Enantioselective β-vinylation of α,β-unsaturated aldehydes using a β-nitroethyl sulfone as vinyl anion equivalent

Article abstract of DOI:10.1002/ejoc.201200150

A concise method for the asymmetric β-vinylation of enals is presented. The success of the reaction lies in the stereoselective organocatalyzed addition of β-nitroethyl sulfone 1 to enals and in the ability of Mg to promote the concomitant elimination of the sulfone moiety and the nitrous acid. The method performed in a three-step one-pot operation allows the synthesis of enantioenriched β-vinyl aldehydes and derivatives thereof. Copyright

Full text of DOI:10.1002/ejoc.201200150

FULL PAPER
DOI: 10.1002/ejoc.201200150
Enantioselective β-Vinylation of α,β-Unsaturated Aldehydes Using a
β-Nitroethyl Sulfone as Vinyl Anion Equivalent
Chiara Gianelli,[a] Rosa Lopez,[a] Ángel Puente,[a] Maitane Zalacain,[a] and
Claudio Palomo*[a]
Keywords: Asymmetric synthesis / One-pot reactions / Organocatalysis / Synthetic methods
A concise method for the asymmetric β-vinylation of enals is
presented. The success of the reaction lies in the stereoselec-
tive organocatalyzed addition of β-nitroethyl sulfone 1 to en-
als and in the ability of Mg to promote the concomitant elimi-
nation of the sulfone moiety and the nitrous acid. The method
performed in a three-step one-pot operation allows the syn-
thesis of enantioenriched β-vinyl aldehydes and derivatives
thereof.
of carrying out a concomitant elimination of both the sulf-
one and nitro groups in intermediate 3, without affecting
the stereochemical integrity of the new stereogenic center,
to directly produce enantiomerically enriched vinyl-substi-
tuted adducts 5 [Equation (1)]. In this way, β-nitroethyl sulf-
one 1 would act as a masked vinyl anion in the conjugate
additions, and the methodology could help to fill the gap
of methods for the direct β-vinylation of enals.[14]
Introduction
The development of methods to allow the rapid assembly
of simple starting materials into valuable building blocks
with very high chemical and stereochemical efficiency is
currently of considerable interest in synthetic organic chem-
istry.[1,2] Over the last two decades, asymmetric catalysis has
provided remarkable results in this area, and several cata-
lytic enantioselective methods based on chiral catalysts are
now available for a diversity of carbon–carbon bond-form-
ing reactions.[3–5] Considerable attention has been given to
the conjugate addition of nitro compounds, because the ni-
tronate nucleophile may be easily generated by treatment
with relatively weak bases,[6–8] and because – after proper
functional group manipulation – the diversity of acceptors
that may be involved in the reaction allows access to a
number of functionalized building blocks.[9] Although the
design of chiral catalysts has been the subject of most of
these studies, little attention has been paid to exploring ni-
troalkanes other than nitromethane or nonfunctionalized
nitroalkanes as substrates.[10] Recently, we reported an
operationally simple method for the stereoselective con-
struction of γ-substituted vinyl sulfones, which involved the
conjugate addition of base-sensitive β-nitroethyl sulfones to
enals promoted by catalyst I (Scheme 1).[11] From this ap-
proach, both the carbon–carbon bond and the new
stereogenic center are generated concurrently in a single
synthetic operation, a notable advantage over traditional
methods.[12] In an effort to expand the synthetic utility of
β-nitroethyl sulfones,[13] we decided to study the feasibility
Scheme 1. One-pot conjugate addition and nitrous acid elimination
to functionalized building blocks.
(1)
Results and Discussion
[a] Department of Organic Chemistry I, Universidad del País
Vasco, UPV/EHU,
In a preliminary experiment, the optimized conditions
previously described were employed to effect the enantiose-
lective conjugate addition of 1 to enal 2a (R = Bu). Once
the organocatalyzed addition was complete, the aldehyde
moiety in the resulting intermediate adduct was acetalyzed,
Apdo. 1072 Manuel de Lardizabal 3, 20018 San Sebastián,
Spain
Fax: +34-943-015270
E-mail: claudio.palomo@ehu.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200150.
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Enantioselective β-Vinylation of α,β-Unsaturated Aldehydes
Table 1. Screening of reaction conditions.[a]
Entry
3, R
Mg [equiv.]
Additives [equiv.]
T [°C], t [h]
Conversion [%][b]
6/7[b]
1
2
3
4
5
6
3a, Bu
3a, Bu
3a, Bu
3a, Bu
3b, Ph
3b, Ph
7.5
7.5
7.5
15
7.5
15
p-TsOH (0.15)
65, 15
r.t., 4
65, 15
65, 2
65, 15
65, 3
mixture[c]
n.r.[d]
90
Ͼ95
90
–
–
1:0
1:0
2:1
1:0
TMSCl, EDB (0.5)
TMSCl, EDB (0.5)
TMSCl, EDB (0.5)
TMSCl, EDB (0.5)
TMSCl, EDB (0.5)
Ͼ95
[a] Reactions conducted on a 0.5 mmol scale in MeOH (1 mL). [b] Reaction conversion and 6/7 ratio determined by 1H NMR spec-
troscopy. [c] A complex mixture was obtained. [d] No reaction was detected.
as presented in Scheme 1, to prevent side reactions.[15] The as 7 (Table 1, compare Entries 5 and 6). On the other hand,
initial study focused on the reaction of isolated adduct 3a the use of either sodium or aluminum amalgam under a
(dr = 1:1) in the presence of different amounts of Mg and variety of conditions produced complex mixtures in which
activators in methanol (see Table 1).[16] The best reactivity vinyl adducts 6 could not be detected.
occurred at refluxing temperature using 15 equiv. of Mg
The feasibility of a one-pot reaction for the vinylation of
with TMSCl (trimethylsilyl chloride) and EDB (ethylene di- enals was checked by adding the proper amounts of Mg
bromide) as additives (Table 1, Entry 4). Under these condi- (15 equiv.) and additives (0.5 equiv. of TMSCl and EDB)
tions aryl-substituted adduct 3b behaved similarly (Table 1, upon the completion of the addition and protection reac-
Entry 6). The analysis of the reaction mixtures before com- tions. To our delight, when these reaction conditions were
pletion revealed that the nitrous acid elimination, very likely applied to enal 2b, vinyl adduct 6b was produced after 3 h
promoted by the presence of Mg(OMe)2,[17] was faster than in 60% overall yield (isomerized 7 was not detected) and
the reductive sulfone elimination. The large excess amount 99%ee.[18] With these reaction conditions in hand, the enal
of metal seemed to accelerate both transformations and scope of the one-pot vinylation reaction was examined (see
helped to avoid the presence of isomerized compounds such Table 2). Under optimized conditions, enals 2a–g were suc-
Table 2. One-pot synthesis of β-vinyl-substituted aldehydes.[a]
[a] Addition reaction conducted on a 0.75 mmol scale using 1.3–1.5 equiv. of 1 in CH2Cl2 (1.5 mL). For the protection step, MeOH
(3.75 mL) was added. [b] Determined by chiral HPLC analysis or by NMR analysis using chiral shift reagents (see Supporting Infor-
mation). [c] Overall yield of isolated product starting from 2. [d] Aldehydes 5 were obtained by adding 6 n HCl to the reaction mixture
and heating at 50 °C (see Experimental Section for details).
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C. Gianelli, R. Lopez, Á. Puente, M. Zalacain, C. Palomo
FULL PAPER
cessfully transformed into the corresponding vinyl-substi- deprotection and subsequent one-pot reduction – afforded
tuted adducts. As the results in Table 2 show, products 6a– 15 in a good diastereomeric ratio, as a result of a concurrent
g were obtained in good yields and with excellent levels of intramolecular oxa-Michael reaction.[20]
enantioselectivity regardless of the nature of the enal substi-
tution. Thus, α,β-unsaturated aldehydes bearing electron-
poor or electron-rich arenes or β-alkyl substituents were
tolerated with equal efficiency. The procedure may also be
Conclusions
We have reported an operationally simple protocol for
applied to functionalized enals such as 2f and 2g to pro-
the β-vinylation of α,β-unsaturated aldehydes that consists
of an enantioselective conjugate addition to α,β-enals of a
β-nitroethyl sulfone, used as a new bench-stable, readily
available formal vinyl anion. The method is performed in a
one-pot, three-step operation without the need for interme-
diate isolation[21] and provides a quick entry to attractive
building blocks for organic synthesis.
duce, from readily available starting materials, highly func-
tionalized vinyl adducts with high chemical and stereo-
chemical efficiency. If vinyl aldehydes 5 are required for fur-
ther manipulation, a deprotection step can also be inte-
grated into the process by treatment with acid (see Table 2,
Entries 3 and 7).
In addition to the interest in vinyl scaffolds, the distinct
functionality of the resulting adducts provides additional
versatility to this procedure. For instance (see Scheme 2),
a palladium-catalyzed coupling reaction of alkyl and aryl
adducts 6 with different aryl halides afforded β-alkenyl-sub-
stituted aldehydes in good yields. On the other hand, 2,3-
disubstituted tetrahydrofurans would be obtained through a
halogen-promoted cyclization[19] after acetal hydrolysis and
aldehyde reduction of adducts 6 (see Scheme 3). Transfor-
mation of 6e into the corresponding alcohol, using standard
reaction conditions, followed by halocyclization afforded 12
and 13 in good yield, albeit with low diastereoselectivity.
Alternatively, 6e – upon treatment with ethyl acrylate and
Grubbs catalyst – provided adduct 14, which – upon acetal
Experimental Section
General Methods: The purification of the reaction products was
carried out by flash column chromatography using silica gel (0.040–
0.063 mm, 230–400 mesh). Thin layer chromatography was per-
formed on aluminium-backed silica plates. The developed chroma-
tograms were visualized by fluorescence quenching using phos-
1
phomolybdic acid. H and 13C NMR spectroscopic data were re-
corded at 300 MHz and 75 MHz, respectively. The chemical shifts
1
are reported in ppm relative to CDCl3 (δ = 7.26 ppm) for the H
NMR spectroscopic data and relative to the central resonances of
CDCl3 (δ = 77.23 ppm) for the 13C NMR spectroscopic data. HR
mass spectra were recorded with an ESI-ion trap mass spectrometer
and a TOF (time-of-flight) detector. All solvents were of p.a. (pro
analysi) quality and, if necessary, were dried by standard pro-
cedures prior to use. Unless otherwise specified, materials were ob-
tained from commercial sources and used without purification.
Catalyst I, β-nitroethyl sulfone 1,[11] and α,β-unsaturated aldehydes
2c,[22] 2e, and 2f[23] were prepared according to reported procedures.
The absolute configuration was determined by chemical correlation
and comparison to literature data[24] (i.e., adduct 6b was trans-
formed into its corresponding carboxylic acid). The absolute con-
figurations of the remaining compounds were assumed on the basis
of a uniform reaction mechanism. Racemic samples of adducts 6a–
g were prepared by employing a general procedure using pyrrolid-
ine (20 mol-%) as the catalyst. The enantiomeric excesses for ad-
1
ducts 6a and 6e were determined by H NMR analysis employing
Scheme 2. Synthesis of enantioenriched β-alkenyl-substituted enals.
chiral shift reagents. For adducts 6b, 6c, and 6d, the enantiomeric
excesses were determined by chiral HPLC analysis of their corre-
sponding carboxylic acids.[25] For adducts 6f and 6g, the enantio-
meric excesses were determined by chiral HPLC analysis of their
corresponding intermediates 4f and 4g,[25] as it was previously
noted that the ee values remain unchanged for vinyl sulfones 4 and
their corresponding vinyl adducts.
General Procedure for the β-Vinylation of Enals: To a solution of
catalyst I (0.075 mmol, 0.1 equiv.) and enal 2 (0.75 mmol, 1 equiv.)
in dry CH2Cl2 (1.5 mL) was added β-nitroethyl sulfone 1 (for reac-
tion with aliphatic enals, 0.23 g, 0.98 mmol, 1.3 equiv.; for reaction
with aromatic enals, 0.26 g, 1.12 mmol, 1.5 equiv.). The reaction
mixture was stirred at the indicated temperature (see Table 2).
When the enal was consumed, as detected by 1H NMR spec-
troscopy, MeOH (3.75 mL), HC(OMe)3 (0.17 mL, 1.5 mmol,
2 equiv.), and p-toluensulfonic acid (0.045 g, 0.225 mmol,
0.3 equiv.) were successively added. The reaction mixture was
stirred at room temperature, typically for 1 h, and then Mg turnings
Scheme 3. Synthesis of enantioenriched 2,3-disubstituted tetra-
hydrofurans.
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Enantioselective β-Vinylation of α,β-Unsaturated Aldehydes
(0.27 g, 11.25 mmol, 15 equiv.), TMSCl (for reaction with aliphatic
enals, 1.5 equiv.; for reaction with aromatic enals, 0.5 equiv.), and
EDB (for reaction with aliphatic enals, 1.5 equiv.; for reaction with
aromatic enals, 0.5 equiv.) were added. The flask was equipped with
a condenser, and the temperature was mantained at 65 °C or room
temperature as indicated in Table 2. When the starting material was
consumed, as detected by TLC, Et2O (10 mL) was added. The re-
sulting mixture was filtered, and the organic solvent was eliminated
from the filtrate. The resulting residue was triturated with Et2O.
The ethereal phases were combined, and the solvent was removed
at reduced pressure and low temperature (because of the volatility
of some of the products) to afford vinyl adducts 6.
1.76–1.65 (m, 1 H), 1.53–1.42 (m, 1 H), 1.41–1.18 (m, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 142.9, 139.6, 115.1, 114.6, 103.5,
53.2, 53.0, 40.5, 38.2, 35.5, 34.2, 29.5, 27.2 ppm.
(R)-tert-Butyl 5-(2,2-Dimethoxyethyl)hept-6-enylcarbamate (6g):
Yellow, pale oil (0.124 g, 55%, 98%ee). [α]2D5 = +5.38 (c = 0.58,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 5.59–5.45 (m, 1 H),
5.01 (s, 1 H), 4.99–4.92 (m, 1 H), 4.48 (br. s, 1 H), 4.38 (dd, J =
7.7, 4.0 Hz, 1 H), 3.30 (s, 3 H), 3.28 (s, 3 H), 3.08 (dd, J = 13.3,
6.4 Hz, 2 H), 2.18–2.03 (m, 1 H), 1.74–1.62 (m, 1 H), 1.53–1.45 (m,
1 H), 1.43 (s, 9 H), 1.36–1.20 (m, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 156.2, 142.6, 115.1, 103.3, 53.0, 52.7, 40.8, 40.2, 38.0,
35.3, 30.2, 28.6, 27.0, 26.8 ppm. HRMS (TOF, CI): calcd. for
C11H18NO2 [M – C4H9O – CH3OH]+ 196.1338; found 196.1353.
(R)-3-(2,2-Dimethoxyethyl)hept-1-ene (6a): Colorless oil (0.119 g,
85%, 97%ee). [α]2D5 = +4.06 (c = 0.66, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 5.63–5.46 (m, 1 H), 5.01 (s, 1 H), 4.99–
4.93 (m, 1 H), 4.39 (dd, J = 4.0, 7.7 Hz, 1 H), 3.31 (s, 3 H), 3.30
(s, 3 H), 2.10 (br. s, 1 H), 1.76–1.65 (m, 1 H), 1.52–1.43 (m, 1 H),
1.26 (m, 6 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 142.8, 114.9, 103.3, 53.0, 52.8, 40.3, 38.0, 35.1, 29.4,
22.9, 14.2 ppm. HRMS (TOF, CI): calcd. for C10H19O [M + H –
CH3OH]+ 155.1436; found 155.1451.
Synthesis of Aldehydes 5b and 5e: To directly obtain aldehydes 5,
the previous procedure was applied through to the filtration. Then,
HCl (6 m solution, 25 mL) was added to the filtrate, and this mix-
ture was heated to reflux for 8 h. After cooling to room tempera-
ture, the ethereal phase was separated and dried with MgSO4, and
the solvent was eliminated at reduced pressure and low temperature
(because of the volatility of some of the products) to afford crude
product 5, which was purified on silica gel by flash column
chromatography (hexane/EtOAc, 98:2).
(R)-(5,5-Dimethoxypent-1-en-3-yl)benzene (6b): Colorless oil
(0.093 g, 60%, 99%ee). [α]2D5 = –10.91 (c = 0.57, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 7.39–7.28 (m, 2 H), 7.28–7.19 (m, 3 H),
6.06–5.95 (m, 1 H), 5.16–5.04 (m, 2 H), 4.28 (t, J = 5.9 Hz, 1 H),
3.48 (q, J = 7.6 Hz, 1 H), 3.34 (s, 3 H), 3.32 (s, 3 H), 2.13–1.96 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.8, 141.8, 128.8,
127.8, 126.6, 114.5, 102.9, 52.9, 52.9, 45.7, 38.1 ppm. HRMS (TOF,
CI): calcd. for C12H14O [M – CH3OH]+ 174.1045; found 175.1030.
(R)-3-Phenylpent-4-enal (5b): Yellow oil (0.061 g, 51%). [α]2D5
=
1
–3.01 (c = 1.2, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 9.73 (t,
J = 2.0 Hz, 1 H), 7.37–7.18 (m, 5 H), 6.00 (ddd, J = 17.1, 10.3,
6.8 Hz, 1 H), 5.16–5.04 (m, 2 H), 3.96 (dd, J = 14.3, 7.2 Hz, 1 H),
2.93–2.76 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 201.4,
142.4, 140.3, 129.4, 128.0, 127.0, 115.3, 48.8, 43.8 ppm. HRMS
(TOF, CI): calcd. for C11H13O [M + H]+ 161.0966; found 161.0978.
(R)-3-Vinylundecanal (5e): Yellow oil (0.088 g, 60%). [α]2D5 = +0.85
(c = 0.47, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 9.75 (t, J =
(R)-1-Chloro-4-(5,5-dimethoxypent-1-en-3-yl)benzene (6c): Yellow
oil (0.119 g, 66%, 94%ee). [α]2D5 = –11.60 (c = 1.39, CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ = 7.31–7.25 (m, 2 H), 7.18–7.11 (m, 2
H), 5.99–5.85 (m, 1 H), 5.09 (dd, J = 2.2, 1.1 Hz, 1 H), 5.04 (dt, J
= 5.7, 1.3 Hz, 1 H), 4.22 (t, J = 5.9 Hz, 1 H), 3.43 (dd, J = 15.2,
7.5 Hz, 1 H), 3.30 (s, 3 H), 3.28 (s, 3 H), 2.09–1.88 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 142.2, 141.3, 132.3, 129.2, 128.9,
114.9, 102.8, 53.0, 52.9, 45.0, 38.0 ppm. HRMS (TOF, CI): calcd.
for C12H14OCl [M + H – CH3OH]+ 209.0733; found 209.0718.
1
2.4 Hz, 1 H), 5.79–5.55 (m, 1 H), 5.11–5.08 (m, 1 H), 5.07–5.03 (m,
1 H), 2.64 (dd, J = 6.0, 13.2 Hz, 1 H), 2.46 (dd, J = 0.8, 2.3 Hz, 1
H), 2.44 (t, J = 2.6 Hz, 1 H), 1.53–1.14 (m, 14 H), 0.92 (t, J =
6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 203.0, 141.5,
115.6, 49.0, 38.8, 35.2, 32.3, 30.0, 29.7, 27.3, 23.1, 14.5 ppm.
HRMS (TOF, CI): calcd. for C13H25O [M + H]+ 197.1905; found
197.1900.
General Procedure for the Synthesis of Compounds 8–11: To a mix-
ture of olefin 6 (0.25 mmol) and the aryl iodide (0.75 mmol,
3 equiv.) in CH3CN (2 mL) were added K2CO3 (0.052 g,
0.375 mmol, 1.5 equiv.), nBu4NOAc (0.151 g, 0.50 mmol, 2 equiv.),
and KCl (0.019 g, 0.25 mmol, 1 equiv.) under nitrogen. Then,
Pd(OAc)2 (3 mol-%, 0.002 g, 7.5 mmol) was added, and the re-
sulting mixture was heated to reflux at 85 °C for 2 h. After cooling
to room temperature, the solvent was evaporated, and the residue
was suspended again in Et2O (5 mL). The mixture was washed with
H2O (3ϫ2 mL). Then, the ethereal layer was dried with MgSO4
and concentrated under reduced pressure to give the crude product,
which was purified by flash column chromatography (hexane/
EtOAc, 98:2).
(R)-1-(5,5-Dimethoxypent-1-en-3-yl)-4-methoxybenzene (6d): Yel-
low oil (0.089 g, 50%, 98%ee). [α]2D5 = –5.19 (c = 0.58, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 7.15–7.09 (m, 2 H), 6.88–6.82
(m, 2 H), 6.00–5.87 (m, 1 H), 5.08–4.99 (m, 2 H), 4.23 (t, J =
5.9 Hz, 1 H), 3.79 (s, 3 H), 3.39 (q, J = 7.5 Hz, 1 H), 3.30 (s, 3 H),
3.28 (s, 3 H), 2.07–1.88 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 158.4, 142.5, 135.6, 128.7, 114.2, 114.1, 102.5, 55.8, 53.3, 45.2,
38.2 ppm. HRMS (TOF, CI): calcd. for C13H17O2 [M + H –
CH3OH]+ 205.1229; found 205.1224.
(R)-3-(2,2-Dimethoxyethyl)undec-1-ene (6e): Colorless oil (0.145 g,
80%, 97%ee). [α]2D5 = +5.50 (c = 0.34, CH2Cl2). 1HNMR
(300 MHz, CDCl3): δ = 5.63–5.45 (m, 1 H), 5.01 (s, 1 H), 4.98–
4.95 (m, 1 H), 4.39 (dd, J = 7.7, 4.0 Hz, 1 H), 3.31 (s, 3 H), 3.29
(s, 3 H), 2.13 (br. s, 1 H), 1.75–1.66 (m, 1 H), 1.52–1.43 (m, 1 H),
1.28 (br. s, 14 H), 0.88 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 142.8, 114.8, 103.3, 52.9, 52.8, 40.3, 38.0,
35.4, 32.1, 29.9, 29.8, 29.5, 27.2, 22.9, 14.3 ppm. HRMS (TOF, CI):
calcd. for C14H27O [M + H – CH3OH]+ 211.2062; found 211.2067.
(R,E)-[3-(2,2-Dimethoxyethyl)undec-1-enyl]benzene (8): Yellow oil
(0.064 g, 81%). [α]2D5 = –3.00 (c = 0.49, CH2Cl2). 1H NMR
(500 MHz, CDCl3): δ = 7.47–7.13 (m, 5 H), 6.39 (d, J = 15.8 Hz,
1 H), 5.99 (dd, J = 9.2, 15.8 Hz, 1 H), 4.44 (dd, J = 3.7, 7.4 Hz, 1
H), 3.35 (s, 3 H), 3.32 (s, 3 H), 2.32 (dd, J = 4.4, 8.5 Hz, 1 H), 1.82
(dd, J = 6.6, 14.6 Hz, 1 H), 1.64–1.53 (m, 1 H), 1.45–1.22 (m, 14
H), 0.90 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 137.7, 134.6, 130.1, 128.5, 126.9, 126.0, 103.0, 52.7, 52.7, 39.5,
(R)-3-(2,2-Dimethoxyethyl)nona-1,8-diene (6f): Yellow, pale oil
(0.080 g, 50%, 91%ee). [α]2D5 = +6.20 (c = 0.55, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 5.90–5.73 (m, 1 H), 5.63–5.47 (m, 1 H), 38.2, 35.6, 31.9, 29.7, 29.6, 29.3, 27.2, 22.7, 14.1 ppm. HRMS
5.02–4.89 (m, 4 H), 4.39 (dd, J = 7.7, 4.0 Hz, 1 H), 3.31 (s, 3 H),
3.30 (s, 3 H), 2.12 (br. s, 1 H), 2.03 (dd, J = 14.2, 6.7 Hz, 2 H),
(TOF, CI): calcd. for C20H31O [M + H – CH3OH]+ 287.2375; found
287.2375.
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(R,E)-1-[3-(2,2-Dimethoxyethyl)undec-1-enyl]-4-methoxybenzene
(9): Yellow oil (0.065 g, 75%). [α]2D5 = –4.17 (c = 0.96, CH2Cl2). 1H
NMR (500 MHz, CDCl3): δ = 7.32 (d, J = 8.5 Hz, 2 H), 6.87 (d,
J = 8.4 Hz, 2 H), 6.34 (d, J = 15.8 Hz, 1 H), 5.84 (dd, J = 9.2,
15.7 Hz, 1 H), 4.44 (dd, J = 3.7, 7.6 Hz, 1 H), 3.83 (s, 3 H), 3.35
(s, 3 H), 3.32 (s, 3 H), 2.34–2.23 (m, 1 H), 1.87–1.75 (m, 1 H), 1.69–
1.52 (m, 1 H), 1.50–1.18 (m, 14 H), 0.90 (t, J = 6.7 Hz, 3 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 132.7, 130.8, 129.7, 127.4, 114.2,
103.4, 55.6, 53.0, 52.9, 39.7, 38.6, 36.0, 32.1, 30.0, 29.8, 29.6, 27.4,
22.9, 14.4 ppm. HRMS (TOF, CI): calcd. for C21H33O2 [M + H –
CH3OH]+ 317.2481; found 317.2485.
32.9 (minor), 31.9 (major), 30.9 (minor), 29.7 (major), 29.5 (major),
29.3 (major), 28.4 (minor), 28.2 (minor), 28.0 (minor), 22.7 (major),
14.1 (minor), 10.5 (major), 6.1 (minor) ppm.
(3R)-2-(Iodomethyl)-3-octyltetrahydrofuran (13): In a darkened ves-
sel was placed a solution of the alcohol (0.050 g, 0.25 mmol) in
CH2Cl2 (1.5 mL). To this solution was added iodine (0.178 g,
0.7 mmol, 2.8 equiv.) and
a saturated solution of NaHCO3
(1.5 mL). The reaction mixture was stirred for 12 h and then
quenched by the addition of a saturated solution of Na2S2O3/
NaHCO3 (1:1). The aqueous layer was extracted with CH2Cl2, and
the combined organic extracts were dried with MgSO4 and filtered.
The solvent was removed under reduced pressure to give crude 13,
which was purified by flash column silica gel chromatography (hex-
ane/EtOAc, 95:5) to afford a yellow oil (0.049 g, 61%) as a 60:40
(R,E)-1-Chloro-4-[3-(2,2-dimethoxyethyl)undec-1-enyl]benzene (10):
Yellow oil (0.070 g, 79%). [α]2D5 = –3.34 (c = 1.10, CH2Cl2). 1H
NMR (500 MHz, CDCl3): δ = 7.34–7.10 (m, 4 H), 6.34 (d, J =
15.8 Hz, 1 H), 5.97 (dd, J = 9.2, 15.8 Hz, 1 H), 4.42 (dd, J = 3.9,
7.3 Hz, 1 H), 3.34 (s, 3 H), 3.32 (s, 3 H), 2.40–2.30 (m, 1 H), 1.61–
1.57 (m, 1 H), 1.89–1.78 (m, 1 H), 1.47–1.23 (m, 14 H), 0.90 (t, J
= 6.7 Hz, 4 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 136.4,
135.2, 132.4, 128.8, 127.2, 102.9, 52.7, 52.5, 39.5, 38.1, 35.6, 31.8,
29.7, 29.5, 29.3, 27.2, 22.7, 14.1 ppm. HRMS (TOF, CI): calcd. for
C20H29OCl [M – CH3OH]+ 320.1907; found 320.1922.
1
mixture of diastereomers. H NMR (300 MHz, CDCl3): δ = 4.17–
4.13 (m, 1 H, minor), 4.06–3.97 (m, 1 H, major), 3.92 (dd, J = 5.5,
7.6 Hz, 2 H, major), 3.88–3.80 (m, 1 H, minor), 3.52 (dd, J = 5.8,
11.0 Hz, 1 H, minor), 3.39 (dd, J = 4.7, 10.3 Hz, 1 H, minor), 3.25
(dd, J = 5.6, 10.2 Hz, 1 H, minor), 3.19 (dd, J = 5.6, 6.8 Hz, 2 H,
major), 2.32–2.22 (m, 1 H, minor), 2.22–2.02 (m, 2 H, major and
minor), 2.01–1.92 (m, 1 H, major), 1.82–1.59 (m, 2 H, major and
minor), 1.44–1.23 (m, 28 H, major and minor), 0.92 (t, J = 4.7 Hz,
6 H, major and minor) ppm. 13C NMR (75 MHz, CDCl3): δ = 83.8
(major), 81.8 (minor), 68.1 (major), 67.4 (minor), 45.5 (major), 42.4
(minor), 33.7 (major), 33.4 (minor), 32.3 (major), 31.4 (minor), 30.1
(major), 29.9 (major), 29.7 (major), 28.8 (minor), 28.6 (minor), 28.5
(minor), 23.1 (major), 14.5 (minor), 10.9 (major), 6.5 (minor) ppm.
HRMS (TOF, CI): calcd. for C13H26IO [M + H]+ 325.1028; found
325.1041.
(R,E)-1-(5,5-Dimethoxy-3-phenylpent-1-enyl)-4-methoxybenzene
(11): Yellow oil (0.050 g, 64%). [α]2D5 = +6.42 (c = 1.06, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 7.41–7.18 (m, 7 H), 6.96–6.88
(m, 2 H), 6.51–6.29 (m, 2 H), 4.33 (t, J = 5.9 Hz, 1 H), 3.84 (s, 3
H), 3.62 (q, J = 7.5 Hz, 1 H), 3.36 (s, 3 H), 3.35 (s, 3 H), 2.24–1.99
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.4, 137.7,
135.9, 133.9, 129.5, 128.8, 128.7, 127.3, 126.4, 114.3, 103.0, 55.5,
53.0, 52.9, 44.1, 38.7 ppm. HRMS (TOF, CI): calcd. for C20H25O3
[M + H]+ 313.1804; found 313.1819.
Synthesis of 2,3-Disubstituted Tetrahydrofuran 15: For step 1, to a
solution of olefin 6e (0.242 g, 1 mmol, 1 equiv.) in dry CH2Cl2
(5 mL) were added ethyl acrylate (0.32 mL, 3 mmol, 3 equiv.) and
a solution of Grubbs II catalyst (10 mol-%, 0.085 g) in CH2Cl2
(1 mL) under argon. The reaction mixture was heated at 40 °C and
stirred for 20 h. Then, the reaction mixture was concentrated under
reduced pressure to give the crude product, which was purified be-
fore the next step by flash column chromatography (hexane/EtOAc,
95:5) to afford olefin 14 as a yellow oil (0.211 g, 67%). Data for
Initial Step for the Synthesis of 2,3-Disubstituted Tetrahydrofurans
12 and 13: To a solution of 5e (0.175 g, 0.89 mmol) in CH2Cl2
(2 mL) was added a dispersion of NaBH4 (0.035 g, 1.80 mmol,
2 equiv.) in EtOH (1 mL) at 0 °C. The resulting suspension was
stirred at this temperature for 20 min, and then H2O (1 mL) was
added. The organic layer was separated, washed with H2O (1 mL),
dried with MgSO4, and concentrated to afford the alcohol as a
yellow oil (0.160 g, 91%), which was used in the next step without
(R,E)-ethyl 4-(2,2-dimethoxyethyl)dodec-2-enoate (14): [α]2D5
=
1
further purification. H NMR (300 MHz, CDCl3): δ = 5.61 (dd, J
1
–2.54 (c = 0.94, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 6.78
(dd, J = 9.4, 15.6 Hz, 1 H), 5.84 (dd, J = 0.7, 15.6 Hz, 1 H), 4.36
(dd, J = 4.4, 7.4 Hz, 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 3.34 (s, 3 H),
3.33 (s, 3 H), 2.43–2.25 (m, 1 H), 1.87–1.75 (m, 1 H), 1.67–1.54 (m,
1 H), 1.34–1.25 (m, 14 H), 0.91 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.1, 153.0, 121.8, 103.1, 60.7, 53.2, 53.2,
39.1, 37.7, 35.0, 32.3, 30.0, 29.9, 29.7, 27.4, 23.1, 14.7, 14.5 ppm.
HRMS (TOF, CI): calcd. for C17H31O3 [M + H – CH3OH]+
283.2273; found 283.2281. For step 2, to a solution of olefin 14
(0.175 g, 0.5 mmol, 1 equiv.), obtained from the previous step, in
Me2CO (2.5 mL) was added HCl (2 m solution, 2 mL). This mix-
ture was stirred at room temperature for 1 h, and then Me2CO was
removed under reduced pressure. The aqueous layer was extracted
with CH2Cl2 (3ϫ2 mL). The organic layer was dried with MgSO4,
= 9.0, 27.2 Hz, 1 H), 5.07 (dt, J = 1.3, 4.8 Hz, 1 H), 5.03–5.00 (m,
1 H), 3.82–3.63 (m, 3 H), 2.21–2.08 (m, 1 H), 1.56–1.45 (s, 2 H),
1.36–1.22 (m, 14 H), 0.92 (t, J = 6.7 Hz, 5 H) ppm.
(3R)-2-(Bromomethyl)-3-octyltetrahydrofuran (12): In a darkened
vessel was placed a solution of the alcohol (0.050 g, 0.25 mmol) in
CH3CN (1.5 mL). To this solution was added N-bromosuccinimide
(0.053 g, 0.3 mmol, 1.2 equiv.), and the reaction mixture was stirred
for 12 h and then quenched by the addition of a saturated solution
of Na2S2O3/NaHCO3 (1:1). The aqueous layer was extracted with
CH2Cl2, and the combined organic extracts were dried with MgSO4
and filtered. The solvent was removed under reduced pressure to
give the crude product 12, which was purified by silica gel
chromatography (hexane/EtOAc, 95:5) to afford a yellow oil
(0.053 g, 76%) as a 60:40 mixture of diastereomers. 1H NMR and the solvent was evaporated under reduced pressure to afford
(300 MHz, CDCl3): δ = 4.24–4.10 (m, 1 H, minor), 4.09–3.96 (m,
the pure unprotected olefin as a yellow oil (0.123 g, 92%). [α]2D5
=
1
1 H, major), 3.96–3.89 (m, 2 H, major), 3.88–3.81 (m, 1 H, minor), –2.26 (c = 1.04, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 9.76
3.80–3.73 (m, 1 H, minor), 3.56–3.50 (m, 1 H, minor), 3.44 (dd, J (t, J = 1.6 Hz, 1 H), 6.83 (dd, J = 8.6, 15.7 Hz, 1 H), 5.87 (dd, J
= 5.5, 10.9 Hz, 2 H, major), 3.37–3.32 (m, 1 H, minor), 2.76–2.66
= 15.7 Hz, 1 H), 4.22 (q, J = 7.1 Hz, 2 H), 2.93–2.74 (m, 1 H), 2.55
(m, 1 H, minor), 2.35–2.25 (m, 1 H, major), 2.20–2.02 (m, 2 H, (dd, J = 1.2, 6.2 Hz, 2 H), 1.70–1.14 (m, 14 H), 0.92 (t, J = 6.6 Hz,
major and minor), 1.80–1.57 (m, 2 H, major and minor), 1.43–1.19
(m, 28 H, major and minor), 0.99–0.84 (m, 6 H, major and minor)
ppm. 13C NMR (75 MHz, CDCl3): δ = 83.4 (major), 81.3 (minor),
67.7 (major), 67.0 (minor), 45.0 (major), 42.0 (minor), 33.2 (major),
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 200.7, 166.3, 150.5,
121.9, 60.4, 48.0, 36.5, 34.5, 31.8, 29.5, 29.4, 29.2, 27.0, 22.6, 14.2,
14.1 ppm. HRMS (TOF, CI): calcd. for C16H29O3 [M + H]+
269.2117; found 269.2127. For step 3, to a solution of the aldehyde
2778
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2774–2779

Enantioselective β-Vinylation of α,β-Unsaturated Aldehydes
lytic Enantioselective Conjugate Addition Reactions: A Powerful
Tool for the Stereocontrolled Synthesis of Complex Molecules,
RSC Publishing, Cambridge, 2010.
(0.054 g, 0.2 mmol, 1 equiv.), obtained in the previous step, in
CH2Cl2 (1 mL) was added a dispersion of NaBH4 (6.0 mg,
0.15 mmol, 0.75 equiv.) in EtOH (1 mL) at –10 °C. The resultant
suspension was stirred for 48 h at this temperature, and then H2O
(1 mL) was added. The organic layer was separated, washed with
H2O (1 mL), dried with MgSO4, and concentrated. The resulting
residue was purified by flash column chromatography (hexane/
EtOAc, 95:5) to afford 15 (yellow oil, 0.036 g, 66%) as a 90:10
mixture of diastereomers. For characterization, an analytical sam-
ple of the major diastereomer was isolated by preparative
chromatography. Data for ethyl 2-[(2S,3S)-2-octyltetrahydrofuran-
[9] R. Ballini, A. Palmieri, P. Righi, Tetrahedron 2007, 63, 12099–
12121.
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P. Dziedzic, J. Sun, C. Bonneau, A. Córdova, Chem. Eur. J.
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[11] R. López, M. Zalacain, C. Palomo, Chem. Eur. J. 2011, 17,
2450–2457.
1
3-yl]acetate (trans-15): [α]2D5 = +4.12 (c = 0.72, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 4.17 (q, J = 7.1 Hz, 2 H), 3.88 (dd, J =
4.5, 7.7 Hz, 1 H), 3.84 (dd, J = 6.1, 7.7 Hz, 2 H), 2.54 (dd, J = 4.5,
15.0 Hz, 1 H), 2.47 (dd, J = 8.1, 15.0 Hz, 1 H), 2.43–2.38 (m, 1 H),
2.09 (dt, J = 6.1, 13.8 Hz, 1 H), 1.86–1.78 (m, 1 H), 1.61–1.53 (m,
2 H), 1.32–1.24 (m, 15 H), 0.89 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 171.5, 80.7, 67.2, 60.5, 44.6, 40.2, 32.8, 32.5,
31.9, 29.8, 29.5, 29.3, 28.3, 22.6, 14.2, 14.1 ppm. HRMS (TOF, CI):
calcd. for C16H31O3 [M + H]+ 271.2273; found 271.2271.
[12] Traditional methods almost remain restricted to the addition of
sulfonyl-stabilized carbanions to chiral α-branched aldehydes,
which must be preformed in a separate operation. For reviews
on this topic, see: a) N. S. Simpkins, Tetrahedron 1990, 46,
6951–6984; b) I. Forristal, J. Sulfur Chem. 2005, 26, 163–195;
c) J. C. Carretero, R. Gómez-Arrayás, J. Adrio in Organosulfur
Chemistry in Asymmetric Synthesis (Eds.: T. Toru, C. Bolm),
Wiley-VCH, Weinheim, 2008, pp. 291–320.
[13] For the use of sulfones in organocatalysis, see: a) M. Nielsen,
C. B. Jacobsen, N. Holub, M. W. Paixao, K. A. Jørgensen, An-
gew. Chem. 2010, 122, 2726; Angew. Chem. Int. Ed. 2010, 49,
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Supporting Information (see footnote on the first page of this arti-
cle): HPLC spectra, assignment of the relative configuration of 15,
1
and copies of H and 13C NMR spectra.
[14] a) L. Sandra, D. W. C. MacMillan, J. Am. Chem. Soc. 2007,
129, 15438–15439; b) M. Nielsen, C. B. Jacobsen, M. W.
Paixao, N. Holub, K. A. Jørgensen, J. Am. Chem. Soc. 2009,
131, 10581–10586.
[15] Aldehyde protection was necessary; otherwise, complex mix-
tures were obtained during the subsequent step of nitrous acid
and sulfone elimination.
Acknowledgments
This work was financially supported by the University of the
Basque Country (UPV/EHU) (UFI 11/22), the Basque Govern-
ment (GV) (grant no. IT-291-07), and the Ministerio de Ciencia e
Innovación (MICNN), Spain (grant no. CTQ 2010-21263-CO2-01).
M. Z. thanks the Ministerio de Educación y Ciencia for the fellow-
ship. We are grateful to S. Giker (UPV/EHU) for the NMR and
HRMS facilities.
[16] C. Nájera, M. Yus, Tetrahedron 1999, 55, 10547–10658.
[17] HNO2 elimination is produced by treatment of
3 with
Mg(OMe)2. Nevertheless, a radical mechanism cannot be ex-
cluded.
[18] For the stereochemical assignment of adduct 6b, accomplished
by chemical correlation, and the determination of the enantio-
meric excesses, see the Supporting Information
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M. C. S. de Mattos, Curr. Org. Synth. 2005, 2, 393–44; b) A. M.
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hydrofurans, see: b) T. H. Graham, C. M. Jones, N. T. Jui,
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Received: February 8, 2012
Published Online: March 27, 2012
Eur. J. Org. Chem. 2012, 2774–2779
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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