Introduction of adjacent oxygen-functionalities in dimethyl heptalenedicarboxylates

Article abstract of DOI:10.1002/hlca.201100150

The bromination of dimethyl 8-methoxy-1,6,10-trimethylheptalene-4,5- dicarboxylate (6; Scheme 2) with N-bromosuccinimide (NBS) in N,N-dimethylformamide (DMF) leads in acceptable yields to the corresponding 9-bromoheptalenedicarboxylate 10 (Table 1). Ether

Full text of DOI:10.1002/hlca.201100150

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Helvetica Chimica Acta – Vol. 94 (2011)
Introduction of Adjacent Oxygen-Functionalities in Dimethyl
Heptalenedicarboxylates
by Frank Rogano1), Danijela Stojnic2), Anthony Linden, Khaled Abou-Hadeed*, and
Hans-Jꢀrgen Hansen*
Organisch-chemisches Institut der Universitꢀt Zꢁrich, Winterthurerstrasse 190, CH-8057 Zꢁrich
(phone: þ 41-44-6354231; fax: þ 41-44-6356833; e-mail: hjhansen@oci.uzh.ch)
Dedicated to Heinz Heimgartner on the occasion of his 70th birthday
The bromination of dimethyl 8-methoxy-1,6,10-trimethylheptalene-4,5-dicarboxylate (6; Scheme 2)
with N-bromosuccinimide (NBS) in N,N-dimethylformamide (DMF) leads in acceptable yields to the
corresponding 9-bromoheptalenedicarboxylate 10 (Table 1). Ether cleavage of 6 with chlorotrimethyl-
silane (Me3SiCl)/NaI results in the formation of oxoheptalenedicarboxylate 13 in good yield (Scheme 4).
The latter can be acetyloxylated to the (acetyloxy)oxoheptalenedicarboxylate 14 with Pb(OAc)4 in
benzene (Scheme 5). Oxo derivative 14, in turn, can be selectively O-methylated with dimethyl sulfate
(DMS) in acetone to the (acetyloxy)methoxyheptalenedicarboxylates 15 and 15’ (Scheme 6). The AcO
group of the latter can be transformed into a benzyl or methyl ether group by treatment with MeONa in
DMF, followed by the addition of benzyl bromide or methyl iodide (cf. Scheme 9). Reduction of the ester
groups of dimethyl 7,8-dimethoxy-5,6,10-trimethylheptalene-1,2-dicarboxylate (25’) with diisobutylalu-
minium hydride (DIBAH) in tetrahydrofuran (THF) leads to the formation of the corresponding
dimethanol 26’, which can be cyclized oxidatively (IBX, dimethyl sulfoxide) to 8,9-dimethoxy-6,7,11-
trimethylheptaleno[1,2-c]furan (27; Scheme 11).
1. Introduction. – Over the past 15 years, we have developed two main approaches
to the synthesis of benzo[a]heptalenes as possible colchicinoid candidates starting with
dimethyl heptalene-4,5-dicarboxylates 1 or their double-bond-shifted (DBS) isomers,
i.e., dimethyl heptalene-1,2-dicarboxylates (Scheme 1; see [1] and lit. cit. therein).
Intermediates of the first approach are heptaleno[1,2-c]furans 2 [2], which easily
undergo thermal DielsꢀAlder reactions with a broad variety of dienophiles [3][4]. The
cycloadducts rearrange on base or acid catalysis to benzo[a]heptalenes, capable to be
further modified to 4 or those with other substitution patterns at the benzo moiety. The
second approach starts with 1 or its DBS isomer, which on treatment with 1-
(phenylsulfonyl)ethyllithium yield directly benzo[a]heptalenes of type 3 [5], which
again can be simply modified to 4 [6]. However, it would chemically be difficult to
introduce O-functions at C(9) and C(10) of 4 to arrive at the tropolone ring C of
colchicines 5. Therefore, we investigated the introduction of adjacent O-functions
already in dimethyl heptalenedicarboxylates 1 and report on these experiments in the
following part.
1
)
)
Part of the M.S. work of F. R., University of Zꢁrich, 2002.
Part of the M.S. work of D. S., University of Zꢁrich, 2004.
2
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 94 (2011)
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Scheme 1
2. Syntheses. – 2.1. Dimethyl 8-Methoxy-1,6,10-trimethylheptalene-4,5-dicarboxylate
(6) and Its DBS Isomer 6’. Since heptalenedicarboxylates of type 1 are accessible by
thermal reaction of azulenes and acetylenedicarboxylates following Hafnerꢃs general
method (see [1][8]), we decided to incorporate the first O-function as methyl ether
already in the azulene reactant. The 6-methoxy-4,8-dimethylazulene (7) is available
from 4-methoxy-2,6-dimethylpyrylium tetrafluoroborate and sodium cyclopentadie-
nide [9]. The transformation of 7 into 6-methoxy-1,4,8-trimethylazulene (8) via the
reduction of the intermediate azulene-1-carboxaldehyde, following earlier work of us
[10], could be managed in a yield of 88% over both steps (Scheme 2). The reaction of 8
with 3 equiv. of dimethyl acetylenedicarboxylate (¼dimethyl but-2-ynedioate; ADM)
in toluene at 1408 gave crystalline 6 as yellow needles in average yields of 31%,
accompanied by almost equal amounts of the azulene-1,2-dicarboxylate 9 as retro-
DielsꢀAlder product (cf. [1]). The DBS isomer 6’ could also be identified in minor
amounts by TLC in the original toluene solution after heating (see below). The yield of
6 could be slightly enhanced to 37% when 8 was treated with 5 equiv. of ADM in DMF
(N,N-dimethylformamide) at 1408 for 24 h3). The structure of 6 was securely
confirmed by an X-ray crystal-structure analysis (see Exper. Part).
It was difficult to isolate the minor amounts of the DBS isomer 6’, i.e., of dimethyl 8-
methoxy-5,6,10-trimethylheptalene-1,2-dicarboxylate, from the original mixture of
products. However, when a 0.1m solution of pure 6 in MeCN was exposed for 8 h to
normal daylight at room temperature, a photostationary mixture of 52% of 6 and 48%
of 6’ was formed (cf. [11a] for former similar results), from which 6’ could be isolated
almost quantitatively and characterized. The two isomers are clearly differentiated by
the vicinal coupling constant of their two adjacent H-atoms at the heptalene skeleton,
3
)
In one experiment (8 þ 3.1 equiv. of ADM, toluene, 1208, 22 h), we isolated a mixture of 6 and 6’ in
a yield of 66%. Unfortunately, we could not repeat a yield of 66% in further experiments.

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 2
which amount to 5.8 Hz for 6 and 11.8 Hz for 6’, in agreement with those of other
heptalene isomers of this type (cf. [11]).
Heptalene-1,2-dicarboxylate 6’ in MeCN solution in the dark at room temperature
is quite stable and isomerizes to its DBS form 6 only very slowly with t1/2 ca. 42 d.
However, in CDCl3 solution in the dark at room temperature, t1/2 amounts to 2 h,
whereby a final equilibrium mixture of 9% of 6’ and 91% of 6 is formed, in good
agreement with the calculated ratio of 94 :6 of dimethyl 1,6,8,10-tetramethylheptalene-
4,5-dicarboxylate and its DBS isomer in tetralin [11a]. We suppose that traces of HCl in
CDCl3 catalyze the thermal DBS process of 6’ and 6 (see [12] for similar observations).
2.2. Bromination Experiments with Dimethyl 8-Methoxy-1,6,10-trimethylheptalene-
4,5-dicarboxylate (6). The fixed C¼C bonds in heptalene 6 should make it possible to
introduce a Br-substituent at C(9) due to the p-donor effect of the adjacent MeO group
at C(8). N-Bromosuccinimide (NBS) in CHCl3 or CH2Cl2 at low temperature has been
successfully applied in electrophilic bromination reactions [13]. Therefore, we
investigated the bromination of 6 with NBS in CH2Cl2. The results are listed in
Table 1. We observed the formation of four products, 10 – 13, in nearly equal amounts
which all could be separated chromatographically and identified spectroscopically.
Only one of them, namely 10, represented the expected 9-bromoheptalene-4,5-
dicarboxylate. Two other heptalene-4,5-dicarboxylates, namely 11 and 12, carried a
BrCH2 group at C(6), and 12, in addition, a second Br-substituent at C(9). The fourth
compound contained no Br-substituent and was characterized as the ether-cleavage
product of 6, namely dimethyl 8,9-dihydro-1,6,10-trimethyl-8-oxoheptalene-4,5-dicar-
boxylate4) (13).
The structures of 10 and 13 were verified by an X-ray crystal-structure analysis (see
Exper. Part and below). Characteristic for 11 and 12 is the missing of the MeꢀC(6)
1
signal in their NMR spectra. Instead of it, one finds in the H-NMR spectra of both
4
)
Since the two ester substituents are the locant-determining groups, the correct name of 13 would be
dimethyl 7,8-dihydro-5,6,10-trimethyl-8-oxoheptalene-1,2-dicarboxylate. However, for the sake of
comparison and to avoid confusion, we use the locants of the original heptalene core (see also
below). The same applies to 14.

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Table 1. Bromination of Heptalene-4,5-dicarboxylate 6 with N-Bromosuccinimide (NBS)
Solvent
NBS [equiv.]
Additive [equiv.]
Time [h]
Temp. [8]
Yield [%]a)
10
11
12
13
CH2Cl2
CH2Cl2
DMF
2
2
1.1
5 (Na2CO3)
–
–
7
4
1
ꢀ 78
ꢀ 78
ꢀ 15
26
22
67
23
17
21
12
19
6
37
24
5
a) Yield of isolated products.
2
compounds an AB system for a BrCH2 group at C(6) with JAB ¼ 10.4 and 10.7 Hz,
respectively.
The bromination-product composition did not alter very much in the presence or
absence of Na2CO3. Therefore, we reduced the amount of NBS and tried DMF as polar
solvent. Under these conditions, we got finally an acceptable yield of 10. However, the
formation of product 11 and its follow-up product 12, resulting from the radical
bromination of MeꢀC(6), could not be suppressed. On the other hand, the yield of the
ether cleavage product 13 was distinctly reduced.
The Br-substituent of 10 could not be exchanged against OH or MeO under strong
basic condition, and with NaOH in MeOH/DMF at room temp., only cleavage of the
sterically less hindered ester group at C(4) was observed (!10a; Scheme 3). Therefore,
we had to look for other ways for the introduction of O-functionalities at C(9) of
heptalenedicarboxylate 6.
Scheme 3
2.3. Acetyloxylation of Dimethyl 8,9-Dihydro-1,6,10-trimethyl-8-oxoheptalene-4,5-
dicarboxylate4) (13). The appearance of nearly equal amounts of 10 and 13 as the result

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of the ionic reaction path of 6 and NBS in CH2Cl2 (Table 1) shows that the ether
function of 6 can be cleaved quite easily by Hþ catalysis. Moreover, the CH2 group in a-
position to the keto group of 13 pointed to the possibility that this favorable structural
situation could be utilized for the direct insertion of an O-function in 13. But first of all,
we had to look for a productive ether cleavage of 6. Olah and co-workers have
described an efficient procedure for the selective cleavage of esters, ethers, and other
O-functions with chlorotrimethylsilane (Me3SiCl) in the presence of NaI [14]. When
we exposed 6 over 5 days to these conditions, we obtained 13 in a yield of 80%,
whereby 14% of 6 could be recovered, so that the chemical yield of 13 amounted to
93% (Scheme 4).
Scheme 4
Onishi and Osawa have described a radical a-acetyloxylation of steroidal ketones
with Pb(OAc)4 in boiling benzene [15], a procedure, which seemed to us very
promising, because an AcO group at C(9) can be modified easily to other O-
functionalities. The X-ray crystal structure of 13 (Fig. 1) as well as its AM1-calculated
structure show Hpro-SꢀC(9) in the (P)-configuration of the heptalene skeleton in a close
to 908 position with respect to the p-plane of the adjacent p-bonds as indicated by the
torsion angles V (Hpro-SꢀC(9)ꢀC(10)¼C(10a)) ¼ 50.98 and V (Hpro-SꢀC(9)ꢀC(8)¼O) ¼
115.28, whereas Hpro-RꢀC(9) occupies a more or less in-plane position with respect to
the adjacent p-bonds (V (Hpro-RꢀC(9)ꢀC(10)¼C(10a)) ¼ 168.38 and V (Hpro-RꢀC(9)ꢀ
C(8)¼O) ¼ ꢀ2.28).
Fig. 1. Stereoscopic view of dimethyl 8,9-dihydro-1,6,10-trimethyl-8-oxoheptalene-4,5-dicarboxylate4)
(13) (50% probability ellipsoids)
Therefore, we were quite optimistic that Hpro-S could easily be attacked and
.
removed by AcO and the thus formed p-stabilized radicals of 13 then combine with

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further acetyloxy radicals (see also below). Instead of 8.7 equiv. of Pb(OAc)4 per equiv.
of ketone [15], we used only 1.1 equiv. of Pb(OAc)4, and the reaction time in boiling
benzene was reduced from 48 h to 3 h. By this modified procedure, we obtained the
expected 9-(acetyloxy)heptalene-4,5-dicarboxylate4) 14 in yields of 52 to 71%,
depending on the purity of the applied Pb(OAc)4 (Scheme 5). By crystallization from
a mixture of hexane/AcOEt/Et2O, we obtained 14 in yellow tablets, suitable for an X-
ray crystal-structure analysis, which allowed determining the relative configuration of
14. The (9R*,P*)-configuration was thus established for 14 (Fig. 2). Since the axis of
chirality of (9R*,P*)-14 could switch principally by double-ring inversion to the (M*)-
configuration of the diastereoisomer of 14 with (9R*,M*)-configuration, we calculated
with AM1 DHf8 of both diastereoisomers. It turned out that (9R*,P*)-14 is with
DDHf8 ¼ ꢀ1.83 kcal molꢀ1 the thermodynamically favored product (see later).
Scheme 5
Fig. 2. Stereoscopic view of dimethyl 9-(acetyloxy)-8,9-dihydro-1,6,10-trimethyl-8-oxoheptalene-4,5-di-
carboxylate4) (14) (50% probability ellipsoids)
The formation of enol ether derivatives of 14 by O-alkylation would allow the re-
entrance in the world of multi-functionalized 12e-heptalenes for further modifications
(cf. Scheme 1). First attempts to alkylate 14 (in analogy to [16]) with MeI in the
presence of K2CO3 failed completely. No defined product at all was formed. The
situation changed when we applied the stronger methylating agent dimethyl sulfate
(DMS) in acetone (in analogy to [17]). Now, we found after 30 h at 508 the expected
heptalene-4,5-dicarboxylate 15 in a yield of 65% accompanied by its DBS isomer 15’
established in 24% yield (Scheme 6). The X-ray crystal analysis of 15’ established
unequivocally its structure (see Exper. Part).

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Scheme 6
The excellent yield of 15 and 15’ together led us to a reproving experiment,
1
stimulated by the fact that we found in the H-NMR spectra of not fully purified 14
weak signals of a further compound, which could possibly belong to an isomer of 14.
Crude 14 was therefore methylated according to Scheme 6, whereby the reaction time
was prolonged to two days. The HPLC analysis of the crude product mixture indicated
the presence of four heptalenedicarboxylates, which could be cleanly separated by
prep. HPLC (Scheme 7). Peak 2 and 4 represented 15’ and 15, respectively, whereas
Peak 1 and 3 belonged to the new heptalenedicarboxylates 17’ and 17, respectively. The
latter two were fully identified by their 1H-NMR spectra (see Exper. Part). The ratio of
(15’ þ 15)/(17’ þ 17) amounted to 8 :1. The origin of the DBS isomers 17 and 17’ must be
the oxoheptalenedicarboxylate 16.
Scheme 7
We suppose that under the conditions of the acetyloxylation of 13 (808, benzene)
and favored by the presence of AcOH in the reaction mixture5), an Hþ-catalyzed
equilibrium mixture of 13 and its isomer 19 is established via their corresponding enol
5
)
AcOH is formed in the course of the reaction; however, more important is the fact that purchased
Pb(OAc)4 contains for stabilization up to 15% AcOH.

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1201
forms 18 and 18’ (Scheme 8)6). The DHf8 values of the four components of the
postulated equilibrium lie quite close together with a maximum difference of 2.5 kcal
molꢀ1, whereby the two oxoheptalenedicarboxylates show DDHf8 ¼ 0.41 kcal molꢀ1 in
favor of 13, in general agreement with the fact that we found 8 times more
heptalenedicarboxylates 15/15’ in comparison to the amount of 17/17’.
Scheme 8
Since 15/15’ and 17/17’ are new and represent positional isomers with respect to the
AcO substituent, we determined the thermal and photochemical equilibrium ratio of
the two DBS pairs. The results are listed in Table 2 together with those of 6/6’. The
ratios of the latter are in good agreement with those of the corresponding 8-
methylheptalenedicarboxylates (ratio on D (tetralin, calc. for 258), 15 :1; ratio on hn
(tBuOMe, high-pressure mercury lamp), 1.2 :1) [11a]. On the other hand, selective
irradiation into heptalene band I of the (acetyloxy)-substituted heptalenedicarbox-
ylates 15/15’ and 17/17’ favors strongly the 1,2-dicarboxylates in the photochemical
equilibrium, in agreement with the slight differences in the absorption of these
heptalenes (see Table 3). The UV/VIS spectra of heptalenes with the same p-bond
pattern like the 8-methoxyheptalene-4,5-dicarboxylates 6, 10, and 15 show almost no
differences in the long-wavelength region of the heptalene band I despite different
substituents (H, Br, AcO) at C(9) (see Fig. 3). On the other hand, it is also of interest
to note that the position of the AcO substituent of the two pairs of heptalenedicarbox-
ylates influences the thermal-equilibrium ratio markedly. Whereas heptalenedicarbox-
ylates 17/17’ exhibit a ꢄnormalꢃ thermal behavior in that it shows a preponderance of the
4,5-dicarboxylate in the thermal equilibrium in quite good agreement with the AM1-
calculated difference of the DHf8 values of 0.51 kcal molꢀ1, the AcO substituent in 15/
15’ favors the 1,2-dicarboxylate, again in good accordance with the AM1-calculated
difference of the DHf8 values of 0.43 kcal molꢀ1.
The AcO group at C(9) of 15 (at C(7) of 15’, resp.) should ideally be suited for
base-catalyzed alkylation reactions without touching the two adjacent ester functions at
the other heptalene-ring moiety. We tested this possibility by the reaction of 15 with
benzyl bromide (BnBr) in the presence of MeONa in DMF (in analogy to [18]) with
the idea that a BnO group could later on be cleaved by hydrogenolysis (cf. [19]). The
result was that we got, after chromatography, a 1:2 mixture of the 9-(benzyloxy)hep-
6
)
It might be that the enol forms 18 and 18’ themselves are the important intermediates, which are
.
oxidized by PbIV to the corresponding radical cations, which combine with AcO and formation of
Pb(OAc)2 and AcOH (cf. [15]).

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Table 2. Thermal and Photochemical Equilibrium Ratios of 8-Methoxyheptalenedicarboxylates 6/6’, 15/
15’, and 17/17’
R1
R2
Conditions D
A/A’
Conditions hn
A/A’
6/6’
15/15’
17/17’
H
AcO
H
H
H
AcO
CDCl3, r.t., 20 h
C6D6, 758, 3 d
C6D6, 758, 3 d
10 : 1
1 : 2.8
1.5 : 1
MeCNa), daylight, 8 h
1.1 : 1
1 : 4.3
1 : 1.6
CH2Cl2b), 366 nmc), 5 min
CH2Cl2b), 366 nmc), 5 min
a) c ¼ 0.1m. b) c ¼ 0.01m. c) Light of a fluorescence tube with lemiss at 366 nm.
Table 3. UV/VIS Maxima of Some 8-Methoxyheptalenedicarboxylatesa)
R1
H
R2
H
Type Solvent Heptalene band
I
II
III
IV
6
A
MeCN 390 (sh, 0.04)
330 (sh, 0.20)
272 (0.81),
290 (sh, 0.63)
275 (1.00)
269 (sh, 0.72),
297 (sh, 0.43)
268 (0.89),
290 (sh, 0.54)
275 (1.00)
238 (sh, 1.00)
6’
H
H
H
A’
A
MeCN 387 (sh, 0.03)
MeCN 385 (0.05)
327 (sh, 0.15)
338 (sh, 0.15)
231 (0.93)
252 (1.00)
10
15
15’ AcO H
Br
AcO H
A
MeCN 387 (sh, 0.05)
327 (sh, 0.19)
240 (1.00)
A’
MeCN 387 (sh, 0.03)
328 (sh, 0.10)
236 (sh, 0.91)
241 (1.00)
225 (0.87)
b
17
H
H
H
AcO A
AcO A’
H
)
)
)
ca. 380 (sh, 0.06) 329 (sh, 0.15)
ca. 380 (sh, 0.04) ca. 329 (0.16)
ca. 370 (sh, 0.06) ca. 320 (sh, 0.17) 261 (1.00),
ca. 280 (sh, 0.87)
268 (1.00)
279 (0.61)
272 (1.00)
b
d
17’
28c)
A
236 (sh, 1.00)
28’c) H
H
A’
)
390 (0.03)
318 (sh, 0.13)
233 (sh, 0.81)
d
a) Wavelength l [nm], sh ¼ shoulder, in parentheses relative band intensities; band numbering according
c
to [20]. b) Hexane/(CH2Cl2 þ 0.5% MeOH) 9 : 1. ) 8-Me instead of 8-MeO. Values are taken from [20].
d) Hexane/iPrOH 25 : 1.
talene-4,5-dicarboxylate 20 and its DBS isomer 20’ in a combined yield of 48%. The
starting material 15 was recovered in a yield of 26% accompanied by 16% of its DBS
isomer 15’ (Scheme 9). The total chemical yield of 20 and 20’ corresponds thus to 90%.

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Fig. 3. UV/VIS Spectra (MeCN) of 8-methoxyheptalene-4,5-dicarboxylate 6 (red curve), 9-bromo-8-
methoxyheptalene-4,5-dicarboxylate 10 (green curve), and 9-(acetyloxy)-8-methoxyheptalene-4,5-dicar-
boxylate 15 (blue curve)
Scheme 9
The reaction was performed without protection against daylight. Therefore, we suppose
that the DBS isomers of 15 and 20 are formed under the influence of the laboratory
light (see later), because the temperature did not exceed room temperature, which is in
the present cases too low for a thermal DBS process.
2.4. Heptaleno[1,2-c]furan Formation. Furans of type 2 (Scheme 1) are available by
reduction of the ester groups of heptalene-1,2- or -4,5-dicarboxylates to the
corresponding heptalenedimethanols, which are then oxidatively cyclized to heptale-
no[1,2-c]furans [2]. We tested, therefore, in some preliminary experiments with the
original heptalenedicarboxylate mixture 15/15’/17/17’ (Scheme 7) the possibility of
heptaleno[1,2-c]furan formation. The reduction was performed with diisobutylalumi-
nium hydride (DIBAH) in tetrahydrofuran (THF), whereby also the AcO group was
cleaved reductively (Scheme 10). The formation of the heptalenedimethanols 21 and 22
and their respective DBS isomers was established by the presence of the signals of the
diastereotopic H-atoms of the 8 different CH2OH groups in the 1H-NMR spectrum of

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Helvetica Chimica Acta – Vol. 94 (2011)
the mixture. The mixture was then taken up in acetone and added to a solution of IBX
(1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide) in DMSO at room temp. Chromatog-
raphy (silica gel, hexane/tBuOMe 2 :3) gave a pure fraction of 23 (35%) and a mixture
23/24. The compounds were unstable so that only 23 could be fully characterized by its
1H-NMR spectrum in C6D6.
Scheme 10
We supposed that the OH group of 23 and 24 was responsible for their instability.
Therefore, we synthesized dimethyl 7,8-dimethoxy-5,6,10-trimethylheptalene-1,2-di-
carboxylate (25’) by methylation of the acetyloxy precursor 15, in analogy to the
benzylation reaction of 15 (Scheme 9). The 1,2-dicarboxylate 25’ was isolated from the
mixture of products by chromatography (silica gel, hexane/AcOEt 2 :1). The reduction
of the ester groups of 25’ caused no problems (Scheme 11), so that the dimethanol 26’
was not further characterized. Reaction of 26’ with IBX in DMSO led to the formation
of the expected 8,9-dimethoxy-6,7,11-trimethylheptaleno[1,2-c]furan (27). The
1H-NMR spectrum of 27 (600 MHz, C6D6) was in full agreement with its structure.
Typical are the coupling patterns and chemical shifts of HꢀC(1) (d-like) at d(H) 7.11,
HꢀC(3) (dd-like m due to coupling with HꢀC(1) and HꢀC(4) or HꢀC(5)) at d(H) 6.94,
and HꢀC(4) and HꢀC(5) at d(H) 6.42 and 5.86, respectively, with Jvic ¼ 11.4 Hz.
HꢀC(10) appeared as a sharp s at d(H) 5.54. The position of the signals of the Me and
1
MeO groups followed unambiguously from H-NOE measurements.
Scheme 11

Helvetica Chimica Acta – Vol. 94 (2011)
1205
Finally, it can be said that our investigations showed that in Scheme 1 the upper path
via 2 as well as the lower path via 3 are principally realizable for the synthesis of
colchicine structures of type 5.
We are thankful to our NMR laboratory for specific NMR measurements, our MS laboratory for
mass spectra, and our laboratory for microanalysis for elemental analyses. Financial support of this work
by the Swiss National Science Foundation is gratefully acknowledged.
Experimental Part
General. M.p.: Homemade apparatus with heating table and microscope; uncorrected. TLC:
Aluminium sheets coated with silica gel 60 F254 (SiO2; Merck) or plastic sheets coated with Al2O3 N/UV254
(Polygramꢅ; MachereyꢀNagel); spot visualization with UV light (254 or 366 nm) or with appropriate
spray reagents. Prep. TLC: SiO2 60 F254 plates (2 mm) or Al2O3 150 F254 plates (1.5 mm). Column
chromatography (CC) and flash chromatography (FC): SiO2 C-560 (0.040 – 0.063 mm; Chemie Uetikon
AG) or Al2O3, type 5016A, basic (0.05 – 0.15 mm; Fluka). HPLC: Spherisorb CN (3 m), 4 ꢁ 125 mm
column. Semi-prep. HPLC: Spherisorb CN (5 m), 20 ꢁ 250 mm column. UV/VIS Spectra: Lambda 19
UV/VIS/NIR spectrophotometer (PerkinꢀElmer); lmax and lmin in nm; molar extinction coefficients e
[1000 cm2 molꢀ1] in log e, or in rel. intensities with a Jasco MD-910 detector in the course of HPLC
separations. IR Spectra: Spectrum-One FT-IR spectrophotometer (PerkinꢀElmer) in KBr pills (ca. 1 mg
of substrate/150 mg of KBr); absorption bands in cmꢀ1; intensities as residual transmission. 1H- and
13C-NMR Spectra: Bruker instruments (ARX 300, DRX-500, and AMX 600); in CDCl3 if not otherwise
stated and SiMe4 as internal standard; chemical shifts d in ppm, coupling constants J in Hz; assignments
by NOESY and COSY measurements; DEPT for the determination of the multiplicities of the 13C
signals. Mass Spectra: MAT-95 instrument (Finnigan), EI at 70 eV, source temp. 2508, CI with NH3; in
m/z (rel. peak intensities in %).
1. Dimethyl 8-Methoxy-1,6,10-trimethylheptalene-4,5-dicarboxylate (6). 1.1. 4-Methoxy-2,6-dimethyl-
pyrylium Tetrafluoroborate. Under N2, 2,6-dimethyl-4H-pyran-4-one (100 g, 0.806 mol; prepared from
dehydracetic acid [21]) and dimethyl sulfate (161 g, 1.276 mol) were stirred for 18 h at 608. The orange
suspension was then cooled to ca. ꢀ 38 and 50% aq. HBF4 soln. (144 g, 0.82 mol) was slowly added under
vigorous stirring. After the addition, stirring was continued at ꢀ 38 for 2 h. Then, tBuOMe (100 ml) was
added and stirring continued for 15 min. The yellow suspension was filtered over a glass frit under a slight
pressure of N2. The yellow filter cake was washed several times (CH2Cl2) and dried under h.v.:
tetrafluoroborate (118.5 g, 65%). M.p. 173 – 1758 ([22]: 174 – 1758).
1.2. 6-Methoxy-4,8-dimethylazulene (7). NaH (60 g, 1.36 mol; 55 – 65% in mineral oil) was placed in a
flame-dried flask under N2. The mineral oil was removed by washing 3 times with hexane, and the NaH
was then suspended in THF (600 ml). The suspension was cooled to ꢀ 158, and cyclopentadiene (90 g,
1.36 mol) was slowly added dropwise taking care that the temp. did not exceed ꢀ 108. After the addition,
the thus prepared sodium cyclopentadienide soln. was stirred for 1 h at 08. Then, 4-methoxy-2,6-
dimethylpyrylium tetrafluoroborate (77 g, 0.341 mol; see 1.1) was added under vigorous stirring and
cooling at ꢀ 108. After the addition, the temp. was raised to 08 and the mixture then heated under reflux
for 24 h. The volume of the brown-red soln. was reduced to 100 ml, poured onto crashed ice, and then
extracted with AcOEt (5ꢁ). The combined extract was washed with brine, dried (Na2SO4), and
concentrated and the residue filtered with hexane several times over Al2O3 to give 7 (30.27 g, 48%) after
evaporation. Red powder. For characterization, a small quantity of 7 (0.10 g) was sublimed (908/h.v.) to
yield 7 as wine-colored plates. M.p. 101 – 1038 ([9]: 100 – 1018). Rf (SiO2, hexane/toluene 2 :1) 0.48. IR:
3424w, 3103w, 3071w, 3010w, 2967w, 2935w, 2839w, 2778w, 2725w, 2561w, 2474w, 2418w, 2304w, 2208w,
2108w, 2021w, 1899w, 1790w, 1738w, 1717w, 1694w, 1578vs, 1541m, 1497m, 1463m, 1455m, 1426m, 1409m,
1373w, 1335vs, 1275w, 1215vs, 1190m, 1174m, 1151m, 1102s, 1083w, 1063vs, 1019m, 965m, 937w, 919w,
896w, 860m, 829m, 800w, 742s, 712m, 609w, 528w, 412w. 1H-NMR (C6D6): 7.68 (t, 3J ¼ 3.9, HꢀC(2)); 7.44
(d, 3J ¼ 3.9, 2 H, HꢀC(1,3)); 6.64 (s, 2 H, HꢀC(5,7)); 3.28 (s, MeOꢀC(6)); 2.63 (s, 6 H, MeꢀC(4,8)).
13C-NMR (C6D6): 164.42 (s, C(6)); 145.45 (s, C(4,8)); 134.37 (s, C(3a,8a)); 130.47 (d, C(2)); 117.58 (d,

1206
Helvetica Chimica Acta – Vol. 94 (2011)
C(1,3)); 112.82 (d, C(5,7)); 55.10 (q, MeOꢀC(6)); 25.18 (q, MeꢀC(4,8)). EI-MS: 187 (15), 186 (100,
.
Mþ ), 185 (5), 171 (11), 155 (7), 143 (28), 142 (9), 141 (22), 129 (7), 128 (38), 127 (9), 115 (15). Anal.
calc. for C13H14O (186.26): C 83.83, H 7.58; found: C 83.84, H 7.55.
1.3. 6-Methoxy-1,4,8-trimethylazulene (8). 1.3.1. 6-Methoxy-4,8-dimethylazulene-1-carboxaldehyde.
The Vilsmeier reagent was prepared at 08 from DMF (5 ml) and POCl3 (1 ml, 11.36 mmol). The reagent
was added through a syringe under stirring to a cooled soln. (38) of 7 (1.863 g, 10.00 mmol) in DMF
(8.2 ml). An intermediately formed orange solid was re-dissolved by addition of further DMF (10 ml).
Stirring was continued for 30 min. The mixture was then poured into ice water what led to a dark red
soln., which was brought to pH 9 with 4n aq. NaOH. H2O was added, and the mixture was extracted 4
times with CH2Cl2 and finally with Et2O. The combined org. phase was washed 3 times with brine, dried
(Na2SO4) and concentrated. FC (SiO2, hexane/CH2Cl2/AcOEt 2 :2 :1) gave the azulene-1-carboxalde-
hyde (1.994 g, 96%). Orange needles. M.p. 128 – 1298. Rf (SiO2, AcOEt/hexane 2 :1) 0.58. IR: 3441w,
3215w, 3106w, 3051w, 3011w, 2981w, 2939w, 2907w, 2839w, 2730w, 2652w, 2588w, 2517w, 2440w, 2400w,
2294w, 2212w, 2160w, 2129w, 2069w, 2035w, 2011w, 1801w, 1619vs, 1585vs, 1558m, 1527w, 1501m, 1465m,
1455m, 1445m, 1434m, 1413w, 1376m, 1355m, 1330vs, 1313m, 1223vs, 1196m, 1180m, 1105m, 1068s, 1033w,
1000w, 969w, 939w, 907w, 895w, 864w, 845w, 787m, 774w, 721m, 714m, 672w, 655w, 621w, 540w, 485w.
1H-NMR: 10.56 (s, CH¼O); 8.08 (d, 3J ¼ 4.5, HꢀC(2)); 7.22 (d, 3J ¼ 4.5, HꢀC(3)); 7.01 (s, HꢀC(7)); 7.00
(s, HꢀC(5)); 3.95 (s, MeOꢀC(6)); 3.10 (s, MeꢀC(8)); 2.86 (s, MeꢀC(4)). 13C-NMR: 187.04 (t, CH¼O);
164.95 (s, C(6)); 148.57 (s, C(8)); 148.46 (s, C(4)); 139.61 (s, C(3a)); 135.15 (d, C(2)); 134.04 (s, C(8a));
130.70 (s, C(1)); 118.79 (d, C(7)); 117.47 (d, C(2)); 117.42 (d, C(5)); 55.95 (q, MeOꢀC(6)); 31.10 (q,
MeꢀC(8)); 26.51 (q, MeꢀC(4)). CI-MS: 216 (15), 215 (100, [M þ 1]þ), 201 (6). Anal calc. for C14H14O2
(214.27): C 78.48, H 6.59; found: C 78.90, H 6.52.
1.3.2. Reduction. Under N2, NaBH4 (3.00 g, 78.08 mmol) was suspended in diglyme (30 ml) in a
flame-dried flask. Concurrently, a soln. of BF3 · Et2O (3.8 ml, 34.81 mmol) in Et2O (60 ml) and a
suspension of the aldehyde (5.50 g, 25.67 mmol; see 1.3.1) in diglyme (60 ml) were added dropwise
(!violet suspension already after a few drops). Stirring was continued for 1 h at r.t. after addition of the
reactants. The dark violet mixture was then poured into ice water (250 ml), and stirring was pursued until
the frothing had ceased. The formed azulene 8 was extracted with hexane (3ꢁ), the extract washed with
brine, dried (Na2SO4), and concentrated, and the residue dried at 60 – 658/h.v. until it solidified. FC
(Al2O3, hexane/AcOEt 20 :1) gave pure 8 (4.70 g, 92%). Dark violet crystals. M.p. 99 – 1008. Rf (SiO2,
hexane/toluene 2 :1) 0.48. IR: 3442w, 3065w, 3007w, 2973w, 2952m, 2940w, 2919w, 2864w, 2839w, 2780w,
2731w, 2640w, 2532w, 2458w, 2407w, 2377w, 2305w, 2257w, 2229w, 2155w, 2106w, 2081w, 2026w, 1922w,
1901w, 1746w, 1704w, 1636w, 1579vs, 1560s, 1531m, 1513s, 1453m, 1441m, 1407m, 1390m, 1365m, 1343s,
1302s, 1267w, 1217vs, 1205s, 1192m, 1171s, 1145m, 1105m, 1066s, 1033m, 957w, 942w, 872m, 834m, 777s,
1
3
3
720m, 714m, 707m, 691w, 531w. H-NMR (C6D6): 7.40 (d, J ¼ 3.9, HꢀC(2)); 7.33 (d, J ¼ 3.9, HꢀC(3));
4
4
6.49 (d, J ¼ 2.5, HꢀC(7)); 6.47 (d, J ¼ 2.5, HꢀC(5)); 3.30 (s, MeOꢀC(6)); 2.76 (s, MeꢀC(1)); 2.70 (s,
MeꢀC(8)); 2.60 (s, MeꢀC(4)). 13C-NMR (C6D6): 164.07 (s, C(6)); 147.02 (s, C(8)); 144.94 (s, C(4)); 135.22
(s, C(3a)); 134.82 (d, C(2)); 131.33 (s, C(8a)); 128.09 (s, C(1)); 116.33 (d, C(3)); 113.61 (d, C(7)); 111.32
(d, C(5)); 54.97 (q, MeOꢀC(6)); 27.91 (q, MeꢀC(8)); 25.67 (q, MeꢀC(4)); 20.03 (q, MeꢀC(1)). EI-MS:
.
201 (14), 200 (100, Mþ ), 199 (70), 185 (31), 157 (8), 156 (7), 155 (9), 153 (8), 152 (8), 143 (7), 142 (20),
141 (26), 128 (9), 115 (14), 57 (7). Anal. calc. for C14H16O (200.28): C 83.96, H 8.05; found: C 84.00, H
7.99.
1.4. Reaction of Azulene 8 with Dimethyl Acetylenedicarboxylate (ADM). 1.4.1. Dimethyl 8-
Methoxy-1,6,10-trimethylheptalene-4,5-dicarboxylate (6) and Dimethyl 6-Methoxy-4,8-dimethylazulene-
1,2-dicarboxylate (9). To a soln. of 8 (1.00 g, 5.00 mmol) in toluene (12 ml) in a flame-dried Schlenk
vessel under N2, ADM (0.62 ml, 15.0 mmol) was added through a syringe. The vessel was closed and the
violet soln. heated at 1408 for 24 h. After cooling, the now yellow-red soln. was poured on ice/water
(10 ml) and further extracted with Et2O (3ꢁ). The combined extract was washed with brine, dried
(Na2SO4), and concentrated and the red-brown residue dried at 608 and then subjected to FC (SiO2,
hexane/AcOEt 3 :1): 6 as yellow prisms (0.528 g, 31%), followed by 9, as blood-red rhombs (0.545 g,
36%).
Data of 6: M.p. 179 – 1808. Rf (SiO2, hexane/AcOEt 2 :1) 0.47. UV/VIS (MeCN; see also Table 3 and
Fig. 3): max. 211 (4.37), 238 (sh, 4.26), 272 (4.17), 290 (sh, 4.06), 331 (sh, 3.57), 390 (sh, 2.91); min. 196

Helvetica Chimica Acta – Vol. 94 (2011)
1207
(4.34), 256 (4.12). IR: 3444w, 3399w, 3016w, 2989w, 2950m, 2932w, 2911w, 2846w, 2832w, 1734vs, 1708vs,
1668w, 1649m, 1627w, 1597m, 1569m, 1535m, 1461m, 1434s, 1393m, 1374w, 1345w, 1296m, 1267vs, 1248vs,
1214s, 1197vs, 1175s, 1151m, 1109m, 1089s, 1052s, 1025w, 991m, 959m, 927w, 864w, 851w, 842m, 827m,
793w, 783m, 772m, 717w, 705w, 683w, 646w, 629w, 610w, 585w, 569w, 535w, 519w, 511w, 476w, 437w.
1H-NMR: 7.52 (d, 3J ¼ 5.8, HꢀC(3)); 6.25 (dd, 3J ¼ 5.8, 4J ¼ 1.0, HꢀC(2)); 6.00 (s, HꢀC(7)); 5.51 (d, 4J ¼
1.1, HꢀC(9)); 3.69 (s, MeOOCꢀC(4)); 3.69 (s, MeOOCꢀC(5)); 3.61 (s, MeOꢀC(8)); 1.99 (s, MeꢀC(1));
1.95 (s, MeꢀC(6)); 1.77 (s, MeꢀC(10)). 13C-NMR: 167.78 (s, COꢀC(5)); 167.52 (s, COꢀC(4)); 159.24 (s,
C(8)); 145.19 (s, C(5a)); 143.98 (s, C(1)); 139.36 (d, C(3)); 133.49 (s, C(6)); 131.17 (s, C(4)); 129.81 (s,
C(10)); 125.67 (d, C(2)); 123.63 (d, C(7)); 122.85 (s, C(10a)); 122.45 (s, C(5)); 105.94 (d, C(9)); 54.56 (q,
MeOꢀC(8)); 51.98 (q, MeOOCꢀC(5)); 51.94 (q, MeOOCꢀC(4)); 23.58 (q, MeꢀC(1)); 22.07 (q,
.
MeꢀC(6)); 19.11 (q, MeꢀC(10)). EI-MS: 343 (22), 342 (100, Mþ ), 327 (31, [M ꢀ Me]þ), 311 (12, [M ꢀ
.
MeO]þ), 295 (33), 283 (34), 268 (12), 251 (29), 244 (24, [M ꢀ MeCꢂCCOOMe]þ ), 224 (12), 223 (14),
.
209 (15), 201 (11), 200 (69, [M ꢀ ADM]þ ), 199 (12), 166 (10), 165 (27). Anal. calc. for C20H22O5
(342.40): C 70.16, H 6.48; found: C 70.13, H 6.49.
The structure of 6 was finally established by an X-ray crystal-structure analysis (Table 4).
Data of 9: M.p. 124 – 1258. Rf (SiO2, hexane/AcOEt 1:1) 0.47. IR: 3388w, 3042w, 2988w, 2953m,
2916w, 2850w, 1727vs, 1702vs, 1662w, 1637w, 1586vs, 1554m, 1529m, 1511m, 1485s, 1455m, 1443m, 1430s,
1415m, 1388m, 1378m, 1371m, 1350s, 1277s, 1250vs, 1222vs, 1211vs, 1198vs, 1139s, 1098s, 1070s, 1054s,
1038m, 985m, 966w, 950w, 934m, 919w, 873m, 847m, 819w, 805w, 780m, 731m, 668w, 655w, 632w, 541w,
447w. 1H-NMR: 7.69 (s, HꢀC(3)); 6.80 (s, HꢀC(5), HꢀC(7)); 3.99 (s, MeOOCꢀC(1)); 3.96 (s,
MeOꢀC(6)); 3.91 (s, MeOOCꢀC(2)); 2.87 (s, MeꢀC(8)), 2.84 (s, MeꢀC(4)). 13C-NMR: 171.30 (s,
COꢀC(1)); 167.45 (s, C(6)); 165.50 (s, COꢀC(2)); 151.83 (s, C(8)); 151.13 (s, C(4)); 132.53 (s, C(8a));
129.31 (s, C(2)); 129.07 (s, C(4a)); 123.26 (s, C(3)); 117.94 (d, C(1)); 116.81 (d, C(7)); 114.12 (d, C(5));
56.02 (q, MeOꢀC(6)); 52.63 (q, MeOOCꢀC(1)); 51.80 (q, MeOOCꢀC(2)); 26.28 (q, MeꢀC(4)); 26.19 (q,
.
MeꢀC(8)). CI-MS: 303 (50, [M þ 1]þ), 271 (100, [M ꢀ MeOH]þ ). Anal. calc. for C17H18O5 (302.33): C
67.54, H 6.00; found: C 67.42, H 5.96.
1.4.2. Dimethyl 8-Methoxy-5,6,10-trimethylheptalene-1,2-dicarboxylate (6’). A soln. of 6 (0.342 g,
1.00 mmol) in MeCN (10 ml) was exposed for 8 h to normal laboratory light. TLC indicated the presence
of almost equal amounts of 6 and 6’. FC (SiO2, hexane/AcOEt 2 :1) gave 6’ (0.156 g, 42%) as orange
powder, followed by 6 (0.177 g, 52%).
Data of 6’: M.p. 123 – 1248. Rf (SiO2, hexane/AcOEt 4 :1) 0.40. UV/VIS (MeCN; see also Table 3):
max. 191 (sh, 4.40), 231 (4.24), 275 (4.27), 327 (sh, 3.44), 387 (sh, 2.78); min. 226 (4.24), 366 (2.75). IR:
3016w, 3005w, 2983w, 2957m, 2950m, 2912w, 2856w, 2834w, 1728vs, 1650w, 1622w, 1608m, 1567s, 1466m,
1451m, 1431s, 1401w, 1368w, 1319m, 1261vs, 1232s, 1204s, 1191s, 1167s, 1123m, 1094s, 1053m, 1036m,
1010w, 995m, 969w, 948w, 935w, 914w, 874w, 836m, 820m, 811w, 794w, 781w, 751m, 732w, 710w, 678w,
1
3
3
640w, 630w, 607w, 580w, 553w, 532w. H-NMR (CD3CN): 6.59 (d, J ¼ 11.8, HꢀC(4)); 6.54 (d, J ¼ 11.8,
HꢀC(3)); 6.04 (t, 4J ¼ 1.4, HꢀC(7)); 5.54 (d, 4J ¼ 1.7, HꢀC(9)); 3.75 (s, MeOOCꢀC(2)); 3.65 (s,
MeOOCꢀC(1)); 3.57 (s, MeOꢀC(8)); 2.00 (d, 4J ¼ 1.3, MeꢀC(6)); 1.76 (s, MeꢀC(5)); 1.64 (s, MeꢀC(10)).
13C-NMR (CD3CN): 168.64 (s, COꢀC(2)); 167.73 (s, COꢀC(1)); 160.68 (s, C(8)); 140.11 (d, C(4)); 139.49
(s, C(5a)); 138.14 (q, C(2)); 137.34 (s, C(6)); 132.81 (s, C(10)); 130.39 (s, C(1)); 130.03 (s, C(5)); 127.31 (d,
C(3)); 125.35 (d, C(7)); 121.27 (s, C(10a)); 106.48 (d, C(9)); 55.16 (q, MeOꢀC(8)); 53.17 (q,
MeOOCꢀC(2)); 53.02 (q, MeOOCꢀC(1)); 22.62 (q, MeꢀC(6)); 18.31 (q, MeꢀC(10)); 17.86 (q,
MeꢀC(5)). CI-MS: 361 (7), 360 (31, [M þ NH4]þ), 345 (6), 344 (18), 343 (100, [M þ 1]þ), 342 (7),
313 (7), 312 (23), 311 (96, [(M þ 1) ꢀ MeOH]þ).
2. Bromination of Heptalene-4,5-dicarboxylate 6 (see also Table 1). 2.1. Formation of 10 – 13. To a
soln. of 6 (0.450 g, 1.31 mmol) in dry DMF (9 ml) cooled to ꢀ 158, a pre-cooled soln. of NBS (0.234 g,
1.31 mmol) in DMF (2 ml) was added via a syringe. The mixture was stirred in the dark for an additional
hour at ꢀ 158. The soln. was then poured on to ice and extracted with AcOEt (3ꢁ), the extract washed
with H2O (5ꢁ), dried (Na2SO4), and concentrated, and the residue subjected to CC (Al2O3, hexane/
AcOEt 3 :1), followed by a second CC (SiO2, hexane/AcOEt 3 :1): dimethyl 6-(bromomethyl)-8-
methoxy-1,10-dimethylheptalene-4,5-dicarboxylate (11) as yellow powder (0.113 g, 21%), dimethyl 9-
bromo-8-methoxy-1,6,10-trimethylheptalene-4,5-dicarboxylate (10)/dimethyl 9-bromo-6-(bromomethyl)-
8-methoxy-1,10-dimethylheptalene-4,5-dicarboxylate (12) as greenish yellow oil, and heptalenone 13

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Helvetica Chimica Acta – Vol. 94 (2011)
Table 4. Crystallographic Data of Compounds 6, 10, 13, 14, and 15’
6
10
13
14
15’
Crystallized from
AcOEt/hexane/ Et2O/hexane/
AcOEt/hexane EtOAc/hexane/ Et2O/hexane/
DMF
MeOH
Et2O
MeCN
Empirical formula
Mr
C20H22O5
342.39
C20H21BrO5
421.28
C19H20O5
328.36
C21H22O7
386.40
C22H24O7
400.42
Crystal color, habit yellow, prism
yellow, needle
yellow, prism
yellow, tablet
orange, prism
Crystal dimensions 0.17 ꢁ 0.17 ꢁ 0.25 0.05 ꢁ 0.12 ꢁ 0.25 0.12 ꢁ 0.12 ꢁ 0.20 0.10 ꢁ 0.22 ꢁ 0.23 0.10 ꢁ 0.25 ꢁ 0.28
[mm]
Temperature [K]
Crystal system
Space group
Z
160 (1)
triclinic
P1
160 (1)
monoclinic
P21/n
160 (1)
triclinic
P1
160 (1)
triclinic
P1
160 (1)
orthorhombic
Pbca
8
¯
¯
¯
2
4
2
2
Reflections for
cell determination
2q Range for cell
determination [8]
Unit cell parameters:
a [ꢆ]
b [ꢆ]
c [ꢆ]
a [8]
b [8]
3946
30307
3652
5624
4514
4 – 55
4 – 60
4 – 55
4 – 60
4 – 52
8.3037(2)
8.4419(2)
12.6946(4)
94.448(2)
94.164(2)
91.583(1)
884.36(4)
364
1.286
0.0917
f and w
55
6.3696(1)
19.6306(3)
15.1721(2)
90
96.1237(5)
90
1886.28(5)
864
1.483
8.2544(2)
10.0085(2)
11.2872(3)
68.919(1)
87.505(1)
71.1181(9)
820.45(3)
348
1.329
0.0957
f and w
55
6.9962(1)
11.2043(2)
13.2844(3)
75.8277(9)
87.3942(8)
76.450(1)
981.45(3)
408
1.307
0.0982
f and w
60
8.6940(1)
21.1417(2
22.1651(3)
90
90
90
4074.08(8)
1696
1.306
0.0971
f and w
52
g [8]
V [ꢆ3]
F(000)
Dx [g cmꢀ3
]
m(MoKa) [mmꢀ1
Scan type
]
2.213
f and w
60
2q(max) [8]
Transmission factors
(min; max)
–
0.675; 0.909
–
–
–
Total reflections
measured
Symmetry-indepen- 4036
dent reflections
20292
47441
5512
19837
3745
29289
5701
46911
4013
Rint
0.041
2999
0.076
4144
0.039
2964
0.048
2930
0.058
Reflections with
I > 2s (I)
Parameters refined 226
236
223
254
263
R(F) (I > 2s(I)
0.0521
0.0399
0.0515
0.0498
0.0472
reflections)a)
wR(F) (I > 2s(I)
reflections)a)
0.0565
0.0407
0.1458a)
0.0505
0.0475
Goodness of fit
Secondary extinction –
coefficient
2.985
1.844
3(1) · 10ꢀ7
1.075
0.050(8)
2.218
2.9(9) · 10ꢀ6
2.673
5(1) · 10ꢀ7
Final Dmax/s
0.0004
0.24; ꢀ 0.28
0.002
0.64; ꢀ 0.42
0.001
1.42; ꢀ 0.19
0.0004
0.26; ꢀ 0.26
0.0005
0.29; ꢀ 0.28
D1 (max; min)
[e ꢆꢀ3
]
a) Refined on F2; wR(F2) calculated using all data.

Helvetica Chimica Acta – Vol. 94 (2011)
1209
(0.021 g, 5%), in this order. Treatment of the oil 10/12 with hexane/AcOEt/MeOH gave pure 10 as yellow
needles (0.363 g, 67%) and pure 12 as deep yellow crystals (0.039 g, 6%).
Data of 10: M.p. 143 – 1448. Rf (SiO2, hexane/AcOEt 2 :1) 0.37. UV/VIS (MeCN; see also Table 3
and Fig. 3): max. 193 (sh, 4.40), 213 (sh, 4.34), 252 (4.32), 269 (sh, 4.18), 297 (sh, 3.94), 338 (sh, 3.49), 3.85
(3.04); min. 228 (4.27). IR: 3412w, 2994w, 2974w, 2949m, 2918w, 2840w, 1717vs, 1675w, 1643m, 1621w,
1585w, 1548m, 1519w, 1440m, 1382w, 1370w, 1358w, 1342w, 1268vs, 1216m, 1194m, 1157m, 1116w, 1091s,
1072m, 1056m, 1040w, 1027w, 1007w, 984w, 965w, 955w, 919w, 880w, 853w, 841w, 831w, 801w, 788w, 767m,
1
3
5
727w, 696w, 676w, 646w, 630w, 573w, 521w, 476w, 459w. H-NMR: 7.58 (dd, J ¼ 5.8, J ¼ 0.5, HꢀC(3));
6.30 (dd, 3J ¼ 6.0, 4J ¼ 1.3, HꢀC(2)); 6.07 (d, 4J ¼ 1.3, HꢀC(7)); 3.80 (s, MeOꢀC(8)); 3.74 (s,
MeOOCꢀC(4)); 3.70 (s, MeOOCꢀC(5)); 2.05 (s, MeꢀC(1)); 1.96 (s, MeꢀC(10)); 1.94 (d, 4J ¼ 1.3,
MeꢀC(6)). 13C-NMR: 167.34 (s, COꢀC(5)); 167.10 (s, COꢀC(4)); 155.64 (s, C(8)); 142.22 (s, C(5a));
141.35 (s, C(1)); 139.07 (d, C(3)); 137.19 (s, C(6)); 130.69 (s, C(4)); 129.18 (s, C(10)); 127.01 (s, C(10a));
125.84 (d, C(2)); 122.77 (s, C(5)); 120.76 (d, C(7)); 112.17 (s, C(9)); 58.47 (q, MeOꢀC(8)); 52.14 (q,
MeOOCꢀC(4)); 52.08 (q, MeOOCꢀC(5)); 23.17 (q, MeꢀC(1)); 21.85 (q, MeꢀC(6)); 18.66 (q,
.
MeꢀC(10)). CI-MS: 441, 439 (21, 23, [M þ NH4]þ), 440, 438 (100, 98), 423, 421 (23, 22, Mþ ), 422 (7),
391, 389 (17, 17), 358 (6), 343 (8), 311 (7), 281 (10), 209 (9).
The structure of 10 was finally established by an X-ray crystal-structure analysis (Table 4).
Data of 11: M.p. 177 – 1788. Rf (SiO2, hexane/AcOEt 2 :1) 0.46. IR: 3398w, 3016w, 2950m, 2931w,
2911w, 2845w, 2832w, 1734vs, 1708vs, 1668w, 1649m, 1627w, 1597m, 1569m, 1535m, 1461m, 1434s, 1392m,
1374w, 1345w, 1296m, 1267vs, 1248vs, 1213s, 1197vs, 1175s, 1151s, 1109m, 1089s, 1052s, 1024w, 991m,
959m, 927w, 864w, 851w, 842m, 827m, 793w, 783m, 772m, 717w, 705w, 683w, 646w, 629w, 610w, 584w, 570w,
535w, 511w, 476w, 437w. 1H-NMR: 7.55 (d, 3J ¼ 6, HꢀC(3)); 6.30 (d, 4J ¼ 1.6, HꢀC(7)); 6.29 (dd, 3J ¼ 5.9,
2
4J ¼ 1.3, HꢀC(2)); 5.59 (d, 4J ¼ 1.5, HꢀC(9)); 4.21, 3.96 (AB, JAB ¼ 10.4, BrCH2ꢀC(6)); 3.70 (s,
MeOOCꢀC(4)); 3.67 (s, MeOOCꢀC(5)); 3.62 (s, MeOꢀC(8)); 2.14 (s, MeꢀC(1)); 1.79 (s, MeꢀC(10)).
13C-NMR: 167.44 (s, COꢀC(4)); 167.41 (s, COꢀC(5)); 157.92 (s, C(8)); 145.12 (s, C(1)); 141.97 (s, C(5a));
140.22 (d, C(3)); 134.01 (s, C(6)); 130.98 (s, C(4)); 130.28 (s, C(10)); 128.45 (d, C(7)); 126.28 (d, C(2));
124.92 (s, C(10a)); 123.88 (s, C(5)); 108.44 (d, C(9)); 54.70 (q, MeOꢀC(8)); 52.06 (q, MeOOCꢀC(4),
MeOOCꢀC(5)); 34.36 (t, BrCH2ꢀC(6)); 24.62 (q, MeꢀC(1)), 19.55 (q, MeꢀC(10)).
Data of 12: M.p. 148 – 1498. Rf (SiO2, hexane/AcOEt 2 :1) 0.37. IR: 3045w, 3000w, 2973w, 2950m,
2920w, 2846w, 1714vs, 1707vs, 1635m, 1615m, 1586m, 1547m, 1502m, 1431s, 1382m, 1341w, 1284s, 1268vs,
1245s, 1229s, 1216m, 1196m, 1162s, 1145m, 1106w, 1087s, 1073m, 1052m, 1030m, 987w, 971m, 945w, 911w,
896w, 874w, 860w, 828m, 807w, 788w, 766m, 732m, 709w, 696w, 681w, 637w, 593w, 576w, 515w, 495w.
1H-NMR: 7.61 (dd, 3J ¼ 6.1, 5J ¼ 0.9, HꢀC(3)); 6.42 (s, HꢀC(7)); 6.34 (dd, 3J ¼ 6.1, 4J ¼ 1.4, HꢀC(2)); 4.21,
2
4
3.88 (ABX, JAB ¼ 10.9, JAX ¼ 4JBX ¼ 0.7, BrCH2ꢀC(6)); 3.79 (s, MeOꢀC(8)); 3.74 (s, MeOOCꢀC(4));
3.69 (s, MeOOCꢀC(5)); 2.20 (d, 4J ¼ 1.0, MeꢀC(1)); 1.99 (s, MeꢀC(10)). 13C-NMR: 167.10 (s, COꢀC(4));
166.97 (s, COꢀC(5)); 154.48 (s, C(8)); 142.53 (s, C(1)); 139.98 (d, C(3)); 138.62 (d, C(5a)); 137.28 (s,
C(6)); 130.47 (s, C(4)); 130.03 (s, C(10)); 128.86 (s, C(10a)); 126.56 (d, C(2)); 125.72 (d, C(7)); 124.47 (s,
C(5)); 115.73 (s, C(9)); 58.67 (q, MeOꢀC(8)), 52.25 (q, MeOOCꢀC(5)); 52.22 (q, MeOOCꢀC(4)), 32.78
(t, BrCH2ꢀC(6)), 24.48 (q, MeꢀC(1)), 19.06 (q, MeꢀC(10)). EI-MS: 502 (12), 500 (24), 422 (44), 405
(13), 390 (100), 375 (22), 361 (20), 348 (37), 340 (23), 325 (20), 309 (25), 281 (57), 266 (43), 251 (24), 235
(16), 178 (23), 165 (30), 157 (92), 151 (27), 129 (20), 106 (20), 91 (67), 75 (28), 44 (23).
2.2. Attempts to Exchange the 9-Bromo Substituent of 10 by an Oxy Group (see Scheme 3). The
conditions that we applied gave no results, except for the saponification of the sterically less hindered
ester group at C(4) of 10 resulting in the formation of 5-methyl 4-hydrogen 9-bromo-8-methoxy-1,6,10-
trimethylheptalene-4,5-dicarboxylate (10a). To a suspension of 10 (0.050 g, 0.119 mmol) in MeOH/H2O
1:1 (5 ml) was added NaOH (0.024 g, 0.60 mmol). The mixture was stirred at r.t. (24 h). The usual
workup and FC (SiO2, AcOEt/hexane 3 :1) gave 10a (0.035 g, 72%). Fine yellow needles. M.p. 1828
(dec.)7). Rf (SiO2, AcOEt) 0.30. IR: 3078w, 2988w, 2950m, 2925w, 2909w, 2851w, 2760 – 2390 (br.),
1718vs, 1636m, 1614w, 1584w, 1547m, 1514w, 1436m, 1376m, 1359m, 1344m, 1274vs, 1259vs, 1221s, 1210s,
1197s, 1165m, 1115m, 1084m, 1073m, 1053m, 1025w, 1009w, 970m, 953w, 939w, 923w, 857w, 832w, 794m,
734m, 702w, 688w, 663w, 628w, 590w, 570w, 543w, 523w, 464w, 439w. 1H-NMR: 7.67 (dd, 3J ¼ 6.0, 5J ¼ 0.8,
7
)
The cyclic anhydride was formed by loss of MeOH (cf. [11b]).

1210
Helvetica Chimica Acta – Vol. 94 (2011)
0.9, HꢀC(3)); 6.33 (dd, 3J ¼ 5.9, 4J ¼ 1.4, HꢀC(2)); 6.08 (d, 4J ¼ 1.4, HꢀC(7)); 3.80 (s, MeOꢀC(8)), 3.70 (s,
MeOOCꢀC(5)); 2.06 (s, MeꢀC(1)); 1.97 (s, MeꢀC(10)); 1.95 (d, 4J ¼ 1.3, MeꢀC(6)). 13C-NMR: 171.38 (s,
HOOCꢀC(4)); 167.22 (s, COꢀC(5)); 155.77 (s, C(8)); 142.79 (s, C(5a)); 142.51 (s, C(1)); 140.80 (d, C(3));
137.11 (s, C(6)); 129.98 (s, C(4)); 129.49 (s, C(10)); 126.85 (s, C(10a)); 125.88 (d, C(2)); 122.51 (s, C(5));
121.01 (d, C(7)); 112.23 (s, C(9)); 58.61 (q, MeOꢀC(8)); 52.26 (q, MeOOCꢀC(5)); 23.34 (q, MeꢀC(1));
21.83 (q, MeꢀC(6)); 18.74 (q, MeꢀC(10)). CI-MS: 426, 424 (20, 20, [M þ NH3]þ), 409, 407 (6, 6, Mþ), 394,
392 (100, 97), 377, 375 (44, 40), 359 (6), 314 (11), 297 (15).
3. Introduction of an O-Functionality at C(9) of 6. 3.1. Dimethyl 8,9-Dihydro-1,6,10-trimethyl-8-
oxoheptalene-4,5-dicarboxylate4) (13). To the dark yellow soln. of 6 (0.100 g, 0.305 mmol) in DMF (3 ml)
were added dry NaI (0.069 g, 0.467 mmol) and then Me3SiCl (0.6 ml, 0.47 mmol). The mixture was stirred
for 5 d at r.t. Thereafter, the mixture was poured on ice and extracted with Et2O (3ꢁ). The combined
Et2O phase was washed with aq. sat. Na2S2O3 soln. and brine, dried (MgSO4), and concentrated, and the
residue subjected to FC (SiO2, hexane/AcOEt 3 :1): 6 (0.014 g, 14%), followed by a yellow oil which
slowly crystallized from AcOEt/hexane to give 13 (0.077 g, 80%). Yellow prisms. M.p. 151 – 1538. Rf
(SiO2, hexane/AcOEt 2 :1) 0.32. UV/VIS (MeCN): max. 195 (sh, 4.34), 223 (sh, 4.05), 261 (4.27), 276 (sh,
4.19), 299 (sh, 3.90), 335 (sh, 3.44), 390 (sh, 2.90); min. 229 (4.04). IR: 3393w, 3289w, 3020w, 3009w,
2980w, 2953m, 2908w, 2879w, 2849w, 1728vs, 1706vs, 1655s, 1610m, 1600w, 1576w, 1520w, 1437s, 1394w,
1378m, 1342w, 1274vs, 1242s, 1211m, 1198m, 1187m, 1155m, 1137m, 1114w, 1092m, 1054s, 988w, 971m,
962w, 944w, 929w, 911w, 874w, 861m, 839w, 822w, 800w, 781m, 772m, 724w, 707w, 663w, 629w, 504w, 450w.
3
5
3
4
4
1H-NMR: 7.57 (dd, J ¼ 6.2, J ¼ 0.8, HꢀC(3)); 6.30 (dd, J ¼ 6.2, J ¼ 1.4, HꢀC(2)); 5.95 (t, J ¼ 1.4, 1.5,
2
2
HꢀC(7)); 3.77 (s, MeOOCꢀC(5)); 3.76 (s, MeOOCꢀC(4)); 3.66 (d, J ¼ 13.1, HꢀC(9)); 2.85 (dd, J ¼
13.7, 4J ¼ 1.8, HꢀC(9)); 2.09 (d, 4J ¼ 1.0, MeꢀC(1)); 1.92 (d, 4J ¼ 1.3, MeꢀC(6)); 1.77 (d, 4J ¼ 0.5,
MeꢀC(10)). 13C-NMR: 196.30 (s, C(8)); 168.02 (s, COꢀC(5)); 166.98 (s, COꢀC(4)); 153.33 (s, C(6));
145.14 (s, C(1)); 141.66 (s, C(5a)); 138.45 (d, C(3)); 135.74 (s, C(10a)); 131.99 (d, C(7)); 129.70 (s, C(4));
129.33 (s, C(10)); 127.48 (s, C(5)); 123.29 (d, C(2)); 52.64 (q, MeOOCꢀC(5)); 52.29 (q, MeOOCꢀC(4));
.
50.07 (t, C(9)); 24.81 (q, MeꢀC(6)); 23.40 (q, MeꢀC(1)); 19.02 (q, MeꢀC(10)). EI-MS: 328 (40, Mþ ), 313
.
(15), 296 (35, [M ꢀ MeOH]þ ), 281 (63, [M ꢀ (MeOH þ Me]þ), 269 (100, [M ꢀ (MeO þ CO)]þ), 253
(34), 237 (78), 231 (50), 209 (62), 195 (26), 181 (34), 165 (62), 152 (37), 141 (19), 115 (20), 89 (6), 77
(7), 59 (11), 43 (9). Anal. for C19H20O5 (328.37): C 69.50, H 6.14; found: C 69.10, H 5.88.
The structure of 13 was finally established by an X-ray crystal-structure analysis (Table 4 and Fig. 1).
3.2. Acetyloxylation of 13. To a soln. of 13 (0.250 g, 0.761 mmol) in benzene (20 ml) under N2,
Pb(AcO)48) (0.480 g, 0.914 mmol) was added (yellow soln. ! brownish). The mixture was heated under
reflux for 3 h. After cooling, the benzene soln. was washed with brine, aq. sat. NaHCO3 soln., and then
again brine, dried (Na2SO4), and concentrated and the residue subjected to FC (SiO2, hexane/AcOEt
3 :1), which gave, after crystallization from hexane/AcOEt/Et2O, dimethyl 9-(acetyloxy)-8,9-dihydro-
1,6,10-trimethyl-8-oxoheptalene-4,5-dicarboxylate4) (14; 0.208 g, 71%). Pale greenish yellow tablets. M.p.
186 – 1888. Rf (SiO2, hexane/AcOEt 1:1) 0.47. UV/VIS (MeCN): max. 195 (sh, 4.33), 221 (sh, 4.01), 266
(4.29), 273 (sh, 4.27), 300 (sh, 3.96), 338 (sh, 3.44), 383 (sh, 3.00); min. 229 (3.98). IR: 3405w, 3348w,
2986w, 2955m, 2911w, 2852w, 1756vs, 1729s, 1714vs, 1686vs, 1603m, 1578w, 1525w, 1440s, 1377m, 1343w,
1287vs, 1256vs, 1227vs, 1174m, 1143m, 1113m, 1088s, 1053s, 1029m, 992w, 970w, 945w, 934w, 912w, 863w,
857w, 802w, 789m, 771m, 745w, 716w, 685w, 667w, 646w, 626w, 597w, 562w, 536w, 518w, 476w, 452w.
1H-NMR: 7.62 (dd, 3J ¼ 6.2, 5J ¼ 0.9, HꢀC(3)); 6.37 (dd, 3J ¼ 6.2, 4J ¼ 1.4, HꢀC(7)); 6.07 (d, 4J ¼ 1.3,
HꢀC(2)); 6.02 (d, 4J ¼ 1.1, HꢀC(9)); 3.80 (s, MeOOCꢀC(5)); 3.76 (s, MeOOCꢀC(4)); 2.19 (s,
AcOꢀC(9)); 2.09 (t, 4J ꢃ 1.0, MeꢀC(1)); 1.94 (d, 4J ¼ 1.3, MeꢀC(6)); 1.73 (d, 4J ¼ 1.1, MeꢀC(10)).
13C-NMR: 190.13 (s, C(8)); 169.08 (s, MeCOOꢀC(9)); 167.73 (s, COꢀC(5)); 166.64 (s, COꢀC(4)); 152.69
(s, C(6)); 143.77 (s, C(1)); 138.57 (d, C(3)); 138.54 (s, C(5a)); 134.35 (s, C(10)); 130.47 (d, C(7)); 129.87
(s, C(4)); 129.39 (s, C(10a)); 128.61 (d, C(5)); 123.85 (d, C(2)); 77.94 (d, C(9)); 52.82 (q, MeOOCꢀC(5));
52.37 (q, MeOOCꢀC(4)); 24.77 (q, MeꢀC(6)); 23.14 (q, MeꢀC(1)); 20.58 (q, MeCOOꢀC(9)); 12.59 (q,
MeꢀC(10)). CI-MS (CI): 405 (24), 404 (100, [M þ NH4]þ), 372 (11), 347 (8), 346 (39), 329 (15). Anal.
calc. for C21H22O7 (386.41): C 65.28, H 5.74; C 65.08, H 5.81.
8
)
Contained 15% AcOH.

Helvetica Chimica Acta – Vol. 94 (2011)
1211
The relative (9R*,P*)-configuration of 14 was confirmed by an X-ray crystal-structure analysis
(Table 4, Fig. 2).
3.3. O-Methylation of 14. 3.3.1. Dimethyl 7-Acetyloxy-8-methoxy-5,6,10-trimethylheptalene-1,2-
dicarboxylate (15’) and Dimethyl 9-(Acetyloxy)-8-methoxy-1,6,10-trimethylheptalene-4,5-dicarboxylate
(15). To a suspension of dry and finely powdered K2CO3 (0.028 g, 0.20 mmol) in dry acetone (1 ml) under
N2, 14 (0.050 g, 0.129 mmol) was added, followed by 1.68 · 10ꢀ3 m DMS in dry acetone (1 ml). The yellow
mixture was stirred for 30 h at 508. After usual workup, the residue was purified by FC (SiO2, hexane/
AcOEt 3 :1): 15’ (0.013 g, 24%) as orange prisms, followed by 15 (0.035 g, 65%), as yellow tablets.
Data of 15: M.p. 131 – 1328. Rf (SiO2, hexane/AcOEt 1:1) 0.46. UV/VIS (MeCN, see also Table 3 and
Fig. 3): max. 190 (sh, 4.81), 212 (4.38), 240 (4.29), 268 (4.24), 327 (sh, 3.56), 387 (sh, 297); min. 202 (4.35),
231 (4.29), 260 (4.24). IR: 3400w, 3003w, 2983w, 2950m, 2910w, 2844w, 1760s, 1713vs, 1670w, 1645m,
1618w, 1593w, 1563m, 1523w, 1502w, 1438s, 1393w, 1375m, 1363m, 1349w, 1323w, 1297m, 1277vs, 1258vs,
1226s, 1210vs, 1198s, 1159m, 1128s, 1108s, 1095m, 1073s, 1054s, 1030m, 1010m, 970m, 942w, 930w, 897m,
874w, 855w, 838w, 812w, 798w, 786m, 771m, 734w, 705w, 692w, 677w, 643w, 612w, 584w, 568w, 481w, 456w.
3
5
3
4
4
1H-NMR: 7.56 (dd, J ¼ 6.0, J ¼ 0.8, 0.7, HꢀC(3)); 6.30 (dd, J ¼ 6.0, J ¼ 1.4, HꢀC(2)); 6.17 (d, J ¼ 1.4,
HꢀC(7)); 3.72 (s, MeOOCꢀC(4)); 3.71 (s, MeOꢀC(8)); 3.70 (s, MeOOCꢀC(5)); 2.20 (s, MeCOOꢀC(9));
2.02 (s, MeꢀC(1)); 1.97 (d, 4J ¼ 1.4, MeꢀC(6)); 1.70 (s, MeꢀC(10)). 13C-NMR: 168.60 (s, MeCOOꢀC(9));
167.41 (s, COꢀC(5)); 167.26 (s, COꢀC(4)); 149.65 (s, C(8)); 143.05 (s, C(5a)); 142.00 (s, C(1)); 139.19 (d,
C(3)); 136.55 (s, C(9)); 133.31 (s, C(6)); 130.95 (d, C(4)); 126.66 (s, C(10)); 126.17 (s, C(2)); 125.27 (d,
C(10a)); 122.74 (d, C(5)); 120.41 (d, C(7)); 58.46 (q, MeOꢀC(8)); 52.11 (q, MeOOCꢀC(4)); 52.03 (q,
MeOOCꢀC(5)); 23.18 (q, MeꢀC(1)); 21.94 (q, MeꢀC(6)); 20.37 (q, MeCOOꢀC(9)); 13.27 (q,
.
MeꢀC(10)). EI-MS: 400 (22, Mþ ), 358 (59), 343 (13), 326 (8), 311 (14), 299 (12), 297 (13), 283 (14),
267 (15), 260 (33), 238 (15), 216 (46), 211 (9), 195 (15), 181 (10), 165 (24), 152 (28), 141 (10), 128 (7),
115 (9), 77 (6), 59 (7), 43 (100). Anal. calc. for C22H24O7 (400.43): C 65.99, H 6.04; found: C 65.90, H 5.79.
Data of 15’: M.p. 162 – 1638. Rf (SiO2, hexane/AcOEt 2 :1) 0.37. UV/VIS (MeCN; see also Table 3):
max. 194 (sh, 4.40), 208 (sh, 4.35), 236 (sh, 4.23), 275 (4.27), 328 (sh, 3.43), 387 (2.78); min. 252 (4.04),
366 (2.75). IR: 3007w, 2956m, 2919m, 2852w, 2837w, 1759vs, 1730vs, 1712vs, 1631m, 1605m, 1588m,
1565m, 1513w, 1506w, 1494w, 1455m, 1440m, 1400m, 1369m, 1334w, 1281vs, 1262vs, 1235s, 1212vs, 1141s,
1111s, 1095s, 1080s, 1033m, 1014m, 971m, 947w, 932w, 899m, 849w, 828m, 805w, 793w, 783w, 752w, 743m,
717w, 683w, 665w, 635w, 597w, 577m, 533w, 501w, 476w, 462w, 420w. 1H-NMR: 6.62 (d, 3J ¼ 11.8, HꢀC(3));
3
6.59 (d, J ¼ 11.8, HꢀC(4)); 5.51 (s, HꢀC(9)); 3.83 (s, MeOOCꢀC(2)); 3.72 (s, MeOOCꢀC(1)); 3.61 (s,
MeOꢀC(8)); 2.24 (s, MeCOOꢀC(7)); 1.85 (s, MeꢀC(6)); 1.84 (s, MeꢀC(5)); 1.74 (s, MeꢀC(10)).
13C-NMR: 168.46 (s, MeCOOꢀC(7)); 167.73 (s, COꢀC(2)); 166.82 (s, COꢀC(1)); 154.12 (s, C(8)); 139.46
(s, C(7)); 138.74 (d, C(4)); 135.65 (s, C(2)); 135.57 (s, C(5a)); 131.81 (s, C(5)); 131.27 (s, C(10)); 130.21 (s,
C(1)); 126.41 (d, C(3)); 125.24 (s, C(6)); 122.80 (s, C(10a)); 106.89 (d, C(9)); 54.94 (q, MeOꢀC(8)); 52.55
(q, MeOOCꢀC(2)); 52.34 (q, MeOOCꢀC(1)); 20.52 (q, MeCOOꢀC(7)); 18.11 (q, MeꢀC(10)); 18.01 (q,
MeꢀC(5)); 16.75 (q, MeꢀC(6)). CI-MS: 419 (10), 418 (39, [M þ NH4]þ), 403 (13), 401 (10), 386 (23), 370
(23), 369 (100, [(M þ H) ꢀ MeOH]þ]). Anal. calc. for C22H24O7 (400.43): C 65.99, H 6.04; found: C 65.84,
H 5.77.
The structure of 15’ was finally established by an X-ray crystal-structure analysis (Table 4).
3.3.2. O-Methylation of Non-Crystallized 14. To a soln. of 13 (1.49 g, 4.50 mmol) in benzene (130 ml),
Pb(AcO)49) (2.82 g, 6.00 mmol) was added and the mixture heated under reflux overnight. The usual
workup and a short FC gave crude 14 (0.86 g, 49%). This material was added to a stirred suspension of
finely powdered dry K2CO3 (0.48 g, 3.50 mmol) in acetone (20 ml), DMS (0.45, 360 mmol) was then
added with a syringe. The mixture was heated at 508 and stirred at 508 during a weekend. The usual
workup procedure gave O-methylated raw material (0.36 g, 41%), which showed by HPLC the presence
of 15 and 15’ and two further heptalenedicarboxylates, namely dimethyl 7-(acetyloxy)-8-methoxy-1,6,10-
trimethylheptalene-4,5-dicarboxylate (17) and dimethyl 9-(acetyloxy)-8-methoxy-5,6,10-trimethylhepta-
lene-1,2-dicarboxylate (17’). All four heptalenedicarboxylates were finally separated by HPLC
(Spherisorb CN (3 m), 4 ꢁ 125 mm column, hexane/(CH2Cl2 þ 0.5% MeOH 9 :1), flow rate 0.8 ml/
min): cf. Scheme 7.
9
)
Content of AcOH was 5%.

1212
Helvetica Chimica Acta – Vol. 94 (2011)
1
3
5
4
Data of 15: See 3.3.1. H-NMR (C6D6): 7.66 (dd, J ¼ 5.9, J ¼ 0.8, HꢀC(3)); 5.96 (d-like, J ¼ 1.4,
HꢀC(7)); 5.86 (dd, 3J ¼ 5.9, 4J ¼ 1.4, HꢀC(2)); 3.43 (s, MeOOCꢀC(4)); 3.39 (s, MeOOCꢀC(5)); 3.27 (s,
MeOꢀC(8)); 1.88 (d-like, J ¼ 1.3, MeꢀC(1)); 1.85 (s, MeCOOꢀC(9)); 1.72 (br. s, MeꢀC(6)); 1.69 (s,
MeꢀC(10)).
Data of 15’: See 3.3.1. 1H-NMR (C6D6): 6.79 (d, 3J ¼ 11.8, HꢀC(3)); 6.29 (d, 3J ¼ 11.8, HꢀC(4)); 5.31
(s, HꢀC(9)); 3.47 (s, MeOOCꢀC(2)); 3.41 (s, MeOOCꢀC(1)); 3.03 (s, MeOꢀC(8)); 1.90 (s, MeꢀC(5));
1.83 (s, MeCOOꢀC(7)); 1.78 (s, MeꢀC(6)); 1.68 (s, MeꢀC(10)).
1
3
5
Data of 17: UV/VIS: Table 3. H-NMR (C6D6): 7.66 (dd, J ¼ 5.8, J ¼ 0.9, HꢀC(3)); 6.09 (d-like,
J(HꢀC(9), MeꢀC(6)) ꢃ 0.6, HꢀC(9)); 5.83 (dd, 3J ¼ 5.8, 4J ¼ 1.4, HꢀC(2)); 3.44 (s, MeOOCꢀC(4)); 3.35
(s, MeOOCꢀC(5)); 3.16 (s, MeOꢀC(8)); 1.86 (d-like, 4J ¼ 1.4, MeꢀC(1)); 1.83 (s, MeCOOꢀC(7)); 1.67 (s,
MeꢀC(10)); 1.64 (d-like, MeꢀC(6)).
Data of 17’: UV/VIS: Table 3. 1H-NMR (C6D6): 6.73 (d, 3J ¼ 11.8, HꢀC(3)); 6.32 (d, 3J ¼ 11.8,
HꢀC(4)); 6.00 (br. s, HꢀC(7)); 3.44 (s, MeOOCꢀC(2)); 3.38 (s, MeOOCꢀC(1)); 3.36 (s, MeOꢀC(8));
2.01 (s, MeꢀC(5)); 1.75 (s, MeCOOꢀC(9)); 1.73 (s, MeꢀC(6)); 1.70 (s, MeꢀC(10)).
3.4. Base-Catalyzed Benzylation of 15. MeONa (0.009 g, 0.167 mmol) was added to dry DMF (2 ml),
followed by 15 (0.050 g, 0.125 mmol) (!dark violet). The soln. was stirred for 5 h at r.t., and then it was
cooled to ꢀ 218. BnBr (21 ml, 0.175 mmol) was added and stirring continued for 18 h, whereby the soln.
slowly warmed up to r.t. The now brownish yellow soln. was poured on to ice. After the usual workup, the
residue was subjected to FC (SiO2, hexane/AcOEt 3 :1): dimethyl 7-(benzyloxy)-8-methoxy-5,6,10-
trimethylheptalene-1,2-dicarboxylate (20’) as yellow oil (0.018 mg, 32%), dimethyl 9-(benzyloxy)-8-
methoxy-1,6,10-trimethylheptalene-4,5-dicarboxylate (20) as yellow oil (0.009 g, 16%), 15’ (0.008 g, 16%),
and the starting material 15 (0.013 g, 26%), in this order. It was not tried to crystallize the two new
heptalenedicarboxylates 20 and 20’ due to the small amounts of available material.
Data of 20: Rf (SiO2, hexane/AcOEt 3 :1) 0.32. IR (CHCl3): 3527w, 3026m, 3015m, 3012m, 2952m,
2841w, 1720vs, 1648w, 1603m, 1565m, 1497w, 1455m, 1436m, 1398w, 1376m, 1263vs, 1223w, 1217w, 1199m,
1163m, 1140m, 1093m, 1077m, 1055m, 1026m, 1009w, 986m, 947w, 910m, 859w, 845w, 823w, 806w.
1H-NMR (500 MHz): 7.59 (dd, 3J ¼ 5.9, 5J ¼ 0.9, HꢀC(3)); 7.30 – 7.25 (m, Ph); 6.31 (dd, 3J ¼ 5.9, 4J ¼ 1.4,
HꢀC(2)); 6.03 (d, 4J ¼ 1.4, HꢀC(7)); 4.75, 4.45 (AB, 2JAB ¼ 11.4, PhCH2OꢀC(9)); 3.75 (s, MeOOCꢀC(4));
4
3.72 (s, MeOOCꢀC(5)); 3.34 (s, MeOꢀC(8)); 2.04 (s, MeꢀC(1)); 1.93 (d, J ¼ 1.4, MeꢀC(6)); 1.79 (s,
MeꢀC(10)). 13C-NMR (125 MHz): 167.53 (s, COꢀC(5)); 167.42 (s, COꢀC(4)); 149.91 (s, C(8)); 144.53 (s,
C(9)); 143.90 (s, C(5a)); 141.99 (s, C(10a)); 139.25 (d, C(3)); 137.18 (s, 1 C of Ph), 132.82 (s, C(6)); 130.81
(s, C(4)); 129.02 (d, 2 C of Ph); 128.13 (d, 2 C of Ph; s, C(10)); 127.82 (d, 1 C of Ph); 126.94 (s, C(1));
125.73 (s, C(2)); 122.34 (s, C(5); d, C(7)); 74.71 (t, PhCH2OꢀC(9)); 58.62 (q, MeOꢀC(8)); 52.14 (q,
MeOOCꢀC(4)); 52.00 (q, MeOOCꢀC(5)); 23.06 (q, MeꢀC(1)); 21.80 (q, MeꢀC(6)); 13.73 (q,
MeꢀC(10)). CI-MS: 466 (100, [M þ NH4]þ), 449 (40, [M þ H]þ), 417 (60, [(M þ H) ꢀ MeOH]þ), 403
(6), 385 (13), 369 (37), 357 (15), 346 (47), 343 (12), 329 (18), 311 (7), 297 (20).
Data of 20’: Rf (SiO2, hexane/AcOEt 3 :1) 0.45. IR (CHCl3): 3025m, 3019m, 1723s, 1603m, 1567m,
1497m, 1456m, 1435m, 1324m, 1264m, 1231m, 1200m, 1177m, 1159m, 1123m, 1097m, 980m, 946m, 909s,
843m, 822m. 1H-NMR (500 MHz): 7.37 – 7.27 (m, Ph); 6.60 (d, 3J ¼ 11.8, HꢀC(3)); 6.57 (d, 3J ¼ 11.8,
HꢀC(4)); 5.56 (s, HꢀC(9)); 4.83, 4.64 (AB, 2JAB ¼ 11.4, PhCH2OꢀC(7)); 3.82 (s, MeOOCꢀC(2)); 3.70 (s,
MeOOCꢀC(1)); 3.69 (s, MeOꢀC(8)); 1.82 (s, MeꢀC(6)); 1.77 (s, MeꢀC(5)); 1.74 (s, MeꢀC(10)).
13C-NMR (150 MHz): 168.04 (s, COꢀC(2)); 167.09 (s, COꢀC(1)); 156.03 (s, C(8)); 146.41 (s, C(7)); 139.01
(d, C(4)); 137.75 (s, 1 C of Ph); 137.54 (s, C(5a)); 135.04 (s, C(2)); 131.19 (s, C(5)); 130.80 (s, C(10a));
130.20 (s, C(1)); 128.77 (d, 2 C of Ph); 128.49 (d, 2 C of Ph); 128.10 (d, 1 C of Ph); 126.01 (d, C(3)); 124.65
(s, C(10)); 123.77 (s, C(6)); 108.24 (d, C(9)); 73.58 (t, PhCH2OꢀC(7)); 55.07 (q, MeOꢀC(8)); 52.80 (q,
MeOOCꢀC(2)); 52.54 (q, MeOOCꢀC(1)); 18.28 (q, MeꢀC(10)); 18.18 (q, MeꢀC(5)); 16.50 (q,
MeꢀC(6)). CI-MS: 466 (38, [M þ NH4]þ), 449 (87, [M þ H]þ), 434 (7), 417 (100, [(M þ H) ꢀ MeOH]þ),
392 (8), 385 (24), 357 (16), 313 (6), 299 (13), 282 (12), 256 (8), 218 (12), 206 (12).
4. 9-Methoxy-6,7,11-trimethylheptaleno[1,2-c]furan-8-ol and -9-ol (23 and 24, resp.). To the original
mixture of the heptalenedicarboxylates 15/15’ and 17/17’ (0.460 g, 1.10 mmol; see 3.3.2) in THF (25 ml)
cooled with an ice bath, 1m DIBAH in hexane (7.5 ml, 7.50 mmol) was added dropwise under stirring.
Stirring was continued for 30 min at 08 and then for 30 min at r.t. Then H2O (200 ml) was added slowly
and dropwise. The mixture was then extracted with AcOEt (2ꢁ), the org. layer washed with H2O, dried

Helvetica Chimica Acta – Vol. 94 (2011)
1213
(MgSO4), and concentrated, and the residue subjected to FC (SiO2, Et2O/hexane 5 :1): mixture of the
four hydroxy-heptalenedimethanols 21/21’ and 22/22’ (0.234 g, 67%), which was not further characterized
(see Scheme 10 and text).
IBX (0.113 g, 0.40 mmol)10) was added to DMSO (2 ml) and the mixture stirred for 2 h at r.t. To the
thus formed clear and colorless soln. was added the above dimethanol mixture (0.039 g, 0.10 mmol),
dissolved in acetone (0.4 ml). Stirring was continued for 5 h at r.t. Then, Et2O (2 ml) and 1m TsOH in
acetone (0.1 ml) were added. The mixture was poured into H2O and extracted with Et2O (2ꢁ). The Et2O
extract was washed with H2O, dried, and concentrated and the residual glutinous yellow material
subjected to CC (SiO2, tBuOMe/hexane 3 :2): 23 (0.013 g, 35%) and 23/24. Both fractions were not very
stable.
Data of 23: 1H-NMR (C6D6): 7.14 (d, 4J ¼ 1.6, HꢀC(1)); 6.99 (dd, 4J ¼ 1.6, 5J ¼ 0.7, HꢀC(3)); 6.30 (d,
3J ¼ 11.5, HꢀC(4)); 5.72 (d, 3J ¼ 11.5, HꢀC(5)); 5.45 (s, HꢀC(10)); 3.13 (s, MeOꢀC(9)); 2.01 (s,
MeꢀC(6)); 1.62 (s, MeꢀC(7)); 1.46 (s, MeꢀC(11)).
5. 8,9-Dimethoxy-6,7,11-trimethylheptaleno[1,2-c]furan (27). 5.1. Dimethyl 7,8-Dimethoxy-5,6,10-
trimethylheptalene-1,2-dicarboxylate (25’). In analogy to 3.4, a mixture of the four (acetyloxy)heptale-
nedicarboxylates 15/15’ and 17/17’ (0.102 g, 0.255 mmol) was added to a soln. of MeONa (0.032 g,
0.59 mmol) in DMF (6 ml). After 6 h stirring of the violet soln. at r.t., it was cooled to ꢀ 258 and MeI
(31 ml, 0.50 mmol) was added. Stirring was continued for 24 h, whereby the temp. slowly rose to r.t. The
1
usual workup and CC (SiO2, hexane/AcOEt 3 :1) gave 25’ (0.022 g, 23%) as a pure fraction. H-NMR
(C6D6): 6.80 (d, 3J ¼ 11.8, HꢀC(3)); 6.30 (d, 3J ¼ 11.8, HꢀC(4)); 5.40 (s, HꢀC(9)); 3.47 (s, MeOOCꢀC(2));
3.45 (s, MeOꢀC(7)); 3.41 (s, MeOOCꢀC(1)); 3.17 (s, MeOꢀC(8)); 2.08 (s, MeꢀC(10)); 1.81 (s,
MeꢀC(6)); 1.55 (s, MeꢀC(5)).
5.2. 7,8-Dimethoxy-5,6,10-trimethylheptalene-1,2-dimethanol (26’). To 25’ (0.0095 g, 0.03 mmol) in
THF (2 ml) cooled with an ice bath, 1m DIBAH, in hexane (0.2 ml, 0.20 mmol) was added with a syringe,
(! reddish soln.). After 25 min, the ice bath was removed and stirring continued for 20 min. H2O (2 ml)
was added to the mixture, which was extracted thereafter with AcOEt. The extracts were washed with
H2O, dried (MgSO4), and concentrated. Purification of the residue was performed with prep. TLC (SiO2,
hexane/AcOEt 2 :1): 26’ (0.0073 g, 90%). Yellow solid. 1H-NMR (C6D6): 6.31, 6.30 (superimp. AB,
2
2
HꢀC(3), HꢀC(4)); 5.48 (s, HꢀC(9)); 4.44, 4.05 (AB, JAB ¼ 12.5, HOCH2ꢀC(1)); 4.18, 4.00 (AB, JAB
¼
11.9, HOCH2ꢀC(2)); 3.54 (s, MeOꢀC(7)); 3.24 (s, MeOꢀC(8)); 2.10 (s, MeꢀC(6)); 1.66 (s, MeꢀC(10));
1.65 (s, MeꢀC(5)).
5.3. Formation of 27. IBX (0.0095 g, 0.03 mmol) was added to DMSO (0.3 ml). The soln. was stirred
for 2 h at r.t. To the colorless soln. was added 26’ (0.0043 g, 0.01 mmol). The mixture was stirred for 4.5 h
at r.t., and was then poured into H2O (1 ml). The product was extracted with Et2O (2ꢁ), the Et2O phase
washed with H2O, dried (Na2SO4), and concentrated, and the residual glutinous yellow mass, purified by
prep. TLC (SiO2, hexane/AcOEt 1:1): 27 (ca. 2 mg, 68%). Yellow solid. 1H-NMR (C6D6): 7.11 (d-like,
HꢀC(1)); 6.94 (dd-like, HꢀC(3)); 6.42 (d, 3J ¼ 11.4, HꢀC(4)); 5.86 (d, 3J ¼ 11.5, HꢀC(5)); 5.54 (s,
HꢀC(10)); 3.53 (s, MeOꢀC(8)); 3.25 (s, MeOꢀC(9)); 2.00 (s, MeꢀC(6)); 1.81 (s, MeꢀC(7)); 1.66 (s,
MeꢀC(11)).
6. X-Ray Crystal-Structure Determinations of Compounds 6, 10, 13, 14, and 15’11). All measurements
were conducted with a Nonius KappaCCD area detector diffractometer [24][25], graphite-monochro-
mated MoKa radiation (l 0.71073 ꢆ), and an Oxford-Cryosystems-Cryostream-700 cooler. The data
collection and refinement parameters are given in Table 4, while views of the molecules of 13 and 14 are
shown in Figs. 1 and 2. The intensities were corrected for Lorentz and polarization effects. A numerical
10
)
Following an established procedure [23], a soln. of Oxoneꢅ (18.17 g, 29.10 mmol; Aldrich) in H2O
(65 ml) was added to 2-iodobenzoic acid (5.40 g, 28.10 mmol). The mixture was heated under
stirring at 708 for 3 h. After cooling by an ice bath, stirring was continued for additional 1.5 h. The
formed suspension was filtered through a glass frit and the filter cake washed with acetone to yield
IBX as colorless powder (3.92 g, 65%).
CCDC-820692 – 820696 contain the supplementary crystallographic data for this article. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
11
)

1214
Helvetica Chimica Acta – Vol. 94 (2011)
absorption correction [26] was applied in the case of 13. Each structure was solved by direct methods with
SIR92 [27], which revealed the positions of all non-H-atoms. The non-H-atoms were refined
anisotropically. All of the H-atoms were placed in geometrically calculated positions, and each H-
atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2 Ueq of its parent
atom (1.5 Ueq for the Me groups of 13). The refinement of each structure was carried out on F (F2 for 13)
by full-matrix least-squares procedures. A correction for secondary extinction was applied, except for 6.
For 6, 10, 13, and 14, five, two, four, and four reflections, resp., whose intensities were considered to be
extreme outliers, were omitted from the final refinement.
For 13, one significant peak of residual electron density remained (1.42 e ꢆꢀ3). The peak is ca. 1.52 ꢆ
from C(7) and is in approximately the correct position (distance and angles) that might be expected if it
represented a C-atom bonded to C(7). Attempts were made to include this peak in the model by defining
it as the C-atom of a Me group and the refinement could be carried out successfully. The site occupation
factor of the Me group refined to ca. 0.20 and the C(7)ꢀC bond length remained at 1.52 ꢆ. With the
model defined in this way, the R-factor decreased by ca. 0.01. A similar result was obtained if it is assumed
that the group is an OH or an NH2 group. As the group, if real, exists in only ca. 20% of the molecules, it
was not possible to locate any of the H-atoms of the group, and the bond length to C(7) is quite imprecise.
Therefore, no definitive conclusion can be drawn about what type of substituent this might be, but on the
crystallographic evidence alone, the assumption that this residual electron density peak is due to a small
amount of a C(7)-substituted compound in the crystal is not entirely unreasonable. Data were collected
from two different crystals, and the same feature was observed in both cases. An examination of the
diffraction patterns did not reveal any evidence of twinning. In the absence of supporting chemical
evidence for a minor by-product, the final refinement was conducted without including this additional
unknown group in the model. This leads to a significant peak of residual electron density, slightly higher
R-factors, and a lower precision of the geometric parameters than for the model where the group was
included.
Neutral-atom scattering factors for non-H-atoms were taken from [28a], and the scattering factors
for H-atoms were taken from [29]. Anomalous dispersion effects were included in Fc [30]; the values for
f’ and f’’ were those of [28b]. The values of the mass attenuation coefficients are those of [28c]. All
calculations were performed with the teXsan crystallographic software package [31] (SHELXL97 [32]
for 13). The crystallographic diagrams were drawn with ORTEPII [33].
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Received April 14, 2011