Intramolecular conjugate addition of alkenyl and aryl functions to enones initiated by lithium-iodine exchange

Article abstract of DOI:10.1021/ol016288u

Equation presented Treatment of each of the substrates 20-26, 29, and 46-48 with t-BuLi in THF, in the presence of HMPA and TMSCI, provides good-to-excellent yields of the intramolecular conjugate addition products 30-36, 37, and 49-51, respectively.

Full text of DOI:10.1021/ol016288u

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3245-3247
Intramolecular Conjugate Addition of
Alkenyl and Aryl Functions to Enones
Initiated by Lithium−Iodine Exchange
Edward Piers,* Cristian L. Harrison, and Carlos Zetina-Rocha
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, British Columbia, Canada V6T 1Z1
epier@interchange.ubc.ca
Received June 15, 2001
ABSTRACT
Treatment of each of the substrates 20−26, 29, and 46−48 with t-BuLi in THF, in the presence of HMPA and TMSCl, provides good-to-excellent
yields of the intramolecular conjugate addition products 30−36, 37, and 49−51, respectively.
A previous report1 from this laboratory described a new
procedure for the efficient, diastereoselective preparation of
alkyl (Z)-3-iodoalk-2-enoates from alkyl alk-2-ynoates. For
example (Scheme 1), treatment (115 °C, 1.5 h) of ethyl but-
This experimentally simple protocol is general, and esters
52 and 6, which are also employed in the current study, are
easily prepared from alkynoates 23 and 3,4 respectively.
Reduction of esters 4-6 with DIBALH, followed by reaction
of the resultant alcohols 7-9 with Ph3P‚Br2 in the presence
of imidazole,5 provides the iodo bromides 10-12, respec-
tively. We reasoned that substances such as 10-12 could
serve as effective synthetic equivalents of synthons of general
structure 13, which, when combined with synthons 14 as
shown schematically in eq 1, would produce bicycles 15. It
turns out that this idea can readily be put into practice and,
accordingly, annulation products of general structure 15 can
be produced efficiently. The final step of the overall process
involves a newly developed method for effecting intramo-
lecular conjugate addition of alkenyl functions to R,â-
unsaturated ketones.
Scheme 1
The substrates employed in this study were prepared via
(2) All new compounds reported herein exhibited spectra (IR and 1H
and 13C NMR) in accord with assigned structures and gave satisfactory
elemental (C, H) combustion analyses and molecular mass determinations
(high-resolution mass spectrometry).
(3) Piers, E.; Chong, J. M.; Morton, H. E. Tetrahedron 1989, 45, 363.
(4) Sauer, D. R.; Schneller, S. W.; Gabrielsen, B. Carbohydr. Res. 1993,
241, 71.
2-ynoate (1) with a suspension of NaI (1.6 equiv) in a small
amount of HOAc (6.4 equiv) provided enoate 4 in 98% yield.
(1) Piers, E.; Wong, T.; Coish, P. D.; Rogers, C. Can. J. Chem. 1994,
72, 1816.
(5) Wiley, G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. J. Org.
Chem. 1964, 86, 964.
10.1021/ol016288u CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/18/2001

Table 1. Intramolecular Conjugate Additions of Alkenyl
Functions Initiated by Lithium-Iodine Exchange
an efficacious method,6 employing the â-alkoxy enones 16,
17, and 18 as starting materials. For example, alkylation of
16 with bromide 10 afforded 19, which, upon sequential
subjection to reduction and acid hydrolysis, gave enone 20
(Scheme 2). On the other hand, reaction of 19 with MeMgBr,
Scheme 2
ketone 309 (see Table 1, entry 1). A number of experimental
parameters were investigated, including (a) the nature of the
alkyllithium reagent used to effect lithium-iodine exchange,
(b) the use of the additives HMPA and TMSCl, and (c) the
reaction time and temperature. It was found that, although
either BuLi or t-BuLi could be profitably employed, the latter
reagent generally gave superior results (cleaner reactions,
better yields) and, consequently, was used throughout the
remainder of this study. It was also found that both HMPA
and TMSCl had (independent) salutary effects on the yields
of 30 and, when used together, further enhanced reaction
efficiency. Finally, the most efficient transformations were
realized when a t-BuLi solution was added to a cold (-78
°C), stirred solution of substrate 20, dry HMPA, and freshly
distilled TMSCl in THF. Thus, these exploratory investiga-
tions led to the development of an experimental procedure10
that consistently produced good-to-excellent yields of the
conjugate addition products. The results derived from use
of substrates 20-26 and 29 are summarized in Table 1.
A perusal of the data given in Table 1 shows that, not
unexpectedly, the placement of an alkyl group on the
â-carbon on the enone acceptor function has a (minor)
deleterious effect on reaction efficiency (cf. entries 1 and
2). On the other hand, the cyclization process appears to
followed by acid hydrolysis of the product, provided 21. In
a similar fashion, each of the enones 22-26 was prepared
by use of the appropriate vinylogous ester (16, 17, or 18)
and the required alkylating agent (10 11, or 12). Finally, the
cyclopentenone substrate 29 was analogously derived from
the enone 277 and the allylic bromide 10 (Scheme 2).
Preliminary experiments toward effecting intramolecular
conjugate additions initiated by lithium-iodine exchange8
involved conversion of substrate 20 into the known bicyclic
(10) The following procedure, involving conversion of 20 into 30, is
typical. A solution of 20 (99 mg, 0.36 mmol), dry HMPA (146 µL, 0.84
mmol), and freshly distilled TMSCl (203 µL, 1.6 mmol) in dry THF (5
mL), under an atmosphere of argon, was stirred at room temperature for 5
min and then was cooled to -78 °C. The cold solution was treated with
t-BuLi (1.4 M solution in pentane, 600 µL, 0.84 mmol) and, after the mixture
had been stirred for 5 min, it was warmed to room temperature over a period
of 15 min. The mixture was treated with 1 mL of water and then was stirred
for 1 h. The phases were separated, and the aqueous phase was extracted
with Et2O (3 × 5 mL). The combined organic extracts were washed (brine),
dried (MgSO4), and concentrated under reduced pressure. Flash chroma-
tography (6 g of silica gel, 4:1 petroleum ether-Et2O) of the crude oil
afforded 49 mg (91%) of pure 30 as a colorless oil.
(6) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775. Stork, G.;
Danheiser, R. L.; Ganem, B. J. Am. Chem. Soc. 1973, 95, 3414.
(7) Panouse, J.; Sanie´, C. Bull. Soc. Chim. Fr. 1956, 1272.
(8) For related studies, see: Cooke, M. P., Jr.; Widener, R. K. J. Org.
Chem. 1987, 52, 1381.
(9) Piers, E.; McEachern, E. J.; Burns, P. A. Tetrahedron 2000, 56, 2753.
3246
Org. Lett., Vol. 3, No. 21, 2001

1, 3, 4, and 6). The examples in which R1 ) CH2OBn (entries
4 and 6) are particularly satisfying, since the ether function
provides a “handle” for subsequent synthetic manipulations.
Finally, the efficient synthesis of the rather strained bicyclo-
[3.3.0]oct-6-en-3-one 37 is also noteworthy (entry 8).
The successful methodological work outlined above led
us to study the possibility of effecting similar intramolecular
conjugate additions of aryl functions to enones. The syn-
theses of the chosen substrates 46-48 and subsequent
conjugate addition results are summarized in Scheme 3.
Directed ortho-metalation11 of 3-methoxybenzyl alcohol (39)
and 1-naphthylmethanol (40), followed by reaction of the
acquired aryllithium intermediates with iodine, afforded
alcohols 41 and 42, respectively. Treatment of each of the
alcohols 38,12 41, and 42 with Ph3P‚Br2-imidazole in
dichloromethane provided the corresponding benzylic bro-
mides 43-45, which, when employed as alkylating agents
in reaction sequences very similar to those summarized in
Scheme 2 (see 16 f 19 f 20), furnished the enones 46-
48, respectively.
Scheme 3
When compound 46 was subjected to reaction conditions
essentially identical with those developed for the ring closure
of substrates 20-26 and 29 (Table 1), the tricycle 49 was
produced in 80% yield (Scheme 3). Similarly, the intramo-
lecular conjugate addition reactions involving substrates 47
and 48 were readily performed and efficiently provided the
structurally novel substances 50 and 51, respectively.
In summary, a new protocol for effecting intramolecular
conjugate additions of alkenyl and aryl functions to enone
acceptors has been developed. The chemistry involved is
relatively simple, and it is clear that the method could readily
be employed for the construction of structurally diverse bi-,
tri-, and tetracyclic compounds.
Acknowledgment. We are very grateful to NSERC of
Canada for financial support and to Fonds FCAR (Que´bec)
for a Predoctoral Fellowship (to C.L.H.).
Supporting Information Available: Procedures for the
preparation of and characterization data for all new organic
intermediates and products. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL016288U
(11) Snieckus, V. Chem. ReV. 1990, 90, 879 and citations therein.
(12) Stara´, I. G.; Stary, I.; Kolla´rovic, A.; Teply, F.; Saman, D.; Fiedler,
P. Tetrahedron 1998, 54, 11209.
tolerate structurally diverse groups on the alkenyl carbon that
is involved in the lithium-iodine exchange process (entries
Org. Lett., Vol. 3, No. 21, 2001
3247