Page 3 of 3
ChemComm
DOI: 10.1039/C3CC47905F
Table 4. Results of the Cu-catalysed mechanochemical‡ coupling of 3a
with cyclohexylisocyanate to form glibenclamide (3b).
α=107.650(2)°, β=93.736(2)°, γ=96.762(2)°, V=2134.1(6) Å3, space group
P1¯ , Z=4, R1=0.0582, wR2=0.1269 (I>2σI), S=0.965; 1b:C14H14N2O2S2,
CCDC 965657, triclinic, a=7.557(4) Å, b=9.922(5) Å, c=11.266(6) Å,
50 α=106.421(6)°, β=103.828(6)°, γ=98.312(6)°, V=766.0(7) Å3, space group
P1¯ , Z=2, R1=0.0533, wR2=0.1281 (I>2σI), S= 0.973; 2a: C13H17ClN2O3S,
CCDC 965659, monoclinic, a=9.3333(8) Å, b=16.065(1) Å, c=19.644(2)
Å, β=97.580(1)°, V=2919.6(4) Å3, space group P21/c, Z=8, R1=0.0336,
wR2=0.0836 (I>2σI), S=1.026; 3a: C16H17ClN2O4S, CCDC 965658,
55 triclinic, a=9.634(2) Å, b=10.046(2) Å, c=10.667(2) Å, α=64.209(3)°,
β=69.198(2)°, γ=72.313(2)°, V=855.1(3) Å3, space group P1¯ , Z=2,
R1=0.0388, wR2=0.0922 (I>2σI), S=0.989;
Catalyst loading Time LAG or Conversion
Entry Catalyst Isocyanate
(% mol)
(h)
2
2
2
2
2
4
2
2
2
2
2
2
2
2
neata of 3a (%)b
1
2
3
CuCl
CuCl
CuCl
1.0 eq
1.0 eq
1.0 eq
5
5
Neat
DMF
54
60
43
38
83
87
50
30
48
100
100
68
66
-
20
20
20
20
20
20
20
20
5
Neat
Neat
4
Cu powder 1.0 eq
5
6
7
CuCl
CuCl
Cu2O
1.0 eq
1.0 eq
1.0 eq
CH3NO2
CH3NO2
Neat
1
S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friščić, F.
Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack, L.
Maini, A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steed and
D. C. Waddell, Chem. Soc. Rev, 2012, 41, 413.
8
CuCl2.2H2O 1.0 eq
Neat
Neat
60
9
CuCl2
CuCl
CuCl
CuCl
CuCl
-
1.0 eq
1.2 eq
1.2 eq
1.1 eq
1.0 eq
1.0 eq
10
11
12
13
14
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
2
V. André, A. Hardeman, I. Halasz., R. S. Stein., G. J. Jackson, D. G.
Reid1, M. J. Duer, C. Curfs, M. T. Duarte and T. Friščić, Angew.
Chem. Int. Ed., 2011, 50, 7858.
5
5
-
65 3 T. Friščić, D. G. Reid, I. Halasz, R. S. Stein, R. E. Dinnebier and M.
J. Duer Angew. Chem. Int. Ed. 2010, 49, 712.
aLAG with = 0.25 mL mg-1; bdetermined using 1H NMR.
4
P. Baláž, M. Achimovičová, M. Baláž, P. Billik, Z. Cherkezova-
Zheleva, J. M. Criado, F. Delogu, E. Dutková, E. Gaffet, F. José
Gotor, R. Kumar, I. Mitov, T. Rojac, M. Senna, A. Streletskii and
K. Wieczorek-Ciurowa, Chem. Soc. Rev., 2013, 42, 7571.
(a) A. Stolle, T. Szuppa, S. E. S. Leonhardt and B. Ondruschka
Chem. Soc. Rev. 2011, 40, 2317; (b) G.-W. Wang, Chem. Soc. Rev.,
2013, 42, 7668.
In summary, we demonstrated two15 mechanochemical, room
temperature procedures for the synthesis of sulfonyl-(thio)ureas,
an important family of pharmaceutically relevant molecules. First
generation anti-diabetic drugs tolbutamide and chlorpropamide
were isolated in >90% yield via a catalytic mechanochemical
5
70
5
6
J. G. Hernández and E. Juaristi, Chem. Commun., 2012, 48, 5396.
procedure which was also incorporated into
a two-step
75 7 (a) T. L. Cook, J. A. Walker and J. Mack, Green Chem. 2013, 15,
617; (b) R. Thorwirth, A. Stolle and B. Ondruschka Green Chem.
2010, 12, 985; (c) D. A. Fulmer. W. C. Shearouse, S. T. Medonza
and J. Mack, Green Chem., 2009, 11, 1821.
10 mechanochemical protocol for making the more complex second
generation drug glibenclamide in ~70% overall yield. Both Cu-
catalysed and base-assisted protocols were readily scaled to 1
gram. By demonstrating the mechanosynthesis of molecules used
in treating a wide-spread disease, such as diabetes12 (estimated22
15 to be affecting ~5% of world population), the presented work
aims to encourage further development of mechanochemical
methods for cleaner, more efficient synthesis of medicinal targets.
We are currently exploring the metal-catalysed coupling of
sulphonamides and isocyanates.
We acknowledge the support of McGill University, Canada
Foundation for Innovation (CFI), NSERC Discovery Grant and
NSERC CREATE in Green Chemistry (D.T.). Prof. D. S. Bohle
and Mr A. Katsenis are acknowledged for aid in obtaining single
crystal structures and Dr A. Wahba for help in obtaining MS data.
8
(a) J. G. Hernández and E. Juaristi, J. Org. Chem., 2010, 75, 7107;
(b) F. Lamaty, J. Martinez, P. Nun and V. Declerck, Angew. Chem.
Int. Ed. 2009, 48, 9318.
80
9
(a) A. M. Flock, C. M. M. Reucher and C. Bolm, Chem. Eur. J.,
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Chem. Int. Ed., 2006, 41, 7078.
85 10 J. Bonnamour, T.-X. Métro, J. Martinez and F. Lamaty, Green
Chem., 2013, 15, 1116.
11 (a) V. Štrukil, D. Margetić, M. D. Igrc, M. Eckert-Maksić and T.
Friščić, Chem. Commun., 2012, 48, 9705; (b) V. Štrukil, M. D. Igrc,
M. Eckert-Maksić and T. Friščić, Chem. Eur. J., 2012, 18, 8464.
90 12 (a) S. Amoroso, H. Schmid-Antomarchi, M. Fosset and M.
Lazdunski, Science, 1990, 247, 852; (b) H. Schmid-Antomarchi, J. D.
Weille, M. Fosset and M. Lazdunski, J. Bio. Chem., 1987, 33, 15840.
13 (a) C. Jiménez-González, D. J. C. Constable and C. S. Ponder, Chem.
Soc. Rev., 2012, 41, 1485; (b) W. C. Shearouse, D. C. Waddell and J.
20
95
Mack, Curr. Opin. Drug Discov. Develop. 2009, 12, 772; (c) H-J.
Federsel, Green Chem. 2013, DOI: 10.1039/c3gc41629a
14 H. Ulrich, Chem. Rev., 1965, 3, 369.
15 Route B is a viable alternative for the mechanosynthesis of sulfonyl-
ureas, which we avoided due to corrosive nature of the reagent: neat
milling of p-toluenesulfonyl-isocyanate and n-butylamine readily
gave 1a (93% yield) without additional base or catalyst (see ESI).
16 P. Anastas and N. Eghbali, Chem. Soc. Rev., 2010, 39, 301.
17 A. Martínez-Asencio, D. J. Ramón and M. Yus, Tetrahedron Lett.,
2010, 51, 325.
25 Notes and references
a Department of Chemistry and FRQNT Centre for Green Chemistry and
Catalysis, McGill University, Montreal, Canada. Fax: +1 514 398 3757;
Tel: +1 514 398 3959; E-mail:tomislav.friscic@mcgill.ca
b On leave from the Division of Organic Chemistry and Biochemistry,
30 Ruđer Bošković Institute, Bijenička cesta 54, HR-10002 Zagreb, Croatia
† Electronic Supplementary Information (ESI): experimental procedures,
100
1
FTIR-ATR, H and 13C NMR, HR-MS and crystallographic data in CIF
format. See DOI: 10.1039/b000000x/
‡ In a typical procedure the reaction was milled in a 10 mL stainless steel
35 jar with one 10 mm diameter ball made of stainless steel or brass, using a
Retsch MM400 mill operating at 30Hz. Aqueous workup and filtration
were sufficient for the purification of all compounds except 1d and 3b
where moisture-induced isocyanate dimerisation yielded small amounts of
a urea sideproduct whose separation requires chromatography.
40 ¶ Synthesis of pharmaceutially relevant sulfonyl-ureas in solution requires
stoichiometric base and excess isocyanate for sulfonamide-isocyanate
coupling, see: H. Ruschig, W. Aumüller, G. Korger, H. Wagner, J.
Scholz, A. Bander, "New benzene sulfonyl ureas; composition and
process for lowering blood sugar therewith" US2968158 A (1961).
45 Crystal data. 1c (K+ salt, acetone solvate): C14H12KN3O4S2·1.25(CH3)2CO,
CCDC 965656, triclinic, a=7.366(1) Å, b=16.466(3) Å, c=18.699(3) Å,
105 18 J. Cervello and T. Sastre Synthesis, 1990, 221.
19 The amount of liquid is expressed as , the ratio of the liquid volume
(in μL) to the weight of reaction mixture (in mg): T. Friščić, S. L.
Childs, S. A. A. Rizvi and W. Jones, CrystEngComm, 2009, 11, 418.
20 T. Friščić, A. V. Trask, W. Jones and W. D. S. Motherwell, Angew.
110
115
Chem. Int. Ed., 2006, 45, 7708.
21 V. Štrukil, B. Bartolec, T. Portada, I. Ðilović, I. Halasz and D.
Margetić, Chem. Commun., 2012, 48, 12100.
22 G. Danaei, M. M. Finucane, Y. Lu, G. M. Singh, M. J. Cowen, C. J.
Paciorek, J. K. Lin, F. Farzadfar, Y.-H. Khang, G. A. Stevens, M.
Rao, M. K. Ali, L. M. Riley, C. A. Robinson and M. Ezzati, Lancet,
2011, 378, 31.
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