Synthesis of alkylidenephthalans through fluoride-induced cyclization of electron-deficient 2-siloxymethylphenylacetylene derivatives

Article abstract of DOI:10.1016/j.tet.2007.01.046

Fluoride-based deprotection of silylated 2-alkynylbenzyl alcohol derivatives featuring carbonyl-substituted alkynes results in the direct synthesis of alkylidenephthalan vinylogous esters. The reaction is selective for the Z alkylidenephthalans in a therm

Full text of DOI:10.1016/j.tet.2007.01.046

Tetrahedron 63 (2007) 2959–2965
Synthesis of alkylidenephthalans through
fluoride-induced cyclization of electron-deficient
2-siloxymethylphenylacetylene derivatives
*
Shaofeng Duan, Karen Cress, Kris Waynant, Elias Ramos-Miranda and James W. Herndon
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003-8001, USA
Received 28 October 2006; revised 18 December 2006; accepted 22 January 2007
Available online 25 January 2007
Abstract—Fluoride-based deprotection of silylated 2-alkynylbenzyl alcohol derivatives featuring carbonyl-substituted alkynes results in the
direct synthesis of alkylidenephthalan vinylogous esters. The reaction is selective for the Z alkylidenephthalans in a thermodynamically
controlled process. Similar compounds are also produced in the coupling of Fischer carbene complexes with 2-alkynylbenzoyl derivatives
in an aqueous solvent system. Subsequent acid-catalyzed inter- or intramolecular Diels–Alder reactions lead to hydronaphthalene or
hydrophenanthrene derivatives.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
followed by either ring opening to afford 10 or dehydration
to afford 11.7 In the absence of a Diels–Alder trap, the
formation of alkylidenephthalans (e.g., 14) has been
Alkylidenephthalans (e.g., 1, Scheme 1) have proven to be
very useful compounds for organic synthesis due to their
equilibration with highly reactive isobenzofurans (2) upon
protonation.1 Alkylidenephthalans that contain remote
alkene functionality can undergo cyclization upon treatment
with acid in a process involving formation of an isobenzo-
furan followed by intramolecular Diels–Alder reaction.2
Alkylidenephthalans are most often prepared through
carbonyl olefination of phthalides.3 Other methods include
oxidative carbonylation of o-alkynylbenzyl alcohols4 and
coupling of Fischer carbene complexes with o-alkynyl-
benzoyl compounds.5
OMe
R1
Cr(CO)5
R1
OMe
Cr(CO)4
5
O
O
6
R2
R2
4
OMe
OMe
R1
R1
Cr(CO)4
O
O
H+
7
R2
R2
8
O
O
O
H
OMe
O
OMe
R1
R1
R1
1
2
3
Scheme 1.
Vs.
H
H
O
In several recent manuscripts, we have reported that net
[5+5]-cycloaddition (coupling of 4 and 5 to produce either
10 or 11, Scheme 2) leading to the hydrophenanthrene ring
system occurs when o-alkynylbenzoyl compounds couple
with g,d-unsaturated Fischer carbene complexes.6 This
process proceeds through a tandem process involving
carbene–alkyne coupling, followed by isobenzofuran forma-
tion, followed by intramolecular Diels–Alder reaction,
11
10
R2
R2
R2
9
OH
OMe
OMe
CHR3
O
R1
R1
R1
CH2R3
CH2R3
O
O
O
R2
R2
R2
12
Scheme 2.
13
14
* Corresponding author. Tel.: +1 505 646 2505; fax: +1 505 646 2649;
e-mail: jherndon@nmsu.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.046

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S. Duan et al. / Tetrahedron 63 (2007) 2959–2965
observed in isolated examples.5 A serious limitation in this
method is that in some cases the g,d-unsaturated carbene
complexes are either difficult to synthesize or are too unsta-
ble to undergo thermal coupling with alkynes.8 As a part of
the program to develop alternatives to the carbene methodol-
ogy, a parallel strategy for the formation of hydrophenan-
threnes from o-substituted phenylacetylene derivatives was
sought. This alternative strategy, depicted in Scheme 3,
would involve an alkyne-based synthesis of alkylidene-
phthalans followed by the Diels–Alder strategy in Scheme
1.9 In a preliminary examination of this synthetic route, it
was noted that the silyl deprotection step resulted in the
alkylidenephthalan. While this work was in progress, a
similar cyclization of alkynylpurinyl benzyl alcohols was
reported.10 This manuscript focuses on the development of
this alkylidenephthalan vinylogous ester synthesis and
subsequent inter- and intramolecular Diels–Alder reactions.
OH
R
X
Y
I
Pd catalyst
OTBS
OH
23
24
O
R
R
X
Y
X
Y
[ox]
(1)
(2)
OTBS
OTBS
25
26
COR
X
1. n-BuLi
X
2. ClCOR or
Me(MeO)NCOR
OTBS
OTBS
Y
Y
27
26
Scheme 4.
O
Li
O
identical 83:17 Z/E mixtures. This observation suggests
that the isomers interconvert on silica gel.
X
Fluoride
source
16
OTBS
OTBS
R2
O
15
17
O
R2
CH3
O
O
Bu4NF
THF
R1
O
OTBS
Base
H+
26a
27a
O
or TM
catalyst
See
Scheme 1
OH
O
CH3
O
R2
O
R2
18
19
O
CH3
O
O
O
or
Z 27a
E 27a
H
O
H
Scheme 5.
R2
R2 OH
R2
20
21
22
A systematic study of the fluoride-induced cyclization reac-
tion was conducted. The results are depicted in Table 1. In all
of the cases employing a primary alcohol-derived silane,
a good yield of alkylidenephthalan was obtained from the
reaction with fluoride ion in methanol at 55 ꢀC. Difficulty
Scheme 3.
2. Results and discussion
General synthetic routes to the 2-alkynylbenzyl alcohol
derivatives used in this study are depicted in Scheme 4.11
The routes involve either Sonogashira coupling of known
2-iodobenzyl alcohol derivatives with propargyl alcohol
derivatives followed by oxidation (Eq. 1), or a strategy that
closely parallels the synthetic plan of Scheme 3 involving
acylation of 2-ethynylbenzyl alcohol derivatives (Eq. 2).
Table 1. Preparation of alkylidenephthalans through treatment of silyl-
protected o-ethynylbenzyl alcohols with fluoride ion
O
O
H
O
R1
R4
R3
R4
R3
R1
R4
R3
KF x 2 H2O
MeOH
O
O
OTBS
R2
28
R2
R2
26
27
Attempted deprotection of the silicon ether 26a (Scheme 5)
with tetrabutylammonium fluoride led to a compound tenta-
tively identified as alkylidenephthalan 27a as a Z/E mixture
(predominantly Z). Despite separation and isolation of a
compound corresponding to a unique TLC spot, the product
always showed the appearance of an n-butyl group in the
NMR spectrum. A pure compound free of contaminants
was obtained when potassium fluoride in methanol was em-
ployed for the desilylation step of the reaction. Although the
Z and E isomers have very different chromatographic prop-
erties, when the isomers were separated by chromatography
the compounds corresponding to each spot appeared as
Entrya R1
R2
R3
R4
Yield of 27 (%) Z/E
A
B
C
D
Ec
F
Me
Ph
OMe
NMe2
Me
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
74
80
98
75
51
83:17
91:9
>95:5
75:25b
H
>95:5
93:7
>95:5
Me
Me
OMe OMe 46
OMe 74
G
H
H
a
Entry letters indicate the substituents in compounds 4 and 26–28.
In this cases the isomeric compounds can be separated.
In this case anhydrous KF in DMF was employed.
b
c

S. Duan et al. / Tetrahedron 63 (2007) 2959–2965
2961
was encountered in secondary alcohol-derived silyl ether in
Entry E. In this case the reaction was sluggish and lower
yielding. Higher temperatures in the polar aprotic solvent
DMF were required for this reaction process. Under these
conditions, a significant amount of the retro-aldol product
28 was observed. In all of the cases the Z alkylidenephthalan
was obtained as the major isomer.
esters, and is supported in those cases through NOE stud-
ies.12 Other investigators noted a similar high chemical shift
proton in a related compound where there is a purine ring in
place of the ketone group, and attributed this observation to
a hydrogen bonding interaction between HA and a nitrogen
atom of the purine ring.10 An ab initio NMR calculation at
the 6-311G** level predicts this unusually high chemical
shift (see Table 2). This unusual chemical shift most likely
arises from an anisotropic interaction with the carbonyl
oxygen of the ketone group.13
A comparison of the fluoride-based alkylidenephthalan
synthesis in Table 1 with carbene complex-based alkylide-
nephthalan synthesis was also conducted (Scheme 6). Alkyl-
idenephthalans were observed as side products in various
failed examples of the [5+5]-cycloaddition reaction con-
ducted in aqueous solvent systems, and these conditions
were employed for the coupling of simple carbene complex
29 with alkyne–carbonyl compounds 4a and 4e.6 The
carbene complex based synthesis was highly efficient in
the two examples depicted, and afforded the alkylidene-
phthalans 27a and 27e in the same E/Z ratio as the fluoride-
based synthesis in Table 1. The carbene complex method
is superior in that the 2-alkynylbenzaldehyde and analogous
acetophenone derivatives are more readily available sub-
strates. All of the silyl ether-based syntheses required
a more lengthy synthesis from commercially available
chemicals.
In general the E configuration is more stable for b-alkoxy
enones primarily due to electronic reasons,14 however, in
our cases there is likely a steric interaction of the carbonyl
group and HA disfavoring the E isomer. The E isomer is
the product of most syntheses of alkylidenetetrahydrofurans
that proceed through intramolecular nucleophilic addition
of an alkoxide to yield an electron-deficient alkyne. In one
case a similar reaction process predominantly led to the Z
isomer and this was attributed to steric effects.15 The Z
isomer was also the major isomer obtained in the alkynyl-
purinyl systems previously reported; this synthetic route
was also based on fluoride-induced desilylation/cyclization,
and alternate conditions employing acid also led to the Z
isomer.10 Even though the Z and E isomers of the alkylidene-
phthalans appear as distinctive TLC spots, in most cases
attempted separation never produced a pure isomer, thus
suggesting that there is interconversion on either the chro-
matography column or in the slightly acidic NMR solvent,
chloroform. In one case (Entry D) the isomers were separa-
ble and did not equilibrate on the chromatography column.
Thus the Z isomer would appear to be more stable
(thermodynamic) product, or possibly both the kinetic and
thermodynamic product. Calculations were performed to
understand the isomer distribution better; the results are
depicted in Table 2. The apparent 83:17 equilibrium ratio
implies that the Z isomer is 1.1 kcal/mol more stable than
the E isomer. Both ab initio16 and semiempirical calculations
suggest that the E isomers are the more stable isomers,
however this number is within the experimental error of
the calculation. The less sophisticated MM2 analysis
suggests that the Z isomer is more stable, however the ob-
served number (Z more stable than E by 6.3 kcal/mol—error
of 4.2 kcal/mol relative to experiment) reflects a bigger error
from experiment than the ab initio calculations (E more
stable than Z by 1.1 kcal/mol—error of 2.2 kcal/mol relative
to experiment). In the MM2-minimized structure of the E
isomer, the C]O and adjacent C]C groups are not copla-
nar (dihedral angle¼26ꢀ), which suggests that the electronic
stabilization present in the vinylogous ester system is poorly
recognized by this basis set. The Z isomer is also likely to be
the kinetic product of the reaction based on the structure of
the enolate intermediate 30. The enolate intermediate has
a bent structure and protonation of the enolate intermediate
obtained from the convex direction would afford the
observed Z alkene. The carbene complex route also leads
to the Z stereoisomer. In this case the Z stereochemistry
can arise through hydrolysis of the enol ether generated
through 1,7-hydrogen shift of the intermediate isobenzo-
furan (see interconversion of 12 and 13 in Scheme 2).17
O
Cr(CO)5
OMe
TMS
29
Me
Me
O
O
70:30 Dioxane: Water
R2
R2
27a, e
4a,e
R2 = H, 76%; R2 = Me, 94%
Scheme 6.
Both the fluoride-induced and the carbene complex-based
alkylidenephthalan synthesis afforded predominantly the Z
isomer in all the cases. The E configuration was assigned
to the minor stereoisomer based on a distinctive feature in
the proton NMR spectrum. The hydrogen labeled HA (see
the picture in Table 2) appears at a very high chemical shift
(d 9.0–9.5) in all of the minor isomers. This observation has
been noted by others for alkylidenephthalan vinylogous
Table 2. Various experimental and theoretical data for the E and Z isomers
of compound 27a
Me
O
Θ = 148°
HB
O
HA
HA
HB
O
O
O
O
30
Z 27a
E 27a
Observation
Value for Z
Value for E
Chemical shift of HA (observed)
7.70–7.35
6.76
5.83
9.35
9.57
6.11
5.61
0
0
0
0
0
Chemical shift of HA (calculated)
Chemical shift of HB (observed)
Chemical shift of HB (calculated)
Energy relative to E (experimental)
Energy relative to E (6-311G**)
Energy relative to E (6-31G*)
Energy relative to E (PM3)
5.28
ꢁ1.1 kcal/mol
+1.0 kcal/mol
+1.1 kcal/mol
+1.4 kcal/mol
ꢁ6.3 kcal/mol
The alkylidenephthalan vinylogous esters readily under-
went Diels–Alder reactions (Scheme 7). Simple treatment
Energy relative to E (MM2)

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S. Duan et al. / Tetrahedron 63 (2007) 2959–2965
of alkylidenephthalan 27d and acetylenedicarboxylate
(DMAD) with a catalytic amount of acetic acid in the
presence of refluxing toluene led to the desired Diels–Alder
adduct 31d. In the original publication on this reaction,2
DMAD was used as the reaction solvent, however under
these conditions the separation of the Diels–Alder adduct
from polymeric DMAD species was quite difficult. The re-
action was not effective for cases where R1 is a phenyl group,
likely due to the greater electron withdrawing power of this
substituent. Although the Diels–Alder reaction was reported
to fail for butenylketones (R1¼–CH2CH2CH]CH2), the
reaction was highly efficient using the analogous compound
27h, which features a gem dimethyl group in the chain. In
this case the Diels–Alder adduct/dehydration product 33
was produced in 78% yield. The success in this case is likely
due to the gem dialkyl effect,18 which introduces a conforma-
tional bias favoring the Diels–Alder reaction.
alkynol (1.0 equiv) and potassium fluoride dihydrate
(5 equiv) in methanol was stirred at 55 ꢀC until TLC analysis
showed complete consumption of starting material (usually
about 2 h). The solvent was removed on a rotary evaporator
and then placed into a mixture of water and dichloromethane
in a separatory funnel. The water layer was extracted two
times with dichloromethane. The combined organic layers
were washed with water and saturated aqueous sodium
chloride solution, and then dried over sodium sulfate. The
solvent was removed on a rotary evaporator and the residue
was purified by flash chromatography on silica gel using
hexane/ethyl acetate mixtures as the eluent.
4.1.1. Preparation of alkylidenephthalan–methyl ketone
27a. General procedure I was followed using alkyne–methyl
ketone 26a (0.285 g, 0.980 mmol) and potassium fluoride
dihydrate (0.288 g, 3.06 mmol) in 20 mL of methanol. Final
purification was achieved by flash chromatography on silica
gel using 4:1 hexane/ethyl acetate followed by 2:1 hexane/
ethyl acetate as an eluent. A single compound identified as
an 83:17 Z/E mixture of compound 27a was obtained
O
O
H
R1
DMAD /
CH3COOH
R1
COOMe
1
(0.109 g, 63% yield). H NMR (CDCl3): d 7.70–7.35 (m,
Toluene / reflux
O
O
4H), 5.83 (s, 1H), 5.58 (s, 2H), 2.46 (s, 3H); 13C NMR
(CDCl3): d 197.6, 167.4, 141.8, 135.6, 132.0, 129.2, 121.8,
98.2, 77.0, 31.4; IR (neat): 1671 (m), 1624 (vs), 1590
(s) cmꢁ1; Mass Spec (EI): 174 (M, 25), 159 (100), 131
(37), 103 (91), 77 (68); HRMS (EI): Calcd for C11H10O2
174.06808, found 174.06751. A minor isomer (18%) can
be detected in the proton NMR spectrum and has been
COOMe
27b, d
31b, d
R1 = NMe2, 69%, R1 = Ph, 0%
O
O
H
CH3COOH
KF
1
assigned as the E enol ether. H NMR (CDCl3): d 9.35 (br
d, 1H, J¼8.0 Hz); 7.70–7.35 (peaks overlap with major
OTBS
Toluene /
reflux
O
MeOH
26h
27h
isomer); 6.11 (s, 1H), 5.39 (s, 2H), 2.27 (s, 3H).
O
O
4.1.2. Preparation of alkylidenephthalan-phenyl ketone
27b. General procedure I was followed using alkyne-phenyl
ketone 26b (0.809 g, 2.31 mmol) and potassium fluoride
dihydrate (1.090 g, 11.56 mmol) in 20 mL of methanol.
Final purification was achieved by flash chromatography
on silica gel using 4:1 hexane/ethyl acetate followed by
1:1 hexane/ethyl acetate as an eluent. A single fraction iden-
tified as a 91:9 Z/E mixture of compound 27b was obtained
O
32
33
Scheme 7.
1
3. Conclusions
(0.435 g, 80% yield). H NMR (CDCl3): d 8.11–7.93 (m,
2H), 7.82–7.70 (d, 1H, J¼8.4 Hz), 7.63–7.35 (m, 6H),
6.65 (s, 1H), 5.65 (s, 2H); 13C NMR (CDCl3): d 187.8,
168.4, 141.4, 139.6, 132.8, 131.2, 128.1, 127.8, 127.7,
127.2, 127.1, 121.2, 121.0, 91.0, 76.5; IR (neat): 1655 (s),
1599 (vs), 1571 (s) cmꢁ1; Mass Spec (EI): 236 (M, 30),
159 (51), 131 (13), 105 (95), 77 (100); HRMS (EI): Calcd
for C16H12O2 236.08373, found 236.08387. A trace amount
of another isomer can be detected in the proton NMR spec-
In summary, simple desilylation of electron-deficient silyl-
ated 2-alkynylbenzyl alcohol derivatives leads directly to
alkylidenephthalan derivatives. The reaction is highly selec-
tive for the formation of Z stereoisomer, which is easily
assigned due to the absence of the anisotropic interactions
expected for the E isomer. The same alkylidenephthalan
can also be prepared through the reaction of 2-alkynylbenz-
oyl derivatives with Fischer carbene–chromium complexes
in aqueous solvent systems. The alkylidenephthalans readily
undergo Diels–Alder reactions when treated with DMAD in
the presence of acid, and undergo intramolecular Diels–
Alder reactions in systems where conformational effects
are favorable.
1
trum and has been assigned as the E enol ether. H NMR
(CDCl3): d 9.41 (br d, 1H, J¼8.0 Hz), 8.11–7.93 (peaks
overlap with major isomer), 7.63–7.35 (peaks overlap with
major isomer), 6.79 (s, 1H), 5.60 (s, 1H), 5.39 (s, 2H).
4.1.3. Preparation of alkylidenephthalan-ester 27c.
General procedure I was followed using alkyne-ester 26c
(0.460 g, 1.51 mmol) and potassium fluoride dihydrate
(0.711 g, 7.56 mmol) in 20 mL of methanol. Final purifi-
cation was achieved by flash chromatography on silica gel
using 9:1 hexane/ethyl acetate followed by 2:1 hexane/ethyl
acetate as an eluent. A single compound identified as a
>95:5 Z/E mixture of compound 27c was obtained
4. Experimental
4.1. General procedure I
Preparation of alkylidenephthalans via fluoride-induced
cyclization: A 0.05–0.10 M solution of silyl-protected

S. Duan et al. / Tetrahedron 63 (2007) 2959–2965
2963
1
(0.233 g, 98% yield). H NMR (CDCl3): d 7.58–7.34 (m,
(m), 1629 (s), 1605 (s) cmꢁ1; Mass Spec (CI): 189 (M+1,
100), 173 (37).
4H), 5.53 (s, 2H), 5.48 (s, 1H), 3.76 (s, 3H); 13C NMR
(CDCl3): d 168.4, 167.1, 141.8, 133.4, 131.7, 128.9, 121.9,
121.7, 86.1, 76.9, 51.3; IR (neat): 1710 (m), 1693 (s), 1634
(vs) cmꢁ1. A trace amount of another isomer can be detected
in the proton NMR spectrum and has been assigned as the E
enol ether. 1H NMR (CDCl3): d 9.41 (br d, 1H, J¼8.0 Hz),
7.58–7.35 (peaks overlap with major isomer), 5.60 (s, 1H),
5.31 (s, 2H), 3.69 (s, 3H). The spectral data were in agree-
ment with those previously reported for this compound.4
4.1.6. Preparation of alkylidenephthalan–methyl ketone
27f. General procedure I was followed using alkyne–methyl
ketone 26f (0.130 g, 0.37 mmol) and potassium fluoride di-
hydrate (0.176 g, 1.87 mmol) in 20 mL of methanol. Final
purification was achieved by flash chromatography on silica
gel using 2:1 hexane/ethyl acetate as an eluent. A single
compound identified as a 93:7 Z/E mixture of alkylidene-
1
phthalan 27f was obtained (0.040 g, 46% yield). H NMR
4.1.4. Preparation of alkylidenephthalan amide 27d.
General procedure I was followed using the alkyne-amide
26d (0.450 g, 1.42 mmol) and potassium fluoride dihydrate
(0.667 g, 7.10 mmol) in 20 mL of methanol. Final purifica-
tion was achieved by flash chromatography on silica gel
using 2:1 hexane/ethyl acetate as an eluent. In the first
experimental run, the Z and E isomers were not separated.
Chromatography afforded a 75:25 Z/E mixture of compound
27d (0.207 g, 72% yield). A more careful chromatography
afforded a nearly baseline separation of two isomers. The
major compound in the second fraction was identified as
the Z isomer of 27d (0.207 g, 72% yield). 1H NMR
(CDCl3): d 7.30 (d, 1H, J¼8.1 Hz), 7.21–7.02 (m, 3H),
5.45 (s, 1H), 5.20 (s, 2H), 2.82 (br s, 3H), 2.76 (br s, 3H);
13C NMR (CDCl3): d 165.9, 162.8, 140.0, 132.6, 129.7,
127.4, 120.6, 120.1, 85.9, 74.9, 37.5 (broadened), 34.0
(broadened); IR (neat): 1647 cmꢁ1; Mass Spec (EI): 203
(12), 173 (29), 159 (100), 149 (15), 131 (36), 103 (61);
HRMS (EI): Calcd for C12H13NO2 203.09463, found
203.09516. The minor compound in the first fraction was
(CDCl3): d 6.97 (s, 1H), 6.87 (s, 1H), 5.68 (s, 1H), 5.48 (s,
2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.41 (s, 3H). The spectral
data agree with those previously reported for this com-
pound.2 A trace amount of another isomer can be detected
in the proton NMR spectrum and has been assigned as the
E enol ether. 1H NMR (CDCl3): d 9.41 (br s, 1H), 6.97 (sig-
nal overlaps with peak for the major isomer), 6.86 (signal
overlaps with peak for the major isomer), 5.93 (s, 1H),
5.30 (s, 2H), 2.23 (s, 3H).
4.1.7. Preparation of alkylidenephthalan–methyl ketone
27g. General procedure I was followed using the alkyne–
methyl ketone 26g (0.140 g, 0.44 mmol) and potassium fluo-
ride dihydrate (0.206 g, 2.20 mmol) in 20 mL of methanol.
Final purification was achieved by flash chromatography
on silica gel using 2:1 hexane/ethyl acetate as an eluent. A
single compound identified as a >95:5 Z/E mixture of com-
1
pound 27g was obtained (0.067 g, 74% yield). H NMR
(CDCl3): d 7.48 (d, 1H, J¼8.8 Hz), 6.94 (dd, 1H, J¼8.8,
2.2 Hz), 6.87 (br s, 1H), 5.68 (s, 1H), 5.48 (s, 2H), 3.85 (s,
3H), 2.39 (s, 3H); 13C NMR (CDCl3): d 196.8, 167.2,
163.0, 143.7, 125.4, 123.2, 116.0, 105.6, 96.3, 76.1, 55.7,
30.7; IR (neat): 1624 (s) cmꢁ1; Mass Spec (EI): 204 (M,
31), 189 (100), 161 (19), 133 (30); HRMS (EI): Calcd for
C12H12O3 204.07864, found 204.07835. A trace amount of
another isomer can be detected in the proton NMR spectrum
and has been assigned as the E enol ether. 1H NMR (CDCl3):
d 9.26 (d, 1H, J¼8.8 Hz), 6.80–7.00 (signal overlaps with
peaks for the major isomer), 5.95 (s, 1H), 5.30 (s, 2H),
3.85 (signal overlaps with major isomer), 2.23 (s, 3H).
1
identified as the E enol ether. H NMR (CDCl3): d 8.82
(dd, 1H, J¼8.0, 2.0 Hz), 7.45–7.25 (m, 3H), 5.82 (s, 1H),
5.30 (s, 2H), 3.17 (2 nearly coalesced singlets, 6H); 13C
NMR (CDCl3): d 167.4, 167.0, 142.9, 131.1, 130.6, 128.1,
127.7, 120.4, 91.9, 73.2, 38.2 (broadened), 35.5 (broadened).
4.1.5. Preparation of alkylidenephthalan-methyl ketone
27e. Dry potassium fluoride19 (0.176 g, 1.88 mmol) was
added to a solution of alkyne-methyl ketone 26e (0.190 g,
0.625 mmol) in DMF (10 mL). The solution was then heated
to 60 ꢀC and stirred for 2 days under a nitrogen atmosphere.
After the reaction had cooled to room temperature, water
(10 mL) was added. The mixture was extracted two times
with ether and washed with saturated aqueous sodium bi-
carbonate solution. Flash chromatography on silica gel using
4:1 hexane/ethyl acetate as an eluent afforded several frac-
tions. The product in the first fraction (0.030 g) was predom-
inantly identified as the recovered starting material. The
product in the second fraction (<0.005 g) was not identified.
The product in the third fraction was identified as retro-aldol
product 28 and the amount varied widely for different exper-
imental runs. 1H NMR (CDCl3): d 7.90–7.30 (m, 4H), 5.54
(q, 1H, J¼6.8 Hz), 1.62 (d, 3H, J¼6.8 Hz); IR (neat):
1765 cmꢁ1. The spectral data were in agreement with those
previously reported for this compound.20 The product in the
fourth fraction was identified as the Z alkylidenephthalan
4.2. General procedure II
Carbene complex-based alkylidenephthalan synthesis: A
mixture of carbene complex 2921 (1.3 equiv) and alkynyl-
phenylketone/aldehyde (1.0 equiv) in 70:30 dioxane/water
was heated to reflux for 12 h. The solution was cooled and fil-
tered through Celite. The filtrate was poured into a mixture of
water and ether in a separatory funnel. The organic layer was
washed with water and saturated aqueous sodium chloride
solution, and then dried over sodium sulfate. The organic
layer was filtered through a pad of silica gel and the solvent
was removed on a rotary evaporator to afford the pure prod-
uct. Use of excess carbene complex was a necessity, other-
wise substantial amounts of unreacted alkyne were observed.
1
27e (0.060 g, 51% yield). H NMR (CDCl3): d 7.56 (d,
4.2.1. Preparation of alkylidenephthalan 27a via the
carbene complex route. General procedure II was followed
using 2-trimethylsilylethynylbenzaldehyde22 (0.507 g,
2.50 mmol) and carbene complex 29 (0.815 g, 3.30 mmol)
in 10 mL of 7:3 dioxane/water. A 90:10 Z/E mixture of com-
pound 27a was obtained (0.331 g, 76% yield). The spectral
1H, J¼7.6 Hz), 7.50 (td, 1H, J¼7.6, 0.4 Hz), 7.41 (t, 1H,
J¼7.6 Hz), 7.33 (dd, 1H, J¼7.6, 0.4 Hz), 5.79 (q, 1H, J¼
6.7 Hz), 5.75 (s, 1H), 2.45 (s, 3H), 1.64 (d, 3H, J¼6.7 Hz);
13C NMR (CDCl3): d 197.2, 165.9, 145.8, 132.8, 131.5,
128.7, 121.8, 121.0, 97.6, 84.5, 25.7, 20.9; IR (neat): 1651

2964
S. Duan et al. / Tetrahedron 63 (2007) 2959–2965
data were in agreement with those reported for this com-
pound prepared via the fluoride-based route.
38.6, 30.3; IR (neat): 1715 cmꢁ1; Mass Spec (EI): 224 (M,
85), 209 (55), 195 (35), 181 (100), 165 (55); HRMS (EI):
Calcd for C16H16O 224.12011, found 224.12038.
4.2.2. Preparation of alkylidenephthalan 27e via the
carbene complex route. General procedure II was followed
using 2-trimethylsilylethynylacetophenone23 (0.444 g,
1.70 mmol) and carbene complex 29 (0.638 g, 2.55 mmol)
in 10 mL of 7:3 dioxane/water. A 95:5 Z/E mixture of
compound 27e was obtained (0.196 g, 94% yield). The
spectral data were in agreement with those reported for
this compound prepared via the fluoride-based route.
Acknowledgements
This research was supported by the MARC and SCORE
programs of NIH.
Supplementary data
4.3. General procedure III
General experimental, syntheses of compounds 26a–h from
known or commercially available chemicals, and photo-
copies of proton and 13C NMR spectra for compounds
27a–e, 27f,g, 31d, and 33. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2007.01.046.
Diels–Alder reactions: A solution of alkylidenephthalan
(1 equiv), if necessary dimethylacetylene dicarboxylate
(DMAD) (5 equiv), and acetic acid (0.05 mL) in toluene
was heated at reflux for a period of 3 h. After the reaction
mixture had cooled to room temperature, the solvent was
removed on a rotary evaporator. The residue was purified
by flash chromatography on triethylamine-treated silica
gel24 using hexane/ethyl acetate mixtures as eluents.
References and notes
1. (a) For a mechanistic discussion, see: Friedrichsen, W. Struct.
Chem. 1999, 10, 47–52 and references therein; (b) For a review
on isobenzofuran chemistry, see: Friedrichsen, W. Adv. Hetero-
cycl. Chem. 1999, 73, 1–96.
2. Meegalla, S. K.; Rodrigo, R. J. Org. Chem. 1991, 56, 1882–
1888.
3. Meegalla, S. K.; Rodrigo, R. Synthesis 1989, 942–944.
4. Bacchi, A.; Costa, M.; Della Ca, N.; Fabbricatore, M.; Fazio,
A.; Gabriele, B.; Nasi, C.; Salerno, G. Eur. J. Org. Chem.
2004, 574–585.
5. Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2, 1267–1269.
6. For the latest example, see: Li, R.; Zhang, L.; Camacho-Davila,
A.; Herndon, J. W. Tetrahedron Lett. 2005, 46, 5117–5120.
7. For the lastest example using this reaction pathway, see:
Camacho-Davila, A.; Herndon, J. W. J. Org. Chem. 2006, 71,
6682–6685.
4.3.1. Diels–Alder reaction of alkylidenephthalan amide
and DMAD. General procedure III was followed using alkyl-
idenephthalan amide 27d (0.080 g, 0.394 mmo1), DMAD
(0.280 g, 1.97 mmol), and acetic acid (0.05 mL) in toluene
(4 mL). The elution solvent in the chromatography was
2:1 hexane/ethyl acetate. A colorless oil identified as Diels–
1
Alder adduct 31d was obtained (0.094 g, 69% yield). H
NMR (CDCl3): d 7.39–7.28 (m, 2H), 7.08–6.97 (m, 2H),
5.88 (s, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.55 (d, 1H,
J¼15.8 Hz), 3.30 (d, 1H, J¼15.8 Hz), 3.03 (s, 3H), 2.92
(s, 2H); 13C NMR (CDCl3): d 168.1, 164.2, 162.1, 153.4,
147.6, 147.3, 146.5, 125.7, 125.6, 120.5, 120.4, 92.6, 76.6,
51.8, 37.3, 35.1, 31.7; IR (neat): 1717 (s), 1651 (s) cmꢁ1
;
Mass Spec (EI): 346 (M+1, 8), 345 (M, 9), 314 (6), 301
(5), 286 (16), 254 (13), 131 (24), 72 (100); HRMS (EI):
Calcd for C18H19NO6 345.12124, found 345.12249.
8. Zhang, Y.; Herndon, J. W. J. Org. Chem. 2002, 67, 4177–4185.
A note concerning this observation appears in the supplemen-
tary material.
4.3.2. Tandem alkylidenephthalan formation and intra-
molecular Diels–Alder reaction. General procedure I was
followed using alkyne–ketone 26h (0.369 g, 1.04 mmol)
and potassium fluoride (0.301 g, 5.20 mmol) in methanol
(10 mL). The crude product before chromatography
(0.250 g, 100% yield) was sufficiently pure for use in the
subsequent Diels–Alder reaction. 1H NMR (CDCl3):
d 7.58 (d, 1H, J¼8.0 Hz), 7.50–7.35 (m, 2H), 7.23 (td, 1H,
J¼8.0, 1.4 Hz), 6.00 (dd, 1H, J¼17.5, 11.5 Hz), 5.82 (s,
1H), 5.54 (s, 2H), 4.96 (dd, 1H, J¼17.5, 1.0 Hz), 4.90 (d,
1H, J¼11.5, 1.0 Hz), 2.65 (s, 2H), 1.16 (s, 6H). General
procedure III was followed using crude alkylidenephthalan
(0.250 g, 1.04 mmol) and glacial acetic acid (0.05 mL) in
toluene (5 mL). The reflux was continued for 12 h. Final
purification was achieved by flash chromatography on silica
gel using 9:1 hexane/ethyl acetate as an eluent to afford a
single compound identified as naphthalene–ketone 33
(0.180 g, 78% yield). 1H NMR (CDCl3): d 7.86 (d, 1H, J¼
8.0 Hz), 7.84 (d, 1H, J¼8.0 Hz), 7.80 (d, 1H, J¼8.8 Hz),
7.60 (d, 1H, J¼8.8 Hz), 7.56 (tt, 1H, J¼8.0, 1.6 Hz), 7.50
(tt, 1H, J¼8.0, 1.6 Hz), 3.98 (s, 2H), 2.69 (s, 2H), 1.43 (s,
6H); 13C NMR (CDCl3): d 209.6, 141.8, 132.5, 131.7,
128.7, 127.7, 127.4, 126.9, 125.8, 123.1, 123.0, 54.3, 41.1,
9. In Ref. 2, the one example of a tandem isobenzofuran genera-
tion/intramolecular Diels–Alder reaction incorporating a car-
bonyl group in the tethering chain was not successful.
10. Berg, T. C.; Bakken, V.; Gundersen, L. L.; Petersen, D.
Tetrahedron 2006, 62, 6121.
11. See the Supplementary data for detailed synthetic procedures
for the preparation of silylated alkynylbenzyl alcohol deriva-
tives from known or commercially available substances.
12. F€urstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000,
122, 6785–6786. See also Ref. 4.
13. Friebolin, H. Basic One- and Two-Dimensional NMR Spectro-
scopy, 2nd ed.; VCH: Weinheim, 1993; pp 45–47.
14. (a) Taskinen, E.; Mukkala, V. M. Tetrahedron 1982, 38, 613–
616; (b) Taskinen, E. Acta Chem. Scand. B 1985, B39, 489–494.
15. Pflieger, D.; Muckensturm, B. Tetrahedron 1989, 45, 2031–
2040.
16. The program Gaussian03 was employed. Frisch, M. J.; Trucks,
G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.;
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Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Menucci, B.;

S. Duan et al. / Tetrahedron 63 (2007) 2959–2965
2965
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Cioslowki, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, A.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, M.; Callacombe, M.; Gill,
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Gaussian, Pittsburgh, PA, 1998.
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19. The drying process was accomplished by placing the dihydrate
in a test tube and heating with a Bunsen burner.
20. Knepper, K.; Ziegert, R. E.; Brase, S. Tetrahedron 2004, 60,
8591–8603.
21. Hegedus, L. S.; McGuire, M. A.; Schultze, L. M. Org. Synth.
Coll. Vol. 8 1987, 65, 140–145 or 216–221.
22. This compound was prepared from Sonogashira coupling of
trimethylsilylacetylene and 2-bromobenzaldehyde according
to a literature procedure. Acheson, R. M.; Lee, G. C. M.
J. Chem. Soc., Perkin Trans. 1 1987, 2321–2332.
23. This compound was prepared from Sonogashira coupling of
trimethylsilylacetylene and 2-iodoacetophenone according to
a literature procedure. Maeyama, K.; Iwasawa, N. J. Am.
Chem. Soc. 1998, 120, 1928–1929.
24. This process involves slurry-packing the column using a 99:1
hexane/triethylamine solution.
17. Selected examples of thermal 1,7-hydrogen shifts: (a) Lian,
J. J.; Lin, C. C.; Chang, H. K.; Chen, P. C.; Liu, R. S. J. Am.
Chem. Soc. 2006, 128, 9661–9667; (b) Hess, B. A., Jr.
J. Org. Chem. 2001, 66, 5897–5900; (c) Baldwin, J. E.;
Reddy, V. P. J. Am. Chem. Soc. 1987, 109, 8051–8056; (d)
Okamura, W. H.; Hoeger, K. J.; Miller, K. J.; Reischl, W.
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