Chapter-1: Part A

Introduction on Enamines.

Chapter – 1: Part A

Introduction on Enamines

1.A.1 History and Literature survey

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 Chapter-1: Part A

Introduction on Enamines.

The term enamine was introduced by, ‘Wittig and Blumenthal’, in 1927
which is structurally related to enols [1]. In 1950, ‘Stork’ demonstrated that
stiochiometric enamines can act as enolates equivalent to undergo reactions
with a range of electrophiles [2]. Stork and co-worker pioneered synthetic route
for the enamine alkylation and acylation of carbonyl compounds in 1954 [3].
In recent times (2011), Javier Vicario and co worker derived a distereoselective
aza-Diels -Alder reaction of α-amino acids with enamines [4].
Today the chemistry of enamine synthesis is very useful in organic chemistry.
The functionalized enamine containing moieties enaminone, enaminonitrile,
enamide, ketene aminal, nitroenamine, azaenamine are known as versatile
reactive intermediates for the synthesis alkaloids, peptides, amino acids,
aminols, natural products and several nitrogen containing heterocyclic
scaffolds such as dihydropyridine, pyazole, pyrrole ,pyrimidine, piperidine,
pyridine, indole which are well known as anti-tumor, anti-inflammatory,
anticonvulsant and antibacterial activity [5-9].
Recently, glycosyl enamines have been used as intermediates for the synthesis
of C-nucleosides and glycosyl pyrazoles. Enamines employed as a nucleophile
in Micheal type reaction, precursors of chiral amine in asymmetric
transformation and also used to form volatile chelate metal complexes with
PdCl2 in amine medium to form palladium β-ketoiminate [7-12].

1.A.2 Definition and Structure

Enamines are the α, β-unsaturated amines (1) which contain an amino group in
α -position and consequently in conjugation with, an olefinic carbon-carbon
double bond. The enamines (1) are structurally related to enol (3) and one of
the substituent at the nitrogen is hydrogen. The enamines (1) show tautomeric
proton exchange to the corresponding imine (2) [13].

The enamine-imine tautomerism may be considered analogous to the keto-enol

tautomerism. In both cases, a hydrogen atom switches its location between the
heteroatom (oxygen or nitrogen) and the second carbon atom.

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Introduction on Enamines.

β α ..
H .. H
N N OH O

enamine imine enol keto

(1) (2) (3) (4)

The enamine (1) contains two nucleophillic centres at nitrogen and β-

carbon while the electrophillic character is exhibited by the carbon [Fig.1.A.1].

Nucleophile Nucleophile
Electrophile

Fig. 1.A.1. Nucleophillic and electrophillic centre of enamine.

The lone pair on nitrogen atom can overlap with the ‘π’- electrons of the double
bond, the enamines are capable existing two mesomeric forms (5 and 6).
The electrophillic attack may occur either at the nitrogen atom of enamine to
give an enamonium cation (7) or at the carbon of the enamine to give an
iminium cation (8) [14].

+
N - N

(5) (6)
R(+)

R
+ R +
N N

(7) (8)

Stork et.al, reported that the alkylation of the pyrolidine enamine of

cyclohexanone with methyl iodide followed by acid hydrolysis leads to
formation of the monoalkylated ketone [Scheme 1.A.1] [3].

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 Chapter-1: Part A

Introduction on Enamines.

+
N N H+ N
+ CH3I

Scheme 1.A.1. Enamines of 2- substituted cyclic ketone.

1.A.3 Classification
1. Substitution at nitrogen [14]

The classification of enamines depends on the extent of substitution on

nitrogen.
a. Primary enamines
Primary enamines (9) contain two hydrogens as substituents on nitrogen. They
tautomerise easily to imine and the resulting imines show cis-trans (syn-anti or,
E, Z) isomerisation around the C=N bond as represented by (10) and (11).
1 1
1 R R
R 2H 2H H
R .. R
R
2
..
NH2
N + 3
N
..
3
3 R H R
R
cis (Z) trans (E)

(9) (10) (11)

Vinyl amine (R1, R2, R3=H) is the simplest primary enamine.

b. Secondary enamines
Secondary enamines (12) have one hydrogen and one alkyl or aryl substituent
on nitrogen.
2
R 1
3
R .. R
N
4
R H

(12)

R1=alkyl or aryl.

c. Tertiary enamines

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Introduction on Enamines.

Tertiary enamines (13) containing two alkyl or two aryl or one alkyl and one
aryl substituent or an alicyclic, heterocyclic, ring substituent’s including
nitrogen as shown in (13)b to (13)d.
1 2
(a) R =R =CH3
3
R 1
4 1 2
R .. R (b) -NR R = N
N
5 2
R R 1 2
(c) - NR R = N

(13) 1 2
(d) -NR R = N O

2. Substitution at the ene part [14]

The double bond of the enamine may be a part of acyclic, endocyclic,

exocyclic, bicyclic or heterocyclic system.
a. Acyclic enamines
The enamine having C=C double bond may be acyclic and are referred as
acyclic enamine. The tertiary enamine, where R3=H are referred as acyclic
enamine (14).
3
R 1
4
R .. R
N
5 2
R R

(14)

R3=H

b. Endocyclic enamine
Enamine containing the C=C double bond as part of a ring and the nitrogen
atom with its substituent as exocyclic part is known endocyclic enamine (15).

N
1 2
R R
(15)

c. Exocyclic enamine

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 Chapter-1: Part A

Introduction on Enamines.

The cyclic amine where nitrogen is a part of cycle with exocyclic C=C double
bond is referred as exocyclic enamine (16).

N CH2
R
(16)

d. Heterocyclic enamines
Enamines which contain the nitrogen and C=C double bond (-C=C-N-) as part
of one ring are called as heterocyclic enamines. Pyrroline (17), pyrrole (18),
indole (19), dihydropyridine (20) and tetrahydropyridine (21) are some
examples of heterocyclic enamine.

N N N N
R H N
H H H
Pyrroline Pyrrole Indole dihydropyridine tetrahydropyridine
(17) (18) (19) (21)
(20)

e. Bicyclic enamine
The enamine containing bicyclic system is called as bicyclic enamine.
e.g. 2-dehydroquinaclidines (22).
R

N
(22)

1.A.4. Nomenclature (diamino derivatives)

Enamines are termed with respect to the parent compound generally as amino
substituted amine i.e. tertiary enamine as (N,N-dialkylamino) alkene. The
correct IUPAC nomenclature is dialkylalkenylamines where the basic
compound is amine and not the alkene.
e.g. (23) is in common notation is 1-N-methylanilino-2-methyl-propene and in
IUPAC notation called as N-methyl-N-(2-methyl-1-propenyl) aniline.

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 Chapter-1: Part A

Introduction on Enamines.

Me Me
N
Me
H

(23)
The functional group at β-position in enamine lead to priority in notation.
e.g.
Me CN Me COOEt

H2N H H2N H
(24) (25)
The β-enaminonitrile (24) is called β-amino crotonic acid nitrile and β -
enaminoketoester (25) is called ethyl β-amino crotonoate.

1.A.5. Basicity and Acidity

Primary enamine and secondary enamine are less basic than corresponding
saturated amine. On the other side, many enamines with tertiary nitrogen atom
(26) show more basic character in aqueous solution. This has been pointed to
resulting quaternary hydroxide (27) which is a stronger base than the saturated
analogues [13].
H
+ -
N + H2O N
+ OH

(26) (27)

Stamhuis and co-worker have determined the basic strengths of pyrrolidine,

piperidine and morpholine enamine of isobutyraldehyde in aqueous solution by
kinetic, potentiometric and spectroscopic method at 25°C. The results observed
showed that these enamines are 200 times weaker than the secondary amine
from which they are formed, and are 30-200 times less basic than the
corresponding saturated tertiary enamines. The base weakening effect has been
attributed to the electron withdrawing inductive effect of the double bond [15].
Smith and Radom [16] investigated acidity of vinyl amine (primary enamine)
by using 6-31+G*/6-31+ G*calculation and the correlation energy at the MP4/6-
311+ G* level, introducing zero level energy. They discuss the acidity of vinyl

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 Chapter-1: Part A

Introduction on Enamines.

amine in terms of a bond separation energy scheme on the basis of isodesmic

process involving neutral forms (Eq. 1).

H3C NH2 (∆E=12 kcal mol )

-1
H2C CH NH2 + CH4 H2C CH2 + - (1)

This involves a stabilizing interaction between the amino and ethylene group.
On the other hand, the isodesmic process involving the anionic forms (Eq. 2).

- -
H2C CH NH + CH4 H2C CH2 + H3C NH (∆E= 41 kcal mol-1) - (2)

indicates that the interaction between the ethylene moiety and NH- group in
vinyl amine anion is 3.4 times higher than that of amino group in neutral form.
As a result of higher stability of the anionic form, vinyl amine is 23 kcalmol-1
more acidic than methyl amine.

H
H N H
(∆H0acid = 376 kcal mol-1)
H H

(28)

H H H
H N (∆H0acid = 399 kcal mol-1)
H H H

(29)

On comparing vinyl amine (28) and its homologue ethylamine (29), it is seen
that the former is 23 kcalmol-1 more acidic than latter. Although the acidic
protons of vinyl amine logically be those of its amino group, whose acidity
increases by a charge transfer to the ethylene group. It would obviously help to
have quantitative information on the acidity of α and β protons. The acidity of
α and β protons of ethylene can increase in presence of electron withdrawing
substituent at the ethylene residue.

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 Chapter-1: Part A

Introduction on Enamines.

e.g. acrylonitrile (30) (∆H°acid =371 kcalmol-1) is intrinsically 5 kcalmol-1 more

acidic than vinyl amine.
365.6
H
H N H

NC H 355.2

(30)

1.A.6. Reactivity
The reactivity of an enamine depends on the amine group and on the degree of
substitution at the α- and β-positions. Alkyl substituents at C-α increase the
electron density and reactivity at C-α, by hyperconjugative and inductive
effects, if steric interactions do not impair the nitrogen lone pair interaction .
On the contrary, the reactivity at C-β will decrease by the steric and electronic
effects of β-substituent. Thus methyl ketone enamines (31) are often complex
to prepare due to their high reactivity and tendency to dimerise, and cyclic or
acyclic ketone enamines (32) are more readily C- alkylated than aldehyde
enamines (33 or 34)[Fig. 1.A.2] [17].

1
R R R R R
.. .. .. .. 1
N N N N R

(31) (32) (33) (34)

Fig. 1.A.2. Reactivity of enamine.

1.A.7. Synthesis of enamines
1. Enamines from aldehyde and ketone
a. By Stork procedure
Stork reported synthesis of enamine from secondary amine (pyrrolidine) and
cyclic ketone (cyclohexanone) in slightly acidic medium [Scheme 1.A.2] [18].

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Introduction on Enamines.

O
H3O+ N

N
+
-H2O
H
0
2 amine Ketone Enamine

Scheme 1.A.2. Synthesis of pyrrolidine enamine.

b. The Mannich - Davidson procedure
Mannich -Davidson derived the synthesis of enamine from aldehyde.
According to this method the aldehydes and secondary amine react in cold
condition in presence of potassium carbonate to form enamine [Scheme 1.A.3]
[19].
RCH2CHO

+ OH
+
H RCH2 N RCH2 N RCH2 N
N

Scheme 1.A.3. Synthesis of enamine from aldehyde.

c. The Herr and Heyl procedure
In 1952 Herr and Heyl, reported a synthesis of enamine by using steroidal
aldehyde and secondary amine [Scheme 1.A.4] [20].

R
R 1
+
H /H2O R
R
1
CHO + HC
N
N
H

Scheme 1.A.4. Synthesis of enamine from steroidal aldehyde.

d.TiCl4 method
White and Weingarten reported a new enamine synthesis in 1967. In this
method the conversion of carbonyl compound in to enamine by using titanium
tetrachloride as a catalyst. This method is also useful for the synthesis of highly
hindered enamines [Scheme 1.A.5] [21].

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Introduction on Enamines.

2
2 R
O R TiCl4 3
R N R
2
R R
+ 1
6 HN
R
3
1
+
2 3
4R R NH2Cl + TiO 2
R

Scheme 1.A.5. Enamine synthesis by TiCl4 catalyst.

2. Enamine from imines
The imine of carbonyl compound and primary amine is converted in to tertiary
enamine by direct N-alkylation to tertiary iminium salt which can be converted
in to the corresponding enamine using appropriate base [Scheme 1.A.6] [14].
MeI + Base Ph Me
Ph N Ph Ph N - Ph N
Me I
Ph

Scheme 1.A.6. Enamine synthesis from imine.

3. Enamines by Horner - Wittig reaction
The Horner - Wittig reaction availed ketone and aldehyde for the synthesis of
enamines where the reaction of lithio aminophosponates with ketones furnishes
the respective enamine [Scheme 1.A.7] [22].
Li
O O Li 1
O R
NH4Cl H
1
R
2 + P N Ph P N O K-H
R Ph
Ph O
2 N
Ph R
1
HO R O
2
R

Scheme 1.A.7. Enamine synthesis from ketone and aminophosphonates.

4. Enamines by reduction method
Birch and Lehmann reported a synthesis of heterocyclic enamine by reduction
method. They introduced the reduction of quinoline using lithium in liquid
ammonia to produces 1,4-dihydroquinoline [Scheme 1.A.8] [23].
Li, liq.NH3

N N
H

Scheme 1.A.8. Enamine synthesis by Li, liq. NH3.

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Volkov and coworker reported catalytic hydrosilylation, to reduced tertiary

amides to their corresponding enamines using a transition metal free catalytic
protocol based on t-BuOK and (MeO)3SiH [Scheme 1.A.9] [24].
O 1
3 R
R Catalytic Hydrosilylation
N 2
1 2 5 mol% KOtBu N R
R R
3
R

Scheme 1.A.9. Enamine synthesis by catalytic reduction silylation.

5. Enamines by mercuric acetate oxidation method
Leonard and coworker have reported the mercuric acetate oxidation of tertiary
cyclic amine to synthesis of heterocyclic enamine. The dehydrogenation of
amine with 5% mercuric acetate in acetic acid at reflux condition. After 1.5 hrs,
the mercuric acetate precipitated and the desired enamine was observed in 60%
yield [Scheme 1.A.10] [25].
Hg(CH3COO)2
N CH3COOH N

Scheme 1.A.10. Enamine synthesis by catalytic reduction silylation.

6. Enamines by multicomponent reaction
Recently, the Yu and co-worker evaluated a heterocyclic enamine synthesis via
multicomponent reaction of ethylacetoacetate, formaldehyde and aniline in
acidic condition to form tetrahydropyridine. The reaction proceeds through
enamine intermediate of ethyl acetoacetate and aniline leading to the formation
of heterocyclic enamine [Scheme 1.A.11] [26].
O O
NH2 OEt
1
O O O O R
L-Proline (20mol%)
R
1
O + + THF, 16oC R
1
N O
H H
R
R

Scheme 1.A.11. Enamine synthesis via multicomponent reaction.

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7. Enamines by coupling reaction

Lu and co worker described a copper catalyzed intramolecular C-N coupling
between sulfonamides and vinyl halides leading to an efficient synthesis of 5,6
and 7 -membered heterocyclic enamines in both exo and endo modes [Scheme
1.A.12] [27].
Ts
Br
NHTs N
Cu(I)
n n
n=1,2,3

Scheme 1.A.12. Enamine synthesis via coupling reaction.

Recently, Ji and coworker reported an oxidative coupling of primary amines
and alkenes using Pd catalyst under molecular oxygen. Under mild condition, it
forms a (Z) - enamines compounds [Scheme 1.A.13] [28].

1 2 [Pd], O2
R 1
R
NH
H
+ H -H2O
R
NH
2
R

Scheme 1.A.13. Enamine synthesis by Pd catalyst.

8. Enamines by organometallic reagent
Fujiwara and Yamamoto depicted a reaction of allylindium reagents with nitrile
having electron withdrawing group at α-position affording a resultant
allylation-enamination product [Scheme 1.A.14] [29].

R THF R
In2I 3
EWG
N + 3
EWG NH2

EWG=CO 2R', CN, COR'

R=H, Ph

Scheme 1.A.14. Enamine synthesis by organometallic reagent.

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9. Enamines by condensation reaction

Martins and coworkers, reported the synthesis enamine under solvent free
condition by condensation reaction methyl ketone and dimethyl formamide
dimethyl acetal using ionic liquid [Bmim][BF4] as a catalyst [Scheme 1.A.15]
[30].
O H3CO [Bmim][BF4] O

R + H3CO
N
solvent free R N

Scheme 1.A.15. Enamine synthesis by ionic liquid.

10. Enamines by dehydrogenation method
A new route for enamine synthesis by dehydrogenation of tertiary amine with,
“pincer-ligated” iridium catalyst was developed by Zhang [Scheme 1.A.16]
[31].
2
PR H
2-
1 2 Ir H 1 2
R R t
2 R R t
N Bu PR N Bu
+ +
R R

Scheme 1.A.16. Enamine synthesis by iridium catalyst.

1.A.8. Synthetic application of enamines in organic chemistry
1. Alkylation
a. Alkylation with halo compounds
Alkylation of enamines with alkyl halide and further hydrolysis to give a 2-
alkyl ketone. According to resonance structure of enamine, they undergo
electrophilic attack on β- carbon [Scheme 1.A.17] [32].

+ - O
N N I
+ CH3
CH3I CH3 H3O

Enamine 2-alkyl Ketone

Scheme 1.A.17. Alkylation of pyrolidine enamine.

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Introduction on Enamines.

b. Alkylation with unsaturated electrophile

Alkylation of enamines with unsaturated electrophile contains α, β- unsaturated
nitrile, ketone, esters etc. followed by hydrolysis to form monoalkylated
ketone. In this reaction, the α, β- unsaturated acceptor process is similar to the
Michael reaction. This reaction can be applied to nearly any ketone or
aldehydes containing at least one α-methylene [Scheme 1.A.18].

N + O
CRH=CHX N - ~H+ N H3O+
CRHCHX CRHCH2X
CRHCH2X
H

Enamine

Scheme 1.A.18. Alkylation of enamine with unsaturated electrophile.

This reaction has been applied to acrylic (R=H) and crotonic (R=CH3) esters
(X-COOCH3), acrylo and acrylonitrile (X=CN).
For synthesis of A-ring steroids the enamine alkylation reaction has been
applied. In the synthesis of 13β - propylnorestradiol the enamine of the
cyclopentanaphthalene was alkylated with 1, 3-dichloro-2-butene.The observed
chloride was hydrolyzed, treated with base and then successively
dehydrogenated [Scheme 1.A.19].
1 1
2 Cl
1 R R OR R OR
R OR Cl
HN
3
R
2
+ Cl 2
R R +
N N
O 3 3
R R

1
1 1 R OR
R OR R OR
O
H3O+ Base

HO
O O

Scheme 1.A.19. Synthesis of steroids through enamine alkylation.

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2. Acylation
Enamines of cyclohexanone react with acyl chloride and further hydrolysis to
form an acylated product of 1, 3 -diketone. This acylated enamines have been
used for synthesis of carboxylic acid by treatment of 1, 3 -diketone with strong
base (KOH) to open the ring and subsequent Wolff-Kishner reduction to give
the resultant acid [Scheme 1.A.20].
O
+ O
N N H3O+ COPh -
PhCOCl KOH COOH Wolff Kishner Ph COOH
COPh Ph 5 6
Et3N H3O+ reduction
Carboxylic acid
1,3-diketone
Enamine
Scheme 1.A.20. Acylation of pyrrolidine enamine.

Acylation of enaminonitrile with acetyl chloride under reflux condition to

afford acetamide [Scheme 1.A.21] [33].
Ar Ar
CN CN
∆ O
N + CH3COCl N
N O NH2 N O N
Ar Ar
H
Enaminonitrile Acetamide

Scheme 1.A.21. Synthesis of acetamide from enaminonitrile.

3. Arylation
2,4-Dichloronitrobenzene react spontaneously with pyrrolidine enamine of
cyclohexanone to give an excellent yield of 2-[2,4-dinitrophenyl]-
cyclohexanone on hydrolysis of imonium salt. In case benzyne type of
intermediate gives poor yield of the product [Scheme 1.A.22] [34].
Cl
N NO 2 + NO 2 NO 2
Et3N N H3O+ O
+
NO 2 NO 2 NO 2

Scheme 1.A.22. Arylation of enamine.

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4. Coupling
Narasaka and co-worker reported an efficient oxidative cross-coupling reaction
of enamines and enols in presence of ceric ammonium nitrate to obtain a stable
enamine [Scheme 1.A.23] [35].
1
R 1
N CAN R O
+ R
2
K2CO3 N 2
3 R
R SiO
COOMe COOMe

Scheme 1.A.23. Cross coupling reaction of enamine.

Liu and coworker reported a metal free C-O cross coupling between enamine
and carboxylic acid to form β-acyloxyl derivatives of enamines using
iodosobenzene as an oxidant and then that β - acyloxy converted to oxazoles
via cyclodehydration [Scheme 1.A.24] [36].
NH2 E NH2 E
R2COOH -H2O 2
O
E 1 O R
R PhIO,DCE, RT 1
O R N 1
2 R
R
1 2
E=CN,COOMe R =Me,Ph R = aryl,alkyl

Scheme 1.A.24. Metal free C-O cross coupling reaction of enamine.

Sasada and coworker developed a single step synthesis of biologically active

pyrimidine derivatives using enamines, triethyl orthoformate and ammonium
acetate by ZnCl2 as a catalyst [Scheme 1.A.25] [37].
1
NH2 ZnCl2 R
N
2 R
1
+ CH(OEt)3 + NH4OAc
PhMe, 100oC
R 2
R N

Scheme 1.A.25. Pyrimidine synthesis from enamine.

5. Cycloaddition
1,2-Cycloaddition reaction of enamines of aliphatic ketone with methyl
acrylate below 30°C formation of cyclobutane derivatives. Simple alkylation of
enamine by olefins depends on α, β - hydrogen of enamines [Scheme 1.A.26]
[38].

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N N
+ CH2=CH-COOCH3 COOCH3

Scheme 1.A.26. Cycloaddition of piperidine enamine and ketone.

Synthesis of substituted aromatic amines in good yield by 3+3 oxidative

cycloaddition reaction of enamines and enones [Scheme 1.A.27] [39].
1
1 R
R O NH
HN
2 4 TFA, Cu(OAc)2 COOCH3
COOCH3 + R
3
R
Toluene, reflux
R 2 4
R R
3
R

Scheme 1.A.27. [3+3] Cycloaddition of enamine and enone.

Synthesis of pyrido [1,2-a] indoles or indolo [1,2-a] hexahydro-1,8-

naphthapyridine with regio and sterioselective control by 4+2 cycloaddition
reaction betweens 2-vinyl indoles acting as hetero-dienes and β-acceptor
substituted cyclic and acyclic enamines via anodic oxidation or photoelectron
transfer using catalyst triarylpyrylium tetrafluoroborates as sensitizers [Scheme
1.A.28] [41].
H3COOC
COOCH3

N CN
+
N N CN
H
H

Scheme 1.A.28. [3+3] Cycloaddition of enamine and enone.

6. Hydroboration
Hydroboration of aldehyde enamines by (9-borabicyclo [3.3.l] nonane 9-BBN),
followed by methanolysis affords the corresponding alkenes with good yields.
The synthesis of pure Z or E alkenes is readily achieved from acyclic ketone
enamines by modifying hydroboration elimination process [Scheme 1.A.29]
[41].

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Introduction on Enamines.

2
R
3
H N R 1
1.9-BBN R
R
1
H 2.CH3OH R + N B
2
R

Scheme 1.A.29. Hydroboration of aldehyde enamine.

7. Halogenation
The halogenations of enamines is dependent on the experimental conditions
engaged such as the temperature, solvent, amine moiety, order of mixing
reagent and molar proportions.
Carlson studied bromination of unsymmetrical enamine at -78°C enamines
quickly converted in to α - bromoiminium salt which on hydrolysis gives α -
bromoketones. In presence of a base (Me3N), dehydrobromination occurs to
give bromoenamines. After further bromination and hydrolysis gives α, α’-
dibromoketones [Scheme 1.A.30] [14].
2 + 2 - 2 + 2 -
NR N R Br NR N R Br
Br2, CH2Cl2 Me3N Br2 Br
o o
-78 C -20 C
Br Br Br

-H2O -H2O

O
O
Br

Br
Br

Scheme 1.A.30. Hydroboration of aldehyde enamine.

8. Photochemical reaction
The reaction of enehydroxyamine with electrophile in the presence of a base to
yield the intermediate which on heating leads to the formation of α - substituted
product in good yield via a 3, 3 - sigmatropic rearrangement [Scheme 1.A.31]
[42].

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Introduction on Enamines.

O
O O
O Ph OCOPh
PhCOCl ∆
R OH o
N i-Pr2NEt, THF, 0 C R O Toluene R
R N NH
R R

Scheme 1.A.31. Photochemical synthesis of α-substituted product.

1.A.9. Enamine as a synthon and reactive intermediate in heterocycles

synthesis
a. Enaminone synthon
Enaminone are the enamines containing ketones used as a synthon in
organic synthesis for the preparation of various heterocycles like
dihydropyridine, pyrazole and pyrimidine derivatives. An abundant synthetic
utility of the enaminones has been reported by researcher in the recent past
[Fig.1.A.3]. The enaminone composed with α, β - unsaturated enone moiety
and enamine subunit. Hence, this molecule simultaneously behaves as an
electrophile and nucleophile.
Longhi K et. al, synthesis of pyarazole (36) derivatives with good yield under
grinding condition from various enaminone (35) and hydrazine sulphate at RT
[43]. The enaminone (35) treated with aldehydes and urea under reflux
condition using acid catalyst to form pyrimidine (37) [44].
Recently, Muthusaravanan S et. al, a pseudo five component Domino reaction
of enaminone (35), formaldehyde and aniline using 1:2:4 molar proportions to
synthesis of hexahydropyrimidine (38) under catalyst free condition. This
transformation involved 4 C-N and 1 C-C bond formation in one pot operation
presumably proceeds via Michael addition-elimination-Mannich type reaction
condensative annulations - reduction sequence [45].
Also, the reaction of enaminones (35), anilines and aldehydes in acetic acid at
reflux temperature afforded the dihydropyridine derivatives (39) [46].
Further, the synthesis of 2, 3, 6-trisubstituted pyridines (40) scaffolds through a
regioselective one pot three component condensation of enaminones (35), 1, 3 -
dicarbonyl compounds and ammonium acetate in the presence of catalytic

19
 Chapter-1: Part A

Introduction on Enamines.

amount of K5CoW12O40.3H2O under solvent free conditions reported by

Kantevari S [47].
O

R
O

DMF-DMA
N
N O N
R R H
Pyridine NH NH2
4O
O O H2N
(40) Ac Pyrazole
N
R (36)

C6H5NH2 Enaminone
NH2CONH 2
Ar-CHO (35)
O Ar O Ar-CHO
C6H5NH2
R HCHO O Ar
R
N NH
R
O N O
H
N Pyrimidine
dihyropyridine R
(39) N (37)

Hexahydropyrimidine
(38)

Fig. 1.A.3. Synthetic utility of enaminone (35).

b. Heterocycles synthesis via enaminone intermediate
In organic synthesis, many heterocycles have been synthesized through
multicomponent reaction with generation of in situ enaminone intermediate.
The enaminone intermediate is reactive species which occurs after Michael
type addition in MCR and forms a different heterocyclic derivative without
isolation of enaminone intermediate.
Maiti S et. al, described a multicomponent coupling synthesis of highly
functionalized pyrrole catalyzed by Fe(III) salts using 1,3-dicarbonyl
compounds, amines, aromatic aldehyde and nitroalkane. The reaction
demonstrated in situ generation of enaminone intermediate from 1,3

20
 Chapter-1: Part A

Introduction on Enamines.

dicarbonyl compound and amine, which on further Michael addition of

intermediate of aldehyde and nitroalkane affords pyrrole [Scheme 1.A.32] [48].
O O O
1 3 1
R NH2 + R - CHO + R
2
R
3 FeCl3
R R

+ reflux
R
2
N H
H3C NO2
R

Scheme 1.A.32. Synthesis of pyrrole.

Sun J. et. al, reported a diversity oriented synthesis of polysubstituted 2-

hydroxyhydropyridine through multicomponent reaction of acetylene
dicarboxylate, amines and aldehydes. The reaction proceeds in aqueous ethanol
via enaminonone intermediate of acetylene dicarboxylate and amine [Scheme
1.A.33] [49].
COOR Ar
ROOC COOR
ArCHO + Ar'NH2 + aq.EtOH
OH
COOR ROOC N COOR
Ar'

Scheme 1.A.33. Synthesis of hydroxypyridine.

Zare A. et. al, described a multicomponent synthesis of hexhydroquinoline

derivatives catalyzed by Brønsted acidic ionic liquid from dimedone, aldehyde,
ethyl acetoacetate and ammonium acetate at solvent free condition. The
reaction proceeds via enaminone intermediate of ethyl acetoacetate and
ammonium acetate followed by Michael addition [Scheme 1.A.34] [50].
O O Ar O
O O
[DsIm][HSO4]
+ Ar-CHO + OR + NH4OAc OR
solvent free, 50oC
O N
H

Scheme 1.A.34. Synthesis of polyhydroquinoline.

Alinezhad H. et. al, described a catalyst multicomponent free synthesis of

trisubstituted pyrazole from ethyl acetoacetate, dimethyl formamide dimethyl
acetal and phenyl hydrazine. The reaction was carried out at room temperature

21
 Chapter-1: Part A

Introduction on Enamines.

using trifluoroethanol as solvent and the formation of pyrazole through

enaminone intermediate of ethyl acetoacetate and dimethyl formamide
dimethyl acetal [Scheme 1.A.35] [51].
O
O O O
H3CO
RT
O + N + Ph-NH-NH2 N
H3CO N
Ph

Scheme 1.A.35. Synthesis of pyrazole.

An aqueous one pot synthesis of pyrimidine and isoxazole derivatives under

microwave condition at 200°C using active methylene ketone, dimethyl
formamide dimethyl acetal and amidines or hydroxyl amine reported by
Molteni V. The enaminoketone formed ‘in situ’ and further it reacts with
amidine or hydroxyl amine to give pyrimidine and isoxazole respectively
[Scheme 1.A.36] [52].
O O
H3CO NH
MW N
+ N + R NH2 H2O
H3CO
n n N R
O
Pyrimidine

O O
H3CO
MW
+ N + NH2-OH
H2O
N
H3CO O
n n
O
Isoxazole
n=1 1,3-cyclohexanedione
n=2 1,3-cycloheptanedione

Scheme 1.A.36. Synthesis of pyrimidine and isoxazole.

1.A.10. Heterocyclic enamine synthesis via multicomponent reaction

Heterocyclic enamines are powerful and versatile intermediates in the synthesis
of natural products and fused heterocyclic compounds. Today, the synthesis of
heterocyclic enamines derivatives pyrroline, pyrrole, dihydropyridine,
tetrahydropyridine, dihydroisoquinoline, piperidine etc. are reported through
multicomponent reaction.

22
 Chapter-1: Part A

Introduction on Enamines.

Ding Q et. al, have explained a multicomponent reaction of 2-

alkynylbenzaldehyde, amines and ketones using silver triflate and proline
catalysis to form a heterocyclic enamine 1,2-dihydroisoquinoline [Scheme
1.A.37] [53].
O
4
O R 3
CHO R
2 3 AgOTf, Proline 2
+ R -NH2 + R
4 EtOH, 50-60oC N
R

1
R 1
R R

Scheme 1.A.37. Synthesis of 1,2-dihydroisoquinoline.

Liu L et. al, reported a three component one pot synthesis of aryl amines, β, γ -
unsaturated α - ketoesters and cyclic 1,3 - dicarbonyl compounds under reflux
condition using Sc(OTf)3 catalyst and DCM solvent to form a heterocyclic
enamine fused bicyclic tetrahydropyridines [Scheme 1.A.38] [54].
1
O O MeOOC R
O
Sc(OTf)3 [10 mol %]
1 OMe
R COOMe + R-NH2 + DCM, reflux
N COOMe
R
Scheme 1.A.38. Synthesis of tetrahydropyridine.

Liu W. et. al, have described a multicomponent synthesis of polysubstituted

pyrroles directly from alkynates and amines in dioxane at 100°C using AgBF4
catalyst and PIDA oxidant. The construction of pyrrole fragment provides a
new way of C-C bonds [Scheme 1.A.39] [55].
2 4 1 3
COR COR R R
AgBF4, PIDA
+ + H2N R
Dioxane, 100oC, 3h 2
COR
4
3 R OC N
1
R R
R

Scheme 1.A.39. Synthesis of pyrrole.

Li Y. et. al, have reported multicomponent synthesis through p-TsOH

promoted fused pyrroles derivatives from cyclic enaminone, dihydroxy ketone
and aryl amines under microwave condition. An efficient N-arylation based

23
 Chapter-1: Part A

Introduction on Enamines.

domino [3+2] heterocyclization promoted by p-TsOH for the synthesis of fused

pyrrole [Scheme 1.A.40] [56].
O O 2
O NH Ar
OH 2 p-TsOH
R
1
+ Ar + H2N Ar
EtOH, MW R
1 Ar
1 NH OH N
R 1 1 1
Ar R Ar

Scheme 1.A.40. Synthesis of fused pyrrole.

Knapp J. et. al, have reported a multicomponent assembly of highly substituted

indole by coupling reaction. The heterocyclic enamine indole formed from aryl
halide, primary amine and cyclic ketone using palladium catalyst [Scheme
1.A.41] [57].
NH2 O
Br [Pd2dba3],Ligand
+ + Base, Solvent N
I 130oC, 48 h

Scheme 1.A.41. Synthesis of indole.

Sun J. et. al, developed a synthesis of polysubstituted dihydropyridine through

one pot four component reaction of aryl aldehydes, active methylene
compounds, aryl amines and acetylene dicarboxylate in ethanol in presence of
triethyl amine as a base promoter [Scheme 1.A.42] [58].
Ar
COOMe
MeOOC R
Et3N
Ar CHO + NC R
+ Ar' NH2 + EtOH
MeOOC N NH2
COOMe
R=CN, COOEt, CONH 2 Ar'

Scheme 1.A.42. Synthesis of polysubstituted dihydropyridine.

Saeed B. et. al, have developed a multicomponent synthesis of 1,8 - dioxo -

decahydroacridine derivatives from aryl aldehydes, dimedone and ammonium
acetate in presence of L-proline at reflux condition in aqueous media. The

24
 Chapter-1: Part A

Introduction on Enamines.

reaction proceed via enaminone intermediate to heterocyclic enamine 1,4 -

dihydropyridine [Scheme 1.A.43] [59].
O Ar O
O
L-Proline
+ Ar CHO + NH4OAc
H2O, reflux
N
O H

Scheme 1.A.43. Synthesis of acridinediones.

A pseudo five component one pot synthesis of densely functionalized

piperidines derivative from 1,3- dicarbonyl compounds, aryl amines and aryl
aldehydes by using bromodimethylsulfonium bromide (BDMS) as a catalyst
under RT condition was described by Khan A. The formation of functionalized
piperidine proceeds through inter and intramolecular Mannich reaction
[Scheme 1.A.44] [60].
2
R
CHO NH O
NH2
O O 3
OR
1 2 Me2S+BrBr-
R + R + R OR
3
RT N 1
1
R R

2
R

Scheme 1.A.44. Synthesis of piperidine.

Tu S. et. al, reported a four component cyclocondensation reaction of

aldehydes, malononitrile, dimedone and ammonium acetate in microwave
irradiation under solvent free condition to form the functionalized
hexahydroquinoline as a heterocyclic enamine [Scheme 1.A.45] [61].
O O R
CN CN
MW
R CHO + + + NH4OAc
CN
N NH2
O H

Scheme 1.A.45. Synthesis of hexahydroquinoline.

25
 Chapter-1: Part A

Introduction on Enamines.

Khaksar S. et. al, have explained a catalyst free multicomponent synthesis of

tetrahydrobenzo [b] pyran by annulations of aldehydes, malononitrile and
dimedone in 2,2,2-trifluoroethanol (TFE) at reflux condition [Scheme 1.A.46]
[62].
O O R
O CN CN
TFE
R H + + reflux
CN O NH2
O

Scheme 1.A.46. Synthesis of benzopyran.

Reddy M. et. al, have developed high yielding, convenient protocol for the
multicomponent synthesis of fused pyanopyrazole from ethyl acetoacetate,
hydrazine hydrate, aryl aldehydes and malononitrile using glycine catalyst at
RT in water [Scheme 1.A.47] [63].

R
CHO
CN O O CN
Glycine
R + + O
+ NH2-NH2.H2O
Water, RT N
CN
N O NH2
H

Scheme 1.A.47. Synthesis of pyranopyrazole.

1.A.11. Multicomponent reactions

Multicomponent reactions are defined as the reactions in which three or more
readily available starting materials are combined in one pot generating product
containing selective extracts of the involved reactants. MCRs have been
developed extensively as tools to achieve highly atom, step and energy-
economic organic syntheses [64,65]. The general concept of MCRs is depicted
in Fig. 1.A.4.
Multicomponent reactions have significant tool for rapid invention of the
molecular diversity and complexity in drug discovery as well as they have
extensive economical and ecological importance in reaction design. MCRs
distinguish in three basic level of diversity (a) combinatorial chemistry
involves the introduction of different appendages to common molecular

26
 Chapter-1: Part A

Introduction on Enamines.

skeleton, resulting in limited overall diversity. (b) Stereochemical diversity

involves the selective generation of as many stereoisomer by changing the
stereochemistry of catalyst. (c) Scaffolds diversity involves the generation of a
collection of compounds with different molecular skeletons [66,67].
The general features of MCRs evaluate constructively with the criteria that
have been set for the ideal synthesis (Fig.1.A.5). In the ideal synthesis, a target
molecule is prepared from easily available starting materials, one pot, simple,
safe, environment friendly, total conversion, bond forming efficiency and
resource efficient operation that proceeds in quantitative yield [68].
Along with numerous familiar multicomponent name reactions the Strecker,
Biginelli, Mannich, Ugi, Hantzsch, Passerini, Gewald and Radziszewski
reactions are important one for the synthesis of heterocycles and chemical
library of drug molecules.

Fig. 1.A.4. Schematic representation Fig. 1.A.5. Ideal chemical synthesis.

of multicomponent reactions.

Strecker reaction
In 1850, Strecker firstly derived multicomponent synthesis α-amino cyanides
from condensation of aldehyde, ammonia and hydrogen cyanide. The α-amino
cyanides further an acid hydrolysis affords desired α-amino acid [Scheme
1.A.48] [69].

27
 Chapter-1: Part A

Introduction on Enamines.

O NH2
NH2 H+
H+ +
NH3 HCN
R R COOH
R CN

Scheme 1.A.48. Synthesis of α-amino acid.

Biginelli reaction
Pietro Biginelli reported a multicomponent synthesis of dihydropyrimidines in
1891 by ethyl acetoacetate, aldehydes and urea using Lewis acid catalyst and
the reaction is now well known by Biginelli reaction [Scheme 1.A.49] [70].

O O O O
Lewis acid
O + H + H2N NH2 EtO NH
OEt N O
H

Scheme 1.A.49. Synthesis of dihydropyrimidines.

Radziszewski reaction
A four component synthesis of imidazole derivatives from 1, 3 - diketone, aryl
aldehyde, primary amine and ammonia described by Radziszewski in 1882
[Scheme 1.A.50] [71].
O
O O N
H
+ + MeNH2 + NH3
N

Scheme 1.A.50. Synthesis of imidazole.

Mannich reaction
A three component condensation reaction of formaldehyde, ketone containing α
- hydrogen atom and primary or secondary amine to form a β - amino carbonyl
compounds also known as Mannich base developed by Carl Mannich in 1912.
This reaction is an example of nucleophilic addition of amine to carbonyl group
followed by dehydration to the Schiff’s base. Then in second step the
electrophillic addition of Schiff’s base with the compound containing acidic
proton [Scheme 1.A.51] [72].

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 Chapter-1: Part A

Introduction on Enamines.

R H R R H R
R R
R
NH + O + -H2O
H R O R H R O

Scheme 1.A.51. Synthesis of β-amino carbonyl compounds.

Ugi reaction
Ugi reported a multicomponent reaction in 1959 involving ketone, amine, acid
and isocyanide to form a bis-amide. The reaction is exothermic and usually
completed within minutes of adding the isocyanide [Scheme 1.A.52] [73].
3
O O R4 R O
1 2 3 5 + - N 5
R R + R NH2 + R4 OH +R N C
O 1 N
R
R R2
H

Scheme 1.A.52. Synthesis of bis-amide.

Hantzsch reaction
In 1881, Arthur Hantzsch reported a multicomponent reaction of
dihydropyridine synthesis between an aldehyde such as formaldehyde, 2
equivalents of β - keto ester such as ethyl acetoacetate and a nitrogen donor
such as ammonium acetate or ammonia. The compound containing 1,4 -
dihydropyridine unit such as nifedipine, amlodipine are important calcium
channel blockers [Scheme 1.A.53] [74,75].
H H
O O OEt O H H O
EtO O H2O
+ reflux
EtO OEt
O
O NH4OAc N
H

Scheme 1.A.53. Synthesis of dihydropyridine.

Passerini reaction
The three component chemical reaction between isocyanide, ketone and
carboxylic acid to form α- hydroxyl amide. It is the first isocyanide based
multicomponent reaction discovered by Mario Passerini in 1921, and currently
it plays a central role in combinatorial chemistry [Scheme 1.A.54] [76,77].

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 Chapter-1: Part A

Introduction on Enamines.

O
O O 1
O R
1 4 2
R OH + R
2
R
3
+ R NC R
3
O
R
N 4
H R

Scheme 1.A.54. Synthesis of α-hydroxyl amide.

Gewald reaction
The German chemist Karl Gewald in 1966 involving a multicomponent
condensation reaction between sulphur, α - methylene carbonyl compound and
α - cyano ester in the presence of base obtained a poly substituted 2-amino
thiophene [Scheme 1.A.55] [78].
O
O O 2 3
R OR
2 3
1
R + OR + S8
1
R CN R S NH2

Scheme 1.A.55. Synthesis of polysubstituted 2-amino thiophene.

1.A.12. The objectives of the current investigation

To synthesis of heterocyclic, endocyclic and exocyclic enamine
derivatives via multicomponent reaction using easily accessible starting
materials.

To synthesis of heterocycles via enamine intermediate through
multicomponent reaction.

To synthesis of heterocycles using enamines as a starting material.

Characterization of these products for the structure elucidation using
by spectroscopic technique such as IR, 1H NMR, 13C NMR, DEPT 135,
Mass and Elemental analyses.

To study hydrogen bonding and stereochemistry of product using X-
ray single crystal analysis.

30