One-Pot Synthesis of Symmetrical Tertiary and Secondary Amines from Carbonyl Compounds, Ammonium Carbonate and Carbon Monoxide as a Reductant

Article abstract of DOI:10.1002/ejoc.201901175

Rh-catalyzed one-step synthesis of tertiary and secondary amines from aldehydes and ketones, ammonium carbonate serving as nitrogen source, and carbon monoxide as a reducing agent has been developed. Aliphatic and aromatic aldehydes lead to the corresponding tertiary symmetrical amines in 69–83 % yields. Aromatic and aliphatic ketones lead to the corresponding secondary symmetrical amines which were obtained in 62–79 % yields.

Full text of DOI:10.1002/ejoc.201901175

DOI: 10.1002/ejoc.201901175
Communication
Amine Synthesis
One-Pot Synthesis of Symmetrical Tertiary and Secondary
Amines from Carbonyl Compounds, Ammonium Carbonate and
Carbon Monoxide as a Reductant
Karim Muratov,[a] Oleg I. Afanasyev,[a] Ekaterina Kuchuk,[a] Sofiya Runikhina,[a] and
Denis Chusov*[a,b]
Abstract: Rh-catalyzed one-step synthesis of tertiary and sec- dehydes lead to the corresponding tertiary symmetrical amines
ondary amines from aldehydes and ketones, ammonium carb- in 69–83 % yields. Aromatic and aliphatic ketones lead to the
onate serving as nitrogen source, and carbon monoxide as a corresponding secondary symmetrical amines which were ob-
reducing agent has been developed. Aliphatic and aromatic al- tained in 62–79 % yields.
Introduction
actions with ammonia may be inconvenient due to the difficul-
ties with transportation, storage and requirements for special
equipment. On the other hand, ammonium salts may be a good
alternative to ammonia in this reaction due to their operational
easiness. Standard protocols for the synthesis of tertiary amines
from aldehydes and ammonium salts often require the use of
borohydride reductants[16] or excess of other reducing agents
to effectively conduct the reaction.[14k] In our previous research
we have shown that carbon monoxide can be potentially one
of the most selective and atom-economical alternatives to the
classical reductants in this process.[17]
We have also recently reported a novel method for the syn-
thesis of symmetrical tertiary amines from aldehydes without
an external hydrogen source.[18] The amine source in this reac-
tion is acetamide. Herein we report a more convenient protocol
for conducting this reaction (Scheme 1). The obvious improve-
ments are the use of cheaper and easier to handle reagents,
the substantial lowering of the catalyst loading in a number
of cases and the extension of substrate scope from aromatic
aldehydes to aromatic and aliphatic aldehydes and even aro-
matic and aliphatic ketones.
Amines are a widespread class of organic compounds. This
structural motif can be found in many biologically active com-
pounds, such as alkaloids, pharmaceuticals and agrochemi-
cals.[1–5] Amines are also used as ligands, extractants, building
blocks for nitrogen-containing organic compounds and syn-
thetic polymers.[6–9] In particular, they can be successfully util-
ized in optoelectronics due to their ability to function as a hole
transport materials.[10,11] Some symmetrical tertiary and sec-
ondary amines are of industrial importance. For example, di-
benzylamine is used in rubber vulcanization process,[12] dicyclo-
hexylamine is useful in manufacture of corrosion inhibitors,[13]
whereas diisopropylamine is mostly used for agrochemicals and
rubber accelerators such as DIBS (N,N-diisopropyl-2-benzothiaz-
ylsulfenamide).[13] Numerous methods have been developed for
the synthesis of amines in the past few decades.[14] They gener-
ally fall into several groups: amination of halogen deriva-
tives,[14a–14d,14p,14t,14u] hydrogen borrowing methodolo-
gy,[14e–14h,14m–14o] hydroaminoalkylation[14i,14j,14q,14r,14s,14v,14w,14x,14y]
of alkenes and reductive amination/alkylation.[14k] The use of
the latter in the synthesis of tertiary amines is very attractive
due to the easy availability of the starting materials and cata-
lysts. Moreover, according to recent research, reductive amin-
ation reaction is increasingly used in the pharmaceutical indus-
try.[15]
Results and Discussion
We started our investigation with catalysts and solvents screen-
ing in the model reaction between 4-mehylbenzaldehyde and
ammonium carbonate (Table 1). Initially, a number of rhodium
and ruthenium metal complexes were screened, among them
IndRhI2,[19] rhodium(II) acetate and rhodium(III) chloride
showed the most promising catalytic activity (Table 1, entries
3, 6–7). It was found that reaction proceeded smoothly in water
in case of IndRhI2 and RhCl3 (Table 1, entries 6–7). After a num-
ber of experiments rhodium(III) chloride was chosen for further
optimization because of its lower price. We found that the best
reaction medium was MeOH/H2O mixture (Table 1, entry 10).
Decreasing the pressure from 50 to 40 atm slightly decreases
It is possible to synthesize symmetrical tertiary/secondary
amines from aldehydes or ketones and ammonia. However, re-
[a] Nesmeyanov Institute of Organoelement Compounds of Russian Academy
of Sciences
Vavilova St. 28, Moscow, 119991, Russian Federation
E-mail: denis.chusov@gmail.com
https://www.ChemistryFor.Me
[b] G.V. Plekhanov Russian University of Economics,
36 Stremyanny Per., Moscow 117997, Russia
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901175.
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Communication
ucts (1j–1l). On the contrary, the majority of ortho-substituted
aldehydes showed poor results. This observation is in good cor-
relation with the increase of the steric hindrance of substituents
(Scheme 3).
Scheme 1. Synthesis of symmetrical secondary and tertiary amines from carb-
onyl compounds and CO.
the yield (Table 1, entry 11). However, further decreasing to
20 atm drops the yield significantly (Table 1, entry 12). Advanta-
geously, when the catalyst loading was lowered to 0.2 mol-%
the yield maintained at appreciable level of 80 % (Table 1, entry
13).
Table 1. Selected optimization studies.
Entry
Catalyst[a]
Solvent
Yield
1[b]
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
RuCl3
IndRhI2
RhCl3
Rh2(OAc)4
Rh2(OAc)4
RhCl3
MeOH
50 %
61 %
69 %
43 %
14 %
80 %
78 %
58 %
79 %
87 %
78 %
58 %
80 %
67 %
2[b]
MeOH/H2O(10 %)
MeOH/H2O(20 %)
EtOH
MeOH
H2O
3[b]
4[b]
5[b]
6[b]
7[b]
H2O
H2O
8[b]
9[b]
MeOH/H2O(60 %)
MeOH/H2O(60 %)
MeOH/H2O(60 %)
MeOH/H2O(60 %)
MeOH/H2O(60 %)
MeOH/H2O(60 %)
10[c]
11[c,d]
12[c,e]
13[c,f]
14[c,g]
RhCl3
RhCl3
RhCl3
RhCl3
Scheme 2. Scope of tertiary amines. 0.5 equiv. of. (NH4)2CO3 (1 eq [NH3]) and
3 equiv. of. aldehyde were used [a] isolated as hydrochloride.
[a] In case of Rh2(OAc)4 1 mol-% per metal was used. [b] 0.66 mmol of alde-
hyde, 0.22 mmol of ammonium carbonate. [c] 1.32 mmol of aldehyde,
0.22 mmol of ammonium carbonate. [d] 40 atm CO. [e] 20 atm CO. [f] 0.2 mol-
% of catalyst were used. [g] 0.1 mol-% of catalyst were used.
Interestingly, the strategy can be adapted to ketones as well.
In this reaction, ketones give secondary amines as the products,
probably, due to the steric factors (Scheme 4). No significant
amounts of corresponding tertiary amines were found. In order
to get a better yield, an increased reaction time (44 h) and
lower temperature were required (120 °C). It was found that
aliphatic ketones generally work better than aromatic ones
(1 mol-% of the catalyst vs. 2 mol-%). Even such sterically hin-
dered ketone as 2-adamantanone can be transformed to the
corresponding secondary amine with moderate yield (2c, 62 %).
To our delight, compounds 2a and 2b were obtained with
With the optimal conditions in hand, we next investigated
the substrate scope of this reaction (Scheme 2). High yields
were observed for substrates with various substitution patterns
(1a–1l). The transformation of aromatic aldehydes with methyl
(1a, 1b), methoxy (1c), heptyloxy (1d), chloride (1h, 1i) groups
successfully proceeded with high yields. The protocol proved
to be acceptable for such condensed aromatic structure as 2-
naphthaldehyde giving the corresponding tertiary amine 1g in
79 % yield. It was found that aliphatic aldehydes (cyclohexyl- 12:1 and 9:1 diastereoselectivity correspondingly. The minor
carbaldehyde, pivaldehyde, isobutyraldehyde) can also be in- diastereomer is meso form. This assignment was made on the
volved in this reaction with good yields of the resulting prod- basis of the previous work.[20]
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The plausible mechanism for the catalytic transformation is
depicted in the Scheme 5.
Conclusions
In summary, we developed a method for the one-step prepara-
tion of symmetrical tertiary and secondary amines by direct
reductive amination using ammonium carbonate as a nitrogen
source and carbon monoxide as a reducing agent. A variety of
aliphatic and aromatic aldehydes and aromatic and aliphatic
ketones were applied. The limitations such as increased steric
hindrance in aromatic aldehydes in ortho-position were demon-
strated.
Scheme 3. Scope of ortho-substituted tertiary amines in the reaction.
0.5 equiv. of. (NH4)2CO3 (1 eq [NH3]) and 3 equiv. of. aldehyde were used.
Experimental Section
General Procedure for the Tertiary Amine Synthesis: A glass vial
in a 10 mL stainless steel autoclave was charged with the catalyst
(0.2–2 mol-%), ammonium carbonate, the corresponding solvent,
an aldehyde or ketone. The autoclave was sealed, flushed with CO
(3 × 10 atm), and then charged with the indicated pressure of CO.
The reactor was placed into a preheated oil bath. After the indicated
time, the reactor was cooled to room temperature and depressur-
ized. The reaction mixture was transferred to a flask, and the auto-
clave was washed with dichloromethane (2 × 1 mL). The reaction
mixture and the dichloromethane rinsing were combined and then
concentrated on a rotary evaporator. The residue was purified by
chromatography on silica gel.
Acknowledgments
The work was financially supported by the Russian Science
Foundation (grant # 16-13-10393). The NMR studies were per-
formed with the financial support from Ministry of Science and
Higher Education of the Russian Federation using the equip-
ment of Center for Molecular Composition Studies of INEOS
RAS.
Scheme 4. Scope of secondary amines. 0.5 equiv. of. (NH4)2CO3 (1 eq [NH3])
and 2 equiv. of. ketone were used [a] 50 h; [b] 160 °C; [c] 1 equiv. of. (NH4)2CO3
(2 eq [NH3]) and 1 equiv. of ketone were used isolated as hydrochloride.
[d]
Keywords: Aldehydes · Ketones · Tertiary amines ·
Secondary amines · Carbon monoxide
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Received: August 8, 2019
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