Room temperature acylketene formation 1,3-dioxin-4-ones via silver(I) activation of phenylthioacetoacetate in the presence of ketones

Article abstract of DOI:10.1021/jo101372v

Silver(I) activation of thioacetoacetates in the presence of ketones produces 1,3-dioxin-4-ones. Mechanistic studies addressing the intermediacy of an acylketene intermediate are described.

Full text of DOI:10.1021/jo101372v

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SCHEME 1. Methods of Acylketene Formation
Room Temperature Acylketene Formation?
1,3-Dioxin-4-ones via Silver(I) Activation of
Phenylthioacetoacetate in the Presence of Ketones
Aaron E. May and Thomas R. Hoye*
Department of Chemistry, University of Minnesota,
Minneapolis, Minnesota 55455
hoye@umn.edu
Received July 12, 2010
SCHEME 2. Activation of Thioacetoacetates as Reported by
Kishi (8 f 9) and Ley (10 f 11) and Co-workers
Silver(I) activation of thioacetoacetates in the presence of
ketones produces 1,3-dioxin-4-ones. Mechanistic studies
addressing the intermediacy of an acylketene intermedi-
ate are described.
Acylketenes 1 are interesting, highly reactive, and useful
intermediates from the perspectives of both mechanism and
complex molecule synthesis.1 The parent acetylketene (1, R1 =
Me, R2 = H) has a half-life of <1 μs in water.2 In most
instances, the fate of acylketenes 1 is to acylate nucleophilic
oxygen or nitrogen functional groups to produce esters/acids or
amides. Many of the known methods for the generation of
acylketenes involve elevated temperatures (Scheme 1), which is
limiting in some instances.3 Thermolysis of 1,3-dioxin-4-ones 2
is the most common and convenient method for forming the
parent acetylketene.4 Thermolysis or photolysis of 2-diazo-1,3-
dicarbonyl species 3 leads to carbene formation and insertion
into a neighboring carbonyl.5 Thermolysis of β-ketoesters 4
leads to the loss of ROH via concerted elimination.6 Furan 2,3-
diones 5 chelotropically extrude carbon monoxide when
heated.7 Acylated ethoxy alkynes 6 undergo a retro-ene reac-
tion to eliminate ethylene.4 Finally, β-ketoacid chlorides such
as 7 are susceptible to elimination of HCl.8
considered. Ester/lactone formation from β-ketothioesters
falls in this category. Reports from the Kishi9 and Ley10
laboratories demonstrate that macrolactonizations can be
effectively achieved using a thiophilic metal to activate the
β-ketothioester moiety present in the cyclization precursor
(cf. 8 f 9 and 10 f 11, Scheme 2). We became intrigued by
the possibility that these reactions might involve the inter-
mediacy of acylketenes, analogous to those described in our
earlier report on dual macrolactonization/pyran hemiketal
formation from a dioxinone precursor.11
From some related acylative reactions, the intermediacy of
acylketenes has not been clearly demonstrated or, perhaps,
(1) For a review on application of acylketene intermediates to natural
product synthesis, see: Reber, K. P.; Tilley, S. D.; Sorensen, E. J. Chem. Soc.
Rev. 2009, 38, 3022–3034.
(2) Chiang, Y.; Guo, H. X.; Kresge, A. J.; Tee, O. S. J. Am. Chem. Soc.
1996, 118, 3386–3391.
(3) Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis 1994, 1219–1248.
(4) Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. J. Org. Chem. 1984, 49,
5105–5108.
The intermediacy of acylketenes was not invoked to
account for the lactonizations shown in Scheme 2, in part
because silver(I) and copper(I) salts were known to also
(5) Horner, L.; Spietschka, E. Chem. Ber. 1952, 85, 225–229.
(6) Freiermuth, B.; Wentrup, C. J. Org. Chem. 1991, 56, 2286–2289.
(7) Kol’tsova, S. V.; Feshin, V. P. Russ. J. Org. Chem. 2001, 37, 1616–
1620.
(9) Park, P. U.; Broka, C. A.; Johnson, B. F.; Kishi, Y. J. Am. Chem. Soc.
1987, 109, 6205–6207.
(10) Booth, P. M.; Fox, C. M.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1
1987, 121–129.
(8) Bell, K.; Sadasivam, D. V.; Gudipati, I. R.; Ji, H.; Birney, D.
Tetrahedron Lett. 2009, 50, 1295–1297.
(11) Hoye, T. R.; Danielson, M. E.; May, A. E.; Zhao, H. Angew. Chem.,
Int. Ed. 2008, 47, 9743–9746.
6054 J. Org. Chem. 2010, 75, 6054–6056
Published on Web 08/06/2010
DOI: 10.1021/jo101372v
r
2010 American Chemical Society

May and Hoye
JOCNote
SCHEME 3. Competitive Activation of Thioesters
SCHEME 5. Dioxinone Formation and Control Experiments
SCHEME 4. Silver Activation of Phenyl Thioacetoacetate
we would not expect dioxinones to be formed in the presence
of alcohols.15 In testing this hypothesis, we observed that the
addition of silver trifluoroacetate to phenyl thioacetoacetate
(12) in the presence of acetone in CDCl3 at room temperature
resulted in formation of dioxinone 23 (Scheme 5, top).16
Additionally, when isopropyl alcohol was present in the
reaction medium (iPrOH/acetone ∼1:1), none of 23 was
observed; instead, isopropyl acetoacetate (14) was formed.
Both of these results are consistent with the intermediacy of
acetylketene (20).17
Control experiments were run to establish that silver(I) is
playing a definitive role in the activation process (Scheme 5,
bottom): (i) Formation of dioxinone 23 in the absence of
AgO2CCF3 is not acid-catalyzed because phenyl thioacetoa-
cetate (12) is unreactive when treated with acetone and TFA.
(ii) Esterification to produce 14 is also not acid-catalyzed
because 12 is unreactive in the presence of iPrOH and TFA.18
Dioxinone 23 is stable when treated with (iii) iPrOH/TFA or
(iv) iPrOH/AgO2CCF3. Taken collectively, these results
show both that silver is necessary and that the observed
selectivity for reaction with alcohols over ketones is kinetic in
nature. In other words, dioxinone 23 is not an intermediate
en route to 14.
We probed some of the generality of this new dioxinone
forming reaction between these acylketenes and various
ketones. Results are shown in Scheme 6. Good yields were
obtained for products 25a-c; more hindered ketones [(iPr)2CO
or Bn2CO] gave only trace amounts of the corresponding
dioxinone. This is likely because the starting acetoacetate
derivative itself contains a relatively unhindered ketone that
will compete with more hindered ketone partners in trapping
the acylketene intermediate. For this reason, we used a 3:1
ratio of 24 to 12 to obtain the indicated yields.19 Substitution
activate simple thioesters lacking β-keto groups.12 However,
we conjectured that there might be significant differences in
the rates of activation of thioesters having a β-keto group
versus those that do not. We first tested this hypothesis by
exposing a 1:1 mixture of phenyl thioacetoacetate (12) and
phenyl thioacetate (13) to isopropyl alcohol with AgO2CCF3
in CDCl3 and found that 12 was preferentially consumed,
giving a 14:1 ratio of isopropyl acetoacetate (14) and iso-
propyl acetate (15) (at ∼80% conversion, Scheme 3 and
Supporting Information).13
This preferential reaction of 12 led us to the mechanistic
considerations presented in Scheme 4. Silver(I) ion could
complex to the thioacetoacetate 12 or its enol 16. Either of
the resulting cationic intermediates 17 and 18, upon proton
loss, would give the zwitterion 19, which could collapse
directly to acetylketene (20) [Douglas and co-workers have
shown14 that E1cb elimination from the anion of thioace-
toacetates (acetoacetyl CoA) is facile]. While acylium ions 21
and 22 (from 17 or 18, respectively) cannot be ruled out as
intermediates, such a pathway seems unlikely given the
observed lower reactivity of phenyl thioacetate (13).
Since acetylketene (20) is known to be trapped by ketones
to form 1,3-dioxin-4-ones (cf. 2), we reasoned it might be
possible to trap the intermediate ketene if thioacetoacetate
activations are proceeding via these reactive species. Addi-
tionally, acylketenes are known to be trapped faster (ca. 3
orders of magnitude) by alcohols [to generate β-ketoesters
(4)] than by ketones [to generate dioxinones (2)]. Therefore,
(16) While we cannot rule out the intermediacy of a mixed anhydride like
MeCOCH2CO2COCF3 in these reactions, it is noteworthy that use of silver
phosphate or silver triflate was also found to effect this transformation.
(17) We did not observe any species attributable to acetylketene when
monitoring reaction progress by 1H NMR spectroscopy. This was not
unexpected given that (i) the only stable acylketenes are those bearing two
sterically demanding groups (e.g., 1, R1 = R2 = tBu), which lock the species
into the less reactive s-trans conformation (Leung-Toung, R.; Wentrup, C. J.
Org. Chem. 1992, 57, 4850-4858), and (ii) acetylketene dimerizes and
oligomerizes upon being warmed from -77 K by itself and reacts with
alcohol traps between -90 and -50 °C.6
(18) Fischer esterification to form iPrO2CCF3 was observed instead.
(19) Experiments in which hindered ketones or no ketone (or alcohol) at
all were used gave rise to detectable (1H NMR spectroscopy) amounts of the
acetylketene homodimer, dehydroacetic acid (3-acetyl-2-hydroxy-6-methyl-
4H-pyran-4-one), along with other byproducts.
(12) For comparisons of mercury, silver, and copper salts for the activa-
tion of thioesters, see: Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W.;
Bates, G. S. J. Am. Chem. Soc. 1977, 99, 6756–6758.
(13) For the synthesis of 12 (by refluxing 2,2,6-trimethyl-4H-1,3-dioxin-
4-one with thiophenol) see: Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985,
50, 2431–2435.
(14) (a) Douglas, K. T.; Yaggi, N. F. J. Chem. Soc., Chem. Commun.
1980, 15, 728–730. (b) Douglas, K. T.; Alborz, M.; Rullo, G. R.; Yaggi, N. F.
J. Chem. Soc., Chem. Commun. 1982, 245–246.
(15) Competitive trapping of acetylketene with a 20-fold excess of cyclo-
hexanone vs pentanol leads to a ∼300:1 ratio of alcohol trapping over ketone
trapping. See: Birney, D. M.; Xu, X. L.; Ham, S.; Huang, X. M. J. Org.
Chem. 1997, 62, 7114–7120.
J. Org. Chem. Vol. 75, No. 17, 2010 6055

May and Hoye
JOCNote
SCHEME 6. Dioxinone Formation from Silver Activation of
Thiophenyl Acetoacetate
with AgO2CCF3 in the presence of ketones. This represents a
simple method for the synthesis of 1,3-dioxin-4-ones. Me-
chanistic studies, including the preferential trapping by
alcohols over ketones, point to the intermediacy of acylk-
etenes. As such, silver activation of β-ketothioesters repre-
sents a mild and convenient set of conditions for the
generation of these reactive intermediates.
Experimental Section
General Experimental Procedure for Dioxinone Formation.
Synthesis of 25b. In a 6 dram screw-capped vial, thioester 12
(0.112 g, 0.577 mmol), 3-pentanone (24b, 0.153 g, 1.78 mmol),
and CDCl3 (2.0 mL) were added. Silver trifluoroacetoacetate
(0.140 g, 0.639 mmol) was added to the stirred reaction mixture.
After 1.5 h, the suspension was filtered through silica gel using
ethyl acetate as the eluent. After concentration in vacuo, the
residue was purified by flash chromatography (20% EtOAc/
hex) to give 25b (70.1 mg, 72%): 1H NMR (500 MHz, CDCl3) δ
5.19 (q, J = 1.0 Hz, 1H), 1.99 (d, J = 1.0 Hz, 3H), 1.98 (dq, J =
15.0, 7.5 Hz, 2H), 1.96 (dq, J = 15.0, 7.5 Hz, 2H), and 0.98 (t,
J = 7.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 169.2, 162.0,
110.8, 93.7, 28.2, 20.1, and 7.6; HRMS (ESI) calcd for (C9H14O3 þ
Naþ) 193.0835, found 193.0853; IR (neat) 2979, 2945, 2886,
1736, 1722, 1642, 1459, 1393, 1348, 1313, 1320, 1209, 1185, 1161,
1060, 1053, 998, 952, 905, and 806 cm-1; TLC Rf = 0.45 in 20%
EtOAc/hexanes.
on thethioacetoacetatewas also tolerated;the allyl-containing
thioacetoacetate derivative 26 was successfully converted to
dioxinone 27 in 75% yield. Finally, an internal competition
experiment was performed using diacetone alcohol (28) as the
trapping agent. Thetertiary alcoholwas preferentiallytrapped
to give 29 in 80% isolated yield (no dioxinone formation was
observed). This selectivity (kalcohol>kketone) is also consistent
with the intermediacy of an acetylketene (20).
Acknowledgment. This investigation was supported by a
grant awarded by the National Cancer Institute (CA-76497)
of the United States National Institutes of Health.
Supporting Information Available: Experimental proce-
dures and 1H NMR, 13C NMR, HRMS, and IR spectral data
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, the transformation of phenyl thioacetoace-
tate to 1,3-dioxin-4-ones can be accomplished by activation
6056 J. Org. Chem. Vol. 75, No. 17, 2010