Nickel-Catalyzed Formal Aminocarbonylation of Unactivated Alkyl Iodides with Isocyanides

Article abstract of DOI:10.1021/acs.orglett.0c01022

Herein, we disclose a Ni-catalyzed formal aminocarbonylation of primary and secondary unactivated aliphatic iodides with isocyanides to afford alkyl amide, which proceeds via the selective monomigratory insertion of isocyanides with alkyl iodides, subsequent β-hydride elimination, and hydrolysis process. The reaction features wide functional group tolerance under mild conditions. Additionally, the selective, one-pot hydrolysis of reaction mixture under acid conditions allows for expedient synthesis of the corresponding alkyl carboxylic acid.

Full text of DOI:10.1021/acs.orglett.0c01022

pubs.acs.org/OrgLett
Letter
Nickel-Catalyzed Formal Aminocarbonylation of Unactivated Alkyl
Iodides with Isocyanides
Wenyi Huang, Yun Wang, Yangyang Weng, Mohini Shrestha, Jingping Qu,* and Yifeng Chen*
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ABSTRACT: Herein, we disclose a Ni-catalyzed formal amino-
carbonylation of primary and secondary unactivated aliphatic
iodides with isocyanides to afford alkyl amide, which proceeds via
the selective monomigratory insertion of isocyanides with alkyl
iodides, subsequent β-hydride elimination, and hydrolysis process.
The reaction features wide functional group tolerance under mild
conditions. Additionally, the selective, one-pot hydrolysis of reaction mixture under acid conditions allows for expedient synthesis of
the corresponding alkyl carboxylic acid.
Scheme 1. Overview of Aminocarbonylation with
Isocyanide
ransition-metal-catalyzed three-component coupling re-
actions represent one of the most frequently applied
T
methods for introducing a carbonyl group in organic
synthesis.1 Among such various types of carbonylative
transformations, palladium-catalyzed aminocarbonylation re-
actions in particular are synthetically useful for expedient
access to amides.2 Nevertheless, the user-friendly method
mainly focuses on the formation of (hetero)aromatic amide
derivatives because of the facile oxidative addition of aryl
(pseudo)halide. Despite the prevalence of alkyl amide in
numerous biologically active compounds, medicines, agro-
chemicals, and polymers,3 the reported Pd-catalyzed amino-
carbonylation of unactivated alkyl halide still requires the use
of high-pressure CO gas, high energy irradiation, or toxic
organotin initiators via radical processes, as well as a multiple
CO insertion pathway.4 More recently, several earth-abundant
transition-metal-catalyzed aminocarbonylations of unactivated
alkyl halides have provided a robust platform to form alkylated
amide synthesis; however, elevated pressure of CO gas is still
required for this successful transformation.5 Therefore, seeking
an easily accessible and environmentally benign CO surrogate
to realize this transformation still remains highly desirable.6
Isocyanides are broadly utilized as an easily accessible
carbon monoxide synthon possessing both electronic and
sterically tunable properties.7 Not surprisingly, the Pd-
catalyzed aminocarbonylation of aryl halides with isocyanides
has been extensively accomplished (Scheme 1a).8 In contrast,
the carbonylation of alkyl electrophiles with isocyanides was
less explored and mostly restricted to activating alkyl
electrophiles. The Zhu and Yang groups realized Pd-catalyzed
aminocarbonylation using the activated alkyl electrophiles
including allyl acetates,9,10 α-haloketones,11 and α-phosphate
benzyl chlorides12 to afford amide moieties, where the
isocyanide served as both the carbonyl and amine source
(Scheme 1a). To the best of our knowledge, the carbonylation
of unactivated alkyl halide with isocyanide remains elusive,
mainly due to the inherent properties of the relatively slow
oxidative addition of alkyl halide with low-valent palladium
catalyst and the susceptibility of undesired β-H elimination of
alkyl palladium intermediate to generate a dehalogenated
alkene side product. We have recently achieved a nickel-
catalyzed highly regioselective allylic carbonyl Negishi reaction
to access the α,β-unsaturated ketones with broad functional
group tolerance under mild conditions.13 Leveraging nickel as
Received: March 20, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01022
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a transition metal catalyst circumvents the overcarbonylation
of isocyanide and unselective regioisomers based on the alkyl
zinc nucleophiles encountered in palladium catalysis.14 There-
by, we reasoned nickel catalysis to be an ideal tool for
unactivated alkyl halide aminocarbonylations with isocyanide
to tackle the above-mentioned challenges.15 Implementing
isocyanides in such Ni-catalyzed carbonylation reactions
remains limited,13,16 mainly owing to the propensity of the
imidoylnickel intermediate toward migratory insertion with
additional isocyanide to form poly(iminomethylene)s which
was broadly applied in polymer chemistry.17 Herein, we report
the Ni-catalyzed formal aminocarbonylation of unactivated
alkyl iodide with isocyanide with broad substrate scope under
mild conditions, and the selective acidic in situ hydrolysis of
the reaction mixture can provide an expedient way for alkyl
carboxylic acid synthesis.
We initiated the aminocarbonylation using commercially
available primary iodoheptane 1a as starting material and tert-
butyl isocyanide as the carbonyl source. To our delight, the
reaction proceeded extremely well with treatment of 10 mol %
of Ni(COD)2 and 2.0 equiv of NaOtBu at 50 °C in toluene,
affording the desired amide 3a in quantitative yield (99%
isolated yield). Nevertheless, the standard conditions were not
suitable for the secondary tert-butyl 4-iodopiperidine-1-
carboxylate (1q), the amides product (3q) was obtained in
trace amount (8%), and the major side product was tert-butyl
3,6-dihydropyridine-1(2H)-carboxylate (3q′) in 42% yield,
which was generated via the undesired β-hydride elimination
pathway as previously mentioned (Table 1, entry 1). The
investigation of ligand effect revealed that the incorporation of
an electron-rich NHC ligand was crucial to promote the
aminocarbonylation presumably due to the acceleration of the
1,1-migratory insertion rate of the alkyl nickel intermediate to
isocyanide (Table 1, entries 2−3). By further reducing the
amount of tert-butyl isocyanide, a higher yield of desired amide
3q (51%) was provided (Table 1, entry 4). When tert-butyl 4-
bromopiperidine-1-carboxylate was selected as the alkyl
electrophile component, the undesired β-H elimination
became the prominent pathway; only 4% of desired product
3q was observed (Table 1, entry 5). It was found that the
sterically bulky tBuOH was a superior solvent (Table 1, entries
6−7). To our delight, addition of 2.0 equiv of water
significantly reduced the byproduct 3q′ (Table 1, entry 8).
t
The optimized ratio of BuOH and water was 10:1 (v/v),
yielding 3q in 92% isolated yield, while only 5% alkenes could
be observed in the GC (Table 1, entry 9). It is possible that the
addition of water may accelerate the rate of migratory insertion
of isocyanide, which is driven by the hydrolysis of ketenimine
intermediate in situ. Other common alcoholic solvents
i
(MeOH, PrOH) were detrimental (Table 1, entries 10−11).
With the optimized conditions in hand, we turned our
attention to examine the substrate scope of the nickel-catalyzed
aminocarbonylation of unactivated alkyl iodides with iso-
cyanides (Scheme 2). Primary and secondary alkyl iodides
bearing different functional groups offered the amides in
moderate to excellent yields. Alkenes (1c, 1d) and an alkyne
(1e) were well tolerated, providing the respective amides in
good yields. It is worth noting that no cyclized products were
detected. When the 6-bromohex-1-ene was utilized as the
starting material, the isolated yield of amide 3d was obtained in
70% isolated yield, which revealed that the primary alkyl
bromide was also a potentially available substrate for this Ni-
catalyzed formal aminocarbonylation protocol. A substrate
with silyl ether (1f) could be perfectly accommodated to afford
3f in 98% isolated yield. Intriguingly, free aliphatic alcohol
(1g) gave the desired product 3g under this basic condition in
moderate yield. In addition, substrates containing Bpin
functionality (1h) could also be tolerated under standard
condition, which could be further converted to other
functionalities via the diverse borane chemistry. The reactive
aromatic bromide and iodide were unreactive to provide the
desired 3i and 3j in 84% and 81% isolated yield, respectively,
which clearly demonstrated the broad functional tolerance in
this nickel chemistry. As shown for product 3l and 3m, the
conditions permitted the coupling of other sterically hindered
isocyanides Subsequently, derivatives of biologically active
natural products were all suitable under the standard
conditions to generate 3k, 3n−3p in 47% to 99% yield,
demonstrating the potential utility in complex molecular
synthesis.
Table 1. Optimization of the Ni-Catalyzed
a
t
Aminocarbonylation of 1q with BuNC
b
b
Entry
Ligand
Solvent
toluene
toluene
toluene
toluene
toluene
dioxane
tBuOH
3q [%]
3q′ [%]
c
1
−
8
42
23
26
17
67
47
31
10
5
c
2
SIPr·HCl
IMes·HCl
IMes·HCl
IMes·HCl
IMes·HCl
IMes·HCl
IMes·HCl
IMes·HCl
IMes·HCl
IMes·HCl
27
30
51
4
0
59
69
We next applied a catalytic combination comprised of 10
mol % Ni(COD)2 and 20 mol % IMes·HCl to the cross-
coupling of the secondary alkyl iodides with alkyl isocyanides
(Scheme 2). Piperidines (1q, 1r, 1s) with different protecting
groups (such as Boc, Ts, and Cbz) which are widely applied in
medicinally vital structures could also be tolerated well in this
reaction. Other alkyl iodides containing heterocycles could also
be employed such as tetrahydropyran (1u) and N-Boc
acetidine (1v). This protocol allowed acyclic secondary alkyl
iodide 1w to convert into amide 3w in 78% yield. A diverse
array of isocyanides proceeded in the aminocarbonylation
yielding the corresponding tertiary amides 3x−3aa in 53% to
92% yields. Currently, the substrate scope of isocyanides is
restricted to the tertiary isocyanides. Unfortunately, no desired
aminocarbonylative amide products (3ab−3ad) were obtained
when the primary 1-isocyanododecane, secondary cyclohexyl
iscaynide, and phenyl isocyanide were employed as a C-1
c
3
4
cd
,
5
6
7
8
9
e
tBuOH
f
tBuOH/H2O = 10/1
MeOH/H2O = 10/1
iPrOH/H2O = 10/1
92 (92)
22
10
11
75
12
27
a
Reaction conditions: 1q (0.1 mmol), tert-butyl isocyanide (0.12
mmol), Ni(COD)2 (0.01 mmol), IMes·HCl (0.02 mmol), NaOtBu
(0.2 mmol), tBuOH (1.0 mL), H2O (0.1 mL) at 100 °C, 12 h. Then 1
b
M HCl (1.0 mL), rt, 5 min. Corrected GC yield with dodecane as an
internal standard. 1.5 equiv tert-butyl isocyanide. tert-Butyl 4-
bromopiperidine-1-carboxylate was used as the starting material. 2.0
equiv of H2O were added. Isolated yield.
c
d
e
f
B
https://dx.doi.org/10.1021/acs.orglett.0c01022
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Scheme 2. Scope of Ni-Catalyzed Aminocarbonylation of Alkyl Iodides with Isocyanides
a
Primary alkyl iodide 1 (1.0 equiv), 2 (1.5 equiv), Ni(COD)2 (10 mol %), NaOtBu (2.0 equiv), toluene (0.1 M), 50 °C, 12 h. Then 1 M HCl, rt, 5
b
min. Secondary alkyl iodide 1 (1.0 equiv), 2 (1.2 equiv), Ni(COD)2 (10 mol %), IMes·HCl (20 mol %), NaOtBu (2.0 equiv), tBuOH/H2O = 10/
1 (v/v, 0.1 M), 100 °C, 12 h. Then 1 M HCl, rt, 5 min. 6-Bromohex-1-ene was used as the starting material.
c
component. When the tertiary (3-iodo-3-methylbutyl)benzene
was employed as the starting material, the reaction failed to
afford the desired amide product 3ae, which demonstrated the
necessity of β-hydride in this protocol.
The validity of our synthetic strategy is illustrated in Scheme
3. The tert-butyl group could be smoothly deprotected in situ
upon treatment of the reaction mixture with Sc(OTf)3 after
solvent exchange to afford the unsubstituted amide in 69%
isolated yield (Scheme 3, condition A),6 which are ubiquitous
motifs in countless biologically relevant molecules and are
difficult to obtain from alkyl halides. The expedient conversion
of alky halide 1a into alkyl carboxylic acid 5 resulted in a 52%
yield upon treatment of the reaction with 12 M HCl, which
provides an alternative way for alkyl carboxylic acid synthesis,18
which is widely synthesized via the in situ generation of a
strong basic organometallic reagent, with subsequent trapping
with CO2 with limited functional group tolerance (Scheme 3,
condition B).
The “radical clock” experiment was designed for mechanistic
studies (Scheme 4). 1ab was selected as the model substrate
under standard conditions. It was found that 41% ring-opening
product 3ab′ was observed along with 18% normal product
C
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Letter
Scheme 3. Direct Formation of Primary Amide and Alkyl
Carboxylic Acid from Alkyl Iodide
Scheme 5. Mechanistic Hypothesis
Scheme 4. Preliminary Mechanistic Study
procedure. Further investigations on nickel-catalyzed carbon-
ylation with isocyanide are underway in our lab.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01022.
Synthetic procedures and analytical data of all
compounds (PDF)
Primary NMR FID files for compounds 1k, 1n, 1o, 1p,
3a−z, 3aa (ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
Yifeng Chen − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, School of Chemistry and Molecular
Engineering, East China University of Science and Technology,
Shanghai 200237, China; orcid.org/0000-0003-3239-
6209; Email: yifengchen@ecust.edu.cn
Jingping Qu − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, School of Chemistry and Molecular
Engineering, East China University of Science and Technology,
Shanghai 200237, China; orcid.org/0000-0002-7576-
0798; Email: qujp@dlut.edu.cn
3ab remained (confirmed by 1H NMR), which clearly
indicated that an alkyl radical intermediate was involved in
this reaction (Scheme 4a). However, when iodide 1d acted as
the substrate, no cyclized product 3d′ was formed (Scheme
4b). The TEMPO trapped radical product was not observed
when 3.0 equiv of TEMPO was employed as a radical
scavenger; amide 3a was obtained in 64% isolated yield
(Scheme 4c).
Based on these experimental results and prior work on cross-
coupling reaction with isocyanides, we propose the following
catalytic mechanism: radical 1′ is formed from alkyl iodides 1
via a single electron transfer (SET), which is followed by
radical rebound to provide nickel species B. Then intermediate
t
D is furnished by the migratory insertion of BuNC into C,
Authors
which then undergoes subsequent β-hydride elimination to
provide the key intermediate, ketenimines 6.9−12 Hydrolysis of
6 under acidic aqueous workup furnishes the desired amide 3
(Scheme 5).
In conclusion, we have developed a nickel-catalyzed direct
transformation from unactivated alkyl iodides to amides via the
formal aminocarbonylation, utilizing the isocyanides as both a
carbonyl source and amine source. The broad scope of the
reaction is highlighted by the tolerance of iodine and bromine
atoms and the Bpin group, providing a handle for subsequent
conversions. Besides, one-pot formation from unactivated alkyl
iodides to primary amides and carboxylic acids is achieved,
demonstrating the potential impact of our aminocarbonylation
Wenyi Huang − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, School of Chemistry and Molecular
Engineering, East China University of Science and Technology,
Shanghai 200237, China
Yun Wang − Key Laboratory for Advanced Materials and Joint
International Research Laboratory of Precision Chemistry and
Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, School of Chemistry and Molecular
Engineering, East China University of Science and Technology,
Shanghai 200237, China
D
https://dx.doi.org/10.1021/acs.orglett.0c01022
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Letter
Campagne, J.-M. Nonclassical Routes for Amide Bond Formation.
Chem. Rev. 2016, 116, 12029−12122.
Yangyang Weng − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, School of Chemistry and Molecular
Engineering, East China University of Science and Technology,
Shanghai 200237, China
Mohini Shrestha − Key Laboratory for Advanced Materials and
Joint International Research Laboratory of Precision Chemistry
and Molecular Engineering, Feringa Nobel Prize Scientist Joint
Research Center, School of Chemistry and Molecular
Engineering, East China University of Science and Technology,
Shanghai 200237, China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01022
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Youth 1000-Talent Plan
Program, East China University of Science and Technology,
NSFC/China (21421004, 21702060), Shanghai Municipal
Science and Technology Major Project (Grant
No.2018SHZDZX03) and the Program of Introducing Talents
of Discipline to Universities (B16017), and the Fundamental
Research Funds for the Central Universities (WJ1814012).
The authors thank Research Center of Analysis and Test of
East China University of Science and Technology for the help
on NMR analysis.
(c) Li, Y.; Zhu, F.; Wang, Z.; Rabeah, J.; Bruckner, A.; Wu, X.-F.
̈
Practical and General Manganese-Catalyzed Carbonylative Coupling
of Alkyl Iodides with Amides. ChemCatChem 2017, 9, 915−919.
(6) Serrano, E.; Martin, R. Nickel-Catalyzed Reductive Amidation of
Unactivated Alkyl Bromides. Angew. Chem., Int. Ed. 2016, 55, 11207−
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Q.; Wu, J. Recent Advances in Isocyanide Insertion Chemistry. Chem.
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