Tandem radical cyclizations on lodoaryl azides: synthesis of the core tetracycle of aspidosperma alkaloids

Article abstract of DOI:10.1021/jo990891x

A new stereoselective approach to the tetracyclic core of Aspidosperma alkaloids is described. Selective attack by tristrimethylsilylsilyl radicals on the aryl carbon-iodine bond of iodoaryl azides was first demonstrated on the simple model 15, thus both extending the recent discoveries of Kim and co-workers on aliphatic C-I bonds and demonstrating that the selectivity can be exploited in cascade radical cyclizations. Extension to the more complex substrate 25 afforded the core ABCE tetracyclic skeleton of the alkaloids in excellent yield and with efficient control of relative stereochemistry.

Full text of DOI:10.1021/jo990891x

7856
J . Org. Chem. 1999, 64, 7856-7862
Ta n d em Ra d ica l Cycliza tion s on Iod oa r yl Azid es: Syn th esis of th e
Cor e Tetr a cycle of Aspid osper m a Alk a loid s
Murat Kizil,‡,§ Balaram Patro,† Owen Callaghan,† J ohn A. Murphy,*,†,‡
Michael B. Hursthouse, and Dai Hibbs
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street,
Glasgow G1 1XL, Scotland; Department of Chemistry, University of Nottingham, University Park,
Nottingham NG7 2RD, U.K.; and EPSRC X-Ray Crystallography Service, Department of Chemistry,
University of Wales, P.O. Box 912, Cardiff CF1 3TB, U.K.
Received J une 2, 1999
A new stereoselective approach to the tetracyclic core of Aspidosperma alkaloids is described.
Selective attack by tristrimethylsilylsilyl radicals on the aryl carbon-iodine bond of iodoaryl azides
was first demonstrated on the simple model 15, thus both extending the recent discoveries of Kim
and co-workers on aliphatic C-I bonds and demonstrating that the selectivity can be exploited in
cascade radical cyclizations. Extension to the more complex substrate 25 afforded the core ABCE
tetracyclic skeleton of the alkaloids in excellent yield and with efficient control of relative
stereochemistry.
In tr od u ction
attack on the top face at the atom adjacent to the cis-
ring fusion.
Indoline-containing alkaloids1 have long been the
subjects of intense interest because of their wide-ranging
biological activities and also because of the challenge
posed by their complex structures. The complexity arises
from three factors: (i) the polycyclic nature of the
structures, (ii) the number and arrangement of stereo-
centers, and (iii) the presence of tetrasubstituted carbon
atoms. Considering these points, radical chemistry has
shown considerable success in the preparation of fused
carbocycles; this results from the rapid rates of cyclization
to form five-membered rings. Furthermore, whereas the
formation of tetrasubstituted carbon centers poses steric
problems for many types of reaction,2 the early transition
state3 which prevails in radical additions to unsaturated
carbon atoms, together with the unsolvated nature of the
radicals, gives a definite advantage to radical approaches
to molecules containing tetrasubstituted carbons.
Discu ssion
At the outset, the difficulty lay in proposing the most
suitable nitrogen-containing group, represented above as
NX2. Our attention was then drawn to the elegant
research of Kim et al.,7 who demonstrated that trialkyl-
silylsilyl radicals selectively attack aliphatic carbon-
iodine bonds in the presence of azide groups. Thus
compounds related to 5 undergo initial removal of iodine
to afford a carbon radical, which then attacks the azide
group to afford 6. This suggested that the azide group
would be an excellent candidate to terminate our pro-
posed tandem cyclization.8,9 However these plans in-
(4) For a few of the many references: (a) Woodward, R. B.; Cava,
M.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. J . Am.
Chem. Soc. 1954, 76, 4749. (b) Wenkert, E. J . Am. Chem. Soc. 1962,
84, 98. (c) Thomas, R. Tetrahedron Lett. 1961, 544. (d) Qureshi, A. A.;
Scott, A. I. J . Chem. Soc., Chem. Commun. 1968, 945, 947, 948. (e)
Battersby, A. R.; Byrne, J . C.; Kapil, R. S.; Martin, J . A.; Payne, T. G.;
Arigoni, D.; Loew, P. J . Chem. Soc., Chem. Commun. 1968, 951. (f)
Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P. Acc. Chem. Res.
1984, 17, 35. (g) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.;
McQuire, L.; Merritt, A.; Vicker, N. J . Am. Chem. Soc. 1992, 114, 4403.
(h) Rawal, V. H.; Mihoud, C.; Monestel, R. F. J . Am. Chem. Soc. 1993,
115, 3030. (i) Angle, S. R.; Fevig, J . M.; Knight, S. D.; Marquis, R. W.,
J r.; Overman, L. E. J . Am. Chem. Soc. 1993, 115, 3966. (j) Knight, S.
D.; Overman, L. E.; Pairaudeau, G. J . Am. Chem. Soc. 1993, 115, 9293.
(k) Benchekroun-Mounir, N.; Dugat, D.; Gramain, J .-C.; Husson, H.-
P. J . Org. Chem. 1993, 58, 6457. (l) Azzouzi, A.; Perrin, B.; Sinibaldi,
M.-E.; Gramain, J .-C.; Lavaud, C. Tetrahedron Lett. 1993, 34, 5451.
(m) Wenkert, E.; Liu, S. J . Org. Chem. 1994, 59, 7677. (n) Desmaele,
D.; d’Angelo, J . J . Org. Chem. 1994, 59, 2292 (o) Azzouzi, A.; Perrin,
B.; Sinibaldi, M. E.; Gardette, D.; Lavaud, C.; Valleegoyet, D.; Gramain,
J .-C.; Kerbal, A. Bull. Soc. Chim. Fr. 1995, 132, 681. (p) Forns, P.;
Diez, A.; Rubiralta, M. J . Org. Chem. 1996, 61, 7882. (q) Schultz, A.
G.; Pettus, L. J . Org. Chem. 1997, 62, 6855.
We propose a novel approach to the Aspidosperma and
related alkaloids such as aspidospermidine4 1 which
would involve stereoselective tandem formation of both
C-C and C-N bonds, shown in Scheme 1 as the conver-
sion 2 f 4. The indoline formation is guaranteed to
produce a cis ring junction from the extensive precedent
in radical reactions5 in which [5,6] fused ring systems
are formed. This places the side chain bearing the
nitrogen-containing group on the top face of the molecule
as shown, and this should guarantee the stereochemistry
of the C-N bond. It has already been observed that cis-
fused cyclohexindolines6 such as 3 show a strong bias for
† University of Strathclyde.
‡ University of Nottingham.
University of Wales.
§ Current address: Chemistry (Kimya) Department, Faculty of
Science, University of Dicle, 21280 Diyarbakir, Turkey.
(1) Saxton, J . E. Nat. Prod. Rep. 1994, 11, 493.
(2) Clive, D. L. J .; Tao, Y.; Khodabocus, A.; Wu, Y. J .; Angoh, A. G.;
Bennett, S. M.; Boddy, C. N.; Bordeleau, L.; Kellner, D.; Middleton,
D. S.; Nichols, C. J .; Richardson, S. R.; Vernon, P. G. J . Am. Chem.
Soc. 1994, 116, 11275.
(5) Clive, D. L. J .; Postema, M. H. D. J . Chem. Soc., Chem. Commun.
1993, 429.
(6) Murphy, J . A.; Rasheed, F.; Gastaldi, S.; Ravishanker, T.; Lewis,
N. J . Chem. Soc., Perkin Trans. 1 1997, 1549.
(7) Kim, S.; J oe, G. H.; Do, J . Y. J . Am. Chem. Soc. 1994, 116, 5521.
(8) For a preliminary account of this work, see: Murphy, J . A.; Kizil,
M. J . Chem. Soc., Chem. Commun. 1995, 1409.
(9) For recent uses of radical cyclization onto azides, see: Santagos-
tino, M.; Kilburn, J . D. Tetrahedron Lett. 1995, 36, 1365.
(3) Fossey, J .; Lefort, D.; Sorba, J . Free Radicals in Organic
Chemistry; J ohn Wiley & Son: Chichester, 1995
10.1021/jo990891x CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/21/1999

Tandem Radical Cyclizations on Iodoaryl Azides
J . Org. Chem., Vol. 64, No. 21, 1999 7857
Sch em e 1
Sch em e 2a
a
Reagents and conditions: (a) (COCl)2, DMSO, Et3N; (b) NaH, (MeO)2PO‚CH2CO2Me, 16 h; (c) DIBALH, 30 min, -78 °C then rt; (d)
DEAD, PPh3, THF, rt, 48h; (e) TBAF, THF, 12 h; (f) MeSO2Cl, NEt3, CH2Cl2, DMAP, rt, 5 h; (g) NaN3, DMF, 60 °C, 5 h; (h) TTMSS,
AIBN, 80 °C, benzene, 5 h; (i) p-TsCl, pyridine, DMAP, 110 °C, 12 h.
volved competition between an aryl iodide and an azide,
whereas Kim’s work had involved an alkyl iodide. Our
own semiempirical calculations (AM1) suggest that an
aryl carbon-iodine bond is considerably stronger than
an aliphatic C-I bond [e.g., C-I bond in iodobenzene is
calculated as 17 kcal/mol stronger than that in iodo-
ethane], and thus the selectivity observed by Kim was
at risk of being overturned. To probe this question of
selectivity, a very simple model compound, 15, was
prepared as shown in Scheme 2.
The scheme used the known intermediates 7,11 8,12 9,13
and 10,13,14 and all steps proceeded well until the forma-
(11) Freeman, F.; Kim, D. H. S. L.; Rodriguez, R. J . Org. Chem.
1992, 57, 1722.
(12) Genera, S.; Patin, H. Bull. Chim. Soc. Fr. 1991, 397.
(13) Murphy, J . A.; Rasheed, F.; Roome, S. J .; Scott, K. A.; Lewis,
N. J . Chem. Soc., Perkin Trans. 1 1998, 2331.
(14) Kim, D.; J ang, Y. M.; Kim, I. O.; Park, S. W. J . Chem. Soc.,
Chem. Commun. 1988, 760.
(10) Callaghan, O.; Lampard, C.; Kennedy, A. R.; Murphy, J . A.
Tetrahedron Lett. 1999, 40, 161.

7858 J . Org. Chem., Vol. 64, No. 21, 1999
Kizil et al.
Sch em e 3a
a
Reagents and conditions: (a) DEAD, PPh3, THF, rt, 48 h; (b) OsO4, NMO, acetone: water (9:1), rt, 12 h; (c) NaIO4, Et2O, H2O, rt, 12
h; (d), NaBH4, MeOH, 10 min; (e) MeSO2Cl, NEt3, CH2Cl2, DMAP, rt, 5 h; (f) NaN3, DMF, 60 °C, 6 h; (g) TTMSS, AIBN, 80 °C, benzene,
5 h; (h) H2O; (i) p-TsCl, pyridine, DMAP, 110 °C, 12 h.
tion of 15. The low yield observed in this step is
attributed to the ease of allylic displacement of the
phenolic leaving group in such reactions, and in line with
this hypothesis, 2-iodophenol was isolated from this
reaction in 20% yield.
subjected to variable-temperature NMR in (CD3)2SO. In
the H NMR spectrum, the peaks due to the NCH and
1
the CdCH-CH2 protons appeared as doubled signals
which were simple in pattern, easily assigned, and clearly
separated from other signals. Heating of the NMR sample
to 100 °C caused complete coalescence of the multiplet
pairs assigned to these protons; recooling the NMR
sample restored the orginal spectrum.
Treatment of 15 with tristrimethysilylsilane afforded
the desired dihydrobenzofuranpyrrolidine 16, albeit in a
low yield of 43%. However, the low yield of this reaction
was likely due to the difficulty in chromatographic
purification of the product, which, as with the cyclization
products of Kim, was extremely polar. When the reaction
was repeated and the crude product mixture subjected
to tosylation, then the sulfonamide 17 was isolated in a
much more promising 65% yield from the azide 15.
Rather than optimize the cyclization of this azide, it was
decided to prepare the more advanced precursor 25, the
direct precursor of the target tetracycle.
Alkene 20 was oxidized via diol 21 to the aldehyde 22.
This oxidation was performed as a two-step process, since
attempts to oxidize analogous compounds in one step had
led, in our hands, to complicated mixtures. Aldehyde 22
was efficiently reduced to the corresponding alcohol 23,
and mesylation and azidation both proceeded smoothly
to give azide 25. Formation of the azide occurred in high
yield with no apparent byproducts, in contrast to the
oxygen-linked substrate 15.
Mitsunobu coupling of sulfonamide 18 with the cyclo-
hexenol 19 gave alkene 20. The spectroscopic data for
this compound and subsequent compounds in the series
were more complicated than might be expected. Speci-
fically, many of the signals in the NMR spectra (1H and
13C) were doubled, indicating the possible presence of
rotational isomers. This was confirmed when 20 was
Cyclization of the iodoazide 25 with tristrimethylsilyl-
silane and AIBN afforded, after workup, tetracycle 27
as a single diastereoisomer in an excellent 83% yield. It
should be noted that the crude reaction mixture appeared
to contain not the amine 27 but the tristrimethylsilylsilyl
derivative 26 [formed by reaction of the amine 27 with

Tandem Radical Cyclizations on Iodoaryl Azides
J . Org. Chem., Vol. 64, No. 21, 1999 7859
(100.6 MHz, CDCl3) δ 28.6 (t), 31.8 (t), 62.2 (t), 69.7 (t), 86.9
(s), 112.8 (d), 122.6 (d), 124.9 (d), 129.3 (d), 134.3 (d), 139.5
(d), 157.2 (s); MS (CI) m/z: 318 (M+, 5); HRMS for C12H15IO2
calcd M+, 318.0117; found M+ (CI), 318.0128.
tristrimethylsilylsilyl iodide], which is apparently hydro-
lyzed during workup (Scheme 3).
To confirm the stereochemistry of amine 27, it was
converted into its toluenesulfonamide 28, which was
subjected to single-crystal X-ray analysis. [As shown in
the Supporting Information, the relative stereochemistry
is confirmed.]
In summary, it has been shown that the tetracyclic core
of the Aspidosperma alkaloids can be conveniently pre-
pared with excellent stereoselectivity by a novel tandem
cyclization route. This route complements our recently
reported approach using the radical-polar crossover reac-
tion.10 These twin novel approaches will afford flexibility
in the design of both the alkaloids themselves and their
analogues, which will be important for biological and
medicinal studies.
2-[(6-Me t h a n e su lfon yloxy)h e x-2-e n yloxy]iod ob e n -
zen e, 14. To a solution of 13 (2.35 g, 7.4 mmol, 1.0 equiv),
DMAP (90 mg, 0.74 mmol, 0.1 equiv), and triethylamine (900
mg, 1.23 mL, 8.89 mmol, 1.2 equiv) in DCM (100 mL) under
nitrogen at 0 °C was added methanesulfonyl chloride (930 mg,
0.63 mL, 8.15 mmol, 1.1 equiv) dropwise over 10 min. After a
further 2 h stirring at 0 °C, the mixture was warmed to room
temperature and stirred for a further 3 h. The reaction mixture
was washed with aqueous HCl (0.5 M), and the aqueous phase
was then extracted with DCM. The combined organic phases
were washed with aqueous sodium hydrogen carbonate solu-
tion (saturated), dried over magnesium sulfate, filtered, evapo-
rated to dryness, and purified by column chromatography on
silica gel eluted with 70% petroleum ether/30% EtOAc to give
14 as a yellow oil (1.82 g, 6.76 mmol, 91%); Rf 0.53 (petroleum
ether/EtOAc ) 7:3); IR (neat) 1351(SO2-), 1173 (SO2-) cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.88 (2H, tt, J 6.9, 6.4 Hz), 2.24
(2H, tdd, J 7.0, 7.0, 0.8 Hz), 2.99 (3H, s), 4.23 (2H, t, J 6.4
Hz), 4.54 (2H, dd, J 5.2, 0.9 Hz), 5.73-5.79 (1H, m), 5.84-
5.91 (1H, m), 6.71 (1H, ddd, J 7.8, 7.3, 1.3 Hz), 6.80 (1H, dd,
J 8.3, 1.3 Hz), 7.27 (1H, m), 7.77 (1H, dd, J 7.8, 1.6 Hz); 13C
NMR (100.6 MHz, CDCl3) δ 28.1 (t), 28.3 (t), 37.2 (q), 69.1 (t),
69.3 (t), 86.7 (s), 112.7 (d), 122.7 (d), 126.0 (d), 129.3 (d), 132.5
(d), 139.4 (d), 157.1 (s); MS (FAB) m/z 396 (M+, 6); HRMS for
Exp er im en ta l Section
Gen er a l In for m a tion . Where necessary, solvents were
dried and/or distilled before use. Tetrahydrofuran was distilled
from sodium benzophenone. Acetonitrile was distilled from
phosphorus(V) oxide. Dichloromethane (DCM) was distilled
from calcium hydride. Diethyl ether, toluene, and benzene
were dried over sodium wire. Unless otherwise stated all petrol
was of boiling range 40-60 °C and was distilled before use.
Chromatography was performed using Sorbsil C60 (May and
Baker), Kieselgel 60 (Art 9385), or Kieselgel HF254 silica gels.
2-[(6-ter t-Bu t yld ip h en ylsilyloxy)h ex-2-en yloxy]iod o-
ben zen e, 12. 2-Iodophenol 11 (1.22 g, 5.5 mmol, 1.5 equiv)
and triphenylphosphine (1.45 g, 5.5 mmol, 1.5 equiv) were
dissolved in dry THF (100 mL). (6-tert-Butyldiphenylsilyloxy)-
hex-2-enol11 (1.30 g, 3.67 mmol, 1.0 equiv) was added, and the
mixture was cooled to 0 °C. Diethyl azodicarboxylate (0.96 g,
0.87 mL, 5.5 mmol, 1.5 equiv) was added dropwise over a 15
min period. After 16 h the mixture was evaporated to dryness,
dissolved in DCM, and washed with NaOH (2 M), aqueous
sodium carbonate (saturated), and water. The organic layer
was dried over sodium sulfate, followed by filtration and
removal of the solvent under reduced pressure to give a yellow
solid. This was purified by column chromatography on silica
gel eluted with 90% petroleum ether/10% EtOAc to give 12 as
a clear yellow oil (1.71 g, 3.09 mmol, 84%); Rf 0.76 (petroleum
ether/EtOAc ) 85:15); 1H NMR (400 MHz, CDCl3) δ 1.05 (9H,
s), 1.67 (2H, tt, J 7.4, 6.3 Hz), 2.20 (2H, td, J 7.4, 6.6 Hz), 3.68
(2H, t, J 6.3 Hz), 4.49 (2H, d, J 5.4 Hz), 5.67 (1H, dt, J 15.6,
5.4 Hz), 5.85 (1H, dt, J 15.6, 6.6 Hz), 6.67 (1H, dd, J 7.4, 7.8
Hz), 6.77 (1H, d, J 8.2 Hz), 7.25 (1H, m, ArH), 7.39 (6H, m,
ArH), 7.66 (4H, m, ArH), 7.75 (1H, d, J 7.8 Hz); 13C NMR (100.6
MHz, CDCl3) δ 20.2 (s), 27.9 (q), 29.6 (t), 32.8 (t), 64.2 (t), 70.8
(t), 87.9 (s), 113.7 (d), 123.5 (d), 125.6 (d), 128.6 (d), 130.3 (d),
130.5 (d), 135.0 (s), 135.6 (d), 136.5 (d), 140.5 (d), 158.3 (s);
MS (CI) m/z 574 [(M + NH4)+, 40]; HRMS for C28H33IO2Si calcd
(M + NH4)+, 574.1638, found (M + NH4)+ (CI), 574.1629.
2-[(6-Hyd r oxy)h ex-2-en yloxy]iod ob en zen e, 13. To a
solution of 12 (1.47 g, 2.65 mmol, 1.0 equiv) in dry THF (50
mL) under nitrogen was added TBAF (1M solution in THF,
5.3 mL, 5.3 mmol, 2.0 equiv) and the mixture stirred for 3 h.
THF was then removed in vacuo and the oily residue parti-
tioned between water and DCM. The aqueous layer was
extracted with further portions of DCM, and the combined
organic extracts were washed with water, dried over magne-
sium sulfate, filtered, and evaporated to dryness. The residue
was purified by column chromatography on silica gel eluted
with 70% petroleum ether/30% EtOAc to give 13 as a yellow
oil (814 mg, 2.5 mmol, 94%); Rf 0.25 (petroleum ether/EtOAc
) 4:1); IR (neat) 3351 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.56
(1H, br s), 1.68 (2H, tt, J 7.6, 6.3 Hz), 2.19 (2H, dt, J 6.7, 7.4
Hz), 3.66 (2H, t, J 6.3 Hz), 4.54 (2H, d, J 5.5 Hz), 5.74 (1H,
dtt, J 15.5, 5.5, 1.2 Hz), 5.90 (1H, dt, J 15.5, 6.7 Hz), 6.69 (1H,
ddd, J 7.8, 7.3, 1.2 Hz), 6.80 (1H, dd, J 8.3, 1.2 Hz), 7.26 (1H,
ddd, J 8.3, 7.3, 1.6 Hz), 7.76 (1H, dd, J 7.8, 1.6 Hz); 13C NMR
C
13H17IO4S calcd M+, 395.9892; found M+ (FAB), 395.9908.
2-[(6-Azid o)h ex-2-en yloxy]iod oben zen e, 15. 2-[(6-Meth-
anesulfonyloxy)hex-2-enyloxy]iodobenzene 14 (760 mg, 2.82
mmol, 1.0 equiv) and sodium azide (368 mg, 5.65 mmol, 2.0
equiv) were dissolved in DMF (15 mL) and heated at 60 °C
under nitrogen, for 5 h. The reaction mixture was then poured
into water and extracted into diethyl ether. The combined
organic extracts were then washed with water, dried over
magnesium sulfate, filtered, evaporated to dryness, and puri-
fied by column chromatography on silica gel eluted with 90%
petrol/10% EtOAc to give 15 as a yellow oil (400 mg, 1.16
mmol, 42%); Rf 0.63 (petroleum ether/EtOAc ) 4:1); IR (neat)
2096, 1678 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.69 (2H, tt, J
7.3, 6.8 Hz), 2.21 (2H, td, J 7.3, 6.7 Hz), 3.28 (2H, t, J 6.8 Hz),
4.54 (2H, d, J 5.4 Hz), 5.75 (1H, dt, J 15.5, 5.4 Hz), 5.88 (1H,
dt, J 15.5, 6.7 Hz), 6.72 (1H, dd, J 7.8, 7.3 Hz), 6.81 (1H, d, J
8.2 Hz), 7.26 (1H, ddd, J 8.2, 7.3, 1.6 Hz), 7.78 (1H, d, J 7.8
Hz); 13C NMR (100.6 MHz, CDCl3) δ 28.1 (t), 29.2 (t), 50.6 (t),
69.4 (t), 86.6 (s), 112.7 (d), 122.7 (d), 125.7 (d), 129.3 (d), 133.0
(d), 139.5 (d), 157.2 (s); MS (EI) m/z 343 (M+, 100); HRMS for
C
12H14IN3O calcd M+, 343.0181; found M+ (CI), 343.0178.
Further elution of the column gave 2-iodophenol (127 mg, 0.57
mmol, 20%), identical to an authentic sample.
Rea ction of 2-[(6-Azid o)h ex-2-en yloxy]iod oben zen e 15
w ith Tr istr im eth ylsilylsila n e/AIBN in Ben zen e. To a
stirred solution of 15 (127 mg, 0.37 mmol, 1.0 equiv) in
refluxing dry degassed benzene (10 mL) were added tris-
(trimethylsilyl)silane (92 mg, 120 µL, 0.37 mmol, 1.0 equiv)
and AIBN (10 mg, 0.037 mmol, 0.1 equiv) under nitrogen. The
mixture was refluxed for 5 h and evaporated to dryness. The
mixture then dissolved in EtOAc and extracted with aqueous
HCl (2 M). The aqueous layer was basified with NaOH (2 M)
and then the aqueous layer extracted with EtOAc, dried over
magnesium sulfate, filtered, evaporated to dryness, and puri-
fied by column chromatography on silica gel eluting with 80%
DCM/20% MeOH to give 2-(2,3-dihydrobenzofuran-3-yl)pyr-
rolidine (16) as a clear yellow oil (30 mg, 0.15 mmol, 43%),
which was a 2:1 mixture of diastereoisomers: Rf 0.35 (DCM/
MeOH ) 4:1); IR (CHCl3) 3206 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 1.38-1.49 (1H, m), 1.66-1.99 (3H, m), 2.13 (1H, br
s), 2.81-3.03 (2H, m), 3.24 (1H, m), 3.43 (1H, m), 4.35-4.38
and 4.49-4.62 (2H, 2 × m), 6.77-6.86 (2H, m), 7.18 (1H, dd,
J 7.7, 7.7 Hz), 7.25 and 7.30 (1H, 2 × d, J 7.3 Hz); 13C NMR
(100.6 MHz, CDCl3) δ 24.9 (t), 25.7 (t), 28.8 (t), 29.7 (t), 46.5
(t), 46.6 (t), 47.3 (d), 47.4 (d), 62.0 (d), 62.3 (d), 74.1 (t), 74.5
(t), 109.6 (d), 109.6 (d), 119.8 (d), 120.1 (d), 120.2 (d), 124.8
(d), 125.1 (d), 128.4 (d), 128.7 (s), 129.3 (s), 160.2 (s), 160.5 (s);

7860 J . Org. Chem., Vol. 64, No. 21, 1999
Kizil et al.
MS (FAB) m/z 190 [(M + H)+, 17]; HRMS for C12H15NO calcd
(M + H)+, 190.1232; found (M + H)+ (FAB), 190.1231.
rotamers (5.34 g, 12.8 mmol, 67%); Rf 0.38 (petroleum ether/
ethyl acetate ) 4:1); mp 90-91 °C (diethyl ether/petroleum
ether); IR (KBr) 1334 (SO2-), 1150 (SO2-) cm-1; 1H NMR (400
MHz, CDCl3) δ 0.72-0.83 and 1.07-1.19 (1H, m), 1.30-1.43
(1H, m), 1.73-2.13 (3H, m), 2.21-2.72 (1H, m), 3.07 (2H, m),
3.06 and 3.25 (3H, 2 × s), 4.68 (1H, m), 5.12-5.27 (2H, m),
5.72 and 5.84 (1H, 2 × m), 5.90-6.05 (1H, m), 7.05-7.20 (1H,
ddd, J 7.9, 7.9, 1.5 Hz), 7.26 (1H, dd, J 7.9, 1.5 Hz), 7.39 (1H,
ddd, J 7.9, 7.9, 1.5 Hz), 8.03 (1H, dd, J 7.9, 1.5 Hz); 13C NMR
(100.6 MHz, CDCl3) δ 17.8 (t), 18.0 (t), 24.6 (t), 24.8 (t), 28.4
(t), 30.0 (t), 39.0 (t), 40.6 (t), 41.0 (q), 42.3 (q), 56.5 (d), 57.6
(d), 102.8 (s), 104.7 (s), 116.1 (t), 116.3 (t), 128.7 (d), 129.0 (d),
129.9 (d), 130.1 (d), 131.4 (d), 133.0 (s), 133.8 (d), 134.2 (d),
134.8 (s), 136.5 (d), 136.9 (d), 140.4 (s), 140.8 (d), 141.2 (s),
2-(2,3-Dih yd r ob en zofu r a n -3-yl)-N-(4-m et h ylb en zen e-
su lfon yl) p yr r olid in e, 17. To a stirred solution of 15 (130
mg, 0.38 mmol, 1.0 equiv) in refluxing dry degassed benzene
(10 mL) were added tris(trimethylsilyl)silane (95 mg, 123 µL,
0.38 mmol, 1.0 equiv) and AIBN (11 mg, 0.038 mmol, 0.1 equiv)
under nitrogen. The mixture was refluxed for 5 h and
evaporated to dryness. To a solution of crude product (as
obtained above) in pyridine (15 mL) were added 4-(dimethyl-
amino)pyridine (6 mg, 0.03 mmol, 0.1 equiv) and p-toluene-
sulfonyl chloride (73 mg, 0.38 mmol, 1.0 equiv). The resulting
mixture was heated to reflux (110 °C) for 16 h. The mixture
was warmed to room temperature, and the whole mixture was
taken into aqueous HCl (2 M) and extracted with DCM. The
organic extract was dried over magnesium sulfate, filtered,
evaporated to dryness, and purified by column chromatography
on silica gel eluted with 90% petrol/10% EtOAc to give 17 as
a colorless oil and a mixture of diastereoisomers [85 mg, 0.24
mmol, 65% (for two steps)]. Crystallization from 20% diethyl
ether/80% petroleum ether afforded a pure single isomer; mp
126-127 °C; data quoted below for single isomer: Rf 0.63
(petroleum ether/EtOAc ) 4:1);. IR (CHCl3) 1349 (SO2-), 1157
(SO2-) cm-1; 1H NMR (400 MHz, CDCl3) δ 1.10-1.28 (2H, m),
1.53-1.65 (2H, m), 2.45 (3H, s), 3.15-3.27 (2H, m), 3.82 (1H,
ddd, J 7.7, 5.2, 5.2 Hz), 4.08 (1H, m), 4.39 (1H, dd, J 9.4, 3.4
Hz), 4.58 (1H, dd, J 9.4, 9.4 Hz), 6.76 (1H, d, J 8 Hz), 6.86
(1H, ddd, J 7.4, 7.4, 0.7 Hz), 7.17 (1H, ddd, J 8.0, 7.4, 0.7 Hz),
7.35 (2H, d, J 8 Hz), 7.43 (1H, d, J 7.4 Hz), 7.76 (2H, d, J 8.2
Hz); 13C NMR (100.6 MHz, CDCl3) δ 21.5 (q), 24.2 (t), 26.9 (t),
46.0 (d), 49.7 (t), 62.9 (d), 74.3 (t), 109.4 (d), 120.6 (d), 126.7
(d), 126.7 (s), 127.6 (d), 128.9 (d), 129.8 (d), 134.4 (s), 143.6
(s), 160.9 (s); MS (FAB) m/z 344 [(M + H)+, 6]; HRMS for
141.3 (d); MS (FAB) m/z 418 [(M + H)+, 3]; HRMS for C16H20
-
INO2S calcd (M + H)+, 418.0338; found (M + H)+ (FAB),
418.0326.
Variable temperature studies were performed on this com-
pound: 1H NMR [400 MHz, (CD3)2SO at 25 °C] δ 0.38 and
0.92-0.97 (1H, m), 1.17-1.19 and 1.34-1.37 (1H, m), 1.60-
1.80 (3H, m), 2.21-2.32 and 2.50-2.54 (1H, 2 × m*), 3.05-
3.20 (2H, m), 3.15 and 3.35 (3H, 2 × s), 4.41 and 4.50 (1H, 2
× m*), 5.01-5.21 (2H, m), 5.56 and 5.65 (1H, 2 × m*), 5.84-
5.95 (1H, m), 7.04-7.14 and 7.68-7.72 (2H, 2 × m), 7.34-
7.45 (1H, m), 7.95-7.97 (1H, m); on heating to 100 °C,
essentially complete coalescence was observed for the multiplet
pairs marked “*”; partial coalescence was observed in other
regions of the spectrum. On recooling to 25 °C, the spectrum
returned to its previous appearance at that temperature.
N-[2-(2,3-Dih yd r oxyp r op yl)-2-cycloh exen -1-yl]-N-(2-io-
d op h en yl)m eth a n esu lfon a m id e, 21. To a stirred solution
of 20 (24.60 g, 59.0 mmol, 1.0 equiv) in acetone/water (1000
mL, 9:1) was added a solution of osmium tetroxide (20 mL of
a 10 mg/mL solution in tert-butyl alcohol, 200 mg, 0.78 mmol,
1.3 mol %) followed by N-methylmorpholine N-oxide (8.27 g,
71.9 mmol, 1.2 equiv), and the mixture was stirred for 16 h.
Sodium bisulfite solution (15 g in 50 mL) was then added, the
mixture was stirred for 1 h and filtered through Celite, and
the filtrate was evaporated to remove acetone before extracting
with DCM. The organic phase was washed with HCl (2 M)
and water, dried over magnesium sulfate, evaporated to
dryness, and purified by column chromatography on silica gel
eluted with 90% DCM/10% MeOH to give 21 as a colorless
solid, formed as a mixture of diastereoisomers and rotamers
C
19H21NO3S Calcd (M + H)+, 344.1320; found (M + H)+,
344.1373.
N-(2-Iod op h en yl)m eth a n esu lfon a m id e, 18. Methane-
sulfonyl chloride (14.50 g, 9.8 mL, 126 mmol, 1.2 equiv),
2-iodoaniline (23 g, 105 mmol, 1.0 equiv), and DMAP (1.30 g,
10.5 mmol, 0.1 equiv) were dissolved in pyridine (75 mL), and
the resulting mixture was heated under reflux for 12 h. The
cooled reaction mixture was diluted with DCM and washed
with aqueous HCl (2 M) and aqueous sodium hydroxide (2 M).
The combined aqueous extracts were acidified with concen-
trated hydrocloric acid and then extracted with DCM. The
combined organic extracts were dried over magnesium sulfate,
filtered, and evaporated to dryness to give 18 as a yellow
crystalline solid (20 g, 70.9 mmol, 68%); mp 96-98 °C (diethyl
ether); Rf 0.66 (petroleum ether/EtOAc ) 1:1); IR (KBr) 3329,
(22.89 g, 50.75 mmol, 86%); Rf 0.24 (DCM/MeOH ) 4:1); mp
-
125-129 °C; IR (CHCl3) 3543 (O-H), 1322 (SO2-), 1143 (SO2
)
cm-1; 1H NMR (400 MHz, CDCl3) δ 0.50-0.52 and 1.01-1.03
(1H, m), 1.20-1.29 and 1.39-1.44 (1H, m), 1.70-2.01 (3H, m),
2.11-2.54 (2H, m), 2.63-2.88 (2H, m), 2.92-3.23 (1H, m), 3.04,
3.07, 3.32 and 3.36 (3H, 4 × s), 3.50-3.94 (3H, m), 4.67 and
4.80 (1H, 2 × br m), 5.80 and 5.85 (1H, 2 × br m), 7.00-7.61
(3H, m), 7.94 (1H, d, J 7.9 Hz); 13C NMR (100.6 MHz, CDCl3)
δ 17.6 (t), 17.7 (t), 18.0 (t), 18.1 (t), 24.7 (t), 24.8 (t), 24.9 (t),
25.0 (t), 28.3 (t), 28.4 (t), 29.9 (t), 30.0 (t), 38.7 (t), 38.8 (t),
40.8 (t), 40.8 (t), 40.5 (q), 40.6 (q), 42.7 (q), 54.9 (d), 56.1 (d),
57.3 (d), 58.4 (d), 66.5 (t), 66.6 (t), 66.7 (t), 66.8 (t), 70.5 (d),
70.6 (d), 73.1 (d), 73.5 (d), 103.3 (s), 103.4 (s), 104.5 (s), 104.6
(s), 128.9 (d), 128.9 (d),130.2 (d), 130.2 (d), 130.5 (d), 131.1(s),
131.2 (d), 132.1 (d), 132.3 (s), 132.7 (s), 133.5 (d), 133.6 (d),
133.7 (s), 134.0 (d), 134.4 (d), 134.7 (d), 140.0 (s), 140.1 (s),
140.8 (s), 140.8 (s), 140.9 (d), 141.0 (d), 141.6 (d), 141.7 (d);
MS (CI) m/z 469 [(M + NH4)+, 10]; HRMS for C16H22INO4S
calcd M+, 451.0314; found M+ (EI), 451.0310. Anal. Calcd for
C16H22INO4S: C, 42.58; H, 4.91; N, 3.10; S, 7.1. Found: C, 42.47;
H, 4.94; N, 3.36; S, 7.1.
1343 (SO2-), 1151 (SO2-) cm-1; H NMR (400 MHz, CDCl3) δ
1
3.02 (3H, s), 6.64 (1H, br), 6.95 (1H, ddd, J 8.0, 8.0, 1.5 Hz),
7.37 (1H, ddd, J 8.0, 8.0, 1.3 Hz), 7.65 (1H, dd, J 8.0, 1.5 Hz),
7.82 (1H, dd, J 8.0, 1.4 Hz); 13C NMR (100.6 MHz, CDCl3) δ
40.0 (q), 92.1 (s), 122.4 (d), 127.2 (d), 129.7 (d), 137.4 (s), 139.3
(d); MS (EI) m/z 297 (M+, 40); HRMS for C7H8INO2S calcd M+,
296.9320; found M+ (EI), 296.9314.
N-(2-Allyl-2-cycloh exen -1-yl)-N-(2-iodoph en yl)m eth an e-
su lfon a m id e, 20. N-(2-Iodophenyl)methanesulfonamide (18)
(5.43 g, 19.2 mmol, 1.0 equiv) and triphenylphosphine (7.55
g, 28.8 mmol, 1.5 equiv) were dissolved in dry THF (100 mL).
2-(Prop-2′-enyl)-cyclohex-2-en-1-ol (19) (3.98 g, 28.8 mmol, 1.5
equiv) was added15 and the mixture cooled to 0 °C. Diethyl
azodicarboxylate (5.01 g, 4.53 mL, 28.8 mmol, 1.5 equiv) was
added dropwise over a 15 min period. After 2 h the mixture
was evaporated to dryness, dissolved in DCM (100 mL), and
washed with NaOH, aqueous sodium carbonate (saturated),
and water. The solution was dried over sodium sulfate,
followed by filtration and removal of the solvent under reduced
pressure to give a yellow solid. This was purified by column
chromatography on silica gel eluted with 80% petrol/20%
EtOAc to give 20 as a colorless solid that was a 4:1 mixture of
N-(2-Iodoph en yl)-N-[2-(oxoeth yl)cycloh ex-2-en yl] m eth -
a n esu lfon a m id e, 22. To a stirred solution of 21 (20 g, 44
mmol, 1.0 equiv) in diethyl ether (500 mL) and ethanol (50
mL) was added sodium periodate (11.76 g, 55 mmol, 1.25
equiv) followed by water (60 mL). The resulting mixture was
stirred for 5 h under nitrogen atmosphere. The mixture was
then diluted with EtOAc (250 mL) and washed with water.
The aqueous phase was then extracted with EtOAc, and the
combined organic extracts were washed with water, dried over
magnesium sulfate, filtered, evaporated to dryness, and puri-
(15) (a) Hong, C. H.; Kado, N.; Overman, L. E. J . Am. Chem. Soc.
1993, 115, 11028. (b) Taber, D. F. J . Org. Chem. 1976, 41, 2649. (c)
Taber, D. F.; Gunn, B. P.; Chiu, I.-C. Organic Syntheses; Wiley: New
York, 1990; Collect. Vol. VII, p 249.

Tandem Radical Cyclizations on Iodoaryl Azides
J . Org. Chem., Vol. 64, No. 21, 1999 7861
fied by column chromatography on silica gel eluted with 50%
petroleum ether/50% EtOAc to give 22 as a yellow oil, formed
as a mixture of rotamers (17.70 g, 42.24 mmol, 96%); Rf 0.49
(petroleum ether/ethyl acetate ) 1:1); IR (neat) 2724, 1720,
INO5S2: C, 38.48; H, 4.44; N, 2.80; S, 12.84; I, 25.24. Found:
C, 38.48; H, 4.53; N, 2.80; S, 12.51; I, 25.40.
N-(2-[2-Azid oeth yl]cycloh ex-2-en yl)-N-(2-iod op h en yl)-
m eth an esu lfon am ide, 25. 2-{6-[2-Iodo(methylsulfonyl)anilino]-
1-cyclohexen-1-yl} ethylmethanesulfonate (24) (15.45 g, 30.90
mmol, 1.0 equiv) and sodium azide (4.03 g, 61.5 mmol, 2.0
equiv) were dissolved in DMF (300 mL) and heated at 60 °C
under nitrogen, for 5 h. The reaction mixture was concentrated
by distilling off DMF (250 mL) under reduced pressure, diluted
with diethyl ether (200 mL), and then washed with water and
extracted into diethyl ether. The combined organic extracts
were then washed with water, dried over magnesium sulfate,
filtered, evaporated to dryness, and purified by column chro-
matography on silica gel eluted with 80% petroleum ether/
20% EtOAc to give 25 as a white solid that was a mixture of
rotamers (13.2 g, 29.59 mmol, 96%); Rf 0.32 (petroleum ether/
EtOAc ) 4:1); mp 92-93 °C; IR (CHCl3) 2099, 1323 (SO2-),
1146 (SO2-) cm-1; 1H NMR (400 MHz, CDCl3) δ 0.56 and 1.04
(1H, m), 1.26-1.48 (1H, m), 1.73-2.00 (3H, m), 2.13-2.58 (2H,
m), 2.93 (1H, m), 3.03 and 3.29 (3H, 2 × s), 3.32-3.52 (2H,
m), 4.64 (1H, br m), 5.74 and 5.84 (1H, 2 × m), 7.04 (1H, ddd,
J 7.9, 7.9, 1.5 Hz), 7.17 (1H, dd, J 7.9, 1.5 Hz), 7.33 (1H, ddd,
J 7.9, 7.9, 1.5 Hz), 7.95 (1H, dd, J 7.9, 1.5 Hz); 13C NMR (100.6
MHz, CDCl3) δ 18.1 (t), 18.4 (t), 25.1 (t), 25.3 (t), 28.6 (t), 30.1
(t), 34.9 (t), 36.6 (t), 40.9 (q), 43.2 (q), 50.7 (t), 50.9 (t), 55.2
(d), 57.4 (d), 103.5 (s), 104.6 (s), 129.2 (d), 130.6 (d), 130.8 (d),
131.6 (s), 131.7 (d), 133.2 (s), 133.9 (d), 134.0 (d), 135.0 (d),
140.4 (s), 141.1 (s), 141.3 (d), 141.9 (d); MS (CI) m/z 464 [(M +
NH4)+, 20]; HRMS for C15H19IN4O2S calcd (M + NH4), 464.0617;
1
1330, 1149 cm-1; H NMR (250 MHz, CDCl3) δ 0.56 and 1.03
(1H, m), 1.15-1.46 (1H, m), 1.70-2.45 (4H, m), 3.00 and 3.25
(3H, 2 × s), 3.18 (1H, m), 3.93 (d, J 17.3 Hz), and 4.08 (1H, br
m), 4.55 and 4.60 (1H, 2 × br s), 5.72 and 5.75 (1H, 2 × br s),
7.04 (1H, m), 7.12-7.53 (2H, m), 7.93 (1H, br d, J 7.9 Hz),
9.75 (1H, br s); 13C NMR (67.8 MHz, CDCl3) δ 18.0 (t), 18.1
(t), 24.6 (t), 24.9 (t), 27.9 (t), 29.1 (t), 40.1 (q), 42.5 (q), 49.3 (t),
51.1 (t), 57.2 (d), 58.4 (d), 103.2 (s), 104.8 (s), 127.6 (s), 128.9
(d), 130.2 (d), 130.4 (d), 133.0 (d), 133.4 (d), 134.2 (d), 135.3
(d), 140.0 (s), 140.9 (d), 141.5 (d), 200.1 (d), 201.3 (d); MS (CI)
m/z 437 (M + NH4)+ 100]; HRMS for C15H18INO3S calcd M+,
419.0052; found M+ (CI), 419.0072.
N-[2-(2-Hydr oxyeth yl)-2-cycloh exen -1-yl]-N-(2-iodoph e-
n yl)m et h a n esu lfon a m id e, 23. To a stirred solution of 22
(17.7 g, 39.2 mmol, 1.0 equiv) in MeOH (50 mL) was added
NaBH4 (1.48 g, 39.2 mmol, 1.0 equiv) and the mixture stirred
for 5 min. Water (50 mL) was added and the mixture
evaporated to remove MeOH before extracting with DCM. The
organic phase was washed with water, dried over magnesium
sulfate, evaporated to dryness, and purified by column chro-
matography on silica gel eluted with diethyl ether to give 23
as a colorless solid that was a mixture of rotamers (15.29 g,
36.3 mmol, 86%); Rf 0.33 (diethyl ether); mp 105-106 °C
(EtOAc/petroleum ether); IR (CHCl3) 3549, 1322, 1145 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.60 and 1.06 (1H, 2 × m), 1.25-
1.46 (1H, m), 1.72-1.92 (3H, m), 2.00-2.08 (1H, m), 2.15-
2.52 (2H, m), 2.83-2.99 (1H, m), 3.04, 3.31 (3H, 2 × s), 3.72-
3.80 (2H, m), 4.71 (1H, m), 5.71 and 5.81 (1H, 2 × m), 7.01
(1H, ddd, J 7.9, 7.9, 1.5 Hz), 7.21 (1H, dd, J 8.0, 1.5 Hz), 7.32
(1H, ddd, J 8.0, 8.0, 1.3 Hz), 7.95 (1H, dd, J 7.9, 1.3 Hz); 13C
NMR (100.6 MHz, CDCl3) δ 18.3 (t), 18.5 (t), 25.0 (t), 25.2 (t),
28.8 (t), 30.2 (t), 38.3 (t), 40.1 (t), 41.2 (q), 43.0 (q), 56.3 (d),
58.3 (d), 62.5 (t), 62.8 (t), 103.3 (s), 104.7 (s), 129.2 (d), 129.2
(d), 130.5 (d), 130.7 (d), 130.8 (d), 132.6 (s), 133.0 (d), 134.1
(d), 134.9 (d), 140.5 (s), 141.3 (d), 141.4 (s), 141.9 (d); MS (FAB)
m/z 422 [(M + H)+, 6]; HRMS for C15H20INO3S calcd 439.0552
(M + NH4)+; found (M + NH4)+ (CI), 439.0538.
found (M + NH4)+ (CI), 464.0616. Anal. Calcd for C15H19
-
IN4O2S: C, 40.37; H, 4.29; N, 12.55. Found: C, 40.75; H, 4.45;
N, 12.32.
Rea ction of N-(2-[2-Azid oeth yl]cycloh ex-2-en yl)-N-(2-
iod op h en yl)m eth a n esu lfon a m id e (25) w ith (TMS)3SiH/
AIBN in Ben zen e. To a stirred solution of 25 (576 mg, 1.28
mmol, 1.0 equiv) in refluxing dry degassed benzene (25 mL)
were added tris(trimethylsilyl)silane (320 mg, 480 µL, 1.28
mmol, 1.0 equiv) and AIBN (24 mg, 0.128 mmol, 0.1 equiv)
under nitrogen. The mixture was refluxed for 6 h and
evaporated to dryness. The mixture was then dissolved in
EtOAc (100 mL) and extracted with aqueous HCl (2 M). The
aqueous layer was basified with sodium hydroxide (2 M) and
then the aqueous layer extracted with EtOAc, dried over
magnesium sulfate, filtered, and evaporated to dryness to give
(()-(3aS*,6aS*,11bR*)-7-methanesulfonyl-2,3,3a,4,5,6,6a,7-oc-
tahydro-1H-pyrrolo[2,3,d]carbazole (27) as a colorless solid
(310 mg, 1.06 mmol, 83%); mp 119-120 °C (diethyl ether/
petroleum ether); Rf 0.21 (DCM/MeOH ) 4:1); IR (CHCl3) 3305,
1352, 1158 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.25-2.25 (9H,
m), 3.02 (3H, s), 3.15-3.18 (2H, m), 3.70 (1H, br s), 4.13 (1H,
dd, J 10.8, 5.4 Hz), 7.06 (1H, dd, J 7.6, 7.3 Hz), 7.17 (1H, d, J
2-{6-[2-Iod o(m et h ylsu lfon yl)a n ilin o]-1-cycloh exen -1-
yl} eth ylm eth a n esu lfon a te, 24. To a stirred solution of 23
(15 g, 35.55 mmol, 1.0 equiv) and DMAP (475 mg, 3.56 mmol,
0.1 equiv) in DCM (400 mL) was added triethylamine (4.32 g,
5.90 mL, 42.52 mmol, 1.2 equiv) under nitrogen at 0 °C.
Methanesulfonyl chloride (4.48 g, 3.07 mL, 39 mmol, 1.1 equiv)
was added dropwise over 10 min. After a further 2 h stirring
at 0 °C, the mixture was warmed to room temperature and
stirred for a further 3 h. The reaction mixture was washed
with aqueous HCl (0.5 M), and the aqueous phase was then
extracted with DCM. The combined organic phases were
washed with aqueous sodium hydrogen carbonate solution
(saturated) and dried over magnesium sulfate, filtered, evapo-
rated to dryness, and purified by column chromatography on
silica gel eluted with 60% EtOAc/40% petrol to give 24 as a
colorless crystalline solid, formed as a mixture of rotamers
(16.4 g, 33.0 mmol, 93%); Rf 0.28 (petroleum ether/EtOAc )
1:1); mp 103-104 °C (decomp); IR (CHCl3) 1354 (SO2-), 1324
7.3 Hz), 7.22 (1H, dd, J 7.9, 7.6 Hz), 7.33 (1H, d, J 7.9 Hz); 13
C
NMR (100.6 MHz, CDCl3) δ 17.1 (t), 27.0 (t), 29.9 (t), 39.6 (q),
42.7 (t), 44.8 (t), 53.1 (s), 59.2 (d), 68.7 (d), 114.3 (d), 123.0 (d),
124.3 (d), 128.8 (d), 136.6 (s), 140.9 (s); MS (EI) m/z 292 (M+,
8); HRMS for C15H20N2O2S calcd M+, 292.1246; found M+ (EI),
292.1250.
(()-(3a S*,6a S*,11b S*)-3-Tolu en esu lfon yl-7-m et h a n e-
su lfon yl-2,3,3a ,4,5,6,6a ,7-oct a h yd r o-1H -p yr r olo[2,3,d ]-
ca r ba zole, 28. To a stirred solution of 30 (52 mg, 0.17 mmol,
1.0 equiv) and DMAP (3 mg, 0.017 mmol, 0.1 equiv) in pyridine
(10 mL) under nitrogen was added p-toluenesulfonyl chloride
(41 mg, 0.21 mmol, 1.2 equiv). The resulting mixture was
heated to reflux (110 °C) for 16 h. The mixture was brought
to room temperature, and the whole mixture was poured into
aqueous HCl (2 M, 50 mL) and extracted with DCM. The
organic extracts were dried (sodium sulfate), filtered, evapo-
rated, and purified by column chromatography on silica gel
eluted with 50% petroleum ether/50% EtOAc to give 28 as a
white crystalline solid (60 mg, 0.13 mmol, 75%); Rf 0.42
(petroleum ether/EtOAc ) 1:1); mp 185-186 °C (EtOAc/petrol);
IR (CHCl3) 1350, 1159, 1102 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.20-1.28 (1H, m), 1.33-1.43 (1H, m), 1.51-1.64 (3H, m),
1.89-1.94 (1H, m), 2.14-2.18 (1H, m), 2.26-2.29 (1H, m), 2.46
(3H, s), 2.99 (3H, s), 3.48-3.53 (1H, m), 3.62-3.68 (1H, m),
1
(SO2-), 1146 (SO2-) cm-1; H NMR (400 MHz, CDCl3) δ 0.51
and 1.01 (1H, 2 × m), 1.25 and 1.38-1.42 (1H, 2 × m), 1.77-
1.94 (3H, m), 2.09-2.15 and 2.43-2.50 (1H, 2 × m), 2.57-
2.74 (1H, 2 × m), 2.90-3.21 (1H, m), 3.02 (3H, s), 3.01 and
3.31 (3H, 2 × s), 4.39 (2H, m), 4.63 (1H, m), 5.76 and 5.85
(1H, 2 × m), 7.04 (1H, ddd, J 8.0, 8.0, 1.6 Hz), 7.16 (1H, dd, J
8.0, 1.6 Hz), 7.33 (1H, ddd, J 8.0, 8.0, 1.5 Hz), 7.96 (1H, dd, J
8.0, 1.6 Hz); 13C NMR (100.6 MHz, CDCl3) δ 17.9 (t), 18.4 (t),
25.0 (t), 25.3 (t), 28.5 (t), 30.0 (t), 34.9 (t), 36.7 (t), 37.9 (q),
38.0 (q), 40.6 (q), 43.3 (q), 54.9 (d), 57.5 (d), 69.7 (t), 69.8 (t),
103.8 (s), 104.5 (s), 129.3 (d), 130.0 (s), 130.7 (d), 130.9 (d),
131.5 (s), 132.7 (d), 133.6 (d), 134.9 (d), 135.0 (d), 140.3 (s),
141.0 (s), 141.3 (d), 142.0 (d); MS (FAB) m/z 422 [(M - SO2-
Me)+, 6]; HRMS for C16H22INO5S2 calcd (M + NH4)+, 517.0328;
found (M + NH4)+ (CI), 517.0321. Anal. Calcd for C16H22
-

7862 J . Org. Chem., Vol. 64, No. 21, 1999
Kizil et al.
3.94-3.95 (1H, br m), 4.05-4.10 (1H, dd, J 11.0, 6.0 Hz), 6.64
(1H, d, J 7.5 Hz), 6.89 (1H, ddd, J 7.5, 7.5, 1.0 Hz), 7.20 (1H,
ddd, J 8.0, 7.5, 1.0 Hz), 7.25-7.28 (1H, d, J 8.0 Hz), 7.37 (2H,
d, J 8.0 Hz), 7.79 (2H, d, J 8.0 Hz); 13C NMR (100.6 MHz,
CDCl3) δ 17.0 (t), 22.1 (q), 27.9 (t), 28.8 (t), 38.6 (t), 40.0 (q),
47.9 (t), 54.1 (s), 61.7 (d), 67.8 (d), 114.4 (d), 122.9 (d), 124.2
(d), 127.9 (d), 129.5 (d), 130.4 (d), 134.0 (s), 135.3 (s), 140.5
(s), 144.4 (s); MS (EI) m/z 446 (M+, 63); HRMS for C22H26N2O4S2
calcd M+, 446.1334; found M+ (EI), 446.1321. Anal. Calcd for
Ack n ow led gm en t. We thank the University of
Dicle (Diyarbakir, Turkey) for a studentship to M.K.,
the EPSRC for funding (O.C. and B.P.), and the EPSRC
Mass Spectrometry Service Centre, Swansea, for high-
resolution mass spectra.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
1
spectra of compounds 7-10, 12-18, 20-25, 27, and 28; H-
1H COSY spectrum of 17; and X-ray structural data for 28.
This material is available free of charge via the Internet at
http://pubs.acs.org.
C
22H26N2O4S2: C, 59.17; H, 5.87; N, 6.27. Found: C, 59.38; H,
5.96; N, 6.61.
X-ray Crystallographic data for 28 are available in the
Supporting Information.
J O990891X