Polyamides Containing Imidazole and Pyrrole Amino Acids
J. Am. Chem. Soc., Vol. 118, No. 26, 1996 6145
reaction was cooled to room temperature and washed with ethyl ether
mixture was filtered concentrated in Vacuo to a volume of 500 mL,
and 5 L of cold anhydrous ethyl ether was added. Addition of HCl
gas provided a white precipitate. The solution was cooled at -20 °C
for 4 h and the precipitate collected by vacuum filtration and dried in
(
1
×
4 × 1000 mL), the pH of the aqueous layer reduced to ca. 3 with
0% (v/v) H SO , and the mixture was extracted with ethyl acetate (4
2000 mL). The combined ethyl acetate extracts were dried (sodium
2
4
sulfate) and concentrated in Vacuo to provide a tan foam. The foam
was dissolved in 500 mL of DCM and 2 L petroleum ether added, and
the resulting slurry was concentrated in Vacuo. The reaction mixture
was redissolved and concentrated three additional times to provide 320
g (78% yield) of 6 as a fine white powder: TLC (7:2 benzene/ethyl
Vacuo to provide 75 g (78% yield) of 10 as a fine white powder: TLC
1
(7:2 benzene/ethyl acetate) R
(DMSO-d
f
(amine) 0.3, R
f
(salt) 0.0; H NMR
6
) δ 10.11 (br s, 3 H), 7.43 (s, 1 H), 4.28 (q, 2 H, J ) 7.1
13
Hz), 3.92 (s, 1 H), 1.28 (t, 3 H, J ) 7.1 Hz) C NMR (DMSO-d ) δ
6
157.6, 132.6, 117.4, 117.3, 61.8, 36.6, 14.5; IR (KBr) 3138, 2883, 1707,
acetate v/v) R
f
(ester) 0.8, R
f
(acid) 0.1. (ethyl acetate), R
f
(acid) 0.6;
1655, 1492, 1420, 1314, 1255, 1152, 1057, 837, 776; FABMS m/e
169.085 (169.084 calcd for C H N O ).
7 11 3 2
1
H NMR (DMSO-d ) δ 12.10 (s, 1 H), 9.05 (s, 1 H), 7.02 (s, 1 H),
6
1
3
6
1
2
.55 (s, 1 H), 3.75 (s, 3H), 1.41 (s, 9 H); C NMR (DMSO-d
62.4, 153.2, 123.3, 120.1, 119.2, 107.9, 78.9, 36.6, 28.7; IR(KBr) 3350,
978, 1700, 1670, 1586, 1458, 1368, 1247, 1112, 887, 779; FABMS
6
) δ
4-[(tert-Butoxycarbonyl)amino]-1-methylimidazole-2-carboxyl-
ic Acid (11). The imidazole amine 10 (75 g, 395 mmol) was dissolved
in 200 mL of DMF. DIEA (45 mL, 491 mmol) was added followed
by di-tert-butyl dicarbonate (99 g, 491 mmol). The mixture was shaken
at 60 °C for 18 h, allowed to assume room temperature, and partitioned
between 500 mL of brine and 500 mL of ethyl ether. The ether layer
was extracted (2 × 200 mL each) with 10% citric acid, brine, saturated
sodium bicarbonate, and brine, dried over sodium sulfate, and concen-
trated in Vacuo to yield the Boc-ester contaminated with 20% Boc-
m/e 241.119 (M + H 241.119 calcd for C11
17 2 4
H N O ).
1
,2,3-Benzotriazol-1-yl 4-[(tert-Butoxycarbonyl)amino]-1-meth-
ylpyrrole-2-carboxylate (7). Boc-Py-acid 6 (31 g, 129 mmol) was
dissolved in 500 mL of DMF, and HOBt (17.4 g, 129 mmol) was added
followed by DCC (34 g, 129 mmol). The reaction mixture was stirred
for 24 h and then filtered dropwise into a well-stirred solution of 5 L
of ice water. The precipitate was allowed to sit for 15 min at 0 °C and
then collected by filtration. The wet cake was dissolved in 500 mL of
DCM, and the organic layer was added slowly to a stirred solution of
cold petroleum ether (4 °C). The mixture was allowed to stand at -20
1
anhydride as indicated by H NMR. The Boc-ester, used without further
purification, was dissolved in 200 mL of 1 M NaOH. The reaction
mixture was allowed to stand for 3 h at 60 °C with occasional agitation.
The reaction mixture was cooled to 0 °C and carefully neutralized with
1 M HCl to pH 2, at which time a white gel formed. The gel was
collected by vacuum filtration and frozen before drying, and remaining
water was lyophilized to yield 10 as a white powder (51 g, 54%
°
C for 4 h and then collected by vacuum filtration and dried in Vacuo
to provide 39 g (85% yield) of 7 as a finely divided white powder:
1
TLC (7:2 benzene/ethyl acetate v/v) R
f
0.6; H NMR (DMSO-d
.43 (s, 1 H), 8.12 (d, 1 H, J ) 8.4 Hz), 7.80 (d, 1 H, J ) 8.2 Hz),
.64 (t, 1 H, J ) 7.0 Hz), 7.51 (m, 2 H), 7.18 (s, 1 H), 3.83 (s, 3 H),
6
) δ
9
7
1
1
yield): 1H NMR (DMSO-d
6
) δ 9.47 (s, 1 H), 7.13 (s, 1 H), 3.85 (s, 3
) δ 160.9, 152.9, 137.5, 134.5,
H), 1.41 (s, 9 H); 1 C NMR (DMSO-d
3
6
1
3
.45 (s, 9 H); C NMR (DMSO-d
6
) δ 156.5, 153.3, 143.2, 129.6, 129.2,
112.4, 79.5, 35.7, 28.6; IR (KBr) 3448, 2982, 1734, 1654, 1638, 1578,
1357, 1321, 1249, 1163, 799; FABMS m/e 241.105 (241.106 calcd for
25.7, 125.2, 124.6, 120.3, 112.8, 110.3, 109.8, 79.5, 36.8, 28.6; IR
(
1
KBr) 3246, 3095, 2979, 1764, 1711, 1588, 1389, 1365, 1274, 1227,
160, 1101, 999, 824, 748; FABMS m/e 358.152 (M + H 358.151
calcd for C17 ).
Ethyl 1-Methylimidazole-2-carboxylate (8). N-Methylimidazole
320 g, 3.9 mol) was combined with 2 L of acetonitrile and 1 L of
C
10
H
15
N
3
O
4
).
4-[[[4-[(tert-Butoxycarbonyl)amino]-1-methylpyrrol-2-yl]carbon-
H
20
N
5
O
4
yl]amino]-1-methylimidazole-2-carboxylic acid (12) was prepared as
described below for 13 substituting Boc-Pyrrole acid for Boc-γ-
(
aminobutyric acid (4.1 g, 91% yield): 1H NMR (DMSO-d
6
) δ 10.58
(s, 1 H), 9.08 (s, 1 H), 7.57 (s, 1 H), 6.97 (s, 1 H), 6.89 (s, 1 H), 3.89
(s, 3 H), 3.75 (s, 3 H), 1.35 (s, 9 H); 13C NMR (DMSO-d
) δ 160.36,
triethylamine in a 12 L flask equipped with a mechanical stirrer, and
the solution was cooled to -20 °C. Ethyl chloroformate (1000 g, 9.2
mol) was added with stirring, the temperature being kept between -20
and -25 °C. The reaction mixture was allowed to slowly warm to
room temperature and stirred for 36 h. Precipitated triethylamine
hydrochloride was removed by filtration and the solution concentrated
in Vacuo at 65 °C. The resulting oil was purified by distillation under
6
159.1, 153.4, 137.9, 132.3, 122.8, 122.3, 118.5, 115.5, 105.5, 105.4,
78.8, 28.7, 24.9; IR 3346, 2929, 1685, 1618, 1529, 1342, 1274, 1179,
997, 761; FABMS m/e 364.161 (364.162 calcd for C16H N O ).
22 5 5
4-[[[3-[(tert-Butoxycarbonyl)amino]propyl]carbonyl]amino]-1-
methylimidazole-2-carboxylic Acid (13). To a solution of Boc-γ-
aminobutyric acid (10 g, 49 mmol) in 40 mL of DMF was added 1.2
equiv of HOBt (7.9 g, 59 mmol) followed by 1.2 equiv of DCC (11.9
g, 59 mmol). The solution was stirred for 24 h and the DCU removed
by filtration. Separately, to a solution of ethyl 4-nitro-1-methylimid-
azole-2-carboxylate (9.8 g, 49 mmol) in 20 mL of DMF was added
Pd/C catalyst (10%, 1 g), and the mixture was hydrogenated in a Parr
reduced pressure (2 Torr, 102 °C) to provide 8 as a white solid (360 g,
8
1
2% yield): TLC (7:2 benzene/ethyl acetate v/v) R
f
0.2; H NMR
(
DMSO-d
6
) δ 7.44 (d, 1 H, J ) 2.8 Hz), 7.04 (d, 1 H, J ) 2.8 Hz),
.26 (q, 2 H, J ) 3.5 Hz), 3.91 (s, 3 H), 1.26 (t, 3 H, J ) 3.5 Hz); 13
) δ 159.3, 129.1, 127.7, 61.0, 36.0, 14.5; IR(KBr)
403, 3111, 2983, 1713, 1480, 1422, 1262, 1134, 1052, 922, 782, 666;
FABMS m/e 155.083 (M + H 155.083 calcd for C ).
4
C
NMR (DMSO-d
6
3
7
H
11
N O
2 2
bomb apparatus (500 psi of H ) for 2 h. The catalyst was removed by
2
Ethyl 1-Methyl-4-nitroimidazole-2-carboxylate (9). Compound
was carefully dissolved in 1000 mL of concentrated sulfuric acid
filtration through Celite and the filtrate immediately added to the OBt
ester solution. An excess of DIEA (15 mL) was then added and the
reaction mixture stirred at 60 °C for 8 h. The reaction mixture was
then added dropwise to a stirred solution of ice water and the resulting
precipitate collected by vacuum filtration to provide crude ethyl 4-[[[3-
[(tert-butoxycarbonyl)amino]propyl]carbonylamino]-1-methylimidazole-
2-carboxylate (5 g, 14.1 mmol). To the crude ester dissolved in 50
mL of methanol was added 50 mL of 1 M NaOH, and the resulting
mixture was stirred for 6 h at 60 °C. Excess methanol was removed
in Vacuo and the resulting solution acidified by the addition of 1 M
HCl. The resulting precipitate was collected by vacuum filtration and
dried in Vacuo to yield a brown powder (4.4 g, 89% yield): H NMR
6
(DMSO-d ) δ 10.50 (s, 1 H), 7.45 (s, 1 H), 6.82 (t, 1 H, J ) 3.6 Hz),
3.86 (s, 3 H), 2.86 (q, 2 H, J ) 4.6 Hz), 2.22 (t, 2 H, J ) 7.4 Hz), 1.57
(quintet, 2 H, J ) 5.9 Hz), 1.29 (s, 9 H); IR 3416, 2950, 2841, 1650,
1538 1449, 1392, 1250, 1165, 1108; FABMS m/e 326.160 (326.159
8
cooled to 0 °C; 90% nitric acid (1 L) was slowly added, a temperature
of 0 °C being maintained. The reaction mixture was then refluxed
with an efficient condenser (-20 °C) in a well-ventilated hood for 50
min. The reaction mixture was cooled with an ice bath and quenched
by pouring onto 10 L of ice. The resulting blue solution was then
extracted with 20 L of DCM, and the combined extracts were dried
sodium sulfate) and concentrated in Vacuo to yield a tan solid, which
was recrystallized from 22 L of 21:1 carbon tetrachloride/ethanol. The
resulting white crystals were collected by vacuum filtration to provide
(
1
pure 9 (103 g, 22% yield): TLC (7:2 benzene/ethyl acetate v/v) R
f
1
0
3
1
1
2
.5; H NMR (DMSO-d
.97 (s, 3 H), 1.29 (t, 3 H, J ) 6.0 Hz); C NMR (DMSO-d
6
) δ 8.61 (s, 1 H), 4.33 (q, 2 H, J ) 6.4 Hz),
1
3
6
) δ 158.2,
45.4, 135.3, 127.4, 62.2, 37.3, 14.5; IR (KBr) 3139, 1719, 1541, 1498,
381, 1310, 1260, 1122, 995, 860, 656; FABMS m/e 200.066 (M + H
00.067 calcd for C
7
H N
10 3
O
4
).
22 4 5
calcd for C14H N O ).
Ethyl 4-Amino-1-methylimidazole-2-carboxylate Hydrochloride
10). The nitroimidazole ethyl ester 9 (103 g, 520 mmol) was dissolved
in 5 L of 1:1 ethanol/ethyl acetate, 20 g of 10% Pd/C slurried in 500
mL of ethyl acetate was added, and the mixture was stirred under a
slight positive pressure of hydrogen (ca. 1.1 atm) for 48 h. The reaction
Solid Phase Syntheses. Activation of Imidazole-2-carboxylic
acid,2a γ-aminobutyric acid, Boc-glycine, and Boc-â-alanine. The
appropriate amino acid or acid (2 mmol) was dissolved in 2 mL of
DMF. HBTU (720 mg, 1.9 mmol) was added followed by DIEA (1
mL) and the solution lightly shaken for at least 5 min.
(