Deconjugative α-Alkylation of Cyclohexenecarboxaldehydes: An Access to Diverse Terpenoids

Article abstract of DOI:10.1021/acs.joc.1c00560

A general and efficient method for the deconjugative α-alkylation of α,β-unsaturated aldehydes promoted by a synergistic effect between tBuOK and NaH, which considerably increases the reaction rate under mild conditions, is reported. The β,γ-unsaturated aldehyde, resulting from the α-alkylation, is transformed in high yield into the corresponding allyl acetate via a lead(IV) acetate-mediated oxidative fragmentation. This strategy could be used for the construction of the carbon skeleton of a wide variety of alkyl or arylterpenoids.

Full text of DOI:10.1021/acs.joc.1c00560

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Article
Deconjugative α‑Alkylation of Cyclohexenecarboxaldehydes: An
Access to Diverse Terpenoids
́
̃
Rachid Chahboun,* José Manuel Botubol-Ares, María Jesus Durán-Pena, Fermín Jiménez,
Ramón Alvarez-Manzaneda, and Enrique Alvarez-Manzaneda
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ABSTRACT: A general and efficient method for the deconjugative
α-alkylation of α,β-unsaturated aldehydes promoted by a
t
synergistic effect between BuOK and NaH, which considerably
increases the reaction rate under mild conditions, is reported. The
β,γ-unsaturated aldehyde, resulting from the α-alkylation, is
transformed in high yield into the corresponding allyl acetate via
a lead(IV) acetate-mediated oxidative fragmentation. This strategy
could be used for the construction of the carbon skeleton of a wide
variety of alkyl or arylterpenoids.
therefore of interest to investigate new approaches to avoid
this inconvenience.
INTRODUCTION
■
Terpenoids are a broad group of natural products, charac-
terized by their structural diversity, that have found extensive
use in medicine and other industries.1−3 However, their
scarcity in their natural, marine, or terrestrial sources often
forces the development of synthetic processes for their
availability. Within the enormous variety of synthetic processes
described to access this type of compounds, those that use
simple terpenoids as a starting product to prepare more
complex molecules deserve to be highlighted.4 This has the
obvious advantage of reducing the number of synthetic
sequence steps. In addition, if the terpene precursor is easily
accessible, and therefore cheap, the process may have
commercial interest.
β-Cyclocitral (1) is a cyclic monoterpene, commercially
available at a low price, which has been used as a precursor of
different terpenoids (Scheme 1). In this way, the reaction of
aldehyde 1 with the suitable benzyllithium derivative 2
afforded the corresponding allyl homobenzyl alcohol, the
precursor of the abietane quinone taxodione (3)5 and the
totarane quinone maytenoquinone (4),6 both with antitumor
properties, or the antifungal tricyclic diterpenoid 5.7 When β-
cyclocitral (1) was treated with the suitable aryllithium
derivative 6, taiwaniaquinoids such as dichroanone (7),8
taiwaniaquinone H (8),8 and dichroanal B (9)8b were
obtained. These processes involve the condensation of a
terpene synthon having electrophilic character with an
aromatic derivative of nucleophile nature.
The construction of the carbon skeleton of compounds such
as 3−5 and 7−9 could be achieved in an alternative way by
performing the α-alkylation of the α,β-unsaturated terpenic
aldehyde 1 with a suitable benzyl halide to afford the
corresponding arylterpenylaldehydes, followed by cyclization.
Despite its synthetic potential, the deconjugative α-alkylation
of aldehydes has been studied very little (Scheme 2). In a
pioneer work, De Graaf et al. described the direct alkylation of
1-cyclohexene-1-carbaldehyde with different agents in liquid
ammonia at −60 °C in the presence of potassium amide,
affording a mixture of products.9 After that, a procedure to
achieve the direct α-alkylation of acyclic aldehydes utilizing
NaOH and a phase-transfer agent in an inert solvent has been
patented.10 Additionally, the palladium- and nickel-catalyzed
deconjugative α-allylation with allyl alcohols of aldehydes,
including a few α,β-unsaturated aldehydes, has also been
described (Scheme 2).11 Other indirect methods, such as the
alkylation of the corresponding dimethylhydrazones, in the
presence of lead lithium diisopropylamide (LDA), have been
described.12 Recently, the copper-catalyzed deconjugative α-
alkylation of cyclic α,β-unsaturated nitriles has been
reported.13
In this paper, we describe the deconjugative α-alkylation of
cyclohexene-1-carboxaldehydes and its synthetic application as
Received: March 9, 2021
Published: June 15, 2021
However, in certain cases, preparation of nucleophilic
aromatic synthons became difficult because of either the
substitution pattern or the presence of electrophilic groups
(e.g., CN, COOR, COR, and so forth) in the aromatic ring,
resulting in the consequent lengthening sequence. It is
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Scheme 1. Synthesis of Terpenoids from β-Cyclocitral (1) and Aryllithium Derivatives
Scheme 2. Previous Direct α-Alkylation of α,β-Unsaturated
Aldehydes
RESULTS AND DISCUSSION
■
Considering our working hypothesis, we initiated the study of
the α-alkylation of β-cyclocitral (1) using allyl bromide (10a)
as the electrophile. The reaction was performed in different
solvents such as tetrahydrofuran (THF), acetonitrile, and
toluene in the presence of tBuOK as a base, and the desired α-
alkylated product ( )-11a, formed selectively from a
trisubstituted dienolate, was obtained in poor to moderate
t
yields (Table 1, entries 1−3). A higher amount of BuOK did
not improve the yield either (Table 1, entry 4). The addition
of 18-crown-6-ether led to a mixture of ( )-11a and the
corresponding O-alkylated derivative 12a in THF, acetonitrile,
and toluene (Table 1, entries 5−7). Then, the effect of other
bases was also considered in the model reaction. LiHMDS
increased the C-/O-alkylation ratio [( )-11a/12a ratio] up to
5:1 (Table 1, entry 8). On the contrary, the deconjugative α-
alkylation of 1 with LDA did not work (Table 1, entry 9). In a
similar fashion, NaH led to unreacted starting material in
toluene, whereas a 1:1 mixture of ( )-11a/12a was obtained
in THF at 60 °C (Table 1, entries 10−11). Gratifyingly, C-
a platform to access challenging terpene frameworks. In
comparison to other existing direct α-alkylation of α,β-
unsaturated aldehydes (Scheme 2), this methodology occurs
under milder metal-free reaction conditions with a wider scope
and compatible with electrophilic groups (Scheme 3).
Scheme 3. Synthetic Approaches to Terpenoids; (a) Conventional Methods for the Synthesis of Terpenoids from β-Cyclocitral
(1) as an Electrophile; (b) Deconjugative α-Alkylation of Cyclohexene-1-carboxaldehydes for the Synthesis of Terpenoids
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With the optimized reaction conditions in hand, the scope
and limitations of the deconjugative α-alkylation of β-
cyclocitral (1) were evaluated with a series of activated alkyl
and benzyl halides. In most cases, it undergoes α-alkylation in
high to moderate yields under smooth conditions and short
reaction times (Table 2). Methyl iodide (10b) and benzyl
bromide (10e) promoted the deconjugative α-alkylation
reaction in higher reaction yields (Table 2, entries 1 and 4)
in comparison to the yields obtained when allylic or
propargylic halides 10c−d were used (Table 2, entries 2−3).
However, the effect of the electron-withdrawing or electron-
releasing character of the benzyl group as well as the position
of the substituents in the aromatic ring appears to affect the
reaction course significantly. Strongly electron-releasing
methoxy groups at meta- or para-positions on the aromatic
ring and 1,3-benzodioxole groups afforded the corresponding
deconjugated aldehydes ( )-11f and ( )-11h−i in moderate
to good yields (Table 2, entries 5−8), whereas ortho-methoxy
groups furnished the corresponding products ( )-11j−l in
moderate yields (Table 2, entries 9−11). Furthermore, the use
of benzyl bromides 10g and 10k gave slightly higher reaction
yields than the corresponding benzyl chlorides 10f and 10j
(Table 2, entry 5 vs entry 6 and entry 9 vs entry 10). Benzyl
bromides bearing a bromo substituent at the ortho-position of
the aromatic ring afforded the desired deconjugated aldehydes
( )-11m−n in good yields (Table 2, entries 12−13). Finally,
the reaction was also compatible with other electrophilic
groups, such as NO2 or CN, on the aromatic ring. Thus,
compounds ( )-11o−p were obtained in the range of 77−
80% yields (Table 2, entries 14−15).
Table 1. Optimization of Deconjugative α-Alkylation of 1
with Allyl Bromide (10a)
a
time
(h)
yield 11a
yield 12a
b
b
entry
base
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
solvent
(%)
(%)
1
2
3
THF
16
16
16
16
6
8
0
CH3CN
toluene
toluene
THF
33
43
48
20
30
69
75
0
0
0
c
4
0
d
5
56
58
26
15
0
0
25
0
d
6
CH3CN
toluene
THF
THF
toluene
THF
toluene
toluene
toluene
toluene
toluene
toluene
6
d
7
6
8
9
LiHMDS
LDA
NaH
4
4
16
6
1
15
2
3
13
5
e
f
10
0
f g
11 ,
NaH
25
83
10
80
73
30
78
f
12
NaH−tBuOK
tBuONa
NaH−tBuONa
KH−tBuONa
NaH−tBuOK
NaH−tBuOK
13
0
h
14
0
0
0
0
i
15
f j
16 ,
f jk
17 , ,
a
The reaction was carried out with 1 (1.0 mmol), the base (1.1
mmol), and the solvent (20 mL). After 45 min, allyl bromide (1.5
b
c
d
t
mmol) was added. Isolated yields. 3 equiv of BuOK was used.
equiv of 18-crown-6-ether was used. The reaction was carried out at
−78 °C and allowed to warm to room temperature. 2 equiv of NaH
60% in the oil mineral was used. The reaction was carried out at 60
1
e
f
In order to demonstrate the general applicability of the
deconjugative α-alkylation and to explore the further use of
this reaction for getting access to other types of terpenoids, the
alkylation of other α,β-unsaturated aldehydes with benzyl
bromides has also been investigated (Table 3).
g
h
°C. Isolated yield after addition of 2 equiv of NaH 60% in the oil
i
j
mineral. 2 equiv of KH 30% in the oil mineral was used. 0.5 equiv of
k
tBuOK was used. Isolated yield after heating at 60 °C.
Cyclohex-1-ene-1-carboxaldehydes 13a and 13b, which lack
substituents on carbon β, underwent benzylation in high yield
in a short reaction time (Table 3, entries 1 and 2). The bicyclic
sesquiterpene aldehydes 13c and 13d, whose absolute
configuration is well known, also underwent this reaction in
high yield, affording benzyl derivatives 14c and 14d, with
complete diastereoselectivity (Table 3, entries 3 and 4). The
disposition of the aldehyde group in both products has been
confirmed by NOE experiments. The behavior of Δ8-drimenals
13c and 13d indicates the possibility of using this type of
sesquiterpene α,β-unsaturated aldehydes to synthesize a large
group of terpenoids such as benzofluorene derivatives by
reaction with the appropriate benzyl halide.21 Finally, the
α,β,γ,δ-unsaturated aldehyde safranal (13e) gave the corre-
sponding α-benzylated β,γ,δ,ε-unsaturated aldehyde 14e in
moderate yield (Table 3, entry 5).
The presence of the aldehyde group in these intermediates
notably increases the synthetic potential of this new strategy.
The formyl group can be removed and allow to introduce
functionality in the final compounds. An interesting example of
the latter would be the direct transformation of the β,γ-
unsaturated aldehyde type 11 into the allyl acetates 15 via a
lead(IV) acetate-mediated oxidative fragmentation. LTA has
been previously used for the oxidative transformation of
homoallyl alcohols to afford allyl acetate derivatives. The
reaction proceeded with complete stereoselectivity; the
acetyloxy group of the rearranged product and the hydrox-
alkylation was selective over O-alkylation by using NaH and
tBuOK in toluene, affording ( )-11a in 83% yield (Table 1,
entry 12). This result pointed out that NaH could facilitate a
fast deprotonation of tBuOH formed from the enolization and
shift the equilibrium toward its conjugate base. In order to rule
t
out that the possible formation in situ of BuONa in the
t
reaction mixture from BuOK and NaH could be responsible
for the improvement of the reaction yield, a control experiment
t
was carried out with just BuONa. A low conversion was
observed for the reaction, which was increased after addition of
t
NaH (Table 1, entries 13−14). The use of BuONa/KH gave
rise to a similar yield for ( )-11a to that observed with the pair
tBuOK/NaH (Table 1, entry 15). These results support that
tBuOH generated in the reaction is quenched by a metal
hydride. Finally, we also tested a decrease of the amount of
tBuOK to 0.5 equiv, giving rise to the lowering of the reaction
conversion in comparison with using a stoichiometric amount
of the base. However, a similar yield was obtained after heating
at 60 °C for 1 h (Table 1, entries 16−17 vs entry 12).
The experiments shown in Table 1 confirm that the
t
synergistic effect between BuOK/tBuONa and metal hydrides
plays a crucial role in the conversion and selectivity of the
deconjugative α-alkylation, influencing the kinetic and
increasing the reaction rate. A cooperative interaction between
tBuOK and strong bases has been previously reported for the
synthesis of 1-indanones from β-alkynyl ketones.14
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Table 2. continued
Table 2. Reaction of β-Cyclocitral (1) with Activated Alkyl
and Benzyl Halides
a
a
Unless specified, the reaction was carried out with 1 (1.0 mmol),
tBuOK (1.1 mmol), NaH (2 mmol), and toluene (20 mL). After 45
b
c
min, alkyl halide (1.5 mmol) was added. Isolated yields. Similar
yields were obtained using 1 equiv of 18-crown-6 in the absence of
NaH.
ymethyl group in the starting material are located at the same
face of the molecule.22
To expand the scope of Preite’s reaction and illustrate the
usefulness of this transformation, some of the synthesized β,γ-
unsaturated aldehydes 11 were tested, and the results are
shown in Table 4. The treatment of β,γ-unsaturated aldehydes
( )-11a, ( )-11e, ( )-11i, ( )-11m, and ( )-11o with
Pb(OAc)4 in refluxing benzene afforded the corresponding
allyl acetates ( )-15a, ( )-15e, ( )-15i, ( )-15m, and
( )-15o, respectively, in high yields and short reaction times
(Table 4). With the aim of confirming the stereoselectivity
previously described for the similar oxidative cleavage of
homoallyl alcohols, we carried out the reaction with compound
14c. Unfortunately, it failed and produced a complex mixture.
However, our results are in agreement with the concerted
mechanistic pathway proposed by Preite et al. where a syn
stereoselectivity was observed, with the hydroxymethyl group
of the starting material and the acetyloxy group of rearranged
compounds located at the same side of the molecule.22
Based on our experimental results and the literature
precsedents,22,23 Scheme 4 shows two tentative mechanistic
pathways for the direct oxidative fragmentation of β,γ-
unsaturated aldehydes. In a first step, one of the acetate
groups of Pb(OAc)4 would be exchanged by the oxygen atom
of the β,γ-unsaturated aldehyde to give intermediate I. Then,
the released acetate ion could attack again the more accessible
Pb(IV), with the simultaneous intramolecular nucleophilic
addition of another Pb(IV) acetate group to the complexed
aldehyde to afford intermediate II. The attack of one of the
acetate groups to the olefin through a nine-membered cyclic
transition state would generate the allyl acetate with the
simultaneous removal of Pb(OAc)2 and mixed anhydride
(pathway 1). However, a seven-membered cyclic transition
state cannot be ruled out to give rise to intermediate III, which
would be hydrolyzed to generate the allyl acetate (pathway 2).
CONCLUSIONS
■
In summary, a new alternative strategy for synthesizing a wide
variety of terpenoid precursors is reported. This approach is
based on the reaction of an electrophilic activated alkyl or
benzyl halide with a nucleophilic terpenic α,β-unsaturated
t
aldehyde. BuOK and NaH interact synergistically, enhancing
notably the kinetics and the selectivity for the C-alkylated
derivatives. The β,γ-unsaturated aldehydes resulting from this
alkylation undergo a lead(IV) acetate-mediated oxidative
fragmentation, affording in high yield the corresponding allyl
acetates. The deconjugative α-alkylation of α,β-unsaturated
aldehydes and deformylation reaction described in this paper
could serve as a platform to access in an efficient and simple
manner to a wide variety of terpenoid skeletons.
EXPERIMENTAL SECTION
■
General Procedures. Aldehydes 1, 13a, 13b, and 13e were
obtained from commercial suppliers and used without further
purification. Unless stated otherwise, reactions were performed in
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a
Table 3. Reaction of α,β-Unsaturated Aldehydes with Benzyl Bromides
a
Unless specified, the reaction was carried out with 1.0 mmol of aldehyde, tBuOK (1.1 mmol), NaH (2 mmol), and toluene (20 mL). After 45 min,
b
c
d
alkyl halide (1.5 mmol) was added. Isolated yields. Similar yields were obtained using 1 equiv of 18-crown-6 in the absence of NaH. An
approximate 1:1 epimeric mixture of 14b was deduced from the 13C NMR spectrum.
oven-dried glassware under an argon atmosphere using dry solvents.
Solvents were dried as follows: THF, diethyl ether (Et2O), and
toluene over Na-benzophenone; dichloromethane (DCM) over
CaH2; and acetonitrile over molecular sieves 4 Å. An oil bath was
used as the heating source for the reactions that require heating. Thin-
layer chromatography (TLC) was performed using F254 precoated
plates (0.25 mm) and visualized by UV fluorescence quenching and
phosphomolybdic acid solution in ethanol staining. Flash chromatog-
raphy was performed on silica gel (230−400 mesh). Chromatography
separations were carried out using a conventional column on silica gel
60 (230−400 mesh) using hexanes−AcOEt (AcOEt−hexane) or
diethyl ether−hexane (ether−hexane) mixtures of increasing polarity.
1H and 13C{1H} NMR spectra were recorded at 600, 500, and 400
MHz and at 150, 125, and 100 MHz, respectively. CDCl3 was treated
with K2CO3. Chemical shifts (δ H) are quoted in parts per million
(ppm) referenced to the appropriate residual solvent peak and
spectra were recorded on a spectrometer utilizing a Q-TOF analyzer
and ESI+ ionization.
General Procedure for the Preparation of Alkyl Bromides
10g−i, 10n, and 10p. To a solution of the corresponding
commercially available alcohol (1 mmol) in diethyl ether (10 mL)
was added PBr3 (1 mmol) at 0 °C, and the mixture was stirred at this
temperature, being monitorized by TLC. Then, it was quenched with
water (3 mL) and diluted with Et2O (20 mL). The organic layer was
washed with water (3 × 10 mL), dried with anhydrous Na2SO4, and
filtered, and the solvent was evaporated under reduced pressure to
give the corresponding alkyl bromides 10g−i, 10n, and 10p.
1-(Bromomethyl)-4-methoxybenzene (10g). Yellow oil [yield 537
mg (89%) from 414.6 mg (3 mmol) of (4-methoxyphenyl)methanol].
The spectroscopic data were in agreement with those described in the
literature.15
1-Bromo-5-(bromomethyl)-2,3-dimethoxybenzene (10h). White
solid [yield 790 mg (85%) from 740.8 mg (3 mmol) of (3-bromo-4,5-
dimethoxyphenyl)methanol]. The spectroscopic data were in agree-
ment with those described in the literature.16
5-(Bromomethyl)benzo[d][1,3]dioxole (10i). White solid [yield
619 mg (96%) from 456.2 mg (3 mmol) of benzo[d][1,3]dioxol-5-
ylmethanol]. The spectroscopic data were in agreement with those
described in the literature.17
1
tetramethylsilane. Data for H NMR spectra are reported as follows:
chemical shift (δ ppm) [multiplicity, coupling constant (Hz), and
integration], with the abbreviations s, br s, d, br d, t, dt, dq, sept, and
m denoting the singlet, broad singlet, doublet, broad doublet, triplet,
doublet triplet, doublet quartet, septet, and multiplet, respectively. J =
coupling constant in hertz (Hz). Data for 13C{1H} NMR spectra are
reported in terms of chemical shift relative to Me4Si (δ 0.0), and the
signals were assigned utilizing DEPT experiments and on the basis of
heteronuclear correlations. Infrared (IR) spectra were recorded as
thin films or as solids on an FTIR spectrophotometer with samples
between sodium chloride plates or as potassium bromide pellets and
are reported in frequency of absorption (cm−1). Only selected
absorbances (νmax) are reported. ([α]D) measurements were carried
out in a polarimeter utilizing a 1 dm length cell and CHCl3 as a
solvent. Concentration is expressed in mg/mL. High-resolution mass
5-Bromo-6-(bromomethyl)benzo[d][1,3]dioxole (10n). White
solid [yield 776 mg (88%) from 693.1 mg (3 mmol) of (6-
bromobenzo[d][1,3]dioxol-5-yl)methanol]. The spectroscopic data
were in agreement with those described in the literature.18
4-(Bromomethyl)benzonitrile (10p). White solid [yield 531 mg
(82%) from 439.8 mg (3 mmol) of 4-(hydroxymethyl)benzonitrile].
The spectroscopic data were in agreement with those described in the
literature.19
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a
Table 4. Transformation of β,γ-Unsaturated Aldehydes 11 into Allyl Acetates 15
a
Unless specified, the reaction was carried out with β,γ-unsaturated aldehyde (1 mmol), Pb(OAc)4 (1.1 mmol), and benzene (7 mL) at 80 °C.
b
Isolated yields.
Scheme 4. Tentative Mechanisms for the LTA-Mediated Transformation of β,γ-Unsaturated Aldehyde into Allyl Acetates
Preparation of 1-(Chloromethyl)-3-isopropyl-2-methoxy-
benzene (10j). A round-bottom flask charged with 2-isopropylphe-
nol (10 g, 73 mmol) and p-formaldehyde (4.4 g, 88.8 mmol) in dry
DCM (150 mL) under an argon atmosphere was cooled at −30 °C.
Then, Et2AlCl (25% wt solution in toluene, 47.6 mL, 87.6 mmol) was
added dropwise, and the reaction mixture was allowed to warm to
room temperature. The reaction mixture was stirred for 3 h and was
quenched with water (50 mL). DCM was evaporated under reduced
pressure, and the aqueous layer was extracted with ethyl acetate (3 ×
100 mL). The combined organic solution was dried over anhydrous
sodium sulfate and filtered. The solvent was evaporated under
reduced pressure to give a crude product which was purified by silica
gel column chromatography (20% AcOEt/hexane), affording 2-
(hydroxymethyl)-6-isopropylphenol. Colorless oil (10.97 g, 90%). 1H
NMR (400 MHz, CD3COCD3): δ 8.46 (br s, OH), 7.14 (dd, J = 7.6,
1.7 Hz, 1H), 6.91 (m, 1H), 6.80 (t, J = 7.6 Hz, 1H), 5.23 (br s, OH),
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4.87 (s, 2H), 3.40 (sept, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H).
13C{1H} NMR (100 MHz, CD3COCD3): δ 154.5 (C), 135.9 (C),
125.9 (CH), 125.8 (C), 125.5 (CH), 120.0 (CH), 64.4 (CH2), 27.1
(CH), 22.9 (CH3). IR (film): 3053, 2965, 1456, 1421, 1264, 733, 704
cm−1. HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C10H14O2Na,
189.0891; found, 189.0887.
1190, 1157, 1039, 937, 852, 821 cm−1. HRMS (ESI/TOF) m/z: [M +
H−H2O]+ calcd for C8H7O3, 151.0395; found, 151.0399.
6-(Hydroxymethyl)benzo[d][1,3]dioxol-5-ol (5.7 g, 34 mmol) was
dissolved in acetone (60 mL), and K2CO3 (7.02 g, 50.9 mmol) was
added and stirred at 0 °C for 15 min. Then, (CH3)2SO4 (3.2 mL, 34
mmol) was added and refluxed overnight. The solvent was
evaporated, and water (40 mL) was added and extracted with diethyl
ether (3 × 50 mL). The organic layer was dried over anhydrous
Na2SO4, concentrated, and purified by flash chromatography on silica
gel (30% Et2O/hexane) to give (6-methoxybenzo[d][1,3]dioxol-5-
yl)methanol (4.3 g, 64.5%), which was used immediately.
Spectroscopic data were consistent with those described in the
literature.24
K2CO3 (13.65 g, 99 mmol) was added at 0 °C to a stirred solution
of 2-(hydroxymethyl)-6-isopropylphenol (10.97 g, 66 mmol) in
acetone (120 mL). After 15 min, Me2SO4 (6.3 mL, 66 mmol) was
added and refluxed overnight. Then, water was added (50 mL) and
the solvent was evaporated under reduced pressure. The aqueous
layer was extracted with two portions of diethyl ether (2 × 80 mL),
dried over anhydrous sodium sulfate, and filtered. The solvent was
evaporated under reduced pressure to give a crude product which was
purified by silica gel column chromatography (40% Et2O/hexane),
affording (3-isopropyl-2-methoxyphenyl)methanol. Colorless oil
(8.18 g, 68.9%). 1H NMR (500 MHz, CD3COCD3): δ 7.32 (m,
1H), 7.22 (dd, J = 7.6, 1.7 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 4.71 (d, J
= 5.7 Hz, 2H), 4.12 (t, J = 5.7 Hz, OH), 3.76 (s, 3H), 3.36 (sept, J =
7.0 Hz, 1H), 1.23 (d, J = 7.0 Hz, 6H). 13C{1H} NMR (125 MHz,
CD3COCD3): δ 155.7 (C), 142.0 (C), 135.9 (C), 126.9 (CH), 126.1
(CH), 125.0 (CH), 62.2 (CH2), 59.9 (CH3), 26.7 (CH), 24.1 (CH3).
IR (film): 3053, 2966, 1451, 1428, 1264, 1206, 1096, 733, 703 cm−1.
HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C11H16O2Na,
203.1048; found, 203.1048.
Finally, the general procedure for the preparation of alkyl bromides
was followed to give 5-(bromomethyl)-6-methoxybenzo[d][1,3]-
dioxole (10l). Amorphous yellow solid (4.1 g, 76.8%). 1H NMR
(500 MHz, CD3COCD3): δ 6.90 (s, 1H), 6.69 (s, 1H), 5.96 (s, 2H),
4.60 (s, 2H), 3.85 (s, 3H). 13C{1H} NMR (125 MHz, CD3COCD3):
δ 154.8 (C), 150.4 (C), 142.2 (C), 119.3 (C), 111.1 (CH), 102.8
(CH), 96.1 (CH2), 57.3 (CH2), 31.2 (CH2). IR (film): 3018, 1504,
1466, 1215, 1040, 745 cm−1. HRMS (ESI/TOF) m/z: [M + H−
HBr]+ calcd for C9H9O3, 165.0552; found, 165.0547.
General Procedure for the Deconjugative α-Alkylation of
α,β-Unsaturated Aldehydes with Alkyl Halides. To a solution of
unsaturated aldehydes 1 or 13a−e (1.0 mmol) in anhydrous toluene
(15 mL) were added successively sodium hydride (2 mmol, 60%
dispersion in mineral oil) and potassium tert-butoxide (1.1 mmol),
and the mixture was stirred for 45 min at room temperature. Then, a
solution of the corresponding alkyl halide (1.5 mmol) in toluene (5
mL) was added; the mixture was stirred under an inert atmosphere for
the specified time, and the course of the reaction was monitored by
TLC. When the starting material was consumed, water (10 mL) was
carefully added and the aqueous layer was extracted with two portions
of ethyl acetate (2 × 20 mL). The combined organic solution was
dried over anhydrous Na2SO4 and filtered, and the solvent was
evaporated under reduced pressure to give a crude, which was purified
by silica gel column chromatography. Elution with petroleum ether/
ethyl acetate mixtures yielded compounds ( )-11a−f, ( )-11h−j,
( )-11l−p, 12a, and ( )-14a−e in the yields indicated in Tables
1−3.
Thionyl chloride (1.94 mL, 27 mmol) was slowly added to a
solution of (3-isopropyl-2-methoxyphenyl)methanol (3.2 g, 18 mmol)
and pyridine (1 drop) in dry CH2Cl2 (75 mL) at 0 °C. The reaction
was allowed to warm to room temperature for 5 h and quenched with
water (20 mL). The aqueous phase was extracted with DCM (3 × 50
mL), and the combined organic solutions were washed with brine (80
mL), dried over anhydrous sodium sulfate, and filtered. Evaporation
of the solvent under reduced pressure yielded 1-(chloromethyl)-3-
isopropyl-2-methoxybenzene (10j), which was used without chroma-
1
tography purification. Colorless oil (2.3 g, 65.0%). H NMR (400
MHz, CDCl3): δ 7.33 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H), 4.75 (s, 2H),
3.93 (s, 3H), 3.43 (sept, J = 6.9 Hz, 1H), 1.32 (d, J = 6.9 Hz, 6H).
13C{1H} NMR (125 MHz, CDCl3): δ 155.5 (C), 142.2 (C), 130.7
(C), 128.4 (CH), 127.4 (CH), 124.7 (CH), 62.5 (CH3), 41.3 (CH2),
26.2 (CH), 23.8 (CH3). IR (film): 2972, 1467, 1429, 1264, 1208,
1094, 1049, 1006, 799, 734, 703 cm−1. HRMS (ESI/TOF) m/z: [M−
Cl]+ calcd for C11H15O, 163.1123; found, 163.1127.
Preparation of 1-(Bromomethyl)-3-isopropyl-2-methoxy-
benzene (10k). The general procedure for the preparation of alkyl
bromides was followed using (3-isopropyl-2-methoxyphenyl)-
methanol (3.8 g, 21.1 mmol) to afford 1-(bromomethyl)-3-
isopropyl-2-methoxybenzene (10k), which was further used without
chromatography purification. Yellow oil (4.3 g, 83.7%). 1H NMR
(400 MHz, CD3COCD3): δ 7.29 (m, 2H), 7.10 (t, J = 7.7 Hz, 1H),
4.66 (s, 2H), 3.86 (s, 3H), 3.34 (sept, J = 6.7 Hz, 1H), 1.22 (d, J = 6.7
Hz, 6H). 13C{1H} NMR (125 MHz, CD3COCD3): δ 156.6 (C),
143.0 (C), 132.1 (C), 129.9 (CH), 128.3 (CH), 125.5 (CH), 62.5
(CH3), 29.4 (CH2), 26.9 (CH), 24.1 (CH3). IR (film): 2961, 2861,
2830, 1463, 1428, 1383, 1256, 1222, 1203, 1168, 1004, 795, 763
cm−1. HRMS (ESI/TOF) m/z: [M + H−HBr]+ calcd for C11H15O,
163.1123; found, 163.1126.
Preparation of 5-(Bromomethyl)-6-methoxybenzo[d][1,3]-
dioxole (10l). To sesamol (5 g, 36 mmol) in water (110 mL) at 0 °C
were added formaldehyde (37% wt in water, 5.5 mL, 72 mmol) and
calcium oxide (1.02 g, 18 mmol). After 1 h, saturated aqueous
ammonium chloride was added and the aqueous layer was extracted
with ether (3 × 150 mL), dried over anhydrous Na2SO4,
concentrated, and purified by column chromatography on silica gel
(30% AcOEt/hexane) to give 6-(hydroxymethyl)benzo[d][1,3]-
dioxol-5-ol. Red solid (5.3 g, 82%), mp 183−185 °C. 1H NMR
(500 MHz, CD3COCD3): δ 6.74 (s, 1H), 6.39 (s, 1H), 5.86 (s, 2H),
4.62 (s, 2H). 13C{1H} NMR (125 MHz, CD3COCD3): δ 151.2 (C),
148.2 (C), 141.6 (C), 120.5 (C), 108.5 (CH), 102.0 (CH), 98.9
(CH2), 61.9 (CH2). IR (film): 3500 (br s), 2922, 2853, 1503, 1484,
( )-1-Allyl-2,6,6-trimethylcyclohex-2-ene-1-carbaldehyde
(( )-11a) and (Z)-6-((Allyloxy)methylene)-1,5,5-trimethylcyclohex-
1-ene (12a). To a solution of β-cyclocitral (1) (200 mg, 1.31 mmol)
t
in toluene (25 mL), NaH (105 mg, 2.62 mmol), BuOK (162 mg,
1.45 mmol), and allyl bromide (10a) (236 mg, 1.96 mmol) were
added and stirred for 1 h. Following the same workup used in the
general procedure and after column chromatography, using 2%
EtOAc/hexane, compound 11a was obtained as a colorless oil (209
1
mg, 83%). (( )-11a): H NMR (500 MHz, CDCl3): δ 9.64 (s, 1H),
5.85 (br s, 1H), 5.80 (m, 1H), 5.09 (d, J = 17.2 Hz, 1H), 4.98 (d, J =
9.9 Hz, 1H), 2.54 (m, 2H), 2.11 (br s, 2H), 1.61 (s, 3H), 1.56 (dt, J =
13.5, 6.7 Hz, 1H), 1.46 (dt, J = 13.5, 6.7 Hz, 1H), 1.03 (s, 3H), 0.96
(s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 204.6 (CH), 136.9
(CH), 130.1 (C), 127.9 (CH), 115.8 (CH2), 59.2 (C), 35.7 (C), 33.8
(CH2), 33.3 (CH2), 25.3 (CH3), 25.1 (CH3), 22.7 (CH2), 20.7
(CH3). IR (film): 2916, 1717, 1674, 1447, 1378, 1225, 1051, 1025,
809 cm−1. HRMS (ESI/TOF) m/z: [M + H]+ calcd for C13H21O,
193.1592; found, 193.1595. (12a) (see Table 1, entries 4−7 and 10):
1H NMR (400 MHz, CDCl3): δ 6.07 (s, 1H), 5.93 (ddt, J = 17.2,
10.5, 5.2 Hz, 1H), 5.44 (m, 1H), 5.32 (dq, J = 17.2, 1.7 Hz, 1H), 5.20
(dq, J = 10.5, 1.7 Hz, 1H), 4.27 (dt, J = 5.2, 1.7 Hz, 2H), 2.05 (m,
2H), 1.72 (q, J = 1.7 Hz, 3H), 1.41 (t, J = 6.2 Hz, 2H), 1.21 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3): δ 142.7 (CH), 134.1 (C), 130.6
(C), 124.0 (CH), 123.6 (CH), 116.9 (CH2), 73.2 (CH2), 39.2
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(CH2), 33.2 (C), 27.3 (2× CH3), 22.8 (CH2), 20.6 (CH3). IR (film):
2927, 1676, 1455, 1127, 929 cm−1. HRMS (ESI/TOF) m/z: [M +
H]+ calcd for C13H21O, 193.1592; found,193.1594.
( )-1-Benzyl-2,6,6-trimethylcyclohex-2-ene-1-carbaldehyde
(( )-11e). To a solution of β-cyclocitral (1) (210 mg, 1.38 mmol) in
t
toluene (25 mL), NaH (110 mg, 2.76 mmol), BuOK (170 mg, 1.52
mmol), and benzyl bromide (10e) (354 mg, 2.07 mmol) were added
and stirred for 30 min. Following the same workup used in the general
procedure and after column chromatography, using 3% EtOAc/
hexane, compound 11e was obtained as a colorless oil (310 mg, 93%).
1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 7.25−7.20 (m, 5H),
5.80 (br s, 1H), 3.47 (d, J = 13.4 Hz, 1H), 2.75 (d, J = 13.4 Hz, 1H),
2.25−2.06 (m, 2H), 1.65 (ddd, J = 13.8, 10.5, 7.0 Hz, 1H), 1.24 (s,
3H), 1.21 (m, 1H), 1.09 (s, 3H), 1.04 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 206.4 (CH), 139.5 (C), 131.2 (C), 130.7 (2× CH),
127.9 (2× CH), 126.6 (CH), 126.0 (CH), 61.0 (C), 36.7 (C), 36.2
(CH2), 32.7 (CH2), 25.3 (CH3), 24.0 (CH3), 22.9 (CH2), 21.9
(CH3). IR (film): 2930, 2860, 1727, 1529, 1470, 1369, 1347, 1241,
1017, 997, 962, 802, 755, 725, 672 cm−1. HRMS (ESI/TOF) m/z:
[M−H2 + H]+ calcd for C17H21O, 241.1592; found, 241.1597.
(
)-1,2,6,6-Tetramethylcyclohex-2-ene-1-carbaldehyde
(( )-11b). To a solution of β-cyclocitral (1) (145 mg, 0.95 mmol) in
t
toluene (15 mL), NaH (76 mg, 1.9 mmol), BuOK (123 mg, 1.1
mmol), and iodomethane (220 mg, 1.55 mmol) were added and
stirred for 1 h. Following the same workup used in the general
procedure and after column chromatography, using 5% EtOAc/
hexane, compound 11b was obtained as a colorless oil (147 mg, 93%).
1H NMR (500 MHz, CDCl3): δ 9.60 (s, 1H), 5.74 (br s, 1H), 2.10
(m, 2H), 1.81 (m, 1H), 1.51 (br s, 3H), 1.38 (dt, J = 12.8, 3.3 Hz,
1H), 1.07 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H). 13C{1H} NMR (125
MHz, CDCl3): δ 203.6 (CH), 131.1 (C), 127.0 (CH), 56.5 (C), 34.4
(C), 33.1 (CH2), 24.9 (CH3), 24.2 (CH3), 22.7 (CH2), 19.9 (CH3),
12.6 (CH3). IR (film): 2963, 2874, 1703, 1634, 1366, 1309, 1233,
1180, 1122, 1079, 1032 cm−1. HRMS (ESI/TOF) m/z: [M + H]+
calcd for C11H19O, 167.1436; found,167.1443.
( )-1-(4-Methoxybenzyl)-2,6,6-trimethylcyclohex-2-ene-1-car-
baldehyde (( )-11f). To a solution of β-cyclocitral (1) (250 mg, 1.64
mmol) in toluene (25 mL), NaH (131 mg, 3.28 mmol), tBuOK (362
mg, 1.80 mmol), and 10g (385 mg, 1.91 mmol) were added and
stirred for 30 min. Following the same workup used in the general
procedure and after column chromatography, using 5% EtOAc/
hexane, compound 11f was obtained as a colorless syrup (326 mg,
( )-2,6,6-Trimethyl-1-(3-methylbut-2-en-yl)cyclohex-2-ene-1-
carbaldehyde (( )-11c). To a solution of β-cyclocitral (1) (178 mg,
t
1.17 mmol) in toluene (20 mL), NaH (94 mg, 2.34 mmol), BuOK
(154 mg, 1.3 mmol), and 10c (261 mg, 1.75 mmol) were added and
stirred for 2 h. Following the same workup used in the general
procedure and after column chromatography, using 2% EtOAc/
hexane, compound 11c was obtained as a colorless oil (239 mg, 64%).
1H NMR (500 MHz, CDCl3): δ 9.61 (s, 1H), 5.82 (br s, 1H), 5.06
(m, 1H), 2.42 (m, 2H), 2.08 (m, 2H), 1.65 (d, J = 1.5 Hz, 3H), 1.62
(d, J = 1.5 Hz, 3H), 1.56 (q, J = 1.8 Hz, 3H), 1.48 (t, J = 6.8 Hz, 2H),
0.98 (s, 3H), 0.88 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ
205.0 (CH), 130.9 (C), 130.6 (C), 127.9 (CH), 122.2 (CH), 59.3
(C), 35.5 (C), 33.8 (CH2), 26.9 (CH2), 25.9 (CH3), 25.4 (CH3),
25.3 (CH3), 22.7 (CH2), 20.7 (CH3), 18.0 (CH3). IR (film): 2923,
1715, 1676, 1453, 1381, 1365, 1138, 1035, 754 cm−1. HRMS (ESI/
TOF) m/z: [M + H]+ calcd for C15H25O, 221.1905; found, 221.1909.
1
73%). H NMR (500 MHz, CDCl3): δ 9.71 (s, 1H), 7.07 (d, J = 8.4
Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 5.73 (br s, 1H), 3.75 (s, 3H), 3.31
(d, J = 13.1 Hz, 1H), 2.64 (d, J = 13.1 Hz, 1H), 2.06 (m, 2H), 1.56
(m, 1H), 1.20 (s, 3H), 1.12 (dd, J = 1.8, 6.6 Hz, 1H), 1.01 (s, 3H),
0.95 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 206.4 (C), 157.9
(C), 131.5 (2× CH), 131.4 (C), 131.3 (C), 126.4 (CH), 113.3 (2×
CH), 60.9 (C), 55.1 (CH3), 36.6 (C), 35.3 (CH2), 32.7 (CH2), 25.2
(CH2), 24.0 (CH3), 22.9 (CH3), 21.9 (CH3). IR (film): 2932, 1715,
1610, 1510, 1462, 1245, 1177, 1034, 821 cm−1. HRMS (ESI/TOF)
m/z: [M + H]+ calcd for C18H25O2, 273.1855; found, 273.1846.
( )-1-(3-Bromo-4,5-dimethoxybenzyl)-2,6,6-trimethylcyclohex-
2-enecarbaldehyde (( )-11h). To a solution of β-cyclocitral (1) (177
mg, 1.16 mmol) in toluene (15 mL), NaH (93 mg, 2.32 mmol),
tBuOK (143 mg, 1.28 mmol), and 10h (540 mg, 1.74 mmol) were
( )-2,6,6-Trimethyl-1-(prop-2-yn-1-yl)cyclohex-2-ene-1-carbal-
dehyde (( )-11d). To a solution of β-cyclocitral (1) (230 mg, 1.51
mmol) in toluene (25 mL), NaH (121 mg, 3.02 mmol), tBuOK (186
mg, 1.66 mmol), and propargyl chloride 10d (169 mg, 2.27 mmol)
were added and stirred for 2 h. Following the same workup used in
the general procedure and after column chromatography, using 5%
EtOAc/hexane, compound 11d was obtained as a colorless oil (192
added and stirred for 1 h. Following the same workup used in the
general procedure and after column chromatography, using 7%
EtOAc/hexane, compound 11h was obtained as a colorless syrup
1
(389 mg, 88%). H NMR (500 MHz, CDCl3): δ 9.67 (s, 1H), 6.92
1
mg, 67%). H NMR (500 MHz, CDCl3): δ 9.57 (s, 1H), 5.90 (br s,
(d, J = 1.9 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 5.76 (br s, 1H), 3.78 (s,
6H), 3.29 (d, J = 13.4 Hz, 1H), 2.53 (d, J = 13.4 Hz, 1H), 2.12 (m,
2H), 1.57 (ddd, J = 13.8, 10.4, 7.0 Hz, 1H), 1.20 (s, 3H), 1.19−1.10
(m, 1H), 1.02 (s, 3H), 0.92 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3): δ 205.9 (CH), 153.0 (C), 144.8 (C), 136.7 (C), 131.0 (C),
126.6 (2× CH), 116.8 (C), 114.3 (CH), 61.0 (CH3), 60.6 (CH3),
56.0 (C), 36.7 (C), 35.7 (CH2), 32.6 (CH2), 25.2 (CH3), 23.8
(CH3), 22.8 (CH2), 22.0 (CH3). IR (film): 2947, 1715, 1595, 1565,
1489, 1463, 1429, 1414, 1313, 1277, 1214, 1184, 1142, 1047, 1001,
1H), 2.75 (dd, J = 17.8, 2.7 Hz, 1H), 2.48 (dd, J = 17.8, 2.7 Hz, 1H),
2.12 (m, 2H), 1.95 (t, J = 2.7 Hz, 1H), 1.64 (s, 3H), 1.76−1.52 (m,
2H), 1.06 (s, 3H), 1.00 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3):
δ 201.8 (CH), 129.0 (CH), 125.4 (C), 83.4 (C), 70.6 (CH), 63.7
(C), 59.2 (CH2), 35.4 (C), 33.8 (CH2), 25.4 (CH3), 22.6 (CH2),
20.1 (CH3), 17.4 (CH3). IR (film): 3324, 2919, 2126, 1715, 1673,
1448, 1374, 1224, 1053, 1032 cm−1. HRMS (ESI/TOF) m/z: [M +
Na]+ calcd for C13H18ONa, 213.1255; found, 213.1249.
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879 cm−1. HRMS (ESI/TOF) m/z: [M + H]+ calcd for C19H26O3Br,
381.1065; found, 381.1056.
(s, 1H), 3.64 (s, 3H), 3.22 (d, J = 13.5 Hz, 1H), 2.87 (d, J = 13.5 Hz,
1H), 2.05 (m, 2H), 1.82 (m, 1H), 1.15 (s, 3H), 1.14−1.10 (m, 1H),
0.97 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ 206.6 (CH),
152.8 (C), 146.3 (C), 140.6 (C), 131.5 (C), 125.8 (CH), 120.0 (C),
111.6 (CH), 100.8 (CH), 94.3 (CH2), 60.5 (C), 56.0 (CH3), 36.7
(C), 32.7 (CH2), 30.6 (CH2), 25.3 (CH3), 23.7 (CH3), 22.9 (CH2),
21.9 (CH3). IR (film): 2949, 2855, 1715, 1503, 1483, 1464, 1190,
1156, 1037, 1006, 935, 861, 824, 759 cm−1. HRMS (ESI/TOF) m/z:
[M + H]+ calcd for C19H25O4, 317.1753; found, 317.1758.
( )-1-(Benzo[d][1,3]dioxol-5-ylmethyl)-2,6,6-trimethylcyclohex-
2-ene-1-carbaldehyde (( )-11i). To a solution of β-cyclocitral (1)
(300 mg, 1.97 mmol) in toluene (25 mL), NaH (158 mg, 3.94
mmol), tBuOK (244 mg, 2.18 mmol), and 10i (634 mg, 2.95 mmol)
were added and stirred for 1 h. Following the same workup used in
the general procedure and after column chromatography, using 5%
EtOAc/hexane, compound 11i was obtained as a white solid (501 mg,
89%). 1H NMR (500 MHz, CDCl3): δ 9.73 (s, 1H), 6.70 (br s, 1H),
6.67 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.89 (s, 2H), 5.76
(br s, 1H), 3.34 (d, J = 13.6 Hz, 1H), 2.60 (d, J = 13.6 Hz, 1H),
2.02−2.24 (m, 2H), 1.64 (m, 1H), 1.25 (s, 3H), 1.17 (m, 1H), 1.06
(s, 3H), 0.96 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 206.3
(CH), 147.2 (C), 145.8 (C), 133.1 (C), 131.3 (C), 126.5 (CH),
123.6 (CH), 111.0 (CH), 107.8 (CH), 100.7 (CH2), 61.0 (C), 36.7
(C), 36.0 (CH2), 32.7 (CH2), 25.2 (CH3), 23.9 (CH3), 22.9 (CH2),
22.06 (CH3). IR (film): 2947, 1718, 1530, 1350, 1261, 1082, 1028,
806, 723, 687 cm−1. HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C18H23O3, 287.1647; found, 287.1651.
( )-1-(2-Bromobenzyl)-2,6,6-trimethylcyclohex-2-ene-1-carbal-
dehyde (( )-11m). To a solution of β-cyclocitral (1) (310 mg, 2.04
mmol) in toluene (25 mL), NaH (163 mg, 4.08 mmol), tBuOK (251
mg, 2.24 mmol), and 10m (765 mg, 3.06 mmol) were added and
stirred for 2 h. Following the same workup used in the general
procedure and after column chromatography, using 3% EtOAc/
hexane, compound 11m was obtained as a colorless oil (602 mg,
92%). 1H NMR (400 MHz, CDCl3): δ 9.70 (s, 1H), 7.45 (dd, J = 7.5,
1.4 Hz, 1H), 7.35 (dd, J = 7.7, 1.8 Hz, 1H), 7.12 (td, J = 7.5, 1.4 Hz,
1H), 6.98 (td, J = 7.7, 1.8 Hz, 1H), 5.67 (br s, 1H), 3.59 (d, J = 13.3
Hz, 1H), 3.06 (d, J = 13.3 Hz, 1H), 2.21−2.11 (m, 2H), 2.10−1.99
(m, 1H), 1.25−1.17 (m, 1H), 1.05 (s, 3H), 0.98 (s, 3H), 0.94 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 206.6 (CH), 139.3 (C), 132.9
(CH), 132.8 (CH), 129.9 (C), 127.74 (CH), 127.70 (CH), 127.0
(CH), 126.1 (C), 60.9 (C), 37.4 (C), 35.7 (CH2), 32.6 (CH2), 25.3
(CH3), 23.3 (CH3), 23.2 (CH2), 21.9 (CH3). IR (film): 2950, 2875,
2834, 1716, 1470, 1438, 1387, 1367, 1025, 873, 765, 747, 659, 569
cm−1. HRMS (ESI/TOF) m/z: [M + Na]+ calcd for C17H22OBrNa,
321.0854; found, 321.0862.
( )-1-(3-Isopropyl-2-methoxybenzyl)-2,6,6-trimethylcyclohex-2-
ene-1-carbaldehyde (( )-11j). To a solution of β-cyclocitral (1)
(112 mg, 0.74 mmol) in toluene (12 mL), NaH (59 mg, 1.48 mmol),
tBuOK (244 mg, 0.81 mmol), and 10k (270 mg, 1.11 mmol) were
added and stirred for 45 min. Following the same workup used in the
general procedure and after column chromatography, using 5%
EtOAc/hexane, compound 11j was obtained as a white solid (162 mg,
1
70%). H NMR (500 MHz, CDCl3): δ 9.75 (s, 1H), 7.07 (m, 1H),
7.02 (dd, J = 7.6, 1.7 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 5.63 (br s,
1H), 3.69 (s, 3H), 3.30 (d, J = 13.6 Hz, 1H), 3.26 (m, 1H), 2.94 (d, J
= 13.6 Hz, 1H), 2.06 (m, 2H), 1.66 (m, 1H), 1.23 (m, 1H), 1.19 (d, J
= 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.14 (br s, 3H), 0.99 (s, 3H),
0.98 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 206.5 (CH),
156.3 (C), 141.8 (C), 132.4 (C), 131.3 (C), 129.7 (CH), 126.7
(CH), 124.7 (CH), 123.8 (CH), 61.5 (CH3), 60.8 (C), 36.8 (C),
32.9 (CH2), 30.2 (CH2), 26.5 (CH), 25.3 (CH3), 24.1 (CH3), 23.9
(CH3), 23.6 (CH3), 22.9 (CH3), 21.6 (CH3). IR (film): 2960, 2864,
1719, 1689, 1458, 1427, 1384, 1254, 1201, 1165, 1060, 1010, 796,
765, 568 cm−1. HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C21H31O2, 315.2324; found, 315.2326.
( )-1-((6-Bromobenzo[d][1,3]dioxol-5-yl)methyl)-2,6,6-trime-
thylcyclohex-2-ene-1-carbaldehyde (( )-11n). To a solution of β-
cyclocitral (1) (110 mg, 0.72 mmol) in toluene (12 mL), NaH (58
mg, 1.44 mmol), tBuOK (89 mg, 0.79 mmol), and 10n (317 mg, 1.08
mmol) were added and stirred for 2 h. Following the same workup
used in the general procedure and after column chromatography,
using 5% EtOAc/hexane, compound 11n was obtained as a white
1
solid (223 mg, 85%). H NMR (400 MHz, CDCl3): δ 9.68 (s, 1H),
6.90 (s, 1H), 6.86 (s, 1H), 5.89 (s, 2H), 5.68 (br s, 1H), 3.45 (d, J =
13.4 Hz, 1H), 2.96 (d, J = 13.4 Hz, 1H), 2.14 (m, 2H), 2.10−1.96 (m,
1H), 1.28−1.15 (m, 1H), 1.10 (s, 3H), 1.04 (s, 3H), 0.91 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 206.7 (CH), 147.0 (C), 146.7
(C), 132.1 (C), 129.9 (C), 127.6 (CH), 116.0 (C), 112.6 (CH),
112.0 (CH), 101.5 (CH2), 60.8 (C), 37.3 (C), 35.7 (CH2), 32.6
(CH2), 25.3 (CH3), 23.3 (CH3), 23.1 (CH2), 22.2 (CH3). IR (film):
2921, 1715, 1502, 1474, 1407, 1388, 1367, 1267, 1227, 1167, 1113,
1037, 936, 873, 831, 756, 570 cm−1. HRMS (ESI/TOF) m/z: [M +
H]+ calcd for C18H22O3Br, 365.0752; found, 365.0750.
( )-1-((6-Methoxybenzo[d][1,3]dioxol-5-yl)methyl)-2,6,6-trime-
thylcyclohex-2-ene-1-carbaldehyde (( )-11l). To a solution of β-
cyclocitral (1) (147 mg, 0.97 mmol) in toluene (15 mL), NaH (78
mg, 1.94 mmol), tBuOK (120 mg, 1.07 mmol), and 10l (355 mg, 1.45
mmol) were added and stirred for 90 min. Following the same
workup used in the general procedure and after column
chromatography, using 5% EtOAc/hexane, compound 11l was
1
obtained as a colorless syrup (239 mg, 78%). H NMR (500 MHz,
( )-2,6,6-Trimethyl-1-(3-nitrobenzyl)cyclohex-2-ene-1-carbalde-
hyde (( )-11o). To a solution of β-cyclocitral (1) (192 mg, 1.26
CDCl3): δ 9.72 (s, 1H), 6.67 (s, 1H), 6.40 (s, 1H), 5.83 (s, 2H), 5.59
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t
mmol) in toluene (15 mL), NaH (101 mg, 2.52 mmol), tBuOK (156
mg, 1.39 mmol), and 10o (408 mg, 1.89 mmol) were added and
stirred for 10 min. Following the same workup used in the general
procedure and after column chromatography, using 8% EtOAc/
hexane, compound 11o was obtained as a yellow syrup (289 mg,
toluene (15 mL), NaH (80 mg, 2 mmol), BuOK (123 mg, 1.1
mmol), and benzyl bromide (10e) (256 mg, 1.5 mmol) were added
and stirred for 20 min. Following the same workup used in the general
procedure and after column chromatography, using 5% EtOAc/
hexane, compound 14b was obtained as a colorless oil (223 mg, 93%,
1
1
80%). H NMR (600 MHz, CDCl3): δ 9.69 (s, 1H), 8.02 (m, 2H),
approx. 1:1 diasteroisomeric ratio). H NMR (400 MHz, CDCl3): δ
7.55 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 5.81 (s, 1H), 3.49
(d, J = 13.3 Hz, 1H), 2.73 (d, J = 13.3 Hz, 1H), 2.23−2.06 (m, 2H),
1.57 (ddd, J = 14.0, 10.6, 7.0 Hz, 1H), 1.20 (ddd, J = 14.0, 7.0, 2.3 Hz,
1H), 1.13 (s, 3H), 1.07 (s, 3H), 0.96 (s, 3H). 13C{1H} NMR (150
MHz, CDCl3): δ 205.6 (CH), 148.0 (C), 141.7 (C), 137.0 (CH),
130.0 (C), 128.7 (CH), 127.5 (CH), 125.4 (CH), 121.2 (CH), 61.1
(C), 36.8 (C), 35.8 (CH2), 32.6 (CH2), 25.3 (CH3), 23.9 (CH3),
22.8 (CH2), 22.0 (CH3). IR (film): 2926, 1716, 1527, 1348, 1261,
1222, 1061, 1029, 804, 756, 723, 687, 672 cm−1. HRMS (ESI/TOF)
m/z: [M + H]+ calcd for C17H22NO3, 288.1600; found, 288.1608.
9.56 (s, 2H), 7.39−7.10 (m, 10H), 5.91−5.86 (m, 2H), 5.68 (br s,
1H), 5.66 (br s, 1H), 4.77 (br s, 1H), 4.73 (br s, 1H), 4.71 (br s, 1H),
4.44 (br s, 1H), 2.91−2.87 (m, 4H), 2.68 (m, 2H), 2.01−1.98 (m,
2H), 1.81−1.61 (m, 4H), 1.69 (s, 6H), 1.55−1.42 (m, 2H). Major
isomer: 13C{1H} NMR (125 MHz, CDCl3): δ 202.7 (CH), 147.8
(C), 136.3 (C), 135.1 (CH), 130.3 (2× CH), 128.1 (2× CH), 127.0
(CH), 126.6 (CH), 110.9 (CH2), 52.1 (C), 42.9 (CH), 42.6 (CH2),
27.1 (CH2), 24.7 (CH2), 20.6 (CH3). Minor isomer: 13C{1H} NMR
(125 MHz, CDCl3): δ 203.0 (CH), 147.1 (C), 136.3 (C), 134.3
(CH), 130.4 (2× CH), 128.1 (2× CH), 126.9 (CH), 126.6 (CH),
111.6 (CH2), 52.3 (C), 42.1 (CH2), 41.8 (CH), 24.7 (CH2), 23.3
(CH2), 21.4 (CH3). IR (film): 2936, 1720, 1644, 1496, 1453, 1374,
892, 831, 762, 735, 700 cm−1. HRMS (ESI/TOF) m/z: [M + H]+
calcd for C17H21O, 241.1592; found, 241.1601.
( )-4-((1-Formyl-2,6,6-trimethylcyclohex-2-en-1-yl)methyl)-
benzonitrile (( )-11p). To a solution of β-cyclocitral (1) (166 mg,
t
1.09 mmol) in toluene (15 mL), NaH (87 mg, 2.18 mmol), BuOK
(135 mg, 1.2 mmol), and 10p (320 mg, 1.63 mmol) were added and
stirred for 15 min. Following the same workup used in the general
procedure and after column chromatography, using 5% EtOAc/
hexane, compound 11p was obtained as a yellow syrup (224 mg,
77%). 1H NMR (500 MHz, CDCl3): δ 9.67 (s, 1H), 7.46 (d, J = 8.4
Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 5.76 (s, 1H), 3.43 (d, J = 13.2 Hz,
1H), 2.66 (d, J = 13.2 Hz, 1H), 2.20−2.03 (m, 2H), 1.64−1.51 (m,
1H), 1.19 (ddd, J = 13.9, 6.8, 2.2 Hz, 1H), 1.09 (s, 3H), 1.04 (s, 3H),
0.92 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 205.4 (CH),
145.5 (C), 131.6 (2× CH), 131.5 (2× CH), 130.2 (C), 127.3 (CH),
119.0 (C), 109.9 (C), 61.3 (C), 36.8 (C), 36.4 (CH2), 32.6 (CH2),
25.2 (CH3), 23.8 (CH3), 22.8 (CH2), 22.0 (CH3). IR (film): 2962,
2228, 1719, 1606, 1365, 1174, 1018, 816, 754, 816, 754 cm−1. HRMS
(ESI/TOF) m/z: [M-CH2+H]+ calcd for C17H20NO, 254.1545;
found, 254.1543.
(1S,4aS,8aS)-1-((6-Bromobenzo[d][1,3]dioxol-5-yl)methyl)-
2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalene-1-
carbaldehyde (14c). To a solution of 13c (76 mg, 0.34 mmol) in
t
toluene (10 mL), NaH (30 mg, 0.75 mmol), BuOK (43 mg, 0.38
mmol), and 10n (153 mg, 0.52 mmol) were added and stirred for 2 h.
Following the same workup used in the general procedure and after
column chromatography, using 5% EtOAc/hexane, compound 14c
was obtained as a colorless syrup (128 mg, 86%). [α]2D0 −3.0 (c 0.6,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.77 (s, 1H), 6.90 (s, 1H),
6.75 (s, 1H), 5.89 (s, 2H), 5.70 (br s, 1H), 3.52 (d, J = 13.3 Hz, 1H),
3.01 (d, J = 13.3 Hz, 1H), 2.19−2.12 (m, 1H), 2.01−1.91 (m, 1H),
1.59−1.42 (m, 5H), 1.26−1.16 (m, 2H), 1.10 (s, 3H), 1.07 (s, 3H),
0.96 (s, 3H), 0.93 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
(ppm) 207.9 (CH), 147.0 (C), 146.7 (C), 132.2 (C), 129.5 (C),
128.4 (CH), 116.1 (C), 112.6 (CH), 112.1 (CH), 101.5 (CH2), 63.0
(C), 42.3 (C), 42.0 (CH2), 41.8 (CH), 36.0 (CH2), 33.9 (CH3), 33.4
(CH2), 33.3 (C), 24.7 (CH2), 22.3 (CH3), 22.0 (CH3), 18.2 (CH2),
17.5 (CH3). IR (film): 2949, 1716, 1672, 1503, 1478, 1367, 1228,
1114, 1039, 936, 882, 841, 655, 567 cm−1. HRMS (ESI/TOF) m/z:
[M + H]+ calcd for C23H30O3Br, 433.1378; found, 433.1365.
( )-1-Benzylcyclohex-2-enecarbaldehyde (( )-14a). To a solu-
tion of 13a (130 mg, 1.18 mmol) in toluene (15 mL), NaH (95 mg,
2.36 mmol), tBuOK (145 mg, 1.3 mmol), and benzyl bromide (10e)
(303 mg, 1.77 mmol) were added and stirred for 20 min. Following
the same workup used in the general procedure and after column
chromatography, using 5% EtOAc/hexane, compound 14a was
obtained as a colorless oil (224 mg, 95%). 1H NMR (500 MHz,
CDCl3): δ 9.55 (s, 1H), 7.30−7.10 (m, 5H), 6.01 (dt, J = 10.0, 3.8
Hz, 1H), 5.58 (d, J = 10.0 Hz, 1H), 2.90 (s, 2H), 2.05−1.88 (m, 3H),
1.64−1.52 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 203.3
(CH), 136.5 (C), 132.0 (CH), 130.3 (2× CH), 128.1 (2× CH),
126.5 (CH), 126.3 (CH), 52.0 (C), 42.6 (CH2), 27.9 (CH2), 24.8
(CH2), 18.8 (CH2). IR (film): 3027, 2934, 2867, 2835, 1722, 1495,
1453, 1069, 762, 729, 701, 679 cm−1. HRMS (ESI/TOF) m/z: [M +
H]+ calcd for C14H17O, 201.1279; found, 201.1282.
(1S,4aS,5S,8aR)-Methyl 5-((6-Bromobenzo[d][1,3]dioxol-5-yl)-
methyl)-5-formyl-1,4a,6-trimethyl-1,2,3,4,4a,5,8,8a-octahydro-
naphthalene-1-carboxylate (14d). To a solution of 13d (83 mg,
t
0.31 mmol) in toluene (10 mL), NaH (26 mg, 0.65 mmol), BuOK
(39 mg, 0.35 mmol), and 10n (138 mg, 0.47 mmol) were added and
stirred for 2 h. Following the same workup used in the general
procedure and after column chromatography, using 5% EtOAc/
hexane, compound 14d was obtained as a colorless syrup (133 mg,
90%). [α]2D0 −26.0 (c 0.3, CHCl3). H NMR (400 MHz, CDCl3): δ
1
9.74 (s, 1H), 6.89 (s, 1H), 6.76 (s, 1H), 5.88 (s, 2H), 5.68 (s, 1H),
3.64 (s, 3H), 3.49 (d, J = 13.3 Hz, 1H), 2.94 (d, J = 13.3 Hz, 1H),
2.71−2.56 (m, 1H), 2.41−2.29 (m, 1H), 2.22−2.06 (m, 2H), 1.90−
(1R,4S) and (1S,4S)-1-Benzyl-4-(prop-1-en-2-yl)cyclohex-2-ene-
carbaldehyde (14b). To a solution of 13b (150 mg, 1 mmol) in
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1.41 (m, 4H), 1.23 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H), 0.87−0.78 (m,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 207.2 (CH), 177.7 (C),
147.0 (C), 146.7 (C), 131.8 (C), 128.3 (C), 128.3 (CH), 116.1 (C),
112.6 (CH), 112.1 (CH), 101.5 (CH2), 62.3 (C), 51.4 (CH3), 44.3
(CH), 44.1 (C), 41.8 (C), 38.0 (CH2), 35.9 (CH2), 33.0 (CH2), 29.1
(CH3), 25.3 (CH2), 21.8 (CH3), 19.0 (CH2), 16.4 (CH3). IR (film):
2949, 1715, 1503, 1477, 1407, 1380, 1226, 1166, 1143, 1113, 1038,
984, 934, 910, 874, 841, 771, 730, 652, 566 cm−1. HRMS (ESI/TOF)
m/z: [M + H]+ calcd for C24H30O5Br, 477.1277; found, 477.1276.
1H), 4.81 (m, 1H), 2.76 (d, J = 5.9 Hz, 2H), 1.99 (s, 3H), 1.84 (m,
1H), 1.64 (m, 1H), 1.54 (m, 1H), 1.51 (s, 3H), 1.31 (ddd, J = 13.3,
7.0, 3.2 Hz, 1H), 0.97 (s, 3H), 0.91 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 171.2 (C), 141.7 (C), 136.5 (CH), 126.8 (C), 114.9
(CH2), 72.7 (CH), 35.3 (C), 34.8 (CH2), 32.8 (CH2), 28.2 (CH3),
26.8 (CH3), 25.4 (CH2), 21.4 (CH3), 16.6 (CH3). IR (film): 1719,
1634, 1469, 1370, 1244, 1174, 1145, 1017, 994, 961, 910, 865 cm−1.
HRMS (ESI/TOF) m/z: [M−OAc]+ calcd for C12H19, 163.1487;
found, 163.1483.
( )-1-Benzyl-2,6,6-trimethylcyclohexa-2,4-diene-1-carbaldehyde
(
)-3-Benzyl-2,4,4-trimethylcyclohex-2-en-1-yl Acetate
(( )-14e). To a solution of 13e (163 mg, 1.08 mmol) in toluene (15
t
(( )-15e). To a solution of 11e (143 mg, 0.59 mmol) in benzene
(4 mL) was added Pb(OAc)4 (288 mg, 0.65 mmol), and the mixture
was heated at 80 °C for 2 h. Following the same workup used in the
general procedure, 15e (114 mg, 71%) was obtained as a colorless
syrup after column chromatography using 5% EtOAc/hexane. 1H
NMR (400 MHz, CDCl3): δ 7.29−7.23 (m, 2H), 7.19−7.10 (m, 3H),
5.27 (d, J = 4.8 Hz, 1H), 3.50 (s, 2H), 2.09 (s, 3H), 1.96 (dddd, J =
14.3, 11.4, 4.8, 3.2 Hz, 1H), 1.75 (dddd, J = 14.3, 7.2, 4.8, 3.2 Hz,
1H), 1.66 (ddd, J = 13.8, 11.4, 3.2 Hz, 1H), 1.54 (s, 3H), 1.40 (ddd, J
= 13.8, 7.2, 3.2 Hz, 1H), 0.96 (s, 3H), 0.93 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 171.2 (C), 141.8 (C), 140.2 (C), 128.2 (2×
CH), 128.0 (C), 127.8 (2× CH), 125.5 (CH), 72.6 (CH), 35.4 (C),
35.0 (CH2), 34.1 (CH2), 28.5 (CH3), 27.2 (CH3), 25.5 (CH2), 21.5
(CH3), 17.3 (CH3). IR (film): 2957, 2935, 2860, 1732, 1494, 1452,
1370, 1243, 1018, 961, 715 cm−1. HRMS (ESI/TOF) m/z: [M +
Na]+ calcd for C18H24O2Na, 295.1674; found, 295.1679.
mL), NaH (84 mg, 2.1 mmol), BuOK (134 mg, 1.19 mmol), and
benzyl bromide (10e) (277 mg, 1.62 mmol) were added and stirred
for 3 h. Following the same workup used in the general procedure and
after column chromatography, using 5% EtOAc/hexane, compound
14e was obtained as a colorless syrup (188 mg, 72%). 1H NMR (500
MHz, CDCl3): δ 9.98 (s, 1H), 7.18−7.10 (m, 5H), 5.90 (m, 2H),
5.35 (m, 1H), 3.27 (d, J = 12.8 Hz, 1H), 2.87 (d, J = 12.8 Hz, 1H),
1.14 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3): δ 206.8 (C), 138.8 (C), 135.8 (CH), 135.1 (C), 130.9
(CH), 127.6 (CH), 125.9 (CH), 121.9 (CH), 121.6 (CH), 61.8 (C),
40.1 (C), 30.8 (CH2), 22.5 (CH3), 22.4 (CH3), 22.0 (CH3). IR
(film): 3028, 2961, 1718, 1494, 1453, 1362, 1076, 726, 700 cm−1.
HRMS (ESI/TOF) m/z: [M−CH3]+ calcd for C16H19O, 227.1436;
found, 227.1443.
Preparation of (4aS,8aS)-2,5,5,8a-Tetramethyl-
3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde
(13c). Compound 13c was prepared following the procedure
described in the literature. The spectroscopic data were in agreement
with those described in the literature.20
Preparation of (1S,4aS,8aR)-Methyl 5-Formyl-1,4a,6-tri-
methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalene-1-carboxy-
late (13d). Compound 13d was prepared following the procedure
described in the literature. The spectroscopic data were in agreement
with those described in the literature.21
( )-3-(Benzo[d][1,3]dioxol-5-ylmethyl)-2,4,4-trimethylcyclohex-
2-en-1-yl Acetate (( )-15i). To a solution of 11i (204 mg, 0.71
mmol) in benzene (5 mL) was added Pb(OAc)4 (348 mg, 0.78
mmol), and the mixture was heated at 80 °C for 50 min. Following
the same workup used in the general procedure, 15i (206 mg, 92%)
was obtained as an amorphous solid after column chromatography
using 3% EtOAc/hexane. 1H NMR (400 MHz, CDCl3): δ 6.71 (d, J =
8.0 Hz, 1H), 6.63 (br s, 1H), 6.59 (br d, J = 8.0 Hz, 1H), 5.91 (s,
2H), 5.25 (t, J = 4.7 Hz, 1H), 3.43 (d, J = 16.3 Hz, 1H), 3.39 (d, J =
16.3 Hz, 1H), 2.09 (s, 3H), 1.94 (m, 1H), 1.76 (m, 1H), 1.65 (ddd, J
= 12.3, 12.3, 3.1, 1H), 1.55 (s, 3H), 1.41 (ddd, J = 13.1, 7.1 3.2 Hz,
1H), 0.95 (s, 3H), 0.93 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 171.2 (C), 147.6 (C), 145.4 (C), 142.0 (CH), 134.1 (C), 128.1
(C), 120.6 (CH), 108.3 (CH), 108.1 (CH), 100.7 (CH2), 72.5 (C),
35.4 (C), 34.9 (CH2), 33.7 (CH2), 28.5 (CH3), 27.2 (CH3), 25.5
(CH2), 21.4 (CH3), 17.3 (CH3). IR (film): 1723, 1605, 1495, 1483,
1434, 1365, 1226, 1344, 1227, 1175, 1146, 1121, 1091, 1037, 1017,
923, 875, 793 cm−1. HRMS (ESI/TOF) m/z: [M + H]+ calcd for
C19H25O4, 317.1753; found, 317.1751.
General Procedure for Deformylation of β,γ-Unsaturated
Aldehydes ( )-11a, ( )-11e, ( )-11i, ( )-11m, and ( )-11o
with Pb(OAc)4. To a solution of the corresponding β,γ-unsaturated
aldehydes ( )-11a, ( )-11e, ( )-11i, ( )-11m, and ( )-11o (1
mmol) in dry benzene (7 mL) was added Pb(OAc)4 (1.1 mmol), and
the solution was heated at 80 °C for 10 min−2 h. Then, the reaction
mixture was quenched with 5% Na2SO3 (5 mL), and the aqueous
layer was extracted with two portions of ethyl acetate (2 × 15 mL).
The combined organic solution was washed with brine (10 mL), dried
over anhydrous sodium sulfate, and filtered. The solvent was
evaporated under reduced pressure to give a crude product which
was purified by silica gel column chromatography (petroleum ether/
ethyl acetate), affording the corresponding allyl acetates ( )-15a,
( )-15e, ( )-15i, ( )-15m, and ( )-15o in the yields shown in
Table 4.
( )-3-Allyl-2,4,4-trimethylcyclohex-2-en-1-yl Acetate (( )-15a).
To a solution of 11a (194 mg, 1.01 mmol) in benzene (7 mL) was
added Pb(OAc)4 (492 mg, 1.11 mmol), and the mixture was heated at
80 °C for 7 min. Following the same workup used in the general
procedure, 15a (204 mg, 91%) was obtained as a colorless syrup after
column chromatography using 3% EtOAc/hexane. 1H NMR (500
MHz, CDCl3): δ 5.68 (m, 1H), 5.09 (t, J = 4.6 Hz, 1H), 4.95 (m,
( )-3-(2-Bromobenzyl)-2,4,4-trimethylcyclohex-2-en-1-yl Ace-
tate (( )-15m). To a solution of 11m (53 mg, 0.16 mmol) in
benzene (1 mL) was added Pb(OAc)4 (80 mg, 0.18 mmol), and the
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mixture was heated at 80 °C for 1 h. Following the same workup used
in the general procedure, 15m (48 mg, 83%) was obtained as a
colorless syrup after column chromatography using 5% EtOAc/
Fermín Jiménez − Departamento de Química Orgánica,
Facultad de Ciencias, Instituto de Biotecnología, Universidad
de Granada, 18071 Granada, Spain
Ramón Alvarez-Manzaneda − Area de Química Orgánica,
Departamento de Química y Física, Universidad de Almería,
04120 Almería, Spain
Enrique Alvarez-Manzaneda − Departamento de Química
Orgánica, Facultad de Ciencias, Instituto de Biotecnología,
Universidad de Granada, 18071 Granada, Spain;
orcid.org/0000-0002-3659-4475
1
hexane. H NMR (500 MHz, CDCl3): δ 7.54 (dd, J = 7.8, 1.3 Hz,
́
1H), 7.22 (td, J = 7.5, 1.3 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.04 (t, J
= 7.5 Hz, 1H), 5.28 (m, 1H), 3.48 (d, J = 17.5 Hz, 1H), 3.44 (d, J =
17.5 Hz, 1H), 2.09 (s, 3H), 1.98 (dddd, J = 14.2, 11.3, 5.0, 3.2 Hz,
1H), 1.80 (dddd, J = 14.2, 7.5, 4.6, 3.2 Hz, 1H), 1.69 (ddd, J = 13.4,
11.3, 3.2 Hz, 1H), 1.48−1.44 (m, 1H), 1.46 (s, 3H), 0.95 (s, 6H).
13C{1H} NMR (125 MHz, CDCl3): δ 171.1 (C), 141.1 (C), 138.7
(C), 132.5 (CH), 129.1 (C), 128.7 (CH), 127.3 (CH), 127.1 (CH),
125.1 (C), 72.4 (CH), 35.3 (C), 34.8 (CH2), 34.7 (CH2), 28.2
(CH3), 27.0 (CH3), 25.4 (CH2), 21.4 (CH3), 17.1 (CH3). IR (film):
1723, 1438, 1387, 1231, 1155, 1095, 1076, 1025, 877, 770 cm−1.
HRMS (ESI/TOF) m/z: [M−OAc]+ calcd for C16H20Br, 291.0748;
found, 291.0754.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00560
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Spanish Ministry of Economy and
Competitiveness (Project CTQ2014-56611-R/BQU) for
financial support and for the predoctoral fellowship granted
to F.J. and the Regional Government of Andalucia (Project
P11-CTS-7651) for financial support and assistance provided
to the FQM-348 group. J.M.B.A. and M.J.D.P. thank the
University of Cádiz for financial support (Ayudas de
Investigación Plan Propio).
( )-2,4,4-Trimethyl-3-(3-nitrobenzyl)cyclohex-2-en-1-yl Acetate
(( )-15o). To a solution of 11o (67 mg, 0.23 mmol) in benzene (2
mL) was added Pb(OAc)4 (115 mg, 0.26 mmol), and the mixture was
heated at 80 °C for 90 min. Following the same workup used in the
general procedure, 15o (62 mg, 85%) was obtained as a colorless
syrup after column chromatography using 3% EtOAc/hexane. 1H
NMR (400 MHz, CDCl3): δ 8.00 (m, 2H), 7.44 (m, 2H), 5.27 (t, J =
4.7 Hz, 1H), 3.60 (d, J = 17.2 Hz, 1H), 3.57 (d, J = 17.2 Hz, 1H),
2.10 (s, 3H), 1.96 (m, 1H), 1.79 (m, 1H), 1.69 (ddd, J = 14.4, 11.6,
3.1 Hz, 1H), 1.52 (s, 3H), 1.43 (m, 1H), 0.94 (s, 3H), 0.93 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 171.1 (C), 148.5 (C), 142.4
(C), 140.6 (C), 134.0 (CH), 129.4 (C), 129.1 (CH), 122.8 (CH),
120.9 (CH), 72.1 (CH), 35.4 (C), 34.7 (CH2), 33.6 (CH2), 28.4
(CH3), 27.1 (CH3), 25.3 (CH2), 21.4 (CH3), 17.4 (CH3). IR (film):
1725, 1469, 1696, 1346, 1231, 1169, 1144, 1095, 1076, 1017, 996,
961, 865, 802 cm−1. HRMS (ESI/TOF) m/z: [M−OAc]+ calcd for
C16H20NO2, 258.1494; found, 258.1488.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00560.
1
Copies of H and 13C{1H} NMR spectra for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
Rachid Chahboun − Departamento de Química Orgánica,
Facultad de Ciencias, Instituto de Biotecnología, Universidad
de Granada, 18071 Granada, Spain; orcid.org/0000-
0001-5303-1183; Phone: (+34) 958 244022;
Email: rachid@ugr.es
■
Authors
José Manuel Botubol-Ares − Departamento de Química
Orgánica, Facultad de Ciencias, Campus Universitario Río
San Pedro s/n, Torre Sur, 4a planta, University of Cádiz,
11510 Cádiz, Spain; orcid.org/0000-0002-2312-612X
́
̃
María Jesus Durán-Pena − Departamento de Química
Orgánica, Facultad de Ciencias, Campus Universitario Río
San Pedro s/n, Torre Sur, 4a planta, University of Cádiz,
11510 Cádiz, Spain
8753
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The Journal of Organic Chemistry
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