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Organic Process Research & Development
Figure 6. Conversion (%) and residence time (h) for the
continuous-flow photoreaction of pyridinium salt 1a at 62
mM using FEP4 reactor
1-allylpyridinium bromide (1b). The reaction mixture was
stirred at 60 ºC overnight. The pyridinium salt 1b was ob-
1
tained in 82% yield as a brown solid. H NMR (300 MHz,
1
2
3
4
5
6
7
8
9
D2O) δ 9.00 (d, J = 5.5 Hz, 2H), 8.72 – 8.67 (m, 1H), 8.22 (t, J
= 7.0 Hz,2H), 6.34 – 6.21 (m, 1H), 5.67 – 5.59 (m, 2H). 5.37
(d, J = 6.0 Hz, 2H). 13C NMR (75 MHz, D2O) δ 148.3, 146.6,
132.3, 132.2, 130.6, 130.6, 125.4, 125.3, 65.8. MS(ESI) m/z:
120.2 [M]+ 1H NMR spectral data in accordance with the
literature.6
In conclusion, this work reports an efficient photochemi-
cal transformation of 1-n-butyl and 1-allyl pyridinium
salts to the corresponding bicyclic-aziridine under con-
tinuous-flow conditions. Three home-made continuous-
flow reactors were developed, which overcome the scal-
able problem of this rearrangement and allowed the
production of bicyclic-aziridines in gram scale. PQT4 gave
the best productivity results (3.7 g L-1 h-1 for 1a and 1.4 g
L-1 h-1 for 1b), that revealed a huge improvement when
compared with the reported literature under batch con-
ditions (8 times and 28 times better, respectively). FEP4
allowed the production of higher quantities of bicyclic-
aziridine, since it is a reactor with more capacity being
efficient for long time operations under continuous-flow
allowing the production of 2 g/day of 2a. PQT2, the reac-
tor with the smaller diameter, also gave a good produc-
tivity for 1a (3.3 g L-1 h-1), however the production is
lower than PQT4. These powerful home-made reactors
could also be explored in a wide variety of organic pho-
tochemistry reactions. The impact of continuous-flow in
the field of organic synthesis as well as organic photo-
chemistry is already high and it is still expected an in-
crease of research in this topic, including for high scale
production.
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General procedure for photochemical transformation of
1-n-butylpyridinium
bromide
to
6-n-butyl-6-
azabicyclo[3.1.0]hex-3-en-2-ol (2a) under batch condi-
tions: Inside a reactor tube (QT4: 23 cm (l) x 0.4 cm (d),
QT2: 22 cm (l) x 0.2 cm (d) and FEP: 23 cm (l) x 0.4 cm (d),
Table 2) was inserted an aqueous solution (Table 2) of
pyridinium salt 1a (Table 2) and potassium carbonate (1.2
mol equiv). The solution was deoxygenated under N2 for
30 minutes and placed inside the Rayonet reactor (equiva-
lent to Model RPR-200, containing 16 Philips TUV lamps
(8W at 254 nm)) and the reaction mixture was irradiated
at room temperature for 8 h, unless stated. To isolate the
bicyclic-aziridine (Table 2, entry 5), the water was evapo-
rated under vacuum and the solid dissolved in diethyl
ether (3x100 mL). The solution was stirred for 15 minutes
and filtered, the solvent was evaporated under vacuum to
give the bicyclic vinyl aziridine 2a as a brown oil.
6-n-Butyl-6-azabicyclo[3.1.0]hex-3-en-2-ol (2a) The com-
1
pound was obtained as a brown oil. H NMR (300 MHz,
CDCl3) δ 6.29 – 6.27 (m, 1H). 5.88 – 5.86 (m, 1H). 4.48 (d, J
= 1.2 Hz,1H), 2.48 – 2.23 (m, 4H), 1.56 – 1.49 (m, 2H), 1.37
– 1.29 (m, 2H). 0.89 (t, J = 7.3 Hz, 3H). Spectral data in
accordance with the literature.16
EXPERIMENTAL SECTION
General methods and materials: All the reagents were ob-
tained commercially and were used without further purifica-
tion. The solvents were obtained from commercial sources as
pure grade and were distilled before.
Table 2. Synthesis of 2a under batch conditions.
1H and 13C NMR spectra were measured on a Bruker Fourier
300 spectrometer. Splitting patterns are indicated as s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak.
S/V
Entry Tube ratio
[m2/m3]
1a
(mmol)/
(mM)
Water
(mL)
Productivity
(g L-1 h-1)
Conv.(%)
1
1
2
3
4
5
6
7
QT4
QT4
QT2
QT2
1000
1000
2000
2000
3
3
0.18/60
0.89/296
91
17
88
33
1.04
0.97
0.96
1.81
The photochemical reactions were followed by H NMR (D2O).
Low resolution mass spectroscopy was performed in a triple
quadrupole mass spectrometer Micromass Quattro Micro API.
Waters. The UV irradiation experiments were performed in a
equivalent Rayonet reactor (Model RPR-200), containing 16
Philips TUV lamps (8W at 254 nm).
0.7 0.04/57
0.7 0.20/285
80
3
QT25(a) 161
5/63
0.19/62
0.89/296
72(b) 0.25(0.65)(c)
FEP
FEP
1000
1000
92
13
1.09
0.73
3
(a)The reaction was irradiated during 28 h, internal diame-
General procedure for synthesis of pyridinium salts: To an
Aldrich ACE pressure tube (Z181064) at room temperature,
was added pyridine (5.1 mL, 0.06 mol) and the respective
brominated derivative (0.06 mol). The solution was heated
at 100 ºC for 40 hours, unless stated. After cooling, the salt
was dissolved in MeOH, transferred to a flask and evapo-
rated under vacuum to obtain the pure salt.
(b)
ter of the quartz tube: 2.5 cm. Isolated yield (%), Isolat-
(c)
ed mass 0.55 g, For a quartz tube with 1.2 cm diame-
ter(d), using 1-n-butylpyridinium chloride (0.96 mmol)
gave 2a in 65% (0.131g of isolated mass) providing 0.65 g
L-1 h-1 of productivity.16
1-n-butylpyridinium bromide (1a) The pyridinium salt 1a
1
was obtained in quantitative yield as a colourless solid. H
General procedure for recirculating continuous-flow pho-
tochemical transformation of pyridinium salts to bicyclic-
aziridines: In an Erlenmeyer was prepared an aqueous
solution at specific concentrations (Tables 3 and 4) of
pyridinium salt and potassium carbonate (1.2 mol equiv).
Using a peristaltic pump (Watson Marlow 120U/DV, Inter-
nal diameter silicon tube (0.8 mm), 50 rpm, measured
NMR (300 MHz, D2O) δ 8.86 (d, J = 5.8 Hz, 2H), 8.58 – 8.52
(m, 1H), 8.09 (d, J = 6.9 Hz, 2H),4.62 (t, J = 7.4 Hz, 2H). 2.03
– 1.98 (m, 2H). 1.40 – 1.33 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).
Spectral data in accordance with the literature.16
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