Nickel-catalyzed site- and stereoselective reductive alkylalkynylation of alkynes

Article abstract of DOI:10.1016/j.chempr.2020.12.024

The development of a catalytic multicomponent reaction by orthogonal activation of readily available substrates for the streamlined di-functionalization of alkynes is a compelling objective in organic chemistry. Alkyne carboalkynylation, in particular, offers a direct entry to valuable 1,3-enynes with different substitution patterns. Here, we show that the synthesis of stereodefined 1,3-enynes featuring a trisubstituted olefin is achieved by merging alkynes, alkynyl bromides, and redox-active N-(acyloxy)phthalimides through nickel-catalyzed reductive alkylalkynylation. Products are generated in up to an 89% yield as single regio- and E isomers. Transformations are tolerant of diverse functional groups and the resulting 1,3-enynes are amenable to further elaboration to synthetically useful building blocks. With olefin-tethered N-(acyloxy)phthalimides, a cascade radical addition/cyclization/alkynylation process can be implemented to obtain 1,5-enynes. This study underscores the crucial role of redox-active esters as superior alkyl group donors compared with haloalkanes in reductive alkyne dicarbofunctionalizations.

Full text of DOI:10.1016/j.chempr.2020.12.024

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Nickel-catalyzed site- and stereoselective
reductive alkylalkynylation of alkynes
Yi Jiang, Jiaoting Pan, Tao Yang,
Yu Zhao, Ming Joo Koh
zhaoyu@nus.edu.sg (Y.Z.)
chmkmj@nus.edu.sg (M.J.K.)
•
HIGHLIGHTS
•
•
A Ni-catalyzed regime for
reductive alkylalkynylation of
alkynes is described
Readily accessible N-(acyloxy)
phthalimides are used as alkyl
group donors
Stereodefined 1,3-enynes bearing
diverse functional groups can be
generated
The method is amenable to
cascade annulation
transformations
Electrophilic redox-active esters and alkynyl halides can be synergistically
employed in alkylalkynylation processes in the presence of a nonprecious Ni-
based catalyst under mild reductive conditions. Diverse 1,3-enyne products can be
obtained in excellent stereochemical purity, and further application to cascade
annulation reactions can be implemented. Mechanistic evidence suggests that N-
(acyloxy)phthalimides are uniquely capable of intercepting an in situ-generated
alkynylnickel species to overcome haloalkyne homocoupling that would otherwise
pose complications with an alkyl halide.
Jiang et al., Chem 7, 993–1005
April 8, 2021 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.12.024

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Nickel-catalyzed site- and stereoselective
reductive alkylalkynylation of alkynes
1,3,
Yi Jiang,1 Jiaoting Pan,1,2 Tao Yang,1 Yu Zhao,1,2, and Ming Joo Koh
*
*
SUMMARY
The bigger picture
Despite key advances in
The development of a catalytic multicomponent reaction by orthog-
onal activation of readily available substrates for the streamlined di-
functionalization of alkynes is a compelling objective in organic
chemistry. Alkyne carboalkynylation, in particular, offers a direct en-
try to valuable 1,3-enynes with different substitution patterns.
Here, we show that the synthesis of stereodefined 1,3-enynes
featuring a trisubstituted olefin is achieved by merging alkynes, al-
kynyl bromides, and redox-active N-(acyloxy)phthalimides through
nickel-catalyzed reductive alkylalkynylation. Products are gener-
ated in up to an 89% yield as single regio- and E isomers. Transfor-
mations are tolerant of diverse functional groups and the resulting
1,3-enynes are amenable to further elaboration to synthetically use-
ful building blocks. With olefin-tethered N-(acyloxy)phthalimides, a
cascade radical addition/cyclization/alkynylation process can be im-
plemented to obtain 1,5-enynes. This study underscores the crucial
role of redox-active esters as superior alkyl group donors compared
with haloalkanes in reductive alkyne dicarbofunctionalizations.
multicomponent reductive
dicarbofunctionalization, alkyl
additions to alkynes remain
limited, and examples involving
sp-hybridized electrophiles have
not been reported. An inherent
challenge is the high propensity of
the alkynyl halide to undergo
undesired homocoupling side
reactions, consequently
suppressing product formation.
As demonstrated here, a Ni-
catalyzed method that selectively
merges alkynes with readily
available electrophilic N-(acyloxy)
phthalimides and alkynyl
bromides have been developed.
This protocol enables access to
valuable structurally sophisticated
and stereodefined 1,3-enynes,
which are amenable to further
derivatization to other useful
building blocks. The mechanistic
insights derived from the
INTRODUCTION
Aliphatic carboxylic acids are abundant feedstock chemicals that have found
extensive utility in chemical synthesis.1,2 With recent advances in cross-coupling
chemistry, these readily available organic molecules, which were once regarded
as non-traditional cross-partners, have emerged as convenient alkyl donors in cata-
lytic decarboxylative C–C bond-forming transformations, either via the innate
carboxyl groups3–10 or their activated ester derivatives.11–23 These developments
are further driven by the much wider commercial availability of alkyl carboxylic acids
as compared with conventional alkyl halides or alkylmetal reagents.12,22,24 A related
class of reactions that utilize N-(acyloxy)phthalimides (or NHPI esters) involve decar-
boxylative alkyl additions to alkynes25 or alkenes.26–37 Intrigued by previous studies,
we speculated if alkyl NHPI esters could be exploited in three-component processes
by merging with an alkyne and an alkynyl halide to deliver synthetically valuable
acyclic 1,3-enyne motifs, conjugated entities commonly embedded within natural
products, pharmaceuticals, agrochemicals, and materials.38–42
synergistic combination of a
redox-active ester and an
organohalide are expected to
provide practical solutions for
addressing other longstanding
problems in catalytic systems that
employ multiple electrophiles.
Various routes to architecturally analogous 1,3-enynes that contain a trisubstituted
alkene moiety43–54 have been developed, but a majority of them focused on two-
component systems involving coupling reactions of elaborated alkynes/alkenes as
starting materials.43,47,48,51,54 Three-component catalytic regimes44–46,49 starting
from simpler, more readily accessible substrates offer a more practical approach
to expeditiously assemble the desired products. However, these methods suffer
from a number of shortcomings. Activated a-functionalized alkyl halides are
frequently employed to generate a stabilized alkyl radical species for alkyne
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addition,44 and a second catalyst is sometimes required to promote C(sp)–C(sp2)
bond formation44,45,49 that limits broad utility.
A growing class of three-component dicarbofunctionalization reactions pertain to
the regioselective addition of carbogenic groups, derived from stable electrophilic
organohalides and/or redox-active esters (versus the more sensitive organometallic
reagents55,56), across C–C p bonds in the presence of a mild reducing agent.57–63 To
date, most reductive alkyl-functionalization processes involve alkyl-aryl or alkyl-al-
kenyl additions to olefins using iodo- or bromoalkanes as the alkyl group donor
(Scheme 1A). In contrast, the corresponding transformations with alkynes are
severely underdeveloped and restricted to alkyl-arylations using organoiodide re-
agents.57 One longstanding challenge that arises from three-component reductive
alkynylation processes is the high propensity of the haloalkyne electrophile to un-
dergo facile homocoupling in the presence of a Ni-based complex, inadvertently
suppressing the desired alkylalkynylation pathway (Scheme 1A, inset; see Scheme
4 for further discussion). Notwithstanding these limitations, we reasoned that the
union of an alkyne, an alkynyl halide, and a redox-active NHPI ester can be achieved
using a Ni-based catalyst under appropriate reductive conditions to give diverse
1,3-enynes with simultaneous control of site and stereoselectivity (Scheme 1B).
Our motivation to pursue this approach is 2-fold: (1) The greater variety of N-(acy-
loxy)phthalimides accessible from aliphatic carboxylic acids (versus alkyl halides)
means that diverse aliphatic units (tertiary, secondary, and primary) can be incorpo-
rated; (2) The ability of NHPI esters to promote challenging alkylalkynylations in
which alkyl halides fail to deliver, by minimizing rampant undesired pathways arising
from homocoupling64,65 and cross-coupling14,16 of the alkynyl halide and NHPI ester
reactants, as well as alkyne cyclotrimerization66 (Scheme 4 for further discussion).
Herein, we disclose the first reductive protocol that accomplishes selective alkyne
alkylalkynylation using NHPI esters as efficient aliphatic group donors.
RESULTS AND DISCUSSION
Reaction optimization
Examination of conditions for the reaction of 1a (1 equiv), 2a (1.2 equiv), and 3a (2.5
equiv) showed that the desired 1,3-enyne product 4a could be obtained in a 67% GC
yield (>95% regio- and E selectivity) in the presence of 10 mol % of the Ni-based
complex derived from NiBr2$diglyme and L1, Mn (2.5 equiv) and DMA as solvent
under ambient conditions (Table 1, entry 1). Switching the reducing agent to Zn or
tetrakis(dimethylamino)ethylene (TDAE) led to poor yields of 4a with excessive by-
product formation from 1a cyclotrimerization66 and 2a homocoupling64,65 (Table
1, entries 2 and 3). Other Ni-based complexes were less effective in promoting
alkylalkynylation (Table 1, entry 4), while less electron-rich bipyridine and phenan-
throline ligands L2ÀL8 afforded 4a in unsatisfactory yields (Table 1, entry 5). Chang-
ing DMA to other polar solvents also did not improve results (Table 1, entry 6).
1Department of Chemistry, National University of
Singapore, 12 Science Drive 2, Singapore 117549,
Republic of Singapore
In order to enhance the catalytic efficiency and/or suppress the undesired formation
of diyne by-products,64,65 various additives were experimented, as detailed in Table
1, entries 7–10. The addition of TMSCl (known to activate the Mn(0) surface67) to the
reaction system was somewhat detrimental (Table 1, entry 7), whereas ZnCl2 or
MgBr2 additives68 also reduced the yield of 4a (Table 1, entries 8 and 9). Considering
the previously reported role of lithium salts in minimizing diyne formation,14 we
found that the use of LiBr (0.5 equiv) indeed improved results, affording 4a in 76%
yield (73% isolated; Table 1, entry 10). It merits mention that decreasing the loading
2Joint School of National University of Singapore
and Tianjin University, International Campus of
Tianjin University, Binhai New City, Fuzhou
350207, China
3Lead contact
*Correspondence: zhaoyu@nus.edu.sg (Y.Z.),
chmkmj@nus.edu.sg (M.J.K.)
https://doi.org/10.1016/j.chempr.2020.12.024
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A
B
Scheme 1. The significance of developing site- and stereoselective reductive alkyne alkylalkynylation
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Table 1. Evaluation of reaction conditions
Entry
Deviation from standard conditions
Conversion (%)a
Yield (%)a
1
2
3
4
none
78
67
Zn instead of Mn
TDAE instead of Mn
>95
36
16
<5
Ni(cod)2, NiCl2$glyme or NiI2 instead of
NiBr2$glyme
74–81
39–57
5
L2-L8 instead of L1
31–82
25–82
77
<5–55
<5–41
25
6
MeCN, DMF or DMSO instead of DMA
TMSCl (0.5 equiv) added
ZnCl2 (0.5 equiv) added
MgBr2 (0.5 equiv) added
LiBr (0.5 equiv) added
7
8
50
15
9
68
36
10
85
76 (73)
Abbreviations: DMA, N,N-dimethylacetamide; DMF, N,N-dimethylformamide; DMSO, dimethyl sulf-
oxide; cod, 1,5-cyclooctadiene; TDAE, tetrakis(dimethylamino)ethylene; TMSCl, trimethylsilyl chloride;
RT, room temperature.
aReactions were performed on a 0.1 mmol scale. Conversions (based on the consumption of 1a) and
yields were determined by GC analysis. Value in parentheses denotes isolated yield.
of 3a to 1.5 equiv led to a diminution in product yield (58% versus 76% with 2.5 equiv
3a, see Table S1 for details).
Scope of the method
To examine the generality of the established conditions, we tested a range of elec-
tronically and sterically diverse aryl- and heteroaryl-substituted alkynes, and the
desired products 4bÀ4aa were isolated in 40%–81% yield as single regio- and E iso-
mers (Scheme 2). Both electron-rich and electron-deficient arenes were tolerated,
including those that contained a NHBoc (4h), Lewis basic aniline (4g), and
electrophilic aldehyde (4k). Synthesis of 4j that is functionalized with a bromoaryl
substituent highlights the transformation’s remarkable chemoselectivity (<5% hy-
drodebromination side products). As demonstrated by the preparation of 4b, the
transformations may be performed on a larger scale (3 mmol) without appreciable
diminution in efficiency.
Products that bear heterocyclic units (4q and 4r), as well as those derived from com-
plex bioactive compounds (4uÀ4w), could be generated. By using a D-substituted
alkyne, tetrasubstituted deuterium-labeled olefins such as 4x, which otherwise
might be difficult to prepare by other means, could be secured through the present
protocol. However, erosion of stereoselectivity was observed in reactions with acti-
vated propiolates (4ab),69 whereas internal alkynes were resistant to alkylalkynyla-
tion (cf. 5; <5% conversion [conv.] to product). Aliphatic alkynes were also found
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Scheme 2. The scope of alkynes and alkynyl bromides in reductive alkylalkynylation
Regioisomeric ratios (r.r.) and E:Z ratios were determined by GC and 1H NMR analysis. Yields are for isolated and purified products.
aThe reaction was conducted on 3 mmol scale.
bThe reactions were conducted with LiBr (1 equiv) and DMSO as solvent.
cThe products were generated in 95:5 E:Z ratio.
dThe product was generated in 94:6 E:Z ratio.
eThe reaction was conducted with 1 (3 equiv) and 2 (1 equiv), and the product was generated in 63:37 Z:E ratio.
to be ineffective substrates under the standard conditions. Besides silyl-substituted
bromoalkynes, aryl- and alkyl-functionalized alkynyl bromides also underwent an
efficient reaction to deliver the expected 1,3-enynes 4yÀ4aa in 46%–53% yield
and 94%–95% E selectivity.
A wide assortment of aliphatic NHPI esters served as effective reagents for alkylalky-
nylation (Scheme 3). These include tertiary alkyl N-(acyloxy)phthalimides (affording
4acÀ4as with quaternary carbon centers), secondary alkyl N-(acyloxy)phthalimides
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Scheme 3. The scope of redox-active esters in reductive alkylalkynylation
Regioisomeric ratios (r.r.), diastereomeric ratios (d.r.) and E:Z ratios were determined by GC and 1H NMR analysis. Yields are for isolated and purified
products.
aThe reactions were conducted with 1 (3 equiv) and 2 (1 equiv).
bThe reactions were conducted with 1 (1 equiv), 2 (1.5 equiv) and C4F9I (1.7–2 equiv).
cThe reaction was conducted with 1 (3 equiv), 2 (1 equiv) and C4F9I (2 equiv) with L7 (12 mol %) as ligand.
dThe reactions were conducted with 1 (3 equiv), 2 (1 equiv) and LiBr (1 equiv) with L4 (12 mol %) as ligand and CuTC (10 mol %) as co-catalyst.
eThe reactions were conducted with 1 (3 equiv), 2 (1 equiv) and LiBr (1 equiv) with L1 (12 mol %) as ligand and CuTC (10 mol %) as co-catalyst.
(affording 4aw and 4ax with tertiary carbon centers), as well as primary alkyl N-(acy-
loxy)phthalimides (4ay and 4az). To facilitate secondary and primary alkyl additions,
an additional 10 mol % of CuTC was added as a co-catalyst to improve yields,
possibly by stabilization of the corresponding alkyl radicals generated.70 The diver-
sity of aliphatic groups which can be installed (such as oxetane 4ag, pyrans 4al and
4am, piperidine 4ao, and acid-labile acetal 4an) compares favorably with previous
methods that employed less readily available haloalkanes.57,60,71
Structurally sophisticated alkyl additions could be implemented as exemplified by
the products 4ar (from ketopinic acid) and 4as (from dehydroabietic acid). To incor-
porate fluoroalkyl units, due to the difficulty of fluoroalkyl NHPI esters to generate
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the requisite fluorinated radical species,72 we turned to perfluoroalkyl iodide to
deliver alkylalkynylation of both aryl- and alkyl-substituted alkynes. In the event,
the F-containing tri- and tetrasubstituted 1,3-enynes 4at–4av were successfully iso-
lated in 36%–53% yield.
Mechanistic studies
As shown in Scheme 4, studies were carried out to elucidate the mechanism of the
reductive alkyne alkylalkynylation process.
Remarkably, control experiments showed that when NHPI ester 3a was replaced by
the corresponding 2-iodo-2-methylpropane 6, there was <5% conv. to the 1,3-enyne
product 4a. Instead, the alkyne 1a was fully consumed in cyclotrimerization66 to form
mixtures of arene side product 8, and homocoupling of bromoalkyne 2a to give diyne
7 was detected (Scheme 4A). Repeating the reaction under previously established
reductive dicarbofunctionalization conditions57 also did not yield 4a (ꢀ40% conv.
of 2a to 7, <5% conv. of 1a to 8). These observations not only highlight the importance
of the redox-active ester component as an effective alkyl donor in these multicompo-
nent reactions but also provide hints that the alkynyl bromide was probably much
more reactive (versus the alkyl iodide), inadvertently suppressing the desired alkylal-
kynylation pathway and causing homocoupling of the bromoalkyne to predominate.
Additional control experiments shed further light on the reaction (Scheme 4B). Under
standard conditions, the reaction between bromoalkyne 2a and 6 led to full conversion
of 2a to diyne 7 (<5% cross-coupling to 9 detected). When alkyne 1a was treated with 2a
under the same conditions, >95% conv. to 7 was also detected and 1a underwent un-
desired cyclotrimerization. In contrast, replacing the iodoalkane 6 with NHPI ester 3a
only afforded trace amounts of 7 (<5% cross-coupling to 9), and 3a was fully consumed
(presumably by decomposition to isobutene/isobutane under the reductive condi-
tions73). These observations imply that the presence of 3a somehow inhibited 2a homo-
coupling by preferentially engaging with an in situ-generated organonickel species,
albeit no productive reaction could occur if alkyne 1a was absent to trap the t-Bu radical
formed (Scheme 5). Notably, subjecting 1a to 3a under the established conditions
selectively furnished Z alkene 10 in 14% GC yield, leading us to deduce that the
CÀC(t-Bu) bond and the adjacent C–Ni bond are generated in an anti configuration
(presumably to minimize steric repulsions) within the alkenylnickel intermediate I
(Scheme 5).10,57 In the absence of the alkynyl bromide, 10 might be formed by adven-
titious protodemetallation of I with residual moisture.
Based on our investigations and related studies,14,60,65 a tentative mechanism is pro-
posed in Scheme 5. Starting from an in situ-generated Ni(0) species i (e.g., from the
reduction of the Ni(II) pre-catalyst14,65), oxidative addition with bromoalkyne 2 fol-
lowed by a single-electron reduction in the presence of Mn gives rise to an alkynyl-
nickel(I) species iii. At this stage, a second molecule of 2 could potentially react with
iii to give dialkynylnickel(III) vii that subsequently reductively eliminates to afford the
undesired diyne side product 7. However, if a NHPI ester 3 is present in the system,
the reaction trajectory could be altered as 3 chemoselectively engages with iii,
through a single-electron transfer (SET) decarboxylative pathway,14 to furnish alky-
nylnickel(II) complex iv with concomitant ejection of CO2, phthalimide anion and
an alkyl radical species. Facile capture of the alkyl radical by alkyne 1 generates an
alkenyl radical that recombines with iv to form E-alkenylnickel(III) complex v. Alterna-
tively, 1 could be activated by associating with the Ni center in iii or iv prior to alkyl
radical addition to give v. The ensuing reductive elimination then generates Ni(I)
phthalimide vi and releases the desired 1,3-enyne 4. Following another single-
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Scheme 4. Mechanistic investigations
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Scheme 5. Proposed catalytic mechanism for reductive alkylalkynylation
electron reduction by Mn, i is regenerated to turn over the catalytic cycle. On the
other hand, a less reactive alkyl halide (versus alkyl NHPI ester) is not capable of effi-
ciently intercepting alkynylnickel(I) complex iii, consequently allowing other side re-
actions such as homocoupling of 2 to become competitive in the system.
Synthetic transformations
Using redox-active esters 11 tethered to a terminal olefin, we postulated that a cascade
pathway74 commencing from alkyl radical addition to the alkyne followed by an intramo-
lecular 5-exo-trig cyclization with the C=C bond to give a second alkyl radical species III
before reassociation with the Ni complex for subsequent alkynylation could occur
(Scheme 6A). This would give rise to complex 1,5-enynes 12 bearing a trisubstituted cy-
clopentene nucleus and an alkyne appendage. Gratifyingly, the Ni-catalyzed cascade
annulation processes proceeded smoothly to generate the desired products 12a–12e
in up to 85% yield, further demonstrating the versatility of the alkylalkynylation regime
by taking advantage of radical-based reactivity modes to construct complex molecules.
The utility of the 1,3-enyne products is showcased through a series of synthetic ma-
nipulations involving both the olefin and alkyne motifs toward the preparation of
diverse molecular structures (Scheme 6B). Using the desilylated derivative 13 from
4b,75 facile transformations of the terminal alkyne moiety to a spectrum of different
products can be affected by partial hydrogenation to the 1,3-diene 14 in 52%
yield,76 Au-catalyzed hydration to ketone 15 in 79% yield,77 and Cu-catalyzed
azide-alkyne cycloaddition to 1,2,3-triazole 16 in 70% yield.78 In another instance,
chemoselective epoxidation of the trisubstituted olefin followed by Au-catalyzed cy-
cloisomerization79 afforded the disubstituted furan derivative 17 in 51% overall
yield. On the other hand, partial cis-selective hydrogenation of the internal alkyne
in 4z generated sterically congested 1,3-diene 18 in 40% yield as a single Z isomer.
Conclusion
To conclude, we have demonstrated that a single Ni-based catalyst is capable of medi-
ating regio- and stereoselective alkyl-alkynyl additions to alkynes to deliver valuable
1,3-enyne products. Access to 1,5-enynes was achieved through a radical-based
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Scheme 6. Application to cascade annulation processes and further derivatization
Regioisomeric ratios (r.r.) were determined by GC and 1H NMR analysis. Yields are for isolated and purified products.
cascade transformation, and our investigations shed light on the superior performance
of redox-active esters in overcoming undesired haloalkyne homocoupling by compet-
itively intercepting a putative alkynylnickel intermediate. In situations where two elec-
trophilic halides proved to be ineffective, the synergistic combination of a redox-active
ester and an organohalide63 may provide viable solutions to address other longstand-
ing challenges in dicarbofunctionalizations that employ multiple electrophiles.
EXPERIMENTAL PROCEDURES
Resource availability
Lead contact
Further information and requests for resources should be directed to and will be ful-
filled by the lead contact, Ming Joo Koh (chmkmj@nus.edu.sg).
Materials availability
All materials generated in this study are available from the lead contact without
restriction.
Data and code availability
This study did not generate any datasets.
SUPPLEMENTAL INFORMATION
Supplemental information can be found online at https://doi.org/10.1016/j.chempr.
2020.12.024.
ACKNOWLEDGMENTS
This paper is dedicated to the memory of Professor Chia-Kuang (Frank) Tsung. This
research was supported by the Ministry of Education of Singapore Academic Research
Funds Tier 1: R-143-000-B57-114 (M.J.K.) and Tier 2: R-143-000-A94-112 (Y.Z.).
AUTHOR CONTRIBUTIONS
Y.J., J.P., and T.Y. developed the catalytic method. M.J.K. and Y.Z. directed the investi-
gations. M.J.K. wrote the manuscript with revisions provided by the other authors.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: November 11, 2020
Revised: December 14, 2020
Accepted: December 23, 2020
Published: January 20, 2021
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