Organic Process Research & Development
Article
loops the two sample solutions were pumped, at the desired
flow rate, toward a T-piece and directed in the coil reactor
heated at the selected temperature. The outflow was collected
in a fraction collector, and the crude mixture was washed with
petroleum ether (2 × 20 mL). The separated aqueous layer was
thus acidified with HCl 3 M and extracted with EtOAc (3 × 30
mL). The combined organic layers were dried over Na SO and
Hz, 1H), 8.25 (dd, J = 8.0, 0.9 Hz), 12.3 (s, 1H). 13C NMR
(DMSO-d6) δ 116.4, 119.2, 120.6, 122.6, 123.3, 126.2, 128.4,
133.1, 134.1, 139.9, 163.2. MS (ES+) m/z 224.4 (M + Na;
100%); (ES-) m/z 200.4 (M − H; 100%).
ASSOCIATED CONTENT
■
2
4
*
S
Supporting Information
concentrated under vacuum to give a crude sample which is
1
then analyzed by H NMR.
Acyl Azide Synthesis. A solution of 3-phenylthiophene-2-
carboxylic acid (3, 0.4 mmol, 0.2 M) and triethylamine (0.4
mmol) in 1,2-dichlorobenzene was pumped and reacted at
room temperature with a solution of DPPA (0.52 mmol, 0.26
M) in 1,2-dichlorobenzene with a total flow rate of 0.2 mL/
min. The desired was acyl azide 5 was collected in a fraction
collector, and the crude mixture was directly submitted to
chromatographic purification to obtain the pure intermediate 5
AUTHOR INFORMATION
■
Author Contributions
P.F. and C.O. contributed equally to the work.
(
77 mg, 0.34 mmol) in 84% yield.
Reactions for Thermal Cyclization Optimization. A
Notes
The authors declare no competing financial interest.
solution of 3-phenylthiophene-2-carbonyl azide (5, 0.2 mmol,
.1 M) in 1,2-dichlorobenzene was pumped at the selected flow
0
rate through a stainless steel coil reactor heated at the
temperature of choice. The outflow was monitored by an UV
detector collecting 10 mL of the crude reaction mixture. The
HPLC sample was prepared dissolving 75 μL of the crude
reaction mixture in 1 mL of methanol.
REFERENCES
■
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Scale Up. Continuous Flow Synthesis of the 3-Phenyl-
thiophene-2-carboxylic Acid (3). A water suspension of the
boronic acid 2 (53.1 mmol, 0.27 M), NaOH (96.6 mmol, 0.48
M), and TBAB (24.1 mmol, 0.12 M) was preheated at 50 °C
until the complete reactant solubilization. The resulting
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(
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carboxylic acid (1, 48.3 mmol, 0.24 M) and Pd(PPh ) (1.45
3
4
mmol, 0.007 M) dissolved in THF−PEG-400 (9:1, v/v) and
the mixture pumped at 1.5 mL/min in a coil reactor (10 mL)
heated at 173 °C. The crude outflow met an additional stream
of petroleum ether pumped at 1.5 mL/min. The flow stream
was then directed toward an Omnifit PEEK column (150 mm
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(
×
6.6 mm) filled with sea sand (50−70 mash). The greenish
biphasic mixture was collected in a separatory funnel, and the
separated water layer was acidified with HCl 37% until
complete precipitation. The white solid formed was filtered
off and dried under vacuum obtaining the pure 3-phenyl-
thiophene-2-carboxylic acid (3, 9 g, 44 mmol) (91% yield,
(
(
Bikker, J. A.; Shah, F.; Bard, J.; Costantino, G.; Gioiello, A.; Robertson,
G. M.; Sabbatini, P.; Venturoni, F.; Liscio, P.; Carotti, A.; Bellocchi, D.;
Cozzi, A.; Wood, A.; Gonzales, C.; Zaleska, M. M.; Ellingboe, J. W.;
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purity > 95%) which was used for the next step without further
1
purifications. Mp: 166−168 °C. H NMR (DMSO-d ) δ 7.25
6
(
9) (a) Oumouna, M.; Datta, R.; Oumouna-Benachour, K.; Suzuki,
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(
d, 1H, J = 5.1 Hz), 7.35−7.41 (m, 3H), 7.44−7.47 (m, 2H),
.94 (d, 1H, J = 5.1 Hz), 12.85 (s, 1H). C NMR (DMSO-d )
13
7
6
1
δ 127.67, 127.78 (2C), 128.11, 129.32 (2C), 131.07, 131.79,
1
35.55, 147.23, 162.91.
Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-
3
(
5
(4H)-one-A (TIQ-A, 6). A solution of 3-phenylthiophene-2-
P.; Matrougui, K.; Boulares, A. H. J. Pharmacol. Exp. Ther. 2009, 329,
150.
carboxylic acid (3) (24.5 mmol, 0.2 M) and Et N (24.5 mmol,
3
0
.2 M) dissolved in 1,2-dichlorobenzene was mixed through a
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T-piece with a solution of DPPA (31.7 mmol, 0.26 M)
dissolved in the same solvent. The main flow stream was
pumped at 0.2 mL/min into a 10 mL coil reactor maintained at
(12) Pellicciari, R.; Camaioni, E.; Costantino, G.; Formentini, L.;
2
5 °C. The outflow fed a second 10 mL stainless steel coil
Sabbatini, P.; Venturoni, F.; Eren, G.; Bellocchi, D.; Chiarugi, A.;
Moroni, F. Chem. Med. Chem. 2008, 3, 914.
heated at 235 °C, and the black solution thus collected was
submitted to flash chromatography to afford TIQ-A (6, 2.7 g,
(13) (a) Venturoni, F.; Gioiello, A.; Sardella, R.; Natalini, B.;
1
3.5 mmol) in 55% yield as pure white solid. Mp: 252−254 °C.
Pellicciari, R. Org. Biomol. Chem. 2012, 10, 4109. (b) Gioiello, A.;
Rosatelli, E.; Teofrasti, M.; Filipponi, P.; Pellicciari, R. ACS Comb. Sci.
2013, 15, 235.
1
H NMR (DMSO-d ) δ 7.23 (d, J = 5.6 Hz, 1H), 7.51 (m, 1H),
6
7
.70 (d, J = 5.3 Hz, 1H), 7.78 (m, 1H), 8.10 (dd, J = 7.4, 1.1
H
dx.doi.org/10.1021/op500074h | Org. Process Res. Dev. XXXX, XXX, XXX−XXX