Two Copper-Carbenes from One Diazo Compound

Article abstract of DOI:10.1021/jacs.1c01483

Many transition-metal complexes MLn decompose diazo compounds N2=CR1R2 generating metal-carbenes LnM=CR1R2 which transfer the carbene group to other substrates, constituting an important tool in organic synthesis. All previous reports have shown that the CR1R2 fragment at the metal-carbene remains intact from the parent diazo compound. Herein we report the detection and isolation of a monosubstituted copper carbene where the CR1R2 ligand has undergone a modification from the initial diazo reagent. When TpMsCu(THF) (TpMs = hydrotris(3-mesityl)pyrazolylborate ligand) was reacted with N,N-diethyl diazoacetamide [N2=C(H)(CONEt2)], the stable copper carbene TpMsCu=C(H)(NEt2) was isolated, resulting from a decarbonylation process, with carbon monoxide being trapped as TpMsCu(CO). The simultaneous observation of products derived from the intramolecular carbene insertion reaction into C-H bonds demonstrates that the expected TpMsCu=C(H)(CONEt2) complex is also formed. Experimental data, DFT calculations, and microkinetic models allow us to propose that the latter undergoes CO loss en route to the former.

Full text of DOI:10.1021/jacs.1c01483

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Two Copper-Carbenes from One Diazo Compound
́
María Alvarez, Maria Besora, Francisco Molina, Feliu Maseras,* Tomás R. Belderrain,*
and Pedro J. Pérez*
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ABSTRACT: Many transition-metal complexes MLn decompose
diazo compounds N2CR1R2 generating metal-carbenes LnM
CR1R2 which transfer the carbene group to other substrates,
constituting an important tool in organic synthesis. All previous
reports have shown that the CR1R2 fragment at the metal-carbene
remains intact from the parent diazo compound. Herein we report
the detection and isolation of a monosubstituted copper carbene
where the CR1R2 ligand has undergone a modification from the
initial diazo reagent. When TpMsCu(THF) (TpMs = hydrotris(3-
mesityl)pyrazolylborate ligand) was reacted with N,N-diethyl
diazoacetamide [N2C(H)(CONEt2)], the stable copper carbene
TpMsCuC(H)(NEt2) was isolated, resulting from a decarbon-
ylation process, with carbon monoxide being trapped as TpMsCu-
(CO). The simultaneous observation of products derived from the intramolecular carbene insertion reaction into C−H bonds
demonstrates that the expected TpMsCuC(H)(CONEt2) complex is also formed. Experimental data, DFT calculations, and
microkinetic models allow us to propose that the latter undergoes CO loss en route to the former.
are diazocarbonyl compounds,4 with a CO group directly
bonded to the diazo functionality: the acceptor nature of the
−COR group favors the transfer of the carbene group toward
INTRODUCTION
■
More than a century after Buchner postulated the existence of
carbene CR2 groups during the thermal decomposition of ethyl
diazoacetate,1 the catalytic transfer of such moiety from diazo
the nucleophile.
compounds yet constitutes an area of continuous growth.2,3
Herein we report the observation of the unprecedented
modification of the carbene unit during the course of a copper-
Such process consists of the metal-induced decomposition of
the diazo reagent in a process in which molecular N2 is
catalyzed transformation. The use of a diazoacetamide
compound (Scheme 1c) bearing a CONR2 substituent leads
to the formation of the expected, undetected, hot, highly
reactive copper carbene MCE (Scheme 1c) which promotes
the intramolecular C−H bond functionalization of the ethyl
groups of the amide fragment. In a parallel manner, MCE
undergoes the loss of CO en route to the formation of the
extruded and a metallocarbene intermediate MC is formed
(Scheme 1a).4 This species is electrophilic5 in nature and
reacts with available nucleophiles transferring the carbene
group, thus liberating the metal to continue the catalytic cycle.
This strategy has been successfully employed in the addition of
carbene groups to unsaturated bonds or in its insertion into
unexpected, stable and isolable, cold, Fischer carbene complex
C−H or other C−X bonds, both intra- and intermolecu-
larly.6−8
MCU (Scheme 1c), which has been structurally characterized.
With the appropriate tuning of the carbene substituents and
RESULTS AND DISCUSSION
the metal precursor, several metallocarbene complexes have
been detected, some of them being isolated and structurally
characterized. All metals from groups 8 to 11 are known to
catalyze the carbene transfer from diazo compounds (Scheme
1b), and at least one detected/isolated example of a metal-
carbene intermediate formed from a diazo compound has been
reported for each of them.8−18 In all cases, the CR1R2 moiety
in the initial diazo compound appears unmodified in the
subsequent metal-carbene intermediate (Scheme 1b), from
where it is further transferred to the nucleophile. From here, it
is assumed that the carbene ligand is always transferred
without modification. One of the most popular diazo reagents
■
Reaction of TpMsCu(THF) and N2C(H)(CONEt2). Our
group has been involved in the area of carbene transfer from
diazo compounds, with emphasis on its application to the
Received: February 10, 2021
Published: March 18, 2021
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© 2021 American Chemical Society
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Scheme 1. Metal-Catalyzed Carbene Transfer from Diazo
Compounds and the Formation of Metalocarbene
Intermediates
Scheme 2. (a) Copper-Catalyzed Intramolecular C−H Bond
Functionalization of N−N-Diethyldiazoacetamide; (b)
13C{1H} NMR Spectrum of the Reaction of Copper
Complex 1 and 13C-Labeled Diazoacetamide (2*)
enriched in 13C at the 13CN2 site, in toluene-d8 (Scheme
2b). Monitoring of the reaction by 13C{1H} NMR spectros-
copy showed the appearance of a resonance centered at 236.6
ppm. This is within the typical region of CuC moieties
reported by Hofmann25 for the complexes [tBu2P(NSiMe3)2-
κ2N]CuC(Ar)C(O)R) (235.8−219.0 ppm), by Warren13
for [β-diketiminate]CuCPh2 (253.1 ppm), or by our group
for complexes TpxCuC(Ph)(CO2Et) (Tpx = TpiPr2, Tp*,
TpMs; 233.9, 236.8, and 248.5 ppm, respectively).20 Under
these conditions, the resonances for 3, 4, and 5 were also
observed, the latter being the major product. The reaction was
immediate, and no free diazo compound 2* was observed after
5 min. Successive registration of 13C{1H} NMR spectra for
hours showed no change in the composition of the mixture.
In view of the apparent stability of the species bearing the
CuC unit, we repeated the reaction at a bench scale (see
Supporting Information (SI) for optimization conditions).
When 0.45 g of 1 were reacted with 5 equiv of diazo 2 in
toluene at room temperature for 1 h, a yellowish solution was
formed from which, after workup, the new compound 7 was
functionalization of C−H bonds of unmodified alkanes,6,19 for
which the design of very active catalysts precluded the
observation of intermediates. However, we recently detected
copper-carbene species20 in solution upon reacting TpMsCu-
(THF) (1) and ethyl phenyldiazoacetate (PheDA), which
were stable at temperatures below 10 °C. After those findings,
we aimed to detect copper-carbene intermediates with
monosubstituted diazo compounds, which yet remains a
challenge, particularly with the most popular catalysts within
this field, i.e., rhodium and copper, for which only
disubstituted carbene species have been detected or
isolated.11,13,21 Toward that end we chose TpMsCu(THF)22
as the copper source, since the TpMs ligand provides a high
degree of steric protection to the metal center and, when
formed, to the carbene ligand. Regarding the diazo reagent, we
selected N,N-diethyl diazoacetamide (2), in view of the
previously reported23 intramolecular carbene insertion into
the C−H bonds of the ethyl N-substituents in the presence of
1 as the catalyst (Scheme 2a), leading to mixtures of lactams 3
and 4. Olefin 5 was also observed from the catalytic reaction of
two molecules of 2.24 Since heating at 70 °C was needed to
reach efficient ratios, we reasoned that perhaps the copper-
carbene intermediate expected from the reaction of 1 and 2,
TpMsCuC(H)(CONEt2) (6), could be stable enough at
room temperature to be detected. Based on this idea, we
started this study carrying out the reaction of TpMsCu(THF)
(1) with 5 equiv of N,N-diethyl diazoacetamide (2*), 100%
1
isolated as crystalline material in 35% yield. The H NMR
spectrum of 7 showed three equivalent pyrazolyl rings, two
inequivalent ethyl groups, and a singlet at 8.02 ppm (Scheme
2c), which corresponds to one proton that correlates in the
2D-HSQC experiment with the aforementioned signal at 236.6
ppm (Scheme 2d). In the sample derived from the 13C-labeled
diazo compound, the singlet at 8.02 in the 1H NMR spectrum
split into a doublet with JC−H = 115 Hz (Scheme 2c).
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Scheme 3. Reaction of TpMsCu(THF) with Doubly
Albeit the above data could support the assignment of
complex 7 as the pursued TpMsCuC(H)(CONEt2), some
other experimental data were not in agreement with that
proposal: neither the FT-IR spectrum showed the expected
absorption for the CO group nor the 13C{1H} NMR spectrum
displayed any resonance within the carbonyl region. We
suspected that a decarbonylation process could have occurred,
an idea that was confirmed when single crystals of this complex
were grown, and the molecular structure determined by X-ray
studies showed the formulation TpMsCuC(H)(NEt2) (7).26
As shown in Figure 1, this complex contains the TpMs ligand
Isotopically Labeled 2** and Region of the 13C{1H} NMR
Spectrum Showing the Labeled Carbene and Carbonyl
Groups of 7* and 8*
Figure 1. Molecular structure of the molecules for complex 7.
Hydrogens have been omitted for clarity.
bonded to copper in a κ3-fashion, and a carbene ligand with
two substituents: a hydrogen and a diethylamido group, the
latter resulting from the loss of the CO present in the initial
diazo compound. The distance Cu1−C1, 1858(5) Å, is similar
to that reported by Warren for [β-diketiminate]CuCPh2
(1.834(3) Å).13 Complex 7 constitutes the first example of a
metal-carbene complex formed from a diazo compound in
which the CR1R2 moiety in the latter is different from that in
the former. Additionally, it is also the first example of a
monosubstituted copper carbene complex.27
Further investigation of the 1H NMR spectrum of the
experiment carried out with a 1:5 ratio (excess of diazo is
employed since C−H bond insertion also occurs in a catalytic
manner to some extent) of 1 and 2* showed that, in addition
to 7, another TpMsCu-containing species was formed, both
accounting for all detectable TpMsCu cores. Such compound
has been identified as TpMsCu(CO) (8) (Scheme 3), as the
result of the trapping of carbon monoxide by 1.22 To gain
further information, we have prepared the doubly isotopically
enriched N2=13C(H)(13CONEt2) (2**) diazo compound and
monitored its reaction with complex 1, observing the
resonances of carbene and carbonyl ligands of 7 and 8,
respectively (see Supporting Information also). Thus, this
observation unambiguously demonstrates the existence of a
decarbonylation process.
Figure 2. (a) Plot of the yields into complex 7 vs temperature (°C).
(b) Variation of the yield of complex 7 with time at different
temperatures.
Supporting Information). We have also monitored the
concentration of complex 7 with time at three different
temperatures (Figure 2b) and have found that at 0 or 25 °C
such concentration remains constant after 24 h. However, at
70 °C, a process involving the disappearance of 7 takes place
with time in such a way that after 12 h it cannot be detected in
solution.
The reactivity of isolated copper carbene 7 has also been
investigated. On one hand, no reaction was observed with
styrene, tert-butanol, benzene, or cyclohexane from room
temperature to 70 °C. It seems clear that the loss of the CO
The yield in complex 7 is dramatically affected by
temperature, as shown in Figure 2a. The reaction of 1 and 2
(1:5 ratio) has been performed within the −30 to +70 °C
range, showing an increase in the reaction yield from 2% to
78%, respectively, in 1 h time experiments. The high yield
preparation and isolation of 7 is better performed at 70 °C (see
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Scheme 4. General Picture of the Reactivity Derived from the Interaction of TpMsCu(THF) (1) and N2C(H)CONEt2 (2)
group modifies the electronic behavior of the carbene
C(H)NEt2 ligand decreasing the electrophilicity from
TpMsCuC(H)(CONEt2) (6) to TpMsCuC(H)NEt2 (7).
Interestingly, heating toluene solutions of isolated 7 at 70 °C
for hours/days did not lead to any transformation, whereas the
same experiment under a CO atmosphere (4 bar) for 6 h
induced a clean conversion of 7 into TpMsCu(CO) (8). NMR
studies have also shown that the olefin (Et2N)(H)C
C(H)(NEt2) (9) derived from the coupling of two of the
carbene units in 7 is formed.This result agrees with the lack of
observation of copper-carbene 7 in the reaction of 1 and 2 at
70 °C for several hours, because of the presence of CO from
the decarbonylation process.
Scheme 5. (a) Wolff Rearrangement of Diazo Compounds;
(b) Reversible Formation of Ketenes from Carbene and CO
Ligands Described by Grotjahn; (c) Plausible Intermediate
for the Conversion of 6 into 7
The reactivity observed from the initial mixture of 1 and 2
(1:5 ratio) is rationalized in Scheme 4. The TpMsCu core is
generated upon decoordination of THF and reacts with the
diazo compound 2 to generate the transient copper carbene 6.
This species undergoes either the intermolecular reaction with
a second molecule of 2 or the intramolecular insertion of the
carbene group into the secondary or primary C−H bonds of
the ethyl groups of the NEt2 fragment, thus yielding lactams 3
and 4, these catalytic cycles taking place at room temperature.
Intermediate 6 can alternatively undergo a decarbonylation
process which generates the isolable copper carbene 7, a
process which occurs, at least, within the −30 to +70 °C
interval. Evolved CO can be trapped by TpMsCu cores leading
to the formation of TpMsCu(CO) (8). At 70 °C, copper-
carbene 7 originates olefin 9 and carbonyl 8 in a process
requiring carbon monoxide. This proposal agrees with the
initial observation of the need for heating at 70 °C to induce
catalysis by 1,23 since the copper−carbonyl 8 under the
reaction conditions in the presence of 2 also generates TpMsCu
cores to catalyze the C−H bond functionalization reaction.
The transformation of 6 into 7 somehow resembles the
Wolff rearrangement of diazo compounds (Scheme 5a), which
originate short-lived ketenes4,28 which further react with
nucleophiles, in a process triggered by light, heating, or
silver(I) salts. Grotjahn and co-workers described a ketene
iridium complex which undergoes the reversible conversion of
the coordinated ketene into a metallocarbene which contains a
CO ligand (Scheme 5b).29 Based on these precedents, it could
be possible that copper-carbene 6 undergoes a related
rearrangement in the coordination sphere of copper, followed
by CO extrusion (Scheme 5c). As mentioned above, the
reverse reaction is not observed in our case, at least apparently,
as inferred from the experiment carried out with 7 and CO.
DFT Studies and Microkinetic Model. Given the
unexpected formation of 7, we further explored the process
with DFT studies (B3LYP-D3 optimizations in solution; see
details in the Supporting Information) and microkinetic
simulations. Computational results are summarized in Figure
3, showing the free energy profile for the conversion from the
starting TpMsCu(THF) complex (1) to compound 7. The
initial steps follow the usual mechanism up to the formation of
metal-carbene 6, with the highest barrier corresponding to
nitrogen extrusion (17.3 kcal/mol−1). Species such as metal-
carbene 6 have been previously shown to be very reactive
toward homocoupling or C−H activation.19,23,24 The novelty
in this system is the availability of an alternative low energy
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Figure 3. (a) Simplified reaction free energy profile from DFT calculations for the generation of copper carbenes 6 and 7. (b) Simplified reaction
mechanisms for the formation of olefin 9.
path via decarbonylation. The latter proceeds through a rather
stable ketene intermediate INTDCO2, with a linear arrange-
ment between the CO and the former carbene carbon (see
Supporting Information for more details). The barrier for the
decarbonylation process is low at 298.15 K (13.8 kcal/mol)
while the reverse barrier is 28.0 kcal·mol−1, too high to take
place significantly at ambient temperature. At 343.15 K the
profile is similar, with a barrier of 13.9 kcal/mol for
decarbonylation and a barrier of 30.3 kcal/mol for the reverse
process. The lack of observation of the reverse pathway when
reacting complex 7 and CO at 70 °C is due to the more
favorable path of formation of olefin 9 and carbonyl adduct 8
(see below). Further calculations were carried out for the case
where the toluene solvent is replaced by dichloromethane, also
reproducing the experimental observation of pyrrolidinone (3)
and azetidinone (4). The detailed computational results for
these cases are given in the Supporting Information.
The formation of 9 has also been investigated. Several paths
previously reported for such carbene coupling have been
discarded based on their high energy barriers: (a) direct
interaction of two molecules of 7;24 (b) carbene C(H)NEt2
dissociation and reaction with 7;24 and (c) coupling of two
dissociated carbene units30 (see Supporting Information). At
variance with that, we have found an accessible route which
involves two molecules of 7 and one of CO. The simplified
mechanism for the formation of olefin 9 is depicted in Figure
3b. The mechanism starts with one molecule of the metal-
carbene 7 adding a molecule of CO to form the above-
mentioned intermediate INTDCO2 which further reacts with
a second molecule of 7. The formation of the olefin 9 must
overcome a barrier of 23.1 kcal/mol. Thus, albeit olefin 9 is
more stable than metal-carbene 7, its formation involves a
higher barrier (see Supporting Information for further details).
The third possible product from the interaction between the
precursor 1 and N,N-diethyl diazoacetamide is olefin 5, which
is also experimentally observed. We also computed the
mechanism of its formation from 6, which is detailed in the
Supporting Information. The key result is that the free energy
barrier for CC bond formation leading to 5 is 8.9 kcal/mol.
This value is significantly lower than the 13.8 kcal/mol
reported above for decarbonylation, which from a simplistic
view would indicate that decarbonylation should not take
place. However, for convoluted mechanisms such as the one
present here, it is better to translate the computed free energy
barriers to rate constants and use those to estimate reaction
times through microkinetic modeling.31 We performed such
microkinetic modeling with additional energy adjustment32
(see Supporting Information for details), and we obtained the
results shown in Figure 4. The agreement between calculations
and experimental data (displayed in Figure 2) is certainly
remarkable, and this strongly supports the validity of our
mechanistic proposal.
CONCLUSION
■
We herein report the first example of the modification of a
carbene group during its metal-catalyzed transfer from a diazo
functionality, a discovery that should result in further
consideration from the community involved in this area.
From now on, the belief that the carbene moiety remains
undisturbed in this type of processes must be reconsidered
when analyzing reaction outcomes, particularly in those
catalytic systems which either seem deactivated or require
anomalous heating. Additionally, the chemistry of these
isolated metal-carbenes is yet to be developed and could find
important applications as surrogates of well-known midtransi-
tion metal Fischer carbene complexes
EXPERIMENTAL SECTION
■
Synthesis and Characterization of Complexes 7 and 7*. In a
250 mL Schlenk flask, TpMsCu(THF) (1, 0.450 g, 0.64 mmol) was
dissolved in 75 mL of toluene, and a solution of 2-diazo-N,N-
diethylacetamide (2, 0.451 g, 3.2 mmol) in the same solvent (37 mL)
was added via canula. The mixture was stirred at 70 °C for 1 h before
the volatiles were removed under reduced pressure. The residue was
washed with dry acetone (5 mL) and cold Et2O (3 × 5 mL) and dried
under vacuum, to afford 0.35 g of a yellow solid corresponding,
according to NMR studies, to a mixture of complexes 7 and 8 (yields
of 47% and 10% referred to initial 1). Crystallization from a mixture
of toluene/hexane (4:4 mL) at −30 °C led to the isolation of complex
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Tomás R. Belderrain − Laboratorio de Catálisis Homogénea,
Unidad Asociada al CSIC, CIQSO-Centro de Investigación
en Química Sostenible and Departamento de Química,
Universidad de Huelva, 21007 Huelva, Spain;
Email: trodri@dqcm.uhu.es
Feliu Maseras − Institute of Chemical Research of Catalonia,
ICIQ, 43007 Tarragona, Spain; Departament de Química,
̀
Universitat Autonoma de Barcelona, 08193 Bellaterra,
Spain; orcid.org/0000-0001-8806-2019;
Email: fmaseras@iciq.es
Authors
́
María Alvarez − Laboratorio de Catálisis Homogénea, Unidad
Asociada al CSIC, CIQSO-Centro de Investigación en
Química Sostenible and Departamento de Química,
Universidad de Huelva, 21007 Huelva, Spain
Maria Besora − Institute of Chemical Research of Catalonia,
ICIQ, 43007 Tarragona, Spain; Departament de Química
̀
Física i Inorganica, Universitat Rovira i Virgili, 43007
Tarragona, Spain; orcid.org/0000-0002-6656-5827
Francisco Molina − Laboratorio de Catálisis Homogénea,
Unidad Asociada al CSIC, CIQSO-Centro de Investigación
en Química Sostenible and Departamento de Química,
Universidad de Huelva, 21007 Huelva, Spain
Figure 4. (a) Computed yield (%) of metallocarbene 7 at 1 h of
reaction for different reaction temperatures (K). (b) Evolution over
time (h) of the yield (%) of metallocarbene 7 at different
temperatures (continuous line obtained from DFT and microkinetic
simulations; dots obtained from experiment).
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01483
7 as yellow crystals in 35% yield (combined crops). Analytically
calculated for C41H51BCuN7 (1): C, 68.75; H, 7.18; N, 13.69%.
Found: C, 69.41; H, 7.12; N, 13.66%. Complex 7* was prepared
following the same procedure, with the corresponding labeled diazo
compound (see SI) with an isolated yield of 28%.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1H NMR (C6D6, 500 MHz): δ 0.28 (t, JHH = 7.3 Hz, 3H,
NCH2CH3), 0.44 (t, JHH = 7.3 Hz, 3H, NCH2CH3), 2.12 (s, 27H,
CH3), 2.23 (q, JHH = 7.3 Hz, 2H, NCH2CH3), 2.41 (q, JHH = 7.3 Hz,
2H, NCH2CH3), 6.01 (d, JHH = 2.0 Hz, 3H, CH), 6.71 (s, 6H, CH),
7.80 (d, JHH = 2.0 Hz, 3H, CH), 8.02 (s, 1H, CuCH). 13C{1H}
NMR (C6D6, 125 MHz): δ 12.9 (CH3), 13.6 (CH3), 20.9 (CH3,Ms),
21.1 (CH3,Ms), 53.1 (NCH2), 54.9 (NCH2), 104.5 (CHpz), 127.8
(CHMs), 133.6 (Cq,Ms), 134.9 (CHpz), 136.2 (Cq,Ms), 138.3 (Cq,Ms),
150.9 (Cq,pz), 236.6 (CuC).
■
We dedicate this work to the memory of Professor Victor
Riera, one of the pioneers in Organometallic Chemistry in
Spain. We acknowledge financial support from the Ministerio
de Ciencia e Innovación (CTQ2017-82893-C2-1-R,
CTQ2017-87792-R, P. O. Feder UHU-1260216 and P. O.
Feder UHU-1254043, and Red Intecat CTQ2016-81923-
REDC).
REFERENCES
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01483.
■
■
sı
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data, and Cartesian coordinates of the optimized
structures (PDF)
Accession Codes
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AUTHOR INFORMATION
Corresponding Authors
Pedro J. Pérez − Laboratorio de Catálisis Homogénea,
Unidad Asociada al CSIC, CIQSO-Centro de Investigación
en Química Sostenible and Departamento de Química,
Universidad de Huelva, 21007 Huelva, Spain; orcid.org/
0000-0002-6899-4641; Email: perez@dqcm.uhu.es
■
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Article
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