"This is the peer reviewed version of the following article: Angew. Chem. Int. Ed. 2016, 55, 5053-5057 which has
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Ni-catalyzed Carboxylation of Benzylic C-N bonds with CO2
Toni Moragas,[a] Morgane Gaydou[a] and Ruben Martin*[a],[b]
Abstract: A user-friendly Ni-catalyzed reductive carboxylation of
benzylic C–N bonds with CO2 is described. This protocol
outperforms state-of-the-art carboxylation techniques of benzyl
electrophiles by avoiding commonly observed parasitic pathways
such as homodimerization or β-hydride elimination, thus leading to
new knowledge in cross-electrophile events.

Cross-electrophile reactions have recently gained considerable
attention, becoming direct and practical alternatives to classical
nucleophile/electrophile regimes based on stoichiometric
organometallic reagents.[1] While the utilization of organic
halides and homogeneous reagents has become routine in
these endeavors,[1] the extension to other coupling partners is
still largely underdeveloped, an important drawback when
compared with the broad applicability of classical
nucleophile/electrophile events.[2] Undoubtedly, new catalytic
protocols based on unconventional, yet practical, electrophilic
partners would be highly rewarding, thus improving our flexibility
in synthetic design.

H

R

H
H

R1

catalyst
CO2
R2-M
path a

R

Stoichiometric R 2
-M
(M = ZnX, MgX)
1 = Me
Limited to R

CO2H

catalyst
CO2

R1

X
reductant R
path b
X = Br, OPiv
Dimerization (R1 = H, alkyl) &
!-hydride elimination (R1 = alkyl)
Limited to R1 = H, Me, Ar

Scheme 1. Reductive carboxylation towards phenylacetic acids.

The utilization of carbon dioxide (CO2) as renewable C1
synthon holds great promise to define new paradigms in
retrosynthetic analysis.[3] Following the pioneering work of
Osakada,[4] we[5] and others[6] have designed reductive
carboxylation techniques of organic (pseudo)halides with CO2,
becoming
alternatives
to
classical
routes
requiring
organometallic species.[7],[8] Despite the advances realized, a
general route towards α-substituted phenylacetic acids,
privileged motifs in a myriad of bioactive molecules, still remains
elusive. It is worth noting that the current cross-electrophile
portfolio of benzyl derivatives, including reductive carboxylation
techniques, is unfortunately plagued by unavoidable
dimerization, β-hydride elimination or the limited set of

[a]

[b]

Dr. T. Moragas, Dr. M. Gaydou, Prof. R. Martin
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona
Institute of Science and Technology
Av. Països Catalans 16, 43007, Tarragona (Spain)
E-mail: rmartinromo@iciq.es
Prof. R. Martin
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluïs Companys, 23, 08010, Barcelona (Spain)
Supporting information for this article is given via a link at the end of
the document.

substitution patterns that can be introduced (Scheme
1).[5e],[5f],[9],[10] Consequently, filling this gap was deemed crucial,
particularly with non-toxic and easy to handle, yet highly reactive,
alternative counterparts. Challenged by such perception, we
wondered whether air and thermally stable ammonium salts,
highly crystalline solids that are readily prepared in one-step
from available amine precursors,[11] could improve upon
carboxylation reactions while leading to a priori inaccessible
building
blocks
via
unconventional
synergistic
C–N
cleavage/CO2 insertion. At the outset of our investigations,
however, it was unclear whether such protocol could ever be
implemented, as ammonium salts were exclusively employed in
nucleophile/electrophile
regimes
using
well-defined
stoichiometric organometallic entities (Scheme 2, top).[12-14] If
successful, such a method would represent a previously
unrecognized opportunity for promoting C–N activation in crosselectrophile endeavors. Herein, we describe our initial
investigations towards this goal (Scheme 2, bottom). This userfriendly and operationally-simple new procedure operates at
atmospheric pressure of CO2 and outperforms all other
carboxylation protocols of benzyl electrophiles (Scheme 1),
demonstrating that ammonium salts are not merely substitutes
of organic (pseudo)halides. We believe these results will pave
the way for utilizing ammonium salts in cross-electrophile
coupling events where homodimerization and β-hydride
elimination pathways can´t be avoided, thus leading to new
knowledge in synthetic design.

Cross-coupling reactions via catalytic C-N bond-cleavage
MLn
R1
R1
L
R1
catalyst
NRn
M
C–N cleavage
R2
R2
NRn
R2
= Nucleophile (known)
Electrophile
= Electrophile (unknown)
Reductive carboxylation via synergistic C(sp3)-N cleavage/CO2 insertion
R1
I Ni catalyst
NMe3
R
R
CO2
this work
1 = H, alkyl
R

R1

! User-friendly
! Wide substrate scope
CO2H
! No R-M reagents
! No dimerization &
"#hydride elimination

Scheme 2. Cross-electrophile events via C-N cleavage.

Our study began by evaluating the reaction of 1a with CO2 at
atmospheric pressure (Scheme 3). Notably, not even traces of
2a were detected under conditions previously employed for
other benzyl electrophiles (Scheme 1, path b),[5e],[5f] indicating
that the activation of C(sp3)–N bonds would be more problematic
than anticipated. After a judicious screening of all reaction
parameters,[15] a cocktail consisting of NiBr2·diglyme and L4, a
bench-stable ligand prepared in multigram scale and in one-step
operation,[15] in combination with Mn as reducing agent in DMF
afforded 2a in 81% isolated yield (entry 1).[16] Importantly, not
even traces of homodimerization were observed in the crude
mixtures, constituting an important bonus when compared with

related carboxylation techniques (Scheme 1, path b).[5e],[5f] While
other Ni(II) sources provided lower yields (entries 2 and 4), we
found that Ni(COD)2 was not competent as precatalyst,
suggesting that COD might compete with substrate binding
(entry 3).[17] As shown in entries 5 and 6, the use of structurally
related DMA, Zn as reducing agent or the inclusion of MgCl2 as
additive had a deleterious effect (entries 4-7).[18] As anticipated,
subtle differences in the ligand backbone exerted a profound
influence on the reaction outcome. Specifically, we found an
increased reactivity of 1,10-phenanthrolines over bipyridines or
terpyridines, presumably due to their significant backbone
rigidity compared to non-fused analogues. Although tentative,
we believe that the greater activity of L4 over the L1-L6 series is
attributed to an intimate interplay of electronic and steric effects
of the substituents on the 1,10-phenanthroline backbone, thus
increasing the robustness, reactivity and stability of the
propagating Ni(0)Ln species.[19] As expected, control experiments
revealed that all reaction parameters were critical for success
(entry 15).[15],[20]
I
NMe3
tBu

NiBr2·diglyme (10 mol%)
L4 (26 mol%)

1a

Mn, CO2 (1 atm)
DMF, 90 ºC

CO2H
tBu

2a

Entry Deviation from standard conditions 2a (%)[a]

ammonium salts containing esters (1h), fluorides (1c), silyl
ethers (1g) or acetals (1m), among others, were perfectly
accommodated. Although one might argue that the inclusion of
thioethers might be problematic due to the strong binding affinity
of sulfur atoms to Ni centers,[22] we found that such motifs do not
interfere with productive formation of 2j. Likewise, the presence
of heteroaryl rings could be tolerated with equal ease (2n). This
operationally simple procedure was also found to be scalable,
and catalyst loadings could be reduced to 5 mol% without
significant erosion in yield (2a; 70% yield).

R

I
NMe3

CO2H

None

2

NiBr2 (10 mol%) as catalyst

73

3

Ni(COD)2 (10 mol%) as catalyst

4

4

Ni(OTf)2 (10 mol%) as catalyst

47

5

DMA as solvent

18

6

Zn as reductant
MgCl2 (1 equiv) as additive

0

8

Using 6,6'-Me2bipy as ligand

20

9

Using 6,6''-Me2terpy as ligand

16

10

Using L1 as ligand

0

11

Using L2 as ligand

26

12

Using L3 as ligand

13

Using L5 as ligand

14

Using L6 as ligand

35 Me
65
nBu
56

15

No NiBr2·diglyme, L4 or Mn

0

CO2H

2a-n
TBDPSO

R
R = tBu, 81%,70%[a] (2a) R = Ph, 75% (2d)
R = OMe, 60% (2e)
R = H, 71% (2b)
R = OBn, 54% (2f)
R = F, 51% (2c)
R
MeO2C
CO2H
CO2H
R = OMe, 65% (2i)
R = SMe, 82% (2j)
O
CO H

CO2H
53% (2g)

Me
CO2H
82% (2k)

6

7

R

CO2H

R

Mn, CO2 (1 atm)
DMF, 90 ˚C

1a-n

52% (2h)

1

NiBr2!diglyme (10 mol%)
L4 (26 mol%)

81[b],74[c]
R
R2

N
N
L1: R = H R
L2: R = Me
L3: R = nBu
R2

N
N
R1
R1
L4: R1 = nBu; R2 = Me
L5: R1 = nBu; R2 = Ph
Me
Me
Me
N

N
L6

nBu

Scheme 3. Screening of the reaction conditions. Reaction conditions: 1a (0.20
mmol), NiBr2·diglyme (10 mol%), ligand (26 mol%), Mn (0.40 mmol), CO2 (1
atm) in DMF (0.40 M) at 90 ºC for 72 h. [a] HPLC yields using anisole as
internal standard. [b] Isolated yield. [c] L4 (10 mol%).

With these conditions in hand, we focused our attention on the
preparative scope of our Ni-catalyzed direct carboxylation of
primary benzyl ammonium salts with CO2 (Scheme 4).
Importantly, 1a-1n were all prepared from the corresponding
amines in one step and used without further purification, thus
representing a bonus from a practical standpoint. As becomes
evident from the results compiled in Scheme 4, our synergistic
C(sp3)–N cleavage/CO2 insertion was largely insensitive to
electronic changes on the aromatic ring and could perfectly
accommodate non-extended π-systems.[21] Similarly, the
inclusion of ortho substituents posed no problems (2i-2k). The
chemoselectivity profile was nicely illustrated by the fact that

CO2H

2

O
63% (2l)

68% (2m)

S

CO2H

Me
58% (2n)

Scheme 4. Carboxylation of primary ammonium salts. Reaction conditions: as
for Scheme 3, entry 1; Isolated yields, average of at least two independent
runs. [a] 1a (1.0 mmol), NiBr2·diglyme (5 mol%).

Prompted by the inherent limitations posed by the available
catalytic reductive carboxylation techniques en route to αsubstituted phenylacetic acids (Scheme 1), we wondered
whether our protocol could be extended to secondary benzyl
ammonium salts possessing β-hydrogens. Although one might
anticipate parasitic homodimerization or β-hydride elimination
pathways, an issue previously observed in a myriad of crosselectrophile endeavors of benzyl derivatives, this was not the
case and we found that a NiCl2/L6 regime afforded 4a in 93%
yield.[23],[24] As for Scheme 4, we found that catalyst loadings
could be reduced to 5 mol% without deterioration in yield at
large scale. Importantly, a number of substrates possessing βhydrogens could successfully be carboxylated with equal ease,
even with sterically encumbered backbones (3h) or groups
possessing an innate proclivity for β-hydride elimination (3e).
Likewise, the reaction was not hampered by the inclusion of
nitriles (4m), esters (4f, 4n), alkenes (4g) as well as ortho
substituents (4o, 4p). Particularly noteworthy was the ability to
couple substrates possessing β-alkyl chains other than methyl
groups (4c-h, 4k), showcasing the utility of this process when
compared to benzyl electrophiles or styrene derivatives
(Scheme 1).[5e],[5f],[9] To put these results into perspective, while
4c was obtained in 85% yield from 3c, the utilization of organic
halides (3c-Br) or pivalate analogues (3c-OPiv) under the

reported optimized conditions[5e],[5f] lead to exclusive β-hydride
elimination and dimerization. Although inherently disposed to
intramolecular C–C bond-formations, the presence of esters (3f)
or alkenes (3g) on the side chain did not interfere, obtaining
exclusively 4f and 4g.[25],[26] Taken together, the results of
Schemes 4-5 illustrate that ammonium salts, conceptually and
practicality aside, cannot be considered as merely substitutes of
organic halides, thus leading to new knowledge in the crosselectrophile coupling arena.[27]
R1
R

R1

NiCl2 (10 mol%)
L6 (26 mol%)

I
NMe3

Mn, CO2 (1 atm)
DMF, 70 ˚C

3a-p
CO2H

4a-p

In summary, we have described the first cross-electrophile
coupling reaction via unconventional C–N cleavage/CO2
insertion. The success is attributed to the use of a new set of
ligands with unprecedented reactivity while preventing parasitic
reaction pathways commonly observed in cross-electrophile
endeavors,
thus
outperforming
previously
developed
carboxylation events. The wide substrate scope and the
generality of this new protocol might lead to new knowledge in
ligand design and augurs well for implementing C–N
counterparts in cross-electrophile events. Further investigations
along these lines are currently underway in our laboratories.

CO2H R

CO2H

Me

CO2H

R

intermediacy of benzyl Ni(I) species[36] or other mechanistic
implications is subject of ongoing investigations.

Me

Me

Me
93%,

90%[a]

(4a)

88% (4b)

CO2H

CO2H

n-Bu
N

R = H, 84% (4c)
R = Et, 61% (4d)[b]
CO2H

N

Ni
N
N n-Bu
Me

R
72% (4g)

R

Me

R = H, 61%
R = OMe, 73% (4j)[c]

54%

(4k)[c]

CO2H

CO2H

Me

Me

63% (4m)[c],[d]

MeO2C

66% (4n)[c],[d]

Me

n-Bu
N

Ni
N
N n-Bu

Ph

Me

81% (4l)[c]
R

n-Bu
N

Me
Me

(4i)[c]

NC

CO2H

MeO

Mn (y equiv)
DMF, 90 ºC

2a

OTf

67% (4h)

CO2H

1a (1 equiv)
CO2 (1 atm)

18% yield (y = 0)
66% yield (y = 2)

5

Me

CO2H

Me

n-Bu

5

R = CH2Ph, 74% (4e)
R = (CH2)4CO2Me, 66% (4f)

Me

n-Bu

6

n-Bu

Me

1a (1 equiv)
CO2 (1 atm)
Mn (y equiv)
DMF, 90 ºC

2a

0% yield (y = 0)
38% yield (y = 2)

6

CO2H
Me

R = Me, 52% (4o)[c]
R = OMe, 50% (4p)[c]

Scheme 5. Carboxylation of secondary ammonium salts. Reaction conditions:
3 (0.20 mmol), NiCl2 (10 mol%), L6 (26 mol%), Mn (0.80 mmol), CO2 (1 atm)
in DMF (0.20 M) at 70 ºC for 16 h; Isolated yields, average of at least two
independent runs. [a] 3a (1.0 mmol), NiCl2 (5 mol%). [b] 4d (1:1 dr). [c] 90 ºC
for 72 h. [d] Isolated as the corresponding methyl ester upon treatment with
TMSCHN2.

Although a comprehensive study detailing the mechanistic
underpinnings of this reaction should await further investigations,
we decided to study the reactivity of Ni(0)(L4)2 (5) and Ni(I)(L4)2
species (6). While 18-electron complex 5 could be prepared in
quantitative yield by reacting Ni(COD)2 and L4 in benzene at 40
ºC, 6 was prepared from 5 upon exposure to AgOTf in THF at
rt.[15],[28] As shown in Scheme 6, both structures were
unambiguously characterized by X-Ray crystallography.[29],[30]
Interestingly, 5 and 6 were found to be catalytically competent
when using 1a as substrate, delivering 2a in 77% and 76% yield,
respectively. Intriguingly, while a non-negligible erosion in yield
of 2a was found when reacting 1a with 5 in a stoichiometric
fashion in the absence of Mn, no reaction took place under
otherwise identical conditions under a 6 regime.[31] Whether
these results indicate the involvement of single electron transfer
processes[32-34] or comproportionation events[35] via the

Scheme 6. Stoichiometric experiments with 5 and 6.

Acknowledgements
We thank ICIQ, the European Research Council (ERC-277883),
MINECO (CTQ2012-34054 & Severo Ochoa Excellence
Accreditation
2014-2018,
SEV-2013-0319)
and
Cellex
Foundation for support. Johnson Matthey, Umicore and Nippon
Chemical Industrial are acknowledged for a gift of metal & ligand
sources. Likewise, Klaus Ditrich (BASF) is acknowledged for a
gift of amine sources. We sincerely thank E. Escudero and E.
Martin for X-Ray crystallographic data.
Keywords: Nickel • C–N activation • Reductive coupling •
Carboxylation • Catalysis
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[23]
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[27]

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[29]

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[31]
[32]

For details see Supporting Information.
The nature of both the substituents on nitrogen and the counterion of
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substitution patterns over the 1,10-phenanthroline backbones on
catalytic performance, see: C. Cheng, J. F. Hartwig, J. Am. Chem. Soc.
2015, 137, 592-595.
While one might argue that 1a might in situ generate benzyl iodide,
control experiments revealed no conversion to 2a with benzyl iodide,
neither in the presence nor absence of NMe3.
It is worth noting that the carboxylation of benzyl C-O electrophiles was
restricted to extended π-systems or to secondary benzyl derivatives
lacking aliphatic side-chains. See ref. 5e.
a) S. R. Dubbaka, P. Vogel, Angew. Chem. 2005, 117, 7848-7859;
Angew. Chem., Int. Ed. 2005, 44, 7674-7684; b) Catalyst Poisoning
(Eds.: L. L. Hegedus, R. W. McCabe), Marcel-Dekker, New York, 1984;
c) S. G. Murray, F. R. Hartley, Chem. Rev. 1981, 81, 365-414.
For details about the optimization, see ref. 15.
We found low yields of 4a with a protocol based on L4, suggesting that
the success of L6 might be attributed to electronic effects. For an
analogous observation in other catalytic endeavors, see ref. 19.
For recent reviews dealing with the catalytic α-functionalization of
carbonyl compounds with activated electrophiles: a) P. Novák, R.
Martin, Curr. Org. Chem. 2011, 15, 3233-3262; b) C. C. C. Johansson,
T. J. Colacot, Angew. Chem. 2010, 122, 686-718; Angew. Chem. Int.
Ed. 2010, 49, 676-707; c) F. Bellina, R. Rossi, Chem. Rev. 2010 ,110,
1082-1146.
For Ni-catalyzed intramolecular C–C bond-formations of alkyl
electrophiles with pending alkenes on the side chain, see for example:
a) H. Cong, G. C. Fu, J. Am. Chem. Soc. 2014, 136, 3788-3791; b) M,
R. Harris, M. O. Konev, E. R. Jarvo, J. Am. Chem. Soc. 2014, 136,
7825-7828.
While preliminary, we have found that 2-naphtyl-trimethylammonium
2
iodide can promote reductive carboxylation event via C(sp )–N
cleavage using dppf as ligand, obtaining 33% yield of the targeted
carboxylic acid.
D. C. Powers, B. L. Anderson, D. G. Nocera J. Am. Chem. Soc. 2013,
135, 18876-18883.
CCDC 1448910 (5) contain the supplementary crystallographic data for
this paper and can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac/uk/data_request/cif.
CCDC 1448911 (6) contain the supplementary crystallographic data for
this paper and can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac/uk/data_request/cif.
Although speculative, these results might suggest that 6 acts as a
precatalyst en route to 5 upon single electron transfer mediated by Mn.
For the intermediacy of Ni(I) species generated upon single electron
transfer processes, see refs. 5b-5f, 6f and the following selected
references: a) C. A. Laskowski, D. J. Bungum, S. M. Baldwin, S. A. Del
Ciello, V. M. Iluc, G. L. Hillhouse, J. Am. Chem. Soc. 2013, 135, 1827218275; b) J. Breitenfeld, J. Ruiz, M. D. Wodrich, X. Hu, J. Am. Chem.
Soc. 2013, 135, 12004-12012; c) S. Biswas, D. J. Weix, J. Am. Chem.
Soc. 2013, 135, 16192-16197.

[33]

[34]

[35]

A significant inhibition was observed in the presence of radical
scavengers such as TEMPO or galvinoxyl for either 2a or 3a (17-45%
yield).
Complete loss of optical purity was observed when promoting the
carboxylation of 3i (99% ee). As control experiments determined that
enantioenriched 4i does not racemize under the reaction conditions,
one might argue that radical intermediates must come into play. Care,
however, must be taken when generalizing this since racemization
3
might occur from bimolecular mechanisms from in situ generated η Ni(II) intermediates upon reaction with Ni(0)Ln species. See for
example: I. M. Yonova, A. G. Johnson, C. A. Osborne, C. E. Moore, N.
S. Morrissette, E. R. Jarvo, Angew. Chem. 2014, 126, 2454-2459;
Angew. Chem. Int. Ed. 2014, 53, 2422-2427.
For selected comproportionation events en route to Ni(I) species, see:
a) ref. 17b; b) A. Velian, S. Lin, A. J. M. Miller, M. W. Day, T. Agapie, J.
Am. Chem. Soc. 2010, 132, 6296-6297; c) V. B. Phapale, E. Bunuel, M.

[36]

García-Iglesias, D. J. Cardenas, Angew. Chem. 2007, 119, 8946-8951;
Angew. Chem., Int. Ed. 2007, 46, 8790-8795; d) G. D. Jones, J. L.
Martin, C. McFarland, O. R. Allen, R. E. Hall, A. D. Haley, R. J.
Brandon, T. Konovalova, P. J. Desrochers, P. Pulay, D. A. Vicic, J. Am.
Chem. Soc. 2006, 128, 13175-13183.
Recently, Ni(I) species have shown to rapidly react with CO2: F. S.
Menges, S. M. Craig, N. Tötsch, A. Bloomfield, S. Ghosh, H.-J. Krüger,
M. A. Johnson Angew. Chem. 2016, 128, 1304-1307; Angew. Chem.,
Int. Ed. 2016, 55, 1282-1285.

COMMUNICATION
Ni-catalyzed reductive carboxylation via
R2
R1

C(sp3)–N

cleavage with CO2

NMe3

CO2 (1 atm)

No !-hydride elimination or dimerization
Wide substrate scope
air & thermally stable
non-toxic & easy to handle
Operationally-simple

Me

R2

Ni catalyst / Ligand
R1

CO2H

R
nBu

30 examples
up to 93% yield

Me
N

N

Toni Moragas, Morgane Gaydou and
Ruben Martin*
Author(s), Corresponding Author(s)*

R
nBu

L4 (R =H)
L6 (R = Me)

A novel & user-friendly Ni-catalyzed reductive carboxylation of benzylic C–N bonds
with CO2 is described. This protocol outperforms state-of-the-art carboxylation
techniques of benzyl electrophiles by avoiding commonly observed parasitic
pathways, thus leading to new knowledge in cross-electrophile events.

Ni-catalyzed Page No.
Carboxylation
Page No. –
Benzylic C-N bonds with CO2.
Title

of