Palladium(II)-catalyzed cross-coupling of diazo compounds and isocyanides to access ketenimines

Article abstract of DOI:10.1021/acscatal.0c02867

Diazo compounds and isocyanides are reactive functionalities and valuable building blocks commonly utilized in organic synthesis. Their cross-coupling for the synthesis of useful isolable ketenimines remains an unsolved challenge in synthetic chemistry. Herein, we report a general method for the preparation of ketenimines via a palladium-catalyzed cross-coupling of easily accessible diazo compounds with isocyanides. The reaction benefits from the use of readily available starting materials, a wide substrate scope, high functional group tolerance, and a high yield in products, and the resultant ketenimines are amenable to further functionalization. Experimental findings and DFT calculations unambiguously corroborate the initial formation of a Pd(II)? isocyanide complex as the active catalytic species, which enables the cross-coupling reaction via a migratory insertion of Pd(II)? carbene into isocyanide, with evidence suggesting that the oxidation state of Pd(II) remains unchanged during the reaction.

Full text of DOI:10.1021/acscatal.0c02867

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Research Article
Palladium(II)-Catalyzed Cross-Coupling of Diazo Compounds and
Isocyanides to Access Ketenimines
Zhaohong Liu,∥ Shanshan Cao,∥ Jiayi Wu, Giuseppe Zanoni, Paramasivam Sivaguru, and Xihe Bi*
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ABSTRACT: Diazo compounds and isocyanides are reactive
functionalities and valuable building blocks commonly utilized in
organic synthesis. Their cross-coupling for the synthesis of useful
isolable ketenimines remains an unsolved challenge in synthetic
chemistry. Herein, we report a general method for the preparation
of ketenimines via a palladium-catalyzed cross-coupling of easily
accessible diazo compounds with isocyanides. The reaction
benefits from the use of readily available starting materials, a
wide substrate scope, high functional group tolerance, and a high yield in products, and the resultant ketenimines are amenable to
further functionalization. Experimental findings and DFT calculations unambiguously corroborate the initial formation of a Pd(II)−
isocyanide complex as the active catalytic species, which enables the cross-coupling reaction via a migratory insertion of Pd(II)−
carbene into isocyanide, with evidence suggesting that the oxidation state of Pd(II) remains unchanged during the reaction.
KEYWORDS: palladium catalysis, cross-coupling, ketenimine, isocyanides, DFT calculations
difficult processability of the substrates, narrow reaction scope,
poor functional group tolerance, or a combination thereof.
More efficient and greener methodologies for the rapid
assembly of isolable ketenimines from readily available starting
materials remain worth exploring.
1. INTRODUCTION
Transition-metal catalyzed cross-coupling reactions of diazo
compounds are widely used for the construction of cumulated
double bonds1 and reactive structural moieties with versatile
synthetic applications.2 As an established example, allenes can
be obtained by copper-catalyzed cross-couplings of diazo
species (or their precursors) and terminal alkynes.3 The Wang
group also reported an elegant palladium(0)-catalyzed carbon-
ylation of diazo compounds with CO to yield ketenes.4
However, the cross-coupling of diazo compounds5 with
isocyanides6 to access isolable ketenimines remains largely
unsuccessful (Figure 1a).7 The transition-metal-catalyzed
cascade reaction of diazo compounds with isocyanides is a
notable recent achievement, formation of ketenimines was
proposed, which further react without prior isolation.8
Ketenimines contain two cumulated reactive functionalities
(CC and CN bonds) and are versatile synthetic
intermediates for the assembly of many nitrogen-containing
compounds.9 Despite the reliability and usefulness of these in
situ-generating strategies,8 the incompatibility between the
reaction conditions for the generation of reactive ketenimines
and their subsequent transformations somehow limit their
application in organic synthesis.9,10 Traditionally, isolated
ketenimines can be prepared through the Wittig reaction of
phosphoranes with isocyanates;11 aza-Wittig reaction of
ketenes with iminophosphoranes;12 or cross-coupling reactions
of isocyanides with stoichiometrically stabilized carbene
complexes,13 α-halophosphonates,14 allyl carbonates, and α-
haloketones15 (Figure 1b). All these methods were constrained
by significant shortcomings, such as poor accessibility or
In consideration of the increasing importance of ketenimines
and our ongoing endeavors in diazo16 and isocyanide
chemistries,17 we embarked on the investigation of a general
and scalable ketenimination reaction via a palladium-catalyzed
cross-coupling reaction between diazo compounds and
isocyanides, whose results and mechanistic insights we are
reporting herein (Figure 1c). This method can utilize either
diazo compounds or N-triftosylhydrazones, affording high-
quality ketenimines with or without an electron-withdrawing
group (EWG) in high yields. Findings stemming from the
synthesis, characterization, and reactivity of the putative
palladium complex enabled a mechanistic understanding of
this synthetically useful transformation. The data obtained
from both experimental and DFT studies suggest that the
formation and the subsequent migratory insertion of Pd(II)−
carbenoid species were the key steps of this cross-coupling
reaction. The oxidation state of palladium remains unchanged
Received: June 30, 2020
Revised: September 29, 2020
https://dx.doi.org/10.1021/acscatal.0c02867
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a
Table 1. Optimization of the Reaction Conditions
amount (mol
%)
yield
b
entry
cat.
AgOAc
solvent
T (°C)
(%)
1
2
3
4
5
6
7
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH3CN
THF
CH2Cl2
1,4-dioxane
1,4-dioxane
1,4-dioxane
60
60
60
60
60
60
60
60
60
60
60
40
80
60
trace
10
10
5
trace
trace
31
66
70
67
97 (90)
88
81
trace
54
Cu(OAc)2
Rh2(OAc)4
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
10
10
10
10
10
10
10
10
10
10
c
9
10
11
12
13
80
55
d
14
a
Reaction conditions: phenyldiazoacetate 1a (0.3 mmol), 2a (1.2
equiv), catalyst, and 4 Å MS (30.0 mg) in 1,4-dioxane (6.0 mL), 40,
b
60, or 80 °C, Ar, 12 h. Yield calculated from the 1H NMR spectrum
c
d
with CH2Br2 as the internal standard. Isolated yield. Without 4 Å
MS.
Figure 1. Synthetic strategies for the formation of cumulated double
bonds. (a) Formation of cumulated double bonds from diazo
compounds. (b) Synthesis of ketenimines by cross-coupling strategies
(previous work). (c) Cross-coupling of diazo compounds with
isocyanides (this work).
control reaction proved that 4 Å MS were necessary for this
reaction; in their absence, the reaction led to poor conversion
(entry 14).
during the reaction, which is different from the previous
The reaction scope was first probed with respect to readily
available stabilized diazo compounds, using t-BuNC (2a) as
the coupling partner under the optimized conditions
summarized in Table 1, entry 8, 10 mol % Pd(OAc)2 in 1,4-
dioxane at 60 °C with 4 Å MS (Scheme 1). A series of aryl
ethyl diazoacetates possessing either electron-withdrawing (Br,
NO2, CO2Et, CN, and CF3) or electron-donating (OMe and
Me) groups on the aryl ring (1b−1i) were suitable substrates,
as they delivered the corresponding target products 3b−3i in
moderate to high yields. Aryl methyl diazoacetates (1j−1l),
phenyl isopropyl diazoacetate (1m), and phenyl benzyl
diazoacetate (1n) also yielded the corresponding ketenimines
3j−3n in high yields. Ethyl diazoacetates 1o and 1p with a
heterocyclic (indolyl and thienyl) substituent also reacted to
afford 3o and 3p in 45 and 78% yields, respectively. Reaction
with α-alkyl diazoacetates fared comparably. For example,
benzyl- and methyl-substituted ethyl diazoacetates were
coupled efficiently with 2a to afford 3q and 3r in 86 and
72% yields, respectively. Excitingly, this transformation is not
restricted to α-diazoacetates, in that α-diazophosphonates
(1s−1u) effectively reacted to deliver the desired phosphono-
ketenimines 3s−3u in moderate to high yields.14
Subsequently, we turned our attention to varying the
isocyanide component (Scheme 2). Under these conditions,
readily available alkyl isocyanides such as 2-isocyano-2,4,4-
trimethylpentane (2b), cyclohexyl isocyanide (2c), and 2-
adamantyl isocyanide (2d) were coupled with 1a to deliver
products 4b−4d in high yields (78−81%). Aryl isocyanides
2e−2g, instead, required 5 mol % of preprepared 1,3-bis[2,6-
di(propan-2-yl)phenyl]imidazolidin-2-ide,3-chloropyridine, di-
chloropalladium (PEPPSI-SIPR) as a catalyst to afford the
corresponding coupling products 4e−4g, albeit in a lower
reports proposing a Pd(II)/Pd(0) catalytic cycle.6d,14,15,18
2. RESULTS AND DISCUSSION
At the outset of this investigation, the parameters for the
reaction of phenyldiazoacetate 1a with tert-butyl isocyanide (t-
BuNC) 2a were screened. The reaction in the absence of any
catalysts with 4 Å molecular sieves (MS) in 1,4-dioxane at 60
°C for 12 h afforded a trace amount of expected ketenimine 3a,
along with the unreacted phenyldiazoacetate being recovered
(entry 1, Table 1). Commonly used transition metals in the
catalytic generation of carbene from diazo compounds, AgOAc
and Cu(OAc)2, were demonstrated as ineffective catalysts,
whereas Rh2(OAc)4 led to the formation of 3a in very low
yields (entries 2−4). Therefore, we turn our attention to
palladium catalysts, which readily coordinate with isocyanide
to form isocyanide-complexed Pd species and then react with
diazo compounds.8a,e−h After some optimization work, it was
found that Pd(OAc)2 showed remarkable activity and
delivered the desired product 3a in 90% isolated yield (entry
8), in contrast to the moderate product yield recorded with
Pd2(dba)3, Pd(PPh3)4, and Pd(PPh3)2Cl2 as catalysts (entries
5−7). Palladium catalysts were significantly superior to other
transition-metal catalysts (entries 5−8 vs 2−4), indicating that
the palladium catalyst prefers to coordinate with isocyanide to
form isocyanide-complexed Pd species,8a,e−h rather than react
with diazo compound to generate palladium carbene.4
Changing the solvent to either CH3CN or THF did not
significantly impact the yield, whereas CH2Cl2 was unsuitable
for the reaction (entries 9−11). The product yield was
significantly lowered when decreasing the reaction temperature
to 40 °C or increasing it to 80 °C (entries 12 and 13). A
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a
modified conditions, t-BuNC (2a) was readily coupled with N-
triftosylhydrazones possessing electron-donating (Me and
OMe) and electron-withdrawing (Cl, F, and CO2Me)
substituents on various positions of the phenyl ring, providing
the corresponding ketenimines 6a−6g in 59−86% yield
(Scheme 3). Substrates featuring biphenyl (5h), naphthyl
Scheme 1. Reaction Scope of Diazo Compounds
Scheme 3. Palladium(II)-Catalyzed Cross-Coupling of N-
a
Triftosylhydrazones with Isocyanides
a
Reaction conditions: 1a−1u (0.3 mmol), 2a (1.2 equiv), Pd(OAc)2
(10 mol %), and 4 Å MS (30.0 mg) in 1,4-dioxane (6.0 mL) at 60 °C
b
under Ar for 12 h; isolated yields. 18 h.
a
Scheme 2. Scope of Isocyanides
a
Reaction conditions: N-triftosylhydrazone 5 (0.3 mmol) and
Cs2CO3 (0.45 mmol) in 1,4-dioxane (5.0 mL) were stirred at room
temperature for 1 h, then 2 (1.2 equiv), Pd(OAc)2 (10 mol %), and 4
Å MS (30.0 mg) were added, after which the mixture was stirred at 60
a
Reaction conditions: phenyldiazoacetate 1a (0.3 mmol), 2b−g (1.2
equiv), Pd(OAc)2 (10 mol %), 4 Å MS (30.0 mg) in 1,4-dioxane (6.0
mL) at 60 °C under Ar for 12 h; isolated yields. PEPPSI-SIPR (5
mol %) was used as the catalyst, and the reaction was performed at 80
b
b
°C for 12 h; isolated yields. The reaction was performed at 40 °C.
°C.
(5i), 2-benzofurenyl (5j), and 2-thienyl (5k) substituents also
delivered the expected ketenimines 6h−6k in moderate to
good yields (49−82%). The influence of the R2 substituent on
the coupling reaction was investigated. For example, N-
triftosylhydrazones with ethyl and cyclohexyl substituents (5l
and 5m) gave products 6l and 6m in 85 and 71% yields,
respectively. The N-triftosylhydrazone derived from α-
ketoester 5n was also tolerated and gave the corresponding
product 6n in 84% yield, thus avoiding the use of a syringe
pump for slow addition of diazo esters. We then turned our
attention toward variously substituted symmetrical N-trifto-
sylhydrazones. Benzophenone derivative 5o coupled with
different isocyanides, such as t-BuNC (2a), n-butyl isocyanide
yield. These poor yields might result from the lower reactivity
of aryl isocyanides, thus making the dimerization of diazo
compounds faster than the reaction with aryl isocyanides.
Being inspired by the success of the cross-coupling of
isocyanides with stabilized diazo compounds, we then turned
our attention to nonstabilized donor-type diazo reagents to
access ketenimines without an EWG substituent, which are
difficult to isolate and used as intermediates in reactions.8
Upon extensive evaluation of reaction conditions, the desired
ketenimine 6o was isolated in 86% yield by the treatment of N-
triftosylhydrazones 5o with t-BuNC 2a in the presence of
Pd(OAc)2, Cs2CO3, and 4 Å MS at 60 °C.19 Under these
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(2h), and cyclohexyl isocyanide (2c), affords the expected
products 6o−6q in 82−86% yield. Sterically hindered
isocyanides 2b and 2d were also coupled efficiently with 5o
to yield ketenimines 6r and 6s in 89 and 83% yields,
respectively, and the fluorenone-derived substrate 5t resulted
in 6t in 83% yield. This cross-coupling reaction is not limited
to ketone-derived N-triftosylhydrazones only; aldehyde-de-
rived N-triftosylhydrazones (5u−5y) could also be cross-
coupled with 2a at 40 °C to provide disubstituted ketenimines
6u−6y in moderate to good yields (51−80%), confirming the
versatility of this cross-coupling reaction.
the Pd(II) center remains tetracoordinated in a square planar
geometry, in which one isocyanide group is strongly
coordinated to the Pd(II) center as a result of ligand exchange
with one of the triphenylphosphine ligands (Scheme 5a).
Scheme 5. Experiments for Mechanistic Investigations; (a)
Isolation of Pd(II) Complex 8; (b) Reaction of Isolated
Pd(II) Complex 8 with 1a.
As a demonstration of scalability of this cross-coupling
method, we performed the reaction under the optimized
conditions with 6 mmol 1a and 2a, obtaining the cross-
coupling ketenimine product 3a in 94% isolated yield (Scheme
4). Product 3a could be transformed into a variety of
Scheme 4. Gram-Scale Reaction and Further Synthetic
a
Transformations
Subsequently, the isolated palladium complex 8 was treated
with 1a in dioxane at 60 °C for 12 h, affording the target
product 4d in 86% NMR yield (Scheme 5b). These results
suggest that when a Pd(II) precatalyst is used, the oxidation
state of palladium does not change during the course of the
catalytic process, which is in contrast to the previously
described Pd(II)-catalyzed isocyanide insertion reac-
tions.6d,14,15,18
A proposed mechanism for the Pd(II)-catalyzed isocyanide
insertion reaction was supported by DFT calculations at the
M06/6-311+G(d,p)-SDD(Pd) level of theory. The Pd(II)−
isocyanide complex 8 was chosen as the starting point for the
free energy profiles for the cross-coupling process with
phenyldiazoacetate 1a (Figure 2; for details, see the Supporting
Information). Because of the spatial extension of the Ph3P and
a
Reagents and conditions: (a) TMSN3 (2.0 equiv), toluene, 50 °C,
overnight; (b) 4-OMePhMgBr (2.0 equiv), THF, 0 °C, Ar, 24 h; (c)
BF3·Et2O (1.0 equiv), CH2Cl2, 0 °C to rt, Ar, 12 h; (d) 1 M HCl/
dimethylformamide, 30 °C, 2 h; and (e) morpholine (1.2 equiv),
Pd(OAc)2 (5 mol %), and PPh3 (15 mol %) in THF, 100 °C, 3 h.
2
isocyanide ligands, which fill the axial Pd dz orbital,
coordination of ligands via the empty axial pz orbital is
blocked, thus a dissociation mechanism is favored over an
association mechanism.20 By virtue of a strong trans effect of
the PPh3 ligand,21 the ligand exchange energy of the chloride
ligand opposed to PPh3 is the lowest among all ligands in 8, as
shown by the relative free energy of Int1-1 compared with
Int1-2 and Int1-3. Here, the ligand exchange refers to the first
dynamic dissociation of the chlorine ligand of 8 and then
coordination with phenyldiazoacetate 1a to form the diazo
complex Int1-1. The ensuing dissociation of N2 to form the
Pd(II)−carbene complex Int3 occurs via TS1, with ΔΔG⧧ =
9.3 kcal/mol, followed by the migratory insertion of Pd(II)−
carbene via a three-membered ring transition state TS2, ΔΔG⧧
= 16.7 kcal/mol, releasing Pd(PPh3)Cl2 and the product 4d.
The migratory insertion of Pd(II)−carbene is the rate-
determining step for the overall reaction, as it presents an
energy barrier (ΔΔG⧧) of 16.7 kcal/mol, easily surmountable
at the temperature (60 °C) established for this experimental
procedure of this reaction. The oxidation state of Pd(II)
remains unchanged during the course of the catalytic process.
derivatives, to attest to the synthetic versatility of keteinimines:
to unprotected benzyl tetrazole 7a by tandem hydroazidation/
[3+2] cycloaddition with TMSN3 (Scheme 4a); to β-enamino
ester 7b by the addition of p-methoxyphenylmagnesium
bromide (Scheme 4b); to ethyl 2-cyano-2-phenylacetate 7c
by cleavage of the ketenimine N−C bond in the presence of
BF3·Et2O (Scheme 4c); and to amide 7d by hydrolysis
(Scheme 4d).15 Interestingly, palladium-catalyzed hydroami-
nation of ketenimine 3a with morpholine exclusively produced
ene-1,1-diamine 7e rather than the expected amidine (Scheme
4e).8h
Our initial screening results showed that this coupling
reaction was effective with both Pd(0) and Pd(II) catalysts
(entries 5−8, Table 1). In previously described Pd(II)-
catalyzed isocyanide insertion reactions, palladium was
assumed to change from the Pd(II) to Pd(0) oxidation state
during the catalytic cycle, albeit no substantive evidence was
presented to support this assertion.14,15,18 To elucidate the
reaction mechanism, we carried out a control reaction between
isocyanide 2c (1 mmol) and Pd(PPh3)2Cl2 (10 mol %) in
THF at room temperature for 6 h, which afforded the bench-
stable Pd(II)−isocyanide complex 8 in 85% yield. The single-
crystal X-ray structure of complex 8 (CCDC no. 1812945; for
details, see the Supporting Information) clearly indicates that
3. CONCLUSIONS
A simple and practical method for the synthesis of ketenimines
via a palladium-catalyzed cross-coupling reaction of diazo
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Figure 2. Gibbs-free energy profile (in kcal/mol) for the cross-coupling of phenyldiazoacetate 1a with Pd(II)−isocyanide complex 8 calculated at
SMD//M06/6-311+G(d,p)-SDD(Pd) level in 1,4-dioxane. AdNC: 2-adamantyl isocyanide. Distances are given in angstroms.
Authors
compounds with isocyanides was established under mild
conditions. The operationally simple protocol is compatible
with substrates ranging from stabilized diazo compounds to N-
triftosylhydrazones as nonstabilized diazo surrogates and
affords ketenimines in good to excellent yield. This synthetic
methodology provides a valuable alternative to the existing
methods that rely on scarcely available substrates. The
combination of experimental results and DFT calculations
provided evidence that the in situ-generated Pd(II)−
isocyanide complex is a key reactive intermediate in the
catalytic cycle. According to the proposed reaction mechanism,
the palladium center preserves its oxidation state of Pd(II),
differently from previously reported Pd-catalyzed cross-
coupling reactions. Further investigations toward an enantio-
selective variant to access axially chiral ketenimines are
currently underway.
Zhaohong Liu − Department of Chemistry, Northeast Normal
University, Changchun 130024, China; orcid.org/0000-
0001-9951-8675
Shanshan Cao − Department of Chemistry, Northeast Normal
University, Changchun 130024, China
Jiayi Wu − Department of Chemistry, Northeast Normal
University, Changchun 130024, China
Giuseppe Zanoni − Department of Chemistry, University of
Pavia, Pavia 27100, Italy
Paramasivam Sivaguru − Department of Chemistry, Northeast
Normal University, Changchun 130024, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c02867
Author Contributions
∥Z.L. and S.C. contributed equally to this work.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c02867.
■
Notes
sı
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Details on reagents and experimental procedures,
optimization of the reaction conditions, characterization
data, synthetic transformations, mechanistic studies,
computational studies, X-ray crystallographic data, and
NMR spectra (PDF)
We are grateful to the NSFC (21961130376 and 21871043),
the Department of Science and Technology of Jilin Province
(20180101185JC, 20190701012GH, 20200801065GH), and
the Fundamental Research Funds for the Central Universities
(2412019ZD001, 2412020ZD003) for financial support.
REFERENCES
AUTHOR INFORMATION
Corresponding Author
Xihe Bi − Department of Chemistry, Northeast Normal
University, Changchun 130024, China; State Key Laboratory of
Elemento-Organic Chemistry, Nankai University, Tianjin
300071, China; orcid.org/0000-0002-6694-6742;
Email: bixh507@nenu.edu.cn
■
■
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