Remote sp2C-H Carboxylation via Catalytic 1,4-Ni Migration with CO2

Article abstract of DOI:10.1021/jacs.0c08810

A remote catalytic reductive sp2 C-H carboxylation of arenes with CO2 (1 bar) via 1,4-Ni migration is disclosed. This protocol constitutes the first catalytic 1,4-Ni migration reported to date, thus offering new vistas in the Ni-catalyzed reductive coupling arena while providing an unconventional new platform for incorporating electrophilic sites at remote sp2 C-H linkages.

Full text of DOI:10.1021/jacs.0c08810

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Remote sp2 C−H Carboxylation via Catalytic 1,4-Ni Migration with
CO2
̈
̈
Marino Borjesson, Daniel Janssen-Muller, Basudev Sahoo, Yaya Duan, Xueqiang Wang,
and Ruben Martin*
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ABSTRACT: A remote catalytic reductive sp2 C−H carboxylation of arenes with CO2 (1 bar) via 1,4-Ni migration is disclosed.
This protocol constitutes the first catalytic 1,4-Ni migration reported to date, thus offering new vistas in the Ni-catalyzed reductive
coupling arena while providing an unconventional new platform for incorporating electrophilic sites at remote sp2 C−H linkages.
ecent years have witnessed the design of catalytic
reductive carboxylations of aryl (pseudo)halides with
whether a new catalytic blueprint could be designed via a
cascade-type process based on a site-selective 1,4-Ni
migration,8 thus setting the stage for a formal CO2 insertion
at remote sp2 C−H bonds (Scheme 2). At the outset of our
R
CO2 en route to benzoic acids,1 privileged motifs in
biologically active molecules.2 Although remarkable levels of
sophistication have been reached, prefunctionalization at the
targeted sp2 reaction site is required prior to CO2 insertion
(Scheme 1, path a).1 Beyond any doubt, the pursuit of an
Scheme 2. sp2 C−H Carboxylation via 1,4−Ni Migration
Scheme 1. sp2 Carboxylation Reactions with CO2
investigations, however, it was unclear whether such a strategy
could be implemented, as (1) catalytic 1,4-Ni translocation9
remains an unknown cartography in cross-coupling reac-
tions10−14 and (2) site-selectivity issues might come into play
because of competitive catalytic carboxylation at the sp3 C−Br
site15 or at the alkyne motif.16 We recognized that, if
successful, such a scenario might offer a conceptually new
reactivity mode in the reductive cross-coupling arena for
tackling the functionalization of otherwise inaccessible sp2 C−
H reaction sites.17 Herein we report the successful realization
of this goal. Our protocol is characterized by its mild
conditions, wide substrate scopeincluding challenging
substrate combinationswithout the need for handling air-
or moisture-sensitive reagents, and an exquisite site-selectivity
pattern.
alternative catalytic carboxylation at previously unfunctional-
ized sp2 C−H sites (path b) might constitute, conceptuality
and practicality aside, a worthwhile endeavor for chemical
invention.3
Prompted by a seminal work of Fujiwara with stoichiometric
amounts of Pd complexes,4 significant efforts have been made
to unlock the potential of sp2 C−H carboxylations by
employing either acidic sp2 C−H linkages5 or strategies
requiring chelating groups (Scheme 1, bottom).6 However,
extensions to non-acidic sp2 C−H bonds are beyond reach in
the former, whereas the absence of chelating groups results in
site-selectivity issues, invariably requiring noble metals and/or
stoichiometric organometallic reagents (bottom left).7 These
observations have contributed to the perception that a de novo
catalytic sp2 C−H carboxylation strategy without recourse to
noble metals or organometallics might provide fundamentally
new knowledge in both sp2 C−H functionalization and
carboxylation processes. Under this premise, we wondered
Received: August 16, 2020
https://dx.doi.org/10.1021/jacs.0c08810
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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Communication
a b
,
Our investigations began by evaluating the remote sp2 C−H
carboxylation of 1a with CO2 (Table 1). As expected,
Table 2. sp2 C−H Carboxylation of Alkyl Bromides
a
Table 1. Optimization of the Reaction Conditions
a
Conditions: 1a (0.20 mmol), NiBr2·diglyme (10 mol %), L5 (20 mol
%), and MnCr alloy (0.25 mmol) in DMF (0.2 M) at 15 °C under
CO2 (1 atm). Determined by H NMR analysis using trimethox-
ybenzene as an internal standard. Isolated yields.
b
1
c
conditions previously employed for the reductive carboxylation
of aryl halides failed to provide even traces of 2a18 and mainly
resulted in statistical mixtures of carboxylic acids arising from
CO2 insertion at the vinyl motif (E,Z-2a′). After a judicious
choice of the reaction parameters, a combination of NiBr2·
diglyme, L5, and Mn89Cr11 was found to be critical for
success,19 delivering 2a in 77% yield with an excellent site-
selectivity profile (94:6).20 As shown in entries 2−5, subtle
changes in the electronic or steric environment of the 2,2′-
bipyridine core had a non-negligible impact on the reactivity.21
Strikingly, erosion of both the yield and site selectivity was
observed when metal reductants other than Mn89Cr11 were
employed (entries 6−8).22 While one might argue that the
presence of Cr atoms might dictate the site-selectivity pattern,
the results shown in entries 7 and 8 indicate otherwise.14 At
present we have no explanation for this behavior. While
inferior results were found with Ni(cod)2 and DMSO (entries
9 and 10), no erosion in yield or selectivity was found when
air- and moisture-stable NiBr2(L5)2 was used, constituting an
additional bonus from a user-friendly standpoint (entry 11).
Encouraged by these findings, we turned our attention to
studying the generality of our cascade process with a host of
unactivated alkyl bromides. As evident from the results
compiled in Table 2, structures containing thioethers (2d),
methoxy arenes (2b), trifluoromethylated derivatives (2c and
2i), or heterocycles (2o) could perfectly be tolerated. Even aryl
halides (2g, 2h, and 2r) or organoboranes (2e) could be
accommodated, thus constituting an orthogonal gateway for
subsequent manipulation via cross-coupling reactions. Notably,
acetylenes end-capped with either sterically hindered arenes
(2m) or aliphatic motifs (2j−l) posed no problems. Equally
relevant was the observation that the targeted carboxylation
occurred regardless of the steric properties at the acetylene
backbone or the employment of secondary unactivated alkyl
bromides (2p and 2q). Interestingly, the inclusion of different
substitution patterns on the arene backbone did not interfere
with productive 1,4-migration, albeit in lower yields (2r and
a
b
Conditions: as in Table 1, entry 11. Isolated yields, averages of two
c
d
e
runs, 2a−w:2a′−w′ ≥ 90:10. 2i:2i′ = 87:13. 2o:2o′ = 76:26. L2
f
(20 mol %) and MnCr (2.5 equiv). NiBr2·diglyme (15 mol %)/L2
(30 mol %) and MnCr (2.5 equiv), 2w:2w′ = 80:20.
2s).23 The successful carboxylation of silicon-tethered alkyl
bromides is particularly important, as the corresponding
carboxylic acids 2t−w could be homologated via C−Si
cleavage at later stages, thus easily accessing nonfused
analogues (Scheme 4, bottom).
The successful preparation of 2a−w suggested that an
otherwise similar 1,4-Ni migration scenario could be within
reach by the use of simple vinyl halides as substrates. As shown
in Scheme 3, this turned out to be the case, and vinyl bromides
containing either alkyl or aromatic substituents could trigger
the targeted sp2 C−H carboxylation en route to 4a and 4b
regardless of whether E/Z mixtures of 3a and 3b, respectively,
were utilized.24 While tentative, this observation suggests an
initial E/Z isomerization of the oxidative addition Ni(II)
species prior to 1,4-Ni migration, probably via the
a b
,
Scheme 3. sp2 C−H Carboxylation of Vinyl Bromides
a
b
Conditions: as in Table 1, entry 11, using DMA. Isolated yields,
c
d
averages of two independent runs. Z:E = 2.4:1. Z:E = 3.3:1.
B
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Communication
intermediacy of carbene-type species.25 The prospective
impact of our 1,4-Ni migration technique is further illustrated
in Scheme 4. As shown, complex molecular isochromanone or
Scheme 5. Preliminary Mechanistic Studies
Scheme 4. Application Profile
state are depicted in Scheme 5 (bottom).32 As anticipated, the
carboxylation of 10 occurred only in the presence of L5, thus
illustrating the importance of 2,2′-bipyridine ligands in the
targeted carboxylation reaction. More importantly, 4a could be
obtained from 10 or 11 in the absence of external metal
reductant, strongly suggesting that both 1,4-Ni migration and
CO2 insertion occur at Ni(II) centers.33 This observation can
hardly be underestimated, as it challenges the prevailing
perception that CO2 insertion occurs at Ni(I)−carbon bonds34
and that a 1,4-shift should take place at Ni(I) centers,9 thus
opening up new knowledge about catalyst design, particularly
in the reductive cross-coupling arena.17 Whether CO2 insertion
occurs at four-coordinate or six-coordinate species via
octahedral complexes is a subject of ongoing studies in this
laboratory.35
In summary, we have documented the first catalytic 1,4-
nickel migration as a vehicle to enable CO2 insertion at remote
and previously unfunctionalized sp2 C−H reaction sites, an
unrecognized opportunity in both the carboxylation and
reductive cross-coupling arena. The salient features of this
protocol are the exquisite chemo- and site selectivity, mild
conditions, and application profile. Further extensions to other
cross-couplings initiated by 1,4-Ni migration are currently
underway in our laboratories.
phthalide architectures could be accessed from 2a or 2b
depending on the reaction conditions utilized. Thus,
bromolactonization to obtain 5 was easily accomplished by
exposing 2a to NBS in TFA,26 whereas clean formation of
phthalide 6 was observed with H2SO4 instead.27 Similarly,
while isochromenone 7 could be obtained via Pd-catalyzed
oxidative regimes,28 the saturated isochromanone analogue 8
was within reach from 2b instead. More importantly, the
successful preparation of 9 in an unoptimized 43% yield tacitly
indicates that the presence of silicon fragments can be turned
into a strategic advantage to access functionalized polyhy-
droxylated carboxylic acids, thus expanding the application
profile of our technology.29
Intrigued by the favorable reactivity profile shown in Table 2
and Schemes 2 and 3, we conducted experiments with
isotopically labeled substrates (Scheme 5, top). As shown,
full deuterium incorporation at the vinyl position (>95% D)
was observed in 4c when 3c was exposed to our optimized
NiBr2/L5 regime, thus corroborating that a [1,4]-Ni migration
occurs at the ortho sp2 C−H bond prior to CO2 insertion.
Interestingly, while a significant intramolecular kinetic isotope
effect was observed in the reductive carboxylation of 3d (kH/kD
= 5:1; Scheme 5, top right), no intermolecular kinetic isotope
effect was found by comparison of the rates of 3a and 3c.19
Although tentative, this observation suggests a rate-determin-
ing step that occurs before or after the 1,4-migration event.30
Still, however, there was a reasonable doubt about whether
[1,4]-Ni migration and the subsequent CO2 insertion occurred
at Ni(I) or Ni(II) centers. Thus, we turned our attention to
unraveling such mechanistic intricacies by isolating the
putative oxidative addition species at either the vinyl or aryl
terminus. Interestingly, 10 and 11 could be prepared by
reacting the aryl (vinyl) halide with Ni(cod)2 and TMEDA or
L2 in THF.31 The structures of these complexes in the solid
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c08810.
■
sı
Crystallographic data for 2a′ (CCDC 1992996) (CIF)
Crystallographic data for 2a (CCDC 1992997) (CIF)
Crystallographic data for 4a (CCDC 1992998) (CIF)
Crystallographic data for 5 (CCDC 1992999) (CIF)
Crystallographic data for 10 (CCDC 1993000) (CIF)
Crystallographic data for NiBr2(L5)2 (CCDC 1993001)
(CIF)
Experimental procedures and spectral and crystallo-
graphic data (PDF)
C
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Communication
10, 3317. (b) Hong, J.; Li, M.; Zhang, J.; Sun, B.; Mo, F. C−H Bond
Carboxylation with Carbon Dioxide. ChemSusChem 2019, 12, 6.
(4) Sugimoto, H.; Kawata, I.; Taniguchi, H.; Fujiwara, Y. Palladium-
catalyzed carboxylation of aromatic compounds with carbon dioxide.
J. Organomet. Chem. 1984, 266, C44.
AUTHOR INFORMATION
■
Corresponding Author
Ruben Martin − Institute of Chemical Research of Catalonia
(ICIQ), The Barcelona Institute of Science and Technology,
43007 Tarragona, Spain; ICREA, 08010 Barcelona, Spain;
orcid.org/0000-0002-2543-0221; Email: rmartinromo@
iciq.es
(5) Selected references on catalytic carboxylations of relatively acidic
sp2 C−H bonds (pKa < 28): (a) Boogaerts, I. I. F.; Fortman, G. C.;
Furst, M. R. L.; Cazin, C. S. J.; Nolan, S. P. Carboxylation of N−H/
C−H Bonds Using N-Heterocyclic Carbene Copper(I) Complexes.
Angew. Chem., Int. Ed. 2010, 49, 8674. (b) Zhang, L.; Cheng, J.;
Ohishi, T.; Hou, Z. Copper-Catalyzed Direct Carboxylation of C−H
Bonds with Carbon Dioxide. Angew. Chem., Int. Ed. 2010, 49, 8670.
(c) Inomata, H.; Ogata, K.; Fukuzawa, S. I.; Hou, Z. Direct C−H
Carboxylation with Carbon Dioxide Using 1,2,3-Triazol-5-ylidene
Copper(I) Complexes. Org. Lett. 2012, 14, 3986. For mechanistic
studies on the matter, see: (d) Johnson, M. T.; Marthinus Janse van
Rensburg, J.; Axelsson, M.; Ahlquist, M. S. G.; Wendt, O. F. Reactivity
of NHC Au(I)−Cs-bonds with electrophiles. An investigation of their
possible involvement in catalytic C−C bond formation. Chem. Sci.
2011, 2, 2373. (e) Ariafard, A.; Zarkoob, F.; Batebi, H.; Stranger, R.;
Yates, B. F. DFT Studies on the Carboxylation of the C−H Bond of
Heteroarenesby Copper(I) Complexes. Organometallics 2011, 30,
6218.
Authors
̈
Marino Borjesson − Institute of Chemical Research of
Catalonia (ICIQ), The Barcelona Institute of Science and
Technology, 43007 Tarragona, Spain
Daniel Janssen-Muller − Institute of Chemical Research of
̈
Catalonia (ICIQ), The Barcelona Institute of Science and
Technology, 43007 Tarragona, Spain
Basudev Sahoo − Institute of Chemical Research of Catalonia
(ICIQ), The Barcelona Institute of Science and Technology,
43007 Tarragona, Spain; orcid.org/0000-0002-9746-9555
Yaya Duan − Institute of Chemical Research of Catalonia
(ICIQ), The Barcelona Institute of Science and Technology,
43007 Tarragona, Spain
(6) Selected references on ortho-directed sp2 C−H carboxylations:
(a) Mizuno, H.; Takaya, J.; Iwasawa, N. Rhodium (I)-Catalyzed
Direct Carboxylation of Arenes with CO2 via Chelation-Assisted C−
H Bond Activation. J. Am. Chem. Soc. 2011, 133, 1251. (b) Sasano, K.;
Takaya, J.; Iwasawa, N. Palladium(II)-Catalyzed Direct Carboxylation
of Alkenyl C−H Bonds with CO2. J. Am. Chem. Soc. 2013, 135,
10954. (c) Fu, L.; Li, S.; Cai, Z.; Ding, Y.; Guo, X.-Q.; Zhou, L.-P.;
Yuan, D.; Sun, Q.-F.; Li, G. Ligand-enabled site-selectivity in a
versatile rhodium(II)-catalysed aryl C−H carboxylation with CO2.
Nat. Catal. 2018, 1, 469. (d) Cai, Z.; Li, S.; Gao, Y.; Li, G.
Rhodium(II)-Catalyzed Aryl C−H Carboxylationof 2-Pyridylphenols
with CO2. Adv. Synth. Catal. 2018, 360, 4005. (e) Huang, R.; Li, S.;
Fu, L.; Li, G. Rhodium(II)-Catalyzed C−H Bond Carboxylation of
Heteroarenes with CO2. Asian J. Org. Chem. 2018, 7, 1376. (f) Song,
L.; Cao, G.-M.; Zhou, W.-J.; Ye, J.-H.; Zhang, Z.; Tian, X.-Y.; Li, J.;
Yu, D.-G. Pd-catalyzed carbonylation of aryl C−H bonds in
benzamides with CO2. Org. Chem. Front. 2018, 5, 2086. (g) Song,
L.; Zhu, L.; Zhang, Z.; Ye, J.-H.; Yan, S.-S.; Han, J.-L.; Yin, Z.-B.; Lan,
Y.; Yu, D.-G. Catalytic Lactonization of Unactivated Aryl C−H Bonds
with CO2: Experimental and Computational Investigation. Org. Lett.
2018, 20, 3776.
Xueqiang Wang − Institute of Chemical Research of Catalonia
(ICIQ), The Barcelona Institute of Science and Technology,
43007 Tarragona, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c08810
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank ICIQ and FEDER/MCI-AEI/PGC2018-096839-B-
I00 for financial support. Prof. A. Berkessel is acknowledged for
a generous gift of Mn/Cr. M.B., B.S. and D.J.-M. thank
MINECO, the European Union’s Horizon 2020 Programme
under Marie Sklodowska-Curie Grant Agreement 795961, and
the Alexander von Humboldt Foundation for predoctoral and
postdoctoral fellowships. We sincerely thank E. Escudero and
E. Martin for X-ray crystallographic data.
(7) Selected references on catalytic carboxylation reactions at non-
acidic sp2 C−H bonds with noble metals or stoichiometric
organometallic reagents: (a) Suga, T.; Mizuno, H.; Takaya, J.;
Iwasawa, N. Direct carboxylation of simple arenes with CO2 through a
rhodium-catalyzed C−H bond activation. Chem. Commun. 2014, 50,
14360. (b) Suga, T.; Saitou, T.; Takaya, J.; Iwasawa, N. Mechanistic
Study of Rhodium-Catalyzed Carboxylation of Simple Aromatic
Compounds with Carbon Dioxide. Chem. Sci. 2017, 8, 1454.
(8) For reviews of catalytic 1,4-migrations, see: (a) Ma, S.; Gu, Z.
1,4-Migration of Rhodium and Palladium in Catalytic Organometallic
Reactions. Angew. Chem., Int. Ed. 2005, 44, 7512. (b) Rahim, A.; Feng,
J.; Gu, Z. 1,4-Migration of Transition Metals in Organic Synthesis.
Chin. J. Chem. 2019, 37, 929.
(9) To the best of our knowledge, 1,4-Ni migration can be affected
only in a stoichiometric manner with dinuclear Ni(I) complexes. See:
(a) Keen, A. L.; Johnson, S. A. Nickel(0)-Catalyzed Isomerization of
an Aryne Complex: Formation of a Dinuclear Ni(I) Complex via C−
H Rather than C-F Bond Activation. J. Am. Chem. Soc. 2006, 128,
1806. (b) Keen, L. A.; Doster, M.; Johnson, A. S. 1,4-Shifts in a
Dinuclear Ni(I) Biarylyl Complex: A Mechanistic Study of C−H
Bond Activation by Monovalent Nickel. J. Am. Chem. Soc. 2007, 129,
810.
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3
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(23) Unfortunately, a cascade consisting of a 5-exo-dig or 7-exo-dig
cyclization followed by 1,4-Ni migration did not result in sp2 C−H
carboxylation. While the former led to exclusive formation of vinyl
carboxylic acids, a complex mixture of carboxylic acids was obtained
in the latter. In this case, a formal 6-exo-dig/1,4-Ni product was
identified as the major product, likely arising from initial 4-hydride
elimination followed by migratory insertion prior to 6-exo-dig
cyclization. Still, the results in Scheme 4 (bottom) show the ability
to access non-benzo-fused benzoic acids. In addition, a screening was
conducted with a representative set of additives to further assess the
functional group compatibility beyond the compounds employed in
Table 2.19.
(24) Similar yields were obtained regardless of whethe the reaction
started with Z- or E-vinyl bromide 3b. Control experiments were
conducted to understand the origin of the E/Z isomerization found
for 4a−d.19
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(32) Although crystals suitable for X-ray diffraction could be
obtained for both 10 and 11, the poor resolution and instability of the
latter prevented us from obtaining high-quality crystallographic data.
(33) This notion was given further credence by the fact that 2a was
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