Synthesis of highly substituted indole alkaloid species via [4+1] cyclization of nucleophilic carbenes and indole isocyanates

Article abstract of DOI:10.3987/COM-05-S(T)38

Thermally induced [4+1] cyclization between indole isocyanates and dimethoxycarbene or bis(propylthio)carbene has been achieved with good chemical efficiency. The methodology provides rapid access to fused pyrroloindole substructures commonly found in a variety of indole alkaloid natural products.

Full text of DOI:10.3987/COM-05-S(T)38

HETEROCYCLES, Vol. 67, No. 2, 2006
643
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 643 - 653. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd July, 2005, Accepted, 22nd September, 2005, Published online, 27th September, 2005. COM-05-S(T)38
SYNTHESIS OF HIGHLY SUBSTITUTED INDOLE ALKALOID
SPECIES VIA [4 + 1] CYCLIZATION OF NUCLEOPHILIC CARBENES
AND INDOLE ISOCYANATES
James H. Rigby* and Patrick J. Burke
Department of Chemistry, Wayne State University, Detroit, MI 49202-3489,
USA. Email: jhr@chem.wayne.edu
Abstract - Thermally induced [4 + 1] cyclization between indole isocyanates and
dimethoxycarbene or bis(propylthio)carbene has been achieved with good
chemical efficiency.
The methodology provides rapid access to fused
pyrroloindole substructures commonly found in a variety of indole alkaloid
natural products.
This paper is dedicated to Barry M. Trost on the occasion of his 65th birthday.
INTRODUCTION
Recently, vinyl isocyanates have been shown to exhibit considerable utility as building blocks for the
formation of functionally elaborate five-membered nitrogen heterocycles via [4 + 1] cyclization with
sulfur-, oxygen-, and nitrogen-based carbenes.1-3 Nucleophilic carbenes, generated from the thermal
decomposition of oxadiazolines, constitute powerful 1,1-dipole equivalents for constructing pyrrolidinone
systems,4-6 and this process has been utilized as a key strategy-level transformation in the total synthesis
of the alkaloids tazettine and mesembrine.7,8 The methodology has also been extended to include the
construction of isatins via [4 + 1] cyclization with aryl isocyanates and bis(alkylthio)carbenes,6,9 a process
O
X
O
X
X
X
R1
R2
NCO
N
N
X
N
!
N
O
X
X
+
X
R1
R1
N2, acetone
R2
R2

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HETEROCYCLES, Vol. 67, No. 2, 2006
that is generally inaccessible with dimethoxycarbene.5,10 For example, bis(propylthio)carbene underwent
[4 + 1] cyclization with phenyl isocyanate to provide isatin (3), while the corresponding reaction with
dimethoxycarbene produces a hydantoin product (Scheme 1).6,10
MeO
PrS
OMe
SPr
N
N
N
N
O
O
1
2
!
!
PrS
SPr
Ph
MeO
OMe
PrS
SPr
O
N
OMe
OMe
NCO
O
N
N
Ph
O
SPr
PrS
3
Scheme 1. The differential reactivity of dimethoxy- and bis(propylthio)-carbenes with phenyl isocyanate.
The fused pyrroloindole ring (A) is a common structural motif present in many biologically active natural
products (Figure 1). For example, the pyrrolo[2,3-b]indole moiety is found in brevianamide E,11
sporidesmin A,12 flustramine B,13 and physostigmine;14 and as a consequence, considerable effort has been
expended to provide entries into these species.15-17 In addition, other isomeric pyrroloindole fused ring
systems are present in biologically relevant compounds;18-20 rapid access to these substructures could
provide key intermediates for the efficient syntheses of numerous indole alkaloids.
O
H
HO
N
N
N
N
H
H
Me
N
H
Br
(-)-brevianamide E
NH
flustramine B
OH
O
S
N
H
HO
H
N
Cl
N
A
O
S
N
Me
N
H
N
MeO
H
O
Me
O
N
Me
(-)-physostigmine
Me
MeO
sporidesmin A
Figure 1. Natural products containing the pyrrolo[2,3-b]indole substructure.
This paper describes the construction of the fused pyrroloindole ring structure at various locations about
the indole ring system via [4 + 1] cyclization between nucleophilic carbenes and indole isocyanates.

HETEROCYCLES, Vol. 67, No. 2, 2006
645
Dimethoxycarbene precursor (1) (Scheme 1), readily available via the procedures of Warkentin,21,22 and
bis(propylthio)carbene precursor (2), available from the published procedures of our laboratory,6 were
employed. The reaction sequence provides fused pyrroloindole species rich in functionality and well-
suited for post-cyclization elaboration.
RESULTS AND DISCUSSION
Indole isocyanates (4-9) were prepared from commercially available indole acids or indole carboxylates
as shown in Scheme 2. Methylindole-2-carboxylic acid and methylindole-3-carboxylic acid were treated
1) (PhO)2P(O)N3,
CO2H
NCO
TEA, (90-95%)
N
N
2) Ph-Y, !
Me
Me
4, 5
Y = Me, Cl, or H
1) NaH, MeI
2) NaOH, EtOH or
MeOH, reflux
OCN
RO2C
3) (PhO)2P(O)N3,
TEA
4) Ph-Y, !
N
N
Me
H
6-9
R = Me or Et
Y = Me, Cl, or H
Scheme 2. Preparation of indole isocyanates.
with diphenylphosphorazidate in the presence of TEA to afford the corresponding acyl azides in good
yield. The analogous indole isocyanates at positions 4-7 were accessed from the corresponding indole
carboxylates. The carboxylates were N-methylated with sodium hydride and methyl iodide, prior to
saponification with sodium hydroxide; the liberated acids were then converted to the requisite acyl azides.
The indole acyl azides underwent smooth thermally-induced Curtius rearrangement to the isocyanates (4-
9) in benzene, toluene, or chlorobenzene.
X
X
N
O
4 equiv.
X
X
N
N
O
NCO
N
X
Ph-Y, Ar, reflux, 15-180 min
Y = H, Me, or Cl
N
Me
X
Me
4
10
[4 + 1]
Scheme 3. [4 + 1] cycloaddition of indole-2-isocyanate with nucleophilic carbene.

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HETEROCYCLES, Vol. 67, No. 2, 2006
With the indole precursors in hand, attention turned to the [4 + 1] cyclization reactions. A typical
example employing indole-2-isocyanate (4) is shown in Scheme 3. The reactions were performed with
four equiv. of carbene to account for the formation of carbene dimer, a ubiquitous side-product of these
reactions.4,23,24 Consistent with related results,3,9 the reactions yielded 2:1 adducts, with the second
carbene equivalent inserting into the N-H bond of the incipient pyrrolidinone ring. Complete results are
compiled in Table 1. In all cases, dimethoxycarbene reacted with good efficiency in yields ranging from
55-75%, and for 12-15 the reported yields are over 4 steps from the starting indole carboxylates.
However, bis(propylthio)carbene performed poorly relative to dimethoxycarbene with the indole
Table 1. [4 + 1] cyclization reaction of indole isocyanates with dimethoxycarbene (1)
and bis(propylthio)carbene (2).
entry
isocyanate
product
yield*
X
X
O
NCO
10a, X=OMe, 65%
10b, X=SPr, trace
1
4
5
N
N
X
N
Me
X
Me
X
X
NCO
O
N
11a, X=OMe, 57%
11b, X=SPr, 21%
2
X
N
N
X
Me
Me
X
O
NCO
N
X
X
X
12a, X=OMe, 75%
12b, X=SPr, 68%
3
4
6
7
N
Me
N
Me
O
X
X
OCN
X
N
13a, X=OMe, 55%
13b, X=SPr, 53%
N
X
Me
N
Me
X
14a, X=OMe, 57%
14b, X=SPr, 58%
N
5
6
8
9
N
O
N
X
OCN
Me
X
Me
X
X
N
15a, X=OMe, 65%
15b, X=SPr, decomp.
N
Me
X
Me
N
X
NCO
O
X
*Yields for 12-15 are over 4 steps from the commercially available indole carboxylates.

HETEROCYCLES, Vol. 67, No. 2, 2006
647
isocyanates substituted at the 2-, 3-, and 7-positions. Cycloadducts (10b) and (11b) were only obtained in
trace amounts and 24% yield respectively, compared to 65% and 57% yields in the analogous reactions
with dimethoxycarbene. Furthermore, decomposition was observed in the reaction with indole isocyanate
(9) and bis(propylthio)carbene; whereas the corresponding reaction between dimethoxycarbene produced
the desired cycloadduct (15a) in 65% yield. Indole substrates with isocyanate substituents in the 4-6
positions reacted with both dimethoxy- and bis(propylthio)carbene providing cycloadducts (12-14) in
good yields. The observed regioselectivity for cycloadducts (13) and (14) is consistent with the frontier
electron density of indole for electrophilic substitution, as calculated by the LCAO-MO method.25
In addition to the natural products shown above in Figure 1, this methodology also provides rapid access
to isomeric pyrroloindole substructures found in other biologically active compounds. A few illustrative
examples are shown in Figure 2. "Twist-free" indolactam-V has been shown to represent the reactive
conformation of the teleocidins - a class of tumor promoters.26 The synthesis of "twist-free" indolactam-
V and related analogues could be efficiently achieved through the elaboration of cycloadduct (12).
Likewise, 5-hydroxytryptamine (5-HT) receptor antagonists19 - a class of molecules that represent
potential therapeutics for psychiatric disorders like anxiety, depression, and migraine - could be rapidly
assembled via cycloadduct (14). CC-1065 has been shown to possess potent in vitro and in vivo
antitumor activity, as well as antimicrobial activity.18 The structure consists of three pyrroloindole units,
represented by B, which could be prepared in an analogous manner to cycloadduct (13).
H
N
X
Me
O
OH
N
X
N
O
X
X
NH
O
X
N
N
N
N
O
N
X
N
Me
Me
N
H
"twist-free"
Indolactam-V
X
X
Me
5-HT receptor antagonist
12
14
O
H2N
HO
MeO
N
Me
HN
N
N
H
NH
N
N
O
N
H
HO
Me
O
O
B
OMe
(+)-CC-1065
Figure 2. Potential synthetic targets containing isomeric fused pyrroloindole ring systems

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HETEROCYCLES, Vol. 67, No. 2, 2006
In summary, dimethoxy- and bis(propylthio)carbene have been shown to effectively participate in [4 + 1]
cyclization reactions with indole isocyanates. The reaction provides fused pyrroloindole structures rich in
functionality, and poised for further elaboration into various classes of indole alkaloids. Significantly,
these results also provide an example of successful [4 + 1] cyclization between dimethoxycarbene and
aryl isocyanates, a process that commonly produces unwanted hydantoin products.5,10
EXPERIMENTAL
General
All reactions were performed in oven-dried glassware. 1H and 13C NMR spectra were collected on a 500
MHz Varian Unity-500 or 400 MHz Varian Mercury-400 spectrometer; IR spectra were collected on a
Perkin Elmer Spectrum RX-1 FT-IR system. Chemical shifts are reported relative to C6D6 (1H: δ 7.15
13
ppm, C: δ 128.0 ppm). Analytical TLC was performed on silica gel 60 F254 precoated glass plates;
compounds were purified by flash chromatography using 60 Å Purisil silica gel 230-400 mesh. New
compounds exhibited spectral (1H NMR, C NMR, and IR) and analytical (HRMS) data consistent with
13
the assigned structures. Dimethoxycarbene21,22 and bis(propylthio)carbene6 oxadiazoline precursors were
prepared as previously described.
General procedure for N-methylation
The indole carboxylates were dissolved in dry DMF (100 mM) under an Ar atmosphere and cooled to 0
°C. Two equiv. of sodium hydride, as a 60% dispersion in mineral oil, was then added and stirring
continued for 1 h at 0 °C. One equiv. of methyl iodide was then added and the reaction was stirred for 30
min at 0 °C, followed by 2 h at room temperature, at which time TLC revealed complete consumption of
starting material. Workup was achieved through the addition of 60 mL 1 M NaHCO3 and 60 mL ethyl
acetate. The aqueous phase was extracted 3x with 60 mL diethyl ether; the combined organics were then
dried with Na2SO4, filtered, and concentrated in vacuo to give the crude products as a clear, colorless oil.
The products were used without further purification.
General procedure for saponification of indole carboxylates
N-Methylated indole methyl (or ethyl) carboxylates were dissolved in a 1 M sodium hydroxide solution
consisting of 80% methanol/ethanol (depending on ester) and 20% water to a concentration of 90 mM.
The reaction mixture was refluxed for 8 h, at which time TLC revealed consumption of starting material.
The reaction was then added to 80 mL 1 M HCl and the aqueous phase was extracted 4x with 100 mL
dichloromethane; the combined organics were washed 1x with 100 mL saturated sodium chloride, dried
over Na2SO4, filtered, and concentrated in vacuo to provide the acid as a white solid, which was used
without further purification.

HETEROCYCLES, Vol. 67, No. 2, 2006
649
General procedure for the preparation of indole acyl azides
To a solution of the indole carboxylic acid dissolved in anhydrous benzene (0.2 M) was added one equiv.
of distilled triethylamine. The solution was stirred at rt for 15 min under Ar; one equiv. of
diphenylphosphorazidate (DPPA) was then added and stirring was continued for 1 h, at which time TLC
revealed complete conversion. The reaction mixture was then purified by silica gel chromatography
(various ratios of hexanes:ethyl acetate) to afford indole acyl azide. In three cases (6-8) the acyl azide
was inseparable from the DPPA byproduct. Therefore, the yields for 12-15 are reported over 4 steps from
the commercially available indole carboxylates.
General procedure for the [4 + 1] cyclization of indole isocyanates with dimethoxycarbene
The indole acyl azide was dissolved in anhydrous chlorobenzene or toluene to a concentration of 10 mM
and refluxed for 1 h under Ar to effect thermal Curtius rearrangement to the corresponding indole
isocyanate. To the refluxing mixture was added 4 equiv. of oxadiazoline (1) via syringe. Following
addition, refluxing continued until reaction was complete, typically 15-60 min in chlorobenzene, or 60-
180 min in toluene. The reaction was allowed to cool to room temperature; the solvent was then removed
in vacuo. The crude residue was purified by silica gel chromatography in varying ratios of hexanes:ethyl
acetate containing 2% triethylamine to yield the pure product as a light yellow, oily residue. The pure
products were characterized by NMR spectroscopy in C6D6. Note: In two cases (11a and 15a) the best
results were obtained by heating the corresponding indole acyl azides to reflux in the presence of the
carbene oxadiazoline precursor.
General procedure for the [4 + 1] cyclization of indole isocyanates with bis(propylthio)carbene
The indole acyl azide was dissolved in anhydrous benzene to a concentration of 10 mM and refluxed for 1
h under Ar to effect thermal Curtius rearrangement to the corresponding indole isocyanate. To the
refluxing mixture was added 4 equiv. of oxadiazoline (2) as a 1 M solution in hexanes in five portions
over 1 h.
The oxadiazoline stock solution was kept at 0 °C over the course of the addition. Following
addition, refluxing continued until reaction was complete, typically 60-120 min. The reaction was
allowed to cool to room temperature; the solvent was removed in vacuo. The crude residue was then
purified by silica gel chromatography in varying ratios of hexanes and ethyl acetate containing 1%
triethylamine, yielding pure product as a light orange, oily residue. The pure products were characterized
by NMR spectroscopy in C6D6.
3,3-Dimethoxy-1-dimethoxymethyl-8-methylpyrrolo[2,3-b]indol-2(1H,3H,8H)-one (10a).
The
corresponding acyl azide (51 mg, 0.25 mmol) precursor to 4, in the presence of dimethoxycarbene
precursor (1) (166 mg, 1.0 mmol), was heated to reflux in chlorobenzene. After 15 min, TLC revealed
consumption of starting material. Pyrrolodinoindole (10a) (52 mg, 65%) was obtained as an oily residue
after column chromatography with 90:8:2 hexanes:ethyl acetate:TEA. TLC (SiO2, 4:1 hexanes/ethyl

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HETEROCYCLES, Vol. 67, No. 2, 2006
acetate): Rf = 0.61. 1H NMR (500 MHz): δ 2.91 (s, 6H), 3.42 (s, 3H), 3.58 (s, 6H), 5.87 (s, 1H), 6.92 (d, J
= 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H). 13C NMR (125
MHz): δ 175.1, 143.9, 138.0, 124.4, 121.8, 120.1, 118.4, 110.3, 102.4, 100.8, 95.7, 54.2, 51.7, 31.6. IR
(neat): υ 2943, 1753, 1556, 1522, 1457, 1107, 1065 cm-1. HRMS calculated for C16H20N2O5 320.1372,
found 320.1385.
3,3-Dimethoxy-1-dimethoxymethyl-4-methylpyrrolo[3,2-b]indol-2(1H,3H,4H)-one (11a).
The
corresponding acyl azide (34 mg, 0.17 mmol) precursor to 5 underwent Curtius rearrangement to the
requisite isocyanate; indole isocyanate (5) and dimethoxycarbene precursor (1) (109 mg, 0.68 mmol)
were heated to reflux in toluene for 180 min. Pyrrolodinoindole (11a) (31 mg, 57%) was obtained as an
oily residue after column chromatography with 80:18:2 hexanes:ethyl acetate:TEA. TLC (SiO2, 2:1
hexanes/ethyl acetate): Rf = 0.42. 1H NMR (400 MHz): δ 3.10 (s, 6H), 3.23 (s, 3H), 3.43 (s, 6H), 6.09 (s,
1H), 6.95 (m, 1H), 7.18 (m, 2H), 8.21 (m, 1H), 7.59 (d, J = 7.5 Hz, 1H). 13C NMR (100 MHz): δ 178.5,
139.2, 138.4, 123.5, 123.1, 121.7, 120.2, 116.4, 110.2, 101.7, 94.8, 53.8, 51.6, 30.6. IR (neat): υ 2945,
1732, 1467, 1365, 1222, 1186, 1069, 994 cm-1. HRMS calculated for C16H20N2O5 320.1372, found
320.1367.
1-(Bis(propylthio)methyl)-4-methyl-3,3-bis(propylthio)pyrrolo[3,2-b]indol-2(1H,3H,4H)-one (11b).
The corresponding acyl azide (51 mg, 0.25 mmol) precursor to 5 underwent Curtius rearrangement to the
requisite isocyanate; indole isocyanate (5) and bis(propylthio)carbene precursor (2) (1.0 mL, 1.0 mmol)
were heated to reflux in benzene for 120 min. Pyrrolodinoindole (11b) (26 mg, 21%) was obtained as an
oily residue after column chromatography with 98:2 hexanes:TEA. TLC (SiO2, 4:1 hexanes/ethyl
acetate): Rf = 0.64. 1H NMR (400 MHz): δ 0.76 (m, 12H), 1.42 (m, 4H), 1.53 (m, 4H), 2.33 (m, 2H), 2.58
(m, 2H), 2.78 (m, 4H), 3.59 (s, 3H), 6.96 (d, J = 10 Hz, 1H), 7.00 (s, 1H), 7.13 (t, J = 10 Hz, 1H), 7.22 (t,
J = 10 Hz, 1H), 8.63 (d, J = 10 Hz, 1H). 13C NMR (125 MHz): δ 175.2, 139.4, 127.2, 122.7, 122.6, 120.5,
117.7, 116.1, 110.1, 73.7, 58.3, 34.9, 32.6, 30.2, 23.0, 22.8, 13.5, 13.4. IR (neat): υ 2961, 1708, 1462,
1404, 1277, 1014, 785 cm-1. HRMS calculated for C20H36N2OS4 496.1711, found 496.1714.
3,3-Dimethoxy-1-dimethoxymethyl-6-methylpyrrolo[2,3-e]indol-2(1H,3H,6H)-one
(12a).
The
corresponding acyl azide (28 mg, 0.14 mmol) precursor to 6 underwent Curtius rearrangement to the
requisite isocyanate; indole isocyanate (6) and dimethoxycarbene precursor (1) (90 mg, 0.56 mmol) was
heated to reflux in toluene for 180 min. Pyrrolodinoindole (12a) (37 mg, 75% over 4 steps) was obtained
as a crystalline solid after column chromatography with 70:28:2 hexanes:ethyl acetate:TEA. TLC (SiO2,
2:1 hexanes/ethyl acetate): Rf = 0.31. 1H NMR (500 MHz): δ 2.86 (s, 3H), 3.10 (s, 6H), 3.58 (s, 6H), 6.34
(s, 1H), 6.54 (d, J = 3.5 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 3.5 Hz, 1H), 7.40 (d, J = 8.0 Hz,
1H). 13C NMR (125 MHz): δ 173.1, 140.1, 133.5, 128.5, 117.9, 115.9, 114.7, 104.4, 103.6, 102.4, 99.0,

HETEROCYCLES, Vol. 67, No. 2, 2006
651
54.0, 50.9, 32.2. IR (neat): υ 2942, 1735, 1622, 1477, 1301, 1111, 1071, 993 cm-1. HRMS [M + Na]+
calculated for C16H20N2O5 343.1264, found 343.1271.
1-(Bis(propylthio)methyl)-6-methyl-3,3-bis(propylthio)pyrrolo[2,3-e]indol-2(1H,3H,6H)-one (12b).
The corresponding acyl azide (48 mg, 0.24 mmol) precursor to 6 underwent Curtius rearrangement to the
requisite isocyanate; indole isocyanate (6) and bis(propylthio)carbene precursor (2) (960 µL, 0.96 mmol)
were heated to reflux in benzene for 90 min. Pyrrolodinoindole (12b) (90 mg, 68% over 4 steps) was
obtained as an oily residue after column chromatography with 99:0:1 to 96:3:1 hexanes:ethyl
acetate:TEA. TLC (SiO2, 4:1 hexanes/ethyl acetate): Rf = 0.50. 1H NMR (500 MHz): δ 0.77 (m, 12H),
1.47 (m, 4H), 1.59 (m, 4H), 2.43 (m, 2H), 2.64 (m, 2H), 2.82 (m, 5H), 2.90 (m, 2H), 6.58 (d, J = 3.5 Hz,
1H), 6.77 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.60 (d, J = 3.5 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H). 13C NMR
(125 MHz): δ 175.6, 139.8, 132.4, 128.7, 118.8, 118.0, 115.3, 105.5, 104,5, 58.4, 57.4, 35.7, 32.8, 32.2,
23.1, 22.9, 13.6, 13.4. IR (neat): υ 2958, 1706, 1615, 1454, 1281, 1185, 715 cm-1. HRMS calculated
for C20H36N2OS4 496.1711, found 496.1721.
8,8-Dimethoxy-6-dimethoxymethyl-3-methylpyrrolo[3,2-e]indol-7(3H,6H,8H)-one
(13a).
The
corresponding acyl azide (60 mg, 0.30 mmol) precursor to 7 underwent Curtius rearrangement to the
requisite isocyanate; indole isocyanate (7) and dimethoxycarbene precursor (1) (192 mg, 1.2 mmol) were
heated to reflux in chlorobenzene for 15 min. Pyrrolodinoindole (13a) (53 mg, 55% over 4 steps) was
obtained as a crystalline solid (mp = 88 °C) after column chromatography with 80:18:2 to 70:28:2
hexanes:ethyl acetate:TEA. TLC (SiO2, 2:1 hexanes/ethyl acetate): Rf = 0.29. 1H NMR (500 MHz): δ
2.81 (s, 3H), 3.14 (s, 6H), 3.63 (s, 6H), 6.24 (s, 1H), 6.50 (d, J = 3.0 Hz, 1H), 6.73 (d, J = 3.0 Hz, 1H),
6.91 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz): δ 172.1, 135.2, 133.6, 131.0,
125.6, 115.2, 111.0, 108.4, 102.8, 100.3, 99.7, 54.2, 51.6, 32.1. IR (neat): υ 2944, 1729, 1594, 1233,
1457, 1117, 1068 cm-1. HRMS calculated for C16H20N2O5 320.1372, found 320.1367.
1-(Bis(propylthio)methyl)-6-methyl-3,3-bis(propylthio)pyrrolo[2,3-e]indol-2(1H,3H,6H)-one (13b).
The corresponding acyl azide (47 mg, 0.24 mmol) precursor to 7 underwent Curtius rearrangement to the
requisite isocyanate; indole isocyanate (7) and bis(propylthio)carbene precursor (2) (960 µL, 0.96 mmol)
were heated to reflux in benzene for 120 min. Pyrrolodinoindole (13b) (62 mg, 53% over 4 steps) was
obtained as a light orange, oily residue after column chromatography with 99:0:1 to 96:3:1 hexanes:ethyl
acetate:TEA. TLC (SiO2, 4:1 hexanes/ethyl acetate): Rf = 0.50. 1H NMR (500 MHz): δ 0.72 (t, J = 5.0
Hz, 6H), 0.79 (t, J = 5.0 Hz, 6H), 1.45 (m, 4H), 1.58 (m, 4H), 2.39 (m, 2H), 2.63 (m, 2H), 2.82 (m, 5H),
2.91 (m, 2H), 6.55 (d, J = 3.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.21 (d, J = 3.0 Hz, 1H),
8.00 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz): δ 174.6, 135.5, 131.5, 130.5, 128.3, 125.1, 110.0, 108.7,
99.6, 58.4, 57.3, 35.1, 32.7, 32.1, 23.1, 22.9, 13.6, 13.4. IR (neat): υ 2960, 1704, 1589, 1421, 1282, 770
cm-1. HRMS calculated for C20H36N2OS4 496.1711, found 496.1709.

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HETEROCYCLES, Vol. 67, No. 2, 2006
8,8-Dimethoxy-6-dimethoxymethyl-1-methylpyrrolo[2,3-g]indol-7(1H,6H,8H)-one
(14a).
The
corresponding acyl azide (63 mg, 0.31 mmol) precursor to 8 underwent Curtius rearrangement to the
requisite isocyanate; indole isocyanate (8) and dimethoxycarbene precursor (1) (198 mg, 1.24 mmol)
were heated to reflux in chlorobenzene for 30 min. Pyrrolodinoindole (14a) (58 mg, 57% over 4 steps)
was obtained as a crystalline solid (mp = 131-132 °C) after column chromatography with 90:8:2
hexanes:ethyl acetate:TEA. TLC (SiO2, 2:1 hexanes/ethyl acetate): Rf = 0.47. 1H NMR (500 MHz): δ
3.11 (s, 6H), 3.39 (s, 6H), 3.65 (s, 3H), 6.20 (s, 1H), 6.39 (d, J = 3.0 Hz, 1H), 6.51 (d, J = 3.0 Hz, 1H),
7.54 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H). 13C NMR (125 MHz): δ 171.1, 136.2, 133.5, 130.0,
125.6, 123.8, 106.7, 105.8, 102.7, 102.5, 100.6, 54.1, 51.3, 47.5, 35.9. IR (neat): υ 2944, 1725, 1592,
1455, 1334, 1235, 1080 cm-1. HRMS calculated for C16H20N2O5 320.1372, found 320.1372.
6-(Bis(propylthio)methyl)-1-methyl-8,8-bis(propylthio)pyrrolo[2,3-g]indol-7(1H,6H,8H)-one (14b).
The corresponding acyl azide (58 mg, 0.29 mmol) precursor to 8 underwent Curtius rearrangement to the
requisite isocyanate; indole isocyanate (8) and bis(propylthio)carbene precursor (2) (1.2 mL, 1.2 mmol)
were heated to reflux in benzene for 180 min. Pyrrolodinoindole (14b) (82 mg, 58% over 4 steps) was
obtained as a light orange, oily residue after column chromatography with 99:0:1 hexanes:ethyl
acetate:TEA. TLC (SiO2, 4:1 hexanes/ethyl acetate): Rf = 0.59. 1H NMR (500 MHz): δ 0.65 (t, J = 7.5
Hz, 6H), 0.73 (t, J = 7.5 Hz, 6H), 1.31 (m, 4H), 1.54 (m, 4H), 2.33 (m, 2H), 2.54 (m, 2H), 2.68 (m, 2H),
2.80 (m, 2H), 4.20 (s, 3H), 6.36 (d, J = 3.0 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 7.07 (s, 1H), 7.51 (d, J = 8.0
Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H). 13C NMR (125 MHz): δ 173.5, 134.8, 133.0, 130.9, 128.8, 122.8,
110.1, 107.4, 103.0, 58.6, 56.3, 39.1, 35.2, 32.7, 23.1, 22.8, 13.5, 13.4. IR (neat): υ 2959, 1704, 1584,
1448, 1284, 799 cm-1. HRMS calculated for C20H36N2OS4 496.1711, found 496.1686.
6,6-Dimethoxy-8-dimethoxymethyl-1-methylpyrrolo[3,2-g]indol-7(1H,6H,8H)-one (15a).
The
corresponding acyl azide (68 mg, 0.34 mmol) precursor to 9, in the presence of dimethoxycarbene
precursor (1) (218 mg, 1.36 mmol), was heated to reflux in chlorobenzene. After 30 min, TLC revealed
consumption of starting material. Pyrrolodinoindole (15a) (71 mg, 65% over 4 steps) was obtained as a
crystalline solid (mp = 198 °C d) after column chromatography with 80:18:2 hexanes:ethyl acetate:TEA.
TLC (SiO2, 2:1 hexanes/ethyl acetate): Rf = 0.44. 1H NMR (500 MHz): δ 2.95 (s, 6H), 3.52 (s, 6H), 3.71
(s, 3H), 6.03 (s, 1H), 6.43 (d, J = 3.0 Hz, 1H), 6.57 (d, J = 3.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.39 (d, J
= 8.0 Hz, 1H). 13C NMR (125 MHz): δ 175.4, 135.6, 133.7, 125.8, 120.4, 117.1, 116.3, 106.4, 102.6,
97.7, 73.7, 54.3, 50.9, 47.5, 37.5. IR (neat): υ 2940, 1737, 1467, 1303, 1183, 1071, 811 cm-1. HRMS
calculated for C16H20N2O5 320.1372, found 320.1378.
ACKNOWLEDGEMENTS
The authors wish to thank the National Science Foundation for their generous support of this research.

HETEROCYCLES, Vol. 67, No. 2, 2006
653
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