Generation of acyl radicals from thioesters by intramolecular homolytic substituition at sulfur

Full text of DOI:10.1021/jo960115e

3566
J . Org. Chem. 1996, 61, 3566-3570
Sch em e 1
Gen er a tion of Acyl Ra d ica ls fr om
Th iolester s by In tr a m olecu la r Hom olytic
Su bstitu tion a t Su lfu r
David Crich* and Qingwei Yao
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
Received J anuary 18, 1996
In tr od u ction
Acyl radicals have considerable potential in organic
synthesis in terms of both intra- and intermolecular
carbon-carbon bond forming reactions.1 In nonreductive
or atom transfer processes, the acyl radical precursors
may be selected from either the acyl tellurides,2 the
acylcobalt(III) derivatives,3 or the S-acyl xanthates,4
according to subsequent requirements. In stannane-
mediated chain sequences the acyl aryl selenides are the
precursors of choice owing to their ease of preparation,
relative stability, and ability to participate smoothly in
chain sequences.5,6 The replacement of acyl selenides by
thiolesters in these tributyltin hydride- and allyltribu-
tylstannane-mediated chain reactions would be attractive
from a number of viewpoints, not least the enhanced
stability under oxidizing conditions and ease of prepara-
tion. Unfortunately, to date it has not been possible to
coax simple S-phenyl thiolesters into chain reactions
propagated by trialkyltin radicals.5d,k The homolytic
dissociation of S-2-naphthyl and other thiolesters as a
means of entry into acyl radicals appears to be limited
inter alia by low quantum yields.7 Here, we report a
solution to this problem based on the philosophy that one
inefficent propagation step can often be replaced advan-
tageously by two efficient ones.8 Thus, we conceived a
strategy wherein the sluggish reaction of stannyl radicals
with thiolesters is substituted by two very efficient free
radical reactions, namely, iodine abstraction by tributyl-
tin or tris(trimethylsilyl)silyl radicals from an aryl iodide
and intramolecular homolytic attack at sulfur9 by aryl
radicals, with release of the acyl radical.
Resu lts a n d Discu ssion
Homolytic substitution (SH2) reactions, both intermo-
lecular and intramolecular, on divalent as well as tet-
ravalent sulfur centers9 have been extensively studied
by several groups.10 The intramolecular SH2 processes
were found to proceed in the exo fashion,9b,10f with
formation of radicals resulting from the cleavage of the
exocyclic bond. The ring closure can be so efficient that
even such reactive species as methyl and phenyl radicals
can be formed. With this in mind, we elected to synthe-
size and investigate the tributyltin hydide-mediated
reaction of substrates of the general type A. It was
anticipated that a highly reactive, electrophilic aryl
radical (B), formed by iodine atom abstraction from A
by the stannyl radical, would rearrange with expulsion
of the acyl radical (C) and concomitant formation of the
five-membered heterocycle (D) (Scheme 1). gem-Di-
methyl groups might be incorporated to speed up the
cyclization (Scheme 1, R ) Me) in the event that
quenching of the intial, unsubstituted (Scheme 1, R )
H) aryl radical by the stannane were a competing process.
Starting from commercially available 2-(2-bromophen-
yl)ethanol (1), thiol 4 was readily prepared in 70% overall
yield through halogen/metal exchange and iodonation of
its TMS ether, followed after deprotection by Mitsunobu
thiolesterification11 and, finally, DIBALH reduction
(Scheme 2).
(1) For reviews on the chemistry of acyl radicals and their applica-
tion in synthesis, see: (a) Crich, D.; Yuan, H. In Advances in Free
Radical Chemistry; Rawal, V. H., Ed.; J AI Press: Greenwich, CT, 1996;
Vol. 2, in press. (b) Na´jera, C.; Yus, M. Org. Prep. Proced. Int. 1995,
27, 383. (c) Thebtaranonth, C.; Thebtaranonth, H. Cyclization Reac-
tions; CPC Press: Boca Raton, FL, 1994; Chapter 3.
(2) (a) Chen, C.; Crich, D.; Papadatos, A. J . Am. Chem. Soc. 1992,
114, 8313. (b) Chen, C.; Crich, D. Tetrahedron Lett. 1993, 34, 1545. (c)
Crich, D.; Chen, C.; Hwang, J .-T.; Yuan, H.; Papadatos, A.; Walter, R.
I. J . Am. Chem. Soc. 1994, 116, 8937.
(3) (a) Patel, V. F.; Pattenden, G.; Thompson, D. M. J . Chem. Soc.,
Perkin Trans. 1 1990, 2729. (b) Pattenden, G.; Tankard, M. J .
Organomet. Chem. 1993, 460, 237. (c) Coveney, D. J .; Patel, V. F.;
Pattenden, G.; Thompson, D. M. J . Chem. Soc., Perkin Trans. 1 1990,
2721 and references cited therein.
(4) (a) Udding, J . H.; Giesselink, J . P. M.; Hiemstra, H.; Speckamp,
W. N. J . Org. Chem. 1994, 59, 6671. (b) Delduc, P.; Tailhan,C.; Zard,
S. Z. J . Chem Soc., Chem. Comm. 1988, 308. (c) Mestre, F.; Tailhan,C.;
Zard, S. Z. Heterocycles 1989, 89, 171.
(5) (a) Pfenninger, J .; Graf, W. Helv. Chim. Acta 1980, 63, 1562. (b)
Pfenninger, J .; Heuberger, C.; Graf, W. Helv. Chim. Acta 1980, 63,
2328. (c) Crich, D.; Fortt, S. M. Tetrahedron Lett. 1988, 29, 2585. (d)
Crich, D.; Fortt, S. M. Tetrahedron 1989, 45, 6581. (e) Crich, D.;
Eustace, K. A.; Fortt, S. M.; Ritchie, T. J . Tetrahedron 1990, 46, 2135.
(f) Batty, D.; Crich, D.; Fortt, S. M. J . Chem. Soc., Chem. Commun.
1989, 1366. (g) Batty, D.; Crich, D. Synthesis 1990, 273. (h) Batty, D.;
Crich, D.; Fortt, S. M. J . Chem. Soc., Perkin Trans. 1 1990, 2875. (i)
Batty, D.; Crich, D. J . Chem. Soc., Perkin Trans. 1 1992, 3193. (j) Batty,
D.; Crich, D. J . Chem. Soc., Perkin Trans. 1 1992, 3205. (k) Boger, D.
L.; Mathvink, R. J . J . Org. Chem. 1988, 53, 3377. (l) Boger, D. L.;
Mathvink, R. J . J . Org. Chem. 1989, 54, 1179. (m) Boger, D. L.;
Mathvink, R. J . J . Am. Chem. Soc. 1990, 112, 4003. (n) Boger, D. L.;
Mathvink, R. J . J . Am. Chem. Soc. 1990, 112, 4008. (o) Boger, D. L.;
Mathvink, R. J . J . Org. Chem. 1992, 57, 1429. (p) Evans, P. A.;
Roseman, J . D. Tetrahedron Lett. 1995, 36, 31.
Preparation of a second, gem-dimethyl-substituted,
thiol (10) was initiated by exhaustive methylation of 512
(8) See, for example: (a) Cole, S. J .; Kirwan, J . N.; Roberts, B. P.;
Willis, C. R. J . Chem. Soc., Perkin Trans. 1 1991, 103. (b) Crich, D.;
Yao, Q. J . Org. Chem. 1995, 60, 84.
(9) For reviews on homolytic processes at sulfur, see: (a) Crich, D.
In Organosulfur Chemistry; Page, P., Ed.; Academic Press: London,
1995; p 49. (b) Beckwith, A. L. J . Chem. Soc. Rev. 1993, 143. (c) Ingold,
K. U.; Roberts, B. P. Free Radical Substitution Reactions, Bimolecular
Homolytic Substitutions at Saturated Multivalent Atoms; Wiley: New
York, 1971; p 200.
(10) (a) Franz, A.; Roberts, D. H.; Ferris, K. F. J . Org. Chem. 1987,
52, 2256. (b) Ferris, K. F.; Franz, A. J . Org. Chem. 1992, 57, 777. (c)
Lyons, J . E.; Schiesser, C. H. J . Organomet. Chem. 1992, 437, 165. (d)
Lyons, J . E.; Schiesser, C. H. J . Chem. Soc., Perkin Trans. 2 1992,
1655. (e) Beckwith, A. L. J .; Boate, D. R. J . Chem Soc., Chem. Commun.
1986, 189. (f) Beckwith, A. L. J .; Boate, D. R. J . Org. Chem. 1988, 53,
4339. (g) Tada, M.; Yoshihara, T.; Sugano, K. J . Chem. Soc., Perkin
Trans. 1 1995, 1941 and references cited therein.
(6) The carbonylation of alkyl radicals generated from alkyl halides
and stannanes, albeit at relatively high pressures, is an attractive
alternative approach. Nagahara, K.; Ryu, I.; Kambe, N.; Komatsu, M.;
Sonoda, N. J . Org. Chem. 1995, 60, 7384 and references therein cited.
(7) Penn, J . H.; Liu, F. J . Org. Chem. 1994, 59, 2608.
(11) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119.
S0022-3263(96)00115-6 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 10, 1996 3567
Sch em e 2
Ch a r t 1
Sch em e 3
with MeI and potassium tert-butoxide in the presence of
18-crown-6 to give 6 in 83% yield. Lithium aluminum
hydride reduction then afforded the bromo alcohol 7, and
direct bromine/lithium exchange with excess n-butyl-
lithium13 followed by quenching with I2 gave the desired
iodo alcohol 8, albeit in only fair yield. Conversion of 8
to 10 was achieved uneventfully through Mitsunobu
thiolesterification and DIBALH reduction (Scheme 3).
With the two thiols in hand, we prepared a number of
thiolesters (11-15) either by reaction of acid chlorides
with the thiols in the presence of DMAP or by direct
coupling of the thiols and the carboxylic acids in the
presence of DCC and DMAP. In all cases, the thiolesters
were obtained in good to excellent yield (see the Experi-
mental Section).
Ta ble 1. Gen er a tion of Acyl Ra d ica ls fr om Th iolester s
Reactions of thiolesters 11-15 (Chart 1) with the three
most commonly used reagents, i.e. tri-n-butylstannane,14
tris(trimethylsilyl)silane,15 and allyltributylstannane16
were conducted with AIBN initiation, and the results are
listed in Table 1. The reaction of 11 with 1.3 equiv of
n-Bu3SnH in refluxing benzene with AIBN initiation for
1 h led to complete consumption of the substrate and
clean formation of the cyclization and reduction products
16 and 17 in a ratio of 96:4 (Table 1, entry 1) as
determined by the 1H-NMR of the crude reaction mixture.
As anticipated dihydrobenzothiophene 24 was also formed
in this reaction. The efficient formation of 16 and 24
substrate
(concn, M)
reagent
(equiv)a
entry
products (% yield)
1
2
3
4
5
6
7
11 (2.4 × 10-2
11 (2.4 × 10-2
12 (2.5 × 10-2
13 (2.5 × 10-2
12 (0.2)
)
)
)
)
A (1.3) 16 (96),b 17 (4),b 24 (94)b
B (1.3) 16 (100),b 17 (0),b 24 (100)b
A (1.3) 16 (100),b 17 (0),b 25 (100)b
A (1.3) 19 + 20 (82%, 94:6),c 25 (100)b
C (4)
16 (10), 18 (56), 25 (91)b
14 (2.5 × 10-2
)
)
A (1.3) 21 (92), 25 (71)b
15 (2.5 × 10-2
A (1.3) 22 (78) + 23 (8),b 24 (86)b
A, Bu3SnH; B, TMS3SiH; C, allyltributylstannane. b Estimated
a
by 1H-NMR spectroscopy. c Inseparable mixture.
clearly establishes the validity of the concept set out in
Scheme 1. It is noteworthy that 17, identified with the
aid of an authentic sample, was formed in only very low
yield, suggesting the cyclization of the initial aryl radical
to be fast relative to hydrogen atom abstraction from the
stannane. As expected, use of the poorer hydrogen atom
donor TMS3SiH as the reducing agent completely elimi-
nated the formation of 17 (Table 1, entry 2). Hydrogen
transfer to the aryl radical could also be completely
eliminated by use of thiol 10 with the cyclization-
enhancing gem-dimethyl group (Table 1, entries 3 and
4) with no indication of the formation of the correspond-
ing reduction products in the crude reaction mixtures.
It should be noted that in the cyclization of 13 (Table 1,
entry 4) a minor amount of the formal 6-endo product
(20) was identified along with the 5-exo product (19),
although it is not yet clear whether this is the result of
direct 6-endo ring closure or the product of a Dowd type17
ring expansion. Entry 5 of Table 1 illustrates the use of
(12) Beckwith, A. L. J .; Gerba, S. Aust. J . Chem. 1992, 45, 289.
(13) TMS ether protection of the hydroxyl group in 7 followed by
bromine/lithium exchange, iodination, and aqueous workup gave, not
8, but rather a very nonpolar product assigned as E resulting from
cyclization of the aryllithium onto the TMS group with expulsion of
MeLi. E: 1H-NMR δ 0.36 (s, 6H), 1.29 (s, 6H), 3.83 (s, 2H), 7.22-7.38
(m, 4H); 13C-NMR δ -0.3, 27.0, 38.3, 73.4, 124.7, 125.5, 129.6, 132.6,
133.0, 154.8; MS m/ z (relative intensity) 206 (M+•, 16), 191 (M+•-Me,
100). This unusual reaction, contrasted with that in Scheme 2,
illustrates the pronounced effect of the gem-dimethyl group on ring
closure reactions. For examples of related displacements at siloxanes,
see: (a) Frye, C. L.; Salinger, R. M.; Fearon, F. W. G.; Klosowski, J .
M.; DeYoung, T. J . Org. Chem. 1970, 35, 1308. (b) Sieburth, S. McN.;
Fensterbank, L. J . Org. Chem. 1993, 58, 6314.
(14) Neumann, W. P. Synthesis 1987, 665.
(15) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(16) Keck, G. E.; Enholm, E. J .; Yates, J . B.; Wiley, M. R. Tetrahe-
dron 1985, 41, 4079.

3568 J . Org. Chem., Vol. 61, No. 10, 1996
Notes
colorless oil: 1H-NMR δ 2.35 (s, 3 H), 2.96-3.14 (m, 4 H), 6.92
(m, 1 H), 7.26-7.32 (m, 2 H), 7.82 (d, J ) 7.7 Hz, 1 H); 13C-
NMR δ 29.0, 30.6, 40.4, 100.3, 128.4, 129.9, 139.5, 142.4, 195.5;
IR (CDCl3, cm-1) 1684. Anal. Calcd for C10H11IOS: C, 39.23;
H, 3.62. Found: C, 39.54; H, 3.55.
2-(2-Iod op h en yl)eth a n eth iol (4). A solution of 3 (1.73 g,
5.65 mmol) in Et2O (50 mL) cooled at -78 °C was treated
dropwise with DIBALH (14 mL, 1 M in CH2Cl2). The reaction
was gradually warmed to 0 °C over 0.5 h and then quenched
with dilute aqueous HCl (3 M, 10 mL). The organic layer was
separated, washed with water and brine, and dried (Na2SO4).
Removal of solvent followed by column chromatography on silica
gel (eluent: hexane) gave 4 (1.46 g, 97%) as a colorless oil: 1H-
NMR δ 1.45 (t, J ) 8.0 Hz, 1 H), 2.74-2.81 (m, 2 H), 3.01-3.05
(m, 2 H), 6.93 (dt, J ) 1.9, 7.4 Hz, 1 H), 7.22-7.30 (m, 2 H),
7.83 (dd, J ) 1.0, 8.0 Hz, 1 H); 13C-NMR δ 24.5, 45.0, 100.3,
128.3, 128.4, 130.0, 139.6, 142.3. Anal. Calcd for C8H9IS: C,
36.38; H, 3.43. Found: C, 36.49; H, 3.44.
Meth yl 2-(2-Br om op h en yl)isobu tyr a te (6). A solution of
5 (6.9 g, 30 mmol), methyl iodide (12.8 g, 90 mmol), and 18-
crown-6 (2.0 g, 7.5 mmol) in THF (250 mL) was treated, with
caution, with potassium tert-butoxide (10.2 g, 90 mmol). The
reaction mixture was stirred at room temperature for 24 h before
NaH (1.2 g, 60% dispersion in mineral oil, 30 mmol) was added.
After a further 12 h of stirring, the reaction mixture was diluted
with water (300 mL) and extracted with EtOAc (3 × 100 mL).
The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated to dryness under reduced pressure.
Column chromatography on silica gel (eluent: EtOAc/hexane,
1/4) gave 6 (6.42 g, 83%) as a colorless oil: 1H-NMR δ 1.64 (s, 6
H), 3.68 (s, 3 H), 7.12 (dt, J ) 1.7, 7.6 Hz, 1 H), 7.32 (dt, J ) 1.3,
7.6 Hz, 1 H), 7.42 (dd, J ) 1.7, 7.9 Hz, 1 H), 7.56 (dd, J ) 1.3,
7.9 Hz, 1 H); 13C-NMR δ 26.4, 48.0, 52.5, 123.8, 127.1, 127.5,
128.3, 134.3, 143.7, 177.4. Anal. Calcd for C11H13BrO2: C,
51.38; H, 5.10. Found: C, 51.50; H, 5.15.
allyltributylstannane as a chain transfer product, en-
abling the isolation of 18 in 56% yield. Interestingly,
chromanone 16 was also isolated from this reaction in
10% yield, suggesting that hydrogen atom abstraction
from the reagent competes with allyl transfer. This new
entry into acyl radicals may also be used for the genera-
tion of tertiary alkyl radicals following decarbonylation.
This is illustrated by entry 6 of Table 1 and the isolation
of the known noroleanene derivative 2118 in excellent
yield. Finally, it is interesting to note (Table 1, entry 7)
that the acyl radical derived from 15 underwent cycliza-
tion more rapidly than decarbonylation.
In summary acyl radicals may be generated very
cleanly from thiolesters by a means of intramolecular SH2
at sulfur as outlined in Scheme 1. When the thiolester
is derived from the gem-dimethyl-substituted thiol 10,
competing reduction of the aryl radical is not observed.
However, the more straightforward preparation of the
simple thiol 4 makes this the reagent of choice, especially
as reduction of the aryl radical may be completely
eliminated by use of TMS3SiH as chain transfer agent.
Finally, we note that although we have here generated
the requisite aryl radical from aryl iodides with stan-
nanes and silanes, almost any other entry into the
appropriate aryl radical B (Scheme 1) should be ap-
plicable, rendering this chemistry potentially extremely
versatile.
Exp er im en ta l Section
Gen er a l. See ref 8b for the general experimental protocol.
2-(2-Iod op h en yl)eth a n ol (2). To a stirred solution of 2-(2-
bromophenyl)ethanol (3.00 g, 14.9 mmol) and NEt3 (3.07 mL,
22 mmol) in THF (150 mL) cooled to 0 °C was added by syringe
TMSCl (2.43 mL, 19.3 mmol). The reaction mixture was stirred
at room temperature for 2 h before water (200 mL) was added,
the organic layer was extracted with EtOAc (3 × 100 mL), and
the combined extracts were washed with saturated NaHCO3 and
brine and dried (Na2SO4). Removal of solvents under reduced
pressure gave the crude silyl ether (4.08 g, 100%) as a colorless
oil: 1H-NMR δ 0.07 (s, 9 H), 2.99 (t, J ) 7.2 Hz, 2 H), 3.80 (t, J
) 7.2 Hz, 2 H), 7.07 (m, 1 H), 7.22-7.26 (m, 2 H), 7.53 (d, J )
8.3 Hz, 1 H). A solution of this silyl ether (4.08 g, 14.9 mmol)
in THF (200 mL) was cooled to -78 °C under N2 and treated
with BuLi (10 mL, 2 M in pentane, 20 mmol). After the mixture
was stirred at -78 °C for 0.5 h, I2 (5.1 g, 20 mmol) was added in
one portion and the reaction mixture brought to room temper-
ature over 0.5 h before being quenched with dilute aqueous HCl
(3 M, 50 mL). The resulting mixture was stirred for another
0.5 h and then extracted with EtOAc (3 × 100 mL). The organic
extracts were washed with saturated NaHCO3 and brine and
dried (Na2SO4). Removal of solvents under reduced pressure
followed by column chromatography on silica gel (eluent: CH2-
Cl2) gave the known alcohol 219 (3.45 g, 93%) as an oil: 1H-NMR
δ 3.02 (t, J ) 6.8 Hz, 2 H), 3.86 (t, J ) 6.8 Hz, 2 H), 6.92 (dt, J
) 2.4, 8.0 Hz, 1 H), 7.26-7.33 (m, 2 H), 7.84 (d, J ) 7.7 Hz, 1
H).
2-(2-Br om op h en yl)-2-m eth ylp r op a n ol (7). To a solution
of 6 (5.04 g, 19.6 mmol) in Et2O (150 mL) was added LiAlH4
(800 mg, 21 mmol) in one portion at -20 °C. After 1 h of stirring
at 0 °C, the reaction was quenched by addition of aqueous HCl
(3 M, 20 mL) and the organic layer separated. The aqueous layer
was extracted with EtOAc (3 × 50 mL), and the combined
organic layers were washed with brine, dried (Na2SO4), and
concentrated to dryness under reduced pressure. Column chro-
matography on silica gel (eluent: EtOAc/hexane, 1/3) gave the
7 (4.09 g, 91%) as colorless oil: 1H-NMR δ 1.51 (s, 6 H), 4.04 (s,
2 H), 7.07 (dt, J ) 1.7, 7.7 Hz, 1 H), 7.28 (m, 1 H), 7.47 (dd, J )
1.7, 8.0 Hz, 1 H), 7.60 (dd, J ) 1.4, 7.8 Hz, 1 H); 13C-NMR δ
25.2, 42.2, 69.6, 122.3, 127.4, 128.1, 130.1, 135.9, 143.6. Anal.
Calcd for C10H13BrO: C, 52.42; H, 5.72. Found: C, 52.61; H,
5.83.
2-(2-Iod op h en yl)-2-m eth ylp r op a n ol (8). A solution of 7
(3.94 g, 17.2 mmol) in THF (200 mL) was cooled to -78 °C under
N2 and treated with BuLi (20 mL, 2 M in hexane, 40 mmol).
After 0.5 h of stirring at this temperature, I2 (11.4 g, 45 mmol)
was added, and the reaction mixture was warmed to 0 °C over
2 h before water (200 mL) was added and the whole extracted
with EtOAc (3 × 70 mL). The combined organic extracts were
washed sequentially with 5% aqueous Na2S2O3, water, and brine
and dried (Na2SO4). Removal of solvents followed by column
chromatography on silica gel (eluent: EtOAc/hexane, 1/3) gave
3.03 g of an inseparable mixture of the iodo alcohol 8 and
2-methyl-2-phenylpropanol. Removal of the latter by careful
Kugelrohr distillation (80-90 °C, 0.7 mbar) gave pure 8 (1.90
g, 40%) as a colorless oil: 1H-NMR δ 1.53 (s, 6 H), 4.04 (s, 2 H),
6.86 (dt, J ) 1.8, 7.5 Hz, 1 H), 7.31 (dt, J ) 1.4, 7.6 Hz, 1 H),
7.45 (dd, J ) 1.7, 8.0 Hz, 1 H), 8.01 (dd, J ) 1.4, 7.8 Hz, 1H);
13C-NMR δ 25.3, 42.1, 69.3, 94.5, 128.0, 128.2, 129.8, 143.7,
146.0. Anal. Calcd for C10 H13IO: C, 43.50; H, 4.75. Found:
C, 43.72; H, 4.80.
S-2-(2-Iod op h en yl)eth yl Th iola ceta te (3). To a mixture
of 2 (2.30 g, 9.3 mmol) and PPh3 (3.67 g, 14 mmol) in THF (70
mL) was added dropwise DEAD (2.44 g, 14 mmol). After 5 min
of stirring, thioacetic acid (1.42 g, 18.6 mmol) was introduced
and the reaction mixture was stirred at room temperature for
20 h. The reaction mixture was then concentrated under
reduced pressure to ca. 10 mL, hexane (100 mL) was added, and
resulting precipitate was removed by filtration. The filtrate was
concentrated and the residue column chromatographed on silica
gel (eluent: CH2Cl2/hexane, 1/3) to give 3 (2.22 g, 78%) as a
S-2-(2-Iod op h en yl)-2-m eth ylp r op yl Th iola ceta te (9). To
a solution of 8 (1.28 g, 4.65 mmol) and PPh3 (2.44 g, 9.3 mmol)
in THF (50 mL) was added dropwise DEAD (1.47 mL, 9.3 mmol).
After the addition was complete, the reaction mixture was stirred
for 5 min before thioacetic acid (1.33 mL, 18.6 mmol) was slowly
introduced. After 16 h of stirring, another portion of thioacetic
acid (0.67 mL, 9.3 mmol) was added, and stirring was continued
for a further 8 h. The reaction mixture was concentrated under
reduced pressure to ca. 10 mL, hexane (100 mL) was added, and
(17) Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091.
(18) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901.
(19) Acheson, R. M.; Lee, G. C. M. J . Chem. Soc., Perkin Trans. 1
1987, 2321.

Notes
J . Org. Chem., Vol. 61, No. 10, 1996 3569
the resulting precipitate was removed by filtration. The filtrate
was concentrated and the residue column chromatographed on
silica gel (eluent: hexane/CH2Cl2, 1/1, then neat CH2Cl2) to give
the title thiolester (907 mg, 58%) as a colorless oil and unreacted
10 (390 mg, 30%). 9: 1H-NMR δ 1.57 (s, 6 H), 2.28 (s, 3 H),
3.75 (s, 2 H), 6.87 (dt, J ) 1.8, 7.4 Hz, 1 H), 7.30 (dt, J ) 1.3, 7.5
Hz, 1H), 7.36 (dd, J ) 1.9, 8.0 Hz, 1 H), 8.00 (dd, J ) 1.3, 7.8
Hz, 1 H); 13C-NMR δ 27.8, 30.5, 38.7, 40.2, 94.6, 127.9, 128.2,
128.7, 143.7, 146.6, 195.5; IR (CDCl3, cm-1) 1688. Anal. Calcd
for C12H15IOS: C, 43.13; H, 4.52. Found: C, 43.27; H, 4.61.
2-(2-Iod op h en yl)-2-m eth ylp r op a n eth iol (10). To a solu-
tion of 9 (710 mg, 2.13 mmol) in Et2O (20 mL) cooled to -78 °C
under N2 was added dropwise DIBALH (5.3 mL, 1 M in CH2-
Cl2). After the addition was complete, the reaction mixture was
slowly warmed to 0 °C over 0.5 h and then quenched with dilute
aqueous HCl (3 M, 10 mL). The organic layer was separated,
washed with water and brine, and dried (Na2SO4). Removal of
solvent followed by column chromatography on silica gel (elu-
ent: hexane/CH2Cl2, 9/1) gave 10 (587 mg, 94%) as a colorless
oil: 1H-NMR δ 0.95 (t, J ) 8.8 Hz, 1 H), 1.59 (s, 6 H), 3.27 (d, J
) 8.8 Hz, 2 H), 6.87 (dt, J ) 1.8, 7.4 Hz, 1 H), 7.32 (dt, J ) 1.3,
7.5 Hz, 1 H), 7.40 (dd, J ) 1.8, 8.0 Hz, 1 H), 8.01 (dd, J ) 1.3,
7.8 Hz, 1 H); 13C-NMR δ 27.7, 34.5, 41.6, 94.4, 128.0, 128.2,
129.6, 143.6, 146.3. Anal. Calcd for C10H13IS: C, 41.11; H, 4.48.
Found: C, 41.22; H, 4.46.
P r ep a r a tion of Th iolester s 11-14, 17 a n d 23. Gen er a l
P r oced u r e via Acyl Ch lor id es. A solution of the appropriate
carboxylic acid (1.0 mmol) in benzene (10 mL) was treated at
room temperature with oxalyl chloride (0.87 mL, 10 mmol) and
a small drop of DMF. After 0.5 h, the solvent and excess reagent
were removed in vacuo and the crude acid chloride was taken
up with CH2Cl2 (15 mL). DMAP (159 mg, 1.3 mmol) was then
added followed by the appropriate thiol (4 or 10). The resulting
mixture was stirred at room temperature until the reaction was
complete (0.5 to 16 h). Hexane (15 mL) was then added, and
the precipitates were removed by filtration. The filtrate was
concentrated to dryness and the product purified by column
chromatography on silica gel.
S-2-(2-Iod op h en yl)eth yl 2-(Allyloxy)th ioben zoa te (11).
11 was prepared from 2-allyloxybenzoic acid (178 mg, 1.0 mmol)
and thiol 4 according to the general procedure. Column chro-
matography on silica gel (eluent: CH2Cl2/hexane, 1/2) gave 11
(400 mg, 94%) as a colorless oil: 1H-NMR δ 3.06 -3.29 (m, 4
H), 4.67 (dt, J ) 5.1, 1.5 Hz, 2 H), 5.31 (dquart, J ) 10.5, 1.4
Hz, 1 H), 5.49 (dquart, J ) 17.3, 1.5 Hz, 1 H), 6.04 -6.16 (m, 1
H), 6.89-7.03 (m, 3 H), 7.27 -7.41 (m, 3 H), 7.78 -7.83 (m, 2
H); 13C-NMR δ 29.5, 40.4, 69.9, 100.4, 113.4, 118.0, 120.6, 127.3,
128.3, 128.4, 129.7, 130.1, 132.6, 133.4, 139.5, 142.9, 156.8, 190.7;
IR (CDCl3, cm-1) 1672. Anal. Calcd for C18H17IO2S: C, 50.95;
H, 4.04. Found: C, 50.97; H, 4.00.
S-2-(2-Iod op h en yl)-2-m eth ylp r op yl 2-(Allyloxy)th ioben -
zoa te (12). 12 was prepared from 2-(allyloxy)benzoic acid (178
mg, 1.0 mmol) and thiol 10 according to the general procedure.
Column chromatography on silica gel (eluent: CH2Cl2/hexane,
1/2) gave 12 (430 mg, 95%) as a colorless oil: 1H-NMR δ 1.64 (s,
6 H), 3.91 (s, 2 H), 4.58 (dt, J ) 5.0, 1.6 Hz, 2 H), 5.23 (ddt, J )
10.7, 1.5, 1.5 Hz, 1 H), 5.41 (ddt, J ) 17.3, 1.5, 1.8 Hz, 1 H),
5.98 (m, 1 H), 6.83 -6.97 (m, 3 H), 7.29 -7.42 (m, 3 H), 7.66
(dd, J ) 1.7, 7.7 Hz, 1 H), 8.01 (dd, J ) 1.4, 7.8 Hz, 1H): 13C-
NMR δ 28.0, 38.9, 40.5, 69.6, 94.8, 113.3, 117.6, 120.5, 127.8,
128.1, 128.9, 129.5, 132.5, 133.0, 143.7, 146.9, 156.3, 191.1.
Anal. Calcd for C20H21IO2S: C, 53.10; H, 4.68. Found: C, 53.13;
H, 4.71.
25.6, 27.1, 27.9, 28.0, 30.6, 32.3, 32.9, 33.8, 34.1, 36.7, 37.7, 38.0,
39.4, 40.5, 40.6, 41.3, 41.5, 46.2, 47.6, 47.8, 54.3, 94.8, 122.8,
127.7, 128.0, 128.9, 143.2, 143.7, 147.0, 170.7, 171.0, 206.2.
Anal. Calcd for C44H63IO5S: C, 63.60; H, 7.64. Found: C, 63.48;
H, 7.65.
S-2-(2-Iod op h en yl)-2-m eth ylp r op yl 2-Allylth ioben zoa te
(13). 13 was prepared from 2-allylbenzoic acid2c (97.5 mg, 0.6
mmol) and thiol 10 according to the general procedure. Column
chromatography on silica gel (eluent: CH2Cl2/hexane, 1/4) gave
13 (254 mg, 97%) as a colorless oil: 1H-NMR δ 1.65 (s, 6 H),
3.54 (d, J ) 6.5 Hz, 2 H), 3.91 (s, 2 H), 4.97-5.04 (m, 2 H), 5.87-
6.00 (m, 1 H), 6.86 (dt, J ) 1.7, 7.5 Hz, 1 H), 7.18-7.41 (m, 5
H), 7.62 (d, J ) 7.8 Hz, 1 H), 8.01 (dd, J ) 1.3, 7.8 Hz, 1 H);
13C-NMR δ 28.0, 37.4, 39.3, 40.53, 94.7, 115.9, 126.0, 127.9,
128.2, 128.3, 128.8, 130.5, 131.4, 136.8, 137.9, 138.0, 143.7, 146.6,
194.2; IR (CDCl3, cm-1) 1665. Anal. Calcd for C20H21IOS: C,
55.05; H, 4.85. Found: C, 55.30; H, 4.76.
S-2-(2-Iod op h en yl)eth yl [((E)-3-P h en ylp r op -2-en yl)oxy]-
th ioa ceta te (15): DCC/DMAP Meth od . A mixture of (cin-
namyloxy)acetic acid20 (135 mg, 0.70 mmol), DMAP (17 mg, 0.14
mmol), and DCC (173 mg, 0.84 mmol) in DCM (10 mL) was
stirred at room temperature for 5 min before thiol 4 (222 mg,
0.84 mmol) was added. After stirring at room temperature
overnight the reaction mixture was concentrated to dryness.
Column chromatography of the residue on silica gel (eluent:
CH2Cl2/hexane, 1/1) gave 15 (289 mg, 94%) as a colorless oil:
1H-NMR δ 2.98-3.18 (m, 4 H), 4.20 (s, 2 H), 4.29 (dd, J ) 6.2,
1.3 Hz, 2 H), 6.30 (dt, J ) 15.9, 6.2 Hz, 1 H), 6.86 (d, J ) 15.9
Hz, 1 H), 6.92 (m, 1 H), 7.24-7.43 (m, 7 H), 7.82 (d, J ) 7.7 Hz,
1 H); 13C-NMR δ 27.8, 40.3, 72.6, 74.6, 100.3, 124.5, 126.5, 127.9,
128.3, 128.5, 129.9, 133.7, 136.2, 139.5, 142.4, 199.8; IR (CDCl3,
cm-1) 1681. Anal. Calcd for C19H19IO2S: C, 52.06; H, 4.37.
Found: C, 51.88; H, 4.29.
S-2-P h en yleth yl 2-(Allyloxy)th ioben zoa te (17): Au th en -
tic Sa m p le. 17 was prepared from O-allylsalicylic acid (35.6
mg, 0.20 mmol) and 2-phenylethanethiol (35 mg, 0.25 mmol)
according to the general procedure except that Et3N (35 µL, 0.25
mmol) was used as the base. Column chromatography on silica
gel (eluent: CH2Cl2/hexane, 1/1) gave 17 (58 mg, 97%) as a
colorless oil: 1H-NMR δ 2.95-3.00 (m, 2 H), 3.25-3.30 (m, 2
H), 4.67 (dt, J ) 5.1, 1.6 Hz, 2 H), 5.31 (dq, J ) 10.6, 1.4 Hz, 1
H), 5.49 (dq, J ) 17.3, 1.6 Hz, 1 H), 6.03-6.16 (m, 1 H), 6.95-
7.03 (m, 2 H), 7.21-7.49 (m, 6 H), 7.79 (dd J ) 7.7, 1.7 Hz, 1 H);
13C-NMR δ 30.9, 35.7, 69.6, 113.3, 117.9, 120.5, 126.3, 127.4,
128.4, 128.6, 129.7, 132.5, 133.3, 140.3, 158.7, 190.8; IR (CDCl3,
cm-1) 1666. Anal. Calcd for C18H18O2S: C, 72.45; H, 6.08.
Found: C, 72.44; H, 6.18.
S-2-P h en yleth yl [((E)-3-P h en ylp r op -2-en yl)oxy]th ioa ce-
ta te (23): Au th en tic Sa m p le. 23 was prepared from (cin-
namyloxy)acetic acid (38.6 mg, 0.20 mmol) in exactly the same
way as for the preparation of 17. Column chromatography on
silica gel (eluent: CH2Cl2/hexane, 1/1, then neat CH2Cl2) gave
23 (58 mg, 93%) as a colorless oil: 1H-NMR δ 2.87-2.92 (m, 2
H), 3.14-3.20 (m, 2 H), 4.19 (s, 2 H), 4.28 (dd, J ) 6.2, 1.1 Hz,
2 H), 6.30 (dt, J ) 15.9, 6.2 Hz, 1 H), 6.65 (d, J ) 15.9 Hz, 1 H),
7.21-7.42 (m, 10 H); 13C-NMR δ 29.2, 35.9, 72.6, 74.6, 124.5,
126.47, 126.53, 127.9, 128.4, 128.5 (2 × C), 133.7, 136.2, 139.9,
199.8; IR (CDCl3, cm-1) 1681. Anal. Calcd for C19H20O2S: C,
73.04; H, 6.45. Found: C, 73.04; H, 6.56.
Rea ction of 11 w ith Bu 3Sn H a n d TMS3SiH: Gen er a l
P r oced u r es for th e Gen er a tion of Acyl Ra d ica ls fr om
Th ioester s. A solution 11 (20 mg, 0.047 mmol), Bu3SnH (18
mg, 1.3 equiv), and AIBN (1 mg, 10%) in degassed benzene (2.0
mL) was heated to reflux under Ar for 1 h. After the mixture
was cooled to room temperature, the solvent was removed in
Hed er a gen in Dia ceta te 2-(2-Iod op h en yl)-2-m eth ylp r o-
p a n eth iol Ester (14). 14 was prepared from hederagenin
diacetate (128 mg, 0.23 mmol) and thiol 10 (73 mg, 0.25 mmol)
according to the general procedure. Column chromatography
on silica gel (eluent: EtOAc/hexane, 1/3) gave 14 (138 mg, 72%)
as a crystalline solid and the starting acid (30 mg, 23%). 14:
mp 102 -103 °C (CH2Cl2); [R]D ) +24° (c 1.8, CHCl3); 1H-NMR
δ 0.71 (s, 3 H), 0.83 (s, 3 H), 0.88 (s, 3 H), 0.89 (s, 3 H), 0.97 (s,
3 H), 1.09 (s, 3 H), 1.54 (s, 3 H), 1.56 (s, 3 H), 0.80-2.05 (m, 22
H), 2.02 (s, 3 H), 2.06 (s, 3 H), 2.88 (dd, J ) 3.7, 13.2 Hz, 1 H),
3.62 (d, J ) 13.5 Hz, 1 H), 3.68 (d, J ) 13.5 Hz, 1 H), 3.69 (d, J
) 11.7 Hz, 1 H), 3.88 (d, J ) 11.6 Hz, 1 H), 4.78 (dd, J ) 5.2,
11.1 Hz, 1 H), 5.24 (t, J ) 3.3 Hz, 1 H), 6.84 (dt, J ) 1.8, 7.6 Hz,
1 H), 7.24-7.35 (m, 2 H), 7.98 (dd, J ) 1.3, 7.8 Hz, 1 H); 13C-
NMR δ 13.1, 15.9, 17.4, 17.9, 20.9, 21.2, 22.9, 23.4, 23.6 (2 × C),
1
vacuo. Examination of the crude reaction mixture by H-NMR
spectroscopy revealed complete consumption of 11 with the
formation of the cyclized product 16, the simple reduction
product 17, and dihydrobenzothiophene (24) in a ratio of 16:17:
24 ) 96:4:94. Replacement of Bu3SnH with TMS3SiH (15 mg,
1.3 equiv) under the same conditions gave 16 and 24 both
1
quantitatively as determined from the H-NMR spectrum of the
crude reaction mixture.
Rea ction of 12 w ith Bu 3Sn H. 12 (45 mg, 0.10 mmol) was
treated with Bu3SnH under the standard conditions to give a
(20) Oh, T.; Wrobel, Z.; Rubenstein, S. M. Tetrahedron Lett. 1991,
32, 4647.

3570 J . Org. Chem., Vol. 61, No. 10, 1996
Notes
1
crude reaction mixture consisting solely of a 1:1 mixture of 16
and 25 and organotin residues. Column chromatography on
silica gel (eluent: hexane then CH2Cl2) gave 25 (12 mg, 73%)
and 16 (14 mg, 86%).
[R]D ) +80° (c ) 1)]. The H-NMR spectrum was identical with
that described in the literature.18
3-Ben zyltetr a h yd r ofu r a n -4-on e (22): 1H-NMR δ 2.65 (dd,
J ) 10.0, 13.8 Hz, 1 H), 2.78 (m, 1 H), 3.16 (dd, J ) 3.9, 13.8
Hz, 1 H), 3.85 (d, J ) 17.5 Hz, 1 H), 3.86 (d, J ) 8.7 Hz, 1 H),
4.07 (d, J ) 17.2 Hz, 1 H), 4.31 (t, J ) 8.7 Hz, 1 H); 13C-NMR δ
33.5, 48.8, 71.2, 71.8, 126.7, 128.6, 128.7, 138.5, 215.7; MS m/z
176 (M•+). This compound proved to be rather unstable,
decomposing substantially within a matter of hours on standing
at room temperature, preventing obtainment of microanalytical
or HRMS data.
Rea ction of 12 w ith Allyltr ibu tylsta n n a n e: 3-(3-Bu te-
n yl)ch r om a n on e (18). A solution of 12 (136 mg, 0.30 mmol),
allyltributylstannane (387 mg, 1.20 mmol), and AIBN (10 mg,
0.06 mmol) in benzene (1.5 mL) was heated to reflux under Ar.
After 6 h another portion of AIBN (5 mg, 0.03 mmol) was added,
and heating was continued for a total of 10 h. After the mixture
was cooled to room temperature, the solvent was removed under
reduced pressure and the residue taken up with CH2Cl2 (1 mL)
and treated with Et3N (50 µL). Column chromatography on
silica gel (eluent: hexane/CH2Cl2, 1/1) gave 18 (34 mg, 56%), a
colorless oil, and 16 (6 mg, 10%). 18: 1H-NMR δ 1.51-1.64 (m,
1 H), 1.96-2.08 (m, 1 H), 2.13-2.29 (m, 2 H), 2.66-2.75 (m, 1
H), 4.27 (dd, J ) 11.4, 8.7 Hz, 1 H), 4.53 (dd, J ) 11.4, 4.4 Hz,
1 H), 5.00-5.11 (m, 2 H), 5.81 (ddt, J ) 17.0, 10.3, 6.6 Hz, 1 H),
6.95 (d, J ) 8.2 Hz, 1 H), 7.02 (dt, J ) 0.9, 7.5 Hz, 1 H), 7.47 (m,
1 H), 7.89 (dd, J ) 1.8, 7.8 Hz, 1 H); 13C-NMR δ 25.3, 30.9, 45.0,
70.2, 115.8, 117.6, 120.5, 121.3, 127.3, 135.5, 137.4, 161.3, 194.4.
Anal. Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C, 76.89;
H, 6.96.
2,3-Dih yd r oben zoth iop h en e (24):22 1H-NMR δ 3.27-3.38
(m, 4 H), 7.00 (t, J ) 7.3 Hz, 1 H), 7.11 (t, J ) 7.3 Hz, 1 H), 7.20
(t, J ) 8.2 Hz, 2 H).
2,3-Dih yd r o-3,3-d im eth ylben zoth iop h en e (25):23 1H-NMR
δ 1.37 (s, 6 H), 3.17 (s, 2 H), 7.04-7.20 (m, 4 H).
Ack n ow led gm en t. We are grateful to the NIH
(Grant CA60500) for support of this work. D.C. is a
Fellow of the A. P. Sloan Foundation and Q.Y. a Dean’s
Scholar of the University of Illinois at Chicago.
3-Meth ylch r om a n on e (16):5e 1H-NMR δ 1.22 (d, J ) 7.0 Hz,
3 H), 2.87 (m, 1 H), 4.15 (t, J ) 11.1 Hz, 1 H), 4.50 (dd, J ) 5.1,
11.3 Hz, 1 H), 6.96 (bd, J ) 8.5 Hz, 1 H), 7.01 (dt, J ) 1.0, 7.5
Hz, 1 H), 7.46 (m, 1 H), 7.90 (dd, J ) 1.7, 7.9 Hz, 1 H).
2-Meth ylin d a n on e (19):21 1H-NMR δ 1.32 (d, J ) 7.3 Hz, 3
H), 2.69-2.77 (m, 2 H), 3.41 (dd, J ) 8.6, 17.8 Hz, 1 H), 7.37 (t,
J ) 7.4 Hz, 1 H), 7.45 (d, J ) 7.7 Hz, 1 H), 7.59 (dt, J ) 1.0, 7.4
Hz, 1 H), 7.76 (d, J ) 7.6 Hz, 1 H).
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H- and
13C-NMR spectra of 22 (2 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 O960115E
3â,24-Dia cetoxy-28-n or olea n -12-en e (21): mp 77-78 °C
(MeOH); [R]D ) +79° (c ) 1.2, CHCl3) [lit.18 mp 114-115 °C;
(22) Crow, W. D.; McNab, H. Aust. J . Chem. 1979, 32, 99.
(23) Spruce, L. W.; Gale, J . B.; Berlin, K. D.; Verma, A. K.; Breitma,
T. R.; J i, X.; van der Helm, D. J . Med. Chem. 1991, 34, 430.
(21) Baddeley, G.; Rasburn, J . W.; Rose, R. J . Chem. Soc. 1958, 3168.