Solid-phase approach to tetrahydroquinolones using a sulfur linker cleaved by SmI2

Article abstract of DOI:10.1021/ol052730n

A sulfur α-heteroatom-substituted carbonyl (HASC) linker has been utilized in a solid-phase approach to tetrahydroquinolones. The route illustrates the compatibility of the linker system with palladium-catalyzed transformations and its utility for library synthesis. The linker is cleaved by electron transfer from samarium(II) iodide.

Full text of DOI:10.1021/ol052730n

ORGANIC
LETTERS
2006
Vol. 8, No. 2
329-332
Solid-Phase Approach to
Tetrahydroquinolones Using a Sulfur
Linker Cleaved by SmI2
Kristy L. Turner,† Thomas M. Baker,† Saidul Islam,† David J. Procter,*,† and
Mark Stefaniak‡
The School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester,
M13 9PL, U.K., and Pfizer Global Research & DeVelopment, Sandwich,
Kent, CT13 9NJ, U.K.
DaVid.J.Procter@manchester.ac.uk
Received November 10, 2005
ABSTRACT
A sulfur
r-heteroatom-substituted carbonyl (HASC) linker has been utilized in a solid-phase approach to tetrahydroquinolones. The route
illustrates the compatibility of the linker system with palladium-catalyzed transformations and its utility for library synthesis. The linker is
cleaved by electron transfer from samarium(II) iodide.
Solid-phase synthesis remains a powerful tool for synthetic
organic chemists. The development of versatile linker designs
is important for continued advancements in the area.1 We
have previously described a new traceless linker strategy for
solid-phase organic synthesis where the link to resin is
cleaved using samarium(II) iodide (SmI2).2 We refer to this
family of linkers as HASC (R-heteroatom-substituted car-
bonyl) linkers. We originally focused on an ether-based
HASC linker3 but have begun to explore the considerable
potential of sulfur-based HASC linkers. For example, R-sul-
fanyl N-aryl acetamides, attached to resin via the sulfur atom,
undergo efficient Pummerer cyclization upon activation of
the sulfur link, to give oxindoles. Heterocyclic products can
then be cleaved from the support in a traceless manner using
SmI2 (Scheme 1).4
Scheme 1
† University of Manchester.
‡ Pfizer Global Research & Development.
(1) For recent reviews on linkers and cleavage strategies for solid-phase
organic synthesis, see: (a) James, I. W. Tetrahedron 1999, 55, 4855. (b)
Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091. (c)
McAllister, L. A.; McCormick, R. A.; Procter, D. J. Tetrahedron 2005, 61,
11527.
(2) For reviews on the use of samarium(II) iodide in organic synthesis,
see: (a) Soderquist, J. A. Aldrichimica Acta 1991, 24, 15. (b) Molander,
G. A. Chem. ReV. 1992, 92, 29. (c) Molander, G. A. Org. React. 1994, 46,
211. (d) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307. (e)
Molander, G. A.; Harris C. R. Tetrahedron 1998, 54, 3321. (f) Kagan, H.;
Namy, J. L. In Lanthanides: Chemistry and Use in Organic Synthesis;
Kobayashi, S., Ed.; Springer: New York, 1999; p 155. (g) Krief, A.; Laval,
A.-M. Chem. ReV. 1999, 99, 745. (h) Steel, P. G. J. Chem. Soc., Perkin
Trans. 1 2001, 2727. (i) Kagan, H. B. Tetrahedron 2003, 59, 10351. (j)
Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004, 104, 3371.
In our approach, the linking sulfur atom operates in a
multifunctional sense, mediating C-C bond formation during
(3) (a) McKerlie, F.; Procter, D. J.; Wynne, G. Chem. Commun. 2002,
584. (b) McKerlie, F.; Rudkin, I. M.; Wynne, G.; Procter, D. J. Org. Biomol.
Chem. 2005, 3, 2805.
10.1021/ol052730n CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/24/2005

and after heterocycle formation, in addition to its fundamental
role as a link to the support.4
In this letter, we further explore the potential of our linker
system in an approach to tetrahydroquinolones.
The tetrahydroquinolone framework can be found in many
natural and nonnatural biologically active compounds and
is therefore an attractive scaffold for synthesis (Figure 1).5
were prepared in which the benzyl sulfanyl group mimics a
benzylic sulfur resin. Although few Heck reactions of N-R-
halophenylamides and carbamates have been reported,6 both
5 and 6 underwent efficient Heck coupling in o-xylene with
tert-butyl acrylate under microwave conditions. Oxidation
of 7 and 8 to the corresponding sulfones and treatment with
K2CO3 gave the anti-tetrahydroquinolones 9 and 10 in good
yield. The relative stereochemistry of 9 and 10 was confirmed
by X-ray crystallography.7 The cleavage reaction was next
investigated in the model system. We have previously shown
that cleavage of the linker can be carried out at both the
sulfide and sulfone oxidation levels.4 Treatment of 9 and 10
with SmI2 using LiCl as a promotor8 gave the expected
products in moderate, unoptimized yields. Further modifica-
tion of 9 was readily achieved by alkylation to give 13, the
relative stereochemistry of which was confirmed by X-ray
crystallography.7 Cleavage using SmI2/LiCl gave 14 as a
∼1:1 mixture of diastereoisomers. Interestingly, the use of
t-BuOH as a proton source in the reduction gave syn-14 as
the major product (5:1 diastereoisomeric ratio) (Scheme 3).
Scheme 3
Figure 1. Tetrahydroquinolone framework.
Our proposed, solid-phase approach to tetrahydroquinolones
1 is outlined in Scheme 2. Heck reactions of immobilized
Scheme 2
The relative stereochemistry of the major diastereoisomer
was confirmed by X-ray crystallography.7
(5) (a) Patel, M.; McHugh, R. J., Jr.; Cordova, B. C.; Klabe, R. M.;
Bacheler, L. T.; Erickson-Viitanen, S.; Rodgers, J. D. Biorg. Med. Chem.
Lett. 2001, 11, 1943. (b) Hayashi, H.; Miwa, Y.; Miki, I.; Ichikawa, S.;
Yoda, N.; Ishii, A.; Kono, M.; Suzuki, F. J. Med. Chem. 1992, 35, 4893.
(c) Carling, R. W.; Leeson, P. D.; Moore, K. W.; Smith, J. D.; Moyes, C.
R.; Mawer, I. M.; Thomas, S.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood,
S.; Kemp, J. A.; Marshall, G. R.; Tricklebank, M. D.; Saywell, K. L. J.
Med. Chem. 1993, 36, 3397. (d) Christopher, E.; Bedir, E.; Dunbar, C.;
Khan, I. A.; Okunji, C. O.; Schuster, B. M.; Iwu, M. M. HelV. Chim. Acta
2003, 86, 2914. (e) Ito, C.; Itoigawa, M.; Otsuka, T.; Tokuda, H.; Nishino,
H.; Furukawa, H. J. Nat. Prod. 2000, 63, 1344.
aryl halides 4 with electron-deficient alkenes should allow
access to key intermediates 3. Base-mediated cyclization will
then furnish the tetrahydroquinolone core 2 which can be
modified before cleavage from the support.
We began our studies by evaluating the route using a
solution-phase model system. R-Sulfanyl amides 5 and 6
(6) For an example, see: Arnold, L. A.; Luo, W.; Guy, R. K. Org. Lett.
2004, 6, 3005.
(7) See Supporting Information for X-ray structures and CCDC num-
bers.
(4) (a) McAllister, L. A.; Brand, S.; de Gentile, R.; Procter, D. J. Chem.
Commun. 2003, 2380. (b) McAllister, L. A.; McCormick, R. A.; Brand, S.;
Procter, D. J. Angew. Chem., Int. Ed. 2005, 44, 452.
330
Org. Lett., Vol. 8, No. 2, 2006

Satisfied that our approach was feasible, we moved on to
the solid phase. Benzyl thiol resin 159 was prepared, and
the loading was determined to be approximately 0.54 mmol
g-1.4 An early reaction sequence on the solid phase is shown
in Scheme 4.
Table 1. Optimizing the Heck Reaction
Scheme 4
a Pd(OAc)2 (5 mol %) and P(o-Tol)3 (5 mol %) NEt3. b Isolated yields.
Immobilization of R-bromoamide 16 gave amide 17. A
microwave-assisted Heck reaction with tert-butyl acrylate
was unsatisfactory using o-xylene because of poor swelling
of the resin and gave low conversion as indicated by FTIR.
The use of a DMF/o-xylene solvent mixture in the Heck
reaction appeared to solve this issue and gave 18. Cyclization
then gave supported tetrahydroquinolone 19. As expected,
treatment of 19 with SmI2/LiCl gave 11, although in a
disappointing overall yield of 15% (for five steps). The
isolation of amide byproducts 20 and 21 indicated that the
Heck reaction was not proceeding efficiently on the solid
phase.10 A more detailed solution-phase study on the pivotal
Heck reaction was therefore carried out to provide improved
conditions for use on the solid phase (Table 1). Although
o-xylene was an excellent solvent for the Heck reaction, in
solution it was clearly unsuitable for use on the solid phase.11
The use of a combination of DMF and o-xylene (3:7) gave
lower conversion (entry 3). In neat DMF, a more suitable
solvent for solid-phase reactions, conversion was acceptable
particularly after a retreatment (entries 4 and 5).
Pleasingly, employing these conditions gave 11 in an
improved 27% overall yield after purification (Figure 2). We
The improved Heck coupling conditions were applied in
the solid-phase sequence with the additional modification
that m-CPBA was used for oxidation to the sulfone.12
(8) (a) Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A., II.
Tetrahedron Lett. 1997, 38, 8157. (b) Miller, R. S.; Sealy, J. M.; Shabangi,
M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A., II. J. Am. Chem. Soc.
2000, 122, 7718. (c) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem.
Soc., Perkin Trans. 1 1999, 1295.
Figure 2. Starting materials and tetrahydroquinolone products.
(9) Kobayashi, S.; Hachiya, I.; Suzuki, S.; Moriwaki, M. Tetrahedron
Lett. 1996, 37, 2809.
(10) The debrominated product 21 most likely results from SmI2 reduction
during the cleavage step, although it is possible that reduction of the aryl
bromide occurs under the conditions of the Heck reaction.
(11) The use of JandaGel, a support more suitable for use with nonpolar
solvents such as o-xylene, also gave 11 in low yield.
(12) The use of oxone for the oxidation caused problems with inorganic
byproducts contaminating the resin after washing. Solution-phase oxidation
of sulfide 7 with m-CPBA gave the corresponding sulfone in 71% yield
(m-CPBA, K2CO3, CH2Cl2, 2 h, room temperature). Longer reaction times
led to some epoxidation of the electron-deficient alkene.
have utilized the approach to prepare a collection of
tetrahydroquinolones using R-bromoamide starting materials
16 and 22-25. Additional diversity was introduced by the
Heck reaction with a different olefin and by alkylation of
an intermediate sulfone.
The expected products were obtained in satisfactory overall
yields for five and six steps on the solid phase. Aryl iodide
22 gave improved yields due to more efficient Heck
Org. Lett., Vol. 8, No. 2, 2006
331

reactions. Alkylations of intermediate sulfones proved to be
more difficult than solution models had predicted, and more
forcing conditions were necessary (50 °C, KI). Products 27
and 28 were obtained with little diastereoselectivity possibly
because of residual moisture in the resin acting as an
alternative proton source to the added t-BuOH (Figure 2).
Finally, we have investigated the feasibility of a cyclative
cleavage strategy using the HASC linker. Pleasingly, treat-
ment of sulfone 31 with SmI2 resulted in cleavage of the
sulfur linkage and cyclization to give 26 in moderate overall
yield (Scheme 5).13
In summary, we have developed a solid-phase approach
to tetrahydroquinolones using a HASC sulfur linker cleaved
using SmI2. The route involves a Heck reaction and a
Michael cyclization as the key steps. Our studies illustrate
the compatibility of sulfur HASC linkers with palladium-
catalyzed transformations and also provide a further illustra-
tion of the multifunctional roles possible using sulfur linkers.
Acknowledgment. We thank the EPSRC and Pfizer for
an Industrial CASE award (K.L.T.), AstraZeneca and Pfizer
for additional untied funding which was used to support
undergraduate project students (T.M.B. and S.I.), Dr. D.
Apperley at the EPSRC Solid State NMR facility for MAS
NMR, and Prof. M. Helliwell (Manchester) and Dr N. Feeder
(Pfizer) for X-ray crystallographic studies.
Scheme 5
Supporting Information Available: Experimental pro-
1
cedures and data for all new compounds, H and 13C NMR
and 13C MAS NMR and IR spectra, and X-ray structures
and crystallographic data for 9, 10, 13, and 14. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL052730N
(13) The cyclization may be either a radical or an anionic process.
332
Org. Lett., Vol. 8, No. 2, 2006