An insight into hexamethylenetetramine: a versatile

ORIGINAL PAPER

An insight into hexamethylenetetramine: a versatile reagentin organic synthesis

Navjeet Kaur • Dharma Kishore

Received: 12 December 2012 / Accepted: 3 April 2013

� Iranian Chemical Society 2013

Abstract Hexamethylenetetramine is a versatile reagent

in organic synthesis. It plays a major role in modern

organic synthesis. This review focuses on hexamine

reagent for its significant role in organic synthesis during

the past decades and is able to provide a valuable per-

spective from synthetic point of view.

Keywords Hexamethylenetetramine � Organic synthesis �Reagent

Introduction

Hexamethylenetetramine (HMTA) (1,3,5,7-tetraazatricy-

clo[3.3.1]decane, C6H12N4) is a fourth-cycled molecule.

Hexamethylenetetramine is known by several other names,

including methenamine, urotropine, and hexamine. Hexa-

methylenetetramine is an organic, heterocyclic chemical

compound, more commonly known as hexamine, is

obtained by the reaction of formaldehyde and excess of

ammonia, either in a aqueous medium or in the vapor phase

(Scheme 1) [1].

In most areas of application, hexamine can be regarded

as a special form of formaldehyde. It has the advantage that

no water is released during conversion and hydrolyzes in

acid media and slowly releases formaldehyde. It has a very

low toxicity and diluted solutions can be broken down

biologically.

Hexamine is a synthetically versatile reagent used in

organic synthesis during the last years. In particular, in the

Duff [2] and Sommelet [3] reactions hexamethylenetetra-

mine acts as the formyl carbon source, while in the Dele-

pine [4] reaction it provides the primary amino groups.

Blazevic et al. [5] in 1979 listed all the experiments carried

out with HMTA in the first 80 years of the last century. The

structure of HMTA is particularly stable, in contrast to the

very reactive behavior shown by its di-hetero-substituted

methylene groups. In addition, nitrated derivatives of

HMTA were used as explosive bombs during the World

War II. It is the starting material for two classic secondary

explosives, RDX and HMX.

Adamantane synthesis

Daigle et al. [6–8] prepared a monophosphorus analog of

hexamine, from hexamine and tris[hydroxymethyl]phos-

phine or tetrakis[hydroxymethyl]phosphonium chloride,

whose oxidation with hydrogen peroxide at room temper-

ature gave phosphoadamantane-7-oxide (Scheme 2) [5].

Daigle et al. [9] prepared a sulfur and phosphorus con-

taining derivative of hexamine 2-thia-1,3,5-triaza-7-phos-

phaadamantane-2,2-dioxide, from tris[hydroxymethy]

phosphine, sulphamide and hexamine in excess of form-

aldehyde (Scheme 3) [5].

Aminoacetone semicarbazone hydrochloride synthesis

Aminoacetone is a versatile starting material for many

syntheses, particularly for the preparation of heterocycles.

The present procedure describes a convenient method for

its preparation in a form which is suitable for storage. The

aminoacetone can be generated from aminoacetone semi-

carbazone hydrochloride in situ. This preparation is based

N. Kaur (&) � D. Kishore

Department of Chemistry, Banasthali University,

Banasthali, Jaipur 304022, Rajasthan, India

e-mail: [email protected]

123

J IRAN CHEM SOC

DOI 10.1007/s13738-013-0260-2

on the procedure used to synthesize 3-acetamido-2-buta-

none. Aminoacetone hydrochloride has been prepared from

isopropylamine via the N,N-dichloroisopropylamine, from

hexamethylenetetramine and chloroacetone (Scheme 4), by

reduction of nitroacetone or isonitrosoacetone, and from

phthalimidoacetone by acid hydrolysis [10].

Benzaldehyde synthesis

The preparation of aromatic aldehydes from benzylic

halides is an attractive route to synthesize aromatic alde-

hydes (Scheme 5). One of such reaction is the Sommelet

[3] reaction using hexamine as a reagent. In this process,

the first step is the reaction of hexamine with the alkyl

halide to form a quaternary salt, which on hydrolysis gives

a primary amine, formaldehyde and ammonia. The primary

amine on reaction with the aldimine, derived from form-

aldehyde and ammonia, forms the corresponding aromatic

aldimine, which on hydrolysis gives the aldehyde. This

reaction is generally possible with active halides such as

benzylic halides, allylic halides, a-halo ketones and pri-

mary iodides. In this reaction, benzyl halides are refluxed

in DMSO along with sodium bicarbonate to give the cor-

responding aldehydes. The reaction has recently been

attempted under microwave irradiation [11].

NN

N

N

P(CH2OH)3 H2CO

NN

N

P

NN

N

P

O

or

P+(CH2OH)4Cl=

H2O2

Scheme 2 Synthesis of

phosphoadamantane-7-oxide

NN

N

NPH(CH2OH)3 H2NSO2NH2

H2CO

N

O2SN

N

PN

O2SN

N

P

O

N

O2SN

N

P

CH3

[0]

J-

H3C-I


hexamine 2-thia-1,3,5-triaza-7-

phosphaadamantane-2,2-

dioxide

H2NOH

O HN

CH3

O

H3C

O

H3NCH3

O Cl-

2 Ac2O

pyridine,heat

HCl

H2O

NH2CONHNH2H3N

CH3

NNHCONH2Cl-

Scheme 4 Synthesis of aminoacetone semicarbazone hydrochloride

H2C O 6 NH36H+

N

N

N

N

6 H2O 2 NH3


hexamine

XR HMTA/DMSO

heat

CHO

RX = NO2, OMe

Scheme 5 Synthesis of benzaldehydes

J IRAN CHEM SOC

123

2-Bromoallylamine synthesis

This method gives better yields than other methods of

preparation of 2-bromoallylamine (Scheme 6), and it is the

most convenient method for the preparation of large

quantities of the compound. The procedure illustrates a

reaction, the so-called Delepine [4] reaction, that has been

used for the preparation of many primary aliphatic amines.

It is especially useful in the preparation of derivatives of

phenacylamine. A number of primary aliphatic amines

have been prepared by this method without isolation of the

intermediate hexaminium salt [12].

Cleavage of epoxides (synthesis of vicinal haloalcohols)

The highly regioselective cleavage of epoxides into cor-

responding vicinal haloalcohols with elemental halogen

has been catalyzed by hexamethylenetetramine

(Scheme 7). This method occurred under neutral and mild

conditions with high yields and short reaction times in

various aprotic solvents even when sensitive functional

groups were present. The preparation of haloalcohols and

the complex formation of heterocyclic compounds con-

taining donor nitrogen atoms, with neutral molecules such

as iodine and bromine, the HMTA compound can be

reactive as a new catalyst in the addition of elemental

halogen to epoxides under mild reaction conditions with

high regioselectivity. As for the regioselectivity, attack of

the nucleophile preferentially occurs at the less substituted

epoxide carbon. This regioselectivity appears to be the

opposite of that observed in ring opening of the same

epoxides with hydrohalogenic acids under classic acidic

conditions [13].

Condensation

Benzylamine and hexamine condense at 190 �C. The

condensation product of benzylamine and hexamine poly-

merizes when heated for an extended period (Scheme 8).

Depending on both temperature and time, different mix-

tures of products are formed [5, 14].

The mixture of products formed from the condensation

of hexamine and benzylamine was identified and converted

into the open-chain isomeric products as shown in

Scheme 9 [5, 15].

In another process, the first step yielded triaza com-

pound on heating the reactants for 0.5 h at 190 �C, whose

further reaction at 180–200 �C produced mixture of three

products (Scheme 10). This mixture protects metals against

corrosion under acidic conditions [5, 16, 17].

Crown ether synthesis

Bichromophoric compound benzophenone-{crown ether}-

naphthalene (Bp-C-Np) was synthesized. 2,3,11,12-Bis(40-formylbenzo)-18-crown-6 (BFBC) compound was pre-

pared according to the literature (Scheme 11). A mixture of

dibenzo-18-crown-6 (DBC), trifluoroacetic acid and hexa-

methylenetetramine was stirred at 90 �C under nitrogen for

12 h. After the mixture was cooled, 50 ml of concentrated

KOH and 200 ml of water were successively added. The

product was precipitated as a brown solid. The crude

product was collected by suction filtration and washed with

acetone several times [18].

Delepine reaction

The Delepine reaction allows the synthesis of primary

amines from alkyl halides by the reaction with hexameth-

ylenetetramine and subsequent acidic hydrolysis of the

resulting quaternary ammonium salt (Scheme 12). An SN2

reaction leads to the hexamethylenetetramine salt. In

chloroform, the starting materials are soluble whereas the

products crystallize out. It is usually not possible to purify

the salt [2].

N

N

N

NH2C

Br

Br

H2C

Br

NC6H12N3Br

H2C

Br

NCl

H2C

Br

NH2

heat

HCl, NaOH,

aq. EtOH H2O

Scheme 6 Synthesis of 2-bromoallylamine

O

R XR

HO

X2

HMTA

rt, CH2Cl2

Scheme 7 Synthesis of vicinal haloalcohols

J IRAN CHEM SOC

123

Reaction of hexamine with substituted oxiranes is a

modification of the Delepine reaction. On reaction with

hexamine 1-amino-2-hydroxy alcohols are only obtained

whereas reactions with primary, secondary, and tertiary

amines gives rise to a mixture of 1-amino-2-hydroxy

alcohol and isomeric 2-amino-1-hydroxy alcohol

(Scheme 13) [5].

Some other applications of hexamine for the introduc-

tion of amino groups cannot be classified as Delepine

reaction. Thus, diazomethyl 5-pyrimidinyl ketone can be

converted to 5-(2-amino-1-hydroxyethyl)-pyrimidine on

treatment with hexamine (Scheme 14) [19].

DL-Valine synthesis

Valine has been prepared through the reaction of hexa-

methylenetetramine with a-bromoisovaleric acid in

dioxane (Scheme 15) or dioxane–xylene (91 % yield) fol-

lowed by hydrolysis [20].

5-Fluorovanillin synthesis

The approach to synthesize fluorinated vanillin analogs is

based on 3-fluoroanisole as the starting compound. From

3-fluoroanisole, the desired products 2-fluoro-isovanillin

and 5-fluorovanillin were synthesized in 45 and 55 %

yields, respectively. 3-Fluoroanisole was reacted with n-

butyllithium and B(OCH3)3 at -78 �C followed by treat-

ment with acetic acid and hydrogen peroxide at 0 �C. This

reaction was 100 % selective for the desired position under

the conditions chosen. The Duff reaction, which employs

hexamethylenetetramine in refluxing trifluoroacetic acid

was used in next step. This reaction was regioselective on

the 1–5 mmol scale, however, when scaled up ([50 mmol)

the reaction lost regioselectivity. The second major product

NN

N

N

6 C6H5CH2NH2190oC

- 4 NH3

C6H5

H2C N CH26

Scheme 8 Condensation of

hexamine and benzylamine

3 C6H5

H2C N CH2

N N

N

H2C C6H5

CH2

C6H5CH2

C6H5

N CH

NH2C N CH3

CH2

C6H5

CH2

C6H5

CH2

C6H5

NH2C N

H2C N CH3

CH

C6H5

CH2

C6H5

CH2

C6H5

190oC

HMTA

Scheme 9 Condensation of hexamine and benzylamine

C6H5

H2C NH26 N N

N

H2C

CH2

CH2

C6H5

C6H5C6H5

HMTA

N CH

H3C

C6H5

N CH2 C6H5

H2C N CH2 C6H5

H2C N C

HC6H5C6H5

cooling

Scheme 10 Condensation of

hexamine and benzylamine

J IRAN CHEM SOC

123

was thought to be 5-fluorovanillin. A regioselective reaction

using dimethylamine and formaldehyde in absolute ethanol

generated the benzylamine. Benzylamine was converted to

the quaternary amine using methyl iodide. This was done to

generate a better leaving group for conversion to the alde-

hyde. Upon treatment with hexamethylenetetramine in

O

O

O

O

O

O

O

O

O

O

O

O

OHC CHO

O

O

O

O

O

O

HOH2C CH2OH

O

O

O

O

O

O

H2COH2C CH2OH

O

O

O

O

O

O

H2COH2C CH2OC

OO

(CH2)6N4

CF3COOH

NaBH4

H2O, C2H5OHNa/DMF

NEt3/DMF

BrH2C

C

O

C Cl

O

Scheme 11 Synthesis of crown ether

N

N

N

N

X

R

R'CHCl3

reflux

N

N

N

N

R

R'

X-

conc. HCl

EtOHNH2

R

R'


primary amines

HMTA

O

R1

HN

R2

R2

R1HC

H2C

OH

N

R2

R2

R1HC

H2C

N

OH

R2 R2

or

Scheme 13 Synthesis of aminohydroxy alcohols

HMTAN

N

OC C

HN2

N

N

HC

H2C NH2

OH

Scheme 14 Synthesis of 5-(2-amino-1-hydroxyethyl)-pyrimidine

J IRAN CHEM SOC

123

refluxing acetic acid the quaternary amine was converted to

5-fluorovanillin (Scheme 16) [21].

Formaldehyde synthesis

The oxidation of hexamine by quinoliniumdichromate has

been investigated in aqueous perchloric acid medium at

constant ionic strength (Scheme 17). Increase in perchloric

acid concentration increases the reaction rate. The added

products chromium(III), formaldehyde and oxime do not

have any significant effect on the rate of reaction. Increase

in ionic strength and decrease in dielectric constant of the

reaction medium increase the rate of reaction [22].

The compound is rather stable, although dihetero-

substituted methylene groups are usually highly reactive. In

neutral, aqueous solution, hexamine remains stable even at

elevated temperatures. Hexamine decomposes in dilute

aqueous acid, and the derived ammonium salts also

decompose to form the amine hydrochloride and formal-

dehyde (Scheme 18). During acidic hydrolysis or ethanol-

ysis, semiaminals are formed first, these further decompose

to yield formaldehyde or the diethylacetal, ammonium salt

and the amine hydrochloride [4].

Formazin preparation

This procedure (Scheme 19) reviews the process required

to synthesize accurate formazin. Further, this procedure

introduces new quantitative analysis information showing

reactants hydrazine sulfate and hexamine to be present in

considerably less quantities compared to presynthesis

concentrations. Formazin is chemically formed through a

condensation reaction between formaldehyde and hydra-

zine. More specifically, two starting reagents, hydrazine

sulfate and hexamethylenetetramine are used. Hexameth-

ylenetetramine reacts with water and sulfuric acid (from

H3C

CH3

CO2HH3C

CH3

CO2H

Br

H3C

CH3

CO2H

NH2

Br2

PCl3, heatNH4OH

Scheme 15 Synthesis of DL-

valine

F

O

F

O

HO

HO

ON

F

O

HO

OF

HO

O

F

O

n-butyl lithium (-78oC),B(OMe)3, AcOH (0oC),

refluxing HMTA in TFA,

40% dimethylamine, 37% formaldehyde in ethanol reflux,

Iodomethane followed by HMTA reflux in acetic acid.

30% H2O2

Scheme 16 Synthesis of 5-fluorovanillin synthesis

3 C6H12N4 H2O 2H+ 6 HCHO 2 Cr(III)Cr

O OH

O OQ

2 QH2C

HNCH2

NH

CH2

N

HC NOH

2

Scheme 17 Oxidation of hexamine

C6H12N4

conc. HCl

EtOH3 NH4Cl 6

NH3Cl

R

H

O

H

Scheme 18 Synthesis of amine

hydrochloride and

formaldehyde

J IRAN CHEM SOC

123

hydrazine sulfate) to form formaldehyde and ammonium

sulfate. Formaldehyde reacts with hydrazine (from hydra-

zine sulfate) to form tetraformal triazine (TFTA) and

water. The TFTA continues to polymerize with excess of

formaldehyde to form the gelatinous formazin precipitate

[23].

Formylation reagent

Formylation is a useful reaction in heterocyclic chemistry

where it is widely used to gain access to multifunctional

compounds. Several methods can be used to prepare het-

erocyclic formyl compounds. Among those several

N

N

N

N

O

H

H

O

H

H

N N

H

H

H

H

N

N N

N

N

Nn H2O

XFormazinHydrazine

n n/2

6

Formaldehyde

6 H2O 2 H2SO4 2 (NH4)2 SO4


formazin

OH OH

H

O

HMTA

CH3COOH, 130oC, 2 hH2SO4

Scheme 20 Synthesis of 3,5-di-

tert-butylsalicylaldehyde

N

N

N

N

Hal

Ar

C6H12N4Br

Ar

H

Ar

O

Heat

H2O

Scheme 21 Sommelet reaction

NN

N

N H2CC6H5

CH2

BrN

N

N+

N

CH2

H2C

C6H5

NN

N

CH2+N

CH2

H2C

C6H5

Br-

Br-

NN

N

N

CH

H2C

C6H5

CH3

OH-

NN

N

N

HC

H2C

C6H5

CH3

H--transfer

OH

NN

NH2

N

CH

H2C

C6H5CH3

O

Scheme 22 Mechanism of Sommelet reaction

J IRAN CHEM SOC

123

methods one is formylation by hexamine-assisted Somm-

elet [3] and Duff [2] reactions.

The Duff [2] reaction or hexamine aromatic formylation

is a formylation reaction used in organic chemistry for the

synthesis of benzaldehydes with hexamine as the formyl

carbon source. The electrophilic species in this electro-

philic aromatic substitution reaction is the iminium ion

CH2?NR2. The initial reaction product is an iminium

which is hydrolyzed to the aldehyde. The reaction requires

strong electron-donating substituents on the aromatic ring

of phenol. Formylation occurs ortho to the electron-

donating substituent preferentially, unless the ortho posi-

tions are blocked, in which case the formylation occurs at

para position. Example is the synthesis of 3,5-di-tert-

butylsalicylaldehyde (Scheme 20).

The Sommelet [3] reaction (Scheme 21) is an organic

reaction in which a benzyl halide is converted to an alde-

hyde by action of hexamine and water. The reaction is

formally an oxidation of the carbon. In the related aldehyde

synthesis, the oxidizing reagent is a combination of pyri-

dine and p-nitrosodimethylaniline. The reaction has proved

useful for the preparation of aldehydes from amines and

halides. Various types of aromatic, heterocyclic, some

aliphatic aldehydes and amines have been prepared by

applying this reaction [24].

The hexaminium salt derived from halide undergoes

hydride transfer to form the carbenium salt which reacts

with the nucleophilic hydroxyl ion present to yield inter-

mediate which, in turn, undergoes cleavage to give the

aldehyde and the amine (Scheme 22) [3, 5].

(a) a- and b-Carboxaldehydes synthesis: Heteroaromatic

a- and b-carboxaldehydes were prepared by the formyla-

tion of a-lithio benzofuran, benzothiophene, N-methyl-

benzimidazole and 10-methylphenothiazine, obtained by

direct lithiation and b-lithio compounds from lithium–

bromine exchange, with DMF. Dialkoxybenzaldehydes

were prepared by the formylation of dialkoxybenzenes

with hexamethylenetetramine (Scheme 23) or by the

alkylation of dihydroxybenzaldehydes with alkyl bromides

or iodides. Similar HMTA formylation of 1,3-diphenoxy-

benzene afforded novel 2,4-diphenoxybenzaldehyde in

57 % yield [25].

(b) p-Chlorobenzaldehyde synthesis: p-Chlorobenzal-

dehyde can be prepared from p-chlorobenzyl chloride with

hexamethylenetetramine and subsequent hydrolysis

(Scheme 24) [26].

(c) 2,6-Dialkoxybenzaldehydes synthesis: The formyla-

tion of 1,3-diphenoxybenzene with n-BuLi/DMF gave a

single regioisomer, 2,6-diphenoxybenzaldehyde, in 70 %

yield. In contrast, the formylation with HMTA in the

mixed-solvent (CF3COOH/CH3COOH = 1:1) produced

solely 2,4-diphenoxybenzaldehyde in 57 % yield

(Scheme 25). The two phenoxy groups activate the

2-position proton for ortho-lithiation by n-BuLi; however,

when it reacts with the larger reagent HMTA, significant

stereo hindrance at the 2-position by the two phenoxy

groups directs the formylation to the less hindered

4-position. Therefore, the formylation with n-BuLi/DMF or

HMTA afforded 2,6-diphenoxybenzaldehyde or 2,4-di-

phenoxybenzaldehyde, respectively, with high regioselec-

tivity [27].

(d) 5-Formyl ethylvanillin synthesis: 5-Formyl ethylva-

nillin (4-hydroxy-5-ethoxy-isophthalaldehyde) obtained by

Duff reaction from ethylvanillin, hexamethylenetetramine

in acid medium was condensed with aromatic amines to

obtain Schiff bases (Scheme 26). The reaction of 5-formyl

ethylvanillin with aromatic amines was realized in equi-

molecular ratio between the reagents. When the Schiff

bases are formed one can observe that from the two formyl

groups of the 5-formyl ethylvanillin, more susceptible in

the reaction is the CHO group, situated in the ortho posi-

tion toward the hydroxyl group. The greater reactivity of

the formyl group, explained by the possibility to form a

chelate with the neighboring OH group was also observed

CHO

HMTARO

RO

RO

RO

Scheme 23 Synthesis of dialkoxybenzaldehydes

CH3

Cl

CHCl2

ClCl

H

OCl2

PCl5

light, heat

H2SO4

H2O

Scheme 24 Synthesis of p-

chlorobenzaldehyde

OPh

OPh HMTA

57%

O O

OHC

Scheme 25 Synthesis of 2,6-

dialkoxybenzaldehydes

J IRAN CHEM SOC

123

in the condensation reactions with bases containing nitro-

gen and with compounds containing ‘‘methylene active’’

groups [28].

(e) 2-R-5-Formyl-1,3,4-thiadiazole synthesis: Taking

into account the high reactivity of the chloromethyl group

the applicability of the Sommelet [3] reaction to the for-

mation of the desired aldehydes had been discussed. The

key intermediates of the Sommelet reaction, the quaternary

hexamethylenetetramine salts were prepared after refluxing

the 2-R-5-chloromethyl-1,3,4-thiadiazole derivatives with

hexamethylenetetramine in chloroform, when the salt

products crystallized out. Hydrolysis of the hexamethy-

lenetetramine salts was performed with 50 % acetic acid

under reflux. The Sommelet reaction allowed the synthesis

of 2-R-5-formyl-1,3,4-thiadiazole derivatives with yields of

65–69 % (Scheme 27) [29].

(f) Isophthalaldehyde synthesis: The procedure descri-

bed is a modification of the general procedure of Angyal

for the preparation of aldehydes from benzylamines by the

Sommelet reaction. Isophthalaldehyde has been prepared

from a,a0-dibromo-m-xylene by the Sommelet reaction

(Scheme 28). Isophthalaldehyde is a valuable intermediate.

Although the yields obtained by some of the other reported

methods of preparation are better than the yield obtained

here, the availability of starting material and the simplicity

of reaction make this method attractive. This appears to be

the first reported case of the Sommelet reaction starting

with a diamine [30].

(g) 1-Naphthaldehyde synthesis: 1-Naphthaldehyde has

been obtained by means of the Sommelet reaction

(Scheme 29) from a-chloro- or a-bromomethylnaphthalene

and hexamethylenetetramine in aqueous alcohol or glacial

acetic acid. This method has been improved in the present

procedure by the use of 50 % acetic acid as a solvent [31].

(h) b-Naphthaldehyde synthesis: b-Naphthaldehyde has

been prepared from b-chloromethylnaphthalene by the use

CHO

OH

C2H5O

CHO

OH

C2H5O CHO

CHO

OH

C2H5OCH

N

H2NC6H12N4/CH3COOH 50%

Scheme 26 Synthesis of 5-formyl ethylvanillin

S

NN

CH2ClR

C6H12N4

CHCl3NO S

NN

CHO50% CH3COOH

Scheme 27 Synthesis of 2-R-5-

formyl-1,3,4-thiadiazole

N

N

N

N

CH2NH2

CH2NH2

CHO

CHOHCl, aq. HOAc, heat

Scheme 28 Synthesis of isophthalaldehyde

N

N

N

N

CH2Cl

HOAc,

CH2.C6H12N4+Cl-

HCl

CHOScheme 29 Synthesis of

1-naphthaldehyde

CN C

Cl

HC

NH

NH . SnCl4 . HCl

HCl SnCl2

HCl

H2O,

heat

CHO


2-naphthaldehyde

J IRAN CHEM SOC

123

of hexamethylenetetramine in ethanol, (Scheme 30) or

from b-bromomethylnaphthalene by the use of hexameth-

ylenetetramine in ethanol or in acetic acid [32].

(i) o-Hydroxy aromatic aldehydes synthesis: Duff [33]

reaction allows the preparation of ortho-hydroxy aromatic

aldehydes. The procedure consists the treatment of phenols

with hexamine in glyceroboric acid (HBO2 in dry glycerol)

or glacial acetic acid. The reaction seems to involve an

aminomethylation, forming secondary amine, which

undergoes the Sommelet reaction to yield an aldehyde

(Scheme 31).

(j) Phenoxazinone synthesis: Alkylation of hydroquinones

and monomethyl ether with methyl iodide was carried out and

the yields of the corresponding dimethyl ethers were excellent

(82–99 %). The introduction of the hydroxyl group onto the

aromatic ring, to form the phenols, was then accomplished via

the Baeyer–Villiger oxidation of the corresponding benzal-

dehydes, which were prepared using the Duff reaction, with

hexamine as the formylating agent, in refluxing trifluoroacetic

acid. No product was isolated from the attempted formylation

of the tert-butyl substituted hydroquinone ethers, presumably

due to the cumulative steric hindrance of the bulky tert-butyl

and methoxy groups. Baeyer–Villiger oxidation of aldehydes

with magnesium monoperoxyphthalate (MMPP), followed by

the hydrolysis of the formate esters, gave the corresponding

phenols (Scheme 32) [34].

H3C

OH

H3C

OH

HN

HO

CH3

H3C

OH

N

HO

CH3 H3C

OH

HC H2N

HO

CH3O

HMTAHMTA

H+


o-hydroxy aromatic aldehydes

OH

OH

OMe

OMe

OMe

OMe

OHC

OMe

OMe

HO

NaH, MeI,

DMF, 40oC,1 h

hexamine,

TFA, reflux

MMPP, MeOH

NaOH then HCl


phenoxazinone

OH

OHHO

OH

OHHO

CHOOHC

CHO

Hexamine, CF3CO2H

HCl

Scheme 33 Synthesis of phloroglucinol

N

N

N

N

OH

MeO OMe

OH

MeO OMe

CHO

, heat

H2SO4, H2O


syringic aldehyde

N

N

N

N

S

CH2Br

S

C6H12N4Br

distill salt

S

CHO


3-thiophenecarboxaldehyde

J IRAN CHEM SOC

123

(k) Phloroglucinol synthesis: Phloroglucinol-based

polyphenolic compounds have been synthesized

(Scheme 33). Polyphenol was synthesized through Vils-

meier–Haack formylation, Schiff-base condensation of

diformyl-phloroglucinol with 4-amino salicylic acid and

Duff formylation reactions, respectively. The polyphenol

has been synthesized through Duff formylation reaction on

phloroglucinol. In a typical synthesis, 1 equivalent phlor-

oglucinol was activated by drying in a 900 �C oven over-

night. This activated phloroglucinol was mixed with

hexamine (2.2 equiv.) and 40 ml of trifluoroacetic acid and

heated to reflux for 3 h under nitrogen atmosphere. To this

3 M HCl was added slowly with continuous stirring and

again refluxed for 1 h. After cooling to room temperature,

the reaction mixture was extracted three times with ethyl

acetate. The combined organic part was concentrated by a

rotary evaporator to get an phloroglucinol [35].

(l) Syringic aldehyde synthesis: This procedure is a

modification of the method described by Manske and

co-workers (Scheme 34). Syringic aldehyde has also been

obtained by numerous other procedures from pyrogallol-

1,3-dimethyl ether from gallic acid, and from vanillin [36].

(m) 3-Thiophenecarboxaldehyde synthesis: 3-thenalde-

hyde has previously been prepared from 3-thienylmagne-

sium iodide and ethyl orthoformate in low yield. The first

application of the method described here was reported by

Campaigne and LeSuer [37] (Scheme 35). 3-Thenaldehyde

also has been obtained from 3-thenoic acid by the Sonn–

Muller procedure and from 3-bromothiophene by treatment

with butyllithium and dimethylformamide.

(n) 2-Thiophenealdehyde synthesis: 2-Thiophenealde-

hyde has been prepared by the hydrolysis of 2-the-

nylmethylhexamethylenetetrammonium chloride in neutral

solution (Scheme 36) [38].

(o) The Duff [2] reaction (HMTA, AcOH or TFA) was

studied on substituted [6?5] heterocyclic compounds. This

reaction provided a useful route to aldehydes for com-

pounds bearing sensitive amide functions. The formation of

an aminomethyl intermediate in the Duff reaction mecha-

nism is unequivocally demonstrated. It has been assumed

that the mechanism of the Duff [2] reaction involves an

aminomethylation (generated from HMTA) of the sub-

strate, followed by the dehydrogenation of the amine to the

corresponding imine, which is hydrolyzed to give the for-

myl group (Scheme 37) [39].

(p) Studies have suggested that the Sommelet [3] reac-

tion involves oxidation–reduction reactions. The amine is

N

N

N

NS

Cl

CHCl3

Cl- H2Oheat

heatN

N

N

NS

HS

O

Scheme 36 Synthesis of 2-thiophenealdehyde

OR1

O

R2HMTA

solvent

A = CH2NH2 or CHO

OR1

O

R2

A

Scheme 37 Duff reaction

NN

N

N

XH2C R

NN

N

N

H2C R X-

H2NH2C R HN CH2

H2OO C

HR NH3 H2N CH3

H+


aldehyde and ammonia

N

N

MeRN

NH2

EtO2CN

N

Me

CHO

HN

O

NEt2

CH3COCH2Cl,EtOH, heat HMTA,

AcOH, 90°C

Scheme 39 Synthesis of formyl derivatives

J IRAN CHEM SOC

123

oxidized by methylamine to the aldehyde and ammonia

(includes hydride transfer step) (Scheme 38) [5, 40]

(q) Position 3 of the imidazo[1,2-a]pyridine ring is the

most preferred position for electrophilic aromatic substi-

tutions. This position can be easily functionalized with a

formyl group. The Vilsmeier–Haack reaction was generally

considered to offer the best yields of formyl derivatives.

Duff formylation (hexamine in acetic acid or TFA), already

used on several heterocyclic systems and also found to be

efficient. Under TFA conditions, no reaction was observed

and only starting material was recovered. In the presence of

acetic acid, the Duff reaction led to acceptable yields of

formyl compounds (Scheme 39) [39].

(r) A modification of Duff reaction uses trifluoroacetic

acid as solvent and a variety of aromatic compounds can be

converted into aldehydes (Scheme 40) [5].

Glycine ethyl ester hydrochloride synthesis

Glycine ethyl ester hydrochloride has been prepared by

several methods. Among these methods one is by the action

of ammonia or hexamethylenetetramine on chloroacetic

acid (Scheme 41), and subsequent hydrolysis with alco-

holic hydrochloric acid [41, 42].

Heterocycles synthesis

Recently, hexamine was used in synthesis of five-, six-, and

seven-membered heterocycles. In these cyclization pro-

cesses, hexamine supplies one or two nitrogen atoms, or a

–CH = N– function, to the newly formed heterocycles.

(a) 1,4-Benzodiazepine synthesis: Hexamine was widely

used for cyclization of 1,4-benzodiazepines. Large rate

differences were observed if substituent is present on

amino group in the starting 2-aminobenzophenones.

N-Unsubstituted 2-aminobenzophenones undergo decom-

position to give imidazolidin-4-one type product. The

NN

N

N

Ar H Ar CHOCF3COOH

H2O

Scheme 40 Synthesis of aldehydes

H2C NCH2CNEtOH, heat

HCl, H2OClH.H2N

OEt

O

Scheme 41 Synthesis of glycine ethyl ester hydrochloride

Cl

N

C6H5

O

NH.HCl

O

Cl N

HN

O

C6H5

C2H5OH


benzodiazepine

Cl

N C

CH3 O

N

C6H5

O

N

N

N

Cl-

Cl

N C

CH3 O

C6H5

N

NNN

OCl

N C

CH3 O

N

N

NN

C6H5O

C2H5OH

Cl

N C

CH3 O

N

N

NN

C6H5O

OC2H5

N

N

H3CO

C6H5

NN

N

OC2H5

OHCl

C2H5OH

N

N

Cl

CH3O

C6H5

Scheme 43 Synthesis of 1,4-benzodiazepine-2-one

J IRAN CHEM SOC

123

imidazolidinone ring recyclized into 1,4-benzodiazepine

under the influence of hexamine (Scheme 42) [5, 43].

The method adopted for the benzodiazepinone synthesis

proceeded in two steps: the first step was the formation of a

hexaminium salt, which in the second step, underwent

alcoholysis to give the desired 1,4-benzodiazepine-2-one

derivative (Scheme 43) [5, 43].

Treatment of the 2-(N-b-haloalky)-amino-5-chlor-

obenzophenone with hexamine in ethanol resulted in ring

closure to give a mixture of 2-deoxy-1,4-benzodiazepines

(Scheme 44). b-Partcipation of the vinylogous-amide-

nitrogen took place during ammonolysis of the 2-(b-hal-

ophenyl) derivatives. However, an intermediate formation

of aziridinium derivatives cannot be conveniently demon-

strated when 2,3-unsubstituted benzodiazepines are the

expected products of reaction, since the same product

would be formed by both direct ring closure, or b-partici-

pation of the N-2 atom. In the preparation of chiral

derivatives, however, different structural and stereoisomers

should arise [5, 44].

Hexamine can be used to oxidize a preformed tetrahydro

seven-membered ring, as in the synthesis of 2,3-dihydro-

1,4-benzodiazepine starting from 1,2,3,4-tetrahydro deriv-

atives (Scheme 45) [45, 46].

Ogata and Motsumoto [47] very elegantly used charac-

teristics of isatin to develop a highly innovative technique

for the synthesis of 5-carbomethoxy-substituted 1,4-ben-

zodiazepine-2-ones and its 7-chloro derivatives from the

corresponding 1-chloroacetyl isatins. Their procedure

consisted of treating 1-chloroacetyl isatin with methanolic

solution of hexamine. Under these conditions, isatin

underwent the cleavage of the ring, followed by the cy-

clocondensation of the ring-opened product, to give the

desired 1,4-benzodiazepine-2-one-5-carboxylate deriva-

tive, in a single step. An attractive feature of this reaction

was that it provided a very convenient one-pot synthetic

entry to the 1,4-benzodiazepine nucleus from 1-chloro-

acetyl isatin (Scheme 46) [48].

A representative of 1,4-benzodiazepine class is alpraz-

olam which contains a 1,2,4-triazole fused to the benzo-

diazepine core. The synthesis of this molecule can be

accomplished in a short sequence of steps starting by

acylation of 2-amino-5-chlorobenzophenone with chloro-

acetyl chloride to give the amide derivative. The latter

undergoes an interesting ring closure reaction in the pres-

ence of hexamine and ammonium chloride and the result-

ing seven-membered lactam can then be converted into its

thioamide analog with P2S5 in pyridine. Finally, the reac-

tion with acetyl hydrazide catalyzed by acetic acid fur-

nishes the triazole ring fused to the benzodiazepine core

(Scheme 47) [49].

1,4-Benzodiazepine is prepared from Boc-protected

3-chloro-aniline via the formation of dianion species with

Cl

N

R1

R3

R2X

C6H5

O

Cl

N

R1

C6H5

O R3

R2

X-

N

N

R1

R2

R3

C6H5

Cl N

N

R1

C6H5

Cl

R2

R3

HMTA

Scheme 44 Synthesis of 2-deoxy-1,4-benzodiazepines

Cl NH

N

H3C

C6H5

Cl N

N

H3C

C6H5

AcOH, 3.5 h, reflux

HMTA


dihydro-1,4-benzodiazepine

R2

HN

O

O

R1

R2

N

O

O

R1

COCH2Cl R2

R1N

HN

O

COOMe

ClCOCH2Cl

MW

Hexamine

methanolMW

Scheme 46 Synthesis of 1,4-benzodiazepine-2-one-5-carboxylate

J IRAN CHEM SOC

123

tert-BuLi followed by deprotection of Boc group

(Scheme 48). Chloroacetylation of compounds with chlo-

roacetyl chloride in the presence of N,N-diisopropylethyl-

amine (DIEA) in dichloromethane (DCM) gave the

corresponding N-(chloroacetyl)-2-aminobenzophenone

derivatives whose reaction with hexamethylenetetramine in

EtOH in the presence of NH4OAc provided 1,4-benzodi-

azepine ring [50].

Aniline derivatives on reaction with benzoyl chloride in

presence of aluminum chloride and CCl4 provided

Cl

NH2

OCl

NH

O

OCl

N

N

Cl

N

HN

Cl

O

N

HN

Cl

S N

N

ClCl

O

NH

NH2

O

hexamine,

NH4Cl,EtOH

P2S5

pyridine n-BuOH, HOAc

alprazolam

Scheme 47 Synthesis of alprazolam

NH2

Cl

NHBoc

Cl

NH2

ClO

NHCOCH2Cl

ClO

Cl N

HN

O

R1

R1R1

(Boc)2 O, DIEA, t-BuLi, 3 N HCl

ClCH2COCl, DIEA, toluene

HMTA, NH4OAc, EtOH,

Reflux

DCM

Scheme 48 Synthesis of 1,4-benzodiazepine

HN

Cl

C

O

CH2ClCOCl

AlCl3

CCl4

Hexamine

ethanol

NH4Cl

HN

Cl

C

O

CH2Cl

O

N

HN

Cl

O

Scheme 49 Synthesis of 7-chloro-5-phenyl-1,3-dihydro-1H,3H-1,4-benzodiazepine-2-one

J IRAN CHEM SOC

123

intermediate whose further reaction with hexamine/NH4Cl

in the presences of absolute ethanol produced 7-chloro-5-

phenyl-1,3-dihydro-1H,3H-1,4-benzodiazepine-2-one

(Scheme 49) [51].

Synthesis of methylflunitrazepam

7-Nitro-1-methyl-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-

benzodiazepin-2-one (Flunitrazepam) is the drug from

family of seven-membered heterocyclic compounds 1,4-

benzodiazepinones. Although a number of methods for the

synthesis of flunitrazepam have been reported in literature,

they suffer because of using anhydrous ammonia or dry

ammonia gas. In this research work, the new method for

synthesis of flunitrazepam from 2-flouroacetamido benzo-

phenone, hexamethylenetetramine and ammonium chloride

in ethanol as solvent to generate ammonia in situ was

reported (Scheme 50). The results indicate that the best

result obtained when the mole ratio of the components

acetamide:NH4Cl:hexamine:ethanol in order was as

1.0:3.5:2.5:20–30 [52].

The 2-amino-40-flouro-benzophenone (ADZ-01) was

reacted with chloroacetylchloride to afford 2-chloro-N-(2-

(40-fluorobenzoyl) phenyl)acetamide (ADZ-02). It was

subsequently converted to 1,4-benzodiazepines (ADZ-03)

by the modification of the known hexamethylenetetramine-

based cyclization reaction (Scheme 51) [53, 54].

A series of some substituted aniline derivatives of

7-chloro-5-phenyl-1,3-dihydro-1H,3H-1,4-benzodiazepine-

NH2

O2NO

F

NHN

O

NO2

F

N

N

N

N

NH4Cl

C2H5OHMeI

Flunitriazepam


flunitrazepam

NH2

O

F

Cl

O

Cl

Toluene

HexamineCH3COONH4

EtOH

NH

O

F

Cl

O

N

HN

O

FADZ-01ADZ-03ADZ-02


benzodiazepines (ADZ-03)

Cl

HN C CH2Cl

O COCl

AlCl3

CCl4

Hexamine

ethanol

NH4Cl Absolute ethanol

H2N

Cl

HNC CH2Cl

O

C

O

N

HN

O

ClN

HN

N

Cl


7-chloro-5-phenyl-1,3-dihydro-

1H,3H-1,4-benzodiazepine-2-

one

J IRAN CHEM SOC

123

2-one were synthesized by treating 7-chloro-5-phenyl-1,3-

dihydro-1H,3H-1,4-benzodiazepine-2-one with the differ-

ent type of aniline derivatives in the presence of absolute

ethanol. N-(2-benzoyl-4-chlorophenyl)-2-chloroacetamide

was dissolved in ethanol after that hexamine and the

ammonium chloride were added and the reaction resulted

in the formation of product (Scheme 52) [55].

(b) Benzothiazole synthesis: The compound was reacted

with N-bromosuccinimide in dry benzene and subsequently

it was reacted with aqueous sodium cyanide in tetrahydro-

furan (THF) to form a benzothiazole vinyl phenyl acetoni-

trile. Similarly, compound was reacted with N-bromo-

succinimide and excess of aqueous hexamethylenetetramine

in chloroform and then refluxed with a mixture of glacial

acetic acid and water to obtain the benzothiazole vinyl

benzaldehyde. The elaboration of the conjugated system was

performed by reacting equimolar quantities of both above

compounds in dry THF and tert-butyl alcohol at 50 �C while

a small amount of tetrabutylammonium hydroxide was

slowly dropped into the mixture (Scheme 53) [56].

(c) Benzo[b]thiophene synthesis: Benzo[b]thiophen-

3(2H)-one-1,1-dioxide is a versatile reagent containing a

sulfonyl group for the synthesis of polycyclic pyridines.

Starting compound with aromatic aldehydes easily formed

2-ylidene derivatives. 1,5-Dicarbonyl derivatives were

obtained in the reaction of compound with aromatic

NH2

SH

HOOC

S

N

S

N

CN

S

N

O

H

S

N

CN

S

N

POCl3, at reflux,

4 h, 80%

NBS, benzene, benzoyl peroxide; 10 h

NaCN/ H2O, THF, 50oC, 24 h, 40%

POCl3, at reflux, 4 h, 80%HMTA/H2O, CHCl3, at reflux, 12 h

AcOH/H2O, at reflux, 2 h, 25%

t-BuOH/THF,n-Bu4OH,1 h, 96%

Scheme 53 Synthesis of benzothiazole

S

O

OO

S

O

OO

SO O

O

SO O

NH

R

S

OO

O

MeI/NaH

RCHO, EtOH/DMF,

rt or reflux

R

SO O

N

R

S

OO

O

Me

HMTA

AcOH/DMF

or Me2SO4/NaH


benzo[b]thiophen-3(2H)-one-

1,1-dioxide

J IRAN CHEM SOC

123

aldehydes in ethanol/DMF mixture in the presence of cat-

alytic piperidine and acetic acid at reflux temperature in

2 h. The condensation of derivatives with hexamethy-

lenetetramine in acidic medium led to the expected new

heterocyclic spirosystems, which might reasonably arise

from an internal Mannich reaction of compounds due to

the steric hindrance of the aryl substituent. The intramo-

lecular addition of amino group to the carbonyl group

furnished dihydrodibenzothienopyridines via Hantzsch

type cyclization. Alkylation of compound required rather

drastic conditions, such as MeI/NaH and Me2SO4/NaH

(Scheme 54) [57].

(d) Chromone synthesis: Rossing method is used for the

synthesis of 2-acylphenoxyacetic acids, via phase transfer

catalyst under nitrogen atmosphere to give rise to either

benzofuran or 2-acetyl benzofurans. Selective formation of

benzofurans and 2-acetyl benzofurans depends on solvent

and structural features of substrates. A mixture of

HO OH

R1

HO OH

R1

CH2R2

O

HO O

R1

O

Ph

R2

HO O

R1

O

Ph

R2

CHO

R2CH2COOHanhy ZnCl2

140oCPhCOCl

acetone/K2CO3

refllux, 8 h

hexamine

AcOH

Scheme 55 Synthesis of chromone

OH

OH

O

H

OH

O

O

Me

Me

OR

O

O

R

Me

CHO

R

O

O

Me

Me

OMe

OMe

O

O

Me

Me

R

H

O

O

Me

Me

N

Me

SiO2 (100%)

Ac2O, NaOAc,

Et3N,HCl (56% overall)

Hexamine, H2O,

AcOH, 100°C, 2.5 h (72%)

HC(OMe)3, CSA,

MeOH, r.t., 24 h (97%)

n-Bu3SnCHCH2CH2,Pd(PPh3)2Cl2, LiCl, PPh3,

BHT, DMF, 18 h (80%)


pyridinechromone

HO OH O

CH3

OHO

EAA

O

CH3

OHO

CHO

H2SO4 (80%)

1 h HCl

Hexamine/GAA

Scheme 57 Synthesis of 3-aryl-[(1-isocyano-4-methyl-7-hydroxycoumarin)]-5-methyl-1,3,4-triazoline-2-one

J IRAN CHEM SOC

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8-formyl-7-hydroxy chromones react with ethyl bromo

acetate in K2CO3 as phase transfer catalyst under nitrogen

atmosphere to give ethylfuro[2,3-h]chromone-8-carboxyl-

ates in good yields (Scheme 55) [58].

When the Kostanecki–Robinson synthetic sequence was

carried out on ketone, it afforded 56 % yield of chromone

intermediate which was immediately subjected to a Duff

formylation.

Experiments toward the oxidative fission of the allyl

moiety were next carried out. Initially, to avoid potential

over oxidation of the substrate, the phenol was protected as

the corresponding mesylate. Therefore, considering the

instability of the mesylate group to the reaction conditions,

the direct transformation was performed under the same

conditions. Although there are scattered precedents sug-

gesting that aldehyde could withstand the conditions of the

Stille cross-coupling reaction, the palladium-catalyzed de-

carbonylation of aromatic aldehydes and the Pd-catalyzed

allylation of aldehydes with allyltributyltin are well-docu-

mented transformations. In fact, when the transforma-

tion was attempted with n-Bu3SnCH2CH2CH2, products

resulting from 1,2-addition to the carbonyl were obtained

when Pd(PPh3)2Cl2 was employed as catalyst. On the other

hand, use of Pd(PPh3)4 resulted in decarbonylation or com-

plete degradation of the starting material. Therefore, the

carbonyl moiety was protected as the corresponding dime-

thyl acetal in 97 % yield with HC(OMe)3 and catalytic

amounts of camphorsulfonic acid in MeOH. Interestingly, it

was observed that the acetal was readily hydrolyzed during

acidic workup. Oximation of aldehyde in the presence of

excess methoxylamine hydrochloride and sodium acetate

as base furnished 76 % of oxime, as a single isomer

(Scheme 56) [59].

(e) Coumarins synthesis: The 3-aryl-[(1-isocyano-4-methyl-

7-hydroxycoumarin)]-5-methyl-1,3,4-triazoline-2-one and its

substituents were obtained by the condensation of amino group

of mono and disubstituted derivatives of 3-methyl-5-oxo-1,2,4-

triazoles with 8-formyl-7-hydroxy-4-methylcoumarin in alco-

hol. The synthesis of 8-formyl-7-hydroxy-4-methyl-coumarin

is assisted by hexamine (Scheme 57) [60].

(f) 1,4-Diazepine synthesis: Chloro acetylation of 1-amino-

2-benzoyl-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]

NO N S

NH2

O

NO N S

HN

O

Cl

O

NO N S

NO N S

HN

O

C6H12N4]+Cl-

O N

HN

O

ClCH2COCl

Dioxane

(CH2)6N4/EtOH

Scheme 58 Synthesis of 5-morpholin-4-yl-8-phenyl-1,2,3,4,10-pentahydro[1,4]diazepino[5,6:4,5]-thieno[2,3-c]isoquinolin-11(12H)-one

MeN

NMe

OH

O

O

MeN

NMe

O

O

MeN

NMe

OH

O

O

Br+O

H1

H9

H7

H8

H2

Br

H4

H3

H6

H5

5-exo trigC6H12N4HBr3,CH2Cl2, 15 min

Scheme 59 Synthesis of 6-bromo-1,3-dimethylhexahydrobenzofuro[3,2-d]pyrimidine-2,4-dione

N

N

Cl

H

N

N

N

N

N

NNaHCO3

meltN

N

N

N

Scheme 60 Synthesis of hexaazapolycycle

J IRAN CHEM SOC

123

isoquinoline using chloroacetyl chloride in dioxin on a

steam bath followed by treating with sodium carbonate

solution afforded N-(2-benzoyl-5-morpholin-4-yl-6,7,8,9-

tetrahydrothieno[2,3-c]isoquinolin-1-yl)-2-chloroacetamide.

Refluxing chloro acetylamino derivative with hexamethy-

lenetetramine in ethanol yielded 5-morpholin-4-yl-8-phenyl-

1,2,3,4,10-pentahydro [1, 4] diazepino[5,6:4,5]thieno[2,3-c]

isoquinolin-11(12H)-one through formation of hexaminium

salt as intermediate (Scheme 58) [61].

(g) Furan synthesis: 6-(Cyclohex-2-enyl)-1,3-dimethyl-

5-hydroxyuracil when treated with hexamine hydrotribro-

mide in methylene chloride at 0–5 �C for 15 min furnished

6-bromo-1,3-dimethylhexahydrobenzofuro[3,2-d]pyrimi-

dine-2,4-dione in 92 % yield. It may be noted that similar

cyclization of o-cyclohexenyl phenols with pyridine

hydrobromide generated bicyclic heterocycles by a 6-endo

cyclization (Scheme 59) [62].

(h) Hexaazapolycycle synthesis: When 2-chlorometh-

ylbenzimidazole, hexamethylenetetramine and NaHCO3

were mixed under argon and the melt was heated within

5 min from 120 to 160 �C hexaazapolycycle dye was

formed (Scheme 60). The raw material was extracted with

CH2Cl2 (to remove other impurities) and water (to remove

the salts). The dried residue obtained was pure [63].

(i) Imidazole synthesis: Several chloro-, bromo-, and

nitro-1H-phenanthro[9,10-d]imidazoles were synthesized

from phenanthroquinones, ammonium acetate, and hexa-

mine (Scheme 61) [5, 64].

Starting from 2-chloroacetamido-5-chlorobenzophe-

none, the hexaminium salt was synthesized, which

decomposed in alcoholic solution giving bis- and mono-

imidazolidin-4-one derivatives (Scheme 62) [65].

(j) Indole synthesis: Dauth and Becker [66] developed a

method for the preparation of 1,3-dihydroisoindole via a

hexaminium salt (Scheme 63).

(k) Isoquinoline synthesis: 2-Substituted benzyl bro-

mides form stable quaternary compounds with hexamine in

acetonitrile. In chloroform solution containing small

amounts of water or ethanol, however, decomposition takes

place, yielding the aldehyde. When compound contained a

O

O

R1

R2

R3

R4

R5

R6

R1

R2

R3

R4

R5

R6

N

HNHMTA/NH4OAc/AcOH


imidazole

HN

O

ClO

C6H5

Cl

HMTA/CH3CN

HN

O

NO

C6H5

Cl

N

NN Cl-

C2H5OH

HCl/C2H5OH

ClO

C6H5

N N

O

N N

O

Cl

C6H5

O

ClO

C6H5

N NH.HCl

O

Scheme 62 Synthesis of bis-

and mono-imidazolidin-4-one

X

X

HMTA/CHCl3

50oC

X

N N

N

N

X-

HCl/C2H5OH

NH


dihydroisoindole

J IRAN CHEM SOC

123

carbonyl group in 2-position of the side chain, the main

products formed were isoquinolines, accompanied by

minor amounts of aldehydes (Scheme 64) [5, 67].

Researchers have envisaged the synthesis of 5-hydroxy-

1-hydroxy (or acyloxy)methylisoquinoline as an efficient

substrate for a new regioselective oxidation of the iso-

quinoline-5,8-dione antibiotics based on a retrosynthetic

analysis. For the preparation of a ketoxime, that is, a

1-azahexatriene system, began with 2,4-dimethoxy-

3-methylbenzaldehyde. 2,4-Dimethoxy-3-methylbenzalde-

hyde was treated with boron tribromide to produce

the 2-hydroxybenzaldehyde, which was converted into the

benzyl ether. The benzaldehyde was subjected to the

Baeyer–Villiger reaction with m-chloroperbenzoic acid to

O

Br

HMTA/CH3CN

O

N

N

N

NBr-

NO

CHO

CHCl3/H2O/C2H5OH


isoquinoline

OMe

CHOMe

MeO

OH

CHOMe

MeO

O

CHOMe

MeO

Ph O

OHMe

MeO

Ph

O

OHMe

MeO

Ph

CHO

O

OTfMe

MeO

Ph

CHO

O

Me

MeO

Ph

CHO

O

Me

MeO

Ph

OH

OH

O

Me

MeO

Ph

OH

OTBDMS

O

Me

MeO

Ph

O

OTBDMS

O

Me

MeO

Ph

NOH

OTBDMS

O

Me

MeO

Ph

N

OTBDMS

BBr3

CH2Cl2

mCPBA

CH2Cl2

(CH2)6N4

AcOH

H2O, Py

CH2Cl2

B2H5, K2CO3

DMF

Bu2Sn

PdCl2(PPh3)2

DMF, 110oC, 1 h

Me2(iPrO)SiCH2ClMg, THF, 0oC, 1 h

KF, KHCO3,30% H2O2, THF,

MeOH, rt, 3 h

TBDMSCl

Et3N, imidazoleDMF, rt, 12 h

PCC

CH2Cl2,rt, 5 h

NH2OH.HCl

AcONa, EtOH,85oC, 1 h

o-dichlorobenzene

180oC, 1 h

Scheme 65 Synthesis of 5-hydroxy-1-hydroxy (or acyloxy)methylisoquinoline

J IRAN CHEM SOC

123

give the phenol. The phenol was subjected to the Duff

reaction with hexamethylenetetramine in acetic acid, fol-

lowed by treatment with trifluoromethanesulfonic anhy-

dride to yield the triflate. The cross-coupling reaction with

vinyl tributyltin in the presence of palladium dichlorobis-

triphenylphosphine gave the ethenylbenzaldehyde whose

Grignard reaction with dimethylisopropyloxysilylmethy-

lmagnesium chloride, followed by treatment with potas-

sium fluoride and 30 % hydrogen peroxide, afforded the

1,2-diol. Selective protection of the 1,2-diol with tert-

butyldimethylsilyl chloride (TBDMSCl) produced the

TBDMS ether, which was oxidized with pyridinium

chlorochromate (PCC) to obtain the ketone. Subsequent

treatment of the ketone with hydroxylamine afforded

the ketoxime as the 1-azahexatriene system, which was

subjected to the thermal electrocyclic reaction in

o-dichlorobenzene at 180 �C to furnish the desired 5-ben-

zyloxyisoquinoline (Scheme 65) [68].

(l) Lactam synthesis: In the more acidic conditions, the

N-1 of the nucleus was largely protonated, decreasing the

electronic density of the amide carbonyl group and favor-

ing attack by the aminomethyl group in position 3 to form

the lactam cycle. In another run in AcOH, with an ethyl

ester instead of the amidic chain in C-5, tricycle was also

obtained in 16 % isolated yield (Scheme 66). This result

unequivocally demonstrated the mechanism of formation

of lactam, the nitrogen atom of the lactam cycle could only

come from the aminomethyl group. Another run with 30 %

AcOH, which offered best overall yields of lactams, raised

the yield of compound to 54 %. This result can be

explained by the oxidative conditions of the reaction. The

aldehyde group on position 5 can be converted into the acid

intermediate, which gives tricyclic compound by periann-

elation [39].

(m) Morpholine synthesis: Taking into account the high

reactivity of the chloromethyl group, we decided to study

the applicability of the Sommelet reaction to the formation

of the desired aldehydes. The key intermediates of the

Sommelet reaction, the quaternary hexamethylenetetramine

salts were prepared after refluxing the 2-R-5-chloromethyl-

1,3,4-thiadiazole derivatives with hexamethylenetetramine

in chloroform, when the salt products crystallized out.

Hydrolysis of the hexamethylenetetramine salts was per-

formed with 50 % acetic acid under reflux. The Sommelet

reaction allowed the synthesis of 2-R-5-formyl-1,3,4-thia-

diazole derivatives with yields of 65–69 % (Scheme 67)

[69].

(n) Oxazoles synthesis: Synthesis of 5-(3-indolyl)oxaz-

oles was started from 3-acetyl-1-benzenesulfonylindole.

N

N

Me

O OEt

HMTA

Solvent, 90oC

N

N

Me

NO

H

Scheme 66 Synthesis of lactam

S

NN

CH2ClR NO S

NN

CH2

NN

N

NCl-

NO S

NN

CHO

C6H12N4

CHCl350% CH3COOH

Scheme 67 Synthesis of morpholine

N

O

SO2C6H5

N

O

OTs

SO2C6H5

N

O

NH2HCl

SO2C6H5

N

O

SO2C6H5

HN R

O

NH

O

N

R

N

SO2C6H5

O

N

R

C6H5I(OH)OTs,

CH3CN, rt

CHCl3HMTA,

HCl, reflux 0-5oC;

RCOCl, Et3N,

PTSA, EtOH,

refluxNaOH, EtOH-H2O,

reflux

Scheme 68 Synthesis of 5-(3-indolyl)oxazoles

J IRAN CHEM SOC

123

The synthesis of novel 3-tosyloxyacetyl-1-benzenesulfo-

nylindole was accomplished by reaction of starting com-

pound with hydroxy(tosyloxy)iodobenzene in an excellent

yield at room temperature. 3-Aminoacetyl-1-benzene-

sulfonyl indole hydrochloride was obtained in very good

yield from the reaction with hexamethylenetetramine

(HMTA) followed by refluxing the reaction mixture in the

presence of dilute hydrochloric acid. 3-Aminoacetyl-1-

benzenesulfonyl indole hydrochloride was acylated with

the appropriate acyl chloride in the presence of triethyl-

amine to give acylaminoketones. Cyclodehydration of

acylaminoketones give 5-(3-indolyl)oxazoles was accom-

plished successfully using p-toluenesulfonic acid. In gen-

eral, cyclodehydration of acylaminoketones into oxazoles

involves harsh reagents such as H2SO4, PCl5, P2O5, SOCl2,

POCl3, Ac2O, and Ph3P. Finally, the benzenesulfonyl

moiety of 5-(3-indolyl)-oxazoles was removed using dilute

sodium hydroxide to afford the 5-(3-indolyl)oxazoles in

good yields (Scheme 68) [70].

(o) 3-Pyrroline: Pure 3-pyrroline has been difficult to

obtain. Commercially available 3-pyrroline was at one time

supplied in 85 % purity, the remaining 15 % being pyr-

rolidine. It is now supplied in only 65 % purity. Material of

97 % purity is available; however, the cost is excessively

high, limiting its use as a starting material. A three-step

preparation, based on the Delepine reaction, describes the

synthesis of this compound in high purity. However, some

difficulties were encountered in the hands of the submitters

following this procedure. Several modifications have now

led to an efficient preparation of 3-pyrroline in high purity

(Scheme 69), and to a procedure that is readily amenable to

large-scale synthesis [71–73].

(p) Quinazolines synthesis: 2-Amino-5-substituted

benzophenones reacted with hexamine, in the presence of

ethyl bromoacetate to give quinazoline derivatives. It was

found that benzophenones with electron-accepting substit-

uents gave a mixture of dihydroquinazoline derivatives

(Scheme 70). But benzophenones with electron-donating

substituents furnished only quinazoline [5, 74].

Recyclization of isatin after ring opening with hexamine

gives rise to the derivatives of the seven-membered 1,4-

benzodiazepine, while ammonia, in a similar reaction,

N

N

N

N

CHCl3

N

N

N

NCl Cl Cl +NH3Cl-

NH

Cl-Cl-

Cl91 %

HCl, EtOH

97 %N

N

63 %

Scheme 69 Synthesis of 3-pyrroline

NH2

O

C6H5

X

N

N

C6H5

X

R

N

N

C6H5

X

HMTA

BrCH2COOC2H5/ROH


quinazolines

N

OCH2C Cl

O

O

X XN

NH2C

OC NH2

Cl

NH3/C2H5OH

HMTA


quinazolones

Cl

HN R1

N R3

HO

R2

C6H5

HMTA/C2H5OH, reflux

N

N

R1

C6H5 O

R3

R2

Cl


9-chloro-10-phenyl-2,3,5,6-

tetrahydrooxazolo[2,3-

d]quinazolines

J IRAN CHEM SOC

123

causes recyclization to six-membered quinazolones

(Scheme 71) [74].

When benzophenone-imine derivatives were reacted

with hexamine in boiling ethanol, then heterocycles with

three condensed rings 9-chloro-10-phenyl-2,3,5,6-tetrahy-

drooxazolo[2,3-d]quinazolines were obtained (Scheme 72)

[74].

(q) Quinolone synthesis: Meldrum’s acid was acylated

using octanoic acid in the presence of 1,3-dicyclohex-

ylcarbodiimide (DCC) and catalytic 4-dimethylaminopyri-

dine (DMAP). This 5-acyl Meldrum’s acid was then heated

at reflux in ethanol to form a b-keto ester. Acid-catalyzed

condensation of the b-keto ester with aniline formed the

imine. The imine isomerises to the thermodynamically

more stable enamine, which undergoes a cyclo-condensa-

tion when heated in a high boiling solvent, such as diphenyl

ether, forming 2-heptyl-4(1H)-quinolone. A formyl group

was introduced at the 3-position using hexamine in the

presence of trifluoroacetic acid (TFA). The formyl group is

then transformed to a hydroxyl group via a Baeyer–Villiger

oxidation, using hydrogen peroxide (Scheme 73) [75].

5-Octanoyl Meldrum’s acid was synthesized by utilizing

the coupling reaction of starting compounds in the presence

of DCC/DMAP. 120 mL of newly distilled dichlorometh-

ane and 4-dimethylaminopyridine was added. This mixture

was stirred at room temperature until all solid was

R

O

OH O

O

O

OO

O

O

O

O

R EtO

O

R

O

NH

R

OEtO

N R

OEtO

NH

R

O

NH

R

O

H

O

NH

R

O

OH

DCC,DMAP,

DCM

EtOH Aniline, p-TSA,

C6H6

Diphenyl ether,

240°C

Hexamine,

TFA

H2O2,EtOH,

NaOH aq

Scheme 73 Synthesis of 2-heptyl-4(1H)-quinolone

HO

O

O O

OO

O O

O

O

O

DCC/DMAP

DCM, rt, 12 h

Toluene

Reflux, 24 h

Ethanol

Reflux, 4 h

Diethyl ether

Reflux, 30 min

Hexamine, TFA

1) N2, Reflux, 30 h2) MeOH/H2O 1 h3) 3M HCl, 30 min

O

O

O

H2N S OH

O

O

NH

O

O

NH

O

NH

O O

NH

O

OH

H2O2,

EtOH, 1 M NaOH

Scheme 74 Synthesis of 3-formyl-2-heptyl-4(1H)-quinolone

J IRAN CHEM SOC

123

dissolved, then dicyclohexylcarbodiimide was added and

the stirring was continued for 1 h. The reaction was allowed

to stir overnight at room temperature. A yellow residue was

recovered after the removal of the solvent, which was re-

dissolved in ethyl acetate. The insoluble DCC was removed

by filtration. The synthesis of 3-formyl-2-heptyl-4(1H)-

quinolone is shown in Scheme 74. A mixture of 2-heptyl-

4(1H)-quinolone and hexamine was dissolved in trifluoro-

acetic acid. The reaction was refluxed under a nitrogen

environment for 30 h. At this time methanol and water were

introduced into the reaction flask and the heating was

allowed to continue for 1 h. A 3 M solution of hydrochloric

acid was then introduced into the reaction, which was

heated for a further 30 min. The reaction was cooled and the

precipitate was recovered by filtration, washed with water,

and triturated by acetone [76, 77].

When 2-aminobenzophenone is treated with hexamine,

formation of 1,4-benzodiazepine took place (Scheme 75).

But if the amount of alcohol used in solvolysis was

insufficient, then it furnished quinoline derivative [78].

Cl

N C

CH3 O

N

C6H5

O

N

N

N

Cl-

Cl

N C

CH3 O

C6H5

N

NNN

OCl

N C

CH3 O

N

N

NN

C6H5O

C2H5OH

Cl

N C

CH3 O

N

N

NN

C6H5O

OC2H5

N

N

H3CO

C6H5

NN

N

OC2H5

OHCl

H

H

Base

:B

N

CH3

O

NH2

C6H5

Cl

Scheme 75 Synthesis of quinoline

HO

S

NH2

O

Br

OEt

O

EtOH

HO

N

S

OEt

O HMTA, PPA,

80oC

HO

N

S

OEt

OOHC

Br

O

N

S

OEt

OOHC

O

N

S

OEt

ONC

O

N

S

OH

ONC

KI, K2CO3,DMF, rt

64%, 2 steps

NH2OH.HCl

HCO2Na

HCO2H, 93%

2 N NaOH,

THF, H2O

Scheme 76 Synthesis of thiazole

J IRAN CHEM SOC

123

(r) Thiazole synthesis: Fabuxostat was discovered by

Teijin pharmaceuticals and was approved in the US for the

treatment of hyperuricemia in patients with gout. The

commercially available and easily prepared 4-hydrox-

ythiobenzamide was reacted with ethyl bromoacetoacetate

in refluxing ethanol to provide the thiazole ester in 60 %

yield after crystallization. The phenolic ester was then

treated with hexamethylenetetramine in polyphosphoric

acid at 80 �C to provide the crude aldehyde. Reaction of

phenol and isobutyl bromide in the presence of potassium

carbonate with catalytic potassium iodide in DMF gave

isobutyl ether. This ether was then converted in one pot to

nitrile in 93 % by reacting the aldehyde with hydroxyl-

amine hydrochloride and sodium formate in refluxing for-

mic acid. Saponification of the ester with aqueous sodium

hydroxide provided fabuxostat (Scheme 76) [79].

(s) Triaza and tetraaza compounds synthesis: Degrada-

tive nitrosation of hexamine in aqueous solution was car-

ried out by simultaneous addition of hydrochloric or acetic

acid and solution of sodium nitrite (Scheme 77). The main

factor determining the nature of products is pH of the

solution. In hydrochloric acid at pH 1, the trinitroso com-

pound is formed mainly, and at pH 2 a mixture of trinitroso

and dinitroso is obtained. Variation of the molar ratio of

C6H12N4:HCl:NaNO2 resulted in the formation of only

trinitroso compound (1:6:1–3), a mixture of trinitroso and

dinitroso compounds (1:3:3), or pure dinitroso compound

(1:6:6). When acetic acid was employed the only product

obtained over a wide range of conditions was the dinitroso

compound [5, 80].

The reaction of hexamine with acetic anhydride has been

studied. The yields of tetraaza compound never exceeded

45 %. Siele et al. [81] reported a simple procedure for the

preparation of triaza compound in[90 % yield (Scheme 78).

Using acetic anhydride, water, and hexamine, at

5–10 �C, acylated tetraaza compound is obtained

(Scheme 79). The yield increases when the reaction con-

ducted in the presence of an inorganic base. Water used in

this reaction shifts the equilibrium toward right (acylation

occurs in presence of water). It was found that ketene could

be substituted for the acetic anhydride [82].

Yoshida et al. [83] have studied the selective ring open-

ing of 1,7-bis[sulphonamido]tetraazabicyclo[3.3.1]nonanes

using the electrophillic species NO? and NO2?. In these

methods, bis[sulphonamido]tetraazabicyclo[3.3.1]nonanes

are produced, when hexamine was reacted with arenesul-

phonyl chlorides (Scheme 80) [5].

(t) Triazine synthesis: A hexahydro-1,3,5-triacyl-s-tri-

azine was first prepared from ammonium chloride, formalin

and benzoyl chloride or from hexamethylenetetramine and

benzoyl chloride (Scheme 81). Procedures similar to the one

described also have been used for the preparation of hexa-

hydro-1,3,5-triacetyl-, tri(b-chloropropionyl)-, triacrylyl-,

trimethacrylyl-, and tribenzoyl-s-triazine. Several of these

compounds also have been prepared from the corresponding

nitriles and paraformaldehyde in the presence of acetic

anhydride and sulfuric acid [84].

Introduction of aminomethyl groups

(a) Preparation of cross-linked polystyrene resin: Chlo-

romethylated 4 % TTEDGA-crosslinked polystyrene resin

was converted to the aminomethyl resin by hexamine

NN

N

N

HNN

NHN

NO

ON

N N

N

NO

NOON

HCl or AcOH/NaNO2 or


tetraaza compounds

NN

N

N NN

NN

OC

OC

R

R

90-100oC

N N

N

ROC

COR

COR

5-10oC

(RCO)2O

Scheme 78 Synthesis of triaza and tetraaza compounds

NN

N

N

NN

NN

OC

OC

R

R

(RCO)2O

H2CO

H2O

H2OHNN

NHN

Scheme 79 Synthesis of acylated tetraaza compounds

NN

N

N

NN

NN

SO2

SO2

Ar

Ar

ArO2S Cl

10% NaOH, pH 8-9, 70-75oC

Scheme 80 Synthesis of bis[sulphonamido]tetraazabicyclo[3.3.1]

nonanes

J IRAN CHEM SOC

123

method. Hence one pot conversion of chloromethyl resin to

aminomethyl, resin by hexamine method was used. In this

method, the chloromethyl resin was treated with a twofold

molar excess of hexamethylenetetramine in DMF at 80 �C

for 10 h. The resulting resin on hydrolysis with ethanolic

HCl followed by neutralization with 10 % triethylamine

(TEA)–CH2C12 afforded aminomethyl TTEGDA-cross-

linked polystyrene resin (Scheme 82). There was no

detectable amount of chlorine in the product resin [85].

(b) Preparation of protected peptides: For the prepara-

tion of protected peptides and peptide amides by photolytic

cleavage, a-bromopropionyl and a-aminopropionyl

anchoring groups were introduced into TTEGDA-cross-

linked polystyrene resin by the polymer analogous. Meth-

ylphenacyl ester linkage has been reported in the case of

polymer-supported synthesis of protected peptide frag-

ments on DVB-crosslinked polystyrene resin (Scheme 83).

This strategy was found successful in the case of the liquid

phase method of peptide synthesis on polyethyleneglycol

supports and in multidetachable resin supports [85].

(c) Preparation of 2-nitrobenzyl ester linkage: The

2-nitrobenzyl ester linkage finds wide spread applications as

protecting and anchoring group in the polymer-supported

methods of peptide synthesis. In solid-phase peptide syn-

thesis, the introduction of anchoring group between the

solid support and the growing peptide chain is a convenient

strategy for the mild non-destructive cleavage of peptides.

For the introduction of the anchoring group 4-bromo-

methyl-3-nitrobenzolc acid was prepared from p-toluic acid

by two step reaction. Aminomethyl TTEGDA-crosslinked

polystyrene resin was prepared from chloromethyl resin by

Gabriel’s phthalimide method and was coupled with

4-bromomethyl-3-nitrobenzoic acid in the presence of

dicyclohexylcarbodiimide to give the photolabile 4-bro-

momethyl-3-nitro benzamidomethyl TTEGDA-crosslinked

polystyrene support (Scheme 84) [85].

(d) Preparation of bis-oxy cyclophanes: Bis(amino-

methyl) m-terphenyl based bis-oxy cyclophanes with amide

group as intra-annular functionality were synthesized. Bis-

oxy cyclophane amides were synthesized from a novel

bis(aminomethyl) m-terphenyl. Reaction of bis(bromo-

methyl) m-terphenyl with hexamine in chloroform at reflux

resulted in the formation of hexammonium salt. Hydrolysis

of hexammonium salt with hydrochloric acid in EtOH–

H2O mixture at reflux afforded diamine in about 90 %

yield and for the synthesis of bis-oxy cyclophane diamide,

Et CN H2C OH2SO4,

heatN N

N33

O Et

Et

O

Et

O


triazine

CH2Cl CH2NH2

1) Hexamine2) HCl-EtOH

3) 10% TEA-CH2Cl2

Scheme 82 Preparation of

cross-linked polystyrene resin

Cl CHC

O

Br

CH3

CHC

CH3

Br

O

CHC

CH3

NH2

OAlCl3

CH2Cl2

HexamineDMF

EtOH, HCl10% CH2Cl2

Scheme 83 Preparation of protected peptides

CH2NH2 CH2NHC

O

CH2Br

NO2

CH2NHC

O

CH2NH2

NO2

Hexamine

HCl/Et3N

DCC

HO C

ONO2

CH2Br

Scheme 84 Preparation of

2-nitrobenzyl ester linkage

J IRAN CHEM SOC

123

1.0 equiv. of diamine was coupled with 1.1 equiv. of dia-

cid chloride in the presence of triethylamine in dry DCM at

room temperature under high dilution conditions. The

reaction afforded the bis-oxy cyclophane diamides

(Scheme 85) [85].

Mannich base synthesis

When hexamine was reacted with 2-naphthol, the product

obtained was incorrectly formulated as bis[2-naphthyl-

oxymethyl]amine (b) [86]. Burke et al. [87] described this

TEA, DCM, rt, 24 h,

OO

ClO2C CO2Cl

NH2NH2

OO

NH

OO

NH

BrBr

Hexamine, CHCl3, rt, 12 h;

Conc.HCl, EtOH-H2O,reflux, 3 h

Scheme 85 Preparation of bis-oxy cyclophanes

OH

OH N

O

OHN O

HN

OH HO

HMTA

a

b

c

Scheme 86 Synthesis of Mannich base

H2C O NH4Cl2 CH3NH2.HCl HCO2HheatScheme 87 Synthesis of

methylamine hydrochloride

NMe2 N+Me3I-MeI NaNH2, NH3 NMe2

Me


2-methylbenzyldimethylamine

J IRAN CHEM SOC

123

product as an o-substituted derivative of 2-naphthol (c).

Later, Mohrle et al. [67] defined the product formed as a

Mannich base a (compound with one additional ring of the

dihydro-1,3-oxazine) (Scheme 86).

Methylamine hydrochloride synthesis

Methylamine can be prepared by the action of formalde-

hyde on ammonium chloride in the presence of hexa-

methylenetetramine (Scheme 87) [88].

2-Methylbenzyldimethylamine synthesis

This procedure is based on the method of Kantor and

Hauser [89]. 2-Methylbenzyldimethylamine has been pre-

pared from o-xylyl bromide and hexamethylenetetramine

(Scheme 88).

Nitrolysis

(a) RDX and HMX synthesis: The nitrolysis of hexamine is

one of the most complex and widely studied processes in

the history of energetic materials synthesis. With so many

reaction routes available during the nitrolysis of hexamine,

it may seem strange that the cyclic nitramines RDX

(Scheme 89) and HMX (Scheme 90) can be isolated in

such high yields. Synthesis of RDX and HMX via the ni-

trolysis of hexamine could be potent. Owing to the sensi-

tivity of this reaction to acid, a mixed reagent of metallic

salts and Ac2O is usually used in highly efficient nitration

or nitrolysis reactions. Herein, a batch of new reagents

M(NO3-)n/Ac2O/NH4NO3 (M = Mg2?, Cu2?, Pb2?, Bi3?,

Fe3?, and Zr4?) were firstly studied in the nitrolysis reac-

tion. Some of these ternary mixed reagents tested to be of

high efficiency were also used in the nitrolysis of hexamine

[90].

(b) 1,5-Dinitroendomethylene-1,3,5,7-tetraazacyclooc-

tane (DPT) synthesis: Dimethyl-olnitramine is known to be

present under the conditions of the Hale nitrolysis. If the

Hale nitrolysis reaction is quenched, the RDX removed by

filtration and the aqueous liquors neutralized to remove

DPT, the remaining filtrate can be extracted into ether and

that solution evaporated over water to give an aqueous

solution of dimethylolnitramine (Scheme 91) [91].

(c) Linear nitramines synthesis: The nitrolysis of hex-

amine can be used to obtain the linear nitramines

depending on the conditions and reagents used. Thus, the

nitrolysis of hexamine with a mixture of fuming nitric

acid in acetic anhydride led to the isolation of BSX,

whereas the addition of 97 % nitric acid to a solution of

hexamine in acetic anhydride formed the mixed nitrate-

acetate ester. The reaction of hexamine with dinitrogen

pentoxide in absolute nitric acid led to the formation of

the dinitrate ester. The nitrate ester groups were readily

displaced and on reaction with sodium acetate in acetic

acid form the corresponding acetate esters; the same

reaction with low molecular weight alcohols formed the

corresponding alkoxy ethers (Scheme 92) [92].

Organometallic synthesis

(a) (R,R)-N,N0-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclo-

hexanediamino manganese(iii) chloride synthesis (a highly

enantioselective epoxidation catalyst): The product of this

preparation is the most enantioselective catalyst developed

to date for asymmetric epoxidation of a broad range of

unfunctionalized olefins. The procedure includes a highly

efficient resolution of trans-1,2-diaminocyclohexane as

well as a convenient analytical method for the determina-

tion of its enantiomeric purity. This method (Scheme 93) is

general for the analysis of chiral 1,2-diamines. The Duff

formylation described in Step B is a highly effective

method for the preparation of 3,5-di-tert-butylsalicylalde-

hyde, and it circumvents the use of hazardous or sensitive

materials, such as tin chloride (SnCl4), which were

employed in previously reported syntheses. The Duff

reaction is applicable to the preparation of other 3,5-

substituted salicylaldehydes, which in turn can be used to

N

N

N

N N N

N

NO2

NO2O2N

nitrolysis

Scheme 89 Synthesis of RDX

N

N

N

N

nitrolysisN

N

N

N

O2N

NO2

NO2

O2N

Scheme 90 Synthesis of HMX

J IRAN CHEM SOC

123

prepare chiral (salen)Mn,[N,N0-bis(salicylideneamino)eth-

ane]Mn, epoxidation catalysts with sterically and elec-

tronically tuned reactivities. As such, a wide range of

(salen)metal complexes can be prepared by adaptation of

the procedure described above, by variation of the diamine,

the salicylaldehyde, or the metal center [93].

(b) The interaction of PhCCH with Cp(CO)2Mn(THF)

led to a mixture of Cp(CO)2Mn(2-PhC CH), vinylidene

complexes. It was evident that the 2-alkyne complexes

Cp(CO)2Mn(2-PhC2 C1R) were formed in the first stage

of reaction, after which they rearranged into the 1-co-

ordinated form, i.e. Cp(CO)2MnClC2HPh. The fact that

these transformations occurred at 5–20 �C seemed most

surprising. It was reported that the hypothetical inter-

mediate phenylvinylidene could be formed from phen-

ylacetylene under very harsh conditions. The acetylene–

vinylidene rearrangement, which occurred in the coor-

dination sphere of the transition metal atom under mild

conditions and resulted in the formation of the stable

vinylidene complexes was without precedent at that time.

The Mn atom played a role of internal catalyst in this

process. The rearrangement is best catalyzed by HMTA,

when added to the UV irradiated mixture of CpMn(CO)3

and PhCCH. The action of acetic acid led to the

2-olefinic complex Cp(CO)2Mn[2-CH2C(Ph)OC(O)Me].

Addition of MeCOOH to the 2-PhCCH ligand followed

Markovnikov’s rule. Free Ph(MeCOO)CCH2, an unstable

liquid, was obtained from PhCCH and MeCOOH in

the presence of (MeCOO)2Hg/BF3�OEt2 as catalyst

(Scheme 94) [94].

Oxidation of glycolic acid

Glycolic acid is a useful intermediate for organic synthesis,

in a range of reactions including: oxidation–reduction,

esterification and long chain polymerization. The oxidation

of glycolic acid by hexamethylenetetramine–bromine

(HABR) has been studied. Glycolic acid is oxidized to give

glyoxylic acid (Scheme 95). The rate of the reaction

increases with increasing in concentration of glycolic acid

and HABR. Temperature influence is quite marked in all

these reactions. It involves the formation of a activated

complex, which decomposes to give the product [95].

Phenacylamine hydrochloride synthesis

Phenacylamine hydrochloride has been prepared by the

hydrolysis of the quaternary salt obtained from phenacyl

bromide and hexamethylenetetramine (the Delepine reac-

tion). The present procedure is adapted from those

of Baumgarten; Bower and Baumgarten; Petersen

(Scheme 96) [96, 97].

C6H12N4Hale nitrolysis HO N OH

NO2

H2C N

N

H2C N CH2

CH2

CH2

N NO2O2NH2N

H2C NH2

Scheme 91 Synthesis of 1,5-dinitroendomethylene-1,3,5,7-tetraazacyclooctane

C6H12N4

NO2NO

NO2

N

NO2

N

NO2

OAc

NAcO

NO2

N

NO2

N

NO2

OAc

NO2NO

NO2

N

NO2

N

NO2

ONO2

NEtO

NO2

N

NO2

N

NO2

OAc

NMeO

NO2

N

NO2

N

NO2

OMe

Ac2O;97% HNO3,

25oC HNO3, N2O5

HNO3, Ac2O,20oC

EtOH 15%

HNO3 54%

HNO3, Ac2O,70oC

MeOH 60%

AcOH,NaOAc

(BSX)

Scheme 92 Synthesis of linear

nitramines

J IRAN CHEM SOC

123

H2N NH2

OH

CO2HHO2C

HO H2N NH3

HO

-O2C CO2-

OH

OH

t-Bu

t-Bu

C6H12N4

OH

t-Bu

t-Bu

OHC

Ot-Bu

N N

HH

t-Bu t-Bu

t-BuO

Mn

ClOHt-Bu

N N

HH

t-Bu t-Bu

t-BuHO

H2O/HOAc

90oC to 5oC

HOAc,130oC, 2h

H2SO4 (aq),105oC

2 eq K2CO3

H2O/EtOH, 80oC

EtOH/toluene

85oC, air, NaCl(aq)

H2N NH3

HO

-O2C CO2-

OH

Scheme 93 Synthesis of (R,R)-N,N0-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclo-hexanediamino manganese(iii) chloride

PhC CHMn CO

OC CO

Mn

OC CO

Ph

H

Mn C

OC CO

C

H

Ph

Mn

OC CO

C C

C

Ph

Ph

C Mn

COOC

5-20oChv = CO

HMTA

+ MeCOOHBase

Mn

OC CO

C

C

OCMe

H

Ph

H

O

Scheme 94 Synthesis of organometallic compound

J IRAN CHEM SOC

123

Phenylethylamine synthesis

(a) a-Phenylethylamine synthesis: The present procedure

was developed from those of Wallach and Freylon, based

upon the general method discovered by Leuckart. a-

Phenylethylamine can also be prepared satisfactorily by the

reduction of acetophenone oxime and hexamethylenetet-

ramine (Scheme 97) [98, 99].

(b) b-Phenylethylamine synthesis: b-Phenylethylamine

has been made by a number of reactions, many of which

are unsuitable for preparative purposes. Benzyl cyanide has

been converted to the amine by the Delepine synthesis

from b-phenylethyl iodide and hexamethylenetetramine.

More recent methods for preparation of the amine include

the lithium aluminum hydride reduction of b-nitrostyrene

and of phenylacetamide. The Raney nickel reduction of the

nitrile in the presence of formamide is reported to give an

87 % yield of the formylated primary amine (Scheme 98)

[100].

Regeneration of carbonyl compounds

(a) From oximes and tosylhydrazones: Hexamethylenete-

traminebromine (HMTAB) has been found to be an effi-

cient and selective reagent for the mild oxidative cleavage

of the C1N of oximes and tosylhydrazones to yield their

corresponding carbonyl compounds in good to excellent

yields under mild conditions. It is most important to note

that most of the reported methods are suitable for the

regeneration of ketones but not for aldehydes from their

oximes and tosylhydrazones, and that yields are low owing

to the over oxidation of regenerated aldehydes to acids.

Therefore, it is desirable that a method which leads to high

recoveries of a wide range aldehydes and ketones should be

available and the present method is an efficient and general

method for the effective and selective cleavage of the C1N

of oximes and tosylhydrazones with HMTAB under neutral

and mild conditions (Scheme 99) [101].

(b) From phenylhydrazones: 2,4-Dinitrophenylhy-

drazones were converted to their parent carbonyl com-

pounds using hexamethylenetetramine–bromine complex

supported onto wet alumina under classical heating and

Scheme 95 Oxidation of glycolic acid

CH3

NH2

CH3

NCl2

CH3

NCl

OCH3

HN

NH3Cl

O

t-BuOCl

benzene, 5oC

NaOMe, MeOH,

heat

HCl, H2O,

heatheat

NaOMe, MeOH,


phenacylamine hydrochloride

Ph CH3

O

Ph CH3

HN H

O

Ph CH3

NH3Cl

Ph CH3

NH2NH4OCHO

heat

H2O,

HCl

NaOH

dl form


1-phenylethylamine

Ph CN PhNH2

H2, Ra (Ni)(2000 psi)

NH3, 130oC

Scheme 98 Synthesis of 2-phenylethylamine

C N

R2

R1

XC O

R2

R1

X = OH, NH-Ts

HMTAB, CCl4, H2O

rt or reflux

Scheme 99 Regeneration of carbonyl compounds from oximes and

tosylhydrazones

NO2

O2N

NHN

O

R

ArCRArHMTAB/wet Al2O3

toluene, reflux/MW

Scheme 100 Regeneration of carbonyl compounds from phen-

ylhydrazones

J IRAN CHEM SOC

123

microwave irradiation. Herein, the results for the mild,

facile, fast and high yielding cleavage of phenylhydrazones

under classical heating and under microwave irradiation in

a solventless system have been reported. Initially, hexam-

ethyleneteramine–bromine was mixed with wet alumina.

This supported reagent was refluxed with an appropriate

2,4-dinitrophenylhydrazone in toluene to regenerate the

corresponding carbonyl compound (Scheme 100). The

supported reagent was mixed with neat 2,4-dini-

trophenylhydrazones, grinding them thoroughly to make an

intimate pair. By placing the mixture in a microwave oven,

the reactions are completed in a couple of seconds [102].

OH

O OH

OH

O OH

O

OH

O O

O

CH3

O

O

CH3

OH

N N

HO

O

O

H3C

O

O

CH3

O

N N

O

O

O

H3CM

inert atmosphere, 3 h reflux

1 eq. HMTA, CF3COOH,

3 h reflux,

H2SO4 (1 eq.), methanol,

0.5 eq. o-phenylenediamine,

methanol, 2 h, rt

Al(NO3)3·9H2O

ethanol, rt

M = Al(NO)3

Scheme 101 Synthesis of Schiff-base

O

O

O

O

Cl

Cl

O

O

H

H

O

O

O

O

OH

H

O

OH

OH

H

H

O

O

O

OH

H

H

O

O

O

O

O

H

O

O

OH

CH2O aq,

HBr aq, CH3 COOH CH2O aq.

HClH2O, HCl

HMTA

Scheme 102 Synthesis of Schiff-base

J IRAN CHEM SOC

123

Schiff-base synthesis

The functionalized Schiff bases have been prepared in

three steps. After the controlled formylation of 4-hy-

droxybenzoic acid with hexamethylenetetramine in triflu-

oroacetic acid through the Duff reaction, the resulting

salicylaldehyde derivative was esterified. The esterification

was classically run in methanol in the presence of sulfuric

acid. The third step was condensation of the ester-func-

tionalized aldehydes with o-phenylenediamine, classically

operated in alcohol. Addition of aluminum nitrate to these

Schiff bases in ethanol gave the complex in good yields

(Scheme 101) [103].

The synthesis starts with the chloromethylation of

commercially available 1,4-dimethoxy-benzene to give

the p-bis(chloromethyl)-benzene. In the subsequent step,

p-bis(chloromethyl)-benzene was subjected to a Sommelet

reaction to afford the dialdehyde. The formation can be

explained by the mechanism of the Sommelet reaction:

addition of hexamethylenetetramine to an organochloride

RCH2Cl led to the formation of a quaternary ammonium

salt [RCH2N(CH2)6N3]Cl which upon hydrolysis liberated

formaldehyde and ammonia. The resulting primary amine

RCH2NH2 was then oxidized to the imine which reacted

further to the desired aldehyde RC(O)H. Alcohol may even

react further with formaldehyde to give acetal. Phenolether

was deprotected to give hydroquinone using hydrobromic

and acetic acid. After the recommended reaction time of

5 h, a mixture of the desired compound and the monom-

ethylated dialdehyde was obtained (Scheme 102) [104].

Sonogashira cross-coupling reaction

The Sonogashira cross-coupling reaction of aryl halides

with terminal alkynes is quite efficient when using water as

the reaction medium in the presence of hexamine as base

under copper-free conditions. This reaction produced dif-

ferent disubstituted aryl alkynes which are dependent upon

the aryl halides, which range from electron-donating to

electron-withdrawing groups and also to sterically hindered

ortho-substituted aryl iodides and heteroaryl iodides. Both

aryl iodides and bromides couple with phenyl acetylene,

producing good to moderate yields of the coupling products.

However, the coupling of aryl bromides is difficult in water

and in the presence of hexamine (Scheme 103) [105–108].

o-Tolualdehyde synthesis

A procedure for the preparation of o-tolualdehyde from

o-toluanilide by the Hesse and Schrodel method has been

published in organic syntheses. In addition to the alterna-

tive methods of preparation listed there, o-tolualdehyde has

been prepared from o-xylyl bromide or chloride and

hexamethylenetetramine (Scheme 104) [109, 110].

tris[Chloromethyl]amine synthesis

Fluck and Meiser [111–113] prepared tis[chloromethyl]

amine by treating hexamine with phosphorus pentachloride

in a 1:3 molar ratio. In addition to tis[chloromethyl]amine

second product also formed (Scheme 105).

Tryptamine synthesis

N-Phthalimido-hydroxy acetic acid was conveniently pre-

pared by the reaction between phthalimide and glyoxalic

acid. The acid was then chlorinated with thionyl chloride to

give the corresponding chloro-substituted acid. The alde-

hyde was obtained by reduction with hexamine in aqueous

acetic acid medium (Scheme 106) [114, 115].

Tschitschibabin cyclization

The formylation of imidazo[1,2-a]pyridinic compounds

(IPs), substituted by an amidic chain at various core posi-

tions was explored. Scheme 107 describes the synthesis of

imidazopyridinic derivatives substituted on the C-2 or C-5-

C-8 positions. Briefly, 2-aminopyridine compounds reacted

with the appropriate halo ketones to give ester substituted

compound (50–63 % isolated yields) by Tschitschibabin

cyclization. Amides were then easily obtained with high

yields ([90 %) by direct amidification using trimethyl-

aluminum as activator [39].

I

NO2

Ar O2N ArPd-LHMS-3 (0.02 g)

H2O, Hexamine,Reflux

Scheme 103 Sonogashira

cross-coupling reaction

CH2Br

CH3

CHO

CH3

2-nitropropane

Na, EtOH

Scheme 104 Synthesis of o-tolualdehyde

J IRAN CHEM SOC

123

Urea synthesis

Hexamine can be used as a catalyst in the preparation of

urea from ammonia and carbon dioxide (Scheme 108). The

reagent serves to increase both the yield of urea and the

degree of utilization of ammonia. It gives rise to an 80 %

yield of urea [116].

Conclusion

Hexamine have played a major role in modern organic

synthesis. This review article shows that hexamine can be

used in many different ways in organic synthesis and

summarizes the reactions involving hexamine for synthesis

of many important organic compounds.

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