Stereochemistry of 3-Alkylindole Dimerization: Acyclic δ1,δ1′-Tryptophan Dimers

Full text of DOI:10.1021/jo970722h

8600
J . Org. Chem. 1997, 62, 8600-8603
Ster eoch em istr y of 3-Alk ylin d ole
Dim er iza tion : Acyclic δ1,δ1′-Tr yp top h a n
Dim er s
Casey C. McComas, Eric J . Gilbert, and
David L. Van Vranken*
Department of Chemistry, University of California,
Irvine, California 92697
Received April 22, 1997
Under acidic conditions, 3-alkylindoles dimerize ste-
reoselectively to produce racemic 2-(2′-indolyl)-3-alkylin-
dolines 1-5 (eq 1). This Mannich-type reaction is a
powerful tool in the synthesis of biindolyl natural
products1-3 and may even be important in the fluorogenic
aging of corneal and lens proteins of the human eye.4-7
While skatole dimer (1) has recently been shown to
possess a trans stereochemistry,8 tryptophan derivatives
have been reported to dimerize in trifluoroacetic acid to
afford one trans (6a ) and one cis (6b) isomer. These
assignments were made on the basis of differences
between J 2,3 1H NMR coupling constants of the salts and
free bases of 6a and 6b.9-11 The seemingly disparate
results obtained with tryptophan, as opposed to achiral
3-alkylindoles 1-5,1,12 have prevented the development
of a consistent model for Mannich dimerization of 3-sub-
stituted indoles. We have reinvestigated the stereochem-
istry of tryptophan dimer formation in TFA and shown
that the reaction follows the same pattern of reactivity
as achiral 3-alkylindoles. In addition we have provided
evidence that the indoline stereochemistry in tryptophan
dimers is trans.
Sch em e 1
Our initial goal was to establish whether the indoline
rings of 6a and 6b possessed the same or opposite relative
stereochemistry by converting the R-amino acid moieties
into achiral groups. N-Sulfonylation of 6a and 6b served
to protect the indoline nitrogen and prevent facile pho-
tooxidation to the fluorescent ditryptophan (Scheme 1).
The esters 7a and 7b were saponified with sodium
hydroxide in aqueous THF to afford the diacids in over
90% yield, contaminated by a small amount of ethyl
acetate. While decarboxylation of R-amino acids with
lead tetraacetate is well-precedented, N-acetyltryptophan
is a poor substrate for this reaction.13 Similarly, attempts
to cleave the corresponding â-acetamido alcohol with lead
(1) Bergman, J .; Koch, E.; Pelcman, B. Tetrahedron Lett. 1995, 36,
3945-3948.
(2) J oyce, R. P.; Gainor, J . A.; Weinreb, S. M. J . Org. Chem. 1987,
52, 1177.
(3) Gilbert, E. J .; Van Vranken, D. L. J . Am. Chem. Soc. 1996, 118,
5500.
tetraacetate gave complex product mixtures.14 As an
alternative to oxidative cleavage we chose to convert the
R-amino acid moieties into oxazoles via azalactone forma-
tion.15 Azalactone formation proceeded easily with DCC
in dioxane, although the bisazalactones were not suf-
ficiently stable to isolate. The azalactones were directly
converted to the more stable oxazoles by O-acylation with
triethylamine and methyl chloroformate.16 The yield for
the two-step sequence of azalactone formation and acy-
lation was 47% for 9a and 62% for 9b.
(4) Sigman, S. In Progress in Tryptophan and Serotonin Research;
Schlossberger, H. G., Ed.; Walter de Gruyter & Co.: New York, 1984.
(5) Inoue, A.; Satoh, K. Bioorg. Med. Chem. Lett. 1993, 3, 345.
(6) Wells-Knecht, M. C.; Huggins, T. G.; Dyer, D. G.; Thorpe, S. R.;
Baynes, J . W. J . Biol. Chem. 1993, 268, 12348.
(7) Uma, L.; Sharma, Y.; Balasubramanian, D. Photochem. Photo-
biol. 1996, 63, 213.
(8) Stalick, W. M.; Mushrush, G. W.; Faour, S. Presented at the
213th National Meeting of the American Chemical Society, San
Francisco, CA, 1997.
(9) Omori, Y.; Matsuda, Y.; Aimoto, S.; Shimonishi, Y.; Yamamoto,
M. Chem. Lett. 1976, 805.
(10) Hashizume, K.; Shimonishi, Y. In Peptide Chemistry 1979;
Yonehara, H., Ed.; Protein Research Foundation: Tokyo, 1980.
(11) Hashizume, K.; Shimonishi, Y. Bull. Chem. Soc. J pn. 1981, 54,
3806-3810.
(12) Gilbert, E. J .; Ziller, J . W.; Van Vranken, D. L. Tetrahedron,
accepted for publication.
(14) Apitz, G.; J a¨ger, M.; J aroch, S.; Kratzel, M.; Scha¨ffeler, L.;
Steglich, W. Tetrahedron 1993, 49, 8223.
(15) Pines, S. H.; Karady, S.; Sletzinger, M. J . Org. Chem. 1968,
33, 1758.
(13) Needles, H. L.; Ivanetich, K. Chem. Ind. 1967, 581.
(16) Steglich, W.; Ho¨fle, G. Chem. Ber. 1969, 102, 883.
S0022-3263(97)00722-6 CCC: $14.00 © 1997 American Chemical Society

Notes
The two indolines 9a and 9b were identical by all
J . Org. Chem., Vol. 62, No. 24, 1997 8601
Ta ble 1. Dia gn ostic J 2,3 Cou p lin g Con sta n ts in
2,3-Disu bstitu ted In d olin es
standard methods of characterization (mp, IR, LRMS,
1
HRMS, and H and 13C NMR) except for optical rotation.
Indoline 9a had a specific rotation of +37.3° (c ) 1.00,
CHCl3) whereas the opposite value was obtained for
indoline 9b ([R]D ) -37.0°, c ) 1.00, CHCl3); 9a and 9b
are clearly enantiomers. Thus the dimerization of tryp-
tophan is stereoselective, such that each diastereomer
possesses the same relative indoline stereochemistry.
More importantly, it can now be stated with confidence
that the dimerization of 3-alkylindoles (with a 3-meth-
ylene group) in TFA proceeds with complete control of
stereoselectivity. It is unsafe to assume that skatole
dimer, formed with stoichiometric sulfonic acids, and
tryptophan dimers, formed in neat TFA, possess the same
relative stereochemistry. In the intramolecular cycliza-
tion of 3-alkylindoles to form six-membered rings, sto-
ichiometric sulfonic acids and neat TFA have been shown
to afford products of kinetic and thermodynamic control,
respectively.12
The lack of X-ray quality crystals prevented a direct
determination of indoline stereochemistry, and the cou-
pling constants provided no information about the rela-
tive stereochemistry of the indoline rings. Indeed, the
J 2,3 coupling constants of 2,3-dialkylindolines are typi-
cally 8-9 Hz for both the cis and trans isomers. How-
ever, Anet has shown that when the indoline nitrogen is
N-protected with nitrosyl or arylsulfonyl, cis-dialkylin-
dolines exhibit a diagnostic J 2,3 coupling constant of 8-9
Hz, while the corresponding coupling constant in the
trans isomer is less than 4 Hz.17
To confirm this relationship, we prepared 2-phenyl-3-
methylindoline as a model system for comparison with
9a and 9b. Reduction of 3-methyl-2-phenylindole with
tin in hydrochloric acid afforded the inseparable indolines
10a and 10b in a 1:10 ratio, respectively (eq 2).18
N-Sulfonylation of the mixture of 10a and 10b with tosyl
chloride in pyridine afforded the requisite model com-
pounds 11a and 11b. Unfortunately, these diastereo-
mers were not readily separable, so the indolines were
N-acetylated to give 12a and 12b, which were easily
separated by silica gel chromatography. The minor
diastereomer 12a and the major diastereomer 12b were
individually hydrolyzed (6 N methanolic HCl, 100 °C) and
N-sulfonylated to afford pure samples of 11a and 11b.
indoline
X
trans J 2,3 (Hz)
cis J 2,3 (Hz)
13
10
13
11
H
H
8.8
9.9
2.7
3.5
8.8
8.7
8.6
9.6
SO2Ph
SO2Ph
are also in agreement with the cis stereoselectivity
previously reported for the tin reduction of 2,3-dialkyl-
indoles.18 On the basis of these results, we conclude that
the coupling constants in 2-aryl-3-alkyl-N-tosylindolines
provide a diagnostic correlation with relative stereochem-
istry. Returning to the N-tosyltryptophan dimers, the
small J 2,3 coupling constants in CDCl3 (1.6 Hz, 1.5 Hz,
and 1.8 Hz for 7a , 7b, and 9a /b) suggest that both of these
compounds are trans indolines. The mechanistic origin
of this stereoselectivity will be the subject of future work.
In conclusion, we have unambiguously demonstrated
that the dimerization of tryptophan derivatives affords
diastereomers with the same relative indoline stereo-
chemistry. We have also shown that coupling constants
in the N-tosyltryptophan dimers are consistent with a
trans indoline stereochemistry. Thus, a consistent pic-
ture emerges for the intermolecular TFA-promoted dimer-
ization of 3-alkylindoles, including tryptophan. The
reaction is stereoselective and, based on 1H NMR evi-
dence, provides exclusively the trans indoline.
Exp er im en ta l Section
All reactions were run under a nitrogen atmosphere. Tet-
rahydrofuran and diethyl ether were purified by distillation
under a nitrogen atmosphere from the sodium ketyl of ben-
zophenone prior to use. Methylene chloride and triethylamine
were distilled from calcium hydride under a nitrogen atmo-
sphere. All other solvents were used as purchased. Analytical
TLC was performed using 0.25 mm EM silica gel 60 F254 plates.
Elemental analyses were carried out by Atlantic Microlabs, Inc.
N-Tosyl-2,2′-in d olylin d olin e 7a . In a dry 25 mL round-
bottom flask, 6a (1.05 g, 2.00 mmol) was dissolved in pyridine
(6 mL) and the temperature was reduced to 0 °C. Freshly
recrystallized p-toluenesulfonyl chloride (0.57 g, 3.0 mmol) was
added. The reaction mixture was stirred at 0 °C for 1 h and
then allowed to warm to room temperature as stirring was
continued for an additional 12 h. After this time, the reaction
mixture was diluted with CH2Cl2 (100 mL), washed with 1 M
NaHSO4 (4 × 150 mL), and dried over MgSO4. Filtration and
concentration of the solvent in vacuo provided the crude product
as a bright pink solid. Purification by silica gel chromatography
(10% MeOH/CHCl3) afforded 7a (0.94 g, 70%) as a white solid.
7a : mp 144-146 °C (CHCl3); Rf ) 0.54 (10% MeOH/CHCl3);
IR (KBr) 3379, 3287, 3060, 2953, 1742, 1659 cm-1; 1H NMR (500
MHz, DMSO-d6) δ 10.61 (s, 1H), 8.30 (d, J ) 8.7, 1H), 8.15 (d, J
) 7.9, 1H). 7.67 (d, J ) 8.3, 3H), 7.53 (d, J ) 7.7, 1H), 7.31 (m,
9H), 5.28 (d, J ) 1.9, 1H), 4.50 (m, 1H), 4.36 (m, 1H), 3.60 (s,
3H), 3.57 (s, 3H), 2.99 (m, 2H), 2.34 (s, 3H), 1.81 (s, 3H), 1.68 (s,
3H), 1.47 (m, 1H), 0.98 (m, 1H); 13C NMR (125 MHz, DMSO-d6)
δ 173.2, 172.5, 170.3, 169.5, 144.8, 140.8, 136.0, 135.8, 134.2,
134.0, 130.3, 128.9, 128.3, 127.1, 125.6, 125.1, 121.6, 119.0, 116.3,
111.9, 107.0, 79.6, 62.9, 53.9, 52.4, 52.3, 50.2, 46.2, 38.1, 26.5,
22.8, 22.5, 21.4; LRMS (FAB) m/z (relative intensity) 697
[MNa]+, 674 (42) [M]+, 545 (38), 259 (98), 130 (100); HRMS
(FAB) calcd for C35H38N4O8S, 675.2488 [MH]+, found 675.2495.
Anal. Calcd for C35H38N4O8S: C, 62.29; H, 5.68; N, 8.31.
Found: C, 62.15; H, 5.64; N, 8.23.
Gratifyingly, the coupling constants of the 2-phenyl-
3-methylindolines 11a and 11b were consistent with the
coupling constants observed by Anet for the correspond-
ing 2,3-dimethylindolines, 13. The unprotected indolines
show little difference in the J 2,3 coupling constants (9.9
Hz for 10a and 8.7 Hz for 10b). However the N-
tosylindolines show the marked difference predicted by
Anet (3.5 Hz for 11a and 9.6 Hz for 11b). These results
(17) Anet, F. A. L.; Muchowski, J . M. Chem. Ind. 1963, 81.
(18) Lanzilotti, A. E.; Littell, R.; Fanshawe, W. J .; McKenzie, T. C.;
Lovell, F. M. J . Org. Chem. 1979, 1979, 4809.

8602 J . Org. Chem., Vol. 62, No. 24, 1997
Notes
N-Tosyl-2,2′-in d olylin d olin e 7b. In a dry 25 mL round-
bottom flask, 6b (0.80 g, 1.5 mmol) was dissolved in pyridine (6
mL) and the temperature was reduced to 0 °C. Freshly
recrystallized p-toluenesulfonyl chloride (0.38 g, 2.0 mmol) was
added. The reaction mixture was stirred at 0 °C for 1 h and
then allowed to warm to room temperature as stirring was
continued for an additional 12 h. After this time, the reaction
mixture was diluted with CH2Cl2 (100 mL), washed with 1 M
NaHSO4 (4 × 150 mL), and dried over MgSO4. Filtration and
concentration of the solvent in vacuo provided the crude product
as a bright pink solid. Purification by silica gel chromatography
(10% MeOH/CHCl3) afforded 7b (0.92 g, 91%) as a white solid.
7b: mp 144-145 °C (CHCl3); Rf ) 0.56 (10% MeOH/CHCl3);
unstable bisazalactone as a yellow solid that was used im-
mediately in the next step without further purification.
In a dry 10 mL round-bottom flask, the bisazalactone (0.37
g, 0.61 mmol) was dissolved in 5 mL of THF. To this stirred
solution was added triethylamine (0.34 mL, 2.4 mmol) via
syringe followed by slow, dropwise addition of methyl chloro-
formate (0.19 mL, 2.4 mmol). The reaction mixture was stirred
at room temperature for 4 h. After this time, the reaction
mixture was diluted with 50 mL ether, washed with H2O (2 ×
50 mL) and brine (2 × 50 mL), and dried over MgSO4. Filtration
and concentration of the solvent in vacuo provided the crude
product. Purification by silica gel chromatography (33% Et2O/
benzene) afforded bisoxazole 9a (0.28 g, 47%) as a white solid.
9a : [R]D +37.3° (c ) 1.00, CHCl3); mp 119-120 °C (Et2O/
petroleum ether); Rf ) 0.38 (10% Et2O/petroleum ether); IR (CH2-
IR (KBr) 3379, 3286, 3063, 2952, 2359, 2248, 1742, 1656 cm-1
;
1H NMR (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.33 (d, J ) 7.5,
1H), 8.28 (d, J ) 7.5, 1H), 7.69 (m, 3H), 7.50 (d, J ) 8.0, 1H),
7.40 (t, J ) 8.0, 1H), 7.34 (d, J ) 8.0, 2H), 7.25 (d, J ) 8.0, 1H),
7.13 (t, J ) 7.5, 1H), 7.05 (m, 2H), 6.98 (t, J ) 7.5, 1H), 5.27 (s,
1H), 4.54 (m, 1H), 4.14 (m, 1H), 3.61 (s, 3H), 3.48 (s, 3H), 3.29
(m, 1H), 3.09 (m, 2H), 2.35 (s, 3H), 1.81 (s, 3H), 1.79 (s, 3H),
1.80 (m, 1H), 0.79 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ
172.6, 172.1, 169.8, 169.5, 144.6, 140.7, 135.7, 133.7, 132.6, 129.8,
128.7, 127.6, 127.0, 125.8, 124.5, 121.4, 118.7, 118.3, 116.3, 111.6,
106.8, 79.2, 63.6, 53.5, 52.0, 51.9, 48.6, 45.0, 37.2, 26.3, 22.4,
22.2, 21.0; LRMS (FAB) m/z (relative intensity) 697 [MNa]+,
674 (60) [M]+, 261 (30), 217 (100); HRMS (FAB) Calcd for
1
Cl2) 3048, 2978, 2296, 1786 cm-1; H NMR (500 MHz, DMSO-
d6) δ 10.65 (s, 1H), 7.61 (m, 3H), 7.37 (d, J ) 4.5, 1H), 7.32 (m,
3H), 7.25 (d, J ) 8.0, 1H), 7.03 (t, J ) 7.3, 2H), 6.94 (d, J ) 7.5,
1H), 6.92 (d, J ) 7.5, 1H), 5.46 (d, J ) 4.0, 1H), 3.89 (d, J )
16.0, 1H), 3.85 (d, J ) 16.0, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.56
(m, 1H), 2.37 (dd, J ) 6.0, 14.5, 1H), 2.32 (s, 3H), 2.25 (s, 3H),
2.23, (s, 3H), 2.02 (dd, J ) 7.5, 14.5, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 154.8, 154.4, 151.6, 151.3, 145.8, 144.5, 144.3, 140.9,
136.0, 135.1, 133.8, 133.0, 129.6, 128.3, 127.2, 127.1, 125.2, 124.2,
121.6, 121.4, 118.9, 118.5, 118.4, 115.2, 111.4, 107.6, 62.4, 56.8,
56.7, 47.0, 29.0, 21.0, 19.1, 13.6 (a 13C resonance is missing; we
believe there may be overlapping signals in the 45-65 ppm
region); LRMS (FAB) m/z (relative intensity) 749 [MNa]+, 727
(62) [MH]+, 571 (32), 307 (20), 154 (100); HRMS (FAB) Calcd
for C37H34N4O10S, 727.2074 [MH]+, found 727.2069. Anal. Calcd
for C37H34N4O10S: C, 61.14; H, 4.72; N, 7.71. Found: C, 61.31;
H, 4.80; N, 7.60.
F or m a tion of N-Tosyl-2,2′-in d olylin d olin e Bisa za la cton e
a n d Con ver sion to th e N-Tosyl-2,2′-in d olylin d olin e Bisox-
a zole 9b. In a dry 25 mL flask, 8b (0.50 g, 0.77 mmol) was
dissolved in 5 mL of dry dioxane. Dicyclohexylcarbodiimide (0.32
g, 1.6 mmol) was added, and the reaction mixture was stirred
at room temperature for 2.5 h. After this time a suspension had
formed and ether (15 mL) was added and the mixture was
filtered. The filtrate was concentrated in vacuo to provide the
unstable bisazalactone as a yellow solid that was used im-
mediately in the next step without further purification.
In a dry 10 mL round-bottom flask, the bisazalactone (0.45
mL, 0.77 mmol) was dissolved in 5 mL of THF. To this stirred
solution was added triethylamine (0.29 mL, 3.1 mmol) via
syringe followed by slow, dropwise addition of methyl chloro-
formate (0.24 mL, 3.1 mmol). The reaction mixture was stirred
at room temperature for 4 h. After this time the reaction
mixture was diluted with 50 mL ether, washed with H2O (2 ×
50 mL) and brine (2 × 50 mL), and dried over MgSO4. Filtration
and concentration of the solvent in vacuo provided the crude
product. Purification of the crude product by silica gel chroma-
tography (5:5:1 Et2O/benzene/petroleum ether) afforded bisox-
azole 9b (0.35 g, 62%) as a white solid.
C
35H38N4O8S, 675.2488 [MH]+, found 675.2476.
Gen er a l P r oced u r e for N-Tosyl-2,2′-in d olylin d olin e Di-
a cid 8a . A 25 mL round-bottom flask was charged with a
solution of 7a (0.82 g, 1.20 mmol) in THF (5 mL) followed by
the addition of 2 M NaOH (4.0 mL, 8.0 mmol). The reaction
mixture was stirred for 4 h at room temperature. After this time
the reaction mixture was diluted with 1 M HCl (100 mL) and
extracted with ethyl acetate (4 × 100 mL). The organics were
combined and washed with H2O (1 × 150 mL) amd brine (2 ×
150 mL), and dried over MgSO4. Filtration and concentration
of the solvent in vacuo provided 8a (0.48, 93%) as a yellow solid.
8a : mp 163-164 °C (dec) (ethyl acetate); Rf ) 0.72 (75:15:10
n-BuOH/HOAc/H2O); IR (KBr) 3369, 3064, 2923, 1721, 1644,
1
cm-1; H NMR (500 MHz, DMSO-d6) δ 12.60 (s(br), 2H), 10.47
(s, 1H), 8.10 (d, J ) 7.5, 1H), 8.04 (d, J ) 8.5, 1H), 7.64 (m, 3H),
5.57 (d, J ) 8.0, 1H), 7.35 (dt, J ) 1.0, 8.0, 1H), 7.23 (m, 4H),
7.14 (t, J ) 7.5, 1H), 7.02 (t, J ) 7.5, 1H), 6.95 (t, J ) 7.5, 1H),
5.31 (d, J ) 2.5, 1H), 4.52 (m, 1H), 4.23 (m, 1H), 3.26 (m, 1H),
3.14 (m, 1H), 3.01 (m, 1H), 2.29 (s, 3H), 1.80 (s, 3H), 1.64 (s,
3H), 1.39 (m, 1H), 1.17 (m, 1H); 13C NMR (125 MHz, DMSO-d6)
δ 174.1, 173.6, 169.9, 169.6, 144.7, 140.9, 136.1, 135.8, 134.3,
133.9, 130.3, 128.9, 128.1, 127.8, 125.8, 124.9, 121.6, 119.3, 118.9,
116.1, 111.8, 108.1, 63.0, 53.8, 50.0, 46.0, 38.3, 26.7, 23.0, 22.5,
21.5; LRMS (FAB) m/z (relative intensity) 647 (100) [M]+, 530
(65), 401 (22), 259 (35); HRMS (FAB) Calcd for C33H34N4O8S,
647.2175 [MH]+, found 647.2180.
N-Tosyl-2,2′-in d olylin d olin e Dia cid 8b . Isomer 7b was
saponified according to the general procedure to afford 8b (0.72
g, 92%) as a yellow solid.
9b : [R]D -37.0° (c ) 1.00, CHCl3); mp 119-121 °C (Et2O/
8b: mp 167-168 °C (dec) (ethyl acetate); Rf ) 0.70 (75:15:10
petroleum ether); Rf ) 0.38 (10% Et2O/petroleum ether); IR (CH2-
1
n-BuOH/HOAc/H2O); IR (KBr) 3369, 3064, 2923, 1733, 1650,
Cl2) 3048, 2978, 2296, 1786 cm-1; H NMR (500 MHz, DMSO-
1
cm-1; H NMR (500 MHz, DMSO-d6) δ 12.60 (s(br), 2H), 10.33
d6) δ 10.65 (s, 1H), 7.61 (m, 3H), 7.37 (d, J ) 4.5, 1H), 7.32 (m,
3H), 7.25 (d, J ) 8.0, 1H), 7.03 (t, J ) 7.3, 2H), 6.94 (d, J ) 7.5,
1H), 6.92 (d, J ) 7.5, 1H), 5.46 (d, J ) 4.0, 1H), 3.89 (d, J )
16.0, 1H), 3.85 (d, J ) 16.0, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.56
(m, 1H), 2.37 (dd, J ) 6.0, 14.5, 1H), 2.32 (s, 3H), 2.25 (s, 3H),
2.23, (s, 3H), 2.02 (dd, J ) 7.54, 14.5, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 154.7, 154.4, 151.6, 151.3, 145.8, 144.5, 144.3, 140.8,
136.0, 135.1, 133.8, 133.0, 129.6, 128.3, 127.2, 127.1, 125.2, 124.1,
121.6, 121.4, 118.9, 118.5, 118.4, 115.2, 111.4, 107.6, 62.4, 56.8,
56.6, 47.0, 29.0, 21.0, 19.1, 13.6 (a 13C resonance is missing; we
believe there may be overlapping signals in the 45-65 ppm
region); LRMS (FAB) m/z (relative intensity) 749 [MNa]+, 727
(100) [MH]+, 571 (65), 154 (50); HRMS (FAB) Calcd for
(s, 1H), 8.30 (d, J ) 8.0, 1H), 8.05 (d, J ) 8.5, 1H), 7.67 (m, 3H),
7.60 (d, J ) 7.5, 1H), 7.40 (t, J ) 8.0, 1H), 7.28 (d, J ) 8.0, 2H),
7.23 (d, J ) 8.0, 1H), 7.12 (m, 2H), 7.03 (t, J ) 7.5, 1H), 6.98 (t,
J ) 7.5, 1H), 5.22 (s, 1H), 4.53 (m, 1H), 4.09 (m, 1H), 3.37 (m,
1H), 3.10 (m, 1H), 3.02 (d, J ) 11.5, 1H), 2.32 (s, 3H), 1.81 (s,
3H), 1.80 (m, 1H), 1.79 (s, 3H), 0.70 (m, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 173.8, 173.3, 169.8, 169.5, 144.8, 140.7, 135.9, 135.5,
133.5, 132.8, 129.8, 128.7, 127.6, 126.9, 126.0, 124.6, 121.5, 118.7,
118.6, 116.4, 111.7, 107.4, 63.5, 53.8, 48.5, 45.0, 37.1, 30.7, 22.5,
22.4, 21.1; LRMS (FAB) m/z (relative intensity) 647 (100) [M]+,
530 (85), 391 (30), 259 (40); HRMS (FAB) Calcd for C33H34N4O8S,
647.2175 [MH]+, found 647.2179.
C
37H34N4O10S, 727.2073 [MH]+, found 727.2078. Anal. Calcd
F or m a tion of N-Tosyl-2,2′-in d olylin d olin e Bisa za la cton e
a n d Con ver sion to th e N-Tosyl-2,2′-in d olylin d olin e Bisox-
a zole 9a . In a dry 25 mL flask, 8a (0.40 g, 0.62 mmol) was
dissolved in 5 mL of dry dioxane. Dicyclohexylcarbodiimide (0.25
g, 1.2 mmol) was added, and the reaction mixture was stirred
at room temperature for 2.5 h. After this time a suspension had
formed and ether (15 mL) was added and the mixture was
filtered. The filtrate was concentrated in vacuo to provide the
for C37H34N4O10S: C, 61.14; H, 4.72; N, 7.71. Found C, 61.20;
H, 4.74; N, 7.76.
cis- a n d tr a n s-2,3-Dih yd r o-3-m eth yl-2-p h en ylin d ole (10a
a n d 10b). To 2-phenylskatole (1.91 g, 9.24 mmol) in ethanol
(42 mL) were added mossy tin (10.9 g, 92.4 mmol) and 12 N
HCl (42.0 mL). The reaction mixture was stirred at 100 °C for
22 h. Upon cooling to room temperature, the reaction mixture

Notes
J . Org. Chem., Vol. 62, No. 24, 1997 8603
was decanted from the residual tin. Addition of 3 N NaOH (75
mL) to the mixture resulted in a white precipitate that was
filtered off. The white precipitate was stirred with hot ethyl
acetate and filtered again. The aqueous layer was extracted
with ethyl acetate (4 × 25 mL). All the organic layers were
combined, washed with H2O (2 × 20 mL) and brine (1 × 30 mL),
and dried over MgSO4. Filtration and evaporation of the solvent
in vacuo afforded an inseparable mixture of cis and trans
indolines 10b and 10a as a 10:1 mixture (1.78 g, 94%) as
determined by 1H NMR.
tr a n s-N-Acetyl-2,3-dih ydr o-3-m eth yl-2-ph en ylin dole (12a)
an d cis-N-Acetyl-2,3-dih ydr o-3-m eth yl-2-ph en ylin dole (12b).
To the mixture of cis- and trans-2,3-dihydro-3-methyl-2-phe-
nylindoles 10a and 10b (0.39 g, 1.9 mmol) in pyridine (6.0 mL)
was added acetic anhydride (0.58 g, 5.7 mmol). The reaction
mixture was stirred at room temperature for 12 h and then
concentrated in vacuo. The residue was taken up into methylene
chloride (100 mL) and washed with 1 N HCl (2 × 20 mL), H2O
(2 × 20 mL), and brine (1 × 30 mL). The organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was preadsorbed on silica gel and purified by silica gel
chromatography (15-30% EtOAc/hexane) to afford trans-N-
acetylindoline 12a (0.050 g, 10%) and cis-N-acetylindoline 12b
(0.26 g, 53%).
MgSO4. Filtration and evaporation of the solvent in vacuo
afforded a residue that was preadsorbed on silica gel and purified
by silica gel chromatography (10% EtOAc/hexane) to afford cis-
N-tosylindoline 11b (0.55 g, 78%).
11b: mp 140-142 °C (CH2Cl2); Rf ) 0.35 in 10% EtOAc/
1
hexane; IR (KBr) 3034, 2966, 2864, 1351, 1167 cm-1; H NMR
(300 MHz, CDCl3) δ 7.68 (d, J ) 8.0, 1H), 7.54 (d, J ) 8.1, 2H),
7.26 (m, 1H), 7.19 (m, 3H), 7.13 (d, J ) 8.0, 2H), 7.06 (m, 3H),
6.99 (d, J ) 7.3, 1H), 5.35 (d, J ) 9.6, 1H), 3.46 (m, 1H), 2.34 (s,
3H), 0.80 (d, J ) 7.1, 3H); 13C NMR (125 MHz, CDCl3) δ 143.6,
142.1, 137.7, 136.2, 135.9, 129.4, 128.1, 127.9, 127.7, 127.3, 126.9,
124.4, 123.9, 115.3, 70.1, 39.7, 21.5, 14.0; MS (CI) 363 (40), 208
(100), 130 (26); HRMS (CI) calcd for C22H21NSO2, 363.1292,
found 363.1290. Anal. Calcd for C22H21NSO2: C, 72.70; H, 5.82;
N, 3.85. Found: C, 72.65; H, 5.88; N, 3.84.
tr a n s-N-(p-Tolu en esu lfon yl)-2,3-dih ydr o-3-m eth yl-2-ph e-
n ylin d ole (11a ). To trans-N-acetylindoline 12a (0.18 g, 0.71
mmol) in methanol (3 mL) was added 12 N HCl (3 mL). The
reaction mixture was stirred at 100 °C for 5 h. Upon cooling to
room temperature, the mixture was basified to pH 9 with 3 N
NaOH. The solution was extracted with EtOAc (3 × 25 mL).
The organic layers were combined, washed with H2O (2 × 10
mL) and brine (1 × 25 mL), and dried over MgSO4. Filtration
and evaporation of the solvent in vacuo afforded the trans
indoline 10a (0.115 g, 79%) which was carried on directly by
taking up in to methylene chloride (2 mL). p-Toluenesulfonyl
chloride (0.160 g, 0.84 mmol) and triethylamine (0.113 g, 1.12
mmol) were added, and the reaction mixture was stirred at room
temperature for 12 h. Methylene chloride (50 mL) was added,
and the mixture was washed with 0.5 N HCl (1 × 20 mL), H2O
(2 × 20 mL), and brine (1 × 30 mL) and dried over MgSO4.
Filtration and evaporation of the solvent in vacuo afforded a
residue that was preadsorbed on silica gel. Purification by silica
gel chromatography (10% EtOAc/hexane) afforded N-tosylindo-
line 11a (0.123 g, 61%).
12a : mp 149-150 °C (CH2Cl2); Rf ) 0.45 in 20% EtOAc/
1
hexane; IR (KBr) 3067, 3033, 2964, 2865, 1649 cm-1; H NMR
(500 MHz, CDCl3) δ 8.32 (m, 1H), 7.27 (m, 4H), 7.10 (m, 4H),
4.85 (s, 1H), 3.19 (m, 1H), 2.01 (s, 3H), 1.44 (d, J ) 7.1, 3H); 13
C
NMR (125 MHz, CDCl3) δ 169.8, 142.6, 142.5, 134.7, 129.1, 127.9,
127.7, 124.8, 124.1, 116.9, 72.0, 46.5, 24.2, 22.7 (a 13C resonance
is missing; we believe there may be overlapping signals in the
120-130 ppm region); MS (CI) 251 (100), 209 (98), 194 (81), 132
(75); HRMS (CI) calcd for C17H17NO, 251.1310, found 251.1307.
Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found:
C, 81.33; H, 6.84; N, 5.53.
12b: mp 107-110 °C (CH2Cl2); Rf ) 0.35 in 20% EtOAc/
11a : mp 117-120 °C (CH2Cl2); Rf ) 0.35 in 10% EtOAc/
1
hexane; IR (KBr) 3038, 2975, 2965, 2861, 1647 cm-1; H NMR
1
hexane; IR (KBr) 3035, 2955, 2923, 1349, 1169 cm-1; H NMR
(300 MHz, CDCl3) δ 8.29 (d, J ) 7.9, 1H), 7.28 (m, 4H), 7.09 (m,
2H), 7.03 (m, 2H), 5.34 (d, J ) 9.5, 1H), 3.93 (m, 1H), 2.02 (s,
3H), 0.92 (d, J ) 7.1, 3H); 13C NMR (125 MHz, CDCl3) δ 169.3,
143.3, 138.1, 134.6, 128.6, 127.9, 127.8, 126.7, 124.1, 123.3, 116.4,
68.9, 39.8, 24.2, 13.9; MS (CI) 251 (99), 209 (100), 194 (79), 132
(69); HRMS (CI) calcd for C17H17NO, 251.1310, found 251.1306.
Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found:
C, 81.34; H, 6.88; N, 5.61.
cis-N-(p -Tolu en esu lfon yl)-2,3-d ih yd r o-3-m et h yl-2-p h e-
n ylin d ole (11b). To cis-N-acetylindoline 12b (0.500 g, 1.99
mmol) in methanol (10 mL) was added 12 N HCl (10 mL). The
mixture was stirred at 100 °C for 5 h. Upon cooling to room
temperature, the mixture was basified to pH 9 with 3 N NaOH.
The mixture was then extracted with ethyl acetate (4 × 20 mL).
The organic layers were combined, washed with H2O (2 × 10
mL) and brine (1 × 30 mL), and dried over MgSO4. Filtration
and evaporation of the solvent in vacuo afforded the cis indoline
10b (0.40 g, 1.9 mmol) which was carried on directly by taking
up into methylene chloride (7.0 mL). p-Toluenesulfonyl chloride
(0.56 g, 2.9 mmol) and triethylamine (0.39 g, 3.9 mmol) were
added, and the reaction mixture was stirred for 12 h at room
temperature. Methylene chloride (50 mL) was added to the
reaction mixture which was then washed with 0.5 N HCl (1 ×
20 mL), H2O (2 × 10 mL), and brine (1 × 30 mL) and dried over
(300 MHz, CDCl3) δ 7.77 (d, J ) 8.1, 1H), 7.60 (d, J ) 8.2, 2H),
7.28 (m, 7H), 7.18 (d, J ) 8.1, 2H), 7.04 (m, 1H), 4.70 (d, J )
3.5, 1H), 3.10 (m, 1H), 2.36 (s, 3H), 0.89 (d, J ) 7.1, 3H); 13C
NMR (125 MHz, CDCl3) δ 143.9, 142.6, 141.3, 135.7, 134.8, 129.4,
128.6, 128.1, 127.6, 127.2, 125.8, 124.3, 124.2, 115.6, 72.9, 46.1,
21.9, 21.5; MS (CI) 363 (41), 208 (100), 193 (19), 130 (16); HRMS
(CI) calcd for C22H21NSO2, 363.1292, found 363.1295. Anal.
Calcd for C22H21NSO2: C, 72.70; H, 5.82; N, 3.85. Found: C,
72.62; H, 5.83; N, 3.85.
Ack n ow led gm en t. This work is supported by the
Camille and Henry Dreyfus Foundaton, the National
Science Foundation (CHE-9523521), and the National
Institute of Health (GM-54523).
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR data are
provided for 7b, 8a , and 8b (3 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
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