 60 °C)
resulted in significantly lower yields (entry 9). Control
experiments highlighted the essential roles of the Ni catalyst,
ligand, photocatalyst, and light (entry 10).
3
Interestingly, benzylic C(sp )−H bond functionalization was
possible with an increased amount (80 mol %) of the Ni
complex (2r). This reaction also proceeded in an efficient
3
manner with α-amino C(sp )−H bonds in dimethylacetamide
After optimization of the reaction conditions, we next
investigated the scope of the reaction. The reactions proceeded
efficiently with various kinds of activated alkynes such as
ynone, ynoate, and ynamide with exclusive α-functionalization
and high E/Z selectivity (Scheme 2), overcoming the
(DMA), leading to a high yield (2s).
Taking advantage of the TIPS group, further transformations
of 2h were performed (Scheme 4). The silyl group was
successfully transformed to halogen functionalities under the
halogenative desilylation conditions previously reported for
8
−11
15
limitations of the previously reported methods.
In all
nonactivated vinyl silanes. The iodinated and brominated
cases, highly Z-selective (mostly >20:1, Z/E) and exclusive α-
products (3a, 3b) were produced in moderate yields, providing
ample scope for additional transformations involving vinyl
halides. For example, the produced vinyl iodide 3a was arylated
maintaining E/Z-stereochemistry (4a) (Figure S6). Further
utilization of the carbonyl group or the ester group was also
1
14
addition products were observed by H NMR spectroscopy.
The reactions with various aliphatic TIPS-protected ynones
2a−2e) proceeded smoothly. Compared to aliphatic ynones,
the aromatic ynones exhibited lower yields. The reaction was
(
B
DOI: 10.1021/acs.orglett.8b02017
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
a
Scheme 3. Scope of C(sp )−H Partners in Hydroalkylation
Scheme 5. Experimental Investigations for Determining the
Reaction Mechanism
a
Alkyne (0.10 mmol), NiCl ·glyme (20 mol %), dtbbpy (30 mol %),
2
Ir[dF(CF )ppy] (dtbbpy)PF (2 mol %), and C−H donor (20
3
2
6
equiv), benzene (1.0 mL) irradiated with a 34 W blue LED. Z/E =
b
c
>
%
20:1. Isolated yields of the Z isomer. 50 °C. NiCl ·glyme (80 mol
2
), dtbbpy (90 mol %).
Scheme 4. Post-functionalization of TIPS Enones
Figure 1. Proposed mechanism.
demonstrated by the synthesis of allylic alcohol (3c) and the
corresponding ynone (2b) through a Weinreb amide.
Notably, the Z geometry was perfectly preserved throughout
the synthetic operations.
catalytic cycle. Such a stepwise process is consistent with
deuterium labeling studies, showing that the vinyl hydrogen
did not originate from THF (Figures S8−S10).
1
6
Based on two control experiments, we believe that our
reaction proceeds through a Ni−alkyl pathway, not a Ni-
hydride pathway. First, less sterically bulky n-butyl ynoate was
used to check the trend in regioselectivity depending on the
C−H coupling partners, as silyl ynoates exhibited exceedingly
high selectivity (Scheme 3 and Table S3). The regioselectivity
is increased with sterically bulkier C−H coupling partners
consistent with a Ni−alkyl pathway (Scheme 5b). If the Ni−H
pathway would be operative, the regioselectivity should not be
changed depending on the sterics of the C−H coupling
A plausible mechanism was proposed based on control
experiments (Scheme 5) and previously reported studies
1
1,12
(Figure 1).
As shown in Table 1, chloride proved to be an
essential component of the Ni/Ir dual system (entries 5−8).
Doyle and co-workers have suggested that the photolysis of
Ni(III)Cl B could generate the chlorine radical, which could
2
12a,b
then abstract a hydrogen atom from THF.
Similarly, the
formation of the THF−TEMPO adduct in a radical quenching
study supported the hypothesis that the reaction also proceeds
via a THF radical intermediate generated by a hydrogen atom
transfer (HAT) process with the chlorine atom (Scheme 5a).
The THF radical generated by this process may rebound to
Ni(II) species C and form the THF-bound Ni(III) complex D.
The alkyl−Ni(III) complex D could be reduced to alkyl−
Ni(II) species E. This nucleophilic alkyl−Ni(II) E can undergo
migratory insertion with 1 to furnish vinyl Ni complex F, as
1
2d
partners.
Second, the reactivity was maintained in
reasonably good yields (50%−60%) even with the addition
of many different bases, although a base can shut down the
generation of a nickel hydride intermediate by abstracting HCl
(Table S4).
In summary, a TIPS-group-induced highly regioselective and
E/Z-selective hydroalkylation of activated alkynes was
developed for the synthesis of trisubstituted enones via
photoredox mediated Ni/Ir dual catalysis. The reaction
delivered the α-selective Z isomer with highly controlled
selectivity that was endowed by the distinguished steric
properties of the TIPS group, which is complementary to the
12d
proposed by the MacMillan group. The innate selectivity of
17
the insertion process, as reported by the Bergman group, and
the sterics of the silyl group endow the high selectivity. The
protodenickelation of F would deliver the desired product with
regeneration of the initial Ni(II) complex A, completing the
C
DOI: 10.1021/acs.orglett.8b02017
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
β-alkylation process via nucleophilic Giese processes and other
formal hydroalkylation reactions of alkynes. Further trans-
formation of the products could provide diverse functionalized
trisubstituted alkenes. A mechanism involving the catalytic
generation of alkyl radicals and insertion of an alkyl−nickel
intermediate into alkynes, which sequentially underwent
protodemetalation to enable the resulting hydroalkylation
reaction, was proposed.
Chem. Soc. 2018, 140, 5701. (e) Kang, B.; Hong, S. H. Chem. Sci.
2
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(
ASSOCIATED CONTENT
Supporting Information
■
(
3
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02017.
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: soonhong@snu.ac.kr.
ORCID
Soon Hyeok Hong: 0000-0003-0605-9735
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Samsung Science and
Technology Foundation under Project Number SSTF-
BA1601-12.
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DOI: 10.1021/acs.orglett.8b02017
Org. Lett. XXXX, XXX, XXX−XXX