Transpositive Tandem Annulation of Phthalides with Allene Carboxylates: Regioselective Synthesis of Arylnaphthalene Lignans

Article abstract of DOI:10.1021/acs.joc.6b02313

Allene carboxylates, scarcely used as Michael acceptors, serve as acceptors in the annulation with phthalides in the presence of LDA and provide a one-pot synthesis of naphtho[c]furanones in very good yields. This tandem annulation is proposed to proceed

Full text of DOI:10.1021/acs.joc.6b02313

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Article
Transpositive tandem annulation of phthalides with allene
carboxylates: regioselective synthesis of arylnaphthalene lignans
Dipakranjan Mal, and Supriti Jana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02313 • Publication Date (Web): 27 Oct 2016
Downloaded from http://pubs.acs.org on October 30, 2016
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The Journal of Organic Chemistry
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Transpositive tandem annulation of phthalides with allene carboxylates: regioselective synthesis
of arylnaphthalene lignans
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Dipakranjan Mal*, and Supriti Jana
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Department of Chemistry, Indian Institute of Technology Kharagpur, 721302, India
ABSTRACT
Allene carboxylates, scarcely used as Michael acceptors, serve as acceptors in the annulation with
phthalides in the presence of LDA, and provide a one-pot synthesis of naphtho[c]furanones in very good
yields. This tandem annulation is proposed to proceed via transposition of the hydroxy group resulting
from the initial annulation.
INTRODUCTION
Annulations of phthalides, namely Hauser annulation1 and Sammes annulation2 are established reactions
for regiodefined synthesis of peri-oxygenated naphthalenes, anthracenes and naphthacene derivatives.
Their applications in the total synthesis of natural products are well documented in the literature.3 These
annulations have been extensively studied with conjugated carboxylates, enones, unsaturated lactones,
pyrones, benzyne precursors, sulfones, etc.4 But, no report is available on the annulation reactivity of
conjugated allene carboxylates, although they are expected to behave like an acrylate. More strikingly,
there are insignificant number of reports on their Michael addition reactivity till 1992.5 One of the
earliest examples of Michael addition of an allene-1-carboxylate is the reaction of diethylacetamido
malonate in the presence of sodium ethoxide in ethanol.6 Phosphines promoted Michael addition
reactivity of activated allenes, is however, extensively studied.7a Likewise, their [4+2] cycloaddition
reactions with unsaturated compounds have been explored for the synthesis of six membered ring
systems.7 Kita et al. and Scheinmann et al. demonstrated heteroannulation reactivity of allene-1-
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caboxylates involving hetero-Michael additions.8,9 But, their studies were confined to only one
symmetrical acceptor.10 These studies, however, revealed the possibilities of an annulation in two
distinct steps forming six-membered carbocycles.
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Prompted by these findings, we envisaged that the annulation of phthalides 1 with unsymmetrical allene
acceptors 2 would generate 1,4-naphthols 4 and 5 (Scheme 1). If path I occurs, the reaction between 1
and 2 would produce Michael adduct 3, which can further react to form naphthol 4. Alternatively, 3 can
form isomeric naphthol 5 via enolate isomerization as in path II.
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Scheme 1. Working hypothesis for the single step synthesis of 1,4-naphthoquinol 4 and 5 from
phthalides
RESULTS AND DISCUSSION
With the background in mind, we initiated this study with racemic allene-1-carboxylates 2 towards the
annulation. For the synthesis of allene carboxylates 8a-8e, we adopted synthetic protocols11 of Kwon et
al. After several experimentations, we prepared them in reasonable yields (Scheme 2). Freshly prepared
acid chlorides 7a-7e, were treated with phosphorane 6 in the presence of triethylamine in DCM at -20
oC to rt. The unknown allene esters 8d and 8e were duly characterized. The yields of the allenes 8d and
8e are delicately sensitive to reaction conditions. Some preparations required critical optimizations of
the reaction conditions.
For the initial studies, 7-methoxyphthalide (9) was reacted with allene carboxylate 8a in the presence of
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LDA in THF at -78 C to rt. Routine work-up of the reaction mixture followed by chromatographic
purification afforded a white solid. 1H NMR spectrum of the product did not match the structure of the
expected product (cf. 4 or 5). A downfield –CH2 group at δ 5.3 ppm and exchangeable hydrogen in the
spectrum led to the proposal for structure 10. It was further supported by an IR band at 1750 cm-1,
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Scheme 2. Synthesis of allene carboxylates 811
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characteristic of a 5-membered lactone ring. Having confirmed the structure 10 by HRMS data, we
optimized the reaction with bases like LiOtBu, LiHMDS, NaH, KOtBu and NaHMDS. From the results
tabulated in Table 1, it is apparent entry 5 is best set of condition for the reaction.
Table 1. Optimization of reaction conditions
With the optimized conditions (Table 1, entry 5), a range of substituted phthalides 11 and allene
carboxylates 8 were screened to establish the scope of this reaction. The reaction of simple phthalide
11a with 8a, afforded naphthofuranone 13 in 73% yield. Next, we looked into the reactivity of the
methoxy substituted phthalides, since a great majority of aromatic polyketides feature methoxy
substitutions. To this end, we prepared phthalides 11b13 following the literature method, and then
subjected it to reaction with allene carboxylate 8a. When the phthalide 11b was reacted with allene
carboxylate 8a, products 14a and 14b were obtained in 45% and 35% yields respectively.
Likewise, naphthalide 15 was obtained in 57% yield (over two steps), when the annulation of phthalide
11a with allene carboxylate 8b was conducted. The intermediate naphthalide 15a (see Experimental
Section for details), was also isolated in ~ 63% yield. Due to purification problem, it was converted into
15 in 91% yield by treating with MeI and K2CO3. On the other hand, naphthol 16a was formed in 65%
yield when 5-bromophthalide 11c was subjected to annulation with allene acceptor 8b. Similarly, 5-
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cyanophthalide 11d reacted smoothly with 8b under same reaction conditions and gave the expected
naphthol 17 in 60% yield. Naphtho[2,3-c]furan-1(3H)-one 18 was formed in 65% yield, when
dimethoxyphthalide 11e was reacted with 8b. The structure of compound 18 was confirmed by a single
crystal structure analysis (vide Supporting Information for details). The results presented in Table 2
showed that there is a great deal of flexibility in the choice of phthalides and allene esters to furnish the
corresponding naphtho[2,3-c]furan-1(3H)-ones 12 in good to excellent yields, and various functional
groups were tolerable.
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Table 2. Scope of the annulation leading to 12a
Reaction conditions: (a) LDA (3 equiv.), THF, -78 °C to rt, 6 – 7 h, quenched with 3 M HCl; (b)
MeI, K2CO3, acetone, rt, 4 - 8 h.
The substituents in 11 could be bromo, cyano, methoxy, methyl and ethyl. As for substituents in 8, it
could be an alkyl group like ethyl. These results indicate that this synthetic method is quite general for
the preparation of naphthalides with diverse substitution patterns. In certain cases, intermediate
naphthols, like 19a and 19b accompanied the naphthalide products. These naphthols could, however, be
further cyclized to the corresponding naphthalides by treating them with either mild acids or bases
(Scheme 3).
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Scheme 3. Intramolecular lactonization of 19 to lactone 13 and 14a
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The formation of naphtho[c]furanones 12 can be explained by the mechanism shown in Scheme 4. The
annulation cascade is initiated by LDA promoted generation of 3-lithiophthalides 20, which undergo
Michael addition to the central carbon of the allene carboxylate 8 to give 21a. The Dieckmann
condensation of 21a leads to the formation of 21c via tricyclic intermediate 21b. With excess of a base,
Scheme 4. Probable mechanism for the formation of naphtho[c]furanones 12
21c is further deprotonated to 22a and 22b. During work-up of the mixture, intermediates 22 combine
with H+ to give 23. Attack of H2O at the electron deficient double bond of 23 forms naphthol 24. Further
cyclization of the naphthol 24 with mild bases gives desired naphtho[c]furanones 12.
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Having established the new tandem annulation, we proceeded to find its application in the synthesis of
bioactive molecules. It is well known that arylnaphthalene lactone lignans are widely distributed in
plants.14 Structurally, they occur in various levels of oxidation. They exhibit valuable medicinal
properties like antiviral, inhibition of calcium release from a fetal long-bone culture, antimicrobial and
anti-platelet activities.15 In particular, justicidin B (25) displays anti-fungal and anti-proliferative
properties.16
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Keeping in mind the importance of lignans and structural complexity of saccharothrixones A−C17,
viridicatumtoxin D (27) and viridicatumtoxin E (28)18 (Figure 1), we planned to apply the developed
method for generation of analogues of arylnaphthalene lignans. As shown in Table 3, the annulation of
phthalides 29 with dienoates 8c-8e would give arylnaphthalene lignan analogues 30.
Figure 1. Biologically important naphtho[c]furanones
A range of the combination of substituted phthalides 29 and allene carboxylates 8 were screened to
probe the scope of this reaction. The results displayed in Table 3 showed that the reaction is robustly
general and furnished the corresponding arylnaphthofuranones 30 in good to excellent yields and
various functional groups were well tolerable. In addition to the phthalides 9, 11a and 11c-11e,
phthalides 29a-29e were also reacted with the allene acceptors 8c-8e. 6-Ethyl-7-methoxyphthalide 29a19
was compatible with the annulation reaction with 8c, forming the product 34 in 70% yield. Similarly, 4-
methoxyphthalide 29b20 and 5-methoxyphthalide 29c, upon annulation, afforded products 35 and 36 in
60% and 65% yields respectively. We then considered 3-allylphthalide 29d, to arrive at 4-substituted
naphtho[c]furanones. Phthalide 29d, prepared by the reported procedure21, was reacted with the
acceptor 8c, and naphthalide 39 was expectedly obtained in 43% yield. Next, we proceeded to check the
reactivity of the angular phthalide 29e, in view of the anomalous behaviour18 in the Hauser annulation.
It was prepared by the Yu lactonization.12 As shown in the Table 3, that the phthalide 29e was as
efficient as the other donors, and produced the expected product 40 in 72% yield. We then focused on
changing the acceptors. To this end, we synthesized new acceptors 8d and 8e in 48% and 65% yields
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The Journal of Organic Chemistry
Table 3. Scope of the annulation leading to 30a
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Reaction conditions: (a) LDA (3 equiv.), THF, -78 °C to rt, 6 – 7 h, quenched with 3 M HCl;
(b) MeI, K2CO3, acetone, rt, 4 - 8 h; (c) crude product, K2CO3, acetone, rt, 3 d.
respectively, and these were reacted with simple phthalide 11a. The desired products 41 and 42 were
obtained in 75% and 72% yields respectively. No complication arose due to a nuclear lithiation/ ortho
lithiation. Thus, the substituents in 29 could be methoxy, bromo, cyano, methyl, ethyl, etc. and those in
8 could be phenyl, 4-methoxyphenyl and 2,5-dimethoxyphenyl.
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In order to demonstrate the utility of the annulation, we synthesized a natural product, namely, justicidin
B (25). Phthalide 432f was reacted with 8a in the presence of LDA to provide 44 in 59% yield.
Naphtho[c]furanone 44 has been converted to justicidin B (25) in 2 steps (Scheme 5).15b
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Scheme 5. Formal synthesis of justicidin B (25) from an active intermediate 44
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a: it was accompanied by 16% of ethyl 6,7-dimethoxy-3-methyl-1,4-dioxo-1,4-
dihydronaphthalene-2-carboxylate (44a, see Experimental Section for details).
CONCLUSION
In conclusion, we report an unprecedented anionic cascade reaction of 2,3-butenoates (allene
carboxylates) with phthalides. It results in a regiodefined synthesis of naphtho[c]furanones. The
regiochemical outcome of the reaction suggests that the first step is a Michael addition followed by
Dieckmann condensation. The second crucial step i.e. transposition of the newly generated hydroxy
groups leads to the formation of products. Extension of the reaction to arylallene carboxylates has led to
an efficient and convenient synthesis of arylnaphthalene lignan analogues. Its synthetic utility in the
synthesis of lignans has briefly been demonstrated by the formal synthesis of justicidin B (25).
EXPERIMENTAL SECTION
General Procedures:
Melting points were determined in open end capillary tubes and are uncorrected. Solvents were dried
and distilled following the standard procedures. TLC was carried out on precoated plates (silica gel 60,
GF254), and the spots were visualized with UV and fluorescent lights. Column chromatography was
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performed on silica gel (60-120 or 230-400 mesh). H spectra for all the compounds were recorded at
400/600 MHz. Chemical shifts were quoted in parts per million (ppm) referenced to the appropriate
solvent peak or 0.0 ppm for tetramethylsilane. The following abbreviations were used to describe peak
splitting patterns when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, dd =
doublet of doublet, td = triplet of doublet, ddd = doublet of doublet of doublet, m = multiplet. Coupling
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constants, J, were reported in hertz unit (Hz). C NMR was recorded on 100 MHz and 150 MHz. The
spectra were fully decoupled by broad band proton decoupling. IR spectra were recorded on an FT-IR
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instrument using a KBr pellet. The phrase “usual workup” or “worked up in usual manner” refers to
washing of the organic phase with water (2 x 1/3 the volume of the organic phase) and brine (1 x 1/4 the
volume of the organic phase), drying (anhydrous Na2SO4), filtration, and concentration under reduced
pressure.
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General Procedure for the preparation of allene carboxylates11:
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Et3N
(5.5
mmol,
1.1
equiv)
was
added
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stirred
solution
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(carbethoxymethylene)triphenylphosphorane (6) (5 mmol, 1 equiv.) in CH2Cl2 (20 mL). After stirring
for 10 min, the required acyl chloride 7 (5 mmol, 1 equiv.) was added drop wise over 10 min at -20 oC
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to 0 C. After stirring overnight, the resulting mixture was poured unto a Büchner funnel packed with
silica gel and was washed with CH2Cl2 several times. The combined filtrate was carefully concentrated
and the resulting crude oil was purified by flash column chromatography (hexane/EtOAc, 20:1) to
provide the 4-substituted 2,3-butadienoates 8.
Ethyl buta-2,3-dienoate (8a22):
Yield: 67%; 1H NMR (600 MHz, CDCl3): δ 5.62 (t, J = 6.6 Hz, 1H), 5.21 (d, J = 6.6 Hz, 2H), 4.20 (q, J
= 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H); NMR (150 MHz, CDCl3) δ 215.7, 165.7, 88.0, 79.2, 61.0, 14.2.
Ethyl hexa-2,3-dienoate (8b23):
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Yield: 97%; H NMR (600 MHz, CDCl3): δ 5.69-5.59 (m, 2H), 4.21-4.17 (m, 2H), 2.18-2.13 (m, 2H),
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2.28 (m, 3H), 1.07 (m, 3H); C NMR (100 MHz, CDCl3) δ 212.1, 166.3, 97.1, 88.9, 60.7, 20.8, 14.2,
13.0.
Ethyl 4-phenylbuta-2,3-dienoate (8c24):
Yield: 53%; 1H NMR (400 MHz, CDCl3): δ 7.36-7.261 (m, 5H), 6.63 (d, J = 6.0 Hz, 1H), 6.02 (d, J =
13
6.4 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 214.8,
165.3, 131.3, 129.0, 128.3, 127.7, 98.8, 92.1, 61.3, 14.4.
Ethyl 4-(4-methoxyphenyl)buta-2,3-dienoate (8d25):
Yield: 48%; 1H NMR (400 MHz, CDCl3): δ 7.23 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.59 (d, J
= 6.4 Hz, 1H), 5.99 (d, J = 6.0 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 214.7, 165.4, 159.7, 128.9, 123.4, 114.5, 98.3, 92.0, 61.8, 55.5, 14.4.
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Ethyl 4-(2,5-dimethoxyphenyl)buta-2,3-dienoate (8e):
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According to the general procedure for the preparation of allene carboxylates, the reaction of
triethylamine (0.8 mL, 5.5 mmol), (carbethoxymethylene)triphenylphosphorane (1.8 gm, 5.0 mmol) and
2,5-dimethoxyphenyl acetylchloride (1.1 gm, 5.0 mmol), we got ethyl 4-(2,5-dimethoxyphenyl)buta-
2,3-dienoate (8e) (805 mg, 65%) as brown oil. 1H NMR (400 MHz, CDCl3): δ 6.97 (d, J = 6.4 Hz, 1H),
6.86 (s, 1H), 6.80 (brs, 2H), 5.98 (d, J = 6.4 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.79 (s, 3 H), 3.75 (s,
3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 215.5, 165.5, 153.9, 151.0, 120.7, 114.7,
113.9, 112.6, 93.2, 91.4, 61.2, 56.5, 55.9, 14.4; HRMS (ESI) calcd. for C14H16O4 [M-C2H4+H]+
221.0814, found 221.0818.
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Method A: General Annulation Procedure with LDA. In a flame-dried flask, LDA (3.2 mmol) was
prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine (3.2 mmol)
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in THF (10 mL) at -78 C under nitrogen atmosphere. After 30 min at -78 C, an appropriate phthalide
(1 mmol) in THF (5 mL) was added drop wise over 15 min. The reaction mixture was stirred at -78 oC
for 30 min, and then a solution of the appropriate Michael acceptor (1.2 mmol) in THF (5 mL) was
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added drop wise over 15 min at -78 C. The reaction mixture was further stirred for 1 h at the same
temperature and allowed to warm under ambient conditions to room temperature over 5-6 h. The
solution was then quenched with 3 M HCl (15 mL) or saturated ammonium chloride solution (15 mL).
The resulting mixture was concentrated under reduced pressure and the residue extracted with ethyl
acetate (3 x 50 mL). The combined extracts were washed with brine (3 1/3 vol), dried (Na2SO4), and
concentrated to obtain the crude product, which was purified by column chromatography on silica gel
using ethyl acetate in petroleum ether to afford the pure products.
Method B: General Annulation Procedure with LiHMDS. To a stirred solution of lithium
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hexamethyldisilazide (3.2 mmol) in THF (10 mL) at -78 C under an inert atmosphere was added a
solution of phthalide (1 mmol) in THF (5 mL). The resulting yellow solution was stirred at -78 oC for 30
min, after which a solution of a Michael acceptor (1.2 mmol) in THF (5 mL) was added to it. The
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cooling bath was removed after about 1 h at -78 C, and the reaction mixture was brought to room
temperature over a period of 1 h and further stirred for 5-6 h. The reaction was then quenched with 3 M
HCl (15 mL), and the resulting solution was concentrated under reduced pressure. The residue was
diluted with ethyl acetate (3 x 50 mL), and the layers were separated. The combined extracts were
washed with brine (3 x1/3 vol), dried (Na2SO4), and concentrated to provide the crude product. The
crude solid product was purified by column chromatography on silica gel using ethyl acetate in
petroleum ether to obtain a pure product.
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General Procedure for the protection of –OH group by MeI and K2CO3:
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To a stirred solution of naphthol compound (1.0 mmol) in 10 mL dry acetone, K2CO3 (5.0 mmol) was
added at 0 oC. After 30 min, MeI (5.0 mmol) was added. Then the reaction further stirred for another 6-
10 h at rt. After completion of reaction (checked by TLC), acetone was evaporated under reduced
pressure. The reaction was extracted with ethyl acetate, extracts were washed with brine (3 x1/3 vol),
dried (Na2SO4), and concentrated to provide the crude product. The crude solid product was purified by
column chromatography on silica gel using ethyl acetate in petroleum ether to obtain a pure product.
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9-Hydroxy-8-methoxynaphtho[2,3-c]furan-1(3H)-one (10):
According to the general procedure for annulation (method A), the condensation of 7-methoxyphthalide
9 (164 mg, 1 mmol) with ethyl buta-2,3-dienoate 8a (134.5 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(3.2 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 10 as a white
o
solid (207 mg, 90%), mp 143-145 C. νmax (KBr, cm-1): 3318, 1750, 1606, 1458, 1380, 1364, 1157o,
1080, 1034, 755, 626; 1H NMR (600 MHz, CDCl3): δ 10.47 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.46 (d, J
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= 7.8 Hz, 1H), 7.25 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.35 (s, 2H), 4.12 (s, 3H); C NMR (150 MHz,
CDCl3): δ 169.5, 158.3, 156.8, 142.9, 140.3, 129.4, 121.8, 114.6, 110.8, 106.3, 104.9, 68.6, 56.6; HRMS
(ESI) calcd. for C13H10O4 [M+H]+ 231.0657, found 231.0649.
9-Hydroxynaphtho[2,3-c]furan-1(3H)-one (1315b):
According to the general procedure for annulation, the condensation of simple phthalide 11a (134 mg, 1
mmol) with ethyl buta-2,3-dienoate 8a (134.5 mg, 1.2 mmol) in the presence LDA (3.2 mmol), was
prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine (3.2 mmol)
in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced a mixture of compound 13 (40.5%) and
19a (35%), the mixture of two compounds on treatment with K2CO3 in acetone produced 13 as a white
solid ( 146 mg, 73%). 1H NMR (400 MHz, CDCl3): δ 8.6 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.85 (d, J =
13
8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 5.47 (s, 2H); C NMR (100 MHz,
CDCl3): δ 173.2, 155.1, 139.0, 138.6, 129.8, 128.0, 125.8, 123.5, 111.8, 104.6, 70.7 ; HRMS (ESI)
calcd. for C12H8O3 [M+H]+ 201.0552, found 201.0546.
9-Hydroxy-6-methoxy-8-methylnaphtho[2,3-c]furan-1(3H)-one (14a):
According to the general procedure for annulation, the condensation of phthalide 11b (366.5 mg, 2
mmol) with ethyl buta-2,3-dienoate 8a (269 mg, 2.4 mmol) in the presence LDA (6.4 mmol), was
prepared by adding n-BuLi (6.4 mmol, 1.6 M in hexane) in a solution of diisopropylamine (6.4 mmol)
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in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 14a as a white solid ( 97.72
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mg, 20%), mp 146-148 C. Compound 14a was formed along with 35% of 14b and 25% of 19b.
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Compound 19b was converted to 14a in 95% yield on the treatment of K2CO3 in acetone. Overall yield
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of 14a is 44% (215 mg). νmax (KBr, cm-1): 3378, 2928, 1749, 1649, 1345, 1220, 760; H NMR (400
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MHz, CDCl3): δ 9.10 (s, 1H), 7.16 (s, 1H), 5.12 (s, 2H), 5.39 (s, 2H), 3.92 (s, 3H), 2.93 (s, 3H); C
9
NMR (100 MHz, CDCl3): δ 174.1, 159.9, 158.2, 142.9, 140.0, 139.8, 120.5, 118.1, 111.2, 104.7, 103.6,
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70.2, 55.3, 24.2, 14.2; HRMS (ESI) calcd. for C14H12O4 [M+H]+ 245.0814, found 245.0820.
Ethyl 6-methoxy-3,8-dimethyl-1,4-dioxo-1,4-dihydronaphthalene-2-carboxylate (14b):
According to the general procedure for annulation, the condensation of phthalide 11b (366.5 mg, 2
mmol) with ethyl buta-2,3-dienoate 8a (269 mg, 2.4 mmol) in the presence LDA (6.4 mmol), was
prepared by adding n-BuLi (6.4 mmol, 1.6 M in hexane) in a solution of diisopropylamine (6.4 mmol)
in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 14b as a yellow solid (
201.8 mg, 35%), mp 120-122 oC as a by-product. νmax (KBr, cm-1): 2932, 1768, 1687, 1598, 1276, 1220,
773 ; 1H NMR (600 MHz, CDCl3): δ 7.52 (d, J = 3.0 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 4.46 (q, J = 7.2
Hz, 2H), 3.95 (s, 3H), 2.73 (s, 3H), 2.15 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3):
δ 185.4, 182.4, 165.2, 162.9, 144.6, 141.3, 141.2, 135.3, 123.5, 122.8, 109.6, 62.0, 55.8, 22.9, 14.23,
13.4; HRMS (ESI) calcd. for C16H16O5 [M+H]+ 289.1076, found 289.1063.
Ethyl 1-hydroxy-3-(1-hydroxypropyl)-2-naphthoate (15a):
According to the general procedure for annulation , the condensation of simple phthalide 11a (134 mg,
1 mmol) with ethyl hexa-2,3-dienoate 8b (168.2 mg, 1.2 mmol) in the presence LDA (3.2 mmol), was
prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine (3.2 mmol)
in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 15a as a white solid ( 172.8
mg, 63%), mp 145-147 oC. νmax (KBr, cm-1): 3420, 2934, 1668, 1560, 1345, 1120; 1H NMR (400 MHz,
CDCl3): δ 12.58 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.59-7.57 (m,
1H), 7.50-7.47 (m, 1H), 5.43-5.41 (m, 1H), 4.50-4.47 (m, 2H), 1.93-1.85 (m, 1H), 1.69-1.62 (m, 1H),
1.47 (t, J = 7.2 Hz, 3H), 1.06 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 172.0, 162.4, 142.1,
136.0,129.9, 127.6, 125.8, 124.1, 116.1, 104.5, 84.1, 73.1, 62.2, 32.3, 14.3, 10.9; HRMS (ESI) calcd. for
C16H18O4 [M-H2O+H]+ 257.1177, found 257.1173.
3-Ethyl-9-methoxynaphtho[2,3-c]furan-1(3H)-one (15):
According to the general procedure for the protection of –OH group, a reaction of compound 15a (172.8
mg, 0.63 mmol) with K2CO3 (435 mg, 3.15 mmol) and MeI (0.20 mL, 3.15 mmol), 15 was obtained as a
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white solid (139.5mg, 91%), mp 135-137 oC. 1H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 8.4 Hz, 1H),
8.86 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.47 (s, 1H), 5.53-5.51 (m,
1H), 4.39 (s, 3H), 2.21-2.15 (m, 1H), 1.93-1.86 (m, 1H), 1.04 (t, J = 8.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 168.5, 157.8, 145.1, 137.9, 129.6, 128.0, 127.9, 126.4, 124.4, 114.8, 111.6, 81.57, 64.0, 28.6,
8.9; HRMS (ESI) calcd. for C15H14O3 [M+H]+ 243.1021, found 243.1026
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6-Bromo-3-ethyl-9-hydroxynaphtho[2,3-c]furan-1(3H)-one (16a):
According to the general procedure for annulation, the condensation of 6-bromophthalide 11c (319.5
mg, 1.5 mmol) with ethyl hexa-2,3-dienoate 8b (252.3 mg, 1.8 mmol) in the presence LDA (4.8 mmol),
was prepared by adding n-BuLi (4.8 mmol, 1.6 M in hexane) in a solution of diisopropylamine (4.8
mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 16a as a white solid (
o
1
300.0 mg, 65%), mp 152-154 C. νmax (KBr, cm-1): 3345, 2928, 2851, 2340, 1758, 772; H NMR (400
MHz, CDCl3): δ 8.66 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.62 (dd, J = 1.6 Hz, 8.8 Hz, 1H),
13
7.19 (s, 1H), 5.60-5.59 (m, 1H), 2.20-2.13 (m, 1H), 1.97-1.89 (m, 1H), 1.05 (t, J = 7.6 Hz, 3H); C
NMR (150 MHz, CDCl3): δ 172.5, 155.1, 144.2, 139.6, 130.4, 129.4, 125.3, 124.7, 122.2, 110.8, 105.8,
84.1, 28.2, 8.9; HRMS (ESI) calcd. for C14H11BrO3 [M+H]+ 306.9970, found 306.9976.
6-Bromo-3-ethyl-9-methoxynaphtho[2,3-c]furan-1(3H)-one (16b):
According to the general procedure for the protection of –OH group, a reaction of compound 16a (300
mg, 0.98 mmol) with K2CO3 (675 mg, 4.9 mmol) and MeI (0.3 mL, 4.9 mmol), compound 16b was
obtained as a white solid (292.5 mg, 93%), mp 164-166 oC.1H NMR (600 MHz, CDCl3): δ 8.28 (d, J =
9.2 Hz, 1H), 8.02 (s, 1H), 7.62 (dd, J = 2.0 Hz, 9.2 Hz, 1H), 7.36 (s, 1H), 5.53-5.50 (m, 1H), 4.40 (s,
3H), 2.21-2.14 (m, 1H), 1.92 (m, 1H), 1.04 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.1,
157.9, 146.6, 138.8, 129.9, 129.9, 126.6, 126.2, 124.5, 113.6, 111.6, 81.5, 64.2, 28.6, 8.9; HRMS (ESI)
calcd. for C15H13BrO3 [M+H]+ 321.0126, found 321.0121.
3-Ethyl-9-hydroxy-1-oxo-1,3-dihydronaphtho[2,3-c]furan-6-carbonitrile (17):
According to the general procedure for annulation, the condensation of 6-cyanophthalide 11d (159 mg,
1 mmol) with ethyl hexa-2,3-dienoate 8b (168.2 mg, 1.2 mmol) in the presence LDA (3.2 mmol), was
prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine (3.2 mmol)
in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 17 as a pale yellow solid (
151.8 mg, 60%), mp 149-151 oC. νmax (KBr, cm-1): 3324, 2925, 1756, 1588, 1455, 1219, 772; 1H NMR
(600 MHz, CDCl3): δ 8.78 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 8.25 (s, 1H), 7.71 (dd, J = 1.2 Hz, 8.4 Hz,
1H), 7.39 (s, 1H), 5.68-5.66 (m, 1H), 2.24-2.20 (m, 1 H), 2.00-1.95 (m,1H), 1.09 (t, J = 7.8 Hz, 3H); 13C
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NMR (150 MHz, CDCl3): δ 172.1, 154.7, 144.8, 137.2, 134.1, 126.5, 125.1, 118.6, 113.3, 112.1, 107.9,
84.2, 28.2, 9.0; HRMS (ESI) calcd. for C15H11NO3 [M+H]+ 254.0817, found 254.0813.
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3-Ethyl-9-hydroxy-7,8-dimethoxynaphtho[2,3-c]furan-1(3H)-one (18):
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According to the general procedure for annulation, the condensation of 6,7-dimethoxy phthalide 11e
(194.2 mg, 1 mmol) with ethyl hexa-2,3-dienoate 8b (168.2 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(3.2 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 18 as a pale
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yellow solid ( 187.4 mg, 65%), mp 145-147 C. The structure of compound 18 was confirmed by a
single crystal structure analysis (vide Supporting Information for details) νmax (KBr, cm-1): 3342, 2934,
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1752, 1634, 1460, 1102; H NMR (600 MHz, CDCl3): δ 10.77 (s, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.43
(d, J = 9.6 Hz, 1H), 7.17 (s, 1H), 5.48-5.5.46 (m, 1H), 4.14 (s, 3H), 4.03 (s, 3H), 2.16-2.12 (m, 1H),
1.91-1.86 (m, 1H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): δ 169.6, 155.6, 148.0, 145.2,
143.6, 134.4, 125.2, 118.5, 118.1, 110.7, 107.1, 81.5, 62.5, 57.2, 28.5, 8.9; HRMS (ESI) calcd. for
C16H16O5 [M+H]+ 289.1076, found 289.1075.
Ethyl 1-hydroxy-3-(hydroxymethyl)-2-naphthoate (19a):
According to the general procedure for annulation, the condensation of simple phthalide 11a (134 mg, 1
mmol) with ethyl buta-2,3-dienoate 8a (134.5 mg, 1.2 mmol) in the presence LDA (3.2 mmol), was
prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine (3.2 mmol)
in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 19a as a white solid ( 98.5
mg, 35%), mp 143-145 oC. νmax (KBr, cm-1): 3411, 2850, 1735, 1630, 1498, 1320, 1182, 1072, 920, 765;
1H NMR (400 MHz, CDCl3): δ 12.82, 8.41 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0, 1H), 7.65-7.61 (m, 1H),
7.56-7.53 (m, 1H), 7.35 (s, 1H), 5.05 (s, 2H), 4.54 (q, J = 7.2, 2H), 1.53 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 171.7, 163.3, 135.5, 133.6, 130.2, 127.5, 126.7, 125.3, 124.3, 122.1, 104.5, 62.4,
48.1, 14.1; HRMS (ESI) calcd. for C14H14O4 [M-H2O+H]+ 229.0864, found 229.0869.
Ethyl 1-hydroxy-3-(hydroxymethyl)-6-methoxy-8-methyl-2-naphthoate (19b):
According to the general procedure for annulation, the condensation of phthalide 11b (366.5 mg, 2
mmol) with ethyl buta-2,3-dienoate 8a (269 mg, 2.4 mmol) in the presence LDA (6.4 mmol), was
prepared by adding n-BuLi (6.4 mmol, 1.6 M in hexane) in a solution of diisopropylamine (6.4 mmol)
in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 19b as a white solid ( 145.2
o
mg, 25%), mp 132-134 C. νmax (KBr, cm-1): 3448, 2989, 1733, 1654, 1596, 1384, 1314, 1247, 1222,
1338, 1065, 874, 722; 1H NMR (600 MHz, CDCl3): δ 13.34 (s, 1H), 7.19 (s, 1H), 6.91 (s, 1H), 6.86 (d,
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J = 1.2 Hz, 1H), 5.00 (s, 2H), 4.53 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 2.93 (s, 3H), 1.52 (t, J = 7.2 Hz,
3H); 13C NMR (150 MHz, CDCl3): δ 172.1, 166.4, 160.1, 140.8, 139.4, 133.8, 121.8, 121.1, 119.5,
104.7, 102.8, 62.0, 55.3, 48.1, 25.1, 14.0; HRMS (ESI) calcd. for C16H18O5 [M-H2O+H]+ 273.1126,
found 273.1124.
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9-Hydroxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (31a):
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According to the general procedure for annulation, the condensation of simple phthalide 11a (134 mg, 1
mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (225.8 mg, 1.2 mmol) in the presence LDA (3.2 mmol),
was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine (3.2
mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 31a as a colorless
o
liquid ( 207 mg, 75 %), mp 152-154 C. νmax (KBr, cm-1): 3413, 2918, 2850, 1726, 1640, 1598, 1319,
1082, 1072, 910, 765; 1H NMR (600 MHz, CDCl3): δ 8.71 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.80 (d, J
= 8.4 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.43-7.42 (m, 3H), 7.39-7.38 (m, 2H),
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7.23 (s, 1H), 6.58 (s, 1H); C NMR (150 MHz, CDCl3): δ 172.6, 154.9, 142.4, 138.6, 136.8, 129.8,
129.4, 129.0, 128.2, 127.2, 126.0, 123.6, 123.5, 113.0, 104.7, 84.1; HRMS (ESI) calcd. for C18H12O3
[M+H]+ 277.0865, found 277.0862.
9-Methoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (31b):
According to the general procedure for the protection of –OH group, a reaction of 31a (207 mg, 0.75
mmol), K2CO3 (517.5 mg, 3.75 mmol) and MeI (0.25 mL, 3.75 mmol), 31b was obtained as a white
solid (209.0 mg, 96%), mp 159-161 oC. νmax (KBr, cm-1): 2924, 2852, 1759, 1630, 1583, 1458, 1336,
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1290, 1088, 912, 764, 705; H NMR (600 MHz, CDCl3): δ 8.46 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4
Hz, 1H), 7.65-7.63 (m, 1H), 7.60-7.57 (m, 1H), 7.42-7.37 (m, 6H), 6.50 (s, 1H), 4.48 (s, 3H); 13C NMR
(150 MHz, CDCl3): δ 168.1, 157.8, 144.9, 137.9, 137.6, 129.6, 129.2, 129.0, 127.9, 127.1, 126.5, 124.3,
116.1, 110.5, 82.0, 64.0; HRMS (ESI) calcd. for C19H14O3 [M+H]+ 291.1021, found 291.1035.
6-Bromo-9-hydroxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (32):
According to the general procedure for annulation, the condensation of 6-bromophthalide 11c (213 mg,
1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (225.8 mg, 1.2 mmol) in the presence LDA (4.8
mmol), was prepared by adding n-BuLi (4.8 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(4.8 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 32 as a light
o
yellow solid ( 230.5 mg, 65%), mp 165-167 C. νmax (KBr, cm-1): 3398, 1725, 1612, 1251, 1076, 991,
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750; H NMR (400 MHz, DMSO-d6): δ 11.32 (brs, 1H), 7.28 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 1.6 Hz,
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1H), 7.67 (dd, J = 1.2 Hz, 8.8 Hz, 1H), 7.43-7.34 (m, 5H), 7.26 (s, 1H), 6.71 (s, 1H); C NMR (150
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MHz, CDCl3): δ 169.4, 154.9, 146.5, 139.7, 138.5, 130.6, 129.7, 129.6, 127.7, 126.5, 124.0, 112.1,
106.2, 81.7; HRMS (ESI) calcd. for C18H11BrO3 [M+H]+ 354.9970, found 354.9974.
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9-Hydroxy-1-oxo-3-phenyl-1,3-dihydronaphtho[2,3-c]furan-6-carbonitrile (33):
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According to the general procedure for annulation , the condensation of 6-cyanophthalide 11d (159 mg,
1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (225.8 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(3.2 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 33 as a pale
yellow solid ( 135.5 mg, 45%), mp 168-170 oC. νmax (KBr, cm-1): 3368, 2936, 1734, 1653, 1127, 1075,
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697; H NMR (400 MHz, CDCl3): δ 8.80 9s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.16 (s, 1H), 7.70 (d, J =
8.8 Hz, 1H), 7.43-7.34 (m, 5H), 7.28 (s, 3H), 6.60 (s, 1H); 13C NMR (150 MHz, CDCl3): δ 171.9,
154.7, 144.6, 137.4, 136.1, 134.1, 129.9, 129.3, 127.2, 126.7, 125.2, 125.2, 118.5, 113.5, 113.5, 107.3,
84.3; HRMS (ESI) calcd. for C19H11NO3 [M+H]+ 302.0817, found 302.0810.
7-Ethyl-9-hydroxy-8-methoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (34):
According to the general procedure for annulation, the condensation of 6-ethyl-7-
methoxyisobenzofuran-1(3H)-one 29a (97 mg, 0.5 mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (113
mg, 0.6 mmol) in the presence LDA (1.6 mmol), was prepared by adding n-BuLi (1.6 mmol, 1.6 M in
hexane) in a solution of diisopropylamine (1.6 mmol) in THF (10 mL) at -78 ºC under nitrogen
o
atmosphere, produced compound 34 as a light red solid ( 117.1 mg, 70%), mp 158-160 C. νmax (KBr,
1
cm-1): 3378, 1735, 1632, 1231, 1046, 945, 730; H NMR (400 MHz, CDCl3): δ 10.60 (brs, 1H), 7.52-
7.44 (m, 2H), 7.37-7.34 (m, 1H), 7.10 (s, 1H), 6.43 (s, 1H), 3.99 (s, 1H), 2.84 (q, J = 7.6 Hz, 2H), 1.32
13
(t, J = 7.6 Hz, 3H); C NMR (150 MHz, CDCl3): δ 169.9, 155.5, 155.0, 144.5, 139.1, 137.4, 133.0,
131.7, 129.1, 128.9, 127.0, 125.2, 117.4, 112.3, 106.1, 82.0, 63.5, 22.03, 15.0; HRMS (ESI) calcd. for
C21H18O4 [M+H]+ 335.1283, found 335.1286.
9-Hydroxy-5-methoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (35):
According to the general procedure for annulation, the condensation of 4-methoxyphthalide 29b (164
mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (225.8 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(3.2 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 35 as a white
solid (183.6 mg, 60%), mp 150-152 oC. νmax (KBr, cm-1): 3408, 1728, 1615, 1232, 1026, 750; 1H NMR
(600 MHz, CDCl3): δ 8.63 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.41-
7.38 (m, 5H), 7.00 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 3.98 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 172.7,
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155.4, 154.5, 141.7, 136.9, 130.8, 129.4, 129.0, 127.3, 126.1, 124.6, 115.3, 107.7, 107.6, 105.2, 55.6;
HRMS (ESI) calcd. for C19H14O4 [M+H]+ 307.0970, found 307.0976.
1
2
3
4
5
9-Hydroxy-6-methoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (36):
6
7
8
9
According to the general procedure for annulation, the condensation of 6-methoxyphthalide 29c (164
mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (225.8 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(3.2 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 36 as a white
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19
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29
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34
35
36
37
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44
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46
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53
54
55
56
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60
o
solid (199 mg, 65%), mp 148-150 C. νmax (KBr, cm-1): 3414, 2930, 1720, 1615, 1451, 1370, 1287,
1219, 1072, 1030, 755, 699; 1H NMR (600 MHz, CDCl3): δ 8.60 (s, 1H), 8.30 (d, J = 9.6 Hz, 1H), 7.41
(brs, 3 H), 7.38 (brs, 2H), 7.21 (d, J = 9.0 Hz, 1H), 7.09 (s, 1H), 7.07 (s, 1H), 6.53 (s, 1H), 3.92 (s, 3H);
13C NMR (150 MHz, CDCl3): δ 172.6, 160.8, 154.9, 143.7, 140.9, 136.9, 129.4, 129.0, 127.1, 125.1,
118.6, 118.5, 111.7, 106.5, 103.2, 83.8, 55.4; HRMS (ESI) calcd. for C19H14O4 [M+H]+ 307.0970, found
307.0973.
9-Hydroxy-8-methoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (37a):
According to the general procedure for annulation, the condensation of 7-methoxyphthalide 9 (164 mg,
1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (225.8 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(3.2 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 37a as a white
o
solid (214.2 mg, 70%), mp 155-157 C. νmax (KBr, cm-1): 3442, 1752, 1613, 1363, 1268, 1198, 1066,
974, 716; 1H NMR (600 MHz, CDCl3): δ 10.53 (s, 1H), 7.48-7.37 (m, 7H), 7.10 (s, 1H), 6.88 (d, J = 7.8
13
Hz, 1H), 6.43 (s, 1H), 4.15 (s, 3H); C NMR (150 MHz, CDCl3): δ 168.9, 158.3, 156.7, 146.2, 140.4,
137.6, 129.4, 129.1, 128.9, 127.0, 122.0, 114.8, 11.9, 106.1, 105.0, 81.5, 56.6; HRMS (ESI) calcd. for
C19H14O4 [M+H]+ 307.0970, found 307.0969.
8,9-Dimethoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (37b):
According to the general procedure for the protection of –OH group, a reaction of compound 37a (214.2
mg, 0.70 mmol), K2CO3 (483.0 mg, 3.5 mmol) and MeI (0.22 mL, 3.5 mmol), compound 37b was
1
obtained as colorless oil (206.3 mg, 92%). H NMR (600 MHz, CDCl3): δ 7.52 (t, J = 8.4 Hz, 1H),
13
7.43-7.28 (m, 7H), 6.92 (d, J = 7.2 Hz, 1H), 6.44 (s, 1H), 4.21 (s, 3H), 4.06 (s, 3H); C NMR (150
MHz, CDCl3): δ 167.9, 158.5, 141.0, 137.5, 129.7, 129.2, 129.0, 127.0, 120.8, 120.7, 117.1, 113.9,
106.5, 81.21, 63.8, 56.4; HRMS (ESI) calcd. for C20H16O4 [M+H]+ 321.1127, found 321.1124.
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9-Hydroxy-7,8-dimethoxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (38):
1
2
3
4
5
6
7
8
9
According to the general procedure for annulation, the condensation of 6,7-dimethoxy phthalide 11e
(194.2 mg, 1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (225.8 mg, 1.2 mmol) in the presence
LDA (3.2 mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of
diisopropylamine (3.2 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced
o
compound 38 as a pale yellow solid ( 302.4 mg, 90%), mp 156-158 C. νmax (KBr, cm-1): 3447, 1750,
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11
12
13
14
15
16
17
18
19
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34
35
36
37
38
39
40
41
42
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44
45
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48
49
50
51
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58
59
60
1617, 1373, 1278, 1198, 1115, 1066, 974, 706; 1H NMR (600 MHz, CDCl3): δ 10.9 (s, 1H), 7.53 (d, J =
13
9.6 Hz, 1H), 7.40-7.37 (m, 5H), 7.39 (s, 1H), 6.41 (s, 1H), 4.16 (s, 3H), 4.02 (s, 3H); C NMR (150
MHz, CDCl3): δ 169.2, 155.5, 148.0, 145.0, 143.4, 137.8, 134,3, 129.1, 128.9, 126.9, 125.2, 118.4,
118.0, 11.9, 106.1, 81.7, 62.4, 57.0; HRMS (ESI) calcd. for C20H16O5 [M+H]+ 337.1076, found
337.1065.
4-Allyl-9-hydroxy-3-phenylnaphtho[2,3-c]furan-1(3H)-one (39):
According to the general procedure for annulation, the condensation of 3-allyl phthalide 29d (174.2 mg,
1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (225.8 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
o
(3.2 mmol) in THF (10 mL) at -78 C under nitrogen atmosphere, produced compound 39 as a pale
yellow solid ( 136 mg, 43%), mp 167-169 oC. νmax (KBr, cm-1): 3356, 1732, 1634, 1257, 1058, 723; 1H
NMR (600 MHz, CDCl3): δ 8.73 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.69 (t, J =
7.2 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.41-7.38 (m, 2H), 7.30 (brs, 2H), 6.53 (s, 1H), 5.60-5.56 (m, 1H),
4.87 (d, J = 10.2 Hz, 1H), 4.72 (d, J = 17.4 Hz, 1H), 3.52 (dd, J = 4.8 Hz, 16.2 Hz, 1H), 3.37 (dd, J =
6.0 Hz, 16.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 172.8, 154.0, 139.9, 137.6, 136.3, 134.6, 129.8,
129.2, 128.6, 125.8, 124.6, 124.2, 121.7, 116.3, 104.8, 84.7, 31.9; HRMS (ESI) calcd. for C21H16O3
[M+H]+ 317.1178, found 317.1175.
11-Hydroxy-8-phenylphenanthro[2,3-c]furan-10(8H)-one (40):
According to the general procedure for annulation, the condensation of angular phthalide 29e (185 mg,
1 mmol) with ethyl 4-phenylbuta-2,3-dienoate 8c (225.8 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(3.2 mmol) in THF (10 mL) at -78 oC under nitrogen atmosphere, produced compound 40 as a colorless
liquid ( 235 mg, 72%). νmax (KBr, cm-1): 3411, 2928, 1736, 1630, 1578, 1309, 1182, 1052, 910, 745; 1H
NMR (600 MHz, CDCl3): δ 9.81 (s, 1H), 9.73 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.89 (d, J =
9.0 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.70-7.66 (m, 2H), 7.45-7.39 (m, 5H), 7.32 (s, 1H), 6.61 (s, 1H);
13C NMR (150 MHz, CDCl3): δ 173.6, 157.4, 144,32, 140.4, 136.4, 132.3, 131.8, 130.8, 129.7, 129.2,
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128.6, 128.5, 128.0, 127.4, 127.0, 119.2, 114.1, 107.5, 84.0; HRMS (ESI) calcd. for C22H14O3 [M+H]+
327.1021, found 327.1031.
1
2
3
4
5
9-Hydroxy-3-(4-methoxyphenyl)naphtho[2,3-c]furan-1(3H)-one (41):
6
7
8
9
According to the general procedure for annulation, the condensation of simple phthalide 11a (134 mg, 1
mmol) with ethyl 4-(4-methoxyphenyl)buta-2,3-dienoate 8d (261.6 mg, 1.2 mmol) in the presence LDA
(3.2 mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of
10
11
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36
37
38
39
40
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48
49
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59
60
o
diisopropylamine (3.2 mmol) in THF (10 mL) at -78 C under nitrogen atmosphere, produced
compound 41 as a white solid ( 230 mg, 75 %), mp 156-158 C. νmax (KBr, cm-1): 3320, 1751, 1610,
o
1
1438, 1345, 1215, 1137, 1040, 755; H NMR (600 MHz, CDCl3): δ 8.72 (s, 1H), 8.42 (d, J = 8.4 Hz,
1H), 7.80 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 9.0 Hz, 2H),
13
7.21 (S, 1H), 6.93 (d, J = 9.0 Hz), 6.55 (s, 1H), 3.84 (s, 3H); C NMR (150 MHz, CDCl3): δ 172.7,
160.7, 155.0, 142.7, 138.8, 129.9, 129.2, 128.8, 128.4, 126.1, 123.8, 123.6, 114.5, 113.2, 105.2, 84.3,
55.5; HRMS (ESI) calcd. for C19H14O4 [M+Na]+ 329.0790, found 329.0776.
3-(2,5-Dimethoxyphenyl)-9-hydroxynaphtho[2,3-c]furan-1(3H)-one (42):
According to the general procedure for annulation, the condensation of simple phthalide 11a (134 mg, 1
mmol) with ethyl 4-(4-methoxyphenyl)buta-2,3-dienoate 8e (298.0 mg, 1.2 mmol) in the presence LDA
(3.2 mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of
o
diisopropylamine (3.2 mmol) in THF (10 mL) at -78 C under nitrogen atmosphere, the crude product
was immediately treated with approximately 5 equiv. of K2CO3 in acetone and reaction was stirred for 3
days at rt, produced compound 42 as a white solid ( 242 mg, 72 %), mp 154-156 C. νmax (KBr, cm-1):
o
1
3412, 1748, 1626, 1324, 1278, 1158, 1105, 1046, 954, 770; H NMR (600 MHz, CDCl3): δ 8.70 (s,
1H), 8.40 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H),
7.31 (s, 1H), 6.57 (s, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.89 (dd, J = 3.0 Hz, 9.0 Hz, 1H), 6.73 (d, J = 3.0
13
Hz, 1H), 3.92 (s, 3H), 3.71 (s, 3H); C NMR (100 MHz, CDCl3): δ 173.1, 154.9, 153.9, 151.5, 142.9,
138.8, 129.7, 128.4, 126.5, 125.9, 123.7, 123.6, 115.0, 113.2, 113.0, 112.5, 104.9, 56.4, 55.9; HRMS
(ESI) calcd. for C20H16O5 [M+Na]+ 359.0895, found 359.0880.
9-Hydroxy-6,7-dimethoxynaphtho[2,3-c]furan-1(3H)-one (4415b):
According to the general procedure for annulation, the condensation of 5,6-dimethoxy phthalide 43
(194 mg, 1 mmol) with ethyl buta-2,3-dienoate 8a (134.5 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(3.2 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, after usual workup we treated the
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crude reaction with K2CO3 in acetone and the reaction was stirred for 2 h, produced compound 44 as a
1
2
3
1
white solid ( 153.5 mg, 59%). Along with compound 44, compound 44a was formed in 14% yield. H
4
5
6
7
NMR (400 MHz, CDCl3): δ 8.45 (brs, 1H), 7.59 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 5.42 (s, 2H), 4.06 (s,
3H), 4.04 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 173.4, 153.5, 152.5, 149.4, 138.2, 135.4, 118.4,
110.3, 106.5, 103.7, 101.6, 70.6, 56.1, 56.0.
8
9
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37
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40
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Ethyl 6,7-dimethoxy-3-methyl-1,4-dioxo-1,4-dihydronaphthalene-2-carboxylate (44a):
According to the general procedure for annulation, the condensation of 5,6-dimethoxy phthalide 43
(194 mg, 1 mmol) with ethyl buta-2,3-dienoate 8a (134.5 mg, 1.2 mmol) in the presence LDA (3.2
mmol), was prepared by adding n-BuLi (3.2 mmol, 1.6 M in hexane) in a solution of diisopropylamine
(3.2 mmol) in THF (10 mL) at -78 ºC under nitrogen atmosphere, produced compound 44a as a bright
o
yellow solid ( 48.7 mg, 16%), mp 121-123 C. νmax (KBr, cm-1): 3443,1926, 1737, 1650, 1578, 1373,
1
1335, 1220, 1103, 1052, 1008; H NMR (600 MHz, CDCl3): δ 7.53 (s, 1H), 7.50 (s, 1H), 4.46 (q, J =
13
7.2 Hz, 2H), 4.04 (s, 3H), 4.03 (s, 3H), 2.18 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H); C NMR (100 MHz,
CDCl3): δ 184.4, 181.4, 164.9, 153.9, 153.8, 143.6, 139.3, 126.7, 126.4, 108.2, 107.9, 76.9, 62.2, 56.7,
14.4, 13.9; HRMS (ESI) calcd. for C16H16O6 [M+H]+ 305.1025, found 305.1021.
ASSOCIATED CONTENT
Supporting Information
13
1H and C NMR spectra of the synthesized compounds, X-ray crystallographic data (CIF file). “This
material is available free of charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
* Email ID: dmal@chem.iitkgp.ernet.in
NOTES
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the Council of Science & Industrial Research, New Delhi for financial
support. SJ is thankful to IIT KHARAGPUR for her research fellowship and contingency grant. We are
also thankful to DST-FIST for financial support for establishing NMR facility.
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