Samarium(II) - mediated linker cleavage - cyclization in fluorous synthesis: Reactions of samarium enolates

Article abstract of DOI:10.1021/ol800070y

Sml₂ has been used to cleave a sulfur linker and trigger cyclizations in strategies for the traceless fluorous synthesis of N-heterocycles. The studies give further Insights Into the reactivity of samarium enolates.

Full text of DOI:10.1021/ol800070y

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1203-1206
Samarium(II)
−Mediated Linker
Cleavage Cyclization in Fluorous
−
Synthesis: Reactions of Samarium
Enolates
Karen M. James,† Nigel Willetts,‡ and David J. Procter*,†
The School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester,
M13 9PL, and Syngenta, Jealott’s Hill International Research Centre, Bracknell,
Berkshire, RG42 6EY, U.K.
daVid.j.procter@manchester.ac.uk
Received January 11, 2008
ABSTRACT
SmI2 has been used to cleave a sulfur linker and trigger cyclizations in strategies for the traceless fluorous synthesis of N-heterocycles. The
studies give further insights into the reactivity of samarium enolates.
Samarium(II) iodide (SmI2) is a one-electron reducing agent
that has found widespread use in organic synthesis.1 The
reagent has been used to mediate many processes ranging
from functional group interconversions to complex carbon-
carbon bond-forming sequences.1 Cyclization reactions are
among the most useful transformations mediated by SmI2,
and these have been used extensively in natural product
synthesis.1j
The development of versatile linker designs is important
for continued advancements in high-throughput synthesis.2
We have previously described a traceless linker strategy for
phase tag-assisted synthesis where the link to the tag is
3
cleaved using SmI2 and have illustrated the utility of the
(2) For 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) Bra¨se, S.;
Dahmen, S. Chem. Eur. J. 2000, 6, 1899. (d) McAllister, L. A.; McCormick,
R. A.; Procter, D. J. Tetrahedron 2005, 61, 11527. (e) Scott, P. J. H.; Steel,
P. G. Eur. J. Org. Chem. 2006, 2251.
† University of Manchester.
‡ Syngenta, Jealott’s Hill International Research Centre.
(1) For reviews on the use of SmI2 in organic synthesis: (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. Lan-
thanides: Chemistry and Use in Organic Synthesis; Kobayashi, S., Ed.;
Springer: Berlin, 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. (k) Dahle´n, A.; Hilmersson,
G. Eur. J. Inorg. Chem. 2004, 3393.
(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. (c) McAllister, L. A.; Brand, S.; de Gentile, R.;
Procter, D. J. Chem. Commun. 2003, 2380. (d) Turner, K. L.; Baker, T.
M.; Islam, S.; Procter, D. J.; Stefaniak, M. Org. Lett. 2006, 8, 329. (e)
McAllister, L. A.; Turner, K. L.; Brand, S.; Stefaniak, M.; Procter, D. J. J.
Org. Chem. 2006, 71, 6497. (f) McAllister, L. A.; McCormick, R. A.; Brand,
S.; Procter, D. J. Angew. Chem., Int. Ed. 2005, 44, 452. (g) McAllister, L.
A.; McCormick, R. A.; James, K. M.; Brand, S.; Willetts, N.; Procter, D.
J. Chem. Eur J. 2007, 13, 1032. (h) McCormick, R. A.; James, K. M.;
Willetts, N.; Procter, D. J. QSAR Comb. Sci. 2006, 25, 709.
10.1021/ol800070y CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/16/2008

linker for the solid phase3a-e and fluorous3f-h synthesis of
N-heterocycles. In phase tag-assisted synthesis, extra steps
to introduce and remove the phase tag are unavoidable. It is
desirable to gain more synthetic value from these steps by
using the construction of the linker and its cleavage to trigger
other reactions that result in the construction of valuable
motifs such as heterocyclic rings (Scheme 1).
to build product scaffolds in a traceless6 fashion while
introducing diversity during the removal of the tag (see
Scheme 1).
We wished to investigate the formation of heterocyclic
rings in cleavage-cyclization reactions using SmI2. An
additional aim was to improve our understanding of the
reactivity of samarium enolates.
We began by studying the formation of heterocycles using
a carbon-carbon bond-forming process triggered by the
removal of the tag. Fluorous-tagged oxindoles 3 and 4 were
modified conveniently by alkylation with divinylsulfone and
DBU to give adducts 5 and 6 in high yield after purification
by fluorous solid-phase extraction (FSPE)7 (Scheme 3). We
Scheme 1
Scheme 3
For example, in our fluorous4 approach, we have devel-
oped a Pummerer-type process5 that allows the fluorous tag
to be introduced, a heterocycle to be constructed, and the
linker system to be established in a one-pot reaction (Scheme
2). After modification of the heterocyclic scaffold, treatment
Scheme 2
envisaged that treatment of 5 and 6 with SmI2 would result
in cleavage of the tag and addition of the resultant reactive
intermediate to the electron-deficient alkene,8 thus generating
a quaternary center where the tag had been located. Pleas-
ingly, treatment with SmI2 gave unusual spirocyclic sulfones
7 and 8 in 62% and 40% yields, respectively (Scheme 3).
The structure of 8 was confirmed by X-ray crystallography.9
As expected, the reduction of 5 in the presence of a proton
source (MeOH) resulted in protonation of the Sm-enolate
intermediate and the isolation of 9 in 72%. When the reaction
of 5 with SmI2 was carried out at higher concentrations (35
vs 10 mM), 10 was isolated as a byproduct (12%) in addition
to 7 (40%). Sulfide 10 arises from removal of the fluorous
tag and its reintroduction via Sm(III) thiolate addition to the
vinylsulfone group (Scheme 3).
of a fluorous-tagged intermediate, such as 1, with SmI2,
releases 2 in high yield.3f,g The cleavage of the linker
proceeds by electron transfer to form a radical intermediate
that is then reduced to a Sm(III)-enolate before protonation
to give products such as 2.
In this Letter, we describe our attempts to construct cyclic
motifs by exploiting the intermediates or products formed
upon removal of the fluorous tag. We envisaged that a
portfolio of cleavage-cyclization processes would allow us
(4) For a discussion of fluorous tagging, see: (a) Studer, A.; Hadida,
S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997,
275, 823. For recent reviews, see: (b) Curran, D. P. In The Handbook of
Fluorous Chemistry; Gladysz, J. A., Curran, D. P., Horva´th, I. T., Ed.;
Wiley-VCH: Weinheim, 2004. (c) Zhang, W. Tetrahedron 2003, 59, 4475.
(d) Zhang, W. Chem. ReV. 2004, 104, 2531.
(6) Comely, A. C.; Gibson, (ne´e Thomas), S. E. Angew. Chem., Int. Ed.
Engl. 2001, 40, 1012.
(7) Curran, D. P.; Luo, Z. J. Am. Chem. Soc. 1999, 121, 9069. See also
ref 4.
(8) Spirocyclic sulfones 7 and 8 could form by a radical or anionic
pathway.
(5) Miller, M.; Tsang, W.; Merritt, A.; Procter, D. J. Chem. Commun.
2007, 498.
(9) See Supporting Information for X-ray crystallographic data and
CCDC number.
1204
Org. Lett., Vol. 10, No. 6, 2008

We have also investigated a cleavage-cyclization process
that constructs a heterocyclic ring through the formation of
carbon-heteroatom bonds. Alkylation of fluorous-tagged
oxindole 11 with 2-nitrobenzyl bromide gave 12 in 92% yield
after FSPE. Treatment of 12 with SmI2 results in sequential
removal of the fluorous tag and reduction of the aryl nitro
group10 to give 13 in moderate overall yield. Acid-mediated
cyclization11 then gave indoloquinoline 14 (Scheme 4). The
Azaspirocycle 15 appears to arise from attack of the
Sm(III)-enolate intermediate at the nitrogen of the nitro
group16 or a nitroso intermediate formed by the reduction
of the nitro group, followed by N-O bond reduction.17 We
believe tertiary alcohol 16 is formed by attack of the Sm-
(III)-enolate intermediate at the oxygen of the nitro group18
followed by N-O bond reduction of an intermediate
heterocycle 18 or of a nitroso intermediate 19, formed by
elimination of a samarium alkoxide from 18 (Scheme 5).
Scheme 4
Scheme 5
overall sequence corresponds to removal of the fluorous tag
and construction of a pyridine ring. The indoloquinoline
framework is found in natural products12 and compounds
displaying significant biological activity. For example,
substituted indoloquinolines show cytoxicity and are DNA
topoisomerase II inhibitors.13
Interestingly, interrupting the SmI2 reduction of 12 allowed
two intermediates to be isolated, giving an insight into the
mechanism of the sequential reduction: azaspirocycle 15 and
tertiary alcohol 16 were obtained in a 1:1 ratio and in 70%
yield (Figure 1). Both intermediates are reduced by SmI2 to
Alcohol 16 is also isolated when the reaction mixture is
thoroughly degassed, suggesting that enolate oxidation is not
responsible for its formation. Additional support for the
proposed origin of 16 was gained by alkylation of 11 with
p-nitrobenzyl bromide and treatment of the adduct with SmI2.
No product analogous to 16 was obtained, suggesting that
an intramolecular reaction of a samarium enolate with the
nitro group is responsible for product formation. To our
knowledge, this is the first report of a samarium enolate
addition to a nitro group.
To illustrate the potential of tag cleavage-cyclization
processes using the linker, a small library synthesis was
(13) (a) Peczynska-Czoch, W.; Pognan, F.; Kaczmarek, L.; Boratynski,
J. J. Med. Chem. 1994, 37, 3503. (b) Osiadacz, J.; Majka, J.; Czarnecki,
K.; Peczynska-Czoch, W.; Zakrzewska-Czerw´ınska, J.; Kaczmarek, L.;
Sokalski, W. A. Biorg. Med. Chem. 2000, 8, 937.
(14) (a) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc.,
Perkin Trans. 1 1999, 1295. (b) Honda, T.; Ishikawa, F. Chem. Commun.
1999, 1065. (c) Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925.
(15) Poornachandran, M.; Raghunathan, R. Tetrahedron 2006, 62, 11274
and references therein.
Figure 1. Intermediates in the reduction of 12.
(16) (a) Preston, P. N.; Tennant, G. Chem. ReV. 1972, 72, 627. (b) Dean,
F. M.; Patampongse, C.; Podimuang, V. J. Chem. Soc., Perkin Trans 1
1974, 583.
(17) For examples, see: (a) Fader, L. D.; Carreira, E. M. Org. Lett. 2004,
6, 2485. (b) Masson, G.; Cividino, P.; Py, S.; Valle´e, Y. Angew. Chem.,
Int. Ed. 2003, 42, 2265.
give 13.14 Azaspirocycles related to 15 display antifungal
and antibacterial activity.15
(10) Brady, E. D.; Clark, D. L.; Keogh, D. W.; Scott, B. L.; Watkin, J.
G. J. Am. Chem. Soc. 2002, 124, 7007 and references therein.
(11) Ho, T.-L.; Jou, D.-G. HelV. Chim. Acta 2002, 85, 3823.
(12) For example, see: Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys,
M.; Vlietinck, A. Tetrahedron Lett. 1996, 37, 1703.
(18) For an example of the addition of an organometallic to the oxygen
of an aryl nitro group, see: Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri,
G.; Petrini, M. J. Chem. Soc., Perkin Trans. 2 1991, 657. For the addition
of an enolate to the oxygen of an aryl nitro group, see: Stolz, D.; Kazmaier,
U.; Pick, R. Synthesis 2006, 3341.
Org. Lett., Vol. 10, No. 6, 2008
1205

carried out using such an approach. Fluorous-tagged oxindole
12 underwent efficient Suzuki-Miyaura coupling19 with
three boronic acids to give products 20-22 in 79-100%
yield after rapid purification using FSPE (Scheme 6).
Scheme 6
Treatment of 20-22 with SmI2 resulted in removal of the
fluorous tag and reduction of the nitro group to give the
expected aniline products 23-25 that could then be converted
to pyridines 26-28 (Figure 2). We have used our improved
understanding of the mechanism of the sequential reduction
to introduce additional diversity during the removal of the
fluorous tag from oxindole 20 by varying the reaction time
with SmI2. As described above, treatment of 20 with SmI2
for 48 h gave aniline 23 that could be converted to 26.
However, treatment of 20 with SmI2 for only 3.5 h gave 29
and 30 (60%) that were readily separable. Thus, from one,
fluorous-tagged intermediate, using a single strategy, removal
of the tag using SmI2 allows four products with different
architectures to be prepared (Figure 2).
Figure 2. Tag cleavage-cyclization in library synthesis.
In summary, SmI2 has been used to mediate reaction
sequences that remove a fluorous tag and introduce diversity
through the formation of heterocyclic rings. These sequential
reactions illustrate how a higher synthetic return can be
obtained from the unavoidable cleavage step at the end of
a phase tag-assisted synthesis using a sulfur linker. Our
studies also shed further light on the behavior of samarium
enolates.
Acknowledgment. We thank Syngenta for a CASE award
(K.M.J) and the University of Manchester for funding. We
thank AstraZeneca and Pfizer for additional untied funding
(D.J.P).
Supporting Information Available: Experimental pro-
1
cedures and data for all new compounds and H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
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