Supporting Information A Convenient Chromatography-Free Method for the Purification of Alkenes ...

92 Pages·2012·2.17 MB·English

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry
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Supporting Information

A Convenient Chromatography-Free Method for
the Purification of Alkenes Produced in the Wittig
Reaction

Peter A. Byrne, Kamalraj V. Rajendran, Jimmy Muldoonand Declan
G. Gilheany

Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,
University College Dublin, Belfield, Dublin 4, Ireland

1. General Experimental 2
2. Synthesis of phosphonium salts 4
3. Procedures for Wittig reactions & phosphine oxide removal 11
4. Characterisation of purified alkenes 15
5. Reduction of phosphine chalcogenides 34
6. Synthesis & isolation of neomenthyl chloride and reduction of
phosphine oxide-by-product 37
7. NMR spectra of phosphonium salts 42
8. NMR spectra of purified alkenes and regenerated phosphines from
Wittig reactions 56
9. NMR spectra of phosphines produced by reduction of phosphine
chalcogenides 85
10. NMR spectra of purified products from Appel-type reactions 90
11. References 91

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1. General Experimental
All chemicals were supplied by Aldrich, with the exception of Zeoprep silica, 2-
methylbenzaldehyde (o-tolualdehyde, Fluka), (tert-butoxycarbonylmethyl)-
triphenylphosphonium bromide (Fluka), 1 mol L-1 LiAlH in THF (Acros Organics) and
4
Merck standardised alumina 90. All chemicals were used without further purification
except diethyl ether, toluene, and THF, which were processed through an Innovative
Technology Inc. Pure Solv-400-3-MD solvent purification (Grubbs still) system and
stored in Strauss flasks under a nitrogen atmosphere, and ethyl acetate and
dichloromethane, which were degassed by passing a stream of dry nitrogen gas (oxygen-
free) through the solvent for one hour for the purposes of work-ups in phosphine
syntheses. All benzaldehydes (supplied by Aldrich) were checked by NMR for the
presence of carboxylic axids, but no trace of acid was found and so the benzaldehydes
were used without further purification. Phosphonium salts were dried in a vacuum
dessicator over P O and, together with KHMDS, NaHMDS, and commercial (tert-
2 5
butoxycarbonylmethyl)triphenylphosphonium bromide, were stored in an MBraun glove
box under an atmosphere of argon. Oxalyl chloride was stored under an atmosphere of
nitrogen in a Young’s flask, and dispensed by nitrogen-flushed syringe. 1,2-O-
isopropylidene-3-O-methyl-α-D-xylopentodialdofuranose-(1,4) was placed in a Schlenk
flask under argon gas, and dissolved in dry THF to give a 0.5 mol L-1 solution. This
solution was stored in the Schlenk flask under nitrogen at -18 ˚C in a freezer. 2-
methylbenzaldehyde (o-tolualdehyde) was stored under nitrogen in a sealed Fluka®
vessel.
NMR chemical shifts are reported in parts per million (ppm), and coupling constants (J)
are reported in hertz (Hz). All NMR samples were made up using CDCl as solvent.
3
NMR spectra were obtained on Varian Inova and VNMRS 300, 400, 500 and 600 MHz
spectrometers, the latter of which is equipped with a triple resonance probe. Double
decoupled 13C {1H, 31P} NMR spectra of new phosphonium salts were obtained on the
600 MHz instrument. 1H and 13C NMR chemical shifts were measured relative to
tetramethylsilane. 31P NMR chemical shifts were measured relative to an external
orthophosphoric acid standard. 19F NMR chemical shifts were measured relative to
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CCl F. In the reporting of characterisation details, the NMR signals due to aromatic
3
hydrogen “j” (where j = 1-6) of a benzyl group are referred to as ArH-j and those due to
phenyl hydrogens as PhH-j, and likewise the corresponding carbons are referred to as
ArC-jand PhC-j respectively. Assignments of signals in 1H and 13C NMR spectra was

done by reference to 13C{1H, 31P}, COSY, g HSQCAD, and gHMBCAD NMR spectra.
The 1D DPFGSE-NOE NMR technique (Double Pulse Field Gradient Spin Echo Nuclear
Overhauser Effect NMR spectroscopy) was used to detect NOE contacts.
High resolution mass spectra were obtained on a LCT electrospray ionisation mass
spectrometer or a GCT Premier GC/MS mass spectrometer by electronic or chemical
ionisation. Samples were dissolved in acetonitrile or methanol. Melting points were
obtained using a Reichert Thermovar melting point apparatus, and are uncorrected. Flash
column chromatography was carried out using Aldrich neutral alumina (Brockmann
grade I) or Zeoprep silica. TLC was done using Merck pre-coated alumina 90 or silica 60
F-254 plates. Realisation of plates was done by UV irradiation.
All reactions described here were carried out under an atmosphere of nitrogen. The inert
atmosphere was established inside a reaction flask by the standard Schlenk pump and fill
technique,1 using a Schlenk manifold that allowed each of five silicone rubber tubes to
each be open either to vacuum or to the nitrogen supply by means of a three-way tap
(third position is closed to both vacuum and nitrogen). The reaction flask was typically
flame dried and attached to the Schlenk manifold by one of the silicone rubber tubes, and
evacuated by application of a vacuum pump (Edwards RV5 rotary vane pump) while hot.
The flask was allowed to cool under vacuum and then filled with nitrogen. It was then
evacuated and re-filled a further two times. This technique was also applied to establish a
nitrogen atmosphere in the tubing connected to a sealed Schlenk flask that already
contained an inert atmosphere (nitrogen or argon gas). The flask could be opened to the
nitrogen supply after the connecting tubing had been evacuated and re-filled three times.
When not in use, the the open end of each length of silicone rubber tubing was fitted with
a syringe barrel with an attached needle. The needle was inserted through a rubber
septum into a conical flask containing dry KOH pellets, and the tip was embedded in
amongst the pellets. In this manner the tubing was kept free of ambient moisture.
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2. Synthesis of phosphonium salts

P-(iso-butyl)triphenylphosphonium bromide2
Br Ph
Ph P Br MeCN P
Ph Ph
Ph 80 oC
Ph
Triphenylphosphine (4.26 g, 16.2 mmol), dry acetonitrile (10 ml), and 1-bromo-2-
methylpropane (2 ml, 18.4 mmol) were added to a flame dried Schlenk flask under an
atmosphere of nitrogen. Stirring gave a clear solution. The flask was fitted with a reflux
condenser (flame dried and connected to nitrogen supply) and the reaction mixture was
heated to 80 ˚C for 3 days under a gentle flow of nitrogen. The progress of the reaction
was periodically checked by taking a 31P NMR spectrum of a small sample of the reaction
mixture diluted with CDCl . After 3 days, the acetonitrile solvent was removed, and the
3
residue was recrystallised from hot chloroform/ethyl acetate to give white crystals of the
product in a yield of 5.5 g (13.8 mmol, 85%). The white crystals thus obtained were
placed in a dessicator under nitrogen and dried using phosphorus pentoxide and calcium
chloride, and then placed in a glove box under an atmosphere of argon.

1H NMR (400 MHz, CDCl ) δ 7.90 (m, 6H, PhH-2), 7.79 (m, 3H, PhH-4), 7.71 (m, 6H,
3
PhH-3), 3.80 (dd, J = 12.9, 6.2, 2H, PCH ), 2.18 – 1.99 (m, 1H, CHMe ), 1.08 (d, J = 6.7,
2 2
6H, CH(CH ) ).2
3 2

31P NMR (162 MHz, CDCl ): δ 23.0.
3

13C NMR (101 MHz, CDCl ) δ 134.9 (d, J = 3.0, PhC-4), 133.7 (d, J = 10.0, PhC-2),
3
130.4 (d, J = 12.5, PhC-3), 119.0 (d, J = 85.3, PhC-1), 30.5 (d, J = 47.4, P-CH ), 24.6 (d,
2
J = 4.3, CHMe ), 24.34 (d, J = 9.2, CH(CH ) ).2
2 3 2

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iso-Butyldiphenylphosphine3
Ph P Cl MgBr THF Ph P
Ph Ph

Chlorodiphenylphosphine (8.5 ml, 46.0 mmol) was transferred from a Young’s flask to a
flame-dried Schlenk tube under a nitrogen atmosphere, and dissolved in dry THF (60 ml).
The yellow solution was cooled to 0 ˚C and a 2.0 mol L-1 solution of iso-propyl
magnesium chloride in Et O (29 ml, 58 mmol) was added dropwise. The solution
2
became cloudy as addition neared completion. Once addition of the Grignard reagent
was complete, the reaction mixture was allowed to warm to room temperature. 31P NMR
(inert atmosphere) of a small sample (0.3 ml) of the reaction mixture diluted with dry
degassed CDCl (0.5 ml) showed it to contain only phosphine (δ = -20 ppm). The
3 P
reaction mixture was quickly poured into a degassed mixture of CH Cl (150 ml) and
2 2
saturated NH Cl solution (150 ml) under a nitrogen atmosphere in a separatory funnel.
4
All remaining manipulations were carried out under inert atmosphere. The biphasic
mixture was shaken, and then the organic layer was allowed to drain into a flame-dried
round bottom flask (connected to nitrogen supply) containing Na SO . After shaking the
2 4
resulting mixture, the supernatatnt solution was transferred by cannula into a frit, and
filtered into a Schlenk flask connected to the frit to remove the drying agent. The solvent
was removed from the filtrate in vacuo. The resulting yellow oil was purified by vacuum
distillation (10-2 mbar, bath temperature 156 ˚C) using a short range distillation apparatus,
giving a clear oil (7.5 g, 68%).

1H NMR (300 MHz, CDCl ) δ 7.46 – 7.38 (m, 4H), 7.36 – 7.27 (m, 6H), 1.99 (d, J = 7.0,
3
2H), 1.68 (dd, J = 14.3, 7.1, 1H), 1.02 (dd, J = 14.0, 6.2, 6H).3

31P NMR (121 MHz, CDCl ) δ -19.9 (lit.3 -19.4)
3

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Di(iso-butyl)diphenylphosphonium bromide
Br
MeCN
P Br
Ph P
Ph 70 oC Ph
Ph
iso-Butylduphenylphosphine (4.8 ml, 20 mmol) and iso-butyl bromide (6.5 ml, 60 mmol)
were dissolved in dry acetonitrile in a flame dried Schlenk flask fitted with a reflux
condenser under a nitrogen atmosphere. The solution was stirred for one week at 70 ˚C.
Reaction progress was monitored periodically by taking a 31P NMR spectrum of a small
sample of the reaction mixture. Once all the phosphine was consumed, the solvent was
removed in vacuo, and the residue was crytallised from hot chloroform/ethyl acetate. The
resulting white crystals were dried under vacuum in a dessicator containing CaCl and
2
P O and stored under argon gas in a glove box. Yield = 6.8 g (90%).
2 5

1H NMR (500 MHz, cdcl ) δ 8.00 – 7.93 (m, 4H), 7.81 – 7.75 (m, 2H), 7.73 – 7.66 (m,
3
4H), 3.35 (dd, J = 12.8, 6.5, 4H), 1.98 – 1.85 (m, 2H), 0.96 (dd, J = 6.7, 0.8, 12H).

13C NMR (101 MHz, CDCl ) δ 134.6 (d, J = 3.0), 133.3 (d, J = 9.4), 130.2 (d, J = 12.0),
3
118.9 (d, J = 80.9), 30.7 (d, J = 46.6), 24.3 (dd, J = 18.6, 6.8).

31P NMR (162 MHz, CDCl ) δ 26.0.
3

HRMS: Calc. for [M]+ = C H P 299.1929; found 299.1928 (0.2 ppm).
20 28

MP (crystallised from CHCl /EtOAc) 183-184 °C.
3

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Benzylmethyldiphenylphosphonium bromide4
Br
Ph P Br Et2O
P
Ph Ph
Ph

A Schlenk flask was charged with nitrogen using the standard Schlenk pump and fill
technique.1 Methyldiphenylphosphine5 (3.50 ml, 18.6 mmol) was transferred from a
Young’s flask to the Schlenk flask by nitrogen-flushed syringe. Dry diethyl ether (30 ml)
was added to give a clear solution of the phosphine. Benzyl bromide (2.5 ml, 21 mmol)
was then added by syringe. The solution turned a cloudy white colour upon addition.
The solution was left to stir for 2 days, after which time a white solid was observed in the
flask. The solid was isolated by filtration under suction. This solid was recrystallised
from hot chlorform/ethyl acetate and the crystals isolated by filtration under suction. The
filtrate was retained and yielded further crystals after standing for a period. The crystals
(6.51g , 94% yield) were dried in a vacuum dessicator over P O and CaCl for several
2 5 2
days before being transferred to a glove box under argon.
1H NMR (500 MHz, CDCl ): δ 7.91 (m, 4H, ArH-2), 7.70 (m, 2H, ArH-4), 7.60 (m, 4H,
3
PhH-3), 7.27 (m, 2H, ArH-2), 7.20 (m, 1H, ArH-4), 7.13 (m, 2H, ArH-3), 4.91 (d, 2J =
PH
15.4, 2H, CH ), 2.70 (d, 2J = 13.7, 3H, CH ).
2 PH 3
31P NMR (202 MHz, CDCl ): δ 23.8.
3
13C NMR (126 MHz, CDCl ): δ 134.5 (d, 4J = 3.2 Hz, PhC-4), 132.9 (d, 2J = 9.9 Hz,
3 PC PC
PhC-2), 130.8 (d, 3J = 5.6 Hz, ArC-2), 129.8 (d, 3J = 12.6 Hz, PhC-3), 128.7 (d, 4J
PC PC PC
= 3.6 Hz, ArC-3), 128.1 (d, 5J = 4.2 Hz, ArC-4), 127.4 (d, 2J = 9.2 Hz, ArC-1), 118.7
PC PC
(d, 1J = 85.0 Hz, PhC-1), 30.5 (d, 1J = 47.6 Hz, CH ), 7.1 (d, 1J = 56.4 Hz, CH ).
PC PC 2 PC 3
HRMS (m/z): Calc. for [M]+ = C H P 291.1303; found 291.1296 (2.4 ppm).
20 20

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2-Methoxybenzylmethyldiphenylphosphonium chloride
Cl
Ph P Cl Et2O
P
Ph Ph
OMe Ph
OMe
A Schlenk flask was charged with nitrogen using the standard Schlenk pump and fill
technique.1 Methyldiphenylphosphine5 (4.1 ml, 4.3 g, 21.6 mmol) was transferred from
a Young’s flask to the Schlenk flask by nitrogen-flushed syringe. Dry diethyl ether (35
ml) was added to give a clear solution of the phosphine. 2-methoxybenzyl chloride (3.3
ml, 3.7 g, 23.8 mmol) was then added by syringe. The solution turned a cloudy white
colour upon addition. The solution was left to stir for 2 days, after which time a white
solid was observed in the flask. The solid was isolated by filtration under suction. This
solid was recrystallised from hot chlorform/ethyl acetate and the crystals isolated by
filtration under suction. The filtrate was retained and yielded further crystals after
standing for a period. The crystals (7.52 g, 98% yield) were dried in a vacuum dessicator
over P O and CaCl for several days before being transferred to a glove box under argon.
2 5 2
1H NMR (500 MHz, CDCl ): δ 7.82 (m, 4H, PhH-2), 7.71 (m, 2H, PhH-4), 7.64 (m, 1H,
3
ArH-6), 7.60 (m, 4H, PhH-3), 7.23 (m, 1H, ArH-4), 6.87 (m, 1H, ArH-5), 6.66 (m, 1H,
ArH-3), 4.79 (2H, d, 2J = 15.2, CH ), 3.20 (s, 3H, OCH ), 2.75 (d, 2J = 13.6, 3H,
PH 2 3 PH
CH ),
3
31P NMR (202 MHz, CDCl ): δ 22.9.
3
13C NMR (126 MHz, CDCl ): δ 156.8 (d, J = 5.6, ArC-5), 134.5 (d, J = 2.8, PhC-4),
3 PC PC
133.0 (d, J = 10.1, PhC-2), 132.8 (d, J = 5.6, ArC-6), 130.0 (d, J = 3.9, ArC-4),
PC PC PC
129.7 (d, J = 12.3, PhC-3), 121.3 (d, J = 3.4, ArC-5), 119.7 (d, 1J = 83.6, PhC-1),
PC PC PC
115.9 (d, 2J = 7.0, ArC-1), 110.3 (d, J = 3.3, ArC-3), 54.8 (s, OCH ), 25.4 (d, 1J =
PC PC 3 PC
48.8, CH ), 8.0 (d, 1J = 56.7, CH ).
2 PC 3
HRMS (m/z): Calc. for [M]+ = C H PO 321.1408; found 321.1410 (0.6 ppm).
21 22
MP (crystallised from CHCl /EtOAc) 188-191 °C.
3

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2-Fluorobenzylmethyldiphenylphosphonium bromide
Br
Ph P Br Et2O
P
Ph Ph
F Ph
F
A Schlenk flask was charged with nitrogen using the standard Schlenk pump and fill
technique.1 Methyldiphenylphosphine5 (3.8 ml, 4.05 g, 20 mmol) was transferred from a
Young’s flask to the Schlenk flask by nitrogen-flushed syringe. Dry diethyl ether (32 ml)
was added to give a clear solution of the phosphine. 2-fluorobenzyl bromide (2.65 ml,
4.16 g, 22 mmol) was then added by syringe. The solution turned a cloudy white colour
upon addition. The solution was left to stir for 2 days, after which time a white solid was
observed in the flask. The solid was isolated by filtration under suction. This solid was
recrystallised from hot chlorform/ethyl acetate and the crystals isolated by filtration under
suction. The filtrate was retained and yielded further crystals after standing for a period.
The crystals (7.59g, 97% yield) were dried in a vacuum dessicator over P O and CaCl
2 5 2
for several days before being transferred to a glove box under argon.
1H NMR (500 MHz, CDCl ): δ 7.96-7.88 (m, 4H, PhH-2), 7.82-7.77 (m, 1H, ArH-6),
3
7.76-7.72 (m, 2H, PhH-4), 7.64-7.60 (m, 4H, PhH-3), 7.24 (m, 1H, ArH-4), 7.06 (t, 2J =
7.6 Hz, 1H, ArH-5), 6.87 (m, 1H, ArH-3), 4.95 (d, 3J = 15.4, 2H, CH ), 2.79 (d, 3J =
PH 2 PH
13.6, 3H, CH ).
3
31P NMR (202 MHz, CDCl ): δ 22.5.
3
13C NMR (126 MHz, CDCl ): δ 160.9 (dd, J = 6.1, J =247.6 , ArC-2), 135.1 (d, J
3 PC FC PC
= 3.1, PhC-4), 133.4 (dd, J = 5.1, 2.7, ArC-6), 133.2 (d, J = 10.0, PhC-2), 130.8 (dd, J
PC
= 3.9, J = 8.2, ArC-4), 130.2 (d, J = 12.6, PhC-3), 125.2 (app t, J = 3.5, ArC-5), 118.8
FC PC
(d, J = 84.6, PhC-1), 115.7 (dd, J = 3.2, J = 21.8, ArC-3), 115.2 (dd, J = 8.6, J
PC PC FC PC FC
=14.9, ArC-1), 24.7 (d, J = 49.8, CH ), 8.0 (d, J = 56.2, CH ).
PC 2 PC 3
HRMS (m/z): Calc. for [M]+ = C H PF 309.1208; found 309.1209 (0.3 ppm).
20 19
MP (crystallised from CHCl /EtOAc) 202-204 °C.
3
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2-fluorobenzyltriphenylphosphonium chloride6
Cl Ph
Cl neat
PhPhP Ph F 100 oC PhPhP
F

Triphenylphosphine (20.0 g, 76.3 mmol) was added to a Schlenk flask under N . The
2
reaction flask containing the triphenylphosphine was then placed in an oil bath and heated
to 100 °C. Triphenylphosphine is a liquid at this temperature,7 and thus can be used as
the reaction solvent. 2-fluorobenzyl chloride (14.4 g, 76.3 mmol) was then added. A
white solid formed in the flask virtually instantly after addition of the benzyl bromide,
and all of the triphenylphosphine was observed to have disappeared. After approximately
10 minutes, the reaction flask was removed from the oil bath and allowed to cool to room
temperature. The white solid was difficult to remove from the sides of the flasks, so
dichloromethane was added to aid removal of the solid from the flask. The suspension of
the salt in the dichloromethane was transferred to a round bottomed flask and the solvent
was removed in vacuo. The white salt was recrystallised from chloroform/ethyl acetate
and the crystals (30.1 g, 88% yield) isolated by filtration under suction.

1H NMR (300 MHz, CDCl ) δ 7.78 – 7.51 (m, 15H), 7.36 (m, 1H), 7.16 (m, 1H), 6.85
3
(app. t, J = 7.5, 1H), 6.72 (app. t, J = 9.1, 1H), 5.35 (d, J = 14.4, 2H).6

31P NMR (121 MHz, CDCl ) δ 22.4.
3

(Ethoxycarbonylmethyl)methyldiphenylphosphonium bromide8
O Br Ph O
Ph P Toluene
Br P
Ph OEt 0 to 20 oC Ph OEt

A solution of methyldiphenylphosphine (0.60 ml, 0.64 g, 3.2 mmol) in dry toluene (3 ml)
was prepared in a Schlenk flask under an atmosphere of nitrogen. This was cooled to 0
oC in an ice bath, and ethyl bromoacetate (0.36 ml, 1.54 g, 3.2 mmol) was added slowly
10