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DOI: 10.1055/s-0031-1289890
Hexamethylenetetramine
Publikationsverlauf
Publikationsdatum:
11. November 2011 (online)
Biographical Sketches

Introduction
Hexamethylenetetramine (HMTA) is a heterocyclic organic compound having a symmetric tetrahedral cage-like structure, whose four ‘corners’ are nitrogen atoms and ‘edges’ are methylene groups. It is also known as hexamine. It behaves like an amine base and known for its versatile role in organic chemistry. It plays an important role in formylation (Duff reaction), [¹] [²] conversion of benzyl halides into corresponding aldehydes (Sommelet reaction), [³] and synthesis of amines (Delépine reaction). [4]
HMTA is a useful reagent in the conversion of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate into ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, an important step in the synthesis of febuxostat (hypouricemic agent). [5] Apart from these applications, hexamethylenetetramine is also known for the synthesis of explosives like RDX (hexogen). [6] Further, it has wide applications in polymer chemistry. [7] HMTA is commercially available and first synthesized by Butlerov via reaction of formaldehyde with ammonia. [8]
Abstracts
(A) Miyazaki et al. reported the preparation of 3,4-dihydroisoquinolines in excellent yield (>90%) using HMTA. [9] |
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(B) The biologically active pharmacophore quinazoline was synthesized from benzocarbamate by treatment with HMTA. [¹0] |
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(C) Efficient aromatization of 1,4-dihydropyridines has been achieved using HMTA iodide. [¹¹] |
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(D) Replacement of the chloro substituent with an ammonium group in the α-chloro ketone was achieved by reaction with HMTA. [¹²] Similarly, Zhang et al. reported the ammoniation of 2-bromo-1-(3,4-dimethoxyphenyl)ethanone using HMTA. [¹³] |
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(E) HMTA has wide applications in mono- as well as diformylations of aromatic compounds. For example, the formylation of 5-nitro-7-azaindole using Duff reaction (HMTA/acetic acid) is reported. [¹4] |
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(F) Cekavicus et al. used HMTA in acidic medium for generating heterocyclic spiro systems via an internal Mannich reaction. [¹5] |
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(G) HMTA has been proven to be an excellent and inexpensive promoter of the Mannich reaction of aryl alkyl ketones, which was followed by a Nazarov cyclization, providing the 2-alkyl indanones in excellent yields. [¹6] |
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(H) 3,3′-Diindolylmethane derivatives have been prepared in one pot from indoles and HMTA. HMTA acts as a methylene group donor. [¹7] |
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- 1
Masurier N.Moreau E.Lartigue C.Gaumet V.Chezal J.-M.Heitz A.Teulade J.-C.Chavignon O. J. Org. Chem. 2008, 73: 5989Reference Ris Wihthout Link - 2
Lewin G.Shridhar NB.Aubert G.Thoret S.Dubois J.Cresteil T. Bioorg. Med. Chem. Lett. 2011, 19: 186Reference Ris Wihthout Link - 3
Li JJ.Corey EJ. Sommelet Reaction, In Name Reactions of Functional Group Transformations Wiley; New York: 2007.Reference Ris Wihthout Link - 4
Rajesh T.Azeez SA.Naresh E.Madhusudhan G.Mukkanti K. Org. Process Res. Dev. 2009, 13: 638Reference Ris Wihthout Link - 5
Liu KKC.Sakya SM.O’Donnell CJ.Flick AC.Li J. Bioorg. Med. Chem. 2011, 19: 1136Reference Ris Wihthout Link - 6
Yi WB.Cai C. J. Hazard. Mater. 2008, 150: 839Reference Ris Wihthout Link - 7
Kirillov AM. Coord. Chem. Rev. 2011, 255: 1603Reference Ris Wihthout Link - 8
Butlerov A. Ann. Chem. 1860, 115: 322Reference Ris Wihthout Link - 9
Miyazaki M.Ando N.Sugai K.Seito Y.Fukuoka H.Kanemitsu T.Nagata K.Odanaka Y.Nakamura KT.Itoh T. J. Org. Chem. 2011, 76: 534Reference Ris Wihthout Link - 10
Chilin A.Conconi MT.Marzaro G.Guiotto A.Urbani L.Tonus F.Parnigotto P. J. Med. Chem. 2010, 53: 1862Reference Ris Wihthout Link - 11
Shaikh AC.Chen C. Bioorg. Med. Chem. Lett. 2010, 20: 3664Reference Ris Wihthout Link - 12
Tsotinis A.Eleutheriades A.Bari LD.Pescitelli G.
J. Org. Chem. 2007, 72: 8928Reference Ris Wihthout Link - 13
Zhang PY.Wong ILK.Yan CSW.Zhang XY.Jiang T.Chow LMC.Wan SB. J. Med. Chem. 2010, 53: 5108Reference Ris Wihthout Link - 14
Ermoli A.Bargiotti A.Brasca MG.Ciavolella A.Colombo N.Fachin G.Isacchi A.Menichincheri M.Molinari A.Montagnoli A.Pillan A.Rainoldi S.Sirtori FR.Sola F.Thieffine S.Tibolla M.Valsasina B.Volpi D.Santocanale C.Vanotti E. J. Med. Chem. 2009, 52: 4380Reference Ris Wihthout Link - 15
Cekavicus B.Vigante B.Liepinsh E.Vilskersts R.Sobolev A.Belyakov S.Plotniece A.Mekss K.Duburs G. Tetrahedron 2008, 64: 9947Reference Ris Wihthout Link - 16
Pellissier H. Tetrahedron 2005, 61: 6479Reference Ris Wihthout Link - 17
Pal C.Dey S.Mahato SK.Vinayagam J.Pradhan PK.Giri VS.Jaisankar P.Hossain T.Baruri S.Raya D.Biswas SM. Bioorg. Med. Chem. Lett. 2007, 17: 4924Reference Ris Wihthout Link
References
- 1
Masurier N.Moreau E.Lartigue C.Gaumet V.Chezal J.-M.Heitz A.Teulade J.-C.Chavignon O. J. Org. Chem. 2008, 73: 5989Reference Ris Wihthout Link - 2
Lewin G.Shridhar NB.Aubert G.Thoret S.Dubois J.Cresteil T. Bioorg. Med. Chem. Lett. 2011, 19: 186Reference Ris Wihthout Link - 3
Li JJ.Corey EJ. Sommelet Reaction, In Name Reactions of Functional Group Transformations Wiley; New York: 2007.Reference Ris Wihthout Link - 4
Rajesh T.Azeez SA.Naresh E.Madhusudhan G.Mukkanti K. Org. Process Res. Dev. 2009, 13: 638Reference Ris Wihthout Link - 5
Liu KKC.Sakya SM.O’Donnell CJ.Flick AC.Li J. Bioorg. Med. Chem. 2011, 19: 1136Reference Ris Wihthout Link - 6
Yi WB.Cai C. J. Hazard. Mater. 2008, 150: 839Reference Ris Wihthout Link - 7
Kirillov AM. Coord. Chem. Rev. 2011, 255: 1603Reference Ris Wihthout Link - 8
Butlerov A. Ann. Chem. 1860, 115: 322Reference Ris Wihthout Link - 9
Miyazaki M.Ando N.Sugai K.Seito Y.Fukuoka H.Kanemitsu T.Nagata K.Odanaka Y.Nakamura KT.Itoh T. J. Org. Chem. 2011, 76: 534Reference Ris Wihthout Link - 10
Chilin A.Conconi MT.Marzaro G.Guiotto A.Urbani L.Tonus F.Parnigotto P. J. Med. Chem. 2010, 53: 1862Reference Ris Wihthout Link - 11
Shaikh AC.Chen C. Bioorg. Med. Chem. Lett. 2010, 20: 3664Reference Ris Wihthout Link - 12
Tsotinis A.Eleutheriades A.Bari LD.Pescitelli G.
J. Org. Chem. 2007, 72: 8928Reference Ris Wihthout Link - 13
Zhang PY.Wong ILK.Yan CSW.Zhang XY.Jiang T.Chow LMC.Wan SB. J. Med. Chem. 2010, 53: 5108Reference Ris Wihthout Link - 14
Ermoli A.Bargiotti A.Brasca MG.Ciavolella A.Colombo N.Fachin G.Isacchi A.Menichincheri M.Molinari A.Montagnoli A.Pillan A.Rainoldi S.Sirtori FR.Sola F.Thieffine S.Tibolla M.Valsasina B.Volpi D.Santocanale C.Vanotti E. J. Med. Chem. 2009, 52: 4380Reference Ris Wihthout Link - 15
Cekavicus B.Vigante B.Liepinsh E.Vilskersts R.Sobolev A.Belyakov S.Plotniece A.Mekss K.Duburs G. Tetrahedron 2008, 64: 9947Reference Ris Wihthout Link - 16
Pellissier H. Tetrahedron 2005, 61: 6479Reference Ris Wihthout Link - 17
Pal C.Dey S.Mahato SK.Vinayagam J.Pradhan PK.Giri VS.Jaisankar P.Hossain T.Baruri S.Raya D.Biswas SM. Bioorg. Med. Chem. Lett. 2007, 17: 4924Reference Ris Wihthout Link
References







