An improved two-step synthetic route to primary allylic alcohols from aldehydes

Article abstract of DOI:10.1039/b9nj00710e

An improved two-step synthetic route to allylic alcohols from aldehydes has been developed. A modification of the HWE reaction in H₂O-2-PrOH (1 : 1) and a convenient protocol to prepare AlH₃ in THF from LiAlH ₄ and n-BuBr are the key factors in the improvement.

Full text of DOI:10.1039/b9nj00710e

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PAPER
www.rsc.org/njc | New Journal of Chemistry
An improved two-step synthetic route to primary allylic alcohols
from aldehydesw
Zheng Liu, Yaqiong Gong, Hoe-Sup Byun and Robert Bittman*
Received (in Montpellier, France) 25th November 2009, Accepted 2nd December 2009
First published as an Advance Article on the web 12th January 2010
DOI: 10.1039/b9nj00710e
An improved two-step synthetic route to allylic alcohols from aldehydes has been developed.
A modification of the HWE reaction in H2O–2-PrOH (1 : 1) and a convenient protocol to
prepare AlH3 in THF from LiAlH4 and n-BuBr are the key factors in the improvement.
Unfortunately, DIBAL-H reduction requires more than 2
equiv., and workup is tedious because it involves the use of
large volume of aqueous potassium sodium tartrate
Introduction
Allylic alcohols are important synthons in organic synthesis,
and asymmetric epoxidation1,2 of allylic alcohols is widely
used at the chiral induction stage in many syntheses of natural
products. Among the many ways to prepare allylic alcohols,
an important two-step route is the Horner–Wadsworth–
Emmons (HWE) olefination reaction of aldehydes with
dialkyl carboalkoxymethylenephosphonates to generate
a,b-unsaturated esters followed by reduction with DIBAL-H.
Most generally, the HWE reaction3 is carried out using a
hydride ion or organometallic base in anhydrous aprotic
solvents under an inert atmosphere. In nonpolar solvents the
reaction of stabilized ylides with aldehydes proceeds very
slowly.4 Moreover, the E/Z stereoselectivity of the HWE
reaction is complicated by several factors, such as the nature
of the metal counterion employed,5 the reaction temperature,5
the size of the phosphonoester reagent used,6 and the
presence of oxygen-containing groups adjacent to the carbonyl
group.3c In contrast to the traditional HWE reaction, the
aqueous HWE reaction7 offers several advantages, such as:
(1) it can be used for large-scale preparations; (2)
wet aldehydes can be used directly in the reaction as
substrates; (3) water is believed to accelerate the reaction;8
(4) it is environmentally benign; (5) base-sensitive functional
groups can survive under the reaction conditions; (6) high
E-selectivities can normally be achieved. For example, HWE
reactions of triethyl phosphonoacetate with aldehydes in
highly concentrated (6–10 M) aqueous solutions of K2CO3
or KHCO3 have been reported.9 However, as the introduction
of water as the essential medium for performing the HWE
reaction utilizing poorly water-soluble aldehydes is very
limited, only isolated examples are known; therefore, phase
transfer catalysts10 and high reaction temperatures7 (up to 100 1C)
are generally required.
a
(Rochelle salt; Seignette salt) solution. Although AlH3 also
reduces a,b-unsaturated esters to allylic alcohols, and in some
instances may be superior to both DIBAL-H and LAH,13 its
preparation is cumbersome. Thus DIBAL-H continues to be
the most commonly used reagent.
Currently, there are three methods of preparation of AlH3.
First, alane can be prepared by the reaction of three equiva-
lents of LAH with AlCl3.14 AlH3 prepared in this way is not
always pristine since a mixed chloroaluminium hydride species
can be formed, depending on the proportions of LAH and
AlCl3.15 In addition, AlCl3 is hygroscopic and difficult to
handle. Second, AlH3 can be prepared by treating LAH with
the theoretical quantity of 100% H2SO4 in THF.16 This
protocol is problematical because it is difficult to prepare a
standardized LAH solution in THF and to control the addi-
tion of the theoretical quantity of the very viscous 100%
H2SO4 into the LAH solution. Indeed, it was reported that
addition of dilute H2SO4 to a solution of LAH in THF led to
an explosion.17 In a third method, a tertiary amine–alane
adduct was utilized.18 This procedure makes the preparation
simpler but still requires the extraction of the amine–
alane complex from LAH under an inert atmosphere.
Reports that AlH3 is formed as a by-product of the reduction
of an alkyl halide with LAH19,20 and that AlH3 generated
in this way reduced ethyl a-(hydroxymethyl)acrylate to
a-(hydroxymethyl)acrolein21 were little noted,22 as evident
from the continued usage of 100% H2SO4 and LAH to
generate AlH3, e.g., in the total synthesis of (ꢀ)-gelsemine.23
In this paper we show that the HWE reaction of a variety of
aldehydes with triethyl phosphonoacetate in the presence of
K2CO3 in H2O–2-PrOH (1 : 1) produced (E)-a,b-unsaturated
esters with convenience and efficiency. We used 2-PrOH as the
co-solvent, and discovered that at room temperature the mixed
solvent broadens the spectrum of substrates that can be used
and improves the reaction yield without any detrimental effect
on their high E-selectivities. We also report an improved
and convenient procedure for the preparation of AlH3
and its in situ reduction of (E)-a,b-unsaturated esters. The
combination of these two provides an improved route to
primary allylic alcohols from aldehydes, especially on a large
scale (Scheme 1).
For the reduction of a,b-unsaturated esters, DIBAL-H11 is
the preferred reagent because other reducing reagents such
12
as LiAlH4 (LAH) and NaBH4 generally give low yields
as a result of competing 1,2- and 1,4-addition reactions.
Department of Chemistry and Biochemistry, Queens College of
The City University of New York, Flushing, NY 11367-1597, USA.
E-mail: robert.bittman@qc.cuny.edu
w Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra of all new compounds. See DOI: 10.1039/b9nj00710e
ꢁc
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Ph3PQCHCO2Me in methanol (ꢂ78 to 20 1C) to yield
a
mixture of diacrylates enriched in the Z,Z isomer
(Z,Z/Z,E/E,E = ca. 12 : 10 : 1).25 Chromatography on silica
gel followed by crystallization in hexane affords the pure Z,Z
isomer of the corresponding dimethyl diacrylate as colorless
crystals.26 In contrast, we found that the reaction of
dialdehyde a6 with the phosphonate in H2O–2-PrOH followed
by column chromatography on silica gel provided the
E,E isomer b6 in 71% yield (entry 2). The reaction with
a-(p-methoxyphenoxy)-acetaldehyde (a7) provided the corres-
ponding (E)-conjugated ester b7 (entry 3), which was also
prepared by a substitution reaction of alkyl 4-bromocrotonate
with 4-methoxyphenol.27 Significantly, this method is effective
for the olefination of base-sensitive aldehydes, probably
because the reaction of triethyl phosphonoacetate with
CO3 in water produces a CO32ꢂ–HCO3 buffer (pH 10.7).
The aldehydes shown in entries 4 and 5 can undergo a base-
induced anomerization via b-elimination followed by an
intramolecular hetero-Michael reaction,28 and thus can be
contaminated by the b-epimer. To our delight, in the olefination
reactions shown in entries 4 and 5, no b-anomer of the
conjugated esters was observed. 4-(p-Methoxybenzyloxy)-
butanal (a10) was prepared by 2,2,6,6-tetramethyl-1-piperdi-
nyloxy (TEMPO) catalyzed oxidation of the corresponding
alcohol with NCS29 because we found that partial deprotection
of the p-methoxybenzyl group occurred during Swern
oxidation of PMBO(CH2)4OH.30 The resulting crude a10
underwent the HWE reaction directly with moderate
E-selectivity as well as eco-friendly character29b (entry 6).
Scheme
1 HWE reaction in H2O–2-PrOH and reduction of
a,b-unsaturated esters by AlH3.
Results and discussion
HWE reactions in H2O–2-PrOH (1 : 1)
The reactions of a1–a4 with triethyl phosphonoacetate
furnished the corresponding (E)-a,b-unsaturated esters b1–b4
in high yield and E-selectivity (Table 1). Wet heptadec-2-ynal
(a4), obtained by formylation of 1-hexadecyne, can be
subjected to our procedure directly without column chromato-
graphy to provide the corresponding enyne ester with
predominantly E-selectivity (entry 4). In comparison, our
previous investigation24 showed that the HWE reaction of
hexadec-2-ynal with triethyl phosphonoacetate using LiBr and
Et3N5b proceeded with an E/Z ratio of 10 : 1 to 15 : 1 in the
enyne ester, but the use of the sterically larger diisopropyl
(ethoxycarbonylmethyl)phosphonate in the reaction, as
expected,6 provided the E isomer exclusively.
2ꢂ
ꢂ
To expand the scope of our modified HWE reaction, we also
examined the conversion of aldehydes a6–a10, which bear
oxygen-containing groups adjacent to the carbonyl group, to
a,b-unsaturated esters b6–b10 (Table 2). It has been reported3c
that the reaction of this type of aldehyde with stabilized
phosphonium ylides (Ph3PQCHCO2R) often results in
abnormal reaction stereochemistry, and in certain cases
furnishes highly Z-rich acrylate mixtures. The aldehydes in
entries 1–5 of Table 2 were prepared by oxidative cleavage of a
vicinal diol with NaIO4, followed by removal of the generated
formaldehyde under reduced pressure without any further
purification. Condensation of glyceraldehyde acetonide a5
with triethyl phosphonoacetate afforded the (E)-conjugated
ester b5 as an 18/1 E–Z mixture (entry 1). A previous study
showed that dialdehyde a6 (entry 2) reacted with
Generation of AlH3 and synthesis of allylic alcohols
The data in Tables 1 and 2 show that generation of AlH3 in
THF from LAH and n-BuBr22 followed by in situ reduction of
(E)-a,b-unsaturated esters b1–b10 provides very high yields of
allylic alcohols c1–c10. In comparison to the commonly
used DIBAL-H-mediated reduction, this procedure has the
following advantages, especially when scale-up is desired: (1)
a,b-unsaturated esters can be reduced with only 1.3 equiv. of
LAH;31 and (2) the workup procedure is very simple, involving
quenching the reaction by the addition of a stoichiometric
quantity of 1 M NaOH solution or Na2SO4ꢃ10H2O (B3 equiv.
of water based on LAH), followed by filtration through a pad
of Celite.
Table 1 HWE reactions of aromatic and aliphatic aldehydes (a)
followed by AlH3 reduction of the resulting a,b-unsaturated esters
(b) to afford allylic alcohols (c)
RCHO
a
Methoxyalane
Yielda (%), E : Zb Yielda (%)
Entry
1
Solvents may have a critical impact on the use of AlH3. When
AlH3 is prepared by the reaction of LAH with AlCl3 in Et2O, a
white precipitate is formed on standing overnight or longer,
which, of course, results in a decrease in its reducing
capacity.16a In THF at reflux, a slow cleavage reaction takes
place to give n-BuOH.16a For this reason, we prepared
AlH2(OMe)32,33 in toluene by the reaction of LAH with
n-BuBr and (CH2O)n at ꢂ78 1C. The yield of c1 obtained by
the AlH2(OMe)-mediated reduction of b1 in toluene was
comparable to that found with AlH3 in THF, indicating that
AlH2(OMe) in toluene may be used for the 1,2-reduction of
a,b-unsaturated esters to allylic alcohols when THF is not a
suitable solvent.
b1
c1
a1
a2
a3
92, 10 : 1
95
b2
c2
2
3
87, E only
83
b3
c3
96
c4
87
95, E only
b4
4
a4
88, E only
a
b
Isolated yields. E/Z ratios were determined by 13C NMR.
ꢁc
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1
Table 2 HWE reaction of aldehydes (a) with oxygen-containing
groups adjacent to the carbonyl group followed by AlH3 reduction
of the resulting a,b-unsaturated esters (b) to afford allylic alcohols (c)
(230–400 ASTM mesh). H NMR spectra were obtained on
400 MHz or 500 MHz spectrometers. Chemical shifts were
referenced on residual solvent peaks: CDCl3 (d = 7.26 ppm
for 1H NMR and 77.00 ppm for 13C NMR), C6D6 (d =
7.16 ppm for H NMR and 128.00 ppm for 13C NMR).
1
RCHO
a
Yielda (%), E : Zb Yielda (%)
Entry
1
Typical procedure for preparation of a,b-unsaturated ester
by HWE reaction in water–2-PrOH: preparation of b8
b5
c5
To a solution of NaIO4 (4.12 g, 19.2 mmol) in 100 mL of water
was added NaHCO3 (160 mg, 1.91 mmol) and then a solution
of 3-(20,30,40,60-tetra-O-benzyl-a-D-galactopyranosyl)-1,2-
propanediol (8.69 g, 14.5 mmol) in 100 mL THF at 0 1C. After
the oxidative cleavage was completed (about 2 h at rt), the mixture
was concentrated under reduced pressure to remove THF and
the formaldehyde formed. The crude aldehyde a8 was used
directly in the HWE reaction without any further purification.
To a mixture of crude aldehyde a8 and triethyl phosphono-
acetate (4.68 g, 20.9 mmol) in 50 mL of 2-PrOH was added
dropwise a solution of K2CO3 (26.0 g, 187 mmol) in 50 mL of
water at 0 1C. The mixture was gradually warmed to rt and
was stirred overnight at rt. The product was extracted with
EtOAc (3 ꢄ 100 mL), and the combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The
product was purified by column chromatography on silica gel
(elution with hexane–EtOAc 10 : 1, 8 : 1, and 6 : 1) to give
8.23 g (89%) of ethyl 4-(20,30,40,60-tetra-O-benzyl-a-D-galacto-
pyranosyl)-2(E)-butenoate (b8) together with 219 mg (2.4%)
of its Z isomer (Z-b8, which was contaminated with the E
a5
85, 18 : 1
75
b6
c6
2
3
a6
71, E only
b7
72
c7
88
a7
86, 28 : 1
b8
c8
87
c9
4
a8
89, >38 : 1
1
b9
isomer) as colorless oils. b834: H NMR (400 MHz, CDCl3) d
5
1.24 (t, 3H, J = 7.1 Hz), 2.36–2.46 (m, 1H), 2.49–2.59 (m, 1H),
3.66 (dd, 1H, J = 4.6, 10.5 Hz), 3.69–3.75 (m, 2H), 3.79–3.87
(m, 1H), 3.97–4.01 (m, 1H), 4.01–4.09 (m, 2H), 4.14 (q, 2H,
J = 7.1 Hz), 4.43–4.73 (m, 8H), 5.87 (d, 1H, J = 15.6 Hz),
6.91 (dt, 1H, J = 7.1, 15.6 Hz), 7.20–7.36 (m, 20H); 13C NMR
(100 MHz, CDCl3) d 14.2, 30.8, 60.1, 66.9, 70.0, 72.7, 73.05,
73.09, 73.2, 74.0, 76.3, 123.2, 127.4, 127.50, 127.54, 127.61,
127.72, 127.79, 127.81, 127.9, 128.25, 128.27, 128.31, 128.34,
a9
87, E only
b10
85
c10
89
6
a10
85, 7 : 1
a
b
Isolated yields. E/Z ratios of entries 1–4 and 6 were determined by
13C NMR; the E/Z ratio of entry 5 was determined by isolation of each
compound.
137.9, 138.24, 138.28, 138.33, 145.4, 166.3. HRMS (ESI)
+
(MNH4
) C40H48NO7 calcd for m/z 654.3425, found
1
654.3427. Z-b8: H NMR (400 MHz, CDCl3) d 1.25 (t, J =
7.1 Hz, 3H), 2.87–2.97 (m, 1H), 3.14–3.27 (m, 1H), 3.51–3.64
(m, 1H), 3.72–3.79 (m, 2H), 3.84–3.92 (m, 1H), 3.97–4.01
(m, 1H), 4.02–4.07 (m, 2H), 4.41–4.81 (m, 8H), 5.83 (d, J =
11.5 Hz, 1H), 6.28 (dt, J = 11.5, 7.1 Hz, 1H), 7.19–7.41
(m, 20H); 13C NMR (100 MHz, CDCl3) d 14.2, 59.8, 67.7,
72.0, 73.0, 73.1, 73.2, 73.4, 73.5, 74.3, 120.9, 127.41, 127.49,
127.56, 127.60, 127.8, 127.9, 128.1, 128.20, 128.24, 128.28,
128.31, 128.39, 138.30, 138.32, 138.45, 138.55, 147.1, 166.4.
Conclusion
In summary, HWE reactions of aldehydes in H2O–2-PrOH
followed by in situ reduction of the (E)-a,b-unsaturated esters
using alane generated from n-BuBr and LAH provide easy
access to primary allylic alcohols.
Experimental
General experimental methods
Typical procedure for AlH3 reduction of an a,b-unsaturated
ester in THF: preparation of c8
All reactions were carried out under
a dry nitrogen
atmosphere using oven-dried glassware and magnetic stirring.
The solvents were dried as follows: THF was heated at reflux
over sodium benzophenone ketyl; toluene was heated at reflux
over sodium. Silica gel 60 F254 aluminium TLC plates of
0.2 mm thickness were used to monitor the reactions. The
spots were visualized with short wavelength ultraviolet light
or by charring after spraying with 15% H2SO4. Flash
chromatography was carried out with silica gel 60
To a mixture of LAH (700 mg, 18.4 mmol, 95% fine powder)
in 100 mL of THF was added n-BuBr (2.0 mL, 18.5 mmol) at
ꢂ78 1C. The reaction mixture was warmed to rt and stirred
overnight. To the mixture was added a solution of b8 (7.96 g,
12.5 mmol) in 50 mL of THF at ꢂ78 1C. After being stirred for
2 h, the mixture was gradually warmed to rt. After all of the
starting ester was consumed (about 2 h at rt), the reaction was
ꢁc
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1H
quenched by addition of 2 mL of 1 M NaOH solution. The
mixture was diluted with 150 mL of CH2Cl2 and passed
through a pad of Celite, which was washed with 250 mL of
EtOAc. The filtrate was concentrated under reduced pressure,
and the residue was purified by column chromatography on
silica gel (elution with hexane–EtOAc 2 : 1 and 1 : 1) to give
(E)-3-(4-Octylphenyl)prop-2-en-1-ol
(c3).
NMR
(500 MHz, CDCl3) d 0.88 (t, J = 7.1 Hz, 3H), 1.21–1.36
(m, 10H), 1.44 (t, 4.9, 1H), 1.55–1.64 (m, 2H), 2.58 (t, J =
7.8 Hz, 2H), 4.31 (t, J = 4.8 Hz, 2H), 6.32 (dt, J = 15.9,
5.9 Hz, 1H), 6.59 (d, J = 15.9 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H),
7.30 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 14.1,
22.7, 29.28, 29.33, 29.5, 31.5, 31.9, 35.7, 63.9, 126.4, 127.4,
126.7, 131.3, 134.0, 142.7.
6.47
g
(87%) of 4-(20,30,40,60-tetra-O-benzyl-a-D-galacto-
pyranosyl)-2(E)-buten-1-ol (c834) as a colorless oil: H NMR
(400 MHz, CDCl3) d 1.71 (br s, 1H), 2.25–2.35 (m, 1H),
2.35–2.45 (m, 1H), 3.60 (dd, 1H, J = 4.2, 10.5 Hz),
3.69–3.78 (m, 2H), 3.79–3.88 (m, 1H), 3.91–4.07 (m, 5H),
4.43–4.73 (m, 8H), 5.53–5.69 (m, 2H), 7.22–7.35 (m, 20H);
13C NMR (100 MHz, CDCl3) d 30.5, 63.4, 67.4, 70.7, 72.3,
72.90, 72.96, 73.02, 73.08, 74.2, 76.3, 76.4, 127.39, 127.46,
127.51, 127.53, 127.7, 127.81, 127.85, 128.19, 128.26, 128.8,
131.3, 138.10, 138.17, 138.29, 138.5.
1
(E)-Ethyl 6-(4-methoxybenzyloxy)hex-2-enoate (b10). Matches
the published data.29b
(E)-6-(4-Methoxybenzyloxy)hex-2-en-1-ol (c10). Matches
the published data.40
1
(E)-Ethyl nonadec-2-en-4-ynoate (b4). H NMR (400 MHz,
CDCl3) d 0.88 (t, J = 7.1 Hz, 3H), 1.19–1.45 (m, 25H),
1.50–1.60 (m, 2H), 2.36 (dt, J = 2.2, 7.1 Hz, 2H), 4.20
(q, J = 7.1 Hz, 2H), 6.13 (d, J = 15.8 Hz, 1H), 6.76
(dt, J = 15.8, 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
14.1, 14.2, 19.7, 22.7, 28.3, 28.8, 29.1, 29.3, 29.5, 29.58, 29.62,
29.65, 29.67, 31.9, 60.5, 77.9, 100.8, 126.1, 129.2, 166.1.
Procedure for reduction of a,b-unsaturated ester b1 with
AlH2(OMe) in toluene: preparation of c1
To a suspension of LAH (2.10 g, 55.3 mmol, 95% fine powder)
in 100 mL of toluene were added n-BuBr (6.0 mL, 55.9 mmol)
and, after 2 h, paraformaldehyde (1.66 g, 55.3 mmol) at
ꢂ78 1C. The mixture was gradually warmed to rt and stirred
overnight. To this AlH2(OMe) mixture was added dropwise a
solution of b1 (13.2 g, 42.5 mmol) in 100 mL of toluene at 0 1C.
After the mixture was gradually warmed to rt and stirred
overnight, it was diluted with 50 mL of dry THF35 and stirred
for 10 min. The reaction was quenched by addition of 6 mL of
1 M NaOH solution, and the mixture was diluted with 100 mL
of CH2Cl2. The mixture was passed through a pad of Celite,
which was rinsed with EtOAc. The filtrate was concentrated
under reduced pressure, and the residue was purified by
column chromatography on silica gel (elution with hexane–
EtOAc 6 : 1) to give 9.82 g (86%) of 2(E)-octadecen-1-ol (c1).
(E)-Nonadec-2-en-4-yn-1-ol (c4). 1H NMR (400 MHz,
CDCl3) d 0.88 (t, J = 7.0 Hz, 3H), 1.18–1.45 (m, 23H),
1.47–1.57 (m, 2H), 2.29 (dt, J = 1.9, 7.0 Hz, 2H), 4.18
(t, J = 4.7 Hz, 2H), 5.72 (dt, J = 15.9, 1.9 Hz, 1H), 6.16
(dt, J = 15.9, 5.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
14.1, 19.4, 22.7, 28.7, 28.9, 29.1, 29.4, 29.5, 29.62, 29.65, 29.67,
29.69, 31.9, 63.1, 78.2, 91.5, 111.4, 140.1.
(E)-Ethyl
3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]acrylate
(b5)41. 1H NMR (400 MHz, C6D6) d 0.98 (t, J = 7.1 Hz,
3H), 1.24 (s, 3H), 1.28 (s, 3H), 3.25–3.30 (m, 1H), 3.66–3.71
(m, 1H), 4.00 (q, J = 7.1 Hz, 2H), 4.20–4.27 (m, 1H), 6.13
(dd, J = 15.6, 1.5 Hz, 1H), 6.85 (dd, J = 15.6, 5.3 Hz, 1H);
13C NMR (100 MHz, C6D6) d 14.2, 25.8, 26.5, 60.3, 68.8, 75.1,
110.0, 122.2, 145.2, 165.7.
(E)-Ethyl octadec-2-enoate (b1). Matches the published
data.36
(E)-3-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]prop-2-en-1-ol (c5)41.
1H NMR (500 MHz, C6D6) d 1.36 (s, 3H), 1.42 (s, 3H), 3.41
(t, J = 7.8 Hz, 1H), 3.73–3.83 (m, 3H), 4.31 (q, J = 6.9 Hz,
1H), 5.55 (ddd, J = 15.5, 6.7 Hz, 1H), 5.63 (dt, J = 15.5,
4.7 Hz, 1H); 13C NMR (100 MHz, C6D6) d 26.1, 26.9, 62.1,
69.5, 76.9, 109.4, 128.2, 133.7.
(E)-Octadec-2-en-1-ol (c1). Matches the published data.37
1H NMR (500 MHz, CDCl3) d 0.88 (t, 3H, J = 6.8 Hz), 1.26
(s, 26H), 1.34–1.39 (m, 2H), 1.56 (s, 1H), 2.04 (q, 2H, J =
7.2 Hz), 4.09 (t, 2H, J = 5.2 Hz), 5.61–5.72 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 14.1, 22.7, 29.1, 29.2, 29.4, 29.5, 29.60,
29.65, 29.68, 31.9, 32.2, 63.8, 128.7, 133.6.
(E)-Ethyl 4-(4-methoxyphenoxy)but-2-enoate (b7). 1H NMR
(400 MHz, CDCl3) d 1.28 (t, J = 7.1 Hz, 3H), 1.71–1.79
(m, 2H), 2.25–2.33 (m, 2H), 3.45 (t, J = 6.3 Hz, 2H), 3.79
(s, 3H), 4.17 (q, J = 7.1 Hz, 2H), 4.42 (s, 2H), 5.82 (dt, J =
15.7, 1.6 Hz, 1H), 6.85–6.89 (m, 2H), 6.96 (dt, J = 15.7,
6.9 Hz, 1H), 7.22–7.27 (m, 2H); 13C NMR (100 MHz, CDCl3)
14.2, 28.0, 28.8, 55.1, 60.2, 68.8, 72.5, 113.6, 121.5, 129.1,
130.3, 148.5, 159.1, 166.5.
(2E,4E)-Ethyl 5-phenylpenta-2,4-dienoate (b2). Matches the
published data.38
(2E,4E)-5-Phenylpenta-2,4-dien-1-ol (c2). Matches the
published data.39
(E)-Ethyl 3-(4-octylphenyl)acrylate (b3). 1H NMR (400 MHz,
CDCl3) d 0.88 (t, J = 7.1 Hz, 3H), 1.16–1.38 (m, 13H),
1.53–1.65 (m, 2H), 2.61 (t, J = 2.6 Hz, 2H), 4.26 (q, J =
7.1 Hz, 2H), 6.39 (d, J = 16.0 Hz, 1H), 7.19 (d, J = 8.0 Hz,
(E)-4-(4-Methoxyphenoxy)but-2-en-1-ol (c7). Matches the
published data.27
2H), 7.44 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 16.0 Hz, 1H); 13
C
(4R,5R)-4,5-O-Isopropylidene-4,5-dihydroxy-2,6-octadiene-
dioate (b6)42. 1H NMR (400 MHz, C6D6) d 0.98 (t, J =
7.1 Hz, 6H), 1.25 (s, 6H), 3.95–4.04 (m, 6H), 6.12
(d, J = 15.6 Hz, 2H), 6.85 (ddd, J = 15.6, 1.8, 3.5 Hz, 2H);
NMR (100 MHz, CDCl3) d 14.1, 14.3, 22.6, 29.21, 29.26, 29.4,
31.2, 31.8, 35.8, 60.4, 117.1, 128.0, 128.9, 131.9, 144.6,
145.7, 167.2.
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13C NMR (100 MHz, C6D6) d 14.56, 27.1 60.8, 80.2, 110.9,
124.0, 142.9, 165.7.
9 (a) J. Villieras and M. Rambaud, Synthesis, 1982, 924; (b) J. Villieras
and M. Rambaud, Synthesis, 1983, 300; (c) J. Villieras and
M. Rambaud, Synthesis, 1984, 406; (d) M. Rambaud, A. del
Vechhhio and J. Villieras, Synth. Commun., 1984, 14, 833;
(e) J. Villieras, M. Rambaud and M. Graff, Synth. Commun.,
1985, 15, 569; (f) J. Villieras, M. Rambaud and M. Graff,
Tetrahedron Lett., 1985, 26, 53.
10 (a) C. Piechucki, Synthesis, 1976, 187; (b) E. D’Incan and
J. Seyden-Penne, Synthesis, 1975, 516; (c) M. Mikolajczyk,
S. Grzejszczak, W. Midura and A. Zatorski, Synthesis, 1975, 278.
11 E. Winterfeldt, Synthesis, 1975, 617.
3-[(4R,5R)-5-(3-Hydroxy-1-(E)-propen-1-yl)-2,2-dimethyl-
[1,3]dioxolan-4-yl]-prop-2-(E)-en-1-ol (c6)43.
1H NMR
(400 MHz, C6D6) d 1.47 (s, 6H), 2.83 (br s, OH, 2H), 3.94,
(d, J = 4.8 Hz, 4H), 4.16–4.21 (m, 2H), 5.73 (ddd, J = 15.5,
4.8, 1.8 Hz, 2H), 5.897 (dt, J = 15.5, 4.8 Hz, 2H); 13C NMR
(100 MHz, C6D6) d 27.3, 62.4, 82.0, 109.1, 126.8, 134.4.
12 M. R. Johnson and B. Rickborn, J. Org. Chem., 1970, 35, 1041.
13 L. Giraud, V. Huber and T. Jenny, Tetrahedron, 1998, 54, 11899.
14 E. Finholt, A. C. Bond Jr. and H. I. Schlesinger, J. Am. Chem.
Soc., 1947, 69, 1199.
15 U. E. Diner, H. A. Davies and R. K. Brown, Can. J. Chem., 1967,
45, 207.
16 (a) H. C. Brown and N. M. Yoon, J. Am. Chem. Soc., 1966, 88,
1464; (b) N. M. Yoon and H. C. Brown, J. Am. Chem. Soc., 1968,
90, 2927.
17 S. Griffin, L. Heath and P. Wyatt, Tetrahedron Lett., 1998, 39,
4405.
18 (a) E. M. Marlett and W. S. Park, J. Org. Chem., 1990, 55, 2968;
(b) T. D. Hubert, D. P. Eyman and D. F. Wiemer, J. Org. Chem.,
1984, 49, 2279; (c) J. S. Cha and H. C. Brown, J. Org. Chem., 1993,
58, 3974.
19 The reaction RX + LAH - RH + AlH3 + LiX was reported by
S. Krishnamurthy and H. C. Brown, J. Org. Chem., 1982, 47, 276.
20 E. C. Ashby, T. N. Pham and A. Amrollah-Madjdabdi, J. Org.
Chem., 1991, 56, 1596.
4-(20-Deoxy-30,40,60-tri-O-benzyl-a-D-galactopyranosyl)-2(E)-
butenoate (b9). 1H NMR (400 MHz, CDCl3)
d 1.25
(t, J = 7.1 Hz, 3H), 1.47–1.55 (m, 1H), 1.98–2.06 (m, 1H),
2.25–2.33 (m, 1H), 2.41–2.50 (m, 1H), 3.68–3.73 (m, 1H),
3.73–3.76 (m, 1H), 3.78–3.83 (m, 1H), 3.90–3.98 (m, 1H),
4.00–4.11 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.50–4.72
(m, 6H), 5.86 (d, J = 15.7 Hz, 1H), 6.91 (dt, J = 15.7, 7.2
Hz, 1H), 7.24–7.37 (m, 15H); 13C NMR (100 MHz, CDCl3) d
14.2, 32.6, 36.3, 60.1, 66.6, 67.3, 71.4, 72.2, 73.11, 73.14, 73.6,
74.9, 123.4, 127.2, 127.41, 127.43, 127.5, 127.6, 127.7, 128.22,
128.26, 138.28, 138.36, 138.46, 144.7, 166.2. HRMS (ESI)
+
(MNH4 ) C33H42NO6 calcd for m/z 548.3007, found
548.3002.
4-(20-Deoxy-30,40,60-tri-O-benzyl-a-D-galactopyranosyl)-2(E)-
buten-1-ol (c9). 1H NMR (400 MHz, CDCl3) d 1.47–1.56
(m, 1H), 1.99–2.08 (m, 1H), 2.10–2.19 (m, 1H), 2.28–2.38
(m, 1H), 3.63–3.69 (m, 2H), 3.72–3.76 (m, 1H),
3.78–3.83 (m, 1H), 3.88–3.95 (m, 1H), 3.96–4.00 (m, 1H),
4.01–4.07 (m, 2H), 4.47–4.74 (m, 6H), 5.61–5.67 (m, 2H),
7.20–7.40 (m, 15H); 13C NMR (100 MHz, CDCl3) d 32.0,
36.1, 63.4, 67.9, 71.2, 72.4, 73.1, 73.2, 73.5, 74.9, 127.3, 127.4,
127.5, 127.8, 128.24, 128.29, 128.34, 128.6, 138.3, 138.4, 138.6.
HRMS (ESI) (MNH4+) C31H40NO5 calcd for m/z 506.2901,
found 506.2899.
21 H.-S. Byun, K. C. Reddy and R. Bittman, Tetrahedron Lett., 1994,
35, 1371.
22 During the preparation of this manuscript a report of the prepara-
tion of AlH3 from BnCl and LAH was published: X. Wang, X. Li,
J. Xue, Y. Zhao and Y. Zhang, Tetrahedron Lett., 2009, 50, 413.
We note that n-BuBr is a much safer reagent than BnCl, and is
especially suitable for producing AlH3 for large-scale synthesis.
23 A. Madin, C. J. O’Donnell, T. Oh, D. W. Old, L. E. Overman and
M. J. Sharp, J. Am. Chem. Soc., 2005, 127, 18054.
24 L. He, H.-S. Byun and R. Bittman, J. Org. Chem., 2000, 65, 7627.
25 A. Krief, W. Dumont and P. Pasau, Tetrahedron Lett., 1988, 29,
1079.
26 T. Onoda, R. Shirai, N. Kawai and S. Iwasaki, Tetrahedron, 1996,
52, 13327.
27 L. He, H.-S. Byun, J. Smit, J. Wilschut and R. Bittman, J. Am.
Chem. Soc., 1999, 121, 3897.
Acknowledgements
28 (a) A. Massi, A. Nuzzi and A. Dondoni, J. Org. Chem., 2007, 72,
10279; (b) Z. Wang, H. Shao, E. Lacroix, S.-H. Wu, H. J. Jennings
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29 (a) P. Kumar and M. S. Bodas, J. Org. Chem., 2005, 70, 360;
(b) P. Kumar, S. V. Naidu and P. Gupta, J. Org. Chem., 2005, 70,
2843.
30 J. Einhorn, C. Einhorn, F. Ratajczak and J.-L. Pierre, J. Org.
Chem., 1996, 61, 7452.
31 Theoretically, reduction of RCO2Et requires 2/3 equiv. of LAH:
2AlH3 + 3RCO2Et - (EtO)Al(OCH2R)2 + (EtO)2Al(OCH2R).
In order to speed up the reaction, a slight excess (1.3 equiv.) of
LAH was used.
This work was supported in part by National Institutes of
Health Grant No. HL083187. We thank Dr William E.
Berkowitz for helpful comments in the preparation of the
manuscript.
Notes and references
1 T. Katsuki and V. S. Martin, Org. React., 1996, 48, 1.
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32 For a theoretical analysis of the reaction of AlH3 with H2CO
to form AlH2(OMe), see: J. M. Coxon and R. T. Luibrand,
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33 AlH2(OMe), which was prepared from AlH3 + MeOH, is less
reactive than AlH3, and was used for the hydrogenolysis of acetals
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34 X. Lu, L. Song, L. S. Metelitsa and R. Bittman, ChemBioChem,
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35 After the reduction was completed, it was difficult to stir the
reaction mixture because of the insolubility of the formed Al(OR)3
in toluene. This problem was overcome by the addition of dry THF
when the reaction approached completion.
36 R. A. Fernandes and P. Kumar, Tetrahedron: Asymmetry, 1999,
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