Direct Synthesis of Cyclic Ketals of Acetophenones by Palladium-Catalyzed Arylation of Hydroxyalkyl Vinyl Ethers

Article abstract of DOI:10.1021/jo971454q

Reaction of 2-hydroxyethyl vinyl ether, 4-hydroxybutyl vinyl ether, or di(ethylene glycol) vinyl ether with aryl triflates, aryl bromides, or iodobenzene in presence of a catalytical amount of palladium acetate and the bidentate ligand DPPP provides a direct entry to cyclic ketals of acetophenones.It is postulated that the reaction proceeds via an initial α-arylation of the vinyl ethers to give labile aryl vinyl ether intermediates, which undergo subsequent ketalization in presence of protons in the reaction media.The method merits attention due to the simplicity of the experimental procedure and the possibility of selective ketal formation in the presence of an additional carbonyl group.

Full text of DOI:10.1021/jo971454q

7858
J . Org. Chem. 1997, 62, 7858-7862
Dir ect Syn th esis of Cyclic Keta ls of Acetop h en on es by
P a lla d iu m -Ca ta lyzed Ar yla tion of Hyd r oxya lk yl Vin yl Eth er s
Mats Larhed and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University,
Box 574, SE-751 23 Uppsala, Sweden
Received August 5, 1997X
Reaction of 2-hydroxyethyl vinyl ether, 4-hydroxybutyl vinyl ether, or di(ethylene glycol) vinyl ether
with aryl triflates, aryl bromides, or iodobenzene in presence of a catalytical amount of palladium
acetate and the bidentate ligand DPPP provides a direct entry to cyclic ketals of acetophenones.
It is postulated that the reaction proceeds via an initial R-arylation of the vinyl ethers to give
labile aryl vinyl ether intermediates, which undergo subsequent ketalization in presence of protons
in the reaction media. The method merits attention due to the simplicity of the experimental
procedure and the possibility of selective ketal formation in the presence of an additional carbonyl
group.
In tr od u ction
of the vinyl ethers, a catalytic amount of palladium
acetate (0.03 equiv), 1,3-bis(diphenylphosphino)propane
(DPPP) as ligand (0.06 equiv), and a stoichiometric
amount of triethylamine (1.5 equiv) as the base in DMF
at 80 °C (Table 1).7 Reactions with the aryl triflates 2a
and 2d provided a good isolated yield of the corresponding
cyclic ketals (entries 1 and 8) while a considerably lower
yield was encountered when the electron deficient 2e was
subjected to the same reaction conditions.8 However,
treatment with dry acetic acid at 80 °C prior to workup
(entry 9) or increasing the temperature to 130 °C after
complete consumption of 2e (entry 10) resulted in good
yields of 3e. Reactions of phenyl triflate with the
4-hydroxybutyl vinyl ether 1b (entry 2) and di(ethylene
glycol) vinyl ether 1c (entry 3) proceeded smoothly, but
we were unable to isolate the nine-membered cyclic ketal
from the arylation of 6-hydroxyhexyl vinyl ether, since
decomposition occurred during attempted purification on
We recently reported an unexpected binding mode of
an HIV protease inhibitor with a cyclic sulfamide as a
core structure.1 A discrete water molecule has been
identified in the space interfacing two aromatic groups
(P1 and P2) of the inhibitor,2 and molecular modelling
suggested to us that the oxygen atoms of certain ketals
(e.g. 1,3-dioxolanes), attached to one of the aromatic
rings, should provide a suitable mimic of the bridging
water molecule. We desired a synthetic method that in
one step would allow substitution of an halide or triflate
on an aromatic ring for a cyclic ketal and that did not
rely on ketalization catalyzed by strong acid.
We herein report a direct synthesis of protected ac-
etophenones3 accomplished by palladium-catalyzed aryl-
ation4 of hydroxyalkyl vinyl ethers5 and subsequent ring-
closing.6
9
silica. Utilizing Pd(0)(DPPP)2 as catalyst gave a com-
Resu lts
parable yield to reactions with the palladium acetate/
DPPP combination (entry 4). Employing bromobenzene
or iodobenzene as arylating agents required addition of
thallium(I) acetate to control the regioselectivity in the
Heck reaction (entries 5 and 6).5b This additive had a
reversed effect on the ketalization rate and was also
found to suppress the reaction rate starting from phenyl
triflate.10 Boosting of the reaction temperature after 24
h or adding dry acetic acid promoted the ring-closing
reactions also in the thallium-assisted reactions (entries
7 and 13). Entries 11-13 demonstrate three examples
where a carbonyl group is attached to the aromatic
substrate. A substitution of the leaving group for the
The arylation studies were performed starting from
three, commercially available, hydroxyalkyl vinyl ethers
1a -c (Table 1). The aryl triflates 2a ,d -g, aryl bromides
2b,h , and iodobenzene 2c were reacted with the vinyl
ethers to furnish the ketals 3a -h (Table 1). The reac-
tions with the triflates were performed by using 2 equiv
X Abstract published in Advance ACS Abstracts, October 1, 1997.
(1) (a) Hulte´n, J .; Bonham, N. M.; Nillroth, U.; Hansson, T.;
Zuccarello, G.; Bouzide, A.; Åqvist, J .; Classon, B.; Danielson, U. H.;
Karle´n, A.; Kvarnstro¨m, I.; Samuelsson, B.; Hallberg, A. J . Med. Chem.
1997, 40, 885-897. (b) Ba¨ckbro, K.; Lo¨wgren, S.; O¨ sterlund, K.; Atepo,
J .; Unge, T.; Hulte´n, J .; Bonham, N. M.; Schaal, W.; Karle´n, A.;
Hallberg, A. J . Med. Chem. 1997, 40, 898-902.
(2) Ba¨ckbro, K.; Hulte´n, J .; Lo¨wgren, S.; Bonham, N. M.; Schaal,
W.; Karle´n, A.; Hallberg, A.; Unge, T. Manuscript in preparation.
(3) (a) Meskens, F. A. J . Synthesis 1981, 501-522. (b) Greene, T.
W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley-
Interscience: New York 1991; pp 175-198. (c) Kunz, H.; Waldmann,
H. Comprehensive Organic Synthesis; Trost, B. M., Flemming, I., Eds.;
Pergamon Press: Oxford 1991; vol. 6, pp 675-684.
(4) For reviews on the Heck reaction see: (a) Heck, R. F. Org React.
1982, 27, 345-363. (b) Heck, R. F. Palladium Reagents in Organic
Synthesis; Academic Press: London 1985; pp 276-290. (c) Heck, R. F.
Comprehensive Organic Synthesis; Trost, B. M., Flemming, I., Eds.;
Pergamon Press: Oxford 1991; vol. 4, pp 833-863. (d) de Meijere, A.;
Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379-2411. (e)
Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7. (f) Tsuji, J .
Palladium Reagents and Catalysts: Innovations in Organic Chemistry;
J ohn Wiley & Sons: Chichester, 1995; pp 125-168. (g) J effery, T.
Advances in Metal-Organic Chemistry; Liebeskind, L. S. Ed.; J AI Press
Inc: Greenwich, CT, 1996; vol. 5, pp 153-260. For Heck arylation of
heteroatom-substituted double bonds see: (h) Daves, G. D., J r.;
Hallberg, A. Chem. Rev. 1989, 89, 1433-1445.
(5) For internal arylation of acyclic vinyl ethers see: (a) Cabri, W.;
Candiani, I.; Bedeschi, A.; Santi, R. J . Org. Chem. 1990, 55, 3654-
3655. (b) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J .
Org. Chem. 1992, 57, 1481-1486. For an earlier report of preferential
formation of internal arylation products see: (c) Hallberg, A.; Westfelt,
L.; Holm, B. J . Org. Chem. 1981, 46, 5414-5415.
(6) For a somewhat related transformation of organic halides or
organic triflates to cyclic hemiacetals see: (a) Mandai, T.; Hasegawa,
S.; Fujimoto, T.; Kawada, M.; Nokami, J .; Tsuji, J . Synlett 1990, 85-
86. (b) Arcadi, A.; Bernocchi, E.; Cacchi, S.; Marinelli, F. Tetrahedron
1991, 47, 1525-1540.
(7) No terminal â-products were detected (GC-MS) in DPPP-
controlled arylations of hydroxyalkyl vinyl ethers.
(8) In this case, only a small amount of product 3e was formed (18%
isolated yield after 120 h at 80 °C).
(9) Mason, M. R.; Verkade, J . G. Organometallics 1992, 11, 2212-
2220.
(10) The addition of 1.2 equiv of TlOAc to a reaction performed
according to entry 1 (Table 1) resulted in a slower formation of 3a (82%
isolated yield after 44 h at 80 °C).
S0022-3263(97)01454-0 CCC: $14.00 © 1997 American Chemical Society

Direct Synthesis of Cyclic Ketals of Acetophenones
J . Org. Chem., Vol. 62, No. 22, 1997 7859
Ta ble 1. P a lla d iu m -Ca ta lyzed Selective Syn th esis of Cyclic Keta ls fr om Ar yl Tr ifla tes or Ar yl Ha lid esa
a
The aryl halide or aryl triflate (5.0 mmol, 1.0 equiv), hydroxyalkyl vinyl ether (10.0 mmol, 2.0 equiv), Pd(OAc)2 (0.15 mmol, 0.03
equiv), DPPP (0.30 mmol, 0.06 equiv), Et3N (7.5 mmol, 1.5 equiv) and, if present, TlOAc (6.0 mmol, 1.2 equiv, entries 5-7 and 13) were
b
heated at 80 °C under nitrogen in 15 mL of DMF. Based on the aryl halide or aryl triflate. >95% Purify by GC-MS. c Pd(0)DPPP2 was
d
utilized as palladium catalyst instead of Pd(OAc)2/DPPP. The reaction temperature was increased to 130 °C after complete consumption
of the aryl halide or aryl triflate (GC-MS). e 5 mL of dry HOAc was added after complete consumption of the aryl bromide or aryl triflate
(GC-MS).
ketal function was achieved in all three cases, and no
products derived from transketalization were observed.
The synthesis of 3g was especially noteworthy since the
protected methyl ketone was introduced in the presence
of an aldehyde functionality. Thus it is possible to
reverse the chemoselectivity and to assemble a molecule
with a blocked ketone without affecting the reactive
aldehyde carbonyl group.11
Finally, we wished to extend our investigation to
include a synthetic process to obtain the complementary
acetal 4. Chelation-controlled terminal (â) phenylation12
and subsequent acetalization of 2-(dimethylamino)ethyl
vinyl ether was examined and observed to afford the
Discu ssion
expected single product 4 in a reasonable isolated yield
(eq 1). This methodology offers a new route to protected
arylacetaldehydes.
For a successful preparative reaction, a highly selective
internal (R) arylation of the hydroxyalkyl vinyl ether is
(11) We are aware of only one additional methodology for selective
ketalization of ketones in the presence of aldehydes (reversed chemose-
lectivity). (a) Kim, S.; Kim, Y. G.; Kim, D. Tetrahedron Lett. 1992, 33,
2565-2566. For a recent example of a selective acetalization of an
aromatic aldehyde in the presence of a ketone see: Tateiwa, J .;
Horiuchi, H.; Uemura, S. J . Org. Chem. 1995, 60, 4039-4043.
(12) (a) Andersson, C.-M.; Larsson, J .; Hallberg, A. J . Org. Chem.
1990, 55, 5757-5761. (b) Larhed, M.; Andersson, C.-M.; Hallberg, A.
Acta. Chem. Scand. 1993, 47, 212-217. (c) Larhed, M.; Andersson, C.-
M.; Hallberg, A. Tetrahedron 1994, 50, 285-304. For an example of
chelating vinyl ethers containing phosphorous derivatives see: (d)
Badone, D.; Guzzi, U. Tetrahedron Lett. 1993, 34, 3603-3606.

7860 J . Org. Chem., Vol. 62, No. 22, 1997
Larhed and Hallberg
a prerequisite. Cabri has rationalized the regiochemical
outcome dictated by bidentate ligands, e.g. DPPP, in
terms of generation of a cationic organopalladium π-com-
plex13 followed by a comparatively rapid,14 electronically
controlled insertion.5a,b In reactions with haloarenes the
required cationic species can be created through addition
of halide abstractors such as thallium15 or silver salts.16
We assume that the ketals are formed according to the
reaction sequence outlined in the eq 2.
vinylic ether.19 Terminal protonation20 (HNEt3+ or HOAc)
of the double bond generates an oxocarbonium ion and
the ketalization arises through internal nucleophilic
attack of the hydroxy group (eq 2). Thus, the slow
cyclization experienced with electron-deficient substrates
(entries 9-13) or after addition of weakly basic thallium-
(I) acetate (entries 5-7 and 13) is explained by insuf-
ficient protonation. In agreement with this proposition,
an increased concentration of the oxygen-stabilized car-
bocation (by acid addition) or an enhanced rate of the
internal nucleophilic attack (by raising the temperature)
affords efficient ketalization. It is noteworthy that, the
ring-closing reaction is not observed with the non-R-
arylated hydroxyalkyl vinyl ethers (1a -1c) under our
reaction conditions.
Additional insight into this mechanistic speculation
was provided by the reaction of the R-arylated vinyl ether
7 (prepared by arylation of the corresponding 4-(tert-
butyldimethylsiloxy)butyl vinyl ether followed by desi-
lylation). This intermediate underwent ketalization upon
distillation (eq 3) or after treatment with acid (HOAc or
NH4Br), rendering support for involvement of an acid-
catalyzed rather than Pd(II)-promoted cyclization.21 Fur-
thermore, the appearance of significant amounts of the
R-arylated, but not ketalized, products in GC-MS samples
obtained during the reactions (entries 5-7 and 9-13)
corroborate a reaction pathway involving an acid-
promoted ring-closure.
We have previously shown that the amino function in
2-(dimethylamino)ethyl vinyl ether has a strong â-direct-
ing effect in the palladium-catalyzed arylation of this
olefin.12a-c However, in the presence of the bidentate
DPPP, R-arylation occurred exclusively, which probably
is a consequence of the lack of a coordination site to
accommodate the olefin amino group.12c It appears that
a similar situation governs the selectivity for R-arylation
in the present reaction. Interestingly, arylation experi-
ments performed with the 2-hydroxyethyl vinyl ether (1a )
or ethylene glycol butyl vinyl ether,17 with monodentate
triphenylphosphine as supporting ligand, resulted in a
mixture of R- and â-arylation in both cases. This result
is not consistent with chelation control by palladium-
oxygen coordination.18
The ketal formation, we anticipate, occurs by acid-
catalyzed ring-closure after internal arylation of the
(13) The triflate anion is fully dissociated from Pd(II) in DMF. See:
(a) J utand, A.; Mosleh, A. Organometallics 1995, 14, 1810-1817. (b)
Brown, J . M.; Hii, K. K. M. Angew. Chem., Int. Ed. Engl. 1996, 35,
657-659.
Con clu sion
(14) (a) Siegbahn, P. E. M. J . Organomet. Chem. 1994, 478, 83-93.
(b) Brown, J . M.; Pe´rez-Torrente, J . J .; Alcock, N. W.; Clase, H. J .
Organometallics 1995, 14, 207-213. (c) Kawataka, F.; Shimizu, I.;
Yamamoto, A. Bull. Chem. Soc. J pn. 1995, 68, 654-660. (d) Crisp, G.
T.; Gebauer, M. G. Tetrahedron 1996, 52, 12465-12474.
(15) Leading references for use of thallium(I) additives. (a) Grigg,
R.; Loganathan, V.; Santhakumar, V.; Sridharan, V.; Teasdale, A.
Tetrahedron Lett. 1991, 32, 687-690. (b) Carfagna, C.; Musco, A.;
Sallese, G.; Santi, R.; Fiorani, T. J . Org. Chem. 1991, 56, 261-263. (c)
Sonesson, C.; Larhed, M.; Nyqvist, C.; Hallberg, A. J . Org. Chem. 1996,
61, 4756-4763. (d) Ripa, L.; Hallberg, A. J . Org. Chem. 1996, 61,
7147-7155. See also ref 5b.
(16) For beneficial effects of silver additives see: (a) Karabelas, K.;
Westerlund, C.; Hallberg, A. J . Org. Chem. 1985, 50, 3896-3900. (b)
Karabelas, K.; Hallberg, A. J . Org. Chem. 1986, 51, 5286-5290. (c)
Abelman, M. M.; Oh, T.; Overman, L. E. J . Org. Chem. 1987, 52, 4130-
4133. (d) Larock, R. C.; Gong, W. H. J . Org. Chem. 1989, 54, 2047-
2050. (e) Sato, Y.; Sodeoka, M.; Shibasaki, M. Chem. Lett. 1990, 1953-
1954. For a recent application of silver additives in Heck reactions
see: (f) Ripa, L.; Hallberg, A. J . Org. Chem. 1997, 62, 595-602.
(17) CH3(CH2)3OCH2CH2OCHdCH2.
(18) For examples of Pd(II)-oxygen coordination in Heck reactions
see: (a) Bernocchi, E.; Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron. Lett. 1992, 33, 3073-3076. (b) J effery, T. Tetrahedron
Lett. 1993, 34, 1133-1136. (c) Kang, S.-K.; J ung, K.-Y.; Park, C.-H.;
Namkoong, E.-Y.; Kim, T.-H. Tetrahedron Lett. 1995, 36, 6287-6290.
(d) Kang, S.-K.; Lee, H.-W.; J ang, S.-B.; Kim, T.-H.; Pyun, S.-J . J . Org.
Chem. 1996, 61, 2604-2605. See also ref 6b.
We have demonstrated that palladium-catalyzed aryl-
ation of commercially available hydroxyalkyl vinyl ethers
constitutes a facile direct method for preparation of ketals
of acetophenones. Although only a limited number of
examples are provided here, we believe that the ease of
operation and, in particular, the suitability of the present
method for the preparation of selectively blocked dicar-
bonyl compounds will prove to be useful in synthetic
work.
(19) For acid-catalyzed cyclization of hydroxyalkyl vinyl ethers
see: (a) McClelland, R. A.; Watada, B.; Lew, C. S. Q. J . Chem. Soc.,
Perkin Trans. 2 1993, 1723-1727. (b) Deslongchamps, P.; Dory, Y. L.;
Li, S. Helv. Chim. Acta 1996, 79, 41-50.
(20) (a) J ones, D. M.; Wood, N. F. J . Chem. Soc. 1964, 5400-5403.
(b) Salomaa, P.; Kankaanpera¨, A.; Lajunen, M. Acta Chem. Scand.
1966, 20, 1790-1801. (c) Kresge, A. J .; Chen, H. J . J . Am. Chem. Soc.
1972, 94, 2818-2822. (d) Burt, R. A.; Chiang, Y.; Kresge, A. J .; Szilagyi,
S. Can. J . Chem. 1984, 62, 74-76.
(21) (a) Heumann, A. Stereochemistry of Organometallic and Inor-
ganic Compounds; Bernal, I., Ed.; Elsevier: Amsterdam, 1994; vol. 5,
pp 557-623. For a recent example of Pd(II)-catalyzed acetalization of
olefins see: (b) Hosokawa, T.; Yamanaka, T.; Itotani, M.; Murahashi,
S.-I. J . Org. Chem. 1995, 60, 6159-67.

Direct Synthesis of Cyclic Ketals of Acetophenones
J . Org. Chem., Vol. 62, No. 22, 1997 7861
washed with saturated NaCl solution (50 mL), dried over K2-
CO3, and concentrated. The resulting crude products were
purified by bulb-to-bulb distillation in a Kugelrohr apparatus
and/or by flash column chromatography to afford pure ketals
3a -h (Table 1, >95% pure by GC-MS).
2-Meth yl-2-p h en yl-1,3-d ioxep a n (3b, Ta ble 1). Yellow
oil, 0.805 g (84%, >95% pure by GC-MS). Bulb-to-bulb
distillation (0.4 mmHg, oven temperature ∼80 °C). MS m/ z
(relative intensity, 70 eV) 177 (87), 147 (48), 105 (100); 1H NMR
(CDCl3, 270 MHz) δ 7.51 (d, J ) 7 Hz, 2H), 7.37-7.25 (m, 3H),
3.84-3.76 (m, 2H), 3.65-3.56 (m, 2H), 1.79-1.54 (m, 4H), 1.50
(s, 3H). Anal. Calcd for C12H16O2: C, 74.97; H, 8.39. Found:
C, 74.87; H, 8.48.
Exp er im en ta l Section
P r oced u r es. All reactions were carried out under nitrogen
in heavy-walled Pyrex tubes sealed with a screw-cap fitted
with a Teflon gasket silicon septum. 1H and 13C NMR spectra
were measured in CDCl3 solution at 270 MHz and 67.8 MHz,
respectively. Mass spectra were recorded at an ionzing voltage
of 70 eV (EI). The mass detector was interfaced with a gas
chromatograph equipped with a HP-1 (25 m × 0.20 mm)
capillary column. Importantly, to be able to monitor the
cyclization of the intermediate R-arylated vinyl ethers (and
avoid ketalization on the column) the GC-column and the
injector must be in good condition. IR spectra were recorded
on a FTIR spectrometer. Column chromatography was per-
formed on silica gel, using Kieselgel S (0.032-0.063 mm,
Riedel-de Haen), or on aluminum oxide, using Aluminiumoxid
90 (0.063-0.200 mm, Merck). Elemental analyses were
performed by Micro Kemi AB, Uppsala, Sweden, or Ana-
lytische Laboratorien, Prof. Dr. H. Malissa und G. Reuter
GmbH, Lindlar, Germany.
Ma ter ia ls. Vinyl ethers 1a -c and ethylene glycol butyl
vinyl ether were obtained from Aldrich. The organic halides,
palladium(II) acetate, 1,3-bis(diphenylphosphino)propane
(DPPP), thallium(I) acetate, ammonium bromide, imidazole,
tert-butyldimethylsilyl chloride (TBDMSCl), p-toluenesulfonic
acid monohydrate, and tetrabutylammonium fluoride in THF
(1 M) were purchased from commercial suppliers and were
used directly as received. Acetic acid was dried over phos-
phorus pentoxide and triethylamine was distilled from potas-
sium hydroxide prior to use. DMF, ethylene glycol, and tert-
butyl methyl ether were stored over 4 Å molecular sieves. The
aryl triflates (trifluoromethanesulfonates) were synthesized
from the corresponding phenols using an excess of triflic
anhydride and 2,4,6-trimethylpyridine, essentially following
a literature procedure22 and are known compounds (2a ,5b 2d ,23
2e,5b 2f,23 and 2g24). Structure and purity of isolated com-
pounds were determined by NMR, GC-MS, and FTIR. Prod-
ucts 3a ,25 3c,26 3d ,25b 3e,27 and 428 are known compounds.
Syn th esis of Cyclic Keta ls (3a -h , Ta ble 1). Gen er a l
P r oced u r e. In a screw-capped Pyrex tube Pd(OAc)2 (0.034
g, 0.15 mmol) and DPPP (0.124 g, 0.30 mmol) were suspended
in 10 mL of dry DMF under nitrogen. To the mixture were
added aryl halide or aryl triflate 2a -h (5.0 mmol), Et3N (0.76
g, 7.5 mmol), hydroxyalkyl vinyl ether 1a -c (10 mmol) and,
if present, TlOAc, (1.58 g, 6.0 mmol, entries 5-7 and 13)
together with 5 mL of DMF. The tube was purged with
nitrogen for 2 min, sealed, and stirred in an oil bath at 80 °C
for 16-144 h (see Table 1 for details). Small aliquots were
periodically removed, partitioned between diethyl ether and
0.1 M NaOH, and the organic phase was analyzed by GC-MS.
After complete consumption of the aryl halide or aryl triflate,
the reaction was either (1) interrupted, or in the case of
incomplete ketal formation, (2) dry HOAc was added (5 mL,
80 °C, entries 9 and 11-13), or alternatively, (3) the reaction
temperature was increased to 130 °C (entries 7 and 10). See
Table 1 for details. After cooling, the reaction mixture was
carefully poured into an aqueous solution of K2CO3 (10%, 50
mL (100 mL in entries 9 and 11-13)) and was extracted with
diethyl ether (3 × 50 mL). The combined organic layers were
2-(4-Acet ylp h en yl)-2-m et h yl-1,3-d ioxola n e (3f, Ta b le
1). White crystals, 0.884 g (86%, >95% pure by GC-MS).
Purified by bulb-to-bulb distillation (0.4 mmHg, oven temper-
ature ∼120 °C) and column chromatography (SiO2, pentane/
diethyl ether 2/1). MS m/ z (relative intensity, 70 eV) 191
(100), 147 (38), 119 (8), 87 (18);1H NMR (CDCl3, 270 MHz) δ
7.92 (d, J ) 8.5 Hz, 2H), 7.56 (d, J ) 8.5 Hz, 2H), 4.08-4.02
(m, 2H), 3.78-3.72 (m, 2H), 2.58 (s, 3H), 1.63 (s, 3H); 13C NMR
(CDCl3, 67.8 MHz) δ 197.7, 148.5, 136.6, 128.3, 125.5, 108.4,
64.5, 27.3, 26.6; IR (neat) 1697 cm-1
.
Anal. Calcd for
C12H14O3: C, 69.89; H, 6.84. Found: C, 70.0; H, 7.0.
2-(3-F or m ylp h en yl)-2-m eth yl-1,3-d ioxola n e (3g, Ta ble
1). Yellow crystals, 0.726 g (76%, >95% pure by GC-MS).
Purified by bulb-to-bulb distillation (0.4 mmHg, oven temper-
ature ∼130 °C) and column chromatography (SiO2, pentane/
diethyl ether 2/1). MS m/ z (relative intensity, 70 eV) 177
1
(100), 133 (48), 105 (10), 87 (23); H NMR (CDCl3, 270 MHz)
δ 10.03 (s, 1H), 8.00 (s, 1H), 7.86-7.72 (m, 2H), 7.51 (t, J )
7.8 Hz, 1H), 4.11-4.00 (m, 2H), 3.83-3.73 (m, 2H), 1.67 (s,
3H), 13C NMR (CDCl3, 67.8 MHz) δ 192.2, 144.7, 136.4, 131.3,
129.0, 128.9, 126.8, 108.2, 64.5, 27.4; IR (neat) 1700 cm-1. Anal.
Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.4; H, 6.2.
2-(4-Ben zoylp h en yl)-2-m eth yl-1,3-d ioxola n e (3h , Ta ble
1). Thick yellow oil, 1.00 g (75%, >95% pure by GC-MS). The
excess of 1a was removed by bulb-to-bulb distillation (8 mmHg,
oven temperature ∼90 °C). Purified by column chromatogra-
phy (SiO2, isohexane/diethyl ether 3/1). MS m/ z (relative
intensity, 70 eV) 253 (100), 209 (22), 152 (5), 105 (12); 1H NMR
(CDCl3, 270 MHz) δ 7.85-7.72 (m, 4H), 7.65-7.53 (m, 3H),
7.48 (app t, J ) 7 Hz, 2H), 4.11-4.01 (m, 2H), 3.83-3.74 (m,
2H), 1.69 (s, 3H), 13C NMR (CDCl3, 67.8 MHz) δ 196.4, 148.0,
137.7, 137.2, 132.5, 130.2, 130.1, 128.4, 125.4, 108.6, 64.7, 27.6;
IR (neat) 1664 cm-1. Anal. Calcd for C17H16O3: C, 76.10; H,
6.01. Found: C, 76.4; H, 6.1.
P r ep a r a tion of P d (0)(DP P P )2.9 In the workup of 3a
(Table 1, entry 1), yellow crystals precipitated in the diethyl
ether/K2CO3 (10%) interface. The crystals were isolated by
filtration, washed with diethyl ether, and dried in vacuo
providing a 55% yield (77 mg) based on Pd(OAc)2. The product
was identified by X-ray crystallography.9
Syn th esis of P h en yla ceta ld eh yd e Eth ylen e Aceta l (4,
Eq 1).28 (E)/(Z)-[2-[2-(Dimethylamino)ethoxy]ethenyl]benzene
was prepared from iodobenzene (0.51 g, 2.5 mmol) and
2-(dimethylamino)ethyl vinyl ether (0.35 g, 3.0 mmol) as
previously described.12a After the reaction mixture was cooled,
diethyl ether (50 mL) was added, and the organic mixture was
washed with 0.1 M NaOH (2 × 25 mL). The combined aqueous
layers were further extracted with diethyl ether (2 × 25 mL).
All three organic layers were combined, washed with saturated
NaCl solution (50 mL), dried with K2CO3, and concentrated.
The crude (E)/(Z)-[2-[2-(dimethylamino)ethoxy]ethenyl]ben-
zene was mixed with p-toluenesulfonic acid monohydrate (1.90
g, 10 mmol) and ethylene glycol (10 mL) in tert-butyl methyl
ether (10 mL). The reaction mixture was stirred at 40 °C until
GC-MS indicated complete consumption of the vinyl ether (18
h). The solution was poured into an aqueous solution of K2-
CO3 (10%, 50 mL) and was extracted with diethyl ether (3 ×
50 mL). The combined organic layers were washed with
saturated NaCl solution (50 mL), dried over K2CO3, and
concentrated. The resulting crude product was purified by
column chromatography on aluminum oxide (pentane/diethyl
ether 19/1) to afford pure 4 (eq 1, >95% pure by GC-MS).
(22) Saa´, J . M.; Dopico, M.; Martorell, G.; Garc´ıa-Raso, A. J . Org.
Chem. 1990, 55, 991-995.
(23) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1987, 109,
5478-5486.
(24) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1988, 110,
1557-1565.
(25) (a) Fife, T. H.; Hagopian, L. J . Org. Chem. 1966, 31, 1772-75.
(b) Bauduin, G.; Bondon, D.; Pietrasanta, Y.; Pucci, B. Tetrahedron
1978, 34, 3269-3274. (c) Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis
1983, 203-205.
(26) (a) Einhorn, J .; Bacquet, C.; Lelandais, D. J . Heterocycl. Chem.
1980, 17, 1345-47. (b) Oshima, T.; Nagai, T. Bull. Chem. Soc. J pn.
1986, 59, 3979-3980.
(27) Korytnyk, W.; Dave, N. A. C.; Caballes, L. J . Med. Chem. 1978,
21, 507-513.
(28) (a) Naidan, V. M.; Dzumedzei, N. V.; Dombrovskii, A. V. Zh.
Org. Khim. 1 1965, 8, 1377-1383. (b) Raber, D. J .; Guida, W. C.
Synthesis 1974, 808-809. (c) The Aldrich Library of 13C and 1H FT-
NMR Spectra; Aldrich Chemical Co.: Milwaukee, 1993.

7862 J . Org. Chem., Vol. 62, No. 22, 1997
Larhed and Hallberg
4-(ter t-Bu tyld im eth ylsilyloxy)bu tyl Vin yl Eth er (5, Eq
3). 5 was prepared according to the method described by
Corey.29 4-Hydroxybutyl vinyl ether 1b (5.81 g, 50 mmol) and
imidazole (10.21 g, 150 mmol) were mixed in DMF (50 mL)
under nitrogen. The reaction mixture was cooled to 0 °C, tert-
butyldimethylchlorosilane (11.31 g, 75 mmol) was added, and
the reaction mixture was allowed to reach room temperature
overnight. The reaction mixture was then poured into diethyl
ether (250 mL) and was washed with water (2 × 150 mL) and
saturated NaCl solution (150 mL). The organic phase was
thereafter dried (K2CO3) and concentrated to a yellow oil.
Purification by column chromatography (SiO2, pentane) and
bulb-to-bulb distillation (10 mmHg, oven temperature ∼115
°C) gave pure 5 (9.39 g, 81%) as a clear oil (>95% pure by
GC-MS). MS m/ z (relative intensity, 70 eV) 215 (1), 173 (24),
131 (67), 101 (100);1H NMR (CDCl3, 270 MHz) δ 6.47 (dd, J )
14.4 Hz, J ) 6.8 Hz, 1H), 4.17 (dd, J ) 14.4 Hz, J ) 2.0 Hz,
1H), 3.97 (dd, J ) 6.9 Hz, J ) 2.0 Hz, 1H), 3.70 (t, J ) 6.3 Hz,
2H), 3.64 (t, J ) 6.3 Hz, 2H), 1.76-1.57 (m, 4H), 0.89 (s, 9H),
0.05 (s, 6H). Anal. Calcd for C12H26O2Si: C, 62.55 ; H, 11.37.
Found: C, 62.7; H, 11.6.
w a s p er for m ed w ith tetr a bu tyla m m on iu m flu or id e in
THF (4.1 m L, 1M) a t r t. After com p lete con su m p tion of
6 (30 m in ), th e r ea ction m ixtu r e w a s d ilu ted w ith d ieth yl
eth er (50 m L) a n d w a s w a sh ed w ith a n a qu eou s solu tion
of K2CO3 (10%, 2 × 25 m L). Ad d ition a l extr a ction of th e
com bin ed a qu eou s p h a ses w a s p er for m ed w ith d ieth yl
eth er (2 × 50 m L). Th e or ga n ic p h a ses w er e com bin ed
a n d th er ea fter w a sh ed w ith sa tu r a ted Na Cl solu tion (50
m L), d r ied (Na 2SO4), a n d con cen tr a ted to a yellow oil.
Attem p ted p u r ifica tion of 7 by bu lb-to-bu lb d istilla tion
(0.5 m m Hg, oven tem p er a tu r e ∼170 °C) ga ve p u r e 3b
(0.21 g, 67%) a s a clea r oil (>95% p u r e by GC-MS). All
a ttem p ts to isola te 7 by colu m n ch r om a togr a p h y r e-
su lted in sign ifica n t k eta liza tion a n d /or h yd r olysis.
Gen er a l P r oced u r e for Acid -Med ia ted Rin g-Closin g of
r-(4-Hyd r oxy-bu toxy)styr en e (7). The deprotected 7 was
prepared from 6 as described under “Ring-Closing of R-(4-
Hydroxybutoxy)styrene upon Heating” and was subjected to
an analogous ether/water workup. The isolated crude 7 was
thereupon heated in the presence or absence of Pd(OAc)2, with
added acids (HOAc or NH4Br) or without added acids. In a
screw-capped Pyrex tube were suspended Pd(OAc)2, if present
(0.00175 g, 0.0078 mmol), and DPPP (0.00645 g, 0.0156 mmol)
in 1.0 mL of dry DMF under nitrogen. To the mixture were
added Et3N (0.039 g, 0.39 mmol) and crude 7 (0.050 g, ∼0.26
mmol) together with the acids, if present (anhydrous HOAc
(0.3 mL), or NH4Br (0.061 g, 0.62 mmol)). The tube was
purged with nitrogen for 20 s, sealed, and stirred in an oil bath
at 80 °C for 16 h. After cooling, the reaction mixture was
poured into an aqueous solution of K2CO3 (10%, 10 mL) and
was extracted with diethyl ether (2 × 10 mL). The combined
organic layers were washed with saturated NaCl solution (10
mL), dried over K2CO3, and concentrated. The resulting crude
products were analyzed by GC-MS and 1H NMR. In summary,
the reactions conducted in absence of added acid produced no
cyclized product while all reactions with added HOAc or NH4-
Br afforded ring-closure. The reactions performed with HOAc
resulted in complete ketalization, but the use of NH4Br
provided mixtures of ketal 3b and vinyl ether 7 (3b/7 ≈ 2).
The addition of Pd(OAc)2 did not promote cyclization.
r-[4-(ter t-Bu tyld im eth ylsilyloxy)bu toxy]styr en e (6, Eq
3). In a screw-capped Pyrex tube Pd(OAc)2 (0.034 g, 0.15
mmol) and DPPP (0.124 g, 0.30 mmol) were suspended in 10
mL of dry DMF under nitrogen. To the mixture were added
phenyl triflate (1.13 g, 5.0 mmol), Et3N (0.76 g, 7.5 mmol), and
5 (1.73 g, 7.5 mmol) was added together with 5 mL of DMF.
The tube was purged with nitrogen for 2 min, sealed, and
stirred in an oil bath at 80 °C for 6 h. After cooling, the
reaction mixture was poured into an aqueous solution of K2-
CO3 (10%, 50 mL) and was extracted with diethyl ether (3 ×
50 mL). The combined organic layers were washed with
saturated NaCl solution (50 mL), dried over K2CO3, and
concentrated. The resulting crude products were purified by
bulb-to-bulb distillation (0.5 mmHg, oven temperature ∼130
°C) to afford 6 (1.36 g, 89%) as a pale yellow oil (>95% pure
by GC-MS). MS m/ z (relative intensity, 70 eV) 249 (34), 177
1
(19), 147 (53), 103 (100); H NMR (CDCl3, 270 MHz) δ 7.67-
7.58 (m, 2H), 7.37-7.29 (m, 3H), 4.63 (d, J ) 2.6 Hz, 1H), 4.19
(d, J ) 2.6 Hz, 1H), 3.87 (t, J ) 6.3 Hz, 2H), 3.69 (t, J ) 6.3
Hz, 2H), 1.92-1.80 (m, 2H), 1.77-1.66 (m, 2H), 0.90 (s, 9H),
0.06 (s, 6H). Anal. Calcd for C18H30O2Si: C, 70.53; H, 9.86.
Found: C, 70.8; H, 10.0.
Ack n ow led gm en t. We thank the Swedish Natural
Science Research Council for financial support and Dr.
Staffan Sundell for performing the X-ray structure
analysis of Pd(0)DPPP2.
Rin g-Closin g of r-(4-Hyd r oxybu toxy)styr en e (7) u p on
Hea tin g (Eq 3). Dep r otection of 6 (0.50 g, 1.63 m m ol)
(29) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190-6191.
J O971454Q