Carbene radicals in cobalt(II)-porphyrin-catalysed carbene carbonylation reactions; A catalytic approach to ketenes

Article abstract of DOI:10.1002/chem.201301731

One-pot radicals: Cobalt(III)-carbene radicals, generated by metallo-radical activation of diazo compounds and N-tosylhydrazone sodium salts with cobalt(II) complexes of porphyrins, readily undergo radical addition to carbon monoxide, allowing the catalytic production of ketenes. These ketenes subsequently react with various amines, alcohols and imines in one-pot tandem transformations to produce differently substituted amides, esters and β-lactams in good isolated yields. Copyright

Full text of DOI:10.1002/chem.201301731

COMMUNICATION
DOI: 10.1002/chem.201301731
Carbene Radicals in Cobalt(II)–Porphyrin-Catalysed Carbene Carbonylation
Reactions; A Catalytic Approach to Ketenes
Nanda D. Paul,[a] Andrei Chirila,[a] Hongjian Lu,[b] X. Peter Zhang,*[b] and
Bas de Bruin*[a]
Ketenes have intrigued chemists with their unusual physi-
cal properties and their unique spectrum of chemical reac-
tivity.[1] Ketenes are usually prepared by thermolysis, pyroly-
sis or in a stoichiometric manner from acyl chlorides using
base-promoted elimination reactions.[2] Synthesis of ketenes
from a-diazoketones by menas of the Wolff rearrange-
ment[2d] is also noteworthy. However, all these synthetic
methods have severe limitations and involve specialised
equipment and/or highly unstable starting materials.
Carbonylation of metal–carbene species[3–6] is an interest-
ing alternative method to produce such highly reactive ke-
tenes, which find synthetic applications in various organic
transformations.[1,4,5] The synthesis of medicinally important
b-lactams by [2+2] ketene–imine cycloaddition reactions is
especially important in this perspective.[5] Carbonylation re-
actions of Fischer carbene complexes have indeed been ap-
plied successfully to synthesise b-lactams.[5a,b] However,
these are stoichiometric transformations, which hamper effi-
ciency. Following the discovery of stoichiometric carbonyla-
tion reactions of Fischer-type carbene complexes, thus far
only a few transition-metal-catalysed processes have been
Scheme 1. ACHTNUTRGENNUG ACHUTNGTRENN(UGN Por)]-catalysed carbene carbonylation leading to ketene
[CoII
developed.[5,6] While interesting results have recently been
obtained with a noble (palladium) metal catalyst,[5c] carbene
carbonylation by base-metal catalysts reported thus far were
associated with low efficiencies and required quite harsh re-
action conditions (elevated temperatures and high CO pres-
sures).[6] Therefore, we focused on the development of new
catalytic carbene carbonylation processes by catalysts based
on abundant first-row transition metals that operate under
comparably mild reaction conditions.
formation in one-pot tandem transformations producing amides, esters
and b-lactams. DFT calculated relative free energies (DGo) in kcalmolÀ1
between brackets (Turbomole, BP86, def2-TZVP, employing Grimmeꢁs
disp3 dispersion corrections).
porphyrins [CoII
ACTHUNRTGNE(GNU Por)] have emerged as a new class of cata-
lysts capable of carbene-transfer reactions[7] proceeding
through radical mechanisms involving discrete CoIII–carbene
radical intermediates C (Scheme 1).[8]
As stable metalloradicals with well-defined open-shell
doublet d7-electronic configuration, cobalt(II) complexes of
In comparison with classic electrophilic Fischer-type car-
benes, the increased nucleophilicity of the carbene radical
intermediate C slows-down unwanted carbene dimerisation
while allowing for catalytic cyclopropanation through radical
addition to olefinic substrates, including electron-deficient
olefins.[7,8] In this respect, we envisioned that similar inter-
mediates might well be effective in carbene carbonylation
reactions, which can be considered as an attack of a nucleo-
philic cobalt–carbene radical (C) at the p-accepting CO sub-
[a] Dr. N. D. Paul, M.Sc. A. Chirila, Prof. Dr. B. de Bruin
Supramolecular and Homogeneous Catalysis
van ꢀt Hoff Institute for Molecular Sciences (HIMS)
University of Amsterdam
Science Park 904, 1098 XH, Amsterdam (The Netherlands)
E-mail: B.deBruin@uva.nl
[b] Dr. H. Lu, Dr. X. P. Zhang
Department of Chemistry
strate. At the same time, both the [CoACTHNUTRGNEUNG(Por)] catalyst and the
University of South Florida
Tampa, Florida 33620-5250 (United States)
E-mail: xpzhang@usf.edu
carbenoid intermediates are expected to interact only
weakly with amines, alcohols, imines and the ketene reac-
tion products. Hence, we expected smooth catalytic ketene
formation under comparatively mild conditions and their
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301731.
Chem. Eur. J. 2013, 19, 12953 – 12958
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12953

Table 1. Conditions of [CoII
CO, EDA and aniline.[a]
ACHTUNGTREN(NUNG Por)]-catalysed b-ketoester synthesis using
subsequent in situ reactions with nucleophiles in one-pot
tandem procedures (see Scheme 1).
Herein we report an efficient one-pot tandem protocol of
the carbonylation of a-diazocarbonyl compounds and a vari-
ety of N-tosylhydrazones catalysed by CoII–porphyrin metal-
loradicals leading to the formation of ketenes, which subse-
quently react with a variety of nucleophiles and imines to
form esters, amides and b-lactams. This system has a broad
substrate scope and can be applied to various combinations
of carbene precursors, nucleophiles and imines. The use of
N-tosylhydrazones as precursors of diazo compounds in
cobalt–porphyrin-based carbene-transfer reactions is unpre-
cedented, and represents an efficient and convenient way to
prepare the key carbenoid intermediates (C in Scheme 1)
responsible for ketene formation. The key ketene formation
steps were further investigated computationally (DFT).
Since ketenes are highly reactive[5,6] and can generally
only be trapped in the presence of a strong nucleophile, we
first evaluated the activity of [CoII(P1)] (P1=tetraphenyl-
porphyrin; Figure 1) in the catalytic carbonylation of ethyl
diazoacetate (EDA; 1) in presence of aniline (2a) under
10 bar CO at 508C. Under these conditions, (ethoxycarbo-
nyl)ketene was formed and trapped by aniline to produce
ethyl 2-(phenylcarbamoyl)acetate (3a) in 57% isolated yield
(Table 1, entry 1). Further initial experiments focused on the
evaluation of ligand and solvent effects on the carbonylation
of EDA in the presence of aniline. Four different CoII–por-
Entry
Catalyst
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P1)]
[CoII(P2)]
[CoII(P3)]
[CoII(P4)]
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
G
PhMe
THF
dioxane
DCE
MeCN
DMF
PhCl
PhMe/K3PO4
PhMe/K2CO3
PhMe/KHCO3
PhMe/NEt3
PhMe/K3PO4
PhMe/K3PO4
PhMe/K3PO4
57
25
50
R
E
T
10–15
<5
–
R
R
R
55
69
65
58
63
70
72
35
N
N
R
E
G
G
A
[a] Stoichiometry EDA:aniline=1:2. [b] Isolated yields after column
chromatography.
phyrin catalysts, including two chiral ones, were employed
in an attempt to improve the catalytic process and to investi-
gate potential asymmetric induction of the reaction
(Figure 1). The catalysts [CoII(P1)], [CoII(P2)], and
[CoII(P3)] (see Supporting Information for experimental de-
tails) showed more or less similar activity, while the catalyst
[Co(P4)] was found to be ineffective for this reaction
(Table 1). No enantioselectivity was obtained using the
chiral catalysts [CoII(P3)] and [CoII(P4)] under the various
reaction conditions applied. This suggests that the ketene in-
termediate is liberated from the catalyst to react subse-
quently with the amine, freely in solution.
Optimisation of the reaction conditions revealed that the
reaction proceeded most efficiently in nonpolar solvents,
such as toluene and chlorobenzene, whereas reactions in sol-
vents of high polarities, such as THF, dioxane, MeCN and
DMF, afforded poor yields (Table 1, entries 2–6). The use of
inorganic bases K2CO3 or K3PO4 further improved the
yields (Table 1, entries 8–11).
Reactions with other nucleophiles were evaluated to in-
vestigate the versatility of the reaction. The experiments
indeed showed that the ketenes generated by the CoII–por-
phyrin-catalysed carbene carbonylation could be trapped by
a wide range of nucleophiles (Table 2). The reaction occur-
red smoothly with substituted aromatic amines (Table 2, en-
tries 1–5), primary and secondary aliphatic amines (Table 2,
entries 6–8) and alcohols (Table 2, entries 9 and 10).
To further investigate the scope of the reaction, imines
were introduced into the reaction medium in an attempt to
produce b-lactams in a one-pot tandem procedure involving
[2+2] cycloaddition of the intermediate ketene with the
imine. Indeed, a 1:2 mixture of ethyl diazoacetate (EDA; 1)
and N-methylbenzaldimine (4a) in dichloroethane (DCE)
under a carbon monoxide atmosphere (20 bar) at 508C in
the presence of a catalytic amount of [CoII(P1)] (2 mol%)
Figure 1. Structures of cobalt(II) complexes of porphyrins. P1=Tetraphe-
nylporphyrin; P2=3,5-DitBu-IbuPhyrin; P3=3,5-DitBu-ChenPhyrin;
P4=21H,23H-porphine-5,10,15,20-tetrakis[(1R,4S,5S,8R)-1,2,3,4,5,6,7,8-
octahydro-1,4:5,8-dimethanoanthracen-9-yl].
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A Catalytic Approach to Ketenes
COMMUNICATION
Table 2.
bonyl compounds and different nucleophiles.[a]
ACHTUNGTRENNUNG ACHTUNGTRENNUNG(Por)]-catalysed b-ketoester synthesis using CO, a-diazocar-
[CoII
Scheme 2. Markedly different behaviour of [CoII
(dba)3] in reactions with a-diazo carbonyl compounds and imines.
ACHTUNGTREN(NUGN Por)] compared to [Pd2-
AHCTUNGTRENNUNG
Entry
R
NuH
Yield[%][b]
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
tBu
CH2Ph
PhNH2
69 (3a)
64 (3b)
61 (3c)
64 (3d)
63 (3e)
67 (3 f)
57 (3g)
53 (3h)
63 (3i)
62 (3j)
75 (3k)
72 (3l)
p-MeOC6H4NH2
p-NO2C6H4NH2
3,4-Cl2C6H3NH2
Ph2NH
PhCH2NH2
nBuNH2
Morpholine
PhACHTNGUTRENNU(G CH2)3OH
EtOH
PhNH2
PhNH2
of free ketene in solution reacting subsequently with the
imine. Introduction of Cinchona alkaloid, quinidine and its
derivatives into the reaction mixture in an attempt to trap
the liberated ketene with a chiral organocatalysts[9] for chir-
ality transfer in a one-pot cascade manner produced the b-
lactams with a low ee of only 5% at 308C. This temperature
is probably much too high for efficient chirality transfer
with these organocatalysts (typically operating at À788C),
but this is the lowest possible temperature at which still
some conversion can be achieved with these cobalt(II)-
based catalysts. Nonetheless, this result reveals the potential
of combining metallo and organo catalysts in cascade proc-
esses, which may become a useful concept to achieve enan-
tioselective ketene reactivity when combined with more
active cobalt catalysts working at lower temperatures in the
future.
10
11
12
[a] Stoichiometry EDA:NuH=1:2. [b] Isolated yields after column chro-
matography.
Table 3.
diazocarbonyl compounds.[a]
ACHTUNGTRENNUNG ACHTUNGTRENNUNG(Por)]-catalysed trans-selective b-lactam synthesis from a-
[CoII
To expand the scope of the catalytic ketene synthesis
methodology, carbonylation reactions were carried out with
N-tosylhydrazones,[10] which are widely used as precursors
for in-situ generation of non-stabilised diazo compounds.
The use of N-tosylhydrazones as precursors of diazo com-
pounds in cobalt–porphyrin-based carbene-transfer reactions
was thus far unprecedented. The easy synthesis of these N-
tosylhydrazones from ketones and aldehydes combined with
Entry
Catalyst
Diazo
Imine
Yield [%][b]
(trans:cis)
1
2
3
4
5
6
A
R=Et
R=Et
R=Et
R=Et
R=Et
R=tBu
R’=Me
R’=Me
R’=Me
R’=CH2Ph
R’=tBu
R’=Me
65 (5a) (>95:5)
65 (5a) (>95:5)
67 (5a) (>95:5)
50 (5b) (>90:5)
55 (5c) (>95:5)
66 (5d) (>95:5)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
the above described [CoACHTUNRGTNE(NUG Por)]-catalysed carbene carbonyla-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
tion methodology offers a convenient method to convert an
organic carbonyl moiety into a ketene functionality, applica-
ble in one-pot three-component tandem transformations.
Reaction of the benzaldehyde tosylhydrazone sodium salt
(6a) and aniline (2a) was catalysed by [CoII(P1)] under sim-
ilar reaction conditions as mentioned above (508C, 10 bar
CO). The benzyl ketene, thus generated in-situ, reacted with
aniline to produce N-2-diphenylacetamide (7a) in 70% iso-
lated yield (Table 4, entry 1). Further optimisation of the re-
action conditions revealed that the yield could be improved
by adding a phase transfer agent (Aliquat 336, trioctyl-
ACHTUNGTRENNUNG
[a] Stoichiometry EDA:imine=1:2. [b] Isolated yields after column chro-
matography.
led to formation of trans-N-methyl-a-ethoxycarbonyl-b-
phenyl-b-lactam (5a) in 60% isolated yield (Table 3). Simi-
lar reactions using other imines PhCH=NR (R=CH2Ph
(4b) and tBu (4c)) also produced the desired b-lactams
(Table 3). Notably, the (ethoxycarbonyl)ketene generated by
[CoII(P1)]-catalysed carbene carbonylation participates se-
lectively in [2+2] cycloaddition reactions with imines to pro-
duce the desired b-lactams (Table 3).
AHCTUNGTREGmNNNU ethylammonium chloride; Table S1 in the Supporting In-
formation). Both polar and nonpolar solvents were suitable
for this reaction (Table S1 in the Supporting Information),
and again toluene was the best solvent. The use of inorganic
bases K2CO3 or K3PO4 further improved the yields
(Table S1 in the Supporting Information).
Reactions with nucleophiles other than aniline were also
investigated. The experiments showed that the ketenes gen-
erated from the tosylhydrazone sodium salts by means of
[CoII(P1)]-catalysed carbene carbonylation method could
also be trapped by different nucleophiles. Expected products
Reactions of other diazoacetates with imines also pro-
duced the desired b-lactams (Table 3). This behaviour is
markedly different from the [4+2] cycloaddition reactions
producing 1,3-dioxin-4-ones reported by Wang and co-work-
ers in related palladium-catalysed reactions (see Sche-
me 2).[5c]
Again, the use of chiral catalyst [CoII(P3)] and [CoII(P4)]
did not lead to any enantioselectivity, pointing to liberation
Chem. Eur. J. 2013, 19, 12953 – 12958
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X. P.Zhang, B. de Bruin et al.
Table 4.
[CoII
E
Table 5.
ferent N-tosylhydrazone sodium salts and imines.[a]
[CoII
ACHUTGTNRENNUG ACHUTTGNREN(NUGN Por)]-catalysed trans-selective b-lactam synthesis using dif-
zone sodium salt and different nucleophiles.[a]
Entry Catalyst
R
R’
R’’
Yield (%)[b]
(trans:cis)
Entry
R
R’
NuH
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
PhNH2
75 (7a)
79 (7b)
72 (7c)
75 (7d)
79 (7e)
75 (7 f)
77 (7g)
65 (7h)
82 (7i)
75 (7j)
72 (7k)
80 (7l)
77 (7m)
56 (7n)
65 (7o)
1
2
3
4
5
6
7
8
9
[CoII(P1)] Ph
[CoII(P2)] Ph
[CoII(P3)] Ph
[CoII(P1)] Ph
[CoII(P1)] Ph
[CoII(P1)] Ph
[CoII(P1)] pMeC6H4
[CoII(P1)] pClC6H4
Ph
Ph
Ph
Ph
Me
Me
Me
64 (8a) (>95:5)
65 (8a) (>95:5)
65 (8a) (>95:5)
p-MeOC6H4NH2
p-NO2C6H4NH2
PhCH2NH2
Ph2NH
nBuNH2
Morpholine
PhCH2 62 (8b) (>90:10)
Me 63 (8c) (>95:5)
73 (8d)(>90:10)
Me
Me
Me
Me
Me
pClC6H4
pOMeC6H4 Me
Ph
Ph
ACHTUNGTRENNUNG
77 (8e) (>95:5)
62 (8 f) (>95:5)
73 (8g) (>85:15)
67 (8h) (>95:5)
52 (8i) (>95:5)
PhACHTNGUTRENNU(G CH2)3OH
p-MeC6H4
o-MeC6H4
p-ClC6H4
p-MeOC6H4
2-naph
Ph
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
G
10
11
A
Ph
AHCTUNGTRENNUNG
[CoII(P1)] PhCH=CH Ph
[a] Stoichiometry: N-tosylhydrazone:imine=1:2. [b] Isolated yields after
column chromatography.
PhCH=CH
[a] Stoichiometry N-Tosylhydrazone:NuH=1:3, PTA used. [b] Isolated
yields after column chromatography.
sodium salt with 20 bar CO produces free diphenyl ketene,
as indicated by observation of a characteristic IR stretch fre-
quency at 2102 cmÀ1 directly after the reaction.[11] Formation
of the diphenyl diazo compound[12] from the diphenyl tosyl-
hydrazone sodium salt was also detected by IR spectroscopy,
as revealed by observation of a characteristic stretch fre-
quency at 2042 cmÀ1. These data are in excellent agreement
with the proposed reaction mechanism shown in Scheme 1.
Repeated attempts to detect the more reactive benzyl
ketene directly after reaction of the corresponding tosylhy-
drazone sodium salt with 20 bar CO were unsuccessful. This
is likely due to too rapid dimerisation/oligomerisation and/
or other side-reactions of the ketene in absence of a nucleo-
phile or imine. The reaction mixture obtained directly after
reacting the benzaldehyde tosylhydrazone salt with 20 bar
CO in the presence of N-methylbenzaldimine does show
characteristic C=O stretch frequency of the b-lactam at
1752 cmÀ1.[5c]
The mechanism of the above carbene carbonylation reac-
tions was further investigated computationally by using
DFT methods (see Supporting Information for details). In
these studies, in contrast to previous investigations reported
by our groups, we decided to include dispersion (VdW) cor-
rections in the geometry optimisations. Remarkably, this
modification had a profound influence on the affinity of the
cobalt center for the diazo compound (bound through
carbon), shifting the association equilibrium from A to B
and resulting in a somewhat lower transition state barrier
TS1 (from B) for formation of the key CoIII–carbene radical
intermediate C (Scheme 1) than reported previously. It is
also worth noting that with dispersion forces, the carbon-
bound methyl diazoacetate (MDA) adduct B was calculated
to be more stable than the nitrogen-bound MDA adduct B’,
while this was reversed in previous calculations without dis-
persion corrections.[8] Apart from this interesting effect of
inclusion of dispersion forces in the calculations, this part of
were obtained with several amines and alcohols (Table 4,
entries 1–8).
These results prompted us to explore the scope of the cat-
alytic carbene carbonylation reactions using a series of N-to-
sylhydrazone sodium salts under the above optimised reac-
tion conditions. The reactions produced the expected acet-
amide derivatives in good to high yields (Table 4, entries 9–
13). The reaction also worked well with disubstituted N-to-
sylhydrazones, although requiring longer reaction times
(Table 4, entry 14). Also a,b-unsaturated N-tosylhydrazones
could be converted to amides, albeit in modest yields
(Table 4, entry 15).
Upon introduction of imines to the reaction medium, the
ketenes generated from these N-tosylhydrazone salts also
reacted smoothly to produce the desired b-lactams. The use
of a phase-transfer agent in this case did not have any influ-
ence. A series of N-tosylhydrazone salts were subjected to
the reaction conditions with different benzaldimines
(Table 5). In all cases, the corresponding b-lactams were ob-
tained in good yields. Interestingly, for most of the sub-
strates, the reactions afforded trans products with excellent
diastereoselectivity. However, again no enantioselectivity
was obtained using either chiral catalysts or by adding quini-
dine-based chiral organocatalysts into the reaction mixture.
To obtain more insight into the mechanistic aspects of
[CoACHTUNGTRENNUNG(Por)]-catalysed ketene formation, several controlled in-
frared studies of the reaction mixtures were carried out.
Since, diphenylketene is known to be more stable than the
corresponding monosubstituted ketenes, diphenyl tosylhy-
drazone sodium salt was intentionally chosen as the carbene
source for IR analysis of the carbene carbonylation reaction
mixtures (see Supporting Information Figure S1–S4).
Indeed, carbonylation of the diphenyl tosylhydrazone
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A Catalytic Approach to Ketenes
COMMUNICATION
the catalytic mechanism is in fact identical to carbenoid for-
mation in the calculated mechanism for olefin cyclopropana-
tion.[8] Carbene radicals C are in equilibrium with “bridging
carbenes” C’ according to these calculations (nearly thermo-
neutral), and both C- and C’-type species were previously
detected by EPR spectroscopy after reacting [CoII(P3)] with
ethyl diazoacetate.[8a]
ACHTUNGTRENNUNG
Subsequent carbonylation of terminal carbenoid C pro-
ceeds by means of a concerted one-step CO addition to the
À
carbene moiety with simultaneous homolysis of the Co C
bond to produce the free ketene, according to DFT. The
ketene has little to no affinity for cobalt, and spontaneously
dissociates from the cobalt center directly after its forma-
tion. These calculations are in good agreement with the de-
tection of free ketene in the above-mentioned IR experi-
ments. The computed carbene carbonylation step has a
Acknowledgements
This work was financially supported by the European Re-
search Council (ERC Grant Agreement 202886-CatCIR;
B.d.B.), the Netherlands Organisation for Scientific Re-
search (NWO-CW VICI grant 016.122.613; B.d.B.), the Na-
tional Science Foundation (CHE-1152767; X.P.Z.), the Na-
tional Institutes of Health (R01-GM098777; X.P.Z.), and the
University of Amsterdam (UvA). We thank Dr. Matthias
Otte for helpful discussions.
somewhat lower energy barrier (DG
°A(TS2)=8.6 kcalmolÀ1
CHTUNGTRENNUNG
from C; DG
CHTUNGTRENNUNG
for formation of C through dinitrogen loss from diazo
adduct B (TS1=13.6 kcalmolÀ1).[8a] The rate-limiting step in
the catalytic cycle according to these calculations under
standard conditions in the gas phase is therefore the forma-
tion of carbene radical C. However, the energy differences
between TS1 and TS2 are not large and at relative low CO
concentrations and relative high EDA concentrations (i.e.,
non-standard conditions as in the catalytic experiments) the
entropy contributions lower the relative barrier of TS1 com-
pared to TS2, allowing side reactions of C (e.g., carbene di-
merisation, reaction with the solvent). This, in combination
with the relatively low solubility of CO in common organic
solvents,[13] most likely explains why CO pressures >10 bar
are required in the experimental catalytic runs.
Keywords: carbenes · carbonylation · cobalt · ketenes ·
radicals · porphyrinoids
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Chem. Eur. J. 2013, 19, 12953 – 12958
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Received: May 4, 2013
Published online: September 3, 2013
12958
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 12953 – 12958