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 Á Organic synthesis Á 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 ( ) Á 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].