Highly selective palladium-catalyzed synthesis of protected α,β-unsaturated methyl ketones and 2-alkoxy-1,3-butadienes. High-speed chemistry by microwave flash heating

Article abstract of DOI:10.1021/jo000070o

A selective and mild procedure is described for the direct synthesis of 2-alkene-2-methyl-1,3-dioxolanes via regiocontrolled Heck vinylation of commercially available 2-hydroxyethyl vinyl ether. The procedure permits chemoselective transformation of a vin

Full text of DOI:10.1021/jo000070o

J . Org. Chem. 2000, 65, 4537-4542
4537
High ly Selective P a lla d iu m -Ca ta lyzed Syn th esis of P r otected
r,â-Un sa tu r a ted Meth yl Keton es a n d 2-Alk oxy-1,3-bu ta d ien es.
High -Sp eed Ch em istr y by Micr ow a ve F la sh Hea tin g
Karl S. A. Vallin, Mats Larhed, Katarina J ohansson, and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Box
574, SE-751 23 Uppsala, Sweden
Received J anuary 19, 2000
A selective and mild procedure is described for the direct synthesis of 2-alkene-2-methyl-1,3-
dioxolanes via regiocontrolled Heck vinylation of commercially available 2-hydroxyethyl vinyl ether.
The procedure permits chemoselective transformation of a vinylic triflate or bromide into a blocked
R,â-unsaturated methyl ketone. Furthermore, a significantly improved and highly regioselective
synthesis of 2-alkoxy-1,3-butadienes has been developed. Flash heating by microwave irradiation
promotes the palladium-catalyzed reactions, and the starting materials are fully converted after
reaction times of 5-7 min.
In tr od u ction
dienes deliver R,â-unsaturated methyl ketones, or alter-
natively they may serve as dienes in Diels-Alder reac-
tions.18,19
Dioxolanation is one of the most widely used protective
techniques for carbonyl compounds.1-3 Frequently, the
presence of sensitive groups might not permit the use of
the standard conditions needed for acetal formation, and
in systems with more than one carbonyl group, a selective
acetalization is often not feasible.1-4 Recently it was
demonstrated that a direct chemoselective synthesis of
cyclic acetals of acetophenones from aryl triflates or
halides could be accomplished via internal palladium-
catalyzed R-arylation of hydroxyalkyl vinyl ethers and
successive ring-closing.5 The preparation of nonprotected
acetophenones by Heck6-10 R-arylation of alkyl vinyl
ethers followed by hydrolysis11 has been known for almost
two decades.12-16 The related regioselective palladium-
catalyzed R-vinylation of alkyl vinyl ethers affords
2-alkoxy-1,3-dienes.17 After subsequent hydrolysis these
Unfortunately, with certain combinations of reactants
the vinylic substitution is hampered with difficulties,19
and an unsatisfactory regiocontrol in the Heck vinyla-
tion19,20 often accounts for the low yields encountered.
Cross-coupling methodologies, despite requiring prepara-
tion of, e.g., vinyl zinc,20 tin,21 and silicon22 reactants,
have therefore up to now attracted more attention when
2-alkoxy-1,3-dienes are desired.
We herein report, first a new bidentate ligand-
controlled, highly regioselective synthesis of 2-alkoxy-1,3-
dienes (3, eq 1) and, second, a mild chemo- and regio-
(1) Meskens, F. A. J . Synthesis 1981, 501-502.
(2) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley & Sons, Inc.: New York, 1999; pp 297-
329.
(3) J arowicki, K.; Kocienski, P. J . Chem. Soc., Perkin Trans. 1 1998,
4005-4037.
(4) Hwu, J . R.; Wetzel, J . M. J . Org. Chem. 1985, 50, 3946-3948.
(5) Larhed, M.; Hallberg, A. J . Org. Chem. 1997, 62, 7858-7862.
(6) Larock, R. C. In Advances in Metal-Organic Chemistry; Liebe-
skind, L. S., Ed.; J AI Press Inc.: Greenwich, CT, 1994; Vol. 3, pp 97-
224.
(7) De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379-2411.
(8) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
(9) J effery, T. In Advances in Metal-Organic Chemistry; Liebeskind,
L. S., Ed.; J AI Press: Greenwich, CT, 1996; Vol. 5, pp 153-260.
(10) Larhed, M.; Hallberg, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Inter-
science: New York, in preparation.
selective procedure for the direct synthesis of 2-alkene-
2-methyl-1,3-dioxolanes (4, eq 1) via Heck vinylation of
commercially available 2-hydroxyethyl vinyl ether (1b,
eq 1). The latter one-pot procedure allows for the facile
transformation of a vinyl triflate or bromide into a
blocked R,â-unsaturated methyl ketone (4).23 Flash heat-
ing by microwave irradiation, as a complement to the
standard thermal heating, was employed to drastically
reduce reaction times.
(11) DeVries, R. A. U.S. Patent 5248829, 1993.
(12) Arai, I.; Daves, G. D., J r. J . Org. Chem. 1979, 44, 21-22.
(13) Hallberg, A.; Westfelt, L.; Holm, B. J . Org. Chem. 1981, 46,
5414-5415.
(18) Paquette, L. A.; Ra, C. S.; Edmonson, S. D. J . Org. Chem. 1990,
55, 2443-2445.
(14) Andersson, C.-M.; Hallberg, A.; Daves, G. D. J . Org. Chem.
1987, 52, 3529-3536.
(19) Oh, J .; Cha, J . K. Synlett 1994, 967-968.
(20) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1990,
31, 1889-1892.
(15) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J . Org. Chem.
1990, 55, 3654-3655.
(21) Kwon, H. B.; Mckee, B. H.; Stille, J . K. J . Org. Chem. 1990,
55, 3114-3118.
(16) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J . Org.
Chem. 1992, 57, 1481-1486.
(22) Hatanaka, Y.; Hiyama, T. J . Org. Chem. 1988, 53, 918-920.
(23) Mcclelland, R. A.; Watada, B.; Lew, C. S. Q. J . Chem. Soc.,
Perkin Trans. 2 1993, 1723-1727.
(17) Andersson, C.-M.; Hallberg, A. J . Org. Chem. 1989, 54, 1502-
1505.
10.1021/jo000070o CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/27/2000

4538 J . Org. Chem., Vol. 65, No. 15, 2000
Vallin et al.
Resu lts
The preparative results after the reaction of a series
of diverse vinyl triflates and bromides 2a -g with butyl
vinyl ether (1a ) or 2-hydroxyethyl vinyl ether (1b) are
summarized in Table 1. Two methods were devised (A
and B). The vinylating agents were allowed to react
either with 2.0 equiv of vinyl ether (1a or 1b), palladium
acetate (0.03 equiv), 1,3-bis(diphenylphosphino)propane
(DPPP), and freshly distilled triethylamine (method A)
or with a larger excess (5.0 equiv) of vinyl ether,24
palladium acetate (0.03 equiv), (R)-(+)-2,2′-bis(di-p-
tolylphosphino)-1,1′-binaphthyl (tol-BINAP), and potas-
sium carbonate as base (method B). Method A was
applied in all dioxolanations and microwave-enhanced
reactions. Utilizing vinyl bromides as starting materials
required stoichiometric addition of thallium(I) acetate25
to afford high internal regioselectivity.16,26 The reactions
were performed in dry DMSO under nitrogen and in the
presence of molecular sieves to suppress the hydrolysis
of products that otherwise were prevalent.20 A very high
R/â regioselectivity (>98/2) was achieved with conven-
tional heating, and both the alkoxy dienes 3a -g and the
R,â-unsaturated acetals 4a -g were isolated in fair to
good yields in most cases after chromatography under
basic conditions.4,27-30 Notably, while the dienylacetal 4g
was smoothly formed from the organotriflate 2g, addition
of dry acetic acid was required to ensure full ring closure
after complete consumption of the vinyl triflates 2a -c
(entries 2, 4, and 6, Table 1). The cyclic vinyl bromide
2f, with a carbonyl group adjacent to the reaction center,
underwent the most sluggish reactions. With this vinyl
bromide a considerable reduction (dehalogenation) oc-
curred, and high temperatures and long reactions times
were needed to fully convert the starting material (entries
11 and 12). The low isolated yields encountered in the
diene synthesis of 3e from the aldehyde 2e seem to be
attributed mainly to a significant and concomitant po-
lymerization (entry 9). The vinyl palladium precursors
2e, 2f, and 2g with aldehyde or keto groups were selected
as substrates to permit assessment of potential transac-
etalizations.5,31 No products derived from transacetaliza-
tion could be traced even after analysis of reactions
conducted at high temperatures (entries 10, 12, and 14).
Thus, the procedure seems to be completely chemoselec-
tive. Although only a few examples are given here
(entries 9-14), we assume that the reactions should
provide a facile route to monoprotected dicarbonyl com-
pounds (eq 2).
previously used flash heating by microwaves for the
acceleration of various palladium-catalyzed transforma-
tions.32-35 This in situ mode of energy conversion provides
many benefits to the organic chemist since microwaves
can heat the reaction mixture very rapidly, uniformly,
and directly, without any problems of heat transfer
through the walls of the reaction vessel.36 The reactions
were conducted with a commercially available single-
mode microwave cavity in septum-sealed heavy-walled
Pyrex tubes. To survey the scope of this heating meth-
odology, the vinyl triflates 2a and 2c, the dienyl triflate
2g, and the slowly reacting vinyl bromide 2f were
selected as representative vinylating agents. The experi-
ments were performed without stirring in DMSO; a
solvent that possesses a very high dissipation factor (tan
δ ) 0.825 at rt).37,38 Microwave treatment with 5-25 W
magnetron input power for 5.0-7.0 min resulted in
complete conversion and almost identical isolated yields
to what was experienced under classical, thermal heating
(entries 1, 2, 5, 6, and 11-14). To obtain full conversion
of 2, it was highly important to find the correct balance
between microwave power and irradiation time. The
preparations of 3c, 3g, 4a , 4c, 4f, and 4g were success-
fully accelerated, and high R/â ratios (>98/2) were
encountered. The high R-selectivity (3/5) was partly lost
in entries 1 and 11. The preparative results are shown
in Table 1.
The important issue of the actual reaction temperature
under microwave irradiation has previously not been
addressed in context with palladium-catalyses in closed
reaction vessels, as no suitable equipment for tempera-
ture measurements was available.39 However, the use of
fluoroptic probes40 has now allowed the determination
of temperature/time/power profiles.41 Figure 1 describes
the temperature profiles for septum-sealed Heck reac-
tions (entries 2, 5, 11, and 12) in DMSO medium under
5-7 min of irradiation at various power inputs. A
microwave power of 20-25 W for 5-7 min rapidlypro-
duced high temperatures (192-216 °C), which apparently
had a negative impact on the regiocontrol in one of the
(32) Larhed, M.; Hallberg, A. J . Org. Chem. 1996, 61, 9582-9584.
(33) Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. J . Org.
Chem. 1999, 64, 1082-1083.
The long reaction times needed for the acetal and diene
syntheses presented in Table 1 encouraged us to exploit
microwaves as a nonconventional and energy-efficient
heating source for promotion of the reactions. We have
(34) Olofsson, K.; Kim, S.-Y.; Larhed, M.; Curran, D. P.; Hallberg,
A. J . Org. Chem. 1999, 64, 4539-4541.
(35) Alterman, M.; Andersson, H. O.; Garg, N.; Ahlsen, G.; Lo¨vgren,
S.; Classon, B.; Danielson, U. H.; Kvarnstro¨m, I.; Vrang, L.; Unge, T.;
Samuelsson, B.; Hallberg, A. J . Med. Chem. 1999, 42, 3835-3844.
(36) Cundy, C. S. Collect. Czech. Chem. Commun. 1998, 63, 1699-
1723.
(37) Generally, solvents with tan δ greater than 0.1 are effective in
microwave flash heating. See ref 38.
(38) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J .; Mingos,
D. M. P. Chem. Soc. Rev. 1998, 27, 213-223.
(39) Clearly, in the absence of a correct temperature profile, a
reaction may not be reproducible when different microwave heating
systems are used.
(24) To ensure full conversion of the vinyl bromide or vinyl triflate
and to suppress homocoupling, 5 equiv of 1a was utilized.
(25) Caution! Thallium acetate is a very toxic salt.
(26) Grigg, R.; Loganathan, V.; Santhakumar, V.; Sridharan, V.;
Teasdale, A. Tetrahedron Lett. 1991, 32, 687-690.
(27) R,â-Unsaturated dioxolanes are very sensitive to hydrolysis,
even that occurring on silica gel or on alumina columns. See refs 28-
30.
(28) Huet, F.; Pellet, M.; Conia, J . M. Tetrahedron Lett. 1977, 3505-
3508.
(29) Brown, J . J .; Lenhard, R. H.; Bernstein, S. J . Am. Chem. Soc.
1964, 86, 2183-2187.
(30) Becker, D.; Brodsky, N. C.; Kalo, J . J . Org. Chem. 1978, 43,
2557-2562.
(31) Kim, S.; Kim, Y. G.; Kim, D.-I. Tetrahedron Lett. 1992, 33,
2565-2566.
(40) Mingos, D. M. P.; Whittaker, A. G. In Chemistry Under Extreme
or Non-Classical Conditions; Van Eldik, R., Hubbard, C. D., Eds.; J ohn
Wiley & Sons and Spektrum Akademischer Verlag: New York, 1997;
pp 479-514.
(41) Kaiser, N.-F. K.; Bremberg, U.; Larhed, M.; Moberg, C.;
Hallberg, A. J . Organomet. Chem., in press.

Methyl Ketone and 2-Alkoxy-1,3-butadiene Synthesis
J . Org. Chem., Vol. 65, No. 15, 2000 4539
Ta ble 1. Th er m a l a n d Micr ow a ve-Hea ted Syn th esis of Alk oxy Dien es 3 a n d Cyclic Aceta ls 4i
a
b
Continuous irradiation (2450 MHz, Microwell 10, magnetron input power 5-25 W). Determined by GC/MS and NMR. c Greater
than 95% purity by GC/MS. A 10.0 equiv sample of vinyl ether was utilized to suppress homocoupling. e Isolated as a mixture of R- and
d
â-regioisomers (3 + 5). f Dry HOAc was added for ring-closure. E/ Z > 97/3, determined by NOE. E/ Z ) 90/10, was determined by
g
h
i
NOE. Reaction conditions: (method A) 1.0 equiv of 2a -g, 2.0 equiv of vinyl ether, 3 mol % Pd(OAc)2, 6 mol % DPPP, 1.5 equiv of Et3N,
molecular sieves (4 Å) in DMSO under N2; (method B) 1.0 equiv of 2b,d ,f, 2.0 equiv, 5.0 equiv of vinyl ether, 3 mol % Pd(OAc)2, 6 mol %
tol-BINAP, 1.5 equiv of K2CO3, molecular sieves (4 Å) in DMSO under N2. Reactions were conducted in Pyrex tubes sealed with a silicon
septum.

4540 J . Org. Chem., Vol. 65, No. 15, 2000
Vallin et al.
regularly found with 1a and 1b, and the only deviation
from this general observation was noted in the microwave-
accelerated vinylation of 2a and 2f (entries 1 and 11,
Table 1). This new ligand-controlled and highly selective
procedure for internal Heck vinylation of 1a is superior
to the previously reported methodology.17
The cyclization of the R-vinylated 1b to the corre-
sponding acetal is probably not catalyzed by palladium.5
The ring closure most likely occurs via an initial proto-
nation at the terminal â-position49-52 (by HNEt3 or
+
HOAc) of the R-vinyl-substituted vinyl ether followed by
an intramolecular nucleophilic attack by the hydroxyl
group at the oxygen-stabilized cation (eq 3).23,53
F igu r e 1. Temperature profiles for Heck reactions in
DMSO: (a) 5 min and 25 W (entry 11); (b) 7 min and 20 W
(entry 12); (c) 5 min and 10 W (entry 2); (d) 5 min and 5 W
(entry 5). Different organohalides or organotriflates did not
change the temperature profiles. The data collection time
started 20 s before and finished 60 s after the irradiation time
of 5 min. Temperature profiles were recorded using fluoroptic
probes.
insertions (entry 11). With the highest power (25 W)
considerable superheating is noted (bp(DMSO) ) 189 °C).
Since the energy carried by microwaves at the output
frequency of 2450 MHz is too small (∼1 J /mol) to induce
any noteworthy direct molecular activation,36 the overall
advantage of microwave heating lies in the direct rapid
in situ heating and in the bulk superheating that easily
can be achieved.42,43 We believe these factors alone can
account for the accelerated reaction rates.
Discu ssion
Intermolecular Heck vinylations generally proceed
with more unpredictable regio- and stereochemical out-
come as compared to the corresponding Heck arylations.9
The selectivity is often low, but with certain alkenes, e.g.,
acrylates, acrylonitriles, or vinylglycine, a range of suc-
cessful terminal â-vinylation procedures have been
reported.44-46 Furthermore, examples of R-vinylations of
alkyl vinyl ethers have previously been disclosed by us.17
The synthesis of the vinyl acetals and alkoxy dienes
reported herein relies on a highly regioselective vinyl
group insertion encountered with cationic π-complexes
(eq 3).8 These cationic intermediates are created by
spontaneous dissociation of the weakly coordinating
triflate anion47 or, when vinyl bromides are utilized, by
addition of thallium acetate.16 The bidentate ligands
introduced by Cabri et al.16 to promote internal arylation
of electron-rich olefins ensure that the reaction follows
the cationic route.48 Importantly, the same R/â ratio was
Con clu sion
In conclusion, the palladium-catalyzed 2-alkoxy-1,3-
diene synthesis provides a facile and experimentally very
simple alternative to other more elaborate cross-coupling
methodologies. In view of the known difficulties in
preparing selectively monoblocked dicarbonyl compounds,
we also believe that the direct preparation of 2-alkene-
2-methyl-1,3-dioxolanes from vinyl triflates or bromides
constitutes a valuable new method. The procedure also
provides a mild synthetic method for the transformation
of ketones, via their vinyl triflates, into protected R,â-
unsaturated methyl ketones, a class of compounds that
are not easily acquired by other methods.29,54-58 Finally,
(49) J ones, D. M.; Wood, N. F. J . Chem. Soc. 1964, 5400-5403.
(50) Salomaa, P.; Kankaanpera¨, A.; Lajunen, M. Acta Chem. Scand.
1966, 20, 1790-1801.
(42) Organic solvents superheat under microwave irradiation even
at atmospheric pressure; see ref 43.
(43) Mingos, D. M. P. Res. Chem. Intermed. 1994, 20, 85-91.
(44) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1991,
32, 1579-1582.
(45) Crisp, G. T.; Glink, P. T. Tetrahedron 1992, 48, 3541-3556.
(46) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427-436.
(47) Amatore, C.; J utand, A. J . Organomet. Chem. 1999, 576, 254-
278.
(48) The bidentate ligand DPPP (method A) or tol-BINAP (method
B) delivered a higher R/â ratio than the monodentate PPh3, which was
employed in the initial studies.
(51) Kresge, A. J .; Chen, H. J . J . Am. Chem. Soc. 1972, 94, 2818-
2822.
(52) Burt, R. A.; Chiang, Y.; Kresge, A. J .; Szilagyi, S. Can. J . Chem.
1984, 62, 74-76.
(53) Deslongchamps, P.; Dory, Y. L.; Li, S. G. Helv. Chim. Acta 1996,
79, 41-50.
(54) Acetal formation from R,â-unsaturated ketones using ethylene
glycol and strong protic acids typically requires a large amount of acid
and often leads to formation of undesirable side products (e.g., â,γ-
unsaturated acetals). See refs 1, 2, 28-30, and 55-58.

Methyl Ketone and 2-Alkoxy-1,3-butadiene Synthesis
J . Org. Chem., Vol. 65, No. 15, 2000 4541
Palladium(II) acetate, thallium(I) acetate,25 1,3-bis(diphen-
ylphosphino)propane (DPPP), oven-dried (300 °C for 48 h)
molecular sieves (4 Å), (R)-(+)-2,2′-bis(di-p-tolylphosphino)-
1,1′-binaphthyl [(R)-(+)-tol-BINAP], and K2CO3 (oven-dried at
300 °C for 48 h) were purchased from commercial suppliers
and were used directly as received. All reactions were per-
formed until complete consumption of the starting vinyl halide
or vinyl triflate was obtained, utilizing an appropriate choice
of thermal heating time and temperature, or microwave power
and irradiation time.
Syn th esis of 2-Alk oxy-1,3-Dien es. Gen er a l Meth od .
Meth od A (3a ,c,e,g). A mixture of the corresponding vinyl
triflate or bromide (0.50 mmol), butyl vinyl ether (0.10 g, 1.0
mmol), Pd(OAc)2 (0.0034 g, 0.0150 mmol), DPPP (0.012 g, 0.030
mmol), triethylamine (0.076 g, 0.750 mmol), molecular sieves
(0.50 g/mmol, 0.25 g), and, if present, TlOAc (0.16 g, 0.60
mmol)25 in 2.0 mL of dry DMSO was stirred under N2 in a
screwcap-sealed tube (for the reaction time and temperature
see Table 1).
Meth od B (3b,d ,f). A mixture of the corresponding vinyl
triflate or bromide (0.50 mmol), butyl vinyl ether (0.100 g, 1.0
mmol), Pd(OAc)2 (0.0034 g, 0.015 mmol), tol-BINAP (0.020 g,
0.030 mmol), K2CO3 (0.102 g, 0.750 mmol), molecular sieves
(0.50 g/mmol, 0.25 g), and, if present, TlOAc (0.16 g, 0.60
mmol)25 in 2.0 mL of dry DMSO was stirred under N2 in a
screwcap-sealed tube (for the reaction time and temperature
see Table 1).
After complete conversion of the starting vinyl triflate or
bromide as analyzed by GC/MS, the reaction mixture was
allowed to cool. The reaction mixture was thereafter poured
into 1 M NaOH and was extracted with diethyl ether. The
combined organic layers were washed with brine and concen-
trated at reduced pressure. The product was purified by
column chromatography or filtration (basic systems, >95%
pure by GC/MS).
1-(1-Bu toxyeth en yl)cycloh exen e (3a ; en tr y 1, m eth od
A):17 colorless oil; eluent diethyl ether, alumina; 1H NMR
(CDCl3) δ 6.28-6.34 (m, 1H), 4.14 (d, 1H, J ) 2.0 Hz), 3.98 (d,
1H, J ) 2.0 Hz), 3.72 (t, 2H, J ) 6.5 Hz), 2.09-2.21 (m, 4H),
1.36-1.79 (m, 8H), 0.95 (t, 3H, J ) 7.3 Hz); 13C NMR δ 160.6,
132.1, 124.8, 80.5, 66.8, 31.2, 25.4, 25.1, 22.7, 22.1, 19.5, 13.9;
MS (70 ev) m/z (relative intensity) 180 (6, M+), 165 (50), 109
(100).
2-Bu toxy-4-eth yl-1,3-h exa d ien e (3b, en tr y 3, m eth od
B):17 colorless oil; eluent diethyl ether, filtration through
Celite and dry K2CO3: 1H NMR (CDCl3) δ 5.57 (s, 1H), 4.04
(d, 1H, J ) 1.6 Hz), 3.98 (d, 1H, J ) 1.6 Hz), 3.69 (t, 2H, J )
6.4 Hz), 2.35 (q, 2H, J ) 7.5 Hz), 2.08 (dq, 2H, J ) 1.3, 7.5
Hz), 1.64-1.75 (m, 2H), 1.28-1,53 (m, 2H), 1.03 (t, 3H, J )
7.5 Hz), 1.02 (t, 3H, J ) 7.6 Hz), 0.95 (t, 3H, J ) 7.5 Hz); 13C
NMR δ 160.2, 148.6, 119.3, 84.6, 67.0, 31.2, 30.3, 24.9, 19.5,
13.9, 13.5, 12.7; MS (70 ev) m/z (relative intensity) 182 (8, M+),
125 (17), 111 (100).
4-(1-Bu t oxyvin yl)-7-m e t h oxy-1,2-d ih yd r on a p h t h a -
len e (3c; en tr y 5, m eth od A): white crystals; eluent pentane/
diethyl ether (19/1, v/v) with 1% (v) triethylamine, silica gel;
1H NMR (CDCl3) δ 7.22 (d, 1H, J ) 9.3 Hz), 6.69-6.72 (m,
2H), 6.16 (t, 1H, J ) 4.6 Hz), 4.29 (d, 1H, J ) 1.7 Hz), 4.22 (d,
1H, J ) 1.7 Hz), 3.81 (s, 3H), 3.80 (t, 2H, J ) 6.5 Hz), 2.76 (t,
2H, J ) 8.0 Hz), 2.30 (dt, 2H, J ) 8.0, 4.6 Hz), 1.72 (tt, 2H, J
) 6.5, 7.4 Hz), 1.45 (sext, 2H, J ) 7.4 Hz), 0.96 (t, 3H, J ) 7.4
Hz); 13C NMR (CDCl3) δ 161.4, 158.4, 138.1, 136.1, 126.5,
126.4, 125.9, 113.4, 110.9, 84.9, 67.3, 55.2, 31.1, 28.4, 23.0, 19.4,
13.8; MS (70 ev) m/z (relative intensity) 258 (45, M+), 186 (100),
115 (99). Anal. Calcd for C17H22O2: C, 79.03; H, 8.58. Found:
C, 78.97; H, 8.71.
application of microwave irradiation as the energy source
resulted in dramatically shortened reaction times, from
hours to a few minutes.
Exp er im en ta l Section
Gen er a l P r oced u r e. All reactions were conducted under
nitrogen in heavy-walled Pyrex tubes59 sealed with a screwcap
fitted with a Teflon gasket silicon septum. 1H NMR and 13C
NMR spectra were recorded in CDCl3 at 270 and 67.8 MHz.
Mass spectra were recorded at an ionizing voltage of 70 eV
(EI). The GC/MS was equipped with a HP-1 (25 m × 0.20 mm)
capillary column. Isomers were assumed to have the same
response factor. Column chromatography was performed using
commercially available silica gel 60 (particle size 0.040-0.063
mm, Merck) or on basic alumina (aluminum oxide 90, 0.063-
0.200 mm, Merck). Microwave heating was performed in a
MicroWell 10 single-mode microwave cavity60 from Personal
Chemistry AB, producing continuous irradiation at 2450 MHz.
Temperature profiles were recorded using a NoEMI-TS Reflex
(NortechFibronic, Inc.) utilizing temperature-sensitive fluor-
optic probes (TPP-01-M2.5-A; Nortech Fibronic). The probe was
positioned 2 cm above the bottom of the reaction tube. The
sampling rate was 3 Hz. After irradiation the samples were
allowed to cool in the cavity for 1 min before being handled.
The inner diameter of the Pyrex tubes was 11 mm, and the
height of the reaction mixture in the tube was 22 mm.
Contrary to conventional conductive heating, the rise in
temperature is dependent on both the volume and the geom-
etry of the reaction mixture. The reactions were performed
without stirring. Caution! Great care should be taken when
pressurized microwave reactions are performed.61 Elemental
analyses were performed by Micro Kemi AB, or Analytische
Laboratories, Prof. Dr. H. Malissa and G. Reuter GmbH. High-
resolution mass spectral (HRMS) data were performed by E.
Nilsson, University of Lund. The isolated products 3a ,b,d have
previously been characterized and the data obtained cor-
responded satisfactorily with MS and NMR literature data.17
Ma ter ia ls. Butyl vinyl ether (1a ) (Aldrich), 2-hydroxyethyl
vinyl ether (1b) (ethylene glycol vinyl ether, Aldrich) and
DMSO (H2O <0.01%, Fluka) were used as received. The vinyl
triflates 2a -c,g and the R-bromoketone 2f are known com-
pounds and were prepared by literature procedures.62-64
R-Bromostyrene (2d ) was purchased from Aldrich in >95%
purity, and (Z)-R-bromocinnamaldehyde65 (2e) was purchased
from Acros. Triethylamine was distilled over potassium hy-
droxide, and acetic acid was dried with P2O5 prior to use.
(55) de Leeuw, J . W.; de Waard, E. R.; Beetz, T.; Huisman, H. O.
Recl. Trav. Chim. Pays-Bas 1973, 92, 1047-1052.
(56) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357-1358.
(57) Otera, J .; Dan-oh, N.; Nozaki, H. Tetrahedron 1992, 48, 1449-
1456.
(58) Torok, D. S.; Figueroa, J . J .; Scott, W. J . J . Org. Chem. 1993,
58, 7274-7276.
(59) Baghurst, D. R.; Mingos, D. M. P. J . Chem. Soc., Dalton Trans
1 1992, 1151-1155.
(60) Stone-Elander, D. P.; Elander, N.; Thorell, J . O.; Solås, G.;
Svennebrink, J . J . Labeled Compd. Radiopharm. 1994, 34, 949-960.
(61) Kingston, H. M.; Walter, P. J .; Engelhart, W. G.; Parsons, P. J .
In Microwave-Enhanced Chemistry; Kingston, H. M., Haswell, S. J .,
Eds.; American Chemical Society: Washington, DC, 1997; pp 697-
745.
(62) BordWell, F. G.; Wellman, K. M. J . Org. Chem. 1963, 28, 2544-
2547.
(63) Pal, K. Synthesis 1995, 12, 1485-1487.
(64) Cacchi, S.; Morera, E.; Ortar, G. Org. Synth. 1990, 68, 138-
147.
2-Bu toxy-3-p h en yl-1,3-bu ta d ien e (3d ; en tr y 7, m eth od
(65) The assignment of the stereochemistry for (Z)-R-bromocinna-
maldehyde (2e) (Acros) is supported by NOE data, confirming the
proximity of the vinylic proton to the formyl group. Similarly, the
geometrical arrangement of the major product (E)-2-(1-formyl-2-
phenylethenyl)-2-methyl-1,3-dioxolane (4e) is confirmed by NOE be-
tween the aldehyde proton and one of the aromatic protons and, to a
lesser extent, between the vinylic proton and the methyl group. The
assignment of the major product (3E)-2-butoxy-3-formyl-4-phenyl-1,3-
butadiene (3e) is confirmed by NOE data between the aldehyde proton
and the vinylic proton.
B):17 pale yellow oil; eluent hexane with 3% (v) dimethylethyl-
1
amine, silica gel; H NMR (CDCl3) δ 7.29-7.39 (m, 5H), 5.72
(s, 1H), 5.22 (s, 1H) 4.27-4.29 (m, 1H), 4.12 (d, 1H, J ) 2.0
Hz), 3.81 (t, 2H, J ) 6.3 Hz), 1.72-1.79 (m, 2H), 1.45-1.60
(m, 2H), 0.98 (t, 3H, J ) 7.3 Hz); 13C NMR δ 160.2, 145.9,
140.4, 128.7, 127.8, 127.4, 114.7, 87.4, 67.4, 31.1, 19.4, 13.9;
MS (70 ev) m/z (relative intensity) 202 (21, M+), 131 (91), 103
(100).

4542 J . Org. Chem., Vol. 65, No. 15, 2000
Vallin et al.
(3E)-2-Bu toxy-3-for m yl-4-p h en yl-1,3-bu ta d ien e (3e; en -
tr y 9, m eth od A):65 colorless oil (mixture of geometrical
isomers, E/ Z ) 97/3); eluent pentane/diethyl ether (1/1, v/v),
alumina. Spectroscopic data are given for the major E-
isomer: 1H NMR (CDCl3) δ 9.59 (s, 1H), 7.59-7.64 (m, 2H),
7.35-7.42 (m, 3H), 7.29 (s, 1H), 4.48 (d, 1H, J ) 2.7 Hz), 4.22
(d, 1H, J ) 2.7 Hz), 3.81 (t, 2H, J ) 6.3 Hz), 1.55-1.67 (m,
2H), 1.24-1.38 (m, 2H), 0.88 (t, 3H, J ) 7.3 Hz); 13C NMR δ
192.5, 153.9, 150.1, 137.7, 133.8, 130.7, 130.6, 128.5, 87.9, 67.4,
30.8, 19.2, 13.7; MS (70 ev) m/z (relative intensity) 230 (17,
M+), 173 (100), 145 (91). Anal. Calcd for C15H18O2: C, 78.2; H,
7.9. Found: C, 78.2; H, 7.9.
2-(3,4-Dih yd r o-6-m eth oxy-1-n a p h th yl)-2-m eth yl-1,3-d i-
oxola n e (4c; en tr y 6): white crystals; eluent pentane/
1
triethylamine (5/1, v/v), silica gel; H NMR (CDCl3) δ 7.77-
7.73 (m, 1H), 6.75-6.71 (m, 2H), 6.25 (t, J ) 4.6 Hz, 1H), 4.05-
3.85 (m, 4H), 3.81 (s, 3H), 2.70 (t, J ) 7.6 Hz, 2H), 2.29-2.22
(m, 2H), 1.66 (s, 3H); 13C NMR δ 158.3, 139.5, 136.7, 126.9,
125.7, 123.9, 113.8, 110.9, 109.2, 64.3, 55.4, 29.3, 26.1, 22.8;
MS (70 eV) m/z (relative intensity) 246 (65, M+), 231 (100),
159 (28), 87 (84). Anal. Calcd for C15H18O2: C, 73.1; H, 7.4.
Found: C, 73.1; H, 7.4.
2-Met h yl-2-(1-p h en ylvin yl)-1,3-d ioxola n e (4d ; en t r y
8): yellow oil; eluent pentane/diethyl ether (19/1, v/v), alumina;
1H NMR (CDCl3) δ 7.54-7.49 (m, 2H), 7.37-7.29 (m, 3H), 5.57
(d, J ) 1.6 Hz, 1H), 5.27 (d, J ) 1.6 Hz, 1H), 4.09-3.96 (m,
4H), 1.50 (s, 3H); 13C NMR δ 149.2, 139.7, 128.4, 128.1, 127.5,
115.0, 109.2, 64.6, 25.2; MS (70 eV) m/z (relative intensity)
190 (2, M+), 87 (100), 43 (27). Anal. Calcd for C12H14O2: C,
75.8; H, 7.4. Found: C, 76.0; H, 7.6.
2-(1-Bu toxyvin yl)-4,4-d im eth yl-2-cycloh exen -1-on e (3f;
en tr y 11, m eth od B): colorless oil; eluent isohexane with 3%
1
(v) dimethylethylamine, alumina; H NMR (CDCl3) δ 6.93 (s,
1H), 4.79 (d, 1H, J ) 1.8 Hz), 3.98 (d, 1H, J ) 1.8 Hz), 3.71 (t,
2H, J ) 7.9 Hz, 2.49-2.54 (m, 2H), 1.82-1.88 (m, 2H), 1.64-
1.75 (m, 2H), 1.36-1.50 (m, 2H), 1.30-1.12 (m, 6H), 0.92-
1.98 (m, 3H); 13C NMR δ 197.1, 156.2, 154.9, 132.1, 87.2, 66.9,
35.9, 35.7, 33.0, 31.0, 27.9, 19.4, 13.9; MS (70 eV) m/z (relative
intensity) 222 (24, M+), 207 (17), 165 (100), 151 (91); high-
resolution MS (EI) calcd for C14H22O2 (M+) 222.1620, found
222.1619. Anal. Calcd for C14H22O2: C, 75.6; H, 10.0. Found:
C, 75.2; H, 10.2.
2-(1-F or m yl-2-p h e n yle t h e n -1-yl)-2-m e t h yl-1,3-d iox-
ola n e (4e; en tr y 10): yellow solid (mixture of geometrical
isomers, E/ Z ) 90/10);65 eluent pentane/diethyl ether (1/1, v/v),
alumina. Spectroscopic data are given for the major E-
isomer: 1H (CDCl3) NMR δ 9.86 (s, 1H), 7.93 (s, 1H), 7.43-
7.31 (m, 5H), 4.10-4.00 (m, 2H), 3.98-3.89 (m, 2H), 1.72 (s,
3H); 13C NMR δ 191.8, 145.0, 140.5, 133.3, 130.3, 129.7, 128.6,
107.8, 64.8, 25.5; MS (70 eV) m/z (relative intensity) 218 (13,
M+), 203 (49), 87 (100). Anal. Calcd for C13H14O2: C, 71.5; H,
6.5. Found: C, 71.6; H, 6.5.
3-(1-Bu toxyvin yl)p r egn a -3,5-d ien -20-on e (3g; en tr y 13,
m eth od A): white solid; eluent hexane/ethyl acetate (19/1,
1
v/v), alumina, with 3% (v) triethylamine, alumina; H NMR
(CDCl3) δ 6.49 (s, 1H), 5.54-5.57 (m, 1H) 4.22 (d, 1H, J ) 2.1
Hz), 4.06 (d, 1H, J ) 2.1 Hz), 3.72 (t, 2H, J ) 6.2 Hz), 2.49-
2.57 (m, 1H), 2.11 (s, 3H), 0.89-1.97 (m, 3H), 0.92 (s, 3H), 0.66
(s, 3H); 13C NMR δ 209.4, 160.2, 141.6, 129.1, 125.6, 125.4,
81.8, 66.9, 57.0, 48.1, 46.2, 44.1, 38.8, 34.8, 33.9, 31.9, 31.7,
31.4, 31.2, 24.4, 22.8, 22.6, 21.1, 19.5, 18.9, 13.9, 13.3; high-
resolution MS (EI) calcd for C27H40O2 (M+) 396.3028, found
396.3029. Anal. Calcd for C27H40O2: C, 81.8; H, 10.2. Found:
C, 80.9; H, 10.0.
Syn th esis of 2-Alk en yl-2-m eth yl-1,3-d ioxola n es (4a -
g). Gen er a l Meth od . A mixture of the corresponding vinyl
triflate or bromide (2.0 mmol), 2-hydroxyethyl vinyl ether (0.35
g, 4.0 mmol), Pd(OAc)2 (0.013 g, 0.060 mmol), DPPP (0.049 g,
0.120 mmol), triethylamine (0.30 g, 3.0 mmol), molecular sieves
(0.5 g/mmol, 1.0 g), and, if present, TlOAc (0.63 g, 2.4 mmol)25
in 6.0 mL of dry DMSO was stirred under N2 in a screwcap-
sealed tube (for the reaction time and temperature see Table
1). After complete conversion of the starting vinyl triflate or
bromide (GC/MS), the reaction mixture was allowed to cool
(entries 8, 10, 12, and 14), or alternatively, the reaction
mixture was stirred with 2.0 mL of dry acetic acid for an
additional 30 min at 40 °C (accomplishing complete ring-
closure, entries 2, 4, and 6). The reaction mixture was
thereafter poured into 1 M NaOH and was extracted with
diethyl ether. The combined organic layers were washed with
brine and concentrated at reduced pressure. The product was
purified by column chromatography (basic systems, >95% pure
by GC/MS).
2-(2-(4,4-Dim eth yl-2-cycloh exen e-1-on e))-2-m eth yl-1,3-
d ioxola n e (4f; en tr y 12): pale yellow oil; eluent pentane/
diethyl ether (2.5/1, v/v), alumina; 1H NMR (CDCl3) δ 6.80 (s,
1H), 3.99-3.89 (m, 2H), 3.85-3.72 (m, 2H), 2.48-2.42 (m, 2H),
1.84-1.78 (m, 2H) 1.78 (s, 3H) 1.33-1.12 (m, 6H); 13C NMR δ
197.8, 155.0, 135.7, 107.3, 64.5, 35.9, 35.8, 32.6, 29.7, 25.1; MS
(70 eV) m/z (relative intensity) 210 (2, M+), 195 (28), 87 (100).
Anal. Calcd for C12H18O3: C, 68.5; H, 8.6. Found: C, 68.3; H,
8.7.
2-(17â-Acetyla n d r osta -3,5-d ien e-3-yl)-2-m eth yl-1,3-d i-
oxola n e (4g; en tr y 14): white solid; eluent hexane with 3%
(v) triethylamine, alumina; 1H NMR (CDCl3) δ 6.10 (s, 1H),
5.48-5.45 (m, 1H), 4.01-3.77 (m, 4H), 2.58-2.51 (m, 1H), 2.13
(s, 3H), 1.49 (s, 3H), 0.91 (s, 3H), 0.66 (s, 3H); 13C NMR δ 209.7,
141.2, 135.9, 124.5, 109.3, 64.7, 64.4, 63.9, 57.3, 48.3, 44.3, 39.0,
35.0, 34.2, 32.0, 31.8, 24.6, 24.1, 23.0, 21.8, 19.1, 13.6; MS (70
eV) m/z (relative intensity) 384 (4, M+), 369 (100), 87 (20); high-
resolution MS (CI, CH4) calcd for C25H37O3 (M+ + 1) 385.2743.
Found: 385.2726. Anal. Calcd for C25H36O3: C, 78.1; H, 9.4.
Found: C, 77.2; H, 9.4.
Syn th esis of Alk oxy Dien es (3a ,c,f,g) a n d 2-Alk en e-2-
Meth yl-1,3-Dioxola n es (4a ,c,f,g) Usin g Micr ow a ve Ir -
r a d ia tion . Gen er a l Meth od . Dry nitrogen gas was for 90 s
passed through a reaction mixture prepared exactly as in the
thermal synthesis of 2-alkoxy-1,3-dienes or synthesis of 2-alk-
ene-2-ethyl-1,3-dioxolanes (method A) on a 0.5 mmol scale. The
reaction tube was sealed (finger-tight) before the contents were
mixed with a Whirlimixer. Heating was therafter applied by
means of microwave irradiation (see Table 1 for details). After
irradiation, the reaction tube was allowed to cool in the
microwave cavity for 1 min before any handling of the mixture
took place. When the reaction tube had reached rt, the
purification was performed as previously presented for the
thermal reactions.
2-(1-Cycloh exen -1-yl)-2-m eth yl-1,3-d ioxola n e (4a ; en -
tr y 2): colorless oil; eluent pentane/diethyl ether (29/1, v/v)
1
with 4% (v) dimethylethylamine, silica gel; H NMR (CDCl3)
δ 5.86-5.83 (m, 1H), 3.89-3.78 (m, 4H), 2.06-1.96 (m, 4H),
1.66-1.49 (m, 4H), 1.43 (s, 3H); 13C NMR δ 137.7, 122.6, 109.6,
64.5, 24.9, 24.0, 23.9, 22.9, 22.4; MS (70 eV) m/z (relative
intensity) 168 (1, M+), 153 (100), 87 (53); high-resolution MS
(CI, CH4) calcd for C10H17O2 (M+ + 1) 169.1229, found
169.1229. Anal. Calcd for C10H16O2: C, 71.4; H, 9.6. Found:
C, 71.7; H, 10.6.
2-(2-Eth yl-1-bu ten yl)-2-m eth yl-1,3-d ioxola n e (4b; en tr y
4): pale yellow oil; eluent pentane with 2% (v) dimethylethyl-
Ack n ow led gm en t. We gratefully acknowledge the
support from the Swedish Natural Science Research
Council. We also thank Dr. Adolf Gogoll for the deter-
minination of the stereochemistry of (Z)-R-bromocinna-
maldehyde and (E)-2-(1-formyl-2-phenylethen-1-yl)-2-
methyl-1,3-dioxolane.
1
amine, silica gel; H NMR (CDCl3) δ 5.18 (s, 1H), 3.96-3.83
(m, 4H), 2.27 (q, J ) 7.5 Hz, 2H), 2.00 (dq, J ) 7.5, 1.3 Hz,
2H), 1.48 (s, 3H), 0.99 (t, J ) 7.5 Hz, 3H), 0.98 (t, J ) 7.5 Hz,
3H); 13C NMR δ 148.6, 124.8, 108.5, 64.2, 28.9, 26.0, 23.6, 13.3,
12.9; MS (70 eV) m/z (relative intensity) 155 (100), 111 (14),
87 (34); high-resolution MS (CI, CH4) calcd for C10H19O2 (M+
+ 1) 171.1385, found 171.1383. Anal. Calcd for C10H18O2: C,
70.5; H, 10.7. Found: C, 69.9; H, 10.6.
J O000070O