Forging C-C Bonds with Hindered Nucleophiles and Carbonyl Electrophiles: Reactivity and Selectivity of Allylic Tin Reagents/n-BuLi

Article abstract of DOI:10.1021/acs.organomet.7b00765

Under activation with n-BuLi, trialkylstannanes containing crotyl-, geranyl-, and phenyldienylmethyl appendages were reacted with efficiency and selectivity to various ketone and enone electrophiles with low reactivity. The straightforward process gives access to tertiary alcohols that are vicinal to quaternary carbons. With α,α′-dimethoxy-γ-pyrone, on the other hand, the grafting of a dienyl side chain was effected to prepare dienyl α′-methoxy-γ-pyrone in a stereo- and regioselective and convergent manner. Furthermore, the advantages of this route were highlighted for the preparation of organolithium species at low temperature with the formation of a minimum amount of salts. Synthetic manipulations were demonstrated to illustrate the potential of the chemistry for constructing acyclic and cyclic terpene scaffolds.

Full text of DOI:10.1021/acs.organomet.7b00765

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Forging C−C Bonds with Hindered Nucleophiles and Carbonyl
Electrophiles: Reactivity and Selectivity of Allylic Tin Reagents/n‑BuLi
Morgan Cormier, Maha Ahmad, Jacques Maddaluno, and Michael De Paolis*
̈
́
Normandie Universite, UNIROUEN, INSA de Rouen, CNRS, Laboratoire COBRA (UMR 6014 & FR 3038), 76000 Rouen, France
S
* Supporting Information
ABSTRACT: Under activation with n-BuLi, trialkylstannanes
containing crotyl-, geranyl-, and phenyldienylmethyl appen-
dages were reacted with efficiency and selectivity to various
ketone and enone electrophiles with low reactivity. The
straightforward process gives access to tertiary alcohols that are
vicinal to quaternary carbons. With α,α′-dimethoxy-γ-pyrone,
on the other hand, the grafting of a dienyl side chain was
effected to prepare dienyl α′-methoxy-γ-pyrone in a stereo-
and regioselective and convergent manner. Furthermore, the
advantages of this route were highlighted for the preparation of
organolithium species at low temperature with the formation
of a minimum amount of salts. Synthetic manipulations were demonstrated to illustrate the potential of the chemistry for
constructing acyclic and cyclic terpene scaffolds.
and tetraalkylstannane. In the case of heteroleptic stannates
such as those derived from allylic trialkylstannanes, the
unsaturated substituent shifts first. Thus, Pulido elegantly
relied on tin−ate complexes for the internal and γ-selective
delivery of crotyllithium to carbonyl compounds containing a
tetraalkylstannane anchor.4,5As representative cases of this
family of reagents, crotyl- and geranyltributylstannane were
however scarcely employed as pronucleophiles upon activation
with n-BuLi, and little is known of their reactivity and selectivity
with enones and ketones. Because many natural products,
flagrance ingredients, and organic materials feature terpene
(crotyl, prenyl, geranyl, or farnesyl) or dienyl appendages, the
chemistry has implications for the formation of C−C bonds
with hindered nucleophiles and poorly reactive electrophiles, a
difficult and fundamental task.
INTRODUCTION
■
Lithium−tin exchange is a handy method to prepare organo-
lithium reagents, which because of their high reactivity are
useful for forging carbon−carbon bonds using hindered
nucleophiles.1 Beyond the addition to carbonyl and imine
electrophiles, these reagents were successfully employed in
palladium-catalyzed couplings with bromoarenes.2 The lith-
ium−tin exchange is often performed by treatment of
elaborated tetraorgano tin reagents with sacrificial organo-
lithium species (typically n-BuLi), which lead to intermediate
ate complexes (Scheme 1a).3 Subsequent fragmentation
releases the desired and most stable organolithium products
Scheme 1
In the course of a program of total synthesis, we performed
the allylation of α,α′-dimethoxy-γ-pyrone 1 into 2 with the
combination of allyltributylstannane/n-BuLi, which contrasted
with allylmagnesium bromide that reacted with 1 following a
different pattern (Scheme 1b).6 Capitalizing on this result, we
sought to couple 1 with more hindered allylic appendages, such
as crotyl, geranyl, and even dienyl using their stannane
counterparts 3−5 (Scheme 1c). Additionally, several carbonyl
electrophiles were exposed to these species to examine α-, γ-, or
ε-selectivity of the couplings. We are pleased to report herein
the results of this study illustrating the capacity of stannane
reagents to regioselectively transfer terpene appendages to
electrophiles having low reactivity.
Received: October 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.7b00765
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cyclohexenone underwent regioselective hydroalkylation upon
exposure to 4/n-BuLi giving 7d in 55% yield. Noteworthy, each
reagent was employed in a stoichiometric amount to prepare
hindered vicinal carbons through intermolecular coupling.16
The stereoselective synthesis of 1,3-diene is a flourishing field
of innovation supported by the occurrence of the motif in
natural products and in push−pull molecular electronic
devices.17 One of the disconnections consists of the direct
transfer of dienyl appendage to carbonyl reagent. Being an
unsymmetrical pronucleophile, stannane 5 could produce at
least three isomers of position (α-,γ-,ε-) upon reaction, this in
addition to isomers of configuration. In the domain, Oppolzer18
and Nakamura19 described the addition of lithiated silylated
diene to carbonyl compounds with γ- or ε-selectivity. Indium-
and aluminum-promoted transfers of symmetrical dienyl
appendage, such as pentadiene, were also reported with γ-
selectivity by Fallis and Martin, respectively.20,21
RESULTS AND DISCUSSION
■
To begin the study, the combination of 3/n-BuLi was tested
with α,α′-dimethoxy-γ-pyrone 1, but the grafting of the crotyl
appendage to 1 consistently failed, whether with α- or γ-
selectivity.7 Curious to evaluate reactivity and selectivity of 3
with other carbonyl electrophiles, we employed various enones
that have low reactivity, like 1 (Scheme 2). With a
Scheme 2. Hydrocrotylation of Enone Reagents (1:1 dr)
To our knowledge, the coupling of dienyl stannane to
carbonyl compounds was not investigated upon activation with
organolithium reagents. Inspired by the related work of
Maruyama,22 the preparation of stannane 5 was undertaken
from cinnamaldehyde by treatment with vinylmagnesium
bromide giving alcohol 8 (Scheme 4). Exposure to SOCl2
stoichiometric ratio of reagents, the combination (E)-3/n-
BuLi proved to be an efficient tool to access allylic alcohols 6a−
c (64−70% yields) with excellent γ-selectivity.8 Similar
selectivity was obtained by reaction of crotylmagnesium
bromide with enones.9 In comparison, the combination (E)-
3/n-BuLi offers the advantages of generating the nucleophilic
species in smooth conditions (at −78 °C) from 3, a stable
pronucleophile, and being convenient for small scale experi-
ment without an excess of reagents. Others strategies were
reported to graft the crotyl appendage to such electrophiles
with titanocenes or indium species.10,11 Combined with Lewis
acids, crotylboronate was also employed for such a purpose.12
Although the addition of the more hindered pronucleophile
4 to 1 failed upon activation with n-BuLi, the hydroalkylation of
enone and ketones was more fruitful, furnishing with γ-
selectivity various scaffolds embedding vicinal quaternary and
tertiary carbons (Scheme 3).13 Thus, γ-adduct 7a was obtained
Scheme 4. Preparation of Diene 5
produced the chlorodiene 9 as a single isomer.23 In what
appears to be the first synthesis of stannane 5, Barbier-type
coupling of 9 with Mg and n-Bu3SnCl under sonication gave
the desired compound in 82% yield with good selectivity
(linear/branched = 5.6:1).24
Reacting with cyclohexanone, the combination 5/n-BuLi
furnished ε-isomer 10a as the major product but always in
mixture with the γ- and α-products (Scheme 5). In an attempt
Scheme 3. Hydrogeranylation of Ketone and Enone
Reagents
Scheme 5. Coupling of Diene 5 with Cyclohexanone
to steer the selectivity of the coupling, the temperature (from
−78 to −90 °C) and the age of the mixture 5/n-BuLi (t = 0−5
min) were modulated, but only minor variations in the
outcome were noted.
Pleasingly though, the regioselectivity reached an interesting
level with α,α′-dimethoxy-γ-pyrone 1 (Scheme 6). Upon
treatment of 5/n-BuLi, the starting material was converted to
dienyl E,E-11/11′ (31% yield) with complete α-selectivity, a
reversal of selectivity that underlines the peculiar behavior of 1
toward nucleophiles. As observed with γ-pyrones 2 and 2′
mentioned at the outset, the mixture of regioisomers 11/11’
in 68% yield by condensation of 4/n-BuLi with cyclohexanone.
So far undocumented, the conversion of the piperidinone
pharmacophore14 into the terpene alkaloid 7b, as the sole γ-
isomer, was carried out in 53% yield (66% brsm). A difficult
electrophile such as tetralone was transformed into alcohol 7c
with excellent regioselectivity albeit in 11% yield (56% brsm,
2:1 dr). However, with regard to the literature data, the
performance of the coupling remains synthetically useful and
pertinent given the versatility of tertiary benzylic alcohols with
olefinic appendage as in radical ring expansion.15 Moreover, 2-
B
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Scheme 6. Coupling of Diene 5 with 1
Scheme 8. Influence of the Nucleophile Aging on the Ratio
of α- and γ-Isomers
(1:2) was likewise recovered due to the isomerization of E,E-
11′ into the conjugated product E,E-11 in basic conditions.
With a stronger acid to quench the reaction, such as CF3CO2H,
a single isomer 11′ was obtained in 34% yield, which given the
conciseness of the route remains synthetically useful. Moreover,
both E,E-11 and E,E-11′ are therefore technically accessible
because the complete isomerization of E,E-11′ → E,E-11 was
demonstrated with 2 → 2′.
yield, and isomeric alcohols (α- and γ-) 12 and 12′ were
produced in 90% yield with diminished γ-selectivity (12:12’,
2.6:1). Aging further the mixture of 4/n-BuLi for 40 min
suppressed the side-product 13 and raised the yield of 12/12′
to 96% while further depleting the γ-selectivity to 1.8:1
(12:12′).
Aging the mixture of 4/n-BuLi resulted in the expected
suppression of alcohol 13, but the concomitant erosion of the
selectivity was puzzling. We tried to amplify the phenomena
associated with the aging by warming the mixture 4/n-BuLi
from −78 to 0 °C (Scheme 9). After 30 min at this
temperature, the mixture was returned to −78 °C before the
introduction of the electrophile.
In a regio- and stereoselective manner, the chemistry
provides a difficult-to-access scaffold ready for further
functionalization. In this regard, the structural proximity with
cyercene is worthy of note.
Even though aldehydes are well-covered electrophiles in the
literature, we were interested in assessing the γ-selectivity of the
combination of geranylstannane 4/n-BuLi with them. As for
why, we noted that, prepared by another route, geranyllithium
produces α-and γ-isomers by reaction with PhCHO. We were
then curious to compare the performance of 4/n-BuLi with this
electrophile.25
Scheme 9
To that end, 4 was reacted with n-BuLi for 5 min, and
PhCHO (0.5 equiv) was subsequently added at −78 °C
(Scheme 7a). Expected benzylic alcohol 12 was recovered in
Scheme 7. Hydroalkylation of PhCHO
Proceeding this way with 2-cyclohexenone formed γ-isomer
7d in only 27% yield, whereas it was obtained in 55% yield
without aging. In contrast with the previous experiment with
PhCHO, the γ-selectivity was not scrambled, but the formation
of geraniol in 18% yield was noted at the expense of 7d.
Probably the result of the oxidation of geranyllithium, geraniol
was spotted as traces in the crude of the experiments carried
out without aging. To some extent, the presence of alkoxide
salts was suspected to subtly impact the selectivity of the
nucleophilic species with a reactive electrophile such as
PhCHO. It is indeed established that polar lithium alkoxides
alter the reactivity of organolithium reagents by promoting the
formation of heteroaggregates (ROLi)x(RLi)y at the expense of
homogeneous ones (RLi)x.26
Alkoxide salts are actually difficult to avoid in such processes
because variable amounts of n-BuOLi salts contaminate
commercial solutions of n-BuLi upon reaction with residual
oxygen. It is therefore conceivable that alkoxide salts, whether
n-BuOLi or lithium geraniol oxide, can form complexes with
geranyllithium, affecting the selectivity of this nucleophile
toward aldehydes. Inferring that aging, high temperature (>
−78 °C), and amounts of PhOLi (produced by reductive
lithiation of geranylphenylether, Scheme 7b) are factors and
salts accelerating the formation of these complexes, this
explanation may account for the low selectivity detailed in
Schemes 7b and 8.
51% yield with a significant level of γ-selectivity (7.5:1, 12/12′).
Incidentally, alcohol 13 was isolated in 27% yield, suggesting
that the addition of n-BuLi to PhCHO competed with the
addition to 4. Because side-products of such were not observed
with ketones and enones, this understanding made sense.
More surprising was the γ-selectivity of the reaction in view
of the literature data describing no selectivity for the reaction of
PhCHO with geranyllithium. When this nucleophile was
prepared from geranylphenoxide and Li°, we consistently
produced a mixture of alcohols 12 and 12′ (1:1) upon reaction
with PhCHO (Scheme 7b).
There was therefore an intriguing discrepancy of selectivity
between the two methods. Leaving this point aside for a
moment, we first attempted to diminish the amount of alcohol
13. To that end, the mixture 4/n-BuLi was purposely aged for
20 min at −78 °C (Scheme 8) before adding PhCHO (0.5
equiv). As a result, the production of 13 was decreased to 7%
Drawing a practical lesson, ate intermediates rapidly form
organolithium species, whereas the concomitant production
and interference of alkoxide salts remain minimal due to the
low temperature at which the process takes place. As noted in
C
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Schemes 8 and 9 with aldehydes and ketone, these factors
impact the outcome of the reaction.
useful intermediates in the synthetic quiver to transfer hindered
terpene appendages.
To demonstrate the versatility of the prepared substrates, we
carried out ring closing metathesis of the olefinic adducts 7a−c
to attain hindered cyclopentenes 14a,b and 15c in fair yields
(44−62%, not optimized) upon treatment with Grubbs catalyst
second generation (Scheme 10). From a retrosynthetic
EXPERIMENTAL SECTION
■
General Remarks. All reactions were performed in oven-dried
glassware. THF and Et2O were dried and purified following standard
procedure. All reagents were purchased from Alfa Aesar, Sigma-
Aldrich, or TCI Europe and were used without further purification.
Commercial solutions (Aldrich) of n-BuLi were titrated against N-
Scheme 10
benzylbenzamide (1 mmol) at −40 °C in THF. H and 13C NMR
1
spectra were recorded in deuterated chloroform on a Bruker DRX 300
MHz spectrometer and were referenced to residual chloroform (7.26
1
ppm, H; 77.36 ppm, 13C). The chemical shifts (δ) are expressed in
parts per million (ppm), and coupling constants are indicated in hertz
(Hz). Abbreviations for signal coupling are as follows: s = singlet, d =
doublet, dd = doublet of doublets, t = triplet, q = quartet, quin =
quintet, m = multiplet, br = broad signal. High-resolution mass spectra
(HRMS) were performed on Q-TOF Micro WATERS by electrospray
ionization (ESI) and electronic impact (EI). Infrared (IR) spectra were
recorded with a PerkinElmer 16 PC FT-IR ATR spectrometer using
the pure product (oil or solid). Thin layer chromatography (TLC) was
run on precoated aluminum plates of silica gel 60 F-254 (Merck).
Flash column chromatography was performed on silica gel column
(Merck silica gel, 40−63 μm) using air pressure. The purity of the
perspective, the disconnection of cyclopentadienyl with
carbonyl compounds as illustrated with 14a,b is not trivial.
To our knowledge, a single route was reported by Knochel in
which the cyclopentadienyl motif was grafted to aldehydes by a
zinc-ene cyclization strategy.27 With the 2-step route described
herein, the cyclopentadienyl motif is assembled to ketones,
resulting in the efficient preparation of simple alkaloids with a
terpene motif such as 14b.
Another appealing extension of this work consisted of the
synthesis of hindered enone 16 from 7d in 81% yield. The
route relies on an oxidative rearrangement of tertiary allylic
alcohol promoted by pyridinium chlorochromate (PCC).28 Of
note is the new disconnection in which quaternary carbons are
connected to enone, which is warranted by the γ-selectivity of
the geranyl transfer. Hinging on geranyl cuprates to access such
an enone connected to quaternary carbons would be
complicated by the α-selectivity displayed by these reagents
as reported by Lipshutz.8b
Although a well-known strategy, the formation of organo-
lithium species from various hindered allylic stannanes has been
under-scrutinized in terms of reactivity and selectivity with
enone and ketone electrophiles. This work sheds some light on
the field while briefly illustrating the synthetic versatility of the
obtained adducts with compounds 14−16. Furthermore,
mechanistic examination suggested that aging the nucleophilic
species was detrimental for the γ-selectivity with aldehyde,
which emphasized the advantages of using allylic stannanes to
rapidly and smoothly generate organolithium species. Given the
broad use of these species, as mentioned at the outset of the
article, these observations are pertinent in various fields.
At the origin of the study, the desymmetrization of α,α′-
dimethoxy-γ-pyrone 1 that was envisaged with crotyl (3) or
geranyl nucleophiles (4) failed, probably due to their steric
hindrance. On the other hand, the combination dienylstannane
5/n-BuLi allowed the grafting to 1 of the dienyl side chain with
regio- and configurational selectivity in a convergent manner.
The process hinges upon substituted allyltributylstannanes
that are readily prepared, stable, and easily activated with
ordinary n-BuLi. The side-product of the chemistry, tetrabutyl-
stannane, does not display particularly high toxicity.29 These
considerations should help tin-ate complexes to be seen as
1
compounds was assessed by H and 13C NMR spectroscopy. As the
stannanes and alcohols prepared in this study were either very apolar
or very polar, some impurities were noted in their spectra.
Allyltributylstannane [24850-33-7]. Although commercially
available, allyltributylstannane was prepared in large quantities as
follows. To a solution of tributyltin chloride (10 mL, 36.9 mmol, 1.0
equiv) in Et2O (300 mL) cooled at 0 °C and stirred under argon was
added allylmagnesium bromide (37 mL, 36.9 mmol, 1.0 equiv, C = 1
M in Et2O), and the resulting cloudy solution was stirred for 1 h at 0
°C. After quenching with NH4Cl (20 mL), the solution was extracted
with Et2O (3 × 40 mL). Combined organic layers were brined (50
mL) and dried on MgSO4. The volatiles were removed under reduced
pressure to give crude allyltributylstannane (colorless oil), which was
1
used without further purification. H NMR (300 MHz, CDCl3): δ
6.07−5.86 (m, 1H), 4.86−4.58 (m, 2H), 1.77 (d, J = 8.6 Hz, 2H),
1.60−1.41 (m, 6H), 1.30 (dq, J = 14.2, 7.1 Hz, 6H), 0.88 (dd, J = 14.8,
7.5 Hz, 15H). 13C NMR (75 MHz, CDCl3): δ 138.3, 109.3, 29.3, 27.5,
16.3, 13.9, 9.3.
(E)-Crotyltributylstannane (3).30 To a solution of trans-crotyl
alcohol (4.3 g, 60 mmol, 1 equiv) in anhydrous Et2O (200 mL) was
added PBr3 (5.7 mL, 60 mmol) at 0 °C. The solution was stirred for 1
h at this temperature. The mixture was diluted with Et2O (50 mL) and
treated with NaHCO3 until pH 7. After extraction with Et2O (3 × 20
mL), the combined organic layers were dried with MgSO4, and the
solvent was removed under vacuum (Caution! Crotyl bromide is
volatile) to give the crude bromide, which was used without further
purification. To a solution of freshly prepared LDA (127 mL, 1.2
equiv, 38.1 mmol, 0.3 M in THF) was added n-Bu3SnH (8.5 mL, 31.7
mmol, 1 equiv) at −78 °C. The solution was stirred at −20 °C for 1 h,
and crotyl bromide (5.1 g, 38.1 mmol, 1.2 equiv) was added neat at
−40 °C. The mixture was stirred at −20 °C for 1 h. After quenching
with NH4Cl (20 mL), the solution was extracted with Et2O (3 × 50
mL). Combined organic layers were brined and dried on MgSO4. The
volatiles were removed under reduced pressure to give an oil that was
purified by distillation (Kugelrohr, bp = 112 °C under 0.5 mmHg) to
give 6.0 g of (Z)-3 product as a colorless oil in 46% yield (2 steps). Rf:
1
0.99 (cyclohexane). H NMR (300 MHz, CDCl3): δ 5.53 (m, 1H),
5.28−5.07 (m, 1H), 1.74−1.40 (m, 10H), 1.36−1.24 (m, 7H), 0.96−
0.77 (m, 15H). 13C NMR (75 MHz, CDCl3): δ 130.1, 119.9, 29.2,
27.3, 17.8, 14.1, 13.7, 9.1.
Geranyltributylstannane (4).31 To a solution of geraniol (2.8 g,
18.1 mmol, 1 equiv) in Et2O (100 mL) was added PBr3 (1.7 mL, 18.1
mmol) at 0 °C. The solution was stirred for 1 h at this temperature.
The mixture was diluted in Et2O (50 mL) and carefully treated with
sat. solution NaHCO3 until pH 7. After extraction, the combined
D
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organic layers were dried with MgSO4, and the solvent was removed
under vacuum to give geranyl bromide, which was used without
further purification. To a solution of freshly prepared LDA (30 mL, 8.9
mmol, 1.2 equiv, 0.3 M in THF) was added Bu3SnH (2 mL, 7.4 mmol,
1 equiv) at −78 °C. The solution was stirred at −20 °C for 1 h, and
geranyl bromide (1.9 g, 8.9 mmol, 1.2 equiv) was added neat at −40
°C. The mixture was stirred at −20 °C for 2 h. After quenching with
NH4Cl (20 mL), the solution was extracted with Et2O (3 × 50 mL).
Combined organic layers were brined and dried on MgSO4. The
volatiles were removed under reduced pressure to give a residue that
was purified by flash chromatography (cyclohexane) to give 1.9 g (50%
1.00 (d, J = 6.9 Hz, 1.5H). 13C NMR (75 MHz, CDCl3): δ 140.4,
140.4, 135.1, 134.7, 134.5, 134.4, 116.1, 116.0, 87.8, 87.8, 47.1, 47.1,
35.6, 34.8, 31.6, 31.4, 15.3, 14.6. IR (υ/cm−1, neat): 3400, 3052, 2964,
2935, 2850, 1633, 1452, 1416, 1280, 1175, 1018, 950, 930, 754. MS
(CI, isobutane) for [M − OH]+ C9H13 calcd, 121; found, 121.
1-(1-Methyl-2-propenyl)-2-cyclohexen-1-ol (6b).10 The reac-
tion of 3 (359 mg, 1.04 mmol, 1 equiv), n-BuLi (0.65 mL, 1.04 mmol),
and 2-cyclohexenone (100 mg, 1.04 mmol) in THF (10 mL) gave
alcohol 6b after 2 h of reaction (111 mg, 70% yield, 1:1 dr determined
1
by H NMR) as a colorless oil after purification (9:1 cyclohexane/
AcOEt). Rf: 0.35 (9:1 cyclohexane/AcOEt). 1H NMR (300 MHz,
CDCl3) 2 diastereoisomers (1:1): δ 5.91−5.71 (m, 2H), 5.69−5.55
(m, 1H), 5.16−4.96 (m, 2H), 2.33−2.19 (m, 1H), 2.15−1.86 (m, 2H),
1.78−1.55 (m, 4H), 1.05 (d, J = 6.9 Hz, 1.5H), 1.00 (d, J = 7.0 Hz,
1.5H). 13C NMR (75 MHz, CDCl3): δ 140.2, 140.2, 131.5, 131.4,
131.4, 130.9, 116.4, 115.7, 71.0 (2C), 48.4, 47.5, 32.6, 31.9, 25.4 (2C),
18.8, 18.6, 15.1, 13.8. IR (υ/cm−1, neat): 3375, 3019, 2931, 2862,
1703, 1649, 1456, 1169, 977, 961, 907, 732, 515, 562, 471. MS (CI,
isobutane) for [M − OH]+ C10H15 calcd, 135; found, 135.
1
yield) of 4 as a colorless oil. Rf: 0.9 (cyclohexane). H NMR (300
MHz, CDCl3): δ 5.25 (t, J = 9.0 Hz, 1H), 5.03 (t, J = 6.7 Hz, 1H),
2.04−1.85 (m, 4H), 1.62−1.33 (m, 18H), 1.23 (m, 6H), 0.82 (t, J =
7.3 Hz, 11H), 0.79−0.73 (m, 3H). 13C NMR (75 MHz, CDCl3): δ
131.0, 129.1, 124.7, 122.9, 39.9, 29.2, 27.4, 27.1, 25.7, 17.6, 15.6, 13.69,
10.6, 9.4. IR (υ/cm−1, neat): 2956, 2922, 2872, 2853, 1456, 1376,
1070, 863, 686, 592, 503.
Tributyl[(2E,4E)-5-phenylpenta-2,4-dien-1-yl]stannane (5).32
To alcohol 833 (1.5 g, 9.31 mmol, 1 equiv) in solution in anhydrous
Et2O (100 mL) was added SOCl2 (1.35 mL, 18.7 mmol, 2 equiv) at 0
°C. The solution was stirred for 2 h at this temperature and then
quenched with sat. NaHCO3 solution until pH 7 before extraction
with Et2O. The combined organic layers were brined, dried (MgSO4),
filtered, and concentrated under reduced pressure. Crude chlorodiene
9 was used without any further purification as it was found instable. 1H
NMR (300 MHz, CDCl3): δ 7.37−7.13 (m, 5H), 6.70 (dd, J = 15.6,
10.4 Hz, 1H), 6.52 (d, J = 15.7 Hz, 1H), 6.39 (dd, J = 14.9, 10.4 Hz,
1H), 5.85 (dt, J = 14.8, 7.3 Hz, 1H), 4.10 (dd, J = 7.3, 0.7 Hz, 2H). 13C
NMR (75 MHz, CDCl3): δ 136.9, 134.8, 134.4, 128.8 (2C), 128.6,
128.1, 127.4, 126.7 (2C), 45.3. In a Schlenk tube under argon, charged
with magnesium turning (0.16 g, 6.62 mmol, 1.3 equiv), a piece of
iodine and n-Bu3SnCl (1.65 g, 5.1 mmol, 1 equiv) in anhydrous THF
(5 mL) were added at 0 °C. Under sonication, crude 9 (1 g, 5.6 mmol,
1.1 equiv, diluted in 5 mL of anhydrous THF) was added to the
mixture over 45 min. Once the addition was completed, sonication was
continued for 15 min at 0 °C, and then H2O was added to the mixture.
The aqueous layer was extracted with Et2O (3 × 100 mL). Organic
layers were brined and dried on Na2SO4. The reaction mixture was
purified by quick filtration under silica gel (washing with cyclohexane)
to give stannane 5 (2 g, 82% of combined yield with linear and
branched products; ratio = 5.6:1, l/b) as a colorless oil. Rf = 0.95
(cyclohexane). Data for the linear isomer: 1H NMR (300 MHz,
CDCl3): δ 7.35−7.26 (m, 2H), 7.19 (m, 2H), 7.08 (m, 1H), 6.66 (dd,
J = 15.6, 9.4 Hz, 1H), 6.22 (d, J = 15.6 Hz, 1H), 5.96 (d, J = 9.1 Hz,
1H), 1.83 (d, J = 7.6 Hz, 2H), 1.42 (m, 6H), 1.23 (m, 6H), 0.81 (m,
16H). 13C NMR (75 MHz, CDCl3): δ 138.3, 136.3, 130.2, 128.6 (2C),
128.5, 126.8, 126.4, 125.8, 29.2, 27.4, 17.5 (3C), 13.7 (3C), 9.6 (3C).
IR (υ/cm−1, neat): 3022, 2955, 2922, 2850, 1627, 1594, 1462, 1071,
980, 689, 498. HRMS (EI, M+) for C23H38Sn calcd, 434.1995; found,
434.1981.
2-(Cyclohex-1-en-1-yl)-3-methylpent-4-en-2-ol (6c).12a The
reaction of 3 (310 mg, 0.9 mmol, 1 equiv), n-BuLi (0.562 mL, 0.9
mmol), and 1-acetyl-1-cyclohexene (100 mg, 0.9 mmol) in THF (9
mL) gave alcohol 6c after 4 h of reaction (103 mg, 64%) as a colorless
oil after purification (9:1 cyclohexane/AcOEt). Rf: 0.56 (9:1
1
cyclohexane/AcOEt) 2 diastereoisomers (1:1): H NMR (300 MHz,
CDCl3): δ 5.97−5.74 (m, 1H), 5.71−5.61 (m, 1H), 5.18−5.02 (m,
2H), 2.52−2.40 (m, 0.5H), 2.35 (m, 0.5 H), 2.06 (m, 2.5H), 2.01−
1.90 (m, 1.5H), 1.59 (m, 4H), 1.22 (s, 3H), 0.97 (d, J = 6.9 Hz, 1.5H),
0.91 (d, J = 6.9 Hz, 1.5H). 13C NMR (75 MHz, CDCl3): δ 142.1,
142.0, 140.6, 140.3, 121.2, 120.3, 116.0, 115.6, 76.4, 76.3, 44.9, 44.2,
25.9, 25.3, 25.2, 25.2, 24.7, 23.4, 23.2, 23.2, 22.5 (2C), 14.5, 14.0. IR
(υ/cm−1, neat): 3476, 2927, 1709, 1635, 1449, 1368, 1139, 1000, 909,
844, 586, 459. MS (CI, isobutane, m/z 163) [M − OH]+ for C12H20
calcd, 163; found, 163.
1-(3,7-Dimethylocta-1,6-dien-3-yl)cyclohexanol (7a).13a The
reaction of 4 (240 mg, 0.55 mmol, 1 equiv), n-BuLi (0.34 mL, 0.55
mmol), and cyclohexanone (54 mg, 0.55 mmol) in THF (5 mL) gave
alcohol 7a after 4 h of reaction (87 mg, 68%) as a colorless oil after
purification (cyclohexane/AcOEt, 95:5). Rf: 0.56 (9:1 cyclohexane/
1
AcOEt). H NMR (300 MHz, CDCl3) δ 5.86 (m, 1H), 5.21 (dd, J =
10.9, 1.6 Hz, 1H), 5.14−5.06 (m, 1H), 5.02 (dd, J = 17.7, 1.6 Hz, 1H),
1.80 (m, 2H), 1.67 (s, 3H), 1.62−1.34 (m, 14H), 1.26 (m, 1H), 1.01
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 143.9, 131.2, 125.3, 115.5,
74.9, 47.8, 34.9, 31.9, 31.1, 26.0, 25.8, 23.5, 22.2, 22.0, 17.7, 16.2. IR
(υ/cm−1, neat): 3493.3, 3080.0, 2929.9, 1856.9, 1633.3, 1448.3,
1413.3, 1375.9, 1257.5, 1124.9, 1044.6, 962.7, 909.9, 839.8, 503.4. MS
(CI, isobutane, m/z 219) [M − OH]+ for C16H27 calcd, 219; found,
219.
1-Benzyl-4-[(6E)-3-methylocta-1,6-dien-3-yl]piperidin-4-ol
(7b). The reaction of 4 (146 mg, 0.26 mmol, 1 equiv), n-BuLi (0.16
mL, 0.26 mmol), and N-benzylpiperidone (50 mg, 0.26 mmol) in
THF (3 mL) gave alcohol 7b after 4 h of reaction (11 mg, 53%, 80%
conversion) as a colorless oil after purification (8:2 CH2Cl2/acetone).
General Procedure for the Hydroxyalkylation of Enones and
Ketones. To a solution of 3 or 4 (1 equiv) in anhydrous THF (C =
0.1 M), was added n-BuLi (1 equiv, C = 1.6 M in hexane) at −78 °C
under an argon atmosphere. The solution was stirred for 5 min at this
temperature, and the electrophile (1 equiv) was added neat. The
solution was stirred at this temperature until the completion of the
reaction. Then, quenching was performed with sat. solution NH4Cl,
and the reaction mixture was extracted with Et2O (3×). The combined
organic layers were washed with brine, dried (MgSO4), filtered, and
concentrated. The alcohols were purified by flash chromatography on
silica gel.
1
Rf: 0.05 (9:1 CH2Cl2/acetone). H NMR (300 MHz, CDCl3): δ 7.24
(m, 5H), 5.77 (dd, J = 17.6, 10.9 Hz, 1H), 5.17 (dd, J = 10.9, 1.0 Hz,
1H), 5.07−4.87 (m, 2H), 3.46 (brs, 2H), 2.73−2.55 (m, 2H), 2.23 (t, J
= 11.8 Hz, 2H), 2.11 (s, 1H), 1.85−1.67 (m, 4H), 1.61 (s, 3H), 1.51
(s, 3H), 1.38 (m, 4H), 0.96 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
143.3, 138.4, 131.4, 129.3 (2C), 128.3 (2C), 127.1, 125.1, 116.1, 73.2,
63.2, 49.7, 49.4, 47.4, 34.8, 31.9, 31.2, 25.8, 23.4, 17.7, 16.2. IR (υ/
cm−1, neat): 3369, 2928, 1636, 1454, 1375, 1107, 1001, 911, 810, 737,
698, 604, 461. HRMS (ESI) [M + H]+ for C22H34NO calcd, 328.2638;
found, 328.2640.
1-(1-Methyl-2-propenyl)-2-cyclopenten-1-ol (6a).10 The re-
action of 3 (420 mg, 1.2 mmol, 1 equiv), n-BuLi (0.763 mL, 1.2
mmol), and cyclopentenone (100 mg, 1.2 mmol) in THF (12 mL)
gave 6a after 2 h of reaction (109 mg, 66% yield) as a colorless oil after
purification (cyclohexane/AcOEt 9:1). Rf: 0.3 (cyclohexane/AcOEt,
1-(3,7-Dimethylocta-1,6-dien-3-yl)-1,2,3,4-tetrahydronaph-
talen-1-ol (7c). The reaction of 4 (146 mg, 0.34 mmol, 1 equiv), n-
BuLi (0.21 mL, 0.34 mmol), and α-tetralone (50 mg, 0.34 mmol) in
THF (3.5 mL) gave alcohol 7c after 8 h of reaction (11 mg, 11% and
56% brsm, 25% conversion) as a colorless oil after purification (95:5
cyclohexane/AcOEt). Rf: 0.5 (9:1 cyclohexane/AcOEt) 2 diaster-
1
9:1). H NMR (300 MHz, CDCl3): δ 5.97−5.74 (m, 2H), 5.71−5.61
(m, 1H), 5.18−5.02 (m, 2H), 2.58−2.34 (m, 2H), 2.34−2.13 (m, 1H),
2.13−1.99 (m, 1H), 1.87−1.68 (m, 2H), 1.03 (d, J = 6.9 Hz, 1.5H),
1
eoisomers (2:1): H NMR (300 MHz, CDCl3): δ 7.58 (m, 0.7H),
E
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Article
7.46−7.39 (m, 1H, 0.3H), 7.12−7.03 (m, 2H), 7.02−6.96 (m, 1H),
6.03−5.78 (m, 1H), 5.31−4.83 (m, 3H), 2.72−2.40 (m, 2H), 2.28−
2.01 (m, 1H), 1.99−1.62 (m, 4H), 1.57 (m, 3H), 1.49−1.44 (m, 3H),
1.20 (m, 3H), 0.96 (s, 1H), 0.89 (s, 2H). 13C NMR (75 MHz,
CDCl3): δ 144.2, 143.8, 140.6, 140.1, 139.8, 139.7, 139.6, 139.5, 131.0,
129.0, 128.4, 128.2, 126.7, 126.6, 125.2, 125.2, 125.1, 124.99, 115.51,
115.0, 76.3, 75.6, 49.5 (2C), 36.9, 36.2, 35.1, 34.6, 30.9, 30.9, 25.7,
25.7, 23.6, 23.4, 21.0, 20.8, 17.66, 17.6, 17.0, 16.9. IR (υ/cm−1, neat):
3467, 2928, 1634, 1448, 1375, 1011, 909, 749, 670, 454. HRMS (EI)
M+ for C20H28O calcd, 284.2140; found, 284.2146.
AcOEt) followed by preparative TLC (95:5 cyclohexane/AcOEt) to
separate the two isomers.
2-Ethyl-2,6-dimethyl-1-phenylhept-5-en-1-ol (12).25 Rf: 0.57
(9:1 cyclohexane/AcOEt). 1H NMR (300 MHz, CDCl3) 2
diastereoisomers (1:1): δ 7.34−7.25 (m, 5H), 5.83 (m, 1H), 5.15
(m, 3H), 4.44 (m, 1H), 2.07−1.94 (m, 1H), 1.86 (m, 2H), 1.65 (s,
3H), 1.55 (s, 3H), 1.46−1.19 (m, 2H), 1.08 (s, 1.5H), 0.93 (s, 1.5H).
13C NMR (75 MHz, CDCl3): δ 144.0, 142.8, 141.4, 140.6, 131.4,
131.3, 128.2, 127.9, 127.6, 127.6, 127.5, 127.4, 124.9, 124.8, 115.9,
115.2, 80.9, 80.2, 46.0, 45.4, 37.7, 36.5, 25.8, 22.9, 19.0, 17.7, 16.3. IR
(υ/cm−1, neat): 3469, 2927, 2857, 2838, 1703, 1636, 1449, 1367,
1139, 1001, 909, 845, 586 cm−1. MS (CI, isobutane, m/z 227) [M −
OH]+ for C17H23 calcd, 227; found, 227.
1-(3,7-Dimethylocta-1,6-dien-3-yl)cyclohex-2-en-1-ol (7d).
The reaction of 4 (222 mg, 0.52 mmol, 1 equiv), n-BuLi (0.325 mL,
0.52 mmol), and 2-cyclohexenone (49 μL, 0.52 mmol) in THF (5
mL) gave alcohol 7d after 4 h of reaction (66 mg, 55%) as a colorless
oil after purification (95:5 cyclohexane/AcOEt). Rf: 0.52 (9:1
(3E)-4,8-Dimethyl-1-phenylnona-3,7-dien-1-ol (12′).25 Rf: 0.5
1
(9:1 cyclohexane/AcOEt). H NMR (300 MHz, CDCl3) δ 7.44−7.25
1
cyclohexane/AcOEt) 2 diastereoisomers (1:1): H NMR (300 MHz,
(m, 5H), 5.17 (t, J = 7.4 Hz, 1H), 5.07 (m, 1H), 4.75−4.62 (m, 1H),
2.47 (m, 2H), 2.06 (m, 4H), 1.69 (s, 3H), 1.61 (s, 6H). 13C NMR (75
MHz, CDCl3): δ 143.9, 139.3, 131.5, 128.0 (2C), 127.1, 125.5 (2C),
123.8, 119.3, 73.6, 39.6, 37.9, 26.2, 25.4, 17.4, 15.9. IR (υ/cm−1, neat):
3370, 2965, 2914, 2857, 1874, 1806, 1494, 1450, 1380, 755, 694. MS
(CI, isobutane, m/z 227) [M−OH]+ for C17H23 calcd, 227; found,
227.
CDCl3): δ 5.98−5.84 (m, 2H), 5.80−5.70 (m, 1H), 5.26−5.18 (m,
1H), 5.13−4.98 (m, 2H), 2.06−1.95 (m, 1H), 1.90 (m, 3H), 1.71−
1.62 (m, 7H), 1.59−1.56 (m, 4H), 1.48−1.36 (m, 2H), 1.02 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 143.5, 143.0, 132.0, 131.5, 131.2,
131.1, 129.8, 129.7, 125.3, 125.2, 115.7, 115.1, 73.2, 72.9, 47.0, 47.0,
34.7, 34.4, 31.12, 30.80, 25.8 (2C), 25.3, 25.3, 23.4, 23.3, 19.1, 18.9,
17.7 (2C), 16.4 (2C). IR (υ/cm−1, neat): 3467, 2931, 2873, 1707,
1633, 1438, 1375, 1168, 1078, 1013, 944, 910, 816, 734, 532. HRMS
(EI) M+ for C16H26O calcd, 234.2017; found, 234.2015.
Preparation of Geranyllithium from Geranyloxybenzene.
The glassware employed consisted of a one-neck flask connected to a
second one-neck flask through a glass bridge equipped with a fritted
glass filter. To the first flask were added THF (5 mL) and freshly cut
pieces of Li° (40 mg, 6 mmol, 3 equiv) at rt. A solution of
geranyloxybenzene (462 mg, 2 mmol, 1 equiv) in anhydrous Et2O (2
mL) was added dropwise. When a color change was observed, the
solution was stirred for an additional 10 min at rt. Then, the solution
was transferred into the second flask through the filter using gravity
and a positive pressure of argon, and the mother solution was cooled
at −78 °C. From the mother solution, 3.5 mL was removed with a
syringe and quickly transferred into a flask cooled at −78 °C. PhCHO
(100 μL, 1 mmol) was added, and the resulting mixture was stirred for
1 h at this temperature. The mixture was quenched with MeOH and
water. After extraction with CH2Cl2, the combined organic layers were
brined, dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification gave 12 and 12′ in equal quantities.
2-Methoxy-3,5-dimethyl-6-[(2E,4E)-5-phenylpenta-2,4-dien-
1-yl]-4H-pyran-4-one (11). A 250 mL, single-necked, round-bottom
flask equipped with a magnetic stirring bar was charged with 5 (471
mg, 1.1 mmol, 2 equiv) and 1 (100 mg, 0.55 mmol, 1 equiv) in
anhydrous THF (10 mL). n-BuLi (0.69 mL, 1.1 mmoL, 2 equiv, C =
1.6 M in hexane) was added at −90 °C. The solution became red and
was stirred for 30 min at this temperature before addition of MeOH
(0.11 mL, 2.72 mmol, 5 equiv) at −90 °C. The bath was removed, and
the solution was allowed to reach a temperature of 20 °C. The mixture
was quenched with sat. NH4Cl and extracted with Et2O (3 × 10 mL).
The combined organic layers were brined, dried (MgSO4), filtered,
and concentrated under reduced pressure. The reaction mixture was
purified by flash chromatography (7:3 cyclohexane/AcOEt) to give the
products 11/11′ (49 mg, 31% combined yield with a ratio 2:1).
Complete selectivity toward 11′ (34%) can be obtained by transferring
with cannula the cold reaction mixture (−90 °C) to a solution of
CF3CO2H (3 equiv) in Et2O at −78 °C.
1-(1-Methylcyclopent-2-en-1yl)cyclohexanol (14a). To a
sealed tube containing 7a (30 mg, 0.13 mmol, 1 equiv) in anhydrous
toluene (1 mL) was added Grubbs catalyst second generation
[246047-72-3] (5 mg, 0.06 mmol, 0.05 equiv) at rt. The solution
was stirred at 110 °C until complete conversion of the starting material
(24 h). The mixture was then concentrated under reduced pressure
and purified by flash chromatography (9:1 cyclohexane/AcOEt) to
give alcohol 14a (12 mg, 50% yield) as a colorless oil. Rf: 0.40 (8:2
1
Data for 11: Rf = 0.40 (6:4 cyclohexane/AcOEt). H NMR (300
MHz, CDCl3): δ 7.32−7.19 (m, 5H), 6.86 (dd, J = 15.3, 10.3 Hz, 1H),
6.42 (dAB, J = 15.3 Hz, 1H), 6.32−6.08 (m, 2H), 4.01 (s, 3), 3.52 (d, J
= 6.6 Hz, 2H), 2.02 (s, 3H), 1.86 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 180.9, 161.7, 152.1, 139.2, 138.7, 133.4, 130.4, 128.7 (2C),
128.6 (2C), 126.4, 119.8, 118.7, 99.6, 55.3, 39.3, 9.5, 6.9. IR (υ/cm−1,
neat): 2955, 2925, 1660, 1574, 1377, 1332, 1257, 1164, 983, 733, 690,
475. HRMS (ESI) m/z for C19H21O3 (M + H)+, 297.1491; calcd,
297.1491. Data for 11′: Rf = 0.3 (6:4 cyclohexane/AcOEt).
1
cyclohexane/AcOEt). H NMR (300 MHz, CDCl3): δ 5.75 (dt, J =
5.7, 2.3 Hz, 1H), 5.62 (dt, J = 5.7, 2.2 Hz, 1H), 2.37−2.28 (m, 2H),
2.18−2.04 (m, 2H), 1.70−1.52 (m, 7H), 1.48−1.39 (m, 3H), 1.25 (s,
1H), 1.05 (s, 3H,). 13C NMR (75 MHz, CDCl3): δ 136.4, 131.3, 75.20,
57.6, 32.6, 32.4, 32.3, 31.7, 26.1, 22.5, 21.9, 21.9. IR (υ/cm−1, neat):
3368, 2926, 2854, 1718, 1449, 1078, 836. HRMS (EI) M+ for C12H20O
calcd, 180.1512; found, 180.1517.
1H NMR (300 MHz, CDCl3): δ 7.34−7.24 (m, 5H), 6.68 (dd, J =
15.6, 10.3 Hz, 1H), 6.45 (d, J = 15.7 Hz, 1H), 6.23 (appdd, J = 15.1,
10.3 Hz, 1H), 5.76 (dt, J = 14.4, 6.6 Hz, 1H), 3.87 (s, 3H), 3.35 (appd,
J = 6.6 Hz, 2H), 1.90 (s, 3H), 1.79 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 181.2, 162.4, 155.7, 137.1, 133.7, 132.6, 128.8 (2C), 128.1,
127.8, 126.7, 126.5 (2C), 119.1, 99.7, 55.5, 34.4, 10.0, 7.0. IR (υ/cm−1,
neat): 2956, 2925, 1663; 1575, 1464, 1412, 1251, 1165, 983, 732, 694,
476. HRMS (ESI) m/z for C19H21O3 (M + H)+, 297.1492; calcd,
297.1491.
1-Benzyl-4-(1-methylcyclopent-2-en-1-yl)piperidin-4-ol
(14b). To a sealed tube containing 7b (20 mg, 0.06 mmol, 1 equiv) in
anhydrous toluene (0.5 mL) was added Grubbs catalyst second
generation (2.5 mg, 0.003 mmol, 0.05 equiv) at rt. The solution was
stirred at 110 °C until complete conversion of the starting material (48
h). The mixture was then concentrated under reduced pressure and
purified by flash chromatography (9:1:0.1 CH2Cl2/MeOH/NH3 aq) to
give alcohol 14b (9 mg, 44%). Rf: 0.3 (9:1:0.1 CH2Cl2/MeOH/
Study of the Hydroalkylation of PhCHO. To a solution of 4
(402 mg, 0.94 mmol, 2 equiv) in anhydrous THF (5 mL) was added n-
BuLi (0. 59 mL, 0. 94 mmol, 1 equiv, C = 1.6 M in hexane) at −78 °C.
The solution was stirred for 5 min at this temperature before the
introduction of PhCHO (48 μL, 0.47 mmol, 1 equiv). The solution
was then stirred at this temperature for 30 min. The mixture was
quenched with sat. NH4Cl solution and extracted with Et2O (3 × 10
mL). The combined organic layers were washed with brine (10 mL),
dried (MgSO4), filtered, and concentrated under reduced pressure.
The crude was purified by flash chromatography (95:5 cyclohexane/
1
NH3 aq). H NMR (300 MHz, CDCl3): δ 7.37−7.27 (m, 5H), 5.7−
5.74 (m, 1H), 5.63−5.54 (m, 1H), 3.56 (br s, 2H), 2.87−2.67 (m,
2H), 2.46−2.24 (m, 4H), 2.18−2.01 (m, 1H), 1.98−1.72 (m, 2H),
1.61−1.37 (m, 4H), 1.06 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
135.9, 132.0, 129.5, 128.4, 127.2, 125.05, 7.4, 57.2, 49.5, 49.3, 32.6,
32.3, 29.8, 22.3. IR (υ/cm−1, neat): 3330, 2927, 2852, 1638, 1448,
1144, 1007, 746, 534. HRMS (ESI) [M + H]+ for C18H26NO calcd,
272.2014; found, 272.2017.
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(1-Methylcyclopent-2-en-1-yl)(phenyl)methanol (15c).27 To
a sealed tube containing 7a (20 mg, 0.08 mmol, 1 equiv) in anhydrous
toluene (1 mL) was added Grubbs catalyst second generation (7 mg,
0.008 mmol, 0.1 equiv) at rt. The solution was stirred at 110 °C until
complete conversion of the starting material (24 h). The mixture was
concentrated under reduced pressure and purified by flash
chromatography (9:1 cyclohexane/AcOEt) to give alcohol 15c (10
mg, 62% yield) as a colorless oil. Rf: 0.43 (8:2 cyclohexane/AcOEt).
1H NMR (300 MHz, CDCl3): δ 7.37−7.28 (m, 5H), 5.81 (dd, J = 5.3,
2.8 Hz, 1H), 5.65−5.55 (m, 1H), 4.53 (d, J = 4.8 Hz, 1H), 2.32 (m,
2H), 2.24−2.10 (m, 1H), 2.08−1.94 (m, 1H), 1.55 (s, 1 H, OH), 1.00
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 142.3, 135.4, 132.2, 127.8,
127.6 (2C), 127.2 (2C), 80.8, 34.5, 32.2, 29.7, 23.8. IR (υ/cm−1, neat):
3342, 2925, 2815, 2315, 1710, 1447, 1190, 684, 413. HRMS (EI) M+
for C13H16O calcd, 188.1201; found, 188.1201.
D.; Tosi, F.; Vila, C.; Stuart, M. C.A.; Elsinga, P. H.; Szymanski, W.;
Feringa, B. L. Angew. Chem., Int. Ed. 2017, 56, 3354−3359.
(3) (a) Reich, H. J.; Phillips, N. H. J. Am. Chem. Soc. 1986, 108,
2102−2103. (b) Reich, H. J.; Phillips, N. H. Pure Appl. Chem. 1987,
59, 1021−1026. (c) Reich, H. J.; H; Borst, J. P.; Coplien, M. B.;
Phillips, N. J. Am. Chem. Soc. 1992, 114, 6577−6579. (d) Reich, H. J. J.
Org. Chem. 2012, 77, 5471−5491.
(4) Barbero, A.; Pulido, F. J.; Rincon
D.; Martínez-García, H. Angew. Chem., Int. Ed. 2001, 40, 2101−2103.
(5) Barbero, A.; Pulido, F. J.; Rincon, J. A. J. Am. Chem. Soc. 2003,
125, 12049−1256.
́
, J. A.; Cuadrado, P.; Galisteo,
́
(6) (a) De Paolis, M.; Rosso, H.; Henrot, M.; Prandi, C.;
d’Herouville, F.; Maddaluno, J. Chem. - Eur. J. 2010, 16, 11229−
11232. (b) Rosso, H.; De Paolis, M.; Collin, V. C.; Dey, S.; Hecht, S.
M.; Prandi, C.; Richard, V.; Maddaluno, J. J. Org. Chem. 2011, 76,
9429−9437.
(7) (a) Despite several variations of experimental parameters such as
the reaction time, temperature, and order of addition of reagents (3
and n-BuLi), 1 was recovered unchanged. Higher temperature of
reaction led to the decomposition of 1; (b) For an overview of the
reactivity of 1 see: De Paolis, M. Targets in Heterocyclic Systems 2016,
20, 63−84.
(8) Generation of crotyllithium from the corresponding stannane has
been described in conjunction with AlMe3: (a) McGarvey, G. J.;
Williams, J. M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J. J. Am. Chem. Soc.
1986, 108, 4943−4952. (b) CuI/LiCl: Lipshutz, B. H.; Ellsworth, E.
L.; Dimock, S. H.; Smith, R. A. J. J. Am. Chem. Soc. 1990, 112, 4404−
4410.
3-(3,7-Dimethylocta-1,6-dien-3-yl)cyclohex-2-en-1one (16).
To a flask containing 7d (10 mg, 0.042 mmol, 1 equiv) in anhydrous
CH2Cl2 (0.5 mL) was added pyridinium chlorochromate (18 mg,
0.085 mmol, 2 equiv) at rt, and the reaction mixture was stirred at this
temperature for 3 h. The mixture was filtered under Florisil and
washed with CH2Cl2. After removal of the solvent, the residue was
purified by flash chromatography (9:1 cyclohexane/AcOEt) to give
enone 16 (8 mg, 81% yield) as a colorless oil. Rf: 0.45 (8:2
1
cyclohexane/AcOEt). H NMR (300 MHz, CDCl3): δ 5.98 (s, 1H),
5.77 (dd, J = 17.5, 10.8 Hz, 1H), 5.18−4.93 (m, 3H), 2.39−2.34 (m,
2H), 2.28 (dd, J = 11.2, 5.6 Hz, 2H), 1.99−1.91 (m, 2H), 1.84 (s, 2H),
1.67 (s, 3H), 1.57 (s, 3H), 1.53−1.42 (m, 2H) 1.20 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 200.5, 170.4, 144.0, 132.0, 125.7, 124.2, 113.9,
46.5, 37.9, 37.8, 26.5, 25.8, 23.4, 23.2, 22.4, 17.8. IR (υ/cm−1, neat):
3424, 2930, 1667, 1454, 1326, 1192, 965, 804, 411. HRMS (EI) M+ for
C16H24O calcd, 232.1827; found, 232.1832.
(9) Addition of crotylmagnesium bromide to enones: (a) Zair, T.;
Santelli-Rouvier, C.; Santelli, M. J. Org. Chem. 1993, 58, 2686−2693.
ketones: (b) Mladenova, M.; Blagoev, B.; Gaudemar, M.; Gaudemar-
Bardone, F.; Lallemand, J. Y. Tetrahedron 1981, 37, 2157−2163.
(c) Hoffmann, R. W.; Sander, T. Chem. Ber. 1990, 123, 145−152.
(10) Takeda, T.; Nishimura, T.; Yoshida, S.; Saiki, F.; Tajima, Y.;
Tsubouchi, A. Org. Lett. 2012, 14, 2042−2045.
ASSOCIATED CONTENT
* Supporting Information
■
S
SI contains . The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.organomet.7b00765.
(11) Li, J. M.; Zha, Z. G.; Sun, L. L.; Zhang, Y.; Wang, Z. Y. Chem.
Lett. 2006, 35, 498−499.
1
Detailed procedures and copies of H and 13C spectra
(12) (a) Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2004, 126, 8910−8911. See also: (b) Marson, C.; Walker, A. J.;
Pickering, J.; Harper, S.; Wrigglesworth, R.; Edge, S. J. Tetrahedron
1993, 49, 10317−10338. (c) Crotylation of difficult ketones with
catalytic indium and crotylboronate: Schneider, U.; Ueno, M.;
Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13824−13825.
(13) Transfer of geranyllithium to ketones: (a) Alonso, E.; Guijarro,
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: michael.depaolis@univ-rouen.fr.
■
́
D.; Martinez, P.; Ramon, J.; Yus, M. Tetrahedron 1999, 55, 11027−
ORCID
11038. (b) Guijarro, D.; Yus, M. J. Organomet. Chem. 2001, 624, 53−
57. (c) in the presence of copper: Tatsuta, K.; Tanaka, Y.; Kojima, M.;
Ikegami, H. Chem. Lett. 2002, 31, 14−15.
Michael De Paolis: 0000-0001-8139-3544
̈
Notes
The authors declare no competing financial interest.
(14) (a) Mimura, M.; Hayashida, M.; Nomiyama, K.; Ikegami, S.;
Sasmal, S.; Iida, Y.; Tamura, M.; Hiyama, Y.; Ohishi, Y. Chem. Pharm.
Bull. 1993, 41, 1971−1986. (b) Sasmal, S.; Balasubrahmanyam, D.;
Kanna Reddy, H. R.; Balaji, G.; Srinivas, G.; Cheera, S.; Abbineni, C.;
Sasmal, P. K.; Khanna, I.; Sebastian, V. J.; Frimurer, T. M.; Rist, Ø.;
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Ministere de l’Education
Nationale for a fellowhisp (M.C.), ISCE-CHEM (Interreg IV,
European Program), Labex SynOrg (ANR-11-LABX-0029),
and ANR (GPYRONE, 14-CE06-0016-01) for financial
support. We thank Masahiro Abe for kindly performing extra
experiments.
Elster, L.; Hogberg, T. Bioorg. Med. Chem. Lett. 2012, 22, 3163−3167.
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(15) Li, L.; Li, Z.-L.; Wang, F.-L.; Guo, Z.; Cheng, Y.-F.; Wang, N.;
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Commun. 2016, 7, 13852−13863.
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́
Szabo, K. J. Angew. Chem., Int. Ed. 2012, 51, 13050−13053. (b)
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