Synthesis of â-Substituted Chlorin Building Blocks
J . Org. Chem., Vol. 65, No. 23, 2000 7927
111.2, 121.3, 127.9, 130.0, 130.4, 134.1, 137.5, 149.8; FAB-MS
obsd 399.0336, calcd 399.0331 (C16H18INO3).
bromodipyrromethane is unstable but can be stored for several
weeks at 0 °C: mp 160 °C dec; 1H NMR δ 2.44 (s, 3H), 4.09 (s,
2H), 6.12 (d, J ) 3.0 Hz, 1H), 6.16 (m, 1H), 6.89 (m, 1H), 7.14
(d, J ) 7.8 Hz, 2H), 7.30 (d, J ) 7.8 Hz, 2H), 7.71 (d, J ) 8.1
Hz, 2H), 7.80 (d, J ) 8.1 Hz, 2H), 10.33 (br, 1H), 11.59 (br,
1H); 13C NMR δ 21.6, 24.9, 91.1, 97.9, 110.2, 110.5, 122.8,
123.5, 125.4, 129.2, 130.2, 130.0, 130.8, 135.2, 135.4, 137.5,
139.9, 142.8, 186.1; FAB-MS obsd 543.9642, calcd 543.9647.
Anal. Calcd for C23H18BrIN2O: C, 50.7; H, 3.3; N, 5.1. Found:
C, 51.3; H, 3.5; N, 5.2.
3-[4-[2-(Tr im et h ylsilyl)et h yn yl]p h en yl]-9-(4-m et h yl-
ben zoyl)d ip yr r om eth a n e (12). Samples of 10 (279 mg, 0.599
mmol), Pd2(dba)3 (42 mg, 0.046 mmol), Ph3As (113 mg, 0.369
mmol), and CuI (9 mg, 0.047 mmol) were added to a 25-mL
Schlenk flask. The flask was evacuated and purged with argon
three times. Then deaerated anhydrous THF/triethylamine (6
mL, 1:1) was added followed by trimethylsilylacetylene (127
µL, 0.90 mmol). The flask was sealed and immersed in an oil
bath (37 °C), and the mixture was stirred overnight. Then CH2-
Cl2 (20 mL) was added, and the mixture was filtered through
a pad of Celite, washed several times with CH2Cl2, and
concentrated. The residue was purified by flash column
chromatography [silica, hexanes/ethyl acetate (3:1)] to afford
a yellow solid (262 mg, quantitative): mp 126-127 °C; 1H
NMR δ 0.26 (s, 9H), 2.43 (s, 3H), 4.19 (s, 2H), 6.16 (m, 1H),
6.28 (m, 1H), 6.55 (m, 1H), 6.85 (m, 1H), 7.28 (d, J ) 8.7 Hz,
2H), 7.38 (d, J ) 8.1 Hz, 2H), 7.49 (d, J ) 8.7 Hz, 2H), 7.77 (d,
J ) 8.1 Hz, 2H), 9.51 (br, 1H), 10.96 (br, 1H); 13C NMR δ 0.0,
21.5, 25.3, 105.4, 108.6, 110.3, 117.4, 119.9, 121.5, 122.3, 124.1,
127.6, 129.0, 129.1, 130.7, 132.0, 135.5, 137.0, 139.5, 142.6,
185.2; FAB-MS obsd 436.1972, calcd 436.1971. Anal. Calcd for
3-(4-Iod op h en yl)-10-N-(ter t-b u t oxyca r b on yl)d ip yr r o-
m eth a n e (8). A solution of 7 (1.2 g, 3.0 mmol) and pyrrole
(3.36 mL, 48 mmol) in 1,4-dioxane (36 mL) at room temper-
ature was treated with 10% aqueous HCl (6.0 mL). The
reaction was monitored by TLC [silica, hexanes/ethyl acetate
(4:1)]. After 4 h, saturated aqueous NaHCO3 (50 mL) and
water (50 mL) were added and the mixture was extracted with
CH2Cl2. The combined organic layers were washed with water
and brine, dried (Na2SO4), concentrated, and purified by flash
column chromatography [silica, hexanes/ethyl acetate (4:1)].
A nonpolar product was isolated in minor amount (uncharac-
terized). The desired product was obtained as a pale brown
solid (920 mg, 68% yield): mp 128-129 °C; 1H NMR δ 1.57 (s,
9H), 4.18 (s, 2H), 5.87 (br, 1H), 6.10 (m, 1H), 6.22 (d, J ) 3.0
Hz, 1H), 6.64 (m, 1H), 7.16 (d, J ) 8.0 Hz, 2H), 7.24 (d, J )
3.6 Hz, 1H), 7.71 (d, J ) 8.0 Hz, 2H), 8.78 (br, 1H); 13C NMR
δ 24.6, 27.8, 84.3, 92.1, 105.8, 107.9, 111.6, 116.3, 121.0, 126.8,
128.5, 130.4, 130.8, 135.0, 137.4, 150.0; FAB-MS obsd 448.0659,
calcd 448.0648. Anal. Calcd for C20H21IN2O2: C, 53.6; H, 4.7;
N, 6.3. Found: C, 54.1; H, 4.9; N, 5.9.
3-(4-Iod op h en yl)-9-(4-m et h ylb en zoyl)-10-N-(ter t-b u t -
oxyca r bon yl)d ip yr r om eth a n e (9). A solution of 8 (448 mg,
1.0 mmol) in anhydrous THF (15 mL) under argon at 0 °C was
treated slowly with EtMgBr (1 M in THF, 2.5 mL, 2.5 mmol).
The mixture was stirred for 30 min at 0 °C. Then, p-toluoyl
chloride (200 µL, 1.5 mmol) was added slowly and stirring was
continued for 1 h at 0 °C. The reaction was quenched with
saturated aqueous NH4Cl and extracted with CH2Cl2. The
combined organic layers were washed with water and brine,
dried (Na2SO4), and concentrated. The product was purified
by flash column chromatography [silica, hexanes/ethyl acetate
(4:1)], affording a pale white solid (375 mg, 66%): mp 120-
C
28H28N2OSi: C, 77.0; H, 6.5; N, 6.4. Found: C, 76.3; H, 6.3;
N, 6.3.
1-Br om o-3-[4-[2-(t r im et h ylsilyl)et h yn yl]p h en yl]-9-(4-
1
121 °C; (due to possible rotamers the H NMR and 13C NMR
m eth ylben zoyl)d ip yr r om eth a n e (13). Following the pro-
cedure for the synthesis of 11, treatment of 12 (150 mg, 0.34
mmol) with NBS (60 mg, 0.34 mmol) afforded a pale yellow
spectra are not very clean) 1H NMR δ 1.56 (s, 9H), 2.42 (s,
3H), 4.29 (s, 2H), 5.95 (m, 1H), 6.26 (m, 1H), 6.76 (m, 1H),
7.09 (m, 2H), 7.25 (m, 2H), 7.31 (m, 1H), 7.71 (d, J ) 8.7 Hz,
2H), 7.77 (d, J ) 8.1 Hz, 2H), 9.95 (br, 1H); 13C NMR δ 25.2,
27.8, 31.7, 84.8, 92.3, 109.3, 111.5, 119.6, 121.5, 125.8, 126.3,
128.9, 129.0, 130.2, 130.6, 134.7, 135.8, 137.5, 138.6, 142.0,
149.7, 183.8. Anal. Calcd for C28H27IN2O3: C, 59.4; H, 4.8; N,
5.0. Found: C, 59.4; H, 4.6; N, 5.1.
1
solid (160 mg, 91%): mp 140 °C dec; H NMR δ 0.26 (s, 9H),
2.44 (s, 3H), 4.12 (s, 2H), 6.17 (m, 2H), 6.89 (m, 1H), 7.31 (m,
4H), 7.50 (d, J ) 9.0 Hz, 2H), 7.80 (d, J ) 8.1 Hz, 2H), 10.16
(br, 1H), 11.42 (br, 1H); 13C NMR δ 0.0, 21.5, 25.0, 94.1, 97.9,
105.2, 110.3, 110.5, 120.4, 123.3, 125.5, 127.7, 129.2, 130.7,
132.1, 135.4, 135.9, 139.7, 142.8, 185.9; FAB-MS obsd 514.1079,
calcd 514.1076. Anal. Calcd for C28H27BrN2OSi: C, 65.2; H,
5.3; N, 5.4. Found: C, 65.1; H, 5.2; N, 5.3.
3-(4-Iod op h e n yl)-9-(4-m e t h ylb e n zoyl)d ip yr r om e t h -
a n e (10). Following a standard method for the deprotection
of BOC-protected pyrroles,20 a solution of 9 (328 mg, 0.58
mmol) in anhydrous THF (4 mL) under argon at room
temperature was treated with methanolic NaOMe (0.7 mL of
the supernatant from the mixture prepared from 200 mg of
NaOMe and 1.0 mL of MeOH). After 25 min, the reaction was
quenched with a mixture of hexanes and water (20 mL, 1:1).
The mixture was extracted with ethyl acetate. The combined
organic layers were washed with water and brine, dried (Na2-
SO4), and concentrated. Purification by flash column chroma-
tography [silica, hexanes/ethyl acetate (3:1)] afforded a pale
3-(4-Iod op h en yl)d ip yr r om eth a n e (14). Following the
deprotection procedure used to prepare 10, a sample of 8 (225
mg, 0.50 mmol) in anhydrous THF (4 mL) under argon at room
temperature was treated with methanolic NaOMe (0.6 mL of
the supernatant of the mixture prepared from 200 mg of
NaOMe and 1.0 mL of MeOH). After 15 min, the reaction was
quenched with hexanes and water (14 mL, 1:1). The resulting
mixture was extracted with ethyl acetate. The combined
organic layers were washed with water and brine, dried (Na2-
SO4), and concentrated. The residue was passed through a
filtration column to yield a light brown solid (160 mg, 92%).
Analytical data are in accord with the literature.14
3-(4-Iod op h e n yl)-1-(4-m e t h ylb e n zoyl)d ip yr r om e t h -
a n e (16). Following a general monoacylation procedure for
unprotected dipyrromethanes,5 EtMgBr (1 M solution in THF,
2.2 mL, 2.2 mmol) was added to a solution of 14 (385 mg, 1.1
mmol) in anhydrous THF (14 mL). After the mixture was
stirred for 10 min, the flask was cooled to -78 °C and a
solution of pyridyl thioester 15 (255 mg, 1.1 mmol) in anhy-
drous THF (3 mL) was added slowly. After a few min, the
cooling bath was removed and stirring was continued for 1 h.
Then saturated aqueous NH4Cl and water were added, and
the mixture was extracted with CH2Cl2. The combined organic
layers were washed with water and brine, dried (Na2SO4), and
concentrated. TLC analysis [silica, hexanes/ethyl acetate
(3:1)] showed two components with Rf ) 0.34 (minor) and Rf
) 0.29 (major). The two regioisomers formed were purified by
two successive flash columns [silica, hexanes/ethyl acetate (3:
1)], affording the minor isomer 16 (130 mg, 25%) and the major
isomer 10 (270 mg, 53%). The identity of 10 was verified by
1
brown solid (216 mg, 80%): mp 185-186 °C; H NMR δ 2.43
(s, 3H), 4.17 (s, 2H), 6.15 (m, 1H), 6.24 (m, 1H), 6.56 (m, 1H),
6.85 (m, 1H), 7.17 (m, 2H), 7.28 (m, 2H), 7.69 (m, 2H), 7.77 (d,
J ) 7.8 Hz, 2H), 9.43 (br, 1H), 10.88 (br, 1H); 13C NMR δ 21.6,
25.2, 90.6, 108.6, 110.3, 117.4, 121.1, 122.3, 123.9, 129.0, 129.1,
130.0, 130.7, 135.5, 136.2, 137.4, 139.4, 142.6, 185.2; FAB-MS
obsd 466.0561, calcd 466.0542. Anal. Calcd for C23H19IN2O: C,
59.2; H, 4.1; N, 6.0. Found: C, 59.3; H, 4.2; N, 5.9.
1-Br om o-3-(4-iod op h en yl)-9-(4-m et h ylb en zoyl)d ip yr -
r om eth a n e (11). Following our earlier procedure,2 a solution
of 10 (120 mg, 0.26 mmol) in anhydrous THF (6 mL) was cooled
to -78 °C under argon. Recrystallized NBS (46 mg, 0.26 mmol)
was added and the reaction mixture was stirred for 1 h (-78
°C). Then the mixture was quenched with a mixture of hexanes
and water (20 mL, 1:1) and allowed to warm to 0 °C. The
aqueous portion was extracted with reagent-grade ether and
the combined organic layers were dried over K2CO3. The
solvent was evaporated under vacuum at room temperature.
Purification by flash column chromatography [silica, hexanes/
ether (2:1)] afforded a yellow solid (120 mg, 85%). The