A convenient approach to cyclic enol phosphates via ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4039(03)00873-6

A strategy employing the second generation Grubbs catalyst in order to facilitate the generation of a variety of cyclic enol phosphates, including 2H-chromen-4-yl, 1,2-dihydroquinolin-4-yl, 2H-thiochromen-4-yl, 2H-thiochromen-4-yl 1,1-dioxide, and benzofu

Full text of DOI:10.1016/S0040-4039(03)00873-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4275–4277
A convenient approach to cyclic enol phosphates via
ring-closing metathesis
Alan Whitehead, Joel D. Moore and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA
Received 20 March 2003; accepted 1 April 2003
Abstract—A strategy employing the second generation Grubbs catalyst in order to facilitate the generation of a variety of cyclic
enol phosphates, including 2H-chromen-4-yl, 1,2-dihydroquinolin-4-yl, 2H-thiochromen-4-yl, 2H-thiochromen-4-yl 1,1-dioxide,
and benzofuran-2-yl enol phosphate scaffolds is described. This work represents the first case of an olefin metathesis reaction in
which one of the groups participating in the metathesis event is an enol phosphate moiety. © 2003 Elsevier Science Ltd. All rights
reserved.
functional groups and facilitate RCM reactions with
olefins bearing a wide array of functionality.8 Recently
Shibasaki and co-workers have carried out successful
examples of RCM with enol silanes employing the
second generation Grubbs catalyst.9 Previous results by
us and others have shown that RCM reactions cata-
lyzed by either the first or second generation Grubbs
catalysts are effective methods for the construction of a
variety of P-heterocycles.10 We herein report the first
examples of RCM reactions on enol phosphate tem-
plates. These transformation are carried out exclusively
with the second generation Grubbs catatyst to generate
an array of heterocyclic enol phosphates.
Enol phosphates represent a versatile intermediate in
the construction of complex organic molecules.1 The
ability to easily convert enol phosphates into a myriad
of functional motifs of synthetic relevance is well
known. In particular, this moiety has proved to be a
robust and versatile precursor for a number of cross-
coupling reactions facilitated by Pd(0) and Ni(0).1 The
ability of the enol phosphate to undergo these cross-
coupling reactions in the presence of various het-
eroatoms, makes it an attractive functional group for
the construction of various substituted heterocyclic sys-
tems. As a powerful extension to this chemistry, Nico-
laou and co-workers developed lactone-derived ketene
acetal phosphates as alternatives to the analogous
ketene acetal triflates, which are often unstable and
demonstrate low yields in both their formation and
subsequent coupling reactions.2 They were able to
incorporate this strategy toward the total synthesis of
the EFGH-core of brevotoxin A.3 Other natural
product syntheses, namely coumarin analogs2 and the
HIJK ring model of ciguatoxin,4 have also utilized the
enol phosphate and ketene acetal phosphate functional
groups respectively. Our interest in the development of
new transition metal-catalyzed processes to phospho-
rus-containing compounds leads us to report an RCM
approach to enol phosphate and ketene acetal phos-
phate heterocyclic building blocks.
We initially began our study with 2-hydroxyacetophe-
none 1 (Scheme 1). The uncyclized enol phosphate 2
was produced in good yield from a Mitsunobu allyla-
tion protocol using allyl alcohol followed by enol phos-
phate formation employing LDA and diethyl
chlorophosphate. Subsequent RCM using 5 mol%
(ImesH2)(PCy3)(Cl)2RuꢀCHPh6,7 delivered the desired
2H-chromen-4-yl enol phosphate 3 in quantative yield
(Scheme 1).
It is well known that the Grubbs ruthenium-based
catalysts [(PCy3)2(Cl)2RuꢀCHPh]5 and [(ImesH2)-
(PCy3)(Cl)2RuꢀCHPh]6,7 are tolerant to a number of
Scheme 1. Reagents and conditions: (a) Ph3P, DEAD, allyl
alcohol, 75%; (b) LDA, THF, ClP(O)(OEt)2, 79%; (c) 5 mol%
(ImesH2)(PCy3)(Cl)2RuꢀCHPh, CH2Cl2, 40°C, 99%.
* Corresponding author. E-mail: phanson@ku.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00873-6

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A. Whitehead et al. / Tetrahedron Letters 44 (2003) 4275–4277
We next turned our attention toward the synthesis of
the 1,2-dihydroquinolinyl enol phosphate system begin-
ning with the allylation of 2-aminoacetophenone (4)
generating N-allyl-2-aminoacetophenone (5) (Scheme
2). As anticipated, problems were encountered in our
attempts to directly proceed to 6 utilizing an unpro-
tected aniline moiety. Therefore, we opted for a tosyla-
tion step prior to these steps. This strategy proved to
work well as the tosylated allylaniline 7 was converted
to the 1,2-dihydroquinolin-4-yl enol phosphate 8 in
good overall yield (Scheme 2).
A
final example in this series to access 2H-
thiochromenyl enol phosphates was carried out begin-
ning with the nucleophilic aromatic substitution of
sodium allylmercaptide with 2-fluoroacetophenone (9)
(Scheme 3). Subsequent enol phosphate generation
delivered metathesis precursor 10. Subjection of this
enol phosphate to RCM conditions was successful in
producing the 2H-thiochromen-4-yl enol phosphates
11, albeit in modest yield (48%). We then investigated
the effect of the oxidation state of sulfur in the metathe-
sis event. Oxidation of the sulfide using m-CPBA deliv-
ered the corresponding sulfone 12 in good yield.
Subsequent RCM proceeded smoothly to afford the
2H-thiochromen-4-yl 1,1-dioxide 13 in excellent yield.
Scheme 3. Reagents and conditions: (a) CH2ꢀCH2CH2SH,
NaH, THF, 90%; (b) LDA, THF, ClP(O)(OEt)2, 80%; (c) 10
mol% (ImesH2)(PCy3)(Cl)2RuꢀCHPh, CH2Cl2, 45°C, 48%; (d)
m-CPBA, CH2Cl2, 82%; (e)
5 mol% (ImesH2)(PCy3)-
(Cl)2RuꢀCHPh, CH2Cl2, 45°C, 85%.
Following the success of these examples, we decided to
investigate the scope of this method by probing its
effectiveness on the more elaborate and more ‘sensitive’
ketene acetal phosphate example outlined below in
Scheme 4. Beginning with the commerically available
acetate derivative of 2-vinyl phenol 14, enol phosphate
formation was found to be most effectively carried out
using KHMDS and ClP(O)(OPh)2 as outlined by Nico-
laou and co-workers2 in place of the analogous LDA/
diethyl chlorophosphate pair as previously used. These
conditions afforded enol phosphate 15 in good yields
(80%). The subsequent key RCM step proceeded with-
Scheme 4. Reagents and conditions: (a) LDA, THF,
ClP(O)(OPh)2, 80%; (b) mol% (ImesH2)(PCy3)(Cl)2-
RuꢀCHPh, CH2Cl2, 40°C, 99%.
5
out incident to produce the versatile benzofuran-2-yl
enol phosphate 16 in quantitative yield.
Conclusion
We have demonstrated that ring-closing metathesis is a
viable method to effectively generate a variety of cyclic
enol phosphates, including 2H-chromen-4-yl, 1,2-dihy-
droquinolin-4-yl, 2H-thiochromen-4-yl, and 2H-
thiochromen-4-yl
1,1-dioxide
enol
phosphates.
Furthermore, we have extended this chemistry to
include a synthetically useful benzofuran-2-yl enol
phosphate scaffold. To the best of our knowledge, this
study represents the first examples of RCM reactions
on substrates of this kind. Additional efforts in this
area are underway and will be reported in due course.
Acknowledgements
This investigation was supported by funds provided by
the National Institutes of Health (National Institute of
General Medical Sciences, RO1-GM58103), the NIH
Dynamic Aspects in Chemical Biology Training Grant
(A.W.), and the Herman Frasch Foundation (442-
Scheme 2. Reagents and conditions: (a) CH2ꢀCH2CH2Br,
Cs2CO3, CH3CN, 64%; (b) TsCl, CH2Cl2, Et3N, 86%, (c)
LDA,
THF,
ClP(O)(OEt)2,
64%;
(d)
5
mol%
(ImesH2)(PCy3)(Cl)2RuꢀCHPh, CH2Cl2, 45°C, 75%.

A. Whitehead et al. / Tetrahedron Letters 44 (2003) 4275–4277
4277
HF97, administered by the American Chemical Soci-
ety). The authors thank Dr. David Vander Velde and
Sarah Neuenswander for assistance with NMR mea-
surements and Dr. Todd Williams for HRMS analysis.
7. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953–956.
8. For recent reviews, see: (a) Trnka, T. M.; Grubbs, R. H.
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S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371–388.
9. Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett.
2001, 42, 8023–8027.
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