The Journal of Organic Chemistry
NOTE
General Procedure for Aza-Wittig Reaction. The phosphine 1
(6.03 g, 4.4 mmol) or 2 (6.86 g, 4.4 mmol) in THF (40 mL) was added
to a 100-mL round-bottomed flask equipped with a magnetic stirrer. A
10-mLTHF solutioncontaining 1-(azidomethyl)-4-methylbenzene (0.59 g,
4.0 mmol) and 4-methylbenzaldehyde (0.48 g, 4.0 mmol) was added to
the reaction flask. The reaction mixture was stirred at rt for 24 h at which
time the evolution of bubbles had ceased. The solvent was removed
under reduced pressure, and heptane (100 mL) and acetonitrile (20 mL)
were added. The heptane phase was separated and washed with
acetonitrile (20 mL Â 5), and then the heptane was removed under
reduced pressure. The residue from the heptane phase was analyzed by
1H and 31P NMR spectroscopy, which showed that the residue was the
PIB-phosphine oxide 19 or 10. The acetonitrile phases were combined,
and the solvent was removed under reduced pressure to give a white
solid which was purified by recrystallization from MeOH to give 8 as
spectroscopy. Concentrating the filtrate solutions, addition of heptane
(15 mL) and acetonitrile (15 mL), followed by separation and washing
of the heptane phase led to a heptane solution that contained a mixture
of 2 and 10 based on 1H and 31P NMR spectroscopy. This mixture could
be reduced and reused as described below.
For eq 5, a slightly different workup procedure was used. In the case of
synthesis of 16 and 17, the crude product PEOlig product precipitated on
cooling. In the case of 17, this crude product was dissolved in toluene at
80 °C and was allowed to react with methanesulfonic acid for 1 h. After
neutralization with triethylamine, the reaction mixture was cooled and
the product aniline was isolated by filtration. In the case of 18, the initial
PEOlig precipitate appeared to be an adduct of the aldehyde with the
diethyl hydrazine-1,2-dicarboxylate based on the appearance of two
1
ÀOCH2CH3 groups in the H NMR spectrum of this initial adduct.
This product was not further characterized but was simply hydrolyzed by
dissolving it in toluene, adding p-TsOH, and adding triethylamine and
water to the 80 °C toluene solution of the PEOlig product. Most of the
water was removed from this mixture by pipet. Cooling formed an
isolable precipitate of the desired PEOlig-modified salicylaldehyde deri-
vative which was characterized by 1H and 13C NMR spectroscopy and
was identical to the PEOlig derivative of salicylaldehyde prepared
previously.21
1
white plates (0.875 g, 3.9 mmol, 98% yield): H NMR (500 MHz,
CDCl3) δ 2.34 (s, 3 H), 2.39 (s, 3 H), 4.77 (s, 2 H), 7.13À7.18 (m, 2 H),
7.19À7.25 (m, 4 H), 7.65À7.69 (m, 2 H), 8.34 (s, 1 H); 13C NMR
(125 MHz, CDCl3) δ 21.1, 21.5, 64.8, 127.9, 128.2, 129.1, 129.3, 133.6,
136.3, 136.5, 141.0, 161.7; mp 84À86 °C (lit.37 mp 83.5À84.5 °C).
Polyisobutyltriarylphosphine oxide (PIB-CH2OC6H4P-
1
(O)Ph2) (10): H NMR (500 MHz, CDCl3) δ 0.65À1.90 (m, 182
Poly(ethylene glycol) 4-Nitrobenzoate (11). The product was
isolated as a white powder (0.245 g, 0.048 mmol, 95% yield): 1H NMR
(500 MHz, CDCl3) δ 3.36 (s, 3 H), 3.46À3.88 (m, 450 H), 4.49À4.53
(m, 2 H), 8.20À8.24 (m, 2 H), 8.26À8.30 (m, 2 H); 13C NMR
(125 MHz, CDCl3) δ 58.8, 64.7, 67.2, 68.7, multiple peaks between
69 and 74, 123.3, 130.6, 135.2, 150.3, 164.4.
N-Poly(ethylene glycol)phthalimide (12). The product was
isolated as a white powder (0.242 g, 0.047 mmol, 94% yield): 1H NMR
(500 MHz, CDCl3) δ 3.36 (s, 3 H), 3.46À3.91 (m, 452 H), 7.69À7.74
(m, 2 H), 7.80À7.86 (m, 2 H). 13C NMR (125 MHz, CDCl3) δ 36.9,
58.7, 67.1, 67.6, multiple peaks between 68 and 74, 122.9, 131.8,
133.7, 167.9.
4-Methyl-N-(4-methylphenyl)-N-poly(ethylene glycol)-
benzenesulfonamide (13). The product was isolated as a white
powder (0.244 g, 0.047 mmol, 93% yield): 1H NMR (500 MHz,
CDCl3): δ 2.33 (s, 3 H), 2.42 (s, 3 H), 3.37 (s, 3 H), 3.47À3.80
(m, 452 H), 6.89À6.94 (m, 2 H), 7.06À7.11 (m, 2 H), 7.21À7.25 (m,
2 H), 7.47À7.51 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 20.8, 21.3,
49.9, 58.7, multiple peaks between 64 and 76, 127.4, 128.4, 129.0, 129.3,
135.1, 136.5, 137.6, 143.0.
H), 1.93À2.00 (m, 1 H), 3.60À3.68 (m, 1 H), 3.77 (dd, J = 8.7, 5.7 Hz, 1
H), 6.85À6.98 (m, 2 H), 7.32À7.42 (m, 4 H), 7.42À7.50 (m, 2 H),
7.50À7.59 (m, 2 H), 7.59À7.69 (m, 4 H); 13C NMR (125 MHz,
CDCl3) δ 20.3, multiple peaks between 28 and 33, 35.7, multiple peaks
between 37 and 39, 49.4, 56.5, multiple peaks between 58 and 60, 74.1,
114.4 (d, J = 13.1 Hz), 123.0 (d, J = 110.6 Hz), 128.2 (d, J = 12.0 Hz),
131.5 (d, J = 2.3 Hz), 131.9 (d, J = 9.8 Hz), 133.0 (d, J = 104.2 Hz), 133.7
(d, J = 11.2 Hz), 162.0 (d, J = 2.6 Hz); 31P NMR (121 MHz, CDCl3)
δ 29.3.
Polyisobutyldiphenylphosphine oxide (PIB-CH2P(O)Ph2)
(19): 1H NMR (500 MHz, CDCl3) δ 0.65À1.80 (m, 182 H), 2.01À2.12
(m, 1 H), 2.18 (ddd, J = 15.0, 11.7, 9.2 Hz, 1 H), 2.32 (ddd, J = 15.0, 10.3,
4.0 Hz, 1 H), 7.38À7.56 (m, 6 H), 7.69À7.82 (m, 4 H). 13C NMR
(125 MHz, CDCl3) δ 24.6, multiple peaks between 29 and 33, 36.2,
multiple peaks between 37 and 40, 55.5, 55.6, 57.0, multiple peaks
between 58 and 60, 128.5 (d, J = 11.7 Hz), 130.6 (d, J = 8.9 Hz), 130.8 (d,
J = 9.3 Hz), 131.5 (d, J = 2.7 Hz), 131.5 (d, J = 2.9 Hz), 133.5 (d, J = 97.2
Hz), 134.3 (d, J = 97.3 Hz); 31P NMR (121 MHz, CDCl3) δ 31.5.
General Procedure for Mitsunobu Reactions. Alcohol
(0.4 mmol), nucleophile (0.8 mmol), 2 (1.25 g, 0.8 mmol), and toluene
(4 mL) were added to a 25-mL round-bottomed flask equipped with a
magnetic stirrer. DEAD (126 μL, 0.8 mmol) was added to reaction
mixture. The flask was immersed in an oil bath regulated at 80 °C, and
the reaction mixture was stirred for 15 h. In the case of eq 3, the reaction
was carried out in THF at rt using 4-nitrobenzoic acid (0.0668 g,
0.4 mmol) as the limiting reagent. Workup procedures varied as follows.
For eq3, the solvent wasremoved under reducedpressure and a mixture of
heptane (40 mL) and acetonitrile (40 mL) was added to the reaction
residue. The heptane phase containing 2 and its phosphine oxide
byproduct 10 was separated from the acetonitrile phase and was washed
with acetonitrile (10 mL Â 4). The acetonitrile solutions were combined
and the solvent was removed under reduced pressure to give a crude
product which was purified by silica gel column chromatography
(hexanes/CH2Cl2 = 4:1) to afford isopropyl 4-nitrobenzoate 9 as a white
solid (0.0795 g, 0.38 mmol, 95% yield): 1H NMR (500 MHz, CDCl3) δ
1.39 (d, J = 6.2 Hz, 6 H), 5.28 (hept, J = 6.2 Hz, 1 H), 8.17À8.22 (m, 2 H),
8.25À8.29 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 21.8, 69.7, 123.4,
130.6, 136.2, 150.4, 164.1; mp 104À106 °C (lit.38 mp 104À106 °C).
Workup for the reactions yielding polymeric products was slightly
different. For eq4, the reaction mixture was cooledto rt and then added, in
a dropwise fashion, to ice-cold Et2O (50 mL). The product PEG polymer
precipitate was isolated and characterized by 1H and 13C NMR
N-Boc-2,6-dimethyl-4-poly(ethylene glycol)aniline (14).
The product was isolated as a white powder (0.241 g, 0.046 mmol, 92%
1
yield): H NMR (500 MHz, CDCl3) δ 1.48 (s, 9 H), 3.36 (s, 3 H),
3.44À3.84 (m, 450 H), 4.03À4.09 (m, 2 H), 6.59 (s, 2 H); 13C NMR
(125 MHz, CDCl3) δ 18.2, 28.0, 58.6, 63.8, multiple peaks between 66
and 76, 79.0, 113.5, 126.8, 136.8, 153.7, 156.6.
Poly(ethylene glycol) 4-(4-(dimethylamino)phenylazo)-
benzoate (15). The product was isolated as an orange powder
1
(0.237 g, 0.045 mmol, 90% yield): H NMR (500 MHz, CDCl3) δ
3.10 (s, 6 H), 3.35 (s, 3 H), 3.42À3.88 (m, 450 H), 4.40À4.52 (m, 2 H),
6.72À6.81 (m, 2 H), 7.80À7.97 (m, 4 H), 8.08À8.16 (m, 2 H); 13C
NMR (125 MHz, CDCl3) δ 40.1, 40.2, 58.8, 64.0, multiple peaks
between 65 and 76, 111.3, 121.7, 125.5, 129.8, 130.4, 134.4, 152.7,
155.6, 166.0.
N-Polyethylphthalimide (16)30. The product was isolated as a
1
white powder (0.25 g, 0.37 mmol, 99% yield): H NMR (500 MHz,
C6D6, 70 °C) δ 0.91 (t, J = 6.58 Hz, 5 H), 1.20À1.49 (brs, 140 H), 1.64
(m, 2 H), 3.58 (t, J = 6.81 Hz, 2 H), 6.96 (m, 2 H), 7.49 (m, 2 H); 13C
NMR (125 MHz, C6D6, 70 °C) δ 12.2, 22.6, 26.8, 28.5, 29.1, 29.3, 29.7,
31.8, 37.8, 122.6, 132.6, 132.9, 167.6.
2,6-Dimethyl-4-polyethylaniline (17). The product was iso-
lated as a light brown powder (0.25 g, 0.37 mmol, 99% yield): 1H NMR
6915
dx.doi.org/10.1021/jo201097x |J. Org. Chem. 2011, 76, 6912–6917