The Journal of Organic Chemistry
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The resulting solid was recrystallized from CH2Cl2/hexane to afford a
pure purple solid (0.095 g, 0.0687 mmol, 18%): mp 150−152 °C; UV/
vis CHCl3 λmax (ln ε): 422.5 (9.64), 517 (9.27), 552 (8.17), 592
(8.24), 653.5 (7.55); 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 8H),
8.44 (d, 4H, J = 8.8 Hz), 7.72 (t, 4H, J = 7.9 Hz), 7.59 (d, 4H, J = 6.6
Hz), 7.36 (s, broad, 4H), 7.29 (t, 4H, J = 7.1 Hz), 7.14−7.03 (m,
20H), 6.20 (t, broad, 4H, J = 5.4 Hz), 4.18 (s, 8H), 3.16 (t, 8H, J = 5.4
Hz), 2.91(m, 8H,), −2.71 (s, 2H); 13C NMR (100 MHz, DMSO) δ
155, 140, 138, 135, 131, 129, 128, 127.32, 127, 121.1, 120.9, 116, 72,
69; HRMS (ESI) calcd for C84H79N12O8 (M + H)+ 1383.6144, found
1383.6151; HRMS (ESI) cald for C84H78N12O8Na (M + Na)+
1405.5963, found 1405.5918.
reaction without further purification: H NMR (400 MHz, CDCl3) δ
1.19 (t, 3H, J = 7.1 Hz), 1.59 (s, broad, 2H), 2.84 (t, 2H, J = 5 Hz),
3.66−3.47 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 15, 42, 67, 70,
70.5, 70.8, 70.9, 74.
α,α,α,α,-5,10,15,20-Tetrakis-(2-(N-(3,6,9-trioxaundecyl)-
ureido)phenyl)porphyrin (4). Dry α,α,α,α-tetra-(o-aminophenyl)-
porphyrin (1) (0.192 g, 0.285 mmol) was dissolved in dry CH2Cl2
(137.2 mL) in a glove box. To the solution was added dry
triethylamine (0.32 mL, 2.27 mmol) followed by the addition of
triposhgene (0.127 g, 0.427 mmol). The mixture was stirred for 1 h at
rt. Dry 2-(2-(2-ethoxyethoxy)ethoxy)ethylamine (7b) (0.262 g, 1.478
mmol), dissolved in dry CH2Cl2 (5 mL), was then added to the
reaction mixture via syringe in one portion, and the reaction was
stirred for 24 h. The reaction mixture was then concentrated under
reduced pressure, and the resulting crude material was purified using
silica gel chromatography (4% ethanol in CH2Cl2). The resultant
product was recrystallized with CH2Cl2/hexanes to yield a pure purple
solid (0.125 g, 0.084 mmol, 30%): mp 173−175 °C; UV/vis CHCl3
λmax (ln ε): 422 (12.14), 516.5 (9.62), 545 (8.72), 590 (8.54), 648
(7.78); 1H NMR (400 MHz, DMSO-d6) δ −2.68 (s, broad, 2H), 0.98
(t, 12H, J = 7 Hz), 2.86−2.94 (m, 8H), 3.13−3.40 (m, 48H), 6.21 (t,
broad, 4H, J = 5.0 Hz), 7.29 (t, 4H, J = 7.4 Hz), 7.36 (s, broad, 4H),
7.60 (d, 4H, J = 7.6 Hz), 7.72 (t, 4H, J = 7.9 Hz), 8.45 (d, 4H, J = 8.4
Hz), 8.73 (s, 8H); 13C NMR (100 MHz, DMSO) δ 15, 65, 69, 69.2,
69.4, 69.5, 69.6, 116, 120.8, 120.9, 129, 130, 135, 140, 155; HRMS
(ESI) calcd for C80H103N12O16 (M + H)+ 1487.7615, found
1487.7577.
α,α,α,α,-5,10,15,20-Tetrakis-(2-(N-(2-hydroxyethyl)ureido)-
phenyl)porphyrin (3). To a reaction mixture containing α,α,α,α-
5,10,15,20-tetrakis-(2-(N-[(2-phenylmethoxy)ethylureido])phenyl)-
porphyrin (2) (0.165 g, 0.119 mmol) dissolved in ethanethiol (22.14
mL, 309 mmol) was added BF3·etherate (0.83 mL, 6.749 mmol).25
The reaction was kept under nitrogen and allowed to stir at room
temperature for 4 h. At this time, the reaction was quenched with a
saturated solution of NaHCO3, and the mixture extracted with ethyl
acetate (3 × 50 mL). The organic layers were combined, and a
precipitate formed that was collected by filtration. This resultant crude
solid was dissolved in a minimum amount of DMF and added to a
radial chromatography plate and air-dried overnight. The product was
purified using silica gel radial chromatography (CH2Cl2/methanol/
water; 84/15/1), affording a pure purple solid (0.031 g, 0.030 mmol,
25%): mp 218 °C, decomp; UV/vis DMF λmax (ln ε): 422.5 (14.31),
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515 (11.91), 550 (10.66), 590 (10.76), 647 (10.13); H NMR (400
α,α,α,α,-5,10,15,20-Tetrakis-(2-(N-(propylureido))phenyl)-
porphyrin (5). To a solution of dry α,α,α,α-tetra-(o-aminophenyl)-
porphyrin (1) (0.413 g, 0.612 mmol) dissolved in dry CH2Cl2 (12.2
mL) was added propyl isocyanate (0.46 mL, 4.90 mmol) via syringe in
one portion, and the reaction mixture was stirred overnight in a
glovebox. The solution was removed from the box and then washed
with water (3 × 25 mL) and with brine (1 × 50 mL). The combined
organic layers were dried over sodium sulfate and concentrated under
reduced pressure. The crude solid was purified using silica gel
chromatography (20% CH2Cl2 in ethyl acetate), and the resultant solid
was recrystallized from CH2Cl2/hexanes to yield a pure purple solid
(0.126 g, 0.124 mmol, 20%): mp 232 °C, decomp; UV/vis CHCl3 λmax
(ln ε): 422 (12.12), 516 (9.51), 554 (8.40), 590 (8.45), 646 (7.86);1H
NMR (400 MHz, DMSO-d6) δ −2.685 (s, broad, 2H), 0.50 (t, 12H, J
= 7.4 Hz), 1.01 (quartet, 8H, J = 7.3 Hz), 2.64 (quartet, 8H, J = 6.4
Hz), 5.89 (t, broad, 4H), 6.95 (s, broad, 4H, J = 5.4 Hz), 7.35 (t, 4H, J
= 11.3 Hz), 7.77−7.72 (m, 8H), 8.35 (d, 4H, J = 8.8 Hz), 8.74 (s, 8H);
13C NMR (100 MHz, DMSO) δ 11, 23, 41, 116, 121.1, 121.5, 129,
MHz, DMSO-d6) δ −2.66 (s, broad, 2H), 2.80−2.81 (m, 8H), 3.09−
3.10 (m, 8H), 4.35 (s, broad, 4H), 6.16 (t, broad, 4H, J = 5.4 Hz), 7.29
(t, 4H, J = 7.4 Hz), 7.38 (s, broad, 4H), 7.61 (d, 4H, J = 7.6 Hz), 7.72
(t, 4H, J = 7.9 Hz), 8.48 (d, 4H, J = 8 Hz), 8.73 (s, 8H); 13C NMR
(100 MHz, DMSO) δ 42, 60, 116, 120.6, 120.7, 129, 130, 135, 140,
155; HRMS (ESI) cald for C56H55N12O 8 (M + H)+ 1023.4266, found
1023.4265.
2-(2-(2-Ethoxyethoxy)ethoxy)ethyl Tosylate (7a).26 Triethy-
lene glycol monoethyl ether (10 g, 56.11 mmol) was dissolved in THF
(20 mL) and the solution brought to 0 °C in an ice bath, whereupon a
solution of sodium hydroxide (4.6 g, 115 mmol) dissolved in water
18.4 mL) was added to the stirred, cold mixture that was kept under
nitrogen. A solution of toluensulfonyl chloride (13.799 g, 72.38 mmol)
dissolved in THF (20 mL) was added dropwise over 15 min, and the
reaction mixture was allowed to warm to ambient temperature and
stirred for 2 h. Diethyl ether (150 mL) was added to the reaction
mixture, and the two layers were separated. The organic layer was
washed with 1 M NaOH (3 × 12.5 mL) without shaking and washed
with water (2 × 12.5 mL). The organic layer was dried with sodium
sulfate and concentrated under reduced pressure to afford a yellow
liquid (15.61 g, 46.97 mmol, 84%), which was used in the next
131, 135, 140, 155; HRMS (ESI) cald for C60H63N12O4 (M + H)+
1015.5095, found 1015.5139; HRMS (ESI) cald forC60H62N12O4Na
(M + Na)+ 1037.4915, found 1037.4960.
1,2-Distearoyl-sn-glycero-3-phospho-sn-1-glycerol, Tetra-
butylammonium Salt (9). 0.52 g (0.65 mmol) amount of 1,2-
distearoyl-sn-glycero-3-phospho-sn-1-glycerol, sodium (8) (Genzyme
Pharmaceuticals, Liestal, Switzerland) was placed in a ternary mixture
of 2 mL of 1.5 M HCl, 12 mL of 2-propanol, and 11 mL of
chloroform. The mixture was stirred at room temperature until
complete solvation occurred (usually around 5 min), at which time the
solvents were removed under reduced pressure (using a rotovap
attached to a Welch pump) at room temperature, which furnished a
white slurry. The neutral phospholipid was precipitated using cold
acetone and collected by filtration as a white, waxy solid (0.47 g, 0.6
mmol, 93% yield). This material was characterized by 31P NMR, 13C
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reaction without further purification: H NMR (400 MHz, CDCl3) δ
1.18 (t, 3H, J = 7 Hz), 2.42 (s, 3H), 3.49 (quartet, 2H, J = 6.9 Hz),
3.61−3.53 (m, 8H), 3.66 (t, 2H, J = 4.8 Hz), 4.14 (t, 2H, J = 4.8 Hz),
7.32 (d, 2H, J = 8.4 Hz), 7.78 (d, 2H, J = 8.4 Hz); 13C NMR (100
MHz, CDCl3) δ 15, 22, 67, 68.9, 69.5, 70, 70.7, 70.9, 71, 128, 130, 133,
145.00.
2-(2-(2-Ethoxyethoxy)ethoxy)ethylamine (7b).26 2-(2-(2-
Ethoxyethoxy)ethoxy)ethyl tosylate (10a) (3 g, 9.02 mmol) was
dissolved in DMF (6.2 mL) under a nitrogen atmosphere, and to this
solution was added potassium phthalimide (2.22 g, 11.99 mmol). The
reaction mixture was heated to 110 °C and stirred for 3 h. After
cooling to rt, diethyl ether (39 mL) was added to the solution and the
resultant precipitate was filtered. The filtrate was washed with 1 M
NaOH (2 × 13 mL) and water (1 × 13 mL). The organic layer was
dried with sodium sulfate and concentrated under reduced pressure.
The crude phthalimide product was dissolved in 6.4 mL of a hydrazine
monohydrate/ethanol (1/1 v/v) mixture and heated to 110 °C
overnight under a nitrogen atmosphere. The reaction mixture was
cooled to rt and extracted with toluene (4 × 21 mL). The combined
organic layers were concentrated under reduced pressure to afford 7b
as a yellow oil (0.99 g, 5.56 mmol, 62%), which was used in the next
NMR, and H NMR. The 31P NMR spectrum showed a single, well-
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resolved peak at 0.8 ppm (in ternary mixture of 3:3:0.5
CD3OD:CDCl3:D2O) while the peak from that of the sodium salt
was at 1.6 ppm in the same solvent mixture. The melting point of the
neutral acid was 134−136 °C, while that of the sodium salt was over
200 °C. The material (0.47 g, 0.6 mmol) was resuspended in 30 mL of
chloroform, and 0.125 g (0.48 mmol) of tetrabutylammonium
hydroxide was added to the mixture. The mixture was stirred at
room temperature for 5 min to dissolve the base and stirred an
additional 5 min before removal of the solvent under high vacuum at
F
dx.doi.org/10.1021/jo302228w | J. Org. Chem. XXXX, XXX, XXX−XXX