J IRAN CHEM SOC DOI 10.1007/s13738-013-0260-2

ORIGINAL PAPER

An insight into hexamethylenetetramine: a versatile reagent in organic synthesis

Navjeet Kaur • Dharma Kishore

Received: 12 December 2012 / Accepted: 3 April 2013 Ó Iranian Chemical Society 2013

Abstract Hexamethylenetetramine is a versatile reagent Duff [2] and Sommelet [3] reactions hexamethylenetetra- in organic synthesis. It plays a major role in modern mine acts as the formyl carbon source, while in the Dele- organic synthesis. This review focuses on hexamine pine [4] reaction it provides the primary amino groups. reagent for its significant role in organic synthesis during Blazevic et al. [5] in 1979 listed all the experiments carried the past decades and is able to provide a valuable per- out with HMTA in the first 80 years of the last century. The spective from synthetic point of view. structure of HMTA is particularly stable, in contrast to the very reactive behavior shown by its di-hetero-substituted Keywords Hexamethylenetetramine Organic synthesis methylene groups. In addition, nitrated derivatives of Reagent HMTA were used as explosive bombs during the World War II. It is the starting material for two classic secondary explosives, RDX and HMX. Introduction

Hexamethylenetetramine (HMTA) (1,3,5,7-tetraazatricy- Adamantane synthesis clo[3.3.1]decane, C6H12N4) is a fourth-cycled molecule. Hexamethylenetetramine is known by several other names, Daigle et al. [6–8] prepared a monophosphorus analog of including methenamine, urotropine, and hexamine. Hexa- hexamine, from hexamine and tris[hydroxymethyl]phos- methylenetetramine is an organic, heterocyclic chemical phine or tetrakis[hydroxymethyl]phosphonium chloride, compound, more commonly known as hexamine, is whose oxidation with hydrogen peroxide at room temper- obtained by the reaction of formaldehyde and excess of ature gave phosphoadamantane-7-oxide (Scheme 2)[5]. ammonia, either in a aqueous medium or in the vapor phase Daigle et al. [9] prepared a sulfur and phosphorus con- (Scheme 1)[1]. taining derivative of hexamine 2-thia-1,3,5-triaza-7-phos- In most areas of application, hexamine can be regarded phaadamantane-2,2-dioxide, from tris[hydroxymethy] as a special form of formaldehyde. It has the advantage that phosphine, sulphamide and hexamine in excess of form- no water is released during conversion and hydrolyzes in aldehyde (Scheme 3)[5]. acid media and slowly releases formaldehyde. It has a very low toxicity and diluted solutions can be broken down biologically. Aminoacetone semicarbazone hydrochloride synthesis Hexamine is a synthetically versatile reagent used in organic synthesis during the last years. In particular, in the Aminoacetone is a versatile starting material for many syntheses, particularly for the preparation of heterocycles. The present procedure describes a convenient method for & N. Kaur ( ) D. Kishore its preparation in a form which is suitable for storage. The Department of Chemistry, Banasthali University, Banasthali, Jaipur 304022, Rajasthan, India aminoacetone can be generated from aminoacetone semi- e-mail: [email protected] carbazone hydrochloride in situ. This preparation is based 123 J IRAN CHEM SOC

Scheme 1 Synthesis of N hexamine H+ 6 H2C O 6 NH3 N N 6 H2O 2 NH3 N

Scheme 2 Synthesis of O phosphoadamantane-7-oxide N P P H O P(CH2OH)3 2 2 H2CO N N or N N N P+(CH OH) Cl= N N 2 4 N N

Scheme 3 Synthesis of O hexamine 2-thia-1,3,5-triaza-7- phosphaadamantane-2,2- P dioxide [0] N N P N N O2S H2CO N PH(CH2OH)3 H2NSO2NH2 CH3 N N - N N J H3C-I P N O2S N N N O2S

- O - O Cl NNHCONH2 O Cl NH CONHNH 2Ac O H HCl 2 2 2 H C N H N 3 H3N 3 H2N CH CH pyridine, 3 H2O CH3 3 OH heat O

Scheme 4 Synthesis of aminoacetone semicarbazone hydrochloride on the procedure used to synthesize 3-acetamido-2-buta- aldimine, which on hydrolysis gives the aldehyde. This none. Aminoacetone hydrochloride has been prepared from reaction is generally possible with active halides such as isopropylamine via the N,N-dichloroisopropylamine, from benzylic halides, allylic halides, a-halo ketones and pri- hexamethylenetetramine and chloroacetone (Scheme 4), by mary iodides. In this reaction, benzyl halides are refluxed reduction of nitroacetone or isonitrosoacetone, and from in DMSO along with sodium bicarbonate to give the cor- phthalimidoacetone by acid hydrolysis [10]. responding aldehydes. The reaction has recently been attempted under microwave irradiation [11].

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, CHO X HMTA/DMSO the first step is the reaction of hexamine with the alkyl R halide to form a quaternary salt, which on hydrolysis gives heat a primary amine, formaldehyde and ammonia. The primary R X = NO , OMe amine on reaction with the aldimine, derived from form- 2 aldehyde and ammonia, forms the corresponding aromatic Scheme 5 Synthesis of benzaldehydes 123 J IRAN CHEM SOC

N

N N Br r N NC6H12N3B NCl NH2 NaOH H C HCl, , 2 H2C H2C H2C heat aq. EtOH H2O Br Br Br Br

Scheme 6 Synthesis of 2-bromoallylamine

2-Bromoallylamine synthesis Condensation

This method gives better yields than other methods of Benzylamine and hexamine condense at 190 °C. The preparation of 2-bromoallylamine (Scheme 6), and it is the condensation product of benzylamine and hexamine poly- most convenient method for the preparation of large merizes when heated for an extended period (Scheme 8). quantities of the compound. The procedure illustrates a Depending on both temperature and time, different mix- reaction, the so-called Delepine [4] reaction, that has been tures of products are formed [5, 14]. used for the preparation of many primary aliphatic amines. The mixture of products formed from the condensation It is especially useful in the preparation of derivatives of of hexamine and benzylamine was identified and converted phenacylamine. A number of primary aliphatic amines into the open-chain isomeric products as shown in have been prepared by this method without isolation of the Scheme 9 [5, 15]. intermediate hexaminium salt [12]. 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 Cleavage of epoxides (synthesis of vicinal haloalcohols) products (Scheme 10). This mixture protects metals against corrosion under acidic conditions [5, 16, 17]. The highly regioselective cleavage of epoxides into cor- responding vicinal haloalcohols with elemental halogen has been catalyzed by hexamethylenetetramine Crown ether synthesis (Scheme 7). This method occurred under neutral and mild conditions with high yields and short reaction times in Bichromophoric compound benzophenone-{crown ether}- various aprotic solvents even when sensitive functional naphthalene (Bp-C-Np) was synthesized. 2,3,11,12-Bis(40- groups were present. The preparation of haloalcohols and formylbenzo)-18-crown-6 (BFBC) compound was pre- the complex formation of heterocyclic compounds con- pared according to the literature (Scheme 11). A mixture of taining donor nitrogen atoms, with neutral molecules such dibenzo-18-crown-6 (DBC), trifluoroacetic acid and hexa- as iodine and bromine, the HMTA compound can be methylenetetramine was stirred at 90 °C under nitrogen for reactive as a new catalyst in the addition of elemental 12 h. After the mixture was cooled, 50 ml of concentrated halogen to epoxides under mild reaction conditions with KOH and 200 ml of water were successively added. The high regioselectivity. As for the regioselectivity, attack of product was precipitated as a brown solid. The crude the nucleophile preferentially occurs at the less substituted product was collected by suction filtration and washed with epoxide carbon. This regioselectivity appears to be the acetone several times [18]. opposite of that observed in ring opening of the same epoxides with hydrohalogenic acids under classic acidic conditions [13]. 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 O HO HMTA reaction leads to the hexamethylenetetramine salt. In X 2 rt, CH Cl chloroform, the starting materials are soluble whereas the 2 2 R X R products crystallize out. It is usually not possible to purify Scheme 7 Synthesis of vicinal haloalcohols the salt [2]. 123 J IRAN CHEM SOC

Scheme 8 Condensation of N o hexamine and benzylamine 190 C H2 N 6 C6H5CH2NH2 6 C6H5 C N CH2 - 4 NH N 3 N

H2 N C N C N CH H 3

CH2 CH2 CH2 H2C C6H5

N C6H5 C6H5 C6H5 H2 HMTA 3 C H C N CH 6 5 2 H H 190oC 2 2 NN N C N C N CH3 C6H5 C C C6H5 H2 H2 CH CH2 CH2

C6H5 C6H5 C6H5

Scheme 9 Condensation of hexamine and benzylamine

Scheme 10 Condensation of H2C C6H5 hexamine and benzylamine N cooling H2 HMTA 6 C6H5 C NH2 NN C6H5 C C C6H5 H2 H2

C6H5 H2 H2 N C N CH C H C H C N CH C6H5 C N C C6H5 H 2 6 5 6 5 2 H

H3C

Reaction of hexamine with substituted oxiranes is a dioxane (Scheme 15) or dioxane–xylene (91 % yield) fol- modification of the Delepine reaction. On reaction with lowed by hydrolysis [20]. 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 5-Fluorovanillin synthesis alcohol and isomeric 2-amino-1-hydroxy alcohol (Scheme 13)[5]. The approach to synthesize fluorinated vanillin analogs is Some other applications of hexamine for the introduc- based on 3-fluoroanisole as the starting compound. From tion of amino groups cannot be classified as Delepine 3-fluoroanisole, the desired products 2-fluoro-isovanillin reaction. Thus, diazomethyl 5-pyrimidinyl ketone can be and 5-fluorovanillin were synthesized in 45 and 55 % converted to 5-(2-amino-1-hydroxyethyl)-pyrimidine on yields, respectively. 3-Fluoroanisole was reacted with n- treatment with hexamine (Scheme 14)[19]. 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 DL-Valine synthesis hexamethylenetetramine in refluxing trifluoroacetic acid was used in next step. This reaction was regioselective on Valine has been prepared through the reaction of hexa- the 1–5 mmol scale, however, when scaled up ([50 mmol) methylenetetramine with a-bromoisovaleric acid in the reaction lost regioselectivity. The second major product

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O O

O O OHC O O CHO (CH2)6N4

CF3COOH O O O O

O O

O NaBH 4 HOH2C O O CH2OH Na/DMF H2O, C2H5OH BrH C O O 2

O

O O O H COH C O O CH OH 2 2 2 C C Cl

O O NEt3/DMF O

O O O

H2COH2C O O CH2OC

O O

O

Scheme 11 Synthesis of crown ether

Scheme 12 Synthesis of N N X- primary amines R' R R' CHCl3 N N conc. HCl X N N NH reflux N 2 R N EtOH R' R

R 1 R 2 R2 H H2 H H R1 C C OH HMTA or HN 2 R1 C C N N O R 2 H R2 O R2 R2

Scheme 13 Synthesis of aminohydroxy alcohols

OH was thought to be 5-fluorovanillin. A regioselective reaction O H H2 using dimethylamine and formaldehyde in absolute ethanol C C N2 H HMTA C C NH2 N N generated the benzylamine. Benzylamine was converted to

N the quaternary amine using methyl iodide. This was done to N generate a better leaving group for conversion to the alde- Scheme 14 Synthesis of 5-(2-amino-1-hydroxyethyl)-pyrimidine hyde. Upon treatment with hexamethylenetetramine in

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Scheme 15 Synthesis of DL- CH3 CH3 CH3 valine Br2 CO2H NH4OH CO2H CO2H PCl , heat H3C H3C H3C 3

Br NH2

F F 40% dimethylamine, O n-butyl lithium (-78oC), HO 37% formaldehyde N o in ethanol reflux, B(OMe)3, AcOH (0 C), HO 30% H2O2 O O F

refluxing HMTA in TFA, Iodomethane followed by HMTA reflux in acetic acid.

O F O O HO HO O F

Scheme 16 Synthesis of 5-fluorovanillin synthesis

HC NOH

N O OH H C CH H O H+ 6 HCHO 2 2 2 Cr(III) 2 Q 3 C6H12N4 2 Cr 2 2 O OQ HN NH C H2

Scheme 17 Oxidation of hexamine refluxing acetic acid the quaternary amine was converted to decompose to form the amine hydrochloride and formal- 5-fluorovanillin (Scheme 16)[21]. dehyde (Scheme 18). During acidic hydrolysis or ethanol- ysis, semiaminals are formed first, these further decompose to yield formaldehyde or the diethylacetal, ammonium salt Formaldehyde synthesis and the amine hydrochloride [4].

The oxidation of hexamine by quinoliniumdichromate has been investigated in aqueous perchloric acid medium at Formazin preparation constant ionic strength (Scheme 17). Increase in perchloric acid concentration increases the reaction rate. The added This procedure (Scheme 19) reviews the process required products chromium(III), formaldehyde and oxime do not to synthesize accurate formazin. Further, this procedure have any significant effect on the rate of reaction. Increase introduces new quantitative analysis information showing in ionic strength and decrease in dielectric constant of the reactants hydrazine sulfate and hexamine to be present in reaction medium increase the rate of reaction [22]. considerably less quantities compared to presynthesis The compound is rather stable, although dihetero- concentrations. Formazin is chemically formed through a substituted methylene groups are usually highly reactive. In condensation reaction between formaldehyde and hydra- neutral, aqueous solution, hexamine remains stable even at zine. More specifically, two starting reagents, hydrazine elevated temperatures. Hexamine decomposes in dilute sulfate and hexamethylenetetramine are used. Hexameth- aqueous acid, and the derived ammonium salts also ylenetetramine reacts with water and sulfuric acid (from

Scheme 18 Synthesis of amine O R hydrochloride and conc. HCl C6H12N4 3 NH4Cl 6 formaldehyde EtOH NH3Cl H H

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Scheme 19 Synthesis of N formazin H N 6 H O N 2 2 H2SO4 6 O 2 (NH4)2 SO4 N H

H H H N N N n O n/2 NN n H2O NNN H H H X Formaldehyde Hydrazine Formazin

Scheme 20 Synthesis of 3,5-di- OH O OH tert-butylsalicylaldehyde

HMTA H

o CH3COOH, 130 C, 2 h H2SO4

Scheme 21 Sommelet reaction N

N N Ar Ar N Ar H2O H Hal Heat C6H12N4Br O

C6H5 C6H5

H2C H2C H2 N N N CH + C6H5 C 2 N N+ C N C N H2 N H2 N - N r N N Br B C Br- H2

C6H5 C6H5 CH CH3 H CH 3 H C C6 5 3 H C 2 2 N N H2C - N - H -transfer OH H N C NH N C 2 H N N N N O N O C N H H

Scheme 22 Mechanism of Sommelet reaction hydrazine sulfate) to form formaldehyde and ammonium Formylation reagent sulfate. Formaldehyde reacts with hydrazine (from hydra- zine sulfate) to form tetraformal triazine (TFTA) and Formylation is a useful reaction in heterocyclic chemistry water. The TFTA continues to polymerize with excess of where it is widely used to gain access to multifunctional formaldehyde to form the gelatinous formazin precipitate compounds. Several methods can be used to prepare het- [23]. erocyclic formyl compounds. Among those several

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CHO benzimidazole and 10-methylphenothiazine, obtained by direct lithiation and b-lithio compounds from lithium– HMTA RO RO bromine exchange, with DMF. Dialkoxybenzaldehydes were prepared by the formylation of dialkoxybenzenes RO RO with hexamethylenetetramine (Scheme 23)orbythe alkylation of dihydroxybenzaldehydes with alkyl bromides Scheme 23 Synthesis of dialkoxybenzaldehydes or iodides. Similar HMTA formylation of 1,3-diphenoxy- benzene afforded novel 2,4-diphenoxybenzaldehyde in methods one is formylation by hexamine-assisted Somm- 57 % yield [25]. elet [3] and Duff [2] reactions. (b) p-Chlorobenzaldehyde synthesis: p-Chlorobenzal- The Duff [2] reaction or hexamine aromatic formylation dehyde can be prepared from p-chlorobenzyl chloride with is a formylation reaction used in organic chemistry for the hexamethylenetetramine and subsequent hydrolysis synthesis of benzaldehydes with hexamine as the formyl (Scheme 24)[26]. carbon source. The electrophilic species in this electro- (c) 2,6-Dialkoxybenzaldehydes synthesis: The formyla- philic aromatic substitution reaction is the iminium ion tion of 1,3-diphenoxybenzene with n-BuLi/DMF gave a CH ?NR . The initial reaction product is an iminium 2 2 single regioisomer, 2,6-diphenoxybenzaldehyde, in 70 % which is hydrolyzed to the aldehyde. The reaction requires yield. In contrast, the formylation with HMTA in the strong electron-donating substituents on the aromatic ring mixed-solvent (CF COOH/CH COOH = 1:1) produced of phenol. Formylation occurs ortho to the electron- 3 3 solely 2,4-diphenoxybenzaldehyde in 57 % yield donating substituent preferentially, unless the ortho posi- (Scheme 25). The two phenoxy groups activate the tions are blocked, in which case the formylation occurs at 2-position proton for ortho-lithiation by n-BuLi; however, para position. Example is the synthesis of 3,5-di-tert- when it reacts with the larger reagent HMTA, significant butylsalicylaldehyde (Scheme 20). stereo hindrance at the 2-position by the two phenoxy The Sommelet [3] reaction (Scheme 21) is an organic groups directs the formylation to the less hindered reaction in which a benzyl halide is converted to an alde- 4-position. Therefore, the formylation with n-BuLi/DMF or hyde by action of hexamine and water. The reaction is HMTA afforded 2,6-diphenoxybenzaldehyde or 2,4-di- formally an oxidation of the carbon. In the related aldehyde phenoxybenzaldehyde, respectively, with high regioselec- synthesis, the oxidizing reagent is a combination of pyri- tivity [27]. dine and p-nitrosodimethylaniline. The reaction has proved (d) 5-Formyl ethylvanillin synthesis: 5-Formyl ethylva- useful for the preparation of aldehydes from amines and nillin (4-hydroxy-5-ethoxy-isophthalaldehyde) obtained by halides. Various types of aromatic, heterocyclic, some Duff reaction from ethylvanillin, hexamethylenetetramine aliphatic aldehydes and amines have been prepared by in acid medium was condensed with aromatic amines to applying this reaction [24]. obtain Schiff bases (Scheme 26). The reaction of 5-formyl The hexaminium salt derived from halide undergoes ethylvanillin with aromatic amines was realized in equi- hydride transfer to form the carbenium salt which reacts molecular ratio between the reagents. When the Schiff with the nucleophilic hydroxyl ion present to yield inter- bases are formed one can observe that from the two formyl mediate which, in turn, undergoes cleavage to give the groups of the 5-formyl ethylvanillin, more susceptible in aldehyde and the amine (Scheme 22)[3, 5]. the reaction is the CHO group, situated in the ortho posi- (a) a- and b-Carboxaldehydes synthesis: Heteroaromatic tion toward the hydroxyl group. The greater reactivity of a- and b-carboxaldehydes were prepared by the formyla- the formyl group, explained by the possibility to form a tion of a-lithio benzofuran, benzothiophene, N-methyl- chelate with the neighboring OH group was also observed

Scheme 24 Synthesis of p- O CH l chlorobenzaldehyde 3 C 2 CHCl2 PCl5 H2SO4 H light, heat H O Cl Cl 2 Cl

Scheme 25 Synthesis of 2,6- O O O O dialkoxybenzaldehydes Ph Ph HMTA 57% OHC

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CHO CHO CHO

H2N C6H12N4/CH3COOH 50%

C N C2H5O C H O CHO 2 5 C2H5O H OH OH OH

Scheme 26 Synthesis of 5-formyl ethylvanillin

Scheme 27 Synthesis of 2-R-5- N N formyl-1,3,4-thiadiazole N N C6H12N4 CHCl 3 CHO CH2Cl O N S R S 50% CH3COOH

N of 2-R-5-formyl-1,3,4-thiadiazole derivatives with yields of 65–69 % (Scheme 27)[29]. CH2NH2 N N CHO (f) Isophthalaldehyde synthesis: The procedure descri- N bed is a modification of the general procedure of Angyal

HCl, aq. HOAc, heat for the preparation of aldehydes from benzylamines by the CH2NH2 CHO Sommelet reaction. Isophthalaldehyde has been prepared from a,a0-dibromo-m-xylene by the Sommelet reaction Scheme 28 Synthesis of isophthalaldehyde (Scheme 28). Isophthalaldehyde is a valuable intermediate. Although the yields obtained by some of the other reported in the condensation reactions with bases containing nitro- methods of preparation are better than the yield obtained gen and with compounds containing ‘‘methylene active’’ here, the availability of starting material and the simplicity groups [28]. of reaction make this method attractive. This appears to be (e) 2-R-5-Formyl-1,3,4-thiadiazole synthesis: Taking the first reported case of the Sommelet reaction starting into account the high reactivity of the chloromethyl group with a diamine [30]. the applicability of the Sommelet [3] reaction to the for- (g) 1-Naphthaldehyde synthesis: 1-Naphthaldehyde has mation of the desired aldehydes had been discussed. The been obtained by means of the Sommelet reaction key intermediates of the Sommelet reaction, the quaternary (Scheme 29) from a-chloro- or a-bromomethylnaphthalene hexamethylenetetramine salts were prepared after refluxing and hexamethylenetetramine in aqueous alcohol or glacial the 2-R-5-chloromethyl-1,3,4-thiadiazole derivatives with acetic acid. This method has been improved in the present hexamethylenetetramine in chloroform, when the salt procedure by the use of 50 % acetic acid as a solvent [31]. products crystallized out. Hydrolysis of the hexamethy- (h) b-Naphthaldehyde synthesis: b-Naphthaldehyde has lenetetramine salts was performed with 50 % acetic acid been prepared from b-chloromethylnaphthalene by the use under reflux. The Sommelet reaction allowed the synthesis

Scheme 29 Synthesis of CH2Cl CH C H N +Cl- 1-naphthaldehyde N 2. 6 12 4 CHO HOAc, HCl N N N

Scheme 30 Synthesis of Cl 2-naphthaldehyde CN C NH HCl SnCl2 HCl

H C CHO NH . SnCl4 . HCl H2O,

heat

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Scheme 31 H Synthesis of H3C o-hydroxy aromatic aldehydes H3C N CH3 HMTA HMTA

OH OH HO

H C N CH H 3 3 H C C O H2N CH3 H+ 3

H H O O OH HO

Scheme 32 Synthesis of OH OMe phenoxazinone OMe OMe NaH, MeI, hexamine, MMPP, MeOH DMF 40oC TFA, reflux , , NaOH then HCl 1 h OHC HO OH OMe OMe OMe

OH OH undergoes the Sommelet reaction to yield an aldehyde OHC CHO (Scheme 31). Hexamine, CF3CO2H (j) Phenoxazinone synthesis: Alkylation of hydroquinones HCl HO OH HO OH and monomethyl ether with methyl iodide was carried out and CHO the yields of the corresponding dimethyl ethers were excellent (82–99 %). The introduction of the hydroxyl group onto the Scheme 33 Synthesis of phloroglucinol aromatic ring, to form the phenols, was then accomplished via the Baeyer–Villiger oxidation of the corresponding benzal- of hexamethylenetetramine in ethanol, (Scheme 30)or dehydes, which were prepared using the Duff reaction, with from b-bromomethylnaphthalene by the use of hexameth- hexamine as the formylating agent, in refluxing trifluoroacetic ylenetetramine in ethanol or in acetic acid [32]. acid. No product was isolated from the attempted formylation (i) o-Hydroxy aromatic aldehydes synthesis: Duff [33] of the tert-butyl substituted hydroquinone ethers, presumably reaction allows the preparation of ortho-hydroxy aromatic due to the cumulative steric hindrance of the bulky tert-butyl aldehydes. The procedure consists the treatment of phenols and methoxy groups. Baeyer–Villiger oxidation of aldehydes with hexamine in glyceroboric acid (HBO2 in dry glycerol) with magnesium monoperoxyphthalate (MMPP), followed by or glacial acetic acid. The reaction seems to involve an the hydrolysis of the formate esters, gave the corresponding aminomethylation, forming secondary amine, which phenols (Scheme 32)[34].

Scheme 34 Synthesis of N syringic aldehyde N H OH N O MeO OMe MeO OMe N , heat

H2SO4, H2O

CHO

Scheme 35 Synthesis of N 3-thiophenecarboxaldehyde r CHO CH2B C6H12N4Br N N

N distill salt

S S S

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N N Cl heat Cl- H2O N N N CHCl N heat H 3 S S S N N

O

Scheme 36 Synthesis of 2-thiophenealdehyde

A co-workers (Scheme 34). Syringic aldehyde has also been O O obtained by numerous other procedures from pyrogallol- HMTA R2 R2 1,3-dimethyl ether from gallic acid, and from vanillin [36]. R solvent 1 O R1 O (m) 3-Thiophenecarboxaldehyde synthesis: 3-thenalde- hyde has previously been prepared from 3-thienylmagne- A = CH NH or CHO 2 2 sium iodide and ethyl orthoformate in low yield. The first Scheme 37 Duff reaction 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– (k) Phloroglucinol synthesis: Phloroglucinol-based Muller procedure and from 3-bromothiophene by treatment polyphenolic compounds have been synthesized with butyllithium and dimethylformamide. (Scheme 33). Polyphenol was synthesized through Vils- (n) 2-Thiophenealdehyde synthesis: 2-Thiophenealde- meier–Haack formylation, Schiff-base condensation of hyde has been prepared by the hydrolysis of 2-the- diformyl-phloroglucinol with 4-amino salicylic acid and nylmethylhexamethylenetetrammonium chloride in neutral Duff formylation reactions, respectively. The polyphenol solution (Scheme 36)[38]. has been synthesized through Duff formylation reaction on (o) The Duff [2] reaction (HMTA, AcOH or TFA) was phloroglucinol. In a typical synthesis, 1 equivalent phlor- studied on substituted [6?5] heterocyclic compounds. This oglucinol was activated by drying in a 900 °C oven over- reaction provided a useful route to aldehydes for com- night. This activated phloroglucinol was mixed with pounds bearing sensitive amide functions. The formation of hexamine (2.2 equiv.) and 40 ml of trifluoroacetic acid and an aminomethyl intermediate in the Duff reaction mecha- heated to reflux for 3 h under nitrogen atmosphere. To this nism is unequivocally demonstrated. It has been assumed 3 M HCl was added slowly with continuous stirring and that the mechanism of the Duff [2] reaction involves an again refluxed for 1 h. After cooling to room temperature, aminomethylation (generated from HMTA) of the sub- the reaction mixture was extracted three times with ethyl strate, followed by the dehydrogenation of the amine to the acetate. The combined organic part was concentrated by a corresponding imine, which is hydrolyzed to give the for- rotary evaporator to get an phloroglucinol [35]. myl group (Scheme 37)[39]. (l) Syringic aldehyde synthesis: This procedure is a (p) Studies have suggested that the Sommelet [3] reac- modification of the method described by Manske and tion involves oxidation–reduction reactions. The amine is

Scheme 38 Synthesis of N N aldehyde and ammonia H+ H H2 2 C X- N X C R N R N N N N

H2 H2O H N C R HN CH O C R NH H N CH 2 2 H 3 2 3

O N H H l NH2 C 3COC 2C , N HMTA Me EtOH heat , , AcOH, 90°C N EtO2C R Me HN N N CHO

NEt2

Scheme 39 Synthesis of formyl derivatives 123 J IRAN CHEM SOC

N (r) A modification of Duff reaction uses trifluoroacetic CF3COOH N Ar H Ar CHO acid as solvent and a variety of aromatic compounds can be H O N 2 converted into aldehydes (Scheme 40)[5]. N

Scheme 40 Synthesis of aldehydes Glycine ethyl ester hydrochloride synthesis

O Glycine ethyl ester hydrochloride has been prepared by EtOH, heat . several methods. Among these methods one is by the action H2C NCH2CN ClH H2N HCl, H2O OEt of ammonia or hexamethylenetetramine on chloroacetic acid (Scheme 41), and subsequent hydrolysis with alco- Scheme 41 Synthesis of glycine ethyl ester hydrochloride holic hydrochloric acid [41, 42]. oxidized by methylamine to the aldehyde and ammonia (includes hydride transfer step) (Scheme 38)[5, 40] Heterocycles synthesis (q) Position 3 of the imidazo[1,2-a]pyridine ring is the most preferred position for electrophilic aromatic substi- Recently, hexamine was used in synthesis of five-, six-, and tutions. This position can be easily functionalized with a seven-membered heterocycles. In these cyclization pro- formyl group. The Vilsmeier–Haack reaction was generally cesses, hexamine supplies one or two nitrogen atoms, or a considered to offer the best yields of formyl derivatives. –CH = N– function, to the newly formed heterocycles. Duff formylation (hexamine in acetic acid or TFA), already (a) 1,4-Benzodiazepine synthesis: Hexamine was widely used on several heterocyclic systems and also found to be used for cyclization of 1,4-benzodiazepines. Large rate efficient. Under TFA conditions, no reaction was observed differences were observed if substituent is present on and only starting material was recovered. In the presence of amino group in the starting 2-aminobenzophenones. acetic acid, the Duff reaction led to acceptable yields of N-Unsubstituted 2-aminobenzophenones undergo decom- formyl compounds (Scheme 39)[39]. position to give imidazolidin-4-one type product. The

Scheme 42 Synthesis of 1,4- O benzodiazepine O NH.HCl H N N C2H5OH O Cl Cl N

C H 6 5 C6H5

CH3 O CH CH 3 O N 3 O N C N C Cl- N C N C2H5OH N N O N N N Cl Cl Cl O N C6H5 N N O C6H5 C6H5 N N

CH3 O CH3 H3C OC2H5 O O N C N N OC2H5 N C2H5OH N Cl Cl N C H N Cl N 6 5 N OH O N C H N C H 6 5 N 6 5

Scheme 43 Synthesis of 1,4-benzodiazepine-2-one 123 J IRAN CHEM SOC

derivatives, however, different structural and stereoisomers R1 R X- 1 should arise [5, 44]. N N R Hexamine can be used to oxidize a preformed tetrahydro HMTA 2 X R2 O seven-membered ring, as in the synthesis of 2,3-dihydro- O R3 Cl R3 Cl 1,4-benzodiazepine starting from 1,2,3,4-tetrahydro deriv- atives (Scheme 45)[45, 46]. C6H5 C H 6 5 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-

R R1 1 R2 zodiazepine-2-ones and its 7-chloro derivatives from the N N R3 corresponding 1-chloroacetyl isatins. Their procedure R2 consisted of treating 1-chloroacetyl isatin with methanolic R3 solution of hexamine. Under these conditions, isatin Cl N Cl N underwent the cleavage of the ring, followed by the cy- H C6H5 C6 5 clocondensation of the ring-opened product, to give the Scheme 44 Synthesis of 2-deoxy-1,4-benzodiazepines desired 1,4-benzodiazepine-2-one-5-carboxylate deriva- tive, in a single step. An attractive feature of this reaction imidazolidinone ring recyclized into 1,4-benzodiazepine was that it provided a very convenient one-pot synthetic under the influence of hexamine (Scheme 42)[5, 43]. entry to the 1,4-benzodiazepine nucleus from 1-chloro- The method adopted for the benzodiazepinone synthesis acetyl isatin (Scheme 46)[48]. proceeded in two steps: the first step was the formation of a A representative of 1,4-benzodiazepine class is alpraz- hexaminium salt, which in the second step, underwent olam which contains a 1,2,4-triazole fused to the benzo- alcoholysis to give the desired 1,4-benzodiazepine-2-one diazepine core. The synthesis of this molecule can be derivative (Scheme 43)[5, 43]. accomplished in a short sequence of steps starting by Treatment of the 2-(N-b-haloalky)-amino-5-chlor- acylation of 2-amino-5-chlorobenzophenone with chloro- obenzophenone with hexamine in ethanol resulted in ring acetyl chloride to give the amide derivative. The latter closure to give a mixture of 2-deoxy-1,4-benzodiazepines undergoes an interesting ring closure reaction in the pres- (Scheme 44). b-Partcipation of the vinylogous-amide- ence of hexamine and ammonium chloride and the result- nitrogen took place during ammonolysis of the 2-(b-hal- ing seven-membered lactam can then be converted into its ophenyl) derivatives. However, an intermediate formation thioamide analog with P2S5 in pyridine. Finally, the reac- of aziridinium derivatives cannot be conveniently demon- tion with acetyl hydrazide catalyzed by acetic acid fur- strated when 2,3-unsubstituted benzodiazepines are the nishes the triazole ring fused to the benzodiazepine core expected products of reaction, since the same product (Scheme 47)[49]. would be formed by both direct ring closure, or b-partici- 1,4-Benzodiazepine is prepared from Boc-protected pation of the N-2 atom. In the preparation of chiral 3-chloro-aniline via the formation of dianion species with

Scheme 45 Synthesis of 2,3- H C H3C dihydro-1,4-benzodiazepine 3 N N HMTA

AcOH, 3.5 h, reflux Cl NH Cl N C H C6H5 6 5

R 2 R R2 COCH Cl 2 H 2 H O N N ClCOCH2Cl N Hexamine O O MW methanol R1 MW N R1 R1 O O COOMe

Scheme 46 Synthesis of 1,4-benzodiazepine-2-one-5-carboxylate 123 J IRAN CHEM SOC

O Cl H O N NH2 O NH Cl O Cl O hexamine, Cl N Cl Cl NH4Cl, EtOH

N H S N N O N

NH2 N P2S5 N H Cl Cl N pyridine n-BuOH, HOAc

alprazolam

Scheme 47 Synthesis of alprazolam

NH2

NH NHBoc O 2 Cl (Boc)2 O, DIEA, t-BuLi, 3 N HCl DCM Cl Cl R1

H O NHCOCH2Cl N

ClCH2COCl, DIEA, HMTA, NH4OAc, EtOH, O toluene Cl Cl N Reflux

R1 R1

Scheme 48 Synthesis of 1,4-benzodiazepine

H O N O O H COCl N C CH Cl HN C CH Cl 2 2 Hexamine Cl N AlCl 3 NH4Cl Cl CCl4 ethanol Cl O

Scheme 49 Synthesis of 7-chloro-5-phenyl-1,3-dihydro-1H,3H-1,4-benzodiazepine-2-one tert-BuLi followed by deprotection of Boc group derivatives whose reaction with hexamethylenetetramine in

(Scheme 48). Chloroacetylation of compounds with chlo- EtOH in the presence of NH4OAc provided 1,4-benzodi- roacetyl chloride in the presence of N,N-diisopropylethyl- azepine ring [50]. amine (DIEA) in dichloromethane (DCM) gave the Aniline derivatives on reaction with benzoyl chloride in corresponding N-(chloroacetyl)-2-aminobenzophenone presence of aluminum chloride and CCl4 provided 123 J IRAN CHEM SOC

Scheme 50 Synthesis of O

flunitrazepam NH2 N HN N O NH Cl F 4 MeI O2N N N Flunitriazepam C2H5OH F N

NO2

Scheme 51 Synthesis of 1,4- O benzodiazepines (ADZ-03) NH 2 O H O NH N O Cl Hexamine Cl Cl O CH3COONH4 Toluene N EtOH

F ADZ-01 F F ADZ-02 ADZ-03

intermediate whose further reaction with hexamine/NH4Cl synthesis of flunitrazepam from 2-flouroacetamido benzo- in the presences of absolute ethanol produced 7-chloro-5- phenone, hexamethylenetetramine and ammonium chloride phenyl-1,3-dihydro-1H,3H-1,4-benzodiazepine-2-one in ethanol as solvent to generate ammonia in situ was (Scheme 49)[51]. 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 Synthesis of methylflunitrazepam 1.0:3.5:2.5:20–30 [52]. The 2-amino-40-flouro-benzophenone (ADZ-01) was 7-Nitro-1-methyl-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4- reacted with chloroacetylchloride to afford 2-chloro-N-(2- benzodiazepin-2-one (Flunitrazepam) is the drug from (40-fluorobenzoyl) phenyl)acetamide (ADZ-02). It was family of seven-membered heterocyclic compounds 1,4- subsequently converted to 1,4-benzodiazepines (ADZ-03) benzodiazepinones. Although a number of methods for the by the modification of the known hexamethylenetetramine- synthesis of flunitrazepam have been reported in literature, based cyclization reaction (Scheme 51)[53, 54]. they suffer because of using anhydrous ammonia or dry A series of some substituted aniline derivatives of ammonia gas. In this research work, the new method for 7-chloro-5-phenyl-1,3-dihydro-1H,3H-1,4-benzodiazepine-

Scheme 52 Synthesis of O 7-chloro-5-phenyl-1,3-dihydro- O COCl C CH2Cl 1H,3H-1,4-benzodiazepine-2- H HN one N C CH2Cl AlCl3

CCl4 Cl Cl C O

H O N H N N Hexamine H2N

ethanol Cl N Absolute ethanol NH4Cl Cl N

123 J IRAN CHEM SOC

NH2 HOOC N POCl3, at reflux,

SH 4 h, 80% S

NBS, benzene, benzoyl peroxide; 10 h POCl3, at reflux, 4 h, 80% o HMTA/H2O, CHCl3, at reflux, 12 h NaCN/ H2O, THF, 50 C, 24 h, 40% AcOH/H2O, at reflux, 2 h, 25%

N N CN O S S H n-Bu H 4O , t-BuOH/THF, 1 h, 96% N CN S

N

S

Scheme 53 Synthesis of benzothiazole

Scheme 54 Synthesis of O O O R benzo[b]thiophen-3(2H)-one- S O O O S 1,1-dioxide RCHO, EtOH/DMF, S HMTA rt or reflux O AcOH/DMF O O

O O R R O O O O S S MeI/NaH S S or Me2SO4/NaH O O N O N O H Me

2-one were synthesized by treating 7-chloro-5-phenyl-1,3- in chloroform and then refluxed with a mixture of glacial dihydro-1H,3H-1,4-benzodiazepine-2-one with the differ- acetic acid and water to obtain the benzothiazole vinyl ent type of aniline derivatives in the presence of absolute benzaldehyde. The elaboration of the conjugated system was ethanol. N-(2-benzoyl-4-chlorophenyl)-2-chloroacetamide performed by reacting equimolar quantities of both above was dissolved in ethanol after that hexamine and the compounds in dry THF and tert-butyl alcohol at 50 °C while ammonium chloride were added and the reaction resulted a small amount of tetrabutylammonium hydroxide was in the formation of product (Scheme 52)[55]. slowly dropped into the mixture (Scheme 53)[56]. (b) Benzothiazole synthesis: The compound was reacted (c) Benzo[b]thiophene synthesis: Benzo[b]thiophen- with N-bromosuccinimide in dry benzene and subsequently 3(2H)-one-1,1-dioxide is a versatile reagent containing a it was reacted with aqueous sodium cyanide in tetrahydro- sulfonyl group for the synthesis of polycyclic pyridines. furan (THF) to form a benzothiazole vinyl phenyl acetoni- Starting compound with aromatic aldehydes easily formed trile. Similarly, compound was reacted with N-bromo- 2-ylidene derivatives. 1,5-Dicarbonyl derivatives were succinimide and excess of aqueous hexamethylenetetramine obtained in the reaction of compound with aromatic

123 J IRAN CHEM SOC

HO OH HO OH anhy ZnCl2 R H H 2C 2COO PhCOCl o CH2R2 R1 140 C R1 O CHO

HO O Ph HO O Ph acetone/K2CO3 hexamine

refllux, 8 h AcOH R R 1 2 R1 R2 O O

Scheme 55 Synthesis of chromone

Scheme 56 Synthesis of OH OR pyridinechromone OH O Hexamine, H O, O Ac2O, NaOAc, 2 CHO O Et N, AcOH, 100°C, 3 O O HCl (56% overall) 2.5 h (72%) R OH Me H Me Me

R

n-Bu3SnCHCH2CH2, O H O OMe Pd(PPh ) Cl , LiCl, PPh , HC(OMe)3, CSA, 3 2 2 3

MeOH, r.t., e BHT, DMF, 18 h (80%) O R O OM Me 24 h (97%) Me Me Me

Me

O N SiO2 (100%) O Me Me

CH3 CH3

H2SO4 (80%) Hexamine/GAA EAA HCl 1 h HO O O HO OH HO O O CHO

Scheme 57 Synthesis of 3-aryl-[(1-isocyano-4-methyl-7-hydroxycoumarin)]-5-methyl-1,3,4-triazoline-2-one aldehydes in ethanol/DMF mixture in the presence of cat- type cyclization. Alkylation of compound required rather alytic piperidine and acetic acid at reflux temperature in drastic conditions, such as MeI/NaH and Me2SO4/NaH 2 h. The condensation of derivatives with hexamethy- (Scheme 54)[57]. lenetetramine in acidic medium led to the expected new (d) Chromone synthesis: Rossing method is used for the heterocyclic spirosystems, which might reasonably arise synthesis of 2-acylphenoxyacetic acids, via phase transfer from an internal Mannich reaction of compounds due to catalyst under nitrogen atmosphere to give rise to either the steric hindrance of the aryl substituent. The intramo- benzofuran or 2-acetyl benzofurans. Selective formation of lecular addition of amino group to the carbonyl group benzofurans and 2-acetyl benzofurans depends on solvent furnished dihydrodibenzothienopyridines via Hantzsch and structural features of substrates. A mixture of

123 J IRAN CHEM SOC

Cl

NH2 HN O ClCH2COCl N Dioxane N O N N S O S O O

O + - H C6H12N4] Cl N

(CH ) N /EtOH HN 2 6 4 O N N N O S N N O S O

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

O O O OH C H N HBr , 6 12 4 3 OH O H MeN CH Cl , 15 min e 5-exo trig 4 2 2 M N MeN H H2 Br+ 7 H1 H O N O N 3 Me Me O N H Me H Br 5 H 8 9 H6

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

H N N N NaHCO N N 3 N N melt N N Cl N N N

Scheme 60 Synthesis of hexaazapolycycle 8-formyl-7-hydroxy chromones react with ethyl bromo resulting from 1,2-addition to the carbonyl were obtained acetate in K2CO3 as phase transfer catalyst under nitrogen when Pd(PPh3)2Cl2 was employed as catalyst. On the other atmosphere to give ethylfuro[2,3-h]chromone-8-carboxyl- hand, use of Pd(PPh3)4 resulted in decarbonylation or com- ates in good yields (Scheme 55)[58]. plete degradation of the starting material. Therefore, the When the Kostanecki–Robinson synthetic sequence was carbonyl moiety was protected as the corresponding dime- carried out on ketone, it afforded 56 % yield of chromone thyl acetal in 97 % yield with HC(OMe)3 and catalytic intermediate which was immediately subjected to a Duff amounts of camphorsulfonic acid in MeOH. Interestingly, it formylation. was observed that the acetal was readily hydrolyzed during Experiments toward the oxidative fission of the allyl acidic workup. Oximation of aldehyde in the presence of moiety were next carried out. Initially, to avoid potential excess methoxylamine hydrochloride and sodium acetate over oxidation of the substrate, the phenol was protected as as base furnished 76 % of oxime, as a single isomer the corresponding mesylate. Therefore, considering the (Scheme 56)[59]. instability of the mesylate group to the reaction conditions, (e) Coumarins synthesis: The 3-aryl-[(1-isocyano-4-methyl- the direct transformation was performed under the same 7-hydroxycoumarin)]-5-methyl-1,3,4-triazoline-2-one and its conditions. Although there are scattered precedents sug- substituents were obtained by the condensation of amino group gesting that aldehyde could withstand the conditions of the of mono and disubstituted derivatives of 3-methyl-5-oxo-1,2,4- Stille cross-coupling reaction, the palladium-catalyzed de- triazoles with 8-formyl-7-hydroxy-4-methylcoumarin in alco- carbonylation of aromatic aldehydes and the Pd-catalyzed hol. The synthesis of 8-formyl-7-hydroxy-4-methyl-coumarin allylation of aldehydes with allyltributyltin are well-docu- is assisted by hexamine (Scheme 57)[60]. mented transformations. In fact, when the transforma- (f) 1,4-Diazepine synthesis: Chloro acetylation of 1-amino- tion was attempted with n-Bu3SnCH2CH2CH2, products 2-benzoyl-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]

123 J IRAN CHEM SOC isoquinoline using chloroacetyl chloride in dioxin on a 5 min from 120 to 160 °C hexaazapolycycle dye was steam bath followed by treating with sodium carbonate formed (Scheme 60). The raw material was extracted with solution afforded N-(2-benzoyl-5-morpholin-4-yl-6,7,8,9- CH2Cl2 (to remove other impurities) and water (to remove tetrahydrothieno[2,3-c]isoquinolin-1-yl)-2-chloroacetamide. the salts). The dried residue obtained was pure [63]. Refluxing chloro acetylamino derivative with hexamethy- (i) Imidazole synthesis: Several chloro-, bromo-, and lenetetramine in ethanol yielded 5-morpholin-4-yl-8-phenyl- nitro-1H-phenanthro[9,10-d]imidazoles were synthesized 1,2,3,4,10-pentahydro [1, 4] diazepino[5,6:4,5]thieno[2,3-c] from phenanthroquinones, ammonium acetate, and hexa- isoquinolin-11(12H)-one through formation of hexaminium mine (Scheme 61)[5, 64]. salt as intermediate (Scheme 58)[61]. Starting from 2-chloroacetamido-5-chlorobenzophe- (g) Furan synthesis: 6-(Cyclohex-2-enyl)-1,3-dimethyl- none, the hexaminium salt was synthesized, which 5-hydroxyuracil when treated with hexamine hydrotribro- decomposed in alcoholic solution giving bis- and mono- mide in methylene chloride at 0–5 °C for 15 min furnished imidazolidin-4-one derivatives (Scheme 62)[65]. 6-bromo-1,3-dimethylhexahydrobenzofuro[3,2-d]pyrimi- (j) Indole synthesis: Dauth and Becker [66] developed a dine-2,4-dione in 92 % yield. It may be noted that similar method for the preparation of 1,3-dihydroisoindole via a cyclization of o-cyclohexenyl phenols with pyridine hexaminium salt (Scheme 63). hydrobromide generated bicyclic heterocycles by a 6-endo (k) Isoquinoline synthesis: 2-Substituted benzyl bro- cyclization (Scheme 59)[62]. mides form stable quaternary compounds with hexamine in (h) Hexaazapolycycle synthesis: When 2-chlorometh- acetonitrile. In chloroform solution containing small ylbenzimidazole, hexamethylenetetramine and NaHCO3 amounts of water or ethanol, however, decomposition takes were mixed under argon and the melt was heated within place, yielding the aldehyde. When compound contained a

Scheme 61 Synthesis of R1 R1 imidazole R2 R2

O H HMTA/NH OAc/AcOH N R3 4 R3

R4 R4 O N

R5 R5

R6 R6

Scheme 62 Synthesis of bis- O O H H N and mono-imidazolidin-4-one N N HMTA/CH CN C2H5OH Cl 3 N N O O N Cl- Cl Cl

C6H5 C6H5

O O O

N N NH.HCl N N N HCl/C2H5OH O Cl O O Cl Cl C6H5 C6H5 C6H5

Scheme 63 Synthesis of 1,3- HMTA/ HCl/ X dihydroisoindole X CHCl C2H5OH 3 N NH X 50oC N N X- N

123 J IRAN CHEM SOC

Scheme 64 Synthesis of isoquinoline

HMTA/CH3CN N O O Br N N - Br N

CHCl3/H2O/C2H5OH

O N CHO

OMe OH O Ph O Ph Me H C O Me CHO Me CHO BBr B H K Me OH 3 2 5, 2CO3 mCPBA CH2Cl2 DMF CH2Cl2 MeO MeO e M O MeO

O Ph O Ph O Ph Me OH H O, Py Me OTf Bu2Sn Me (CH2)6N4 2

AcOH CH2Cl2 PdCl2(PPh3)2 MeO CHO MeO CHO DMF, 110oC, 1 h MeO CHO

O Ph O Ph

Me2(iPrO)SiCH2Cl Me Me TBDMSCl Mg, THF, 0oC, 1 h PCC OH Et N imidazole KF, KHCO , 3 , OH CH2Cl2, 3 MeO DMF, rt, 12 h MeO rt, 5 h 30% H2O2, THF, MeOH, rt, 3 h OH OTBDMS

O Ph O Ph O Ph Me Me Me NH2OH.HCl o-dichlorobenzene

AcONa, EtOH, NOH 180oC, 1 h N O o MeO 85 C, 1 h MeO MeO

OTBDMS OTBDMS OTBDMS

Scheme 65 Synthesis of 5-hydroxy-1-hydroxy (or acyloxy)methylisoquinoline carbonyl group in 2-position of the side chain, the main analysis. For the preparation of a ketoxime, that is, a products formed were isoquinolines, accompanied by 1-azahexatriene system, began with 2,4-dimethoxy- minor amounts of aldehydes (Scheme 64)[5, 67]. 3-methylbenzaldehyde. 2,4-Dimethoxy-3-methylbenzalde- Researchers have envisaged the synthesis of 5-hydroxy- hyde was treated with boron tribromide to produce 1-hydroxy (or acyloxy)methylisoquinoline as an efficient the 2-hydroxybenzaldehyde, which was converted into the substrate for a new regioselective oxidation of the iso- benzyl ether. The benzaldehyde was subjected to the quinoline-5,8-dione antibiotics based on a retrosynthetic Baeyer–Villiger reaction with m-chloroperbenzoic acid to

123 J IRAN CHEM SOC

N N electronic density of the amide carbonyl group and favor- Me Me ing attack by the aminomethyl group in position 3 to form HMTA N N the lactam cycle. In another run in AcOH, with an ethyl Solvent, 90oC ester instead of the amidic chain in C-5, tricycle was also O OEt O N obtained in 16 % isolated yield (Scheme 66). This result H unequivocally demonstrated the mechanism of formation Scheme 66 Synthesis of lactam 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 give the phenol. The phenol was subjected to the Duff the yield of compound to 54 %. This result can be reaction with hexamethylenetetramine in acetic acid, fol- explained by the oxidative conditions of the reaction. The lowed by treatment with trifluoromethanesulfonic anhy- aldehyde group on position 5 can be converted into the acid dride to yield the triflate. The cross-coupling reaction with intermediate, which gives tricyclic compound by periann- vinyl tributyltin in the presence of palladium dichlorobis- elation [39]. triphenylphosphine gave the ethenylbenzaldehyde whose (m) Morpholine synthesis: Taking into account the high Grignard reaction with dimethylisopropyloxysilylmethy- reactivity of the chloromethyl group, we decided to study lmagnesium chloride, followed by treatment with potas- the applicability of the Sommelet reaction to the formation sium fluoride and 30 % hydrogen peroxide, afforded the of the desired aldehydes. The key intermediates of the 1,2-diol. Selective protection of the 1,2-diol with tert- Sommelet reaction, the quaternary hexamethylenetetramine butyldimethylsilyl chloride (TBDMSCl) produced the salts were prepared after refluxing the 2-R-5-chloromethyl- TBDMS ether, which was oxidized with pyridinium 1,3,4-thiadiazole derivatives with hexamethylenetetramine chlorochromate (PCC) to obtain the ketone. Subsequent in chloroform, when the salt products crystallized out. treatment of the ketone with hydroxylamine afforded Hydrolysis of the hexamethylenetetramine salts was per- the ketoxime as the 1-azahexatriene system, which was formed with 50 % acetic acid under reflux. The Sommelet subjected to the thermal electrocyclic reaction in reaction allowed the synthesis of 2-R-5-formyl-1,3,4-thia- o-dichlorobenzene at 180 °C to furnish the desired 5-ben- diazole derivatives with yields of 65–69 % (Scheme 67) zyloxyisoquinoline (Scheme 65)[68]. [69]. (l) Lactam synthesis: In the more acidic conditions, the (n) Oxazoles synthesis: Synthesis of 5-(3-indolyl)oxaz- N-1 of the nucleus was largely protonated, decreasing the oles was started from 3-acetyl-1-benzenesulfonylindole.

N Cl- N N N N N N C6H12N4 N N N 50% CH3COOH C CHO R CH2Cl CHCl3 O N O N S S H2 S

Scheme 67 Synthesis of morpholine

O O O

OTs NH HCl C6H5I(OH)OTs, 2 HMTA, CHCl3 RCOCl, Et3N, N CH CN, rt HCl, reflux 3 N N 0-5oC; SO2C6H5 SO2C6H5 SO2C6H5 N O N H N R R O R PTSA, EtOH, O NaOH, EtOH-H2O, O reflux N reflux N N SO C H H SO2C6H5 2 6 5

Scheme 68 Synthesis of 5-(3-indolyl)oxazoles 123 J IRAN CHEM SOC

The synthesis of novel 3-tosyloxyacetyl-1-benzenesulfo- supplied in 85 % purity, the remaining 15 % being pyr- nylindole was accomplished by reaction of starting com- rolidine. It is now supplied in only 65 % purity. Material of pound with hydroxy(tosyloxy)iodobenzene in an excellent 97 % purity is available; however, the cost is excessively yield at room temperature. 3-Aminoacetyl-1-benzene- high, limiting its use as a starting material. A three-step sulfonyl indole hydrochloride was obtained in very good preparation, based on the Delepine reaction, describes the yield from the reaction with hexamethylenetetramine synthesis of this compound in high purity. However, some (HMTA) followed by refluxing the reaction mixture in the difficulties were encountered in the hands of the submitters presence of dilute hydrochloric acid. 3-Aminoacetyl-1- following this procedure. Several modifications have now benzenesulfonyl indole hydrochloride was acylated with led to an efficient preparation of 3-pyrroline in high purity the appropriate acyl chloride in the presence of triethyl- (Scheme 69), and to a procedure that is readily amenable to amine to give acylaminoketones. Cyclodehydration of large-scale synthesis [71–73]. acylaminoketones give 5-(3-indolyl)oxazoles was accom- (p) Quinazolines synthesis: 2-Amino-5-substituted plished successfully using p-toluenesulfonic acid. In gen- benzophenones reacted with hexamine, in the presence of eral, cyclodehydration of acylaminoketones into oxazoles ethyl bromoacetate to give quinazoline derivatives. It was involves harsh reagents such as H2SO4, PCl5,P2O5, SOCl2, found that benzophenones with electron-accepting substit- POCl3,Ac2O, and Ph3P. Finally, the benzenesulfonyl uents gave a mixture of dihydroquinazoline derivatives moiety of 5-(3-indolyl)-oxazoles was removed using dilute (Scheme 70). But benzophenones with electron-donating sodium hydroxide to afford the 5-(3-indolyl)oxazoles in substituents furnished only quinazoline [5, 74]. good yields (Scheme 68)[70]. Recyclization of isatin after ring opening with hexamine (o) 3-Pyrroline: Pure 3-pyrroline has been difficult to gives rise to the derivatives of the seven-membered 1,4- obtain. Commercially available 3-pyrroline was at one time benzodiazepine, while ammonia, in a similar reaction,

N

N N N - N Cl Cl- N HCl, EtOH N N + - N Cl NH3Cl Cl Cl H l 97 % C C 3 N 63 % N 91 % Cl H

Scheme 69 Synthesis of 3-pyrroline

Scheme 70 Synthesis of R quinazolines NH N N 2 HMTA

O BrCH2COOC2H5/ROH N N X X X C H C H C6H5 6 5 6 5

Scheme 71 Synthesis of H2 quinazolones OC C Cl H2 N C Cl N HMTA O N NH3/C2H5OH X X

O OC NH2

Scheme 72 Synthesis of R1 9-chloro-10-phenyl-2,3,5,6- H HO N R1 N tetrahydrooxazolo[2,3- reflux R2 HMTA/C2H5OH, d]quinazolines N Cl N R3 Cl R3 C6H5 C6H5 O

R2

123 J IRAN CHEM SOC

O O O O O DCC, O O EtO DMAP, t O O E OH Aniline, p-TSA, DCM R OH O R O EtO R C6H6 O O N R O O O O O EtO H O OH Diphenyl ether, 2 2, Hexamine, H EtOH, 240°C TFA NaOH aq N R N R N R N R H H H H

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

O O O O OO DCC/DMAP Ethanol HO DCM, rt, 12 h O Reflux, 4 h O O O

O O

O Toluene Diethyl ether NH O Reflux, 30 min O Reflux, 24 h OH O H2N S O

O O O

Hexamine, TFA H2O2,

1) N2, Reflux, 30 h EtOH, 1 M NaOH N 2) MeOH/H O 1 h N H 2 H 3) 3M HCl, 30 min

O OH

N H

Scheme 74 Synthesis of 3-formyl-2-heptyl-4(1H)-quinolone causes recyclization to six-membered quinazolones imine. The imine isomerises to the thermodynamically (Scheme 71)[74]. more stable enamine, which undergoes a cyclo-condensa- When benzophenone-imine derivatives were reacted tion when heated in a high boiling solvent, such as diphenyl with hexamine in boiling ethanol, then heterocycles with ether, forming 2-heptyl-4(1H)-quinolone. A formyl group three condensed rings 9-chloro-10-phenyl-2,3,5,6-tetrahy- was introduced at the 3-position using hexamine in the drooxazolo[2,3-d]quinazolines were obtained (Scheme 72) presence of trifluoroacetic acid (TFA). The formyl group is [74]. then transformed to a hydroxyl group via a Baeyer–Villiger (q) Quinolone synthesis: Meldrum’s acid was acylated oxidation, using hydrogen peroxide (Scheme 73)[75]. using octanoic acid in the presence of 1,3-dicyclohex- 5-Octanoyl Meldrum’s acid was synthesized by utilizing ylcarbodiimide (DCC) and catalytic 4-dimethylaminopyri- the coupling reaction of starting compounds in the presence dine (DMAP). This 5-acyl Meldrum’s acid was then heated of DCC/DMAP. 120 mL of newly distilled dichlorometh- at reflux in ethanol to form a b-keto ester. Acid-catalyzed ane and 4-dimethylaminopyridine was added. This mixture condensation of the b-keto ester with aniline formed the was stirred at room temperature until all solid was

123 J IRAN CHEM SOC

CH3 O CH CH 3 O N 3 O N C N C Cl- N C N C2H5OH N N O N N N Cl Cl Cl O N C6H5 N N O C6H5 C6H5 N N

CH3 O :B CH H3C OC2H5 3 O N C N N O OC2H5 H N Base N Cl H Cl NH C H N Cl N 2 6 5 N OH O N N C6H5 N C6H5

Scheme 75 Synthesis of quinoline

O O

HO HO OEt

Br O HMTA, PPA, S S EtOH 80oC N OEt NH2

Br HO O

O S O OHC S KI, K2CO3,DMF, rt OHC N OEt 64%, 2 steps N OEt

O O

NH OH.HCl O O 2 S 2 NNaOH, S NC NC HCO2Na THF, H O 2 N OH HCO2H, 93% N OEt

Scheme 76 Synthesis of thiazole dissolved, then dicyclohexylcarbodiimide was added and introduced into the reaction flask and the heating was the stirring was continued for 1 h. The reaction was allowed allowed to continue for 1 h. A 3 M solution of hydrochloric to stir overnight at room temperature. A yellow residue was acid was then introduced into the reaction, which was recovered after the removal of the solvent, which was re- heated for a further 30 min. The reaction was cooled and the dissolved in ethyl acetate. The insoluble DCC was removed precipitate was recovered by filtration, washed with water, by filtration. The synthesis of 3-formyl-2-heptyl-4(1H)- and triturated by acetone [76, 77]. quinolone is shown in Scheme 74. A mixture of 2-heptyl- When 2-aminobenzophenone is treated with hexamine, 4(1H)-quinolone and hexamine was dissolved in trifluoro- formation of 1,4-benzodiazepine took place (Scheme 75). acetic acid. The reaction was refluxed under a nitrogen But if the amount of alcohol used in solvolysis was environment for 30 h. At this time methanol and water were insufficient, then it furnished quinoline derivative [78].

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Scheme 77 Synthesis of NO N tetraaza compounds ON NH HCl or AcOH/NaNO N N 2 or N N N N NN ON NO HN NO

O R C SO2 Ar N O N 2 N N Ar S Cl 5-10oC N N N N o N N N 10% NaOH, pH 8-9, 70-75 C N N OC R N (RCO)2O N SO2 Ar N COR Scheme 80 Synthesis of bis[sulphonamido]tetraazabicyclo[3.3.1] 90-100oC N nonanes

NN ROC COR dinitroso compounds (1:3:3), or pure dinitroso compound (1:6:6). When acetic acid was employed the only product Scheme 78 Synthesis of triaza and tetraaza compounds obtained over a wide range of conditions was the dinitroso compound [5, 80]. (r) Thiazole synthesis: Fabuxostat was discovered by The reaction of hexamine with acetic anhydride has been Teijin pharmaceuticals and was approved in the US for the studied. The yields of tetraaza compound never exceeded treatment of hyperuricemia in patients with gout. The 45 %. Siele et al. [81] reported a simple procedure for the commercially available and easily prepared 4-hydrox- preparation of triaza compound in[90 % yield (Scheme 78). ythiobenzamide was reacted with ethyl bromoacetoacetate Using acetic anhydride, water, and hexamine, at in refluxing ethanol to provide the thiazole ester in 60 % 5–10 °C, acylated tetraaza compound is obtained yield after crystallization. The phenolic ester was then (Scheme 79). The yield increases when the reaction con- treated with hexamethylenetetramine in polyphosphoric ducted in the presence of an inorganic base. Water used in acid at 80 °C to provide the crude aldehyde. Reaction of this reaction shifts the equilibrium toward right (acylation phenol and isobutyl bromide in the presence of potassium occurs in presence of water). It was found that ketene could carbonate with catalytic potassium iodide in DMF gave be substituted for the acetic anhydride [82]. isobutyl ether. This ether was then converted in one pot to Yoshida et al. [83] have studied the selective ring open- nitrile in 93 % by reacting the aldehyde with hydroxyl- ing of 1,7-bis[sulphonamido]tetraazabicyclo[3.3.1]nonanes amine hydrochloride and sodium formate in refluxing for- using the electrophillic species NO? and NO2?. In these mic acid. Saponification of the ester with aqueous sodium methods, bis[sulphonamido]tetraazabicyclo[3.3.1]nonanes hydroxide provided fabuxostat (Scheme 76)[79]. are produced, when hexamine was reacted with arenesul- (s) Triaza and tetraaza compounds synthesis: Degrada- phonyl chlorides (Scheme 80)[5]. tive nitrosation of hexamine in aqueous solution was car- (t) Triazine synthesis: A hexahydro-1,3,5-triacyl-s-tri- ried out by simultaneous addition of hydrochloric or acetic azine was first prepared from ammonium chloride, formalin acid and solution of sodium nitrite (Scheme 77). The main and benzoyl chloride or from hexamethylenetetramine and factor determining the nature of products is pH of the benzoyl chloride (Scheme 81). Procedures similar to the one solution. In hydrochloric acid at pH 1, the trinitroso com- described also have been used for the preparation of hexa- pound is formed mainly, and at pH 2 a mixture of trinitroso hydro-1,3,5-triacetyl-, tri(b-chloropropionyl)-, triacrylyl-, and dinitroso is obtained. Variation of the molar ratio of trimethacrylyl-, and tribenzoyl-s-triazine. Several of these C6H12N4:HCl:NaNO2 resulted in the formation of only compounds also have been prepared from the corresponding trinitroso compound (1:6:1–3), a mixture of trinitroso and nitriles and paraformaldehyde in the presence of acetic anhydride and sulfuric acid [84].

OC R NH N N H O (RCO) O 2 N 2 N Introduction of aminomethyl groups N N N N N H CO H O 2 HN 2 N (a) Preparation of cross-linked polystyrene resin: Chlo- OC R romethylated 4 % TTEDGA-crosslinked polystyrene resin Scheme 79 Synthesis of acylated tetraaza compounds was converted to the aminomethyl resin by hexamine 123 J IRAN CHEM SOC

Scheme 81 Synthesis of O Et triazine

H SO , N 3 Et CN 2 4 3 H2C O heat Et NNEt

O O

Scheme 82 Preparation of 1) Hexamine cross-linked polystyrene resin 2) HCl-EtOH H NH CH2Cl C 2 2 3) 10% TEA-CH2Cl2

O O Hexamine O H AlCl3 H DMF H Cl C C Br C C NH2 C C Br CH2Cl2 EtOH, HCl CH3 CH3 CH3 10% CH2Cl2

Scheme 83 Preparation of protected peptides method. Hence one pot conversion of chloromethyl resin to methods of peptide synthesis. In solid-phase peptide syn- aminomethyl, resin by hexamine method was used. In this thesis, the introduction of anchoring group between the method, the chloromethyl resin was treated with a twofold solid support and the growing peptide chain is a convenient molar excess of hexamethylenetetramine in DMF at 80 °C strategy for the mild non-destructive cleavage of peptides. for 10 h. The resulting resin on hydrolysis with ethanolic For the introduction of the anchoring group 4-bromo- HCl followed by neutralization with 10 % triethylamine methyl-3-nitrobenzolc acid was prepared from p-toluic acid

(TEA)–CH2C12 afforded aminomethyl TTEGDA-cross- by two step reaction. Aminomethyl TTEGDA-crosslinked linked polystyrene resin (Scheme 82). There was no polystyrene resin was prepared from chloromethyl resin by detectable amount of chlorine in the product resin [85]. Gabriel’s phthalimide method and was coupled with (b) Preparation of protected peptides: For the prepara- 4-bromomethyl-3-nitrobenzoic acid in the presence of tion of protected peptides and peptide amides by photolytic dicyclohexylcarbodiimide to give the photolabile 4-bro- cleavage, a-bromopropionyl and a-aminopropionyl momethyl-3-nitro benzamidomethyl TTEGDA-crosslinked anchoring groups were introduced into TTEGDA-cross- polystyrene support (Scheme 84)[85]. linked polystyrene resin by the polymer analogous. Meth- (d) Preparation of bis-oxy cyclophanes: Bis(amino- ylphenacyl ester linkage has been reported in the case of methyl) m-terphenyl based bis-oxy cyclophanes with amide polymer-supported synthesis of protected peptide frag- group as intra-annular functionality were synthesized. Bis- ments on DVB-crosslinked polystyrene resin (Scheme 83). oxy cyclophane amides were synthesized from a novel This strategy was found successful in the case of the liquid bis(aminomethyl) m-terphenyl. Reaction of bis(bromo- phase method of peptide synthesis on polyethyleneglycol methyl) m-terphenyl with hexamine in chloroform at reflux supports and in multidetachable resin supports [85]. resulted in the formation of hexammonium salt. Hydrolysis (c) Preparation of 2-nitrobenzyl ester linkage: The of hexammonium salt with hydrochloric acid in EtOH–

2-nitrobenzyl ester linkage finds wide spread applications as H2O mixture at reflux afforded diamine in about 90 % protecting and anchoring group in the polymer-supported yield and for the synthesis of bis-oxy cyclophane diamide,

Scheme 84 Preparation of NO2 2-nitrobenzyl ester linkage O NO2 HO C CH2Br O r CH2NH2 CH2NHC CH2B DCC

NO2 O Hexamine CH2NHC CH2NH2 HCl/Et3N

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Hexamine, CHCl3, rt, 12 h;

Conc.HCl, EtOH-H2O, reflux, 3 h NH NH Br Br 2 2

O O O O

O O NH NH

ClO2C CO2Cl

TEA, DCM, rt, 24 h,

Scheme 85 Preparation of bis-oxy cyclophanes

H O N O OH HMTA OH N

O b

a

H N

OH HO c

Scheme 86 Synthesis of Mannich base

Scheme 87 Synthesis of heat H l methylamine hydrochloride 2 H2C O N 4C CH3NH2.HClHCO2H

Scheme 88 Synthesis of NMe MeI N+Me I- NaNH NH 2-methylbenzyldimethylamine 2 3 2, 3 NMe2

Me

1.0 equiv. of diamine was coupled with 1.1 equiv. of dia- Mannich base synthesis cid chloride in the presence of triethylamine in dry DCM at room temperature under high dilution conditions. The When hexamine was reacted with 2-naphthol, the product reaction afforded the bis-oxy cyclophane diamides obtained was incorrectly formulated as bis[2-naphthyl- (Scheme 85)[85]. oxymethyl]amine (b) [86]. Burke et al. [87] described this

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NO O2N N 2 nitrolysis N N N N N nitrolysis N NO2 NN O N N N N 2 O N NO N 2 2 N N

Scheme 89 Synthesis of RDX NO2 product as an o-substituted derivative of 2-naphthol (c). Scheme 90 Synthesis of HMX Later, Mohrle et al. [67] defined the product formed as a Hale nitrolysis reaction is quenched, the RDX removed by Mannich base a (compound with one additional ring of the dihydro-1,3-oxazine) (Scheme 86). 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 Methylamine hydrochloride synthesis solution of dimethylolnitramine (Scheme 91)[91]. (c) Linear nitramines synthesis: The nitrolysis of hex- amine can be used to obtain the linear nitramines Methylamine can be prepared by the action of formalde- hyde on ammonium chloride in the presence of hexa- depending on the conditions and reagents used. Thus, the nitrolysis of hexamine with a mixture of fuming nitric methylenetetramine (Scheme 87)[88]. acid in acetic anhydride led to the isolation of BSX, whereas the addition of 97 % nitric acid to a solution of 2-Methylbenzyldimethylamine synthesis hexamine in acetic anhydride formed the mixed nitrate- acetate ester. The reaction of hexamine with dinitrogen This procedure is based on the method of Kantor and pentoxide in absolute nitric acid led to the formation of the dinitrate ester. The nitrate ester groups were readily Hauser [89]. 2-Methylbenzyldimethylamine has been pre- displaced and on reaction with sodium acetate in acetic pared from o-xylyl bromide and hexamethylenetetramine (Scheme 88). acid form the corresponding acetate esters; the same reaction with low molecular weight alcohols formed the corresponding alkoxy ethers (Scheme 92)[92]. Nitrolysis

(a) RDX and HMX synthesis: The nitrolysis of hexamine is Organometallic synthesis one of the most complex and widely studied processes in the history of energetic materials synthesis. With so many (a) (R,R)-N,N0-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclo- reaction routes available during the nitrolysis of hexamine, hexanediamino manganese(iii) chloride synthesis (a highly it may seem strange that the cyclic nitramines RDX enantioselective epoxidation catalyst): The product of this (Scheme 89) and HMX (Scheme 90) can be isolated in preparation is the most enantioselective catalyst developed such high yields. Synthesis of RDX and HMX via the ni- to date for asymmetric epoxidation of a broad range of trolysis of hexamine could be potent. Owing to the sensi- unfunctionalized olefins. The procedure includes a highly tivity of this reaction to acid, a mixed reagent of metallic efficient resolution of trans-1,2-diaminocyclohexane as salts and Ac2O is usually used in highly efficient nitration well as a convenient analytical method for the determina- or nitrolysis reactions. Herein, a batch of new reagents tion of its enantiomeric purity. This method (Scheme 93)is - 2? 2? 2? 3? M(NO3 )n/Ac2O/NH4NO3 (M = Mg ,Cu ,Pb ,Bi , general for the analysis of chiral 1,2-diamines. The Duff Fe3?, and Zr4?) were firstly studied in the nitrolysis reac- formylation described in Step B is a highly effective tion. Some of these ternary mixed reagents tested to be of method for the preparation of 3,5-di-tert-butylsalicylalde- high efficiency were also used in the nitrolysis of hexamine hyde, and it circumvents the use of hazardous or sensitive [90]. materials, such as tin chloride (SnCl4), which were (b) 1,5-Dinitroendomethylene-1,3,5,7-tetraazacyclooc- employed in previously reported syntheses. The Duff tane (DPT) synthesis: Dimethyl-olnitramine is known to be reaction is applicable to the preparation of other 3,5- present under the conditions of the Hale nitrolysis. If the substituted salicylaldehydes, which in turn can be used to

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H C N CH H2 2 2 Hale nitrolysis HO N OH H2N C NH2 C6H12N4 O2N N CH2 N NO2 NO2 H2C N CH2

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

Scheme 92 Synthesis of linear Ac2O; C6H12N4 nitramines 97% HNO , 3 HNO N O 25oC 3, 2 5

HNO3, Ac2O, o NO2 NO2 NO2 NO2 NO2 NO2 20 C

O2NO N N N ONO2 O2NO N N N OAc

HNO3 54% AcOH, NaOAc EtOH 15% NO2 NO2 NO2 MeOH 60% AcO N N N OAc

(BSX)

NO2 NO2 NO2 HNO3, Ac2O, o e e NO2 NO2 NO2 70 C M O N N N OM EtO N N N OAc prepare chiral (salen)Mn,[N,N0-bis(salicylideneamino)eth- liquid, was obtained from PhCCH and MeCOOH in ane]Mn, epoxidation catalysts with sterically and elec- the presence of (MeCOO)2Hg/BF3OEt2 as catalyst tronically tuned reactivities. As such, a wide range of (Scheme 94)[94]. (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]. Oxidation of glycolic acid

(b) The interaction of PhCCH with Cp(CO)2Mn(THF) led to a mixture of Cp(CO)2Mn(2-PhC CH), vinylidene Glycolic acid is a useful intermediate for organic synthesis, complexes. It was evident that the 2-alkyne complexes in a range of reactions including: oxidation–reduction,

Cp(CO)2Mn(2-PhC2 C1R) were formed in the first stage esterification and long chain polymerization. The oxidation of reaction, after which they rearranged into the 1-co- of glycolic acid by hexamethylenetetramine–bromine ordinated form, i.e. Cp(CO)2MnClC2HPh. The fact that (HABR) has been studied. Glycolic acid is oxidized to give these transformations occurred at 5–20 °C seemed most glyoxylic acid (Scheme 95). The rate of the reaction surprising. It was reported that the hypothetical inter- increases with increasing in concentration of glycolic acid mediate phenylvinylidene could be formed from phen- and HABR. Temperature influence is quite marked in all ylacetylene under very harsh conditions. The acetylene– these reactions. It involves the formation of a activated vinylidene rearrangement, which occurred in the coor- complex, which decomposes to give the product [95]. 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. Phenacylamine hydrochloride synthesis The Mn atom played a role of internal catalyst in this process. The rearrangement is best catalyzed by HMTA, Phenacylamine hydrochloride has been prepared by the when added to the UV irradiated mixture of CpMn(CO)3 hydrolysis of the quaternary salt obtained from phenacyl and PhCCH. The action of acetic acid led to the bromide and hexamethylenetetramine (the Delepine reac-

2-olefinic complex Cp(CO)2Mn[2-CH2C(Ph)OC(O)Me]. tion). The present procedure is adapted from those Addition of MeCOOH to the 2-PhCCH ligand followed of Baumgarten; Bower and Baumgarten; Petersen

Markovnikov’s rule. Free Ph(MeCOO)CCH2, an unstable (Scheme 96)[96, 97].

123 J IRAN CHEM SOC

HO OH H2N NH3 H2O/HOAc

o o HO C CO H 90 C to 5 C - - 2 2 O2C CO2 H2N NH2

HO OH

OH OH

t-Bu HOAc, OHC t-Bu H2N NH3 2 eq K CO 130oC, 2h 2 3 C6H12N4 H O/EtOH 80oC H2SO4 (aq), - - 2 , O2C CO2 105oC t-Bu t-Bu HO OH

H H H H EtOH/toluene N N N N o 85 C, air, NaCl(aq) Mn t- u t- u t-Bu OH HO t-Bu B O Cl O B

t- u t- u t-Bu t-Bu B B

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

Ph Ph hv = CO 5-20oC PhCCH Mn Mn CO HMTA Mn C C OC O CO OC C CO H CO H

+ MeCOOH Base

O

Ph Ph OCMe C Mn C C OC CO Mn OC n C CO C C M OC CO H H Ph

Scheme 94 Synthesis of organometallic compound

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Scheme 95 Oxidation of glycolic acid

Scheme 96 Synthesis of NH2 NCl2 NCl phenacylamine hydrochloride CH t-BuOCl CH NaOMe, MeOH, 3 3 CH3 benzene, 5oC heat

H O N

NH3Cl NaOMe, MeOH, OCH3 HCl, H2O, heat heat

Scheme 97 Synthesis of O 1-phenylethylamine O NH Cl NH NH OCHO 3 2 4 HN H H2O, NaOH heat Ph CH3 HCl Ph CH Ph CH Ph CH 3 3 3 dl form

H2, Ra (Ni) been converted to the amine by the Delepine synthesis (2000 psi) NH2 from b-phenylethyl iodide and hexamethylenetetramine. Ph Ph CN o NH3, 130 C More recent methods for preparation of the amine include the lithium aluminum hydride reduction of b-nitrostyrene Scheme 98 Synthesis of 2-phenylethylamine and of phenylacetamide. The Raney nickel reduction of the nitrile in the presence of formamide is reported to give an R1 R1 87 % yield of the formylated primary amine (Scheme 98) HMTAB, CCl4, H2O C N X [100]. rt or reflux C O

R2 X = OH, NH-Ts R2 Regeneration of carbonyl compounds Scheme 99 Regeneration of carbonyl compounds from oximes and tosylhydrazones (a) From oximes and tosylhydrazones: Hexamethylenete- traminebromine (HMTAB) has been found to be an effi- Phenylethylamine synthesis cient and selective reagent for the mild oxidative cleavage of the C N of oximes and tosylhydrazones to yield their (a) a-Phenylethylamine synthesis: The present procedure 1 corresponding carbonyl compounds in good to excellent was developed from those of Wallach and Freylon, based yields under mild conditions. It is most important to note upon the general method discovered by Leuckart. a- that most of the reported methods are suitable for the Phenylethylamine can also be prepared satisfactorily by the regeneration of ketones but not for aldehydes from their reduction of acetophenone oxime and hexamethylenetet- oximes and tosylhydrazones, and that yields are low owing ramine (Scheme 97)[98, 99]. to the over oxidation of regenerated aldehydes to acids. (b) b-Phenylethylamine synthesis: b-Phenylethylamine Therefore, it is desirable that a method which leads to high has been made by a number of reactions, many of which recoveries of a wide range aldehydes and ketones should be are unsuitable for preparative purposes. Benzyl cyanide has available and the present method is an efficient and general

method for the effective and selective cleavage of the C1N NO2 of oximes and tosylhydrazones with HMTAB under neutral NHN CRAr Ar and mild conditions (Scheme 99)[101]. HMTAB/wet Al2O3 O toluene, reflux/MW (b) From phenylhydrazones: 2,4-Dinitrophenylhy- O2N R drazones were converted to their parent carbonyl com- Scheme 100 Regeneration of carbonyl compounds from phen- pounds using hexamethylenetetramine–bromine complex ylhydrazones supported onto wet alumina under classical heating and 123 J IRAN CHEM SOC

OH OH OH

H SO (1 eq.), 1 eq. HMTA, CF3COOH, O 2 4 methanol, O inert atmosphere, 3 h reflux 3 h reflux,

O OH CH3 O OH O O

N N H3C O O Al(NO3)3·9H2O 0.5 eq. o-phenylenediamine, OH HO ethanol, rt methanol, 2 h, rt O O

CH3

N N H3C O M O O O O O

CH3 M = Al(NO)3

Scheme 101 Synthesis of Schiff-base

O O O O O

H OH CH2O aq, Cl HMTA HCl H H Cl H2O, HCl

O O O O O O

HBr aq, CH COOH 3 CH2O aq.

O O O OH O

O H H H H H O

O OH O O O OH OH

Scheme 102 Synthesis of Schiff-base microwave irradiation. Herein, the results for the mild, 2,4-dinitrophenylhydrazone in toluene to regenerate the facile, fast and high yielding cleavage of phenylhydrazones corresponding carbonyl compound (Scheme 100). The under classical heating and under microwave irradiation in supported reagent was mixed with neat 2,4-dini- a solventless system have been reported. Initially, hexam- trophenylhydrazones, grinding them thoroughly to make an ethyleneteramine–bromine was mixed with wet alumina. intimate pair. By placing the mixture in a microwave oven, This supported reagent was refluxed with an appropriate the reactions are completed in a couple of seconds [102].

123 J IRAN CHEM SOC

Scheme 103 Sonogashira I cross-coupling reaction Pd-LHMS-3 (0.02 g) Ar O2N Ar H2O, Hexamine, Reflux

NO2

Schiff-base synthesis CH Br CHO 2 2-nitropropane

The functionalized Schiff bases have been prepared in Na, EtOH CH3 CH3 three steps. After the controlled formylation of 4-hy- droxybenzoic acid with hexamethylenetetramine in triflu- Scheme 104 Synthesis of o-tolualdehyde oroacetic acid through the Duff reaction, the resulting salicylaldehyde derivative was esterified. The esterification o-Tolualdehyde synthesis was classically run in methanol in the presence of sulfuric acid. The third step was condensation of the ester-func- A procedure for the preparation of o-tolualdehyde from tionalized aldehydes with o-phenylenediamine, classically o-toluanilide by the Hesse and Schrodel method has been operated in alcohol. Addition of aluminum nitrate to these published in organic syntheses. In addition to the alterna- Schiff bases in ethanol gave the complex in good yields tive methods of preparation listed there, o-tolualdehyde has (Scheme 101)[103]. been prepared from o-xylyl bromide or chloride and The synthesis starts with the chloromethylation of hexamethylenetetramine (Scheme 104)[109, 110]. 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 tris[Chloromethyl]amine synthesis reaction to afford the dialdehyde. The formation can be explained by the mechanism of the Sommelet reaction: Fluck and Meiser [111–113] prepared tis[chloromethyl] addition of hexamethylenetetramine to an organochloride amine by treating hexamine with phosphorus pentachloride

RCH2Cl led to the formation of a quaternary ammonium in a 1:3 molar ratio. In addition to tis[chloromethyl]amine salt [RCH2N(CH2)6N3]Cl which upon hydrolysis liberated second product also formed (Scheme 105). 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 Tryptamine synthesis react further with formaldehyde to give acetal. Phenolether was deprotected to give hydroquinone using hydrobromic N-Phthalimido-hydroxy acetic acid was conveniently pre- and acetic acid. After the recommended reaction time of pared by the reaction between phthalimide and glyoxalic 5 h, a mixture of the desired compound and the monom- acid. The acid was then chlorinated with thionyl chloride to ethylated dialdehyde was obtained (Scheme 102)[104]. give the corresponding chloro-substituted acid. The alde- hyde was obtained by reduction with hexamine in aqueous acetic acid medium (Scheme 106)[114, 115]. Sonogashira cross-coupling reaction

The Sonogashira cross-coupling reaction of aryl halides Tschitschibabin cyclization with terminal alkynes is quite efficient when using water as the reaction medium in the presence of hexamine as base The formylation of imidazo[1,2-a]pyridinic compounds under copper-free conditions. This reaction produced dif- (IPs), substituted by an amidic chain at various core posi- ferent disubstituted aryl alkynes which are dependent upon tions was explored. Scheme 107 describes the synthesis of the aryl halides, which range from electron-donating to imidazopyridinic derivatives substituted on the C-2 or C-5- electron-withdrawing groups and also to sterically hindered C-8 positions. Briefly, 2-aminopyridine compounds reacted ortho-substituted aryl iodides and heteroaryl iodides. Both with the appropriate halo ketones to give ester substituted aryl iodides and bromides couple with phenyl acetylene, compound (50–63 % isolated yields) by Tschitschibabin producing good to moderate yields of the coupling products. cyclization. Amides were then easily obtained with high However, the coupling of aryl bromides is difficult in water yields ([90 %) by direct amidification using trimethyl- and in the presence of hexamine (Scheme 103)[105–108]. aluminum as activator [39].

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Scheme 105 Synthesis of N tris[chloromethyl]amine o C6H6, 100 C N 3 PCl5 N(CH2Cl)3 N(CH2-PCl4) N N

Scheme 106 Synthesis of O O O tryptamine O OH NH THF O N THF H O Reflux, 3 h OH SO2Cl2 O H O

O O O O OH H Hexamine/Dil. CH3COOH N N Reflux, 2 h Cl Cl O O

NH2 BrCH2COCO2Et, N HMTA , N O EtOH AcOH, 90°C R N N N HN

CHO NEt2

Scheme 107 Synthesis of Tschitschibabin cyclization

NH2 3. P.L. Henaff, C.R. Acad, Sci. Paris 253, 2706 (1961) HMTA 4. I.M. Lapina, A.A. Pevzner, A.A. Potekhin, Russ. J. Gen. Chem. NH CO 3 2 O C 76, 1304 (2006) 5. N. Blazevic, D. Kolbah, Synthesis, 3, 161 (1979) NH2 6. D.J. Daigle, A.B. Pepperman, S.L. Vail, J. Heterocycl. Chem. Scheme 108 Synthesis of urea 11, 407 (1974) 7. D.J. Daigle, A.B. Pepperman, US Patent 391, 189 (1973); C.A. Urea synthesis 81 (1974) 120 788 8. D.J. Daigle, A.B. Pepperman, J. Heterocycl. Chem. 12, 579 (1975) Hexamine can be used as a catalyst in the preparation of 9. D.J. Daigle, A.B. Pepperman, G. Bondreaux, J. Heterocycl. urea from ammonia and carbon dioxide (Scheme 108). The Chem. 11, 1085 (1974) reagent serves to increase both the yield of urea and the 10. H.E. Baumgarten, F.A. Bower, J. Am. Chem. Soc. 76, 4651 degree of utilization of ammonia. It gives rise to an 80 % (1954) 11. S.W. Kshirsagar, N.R. Patil, S.D. Samant, Tetrahedron Lett. 49, yield of urea [116]. 1160 (2008) 12. A.T. Bottini, V. Dev, J. Org. Chem. 27, 968 (1962) 13. H.J. Naeimi, Chin. Chem. Soc. 55, 1156 (2008) Conclusion 14. E.V. Zakharov, S.A. Balezin, E.S. Murashova, N.J. Ivanov, N.V. Lardash, Zh. Prikl. Khim. 47, 2351 (1974) 15. G. Olkoks, Geterocikliceskie Soedineija I Polimeri na jih os- Hexamine have played a major role in modern organic nove, Mir, Moskva, 22, 136 (1970) synthesis. This review article shows that hexamine can be 16. O.P. Murashova, L.I. Virin, V.R. Rozenberg, G.V. Motsarev, used in many different ways in organic synthesis and V.J. Kolbasov, Y.A. Safin, R.V. Dzhagatspanyan, Zh. Prikl. Khim. 48, 1802 (1975) summarizes the reactions involving hexamine for synthesis 17. G.L. Nemchanimova, K.E. Peredelskiy, Zh. Prikl. Khim. 47, of many important organic compounds. 1879 (1974) 18. X.H. Xu, B. Chen, L.Z. Wu, L.P. Zhang, C.H. Tung, ARKIVOC ii, 182 (2003) 19. E. Reimann, Justus Liebigs Ann. Chem. 1252, 7 (1975) 20. S. Cheronis, J. Org. Chem. 6, 349 (1945) References 21. A. Adejare, S. Sun, Curr. Top. Med. Chem. 6, 1457 (2006) 22. S.A. Chimatadar, S.V. Madawale, S.T. Nandibewoor, Ind. 1. M. Fatehi, J. Ethnopharmacol. 102, 46 (2005) J. Chem. Technol. 14, 459 (2007) 2. J.C. Duff, E.J. Bills, J. Chem. Soc. 547, 276 (1945) 23. J.C. Hoekstra, D.C. Johnson, Anal. Chem. 70, 83 (1998)

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