H
M. Pirola et al.
Feature
Synthesis
(S)-N,N′-Diacetyl-1-phenylethane-1,2-diamine (7) by Two-Step
Synthesis
(4) Ferraro, A.; Bernardi, L.; Fochi, M. Adv. Synth. Catal. 2016, 358,
1561.
(5) For reviews on organocatalyzed enantioselective reductions
see: (a) Benaglia, M.; Genoni, A.; Bonsignore, M. Enantioselective
Organocatalytic Reductions, In Stereoselective Organocatalysis:
Bond Formation Methodologies and Activation Modes; Rios
Torres, R., Ed.; Wiley: Hoboken, 2013, 559–585. (b) Rossi, S.;
Benaglia, M.; Massolo, E.; Raimondi, L. Catal. Sci. Technol. 2014,
9, 2708.
(6) Massolo, E.; Benaglia, M.; Orlandi, M.; Rossi, S.; Celentano, G.
Chem. Eur. J. 2015, 21, 3589.
(7) (a) Genoni, A.; Benaglia, M.; Massolo, E.; Rossi, S. Chem.
Commun. 2013, 49, 8365. For reviews see: (b) Guizzetti, S.;
Benaglia, M. Eur. J. Org. Chem. 2010, 5529. (c) Jones, S.; Warner,
C. J. A. Org. Biomol. Chem. 2012, 10, 2189.
(8) Recent reviews: (a) Atodiresei, I.; Vila, C.; Rueping, M. ACS Catal.
2015, 5, 1972. (b) Puglisi, A.; Benaglia, M.; Porta, R.; Coccia, F.
Curr. Organocatal. 2015, 2, 79. (c) Munirathinam, R.; Huskens, J.;
Verboom, W. Adv. Synth. Catal. 2015, 357, 1093. (d) Rodríguez-
Escrich, C.; Pericàs, M. A. Eur. J. Org. Chem. 2015, 1173. Some
very recent examples of continuous-flow synthetic methods:
(e) Poh, J.-S.; Tran, D. N.; Battilocchio, C.; Hawkins, J. M.; Ley, S.
V. Angew. Chem. Int. Ed. 2015, 54, 7920. (f) Fabry, D. C.; Ronge,
M. A.; Rueping, M. Chem Eur. J. 2015, 21, 5350. (g) Tran, D. N.;
Battilocchio, C.; Lou, S.-B.; Hawkins, J. M.; Ley, S. V. Chem. Sci.
2015, 6, 1120. Reviews on the synthesis of APIs under continu-
ous-flow conditions: (h) Gutmann, B.; Cantillo, D.; Kappe, C. O.
Angew. Chem. Int. Ed. 2015, 54, 6688. (i) Porta, R.; Benaglia, M.;
Puglisi, A. Org. Process Res. Dev. 2016, 20, 2.
Syringe A was filled with nitroenamine 3b (0.33 M soln, 1 mL) catalyst
B (0.2 equiv); syringe B was filled with 5 (0.1 M soln, 4 mL); syringe C
was filled with DIPEA (6 equiv) in CH2Cl2 (2.5 mL, total volume);
syringe D was filled with HSiCl3 (8 equiv) in CH2Cl2 (2.5 mL, total vol-
ume). Syringes A and B were pumped into a 500-μL mesoreactor heat-
ed to 60 °C, at two different flow rates, in order to have a residence
time of 20 min (overall rate: 25 μL/min, 5 μL/min for syringe A, 20
μL/min for syringe B), and a concentration of 0.08 M of 3b in the reac-
tor. Syringes C and D were pumped at the same flow rate into a 100-
μL mesoreactor cooled to 0 °C, in order to premix the reducing agent
and the Lewis base.
The outcome of the reactors was collected in the same round-bot-
tomed flask under N2 atmosphere cooled to 0 °C, where the nitro re-
duction took place, after the first two volumes were discharged. After
stirring at rt overnight, the reaction was quenched with stoichiomet-
ric 4 M NaOH soln, dried (Na2SO4), filtered, and evaporated under re-
duced pressure. The crude was directly subjected to derivatization.
A stirred solution of the crude in toluene (4 mL) was cooled to 0 °C,
and to this was added Et3N (4.0 equiv) followed by Ac2O (3.0 equiv).
The cooling bath was then removed and the solution was stirred at
45 °C overnight. The mixture was then concentrated under vacuum
and the residue was purified by flash column chromatography (silica
gel, CH2Cl2/MeOH 9:1) to afford 7 (16 mg, 27%) as a yellow solid. All
analytical data are in agreement with the literature.18 The enantio-
meric excess was determined by HPLC (chiral stationary phase, Daicel
Chiralcel OJ-H column, eluent hexane/i-PrOH 9:1, flow rate 0.8
mL/min, λ = 210 nm): tR = 9 (minor), 10.4 min (major). In all the cases
the enantiomeric excess was maintained during the reduction of the
nitro group.
(9) For the detailed synthesis of nitroenamines, please see the Sup-
porting Information.
(10) Brenna, D.; Porta, R.; Massolo, E.; Raimondi, L.; Benaglia, M.
ChemCatChem 2017, 9, 941.
(11) Although different experimental conditions were investigated
(flow rate, temperature, stoichiometry, solvents, use of addi-
tives like thiourea), the maximum yield was 33%; low conver-
sion and the appearance of some side products due to starting
material degradation were observed and were responsible for
the disappointing results.
1H NMR (300 MHz, CD3OD): δ = 7.36–7.20 (m, 5 H, Ph), 5.07 (m, 1 H,
CHNHAc), 3.49 (m, 2 H, CH2NHAc), 2.00 (s, 3 H, COCH3), 1.92 (s, 3 H,
COCH3).
Funding Information
(12) For a recent review on nitro reduction, see: Orlandi, M.; Brenna,
D.; Harms, R.; Jost, S.; Benaglia, M. Org. Process Res. Dev. 2016,
DOI: 10.1021/acs.oprd.6b00205.
M.P. acknowledges Università degli Studi di Milano for a pre-doctoral
fellowship. M.B. thanks Università degli Studi di Milano for a H2020-
Transition Grant. M.E.C. thanks Fondazione Cariplo for a postdoctoral
(13) Review on continuous-flow hydrogenation: Cossar, P. J.;
Hizartzidis, L.; Simone, M. I.; McCluskey, A.; Gordon, C. P. Org.
Biomol. Chem. 2015, 13, 7119.
grant.
)(
(14) (a) Orlandi, M.; Tosi, F.; Bonsignore, M.; Benaglia, M. Org. Lett.
2015, 17, 3941. (b) Orlandi, M.; Benaglia, M.; Tosi, F.;
Annunziata, R.; Cozzi, F. J. Org. Chem. 2016, 81, 3037. (c) The
methodology is described in a patent: Bonsignore, M.; Benaglia,
M. EP 2892862, 2016.
Supporting Information
Supporting information for this article is available online at
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(15) For the application of flow chemistry for multistep organic syn-
thesis, see: (a) Newton, S.; Carter, C. F.; Pearson, C. M.; Alves, L.
C.; Lange, H.; Thansandote, P.; Ley, S. V. Angew. Chem. Int. Ed.
2014, 53, 4915. (b) Wegner, J.; Ceylan, S.; Kirschning, A. Adv.
Synth. Catal. 2012, 354, 17. (c) Baumann, M.; Baxendale, I. R.;
Ley, S. V. Mol. Divers. 2011, 3, 613. For some other recent repre-
sentative contributions, see: (d) Chen, M.; Buchwald, S. Angew.
Chem. Int. Ed. 2013, 52, 4247. (e) Baxendale, I. R.; Ley, S. V.;
Mansfield, A. C.; Smith, C. D. Angew. Chem. Int. Ed. 2009, 48,
4017.
References
(1) Chiral Amine Synthesis: Methods, Developments and Applica-
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(3) Liu, X. W.; Yan, Y.; Wang, Y.-Q.; Wang, C.; Sun, J. Chem. Eur. J.
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(16) Yan, Q.; Liu, M.; Kong, D.; Zi, G.; Hou, G. Chem. Commun. 2014,
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I