Synthesis of tri-, tetra-, and pentacarbonyl derivatives via ozonolysis of 1,4-dienes and cyclization to polyaromatic systems

Article abstract of DOI:10.1021/jo502308d

The aim of this work was the synthesis of polyaromatic systems by cyclization of β-polycarbonyls. Useful synthons for β-polycarbonyl derivatives are branched 1,4-dienes generated by cobalt-catalyzed hydrovinylation of terminal alkenes and 2,3-dimethyl-1,3

Full text of DOI:10.1021/jo502308d

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Article
Synthesis of Tri-, Tetra- and Pentacarbonyl Derivatives via
Ozonolysis of 1,4-Dienes and Cyclization to Polyaromatic Systems
Laura Kersten, Klaus Harms, and Gerhard Hilt
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502308d • Publication Date (Web): 05 Nov 2014
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Synthesis of Tri-, Tetra- and Pentacarbonyl Derivatives via Ozonolysis
of 1,4-Dienes and Cyclization to Polyaromatic Systems
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Laura Kersten, Klaus Harms and Gerhard Hilt*
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Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Str. 4
35043 Marburg, Germany
hilt@chemie.uniꢀmarburg.de
Abstract
The aim of this work was the synthesis of polyaromatic systems by cyclization of βꢀ
polycarbonyls. Useful synthons for βꢀpolycarbonyl derivatives are branched 1,4ꢀdienes
generated by cobaltꢀcatalyzed hydrovinylation of terminal alkenes and 2,3ꢀdimethylꢀ1,3ꢀ
butadiene. Thus a series of triꢀ, tetraꢀ and pentacarbonyl synthons was successfully
synthesized. Subsequently, these synthons were examined in an ozonolysis/cyclization
reaction sequence. Polyaromatic derivatives were obtained in good yields and the method
was applied in the synthesis of the natural product Kwanzoquinone A.
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Introduction
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Nature uses βꢀpolycarbonyls to generate polyketides such as phenols, naphthols and
anthrols. Polyketides are one of the largest classes of natural compounds with great
structural diversity. The division of this class is based on their common biosynthesis
pathway. The formation of polyketides contains a repeating Claisenꢀtype condensation of
acetylꢀCoA to form, for example, β−polycarbonyl compounds, followed by its
intramolecular condensation (SCHEME 1).1,2 A wide range of complex functionalized
compounds is generated because after each step of chain elongation the βꢀoxofunction
can also be modified by further enzymes, such as a ketoreductase. Therefore, βꢀ
polycarbonyls are not formed in the polyketide biosynthesis pathway exclusively.
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CHEME 1.
The biomimetic synthesis of polycarbonyl compounds is of great interest for organic
chemists with respect to the construction of complex molecules with bioactive properties.
A pioneer in the field of the synthesis and investigation of polycarbonyls was Thomas
Harris, who used condensation of polyanions of polyketones with acylating agents.3
Later, Yamaguchi explored a very similar strategy based on the condensation of the
methyl acetoacetate dianion with glutarates (1) and successive intramolecular
condensation to form polycyclic moieties 3.4,5 Recently, Barrett reported an approach
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using diketoꢀdioxinones as masked βꢀtetracarbonyl synthons. The transient ketene 5
derived from dioxinone 4 is further trapped by an alcohol which results in the formation
of a βꢀtriketoester. Lateꢀstage biomimetic aromatization gives resorcylate derivatives 6
(SCHEME 2).6,7 This powerful methodology based on the cyclization of triketoester
derivatives, and a similar method based on the cyclization of dioxinone derivatives to
produce resorcylates, were applied in a multitude of natural product syntheses.8,9
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CHEME 2.
An alternative approach to βꢀpolycarbonyl compound formation was reported by Birch in
the early 20th century.10 He employed aromatic rings as synthetic equivalents for βꢀ
polycarbonyl compounds. Initiated by reduction with sodium in liquid ammonia,
aromatic derivatives were converted to cyclic 1,4ꢀdienes (Birch reduction), which were
then applied in an ozonolysis reaction to generate 1,3ꢀdicarbonyls. Evans applied this
reaction sequence for the synthesis of nonꢀaromatic polyketide arrays.11 Inspired by
Birch, we proved in previous work that branched 1,4ꢀdienes are useful moieties for the
synthesis of 1,3ꢀdicarbonyl derivatives by ozonolysis.12 These branched 1,4ꢀdienes were
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generated under mild conditions via 1,4ꢀhydrovinylation of terminal alkenes with a
cobaltꢀcatalyst system.13 Accordingly, the harsh conditions of the Birch reduction were
circumvented. For the isolation and characterization of the βꢀpolyketones, the 1,3ꢀ
dicarbonyl function was complexed with a BF2ꢀfragment, eliminating the ketoꢀenol
tautomerization. In addition to the transformations described thus far,14,15 we were
interested in the follow up chemistry of these polycarbonyl derivatives. Hence, the scope
of this investigation is the ozonolysis of 1,4ꢀpolyenes to polycarbonyls and subsequent
biomimetic cyclization to aromatic and polycyclic systems. Our strategy is based on the
application of aromaticꢀsubstituted polyenes, such as 7, as polycarbonyl precursors. There
are several possible condensation reaction pathways. Due to steric repulsion, alternative
“bent” cyclization modes of the corresponding aromaticꢀsubstituted polycarbonyl
compound 8 should be inhibited by the aromatic backbone, favoring the shown linear
cyclization mode instead.4 Finally, the reaction sequence should be applied in the natural
product synthesis of Kwanzoquinone A. A different method based on an intramolecular
cobaltꢀcatalyzed [2+2+2] cycloaddition for the synthesis of anthraquinone derivatives,
including natural products, was reported by Groth.16
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Results and Discussion
We began our studies by exploring the synthesis of aromatic βꢀpolycarbonyl synthons via
cobaltꢀcatalyzed DielsꢀAlder and 1,4ꢀhydrovinylation reactions. For this purpose, two
different hydroxylꢀfunctionalized enynes 10 and 11 were converted to unsaturated
benzaldehydes in a DielsꢀAlder reaction (for 12, 13) or combined DielsꢀAlder/1,4ꢀ
hydrovinylation reaction (for 14), and subsequent DDQ (2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀ
benzoquinone) oxidation (SCHEME 3).14
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CHEME 3.
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Aldehydes 12 and 14 were synthesized using cobalt 1,2ꢀbis(diphenylphosphino)ethane
dibromide as catalyst precursor and were obtained in good yields after DDQ oxidation
(73–77%). Aldehyde 13 was isolated in moderate yield (40%) by applying cobalt 2,2’ꢀ
bipyridine dibromide as preꢀcatalyst in the DielsꢀAlder reaction. Since it was necessary to
suppress the 1,4ꢀhydrovinylation to obtain aldehyde 13 instead of 14 this catalyst
precursor, which catalyzes the DielsꢀAlder reaction selectively, was applied.17
Aldehyde 14, bearing a branched 1,4ꢀdiene unit, already constitutes a tricarbonyl synthon
and was additionally used for the generation of tetraꢀ and pentacarbonyl synthons 18, 21
and 7. The synthons were generated in a two step procedure in good yields starting with
the synthesis of the corresponding alcohol and further oxidation (SCHEME 4). For the
syntheses of the tetracarbonyl synthons 18 and 21, a Grignard reaction or an indiumꢀ
mediated Barbierꢀtype reaction, respectively, were performed as the first step. The
pentacarbonyl precursor was obtained by an allylboration of aldehyde 14, with a boronꢀ
functionalized 1,4ꢀdiene 15 that is easily accessible by cobaltꢀcatalyzed 1,4ꢀ
hydrovinylation.15 Finally, the alcohols were oxidized to the corresponding ketones 18,
21 and 7 utilizing pyridinium chlorochromate (PCC). The same methodology was applied
to convert the other two benzaldehydes 12 and 13 to triꢀ and tetracarbonyl synthons 16,
17, 19, 20, and 22.
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CHEME 4.
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The described approach for the synthesis of an aldehyde bearing a branched 1,4ꢀdiene
group was successful, but the diversification via combined DielsꢀAlder/1,4ꢀ
hydrovinylation/oxidation reaction is limited to accessible and applicable 1,3ꢀdienes. A
second approach was accomplished for the synthesis of this kind of aldehydes by cobaltꢀ
catalyzed 1,4ꢀhydrovinylation of allylphenyldioxolane 24 with 2,3ꢀdimethylꢀ1,3ꢀ
butadiene (DMB) and successive acidic workꢀup (SCHEME 5). Thereby, the
corresponding aldehyde 25 is obtained in excellent yield. Prolonged reaction times
resulted in the formation of naphthalene 23 as a side product. Naphthalene derivate 23
was obtained as the main product when additional amounts of ZnI2 were added and the
mixture was stirred for two days. The advantage of this pathway to aldehydes with a 1,4ꢀ
diene subunit is the easier functionalization of the dioxolanes, which leads to better
access to more complex products.
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Subsequently, we focused on the transformation of the successfully prepared
polycarbonyl synthons to polyaromatic systems by ozonolysis and subsequent
cyclization. The cyclization behavior of several tricarbonyls with different terminal
carbonyl groups (aldehyde, ketone) generated by ozonolysis was examined. We started
with the less complex tricarbonyl synthon 14 with a nonꢀenolizable aldehyde function
(SCHEME 6). Thereafter, increasingly more complex molecules should be examined.
Trimethyl phosphite was applied as reducing agent after ozonolysis, since trimethyl
phosphate is easy to remove by aqueous extraction and good results had been obtained by
our group in an earlier work regarding the synthesis of pentacarbonyl derivatives.14
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CHEME 6.
Ozonolysis of diene 14, reduction with trimethyl phosphite and aqueous workꢀup resulted
in almost quantitative formation of tricarbonyl 26 (keto:enol form = 31:69), as well as
naphthol 27, as observed by NMR spectroscopy of the crude product. Purification of the
tricarbonyl derivative by flash column chromatography over silica gel resulted in the
isolation of the desired cyclic product 27 in 38% yield, whereas no tricarbonyl 26 was
obtained (entry 1, TABLE 1). This was not surprising, since in several reactions described
in the literature silica gel was sufficient to perform cyclization reactions.6,9 The results of
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further optimization experiments of the reaction sequence illustrated in SCHEME 6 are
summarized in TABLE 1.
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T
ABLE 1. Optimization of the ozonolysis of diene 14 and subsequent cyclization
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entry
reducing agenta
cyclization
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P(OMe)3
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SiO2 1–7 d
SiO2, ))), 1 d
NaOHaq (5 w%), 1 h
NaOHaq (5 w%), 1 h
HOAc, 1 h
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PPh3
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Conditions of the ozonolysis: 1.) Diene (1.0 eq), O3, CH2Cl2, –78 °C. 2.) Addition of the
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reducing agent (3.0 eq) –78 °C → rt, 1 h.
The product was purified by flash column
chromatography. c The polycarbonyl derivative was purified by aqueous extraction. d The solvent
was removed under reduced pressure and the crude polycarbonyl derivative was further treated as
described for the cyclization.
The addition of silica gel to the crude tricarbonyl 26 after aqueous work up only slightly
improved the yield. Neither prolonged reaction times nor performing the reaction in an
ultrasonic bath increased the yield above 47% (entry 2, 3). Furthermore, performing the
cyclization under basic conditions with aqueous NaOH (5 w%) increased the yield to
58% (entry 4). Changing of the reducing agent to triphenylphosphine resulted in the best
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yield of 75% (entry 5). Acidic conditions, as well as using Zn/HOAc as reducing agent,
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did not further improve the yield of the desired product 27 (entry 6, 7).
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After the successful optimized synthesis of naphthol 27 in good yield, the investigations
were expanded to tricarbonyls with an enolizable aldehyde function. Initially, mild
conditions were applied. Trimethyl phosphite was used as reducing agent and silica gel
was added for the cyclization. Surprisingly, trimethyl phosphite was not strong enough to
reduce the ozonide functions entirely. The main product was identified to be the
ozonide 28, which was isolated in 23% yield, whereas naphthol 29 was formed in only
5% yield (SCHEME 7).
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CHEME 7.
Thereafter, the ozonides were treated with triphenylphosphine (2.5 eq) followed by
addition of aqueous NaOH (5 w%) and the desired product 29 was obtained in good yield
(83%) in two steps. Under the same reaction conditions, synthon 16 was converted to the
naphthol derivative 31 with an easily functionizable aldehyde group in 64% yield
(SCHEME 8). Upon applying SiO2 for the cyclization, instead of NaOH, product 29 was
obtained in 59% yield after stirring for 1 d.
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CHEME 8.
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Subsequently, for triketone synthon 20 the ozonolysis/cyclization reaction sequence was
explored. Triphenylphosphine was added and, at first, silica gel was chosen to perform
the cyclization. After purification by flash column chromatography a series of partially
reduced secondary ozonides 32, 33, 34 was isolated, as well as the desired naphthol 35 in
15% yield (SCHEME 9). Ozonides of type 33 are formed by intramolecular reaction of the
intermediate carbonyloxid with the already existing benzylic carbonyl group. Similar
ozonides are generated after the ozonolysis of indene derivatives and have been described
in the literature as relatively stable compounds,18 explaining the isolation of ozonides 32,
33 and 34 by flash column chromatography.
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CHEME 9.
Further attempts were undertaken to increase the yield for naphthol 35 in this reaction
sequence (SCHEME 10) by reducing the unwanted ozonides entirely. The results are
summarized in TABLE 2.
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CHEME 10.
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To ensure complete reduction of all ozonides, zinc and glacial acetic acid were added as
additional reductants (entry 1). The yield increased to 56% and no ozonides were
detected by thin layer chromatography (TLC). Using Zn/HOAc alone did not improve the
yield of 35 (entry 2). When a large excess of triphenylphosphine (8.0 eq) was applied
after ozonolysis, no more ozonides were detected by TLC after stirring overnight. The
subsequent usage of NaOH (5 w%) for the cyclization brought no improvement (entry 3).
The best result was obtained when applying 5.0 equivalents of triphenylphosphine as
reducing agent and applying glacial acetic acid for the cyclization. The naphthol
derivative 35 was obtained in 67% yield (entry 4).
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T
ABLE 2. Optimization of the ozonolysis of diene 20 and subsequent cyclization
entry
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reducing agenta
cyclization
yield
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+Zn/HOAc, 1 h
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Zn/HOAc, 1 h
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37%
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PPh3 (5.0 eq), 18 hb
NaOHaq (5 w%), 2 h
HOAc, 16 h
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Conditions of the ozonolysis: 1.) Diene (1.0 eq), O3, CH2Cl2, –78 °C. 2.) Addition of the
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reducing agent –78 °C → rt, 1 h. The solvent was removed under reduced pressure and the
crude polycarbonyl derivative 36 was treated as described for the cyclization.
Finally, tricarbonyl synthon 17 was converted to naphthaldehyde 37. The best result was
achieved by addition of triphenylphosphine after ozonolysis and further stirring for four
hours (SCHEME 11). Apparently, no additional reagent was necessary, due to the
increased reactivity of the intermediate tricarbonyl compound containing an aldehyde
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function, compared to triketone 36. Using triphenylphosphine (2.5 eq, 2 h) as a reductant,
and subsequent addition of silica gel (1 d) or addition of Zn/HOAc (1 h), resulted in
diminished yields for product 37.
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CHEME 11.
Overall, the cyclization of tricarbonyl derivatives, as well as their formation by
ozonolysis, was accomplished in good yields. The formation of stable ozonides was
found to be one reason for the initial low yields of naphthols after ozonolysis of
tricarbonyl precursors and subsequent cyclization. The results were improved by applying
an excess of triphenylphosphine and longer reaction times.
The synthesis and cyclization of tetracarbonyl compounds was envisaged further. The
ozonolysis of triene 22 and subsequent acetic cyclization led to the formation of the semiꢀ
acetal 39, as well as the dehydrated benzopyrone 40 (SCHEME 12). Complete dehydration
to obtain benzopyrone 40 as the main product might be possible by applying other acids,
but was not further examined.
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CHEME 12.
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Using the same reaction conditions for tetraketone precursor 21, the desired product 41
was obtained in a good yield of 74%. Under the same conditions, the product 42 was
obtained in moderate 52% yield starting from the tetracarbonyl synthon 18. Nevertheless,
the naphthaldehyde 42 was obtained in good 79% yield by reducing the reaction time of
the reduction and further adding Zn/HOAc (SCHEME 13). These results can be explained
by the fact that higher substituted ozonides derived from synthon 21 are more stable, and
the increased reactivity of the tetracarbonyl derivative derived from 18 containing an
aldehyde function. Therefore, a short reaction time was sufficient to reduce the ozonides
of tetraene 18, perform the cyclization, and circumvent the formation of side products.
When applying these conditions to triene 21, the product 41 was obtained in only 26%
yield.
S
CHEME 13.
The knowledge gained concerning the treatment of ozonides, and the cyclization behavior
of triꢀ and tetracarbonyl derivatives, was applied to the transformation of the complex
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pentacarbonyl synthon 7. Since our goal was the application of the ozonolysis/cyclization
reaction sequence in the total synthesis of the anthraquinone Kwanzoquinone A (44), the
desired cyclization product was anthrone 43 (SCHEME 14). The pentacarbonyl synthon 7
was chosen as a test substrate, as it is more easily accessible by cobalt catalysis.
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S
CHEME 14.
Surprisingly, and in contrast to prior examined polyketones, we found that the
pentacarbonyl compound 8 undergoes different cyclization modes depending on the
reaction conditions (SCHEME 15). The pentacarbonyl precursor 7 was ozonolyzed, an
excess triphenylphosphine was used as reducing agent to ensure complete reduction of
the ozonides. Purification of the crude polycarbonyl derivative 8 by flash column
chromatography over silica gel gave a mixture of two trioxaadamantane isomers, 45
and 46. Addition of silica gel to the crude pentacarbonyl compound 8, and additional
stirring for 18 h,19 did not improve the yield of the trioxaadamantane.
The structure of the main isomer 45 was confirmed by Xꢀray analysis (see SI). The
structure of the minor isomer 46 could not be determined unambiguously by NMR
spectroscopy, the two potential structures are shown in SCHEME 15.
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CHEME 15.
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Moreover, pentacarbonyl 8 underwent cyclization using glacial acid to give the
benzochromenꢀ4ꢀone 48 as the main product. The product was obtained in 32% yield,
which could not be improved by the application of trifluoracetic acid, instead of HOAc.
The treatment of the pentacarbonyl derivative 8 with calcium acetate to obtain anthrone 9
according to a procedure by Yamaguchi,4 afforded the bisanthrone 47 as the main product
in 40% yield, as well as the desired anthraquinone 9 in only 14% yield. The formation of
the products proceeded via dimerization and oxidation of anthrone 43, which was not
isolated. The structure of the bisanthrone 47 was confirmed by Xꢀray analysis (see SI).
Finally, we focused on the formation of anthraquinone 9 as the main product (TABLE 3).
We tried to suppress the dimerization, and to favor the oxidation of anthrone 43 to
anthraquinone 9. Since the anthrone 43 was formed as an intermediate in over 50% yield
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in the reaction described above, by applying Ca(OAc)2 we were confident to obtain the
6
7
anthraquinone 9 in good yields.
8
9
The reactions were performed under conditions inspired by the literature procedures of
similar cyclization reactions (TABLE 3). The best result was obtained by cyclization with
potassium carbonate, after ozonolysis followed by acidification according to a procedure
by Krohn,20 which resulted in the formation of anthraquinone 9 as the main product in
29% yield (entry 4). Other conditions were tested to increase the yield of the desired
anthraquinone 9. Anthrone 43 was not isolated in any case. Oxidation of the anthrone
with K2CO3/O2, after cyclization with Ca(OAc)2 following a procedure of Yamaguchi,4
yielded the product in 21% (entry 1). Similar results were obtained by applying CsOAc in
methanol (entry 2), or Cs2CO3 in THF, according to a procedure described by Barrett
(entry 3).6 The use of K2CO3 under oxygen atmosphere (entry 6), as well as the addition
of molecular sieve (entry 5), brought no improvement and, as a side product, the
trioxaadamantane 45 was obtained in both cases.
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T
ABLE 3. Optimization of the reaction sequence to synthesize anthraquinone 9
entry
1
cyclizationa
solvent
time
yield (9)
Ca(OAc)2 (5 eq) then
K2CO3 (7 eq)/O2
MeOH
CH2Cl2
4h
16 h
21%
2
3
4
CsOAc (10 eq)
Cs2CO3 (3 eq)
K2CO3 (10 eq)
MeOH
THF
2 d
2 d
24%
22%
29%
iPrOH/CH2Cl2
16 h
K2CO3 (10 eq),
3Å MSb
22%
+15% 45
iPrOH/CH2Cl2
16 h
5
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12%
6
K2CO3 (10 eq)/O2
CH2Cl2
3 d
+15% 45
7
8
9
a
Conditions of the ozonolysis: 1.) Tetraene 7 (1.0 eq), O3, CH2Cl2, –78 °C. 2.) Addition of PPh3
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(10 eq) –78 °C → rt, 16–24 h. 3.) The solvent was removed under reduced pressure and the crude
polycarbonyl derivative 8 was treated as described for the cyclization. b Molecular sieve.
The established reaction sequence for the synthesis of anthraquinone 9 by ozonolysis of
tetraene 7, and successive cyclization, was then applied in the natural product synthesis of
Kwanzoquinone A (44) (SCHEME 16). The anthraquinone 44 was obtained in an overall
yield of 4% over eight steps.
S
CHEME 16.
The low yield observed for the first four steps is attributed to the cobaltꢀcatalyzed Dielsꢀ
Alder reaction with isoprene. The problem lies within the separation of the resulting
regioisomers of 49, as well as the diminished yield of the DielsꢀAlder reaction when
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using CoBr2(bipy) instead of CoBr2(dppe) as the catalyst precursor (compare SCHEME 3).
Initially, CoBr2(pyimin) was tested as preꢀcatalyst for the DielsꢀAlder reaction with
isoprene. After 1,4ꢀhydrovinylation with DMB, and subsequent oxidation with DDQ, the
desired aldehyde 49 was isolated isomerically pure in 17% yield. The structure of
aldehyde 49 was determined by 2 D NMR spectroscopy (HMBC). The next step was the
allylboration with a boronꢀfunctionalized 1,4ꢀdiene 15 that is accessible by cobalt–
catalyzed 1,4ꢀhydrovinylation. Alcohol 50 was obtained in 81% yield. In a second
approach, CoBr2(bipy) was tested in the DielsꢀAlder reaction, since it has shown similar
selectivity and slightly improved yields compared to CoBr2(pyimin) in earlier works.
This time, the regioisomeric mixture of aldehyde 49 was converted immediately to
alcohol 50, because we hoped that the regioisomeric mixture of alcohols would be more
easily separable by column chromatography on silica gel. This was not the case. Similar
results were obtained compared to the route over two steps. The alcohol was obtained
with a purity of 94% in 16% yield (starting from enyne 10).
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The following oxidation of the alcohol 50 was performed with PCC in good yield (85%).
Subsequently, the polyene 51 was converted to the corresponding pentacarbonyl
derivative by ozonolysis. The cyclization and oxidation with air to anthraquinone 44 was
accomplished by K2CO3 in isoꢀpropanol/dichloromethane in 33% over three steps
(ozonolysis, cyclization and oxidation).
Conclusion
In summary, we present a straightforward way to access aromaticꢀsubstituted 1,4ꢀdienes
and polyenes via mild cobaltꢀcatalyzed reactions. These derivatives are βꢀpolycarbonyl
synthons, and the synthesized triꢀ, tetraꢀ and pentacarbonyl precursors were examined in
an ozonolysis/cyclization reaction sequence. In the case of tricarbonyl precursors, the
formation of stable ozonides was found to be the main reason for the initial low yields of
naphthols. This problem was solved by applying an excess of triphenylphosphine as
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reductant, in conjunction with longer reaction times. The cyclization of triꢀ and
tetracarbonyl derivatives was accomplished using basic, as well as acidic conditions, and
the corresponding naphthol derivatives were obtained in good yields. Furthermore, even
triꢀ and tetracarbonyl synthons with terminal double bonds can be applied, and naphthols
with easily functionalizable aldehyde groups are accessible. Moreover, pentacarbonyl
synthon 7 was examined in the ozonolysis/cyclization reaction sequence, and different
products were formed depending on the reaction conditions. After column
chromatography, a trioxaadamantane was obtained as a mixture of two diastereomeres,
whereas a benzochromenꢀ4ꢀone was isolated under acetic conditions. A bisanthrone was
formed as the main product when using Ca(OAc)2 in methanol. The best yield for the
desired anthraquinone was obtained under basic conditions using K2CO3. Finally, the
established reaction sequence for the anthraquinone was successfully applied in the
synthesis of the natural product Kwanzoquinone A. The anthraquinone was obtained in
an overall yield of 4% over eight steps.
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Experimental Section
General Methods. All reactions were carried out under an argon atmosphere in heat gunꢀ
dried glassware. Unless otherwise noted, all reactions were performed with anhydrous
solvents. ZnI2 was dried in vacuo at 150 °C prior to use. Commercially available
materials were used without further purification. Ozonolysis was conducted using an
ozone generator; O2/O3 mixture was dried by a P4O5 column. Flash column
chromatography was performed on silica gel 60 (230–400 mesh), and analytical thin layer
chromatography (TLC) was carried out on silica gel 60 Fꢀ254 preꢀcoated aluminum
plates.
The enynes hexꢀ5ꢀenꢀ2ꢀynꢀ1ꢀol (10)21 and 5ꢀmethylhexꢀ5ꢀenꢀ2ꢀynꢀ1ꢀol (11)22 were
prepared following a literature procedure.21 2ꢀ(4,5ꢀDimethylꢀ2ꢀmethylenehexꢀ4ꢀenyl)ꢀ
4,5ꢀdimethylbenzaldehyde (14) was prepared following a tandem DielsꢀAlder / 1,4ꢀ
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hydrovinylation / DDQꢀoxidation sequence.14 These are known compounds, and the
analytical data for these compounds were in accordance with the literature.
7
8
9
General Procedure 1 for the Cobalt-Catalyzed Diels-Alder / DDQ-Oxidation
Sequence with 2,3-dimethyl-1,3-butadiene (DMB) (GP 1). Zinc iodide (20–30 mol%),
zinc powder (20–30 mol%) and CoBr2(L) (10–15 mol%) (L = 2,2’ꢀbipyridin (for
aldehyde 13); L = 1,2ꢀbis(diphenylphosphino)ethane (for aldehyde 12)) were suspended
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in dichloromethane (1.0 M). Then 2,3ꢀdimethylꢀ1,3ꢀbutadiene (1.2–1.4 eq) and the enyne
(1.0 eq) were added and the mixture was stirred at room temperature until complete
conversion of the starting material. Afterwards the suspension was filtered over a short
pad of silica gel and the solvent was removed in vacuo. The residue was dissolved in
toluene (0.1 M) and was treated with 2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone (2.6 eq,
DDQ). The mixture was stirred at room temperature until complete oxidation was
monitored by GC/MS analysis and was then filtered over a short pad of deactivated silica
gel. The solvent was removed in vacuo and the residue was purified by flash column
chromatography on silica gel.
4,5-Dimethyl-2-(2-methylallyl)benzaldehyde (12): colorless oil; 139 mg (0.74 mmol,
1
78%); eluent: pentane:diethyl ether = 25:1; H NMR (300 MHz, CDCl3) δ 10.16 (s, 1H),
7.62 (s, 1H), 7.03 (s, 1H), 4.82 (s, 1H), 4.46 (s, 1H), 3.66 (s, 2H), 2.32 – 2.28 (m, 6H),
1.76 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 192.0, 145.6, 143.7, 139.8, 135.5, 133.1,
132.4, 131.7, 112.3, 39.8, 23.0, 20.2, 19.3; MS (EI) m/z (%) 188 (13, M+), 173 (100), 155
(15), 145 (16), 128 (15), 115 (13), 91 (9), 77 (7); HRMS (EI, m/z) calcd for C13H16O
188.1201, found 188.1198; IR (film, cmꢀ1) 2971, 2921, 2859, 1687, 1650, 1610, 1560,
1500, 1449, 1399, 1373, 1293, 1258, 1217, 1184, 1072, 1022, 890, 777.
2-Allyl-4,5-dimethylbenzaldehyde (13): colorless oil; 183 mg (1.05 mmol, 40%);
eluent: pentane:diethyl ether = 25:1; 1H NMR (300 MHz, CDCl3) δ 10.17 (s, 1H), 7.60 (s,
1H), 7.05 (s, 1H), 6.02 (ddt, J = 16.4, 10.1, 6.2 Hz, 1H), 5.06 (dq, J = 10.1, 1.5 Hz, 1H),
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4.98 (dq, J = 17.1, 1.7 Hz, 1H), 3.75 (d, J = 6.2 Hz, 2H), 2.31 (s, 3H), 2.30 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 192.2, 143.9, 139.9, 137.5, 135.4, 132.8, 132.6, 131.9,
116.2, 36.2, 20.2, 19.3; MS (EI) m/z (%) 174 (21, M+), 159 (100), 146 (15), 141 (22), 131
(31), 115 (51), 103 (11), 91 (37), 77 (23), 63 (14); HRMS (EI, m/z) calcd for C12H14O
174.1045, found 174.1048; IR (film, cmꢀ1) 3346, 2924, 1688, 1614, 1565, 1452, 1413,
1381, 1323, 1297, 1259, 1225, 1193, 1102, 1063, 1022, 998, 889, 775.
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2-(2,3-Dimethylbut-2-enyl)naphthalene (23): Zinc iodide (20 mol%), zinc powder
(20 mol%) and cobalt 1,2ꢀbis(diphenylphosphino)ethane dibromide (10 mol%) were
suspended in dichloromethane (1 mL). Then DMB (1.71 mmol) and 2ꢀ(2ꢀallylphenyl)ꢀ
1,3ꢀdioxolane (24) (1.18 mmol) were added and the mixture was stirred at room
temperature (3 h). Additional ZnI2 (0.94 mmol) was added and the reaction mixture was
stirred for 2 d. Afterwards, the suspension was filtered over a short pad of silica gel and
1
the solvent was removed in vacuo. Pale yellow oil; 216 mg (1.03 mmol, 87%). H NMR
(300 MHz, CDCl3) δ 7.83 – 7.77 (m, 3H), 7.57 (s, 1H), 7.49 – 7.37 (m, 2H), 7.30 (d, J =
8.5 Hz, 1H), 3.56 (s, 2H), 1.85 (s, 3H), 1.78 (s, 3H), 1.63 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 138.8, 133.8, 132.2, 127.9, 127.7, 127.60, 127.56, 126.5, 126.4,
126.2, 125.9, 125.2, 40.5, 20.9, 20.8, 18.6; MS (EI) m/z (%) 210 (65, M+), 195 (100), 180
(23), 165 (40), 153 (19), 141 (37), 128 (38), 115 (28); HRMS (EI, m/z) calcd for C16H18
210.1409, found 210.1409; IR (film, cmꢀ1) 3052, 2957, 2922, 2862, 1634, 1599, 1508,
1451, 1374, 1163, 1120, 1019, 954, 892, 851, 811, 778, 747, 620.
2-(4,5-Dimethyl-2-methylenehex-4-enyl)benzaldehyde (25): Zinc iodide (20 mol%),
zinc powder (20 mol%) and cobalt 1,2ꢀbis(diphenylphosphino)ethane dibromide
(10 mol%) were suspended in dichloromethane (4 mL). Then DMB (4.80 mmol) and
2ꢀ(2ꢀallylphenyl)ꢀ1,3ꢀdioxolane (24) (3.67 mmol) were added and the mixture was stirred
at room temperature until complete conversion of the alkene was monitored by GC/MS
analysis (5 h). Afterwards the suspension was filtered over a short pad of silica gel and
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the solvent was removed in vacuo. The residue was dissolved in acetone (20 mL) and was
treated with paraꢀtoluenesulfonic acid (0.32 mmol, pTsOH). After stirring for an
additional hour, the mixture was neutralized with saturated aqueous NaHCO3 solution.
The product was extracted with ethyl acetate (3x), the combined organic phases were
washed with brine and dried over anhydrous magnesium sulfate. The solvent was
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removed in vacuo. Pale yellow oil; 827 mg (3.63 mmol, 98%); H NMR (300 MHz,
CDCl3) δ 10.20 (s, 1H), 7.87 (dd, J = 7.7, 1.4 Hz, 1H), 7.52 (dt, J = 7.5, 1.5 Hz, 1H), 7.38
(t, J = 7.2 Hz, 1H), 7.29 – 7.24 (m, 1H), 4.83 (dd, J = 2.7, 1.3 Hz, 1H), 4.42 – 4.39 (m,
1H), 3.67 (s, 2H), 2.82 (s, 2H), 1.69 (s, 3H), 1.63 – 1.57 (m, 6H); 13C{1H} NMR
(75 MHz, CDCl3) δ 192.0, 147.7, 142.4, 134.5, 133.9, 131.8, 130.2, 127.0, 126.9, 124.8,
112.6, 41.9, 38.4, 20.8, 20.6, 18.4; HRMS (ESI, m/z) calcd for C16H20O+H+ 229.1587,
found 229.1588; IR (film, cmꢀ1) 3072, 2987, 2912, 2859, 2732, 2359, 1694, 1646, 1598,
1447, 1376, 1288, 1203, 1114, 896, 809, 755, 637.
General Procedure 2 for the Grignard Reaction with Allylmagnesium Bromide
(GP 2): Allylmagnesium bromide (1.2–1.3 eq; 1.0
M in THF) was added dropwise to the
aldehyde (1.0 eq) dissolved in THF at 0 °C and the mixture was stirred at room
temperature. After complete conversion of the aldehyde, saturated aqueous NH4Cl
solution was added, and the product was extracted with diethyl ether (3x). The combined
organic phases were washed with water and brine, and then dried over anhydrous
magnesium sulfate. The solvent was removed in vacuo and the residue was purified by
flash column chromatography. The products were converted to the corresponding
ketones, see below.
General Procedure 3 for the Indium-Mediated Barbier-Type Reaction (GP 3).
Following a literature procedure,23 indium (1.5 eq) was added to dimethylformamide
(1 mL). After addition of 2ꢀmethylꢀ3ꢀbromopropen (2.5–3.0 eq), the reaction mixture was
stirred at room temperature for 10 min until the colorless solution turned yellow. Then the
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aldehyde (1.0 eq) dissolved in dimethylformamid (1 mL) was added, and the solution was
stirred for 1 h at room temperature. After acidification of the mixture with HCl (2 ), the
M
8
9
product was extracted with diethyl ether (3x). The combined organic phases were dried
over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue
was purified by flash column chromatography. The products were converted to the
corresponding ketones, see below.
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General Procedure 4 for the Cobalt-Catalyzed 1,4-Hydrovinylation – Allylboration
Reaction Sequence (GP 4). Zinc iodide (20–40 mol%), zinc powder (20–40 mol%) and
cobalt 1,2ꢀbis(diphenylphosphino)ethane dibromide (10–20 mol%) were suspended in
dichloromethane (1.0 M). Then 2,3ꢀdimethylꢀ1,3ꢀbutadiene (DMB) (1.7 eq) and the 2ꢀ
allylꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolane (1.5 eq) were added, and the mixture was
stirred at room temperature until complete conversion of the alkene monitored by GC/MS
analysis. Afterwards, the reaction was cooled to 0 °C and the aldehyde (1.0 eq) was
added. The reaction mixture was stirred at 0 °C for an hour and another hour at room
temperature. Triethanolamine (1.8–2.0 eq) was added and the reaction mixture was
stirred for an additional hour. The mixture was filtered over a short pad of silica gel, the
solvent was removed in vacuo and the residue was purified by flash column
chromatography.
1-(2-(4,5-Dimethyl-2-methylenhex-4-enyl)-4-methylphenyl)-5,6-dimethyl-3-
methylene-hept-5-en-1-ol (50): Zinc iodide (20 mol%), zinc powder (20 mol%) and
cobalt 2,2’ꢀbipyridine dibromide (10 mol%) were suspended in dichloromethane (2 mL).
Then isoprene (3.0 mmol) and the enyne 10 (2.10 mmol) were added and the mixture was
stirred at room temperature until complete conversion of the enyne (15 h). Afterwards,
the suspension was filtered over a short pad of silica gel and the solvent was removed in
vacuo. The residue was dissolved in dichloromethane (2.0 mL) and added to zinc iodide
(20 mol%), zinc powder (20 mol%) and cobalt 1,2ꢀbis(diphenylphosphino)ethane
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dibromide (10 mol%) and 2,3ꢀdimethylꢀ1,3ꢀbutadiene (2.6 mmol) in 2.0 mL
dichloromethane and stirred for 3 h at room temperature. The suspension was filtered
over a short pad of silica gel and the solvent was removed in vacuo. The residue was
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dissolved in toluene (0.1 M) and was treated with 2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀ
benzoquinone (5.0 mmol, DDQ). The mixture was stirred at room temperature for 18 h
and was then filtered over a short pad of deactivated silica gel. The solvent was removed
in vacuo and the residue was purified by flash column chromatography. The obtained
aldehyde 49 was then applied in a cobaltꢀcatalyzed 1,4ꢀhydrovinylation – allylboration
reaction sequence as described in the GP 4. Colorless oil; 122 mg (0.33 mmol, 16%;
purity: 94%); eluent: pentane:diethyl ether = 20:1; 1H NMR (300 MHz, CDCl3) δ 7.43 (d,
J = 7.9 Hz, 1H), 7.08 (dd, J = 7.9, 1.3 Hz, 1H), 6.94 (s, 1H), 4.99 – 4.91 (m, 2H), 4.86
(dd, J = 3.4, 1.6 Hz, 1H), 4.81 (d, J = 1.3 Hz, 1H), 4.50 (s, 1H), 3.38 – 3.22 (m, 2H), 2.78
(s, 4H), 2.37 – 2.30 (m, 5H), 2.02 (s, 1H), 1.69 (s, 6H), 1.67 – 1.59 (m, 12H);
13C{1H} NMR (75 MHz, CDCl3) δ 147.5, 144.9, 139.8, 136.8, 136.0, 131.3, 127.7, 126.8,
126.7, 125.9, 125.0, 124.9, 112.8, 111.8, 67.9, 45.8, 41.8, 41.3, 39.2, 21.2, 20.8, 20.7,
20.6, 20.6, 18.6, 18.5; MS (EI) m/z (%) 366 (<1, M+), 348 (8), 265 (19), 243 (13), 225
(33), 209 (23), 195 (18), 155 (38), 143 (51), 109 (15), 83 (100), 55 (40); HRMS (EI, m/z)
calcd for C26H38O 366.2923, found 366.2918; IR (film, cmꢀ1) 3444, 3075, 2987, 2915,
2861, 1741, 1644, 1497, 1441, 1377, 1335, 1277, 1218, 1109, 1049, 894, 819.
General Procedure 5 for the Oxidation of Alcohols with Pyridinium
Chlorochromate (PCC) (GP 5). Alcohol (1.0 eq) was added to pyridinium
chlorochromate (1.5 equiv, PCC) suspended in dichloromethane (0.2 M) at 0 °C. The
reaction mixture was stirred at room temperature until complete conversion of the starting
material. Afterwards, the suspension was filtered over silica gel, followed by evaporation
of the solvent. Then the residue was purified by flash column chromatography. For the
synthesis of ketone 22, DessꢀMartinꢀperiodinane was used instead of PCC.
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1-(2-Allyl-4,5-dimethylphenyl)but-3-en-1-one (16): colorless oil; 85 mg (0.40 mmol,
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50%); eluent: pentane:diethyl ether = 50:1; H NMR (300 MHz, CDCl3) δ 7.43 (s, 1H),
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7.04 (s, 1H), 6.12 – 5.87 (m, 2H), 5.24 – 5.13 (m, 2H), 5.06 – 4.93 (m, 2H), 3.67 (dt, J =
6.8, 1.4 Hz, 2H), 3.58 (d, J = 6.5 Hz, 2H), 2.28 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3)
δ 201.7, 140.8, 138.0, 137.8, 135.3, 134.4, 132.8, 131.5, 130.2, 118.5, 115.4, 46.5, 37.8,
19.9, 19.5; MS (EI) m/z (%) 214 (7, M+), 199 (19), 173 (100), 158 (13), 145 (90), 130
(48), 115 (37), 105 (15), 91 (13), 77 (9); HRMS (EI, m/z) calcd for C15H18O 214.1358,
found 214.1358; IR (film, cmꢀ1) 3078, 3013, 2976, 2920, 1682, 1638, 1611, 1556, 1500,
1445, 1392, 1319, 1266, 1225, 1199, 1117, 1088, 993, 913, 877.
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1-(4,5-Dimethyl-2-(2-methylallyl)phenyl)but-3-en-1-one (17): colorless oil; 256 mg
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(1.12 mmol, 75%); eluent: pentane:diethyl ether = 100:1; H NMR (300 MHz, CDCl3)
δ 7.39 (s, 1H), 7.02 (s, 1H), 6.02 (ddt, J = 17.1, 10.4, 6.8 Hz, 1H), 5.24 – 5.10 (m, 2H,),
4.75 (s, 1H), 4.45 (s, 1H), 3.63 (dt, J = 6.8, 1.4 Hz, 2H), 3.52 (s, 2H), 2.28 (s, 3H), 2.27
(s, 3H), 1.71 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 202.1, 145.8, 140.4, 137.0,
136.1, 134.4, 133.2, 131.6, 130.0, 118.5, 111.5, 46.6, 41.0, 23.0, 19.9, 19.5; MS (EI) m/z
(%) 228 (13, M+), 213 (100), 199 (10), 186 (22), 172 (23), 159 (15), 141 (14), 128 (27),
115 (16), 91 (9), 77 (8), 69 (18); HRMS (EI, m/z) calcd for C16H20O 228.1514, found
228.1519; IR (film, cmꢀ1) 3078, 3014, 2970, 2938, 2920, 1685, 1644, 1612, 1557, 1499,
1447, 1388, 1373, 1319, 1266, 1197, 1117, 1089, 1022, 992, 978, 913, 887, 772.
1-(2-(4,5-Dimethyl-2-methylenehex-4-enyl)-4,5-dimethylphenyl)but-3-en-1-one (18):
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colorless oil; 983 mg (3.32 mmol, 80%); eluent: pentane:diethyl ether = 50:1; H NMR
(300 MHz, CDCl3) δ 7.37 (s, 1H), 7.01 (s, 1H), 6.01 (ddt, J = 17.1, 10.3, 6.8 Hz, 1H),
5.22 – 5.12 (m, 2H), 4.71 (s, 1H), 4.41 (s, 1H), 3.62 (dt, J = 6.8, 1.3 Hz, 2H), 3.47 (s,
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2H), 2.73 (s, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 1.68 (s, 3H), 1.59 (br s, 6H); C{1H} NMR
(75 MHz, CDCl3) δ 202.0, 147.6, 140.0, 136.8, 136.2, 134.1, 133.1, 131.5, 129.7, 126.2,
125.1, 118.2, 110.9, 46.4, 41.6, 39.4, 20.5, 20.4, 19.7, 19.3, 18.4; HRMS (ESI, m/z) calcd
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for C21H28O+H+ 297.2213, found 297.2213; IR (film, cmꢀ1) 3078, 2981, 2917, 2862,
1687, 1641, 1612, 1557, 1499, 1446, 1390, 1320, 1264, 1221, 1117, 1088, 988, 911, 892.
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1-(2-Allyl-4,5-dimethylphenyl)-3-methylbut-3-en-1-one (19): colorless oil; 231 mg
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(1.01 mmol, 66%); eluent: pentane:diethyl ether = 25:1; H NMR (300 MHz, CDCl3)
δ 7.45 (s, 1H), 7.04 (s, 1H), 5.98 (ddt, J = 17.7, 9.4, 6.5 Hz, 1H), 5.04 – 4.96 (m, 3H),
4.83 (s, 1H), 3.58 (m, 4H), 2.27 (s, 6H), 1.80 (s, 3H); C{1H} NMR (75 MHz, CDCl3)
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δ 201.7, 140.8, 140.0, 138.0, 137.8, 135.5, 134.3, 132.8, 130.4, 115.4, 115.0, 50.7, 37.8,
23.0, 19.9, 19.5; MS (EI) m/z (%) 228 (14, M+), 213 (70), 198 (17), 185 (30), 173 (100),
157 (23), 145 (82), 141 (18), 128 (46), 115 (40), 105 (15), 91 (17), 77 (15); HRMS (EI,
m/z) calcd for C16H20O 228.1514, found 228.1511; IR (film, cmꢀ1) 3077, 2974, 2919,
1682, 1644, 1610, 1556, 1499, 1379, 1320, 1264, 1226, 1100, 995, 949, 896.
1-(4,5-Dimethyl-2-(2-methylallyl)phenyl)-3-methylbut-3-en-1-one (20): colorless oil;
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342 mg (1.41 mmol, 88%); eluent: pentane:diethyl ether = 100:1; H NMR (300 MHz,
CDCl3) δ 7.41 (s, 1H), 7.02 (s, 1H), 4.96 (s, 1H), 4.82 (s, 1H), 4.76 (s, 1H), 4.46 (s, 1H),
3.57 (s, 2H), 3.53 (s, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 1.79 (s, 3H), 1.72 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 201.9, 145.8, 140.3, 140.0, 136.9, 136.3, 134.2, 133.1,
130.1, 115.0, 111.5, 50.8, 40.9, 22.97, 22.95, 19.8, 19.5; MS (EI) m/z (%) 242 (15, M+),
227 (69), 209 (38), 187 (100), 179 (23), 159 (94), 144 (24), 128 (34), 115 (23), 91 (9), 77
(10); HRMS (EI, m/z) calcd for C17H22O 242.1671, found 242.1671; IR (film, cmꢀ1) 3077,
2971, 2922, 1684, 1649, 1612, 1556, 1499, 1445, 1376, 1320, 1262, 1226, 1098, 1020,
950, 889, 772.
1-(2-(4,5-Dimethyl-2-methylenehex-4-enyl)-4,5-dimethylphenyl)-3-methylbut-3-en-1-
one (21): colorless oil; 597 mg (1.92 mmol, 84%); eluent: pentane:diethyl ether = 50:1;
1H NMR (300 MHz, CDCl3) δ 7.41 (s, 1H), 7.01 (s, 1H), 4.95 (s, 1H), 4.81 (s, 1H), 4.72
(s, 1H), 4.43 (s, 1H), 3.56 (d, J = 0.6 Hz, 2H), 3.49 (s, 2H), 2.75 (s, 2H), 2.28 (s, 3H),
2.26 (s, 3H), 1.79 (s, 3H), 1.68 (s, 3H), 1.62 – 1.58 (m, 6H); C{1H} NMR (75 MHz,
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CDCl3) δ 202.0, 147.7, 140.2, 140.0, 137.0 , 136.5, 134.1, 133.2, 130.1, 126.4, 125.2,
114.9, 111.0, 50.7, 41.7, 39.5, 23.0, 20.7, 20.5, 19.8, 19.5, 18.6; MS (EI) m/z (%) 310 (3,
[M+]), 292 (7), 255 (12), 227 (100), 211 (4), 185 (11), 173 (11), 128 (7), 91 (5), 83 (11),
55 (16); HRMS (EI, m/z) calcd for C22H30O 310.2297, found 310.2296; IR (film, cmꢀ1)
3077, 2977, 2917, 2863, 1737, 1685, 1646, 1611, 1556, 1499, 1445, 1377, 1320, 1263,
1223, 1098, 1020, 951, 891, 771.
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1-(4,5-Dimethyl-2-(2-methylallyl)phenyl)-5,6-dimethyl-3-methylenehept-5-en-1-one
(22): colorless oil; 125 mg (0.40 mmol, 62%); eluent: pentane:diethyl ether = 30:1;
1H NMR (300 MHz, CDCl3) δ 7.38 (s, 1H), 7.01 (s, 1H), 4.92 (d, J = 1.5 Hz, 1H), 4.84
(s, 1H), 4.77 (d, J = 0.9 Hz, 1H), 4.47 (s, 1H), 3.54 (s, 2H), 3.50 (s, 2H), 2.83 (s, 2H),
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2.27 (s, 6H), 1.72 (s, 3H), 1.69 (s, 3H), 1.61 (s, 6H); C{1H} NMR (75 MHz, CDCl3)
δ 202.0, 145.8, 142.0, 140.2, 137.0, 136.3, 134.2, 133.0, 130.3, 127.0, 124.9, 114.5,
111.6, 48.6, 41.7, 40.9, 23.0, 20.8, 20.6, 19.8, 19.5, 18.4; MS (EI) m/z (%) 310 (9, M+),
295 (17), 292 (30), 249 (14), 226 (30), 208 (13), 187 (100), 170 (16), 159 (75), 144 (14),
129 (18), 107 (10), 91 (9); HRMS (EI, m/z) calcd for C22H30O 310.2297, found 310.2295;
IR (film, cmꢀ1) 3077, 2968, 2919, 2858, 1682, 1647, 1612, 1557, 1498, 1446, 1373, 1317,
1266, 1218, 1198, 1152, 1094, 1022, 985, 945, 888, 845, 779.
1-(2-(4,5-Dimethyl-2-methylenehex-4-enyl)-4,5-dimethylphenyl)-5,6-dimethyl-3-
methylenehept-5-en-1-one (7): colorless oil; 761 mg (2.01 mmol, 87%); eluent:
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pentane:diethyl ether = 50:1; H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), 7.00 (s, 1H),
4.91 (d, J = 1.6 Hz, 1H), 4.83 (d, J = 0.7 Hz, 1H), 4.71 (s, 1H), 4.43 (d, J = 0.8 Hz, 1H),
3.48 (s, 4H), 2.83 (s, 2H), 2.75 (s, 2H), 2.27 (s, 6H), 1.68 (s, 6H), 1.60 (s, 12H);
13C{1H} NMR (75 MHz, CDCl3) δ 202.1, 147.7, 142.0, 140.1, 137.1, 136.4, 134.1, 133.2,
130.3, 127.0, 126.4, 125.3, 125.0, 114.4, 111.0, 48.6, 41.8, 41.7, 39.6, 20.8, 20.7, 20.63,
20.56, 19.8, 19.5, 18.6, 18.4; HRMS (ESI, m/z) calcd for C27H38O+H+ 379.2995, found
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379.2992; IR (film, cmꢀ1) 3077, 2984, 2914, 1682, 1643, 1612, 1556, 1498, 1443, 1376,
1317, 1266, 1216, 1154, 1093, 1019, 985, 950, 890.
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1-(2-(4,5-Dimethyl-2-methylenehex-4-enyl)-4-methylphenyl)-5,6-dimethyl-3-
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methylenehept-5-en-1-one (51): colorless oil; 136 mg (0.37 mmol, 85%); eluent:
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pentane:diethyl ether = 30:1; H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 8.3 Hz, 1H),
7.07 (m, 2H), 4.91 (d, J = 1.6 Hz, 1H), 4.84 (s, 1H), 4.73 (s, 1H), 4.43 (s, 1H), 3.53 (s,
2H), 3.49 (s, 2H), 2.82 (s, 2H), 2.75 (s, 2H), 2.35 (s, 3H), 1.68 (s, 6H), 1.60 (s, 12H);
13C{1H} NMR (75 MHz, CDCl3) δ 201.9, 147.6, 141.9, 141.5, 139.8, 136.1, 132.6, 129.1,
127.0, 126.7, 126.4, 125.2, 124.9, 114.5, 111.2, 48.6, 41.8, 41.7, 40.0, 21.5, 20.74, 20.71,
20.6, 20.5, 18.6, 18.4; MS (EI) m/z (%) 364 (3, M+), 346 (30), 321 (9), 303 (6), 281 (33),
261 (13), 241 (29), 233 (18), 221 (22), 207 (19), 193 (25), 171 (23), 159 (48), 109 (23),
91 (24), 83 (100), 55 (82); HRMS (EI, m/z) calcd for C26H36O 364.2766, found 364.2766;
IR (film, cmꢀ1) 2985, 2912, 2859, 1749, 1682, 1643, 1607, 1564, 1435, 1374, 1315, 1264,
1210, 1114, 1005, 890, 808.
General Procedure 6 for the Ozonolysis Reaction (GP 6). The polyene (1.0 eq) was
dissolved in dichloromethane and the solution was cooled to −78 °C. A mixture of
oxygen and ozone was bubbled through the solution until a blue color appeared. The
mixture was purged with oxygen to obtain a colorless or slightly yellowish solution
which was directly treated with the corresponding reducing agent and allowed to warm to
room temperature.
General Procedure 7 for the Cyclization of Tricarbonyl Compounds with aqueous
NaOH (5 w%) (GP 7). After ozonolysis of polyene (0.4 mmol) in dichloromethane
(12 mL), following the GP 6 for the ozonolysis reaction, triphenylphosphine (1.0 mmol)
was added and the reaction mixture was warmed to room temperature over an hour. The
solvent was removed in vacuo and aqueous NaOH (6.4 mL, 5 w%) was added. After
stirring for an hour, the suspension was acidified with 2
M HCl, the product was extracted
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with dichloromethane (3x), washed with brine and dried over anhydrous magnesium
sulfate. Silica gel was added and after evaporation of the solvent the residue was purified
by flash column chromatography.
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1-Hydroxy-3,6,7-trimethyl-2-naphthaldehyde (27): yellow solid; 63 mg (0.30 mmol,
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75%); eluent: pentane:diethyl ether = 10:1; m.p. = 168–171 °C; H NMR (500 MHz,
CDCl3) δ 11.54 (s, 1H), 8.21 (s, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.14 (s, 1H), 2.75 (d, J =
0.8 Hz, 3H), 2.40 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 204.7,
156.8,140.5, 137.4, 133.9, 132.6, 128.6, 126.0, 125.9, 120.8, 111.3, 26.9, 20.6, 20.0; MS
(EI) m/z (%) 214 (75, M+), 199 (100), 171 (11), 143 (53), 128 (30), 115 (30), 102 (5), 77
(8); HRMS (EI, m/z) calcd for C14H14O2 214.0994, found 214.0991; IR (film, cmꢀ1) 3010,
2921, 2857, 1650, 1569, 1459, 1381, 1337, 1288, 1220, 1157, 1112, 1056, 1021, 952,
899, 857, 770, 715.
1-(2-((1,2,4-Trioxolan-3-yl)methyl)-4,5-dimethylphenyl)-2-(3-methyl-1,2,4-trioxolan-
3-yl)ethanon (28): After ozonolysis of diene 19 (0.32 mmol) in dichloromethane
(12 mL), following GP 1 for the ozonolysis reaction, triphenylphosphine (0.95 mmol)
was added and the reaction mixture was warmed to room temperature over a period of an
hour. Silica gel was added and the reaction mixture was stirred for 1 h at room
temperature. The solvent was removed under reduced pressure and the residue was
purified by flash chromatography. Eluent: pentane:diethyl ether = 5:1; 29: pale yellow
solid, 3 mg (0.02 mmol, 5%); analytical data see publication; 28: colorless oil; 23 mg
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(0.07 mmol, 23%); eluent: pentane:diethyl ether = 5:1; H NMR (500 MHz, CDCl3)
δ 7.49 (s, 1H), 7.10 (s, 1H), 5.49 (dd, J = 9.9, 4.5 Hz, 1H), 5.17 (s, 1H), 5.11 (s, 1H), 5.08
(s, 1H), 5.05 (s, 1H), 3.40 (dd, J = 15.5, 3.7 Hz, 1H), 3.34 (dd, J = 15.4, 4.0 Hz, 1H), 3.29
(dd, J = 13.6, 4.5 Hz, 1H), 3.18 (dd, J = 13.5, 5.4 Hz, 1H), 2.29 (s, 6H), 1.68 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 198.9, 198.8, 141.49, 141.47, 135.8, 135.7, 135.6,
134.71, 134.68, 132.71, 132.68, 131.12, 131.08, 108.0, 103.62, 103.60, 94.21, 94.19 ,
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