A sulfoxide-based ring annelation approach to fused, many-membered ring N,S-heterocycles

Article abstract of DOI:10.1021/jo9805044

An approach to many-membered ring N,S-heterocycles involving sulfoxide electrophilic sulfenylation (SES) followed by ring expansion of the derived sulfonium salt intermediate (in situ) is illustrated for 9- and 10-membered- ring compounds. Treatment of readily prepared sulfoxides 10a, 10b, 18a, 18b, 23a, and 23b with triflic anhydride (pyridine, CH₂Cl₂, 0 °C) provides heterocycles 13a (65%), 13b (60%), 19a (67%), 19b (67%), 24a (42%), and 24b (80%), respectively. Sulfoxides 5a and 5b, under several different conditions, give only the Pummerer dehydration products 6a and 6b, respectively. Diastereomeric sulfoxides 18a' and 18b', upon treatment with triflic anhydride, do not produce clean product mixtures or any of the desired heterocyclic products but, upon heating in toluene, are converted to the more stable isomers 18a and 18b, respectively. Conducting this isomerization in the presence of 2-mercaptobenzothiazole produces a disulfide indicative of the intermediacy of a sulfenic acid. However, the importance of sulfenic acid derivatives in the SES process leading to many-membered ring heterocycles remains to be determined.

Full text of DOI:10.1021/jo9805044

9190
J . Org. Chem. 1998, 63, 9190-9196
A Su lfoxid e-Ba sed Rin g An n ela tion Ap p r oa ch to F u sed ,
Ma n y-Mem ber ed Rin g N,S-Heter ocycles1
Dallas K. Bates* and Mingde Xia2
Department of Chemistry, Michigan Technological University, Houghton, Michigan 49931
Received March 17, 1998
An approach to many-membered ring N,S-heterocycles involving sulfoxide electrophilic sulfenylation
(SES) followed by ring expansion of the derived sulfonium salt intermediate (in situ) is illustrated
for 9- and 10-membered-ring compounds. Treatment of readily prepared sulfoxides 10a , 10b, 18a ,
18b, 23a , and 23b with triflic anhydride (pyridine, CH2Cl2, 0 °C) provides heterocycles 13a (65%),
13b (60%), 19a (67%), 19b (67%), 24a (42%), and 24b (80%), respectively. Sulfoxides 5a and 5b,
under several different conditions, give only the Pummerer dehydration products 6a and 6b,
respectively. Diastereomeric sulfoxides 18a ′ and 18b′, upon treatment with triflic anhydride, do
not produce clean product mixtures or any of the desired heterocyclic products but, upon heating
in toluene, are converted to the more stable isomers 18a and 18b, respectively. Conducting this
isomerization in the presence of 2-mercaptobenzothiazole produces a disulfide indicative of the
intermediacy of a sulfenic acid. However, the importance of sulfenic acid derivatives in the SES
process leading to many-membered ring heterocycles remains to be determined.
We have developed sulfoxide electrophilic sulfenylation
SES reactions proceed through a sulfonium salt that
typically undergoes nucleophilic displacement.9,10 In this
paper, we describe an elimination-based ring expansion
of sulfoxide-generated sulfonium salts leading to novel
fused, large-ring heterocycles.
(SES) as a mild procedure for intramolecular C-sulfeny-
lation of electron-rich heterocycles,3 which takes place
under conditions and with reagents identical to those
often used for Pummerer reactions. The process is
thought to proceed by the same mechanism as the
Pummerer reaction4 except that attack occurs at sulfur
before proton loss to a thionium ion5 (the traditional
Pummerer intermediate). The SES process often pre-
dominates “unexpectedly” over planned normal Pum-
merer reactions in substrates containing the sulfoxide
tethered to an electron-rich aromatic6 or heteroaromatic7
ring.
Resu lts a n d Discu ssion
SES reactions take place with an alkylsulfinyl moiety
“tethered” in some way to an electron-rich aromatic ring,
typically indole or pyrrole. The first compound studied,
tetrahydrothiophene-2-carboxylic acid (1),11 contains a
one-carbon tether. Treatment of the derived acid chloride
(2) with NH4OH produced amide 3, which gave12 the
pyrrole 4b in 69% yield. We were surprised to discover
that 1,4-dichloro-1,4-dimethoxybutane13 gave indole 4a
in 55% yield. Examination of the literature revealed,
however, that further reaction of initially formed pyrroles
to indoles or carbazoles with both 1,4-dichloro-1,4-
dimethoxybutane14 and 2,5-dimethoxytetrahydrofuran15
SES also may be accomplished in some instances by
simply heating the sulfoxide in an inert solvent,8 provid-
ing the cyclized product and an alcohol (methanol from
aryl methyl sulfoxides) as the only other product.
* To whom correspondence should be addressed. Phone: (906) 487
2059. Fax: (906) 487 2061. E-mail: dbates@mtu.edu.
(1) Presented in part at the 35th National Organic Chemistry
Symposium, San Antonio, TX, J une 1997.
(2) (a) Departmental Awardee for Excellence in the First Year of
Graduate Study, 1994. (b) Graduate School Research Fellowship,
1995-1996. (c) Summer Alumni Research Fellowship 1997. (d) Current
address: Department of Chemistry, Yale University, New Haven, CT
06511.
(9) Picard, J . A.; Chen, S.; Bates, D. K. Heterocycles 1994, 38, 1775.
This is an important point since other work, particularly with penem
sulfoxides9a and other tertiary sulfoxides,9b,c established that electro-
philic reactions of sulfoxides often take place in “reverse” order (to the
SES reaction) involving cleavage of an S-C bond to produce a sulfenic
acid as a prelude to electrophilic reaction rather than electrophilic
reaction at sulfur to give, ultimately, a sulfonium salt followed by
cleavage of the S-C bond by nucleophilic displacement of the alkyl
group. (a) Sammes, P. G. Chem. Rev. 1976, 76, 113. (b) Wright, S. W.;
Abelman, M. M.; Bostrom, L. L.; Corbett, R. L. Tetrahedron Lett. 1992,
33, 153. (c) Brichard, M.-H.; Musick, M.; J anousek, Z.; Viehe, H. G.
Synth. Commun. 1990, 20, 2379.
(10) (a) Amat, M.; Bennasar, M.-L.; Hadida, S.; Sufi, B. A., Zulaica,
E.; Bosch, J . Tetrahedron Lett. 1996, 37, 5217. (b) Kawasaki, T.; Suzuki,
S.; Nakanishi, H.; Sakamoto, M. Tetrahedron Lett. 1997, 38, 3252.
(11) (a) Wro´bel, J . T.; Hejchman, E. Synthesis 1987, 452. (b) Ernst,
F. Ber. Dtsch. Chem. Ges. 1887, 20, 518.
(12) Elming, N.; Clauson-Kaas, N. Acta Chem. Scand. 1952, 6, 867.
(13) Chan, T. H.; Lee, S. D. J . Org. Chem. 1983, 48, 3059.
(14) Chung, B. Y.; Bae, D. J .; J in, J . I.; Lee, S. D. J . Korean Chem.
Soc. 1992, 36, 603; Chem. Abstr. 1992, 117, 191626a.
(15) (a) Kashima C.; Hibi, S.; Maruyama, T.; Omote, Y. Tetrahedron
Lett. 1986, 27, 2131. (b) Kashima C.; Hibi, S.; Maruyama, T.; Harada,
K.; Omote, Y. J . Heterocycl. Chem. 1987, 24, 913.
(3) (a) Bates, D. K.; Tafel; K. A.; Xu, J . Heterocycl. Commun. 1996,
2, 115. (b) Bates, D. K.; Habib, Q. A. J . Heterocycl. Chem. 1995, 32,
1477. (c) Bates, D. K.; Tafel, K. A. J . Org. Chem. 1994, 59, 8076. (d)
Bates, D. K.; Winters, R. T.; Picard, J . A. J . Org. Chem. 1992, 57, 3094.
Dimethyl sulfoxide has been used in an analogous intermolecular
process: (e) Wendebourg. H. H.; Hartke, K. Arch. Pharm. (Weinheim)
1989, 322, 473. (f) Hartke, K.; Teuber, D.; Gerber, H.-D. Tetrahedron,
1988, 44, 3261. (g) Hartke, K.; Strangemann, D. Heterocycles 1986,
24, 2399. (h) Hocker, J .; Ley, K.; Merten, R. Synthesis 1975, 334.
(4) Oae, S.; Numata, T. In Isotopes in Organic Chemistry; Buncel,
E., Lee, C. C., Eds.; Elsevier: New York, 1980; pp 45-102.
(5) R-Thiocarbocations have been variously called thionium ions
(Trost, B. M.; Reiffen, M.; Crimmin, M. J . Am. Chem. Soc. 1979, 101,
257) or sulfenium ions (Vankar, Y. D.; Rao, C. T. Tetrahedron 1985,
41, 3405).
(6) Pyne, S. G.; Hajipour, A. R. Tetrahedron 1994, 50, 13501.
(7) Amat, M.; Hadida, S.; Pschenichnyi, G.; Bosch, J . J . Org. Chem.
1997, 62, 3158.
(8) Tafel, K. A.; Bates, D. K. J . Org. Chem. 1992, 57, 3676.
10.1021/jo9805044 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/18/1998

Sulfoxide-Based Ring Annelation Approach
J . Org. Chem., Vol. 63, No. 25, 1998 9191
have been reported. Indole 4a could also be prepared
by acylation of indole with 2 under phase-transfer
conditions.16 Oxidation to sulfoxides (5a ,b) proceeded
well using Oxone,17 producing predominately one of the
two possible diastereomers.
acid chloride 8 (to 9a ) followed by oxidation (NaIO4)21
produced sulfoxide 10a . Acid chloride 8 also readily
provides pyrrole sulfide 9b and sulfoxide 10b. In each
case, the sulfoxide isolated was predominately a single
diastereomer.
Initial reactions of sulfoxide 10a were disappointing.
As with 5, TFAA/pyridine in CH2Cl2 produced only the
Pummerer dehydration product 11a , while heating in
p-xylene caused sulfoxide disproportionation22 to 9a and
12.
Treatment of either 5a or 5b with TFAA/pyridine in
CH2Cl2 gave only Pummerer dehydration18 products 6a
and 6b, respectively. The same products were formed
when either sulfoxide was subjected to prolonged reflux
in p-xylene.
The failure of these reactions to produce ring expansion
may be attributed to the acidity of the proton between
the carbonyl and sulfoxide. Consequently, 2-tetrahy-
drothiophene acetic acid (7) having a less acidic proton
R- to the sulfoxide (which incidentally provides a two-
carbon atom tether) was prepared. Compound 7 was
conveniently prepared by ionic hydrogenation19 of com-
mercially available thiophene-2-acetic acid in TFA con-
taining a small amount of superacid (HSbF6). This one-
pot reaction provides 7 in a yield superior to the reported20
process (58% vs 21%). Indole acylation using the derived
Conversion of the sulfoxide oxygen into a leaving group
better than trifluoroacetate using trifluoromethanesulfon-
ic anhydride23 (triflic anhydride, Tf2O) was next consid-
ered as a strategy for coaxing the acylated oxysulfonium
ion intermediate to undergo attack at sulfur in preference
to the elimination pathway leading to 6 or 11a . To our
satisfaction, treatment of 10a b with triflic anhydride/
(16) Illi, V. O. Synthesis 1979, 387.
(17) (a) Webb, K. S. Tetrahedron Lett. 1994, 35, 3457. (b) Volkmann,
R. A.; Kelbaugh, P. R.; Nason, D. M.; J asys, V. J . J . Org. Chem. 1992,
57, 4352.
(18) Lakshmikantham, M. V.; Cava, M. P. J . Org. Chem. 1978, 43,
82. For a review of examples, see: De Lucchi, O.; Miotti, U.; Modena,
G. In Organic Reactions; Paquette, L. A., Ed.; Wiley: New York, 1991;
Vol. 40, pp 172-174.
(21) Leonard, N. J .; J ohnson, C. R. J . Org. Chem. 1962, 27, 282.
(22) The Chemistry of Sulfones and Sulfoxides; Patai, S., Rappoport,
Z., Stirling, C., Eds.; Wiley: Chicester, U.K., 1988; pp 925-968.
(23) For applications of triflic anhydride to Pummerer rearrange-
ments, see: (a) Hendrickson, J . B.; Schwartzman, S. M. Tetrahedron
Lett. 1975, 273. (b) Hartman, G. D.; Schwering, J . E.; Hartman, R. D.
Tetrahedron Lett. 1983, 24, 11011. (c) Crich, D.; Sun, S. J . Am. Chem.
Soc. 1997, 199, 11217.
(19) Kursanov, D. N.; Parnes, Z. N.; Bolestova, G. I.; Belen’kii, L. I.
Tetrahedron 1975, 31, 311.
(20) Bunce, R. A.; Peeples, C. J .; J ones, P. B. J . Org. Chem. 1992,
57, 1727.

9192 J . Org. Chem., Vol. 63, No. 25, 1998
Bates and Xia
Sch em e 1a
a
Key: (a) (COCl)2, CH2Cl2, rt, 4 h; (b) for 17a : indole, Bu4NHSO4, NaOH, H2O/CH2Cl2, rt, 3 h (63%); (c) for 17b: (MeO)2 THF, HOAc,
reflux, 7 h (66%); (d) NaIO4, H2O/CH2Cl2/MeOH, rt; for indole series: (82%) 18a :18a ′ ratio is 5:1; for pyrrole series (70%) 18b:18b′ ratio
is 1.1:1; (e) benzene, reflux; (f) Tf2O, pyr, CH2Cl2, rt, 3 h (19a , 67%), (19b, 67%).
pyridine in CH2Cl2 gave the novel heterocycles 13a (65%)
and 13b (60%), respectively. This is an unprecedented
reaction of sulfoxides and potentially provides entry into
a myriad of novel fused, many-membered ring hetero-
cycles.
Although the aromatic and olefinic proton absorptions
in the NMR of 13a are sharp at 25 °C, the three
methylene groups of the nine-membered ring are very
broad, indicating slow (on the NMR time scale) confor-
mational changes taking place in this ring at room
temperature. These absorptions sharpen considerably at
-20 °C.
shifts (ASIS),26 1H-1H COSY, and NOE difference spec-
tra, and the assignments agree with the general chro-
matographic order of elution observed for diastereomeric
sulfoxides.27
Reaction of diastereomers 18a and 18a ′ with triflic
anhydride produced interesting results. Only diastere-
omer 18a gave the expected SES product 19a (67%).
Isomer 18a ′ did not give a clean product mixture, and
(25) The ease of conversion of 18a ′ suggests the intermediacy of a
sulfenic acid rather than pyramidal inversion at sulfur or homolytic
scission-recombination.25a Thermal epimerization of penicillin sulfox-
ides in refluxing benzene via sulfenic acids is a well-known process,25b-d
and γ-keto sulfoxides form sulfenic acid intermediates even more
easily.25e Formation of sulfenic acids in these processes is a stereospe-
cific, sigmatropic process in which the proton removed is on the group
“cis” to the sulfoxide oxygen. If sulfenic acids are intermediates in
epimerization of sulfoxides 18a ′b′, recyclization to sulfoxide is the sole
reaction pathway since no products other than 18a b are observed.
Preliminary experiments indicate these sulfoxide epimerizations do
indeed proceed via a sulfenic acid. For example, refluxing a mixture
of pure 18a in toluene for 1 h in the presence of excess benzothiazole
2-thiol25f gives a compound tentatively identified as ia (partial 1H NMR
trans R,â-unsaturated amide (δ 8.38, 7.14, J ) 15.3 Hz) and ArCH2-
SO (δ 4.38). A similar experiment (4 h) with an 18b/18b′ mixture gave
a very similar compound tentatively identified as ib (partial 1H NMR
trans R,â-unsaturated amide (δ 8.39, 7.10, J ) 15.3 Hz) and ArCH2-
SO (δ 4.35)). (a) Cooper, R. D. G.; Hatfield, L. D.; Spry, D. O. Acc. Chem.
Res. 1973, 6, 32. (b) Archer, R. A.; Demarco, P. V. J . Chem. Soc. C
1969, 1530. (c) Cooper, R. D. G. J . Am. Chem. Soc. 1970, 92, 5010. (d)
Spry, D. O. J . Am. Chem. Soc. 1970, 92, 5006. (e) Berges, D. A.;
Taggart, J . J . J . Org. Chem. 1985, 50, 413. (f) Kamiya, T.; Teraji, T.;
Saito, Y.; Hashimoto, M.; Nakaguchi, O.; Oku, T. Tetrahedron Lett.
1973, 3001.
Unfortunately, treatment of 5a b with triflic anhydride
did not change the course of the reaction, producing only
Pummerer products 6a and 6b.
To explore the general utility of this annelation process,
we selected two additional two-carbon-atom spaced sub-
strates. Required acids 1,3-dihydrobenzo[c]thiophene-1-
acetic acid (15)20,24 and 3,4-dihydro-1H-2-benzothiopyran-
1-acetic acid (20)20 are readily converted to the correspond-
ing indole and pyrrole sulfoxides (Schemes 1 and 2).
In the case of sulfide 17a , oxidation using NaIO4
produced a mixture of diastereomers 18a and 18a ′
(relative stereochemistry implied) in a 5:1 ratio, which
could be separated chromatographically. Upon heating
in benzene, both 18a ′b′ were converted to a thermody-
namic mixture containing predominately 18a b.25
The relative stereochemistry of these compounds was
(26) (a) Laszlo, P. In Progress in Nuclear Magnetic Resonance
Spectroscopy; Emsley, J . W., Sutcliffe, L. H., Eds.; Pergamon Press:
London, 1967; Vol. 3, p 348. (b) Ledaal, T. Tetrahedron Lett. 1968, 1683.
(c) Cooper, R. D. G.; DeMarco, P. V.; Cheng, J . C.; J ones, N. D. J . Am.
Chem. Soc. 1969, 91, 1408.
(27) (a) Portoghese, P. S.; Telang, V. G. Tetrahedron 1971, 27, 1823.
(b) J ohnson, C. R.; Diefenbach, H.; Keiser, J . E.; Sharp, J . C.
Tetrahedron 1969, 25, 5649. (c) J ohnson, C. R.; Siegl, W. O. J . Am.
Chem. Soc. 1969, 91, 2796.
1
determined by H NMR using aromatic solvent-induced
(24) Norcross, B. E.; Lansinger, J . M.; Martin, R. L. J . Org. Chem.
1977, 42, 369.

Sulfoxide-Based Ring Annelation Approach
J . Org. Chem., Vol. 63, No. 25, 1998 9193
Sch em e 2a
very difficult to purify, while the reaction to produce the
corresponding pyrrole derivative 24b was straightfor-
ward.
Con clu sion
Synthesis of novel large-ring N,S-heterocyclic com-
pounds via intermediates generated under Pummerer
rearrangement conditions is demonstrated. This anne-
lation approach has the potential to provide a wide range
of novel compounds from carboxylic acids derivatives
available from several synthetic protocols20,29-31 for at-
tachment via a two-carbon tether to an electron-rich
heteroaromatic ring. Questions of utility (nonamide
tethers, longer tethers, larger ring cyclic sulfides, other
electron-rich rings, etc.) and mechanism (reactivity of
sulfenic acid derivatives derived from trapped sulfenic
acids, intermediacy of sulfenic acid derivatives vs direct
attack of an electron-rich ring on tricoordinate sulfur) are
under study.
a
Key: (a) (COCl)2, CH2Cl2, rt, 2 h; (b) indole, Bu4NHSO4,
NaOH, H2O/CH2Cl2, rt, 2.5 h (68%); (c) (1) NH4OH, rt, (84%), (2)
dimethoxy THF, HOAc, reflux, 12 h (71%); (d) for 22a : NaIO4,
H2O/CH2Cl2/acetone, rt, 48 h (54%); for 22b: NaIO4, H2O/CH2Cl2/
acetone, rt, 30 h (80%) (e) Tf2O, pyr, CH2Cl2, 0 °C, 3 h (24a , 42%)
(24b, 80%).
Exp er im en ta l Section
All reagents were used without purification unless otherwise
noted. Chromatography refers to column chromatography on
silica gel (70-230 mesh, 60 Å) with CHCl3 as elution solvent
unless otherwise indicated. Melting points were determined
on a Fisher J ohns melting point apparatus and are uncor-
rected. Mass spectra were recorded under electron impact at
70 eV. NMR spectra were recorded in CDCl3 unless otherwise
noted. Elemental analyses were performed by Galbraith
Laboratories, Inc. (Knoxville, TN).
from the single product isolated (structure unknown), it
is apparent no cyclization to the indole ring has taken
place. One explanation for this behavior is that the two
diastereomers have very different abilities to achieve
conformations suitable for bond formation between sulfur
and C-2 of the indole.28
Due to the complicated behavior of 18a ′ in the presence
of triflic anhydride, the corresponding pyrrole diastere-
omer 18b′ has not been studied. However, 18b, when
treated with triflic anhydride under standard conditions,
produces the SES/ring expansion product 19b in 67%
yield.
Sulfoxides 23a b from the indole sulfide 22a and
pyrrole sulfide 22b were isolated as single diastereomers.
Without both diastereomers available it is not possible
to clearly identify the relative stereochemistry of the
compound isolated in the manner described above. How-
ever, on the basis of the relative stabilities of 18a and
18a ′, it seems plausible that 23a b have the sulfoxide
oxygen and the heterocyclic side-chain in the same “cis”-
orientation.
2,3,4,5-Tetr a h yd r oth iop h en e-2-ca r boxa m id e (3). A so-
lution of tetrahydrothiophene-2-carboxylic acid11 (3.2 g, 0.024
mol) and thionyl chloride (7.4 mL, 0.101 mol) was stirred for
6 h. Excess thionyl chloride was removed, and the residue
was distilled in vacuo to give 3.1 g (86%) of a colorless liquid
(62-65 °C/1.5 Torr), which was added dropwise to concen-
trated ammonium hydroxide (20 mL) with stirring. Extraction
with chloroform (3 × 20 mL), washing the combined organic
layers with water (2 × 20 mL), drying (MgSO4), and solvent
removal gave (3) as a white solid (3.0 g, 95%): mp 145-147
°C; 1H NMR (200 MHz) δ 6.91 (br s, 2H), 3.85 (dd, J ) 7.3, 4.8
Hz, 1H), 2.93 (m, 2H), 2.21 (m, 2H), 1.99 (m, 2H); IR (KBr)
3345, 3169, 2927, 1649, 1440 cm-1; MS [m/z (rel intensity)]
131 (M+, 25), 87 (80), 45 (100). Anal. Calcd for C5H9NOS: C,
45.77; H, 6.92; N, 10.67. Found: C, 45.68; H, 6.95; N, 10.47.
Oxalyl chloride may be substituted for thionyl chloride as
the following preparation of 2,3,4,5-tetr a h yd r oth iop h en e-
2-a ceta m id e illustrates. Oxalyl chloride (16 mL, 0.18 mol)
was added dropwise with efficient stirring to a solution of
tetrahydrothiophene-2-acetic acid (3.0 g, 0.02 mol) in CH2Cl2
(20 mL) in an ice-water bath. After 2 h at 25 °C, volatiles
were thoroughly removed to give tetrahydrothiophene-2-acetyl
chloride, which was added dropwise to stirred concentrated
ammonium hydroxide (30 mL). This was worked up as usual
to give tetrahydrothiophene-2-acetamide as a white solid (2.5
g, 84%): mp 123-125 °C; 1H NMR (200 MHz) δ 5.65 (br s,
2H), 3.74 (m, 1H), 2.90 (m, 2H), 2.50 (m, 2H), 2.18 (m, 1H),
2.01 (m, 2H), 1.62 (m, 1H); 13C NMR (50 MHz) δ 173.6, 44.5,
Treatment of these sulfoxides with triflic anhydride
produced the fused, 10-membered ring-containing het-
erocycles 24a and 24b in yields of 42% and 80%,
respectively. For reasons not yet understood, the reac-
tion producing 24a was not clean, and the product was
(28) However, the intervention of sulfenic acid chemistry must again
be considered, especially in light of the report (Lee, W. S.; Hahn, H.
G.; Nam, K. D. J . Org. Chem. 1986, 51, 2789) that only the “cis”
diastereomer, which readily forms
a sulfenic acid intermediate,
undergoes a ring-opening reaction, whereas the “trans” isomer reacts
only under much harsher conditions. This behavior parallels the
observation that “cis”-18a forms a macrocycle, but the “trans” isomer
(18a ′) does not. Nonetheless, sulfenic acid intermediates must be
considered improbable because direct cyclization of an open-chain
sulfenic acid such as i to a nine-membered ring in high yield seems
unlikely. Additional experiments are underway to study the chemistry
of sulfenic acid derivatives such as i generated from trapped sulfenic
acids.
43.6, 37.0, 32.6, 30.1; IR (KBr) 3371, 3186, 2951, 1661 cm-1
;
MS [m/z (rel intensity)] 145 (M+, 100). Anal. Calcd for C6H11
-
NOS: C, 49.62; H, 7.64; N, 9.65. Found: C, 49.72; H, 7.82;
N, 9.53.
This procedure was also used to prepare 3,4-d ih yd r o-
1H -2-b en zot h iop yr a n -1-a cet a m id e: white solid (89%);
(29) (a) Vedejs, E.; Mullins, M. J .; Renga, J . M.; Singer, S. P.
Tetrahedron Lett. 1978, 519. (b) Sashida, H.; Tsuchiya, T. Heterocycles
1982, 19, 2147.
(30) (a) Hesse, M. Ring Enlargement in Organic Chemistry; VCH:
New York, 1991; pp 83-94. (b) Vedejs, E. Acc. Chem. Res. 1984, 17,
358.
(31) Molander, G. A.; Harris, C. R. J . Org. Chem. 1997, 62, 7418.

9194 J . Org. Chem., Vol. 63, No. 25, 1998
Bates and Xia
mp 91-93 °C; 1H NMR (400 MHz) δ 7.17 (m, 3H), 7.11 (m,
1H), 5.71 (br s, 2H), 4.38 (dd, J ) 8.8, 5.5 Hz, 1H), 3.03 (m,
2H), 2.93 (m, 1H), 2.81 (m, 3H); 13C NMR (100 MHz) δ 172.6,
137.2, 136.3, 129.6, 127.3, 127.0, 126.6, 44.5, 37.4, 30.7, 24.4;
IR (KBr) 3500-3100, 3057, 2925, 1715, 1665 cm-1; MS [m/z
mmol) in acetonitrile (25 mL) was added 1,4-dichloro-1,4-
dimethoxybutane13 (5.6 g, 29.9 mmol) dropwise over 5 min.
The solid dissolved to give a brown solution to which Amberlyst
A-21 resin (8 g) was added in portions. The solution was
heated at 55-60 °C for 24 h. The black mixture was filtered,
and the solvent was removed in vacuo to give a black oil that
was chromatographed to yield 4a (1.5 g, 55%).
Meth od B. Acyla tion of In d ole. To a well-stirred, ice-
bath-cooled solution of indole (1.23 g, 10.5 mmol) and tetrabu-
tylammonium hydrogensulfate (0.036 g, 0.105 mmol) in me-
thylene chloride (30 mL) was added powdered sodium hydroxide
(1.26 g, 31.5 mmol) followed by 7 (3.1 g, 20.6 mmol). After 30
min, the mixture was filtered, and the filtrate, after washing
with water followed by solvent evaporation, gave a yellow oil.
Chromatography gave 4a (2.3 g, 95%) as a white solid: mp
96-98 °C; 1H NMR (200 MHz) δ 8.47 (dd, J ) 7.9, 1.6 Hz,
1H), 7.56 (dd, J ) 7.4, 1.8 Hz, 1H), 7.42 (d, J ) 3.8 Hz, 1H),
7.29 (m, 2H), 6.64 (d, J ) 3.8 Hz, 1H), 4.52 (dd, J ) 6.8, 4.4
Hz, 1H), 3.02 (m, 2H), 2.69 (m, 1H), 2.35 (m, 1H), 2.19 (m,
2H); 13C NMR (50 MHz) δ 170.8, 136.0, 130.5, 125.2, 124.6,
123.8, 120.9, 116.7, 109.5, 47.6, 34.0, 32.6, 31.3; IR (KBr) 3116,
2940, 1699 cm-1; MS [m/z (rel intensity)] 231 (M+, 25), 87 (100).
Anal. Calcd for C13H13NOS: C, 67.50; H, 5.67; N, 6.06.
Found: C, 67.45; H, 5.80; N, 5.91.
(rel intensity)] 207 (M+, 14), 115 (100). Anal. Calcd for C11H13
-
NOS: C, 63.73; H, 6.32; N, 6.76. Found: C, 63.52; H, 6.43;
N, 6.71.
Rep r esen ta tive P r ep a r a tion of P yr r oles fr om Am id es.
1-[(2,3,4,5-Tetr ah ydr o-2-th ien yl)car bon yl]-1H-pyr r ole (4b).
A solution of 2,5-dimethoxytetrahydrofuran (3.2 g, 0.024 mol)
and 3 (2.2 g, 0.017 mol) in glacial acetic acid (18 mL) was
refluxed under nitrogen for 12 h, at which time TLC showed
no starting material. The reaction mixture was cooled,
neutralized with 50% NaOH, and extracted with chloroform
(3 × 30 mL). Removal of solvent from the chloroform extract
left a thick brown oil that was purified by vacuum distillation
to give 4b (2.1 g, 69%) as a colorless oil: bp 123 °C/1 Torr; 1H
NMR (200 MHz) δ 7.26 (apparent t, J ) 2.3 Hz, 2H), 6.27
(apparent t, J ) 2.3 Hz, 2H), 4.42 (dd, J ) 6.9, 4.2 Hz, 1H),
2.93 (m, 2H), 2.52 (m, 1H), 2.23-1.98 (m, 3H); 13C NMR (50
MHz) δ 171.0, 120.3, 114.4, 47.5, 35.0, 33.5, 32.2; IR (KBr)
3144, 2998, 1714, 1468 cm-1; MS [m/z (rel intensity)] 181 (M+,
36), 87 (100).
This procedure was used to prepare the following com-
pounds.
Method B was used to prepare the following acyl indoles.
1-[(2,3,4,5-Tetr a h yd r o-2-th ien yl)a cetyl]-1H-in d ole (9a ):
white solid (86%); mp 99.5-101.5 °C; H NMR (200 MHz) δ
1
1-[(2,3,4,5-Te t r a h yd r o-2-t h ie n yl)a ce t yl]-1H -p yr r ole
(9b): light yellow oil (66%); 1H NMR (200 MHz) δ 7.25
(apparent t, J ) 2.3 Hz, 2H), 6.24 (apparent t, J ) 2.3 Hz,
2H), 3.84 (m, 1H), 3.09 (d, J ) 7.2 Hz, 2H), 2.84 (m, 2H), 2.19
(m, 1H), 2.01 (m, 2H), 1.65 (m, 1H); 13C NMR (50 MHz) δ 168.7,
118.9, 113.1, 43.1, 42.5, 36.8, 32.5, 30.1; IR (KBr) 3146, 2945,
1714 cm-1; MS [m/z (rel intensity)] 195 (M+, 51), 87 (100).
1-[(1,3-Dih yd r o-2-b e n zot h ie n yl)a ce t yl]-1H -p yr r ole
(17b): yellow semisolid (66%); 1H NMR (400 MHz) δ 7.27 (m,
6 H), 6.29 (apparent t, J ) 2.3 Hz, 2H), 5.21 (m, 1H), 4.33 (dd,
J ) 14.0, 2.7 Hz, 1H), 4.20 (d, J ) 14.0 Hz, 1H), 3.53 (dd, J )
17.1, 4.3 Hz, 1H), 3.37 (dd, J ) 17.1, 9.5 Hz, 1H); IR (KBr)
3049, 2934, 1715 cm-1; MS [m/z (rel intensity)] 243 (M+, 7).
In the preparation of this compound, we found it convenient
to oxidize this sulfide directly to the sulfoxide, at which time
it was much easier to chromatographically separate the desired
product from a pyrrole derived from an unbrominated cinnamic
acid derivative carried along through the sequence from an
earlier incomplete reaction.
1-[(3,4-Dih yd r o-1H-2-ben zoth iop yr a n -3-yl)a cetyl]-1H-
p yr r ole (22b): yellow semisolid (71%); 1H NMR (400 MHz) δ
7.29 (m, 2 H), 7.18 (m, 4H), 6.29 (apparent t, J ) 2.3 Hz, 2H),
4.61 (dd, J ) 9.0, 5.2 Hz, 1H), 3.49 (dd, J ) 16.5, 9.0 Hz, 1H),
3.33 (dd, J ) 16.5, 5.2 Hz, 1H), 3.08 (m, 2H), 2.96 (m, 1H),
2.84 (m, 1H); 13C NMR (100 MHz) δ 167.9, 136.7, 136.4, 129.8,
127.5, 127.2, 126.7, 118.9, 113.4, 43.7, 36.6, 30.8, 24.4; IR (KBr)
3058, 3018, 2923, 1714 cm-1; MS [m/z (rel intensity)] 257 (M+,
11), 149 (100).
2,3,4,5-Tetr a h yd r oth iop h en e-2-a cetic Acid (7). Ion ic
Hyd r ogen a tion in th e P r esen ce of BF 3(OEt2). Trifluoro-
acetic acid (8.1 mL, 0.105 mol) and boron trifluoride diethyl
etherate (2 mL, 0.015 mol) were slowly added to the mixture
of 2-thiopheneacetic acid (2.1 g, 0.015 mol) and triethylsilane
(7.0 g, 0.06 mol) with stirring. The resulting solution was
refluxed for 107 h. After cooling and neutralization with 10%
Na2CO3 and extraction with ether (3 × 30 mL), the combined
organics were dried (Na2SO4). Solvent removal afforded 7 (1.0
g, 46%) as a light brown oil.
Ion ic Hyd r ogen a tion in th e P r esen ce of SbF 5‚HF . A
mixture of trifluoroacetic acid (16.2 mL, 0.21 mol) and HSbF6
(three drops) was slowly added to the mixture of 2-thiophe-
neacetic acid (4.2 g, 0.03 mol) and triethylsilane (10.5 g, 0.09
mol) with stirring. The resulting solution was refluxed for 56
h and then worked up as described above to afford 7 (2.54 g,
58%) as a light brown oil that was identical in all respects
with authentic 7 made according to the literature.20
1-[(2,3,4,5-Tet r a h yd r o-2-t h ien yl)ca r b on yl]-1H -in d ole
(4a ). Meth od A. Rea ction of 8 w ith 1,4-Dich lor o-1,4-
d im eth oxybu ta n e. To a stirred suspension of 3 (2.2 g, 16.8
8.45 (d, J ) 8.2 Hz, 1H), 7.55 (d, J ) 8.0 Hz, 1H), 7.42 (d, J )
3.9 Hz, 1H), 7.30 (m, 2H), 6.63 (d, J ) 3.9 Hz, 1H), 3.95 (m,
1H), 3.22 (d, J ) 7.0 Hz, 2H), 2.90 (m, 2H), 2.28 (m, 1H), 2.08
(m, 2H), 1.69 (m, 1H); 13C NMR (50 MHz) δ 169.6, 135.6, 130.3,
125.1, 124.3, 123.7, 120.8, 116.6, 109.3, 43.8, 43.4, 36.9, 32.5,
30.2; IR (KBr) 3119, 2936, 1704 cm-1; MS [m/z (rel intensity)]
245 (M+, 12), 129 (7), 117 (100). Anal. Calcd for C14H15NOS:
C, 68.54; H, 6.16; N, 5.71. Found: C, 68.34; H, 6.26; N, 5.68.
1-[(1,3-D ih y d r o -2-b e n zo t h ie n y l)a c e t y l]-1H -in d o le
(17a ): white solid (63%); mp 146-148 °C; 1H NMR (400 MHz)
δ 8.51 (d, J ) 7.6 Hz, 1H), 7.55 (d, J ) 7.9 Hz, 1H), 7.27 (m,
7H), 6.62 (d, J ) 3.7 Hz, 1H), 5.28 (m, 1H), 4.34 (d, J ) 14.3
Hz, 1H), 4.23 (d, J ) 14.3 Hz, 1H), 3.64 (d, J ) 16.8 Hz, 1H),
3.46 (dd, J ) 16.8, 9.5 Hz, 1H); 13C NMR (100 MHz) δ 170.3,
143.5, 141.7, 136.7, 131.4, 128.7, 128.2, 126.4, 126.3, 125.4,
124.9, 122.0, 117.8, 110.6, 50.0, 47.5, 38.0; 13C NMR (100 MHz,
CD3COCD3) δ 171.0, 143.9, 141.9, 136.6, 131.7, 128.3, 127.9,
126.7, 126.1, 125.7, 125.6, 124.6, 121.9, 117.3, 109.6, 49.9, 46.9,
37.0; 1H NMR (400 MHz, C6D6) δ 8.85 (d, J ) 7.9 Hz, 1H),
7.40 (d, J ) 7.6 Hz, 1H), 7.23 (m, 1H), 7.15 (m, 1H), 6.96 (m,
3H), 6.82 (m, 1H), 6.52 (m, 1H), 6.19 (d, J ) 3.7 Hz, 1H), 5.20
(m, 1H), 3.96 (dd, J ) 14.0, 2.8 Hz, 1H), 3.82 (d, J ) 14.0 Hz,
1H), 2.84 (d, J ) 6.7 Hz, 2H); IR (KBr) 3047, 2914, 1709 cm-1
;
MS [m/z (rel intensity)] 293 (M+, 8), 135 (100). Anal. Calcd
for C18H15NOS: C, 73.69; H, 5.15; N, 4.77. Found: C, 73.63;
H, 5.16; N, 4.65.
1-[(3,4-Dih yd r o-1H-2-ben zoth iop yr a n -3-yl)a cetyl]-1H-
in d ole (22a ): white solid (68%); mp 121-123 °C; 1H NMR (400
MHz) δ 8.54 (d, J ) 8.2 Hz, 1H), 7.57 (d, J ) 7.9 Hz, 1H), 7.38
(m, 2H), 7.29 (td, J ) 7.6, 0.9 Hz, 1H), 7.21 (m, 4H), 6.64 (d,
J ) 3.4 Hz, 1H), 4.71 (dd, J ) 9.2, 4.9 Hz, 1H), 3.59 (dd, J )
16.5, 9.2 Hz, 1H), 3.44 (dd, J ) 16.5, 4.9 Hz, 1H), 3.11 (m,
2H), 2.99 (m, 1H), 2.87 (m, 1H); 13C NMR (100 MHz) δ 168.7,
136.8, 136.5, 135.6, 130.3, 129.7, 127.4, 127.1, 126.7, 125.2,
124.2, 123.8, 120.8, 116.7, 109.4, 44.8, 36.7, 30.8, 24.5; IR (KBr)
3020, 2924, 1705, 1452 cm-1; MS [m/z (rel intensity)] 307 (M+,
12), 117 (100). Anal. Calcd for C19H17NOS: C, 74.23; H, 5.58;
N, 4.56. Found: C, 74.49; H, 5.67; N, 4.47.
Rep r esen ta tive P r oced u r e for Su lfid e Oxid a tion w ith
Oxon e. 1-[(2,3,4,5-Tet r a h yd r o-2-t h ien yl)ca r b on yl]-1H -
in d ole S-Oxid e (5a ). To a solution of 4a (1.5 g, 6.5 mmol) in
THF (13 mL) and methanol (12 mL) was added Oxone (2.6 g,
4.23 mmol) in water (12 mL) at 0 °C. The mixture was stirred
at 0 °C for 40 min and at 28 °C for 4 h, at which time TLC
showed no starting material. Extractive workup with CH2-
Cl2 afforded a light yellow crude product that was chromato-
graphed to give the sulfoxide 10a (1.5 g, 93%) as a white
solid: mp 134-136 °C; 1H NMR (200 MHz) δ 8.40 (d, J ) 7.9

Sulfoxide-Based Ring Annelation Approach
J . Org. Chem., Vol. 63, No. 25, 1998 9195
Hz, 1H), 7.63 (d, J ) 3.8 Hz, 1H), 7.57 (m, 1H), 7.33 (m, 2H),
6.72 (d, J ) 3.8 Hz, 1H), 4.44 (t, J ) 7.0 Hz, 1H), 3.09 (m,
1H), 3.01 (m, 1H), 2.73 (m, 2H), 2.53 (m, 2H); 13C NMR (50
MHz) δ 167.3, 136.3, 131.3, 126.2, 125.1, 121.8, 117.3, 111.5,
1-[(1,3-Dih yd r o-2-ben zoth ien yl)a cetyl]-1H-p yr r ole S-
Oxid es (18b a n d 18b ′). Sulfoxide 18b (light yellow solid,
37%): mp 188-190 °C; H NMR (400 MHz) δ 7.33 (m, 6H),
1
6.30 (t, J ) 2.4 Hz, 2H), 4.86 (dd, J ) 8.6, 5.2 Hz, 1H), 4.32 (d,
J ) 16.2 Hz, 1H), 4.09 (d, J ) 16.2 Hz, 1H), 3.80 (dd, J )
18.0, 8.6 Hz, 1H), 3.46 (dd, J ) 18.0, 5.2 Hz, 1H); 13C NMR
(100 MHz) δ 167.9, 137.5, 135.0, 129.0, 128.6, 126.8, 125.8,
119.1, 113.7, 61.3, 56.9, 31.2; 1H NMR (400 MHz, C6D6) δ 7.06
(m, 1H), 6.90 (m, 4H), 6.68 (m, 1H), 6.00 (t, J ) 2.4 Hz, 2H),
4.33 (m, 1H), 3.47 (dd, J ) 18.0, 7.9 Hz, 1H), 3.41 (d, J ) 16.2
Hz, 1H), 3.24 (d, J ) 16.2 Hz, 1H), 2.67 (dd, J ) 18.0, 5.5 Hz,
1H); IR (KBr) 3012, 1714, 1470, 1039 cm-1; MS [m/z (rel
74.7, 55.5, 30.4, 27.5; IR (KBr) 3102, 2942, 1693, 1035 cm-1
;
MS [m/z (rel intensity)] 247 (M+, 26), 117 (100). Anal. Calcd
for C13H13NO2S: C, 63.13; H, 5.30; N, 5.66. Found: C, 63.19;
H, 5.44; N, 5.60.
This procedure was also used to prepare 1-[(2,3,4,5-tet-
r a h yd r o-2-th ien yl)ca r bon yl]-1H-p yr r ole S-oxid e (5b): col-
1
orless oil (97%); H NMR (200 MHz) δ 7.37 (apparent t, J )
2.3 Hz, 2H), 6.34 (apparent t, J ) 2.3 Hz, 2H), 4.33 (t, J ) 6.9
Hz, 1 H), 3.06 (m, 1H), 2.86 (m, 1H), 2.62 (m, 2H), 2.41 (m,
2H); 13C NMR (50 MHz) δ 166.0, 119.3, 114.5, 73.0, 54.7, 29.7,
26.8; IR (KBr) 3138, 2946, 1700, 1472, 1041 cm-1; MS [m/z
(rel intensity)] 197 (M+, 8), 67 (100).
intensity)] 259 (M+, 1.0), 193 (100). Anal. Calcd for C14H13
-
NO2S: C, 64.84; H, 5.05; N, 5.40. Found: C, 64.62; H, 5.11;
N, 5.28.
Sulfoxide 18b′ (yellow semisolid, 33%): 1H NMR (400 MHz)
δ 7.28 (m, 6H), 6.25 (t, J ) 2.4 Hz, 2H), 4.66 (t, J ) 6.1 Hz,
1H), 4.61 (d, J ) 16.2 Hz, 1H), 4.03 (d, J ) 16.2 Hz, 1H), 3.49
(poorly resolved t, 2H); 13C NMR (100 MHz) δ 166.8, 137.7,
135.7, 128.9, 128.5, 126.5, 125.6, 118.9, 113.8, 69.7, 58.4, 36.0;
IR (KBr) 3010, 1716, 1470, 1037 cm-1; MS [m/z (rel intensity)]
242 (M+ - OH, 0.8). This compound could not be obtained
free from 18b (epimerization apparently takes place at room
temperature on the chromatography column).
1-[(3,4-Dih yd r o-1H-2-ben zoth iop yr a n -3-yl)a cetyl]-1H-
in d ole S-oxid e (23a ): white solid (54%); mp 191-193 °C; 1H
NMR (400 MHz) δ 8.43 (d, J ) 8.5 Hz, 1H), 7.58 (d, J ) 8.2
Hz, 1H), 7.56 (d, J ) 3.4 Hz, 1H), 7.36 (td, J ) 8.2, 1.2 Hz,
1H), 7.29 (td, J ) 7.6, 0.9 Hz, 1H), 7.24 (m, 4H), 6.71 (d, J )
3.4 Hz, 1H), 4.54 (dd, J ) 8.5, 4.0 Hz, 1H), 3.88 (dd, J ) 17.1,
4.0 Hz, 1H), 3.70 (dd, J ) 17.1, 8.5 Hz, 1H), 3.53 (m, 1H), 3.17
(m, 3H); 13C NMR (100 MHz) δ 167.5, 136.2, 135.7, 130.5,
130.3, 128.7, 128.3, 127.6, 127.4, 125.5, 124.1, 124.0, 121.0,
116.7, 110.3, 58.4, 46.8, 35.3, 24.3; IR (KBr) 3055, 3025, 2928,
1698, 1452, 1041 cm-1; MS [m/z (rel intensity)] 323 (M+, 6),
116 (100). Anal. Calcd for C19H17NO2S: C, 70.56; H, 5.30; N,
4.33. Found: C, 70.85; H, 5.39; N, 4.15.
1-[(3,4-Dih yd r o-1H-2-ben zoth iop yr a n -3-yl)a cetyl]-1H-
p yr r ole S-oxid e (23b): yellow semisolid (80%); 1H NMR (400
MHz) δ 7.37 (apparent s, 2H), 7.25 (m, 3H), 7.18 (m, 1H), 6.34
(t, J ) 2.3 Hz, 2H), 4.47 (dd, J ) 8.4, 4.6 Hz, 1H), 3.72 (dd, J
) 17.4, 4.6 Hz, 1H), 3.58 (dd, J ) 17.4, 8.4 Hz, 1H), 3.50 (m,
1H), 3.15 (m, 3H); 13C NMR (100 MHz) δ 166.8, 135.8, 130.3,
128.7, 128.2, 127.5, 119.0, 113.8, 57.9, 46.1, 34.4, 23.9; 1H NMR
(400 MHz, CD3COCD3) δ 7.49 (t, J ) 2.3 Hz, 2H), 7.33 (m,
1H), 7.24 (m, 3H), 6.31 (t, J ) 2.3 Hz, 2H), 4.49 (t, J ) 6.7 Hz,
1H), 3.65 (d, J ) 6.7 Hz, 2H), 3.45 (m, 1H), 3.20 (m, 1H), 3.03
(m, 2H); 13C NMR (100 MHz, CD3COCD3) δ 168.8, 136.4, 132.6,
130.7, 130.0, 128.6, 128.0, 120.4, 114.1, 57.0, 43.1, 37.2, 22.5;
1H NMR (400 MHz, C6D6) δ 7.11 (apparent s, 2H), 6.85 (m,
3H), 6.68 (d, J ) 7.3 Hz, 1H), 6.02 (t, J ) 2.4 Hz, 2H), 4.30
(dd, J ) 8.5, 4.6 Hz, 1H), 3.20 (dd, J ) 17.4, 4.6 Hz, 1H), 2.93
(dd, J ) 17.4, 8.5 Hz, 1H), 2.89 (m, 1H), 2.45 (m, 1H), 2.25 (m,
2H); IR (KBr) 3061, 3022, 2924, 1713, 1040 cm-1; MS [m/z (rel
intensity)] 273 (M+, 6), 115 (100).
Rep r esen ta tive P r oced u r e for Su lfid e Oxid a tion w ith
Na IO4. 1-[(2,3,4,5-Tet r a h yd r o-2-t h ien yl)a cet yl]-1H -in -
d ole S-Oxid e (10a ). A solution of NaIO4 (0.36 g, 1.70 mmol)
in water (4 mL) was added to a solution of 9a (0.4 g, 1.63 mmol)
in acetone (8 mL). The mixture was stirred for 26 h, at which
time TLC showed no sulfide. The volatile was removed in
vacuo. Extractive workup with CHCl3/H2O afforded a crude
product that was chromatographed to give of 10a (0.36 g, 85%)
1
as a white solid: mp 172-174 °C; H NMR (200 MHz) δ 8.42
(d, J ) 8.2 Hz, 1H), 7.50 (m, 1H), 7.44 (d, J ) 3.8 Hz, 1H),
7.27 (m, 2H), 6.60 (d, J ) 3.8 Hz, 1H), 3.57 (m, 1H), 3.12 (m,
3H), 2.80 (m, 1H), 2.30 (m, 2H), 2.08 (m,1H), 1.90 (m, 1H); 13
C
NMR (50 MHz) δ 168.7, 135.6, 130.4, 125.2, 124.3, 123.9, 120.9,
116.5, 109.8, 58.7, 54.6, 33.0, 30.7, 24.8; IR (KBr) 3140, 2945,
1707, 1016 cm-1; MS [m/z (rel intensity)] 261 (M+, 7), 145 (100).
Anal. Calcd for C14H15NO2S: C, 64.34; H, 5.79; N, 5.36.
Found: C, 64.04; H, 5.94; N, 5.32.
1-[(2,3,4,5-Tetr a h yd r o-2-th ien yl)a cetyl]-1H-p yr r ole S-
1
oxid e (10b): white solid (68%); mp 96-98 °C; H NMR (200
MHz) δ 7.32 (t, J ) 2.3 Hz, 2H), 6.29 (t, J ) 2.3 Hz, 2H), 3.54
(m, 1H), 3.20 (m, 3H), 2.85 (m, 1H), 2.38 (m, 2H), 1.92-2.12
(m, 2H); 13C NMR (50 MHz) δ 168.1, 118.9, 113.5, 58.3, 54.5,
31.8, 30.6, 24.7; IR (KBr) 3098, 2931, 1715, 1007 cm-1; MS
[m/z (rel intensity)] 211 (M+, 2), 145 (100). Anal. Calcd for
C
10H13NO2S: C, 56.85; H, 6.20; N, 6.63. Found: C, 57.03; H,
6.39; N, 6.59.
1-[(1,3-Dih yd r o-2-b en zot h ien yl)a cet yl]-1H -in d ole S-
Oxid es (18a a n d 18a ′). Sulfoxide 18a (white solid, 68%): mp
1
198-201 °C; H NMR (400 MHz) δ 8.48 (d, J ) 7.9 Hz, 1H),
7.56 (d, J ) 7.6 Hz, 1H), 7.53 (d, J ) 3.9 Hz, 1H), 7.35 (m,
6H), 6.66 (d, J ) 3.9 Hz, 1H), 4.96 (dd, J ) 8.2, 5.2 Hz, 1H),
4.35 (d, J ) 16.4 Hz, 1H), 4.13 (d, J ) 16.4 Hz, 1H), 3.91 (dd,
J ) 17.7, 8.2 Hz, 1H), 3.56 (dd, J ) 17.7, 5.2 Hz, 1H); 13C NMR
(100 MHz) δ 168.5, 137.7, 135.7, 135.2, 130.4, 129.0, 128.6,
126.9, 125.9, 125.4, 124.3, 124.0, 121.0, 116.6, 110.1, 61.7, 57.1,
32.3; 1H NMR (400 MHz, C6D6) δ 8.84 (d, J ) 8.2 Hz, 1H),
7.39 (d, J ) 7.6 Hz, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.96 (m,
3H), 6.74 (m, 2H), 6.19 (d, J ) 3.7 Hz, 1H), 4.47 (dd, J ) 7.9,
5.8 Hz, 1H), 3.56 (dd, J ) 17.7, 7.9 Hz, 1H), 3.49 (d, J ) 16.1
Hz, 1H), 3.29 (d, J ) 16.1 Hz, 1H), 2.76 (dd, J ) 17.7, 5.8 Hz,
1H); IR (KBr) 3049, 2902, 1695, 1025 cm-1; MS [m/z (rel
Rep r esen ta tive Rea ction of Su lfoxid es w ith TF AA. To
a well-stirred solution of TFAA (1.3 mL, 8.0 mmol) in CH2Cl2
intensity)] 309 (M+, 5), 193 (100). Anal. Calcd for C18H15
-
(13 mL) at 0 °C was added pyridine (0.7 mL, 8.0 mmol).
A
NO2S: C, 69.88; H, 4.89; N, 4.53. Found: C, 69.67; H, 4.85;
N, 4.40.
solution of sulfoxide 5a (0.49 g, 2.0 mmol) in CH2Cl2 (5 mL)
was then added. The mixture was stirred at 0 °C for 3 h and
at room temperature for 0.5 h. The solution was poured into
10% aqueous Na2CO3 (30 mL). The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 15 mL).
The combined organics were washed with 5% HCl and water
and dried (Na2SO4). The solvent was removed in vacuo, and
the residue was chromatographed (CHCl3/hexane) to afford
1-[(4,5-d ih yd r o-2-th ien yl)]ca r bon yl]-1H-in d ole (6a ) (0.43
g, 94%) as a yellow semisolid: 1H NMR (200 MHz) δ 8.39 (d,
J ) 7.8 Hz, 1H), 7.60 (d, J ) 3.8 Hz, 1H), 7.55 (m, 1H), 7.32
(m, 2H), 6.61 (d, J ) 3.8 Hz, 1H), 6.28 (t, J ) 3.0 Hz, 1H),
3.41 (t, J ) 8.6 Hz, 2H), 3.02 (td, J ) 8.6, 3.0 Hz, 2H); 13C
NMR (50 MHz) δ 162.7, 137.5, 135.5, 131.7, 130.7, 126.5, 124.9,
124.0, 120.8, 116.4, 108.8, 36.7, 32.8; IR (KBr) 3117, 3052,
2936, 1677 cm-1; MS [m/z (rel intensity)] 229 (M+, 78), 113
(100).
Sulfoxide 18a ′ (bright yellow semisolid, 14%): 1H NMR (400
MHz) δ 8.36 (d, J ) 7.9 Hz, 1H), 7.51 (d, J ) 7.3 Hz, 1H), 7.27
(m, 7 H), 6.60 (d, J ) 3.9 Hz, 1H), 4.71 (dd, J ) 6.1, 5.8 Hz,
1H), 4.65 (d, J ) 16.1 Hz, 1H), 4.04 (d, J ) 16.1 Hz, 1H), 3.52
(m, 2H); 13C NMR (100 MHz) δ 167.3, 137.9, 135.7, 135.3,
130.1, 128.7, 128.4, 126.5, 125.6, 125.3, 124.0, 120.9, 116.4,
110.0, 69.8, 58.3, 37.0; 13C NMR (100 MHz, CD3COCD3) δ
170.0, 140.7, 138.2, 136.5, 131.6, 129.4, 129.0, 127.7, 127.5,
126.6, 125.8, 124.7, 121.9, 117.2, 109.9, 70.7, 58.4, 37.5; 1H
NMR (400 MHz, C6D6) δ 8.63 (d, J ) 7.0 Hz, 1H), 7.37 (d, J )
7.3 Hz, 1H), 7.15 (m, 2H), 6.94 (m, 3H), 6.77 (m, 1H), 6.46 (m,
1H), 6.19 (d, J ) 3.7 Hz, 1H), 4.54 (dd, J ) 7.0, 5.5 Hz, 1H),
3.93 (d, J ) 15.9 Hz, 1H), 3.65 (d, J ) 15.9 Hz, 1H), 2.69 (dd,
J ) 17.7, 5.5 Hz, 1H), 2.52 (dd, J ) 17.7, 7.0 Hz, 1H); IR (KBr)
3069, 2982, 1702, 1035 cm-1; MS [m/z (rel intensity)] 309 (M+,
13), 117 (100).

9196 J . Org. Chem., Vol. 63, No. 25, 1998
Bates and Xia
The following products were formed from the same proce-
dure (variations in reactions times are given in parentheses).
1-[(4,5-Dih yd r o-2-th ien yl)]ca r bon yl]-1H-p yr r ole (6b):
4 h at 0 °C and 3 h at 25 °C; 88%; yellow oil: 1H NMR (200
MHz) δ 7.34 (t, J ) 2.0 Hz, 2H), 6.33 (t, J ) 3.1 Hz, 1H), 6.28
(t, J ) 2.0 Hz, 2H), 3.38 (t, J ) 8.5 Hz, 2H), 3.00 (td, J ) 8.5,
3.1 Hz, 2H); 13C NMR (50 MHz) δ 161.7, 136.9, 133.4, 120.3,
113.3, 36.8, 32.6; IR (KBr) 3148, 2936, 1688, 1588 cm-1; MS
[m/z (rel intensity)] 179 (M+, 21), 45 (100).
°C) δ 167.3, 142.3, 138.3, 133.2, 128.5, 125.7, 124.8, 123.8,
121.5, 120.1, 116.7, 42.6, 27.4, 24.4; IR (KBr) 3068, 2921, 1677
cm-1; MS [m/z (rel intensity)] 243 (M+, 100); 1H NMR (400
MHz, -20 °C) δ 8.33 (d, J ) 8.2 Hz, 1H), 7.52 (dd, J ) 7.7, 1.3
Hz, 1H), 7.37 (m, 1H), 7.27 (m, 1H), 7.01 (s, 1H), 6.24 (m, 2H),
3.34 (m, 1H), 2.94 (m, 1H), 2.26 (m, 1H), 2.18 (m, 1H), 1.89
(m, 1H), 1.76 (m, 1H); 13C NMR (100 MHz, -20 °C) δ 167.4,
143.5, 138.2, 133.5, 128.5, 125.9, 124.5, 124.0, 121.8, 120.3,
116.8, 43.4, 27.5, 24.5.
3,4-Dih ydr opyr r olo[2,1-b][1,3]th iazon in -7(2H)-on e (13b):
15 min at 0 °C and 7 h at room temperature (60%); light yellow
oil; 1H NMR (400 MHz, 23 °C) δ 7.64 (dd, J ) 3.6, 1.9 Hz, 1H),
6.60 (dd, J ) 3.1, 1.9 Hz, 1H), 6.26 (m, 2H), 6.10 (d, J ) 12.0
Hz, 1H), 2.62-3.19 (br s, 2H), 2.21 (m, 2H), 1.80 (m, 2H); 13C
NMR (100 MHz, 23 °C) δ 166.9, 145.0, 127.3, 127.1, 125.6,
1-[[4,5-Dih yd r o-2(3H )-t h iop h en ylid en ]a cet yl]-1H -in -
d ole (11a ): 15 min at 0 °C and 3 h at room temperature; white
1
solid (73%); mp 143-146 °C; H NMR (400 MHz) δ 8.59 (d, J
) 8.2 Hz, 1H), 7.56 (d, J ) 7.6 Hz, 1H), 7.50 (d, J ) 3.9 Hz,
1H), 7.33 (m, 1H), 7.24 (m, 1H), 6.72 (t, J ) 1.2 Hz, 1H), 6.61
(d, J ) 3.9 Hz, 1H), 3.11 (t, J ) 6.4 Hz, 2H), 2.92 (td, J ) 7.0,
1.2 Hz, 2H), 2.09 (p, J ) 6.7 Hz, 2H); 13C NMR (100 MHz) δ
172.4, 164.3, 135.7, 130.3, 124.43, 124.35, 123.0, 120.6, 116.5,
123.4, 113.0, 43.6, 28.8, 25.6; IR (KBr) 3146, 2920, 1683 cm-1
;
MS [m/z (rel intensity)] 193 (M+, 20), 67 (100).
108.0, 105.0, 40.1, 35.3, 27.9; IR (KBr) 3033, 2956, 1655 cm-1
;
In d olo[2,1-b][1,3]ben zo[g]th ia zon in -9(2H)-on e (19a ): 15
MS [m/z (rel intensity)] 243 (M+, 30), 117 (100). Anal. Calcd
for C14H13NOS: C, 69.10; H, 5.38; N, 5.76. Found: C, 69.32;
H, 5.31; N, 5.57.
min at 0 °C and 3 h at room temperature; yellow solid (67%);
1
mp 169-172 °C; H NMR (400 MHz) δ 7.96 (d, J ) 8.5 Hz,
1H), 7.28 (m, 2 H), 7.19 (m, 1H), 7.08 (m, 1H), 6.88 (m, 4H),
6.62 (d, J ) 12.1 Hz, 1H), 6.57 (s, 1H), 4.02 (d, J ) 10.7 Hz,
1H), 3.86 (d, J ) 10.7 Hz, 1H); 13C NMR (100 MHz) δ 167.0,
138.0, 136.3, 136.1, 132.6, 130.6, 129.0, 128.4, 127.65, 127.59,
126.4, 126.3, 125.5, 123.4, 123.2, 120.1, 115.4, 38.5; IR (CHCl3)
3070, 2929, 1672 cm-1; MS [m/z (rel intensity)] 291 (M+, 33),
115 (100). Anal. Calcd for C18H13NOS: C, 74.20; H, 4.50; N,
4.81. Found: C, 74.01; H, 4.63; N, 4.72.
Rep r esen ta tive P r oced u r e for Th er m a l Rea ction s of
Su lfoxid es. Sulfoxide 5a (0.95 g, 3.85 mmol) was refluxed
in p-xylene (30 mL) for 53 h during which time TLC indicated
formation of a new product. Solvent evaporation and chro-
matography (chloroform/hexane) yielded 0.24 g (57% based on
0.5 g recovered starting material) of 6a as a yellow semisolid,
which was spectroscopically and chromatographically identical
to the sample obtained from the TFAA reaction.
P yr r olo[2,1-b][1,3]ben zo[g]th ia zon in -9(2H)-on e (19b):
The following compounds were obtained by the same
procedure. If no spectral data are provided, the compound
identity was verified by comparing spectroscopic and chro-
matographic behavior with samples obtained using a different
method.
1-[(4,5-Dih yd r o-2-th ien yl)]ca r bon yl]-1H-p yr r ole (6b):
48 h gave 60% conversion of starting material and a 55% yield
(based on recovered starting material) of 6b.
15 min at 0 °C and 3 h at room temperature; brownish
semisolid (67%); H NMR (400 MHz) δ 7.32 (d, J ) 12.0 Hz,
1
1H), 7.14 (dd, J ) 3.7, 1.8 Hz, 1H), 7.05 (m, 2H), 6.93 (m, 1H),
6.86 (m, 1H), 6.53 (d, J ) 12.0 Hz, 1H), 6.19 (dd, J ) 3.3, 1.8
Hz, 1H), 5.90 (t, J ) 3.3 Hz, 1H), 3.92 (d, J ) 11.0 Hz, 1H),
3.72 (d, J ) 11.0 Hz, 1H); 13C NMR (100 MHz) δ 165.9, 137.8,
136.0, 133.0, 130.7, 127.94, 127.89, 127.4, 127.3, 126.7, 124.6,
119.0, 112.1, 38.7; IR (KBr) 3010, 1687 cm-1; MS [m/z (rel
intensity)] 241 (M+, 46), 115 (100).
Red ox P r od u cts 9a a n d 12: 24 h; sulfide 9a (37%)
(identical to the compound used to prepare sulfoxide 10a ).
2,3-Dih yd r o-10H -in d olo[2,1-b][1,3]b en zo[g]t h ia zecin -
10-on e (24a ): 15 min at 0 °C and 4 h at room temperature;
yellow semisolid (42%); 1H NMR (400 MHz) δ 7.94 (d, J ) 8.2
Hz, 1H), 7.47 (d, J ) 11.9 Hz, 1H), 7.13 (m, 3H), 6.93 (m, 1H),
6.81 (m, 1H), 6.64 (m, 1H), 6.62 (d, J ) 11.9 Hz, 1H), 6.43 (td,
J ) 7.6, 0.9 Hz, 1H), 6.33 (s, 1H), 3.35 (m, 2H), 3.08 (m, 2H);
13C NMR (100 MHz) δ 168.0, 142.2, 137.4, 136.4, 135.4, 129.7,
128.6, 128.1, 127.3, 126.2, 125.9, 124.5, 122.9, 118.9, 116.6,
114.2, 43.4, 34.8; IR (CHCl3): 3020, 1682 cm-1; MS [m/z (rel
intensity)] 305 (M+, 15). Unlike 24b, this compound was not
stable and could not purified to an acceptable level of purity.
The data provided here is from this impure material, but
spectra contained other unidentified peaks.
2,3-Dih yd r o-10H-p yr r olo[2,1-b][1,3]ben zo[g]th ia zecin -
10-on e (24b): 15 min at 0 °C and 3 h at room temperature;
yellow semisolid (80%); 1H NMR (400 MHz) δ 7.50 (d, J ) 11.9
Hz, 1H), 7.07 (m, 2H), 6.96 (m, 3H), 6.55 (d, J ) 11.9 Hz, 1H),
6.11 (dd, J ) 3.3, 1.8 Hz, 1H), 5.88 (t, J ) 3.3 Hz, 1H), 3.21
(m, 2H), 3.1-2.9 (m, 2H); 13C NMR (100 MHz) δ 167.1, 141.8,
137.1, 135.3, 128.6, 128.5, 127.9, 127.1, 126.5, 123.2, 123.10,
123.07, 112.0, 43.0, 34.9; IR (KBr) 1687, 1617 cm-1; MS [m/z
(rel intensity)] 255 (M+, 18), 153 (100).
1
Sulfone 12 (35%) is a light brown solid: mp 189-191 °C; H
NMR (200 MHz) δ 8.41 (d, J ) 8.1 Hz, 1H), 7.56 (m, 1H), 7.45
(d, J ) 3.8 Hz, 1H), 7.31 (m, 2H), 6.67 (d, J ) 3.8 Hz, 1H),
3.55 (m, 2H), 3.14 (m, 3H), 2.95 (m, 1H), 2.21 (m, 2H), 1.90
(m, 1H); 13C NMR (50 MHz) δ 167.5, 135.6, 133.9, 130.3, 125.4,
124.0, 121.0, 116.5, 110.1, 56.5, 51.0, 34.6, 29.5, 20.2; IR (KBr)
3137, 2966, 1705, 1324, 1127 cm-1; MS [m/z (rel intensity)]
277 (M+, 8), 117 (100). Anal. Calcd for C14H15NO3S: C, 60.63;
H, 5.45; N, 5.05. Found: C, 60.43; H, 5.61; N, 5.01.
Rep r esen ta tive Rea ction of Su lfoxid es w ith Tr iflu o-
r om eth a n esu lfon ic An h yd r id e. To a well-stirred solution
of trifluoromethanesulfonic anhydride (0.45 mL, 2.69 mmol)
in CH2Cl2 (5 mL) at 0 °C was added pyridine (0.23 mL, 2.91
mmol) followed by a solution of sulfoxide 5a (0.18 g, 0.728
mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred
for 15 min at 0 °C and 3 h at room temperature. The solution
was poured into 10% Na2CO3 (10 mL) and stirred for 10 min.
The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 8 mL). The combined organics
were washed with 5% HCl and water and dried (Na2SO4). The
solvent was removed in vacuo, and the residue was chromato-
graphed (CHCl3/hexane) to afford 6a (0.12 g, 72%) as a yellow
semisolid that was spectroscopically and chromatographically
identical to the sample obtained from the TFAA reaction.
The following compounds were obtained by the same
procedure (variations in reactions times are given in paren-
theses). If no spectral data are provided, compound identity
was verified by comparing spectroscopic and chromatographic
behavior with samples obtained using a different method.
1-[(4,5-Dih yd r o-2-th ien yl)]ca r bon yl]-1H-p yr r ole (6b):
30 min at 0 °C and 3 h at room temperature; 70% yield.
3,4-Dih yd r oin d olo[2,1-b][1,3]th ia zon in -7(2H)-on e (13a ):
30 min at 0 °C and 3 h at room temperature; light yellow
semisolid (65%); 1H NMR (400 MHz, 23 °C) δ 8.36 (d, J ) 8.5
Hz, 1H), 7.53 (dd, J ) 7.8, 1.4 Hz, 1H), 7.37 (m, 1H), 7.27 (m,
1H), 7.00 (s, 1H), 6.24 (m, 2H), 2.82-3.39 (br s, 2H), 2.18-
2.30 (br s, 2H), 1.75-1.90 (br s, 2H); 13C NMR (100 MHz, 23
Ack n ow led gm en t. The authors wish to thank the
NSF for an equipment grant (CHE-9512445) and the
Michigan Technological University Graduate School (for
fellowship support to M.X.).
Su p p or tin g In for m a tion Ava ila ble: 1H (400 MHz) and
13C NMR (100 MHz) spectra for 19b, 22b, 23b, and 24b and
13C NMR (50 MHz) spectra for 4b, 5b, 6a ,b, 9b, and 13b (14
pages). This material is contained in libraries on microfiche,
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.
J O9805044