Air-Assisted 2-Oxo-Driven Dehydrogenative α,α-Diamination of 2-Oxo Aldehydes to 2-Oxo Acetamidines

Article abstract of DOI:10.1002/ejoc.201600587

An air-assisted, functional-group-driven, mild, additive-free, three-component synthetic approach to different 2-oxo acetamidines from 2-oxo aldehydes, secondary amines, and anilines was successfully developed. Mechanistically, the transformation proceeds through a highly unstable system (RCOCHN¹N²) that rearranges at room temperature and undergoes air-assisted dehydrogenation to different 2-oxo acetamidines.

Full text of DOI:10.1002/ejoc.201600587

DOI: 10.1002/ejoc.201600587
Communication
Amination
Air-Assisted 2-Oxo-Driven Dehydrogenative α,α-Diamination of
2-Oxo Aldehydes to 2-Oxo Acetamidines
Atul Kumar,[a,b] Narsaiah Battini,[a,b] Raju Ranjith Kumar,[c] S. Athimoolam,[d] and
Qazi Naveed Ahmed*[a,b]
Abstract: An air-assisted, functional-group-driven, mild, addi- formation proceeds through
a highly unstable system
tive-free, three-component synthetic approach to different 2- (RCOCHN1N2) that rearranges at room temperature and under-
oxo acetamidines from 2-oxo aldehydes, secondary amines, and goes air-assisted dehydrogenation to different 2-oxo acet-
anilines was successfully developed. Mechanistically, the trans- amidines.
Introduction
ited substrate scope. For example, in comparison to Jiao's
method,[4b] the methods of Fokin[4c] and Lee[4d] are extensions
of Chang's[5] method. The Sukbok group reported an unprece-
dented copper-catalyzed reaction that resulted in the synthesis
of amidines upon treating azides with phenylacetylenes in the
presence of secondary amines. This result contrasts significantly
with click chemistry.[6] In contrast, we also described a change
in reactivity of 2-oxo aldehydes towards secondary amines in
the presence of anilines. Even though the reactions of 2-oxo
aldehydes (OAs) with amines are known to achieve the synthe-
sis of α-ketoamides by using metal and metal-free approaches
though 2-oxo iminium[7a] and imine[7e] intermediates, there are
A pivotal aim in organic synthesis is advancements in building
new valuable structures/C–X bonds.[1] In particular, α-amination
on systems containing an adjacent carbonyl group is an inter-
esting field owing to the innate ability of such groups to serve
as versatile synthetic handles to approach a diverse spectrum
of complex structures.[2] Given that amidines are well-known
structural motifs that are present in numerous bioactive natural
products, pharmacophores, and synthetic intermediates, in ad-
dition to the fact that they can also act as efficient coordinating
ligands,[3] the synthesis of 2-oxo acetamidines, in particular, by
employing a mild method is desirable. Owing to unfortunate
timing, the Hulme group reported the cesium carbonate pro-
moted three-component reaction of N–H-containing hetero-
cycles/amines, 2-oxo aldehydes, and anilines for the generation
of 2-oxo acetamidines.[4a] The crucial step in that approach was
the generation of the α-imino ketone, followed by air-mediated
oxidation to the α-oxoacetamidine. In a similar way, our
method involves the production of 2-oxo acetamidines through
initial formation of 2-oxo iminium ions followed by amination
to α,α-diaminated products. Traditional methods for the synthe-
sis of 2-oxo acetamidines, in general, rely on metal-catalyzed
coupling reactions.[4] These methods involve metal salts, require
expensive substrates, need more than one step, and have lim-
[a] Medicinal Chemistry Division, Indian Institute of Integrative Medicine (IIIM),
180001, Canal Road, Jammu, Jammu & Kashmir, India
E-mail: naqazi@iiim.ac.in
http://www.iiim.res.in/People/CV/cv_naveed.php
[b] Academy of Scientific and Innovative Research (AcSIR), Indian Institute of
Integrative Medicine (IIIM),
180001, Canal Road, Jammu, Jammu & Kashmir, India
[c] Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University,
625021, Madurai, India
[d] Department of Physics, University College of Engineering Nagercoil, Anna
University of Technology,
629004, Tirunelveli, Nagercoil, India
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600587.
Scheme 1. Summary of work (DCE = 1,2-dichloroethane).
1 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
no reports on additive-free, dehydrogenative α,α-diamination (0.895 mmol), 2a (0.746 mmol), and 3a (0.746 mmol) was stirred
reactions of 2-oxo aldehydes to 2-oxo acetamidines through 2- for 12 h in toluene at room temperature (Table 1, entry 6).
oxo iminium ions (Scheme 1).
Having observed that our reaction gave the best results if
In the past few years, we have focused on the application of the mixture was stirred at room temperature, we primarily in-
2-oxo-driven unconventional reactions towards the generation vestigated the substrate scope of the reaction with respect to
of different exigent structures.[7] Recently, we learned that the 2-oxo aldehydes 1 (Table 2). We were gratified to observe that
reaction of in situ generated 2-oxo iminium ions with different in all reactions tested desired products 4 were produced in
nitrogenous systems resulted in a highly unstable system good yields (83–91 %). Even though the electronic environment
(RCOCHN1N2) that ultimately rearranged in a novel fashion to of the phenyl ring in substrate 1 had no significant effect on
various valuable structures.[7b,7c] Herein, we demonstrate that
2-oxo iminum ions can also react with anilines at room temper-
ature and can undergo dehydrogenative α,α-diamination in the
Table 2. Scope of the reaction with respect to various 2-oxo aldehydes.[a]
presence of air to different 2-oxo acetamidines. The result of
this reaction is the stereoselective generation of novel 2-oxo
amidines by avoiding the use of any external catalyst/oxidant
or additive. This reaction is a good example of the functional-
group-directed synthesis of valuable structures by circumvent-
ing the use of additives/reagents.
Results and Discussion
In our preliminary study, we endeavored to interpret the nature
of the reaction between 2-(2,4-dimethylphenyl)-2-oxoacetalde-
hyde (1a, 0.746 mmol) and morpholine (3a, 0.746 mmol) in the
presence of aniline (2a, 0.746 mmol)) in toluene at 100 °C
(Table 1, entry 1). To our delight, we monitored a different prod-
uct by thin-layer chromatography (TLC). Upon conducting the
same reaction at 80 °C, the yield of product 4a increased up to
10 % yield (Table 1, entry 2). Further, to improve the yield of
4a, we probed the reaction in terms of changes in temperature,
concentration, and time (Table 1, entries 3–8). We initiated our
studies by varying the reaction temperature (Table 1, entries 2–
5). To our surprise, the yield of product 4a increased tremen-
dously to 85 % within 12 h upon conducting the reaction at
room temperature (Table 1, entry 5). Further, screening of the
reaction at various concentrations of the reactants revealed that
[a] Conditions: 2-oxo aldehyde 1 (0.895 mmol), aniline (2a, 0.746 mmol), and
morpholine (3a, 0.746 mmol) in toluene. [b] Yields of isolated products are
the best yield of product 4a was observed if a mixture of 1a
given.
Table 1. Optimization of the reaction conditions.[a]
Entry
1a
[mmol]
2a
[mmol]
3a
[mol-%]
Temperature
[°C]
Time
[h]
Yield[b] [%]
4a
5a
1
2
3
4
5
6
7
8
0.746
0.746
0.746
0.746
0.746
0.895
0.746
0.746
0.746
0.746
0.746
0.746
0.746
0.746
0.895
0.746
0.746
0.746
0.746
0.746
0.746
0.746
0.746
0.895
100
80
60
45
r.t.
r.t.
r.t.
r.t.
24
24
24
12
12
12
12
12
5
95
80
65
10
4
–
–
5
10
30
68
85
91
86
87
[a] Reaction conditions: 2-oxo aldehyde 1a (0.895 mmol), aniline (2a, 0.746 mmol), and morpholine (3a, 0.746 mmol) in toluene. [b] Yield of isolated product.
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Communication
the yields, the OAs bearing electron-donating groups, for exam-
ple, Me (see products 4a, 4b, and 4d) and OMe (see product
4e), afforded slightly higher yields than those with electron-
withdrawing groups, for example, F (see product 4f), Cl (see
product 4g) Br (see product 4h), and CF3 (see products 4i and
4j). Along with these results, a good yield was also observed
(see product 4k) for the reaction with a strong electron-with-
drawing 2-oxo aldehyde. In continuation, different trial reac-
tions were executed between phenylglyoxal 1c, anilines 2, and
secondary amines 3 under the optimized conditions (Table 3).
In general, we observed that irrespective of the nature of the
substitution pattern, all the tested reactions allowed efficient
transformation into products 4 (see products 4c and 4l–u). Fi-
nally, we verified the general substrate scope of the reaction by
varying OAs 1, anilines 2, and secondary amines 3 (see products
4v–ab, Table 4). These reactions were very compatible to all
sorts of secondary amines 3, anilines 2, and 2-oxo aldehydes 1.
Table 4. General substrate scope of the reaction.
Table 3. Scope of the reaction with respect to 2 and 3.[a]
[a] Conditions: 2-oxo aldehyde 1 (0.895 mmol), aniline 2 (0.746 mmol), and
secondary amine 3 (0.746 mmol) in toluene. [b] Yields of isolated products
are given.
[a] Conditions: Phenylglyoxal 1a (0.895 mmol), aniline 2 (0.746 mmol), and
secondary amine 3 (0.746 mmol) in toluene. [b] Yields of isolated products
are given.
The structures of all 2-oxo acetamidines 4 were revealed with
the help of HRMS, 1H NMR and 13C NMR spectroscopy, and
DEPT analysis. The structures of compounds 4a and 4o were
further confirmed by variable-temperature NMR spectroscopy
and single-crystal X-ray diffraction studies (Figure 1; for details,
see the Supporting Information, pages S23–S25 and S3–S9), re-
spectively.
In addition, to gain insight into the reaction mechanism and
to prove the significance of the different groups/reagents, we
performed a few control experiments (Figure 2, a). As evidenced
from experiment 1, the presence of the 2-oxo group in the OA
was compulsory for self-promotion of the reaction through ini-
tial formation of the 2-oxo iminium ion. Also, reaction between
1c, 2a, and 3a in toluene on heating at 100 °C gave exclusively
Figure 1. ORTEP diagrams of 4a and 4o.
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Communication
α-ketoamide 5a (experiment 2). This clearly indicated that aero- secondary amine 3 to form the 2-oxo iminium ion (intermediate
bic oxidation of the 2-oxo iminium to the α-ketoamide is facili- A). Intermediate A at room temperature reacts with aniline 2
tated by an increase in the temperature and thus can be and generates the expected reactive system RCOCHN1N2 (inter-
avoided at room temperature. However, upon conducting the mediate B), which possibly generates intermediate D through
same reaction under dry conditions under an argon atmos- reaction of tautomeric state C with atmospheric oxygen. Finally,
phere, the 2-oxo acetamidine was not produced, which empha- intermediate D rearranges to required acetamidine 4 through
sized the need for air to assist in the reaction (experiment 3). loss of hydrogen peroxide.
Furthermore, failure of methylglyoxal to react with aniline (2a)
and morpholine (3a) certainly indicated the crucial role of arene
conjugation in facilitating attack of the aniline on the iminium
carbon atom (experiment 4). In addition, isolation of 4c in a
comparable yield under the optimized conditions in the pres-
ence of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) ruled out
the possibility of a free-radical mechanism (experiment 5). The
same was confirmed by different-time electron paramagnetic
resonance (EPR) spectroscopy studies (for details, see the Sup-
porting Information, pages S10–S11). In experiment 6, the ab-
sence of the desired product clearly justifies that the mecha-
nism proceeds through a 2-oximinium pathway. Finally, the
structural overlay diagrams of 4a and 4o show the same orien-
tation of the substituents (Figure 2, b), which thereby validates
the reaction results in the synthesis of the E isomers, as re-
ported previously for the synthesis of acetamidines.[8]
Figure 3. Plausible mechanism.
Conclusions
In conclusion, we developed an efficient, additive-free, mild, air-
assisted, 2-oxo-driven protocol for the generation of 2-oxo acet-
amidines from 2-oxo aldehydes, anilines, and secondary amines.
Mechanistically, the transformation proceeds through initial
generation of a RCOCHN1N2 system, which undergoes air-as-
sisted dehydrogenation to different 2-oxo acetamidines. Further
investigations into the scope and synthetic applications of this
reaction are now in progress.
Experimental Section
General Procedure for the Synthesis of 4a–ab: A reaction vessel
was charged with 2-oxo aldehyde 1 (0.75 mmol), secondary amine
2 (0.75 mmol), arylamine 3 (0.75 mmol), and toluene (2 mL). The
mixture was stirred at room temperature for 12 h. Upon completion
of the reaction, as confirmed by TLC, the solvent was removed un-
der reduced pressure. The crude mixture was purified by column
chromatography (silica gel 100–200#, hexane/EtOAc, 9:1), which af-
forded product 4 in good yield (79–91 %).
Acknowledgments
A. K. and N. B. thank the University Grants Commission (UGC)
Figure 2. (a) Control experiments. (b) Structural overlay diagrams of 4a and
4o.
On the basis of previous experience on activation through a for the awards of JRF and SRF, respectively. The authors also
RCOCHN1N2 system[7b,7c] and the abovementioned results, we thank Dr. Akhila K. Sahoo (Associate Professor, School of Chem-
propose a mechanism for these reactions, as depicted in Fig- istry, University of Hyderabad, Hyderabad, India), Mr. Anil K.
ure 3. The initial step involves reaction of 2-oxo aldehyde 1 with Padala, and the analytical department of IIIM. Finally, financial
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Communication
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IIIM/ 1905/2016.
Keywords: Multicomponent reactions · Rearrangement ·
Amination · Dehydrogenation · Iminium ions
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Received: March 13, 2016
Published Online: ■
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Communication
Amination
A. Kumar, N. Battini, R. R. Kumar,
S. Athimoolam, Q. N. Ahmed* ....... 1–6
Air-Assisted 2-Oxo-Driven Dehydro-
genative α,α-Diamination of 2-Oxo
Aldehydes to 2-Oxo Acetamidines
An air-assisted, 2-oxo-driven, mild, ad- ines from 2-oxo aldehydes, secondary
ditive-free, three-component synthetic amines, and anilines is developed.
approach to different 2-oxo acetamid-
DOI: 10.1002/ejoc.201600587
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim