MORPHOLINE

1

Morpholine

N
H

O

[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

; pK

a

8.8.

Solubility:

miscible with water, acetone, diethyl ether.

Form Supplied in:

liquid, >99%.

Purification:

dried with KOH, fractionally distilled, dried for a

second time over sodium metal, then redistilled.

1

Handling, Storage, and Precautions:

eye and skin irritant; flamm-

able liquid; use in a fume hood.

Original Commentary

David Goldsmith

Emory University, Atlanta, GA, USA

Willgerodt Reaction.

2

Morpholine is employed as the amine

component of the Kindler modification 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.

(1)

O

O

NH

N

O

S

S, p-TsOH, 130

°C

94%

O

O

O

O

NH

CO

2

H

HO

2

C

CO

2

H

S, heat

(2)

reflux

75%

H

3

O

+

Willgerodt-like processes are effected by treatment of benzyl-

phosphonates

5

and chlorides

6

with morpholine and Sulfur (eqs 3

and 4).

P(O)(OEt)

2

O

NH

N

S

O

S, THF

69%

(3)

Cl

O

2

N

O

NH

N

S

O

O

2

N

S, DMF

(4)

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 significantly
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

O

t

-Bu

O

t

-Bu

O

NH

N

O

t

-Bu

O

t

-Bu

(5)

+

+

Morpholine enamines of saturated ketones and aldehydes are

prepared by heating the base and the carbonyl compound alone in
benzene solution (eq 6),

10

by catalysis with p-Toluenesulfonic

Acid in toluene (eq 7),

13

and by catalysis with Titanium(IV)

Chloride (eq 8).

14

Aldehyde enamines may also be prepared by

decarboxylation of the morpholine enamines of substituted
pyruvic acids (eq 9).

15

O

NH

O

(6)

N

O

benzene, reflux

85%

O

NH

O

(7)

N

O

p

-TsOH

72–80%

O

NH

(8)

O

N

O

TiCl

4

88%

CO

2

H

O

O

NH

N

O

benzene, p-TsOH

heat, 94%

(9)

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

O

NH

(10)

OH

OH

N

OH

O

O

MnO

2

, ether

86%

CHO

Cl

O

NH

N

O

CHO

TEA, THF

35%

(11)

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

(12)

N

O

Cl

O

O

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

Br

Br

O

NH

DMSO

Br

(13)

(14)

O

NH

I

2

, 96%

OH

OH

I

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

(15)

O

NH

SOCl

2

85%

O

O

O

Under high pressure, p-nitrophenyl triflate undergoes addition–

elimination with morpholine (eq 16).

22

OSO

2

CF

3

O

2

N

O

NH

N

O

2

N

O

MeCN

high pressure

100%

(16)

Morpholine, like other secondary amines, may be used for

Mannich-type condensations (eq 17).

23

(17)

N

CHO

O

NH

2

Cl

N

N

O

+

56%

First Update

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

CHO

R

S,

N

S

O

R

CO

2

H

R

MW, 4 min

MW, 1 min

N
H

O

15% NaOH

90–97%

(18)

65–100%

R

S,

S

N

O

R

MW, 8–10 min

N
H

O

(19)

63–82%

A list of General Abbreviations appears on the front Endpapers

MORPHOLINE

3

O

R

S,

N

S

O

R

PTC

CO

2

H

R

N
H

O

p

-TsOH

20% NaOH

reflux

55–80%

(20)

130

°C

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 triflate 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 triflates to ketones’ as the
direct transformation is generally low yielding.

O

N

O

N
H

O

(21)

MW, 8 min

97%

K 10 clay

OTf

CMe

3

N

O

CMe

3

N
H

O

(22)

100%

Pd(OAc)

2

, BINAP

Cs

2

CO

3

, toluene

80

°C

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

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.

O

NBoc

N

O

PhOCH

2

COCH

CH

2

O

O

Boc
N

O

(23)

0

°C

48%

Benzene

reflux

N

N

O

R

CH

2

CHCOCl

N

R

O

O

(24)

80

°C

80–85%

benzene

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 regiospecific, inverse-electron
demand Diels–Alder reaction (eq 25).

H
N

O

N

O

R

O

N

H

2

N

HO

R

MeOH

HN

O

R

(25)

55–65%

Pt anode

rt

Under solvent-free conditions, Hamelin’s group has success-

fully oxidized β,β-disubstituted morpholino enamines into car-
bonyl compounds with Potassium Permanganate/Aluminum
Oxide using microwave irradiation (eq 26).

38

N

O

H

Ph

Ph

MW

O

N

O

H

O

R

2

R

1

(26)

Al

2

O

3

/KMnO

4

+

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 (pKa

H

8.4) is a weaker base than

triethylamine (pKa

H

10.7) or piperidine (pKa

H

11.2) but stronger

than pyridine (pKa

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

MW

R

R

R

, Al

2

O

3

N
H

O

CuX

(27)

40–90%

The use of morpholine as a weak base in an unusual conversion

of α-halosulfones to olefins (Ramberg–Bäcklund rearrangement)
allows a facile preparation of dichloromethylene compounds with
interesting biological activities (eq 28).

45

N
H

O

SO

2

CCl

3

Cl

Cl

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 efficient proton scavenger in
aromatic nucleophilic substitution (S

N

Ar) for the synthesis of ben-

zodiazepines (eq 29).

48

CF

3

CO

2

–

O

2

N

F

N

O

R

2

R

1

O

NHR

3

+

H

3

N

DMF

O

2

N

N
H

N

O

R

2

R

1

O

NHR

3

(29)

PS morpholine

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

or carbohydrate

synthesis.

50

Typically, treatment of the N-Fmoc-derivatized car-

bohydrate with morpholine in polar solvent (DMF, THF) provides
the free amine in average to high yields (eq 30).

51

O

HO

HO

OH

OH

FmocHN

H
N

O

OMe

O

O

HO

HO

OH

OH

H

2

N

H
N

O

OMe

O

N
H

O

, DMF

(30)

rt

quant

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
π

-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

BzO

BzO

OBz

O

NHCbz

O

O

Pd(PPh

3

)

4

N
H

O

O

BzO

BzO

OBz

O

NHCbz

OH

O

(31)

, THF

rt

97%

Decarboxylation might occur in the course of the deallylation

of allylic β-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).

Pd(PPh

3

)

4

N
H

O

H

R

O

CHO

O

CO

2

All

H

R

O

CHO

O

(32)

, THF

63%

rt

A list of General Abbreviations appears on the front Endpapers

MORPHOLINE

5

Pd

2

(dba)

3

-dppp

N
H

O

O

TBSO

CO

2

All

C

5

H

11

TBSO

O

TBSO

CO

2

H

C

5

H

11

TBSO

(33)

, THF

83%

35

°C

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

0.05 mol % Pd(OAc)

2

N
H

O

1 mol % PPh

3

NH

O

O

Ph

O

O

Ph

H

2

N

O

OH

(34)

, EtOH

85%

reflux

N
H

O

Pd(PPh

3

)

4

NHFmoc

OtBu

O

O

O

NHFmoc

OtBu

HO

(35)

, THF

70%

(1 equiv)

rt

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

N
H

O

S

O

O

PCy

2

BH

3

S

O

O

PCy

2

(36)

quant

110

°C

N
H

O

S

S

O

R

(CH

2

)

10

R

HS

SH

(CH

2

)

10

(37)

75%

reflux

benzene

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

N
H

O

R

1

O

R

2

CN

CO

2

Et

EtOH

S

NH

2

CO

2

Et

R

2

R

1

(38)

70–80%

+

S

8

,

45–60

°C

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, trifluoroethanol), 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

Avoid Skin Contact with All Reagents

6

MORPHOLINE

N

N

HO

NH

2

X

O

O

CO

2

Bn

N

HO

N
H

X

CO

2

Bn

H

H

N

HO

N
H

X

CO

2

Bn

H

H

(39)

conditions

+

cis

trans

Conditions

X = O

X = NSO

2

Ar

X = NH

+
2

Morpholine-HOAc,

80%, 4:1

61%, 6:1

42%, trans

CF

3

CH

2

OH, 60

◦

C

(cis:trans)

(cis:trans)

PPE, DCM

80%, 1:4

61%, 1:20

N/A

(cis:trans)

(cis:trans)

Finally, triazines have been obtained with high regioselectiv-

ity from morpholino-ketoaminals upon condensation with amino-
guanidine in MeOH in the presence of acetic acid. The aminals are
generated by nucleophilic displacement of α,α-dibromoketones
with morpholine (eq 40).

74

N
H

O

THF

R

O

Br

Br

R

O

N

N

O

O

N
H

NH

NH

2

H

2

N

N

N

N

R

NH

2

(40)

MeOH, AcOH

45–76%

>95%

regioselectivity

45–70

°C

rt

70

°C

Morpholino Amides. Morpholino amides, obtained from the

reaction of morpholine with carboxylic acids, acyl chlorides, or
esters, react with both Grignard and organolithium reagents to
form ketones without contamination by tertiary alcohols.

75,76

Due

to the mild conditions, the configuration of the α-stereocenter
is retained (eq 41). Furthermore, the reaction is cleaner and
affords the final ketones in better yield compared to pyrrolidino
amides. The reaction is believed to proceed through a stable,
metal-chelated intermediate similar to the Weinreb amide
intermediate.

77

Like Weinreb amides, morpholino amides can also

be reduced with Lithium Aluminum Hydride to give clean α-
amino aldehydes (eq 42).

78

OBn

N

O

O

EtMgCl

THF

OBn

O

(41)

30 min, 0

°C

94%

BocHN

OH

O

HBTU, DIEA

N
H

O

BocHN

N

O

O

LiAlH

4

THF

BocHN

O

H

(42)

75%

, DCM

rt

85%

0

°C

Morpholine–Iodine Complex. Morpholine complexes with

iodine to give a charge transfer complex that is particularly handy
for the iodination of arenes, heteroarenes, and alkynes.

20,79

Pre-

pared as an isolable solid or in situ, it provides a reliable iodination
agent where other reagents failed. It is believed that, by complex-
ing with morpholine, the central iodine atom is activated to nucle-
ophilic attack. Various examples have been described in the liter-
ature such as iodination of phenols (eq 43),

80

simple alkynes,

81

or indoles.

82

Most of the reactions are performed in anhydrous

organic solvents (alcohols, DCM, benzene) as the complex is
water sensitive. However, if the complex is added portionwise over
a long period of time into an aqueous basic solution, iodination of
naphthoquinones proceeds smoothly in high yield (eq 44).

79

OMe

OMe

OH

MeO

2

C

N
H

O

DCM

OMe

OMe

OH

MeO

2

C

I

, I

2

rt

76%

(43)

N
H

O

O

O

OH

O

O

OH

I

, I

2

K

2

CO

3

, H

2

O

rt

87%

(44)

Reduction.

Morpholine has been employed as a catalyst

‘modifier’ for hydrogenation of labile halogenated stilbenes. In
conjunction with Pt or Rh metal, the risk of dehalogenation of the
aromatic ring is reduced (eq 45).

83

A list of General Abbreviations appears on the front Endpapers

MORPHOLINE

7

N
H

O

Br

NO

2

R

2

R

1

Br

O

2

N

R

2

R

1

EtOH/MeOH

82–98%

(45)

, 5% Rh/C

rt

Sodium Bis(2-methoxyethoxy)aluminum Hydride (SMEAH),

when modified with morpholine, is reported to reduce methyl
benzoate to benzaldehyde under mild conditions and in excel-
lent yields.

84

It is a good alternative to the diisobutylaluminum

hydride (DIBALH) reduction of esters to aldehydes. The method
can also be applied to the reduction of amides to the correspond-
ing aldehydes (eq 46).

85

No trace of reduced amine or alcohol is

observed.

N
H

O

O

O

CONMe

2

OH

R

O

O

CHO

OH

R

72%

(46)

–45

°C

SMEAH

, THF

Miscellaneous.

Morpholine has been reported as a ‘pro-

moter’ of the thionation of amides in conjunction with Lawesson’s
Reagent or Tetraphosphorous Decasulfide (eq 47). The nucleo-
philic properties of the morpholine are supposed to play a major
role in the breaking of P–S bonds, thereby leading to a more
powerful thionating agent.

86

N

N

Ph

O

O

Ph

N

N

Ph

S

S

Ph

N
H

O

, P

4

S

10

dioxane

reflux

85%

(47)

Interestingly, an organic catalyst designed around the morpho-

line ring promotes the enantioselective addition of diethylzinc
to aldehydes in up to 99% enantiomeric excess (eq 48). The
morpholine core plays a major role in controlling the enantios-
electivity of the reaction through the ether function.

87

The cata-

lyst can be obtained by addition of morpholine to trans-stilbene
oxide.

88

R

H

O

R

H

OH

Ph

OH

N

O

Et

2

Zn, Toluene

70–98%

(48)

5%

98–99% ee

rt

The

ring

opening

of

epoxides

to

the

corresponding

β

-chlorohydrins proceeds regio- and stereoselectively by the ac-

tion of 2,4,6-Trichloro-1,3,5-triazine (TCT) in H

2

O in the pres-

ence of morpholine.

89

This regio- and stereoselectivity is a func-

tion of the substituents that flank the epoxide. For example, the
ring opening of bicyclic epoxides gives the trans-chlorohydrins
exclusively (eq 49).

N
H

O

O

OH

Cl

N

N

N

Cl

Cl

Cl

(49)

, H

2

O

rt

98%

Access to pyrophosphate bonds can be achieved by coupling a

monophosphate derivative with a nucleotide in the presence of a
Lewis acid catalyst.

90

Prior to the coupling reaction, the appropri-

ate nucleotide monophosphate is activated to the corresponding
phosphoromorpholidate by treatment with morpholine, Dipyridyl
Disulfide, and Triphenylphosphine in DMSO (eq 50).

91

Then the

coupling is carried out in the presence of Manganese(II) Chloride
and Magnesium Sulfate (eq 51).

N
H

O

O

HO

OH

O

N

N

N

NH

O

P

O

–

O

O

–

Br

O

HO

OH

O

N

N

N

NH

O

P

O

N

O

–

Br

O

PPh

3

(50)

, DMSO

rt

92%

dipyridyl disulfide

The utilization of morpholine in the Mannich reaction has

gained interest during the last decades. Reaction of ketones, such
as N-methyltetrahydrocarbazole, with Formaldehyde in the pres-
ence of either a catalytic or a stoichiometric amount of morpholine
gives the corresponding α-methylene products (eq 52).

92

Avoid Skin Contact with All Reagents

8

MORPHOLINE

O

HO

OH

O

N

N

N

NH

O

P

O

N

OH

Br

O

O

HO

OH

O

N

+

H

2

NOC

P

O

OH

OH

HCONH

2

O

HO

OH

O

N

+

H

2

NOC

P

O

OH

O

O

HO

OH

O

N

N

N

NH

O

P

OH

Br

O

MnCl

2

–MgSO

4

(51)

rt

65%

+

N
H

O

AcOH

N
Me

O

N
Me

O

(52)

, HCHO

reflux

85%

Related Reagents. N-Chloromorpholine; 1-Cyclohexyl-3-(2-

morpholinoethyl)carbodiimide; 1-Cyclohexyl-3-(2-morpholino-
ethyl)carbodiimide

Metho-p-toluenesulfonate;

N,N

′

-Dicyclo-

hexyl-4-morpholinecarboximidamide; Diethyl Morpholinome-
thylphosphonate; Lithium Morpholide; N-Methylmorpholine
N

-Oxide; 2-Morpholinoethyl Isocyanide; N-Morpholinomethyl-

diphenylphosphine Oxide; Osmium Tetroxide–N-Methylmorpho-
line N-Oxide .

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Avoid Skin Contact with All Reagents