Direct Catalytic Asymmetric Addition of Alkylnitriles to Aldehydes with Designed Nickel–Carbene Complexes

Article abstract of DOI:10.1002/anie.202016690

A direct catalytic asymmetric addition of acetonitrile to aldehydes that realizes over 90 % ee is the ultimate challenge in alkylnitrile addition chemistry. Herein, we report achieving high enantioselectivity by the strategic use of a sterically demanding Ni^II pincer carbene complex, which afforded highly enantioenriched β-hydroxynitriles. This highly atom-economical process paves the way for exploiting inexpensive acetonitrile as a promising C2 building block in a practical synthetic toolbox for asymmetric catalysis.

Full text of DOI:10.1002/anie.202016690

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 8739–8743
International Edition: doi.org/10.1002/anie.202016690
German Edition: doi.org/10.1002/ange.202016690
Homogeneous Catalysis
Direct Catalytic Asymmetric Addition of Alkylnitriles to Aldehydes
with Designed Nickel–Carbene Complexes
Akira Saito, Shinya Adachi, Naoya Kumagai,* and Masakatsu Shibasaki*
Abstract: A direct catalytic asymmetric addition of acetonitrile
to aldehydes that realizes over 90% ee is the ultimate challenge
in alkylnitrile addition chemistry. Herein, we report achieving
high enantioselectivity by the strategic use of a sterically
demanding NiII pincer carbene complex, which afforded highly
enantioenriched b-hydroxynitriles. This highly atom-econom-
ical process paves the way for exploiting inexpensive acetoni-
trile as a promising C2 building block in a practical synthetic
toolbox for asymmetric catalysis.
serious and has only been partly addressed.[9,10] Our group
recently reported a highly enantioselective (average 95% ee)
acetonitrile addition to sterically biased N-diphenylphosphi-
noyl (N-Dpp) imines[11] with a specific NiII complex having
a deep vaulted architecture.[9h] Direct addition of acetonitrile
to aldehydes providing b-hydroxynitriles, however, remained
a challenge and the enantioselectivity was only moderate (up
to 77% ee).[9b] Herein, we disclose the catalytic conditions
that directly produce b-hydroxynitriles from aldehydes and
alkylnitriles with the highest enantioselectivity yet reported.
While the enantioselectivity is sensitive to the aldehyde
structure, this achievement is an important step toward the
prospective development of general catalytic asymmetric
conditions for alkylnitrile addition reactions.
Catalytic asymmetric addition reactions of anionic carbon
nucleophiles are critical in organic synthesis for constructing
highly complex enantioenriched molecular architectures.
Despite the widespread application of enolates as common
active nucleophiles for this purpose, chemists have paid little
attention to a-cyanocarbanions because of their limited
accessibility. Nitriles, direct precursors of a-cyanocarbanions,
are generally stable and regarded as solvents for chromatog-
raphy and various reactions owing to their inert nature toward
a wide range of chemical transformations.[1] Acetonitrile is the
most widely used nitrile-based common solvent, but has little
utility as a carbon pronucleophile in catalytic asymmetric
reactions because 1) its high pKa (31.3 in DMSO) significantly
interferes with catalytic generation of the corresponding a-
cyanocarbanion,[2–7] and 2) the minimal steric bias of the a-
cyanocarbanion significantly raises the hurdle for decent
stereocontrol at the stage of carbon-carbon bond formation
with certain electrophiles (Scheme 1). Although recent
advances in catalysis with well-designed metal complexes
allow for catalytic promotion of direct addition of acetonitrile
to various electrophiles,[8] the issue of stereocontrol is more
We began our study by evaluating the previously identi-
fied NiII carbene complex capable of highly enantioselective
addition of acetonitrile to N-Dpp imines.[9h] The reaction of
acetonitrile with 2-naphthaldehyde 1a under the previously
determined optimal conditions from the reaction with N-Dpp
imines using NiII pincer complex C1 unexpectedly afforded
the corresponding product 2a with only 63% ee (Table 1,
entry 1).[12,13] Tracing the enantiopurity of 2a in the course of
the reaction at room temperature revealed the gradual
erosion of enantiopurity, indicating that a retro reaction
occurred (Figure 1). We next examined the effects of a co-
solvent system with alcoholic solvents to suppress the
undesired retro reaction. While MeOH halted the catalysis
and tBuOH was barely impactful, a CH3CN/iPrOH mixed
solvent system improved the enantioselectivity of 2a to 76%
ee (entries 2–4). Lowering the reaction temperature further
improved the enantioselectivity to 93% ee (entry 5). Under
these satisfactory conditions, we systematically investigated
the substituent effect of the NiII pincer complex (entries 6–
12). Complexes C2–4 armed with alkyl substituents (iPr, tBu,
Bn) were generally ineffective and delivered product 2a in
low to modest yield and enantioselectivity (entries 6–8).
Anticipating more sterically biasing Ni complexes with
aromatic substituents, methylated benzenes and naphthyl
units were tested (entries 9–12). Unexpectedly, complex C5
with a larger mesityl substituent afforded only trace amounts
of 2a with lower enantioselectivity (77% ee), presumably due
to excessive steric bias (entry 9). Complex C6 bearing
a modestly biasing unit of 3,5-xylyl groups produced 2a with
94% ee (entry 10). Although complex C7 with 1-naphthyl
groups provided a narrower pocket en route to the NiII center
than complex C8 with 2-naphthyl groups, the resulting
enantioselectivity was only slightly inferior, and C8 produced
enantioselectivity similar to that of C1 and C6 (entries 11, 12).
Based on the yield and broad availability of the ligand
skeleton (from (R)-phenylglycine), the conditions of entry 5
Scheme 1. Catalytic asymmetric addition of acetonitrile to aldehydes.
[*] Dr. A. Saito, Dr. S. Adachi, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
E-mail: nkumagai@bikaken.or.jp
mshibasa@bikaken.or.jp
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016690.
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Table 1: Optimization of direct catalytic addition of acetonitrile to 2-naphthaldehyde 1a.[a]
using complex C1 were considered
optimal for further study. It should
be noted that the present catalysis
was capable to promote the direct
addition of propionitrile to 1a to
give anti-3a as a major diastereo-
mer with high enantioselectivity
(Scheme 2), albeit the diastereose-
lectivity needs further improve-
ment.
Entry
Ni
R
Solvent[b]
T [8C]
Yield [%]
ee [%]
complex
1
2
3
4
5
6
7
8
C1
C1
C1
C1
Ph
Ph
Ph
Ph
Ph
iPr
tBu
Bn
mesityl
3,5-xylyl
1-naph
2-naph
CH3CN
0
0
0
88
–
63
–
76
64
CH3CN/MeOH
CH3CN/iPrOH
CH3CN/tBuOH
CH3CN/iPrOH
CH3CN/iPrOH
CH3CN/iPrOH
CH3CN/iPrOH
CH3CN/iPrOH
CH3CN/iPrOH
CH3CN/iPrOH
CH3CN/iPrOH
91
92
>99
63
23
5
The proposed catalytic cycle is
93 delineated in Figure 2a. On the
0
C1
À20
À20
À20
À20
À20
À20
À20
À20
C2[c]
C3[c]
C4[c]
C5
45
basis of the detailed DFT study
reported by Ariafard et al.,[8l] N-
bound cyanocarbanion/C1 complex
I formed from C1 and tBuOK,
which is in equilibrium with C-
bound complex II, is a plausible
intermediate en route to the enan-
tioselective addition to aldehyde 1.
To gain insight into the effective-
ness of complex C1, a steric map of
the catalytic pocket was generated
with the SambVca 2.1 Web tool
based on the crystal structure of Cl
salt of C1 (Figure 2).[14,15] The
buried volume of 57.4% indicates
48
44
77
94
87
92
9
5
10
11
12
C6
C7
C8
83
88
87
C1: R=Ph
C2: R=iPr
C3: R=tBu
C4: R=Bn
(X=NCCH3)
C5: R=mesityl
C6: R=3,5-xylyl
C7: R=1-naph
C8: R=2-naph
[a] 1a: 0.1 mmol, 0.1 M on 1a. [b] For mixed solvent conditions, a 1/1 (v/v) ratio of solvents was used.
[c] The catalyst was prepared from Ni-Cl complex and AgPF6, which was directly used without isolation.
a highly congested environment around the NiII center, which
is geometrically visualized with altimetric contour levels
Figure 1. Time course of the reaction of naphthaldehyde 1a and
acetonitrile at room temperature.
Figure 2. a) Proposed catalytic cycle. b) X-ray crystal structure of Cl
salt of C1, buried volume, and corresponding steric map. Bondi radii
scaled by 1.17, sphere radius 3.5 ꢀ, and mesh spacing 0.1 ꢀ.
Scheme 2. Catalytic asymmetric addition of propionitrile to 2-naphthal-
dehyde 1a.
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deviated from the horizontal plane containing the Ni center.
Aldehydes with an indole unit are structurally similar to the
The steric bias is mainly located in the northwestern and
southeastern quadrants, while northeastern and southwestern
trajectories are opened to achieve high enantioselectivity. The
thus-formed zwitterionic intermediate III is likely responsible
for deprotonation of acetonitrile to drive the following
catalytic cycle.
privileged styryl unit and afforded the products 2g and 2h
with high enantioselectivity, while the N-Me derivative 1g
produced a low yield, likely due to lower electrophilicity. The
thiophene architecture was recognized as a privileged struc-
ture and product 2i was isolated with the highest enantiose-
lectivity (96% ee). A different heteroatom substitution
pattern on the privileged structural unit led to a marginal
loss in enantioselectivity (below 90% ee) (2j–n). Embedding
an ethylene unit into the privileged structure resulted in
eroded enantioselectivity (aldehyde 1b vs. 1o), indicating the
pivotal role of the styryl unit to assure enantiodifferentiation.
The reduced enantioselectivity observed for benzaldehyde
derivatives further supported this trend; while p-MeO, -Cl,
-Br, or m-MeO substituted aldehydes 1p–s exhibited no less
than 80% ee, p-F or m-Cl derivatives 1u,v as well as
benzaldehyde 1t gave the corresponding products with less
satisfactory enantioselectivity. Bulkier catalyst C6 partly
improved the enantioselectivity of 1t and 1u, and stereodif-
ferentiation of sterically larger piperonal 1w was more
significantly enhanced to 87% ee.
With the optimal conditions in hand, the substrate scope
was systematically studied as summarized in Table 2.[16,17] The
present catalysis is scalable and the reaction of 1a was
performed on a one-gram scale without any detrimental
effects. Intriguingly, enantioselectivity is highly sensitive to
the aldehyde structure, revealing that the styryl unit is
privileged to reach > 90% ee. Other than naphthaldehyde
1a, (E)-cinnamaldehyde 1b was suitable for the present
catalytic conditions to give 2b in 91% ee, albeit with
somewhat eroded yield. para-Substituents barely interfered
with the enantioselectivity, irrespective of their electron-
withdrawing or -donating nature (2c,d). Quinoline-5-carbox-
aldehyde 1e, sharing the privileged unit, gave the correspond-
ing product 2e in 93% ee, demonstrating that a Lewis basic
functionality located far from the carbonyl moiety is toler-
ated. p-Extended aldehyde 1 f with a pyrene unit was also
accommodated, resulting in high enantioselectivity (93% ee).
The cyano groups of the product can be treated as masked
amine and carboxyl functionalities (Scheme 3). 1,3-Amino
alcohol 4 was generated by treatment with BH3·SMe2 in
Table 2: Substrate scope of direct catalytic asymmetric addition of acetonitrile to aldehydes.[a]
[a] 1: 0.1 mmol, 0.1 M on 1. [b] 1.0 g of 1a was used. [c] 5 mol% of C1 and tBuOK were used. [d] C6 instead of C1 was used as catalyst.
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Acknowledgements
This work was financially supported by JSPS KAKENHI
Grant Number JP20H03371 (Grant-in-Aid for Scientific
Research (B)) to M.S., and JP19K22192 (Grant-in-Aid for
Exploratory Research) and JP20H02746 (Grant-in-Aid for
Scientific Research (B)) to N.K. We are grateful to Dr.
Ryuichi Sawa, Ms. Yumiko Kubota, and Dr. Kiyoko Iijima at
the Institute of Microbial Chemistry for technical support in
NMR.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: aldehydes · enantioselectivity ·
homogeneous catalysis · nickel · nitriles
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[17] The reaction using ketone needs to be further development:
methyl benzoylformate gave the corresponding product in 45%
yield and 45% ee (w/o iPrOH, 08C, 24 h).
[15] The crystallographic data is associated with Ref. [8h].
[16] The reaction using aliphatic aldehyde needs further develop-
ment: the reaction of acetonitrile and cyclohexanecarboxalde-
hyde gave the corresponding product in 14% yield (potassium
salt of BHT was used instead of tBuOK, rt, 24 h).
Manuscript received: December 16, 2020
Revised manuscript received: January 22, 2021
Accepted manuscript online: February 2, 2021
Version of record online: March 10, 2021
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