I
L. Bannwart et al.
Paper
Synthesis
h (conversion >95% a/a, LC/MS). The reaction mixture was quenched
at 10 °C with aq. half-saturated Na2CO3 (50 mL, caution: foaming ob-
served). The product precipitated during the quench and was recov-
ered by filtration, washing with H2O, to give pure amide 26.
Supporting Information
Supporting information for this article is available online at
S
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Yield: 3.98 g (77%); off-white solid; mp 116–117 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.36 (d, J = 2.8 Hz, 1 H), 8.26 (dd, J =
2.8, 9.2 Hz, 1 H), 7.48–7.57 (m, 4 H), 7.41 (d, J = 7.6 Hz, 1 H), 5.44 (s,
2 H), 2.99 (s, 3 H), 2.90 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 170.18, 159.26, 141.37, 137.20,
136.24, 129.14, 129.03, 127.37, 126.67, 125.95, 125.09, 122.53,
114.38, 71.06, 39.51, 35.26.
References
(1) For a review on amide bond formation, see: Valeur, E.; Bradley,
M. Chem. Soc. Rev. 2009, 38, 606.
(2) Ding, S.; Jiao, N. Angew. Chem. Int. Ed. 2012, 51, 9226.
(3) (a) SOCl2: Kumagai, T.; Anki, T.; Ebi, T.; Konishi, A.; Matsumoto,
K.; Kurata, H.; Kubo, T.; Katsumoto, K.; Kitamura, C.; Kawase, T.
Tetrahedron 2010, 66, 8968. (b) P2O5: Schindlbauer, H. Monatsh.
Chem. 1968, 99, 1799. (c) P2O5: Ciszek, J. W.; Keane, Z. K.; Cheng,
L.; Stewart, M. P.; Yu, L. H.; Natelson, D.; Tour, J. M. J. Am. Chem.
Soc. 2006, 128, 3179. (d) 1,1-Carbonyldimidazole with N,N-
dimethylacetamide: Aavula, S. K.; Chikkulapally, A.;
Hanumanthappa, N.; Jyothi, I.; Kumar, C. H. V.; Manjunatha, S.
G.; Sythana, S. K. J. Chem. Res. 2013, 155.
(4) (a) Santhosh Kumar, P.; Sathish Kumar, G.; Arun Kumar, R.;
Veera Reddy, N.; Rajender Reddy, K. Eur. J. Org. Chem. 2013,
1218. (b) Priyadarshini, S.; Amal Joseph, P. J.; Lakshmi Kantam,
M. RSC Adv. 2013, 3, 18283. (c) Xie, Y.-X.; Song, R.-J.; Yang, X.-H.;
Xiang, J.-N.; Li, J.-H. Eur. J. Org. Chem. 2013, 5737. (d) Liu, H. Q.;
Liu, J.; Zhang, Y.-H.; Shao, C.-D.; Yu, J.-X. Chin. Chem. Lett. 2015,
26, 11. (e) From cinnamic acids: Yan, H.; Yang, H.; Lu, L.; Liu, D.;
Rong, G.; Mao, J. Tetrahedron 2013, 69, 7258. (f) From cinnamic
acids: Li, H.; Pan, C.; Cheng, Y.; Zhu, C. Tetrahedron Lett. 2013,
54, 6679. (g) From α-oxocarboxylic acids: Wang, H.; Guo, L.-N.;
Duan, X.-H. Org. Biomol. Chem. 2013, 11, 4573. (h) From α-oxo-
carboxylic acids: Li, D.; Wang, M.; Liu, J.; Zhao, Q.; Wang, L.
Chem. Commun. 2013, 49, 3640. (i) From aldehydes: Liu, Z.;
Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew. Chem. Int. Ed.
2012, 51, 3231. (j) From alcohols: Xu, K.; Hu, Y.; Zhang, S.; Zha,
Z.; Wang, Z. Chem. Eur. J. 2012, 18, 9793.
(5) (a) Dunetz, J. R.; Xiang, Y.; Baldwin, A.; Ringling, J. Org. Lett.
2011, 13, 5048. (b) Millbanks, C. In e-EROS Encyclopedia of
Reagents for Organic Synthesis [Online]; Wiley & Sons: New York,
2001. (c) Koch, P.; Vedder, C.; Schaffer, T. Chim. Oggi 2008, 26, 6.
For additional applications of T3P® see: (d) Review: Augustine, J.
K.; Vairaperumal, V.; Narasimhan, S.; Alagarsamy, P.;
Radharkrishnan, A. Tetrahedron 2009, 65, 9989. (e) Review:
Vishwanatha, B. T. M.; Panguluri, N. R.; Sureshbabu, V. V. Syn-
thesis 2013, 45, 1569. (f) Augustine, J. K.; Bombrun, A.; Mandal,
A. B.; Alagarsamy, P.; Atta, R. N.; Selvam, P. Synthesis 2011, 1477.
(6) T3P® is also used as dehydrating agent to form nitriles. For rep-
resentative examples, see: (a) Herold, P.; Mah, R.; Tschinke, V.;
Stajanovic, A.; Behnke, D.; Marti, C.; Stutz, S.; Jelakovic, S.
EP1958634A2, 2008. (b) Meudt, A.; Scherer, S.; Nerdinger, S.
WO2005/070879A1, 2005. (c) Augustine, J. K.; Atta, R. N.;
Ramappa, B. K.; Boodappa, C. Synlett 2009, 3378. (d) The exact
role of Et4NCl is unclear; however, it can be postulated that it
acts as a weak acid that could enhance DMF cleavage, therefore
promoting the reaction.
MS: m/z = 335.04 [M + 1]+.
Synthesis of Triazinate 2715
A mixture of amide 26 (3.9 g, 11.7 mmol, 1 equiv) and Raney/Ni (ca.
2.5 g) in EtOH (60 mL) was stirred at 30 °C under 10 bar of hydrogen
until full conversion was observed (ca. 20 h). The suspension was fil-
tered over Celite, washing with EtOH (ca. 30 mL) and the filtrate was
concentrated under reduced pressure to dryness to provide the corre-
sponding aniline.
Yield: 3.45 g (97%, >95% a/a); brown oil.
1H NMR (500 MHz, CDCl3): δ = 7.51 (s, 2 H), 7.38–7.44 (m, 2 H), 6.73–
6.85 (m, 2 H), 6.51 (dd, J = 2.5, 8.6 Hz, 1 H), 5.07 (s, 2 H), 3.13 (s, 3 H),
2.98 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 171.40, 146.89, 141.53, 137.41,
136.53, 128.64, 128.45, 126.66, 125.98, 124.50, 117.18, 117.08,
114.28, 71.86, 39.64, 35.42.
MS: m/z = 305.17 [M + 1]+.
The amine was of sufficient purity to be used in the next step without
any further purification.
To a solution of amine intermediate (3.38 g, 11.1 mmol, 1 equiv) in
acetone (35 mL) was added ethylsulfonic acid (0.96 mL, 11.6 mmol,
1.05 equiv) and cyanoguanidine in one portion (1.03 g, 12.2 mmol,
1.1 equiv). The resulting mixture was heated to reflux and the forma-
tion of a precipitate was observed over the time. After reaching full
conversion (6 h) the suspension was cooled to 0 °C, filtered, and the
was solid washed with acetone (ca. 20 mL) to give triazinate 27.
Yield: 4.61 g (77%); off-white solid; mp 212–213.5 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.86 (s, 1 H), 7.49–7.57 (m, 4 H),
7.37–7.41 (m, 3 H), 5.31 (m, 2 H), 3.00 (s, 3 H), 2.91 (s, 3 H), 2.47 (q, J =
7.4 Hz, 2 H), 1.34 (s, 3 H), 1.33 (s, 3 H), 1.10 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 170.27, 157.89, 157.86, 154.90,
137.14, 136.94, 132.06, 130.74, 129.08, 128.93, 128.42, 127.17,
126.51, 122.71, 115.25, 70.43, 70.29, 45.69, 35.26, 27.68, 27.58, 10.33.
MS: m/z = 429.12 [M + 1]+.
Acknowledgment
Dr. Hasim Ibrahim is thanked for discussions and encouragement. Dr.
Peter Pojarliev from Euticals is thanked for generous gifts of T3P®
samples. We would also like to thank François Le Goff and Jürgen Sei-
fert for HRMS and IR analyses.
(7) Pure TfOH, TsOH, and TFA were employed; for HBr and H2SO4,
aqueous concentrated solutions were used.
(8) An efficient method for the synthesis of sterically hindered sec-
ondary amides has been reported, see: Schäfer, G.; Matthey, C.;
Bode, J. W. Angew. Chem. Int. Ed. 2012, 51, 9173.
(9) N,N-Diethyl-2-phenylacetamide (DEPA): (a) Martensson, O.;
Nilsson, E. Acta Chem. Scand. 1960, 14, 1129. (b) Hougard, J.-M.;
Pennetier, C. US2007/122437 A1, 2007. (c) Von Deyn, W.;
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J