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Synthesis 2007(22): 3497-3506  
DOI: 10.1055/s-2007-990813
PAPER
© Georg Thieme Verlag Stuttgart · New York

Preparation of Mono-, Di-, and Trisubstituted Ureas by Carbonylation of Aliphatic Amines with S,S-Dimethyl Dithiocarbonate

Emma Artuso, Iacopo Degani, Rita Fochi*, Claudio Magistris
Dipartimento di Chimica Generale ed Organica Applicata dell’Università, Università degli Studi di Torino, C. so M. D’Azeglio 48, 10125 Torino, Italy
e-Mail: rita.fochi@unito.it;
Further Information

Publication History

Received 19 July 2007
Publication Date:
25 September 2007 (online)

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Abstract

General procedures are reported to prepare N-alkylureas, N,N′-dialkylureas (both symmetrical and unsymmetrical), and N,N,N′-trialkylureas by carbonylation of aliphatic amines, employing S,S-dimethyl dithiocarbonate (DMDTC) as a phosgene substitute. All reactions were carried out in water. Symmetrical disubstituted ureas were prepared directly working at 60 °C with a molar ratio of DMDTC:amine = 1:2, preferably under nitrogen. Unsymmetrical ureas were prepared in two steps via S-methyl N-alkyl­thiocarbamate intermediates, which are formed selectively in the first step at room temperature. These intermediates react in the second step with ammonia or various aliphatic amines, both primary and secondary, at temperatures varying between 50 and 70 °C. All the target ureas were obtained in high yields (28 examples, average yield 94%) and with very high purity (generally >99.2%). Also to be noted is the recovery of a co-product of industrial interest, methanethiol, in an amount of two moles for each mole of DMDTC, with complete exploitation of the reagent.

Key words

ureas - carbonylation - amines - dithiocarbonates - thiocarbamates

    References

  • For reviews on ureas, see:
  • 2a Sartori G. Maggi R. In Science of Synthesis   Vol. 18:  Knight JG. Thieme Verlag; Stuttgart: 2005.  p.665-758  
    CrossrefSearch in Google Scholar
  • 2b Bigi F. Maggi R. Sartori G. Green Chem.  2000,  2:  140 
    CrossrefSearch in Google Scholar
  • 2c Tafesh AM. Weiguny J. Chem. Rev.  1996,  96:  2035 
    CrossrefSearch in Google Scholar
  • 2d Petersen H. In Ullmann’s Encyclopedia of Industrial Chemistry   5th ed., Vol. A27:  Elvers B. Hawkins S. VCH; Weinheim: 1996.  p.355-365  
    CrossrefSearch in Google Scholar
  • 2e Vishnyakova TP. Golubeva IA. Glebova EV. Russ. Chem. Rev.  1985,  54:  249 
    CrossrefSearch in Google Scholar
  • 2f Petersen U. In Houben-Weyl   4th ed., Vol. E4:  Hagemann H. Thieme Verlag; Stuttgart: 1983.  p.334-367  ; and references cited therein
    CrossrefSearch in Google Scholar
  • 2g Melnikov NN. In Chemistry of Pesticides   Gunther FA. Gunther JD. Springer-Verlag; Berlin: 1971.  p.225-239  
    Crossref
  • 3 For a plentiful recent literature (until 2003) on the synthesis and applications of substituted ureas see: Gabriele B. Salerno G. Mancuso R. Costa M. J. Org. Chem.  2004,  69:  4741 ; and references cited therein
    CrossrefSearch in Google Scholar
  • Some recent references (after 2003) on new applications of substituted ureas:
  • 4a Martinez Gil A, Medina Padilla M, Castro Morera A, Alonso Cascon M, Martin Aparicio E, Fuertes Huerta A, Navarro Rico ML, and Perez Puerto MJ. inventors; Neuropharma S. A., Spain, EP  1749523.  ; Chem. Abstr. 2007, 146, 206112
  • 4b Bhalay G, Dunstan A, Glen A, Howe TJ, and McCarthy C. inventors; Novartis AG Switzerland, Novartis Pharma GmbH,  WO 015852.  2006; Chem. Abstr. 2006, 144, 232805
  • 4c Dasseux J.-LH, and Oniciu DC. inventors; Esperion Therapeutics Inc. USA,  WO 068420.  ; Chem. Abstr. 2005, 143, 172557
  • 4d Carruthers NI, Shah CR, and Swanson DM. inventors; Janssen Pharmaceutica, N. V., Belgium,  WO 014580.  ; Chem. Abstr. 2005, 142, 240468
  • 4e Defossa E, Kadereit D, Klabunde T, Burger H.-J, Herling A, Wendt K.-U, Von Roedern E, Schoenafinger K, and Enhsen A. inventors; Aventis Pharma Deutschland GmbH, Germany,  WO 065356.  ; Chem. Abstr. 2004, 141, 173980
  • Some recent references (after 2003) on the use of monoalkyl-, dialkyl-, and trialkylureas in organic synthesis:
  • 5a Fritz JA. Nakhla JS. Wolfe JP. Org. Lett.  2006,  8:  2531 
    CrossrefSearch in Google Scholar
  • 5b Sigachev AS. Kravchenko AN. Gazieva GA. Belyakov PA. Kolotyrkina NG. Lebedev OV. Makhova NN. Lyssenko KA. J. Heterocycl. Chem.  2006,  43:  1295 
    CrossrefSearch in Google Scholar
  • 5c Gel’mbol’dt VO. Koroeva LV. Filinchuk Ya E. Russ. J. Coord. Chem.  2005,  31:  775 
    CrossrefSearch in Google Scholar
  • 5d Natarajan A. Guo Y. Arthanari H. Wagner G. Halperin JA. Chorev M. J. Org. Chem.  2005,  70:  6362 
    CrossrefSearch in Google Scholar
  • 5e Hansen AL. Skrydstrup T. J. Org. Chem.  2005,  70:  5997 
    CrossrefSearch in Google Scholar
  • 5f Kravchenko AN. Sigachev AS. Maksareva EY. Gazieva GA. Trunova NS. Lozhkin BV. Pivina TS. Il’in MM. Lyssenko KA. Nelyubina YV. Davankov VA. Lebedev OV. Makhova NN. Tartakovsky VA. Russ. Chem. Bull.  2005,  54:  691 
    CrossrefSearch in Google Scholar
  • 5g Zhou X, Chen Y, and Liu B. inventors; Faming Zhuanli Shenqing Gongkai Shuomingshu,  CN 1515540 A.  ; Chem. Abstr. 2005, 143, 77851
    Crossref
  • Some recent references (after 2003) on the synthesis of monoalkyl-, dialkyl-, and trialkylureas:
  • 6a Peng X. Li F. Xia C. Synlett  2006,  1161 ; and references cited therein
    Crossref
  • 6b Mizuno T. Mihara M. Iwai T. Ito T. Ishino Y. Synthesis  2006,  2825 ; and references cited therein
    Crossref
  • 6c Zhu B. Angelici RJ. J. Am. Chem. Soc.  2006,  128:  14460 
    CrossrefSearch in Google Scholar
  • 6d Orito K. Miyazawa M. Nakamura T. Horibata A. Ushito H. Nagasaki H. Yuguchi M. Yamashita S. Yamazaki T. Tokuda M. J. Org. Chem.  2006,  71:  5951 ; and references cited therein
    CrossrefSearch in Google Scholar
  • 6e Fan X, Rui B, Yan L, and Li C. inventors; Faming Zhuanli Shenqing Gongkai Shuomingshu,  CN 1827594 A.  ; Chem. Abstr. 2006, 145, 397096
    Crossref
  • 6f Wang C, Li Y, Du M, Xu S, Zheng C, Wang C, Yang X, Shi L, and Wang W. inventors; Faming Zhuanli Shenqing Gongkai Shuomingshu,  CN 1740140 A.  ; Chem. Abstr. 2006, 145, 10086
    Crossref
  • 6g Li Z. Wang Z.-Y. Zhu W. Xing Y.-L. Zhao Y.-L. Synth. Commun.  2005,  35:  2325 
    CrossrefSearch in Google Scholar
  • 6h Nishiyama Y. Kawamatsu H. Sonoda N. J. Org. Chem.  2005,  70:  2551 
    CrossrefSearch in Google Scholar
  • 6i Perveen S. Abdul Hai SM. Khan RA. Khan KM. Afza N. Sarfaraz TB. Synth. Commun.  2005,  35:  1663 
    CrossrefSearch in Google Scholar
  • 6j Enquist P.-A. Nilsson P. Edin J. Larhed M. Tetrahedron Lett.  2005,  46:  3335 
    CrossrefSearch in Google Scholar
  • 6k Fujita S. Bhanage BM. Kanamaru H. Arai M. J. Mol. Catal. A: Chem.  2005,  230:  43 ; and references cited therein
    CrossrefSearch in Google Scholar
  • 6l Pourali AR. Monatsh. Chem.  2005,  136:  733 
    CrossrefSearch in Google Scholar
  • 6m Grzyb JA. Shen M. Yoshina-Ishii C. Chi W. Brown RS. Batey RA. Tetrahedron  2005,  61:  7153 
    CrossrefSearch in Google Scholar
  • 6n Yang C. inventors; Faming Zhuanli Shenqing Gongkai Shuomingshu,  CN 1660795 A.  ; Chem. Abstr. 2006, 144, 469979
    Crossref
  • 6o Hiwatari K. Kayaki Y. Okita K. Ukai T. Shimizu I. Yamamoto A. Bull. Chem. Soc. Jpn.  2004,  77:  2237 
    CrossrefSearch in Google Scholar
  • 6p Zhang Q. Shi F. Deng Y. Cuihua Xuebao  2004,  25:  607 ; Chem. Abstr. 2005, 142, 373529
    CrossrefSearch in Google Scholar
  • 6q Fujita S. Bhanage BM. Arai M. Chem. Lett.  2004,  742 ; Chem. Abstr. 2004, 141, 156829
    Crossref
  • 6r Qian WX. Ju FY. Zhang YM. Bao WL. Chin. Chem. Lett.  2004,  15:  1269 ; Chem. Abstr. 2005, 142, 155314
    CrossrefSearch in Google Scholar
  • 6s Porwanski S. Menuel S. Marsura X. Marsura A. Tetrahedron Lett.  2004,  45:  5027 
    CrossrefSearch in Google Scholar
  • 7 Degani I. Fochi R. Regondi V. Synthesis  1981,  149 
    Thieme Connect
  • 9a Degani I, Fochi R, and Regondi V. inventors; CNR, Italy, Eur. Pat. Appl.  63327.  ; Chem. Abstr. 1983, 98: 160238
    Thieme Connect
  • 9b Degani I. Fochi R. Regondi V. Synthesis  1983,  630 
    Thieme Connect
  • 9c Degani I. Fochi R. Regondi V. Synthesis  1986,  1070 
    Thieme Connect
  • 9d Degani I, Fochi R, and Regondi V. inventors; CNR, Italy,  IT 1173436. 
    Thieme Connect
  • 10 Cadamuro S. Degani I. Fochi R. Regondi V. Chem. Ind. (London)  1986,  671 
  • 11a Barbero M, Degani I, Fochi R, and Regondi V. inventors; CNR, Italy, Eur. Pat. Appl.  234249.  ; Chem. Abstr. 1988, 108, 23697
  • 11b Barbero M. Cadamuro S. Degani I. Fochi R. Regondi V. Synthesis  1989,  857 
  • 12 Leung M.-kit. Lai J.-L. Lau K.-H. Yu H.-hua. Hsiao H.-J. J. Org. Chem.  1996,  61:  4175 
    CrossrefSearch in Google Scholar
  • 13 Carvoli G, Degani I, Pallucca E, Fochi R, Serri AM, Cadamuro S, Gazzetto S, and Migliaccio M. inventors; Oxon Italia S.p.A., Italy,  MI 2004A 002402. IT patent pending: patent request No.(16.12.2004)
  • 14 Artuso E. Carvoli G. Degani I. Fochi R. Magistris C. Synthesis  2007,  1096 
    Thieme Connect
  • For example, for toxicity of phosgene, see:
  • 15a Sax NI. In Dangerous Properties of Industrial Materials   Van Nostrand Reinhold Company; New York: 1984.  p.2210-2211  
  • 15b Senet J.-P. In The Recent Advance in Phosgene Chemistry   Vol. 1:  GPA; Nanterre: 1997.  p.10-11  
    Search in Google Scholar
  • 15c Cotarca L. Eckert H. In Phosgenations - A Handbook   Wiley-VCH; Weinheim: 2003.  p.9 
  • 16 Carvoli G, Degani I, Pallucca E, Fochi R, Gazzetto S, Artuso E, Lazzaroni M, and Cadamuro S. inventors; Oxon Italia S.p.A., Italy,  MI 2005A 001284. Details are reported in an IT patent pending: patent request No.(07.07.2005)
  • 17 Dictionary of Organic Compounds on CD-ROM   Chapman & Hall, Electronic Publishing Division; London: 2007.  Version 15.1 [CD ROM]
  • 18a Atanassova IA. Petrov JS. Mollov NM. Synth. Commun.  1989,  19:  147 
    Search in Google Scholar
  • 18b Hayashi T. Kuyama M. Nat. Sci. Rep. Ochanomizu Univ. (Tokyo)  1951,  2:  79 ; Chem. Abstr. 1954, 48, 1274b
    Search in Google Scholar
  • 19 Bakibaev AA. Russ. J. Org. Chem.  1994,  30:  1772 
    Search in Google Scholar
  • 20 Troyanskii EA. Ioffe VA. Mizintsev VV. Nikishin GI. Bull. Acad. Sci. USSR  1984,  33:  1661 
    CrossrefSearch in Google Scholar
  • 21 Lutsenko VV. Blyum RA. Knunyants IL. J. Chem. Org. USSR  1971,  7:  1182 
    Search in Google Scholar
  • 22 Martinelli LC. DeWitt Blauton C. Whidby JF. J. Am. Chem. Soc.  1971,  93:  5111 
    CrossrefSearch in Google Scholar
  • 23 Kim HO. Ji X. Melman N. Olah ME. Stiles GL. Jacobson KA. J. Med. Chem.  1994,  37:  3373 
    CrossrefSearch in Google Scholar
  • 24 Wiloth F. Schindler E. Chem. Ber.  1970,  103:  757 
    CrossrefSearch in Google Scholar
  • 25 Nowick JS. Abdi M. Bellamo KA. Love JA. Martinez EJ. Noronha G. Smith EM. Ziller JW. J. Am. Chem. Soc.  1995,  117:  89 
    CrossrefSearch in Google Scholar
  • 27 McCusker JE. Main AD. Johnson KS. Grasso CA. McElwee-White L. J. Org. Chem.  2000,  65:  5216 
    CrossrefPubMedSearch in Google Scholar
  • 28a Kochansky JP. Feldmesser J. J. Nematol.  1989,  21:  158 
    CrossrefSearch in Google Scholar
  • 28b Kochansky JP. Feldmesser J. J. Econ. Entomol.  1985,  78:  599 
    CrossrefSearch in Google Scholar
  • 29 Rouzer CA. Sabourin M. Skinner TL. Thompson EJ. Wood TO. Chmurny GN. Klose JR. Roman JM. Smith RH. Michejda CJ. Chem. Res. Toxicol.  1996,  9:  172 
    CrossrefSearch in Google Scholar
  • 30 Pallucca E, Degani I, Serri AM, Fochi R, Gazzetto S, Fenoglio C, Ornati C, Migliaccio M, Cadamuro S, and Carvoli G. inventors; Oxon Italia S.p.A., Italy,  EP 1334965.  ; Chem. Abstr. 2003, 139, 164529
1

Professor Emeritus, University of Turin, Italy.

8

Oxon Italia S.p.A. (Italy).

26

Spectral Data Base for Organic Compounds SDBS (National Institute of Advanced Industrial Science and Technology). SDBS Web: http://www.aist.go.jp/RIODB/SDBS.