Interception of cobalt-based carbene radicals with α-aminoalkyl radicals: A tandem reaction for the construction of β-ester-γ-amino ketones

Article abstract of DOI:10.1002/anie.201408874

The interception of cobalt-based carbene radicals with α-aminoalkyl radicals was combined with the Kornblum-DeLaMare reaction and provides β-ester-γ-amino ketones, which are otherwise difficult to obtain in high chemoselectivity. Mechanistically, this transformation is an interplay of cobalt-based carbene radicals, organoradicals, and ionic intermediates and involves the construction of two C-C bonds and one C=O bond in a one-pot process. The reaction also features a wide substrate scope and is highly efficient and insensitive to moisture and air. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.201408874

Angewandte
Chemie
DOI: 10.1002/anie.201408874
One-Pot Processes
Interception of Cobalt-Based Carbene Radicals with a-Aminoalkyl
Radicals: A Tandem Reaction for the Construction of b-Ester-g-amino
Ketones**
Jie Zhang, Jiewen Jiang, Dongmei Xu, Qiang Luo, Hongxiang Wang, Jijun Chen, Huihuang Li,
Yaxiong Wang, and Xiaobing Wan*
Abstract: The interception of cobalt-based carbene radicals
with a-aminoalkyl radicals was combined with the Kornblum–
DeLaMare reaction and provides b-ester-g-amino ketones,
which are otherwise difficult to obtain in high chemoselectivity.
Mechanistically, this transformation is an interplay of cobalt-
based carbene radicals, organoradicals, and ionic intermediates
À
=
and involves the construction of two C C bonds and one C O
bond in a one-pot process. The reaction also features a wide
substrate scope and is highly efficient and insensitive to
moisture and air.
T
he metal–carbon bond in transition-metal carbene com-
plexes, such as those of Cu, Ru, Rh, Pd, or Au, is generally
considered as a double bond.[1] In sharp contrast, cobalt
carbene complexes are of a fundamentally different type;
their metal–carbon bonds display a strong single-bond
character, and these complexes thus behave as carbene
radicals.[2] This special property has been exploited by
synthetic chemists on numerous occasions to create cyclo-
propane moieties from olefins and diazo compounds. Since
the pioneering studies by the groups of Nakamura, Yamada,
and Katsuki, who disclosed that cobalt carbene complexes are
capable of olefin cyclopropanation reactions,[3] the current
state-of-the-art reactions have been developed by the groups
of Zhang and de Bruin.[4] Unlike cyclopropanations catalyzed
by other metals,[5] Co-based cyclopropanation reactions are
distinguished by their wide substrate scopes, tolerating both
electron-rich and electron-poor alkenes and several classes of
diazo compounds, as well as their simpler operation proce-
dures as the diazo compounds do not need to be added slowly
to minimize undesirable carbene dimerization processes.
Mechanistic studies generally support a reaction model that
involves an unusual cobalt-based carbene radical intermedi-
ate, which undergoes sequential radical addition and sub-
stitution (Scheme 1a).[2] Aside from the cyclopropanation
Scheme 1. Interception of cobalt-based carbene radicals with olefins
and a-aminoalkyl radicals.
reactions of olefins, alkynes and carbon monoxide could also
be used as the acceptors of cobalt-based carbene radicals to
construct b-lactams[4h] and 2H-chromenes.[4i]
Even though cobalt-based carbene radicals have already
been used for a wide range of applications, particularly in the
area of cyclopropanation, their synthetic utility is still far from
being fully explored. Recently, radical tandem reactions[4h,i,6]
have attracted significant interest as a synthetic strategy of
considerable untapped potential. Thus, we envisaged that
once the cobalt-based carbene radical intermediate is gen-
erated, instead of adding to an olefin, alkyne, or CO, it can
alternatively be intercepted by another radical species, which
could open up a range of new opportunities for synthetic
chemistry. We recently developed an oxidative cyanation
reaction of tertiary amines involving the in situ generation of
a-aminoalkyl radicals.[7a] On the other hand, we previously
succeeded in combining the addition of organocobalt species
to olefins and the Kornblum–DeLaMare reaction[8] for the
construction of 1,4-dicarbonyl compounds using tert-butyl
hydroperoxide (TBHP) as the primary oxidant.[7b] Based on
these results, we hypothesized that incorporating a tertiary
amine and TBHP into the Co-catalyzed cyclopropanation
system might trigger a novel reaction pathway. As shown in
Scheme 1b, rather than adding to an olefin, cobalt carbene
radical I can be intercepted by a-aminoalkyl radical III, which
is generated in situ from the tertiary amine, to form organo-
cobalt species IV, which can then be coupled with the olefin
[*] J. Zhang, J. Jiang, D. Xu, Q. Luo, H. Wang, J. Chen, H. Li, Y. Wang,
Prof. Dr. X. Wan
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering and Materials Science
Soochow University
Suzhou 215123 (China)
E-mail: wanxb@suda.edu.cn
[**] We gratefully acknowledge the Priority Academic Program Devel-
opment of Jiangsu Higher Education Institutions (PAPD) and the
Natural Science Foundation of China (21272165).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408874.
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and TBHP to afford peroxide V. Subsequently, Kornblum–
DeLaMare reaction of V delivers the desired product VI.
Consequently, this reaction sequence combines a carbene
radical, an organoradical, and an ionic Kornblum–DeLaMare
reaction step into a single catalytic cycle, a strategy that has so
far remained underexplored. Aside from its novel mecha-
nism, this tandem process provides direct access to a variety
of b-substituted g-amino ketones, which are otherwise
difficult to synthesize from easily available a-diazo esters,
amines, and olefins.
The successful development of this one-pot multicompo-
nent reaction, however, hinges on the resolution of two major
challenges. The first technical difficulty concerns the high
reactivity, and consequently, the instability of both carbene
radical I and organoradical III, necessitating a careful choice
of reagents and reaction conditions that can divert the
intermediates towards the selective formation of organo-
cobalt species IV instead of towards the well-studied and
understood radical addition pathway (Scheme 1a). The
second, equally important challenge is the demand of this
process for an oxidative environment, which is in stark
contrast to the fact that Co-catalyzed reactions of olefins and
diazo reagents usually require inert atmospheres.
Scheme 2. Variation of the styrene. Reaction conditions: 1 (0.5 mmol),
2a (1.0 mmol), 3a (2.5 mmol), [Co(acac)2] (0.05 mmol), TBHP
(1.85 mmol), and 4 ꢀ M.S. (200 mg) were stirred in 1,4-dioxane/
CH2Cl2 (1.0 mL each) at 608C for 8 h. M.S.=molecular sieves.
As a start, we conducted a few pilot reactions using
[Co(TPP)]
(cobalt(II)
meso-tetraphenylporphyrin),[4a]
a common catalyst for olefin cyclopropanation, to evaluate
the feasibility of the proposed coupling reaction. With TBHP
as the oxidant, the reaction mixture containing 1-(tert-butyl)-
4-vinylbenzene (1a), ethyl diazoacetate (2a), and triethyl-
amine (3a) afforded the desired b-ester-g-amino ketone 4a in
32% yield. To improve the efficiency of the process, we took
a page from the [Co(acac)2] catalyzed synthesis of 1,4-
dicarbonyl compounds that we recently developed[7b] and
found that switching to [Co(acac)2] substantially increased the
yield of 4a to 72% (acac = acetylacetonate; for detailed
information on the optimization of the reaction conditions,
see the Supporting Information, Table S1). This one-pot
multicomponent reaction only requires mildly oxidative
conditions, can even be performed in an open flask exposed
to air, and can be conveniently scaled up to 10 mmol while
still retaining a satisfactory yield of 67%. Interestingly,
oxygen had no significant effect on the efficiency, and
a comparable yield was obtained under argon.
Similarly, our Co-catalyzed transformation was also
shown to be compatible with a variety of diazo reagents
(Scheme 3). A synthetically useful allyl group was well
tolerated in the reaction, and 5c was generated in moderate
yield. Dimethyl diazoacetamide also proved to be an effective
coupling partner and furnished product 5e in 31% yield.
Unfortunately, only trace amounts of product 5 f were
obtained when ethyl 2-diazobutanoate was used as the
starting material.
Results obtained with different tertiary amines are
summarized in Scheme 4. In all cases, the expected b-ester-
g-amino ketones were obtained in satisfactory yields. Inter-
Having established the optimized coupling conditions, we
next assessed the substrate scope of the reaction with
a
representative selection of styrenes. As shown in
Scheme 2, a variety of substituted styrenes could be selec-
tively oxidized to the corresponding b-ester-g-amino ketones
in satisfactory yields and moderate diastereomeric ratios,
attesting to the broad tolerance of the reaction for electron-
withdrawing and -donating substituents, such as halide, ether,
À
trifluoromethyl, or cyano groups, and benzylic C H bonds.
Notably, when the aryl ring of the styrene coupling partner
was replaced with a bromothiophene moiety, 4q was gen-
erated in moderate yield. Steric effects were responsible for
the improved diastereomeric ratios observed for the synthe-
ses of 4n, 4o, and 4p. The relative configuration of the major
stereoisomer of 4g formed in the reaction was determined by
single-crystal X-ray crystallography (Scheme S1, Table S2–3).
Scheme 3. Variation of the diazo reagent. Reaction conditions: 1a
(0.5 mmol), 2 (1.0 mmol), 3b (2.5 mmol), [Co(acac)2] (0.05 mmol),
TBHP (1.85 mmol), and 4 ꢀ M.S. (200 mg) were stirred in 1,4-dioxane/
CH2Cl2 (1.0 mL each) at 608C for 8 h.
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a reactive iminium cation, we employed an iminium salt
instead of the tertiary amine and did not observe the
formation of the desired b-ester-g-amino ketone, thereby
effectively ruling out the hypothesis that the iminium ion is an
intermediate of this transformation (Scheme 5d). Repeating
the standard reaction at room temperature led to the isolation
of peroxide 8 in 18% yield (Scheme 5e). When a reaction
mixture containing 8 but no [Co(acac)2] or TBHP was heated
to 608C, the desired product 5a was formed in 62% yield
(Scheme 5 f). However, 5a could not be detected in the
absence of amine 3b (Scheme 5g), which indicates that the
reaction proceeds by the in situ formation of a peroxide
intermediate and a subsequent Kornblum–DeLaMare reac-
tion.
Combining the above results and literature precedents, we
propose a plausible mechanism (Scheme 6). The reaction
begins with cobalt(II)-promoted homolytic decomposition of
TBHP to yield tBuOC (A) and tBuOOC (B; step a).[7b,9] Both
radical intermediates are capable of abstracting an a-hydro-
gen atom from the tertiary amine to form a-aminoalkyl
radical C (b).[7a] In the meantime, activation of the diazo
Scheme 4. Variation of the tertiary amine. Reaction conditions: 1a
(0.5 mmol), 2a (1.0 mmol), 3 (2.5 mmol), [Co(acac)2] (0.05 mmol),
TBHP (1.85 mmol), and 4 ꢀ M.S. (200 mg) were stirred in 1,4-dioxane/
CH2Cl2 (1.0 mL each) at 608C for 8 h. [a] 808C.
estingly, bulky substituents on the nitro-
gen atom of the amine had no significant
impact on its reactivity. When unsym-
metric tertiary amines were used, func-
tionalization occurred preferentially on
3
À
the primary C(sp ) H bond (5a–e, 6a–
b), presumably because of steric effects.
When the reaction was conducted
using [D]-2a, the product [D]-5a was
generated in 60% yield (Scheme 5a).
The presence of deuterium in the prod-
uct constitutes direct evidence against
a
plausible alternative mechanism,
which attributes the origin of the diazo-
derived radical intermediate to a-hydro-
gen abstraction. On the other hand, the
use of deuterated Et3N in place of its
non-deuterated counterpart led to [D14]-
4a in satisfactory yield (Scheme 5b).
This result indicates that a cross-cou-
pling between the Co-based carbene
radical and the a-aminoalkyl radical
has occurred; this mechanism is distinct
À
from those of C H functionalization
processes with the widely studied dirho-
dium- and copper-based carbene sys-
tems.[1c,e–h] When the model reaction
was conducted in the absence of an
olefin, a small amount of compound 7
was detected by GC analysis, which
further confirmed that the process oc-
curred by cross-coupling of the Co-based
carbene radical and the a-aminoalkyl
radical (Scheme 5c). To determine
whether the tertiary amine could have
participated in the reaction by forming Scheme 5. Mechanistic investigations.
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tion,[11] was subjected to the standard conditions, and the
corresponding oxindole 14 could be isolated, albeit in a low
yield of 15%, which indicated that the cobalt carbene radical
had been intercepted with an a-aminoalkyl radical (Sche-
me S2d).
The involvement of reactive radical intermediates was
also validated by the finding that the addition of radical traps,
such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 3,5-
di-tert-butyl-4-hydroxytoluene (BHT), could halt the forma-
tion of the b-ester-g-amino ketones (Scheme S3). Four radical
adducts whose formation was predicted by our proposed
mechanism could be detected from the resulting reaction
mixture, including those of the cobalt-based carbene radical E
with radicals C, G, or H. As expected, when [D]-2a was used
instead of 2a, the corresponding deuterated adducts of
radicals E, G, and H were also detected.
In summary, we have developed an unprecedented
tandem process that features a cobalt-based carbene radical
and involves radical and ionic reactions. The interception of
the cobalt-based carbene radical with an a-aminoalkyl
radical, followed by the Kornblum–DeLaMare reaction,
allowed the efficient synthesis of various highly functional-
ized b-ester-g-amino ketones. During this one-pot process,
À
=
two C C bonds and one C O bond are constructed. Future
research will focus on further studies of the unique reactivity
of the cobalt-based carbene radicals through the development
of more interception reactions.
Scheme 6. Proposed mechanism for the formation of b-ester-g-amino
ketones.
compound by the cobalt(II) complex leads to cobalt-based
carbene radical E (c),[2] which is immediately trapped by C to
afford organocobalt intermediate F (d). Notably, the high- Experimental Section
Cobalt(II) acetylacetonate (0.05 mmol) and 4 ꢀ M.S. (200 mg) were
added to test tube. 1,4-Dioxane (1.0 mL), dichloromethane
resolution mass spectrum features a peak at m/z 344.0698,
which corresponds to the organocobalt species E–H, which
are generated in situ by hydrogen abstraction from cobalt-
based carbene radical E (for details, see the Supporting
Information). Next, the addition of radical G, which is formed
by the reversible homolytic cleavage of F, to styrene generates
the more stabilized benzyl radical H (e), which can then be
selectively coupled with tBuOOC (B) to produce peroxide
intermediate J (f). Finally, peroxide intermediate J undergoes
a Kornblum–DeLaMare reaction[8] to give the desired b-ester-
g-amino ketone (g). Because of the well-established carbo-
philicity of cobalt, these carbon-centered radicals could be
reversibly trapped by CoII to form organocobalt intermedi-
ates.[10]
Several model studies were designed to better understand
the mechanism of this transformation (Scheme S2). a-Bro-
moester 9, which can serve as a precursor to an organoradical
intermediate, was shown to be a suitable replacement for the
diazo substrate, and the reaction afforded product 10 in good
yield under the standard conditions (Scheme S2a). In con-
trast, when b-amino ester 11 was used as the coupling partner,
the corresponding product was not detected (Scheme S2b).
Similarly, the fact that compound 12 (a precursor to an
organoradical species) was also a poor choice of substrate
(Scheme S2c) indicated that the b-ester-g-amino ketone is not
formed by the reaction of the a-diazo reagent with the olefin
followed by coupling with the amine. N-Methyl-N-phenyl-
methacrylamide (13), an efficient radical acceptor for the
construction of oxindoles by homolytic aromatic substitu-
a
(1.0 mL), the alkene (0.5 mmol), amine (2.5 mmol), diazoacetic
ester (1.0 mmol), and TBHP, (1.85 mmol, 0.25 mL, 70% solution in
water) were added by syringe. A balloon was put on the test tube. The
reaction mixture was stirred at 608C for 8 h. It was then quenched (to
consume residual TBHP) with a saturated Na2SO3 solution and
extracted with ethyl acetate. The organic layers were combined and
dried with Na2SO4. Removal of the solvents followed by flash column
chromatography (petroleum/ethyl acetate) on silica gel afforded the
desired product.
Received: September 7, 2014
Published online: && &&, &&&&
Keywords: carbene radicals · cobalt · Kornblum–
.
DeLaMare reaction · radical reactions · tandem reactions
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Communications
One-Pot Processes
J. Zhang, J. Jiang, D. Xu, Q. Luo, H. Wang,
J. Chen, H. Li, Y. Wang,
X. Wan*
&&&& — &&&&
Radical combination: The interception of
cobalt-based carbene radicals witha-
aminoalkyl radicals in combination with
a Kornblum–DeLaMare reaction leads to
b-ester-g-amino ketones, which are oth-
erwise difficult to obtain with high che-
moselectivity. The transformation fea-
tures a wide substrate scope and is highly
efficient and insensitive to moisture and
air.
Interception of Cobalt-Based Carbene
Radicals with a-Aminoalkyl Radicals: A
Tandem Reaction for the Construction of
b-Ester-g-amino Ketones
6
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