Palladium hydroxide catalyzed transformation of primary propargylic alcohols into aldehydes: Application to the synthesis of the tetrahydrofuran core

Article abstract of DOI:10.1055/s-0031-1291004

A palladium-catalyzed one-pot, two-step sequence involving redox isomerization/reduction of primary propargylic alcohols into the corresponding aldehydes has been achieved at room temperature for the first time in good to excellent yields under mild conditions. The functional group compatibility in this reaction is studied and this new methodology has been successfully applied in the synthesis of the 2,5-trans-tetrahydrofuran ring system of amphidinolides. It is noteworthy that aromatic substituted propargylic alcohols gave a mixture of unsaturated and saturated aldehydes, whereas aliphatic propargylic alcohols gave only saturated aldehydes. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291004

PAPER
▌1657
paper
Palladium Hydroxide Catalyzed Transformation of Primary Propargylic
Alcohols into Aldehydes: Application to the Synthesis of the Tetrahydrofuran
Core
Transformation of Primary Propargylic Alcohols into Aldehydes
Gowravaram Sabitha,* A. Yagundar Reddy, Sambit Nayak, Jhillu S. Yadav
Natural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax +91(40)27160512; E-mail: gowravaramsr@yahoo.com; E-mail: sabitha@iict.res.in
Received: 02.02.2012; Accepted after revision: 06.04.2012
by a two-step sequence involving reduction of the triple
Abstract: A palladium-catalyzed one-pot, two-step sequence in-
bond, followed by oxidation of the alcohol to the alde-
volving redox isomerization/reduction of primary propargylic alco-
hyde. We herein report our results on the first catalytic
conversion of primary propargylic alcohols into saturated
hols into the corresponding aldehydes has been achieved at room
temperature for the first time in good to excellent yields under mild
conditions. The functional group compatibility in this reaction is aldehydes using H2-preactivated Pd(OH)2/C catalyst. Al-
though there is literature precedent5 for a two-metal cata-
lytic system or ruthenium-catalyzed redox isomerization
studied and this new methodology has been successfully applied in
the synthesis of the 2,5-trans-tetrahydrofuran ring system of am-
phidinolides. It is noteworthy that aromatic substituted propargylic
of propargylic alcohols to α,β-unsaturated aldehydes, to
alcohols gave a mixture of unsaturated and saturated aldehydes,
whereas aliphatic propargylic alcohols gave only saturated alde-
our knowledge, there are no reports on a one-pot, two-step
sequence involving redox-isomerization and reduction of
primary propargylic alcohols to give saturated aldehydes.
hydes.
Key words: palladium, alkynes, aldehydes, tetrahydrofuran, one-
pot reactions
H2-pre-activated
Pd(OH)2/C
CHO
CHO
OH
or
R1
R1
benzene, r.t.
30 min to 3 h
R1
R
Aldehyde products have importance in commodity syn-
thesis and are versatile moieties that can be converted into
alcohols by reduction or oxidized to carboxylic acids.
Their use in medical and industrial applications is exten-
sive and linear aldehydes are widely used for the produc-
tion of detergents, plasticizers, various pharmaceuticals
(e.g., as a key starting material for the synthesis of enala-
pril, which is marketed by Merck & Co. as a drug for low-
ering blood pressure1),2 agrochemicals, and other fine
chemicals.3 Thus, growing effort has been directed to-
wards the efficient and selective preparation of various al-
dehydes. Previously, we have reported Pd(OH)2/C
catalyzed redox isomerization of primary allylic alcohols4
to saturated aldehydes. We then focused on the direct ap-
plication of these conditions to the isomerization of pri-
mary propargylic alcohols to give the corresponding α,β-
unsaturated aldehydes. To our surprise, although the ap-
plication of these conditions to primary propargylic alco-
hols promoted isomerization to give the α,β-unsaturated
aldehydes, these were subsequently converted into satu-
rated aldehydes. The reaction proceeds through isomeri-
zation of propargylic alcohols into the unsaturated
aldehydes followed by reduction of the carbon–carbon
double bond to generate the saturated aldehyde (Scheme
1). This new strategy for the direct synthesis of saturated
aldehydes from primary propargylic alcohols was consid-
ered highly valuable. Generally, the propargylic alcohols
are converted into the corresponding saturated aldehydes
2a–g,i
R
1 = alkyl
2h,j
1 = aryl
1a–i
1 = alkyl, aryl
R
Scheme 1 Sequential isomerization and reduction
For the first reaction, the catalyst, Pd(OH)2/C (20% wt, 7
mol%), was stirred in benzene and activated at room tem-
perature for 30 min by purging the mixture with hydrogen
gas using a balloon. The hydrogen balloon was removed
and the mixture was stirred for 10 minutes. A solution of
2-hexyn-1-ol (1a; 1 mmol) in benzene was then added and
stirring was continued at the same temperature for 30 min-
utes. This procedure resulted in the formation of a mixture
of hexanal (2a) and hexanol (3a) in a 95:5 ratio and a total
yield of 95% (Table 1, entry 1). These products were sep-
arated by column chromatography. With this result in
hand, the reaction of phenyl and methoxymethyl (MOM)
protected propargylic alcohols was studied. 4-Phenoxy-
but-2-yn-1-ol (1b) yielded saturated aldehyde 2b in 99%
yield exclusively, whereas 4-(methoxymethoxy)but-2-yn-
1-ol (1c) furnished aldehyde 2c together with alcohol 3c
in a 95:5 ratio (Table 1, entries 2 and 3). Further studies
revealed that the use of base (Et3N or Na2CO3) was neces-
sary to prevent deprotection of Bn, PMB and TBS groups
present in the substrate. Thus, substrates having Bn, PMB,
TBS or TBDMS groups (Table 1, entries 4–7 and 10) re-
quired the addition of 5 mol% triethylamine during the
formation of aldehydes. Propargylic alcohols bearing an
adjacent hydroxy substituent (monoprotected butyne diols
1f and 1g) also underwent clean conversion, giving good
yields of saturated aldehydes (Table 1, entries 6 and 7).
Substrates bearing the TBDPS group (1g) require slightly
SYNTHESIS 2012, 44, 1657–1662
Advanced online publication: 10.05.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291004; Art ID: SS-2012-Z0106-OP
© Georg Thieme Verlag Stuttgart · New York

1658
G. Sabitha et al.
PAPER
longer reaction time compared to substrates bearing a
TBDMS group (1f).
H2-pre-activated
Pd(OH)2/C
CHO
CHO
benzene, r.t.,
90 min, 91%
However, in the case of propargylic alcohols substituted
with an aromatic ring, we were able to isolate the isomer-
ized products. 3-Phenyl-2-propyn-1-ol (1h) reacted slow-
ly (1 h) to give the isomerized product, cinnamaldehyde
(2h) as the sole product in 30% yield (Table 1, entry 8).
Extending the reaction time for 2–3 hours instead gave
saturated aldehyde 2i in 92% yield, without formation of
unsaturated aldehyde (Table 1, entry 9). Substituted phe-
nyl propargylic alcohol, 3-[4-(benzyloxy)-3-methoxyphe-
nyl]prop-2-yn-1-ol (1i; Table 1, entry 10) gave a mixture
of unsaturated aldehyde 2j together with saturated alcohol
within 30 minutes in a 2:8 ratio.
H2-pre-activated
Pd(OH)2/C
CHO
CHO
MeO
BnO
MeO
BnO
benzene, r.t.
60 min, 82%
Scheme 2 Reduction of the carbon–carbon double bond leaving the
aldehyde unaffected
reduced under these conditions to give the saturated alde-
hydes in good yields (Scheme 2). From these experiments
it was clear that the reaction proceeds through isomeriza-
tion of the substrate to the unsaturated aldehyde followed
by selective reduction of the carbon–carbon double bond,
leaving the aldehyde functional group intact. We assume
To investigate the pathway followed in these reactions,
cinnamaldehyde and substituted cinnamaldehyde were
submitted to the optimized reaction conditions; it was
found that the carbon–carbon double bond was selectively
Table 1 H2-Preactivated Pd(OH)2/C Catalyzed Transformation of Propargylic Alcoholsa
Entry Alcohol 1
Aldehyde 2
Alcohol 3
Time Yield Ratio
(h)
(%)b 2/3c
( )
OH
OH
CH2OH
( )3
1
1a
2a
3a
0.5
95
95:5
CHO
3
PhO
2
3
1b
1c
2b
2c
2d
2e
CHO
CHO
–
0.5
1
99
95
96
96
100:0
95:5
96:4
96:4
PhO
CH2OH
OH
( )
( )
MOMO
MOMO
BnO
3c
3d
3e
MOMO
2
2
OH
( )
( )
CHO
4d 1d
5d 1e
1
BnO
CH2OH
2
2
BnO
OH
( )
( )
2
PMBO
CH2OH
PMBO
BnO
CHO
1
2
PMBO
BnO
OTBS
OTBS
6d 1f
2f
–
0.75
1.2
96
98
100:0
100:0
CHO
OH
OTBDPS
OTBDPS
7d 1g
2g
–
–
–
PMBO
PMBO
CHO
OH
OH
OH
CHO
CHO
8
9
1h
1h
2h
2i
1
30
92
90
100:0
100:0
20:80
2–3
0.5
OH
MeO
BnO
CHO
MeO
CH2OH
MeO
BnO
10d 1i
2j
3j
BnO
a Reactions carried out at room temperature with 20 wt% Pd(OH)2/C (7 mol%).
b Combined yield of 2 + 3.
c Product ratio (aldehyde/alcohol) was determined after purification.
d Et3N (5 mol%) was used.
Synthesis 2012, 44, 1657–1662
© Georg Thieme Verlag Stuttgart · New York

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Transformation of Primary Propargylic Alcohols into Aldehydes
1659
that the hydrogen gas adsorbed on carbon may be respon-
sible for the reduction of the double bond, which is very
fast, and thus it was not possible to isolate the unsaturated
aldehydes.
H2-preactivated
Pd(OH)2/C (7 mol%)
OH
BnO
OH
OH
Et3N (5 mol%), benzene
r.t., 1 h
4
Our methodology was applied to the synthesis of the
trans-2,5-substituted tetrahydrofuran core of amphidino-
lides (Figure 1),6 which are bioactive secondary metabo-
lites isolated from the marine origin, dinoflagellate
Amphidinium sp.
Ph3P=CHCOOEt
BnO
O
benzene, reflux, 3 h
5
Triton B, r.t.
BnO
BnO
MeOH, 15 min
O
OH
COOEt
70%
O
6
OH
H
O
R
COOMe
OH
O
H
H
H
O
7
O
Scheme 3 One-pot synthesis of the 2,5-trans-tetrahydrofuran ring
system
OH
O
OH
Thus, starting from easily accessible propargylic alcohols,
we could implement the Pd(OH)2 catalyzed reaction in
several one-pot protocols (isomerization, hydrogenation,
Wittig olefination and oxa-Michael addition), represent-
ing a new way for the expeditious assembly of tetrahydro-
furan-containing natural products in an atom-economic
manner. Extension of this methodology toward the devel-
opment of new strategies is underway.
R =
amphidinolide C
R =
amphidinolide F
In summary, we have discovered the first example of a
palladium-catalyzed sequential isomerization and reduc-
tion of primary propargylic alcohols to furnish the corre-
sponding saturated aldehydes. The approach has been
successfully applied to the synthesis of a 2,5-trans-tetra-
hydrofuran core of amphidinolides. Further applications
and extensions of the methodology are ongoing in our lab-
oratory and will be reported in due course.
Figure 1 Amphidinolides core structure
In the case of substrates containing a free hydroxy group
such as the butyne-1,4-diol moiety in 47,8 (Scheme 3), we
first investigated a sequential one-pot isomerization,
reduction and Wittig olefination using 4 as the hydroxy-
substituted propargylic alcohol and ethyl (triphenyl-
phosphoranylidene)acetate as the Wittig reagent. During
the sequential isomerization and reduction reaction of 4
we observed a chemoselectivity between the primary and
secondary hydroxy groups, and the reaction furnished
IR spectra were recorded with a Perkin–Elmer RX FT-IR spectro-
photometer. ESIMS were recorded with a VG-Autospec micromass
spectrometer and HRMS with a Hybrid MS system. NMR spectra
hemiacetal 5 (the formation of which was monitored by were recorded on Bruker VX NMR FT-300 MHz (1H and 13C) and
Varian Unity 500 (1H) spectrometers. The solvent peak (CDCl3)
TLC). Benzene was added, followed by addition of the
Wittig reagent to the crude reaction mixture to produce
the α,β-unsaturated ester 6 at reflux temperature. When
TLC analysis indicated formation of enoate 6, the reaction
was used as internal reference (δH = 7.26 ppm; δC = 77.0 ppm). Data
are reported in the following order: chemical shift (δ in ppm), mul-
tiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qt = quin,
m = multiplet), coupling constant (J in Hz). All reactions were mon-
mixture was cooled to room temperature and the solvent
was removed by rotary evaporation. A 40% methanolic
solution of Triton B9 was added to the residue, which was
directly subjected to the oxa-Michael conditions while
stirring at room temperature for 15 minutes to provide
trans-2,5-substituted tetrahydrofuran 7 as the sole product
in a one-pot fashion with an overall yield of 70% (use of
MeOH resulted in transesterification of the ethyl ester to
the methyl ester). To our knowledge, this sequence repre-
sents the first sequential one-pot isomerization, reduction,
Wittig olefination and oxa-Michael addition (Scheme 3).
itored by thin-layer chromatography (TLC) using silica gel F254 pre-
coated plates. Visualization was accomplished with UV light or I2
stain. Pd(OH)2/C (20 wt%) was purchased from Sigma-Aldrich
(Catalog No. 212911). Solvents for the catalytic reactions were
technical grade. Solvents for chromatography (EtOAc and hexane)
were technical grade and distilled prior to use.
Conversion of Primary Propargylic Alcohols into Aldehydes;
General Procedure
A 50 mL two-neck, round-bottomed flask was charged with
Pd(OH)2/C (0.027–0.033 g, 7 mol%), and benzene (3 mL) was add-
ed. The mixture was stirred and a balloon of H2 gas was placed over
the flask for 30 min (for activation of the catalyst). The balloon was
removed and stirring was continued for 10 min (to allow the remain-
ing gas to be adsorbed on carbon) after which a solution of propar-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1657–1662

1660
G. Sabitha et al.
PAPER
gylic alcohol 1 (0.5 mmol) in benzene (3 mL) was added. The
reaction mixture was stirred for the specified time. Upon comple-
tion of the reaction (as indicated by TLC), the reaction mixture was
filtered through a Celite pad, which was washed with EtOAc (10
mL). The filtrate was concentrated in vacuo and the residue was pu-
rified by silica gel column chromatography (EtOAc–hexane,
2→30%) to afford the aldehyde 2 and, in some cases, associated al-
cohol 3.
5-(4-Methoxybenzyloxy)pentanal (2e)
Prepared from 1e (100 mg. 0.45 mmol) following the general pro-
cedure.
Yield: 93 mg (92%); colorless liquid.
IR (neat): 2939, 2861, 2724, 1722, 1611, 1513, 1459, 1362, 1300,
1247, 1175, 1095, 1033, 821 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.72 (t, J = 1.3 Hz, 1 H), 7.18 (d,
J = 8.5 Hz, 2 H), 6.81 (d, J = 8.5 Hz, 2 H), 4.38 (s, 2 H), 3.78 (s,
3 H), 3.40 (t, J = 6.0 Hz, 2 H), 2.41 (dt, J = 7.0, 1.3 Hz, 2 H), 1.77–
1.57 (m, 4 H).
13C NMR (75.0 MHz, CDCl3): δ = 202.4, 159.0, 130.3, 129.1,
113.7, 72.5, 69.3, 55.2, 43.5, 29.1, 18.9.
HRMS (ESI): m/z [M + Na]+ calcd for C13H18O3Na: 245.1153;
found: 245.1127.
Hexanal (2a)
Prepared from 1a (100 mg, 1 mmol) following the general proce-
dure.
Yield: 92 mg (90%); colorless liquid.
IR (neat): 2924, 2856, 1722, 1461, 1280 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.74 (s, 1 H), 2.39 (t, J = 5.9 Hz,
2 H), 1.63 (qt, J = 6.9 Hz, 2 H), 1.37–1.30 (m, 4 H), 0.92 (t,
J = 6.9 Hz, 3 H).
13C NMR (75.0 MHz, CDCl3): δ = 202.8, 43.8, 31.2, 22.3, 21.7,
13.7.
MS (EI): m/z = 100 [M]+.
(R)-5-(Benzyloxy)-4-(tert-butyldimethylsilyloxy) pentanal (2f)
Prepared from 1f (100 mg, 0.31 mmol) following the general proce-
dure.
27
Yield: 97 mg (96%); light yellow liquid; [α]D +19.0 (c 0.3,
CHCl3).
IR (neat): 3035, 2930, 2726, 1723, 1595, 1495, 1390, 1296, 1243,
1172, 1040, 882, 755, 691 cm–1.
4-Phenoxybutanal (2b)
Prepared from 1b (100 mg, 0.61 mmol) following the general pro-
cedure.
1H NMR (300 MHz, CDCl3): δ = 9.74 (t, J = 1.5 Hz, 1 H), 7.34–
7.23 (m, 5 H), 4.48 (ABq, J = 15.2, 12.0 Hz, 2 H), 3.91–3.82 (m,
1 H), 3.40–3.26 (m, 2 H), 2.46 (dt, J = 7.1, 1.5 Hz, 2 H), 1.99–1.87
(m, 1 H), 1.82–1.70 (m, 1 H), 0.86 (s, 9 H), 0.03 (s, 3 H), 0.02 (s,
3 H).
13C NMR (75.0 MHz, CDCl3): δ = 202.6, 138.1, 128.3, 127.6 (2C),
73.9, 73.3, 70.1, 39.4, 26.9, 25.8, 18.0, –4.4, –4.8.
Yield: 101 mg (99%); light yellow liquid.
IR (neat): 2936, 2860, 1716, 1598, 1479, 1425, 1376, 1270, 1227,
1165, 881, 835 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.83 (s, 1 H), 7.21 (d, J = 8.1 Hz,
2 H), 6.89 (t, J = 7.1 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 2 H), 3.98 (t,
J = 6.0 Hz, 2 H), 2.66 (t, J = 6.7 Hz, 2 H), 2.11 (qt, J = 6.4 Hz,
2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H30O3SiNa: 345.1862;
found: 345.1870.
13C NMR (75.0 MHz, CDCl3): δ = 201.8, 158.6, 129.4, 120.8,
114.4, 66.5, 40.6, 22.0.
MS (ESI): m/z = 187 [M + Na]+.
(R)-4-(tert-Butyldiphenylsilyloxy)-6-(methoxybenzyl-
oxy)hexanal (2g)
Prepared from 1g (100 mg, 0.20 mmol) following the general pro-
4-(Methoxymethoxy)butanal (2c)
cedure.
Prepared from 1c (100 mg, 0.76 mmol) following the general pro-
Yield: 98 mg (98%); light yellow liquid; [α]D27 +5.6 (c 0.7, CHCl3).
cedure.
IR (neat): 3026, 2926, 2859, 2721, 1726, 1600, 1498, 1452, 1365,
1035, 914, 745, 699 cm–1.
Yield: 84 mg (82%); colorless liquid.
IR (neat): 2929, 2726, 1725, 1458, 1362, 1247, 1175, 1097,
1036 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.80 (s, 1 H), 4.60 (s, 2 H), 3.56
(t, J = 5.7 Hz, 2 H), 3.35 (s, 3 H), 2.55 (t, J = 6.9 Hz, 2 H), 1.94 (p,
J = 6.9 Hz, 2 H).
13C NMR (75.0 MHz, CDCl3): δ = 201.9, 96.3, 66.5, 55.1, 40.8,
22.4.
1H NMR (500 MHz, CDCl3): δ = 9.56 (s, 1 H), 7.67–7.63 (d,
J = 7.0 Hz, 4 H), 7.44–7.40 (t, J = 8.0 Hz, 2 H), 7.38–7.33 (t, J =
8.0 Hz, 4 H), 7.14 (d, J = 8.0 Hz, 2 H), 6.84 (d, J = 8.0 Hz, 2 H),
4.25 (ABq, J = 15.6, 12.0 Hz, 2 H), 3.97 (qt, J = 6.0 Hz, 1 H), 3.80
(s, 3 H), 3.45–3.34 (m, 2 H), 2.39 (t, J = 7.0 Hz, 2 H), 1.83–1.65 (m,
4 H), 1.04 (s, 9 H).
13C NMR (75.0 MHz, CDCl3): δ = 202.4, 159.0, 135.9, 135.8,
129.7, 129.2, 127.6, 127.5, 113.6, 72.4, 69.9, 66.4, 55.2, 39.2, 36.3,
28.7, 27.0, 19.3.
MS (EI): m/z = 132 [M]+.
HRMS (ESI): m/z [M + Na]+ calcd for C30H38O4SiNa: 513.2431;
found: 513.2452.
5-(Benzyloxy)pentanal (2d)
Prepared from 1d (100 mg, 0.56 mmol) following the general pro-
cedure.
Cinnamaldehyde (2h)
Yield: 92 mg (91%); colorless liquid.
Prepared from 1h (100 mg, 0.75 mmol) following the general pro-
IR (neat): 2925, 2856, 2720, 1723, 1453, 1363, 1205, 1102, 738,
697, 608 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.74 (t, J = 1.3 Hz, 1 H), 7.24–
7.20 (m, 5 H), 4.46 (s, 2 H), 3.45 (t, J = 5.6 Hz, 2 H), 2.44 (dt,
J = 7.2, 1.3 Hz, 2 H), 1.78–1.69 (m, 2 H), 1.68–1.59 (m, 2 H).
13C NMR (75.0 MHz, CDCl3): δ = 202.4, 138.4, 128.3, 127.6,
127.5, 72.9, 69.7, 43.5, 29.1, 18.9.
cedure.
Yield: 10 mg (10%); colorless liquid.
IR (neat): 3025, 2611, 1682, 1491, 1447, 1315, 1286, 977, 934,
871 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.70 (d, J = 7.7 Hz, 1 H), 7.58–
7.52 (m, 2 H), 7.47–7.40 (m, 4 H), 6.60 (dd, J = 16.0, 7.5 Hz, 1 H).
13C NMR (75.0 MHz, CDCl3): δ = 193.6, 152.7, 133.8, 131.1,
128.9, 128.4 (2C).
MS (ESI): m/z = 215 [M + Na]+.
MS (EI): m/z = 132 [M]+.
Synthesis 2012, 44, 1657–1662
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Transformation of Primary Propargylic Alcohols into Aldehydes
1661
3-Phenylpropanal (2i)
(3 × 10 mL). The combined extracts were dried (Na2SO4) and con-
centrated. The residual oil was purified by column chromatography
on silica gel (30 g; hexane–EtOAc, 9:1) to give 2,5-trans-tetrahy-
drofuran 7.
Prepared from 1h (100 mg, 0.75 mmol) following the general pro-
cedure.
Yield: 93 mg (92%); colorless liquid.
27
Yield: 0.224 g (70% for 3 steps); colorless oil; [α]D +5.0 (c 1.0
IR (neat): 3082, 3027, 2932, 2724, 1951, 1878, 1716, 1602, 1494,
1449, 1412, 1133, 1044, 946, 745, 697, 565 cm–1.
CHCl3).
1H NMR (500 MHz, CDCl3): δ = 9.80 (t, J = 0.7 Hz, 1 H), 7.28–7.12
(m, 5 H), 2.94 (t, J = 7.5 Hz, 2 H), 2.75 (dt, J = 0.7, 7.5 Hz, 2 H).
IR (neat): 2948, 2864, 1736, 1365, 1443, 1275, 1199, 1076, 741,
699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.34–7.20 (m, 5 H), 4.59 (s, 2 H),
4.34 (qt, J = 6.8 Hz, 1 H), 4.27–4.15 (m, 1 H), 3.67 (s, 3 H), 3.49–
3.37 (m, 2 H), 2.60 (dd, J = 15.1, 6.7 Hz, 1 H), 2.43 (dd, J = 15.1,
5.7 Hz, 1 H), 2.20–1.90 (m, 2 H), 1.83–1.68 (m, 1 H), 1.66–1.51
(m, 1 H).
13C NMR (75.0 MHz, CDCl3): δ = 171.6, 138.3, 128.2, 127.6,
127.4, 78.3, 75.4, 73.3, 72.6, 51.5, 40.4, 31.5, 28.3.
13C NMR (75.0 MHz, CDCl3): δ = 201.6, 140.2, 128.5, 128.2,
126.2, 45.2, 28.1.
MS (EI): m/z = 134 [M]+.
(E)-3-[4-(Benzyloxy)-3-methoxyphenyl]acrylaldehyde (2j)
Prepared from 1i (100 mg, 0.37 mmol) following the general proce-
dure.
Yield: 18 mg (18%); white crystalline solid; mp 89 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20O4Na: 287.1259;
found: 287.1247.
IR (neat): 2924, 2855, 2727, 1667, 1588, 1508, 1461, 1266, 1130,
1001, 972, 796 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.63 (d, J = 7.5 Hz, 1 H), 7.43–
7.28 (m, 6 H), 7.07–7.02 (m, 2 H), 6.86 (d, J = 8.3 Hz, 1 H), 6.56
(dd, J = 15.8, 7.5 Hz, 1 H), 5.17 (s, 2 H), 3.92 (s, 3 H).
13C NMR (75.0 MHz, CDCl3): δ = 193.5, 152.8, 151.0, 149.8,
136.2, 128.6, 128.1, 127.2, 127.1, 126.7, 123.1, 113.2, 110.3, 70.8,
60.0.
Acknowledgment
Y.R and S.N. thank CSIR, New Delhi for the award of fellowships.
J.S.Y. acknowledges partial support by the King Saud University
for Global Research Network for Organic Synthesis (GRNOS).
HRMS: m/z [M + Na]+ calcd for C17H16O3Na: 291.0997; found:
291.0991.
References
(1) (a) Lacklock, T. J.; Shuman, R. F.; Butcher, J. W. Jr.;
Shearin, W. E.; Budavari, J.; Grenda, V. J. J. Org. Chem.
1988, 53, 836. (b) Chang, H. S.; Woo, J. C.; Lee, K. M.; Ko,
Y. K.; Moon, S.-S.; Kim, D.-W. Synth. Commun. 2002, 32,
31. (c) Fukuda, Y.; Maeda, Y.; Ishii, S.; Kondo, K.;
Aoyama, T. Synthesis 2006, 589.
(R)-5-(Benzyloxy)pent-2-yne-1,4-diol (4)
To a stirred solution of TBS-protected compound6 (0.8 g, 2.5 mmol)
in MeOH (15 mL), a catalytic amount of PTSA was added. The re-
action mixture was stirred at r.t. for 2 h. After completion of the re-
action, solid NaHCO3 was added to neutralize PTSA and the
mixture was filtered. The filtrate was concentrated under reduced
pressure and purified by silica gel column chromatography
(EtOAc–petroleum ether, 3:7) to afford pure 4.
(2) (a) Carroll, F. I.; Melvin, M. S.; Nuckols, M. C.; Mascarella,
S. W.; Navarro, H. A.; Thomas, J. B. J. Med. Chem. 2006,
49, 1781. (b) Garner, P.; Kaniskan, H. U.; Hu, J.; Youngs,
W. J.; Panzner, M. Org. Lett. 2006, 8, 3647. (c) Jones, M. C.;
Marsden, S. P.; Subtil, D. M. M. Org. Lett. 2006, 8, 5509.
(d) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc.
2007, 129, 3830. (e) Tennakoon, M. A.; Henninger, T. C.;
Abbanat, D.; Foleno, B. D.; Hilliard, J. J.; Bush, K.;
Macielag, M. J. Bioorg. Med. Chem. Lett. 2006, 16, 6231.
(3) (a) Organic Syntheses via Metal Carbonyls; Wender, I.;
Pino, P., Eds.; Wiley: New York, 1977. (b) New Syntheses
with Carbon Monoxide; 1; Falbe, J., Ed.; Springer: Berlin,
1980, 225. (c) Kohlpaintner, C. W.; Frohning, C. D. In
Applied Homogeneous Catalysis with Organometallic
Compounds; Vol. 1; Cornils, B.; Herrmann, W. A., Eds.;
VCH: Weinheim, 1996, 1–39.
Yield: 0.44 g (87%); colorless liquid; [α]D27 +2.0 (c 0.2, CHCl3).
IR (neat): 3446, 2922, 1634, 1455, 1218, 1071, 1019, 770 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.26 (m, 5 H), 4.59 (ABq,
J = 13.5, 12.0 Hz, 2 H), 4.23 (d, J = 1.5 Hz, 2 H), 3.60 (dd, J = 9.8,
3.7 Hz, 1 H), 3.52 (dd, J = 9.8, 7.5 Hz, 1 H), 2.70 (br s, 1 H), 1.50
(br s, 1 H).
13C NMR (75.0 MHz, CDCl3): δ = 137.3, 128.4, 127.9, 127.8, 84.1,
83.3, 73.4, 73.3, 61.4, 50.6.
HRMS (ESI): m/z [M + Na]+ calcd for C12H14O3Na: 229.0840;
found: 229.0853.
Methyl 2-[(2R,5R)-5-(Benzyloxymethyl)tetrahydrofuran-2-
yl]acetate (7)
(4) Sabitha, G.; Nayak, S.; Bhikshapathi, M.; Yadav, J. S. Org.
Lett. 2011, 13, 382.
A 50 mL two-neck, round-bottomed flask was charged with
Pd(OH)2/C (7 mol%). Benzene (3 mL) was added and a H2 filled
balloon was placed over the mixture for 30 min (to activate the cat-
alyst). The balloon was removed and stirring was continued for 10
min, after which a solution of diol 4 (1.21 mmol) in benzene (3 mL)
was added. The reaction mixture was stirred for a further 60 min.
After complete conversion of the diol into the corresponding lactol
5 (indicated by TLC), stable Wittig ylide (1.57 mmol) was added
and the mixture was stirred at reflux temperature for 3 h. The reac-
tion mixture was cooled r.t. and the solvent was removed to afford
the crude product, which was used for the next reaction without fur-
ther purification. To a stirred solution of α,β-unsaturated ester 6 (0.8
g) described above in MeOH (15 mL), a 40 wt% MeOH solution of
Triton B (0.196 mL, 1.07 mmol) was added at r.t., and the mixture
was stirred at r.t. for 15 min. After cooling to 0 °C, the mixture was
diluted with sat. aq NH4Cl (10 mL) and extracted with EtOAc
(5) (a) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 1995,
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(6) (a) Morra, N. A.; Pagenkopf, B. L. Org. Lett. 2011, 13, 572.
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Tetrahedron Lett. 2010, 51, 5736. (b) Kanger, T.; Liiv, M.;
Pehk, T.; Lopp, M. Synthesis 1993, 91. (c) Takano, S.;
Sekiguchi, Y. Heterocycles 1992, 33, 743. (d) Takano, S.;
Samizu, K.; Sugihara, T.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1989, 1344.
(8) Obtained from 4-benzyloxybut-2-en-1-ol by Sharpless
asymmetric epoxidation reaction followed by base-induced
double elimination reaction and formylation (Scheme 4).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1657–1662

1662
G. Sabitha et al.
PAPER
(9) (a) Hayakawa, I.; Ueda, M.; Yamaura, M.; Ikeda, Y.;
O
OH
X
Suzuki, Y.; Yoshizato, K.; Kigoshi, H. Org. Lett. 2008, 10,
859. (b) Ko, S.; Klein, L.; Pfaff, K.; Kishi, Y. Tetrahedron
Lett. 1982, 23, 4415.
BnO
BnO
X = OH
X = Cl
OR
OR
BnO
BnO
OH
R = H
R = TBS
R = TBS (TBS protected
4
;
R = H
compound)
Scheme 4
Synthesis 2012, 44, 1657–1662
© Georg Thieme Verlag Stuttgart · New York