Applications of [4+2] Anionic Annulation and Carbonyl-Ene Reaction in the Synthesis of Anthraquinones, Tetrahydroanthraquinones, and Pyranonaphthoquinones

Article abstract of DOI:10.1021/acs.joc.7b01987

Hexa-2,5-dienoates, susceptible to isomerization by acids and bases, are suitable for the [4+2] anionic annulation to give 3-(2-alkenyl)naphthoates in regiospecific manner. When combined with intramolecular carbonyl-ene reaction (ICE), the accessibility of the naphthoates culminates in a new synthesis of anthraquinones and diastereoselective synthesis of tetrahydroanthraquinones. This strategy has also resulted in a 3-step synthesis of dehydroherbarin from a 3-methallylnaphthoate.

Full text of DOI:10.1021/acs.joc.7b01987

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Article
Applications of [4 + 2] Anionic Annulation and Carbonyl-
Ene Reaction in the Synthesis of Anthraquinones,
Tetrahydroanthraquinones and Pyranonaphthoquinones
Shyam Basak, and Dipakranjan Mal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01987 • Publication Date (Web): 29 Sep 2017
Downloaded from http://pubs.acs.org on September 29, 2017
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Applications of [4 + 2] Anionic Annulation and
Carbonyl-Ene Reaction in the Synthesis of
Anthraquinones, Tetrahydroanthraquinones and
Pyranonaphthoquinones
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Shyam Basak and Dipakranjan Mal*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India
Supporting Information Placeholder
ABSTRACT: Hexaꢀ2,5ꢀdienoates, susceptible to isomerization by acids and bases, are
suitable for the [4 + 2] anionic annulation to give 3ꢀ(2ꢀalkenyl)naphthoates in regiospecific
manner. When combined with intramolecular carbonylꢀene reaction (ICE), the accessibility
of the naphthoates culminates in a new synthesis of anthraquinones and diastereoselective
synthesis of tetrahydroanthraquinones. This strategy has also resulted in a 3ꢀstep synthesis of
dehydroherbarin from a 3ꢀmethallylnaphthoate.
INTRODUCTION
Quinones are one of the largest and most diverse class of natural products, which
include several distinguished subclasses like i) anthracyclines, ii) angucyclines, iii)
anthraquinones, iv) pyranonaphthoquinones and v) hydroanthraquinones.1a,b Many of
them have received much attention due to their anticancer activities and other
cytotoxicities.1c For example, rhein, a natural product, has been found useful in the
treatment of degenerative osteoarthritis of the joints.1d Furthermore, anthraquinones
are useful as chemical sensors,1e building blocks for the synthesis of more complex
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molecules,1f organogelators,1g liquid crystals,1h and organic semiconductors1i. Alkyl
anthraquinones are of special interest due to their commercial uses in the production of
hydrogen peroxide.1jIn view of the above importance and usefulness, many synthetic
strategies have been developed.2 These strategies include Friedel–Crafts reaction of
benzene derivatives,2a DielsꢀAlder reaction followed by aromatization,2b–d cyclization
of polyketides,2e transitionꢀmetal mediated [2 + 2 + 2] cycloaddition,2f DielsꢀAlder
reaction followed by aromatization and FriedelꢀCrafts reaction,2g [4 + 2] anionic
annulation of phthalides2h. Recently, Lee group has developed a method based upon
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organocatalyzed benzannulation of naphthoquinones with α,βꢀunsaturated aldehydes at
elevated temperature (Scheme 1, eq. (1)).2i Hong group combined photooxidation with
Heck type of reaction of diarylacetic acids to construct anthraquinones (Scheme 1, eq.
(2)).2j We reported a single example of oneꢀpot formation of methylanthraquinone
from 3ꢀmethallylnaphthaleneꢀ2ꢀcarboxaldehyde (Scheme 1, eq. (3)) via ICE reaction.2k
Scheme 1. Recent syntheses of anthraquinones
Furthermore, hydroanthraquinones are of much importance.3 The structures of few
recently isolated hydroanthraquinones, i.e 1–6 are displayed in Figure 1.3a–e A good majority
of them display interesting biological activities, such as antibacterial activity,3a antitumor
activity,3b cytotoxicity,3d anticancer activity,3f etc (Figure 1). However, very few synthetic
strategies have been reported.2c,4,5
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Figure 1. Some recently isolated tetrahydroanthraquinones
Similarly, pyranonaphthoquinones, namely, dehydroherbarin, thysanone, nanaomycin
D, have been of synthetic interest and their chemistry is periodically reviewed.6a–b
Consequently, many synthetic approaches for the titled classes have been reported in the
literature. The use of 3ꢀallylꢀ2ꢀnaphthoates as intermediates in the synthesis of tricyclic
molecules like pyranonaphthoquinones, anthracenes is an attractive approach.6a–i However,
the installation of an allyl group ortho to an ester group of aromatic ring is often
problematic.6j,k In some of the approaches, the allyl group attached to an aromatic ring
isomerizes under the reaction conditions due to the added stability originating from extended
conjugation.6j,k Konig synthesis of anthracenes and Dehydroherbarin resorted to Stobbe
condensation and Claisen rearrangement for the access to an allylnaphthoate from aromatic
aldehydes.6c,d Recently, we employed Claisen rearrangement route for the synthesis of 3ꢀ
methallylꢀ2ꢀnaphthoates.2k De Kimpe group utilized KochiꢀAnderson reaction of a
bromonaphthoquinone.6e Other approaches are based on metal mediated allylation of
quinones,6f–h WulffꢀDötz annulation,6i modification of allyl group by cross metathesis
reaction6g (Scheme 2).
Scheme 2. Previous works on the synthesis allyl naphthoates
In order to generalize our finding (Scheme 1, eq. (3)) on the synthesis of
anthraquinones and tetrahydroanthraquinones via ICE, we needed an easy access to 3ꢀ
allylnaphthoates. It may be mentioned that carbonylꢀene reaction is a fundamentally
important atomꢀeconomic carbonꢀcarbon single bond forming reaction.7a–g Its application has
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allowed novel synthesis of many natural products including anthracyclinones.7h–i The aim of
this study was, therefore, twoꢀfold: i) to extend our previous study on the aromatic carbonylꢀ
eneꢀreaction2k for the development of a new synthesis of oxygenated anthraquinones and ii)
to develop a general route for the synthesis of tricyclic quinone natural products.
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Herein, we report a general and regiospecific synthesis of the 3ꢀallylnaphthoates by [4
+ 2] anionic annulations as well as their elaboration into alkylanthraquinones by tandem
intramolecular carbonylꢀene reactionꢀdehydrationꢀphotooxidation. We also report
diastereoselective synthesis of tetrahydroanthraquinones, and a short synthesis of
dehydroherbarin.
RESULTS AND DISCUSSION
In order to resolve the regiochemical problems in the synthesis of 3ꢀallylnaphthoates, we
conceived [4 + 2] anionic annulation8a–c of 3ꢀnucleofugal phthalides with skipped (1,4ꢀ
dienes) dienoates. Such a concept was tested by Rho et al. with the sole annulation between
sulfone phthalide 7 with dienoate 8 (synthesized from 9) (Scheme 3).8d Unfortunately,
isomerized product 10 was obtained and the desired product was not obtained. It may be
noted that Rho et al. wrongly proposed the structure 11 for the product. On careful scrutiny of
the reported NMR data for the product 11 (1H NMR data reported by Rho et al. δ 7.71 (d, J
= 7.97 Hz, 1H, ArH), 7.47 (t, J = 7.97, 1H, ArH), 6.91 (d, J = 7.97, 1H, ArH), 6.17 (br s, 1H,
CH=), 4.01, 3.88, 3.87, 3.77 (3H each, s, OMe), 1.92, 1.75, (3H each, s, CH3)), we found it to
be incorrect. On the basis of the two singlets at δ 1.92 and 1.75 and one singlet at 6.17, we
proposed structure 10 as the annulation product (Scheme 3).
Scheme 3. Reinterpretation of Rho’s work
Therefore, we concluded that CC double bond isomerization of the immediate
annulation product 12 or its dimethyl derivative 11 or acceptor 8 led to the formation of 13
and then 10.
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Anticipating that the Hauser annulation with 3ꢀcyanophthalides is faster than that of
phthalide sulfones (cf. 7), the revisit of the annulation with a cyanophthalide was deemed
prudent. Accordingly, we synthesized acceptor 14a (cf. 8) according to the method of Snider
et al.8e,f Intermolecular ene reaction of ethyl propiolate with isobutylene in the presence of
Et2AlCl afforded 14a in 92% yield. When the acceptor 14a was submitted to annulation with
cyanophthalide 15a8g in presence of different bases (vide Table 1), mixtures of two
inseparable annulation products 16aa and 16ab were formed.
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Table 1. Preliminary annulation study
Thus it is feasible to synthesize 3ꢀmethallylꢀ2ꢀnaphthoates (cf. 16aa) by the
annulation. To prevent the formation of the isomerized product 16ab and to identify the step
in which methallyl double bond was isomerized, compounds 14a and 16aa were separately
treated with NaH, LiOtBu and LiHMDS. The compound 16aa was found to be resistant to all
the three bases. Interestingly, the acceptor 14a was found to be inert only to LiHMDS.
Accordingly, LiHMDS was used for the annulation reaction of the compound 15a with
acrylate 14a to furnish the desired product 16aa as the sole product. On optimization, the
yield of the annulation product 16aa could be increased up to 94% by carrying out the
reaction in the presence of LiHMDS in MTBE (methyl tertꢀbutyl ether)ꢀTHF (Table 2).
Table 2. Optimization study of the annulation of 15a with 14a
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For the evaluation of the substrate scope, cyanophthalides 15a–g2h,8g–i were submitted
to the annulation with acceptor 14a. Expectedly, the desired annulation products 16a–g were
obtained under the optimized conditions in good to excellent yields. Another skipped
dienoate i.e. 14b was prepared by intermolecular ene reaction of ethyl propiolate with 2ꢀ
ethylꢀ1ꢀbutene in the presence of Et2AlCl as 1.3:1 diastereomeric mixture in 84% yield.8e,f
When it was submitted to the annulation with the cyanophthalides 15b and 15f, products
16h–i were obtained in good yields without any isomerization of the CC double bonds. In
conjunction with the study, the annulation reactivity of 15h8j, which does not have a
nucleofuge, was also examined. Its reaction with the acceptor 14a under the same conditions
afforded hydroaromatic products 16ja and 16jb (Table 3).
Table 3. Scope of Hauser annulation with skipped dienoates 14a–b
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To examine the scope of the acceptors, skipped dienoates 14c–d were synthesized
from 17a–b by selective hydrogenation with 10% PdꢀC/H2 poisoned with quinoline or
Lindlar catalyst (Scheme 4).
Scheme 4. Synthesis of acceptor 14c–d
An interesting result was obtained when the cyanophthalide 15b was reacted with the
acceptor 14c (vide Table 4). Autooxidized annulation product 16k was isolated in 66% yield.
This kind of oxidation is invoked in the biogenesis of complex dimeric Rubiaceae natural
products.6g,9a–b Furthermore, it is to be noted that the corresponding napthoquinone of the
naphthoate 16k is the putative intermediate for these natural products.
For the simple allylacrylate 14d, the annulation with 15b afforded an inseparable
mixture of products 16la, 16lb and 16lc. The formation of product 16la is the result of the
annulation between cyanophthalide 15b and skipped dienoate 14d and the products 16lb and
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16lc from the annulation between 15b and the acceptor which is isomerized product of 14d
(Table 4).
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Table 4. Scope of Hauser annulation with skipped dienoates 14c–d
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The mechanism of the annulation between 3ꢀnucleofugal phthalides (15a–g) and
skipped dienoates (14a–b,14d) is shown in Scheme 5. Under basic conditions of the
annulation, 2,5ꢀhexadienoates (14a–b,14d) may be in equilibrium with their isomers, i.e. 2,4ꢀ
hexadienoates 18. At low temperature, the incipient phthalide anions 19 add to the acrylates
14a–b,14d,18 in Michael addition mode to form new anions 20. These anions 20 then
undergo ring closure at the phthalide carbonyl group resulting in the displacement of
nucleofuge Y as anion to produce dihydronaphthoquinones 21. The deprotonation of 21 by
bases give enolate intermediates 22, which upon in situ methylation with Me2SO4, form the
products 16a–i,16l (Scheme 5).
Scheme 5. Mechanism of annulation between 3-nucleofugal phthalides and skipped
dienoates
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The mechanism of annulation between phthalide 15h and skipped dienoate 14a is
presented in Scheme 6. At low temperature, the phthalide anion 23 undergoes Michael
addition to the acrylate 14a give anion 24. This anion 24 then attacks at the phthalide
carbonyl group resulting in the formation of anions 25 and 26, which upon in situ methylation
form the keto and enol products 16ja and 16jb (Scheme 6).
Scheme 6. Mechanism of annulation between phthalide 15h and skipped dienoate 14a
The formation of 16k from 15b and 14c is accounted for by the brief mechanism
presented in Scheme 7. The initial annulation product 27 is transformed to peroxo
intermediate 28 after the ene reaction of the prenyl side chain with singlet oxygen. The
intermediate 28 then undergoes disproportion to furnish the product 16k. To confirm the
structure of the product 16k and presence of hydroxyl group, we performed acid catalyzed
dehydration on 16k, affording the dehydrated product 16ka (Scheme 7).
Scheme 7. Proposed mechanism for the formation of 16k and dehydration experiment
on 16k
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Synthesis of anthraquinones from 3-allylnaphthoates:
In an earlier study, we reported only one example of a novel formation of anthraquinone
based upon ICE reaction of 3ꢀmethallylnaphthaleneꢀ2ꢀcarboxaldehyde.2k Generalization of
the finding was impeded by the accessibility of the precursor aldehydes. With naphthoates
16a–f, 16h–i (Table 3) in hand, we elaborated them to the respective anthraquinones. The
naphthoates 16a–f, 16h–i were transformed to alcohols 29a–h by DIBALꢀH
(diisobutylaluminium hydride) reduction and then to aldehydes 30a–h by DMP (Dess–Martin
periodinane) oxidation (Table 5) in good yields.
Table 5. Preparation of o-allyl naphthalaldehyde
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The aldehydes 30a–h were then treated with BINOLꢀPO2H (racꢀBINOL phosphoric
acid) in chloroform at rt in the presence of air. The corresponding anthraquinones 31a–h
were formed. But, along with some amounts of anthracenes 32a–h were also formed in the
range traceꢀ54% yield. Since, the anthracenes were not stable to light and air, their full
characterizations were difficult. However, we could characterize four anthracenes 32b, 32c,
32e and 32h (vide Table 6 for yields of 32b, 32c, 32e and 32h; vide experimental section for
yields of unidentified anthracenes). According to the mechanism,2k earlier proposed by us, for
the formation of anthraquinones 31a–h, water and light are needed along with air (Scheme 8).
Therefore, we repeated the reactions of 30a–h with BINOLꢀPO2H in the presence of water,
air under the exposure of 100 W lamp. In each case, the corresponding anthraquinone (31a–
h) was obtained almost in quantitative yield (Table 6).
Table 6. Substrate scope for the new anthraquinone synthesis
Reaction conditions A: 10 mol% of BINOLꢀPO2H added to a stirred solution of oꢀpropenyl
naphthalene aldehydes in a screw capped vial and stirred for 4–5 d.
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Reaction conditions B: 10 mol% of BINOLꢀPO2H added to a stirred solution of oꢀpropenyl
naphthalene aldehydes in a screw capped vial and stirred for 4–5 d. After completion of
reaction, water (2 mL/mmol) was added and stirred under the exposure of 100 W lamp for 15
h.
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aYields refer to the conditions A in the discussion above, bYields refer to the conditions B in
the discussion above
Akin to the already proposed mechanism,2k the aldehydes 30a–h undergo carbonylꢀ
ene reaction to form ene cyclized products 33, followed by dehydration under acidic
conditions to furnish the anthracenes 32a–h. These anthracenes act as photosensitizers and
react with in situ generated singlet oxygen to form cycloaddition adducts 34. The
cycloaddition adducts break down to form bisoxocarbenium ions 35, which on water addition
form 36. Loss of methanol from 36 furnishes anthraquinones 31a–h (Scheme 8).
Scheme 8. Proposed mechanism for the formation of 31a–h
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To prepare the natural product 37, the anthraquinone 31d was treated with BBr3 in
DCM. Expectedly, natural product 37 was formed in 86% yield (Scheme 9).
Scheme 9. Synthesis of natural product 6-methylxanthopurpurin-3-O-methyl ether (37)
Synthesis of tetrahydroanthraquinones from 3-allylnaphthoates:
This part of the study was directed to the utilization of the naphthoates (cf. 16aa, 16b) in the
synthesis of hydroanthraquinone embedded natural products. It may be noted that the
synthesis of these natural products (1–6) (Figure 1, Scheme 10) are of interest due to their
complex and varied oxygen functionalities. The carbonylꢀene reaction of electronically rich
methoxy naphthoxaldehydes 30a–h directly leads to the formation of anthraquinones (Table
6). Alternatively, we conceived the strategies presented in Scheme 10, where affording the
nonꢀaromatized ene products is much more feasible.
Scheme 10. Strategies for the synthesis of tetrahydroanthraquinones
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First, we contemplated the access to anthracenones 38a–b as key intermediates so as
to fabricate the corresponding hydroaromatics. When alcohols 39a–b, obtained by CAN
(ceric ammonium nitrate) oxidation of the alcohols 29a–b, were treated with DMP, aldehydes
40aꢀb were obtained. Due to their instability in silica gel, they were as such subjected to
reaction with SnCl4·5H2O. These reactions afforded anthraquinones 31a–b and 41a–b in
moderate yields. Isolation of the immediate ene products 38a–b were of no avail (Scheme
11).
Scheme 11. Intramolecular carbonyl-ene reactivity of naphthoquinonyl carboxaldehyde
Alternatively, we explored eneꢀchemistry of epoxy aldehydes (±)ꢀ42a–b. The epoxy
alcohols (±)ꢀ43a–b were prepared by epoxidation of naphthoquinones 39a–b. Treatment of
epoxy alcohol (±)ꢀ43a with DMP provided aldehyde (±)ꢀ42a along with ene product (±)ꢀ44a
as single diastereomer. The epoxy alcohol (±)ꢀ43b, however, furnished aldehyde (±)ꢀ42b as
the sole product on oxidation with DMP. When the aldehydes (±)ꢀ42a–b were treated with
SnCl4·5H2O in DCM, ene products (±)ꢀ44a–b were obtained in almost quantitative yields as
single diastereomers. The trans stereochemistry of the ene cyclized products were confirmed
from the crystal structure of the silylated product of (±)ꢀ44a i.e. (±)ꢀ45. Most notably, many
hydroanthraquinone natural products bear this kind trans stereochemistry (cf. 2–6; Figure 2,
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Scheme 10). On the contrary, treatment of (±)ꢀ42b with BINOLꢀPO2H gave 1:1
diastereomeric mixture (±)ꢀ44c (Scheme 12).
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Scheme
12.
Intramolecular
ene-reaction
of
epoxydihydronaphthoquinone
carboxaldehydes
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O
O
O
O
H2O2, Na2CO3
EtOHꢀH2O, rt
DMP, NaHCO3
O
O
O
0 °C
rt
CHO
R
O
R
O
OH
R
O
OH
R
O
OH
(±)-42a
R = OCH3; (±)-42b(98%)
R = H;
(46%)
R = H; (±)-43a(89%)
R = OCH3; (±)-43b(91%)
(±)-44a
R = H, 52% (single
diastereomer)
R = H; 39a
R = OCH3; 39b
TIPSOTf
(triisopropylsilyl
trifluoromethanesulfonate)
imidazole
O
O
O
SnCl4—5H2O
DCM, rt
rt
O
O
60%
O
OTIPS
R
OH
(±)-45
(±)-44a
R = H;
(97%)
R = OCH3; (±)-44b(96%)
Single diasteromer
O
O
O
BINOLꢀPO2H
DCM, rt, 4 d
O
O
94%
CHO
O
O
O
OH
42b
(±)-44c(dr 1:1)
Explanation for the anomaly in stereoselectivity observed in ene reaction of (±)-42a–b:
Excess NaHCO3 was used during the DMPꢀoxidation of (±)ꢀ43a to quench acetic acid byꢀ
product. So, acetic acid catalyzed ene reaction of (±)ꢀ42a during DMPꢀoxidaion is ruled out.
The aldehyde (±)-42a is stable at room temperature and we carried out the DMPꢀoxidation on
(±)ꢀ43a at 0 °Cꢀrt. Therefore, the thermal ene reaction of (±)ꢀ42a at room temperature is also
ruled out. We, therefore, propose that diastereoselectivity of the reaction of (±)ꢀ42a under
DMPꢀoxidation conditions is due to DMP or acetoxy iodinane. This kind of ene reaction is
not observed for the substrate (±)ꢀ42b under the DMPꢀoxidation conditions, probably due to
the periꢀeffect originating from the methoxy group in the substrate (±)ꢀ42b. The substrates
30a–h are also stable under DMPꢀoxidation conditions. This must be due to the reduced
reactivity arising from conjugation with aromatic ring in 30a–h.
When Lewis acid catalysts are employed for the ene reaction, there may be a
continuum between concerted and stepwise mechanisms.7b However, we have conceived
transition states for the concerted mechanism for explaining the product diastereoselectivity.
During SnCl4·5H2O catalyzed ene reaction of (±)ꢀ42a–b or DMP/acetoxy iodinane catalyzed
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ene reaction of (±)ꢀ42a, 6ꢀmembered chelation occurs as shown in transition states 46 and 47,
providing conformational bias in the transition states. For the requirement of lower activation
energy, reaction occurs in such a conformation that hydroxyl group becomes trans to epoxy
group in product (±)ꢀ44a–b. Representative orbital picture of the transition states is shown as
48. For BINOLꢀPO2H catalyzed reaction of (±)ꢀ42b, the only driving force is weaker Hꢀ
bonding so conformational restriction of aldehyde functionality does not occur. Ene reaction
of (±)ꢀ42b occurs with two different conformations of aldehyde functionality with BINOLꢀ
PO2H as shown in transition states 49, 50 producing two different diastereomers in 1:1 ratio
(Figure 2).
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Figure 2. Plausible transition states for the diastereselective ene reaction of (±)ꢀ42a–b
Synthesis of pyaranonaphthoquinone natural product dehydroherbarin (51):
With the naphthylmethanol 29d in hand, we were tempted to achieve a short synthesis of
pyranonapthaquinone natural product, dehydroherbarin (51). It was isolated from
dematiaceous fungus Torula herbarum10a and shown to exhibit antimicrobial and antiamoebic
activity, as well as inhibit both metastatic prostate and breast cancers (PCꢀ3M and MDAꢀMBꢀ
231 respectively).6f,10b Till date, three total syntheses10c–d,6d of 51 have been reported. When
alcohol 29d was subjected to OsO4 catalyzed LemieuxꢀJohnson oxidation, tricyclic product
52 was formed in 81% yield, thus constituting a formal short synthesis of 516d (Scheme 13).
Scheme 13. Synthesis of dehydroherbarin (51)
O
O
O
OsO4, NaIO4
1,4ꢀdioxane, H2O
O
O
O
one step6d
O
O
81%
O
O
O
O
O
O
OH
29d
52
51
dehydroherbarin
CONCLUSION
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A regiospecific synthesis of 3ꢀ(2ꢀalkenyl)naphthoates is achieved, by the use of [4 + 2]
anionic annulations. An autooxidized annulation product, i.e. 16k was obtained when
annulation was performed with prenyl chain containing dienoate. The ready accessibility of
the naphthoates has allowed development of a room temperature synthesis of anthraquinones
via a sequence of intramolecular carbonylꢀene reactionꢀdehydrationꢀphotooxidation.
Diastereoselective synthesis of tetrahydroanthraquinones has been feasible with similar
strategy. A short synthesis of dehydroherbarin (51) is accomplished utilizing one of the
methallylnaphthoates.
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EXPERIMENTAL SECTION
General Procedures. All reactions utilizing moistureꢀsensitive reagents were performed
under an inert atmosphere. All solvents were dried prior to use, according to the standard
protocols. Benzene, toluene, diethyl ether, THF, MTBE were distilled from
Na/benzophenone. CH3CN, CHCl3 and DCM were dried over CaH2. EtOH and MeOH were
dried over CaO and then over magnesium turnings. Ethyl acetate, hexane, petroleum ether
and acetone were distilled from CaCl2. Melting points were determined in open capillary
tubes and are reported as uncorrected. TLC was carried out on precoated plates (silica gel 60
F254), and the spots were visualized with UV and fluorescent lights or by staining with iodine,
pꢀanisaldehyde, KMnO4 stains. Column chromatography was performed on silica gel (60–
1
120 or 230–400 mesh). H and 13C NMR spectra for all the compounds were recorded at
400/600 and 100/150 MHz (Bruker UltrashieldTM 400, AscendTM 600), respectively. The
following abbreviations are used to describe peak splitting patterns when appropriate: br =
broad, s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of
doublets, ddd = doublet of doublets of doublets, m = multiplet. Coupling constants, J, are
reported in Hertz (Hz). IR spectra were recorded with a Perkin–Elmer FTIR instrument using
a KBr pellet. The phrase “usual workꢀup” refers to washing of the organic phase with water
(2 x 1/4 of the volume of the organic phase) and brine (1 x 1/4 of the volume of the organic
phase), drying (Na2SO4), filtration, and concentration under reduced pressure.
Preparation of skipped dienoates
Ethyl (E)-5-methylhexa-2,5-dienoate (14a).8e–f Ethylaluminium dichloride (40.8 mL 25 wt
% in toluene, 80.0 mmol) was added to a solution of ethyl propiolate ( 7.84 g, 80.0 mmol) in
30 mL DCM in 250 mL sealed tube. An excess of isobutylene gas was then condensed into
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the solution at ꢀ25 °C and the tube was sealed and stirred at 25 °C for 1 day. The reaction
mixture was poured into saturated sodium bicarbonate solution and filtered to remove
precipitated aluminum salts. The filtrate was then extracted with DCM (3 x 100 mL). The
combined extracts were washed with brine (2 x 100 mL), dried over Na2SO4 and
concentrated to afford crude product 14a in 92% yield (11.3 g, 73.6 mmol). The crude
product was of high purity to perform reactions. 1H NMR (600 MHz, CDCl3) δ 6.98–6.93 (m,
1H), 5.84 (d, J = 15.5 Hz, 1H), 4.82 (s, 1H), 4.74 (s, 1H), 4.18 (q, J = 7.0 Hz, 2H), 2.87 (d, J
= 7.2 Hz, 2H), 1.73 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 166.7,
146.5, 142.4, 122.8, 112.7, 60.4, 40.7, 22.7, 14.5.
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Ethyl (2E)-5-ethylhepta-2,5-dienoate (14b).8e–f The compound 14b was obtained as 1.3:1
diastereomeric mixture from intermolecular ene reaction between ethyl propiolate (1.94 g, 20
mmol) and 2ꢀethylꢀ1ꢀbutene (2.36 g, 28 mmol) as yellowish liquid (3.06 g, 16.8 mmol) in
84% yield. Experimental procedure is similar to that described for the synthesis of the
1
compound 14a. Crude product was of high purity to perform reactions. H NMR (600 MHz,
CDCl3) δ 6.92–6.83 (m, 1H), 5.79–5.75 (m, 1H), 5.34–5.17 (m, 1H), 4.16–4.11 (m, 2H),
2.89–2.81 (m, 2H), 2.02–1.94 (m, 2H), 1.58 – 1.52 (m, 3H), 1.24 (t, J = 7.2 Hz, 3H), 0.95–
0.90 (m, 3H). 13C NMR (150 MHz, CDCl3) δ 166.8, 166.7, 147.8, 146.7, 138.3, 137.3, 122.2,
121.6, 121.1, 120.1, 60.3, 60.2, 39.4, 33.2, 30.0, 23.1, 14.4, 13.4, 13.2, 12.7.
Methyl 6-methylhept-5-en-2-ynoate (17a).11a The compound 17a was prepared from ethyl
propiolate and prenyl bromide following the literature procedure.11a 1H NMR (600 MHz,
CDCl3) δ 5.17–5.14 (m, 1H), 3.74 (s, 3H), 3.02 (d, J = 7.0 Hz, 2H), 1.71 (d, J = 1.2 Hz, 3H),
1.63 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 154.2, 135.8, 115.9, 88.2, 72.1, 52.4, 25.4, 17.7.
IR (KBr): ν̃
= 3422, 2957, 2219, 1717, 1437, 1251, 1098, 963, 750 cmꢀ1. HRMS (ESIꢀTOF)
m/z: [M + H]+ Calcd for C9H13O2 153.0916; Found 153.0902.
Methyl (Z)-6-methylhepta-2,5-dienoate (14c).11b The compound 17a (1.01 g, 6.5 mmol)
was dissolved in 10 mL methanol. Catalytic amount of 10 % PdꢀC (50 mg) and quinoline (50
mg) was added and stirred for 24 h at rt under atmospheric pressure of H2. The reaction
mixture was filtered through celite and methanol was evaporated carefully under reduced
pressure at low temperature. The crude product was purified by column chromatography on
silica gel with petroleum ether as solvent to obtain pure compound 14c in 70% yield (0.7 g,
4.55 mmol) as sole product. Colourless liquid; Rf (hexane) 0.3; 1H NMR (400 MHz, CDCl3):
δ 6.20–6.13 (m, 1H), 5.77–5.73 (m, 1H), 5.17–5.13 (m, 1H), 3.71 (s, 3H), 3.38–3.35 (m, 2H),
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1.71 (s, 3H), 1.65 (s, 3H). C NMR (100 MHz, CDCl3) δ 167.0, 149.3, 134.1, 120.8, 118.7,
51.2, 28.5, 25.8, 18.0.
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Ethyl hex-5-en-2-ynoate (17b).11a The compound 17b was prepared following the
literature procedure.11a 1H NMR (600 MHz, CDCl3) δ 5.78–5.72 (m, 1H), 5.33–5.30 (m, 1H),
5.17–5.14 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.09–3.07 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). 13C
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NMR (150 MHz, CDCl3) δ 153.8, 129.9, 117.9, 85.6, 75.2, 62.0, 23.0, 14.2. IR (KBr): ν̃ =
3416, 2986, 2238, 1714, 1370, 1262, 1098, 1014, 860, 752 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M
+ H]+ Calcd for C8H11O2 139.0759; Found 139.0735.
Ethyl (Z)-hexa-2,5-dienoate (14d).11c The compound 17b (1.1 g, 8 mmol) was dissolved
in 10 mL methanol. Catalytic amount of Lindlar catalyst was added and stirred for 24 h at rt
under atmospheric pressure of H2. The reaction mixture was filtered through celite and
methanol was evaporated carefully under reduced pressure at low temperature. The crude
product was purified by column chromatography on silica gel with petroleum ether as solvent
to obtain pure compound 14d in 90% yield (1.0 g, 7.2 mmol) as sole product. Colourless
1
liquid; Rf (hexane) 0.3; H NMR (400 MHz, CDCl3): δ 6.23–6.14 (m, 1H), 5.89 – 5.72 (m,
2H), 5.12 – 4.97 (m, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.41–3.37 (m, 2H), 1.26 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 166.4, 146.9, 135.4, 120.4, 116.2, 60.0, 33.3, 14.4. IR
(KBr): ν̃
= 2982, 1720, 1640, 1412, 1182, 1036, 916, 818 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M +
H]+ Calcd for C8H13O2 141.0916; Found 141.0922.
Ethyl 1,4,8-trimethoxy-3-(2-methylallyl)-2-naphthoate (16aa) and ethyl 1,4,8-
trimethoxy-3-(2-methylprop-1-en-1-yl)-2-naphthoate (16ab).
Annulation with NaH. A suspension of NaH (60% in oil, 40 mg, 1.0 mmol) in THF (5 mL)
was added to a solution of methoxycyanophthalide 15a (94.5 mg, 0.5 mmol) and 14a (84.1
mg, 0.6 mmol) in 8 mL THF at 0 °C. The reaction mixture was warmed to rt and stirred for 2
h. The reaction mixture was cooled to 0 °C and NaH (60% in oil, 40 mg, 1.0 mmol) was
added to the reaction mixture followed by addition of Me2SO4 (0.47 mL, 5 mmol). The
reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was
again cooled to 0 °C and quenched with saturated NH4Cl. THF was evaporated under reduced
pressure. The residue was then extracted with EtOAc (3 x 20 mL). The combined extracts
were washed with brine (3 x 10 mL), dried over Na2SO4 and concentrated to afford crude
product. This crude product was purified by column chromatography on silica gel with
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EtOAc/petroleum ether (1:20) as solvent to obtain mixture of 16aa and 16ab in 45% yield
(78 mg, 0.23 mmol) in 2:1 ratio.
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Annulation with LiOtBu. A solution of 3ꢀcyanophthalide 15a (94.5 mg, 0.5 mmol) in dry
THF (2 mL) was added to stirred suspension of LiOtBu (240 mg, 3 mmol) in dry THF (8
mL) at ꢀ60 ⁰C under an inert atmosphere. The resulting solution was stirred at ꢀ60 ⁰C for 30
min after which a solution of 14a (84.1 mg, 0.6 mmol) in dry THF (2 mL) was added. The
reaction mixture was stirred for another 30 min at ꢀ60 ⁰C followed by 6–8 h stirring at room
temperature. The reaction mixture was cooled to 0 °C and NaH (60% in oil, 40 mg, 1.0
mmol) was added to the reaction mixture followed by addition of Me2SO4 (0.47 mL, 5
mmol). The reaction mixture was again cooled to 0 °C and quenched with saturated NH4Cl.
THF was evaporated under reduced pressure. The residue was then extracted with EtOAc (3
x 20 mL). The combined extracts were washed with brine (3 x 10 mL), dried over Na2SO4
and concentrated to afford crude product. This crude product was purified by column
chromatography on silica gel with EtOAc/petroleum ether (1:20) as solvent to obtain mixture
of 16aa and 16ab in 25% yield (43 mg, 0.13 mmol) in 2:3 ratio.
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Optimized general annulation procedure with LiHMDS. A solution of 3ꢀcyanophthalide
(1.0 mmol) in dry THF (5 mL) was added to stirred solution of LiHMDS (3 mmol) in mixture
of dry THF (5 mL) and MTBE (5 mL) at ꢀ78 ⁰C under an inert atmosphere. The resulting
solution was stirred at ꢀ78 ⁰C for 30 min after which a solution of skipped dienoate acceptor
(1.2 mmol) in dry THF (2 mL) was added. The reaction mixture was stirred for another 30
min at ꢀ78 ⁰C followed by 6–8 h stirring at room temperature. The reaction mixture was
cooled to 0 °C and NaH (60% in oil, 160 mg, 4.0 mmol) was added to the reaction mixture
followed by addition of Me2SO4 (0.95 mL, 10 mmol). The reaction mixture was again cooled
to 0 °C and quenched with saturated NH4Cl. THF was evaporated under reduced pressure.
The residue was then extracted with EtOAc (3 x 40 mL). The combined extracts were washed
with brine (3 x 15 mL), dried over Na2SO4 and concentrated to afford crude product. This
crude product was purified by column chromatography on silica gel with EtOAc/petroleum
ether as solvent to obtain pure compound.
Data for 16aa. Annulation reaction was performed between 15a and 14a with LiHMDS
following the optimized procedure. Annulation crude product was purified by column
chromatography on silica gel with EtOAc/petroleum ether (1:15) as solvent to obtain pure
compound 16aa in 94% yield (323.5 mg, 0.94 mmol) as sole product. Yellowish liquid; Rf
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(1:15 EtOAc (Ethyl acetate)/hexane) 0.25; H NMR (600 MHz, CDCl3): δ 7.69 (dd, J = 8.5,
1.0 Hz, 1H), 7.47–7.43 (m, 1H), 6.88 (dd, J = 7.7, 1.0 Hz, 1H), 4.82–4.78 (m, 1H), 4.54–4.53
(m, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.54 (s, 2H), 1.75
13
(s, 3H), 1.36 (t, J = 7.2 Hz, 3H). C NMR (150 MHz, CDCl3) δ 168.1, 156.8, 150.6, 150.2,
143.8, 131.9, 127.8, 127.5, 126.1, 119.8, 115.3, 112.1, 106.4, 64.1, 62.3, 61.3, 56.3, 35.2,
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23.1, 14.4. IR (KBr): ν̃ = 2933, 2842, 1726, 1573, 1448, 1372, 1341, 1272, 1251, 1220, 1190,
1109, 1072, 1048, 772 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C20H25O5 345.1702;
Found 345.1711.
Data for 16ab.8d As the compound 16ab was obtained as a mixture with the compound 16aa
from annulation reaction with NaH and LiOtBu, we determined the data of the compound
16ab comparing the NMR of pure 16aa and NMR of mixture of 16aa and 16ab. Rf (1:20
1
EtOAc/hexane) 0.1; H NMR (600 MHz, CDCl3): δ 7.76 (d, J = 8.4 Hz, 1H), 7.45–7.42 (m,
1H), 6.89 (d, J = 7.8 Hz, 1H), 6.17–6.16 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 3.87
(s, 3H), 3.76 (s, 3H), 1.91 (s, 3H), 1.59 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). 13C NMR (600 MHz,
CDCl3): δ 168.0, 156.7, 149.8, 149.3, 139.6, 132.1, 127.9, 127.3, 125.6, 119.8, 117.8, 115.4,
106.6, 64.1, 61.2, 61.1, 56.4, 25.8, 20.4, 14.5.
Ethyl 1,4-dimethoxy-3-(2-methylallyl)-2-naphthoate (16b). Annulation reaction was
performed between 15b (240 mg, 1.5 mmol) and 14a (277 mg, 1.8 mmol) with LiHMDS (4.5
mmol) following the general procedure. Annulation crude product was purified by column
chromatography on silica gel with EtOAc/petroleum ether (1:20) as solvent to obtain pure
compound 16b in 68% yield (314 mg, 1.0 mmol) as sole product. Yellowish liquid; Rf (1:20
1
EtOAc/hexane) 0.4; H NMR (600 MHz, CDCl3): δ 8.12–8.08 (m, 2H), 7.59–7.50 (m, 2H),
4.81–4.80 (m, 1H), 4.51 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 3.89 (s, 3H), 3.61 (s,
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2H), 1.77 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). C NMR (100 MHz, CDCl3) δ 167.9, 150.8,
150.3, 144.2, 129.6, 127.9, 127.4, 126.4, 125.9, 125.7, 123.2, 122.9, 112.0, 63.7, 62.5, 61.5,
34.9, 23.1, 14.4. IR (KBr): ν̃ = 2979, 2938, 1727, 1590, 1457, 1418, 1356, 1283, 1233, 1158,
1087, 1047, 968, 891, 777, 754 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C19H22O4Na 337.1416, [M + H]+ Calcd for C19H23O4 315.1596; Found 337.1415, 315.1599.
Ethyl 1,4,5-trimethoxy-3-(2-methylallyl)-2-naphthoate (16c). Annulation reaction was
performed between 15c (189 mg, 1.0 mmol) and 14a (185 mg, 1.2 mmol) with LiHMDS (3.0
mmol) following the general procedure. Annulation crude product was purified by column
chromatography on silica gel with EtOAc/petroleum ether (1:10) as solvent to obtain pure
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compound 16c in 79% yield (272 mg, 1.0 mmol) as sole product. Yellowish liquid; Rf (1:10
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EtOAc/hexane) 0.4; H NMR (600 MHz, CDCl3): δ 7.70 (d, J = 8.4 Hz, 1H), 7.42–7.38 (m,
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1H), 6.91 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H), 4.50 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.99 (s,
3H), 3.94 (s, 3H), 3.77 (s, 3H), 3.59 (s, 2H), 1.76 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 167.8, 156.2, 151.0, 149.5, 144.4, 130.3, 126.6, 126.5, 126.4, 121.6,
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115.4, 111.8, 107.5, 63.4, 62.7, 61.4, 56.4, 34.7, 23.1, 14.3. IR (KBr): ν̃ = 2934, 2841, 1727,
1573, 1460, 1370, 1337, 1269, 1156, 1065, 1048, 980, 890, 769 cmꢀ1. HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C20H24O5Na 367.1521, [M + H]+ Calcd for C20H25O5 345.1702; Found
367.1524, 345.1714.
Ethyl 1,4,6,8-tetramethoxy-3-(2-methylallyl)-2-naphthoate (16d). Annulation reaction
was performed between 15d (217 mg, 1.0 mmol) and 14a (185 mg, 1.2 mmol) with LiHMDS
(3.0 mmol) following the general procedure. Annulation crude product was purified by
column chromatography on silica gel with EtOAc/petroleum ether (1:10) as solvent to obtain
pure compound 16d in 76% yield (284 mg, 0.76 mmol) as sole product. Yellowish liquid; Rf
(1:10 EtOAc/hexane) 0.5; 1H NMR (600 MHz, CDCl3): δ 6.99 (d, J = 2.4 Hz, 1H), 6.54 (d, J
= 2.4 Hz, 1H), 4.83–4.75 (m, 1H), 4.54 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.93 (s,
3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.52 (s, 2H), 1.75 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR
(150 MHz, CDCl3) δ 168.2, 159.4, 158.1, 150.6, 149.6, 143.9, 132.7, 126.8, 125.5, 115.6,
112.0, 99.4, 93.5, 64.1, 61.6, 61.2, 56.3, 55.6, 35.3, 23.0, 14.4. IR (KBr): ν̃ = 2928, 2851,
1725, 1619, 1582, 1411, 1381, 1346, 1240, 1213, 1189, 1155, 1058, 973, 834 cmꢀ1. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C21H26O6Na 397.1627, [M + H]+ Calcd for C21H27O6
375.1808; Found 397.1605, 375.1812.
Ethyl 1,4,5,7-tetramethoxy-3-(2-methylallyl)-2-naphthoate (16e). Annulation reaction
was performed between 15e (325.5 mg, 1.5 mmol) and 14a (277.2 mg, 1.8 mmol) with
LiHMDS (4.5 mmol) following the general procedure. Annulation crude product was
purified by column chromatography on silica gel with EtOAc/petroleum ether (1:10) as
solvent to obtain pure compound 16e in 71% yield (398 mg, 1.1 mmol) as sole product.
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Yellowish liquid; Rf (1:10 EtOAc/hexane) 0.3; H NMR (400 MHz, CDCl3): δ 6.98 (d, J =
2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 4.80–4.73 (m, 1H), 4.51–4.46 (m, 1H), 4.36 (q, J = 7.1
Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.74 (s, 3H), 3.54 (s, 2H), 1.74 (s, 3H), 1.36
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.9, 158.6, 157.5, 151.3, 148.5, 144.6,
130.9, 127.2, 123.9, 117.5, 111.6, 100.3, 93.4, 62.8, 62.7, 61.3, 56.3, 55.5, 34.5, 23.0, 14.3.
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IR (KBr): ν
̃
= 2941, 2842, 1719, 1618, 1591, 1468, 1448, 1411, 1342, 1251, 1342, 1219,
1155, 1047, 960, 849, 668 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C21H26O6Na
397.1627, [M + H]+ Calcd for C21H27O6 375.1808; Found 397.1603, 375.1815.
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Ethyl 1,4,6,7-tetramethoxy-3-(2-methylallyl)-2-naphthoate (16f). Annulation reaction
was performed between 15f (325 mg, 1.5 mmol) and 14a (277 mg, 1.8 mmol) with LiHMDS
(4.5 mmol) following the general procedure. Annulation crude product was purified by
column chromatography on silica gel with EtOAc/petroleum ether (1:5) as solvent to obtain
pure compound 16f in 85% yield (477 mg, 1.3 mmol) as sole product. Yellowish liquid; Rf
(1:5 EtOAc/hexane) 0.3; 1H NMR (600 MHz, CDCl3): δ 7.35 (s, 1H), 7.34 (s, 1H), 4.79–4.78
(m, 1H), 4.51–4.50 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 4.01 (s, 3H), 3.95 (s, 3H),
3.86 (s, 3H), 3.57 (s, 2H), 1.75 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3)
δ 168.1, 150.9, 150.1, 149.7, 149.3, 144.4, 125.4, 124.2, 124.1, 123.3, 111.7, 101.9, 101.6,
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63.2, 62.0, 61.3, 56.2, 56.1, 34.9, 23.1, 14.4. IR (KBr): ν̃ = 3448, 2937, 1720, 1450, 1332,
1259, 1231, 1209, 1169, 1093, 1046, 1013, 859 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C21H26O6Na 397.1627, [M + H]+ Calcd for C21H27O6 375.1808; Found 397.1620,
375.1792.
Ethyl 6ꢀbromoꢀ1,4ꢀdimethoxyꢀ3ꢀ(2ꢀmethylallyl)ꢀ2ꢀnaphthoate (16g). Annulation reaction was
performed between 15g (237 mg, 1.0 mmol) and 14a (185 mg, 1.2 mmol) with LiHMDS (3.0
mmol) following the general procedure. Annulation crude product was purified by column
chromatography on silica gel with EtOAc/petroleum ether (1:15) as solvent to obtain pure
compound 16g in 48% yield (188 mg, 0.48 mmol) as sole product. Yellowish liquid; Rf (1:15
EtOAc/hexane) 0.3; 1H NMR (600 MHz, CDCl3): δ 8.23 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 8.9
Hz, 1H), 7.59 (dd, J = 9.0, 2.1 Hz, 1H), 4.84–4.76 (m, 1H), 4.49 (s, 1H), 4.37 (q, J = 7.2 Hz,
2H), 3.96 (s, 3H), 3.87 (s, 3H), 3.59 (s, 2H), 1.75 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 167.6, 150.5, 149.9, 143.9, 130.7, 129.9, 127.3, 126.4, 126.3, 125.3,
125.2, 122.3, 112.2, 63.8, 62.7, 61.6, 35.0, 23.1, 14.4. IR (KBr): ν̃ = 2975, 2937, 2850, 1772,
1730, 1616, 1582, 1449, 1367, 1341, 1274, 1225, 1092, 1046, 968, 889, 825 cmꢀ1. HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C19H22BrO4 393.0701; Found 393.0711.
Ethyl 3-(2-ethylbut-2-en-1-yl)-1,4-dimethoxy-2-naphthoate (16h). Annulation reaction
was performed between 15b (159 mg, 1.0 mmol) and 14b (219 mg, 1.2 mmol) with LiHMDS
(3.0 mmol) following the general procedure. Annulation crude product was purified by
column chromatography on silica gel with EtOAc/petroleum ether (1:10) as solvent to obtain
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1.3:1 diastereomeric mixture of compound 16h in 84% yield (288 mg, 0.84 mmol).
Yellowish liquid; Rf (1:10 EtOAc/hexane) 0.3; 1H NMR (600 MHz, CDCl3): δ 8.11–8.08 (m,
4.6H), 7.56–7.49 (m, 4.6H), 5.35 (q, J = 6.6 Hz, 1.3H), 4.95 (q, J = 6.6 Hz, 1H), 4.38–4.32
(m, 4.6H), 3.98 (s, 3H), 3.97 (s, 3.9H), 3.89 (s, 3.9H), 3.87 (s, 3H), 3.73 (s, 2.6H), 3.63 (s,
2H), 2.08 (q, J = 7.8 Hz, 2H), 1.79 (q, J = 7.2 Hz, 2.6H), 1.75 (d, J = 6.6 Hz, 3.9H), 1.56 (d, J
= 6.6 Hz, 3H), 1.40–1.36 (m, 6.9H), 1.02 (t, J = 7.8 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3.9H). 13C
NMR (150 MHz, CDCl3) δ 167.9, 167.9, 151.0, 150.8, 150.1, 150.0, 140.0, 139.3, 129.5,
129.4, 127.7, 127.6, 127.3, 127.3, 126.4, 126.2, 126.2, 126.1, 126.1, 123.1, 123.0, 122.8,
122.8, 119.8, 118.7, 63.5, 62.5, 62.2, 61.4, 61.3, 33.4, 28.4, 27.5, 23.8, 14.3, 14.2, 13.7, 13.2,
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12.9, 12.6. IR (KBr): ν̃ = 3448, 2964, 2936, 1727, 1458, 1419, 1355, 1280, 1234, 1158, 1086,
1039, 969, 778, 749 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C21H26O4Na
365.1729, [M + H]+ Calcd for C21H27O4 343.1909; Found 365.1731, 343.1921.
Ethyl (E)-3-(2-ethylbut-2-en-1-yl)-1,4,6,7-tetramethoxy-2-naphthoate (16i). Annulation
reaction was performed between 15f (219 mg, 1.0 mmol) and 14b (218 mg, 1.2 mmol) with
LiHMDS (3.0 mmol) following the general procedure. Annulation crude product was
purified by column chromatography on silica gel with EtOAc/petroleum ether (1:5) as solvent
to obtain 1:1 diastereomeric mixture of compound 16i in 82% yield (330 mg, 0.82 mmol).
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Yellowish liquid; Rf (1:5 EtOAc/hexane) 0.4; H NMR (600 MHz, CDCl3): δ 7.33 (s, 3H),
7.31 (s, 1H), 5.30 (q, J = 6.6 Hz, 1H), 4.90 (q, J = 6.6 Hz, 1H), 4.36–4.23 (m, 4H), 4.01 (s,
3H), 4.00 (s, 3H), 3.98 (s, 6H), 3.93 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.65 (s,
2H), 3.55 (s, 2H), 2.03 (q, J = 7.4 Hz, 2H), 1.75 (q, J = 7.5 Hz, 2H), 1.71 (d, J = 6.8 Hz, 3H),
1.51 (d, J = 6.7 Hz, 3H), 1.36–1.33 (m, 6H), 0.97 (t, J = 7.5 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H).
13C NMR (150 MHz, CDCl3) δ 168.2, 168.1, 150.8, 150.0, 149.9, 149.7, 149.1, 148.9, 140.2,
139.5, 125.3, 125.2, 124.8, 124.6, 124.5, 124.5, 123.0, 128.9, 119.6, 118.4, 101.8, 101.7,
101.6, 101.6, 63.0, 62.0, 61.8, 61.3, 61.2, 56.1, 56.0, 33.3, 28.4, 27.4, 23.7, 14.3, 14.2, 13.7,
13.2, 12.8, 12.6. IR (KBr): ν̃ = 3448, 2935, 1724, 1507, 1475, 1428, 1332, 1259, 1231, 1207,
1170, 1092, 1039, 1016, 975, 859 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C23H31O6
403.2121; Found 403.2139.
Ethyl
4,8-dimethoxy-3-(2-methylallyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-
carboxylate (16ja) and Ethyl 1-hydroxy-4,8-dimethoxy-3-(2-methylallyl)-3,4-
dihydronaphthalene-2-carboxylate (16jb). Annulation reaction was performed between
15h (246 mg, 1.5 mmol) and 14a (277 mg, 1.8 mmol) with LiHMDS (4.5 mmol) following
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the general procedure. Annulation crude product was purified by column chromatography on
silica gel with EtOAc/petroleum ether (1:10) as solvent to obtain two products 16ja in 32%
yield (160 mg, 0.48 mmol) and 16jb in and 27% yield (135 mg, 0.41 mmol) respectively.
Data for 16ja. Yellowish liquid; Rf (1:3 EtOAc/hexane) 0.40; 1H NMR (400 MHz, CDCl3): δ
13.14 (s, 1H), 7.40–7.36 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 4.75 (s,
1H), 4.50 (s, 1H), 4.39 – 4.26 (m, 1H), 4.26 – 4.18 (m, 1H), 3.98–3.94 (m, 1H), 3.94 (s, 3H),
3.29–3.25 (m, 1H), 3.21 (s, 3H), 2.08–2.04 (m, 1H), 1.80 (s, 3H), 1.77–1.68 (m, 1H), 1.34 (t,
J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 173.2, 166.0, 159.1, 143.4, 137.5, 131.6,
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123.5, 117.6, 113.9, 112.8, 99.8, 79.3, 60.7, 56.7, 56.2, 39.5, 35.3, 22.1, 14.4. IR (KBr): ν̃ =
3430, 2928, 1736, 1638, 1610, 1472, 1376, 1270, 1250, 1094, 1076, 962, 894, 770 cmꢀ1.
HRMS (ESIꢀTOF) m/z: [M ꢀ 2H2O + H]+ Calcd for C19H21O3 297.1491; Found 297.1499.
Data for 16jb. Yellowish liquid; Rf (1:3 EtOAc/hexane) 0.35; 1H NMR (400 MHz, CDCl3): δ
7.48–7.44 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 4.78 (s, 1H), 4.60 (s,
1H), 4.38 (d, J = 5.6 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 3.83 (d, J = 5.2 Hz, 1H),
3.17 (s, 3H), 2.56–2.51 (m, 1H), 2.14–2.10 (m, 1H), 2.02–1.98 (m, 1H), 1.75 (s, 3H), 1.11 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 195.6, 172.8, 158.9, 143.4, 143.1, 133.4,
122.2, 120.2, 113.0, 112.2, 79.5, 61.1, 56.5, 56.2, 45.1, 38.3, 23.7, 21.9, 14.1. IR (KBr): ν̃ =
3451, 2922, 1736, 1594, 1470, 1376, 1276, 1074, 960, 892, 772 cmꢀ1. HRMS (ESIꢀTOF) m/z:
[M ꢀ 2H2O + H]+ Calcd for C19H21O3 297.1491; Found 297.1499.
Methyl (E)-3-(3-hydroxy-3-methylbut-1-en-1-yl)-1,4-dimethoxy-2-naphthoate (16k).
Annulation reaction was performed between 15b (159 mg, 1.0 mmol) and 14c (168 mg, 1.2
mmol) with LiHMDS (3.0 mmol) following the general procedure. Annulation crude product
was purified by column chromatography on silica gel with EtOAc/petroleum ether (1:7) as
solvent to obtain pure compound 16k in 66% yield (218 mg, 0.66 mmol) as sole product.
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Yellowish liquid; Rf (1:5 EtOAc/hexane) 0.5; H NMR (600 MHz, CDCl3): δ 8.14–8.06 (m,
2H), 7.58–7.52 (m, 2H), 6.81 (d, J = 16.4 Hz, 1H), 6.33 (d, J = 16.4 Hz, 1H), 3.99 (s, 3H),
3.94 (s, 3H), 3.85 (s, 3H), 1.69 (bs, 1H), 1.43 (s, 6H). 13C NMR (150 MHz, CDCl3) δ 168.7,
150.5, 150.1, 143.5, 129.7, 127.9, 127.7, 126.9, 124.6, 123.7, 123.0, 123.0, 119.8, 71.4, 63.8,
61.5, 52.6, 30.0. IR (KBr): ν̃ = 3448, 2970, 1734, 1441, 1356, 1296, 1226, 1160, 1086, 1048,
968, 777, 743 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M ꢀH2O + H]+ Calcd for C19H21O4 313.1440;
Found 313.1444.
Methyl (E)-1,4-dimethoxy-3-(3-methylbuta-1,3-dien-1-yl)-2-naphthoate (16ka). To a
stirred solution of 16k (106 mg, 0.32 mmol) in 5 ml of THF was added dropwise 1 N aqueous
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HCl (1 mL) at 0 °C. Then the reaction mixture was allowed to warm and stirred at rt for 1 h.
THF was evaporated at reduced pressure. Then the reaction mixture was extracted with DCM
(15 mL x 3) and dried over Na2SO4. Evaporation of solvent under reduced pressure afforded
crude product, which was purified by column chromatography on silica gel with
EtOAc/petroleum ether (1:10) as solvent to obtain pure compound 16ka in 74% yield (74 mg,
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0.24 mmol) as sole product. Yellowish liquid; Rf (1:10 EtOAc/hexane) 0.4. H NMR (600
MHz, CDCl3) δ 8.13 (dd, J = 8.1, 1.4 Hz, 1H), 8.09–8.06 (m, 1H), 7.58–7.52 (m, 2H), 6.90
(d, J = 16.5 Hz, 1H), 6.72 (d, J = 16.5 Hz, 1H), 5.12 (s, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 3.86
(s, 3H), 2.00 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.9, 150.8, 150.2, 142.6, 137.1, 129.8,
127.9, 127.7, 126.9, 124.5, 123.9, 123.0, 122.0, 118.5, 63.9, 61.6, 52.7, 18.5. IR (KBr): ν̃ =
3448, 2936, 1734, 1438, 1356, 1286, 1225, 1160, 1086, 1045, 970, 777 cmꢀ1. HRMS (ESIꢀ
TOF) m/z: [M + H]+ Calcd for C19H21O4 313.1440; Found 313.1416.
Mixture of ethyl 3-allyl-1,4-dimethoxy-2-naphthoate (16la) and 7-(ethoxycarbonyl)-
5,8-dimethoxy-6-(prop-1-en-1-yl)naphthalen-2-ylium (16lb), and ethyl (E)-3-(1,4-
dimethoxy-3-methylnaphthalen-2-yl)acrylate (16lc). Annulation reaction was performed
between 15b (238 mg, 1.5 mmol) and 14d (252 mg, 1.8 mmol) with LiHMDS (4.5 mmol)
following the general procedure. Annulation crude product was purified by column
chromatography on silica gel with EtOAc/petroleum ether (1:50) as solvent to obtain 3:2
mixture of 16la and 16lb in 27% yield (122 mg, 0.41 mmol) and pure 16lc in 52% yield (234
mg, 0.78 mmol).
Data for mixture of 16la and 16lb. Yellowish liquid; Rf (1:15 EtOAc/hexane) 0.3; 16la: 1H
NMR (600 MHz, CDCl3): δ 8.12–8.09 (m, 2H), 7.57–7.4.9 (m, 2H), 6.01–5.94 (m, 1H), 5.07
(dq, J = 8.4, 1.8 Hz, 1H), 5.05 (t, J = 1.8 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 3.91
(s, 3H), 3.64 (dt, J = 6.0, 1.8 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
167.9, 150.6, 150.3, 129.7, 129.7, 127.4, 126.4, 125.8, 125.6, 123.1, 122.9, 122.8, 116.1,
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63.7, 62.7, 61.6, 31.7, 14.4. 16lb: H NMR (600 MHz, CDCl3): δ 8.09–8.05 (m, 2H), 7.57–
7.4.9 (m, 2H), 6.60 (dq, J = 16.2, 1.8 Hz, 1H), 6.26 (dq, J = 16.2, 6.6 Hz, 1H), 4.44 (q, J =
7.2 Hz, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 1.93 (dd, J = 6.6, 1.8 Hz, 3H), 1.41 (t, J = 7.2 Hz,
3H). 13C NMR (150 MHz, CDCl3) δ 168.3, 150.1, 149.8, 136.6, 131.8, 127.8, 127.6, 127.4,
126.5, 125.1, 124.3, 124.2, 122.9, 63.8, 61.6, 61.4, 19.6, 14.5. HRMS (ESIꢀTOF) m/z: [M +
H]+ Calcd for C18H21O4 301.1440; Found 301.1436.
Data for 16lc. Colourless liquid; Rf (1:15 EtOAc/hexane) 0.3; 1H NMR (600 MHz, CDCl3): δ
8.12–8.11 (m, 2H), 8.00 (d, J = 16.3 Hz, 1H), 7.54–7.47 (m, 2H), 6.75 (d, J = 16.2 Hz, 1H),
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4.31 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.50 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 13C
NMR (150 MHz, CDCl3) δ 167.7, 152.6, 150.4, 139.2, 129.3, 127.6, 127.4, 126.0, 124.6,
123.9, 123.2, 122.4, 61.6, 61.5, 60.7, 14.5, 13.7. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C18H21O4 301.1440; Found 301.1442.
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General procedure for reduction with DIBAL-H. A solution of 1 M DIBALꢀH in
cyclohexanes (4 equiv) was added to a solution of corresponding esters (1 equiv) in toluene
(20 mL/mmol) at ꢀ20 °C. The reaction mixture was allowed to warm slowly and stirred for 10
h at rt. When the reaction is complete, excess DIBALꢀH was quenched with aqueous
saturated Na2SO4 solution. Then it was filtered through celite pad. Residue part was
thoroughly washed with EtOAc. Crude product was obtained after removal of solvent. Flash
column chromatography was done on silica gel with EtOAc/hexane to afford pure alcohols.
(1,4-Dimethoxy-3-(2-methylallyl)naphthalen-2-yl)methanol (29a). General procedure for
reduction with DIBALꢀH was performed on 16b to afford the alcohol 29a in 94% yield (182
mg, 0.67 mmol). Yellowish liquid; Rf (1:3 EtOAc/hexane) 0.5. 1H NMR (400 MHz, CDCl3) δ
8.16–8.00 (m, 2H), 7.58–7.46 (m, 2H), 4.83–4.82 (m, 1H), 4.81 (s, 2H), 4.34 (s, 1H), 4.00 (s,
3H), 3.88 (s, 3H), 3.67 (s, 2H), 2.20 (bs, 1H), 1.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
151.9, 150.9, 147.0, 129.6, 128.9, 128.01, 128.0, 126.6, 126.1, 122.8, 122.7, 111.1, 63.5,
62.5, 57.9, 34.4, 23.8. IR (KBr): ν̃ = 3432, 2936, 1592, 1448, 1355, 1271, 1194, 1100, 1061,
1030, 1003, 970, 891, 774, 719 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C17H20O3Na 295.1310; Found 295.1317.
(1,4,5-Trimethoxy-3-(2-methylallyl)naphthalen-2-yl)methanol (29c). General procedure
for reduction with DIBALꢀH was performed on 16c to afford the alcohol 29c in 96% yield
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(224 mg, 0.74 mmol). Yellowish liquid; Rf (1:2 EtOAc/hexane) 0.4. H NMR (400 MHz,
CDCl3) δ 7.71 (dd, J = 8.4, 1.0 Hz, 1H), 7.44–7.35 (m, 1H), 6.90 (dd, J = 7.7, 1.0 Hz, 1H),
4.81–4.80 (m, 1H), 4.79 (s, 2H), 4.34–4.30 (m, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.77 (s, 3H),
3.66 (s, 2H), 2.33 (bs, 1H), 1.91 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 156.3, 151.5, 151.0,
147.6, 130.5, 130.3, 129.0, 126.2, 121.0, 115.3, 111.0, 106.8, 63.3, 62.7, 58.1, 56.4, 34.2,
23.8. IR (KBr): ν̃ = 3448, 2933, 2838, 1594, 1575, 1461, 1448, 1369, 1336, 1265, 1118,
1073, 982, 899, 764 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H22O4Na
325.1416, [M ꢀ H2O + H]+ Calcd for C18H21O3 285.1491; Found 325.1429, 285.1508.
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(1,4,6,8-Tetramethoxy-3-(2-methylallyl)naphthalen-2-yl)methanol
(29d).
General
procedure for reduction with DIBALꢀH was performed on 16d to afford the alcohol 29d,
which could not be purified by column chromatography. So impure product, obtained after
column chromatography, was directly used for the next step. Yellowish liquid; Rf (1:1
EtOAc/hexane) 0.5.
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(1,4,5,7-Tetramethoxy-3-(2-methylallyl)naphthalen-2-yl)methanol
(29e).
General
procedure for reduction with DIBALꢀH was performed on 16e to afford the alcohol 29e in
91% yield (269 mg, 0.81 mmol). Yellowish liquid; Rf (1:1 EtOAc/hexane) 0.5. 1H NMR (600
MHz, CDCl3) δ 7.00 (d, J = 2.3 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 4.79–4.78 (m, 1H), 4.76 (s,
2H), 4.32–4.31 (m, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.74 (s, 3H), 3.61 (s, 2H),
2.41 (bs, 1H), 1.89 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 158.4, 157.6, 151.2, 150.6, 147.7,
131.0, 130.7, 126.5, 116.8, 110.9, 99.7, 93.3, 62.7, 62.6, 58.1, 56.3, 55.5, 34.0, 23.7. IR
(KBr): ν̃ = 3449, 2930, 2838, 1620, 1598, 1449, 1410, 1379, 1340, 1262, 1235, 1204, 1158,
1121, 1083, 1059, 998, 889, 833 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C19H25O5
333.1702; Found 333.1717.
(1,4,6,7-Tetramethoxy-3-(2-methylallyl)naphthalen-2-yl)methanol
(29f).
General
procedure for reduction with DIBALꢀH was performed on 16f to afford the alcohol 29f in
95% yield (229 mg, 0.69 mmol). Yellowish liquid; Rf (1:1 EtOAc/hexane) 0.5. 1H NMR (600
MHz, CDCl3) δ 7.36 (s, 1H), 7.34 (s, 1H), 4.81 (t, J = 2.0 Hz, 1H), 4.77 (s, 2H), 4.35 (d, J =
2.2 Hz, 1H), 4.02 (d, J = 2.0 Hz, 6H), 3.99 (s, 3H), 3.86 (s, 3H), 3.62 (s, 2H), 2.19 (s, 1H),
1.90 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 151.0, 150.3, 149.9, 149.8, 147.4, 128.0, 126.3,
124.5, 123.5, 111.0, 101.7, 63.1, 62.0, 58.0, 56.2, 56.1, 34.4, 23.7. ν̃ = 3428, 2820, 1590,
1508, 1476, 1428, 1382, 1320, 1258, 1220, 1170, 772 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C19H24O5Na 355.1521, [M ꢀ H2O + H]+ Calcd for C19H23O4 315.1596; Found
355.1518, 315.1594.
(3-(2-Ethylbut-2-en-1-yl)-1,4-dimethoxynaphthalen-2-yl)methanol
(29g).
General
procedure for reduction with DIBALꢀH was performed on 16h to afford 1:1 diastereomeric
mixture of the alcohol 29g in 97% yield (228 mg, 0.76 mmol). Yellowish liquid; Rf (1:3
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EtOAc/hexane) 0.3. H NMR (600 MHz, CDCl3) δ 8.15–8.01 (m, 4H), 7.54–7.48 (m, 4H),
5.41 (q, J = 6.8 Hz, 1H), 4.83 (s, 2H), 4.80 (s, 2H), 4.75 (q, J = 6.7 Hz, 1H), 4.01 (s, 3H),
4.00 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.83 (s, 2H), 3.68 (s, 2H), 2.37 (s, 1H), 2.22 (q, J =
7.6 Hz, 2H), 1.86 (d, J = 6.8 Hz, 3H), 1.79 (q, J = 7.4 Hz, 2H), 1.54 (d, J = 6.7 Hz, 3H), 1.14
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(t, J = 7.6 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). C NMR (150 MHz, CDCl3) δ 152.0, 151.8,
151.3, 151.0, 142.9, 141.8, 129.9, 129.9, 128.9, 128.9, 128.9, 128.8, 128.2, 128.0, 128.0,
126.6, 126.6, 126.0, 126.0, 122.9, 122.9, 122.8, 122.7, 118.9, 118.3, 63.6, 63.5, 62.44, 62.2,
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57.9, 57.6, 32.9, 28.4, 27.5, 24.7, 13.6, 13.1, 13.0, 12.9. IR (KBr): ν̃ = 3432, 2934, 1591,
1458, 1355, 1269, 1193, 1100, 1054, 1000, 972, 772, 727 cmꢀ1. HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C19H24O3Na 323.1623, [M ꢀ H2O + H]+ Calcd for C19H23O2 283.1698; Found
323.1616, 283.1704.
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(3-(2-Ethylbut-2-en-1-yl)-1,4,6,7-tetramethoxynaphthalen-2-yl)methanol
(29h).
General procedure for reduction with DIBALꢀH was performed on 16i to afford 1:1
diastereomeric mixture of the alcohol 29h in 84% yield (321mg, 0.89 mmol). Yellowish
liquid; Rf (1:2 EtOAc/hexane) 0.4. 1H NMR (600 MHz, CDCl3) δ 7.35 (s, 0.7H), 7.34 (s, 2H),
7.33 (s, 0.7H), 5.38 (q, J = 6.8 Hz, 1H), 4.78 (s, 2H), 4.75 (s, 1.4H), 4.74 (q, J = 6.6 Hz,
0.7H), 4.02 (s, 3H), 4.01 (s, 2.1H), 4.01 (s, 2.1H), 4.01 (s, 3H), 3.98 (s, 2.1H), 3.96 (s, 3H),
3.86 (s, 3H), 3.83 (s, 2.1H), 3.76 (s, 2H), 3.62 (s, 1.4H), 2.19 (q, J = 7.2 Hz, 1.4H), 1.83 (d, J
= 6.8 Hz, 3H), 1.77 (q, J = 7.2 Hz, 2H), 1.52 (d, J = 6.6 Hz, 2.1H), 1.11 (t, J = 7.2 Hz, 2.1H),
0.89 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 151.0, 150.8, 150.3, 150.2, 150.2,
149.9, 149.8, 149.7, 143.1, 142.1, 128.2, 128.1, 127.2, 126.5, 124.5, 124.3, 123.4, 123.3,
118.7, 118.1, 101.7, 101.7, 101.6, 101.6, 63.1, 63.1, 61.9, 61.7, 57.9, 57.6, 56.1, 56.1, 32.8,
28.3, 27.3, 24.6, 13.6, 13.1, 13.0, 12.8. IR (KBr): ν̃ = 3518, 2930, 1626, 1600, 1507, 1473,
1457, 1428, 1325, 1258, 1207, 1192, 1170, 1107, 1027, 1012, 979, 853, 779 cmꢀ1. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C21H28O5Na 383.1834; Found 383.1844.
General procedure for oxidation with DMP. To a stirred solution of alchols (1 equiv)
in dry DCM (20 mL/ mmol) was added NaHCO3 (5 equiv), DMP (1.3 equiv) at 0 °C. The
reaction mixture was allowed to warm and stirred for 4 h at rt. The reaction mixture was
diluted with DCM. The extract was washed with Na2S2O3, NaHCO3 and brine solution and
dried over Na2SO4. Removal of the solvent under reduced pressure followed by flash column
chromatography on silica gel with EtOAc/haxane afforded the desired aldehydes in very good
yields.
1,4-Dimethoxy-3-(2-methylallyl)-2-naphthaldehyde (30a). General procedure for
oxidation with DMP was performed on alcohol 29a to afford the aldehyde 30a in 88% yield
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(154 mg, 0.57 mmol). Yellowish liquid; Rf (1:20 EtOAc/hexane) 0.3. H NMR (600 MHz,
CDCl3) δ 10.60 (s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.67 (t, J = 7.6 Hz,
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