Full Papers
doi.org/10.1002/ejoc.202100761
CHCl3 :EtOH (1.981 mL), and the solution injected into the continu-
Continuous Flow System
ous solvent stream through the resin bed (0.50 mLminÀ 1, 60 C).
°
A continuous stream of solvent was pumped through an attached
in-line glass reaction column (Omnifit®, L×I.D.=100 mm×10 mm,
bed volume=5.6 mL, adjustable ends) containing polymer-sup-
ported triphenylphosphine (PS-PPh3) and base (K2CO3) using a HPLC
pump (Waters 600 Controller). The reaction column was heated and
its temperature maintained using a heating block (FRX Volcano). A
sample injector (Rheodyne®) fitted with a 2 mL injection loop was
attached in-line for direct sample injection to the reaction column.
The injected sample solution was pumped through the heated
reaction coil before traversing through the reaction column.
Collection of the resulting eluent, followed by silica gel filtration
and concentration in vacuo, afforded the pure olefin products as
detailed within the characterisation data.
Analysis of the resulting column eluent via HPLC revealed a near-
quantitative (99%) conversion of 6 to stilbene 2.
General Procedure D: Flow-Assisted In Situ PS-Wittig Reaction
(Aldehyde)
To a pre-assembled reaction column was added PS-PPh3 resin 1
(0.100 g, 0.235 mmol, loading= 2.35 mmol/g, 1 eq.) and K2CO3
(0.065 g, 0.470 mmol, 2 eq.), and the column was placed in-line
under
a continuous stream of anhydrous 1:1 CHCl3 :EtOH.
Following resin swelling, which was effected at a flow rate of
0.50 mLminÀ 1 with a column temperature of 60 C, the Rheo-
°
dyne® injection loop was loaded with
a
2.00 mL solution
consisting of benzyl bromide 14 (0.080 g, v=0.055 mL,
0.470 mmol, 0.23 M, 2 eq.) and aldehyde (0.188 mmol, 0.09 M,
0.8 eq.) in 1:1 CHCl3 :EtOH. The solution was then injected into
the continuous solvent stream through the resin bed
General and Experimental Procedures
General Procedure A: Flow-Assisted Alkylation of PS-PPh3
(0.50 mLminÀ 1, 60 C). Collection of the resulting column eluent,
followed by silica gel filtration and concentration in vacuo,
afforded the desired olefin products as described within the
characterisation details.
°
To a pre-assembled reaction column was added PS-PPh3 resin 1
(0.100 g, 0.235 mmol, loading=2.35 mmol/g, 1 eq.), and the col-
umn was placed in-line under a continuous stream of anhydrous
CHCl3. Following resin swelling, which was effected at a flow rate of
0.50 mLminÀ 1 with a column temperature of 60 C, the Rheodyne®
°
Procedure E: Synthesis of PS-(2-nitrobenzyl)
triphenylphosphonium Bromide
injection loop was loaded with a 2.00 mL solution consisting of
benzyl bromide 14 (0.080 g, v=0.055 mL, 0.470 mmol, 0.23 M,
2 eq.) in CHCl3 (1.945 mL). The solution was then injected into the
Synthesised according to ‘General Procedure A’ using a 2.00 mL
solution consisting of 2-nitrobenzyl bromide 26 (0.101 g,
0.470 mmol, 0.23 M, 2 eq.) in CHCl3 (2.00 mL). PS-(2-nitrobenzyl)
triphenylphosphonium bromide resin 27 was obtained in 95% yield
(0.143 g), as deduced by the mass increase of the resin.
continuous solvent stream through the resin bed (0.50 mLminÀ 1
,
°
60 C). After this period, the reaction column was flushed with
additional CHCl3 at a flow rate of 2.00 mLminÀ 1 for 15 minutes, and
the resulting alkylated resin was collected and dried in vacuo for
16 hours. The desired PS-benzyltriphenylphosphonium bromide
resin 13 was obtained in 97% yield (0.136 g), as deduced by the
mass increase of the resin.
Procedure F: Synthesis of PS-(2-aminobenzyl)
triphenylphosphonium Bromide
Following literature precedence,[22] to a 50 mL two-neck round
bottom flask was added resin 27 (0.143 g, 0.223 mmol, 1 eq.) in
EtOH (15 mL), and the reaction was heated to reflux for
20 minutes. Following this period, a solution of sodium dithionite
(0.194 g, 1.115 mmol, 5 eq.) in H2O (10 mL) was added dropwise
to the refluxing mixture over 30 minutes and heating was
continued for a further 90 minutes. After this time, a sample of
polymer was taken from the reaction mixture, and treatment
with dilute NaOH in MeOH (0.1 M, 1 mL) provided a negative
nitro-ylide result (no dark coloration of the resin was observed).
Following filtration of the reaction mixture, the resin was washed
successively with H2O (2×10 mL), EtOH (2 ×10 mL), and Et2O (2 ×
10 mL), and the resin was resuspended in a 1:1 Dioxane:MeOH
solvent system (20 mL). To the suspended reaction mixture was
added 48% HBr (aq) (10 mL) dropwise and the reaction was left
to stir for 6 hours. The reaction mixture was then filtered and the
resin was washed with dioxane (2×5 mL), MeOH (2× 5 mL), and
Et2O (2 ×5 mL). Upon drying of the resin in vacuo for 16 hours,
the desired PS-(2-aminobenzyl)triphenylphosphonium bromide
resin 28 was obtained in quantitative yield (0.136 g), as deduced
by the mass decrease of the resin.
General Procedure B: Flow-Assisted Base Optimisation for
Wittig Olefination
To a pre-assembled reaction column was added resin 13 (0.136 g,
0.228 mmol, 1 eq.), base (0.456 mmol, 2 eq.) and anhydrous CHCl3
(1.00 mL), and the resin was allowed to swell for 10 minutes.
Following this initial period of resin swelling and ylide generation,
the column was placed in-line under a continuous stream of
anhydrous CHCl3 at a flow rate of 0.50 mLminÀ 1 with a column
°
temperature of 60 C. To the Rheodyne® injection loop was loaded
a 2.00 mL solution consisting of benzaldehyde 6 (0.019 g, v=
0.019 mL, 0.188 mmol, 0.09 M, 0.8 eq.) in CHCl3 (1.981 mL), and the
solution injected into the continuous solvent stream through the
resin bed (0.50 mLminÀ 1, 60 C). Analysis of the resulting column
°
eluent via HPLC revealed
(NaOHÀ K2CO3) of 6 to stilbene 2.
a
varying 5–72% conversion
General Procedure C: Flow-Assisted Solvent Optimisation for
Wittig Olefination
To a pre-assembled reaction column was added resin 13 (0.136 g,
0.228 mmol, 1 eq.), K2CO3 (0.063 g, 0.456 mmol, 2 eq.) and anhy-
drous 1:1 CHCl3 :EtOH (1.00 mL), and the resin was allowed to swell
for 10 minutes. Following this initial period of resin swelling and
ylide generation, the column was placed in-line under a continuous
stream of anhydrous 1:1 CHCl3 :EtOH at a flow rate of 0.50 mLminÀ 1
Procedure G: Synthesis of 2-(3-nitrophenyl)-1H-indole
To
a pre-assembled reaction column was added resin 28
(0.136 g, 0.223 mmol, 1 eq.) and K2CO3 (0.062 g, 0.446 mmol,
2 eq.), and the column was placed in-line under a continuous
stream of anhydrous 1:1 CHCl3 :EtOH. Following resin swelling,
°
with a column temperature of 60 C. To the Rheodyne® injection
loop was loaded a 2.00 mL solution consisting of benzaldehyde 6
(0.019 g, v=0.019 mL, 0.188 mmol, 0.09 M, 0.8 eq.) in 1:1
Eur. J. Org. Chem. 2021, 4184–4194
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