Enantioselective allylation of α,β-unsaturated aldehydes with allyltrichlorosilane catalyzed by METHOX

Article abstract of DOI:10.1021/jo200712p

α,β-Unsaturated aldehydes 6a-j undergo an enantioselective allylation with allylic trichlorosilanes 2a,b in the presence of METHOX (4) as a Lewis basic catalyst (≤10 mol %) to produce the homoallylic alcohols 7a-l at good to high enantioselectivity (83-96% ee). This study shows that the reactivity scope of METHOX can be extended from aromatic to nonaromatic aldehydes.

Full text of DOI:10.1021/jo200712p

NOTE
pubs.acs.org/joc
Enantioselective Allylation of r,β-Unsaturated Aldehydes with
Allyltrichlorosilane Catalyzed by METHOX
Andrei V. Malkov,*,†,‡ Maciej Barzꢀog,† Yvonne Jewkes,†,z Jiꢁrí Mikuꢁsek,†,§ and Pavel Koꢁcovskꢀy*,†
†Department of Chemistry, WestChem, University of Glasgow, Glasgow G12 8QQ, U.K.
S Supporting Information
b
ABSTRACT: R,β-Unsaturated aldehydes 6aꢀj undergo an
enantioselective allylation with allylic trichlorosilanes 2a,b in
the presence of METHOX (4) as a Lewis basic catalyst (e10
mol %) to produce the homoallylic alcohols 7aꢀl at good to
high enantioselectivity (83ꢀ96% ee). This study shows that the
reactivity scope of METHOX can be extended from aromatic to nonaromatic aldehydes.
llylation of aldehydes 1 with allylsilanes constitutes a power-
ful methodology that can create up to two chiral centers
Scheme 1. Allylation of Aromatic Aldehydes
A
(Scheme 1). Its classical version, using allylic trialkylsilanes, re-
quires a Lewis acid as catalyst and in the case of crotyl-type silanes
produces syn-configured homoallylic alcohols 3c, irrespective of
the E/Z-configuration of the reagent. The latter outcome is be-
lieved to originate from an open transition state, in which a de-
liberate control of diastereoselectivity is difficult to attain.1 Further-
more, the Me3SiX, being released during the reaction, can itself
act as a Lewis acid and compete with the chiral Lewis acidic catalyst,
which has a negative effect on the enantioselectivity.1,2 By con-
trast, the more recently developed allylation/crotylation with allylic
trichlorosilanes 2aꢀc requires catalysis by a Lewis base,3 pro-
ceeds via a cyclic transition state, and as a result exhibits high
levels of stereocontrol,3 mimicking the allylation with allylbor-
anes and boronates.4 Another positive feature of this allylation is
the aqueous workup with NaHCO3, which generates innocuous,
readily separable inorganic byproducts (SiO2 and NaCl).3 There-
fore, this new methodology3 can be viewed as a robust alternative
to the existing and well-established protocols, which require stoi-
chiometric chiral auxiliaries or metal-based Lewis acids.4
Scheme 2. Allylation of r,β-Unsaturated Aldehydesa
In the past few years, we have developed novel pyridine
N-oxides,5ꢀ7 such as METHOX (4),6 which can be regarded
as one of the most successful organocatalysts for the asymmetric
allylation of aromatic aldehydes 1 with allylic trichlorosilanes 2
(e99% ee at 1ꢀ5 mol % catalyst loading).8ꢀ10 However, to date,
the scope of METHOX (4) and related N-monoxides, such as
QUINOX (5),7 was limited to aromatic aldehydes. We have
now endeavored to extend this methodology to the realm of
R,β-unsaturated aldehydes 6 (Scheme 2), which in view of the
previous experience was expected to proceed via the transition
state TS. To this end, we have selected representative aldehydes
with one or two conjugated double bonds 6aꢀe, R-branched
aldehydes 6f,g, and R-methylene aldehydes 6 hꢀj (Chart 1).
Aldehydes 6aꢀg are either commercially available or were
prepared by standard routes, involving Wittig-type chemistry
(6b). The R-methylene-aldehydes 6hꢀj were synthesized from
the corresponding aldehydes via the aldol condensation with
a For R1ꢀR3, see Charts 1 and 2.
formaldehyde, catalyzed by pyrrolidine and benzoic acid, follow-
ing the Pihko protocol.11
Received: April 6, 2011
Published: May 02, 2011
r
2011 American Chemical Society
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NOTE
Chart 1. R,β-Unsaturated Aldehydes
Chart 2. Products of Allylation of Aldehydes 6aꢀj with 2a,b
Catalyzed by METHOX (4)
Allylation of the R,β-unsaturated aldehydes 6 with 2a followed
our optimized protocol: MeCN as solvent, 1.5 equiv of 2a,
ꢀ30 °C, 10 mol % of METHOX (þ)-(4), and an excess of H€unig
base.12 Under these conditions, all of the aldehydes were found
to react with a practically full conversion within 3ꢀ5 days, as
1
shown by the H NMR spectra of the crude products.13 How-
ever, due to the volatility of some of the products and the small
scale of these experiments, which did not allow efficient recovery
of the products on the removal of the solvent, the isolated yields
turned out not to be as high as expected from the conversions.
Nevertheless, the enantiopurities of the products 7aꢀi (Chart 2)14
proved to be high (e93% ee), on average only ca. 5% below
those attained with aromatic aldehydes 1. Neither the R-branch-
ing (7f,g) nor the R-methylene pattern (7h,i) was detrimental to
the enantioselectivity.15 In the case of the R-methylene derivative
of citronellal 6j, the mismatched (R)-enantiomer afforded mainly
the syn-configured 7j as a ∼2:1 mixture of diastereoisomers,
whereas (S)-6j furnished the anti-diastereoisomer 7k (6:1 dr), as
1
revealed by the H NMR spectra of the crude product.16 The
same reaction catalyzed by DMF17 afforded a ∼1:1 anti/syn
mixture. Crotylation of aldehyde 6d with 2b, carried out under
the same conditions, gave rise to the expected anti-diastereoi-
somer 7l as the only product with the highest enantiomeric excess
(96% ee). It is pertinent to note that METHOX was always
recovered almost quantitatively by chromatography in all these
reactions.18
These results show that the scope of METHOX (4) as or-
ganocatalyst is not limited to aromatic aldehydes and that it
can be successfully employed in the allylation and crotylation of
R,β-unsaturated aldehydes. The latter catalyst thus supplements
the bipyridine-type N,N0-dioxides, recently developed by Kotora
(e97% ee), whose synthesis is rather more complicated.9j,l,m
Of particular importance is the finding that the R-branching, as in
6f,g, is not detrimental to the enantioselection, which was not
observed in the previous studies.9j,l,m
sector mass spectrometer using direct inlet and the lowest temperature
enabling evaporation. Reactions were performed under an atmosphere
of dry, oxygen-free nitrogen in oven-dried glassware twice evacuated and
filled with the nitrogen. Solvents and solutions were transferred by syringe-
septum technique. THF was obtained from Pure-Solv Solvent Purifica-
tion System (Innovative Technology); acetonitrile, dichloromethane, and
H€unig base were freshly distilled from CaH2. Petroleum ether (PE)
refers to the fraction boiling in the range of 40ꢀ60 °C, AcOEt refers to
ethyl acetate, MeOH refers to methanol. The identity of the products
prepared by different methods was checked by comparison of their
NMR, IR, and MS data and by the TLC behavior. Allyltrichlorosilane
(2a) is commercially available. Trichlorocrotylsilane 2b was prepared
from the commercial trans-crotyl chloride (6:1) as a 6:1 trans/cis
mixture,5ꢀ7 which was not separated, as METHOX is known to exhibit
strong kinetic preference for the trans-isomer 2b.5ꢀ7 Aldehydes 6hꢀj
were prepared according to Pihko’s protocol.11
General Procedure for the Reaction of Allyltrichlorosilane
(2a) and Crotyltrichlorosilane (2b) with Aldehydes 6. An
oven-dried flask was filled with argon and charged with Methox (þ)-4
or Quinox (R)-(þ)-5 (0.075 mmol), followed by acetonitrile (5 mL, in
the case of Methox) or dichloromethane (5 mL, in the case of Quinox),
diisopropylethylamine (478 mg, 3.7 mmol), and aldehyde 6 (0.75 mmol).
The mixture was then cooled to ꢀ45 °C, and allyltrichlorosilane or
crotyltrichlorosilane (1.10 mmol) was added dropwise. The mixture was
stirred at ꢀ45 °C for 4 h and then kept in a freezer at ꢀ30 °C for 5 days.
The reaction was quenched with aqueous satd NaHCO3, the product
was extracted with ethyl acetate, and the organic solution was dried with
’ EXPERIMENTAL SECTION
General Methods and Materials. Melting points were deter-
mined on a Kofler block and are uncorrected. The NMR spectra were
recorded for CDCl3 solutions, 1H at 400 MHz and 13C at 100.6 MHz
with chloroform-d1 (δ 7.26, 1H; δ 77.0, 13C) or TMS as internal standard
unless otherwise indicated. Various 2D techniques and DEPT experi-
ments were used to establish the structures and to assign the signals. The
IR spectra were recorded for a thin film of CHCl3 solutions between
NaCl plates. The mass spectra (EI and/or CI) were measured on a dual
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NOTE
MgSO4 and evaporated The crude product was purified by chromatog-
raphy on a column of silica gel (15 cm ꢁ 1.5 cm) with a mixture of
petroleum ether and ethyl acetate (95:5). In all cases the conversions
were g95%, as revealed by GC and NMR analysis of the crude mixtures.
The isolated yields of 7 and ee are given in Chart 2. The enantiopurity of
the resulting alcohol was determined by chiral GC, or HPLC, or by
Mosher derivatization (see below).
(4S,5E,7E)-(ꢀ)-1,5,7-Nonatrien-4-ol (7e). Obtained as a yel-
lowish oil (151 mg, 42%): [R]D ꢀ7.7 (c 1.8, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 1.67 (d, J = 3.9, 1H), 1.76 (dd, J = 6.7, 1.2 Hz, 3H), 2.25ꢀ2.38
(m, 2H), 4.16ꢀ4.22 (m, 1H), 5.11ꢀ5.17 (m, 2H), 5.57 (dd, J = 15.2,
6.6 Hz, 1H). 5.71 (dd, J = 15.0, 6.8 Hz, 1H), 5.80 (dddd, J = 17.0, 10.3,
7.4, 6.8 Hz, 1H), 6.04 (ddd, J = 15.1, 10.5, 1.5 Hz, 1H), 6.20 (dd, J = 15.1,
10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 18.2 (CH3), 42.0 (CH2),
71.5 (CH), 118.3 (CH2), 130.2 (CH), 130.7 (CH), 131.0 (CH), 132.3
(CH), 134.2 (CH); IR ν 3362, 3078, 3018, 2916, 1435, 1261, 1025, 985,
913 cmꢀ1; MS (EIþ) m/z (%) 138 (Mþ, 23), 97 (100), 79 (41); HRMS
(EIþ) 138.1048 (C9H14O requires 138.1045), all consistent with the
literature data.21,22 19F NMR of the corresponding Mosher ester showed
g86% ee (δR = ꢀ71.47, δS = ꢀ71.53).22
(S,E)-(ꢀ)-1-Phenyl-hexa-1,5-dien-3-ol (7a). Obtained as a
1
yellowish oil (445 mg, 75%): [R]D ꢀ25.6 (c 1.0, CHCl3); H NMR
(400 MHz, CDCl3) δ 1.72 (br d, J = 4.0 Hz, 1H), 2.27ꢀ2.41 (m, 2H),
4.29 (m, 1H), 5.08ꢀ5.15 (m, 2H), 5.74ꢀ5.84 (dddd, J = 17.1, 10.2, 7.4,
6.9 Hz, 1H), 6.17 (dd, J = 15.9 and 6.3 Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H),
7.15ꢀ7.33 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 42.0 (CH2), 71.7
(CH), 118.5 (CH2), 126.5 (2 ꢁ CH), 127.7 (CH), 128.6 (2 ꢁ CH),
130.4 (CH), 131.6 (CH), 134.1 (CH), 136.7C); IR ν 3371, 3070, 3026,
2926, 2850, 1495, 1449, 1217, 1030, 997, 966, 916, 748 cmꢀ1; MS (CI/
isobutane) m/z (%) 157 (100, MꢀOH), 133 (24); HRMS (CI/
isobutane) 157.1016 (C12H13 requires 157.1017), all identical to the
data of an authentic sample of the (þ)-enantiomer;5a chiral HPLC
(4S,5E)-(ꢀ)-5-Methyl-1,5-octadien-4-ol (7f)23. Obtained as a
1
colorless oil (196 mg 65%): [R]D ꢀ11.6 (c 0.9, CHCl3); H NMR
(400 MHz, CDCl3) δ 0.96 (t, J = 7.5 Hz, 3H), 1.61 (s, CH3 and OH),
2.03 (quintet, J = 7.4 Hz, 2H), 1.99ꢀ2.38 (m, 2H), 4.01ꢀ4.05 (m, 1H),
5.07ꢀ5.15 (m, 2H), 5.40 (dt, J = 7.1, 1.1 Hz, 1H), 5.76 (dddd, J = 17.2,
10.2, 7.3, 6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 11.5 (CH3), 14.0
(CH3), 20.8 (CH2), 39.9 (CH2), (CH), 117.6 (CH2), 128.5 (CH),
134.9 (CH), 135.7 (C); IR ν 3369, 2963,2934, 2874, 1641, 1125,
1066 cmꢀ1; MS (CI/isobutane) m/z (%) 123 [(M ꢀ OH)þ, 100], 99
(15), 81 (10), 69 (10); HRMS (CI/isobutane) 123.1167 (C9H15
requires 123.1168); GC analysis (Supelco γ-DEX 120 column, oven:
70 °C, then 0.5 °C minꢀ1 to 90 °C) showed 93% ee (tR = 32.52 min, tS =
33.62 min).
(Chiralcel IB column, hexane/2-propanol = 97:3, 0.75 mL minꢀ1
)
showed 88% ee (tR = 18.5 min, tS = 27.7 min).
(S,E)-(ꢀ)-8-Phenylocta-1,5-dien-4-ol (7b). Obtained as a light
yellow oil (78 mg, 49%): [R]D ꢀ12.5 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 2.13ꢀ2.25 (m, 2H), 2.24ꢀ2.31 (m, 2H), 2.62 (dd, J = 8.1, 7.4
Hz, 2H), 4.03 (br q, J = 6.3 Hz, 1H), 5.02ꢀ5.07 (m, 2H), 5.42 (tdd, J =
15.4, 6.7, 1.3 Hz, 1H), 5.63 (dtd, J = 15.4, 6.7, 0.9 Hz, 1H), 5.70 (dddd,
J = 18.0, 10.6, 7.3, 6.8 Hz, 1H), 7.09ꢀ7.13 (m, 3H), 7.17ꢀ7.22 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 32.9 (CH2), 34.5 (CH2), 40.9 (CH2),
70.7 (CH), 117.1 (CH2), 124.8 (CH), 127.3 (2 ꢁ CH), 127.4 (2 ꢁ
CH), 130.1 (CH), 131.8 (CH), 133.3 (CH), 140.7 (C); IR ν 3315, 3055,
2932, 1435, 1265, 972, 918, 708 cmꢀ1; MS (CI/isobutane) m/z (%) 185
(M ꢀ OH, 100), 161 (43), 142 (81), 117 (19), 91 (16), 81 (9); HRMS
(CI/isobutane) 185.1327 (C14H17 requires 185.1330); HPLC analysis
(Chiralcel OJ-H, hexane/2-propanol 95:5, 0.75 mL minꢀ1) showed 89%
ee (tR = 14.8 min, tS = 17.1 min).
(S)-(ꢀ)-(10-Cyclohexen-10-yl)but-3-en-1-ol (7g). Obtained as
a colorless oil (73 mg, 37%): [R]D ꢀ17.5 (c 1.0, CHCl3); 1H NMR (400
MHz; CDCl3) δ 1.50ꢀ1.71 (m, 4H þ 1H (OH)), 1.89ꢀ1.96 (m, 1H)],
1.98ꢀ2.11 (m, 3H), 2.25ꢀ2.38 (m, 2H), 3.94 (t, J = 6.5 Hz, 1H),
5.02ꢀ5.08 (m, 2H), 5.61 (br s, 1H), 5.72 (dddd, J = 17.1, 10.2, 7.4, 6.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.62 (CH2), 22.63 (CH2),
23.9 (CH2), 25.0 (CH2), 39.9 (CH2), 75.2 (CH), 117.7 (CH2), 123.1
(CH), 135.0 (C), 139.2 (CH); IR ν 3347, 2926 2858, 2837, 1641, 1298,
1269, 1137, 1030 cmꢀ1; MS (CI/isobutane) m/z (%) 135 (M ꢀ OH,
35), 113 (57), 107 (90), 97 (40), all consistent with the literature data;24
HRMS (CI/isobutane) 135.1177 (C10H15 requires 135.1174); 19F
NMR of the corresponding Mosher’s ester showed 83% ee (δR = ꢀ71.32,
δS = ꢀ71.57).
(4S,5E,7E)-(ꢀ)-8-Phenyl-1,5,7-octatrien-4-ol (7c). Obtained
1
as a yellowish oil (183.7 mg, 73%): [R]D ꢀ23.6 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3) 1.65 (d, J = 4.0 Hz, 1H), 2.23ꢀ2.37 (m, 2H),
4.19ꢀ4.25 (m, 1H), 5.08ꢀ5.14 (m, 2H), 5.72ꢀ5.82 (m, 2H), 6.35 (dd,
J = 15.2, 10.5 Hz, 1H), 6.47 (d, J = 15.7 Hz, 1H), 6.70 (dd, J = 15.5, 10.6
Hz, 1H), 7.13ꢀ7.36 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 42.0
(CH2), 71.4 (CH), 118.5 (CH2), 126.4 (2 ꢁ CH), 127.6 (CH), 128.2
(CH) 128.6 (2 ꢁ CH), 130.8 (CH), 132.8 (CH), 134.0 (CH), 135.6
(CH), 137.2 (C); IR ν 3364, 3078, 3024, 2905, 1641, 1492, 1447, 1297,
1071, 1026, 986, 914, 746, 691 cmꢀ1; MS (CI/isobutane) m/z (%) 183
(100, M ꢀ OH), 159 (10), 107 (15), 81 (10), 73 (10); HRMS (CI/
isobutane) 183.1172 (C14H15 requires 183.1168), all in accordance with
the literature data given for the racemate;19 HPLC analysis (Chiralcel
OD-H, hexane/propan-2-ol, 96:4, 0.75 mL minꢀ1) showed 88% ee (tR =
18.54 min, tS = 22.78 min).
(S)-(ꢀ)-2-Benzylhexa-1,5-dien-3-ol (7h). Obtained as a color-
less oil (68 mg, 46%): [R]D ꢀ3.2 (c 0.5, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 1.63 (d, J = 3.8 Hz, 1H), 2.23 (dt, J = 14.2, 7.7 Hz, 1H),
2.32ꢀ2.38 (m, 1H), 3.27 (d, J = 15.6 Hz, 1H), 3.41 (d, J = 15.6 Hz, 1H),
4.04ꢀ4.08 (m, 1H), 4.73 (d, J = 1.2 Hz, 1H), 5.05 (d, J = 1.2 Hz, 1H),
5.05 (br s, 1H), 5.07ꢀ5.10 (m, 1H), 5.09 (d, J = 1,2 Hz, 1H), 5.67ꢀ5.77
(m, 1H), 7.12ꢀ7.25 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 39.2
(CH2), 40.4 (CH2), 73.2 (CH), 112.4 (CH2), 118.4 (CH2), 126.4
(CH), 128.5 (2 ꢁ CH), 129.3 (2 ꢁ CH), 134.6 (CH), 139.3 (C), 150.6
(C); IR ν 3321, 3055, 2924, 1435, 1265, 910, 740 cmꢀ1; MS (CI/
isobutane) m/z (%) 171 (47, MþꢀOH), 129 (20), 113 (21), 97 (27);
HRMS (CI/isobutane) 171.1177 (C13H15 requires 171.1174); chiral
GC analysis (Supelco β-DEX 120 column, oven at 100 °C for 2 min then
1 °C minꢀ1) showed 88% ee for the Methox experiment carried out at
ꢀ45 °C, 70% ee for the Methox experiment carried out at ꢀ30 °C, and
80% ee (opposite enantiomer) for the (R)-(þ)-Quinox experiment
carried out at ꢀ30 °C (tR = 50.14 min, tS = 50.49 min).
(4S,5E)-(ꢀ)-1,5-Nonadien-4-ol (7d). Obtained as a yellowish oil
1
(244 mg, 68%): [R]D ꢀ14.1 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 0.90 (t, J = 7.4 Hz, 3H), 1.40 (sext, J = 7.4 Hz, 2H), 1.63 (br s
1H), 1.95 (q, J = 7.1 Hz, 2H), 2.23ꢀ2.36 (m, 2H), 4.12 (q, J = 6.3 Hz,
1H), 5.10ꢀ5.16 (m, 2H), 5.48 (ddd, J = 15.4, 6.7, 1.4 Hz, 1H), 5.61 (dt,
J = 15.4, 6.7 Hz, 1H), 5.80 (dddd, J = 17.1, 10.4, 7.4, 6.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.7 (CH3), 22.3 (CH2), 34.3 (CH2), 42.1
(CH2), 71.9 (CH), 118.0 (CH2), 132.1 (CH), 132.2 (CH), 134.5 (CH);
IR ν 3433, 3414, 3333, 2960, 2930, 2911, 2873, 1436, 1261, 1027, 995,
968, 914 cmꢀ1; MS (CI/isobutane) m/z (%) 123 [(M ꢀ OH)þ, 100],
113 (5), 99 (45), 81 (20), 67 (10) in agreement with the literature;20
HRMS (CI/isobutane) 123.1160 (C9H15 requires 123.1174); 19F NMR
of the corresponding Mosher ester showed 87% ee (δR = ꢀ71.46,
δS = ꢀ71.51).
(S)-(ꢀ)-2-Ethyl-1,5-hexadien-3-ol (7i). Obtained as a yellowish
oil (215 mg, 48%): [R]D ꢀ30.3 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 1.08 (t, J = 7.4 Hz, 3H), 1.68 (d, J = 3.9 Hz, 1H), 2.02 (dq, J =
16.5, 7.4 Hz, 1H), 2.13 (dq, J = 16.3, 7.5 Hz, 1H), 2.28 (dt, J = 14.2, 7.7
Hz, 1H), 2.37ꢀ2.44 (m, 1H), 4.12ꢀ4.16 (m, 1H), 4.87 (d, J = 1.4 Hz,
1H), 5.05 (t, J = 1.1 Hz, 1H), 5.11ꢀ5.18 (m, 2H), 5.80 (dddd, J = 17.1,
10.2, 7.4, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 12.2 (CH3), 24.4
(CH2), 40.4 (CH2), 74.0 (CH), 108.5 (CH2), 118.1 (CH2), 134.7 (CH),
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NOTE
152.7 (C); IR ν 3380, 3078, 3025, 2931, 1641, 1434, 1297, 989, 915, 748,
692 cmꢀ1; MS (CI/isobutane) m/z (%) 1109 (MþꢀOH, 100), 95 (19),
85 (30); HRMS (CI/isobutane) 109.1019 (C8H13 requires 109.1017); GC
analysis (Supelco γ-DEX 120 column, oven: 50 °C for 2 min, then 0.5 °C
minꢀ1 to 70 °C) showed 89% ee (tR = 36.06 min, tS = 36.44 min).
(4S,6R)-(ꢀ)-6,10-Dimethyl-5-methyleneundeca-1,9-dien-
4-ol (7j). Obtained as a yellowish oil (46 mg, 60%): [R]D ꢀ27.6 (c 0.5,
CHCl3); 1H NMR (400 MHz, CDCl3, main diastereoisomer) δ 1.05 (d,
J = 6.9 Hz, 3H), 1.30ꢀ1.40 (m, 1H), 1.45ꢀ1.50 (m, 1H), 1.52 (s, 3H),
1.56 (d, J = 3.8 Hz, 1H), 1.61 (s, 3H) 1.87ꢀ1.93 (m, 2H), 2.01ꢀ2.08 (m,
1H), 2.15ꢀ2.22 (m, 1H), 2.30ꢀ2.37 (m, 1 H), 4.00ꢀ4.04 (m, 1H), 4.84
(s, 1H), 5.00ꢀ5.10 (m, 4H), 5.71ꢀ5.82 (m, 1H); 13C NMR (100 MHz,
CDCl3; major diastereoisomer) δ 17.7 (CH3), 21.6 (CH3), 25.7 (CH3),
26.1 (CH2), 35.6 (CH), 36.5 (CH2), 40.9 (CH2), 73.1 (CH), 108.0
(CH2), 117.9 (CH2), 124.6 (CH), 131.5 (C), 134.9 (CH), 157.1 (C);
IR ν 3335, 3055, 2924, 1442, 1381, 1265, 1049, 995, 733 cmꢀ1; MS (CI/
isobutane) m/z (%) 191 (M ꢀ OH, 80), 167 (17), 149 (20), 135 (39),
109 (29), 81 (69), 69 (100); HRMS (CI/isobutane) 191.1797 (C14H23
requires 191.1800).
(4S,6S)-(þ)-6,10-Dimethyl-5-methyleneundeca-1,9-dien-
4-ol (7k). Obtained as a colorless oil (55 mg, 57%): [R]D þ7.5 (c 0.5,
CHCl3); 1H NMR (400 MHz, CDCl3, main diastereoisomer) δ 1.08 (d,
J = 6.9 Hz, 3H), 1.30ꢀ1.40 (m, Hz, 1H), 1.49 (ddt, J = 15.7, 8.9, 6.7 Hz,
1H), 1.59 (s, 3H), 1.69 (br s, 4H), 1.84ꢀ1.92 (m, 2H), 2.02 (sxt, J = 6.9
Hz, 1H), 2.18 (br pent, J = 6.9 Hz, 1H), 2.31ꢀ2.38 (m, 1H), 4.01ꢀ4.05
(m, 1H), 4.85 (s, 1H), 5.00ꢀ5.12 (m, 4H), 5.75 (dddd, J = 17.0, 10.3,
7.5, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3; δ 17.7 (CH3), 20.7
(CH3), 25.7 (CH3), 25.9 (CH2), 35.4 (CH), 37.4 (CH2), 40.8 (CH2),
73.3 (CH), 107.8 (CH2), 118.1 (CH2), 124.4 (CH), 131.6 (C), 134.8
(CH), 157.1 (C); IR ν 3389, 3077, 2965, 2916, 2857, 1642, 1452, 1437,
1377, 1109, 1047, 901 cmꢀ1; MS (CI/isobutane) m/z (%) 209 (M þ
H, 9), 191 (M ꢀ OH, 100), 167 (16) 149 (24), 135 (58), 124 (15), 109
(31), 95 (41), 81 (28); HRMS (CI/isobutane) 209.1901 (C14H25O
requires 209.1905).
Present Addresses
‡Department of Chemistry, Loughborough University, Lough-
borough, Leics LE11 3TU, UK.
zCharles River Laboratories, Tranent, Edinburgh EH33 2NE,
UK.
Notes
§Exchange Erasmus student from the Faculty of Pharmacy,
Charles University, 500 05 Hradec Krꢀalovꢀe, Czech Republic.
’ ACKNOWLEDGMENT
We thank the EPSRC for grant No. EP/E011179/1 and the
Erasmus Exchange Program for support to J.M.
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(3S,4R,E)-(ꢀ)-3-Methylnona-1,5-dien-4-ol (7l). Obtained as a
colorless oil (103 mg, 67%): [R]D ꢀ3.3 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 0.90 (t, J = 7.4 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H),
1.34ꢀ1.47 (m, 2H), 1.73 (br s, 1H), 1.96ꢀ2.10 (m, 2H), 2.17ꢀ2.26
(m, 1H), 3.79 (t, J = 7.3 Hz, 1H), 5.05ꢀ5.10 (m, 2H), 5.42 (tdd, J = 15.4,
7.5, 1.3 Hz, 1H), 5.60 (dt, J = 15.4, 6.7, 1H), 5.69 (ddd, J = 16.7, 10.8, 8.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.8 (CH3), 16.3 (CH3), 22.4
(CH2), 34.5 (CH2), 44.7 (CH), 76.5 (CH), 116.5 (CH2), 130.8 (CH),
133.8 (CH), 140.8 (CH); IR ν 3385, 2957, 2925, 2855, 1639,1260,
1015 cmꢀ1; MS (CI/isobutane) m/z (%) 137 (M ꢀ OH, 35), 91 (49),
69 (100); HRMS (CI/isobutane) 137.1307 (C10H17 requires 137.1330);
GC analysis (Supelco R-DEX 120 column, oven: 50 °C, then 1 °C
(7) (a) Malkov, A. V.; Dufkovꢀa, L.; Farrugia, L.; Koꢁcovskꢀy, P. Angew.
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minꢀ1) showed 36:1 dr and 96% ee for the major enantiomer (t3S,4R
43.21 min, t3R,4S = 43.62 min).
=
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’ ASSOCIATED CONTENT
S
Supporting Information. General experimental methods
b
and 1H and 13C NMR spectra for new allylation products (7b, 7f,
7h, 7i, and 7l) and chiral HPLC/GC traces (7aꢀc, 7f, 7h, 7i,
and 7l) and 19F NMR spectra of the Mosher derivatives (7d, 7e,
and 7g). This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: a.malkov@lboro.ac.uk; pavelk@chem.gla.ac.uk.
4803
dx.doi.org/10.1021/jo200712p |J. Org. Chem. 2011, 76, 4800–4804

The Journal of Organic Chemistry
NOTE
Valterovꢀa, I.; Hodaꢁcovꢀa, J.; Císaꢁrovꢀa, I.; Kotora, M. Adv. Synth. Catal.
2008, 350, 1449. (j) Hrdina, R.; Boyd, T.; Valterovꢀa, I.; Hodaꢁcovꢀa, J.;
Kotora, M. Synlett 2008, 3141–3144. (k) Hrdina, R.; Opekar, F.;
Roithovꢀa, J.; Kotora, M. Chem. Commun. 2009, 2314. (l) Kadlꢁcíkovꢀa,
A.; Hrdina, R.; Valterovꢀa, I.; Kotora, M. Adv. Synth. Catal. 2009,
351, 1279. (m) Kadlꢁcíkovꢀa, A.; Valterovꢀa, I.; Duchꢀaꢁckovꢀa, L.; Roithovꢀa,
J.; Kotora, M. Chem.—Eur. J. 2010, 16, 9442. (n) Duchꢀaꢁckovꢀa, L.;
Kadlꢁcíkovꢀa, A.; Kotora, M.; Roithovꢀa, J. J. Am. Chem. Soc. 2010,
132, 12660. (o) Vlaꢁsanꢀa, K.; Hrdina, R.; Valterovꢀa, I.; Kotora, M. Eur.
J. Org. Chem. 2010, 7040. (p) For an overview, see: Kotora, M. Pure Appl.
Chem. 2010, 82, 1813.
(24) Kimura, M.; Shimizu, M.; Tanaka, S.; Tamaru, Y. Tetrahedron
2005, 61, 3709.
(10) For analogous N,N0,N00-trioxides, see: (a) Wong, W.-L.; Lee,
C.-S.; Leung, H. K.; Kwong, H.-L. Org. Biomol. Chem. 2004, 1967. For
polymeric poly-N-oxides, see: (b) M€uller, C. A.; Hoffart, T.; Holbach,
M.; Reggelin, M. Macromolecules 2005, 38, 5375.
(11) Erkkil€a, A.; Pihko, P. M. Eur. J. Org. Chem. 2007, 4205.
(12) The higher reactivity of aromatic aldehydes allowed the use of
as little as 1ꢀ5 mol% of METHOX. Here, the higher loading was
required to attain reasonable reaction times.
(13) In the case of aldehyde 6h, the reaction was carried out at
ꢀ45 °C (approximately the freezing point of the mixture) for 5 h and
then quenched. The conversion to 7h was therefore rather low: the
crude product was a ∼3:2 mixture of the unreacted aldehyde to alcohol,
as revealed by NMR spectroscopy.
(14) The absolute configuration of alcohols 7 has not been rigor-
ously established but is assumed to be (S) as shown, in analogy with their
aromatic counterparts.5ꢀ7
(15) In the Methox-catalyzed reaction, 7h was obtained in 88% ee at
ꢀ45 °C and in 70% ee at ꢀ30 °C. With (R)-(þ)-Quinox, an opposite
enantiomer of 7h was obtained in 80% ee at ꢀ30 °C.
(16) The relative configuration is proposed on the assumption that
the allylations catalyzed by METHOX (þ)-4 afford the (S)-configured
alcohols.6
(17) For activation of trichlorosilyl derivatives by DMF and other
Lewis bases, see ref 3 and the following: (a) Kobayashi, S.; Nishio, K.
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(18) The recovered METHOX, collected from several experiments
and combined, can be purified by crystallization and used again. No
difference has been observed between the “new” and “second-hand”
samples of METHOX, as will be fully demonstrated in a separate paper.
(19) Kostikov, R. R. Zh. Org. Khim. 1971, 7, 2297.
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(22) The starting aldehyde 6e has to be stored at ꢀ20 °C to prevent
partial trans/cis isomerization of the double bond. The NMR spectra of
the samples of alcohol 7e contained minor peaks corresponding to that
isomerization. Inevitably, the 19F NMR spectrum of the Mosher ester of
racemic 7e showed a pair of major peaks (1:1) and another pair of minor
peaks. In the spectrum of the enantiomerically enriched 7e one of the
two major peaks remained, whereas its partner peak was very small and
partly overlapped with one of the pair of the minor peaks. Therefore, the
enantiomeric ratio could not be determined with the accuracy attained
with other members of the series. Hence, the final figure (g86% ee)
represents a conservative estimate and might be actually slightly higher.
(23) For the corresponding racemate, see: Knorr, A. German Patent
544,388, 1930; Chem. Abstr. 1932, 26, 2466.
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