A concise access to 3-substituted 2-pyrones

Article abstract of DOI:10.1021/jo101843a

The development of a modular synthesis of 3-substituted-2-pyrones is described. The attainment of this strategy hinges on a new electrophilic pyrone derivative which can be readily prepared on a multigram scale and which performs very competently in metal-catalyzed cross-coupling reactions with a variety of nucleophiles.

Full text of DOI:10.1021/jo101843a

pubs.acs.org/joc
Within the context of a research program aimed at ex-
A Concise Access to 3-Substituted 2-Pyrones.
ploiting the photochemistry of 2-pyrones,3 we required an
expeditious access to various 3-substituted (alkyl, alkenyl,
aryl) 2-pyrones. Much to our surprise, the synthesis of such
simple derivatives, lacking any additional activating func-
tional groups,2g,h,4 is poorly precedented and frequently
cumbersome. For example, the literature synthesis of per-
haps the simplest derivative, 3-methyl-2-pyrone, requires
five chemical steps from commercially available δ-valerolac-
tone (involving an enolate alkylation with methyl iodide).4
Furthermore, the extension of this synthesis to other 3-alkyl-
2-pyrones is not feasible: the enolate of δ-valerolactone
failed to produce alkylated products with more complex
electrophiles in synthetically useful yields.5
ꢀ ꢀ
Frederic Frebault, Maria Teresa Oliveira,
Eckhard Wostefeld, and Nuno Maulide*
ꢀ
€
Max-Planck-Institut fu€r Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mu€lheim an der Ruhr,
Germany
maulide@mpi-muelheim.mpg.de
Received September 17, 2010
We therefore became interested in developing a rapid and
modular access to 3-substituted 2-pyrones. In particular, it
appeared logical to employ a “universal” electrophilic 2-pyr-
one reagent 1 that could be cross-coupled to a variety of
readily available organometallic nucleophiles 2 under transi-
tion metal catalysis (Scheme 1). Literature precedent, how-
ever, was not favorable to our prospects: what would have
been a logical candidate, 3-bromo-2-pyrone (3), was report-
edly unresponsive to palladium catalysis, which eventually
stimulated the previous development of 3-stannyl-2-pyrone
derivatives for use as nucleophiles.2a
The development of a modular synthesis of 3-substituted-
2-pyrones is described. The attainment of this strategy
hinges on a new electrophilic pyrone derivative which can
be readily prepared on a multigram scale and which performs
very competently in metal-catalyzed cross-coupling reac-
tions with a variety of nucleophiles.
SCHEME 1. Proposed Modular Blueprint to Access 3-Substi-
tuted 2-Pyrones
2-Pyrones are an important class of organic compounds
forming the backbone of many naturally occurring, biologi-
cally active substances.1 The synthesis of substituted 2-pyr-
ones through cross-coupling chemistry has been extensively
studied, and 5-bromo- and 3,5-dibromo-2-pyrones were by
far the most often-studied electrophiles thus far. These
derivatives have been employed in metal-catalyzed coupling
reactions with nucleophilic arylstannanes, alkynes, and ar-
ylboronic acids or themselves converted to the correspond-
ing tin, boron, zinc, and copper derivatives for cross-
coupling with electrophiles.1d,2
We nevertheless decided to begin our investigations with 3
and turned our attention to cross-coupling reactions with
Grignard reagents. Iron catalysis in cross-coupling reactions
has recently received much attention, after its revival at the
end of last century.6 In particular, iron(III) salts have been
shown to display reactivity more commonly associated with
d-block metals while retaining the environmental and tox-
icity benefits typical of alkali or alkaline earth metals.7 In
addition to the low cost and ready availability of the required
iron salts, the high reaction rates and mild conditions
employed make these cross-coupling reactions very appeal-
ing to the synthetic practitioner.8
(1) (a) McGlacken, G. P.; Fairlamb, I. J. S. Nat. Prod. Rep. 2005, 22, 369.
(b) Schlingmann, G.; Milne, L.; Carter, G. T. Tetrahedron 1998, 54, 13013. (c)
Barrero, A. F.; Oltra, J. E.; Herrador, M. M.; Sanchez, J. F.; Quilez, J. F.;
Rojas, F. J.; Reyes, J. F. Tetrahedron 1993, 49, 141. (d) Fairlamb, I. J. S.;
Marrison, L. R.; Dickinson, J. M.; Lu, F.-J.; Schmidt, J. P. Bioorg. Med.
Chem. 2004, 12, 4285. (e) Wu, P.-L.; Hsu, Y.-L.; Wu, T.-S.; Bastow, K. F.;
Lee, K.-H. Org. Lett. 2006, 8, 5207.
(2) (a) Liu, Z.; Meinwald, J. J. Org. Chem. 1996, 61, 6693. (b) Kim, W.-S.;
Kim, H.-J.; Cho, C.-G. J. Am. Chem. Soc. 2003, 125, 14288. (c) Thanh Tam,
N.; Cho, C.-G. Org. Lett. 2008, 10, 601. (d) Thanh Tam, N.; Chang, J.; Jung,
E.-J.; Cho, C.-G. J. Org. Chem. 2008, 73, 6258. (e) Thanh Tam, N.; Jung,
E.-J.; Cho, C.-G. Org. Lett. 2010, 12, 2012–2016. (f) Lee, J.-H.; Park, J.-S.;
Cho, C.-G. Org. Lett. 2002, 4, 1171. (g) Kim, W.-S.; Kim, H.-J.; Cho, C.-G.
Tetrahedron Lett. 2002, 43, 9015. (h) Lee, J.-H.; Kim, W.-S.; Lee, Y. Y.; Cho,
C.-G. Tetrahedron Lett. 2002, 43, 5779. (i) Ryu, K.; Cho, Y.-S.; Jung, S.-I.;
Cho, C.-G. Org. Lett. 2006, 8, 3343. (j) Posner, G. H.; Harrison, W.;
Wettlaufer, D. G. J. Org. Chem. 1985, 50, 5041.
(4) Shi, X.; Leal, W. S.; Liu, Z.; Schrader, E.; Meinwald, J. Tetrahedron
Lett. 1995, 36, 71.
(5) For a rare example, see: Khouri, F. F.; Khaloustian, M. K. J. Am.
Chem. Soc. 1986, 108, 6683.
€
(6) (a) Sherry, B. D; Furstner, A. Acc. Chem. Res. 2008, 41, 1500. (b)
€
ꢀ
Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem. Soc. 2002,
124, 13856. (c) Czaplik, W. M.; Mayer, M.; Cvengros, J.; Wangelin, A. J.
ChemSusChem 2009, 2, 396. (d) Hatakeyama, T.; Hashimoto, T.; Kondo, Y.;
Fujiwara, Y.; Seike, H.; Takaya, H.; Tamada, Y.; Ono, T.; Nakamura, M. J.
Am. Chem. Soc. 2010, 132, 10674.
(7) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104,
6217. (b) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061. (c)
€
Furstner, A. Angew. Chem., Int. Ed. 2009, 48, 1364.
ꢀ
(3) Frebault, F.; Luparia, M.; Oliveira, M. T.; Maulide, N. Angew.
Chem., Int. Ed. 2010, 49, 5672; Angew. Chem. 2010, 122, 5807.
7962 J. Org. Chem. 2010, 75, 7962–7965
Published on Web 10/29/2010
DOI: 10.1021/jo101843a
2010 American Chemical Society
r

ꢀ
Frebault et al.
JOCNote
TABLE 1. Iron-Catalyzed Couplings of 3, 6, and 7 with Grignard
Reagents
SCHEME 2. Synthesis of 3-Tosyloxy- and 3-Triflyloxy-2-pyronea
entry
Y
RMgX
MeMgBr
BuMgCl
products
yielda (%)
1
2
3
4
5
6
7
8
9
Br (3)
Br (3)
Br (3)
OTs (6)
OTf (7)
OTf (7)
OTf (7)
OTf (7)
OTf (7)
4a
4b
4c
4a
4a
4b
4d
4d
85
(60)
(33)
30b
44
iPrMgBr
aReagents and conditions: (a) KH2PO4, P4O10, neat, 150 °C, 40%; (b)
TsCl, NEt3, DMAP, r.t., 70%; (c) Tf2O, 2,6-collidine, DCM, 0 °C, 85%.
MeMgBr
MeMgBr
BuMgCl
PhMgCl
PhMgBr
CH2dCHMgCl
37
(40)
(63)
0
TABLE 2. Optimization of the Suzuki Coupling between 7 and 8aa
aIsolated yield of pure product. Conversions are listed in parentheses
(as determined by 1H NMR). bReaction performed at -15 °C.
In the event (Table 1), and after extensive screening of
reaction conditions, the coupling of 3 with methylmagne-
sium bromide could be induced to proceed in excellent isolated
yield (on a 0.3 mmol scale).9 Unfortunately, conversions
dropped significantly as soon as higher homologues were
employed, and the isolated yields consequently plummeted.
It appears that 3 is indeed an electrophile with limited
reactivity toward most cross-coupling protocols. At this
juncture, we also acknowledged that the low-yielding stan-
dard three-step synthesis of 3 from the expensive 5,6-dihydro-
2-pyrone10 was detrimental to our aims of efficiency and
sought the development of a different surrogate to the electro-
philic synthon 1. Inspired by precedent suggesting that tosy-
lates and triflates would fare better as leaving groups,6a,11 we
targeted the preparation of 3-tosyloxy-2-pyrone (6) and
3-triflyloxy-2-pyrone (7) for use as coupling partners.
The common precursor for these two electrophiles was
3-hydroxy-2-pyrone (5) (Scheme 2), which was prepared as
previously reported through large-scale pyrolysis of the
cheap mucic acid.12 Treatment of 5 with either tosyl chloride
or triflic anhydride delivered the (to the best of our
knowledge) hitherto unknown pyrones 6 and 7.
As depicted in Table 1, while 6 proved to be a weak
coupling partner (entry 4), 3-triflyloxy-2-pyrone (7) was
more promising (entries 5-8). Its higher reactivity was
highlighted by the full conversions observed with methyl-
and butylmagnesium halides. Unfortunately, significant de-
composition induced by the Grignard reagent (confirmed
through background experiments) lowered the isolated
yields. In addition, less reactive aryl and alkenyl Grignard
reagents still did not provide acceptable results.
entry
conditionsa
yieldb (%)
1
2
3
4
Pd(OAc)2, P(tBu) 2(bph), KF, THF, 50 °C, 24 h
Pd(OAc)2, PPh3, KF, dioxane/H2O, rt, 3 h
Pd(OAc)2, PPh3, K3PO4, dioxane/H2O, rt, 2 h
Pd(OAc)2, PPh3, Cs2CO3, dioxane/H2O, rt, 3 h
PdCl2(dppf), K3PO4, THF/H2O, rt, 1 h
42
49
62
57
88
57
5
6c
PdCl2(dppf), K3PO4, THF/H2O, rt, 7 h
aIn all reactions, 5 mol % of Pd catalyst and 10 mol % of ligand were
used. bIsolated yield of pure product. 3-Bromo-2-pyrone (3) used as
starting material.
c
Though disappointing, these initial setbacks provided us
with new, previously untested pyrone electrophiles 6 and 7.
Their short and efficient syntheses additionally made them
auspicious candidates for the fulfillment of the original strategy
outlined in Scheme 1. We therefore decided to investigate the
Suzuki coupling reaction13 between 7and organoboron reagents.
The catalytic merger of 7 and cyclopentenyl boronic acid
pinacol ester 8a14 was investigated under diverse conditions,
as summarized in Table 2. It was found early on that the
presence of water in the mixture dramatically increased the
reaction rate (entries 1 and 2), whereas changing the base did
not have a marked impact (entries 2-4). PdCl2(dppf) proved
to be the catalyst of choice as it led to very fast coupling in an
excellent yield of 88% (entry 5). As might be expected,
employing 3-bromo-2-pyrone (3) as electrophilic partner
(entry 6) resulted in a significantly lower reaction rate and
poorer chemical yield. This rate difference between 7 and 3 is
probably caused by the reported ability of triflate, as a
leaving group, to accelerate the transmetalation process.15
Under the best conditions, we proceeded to investigate the
scope of this transformation, beginning with alkenyl- and
alkylboron derivatives (Table 3). Five- to seven-membered
€
(8) (a) Scheiper, B.; Bonnekessel, M.; Krause, H.; Furstner, A. J. Org.
Chem. 2004, 69, 3943. (b) Maulide, N.; Vanherck, J.-C.; Marko, I. E. Eur. J.
ꢀ
Org. Chem. 2004, 3962. (c) Nicolaou, K. C.; Chakraborty, T. K; Piscopio,
A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc. 1993, 115, 4419. (d)
Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1992, 114, 2260. For further
examples of application to total synthesis, see ref 6b and references cited
therein.
(9) See the Supporting Information for details.
(13) (a) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Chapter 2.
For reviews, see: (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (c)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(10) Posner, G. H.; Afarinkia, K.; Dai, H. Org. Synth. 1998, 9, 112. For
an alternative synthesis of 3 by decarboxylation, see: Cho, C.-G.; Park, J.-S.;
Jung, I.-H.; Lee, H. Tetrahedron Lett. 2001, 42, 1065.
(11) Gøgsig, T. M.; Lindhardt, A. T.; Skrydstrup, T. Org. Lett. 2009, 11,
4886.
(12) Profitt, J. A.; Jones, T.; Watt, D. S. Synth. Commun. 1975, 5, 457.
(14) Prepared from cyclopentanone via Shapiro reaction of the corre-
sponding hydrazone; see: Rauniyar, V.; Zhai, H.; Hall, D. G. Synth.
Commun. 2008, 38, 3984.
J. Org. Chem. Vol. 75, No. 22, 2010 7963

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Frebault et al.
JOCNote
TABLE 3. Suzuki Couplings of 7 Alkenyl- and Alkylboron Derivatives
TABLE 4. Suzuki Couplings of 7 with Arylboronic Acids
aIsolated yield of pure product. bReaction carried out at 0 °C.
cCommercially available 1 M solutions of 8f-g in hexane were used.
ring cycloalkenylboronic acid pinacol esters coupled readily
with pyrone 7 (entries 1-3). (E)-Alkenylboronic acids af-
forded the cross-coupled products in moderate to good
yields with complete retention of double bond geometry
(entries 4 and 5). Under similar conditions, coupling of
triethylborane was facile and yielded the desired 3-ethyl-
2-pyrone (9f) in good yield. Reaction with tributylborane
was slower but still delivered the coupled product 9g in 43%
yield.16 The expeditious access to the previously unreported
3-alkyl-2-pyrones 9f and 9g presented herein stands in sharp
contrast with the tedious route described for 3-methyl-
2-pyrone,4 a route which is furthermore not even applicable
to higher homologues (such as 9f,g).
We next examined Suzuki cross-coupling reactions of 7
with various arylboronic acids 10 (Table 4).
Once again, a broad variety of 3-aryl-2-pyrones could be
obtained under the conditions optimized previously. Re-
markably, both strong electron-withdrawing substituents
(such as nitro- or trifluoromethyl, entries 6 and 9) and
electron-donating moieties (entries 2, 3, and 5) led to facile
coupling with 6 in less than 2 h at room temperature, giving
the desired products in excellent yields. In addition, ortho-
substituted boronic acids (entry 4) and heteroaryl derivatives
aIsolated yield of pure product.
(entries 10-13) were successful coupling partners. The reac-
tion conditions tolerate the presence of a formyl functional
group (entry 7) and no homocoupling product was observed
with p-bromophenylboronic acid (entry 8).
In summary, we have developed a concise and efficient
route toward 3-substituted 2-pyrones. Crucial to this end
was the establishment of 3-triflyloxy-2-pyrone (7) as a read-
ily available, highly reactive electrophilic synthon for metal-
catalyzed cross-coupling reactions. Compound 7 underwent
facile Suzuki reactions with a plethora of cycloalkenylbo-
ronic acid pinacol esters, alkenylboronic acids, trialkylboranes,
(15) (a) Stang, P. J.; Kowalski, M. H.; Schiavelli, M. D.; Longford, D. J.
J. Am. Chem. Soc. 1989, 111, 3347. (b) Stang, P. J.; Kowalski, M. H. J. Am.
Chem. Soc. 1989, 111, 3356. (c) Hinkle, R. J.; Stang, P. J.; Kowalski, M. H. J.
Org. Chem. 1990, 55, 5033. (d) Stang, P. J.; Cao, D. H.; Poulter, G. T.; Arif,
A. M. Organometallics 1995, 14, 1110.
(16) Both triisopropyl- and tricyclohexylborane failed to give the desired
products under these reaction conditions.
7964 J. Org. Chem. Vol. 75, No. 22, 2010

ꢀ
Frebault et al.
JOCNote
as well as aryl- and heteroarylboronic acids to give the
corresponding 3-substituted 2-pyrones in good to excellent
yields. As triflate 7 can be prepared in multigram scale in only
two simple steps, the sequences presented herein effectively
constitute scalable17 and highly modular three-step synthe-
ses of substituted pyrones.
(5 mL), dried (Na2SO4), and concentrated under reduced
pressure. Purification by flash chromatography on a silica
gel column using pentane/ethyl acetate (9:1) as eluant gave the
title compound (21 mg, 88%) as a white solid: mp 54-55 °C;
FTIR (neat) νmax 3102, 2965, 2897, 2844, 1706, 1620, 1540; 1H
NMR (500 MHz, CDCl3) δ 7.39 (dd, J = 5.0, 1.9, 1H), 7.11
(dd, J = 6.7, 1.9, 1H), 7.04 (m, 1H), 6.25 (dd, J = 6.7, 5.0, 1H),
2.61-2.68 (m, 4H), 1.95 (q, J = 7.5, 2H); 13C NMR (125 MHz,
CDCl3) δ 160.9, 148.9, 136.0, 135.8, 135.2, 124.4, 106.6, 34.6,
33.6, 22.5; HRMS (ESI) calcd for C10H10O2 [M]þ 162.0683,
found 162.0681.
Experimental Section
Representative Procedure for the Preparation of 3-Cyclopen-
tenyl-2H-pyran-2-one (9a). A flask was charged with 3-(tri-
fluoromethanesulfonyloxy)pyran-2-one (7) (37 mg, 0.15
mmol), PdCl2(dppf) (6 mg, 5 mol %), K3PO4 (95 mg, 0.45
mmol, 3.0 equiv), and the boronic ester 8a (35 mg, 0.18 mmol,
1.2 equiv). The flask was evacuated and backfilled with argon
three times, and THF (0.7 mL) followed by water (0.07 mL)
were added at rt. The mixture was stirred for 1 h and then
diluted with EtOAc (10 mL). The organic layer was washed
with saturated aqueous NH4Cl solution (5 mL) and brine
Acknowledgment. We are grateful to the Deutsche For-
schungsgemeinschaft (DFG Grant No. MA4861/3-1), the
€
Max-Planck Society, and the Max-Planck-Institut fur Koh-
lenforschung for generous funding of our research programs.
Supporting Information Available: Experimental proce-
dures, full characterization, and copies of NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) A 6 mmol scale reaction of 7 with 8a gave the desired pyrone 9a in
84% yield after the same period of time reported herein.
J. Org. Chem. Vol. 75, No. 22, 2010 7965