New approaches to bicylic vinyl heterocycles from propargylic acetals

Article abstract of DOI:10.1021/jo048794d

(Chemical Equation Presented) The paper describes further studies on the intramolecular carbolithiation of propargylic acetals with aryllithiums leading to 2-vinylbenzofurans and 3-vinylfuropyridines. Attempts to extend the cascade to [4.4.0] binuclear he

Full text of DOI:10.1021/jo048794d

New Approaches to Bicylic Vinyl Heterocycles from
Propargylic Acetals
Fre´de´ric Le Strat,† David C. Harrowven,‡ and Jacques Maddaluno*,†
Contribution from the Laboratoire des Fonctions Azote´es & Oxyge´ne´es Complexes de l’IRCOF, UMR 6014
CNRS, INSA and Universite´ de Rouen, 76821-Mont St Aignan Cedex, France and Department of
Chemistry, Southampton University, Highfield, Southampton SO17 1BJ, U.K.
jmaddalu@crihan.fr
Received July 15, 2004
The paper describes further studies on the intramolecular carbolithiation of propargylic acetals
with aryllithiums leading to 2-vinylbenzofurans and 3-vinylfuropyridines. Attempts to extend the
cascade to [4.4.0] binuclear heterocycles met with limited success. An alternative, two-step entry
to such ring systems has been developed using the palladium-induced cyclization/hydride capture
methodology. A new route to isoquinilinones from simple benzamides is also disclosed.
Introduction
egies have also been examined and used in the synthesis
of a number of indole alkaloids.9
A large number of polynuclear heterocycles are to be
found in nature, and many exhibit interesting and useful
biological activity.1 The Diels-Alder cycloaddition reac-
tion is frequently used to access such skeletons when they
include a nonaromatic six-membered ring fused to the
heterocyclic core.2 In that context, the use of vinyl
heterocycles as the dienic component has been studied
extensively in recent years. Indeed, the work of Pindur’s
team and others provides ample evidence of the useful-
ness of the approach when the reactivity of the diene is
not compromised to any great extent by the aromatic
character of one of the double bonds. Polycyclic structures
have been prepared in this way from vinylbenzofurans,3
vinylindoles,4 and vinylisoquinolinones5 through reaction
with activated dienophiles such as dimethyl acetylene
dicarboxylate,4b,6 tetracyanoethylene,3a arynes,7 quino-
nes,6,8 and maleimides.3a,c,4a Related intramolecular strat-
Vinyl-heterocycles have been prepared by a variety of
methods, including Wittig-type olefinations,9a,c,d,10 the
O-alkylation of enolates,4d,9b elimination4b,6 and croton-
ization4c procedures, and metal-catalyzed coupling reac-
tions.11 Recently, we reported a new approach to vinyl-
(4) See inter alia for 3-vinylindoles: (a) Pfeuffer, L.; Pindur, U. Helv.
Chim. Acta 1987, 70, 1419-1428. (b) Pindur, U.; Pfeuffer, L. Tetra-
hedron Lett. 1987, 28, 3079-3082. (c) Noland, W. E.; Konkel, M. J.;
Tempesta, M. S.; Cink, R. D.; Powers, D. M. J. Heterocycl. Chem. 1993,
30, 183-192. (d) Pindur, U.; Rogge, M. Heterocycles 1995, 41, 2785-
2793. For 2-vinylindoles, see: (e) Pindur, U. Heterocycles 1988, 27,
1253-1268. (f) Eitel, M.; Pindur, U. J. Org. Chem. 1990, 55, 5368-
5374. (g) Rosillo, M.; Dom´ınguez, G.; Casarrubios, L.; Amador, U.;
Pe´rez-Castells, J. J. Org. Chem. 2004, 69, 2084-2093.
(5) See inter alia for 4-vinylisoquinolinones: (a) Dyke, S. F.; Sains-
bury, M.; Brown, D. W.; Clipperton, R. D. J. Tetrahedron 1970, 26,
5969-5980. (b) Grigg, R.; Loganathan, V.; Sridharan, V.; Stevenson,
P.; Sukirthalingam, S.; Worakun, T. Tetrahedron 1996, 52, 11479-
11502.
(6) Saroja, B.; Srinivasan, P. C. Synthesis 1986, 748-749.
(7) Gonzalez, E.; Pindur, U.; Schollmeyer, D. J. Chem. Soc., Perkin
Trans. 1 1996, 1767-1771.
(8) Pindur, U.; Kim, M. H.; Rogge, M.; Massa, W.; Molinier, M. J.
Org. Chem. 1992, 57, 910-915.
(9) (a) Eberle, M. K.; Shapiro, M. J.; Stucki, R. J. Org. Chem. 1987,
52, 4661-4665. (b) Kraus, G. A.; Thomas, P. J.; Bougie, D.; Chen, L.
J. Org. Chem. 1990, 55, 1624-1627. (c) Simoji, Y.; Saito, F.; Tomita,
K.; Morisawa, Y. Heterocycles 1991, 32, 2389-2397. (d) Fukazawa, T.;
Shimoji, Y.; Hashimoto, T. Tetrahedron: Asymmetry 1996, 7, 1649-
1658.
† Universite´ de Rouen.
‡ Southampton University.
(1) An excellent overview is available, see: Dewick, P. M. Medicinal
natural products. A biosynthetic approach; John Wiley & Sons Ltd.:
Chichester, U.K., 2002.
(2) For general references, see: Fringuelli, F.; Taticchi, A. The
Diels-Alder reaction. Selected practical methods; John Wiley & Sons
Ltd.: New York, 2002.
(3) See inter alia for 3-vinylbenzofurans: (a) Pearson, J. R.; Porter,
Q. N. Aust. J. Chem. 1991, 44, 1085-1095. For 2-vinylbenzofurans,
see: (b) Kamthong, B.; Robertson, A. J. Chem. Soc. 1939, 925-933.
(c) Brewer, J. D.; Elix, J. A. Aust. J. Chem. 1975, 28, 1059-1081. (d)
De Capite, P. M.; Puar, M. S. Tetrahedron 1990, 46, 7663-7666. (e)
Marrocchi, A.; Minuti, L.; Taticchi, A.; Scheeren, H. W. Tetrahedron
2001, 57, 4959-4965.
(10) (a) Pindur, U.; Pfeuffer, L. Heterocycles 1987, 26, 325-327. (b)
Pindur, U.; Pfeuffer, L. Monatsh. Chem. 1989, 120, 157-162. (c)
Pindur, U.; Lutz, G.; Rogge, M. J. Heterocyl. Chem 1995, 32, 201-
206.
(11) Hegedus, L. S.; Toro, J. L.; Miles, W. H.; Harrington, P. J. J.
Org. Chem. 1987, 52, 3319-3322.
10.1021/jo048794d CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/23/2004
J. Org. Chem. 2005, 70, 489-498
489

Le Strat et al.
SCHEME 1. Synthesis of Furo[2,3-c]pyridine 6
Attempted Extensions of the Procedure to [4.4.0]
Bicyclic Heterocycles. We next sought to extend the
method by homologation to access various [4.4.0] bicyclic
heterocycles, although those have rarely been prepared
by carbanionic routes.16 To that end, we prepared prop-
argyl acetals 9, 12, 14, and 15 and allenic acetals 11 and
1617 as described in Scheme 2. Disappointingly, only 12
gave the anticipated vinyl-heterocycle 13 on treatment
with BuLi and in modest yield. The reaction displayed
good stereoselectivity, giving an E:Z ratio of 4:1 when
BuLi was added to a THF solution of 12 and 10:1 when
the order of addition was reversed. In every other case
studied a complex and intractable product mixture was
returned. Replacing n-BuLi by mesityllithium18 did not
improve these results.
At first we presumed that isoquinolinone 13 had been
formed by sequential halogen-to-lithium exchange, cy-
clization to the proximal alkyne, and isomerization of the
resulting allene. However, we later found that benzamide
17 also gave isoquinolinone 13 in low yield on treatment
with BuLi and 50% yield on treatment with t-BuOK in
THF. In the latter case, acetal 21 was observed as a
minor product in 18% yield. These results led us to recon-
sider the mechanistic course of the reaction as directed
orthometalation of 17 seemed improbable under such
conditions. A more plausible explanation is that alkyne
to allene isomerization and amide deprotonation first
gives 19 and that this intermediate then undergoes the
electrocyclization and hydride shift sequence indicated
in Scheme 3. Related oxidative cyclizations of aniline-
derived benzamides using oxygen and a Pd catalyst19 or
phenyliodine(III) bis(trifluoroacetate) (PIFA)20 are known
but follow different mechanistic pathways. An electro-
cyclization reaction related to that postulated was the
subject of a recent theoretical examination.21
heterocycles featuring a carbanionic cyclization to a
propargylic acetal. The method was effective for the
synthesis of 3-vinylindoles and benzofurans as well as
the more exotic furo[3,2-b]pyridine ring system.12 We now
report some extensions to that work leading, in some
cases surreptitiously, to 2-vinylbenzofurans, 3-vinylfuro-
[2,3-c]pyridine, 4-vinylisochromenes, and 4-vinylisoquin-
olinones.
Results and Discussion
Two related systems, the isomeric propargyl acetals,
24 and 31, also gave unexpected outcomes that are
worthy of comment. Thus, all attempts to induce the
halogen-to-metal exchange and cyclization sequence with
o-iodobenzyl propargyl ether 24 failed. However, on
treatment with potassium hexamethyldisilazane (KH-
MDS) in toluene at 0 °C, 24 was transformed into a 10:1
mixture of (E)- and (Z)-vinylbenzofuran 28 in 49% yield
(Scheme 4). The reaction is thought to proceed by
deprotonation to 25 and cyclization to dihydrobenzofuran
26. A second deprotonation then leads to allene 27, a
precursor of 2-vinylbenzofuran 28.22A related ring closure
leading to a dihydrobenzofuran provides some support
for this mechanism.23
To extend the scope of our carbanionic heterocycliza-
tion method to 3-vinylfuro[2,3-c]pyridines, we first pre-
pared 4-iodo-3-hydroxypyridine 2 from 3-hydroxypyridine
113 and effected its union with propargylic bromide 7.12
On treatment of the resulting iodopyridyl ether 3 with
t-BuLi,14 cyclization to 6 was found to be a minor
pathway, with deiodinated allene 5 being tentatively
identified as the main component of the product mixture.
The result suggested that iodine-lithium exchange was
followed by deprotonation at the propargylic center and
that this had suppressed cyclization. If true, we reasoned
that the unwanted side reaction might be overcome by
deliberately effecting the alkyne to allene isomerization
before triggering cyclization by iodine-lithium exchange.
The isomerization of 3 to 4 was duly achieved through
the action of t-BuOK in THF. Pleasingly, when 4 was
treated with n-BuLi at -78 °C, the expected 3-vinylfuro-
[2,3-c]pyridine was formed in modest yield and with
satisfying stereoselectivity (E:Z ∼ 9:1). We presume that
addition of the intermediate aryllithium occurs at the
central carbon of the allenic moiety and that this induces
elimination of lithium ethoxide (Scheme 1).15
(16) (a) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646,
59-67. (b) Pedrosa, R.; Andre´s, C.; Iglesias, J. M.; Pe´rez-Encabo, A.
J. Am. Chem. Soc. 2001, 123, 1817-1821.
(17) For other examples of cyclization utilizing allenylic structures,
see: Nagao, Y.; Sano, S. J. Synth. Org. Chem., Jpn. 2003, 61, 1088-
1098.
(18) Kondo, Y.; Asai, M.; Miura, T.; Uchiyama, M.; Sakamoto, T.
Org. Lett. 2001, 3, 13-15.
(19) Hagelin, H.; Oslob, J. D.; Åkermark, B. Chem. Eur. J. 1999, 5,
2413-2416.
(20) Moreno, I. Tellitu, I.; Etayo, J.; SanMart´ın, R.; Dom´ınguez, E.
Tetrahedron 2001, 57, 5403-5411.
(12) Le Strat, F.; Maddaluno, J. Org. Lett, 2002, 4, 2791-2793.
(13) Winkle, M. R.; Ronald, R. C. J. Org. Chem. 1982, 47, 2101-
2108.
(14) For a recent review on the metalation of heterocycles, see:
Chinchilla, R.; Na´jera, C.; Yus, M. Chem. Rev. 2004, 104, 2667-2722.
(15) Le Strat, F.; Maddaluno, J. Tetrahedron Lett. 2000, 41, 5367-
5371.
(21) Rodr´ıguez-Otero, J.; Cabalero-Lago, E. M. Chem. Eur. J. 2003,
9, 1837.
(22) A Pd-catalyzed isomerization of 2-vinylidenhydrofurans into
2-vinyl dihydrofurans has been reported recently, see: Wavrin, L.;
Nicolas, C.; Viala, J.; Rodriguez, J. Synlett 2004, 1820-1822.
(23) Edwards, C. R.; Readhead, M. J.; Tweddle, N. J. J. Heterocycl.
Chem. 1987, 24, 495-496.
490 J. Org. Chem., Vol. 70, No. 2, 2005

Metal-Controlled Cyclization of Propargylic Acetals
SCHEME 2. Attempted Synthesis of [4.4.0] Bicyclic Heterocycles
The isomeric homopropargylic ether 31 was readily
prepared in two steps from alkyne 29. Deprotonation
with BuLi followed by addition of ethylene oxide gave
alcohol 30 in 94% yield when 10% HMPA was included
as a cosolvent.24 A Mitsunobu condensation between 30
and 2-iodophenol then gave aryl ether 31.25 To our
surprise, treatment of 31 with an excess of n-BuLi gave
cumulene 35 as a 1:1 mixture of E- and Z-isomers in 89%
yield (Scheme 4)!26 Its formation is presumed to begin
with a halogen-metal exchange to aryllithium 32. An
intramolecular deprotonation of the propargylic carbon
next facilitates elimination of lithium phenoxide. Re-
sidual butyllithium then adds to the newly created olefin
34, triggering loss of lithium ethoxide and the formation
of cumulene 35 (Scheme 5).
SCHEME 3. Proposed Mechanism for the
Formation of Vinylisoquinolinone 13
Synthesis of [4.4.0] Bicyclic Heterocycles from
Propargyl Acetals by Palladium-Catalyzed Cycliza-
tions. The shortcomings of the carbolithiation methodol-
ogy with respect to the synthesis of vinylchromenes,
isochromenes, and isoquinolinones prompted us to ex-
amine an alternative approach based on palladium-
mediated cyclizations. We reasoned that a palladium-
catalyzed cyclization and hydride capture sequence ought
to generate the desired bicyclic skeletons efficiently.5b,27
The resulting exocyclic R,â-unsaturated acetals could
then, in a separate step, undergo δ-elimination to the
vinyl-heterocycle.
To that end, a solution of homopropargyl ether 31,
palladium acetate, triphenylphosphine, formic acid, tet-
raethylammonium bromide, and piperidine was warmed
to 60 °C in acetonitrile. The expected chromane 37 was
produced in reasonable yield (51%), though it could not
be separated from a byproduct, alkyne 36, by chroma-
tography on silica gel (Scheme 6). The same product ratio
was given when tetraethylammonium bromide was re-
placed with either thallium(I) or thallium(II) salts.28,18b
The mixture was treated with various acids, Lewis acids,
and Lewis bases in an attempt to promote δ-elimination
(25) Hughes, D. L. Org. React. 1992, 42, 335-395.
(26) For a recent application of cumulenes in synthesis, see: Leclerc,
E.; Tius, M. A. Org. Lett. 2003, 5, 1171-1174.
(27) (a) Burns, B.; Grigg, R.; Sridharan, V.; Worakun, T. Tetrahedron
Lett. 1988, 34, 4325-4328. (b) Barberan, O.; Alami, M.; Brion, J. D.
Tetrahedron Lett. 2001, 42, 2657-2659.
(24) Takeuchi, N.; Goto, K.; Sasaki, Y.; Fujita, T.; Okazaki, K.;
Kamata, K.; Tobinaga, S. Heterocycles 1992, 33, 357-374.
J. Org. Chem, Vol. 70, No. 2, 2005 491

Le Strat et al.
SCHEME 4. Synthesis of 2-Vinylbenzofuran 11
to the corresponding vinyl chromene but without success.
The destructive removal of alkyne 36 from the product
mixture was observed on reaction with t-BuLi, giving
access to 37 in pure form.
as a single stereoisomer in good yield (Scheme 7).
Treatment of a THF solution of 38 with tert-butyllithium
at -78 °C failed to induce the anticipated δ-elimination
to vinylisochromene 39, giving instead dienol 42. Pleas-
ingly, elimination could be induced with TMSOTf, leading
to an inseparable 1:2 mixture of (E)- and (Z)-39.
The formation of diene 42 is presumed to occur via
deprotonation of the benzylic carbon in 38. Conjugate
elimination of lithium ethoxide next gives aldehyde 41,
which in turn is captured by a second equivalent of tert-
butyllithium (Scheme 7). The intermediate aldehyde was
not observed when a single equivalent of the organo-
lithium reagent was employedsTLC monitoring showing
only the presence of starting material 38 and alcohol 42.
This suggests that the elimination and addition steps
outpace deprotonation at the benzylic carbon.
SCHEME 5. Synthesis and Reactivity of
Homopropargyl Ether 30
SCHEME 7. Synthesis of Vinylisochromene 39
The palladium-catalyzed cyclization was next applied
to propargylic acetal 9. Using conditions similar to those
described above, methyleneisochromene 38 was furnished
SCHEME 6. Synthesis of Chromene 37
The palladium-catalyzed cyclization-hydride capture
process also proceeded smoothly with tertiary amides 14
and 15, giving methyleneisoquinolinones 44 and 43,
respectively, in good yields and as their Z-isomers
492 J. Org. Chem., Vol. 70, No. 2, 2005

Metal-Controlled Cyclization of Propargylic Acetals
SCHEME 8. Synthesis of Vinylisoquinolinones 45
and 46
of little value in the synthesis of homologous [4.4.0]
systems. The latter are readily prepared by means of a
two-step procedure involving a palladium-induced cy-
clization and hydride capture sequence, followed by an
acid- or Lewis-acid-promoted δ-elimination. New routes
to cumulenes, vinylbenzofurans, and vinylisoquinolino-
nes, initiated by the deprotonation of propargyl acetals,
have been uncovered.
Experimental Section
4-Iodopyridin-3-ol (2). To a solution of 3-hydroxypyridine
(2.85 g, 30 mmol) in a DMF/THF mixture (8:3, 21 mL) at -15
°C under a nitrogen atmosphere was added potassium tert-
butoxide (3.71 g, 33 mmol, 1.1 equiv). After 20 min methoxy-
methyl chloride (MOMCl, 2.5 mL, 31.5 mmol, 1.05 equiv) was
added, and after a further 1 h brine (20 mL) and water (20
mL) were added successively. The mixture was extracted with
ethyl acetate (3 × 30 mL), and the combined organic phases
were washed with brine (2 × 40 mL), dried with magnesium
sulfate, and concentrated in vacuo. The residue was distilled
under vacuum to provide 3-methoxymethoxy-pyridine (2.76 g,
19.8 mmol, 66%), giving spectral and physical data consistent
with those described in the literature.13 To a solution of
3-methoxymethoxypyridine (1.39 g, 10 mmol) in anhydrous
Et2O (50 mL) at -78 °C under a nitrogen atmosphere was
added a solution of tert-butyllithium (1.35 M in pentane, 8.2
mL, 11 mmol, 1.1 equiv). After 20 min iodine (3.04 g, 12 mmol,
1.2 equiv) in Et2O (30 mL) was added, and the reaction mixture
was kept at -78 °C for 1 h. Water (40 mL) was added and the
phases separated. The aqueous phase was extracted with Et2O
(2 × 25 mL), and the combined organic phases were washed
with brine (40 mL), dried with magnesium sulfate, and
concentrated in vacuo. The residue was purified by column
chromatography (50% ethyl acetate in heptane) to give 4-iodo-
3-methoxymethoxypyridine (2.05 g, 7.73 mmol, 77%), giving
spectral and physical data consistent with those described in
the literature.13 4-Iodo-3-methoxymethoxypyridine (1.55 g, 5.84
mmol) and PTSA (100 mg) were partitioned between water
(10 mL) and Et2O (5 mL). The resulting mixture was heated
at reflux for 16 h; then the ether was evaporated and a further
aliquot of water (10 mL) was added. After a further 8 h at
reflux, the mixture was cooled to RT and the precipitated beige
solid, 4-iodo-pyridin-3-ol 2 (807 mg, 3.65 mmol, 62%), was
collected by filtration. Spectral and physical data were con-
sistent with those described in the literature.30 Mp 148 °C (lit.
140 °C); 1H NMR (300 MHz, DMSO-d6) δ 10.75 (bs, 1H), 8.08
(s, 1H), 7.73 (d, J ) 4.9 Hz, 1H), 7.68 (d, J ) 4.9 Hz, 1H); MS
(CI+) m/z (%) 250 (8) [M + Et]+, 222 (100) [M + H]+.
exclusively (Scheme 8).5b When cyclization of 15 was
carried out at 80 °C, we noted the formation of 45 as a
minor byproduct. That observation provided us with a
useful means of transforming the methyleneisoquinoli-
nones into the corresponding vinylisoquinolinones. In-
deed, simply warming an acetonitrile solution of either
43 or 44 at reflux in the presence of formic acid brought
about their smooth conversion to 45 and 46, respectively.
That these dienes may serve as synthons for alkaloids
of the amarylidaceae family is noteworthy.29
For completeness, two further experiments deserve
mention. Through the action of 1.2 equiv of t-BuLi, 43
was transformed into tert-butyl ketone 48, while treat-
ment of 43 with 2.2 equiv of KHMDS induced double-
bond migration to give isoquinolinone 47 as the major
product (Scheme 9).
SCHEME 9. Reactions of 43 with Strong Bases
3-(4,4-Diethoxybut-2-ynyloxy)-4-iodopyridine (3). Po-
tassium tert-butoxide (0.45 g, 3.94 mmol, 1.2 equiv) was added
to a solution of 4-iodo-pyridin-3-ol 2 (872 mg, 3.94 mmol, 1.2
equiv) in a mixture of DMF and THF (8/3, 12 mL) at -15 °C
under a nitrogen atmosphere. After 15 min, a solution of
bromide 3 (738 mg, 3.29 mmol) in the same mixture of solvents
(4 mL) was added and the reaction was allowed to warm to
RT. After a further 90 min, water (20 mL) and brine (20 mL)
were successively added. The aqueous phase was separated
and extracted with ethyl acetate (3 × 25 mL). The combined
organic phases were washed with water (2 × 20 mL) and brine
(2 × 20 mL), dried with magnesium sulfate, and concentrated
in vacuo to provide acetal 3 (1.00 g, 2.77 mmol, 84%) as a beige
solid. Mp 66-67 °C; νmax/cm-1 2971, 1139; 1H NMR (300 MHz,
CDCl3) δ 8.23 (s, 1H), 7.88 (d, J ) 4.9 Hz, 1H), 7.71 (d, J ) 4.9
Hz, 1H), 5.25 (s, 1H), 4.88 (s, 2H), 3.66 (dq, J ) 9.4 7.2 Hz,
2H), 3.52 (dq, J ) 9.4, 7.2 Hz, 2H), 1.17 (t, J ) 7.2 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 153.9, 144.3, 135.5, 134.8, 98.3,
91.5, 84.5, 79.0, 61.5, 58.0, 15.4; MS (CI+, CH4) m/z (%) 390
Conclusions
Vinyl-heterocycles are useful in Diels-Alder cycload-
dition reactions with classical dienophiles. Our study,
reported here and in a previous publication,12 has shown
that the intramolecular carbolithiation of propargylic
acetals with aryllithiums provides a useful entry to a
broad range of vinyl-[4.3.0] binuclear heterocycles but is
(28) Grigg, R.; Loganathan, V.; Sukirthalingam, S.; Sridharan, V.
Tetrahedron Lett. 1990, 31, 6573-6576.
(29) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg,
M.; Schmidt, J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y. J. Nat.
Prod. 1986, 49, 995-1002.
(30) Lindstro¨m, S.; Ripa, L.; Hallberg, A. Org. Lett. 2000, 2, 2291-
2293.
J. Org. Chem, Vol. 70, No. 2, 2005 493

Le Strat et al.
(28) [M + Et]+, 362 (19) [M + H]+, 222 (19), 141 (100); HRMS
(CI, NH3) m/z 362.0248, C13H17NO3I (M + H) requires 362.0253.
Anal. Calcd for C13H16NO3I: C, 43.23; H, 4.47; N, 3.88.
Found: C, 43.21; H, 4.48; N, 3.82.
Aqueous ammonia (28%, 200 mL) was added to the residue,
and this mixture was stirred at RT for 150 min. After
extraction with ethyl acetate (200 then 100 mL), the combined
organic phases were washed with brine (50 mL), dried with
magnesium sulfate, and concentrated in vacuo to provide
amine 10 (5.04 g, 32.0 mmol, 91%) as a yellow oil, which was
3-(4,4-Diethoxybuta-1,2-dienyloxy)-4-iodopyridine (4).
Potassium tert-butoxide (180 mg, 1.60 mmol, 1.6 equiv) was
added to a solution of alkyne 3 (361 mg, 1.0 mmol) in
anhydrous THF (10 mL) at 0 °C under a nitrogen atmosphere.
After 20 min, water (10 mL) and brine (25 mL) were succes-
sively added. The aqueous phase was separated and extracted
with Et2O (2 × 25 mL). The combined organic phases were
washed with brine (2 × 20 mL), dried with magnesium sulfate,
and concentrated in vacuo. The residue was purified by column
chromatography (60% ethyl acetate in heptane) to provide
allene 4 (206 mg, 0.57 mmol, 57%) as a brown oil. νmax/cm-1
used without further purification. Known compound.31 νmax
/
1
cm-1 3371, 2973, 1129; H NMR (300 MHz, CDCl3) δ 5.24 (s,
1H), 3.70 (dq, J ) 9.4, 7.2 Hz, 2H), 3.54 (dq, J ) 9.4, 7.2 Hz,
2H), 3.44 (s, 2H), 1.50 (bs, 2H), 1.20 (t, J ) 7.2 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 91.7, 86.6, 78.1, 61.1, 31.8, 15.4.
1-(4,4-Diethoxybuta-1,2-dienyloxy)methyl)-2-iodoben-
zene (11). To a solution of alkyne 9 (604 mg, 1.61 mmol) in
anhydrous THF (10 mL) at 0 °C under a nitrogen atmosphere
was added a solution of KHMDS (0.5 M in THF, 6.44 mL, 3.22
mmol, 2 equiv). After 20 min, water (5 mL) was added. The
aqueous phase was separated and extracted with Et2O (2 × 5
mL). The combined organic phases were dried with magnesium
sulfate and concentrated in vacuo to provide allene 11 (598
mg, 1.60 mmol, 99%) as a yellow oil, which was used without
1
2973, 1972, 1055; H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H),
7.92 (d, J ) 5.1 Hz, 1H), 7.70 (d, J ) 5.1 Hz, 1H), 6.99 (d, J )
5.1 Hz, 1H), 5.79 (t, J ) 5.1 Hz, 1H), 4.90 (d, J ) 5.1 Hz, 1H),
3.60-3.31 (m, 4H), 1.14 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
196.7, 153.6, 145.7, 140.6, 134.5, 121.3, 107.1, 99.7, 99.5, 61.8,
61.5, 15.5.
1
further purification. H NMR (200 MHz, CDCl3) δ 7.79 (d, J
) 8.0 Hz, 1H), 7.41-7.28 (m, 2H), 7.01-6.93 (m, 2H), 5.88 (t,
J ) 5.7 Hz, 1H), 4.82 (dd, J ) 5.7, 1.0, 1H), 4.59 (s, 2H), 3.52-
3.37 (m, 4H), 1.19 (t, J ) 7.0 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 194.4, 137.9, 137.8, 128.0, 127.3, 126.8, 121.6, 105.0,
99.3, 96.0, 73.2, 60.1, 13.9.
3-(Ethoxyvinyl)furo[2,3-c]pyridine (6). To a solution of
allene 4 (213 mg, 0.59 mmol) in anhydrous THF (6 mL) at
-78 °C under a nitrogen atmosphere was added a solution of
n-butyllithium (2.45 M in hexane, 0.58 mL, 1.41 mmol, 2.4
equiv). After 20 min, water (5 mL) was added and the reaction
was warmed to RT. The aqueous phase was separated and
extracted with Et2O (2 × 5 mL). The combined organic phases
were washed with brine (5 mL), dried with magnesium sulfate,
and concentrated in vacuo. The residue was purified by column
chromatography (60% ethyl acetate in heptane) to provide an
inseparable 9:1 mixture of (E)- and (Z)-furopyridines 6 (49.5
mg, 0.26 mmol, 44%) as a brown oil. νmax/cm-1 2978, 1655,
1606, 1162, 1093. E-Isomer: 1H NMR (300 MHz, CDCl3) δ 8.83
(s, 1H), 8.42 (d, J ) 5.3 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J ) 5.3
Hz, 1H), 7.04 (d, J ) 13.2 Hz, 1H), 5.78 (d, J ) 13.2 Hz, 1H),
3.93 (q, J ) 7.2 Hz, 2H), 1.32 (t, J ) 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 153.0, 149.3, 143.2, 142.7, 134.5, 133.0, 117.1,
115.7, 94.3, 66.0, 15.1; MS (EI+) m/z (%) 189 (19) M•+, 161 (10),
132 (29), 103 (100). Z-Isomer: 1H NMR (300 MHz, CDCl3) δ
5.33 (d, J ) 9.0 Hz, 1H), 6.41 (d, J ) 9.0 Hz, 1H), 8.10 (s, 1H).
Other signals are superimposed with those of E-isomer.
1-((4,4-Diethoxybut-2-ynyloxy)methyl)-2-iodoben-
zene (9). To a suspension of sodium hydride (60% in mineral
oil, 0.81 g, 20 mmol, 2 equiv) in anhydrous THF (15 mL) under
a nitrogen atmosphere was added a solution of alcohol 8 (1.58
g, 10 mmol) in anhydrous THF (15 mL) at RT. The mixture
was stirred at this temperature for 20 min, and a solution of
2-iodobenzyl bromide (3.12 g, 10 mmol, 1 equiv) in THF (15
mL) was added. The mixture was refluxed for 90 min before
carrying out the hydrolysis at RT with water (20 mL). The
aqueous phase was extracted with Et2O (2 × 20 mL). The
combined organic phases were dried with magnesium sulfate
and concentrated in vacuo to give benzylic ether 9 (3.65 g, 9.75
mmol, 97%) as a yellow oil, which was used without further
purification. νmax/cm-1 2925, 1137; 1H NMR (300 MHz, CDCl3)
δ 7.80 (d, J ) 7.5 Hz, 1H), 7.41 (dd, J ) 1.5, 7.5 Hz, 1H), 7.32
(t, J ) 7.5 Hz, 1H), 6.97 (dt, J ) 1.5, 7.5 Hz, 1H), 5.32 (t, J )
1.1 Hz, 1H), 4.56 (s, 2H), 4.31 (d, J ) 1.1 Hz, 2H), 3.75 (dq, J
) 9.4, 7.2 Hz, 2H), 3.58 (dq, J ) 9.4, 7.2 Hz, 2H), 1.23 (t, J )
7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 140.1, 139.6, 129.8,
129.4, 128.3, 98.3, 91.7, 82.5, 81.5, 75.6, 61.4, 58.3, 15.5; MS
(EI+) m/z (%) 374 (10) M•+, 217 (100). Anal. Calcd for C15H19-
IO3: C, 48.14; H, 5.12. Found: C, 47.97; H, 4.98.
N-(4,4-Diethoxy-but-2-ynyl)-2-iodobenzamide (12). A
solution of DCC (3.73 g, 18.1 mmol, 1 equiv) in anhydrous THF
(30 mL) was added to a mixture of 2-iodobenzoic acid (2.84 g,
18.1 mmol, 1 equiv) and pentafluorophenol (3.70 g, 19.91
mmol, 1.1 equiv) in THF (40 mL) at RT under a nitrogen
atmosphere. After 1 h, the mixture was filtered and concen-
trated in vacuo. Dicyclohexylurea was then removed by
precipitation from EtOAc. The filtrate was concentrated in
vacuo, and the residue was dissolved in anhydrous CH2Cl2 (40
mL) and placed under an atmosphere of nitrogen. Amine 10
(2.84 g, 18.1 mmol) and diisoproylethylamine (7 mL, 40 mmol,
2.2 equiv) were successively added to the solution dropwise
over 10 min. After 16 h, water (25 mL) was added. The aqueous
phase was separated and extracted with CH2Cl2 (15 mL). The
combined organic phases were washed with saturated NaHCO3
(15 mL), dried with magnesium sulfate, and concentrated in
vacuo. Purification by column chromatography (45% ethyl
acetate in heptane) gave benzamide 12 (5.50 g, 14.2 mmol,
79%) as a yellow solid. Mp 76-78 °C; νmax/cm-1 3243, 2969,
1642, 1141; 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J ) 7.9 Hz,
1H), 7.38-7.35 (m, 2H), 7.11-7.06 (m, 1H), 5.64 (bs, 1H), 5.26
(t, J ) 1.5 Hz, 1H), 4.30 (dd, J ) 1.5, 5.3 Hz, 2H), 3.72 (dq, J
) 9.4, 7.2 Hz, 2H), 3.56 (dq, J ) 9.4, 7.2 Hz, 2H), 1.21 (t, J )
7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 169.2, 141.6, 140.3,
131.8, 128.7, 128.6, 92.7, 91.6, 80.9, 79.8, 61.4, 30.3, 15.4; MS
(CI+, NH3) m/z (%) 405 (37) [M + NH4]+, 342 (100). Anal. Calcd
for C15H18INO3: C, 46.53; H, 4.69; N, 3.62. Found: C, 46.58;
H, 4.62; N, 3.61.
4-(2-Ethoxyvinyl)isoquinolin-1(2H)-one (13). From Io-
dobenzamide (12), Normal Addition. To a solution of iodoben-
zamide 12 (387 mg, 1.0 mmol) in anhydrous THF (10 mL) at
-78 °C under a nitrogen atmosphere was added a solution of
n-butyllithium (2.1 M in hexane, 2.2 mL, 4.4 mmol, 4.4 equiv)
dropwise over 5 min. After 30 min, water (5 mL) was added
and the mixture was allowed to warm to RT. The aqueous
phase was separated and extracted with Et2O (2 × 5 mL). The
combined organic phases were dried with magnesium sulfate
and concentrated in vacuo. Purification by column chroma-
tography (30% ethyl acetate in heptane) gave an inseparable
4:1 mixture of (E)- and (Z)-isoquinolinones 13 (60 mg, 0.28
mmol, 28%) as a brown oil.
4,4-Diethoxy-2-yn-1-amine (10). To a solution of alcohol
8 (5.53 g, 35 mmol) and triethylamine (15.0 mL, 105 mmol, 3
equiv) in anhydrous Et2O (140 mL) at 0 °C under a nitrogen
atmosphere was added dropwise methanesulfonyl chloride
(3.25 mL, 42 mmol, 1.2 equiv). After 1 h, saturated NaHCO3
(70 mL) was added. The aqueous phase was separated and
extracted with Et2O (2 × 40 mL). The combined organic phases
were dried with magnesium sulfate and concentrated in vacuo.
From Iodobenzamide (12), Reversed Addition. To a solution
of n-butyllithium (2.1 M in hexane, 5.4 mL, 11.3 mmol, 4.4
(31) Haidoune, M.; Giffard, M.; Mornet, R.; Gorgues, A. Tetrahedron
Lett. 1989, 30, 3967-3968.
494 J. Org. Chem., Vol. 70, No. 2, 2005

Metal-Controlled Cyclization of Propargylic Acetals
equiv) at -78 °C under a nitrogen atmosphere were added
successively anhydrous THF (4 mL) and a solution of iodo-
benzamide 12 (1.00 g, 2.58 mmol) in anhydrous THF (20 mL).
After 30 min, water (15 mL) was added and the solution was
allowed to warm to RT. The aqueous phase was separated and
extracted with Et2O (2 × 10 mL). The combined organic phases
were dried with magnesium sulfate and concentrated in vacuo.
Purification by column chromatography (30% ethyl acetate in
heptane) gave an inseparable 9:1 mixture of (E)- and (Z)-
isoquinolinones 13 (180 mg, 0.84 mmol, 32%) as a brown oil.
3.78-3.48 (m, 4H), 2.87 (s, 3H), 1.21 (t, J ) 7.2 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 170.7, 142.2, 139.6, 130.7, 128.8,
127.4, 92.5, 91.6, 80.2, 79.9, 61.3, 36.7, 36.0, 15.5. Minor
rotamer: 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J ) 8.3 Hz,
1H), 7.40-7.02 (m, 3H), 5.23 (t, J ) 1.5 Hz, 1H), 3.92 (bs, 2H),
3.78-3.48 (m, 4H), 3.16 (s, 3H), 1.20 (t, J ) 7.2 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 170.6, 142.0, 139.6, 130.9, 128.8,
127.6, 92.8, 91.5, 81.1, 79.4, 61.3, 41.2, 32.6, 15.5; MS (EI+)
m/z (%) 401 (0.5), 400 (2) [M - H]•+, 372 (18), 231 (100); HRMS
(CI, NH3) m/z, 356.0145, C14H15INO2 (M + H+ - EtOH)
requires 356.1847. Anal. Calcd for C16H20INO3: C, 47.88; H,
4.99; N, 3.49. Found: C, 47.74; H, 4.93; N, 3.42.
From Benzamide (17). To a solution of benzamide 17 (131
mg, 0.5 mmol) in anhydrous THF (5 mL) at 0 °C under a
nitrogen atmosphere was added potassium tert-butoxide (150
mg, 1.25 mmol, 2.5 equiv). After 30 min, water (10 mL) was
added. The aqueous phase was separated and extracted with
Et2O (2 × 5 mL). The combined organic phases were dried with
magnesium sulfate and concentrated in vacuo to provide an
inseparable mixture (77 mg) of (E)- and (Z)-isoquinolines 13
(0.25 mmol, 50%, E/Z ) 3:1) and 4-(2,2-diethoxyethyl)isoquino-
N-(4,4-Diethoxybuta-1,2-dienyl)-2-iodo-N-methyl-ben-
zamide (16). To a solution of benzamide 15 (452 mg, 1.126
mmol) in anhydrous THF (10 mL) at 0 °C under a nitrogen
atmosphere was added potassium tert-butoxide (193 mg, 1.69
mmol, 1.5 equiv). After 10 min, water (10 mL) was added. The
aqueous phase was separated and extracted with Et2O (2 ×
10 mL). The combined organic phases were washed with brine
(10 mL), dried with magnesium sulfate, and concentrated in
vacuo to provide allene 16 (397 mg, 0.99 mmol, 88%) as a
lin-1(2H)-one 25 (0.087 mmol, 18%). Isoquinolinone 13: νmax
/
cm-1 2924, 1654, 1179, 909, 735. E-Isomer: 1H NMR (300
MHz, CDCl3) δ 8.01-7.96 and 7.44-7.37 (m, 4H), 7.11 (d, J )
12.8 Hz, 1H), 6.82 (s, 1H), 5.68 (d, J ) 12.8 Hz, 1H), 3.90 (q,
J ) 7.2 Hz, 2H), 1.36 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.8, 149.7, 149.4 (2 carbons), 130.2, 129.0, 128.0,
126.4, 126.3, 122.6, 93.1, 66.3, 15.1. Z-Isomer: 1H NMR (300
MHz, CDCl3) δ 8.01-7.96 and 7.44-7.37 (m, 4H), 7.27 (s, 1H),
6.21 (d, J ) 6.6 Hz, 1H), 5.42 (d, J ) 6.6 Hz, 1H), 4.06 (q, J )
7.2 Hz, 2H), 1.31 (t, J ) 7.2 Hz, 3H); MS (EI+) m/z (%) 215
(100) M•+, 186 (44), 158 (44), 83 (76). 4-(2,2-Diethoxyethyl)-
isoquinolin-1(2H)-one 21: 1H NMR (200 MHz, CDCl3) δ 7.95
and 7.30 (m, 4H), 6.93 (s, 1H), 4.77 (t, J ) 5.8 Hz, 1H), 3.70-
3.40 (m, 4H), 3.02 (d, J ) 5.8 Hz, 2H), 1.16 (t, J ) 7.0 Hz,
6H).
yellow oil comprised of two rotamers in a ratio of 55:45. νmax
/
cm-1 2973, 1656, 1072; 1H NMR (300 MHz, CDCl3) δ 7.84-
7.76 (m, 1H), 6.48 (1H, d, J = 6.5 Hz, 1H), 7.38 (t, J ) 7.6 Hz,
1H), 7.24 (m, 1H), 7.09 (dt, J ) 1.5, 7.6 Hz, 1H), 5.92-5.82
(m, 1H), 5.00-4.92 (m, 1H), 3.72-3.46 (m, 4H), 3.15 and 2.83
(two s, 3H), 1.25-1.14 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
198.2, 195.6, 169.2, 142.0, 141.5, 139.8, 139.6, 131.1, 130.9,
128.8, 128.2, 127.7, 104.7, 103.2, 103.0, 102.7, 101.7, 100.7,
93.2, 92.6, 62.0, 35.1, 31.2, 15.7, 15.6; MS (CI+, CH4) m/z (%)
402 (60) [M + H]+, 356 (52), 229 (95), 103 (100).
N-(4,4-Diethoxy-but-2-ynyl)benzamide (17). A solution
of DCC (1.48 g, 7.2 mmol, 1.6 equiv) in anhydrous THF (12
mL) was added to a mixture of benzoic acid (0.73 g, 6 mmol,
1.3 equiv) and pentafluorophenol (1.21 g, 6.6 mmol, 1.4 equiv)
in THF (13 mL) at RT under a nitrogen atmosphere. After 1
h, the mixture was filtered and the filtrate concentrated in
vacuo. Dicyclohexylurea was then removed by precipitation
from EtOAc (10 mL). The filtrate was concentrated in vacuo,
dissolved in anhydrous CH2Cl2 (40 mL), and placed under an
atmosphere of nitrogen. Amine 10 (0.70 g, 4.5 mmol) and
diisoproylethylamine (1.8 mL, 10.3 mmol, 2.3 equiv) were
successively added to the solution. After 16 h, water (15 mL)
was added. The aqueous phase was separated and extracted
with CH2Cl2 (2 × 15 mL). The combined organic phases were
washed with 4 M NaOH (2 × 15 mL), dried with magnesium
sulfate, and concentrated in vacuo to provide benzamide 17
(0.90 g, 3.44 mmol, 77%) as a white solid. Mp 122-124 °C;
νmax/cm-1 3219, 2971, 1639, 1054; 1H NMR (300 MHz, CDCl3)
δ 7.75 (dd, J ) 1.4, 7.7 Hz, 2H), 7.50-7.37 (m, 3H), 6.27 (bs,
1H), 5.27 (t, J ) 1.5 Hz, 1H), 4.31 (dd, J ) 1.5, 5.1 Hz, 2H),
3.72 (dq, J ) 9.4, 7.2 Hz, 2H), 3.56 (dq, J ) 9.4, 7.2 Hz, 2H),
1.22 (t, J ) 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 167.4,
134.1, 132.1, 129.0, 127.4, 91.6, 81.4, 79.5, 61.4, 30.2, 15.4; MS
(EI+) m/z (%) 215 (95) [M - EtOH]•+, 149 (69), 105 (100).
(2-(4,4-Diethoxybut-2-ynyloxy)phenyl)methanol (22).
Freshly ground potassium hydroxide (9.0 g, 160 mmol, 8 equiv)
was added to a solution of alcohol 8 (3.04 g, 19.2 mmol) and
tosyl chloride (4.03 g, 21.1 mmol, 1.1 equiv) in THF (90 mL)
at -30 °C. After 40 min, water (45 mL) was added and the
reaction mixture was warmed to RT. The aqueous phase was
separated and extracted with Et2O (2 × 20 mL). The combined
organic phases were washed with brine (50 mL), dried with
magnesium sulfate, and concentrated in vacuo to provide 4,4-
diethoxybut-2-ynyl 4-methylbenzenesulfonate (6.00 g, 19.2
mmol, 100%), which was used without further purification. A
solution of 2-(hydroxymethyl)phenol (2.71 g, 19.2 mmol, 1
equiv) and potassium carbonate (3.45 g, 25 mmol, 1.3 equiv)
in freshly distilled acetone (25 mL) was stirred for 15 min at
RT before being added to a solution of 4,4-diethoxybut-2-ynyl
4-methylbenzenesulfonate (6.00 g, 19.2 mmol) in acetone (25
mL). The mixture was refluxed for 20 h, concentrated in vacuo,
N-(4,4-Diethoxy-but-2-ynyl)-2-iodo-N-(4-methoxyben-
zyl)benzamide (14). To a suspension of sodium hydride (60%
in mineral oil, 240 mg, 6.0 mmol, 1 equiv) in anhydrous DMF
(10 mL) at RT under a nitrogen atmosphere was added a
solution of amide 12 (2.32 g, 6.0 mmol) in DMF (30 mL). After
10 min, the solution was cooled to 0 °C and p-methoxybenzyl
chloride (1.0 mL, 7.2 mmol, 1.2 equiv) added. After a further
1 h at RT, water (40 mL) was added. The aqueous phase was
separated and extracted with ethyl acetate (3 × 30 mL). The
combined organic phases were washed with brine (30 mL),
dried with magnesium sulfate, and concentrated in vacuo.
Purification by column chromatography (50% ethyl acetate in
heptane) gave amide 14 (2.29 g, 4.51 mmol, 75%) as viscous
yellow oil comprised of two rotamers. νmax/cm-1 2971, 1646,
1
1138; H NMR (300 MHz, CDCl3) δ 7.83-6.80 (m, 8H), 5.27
and 4.35 (two m, 1H + 2H), 4.70 (d, J = 16.9 Hz, 1H), 3.95 (d,
J = 16.9 Hz, 1H), 3.79-3.50 (m, 7H), 1.22 (t, J ) 7.2 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 170.8, 170.6, 159.8, 159.7, 141.8,
139.7, 131.0, 130.9, 130.8, 129.5, 129.0, 128.7, 128.2, 127.8,
127.7, 127.4, 114.5, 114.3, 93.2, 92.7, 91.7, 91.5, 80.9, 80.0, 79.9,
79.7, 61.3, 55.7, 51.2, 46.8, 37.7, 33.2, 15.5; MS (EI+) m/z (%)
461 (7) [M - EtOH]•+, 231 (52), 121 (100).
N-(4,4-Diethoxybut-2-ynyl)-2-iodo-N-methylbenza-
mide (15). To a suspension of sodium hydride (60% in mineral
oil, 113 mg, 2.58 mmol, 1 equiv) in anhydrous DMF (5 mL) at
RT under a nitrogen atmosphere was added a solution of
benzamide 12 (1.00 g, 2.58 mmol) in DMF (10 mL). After 10
min, the solution was cooled to 0 °C and methyl iodide (0.3
mL, 4.84 mmol, 1.9 equiv) added. After a further 16 h at RT,
water (15 mL) was added. The aqueous phase was separated
and extracted with ethyl acetate (3 × 10 mL). The combined
organic phases were dried with magnesium sulfate and
concentrated in vacuo. Purification by column chromatography
(30% ethyl acetate in heptane) gave amide 15 (0.87 g, 2.17
mmol, 84%) as viscous yellow oil comprised of two rotamers
in a 3:2 ratio. νmax/cm-1 2969, 2243, 1640, 1141. Major
rotamer: 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J ) 8.3 Hz,
1H), 7.40-7.02 (m, 3H), 5.27 (t, J ) 1.5 Hz, 1H), 4.46 (bs, 2H),
J. Org. Chem, Vol. 70, No. 2, 2005 495

Le Strat et al.
and partitioned between water (50 mL) and chloroform (30
mL). The aqueous phase was separated and extracted with
chloroform (2 × 30 mL). The combined organic phases were
washed with 4 M sodium hydroxide (30 mL), dried with
magnesium sulfate, and concentrated in vacuo, and the residue
was purified by column chromatography (30% ethyl acetate
in heptane) to provide alcohol 22 (4.57 g, 17.3 mmol, 90%) as
a colorless oil. νmax/cm-1 3448, 2975, 1118; 1H NMR (300 MHz,
CDCl3) δ 7.26-7.17 (m, 2H), 6.95-6.89 (m, 2H), 5.20 (t, J )
1.5 Hz, 1H), 4.73 (d, J ) 1.5 Hz, 2H), 4.62 (s, 2H), 3.61 (dq, J
) 9.4, 7.2 Hz, 2H), 3.48 61 (dq, J ) 9.4, 7.2 Hz, 2H), 2.27 (bs,
1H), 1.13 (t, J ) 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
155.7, 130.3, 129.3, 129.1, 122.1, 112.4, 91.5, 83.3, 80.4, 61.9,
61.4, 56.5, 15.4; MS (EI+) m/z (%) 264 (4) M•+, 219 (5), 96 (100).
Anal. Calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 68.17;
H, 7.69.
(2.2 M in hexane (18.5 mL, 40.7 mmol, 1 equiv). After 30 min,
a large excess of ethylene oxide was condensed into the
reaction mixture by means of a dry ice condenser. The mixture
was stirred at RT until the starting material had been
consumed (TLC monitoring), whereupon water (50 mL) was
added. The aqueous phase was separated and extracted
successively with Et2O (30 mL) and ethyl acetate (2 × 30 mL).
The combined organic phases were washed with a solution of
50% saturated solution of ammonium chloride (4 × 50 mL),
dried with magnesium sulfate, and concentrated in vacuo to
give alcohol 30 (6.47 g, 37.5 mmol, 94%) as a yellow oil, which
was used without further purification. νmax/cm-1 3466, 2977,
1
1120; H NMR (300 MHz, CDCl3) δ 5.20 (t, J ) 1.5 Hz, 1H),
3.73-3.63 (m, 4H), 3.52 (dq, J ) 9.4, 7.2 Hz, 2H), 2.46 (dt, J
) 1.5 ,6.4 Hz, 2H), 1.18 (t, J ) 7.2 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 91.7, 83.4, 77.7, 61.1, 61.0, 23.3, 15.4); MS (EI+) m/z
(%) 171 (3) [M - H]•+, 127 (100) [M - OEt]•+; HRMS (CI, NH3)
m/z 190.1419, C9H20O3N (M + NH4+) requires 190.1443.
1-(4,4-Diethoxybut-2-ynyloxy)-2-(iodomethyl)ben-
zene (24). To a solution of alcohol 22 (4.62 g, 17.47 mmol) in
anhydrous THF (30 mL) at -78 °C under a nitrogen atmo-
sphere was added a solution of n-butyllithium (2.4 M in
hexane, 8.0 mL, 19.2 mmol, 1.1 equiv). After 20 min, a solution
of p-toluenesulfonyl chloride (3.33 g, 17.47 mmol, 1 equiv) in
THF (20 mL) was added, and the mixture was allowed to
warmed to -10 °C. After 30 min, water (20 mL) was added.
The aqueous phase was separated and extracted with Et2O (2
× 15 mL). The combined organic phases were dried with
magnesium sulfate and concentrated in vacuo without heating.
The residue was dissolved in acetone (150 mL), cooled to 0 °C,
and sodium iodide (17.0 g, 110 mmol, 6.5 equiv) added. After
1 h at RT, water (50 mL) was added. The resulting solution
was concentrated in vacuo to ca. 50 mL and then extracted
with ethyl acetate (3 × 50 mL). The combined organic phases
were washed with brine (50 mL), dried with magnesium
sulfate, and concentrated in vacuo to give alkyne 24 (6.36 g,
17.0 mmol, 97%) as a yellow solid, which was used without
1-(5,5-Diethoxypent-3-ynyloxy)-2-iodobenzene (31). Di-
isopropyl azodicarboxylate (7.25 mL, 35 mmol, 1 equiv) was
added dropwise to a mixture of 2-iodophenol (7.85 g, 35 mmol,
1 equiv), alcohol 30 (6.02 g, 35 mmol), and triphenylphosphine
(9.18 g, 35 mmol, 1 equiv) in anhydrous Et2O (180 mL) at 0
°C under a nitrogen atmosphere. After 4 h, the mixture was
allowed to warm to RT and then stirred at that temperature
for 16 h. The mixture was filtered, concentrated in vacuo to
ca. 50 mL, and then washed with 0.4 M sodium hydroxide (3
× 50 mL). The organic phase was separated, dried with
magnesium sulfate, and concentrated in vacuo. Triphenylphos-
phine oxide was then removed by precipitation and filtration,
first from Et2O and then from pentane. Purification by column
chromatography (10% ethyl acetate in heptane) provided
alkyne 31 (8.61 g, 23.0 mmol, 66%) as a yellow oil. νmax/cm-1
1
2975, 1121; H NMR (300 MHz, CDCl3) δ 7.74 (dd, J ) 7.9,
1.5 Hz, 1H), 7.25 (m, 1H), 6.77 (dd, J ) 8.1, 1.5 Hz, 1H), 6.69
(dt, J ) 1.5, 7.9 Hz, 1H), 5.25 (t, J ) 1.5 Hz, 1H), 4.11 (t, J )
7.2 Hz, 2H), 3.73 (dq, J ) 9.4, 7.2 Hz, 2H), 3.55 (dq, J ) 9.4,
7.2 Hz, 2H), 2.78 (dt, J ) 1.5, 7.2 Hz, 2H), 1.21 (t, J ) 7.2 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 157.4, 140.0, 129.8, 123.4,
112.9, 91.7, 87.1, 82.2, 77.9, 67.4, 61.2, 20.0, 15.5; MS (EI+)
m/z (%) 374 (2) M•+, 220 (100). Anal. Calcd for C15H19IO3: C,
48.14; H, 5.12. Found: C, 48.12; H, 5.46.
1
further purification. Mp 56-58 °C; νmax/cm-1 2974, 1137; H
NMR (300 MHz, CDCl3) δ 7.31-7.20 (m, 2H), 6.94-6.87 (m,
2H), 5.27 (t, J ) 1.1 Hz, 1H), 4.83 (d, J ) 1.1 Hz, 2H), 4.46 (s,
2H), 3.68 (dq, J ) 9.4, 7.2 Hz, 2H), 3.54 (dq, J ) 9.4, 7.2 Hz,
2H), 1.19 (t, J ) 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
155.4, 128.4, 130.7, 129.7, 121.9, 112.9, 91.5, 83.0, 80.4, 61.3,
56.3, 15.3, 1.0; MS (EI+) m/z (%) 329 (1) [M - OEt]•+, 247 (15)
[M - I]•+, 202 (42); 68 (100). Anal. Calcd for C15H19IO3: C,
48.14; H, 5.12. Found: C, 48.09; H, 5.29.
1-Ethoxynona-1,2,3-triene (35). A solution of n-butyl-
lithium (2.1 M in hexane, 0.80 mL, 1.70 mmol, 3.4 equiv) was
added to a solution of alkyne 31 (187 mg, 0.50 mmol) in
anhydrous THF (5 mL) at -78 °C under a nitrogen atmo-
sphere. After 20 min, water (5 mL) was added. The aqueous
phase was separated and extracted with Et2O (2 × 5 mL). The
combined organic phases were dried with magnesium sulfate
and concentrated in vacuo to provide a mixture of isomers E
and Z (E/Z ) 1:1) of trienes 35 (74 mg, 0.445 mmol, 89%) as
2-(3,3-Diethoxyprop-1-enyl)benzofuran (28). To a solu-
tion of alkyne 24 (414 mg, 1.1 mmol) in anhydrous toluene
(11 mL) at 0 °C under a nitrogen atmosphere was added a
solution of KHMDS (0.5 M in toluene, 5.5 mL, 2.75 mmol, 2.5
equiv). After 30 min, water (10 mL) was added. The aqueous
phase was separated and extracted with Et2O (2 × 10 mL).
The combined organic phases were washed with brine (10 mL),
dried with magnesium sulfate, and concentrated in vacuo. The
residue was then purified by column chromatography (5%
ethyl acetate in heptane) to give an inseparable 9:1 mixture
of (E)- and (Z)-benzofuran 28 (120 mg, 0.49 mmol, 49%) as a
yellow oil. νmax/cm-1 2970, 1680, 1121, 1051. E-Isomer: 1H
NMR (300 MHz, CDCl3) δ 7.50 (d, J ) 7.9 Hz, 1H), 7.42 (d, J
) 7.9 Hz, 1H), 7.28-7.14 (m, 2H), 6.67 (d, J ) 16.3 Hz, 1H),
6.61 (s, 1H), 6.40 (dd, J ) 4.5, 16.3 Hz, 1H), 5.12 (d, J ) 4.5
Hz, 1H), 3.71 (dq, J ) 9.4, 7.2 Hz, 2H), 3.56 (dq, J ) 9.4, 7.2
Hz, 2H), 1.25 (t, J ) 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 155.3, 154.2, 129.2, 129.1, 125.2, 123.5, 121.6, 121.4, 111.4,
106.1, 100.7, 61.4, 15.7. Z-Isomer: 1H NMR (300 MHz, CDCl3)
δ 7.55-7.14 (m, 4H), 6.79 (s, 1H), 6.45 (m, 1H), 5.79 (m, 2H),
3.71 (dq, J ) 9.4, 7.2 Hz, 2H), 3.56 (dq, J ) 9.4, 7.2 Hz, 2H),
1.25 (t, J ) 7.2 Hz, 6H); MS (CI+, CH4) m/z (%) 247 (28) [M +
H]+, 217 (5), 201 (100); HRMS (CI, NH3) m/z 246.1234,
C15H18O3 requires 246.1256.
1
a yellow oil. H NMR (200 MHz, CDCl3) δ 6.56 (m, 1H), 5.13
(dt, J ) 5.6, 7.5 Hz, 0.5H), 5.04 (dt, J ) 6.0, 7.1 Hz, 0.5H),
3.94-3.84 (m, 2H), 2.18-2.09 (m, 2H), 1.50-1.23 (m, 12H);
13C NMR (75 MHz, CDCl3) δ 125.9, 125.7, 95.8, 95.7, 65.5, 65.4,
31.8, 31.7, 31.3, 30.9, 29.3, 29.1, 23.0, 22.9, 14.9, 14.4; MS (EI+)
m/z (%) 166 (17) M•+, 109 (23), 81 (100); HRMS (EI) m/z
166.1364, C11H18O requires 166.1358.
(E)-4-(2,2-Diethoxyethylidene)-3,4-dihydro-2H-
chromene (37). A mixture of alkyne 31 (748 mg, 2 mmol),
palladium acetate (44 mg, 0.2 mmol, 0.1 equiv), triphenylphos-
phine (106 mg, 0.4 mmol, 0.2 equiv), tetraethylammonium
bromide (480 mg, 2.2 mmol, 1.1 equiv), formic acid (0.22 mL,
5.8 mmol, 2.9 equiv), and piperidine (0.81 mL, 8.1 mmol, 4
equiv) in acetonitrile (60 mL) was stirred at 60 °C under a
nitrogen atmosphere for 16 h and then cooled to RT, filtered,
and concentrated in vacuo. The residue was dissolved in Et2O
(30 mL) and washed with water (20 mL). The organic phase
was dried with magnesium sulfate and concentrated in vacuo.
Purification by column chromatography (10% ethyl acetate in
heptane) gave a yellow oil (0.33 g) comprised of an inseparable
5,5-Diethoxypent-3-yn-1-ol (30). To a solution of propi-
olaldehyde diethyl acetal 29 (5.28 g, 40 mmol) in anhydrous
THF (55 mL) containing HMPA (5 mL), at -30 °C under a
nitrogen atmosphere was added a solution of n-butyllithium
3:1 mixture of chromene 37 (51%) and alkyne 36 (15%). νmax
/
496 J. Org. Chem., Vol. 70, No. 2, 2005

Metal-Controlled Cyclization of Propargylic Acetals
cm-1 2974, 1600, 1050. Chromene 37: 1H NMR (200 MHz,
CDCl3) δ 7.53-6.76 (m, 4H), 6.02 (d, J ) 6.2 Hz, 1H), 5.28 (d,
J ) 6.2 Hz, 1H), 4.15 (t, J ) 5.4 Hz, 2H), 3.68-3.42 (m, 4H),
2.71 (t, J ) 5.4 Hz, 2H), 1.17 (t, J ) 7.0 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 155.4, 133.3, 129.9, 124.7, 121.8, 121.2, 119.8,
118.0, 98.6, 66.2, 60.7, 26.7, 15.7; MS (CI+, CH4) m/z (%) 249
(7) [M + H]+, 203 (100). Alkyne 36: 1H NMR (200 MHz, CDCl3)
δ 7.20-6.76 (m, 5H), 5.21 (s, 1H), 4.04 (t, J ) 7.2 Hz, 2H),
3.68-3.42 (m, 4H), 2.71 (t, J ) 7.2 Hz, 2H), 1.17 (t, J ) 7.0
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 158.8, 121.4, 119.9,
114.8, 91.8, 82.5, 78.0, 66.0, 61.1, 20.1, 15.7.
127.5, 127.3, 114.8, 110.4, 77.9, 66.1, 36.7, 27.0, 15.1; MS (EI+)
m/z (%) 245 (11) [M - CH3]•+, 173 (51), 129 (76), 57 (100).
(Z)-4-(2,2-Diethoxyethylidene)-3,4-dihydro-2-methyl-
isoquinolin-1(2H)-one (43). A mixture a alkyne 15 (0.75 g,
1.87 mmol), palladium acetate (44 mg, 0.2 mmol, 0.1 equiv),
triphenylphosphine (108 mg, 0.41 mmol, 0.2 equiv), tetraethyl-
ammonium bromide (427 mg, 2 mmol, 1 equiv), formic acid
(0.21 mL, 5.5 mmol, 3 equiv), and piperidine (0.76 mL, 7.6
mmol, 4 equiv) in acetonitrile (60 mL) was stirred at 60 °C
under a nitrogen atmosphere for 16 h then cooled to RT,
filtered, and concentrated in vacuo. Purification by column
chromatography (30% ethyl acetate in heptane) gave isoquino-
linone 43 (0.44 g, 1.60 mmol, 85%) as a brown oil. νmax/cm-1
2973, 1640, 1599, 1117; 1H NMR (300 MHz, CDCl3) δ 8.13 (d,
J ) 7.9 Hz, 1H), 7.54 (d, J ) 7.5 Hz, 1H), 7.41 (m, 2H), 6.11
(dt, J ) 5.3, 1.9 Hz, 1H), 5.32 (d, J ) 5.3 Hz, 1H), 4.32 (d, J )
1.9 Hz, 2H), 3.65 (dq, J ) 9.4, 7.2 Hz, 2H), 3.54 (dq, J ) 9.4,
7.2 Hz, 2H), 3.14 (s, 3H), 1.21 (t, J ) 7.2 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 163.4, 135.7, 132.4, 128.1, 132.2, 129.2,
128.6, 125.4, 123.1, 98.1, 60.7, 49.8, 35.2, 15.6; MS (EI+) m/z
(%) 230 (36) [M - OEt]•+, 229 (100), 200 (65); HRMS (CI, NH3)
m/z 276.1581, C16H22NO3 (MH+) requires 276.1600.
(Z)-4-(2,2-Diethoxyethylidene)-3,4-dihydro-1H-isoch-
romene (38). A mixture of alkyne 9 (1.87 g, 5 mmol),
palladium acetate (110 mg, 0.5 mmol, 0.1 equiv), triphen-
ylphosphine (264 mg, 1 mmol, 0.2 equiv), tetraethylammonium
bromide (1.07 g, 5 mmol, 1 equiv), formic acid (0.57 mL, 15
mmol, 3 equiv), and piperidine (2 mL, 20 mmol, 4 equiv) in
acetonitrile (150 mL) was stirred at 60 °C under a nitrogen
atmosphere for 16 h. The mixture was then cooled to RT,
filtered, and concentrated in vacuo. Purification by column
chromatography (10% ethyl acetate in heptane) gave iso-
chromene 38 (0.89 g, 3.58 mmol, 72%) as a yellow oil. νmax
/
cm-1 2974, 1104, 1485; 1H NMR (300 MHz, CDCl3) δ 7.65 (dd,
J ) 3.0 4.5 Hz, 1H), 7.21 (m, 2H), 7.01 (dd, J ) 3.6, 5.3 Hz,
1H), 6.11 (dt, J ) 5.4, 2.0 Hz, 1H), 5.28 (d, J ) 5.4 Hz, 1H),
4.71 (s, 2H), 4.60 (d, J ) 2.0 Hz, 2H), 3.65 (dq, J ) 9.4, 7.2
Hz, 2H), 3.52 (dq, J ) 9.4, 7.2 Hz, 2H), 1.20 (t, J ) 7.2 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 135.4, 134.5, 131.2, 128.4,
127.5, 125.1, 123.7, 120.8, 98.3, 68.9, 66.7, 60.9, 15.7; MS (EI+)
m/z (%) 202 (100) [M - EtOH]•+, 115 (55); HRMS (CI, NH3)
m/z 266.1745, C15H24NO3 (M + NH4+) requires 266.1756.
(Z)-2-(4-Methoxybenzyl)-4-(2,2-diethoxyethylidene)-
3,4-dihydroisoquinolin-1(2H)-one (44). A mixture a alkyne
14 (2.14 g, 4.22 mmol), palladium acetate (97 mg, 0.42 mmol,
0.1 equiv), triphenylphosphine (232 mg, 0.84 mmol, 0.2 equiv),
tetraethylammonium bromide (0.89 g, 4.22 mmol, 1 equiv),
formic acid (0.48 mL, 12.6 mmol, 3 equiv), and piperidine (1.7
mL, 17 mmol, 4 equiv) in acetonitrile (130 mL) was stirred at
60 °C under a nitrogen atmosphere for 16 h and then cooled
to RT, filtered, and concentrated in vacuo. Purification by
column chromatography (40% ethyl acetate in heptane) gave
4-(Ethoxyvinyl)-1H-isochromene (39). To a solution of
isochromene 38 (1.24 g, 5 mmol) and diisopropylethylamine
(2.61 mL, 15 mmol, 3 equiv) in anhydrous dichloromethane
(25 mL) at -40 °C under a nitrogen atmosphere was added
trimethylsilyl trifluoromethanesulfonate (2.26 mL, 12.5 mmol,
2.5 equiv). After 40 min, 1 M NaOH (0.46 mL) and pentane
(35 mL) were successively added. The mixture was maintained
at -20 °C for 36 h and then filtered, dried with magnesium
sulfate, and concentrated in vacuo. Purification by column
chromatography (10% ethyl acetate and 1% triethylamine in
heptane) gave an inseparable 1:2 mixture of (E)- and (Z)-
isoquinolinone 44 (1.18 g, 3.09 mmol, 73%) as a brown oil. νmax
/
cm-1 2971, 1647, 1600, 1245; 1H NMR (300 MHz, CDCl3) δ
8.18 (d, J ) 7.2 Hz, 1H), 7.53-7.37 (m, 3H), 7.25 (d, J ) 9.1
Hz, 2H), 6.83 (d, J ) 9.1 Hz, 2H), 6.03 (dt, J ) 5.3, 1.5 Hz,
1H), 5.06 (d, J ) 5.3 Hz, 1H), 4.72 (s, 2H), 4.21 (d, J ) 1.5 Hz,
2H), 3.76 (s, 3H), 3.53 (dq, J ) 9.4, 7.2 Hz, 2H), 3.41 (dq, J )
9.4, 7.2 Hz, 2H), 1.14 (t, J ) 7.2 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 163.2, 159.4, 136.0, 132.5, 129.9, 129.3, 128.3, 125.6,
132.3, 129.1, 128.9, 123.2, 114.3, 98.0, 60.8, 55.4, 49.9, 46.7,
15.6; MS (EI+) m/z (%) 381 (3) M•+, 231 (4), 121 (100); HRMS
(CI, NH3) m/z 382.2020, C23H28NO4 (M + H) requires 382.2019.
isochromenes 39 (0.50 g, 2.47 mmol, 49%) as a yellow oil. νmax
/
cm-1 2972, 1655, 1150, 1097. E-Isomer: 1H NMR (300 MHz,
CDCl3) δ 7.33-7.00 (m, 4H), 6.62 (d, J ) 12.8 Hz, 1H), 6.57
(s, 1H), 5.58 (d, J ) 12.8 Hz, 1H), 4.98 (s, 2H), 3.86 (q, J ) 6.8
Hz, 2H), 1.27 (t, J ) 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 147.3, 141.7, 132.0, 128.9, 128.5, 127.2, 124.4, 121.4, 114.3,
98.9, 68.8, 65.9, 15.3. Z-Isomer: 1H NMR (300 MHz, CDCl3) δ
7.40 (s, 1H), 7.33-7.00 (m, 4H), 6.21 (d, J ) 7.2 Hz, 1H), 5.06
(d, J ) 7.2 Hz, 1H), 4.98 (s, 2H), 3.92 (q, J ) 6.8 Hz, 2H), 1.33
(t, J ) 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 147.1, 145.7,
131.5, 129.0, 128.5, 126.7, 124.4, 120.9, 112.6, 97.4, 69.1, 68.5,
15.8; MS (EI+) m/z (%) 202 (65) M•+, 173 (7), 115 (77), 57 (100).
4-(2-Ethoxyvinyl)-2-methylisoquinolin-1(2H)-one (45).
A mixture of acetal 43 (1.93 g, 7.0 mmol) and formic acid (0.81
mL, 21.0 mmol, 5 equiv) in acetonitrile (70 mL) was refluxed
for 1 h and then concentrated in vacuo. The residue was
dissolved in Et2O (40 mL) and washed with saturated NaHCO3
(2 × 20 mL). The organic phase was separated, dried with
magnesium sulfate, and concentrated in vacuo to provide an
inseparable 10:3 mixture of (E)- and (Z)-isoquinolinones 45
(1.19 g, 5.19 mmol, 74%) as a brown oil. νmax/cm-1 2977, 1644,
1619, 1599, 1185. E-Isomer: 1H NMR (300 MHz, CDCl3) δ 8.44
(dd, J ) 7.9, 1.0 Hz, 1H), 7.73-7.45 (m, 3H), 6.96 (s, 1H), 6.64
(d, J ) 12.4 Hz, 1H), 5.90 (d, J ) 12.4 Hz, 1H), 3.92 (q, J )
7.2 Hz, 2H), 3.58 (s, 3H), 1.34 (t, J ) 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 162.2, 148.4, 136.9, 132.9, 128.7, 128.0,
126.9, 125.8, 123.7, 113.5, 99.1, 65.8, 37.0, 15.1. Z-Isomer: 1H
NMR (300 MHz, CDCl3) δ 8.46 (d, J ) 7.9 Hz, 1H), 7.73-7.45
(m, 3H), 6.78 (s, 1H), 6.31 (d, J ) 7.1 Hz, 1H), 5.42 (d, J ) 7.1
Hz, 1H), 4.10 (q, J ) 7.2 Hz, 2H), 3.61 (s, 3H), 1.23 (t, J ) 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.8, 146.1, 136.2,
132.9, 131.9, 128.1, 126.5, 125.9, 122.7, 111.3, 97.1, 69.2, 37.5,
15.7; MS (EI+) m/z (%) 229 (100) M•+, 200 (66).
1-(2-((E)-4-Ethoxybuta-1,3-dien-2-yl)phenyl)-2,2-dime-
thylpropan-1-ol (42). To a solution of isochromene 38 (246
mg, 0.99 mmol) in anhydrous THF (6 mL) at -78 °C under a
nitrogen atmosphere was added dropwise a solution of tert-
butyllithium (1.45 M in pentane, 1.38 mL, 2 mmol, 2 equiv).
After 20 min, water (5 mL) was added and the reaction was
allowed to warm to RT. The aqueous phase was extracted with
Et2O (2 × 5 mL). The combined organic phases were washed
with brine (10 mL), dried with magnesium sulfate, and
concentrated in vacuo. Purification by column chromatography
(10% ethyl acetate in heptane) gave alcohol 42 (98 mg, 0.38
2-(4-Methoxybenzyl)-4-(2-ethoxyvinyl)isoquinolin-1(2H)-
one (46). A mixture of acetal 44 (134 mg, 0.35 mmol) and
formic acid (0.40 mL, 1.0 mmol, 2.8 equiv) in acetonitrile (10
mL) was refluxed for 1 h, concentrated in vacuo, and parti-
tioned between Et2O (10 mL) and saturated NaHCO3 (10 mL).
The organic phase was dried with magnesium sulfate and
concentrated in vacuo to provide an inseparable 7:3 mixture
of (E)- and (Z)-isoquinolinones 46 (88.5 mg, 0.26 mmol, 75%)
1
mmol, 38%) as a colorless oil. νmax/cm-1 3424, 1725, 1108; H
NMR (300 MHz, CDCl3) δ 7.53 (dd, J ) 1.5, 7.9 Hz, 1H), 7.30-
7.17 (m, 2H), 7.05 (dd, J ) 1.5, 7.1 Hz, 1H), 5.95 (d, J ) 12.4
Hz, 1H), 5.81 (d, J ) 12.4 Hz, 1H), 5.15 (d, J ) 2.2 Hz, 1H),
4.71 (d, J ) 2.2 Hz, 1H), 4.65 (s, 1H), 3.70 (q, J ) 7.2 Hz, 2H),
1.88 (bs, 1H), 1.19 (t, J ) 7.2 Hz, 3H), 0.89 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 151.2, 145.9, 140.7, 140.3, 130.1, 123.9,
J. Org. Chem, Vol. 70, No. 2, 2005 497

Le Strat et al.
as a brown oil. νmax/cm-1 2976, 1644, 1615, 1175. E-Isomer:
1H NMR (300 MHz, CDCl3) δ 8.45 (d, J ) 8.3 Hz, 1H), 7.73-
7.27 (m, 5H), 6.99 (d, J ) 0.8 Hz, 1H), 6.83 (d, J ) 8.7 Hz,
2H), 6.58 (d, J ) 12.4 Hz, 1H), 5.86 (dd, J ) 12.4, 0.8 Hz, 1H),
5.15 (s, 2H), 3.89 (q, J ) 7.2 Hz, 2H), 3.75 (s, 3H), 1.32 (t, J )
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.7, 149.0, 137.2,
132.8, 130.2, 129.9, 129.1, 129.0, 128.7, 127.3, 125.8, 124.0,
115.4, 114.7, 99.2, 66.1, 55.7, 52.0, 15.2. Z-Isomer: 1H NMR
(300 MHz, CDCl3) δ 8.48 (d, J ) 8.3 Hz, 1H), 7.86 (s, 1H),
7.73-7.27 (m, 5H), 6.83 (d, J ) 8.7 Hz, 2H), 6.29 (d, J ) 7.0
Hz, 1H), 5.40 (d, J ) 7.0 Hz, 1H), 5.17 (s, 2H), 3.91 (q, J ) 7.2
Hz, 2H), 3.75 (s, 3H), 1.25 (t, J ) 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 162.7, 146.8, 136.4, 132.7, 130.0, 129.9, 129.1,
129.0, 127.6, 127.1, 125.8, 123.0, 114.6, 112.9, 97.2, 69.4, 55.7,
52.3, 15.7; MS (EI+) m/z (%) 335 (2) M•+, 121 (100).
1-(2-((Z)-4,4-Diethoxy-1-(methylamino)but-2-en-2-yl)-
phenyl)-2,2-dimethylpropan-1-one (48). To a solution of
isoquinolinone 43 (208 mg, 0.755 mmol) in anhydrous THF
(10 mL) at -78 °C under a nitrogen atmosphere was added
tert-butyllithium (1.6 M solution in pentane, 0.57 mL, 0.91
mmol, 1.2 equiv). After 20 min, water (10 mL) and ether (10
mL) were added and the mixture was allowed to warm to RT.
The aqueous phase was separated and extracted with Et2O (2
× 10 mL). The combined organic phases were dried with
magnesium sulfate and concentrated in vacuo to give ketone
48 (209 mg, 0.627 mmol, 83%) as a yellow oil. νmax/cm-1 3335,
1
2973, 1685, 1650, 1050; H NMR (200 MHz, CDCl3) δ 7.30-
7.24 (m, 4H), 5.51 (d, J ) 6.2 Hz, 1H), 5.27 (d, J ) 6.2 Hz,
1H), 3.72-3.72 (m, 6H), 2.36 (s, 3H), 1.50 (bs, 1H), 1.23-1.16
(m, 15H); MS (EI+) m/z (%) 335 (2) [M•+], 121 (100); MS (EI+)
m/z (%) 287 (4) [M - EtOH]•+, 241 (32), 230 (42) 184 (100).
4-(2,2-Diethoxethyl)-2-methylisoquinolin-1(2H)-one (47).
To a solution of isoquinolinone 43 (275 mg, 1.0 mmol) in
anhydrous THF (10 mL) at 0 °C under a nitrogen atmosphere
was added a solution of KHMDS (0.5 M in toluene, 4.4 mL,
2.2 mmol, 2.2 equiv). After 20 min, water (10 mL) was added.
The aqueous phase was separated and extracted with Et2O (2
× 10 mL). The combined organic phases were washed with
brine (10 mL), dried with magnesium sulfate, and concentrated
in vacuo. Purification by column chromatography (50% ethyl
acetate in heptane) gave a yellow oil (180 mg) comprised of
an inseparable mixture of 45 (0.13 mmol, 13%) and 47 (0.54
Acknowledgment. F.L.S. thanks the Ministe`re de
la Recherche et de la Technologie for a doctoral grant.
Novartis (ACE 2000 Scheme) and the PUNCHorga
interregional French network are gratefully acknowl-
edged for facilitating exchange visits between our
laboratories. The assistance of M. Albert Marcual
(CRUS, Rouen) with the HRMS spectra has been
appreciated.
1
mmol, 54%). νmax/cm-1 2975, 1653, 1116; H NMR (300 MHz,
CDCl3) δ 8.44 (d, J ) 7.9 Hz, 1H), 7.68-7.42 (m, 3H), 6.98 (s,
1H), 4.63 (t, J ) 5.6 Hz, 1H), 3.65 (dq, J ) 9.0, 7.2 Hz, 2H),
3.56 (s, 3H), 3.41 (dq, J ) 9.0, 7.2 Hz, 2H), 2.93 (d, J ) 5.6
Hz, 2H), 1.12 (t, J ) 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3)
δ 162.5, 137.2, 132.5, 132.1, 128.4, 126.8, 126.3, 123.3, 111.6,
102.7, 62.7, 37.1, 34.7, 15.6; MS (CI+, CH4) m/z (%) 276 (11)
[M + H]+, 230 (100).
Supporting Information Available: Analytical data (1H
and/or 13C NMR spectra) for compounds 6, 11, 13, 15, 17-19,
and 21-33. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO048794D
498 J. Org. Chem., Vol. 70, No. 2, 2005