A general synthesis of pyrroles and fused pyrrole systems from ketones and amino acids

Article abstract of DOI:10.1021/jo960401q

The lithium enolates of ketones react with BOC-α-amino aldehydes and BOC-α-amino ketones to afford aldol intermediates that cyclize under acidic conditions to yield pyrroles. The BOC-amino aldehydes and ketones are readily available from α-amino acids. The method allows incorporation of a wide variety of substituents at any of the five atoms of the pyrrole ring and is also suitable for the preparation of fused pyrrole systems.

Full text of DOI:10.1021/jo960401q

J . Org. Chem. 1996, 61, 4999-5003
4999
A Gen er a l Syn th esis of P yr r oles a n d F u sed P yr r ole System s fr om
Keton es a n d Am in o Acid s
Pamela Nagafuji and Mark Cushman*
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and
Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907
Received February 27, 1996X
The lithium enolates of ketones react with BOC-R-amino aldehydes and BOC-R-amino ketones to
afford aldol intermediates that cyclize under acidic conditions to yield pyrroles. The BOC-amino
aldehydes and ketones are readily available from R-amino acids. The method allows incorporation
of a wide variety of substituents at any of the five atoms of the pyrrole ring and is also suitable for
the preparation of fused pyrrole systems.
Sch em e 1
The importance of the pyrrole ring system has contin-
ued to stimulate a great deal of interest in the develop-
ment of new methodologies for the synthesis of substi-
tuted pyrroles. Several recent reviews on this topic are
now available.1-3 We have been concerned with the
potential elaboration of a new pyrrole synthesis in which
BOC-R-amino aldehydes (1, R2 ) H) or ketones (1, R2 )
CH3) are reacted with the lithium enolates derived from
ketones 2 to afford, after protonation, aldol intermediates
3, which then cyclize to the desired pyrroles 4 under mild
acidic conditions (Scheme 1).4 Although conceptually
related to the familiar Knorr pyrrole synthesis, in which
R-oximino ketones are reduced to R-amino ketones and
then reacted with â-diketones or â-keto esters to afford
substituted pyrroles,5 the present method would offer the
advantage of employment of BOC-R-amino aldehydes or
ketones 1 that are readily available from a wide variety
of amino acids. The advantageous application of amino
acids as synthons for various heterocyclic systems,
including pyrroles, has recently been summarized.6 In
addition, the pyrrole synthesis outlined in Scheme 1
utilizes simple ketones instead of the â-diketones or
â-keto esters that are normally used in the Knorr
synthesis, and it avoids the dicarbonyl intermediate 5
and subsequent alternative aldol reactions that lead to
Fischer-Fink products 8 and 9 as well as the Knorr
product 6 in the Knorr pyrrole synthesis (Scheme 2).5
A preliminary paper documented a limited number of
examples of the strategy outlined in Scheme 1 for the
synthesis of fused pyrrole systems.4 The present study
was undertaken in order to investigate the utility and
scope of this new pyrrole synthesis.
Sch em e 2
Resu lts a n d Discu ssion
The R-amino aldehydes and ketones were prepared
from commercially available BOC-amino acids as out-
lined in Scheme 3.7-10 Conversion of the starting materi-
* To whom correspondence should be addressed. Phone: (317) 494-
1465. Fax: (317) 494-6790. E-mail: cushman@sage.cc.purdue.edu.
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
(1) Sundberg, R. J .; Nguyen, P. V. Prog. Heterocycl. Chem. 1994, 6,
110-128.
(2) Sundberg, R. J . Prog. Heterocycl. Chem. 1992, 1992, 81-94.
(3) Gilchrist, T. L. Contemp. Org. Synth. 1994, 1, 205-217.
(4) Konieczny, M.; Cushman, M. Tetrahedron Lett. 1992, 33, 6939-
6940.
als 10 to Weinreb amide intermediates 11 was carried
out in the presence of (benzotriazol-1-yloxy)tris(dimeth-
ylamino)phosphonium hexafluorophosphate (BOP re-
(5) J ones, A. R.; Bean, G. P. The Chemistry of Pyrroles; Academic
Press: New York, 1977; pp 51-57.
(6) Tic¸ler, M.; Kolar, P. Adv. Heterocycl. Chem. 1995, 64, 1-79.
(7) Nahm, S.; Weinreb, S. Tetrahedron Lett. 1981, 22, 3815-3818.
(8) Fehrentz, J .-A.; Castro, B. Synthesis 1983, 676-678.
(9) Graham, S. L.; deSolms, S. J .; Giuliani, E. A.; Kohl, N. E.;
Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Breslin, M. J .;
Deana, A. A.; Garsky, V. M.; Scholz, T. H.; Gibbs, J . B.; Smith, R. L.
J . Med. Chem. 1994, 37, 725-732.
(10) Zlatoidsky, P. Helv. Chim. Acta 1994, 77, 575-578.
S0022-3263(96)00401-X CCC: $12.00 © 1996 American Chemical Society

5000 J . Org. Chem., Vol. 61, No. 15, 1996
Nagafuji and Cushman
Sch em e 3
The possibility of dehydrogenating 39 to a benzindole
system was also investigated. Treatment of 39 with DDQ
in benzene at room temperature afforded the desired
benzindole 49.
agent) and N,O-dimethylhydroxylamine. The N-meth-
oxy-N-methylamides 11 were either reduced with lithium
aluminum hydride to BOC-R-amino aldehydes 1 (R2 )
H) or treated with methylmagnesium bromide to afford
BOC-R-amino ketones 1 (R2 ) CH3).
Seventeen examples of the conversion of BOC-R-amino
aldehydes or ketones 1 to various substituted pyrroles
and fused pyrrole systems are listed in Table 1. The
reactions were performed by adding the BOC-R-amino
aldehydes or ketones 1 to solutions of the lithium enolates
of the ketones 2 in THF at -78 °C. The aldol products
3 were obtained as crude diastereomeric mixtures that
were cyclized without purification under mild acidic
conditions in methylene chloride at room temperature.
The products were usually obtained as oils in moderate
yields after thin-layer or column chromatography on
silica gel.
Examination of the results in Table 1 shows that the
method has considerable versatility. Reaction of BOC-
L-alaninal (12) and BOC-L-phenylalaninal (15) with
acetone (13) gave the corresponding 1,2,5-trisubstituted
pyrroles 1411 and 16, respectively. As demonstrated by
the reaction of BOC-S-trityl-L-cysteinal (17) with diethyl
ketone 18 to afford pyrrole 19, the use of a larger ketone
18 (relative to 13) leads to 1,2,3,5-substituted pyrroles.
The reaction of 2-acetyl-5-methylfuran (21) with BOC-
L-methioninal (20) provided the pyrrole 22 having an
aromatic substituent. Various fused pyrrole systems 24,
26, 27, 29, 32, 33, 35, 37, and 39 were readily obtained
when cyclic ketones were reacted with BOC-L-amino
aldehydes. Reaction of BOC-R-amino ketones 40 or 42
with ketones 13, 23, 44, or 36 afforded pyrroles 41, 43,
45, and 46 having alkyl groups on the pyrrole carbon
derived from the amino acid carboxyl group. The pyrrole
synthesis presented here should also accommodate a
variety of amino acid protecting groups, leading to
different N-1 substituents on the pyrrole. This was
investigated in a limited sense with N-[(carbobenzyloxy)-
carbonyl]-L-leucinal (28), which gave the corresponding
N-CBZ-2-isobutyl-4,5,6,7-tetrahydroindole (29). It is
therefore possible to incorporate substituents at any of
the five positions of the pyrrole ring using this method.
The deprotection of the BOC-pyrroles was investigated
in a limited number of cases. Treatment of the substi-
tuted pyrrole 16 with sodium methoxide in a mixture of
methanol and THF, followed by acidification with a 10%
solution of acetic acid in methanol, afforded 2-benzyl-5-
methylpyrrole (47).12 Similarly, the BOC group was
removed from 32 under the same conditions to give the
corresponding pyrrole 48.
The present pyrrole synthesis, passing through aldol
intermediates 3, bears some resemblance to several
syntheses of 3-methylpyrrole (50) that have appeared in
the literature. The 4-amino acetal 51, prepared by
opening of an epoxide with ammonia, cyclized and
dehydrated to 3-methylpyrrole (50) when treated with
aqueous citric acid (Scheme 4).13 Similarly, intermediate
52 has been synthesized by conversion of â-ketobutyral-
dehyde dimethyl acetal to the cyanohydrin and protection
of the alcohol as the THP ether, followed by reduction of
the nitrile and acetylation of the resulting amine.14
Compound 52 has also been converted to 3-methylpyrrole
(50) by treatment with p-toluenesulfonic acid in refluxing
acetone, followed by hydrolysis of the resulting N-
acylpyrrole under basic conditions (Scheme 4).14 How-
ever, both of the approaches summarized in Scheme 4
involve multistep procedures and are tedious in compari-
son to the present approach outlined in Scheme 1. In
any case, the fact that pyrroles have been obtained from
intermediates such as 51 and 52 under acidic conditions,
together with the reported additions of a wide variety of
nucleophiles to the aldehyde groups of BOC-amino alde-
hydes,15 supports the pathway proposed in Scheme 1. The
pathway 1 + 2 f 3 f 4 in Scheme 1, in which CC bond
formation precedes CN bond formation, is fundamentally
different from the suggested pathway for the Knorr
synthesis (Scheme 2), in which CN bond formation,
resulting in 5, precedes CC bond formation.5
The overall yields of the substituted pyrroles in Table
1 obtained from BOC-amino aldehydes and ketones were
not optimized and ranged from 42% for 24 to 5% for 37
and 46, which contain an acid-sensitive ketal. Although
the yields are far from ideal and do diminish the
attractiveness of the approach, it can be pointed out that
the yields reported in the Experimental Section are of
analytically pure material isolated after chromatography
and that they refer to overall yields after two synthetic
steps (generation of the aldol 3 as well as its cyclization).
On the other hand, the results indicate that the present
pyrrole synthesis has considerable versatility, since a
variety of substituted pyrroles and fused pyrrole systems
have been obtained from readily available starting
materials. In addition, the overall route offers the
advantage of being relatively short. These considerations
suggest that the present synthetic method may offer
certain advantages when pyrroles are desired.
(12) Butler, A. R.; Shepherd, P. T. J . Chem. Soc., Perkin Trans. 2
1980, 113-116.
(13) Cornforth, J . W.; Firth, M. E. J . Chem. Soc. 1958, 1091-1099.
(14) Plieninger, H.; Bauer, H.; Bu¨hler, W.; Kurze, J .; Lerch, U.
Liebigs Ann. Chem. 1964, 680, 69-82.
(11) Kaiser, H.-P.; Muchowski, J . M. J . Org. Chem. 1984, 49, 4203-
4209.
(15) J urczak, J .; Golebiowski, A. Chem. Rev. 1989, 89, 149-164.

Synthesis of Pyrroles and Fused Pyrrole Systems
J . Org. Chem., Vol. 61, No. 15, 1996 5001
Ta ble 1. Syn th esis of P yr r oles a n d F u sed P yr r ole System s
as noted. Chemical ionization mass spectra (CIMS) were de-
termined using isobutane as the reagent gas. Microanalyses
were performed at the Purdue University Microanalysis Lab-
oratory. THF was distilled from potassium metal and benzo-
phenone under argon to remove moisture and oxygen. Diiso-
propylamine was dried over calcium hydride and then distilled
Exp er im en ta l Section
Melting points were determined in capillary tubes and are
uncorrected. Infrared spectra were obtained using CHCl3 as
the solvent unless otherwise specified. 1H NMR spectra were
obtained using CDCl3 as solvent and TMS as internal stan-
dard. 1H NMR spectra were determined at 200 or 300 MHz

5002 J . Org. Chem., Vol. 61, No. 15, 1996
Nagafuji and Cushman
N-(ter t-Bu toxycar bon yl)-2-m eth yl-4,5,6,7-tetr ah ydr oin -
d ole (24). Chromatography (SiO2), eluting with hexane:CHCl3
(5:1), gave the product as an oil in 42% yield: IR (thin film)
2930, 2850, 1731, 1547, 1478, 1455, 1360, 1256, 1087, 1002,
854, 794 cm-1; 1H NMR (CDCl3, 300 MHz) δ 5.71 (s, 1 H), 2.78
(t, 2 H, J ) 6 Hz), 2.38 (m, 5 H), 1.71 (m, 4 H), 1.57 (s, 9 H);
CIMS m/ z (relative intensity) 236 (MH+, 45), 180 (MH+ - 56,
100), 136 (MH+ - 100, 17). Anal. Calcd for C14H21NO2: C,
71.46; H, 8.99; N, 5.95. Found: C, 71.84; H, 9.32; N, 5.71.
Sch em e 4
N-(ter t-Bu t oxyca r b on yl)-2-isop r op yl-4,5,6,7-t et r a h y-
d r oin d ole (26). Chromatography (SiO2), eluting with hexane:
CHCl3 (5:1), gave the product as a colorless oil in 27% yield:
IR (thin film) 2967, 2931, 1732, 1370, 1325, 1157, 1129, 1084,
prior to use. All reactions were performed under argon
atmosphere. Analytical thin-layer chromatography was car-
ried out on Analtech silica gel GF 1000 µm glass plates.
Compounds were visualized with short wavelength UV light,
phosphomolybdic acid, or ninhydrin indicator. Silica gel flash
chromatography was performed using 230-400 mesh silica gel.
With the exception of 42, the BOC-amino aldehydes and
ketones were prepared according to published procedures.7-10
Typ ica l P r oced u r e. N-(ter t-Bu t oxyca r b on yl)-2,5-d i-
m eth ylp yr r ole (14). Acetone (0.73 mL, 10 mmol) was added
to a stirred solution of freshly prepared LDA (11 mmol) in THF
(40 mL) at -78 °C under an Ar atmosphere, and the reaction
was allowed to proceed for 1.5 h. N-(tert-Butoxycarbonyl)-L-
alaninal (12) (0.9 g, 5 mmol) was dissolved in THF (7 mL)
and cooled to -78 °C before it was added dropwise to the
reaction mixture. Stirring continued at -78 to +23 °C
overnight, and H2O (25 mL) was added followed by ether (400
mL). The solution was washed with water (4 × 100 mL) and
saturated sodium chloride (100 mL) and dried over magnesium
sulfate and the solvent evaporated to yield a diastereomeric
mixture of aldol products (1.3 g). The aldol products were
dissolved in methylene chloride (20 mL), and four drops of
concd HCl was added. The yellow solution became orange and
was stirred for 1 h at room temperature before methylene
chloride (20 mL) was added, the mixture was washed with
saturated sodium bicarbonate (3 × 10 mL) and saturated
sodium chloride (3 × 10 mL), dried (MgSO4), and the solvent
was evaporated. Chromatography (SiO2), eluting with hexane:
CHCl3 (2:1), gave 1411 as a colorless oil (0.27 g, 28%): IR (thin
film) 2977, 2930, 1738, 1544, 1478, 1455, 1389, 1370, 1334,
1
1057, 854 cm-1; H NMR (CDCl3, 300 MHz) δ 5.80 (s, 1 H),
3.49 (p, 1 H, J ) 6.7 Hz), 2.76 (t, 2 H, J ) 5.7 Hz), 2.41 (t, 2
H, J ) 5.7 Hz), 1.70 (m, 4 H), 1.59 (s, 9 H), 1.21 (d, 6 H, J )
6.7 Hz); CIMS m/ z (relative intensity) 264 (MH+, 7), 208 (MH+
- 56, 71), 164 (MH+ - 100, 100). Anal. Calcd for C16H25NO2:
C, 72.97; H, 9.57; N, 5.32. Found: C, 73.29; H, 9.86; N, 5.16.
N-(ter t-Bu toxyca r bon yl)-2-[(tr itylth io)m eth yl]-4,5,6,7-
tetr a h yd r oin d ole (27). Chromatography (SiO2), eluting with
hexane:Et2O (10:1), gave the product as a colorless oil in 8%
yield: IR (thin film) 2930, 2850, 1734, 1539, 1489, 1444, 1366,
1318, 1257, 1137, 1084, 1033, 849, 746, 700 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 7.17-7.42 (m, 15 H), 5.41 (s, 1 H), 3.63
(s, 2 H), 2.73 (t, 2 H, J ) 5.5 Hz), 2.30 (t, 2 H, J ) 5.8 Hz),
1.72 (m, 2 H), 1.60 (m, 2 H), 1.54 (s, 9 H); CIMS m/ z (relative
intensity) 510 (MH+, 30), 243 (MH+ - 267, 100). Anal. Calcd
for C33H35NO2S: C, 77.76; H, 6.92; N, 2.75; S, 6.29. Found:
C, 78.05; H, 7.17; N, 2.74; S, 6.05.
N-[(Ca r b ob en zyloxy)ca r b on yl]-2-isob u t yl-4,5,6,7-t et -
r a h yd r oin d ole (29). Chromatography (SiO2), eluting with
hexane:CHCl3 (3:1), gave the product as an oil in 15% yield:
IR (thin film) 2952, 2930, 2850, 1732, 1543, 1389, 1358, 1321,
1298, 1256, 1216, 1164, 1137, 1096, 1071, 982, 911, 829 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.44-7.35 (m, 5 H), 5.73 (s, 1
H), 5.30 (s, 2 H), 2.76 (t, 2 H, J ) 5.8 Hz), 2.61 (d, 2 H, J ) 6.8
Hz), 2.38 (t, 2 H, J ) 5.8 Hz), 1.79-1.65 (m, 5 H), 0.84 (d, 6 H,
J ) 6.6 Hz); CIMS m/ z (relative intensity) 312 (MH+, 99).
Anal. Calcd for C20H25NO2: C, 77.14; H, 8.09; N, 4.50.
Found: C, 76.97; H, 8.07; N, 4.86.
1
1312, 1248, 1174, 1124, 982, 853, 783 cm-1; H NMR (CDCl3,
300 MHz) δ 5.78 (s, 2 H), 2.38 (s, 6 H), 1.59 (s, 9 H); CIMS
m/ z (relative intensity) 196 (MH+, 100), 140 (MH+ - 56, 49),
96 (MH+ - 100, 6). Anal. Calcd for C11H17NO2: C, 67.66; H,
8.78; N, 7.17. Found: C, 67.83; H, 9.06; N, 7.36.
N-(ter t-Bu toxyca r bon yl)-4,6,7-tr ih yd r o-2-isobu tylp yr -
a n o[4,3-b]p yr r ole (32). Preparative thin-layer chromatog-
raphy (SiO2), eluting with hexane:EtOAc (3:1), gave the
product as a yellow oil in 26% yield: IR (thin film) 2955,
2866, 2846, 1736, 1539, 1462, 1369, 1369, 1328, 1216, 1258,
N-(ter t-Bu toxycar bon yl)-2-ben zyl-5-m eth ylpyr r ole (16).
Chromatography (SiO2), eluting with hexane:CHCl3 (2:1), gave
the product as a colorless oil in 13% yield: IR (thin film) 2978,
2929, 1739,1536, 1494, 1453, 1388, 1369, 1330, 1313, 1254,
1171, 1121, 851, 787, 698 cm-1; 1H NMR (CDCl3, 200 MHz) δ
7.10-7.30 (m, 5 H), 5.82 (dd, 1H, J ) 3.0, 1.0 Hz), 5.66 (d,1 H,
J ) 3.2 Hz), 4.16 (s, 2 H), 2.39 (s, 3 H), 1.44 (s, 9 H); CIMS
m/ z (relative intensity) 272 (MH+, 100), 216 (MH+ - 56, 86),
172 (MH+ - 100, 26). Anal. Calcd for C17H21NO2: C, 75.25;
H, 7.80; N, 5.16. Found: C, 74.97; H, 7.89; N, 5.13.
1138, 1101, 978, 901, 791, 770 cm-1 1H NMR (CDCl3, 300
;
MHz) δ 5.77 (s, 1 H), 4.55 (t, 2 H, J ) 1.8 Hz), 3.88 (t, 2 H, J
) 5.5 Hz), 2.87 (t, 2 H, J ) 6.0 Hz), 1.59 (s, 9 H), 1.44 (d, 2 H,
J ) 5.1 Hz), 1.24 (d, 6 H, J ) 6.8 Hz); CIMS m/ z (relative
intensity) 280 (MH+, 50), 224 (MH+ - 56, 55), 180 (MH+
-
100, 100). Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02; N,
5.01. Found: C, 68.59; H, 9.08; N, 5.04.
N-(ter t-Bu toxycar bon yl)-2-ben zyl-4,6,7-tr ih ydr opyr an o-
[4,3-b]p yr r ole (33). Chromatography (SiO2), eluting with
CHCl3:hexane (3:2), gave the product as a colorless oil in 25%
yield: IR (thin film) 2976, 2845, 1736, 1494, 1453, 1423, 1368,
N-(ter t-Bu t oxyca r b on yl)-5-et h yl-4-m et h yl-2-[(t r it yl-
th io)m eth yl]p yr r ole (19). Chromatography (SiO2), eluting
with hexane:CHCl3 (2:1), gave the product as a colorless oil in
10% yield: IR (thin film) 2976, 2930, 1737, 1532, 1489, 1444,
1380, 1369, 1354, 1326, 1291, 1137, 1099, 1035 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.24-7.39 (m, 15 H), 5.43 (s, 1 H), 3.58
(s, 2 H), 2.72 (q, 2 H, J ) 7.4 Hz), 1.85 (s, 3 H), 1.54 (s, 9 H),
1.26 (t, 3 H, J ) 7.3 Hz); CIMS m/ z (relative intensity) 498
1
1325, 1171, 1135, 1099, 976, 900, 851 cm-1; H NMR (CDCl3,
300 MHz) δ 7.23-7.10 (m, 5 H), 5.50 (s, 1 H), 4.51 (s, 2 H),
4.20 (s, 2 H), 3.90 (t, 2 H, J ) 5.4 Hz), 2.91 (t, 3 H, J ) 5.4
Hz), 1.62 (s, 9 H); CIMS m/ z (relative intensity) 314 (MH+,
38), 258 (MH+ - 56, 29), 214 (MH+ - 100, 100). Anal. Calcd
for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C, 72.44;
H, 7.73; N, 4.45.
(MH+, 14), 243 (MH+ - 255, 100). Anal. Calcd for C32H35
-
NO2S: C, 77.23; H, 7.09; N, 2.81; S, 6.44. Found: C, 77.51;
H, 7.38; N, 2.64; S, 6.77.
N-(ter t-Bu t oxyca r b on yl)-4,6,7-t r ih yd r o-2,5-d im et h yl-
1H-p yr r olo[3,2-c]p yr id in e (35). Chromatography (SiO2),
eluting with hexane:EtOAc (1:1) containing 1% triethylamine,
gave the product as a yellow oil in 17% yield: IR (thin film)
2974, 2936, 2779, 1737, 1386, 1359, 1329, 1315, 1307, 1250,
1159, 1148, 1116, 1083, 1044, 976, 851, 799, 770 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 5.67 (s, 1 H), 3.28 (s, 2 H), 2.89 (t, 2 H, J
) 5.7 Hz), 2.63 (t, 2 H, J ) 5.8 Hz), 2.41 (s, 3 H), 2.36 (s, 3 H),
1.55 (s, 9 H); CIMS m/ z (relative intensity) 251 (MH+, 100),
195 (MH+ - 56, 87), 151 (MH+ - 100, 36). Anal. Calcd for
N -(t er t -Bu t oxyca r b on yl)-2-(5-m e t h yl-2-fu r yl)-5-[2-
(m eth ylth io)eth yl]p yr r ole (22). Chromatography (SiO2),
eluting with hexane:CHCl3 (1:2), gave the product as an oil in
5% yield: IR (thin film) 2979, 2920, 1742, 1388, 1369, 1313,
1257, 1219, 1150, 1079, 1020, 953, 847, 784 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 6.18 (dd, 2 H, J ) 3.2, 1.3 Hz), 5.99 (d, 1
H, J ) 3.3 Hz), 5.97 (dd, 1 H, J ) 3.0, 1.1 Hz), 3.11 (t, 2H, J
) 7.7 Hz), 2.76 (t, 2 H, J ) 7.7 Hz), 2.30 (s, 3 H), 2.13 (s, 3 H),
1.38 (s, 9 H); CIMS m/ z (relative intensity) 322 (MH+, 100),
278 (MH+ - 44, 35), 266 (MH+ - 56, 30), 222 (MH+ - 100,
90). Anal. Calcd for C17H23NO3S: C, 63.52; H, 7.21; N, 4.36;
S, 9.97. Found: C, 63.87; H, 7.41; N, 4.15; S, 9.69.
C
14H22N2O2: C, 67.17; H, 8.86; N, 11.19. Found: C, 67.08; H,
9.07; N, 11.37.

Synthesis of Pyrroles and Fused Pyrrole Systems
J . Org. Chem., Vol. 61, No. 15, 1996 5003
N-(ter t-Bu toxyca r bon yl)-5-oxotetr a h yd r oin d ole eth -
ylen e k eta l (37). Preparative TLC (SiO2), eluting with
hexane:EtOAc (3:1), gave the product as an oil in 5% yield:
IR (thin film) 2974, 1737, 1370, 1314, 1268, 1151, 1097, 1061,
by flash chromatography (SiO2). Elution with hexane-ethyl
actetate (4:1) afforded the least polar component 46 as a pale
yellow oil in 40% yield: IR (thin film) 2976, 1733, 1391, 1369,
1252, 1162, 1059, 946, 856, 771 cm-1 1H NMR (CDCl3, 300
;
1
1027, 947, 850, 771, 772 cm-1; H NMR (CDCl3, 300 MHz) δ
MHz) δ 6.9 (s, 1 H), 4.03 (s, 4 H), 2.98 (t, 2 H, J ) 6.5 Hz),
2.58 (s, 2 H), 1.89 (t, 2 H, J ) 6.6 Hz), 1.53 (s, 9 H); CIMS
m/ z (relative intensity) 294 (MH+, 100), 238 (MH+ - 56, 98),
194 (MH+ - 100, 69). Anal. Calcd for C16H23NO4: C, 65.51;
H, 7.90; N, 4.77. Found: C, 65.18; H, 8.16; N, 5.09.
7.18 (d, 1 H, J ) 3.4 Hz), 5.96 (d, 1 H, J ) 3.4 Hz), 4.00 (s, 4
H), 3.01 (t, 2 H, J ) 6.5 Hz), 2.69 (s, 2 H), 1.94 (t, 2 H, J ) 6.5
Hz), 1.57 (s, 9 H); CIMS m/ z (relative intensity) 280 (MH+,
53), 224 (MH+ - 56, 38), 180 (MH+ - 100, 100). Anal. Calcd
for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.14;
H, 7.85; N, 5.23.
N-(ter t-Bu toxyca r bon yl)-4,5-d ih yd r o-2-m eth yl-1H-ben -
z[g]in d ole (39). Chromatography (SiO2), eluting with hexane:
CH2Cl2 (3:1), gave the product as a white solid in 23% yield:
mp 80-81 °C; IR (thin film) 2979, 2930, 2990, 2890, 1739,
1516, 1489, 1368, 1344, 1327, 1301, 1153, 1109, 1081, 991, 850,
755, cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.18 (s, 1 H), 7.15 (d,
2 H, J ) 3.9 Hz), 7.05 (m, 1 H), 5.85 (s, 1 H), 2.83 (t, 2 H, J )
7.3 Hz), 2.49 (t, 2 H, J ) 7.3 Hz), 2.41 (s, 3 H), 1.57 (s, 9 H);
CIMS m/ z (relative intensity) 284 (MH+, 58), 283 (M+, 94),
228 (MH+ - 56, 100), 184 (MH+ - 100, 26). Anal. Calcd for
C18H21NO2: C, 76.30; H, 7.47; N, 4.94. Found: C, 76.39; H,
7.34; N, 4.85.
1H-2-Ben zyl-5-m eth ylp yr r ole (47). The pyrrole 16 (0.24
g, 0.9 mmol) was stirred in THF (1 mL). A solution of sodium
methoxide (0.15 g, 2.7 mmol) in methanol (0.8 mL) was added
to the colorless solution. The solution became yellow, and a
white precipitate formed. After 2 h, the reaction mixture was
diluted with ether (40 mL) and neutralized by dropwise
addition of a 10% solution of acetic acid in methanol (10 mL).
The organic layer was extracted with brine (3 × 15 mL) and
dried (MgSO4) and the solvent removed under reduced pres-
sure. The resulting light yellow oil was purified on a prepara-
tive TLC plate (1000 µm SiO2) that had been previously
deactivated with 5% triethylamine in hexane. Elution with
hexane:CHCl3 (1:1) gave 4712 (0.07 g, 46%) as a yellow oil: IR
(thin film) 3414, 3365, 3026, 3899, 1591, 1492, 1452, 1420,
1399, 1255, 1173, 1074, 1035, 763, 708 cm-1; 1H NMR (CDCl3,
300 MHz) δ 7.43 (s, 1 H, broad), 7.31-7.17 (m, 5 H), 5.82 (t, 1
H, J ) 2.6 Hz), 5.76 (s, 1 H), 3.88 (s, 2 H), 2.15 (s, 3 H); CIMS
m/ z (relative intensity) 172 (MH+, 100). Anal. Calcd for
C12H13N: C, 84.17; H, 7.65; N, 8.18. Found: C, 83.99; H, 7.60;
N, 8.04.
N -(t er t -Bu t oxyca r b on yl)-2-b e n zyl-3,5-d im e t h ylp yr -
r ole (41). The product was purified by preparative TLC (1000
µm SiO2). Elution with hexane:chloroform (3:1) afforded the
least polar component 41 as a pale yellow oil in 40% yield: IR
(thin film) 2977, 2926, 1737,1603, 1546, 1494, 1453,1385, 1351,
1328, 1280, 1257, 1176, 1135, 1077, 851, 799, 770, 728 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.26 (m, 5 H), 5.94 (s, 1 H), 4.34
(s, 2 H), 2.51 (s, 3 H), 2.12 (s, 3 H), 1.47 (s, 9 H); CIMS m/ z
(relative intensity) 286 (MH+, 100), 230 (MH+ - 56, 17), 186
(MH+ - 100, 49). Anal. Calcd for C18H23NO2: C, 75.76; H,
8.12; N, 4.91. Found: C, 76.09; H, 8.15; N,4.81.
1H-4,6,7-Tr ih yd r o-2-isobu tylp yr a n o[4,3-b]p yr r ole (48).
The pyrrole 32 (0.28 g, 1.0 mmol) was stirred in THF (1 mL).
A solution of sodium methoxide (0.16 g, 3.0 mmol) in methanol
(2.0 mL) was added to the colorless solution. The solution
became cloudy. After being stirred overnight, the reaction
mixture was diluted with ether (40 mL) and neutralized by
dropwise addition of a 10% solution of acetic acid in methanol
(10 mL). The organic layer was extracted with brine (3 × 15
mL) and dried (MgSO4) and the solvent removed under
reduced pressure. The resulting red oil was purified on a
preparative TLC plate (1000 µm SiO2) that had been previously
deactivated with 5% triethylamine in hexane. Elution with
hexane:EtOAc (3:1) gave the product as a white glass (0.08 g,
45%): IR (thin film) 3308, 2953, 2842, 1462, 1381, 1298, 1214,
N-(ter t-Bu toxycar bon yl)-3-am in o-2-pr opan on e (42). N-
(tert-Butoxycarbonyl)glycine N-methoxy-N-methylamide (2.2
g, 10 mmol) was dissolved in THF (50 mL), and a 1.0 M
solution of methylmagnesium bromide in ether (30 mL, 30
mmol) was added via syringe. After 15 min, the reaction
mixture was diluted with ether (300 mL), and a 25% aqueous
solution of ammonium chloride (35 mL) was slowly added. The
mixture was extracted with saturated sodium bicarbonate
solution (3 × 100 mL) and saturated sodium chloride solution
(3 × 100 mL), dried (MgSO4), and concentrated to give a pale
yellow oil, which after drying in vacuo gave a white crystalline
solid (1.84 g, 85%): mp 48-49 °C; IR (thin film) 3361, 2978,
1155, 1076, 1059, 961, 928, 864, 845, 774 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 7.54 (brs, 1 H), 5.62 (d, 1 H, J ) 2.3 Hz),
4.64 (d, 2 H, J ) 1.3 Hz), 3.95 (t, 2 H, J ) 5.5 Hz), 2.66 (t, 2
H, J ) 5.5 Hz), 2.41 (d, 2 H, J ) 7.1 Hz), 1.80 (p, 1 H, J ) 6.6
Hz), 0.93 (d, 6 H, J ) 6.6 Hz); CIMS m/ z (relative intensity)
180 (MH+, 100). Anal. Calcd for C11H17N0: C, 73.70; H, 9.56;
N, 7.81. Found: C, 73.45; H, 9.90; N, 7.90.
1713, 1514, 1504, 1366, 1285, 1250, 1164 cm-1 1H NMR
;
(CDCl3) δ 5.23 (broad), 3.96 (d, 2 H, J ) 4.5 Hz), 2.11 (s, 3 H),
1.38 (s, 9 H); CIMS m/ z (relative intensity) 174 (MH+, 54),
118 (MH+ - 56, 100), 74 (MH+ - 100, 46). Anal. Calcd for
C8H15NO3: C, 55.47; H, 8.73; N, 8.09. Found: C, 55.17; H,
8.91; N, 7.86.
N-(ter t-Bu toxycar bon yl)-4,5,6,7-tetr ah ydr o-3-m eth ylin -
d ole (43). The product was purified by flash chromatography
(SiO2). Elution with hexane:chloroform (3:1) afforded the least
polar component as a pale yellow oil in 44% yield: IR (thin
film) 2933, 2854, 1735, 1390, 1369, 1346, 1332, 1314, 1248,
1162, 1082, 1047, 1016, 850 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 6.89 (s, 1 H), 2.80 (t, 2 H, J ) 5.5 Hz), 2.34 (t, 2 H, J ) 5.6
Hz), 1.93 (s, 3 H), 1.75 (m, 4 H), 1.56 (s, 9 H); CIMS m/ z
(relative intensity) 236 (M+, 100), 180 (MH+ - 56, 80), 136
(MH+ - 100, 78). Anal. Calcd for C14H21NO2: C, 71.46; H,
8.99; N, 5.95. Found: C, 71.08; H, 9.21; N, 5.91.
N-(ter t-Bu t oxyca r b on yl)-2-m et h yl-1H -b en z[g]in d ole
(49). Pyrrole 39 (0.04 g, 0.14 mmol) was dissolved in benzene
(10 mL), and DDQ (0.03 g, 0.14 mmol) was added. The
reaction mixture was stirred for 40 min at room temperature,
and the mixture was filtered. The filtrate was extracted
with saturated aqueous sodium bicarbonate (3 × 10 mL)
followed by saturated sodium chloride (3 × 10 mL) and dried
over magnesium sulfate. Evaporation of solvent gave a dark
brown oil which was purified by preparative TLC (1000 µm
SiO2). Elution with hexane:EtOAc (3:1) afforded the least
polar component 49 (0.02 g, 48%) as a solid: mp 54-56 °C; IR
(thin film) 2979, 1737, 1387, 1369, 1345, 1311, 1258, 1202,
1
1153, 1113, 1075, 846, 816, 739, 686 cm-1; H NMR (CDCl3,
N-(ter t-Bu toxyca r bon yl)-2-ben zyl-3-m eth ylcyclop en ta -
[b]p yr r ole (45). Purification of the product was achieved by
flash chromatography. Elution with hexane-chloroform (3:
1) afforded the least polar component 45 as an off-white glass
in 30% yield: mp 77-79 °C; IR (thin film) 2931, 2856, 1735,
300 MHz) δ 8.17 (d, 1 H, J ) 8.1 Hz), 7.89 (d, 1 H, J ) 8.2
Hz), 7.61 (d, 1 H, J ) 8.5 Hz), 7.54 (d, 1 H, J ) 8.5 Hz), 7.44
(td, 1 H, J ) 8.2, 1.4 Hz), 7.36 (td, 1 H, J ) 6.9, 1.4 Hz), 6.40
(s, 1 H), 2.49 (s, 3 H), 1.70 (s, 9H); CIMS m/ z (relative
intensity) 282 (MH+, 28), 226 (MH+ - 56, 100), 182 (MH+
-
1392, 1356, 1337, 1145, 1122, 844, 768, 724 cm-1 1H NMR
;
100, 50). Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N,
4.98. Found: C, 76.98; H, 6.87; N, 4.68.
(CDCl3, 300 MHz) δ 7.25 (m, 5 H), 4.32 (s, 2 H), 2.98 (t, 2 H,
J ) 7.1 Hz), 2.62 (t, 2 H, J ) 7.1 Hz), 2.43 (p, 2 H, J ) 6.9
Hz), 2.04 (s, 3 H), 1.49 (s, 9 H); CIMS m/ z (relative intensity)
312 (MH+, 100), 256 (MH+ - 56, 31), 212 (MH+ - 100, 28).
Anal. Calcd for C20H25NO2: C, 77.14; H, 8.09; N, 4.50.
Found: C, 76.94; H, 8.35; N, 4.38.
Ack n ow led gm en t. This research was made possible
by a research grant from the Indiana Elks, as well as
NIH Contract NO1-CM-17513.
N-(ter t-Bu t oxyca r b on yl)-4,5,6,7-t et r a h yd r o-5-oxo-3-
m eth ylin dole Eth ylen e Ketal (46). Purification was achieved
J O960401Q