Metal free biomimetic deaminative direct C-C coupling of unprotected primary amines with active methylene compounds

Article abstract of DOI:10.1039/c9ob02163a

An unprecedented direct C-C coupling reaction of unprotected primary amines with active methylene compounds is reported. The reaction involves a biomimetic deamination of amines which was achieved under conditions free of metallic reagents and strong oxidizing agents. A wide range of primary amines was reacted with different active methylene compounds to provide structurally diverse trisubstituted alkenes and dihydropyridines. A kinetic study revealed an activation barrier of 10.1 kcal mol^-1 for the conversion of a key intermediate of the reaction.

Full text of DOI:10.1039/c9ob02163a

Organic &
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Metal free biomimetic deaminative direct C–C
coupling of unprotected primary amines with
active methylene compounds†
Cite this: Org. Biomol. Chem., 2019,
17, 10153
Received 7th October 2019,
Accepted 19th November 2019
Santanu Ghosh and Chandan K. Jana
*
DOI: 10.1039/c9ob02163a
rsc.li/obc
An unprecedented direct C–C coupling reaction of unprotected aldehyde (eqn (2)).2–5 In some cases, the imine formed was
primary amines with active methylene compounds is reported. The subsequently reacted with heteronucleophiles to produce the
reaction involves a biomimetic deamination of amines which was corresponding imidazole, oxazole, thiazole or quinoxaline.6
achieved under conditions free of metallic reagents and strong oxi- However, the reaction of the imine generated in situ via dehy-
dizing agents. A wide range of primary amines was reacted with drogenation of an amine with the carbon-based nucleophile
different active methylene compounds to provide structurally like an active methylene compound is uncommon.7 Moreover,
diverse trisubstituted alkenes and dihydropyridines. A kinetic study to the best of our knowledge, no report on the direct coupling
revealed an activation barrier of 10.1 kcal mol−1 for the conversion of unprotected primary amines with active methylene com-
of a key intermediate of the reaction.
pounds producing alkenes and dihydropyridines is known in
the literature. This is probably because the active methylene
compounds are susceptible towards oxidation/decomposition
under strong oxidizing conditions.8 Moreover, propensity
towards the over-oxidation of amines to nitriles and high
nucleophilicity of free primary amines put further challenges
for the success of C–C coupling of free primary amines and
active methylene compounds. Therefore, the development of a
method that can operate under mild conditions without the
aid of strong oxidants and metallic reagents would allow the
Monoamine oxidase (MAO) oxidizes a variety of primary and
secondary amines, polyamines, and amino acids in the bio-
logical system. Flavin adenine dinucleotide (FAD) acts as the
coenzyme for these deamination reactions. In the first step, an
amine is dehydrogenated to form an imine while FAD is
reduced to FADH2. The imine is hydrolyzed subsequently
to produce the corresponding carbonyl compounds (Scheme 1,
eqn (1)).1
A large number of methods have been developed for the
transformation of amines to imines (eqn (2)). The reported
methods for the conversion of amines to the corresponding
imines employed stoichiometric/catalytic amounts of oxidants2
(e.g. IBX, DDQ, iminoquinone, etc.) and metallic reagents or cat-
alysts3 (e.g. Ru, Pt, Rh, Au, etc.) in the presence or absence of
oxidants. Molecular oxygen or air was also used as the oxidant
for the amine to imine oxidation in the presence of metallic
reagents.4 Aerobic photooxidation of primary benzylamines
using catalytic amounts of hindered acridinium salts, BiVO4 or
Ru-based complex was also reported.5 These methods are
efficient, but often require harsh reaction conditions, strong oxi-
dants, metallic reagents, and other additives.
In most of the aforementioned methods, the amine func-
tionality was converted to the corresponding imine, nitrile or
Department of Chemistry, Indian Institute of Technology Guwahati, 780139, India.
E-mail: ckjana@iitg.ac.in
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02163a
Scheme 1 Dehydrogenation of amines and subsequent coupling
reactions.
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Table 2 Scope for the olefin syntheses
subsequent one-pot reaction of imines with suitable nucleo-
phile like active methylene compounds.
Along the line of our interest for the development of metal-
and hazardous oxidant-free organic transformations,9 we have
developed a biomimetic deaminative coupling of primary
amines with active methylene compounds using a simple
imine derivative as the FAD mimic under conditions free of
strong oxidizing agents and metallic reagents (eqn (3)).
Entry
Ar/R′
R
Alkene
Yield (%)
1
2
3
4
5
6
7
8
4-Me-Ph
4-MeO-Ph
4-Cl-Ph
4-CF3O-Ph
4-F-Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Bn
Bn
Et
Et
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
67
64
69
68
68
60
65
70
65
64
62
63
64
72
60
51
Our investigation started with a reaction of benzylamine
(1), 9-fluorenone imine (2) and diethyl malonate in refluxing
toluene under an argon atmosphere. The desired alkene 3a
was isolated with 35% yield after 12 h of reaction (Table 1).
The yield of the product increased to 68% when the reaction
was carried out for a longer time (48 h). However, the same
reaction performed at room temperature did not provide the
desired product. Different reaction conditions, such as sol-
vents, temperatures, reactant stoichiometry, reaction time, etc.,
were evaluated to increase the yield of the alkene. Solvents
with low boiling points provided lower yields as compared to
toluene and xylene. The addition of inorganic/organic bases
with either catalytic or stoichiometric amounts did not
improve the yield of the product. Interestingly, the use of
9-fluorenone, replacing 9-fluorenone imine, did not yield the
desired alkene under the same conditions. However, reaction
in the presence of 9-fluorenone-1-carboxylic acid provided the
desired product with 25% yield.
2-F-Ph
2-Cl-Ph
2-MeO-Ph
3,4-Cl-Ph
3-MeO-Ph
Ph
2-MeO-Ph
Ph
2-MeO-Ph
2-Furyl
nBu
9
10
11
12
13
14
15
16
(e.g., OR, NR2, F, Cl) in the aromatic ring of arylmethyl amines
were tolerated under these reaction conditions. Substrates
having both electron-donating (e.g., Me, OMe) and electron-
withdrawing (e.g., F, Cl) groups were efficiently reacted to
produce the desired products. Heteroarylmethyl amines also
participated in the reaction to produce the desired compound
3p with good yield under the optimized reaction conditions.
Alkyl amines also successfully participated in the reaction to
provide the desired alkene 3q. In addition to the symmetrically
substituted malonates, unsymmetrical malonates such as ethyl
acetoacetate (4a) reacted smoothly to produce the desired pro-
ducts 3r (1.3 : 1) and 3s (1.5 : 1) as the mixture of E/Z-isomers
(eqn (4)). Interestingly, the reaction with malonic acid (4b)
afforded cinnamic acid derivatives 3t–u with good yields
(eqn (5)). Additionally, the reaction was found to be effective in
gram-scale synthesis, which indicated its potential for practical
application (see Scheme s1†).
The scope of the metal-free deaminative coupling of amines
was tested next. Different aryl and heteroaryl amines reacted
smoothly to produce the corresponding trisubstituted alkenes
3b–r with good yields (Table 2). Various functional groups
Table 1 Optimization of biomimetic deaminative direct coupling reac-
tion of benzyl aminea
Entry
Conditions
Yieldb (%)
ð4Þ
ð5Þ
1
Toluene, reflux, 12 h
Toluene, reflux, 48 h
Toluene, reflux, 48 h
Toluene, reflux, 60 h
Toluene, rt, 12 h
Xylene, reflux, 48 h
DCE, reflux, 48 h
MeOH, reflux, 48 h
DMF, reflux, 48 h
Benzene, reflux, 48 h
DCM, reflux, 48 h
Toluene, reflux, 48 h, Et3N (1 eq.)
Toluene, reflux, 48 h, DBU (1 eq.)
Toluene, reflux, 48 h, KOH (1 eq.)
DMF, reflux, 48 h, K2CO3 (1 eq.)
Toluene, reflux, 48 h, NaH (1 eq.)
THF, reflux, 48 h
35
70
70
69
0
68
40
20
55
50
15
69
65
30
64
40
50
2
3c
4
5
6
7
8
The classical method for the preparation of 1,4-dihydropyri-
dines involves the pseudo four component condensation reac-
tion of an aldehyde, acetoacetic ester, and ammonia or
amines.10 The Knoevenagel condensation product of acetoace-
tic ester and aldehyde acts as the key intermediate in the reac-
tion. As this novel deaminative coupling reaction produces the
related alkene, the scope of this method for the synthesis of
1,4-dihydropyridines was investigated next (Table s1†). The
coupling reaction in the presence of 9-fluorenone imine
releases one equivalent of ammonia. Therefore, on employing
9
10
11
12
13
14
15
16
17
a 1 eq. (0.56 mmol) of benzyl amine, 1 eq. of 9-fluorenone imine
(0.56 mmol) and 1 eq. of diethyl malonate were (0.56 mmol) reacted.
b Isolated yield. c 1.2 eq. of 9-fluorenone imine was used.
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our deaminative coupling reaction, the dihydropyridines can
be synthesized without using an additional ammonia source.
As expected, the reaction of benzylamine, ethyl acetoacetate (5,
R′ = Et), and 9-fluorenone imine (2) in the absence of an
additional ammonia source provided the desired dihydropyri-
dine 6a with a maximum yield of 51% (Table s1,† entry 7).
Various reaction conditions were screened to increase the yield
of dihydropyridines. However, the addition of ammonium
acetate as the additional ammonia source increased the yield
of the desired product (68%). Large varieties of benzylamines
containing both electron-withdrawing and electron-donating
groups in the aryl moiety reacted efficiently to provide the
desired 1,4-dihydropyridines 6a–6u with good yields
(Scheme 2). Other than ethyl acetoacetate, methyl and benzyl
acetoacetate also reacted smoothly to produce the corres-
ponding dihydropyridines 6o–6q. The reaction with dimedone
provided the expected tricyclic dihydropyridines 6t–6u.
ð6Þ
After the success of direct coupling of the amine with a
carbon-based nucleophile, the possibility of the reaction with
hetero-dinucleophiles was investigated. Accordingly, benzimi-
dazole derivatives 9a–c were formed, when 2-amino aniline 8
was reacted with an amine and 2 under the same reaction con-
ditions (eqn (6)).
Additional reactions were conducted to understand the
possible reaction pathway (Scheme 3a). The reaction in the
absence of 9-fluorenone imine (eqn (7)) did not provide the
desired coupling product. In addition, a pre-formed imine pro-
vided the desired products 3a and 6a from separate reactions
under standard conditions (eqn (8) and (9)). These results indi-
cate that the 9-fluorenone imine is essential for the reaction
and the reaction proceeded via imine intermediate 10.
Interestingly,
simple
1,3-cyclohexadienone
gave
the
N-benzylated dihydropyridines 6r–6s with good yields.
On the basis of experimental evidence, a plausible mecha-
nism for the metal-free deaminative direct coupling of a
primary amine with active methylene compounds is proposed
in Scheme 3b. The condensation of amine 1 and 9-flurenone
imine (2) occurred to provide the corresponding ketimine 11.
The isomerization of 11 furnished the regioisomeric aldimine
12 (identified by NMR, see Fig. s1†) which on subsequent reac-
tion with active methylene compound 13 provided the corres-
ponding alkene 14. The related addition reaction of the active
methylene compound to an imine/iminium ion is well known
in primary/secondary amine-catalyzed Knoevenagel reac-
tions.11 However, in this reaction, the addition of the active
In addition to the benzylamines, alkyl amines with varying
chain lengths participated in the reaction to produce the
corresponding dihydropyridines 7a–7e with good yields.
Interestingly, a simple methyl amine acted as the substitute of
formaldehyde to afford the desired dihydropyridine 6l,
however, with poor yield.
Scheme 3 (a) Controlled experiments. (b) Proposed mechanism of C–
C coupling of amines and active methylene compounds. (c) Mechanism
of Knoevenagel reactions. Fl-NH2 = 9-aminofluorene.
Scheme 2 Scope for the synthesis of dihydropyridines. a Reaction was
carried out in the absence of NH4OAc (see Table s1†).
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methylene compound occurs to the amine carbon in contrast dihydropyridines starting from primary amines would bring
to Knoevenagel reactions where addition occurs to carbonyl the diversity in synthetic planning.
carbon (Scheme 3c). In the reaction with acetoacetate, the
corresponding alkene reacted further with ammonia, which
was either generated during the condensation of 1 and 2 or Conflicts of interest
from NH4OAc, and another equivalent of acetoacetate to
There are no conflicts to declare.
provide the dihydropyridines following the standard pathway.
Acknowledgements
We acknowledge Science and Engineering Research Board
(SERB), New Delhi for funding.
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