Indolecarbonyl Coupling Reactions Promoted by Samarium Diiodide. Application to the Synthesis of Indole-Fused Compounds

Article abstract of DOI:10.1021/jo9720795

By the assistance of an N-sulfonyl group or a cyano group at the C-2 position, hydroxyalkylations of indole-3-carbonyls were achieved by the promotion of samarium diiodide. The indolecarbonyl coupling reactions proceeded in high stereoselectivity via chel

Full text of DOI:10.1021/jo9720795

J . Org. Chem. 1998, 63, 2909-2917
2909
In d oleca r bon yl Cou p lin g Rea ction s P r om oted by Sa m a r iu m
Diiod id e. Ap p lica tion to th e Syn th esis of In d ole-F u sed
Com p ou n d s
Shu-Chen Lin, Fwu-Duo Yang, J iann-Shyng Shiue, Shyh-Ming Yang, and J im-Min Fang*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, Republic of China
Received November 11, 1997
By the assistance of an N-sulfonyl group or a cyano group at the C-2 position, hydroxyalkylations
of indole-3-carbonyls were achieved by the promotion of samarium diiodide. The indolecarbonyl
coupling reactions proceeded in high stereoselectivity via chelate transition states. Intramolecular
indolecarbonyl couplings of 1-(3-oxopropyl)indole-3-carboxaldehydes were realized as the indole-
carbonyl group was more reactive toward SmI2 than the aliphatic carbonyl group. Elaboration of
the coupling products with oxidizing agents, acid, phosphorus pentasulfide (or Lawesson’s reagent),
amines, and hydrazine led to a variety of indole derivatives and indole-fused polycyclic compounds
of synthetic interest and pharmaceutical uses.
Ta ble 1. Self-Cou p lin g Rea ction s of
In d ole-3-ca r boxa ld eh yd es P r om oted by Sm I2 in THF
Solu tion
In tr od u ction
The chemistry of indole compounds1 has been exten-
sively studied, partly due to their uses in pharmaceutical
and industrial products. However, most studies of indole-
3-carbonyls are limited to the conventional reactions,
such as reductions, oxidations (for indole-3-carboxalde-
hydes), nucleophilic reactions of organometallic reagents,
condensations with active methylene compounds, and
aldol reactions (for 3-acetylindoles), similar to those found
in common aromatic aldehydes and ketones. In a previ-
ous paper,2 we demonstrated a new method for hydroxy-
alkylations at the C-2 positions of indole-3-carbonyls by
the SmI2-promoted coupling reactions. We report herein
the scope and application of this method.
Resu lts a n d Discu ssion
On treatment with SmI2 (2 equiv) in THF at ambient
temperature for 1 h, 1-(methylsulfonyl)indole-3-carbox-
aldehyde (1b) underwent a reductive coupling reaction
HMPA
products
(yield/%)
entry reactant
R1
R2 equiv
1a
2a
3a
4a
5a
6a
7a
8e
1a
1b
1b
1c
1d
1e
2a
2a
Me
H
H
H
H
H
H
CN
CN
8
0
8
0
0
0
8
8
3a (44)
1
to give 4b in 66% yield (Table 1). According to the H
MeSO2
MeSO2
p-MeC6H4SO2
C6H5SO2
t-BuOCO
Me
4b (66)
4b (15)b
NMR analysis, compound 4b consisted of three isomers
(92:6:2), of which the major isomer was isolated and
determined to have the (1R*,3S*,3aS*,8bR*) configura-
tion by X-ray diffraction. The large coupling constant
(8.5 Hz) between H-3a and H-8b was in agreement with
their cis relationship. The analogous indolecarboxalde-
hydes 1c and 1d containing p-tolylsulfonyl or phenylsul-
fonyl groups at the 1-position also underwent similar self-
coupling reactions to give 4c and 4d in 50% and 37%
yields, respectively. Some pinacolic coupling products 3c
(15%) and 3d (6%) were also found.3 Under similar
3c (15) + 4c (50)
3d (6) + 4d (37)
4e (9)c
5 (30)d
5 (62)
Me
a
The THF solution of reactant (1 or 2a ) was added to the freshly
b
prepared SmI2 solution. The starting material 1b (11%) and its
desulfonylation product, indole-3-carboxaldehyde (42%), were also
obtained. c The starting material 1e (36%) was recovered. e The
SmI2-HMPA solution was added to the THF solution of 2a .
reaction conditions, 1-(tert-butoxycarbonyl)indole-3-car-
boxaldehyde (1e) only yielded a small amount (9%) of self-
coupling product 4e, while a large amount (36%) of the
starting material was recovered. The reaction of 1-me-
thylindole-3-carboxaldehyde (1a ) was very sluggish; no
apparent reaction occurred on treatment with SmI2 in
(1) (a) Remers, W. A. In Heterocyclic Compounds; Houlihan, W. J .,
Ed.; Wiley: New York, 1979; Vol. 25, Part III, pp 357-527. (b) Saxton,
J . E. In The Chemistry of Heterocyclic Compounds; Academic Press:
New York, 1983; Vol. 25, Part 4. (c) Gribble, G. W. In The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 1990; Vol. 39, p 239. (d)
Sundberg, R. J . Indoles; Academic Press: New York, 1996.
(2) (a) Shiue, J .-S.; Fang, J .-M. J . Chem. Soc., Chem. Commun. 1993,
1277. For related study on the phenyl and thiophene systems: (b)
Shiue, J .-S.; Lin, C.-C.; Fang, J .-M. Tetrahedron Lett. 1993, 34, 335.
(c) Yang, S.-M.; Fang, J .-M. J . Chem. Soc., Perkin Trans. 1 1995, 2669.
(d) Yang, S.-M.; Fang, J .-M. Tetrahedron Lett. 1997, 38, 1589. (e) Shiue,
J .-S.; Lin, M.-H.; Fang, J .-M. J . Org. Chem. 1997, 62, 4643.
(3) To our knowledge, there is no report on the pinacolic coupling
reaction of indolecarboxaldehydes. For general pinacolic coupling
reactions promoted by SmI2, see: Girard, P.; Namy, J . L.; Kagan, H.
B. J . Am. Chem. Soc. 1980, 102, 2693.
S0022-3263(97)02079-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/11/1998

2910 J . Org. Chem., Vol. 63, No. 9, 1998
Lin et al.
Sch em e 1
tive transition state by placing the indole ring (RL)
adjacent to the sulfonyl group (P) was less favorable due
to the steric effect. Protonation of the samarium enolate
E should occur on the less hindered exo face to furnish
4b (open form), which existed as a thermodynamically
stable cyclic form of hemiacetal. On the other hand, such
stabilization at C-2 would be void in the case of 1a with
a 1-methyl group. Thus, no coupling reaction at the C-2
position of 1a could occur.
As stabilization of the C-2 radical or anion is a
prerequisite factor to achieve the indolecarbonyl coupling
reaction, we consider that introduction of a cyano sub-
stituent at C-2 may exert a beneficial effect. Indeed, the
coupling reaction of 2-cyano-1-methylindole-3-carboxal-
dehyde (2a ), followed by in situ elimination of HCN,
occurred on treatment with SmI2-HMPA in THF to give
a 30% yield of compound 5 (entry 7, Table 1).
A
significant amount of starting material 2a (23%) was
recovered. The yield of 5 was improved to 62% by an
inverse addition of the SmI2-HMPA solution to the
substrate 2a . By inverse addition, the radical anion of
2a could be generated and reacted instantly with the
remaining molecules of 2a . The cyano group was selected
as the C-2 substituent for three reasons: (i) the electron-
withdrawing property and resonance effect of cyano
group can stabilize the C-2 anion,6a (ii) together with the
amino group, they can exert a captodative effect to
enhance the formation of C-2 radical,6b,c and (iii) the
cyano group is of a small enough size to minimize the
steric effect in the addition of a second indolecarbonyl.
Compound 2a was prepared by a Vilsmeier reaction7 of
2-cyano-1-methylindole, which was efficiently obtained
by cyanation of 1-methylindole using an electrochemical
method.8
Cross-coupling reactions of indole-3-carboxaldehydes
(1b and 2a ) with various aromatic and aliphatic carbonyl
compounds were also carried out to afford 7a -d and
8a -f (Table 2). On treatment of 1b with SmI2 in the
absence of HMPA, the self-coupling reaction (giving 4b)
competed with the cross-coupling reaction. Side products
formed by pinacolic couplings of aromatic aldehydes,
giving 6a ,b, were also found in entries 1 and 2 (Table 2).
Compound 1b failed to undergo cross-coupling with
acetophenone; instead, the self-coupling product 4b was
obtained in 81% yield. According to the NOE studies,
the indolecarbonyl coupling products 7b and 7d also had
(1R*,3S*,3aS*,8bR*) configurations, like 4b. Thus, ir-
radiation of H-3a (at δ 5.26, dd, J ) 8.5, 5.9 Hz) in
compound 7b caused 19% enhancement of H-3 (at δ 5.49,
d, J ) 5.9 Hz) and 16% enhancement of H-8b (at δ 4.19,
d, J ) 8.5 Hz). Irradiation of H-3a (at δ 4.84, dd, J )
8.5, 5.8 Hz) in compound 7d caused 14% enhancement
of H-3 (at δ 4.34, ddd, J ) 9.4, 5.8, 3.1 Hz) and 12%
enhancement of H-8b (at δ 4.11, d, J ) 8.5 Hz). The
coupling reaction of 1b with p-methoxybenzaldehyde in
the absence of HMPA gave 7a as a single isomer with a
(1R*,3S*,3aS*,8bR*) configuration. However, the reac-
tion in the presence of HMPA gave 7a and two isomers
in a ratio of 43:29:29. The two minor products had
THF for a similar period (1 h). However, a pinacol 3a
(diastereomeric ratio 10:1) could be isolated after stirring
for 7 days in the presence of a dipolar cosolvent HMPA,
which is often used to enhance the reactivity of SmI2.4
When 1b-d were treated with SmI2 in the presence of
HMPA, severe cleavage of the sulfonyl groups occurred
to give the corresponding indole-3-carboxaldehyde as the
main product.5
A reaction mechanism, as exemplified by the formation
of 4b (Scheme 1), is proposed to account for the stereo-
chemistry observed in the self-coupling reactions. The
reaction was presumably initiated by one-electron trans-
fer from SmI2 to the indolecarbonyl group of 1b. The
intermediate C-2 radical anion B was further reduced
by SmI2 to give an organosamarium C, which was
stabilized by the adjacent sulfonyl group.6a Addition of
a second molecule of 1b to the intermediate C might
proceed with a chelate transition state D.2 The alterna-
(4) The original paper for the effect of HMPA on reduction of organic
halides with SmI2: (a) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem.
Lett. 1987, 1485. For reviews for various reactions of SmI2 and the
effect of HMPA, see: (b) Kagan, H. B.; Namy, J . L. Tetrahedron 1986,
42, 6573. (c) Inanaga, J . J . Synth. Org. Chem. 1989, 47, 200. (d)
Soderquist, J . A. Aldrichim. Acta 1991, 24, 15. (e) Molander, G. A.
Chem. Rev. 1992, 92, 29. (f) Brandukova, N. E.; Vygodskii, Y. S.;
Vinogradova, S. V. Russ. Chem. Rev. 1994, 63, 345. (g) Molander, G.
A.; Harris, C. R. Chem. Rev. 1996, 96, 307.
(5) (a) Vedejs, E.; Lin, S. J . Org. Chem. 1994, 59, 1602. (b) Goulaouic-
Dubois, C.; Guggisberg, A.; Hesse, M. J . Org. Chem. 1995, 60, 5969.
(c) Ku¨nzer, H.; Stahnke, M.; Sauer, G.; Wiechert, R. Tetrahedron Lett.
1991, 32, 1949. (d) de Pouilly, P.; Che´nede´, A.; Mallet, J .-M.; Sinay¨, P.
Tetrahedron Lett. 1992, 33, 8065. (e) Ihara, M.; Suzuki, S.; Taniguchi,
T.; Tokunaga, Y.; Fukumoto, K. Synlett 1994, 859.
(6) (a) Saulnier, M. G.; Gribble, G. W. J . Org. Chem. 1982, 47, 757.
(b) Viehe, H. G.; J anousek, Z.; Mere´nyi, R. Acc. Chem. Res. 1985, 18,
148. (c) Yang, C.-C.; Chang, H.-T.; Fang, J .-M. J . Org. Chem. 1993,
58, 3100.
(7) Blatt, A. H. Organic Syntheses; Wiley: New York, 1967; Collect.
Vol. IV, p 539.
(8) (a) Yoshida, K. J . Am. Chem. Soc. 1979, 101, 2116. (b) Lin, C.-
D.; Fang, J .-M. J . Chin. Chem. Soc. 1993, 40, 571.

Indolecarbonyl Coupling Reactions Promoted by SmI2
J . Org. Chem., Vol. 63, No. 9, 1998 2911
Ta ble 2. Sm I2-P r om oted Cr oss-Cou p lin g Rea ction s of
In d ole-3-ca r boxa ld eh yd es w ith Oth er Ca r bon yl
Com p ou n d s
Sch em e 2
entry
reactants
HMPA (equiv) products (yield/%)
1a 1b + p-MeOC6H4CHO
2a 1b + p-CH3C6H4CHO
3a 1b + CH3CH2CHO
4a 1b + CH3(CH2)4CHO
0
0
0
0
0
8
8
8
8
8
6a (4) + 7a (42)
6b (14) + 7b (38)
7c (51)
7d (31)
8a (63)
8b (73)
8c (38)
8d (51)
8e (75)
5
6
2a + p-MeOC6H4CHO
2a + p-CH3C6H4CHO
2a + CH3CHO
2a + CH3(CH2)4CHO
2a + C6H5COCH3
2a + C2H5COCH3
7
8
9
10
8f (67)
a
The self-coupling product 4b was also obtained in significant
amounts (40-46%).
(1R*,3R*,3aS*,8bR*) and (1S*,3R*,3aS*,8bR*) configu-
rations, respectively, as determined by the NMR analyses
and their subsequent transformations into an indoline
lactone 23 (see Scheme 5 ). The indole-carbonyl coupling
reaction of 1b with propionaldehyde was less selective,
giving 7c as a mixture of three isomers (63:26:11). The
preference of the (3S*,3aS*) relationship in the coupling
products can be attributable to chelate transition states
similar to that shown in Scheme 1 (RL ) p-MeOC6H4,
p-CH3C6H4, or butyl group). The dipolar cosolvent HMPA
may interfere with the chelate transition state, and the
coupling reaction may also proceed with an open transi-
tion state to give (3R*,3aS*) products. The selectivity
in 7c decreases as the incoming aldehyde becomes
smaller (RL ) ethyl group).
The cross-coupling reactions of 2a were facilitated by
the cyano group at the C-2 position. The reactions
proceeded smoothly with aromatic and aliphatic alde-
hydes and ketones, even in the presence of HMPA, to give
simply the desired indolecarbonyl coupling products 8a -f
without interference of side reactions.
On treatment with SmI2-HMPA in THF for 1 h,
1-methyl-3-acetylindole (9) underwent a cross-coupling
reaction with p-methoxybenzaldehyde (Scheme 2); how-
ever, the reaction with acetophenone failed due to a
competitive dimerization of acetophenone.2e The 2,3-cis
configuration of the coupling product 10 was inferred
from a large coupling constant of 8.7 Hz between H-2 and
H-3 in the 1H NMR spectrum.6b,9 The cross-coupling
reactions of 3-acetyl-2-cyano-1-methylindole (2b) with
aromatic and aliphatic aldehydes were similarly carried
out to give 11a -c in better yields, presumably due to
the beneficial effect of the cyano substituent. A cross-
coupling reaction of methyl 2-cyano-1-methylindolecar-
boxylate (2c) with acetaldehyde, giving 12 (25%), also
occurred after stirring for a prolonged period (12 h) at
room temperature. However, a reductive decyanation
predominated in such case to give 13 (60%).
Comins and Killpack10 have reported the C-2 methyl-
ation of 1-methylindole-3-carboxaldehyde and 1-(meth-
oxymethyl)indole-3-carboxaldehyde by sequential treat-
ments with lithium N-methylpiperazine, BuLi (3 equiv),
and MeI. It is suggested that addition of lithium piper-
azide onto the aldehyde group can form an aminal
intermediate to induce the ortho-metalation (at C-2) and
the subsequent alkylation. However, this procedure is
somewhat tedious, and attempted metalations with N-
(phenylsulfonyl)- or N-(tert-butoxycarbonyl)indole-3-car-
boxaldehydes (1d or 1e) fail as decomposition occurs. This
method is not applicable to introduction of C-2 substit-
uents on indole ketones such as 2b or 9. For a compari-
son of our method with that using the ortho-metalation
procedure,11 we also investigated the transformation
illustrated in Scheme 3. Metalation of 1-methylindole
with BuLi and the subsequent hydroxyalkylation with
CH3CHO gave 15, which reacted with BuLi and Ac2O to
give a low yield (24%) of the desired C-3 acetylation
(10) (a) Comins, D. L.; Killpack, M. O. J . Org. Chem. 1987, 52, 104.
(b) Comins, D. L. Synlett 1992, 615. (c) Davis, J . E.; Raithby, P. R.;
Snaith, R.; Wheatley, A. E. H. Chem. Commun. 1997, 1721.
(11) Snieckus, V. Chem. Rev. 1990, 90, 879.
(9) (a) Chapman, O. L.; Eian, G. L.; Bloom, A.; Clardy, J . J . Am.
Chem. Soc. 1971, 93, 2918. (b) Schultz, A. G.; Sha, C.-K. Tetrahedron
1980, 36, 1757.

2912 J . Org. Chem., Vol. 63, No. 9, 1998
Lin et al.
Sch em e 3a
Sch em e 5a
a
Reagents and conditions: (i) BuLi, THF, -78 °C (1 h) to 0 °C
(2 h), then CH3CHO, rt (6 h), 82%; (ii) BuLi, THF, -78 °C to rt (6
h), then Ac2O, 0 °C to rt (12 h), 16 (70%), 17 (24%); (iii) AlCl3,
Ac2O, CH2Cl2, 0 °C to rt (4 h), 11b (13%), 18 (41%).
Sch em e 4a
a
Reagents and conditions: (i) NaH, THF, BrCH2CH2CH[O-
(CH2)3O], 25 °C, 48 h; (ii) 70% aqueous AcOH, reflux 1 h; (iii) SmI2,
THF, HMPA, 0 °C (10 min) to 25 °C (1 h).
product 17. Alternatively, alcohol 15 was treated with
a mixture of Ac2O and AlCl3 to give the indole ketone
11b (13%) and a dimeric condensation product 1812 (41%,
cis/trans isomers ) 83:17). Our method using SmI2-
promoted coupling reactions appeared to have the ad-
vantages of simple operation and good selectivity.
Application . Since the indolecarbonyl group in 20a-c
is considered to be more reactive toward SmI2 than the
aliphatic carbonyl group, the intramolecular coupling
reactions can be anticipated to occur in the indolecarbonyl
coupling manner. The indole dialdehydes 20a -c were
prepared by alkylation of the 3-formylindoles 19a -c
individually with 2-(2-bromoethyl)-1,3-dioxane followed
by hydrolysis (Scheme 4). The desired intramolecular
indolecarbonyl coupling proceeded smoothly on treatment
with SmI2 to give the pyrrolidino[1,2-a]indolecarboxal-
dehydes 21a -c with a mytomycin skeleton.13 Activation
by a C-2 cyano group or N-sulfonyl group was unneces-
sary in such intramolecular cyclizations. The reaction
involved a rearomatization of the indoline intermediate
presumably via autoxidation on workup.
a
Reagents and conditions: (i) DDQ, PhH, rt, 16 h, 22, 57%; (ii)
PDC, sieves, CH2Cl2, rt, 4-15 h, 23, 83%, 25a , 94%, 25b, 73%,
25c, 62%, 25d , 55%; (iii) DDQ, PhH, reflux, 2 h, 24, 86%.
jected to oxidation with DDQ or PDC (Scheme 5). The
indoline hemiacetal 4b with (1R*,3S*,3aS*,8aR*)-con-
figuration was oxidized by DDQ at room temperature to
give the corresponding indoline lactone 22 with a
(3S*,3aS*,8aR*) configuration. Oxidation of a sample
containing the (1R*,3R*,3aS*,8bR*) and (1S*,3R*,3aS*,
8bR*) isomers of 7a with PDC afforded a single indoline
lactone 23 with a (3R*,3aS*,8aR*) configuration. Com-
pound 23 with a cis junction also exhibited a large
coupling constant (J 3a,8b ) 10.0 Hz) comparable to that
of 4b. The coupling constant between H-3 and H-3a in
23 was small (1.7 Hz) by comparison with that of 4b (5.7
Hz) or 22 (7.6 Hz), indicating that the orientation of the
aryl group in 23 differs from that of 4b. Oxidations of
2-(hydroxyalkyl)indoles 8a ,b,d and 11b with PDC yielded
the corresponding indole ketones 25a -d . Vigorous oxi-
dation of hemiacetal (1R*,3S*,3aS*,8aR*)-7a with DDQ
in refluxing benzene also led to an indole ketone 24.
The hydroxyalkylated compounds obtained from inter-
molecular indolecarbonyl coupling reactions were sub-
(12) Katritzky, A. R.; Li, J .; Stevens, C. V. J . Org. Chem. 1995, 60,
3401.
(13) (a) Franck, R. W. In Progress in the Chemistry of Organic
Natural Products; Herz, W., Grisebach, H., Kirby, G. W., Eds.;
Springer-Verlag: Wien, 1979, p 1. (b) Verboom, W.; Reinhoudt, D. N.
Recl. Trav. Chim. Pays-Bas 1986, 105, 199. (c) Kinugawa, M.; Arai,
H.; Nishikawa, H.; Sakaguchi, A.; Ogasa, T.; Tomioka, S.; Kasai, M.
J . Chem. Soc., Perkin Trans. 1 1995, 2677. (d) Cotterill, A. S.; Moody,
C. J .; Roffey, J . R. A. Tetrahedron 1995, 51, 7223.

Indolecarbonyl Coupling Reactions Promoted by SmI2
J . Org. Chem., Vol. 63, No. 9, 1998 2913
Sch em e 6a
Sch em e 7
10.32). The acid-catalyzed condensation of 11a gave a
furo[3,4-b]indole 27. In a similar reaction mode, 8a was
treated with Lawesson’s reagent or benzylamine to give
thieno[3,4-b]indole 28 and pyrrolo[3,4-b]indole 29. Com-
pounds 27-29 are equivalents of indole-2,3-quinodi-
methane employed as diene substrates in Diels-Alder
reactions.14a-c For example, the indolecarbonyl coupling
product 11b can be elaborated and utilized in a Diels-
Alder reaction with pyridyne to give 6-methylellip-
ticine.14a-c The acid-catalyzed reaction of 11c proceeded
differently to give a pentane[b]indole 30. This reaction
was presumably initiated by an intramolecular hydride
shift15 to give the intermediate G, which underwent an
R-alkylation via the intermediate H to furnish the
observed product. Compound 30 could be the thermo-
dynamically favored product or obtained from a less steric
demanding transition state I. The small coupling con-
stant (J ) 2.0 Hz) between H-1 and H-2 as well as an
NOE experiment (as illustration) were in agreement with
the trans configuration of 30.
The reaction of 8a with NH4OAc afforded a product
31 containing both pyrrolo[3,4-b]indole and furo[3,4-b]-
indole moieties (Scheme 7). The reaction was presum-
ably initiated by formation of an aminal intermediate J ,
which could be trapped by a second molecule of 8a .
Subsequent oxidative aromatization of the intermediate
K would furnish the observed product 31.
a
Reagents and conditions: (i) p-TsOH, PhMe or PhH, reflux,
5-24 h; 26, 85%, 27, 82%, 30, 63%; (ii) [p-MeOC6H4P(dS)S]2, 1,4-
dioxane, reflux, 4 h, 28, 63%; (iii) PhCH2NH2, p-TsOH, PhMe,
reflux, 6 days, 29, 46%.
Two molecules of 8a condensed with one molecule of
hydrazine to form a bishydrazone 32 (Scheme 8). Upon
workup, compound 32 existed as a mixture of two isomers
as shown by the 1H NMR spectrum, but the isomeric
mixture degenerated to a single isomer on standing at
ambient temperature. We assumed that the (E,E)-isomer
with hydrogen-bonded seven-membered rings was more
stable than the (Z,Z)-isomer with hydrogen-bonded eight-
membered rings. Treatment of 32 with DDQ or MnO2
gave the corresponding diketone 33 (ca. 30%), along with
a degradative product 25a (ca. 12%). Diketone 25a
reacted with hydrazine afforded a 1:1 condensation
product 34a . The reaction of 25b with hydrazine pro-
ceeded in a similar manner to give a pyridazino[4,5-b]-
indole 34b. The reactions of 25a and 25c with P2S5
yielded mercaptothieno[2,3-b]indole 35 and thieno[2,3-
b]indole-1-thione 36, respectively. Upon treatment with
The indolecarbonyl coupling products were elaborated
to a series of heterocycle-fused indoles.14 Treatment of
hemiacetal 4b with p-TsOH in refluxing benzene afforded
a single product 26 (85%), presumably via the dehydra-
tion intermediate F followed by elimination of a meth-
ylsulfonyl group (Scheme 6). The E-configuration of 26
was verified by an NOE experiment, i.e., irradiation of
the vinyl proton (at δ 7.63), causing enhancements of the
signals of the iminyl and formyl protons (at δ 9.17 and
(14) (a) Pindur, U.; Erfanian-Abdoust, H. Chem. Rev. 1989, 89, 1681.
(b) 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. (c) Sha, C.-K.; Chuang, K.-S.; Yang, J .-J . J .
Chem. Soc., Chem. Commun. 1984, 1552. (d) Kuroda, T.; Takahashi,
M.; Ogiku, T.; Ohmizu, H.; Nishitani, T.; Kondo, K.; Iwasaki, T. J .
Org. Chem. 1994, 59, 7353. (e) Shafiee, A.; Sattari, S. J . Heterocycl.
Chem. 1982, 19, 227. (f) Monge, A.; Aldana, I.; Alvarez, I.; Font, M.;
Santiago, E.; Latre, J . A.; Bermejillo, M. J .; Lopez-Unzu, J . J . Med.
Chem. 1991, 34, 3023. (g) Mincey, T.; Traylor, T. G. J . Am. Chem. Soc.
1979, 101, 766.
(15) Djerassi, C. Org. React. 1951, 6, 207.

2914 J . Org. Chem., Vol. 63, No. 9, 1998
Lin et al.
Sch em e 8a
intermolecularly by the assistance of an N-sulfonyl group
or a cyano group at C-2. The coupling reactions appeared
to proceed in high stereoselectivity via chelate transition
states as illustrated in Scheme 1. Elaboration of the
coupling products with oxidizing agents, acid, P2S5 (or
Lawesson’s reagent), amines, and hydrazine led to a
variety of indole derivatives and indole-fused polycyclic
compounds of synthetic interest and pharmaceutical uses.
For example, furo[3,4-b]indole 27 can be utilized as an
equivalent of indole-2,3-quinodimethane for Diels-Alder
reactions.14 Pyrrolidino[1,2-a]indolecarboxaldehydes
21a -c construct a prototype of mytomycins.13
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR spectra were
recorded at 200, 300, or 400 MHz; 13C NMR spectra were
recorded at 50, 75, or 100 MHz. Tetramethylsilane and
CDCl3 were used as internal standards in 1H and 13C
NMR spectra, respectively. Mass spectra were recorded
at an ionizing voltage of 70 or 20 eV. Merck silica gel
60F sheets were used for analytical thin-layer chroma-
tography. Column chromatography was performed on
SiO2 (70-230 mesh); gradients of EtOAc and n-hexane
were used as eluents. High-pressure liquid chromatog-
raphy was carried out on a liquid chromatograph equipped
with a refractive index detector. The samples were
analyzed and/or separated on a Hibar Lichrosorb Si 60
(7 µm) column (25 cm × 1 cm) with the indicated eluent
with a 5 mL/min flow rate. THF was distilled from
sodium benzophenone ketyl under N2.
1-Methylindole-3-carboxaldehyde (1a , mp 68-69 °C),8b
1-(methylsulfonyl)indole-3-carboxaldehyde (1b, mp 169.5-
170.5 °C),14b 1-(4-tolylsulfonyl)indole-3-carboxaldehyde
(1c, mp 144.5-146 °C),14b 1-(phenylsulfonyl)indole-3-
carboxaldehyde (1d , mp 156-158 °C),14b 1-(tert-butoxy-
carbonyl)indole-3-carboxaldehyde (1e, mp 125-126 °C),14b
3-formyl-1-methylindole-2-carbonitrile (2a , mp 165-166
°C),8b and 3-acetyl-1-methylindole-2-carbonitrile (2b, mp
152-154 °C)8b were prepared according to reported
methods. Methyl 2-cyano-1-methylindole-3-carboxylate
(2c), mp 141-143 °C, was prepared in 98% yield by
treatment of the aldehyde 2a with MnO2/NaCN/HOAc
in MeOH at room temperature for 17 h.17 Indole-3-
carboxaldehydes (19a -c) were treated with NaH and
2-(2-bromoethyl)-1,3-dioxane in THF, followed by hy-
drolysis in aqueous HOAc, to give 1-(3-oxopropyl)indole-
3-carboxaldehydes (20a -c) in 75-81% yield.
Gen er a l P r oced u r e for th e Rea ction s of In d ole-
ca r bon yls w ith Sm I2. Samarium metal (0.36 g, 2.4
mmol) and 1,2-diiodoethane (0.56 g, 2 mmol) in anhy-
drous THF (20 mL) were stirred at room temperature
under an argon atmosphere for 1 h to give a deep blue
solution. HMPA (1.4 mL, 8 mmol) was added in certain
cases. The mixture was cooled to 0 °C in an ice bath, a
THF solution (2 mL) of indolecarbonyl compound (1
mmol), along with an appropriate aldehyde (1-1.7 mmol)
in the case of cross-coupling reactions, was added drop-
wise over a period of 2 min. The light green mixture was
stirred at 0 °C for 30 min and warmed to room temper-
ature over a period of 0.5-2 h. The serum cap was
removed, and Et2O (10 mL) was added. The mixture was
then filtered and rinsed with EtOAc (15 mL). The
a
Reagents and conditions: (i) N2H4‚H2O, EtOH, reflux, 12 h,
32, 84%, 34a , 89%, 34b, 82%; (ii) MnO2 or DDQ, 33, 30%; (iii)
P2S5, 1,4-dioxane, reflux, 1-4 h, 35, 51%, 36, 68%.
P2S5, the two carbonyl groups in 25a (or 25c) might be
converted to thiocarbonyls such as in the intermediate
L. The thial group could react further with a second
molecule of P2S5 to form a dithioacetal analogue M. The
subsequent intramolecular hydride shift and cyclization
would afford a thieno[2,3-b]indole-1-thione such as 36.
If the C-3 substituent R is an aromatic group such as
that derived from 25a , tautomerization could be facili-
tated to give a mercaptothieno[2,3-b]indole such as 35.
Compound 36 showed a resonance at δ 213.3 attributable
to the thione group in the 13C NMR spectrum,16 but no
carbonyl absorption in the IR spectrum was observed.
Con clu sion . We have demonstrated in this study that
indolecarbonyl coupling reactions can be achieved in two
ways: (i) intramolecularly by monitoring the different
reactivities of indolecarbonyl and aliphatic carbonyl
groups toward SmI2 as shown in Scheme 4 and (ii)
(17) Corey, E. J .; Gilman, N. W.; Ganem, B. E. J . Am. Chem. Soc.
1968, 90, 5616.
(16) Still, I. W. J .; Plavac, N. Can. J . Chem. 1976, 54, 280.

Indolecarbonyl Coupling Reactions Promoted by SmI2
J . Org. Chem., Vol. 63, No. 9, 1998 2915
organic phase was concentrated under reduced pressure
and chromatographed on a silica gel column with elution
of EtOAc/hexane to give products.
) 10.0, 7.6 Hz), 6.20 (1 H, d, J ) 7.6 Hz), 6.88-7.04 (3
H, m), 7.19-7.30 (4 H, m), 7.67 (1 H, d, J ) 7.2 Hz), 7.86
(1 H, d, J ) 8.8 Hz); 13C NMR (CD3CN, 50 MHz) δ 36.8,
41.4, 48.2, 66.4, 81.2, 114.0, 115.6, 118.3, 121.4, 124.0,
125.8, 126.0, 126.3, 127.2, 127.9, 130.0, 130.8, 136.0,
142.8, 175.5; MS m/z (rel intensity) 446 (18, M+), 195 (98),
144 (68), 116 (100), 89 (25); HRMS calcd for C20H18N2O6S2
446.0606, found 446.0598.
1,3,3a,8b-Tetr ah ydr o-1-h ydr oxy-4-(m eth ylsu lfon yl)-
3-[1-(m eth ylsu lfon yl)in dol-3-yl]fu r o[3,4-b]in dole (4b).
According to the general procedure, treatment of 1-(me-
thylsulfonyl)indole-3-carboxaldehyde (1b) with SmI2 gave
the self-coupling product (66%, three isomers (92:6:2)).
The major isomer was isolated by recrystallization and
determined to have the (1R*,3S*,3aS*,8bR*) configura-
tion by an X-ray diffraction analysis: solid; mp 199-200
°C (from CHCl3-cyclohexane); TLC (EtOAc/hexane (1:
3a ,8b -Dih yd r o-4-(m et h ylsu lfon yl)-3-(4-m et h oxy-
p h en yl)fu r o[3,4-b]in d ol-1-on e (23). A mixture of the
(1R*,3R*,3aS*,8bR*) and (1S*,3R*,3aS*,8bR*) isomers
of 7a (17 mg, 0.05 mmol) was treated with PDC (40 mg,
0.10 mmol) and molecular sieves (4 Å, 1 g) in CH2Cl2 (6
mL) at room temperature (25 °C) for 4 h. The mixture
was concentrated and chromatographed on a silica gel
column by elution with EtOAc/hexane (1:3) to give a
lactone (3R*,3aS*,8bR*)-23 (14 mg, 83%): oil; TLC
(EtOAc/hexane (3:7)) Rf ) 0.17; IR (neat) 1781, 1355,
1251, 1164, 754 cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.86
(3 H, s), 3.80 (3 H, s), 4.39 (1 H, d, J ) 9.1 Hz), 4.86 (1 H,
dd, J ) 9.1, 1.7 Hz), 5.87 (1 H, d, J ) 1.7 Hz), 6.94 (2 H,
d, J ) 8.8 Hz), 7.17 (1 H, t, J ) 7.5 Hz), 7.31-7.38 (1 H,
m), 7.36 (2 H, d, J ) 8.8 Hz), 7.46 (1 H, d, J ) 7.5 Hz),
7.56 (1 H, d, J ) 7.5 Hz); 13C NMR (CDCl3, 75 MHz) δ
35.6, 46.0, 55.3, 71.0, 87.0, 114.1, 114.4 (2 C), 125.1, 125.2,
126.0, 126.7 (2 C), 129.5, 130.3, 141.0, 160.0, 173.8; MS
m/z (rel intensity) 359 (31, M+), 315 (3), 280 (11), 236
(19), 195 (100), 144 (26), 116 (64); HRMS calcd for C18H17-
NO5S 359.0827, found 359.0835.
1-(Meth ylsu lfon yl)-2-(3H-in dol-3-yliden e)m eth ylin -
d ole-3-ca r b oxa ld eh yd e (26). Hemiacetal (1R*,3S*,
3aS*,8bR*)-4b (50 mg, 0.11 mmol) was treated with
p-TsOH (21 mg, 0.11 mmol) in refluxing benzene (25 mL)
for 24 h. A Dean-Stark apparatus was equipped for
removal of water. The mixture was cooled, filtered
through a pad of silica gel, and rinsed with EtOAc/hexane
(1:1). The organic phase was concentrated and chro-
matographed on a silica gel column by elution with
EtOAc/hexane (1:4) to give 26 (33 mg, 85%): oil; TLC
(EtOAc/hexane (1:4)) Rf ) 0.10; IR (neat) 2848, 1684,
1363, 1167, 1128 cm-1; 1H NMR (CDCl3, 200 MHz) δ 3.28
(3 H, s), 7.37-7.57 (3 H, m), 7.63 (1 H, s, vinyl H), 7.71-
7.86 (2 H, m), 8.01 (1 H, d, J ) 8.0 Hz), 8.21 (1 H, dd, J
) 8.0, 1.5 Hz), 8.96 (1 H, dd, J ) 8.0, 1.5 Hz), 9.17 (1 H,
s, HCdN), 10.32 (1 H, s, CHO); 13C NMR (CDCl3, 75
MHz) δ 41.4, 113.4, 116.2, 120.2, 123.2, 124.6, 125.3,
126.1, 127.1, 129.1, 129.7, 129.8, 130.1, 130.2, 134.8,
135.2, 148.4, 152.2, 193.2; MS m/z (rel intensity) 350 (35,
M+), 271 (100), 243 (61), 216 (33); HRMS calcd for
C19H14N2O3S 350.0725, found 350.0722.
1)) Rf ) 0.18; IR (neat) 3483, 2928, 1593, 1347, 1158 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 2.52 (3 H, s), 3.06 (3 H, s),
3.26 (1 H, s), 4.26 (1 H, d, J ) 8.5 Hz), 5.07 (1 H, dd, J
) 8.5, 5.7 Hz), 5.70 (1 H, s), 5.80 (1 H, d, J ) 5.7 Hz),
7.06-7.35 (8 H, m), 7.89 (1 H, d, J ) 8.1 Hz); 13C NMR
(CDCl3, 50 MHz) δ 35.8, 40.4, 54.2, 68.4, 77.4, 102.3,
113.0, 115.0, 118.0, 120.9, 123.1, 124.8, 124.9, 125.3,
125.9, 129.2, 130.0 (2 C), 135.1, 142.2; MS m/z (rel
intensity) 448 (10, M+), 224 (64), 146 (59), 118 (100), 79
(6); HRMS calcd for C20H20N2O6S2 448.0763, found,
448.0766. The structure was confirmed by an X-ray
diffraction.
3-Acetyl-2-[1-h yd r oxy-(4-m eth oxyp h en yl)m eth yl]-
1-m eth ylin d ole (11a ). According to the general proce-
dure, treatment of 3-acetyl-1-methylindole-2-carbonitrile
(2b) and p-methoxybenzaldehyde (1:1.5) with SmI2 in the
presence of HMPA gave the indolecarbonyl coupling
product 11a (85%): oil; TLC (EtOAc/hexane (3:7)) Rf )
0.33; IR (neat) 3380, 1607, 1505, 1466, 1172, 972 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 2.70 (3 H, s), 3.72 (3 H, s),
3.73 (3 H, s), 6.25 (1 H, br s), 6.71 (2 H, d, J ) 8.7 Hz),
7.11 (2 H, d, J ) 8.7 Hz), 7.14-7.35 (3 H, m), 7.84-7.89
(1 H, m); 13C NMR (CDCl3, 75 MHz) δ 30.8, 31.5, 55.2,
68.1, 110.5, 113.8 (2 C), 114.4, 120.8, 122.7, 122.8, 126.4,
127.3 (2 C), 133.2, 136.7, 150.7, 159.0, 196.4; MS m/z (rel
intensity) 309 (100, M+), 294 (20), 262 (7), 200 (10), 186
(26), 135 (15); HRMS calcd for C19H19O3N 309.1365, found
309.1363.
2,3-Dih yd r o-1-h yd r oxy-1H-p yr r olo[1,2-a ]in d ole-9-
ca r boxa ld eh yd e (21a ). According to the general pro-
cedure, a solution of 20a (135 mg, 0.67 mmol) in THF (8
mL) was added via syringe pump to the SmI2-HMPA
solution over a period of 30 min to give 21a (86 mg,
64%): solid; mp 113-115 °C; TLC (EtOAc/hexane (7:3))
Rf ) 0.34; IR (KBr) 3351, 1632, 1567, 1428, 1255 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 2.58-2.72 (1 H, m), 2.98-
3.09 (1 H, m), 4.01-4.14 (1 H, m), 4.28-4.39 (1 H, m),
5.59 (1 H, dd, J ) 7.7, 6.2 Hz), 7.23-7.35 (3 H, m), 7.94-
8.00 (1 H, m), 10.08 (1 H, s); 13C NMR (CDCl3, 50 MHz)
δ 36.0, 44.2, 68.1, 110.1, 110.9, 119.5, 123.0, 123.2, 130.5,
132.5, 154.4, 185.0; MS m/z (rel intensity) 201 (100, M+),
184 (22), 172 (14), 154 (15), 145 (20); HRMS calcd for
C12H11O2N 201.0790, found 201.0792.
1,4-Dim et h yl-3-(4-m et h oxyp h en yl)fu r o[3,4-b]in -
d ole (27). By a procedure similar to that for 26,
treatment of 11a (20 mg, 0.065 mmol) with p-TsOH in
refluxing benzene for 5 h gave 27 (15 mg, 82%): oil; TLC
(EtOAc/hexane (3:7)) Rf ) 0.19; IR (neat) 2937, 1608,
1513, 1460, 1263 cm-1; 1H NMR (CDCl3, 300 MHz) δ 2.49
(3 H, s), 3.63 (3 H, s), 3.85 (3 H, s), 6.50 (2 H, dd, J ) 7.0,
2.0 Hz), 6.86 (2 H, dd, J ) 7.0, 2.0 Hz), 7.25-7.38 (3 H,
m), 7.90-7.93 (1 H, m); 13C NMR (CDCl3, 75 MHz) δ 30.7,
30.9, 55.0, 110.5, 113.2 (2 C), 115.6, 120.8, 122.1, 122.4,
126.1, 129.5 (2 C), 129.9, 131.7, 133.9, 136.8, 145.9, 158.7;
MS m/z (rel intensity) 291 (79, M+), 279 (78), 224 (100),
197 (48), 143 (98); HRMS calcd for C19H17O2N 291.1259,
found 291.1252.
3a ,8b-Dih yd r o-4-(m eth ylsu lfon yl)-3-[(1-m eth ylsu l-
fon yl)in d ol-3-yl]fu r o[3,4-b]in d ol-1-on e (22). Hemi-
acetal (1R*,3S*,3aS*,8bR*)-4b (23 mg, 0.05 mmol) was
treated with DDQ (45 mg, 0.2 mmol) in benzene (10 mL)
at room temperature (27 °C) for 16 h. The mixture was
concentrated and chromatographed on a silica gel column
by elution with EtOAc/hexane (1:1) to give lactone (3S*,
3aS*,8bR*)-22 (13 mg, 57%): solid; mp 210-211 °C; TLC
(EtOAc/hexane (2:3)) Rf ) 0.09; IR (neat) 1753, 1361,
1
1158 cm-1; H NMR (CDCl3, 200 MHz) δ 2.64 (3 H, s),
3-(4-Meth oxyph en yl)th ien o[3,4-b]in dole (28). Com-
pound 8a (35 mg, 0.12 mmol) was treated with Lawes-
3.03 (3 H, s), 4.61 (1 H, d, J ) 10.0 Hz), 5.49 (1 H, dd, J

2916 J . Org. Chem., Vol. 63, No. 9, 1998
Lin et al.
son’s reagent (65 mg, 0.16 mmol) in refluxing 1,4-dioxane
(10 mL) for 4 h. The mixture was concentrated and
partitioned between aqueous NaOH (10%, 10 mL) and
CH2Cl2 (10 mL). The aqueous layer was extracted with
CH2Cl2 (10 mL × 2). The organic phase was dried (Na2-
SO4), concentrated and chromatographed on a silica gel
column by elution with EtOAc/hexane (1:9) to give 28 (22
mg, 63%): oil; TLC (EtOAc/hexane (1:3)) Rf ) 0.53; IR
(neat) 2921, 2849, 1583, 1242 cm-1; 1H NMR (CDCl3, 200
MHz) δ 3.45 (3 H, s), 3.86 (3 H, s), 6.96 (2 H, dd, J ) 8.6,
2.0 Hz), 7.07 (1 H, t, J ) 7.6 Hz), 7.09 (1 H, d, J ) 7.6
Hz), 7.36 (1 H, t, J ) 7.6 Hz), 7.38 (1 H, s), 7.48 (2 H, dd,
J ) 8.6, 2.0 Hz), 7.78 (1 H, d, J ) 7.6 Hz); 13C NMR
(CDCl3, 50 MHz) δ 31.4, 55.3, 108.5, 109.0, 110.5, 113.8
(2 C), 118.7, 119.7, 121.0, 125.4, 126.4, 131.6 (2 C), 134.2,
141.6, 150.1, 159.0; MS m/z (rel intensity) 293 (100, M+),
278 (41), 135 (12), 147 (13); HRMS calcd for C18H15ONS
293.0874, found 293.0871.
H, s), 8.10 (1 H, d, J ) 7.7 Hz), 8.16 (1 H, d, J ) 8.0 Hz);
13C NMR (CDCl3, 75 MHz) δ 31.2, 33.0, 55.2, 55.4, 109.7,
110.0, 113.0 (2 C), 113.1, 113.2 (2 C), 119.6, 121.0, 121.3,
121.4, 121.5, 124.2, 125.6, 128.2, 130.65, 130.7, 130.9 (2
C), 131.7, 131.9 (2 C), 132.1, 133.3, 134.4, 138.4, 142.3,
143.18, 143.24, 160.0, 162.7, 190.0; MS m/z (rel intensity)
551 (M+, 100), 276 (1), 135 (17), 121 (6); FAB-MS m/z
552.2 (M+ + 1); HRMS calcd for C36H29N3O3 551.2208,
found 551.2209.
Bis{2-[1-h ydr oxy-(4-m eth oxyph en yl)m eth yl]-1-m e-
th ylin d ole-3-ca r boxa ld eh yd e} Hyd r a zon e (32).
A
mixture of 8a (42 mg, 0.14 mmol) and hydrazine mono-
hydrate (0.1 mL, 2 mmol) in EtOH (10 mL) was stirred
at room temperature (25 °C) for 1 h and then heated
under reflux for 12 h. The mixture was concentrated and
chromatographed on a silica gel column by elution with
EtOAc/hexane (1:3) to give 32 (35 mg, 84%). The
prepared sample consisted of two isomers, but it degener-
ated to one (E,E)-isomer on standing. (Z,Z)-Isomer: TLC
(EtOAc/hexane (1:3)) Rf ) 0.07; IR (neat) 3330, 1603,
2-(P h en ylm et h yl)-3-(4-m et h oxyp h en yl)-4-m et h -
ylp yr r olo[3,4-b]in d ole (29). Compound 8a (26 mg, 0.08
mmol) was treated with benzylamine (0.02 mL) and
p-TsOH (2 mg) in refluxing toluene (15 mL) for 6 days.
A Dean-Stark apparatus was equipped for removal of
water. The mixture was concentrated and chromato-
graphed on a silica gel column by elution with EtOAc/
hexane (1:9) to give 29 (12 mg, 46%) along with a 46%
recovery of 8a : oil; TLC (EtOAc/hexane (1:9)) Rf ) 0.41;
1
1503, 1243 cm-1; H NMR (CDCl3, 200 MHz) δ 3.54 (6
H, s), 3.73 (6 H, s), 6.09 (2 H, s), 6.77 (4 H, dd, J ) 8.7,
2.0 Hz), 7.15-7.25 (10 H, m), 7.81 (2 H, d, J ) 6.7 Hz),
8.17 (2 H, s); 13C NMR (CDCl3, 75 MHz) δ 30.4, 55.2, 68.0,
107.7, 109.5, 113.7, 113.9, 118.8, 120.6, 122.3, 126.4,
127.7, 127.8, 134.0, 136.5, 139.9, 141.3, 158.9. (E,E)-
Isomer: solid; mp 233-235 °C dec; TLC (EtOAc/hexane
IR (neat) 2929, 1630, 1593, 1503, 1242, 740, 696 cm-1
;
(1:3)) Rf ) 0.07; IR (KBr) 3284, 1598, 1503, 1245 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 3.33 (3 H, s), 3.67 (3 H, s),
5.07 (2 H, s), 6.80-7.22 (13 H, m), 7.62 (1 H, d, J ) 7.7
Hz); 13C NMR (CDCl3, 50 MHz) δ 31.0, 51.4, 55.3, 107.8,
108.1, 109.1, 113.6 (2 C), 115.6, 117.6, 120.2, 120.4, 123.6,
123.9, 126.4 (2 C), 128.5 (2 C), 132.6 (2 C), 134.8, 139.3,
146.8, 158.9; MS (rel intensity) 366 (100, M+), 275 (14);
HRMS calcd for C25H22N2O 366.1732, found 366.1740.
2-Bu t yl-1,4-d im et h ylcyclop en t a n e[b]in d ol-3-on e
(30). By a procedure similar to that for 26, treatment of
11c (51 mg, 0.19 mmol) with p-TsOH in refluxing
benzene for 4 h gave 30 (trans, 30 mg, 63%): oil; TLC
(EtOAc/hexane (1:9)) Rf ) 0.36; IR (neat) 2957, 1679,
1483, 1204, 742 cm-1; 1H NMR (CDCl3, 200 MHz) δ 0.91
(3 H, t, J ) 6.7 Hz), 1.25-1.65 (8 H, m), 1.88-2.01 (1 H,
m), 2.49 (1 H, ddd, J ) 9.0, 8.7, 2.0 Hz), 3.19 (1 H, qd, J
) 7.0, 2.0 Hz), 3.89 (3 H, s), 7.10-7.74 (4 H, m); 13C NMR
(CDCl3, 75 MHz) δ 14.0, 20.6, 22.9, 29.6, 30.1, 31.2, 35.1,
62.0, 111.0, 120.1, 121.9, 122.7, 126.5, 137.7, 145.0, 147.6,
196.9; MS m/z (rel intensity) 255 (43, M+), 240 (5), 212
(27), 199 (100), 184 (21); HRMS calcd for C17H21NO
255.1623, found 255.1631.
1H NMR (CDCl3, 300 MHz) δ 3.67 (6 H, s), 3.72 (6 H, s),
6.18 (2 H, s), 6.76-6.82 (4 H, m), 7.22-7.32 (10 H, m),
7.78 (2 H, br s, OH), 7.92-7.94 (2 H, m), 8.90 (2 H, s);
13C NMR (CDCl3, 75 MHz) δ 30.8, 55.2, 68.7, 107.6, 109.8,
113.9, 119.1, 121.6, 122.9, 127.6, 127.9, 133.8, 136.9,
145.1, 153.8, 159.1; MS m/z (rel intensity) 568 (2, M+
-
H2O), 293 (100), 276 (46), 264 (80), 249 (72), 157 (29),
135 (34); FAB-MS m/z 587 (M+ + 1), 569 (M+ - H2O +
1); HRMS calcd for C36H32N4O3 568.2474 (M+ - H2O),
found 568.2489.
Bis[2-(4-m et h oxyb en zoyl)-1-m et h ylin d ole-3-ca r -
boxa ld eh yd e] Hyd r a zon e (33). Diol 32 (34 mg, 0.058
mmol) was treated with MnO2 (101 mg, 0.12 mmol) in
refluxing benzene (10 mL) for 12 h. The mixture was
cooled, filtered through a pad of Celite, and rinsed with
EtOAc. The filtrate was concentrated and chromato-
graphed on a silica gel column by elution with EtOAc/
hexane (1:3) to give diketone 33 (8.3 mg, 25%). Treat-
ment of 32 (17 mg) with DDQ (28 mg) in benzene at room
temperature for 13 h gave 33 (5 mg, 30%): solid; mp
297-298 °C dec; TLC (EtOAc/hexane (1:3)) Rf ) 0.15; IR
(neat) 1622, 1604, 1582, 1253 cm-1; 1H NMR (CDCl3, 300
MHz) δ 3.77 (6 H, s), 3.88 (6 H, s), 6.96 (4 H, dd, J ) 8.8,
1.8 Hz), 7.23-7.28 (2 H, m), 7.36-7.43 (4 H, m), 7.88 (4
H, dd, J ) 8.8, 1.8 Hz), 8.45 (2 H, d, J ) 8.0 Hz), 8.56 (2
H, s); 13C NMR (CDCl3, 75 MHz) δ 31.8, 55.6, 109.9, 114.2
(2 C), 114.8, 122.3, 124.5, 124.8, 125.2, 131.6, 132.9 (2
C), 138.5, 139.3, 155.6, 164.4, 188.0; MS m/z (rel inten-
sity) 582 (51, M+), 447 (100), 291 (70), 264 (43), 249 (32),
135 (95); HRMS calcd for C36H30N4O4 582.2267, found
582.2261.
3-(4-Met h oxyp h en yl)-1-[3-(4-m et h oxyp h en yl)-4-
m eth ylp yr r olo[3,4-b]in d ol-2-yl]-4-m eth ylfu r o[3,4-b]-
in d ole (31). A mixture of 8a (30 mg, 0.1 mmol) and
ammonium acetate (400 mg, 5.2 mmol) in acetic acid (5
mL) was heated under reflux for 12 h. The mixture was
cooled, and aqueous Na2CO3 (10%, 5 mL) and water (5
mL) were added. The mixture was extracted with EtOAc
(15 mL × 3). The organic phase was dried (Na2SO4),
concentrated, and chromatographed on a silica gel col-
umn by elution with EtOAc/hexane (1:9) to give 31 (9 mg,
32%): oil; TLC (EtOAc/hexane (1:3)) Rf ) 0.28; IR (neat)
1592, 1246, 744 cm-1; UV λmax (ꢀ) (MeOH) 373 (10 358),
273 (42 856), 226 (52 427) nm; 1H NMR (CDCl3, 300 MHz)
δ 3.41 (3 H, s), 3.58 (3 H, s), 3.88 (3 H, s), 3.89 (3 H, s),
6.47 (2 H, dd, J ) 8.8, 2.0 Hz), 6.96 (2 H, dd, J ) 8.8, 2.0
Hz), 7.24-7.39 (6 H, m), 7.44 (2 H, t, J ) 8.0 Hz), 7.55 (1
H, t, J ) 7.7 Hz), 7.68 (2 H, dd, J ) 8.8, 2.0 Hz), 8.05 (1
4-(4-Met h oxyp h en yl)-5-m et h ylp yr id a zin o[4,5-b]-
in d ole (34a ). By a procedure similar to that for 32,
treatment of 25a (64 mg, 0.22 mmol) with hydrazine
monohydrate (0.02 mL, 0.41 mmol) in refluxing EtOH
(10 mL) gave 34a (52 mg, 82%): solid; mp 182-183 °C;
TLC (MeOH/CH2Cl2 (1:19)) Rf ) 0.24; IR (KBr) 3006,
2935, 1604, 1501, 1244, 829, 755 cm-1; 1H NMR (CDCl3,

Indolecarbonyl Coupling Reactions Promoted by SmI2
J . Org. Chem., Vol. 63, No. 9, 1998 2917
200 MHz) δ 3.57 (3 H, s), 3.90 (3 H, s), 7.05-7.11 (2 H,
m), 7.38-7.66 (5 H, m), 8.21 (1 H, d, J ) 7.1 Hz), 9.73 (1
H, s); 13C NMR (CDCl3, 50 MHz) δ 32.6, 55.3, 110.2, 113.8
(2 C), 119.5, 119.8, 121.5, 121.6, 128.9, 131.0 (2 C), 134.9
(2 C), 141.7, 142.8, 148.4, 160.3; MS m/z (rel intensity)
289 (64, M+), 288 (100), 273 (8), 246 (6), 217 (11), 203
(12); HRMS calcd for C18H15N3O 289.1215, found 289.1217.
1-Mer ca p to-4-m eth yl-3-(4-m eth oxyp h en yl)th ien o-
[3,4-b]in d ole (35). By a procedure similar to that for
28, treatment of 25a (30 mg, 0.1 mmol) with P2S5 (32
mg, 0.14 mmol) in refluxing 1,4-dioxane (10 mL) for 1 h
gave 35 (17 mg, 51%): deep red solid; mp 199-200 °C;
TLC (EtOAc/hexane (3:7)) Rf ) 0.25; IR (neat) 1600, 1527,
mmol) in refluxing 1,4-dioxane (15 mL) for 4 h gave 36
(45 mg, 68%): oil; TLC (EtOAc/hexane (1:4)) Rf ) 0.27;
1
IR (neat) 2927, 1503, 1469, 1201, 1080 cm-1; H NMR
(CDCl3, 300 MHz) δ 0.88 (3 H, t, J ) 6.8 Hz), 1.21-1.59
(6H, m), 1.92 (1 H, dtd, J ) 9.6, 7.9, 3.2 Hz), 2.21 (1 H,
tdd, J ) 7.9, 3.4, 3.2 Hz), 3.76 (3 H, s), 4.63 (1 H, dd, J
) 9.6, 3.2 Hz), 7.23-7.35 (3 H, m), 8.32-8.37 (1 H, m);
13C NMR (CDCl3, 75 MHz) δ 13.9, 22.3, 27.4, 31.4, 31.4,
33.0, 50.8, 109.9, 120.3, 121.8, 123.4, 124.3, 129.9, 142.9,
160.4, 213.3 (CdS); MS m/z (rel intensity) 289 (25, M+),
232 (34), 218 (18), 71 (100); HRMS calcd for C16H19NS2
289.0959, found 289.0950.
1
1489, 1464, 1244, 1032, 831 cm-1; H NMR (CDCl3, 300
Ack n ow led gm en t. We thank the National Science
Council for financial support (Grant NSC87-2113-M002-
042).
MHz) δ 1.57 (1 H, s, SH), 3.13 (3 H, s), 3.87 (3 H, s), 6.69-
6.79 (2 H, m), 6.95-6.98 (2 H, m), 7.09-7.14 (1 H, m),
7.36-7.40 (2 H, m), 7.53 (1 H, d, J ) 7.6 Hz); 13C NMR
(CDCl3, 75 MHz) δ 31.1, 55.4, 107.8, 113.9 (2 C), 118.2,
118.3, 119.3, 119.4, 120.9, 124.8, 126.5, 131.3 (2 C), 139.7,
141.4, 149.6, 159.4; MS m/z (rel intensity) 325 (100, M+),
310 (24), 293 (30), 278 (19); HRMS calcd for C18H15NOS2
325.0595, found 325.0589.
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental procedures, ORTEP drawings and crystal data of
compounds 4b and 18, and spectral data of new compounds
(72 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
4-Met h yl-3-p en t yl-3H -t h ien o[3,4-b]in d ole-3-t h i-
on e (36). By a procedure similar to that for 28, treat-
ment of 25c (59 mg, 0.22 mmol) with P2S5 (93 mg, 0.42
J O9720795