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1
MORPHOLINE
Morpholine
S
O
H
Cl
N
(4)
S, DMF
O
O
O
2
N
O
2
N
N
H
Enamine Formation and Utilization.
Morpholine is one of
the three principal secondary amines used in the formation of
enamines.
7
–
10
A weaker base than either
Piperidine
or
Pyrroli-
dine
, it forms enamines more slowly than the other two bases. The
regioselectivity of morpholine enamine formation is signicantly
less than with pyrrolidine.
11
The lower reactivity of morpholine has been used as a method
for the separation of monoalkylated cyclohexanones from unalky-
lated material (eq 5).
12
[110-91-8]
C
4
H
9
NO
(MW 87.14)
InChI = 1/C4H9NO/c1-3-6-4-2-5-1/h5H,1-4H2
InChIKey = YNAVUWVOSKDBBP-UHFFFAOYAU
(secondary amine base; reagent for enamine formation and
utilization; condensation catalyst for Mannich condensations)
Physical Data:
bp 128.9
◦
C;
d
1.007 g cm
−
3
;p
K
a
8.8.
Solubility:
miscible with water, acetone, diethyl ether.
Form Supplied in:
liquid,
>
99%.
Purication:
dried with KOH, fractionally distilled, dried for a
second time over sodium metal, then redistilled.
1
Handling, Storage, and Precautions:
eye and skin irritant; amm-
able liquid; use in a fume hood.
O
O
O
O
O
H
N
+
+
(5)
t
-Bu
t
-Bu
t
-Bu
t
-Bu
Original Commentary
Morpholine enamines of saturated ketones and aldehydes are
prepared by heating the base and the carbonyl compound alone in
benzene solution (eq 6),
10
David Goldsmith
Emory University, Atlanta, GA, USA
by catalysis with
p-Toluenesulfonic
Acid
in toluene (eq 7),
13
and by catalysis with
Titanium(IV)
Willgerodt Reaction.
2
Morpholine is employed as the amine
component of the Kindler modication of the Willgerodt reac-
tion. The process effects the rearrangement of aryl alkyl ketones
to carboxylic acid derivatives (eqs 1 and 2).
3
,
4
Morpholine is par-
ticularly useful in the reaction as its high boiling point makes the
use of sealed tubes unnecessary.
Chloride
(eq 8).
14
Aldehyde enamines may also be prepared by
decarboxylation
of
the
morpholine
enamines
of
substituted
pyruvic acids (eq 9).
15
O
O
O
H
N
(6)
benzene, reflux
85%
O
O
N
O
H
(1)
S
S,
p
-TsOH, 130
°C
94%
O
O
O
H
N
O
O
(7)
p
-TsOH
72–80%
O
H
H
3
O
+
HO
2
C
CO
2
H
S, heat
reflux
75%
(2)
O
CO
2
H
O
H
N
(8)
Willgerodt-like processes are effected by treatment of benzyl-
phosphonates
5
and chlorides
6
with morpholine and
Sulfur
(eqs 3
and 4).
TiCl
4
88%
O
O
S
O
CO
2
H
O
H
O
H
N
(9)
P(O)(OEt)
2
N
O
(3)
benzene,
p
-TsOH
heat, 94%
S, THF
69%
O
Avoid Skin Contact with All Reagents
2
MORPHOLINE
Enaminones may be prepared by conjugate addition of morpho-
line to an alkynic ketone (eq 10),
16
and the morpholine enamine
of pyruvaldehyde has been prepared by conjugate addition and
rearrangement of 2-chloroacrolein (eq 11).
17
Under high pressure,
p
-nitrophenyl triate undergoes addition–
elimination with morpholine (eq 16).
22
O
O
H
OSO
2
CF
3
N
(16)
O
MeCN
high pressure
100%
O
2
N
O
2
N
OH
O
H
O
N
OH
OH
Morpholine, like other secondary amines, may be used for
Mannich-type condensations (eq 17).
23
MnO
2
, ether
86%
(10)
N
N
O
+
O
2
Cl
CHO
NO
O
H
Cl
56%
(11)
N
CHO
TEA, THF
35%
(17)
CHO
First Update
Utilization of Morpholine Enamines.
The less reactive mor-
pholine enamines have been shown to acylate in better yield than
the corresponding pyrrolidine derivatives.
10
A typical example
is the acylation of the morpholine enamine of cyclopentanone
(eq 12).
18
Laurent Legentil
Industrial Research Limited, Lower Hutt, New Zealand
Willgerodt–Kindler Reaction.
The conversion of aldehydes
and aryl alkyl ketones into thiomorpholides (Willgerodt–Kindler
reaction) by the combined action of
Sulfur
and morpholine has re-
cently been achieved under microwave irradiation in solvent-free
conditions.
24
The hydrolysis of thiomorpholides into carboxylic
acids can also proceed using microwave dielectric heating (eq 18).
Both reactions are faster and give better yields when compared
against conventional heating methods. The same procedure can
interestingly be applied for the transformation of styrenes to the
corresponding thioamides (eq 19).
25
Furthermore, hydrolysis of thiomorpholides under basic condi-
tions has been reported.
26
For example, benzyl thiomorpholides
have been transformed into phenylacetic acid derivatives by the
action of sodium hydroxide in the presence of a phase-transfer cat-
alyst (PTC) such as
Tetrabutylammonium Bromide
(eq 20).
27
,
28
O
O
O
N
Cl
+
(12)
O
Miscellaneous Reactions.
Morpholine is used as a base for
dehydrobromination (eq 13)
19
and in conjunction with molecular
Iodine
for the iodination of alkynic alcohols (eq 14).
20
O
H
Br
Br
(13)
DMSO
Br
O
S
S,
CHO
N
H
OH
OH
N
15% NaOH
O
H
I
MW, 4 min
O
MW, 1 min
(14)
R
90–97%
65–100%
R
I
2
, 96%
CO
2
H
Treatment of benzyl phenyl ketone with
Thionyl Chloride
and
morpholine results in the formation of benzil, a reaction which
presumably occurs through the intermediacy of the ketone enam-
ine (eq 15).
21
(18)
R
O
O
S,
O
O
H
N
H
N
(15)
(19)
SOCl
2
85%
MW, 8–10 min
S
O
O
R
63–82%
R
A list of General Abbreviations appears on the front Endpapers
3
MORPHOLINE
O
react with the morpholino enamine of
N
-carboxy-4-piperidones,
thereby providing access to bicyclo[3.3.1]nonane-6,9-diones
(eq 24).
36
Compared to reactions with pyrrolidino or piperidino
enamines, morpholino enamines give better yields.
S,
O
O
N
H
20% NaOH
N
p
-TsOH
PTC
130
°C
S
reflux
R
R
O
O
CO
2
H
(20)
PhOCH
2
COCH
CH
2
NBoc
O
R
Benzene
reflux
O
Boc
N
(23)
N
0
°C
55–80%
48%
O
Enamine Formation.
Morpholine enamines are useful key
intermediates in important transformations that include alky-
lation and acylation (Stork’s reaction), annulation cascades,
cycloadditions, and a range of heterocycle syntheses.
29
As a cyclic
secondary amine, morpholine presents a higher nucleophilicity
compared to secondary acyclic amines, the result of which is an
enhancement in the yield of enamine formation.
30
However, the
selectivity of Stork’s reactions, for example, on such enamines is
rather low compared to the pyrrolidine and piperidine enamines.
New methodologies for the syntheses of morpholino enamines
include the use of solid
KSF Clay
31
as a mild acidic catalyst. When
montmorillonite
K 10 Clay
32
is employed, the reaction proceeds
conveniently under microwave irradiation and solvent-free con-
ditions to afford the enamines of various ketones, for example,
cyclohexanone (eq 21).
Morpholino enamines have also been generated under acid-
free conditions. Thus, a vinyl triate leads to the corresponding
morpholino enamine under
Palladium Acetate
catalysis in the
presence of
BINAP
and
Cesium Carbonate
(eq 22).
33
Hydrolysis
of the enamine under mild acid conditions regenerates the parent
ketone. This is a useful route from ‘enol triates to ketones’ as the
direct transformation is generally low yielding.
O
O
O
N
CH
2
CHCOCl
benzene
(24)
80
°C
80–85%
N
R
N
R
Utilization of 4-cyclohexylidenemethylmorpholine in an elec-
trochemically induced Diels–Alder reaction gives rise to highly
substituted 1,4-benzoxazines.
37
The anodic oxidation of 3,4-
aminophenol derivatives produces chemically unstable
o
-
azaquinone heterodienes, which can be trapped in situ by the
enamine dienophile through a regiospecic, inverse-electron
demand Diels–Alder reaction (eq 25).
O
N
HN
Pt anode
H
2
N
MeOH
R
O
R
K 10 clay
rt
O
HO
O
O
N
N
H
H
N
(21)
MW, 8 min
97%
R
(25)
N
O
O
O
O
55–65%
N
H
OTf
N
Pd(OAc)
2
, BINAP
Cs
2
CO
3
, toluene
80
°C
Under solvent-free conditions, Hamelin’s group has success-
fully oxidized
,
-disubstituted morpholino enamines into car-
bonyl compounds with
Potassium Permanganate/Aluminum
Oxide
using microwave irradiation (eq 26).
38
(22)
100%
CMe
3
CMe
3
Utilization of Morpholino Enamines.
Morpholino enam-
ines are extensively used as nucleophiles in organic synthesis.
They are key intermediates in the Robinson annulation reaction
between aldehydes
34
or ketones
35
and vinyl ketones (eq 23). Fur-
thermore, bis-electrophilic agents such as
Acryloyl Chloride
can
O
O
N
R
2
N
Ph
Al
2
O
3
/KMnO
4
(26)
O
+
O
MW
R
1
H
H
Ph
83%
Avoid Skin Contact with All Reagents
4
MORPHOLINE
Morpholine as a Base.
For the most part, morpholine under-
goes chemical reactions typical of secondary amines, though the
presence of the electron-withdrawing ether renders it less nucle-
ophilic and less basic than other structurally similar amines. As
a matter of fact, morpholine (p
K
a
H
8.4) is a weaker base than
triethylamine (p
K
a
H
10.7) or piperidine (p
K
a
H
11.2) but stronger
than pyridine (p
K
a
H
5.2).
39
Thus, morpholine turns out to be the
best choice when mild basic conditions are required.
Morpholine has been successfully used as a base for vari-
ous reactions such as Wittig.
40
, Knoevenagel,
41
or Glaser.
42
In
the Glaser homo coupling, reaction occurs in the presence of a
catalytic amount of copper halide under microwave irradiation,
which is an improvement over the original method (eq 27). Mor-
pholine can also replace other bases such as triethylamine or
diisopropylamine in cross-coupling reactions.
43
,
44
bohydrate with morpholine in polar solvent (DMF, THF) provides
the free amine in average to high yields (eq 30).
51
O
OH
HO
O
H
N
O
N
H
, DMF
HO
OH
OMe
rt
quant
O
FmocHN
OH
HO
O
O
H
N
(30)
HO
OH
OMe
O
H
2
N
CuX
The allyl group has proven to be a very attractive protecting
group for carboxylic acids and phenols or as a carbamate for
amines and hydroxyls (allyloxycarbonyl (Alloc)). It can be used
in conjunction with N-terminal
Z
- and Boc-protecting groups and
can be removed selectively under a mild palladium-catalyzed pro-
cess with morpholine as the allyl scavenger.
52
,
53
Typically,
Tetrakis(triphenylphosphine)palladium(0)
as the
palladium catalyst coordinates with the alkene to provide a
-palladium complex. Morpholine as a nucleophile attacks the
complex at the least substituted terminus leading, after dissocia-
tion, to the free molecule and
N
-allylmorpholine. Due to the mild
conditions, this methodology has been applied routinely to cleave
allyl carboxylate
54
,
55
or phosphate
56
in peptide/glycopeptide
chemistry. The deprotection is compatible with sensitive pro-
tective groups (e.g.
O
-SEM (2-(trimethylsilyl)ethoxyethyl) or
O
-
TBDMS) or glycosyl serine and threonine bonds that are known
to be acid and base labile (eq 31).
57
Moreover, the procedure can
be employed in solid-phase synthesis to cleave polymer supports
connected to the peptide through an allylic handle.
58
O
N
H
, Al
2
O
3
R
R
R
(27)
MW
40–90%
The use of morpholine as a weak base in an unusual conversion
of
-halosulfones to olens (Ramberg–Bäcklund rearrangement)
allows a facile preparation of dichloromethylene compounds with
interesting biological activities (eq 28).
45
O
Cl
Cl
SO
2
CCl
3
N
H
CHCl
3
(28)
rt
100%
New amine-supported resins have attracted growing interest
because they can provide attractive and practical methods for com-
binatorial chemistry and solid-phase synthesis in the preparation
of heterocycles and small molecules.
46
,
47
Interestingly, morpho-
line can be attached to a resin (polymer-supported morpholine or
PS morpholine) to act as an efcient proton scavenger in
aromatic nucleophilic substitution (S
N
Ar) for the synthesis of ben-
zodiazepines (eq 29).
48
Pd(PPh
3
)
4
O
NHCbz
N
H
O
, THF
O
Bz
BzO
O
rt
97%
O
OBz
CF
3
CO
2
–
NHCbz
+
H
3
N
R
1
O
O
OH
Bz
BzO
(31)
O
O
2
N
NHR
3
O
OBz
PS morpholine
N
R
2
O
DMF
F
Decarboxylation might occur in the course of the deallylation
of allylic -ketoester (eq 32)
59
or allylic alkyne ester.
60
How-
ever, using morpholine and a bidentate diphosphine ligand such
as
[Pd
2
(dba)
3
]-dppp
prevents decarboxylation (eq 33).
O
R
2
O
2
N
N
NHR
3
(29)
O
N
H
R
1
Pd(PPh
3
)
4
O
O
O
R
R
CHO
CHO
N
H
, THF
Cleavage of Fmoc- and Allyl-protecting Groups.
As a weak
amine base, morpholine has been employed to lyse the Fmoc-
protecting group. It is mostly useful in peptide
49
H
H
rt
(32)
O
CO
2
All
O
63%
or carbohydrate
synthesis.
50
Typically, treatment of the
N
-Fmoc-derivatized car-
A list of General Abbreviations appears on the front Endpapers
5
MORPHOLINE
Pd
2
(dba)
3
-dppp
O
BH
3
O
O
PCy
2
N
H
PCy
2
N
H
, THF
(36)
CO
2
All
O
O
S
110
°C
S
quant
35
°C
O
O
C
5
H
11
83%
TBSO
TBSO
O
O
CO
2
H
(33)
N
H
R
(CH
2
)
10
C
5
H
11
benzene
TBSO
O
S
TBSO
reflux
75%
S
Generally, the deprotection of phenoxyallyl
61
and
N
-or
O
-
Alloc
62
derivatives requires an excess of morpholine to avoid
competitive trapping of the allyl function by the free amine or
hydroxyl.
Palladium Acetate
may also be used as the catalyst in
conjunction with
Triphenylphosphine
as a ligand to increase the
electrophilic nature of the palladium complex (eq 34).
63
Furthermore, by using an equimolar quantity of morpholine,
combined with tetrakis(triphenylphosphine) palladium as cata-
lyst, it is possible to selectively cleave the allyl carboxylate
without hydrolyzing the Fmoc-protecting group (eq 35).
64
R
SH
(CH
2
)
10
HS
(37)
Morpholine in Heterocyclic Chemistry.
Morpholine can
be involved directly or as a base in different heterocycle-forming
processes. It has been employed for the synthesis of 2-aminothio-
phenes in the so-called Gewald synthesis. Molecules containing
such an aminothiophene moiety have a high incidence of biologi-
cal activity.
68
,
69
Typically, a one-pot thiolation–heterocyclization
reaction between carbonyl compounds with activated nitriles and
elemental sulfur in the presence of morpholine leads to 2-amino-
thiophenes in high yields (eq 38).
70
0.05 mol % Pd(OAc)
2
1 mol % PPh
3
O
N
H
, EtOH
O
reflux
O
NH
85%
O
O
Ph
Ph
O
(34)
OH
H
2
N
S
8
,
N
H
O
R
1
S
CN
NH
2
R
1
EtOH
+
(38)
45–60
°C
CO
2
Et
R
2
O
Pd(PPh
3
)
4
70–80%
R
2
CO
2
Et
O
N
H
, THF
O
OtBu
OtBu
(1 equiv)
During the last decade, a tethered Biginelli condensation
employing morpholinium acetate as an amine base has been
developed to access guanidine derivatives.
71
The stereoselectiv-
ity of the reaction is controlled by the reaction conditions and the
structure of the guanidine moiety. Thus, the condensation of mor-
pholino aminals (generated by ozonolysis of unsaturated acyclic
ureas) with benzyl acetoacetate gives a mixture of
cis
- and
trans
-
guanidine in good yields. Under standard Knoevenagel conditions
(morpholinium acetate, triuoroethanol),
cis
-stereoselectivity is
observed, while under mineral acid treatment (PPE, DCM), the
trans
-isomer is favored. However, when the aminal substrates
contain an unprotected guanidine (X = NH
2
), only the
trans
-
isomer is obtained (eq 39). This remarkable result was applied
to the synthesis of various natural alkaloids.
72
,
73
O
O
HO
rt
70%
NHFmoc
NHFmoc
(35)
Morpholine as a Scavenger.
Morpholine can be successfully
used as a scavenger for other protecting group hydrolyses. Thus,
deprotection of phosphine borane adducts by morpholine yields
the free phosphine and the morpholino-borane adduct (eq 36). This
adduct can be easily removed under high vacuum
65
or by column
chromatography on alumina.
66
In a similar way, morpholinolysis
of xanthates gives the free thiol group in high yield (eq 37).
67
Avoid Skin Contact with All Reagents
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