2582 J. Am. Chem. Soc., Vol. 118, No. 11, 1996
Keating and Armstrong
1-Formamidocyclohexene.22 1-Cyano-1-formamidocyclohexane (7)
(2.0 g, 13.2 mmol) and anhydrous potassium tert-butoxide (5.9 g, 52.6
mmol) were dissolved in 50 mL of THF. After heating to reflux for
6 h, the reaction mixture was poured into 200 mL of 0.5 M Na2CO3.
The layers were separated and extracted 3× with ethyl acetate. The
organics were combined and dried over Na2SO4. Silica gel chroma-
tography (1:1 to 1:2 hexanes/ethyl acetate) yielded 1.22 g (74%) of a
white crystalline solid along with 177 mg (9%) of starting material.
The title compound exists as two rotamers in a 3:1 ratio at room
temperature in chloroform. 1H NMR (400 MHz): (major rotamer) δ
8.35 (d, 1, J ) 11.5), 7.55 (br, 1), 5.30 (t, 1, J ) 3.9), 2.15-2.07 (m,
4), 1.73-1.58 (m, 4); (minor rotamer) δ 8.21 (d, 1, J ) 13.5), 8.15 (d,
1, J ) 1.6), 6.12 (t, 1, J ) 3.9), 2.33 (m, 4), 1.85 (m, 4).
6.87 (d, 2, J ) 8.6), 4.37 (s, 1), 4.12 (dd, 1, J ) 18.3, 6.0), 4.00 (dd,
1, J ) 18.3, 5.3), 3.82 (d, 1, J ) 13.0), 3.80 (s, 3), 3.78 (d, 1, J )
13.0), 3.77 (s, 3), 2.45 (br, 1). HRMS (EI): m/z (M+) calcd 343.1658,
found 343.1659.
(R,S)-1-(1-Piperidino)phenylacetamide (29). IR (neat): 3403,
3185, 2934, 1661. 1H NMR (500 MHz): δ 7.35-7.27 (m, 5), 7.16
(br, 1), 5.51 (br, 1), 3.85 (s, 1), 2.39 (br, 4), 1.63 (br, 4), 1.42 (br, 2).
HRMS (EI): m/z [(M + H)+] calcd 219.1497, found 219.1499.
Dimethyl 1-(4-Methoxybenzyl)-2-methyl-5-phenylpyrrole-3,4-di-
carboxylate (34). Yield: 63%. IR (neat): 1707, 1514, 1248, 1175.
1H NMR (400 MHz): δ 7.33-7.24 (m, 5), 6.80 (d, 2, J ) 8.7), 6.77
(d, 2, J ) 8.9), 4.91 (s, 2), 3.83 (s, 3), 3.79 (s, 3), 3.65 (s, 3), 2.37 (s,
3). 13C NMR (101 MHz): δ 166.1, 165.4, 158.9, 135.6, 135.3, 130.4,
130.3, 128.6, 128.2, 126.8, 115.0, 114.2, 112.1, 55.2, 51.6, 51.4, 47.2,
11.4. HRMS (EI): m/z [(M + H)+] calcd 394.1654, found 394.1652.
Dimethyl 1-butyl-2,5-diphenylpyrrole-3,4-dicarboxylate (35). Yield
) 35%. IR (neat): 2953, 1717, 1198, 1167. 1H NMR (400 MHz): δ
7.45-7.40 (m, 10), 3.68 (t, 2, J ) 7.7), 3.65 (s, 6), 1.14 (tt, 2, J ) 7.5,
7.5), 0.83 (tq, 2, J ) 7.5, 7.5), 0.49 (t, 3, J ) 7.4). 13C NMR (101
MHz): δ 165.4, 136.5, 131.0, 130.5, 128.7, 128.2, 114.3, 51.6, 44.6,
32.3, 19.3, 13.1. HRMS (EI): (M+H)+ calcd 392.1862, found
392.1866.
1-Isocyanocyclohexene (8).20,22,23 1-Formamidocyclohexene (6.0 g,
48.0 mmol) and diazabicyclo[2.2.2]octane (DABCO, triethylenedi-
amine) (16.2 g, 144.0 mmol) were dissolved in 120 mL of CH2Cl2. To
the cooled solution (0 °C), 10% w/v triphosgene in CH2Cl2 (95 mL,
32.0 mmol) was added dropwise. After stirring for 0.5 h, the reaction
mixture was poured into 500 mL of a 0.5 M Na2CO3 solution. This
was extracted 3× with CH2Cl2, dried over Na2SO4, and rapidly
chromatographed on triethylamine-deactivated silica gel (9:1 hexanes/
ethyl acetate) to yield 3.1 g (60%) of a clear, colorless oil. The product
is conveniently stored under argon at -30 °C as a 1 M solution in
hexanes. 1H NMR: δ 6.05 (m, 1), 2.23 (m, 2), 2.11 (m, 2), 1.69 (m,
2) 1.57 (m, 2).
(R,S)-2-(N-Butylbenzamido)phenylacetic Acid (11). NMR spectra
of the title compound suffer extreme peak broadening due to rotational
isomerism. This compound was characterized by 1H NMR and HRMS,
and by conversion into 12. 1H NMR (400 MHz): δ 7.47-7.38 (m,
5), 5.67 (s, 1), 3.38 (br, 1), 3.24 (br, 1), 1.41 (br, 1), 1.24 (br, 1), 0.96-
0.86 (br, 2), 0.67 (br, 3). HRMS (EI): m/z (M+) calcd 311.1521, found
311.1521.
Methyl 1-(4-Methoxybenzyl)-2-methyl-5-phenyl-3-pyrrolecar-
boxylate (36). Yield: 24% (isolated as a 3.3:1 mixture with 37).
1
Assignment of major and minor regioisomers was on the basis of H
NMR chemical shifts, coupling constants, observed NOE of the pyrrole
proton from irradiation of the pyrrole methyl in the minor regioisomer,
and published data on analogous compounds.27,28 IR (neat): 2928, 1701,
1514, 1248. 1H NMR (400 MHz): δ 7.33-7.26 (m, 5), 6.84 (s, 4),
6.65 (s, 1), 5.07 (s, 2), 3.82 (s, 3), 3.79 (s, 3), 2.46 (d, 3, J ) 3.3).
HRMS (EI): m/z (M+) calcd 335.1521, found 335.1526.
Methyl 1-(4-Methoxybenzyl)-5-methyl-2-phenyl-3-pyrrolecar-
boxylate (37). Yield: 24% (isolated as a 1:3.3 mixture with 36). IR
(neat): 2928, 1701, 1514, 1248. 1H NMR (400 MHz): δ 7.33-7.26
(m, 5), 6.80 (d, 2, J ) 8.9), 6.75 (d, 2, J ) 8.9), 6.47 (d, 1, J ) 0.7),
4.85 (s, 2) 3.78 (s, 3), 3.65 (s, 3), 2.12 (d, 2, J ) 0.6). HRMS (EI):
m/z (M+) calcd 335.1521, found 335.1526.
(R,S)-2-(N-Butylbenzamido)phenylacetic Acid Methyl Ester (12).
Yield: 98%. IR (neat): 2957, 1748, 1638. 1H NMR (500 MHz): δ
7.44-7.38 (m, 10), 5.97 (br, 1), 3.80 (s, 3), 3.17 (br, 2), 1.63 (br, 2),
0.81 (br, 2), 0.52 (br, 3). 13C NMR (126 MHz): δ 170.9, 136.5, 134.4,
129.5, 128.8, 128.7, 128.4, 126.5, 62.0, 52.4, 47.5, 31.5, 19.6, 13.2.
HRMS (EI): m/z (M+) calcd 325.1678, found 325.1681.
Methyl 1-Butyl-2,5-diphenyl-3-pyrrolecarboxylate (38). Yield:
24%. IR (neat): 2957, 2928, 1717, 1475, 1196. 1H NMR (400
MHz): δ 7.46-7.36 (m, 10), 6.67 (s, 1), 3.83 (t, 3, J ) 7.5), 3.65 (s,
3), 1.18 (tt, 2, J ) 7.3, 7.3), 0.85 (tq, 2, J ) 7.4, 7.4), 0.53 (t, 3, J )
7.4). 13C NMR (101 MHz): δ 165.2, 139.7, 134.6, 133.1, 132.3, 130.7,
129.2, 128.5, 128.3, 128.0, 127.6, 113.0, 110.5, 50.8, 44.7, 32.5, 19.3,
13.2. HRMS (EI): m/z (M+) calcd 333.1719, found 333.1722.
(R,S)-N-(1-Cyclohexenyl)-2-(N′-(4-methoxybenzyl)formamido)-
phenylacetamide (24). Yield: 72%. IR (neat): 3308, 2932, 1655,
1514, 1248. The title compound exists at room temperature as a 1.3:1
mixture of rotamers. When peaks corresponding to the same proton-
(s) from each rotamer can be identified, they are listed separately as
major and minor. 1H NMR (400 MHz): (major rotamer) δ 8.23 (s,
1), 7.28-7.27 (m, 5), 7.13 (d, 2, J ) 8.4), 6.71 (d, 2, J ) 8.4), 6.03
(br, 1), 5.77 (s, 1), 4.51 (d, 1 J ) 15.4), 4.29 (d, 1, J ) 15.3), 3.73 (s,
3), 2.30 (t, 1, J ) 6.4), 2.06-1.52 (m, 7); (minor rotamer) δ 8.15 (s,
1), 7.28-7.27 (m, 5), 6.89 (d, 2 J ) 7.5), 6.81 (d, 2, J ) 7.5), 6.03
(br, 1), 4.97 (s, 1), 4.71 (d, 1, J ) 14.7), 4.27 (d, 1 J ) 14.9), 3.75 (s,
3), 2.06-1.52 (m, 8). 13C NMR (101 MHz): δ 167.0, 166.6, 163.8,
159.0 (2), 134.6, 134.1, 132.3, 132.2, 129.9 (2), 129.5, 129.3, 129.0
(2), 128.7, 128.6, 128.5 (2), 128.3, 128.2, 114.2, 114.0, 113.8, 113.6,
64.8, 61.0, 55.1, 49.7, 46.6, 41.8, 27.6, 27.5, 26.9, 24.9, 23.9, 23.8,
22.3 (2), 21.8, 21.7. HRMS (EI): m/z (M+) calcd 378.1943, found
378.1939.
Dimethyl 2-Isopropyl-1-(4-methoxybenzyl)-5-methylpyrrole-3,4-
dicarboxylate (39). Yield: 13% (method A), 5% (method B). IR
(neat): 2951, 1705, 1514, 1215. 1H NMR (400 MHz): δ 6.84 (d, 2,
J ) 8.9), 6.80 (d, 2, J ) 8.9), 5.03 (s, 2), 3.84 (s, 3), 3.78 (s, 6), 3.01
(qq, 1, J ) 7.1, 7.1), 2.35 (s, 3), 1.19 (d, 6, J ) 7.1). 13C NMR (101
MHz): δ 168.1, 165.3, 159.0, 138.8, 134.3, 128.4, 126.6, 114.3, 111.1,
55.3, 51.9, 51.2, 46.4, 29.7, 26.1, 21.7, 11.1. HRMS (EI): m/z (M+)
calcd 359.1733, found 359.1735.
2,3-Di-O-benzyl-4,5-O-isopropylidene-D-arabinose Diethyl Dithio-
acetal. 4,5-O-Isopropylidene-D-arabinose diethyl dithioacetal34 (2.0 g,
6.75 mmol) was dissolved in anhydrous DMF (50 mL). Deoiled sodium
hydride (324 mg, 13.5 mmol) was added in one portion to the stirred
solution. After 1 h, the solution was cooled in an ice bath, and benzyl
bromide (3.2 mL, 27.0 mmol) was added slowly. Another 324 mg of
sodium hydride was added after 1 h, and the solution was stirred for
an additional 12 h. The reaction was quenched with methanol and
then with saturated aqueous ammonium chloride. As much solvent as
possible was removed with a rotary evaporator, and then the residue
was partitioned between saturated aqueous ammonium chloride and
methylene chloride. The aqueous layer was extracted three times with
methylene chloride, and then the organic extracts were combined and
dried over sodium sulfate. After removal of solvent in vacuo,
purification was via flash column chromatography (silica, hexanes to
3:1 hexanes/ethyl acetate gradient), to obtain 2.48 g (77%) of the title
compound. 1H NMR (360 MHz): δ 7.41-7.27 (m, 10), 4.93 (d, 1, J
) 10.9), 4.80 (d, 1, J ) 11.4), 4.76 (d, 1, J ) 11.5), 4.75 (d, 1, J )
11.0), 4.25 (dd, 1, J ) 12.7, 6.4), 4.18-4.09 (m, 2), 4.04 (dd, 1, J )
(R,S)-Methyl
2-(2-(N-(4-Methoxybenzyl)formamido)phen-
ylacetamido)acetate (26). Yield: 43%. IR (neat): 3304, 2953, 1754,
1663, 1514, 1250, 1211, 1179. The title compound exists at room
temperature as a 1:1 mixture of rotamers. When peaks corresponding
to the same proton(s) from each rotamer can be identified, they are
listed together. 1H NMR (400MHz): δ 8.19 and 8.11 (s, 1), 7.28-
7.25 (m, 5), 7.15 and 7.04 (br t, 1), 7.12 and 6.89 (d, 2, J ) 8.7 and
8.6), 6.80 and 6.70 (d, 2, J ) 8.5 and 8.6), 5.75 and 5.04 (s, 1), 4.77
and 4.48 (d, 1, J ) 14.7 and 15.4), 4.24 and 4.21 (d, 1, J ) 15.3 and
14.7), 4.02-3.86 (m, 2), 3.74 and 3.72 (s, 3), 3.68 and 3.67 (s, 3). 13
C
NMR (101 MHz): δ 169.8, 169.7, 169.2, 169.1, 163.8, 163.7, 159.0,
158.9, 134.1, 133.8, 129.9, 129.4, 129.0, 128.9, 128.7, 128.6 (2), 128.6,
128.2, 128.1, 113.9, 113.8, 64.0, 60.2, 55.1, 52.2, 52.1, 49.6, 46.5, 41.2,
41.1. HRMS (EI): m/z (M+) calcd 370.1529, found 370.1532.
(R,S)-Methyl 2-(2-((4-Methoxybenzyl)amino)phenylacetamido)-
acetate (27). IR (neat): 3322, 2926, 1752, 1671, 1514, 1248. 1H NMR
(400MHz): δ 7.86 (br t, 1), 7.42-7.30 (m, 5), 7.27 (d, 2, J ) 8.5),