Carbonylative C-C bond activation of aminocyclopropanes using a temporary directing group strategy

Article abstract of DOI:10.1021/jacs.0c08973

Temporary directing groups (TDGs) underpin a range of C-C bond activation methodologies; however, the use of TDGs for the regiocontrolled activation of cyclopropane C-C bonds is underdeveloped. In this report, we show how an unusual ring contraction process can be harnessed for TDG-based carbonylative C-C bond activations of cyclopropanes. The method involves the transient installation of an isocyanate-derived TDG, rather than relying on carbonyl condensation events as used in previous TDG-enabled C-C bond activations.

Full text of DOI:10.1021/jacs.0c08973

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Communication
Carbonylative C−C Bond Activation of Aminocyclopropanes Using a
Temporary Directing Group Strategy
Gang-Wei Wang,+ Olga O. Sokolova,+ Tom. A. Young, Ektor M. S. Christodoulou, Craig P. Butts,
and John F. Bower*
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ABSTRACT: Temporary directing groups (TDGs) underpin a range of C−C bond activation methodologies; however, the use of
TDGs for the regiocontrolled activation of cyclopropane C−C bonds is underdeveloped. In this report, we show how an unusual
ring contraction process can be harnessed for TDG-based carbonylative C−C bond activations of cyclopropanes. The method
involves the transient installation of an isocyanate-derived TDG, rather than relying on carbonyl condensation events as used in
previous TDG-enabled C−C bond activations.
ethods based on catalytic C−C bond activation
carbonylative processes, where tractable rhodacyclopenta-
nones9 I are generated from aminocyclopropanes10 1 (and
related species) with very high levels of regiocontrol (Scheme
1B).7 Using this approach, a variety of multicomponent
cycloadditions,11 heterocyclizations,12 and polycyclizations13
have been achieved. A key feature of our processes is the use of
an N-carbonyl-based directing group, which either becomes
part of the new ring system or, in some cases (e.g., N-Cbz), can
be removed after the C−C bond activation process. On first
inspection, none of our previous processes are easily extended
to a TDG-based scenario; however, in this report, we show
how this can be achieved by exploiting an unusual ring
contraction. The method, which involves the installation and
subsequent expulsion of an isocyanate-derived TDG, provides
diverse γ-lactams and offers a unique framework for developing
TDG-based C−C bond activations (Scheme 1C).
We have previously shown that carbonylative heterocycliza-
tion of 1aa delivers 2aa and 3aa in a 20:1 ratio at 100 °C
(Scheme 2A).12a In this process, the initially generated
rhodacyclopentanone I′ is converted to II in advance of C−
N bond forming reductive elimination, which provides III.
From here, 2aa and 3aa are generated by β-hydride elimination
and protodemetalation, respectively. When this reaction was
conducted at 130 °C under slightly modified conditions, 3aa
was not observed, and lactam 4a formed instead, along with
expected product 2aa (1:8 ratio) (Scheme 2B, Eqn 1).14 Re-
exposure of 2aa to the reaction conditions led only to
decomposition, and lactam 4a was not formed. However, when
the alkene unit of 2aa was reduced by hydrogenation of the
crude heterocyclization mixture, which was achieved in one pot
M
commonly require directing groups (DGs) to accelerate
the rate and control the regioselectivity of metal insertion.1
“Permanent” directing groups have been used to facilitate the
activation of a relatively broad range of C−C bonds.2
“Temporary” (or “transient”)3 directing groups (TDGs) are
potentially more powerful because they can avoid the need for
discrete DG installation and removal steps. Jun’s seminal work
achieved activations of ketone-based substrates via condensa-
tion with 2-amino-3-picoline to generate the corresponding
imines (Scheme 1A, Eqn 1), and this strategy has been
developed significantly by Dong and co-workers.4 Of particular
relevance are examples involving 4-membered ring systems,
specifically those based on cyclobutanones (Eqn 2).5 By
contrast, the use of TDGs for the activation of 3-membered
carbocycles (e.g., cyclopropanes) is virtually unknown. Perhaps
the closest precedent is Montgomery’s use of cyclopropanal-
derived imines in Ni-catalyzed (3 + 2) cycloadditions (Eqn
3);6 here, discrete steps were required for DG installation and
removal, although there is evident potential for refinement to a
“full” TDG-based protocol. An impediment in this area is that,
until recently, most C−C bond activation methodologies
involving 3-membered carbocycles required highly activated or
specialized variants (e.g., spirocyclopropanes, cyclopropenes,
alkylidene cyclopropanes)1b that are not easily adapted to
TDG-based settings.
Efforts in our laboratory have focused on the development of
C−C bond activations of less activated 3-membered carbo-
cycles.7 There are significant benefits to such an approach
because “simple” cyclopropanes are easy to access with a range
of substitution patterns and in enantiopure form. Conse-
quently, in principle, they can function as “spring loaded”
initiating motifs for the stereospecific installation of 3-carbon
units. However, the realization of such processes is hampered
by (a) controlling the regioselectivity of C−C bond activation
and (b) the instability of the incipient metallacyclobutane,
which is prone to deleterious β-hydride elimination.8 To
address these issues, we have developed DG controlled
Received: August 20, 2020
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© XXXX American Chemical Society
A

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a
Scheme 1
Scheme 2. Reaction Discovery and Development
by addition of H2 (1 atm) and xantphos (15 mol %) and
heating at 140 °C, lactam 4a could be isolated in 75% yield
(Eqn 2). Because hydrogenation of 2aa did not occur at lower
temperatures, we were unable to halt the process at the stage of
3aa. Nevertheless, the collective observations (as well as those
described later) suggest that lactam 4a originates from 3aa and
not 2aa. Interestingly, NH-system 3b, which is easy to access
with C4−C5 saturation,12a did not undergo ring contraction
upon heating (Eqn 3).15
To improve the overall efficacy of the process, we sought
carbonylation conditions that would generate directly C4−C5
saturated systems (cf. 3aa) and so allow the direct formation of
4a. Variation of the R group offered partial success; switching
this from Bn to c-Hex improved the yield and selectivity for
lactam 4a (Eqn 1). The most pronounced improvement was
achieved by instead employing thiourea 1ad, which led directly
to lactam 4a in 68% yield (Eqn 4); here, the C4−C5
unsaturated variant of 3ad was not observed. The thiourea unit
can be installed in situ by reaction of cyclopropylamine 5a with
isothiocyanate 6, and direct exposure of the resulting mixture
to the carbonylation conditions provided lactam 4a in 70%
yield (eqn 5). Thus, the directing group is installed and
disappears in the same pot. Extension of the ring contraction to
more heavily substituted cyclopropanes 1c and 1d was
challenging because we were unable to identify conditions
that avoided the predominant generation of the C4−C5
unsaturated product (Scheme 2C). Thus, we isolated alkenes
a
The following numbering system is used here and throughout: 1 =
cyclopropyl (thio)urea, 2 = C4−C5 unsaturated diazepane, 3 = C4−
C5 saturated diazepane, 4 = lactam, 5 = cyclopropylamine precursor,
first letter = structural variant w.r.t the cyclopropylamine unit, second
letter = structural variant w.r.t the urea/thiourea unit. Yield for urea/
thiourea formation (see the SI). C6H5OCH2CO2H (200 mol %) was
b
c
d
used. Traces of regioisomer (<10%) derived from C−C bond
activation of the less hindered proximal C−C bond of 1d were also
observed.
B
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2c and 2d, which were formed efficiently from cyclopropanes
1c and 1d, and reduced them (Pd/C, H2)16 prior to thermally
promoted ring contraction, which provided α- and β-
substituted lactams 4c and 4d. In the former case, complete
transfer of enantiopurity was observed, such that the
challenging α-methyl stereocenter of 4c was installed in 98:2
e.r. The regiochemical outcomes for the conversions of 1c to
2c and 1d to 2d have been rationalized in our earlier work.12a
Further refinement of these processes can be envisaged, but as
outlined later, we instead opted to explore more ambitious
applications of this TDG strategy. The use of thiourea
analogues of 1c and 1d was investigated, but heterocyclization
occurred in low yield and regiocontrol for C−C bond
activation was incomplete.
Scheme 3. TDG-Mediated Tandem C−C Carbonylation
Processes
The ring contraction of 3 to 4 is unusual,17 and we are not
aware of any examples that have been interrogated
mechanistically. Accordingly, we performed DFT analysis of
the current process using simplified system 3a′ (Figure 1).
Figure 1. Free energy profiles computed at SMD(DCB)-DLPNO−
CCSD(T)/def2-TZVPP//PBE0-D3BJ/def2-TZVP, 423.15 K. 3D
geometries with key distances are quoted in Å.
a
b
Yield for urea formation (see the SI). A yield for the installation of
the urea unit was not obtained as this substrate was synthesized using
in a one-pot multistep procedure.
These studies revealed an energetically feasible concerted
pathway which results in expulsion of methyl isocyanate via
attack of N6 onto C2 and concomitant cleavage of the C2−N1
bond (ΔG‡ = 33.5 kcal mol−1). A more conventional stepwise
addition−elimination mechanism (proceeding via a tetrahedral
intermediate) was found to be energetically unfeasible (see the
Supporting Information (SI)). The concerted nature of the
ring contraction process is similar to recently reported ring
contractions of cyclic N-carboxyanhydrides.18 In the current
process, the nucleophilicity of the N6 center is key: ring
contraction of unsaturated system 2a′, where cross-conjugation
with the alkene likely diminishes the nucleophilicity of the
nitrogen lone pair, has a higher barrier (ΔG‡ = 39.7 kcal
mol−1). This result is consistent with the observation that 2aa
does not undergo ring contraction to dehydro-4a (or 4a).15
The studies outlined so far show that ring contraction only
occurs for diazepanes that possess C4−C5 saturation.
Accordingly, we envisaged designing processes that exploit
removal of the easily installed C4−C5 unsaturation in further
bond formations. To this end, ureas 1e and 1f were exposed to
carbonylative heterocyclization conditions, which generated 2e
and 2f in 92% and 77% yield, respectively (Scheme 3A).
Exposure of these products to TFA at high temperature
effected Pictet−Spengler-like cyclization, which removed the
C4−C5 unsaturation and triggered ring contraction to tricyclic
lactams 4e and 4f. A one-pot procedure was also investigated,
wherein TFA was added directly after complete consumption
of 1e/f; this method provided 4e and 4f in 70% and 37% yield,
respectively, without the need for isolation of 2e/f. The
protocol extended to disubstituted cyclopropanes 1g and 1h
which provided targets 4g and 4h with good levels of
diastereo- and regiocontrol. In the case of 1g, complete
transfer of enantiopurity was observed.19
Other types of tandem process are also possible. For
example, carbonylative heterocyclization of dienyl systems 1i
and 1j at 140 °C provided synthetically challenging tricyclic
systems 4i and 4j in 51% and 47% yield, respectively, and as
single diastereomers (Scheme 3B). Here, initial Rh-catalyzed
cyclization to 2i/j is likely followed by thermally promoted
Diels−Alder cycloaddition which provides adducts 3i and 3j.
At this stage, the C4−C5 unsaturation present in 2i/j is
removed and so ring contraction can occur spontaneously to
provide the target. For these processes, the inclusion of
dimethyl fumarate (rather than a carboxylic acid additive) was
found to be optimal.11a Additionally, BHT was employed as an
additive to suppress radical polymerization of the diene
substrate during the reaction.20
C
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To extend the scope of the TDG strategy further, we sought
processes where the initial formation of C4−C5 unsaturated
products might be avoided by harnessing the alkyl-Rh(I)
intermediate (cf. III, Scheme 2A) in further bond formations.
To this end, we examined carbonylative cyclization of 1k  in
this system, the initially generated alkyl-Rh(I) species III′
undergoes syn-stereospecific carbometalation of the pendant
alkyne prior to protodemetalation to provide 3k (Scheme
4A).13 Accordingly, the rhodacyclopentanone functions as an
ambiphilic unit, with its electrophilicity promoting the first
cyclization and the nucleophilicity of the ensuing alkyl-Rh(I)
species III′ facilitating the second. When the reaction was run
at 100 °C only diazepane 3k was observed. However, as the
temperature was increased to 140 °C, lactam 4k was isolated as
the sole product, thereby confirming the requirement for
elevated temperatures for the ring contraction process. The
protocol could be extended to a “full” TDG setting by
premixing amine 5k with cyclohexyl isocyanate prior to
addition of the components required for the carbonylative
heterocyclization/ring contraction sequence (Scheme 4B).
Using this method, and by switching the ligand from P(4-
FC6H4)3 to PPh3, adduct 4k was formed in 77% yield. The
protocol extended to a range of different alkynes which
provided targets 4l−p in 54−77% yield. To corroborate the
mechanism of these processes, diazepane 3k was isolated and
heated at 140 °C, which, as expected, effected ring contraction
to 4k (90% yield, Scheme 4C, Eqn 1). Here, we were also able
to isolate urea 7, a byproduct that is consistent with release of
cyclohexyl isocyanate during ring contraction.21 To add further
support to this, the optimized protocol for the conversion of
5k to 4k was run in the presence of benzyl alcohol (Eqn 2).
This led to the isolation of carbamate 8 in 95% yield, a result
that is also consistent with the release of cyclohexyl isocyanate.
In summary, we demonstrate that readily available iso-
(thio)cyanates can function as temporary directing groups in
carbonylative C−C bond activations of aminocyclopropanes.
In so doing, this reactivity manifold now extends, for the first
time, to the direct preparation of complex γ-lactams, including
variants bearing stereodefined substituents. The chemistry is
underpinned by an unusual ring contraction process, and
through understanding key mechanistic features of this,
tandem and cascade processes have been developed that
exploit either classical reactivity or the ambiphilic nature of the
key rhodacyclopentanone intermediates. In broader terms,
these studies validate a conceptually unique TDG-based
strategy for C−C bond activation. Specifically, the processes
are the first in this area that do not harness carbonyl
condensation and imine hydrolysis for TDG installation and
removal.
Scheme 4. TDG-Mediated Tandem C−C Carbonylation
Cascades and Key Observations
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c08973.
Experimental details, characterization data, and crystallo-
graphic data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
John F. Bower − School of Chemistry, University of Bristol,
Bristol BS8 1TS, United Kingdom; Department of Chemistry,
University of Liverpool, Liverpool L69 7ZD, United Kingdom;
orcid.org/0000-0002-7551-8221; Email: john.bower@
liverpool.ac.uk
Authors
Gang-Wei Wang − School of Chemistry, University of Bristol,
Bristol BS8 1TS, United Kingdom
Olga O. Sokolova − School of Chemistry, University of Bristol,
Bristol BS8 1TS, United Kingdom
Tom. A. Young − Physical and Theoretical Laboratory,
University of Oxford, Oxford OX1 3QZ, United Kingdom;
orcid.org/0000-0002-8432-7769
a
b
Yield for urea formation (see the SI). BnOH was added with the
Rh-catalyst.
D
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(3) The term “transient” has been used to describe a DG that can be
installed and expelled in situ, see: Gandeepan, P.; Ackermann, L.
Transient Directing Groups for Transformative C−H Activation by
Synergistic Metal Catalysis. Chem. 2018, 4, 199. Clearly, the finer
points of this definition are open to interpretation, and so we use the
broader term of “temporary” DG, because, in some cases described
here, greater efficiencies are achieved via ex situ installation of the DG,
whereas in other examples in situ installation is optimal. We
considered the terms “disappearing” or “in situ removable” DG, but
these do not convey (or require) that the DG is released as the same
species used for its installation. For elegant examples of the use of
disappearing DGs in C−C bond activation, see: Xu, Y.; Qi, X.; Zheng,
P.; Berti, C. C.; Liu, P.; Dong, G. Nature 2019, 567, 373.
(4) (a) Jun, C.-H.; Lee, H. Catalytic Carbon−Carbon Bond
Activation of Unstrained Ketone by Soluble Transition-Metal
Complex. J. Am. Chem. Soc. 1999, 121, 880. (b) Jun, C.-H.; Lee,
D.-Y.; Kim, Y.-H.; Lee, H. Catalytic Carbon−Carbon Bond Activation
of sec-Alcohols by a Rhodium (I) Complex. Organometallics 2001, 20,
2928. (c) Jun, C.-H.; Lee, H.; Lim, S.-G. The C−C Bond Activation
and Skeletal Rearrangement of Cycloalkanone Imine by Rh(I)
Catalysts. J. Am. Chem. Soc. 2001, 123, 751. (d) Ahn, J.-A.; Chang,
D.-H.; Park, Y. J.; Yon, Y. R.; Loupy, A.; Jun, C.-H. Solvent Free
Chelation Assisted Catalytic C-C Bond Cleavage of Unstrained
Ketone by Rhodium(I) Complexes under Microwave Irradiation. Adv.
Synth. Catal. 2006, 348, 55. (e) Xia, Y.; Lu, G.; Liu, P.; Dong, G.
Catalytic Activation of Carbon−Carbon Bonds in Cyclopentanones.
Nature 2016, 539, 546. (f) Xia, Y.; Wang, J.; Dong, G. Suzuki-Miyaura
Coupling of Simple Ketones via Activation of Unstrained Carbon−
Carbon Bonds. J. Am. Chem. Soc. 2018, 140, 5347. (g) Rong, Z. Q.;
Lim, H. N.; Dong, G. Intramolecular Acetyl Transfer to Olefins by
Catalytic C-C Bond Activation of Unstrained Ketones. Angew. Chem.,
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Ring Expansion of 1-Indanones via Insertion of Ethylene Into
Carbon−Carbon Bonds. J. Am. Chem. Soc. 2019, 141, 13038.
(5) Ko, H. M.; Dong, G. Cooperative Activation of Cyclobutanones
and Olefins Leads to Bridged Ring Systems by a Catalytic [4 + 2]
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Ektor M. S. Christodoulou − School of Chemistry, University of
Bristol, Bristol BS8 1TS, United Kingdom
Craig P. Butts − School of Chemistry, University of Bristol,
Bristol BS8 1TS, United Kingdom; orcid.org/0000-0001-
6678-8839
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c08973
Author Contributions
+G.W. and O.O.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the European Research Council (Grant 639594
CatHet), the Royal Society (K. C. Wong Fellowship to G.-
W.W. and URF to J.F.B.), the Leverhulme Trust (Philip
Leverhulme Prize to J.F.B.), and the EPSRC (Summer
Vacation Bursary to E.M.S.C.). We also thank the EPSRC
Centre for Doctoral Training in Theory and Modelling in
Chemical Sciences (EP/L015722/1) for providing a student-
ship to T.A.Y., generously supported by AWE, and access to
the Dirac cluster at Oxford.
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Elimination from Rhodacyclopentanones. J. Am. Chem. Soc. 2016,
138, 11465. (b) Wang, G.-W.; Bower, J. F. Modular Access to
Azepines by Directed Carbonylative C−C Bond Activation of
Aminocyclopropanes. J. Am. Chem. Soc. 2018, 140, 2743. (c) Boyd,
O.; Wang, G.-W.; Sokolova, O. O.; Calow, A. D. J.; Bertrand, S. M.;
Bower, J. F. Modular Access to Eight-Membered N-Heterocycles by
Directed Carbonylative C-C Bond Activation of Aminocyclopropanes.
Angew. Chem., Int. Ed. 2019, 58, 18844.
(13) Wang, G.-W.; Boyd, O.; Young, T. A.; Bertrand, S. M.; Bower,
J. F. Rhodacyclopentanones as Linchpins for the Atom Economical
Assembly of Diverse Polyheterocycles. J. Am. Chem. Soc. 2020, 142,
1740.
(14) A wide range of acid additives were screened to improve the
ratio of 2aa:3aa and thereby facilitate ring contraction. From these
studies, 4-NMe2C6H4CO2H emerged as the optimal choice. When the
conditions in Eqn 1 were used at 100 °C, 2aa and 3aa formed in 68%
and 6% yield, respectively, and 4a was not observed (cf. Scheme 2A).
(15) The SI outlines DFT studies on a simplified system related to
3b that are analogous to those in Figure 1. These indicate that the
barrier for ring contraction in this case (ΔG‡ = 38.4 kcal mol−1) is
higher than that for 3a′. This is tentatively attributed to the lower
nucleophilicity of the NH vs N-alkyl center. Under basic conditions,
3b does undergo ring contraction; DFT studies indicate a stepwise
mechanism is operative in this case.
1
(16) The crude reduction product was characterized by H NMR
spectroscopy (see the SI).
(17) (a) Felix, A. M.; Fryer, R. I. Oxidation of 2,4-Benzodiazepin-3-
ones. J. Heterocycl. Chem. 1968, 5, 291. (b) Bocelli, G.; Catellani, M.;
Cugini, F.; Ferraccioli, R. A New and Efficient Palladium-Catalyzed
Synthesis of a 2,3,4,5-Tetrahydro-1H-2,4-benzodiazepine-1,3-dione
Derivative. Tetrahedron Lett. 1999, 40, 2623.
(18) Romero-Ibanez, J.; Cruz-Gregorio, S.; Sandoval-Lira, J.;
̃
́
́
Hernandez-Perez, J. M.; Quintero, L.; Sartillo-Piscil, F. Transition-
Metal-Free Deconstructive Lactamization of Piperidines. Angew.
Chem., Int. Ed. 2019, 58, 8867.
(19) For these processes, the TFA promoted cyclization step was
conducted at 60 °C (vs 150 °C for 1e and 1f) prior to heating at 150
°C for the ring contraction. This modification enhanced diaster-
eoselectivity, because this aspect is controlled by the TFA-promoted
step. When the TFA promoted cyclization was conducted at 150 °C
in 1,2-DCB, 4g was formed in 2.6:1 d.r. The optimized conditions
employ a solvent switch from CH2Cl2 to 1,2-DCB. When 1,2-DCB
was used for both steps, 4g was formed with lower diastereoselectivity
(4:1 d.r. vs 5:1 d.r. under optimized conditions).
(20) In the absence of BHT, the processes in Scheme 3B give <40%
yield. For the use of BHT in C−C bond activation processes, see:
Murakami, M.; Itahashi, T.; Ito, Y. Catalyzed Intramolecular Olefin
Insertion into a Carbon−Carbon Single Bond. J. Am. Chem. Soc. 2002,
124, 13976.
F
https://dx.doi.org/10.1021/jacs.0c08973
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX