Preparation of 2-alkyl- and 2-acylpropenals from 5-(trifluoromethanesulfonyloxy)-4H-1,3-dioxin: A versatile acrolein α-cation synthon

Article abstract of DOI:10.1016/S0040-4020(00)00872-3

5-(Trifluoromethanesulfonyloxy)-4H-1,3-dioxin (3) participates in a variety of nucleophilic substitution reactions with cuprate reagents or in palladium catalyzed cross-coupling reactions to provide 5-substituted-4H-1,3-dioxins 5. Upon thermolysis, these compounds undergo facile retrocycloaddition reactions to generate the corresponding 2-substituted acroleins which, if necessary, can be trapped in situ with dienes or heterodienophiles. In particular, the heretofore unknown 2-acylacroleins can be generated using this methodology and trapped with enol ethers to afford 5-acyl-3,4-dihydro-2H-pyrans (6g,h), a substructural unit common to many natural products. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00872-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 10275±10281
Preparation of 2-Alkyl- and 2-Acylpropenals from
5-(Tri¯uoromethanesulfonyloxy)-4H-1,3-dioxin: A Versatile
Acrolein a-Cation Synthon
*
Stephen P. Fearnley, Raymond L. Funk and Robert J. Gregg
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 13 February 2000; accepted 10 March 2000
AbstractÐ5-(Tri¯uoromethanesulfonyloxy)-4H-1,3-dioxin (3) participates in a variety of nucleophilic substitution reactions with cuprate
reagents or in palladium catalyzed cross-coupling reactions to provide 5-substituted-4H-1,3-dioxins 5. Upon thermolysis, these compounds
undergo facile retrocycloaddition reactions to generate the corresponding 2-substituted acroleins which, if necessary, can be trapped in situ
with dienes or heterodienophiles. In particular, the heretofore unknown 2-acylacroleins can be generated using this methodology and trapped
with enol ethers to afford 5-acyl-3,4-dihydro-2H-pyrans (6g,h), a substructural unit common to many natural products. q 2000 Elsevier
Science Ltd. All rights reserved.
The Diels±Alder reaction is arguably the premier reaction
for the construction of six-membered carbocycles and
heterocycles. Nevertheless, Diels±Alder chemistry is not
without restrictions, particularly in matching frontier orbi-
tals of the reacting partners to achieve acceptable stereo-
and regioselectivity. Thus, the further development of this
reaction rests, in part, on the discovery of new dienes/dieno-
philes which is often stimulated by natural product total
synthesis endeavors. For example, a hypothetical approach
to the cytotoxic agent euplotin A, one of many natural
products which embodies an 5-acyl-3,4-dihydro-2H-pyran
substructural unit,1 might proceed quite ef®ciently through
an intramolecular cycloaddition of the activated heterodiene
moiety of 1 with the cyclic enol ether.2 However, method-
ology capable of stereoselectively generating the labile
2-acyl-b-substituted acrolein heterodiene unit of 1 under
the mild conditions most likely required for the successful
execution of this plan is lacking.3 Since we have previously
demonstrated that 4-alkyl4a and 5-(acyloxy)4b substituted
4H-1,3-dioxins undergo smooth retrocycloaddition at 90±
1008C to the corresponding 3-alkyl- and 2-(acyloxy)acro-
leins, respectively, we considered the preparation of the 5-
acyl-dioxin 2 and its thermal transformation to 1 as well as
additional substrates for similar applications of this type of
intramolecular heterocycloaddition reaction.5 As a ®rst step
toward this goal, we report herein the preparation of
the tri¯ate 3, document its utility as a novel acrolein
a-cation synthon, and demonstrate that 5-acyl-4H-1,3-
dioxins are viable precursors to the heretofore unknown
2-acylacroleins.6
The tri¯ate 3 was prepared from ketone 47 following a
procedure similar to the one previously reported for the
preparation of 2-(acyloxy)-4H-1,3-dioxins.4b Thus, addition
of tri¯ic anhydride to a mixture of ketone 4, triethylamine
(1 equiv.), and DMAP (1 equiv.) in CH2Cl2 (08C to 2238C,
24 h), followed by evaporation of the solvent and puri®ca-
tion of the residue by ¯ash chromatography afforded pure
tri¯ate 3. Tri¯ate 3 is stable for extended periods of time
if kept below 08C, but does undergo a quantitative and
especially facile cycloreversion upon re¯uxing in
benzene-d6 (1.5 h, NMR analysis) to afford 2-(tri¯uoro-
methanesulfonyloxy)-2-propenal.
The tri¯ate 3 was subjected to a variety of nucleophilic
substitution reactions which commonly employ vinyl or
aryl tri¯ates8 as starting materials. As shown in Table 1,
tri¯ate 3 is no exception and participates in cuprate reactions
Keywords: hetero Diels±Alder reaction; retrocycloaddition; 2-substituted
acroleins.
* Corresponding author. E-mail: rlf@chem.psu.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00872-3

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S. P. Fearnley et al. / Tetrahedron 56 (2000) 10275±10281
Table 1. Preparation of 5-substituted 4H-1,3-dioxins from tri¯ate 3 and retrocycloaddition/cycloaddition reactions
(entry a) as well as palladium catalyzed cross-coupling
reactions with aryl stannanes (entry b), aryl boronic acids
(entry c), terminal acetylenes (entry e), enol ethers (entry f)
and carbon monoxide insertions (entries g and h). Moreover,
the products of some of these reactions were shown to be
useful for the preparation of additional substrates for subse-
quent retrocycloaddition reactions, for example, the conver-
sions of aldehyde 5c to oxime ether 5d and Weinreb-type
amide 5h to ketone 5i.
retrocycloaddition product 6b afforded the corresponding
known dimer.9b It was gratifying to observe that oxime
ether 5d was directly converted to the desired quinoline
carbaldehyde 6d upon heating in ortho-dichlorobenzene.
An electrocyclization of the intermediate 2-arylacrolein
and concomitant elimination of methanol may be the opera-
tive pathway. Not unexpectedly, thermolysis of 5e gave the
corresponding dimer derived from a hetero Diels±Alder
reaction.9 However, the intermediate 2-alkynylacrolein
could be ef®ciently intercepted with Danishefsky's diene
to afford the adduct 6e as a 4:1 mixture of stereoisomers.
Surprisingly, the 2-acylacrolein derived from the therm-
olysis of diethylamide 5g was stable and showed no
tendency to dimerize, although similar treatment of ketone
5f and amide 5h afforded polymer. However, each of the
intermediate 2-acylacroleins of entries f, g, h could be
The retrocycloaddition reaction for each of the dioxins 5
was ®rst examined in the absence of any diene or hetero-
dienophile trapping agent. Thus, the thermolyses of
dioxins 5a,b,c were uneventful and cleanly transformed
(NMR analysis) to the corresponding 2-substituted acro-
leins 6a,b,c, respectively. However, concentration of the

S. P. Fearnley et al. / Tetrahedron 56 (2000) 10275±10281
10277
trapped, either as the Diels±Alder adduct 6f derived from
cyclization with isoprene or, more importantly, the products
6g and 6h produced from heterocycloaddition with
isobutyl vinyl ether. Finally, the feasibility of performing
a retrocycloaddition±intramolecular cycloaddition sequence
is documented in entry i, although the stereoselectivity of
the reaction is poor and presumably re¯ects the competition
by each of the carbonyl groups for secondary orbital inter-
action with the diene.10
suspension of CuI (370 mg, 1.94 mmol) in dry THF
(4 mL), cooled to 08C, was added dropwise a 2.0 M solution
n
of hexyl lithium in hexanes (1.40 mL, 2.80 mmol). After
20 min, the black suspension was cooled to 2158C and a
solution of tri¯ate 3 (150 mg, 0.57 mmol) in dry THF
(2 mL) added dropwise. After 20 h, the mixture was ®ltered
over Florisil with hexanes and reduced in vacuo to yield a
pale yellow oil. Further puri®cation by ¯ash chroma-
tography (silica ratio 50:1, pentane/Et2O 50:1) yielded a
colorless oil (86.5 mg, 76%). Rf: 0.31 (pentane/Et2O
1
In summation, the synthetic equivalency of (tri¯uoro-
methanesulfonyloxy)dioxin 3 with an acrolein a-cation
synthon has been demonstrated in several two-step alkyla-
tion, retrocycloaddition processes. A valuable aspect of this
methodology is that the sensitive acrolein functionality can
be slowly generated under mild and neutral conditions
which are advantageous for cycloaddition reactions employ-
ing reactive/labile dienophiles. Indeed, a new class of 1,1-
diactivated alkenes, 2-acylacroleins, is now available for
synthesis applications. These possibilities as well as those
enumerated above are under active investigation.
40:1); H NMR: (200 MHz, CDCl3) d 6.18 (s, 1H), 4.06
(s, 2H), 1.82 (bt, Jˆ6.8 Hz, 1H), 1.38 (s, 6H), 1.30±1.15
(bm, 8H), 0.82 (t, Jˆ6.5 Hz, 3H); 13C NMR: (50 MHz,
CDCl3) d 135.8, 111.4, 98.0, 61.3, 31.3, 28.9, 28.5, 27.5,
23.8, 22.2, 13.5; IR: (neat) nmax 2926.4, 1675.8, 1233.5,
1125.0 cm21; MS: (CI) m/z 199 [M1H]1 52%; HRMS:
(EI) m/z 198.1634 (198.1620 calcd for C12H22O2).
2,2-Dimethyl-5-phenyl-4H-1,3-dioxin (5b). To a stirred
solution of tri¯ate 3 (550.5 mg, 2.10 mmol) in N-methyl
pyrrolidinone (10 mL), previously purged with a stream
of argon, was added triphenylarsine (32 mg, 0.168 mmol)
and Pd2(dba)3´CHCl3 (22 mg, 0.021 mmol) at rt. After
10 min, Bu3SnPh (680 mL, 2.10 mmol) was added. After
45 h, further Bu3SnPh (170 mL, 0.525 mmol) and
Pd2(dba)3.CHCl3 (5 mg, 0.005 mmol) were added. After
50 h total, water (25 mL) was added and the resultant
mixture extracted with hexanes (2£25 mL). The combined
organic fractions were washed with water (25 mL), stirred
over sat. KF (50 mL) for 30 min, washed with brine
(25 mL), dried (MgSO4), ®ltered and reduced in vacuo to
yield a black oil. Further puri®cation by ¯ash chroma-
tography (silica ratio 30:1, benzene/Et20 97:3) yielded a
colorless solid (100 mg, 75%). Rf: 0.64 (hexane/EtOAc
Experimental
All non-aqueous reactions were carried out under argon
using standard techniques for the exclusion of air and moist-
ure. All solvents used were obtained anhydrous, either by
appropriate distillation or by direct purchase. Where neces-
sary, reagents were dried and puri®ed according to the
recommended methods. Thin layer chromatography was
carried out on Analtech Uniplate Silica Gel HLF 250 mM
glass plates. Flash chromatography was performed over
ICN Siliech 32±36D 6A silica. Melting points were deter-
mined on an electrothermal apparatus and are uncorrected.
Infra-red absorption spectra were recorded on a Perkin±
Elmer FT-1600 instrument, as thin ®lms, CHCl3 solutions,
or KBr discs. Both 1H and 13C NMR spectra were recorded
on a Bruker AC-200 instrument at 200 and 50 MHz respec-
tively, referenced to the appropriate deuterium lock. J values
are given in Hz. Mass spectra were measured on Kratos MS-
25 (CI, isobutane) and Kratos MS9/50 (EI, 70 eV; 1FAB,
xenon) instruments. Percentile ®gures refer to relative inten-
sity as a proportion of the base peak.
1
19:1); H NMR: (200 MHz, CDCl3) d 7.3±7.1 (m, 5H),
6.82 (bs, 1H), 4.46 (d, Jˆ1.5 Hz, 2H), 1.40 (s, 6H); 13C
NMR: (50 MHz, CDCl3) d 138.8, 136.0, 129.0, 126.8,
124.0, 111.6, 98.9, 60.1, 23.9; IR: (neat) nmax 2993.2,
2844.4, 1645.5, 1211.4, 1135.3 cm21; MS: (EI) m/z 190
[M]1 16.3%; HRMS: (EI) m/z 190.0998 (190.0994 calcd
for C12H14O2).
2,2-Dimethyl-5-(2-formylphenyl)-4H-1,3-dioxin (5c). To
a solution of tri¯ate 3 (200 mg, 0.763 mmol), 2-formyl-
phenyl boronic acid (172 mg, 1.144 mmol), triphenylarsine
(23.4 mg, 0.076 mmol) and Cs2CO3 (447 mg, 1.373 mmol)
in dimethylformamide/THF/H2O 1:1:1 (9 mL), was added,
in one portion, bis(benzonitrile) palladium (II) chloride
(14.6 mg, 0.0381 mmol) with stirring at rt. After 14 h,
water (20 mL) was added and the resultant mixture
extracted with Et2O (4£20 mL). The combined organic frac-
tions were dried (MgSO4), ®ltered and reduced in vacuo to
yield a pale brown oil. Further puri®cation by ¯ash chroma-
tography (silica ratio 75:1, hexane/EtOAc gradient elution
19:1 to 9:1) yielded a colorless oil, (147.1 mg, 88%). Rf:
2,2-Dimethyl-5-tri¯uoromethanesulfonyloxy-4H-1,3-dioxin
(3). To a stirred solution of ketone 4 (1.00 g, 7.68 mmol),
triethylamine (1.07 mL, 7.68 mmol) and DMAP (0.939 g,
7.68 mmol) in CH2Cl2 (15 mL) cooled to 08C was added
dropwise neat tri¯ic anhydride (1.29 mL, 7.68 mmol).
After 24 h at 2238C, the dark brown solution was partially
reduced in vacuo to yield a mobile black residue. Immediate
further puri®cation by ¯ash chromatography (silica ratio
20:1 of total reagent mass, pentane/CH2Cl2 gradient elution
9:1 to 4:1) yielded a colorless oil (1.27 g, 63%). Rf: 0.18
(pentane/CH2Cl2 7:1); 1H NMR: (200 MHz, CDCl3) d 6.76
(t, Jˆ1.3 Hz, 1H), 4.31 (d, Jˆ1.4 Hz, 2H), 1.45 (s, 6H); 13C
NMR: (50 MHz, CDCl3) d 137.8, 129.1, 115.7, 100.9, 58.6,
23.0; IR: (neat) nmax 3001.1, 1688.2, 1425.8, 1215.6,
1140.3, 1118.6 cm21; MS: (EI) m/z 262 [M]1 8.1%;
HRMS: (EI) m/z 262.0130 (262.0123 calcd for C7H9O5F3S).
1
0.32 (hexane/EtOAc 6:1); H NMR: (200 MHz, CDCl3) d
10.32 (s,1H), 7.94 (dd, Jˆ7.7, 0.6 Hz, 1H), 7.57 (tdd, Jˆ7.6,
1.4, 0.9 Hz, 1H), 7.37 (m, 2H), 6.38 (m, 1H), 4.48 (m, 2H),
1.54 (s, 6H); 13C NMR: (50 MHz, CDCl3) d 192.2, 142.3,
139.8, 135.2, 134.0, 130.2, 129.1, 127.9, 109.2, 99.2, 62.0,
24.1; IR: (neat) nmax 2993.4, 1689.4, 1211.9, 1133.9 cm21
;
MS: (EI) m/z 218 [M]1 2.5%; HRMS: (EI) m/z 218.0952
(218.0943 calcd for C13H14O3).
2,2-Dimethyl-5-hexyl-4H-1,3-dioxin (5a). To a stirred

10278
S. P. Fearnley et al. / Tetrahedron 56 (2000) 10275±10281
2,2-Dimethyl-5-[2-(methoxyiminyl)phenyl]-4H-1,3-dioxin
(5d). To a suspension of aldehyde 5c (21.8 mg, 0.10 mmol)
triphenylphosphine (39.3 mg, 0.15 mmol) in dimethyl-
formamide/diethylamine 5:1 (18 mL), previously purged
with a stream of CO, was added triethylamine (280 mL,
2.00 mmol) and Pd(OAc)2 (16.8 mg, 0.075 mmol), with stir-
ring under an atmosphere of CO at rt. After 24 h, water
(50 mL) was added and the resultant mixture extracted
with Et2O (4£25 mL). The combined organic fractions
were dried (MgSO4), ®ltered and reduced in vacuo to
yield a black oil. Further puri®cation by ¯ash chroma-
tography (silica ratio 50:1, hexane/EtOAc 4:1) yielded a
colorless oil, (127 mg, 60%). Rf: 0.22 (hexane/EtOAc
Ê
and 4 A mol. sieves (35 mg) in pyridine (0.5 mL), was added
methoxyamine hydrochloride (9.6 mg, 0.115 mmol) with stir-
ring at rt. After 80 min, the solvent was removed in vacuo, the
residue taken up in CH2Cl2, ®ltered through a plug of silica,
and evaporated. Further puri®cation by ¯ash chromatography
(silica ratio 60:1, hexane/EtOAc 19:1) yielded a colorless oil
1
(21.9 mg, 89%). Rf: 0.38 (hexane/EtOAc 9:1); H NMR:
(200 MHz, CDCl3) d 8.31 (s, 1H), 7.84 (dd, Jˆ7.6, 2.0 Hz,
1H), 7.4±7.15 (m, 3H), 6.37 (s, 1H), 4.35 (d, Jˆ1.5 Hz, 2H),
3.96 (s, 3H), 1.52 (s, 6H); 13C NMR: (50 MHz, CDCl3) d
147.9, 141.0, 136.2, 131.1, 130.0, 129.9, 127.9, 126.9,
110.5, 98.8, 62.0, 61.8, 24.0; IR: (neat) nmax 2993.0, 2938.4,
1657.0, 1052.6 cm21; MS: (EI) m/z 247 [M]1 5.5%; HRMS:
(EI) m/z 247.1204 (247.1208 calcd for C14H17NO3).
1
4:1); H NMR: (200 MHz, CDCl3) d 6.52 (s, 1H), 4.33
(s, 2H), 3.35 (q, Jˆ7.0 Hz, 4H), 1.41 (s, 6H), 1.08
(t, Jˆ7.0 Hz, 6H); 13C NMR: (50 MHz, CDCl3) d 168.1,
143.2, 108.4, 99.7, 59.3, 41.0, 23.9, 13.1; IR: (neat) nmax
2989.9, 1648.4, 1610.6, 1232.5 cm21; MS: (CI) m/z 214
[M1H]1 8.2%; HRMS: (EI) m/z 213.1368 (213.1365
calcd for C11H19NO3).
2,2-Dimethyl-5-(triisopropylsilylethynyl)-4H-1,3-dioxin
(5e). To a stirred solution of tri¯ate 3 (166.2 mg,
0.634 mmol) in diethylamine (3 mL), previously purged
with a stream of argon, was added triisopropylsilylacetylene
(284 mL, 1.27 mmol), CuI (6.0 mg, 0.032 mmol) and
Pd(PPh3)4 (22 mg, 0.019 mmol) at rt. After 32 h, water
(20 mL) was added and the resultant mixture extracted
with Et2O (4£20 mL). The combined organic fractions
were dried (MgSO4), ®ltered and reduced in vacuo to
yield a black oil. Further puri®cation by ¯ash chromato-
graphy (silica ratio 100:1, hexane/EtOAc 50:1) yielded a
colorless oil (152.4 mg, 82%). Rf: 0.60 (hexane/EtOAc
2,2-Dimethyl-5-(N,O-dimethylhydroxyaminocarbonyl)-
4H-1,3-dioxin (5h). To a solution of tri¯ate 3 (390.6 mg,
1.489 mmol) and dppp (46.2 mg, 0.112 mmol) in dimethyl-
formamide/N,O-dimethylhydroxylamine 4:1 (10 mL), prev-
iously purged with a stream of CO, was added triethylamine
(418 mL, 2.98 mmol) and Pd(OAc)2 (25.1 mg, 0.112 mmol)
with stirring under an atmosphere of CO at rt. After 4 h, ice
water (50 mL) was added and the resultant mixture extracted
with Et2O (4£25 mL). The combined organic fractions were
dried (MgSO4), ®ltered and reduced in vacuo to yield a
black oil. Further puri®cation by ¯ash chromatography
(silica ratio 30:1, hexane/EtOAc 2:1) yielded a colorless
oil (150.0 mg, 50%). Rf: 0.20 (hexane/EtOAc 2:1); 1H
NMR: (200 MHz, CDCl3) d 7.60 (bs, 1H), 4.44 (d, Jˆ
1.4 Hz, 2H), 3.62 (s, 3H), 3.18 (s, 3H), 1.44 (s, 6H); 13C
NMR: (50 MHz, CDCl3) d 167.0, 151.8, 105.9, 100.2, 60.7,
59.2, 32.9, 23.9; IR: (neat) nmax 2993.7, 1652.3, 1603.0,
1231.7 cm21; MS: (EI) m/z 201 [M]1 4.6%; HRMS: (EI)
m/z 201.0999 (201.1001 calcd for C9H15NO4).
1
19:1); H NMR: (200 MHz, CDCl3) d 6.82 (s, 1H), 4.18
(s, 2H), 1.43 (s, 6H), 1.03 (bs, 21H); 13C NMR: (50 MHz,
CDCl3) d 148.2, 101.9, 99.5, 96.4, 91.4, 60.8, 24.1, 18.2,
10.8; IR: (neat) nmax 2942.8, 2865.3, 2140.5, 1632.8,
1232.8 cm21; MS: (CI) m/z 295 [M1H]1 47.7%; HRMS:
(EI) m/z 294.2003 (294.2015 calcd for C17H30O2Si).
5-Acetyl-2,2-dimethyl-4H-1,3-dioxin (5f). To a solution of
tri¯ate 3 (525 mg, 2.0 mmol) in dimethyl sulfoxide
(15 mL), was added sequentially ethyl vinyl ether
(957 mL, 10.0 mmol), triethylamine (558 mL, 4.0 mmol)
and Pd(OAc)2 (13.5 mg, 0.06 mmol) with stirring at rt.
After 24 h, the mixture was cooled to 08C, ice water
(75 mL) was added and the resultant mixture extracted
with Et2O (4£50 mL). The combined organic fractions
were dried (MgSO4), ®ltered and reduced in vacuo to
yield a brown oil, the intermediate enol ether (1H NMR:
(200 MHz, CDCl3) d 6.93 (bs, 1H), 4.27 (d, Jˆ1.4 Hz,
2H), 3.86 (d, Jˆ2.7 Hz, 1H), 3.76 (q, Jˆ7.0 Hz, 2H), 3.66
(d, Jˆ2.8 Hz, 1H), 1.41 (s, 6H), 1.27 (t, Jˆ7.0 Hz, 3H). The
residue was taken up in CHCl3 (15 mL), water was added
(5 drops), and the resultant mixture stirred at rt. After 24 h,
solvent was removed in vacuo to yield a brown oil. Further
puri®cation by ¯ash chromatography (silica ratio 30:1,
pentane/Et2O 3:1) yielded a colorless oil (210.5 mg, 67%).
Rf: 0.18 (pentane/Et2O 3:1); 1H NMR: (200 MHz, CDCl3) d
7.50 (s, 1H), 4.37 (s, 2H), 2.13 (s, 3H), 1.41 (s, 6H); 13C
NMR: (50 MHz, CDCl3) d 195.1, 154.3, 115.3, 101.3, 77.2,
2,2-Dimethyl-5-(5,7-octadienoyl)-4H-1,3-dioxin (5i). To a
stirred solution of 7-iodohepta-1,3-diene (111 mg,
0.50 mmol11) in Et2O (3.5 mL), cooled to 2788C, was
added dropwise a solution of t-BuLi in pentane (1.5 M,
0.60 mL, 0.90 mmol). After 2 h, this solution was added,
via cannula, to a stirred solution of amide 5h (40.2 mg,
0.20 mmol) in Et20 (1 mL) cooled to 08C, and then allowed
to warm to rt. After 75 min, sat. NH4Cl (10 mL) and water
(10 mL) were added and the resultant mixture extracted
with Et2O (4£20 mL). The combined organic fractions
were dried (MgSO4), ®ltered and reduced in vacuo to
yield a yellow oil. Further puri®cation by ¯ash chroma-
tography (silica ratio 150:1, hexane/EtOAc/1% NEt3 gradi-
ent elution 12:1 to 9:1) yielded a colorless oil (26.6 mg,
0.113 mmol, 56%). Rf: 0.18 (hexane/EtOAc 9:1); 1H
NMR: (200 MHz, CDCl3) d 7.54 (s, 1H), 6.29 (dt, Jˆ
16.9, 2£1.3 Hz, 1H), 6.04 (dd, Jˆ15.1, 10.5 Hz, 1H), 5.64
(~p, Jˆ7.3 Hz, 1H), 5.00 (m, 2H), 4.40 (d, Jˆ1.2 Hz, 2H),
2.44 (t, Jˆ7.5 Hz, 2H), 2.06 (q, Jˆ7.2 Hz, 2H), 1.69
(q, Jˆ7.3 Hz, 2H), 1.42 (s, 6H); 13C NMR: (50 MHz,
CDCl3) d 198.3, 154.0, 137.6, 134.7, 132.3, 115.6, 115.0,
101.5, 58.1, 35.0, 31.5, 23.8, 23.6; IR: (neat) nmax 2941.0,
1628.0, 1251.1, 1125.4 cm21; MS: (1ve FAB) m/z 237
58.0, 23.9; IR: (neat) nmax 2995, 1656, 1629, 1242 cm21
;
MS: (EI) m/z 156 [M]1 10.5%; HRMS: (EI) m/z 156.0787
(156.0786 calcd for C8H12O3).
5-(Diethylaminocarbonyl)-2,2-dimethyl-4H-1,3-dioxin (5g).
To a stirred solution of tri¯ate 3 (262 mg, 1.00 mmol) and

S. P. Fearnley et al. / Tetrahedron 56 (2000) 10275±10281
10279
1
[M1H]1 23%; HRMS: (EI) m/z 221.1185 [M2CH3]1
(221.1178 calcd for C13H17O3).
mixture. H NMR: (200 MHz, C7D8) d 8.97 (s, 1H), 5.94
(s, 1H), 4.43 (s, 1H), 1.1 (bm, 21H). Additional heating for
12 h afforded the dimer: d 9.19 (s, 1H), 6.78 (s, 1H), 2.32
(m, 1H), 1.92 (dm, Jˆ16.4 Hz, 1H), 1.71 (m, 1H), 1.50 (m,
1H), 1.1±0.9 (m, 42H). IR: (neat) nmax 2941.9, 2861.7,
2141.5, 1749.0, 1625.9, 1167.4 cm21; MS: (EI) m/z 472
[M1H]1 79%; HRMS: (EI) m/z 472.3184 (472.3193 calcd
for C28H48O2Si2).
Representative procedure for retrocycloaddition
A solution of dioxin (5±10 mg) in an appropriate deuterated
solvent (,0.7 mL) was transferred to a resealable NMR
tube and purged with a stream of argon for 20 min. A
trace of hydroquinone was added, the tube sealed and a
preliminary NMR recorded. The tube was placed in a sand
bath, the temperature increased until a reasonable rate of
retrocycloaddition was evident by NMR, and then main-
tained until completion of the reaction.
2-Methoxy-1-triisopropylsilylethynyl-4-trimethylsilyloxy-
3-cyclohexene-1-carboxaldehyde (6e). To a stirred solu-
tion of dioxin 5e (51.0 mg, 0.173 mmol) in toluene
(3 mL), was added neat Danishefsky's diene (67 mL,
0.346 mmol), and the mixture brought to re¯ux. After 5 h,
solvent was removed in vacuo to yield a pale yellow oil as a
4:1 mixture of diastereoisomers (78.9 mg, 100%). 1H NMR:
(200 MHz, CDCl3) d 9.64 (minor) and 9.51 (major) (2£s,
1H total), 5.06 (major) (dd, Jˆ5.3, 1 Hz) and 4.92 (minor)
(dm, Jˆ4.4 Hz) (1H total), 4.12 (m, 1H), 3.34 (minor) and
3.27 (major) (2£s, 3H total), 2.4±1.8 (m, 4H), 0.98 (m,
21H), 0.14 (m, 9H). This initial adduct mix was further
characterized as the corresponding 4-formyl-4-triisopropy-
lethynyl-2-cyclohexen-1one by mild acid hydrolysis. The
residue was taken up in THF (2 mL), THF-0.005 M HCl
2:1 (3 mL) added, and the resultant mixture stirred at rt.
After 5 h, water (10 mL) was added and the resultant
mixture extracted with Et2O (4£10 mL). The combined
organic fractions were dried (MgSO4), ®ltered and reduced
in vacuo to yield a pale yellow oil. Further puri®cation by
¯ash chromatography (silica ratio 100:1, pentane/Et2O 4:1)
proved problematic, due to co-elution of the corresponding
b-methoxyketones. However, preparative tlc. (20£20 cm
analytical plate, pentane/Et2O 4:1, 3 elutions) yielded a
sample of pure enone as a colorless oil (14.0 mg,
0.046 mmol, 27% isolated). Rf: 0.14 (pentane/Et2O 4:1);
1H NMR: (200 MHz, CDCl3) d 9.57 (s, 1H), 6.89
(d, Jˆ10.1 Hz, 1H), 6.12 (d, Jˆ10.1 Hz, 1H), 2.8±2.2
(m, 4H), 0.98 (s and m, 21H); 13C NMR: (50 MHz,
CDCl3) d 198.5, 194.3, 144.7, 131.0, 101.3, 90.4, 49.1,
33.5, 29.7, 17.9, 10.3; IR: (CHCl3) nmax 2945.1, 2162.2,
1736.2, 1688.6 cm21; MS: (EI) m/z 304 [M]1 5.2%;
HRMS: (EI) m/z 304.1856 (304.1858 calcd for C18H28O2Si).
2-Tri¯uoromethanesulfonyloxy-2-propenal. Dioxin
3
1
was heated in d6-benzene for 1.5 h at 808C. H NMR:
(200 MHz, C6D6) d 8.26 (s, 1H), 5.06 (d, Jˆ4.0 Hz, 1H),
4.52 (d, Jˆ4.0 Hz, 1H).
2-Hexyl-2-propenal (6a). Dioxin 5a was heated in CDCl3
for 3 h at 1158C with omission of dihydroquinone. Careful
evaporation of the solvent afforded a colorless oil (7.5 mg,
1
0.0535 mmol, 79%) H NMR: (200 MHz, CD2Cl2) d 9.54
(s, 1H), 6.23 (m, 1H), 5.98 (s, 1H), 2.24 (t, Jˆ6.8 Hz, 2H),
1.5±1.2 (bm, 8H), 0.88 (t, Jˆ6.7 Hz, 3H).
2-Phenyl-2-propenal (6b). Dioxin 5b was heated in d8-
toluene for 70 min at 120±1408C. H NMR: (200 MHz,
1
C7D8) d 9.42 (s, 1H), 7.37 (m, 2H), 7.12 (m, 3H), 5.95 (s,
1H), 5.36 (s, 1H). Extended reaction times and/or evapora-
tion of the solvent afforded the dimer as a colorless oil
1
(7.4 mg, 0.028 mmol, 97%). H NMR: (200 MHz, CDCl3)
d 9.56 (s, 1H), 7.5±7.1 (m, 11H), 2.6±2.1 (m, 4H); 13C
NMR (50 MHz, CDCl3) d 200.7, 140.6, 138.8, 136.9,
129.2, 128.9, 126.9, 126.0, 124.8, 115.2, 84.4, 27.5, 19.8;
IR (neat) nmax 2918.9, 1734.7, 1638.9, 1166.1 cm21
.
2-(1-Formylethenyl)benzaldehyde (6c). Dioxin 5c was
heated in CDCl3 for 48 h at 1308C with omission of dihydro-
quinone. Evaporation of the solvent afforded a colorless oil.
(6.6 mg, 0.041 mmol, 88%). 1H NMR: (200 MHz, CDCl3) d
9.94 (s, 1H), 9.83 (s, 1H), 7.94 (dd, Jˆ7.1, 2.0 Hz, 1H), 7.61
(m, 2H), 7.26 (m, 2H), 6.48 (s, 1H), 6.43 (s, 1H); 13C NMR:
(50 MHz, CDCl3) d 193.0, 192.4, 149.6, 136.6, 136.1,
134.9, 134.5, 131.7, 131.5, 129.7; IR: (neat) nmax 2923.4,
2850.0, 1692.6, 1198.0 cm21; MS: (EI) m/z 160 [M]1 60%;
HRMS: (EI) m/z 160.0521 (160.0524 calcd for C12H22O2).
3-Formyl-3-butenone (entry f, no diene). Heating dioxin
5f in d8-toluene for 2 h at 858C resulted in extensive decom-
position and/or polymerization, although signals attribu-
table to the initial retrocycloaddition product were evident
in the reaction mixture. 1H NMR: (200 MHz, C7D8) d 9.51
(s, 1H), 5.82 (s, 1H), 5.63 (s, 1H), 1.84 (s. 3H).
Isoquinoline-4-carbaldehyde (6d). Heating dioxin 5d in
d4-o-dichlorobenzene for 70 min at 1308C resulted in
clean retrocycloaddition, electrocyclization and aromatiza-
tion. 1H NMR: (200 MHz, d4-o-dcb) d 10.32 (d, Jˆ1.7 Hz,
1H), 9.28 (d, Jˆ0.7 Hz, 1H), 9.16 (d, Jˆ8.8 Hz, 1H), 8.83
(d, Jˆ1.5 Hz, 1H), 7.81 (d, Jˆ8.1 Hz, 1H), 7.71 (,tm,
Jˆ,7.7 Hz, 1H), 7.52 (bt, Jˆ7.5 Hz, 1H), 7.01 (s, 1H).
Evaporation, followed by ¯ash chromatography (silica
ratio 150:1, hexane/EtOAc 1:1) afforded an off-white solid
(4.9 mg, 97%). Mp: 100±1018C (lit.12 101±1038C.).
1-Acetyl-3-methyl-3-cyclohexene-1-carboxaldehyde and
1-acetyl-4-methyl-3-cyclohexene-1-carboxaldehyde (6f).
To a stirred solution of ketone 5f (50 mg, 0.32 mmol) in
benzene (3 mL), previously purged with a stream of
argon, was added isoprene (320 mL, 3.20 mmol) and the
mixture heated to re¯ux. After 7 h, additional isoprene
(160 mL, 1.60 mmol) was added and heating was continued
for 40 h. The solvent was removed in vacuo to yield a brown
oil. Further puri®cation by ¯ash chromatography (silica
ratio 100:1, hexane/EtOAc 6:1) yielded a colorless oil
Bis-2,5-(trimethylsilylethynyl)-3,4-dihydro-2H-pyran-2-
carbaldehyde (entry e, no diene). Dioxin 5e was heated in
d8-toluene at 1008C. Resonances attributable to the initial
retrocycloaddition product were evident in the reaction
1
(25.6 mg, 48%) which H NMR analysis revealed to be
a 4.5:1 mixture of the inseparable regioisomers. Rf: 0.36
1
(hexane/EtOAc 4:1); H NMR: (200 MHz, CDCl3) d 9.52

10280
S. P. Fearnley et al. / Tetrahedron 56 (2000) 10275±10281
(s, 1H), 5.42 (major) and 5.11 (minor) (2£bm, 1H total),
2.6±2.2 (m, 2H), 2.12 (s, 3H), 2.2±1.9 (m, 4H), 1.70 (minor)
and 1.60 (major) (2£bs, 3H total); 13C NMR: (50 MHz,
CDCl3) d 207.2, 201.6, 135.0, 121.3, 117.7, 63.9, 31.4,
27.2, 26.7, 26.3, 25.2, 24.8, 23.3, 22.9, 21.8; IR: (neat)
nmax 2925.6, 1703.6, 1440.5, 1355.8 cm21; MS: (CI) m/z
167 [M1H]1 84.5%; HRMS: (EI) m/z 166.0979
(166.0994 calcd for C10H14O2).
Acknowledgements
We appreciate the ®nancial support provided by the
National Institutes of Health (GM28553).
References
1. For selected examples, see: Euplotins: (a) Guella, G.; Dini, F.;
Tomei, A.; Pietra, F. J. Chem. Soc. P.T. 1 1994, 17, 161. Iridoids
and secoiridoids: (b) Kupchan, S. M.; Dessertine, A. L.; Blaylock,
B. T.; Bryan, R. F. J. Org. Chem. 1974, 39, 2477. (c) Tietze, L-F.
Angew. Chem., Int. Ed. Engl. 1983, 22, 828. (d) Ray, S.;
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9973. Heteroyohimbine alkaloids: (g) Wenkert, E.; Wickberg, B.;
Leicht, C. L. J. Am. Chem. Soc. 1961, 83, 5037. (h) Shamma M.;
Moss, J. B. J. Am. Chem. Soc. 1961, 83, 5038. Macroline alkaloids:
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Tetrahedron Lett. 1997, 38, 477. Secoaromadendrane
sesquiterpenoids: (j) Asakawa, Y.; Shigeru, T.; Tori, M.;
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2. For a novel application of this basic strategy in the synthesis of
heteroyohimbine alkaloids wherein an activated heterodienophile
(2-buteneamide) underwent an intramolecular cycloaddition with
an unactivated heterodiene (b-substituted acrolein), see: Martin,
S. F.; Clark, C. W.; Corbett, J. W. J. Org. Chem. 1995, 60, 3236.
(b) Martin, S. F.; Benage, B. Geraci, L. S.; Hunter, J. E.;
Mortimore, M. J. Am. Chem. Soc. 1991, 113, 6161. For the
synthesis of deoxyloganin and ajmalicine via intramolecular
cycloaddition reactions of alkylidine Meldrum's acid derivatives,
see respectively: (c) Tietze, L. F.; Denzer, H.; Holdgrun, X.;
Neumann, M. Angew. Chem. Int. Ed. Engl. 1987, 26, 1295.
(d) Takano, S.; Sataoh, S.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1988, 59.
N,N-Diethyl-2-formylpropenamide (entry g, no diene).
Heating dioxin 5g in d8-toluene for 2.75 h at 1008C resulted
in clean retrocycloaddition. H NMR: (200 MHz, C7D8) d
9.04 (s, 1H), 5.77 (s, 1H), 5.32 (s, 1H), 3.21 (q, Jˆ7.2 Hz,
2H), 2.56 (q, Jˆ7.2 Hz, 2H), 0.97 (t, Jˆ7.1 Hz, 3H), 0.68
(t, Jˆ7.1 Hz, 3H).
1
N,N-Diethyl-2-isobutoxy-4H-2,3-dihydropyran-4-carbox-
amide (6g). A stirred solution of dioxin 5g (12.0 mg,
0.056 mmol) in isobutyl vinyl ether (2 mL), previously
purged with a stream of argon for 15 min, was heated to
re¯ux. After 48 h the solvent was removed in vacuo to yield
a brown oil. Further puri®cation by ¯ash chromatography
(silica ratio 65:1, hexane/EtOAc 3:1) yielded a colorless oil
1
(13.1 mg, 92%). Rf: 0.29 (hexane/EtOAc 1:1); H NMR:
(200 MHz, CDCl3) d 6.53 (s, 1H), 5.01 (t, Jˆ2.9 Hz, 1H),
3.51 (dd, Jˆ9.3, 7.0 Hz, 1H), 3.36 (q, Jˆ7.0 Hz, 4H), 3.27
(dd, Jˆ9.3, 6.3 Hz, 1H), 2.25 (m, 2H), 1.82 (m, 3H), 1.54
(s, 6H), 1.09 (t, Jˆ7.2 Hz, 6H), 0.85 (d, Jˆ6.8 Hz, 6H); 13C
NMR: (50 MHz, CDCl3) 171.4, 142.0, 111.3, 97.0, 75.0,
40.9, 28.1, 25.6, 18.7, 17.3, 13.2; IR: (neat) nmax 2961.8,
1651.4, 1622.0, 1058.9 cm21; MS: (CI) m/z 256 [M1H]1
100%; HRMS: (EI) m/z 255.1817 (255.1834 calcd for
C14H25NO3).
N-Methoxy-N-methyl-2-isobutoxy-4H-2,3-dihydropyran-
4-carboxamide (6h). A stirred solution dioxin 5h (11.2 mg,
0.0556 mmol) in isobutyl vinyl ether (2 mL), previously
purged with a stream of argon for 15 min, was heated to
re¯ux. After 26 h, solvent was removed in vacuo to yield a
brown oil. Further puri®cation by ¯ash chromatography
(silica ratio 100:1, hexane/EtOAc gradient elution 3:1
to 2:1) yielded a colorless oil (9.4 mg, 70%). Rf: 0.40
3. For the preparation of akylidenemalonaldehydes and their inter-
molecular cycloaddition reactions with enol ethers, see: (a) Tietze,
L.-F.; Glusenkamp, K-H.; Holla, W. Angew. Chem. Int. Ed. Engl.
1982, 21, 793. (b) Arnold, Z.; Kryshtal, G. V.; Kral, V.; Dvorak,
D.; Yanovskaya, L. A. Tetrahedron Lett. 1988, 29, 2861. (c) For
the cycloaddition reactions of the alkylidene derivatives of 4,4,4-
trichloro-3-oxobutanal, see: Tietze, L. F.; Meier, H.; Nutt, H.
Liebigs Ann. Chem. 1990, 253.
1
(hexane/EtOAc 1:1); H NMR: (200 MHz, CDCl3) d 7.30
(s, 1H), 5.05 (t, Jˆ3.1 Hz, 1H), 3.60 (s, 3H), 3.51 (dd,
Jˆ9.3, 6.9 Hz, 1H), 3.29 (dd, Jˆ9.4, 6.3 Hz, 1H), 3.19
(s, 3H), 2.55±2.2 (m, 2H), 1.95±1.65 (m, 3H), 0.847 and
0.842 (2£d, Jˆ6.7 Hz, 2£3H); 13C NMR: (50 MHz, CDCl3)
d 170.5, 149.9, 109.1, 97.7, 75.2, 60.5, 33.4, 28.1, 25.8, 18.8
(£2), 16.8; IR: (neat) nmax 2958.3, 1649.8, 1100.2,
1051.8 cm21; MS: (CI) m/z 244 [M1H]1 100%.
4. (a) Funk, R. L.; Bolton, G. L. J. Am. Chem. Soc. 1988, 110,
1290. (b) Funk, R. L.; Yost III, K. J. J. Org. Chem. 1996, 61, 2598.
5. For reviews, see: (a) Desimoni, G.; Tacconi, G. Chem. Rev.
1975, 75, 651. (b) Waldmann, H. Synthesis 1994, 535. (c) Tietze,
L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1.
6. For other examples of 1,1-diactivated alkenes and their high reac-
tivity, see: Methylenemalonates: (a) Roberts, B. W.; Ballesteros, P.;
Wong, J. J. Org. Chem. 1983, 48, 3603. a-Methylene-b-diketones
and a-methylene-b-keto esters: (b) Reich, H. J.; Renga, J. M.;
Reich, I. L. J. Org. Chem. 1974, 39, 2133. (c) Hoye, T. R.; Caruso,
A. J.; Magee, A. S. J. Org. Chem. 1982, 47, 4152. (d) Yamauchi,
M.; Katayama, S.; Watanabe, T. Synthesis 1982, 935.
(e) Yamauchi, M.; Honda, Y.; Matsuki, N.; Watanabe, T.; Date,
K.; Hiramatsu, H. J. Org. Chem. 1996, 61, 2179. (f) Hoffmann,
H. M. R.; Gassner, A.; Eggert, U. Chem. Ber. 1991, 124, 2475.
a-Methylene-b-keto sulfones and a-methylene-b-keto sulfoxides:
(g) Hoffmann, H. M. R.; Weichert, A. Chem. Ber. 1991, 56, 4098.
(h) Maignan, C.; Dujardin, G.; Hayes, P. Tetrahedron Lett. 1996,
cis- and trans-1-Decalones 6i. Dioxin 5i was heated in d6-
benzene for 14 h at 708C. 1H NMR: (200 MHz, C6D6) d 9.63
(minor) and 9.06 (major) (2£s, 1H total), 5.5±5.3 (m, 1H),
5.23 (minor) (dm, Jˆ9.9 Hz) and 5.08 (major) (dm,
Jˆ10.0 Hz) (1H total), 2.54 (major) and 2.37 (minor)
(2£m, 1H total), 2.2±1.8 (m, 4H), 1.8±1.0 (m, 6H).
Evaporation of the solvent and ®ltration through silica gel
yielded a colorless oil (3.7 mg, 80%), as a 2:1 mixture of
inseparable stereoisomers. Rf: 0.47 (hexane/EtOAc 4:1); IR:
(CHCl3) nmax 2932, 1727, 1701, 1120 cm21; MS: (EI) m/z
178 [M]1 16%; HRMS: (EI) m/z 178.0998 (178.0994 calcd
for C11H14O2).

S. P. Fearnley et al. / Tetrahedron 56 (2000) 10275±10281
10281
37, 3687. 1,1-Bis(benzenesulfonyl)ethylene: Lucchi, O. D.;
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7. Hoppe, D.; Schmincke, H.; Kleemann, H.-W. Tetrahedron
1989, 45, 687.
endo transition state although the cis/trans product ratio is depen-
dent upon the oxidant employed (Na2Cr2O7, H2SO4, Et2O/H2O; 4:1
or active MnO2, HCCl3; 19:1) and is suggestive of an acid-
catalyzed cycloaddition and/or subsequent equilibration, see:
Gras, J.-L.; Bertrand, M. Tetrahedron Lett. 1979, 10, 4549. The
cyclization of 2-methylene-1,7,9-decatrienal is unknown. An
examination of the cycloadditions of these two compounds under
strictly neutral conditions is warranted.
8. Ritter, K. Synthesis 1993, 735.
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