Methoxycarbonyl migration in 3-methylene-1,4-cyclohexadienes. An extension of the von Auwers rearrangement This article is dedicated to Professor Neil Garg, recipient of the 2015 Tetrahedron Young Investigator award

Article abstract of DOI:10.1016/j.tet.2016.03.032

Upon heating, 3-methylene-1,4-cyclohexadienes possessing an alkoxycarbonyl substituent in position 6 undergo rearrangement and concomitant aromatization to give the corresponding arylacetates. This transformation represents a modification of the von Auwers rearrangement and proceeds by a radical chain mechanism. The intermediate alkoxycarbonyl radical can be intercepted allowing further useful synthetic variations.

Full text of DOI:10.1016/j.tet.2016.03.032

Accepted Manuscript
Methoxycarbonyl Migration in 3-Methylene-1,4-cyclohexadienes. An Extension of the
von Auwers Rearrangement
Mehdi Boumediene, Raphaël F. Guignard, Samir Z. Zard
PII:
S0040-4020(16)30164-8
10.1016/j.tet.2016.03.032
TET 27572
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 January 2016
Revised Date: 7 March 2016
Accepted Date: 8 March 2016
Please cite this article as: Boumediene M, Guignard RF, Zard SZ, Methoxycarbonyl Migration in 3-
Methylene-1,4-cyclohexadienes. An Extension of the von Auwers Rearrangement, Tetrahedron (2016),
doi: 10.1016/j.tet.2016.03.032.
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ACCEPTED MANUSCRIPT
Methoxycarbonyl Migration in 3-Methylene-1,4-cyclohexadienes. An Extension of the von
Auwers Rearrangement.
Mehdi Boumediene, Raphaël F. Guignard and Samir Z. Zard*
Graphical abstract
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Methoxycarbonyl Migration in 3-Methylene-1,4-cyclohexadienes. An Extension of the von
Auwers Rearrangement.
Mehdi Boumediene, Raphaël F. Guignard and Samir Z. Zard*
Laboratoire de Synthèse Organique associé au C. N. R. S., Département de Chimie, Ecole
Polytechnique, F-91128 Palaiseau, France.
Fax: +33 169335972; Tel: +33 169335971
E-mail: samir.zard@polytechnique.edu
† This article is dedicated to Prof. Neil Garg, recipient of the 2015 Tetrahedron Young
Investigator award
Abstract: Upon heating, 3-methylene-1,4-cyclohexadienes possessing an alkoxycarbonyl
substituent in position 6 undergo rearrangement and concomitant aromatization to give the
corresponding arylacetates. This transformation represents a modification of the von Auwers
rearrangement and proceeds by a radical chain mechanism. The intermediate alkoxycarbonyl
radical can be intercepted allowing further useful synthetic variations.
Keywords: von Auwers rearrangement; radical chain; aromatics.
1
Introduction
In connection with an industrial project, we required a concise synthesis of aromatic
structures related to compounds 1-3. These belong to a family of potent antagonists of
specific receptors of human thromboxane A2, a most powerful inducer of platelet
aggregation, bronchoconstriction and vasoconstriction. Ramatroban, for example, has found
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clinical use against allergic rhinitis and asthma.1 Our task was to devise an original route to
Terutroban and analogs thereof.
Figure 1. Examples of antagonists of thromboxane A2 receptors.
One promising route to the Terutroban family, outlined in Scheme 1, relied on a classical
Robinson annelation between ketoester 4 and enones 5a,b. The Michael addition leading to
the corresponding adducts 6a,b could be induced with triethylamine in methanol and
proceeded smoothly and quantitatively. The ring-closing aldol and crotonization were
accomplished with sodium methylate. The resulting cyclohexenones 7a,b were next
dehydrogenated by oxidation with selenium dioxide into the corresponding
cyclohexadienones 8a,b followed by addition of methylithium to give dienols 9a,b in
acceptable, non-optimized overall yield. The subsequent key step in the sequence called for a
Krapcho-type cleavage of the methyl ester2 and concomitant decarboxylation and
aromatisation by elimination of a water molecule (9a,b → 10a,b → 11a,b). Heating 9a or 9b
with lithium chloride in DMSO resulted in a clean transformation; however, the product,
isolated in good yield in either case, was neither 11a nor 11b. The spectroscopic data
indicated the structures to be 12a and 12b, respectively. An nmr experiment in deuterated
DMSO indicated that lithium chloride is not necessary and that elimination of water starts
taking place at around 75 °C, but the rearrangement only starts at temperatures higher than
110 °C.
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Scheme 1. An unexpected von Auwers rearrangement.
2
Results and Discussion
The most plausible mechanistic pathway for this transformation is displayed in Scheme 2 and
involves a radical chain process that sets in after a dehydration step leading to triene
intermediates 13a,b. Thermolysis leads to the formation of a small amount of
methoxycarbonyl radicals 14 which initiate the addition-fragmentation chain reaction.
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Scheme 2. A radical chain mechanism.
Cleavage of a carbon-carbon bond in 1,4-cyclohexadienyl and related radicals is well
precedented, even if the process has not received the attention it deserves from synthetic
organic chemists. As early as 1897, Guareschi described the reaction that bears his name,
whereby exposure of cyclic imide 16 to ammonia or magnesium hydroxide causes its gradual
conversion into 17 with release of ethane gas (Scheme 3).3 This transformation is believed to
proceed via fragmentation of intermediate hydropyridinyl radical (c.f. all carbon analog 19)
to furnish an ethyl radical (an not the less stable methyl radical). Later, it was found that
addition of radicals to aromatic rings is a reversible process, even for unstabilized radicals
such as methyl or even aryl radicals.4 This ready reversibility, due to the important energy
gain when aromaticity is restored, is indeed the key element that allows benzene and other
aromatic solvents to be used as media for many radical reactions. The reversible addition of
radicals to aromatic solvents can nevertheless cause a considerable slowing down of the
overall radical process.5 More recently, Studer and Walton have exploited the aromatisation
to generate carbon, nitrogen and silicon centered radicals from the appropriate 1,4-
dihydrobenzene precursors (Scheme 3).6
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Scheme 3. Fragmentations of cyclohexadienyl and related radicals.
Thus, hydrogen atom abstraction from cyclohexadienes 18 generates radical 19, which
undergoes fragmentation to produce methoxycarbonyl radical 14.7 Precursors 18 are readily
obtained through the Birch reduction but the competing generation of radical R• diminishes
somewhat the synthetic utility of this approach. Walton and collaborators extended this
strategy to the formation of carbamoyl radicals by starting with the amide analogs 20.8 Studer
expanded this concept to organosilicon derivative 21, a reagent allowing the convenient
generation of silyl radicals which can then be engaged in various reactions typical of these
species.9 In yet another variation, Studer proposed derivatives 22 and 23 as sources of
nitrogen centered radicals.10 The latter, hydrazide based reagents are easily accessible and
therefore particularly attractive.
A closer analogy to our work is the rearrangement discovered by von Auwers at the turn of
the 20th century. It concerns the isomerization of cylohexadienes 24 into aromatic derivatives
25.11 This transformation was initially thought to proceed by an ionic mechanism but, some
50 years later, evidence adduced first by Bird and Cookson and subsequently by a few other
groups pointed firmly to a radical chain mechanism analogous to the one displayed in Scheme
2.12 The rearrangement was also extended to allylic and benzylic groups by Miller and Lai in
1972 (Scheme 4, 26 → 27),12d but, as far as we know, no isomerizations involving
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alkoxycarbonyl groups have been described.
Scheme 4. Early examples of the von Auwers rearrangement.
We accidentally stumbled into this variation of the von Auwers rearrangement and, while it
was ancillary to the initial purpose of accessing analogs of Terutroban 3, we were curious to
explore, even briefly, its scope and synthetic potential. We therefore prepared a series of
similar substrates and examined their behavior. Five-, six-, and seven-membered ring
ketoesters 28a-c were thus subjected to the Robinson annelation sequence to give bicyclic
enones 30a-c (Scheme 5). In the case of the five- and six-membered Michael adducts 29a and
29b, heating with catalytic amounts of piperidine and acetic acid in refluxing toluene proved
effective for the ring-closure, whereas the seven-membered ring congener 29c required
heating with sodium methylate in methanol. Dehydrogenation with selenium dioxide,
addition of methyl lithium and dehydration gave a moderate overall yield of the
corresponding key precursors 32a-c for the von Auwers rearrangement. Disappointingly,
heating 32a in DMSO led mostly to decomposition, in contrast to 32b and 32c which
furnished a reasonable yield of the rearranged products 33b and 33c respectively (Scheme 5).
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Scheme 5. Further examples of methoxycarbonyl migration.
The conditions for rearrangement could perhaps have been rendered milder by inducing the
chain reaction at a lower temperature with the help of added radical initiators. This was not
done in this case but it is certainly feasible (c.f. reaction in Scheme 9 below). We also noticed
a complication arising from the propensity of compounds 32a-c, and especially 32a, to
isomerize into compounds 34a-c (Scheme 6). This occurred even upon standing in deuterated
chloroform which had been filtered through a pad of alumina. Traces of acid and/or metallic
salts could catalyze this process. Halogenated solvents are known to contain sometimes trace
amounts of copper and iron salts. Isomers 34a-c cannot obviously undergo the desired
rearrangement.
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Scheme 6. Acid induced alkene shift.
With these considerations in mind, we next studied the rearrangement of substrates 38a and
38b, which cannot undergo the above isomerization. They were prepared by an identical
sequence starting from aromatic ketoesters 35a and 35b (Scheme 7). We were pleased to find
that heating compounds 38a and 38b in DMSO triggered the desired transformation leading
to aromatized products 39a and 39b respectively in high yield. We made an interesting
observation when we attempted to convert the ester group in 38b into an amide and thus
extend the von Auwers rearrangement to the amide series. All our attempts at accomplishing
this transformation using a number of primary and secondary amines under typical aminolysis
conditions failed, in all likelihood because of the congested environment of the tertiary ester
group. In a last desperate essay, we tried to activate the ester with anhydrous aluminum
trichloride in cold dichloromethane according to a procedure recommended by Wenkert and
Liu.13 A clean reaction ensued to give rearranged product 40 in nearly quantitative yield
(Scheme 7). This reaction was complete in a few seconds and occurred in the presence or
absence of the amine partner. The mechanism is presumably cationic, of the Friedel-Crafts
type, but whether it is an intra- or inter-molecular process will have to be determined by
further experimentation. Its generality also needs to be ascertained as, from a synthetic
standpoint, it could serve as a convenient route to aromatic structures with unusual
substitution patterns.
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Scheme 7. Examples starting with aromatic ketoesters.
Transesterification proved easier to accomplish and, by exposing compound 38b to 3-buten-
1-ol in the presence of lithium hydride, we could convert the methyl ester into butenyl ester
41 in good yield (Scheme 8). Heating this substance in DMSO gave rise to lactone 42, also in
good yield. In this case, the alkoxycarbonyl radical intermediate 43 can cyclise into primary
radical 44,14 which then undergoes addition on the more reactive exocyclic alkene in substrate
41. This transformation illustrates some of the synthetic potential of the present
rearrangement and further confirms the radical nature of the process.
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Scheme 8. Example of lactone formation.
Finally, we performed the rearrangement in the presence of xanthate 45 as a radical relay
(Scheme 9). The underlying assumption is that the methoxycarbonyl radical intermediate 14
will react with the radicophilic xanthate 45 to generate the more stable cyanomethyl radical
47, and this in turn will react with substrate 38b to give nitrile 46. The reaction of
cyanomethyl radical 47 with its xanthate precursor 45 is reversible and degenerate, and does
not compete with the desired transformation.15 In the event, heating a solution of compound
38b and xanthate 45 in refluxing heptane in the presence of 3 x 10 mol% of lauroyl peroxide
led to a 1:0.3 mixture of the desired product 46 and the “normal” von Auwers rearrangement
product 39b. These could not be separated easily by chromatography and the mixture was
thus treated with methanolic potassium hydroxide at room temperature; this caused selective
saponification of the latter and allowed clean separation from the former. In this manner,
nitrile 46 was obtained in a modest but unoptimized 40% yield. The generality and scope of
this variation remain to be determined by further experimentation but this promising
preliminary result is very encouraging.
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Scheme 9. Another variation on the von Auwers rearrangement.
3
Conclusion
In summary, we have described a synthetically useful variation on the venerable, but little
known von Auwers rearrangement. Our results are preliminary and require a more systematic
optimization of the experimental conditions and a better delineation of the substrate scope.
There are also numerous conceivable modifications and extensions that have to be tested.
Nevertheless, this study opens the way for interesting and unusual approaches to aromatic
derivatives and it is hoped that it will encourage synthetic chemists to revisit this chemistry
and explore its potential.
4
Experimental
4.1 General Experimental Methods
Purification procedures were in accordance with the instructions in D. D. Perrin and W. L. F.
Armarego, “Purification of Laboratory Chemicals”, Fourth Edition, The Bath Press, Bath,
2002. All reactions were carried out under dry, oxygen free nitrogen. Flash chromatography
was performed on silica gel (SDS, 60 Å C. C. 40-63 mm) as the stationary phase. Thin Layer
Chromatography (TLC) was performed on alumina plates pre-coated with silica gel (Merck
silica gel, 60 F254), which were visualized by the quenching of UV fluorescence when
applicable (λmax = 254 nm and/or 366 nm) and/or by staining with vanillin or anisadehyde in
acidic ethanol followed by heating. Infrared spectra were recorded as solutions in CH2Cl2
using NaCl cells, on a Perkin-Elmer FT 2000. Absorption maxima (nmax) are reported in
wavenumbers (cm−1) and only selected peaks are reported. Magnetic resonance spectra were
recorded at room temperature on a Bruker Avance DPX 400 instrument. Proton magnetic
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resonance spectra (1H NMR) were recorded at 400 MHz and coupling constants (J) are
reported to ± 0.5 Hz. The following abbreviations were utilized to describe peak patterns
when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, quint =
quintuplet, hex = hexuplet, hept = heptuplet, oct = octuplet and m = multiplet. Carbon
magnetic resonance spectra (13C NMR) were recorded in the same instrument at 100.6 MHz.
Chemical shifts (δH, δC) are quoted in parts per million (ppm) and are referenced to TMS (0
ppm). Low-resolution mass spectra (m/z) were recorded by chemical ionization (CI/NH3) on
a Hewlett-Packard HP 5989B and only report molecular species ([M+H]+, [M+NH4]+) and
other major fragments. High-resolution mass spectra were recorded by positive electron
impact ionization (EI+) at 70 e.V. on a JEOL JMS-GCmate II mass spectrometer. The quoted
masses are accurate to ± 5 ppm. The names of the molecules that appear in the following
pages were generated using either Beilstein AutoNom 2000 (CAS) or ChemBioDraw Ultra
11.0. Ketoesters 4, 28a,b,c, and 35a,b were prepared by literature procedures.16
4.2 General procedures
4.2.1 General procedure for the preparation of methyl β-ketoesters
A solution of freshly distilled dimethyl carbonate (12 eq.) and ketone (1 eq.) in anhydrous THF
(0.5 mL/mmol of ketone) was added to a suspension of NaH (60%wt, 1.4 eq., previously washed
with n-pentane under nitrogen) in anhydrous THF (1 mL/mmol of ketone). The mixture was
refluxed until starting ketone was totally consumed (about 3 h) then cooled to 0 °C and acetic
acid (1.6 mL of a 10% aqueous solution per mmol of ketone) was added. The organic layer was
separated and the aqueous phase further extracted with Et2O. The combined organic layers were
washed with saturated sodium hydrogen carbonate solution and brine, dried over magnesium
sulfate, filtrated and concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel to yield the desired β-ketoester.
4.2.2 General procedure for the Michael addition and Robinson annulation
The vinyl ketone (2 eq.) was added to a solution of β-ketoester (1 eq.) in methanol (2 mL/mmol
of β-ketoester). Triethylamine (0.3 eq.) was then added and the mixture was refluxed until the
starting β-ketoester was totally consumed (1 to 3 h). The mixture was concentrated under reduced
pressure and the resulting oil was purified by flash column chromatography on silica gel to yield
the desired diketone.
Sodium methylate was prepared by dissolving sodium (2.5 eq.) in methanol (7 mL/mmol of
diketone), and this solution was added to the diketone (1 eq.). The mixture was refluxed until the
diketone was totally consumed (about 2 h). The solvent was removed under reduced pressure,
Et2O and water were then added, the organic layer was separated and the aqueous phase extracted
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with Et2O. The combined organic layers were washed with brine, dried over magnesium sulfate,
filtrated and concentrated under reduced pressure to yield the desired enone.
4.2.3 General procedure for oxidation using selenium dioxide
A solution of the enone (1 eq.), selenium dioxide (2.4 eq.), and pyridine (1 drop/mmol of enone)
in t-butanol (20 mL/mmol of enone) was stirred at reflux until the enone was totally consumed
(24 to 48 h). The mixture was filtered over silica gel (elution with ethyl acetate), and
concentrated under reduced pressure. The residue was purified by flash column chromatography
on silica gel to yield the desired dienone.
4.3 Experimental Procedures and Spectroscopic Data
4.3.1 Methyl 8-Oxo-7-(3-oxo-butyl)-1,4-dioxa-spiro[4.5]decane-7-carboxylate (6a)
Following the general procedure for Michael addition, the reaction was carried out using
ketoester 4 (3.63 g, 16.9 mmol) and methyl vinyl ketone (2.75 mL, 33.9 mmol) as Michael
acceptor. Flash column chromatography (ethyl acetate-petroleum ether: 90-10 to 75-25) gave 6a
1
(4.81 g, quant.) as a pale yellow oil. H NMR (400 MHz, CDCl3): δH 4.06-3.91 (m, 4H), 3.73 (s,
3H), 3.09-2.97 (m, 1H), 2.72 (ddd, 1H, J = 4.8, 10.6, 16.0 Hz), 2.58 (d, 1H, J = 13.0 Hz), 2.47 (td,
1H, J = 4.2, 14.4 Hz), 2.23 (ddd, 1H, J = 5.1, 10.9, 16.2 Hz), 2.12 (s, 3H), 2.06-1.95 (m, 3H),
13
1.85-1.73 (m, 1H), 1.76 (d, 1H, J = 13.8 Hz). C NMR (100 MHz; CDCl3): δC 207.5, 207.1,
172.7, 106.5, 64.9, 64.3, 57.2, 52.3, 42.5, 38.9, 37.7, 35.3, 29.9, 28.9. IR (CCl4): νmax (cm-1) 2954,
1751, 1732, 1164. HRMS (EI, m/z): calculated (found) for C14H20O6, 284.1260 (284.1258).
4.3.2 Methyl 8-oxo-7-(3-oxo-octyl)-1,4-dioxa-spiro[4.5]decane-7-carboxylate (6b)
Following general procedure for Michael addition, the reaction was carried out using ketoester 4
(1.70 g, 7.94 mmol) and 2-octen-3-one (2.0 g, 15.9 mmol) as Michael acceptor. Flash column
chromatography (ethyl acetate-petroleum ether: 90-10 to 75-25) gave 6b (2.70 g, quant.) as a pale
1
yellow oil. H NMR (400 MHz, CDCl3): δH 4.03-3.85 (m, 4H), 3.68 (s, 3H), 3.05-2.91 (m, 1H),
2.62 (ddd, 1H, J = 4.9, 10.9, 17.4 Hz), 2.53 (d, 1H, J = 13.9 Hz), 2.41 (td, 1H, J = 3.9, 14.5 Hz),
2.32 (t, 2H, J = 7.3 Hz), 2.15 (m, 1H), 2.04-1.91 (m, 3H), 1.80-1.71(m, 1H), 1.72 (d, 1H, J = 13.9
13
Hz), 1.50 (q, 2H, J = 7.4 Hz), 1.31-1.14 (m, 4H), 0.83 (t, 3H, J = 7.0 Hz). C NMR (100 MHz;
CDCl3): δC 209.8, 206.9, 172.6, 106.4, 64.8, 64.2, 57.2, 52.2, 42.7, 42.4, 37.8, 37.6, 35.2, 31.3,
28.8, 23.4, 22.3, 13.8. IR (CCl4): νmax (cm-1) 2958, 1751, 1728, 1160. HRMS (EI, m/z) calculated
(found) for C18H28O6, 340.1886 (340.1886).
4.3.3 Methyl 6'-Oxo-4',6',7',8'-tetrahydro-3'H-spiro[[1,3]dioxolane-2,2'-naphthalene]-8'a-
carboxylate (7a)
Following general procedure for Robinson annulation, the reaction was carried out starting with
diketone 6a (4.32 g, 15.2 mmol) and gave crude 7a (2.71 g, 67%) as a pale yellow oil. 1H NMR
(400 MHz, CDCl3): δH 5.97 (s, 1H), 4.05-3.83 (m, 4H), 3.73 (s, 3H), 2.96-2.84 (m, 1H), 2.61 (dd,
1H, J = 2.7, 13.7 Hz), 2.52-2.44 (m, 1H), 2.38-2.28 (m, 2H), 2.25-2.14 (m,1H), 1.97-1.72 (m,
13
3H), 1.51 (d, 1H, J = 13.7 Hz). C NMR (100 MHz; CDCl3): δC 198.3, 173.9, 160.3, 127.2,
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107.0, 64.7, 64.3, 52.6, 48.4, 43.9, 35.8, 34.8, 34.4, 31.6. IR (CCl4): νmax (cm-1) 2953, 1736, 1684,
1223. HRMS (EI, m/z) calculated (found) for C14H18O5, 266.1154 (266.1161).
4.3.4 Methyl 5'-butyl-6'-oxo-4',6',7',8'-tetrahydro-3'H-spiro[[1,3]dioxolane-2,2'-
naphthalene]-8'a-carboxylate (7b)
Following the general procedure for the Robinson annulation, the reaction was carried out
starting with diketone 6b (2.00 g, 5.88 mmol) and gave crude 7b (1.36 g, 72%) as a pale yellow
1
oil. H NMR (400 MHz, CDCl3): δH 4.06-3.85 (m, 4H), 3.71 (s, 3H), 2.94-2.85 (m, 1H), 2.70-
2.63 (m, 1H), 2.58 (dd, J = 3.0, 13.7 Hz, 1H), 2.48-2.30 (m, 3H, CH 10), 2.29-2.14 (m, 2H), 1.94-
1.82 (m, 2H, CH-5), 1.77-1.68 (m, 1H), 1.54 (d, 1H, J = 13.7 Hz), 1.38-1.24 (m, 4H), 0.90 (t, 3H,
J = 6.2 Hz). 13C NMR (100 MHz; CDCl3): δC 197.5, 174.6, 153.0, 136.8, 106.9, 64.6, 64.2, 52.4,
49.1, 44.5, 35.3, 34.8, 34.7, 31.4, 26.9, 25.1, 22.7, 14.0. IR (CCl4): νmax (cm-1) 2958, 1742, 1675,
1220. HRMS (EI, m/z) calculated (found) for C18H26O5, 322.1780 (322.1782).
4.3.5 Methyl 6'-oxo-4',6'-dihydro-3'H-spiro[[1,3]dioxolane-2,2'-naphthalene]-8'a-
carboxylate (8a)
Following the general procedure for oxidation with selenium dioxide, the reaction was carried out
starting with enone 7a (2.71 g, 10.2 mmol). Purification by flash column chromatography
(petroleum ether-ethyl acetate: 80-20) gave dienone 8a (1.36 g, 51%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): δH 6.74 (d, 1H, J = 9.8 Hz), 6.30-6.24 (m, 2H, CH-2), 4.08-3.90 (m, 4H),
3.73 (s, 3H), 3.02 (tdd, 1H, J = 1.5, 5.3, 14.1 Hz), 2.77 (dd, 1H, J = 3.0, 13.4 Hz), 2.53 (ddd, 1H,
J = 2.2, 4.8, 14.0 Hz), 1.93 (ddt, 1H, J = 2.6, 5.3, 12.7 Hz), 1.75 (td, 1H, J = 4.9, 14.1 Hz), 1.52
(d, 1H, J = 13.4 Hz). 13C NMR (100 MHz; CDCl3): δC 185.7, 170.1, 158.7, 147.7, 129.4, 127.0,
107.2, 64.9, 64.3, 53.1, 52.0, 42.3, 35.8, 31.6. IR (CCl4): νmax (cm-1) 2954, 2887, 1737, 1671.
HRMS (EI, m/z) calculated (found) for C14H16O5, 264.0998 (264.099).
4.3.6 Methyl 5'-butyl-6'-oxo-4',6'-dihydro-3'H-spiro[[1,3]dioxolane-2,2'-naphthalene]-8'a-
carboxylate (8b)
Following the general procedure for oxidation with selenium dioxide, the reaction was carried out
starting with enone 7b (530 g, 1.64 mmol). Purification by flash column chromatography
1
(petroleum ether-ethyl acetate: 80-20) gave dienone 8b (400 mg, 76%) as a colorless oil. H
NMR (400 MHz, CDCl3): δH 6.67 (d, 1H, J = 9.8 Hz), 6.28 (d, 1H, J = 9.8 Hz), 4.09-3.92 (m,
4H), 3.71 (s, 3H), 3.02 (ddd, 1H, J = 2.8, 4.5, 14.3 Hz), 2.75 (td, 1H, J = 4.8, 14.7 Hz), 2.75 (d,
1H, J = 13.4 Hz), 2.57-2.41 (m, 2H), 1.97-1.89 (m, 1H), 1.66 (ddd, 1H, J = 4.7, 12.9, 14.3 Hz),
13
1.51 (d, 1H, J = 13.4 Hz), 1.41-1.28 (m, 4H), 0.91 (t, 3H, J = 7.0 Hz). C NMR (100 MHz;
CDCl3): δC 185.0, 170.7, 151.9, 146.7, 136.9, 129.2, 107.3, 64.8, 64.2, 52.9, 52.0, 42.5, 35.7,
31.6, 22.7, 26.7, 24.7, 14.0. IR (CCl4): νmax (cm-1) 2963, 2872, 1728, 1674. HRMS (EI, m/z)
calculated (found) for C18H24O5, 320.1624 (320.1624).
4.3.7 Methyl 6'-hydroxy-6'-methyl-4',6'-dihydro-3'H-spiro[[1,3]dioxolane-2,2'-
naphthalene]-8'a-carboxylate (9a)
To a solution of dienone 8a (833 mg, 3.2 mmol) in Et2O (12.5 mL) maintained at -78°C was
slowly added ethereal methyllithium (1.2 M, 2.65 mL, 3.2 mmol). The mixture was stirred at –
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78°C for 1 h then poured onto a saturated ammonium chloride solution, and the layers were
separated. The aqueous layer was extracted with Et2O and the combined organic layers were
washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced
pressure. Purification by flash column chromatography (petroleum ether-ethyl acetate: 80-20)
gave carbinol 9a (662 mg, 75%) as colorless oil, consisting of an inseparable mixture of two
1
diastereoisomers (dr = 85:15) which was used directly in the next step. H NMR (400 MHz,
CDCl3): δH 7.26 (s, 1H), 6.73 (d, 1H, J = 8.2 Hz), 6.59 (d, 1H, J = 8.2 Hz), 4.03-3.99 (m, 4H),
2.94-2.89 (m, 4H), 2.59 (t, 2H, J = 7.3 Hz), 1.94 (t, 2H, J = 6.9 Hz), 1.51-1.35 (m, 4H), 0.93 (t,
13
3H, J = 7.0 Hz). C NMR (100 MHz; CDCl3; major diastereoisomer): δC 173.0, 136.5, 133.2,
128.9, 128.6, 107.8, 65.6, 64.5, 64.0, 52.3, 48.5, 42.6, 36.4, 30.8, 28.8.
4.3.8 Methyl 5'-butyl-6'-hydroxy-6'-methyl-4',6'-dihydro-3'H-spiro[[1,3]dioxolane-2,2'-
naphthalene]-8'a-carboxylate (9b) and olefin (13b)
To a solution of dienone 8b (259 mg, 0.81 mmol) in Et2O (3.5 mL) maintained at -78°C was
slowly added ethereal methyllithium (1.2 M, 675 ꢀL, 0.81 mmol). The mixture was stirred at -
78°C for 1 h then poured onto a saturated ammonium chloride solution, and the layers were
separated. The aqueous layer was extracted with Et2O and the combined organic layers were
washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced
pressure. Purification by flash column chromatography (petroleum ether-ethyl acetate: 80-20)
gave 9b (253 mg, 93%) as colorless oil, consisting of an inseparable mixture of 2
diastereoisomers, which rapidly evolved into a mixture with olefin 13b. This carbinol was
1
therefore used quickly in the next step. NMR data for olefin 13b : H NMR (400 MHz, CDCl3):
δH 6.21 (d, 1H, J = 9.6 Hz), 5.56 (d, 1H, J = 9.6 Hz), 5.11 (s, 1H), 4.89 (s, 1H), 4.02-3.86 (m,
4H), 3.67 (s, 3H), 2.88-2.80 (m, 1H,), 2.67-2.55 (m, 1H), 2.58-2.47 (m, 1H), 2.44-2.37 (m, 1H),
1.86-1.78 (m, 1H), 1.67-1.57 (m, 1H), 1.52 (d, 1H, J = 13.3 Hz), 1.43-1.32 (m, 4H), 0.93 (t, 3H, J
= 7.0 Hz). 13C NMR (100 MHz; CDCl3): δC 173.2, 137.9, 134.1, 131.0, 129.5, 129.4, 111.7,
107.7, 64.5, 64.0, 52.2, 51.3, 43.6, 36.2, 31.4, 22.9, 27.1, 25.7, 14.1.
4.3.9 Methyl (3',4'-dihydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalen]-6'-yl)-acetate (12a)
A solution of the diasteriomeric mixture of carbinols 9a (36 mg, 0.13 mmol) in DMSO-d6 (0.4
mL) was heated at 180°C for 1 h. The mixture was cooled to room temperature, and without
concentration, purification by flash column chromatography (petroleum ether-ethyl acetate: 90-
1
10) gave rearranged product 12a (27 mg, 80%) as colorless oil. H NMR (400 MHz, CDCl3): δH
7.06-6.98 (m, 3H), 4.05-4.00 (m, 4H), 3.67 (s, 3H), 3.55 (s, 2H), 3.00-2.94 (m, 4H), 1.95 (t, 2H).
13C NMR (100 MHz; CDCl3): δC 172.2, 135.5, 133.3, 131.6, 129.5, 129.3, 126.8, 108.2, 64.5,
52.0, 40.8, 38.8, 31.7, 27.9. IR (CCl4): νmax (cm-1) 2953, 2881, 1742, 1262. HRMS (EI, m/z)
calculated (found) for C15H18O4, 262.1205 (262.1202).
4.3.10 Methyl (5'-butyl-3',4'-dihydro-1'H-spiro[[1,3]dioxolane-2,2'-naphthalen]-6'-yl)-
acetate (12b)
A solution of 9b (55 mg, 0.16 mmol), lithium chloride (14 mg, 0.32 mmol) and a drop of water in
DMSO (0.3 mL) was heated at 180°C for 3 h. The mixture was cooled to room temperature,
diluted with Et2O, washed with water, and the aqueous layer was extracted with Et2O. The
combined organic layers were washed with brine, dried over magnesium sulfate, filtered and
16

ACCEPTED MANUSCRIPT
concentrated under reduced pressure. Purification by flash column chromatography (petroleum
1
ether-ethyl acetate: 90-10) gave 12b (46 mg, 88%) as a colorless oil. H NMR (400 MHz,
CDCl3): δH 7.02 (d, 1H, J = 7.8 Hz), 6.87 (d, 1H, J = 7.8 Hz), 4.03 (s, 4H), 3.67 (s, 3H), 3.62 (s,
2H), 3.00-2.92 (m, 4H, CH2-4), 2.64-2.57 (m, 2H), 1.98 (t, 2H, J = 6.7 Hz), 1.49-1.36 (m, 4H),
13
0.96 (t, 3H, J = 6.9 Hz). C NMR (100 MHz; CDCl3): δC 172.5, 139.4, 134.0, 133.7, 130.1,
128.5, 127.2, 107.9 (C-6), 64.5, 52.0, 39.4, 38.7, 31.9, 31.6, 23.3, 29.0, 25.4, 13.9. IR (CCl4): νmax
(cm-1) 2955, 2875, 1740, 1262. HRMS (EI, m/z) calculated (found) for C19H26O4,
318.1831(318.1831).
4.3.11 Methyl 7-oxo-1,2,3,4,4a,7-hexahydronaphthalene-4a-carboxylate (31b)
A solution of compound 30b (600 mg, 2.88 mmol, 1.0 eq.), prepared from keto-ester 28b
according to the general procedure above, SeO2 (768 mg, 6.92 mmol, 2.4 eq.) and pyridine (3
drops) in tBuOH (58 mL) was refluxed for 33 h. The mixture was then cooled to room
temperature and filtrated on silica gel with AcOEt as solvent. The crude was evaporated under
reduced pressure and the residue was purified by column chromatography (petroleum
ether/AcOEt: from 85/15 to 75/25) to give dienone 31b as a yellow solid (394 mg, 1.91 mmol, 66
%). 1H NMR (400 MHz, CDCl3): δH 6.73 (d, 1H, J = 9.9 Hz), 6.29 (dd, 1H, J1 = 1.4 Hz, J2 = 9.9
Hz), 6.21 (tapp, 1H, J = 1.6 Hz), 3.71 (s, 3H), 2.67 (ddd, 1H, J1 = 2.6 Hz, J2 = 4.9 Hz, J3 = 13.1
Hz), 2.54 – 2.48 (m, 1H), 2.36 (dddd, 1H, J1 = 1.4 Hz, J2 = 4.9 Hz, J3 = 13.4 Hz, J4 = 13.5 Hz),
2.01 – 1.94 (m, 1H), 1.83 – 1.75 (m, 1H), 1.55 (ddt, 1H, J1 = 3.6 Hz, J2 = 13.5 Hz, J3 = 13.6 Hz),
1.37 (ddt, 1H, J1 = 4.0 Hz, J2 = 13.0 Hz, J3 = 13.1 Hz), 1.35 (dt, 1H, J1 = 3.9 Hz, J2 = 13.3 Hz).
13C NMR (100 MHz; CDCl3): δC 186.19, 170.39, 161.18, 147.96, 129.55, 125.97, 53.62, 53.08,
37.42, 34.57, 27.56, 22.84. IR (CCl4): νmax (cm-1) 2944, 1739, 1669, 1541, 1222. HRMS (EI+)
calculated (found) for C12H14O3: 206.0943 (206.0941).
4.3.12 Methyl 2-oxo-4a,5,6,7,8,9-hexahydro-2H-benzo[7]annulene-4a-carboxylate (31c)
A solution of compound 30c (600 mg, 2.70mmol, 1.0 eq.) prepared from ketoester 28c according
to the general procedure above, SeO2 (720 mg, 6.49 mmol, 2.4 eq.) and pyridine (3 drops) in
tBuOH (54 mL) was refluxed for 33 h. The mixture was then cooled to room temperature and
filtrated over silica gel with AcOEt as solvent. The filtrate was evaporated under reduced
pressure and the residue was purified by column chromatography (petroleum ether/AcOEt:
1
80/20) to give dienone 31c as a yellow oil (363 mg, 1.65 mmol, 61 %). H NMR (400 MHz,
CDCl3): δH 6.76 (d, 1H, J = 9.8 Hz), 6.32 (d, 1H, J = 9.8 Hz), 6.27 (bs, 1H), 3.67 (s, 3H), 2.58
(ddd, 1H, J1 = 2.7 Hz, J2 = 5.2 Hz, J3 = 12.8 Hz), 2.39 – 2.29 (m, 2H), 2.06 (dd, 1H, J1 = 8.8 Hz,
J2 = 14.6 Hz), 2.00 – 1.94 (m, 1H), 1.77 – 1.65 (m, 2H), 1.48 – 1.33 (m, 2H), 1.14 – 1.03 (m,
13
1H). C NMR (100 MHz; CDCl3): δC 186.17, 170.97, 163.55, 149.70, 129.99, 129.40, 55.77,
53.17, 35.64, 34.32, 30.46, 29.70, 23.14. IR (CCl4): νmax (cm-1) 2931, 2858, 1736, 1669, 1223.
HRMS (EI+) calculated (found) for C13H16O3: 220.1099 (220.1104).
4.3.13 Methyl 3-oxo-9,9a-dihydro-3H-fluorene-9a-carboxylate (37a)
A solution of compound 36a (980 mg, 4.05 mmol, 1.0 eq.) prepared from ketoester 35a by the
general, SeO2 (1.08 g, 9.72 mmol, 2.4 eq.) and pyridine (4 drops) in tBuOH (81 mL) was refluxed
for 28 h. The mixture was then cooled to room temperature and filtrated over silica gel with
AcOEt as solvent. The filtrate was evaporated under reduced pressure and the residue was
17

ACCEPTED MANUSCRIPT
purified by column chromatography (petroleum ether/AcOEt: 80/20) to give enone 37a as a
1
yellow solid (491 mg, 2.05 mmol, 51 %). H NMR (400 MHz, CDCl3): δH 7.59 (d, 1H, J = 7.5
Hz), 7.39 – 7.36 (m, 2H), 7.35 – 7.30 (m, 1H), 7.05 (d, 1H, J = 9.7 Hz), 6.58 (d, 1H, J = 1.4 Hz),
6.41 (dd, 1H, J1 = 1.4 Hz, J2 = 9.7 Hz), 3.86 (d, 1H, J = 15.1 Hz), 3.58 (s, 3H), 3.06 (d, 1H, J =
15.1 Hz). 13C NMR (100 MHz; CDCl3): δC 186.66, 170.15, 162.26, 145.21, 143.00, 137.23,
132.10, 131.24, 127.88, 125.69, 122.44, 120.75, 59.78, 53.80, 39.47. IR (CCl4): νmax (cm-1) 3028,
2954, 2842, 1737, 1665, 1606, 1230, 1214. HRMS (EI+) calculated (found) for C15H12O3
240.0786 (240.0792).
4.3.14 Methyl 6-oxo-6,8a,9,10-tetrahydrophenanthrene-8a-carboxylate (37b)
A solution of enone 36b (12.8 g, 50.0 mmol, 1.0 eq.) prepared from ketoester 35b by the general
procedure, SeO2 (13.3 g, 120 mmol, 2.4 eq.) and pyridine (50 drops) in tBuOH (1.0 L) was
refluxed for 28 h. The mixture was then cooled to room temperature and filtrated over silica gel
with AcOEt as solvent. The crude was evaporated under reduced pressure and the residue was
purified by column chromatography (petroleum ether/AcOEt: 80/20) to give dienone 37b as a
1
yellow solid (7.5 g, 29.5 mmol, 59 %). H NMR (400 MHz, CDCl3): δH 7.66 (dd, 1H, J1 = 0.8
Hz, J2 = 7.8 Hz), 7.33 (dt, 1H, J1 = 1.3 Hz, J2 = 7.4 Hz), 7.29 – 7.25 (m, 1H), 7.17 (d, 1H, J = 7.6
Hz), 6.88 (d, 1H, J = 9.8 Hz), 6.68 (d, 1H, J = 1.6 Hz), 6.42 (dd, 1H, J1 = 1.6 Hz, J2 = 9.8 Hz),
3.57 (s, 3H), 3.14 (ddd, 1H, J1 = 6.0 Hz, J2 = 12.3 Hz, J3 = 18.1 Hz), 2.99 (dd, 1H, J1 = 6.0 Hz, J2
= 17.7 Hz), 2.77 (ddd, 1H, J1 = 1.3 Hz, J2 = 5.9 Hz, J3 = 13.2 Hz), 1.92 (ddd, 1H, J1 = 6.3 Hz, J2 =
12.4 Hz, J3 = 13.1 Hz). 13C NMR (100 MHz; CDCl3): δC 186.25, 169.85, 154.74, 147.19, 136.13,
132.93, 130.37, 130.24, 129.19, 126.93, 125.41, 123.68, 53.21, 51.31, 32.40, 26.14. IR (CCl4):
νmax (cm-1) 3023, 2955, 2933, 2849, 1736, 1665, 1228. HRMS (EI+) calculated (found) for
C16H14O3 254.0943 (254.0945).
4.3.15 Methyl 7-methylene-1,2,3,4,4a,7-hexahydronaphthalene-4a-carboxylate (32b)
To a solution of compound 31b (370 mg, 1.8 mmol, 1.0 eq.) in diethyl ether (7.2 mL) at - 78 °C
under a nitrogen atmosphere was added MeLi (1.8 mmol, 1.0 eq.) drop-wise. After 1 h at -78°C,
NH4Cl (aq. sat.) was added to the reaction mixture and then water. The water layer was extracted
three times with diethyl ether. The combined organic layers were washed with NaCl (aq. sat.),
dried over magnesium sulfate and concentrated under reduced pressure. The crude was then
dissolved in MeOH (10 mL). HC(OMe)3 (1.2 mL) and p-TSA (1 crystal) were added to the
reaction mixture which was then refluxed for 20 min. Water was added and the water layer was
extracted three times with diethyl ether. The combined organic layers were washed with NaCl
(aq. sat.), dried over magnesium sulfate and concentrated under reduced pressure. The residue
was purified by column chromatography (pentane/diethyl ether: 90/10) to give olefin 32b as a
1
colorless oil (253 mg, 1.24 mmol, 69 %). H NMR (400 MHz, CDCl3): δH 6.23 (d, 1H, J = 9.6
Hz), 6.12 (s, 1H), 5.62 (d, 1H, J = 9.6 Hz), 4.86 (s, 1H), 4.82 (s, 1H), 3.70 (s, 3H), 2.44 – 2.38
(m, 1H); 2.33 – 2.17 (m, 2H), 1.85 – 1.76 (m, 1H), 1.74 – 1.67 (m, 1H), 1.51 – 1.30 (m, 3H). 13C
NMR (100 MHz; CDCl3): δC 173.18, 141.38, 137.76, 131.39, 127.83, 122.84, 111.99, 52.45,
52.25, 37.76, 34.05, 27.77, 23.63. IR (CCl4): νmax (cm-1) 2937, 2860, 1732, 1217. HRMS (EI+)
calculated (found) for C13H16O2: 204.1150 (204.1157).
18

ACCEPTED MANUSCRIPT
4.3.16 Methyl 2-methylene-4a,5,6,7,8,9-hexahydro-2H-benzo[7]annulene-4a-carboxylate
(32c)
To a solution of compound 32c (350 mg, 1.6 mmol, 1.0 eq.) in diethyl ether (6.4 mL) at - 78 °C
under a nitrogen atmosphere was added MeLi (1.6 mmol, 1.0 eq.) drop-wise. After 1 h at -78°C,
NH4Cl (aq. sat.) was added to the reaction mixture and then water. The water layer was extracted
three times with diethyl ether. The combined organic layers were washed with NaCl (aq. sat.),
dried over magnesium sulfate and concentrated under reduced pressure. The crude was then
dissolved in MeOH (10 mL). HC(OMe)3 (1.0 mL) and p-TSA (1 crystal) were added to the
reaction mixture which was then refluxed for 20 min. Water was added and the water layer was
extracted three times with diethyl ether. The combined organic layers were washed with NaCl
(aq. sat.), dried over magnesium sulfate and concentrated under reduced pressure. The residue
was purified by column chromatography (pentane/diethyl ether: 90/10) to give alkene 32c as a
yellow oil (216 mg, 0.99 mmol, 62 %). 1H NMR (400 MHz, CDCl3): δH 6.30 (d, 1H, J = 9.6 Hz),
6.21 (s, 1H), 5.66 (d, 1H, J = 9.6 Hz), 4.88 (s, 1H), 4.86 (s, 1H), 3.66 (s, 3H), 2.44 – 2.38 (m,
1H), 2.19 – 2.10 (m, 2H), 1.96 – 1.83 (m, 2H), 1.77 – 1.68 (m, 1H), 1.67 – 1.58 (m, 1H), 1.38 –
13
1.18 (m, 3H). C NMR (100 MHz; CDCl3): δC 174.06, 143.21, 137.95, 132.97, 128.44, 126.63,
112.07, 54.03, 52.44, 38.25, 33.82, 31.14, 30.25, 23.31. IR (CCl4): νmax (cm-1) 2929, 2856, 1732,
1223. HRMS (EI+) calculated (found) for C14H18O2: 218.1307 (218.1310).
4.3.17 Methyl 2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetate (33b)
A solution of compound 32b (102 mg, 0.50 mmol) in DMSO (1.25 mL) was heated at 180 °C for
40 min. Then water was added to the reaction mixture. The water layer was extracted three times
with diethyl ether. The combined organic layers were dried over magnesium sulfate and
concentrated under reduced pressure. The residue was then purified by column chromatography
(pentane/diethyl ether: 95/5) to give rearranged product 33b as a colorless oil (63 mg, 0.31 mmol,
1
62 %). H NMR (400 MHz, CDCl3): δH 7.06 – 6.99 (m, 3H), 3.71 (s, 3H), 3.58 (s, 2H), 2.79 –
13
2.74 (m, 4H), 1.84 – 1.77 (m, 4H). C NMR (100 MHz; CDCl3): δC 172.17, 137.18, 135.83,
130.75, 129.71, 129.19, 129.13, 51.83, 40.67, 29.17, 28.91, 23.03, 22.98. IR (CCl4): νmax (cm-1)
2933, 1743, 1436, 1259. HRMS (EI+) calculated (found) for C13H16O2: 204.1150 (204.1158).
4.3.18 Methyl 2-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetate (33c)
A solution of compound 32c (102 mg, 0.47 mmol) in DMSO (1.25 mL) was heated at 180 °C for
40 min. Then water was added to the reaction mixture. The water layer was extracted three times
with diethyl ether. The combined organic layers were dried over magnesium sulfate and
concentrated under reduced pressure. The residue was then purified by column chromatography
(pentane/diethyl ether: 95/5) to give the rearranged product 33c as a colorless oil (43 mg, 0.19
1
mmol, 42 %). H NMR (400 MHz, CDCl3): δH 7.06 (d, 1H, J = 7.5 Hz), 7.02 (bs, 1H), 7.00 (dd,
1H, J1 = 1.7 Hz, J2 = 7.5 Hz), 3.70 (s, 3H), 3.57 (s, 2H), 2.79 – 2.75 (m, 4H), 1.87 – 1.79 (m, 2H),
13
1.67 – 1.60 (m, 4H). C NMR (100 MHz; CDCl3): δC 172.29, 143.68, 142.28, 131.32, 129.88,
129.24, 129.55, 51.95, 40.73, 36.63, 36.29, 32.69, 28.24, 28.21. IR (CCl4): νmax (cm-1) 2925,
2852, 1742, 1439, 1264, 1153, 1019. HRMS (EI+) calculated (found) for C14H18O2: 218.1307
(218.1310).
19

ACCEPTED MANUSCRIPT
4.3.19 Methyl 3-methylene-9,9a-dihydro-3H-fluorene-9a-carboxylate (38a)
To a solution of compound 37a (480 mg, 2.0 mmol, 1.0 eq.) in THF (20 mL) at -78 °C under a
nitrogen atmosphere was added MeLi (2.0 mmol, 1.0 eq.) drop-wise. After 1 h at - 78°C, NH4Cl
(aq. sat.) was added to the reaction mixture and then water. The water layer was extracted three
times with diethyl ether. The combined organic layers were washed with NaCl (aq. sat.), dried
over magnesium sulfate and concentrated under reduced pressure. The crude was then dissolved
in MeOH (10 mL). HC(OMe)3 (1 mL) and p-TSA (1 crystal) were added to the reaction mixture
which was then refluxed for 20 min. Water was added and the water layer was extracted three
times with diethyl ether. The combined organic layers were washed with NaCl (aq. sat.), dried
over magnesium sulfate and concentrated under reduced pressure. The residue was purified by
column chromatography (pentane/diethyl ether: 90/10) to give alkene 38a as a yellow solid (230
1
mg, 0.97 mmol, 48 %). H NMR (400 MHz, CDCl3): δH 7.54 – 7.50 (m, 1H), 7.28 – 7.22 (m,
3H), 6.75 (s, 1H), 6.41 (s, 1H), 6.41 (d, 1H, J = 9.4 Hz), 6.09 (d, 1H, J = 9.5 Hz), 5.21 (s, 1H),
13
5.03 (s, 1H), 3.71 (d, 1H, J = 15.3 Hz), 3.57 (s, 3H), 2.97 (d, 1H, J = 15.3 Hz). C NMR (100
MHz; CDCl3): δC 173.41, 143.62, 142.22, 139.10, 138.60, 130.26, 128.67, 128.08, 127.19,
125.28, 120.84, 119.79, 115.99, 57.91, 52.90, 40.74. IR (CCl4): νmax (cm-1) 3027, 2953, 1732,
1435. HRMS (EI+) calculated (found) for C16H14O2: 238.0994 (238.0985).
4.3.20 Methyl 6-methylene-6,8a,9,10-tetrahydrophenanthrene-8a-carboxylate (38b)
To a solution of compound 37b (550 mg, 2.16 mmol, 1.0 eq.) in THF (22 mL) at -78 °C under a
nitrogen atmosphere was added MeLi (2.16 mmol, 1.0 eq.) drop-wise. After 1 h at - 78°C, NH4Cl
(aq. sat.) was added to the reaction mixture and then water. The water layer was extracted three
times with diethyl ether. The combined organic layers were washed with NaCl (aq. sat.), dried
over magnesium sulfate and concentrated under reduced pressure. The crude was then dissolved
in MeOH (10 mL). HC(OMe)3 (1 mL) and p-TSA (1 crystal) were added to the reaction mixture
which was then refluxed for 20 min. Water was added and the water layer was extracted three
times with diethyl ether. The combined organic layers were washed with NaCl (aq. sat.), dried
over magnesium sulfate and concentrated under reduced pressure. The crude was purified by
column chromatography (pentane/diethyl ether: 90/10) to give alkene 38b as a yellow solid (320
1
mg, 1.27 mmol, 59 %). H NMR (400 MHz, CDCl3): δH 7.67 – 7.63 (m, 1H), 7.22 – 7.16 (m,
1H), 7.09 – 7.05 (m, 1H), 6.75 (s, 1H), 6.35 (d, 1H, J = 9.6 Hz), 5.82 (d, 1H, J = 9.6 Hz), 5.10 (s,
1H), 5.03 (s, 1H), 3.56 (s, 3H), 3.02 (ddd, 1H, J1 = 6.1 Hz, J2 = 12.7 Hz, J3 = 17.6 Hz), 2.87 (dd,
1H, J1 = 5.8 Hz, J2 = 17.5 Hz), 2.53 (ddd, 1H, J1 = 0.9 Hz, J2 = 5.8 Hz, J3 = 13.1 Hz), 1.91 (ddd,
13
1H, J1 = 6.2 Hz, J2 = 12.8 Hz, J3 = 12.9 Hz). C NMR (100 MHz; CDCl3): δC 172.76, 137.96,
136.74, 135.32, 134.78, 131.01, 129.08, 128.18, 127.70, 126.23, 124.39, 122.57, 114.45, 123.68,
52.53, 50.06, 33.45, 26.74. IR (CCl4): νmax (cm-1) 3023, 2952, 1732, 1687, 1435, 1216. HRMS
(EI+) calculated (found) for C17H16O2: 252.1150 (252.1154).
4.3.21 Methyl 2-(9H-fluoren-3-yl)acetate (39a)
A solution of compound 38a (100 mg, 0.43 mmol) in DMSO (2.0 mL) was heated at 180 °C for 1
h. Then water was added to the reaction mixture. The water layer was extracted three times with
diethyl ether. The combined organic layers were dried over magnesium sulfate and concentrated
under reduced pressure. The residue was then purified by column chromatography
20

ACCEPTED MANUSCRIPT
(pentane/DCM: from 85/15 to 70/30) to give rearranged product 39a as a white solid (79 mg,
0.34 mmol, 79 %). 1H NMR (400 MHz, CDCl3): δH 7.78 (d, 1H, J = 7.5 Hz), 7.71 (bs, 1H), 7.54
(bd, 1H, J = 7.4 Hz), 7.50 (d, 1H, J = 7.7 Hz), 7.38 (t, 1H, J = 7.4 Hz), 7.30 (dt, H, J1 = 1.1 Hz, J2
13
= 7.4 Hz), 7.22 (dd, 1H, J1 = 1.3 Hz, J2= 7.7 Hz), 3.88 (s, 2H), 3.74 (s, 2H), 3.72 (s, 3H). C
NMR (100 MHz; CDCl3): δC 172.25, 143.51, 142.20, 142.11, 141.35, 132.51, 127.74, 126.81,
126.71, 125.08, 125.00, 120.73, 119.94, 52.09, 41.32, 36.64. IR (CCl4): νmax (cm-1) 3073, 3051,
3020, 2952, 2900, 1734, 1453, 1435, 1255, 1155, 1018. HRMS (EI+) calculated (found) for
C16H14O2: 238.0994 (238.0993).
4.3.22 Methyl 2-(9,10-dihydrophenanthren-3-yl)acetate (39b)
A solution of compound 38b (180 mg, 0.71 mmol) in DMSO (2.4 mL) was heated at 180 °C for 1
h. Then water was added to the reaction mixture. The water layer was extracted three times with
diethyl ether. The combined organic layers were dried over magnesium sulfate and concentrated
under reduced pressure. The residue was then purified by column chromatography
(pentane/DCM: from 85/15 to 70/30) to give the rearranged product 39b as a white solid (140
mg, 0.55 mmol, 78 %). 1H NMR (400 MHz, CDCl3): δH 7.76 (d, 1H, J = 7.7 Hz, C5H); 7.67 (bs,
1H), 7.33 – 7.29 (m, 1H), 7.25 – 7.22 (m, 2H), 7.20 (d, 1H, J = 7.7 Hz), 7.15 (bd, 1H, J = 7.7 Hz),
3.72 (s, 3H), 3.68 (s, 2H), 2.86 (bs, 4H). 13C NMR (100 MHz; CDCl3): δC 172.16, 137.39,
136.23, 134.72, 134.17, 132.48, 128.34, 128.15, 128.10, 127.47, 126.90, 124.61, 123.72, 52.07,
41.15, 29.01, 28.67. IR (CCl4): νmax (cm-1) 3022, 2952, 1897, 2839, 1743, 1614, 1435, 1258,
1157, 1017. HRMS (EI+) calculated (found) for C17H16O2: 252.1150 (252.1146).
4.3.23 Methyl 3-methyl-9,10-dihydrophenanthrene-2-carboxylate (40)
A solution of compound 48b (159 mg, 0.63 mmol, 1.0 eq.) in CH2Cl2 (3 mL) was added
dropwise to a suspension of anhydrous AlCl3 (168 mg, 1.26 mmol, 2.0 eq.) in CH2Cl2 (3 mL) at
25 °C. After 10 min, the reaction mixture was poured onto ice water, and the layers were
separated. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were
washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash
colum chromatography (petroleum ether-diethyl ether: 90-10) gave 40 (71 mg, 45%) as an orange
oil.1H NMR (400 MHz, CDCl3) : δH 7.68 (d, J = 7.4 Hz, 2H), 7.58 (d, J = 1.0 Hz, 1H), 7.31 – 7.26
(m, 1H), 7.24 – 7.18 (m, 2H), 3.89 (s, 3H), 3.26 – 3.11 (m, 2H), 2.84 – 2.70 (m, 2H), 2.39 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 168.7, 137.7, 136.0, 135.9, 134.2, 129.8, 129.8, 128.5,
127.9, 127.8, 127.0, 124.1, 52.1, 28.8, 25.5, 21.3. IR (neat): νmax (cm-1) 2948, 1722 1435 1325
1248, 1195. HRMS (EI+) calculated (found) for C17H16O2: 252.1150 (252.1147).
4.3.24 But-3-enyl 6-methylene-6,8a,9,10-tetrahydrophenanthrene-8a-carboxylate (41)
A solution of LiH (16 mg, 2.0 mmol, 1.0 eq.) in but-3-en-1-ol (2.0 mL) was heated at 40 °C for 5
min. Compound 38b (504 mg, 2.0 mmol, 1.0 eq.) was added and the reaction mixture was
refluxed in a Dean-Stark apparatus for 4.5 h. Then water and NH4Cl (aq. sat.) were added to the
reaction mixture. The water layer was extracted two times with AcOEt. The combined organic
layers were washed with NaCl (aq. sat.), dried over magnesium sulfate and concentrated under
reduced pressure. The residue was then purified by column chromatography (petroleum
ether/AcOEt: from 100/0 to 96/4) to give ester 41 as a colorless oil (420 mg, 1.44 mmol, 72 %).
1H NMR (400 MHz, CDCl3): δH 7.66 – 7.61 (m, 1H), 7.21 – 7.14 (m, 2H), 7.08 – 7.04 (m, 1H),
21

ACCEPTED MANUSCRIPT
6.74 (s, 1H), 6.34 (d, 1H, J = 9.6 Hz), 5.83 (d, 1H, J = 9.6 Hz), 5.55 – 5.45 (m, 1H), 5.09 (s, 1H),
5.02 (s, 1H), 4.94 – 4.88 (m, 2H), 4.08 (dt, 1H, J1 = 6.6 Hz, J2 = 10.8), 3.95 (dt, 1H, J1 = 6.5 Hz,
J2 = 10.8), 3.01 (ddd, 1H, J1 = 6.0 Hz, J2 = 12.6 Hz, J3 = 18.3 Hz), 2.86 (dd, 1H, J1 = 5.9 Hz, J2 =
17.5), 2.52 (dd, 1H, J1 = 5.3 Hz, J2 = 13.0 Hz), 2.19 – 2.13 (m, 2H), 1.90 (ddd, 1H, J1 = 6.2 Hz, J2
= 12.6 Hz, J3 = 12.8 Hz). 13C NMR (100 MHz; CDCl3): δC 172.20, 138.02, 136.81, 135.25,
134.96, 133.61, 131.06, 129.00, 128.11, 127.61, 126.17, 124.38, 122.40, 117.03, 114.23, 64.20,
50.09, 33.48, 32.84, 26.69. IR (CCl4): νmax (cm-1) 3074, 2932, 1728, 1687, 1230, 1188. HRMS
(EI+) calculated (found) for C20H20O2: 292.1463 (292.1463).
4.3.25 3-(2-(9,10-dihydrophenanthren-3-yl)ethyl)dihydrofuran-2(3H)-one (42)
A solution of ester 41 (140 mg, 0.48 mmol) in DMSO (1.5 mL) was heated at 170 °C for 20 min.
Then water was added to the reaction mixture. The water layer was extracted three times with
diethyl ether. The combined organic layers were dried over magnesium sulfate and concentrated
under reduced pressure. The residue was then purified by column chromatography
(pentane/AcOEt: from 98/2 to 0/100) to give lactone 42 as a yellowish oil (103 mg, 0.35 mmol,
74 %). 1H NMR (400 MHz, CDCl3): δH 7.76 (d, 1H, J = 7.7 Hz), 7.60 (d, 1H, J = 1.7 Hz), 7.34 –
7.28 (m, 1H), 7.25 – 7.22 (m, 2H), 7.17 (d, 1H, J = 7.6 Hz), 7.08 (dd, 1H, J1 = 1.6 Hz, J2 = 7.6
Hz), 4.36 (ddd, 1H, J1 = 2.7 Hz, J2 = 8.5 Hz, J3 = 9.0 Hz), 4.18 (ddd, 1H, J1 = 6.6 Hz, J2 = 9.1 Hz,
J3 = 9.7 Hz), 2.90 – 2.73 (m, 2H), 2.86 (bs, 4H), 2.59 – 2.50 (m, 1H), 2.41 (dddd, 1H, J1 = 2.7 Hz,
J2 = 6.7 Hz, J3 = 9.3 Hz, J4 = 12.5 Hz), 2.30 (dddd, 1H, J1 = 5.2 Hz, J2 = 7.1 Hz, J3 = 9.0 Hz, J4 =
14.1 Hz), 1.99 (dddd, 1H, J1 = 8.4 Hz, J2 = 9.7 Hz, J3 = 10.0 Hz, J4 = 12.4 Hz), 1.81 (dddd, 1H, J1
13
= 6.0 Hz, J2 = 8.8 Hz, J3 = 8.8 Hz, J4 = 14.8 Hz). C NMR (100 MHz; CDCl3): δC 179.32,
139.24, 137.42, 135.29, 134.53, 134.31, 128.24, 128.12, 127.38 (2 carbons), 126.88, 123.73,
123.58, 66.41, 38.37, 33.22, 32.05, 29.09, 28.81, 28.60. IR (CCl4): νmax (cm-1) 3016, 2938, 2838,
1781, 1492, 1450, 1372, 1145, 1031. HRMS (EI+) calculated (found) for C20H20O2: 292.1463
(292.1469).
4.3.26 3-(9,10-dihydrophenanthren-3-yl)propanenitrile (46)
To a solution of compound 38b (2.0 mmol, 1.0 eq.) and S-cyanomethyl-O-ethyl xanthate 45 (5.0
mmol, 2.5 eq.) in refluxing heptane (20 mL) under a nitrogen atmosphere was added 10 mol% of
DLP every 90 min until completion of the reaction. This took 30 mol% of DLP in total. The
solvent was evaporated under reduced pressure and then KOH (1M, 2 mL) and MeOH (1 mL)
were added to the residue. After 1 h at 40 °C, the reaction mixture was extracted three times with
diethyl ether. The combined organic layers were washed with NaCl (aq. sat.), dried over
magnesium sulfate and concentrated under reduced pressure. The residue was purified by column
chromatography (petroleum ether/AcOEt: from 98/2 to 95/5) to give nitrile 46 as a colorless oil
(17 mg, 0.81 mmol, 40 %). 1H NMR (400 MHz, CDCl3): δH 7.75 (d, 1H, J = 7.7 Hz), 7.61 (d, 1H,
J = 1.4 Hz), 7.34 – 28 (m, 1H), 7.25 -7.23 (m, 2H), 7.21 (d, 1H, J = 7.6 Hz), 7.10 (dd, 1H, J1 =
1.7 Hz, J2 = 7.6 Hz), 3.01 (t, 2H, J = 7.4 Hz), 2.86 (bs, 4H), 2.66 (t, 2H, J = 7.4 Hz).13C NMR
(100 MHz; CDCl3): δC 137.43, 136.63, 136.38, 134.98, 134.05, 128.59, 128.17, 127.61, 127.11,
126.99, 123.64, 123.59, 119.20, 31.5, 28.98, 28.65, 19.53. IR (CCl4): νmax (cm-1) 3019, 2936,
2898, 2249, 1730, 1261. HRMS (EI+) calculated (found) for C17H15N: 233.1204 (233.1202).
5
Acknowledgement
22

ACCEPTED MANUSCRIPT
We thank Oril Industrie and Ecole Polytechnique for scholarships to M. B. and R. G.,
respectively, and Lucile Anthore for repeating the synthesis of compound 40.
6
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