Nickel-Catalyzed Isomerization/Allylic Cyanation of Alkenyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.1c02143

Herein reported is a nickel-catalyzed isomerization/allylic cyanation of alkenyl alcohols, which complements current methods for the allylic substitution reactions. The specific diphosphite ligand and methanol as the solvent are crucial for the success for this transformation. A gram-scale regioconvergent experiment and formal synthesis of quebrachamine demonstrate the high potential of this methodology.

Full text of DOI:10.1021/acs.orglett.1c02143

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Letter
Nickel-Catalyzed Isomerization/Allylic Cyanation of Alkenyl Alcohols
Ying Ding, Jinguo Long, Feilong Sun, and Xianjie Fang*
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ABSTRACT: Herein reported is a nickel-catalyzed isomerization/allylic cyanation of alkenyl alcohols, which complements current
methods for the allylic substitution reactions. The specific diphosphite ligand and methanol as the solvent are crucial for the success
for this transformation. A gram-scale regioconvergent experiment and formal synthesis of quebrachamine demonstrate the high
potential of this methodology.
ince cyano groups find potential utility in pharmaceuticals
metal along the chain and end up with the β-hydride
elimination on the hydroxyl group to afford ketone (Scheme
1a).6,7b,8
S
and biologically important compounds1 and can be readily
converted into a wide variety of functional groups such as
amines, carboxylic acid derivatives, ketones, and so on,2 their
introduction is of great interest for chemists. In this context,
cyanation of allylic alcohol and its derivatives has attracted
increasing attention.3 However, these methods suffer from the
following drawbacks: (1) prior conversion of the allyl alcohols
to the derivatives bearing good leaving groups is usually
necessary,3a−c and (2) when a free allyl alcohol is used as the
starting material, Lewis3d or Brønsted3e acids are often added
to activate the hydroxyl group, which limits the functional
group tolerance. Consequently, the development of unique and
efficient redox-neutral strategies for the cyanation of allyl
alcohol is highly desirable. Recently, we reported a dual
catalytic cycle that merges the Ni-catalyzed allylic cyanation
and asymmetric hydrocyanation.3f However, the alkenes must
be installed at the neighborhood of the alcohol and thus only
limited substrate scope is amenable. Therefore, we envisioned
that it will be an interesting complement to our previous work
if we could install the starting alkene at a different position of
the starting alcohol to achieve the allylic cyanation via the
alkene isomerization strategy, which has attracted considerable
attention in the last decades.
Remote functionalization mediated by alkene isomerization
is a powerful strategy for the construction of valuable
molecules from readily available materials.4−9 In this content,
alkenyl alcohols are considered as versatile substrates for these
transformations. The isomerization of alkenyl alcohols to
ketones through olefin migration has been catalyzed by using
various metals including Pd6, Rh7, Ru8, and Fe9. This process is
usually triggered by the CC bond insertion into metal-
hydride or metal-arylate species, followed by the iterative β-H
eliminations and migratory insertions to change the site of
Inspired by the isomerization of alkenyl alcohols to ketones,
we wonder if the key intermediate B (Scheme 1b) could
undergo other transformations, such as allylic substitution
reactions (Scheme 1b, B to D) which have gained extra
attention for C−C and C−X (X = N, O, S, etc.) bond
formation,10 instead of continuing to isomerize to ketone
(Scheme 1b, B to C). Once achieved, this methodology can
provide a novel synthetic pathway for allylic substitution
reactions. Although it was feasible theoretically, some
challenges must be addressed: (1) due to the strong
thermodynamic driving force to furnish ketone when the
migration of a double bond is initiated, trapping the allyl
alcohol intermediate is challenging, and (2) combination of
multistep by using a single catalytic system would offer the
advantage of operational simplicity, leading to a higher step
economy, yet it would pose extra difficulty to identify a catalyst
that would exhibit sufficient reactivity and accurate selectivity
in each of the key steps.
Based on the above assumptions and our previous work,3f,11
we envisaged that the system of acetone cyanohydrin and
nickel allows the possibility of achieving this conversion
because we have achieved migratory hydrocyanation and allylic
cyanation in this system, respectively. Herein, we expect to
Received: June 25, 2021
Published: July 23, 2021
https://doi.org/10.1021/acs.orglett.1c02143
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6073−6078
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a
Scheme 1. Catalytic Remote Functionalization of Alkenyl
Alcohols
Table 1. Reaction Optimization with Substrate 1a
b
b
entry
ligand
Dppe
solvent
2a yield (%) 3a yield (%)
g
g
g
g
g
g
g
g
g
1
2
3
4
5
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
n-hexane
ND
ND
ND
ND
ND
ND
ND
2
42
47
28
31
36
26
33
28
Dppf
Xantphos
DPEphos
BINAP
P(OPh)3
L1
L2
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
c
6
7
8
9
4
13
10
11
12
13
14
15
16
17
18
19
20
21
22
ND
5
85
62
toluene
CH3CN
ND
2
27
24
THF
1,4-dioxane
DMA
2
24
report the first Ni-catalyzed isomerization/allylic cyanation of
alkenyl alcohols (Scheme 1c).
11
24
DMF
H2O
24
20
With the hypothesis in mind, we began our study by testing
the reactivity of the model reaction undertaking different
ligands in the presence of Ni(cod)2 and acetone cyanohydrin
(Table 1). When commercially available ligands such as Dppe,
Dppf, xantphos, DPEphos, BINAP, or P(OPh)3 were used, no
desired product 2a was observed, and ketone 3a was detected
in 26−47% yield (entries 1−6). Hypophosphite ligand L1 was
ineffective for the conversion of alkenyl alcohol 1a to 2a (entry
7). Then, bidentate phosphite L2 and L3 were tested, and we
were delighted to find the formation of 2a albeit with only 2
and 4% yield, respectively (entries 8 and 9). Solvent screening
indicated that the polarity of the solvents plays a key role in the
chemoselectivity. Non-polar solvents such as n-hexane and
toluene led to large amounts of ketone 3a, while almost no
desired product 2a was observed (entries 10 and 11). In
addition to acetonitrile, polar solvents are beneficial to the
formation of 2a (entries 12−16). It is worth mentioning that
the desired product 2a will further undergo a hydrocyanation
reaction to form the corresponding dinitrile compound when
using water as a solvent (entry 17). When switching water to
methanol as solvent, the yield of 2a was encouragingly
increased to 69% (entry 18). The solvent effect phenomena
might be attributable to methanol (a hydrogen-bonding
solvent) accelerating the formation of the key intermediate
π-allylmetal complex by lowering the activation barrier.12 In
order to improve the yield of 2a, we tried to adjust other
reaction conditions. The yield was further improved to 80%
while decreasing the catalyst loading to 2 mol % (entry 19).
When shortening the reaction time to 3 h, 2a can be obtained
with the same GC yield and 74% isolated yield (entry 20).
ND
69
9
MeOH
MeOH
MeOH
MeOH
trace
trace
trace
trace
ND
d
80
e
f
L3
L3
L3
80(74)
72
h
i
MeOH
ND
a
The reactions were carried out at 80 °C for 12 h with 1a (0.1 mmol),
Me2C(OH)CN (0.11 mmol), and solvent (0.3 mL) in the presence of
Ni(cod)2 (5 mol %) and ligand (5 mol %) under a N2 atmosphere,
b
ND = not detected. The yields were determined by GC analysis
c
using n-dodecane as the internal standard. Ligand (10 mol %).
d
e
Ni(cod)2 (2 mol %) and ligand (2 mol %). Reaction time (3 h).
f
g
h
Isolated yield. 1,4-Dioxane/H2O (50/1, v/v). Ni(4‑tBustb)3 (2 mol
i
%) instead of Ni(cod)2. NiCl2·6H2O (2 mol %) and Zn (20 mol %)
instead of Ni(cod)2.
this reaction was also carried out, yet no excellent
enantioselectivity was presented (for more details, see Table
S1).
We next investigated the scope of substrates with the
optimized conditions (Table 1, entry 20). Whether the
substituent on the phenyl group is an electron-withdrawing
group or an electron-donating group, the corresponding allylic
nitriles can be obtained in moderate to good yields (Scheme
2a, 2b−2j, 43−93%). Surprisingly, substrates bearing un-
protected −OH or −NH2 were tolerated (2e and 2h). When
R1 was a heterocyclic group such as thiophene, the product 2k
was afforded in 52% yield. When R1 was naphthyl, the desired
product 2l was obtained in 54% yield. Afterward, we focused
on the impact of chain length on the reaction (Scheme 2b).
Comparing the results of 2m−2s and 2a, we found that the
longer the methylene intervals between the alkene and −OH,
the lower the yield of the hydrocyanated product. Although the
overall trend is declining, the yield can still reach 51% when
13
Moreover, air stable catalyst Ni(4‑tBustb)3 was tested and
proved to be efficient in this transformation (entry 21), while
the catalytic system of NiCl2·6H2O and Zn was found inactive
(entry 22). Additionally, as this isomerization/allylic cyanation
features an enantioselective potential, an asymmetric version of
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a
tolerated in this transformation and tended to bring a branched
allyl substituted product that then isomerizes to give 2x in 45%
yield (Scheme 2e).
Scheme 2. Reaction Scope
Furthermore, to illustrate the synthetic utility of this
migration/allylic substitution reaction, a gram-scale regiocon-
vergent reaction was conducted with 1:1:1:1 of regioisomers of
alkenyl alcohols, furnishing 2a in 90% yield (Scheme 3a). The
Scheme 3. Gram-Scale Regioconvergent Reaction and
Synthetic Application
a
The reaction was carried out at 80 °C for 3 h with a mixture of 1a
(2.16 mmol, 350 mg), 1t (2.16 mmol, 350 mg), 1a-1 (2.16 mmol, 350
mg), 1a-2 (2.16 mmol, 350 mg), Me2C(OH)CN (9.5 mmol, 808
mg), and MeOH (26 mL) in the presence of Ni(cod)2 (2 mol %, 47.5
b
mg) and L3 (2 mol %, 189.8 mg) under a N2 atmosphere. The
reaction was carried out at 100 °C for 24 h with 1y (0.1 mmol, 34.1
mg), Me2C(OH)CN (0.11 mmol, 9.4 mg), and MeOH (0.3 mL) in
the presence of Ni(cod)2 (5 mol %, 1.3 mg) and L3 (5 mol %, 5.5
mg) under a N2 atmosphere.
reported route for the total synthesis of the natural product
quebrachamine14 required five steps from the aldehyde to the
key intermediate (2y). However, herein, our method stream-
lined the route to two steps from the same aldehyde via the
Grignard reaction and isomerization/allylic cyanation reaction
(Scheme 3b).
To gain more insight about this transformation, the reaction
1
with 1m as substrate was monitored by H NMR analysis by
using mesitylene as an internal standard (see Table S2 and
Figure S1). Allyl alcohol 1m-m (see Figure S1) was indeed the
intermediate in this transformation and was nearly fully
consumed within 30 min. In addition, several deuterium
labeling experiments were carried out for further study
(Scheme 4). The protected substrate 1a-P was submitted
with fully deuterium-labeled acetone cyanohydrin under the
standard reaction conditions and the corresponding product
D-2a was gathered with the deuterium incorporated at C2
(0.01D), C3 (0.79D), C4 (1.65D), and C5 (2.48D) in 68%
yield, proving an iterative β-H elimination/migratory insertion
mechanism. D-2u was gathered with the deuterium incorpo-
rated at C2 (0.06D), C3 (0.68D), C4 (1.64D), C5−C6
(3.33D), and C7 (2.52D) in 49% yield using 1u-P as substrate.
a
Reactions were conducted on a 0.2 mmol scale. Yields of isolated
b
c
products. Reactions were conducted on a 0.1 mmol scale. Reaction
conducted at 50 °C for 12 h.
olefins migrate across eight carbons. Moreover, the trans-
internal olefin can provide 2t in 83% yield, and the cis-internal
olefin 1u can also generate 2u in 67% yield (Scheme 2c). In
order to figure out whether R1 must be an aryl group, we
designed 1v and 1w to give the corresponding 2v and 2w in 61
and 40% yield, respectively, indicating that conjugated non-aryl
substituted substrates are also applicable in this catalytic
system (Scheme 2d). Unexpectedly, primary alcohol 1x was
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etc.) along the alkyl chain. The subsequent β-H elimination of
VI delivers the allyl alcohol VII. Subsequently, species I
undergoes oxidative addition with the allyl alcohol VII and
then would react with acetone cyanohydrin to generate species
IX. Finally, reductive elimination of IX furnishes allylic nitrile 2
and regenerates Ni0 complex I.
Scheme 4. Deuterium-Labeling Experiments
In summary, we reported the first nickel-catalyzed tandem
isomerization/allylic cyanation reaction of alkenyl alcohols.
This methodology provides a novel synthetic pathway for
allylic substitution reaction. The catalytic system tolerated a
variety of functional groups and proved to be efficient when
olefin could migrate up to eight carbons. A gram-scale
synthesis and a synthetic application demonstrated the
potential of this transformation. Further mechanistic studies
support a novel sequential alkene isomerization (chain-
walking)/allylic cyanation pathway.
This result indicated that the isomerization of olefins is
bidirectional and reflected the poor site selectivity for [H−
NiL3II−CN] migratory insertion.
Based on reaction monitoring profiles and deuterium
labeling experiments, we proposed the mechanism of this
reaction (Scheme 5). First, precatalyst Ni(cod)2 undergoes
ligand exchange with L3 to form active species I. Then, [H−
NiL3II−CN] species II was generated through oxidative
addition of acetone cyanohydrin with active species I. Species
II would undergo hydronickelation of 1 to trigger a reversible
sequence of β-H elimination/migratory reinsertion steps to
access a series of alkyl−Ni(II)−CN intermediates (III, V, VI,
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02143.
Experimental procedures, characterization data, and
copies of NMR spectra for all new products (PDF)
Scheme 5. Proposed Catalytic Cycle
AUTHOR INFORMATION
Corresponding Author
■
Xianjie Fang − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and
Chemical Engineering, Shanghai Jiao Tong University,
Shanghai 200240, China; orcid.org/0000-0002-3471-
8171; Email: fangxj@sjtu.edu.cn
Authors
Ying Ding − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and
Chemical Engineering, Shanghai Jiao Tong University,
Shanghai 200240, China
Jinguo Long − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and
Chemical Engineering, Shanghai Jiao Tong University,
Shanghai 200240, China
Feilong Sun − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and
Chemical Engineering, Shanghai Jiao Tong University,
Shanghai 200240, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02143
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Recruitment Program of
Global Experts and the startup funding from Shanghai Jiao
Tong University. We thank Prof. Yong-Qiang Tu (Shanghai
Jiao Tong University) for his long-term support.
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