MINIREVIEW

Catalytic Reductive N-Alkylations using CO2 and Carboxylic Acid

Derivatives: Recent Progress and Developments
Jose R. Cabrero-Antonino,*[a, b] Rosa Adam,[a, b] and Matthias Beller*[a]

Abstract: N-Alkylamines are key intermediates in the synthesis of Instead of using strong electrophiles, reductive methods
fine chemicals, dyes and natural products, hence being highly employing carbonyl compounds (reductive amination) [7] or, much
valuable building blocks in organic chemistry. Consequently, the less frequently, phenols/ethers[8] are valuable methodologies. In
development of greener and more efficient protocols for their fact, reductive aminations are commonly used in industry,
production continues to attract the interest of both academic and especially for the synthesis of methyl amines (e. g. Eschweiler-
industrial chemists. So far, reductive protocols such as reductive Clarke methodology using formaldehyde as C1 source). [7a, 7b, 7d]
amination or N-alkylation through hydrogen autotransfer employing In this respect, the tandem olefin hydroformylation/reductive
carbonyl compounds or alcohols as alkylating agents prevail for the amination, so-called hydroaminomethylation, deserves also to
synthesis of amines. In addition, in the last years, be highlighted being an atom-economical approach to obtain
carboxylic/carbonic acid derivatives and carbon dioxide have been aliphatic amines.[7i, 9]
introduced as alternative convenient alkylating sources. The safety,
easy accessibility and high stability of these reagents makes the
development of new reductive transformations using them as N-
alkylating agents a useful alternative to existing protocols. In this
minireview, we will summarize all the reported examples up to date
dealing with the one-pot reductive N-alkylation methods using
carboxylic/carbonic acid derivatives or carbon dioxide as alkylating
agents.

1. Introduction

N-Alkylamines play a central role in nature as they are present in

essential compounds for life, such as amino acids, nucleotides,
Figure 1. Some examples of N-alkylamines with relevant biological activity.
and alkaloids.[1] Notably, the majority of the currently marketed
drugs and agrochemicals present N-alkyl groups in their
structure (Figure 1). Thus, the biological activity of products
In addition, most of the available methods for the synthesis of
containing amino groups has been intensively studied. In
chiral alkylamines are based on the asymmetric hydrogenation
addition, N-alkylamines -including methylamines- are used as
of imines.[7f, 7g, 10] Closely related with reductive amination, N-
highly valuable intermediates for the synthesis of fine chemicals,
alkylation with alcohols or amines by hydrogen borrowing or
dyes and natural products.[1-2] Consequently, the development of
autotransfer has emerged as a growing methodology.[11] For
novel green and efficient N-alkylation methodologies continues
example, the N-methylation of amines using methanol in the
to be of great interest for chemists.
presence of zeolites is in use in the chemical industry.[11a, 11b]
Among the general methods for the direct N-alkylation of
Apart from reductive methods, hydroamination using alkenes
amines (Scheme 1, up), the use of strong electrophiles prevailed
or alkynes is another straightforward approach for the synthesis
at gram scale.[3] Traditionally, alkyl halides, diazo or triflates,
of N-alkylamines.[12] Moreover, although more far from the topic
dimethyl sulfate and trimethyloxonium tetrafluoroborate have
of this review, the Buchwald-Hartwig Pd-catalyzed amination of
been employed as alkylating agents.[1b-d, 2-3] However, the toxicity
aromatic halides or triflates is worth mentioning due to its
of these compounds and the inherent waste formation led to
utility.[13]
their substitution by other milder electrophilic reagents, as trialkyl
Tandem or domino processes, such as reductive amination or
orthoesters,[4] dialkyl carbonates[5] and dimethyl sulfoxide.[6]
N-alkylation through hydrogen autotransfer, have been widely
employed to avoid multi-step transformations[14] using safe
[a] Dr. J. R. Cabrero-Antonino, Dr. R. Adam, Prof M. Beller carbonyl compounds or alcohols as alkylating agents. In contrast,
Leibniz-Institut für Katalyse e.V. the same strategy with the more oxidized carboxylic acid
Albert-Einstein-Str. 29a, 18059 Rostock (Germany) derivatives or carbon dioxide as alkylating agents has been less
E-mail: [email protected]
[b] Dr. J. R. Cabrero-Antonino, Dr. R. Adam
investigated, due to the lower reactivity of these compounds.
Instituto de Tecnología Química. Universitat Politécnica de However, the employment of these building blocks with a higher
València-Consejo Superior Investigaciones Científicas (UPV-CSIC) oxidation state can entail advantages from the points of view of
Avda. de los Naranjos s/n, 46022 Valencia (Spain) their high stability and safety, as well as their availability.
E-mail: [email protected]
MINIREVIEW

Indeed, carbon dioxide, is a non-toxic, cheap and widely production have been disclosed, although the generalization of
available compound, present in the atmosphere –although low these protocols still remains a current task. [18]
concentrations (>400 ppm)- as a greenhouse gas.[15] In recent Carboxylic and carbonic acid derivatives (mainly acids,
years, its use for applications in energy storage or for the anhydrides, acid chlorides, esters, amides and dialkyl
synthesis of bulk chemicals, e.g. methanol or formic acid have carbonates) are polar organic functionalities with a poorly
found significant attention.[15c, 15h, 16] Apart from that, carbon electrophilic carbonyl group.[19] Because of its high stability,
dioxide constitutes an attractive building block for making fine accessibility and safe manipulation, their use as N-alkylation
chemicals. The problem is that owing to its inherent agents is desirable.
thermodynamic stability and kinetic inertness, CO2 utilization is In the last two decades, general routes for the synthesis of
challenging.[17] In the past decade, advancements in catalysis alkylamines using carboxylic acid derivatives mainly focused in
and organometallic chemistry provided new practical the two-step amide formation[20] followed by C-O reduction
transformations for the production of valuable synthetic organic (Scheme 1, bottom, A). The amide C-O reduction has been
molecules using CO2 as building block.[17] However, the most performed either by using a large excess of metal hydrides[21] or
important process, the formation of urea on >150 million ton- by the greener catalytic reduction.[19d, 19f, 21c, 22] On the other hand,
scale from CO2 and NH3 by the Bosch-Meiser process, has the direct N-alkylation of amines using carboxylic acid
existed already for a long time.[15a] derivatives has employed over-stoichiometric amounts of metal
hydride reagents that produce large amounts of waste products
(Scheme 1, bottom, B).[21b, 23]
More recently, homogeneous and heterogeneous catalysts
have been successfully applied to this transformation using
different reducing agents (Scheme 1, bottom, C). These
protocols constitute underrated strategies to directly alkylate
amines using readily available alkyl sources. The stability of CO2
and carboxylic/carbonic acid derivatives are important
advantages of these reactions that normally avoid the formation
of secondary products.
In this minireview, we summarize the reported examples
employing CO2 and carboxylic/carbonic acid derivatives as alkyl
sources in catalytic reductive N-alkylation processes. Although
nitriles are not considered carboxylic acid derivatives, examples
where they are used as N-alkyl sources will be also commented
due to their close relationship with carboxylic acid derivatives as
nitrile hydration affords an amide.

Jose R. Cabrero-Antonino (Torrent, Spain,

1985) obtained his PhD in 2013 with honors
under the supervision of Prof. Corma and Dr.
Leyva-Pérez at the Instituto de Tecnología
Química (ITQ). As recipient of Ramon Areces
fellowship, he performed a postdoctoral stay
from 2014 to 2017, at the Leibniz Institute Für
Katalyse (LIKAT) in Rostock (Germany) at
the group of Prof. Beller. In 2017 he came
back to the group of Prof. Corma and recently he was granted with a Ramon
y Cajal contract. His scientific work has been focused in the design and
Scheme 1. Up: methods for the direct N-alkylation of amines. Bottom: (A) development of new metal catalysts and their application in organic
two-step amide formation followed by reduction using an excess of metal
hydride or catalytic reduction with a mild reductant; (B) direct N-alkylation of transformations.
amines with carboxylic acid derivatives using stoichiometric amounts of
metal hydrides; (C) catalytic reductive one-pot N-alkylation of amines using
CO2 and carboxylic and carbonic acid derivatives, topic of this review.

More recently, the reduction of CO2 in the presence of

nucleophiles such as amines allowed developing green and one-
pot reductive alkylation processes.[18] In this respect, also
straightforward valorizations of CO2 for the direct N-alkylamine
MINIREVIEW

Shortly after, Beller’s group developed an efficient and

Rosa Adam (Llombai, Spain, 1985) selective ruthenium-catalyzed protocol in the presence of the
received her PhD degree with honors in suitable phosphine ligand (BuPAd2).[26] More than 20 different
2013 under the supervision of Prof. amines were subjected to the reaction conditions affording high
Abarca and Prof. Ballesteros at the yields of the desired products (Table 1, entry 2).
Universitat de València. From 2014 to After these two initial examples, several protocols appeared
2017 she worked at the group of Prof. showing the importance of this novel catalytic transformation
Beller at LIKAT (Rostock, Germany) as a (Table 1, entries 3-17).[27-41] Both metal or metal-free based
Ramon Areces fellow. In 2017, she joined catalytic systems under different reaction conditions were
the group of Prof. Corma and Dr. Leyva- developed, allowing to prepare in general, the corresponding N-
Pérez at the Instituto de Tecnología
methyl amines in good to excellent yields. Notably, a catalyst-
Química (ITQ). Since September 2018 she is fellow from “La Caixa” Junior
free strategy for the N-methylation of amines with CO2 and
Leader Incoming program at the ITQ. Her research interests are related with
PhSiH3 was reported by the group of Chiang and Lei (Table 1,
the development of new homogeneous and heterogeneous catalysts for
entry 13).[37]
synthetic applications.

Table 1. Catalytic N-methylation of amines using CO2 and silanes

Matthias Beller (Gudensberg, Germany,

1962) obtained his Ph.D. in 1989 under the
supervision of Prof. Tietze at the University
of Göttingen. After one year of postdoctoral
stay with Prof. Barry Sharpless at MIT Entry Catalyst Reaction conditions Scope Ref.
(USA), he worked at Hoechst AG in
Frankfurt (1991-1995). He then started his [(IPr)ZnCl2] PhSiH3 (2-3 eq), CO2 [25]
1 19 ex.
career at T. U. Munich for inorganic (5 mol%) (1-5 bar), THF,
chemistry professor. In 1998, he relocated 100 °C, 20-72 h
to Rostock to head the Institute for Organic
Catalysis, which became the Leibniz- [26]
2 [RuCl2(dmso)4] / PhSiH3 (4 eq), CO2 23 ex.
Institute for Catalysis in 2006. Prof. Beller is head of the German Chemical n-BuPAd2 (30 bar), toluene,
Society working group “Sustainable Chemistry” and a member of three (2/4 mol%) 100 °C, 10-36 h
German Academies of Sciences. His research is mainly focused on applying
[27]
homogeneous and heterogeneous catalysis for the synthesis of fine and 3 Free [NHC] Ph2SiH2 (3-4 eq), CO2 27 ex.
bulk chemicals as well as energy technology. (5 mol%) (1 bar), DMF, 50 °C,
24-48 h

[28]
4 [Fe(acac)2] / PP3 PhSiH3 (4 eq), CO2 (1 4 ex.
(10/10 mol%) bar), THF, 100 °C, 18
2. Catalytic reductive N-alkylation of amines h
using hydrosilanes as reductor
5 [(dippe)Ni(-H)]2 or PhSiH3 (2-4 eq), CO2 7 ex. [29]

Hydrosilanes have been used extensively as selective and easy- [Ni(COD)2]/dppe (1 bar), toluene,
to-use reducing agents in organic chemistry.[16i, 19k, 22f, 24] Their (4 or 4/4 mol%) 100 °C, 20 h
polarized Si-H bonds allow them to act as mild hydride sources,
[30]
showing increased chemoselectivity for the reduction of carbonyl 6 [(IMes)CuOt-Bu] PhSiH3 (2-4 eq), CO2 13 ex.
groups.[24a-c] Hence, they have been also used for the catalytic (10 mol%) (2 bar), PhMe,
KOt-Bu (0.1 eq),
reductive N-alkylation of amines using CO2 or
100 °C, 20 h
carboxylic/carbonic acid derivatives as alkylating sources. In
these protocols, amines are selectively functionalized preserving [31]
7 [B(C6F5)3] PhSiH3 (2-4 eq), CO2 14 ex.
the nature of other reducible moieties. (5 mol%) (5 bar), CH3CN,
In Table 1 the reported procedures for the silane-mediated 140 °C, 24 h
catalytic N-methylation of amines using carbon dioxide as
methyl source are summarized. These methodologies allow 8 [Thiazolium carb.] PMHS (4 eq), CO2 (1 2 ex.
[32]

obtaining secondary and tertiary N-methyl amines with good to (7.5 mol%) bar), DMA, 100 °C,
excellent yields using CO2. Original work on this N-methylation 24 h
using carbon dioxide was described by Cantat et al. in 2013
(Table 1, entry 1).[25] In their work, a wide range of amines were 9 [Cs2CO3] Ph2SiH2 (3-6 eq), 21 ex.
[33]

efficiently methylated using as catalyst a novel zinc N- (5-10 mol%) CO2 (1 bar), CH3CN,
80 °C, 24-72 h
heterocyclic carbene [(IPr)ZnCl2] and PhSiH3.
MINIREVIEW

10 [Bis(tzNHC)Rh]OTf Ph2SiH2 (4.5 eq), CO2 7 ex.

[34] (indole/indoline)pyrrolidines from N-aryl-2-alkyltryptamines and
(0.5 mol%) (25 bar), DCM, CO2 (Scheme 4).[44]
25 °C, 24 h

[35]
11 [TBAF] PhSiH3 (3-6 eq), CO2 15 ex.
(5 mol%) (1 bar), CH3CN,
50 °C, 12 h

[36]
12 [HCO2Cs] Ph2SiH2 (4-8 eq), 15 ex.
(5 mol%) CO2 (1 bar), CH3CN,
50 °C, 6-12 h

[37]
13 none PhSiH3 (2 eq), CO2 20 ex.
(1 bar), DMF, 90 °C,
24 h

[38]
14 [Glycine betaine] PhSiH3 (4 eq), CO2 8 ex.
(3 mol%) (3 bar), CH3CN,
100 °C, 6 h

[39]
15 [NHP]H Ph2SiH2 (3 eq), CO2 1 ex.
(20 mol%) (45 mg), CD3CN,
50 °C, 12 h
Scheme 2. Synthesis of benzimidazoles and 3,4-dihydroquinazolines
from CO2 and diamines. Bn = benzyl. Yields of isolated products are
[40]
16 [K2WO4] PhSiH3 (3 eq), CO2 15 ex. given.
(7.5 mol%) (1 bar), CH3CN,
70 °C, 12 h

[41]
17 [Lecithin] PhSiH3 (4 eq), CO2 7 ex.
(5 mol%) (3 bar), CH3CN,
100 °C, 10 h

IPr = 1,3-bis(2,2-diisopropylphenyl)-imidazolium. THF = tetrahydrofurane.

DMSO = dimethyl sulfoxide. Ad = adamantyl. NHC = N-heterocyclic
carbene. DMF = N,N-dimethylformamide. Acac = acetylacetonate. PP3 =
Tris[2-(diphenylphosphino)ethyl]phosphine. Dippe = 1,2-
bis(diisopropylphosphino)ethane. COD = 1,5-cyclooctadiene. Dppe = 1,3-
bis(diphenylphosphino)ethane. IMes = 1,3-bis(2,4,6-trimethylphenyl)-
imidazolium. PMHS = polymethylhydrosiloxane. DMA = N,N-
dimethylacetamide. tz = 1,2,3-triazol-5-ylidene. Tf =
trifluoromethanesulfonyl. DCM = dichloromethane. TBAF = tetra-n-
butylammonium fluoride. [NHP]H = 1,3,2-diazaphospholene.

In addition to the results summarized in Table 1, other elegant

metal-free examples employing carbon dioxide and silanes for
formations of C-N bonds were reported (Scheme 2-4). More
specifically, Cantat and co-workers described in 2013 NHC-
catalyzed reactions for the efficient synthesis of benzimidazoles
and 3,4-dihydroquinazolines from carbon dioxide and diamines
(Scheme 2).[42] Two years later, the same group performed the
one-pot synthesis of symmetrical and unsymmetrical aminals
from CO2 and secondary amines.[43] Here, using TBD (5 mol%)
as organocatalyst more than 20 different aminals could be
obtained in good to excellent yields (Scheme 3).
Complementarily, the groups of Song and Han reported the
synthesis of two different aminal derivatives by using glycine Scheme 3. Organocatalyzed one-pot synthesis of aminals from CO2 and
secondary amines. TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene. 1H NMR yields
betaine as catalyst (see also Table 1, entry 14). Finally, the and the relative selectivity of the products AB, AA and BB are given between
group of Xia reported this year an attractive tandem C-C and C- parentheses.
N bond formation strategy for the synthesis of spiro-
MINIREVIEW

Employing also TBD (20 mol%) as organocatalyst, a wide Due to its environmentally-benign properties, facile use and
range of tricyclic organic derivatives were obtained with high storage, formic acid offers stimulating prospective as C1-
yields in a straightforward fashion. In the case of the spiro- alkylating source for the N-methylation of amines. In Scheme 5,
indoline based derivatives, good to excellent the reported examples for the synthesis of methylamines using
diastereoselectivities were observed after reduction of the formic acid as C1 feedstock and silanes as hydride source are
former spiro-indole fragment with NaBH4. illustrated.[47] Originally, Beller and co-workers developed in
Formic acid is, compared to carbon dioxide, a liquid under 2014 the first protocol based on the use of formic acid as
ambient conditions, which makes it more convenient to use. This methylating agent under reductive conditions (Scheme 5, A).[47a]
compound is mainly produced through reaction of carbon The active platinum catalyst allowed to perform the one-pot
monoxide and methanol to methyl formate and subsequent synthesis of more than 35 methylamines in high yields.
hydrolysis, but also can be accessed by CO 2 hydrogenation or After this first example, additional homogeneous and
via oxidation from biomass.[16a-g, 16i-l, 17b] Formic acid, although heterogeneous systems were chronologically presented as
known for a long time as mild transfer hydrogenation reagent, active catalysts for this transformation by the groups of Fu and
recently attracted substantial interest as a potential hydrogen Shang (Scheme 5, B),[47b, 47c] Zhu (Scheme 5, C)[47d] and He
storage material in hydrogen production processes[45] and (Scheme 5, D).[47e] In all cases, good to excellent yields of the
modern reduction reactions.[46] desired methylamines were obtained under the different reaction
conditions noted.

Scheme 5. N-methylation of amines using formic acid as C1 source. Dppp =

1,3-bis(diphenylphosphino)propane.

In the context of the use of greener N-methylation reagents,

dialkyl carbonates (carbonic acid derivatives) and more
specifically dimethyl carbonate (DMC, a biodegradable and safe
compound which is applied in the chemical industry) offer
attractive alternative alkylating agents.[5] The growing worldwide
production of DMC (around 1000 barrels/day) is mainly based
on the transesterification of cyclic carbonates or the oxidative
carbonylation of methanol, albeit emerging protocols using
directly CO2 have been proposed.[5a-d] In this context, the
development of N-methylation reactions using DMC offers the
possibility to perform eco-friendly processes and constitutes a
way towards the indirect valorization of CO2.
Traditionally, DMC has been used as a green N-methylation
agent of primary aromatic amines through a BAL2 mechanism.[5]
In this reaction a nucleophile attack of the amine to the activated
methyl carbon of the methoxy group occurs, requiring harsh
reaction conditions. Up to date, only two examples based on the
reductive silane-mediated N-methylation of amines by dialkyl
Scheme 4. TBD-catalyzed synthesis of spiro-(indole/indoline)pyrrolidines from carbonates have been reported.[48] In these protocols the C=O
N-aryl-2-alkyltryptamines and CO2 in one-pot fashion. Yields of isolated
products are given. Diastereoselectivity (d.r.) was determined by crude 1H moiety is the one used for the methylation, instead of the methyl
NMR after in situ reduction. carbon of the methoxy group (Scheme 6).
MINIREVIEW

Beside from the N-methylation of amines using C1 sources

and with the aim to further functionalize the amine group,
carboxylic acids have emerged recently as novel N-alkylating
agents of amines. Carboxylic acids are promising alkyl sources
due to their wide (bio)availability, stability and large structural
diversity.[19d, 19g, 19i, 19k]
In Scheme 7 the methodologies for the N-alkylation of amines
with carboxylic acids in the presence of silanes are
summarized.[34, 47b, 47c, 49] Pioneering work was reported by
Beller’s group in 2014, where a [platinum/dppe] complex was
Scheme 6. Reductive N-methylation of amines using dialkyl carbonates found as an effective catalyst for the N-alkylation of a wide
catalyzed by: (A) iron complex and (B) platinum system. Cp = cyclopentadienyl. scope of amines under comparably mild reaction conditions
(Scheme 7, A).[49a] In 2015 the group of Fu and Shang published
an elegant methodology using a boron-based Lewis acid system
The first protocol, catalyzed by a photoactive half-sandwich where more than twenty N-alkylamines were obtained in
iron complex, was described by the group of Darcel and Sortais excellent yields after reaction with different carboxylic acids
in 2014 (Scheme 6, A).[48a] Different secondary aromatic and (Scheme 7, B).[47b, 47c] Complementarily to these two early
aliphatic amines could be efficiently converted into the described procedures, novel homogeneous systems were found
corresponding N-methyl derivatives. One year later, our group by the groups of Kobayashi,[34] Denton,[49b] and Minakawa[49c] as
developed an efficient [Pt]-catalyzed methodology for the same powerful catalysts for the same transformation (Scheme 7, C-E,
transformation achieving the desired methylamines in very good respectively).
yields (Scheme 6, B).[48b] In both cases, mild reaction conditions Remarkably, last year a new practical and catalyst-free
were used but the substrate scope was limited to the approach for the trifluoroethylation of amines with trifluoroacetic
methylation of secondary amines, with the only exception of acid and phenylsilane was presented by the group of Denton.[50]
aniline, which could be moderately converted with the Pt system. In this work the authors showed that the trifluoroethylation of a
wide range of amines, in the absence of any catalyst, proceeds
with excellent yields under mild reaction conditions and avoiding
product degradation.

Scheme 8. Amides as N-alkylating sources of amines catalyzed by (A)

ruthenium complex and (B) indium salt. [a] Yield of isolated product is given.

Apart from carboxylic acids, amides [19d-g] can also be employed

as stable and safe alkyl sources for the N-alkylation of the amino
Scheme 7. Catalytic N-alkylation of amines using carboxylic acids and group under reductive conditions. So far, only two reported
catalyzed by: (A) platinum, (B) boron, (C) rhodium, (D) iridium and (E)
ruthenium. catalytic procedures are known for this transformation (Scheme
8).[51] Considering the work with other carboxylic acid derivatives,
it is clear that additional catalytic protocols are feasible and will
MINIREVIEW

be developed in the future. For the first time, in 2013, Darcel et The N-alkylation of amine related compounds such as amides,[42,
51a]
al. described an example of a ruthenium-catalyzed N-alkylation imines,[47d] nitro compounds[54] and tosylamides[55] has also
of p-anisidine with dodecanamide in the presence of silanes been reported in the literature. These one-pot reductive
(Scheme 8, A).[51a] procedures employ different starting materials to afford the
The authors proposed a reaction mechanism in which the desired N-alkyl amines under the suitable reaction conditions.
catalyst and the silane promoted the dehydration of the amide to As an example already reported in 2013, the group of Cantat
a nitrile, which is reduced to an imine that reacted with the p- presented a metal-free example that used carbon dioxide and
anisidine to afford a secondary imine, that finally is reduced to silanes to form new C-N bonds in the reductive N-alkylation of
give the desired alkylated product. Later, the group of Sakai anthranilamide derivatives, to give 4-quinazolinones as main
described a general and effective indium tribromide-catalyzed products (Scheme 10).[42] At the same time, a ruthenium-
methodology, where more than 25 alkylamines were obtained in catalyzed procedure for the reductive self N-alkylation of amides
high yields by using different amides as N-alkylating sources to form secondary amines was described by Darcel and co-
(Scheme 8, B).[51b] In the same year, the groups of Liu and Sun workers (Scheme 11).[51a] The reaction mechanism, depicted in
reported an elegant catalyst-free methodology for the synthesis Scheme 10, also proceeds via the nitrile, as it as the case of the
of benzimidazoles by the N-methylation of o-phenylenediamines example of the same authors in Scheme 8A.
with DMF derivatives and PhSiH3.[52] More than 15 different
compounds were obtained in good to excellent yields.
Additionally, -ketoesters have also been used as alkyl
sources in the presence of silanes (Scheme 9). This year, Xu,
Fan and Xiao et al. reported an interesting boron-catalyzed
methodology for the synthesis of tetrahydroquinoxalines and
their 2(1H)-one analogues from 1,2-diaminobenzenes and -
ketoesters.[53] In this metal-free strategy, a fine-tuning of the
reaction conditions allowed to selectively obtain several class of
derivatives in excellent isolated yields (more than 65 compounds
were synthetized). Using a chiral ligand, the asymmetric version
of the present protocol was performed, albeit moderate
enantiomeric purities were achieved (48-87% ee).
Scheme 10. One-pot synthesis of 4-quinazolinones from CO2 and
anthranilamide derivatives. Isolated yields are given.

Scheme 9. Synthesis of tetrahydroquinoxaline derivatives and their 2(1H)-one

analogues through the boron-catalyzed N-methylation of 1,2-diaminobenzenes
using -ketoesters.

Scheme 11. Ru-catalyzed synthesis of secondary amines from primary

amides. Yields of isolated products are given.
2.1. Catalytic reductive N-alkylation of amides, nitro
compounds, imines and tosylamides using hydrosilanes as
reductant On the other hand, the use of formic acid as alkyl source in the
N-methylation of imines and nitro derivatives has been studied.
MINIREVIEW

In 2016, Zhu and collaborators described the [Pt/C]-catalyzed Furthermore, the synthesis of azacycloalkanes and
one-pot N-methylation of aromatic imines to the corresponding azaspirocycles could also be achieved with this elegant
methylamines using silanes (Scheme 12).[47d] Several procedure.
methylated amines were synthetized from the former imines and
formic acid in straightforward manner.
One year later, in a joint effort the groups of Sorribes, Llusar,
and Beller reported a general methodology using a specific well-
defined cubane-type [Mo3Pt(PPh3)S4Cl3(dmen)3]BF4 cluster,
formed in situ from a mixture of [Mo3S4Cl3(dmen)3]BF4 and
[Pt(PPh3)4] complexes in a (3:1) molar ratio, as unusual catalyst
for the dimethylation of nitro compounds to N,N-dimethylamines
(Scheme 13).[54] Apart from nitrobenzenes, benzylic and aliphatic
nitro derivatives could be directly methylated with formic acid
under mild conditions employing this domino transformation.

Scheme 12. Synthesis of tertiary amines by N-methylation of aromatic imines

using formic acid and silanes. Yields of isolated products are given.

Scheme 14. Ru-catalyzed inter- and intramolecular N-alkylation of

sulfonamides with esters. Ts = 4-toluenesulfonyl. TMDS = 1,1,3,3-
tetramethyldisiloxane. Yields of isolated products are given.

3. Catalytic reductive N-alkylation of amines

using hydroboranes

Boranes are classic strong organic reductants with polarized B-

H bonds which have been used in numerous reductive catalytic
transformations,[24c, 24e, 56] like Si-H bond in silanes. Not
surprisingly, few protocols for the N-methylation of amines with
carbon dioxide using hydroboranes as reducing agents have
been developed recently.[57]
As a first example, the group of Cantat described a novel
Scheme 13. Direct N-dimethylation of nitro compounds catalyzed by an in situ
formed well-defined [Mo3Pt(PPh3)S4Cl3(dmen)3]BF4 cubane-type complex methodology to produce N-methylamines under metal-free
catalyst. Dmen: N,N’-dimethylethylenediamine. Yields of isolated products are conditions (Scheme 15, A).[57a] In this work, proazaphosphatrane
given. superbases were presented as highly active catalysts for the
borane-mediated N-methylation of a wide range of amines under
mild conditions. In 2015, Ong and co-workers described another
Moreover, the alkylation of tosylamides with carboxylic acid metal-free method of boron activation for the reductive N-
derivatives was described already in 2012 by the group of methylation of amines with CO2 catalyzed by carbodicarbenes
Nagashima using a ruthenium-based protocol (Scheme 14).[55] In (CDCs) (Scheme 15, B).[57b] Finally, the groups of Sabo-Etienne
this work, the authors made use of simple esters as N-alkylating and Bontemps reported an iron-catalyzed reduction of CO2 into
agents for the first time. With this novel methodology in hand, methylene followed by C-N bond formation to afford N-alkyl
both inter- and intramolecular alkylations of the amino group functionalities (Scheme 16).[57c]
were performed with very high yields in the presence of silanes.
MINIREVIEW

Cantat et al., reported in 2014, the only example describing the

one-pot reductive N-methylation of nitrobenzenes with CO2 as
methylating agent and boranes as hydride source (Scheme
17).[57a] Using a superbase as catalyst (see also Scheme 15, A),
different nitro derivatives could be converted into the desired
dimethylamines in good to excellent yields.

Scheme 17. Metal-free direct N-methylation of nitrobenzenes to

dimethylanilines with CO2 and boranes. GC yields are shown between
parentheses.

4. Catalytic reductive N-alkylation of amines

using molecular hydrogen
Scheme 15. N-methylation of primary and secondary amines using CO2 as C1
source and 9-borabicyclo[3.3.1]nonane (9-BBN). Dipp = 2,6-diisopropylphenyl. The general advantages of reductive N-alkylation methodologies
using hydrosilanes and hydroboranes are the mild conditions,
which are applied in these protocols. However, as a downside
these methods suffer from low atom-efficiency and tedious work-
up procedures. In addition, due to the price of the stoichiometric
reductant, such methods are mainly limited to gram scale
synthesis. In this respect, the use of molecular hydrogen as a
greener and more practical reducing agent offers possibilities for
large scale applications.[19d, 19f, 19g, 24c, 24e, 58] Specifically, the
industrial synthesis of methylamines is interesting. In this part of
the review the methodologies for the reductive N-alkylation of
amines (including ammonia) and related compounds using CO2
and carboxylic acid derivatives in the presence of hydrogen will
be summarized.

Scheme 16. Iron-catalyzed C-N bond formation using CO2 as C1 source and
9-BBN. Dmpe = 1,2-Bis(dimethylphosphino)ethane.

3.1. Catalytic reductive N-alkylation of nitrobenzenes using

boranes

Interestingly, boranes have also been employed as mild

reducing agents in the direct methylation of nitrobenzenes.
MINIREVIEW

Tris(diphenylphosphinomethyl)ethane] able to perform the

selective methylation of ammonia or ammonium chloride with
CO2 and H2, under milder conditions than the previously
described heterogeneous systems (Scheme 18, E).[59f] On the
other hand, Shimizu and Toyao groups showed that the
heterogeneous catalyst [Pt-MoOx/TiO2] can promote the
synthesis of TMA starting from ammonia or different surrogates
(Scheme 18, F).[59g]
Closely related with the methylation of ammonia, several
homogeneous and heterogeneous systems have been
described as active catalysts for the reductive methylation of
amines with CO2 and H2 (Scheme 19).[60] In 2013, the groups of
Klankermayer and Beller simultaneously described the first
homogeneous catalyst systems able to directly synthesize
methylamines from CO2 and H2 (Scheme 19, A and B,
respectively).[60a, 60b] Both examples used a [Ru/Triphos] complex
in combination with the suitable acid additive (HNTf2, CH3SO3H
or LiCl) as co-catalyst, under similar temperatures and
pressures. While the example reported by Klankermayer
focused on the methylation of aromatic amines to give N,N-
dimethylanilines,[60a] Beller’s protocol could be applied for both
aromatic and aliphatic amines by changing the acid co-catalyst
(MSA for aromatic amines and LiCl for the aliphatic ones). [60b]
Moreover, the selective monomethylation of a few primary
anilines was carried out under the suitable reaction conditions.
In addition, the selective monomethylation of aromatic diamines
with different electronic character was showcased. Despite the
reductive conditions of these methylation processes, both
methodologies showed good tolerance for different sensitive
groups such as halogens, ester, and hydroxyl groups. In one
example also the more challenging alkene moiety was
preserved, although a high degree of substitution was required.
From a mechanistic point of view, both groups proposed a
sequential formylation of the amine followed by the formamide
reduction as the main pathway of the process.
Next, Shi and collaborators described the heterogeneous
Scheme 18. Synthesis of monomethylamine (MMA), dimethylamine (DMA)
and trimethylamine (TMA) by catalytic N-methylation of NH3 and its surrogates systems [CuAlOx] (Scheme 19, C)[60c] and [Pd/CuZrOx]
using (CO2/H2). LDH = lamellar double hydroxides. (Scheme 19, D)[60d] as active catalysts for the N-methylation of a
broad scope of amines with CO2/H2 mixtures. In the case of the
Pd-based system, milder reaction conditions were required in
Concerning the methylation of ammonia,[59] more than twenty comparison with the copper-aluminum oxide catalyst.
years ago, Baiker et al. reported the first example of the Complementary to these works, other heterogeneous
synthesis of methylamines (MMA, DMA and TMA) using a materials such as [Pt-MoOx/TiO2],[60e] [Au/Al2O3-VS],[60f, 60g]
mixture of NH3, H2 and CO2 (Scheme 18, A).[59a, 59b] The reaction [PdGa/TiO2][60h] and [Re/TiO2][60i] were reported by the groups of
was catalyzed by a heterogeneous [Cu/Al 2O3] system under Shimizu, Toyao, Wang and Su, and Lin, Yu and Zhao (Scheme
harsh reaction conditions. Based on this original work, the same 19, E-H) as efficient catalysts for the same transformation.
group developed other related heterogeneous catalysts for this Notably, the [Au/Al2O3-VS][60f, 60g] catalyst described by the
reaction (Scheme 18, B-D).[59c-e] Thus, [metal/Al2O3],[59c] groups of Wang and Su was also able to produce unsymmetrical
[Cu/metal oxide][59d] and [Cu-Mg-Al] lamellar double hydroxides N-tertiary alkylamines from primary amines, aldehydes and CO 2
(LDH)[59e] (Scheme 18, B, C and D, respectively) were studied as in one-pot.
novel catalysts for the selective methylation of ammonia using In 2013, Liu and co-workers described a synthetic application
carbon dioxide and molecular hydrogen. of this methodology for obtaining benzimidazoles in high yields
After the seminal work of Baiker et al., two examples from o-phenylenediamines using a CO2/H2 mixture in the
synthesizing trimethylamine (TMA) from ammonia, or its presence of a ruthenium complex (Scheme 20).[61] This work
surrogates, and CO2 have been recently described.[59f, 59g] On complements the protocol reported by Cantat in the same year
the one hand, the groups of Leitner and Klankermayer found a but employing silanes (see Scheme 2 of this review).[42]
homogeneous [Ru/Triphos/Al] system [Triphos = 1,1,1-
MINIREVIEW

Scheme 20. Ruthenium-catalyzed direct synthesis of benzimidazoles using

CO2/H2 and o-phenylenediamines. Yields of isolated products are given.

Scheme 19. Synthesis of N-methyl and N,N-dimethylamines by catalytic

N-methylation of amines using CO2/H2. Tmm = trimethylene methane. MSA =
methanesulfonic acid.

Alternatively to the use of CO2/H2 mixtures for the direct Scheme 21. N-methylation of aromatic amines using formic acid as the unique
synthesis of N-methylamines, Cantat et al. developed in 2014 an carbon and hydrogen source, catalyzed by: (A) [Ru/Triphos/acid] system and
appealing strategy where formic acid acts as the unique source (B) heterogeneous PdAg nano-alloy catalyst. N-rGO = nitrogen-doped
reduced graphene oxide.
of carbon and hydrogen (Scheme 21, A).[62] This methodology
was the first example where no sacrificial external reductant is
required to perform the reductive N-methylation of an amine.
Dimethyl carbonate (DMC) vide supra is an attractive C1
The catalyst is based on the previously studied [Ru/Triphos]
source for synthetic and industrial chemists due to its safety and
complex in combination with acid additives. One year later, Kim
availability.[5] In 2016, Beller et al. reported the only example in
and co-workers developed a new heterogeneous PdAg nano-
which DMC has been used as methylating agent in the presence
alloy supported on magnetite/graphene oxide
of H2 as reductor (Scheme 22).[64] In this work, again a
[Pd47Ag53/Fe3O4/N-rGO], able to perform the same
[Ru/Triphos/additive] catalyst combination was able to carry out
transformation without additives but using a large excess of
the methylation of aromatic and aliphatic primary and secondary
formic acid (Scheme 21, B).[63]
amines (more than 40 examples) using the carbonyl function of
DMC as methyl source.
MINIREVIEW

Scheme 22. Ru-catalyzed synthesis of methylamines by using dimethyl

carbonate and H2. Yields of isolated products are given.

This process represents an improvement when compared with

the earlier described protocols for the same reaction but using
silanes (see Scheme 5).[48]
As we previously commented, the use of carboxylic
acids/esters as alkyl sources in N-alkylation is attractive to
produce a variety of functionalized alkylamines. In addition, the
employment of H2 as reductant in combination with these alkyl
sources is highly desired. In 2007, following this general idea
Cole-Hamilton and co-workers reported a [Ru/Triphos]-catalyzed
hydrogenation of nonanoic acid in the presence of ammonia,
affording a mixture of nonylamine and dinonylamine, albeit in
relatively low yields and selectivities.[65]
Based on this pioneering work, Beller’s group developed
during the last three years several methodologies[66] for the
reductive N-alkylation of amines using carboxylic acids (also in
combination with CO2),[66a] natural occurring triglycerides from
biomass and esters[66b, 67] (Scheme 23, A-B, C and D,
respectively). An in situ [Ru(acac)3/Triphos/HNTf2] system was
the active catalyst in all these transformations, affording
excellent yields of a wide range of N-alkylated products.
Remarkably, multicomponent selective couplings between
aniline, CO2 and a carboxylic acid were efficiently performed to
produce tertiary N-alkylamines in a one-pot strategy (Scheme 23,
B).[66a] Moreover, sunflower oil[67b, 67c] was directly used as a
highly effective N-alkylating source (Scheme 23, C).[66b] From a
mechanistic standpoint, an amide formation and its subsequent Scheme 23. Reductive catalytic one-pot synthesis of N-alkylated amines using
hydrogenation was postulated as a major pathway of the overall H2 and: (A) carboxylic acids, (B) carboxylic acids and CO2, (C) triglycerides
process. Very recently, a related tailor-made homogeneous and (D) methyl esters. Yields of isolated products are given. Between
cobalt catalyst formed in situ from [Co(BF4)2·6H2O] and the (p- parentheses are shown GC yields.

anisole)-Triphos ligand, was also developed by our group for the

additive-free N-alkylation of amines with carboxylic acids.[68]
Complementarily, Cole-Hamilton and co-workers described an
interesting methodology for the direct synthesis of aliphatic N-
phenyl heterocycles from diesters and aniline. [69] The desired
heterocycles were efficiently produced through the double N-
MINIREVIEW

alkylation of the amine. The authors postulate a main pathway in

which one of the ester groups is partially hydrogenated to
aldehyde and then affords the monoalkylated amine through the
reductive amination at low hydrogen pressure (10 bar). Next, the
hydrogenation of the second ester group gives an aldehyde
which intramolecularly reacts with the secondary amine
producing the final desired N-phenyl heterocycle. However,
hydrogen borrowing reactions between the diol (formed from the
total hydrogenation of both ester groups) or methanol and the
amine are also postulated as a minor pathway and explain some
of the by-products. The in situ [Ru/Triphos/MSA] combination is
used as catalyst and high temperatures (220 ºC) are required.
Closely related with this protocol, the same authors described
the synthesis of ,-diamines using dicarboxylic acids and their
esters with the same catalytic system under similar conditions.[70]
Interestingly, primary diamines could also be obtained from
aqueous ammonia and diacids or diesters, although by a
sequential one pot reaction involving a first hydrogenation of the
diacid or diester to diol followed by addition of ammonia.
Finally, Shimizu and co-workers reported in 2017 the first
heterogeneous catalyst [Re/TiO2] able to perform the N-
alkylation of amines with carboxylic acids or esters.[60i]
Specifically, the authors performed the N-alkylation of
dimethylamine with 3-phenylpropionic acid and the methyl ester
in good yields at 200 ºC.

4.1. Catalytic reductive N-alkylation of amides,

nitrobenzenes, nitriles, imines and quinoline derivatives
using hydrogen

The one pot reductive N-alkylation of amine related compounds

such as amides,[60a] nitro,[60c, 60d] nitriles,[60c] imines,[71] and
quinoline[72] derivatives using hydrogen and the corresponding Scheme 24. Synthesis of N-methylamine derivatives by reductive methylation
of: (A) amides, (B) nitrobenzenes, (C) nitriles, (D) imines and (E) quinoline
alkylating agent was also developed in the last years. In fact, compounds using CO2/H2.
several homogeneous and heterogeneous catalysts with good
activity for the N-alkylation of amines are able to perform such
related one-pot reductive methylations using CO2 (Scheme 24).
Elegant examples have been reported by the groups of
Klankermayer (Scheme 24, A and E),[60a, 71] Shi (Scheme 24, B-
D),[60c, 60d] and Liu and Han (Scheme 24, F)[72] since 2013.
Generally, good to excellent yields of the corresponding N-
methylated products could be obtained in one-pot fashion.
Moreover, Cao et al. employed formic acid as alkylating
source for the one-pot N,N-dimethylation of nitrobenzenes in the
presence of H2 and using [Au/rutile] as heterogeneous catalyst
(Scheme 25, A).[73] Interestingly, the same system catalyzed the
direct formation of benzimidazoles from o-dinitrobenzenes
without requiring hydrogen (Scheme 25, B). Both
dimethylanilines and N-heterocycles were synthesized in very
high yields using gold catalysis.

Scheme 25. [Au/rutile]-catalyzed (A) one-pot N,N-dimethylation of

nitrobenzenes and (B) direct synthesis of benzimidazoles from o-dinitroarenes
by using formic acid with or without H2. Yields of isolated products are given.
MINIREVIEW

5. Catalytic reductive N-alkylation of amines 5.1. Catalytic reductive N-alkylation of nitrobenzenes and
using nitriles as alkylating sources nitriles using nitrile derivatives as alkylating sources

Nitriles are important building blocks for polymers, Nitriles can also participate as N-alkylating sources of amine
agrochemicals, molecular electronics, and high-performance related compounds in a one pot procedure. In this regard in
materials.[74] In organic synthesis, they serve as key 2012, the group of Sajiki reported a protocol in which
intermediates for obtaining heterocycles as well as precursors nitrobenzenes are reduced and alkylated with nitriles using
for different valuable fine chemicals.[74-75] In the last years, only [Pd/C] as catalyst (Scheme 27) in the presence of hydrogen.[76a]
two examples of reductive procedures using nitriles as N-
alkylating sources have been reported.[76]
In this respect, original work was published by the group of
Sajiki in 2012 (Scheme 26, A and B).[76a] In this contribution,
more than 45 different alkylated amines were efficiently
produced using [Pd/C] in the presence or H2 under mild reaction
conditions (Scheme 26, A). In addition, selective N-
monoalkylation reactions of primary aliphatic amines were
performed with [Rh/C] as catalyst enhancing the possibilities of
this methodology (Scheme 26, B).
Very recently, a general and selective non noble metal-
catalyzed N-alkylation of amines with nitriles in the presence of
ammonia borane as hydride source was described by Zhou, Liu
and co-workers (Scheme 26, C).[76b] In this work, a novel well-
defined cobalt NNP-chelated pincer complex was shown to be
highly active for the synthesis of a wide range of N-alkylated
amines from nitriles and amines. Scheme 27. [Pd/C]-catalyzed preparation of aromatic secondary amines from
Closely connected with this approach are several examples nitrobenzenes. [a] NH4OAc (1 eq) was added. Yields of isolated products are
reported[77] by the groups of García,[77a] Milstein,[77b, 77e] Berke,[77c] given.
and Prechtl[77d] that imply nitrile self-coupling or cross-coupling
with an amine to afford imines.

Scheme 28. Cobalt-catalyzed synthesis of secondary amines from nitriles and

ammonia borane. Yields of isolated products are given.

Scheme 26. (A) [Pd/C]-catalyzed N-alkylation of primary and secondary

amines with nitriles and H2. N-monoalkyl products are formed exclusively
Finally, Zhou and Liu et al. developed in 2016, the only up to
when (R1 = aryl) and N,N-dialkyl products when (R1 = alkyl). (B) [Rh/C]- date described methodology able to afford secondary
catalyzed selective N-monoalkylation of primary alkylamines using nitriles. (C) amines from the self-coupling of a nitrile (Scheme 28).[76b] The
Synthesis of N-alkylated amines with a cobalt pincer catalyst using nitriles and
ammonia borane. HFIP = hexafluoroisopropanol. authors employed ammonia borane as reducing agent and a
cobalt complex as catalyst to synthetize several secondary
amines in one-pot fashion. Contrary to previously reported
systems,[77] the active catalyst was able to hydrogenate the
secondary imine intermediate using low catalyst loadings.
MINIREVIEW

6. Summary and Outlook [1] a) J. M. Adams, S. Cory, Nature 1975, 255, 28-33; b) M. F. Ali, B. E. Ali,
J. G. Speight, Handbook of Industrial Chemistry: Organic Chemicals,
McGraw-Hill Education, New York, 2005; c) S. A. Lawrence, Amines:
The development of new synthetic tools for the N-alkylation of
Synthesis, Properties and Applications, Cambridge University Press,
amines is an important topic for organic synthesis and catalysis
Cambrigde, 2006; d) A. Kleemann, J. Engel, B. Kutschner, D. Reichert,
due to the large number of applications of these compounds. In Pharmaceutical Substances: Syntheses, Patents, Applications, 5th ed.,
the last 5 years, a number of interesting catalytic reductive N- Thieme, Stuttgart, New York, 2009; e) D. Dominissini, S. Moshitch-
alkylation procedures using compounds with a high oxidation Moshkovitz, S. Schwartz, M. Salmon-Divon, L. Ungar, S. Osenberg, K.
state as alkyl sources have been described. CO2 and carboxylic Cesarkas, J. Jacob-Hirsch, N. Amariglio, M. Kupiec, R. Sorek, G.
acid derivatives are now feasible N-alkylating agents, at least at Rechavi, Nature 2012, 485, 201-206; f) J. Chatterjee, F. Rechenmacher,
the laboratory scale. The wide availability of CO 2, the great H. Kessler, Angew. Chem. Int. Ed. 2013, 52, 254-269; g) V. Froidevaux,
C. Negrell, S. Caillol, J.-P. Pascault, B. Boutevin, Chem. Rev. 2016,
structural diversity of carboxylic acid derivatives and the stability
116, 14181-14224.
and non-toxicity of these compounds make them ideal alkyl
[2] a) The Chemistry of Anilines, Part 1 (Ed: Z. Rappoport), Wiley
sources. This impressive development probably responds to our Interscience, 2007; b) Modern Amination Methods (Ed: A. Ricci), Wiley-
higher capacity for better designing more powerful catalysts with VCH, Weinheim, 2008.
better selectivities. In this review we tried to show an updated [3] a) M. B. Smith, J. March, Advanced Organic Chemistry, 5th ed., Wiley-
picture of the currently available methods to perform the Interscience, New York, 2001; b) R. N. Salvatore, C. H. Yoon, K. W.
reductive N-alkylation of amines using CO2 or carboxylic acid Jung, Tetrahedron 2001, 57, 7785-7811; c) G. Lamoureux, C. Aguero,
derivatives in a one pot fashion. ARKIVOC 2009, 251-264; d) H. Luo, G. Wu, Y. Zhang, J. Wang, Angew.
Chem. Int. Ed. 2015, 54, 14503-14507.
It is important to consider the growing interest in greener
[4] a) M. Selva, F. Trotta, P. Tundo, J. Chem. Soc., Perkin Trans. 2 1992,
alkylation protocols that avoid the generation of large amounts of
519-522; b) S. Padmanabhan, N. L. Reddy, G. J. Durant, Synth.
waste and use safer reagents, especially for industrially relevant Commun. 1997, 27, 691-699.
processes. In this context, the existing methodologies that use [5] a) F. Rivetti, U. Romano, D. Delledonne, ACS Symp. Ser. 1996, 626,
silanes or boranes as reducing agents have the advantage of 70-80; b) Y. Ono, App. Catal. A: Gen. 1997, 155, 133-166; c) M. A.
employing very mild conditions, but are less desirable from the Pacheco, C. L. Marshall, Energy Fuels 1997, 11, 2-29; d) D.
point of view of the waste generation. Due to these reasons, the Delledonne, F. Rivetti, U. Romano, Appl. Catal., A 2001, 221, 241-251;
future development in this field will be probably more e) P. Tundo, M. Selva, Acc. Chem. Res. 2002, 35, 706-716; f) M. Selva,
P. Tundo, A. Perosa, J. Org. Chem. 2003, 68, 7374-7378; g) P. Tundo,
concentrated in the design of new catalysts, either homogenous
L. Rossi, A. Loris, J. Org. Chem. 2005, 70, 2219-2224; h) M. Selva, A.
or heterogeneous, able to perform the N-alkylation of amines
Perosa, P. Tundo, D. Brunelli, J. Org. Chem. 2006, 71, 5770-5773; i) M.
using H2 as reducing agent. Obviously, this topic will evolve Selva, Pure Appl. Chem. 2007, 79, 1855-1867; j) M. Selva, A. Perosa,
parallel to the development of more efficient hydrogenation Green Chem. 2008, 10, 457-464; k) A. Dhakshinamoorthy, M. Álvaro, H.
catalysts, able to work at lower concentrations and milder García, Appl. Catal. A: Gen. 2010, 378, 19-25.
conditions. On the homogeneous side is interesting to pay [6] a) K. Kawai, Y.-S. Li, M.-F. Song, H. Kasai, Bioorg. Med. Chem. Lett.
attention to the design of new ligands and to metal ligand 2010, 20, 260-265; b) X. Jiang, C. Wang, Y. Wei, D. Xue, Z. Liu, J. Xiao,
cooperation catalysts, frequently enabling the employment of Chem. Eur. J. 2014, 20, 58-63; c) B. N. Atkinson, J. M. J. Williams,
ChemCatChem 2014, 6, 1860-1862.
less expensive base metals. On the heterogeneous area, the
[7] a) W. Eschweiler, Ber. Dtsch. Chem. Ges. 1905, 38, 880-882; b) H. T.
design of new materials with improved metal-support
Clarke, H. B. Gillespie, S. Z. Weisshaus, J. Am. Chem. Soc. 1933, 55,
interactions and fine-tuned structures is currently experiencing a 4571-4587; c) S. Kim, C. H. Oh, J. S. Ko, K. H. Ahn, Y. J. Kim, J. Org.
growing development that will probably find practical Chem. 1985, 50, 1927-1932; d) F. Fache, L. Jacquot, M. Lemaire,
applications in hydrogenation chemistry. Tetrahedron Lett. 1994, 35, 3313-3314; e) S. Gomez, J. A. Peters, T.
We hope that this minireview inspire to homogeneous and Maschmeyer, Adv. Synth. Catal. 2002, 344, 1037-1057; f) D.
heterogeneous catalytic chemists to explore the potential of their Steinhuebel, Y. Sun, K. Matsumura, N. Sayo, T. Saito, J. Am. Chem.
new materials in this class of N-alkylation reactions. Moreover, Soc. 2009, 131, 11316-11317; g) V. N. Wakchaure, J. Zhou, S.
Hoffmann, B. List, Angew. Chem. Int. Ed. 2010, 49, 4612-4614; h) D.
these methodologies already show interesting synthetic
Chusov, B. List, Angew. Chem. Int. Ed. 2014, 53, 5199-5201; i) S.
applications (e. g. synthesis of heterocycles or diamines) that
Raoufmoghaddam, Org. Biomol. Chem. 2014, 12, 7179-7193; j) R. V.
will certainly undergo a further development in the near future. Jagadeesh, K. Murugesan, A. S. Alshammari, H. Neumann, M.-M. Pohl,
J. Radnik, M. Beller, Science 2017, 358, 326-332.
[8] a) H. Hideaki, Y. Makoto, K. Yasushi, M. Takehiko, W. Katsuhiko, Bull.
Acknowledgements Chem. Soc. Jap. 1985, 58, 1551-1555; b) Z. Chen, H. Zeng, H. Gong,
H. Wang, C.-J. Li, Chem. Sci. 2015, 6, 4174-4178; c) X. Cui, K. Junge,
M. Beller, ACS Catal. 2016, 6, 7834-7838; dL. Yan, X.-X. Liu, Y. Fu,
This work was supported by the state of Mecklenburg- RSC Adv. 2016, 6, 109702-109705.
Vorpommern and the BMBF. [9] a) B. Zimmermann, J. Herwig, M. Beller, Angew. Chem. Int. Ed. 1999,
38, 2372-2375; b) J. F. Hartwig, Science 2002, 297, 1653-1654; c) M.
Keywords: amines • N-alkylation • reductive transformations • Ahmed, A. M. Seayad, R. Jackstell, M. Beller, J. Am. Chem. Soc. 2003,
hydrosilanes • hydroboranes • hydrogen • carbon dioxide • 125, 10311-10318; d) M. Ahmed, C. Buch, L. Routaboul, R. Jackstell, H.
Klein, A. Spannenberg, M. Beller, Chem. Eur. J. 2007, 13, 1594-1601;
carboxylic/carbonic acid derivatives • nitriles • heterocycles
e) A. Böerner, M. Beller, B. Wuensch, Sci. Synth. 2009, 40a, 111-117;
f) D. Crozet, M. Urrutigoity, P. Kalck, ChemCatChem 2011, 3, 1102-
1118; g) S. Guelak, L. Wu, Q. Liu, R. Franke, R. Jackstell, M. Beller,
MINIREVIEW

Angew. Chem. Int. Ed. 2014, 53, 7320-7323; h) C. Chen, X.-Q. Dong, X. Angelini, Chem. Rev. 2014, 114, 1709-1742; g) P. Lanzafame, G. Centi,
Zhang, Org. Chem. Front. 2016, 3, 1359-1370; i) P. H. Gehrtz, V. S. Perathoner, Chem. Soc. Rev. 2014, 43, 7562-7580; h) C. Maeda, Y.
Hirschbeck, B. Ciszek, I. Fleischer, Synthesis 2016, 48, 1573-1596. Miyazaki, T. Ema, Catal. Sci. Technol. 2014, 4, 1482-1497.
[10] a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069-1094; b) B. H. [16] a) P. G. Jessop, T. Ikarlya, R. Noyori, Nature 1994, 368, 231-233; b) W.
Lipshutz, H. Shimizu, Angew. Chem. Int. Ed. 2004, 43, 2228-2230; c) K. Leitner, Angew. Chem. Int. Ed. 1995, 34, 2207-2221; c) P. G. Jessop, Y.
A. Nolin, R. W. Ahn, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 12462- Hsiao, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 344-355; d)
12463; d) N. Mrsic, A. J. Minnaard, B. L. Feringa, J. G. de Vries, J. Am. P. G. Jessop, F. Joo, C.-C. Tai, Coord. Chem. Rev. 2004, 248, 2425-
Chem. Soc. 2009, 131, 8358-8359; e) T. C. Nugent, M. El-Shazly, Adv. 2442; e) C. Federsel, R. Jackstell, M. Beller, Angew. Chem. Int. Ed.
Synth. Catal. 2010, 352, 753-819; f) J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, 2010, 49, 6254-6257; f) W. Wang, S. Wang, X. Ma, J. Gong, Chem.
Chem. Rev. 2011, 111, 1713-1760; g) S. Zhou, S. Fleischer, K. Junge, Soc. Rev. 2011, 40, 3703-3727; g) J. F. Hull, Y. Himeda, W.-H. Wang,
M. Beller, Angew. Chem. Int. Ed. 2011, 50, 5120-5124; h) A. B. Hashiguchi, R. Periana, D. J. Szalda, J. T. Muckerman, E. Fujita, Nat.
Bartoszewicz, N. Ahlsten, B. Martín-Matute, Chem. Eur. J. 2013, 19, Chem. 2012, 4, 383-388; h) S. Wesselbaum, T. vom Stein, J.
7274-7302; i) P. Etayo, A. Vidal-Ferrán, Chem. Soc. Rev. 2013, 42, Klankermayer, W. Leitner, Angew. Chem. Int. Ed. 2012, 51, 7499-7502;
728-754; j) P. O. Lagaditis, P. E. Sues, J. F. Sonnenberg, K. Y. Wan, A. i) F. J. Fernández-Alvarez, A. M. Aitani, L. A. Oro, Catal. Sci. Technol.
J. Lough, R. H. Morris, J. Am. Chem. Soc. 2014, 136, 1367-1380; k) S. 2014, 4, 611-624; j) S. Moret, P. J. Dyson, G. Laurenczy, Nat. Commun.
Rossi, M. Benaglia, E. Massolo, L. Raimondi, Catal. Sci. Technol. 2014, 2014, 5, 4017 DOI: 4010.1038/ncomms5017; k) N. von Wolff, G.
4, 2708-2723; l) K. H. Hopmann, A. Bayer, Coord. Chem. Rev. 2014, Lefevre, J. C. Berthet, P. Thuery, T. Cantat, ACS Catal. 2016, 6, 4526-
268, 59-82; m) D. Ghislieri, N. J. Turner, Top. Catal. 2014, 57, 284-300; 4535; l) A. Alvarez, A. Bansode, A. Urakawa, A. V. Bavykina, T. A.
n) J. H. Schrittwieser, S. Velikogne, W. Kroutil, Adv. Synth. Catal. 2015, Wezendonk, M. Makkee, J. Gascon, F. Kapteijn, Chem. Rev. 2017, 117,
357, 1655-1685; o) C. Zhu, K. Saito, M. Yamanaka, T. Akiyama, Acc. 9804-9838; m) J. Schneidewind, R. Adam, W. Baumann, R. Jackstell,
Chem. Res. 2015, 48, 388-398. M. Beller, Angew. Chem. Int. Ed. 2017, 56, 1890-1893; n) K. Sordakis,
[11] a) T. Oku, T. Ikariya, Angew. Chem. Int. Ed. 2002, 41, 3476-3479; b) T. C. Tang, L. K. Vogt, H. Junge, P. J. Dyson, M. Beller, G. Laurenczy,
Oku, Y. Arita, H. Tsuneki, T. Ikariya, J. Am. Chem. Soc. 2004, 126, Chem. Rev. 2018, 118, 372-433.
7368-7377; c) D. Hollmann, S. Baehn, A. Tillack, M. Beller, Angew. [17] a) P. Braunstein, D. Matt, D. Nobel, Chem. Rev. 1988, 88, 747-764; b)
Chem., Int. Ed. 2007, 46, 8291-8294; d) D. Hollmann, S. Baehn, A. M. Aresta, A. Dibenedetto, Dalton Trans. 2007, 2975-2992; c) I. I. F.
Tillack, M. Beller, Chem. Commun. 2008, 3199-3201; e) O. Saidi, A. J. Boogaerts, S. P. Nolan, J. Am. Chem. Soc. 2010, 132, 8858-8859; d) K.
Blacker, M. M. Farah, S. P. Marsden, J. M. J. Williams, Angew. Chem. Huang, C.-L. Sun, Z.-J. Shi, Chem. Soc. Rev. 2011, 40, 2435-2452; e)
Int. Ed. 2009, 48, 7375-7378; f) G. Guillena, D. J. Ramón, M. Yus, Q. Liu, L. Wu, R. Jackstell, M. Beller, Nat. Commun. 2015, 6, 5933 DOI:
Chem. Rev. 2010, 110, 1611-1641; g) Y. Zhao, S. W. Foo, S. Saito, 5910.1038/ncomms6933; f) F. Julia-Hernandez, T. Moragas, J.
Angew. Chem. Int. Ed. 2011, 50, 3006-3009; h) S. Bähn, S. Imm, L. Cornella, R. Martin, Nature 2017, 545, 84-88.
Neubert, M. Zhang, H. Neumann, M. Beller, ChemCatChem 2011, 3, [18] a) A. Tlili, X. Frogneux, E. Blondiaux, T. Cantat, Angew. Chem. Int. Ed.
1853-1864; i) B. Abarca, R. Adam, R. Ballesteros, Org. Biomol. Chem. 2014, 53, 2543-2545; b) J. Klankermayer, W. Leinter, Science 2015,
2012, 10, 1826-1833; j) Q. Yang, Q. Wang, Z. Yu, Chem. Soc. Rev. 350, 629-630; c) G. Yan, A. J. Borah, L. Wang, M. Yang, Adv. Synth.
2015, 44, 2305-2329; k) Z. Yin, H. Zeng, J. Wu, S. Zheng, G. Zhang, Catal. 2015, 357, 1333-1350; d) A. Tlili, E. Blondiaux, X. Frogneux, T.
ACS Catalysis 2016, 6, 6546-6550; l) P. T. K. Arachchige, H. Lee, C. S. Cantat, Green Chem. 2015, 17, 157-168; e) J. Klankermayer, S.
Yi, J. Org. Chem. 2018, 83, 4932-4947. Wesselbaum, K. Beydoun, W. Leitner, Angew. Chem. Int. Ed. 2016, 55,
[12] a) T. E. Müller, M. Beller, Chem. Rev. 1998, 98, 675-703; b) M. Beller, J. 7296-7343; f) Y. Li, X. Cui, K. Dong, K. Junge, M. Beller, ACS Catal.
Seayad, A. Tillack, H. Jiao, Angew. Chem. Int. Ed. 2004, 43, 3368- 2017, 7, 1077–1086.
3398; c) T. E. Mueller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, [19] a) R. Bruckner, Carbonic Acid Derivatives and Heterocumulenes and
Chem. Rev. 2008, 108, 3795-3892; d) A. Leyva-Pérez, J. R. Cabrero- Their Interconversion in Organic Mechanisms: Reactions,
Antonino, A. Cantín, A. Corma, J. Org. Chem. 2010, 75, 7769-7780; e) Stereochemistry and Synthesis (Ed.: M. Harmata), Springer-Verlag
J. C. H. Yim, L. L. Schafer, Eur. J. Org. Chem. 2014, 2014, 6825-6840; Berlin Heidelberg, Berlin, Heidelberg, 2010, pp. 339-358; b) B.
f) J. Gui, C.-M. Pan, Y. Jin, T. Qin, J. C. Lo, B. J. Lee, S. H. Spergel, M. Schaffner, F. Schaffner, S. P. Verevkin, A. Börner, Chem. Rev. 2010,
E. Mertzman, W. J. Pitts, T. E. La Cruz, M. A. Schmidt, N. Darvatkar, S. 110, 4554-4581; c) E. Balaraman, C. Gunanathan, J. Zhang, L. J. W.
R. Natarajan, P. S. Baran, Science 2015, 348, 886-891; g) L. Huang, M. Shimon, D. Milstein, Nat. Chem. 2011, 3, 609-614; d) P. A. Dub, T.
Arndt, K. Goossen, H. Heydt, L. J. Goossen, Chem. Rev. 2015, 115, Ikariya, ACS Catal. 2012, 2, 1718-1741; e) T. Ikariya, Y. Kayaki, Pure
2596-2697; h) Y. Yang, S.-L. Shi, D. Niu, P. Liu, S. L. Buchwald, Appl. Chem. 2014, 86, 933-943; f) A. M. Smith, R. Whyman, Chem.
Science 2015, 349, 62-66; i) M. T. Pirnot, Y.-M. Wang, S. L. Buchwald, Rev. 2014, 114, 5477-5510; g) S. Werkmeister, K. Junge, M. Beller,
Angew. Chem. Int. Ed. 2016, 55, 48-57. Org. Process Res. Dev. 2014, 18, 289-302; h) X. Just-Baringo, D. J.
[13] a) J. F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046-2067; b) J. F. Procter, Acc. Chem. Res. 2015, 48, 1263-1275; i) J. Pritchard, G. A.
Hartwig, Acc. Chem. Res. 2008, 41, 1534-1544; c) D. S. Surry, S. L. Filonenko, R. van Putten, E. J. M. Hensen, E. A. Pidko, Chem. Soc.
Buchwald, Chem. Sci. 2011, 2, 27-50; d) A. T. Brusoe, J. F. Hartwig, J. Rev. 2015, 44, 3808-3833; j) D. S. Merel, M. L. T. Do, S. Gaillard, P.
Am. Chem. Soc. 2015, 137, 8460-8468. Dupau, J.-L. Renaud, Coord. Chem. Rev. 2015, 288, 50-68; k) H.
[14] a) L. F. Tietze, Chem. Rev. 1996, 96, 115-136; b) A. Padwa, S. K. Bur, Nagashima, Synlett 2015, 26, 866-890.
Tetrahedron 2007, 63, 5341-5378; c) A. Padwa, Chem. Soc. Rev. 2009, [20] a) P. Crochet, V. Cadierno, Top. Organomet. Chem. 2015, 48, 81-118;
38, 3072-3081; d) L. F. Tietze, T. Kinzel, C. C. Brazel, Acc. Chem. Res. b) R. M. deFigueiredo, J.-S. Suppo, J.-M. Campagne, Chem. Rev. 2016,
2009, 42, 367-378. 116, 12029-12122; c) I. Kreituss, J. W. Bode, Acc. Chem. Res. 2016,
[15] a) T. Sakakura, J.-C. Choi, H. Yasuda, Chem. Rev. 2007, 107, 2365- 49, 2807-2821; d) A. Ojeda-Porras, D. Gamba-Sánchez, J. Org. Chem.
2387; b) M. Aresta, A. Dibenedetto, Woodhead Publ. Ser. Energy 2010, 2016, 81, 11548-11555; e) H. Noda, M. Furutachi, Y. Asada, M.
8, 377-410; c) M. Mikkelsen, M. Jörgensen, F. C. Krebs, Energy Shibasaki, N. Kumagai, Nat. Chem. 2017, 9, 571-577.
Environ. Sci. 2010, 3, 43-81; d) M. Peters, B. Koehler, W. [21] a) H. C. Brown, S. Narasimhan, Y. M. Choi, Synthesis 1981, 441-442;
Kuckshinrichs, W. Leitner, P. Markewitz, T. E. Mueller, ChemSusChem b) G. W. Gribble, Chem. Soc. Rev. 1998, 27, 395-404; c) D. L. Dodds,
2011, 4, 1216-1240; e) P. Markewitz, W. Kuckshinrichs, W. Leitner, J. D. J. Cole-Hamilton, Catalytic Reduction of Amides Avoiding LiAlH4 or
Linssen, P. Zapp, R. Bongartz, A. Schreiber, T. E. Mueller, Energy B2H6 in Sustainable Catalysis: Challenges and Practices for the
Environ. Sci. 2012, 5, 7281-7305; f) M. Aresta, A. Dibenedetto, A. Pharmaceutical and Fine Chemical Industries (Eds: P. J. Dunn, K. K.
MINIREVIEW

Hii, M. J. Krische and M. T. Williams), John Wiley & Sons, Inc., [42] O. Jacquet, C. Das Neves Gomes, M. Ephritikhine, T. Cantat,
Hoboken, New Jersey, 2013, pp. 1-36. ChemCatChem 2013, 5, 117-120.
[22] a) G. Pelletier, W. S. Bechara, A. B. Charette, J. Am. Chem. Soc. 2010, [43] X. Frogneux, E. Blondiaux, P. Thuery, T. Cantat, ACS Catal. 2015, 5,
132, 12817-12819; b) J. Coetzee, D. L. Dodds, J. Klankermayer, S. 3983-3987.
Brosinski, W. Leitner, A. M. Z. Slawin, D. J. Cole-Hamilton, Chem. Eur. [44] D.-Y. Zhu, L. Fang, H. Han, Y. Wang, J.-B. Xia, Org. Lett. 2017, 19,
J. 2013, 19, 11039-11050; c) M. Stein, B. Breit, Angew. Chem. Int. Ed. 4259–4262.
2013, 52, 2231-2234; d) T. vom Stein, M. Meuresch, D. Limper, M. [45] a) A. Boddien, D. Mellmann, F. Gärtner, R. Jackstell, H. Junge, P. J.
Schmitz, M. Hoelscher, J. Coetzee, D. J. Cole-Hamilton, J. Dyson, G. Laurenczy, R. Ludwig, M. Beller, Science 2011, 333, 1733-
Klankermayer, W. Leitner, J. Am. Chem. Soc. 2014, 136, 13217-13225; 1736; b) D. Mellmann, P. Sponholz, H. Junge, M. Beller, Chem. Soc.
e) J. R. Cabrero-Antonino, E. Alberico, K. Junge, H. Junge, M. Beller, Rev. 2016, 45, 3954-3988; c) Z. Li, Q. Xu, Acc. Chem. Res. 2017, 50,
Chem. Sci. 2016, 7, 3432-3442 ; f) B. Li, J.-B. Sortais, C. Darcel, RSC 1449-1458.
Adv. 2016, 6, 57603-57625; g) D. Mukherjee, S. Shirase, K. Mashima, [46] a) G. Wienhöfer, I. Sorribes, A. Boddien, F. Westerhaus, K. Junge, H.
J. Okuda, Angew. Chem. Int. Ed. 2016, 55, 13326-13329; h) A. Volkov, Junge, R. Llusar, M. Beller, J. Am. Chem. Soc. 2011, 133, 12875-
F. Tinnis, T. Slagbrand, P. Trillo, H. Adolfsson, Chem. Soc. Rev. 2016, 12879; b) J. R. Cabrero-Antonino, R. Adam, K. Junge, R. Jackstell, M.
45, 6685-6697; i) T. Mitsudome, K. Miyagawa, Z. Maeno, T. Mizugaki, Beller, Catal. Sci. Technol. 2017, 7, 1981-1985.
K. Jitsukawa, J. Yamasaki, Y. Kitagawa, K. Kaneda, Angew. Chem. Int. [47] a) I. Sorribes, K. Junge, M. Beller, Chem. Eur. J. 2014, 20, 7878-7883;
Ed. 2017, 56, 9381-9385. b) M.-C. Fu, R. Shang, W.-M. Cheng, Y. Fu, Angew. Chem. Int. Ed.
[23] a) G. W. Gribble, P. W. Heald, Synthesis 1975, 650-652; b) P. Marchini, 2015, 54, 9042-9046; c) Q. Zhang, M.-C. Fu, H.-Z. Yu, Y. Fu, J. Org.
G. Liso, A. Reho, F. Liberatore, F. Micheletti Moracci, J. Org. Chem. Chem. 2016, 81, 6235-6243; d) L. Zhu, L.-S. Wang, B. Li, W. Li, B. Fu,
1975, 40, 3453-3456; c) G. W. Gribble, J. M. Jasinski, J. T. Pellicone, J. Catal. Sci. Technol. 2016, 6, 6172-6176; e) C. Qiao, X.-F. Liu, X. Liu,
A. Panetta, Synthesis 1978, 766-768; d) G. Trapani, A. Reho, A. L.-N. He, Org. Lett. 2017, 19, 1490–1493.
Latrofa, Synthesis 1983, 1013-1014; e) C. Perrio-Huard, C. Aubert, M.- [48] a) J. Zheng, C. Darcel, J.-B. Sortais, Chem. Commun. 2014, 50, 14229-
C. Lasne, J. Chem. Soc., Perkin Trans. 1 2000, 311-316. 14232; b) Y. Li, I. Sorribes, C. Vicent, K. Junge, M. Beller, Chem. Eur. J.
[24] a) M. Akita, Appl. Catal., A 2000, 200, 153-165; b) J.-F. Carpentier, V. 2015, 21, 16759-16763.
Bette, Curr. Org. Chem. 2002, 6, 913-936; c) G. J. Kubas, Adv. Inorg. [49] a) I. Sorribes, K. Junge, M. Beller, J. Am. Chem. Soc. 2014, 136,
Chem. 2004, 56, 127-177; d) D. Addis, S. Das, K. Junge, M. Beller, 14314-14319; b) K. G. Andrews, D. M. Summers, L. J. Donnelly, R. M.
Angew. Chem. Int. Ed. 2011, 50, 6004-6011; e) S. C. A. Sousa, I. Denton, Chem. Commun. 2016, 52, 1855-1858; c) M. Minakawa, M.
Cabrita, A. C. Fernandes, Chem. Soc. Rev. 2012, 41, 5641-5653; f) J. Okubo, M. Kawatsura, Tetrahedron Lett. 2016, 57, 4187-4190.
Y. Corey, Chem. Rev. 2016, 116, 11291-11435. [50] K. G. Andrews, R. Faizova, R. M. Denton, Nat. Commun. 2017, 8,
[25] O. Jacquet, X. Frogneux, C. Das Neves Gomes, T. Cantat, Chem. Sci. 15913 DOI: 15910.11038/ncomms15913
2013, 4, 2127-2131. [51] a) B. Li, J.-B. Sortais, C. Darcel, Chem. Commun. 2013, 49, 3691-
[26] Y. Li, X. Fang, K. Junge, M. Beller, Angew. Chem. Int. Ed. 2013, 52, 3693; b) Y. Ogiwara, W. Shimoda, K. Ide, T. Nakajima, N. Sakai, Eur. J.
9568-9571. Org. Chem. 2017, 20, 2866-2870.
[27] S. Das, F. D. Bobbink, G. Laurenczy, P. J. Dyson, Angew. Chem. Int. [52] J. Zhu, Z. Zhang, C. Miao, W. Liu, W. Sun, Tetrahedron 2017, 73,
Ed. 2014, 53, 12876-12879. 3458-3462.
[28] X. Frogneux, O. Jacquet, T. Cantat, Catal. Sci. Technol. 2014, 4, 1529- [53] Y. Pan, C. Chen, X. Xu, H. Zhao, J. Han, H. Li, L. Xu, Q. Fan, J. Xiao,
1533. Green Chem. 2018, 20, 403-411.
[29] L. Gonzalez-Sebastian, M. Flores-Alamo, J. J. Garcia, Organometallics [54] E. Pedrajas, I. Sorribes, E. Guillamón, K. Junge, M. Beller, R. Llusar,
2015, 34, 763-769. Chem. Eur. J. 2017, 23, 13205-13212.
[30] O. Santoro, F. Lazreg, Y. Minenkov, L. Cavallo, C. S. J. Cazin, Dalton [55] T. Nishikata, H. Nagashima, Angew. Chem. Int. Ed. 2012, 51, 5363-
Trans. 2015, 44, 18138-18144. 5366.
[31] Z. Yang, B. Yu, H. Zhang, Y. Zhao, G. Ji, Z. Ma, X. Gao, Z. Liu, Green [56] a) D. S. Matteson, Sci. Synth. 2004, 6, 5-79; b) M.-A. Courtemanche,
Chem. 2015, 17, 4189-4193. M.-A. Legare, L. Maron, F.-G. Fontaine, J. Am. Chem. Soc. 2013, 135,
[32] S. Das, F. D. Bobbink, S. Bulut, M. Soudani, P. J. Dyson, Chem. 9326-9329; c) C. Das Neves Gomes, E. Blondiaux, P. Thuery, T.
Commun. 2016, 52, 2497-2500. Cantat, Chem. Eur. J. 2014, 20, 7098-7106; d) S. Bontemps, Coord.
[33] C. Fang, C. Lu, M. Liu, Y. Zhu, Y. Fu, B.-L. Lin, ACS Catal. 2016, 6, Chem. Rev. 2016, 308, 117-130; e) S. Park, S. Chang, Angew. Chem.
7876-7881. Int. Ed. 2017, 56, 7720-7738.
[34] T. V. Q. Nguyen, W.-J. Yoo, S. Kobayashi, Adv. Synth. Catal. 2016, [57] a) E. Blondiaux, J. Pouessel, T. Cantat, Angew. Chem. Int. Ed. 2014,
358, 452-458. 53, 12186-12190; b) W.-C. Chen, J.-S. Shen, T. Jurca, C.-J. Peng, Y.-H.
[35] X.-F. Liu, R. Ma, C. Qiao, H. Cao, L.-N. He, Chem. Eur. J. 2016, 22, Lin, Y.-P. Wang, W.-C. Shih, G. P. A. Yap, T.-G. Ong, Angew. Chem.
16489-16493. Int. Ed. 2015, 54, 15207-15212; c) G. Jin, C. G. Werncke, Y. Escudie, S.
[36] X.-F. Liu, C. Qiao, X.-Y. Li, L.-N. He, Green Chem. 2017, 19, 1726- Sabo-Etienne, S. Bontemps, J. Am. Chem. Soc. 2015, 137, 9563-9566.
1731. [58] a) R. Schmid, Chimia 1996, 50, 110-113; b) H. U. Blaser, F. Spindler, M.
[37] H. Niu, L. Lu, R. Shi, C.-W. Chiang, A. Lei, Chem. Commun. 2017, 53, Studer, Appl. Catal., A 2001, 221, 119-143; c) G. J. Kubas, Chem. Rev.
1148-1151. 2007, 107, 4152-4205; d) J. Tollefson, Nature 2010, 464, 1262-1264.
[38] C. Xie, J. Song, H. Wu, B. Zhou, C. Wu, B. Han, ACS Sustainable [59] a) S. V. Gredig, R. A. Koeppel, A. Baiker, J. Chem. Soc., Chem.
Chem. Eng. 2017, 5, 7086-7092. Commun. 1995, 73-74; b) S. V. Gredig, R. A. Koeppel, A. Baiker, Catal.
[39] Y. Lu, Z.-H. Gao, X.-Y. Chen, J. Guo, Z. Liu, Y. Dang, S. Ye, Z.-X. Today 1996, 29, 339-342; c) S. V. Gredig, R. A. Koeppel, A. Baiker,
Wang, Chem. Sci. 2017, 8, 7637-7650. App. Catal. A: Gen. 1997, 162, 249-260; d) S. V. Gredig, R. Maurer, R.
[40] M.-Y. Wang, N. Wang, X.-F. Liu, C. Qiao, L.-N. He, Green Chem. 2018, A. Koeppel, A. Baiker, J. Mol. Catal. A: Chem. 1997, 127, 133-142; e) S.
20, 1564-1570. M. Auer, S. V. Gredig, R. A. Koppel, A. Baiker, J. Mol. Catal. A: Chem.
[41] Y. Hu, J. Song, C. Xie, H. Wu, Z. Wang, T. Jiang, L. Wu, Y. Wang, B. 1999, 141, 193-203; f) K. Beydoun, K. Thenert, E. S. Streng, S.
Han, ACS Sustainable Chem. Eng. 2018, DOI: Brosinski, W. Leitner, J. Klankermayer, ChemCatChem 2016, 8, 135-
10.1021/acssuschemeng.1028b03245. 138; g) T. Toyao, S. M. A. H. Siddiki, K. Ishihara, K. Kon, W. Onodera,
K.-i. Shimizu, Chem. Lett. 2017, 46, 68-70.
MINIREVIEW

[60] a) K. Beydoun, T. vom Stein, J. Klankermayer, W. Leitner, Angew. ChemCatChem 2015, 7, 1023-1028; e) S. Chakraborty, G. Leitus, D.
Chem. Int. Ed. 2013, 52, 9554-9557; b) Y. Li, I. Sorribes, T. Yan, K. Milstein, Angew. Chem. Int. Ed. 2017, 56, 2074-2078.
Junge, M. Beller, Angew. Chem. Int. Ed. 2013, 52, 12156-12160; c) X.
Cui, X. Dai, Y. Zhang, Y. Deng, F. Shi, Chem. Sci. 2014, 5, 649-655; d)
X. Cui, Y. Zhang, Y. Deng, F. Shi, Chem. Commun. 2014, 50, 13521-
13524; e) K. Kon, S. M. A. H. Siddiki, W. Onodera, K. i. Shimizu, Chem.
Eur. J. 2014, 20, 6264-6267; f) G. Tang, H.-L. Bao, C. Jin, X.-H. Zhong,
X.-L. Du, RSC Adv. 2015, 5, 99678-99687; g) X.-L. Du, G. Tang, H.-L.
Bao, Z. Jiang, X.-H. Zhong, D. S. Su, J.-Q. Wang, ChemSusChem
2015, 8, 3489-3496; h) X. Su, W. Lin, H. Cheng, C. Zhang, Y. Li, T. Liu,
B. Zhang, Q. Wu, X. Yu, F. Zhao, RSC Adv. 2016, 6, 103650-103656; i)
T. Toyao, S. M. A. H. Siddiki, Y. Morita, T. Kamachi, A. S. Touchy, W.
Onodera, K. Kon, S. Furukawa, H. Ariga, K. Asakura, K. Yoshizawa, K.-
i. Shimizu, Chem. Eur. J. 2017, 23, 14848-14859.
[61] B. Yu, H. Zhang, Y. Zhao, S. Chen, J. Xu, C. Huang, Z. Liu, Green
Chem. 2013, 15, 95-99.
[62] S. Savourey, G. Lefevre, J.-C. Berthet, T. Cantat, Chem. Commun.
2014, 50, 14033-14036.
[63] A. K. Singh, Y.-H. Hwang, D.-P. Kim, NPG Asia Mater. 2015, 7, e222.
[64] a) J. R. Cabrero-Antonino, R. Adam, K. Junge, M. Beller, Catal. Sci.
Technol. 2016, 6, 7956-7966; b) J. R. Cabrero-Antonino, R. Adam, J.
Wårna, D. Y. Murzin, M. Beller, Chem. Eng. J. 2018, 351, 1129-1136.
[65] a) A. A. Núñez Magro, G. R. Eastham, D. J. Cole-Hamilton, Chem.
Commun. 2007, 3154-3156; b) D. L. Dodds, J. Coetzee, J.
Klankermayer, S. Brosinski, W. Leitner, D. J. Cole-Hamilton, Chem.
Commun. 2012, 48, 12249-12262.
[66] a) I. Sorribes, J. R. Cabrero-Antonino, C. Vicent, K. Junge, M. Beller, J.
Am. Chem. Soc. 2015, 137, 13580-13587; b) R. Adam, J. R. Cabrero-
Antonino, K. Junge, R. Jackstell, M. Beller, Angew. Chem. Int. Ed. 2016,
55, 11049-11053.
[67] a) A. Corma, S. Iborra, A. Velty, Chem. Rev. 2007, 107, 2411-2502; b)
M. A. R. Meier, J. O. Metzger, U. S. Schubert, Chem. Soc. Rev. 2007,
36, 1788-1802; c) U. Biermann, U. Bornscheuer, M. A. R. Meier, J. O.
Metzger, H. J. Schäfer, Angew. Chem. Int. Ed. 2011, 50, 3854-3871; d)
M. Besson, P. Gallezot, C. Pinel, Chem. Rev. 2014, 114, 1827-1870; e)
P. J. Deuss, K. Barta, J. G. de Vries, Catal. Sci. Technol. 2014, 4,
1174-1196.
[68] W. Liu, B. Sahoo, A. Spannenberg, K. Junge, M. Beller, Angew. Chem.,
Int. Ed. 2018, 57, 11673-11677.
[69] Y. Shi, P. C. J. Kamer, D. J. Cole-Hamilton, M. Harvie, E. F. Baxter, K.
J. C. Lim, P. Pogorzelec, Chem. Sci. 2017.
[70] Y. Shi, P. C. J. Kamer, D. J. Cole-Hamilton, Green Chem. 2017, 19,
5460-5466.
[71] K. Beydoun, G. Ghattas, K. Thenert, J. Klankermayer, W. Leitner,
Angew. Chem. Int. Ed. 2014, 53, 11010-11014.
[72] Z. He, H. Liu, Q. Qian, L. Lu, W. Guo, L. Zhang, B. Han, Sci. China
Chem. 2017, 60, 927-933.
[73] L. Yu, Q. Zhang, S.-S. Li, J. Huang, Y.-M. Liu, H.-Y. He, Y. Cao,
ChemSusChem 2015, 8, 3029-3035.
[74] F. F. Fleming, Nat. Prod. Rep. 1999, 16, 597-606.
[75] a) A. Martin, B. Lucke, Catal. Today 2000, 57, 61-70; b) M. Movassaghi,
M. D. Hill, Nat. Protoc. 2007, 2, 2018-2023; c) A. Martin, V. N. Kalevaru,
ChemCatChem 2010, 2, 1504-1522; d) F. F. Fleming, L. Yao, P. C.
Ravikumar, L. Funk, B. C. Shook, J. Med. Chem. 2010, 53, 7902-7917;
e) P. Anbarasan, T. Schareina, M. Beller, Chem. Soc. Rev. 2011, 40,
5049-5067.
[76] a) T. Ikawa, Y. Fujita, T. Mizusaki, S. Betsuin, H. Takamatsu, T.
Maegawa, Y. Monguchi, H. Sajiki, Org. Biomol. Chem. 2012, 10, 293-
304; b) Z. Shao, S. Fu, M. Wei, S. Zhou, Q. Liu, Angew. Chem. Int. Ed.
2016, 55, 14653-14657.
[77] a) P. Zerecero-Silva, I. Jiménez-Solar, M. G. Crestani, A. Arévalo, R.
Barrios-Francisco, J. J. García, App. Catal. A: Gen. 2009, 363, 230-
234; b) D. Srimani, M. Feller, Y. Ben-David, D. Milstein, Chem.
Commun. 2012, 48, 11853-11855; c) S. Chakraborty, H. Berke, ACS
Catal. 2014, 4, 2191-2194; d) J.-H. Choi, M. H. G. Prechtl,
 MINIREVIEW
Entry for the Table of Contents (Please choose one layout)

MINIREVIEW
Jose R. Cabrero-Antonino,* Rosa Adam
and Matthias Beller*

Page No. – Page No.

Catalytic Reductive N-Alkylations

using CO2 and Carboxylic Acid
Derivatives: Recent Progress and
Text for Table of Contents
Developments

Oxidized alkyl partners in reductive N-alkylations: CO2 and carboxylic/carbonic acid

derivatives can be employed as safe and readily available N-alkylating agents through
reductive methodologies. A wide range of N-alkylamines and heterocycles have been
directly obtained using these protocols. An overview of these processes, intensively
developed in the last five years, is summarized in this minireview.