Organic Letters
Letter
Table 2. E Factors and Recycling Study
REFERENCES
■
(
1
1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
0257.
(2) Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9, 2265.
(3) “Best-selling” is defined herein as emerging onto a list of top 200
from 1999−2011 either based on U.S. sales or the number of outpatien4t
prescriptions given by surveys conducted by the Njardarson group
E Factors
based on
reaction
first recycle
second recycle
total organic solvent
4.1
7.7
4.6
4.6
4.8
4.8
(b) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ.
(
(
aqueous waste included
a
Conditions: amine (1 equiv), K PO (1 equiv), 2 wt % TPGS-750-
3
4
b
M/H O. Conditions: amine (1.5 equiv), K PO (1 equiv), 2 wt %
2
3
4
6) Abacavir, levofloxacin, moxifloxacin, and timolol are on the World
TPGS-750-M/H O.
2
Health Organization’s List of Essential Medicines. WHO Model List of
Additional base and different coupling partners were then added
to the vial for use in the first recycle of the original water/
surfactant mixture. This approach results in E Factors, based on
organic solvent used, in the range of only 4−5 for each step. With
water included in the calculation, an E Factor of only 7.7 was
initially obtained. These values, however, drop to that based on
organic solvent used per extraction, as no additional water needs
be invested in subsequent cycles.
In summary, micellar catalysis has been shown to enable
nucleophilic aromatic substitution reactions to be performed in
water under mild conditions. These micelles in water serve as
nanoreactors that can be viewed as a “green” replacement for
dipolar, aprotic solvents such as DMF, which is one of several
commonly used for such bond constructions. Oxygen-, nitrogen-,
(
7) Terrier, F. Modern Nucleophilic Aromatic Substitution; Wiley-VCH:
Weinheim, 2013.
(8) Ashcroft, C. P.; Dunn, P. J.; Hayler, J. D.; Wells, A. S. Org. Process
Res. Dev. 2015, 19, 740.
(
Pharmaceutical Process Development; Blacker, J. A., Williams, M. T., Eds.;
Royal Society of Chemistry: London, 2011; Chapter 6. (c) Jimenez-
Gonzales, C.; Constable, D. J. Green Chemistry and Engineering: A
Practical Approach; Wiley: New York, 2011.
9) (a) Laird, T. Org. Process Res. Dev. 2012, 16, 1. (b) Dunn, P. J.
(
10) (a) Bryan, M. C.; Dillon, B.; Hamann, L. W.; Hughes, G. J.;
Kpoach, M. E.; Peterson, E. A.; Pourashraf, M.; Raheem, I.; Richardson,
P.; Richter, D.; Sneddon, H. F. J. Med. Chem. 2013, 56, 6007.
(b) Kemeling, G. M. ChemSusChem 2012, 5, 2291. (c) Watson, W. J. W.
Green Chem. 2012, 14, 251.
and sulfur-based nucleophiles all participate in these S Ar
N
reactions. Opportunities also exist for tandem processes that take
place in a single pot. Lastly, given the complete absence of
organic solvent in the reaction medium, along with in-flask
extraction and recycling, the green nature of this chemistry is
evidenced by the associated low E Factors. Further reports from
these laboratories that illustrate the potential of designer
surfactants in water to “get organic solvents out of organic
reactions” will be forthcoming.
(11) (a) Dunn, P.; Henderson, R.; Mergelsberg, I.; Wells, A.
Collaboration to Deliver a Solvent Selection Guide for the Pharmaceutical
Industry Moving towards Greener Solvents for Pharmaceutical Manufactur-
ing - An Industry Perspective; ACS GCI Pharmaceutical Roundtable,
Hanefeld, U. Green Chemistry and Catalysis; Wiley-VCH: Weinheim,
2
(
007.
12) Lipshutz, B. H.; Ghorai, S. Green Chem. 2014, 16, 3660. See
references therein for additional information on micellar catalysis.
13) (a) Lipshutz, B. H.; Isley, N. A.; Fennewald, J. C.; Slack, E. D.
ASSOCIATED CONTENT
Supporting Information
■
(
*
S
Angew. Chem., Int. Ed. 2013, 52, 10952 , and references cited therein. (b)
Our E factor calculations take organic solvent only into consideration as
waste. (c) For a recent overview of various metrics, see: Roschangar, F.;
Sheldon, R. A.; Senanayake, C. H. Green Chem. 2015, 17, 752.
Experimental procedures, additional comparison of rates
(14) Degoey, D. A.; Kati, W. M.; Hutchins, C. W.; Donner, P. L.;
(
DMF vs TPGS-750-M), references for reported S Ar
N
Krueger, A. C.; Randolph, J. T.; Motter, C. E.; Nelson, L. T.; Patel, S. V.;
Matulenko, M. A.; Keddy, R. G.; Jinkerson, T. K.; Soltwedel, T. N.; Liu,
D.; Pratt, J. K.; Rockway, T. W.; Maring, C. J.; Hutchinson, D. K.;
Flentge, C. A.; Wagner, R.; Tufano, M. D.; Betebenner, D. A.; Lavin, M.
J.; Sarris, K.; Woller, K. R.; Wagaw, S. H.; Califano, J. C.; Li, W.; Caspi, D.
D.; Bellizzi, M. E. Anti-Viral Compounds. US2010/317568 A1, Dec 16,
data for all compounds (PDF)
AUTHOR INFORMATION
■
2
(
010.
15) Gerusz, V.; Denis, A.; Faivre, F.; Bonvin, Y.; Oxoby, M.; Briet, S.;
Notes
LeFralliec, G.; Oliveira, C.; Desroy, N.; Raymond, C.; Peltier, L.;
Moreau, F.; Escaich, S.; Vongsouthi, V.; Floquet, S.; Drocourt, E.;
Walton, A.; Prouvensier, L.; Saccomani, M.; Durant, L.; Genevard, J.-M.;
Sam-Sambo, V.; Soulama-Mouze, C. J. Med. Chem. 2012, 55, 9914.
(16) Li, J. J.; Johnson, D. S.; Sliskovic, D. R.; Roth, B. D. Contemporary
Drug Synthesis; John Wiley & Sons, Inc.: Hoboken, NJ, 2004.
(17) Kelly, S. M.; Lipshutz, B. H. Org. Lett. 2014, 16, 98.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support provided by Novartis and the NIH Shared
Instrumentation Grant (SIG) 1S10OD012077-01A1 is warmly
acknowledged with thanks.
D
Org. Lett. XXXX, XXX, XXX−XXX