Synthesis of tetrahydrodibenzofuran and tetrahydrophenanthridinone skeletons by intramolecular nucleopalladation/oxidative heck cascades

Article abstract of DOI:10.1002/ejoc.201101297

Functionalized alkylidene-1,2,3,4-tetrahydrodibenzo[b,d]furans and -phenanthridin-6(5H)-ones have been synthesized regio- and stereoselectively from either o-iodophenols or -benzamides and alkynes by consecutive Pd-catalyzed Sonogashira coupling and nucle

Full text of DOI:10.1002/ejoc.201101297

FULL PAPER
DOI: 10.1002/ejoc.201101297
Synthesis of Tetrahydrodibenzofuran and Tetrahydrophenanthridinone
Skeletons by Intramolecular Nucleopalladation/Oxidative Heck Cascades
Claudio Martínez,[a] José M. Aurrecoechea,*[b] Youssef Madich,[b][‡] J. Gabriel Denis,[a]
Angel R. de Lera,[a] and Rosana Álvarez*[a]
Keywords: Nitrogen heterocycles / Fused ring systems / Palladium / Cascade reactions / Heck reaction
Functionalized
alkylidene-1,2,3,4-tetrahydrodibenzo[b,d]-
Heck-type coupling cascade reactions. In the case of iodo-
benzamide substrates, the whole sequence can be conve-
niently carried out without the isolation of intermediates.
Maleic anhydride has been found to be useful as an additive
in the Heck coupling step.
furans and -phenanthridin-6(5H)-ones have been synthe-
sized regio- and stereoselectively from either o-iodophenols
or -benzamides and alkynes by consecutive Pd-catalyzed
Sonogashira coupling and nucleophilic addition/oxidative
providing an additional fused ring in each instance. The re-
action products contain substructures that have recently at-
tracted attention because they are structurally related to nat-
ural products and other biologically interesting mole-
cules.[17–19]
Introduction
Within the realm of rapidly expanding palladium-cata-
lyzed oxidative coupling reactions,[1] a particular set of ap-
plications, those in which a heterocyclization step precedes
a Heck-type coupling[2] in a cascade process, has attracted
increasing attention because it offers the possibility of a ra-
pid access to structurally diverse functionalized heterocyclic
motifs.[3–14] An even higher level of complexity could be
reached if the coupling step was an intramolecular reaction,
yielding functionalized polycyclic structures. However, so
far the application of this kind of strategy has been rare
and examples are limited to 5-exo-amidopalladations of
2-allyl-[9,12,13] or 2-alkynylanilides[4] followed by a Heck-type
reaction with a tethered alkene partner.[15] The extension of
this strategy to a wider range of alkynes as electrophilic
partners in combination with both N- and O-nucleophiles,
as well as its application to the formation of six-membered
heterocyclic structures, would be a valuable addition to the
current synthetic repertoire. We have previously reported a
Pd-catalyzed heterocyclization/oxidative Heck cascade pro-
cess that leads to alkenyl-substituted benzofurans, indoles,
and isoquinolones.[14,16] In this contribution we report the
application of this methodology to cases in which the oxi-
dative Heck coupling is performed intramolecularly, thus
The underlying general synthetic idea is outlined in
Scheme 1. After Sonogashira coupling between nucleo-
[a] Departamento de Química Orgánica, Facultade de Química,
Universidade de Vigo,
36310 Vigo, Spain
Fax: +34-986-818622
E-mail: rar@uvigo.es
[b] Departamento de Química Orgánica II, Facultad de Ciencia y
Tecnología, Universidad del País Vasco,
Apartado 644, 48080 Bilbao, Spain
[‡] Student on leave from Laboratoire de Chimie Bio-Organique et
Macromoléculaire, Faculté des Sciences et Techniques
Marrakech, Université Cadi
Ayyad, BP 549, Marrakech, Morocco
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101297.
Scheme 1. General outline of the consecutive Sonogashira and oxi-
dative intramolecular nucleopalladation/Heck coupling cascade.
Eur. J. Org. Chem. 2012, 99–106
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
99

J. M. Aurrecoechea, R. Álvarez et al.
FULL PAPER
phile-containing aryl halides 1 or 2 and enynes 3, the re- methoxy-substituted tetrahydrodibenzo[b,d]furans 9d and
sulting 2-alkynylphenols 4 or -benzamides 5 (depending on 9e (entries 4 and 5, respectively), which contain a substruc-
the identity of the nucleophilic center Y = O or CONR, ture present in the tricyclic core of JBIR-23 and JBIR-24,
respectively) would be expected to undergo a palladium- two natural products with cytotoxic activity.[20] However,
catalyzed nucleopalladation/Heck-type coupling cascade to the use of an electron-withdrawing group (R1 = CO2Me),
afford polycyclic products 8–10 stereoselectively. The oxi- effective in analogous intermolecular reactions,[14] was ham-
dation of the Pd0 released in the last step is needed to regen- pered in this case by the apparent high tendency of sub-
erate the catalytic PdX2 species. Regiochemical variants are strate 4 (R1 = CO2Me; R2 = R3 = H; R4 = CO2Et) to
possible in the case of benzamides, for which the two pos- cycloisomerize under the Sonogashira conditions that pre-
sible modes of nucleopalladation, exo and endo, would lead sumably had led to its formation [Equation (1)]. On the
to the corresponding isoindolone- (8) or phenanthridinone- other hand, other tether lengths did not prove useful. For
type (10) structures, respectively. Similarly, depending on example, starting from Sonogashira adduct 4 with a homol-
the size of the tether (n), exo and endo pathways could also ogated tether (n = 2; R = H; A = CO2Et, in Scheme 1), a
compete in the Heck coupling reaction (only the exo prod- mixture of endo/exo Heck regioisomers was formed.
uct is shown).
Attempts to form other fused ring sizes led to either the
recovery of the starting phenol (n = 0) or decomposition
products (n = 3).
Results and Discussion
Table 2. Preparation of alkylidenetetrahydrodibenzo[b,d]furans.[a]
The reaction conditions were briefly surveyed by using
phenol 4a derived from 2-iodophenol 1a (R = H) and
alkyne 3a (n = 1; A = CO2Et), and the results are collected
in Table 1. The application of conditions analogous to those
previously used in the corresponding intermolecular cou-
plings[14] afforded a reasonable yield of the desired coupling
product 9a (entry 1). Interestingly, the use of maleic anhy-
dride (MA) as additive in stoichiometric amounts produced
a considerable improvement in yield (entry 2). However, the
change from PdCl2 to a phosphane-containing catalyst re-
sulted in a diminished yield of 9a (entry 3). A control ex-
periment at 80 °C (entry 4) showed that higher tempera-
tures were indeed needed. Accordingly, the conditions of
entry 2 were taken as standard for subsequent reactions.
Entry
4
R1, R2, R3, R4
9, Yield [%]
1
2
3
4a
4b
4c
4d
4e
4f
H, H, H, CO2Et
tBu, H, tBu, CO2Et
H, H, H, COMe
OMe, H, H, CO2Et
OMe, H, H, COMe
H, OMe, H, CO2Et
9a, 91
9b, 62
9c, 72
4
9d, 62[c]
9e, 60[c]
9f, 53[c]
5[b]
6
[a] Unless otherwise indicated, the conditions of entry 2 in Table 1
were employed. [b] Reaction performed at 140 °C with 10 mol-%
PdCl2.
Table 1. Optimization of the reaction conditions for phenol 4a.
Entry Conditions[a]
Yield[b] [%]
1
2
3
4
PdCl2, KI, DMF, 100 °C, air
55
91
45
PdCl2, KI, MA, DMF, 100 °C, air
[PdCl2(PPh3)2], KI, MA, DMF, 100 °C, air
PdCl2, KI, MA, DMF, 80 °C, air
[c]
–
[a] Relative amounts of reagents: Pd catalyst (5 mol-%), KI
(0.5 mol-equiv.), MA (1 mol-equiv.), DMF (4ϫ10–2 m), 20 h. MA
= maleic anhydride. [b] Yield of the isolated product. [c] Starting
material was recovered.
Alkene (Z)-4a with a Z double bond was also incorpo-
rated into the study to determine the effect of double-bond
geometry on reactivity. As shown in Equation (2), 9a was
formed in 63% yield under the standard conditions. There-
The optimized conditions were then applied to various fore the same product is obtained irrespective of the geome-
alkynylphenols (Table 2). In this manner, tetrahydrodi- try (E or Z) of the double bond. Presumably, hydropallad-
benzo[b,d]furans 9 were formed efficiently from alkynyl- ation/dehydropalladation equilibria intervene to isomerize
phenols 4 containing a tethered α,β-unsaturated ester or the expected initial Z double bond geometry to the final
ketone. Electron-donating groups on the phenol moiety more stable E configuration of the observed product
were well tolerated and this enabled the preparation of 9a.[21,22]
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Synthesis of Tetrahydrodibenzofurans and -phenanthridinones
reaction, we performed an experiment in which 5 equiv. of
Et3N were added at the same stage (entry 3). This con-
firmed the negative impact of the presence of Et3N on the
aminopalladation/Heck cascade as 10a was obtained in
only 22% yield. In line with the results obtained in the ben-
zofuran series, omitting the use of maleic anhydride under
otherwise identical conditions again resulted in inferior re-
sults (entry 4). However, use of the analogous ethyl acrylate
was not successful either (entry 5), yielding a very similar
result to that obtained in the absence of additives (entry 4),
which suggests that this alkene has no effect on the coupling
reaction. Recent reports on copper-catalyzed coupling reac-
tions involving benzamide nucleophiles and alkynes,[24] as
well as other nucleophiles and coupling agents,[25,26]
prompted us to consider the possibility that the presence of
Cu salts (left over from the Sonogashira reaction) could be
partially responsible for the formation of the byproducts in
these reactions. Accordingly, catechol was introduced as a
possible Cu trap[27] (entry 6). In fact, this led to a cleaner
reaction and a more efficient formation of 10a, which was
isolated in a very respectable 70% yield. As a result, the
conditions of entry 6 were used as standard in subsequent
applications.
The results of the application of the reaction conditions
of entry 6 to different 2-iodobenzamides 2a–f and enyne 3a
are collected in Table 4. In common with phenol substrates,
substitution on the benzamide ring is also well tolerated
(entry 2). In addition, the benzamides offer the possibility
of substitution at the nitrogen as a means of structure diver-
sification. This is highlighted by entries 3–6, in which sub-
strates derived from anilines with substituents of different
electronic character all participate effectively (entries 3–5)
and alkyl substitution at the N atom is seen to be equally
effective (entry 6). As pointed out earlier, the issue of regi-
ochemical control is always a concern with benzamide sub-
strates as the two possible cyclization modes, 5-exo and 6-
endo, have previously been reported for 2-alkynylbenz-
amides under Pd-catalyzed conditions.[28–30] However, in
line with observations made in the corresponding intermo-
lecular cases, these benzamides display a remarkable prefer-
This methodology was also applied to benzamides. It was
noted that in analogous intermolecular reactions of these
substrates, [PdCl2(PPh3)2] was the universally employed cat-
alyst and was also used in the Sonogashira couplings lead-
ing to the required starting materials. Therefore the pos-
sibility of performing the sequential Sonogashira/heterocy-
clization/intramolecular Heck transformation without iso-
lation of the intermediates was considered. We explored this
idea with representative 2-iodobenzamide 2a and alkyne 3a
(Table 3). Initially we attempted to perform the Sonoga-
shira reaction in DMF as this was the solvent used in the
subsequent Heck coupling. However, this led to a sluggish
reaction at 55 °C and degradation at 80 °C. Thus, as an
alternative, we used the standard conditions for the Sonoga-
shira coupling reactions of benzamides in an amine sol-
vent.[14] When complete consumption of the starting iodo-
benzamide 2a and formation of the Sonogashira coupling
product 5a (Scheme 1; R = H; RЈ = Ph; n = 1; A = CO2-
Et)[23] were observed by TLC, maleic anhydride and air
were introduced into the system and the mixture was heated
at 80 °C. The expected tetrahydrophenanthridinone 10a was
obtained, albeit in moderate yield (47%, entry 1, Table 3).
Small amounts of what appeared to be other regioisomers
1
were also observed in the crude H NMR spectrum. Re-
placement of Et3N by DMF in the second stage of the reac-
tion led to a significant improvement in the yield of 10a
(60%) and a reduction in the amounts of byproducts (en-
try 2). To check the effect of Et3N on the Heck coupling
Table 3. Survey of reaction conditions for consecutive Sonogashira/
aminocyclization/intramolecular Heck coupling cascade of benz-
amide 2a.[a]
Table 4. Preparation of 1,2,3,4-tetrahydrophenanthridin-6(5H)-
ones.
Entry Conditions for step 2
Yield [%]
1[b]
2
MA, air, 80 °C
47
60
22
37
37
70
(i) Evaporate Et3N; (ii) MA, DMF, air, 80 °C
(i) Evaporate Et3N; (ii) Et3N,[c] MA, DMF, air, 80 °C
(i) Evaporate Et3N; (ii) DMF, air, 80 °C
3
4[b]
5[b]
6
Entry
2
R1
R2
10, Yield [%]
(i) Evaporate Et3N; (ii) ethyl acrylate,[d] DMF, air, 80 °C
(i) Evaporate Et3N; (ii) MA, DMF, catechol, air, 80 °C
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
H
OMe
H
H
H
Ph
Ph
10a, 70
10b, 56
10c, 49
10d, 76
10e, 66
10f, 67
[a] Relative amounts of reagents: [PdCl2(PPh3)2] (5 mol-%), CuI
(1 mol-%), Et3N, 55 °C, MA (1 mol-equiv.), catechol (2 mol-%). [b]
Yield in the crude as determined by 1H NMR using (3,4-dimeth-
oxyphenyl)acetonitrile as internal standard. [c] 5 mol-equiv. of
Et3N were used. [d] 1 mol-equiv. of ethyl acrylate was used.
pMeOC6H4
pMeC6H4
pClC6H4
nBu
H
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101

J. M. Aurrecoechea, R. Álvarez et al.
FULL PAPER
ence for the 6-endo mode in the initial intramolecular ad- oxidative indole–alkene coupling reactions.[33] Alternatively,
dition of the amide N onto the triple bond, and this leads as has been observed for benzoquinone ligands, maleic an-
to the predominant formation of tetrahydrophenanthridin- hydride could conceivably stabilize Pd0, eventually formed
6(5H)-ones 10a–f rather than the alternative regioisomeric upon β-elimination, as well as facilitate its reoxidation to
isoindolones 8 (Scheme 1). As a result, a convenient two- PdII, thus preventing precipitation of “Pd black” and the
step sequential protocol becomes available for the regio- subsequent interruption of the catalytic cycle.[34] Whatever
selective preparation of phenanthridinones, directly from the origin of the effect, these and related[33] results suggest
iodobenzamides, without isolation of intermediates.
the possibility of a more general use of maleic anhydride as
Inspection of Table 2 and Table 4 reveals that for the het- a useful additive in oxidative coupling reactions.
erocyclization/Heck cascade process (either with or without
isolation of the Sonogashira product) very similar reaction
conditions, with minor adjustments in catalyst and tem-
Conclusions
perature, are suitable for phenol and benzamide nucleo-
philes, despite significant differences in acidity.[31] One ap-
We have developed a straightforward approach to tetra-
parent difference between the two sets of conditions is the hydrodibenzofurans and -phenanthridinones that is based
absence of KI when the oxidative coupling reaction is per- on consecutive Pd-catalyzed Sonogashira/nucleopallad-
formed without isolation of the Sonogashira adduct. How- ation/oxidative intramolecular Heck sequences, the last two
ever, in this case, the Et3NHI byproduct formed upon Son- reactions in tandem, starting from o-iodophenols and
ogashira coupling probably plays the same role, which -benzamides (without isolation of the intermediate alkynes
could be related to the participation of iodide anions in the in the latter case). An intriguing beneficial role of maleic
reoxidation of Pd0 (Scheme 1), as previously noted.[14]
anhydride in the Heck reaction has been discovered that
A reasonable mechanism for the cascade oxidative pro- merits further investigation. Given that structural diversifi-
cess involving nucleopalladation, insertion, and β-elimi- cation is feasible by the appropriate selection of the starting
nation steps is given in Scheme 2. Oxidation of the Pd0 components, the rapid construction of these heterocyclic
eventually released upon formation of products 9 or 10 scaffolds will also be of interest in Medicinal Chemistry.
would then regenerate the catalytic PdX2 species.
Experimental Section
General: See refs.[10,11] for general details. In addition, COSY, NOE,
HSQC, and HMBC data were recorded to enable interpretation of
the NOE data and to establish the structure of phenanthridinones
10. Iodoamides 2a–f were prepared from the corresponding acids
according to a literature procedure,[35] but by using toluene in place
of benzene. Compounds 2a,[36] 2c,[36] 2d,[29] 2e,[37] and 2f[38] were
characterized by comparison with literature data.
2-Iodo-4,5-dimethoxy-N-phenylbenzamide (2b): Yield: 99%; m.p.
164–166 °C. 1H NMR (300 MHz, CDCl3): δ = 7.66–7.63 (m, 3 H),
7.38 (t, J = 7.8 Hz, 2 H), 7.25 (s, 1 H), 7.17 (t, J = 7.4 Hz, 1 H),
7.11 (s, 1 H), 3.87 and 3.83 (2 s, 6 H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 166.8 (s), 150.6 (s), 149.1 (s), 137.6 (s), 134.2 (s), 129.0
(d), 124.7 (d), 121.9 (d), 119.9 (d), 111.9 (d), 81.0 (s), 56.2 (q), 56.0
(q) ppm. IR (film): ν = 3277 (m, NH), 1655 (s, C=O) cm–1. MS
˜
(EI): m/z (%) = 383 (8) [M]+. HRMS: calcd. for C15H14INO3
383.0018; found 383.0017.
Ethyl (E)-Oct-2-en-7-ynoate (3a):[39] A solution of 5-hexyn-1-ol
(4.06 g, 41.4 mmol) in CH2Cl2 (2.0 mL) was added dropwise to a
suspension of pyridinium chlorochromate (PCC; 13.4 g,
62.1 mmol) and Celite® (13.5 g) in CH2Cl2 (83 mL), and the mix-
ture was stirred at room temp. for 24 h. Ethyl (triphenylphosphor-
anylidene)acetate (24.5 g, 70.3 mmol) was then added and the reac-
tion mixture was stirred at room temperature for 24 h. After the
addition of Et2O (150 mL), the reaction mixture was filtered
through Celite® and the solids were washed with hexanes/EtOAc
(9:1, 500 mL). The filtrate and washings were combined, the sol-
vent was removed, and the residue was purified by flash chromatog-
raphy (silica gel, 98:2 hexanes/EtOAc) to afford 3a (4.65 g, 68%)
as a colorless liquid, the spectral properties of which were in good
agreement with those reported in the literature for the same com-
Scheme 2. Mechanism proposed for the formation of products 9
and 10.
A beneficial effect of maleic anhydride on the coupling
reaction was observed with both types of substrates, phenol
and benzamide. This effect could be related to the stabiliza-
tion of palladium species at different stages of the reaction,
as previously documented for the related dba ligand.[32] In
addition, as a π-acidic ligand, it could provide a more ef-
ficient PdII promoter for nucleophilic attack on the interme-
diate alkyne–Pd complex 12, thereby accelerating the initial
intramolecular nucleopalladation (Scheme 2). This type of
role has previously been suggested for the same ligand in pound.[39]
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Synthesis of Tetrahydrodibenzofurans and -phenanthridinones
(E)-Non-3-en-8-yn-2-one (3b): Hex-4-yn-1-ol (0.360 g, 3.67 mmol)
was added to a mixture of PCC (1.19 g, 5.50 mmol) and Celite®
(3.60 g) in CH2Cl2 (31 mL). After stirring for 24 h at 25 °C, the
resulting mixture was filtered through Celite®, the solids were
washed with CH2Cl2, and the solvent (filtrate and washings) was
evaporated. The residue was dissolved in CH2Cl2 (10 mL), 1-tri-
phenylphosphoranylidene-2-propanone (1.98 g, 6.24 mmol) was
added, and the mixture was stirred for 5 h at 37 °C. The solvent
was evaporated and the residue was purified by column chromatog-
raphy (silica gel, 80:20 hexane/EtOAc) to afford 0.254 g (50% for
two steps) of 3b as a colorless oil. 1H NMR (400.16 MHz, CDCl3):
δ = 6.76 (dt, J = 15.9, 6.9 Hz, 1 H), 6.08 (dt, J = 15.9, 1.5 Hz, 1
H), 2.4–2.3 (m, 2 H), 2.3–2.2 (m, 2 H), 2.21 (s, 3 H), 1.95 (t, J =
14.3 (q) ppm. IR (NaCl): ν = 3600–3100 (br, O–H), 1719 (s,
˜
C=O) cm–1. MS (EI): m/z (%) = 370 (26) [M]+. HRMS (EI): calcd.
for C24H34O3 370.2508; found 370.2511.
(E)-9-(2-Hydroxyphenyl)non-3-en-8-yn-2-one (4c): Procedure B was
followed starting with 2-iodophenol and 3b to afford 4c (80%).
1
Brown oil. H NMR (400.16 MHz, CDCl3): δ = 7.29 (dd, J = 7.7,
1.6 Hz, 1 H), 7.2–7.1 (m, 1 H), 6.93 (dd, J = 8.2, 0.8 Hz, 1 H), 6.9–
6.7 (m, 2 H), 6.14 (dt, J = 15.9, 1.5 Hz, 1 H), 5.77 (br., 1 H), 2.54
(t, J = 7.0 Hz, 2 H), 2.5–2.4 (m, 2 H), 2.25 (s, 3 H), 1.9–1.8 (m, 2
H) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 198.6 (s), 156.6 (s),
146.9 (d), 131.7 (d, 2ϫ), 129.7 (d), 119.9 (d), 114.5 (d), 109.9 (s),
95.9 (s), 75.7 (s), 31.3 (t), 26.9 (t), 26.8 (q), 19.0 (t) ppm. IR (NaCl):
ν = 3600–3100 (br, O–H), 1672 (s, C=O) cm–1. MS (EI): m/z (%) =
˜
2.6 Hz,
(100.62 MHz, CDCl3): δ = 198.8 (s), 147.2 (d), 141.4 (d), 83.6 (s),
1 H), 1.68 (q, J =
7.1 Hz, 2 H) ppm. 13C NMR
228 (33) [M]+. HRMS (EI): calcd. for C15H16O2 228.1150; found
228.1153.
68.3 (d), 31.6 (t), 27.2 (q), 26.9 (t), 18.1 (t) ppm. IR (NaCl): ν =
˜
3294 (w, CϵH), 2215 (w, CϵC), 1674 (s, C=O) cm–1. MS (EI): m/z
(%) = 135 (18) [M – 1]+. HRMS (EI): calcd. for C9H11O [M – 1]+
135.0816; found 135.0810.
Ethyl (E)-8-(2-Hydroxy-5-methoxyphenyl)oct-2-en-7-ynoate (4d):
Procedure C was followed starting with 2-iodo-4-methoxyphenol[41]
and 3a to afford 4d (96%). Yellow oil. 1H NMR (400.16 MHz,
CDCl3): δ = 6.96 (dt, J = 15.5, 7.0 Hz, 1 H), 6.9–6.7 (m, 3 H), 5.87
(d, J = 15.6 Hz, 1 H), 5.56 (br., 1 H), 4.18 (q, J = 7.1 Hz, 2 H),
3.73 (s, 3 H), 2.50 (t, J = 7.0 Hz, 2 H), 2.37 (q, J = 7.2 Hz, 2 H),
1.79 (q, J = 7.2 Hz, 2 H), 1.27 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(100.62 MHz, CDCl3): δ = 166.6 (s), 152.9 (s), 150.9 (s), 148.2 (d),
122.2 (d), 116.6 (d), 115.6 (d), 115.3 (d), 110.1 (s), 96.3 (s), 75.7 (s),
60.3 (t), 55.8 (q), 31.2 (t), 27.0 (t), 19.1 (t), 14.3 (q) ppm. IR (NaCl):
Sonogashira Coupling Reactions with Iodophenols 1
Procedure A: A solution of 1, [PdCl2(PPh3)2] (5 mol-%), CuI
(4 mol-%), 3 (2 mol equiv.), and Et3N (2 mol equiv.) in DMF
(5 mL/mmol) was stirred at 25 °C for 19 h under Ar. A saturated
NH4Cl solution was added and the mixture was extracted with
CH2Cl2. The combined organic layers were dried (Na2SO4) and
the solvent was evaporated. The residue was purified by column
chromatography (silica gel, hexane/EtOAc) to afford 4.
ν = 3600–3100 (br, OH), 1715 (s, C=O) cm–1. MS (EI): m/z (%) =
˜
288 (40) [M]+. HRMS (EI): calcd. for C17H20O4 288.1372; found
288.1362.
Procedure B: The same as for procedure A using [PdCl2(PPh3)2]
(4 mol-%), CuI (13 mol-%), 3 (1.2 mol-equiv.), and Et3N (2 mol-
equiv.) in THF (3 mL/mmol).
(E)-9-(2-Hydroxy-5-methoxyphenyl)non-3-en-8-yn-2-one (4e): Pro-
cedure C was followed starting with 2-iodo-4-methoxyphenol[41]
and 3b to afford 4e (81%). Yellow oil. 1H NMR (400.16 MHz,
CDCl3): δ = 6.8–6.7 (m, 4 H), 6.14 (d, J = 16.0 Hz, 1 H), 5.43 (br.,
1 H), 3.74 (s, 3 H), 2.53 (t, J = 7.0 Hz, 2 H), 2.41 (q, J = 7.4 Hz,
2 H), 2.25 (s, 3 H), 1.82 (quint., J = 7.2 Hz, 2 H) ppm. 13C NMR
(100.62 MHz, CDCl3): δ = 198.7 (s), 152.9 (s), 151.0 (s), 147.1 (d),
147.0 (d), 131.8 (d), 116.5 (d), 115.8 (d), 110.1 (s), 95.9 (s), 66.1 (s),
Procedure C: A solution of 1, Et3N (2 mol-equiv.), [PdCl2(PPh3)2]
(3.5 mol-%), and CuI (4 mol-%) in DMF (8 mL/mmol) was stirred
for 20 min at 25 °C under Ar before the addition of 3 (1.2 mol-
equiv.). The reaction mixture was stirred for 24 h at 25 °C, and then
it was poured into H2O and extracted with EtOAc. Subsequently,
procedure A was followed.
55.8 (q), 31.5 (t), 27.0 (t), 26.9 (q), 19.1 (t) ppm. IR (NaCl): ν =
˜
3600–3100 (br, OH), 1671 (s, C=O) cm–1. MS (EI): m/z (%) = 258
(34) [M]+. HRMS (EI): calcd. for C16H18O3 258.1256; found
258.1262.
Ethyl (E)-8-(2-Hydroxyphenyl)oct-2-en-7-ynoate (4a): Procedure A
was followed starting with 2-iodophenol and 3a to afford 4a (97%).
Yellowish oil. 1H NMR (400.16 MHz, CDCl3): δ = 7.29 (dd, J =
7.7, 1.3 Hz, 1 H), 7.19 (t, J = 8.2 Hz, 1 H), 6.96 (dt, J = 15.6,
6.9 Hz, 1 H), 6.91 (dd, J = 8.2, 0.8 Hz, 1 H), 6.85 (td, J = 8.2,
0.8 Hz, 1 H), 5.89 (d, J = 15.6 Hz, 1 H), 5.91 (s, 1 H), 4.20 (q, J =
7.1 Hz, 2 H), 2.52 (t, J = 7.0 Hz, 2 H), 2.39 (dd, J = 14.5, 7.2 Hz,
2 H), 1.9–1.7 (m, 2 H), 1.29 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(100.62 MHz, CDCl3): δ = 166.5 (s), 156.5 (s), 147.7 (d), 131.7 (d),
129.7 (d), 122.2 (d), 120.2 (d), 114.5 (d), 109.9 (s), 96.5 (s), 75.5 (s),
Ethyl (E)-8-(2-Hydroxy-4-methoxyphenyl)oct-2-en-7-ynoate (4f):
Procedure B was followed starting with 2-iodo-5-methoxyphenyl
acetate[42] (50 mg, 0.17 mmol) and 3a (57 mg, 0.34 mmol) in DMF
and by heating at 50 °C for 17 h. The purified product (54 mg) was
treated with K2CO3 (40 mg, 0.28 mmol) in EtOH (12 mL) to afford
1
4f (37 mg, 75% for two steps). H NMR (400.16 MHz, CDCl3): δ
= 7.18 (d, J = 8.6 Hz, 1 H), 6.96 (dt, J = 15.6, 7.0 Hz, 1 H), 6.48
(d, J = 2.5 Hz, 1 H), 6.41 (dd, J = 8.6, 2.5 Hz, 1 H), 5.85 (dt, J =
15.6, 1.5 Hz, 1 H), 5.76 (s, 1 H, OH), 4.18 (q, J = 7.1 Hz, 2 H),
3.76 (s, 3 H), 2.49 (t, J = 7.0 Hz, 2 H), 2.36 (qd, J = 7.5, 1.4 Hz, 2
H), 1.77 (quint., J = 7.2 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (100.62 MHz, CDCl3): δ = 166.6 (s), 161.0 (s), 157.9 (s),
147.9 (d), 132.3 (d), 122.2 (d), 107.0 (d), 102.4 (s), 100.0 (d), 95.1
(s), 75.3 (s), 60.3 (t), 55.4 (q), 31.2 (t), 27.1 (t), 19.1 (t), 14.3
60.3 (t), 31.2 (t), 26.9 (t), 19.1 (t), 14.2 (q) ppm. IR (NaCl): ν =
˜
3600–3100 (br, O–H), 2224 (w, CϵC), 1716 (s, C=O), 1653 (m,
C=C) cm–1. MS (EI): m/z (%) = 258 (17) [M]+. HRMS (EI): calcd.
for C16H18O3, 258.1256; found 258.1268.
Ethyl
(E)-8-(3,5-Di-tert-butyl-2-hydroxyphenyl)oct-2-en-7-ynoate
(4b): Procedure B was followed starting with 2,4-di-tert-butyl-6-
1
iodophenol[40] and 3a to afford 4b (98%). Colorless oil. H NMR
(q) ppm. IR (NaCl): ν = 1716 (s, C=O) cm–1. MS (EI): m/z (%) =
˜
(400.16 MHz, CDCl3): δ = 7.25 (d, J = 2.4 Hz, 1 H), 7.17 (d, J =
2.3 Hz, 1 H), 6.98 (dt, J = 15.7, 6.9 Hz, 1 H), 6.00 (s, 1 H), 5.89
(dt, J = 15.7, 1.5 Hz, 1 H), 4.13 (q, J = 7.1 Hz, 2 H), 2.53 (t, J =
7.0 Hz, 2 H), 2.4–2.3 (m, 2 H), 1.8–1.7 (m, 2 H), 1.40 (s, 9 H), 1.29
(t, J = 7.1 Hz, 3 H), 1.28 (s, 9 H) ppm. 13C NMR (100.62 MHz,
CDCl3): δ = 166.3 (s), 153.0 (s), 147.7 (d), 141.8 (s), 134.6 (s), 125.8
(d), 124.5 (d), 122.3 (d), 109.8 (s), 96.0 (s), 76.5 (s), 60.2 (t), 34.9
288 (31) [M]+. HRMS (EI): calcd. for C17H20O4 288.1362; found
288.1360.
Ethyl (Z)-8-(2-Hydroxyphenyl)oct-2-en-7-ynoate (Z-4a): Procedure
B was followed starting with 2-iodophenol and ethyl (Z)-oct-2-en-
7-ynoate[43] to afford (Z)-4a (80%). Colorless oil. 1H NMR
(400.16 MHz, CDCl3): δ = 7.29 (dd, J = 7.7, 1.5 Hz, 1 H), 7.19 (t,
(s), 34.2 (s), 31.6 (q, 3ϫ), 31.2 (t), 29.5 (q, 3ϫ), 27.2 (t), 19.1 (t), J = 7.1 Hz, 1 H), 6.92 (d, J = 8.2 Hz, 1 H), 6.83 (t, J = 7.5 Hz, 1
Eur. J. Org. Chem. 2012, 99–106
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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103

J. M. Aurrecoechea, R. Álvarez et al.
FULL PAPER
H), 6.82 (dt, J = 11.6, 7.7 Hz, 1 H), 5.84 (d, J = 11.6 Hz, 1 H),
4.18 (q, J = 7.1 Hz, 2 H), 2.86 (q, J = 7.7 Hz, 2 H), 2.51 (t, J =
6.9 Hz, 2 H), 1.79 (quint., J = 7.1 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 3
H) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 166.4 (s), 156.8 (s),
148.9 (d), 131.7 (d), 129.5 (d), 120.8 (d), 119.9 (d), 114.7 (d), 110.1
(s), 98.7 (s), 75.2 (s), 60.0 (t), 27.8 (t), 27.7 (t), 19.0 (t), 14.1 (q) ppm.
(t), 22.8 (t) ppm. IR (NaCl): ν = 1674 (s, C=O), 1590 (s) cm–1. MS
˜
(EI): m/z (%) = 226 (70) [M]+. HRMS (EI): calcd. for C15H14O2
226.0994; found 226.0994.
Ethyl
(E)-2-[8-Methoxy-3,4-dihydrodibenzo[b,d]furan-1(2H)-ylid-
ene]acetate (9d): White solid; m.p. 102 °C (hexane/EtOAc). 1H
NMR (400.16 MHz, CDCl3): δ = 7.35 (d, J = 8.9 Hz, 1 H), 7.27
(d, J = 2.4 Hz, 1 H), 6.88 (dd, J = 8.9, 2.5 Hz, 1 H), 6.26 (s, 1 H),
4.22 (q, J = 7.1 Hz, 2 H), 3.89 (s, 3 H), 3.21 (dd, J = 8.9, 3.6 Hz,
2 H), 2.87 (t, J = 6.3 Hz, 2 H), 2.1–1.9 (m, 2 H), 1.34 (t, J = 7.1 Hz,
3 H) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 167.3 (s), 162.6
(s), 156.5 (s), 150.6 (s), 149.7 (s), 125.5 (s), 114.4 (s), 111.6 (d),
111.4 (d), 110.5 (d), 104.9 (d), 59.7 (q), 56.2 (t), 26.7 (t), 24.2 (t),
IR (NaCl): ν = 3600–3100 (br, O–H), 1714 (s, C=O) cm–1. MS (EI):
˜
m/z (%) = 258 (8) [M]+. HRMS (EI): calcd. for C16H17O3 [M –
1]+ 257.1178; found 257.1179.
Methyl (E)-2-[5-(Ethoxycarbonyl)pent-4-en-1-yl]benzofuran-5-carb-
oxylate (11): Procedure B was followed starting with methyl 4-hy-
droxy-3-iodobenzoate and 3a using DMF instead of THF to afford
11 (92%). Yellow oil. 1H NMR (400.16 MHz, CDCl3): δ = 8.22 (d,
J = 1.7 Hz, 1 H), 7.95 (dd, J = 8.6, 1.7 Hz, 1 H), 7.42 (d, J =
8.6 Hz, 1 H), 6.97 (td, J = 15.6, 6.9 Hz, 1 H), 6.46 (s, 1 H), 5.86
(d, J = 15.6 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 3.93 (s, 3 H), 2.82
(t, J = 7.5 Hz, 2 H), 2.3–2.2 (m, 2 H), 1.94 (q, J = 7.5 Hz, 2 H),
1.29 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100.62 MHz, CDCl3): δ
= 167.4 (s), 166.5 (s), 159.9 (s), 157.2 (s), 147.7 (d), 128.7 (s), 125.1
(d), 124.7 (s), 122.6 (d), 122.0 (d), 110.5 (d), 102.6 (d), 60.1 (t), 51.9
22.7 (t), 14.5 (q) ppm. IR (NaCl): ν = 1708 (s, C=O), 1615 (s,
˜
C=C) cm–1. MS (EI): m/z (%) = 286 (100) [M]+. HRMS (EI): calcd.
for C17H18O4 286.1205; found 286.1204.
(E)-1-[8-Methoxy-3,4-dihydrodibenzo[b,d]furan-1(2H)-ylidene]-
propan-2-one (9e): Reaction temperature was 140 °C. Colorless so-
1
lid; m.p. 119 °C (hexane/EtOAc). H NMR (400.16 MHz, CDCl3):
δ = 7.35 (d, J = 8.9 Hz, 1 H), 7.25 (d, J = 2.5 Hz, 1 H), 6.87 (dd,
J = 8.9, 2.5 Hz, 1 H), 6.65 (s, 1 H), 3.87 (s, 3 H), 3.2–3.1 (m, 2 H),
2.85 (t, J = 6.3 Hz, 2 H), 2.31 (s, 3 H), 2.04–1.95 (m, 2 H) ppm.
13C NMR (100.62 MHz, CDCl3): δ = 198.8 (s), 164.2 (s), 156.6 (s),
149.9 (s), 149.7 (s), 125.7 (s), 118.3 (d), 114.4 (s), 111.8 (d), 111.1
(q), 31.3 (t), 27.6 (t), 25.7 (t), 14.2 (q) ppm. IR (NaCl): ν = 1719
˜
(s, C=O), 1654 (s, C=O) cm–1. MS (EI): m/z (%) = 285 (17). HRMS
(EI): calcd. for C18H20O5 316.1312; found 316.1311.
Representative Procedure for Pd-Catalyzed Oxidative Cyclization (d), 105.5 (d), 56.4 (q), 32.6 (q), 27.2 (t), 24.4 (t), 22.9 (t) ppm. IR
Cascades: PdCl2 (0.001 g, 0.004 mmol), KI (0.006 g, 0.040 mmol),
and maleic anhydride (0.007 g, 0.080 mmol) was added to a solu-
tion of phenol 4 (0.080 mmol) in DMF (2 mL) and the mixture
was stirred at 100 °C for 20 h. After allowing the mixture to cool
to 25 °C, water was added. The mixture was extracted with EtOAc,
the combined organic layers were dried (Na2SO4), and the solvent
was removed. The product 9 was purified by column chromatog-
raphy (silica gel, hexane/EtOAc).
(NaCl): ν = 1672 (s, C=O), 1580 (s, C=C) cm–1. MS (EI): m/z (%)
˜
= 256 (62) [M]+. HRMS (EI): calcd. for C16H16O3 256.1100; found
256.1099.
Ethyl (E)-2-[7-Methoxy-3,4-dihydrodibenzo[b,d]furan-1(2H)-ylidene]-
acetate (9f): White solid; m.p. 100–101 °C (Et2O). 1H NMR
(400.16 MHz, CDCl3): δ = 7.67 (d, J = 8.6 Hz, 1 H), 7.00 (d, J =
2.3 Hz, 1 H), 6.91 (dd, J = 8.6, 2.3 Hz, 1 H), 6.29 (s, 1 H), 4.22 (q,
J = 7.1 Hz, 2 H), 3.85 (s, 3 H), 3.20 (t, J = 5.6 Hz, 2 H), 2.86 (t, J
= 6.3 Hz, 2 H), 2.1–2.0 (quint., J = 6.3 Hz, 2 H), 1.33 (t, J = 7.1 Hz,
3 H) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 167.3 (s), 160.9
(s), 157.6 (s), 155.8 (s), 150.7 (s), 120.8 (d), 118.2 (s), 114.2 (s),
111.6 (d), 110.4 (d), 96.5 (d), 59.7 (t), 55.7 (q), 26.6 (t), 24.0 (t),
Ethyl
(E)-2-[3,4-Dihydrodibenzo[b,d]furan-1(2H)-ylidene]acetate
(9a): White solid; m.p. 65 °C (hexane/EtOAc). 1H NMR
(400.16 MHz, CDCl3): δ = 7.9–7.8 (m, 1 H), 7.47 (dd, J = 6.1,
3.1 Hz, 1 H), 7.4–7.2 (m, 2 H), 6.37 (s, 1 H), 4.24 (q, J = 7.1 Hz,
2 H), 3.3–3.2 (m, 2 H), 2.91 (t, J = 6.3 Hz, 2 H), 2.1–2.0 (m, 2 H),
22.8 (t), 14.5 (q) ppm. IR (NaCl): ν = 1706 (m, C=O), 1672 (s),
˜
1.35 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100.62 MHz, CDCl3): δ 1580 (s, C=C) cm–1. MS (EI): m/z (%) = 283 (64) [M]+. HRMS
= 167.3 (s), 161.7 (s), 154.7 (s), 150.6 (s), 124.9 (s), 124.2 (d), 123.5
(d), 120.6 (d), 114.3 (s), 111.4 (d), 110.7 (d), 59.7 (t), 26.6 (t), 24.0
(EI): calcd. for C17H18O4 286.1205; found 286.1205.
Representative Procedure for Consecutive Sonogashira/Oxidative
(t), 22.7 (t), 14.4 (q) ppm. IR (NaCl): ν = 1707 (s, C=O), 1615 (s,
˜
Cascade
Cyclization
Reactions:
[PdCl2(PPh3)2]
(0.011 g,
C=C) cm–1. MS (EI): m/z (%) = 256 (88) [M]+. HRMS (EI): calcd.
0.015 mmol) and CuI (0.6 mg, 0.003 mmol) were added to a solu-
tion of amide 2 (0.310 mmol) and 3a (0.062 g, 0.371 mmol) in Et3N
(2.6 mL). The resulting mixture was heated under Ar at 55 °C for
2.5 h and then Et3N was removed in vacuo. Maleic anhydride
(0.030 g, 0.309 mmol), 1,2-dihydroxybenzene (0.7 mg, 0.006 mmol),
and DMF (2.6 mL) were added and the mixture was stirred at
80 °C for 3–6 h in air. After cooling to 25 °C, saturated NaHCO3
was added and the mixture was extracted with EtOAc. The com-
bined organic extracts were washed with water and dried with
Na2SO4. The solvent was evaporated and the product 10 was puri-
fied by flash chromatography (silica gel saturated with Et3N, hex-
for C16H16O3 256.1099; found 256.1104.
Ethyl (E)-2-[6,8-Di-tert-butyl-3,4-dihydrodibenzo[b,d]furan-1(2H)-
ylidene]acetate (9b): Yellow solid; m.p. 90 °C (hexane/EtOAc). 1H
NMR (400.16 MHz, CDCl3): δ = 7.64 (d, J = 1.7 Hz, 1 H), 7.27
(d, J = 1.7 Hz, 1 H), 6.35 (s, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 3.3–
3.2 (m, 2 H), 2.92 (t, J = 6.2 Hz, 2 H), 2.1–2.0 (m, 2 H), 1.51 (s, 9
H), 1.42 (s, 9 H), 1.40 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(100.62 MHz, CDCl3): δ = 167.5 (s), 160.9 (s), 151.2 (s), 151.0 (s),
146.3 (s), 133.7 (s), 125.0 (s), 118.9 (d), 114.7 (d), 113.9 (s), 110.3
(d), 59.6 (t), 35.0 (s), 34.5 (s), 31.9 (q, 3ϫ), 29.9 (q, 3ϫ), 26.9 (t),
24.2 (t), 22.9 (t), 14.5 (q) ppm. IR (NaCl): ν = 1712 (s, C=O), 1620 anes/EtOAc/Et3N).
˜
(s, C=C) cm–1. MS (EI): m/z (%) = 368 (46) [M]+. HRMS (EI):
Ethyl (E)-[6-Oxo-5-phenyl-3,4,5,6-tetrahydrophenanthridin-1(2H)-
ylidene]acetate (10a): Yellowish solid; m.p. 100–101 °C. 1H NMR
(E)-1-[3,4-Dihydrodibenzo[b,d]furan-1(2H)-ylidene]propan-2-one (9c): (300 MHz, CDCl3): δ = 8.40 (d, J = 8.0 Hz, 1 H), 7.80 (d, J =
calcd. for C24H32O3 368.2351; found 368.2345.
1
White solid; m.p. 75 °C (hexane/EtOAc). H NMR (400.16 MHz,
CDCl3): δ = 7.9–7.8 (m, 1 H), 7.6–7.5 (m, 1 H), 7.4–7.3 (m, 2 H),
6.77 (s, 1 H), 3.2–3.1 (m, 2 H), 2.90 (t, J = 6.3 Hz, 2 H), 2.34 (s, 3
H), 2.1–2.0 (m, 2 H) ppm. 13C NMR (100.62 MHz, CDCl3): δ =
198.7 (s), 163.1 (s), 154.8 (s), 149.4 (s), 124.8 (s), 124.3 (d), 123.6
(d), 120.6 (d), 118.4 (d), 114.2 (s), 111.5 (d), 32.4 (q), 26.9 (t), 24.1
7.9 Hz, 1 H), 7.6–7.5 (m, 1 H), 7.5–7.4 (m, 1 H), 7.4–7.3 (m, 2 H),
7.18 (d, J = 8.2 Hz, 2 H), 7.10 (t, J = 7.3 Hz, 1 H), 6.19 (s, 1 H),
4.21 (q, J = 7.1 Hz, 2 H), 3.15 (t, J = 6.4 Hz, 2 H), 2.50 (t, J =
6.5 Hz, 2 H), 2.0–1.9 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 166.9 (s), 155.6 (s), 150.9 (s), 148.3
(s), 146.1 (s), 132.0 (d), 131.1 (s), 128.7 (d), 128.2 (d), 127.6 (d),
104
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 99–106

Synthesis of Tetrahydrodibenzofurans and -phenanthridinones
124.6 (s), 123.8 (d), 123.6 (d), 122.7 (d), 115.6 (d), 112.2 (s), 59.9
Ethyl
(E)-[5-Butyl-6-oxo-3,4,5,6-tetrahydrophenanthridin-1(2H)-
1
(t), 27.4 (t), 27.3 (t), 21.6 (t), 14.3 (q) ppm. IR (KBr): ν = 1709 (s, ylidene]acetate (10f): Yellow oil. H NMR (300 MHz, CDCl3): δ =
˜
OC=O), 1654 (s, NC=O), 1590 (s, C=C) cm–1. MS (EI): m/z (%)
= 359 (63) [M]+. HRMS: calcd. for C23H21NO3 359.1521; found
359.1525.
8.18 (dd, J = 7.9, 1.1 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.5–7.4
(m, 1 H), 7.3–7.2 (m, 1 H), 6.16 (s, 1 H), 4.19 (q, J = 7.1 Hz, 2 H),
3.49 (t, J = 7.0 Hz, 2 H), 3.2–3.1 (m, 2 H), 2.56 (t, J = 6.5 Hz, 2
H), 2.0–1.9 (m, 2 H), 1.7–1.6 (m, 2 H), 1.5–1.4 (m, 2 H), 1.30 (t, J
= 7.1 Hz, 3 H), 0.96 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 167.1 (s), 155.9 (s), 151.3 (s), 148.6 (s),
131.0 (d), 130.3 (s), 127.3 (d, 2ϫ), 125.1 (s), 123.5 (d), 114.9 (d),
111.5 (s), 59.8 (t), 46.0 (t), 32.9 (t), 27.5 (t, 2ϫ), 21.6 (t), 20.7 (t),
Ethyl
(E)-[8,9-Dimethoxy-6-oxo-5-phenyl-3,4,5,6-tetrahydrophen-
anthridin-1(2H)-ylidene]acetate (10b): A mixture of Et3N/THF
(4:1.5; 10.5 mL/mmol) was used instead of Et3N. Yellow solid; m.p.
1
171–173 °C. H NMR (300 MHz, CDCl3): δ = 7.84 (s, 1 H), 7.4–
7.3 (m, 2 H), 7.25 (s, 1 H), 7.18 (d, J = 8.1 Hz, 2 H), 7.08 (t, J =
7.3 Hz, 1 H), 6.22 (s, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 4.01 (s, 3 H),
3.95 (s, 3 H), 3.15 (t, J = 6.4 Hz, 2 H), 2.49 (t, J = 6.5 Hz, 2 H),
2.0–1.9 (m, 2 H), 1.30 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 166.9 (s), 154.7 (s), 152.4 (s), 151.6 (s),
148.8 (s), 148.4 (s), 146.4 (s), 128.6 (d, 2ϫ), 125.6 (s), 123.4 (d),
122.7 (d, 2ϫ), 117.6 (s), 115.1 (d), 111.9 (s), 109.0 (d), 105.6 (d),
59.8 (t), 56.2 (q), 56.0 (q), 27.3 (t), 27.1 (t), 21.6 (t), 14.3 (q) ppm.
14.3 (q), 14.0 (q) ppm. IR (KBr): ν = 1713 (s), 1668 (s), 1627
˜
(m) cm–1. HRMS (ESI): calcd. for C21H26NO3 [M + H]+ 340.1907;
found 340.1902.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all new compounds.
Acknowledgments
IR (KBr): ν = 1710 (s, OC=O), 1652 (s, NC=O), 1591 (s,
˜
C=C) cm–1. MS (EI): m/z = 419 (base) [M]+. HRMS: calcd. for
We thank the Spanish Ministerio de Ciencia e Innovación (MIC-
INN) (grant numbers CTQ2008-06647 and CTQ2009-14186),
Fondos Europeos para el Desarrollo Regional (FEDER), Xunta
de Galicia (INBIOMED, contract to C. M.), the Universidad del
País Vasco (fellowship to Y. M.) and the Universidade de Vigo (fel-
lowship to J. G. D.) for financial support.
C25H25NO5 419.1733; found 419.1731.
Ethyl
(E)-[5-(4-Methoxyphenyl)-6-oxo-3,4,5,6-tetrahydrophen-
anthridin-1(2H)-ylidene]acetate (10c): Yellow solid; m.p. 129–
131 °C. 1H NMR (300 MHz, CDCl3): δ = 8.39 (d, J = 8.0 Hz, 1
H), 7.78 (d, J = 8.1 Hz, 1 H), 7.6–7.5 (m, 1 H), 7.40 (t, J = 7.7 Hz,
1 H), 7.3–7.2 (m, 2 H), 6.9–6.8 (m, 2 H), 6.19 (s, 1 H), 4.21 (q, J
= 7.1 Hz, 2 H), 3.83 (s, 3 H), 3.17 (t, J = 6.5 Hz, 2 H), 2.55 (t, J =
6.5 Hz, 2 H), 2.0–1.9 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 166.9 (s), 156.3 (s), 155.6 (s), 150.9
(s), 147.5 (s), 138.7 (s), 131.6 (d), 130.9 (s), 128.0 (d), 127.5 (d),
124.9 (s), 124.6 (d, 2ϫ), 123.5 (d), 115.4 (d), 113.8 (d, 2ϫ), 112.1
(s), 59.9 (t), 55.4 (q), 27.4 (t), 27.3 (t), 21.6 (t), 14.3 (q) ppm. IR
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(KBr): ν = 1710 (s, OC=O), 1653 (s, NC=O), 1506 (s, C=C) cm–1.
˜
MS (EI): m/z = 389 (base) [M]+. HRMS: calcd. for C24H23NO4
389.1627; found 389.1625.
Ethyl (E)-[6-Oxo-5-(p-tolyl)-3,4,5,6-tetrahydrophenanthridin-1(2H)-
ylidene]acetate (10d): Yellow viscous oil. 1H NMR [300 MHz,
(CD3)2CO]: δ = 8.34 (d, J = 7.8 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1
H), 7.7–7.6 (m, 1 H), 7.44 (t, J = 7.5 Hz, 1 H), 7.14 (s, 4 H), 6.13
(s, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.14 (t, J = 6.4 Hz, 2 H), 2.52
(t, J = 6.5 Hz, 2 H), 2.30 (s, 3 H), 1.9–1.8 (m, 2 H), 1.26 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR [75.5 MHz, (CD3)2CO]: δ = 166.9 (s),
156.8 (s), 151.6 (s), 148.2 (s), 144.2 (s), 133.9 (s), 132.8 (d), 131.8
(s), 129.9 (d, 2ϫ), 128.7 (d), 128.4 (d), 125.5 (s), 124.3 (d), 123.9
(d, 2ϫ), 116.2 (d), 112.5 (s), 60.2 (t), 27.8 (t), 27.7 (t), 22.4 (t), 21.00
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(q), 14.7 (q) ppm. IR (KBr): ν = 1711 (s, OC=O), 1655 (s, NC=O),
˜
1602 (m, C=C) cm–1. MS (EI): m/z (%) = 373 (90) [M]+. HRMS:
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Ethyl
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105 °C. H NMR [300 MHz, (CD3)2CO]: δ = 8.35 (d, J = 7.8 Hz,
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1 H), 7.84 (d, J = 8.2 Hz, 1 H), 7.7–7.6 (m, 1 H), 7.5–7.4 (m, 1 H),
7.34 (d, J = 8.7 Hz, 2 H), 7.24 (d, J = 8.7 Hz, 2 H), 6.15 (s, 1 H),
4.17 (q, J = 7.1 Hz, 2 H), 3.2–3.1 (m, 2 H), 2.55 (t, J = 6.5 Hz, 2
H), 2.0–1.9 (m, 2 H), 1.26 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
[75.5 MHz, (CD3)2CO]: δ = 166.9 (s), 156.6 (s), 151.4 (s), 149.5 (s),
146.0 (s), 133.3 (d), 132.0 (s), 129.4 (d, 2ϫ), 129.2 (s), 128.9 (d),
128.6 (d), 125.5 (d, 2ϫ), 125.1 (s), 124.4 (d), 116.5 (d), 112.8 (s),
60.3 (t), 27.8 (t), 27.7 (t), 22.4 (t), 14.7 (q) ppm. IR (KBr): ν = 1711
˜
(s, OC=O), 1654 (s, NC=O), 1610 (m, C=C) cm–1. MS (EI): m/z
(%) = 395 (27) [M]+. HRMS: calcd. for C23H2035ClNO3 393.1132;
found 393.1129; calcd. for C23H2037ClNO3 395.1102; found
395.1108.
Eur. J. Org. Chem. 2012, 99–106
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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105

J. M. Aurrecoechea, R. Álvarez et al.
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Received: September 5, 2011
Published Online: November 14, 2011
106
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Eur. J. Org. Chem. 2012, 99–106