Regioselective 1,3-dipolar cycloaddition reactions of unsymmetrical munchnones (1,3-oxazolium-5-olates) with 2- and 3-nitroindoles. A new synthesis of pyrrolo[3,4-b]indoles

Article abstract of DOI:10.1016/S0040-4020(00)00858-9

The unsymmetrical mesoionic munchnones 13 (3-benzyl-2-methyl-4-phenyl-1,3-oxazolium-5-olate) and 14 (3-benzyl-4-methyl-2-phenyl-1,3-oxazolium-5-olate) react with the N-protected 2- and 3-nitroindoles 1 (ethyl 2-nitroindole-1-carboxylate), 6 (3-nitro-1-(phenylsulfonyl)indole), and 17 (ethyl 3-nitroindole-carboxylate) in refluxing THF to afford in good to excellent yields the pyrrolo[3,4-b]indoles 15 (2-benzyl-1-methyl-3-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 16 (2-benzyl-3-methyl-1-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 18 (2-benzylmethyl-3-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole), and 19 (2-benzyl-3-methyl-1-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indol e). In several cases the regiochemistry, which is opposite to that predicted by FMO theory, is very high and leads essentially to a single pyrrolo[3,4-b]indole; e.g., 6+ 13→19 in 74% yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00858-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 10133±10140
Regioselective 1,3-Dipolar Cycloaddition Reactions of
È
Unsymmetrical Munchnones (1,3-Oxazolium-5-olates) with 2- and
3-Nitroindoles. A New Synthesis of Pyrrolo[3,4-b]indoles
*
Gordon W. Gribble, Erin T. Pelkey, Wendy M. Simon and Hernando A. Trujillo
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
Received 18 November 1999; accepted 27 January 2000
AbstractÐThe unsymmetrical mesoionic muÈnchnones 13 (3-benzyl-2-methyl-4-phenyl-1,3-oxazolium-5-olate) and 14 (3-benzyl-4-methyl-
2-phenyl-1,3-oxazolium-5-olate) react with the N-protected 2- and 3-nitroindoles 1 (ethyl 2-nitroindole-1-carboxylate), 6 (3-nitro-1-(phenyl-
sulfonyl)indole), and 17 (ethyl 3-nitroindole-1-carboxylate) in re¯uxing THF to afford in good to excellent yields the pyrrolo[3,4-b]indoles
15 (2-benzyl-1-methyl-3-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 16 (2-benzyl-3-methyl-1-phenyl-4-carboethoxy-2,4-
dihydropyrrolo[3,4-b]indole), 18 (2-benzyl-1-methyl-3-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole), and 19 (2-benzyl-3-
methyl-1-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole). In several cases the regiochemistry, which is opposite to that
predicted by FMO theory, is very high and leads essentially to a single pyrrolo[3,4-b]indole; e.g., 6113!19 in 74% yield. q 2000 Elsevier
Science Ltd. All rights reserved.
Pyrrolo[3,4-b]indoles are valuable synthetic analogues of
indole-2,3-quinodimethanes and there is great interest in
their synthesis and subsequent chemistry, particularly that
involving cycloaddition reactions leading to carbazoles,
carbolines, and related natural products.1 Following the
inaugural synthesis of a pyrrolo[3,4-b]indole by Welch,2
subsequent syntheses of this ring system were reported by
Sha,3±5 Kreher,6,7 Srinivasan,8 Snyder,9 and ourselves.10,11
In our pursuit of a simple, one-step synthesis of pyrrolo-
[3,4-b]indoles,10,11 we recently reported the 1,3-dipolar
cycloaddition reaction of mesoionic muÈnchnones (1,3-
oxazolium-5-olates) 2 and 3 with both 2- and 3-nitroindoles
(1 and 6) to give in one operation the corresponding
pyrrolo[3,4-b]indoles 4, 5, 7, 8 as shown in Scheme 1.12
This reaction is presumed to involve formation of a cyclo-
adduct that loses the elements of nitrous acid and carbon
Scheme 1.
Keywords: muÈnchnone; 2-nitroindole; 3-nitroindole; 1,3-dipolar cycloaddition; 1,3-oxazolium-5-olates; pyrrolo[3,4-b]indole.
* Corresponding author. Tel.: 11-603-646-2501; fax: 11-603-646-3946; e-mail: grib@dartmouth.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00858-9

10134
G. W. Gribble et al. / Tetrahedron 56 (2000) 10133±10140
Scheme 2.
Scheme 3.
dioxide to afford the pyrrolo[3,4-b]indole in good to
excellent yield.
acylation with acetyl or benzoyl chloride, and saponi®-
cation.
We now describe 1,3-dipolar cycloaddition reactions of 2-
and 3-nitroindoles with the unsymmetrical muÈnchnones 13
(3-benzyl-2-methyl-4-phenyl-1,3-oxazolium-5-olate) and
14 (3-benzyl-4-methyl-2-phenyl-1,3-oxazolium-5-olate),
which were generated in situ as shown in Scheme 2 from
the N-acylamino acids 11 and 12, respectively, using diiso-
propylcarbodiimide (DIPC) as the dehydrating agent.13
Compounds 11 and 12 were synthesized from ethyl
a-bromophenylacetate (9) and ethyl a-bromopropionate
(10), respectively, by a sequence of benzylamine alkylation,
The reactions of 2-nitroindole 114 with muÈnchnones 13 and
14 are highly regioselective and afford pyrroloindoles 15
and 16 as reasonably stable crystalline solids in excellent
yields (Scheme 3). The isomer ratios were determined by
1H NMR peak integration of the crude products before
chromatography. The products 15 and 16 were separated
by ¯ash chromatography, fully characterized, and distin-
guished by an NOE between the C-3 methyl protons and
the carboethoxy methyl protons in 16 but not in 15. More-
over, the chemical shift of the carboethoxy protons indicates
Scheme 4.

G. W. Gribble et al. / Tetrahedron 56 (2000) 10133±10140
10135
Scheme 5.
pronounced shielding by the C-3 phenyl group in 15 but not
in 16. Thus, in the carboethoxy group the methylene protons
appear at 3.8 ppm and the methyl protons appear at 0.8 ppm,
compared with 4.5 ppm and 1.5 ppm, respectively, for the
corresponding protons in 16.
The structure of the major isomer 19 was con®rmed by
X-ray crystallography.17 This isomer shows deshielding of
the C-3 methyl protons (2.66 ppm) relative to that chemical
shift in the minor isomer 18 (2.33 ppm), presumably due to
the phenylsulfonyl group. The structure of the minor isomer
18 was con®rmed by independent synthesis (Scheme 6)
using the general method of Srinivasan.18 Lithiation of
indole 2019 and quenching with benzaldehyde, followed
by oxidation yielded ketone 21.19 Bromination and ami-
nation afforded 18, identical with the minor isomer obtained
from 6 and 14 in Scheme 5.
Perhaps surprisingly, the expected regioselectivity from
frontier molecular orbital (FMO) theory is not observed,
and the major product, 15 and 16, respectively, from each
reaction with 2-nitroindole 1 derives from the presumed
positive end of the 1,3-dipole (C-2) bonding with the
electron-de®cient indole C-3 position and the presumed
negative site (enolate carbon) of the 1,3-dipole (C-3) bond-
ing with the electron-rich indole C-2 position of 1. These
FMO-based predictions are discussed later.
An electron-withdrawing group on the indole nitrogen
appears to be required for these cycloadditions to occur,
since, for example, 1-methyl-3-nitroindole fails to react
with muÈnchnone 14 after 24 h of re¯ux in THF or digylme;
at most, ,1% of products are formed.
Similarly, reaction of 1-carboethoxy-3-nitroindole (17)11,15
with muÈnchnone 13 also affords nearly exclusively the
`anti-FMO' product 16, whereas muÈnchnone 14 with 17
gives 15 and 16 in nearly equal amounts (Scheme 4).16
We performed AM1 calculations through Spartan, and these
FMO predictions are consistent with the fact that the
observed cycloaddition regiochemistry is generally `anti-
FMO'. The HOMO/LUMO energies are listed in Table 1,
and Scheme 7 depicts the coef®cients for the favored
HOMO (muÈnchnone)1LUMO (nitroindole) interaction.
Reactions of 3-nitro-1-(phenylsulfonyl)indole (6)11,15 with
muÈnchnones 13 and 14 have also been investigated (Scheme
5). The former cycloaddition reaction proceeds to give
exclusively the anti-FMO pyrroloindole 19 in good yield.
However, reaction of 6 with muÈnchnone 14 yields pyrro-
loindoles 18 and 19, with the FMO product 19 somewhat
favored.
Thus, a comparison of the HOMO±LUMO energies (Table
2) predicts that the 1,3-dipolar cycloaddition should involve
the HOMO of the muÈnchnone (1,3-dipole) interacting with
Scheme 6.

10136
G. W. Gribble et al. / Tetrahedron 56 (2000) 10133±10140
Table 1. AM1 Calculation results performed through spartan
Table 2. Comparison of LUMO±HOMO energy differences, eV (energy
values are taken from Table 1)
Energies, eV
Reaction E (LUMO nitroindole)2E E (LUMO muÈnchnone)2E DeV
(HOMO muÈnchnone), eV (HOMO nitroindole), eV
cpd
HOMO
LUMO
1
6
17
13
14
29.512
29.536
29.514
27.674
27.743
21.247
21.562
21.141
20.423
20.683
113
6.428
6.497
6.112
6.181
6.533
6.602
8.089
8.829
9.113
8.853
9.091
8.831
1.661
2.332
3.001
2.672
2.558
2.229
1114
6113
6114
17113
17114
the LUMO of the nitroindole (dipolarophile). These energy
differences are lower by 1.7±3.0 eV than the reverse situa-
tion involving the LUMO of the muÈnchnone and the HOMO
of the nitroindole. However, in only one case is the FMO-
predicted regiochemistry realized to any extent. The
reaction of 3-nitroindole 6 with muÈnchnone 14 gives a
preponderance of pyrroloindole 19 over the isomeric 18
(Scheme 5). The reaction of 3-nitroindole 17 with
muÈnchnone 14 gives perhaps a slight excess of the FMO-
product 16 (Scheme 4).
regiochemistry. Moreover, the exact mechanism and
sequence of nitrous acid and carbon dioxide loss remains
to be established, and we are continuing our work in this
area.
Experimental
General considerations
One feature of the regiochemistry is that in every case but
one the major or exclusive product is the one where the
phenyl group of the muÈnchnone is syn to the nitro group
in the indole (Schemes 3±5). This may suggest a favorable
transition state p-interaction between the phenyl ring of the
muÈnchnone and the nitro group leading to the observed
regiochemistry that is anti-FMO, or it may simply be a
consequence of a highly nonsynchronous transition state
where bond making between the methyl ring carbon of the
muÈnchnone and the electron-de®cient carbon of the nitro-
indole double bond precedes, for steric reasons, bond
making involving the phenyl ring carbon of the muÈnchnone.
Another interesting possibility is that there is a favorable
interaction between the `enolate' oxygen of the muÈnchnone
and the nitrogen of the nitro group. Transition state calcula-
tions may help to answer this question. Clearly, further work
is needed to understand the regiochemistry observed in
these reactions.
Tetrahydrofuran (THF) was distilled under nitrogen from
sodium benzophenone ketyl before use. 1H (300 MHz)
and 13C{1H} NMR spectra (75 MHz) were obtained on a
Varian Unity-300 NMR spectrometer. Chemical shifts are
given as ppm down®eld of TMS; coupling constants are in
Hz. An asterisk after a chemical shift denotes a quaternary
carbon. IR spectra were obtained as KBr pellets on a
Perkin±Elmer 1600 FTIR spectrometer. UV±VIS spectra
were obtained in ethanol on a HP-8451 diode array spectro-
photometer; approximate e values are reported in paren-
theses. Melting Points were obtained in nitrogen-®lled
capillaries on a Mel-Temp apparatus, and are uncorrected.
Flash chromatography was performed using Flash silica
obtained from Selecto Scienti®c; samples were generally
adsorbed onto Celite prior to application to the column.
N,N0-Diisopropylcarbodiimide (DIPC) was purchased
from Aldrich. N-Benzyl-N-benzoylalanine, N-acetyl-N-
benzyl-a-phenylglycine,
N-benzyl-N-benzoyl-a-phenyl-
Other workers who have explored unsymmetrical muÈnch-
none cycloaddition reactions have encountered similar
vagaries in the regiochemical outcome.20±25 However, in
some cases the regiochemistry can be satisfactorily
explained with ab initio molecular orbital calculations.24
glycine, were prepared as described in the literature. 2-
and 3-Nitro-1-phenylsulfonylindole, 3-nitro-1-ethoxycarbo-
nylindole, and 1-methyl-3-nitroindole were prepared as
described in references 14 and 15. Low resolution mass
spectra were also obtained from the Boston University
School of Medicine Mass Spectrometry Resource, which
is supported by NIH/NCRR Grant No. P41-RR10888 (to
C. E. Costello). High-resolution mass spectrometry
(HRMS) was performed at University of Illinois
(UrbanaÐChampaign) mass spectrometry laboratory or
by SOCAL Mass Spectrometry Facility at University of
California (Riverside). Elemental analyses were performed
by Atlantic Microlabs, Inc. (Norcross, GA).
In summary, the reaction of 2- and 3-nitroindoles with
muÈnchnones 13 and 14 can be highly regioselective to
afford 1,3-disubstituted pyrrolo[3,4-b]indoles in one
operation. The factors governing the regiochemical
outcome are unclear but probably re¯ect a combination of
electronic, steric, and possibly dipole interactions. In any
event, simple FMO theory fails to account for the observed
Scheme 7.

G. W. Gribble et al. / Tetrahedron 56 (2000) 10133±10140
10137
Ethyl 2-nitroindole-1-carboxylate (1). To a 08C stirred
suspension of sodium hydride (152 mg, 6.00 mmol) in
anhydrous DMF (20 mL) was added a solution of 2-nitro-
indole (486 mg, 3.00 mmol) dissolved in anhydrous DMF
(20 mL) dropwise via syringe. The reaction mixture was
stirred at 08C for 1 h and then freshly distilled ethyl
chloroformate (651 mg, 6.00 mmol) was added dropwise.
The reaction mixture was allowed to slowly warm to rt
and stirred stirred at rt for 12 h. The reaction mixture was
poured into externally cooled distilled water (50 mL) and
extracted with ether (3£80 mL). The combined organic
extracts were washed with brine (200 mL) and dried over
sodium sulfate. Removal of the solvent in vacuo gave a
brown oil (1 g) which was puri®ed by ¯ash chromatography
(hexanes; 1:2 CH2Cl2/hexanes). The desired product 1 was
obtained as an analytically pure orange powder (522 mg,
2.23 mmol, 74%): mp 55±578C; Rfˆ0.65 (3:1 hexanes/
CH2Cl2); IR (PTFE) 2983, 1746 (CvO), 1548, 1519,
1475, 1375, 1327, 1255, 1201, 1146, 1072, 1020, 943,
6.00 mmol) was added dropwise via syringe. The reaction
mixture was stirred at rt for 10 h and then poured into cooled
distilled water (50 mL) and ether (50 mL) was added. The
organic layer was separated and the aqueous layer was
extracted with ether (2£60 mL). The combined organic
layers were washed with distilled water (150 mL), brine
(150 mL), and dried over sodium sulfate. Removal of
solvent in vacuo gave a crude purple solid (1.5 g) which
was puri®ed by ¯ash chromatography (hexanes; 1:1
CH2Cl2/hexanes). The desired product 6 was obtained as a
white powder (1.30 g, 4.30 mmol, 86%) with spectral data
(1H NMR) consistent with that reported: mp 131±1338C;
Rfˆ0.50 (1:1 CH2Cl2/hexanes); IR (KBr) 3118, 3061,
1583, 1540, 1477, 1443, 1385 (SO2), 1296, 1267, 1223,
1183, 1137, 1089, 956, 823, 752 cm21; UV (EtOH) lmax
1
210, 236, 270 (sh), 278 (sh), 324 nm; H NMR (CDCl3) d
8.58 (s, 1H), 8.23±8.27 (m, 1H), 8.00±8.05 (m, 3H), 7.46±
7.69 (m, 5H); 13C NMR (CDCl3) d 137.0, 135.4, 133.8,
133.5, 130.1, 128.0, 127.6, 127.1, 126.2, 122.0, 121.5,
113.8; MS m/z 302 (M1), 286, 191, 165, 141, 125, 103,
77 (100%), 62.
1
860, 842, 759 cm21; UV (EtOH) lmax 218, 326 nm; H
NMR (CDCl3) d 8.03±8.07 (m, 1H), 7.69±7.71 (m, 1H),
7.54±7.60 (m, 1H), 7.44 (s, 1H), 7.35±7.40 (m, 1H), 4.50 (q,
2H, Jˆ7.2 Hz), 1.43 (t, 3H, Jˆ7.2 Hz); 13C NMR (CDCl3) d
149.6, 142.7, 136.8, 129.7, 124.9, 123.8, 115.0, 112.4,
111.5, 65.2, 14.0; MS m/z 235 (M111), 234 (M1), 162,
145, 132 (100%), 115, 104, 89, 77, 63. HRMS calcd for
C11H10N2O4 (M1) 234.0641, found 234.0641. Anal. Calcd
for C11H10N2O4: C, 56.46; H, 4.30; N, 11.96. Found: C,
56.54; H, 4.34; N, 11.85.
Ethyl 3-nitroindole-1-carboxylate (17). To a 08C stirred
suspension of sodium hydride (152 mg, 6.00 mmol) in DMF
(15 mL) was added a solution of 3-nitroindole (486 mg,
3.00 mmol) dissolved in DMF (15 mL). The reaction
mixture was stirred at 08C for 2 h and then freshly distilled
ethyl chloroformate (434 mg, 4.00 mmol) was added and
the reaction mixture was allowed to slowly warm to rt and
then stirred for 18 h. The reaction mixture was poured into
externally cooled distilled water (50 ml) and extracted with
ether (4£60 mL). The combined organic extracts were
washed with brine (200 mL) and dried over sodium sulfate.
Removal of solvent in vacuo gave a brown amorphous solid
(0.8 g) which was puri®ed by ¯ash chromatography
(hexanes; 1:1 CH2Cl2/hexanes). The desired product 17
was obtained as a white amorphous solid (350 mg,
1.50 mmol, 50%, mp 124±1268C). Recrystallization (1:4
CH2Cl2/hexanes) gave 17 as a white powder: mp 129±
1308C; Rfˆ0.27 (1:2 CH2Cl2/hexanes); IR (PTFE) 3173,
2977, 1762 (CvO), 1551, 1494, 1450, 1368, 1336, 1302,
1254, 1209, 1142, 1077, 1030, 767 cm21; UV (EtOH) lmax
216, 242, 330 nm; 1H NMR (CDCl3) d 8.60 (s, 1H), 8.24±
8.29 (m, 2H), 7.47±7.50 (m, 2H), 4.60 (q, 2H, Jˆ7.2 Hz),
1.55 (t, 3H, Jˆ7.2 Hz); 13C NMR (CDCl3) d 149.9, 134.5,
133.2, 127.7, 127.0, 125.9, 121.7, 121.0, 115.7, 65.2, 14.5;
MS m/z 235 (M111), 234 (M1, 100%), 175, 162, 132, 116,
103, 90, 76, 62. Anal. Calcd for C11H10N2O4: C, 56.41; H,
4.30; N, 11.96. Found: C, 56.34; H, 4.35; N, 12.05.
3-Nitroindole. To a 08C stirred mixture of silver nitrate
(10.2 g, 60.0 mmol) in acetonitrile (40 mL) was added a
solution of benzoyl chloride (7.73 g, 55.0 mmol) dissolved
in acetonitrle (20 mL) dropwise via addition funnel over
5 min. The benzoyl nitrate solution thus formed was
added to a 2108C stirred solution of indole (5.86 g,
50.0 mmol) dissolved in acetonitrile (60 mL). The reaction
mixture was stirred at 2108C for 1 h and then at rt for
30 min. The reaction mixture was then poured into
externally cooled distilled water (300 mL) and extracted
with acetate (8£150 mL). The combined organic extracts
were washed with brine (1 L), dried over sodium sulfate,
and concentrated in vacuo to give a dark purple amorphous
solid (15 g) which was puri®ed by ¯ash chromatography
(hexanes; 1:1 CH2Cl2/hexanes). The desired product was
obtained as an orange amorphous solid (1.90 g,
11.7 mmol, 23%). Recrystallization (aq. EtOH) gave green-
ish crystals: mp 215±2178C; Rfˆ0.29 (CH2Cl2); IR (PTFE)
3223 (NH), 3125, 2924, 1504, 1444, 1377, 1322, 1277,
1238, 1211, 1151, 1128, 830, 748 cm21; UV (EtOH) lmax
1
212, 234 (sh), 267 (sh), 350 nm; H NMR (D6-DMSO) d
Ethyl 2-(benzylamine)propionate. To a 08C stirred solu-
tion of benzylamine (11.8 g, 0.11 mol, 12.0 mL), and
triethylamine (11.1 g, 0.11 mol, 15.3 mL) dissolved in
THF (30 mL), was added a solution of ethyl 2-bromopro-
pionate (10) (18.1 g, 0.10 mol, 13.0 mL), dissolved in THF
(30 mL) dropwise via addition funnel over the period of
30 min. The reaction mixture was stirred at 08C for 2 h
and then at rt for 45 h. The mixture was ®ltered through a
plug of Celite and washed with THF (20 mL). The ®ltrate
was concentrated in vacuo. Ether (100 mL) was added to the
solution. The white milky product was concentrated in
vacuo and the residue was dissolved in ethyl acetate. The
usual workup and concentration in vacuo gave a yellow oil.
12.65 (br s, 1H), 8.65 (s, 1H), 8.07±8.10 (m, 1H), 7.55±7.58
(m, 1H), 7.30±7.38 (m, 2H); 13C NMR (D6-DMSO) d 135.1,
130.5, 128.5, 124.2, 123.7, 119.8, 119.4, 113.4; MS m/z 163
(M111), 162 (M1, 100%), 146, 132, 116, 104, 89, 77, 63.
3-Nitro-1-(phenylsulfonyl)indole (6). To a 08C stirred
suspension of sodium hydride (152 mg, 6.02 mmol)
suspended in anhydrous DMF (15 mL) was added a solution
of 3-nitroindole (811 mg, 5.00 mmol) dissolved in anhy-
drous DMF (15 mL) dropwise via an addition funnel. The
resulting reddish-purple solution was stirred at 08C for
30 min and then neat benzenesulfonyl chloride (1.06 g,

10138
G. W. Gribble et al. / Tetrahedron 56 (2000) 10133±10140
Fractional distillation under reduced pressure gave 13.5 g
(65%): bp 124±1258C (3 Torr); H NMR (CDCl3) d 7.33±
144.4p, 138.8p, 136.2p, 133.3, 132.0p, 129.3p, 128.9 (2C),
128.8 (2C), 128.3p, 127.6, 127.3, 127.2 (2C), 126.4p,
125.5 (2C), 125.0, 124.6, 122.6p, 119.3, 117.6, 177.3p,
114.1p, 48.3, 11.4; IR (KBr) 1630 m, 1354 vs, 1176 vs
cm21; UV±VIS (CH2Cl2, 2£1025 M) 230 (10,000), 268
(6000), 332 (4000) nm; UV±VIS (EtOH): 208, 220 sh,
266, 330 nm. Anal. Calcd for C30H24N2O2S: C, 75.61; H,
5.07; N, 5.88; S, 6.73. Found: C, 75.73; H, 5.09; N, 5.93; S,
6.73.
1
7.34 (m, 5H), 4.20 (q, 2H, Jˆ7.2 Hz), 3.66±3.84 (m, 2H),
3.38 (q, 1H, Jˆ6.9 Hz), 1.86 (bs, 1H), 1.31 (t, 3H,
Jˆ7.2 Hz), 1.28 (d, 3H, Jˆ 6.9 Hz); 13C NMR (CDCl3) d
176.0, 140.0, 128.6, 128.4, 127.3, 60.9, 56.2, 52.2, 19.3,
14.5.
N-Benzoyl-N-benzylalanine ethyl ester. To a 08C stirred
solution of ethyl 2-(benzylamine)propionoate (11.9 g,
0.057 mol) dissolved in CH2Cl2 (100 mL) in a 250 mL
3-necked ¯ask was added neat triethylamine (6.39 g,
0.063 mol) followed by the dropwise addition of benzoyl
chloride (8.48 g, 0.060 mol) via addition funnel over the
period of 2 h. The solution was left at rt for 44 h. The reac-
tion mixture was partitioned between methylene chloride
and 10% HCl. This mixture was then washed with 10%
HCl. After usual workup 17.9 g (100%) of solid product
remained, which was utilized without further puri®cation
in the next reaction.
An analytical sample of isomer 18 was recrystallized from
MeOH/CH2Cl2. Mp: 157±1588C; 1H NMR (CDCl3) d 8.10
(m, 1H), 7.2±7.6 (m, 16H), 6.72 (m, 2H), 5.02 (s, 2H, CH2),
2.33 (s, 3H, CH3); 13C{1H} NMR (CDCl3) d 143.9p, 138.9p,
136.5p, 133.2, 132.3p, 131.7 (2C), 128.9 (2C), 128.4 (2C),
128.2, 128.1 (2C), 127.8p, 127.3, 127.2 (2C), 126.7p, 125.5
(2C), 124.7, 124.5, 119.5, 117.8p, 117.6, 117.2p, 116.4p,
48.0, 12.0; IR (KBr) 1631 m, 1602 m, 1365 vs, 1349 s,
1176 vs cm21; UV±VIS (EtOH): 208, 262, 303 (sh) nm.
Anal. Calcd for C30H24N2O2S: C, 75.61; H, 5.07; N, 5.88;
S, 6.73. Found: C, 75.64; H, 5.09; N, 5.92; S, 6.75.
N-Benzoyl-N-benzylalanine (12). To
a solution of
N-benzoyl-N-benzylalanine ethyl ester (17.9 g, 0.057 mol)
dissolved in ethanol (60 mL) and distilled water (20 mL)
was added freshly crushed sodium hydroxide (4.56 g,
0.114 mol). The reaction mixture was heated to re¯ux for
6 h and then stirred at rt for 64 h. The aqueous solution was
treated with water (100 mL) and ethyl acetate (100 mL).
The organic layer was separated and washed with 1.0 M
NaOH (2£100 mL). The aqueous layers were acidi®ed
with HCl to pH 2 with ice added and external cooling.
The acidic solution was extracted with ethyl acetate
(2£200 mL). After the usual workup the resulting yellow
oil was dissolved in ether (40 mL). After gravity ®ltration
and refrigeration, the product crystallized out. The resulting
crystals were dried in vacuo to a yield 8.2 g (50%): mp 139±
b. From n-acetyl-n-benzyl-a-phenylglycine (11): A solution
of 3-nitro-1-phenylsulfonylindole (299 mg, 0.99 mmol) and
N-acetyl-N-benzyl-a-phenylglycine (11) (826 mg, 3.0
mmol, 3 equiv.) in THF (30 mL) was treated with DIPC
(0.47 mL, 3.0 mmol, 3.0 equiv.). The resulting yellow solu-
tion was heated at re¯ux for 23 h. Saturated aqueous
NaHCO3 (30 mL) was added to the cooled mixture, which
was extracted with ether (2£0 mL). The combined organic
extracts were washed with water (3£30 mL), dried over
1
brine (20 mL) and MgSO4, and evaporated. The H NMR
of the crude product showed a 94:6 ratio of 19 and 18.
Chromatography on alumina (basic, activity III) with
hexanes/CH2Cl2 (5:1) gave 19 as a yellow solid (356 mg,
74%).
1
1408C; H NMR (D6-DMSO) d 12.78 (bs, 1H), 7.25±7.46
(m, 10H), 4.13±5.08 (m, 3H), 1.28±1.36 (m, 3H). For major
rotamer 13C NMR (D6-DMSO) d 172.4, 171.0, 137.5, 136.3,
129.6, 128.5, 128.2, 127.3, 126.9, 126.2, 54.9, 52.8, 14.5.
2-Benzyl-3-methyl-1-phenyl-4-carboethoxy-2,4-dihydro-
pyrrolo[3,4-b]indole (16) and 2-benzyl-1-methyl-3-phen-
yl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole (15).
a. From n-benzyl-n-benzoylalanine (12) and 1-carboxy-
ethyl-3-nitroindole. A solution of 1-carboethoxy-3-nitro-
indole (17) (236 mg, 1.3 mmol) and N-benzyl-N-
benzoylalanine (12) (857 mg, 3.6 mmol, 2.8 equiv.) in
THF (25 mL) was treated with DIPC (0.47 mL, 3.0 mmol,
2.4 equiv.) at rt. The resulting mixture was heated at re¯ux
for 24 h, cooled to rt, poured into saturated aqueous
NaHCO3 (25 mL), and extracted with ether (3£25 mL).
The combined extracts were washed with water
(4£25 mL), dried over brine (25 mL) and Na2SO4, and
2-Benzyl-3-methyl-1-phenyl-4-(phenylsulfonyl)-2,4-di-
hydropyrrolo[3,4-b]indole (19) and 2-benzyl-1-methyl-3-
phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]in-
dole (18). a. From n-benzyl-n-benzoylalanine (12). A
solution of 3-nitro-1-(phenylsulfonyl)indole (6) (296 mg,
0.98 mmol) and N-benzyl-N-benzoylalanine (0.86 g,
3.0 mmol, 3.0 equiv.) in THF (30 mL) was treated with
DIPC (0.47 mL, 3.0 mmol, 3.0 equiv.). The resulting yellow
mixture was re¯uxed under nitrogen for 24 h, cooled,
poured into saturated aqueous NaHCO3 (25 mL), and
extracted with ether (2£25 mL). The combined organic
layers were washed with saturated aqueous NaHCO3
1
evaporated. H NMR of the residue showed a 60:40 ratio
of 16 and 15. Flash chromatography (2:1 hexanes/CH2Cl2)
gave the mixed product isomers as a red oil (270 mg, 53%).
On dissolution of this oil in hexanes and chilling, 16 pre-
cipitated as a yellow powder. An analytical sample of each
isomer was prepared by recrystallization from CH2Cl2/
1
(25 mL), dried over brine and MgSO4, and evaporated. H
NMR of the crude product showed a 70:30 mixture of 19
and 18. Flash chromatography (2:1 hexanes/CH2Cl2) of the
residue gave 19 (241 mg beige crystals, 73%) followed by
18 (120 mg orange oil, 85%). An analytical sample of 19
was recrystallized from CH2Cl2 to give colorless blocks:
1
hexanes. 16: mp: 175±1768C; H NMR (CDCl3) d 8.19
(d, Jˆ8.1 Hz, 1H), 7.2±7.6 (m, 11H), 7.09 (t, Jˆ7.6 Hz,
1H), 6.94 (d, Jˆ7.1 Hz, 2H), 5.26 (s, 2H, CH2Ph), 4.49
(q, Jˆ7.2 Hz, 2H, CH2CH3), 2.54 (s, 3H, CCH3), 1.47 (t,
Jˆ7.1 Hz, 3H, CH2CH3); 13C{1H} NMR (CDCl3) d 152.4p,
139.1, 132.7p, 132.2p, 129.6 (2C), 129.1 (2C), 129.0 (2C),
127.6, 127.5p, 127.3, 125.8 (2C), 125.0, 124.5 (2C), 123.0,
1
mp: 171±1728C; H NMR (CDCl3) d 8.18 (d, Jˆ8.3 Hz
1H), 7.57 (m, 2H), 7.44 (tt, Jˆ8.1, 1.5 Hz, 1H), 7.2±7.4
(m, 12H), 7.08 (td, Jˆ7.0, 1.0 Hz, 1H), 6.39 (m, 2H), 5.31
(s, 2H, CH2), 2.66 (s, 3H, CH3); 13C{1H} NMR (CDCl3) d

G. W. Gribble et al. / Tetrahedron 56 (2000) 10133±10140
10139
122.3p, 119.2, 116.8. 116.1p, 111.4p, 62.7, 48.6, 14.9, 12.3.
One quaternary carbon could not be located unambiguously.
and treated with freshly distilled benzaldehyde (378 mg,
3.56 mmol). The reaction mixture was stirred at 2708C
and then at rt for 10 h and then was poured into a solution
of saturated aqueous ammonium chloride (50 mL). The
organic layer was separated and the aqueous layer was
extracted with ether (2£60 mL). The combined organic
extracts were washed with brine (150 mL) and dried over
sodium sulfate. Removal of the solvent in vacuo gave an
orange oil (1 g) which was puri®ed by ¯ash chromatography
(hexanes; 3:1 CH2Cl2/hexanes). The desired product was
obtained as a yellow oil (580 mg, 1.48 mmol, 63%) with
spectral data (1H NMR and 13C NMR) consistent with that
reported: Rfˆ0.56 (CH2Cl2); 1H NMR (CDCl3) d 8.09±8.12
(m, 1H), 7.23±7.57 (m, 12H), 6.45±6.49 (m, 1H), 4.36 (d,
1H, Jˆ10.2 Hz), 2.70±2.78 (m, 2H), 1.66 (br s, 1H), 1.18 (t,
3H, Jˆ7.2 Hz); 13C NMR (CDCl3) d 142.3, 138.7, 137.0,
136.6, 133.8, 130.1, 129.2, 128.5, 127.3, 127.1, 126.8,
125.9, 125.7, 123.9, 119.8, 115.3, 67.0, 18.2, 15.0.
IR (KBr) 1707 vs, 1638 m, 1601 m, 1452 m, 1419 m cm21
;
UV±VIS (EtOH, 1£1024 M) 208 (10,000), 268 (4000), 294
(2000, sh), 336 (2000) nm. Anal. Calcd for C27H24N2O2: C,
79.39; H, 5.92; N, 6.86. Found: C, 79.42; H, 5.88; N, 6.81.
15: colorless needles, mp: 122±1238C; 1H NMR (CDCl3) d
8.32 (m, 1H), 7.67 (m, 1H), 7.24 (m, 10H), 6.82 (d, Jˆ
7.6 Hz, 2H), 4.98 (s, 2H, CH2Ph), 3.74 (q, Jˆ7.1 Hz, 2H,
CH2CH3), 2.47 (s, 3H, CCH3), 0.78 (t, Jˆ7.1 Hz, 3H,
CH2CH3); 13C{1H} NMR (CDCl3) d 152.1p, 142.9p,
138.9p, 134.3, 132.1 (2C), 128.8 (2C), 127.6, 127.5 (2C),
127.3p, 127.2, 125.8 (2C), 124.7p, 124.4, 123.1, 119.2,
117.5, 116.4, 115.0p, 114.9p, 61.6, 48.2, 14.2, 12.1. One
quaternary carbon could not be unambiguously located. IR
(KBr) 1707 vs, 1639 s, 1601 m, 1451 s, 1414 vs cm21; UV±
VIS (EtOH, 8£1025 M) 208 (20,000), 252 (10,000), 273
(8000, sh), 309 (4000), 317 (3000, sh) nm. Anal. Calcd
for C27H24N2O2: C, 79.39; H, 5.92; N, 6.86. Found: C,
79.33; H, 5.94; N, 6.85.
2-Benzoyl-3-ethyl-1-(phenylsulfonyl)indole (21). To a rt
stirred solution of 3-ethyl-2-(a-hydroxyphenylmethyl)-1-
(phenylsulfonyl)indole (387 mg, 1.00 mmol) dissolved in
CH2Cl2 (25 mL) was added black MnO2 (870 mg,
10.0 mmol) and the reaction mixture was heated to re¯ux
for 11 h and then allowed to cool to rt. The mixture was
®ltered through celite and the ®lter plug was washed with
CH2Cl2 (5£30 mL). The organic solution was washed with
brine (150 mL) and dried over sodium sulfate. Removal of
the solvent in vacuo gave a tan amorphous solid which was
puri®ed by ¯ash chromatography (hexanes; 1:1 CH2Cl2/
hexanes). The desired product 21 was obtained as an off-
white powder (290 mg, 0.749 mmol, 75%): mp 141±1428C
(lit.19 mp 142.5±1438C); Rfˆ0.77 (CH2Cl2); 1H NMR
(CDCl3) d 8.09±8.12 (m, 1H), 7.91±7.94 (m, 2H), 7.80±
7.83 (m, 2H), 7.28±7.62 (m, 9H), 2.64 (q, 2H, Jˆ7.5 Hz),
1.12 (t, 3H, Jˆ7.5 Hz); 13C NMR (CDCl3) d 189.8, 138.7,
136.9, 136.6, 134.0, 133.6, 133.3, 131.4, 130.6, 129.8,
129.0, 128.8, 127.5, 126.8, 124.6, 120.7, 115.7, 17.9, 14.8.
b. From n-acetyl-n-benzyl-a-phenylglycine (11) and 1-
carboxyethyl-3-nitroindole. A solution of 1-carboethoxy-
3-nitroindole (17) (430 mg, 1.8 mmol, 2.8 equiv.) in THF
(12 mL) was treated with DIPC at rt. The resulting yellow
mixture was re¯uxed for 24 h under nitrogen, then cooled.
Crystalline diisopropylurea was removed by ®ltration, the
®ltrate poured into saturated aqueous NaHCO3 (15 mL), and
the mixture extracted with ether (3£15 mL), dried over
brine and MgSO4, and evaporated. Flash chromatography
of the residue (1:1 CH2Cl2/hexanes) left a yellow solid
(145 mg) containing unreacted indole and a 95:5 mixture
of 16 and 15 (48 mg, 19%, estimated by NMR).
c. From n-benzyl-n-benzoylalanine (12) and 1-carboxy-
ethyl-2-nitroindole. A rt solution of 1-carboxyethyl-2-
nitroindole (1) (117 mg, 0.50 mmol) and N-benzyl-N-
benzoylalanine (12) (428 mg, 1.5 mmol) in THF (15 mL)
was treated with DIPC (0.234 mL, 1.5 mmol, 3.0 equiv.).
The mixture was re¯uxed with stirring for 30 h, cooled to
rt, ®ltered through Celite, and concentrated. Flash chroma-
tography of the residue (2:1 hexanes/CH2Cl2) provided 16
(173 mg, 80%), mp 162±1638; 1H and 13C{1H} NMR
spectra as described above.
2-Benzoyl-3-(bromomethyl)-1-(phenylsulfonyl)indole.
To a rt stirred solution of 2-benzoyl-3-ethyl-1-(phenylsul-
fonyl)indole (21) (217 mg, 0.560 mmol) and N-bromosuc-
cinimide (110 mg, 0.620 mmol) dissolved in carbon
tetrachloride (10 mL) was added AIBN (10 mg) and the
reaction mixture was heated to re¯ux for 8 h. After cooling
to 08C, the succinimide which formed was separated by
®ltration. Removal of the solvent in vacuo gave a crude
yellow amorphous solid (0.3 g). Recrystallization (ether/
hexanes) gave the desired product as tan plates (160 mg,
0.343 mmol, 61%): mp 109±1118C (lit.19mp 112±1148C);
d. From n-acetyl-n-benzyl-a-phenylglycine (11) and 1-
carboxyethyl-2-nitroindole. A rt solution of 1-carboxy-
ethyl-2-nitroindole (1) (117 mg, 0.50 mmol) and N-acetyl-
N-benzyl-a-phenylglycine (11) (438 mg, 1.50 mmol,
3 equiv.) was treated with DIPC (0.234 mL, 1.5 mmol,
3.0 equiv.). The mixture was re¯uxed for 23 h, cooled to
rt, and ®ltered through Celite. The ®ltrate was washed
with brine, dried over Na2SO4, and evaporated. The residue
was recrystallized from EtOH to give 15 (80 mg. 39%). 1H
and 13C{1H} NMR spectra as reported above.
1
Rfˆ0.67 (3:1 CH2Cl2/hexanes); H NMR (CDCl3) d 8.09±
8.12 (m, 1H), 7.86±7.96 (m, 5H), 7.34±7.66 (m, 8H), 5.19
(q, 1H, Jˆ6.9 Hz), 2.04 (d, 3H, Jˆ6.9 Hz); 13C NMR
(CDCl3) d 189.5, 137.8, 136.8, 136.7, 134.4, 134.3, 129.9,
129.5, 129.3, 129.0, 128.9, 127.9, 127.6, 126.9, 124.4,
122.5, 115.4, 40.0, 26.5.
3-Ethyl-2-(a-hydroxyphenylmethyl)-1-(phenylsulfonyl)-
indole. To a 2708C stirred solution of 3-ethyl-1-(phenyl-
sulfonyl)indole (20) (677 mg, 2.37 mmol) dissolved in THF
(40 mL) was added a solution of sec-butyllithium (2.60
mmol, 1.3 M in cyclohexane, 2.00 mL) dropwise. The
reaction mixture was stirred at 2708C for 3 h and then at
08C for 3 h. The reaction mixture was recooled to 2708C
2,4-Dihydro-1-methyl-3-phenyl-2-benzyl-4-(phenylsul-
fonyl)pyrrolo[3,4-b]indole (18). To a rt stirred solution
of 2-benzoyl-3-(a-bromoethyl)-1-(phenylsulfonyl)indole
(47 mg, 0.10 mmol) and benzylamine (21 mg, 0.20 mmol)
dissolved in chloroform (2 mL) was added potassium car-
bonate (55 mg, 0.40 mmol) and the reaction mixture was

10140
G. W. Gribble et al. / Tetrahedron 56 (2000) 10133±10140
9. Daly, K.; Nomak, R.; Snyder, J. K. Tetrahedron Lett. 1997, 38,
8611±8614.
stirred at rt for 10 h and then at re¯ux for 11 h. The reaction
mixture was partitioned between chloroform (15 mL) and
distilled water and acidi®ed with a solution of HCl (2.0 M,
1 mL). The organic layer was separated and washed with
brine (20 mL) and dried over sodium sulfate. Removal of
the solvent in vacuo gave a green oil (0.1 g) which was
puri®ed by ¯ash chromatography (hexanes; 1:2 CH2Cl2/
hexanes). The desired product 18 was obtained as a green
amorphous solid (23 mg, 0.048 mmol, 48%) identical (TLC,
1H NMR) to the minor isomer obtained by the reaction of
3-nitro-1-(phenylsulfonyl)indole (6) and the muÈnchnone
derived by the cyclodehydration (DIPC) of N-benzyl-N-
benzoylalanine: Rfˆ0.58 (1:1 CH2Cl2/hexanes).
10. Pelkey, E. T.; Chang, L.; Gribble, G. W. J. Chem. Soc, Chem.
Commun. 1996, 1909±1910.
11. Pelkey, E. T.; Gribble, G. W. Chem. Commun. 1997, 1873±
1874.
12. Gribble, G. W.; Pelkey, E. T.; Switzer, F. L. Synlett 1998,
1061±1062.
13. MuÈnchnones 13 and 14 were generated from the readily
synthesized N-acylamino acids 11 and 12 using the general method
of Huisgen (Huisgen, R.; Gotthardt, H.; Bayer, H. O.; Schaefer,
F. C. Chem. Ber. 1970, 103, 2611±2624) as modi®ed by Anderson
and Heider, who used N-ethyl-N0-dimethylaminopropylcarbo-
diimide as a cyclodehydrating agent (Anderson, W. K.; Heider,
A. R. Synth. Commun. 1986, 16, 357±364).
Acknowledgements
14. Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38,
5603±5606.
We thank the Donors of the Petroleum Research Fund
(PRF), administered by the American Chemical Society
(ACS), P®zer, and Wyeth-Ayerst for support of this project,
the PRF for a summer faculty fellowship to H. A. T. and
SmithKline±Beecham for sponsoring a Division of Organic
Chemistry ACS Graduate Fellowship to E. T. P. We thank
Dr Frank L. Switzer for the preparation of 11. Mass spectral
data were provided by the Boston University School of
Medicine Mass Spectrometry Resource, which is supported
by NIH/NCRR Grant No. P41-RR10888 (to C. E. Costello),
and by Mr Ron New and Dr Mary K. Young of the SOCAL
Mass Spectrometry Facility, University of California,
Riverside.
15. Pelkey, E. T.; Gribble, G. W. Synthesis 1999, 1117±1122.
16. Competition experiments with muÈnchnones 13 and 14, in reac-
tions with one equivalent of the dipolarophiles 2-nitrobenzo[b]-
furan, b-nitrostyrene, and phenylacetylene (unpublished results),
reveal that muÈnchnone 14 is 2±4.5 times more reactive than
muÈnchnone 13. This may account for the lower regioselectivity
seen with 14 in cycloaddition reactions with 17 and 18.
17. Simon, W. M.; Trujillo, H. A.; Pelkey, E. T.; Gribble, G. W.;
Jasinski, J. P. Acta Crystallogr. 2000, in press.
18. Jeevenandam, A.; Srinivasan, P. C. J. Chem. Soc., Perkin
Trans. 1 1995, 2663±2665.
19. Gribble, G. W.; Keavy, D. J.; Davis, D. A.; Saulnier, M. G.;
Pelcman, B.; Barden, T. C.; Sibi, M. P.; Olson, E. R.; BelBruno,
J. J. J. Org. Chem. 1992, 57, 5878±5891.
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