Chelation-assisted intramolecular hydroacylation: Synthesis of medium ring sulfur heterocycles

Article abstract of DOI:10.1016/S0040-4039(02)01552-6

Medium ring sulfur heterocycles are prepared from ω-alkenals and alkynals containing a sulfur tether atom via a novel chelation-assisted intramolecular hydroacylation catalyzed by rhodium(I).

Full text of DOI:10.1016/S0040-4039(02)01552-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7031–7034
Chelation-assisted intramolecular hydroacylation: synthesis of
medium ring sulfur heterocycles
Holly D. Bendorf,* Christine M. Colella, Elizabeth C. Dixon, Melissa Marchetti,
Alicia N. Matukonis, Jeffrey D. Musselman and Tara A. Tiley
Department of Chemistry, Lycoming College, Williamsport, PA 17701, USA
Received 5 July 2002; accepted 26 July 2002
Abstract—Medium ring sulfur heterocycles are prepared from v-alkenals and alkynals containing a sulfur tether atom via a novel
chelation-assisted intramolecular hydroacylation catalyzed by rhodium(I). © 2002 Elsevier Science Ltd. All rights reserved.
Rhodium-catalyzed intramolecular hydroacylation is an
attractive synthetic tool because the yields of cyclized
products are high, the reaction conditions are mild, and
a variety of functional groups are tolerated.1 4-Pente-
nals are converted to cyclopentanones via the mecha-
nism outlined in Scheme 1. Extensions of this chemistry
include asymmetric hydroacylation of substituted 4-
pentenals using rhodium(I) catalysts with chiral diphos-
phine ligands2 and hydroacylation of 4-pentynals to
produce cyclopentenones.3 Until recently, attempts to
synthesize rings containing more than five atoms via
intramolecular hydroacylation have been unsuccessful
as ring closure to form the requisite medium ring
metallcycle intermediates is kinetically unfavorable and
competing reactions such as decarbonylation prevail.4
5-Hexenals undergo hydroacylation, but yield 2-methyl-
O
O
O
O
Ln
Rh
-RhLn
RhLn
LnRh
H
H
1
2
3
4
Scheme 1.
O
CHO
5-10 mol % Rh(PPh3)3Cl
S
n
CH2Cl2
rt, 4-12 hr
S
n
5
8
RhLn
-RhLn
O
O
H
Ln
RhLn
S
Rh
S
n
n
7
6
Scheme 2.
* Corresponding author. Tel.: (570) 321-4365; fax: (570) 321-4073; e-mail: bendorf@lycoming.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01552-6

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H. D. Bendorf et al. / Tetrahedron Letters 43 (2002) 7031–7034
COOH
SH
CH2OH
SH
CHO
a
b, c
S
9
10
11
Scheme 3. Reagents and conditions: (a) LiAlH4, THF, 89%; (b) 4-bromo-1-butene, DBU, benzene, 93%; (c) MnO2, benzene, 76%.
cyclopentanones instead of cyclohexanones; and 6,7-
unsaturated aldehydes such as citronellal do not
undergo hydroacylation.1b Strategies aimed at the syn-
thesis of medium rings must avoid direct ring closure to
medium ring metallacycle intermediates. For example,
cyclooctenones have been prepared via hydroacylation
of 5-cyclopropyl-4-pentenals, which initially produce
six-membered metallacycles upon reaction with the
rhodium catalyst.5 Ring expansion affords the nine-
membered intermediate metallacycle which yields the
Table 1.

H. D. Bendorf et al. / Tetrahedron Letters 43 (2002) 7031–7034
7033
O
acylation of internal alkynes were generally obtained in
higher yield than those obtained from terminal alkynes
with the same cyclization trends as observed for the
alkene substrates (entries 6–9). The difference in yield is
attributed to the greater reactivity of the methylidene
products toward nucleophilic attack or dimerization as
compared to the more hindered ethylidene products.14
Comparison of entries 2 and 10 suggests that the system
is sensitive to the distance between the sulfur tethering
atom and the aldehyde. 1,1- and 1,2-Disubstituted alke-
nes do not undergo cyclization as illustrated by entries
11 and 12. However, substitution alpha to sulfur does
not negatively affect the reaction (entry 9). The failure
of substrates 13a and b (Scheme 4) to cyclize suggests
that coordination of the Lewis-basic tether atom is a
prerequisite for hydroacylation and that the choice of
heteroatom is crucial.
CHO
X
X
13
a, X = O
b, X = CH2
14
Scheme 4.
cyclooctenone product upon reductive elimination of
the metal.
Efforts in our laboratory have focused on exploiting a
chelation-assisted6 approach for the synthesis of
medium ring heterocycles (Scheme 2). The hydroacyl-
ation substrates, 5, are v-alkenals and alkynals that
possess a Lewis basic tether atom, such as sulfur.
Coordination of both the tether atom and the alkene or
alkyne to the metal center and oxidative addition of the
aldehyde, likely affords metallabicyclic intermediate, 6,
avoiding direct ring closure to medium ring metallacy-
cles. Subsequent insertion of the alkene or alkyne into
the RhꢀH bond and reductive elimination affords the
heterocyclic product. A series of sulfur-containing sub-
strates has been prepared and subjected to hydro-
acylation conditions affording dihydrobenzothiepinones,
dihydrobenzothiocinones, and related compounds in
moderate to high yields.7 The chemistry presented in
this letter offers a facile route into these ring systems
and is, to the best of our knowledge, the first example
of heterocycle synthesis via hydroacylation.
In summary, the results presented here demonstrate
that medium ring heterocycles can be prepared via a
chelation-assisted intramolecular hydroacylation, pro-
vided a suitable tether atom is present and correctly
positioned relative to the alkene and aldehyde func-
tional groups. Future work will explore the use of
functional groups other than sulfides to provide a tether
atom and expand the range of heterocycles available by
this methodology.
Acknowledgements
Acknowledgement is made to the donors of the
Petroleum Research Fund, administered by the ACS,
for support of this research. The GC–MS used in this
study was funded in part by the National Science
Foundation (DUE-0087767). The authors are indebted
to Dr. Chriss McDonald and Dr. Craig Merlic for
helpful discussions.
Scheme 3 is illustrative of the strategies used to prepare
the substrates. Lithium aluminum hydride reduction of
the commercially available 2-mercaptobenzoic acid, 9,
yields the air-sensitive 2-mercaptobenzyl alcohol, 10,
which can be stored under argon for several months
without appreciable decomposition.8 Alkylation on sul-
fur with the appropriate alkyl halide or mesylate fol-
lowed by MnO2 oxidation yields the hydroacylation
substrate.9,10
References
Hydroacylation experiments were run in methylene
chloride solvent with 5–10 mol% Rh(PPh3)3Cl at room
temperature. Reaction progress was monitored by GC
and reactions were normally complete within 4–12 h as
determined by the absence of starting material. Solvent
was removed in vacuo and the cyclized product purified
by silica gel chromatography.11
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tions of this reaction are summarized in Table 1.
Entries 1–5 suggest that the distance between the sulfur
atom and the alkene functional group is critical.
Homoallylic and bis-homoallylic sulfides (entries 1–3)
readily undergo hydroacylation to yield seven- and
eight-membered rings, respectively. Cyclization to give
either six- or nine-membered rings did not occur in the
case of the allyl and 5-hexenyl substrates (entries 4, 5).
The failure of the allyl sulfide to cyclize may be
attributed to competitive rhodium-mediated cleavage of
allylꢀsulfur bonds.12,13 Products from the hydro-
3. Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123,
11492–11493.

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H. D. Bendorf et al. / Tetrahedron Letters 43 (2002) 7031–7034
4. An exception where hydroacylation yields a 5–6 fused
argon atmosphere, was added CH2Cl2 (14 mL, distilled
from CaH2) and Rh(PPh3)3Cl (0.017 g, 0.018 mmol). The
orange–yellow solution was stirred overnight, then con-
centrated in vacuo. The crude reaction mixture was sub-
jected to column chromatography (silica gel, 95:5
hexane–ethyl acetate) to yield 4-methyl-3,4-dihydro-2H-
benzo[b]thiepin-5-one (0.064 g, 0.33 mmol, 92%) as a pale
yellow oil. IR (film) w 3056, 2969, 2931, 1679, 1585, 1458,
1431, 1273, 1202, 742 cm−1; 1H NMR (300 MHz, CDCl3),
l 7.82 (1H, ddd, J=7.6, 1.7, 0.4 Hz), 7.46 (1H, ddd,
J=7.8, 1.5, 0.4 Hz), 7.29 (2H, m), 3.63 (1H, m), 3.16 (1H,
ddd, J=14.8, 6.5, 1.3 Hz), 2.75 (1H, ddd, J=14.8, 13.6,
5.5 Hz), 2.29 (1H, m), 2.00 (1H, m), 1.25 (3H, d, J=6.5
Hz); 13C NMR (75 MHz, CDCl3), l 205.7, 142.0, 138.0,
130.6, 130.4, 129.7, 125.6, 43.0, 39.7, 34.2, 15.3; LRMS
(EI) m/z (%): 192 (65), 145 (100), 136 (28), 131 (18), 121
(25), 108 (18); HRMS (EI) m/z: calcd: 192.0608. Found:
192.0599.
ring system in preference to the strained 5–5 system is
found in the work of Gable and Benz: Gable, K. P.;
Benz, G. A. Tetrahedron Lett. 1991, 32, 3473–3476.
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Soc. 2000, 122, 12610–12611.
6. For chelation-assisted intermolecular hydroacylation, see:
(a) Jun, C. H.; Hong, J. B.; Lee, D. Y. Synlett 1999, 1–12;
(b) Jun, C. H.; Lee, H.; Hong, J. B. J. Org. Chem. 1997,
62, 1200–1201.
7. Derivatives of these compounds, most notably the tetra-
hydrobenzothiepines, exhibit diverse biological activity.
For examples, see: (a) Shiraishi, M.; Baba, M.; Aramaki,
Y.; Nishimura, O.; Kanzaki, N. US Patent 6 096 780,
2000; (b) Lee, L. F.; Banerjee, S. C.; Huang, H. C.; Li, J.
J.; Miller, R. E.; Reitz, D. B.; Tremont, S. J. US Patent
5 994 391, 1999; (c) Frick, W.; Enhsen A.; Glombik, H.;
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8. Arnoldi, A.; Carughi, M. Synthesis 1988, 155–157.
9. Ono, N.; Miyake, H.; Saito, T.; Kaji, A. Synthesis 1980,
952–954.
10. Kasmai, H. S.; Mischke, S. G. Synthesis 1989, 763–765.
11. Typical procedure for hydroacylation—entry 1, Table 1:
12. Osakada, K.; Matsumoto, K.; Yamamoto, T.;
Yamamoto, A. Organometallics 1985, 4, 857–862.
13. Propargyl sulfides similarly failed to cyclize.
14. 4-Methylene-1-benzothiepin-5(2H,3H)-one is known to
dimerize: Traynelis, V. J.; Sih, J. C.; Borgnaes, D. M. J.
Org. Chem. 1973, 38, 2629–2637.
To
a
Schlenk tube containing 2-(3-butenylsulf-
anyl)benzaldehyde 11 (0.069 g, 0.36 mmol) under an