A Method for the Preparation of β-Amino-α,β-unsaturated Carbonyl Compounds: Study of Solvent Effect and Mechanism

Article abstract of DOI:10.1021/acs.orglett.9b04531

An efficient method for the preparation of β-amino-α,β-unsaturated carbonyl compounds is demonstrated. Bench-stable sodium 3-oxo-enolates were prepared from carbonyl compounds, and reacted with amines in the presence of an acid and a desiccant. DFT studie

Full text of DOI:10.1021/acs.orglett.9b04531

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A Method for the Preparation of β‑Amino-α,β-unsaturated Carbonyl
Compounds: Study of Solvent Effect and Mechanism
Reyno R. S., Akash Sugunan, Ranganayakulu S., Cherumuttathu H. Suresh, and Goreti Rajendar*
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ABSTRACT: An efficient method for the preparation of β-amino-
α,β-unsaturated carbonyl compounds is demonstrated. Bench-
stable sodium 3-oxo-enolates were prepared from carbonyl
compounds, and reacted with amines in the presence of an acid
and a desiccant. DFT studies revealed contrasting mechanisms
toward the reactivity of aliphatic amines in protic solvents and
aromatic amines in aprotic solvents. While the former proceeds
through the formation of an imine, the latter passes through the
Michael addition−elimination mechanism.
Scheme 1. Direct Conversion of Carbonyl Compounds to
Enaminones by One-Carbon Homologation Amination
β-Amino-α,β-unsaturated carbonyl compounds (enaminones)
are powerful synthons in organic chemistry. The presence of
multifunctional groups and heteroatoms in enaminones
facilitate multiple nucleophilic and electrophilic additions at
different positions to produce complex molecular structures.1
Enaminones are well utilized in the preparation of electron-
rich dienes for Diels−Alder reaction2 and in synthesis of
various heterocyclic and carbocyclic compounds.3 β-Amino-
α,β-unsaturated carbonyl functionality is an integral part of
several bioactive natural products.4
Purification of enaminones is a tedious job since they are
mostly unstable on silica gel for chromatographic purification
or require extreme care for fractional distillation. Hence, it is
highly desirable to develop methods that can produce
enaminones obviating the need of purification. Herein, an
improved method with systematic investigation is presented
for the preparation of enaminones. Bench-stable and easily
accessible sodium 3-oxo-enolate derivatives of carbonyl
compounds were used as reactive intermediates, with various
amines in the presence of an acid and a desiccant. The
products obtained after hydrocarbon extraction were found to
be pure.
Scheme 1 shows various methods, which directly use
carbonyl compounds as substrates for the synthesis of
enaminones.2c,5−11 Each of these methods has its own
drawback, either limiting to carbonyl part or limiting to
amine part. For instance, cyclic ketones can be accessed with
only few methods,12 whereas few methods are applicable only
for arylketones.9,10,13 Moreover, other functional enaminones
obtained from esters, amides, lactones, and lactams can be
accessed only by few methods with great limitations. Many
such methods also show limitations toward amine function-
ality; for example, methods ii, iii, and v lead to enaminones
derived only from secondary amines, while method iv
provides enaminones of primary amine derivatives. To the
best of our knowledge, no single report describes the
synthesis of enaminones from all class of carbonyl
compounds using a wide range of amines. Despite, the
well-known application of sodium-3-oxo enolates as reactive
Received: December 20, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04531
© XXXX American Chemical Society
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intermediates in preparation of enaminones,5,7 no systematic
investigations have been carried out to apply this method to
wide range of substrates and no proper mechanistic studies
are reported.7
The present study started by examining a model reaction
between sodium (E)-3-oxobut-1-en-1-olate14 1 with benzyl-
amine in the presence of a Brønsted acid to produce
enaminone 1a (entries 1−11, Scheme 2). Among many acids,
96% yield after chromatographic purification, confirming the
formation of 1a in pure form.17
Similarly, other primary amines upon reaction with enolate
1 produced enaminones 1b−1m in 84−98% isolated yields.
Use of amino acid derivatives such as amino esters, amino
alcohols and amino amide provided chiral enaminones (1k−
1n) in very good to excellent yields. Likewise, the reaction of
salt 1 with secondary amines and cyclic amines provided
products 1o−1u, mainly as E-enaminones. After the
successful conductance of the reaction with different amines
and enolate 1, further we prepared the enolates 2, 3, 4, and 5
from acetophenone, 3-pentanone, 4-phenyl-2-butanone, and
aceto-2-nathone, respectively. Enolate 2, showed very good
reactivity toward all classes of amines to produce enaminones
2a−2e in very good to excellent isolated (84−96%) yields.
Compounds 3, 4, and 5 with benzylamine provided 3a, 4a,
and 5a (85%, 88%, and 92% yields). Similarly, enolates 6 and
7 prepared from cyclopentanone and cyclohexanone upon
reaction with various amines following method A produced
enaminones 6a−6e and 7a and 7b in very good to excellent
yields.18
Scheme 2. Preparation of (E)-4-(Benzylamino)but-3-en-2-
one from Acetone*
In the process of systematic investigation, we prepared
lithium and potassium salts from acetophenone.19 When
compared with sodium salt, lithium salt is more stable, and
less moisture sensitive whereas potassium salt is hygroscopic.
The reaction of lithium and potassium salts with benzylamine
produced product 2a in 46% and 66% respectively with large
amount of unidentified byproducts. It was clear that
counterion Na+ is more appropriate to provide adequate
stability for enolate and to facilitate the reaction under
optimized conditions. Apart from success with two step
procedure, a one-pot method20 was also tried by the in situ
preparation of sodium salt 1 followed by sequential addition
of desiccant, amine, and acid, but it provided lesser
conversion and moderate yields of enaminone 1a (70%).21
Surprisingly, reaction of aniline with compound 1 in
ethanol did not provide the desired enaminone 1aa (Figure
1). The reversal of reactivity of aniline from general trend
may be attributed to the decreased nucleophilicity of anilines.
This was evident from the enhanced reactivity of aniline with
sodium salt 1 in aprotic solvent (dichloromethane) under
same reaction conditions, which produced enaminone 1aa as
an exclusive product (method B, Scheme 3). Our results
indicate that the excellent reactivity of aliphatic amines in
protic solvent (ethanol) is due to the stabilizing hydrogen
bonding influence of the solvent on reaction intermediates
and transition states whereas for aromatic amines a
preference of aprotic solvent suggests a totally different
mechanistic pathway for the formation of enaminones.
Following method B, other anilines with electron-donating
groups yielded Z-selective enaminones18 1ab−1ae in 96−98%
yields. The more challenging electron-deficient anilines such
as 2-bromoaniline, 4-cyanoaniline, and 4-nitroaniline6b,22,23
provided enaminones 1af, 1ag, and 1ah23 in excellent yields
(97%, 87%, 98%) under mild reaction conditions. Similarly,
N-methylanilines upon reaction with enone 1 provided
enaminones 1ai and 1aj in excellent yields with E-selectivity.
The sodium salts of acetophenone, cyclopentanone and
cyclohexanone derivatives also exerted same reactivity with
aniline to provide enaminones 2aa, 2ab, 6aa, and 7aa.
After successful results with ketones, other carbonyl
compounds such as esters, lactones, and amides (Figure 2)
were converted to their corresponding enaminones using
*
Reaction conditions: amine (2 mmol), salt (2.5 mmol), solvent (10
a
mL/mmol), and acid (3 mmol), 0 °C to rt, 14 h. Yields after
Kugelrohr distillation; Method A: reaction conducted with 1 equiv of
amine, 1.2 equiv of sodium salt 1, 1.5 equiv of acid, and MgSO4 (1 g/
mmol) in anhydrous ethanol. No change in yields before and after
b
c
Kugelrohr distillation.
TFA and PTSA provided better results for enaminone 1a
with 100% conversion of amine. It was also observed that the
results for the same reaction were inconsistent from batch to
batch. The liberated water molecule during condensation,
preventing the reaction either by quenching the acid or by
diverting the reaction for unwanted byproducts.15 After
screening several dehydrating agents MgSO4 was found as
an effective desiccant (entry 19, Scheme 2) to remove water
and to drive the reaction in a clean manner.16 Under the
standard reaction conditions using method A, the product 1a
was produced on multigram scale (10 g, 98% yield) after
hydrocarbon extraction. The purity of the product was
estimated by NMR analysis using an internal standard.
Further, compound 1a was directly treated with Boc
anhydride to obtain N-boc protected enaminone 1aBoc in
B
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Scheme 3. Reaction of Enolates of Various Ketones with
a
Aromatic Amines
a
Method B: reaction conducted with 1 equiv of aniline, 1.2 equiv of
sodium salt 1, 1.5 equiv of acid, and MgSO4 (1 g/mmol) in
dichloromethane (10 mL/mmol).
Figure 2. Enaminones prepared from enolates of esters, lactones,
and amides with various amines.
Addition of TFA to sodium (E)-3-oxobut-1-en-1-olate (1)
gives 4-hydroxybut-3-en-2-one (I). B3LYP/SMD/6-311+G-
(d,p) level DFT calculation25 shows that enol form of I
(Ienol) has the “Z” configuration due to intramolecular OH···
O hydrogen bond (Figure 3) while aldehyde form (Iald) is 2.6
kcal/mol higher in energy in ethanol. The NMR experiments
also proved the Z-configuration of Ienol by observing two
olefinic signals at δ 5.63 and 7.97 as doublets with J = 4.5 Hz
whereas the signals at δ 3.59 and 9.78 indicated the presence
of tautomer Iald; the enol to aldehyde ratio being 10:1 at
room temperature. For the reactions conducted in ethanol
with primary amines, formation of enaminones through the
imine formation is computed using DFT (Scheme 4a). The
enol···benzylamine complex (II) formation is exothermic by
5.3 kcal/mol owing to the intramolecular OH···N hydrogen
bond. The proton transfer from enol to amine is barierless
and gives III at relative energy (Erel) −6.5 kcal/mol. The
quarternized nitrogen in III transfers the proton to olefinic
carbon via ts2 with activation energy (Eact) 11.8 kcal/mol to
yield the tautomeric Iald...benzylamine complex IV which
undergoes nucleophilic addition via ts3 (Eact 3.9 kcal/mol) to
yield the zwitterionic product V and subsequently a proton
transfer in V via ts4 produces the carbinolamine VI. Proton
transfer appears as a rate-determining step with Eact 19.7
Figure 1. Enaminones prepared from enolates of ketones with
various amines.
method A for aliphatic amines and method B for aromatic
amines. Enamino esters (8a, 8b, and 8aa) from ethyl
acetate,24 enamino lactones (9a, 10a, and 10aa) from
butyrolactone and velarolactone, and enamino amides (11a,
12a, 12b, and 12aa) from N,N-dimethylacetamide and N-
phenyl-N-methylacetamide were isolated in excellent yields
(Figure 2). Enolates prepared from lactams such as
compounds 13 and 14 upon reaction with amines did not
provide any enamino derivatives even after prolonged
reaction times and heating conditions. Similarly, the sodium
salts 15 and 16 obtained from 1,3-dicarbonyl componds did
not provide any desired enaminone.
C
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Figure 3. Energy profile for β-enamino carbonyl compound. Transition states in ball and stick model and distances in angstroms.
Figure 4. Energy profile for (a) nucleophilic addition of aniline and (b) elimination of water. Transition states in ball and stick model and
distances in angstroms.
kcal/mol. The trifluoroacetic acid may assist this proton
transfer. Elimination of H2O in VI occurs instantenously by
the protonation of its hydroxy group to provide iminium
intermediate VIIiminium to yield the final product, β-enamino
carbonyl compound VII. The cis arrangement of keto and
amino group in VII is preferred due to the formation of
intramolecular H-bond by Z-configuration. Overall, the
reaction is exothermic by 14.5 kcal/mol. The energy profile
clearly suggests that the key step of C−N bond formation via
ts3 is a very facile process and the active form of reactant is
Iald. It is worth mentioning that C−N bond formation
transition state ts3 is not observed with the aromatic amine.
In the second possible pathway (Scheme 4b), protonated
form of enol, Ienol·H+ is the active species which reacts with
aniline in dichloromethane. DFT calculations show that Ienol·
H+ is characterized by an intramolecular O···H hydrogen
bond. The prereaction complex Ienol·H+···aniline (VIII)
(Figure 4a) undergoes nucleophilic addition of aniline on
the CC double bond of Ienol·H+ via ts5 with Eact 2.4 kcal/mol
to form IX. Deprotonation of IX gives the hemiaminal
compound X (Figure 4b). From X, elimination of water
occurs via ts6 with Eact 13.6 kcal/mol to yield the final
product, β-enamino carbonyl compound XI. Here too, C−N
bond formation is very easy while the rate-determining step is
elimination of water. It is notewothy that a transition state
similar to ts5 for nucleophilic addition is not observed with
an aliphatic amine. The DFT study clearly suggests that in
protic solvent Iald reacts with aliphatic amine whereas in
D
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Scheme 4. Possible Mechanism for the Reaction of Enolate
1 with Aliphatic and Aromatic Amines
AUTHOR INFORMATION
Corresponding Author
■
Goreti Rajendar − School of Chemistry, Indian Institute of
Science Education and Research, Thiruvananthapuram
695551, India; orcid.org/0000-0003-3742-319X;
Email: rajendar@iisertvm.ac.in
Authors
Reyno R. S. − School of Chemistry, Indian Institute of Science
Education and Research, Thiruvananthapuram 695551, India
Akash Sugunan − School of Chemistry, Indian Institute of
Science Education and Research, Thiruvananthapuram
695551, India
Ranganayakulu S. − School of Chemistry, Indian Institute of
Science Education and Research, Thiruvananthapuram
695551, India
Cherumuttathu H. Suresh − Chemicals Sciences and
Technology Division, CSIR-NIIST, Thiruvananthapuram
695564, India; orcid.org/0000-0001-7237-6638
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04531
Notes
aprotic solvent Ienol·H+ reacts with aromatic amine to yield
the final products.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
In summary, we have demonstrated a simple and efficient
method for the conversion of carbonyl compounds to β-
amino-α,β-unsaturated carbonyl compounds using bench-
stable sodium enolates under mild reaction conditions. The
method is very effective when a desiccant is used to trap the
in situ generated water molecule. The method worked well
with carbonyl compounds such as ketones, cyclic ketones,
esters, lactones and amides along with aliphatic amines, cyclic
amines, and anilines. Even very weak nucleophilic amines like
4-nitroaniline and 4-cyanoaniline provided excellent yields.
The influence of electronic effects of amines in different
solvent systems has been studied, and it has been found that
the reaction of aliphatic amines proceeds through the imine
formation while aromatic amines pass through the Michael
addition−elimination mechanism as supported by DFT
mechanistic studies. Clean conversion, easy hydrocarbon
extraction, no extra purification, and multigram-scale
preparation are shown as practical advantages of the method.
■
We acknowledge SERB-India for Ramanujan Research Grant,
File No. SB/S2/RJN-071/2015. R.R.S. thanks UGC-India for
a NET-JRF fellowship. R.S. Thanks SERB-India for an
INSPIRE fellowship. We thank Mr. Alex, IISER Trivandrum,
for X-ray crystallographic analysis.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04531.
Experimental procedures, spectral data of prepared
compounds, and X-ray data of compounds 1ab and
1ah (PDF)
Accession Codes
CCDC 1972196 and 1972363 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_-
request/cif, or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
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(20) See the Supporting Information for one pot method.
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(18) A general trend is observed for formation of Z-selective
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6h) and cyclohexanone (7b) significant amount of E/Z ratio is
observed.
F
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