Synthesis of furan-3-carboxylic and 4-methylene-4,5-dihydrofuran-3- carboxylic esters by direct palladium iodide catalyzed oxidative carbonylation of 3-yne-1,2-diol derivatives

Article abstract of DOI:10.1021/jo301628n

A variety of 3-yne-1,2-diol derivatives 1, bearing a primary or secondary alcoholic group at C-1, have been efficiently converted into high value added furan-3-carboxylic esters 2 in one step by PdI₂/KI-catalyzed direct oxidative carbonylation, carried out in alcoholic media under relatively mild conditions (100 °C under 40 atm of a 4/1 mixture of CO and air). Carbonylated furans 2 were obtained in fair to excellent isolated yields (56-93%) through a sequential 5-endo-dig heterocyclization-alkoxycarbonylation- dehydration process, using only oxygen as the external oxidant. Under similar conditions, 2-methyl-3-yne-1,2-diols 3, bearing a tertiary alcoholic group, afforded 4-methylene-4,5-dihydrofuran-3-carboxylates 4 in satisfactory yields (58-70%).

Full text of DOI:10.1021/jo301628n

Article
pubs.acs.org/joc
Synthesis of Furan-3-carboxylic and 4‑Methylene-4,5-dihydrofuran-
3-carboxylic Esters by Direct Palladium Iodide Catalyzed Oxidative
Carbonylation of 3‑Yne-1,2-diol Derivatives
Bartolo Gabriele,*,† Raffaella Mancuso,‡ Vito Maltese,‡ Lucia Veltri,‡ and Giuseppe Salerno‡
†Dipartimento di Scienze Farmaceutiche and ‡Dipartimento di Chimica, Universita
Italy
̀
della Calabria, 87036 Arcavacata di Rende (CS),
S
* Supporting Information
ABSTRACT: A variety of 3-yne-1,2-diol derivatives 1, bearing
a primary or secondary alcoholic group at C-1, have been
efficiently converted into high value added furan-3-carboxylic
esters 2 in one step by PdI2/KI-catalyzed direct oxidative
carbonylation, carried out in alcoholic media under relatively
mild conditions (100 °C under 40 atm of a 4/1 mixture of CO
and air). Carbonylated furans 2 were obtained in fair to
excellent isolated yields (56−93%) through a sequential 5-
endo-dig heterocyclization−alkoxycarbonylation−dehydration process, using only oxygen as the external oxidant. Under similar
conditions, 2-methyl-3-yne-1,2-diols 3, bearing a tertiary alcoholic group, afforded 4-methylene-4,5-dihydrofuran-3-carboxylates 4
in satisfactory yields (58−70%).
Scheme 1. Mechanism of PdI2-Promoted Heterocyclization−
Carbonylation of Acetylenic Substrates Bearing a Suitably
Placed Nucleophilic Group (Y = O, NR′; NuH = OH, NR″)
INTRODUCTION
■
PdI2/KI-catalyzed heterocyclization−alkoxycarbonylation or
heterocyclization−aminocarbonylation of acetylenic substrates
bearing a suitably placed nucleophilic group is a powerful
methodology for the direct synthesis of important carbonylated
heterocycles.1−3 The heterocyclization−carbonylation sequence
is promoted by PdI2, which is then reduced to Pd(0) at the end
of the cycle (Scheme 1; in this and in the following schemes
anionic iodide ligands are omitted for clarity).
Therefore, the presence of an oxidant is needed in order to
make the process catalytic. In some particular cases, an external
oxidant is not needed if the product initially ensuing from the
carbonylation process still possesses a reducible functional
group able to reoxidize Pd(0) to Pd(II), as exemplified in
Scheme 2.1,2 Usually, however, the reaction is carried out under
oxidative conditions,1,3 in the presence of oxygen as the
external oxidant, which is able to reconvert Pd(0) to PdI2
through the oxidation of HI (also ensuing from the
carbonylation process) to I2 followed by oxidative addition of
the latter to Pd(0) (Scheme 3).2
In this paper, we report a full account of the PdI2/KI-
catalyzed oxidative 5-endo-dig heterocyclodehydration−alkox-
ycarbonylation of readily available 3-yne-1,2-diol derivatives 1
and 3 to give furan-3-carboxylic and methylenedihydrofuran-3-
carboxylic esters 2 and 4, respectively (Scheme 4). In these
reactions, the heterocyclization−alkoxycarbonylation process is
accompanied by dehydration, either from the R1CHC(2)OH
moiety of 1 (resulting in aromatization and leading to 2) or
from the MeC(2)OH moiety of 3 (leading to 4). To our
knowledge, this is the first example of synthesis of these
important classes of heterocycles via a direct carbonylation
approach of acyclic precursors.4−8
RESULTS AND DISCUSSION
■
2-Methyloct-3-yne-1,2-diol (1a; R1 = H, R2 = Me, R3 = Bu),
readily available by alkynylation of hydroxyacetone (see the
Received: August 1, 2012
© XXXX American Chemical Society
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Scheme 2. Mechanism of PdI2-Catalyzed Heterocyclization−Carbonylation of Acetylenic Substrates Bearing a Suitably Placed
Nucleophilic Group and a Reducible Function (Y = O, NR′; NuH = OH, NR″)
formation of 2a. A similar effect was observed when the
substrate concentration was decreased (entry 3) and when the
KI/PdI2 ratio was lowered to 5 (entry 5). A significant augment
of the total yield (81%, by GLC) was obtained when the total
pressure was increased to 40 atm (entry 7). When the reaction
was carried out under the conditions thus optimized (1a/KI/
PdI2 molar ratio 1/5/100, 100 °C, 32 atm of CO, 8 atm of air,
1a concentration 0.05 mmol/mL of MeOH), methyl 2-butyl-4-
methylfuran-3-carboxylate (2a) was selectively obtained in 76%
GLC yield (69% isolated; Table 2, entry 1). An even higher
yield (81% isolated) could be obtained using a higher catalyst
loading (2 mol %; Table 2, entry 2).
The generality of the process was then verified by testing the
reactivity of other differently substituted 3-yne-1,2-diols 1b−r,
bearing a primary or secondary alcoholic group at C-1, as well
as different substituents at C-2 and C-4. As can be seen from
the results reported in Table 2, entries 2−19, the process was
quite general, the corresponding furan-3-carboxylic esters 2b−r
being consistently obtained in satisfactory isolated yields (56−
93%). It is worth noting that the reaction also worked nicely
with dialkynyl substrates, such as 2-(hex-1-ynyl)oct-3-yne-1,2-
diol (1d) and (S)-3-(hex-1-ynyl)non-4-yne-2,3-diol (1f), which
were converted into the corresponding furan-3-carboxylic esters
2d,f without affecting the alkynyl substituent at C-3 (Table 2,
entries 5 and 7), which would allow further functionalization at
the furan ring. As can be seen from entries 20 and 21 (Table 2),
a higher alcohol, such as EtOH, could also be used instead of
MeOH, still with satisfactory results.9
Scheme 3. Mechanism of Reoxidation of Pd(0) to PdI2 in the
Presence of O2 as External Oxidant
Experimental Section for details), was chosen as a model
substrate for assessing the reactivity of 3-yne-1,2-diol derivatives
1 bearing a primary alcoholic group at C-1 under oxidative
carbonylation conditions in the presence of catalytic amounts
of PdI2/KI. The reaction was initially conducted at 80 °C in
MeOH as the solvent (1a concentration 0.25 mmol per mL of
MeOH, 1a/KI/PdI2 molar ratio 1/10/100) under 20 atm of a
4/1 mixture of CO and air. A mixture of the desired furan-
carboxylic methyl ester derivative 2a (28% GLC yield) and 2-
hydroxy-2-methyloct-3-ynyl 2-butyl-4-methylfuran-3-carboxy-
late (5a) (clearly deriving from nucleophilic displacement by
substrate 1a rather than MeOH, 13% GLC yield) at a substrate
conversion of 70% was obtained under these conditions, as
shown in Table 1, entry 1. Although 5a could not be isolated in
a pure state by conventional chromatographic techniques, its
formation was strongly suggested by the GC-MS analysis of the
crude reaction mixture (see the Experimental Section for
details).
In order to improve this initial result, we then screened the
reaction parameters; the results obtained are shown in Table 1,
entries 2−7. As can be seen from Table 1, entry 2, an increase
of the temperature to 100 °C caused an improvement of both
the total yield and the selectivity of the process toward the
Scheme 4. Formation of Furan-3-carboxylic and 4-Methylene-5,6-dihydrofuran-3-carboxylic Esters 2 and 4 by Direct Palladium
Iodide Catalyzed Oxidative Carbonylation of 3-Yne-1,2-diol Derivatives 1 and 3, Respectively
B
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a
Table 1. PdI2/KI-Catalyzed Oxidative Carbonylation Reactions of 2-Methyloct-3-yne-1,2-diol (1a) Under Different Conditions
b
c
c
entry
KI/PdI2 molar ratio
T (°C)
substrate concn
PCO/Pair (atm)
yield of 2a (%)
yield of 5a (%)
total yield (%)
d
1
10
10
10
10
5
80
100
80
0.25
0.25
0.05
0.02
0.25
0.25
0.25
16/4
16/4
16/4
16/4
16/4
16/4
32/8
28
55
60
45
52
37
49
13
9
41
64
62
46
67
46
81
2
3
4
5
6
7
2
80
1
80
15
9
2
80
10
80
32
a
All reactions were carried out in MeOH for 2 h in the presence of 1 mol % of PdI2. Unless otherwise noted, substrate conversion was quantitative.
b
c
In units of mmol of starting 1a/mL of MeOH. Based on starting 1a, by GLC. The formation of unidentified heavy products (chromatographically
d
immobile materials) accounted for the difference between the substrate conversion and the product yield. Substrate conversion was ca. 70%
(determined by GLC).
We also tested the reactivity of 2-methyl-3-yne-1,2-diols 3,
bearing a tertiary alcoholic group, for which aromatization is
clearly not possible. Interestingly, when we reacted 2,3-
dimethyl-5-phenylpent-4-yne-2,3-diol (3a) under the condi-
tions already optimized for substrates 1, using 1 mol % of PdI2
for 5 h, methyl 5,5-dimethyl-4-methylene-2-phenyl-4,5-dihy-
drofuran-3-carboxylate (4a) was obtained in 65% isolated yield,
resulting from 5-endo-dig cyclization−alkoxycarbonylation with
simultaneous dehydration from the MeC(3)OH moiety (Table
3, entry 1). This yield remained practically the same on working
with a higher catalyst loading (Table 3, entry 2). Since this kind
of reactivity could represent a convenient entry to an important
class of functionalized heterocycles starting from simple and
available building blocks, we then applied our method to other
similar substrates 3b−e, bearing different substituents on the
triple bond. As shown in Table 3, entries 3−6, the
corresponding 4-methylene-4,5-dihydrofuran-3-carboxylates
4b−e were obtained in good yields with all the substrates
tested. In the case of 2,3-dimethylnon-4-yne-2,3-diol (3b),
better results were obtained working at 80 °C under more
concentrated conditions (Table 3, entry 2). The reaction could
also be carried out successfully in EtOH as the solvent, as
shown by entry 7 (Table 3).
The proposed catalytic cycle for the overall transformation
from 3-yne-1,2-diols 1 and 3 to give furan-3-carboxylic esters 2
and methylenedihydrofuran-3-carboxylic esters 4, respectively,
is shown in Scheme 5 (anionic iodide ligands are omitted for
clarity). It involves the coordination of the substrate to PdI2,
followed by intramolecular 5-endo-dig nucleophilic attack by the
hydroxyl group at C-1 at the coordinate triple bond to give the
vinylpalladium intermediate I. Carbon monoxide insertion, to
give acylpalladium complex II, followed by nucleophilic
displacement by the external alcohol and dehydration (or vice
versa) eventually leads to the final product and Pd(0). The
latter is then reoxidized back to PdI2 according to the
mechanism shown in Scheme 3.
ylic esters 4 starting from very simple building blocks (3-yne-
1,2-diol derivatives 1 or 3, respectively, CO, O2, and ROH),
which are sequentially assembled under the promoting action
of the metal catalyst. The catalytic system employed is very
simple (PdI2 + 5 KI), and the reaction conditions,
corresponding to an oxidative carbonylation process with
only O2 as the external oxidant, are relatively mild. The
generality of the process has been assessed with a variety of
differently substituted 3-yne-1,2-diols 1 and 3, with the
corresponding heterocyclic derivatives 2 and 4, respectively,
being consistently obtained in fair to excellent yields.
EXPERIMENTAL SECTION
■
General Experimental Methods. Melting points are uncorrected.
1H NMR and 13C NMR spectra were recorded at 25 °C in CDCl3 or
DMSO-d6 solutions at 300 and 75 MHz, respectively, with Me4Si as
internal standard. Chemical shifts (δ) and coupling constants (J) are
given in ppm and in Hz, respectively. IR spectra were taken with an
FT-IR spectrometer. Mass spectra were obtained using a GC-MS
apparatus at 70 eV ionization voltage or a mass spectrometer equipped
with a turbo ion spray ionization source in the positive mode (ion
spray voltage (IS) 4500 V; curtain gas 10 psi; temperature 25 °C; ion
source gas (1) 20 psi; declustering and focusing potentials 50 and 400
V, respectively). Microanalyses were carried out at our analytical
laboratory. All reactions were analyzed by TLC on silica gel 60 F254 or
on neutral alumina and by GLC using a gas chromatograph and
capillary columns with polymethylsilicone +5% phenylsilicone as the
stationary phase. Column chromatography was performed on silica gel
60 (70−230 mesh). Evaporation refers to the removal of solvent under
reduced pressure.
Preparation of Substrates 1. Substrates 1 were prepared by
alkynylation of the appropriate α-hydroxy aldehyde, α-hydroxy ketone
or α-hydroxy ester using an excess of R3CCLi or R3CCMgBr, as
described below.
General Procedure for the Preparation of 3-Yne-1,2-diols
1a,b,e,h,i,k−m,o−r. To a solution of BuLi in hexane (1.6 M; 25 mL,
40 mmol) was added anhydrous THF (6 mL) and hexane (25 mL)
under nitrogen. The resulting mixture was cooled to −40 °C and
maintained with stirring. A solution of the 1-alkyne (44.5 mmol: 1-
hexyne, 3.66 g; tert-butylacetylene, 3.66 g; phenylacetylene, 4.54 g; 3-
ethynylthiophene, 4.81 g; 1-ethynylcyclohex-1-ene, 4.72 g; p-
bromophenylacetylene, 8.06 g; p-methylphenylacetylene, 5.17 g) in
anhydrous THF (6 mL) was added dropwise under nitrogen to the
cooled mixture followed by a solution of LiBr (1.56 g, 18.0 mmol) in
CONCLUSIONS
■
In conclusion, we have reported a general, convenient, and
atom-economical method for the one-step synthesis of furan-3-
carboxylic esters 2 and 4-methylene-4,5-dihydrofuran-3-carbox-
C
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Table 2. Synthesis of Furan-3-carboxylic Esters 2 by PdI2/KI-Catalyzed Oxidative Carbonylation of 3-Yne-1,2-diols 1 Bearing a
a
Primary or Secondary Alcoholic Group at C-1
a
Unless otherwise noted, all carbonylation reactions were carried out at 100 °C for 2 h under 40 atm (at 25 °C) of a 4/1 mixture of CO and air, in
ROH as the solvent (0.05 mmol of starting 1/mL of solvent) in the presence of PdI2 (2 mol %) and KI (KI/PdI2 molar ratio of 5). Conversion of 1
was quantitative in all cases. Isolated yield based on starting 1. The reaction was carried out with 1 mol % of PdI2. The GLC yield of 2a was 76%.
b
c
d
anhydrous THF (6 mL). After the mixture was stirred for 0.5 h at −40
°C, a solution of the appropriate α-hydroxy ketone (17 mmol) (α-
hydroxyacetone (purity 90%), 1.40 g; 3-hydroxybutan-2-one, 1.50 g;
α-hydroxyacetophenone, 2.31 g) in anhydrous THF (5 mL) was
added under nitrogen. The mixture was stirred at the same
temperature for 2 h, and then it was warmed to room temperature.
Saturated aqueous NH4Cl (40 mL) was added, followed by Et2O (50
mL). Phases were separated, and the aqueous phase was extracted with
Et2O (50 mL × 3). The collected organic phases were washed with
brine to neutral pH and dried over Na2SO4. After filtration and
evaporation of the solvent, products 1b,e,i,k−m,p,q were purified by
column chromatography on silica gel using the following mixtures as
eluent: 6/4 hexane/AcOEt (1b,l), 7/3 hexane/AcOEt (1e,m), 8/2
hexane/acetone (1i,q), 9/1 hexane/acetone (1k), 95/5 hexane/
D
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Table 3. Synthesis of 4-Methylene-4,5-dihydrofuran-3-carboxylates 4 by PdI2/KI-Catalyzed Oxidative Carbonylation of 2-
a
Methyl-3-yne-1,2-diols 3 Bearing a Tertiary Alcoholic Group at C-1
a
Unless otherwise noted, all carbonylation reactions were carried out at 100 °C for 2 h under 40 atm (at 25 °C) of a 4/1 mixture of CO and air, in
ROH as the solvent (0.05 mmol of starting 3/mL of MeOH) and with a substrate/KI/PdI2 molar ratio of 100/5/1. Conversion of 3 was quantitative
in all cases. Isolated yield based on starting 3. The reaction was carried out with 2 mol % of catalyst. The reaction was carried out at 80 °C with a
b
c
d
substrate concentration of 0.2 mmol of 3b/mL of MeOH.
acetone (1p). Crude products 1a,h,o,r were sufficiently pure to be
used as such for the subsequent carbonylation reaction.
2-Phenyloct-3-yne-1,2-diol (1b). Yield: 3.33 g, starting from 2.31 g
of α-hydroxyacetophenone (90%). Yellow oil. IR (film): ν 3341 (m,
br), 2931 (m), 2247 (w), 1588 (m), 1495 (m), 1386 (m), 1245 (s),
2-Methyloct-3-yne-1,2-diol (1a). Yield: 2.39 g, starting from 1.40 g
of α-hydroxyacetone (90%). Colorless amorphous solid. Mp: 33−35
°C (lit.10 mp 32−34 °C). IR (KBr): ν 3367 (m, br), 2937 (m), 2247
(w), 1469 (m), 1380 (m), 1256 (m), 1147 (m), 1200 (m), 1059 (m),
950 (m), 919 (w) cm−1. 1H NMR (300 MHz, CDCl3): δ 3.61
(distorted d, J = 11.0, 1 H), 3.47 (distorted d, br, J = 11.0, 1 H), 3.30
(s, br, 2 H), 2.20 (t, J = 6.7, 2 H), 1.54−1.33 (m, 4 H), 1.43 (s, 3 H),
0.91 (t, J = 7.3, 3 H). 13C NMR (75 MHz, CDCl3): δ 85.3, 82.1, 71.0,
68.7, 30.9, 25.9, 22.0, 18.4, 13.5. GC-MS (EI, 70 eV): m/z 156
(absent) [M+], 125 (100), 95 (10), 91 (14), 81 (21), 79 (24), 69 (50),
67 (25), 55 (42). Anal. Calcd for C9H16O2 (156.22): C, 69.19; H,
10.32. Found: C, 69.13; H, 10.35.
1
1074 (m), 1034 (m), 903 (m), 758 (s) cm−1. H NMR (300 MHz,
CDCl3): δ 7.65−7.58 (m, 2 H), 7.40−7.26 (m, 3 H), 3.69 (distorted
dd, J = 10.9, 4.2, 1 H), 3.61 (distorted dd, J = 10.9, 6.3, 1 H), 3.23 (s, 1
H), 2.48−2.38 (m, 1 H), 2.29 (t, J = 6.9, 2 H), 1.60−1.36 (m, 4 H),
0.92 (t, J = 7.3, 3 H). 13C NMR (75 MHz, CDCl3): δ 141.5, 128.3,
128.0, 125.9, 87.8, 80.7, 73.9, 72.3, 30.7, 22.0, 18.5, 13.6. GC-MS (EI,
70 eV): m/z 218 (absent) [M+], 188 (52), 187 (100), 141 (11), 128
(26), 115 (53), 109 (58), 105 (67), 91 (37), 79 (46), 77 (52), 66 (38).
Anal. Calcd for C14H18O2 (218.29): C, 77.03; H, 8.31. Found: C,
77.12; H, 8.29.
3-Methylnon-4-yne-2,3-diol (1e). Yield: 1.71 g, starting from 1.50 g
of 3-hydroxybutan-2-one (59%). Mixture of diastereomers A + B, A/B
E
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Mp: 105−106 °C (lit.12 mp 105−106 °C). IR (KBr): ν 3398 (s, br),
2977 (w), 2932 (m), 2232 (vw), 1491 (m), 1403 (m), 1376 (m), 1341
(m), 1283 (m), 1136 (m), 1090 (m), 1050 (s), 1028 (m), 986 (w),
Scheme 5. Proposed Catalytic Cycle for the PdI2/KI-
Catalyzed Oxidative Carbonylation of 3-Yne-1,2-diol
Derivatives 1 and 3 Leading to Furan-3-carboxylic and 4-
Methylene-5,6-dihydrofuran-3-carboxylic Esters 2 and 4,
Respectively
1
900 (m), 764 (s), 696 (m), 677 (m) cm−1. H NMR (300 MHz,
DMSO-d6): δ 7.45−7.33 (m, 5 H), 5.42 (s, 1 H), 5.02 (t, J = 6.3, 1 H),
3.52−3.26 (m, 2 H), 1.42 (s, 3 H). 13C NMR (75 MHz, DMSO-d6): δ
131.2, 128.5, 128.2, 122.7, 94.2, 81.9, 69.6, 67.7, 26.2. GC-MS (EI, 70
eV): m/z 176 (3) [M+], 146 (18), 145 (100), 129 (11), 115 (11), 102
(8), 77 (10). Anal. Calcd for C11H12O2 (176.21): C, 74.98; H, 6.86.
Found: C, 75.12; H, 6.84.
2,4-Diphenylbut-3-yne-1,2-diol (1l). Yield: 3.44 g, starting from
2.31 g of α-hydroxyacetophenone (85%). Colorless amorphous solid.
Mp: 104−105 °C (lit.13 mp 106 °C). IR (KBr): ν 3352 (s, br), 3222
(s, br), 2215 (w), 1489 (m), 1412 (m), 1100 (m), 1069 (s), 1033 (m),
1
903 (m), 758 (s), 690 (m) cm−1. H NMR (300 MHz, DMSO-d6): δ
7.70−7.64 (m, 2 H), 7.51−7.45 (m, 2 H), 7.42−7.26 (m, 6 H), 3.89−
3.67 (m, 2 H), 3.54 (s, br, 1 H), 2.65 (s, br, 1 H). 13C NMR (75 MHz,
DMSO-d6): δ 141.04, 141.01, 131.9, 128.8, 128.43, 128.38, 128.26,
126.0, 89.5, 86.7, 74.2, 72.2. GC-MS (EI, 70 eV): m/z 238 (<0.5)
[M+], 208 (49), 207 (100), 191 (13), 189 (15), 178 (18), 130 (24),
129 (93), 105 (66), 77 (54). Anal. Calcd for C16H14O2 (238.28): C,
80.65; H, 5.92. Found: C, 80.71; H, 5.90.
3-Methyl-5-phenylpent-4-yne-2,3-diol (1m). Mixture of diaster-
1
eomers A + B, A/B ratio ca. 1.5/1, determined by H NMR. Yield:
1.91 g, starting from 1.50 g of 3-hydroxybutan-2-one (59%). Colorless
amorphous solid. Mp: 61−62 °C. IR (KBr): ν 3568 (m, br), 3301 (m,
br), 2986 (m), 2231 (w), 1598 (w), 1490 (m), 1443 (m), 1370 (m),
1123 (s), 1077 (m), 961 (m), 939 (m), 846 (w), 756 (s), 691 (s)
cm−1. 1H NMR (300 MHz, CDCl3): δ 7.48−7.39 [A (m, 2 H) + B (m,
2 H)], 7.35−7.28 [A (m, 3 H) + B (m, 3 H)], 3.92 [A (q, J = 6.2, 1
H)], 3.71 [B (q, J = 6.2, 1 H)], 2.93 [B (s, br, 1 H)], 2.44 [A (s, br, 1
H)], 2.34 [A (s, br, 1 H)], 2.03 [B (s, br, 1 H)], 1.53 [B (s, 3 H)], 1.52
[A (s, 3 H)], 1.38 [B (distorted d, J = 6.2, 3 H), 1.31 [A (distorted d, J
= 6.2)]. 13C NMR (75 MHz, CDCl3): δ 131.86 (B), 131.82 (A),
128.61 (A), 128.56 (B), 128.4 (A + B), 122.6 (A or B), 122.5 (B or A),
91.2 (A), 89.9 (B), 85.5 (B), 84.9 (A), 74.6 (B), 73.9 (A), 72.5 (B),
71.8 (A), 25.9 (B), 23.6 (A), 18.6 (B), 16.8 (A). MS (ESI+, direct
infusion): m/z 213 [(M + Na)+]. Anal. Calcd for C12H14O2 (190.24):
C, 75.76; H, 7.42. Found: C, 75.83; H, 7.40.
2-Methyl-4-p-tolylbut-3-yne-1,2-diol (1o). Yield: 2.72 g, starting
from 1.40 g of α-hydroxyacetone (84%). Colorless amorphous solid.
Mp: 89−90 °C (lit.14 mp 88−90 °C). IR (KBr): ν 3386 (s, br), 3312
(s, br), 2235 (vw), 1637 (m), 1510 (m), 1384 (m), 1265 (m), 1122
(m), 1057 (m), 951 (w), 815 (m) cm−1. 1H NMR (300 MHz,
CDCl3): δ 7.35−7.26 (m, 2 H), 7.11−7.03 (m, 2 H), 3.75 (distorted d,
J = 11.2, 1 H), 3.57 (distorted d, J = 11.2, 1 H), 3.39 (s, br, 2 H), 2.31
(s, 3 H), 1.52 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 138.6, 131.7,
129.0, 119.2, 89.9, 84.5, 70.6, 69.0, 25.4, 21.5. GC-MS (EI, 70 eV): m/
z 190 (6) [M+], 172 (3), 159 (100), 143 (9), 128 (10), 115 (25), 91
(6), 89 (6), 77 (5). Anal. Calcd for C12H14O2 (190.24): C, 75.76; H,
7.42. Found: C, 75.81; H, 7.41.
4-(4-Bromophenyl)-2-methylbut-3-yne-1,2-diol (1p). Yield: 3.47 g,
starting from 1.40 g of α-hydroxyacetone (80%). Yellow amorphous
solid. Mp: 84−85 °C. IR (KBr): ν 3304 (s, br), 2930 (m), 2233 (vw),
1490 (m), 1384 (m), 1139 (m), 1064 (s), 952 (m), 755 (s), 669 (s)
cm−1. 1H NMR (300 MHz, DMSO-d6): δ 7.50−7.23 (m, 4 H), 5.40 (s,
1 H), 5.00 (t, br, J = 6.2, 1 H), 3.49−3.34 (m, 2 H), 1.40 (s, 3 H). 13C
NMR (75 MHz, DMSO-d6): δ 131.2, 128.5, 125.8, 122.6, 94.2, 81.8,
69.5, 67.7, 26.2. GC-MS (EI, 70 eV): m/z 254 (absent) [M+], 176 (2),
145 (100), 129 (11), 115 (11), 102 (8), 89 (4), 77 (11). Anal. Calcd
for C11H11BrO2 (255.11): C, 51.79; H, 4.35; Br, 31.32. Found: C,
51.81; H, 4.31; Br, 31.30.
2-Methyl-4-thiophen-3-ylbut-3-yne-1,2-diol (1q). Yield: 2.63 g,
starting from 1.40 g of α-hydroxyacetone (85%). Yellow amorphous
solid. Mp: 81.0−83.0 °C. IR (KBr): ν 3334 (s, br), 3237 (s, br), 2232
(vw), 1384 (m), 1357 (w), 1168 (m), 1127 (m), 1053 (s), 952 (w),
780 (s), 627 (m) cm−1. 1H NMR (300 MHz, DMSO-d6): δ 7.74−7.64
(m, 1 H), 7.58 (dd, J = 4.9, 3.2, 1 H), 7.11 (d, br, J = 4.9, 1 H), 5.37 (s,
1 H), 4.98 (t, J = 6.1, 1 H), 3.50−3.31 (m, 2 H), 1.38 (s, 3 H). 13C
NMR (75 MHz, DMSO-d6): δ 129.5, 128.9, 126.4, 121.5, 93.4, 77.3,
ratio ca. 3/1, determined by 1H NMR. Yellow oil. IR (film): ν 3388 (s,
br), 2873 (m), 2244 (m), 1458 (m), 1372 (m), 1107 (m), 1076 (m),
929 (w), 904 (w) cm−1. 1H NMR (300 MHz, CDCl3): δ 3.77 [A (q, 1
H, J = 6.5)], 3.59 [B (q, 1 H, J = 6.5)], 3.13 [B, (s, br, 1 H)], 2.78 [A
(s, br, 1 H)], 2.66 [A (s, br, 1 H)], 2.42 [B (s, br, 1 H)], 2.23 [B (t, J =
7.1, 2 H)], 2.20 [A (t, J = 7.1, 2 H)], 1.56−1.35 [A (m, 4 H), + B (m,
4 H)], 1.40 [B (s, 3 H)], 1.39 [A (s, 3 H)], 1.27 [B (d, J = 6.5, 3 H)],
1.22 [A (d, J = 6.5, 3 H)], 0.91 [A (t, J = 7.3, 3 H) + B (t, J = 7.3, 3
H)]. 13C NMR (75 MHz, CDCl3): δ 86.1 (B), 85.5 (A), 82.5 (A + B),
74.5 (B), 74.0 (A), 72.1 (B), 71.3 (A), 30.9 (B), 30.8 (A), 26.1 (A +
B), 23.7 (B), 22.0 (A), 18.3 (B), 16.7 (A), 13.6 (B), 13.5 (A). MS (ESI
+, direct infusion) m/z 193 [(M + Na)+]. Anal. Calcd for C10H18O2
(170.25): C, 70.55; H, 10.66. Found: C, 70.61; H, 10.64.
2,5,5-Trimethylhex-3-yne-1,2-diol (1h). Yield: 2.12 g, starting from
1.40 g of α-hydroxyacetone (80%). Colorless amorphous solid. Mp:
90−91 °C (lit.11 mp 95.5−96 °C). IR (KBr): ν 3362 (m, br), 3222 (m,
br), 2968 (m), 2226 (vw), 1458 (m), 1422 (m), 1360 (m), 1267 (m),
1
1188 (m), 1147 (m), 1059 (s), 960 (m), 716 (m) cm−1. H NMR
(300 MHz, CDCl3): δ 3.61 (distorted d, J = 11.0, 1 H), 3.46 (distorted
d, J = 11.0, 1 H), 3.39 (s, br, 1 H), 3.05 (s, br, 1 H), 1.43 (s, 3 H), 1.21
(s, 9 H). 13C NMR (75 MHz, CDCl3): δ 93.6, 80.3, 70.9, 68.6, 31.1,
27.3, 25.8. GC-MS (EI, 70 eV): m/z 156 (M+, absent), 125 (100), 107
(14), 95 (18), 91 (20), 79 (24), 69 (22), 67 (20), 57 (16). Anal. Calcd
for C9H16O2 (156.22): C, 69.19; H, 10.32. Found: C, 69.12; H, 10.34.
3,6,6-Trimethylhept-4-yne-2,3-diol (1i). Mixture of diastereomers
1
A + B, A/B ratio ca. 2.5/1, determined by H NMR. Yield: 1.88 g,
starting from 1.50 g of 3-hydroxybutan-2-one (65%). Colorless
amorphous solid. Mp: 50−52 °C. IR (KBr): ν 3427 (s, br), 3231
(m, br), 2968 (m), 2220 (vw), 1631 (m), 1456 (m), 1384 (m), 1268
(m), 1099 (m), 1011 (w), 974 (m), 927 (m), 894 (w), 842 (w) cm−1.
1H NMR (300 MHz, CDCl3): δ 3.76 [A (q, J = 6.1, 1 H)], 3.58 [B (q,
J = 6.1, 1 H)], 3.10 [B (s, br, 1 H)], 2.78 [A (s, br, 1 H)], 2.65 [A (s,
br, 1 H)], 2.35 [B (s, br, 1 H)], 1.39 [B (s, 3 H)], 1.38 [A (s, 3 H)],
1.26 [B (d, J = 6.1, 3 H)], 1.22 [B (s, 9 H)], 1.21 [A (s, 9 H)], 1.21 [A
(d, J = 6.1, 3 H)]. 13C NMR (75 MHz, CDCl3): δ 94.4 (B), 93.9 (A),
80.9 (A + B), 74.4 (B), 74.0 (A), 71.8 (B), 71.2 (A), 31.1 (B), 31.0
(A), 27.3 (B), 26.2 (A), 23.6 (A + B), 18.4 (B), 16.8 (A). MS (ESI+,
direct infusion): m/z 193 [(M + Na)+]. Anal. Calcd for C10H18O2
(170.25): C, 70.55; H, 10.66. Found: C, 70.61; H, 10.63.
2-Methyl-4-phenylbut-3-yne-1,2-diol (1k). Yield: 2.55 g, starting
from 1.40 g of α-hydroxyacetone (85%). Colorless amorphous solid.
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69.5, 67.7, 26.2. GC-MS (EI, 70 eV): m/z 182 (7) [M+], 151 (100),
135 (9), 121 (5), 109 (11), 89 (5), 77 (6), 63 (14). Anal. Calcd for
C9H10O2S (182.24): C, 59.32; H, 5.53; S, 17.59. Found: C, 59.39; H,
5.51; S; 17.58.
1-Hex-1-ynylcyclohexane-1,2-diol (1g). Mixture of diastereomers
A + B, A/B ratio ca. 1.1:1, determined by H NMR. Yield: 2.39 g,
starting from 1.60 g of 2-hydroxycyclohexanone dimer (87%). Yellow
1
oil. IR (film): ν 3410 (m, br), 2934 (s), 2854 (m), 2238 (w), 1449 (s),
1
1250 (w), 1172 (w), 1063 (s), 1000 (m), 866 (m) cm−1. H NMR
4-Cyclohex-1-enyl-2-methylbut-3-yne-1,2-diol (1r). Yield: 2.57 g,
starting from 1.40 g of α-hydroxyacetone (84%). Yellow amorphous
solid. Mp: 33−34 °C. IR (KBr): ν 3447 (s, br), 2933 (w), 2218 (vw),
1631 (m), 1384 (s), 1056 (m) cm−1. 1H NMR (300 MHz, CDCl3): δ
6.16−6.04 (m, 1 H), 3.81−3.21 (m, 2 H), 3.66 (distorted d, J = 11.3, 1
H), 3.50 (distorted d, J = 11.3, 1 H), 2.17−2.01 (m, 4 H), 1.69−1.52
(m, 4 H), 1.46 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 135.5, 119.9,
87.9, 86.1, 70.6, 68.8, 29.2, 25.6, 25.5, 22.2, 21.4. GC-MS (EI, 70 eV):
m/z 180 (9) [M+], 150 (18), 149 (100), 115 (3), 105 (9), 91 (19), 79
(15), 77 (16), 65 (7). Anal. Calcd for C11H16O2 (180.24): C, 73.30; H,
8.95. Found: C, 73.38; H, 8.93.
(300 MHz, CDCl3): δ 3.70 [A (dd, J = 7.3, 4.0, 1 H)], 3.39 [B (dd, J =
11.3, 4.4, 1 H)], 2.89 [A (s, br, 2 H) + B (s, br, 2 H)], 2.26 [B (t, J =
6.9, 2 H)], 2.21 [B (t, J = 6.7, 2 H)], 2.06−1.85 [A (m, 2 H) + B (m, 2
H)], 1.83−1.23 [A (m, 10 H) + B (m, 10 H)], 0.92 [B (t, J = 7.3, 3
H)], 0.91 [A (t, J = 7.3, 3 H)]. 13C NMR (75 MHz, CDCl3): δ 88.1 (A
or B), 85.5 (B or A), 82.6 (A or B), 79.6 (B or A), 77.0 (A or B), 74.2
(B or A), 74.0 (A or B), 70.3 (B or A), 38.0 (A or B), 35.6 (B or A),
32.1 (A or B), 30.9 (B or A), 30.8 (A or B), 28.7 (B or A), 24.2 (A or
B), 23.3 (B or A), 22.02 (A or B), 21.98 (B or A), 21.61 (A or B),
21.56 (B or A), 18.4 (A + B), 13.6 (A + B). GC-MS (EI, 70 eV): A:
m/z 196 (absent) [M+], 168 (3), 154 (86), 149 (9), 137 (46), 136
(30), 121 (27), 118 (44), 108 (71), 107 (60), 97 (31), 95 (56), 94
(39), 93 (57), 91 (52), 81 (54), 79 (98), 68 (71), 67 (70), 55 (100);
B: m/z 196 (absent) [M+], 168 (3) 154 (91), 149 (7), 137 (42), 136
(28), 121 (28), 118 (48), 108 (68), 107 (60), 97 (37), 95 (55), 94
(34), 93 (56), 91 (47), 81 (54), 79 (90), 77 (48), 69 (55), 68 (75), 67
(69), 55 (100). Anal. Calcd for C12H20O2 (196.29): C, 73.43; H,
10.27. Found: C, 73.51; H, 10.25.
Preparation of Oct-3-yne-1,2-diol (1c). To a suspension of Mg
turnings (1.88 g, 77.4 mmol) in anhydrous THF (16 mL), maintained
under nitrogen and under reflux, was added pure ethyl bromide (1.4
mL) to start the formation of the Grignard reagent. The remaining
bromide was added dropwise in THF solution (4.0 mL of EtBr in 44
mL of THF; total amount of EtBr added 7.88 g, 72.3 mmol). The
mixture was then refluxed for an additional 20 min. After cooling, the
resulting solution of EtMgBr was transferred under nitrogen to a
dropping funnel and added dropwise under nitrogen to a solution of 1-
hexyne (5.91 g, 71.9 mmol) in anhydrous THF (21.6 mL) at 0 °C with
stirring. After additional stirring at 0 °C for 15 min, the mixture was
warmed to room temperature and then maintained at 50 °C for 2 h.
While warm (ca. 40−45 °C), the solution of 1-hexynylmagnesium
bromide thus obtained was then added dropwise under nitrogen to a
preheated (50 °C) solution of glycolaldehyde (36 mmol) in anhydrous
THF (obtained from glycolaldehyde dimer (2.16 g) in anhydrous
THF (44 mL)). The resulting mixture was stirred at 50 °C for an
additional 2 h. After the mixture was cooled to room temperature,
saturated NH4Cl (100 mL) and AcOEt (40 mL) were sequentially
added. Phases were separated, and the aqueous phase was extracted
with AcOEt (3 × 100 mL). The collected organic layers were washed
with brine and dried over Na2SO4. After filtration and evaporation of
the solvent, the product was purified by column chromatography on
silica gel using 6/4 hexane/acetone as the eluent to give pure oct-3-
yne-1,2-diol (1c). Yield: 2.10 g, starting from 2.16 g of glycolaldehyde
dimer (41%). Colorless oil. IR (film): ν 3397 (m, br), 2957 (m), 2239
(w), 1647 (m), 1464 (w), 1149 (m), 1087 (m), 1039 (m), 876 (w)
1-(3,3-Dimethylbut-1-ynyl)cyclohexane-1,2-diol (1j). Mixture of
1
diastereomers A + B, A/B ratio ca. 1/1, determined by H NMR.
Yield: 2.28 g, starting from 1.60 g of 2-hydroxycyclohexanone dimer
(83%). Colorless amorphous solid. Mp: 67−68 °C. IR (KBr): ν 3387
(s, br), 2966 (m), 2939 (m), 2861 (m), 2233 (vw), 1633 (m), 1384
1
(m), 1361 (w), 1263 (m), 1079 (m), 997 (w), 866 (w) cm−1. H
NMR (300 MHz, CDCl3): δ 3.70 [A (dd, J = 6.5, 4.0, 1 H)], 3.38 [B
(dd, J = 11.1, 4.2, 1 H)], 2.90 [A (s, br, 2 H) + B (s, br, 2 H)], 2.07−
1.85 [A (m, 2 H) + B (m, 2 H)], 1.83−1.23 [A (m, 6 H) + B (m, 6
H)], 1.25 [A or B (s, 9 H)], 1.22 [B or A (s, 9 H)]. 13C NMR (75
MHz, CDCl3): δ 96.7 (A or B), 94.1 (B or A), 80.8 (A or B), 77.9 (B
or A), 77.5 (A or B), 74.0 (B or A), 73.8 (A or B), 70.1 (B or A), 38.0
(A or B), 35.3 (B or A), 32.2 (A or B), 31.1 (B or A), 31.0 (A or B),
28.7 (B or A), 27.4 (A or B), 27.3 (B or A), 24.2 (A or B), 23.3 (B or
A), 21.9 (A or B), 21.1 (B or A). GC-MS (EI, 70 eV): A or B: m/z 196
(absent) [M+], 181 (3), 163 (6), 145 (4), 135 (14), 126 (22), 111
(100), 109 (24), 107 (21), 95 (20), 93 (29), 91 (28), 83 (25), 81 (22),
79 (31), 77 (24), 67 (36), 57 (37), 55 (37); B or A: m/z 196 (absent)
[M+], 181 (4), 163 (8), 145 (5), 137 (13), 135 (16), 126 (22), 111
(100), 109 (28), 107 (25), 95 (21), 93 (30), 91 (30), 83 (24), 81 (24),
79 (33), 77 (25), 67 (37), 57 (35), 55 (38). Anal. Calcd for C12H20O2
(196.29): C, 73.43; H, 10.27. Found: C, 73.52; H, 10.25.
1
cm−1. H NMR (300 MHz, CDCl3): δ 4.48−4.41 (m, 1 H), 3.71
(distorted dd, J = 11.3, 3.4, 1 H), 3.61 (distorted dd, J = 11.3, 7.3, 1
H), 3.51 (s, br, 1 H), 3.29 (s, br, 1 H), 2.21 (td, J = 7.1, 2.0, 2 H),
1.55−1.32 (m, 4 H), 0.91 (t, J = 7.3, 3H). 13C NMR (75 MHz,
CDCl3): δ 87.2, 78.0, 67.0, 63.6, 30.7, 22.0, 18.4, 13.5. GC-MS (EI, 70
eV): m/z 142 (absent) [M+], 125 (77), 111 (43), 110 (11), 107 (16),
95 (20), 93 (47), 91 (37), 83 (27), 79 (27), 77 (29), 71 (40). Anal.
Calcd for C8H14O2 (142.20): C, 67.57; H, 9.92. Found: C, 67.53; H,
9.90.
1-Phenylethynylcyclohexane-1,2-diol (1n). Mixture of diaster-
1
eomers A + B, A/B ratio ca. 1/1, determined by H NMR. Yield:
2.39 g, starting from 1.60 g of 2-hydroxycyclohexanone dimer (79%).
Yellow oil. IR (film): ν 3369 (m, br), 2937 (s), 2860 (m), 2225 (vw),
1598 (w), 1489 (m), 1443 (m), 1385 (m), 1353 (m), 1268 (m), 1059
(s), 1008 (m), 972 (w), 949 (w), 867 (m), 755 (s), 691 (s) cm−1. 1H
NMR (300 MHz, CDCl3): δ 7.51−7.39 [A (m, 2 H), + B (m, 2 H)],
7.35−7.20 [A (m, 3 H), + B (m, 3 H)], 3.85 [A (dd, J = 7.3, 4.0, 1
H)], 3.52 [B (dd, J = 11.3, 4.4, 1 H)], 3.37 [A (s, br, 2 H) + B (s, br, 2
H)], 2.21−1.15 [A (m, 8 H) + B (m, 8 H)]. 13C NMR (75 MHz,
CDCl3): δ 132.1 (A or B), 131.8 (B or A), 131.7 (A or B), 128.41 (B
or A), 128.37 (A or B), 128.28 (B or A), 128.23 (A or B), 122.5 (B or
A), 91.6 (A or B), 88.8 (B or A), 87.3 (A or B), 84.8 (B or A), 77.2 (A
or B), 74.4 (B or A), 73.9 (A or B), 70.6 (B or A), 37.9 (A or B), 35.4
(B or A), 32.0 (A or B), 28.9 (B or A), 24.2 (A or B), 23.3 (B or A),
21.56 (A or B), 21.47 (B or A). GC-MS (EI, 70 eV): A or B: m/z 216
(13) [M+], 198 (5), 187 (12), 170 (20), 157 (42), 154 (20), 146
(100), 145 (57), 141 (39), 131 (78), 129 (93), 115 (85), 103 (37),
102 (45), 97 (28), 91 (42), 77 (45), 75 (23), 55 (43); B: m/z 216
(16) [M+], 198 (6), 187 (15), 170 (24), 157 (49), 146 (97), 145 (56),
142 (31), 141 (45), 131 (79), 129 (100), 115 (97), 103 (38), 102
(50), 97 (34), 91 (46), 77 (50), 55 (48). Anal. Calcd for C14H16O2
(216.28): C, 77.75; H, 7.46. Found: C, 77.82; H, 7.44.
Preparation of 3-Yne-1,2-diols 1g,j,n. To a cooled (0 °C),
stirred solution of the 1-alkyne (30.8 mmol: 1-hexyne, 3.66 g; tert-
butylacetylene, 3.66 g; phenylacetylene, 4.54 g; 3-ethynylthiophene,
4.81 g; 1-ethynylcyclohex-1-ene, 4.72 g; p-bromophenylacetylene, 8.06
g; p-methylphenylacetylene, 5.17 g) in anhydrous THF (75 mL)
maintained under nitrogen was added dropwise a solution of BuLi in
hexane (1.6 M; 19.3 mL, 30.9 mmol). The resulting mixture was
stirred at 0 °C for 0.5 h. Dodecahydrodibenzo[b,e][1,4]dioxine-4a,9a-
diol (2-hydroxycyclohexanone dimer; 1.60 g, 7.0 mmol, corresponding
to 14.0 mmol of 2-hydroxycyclohexanone) was added under nitrogen
in portions. After additional stirring at 0 °C for an additional 0.5 h, the
mixture was warmed to room temperature and then saturated aqueous
NH4Cl was added followed by Et2O (50 mL). The phases were
separated, and the aqueous phase was extracted with Et2O (50 mL ×
3). The collected organic phases were washed with brine to neutral pH
and dried over Na2SO4. After filtration and evaporation of the solvent,
crude products 1g,j,n were sufficiently pure to be used as such for the
carbonylation reaction.
Preparation of 1,1-Dialkynyl-1,2-diols 1d,f. A solution of 1-
hexyne (4.19 g, 51.0 mmol) in anhydrous THF (8 mL) was added
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dropwise under nitrogen to a stirred, cooled (−78 °C) mixture of BuLi
(34 mL of a 1.6 M solution in hexanes, 54.4 mmol) in anhydrous THF
(22 mL) and anhydrous hexane (34 mL). To the resulting mixture,
maintained at −78 °C, was added, with stirring, a solution of LiBr
(2.13 g, 24.5 mmol) in THF (7 mL). After 0.5 h, the appropriate α-
hydroxyacetic acid ester (17 mmol: α-hydroxyacetic acid methyl ester,
1.53 g; (S)-α-hydroxypropionic acid ethyl ester, 2.01 g) diluted in
anhydrous THF (5 mL) was slowly added under nitrogen at the same
temperature. The resulting mixture was stirred for an additional 2 h
and then warmed to room temperature. After quenching with a
saturated solution of NH4Cl (20 mL), the mixture was extracted with
Et2O (3 × 50 mL). The combined organic layers were washed with
water (40 mL) and then dried oven Na2SO4. After filtration and
evaporation of the solvent, the crude products were purified by column
chromatography using 8/2 hexane/AcOEt as eluent.
2-Hex-1-ynyloct-3-yne-1,2-diol (1d). Yield: 2.80 g, starting from
1.53 g of α-hydroxyacetic acid methyl ester (74%). Yellow solid. Mp:
30−32 °C. IR (KBr): ν 3339 (m, br), 2934 (m), 2241 (w), 1465 (w),
1382 (w), 1263 (m), 1175 (m), 1084 (m), 912 (w), 679 (m) cm−1. 1H
NMR (300 MHz, CDCl3): δ 3.70 (s, 2 H), 3.00 (s, br, 2 H), 2.24 (t, J
= 6.9, 4 H), 1.60−1.30 (m, 8 H), 0.91 (t, J = 7.1, 6 H). 13C NMR (75
MHz, CDCl3): δ 85.4, 78.5, 71.0, 64.5, 30.5, 22.0, 18.4, 13.6. GC-MS
(EI, 70 eV): m/z 222 (absent) [M+], 192 (15), 191 (100), 135 (3),
115 (4), 105 (7), 91 (17), 79 (20), 77 (12). Anal. Calcd for C14H22O2
(222.32): C, 75.63; H, 9.97. Found: C, 75.55; H, 9.99.
(S)-3-Hex-1-ynylnon-4-yne-2,3-diol (1f). Yield: 3.21 g, 80% based
on (S)-α-hydroxypropionic acid ethyl ester. Yellow oil. [α]25D(MeOH,
c = 9.1 × 10−3 g mL−1) = −22°. IR (film): ν 3399 (m, br), 2933 (m),
2237 (w), 1466 (w), 1378 (w), 1363 (w), 1270 (w), 1119 (m), 1012
(m), 889 (m) cm−1. 1H NMR (300 MHz, CDCl3): δ 3.90−3.77 (m, 1
H), 3.37 (s, br, 1 H), 2.70 (s, br, 1 H), 2.29−2.19 (m, 4 H), 1.58−1.33
(m, 8 H), 1.37 (d, J = 6.5, 3 H), 0.96−0.87 (m, 6 H). 13C NMR (75
MHz, CDCl3): δ 85.9, 85.4, 79.1, 77.8, 74.4, 68.0, 30.5, 30.4, 22.00,
21.97, 18.44, 18.40, 17.5, 13.6. GC-MS (EI, 70 eV): m/z 236 (absent)
[M+], 191 (73), 150 (16), 131 (28), 121 (75), 117 (50), 108 (100),
107 (61), 91 (99), 79 (81). Anal. Calcd for C15H24O2 (236.35): C,
76.23; H, 10.24. Found: C, 76.13; H, 10.25.
PdI2/KI-Catalyzed Oxidative Carbonylation of 2-Methyloct-
3-yne-1,2-diol (1a) Leading to a Mixture of Methyl 2-Butyl-4-
methylfuran-3-carboxylate (2a) and 2-Hydroxy-2-methyloct-3-
ynyl 2-Butyl-4-methylfuran-3-carboxylate (5a) (Table 1, Entry
7). A 50 mL stainless steel autoclave was charged in the presence of air
with PdI2 (5.0 mg, 1.39 × 10−2 mmol), KI (23.0 mg, 0.14 mmol),
anhydrous MeOH (5.6 mL), and 2-methyloct-3-yne-1,2-diol (1a; 217
mg, 1.39 mmol). The autoclave was sealed and, while the mixture was
stirred, the autoclave was pressurized with CO (32 atm) and air (up to
40 atm). After the mixture was stirred at 80 °C for 2 h, the autoclave
was cooled, degassed, and opened. GLC-MS analysis of the crude
reaction mixture was consistent with the formation of methyl 2-butyl-
4-methylfuran-3-carboxylate (2a; 49% GLC yield) and 2-hydroxy-2-
methyloct-3-ynyl 2-butyl-4-methylfuran-3-carboxylate (5a; 32% GLC
yield). After evaporation of the solvent, only compound 2a could be
isolated in a pure state by column chromatography on silica gel using
99/1 hexane/Et2O as eluent. Compound 2a was then fully
characterized by spectroscopic techniques and elemental analysis
(see below). The GC-MS spectrum of 5a (EI, 70 eV) was in
agreement with the proposed structure: m/z 302 (14) [M+], 259 (14),
245 (100), 217 (14), 203 (27), 189 (8), 175 (28), 135 (40), 123 (34),
91 (11), 77 (14), 65 (19). Additional evidence for the proposed
structure for 5a was the observation that, when the carbonylation
reaction was carried out for a longer reaction time (8−15 h), partial
conversion of 5a into 2a was observed, deriving from methanolysis of
the estereal linkage of 5a.
CO (32 atm) and air (up to 40 atm). After the mixture was stirred at
100 °C for the required time (see Table 2), the autoclave was cooled,
degassed, and opened. The solvent was evaporated, and the products
2a−r were purified by column chromatography on silica gel using the
following mixtures as eluent: 9/1 hexane/acetone (2a,e,k,p,r), 98/2
hexane/AcOEt (2a′), 95/5 hexane/AcOEt (2b,h,l), 6/4 hexane/
acetone (2c), 99/1 hexane/AcOEt (2d,f), 9/1 hexane/AcOEt
(2g,n,o), 8/2 hexane/acetone (2i,j), 8/2 hexane/AcOEt (2m), 7/3
hexane/acetone (2q).
Methyl 2-Butyl-4-methylfuran-3-carboxylate (2a). Yield: 220 mg,
starting from 217.0 mg of 1a (81%) (Table 2, entry 2). Yellow oil. IR
(film): ν 2957 (m), 1739 (s), 1442 (m), 1391 (w), 1256 (m), 971 (w),
763 (m) cm−1. 1H NMR (300 MHz, CDCl3): δ 7.04 (s, br, 1 H), 3.82
(s, 3 H), 2.98−2.90 (m, 2 H), 2.13 (s, br, 3 H), 1.69−1.57 (m, 2 H),
1.42−1.28 (m, 2 H), 0.92 (t, J = 7.3, 3 H). 13C NMR (75 MHz,
CDCl3): δ 165.2, 164.3, 137.9, 121.2, 113.2, 50.8, 30.2, 27.9, 22.4, 13.7,
9.9. GC-MS (EI, 70 eV): m/z 196 (25) [M+], 167 (11), 165 (12), 154
(32), 153 (100), 139 (32), 137 (16), 135 (44), 123 (47), 122 (16),
121 (29), 95 (15), 79 (11), 77 (18), 65 (45). Anal. Calcd for
C11H16O3 (196.24): C, 67.32; H, 8.22. Found: C, 67.23; H, 8.24.
Ethyl 2-Butyl-4-methylfuran-3-carboxylate (2a′). Yield: 228 mg,
starting from 217.0 mg of 1a (78%) (Table 2, entry 20). Colorless oil.
IR (film): ν 2960 (m), 2932 (m), 1720 (s), 1608 (w), 1557 (w), 1383
1
(w), 1267 (m), 1073 (m), 1029 (w), 787 (w) cm−1. H NMR (300
MHz, CDCl3): δ 7.04 (q, J = 1.3, 1 H), 4.29 (q, J = 7.2, 2 H), 2.98−
2.91 (m, 2 H), 2.14 (d, J = 1.3, 3 H), 1.69−1.58 (m, 2 H), 1.42−1.26
(m, 2 H), 1.35 (t, J = 7.2, 3 H), 0.92 (t, J = 7.5, 3 H). 13C NMR (75
MHz, CDCl3): δ 164.8, 164.1, 137.8, 121.2, 113.2, 59.8, 30.3, 28.0,
22.4, 14.4, 13.8, 10.0. GC-MS (EI, 70 eV): m/z 210 (29) [M+], 181
(18), 168 (14), 167 (13), 165 (12), 140 (11), 139 (100), 135 (15),
123 (13), 121 (10), 95 (6), 77 (6), 65 (9). Anal. Calcd for C12H18O3
(210.27): C, 68.54; H, 8.63. Found: C, 68.53; H, 8.64.
Methyl 2-Butyl-4-phenylfuran-3-carboxylate (2b). Yield: 265 mg,
starting from 303.5 mg of 1b (74%) (Table 2, entry 3). Colorless oil.
IR (film): ν 2963 (m), 1718 (s), 1438 (m), 1391 (m), 1292 (m), 1121
(m), 1038 (w), 758 (m) cm−1. 1H NMR (300 MHz, CDCl3): δ 7.38−
7.29 (m, 5 H), 7.27 (s, 1 H), 3.70 (s, 3 H), 3.04−2.96 (m, 2 H), 1.76−
1.64 (m, 2 H), 1.47−1.33 (m, 2 H), 0.95 (t, J = 7.3, 3 H). 13C NMR
(75 MHz, CDCl3): δ 164.6, 164.2, 138.4, 132.2, 129.2, 127.9, 127.3,
112.3, 51.0, 30.2, 27.9, 22.4, 13.8. GC-MS (EI, 70 eV): m/z 258 (41)
[M+], 226 (17), 215 (39), 197 (100), 183 (54), 155 (23), 141 (12),
128 (34), 127 (49), 115 (28), 77 (19). Anal. Calcd for C16H18O3
(258.31): C, 74.39; H, 7.02. Found: C, 74.29; H, 7.03.
Methyl 2-Butylfuran-3-carboxylate (2c). Yield: 215 mg, starting
from 197.5 mg of 1c (85%) (Table 2, entry 4). Colorless oil. IR (film):
ν 2962 (m), 1720 (s), 1605 (m), 1442 (m), 1307 (m), 1201 (m), 1123
1
(w), 1039 (m), 736 (m) cm−1. H NMR (300 MHz, CDCl3): δ 7.24
(d, J = 2.0, 1 H), 6.63 (d, J = 2.0, 1 H), 3.82 (s, 3 H), 3.00 (t, J = 7.7, 2
H), 1.72−1.59 (m, 2 H), 1.42−1.29 (m, 2 H), 0.93 (t, J = 7.3, 3 H).
13C NMR (75 MHz, CDCl3): δ 164.5, 163.5, 140.4, 113.0, 110.7, 51.2,
30.1, 27.3, 22.3, 13.7. GC-MS (EI, 70 eV): m/z 182 (56) [M+], 153
(42), 151 (25), 140 (8), 139 (87), 125 (47), 121 (74), 109 (100), 81
(23). Anal. Calcd for C10H14O3 (182.22): C, 65.91; H, 7.74. Found: C,
65.79; H, 7.72.
Methyl 2-Butyl-4-hex-1-ynylfuran-3-carboxylate (2d). Yield: 290
mg, starting from 309.5 mg of 1d (80%) (Table 2, entry 5). Yellow oil.
IR (film): ν 2958 (m), 2873 (w), 2221 (vw), 1719 (s), 1438 (m), 1320
(w), 1231 (m), 970 (w), 764 (m) cm−1. 1H NMR (300 MHz, CDCl3):
δ 7.40 (s, 1 H), 3.84 (s, 3 H), 2.95 (t, J = 7.7, 2 H), 2.42 (t, J = 6.9, 2
H), 1.70−1.25 (m, 8 H), 0.94 (t, J = 7.3, 3 H), 0.91 (t, J = 7.3, 3 H).
13C NMR (75 MHz, CDCl3): δ 163.9, 163.8, 143.9, 113.4, 108.5, 93.8,
70.4, 51.3, 30.8, 29.9, 27.6, 22.2, 21.9, 19.3, 13.7, 13.6 . GC-MS (EI, 70
eV): m/z 262 (77) [M+], 233 (26), 231 (26), 220 (77), 219 (50), 201
(100), 191 (54), 188 (62), 176 (26), 173 (33), 161 (23), 160 (36),
145 (40), 131 (42), 117 (42), 116 (24), 115 (49), 105 (32), 91 (84),
89 (40), 77 (57). Anal. Calcd for C16H22O3 (262.34): C, 73.25; H,
8.45. Found: C, 73.23; H, 8.44.
General Procedure for the Synthesis of Furan-3-carboxylic
Esters 2a−r. A 250 mL stainless steel autoclave was charged in the
presence of air with PdI2 (5.0 mg, 1.39 × 10−2 mmol or 10.0 mg, 2.78
× 10−2 mmol; see Table 2), KI (11.5 mg, 6.93 × 10−2 mmol or 23.0
mg, 0.14 mmol; see Table 2), anhydrous ROH (R = Me, Et, 28 mL),
and the 3-yne-1,2-diol 1a−r (1.39 mmol). The autoclave was sealed
and, while the mixture was stirred, the autoclave was pressurized with
Methyl 2-Butyl-4,5-dimethylfuran-3-carboxylate (2e). Yield: 228
mg, starting from 237 mg of 1e (78%) (Table 2, entry 6). Yellow oil.
IR (film): ν 2969 (m), 2931 (m), 2864 (w), 1715 (s), 1577 (m), 1439
H
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(m), 1382 (w), 1294 (m), 1211 (m), 1077 (m), 736 (s) cm−1. H
NMR (300 MHz, CDCl3): δ 3.80 (s, 3 H), 2.90 (t, J = 7.5, 2 H), 2.16
(s, 3 H), 2.05 (s, 3H), 1.68−1.55 (m, 2 H), 1.43−1.28 (m, 2 H), 0.92
(t, J = 7.5, 3 H). 13C NMR (75 MHz, CDCl3): δ 165.5, 161.5, 145.8,
114.4, 113.1, 50.8, 30.4, 27.7, 22.4, 13.8, 11.0, 9.9. GC-MS (EI, 70 eV):
m/z 210 (55) [M+], 179 (17), 167 (100), 153 (33), 151 (38), 137
(27), 135 (57), 109 (14), 97 (6), 77 (13), 65 (16), 55 (18). Anal.
Calcd for C12H18O3 (210.27): C, 68.54; H, 8.63. Found: C, 68.64; H,
8.61.
Methyl 2-Butyl-4-hex-1-ynyl-5-methylfuran-3-carboxylate (2f).
Yield: 280 mg, starting from 329.0 mg of 1f (73%) (Table 2, entry
7). Yellow oil. IR (film): ν 2960 (m), 2932 (m), 2217 (vw), 1712 (s),
1439 (m), 1216 (s), 1147 (w), 1060 (w), 754 (s) cm−1. 1H NMR (300
MHz, CDCl3): δ 3.82 (s, 3 H), 2.90 (t, J = 7.4, 2 H), 2.44 (t, J = 6.9, 2
H), 2.30 (s, 3 H), 1.67−1.24 (m, 8 H), 0.95 (t, J = 7.1, 3 H), 0.91 (t, J
= 7.3, 3 H). 13C NMR (75 MHz, CDCl3): δ 164.1, 161.5, 154.4, 113.4,
103.9, 94.4, 71.5, 51.1, 31.0, 30.2, 27.4, 22.3, 21.9, 19.4, 13.8, 13.7,
12.3. GC-MS (EI, 70 eV): m/z 276 (51) [M+], 245 (15), 233 (73),
219 (17), 215 (25), 205 (17), 202 (24), 191 (16), 187 (15), 175 (24),
173 (22), 159 (13), 147 (11), 131 (13), 115 (16), 91 (16), 77 (14).
Anal. Calcd for C17H24O3 (276.37): C, 73.88; H, 8.75. Found: C,
73.83; H, 8.73.
2939 (s), 2851 (m), 1718 (s), 1537 (m), 1435 (w), 1384 (m), 1316
(m), 1282 (m), 1244 (m), 1218 (m), 1117 (m), 1051 (m), 1027 (w),
936 (w), 803 (w), 789 (w) cm−1. 1H NMR (300 MHz, CDCl3): δ 3.79
(s, 3 H), 2.58−2.48 (m, 4 H), 1.84−1.65 (m, 4 H), 1.40 (s, 9 H). 13C
NMR (75 MHz, CDCl3): δ 166.1, 165.5, 147.6, 118.2, 111.6, 51.0,
34.5, 28.4, 23.0, 22.9, 22.7, 22.6. GC-MS (EI, 70 eV): m/z 236 (22)
[M+], 221 (77), 205 (9), 189 (100), 161 (5), 147 (2), 134 (3), 119
(3), 105 (8), 91 (16), 77 (9), 65 (6). Anal. Calcd for C14H20O3
(236.31): C, 71.16; H, 8.53. Found: C, 71.23; H, 8.52.
1
Methyl 4-Methyl-2-phenylfuran-3-carboxylate (2k). Yield: 214
mg, starting from 245.0 mg of 1k (71%) (Table 2, entry 12). Yellow
oil. IR (film): ν 3030 (m), 2957 (m), 1728 (s), 1448 (m), 1386 (w),
1
1225 (m), 960 (w), 758 (m) cm−1. H NMR (300 MHz, CDCl3): δ
7.79−7.74 (m, 1 H), 7.45−7.36 (m, 4 H), 7.24 (q, J = 0.9, 1 H), 3.80
(s, 3 H), 2.20 (d, J = 0.9, 3 H). 13C NMR (75 MHz, CDCl3): δ 164.9,
158.0, 139.2, 129.4, 129.1, 128.4, 128.1, 128.0, 122.6, 51.2, 10.0. GC-
MS (EI, 70 eV): m/z 216 (82) [M+], 185 (100), 156 (16), 129 (23),
128 (53), 127 (33), 115 (10), 102 (15), 77 (38). Anal. Calcd for
C13H12O3 (216.23): C, 72.21; H, 5.59. Found: C, 72.30; H, 5.60.
Methyl 2,4-Diphenylfuran-3-carboxylate (2l). Yield: 250 mg,
starting from 331.2 mg of 1l (65%) (Table 2, entry 13). Yellow
solid. Mp: 27−28 °C. IR (KBr): ν 3051 (m), 2942 (m), 1717 (s),
1541 (m), 1482 (m), 1386 (m), 1266 (m), 1152 (m), 924 (m), 768
(m) cm−1. 1H NMR (300 MHz, CDCl3): δ 7.83−7.77 (m, 2 H), 7.50
(s, 1 H), 7.47−7.30 (m, 8 H), 3.68 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ 165.1, 156.6, 139.2, 131.7, 130.1, 129.2, 128.6, 128.33,
128.26, 127.7, 127.6, 113.7, 51.6. GC-MS (EI, 70 eV): m/z 278 (100)
[M+], 247 (92), 191 (43), 189 (55), 165 (15), 139 (12), 105 (42), 94
(20), 77 (43), 63 (20). Anal. Calcd for C18H14O3 (278.30): C, 77.68;
H, 5.07. Found: C, 77.60; H, 5.07.
Methyl 2-Butyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (2g).
Yield: 246 mg, starting from 273 mg of 1g (75%) (Table 2, entry 8).
Yellow oil. IR (film): ν 2935 (m), 2857 (m), 1719 (s), 1577 (m), 1440
(m), 1345 (w), 1273 (m), 1213 (m), 1056 (m), 956 (w), 869 (w), 784
1
(m) cm−1. H NMR (300 MHz, CDCl3): δ 3.79 (s, 3 H), 2.93 (t, J =
7.7, 2 H), 2.62−2.49 (m, 4 H), 1.86−1.56 (m, 6 H), 1.44−1.29 (m, 2
H), 0.92 (t, J = 7.3, 3 H). 13C NMR (75 MHz, CDCl3): δ 165.4, 161.9,
149.2, 117.2, 112.2, 50.8, 30.5, 27.6, 22.9, 22.7, 22.43, 22.36, 13.8. GC-
MS (EI, 70 eV): m/z 236 (M+, 26), 221 (3), 205 (7), 193 (100), 179
(16), 177 (24), 161 (17), 147 (4), 133 (9), 119 (3), 105 (12), 91 (16),
79 (11), 77 (12). Anal. Calcd for C14H20O3 (236.31): C, 71.16; H,
8.53. Found: C, 71.20; H, 8.51.
Methyl 4,5-Dimethyl-2-phenylfuran-3-carboxylate (2m). Yield:
180 mg, starting from 265 mg of 1m (56%) (Table 2, entry 14) Yellow
oil. IR (film): ν 2957 (w), 1717 (s), 1603 (w), 1449 (m), 1242 (m),
1
1112 (w), 757 (m), 697 (w) cm−1. H NMR (300 MHz, CDCl3): δ
Ethyl 2-Butyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (2g′).
Yield: 240 mg, starting from 273 mg of 1g (69%) (Table 2, entry 21).
Yellow oil. IR (film): ν 2934 (m), 2853 (m), 1713 (s), 1576 (m), 1444
(m), 1367 (w), 1325 (m), 1273 (m), 1212 (m), 1104 (m), 1056 (m),
7.76−7.71 (m, 2 H), 7.42−7.28 (m, 3 H,), 3.77 (s, 3 H), 2.25 (s, 3 H),
2.10 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 165.2, 155.2, 147.7,
130.6, 128.6, 128.1, 128.0, 116.3, 114.4, 51.1, 11.2, 10.0. GC-MS (EI,
70 eV): m/z 230 (100) [M+], 215 (4), 199 (62), 170 (15), 159 (6),
143 (4), 128 (17), 115 (7), 105 (21), 77 (27). Anal. Calcd for
C14H14O3 (230.26): C, 73.03; H, 6.13. Found: C, 73.14; H, 6.11.
Methyl 2-Phenyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate
(2n). Yield: 250 mg, starting from 300 mg of 1n (70%) (Table 2,
entry 15). Colorless amorphous solid. Mp: 49−50 °C. IR (KBr): ν
2939 (m), 2851 (w), 1714 (s), 1636 (w), 1547 (m), 1497 (m), 1437
(m), 1384 (w), 1326 (w), 1282 (m), 1218 (s), 1090 (s), 1021 (w),
1
957 (w), 869 (w), 783 (m) cm−1. H NMR (300 MHz, CDCl3): δ
4.25 (q, J = 7.1, 2 H), 2.93 (t, J = 7.5, 2 H), 2.63−2.48 (m, 4 H), 1.85−
1.56 (m, 6 H), 1.44−1.29 (m, 2 H), 1.33 (t, J = 7.1, 3 H), 0.92 (t, J =
7.3, 3 H). 13C NMR (75 MHz, CDCl3): δ 164.9, 161.7, 149.2, 117.3,
112.5, 59.6, 30.5, 27.7, 23.0, 22.8, 22.5, 22.4, 14.4, 13.8. GC-MS (EI, 70
eV): m/z 250 (M+, 39), 221 (33), 207 (81), 193 (5), 179 (100), 177
(28), 161 (17), 147 (3), 133 (9), 119 (5), 105 (10), 91 (14), 79 (10),
77 (10). Anal. Calcd for C15H22O3 (250.33): C, 71.97; H, 8.86. Found:
C, 72.04; H, 8.84.
1
920 (w), 774 (m), 758 (m), 688 (m) cm−1. H NMR (300 MHz,
CDCl3): δ 7.87−7.78 (m, 2 H), 7.45−7.31 (m, 3 H), 3.79 (s, 3 H),
2.70−2.58 (m, 4 H), 1.91−1.71 (m, 4 H). 13C NMR (75 MHz,
CDCl3): δ 165.0, 155.9, 150.9, 130.6, 128.7, 128.2, 128.0, 119.1, 113.2,
51.2, 23.1, 22.9, 22.62, 22.55. GC-MS (EI, 70 eV): m/z 256 (100)
[M+], 241 (4), 228 (26), 196 (16), 170 (38), 141 (15), 128 (11), 115
(19), 105 (34), 91 (11), 77 (37). Anal. Calcd for C16H16O3 (256.30):
C, 74.98; H, 6.29. Found: C, 75.07; H, 6.27.
Methyl 2-tert-Butyl-4-methylfuran-3-carboxylate (2h). Yield: 165
mg, starting from 217.0 mg of 1h (60%) (Table 2, entry 9). Yellow oil.
IR (film): ν 2958 (m), 1720 (s), 1531 (m), 1435 (w), 1364 (w), 1283
1
(m), 1228 (m), 1084 (s), 939 (w), 750 (w) cm−1. H NMR (300
MHz, CDCl3): δ 7.00 (q, J = 1.3, 1 H), 3.83 (s, 3 H), 2.07 (d, J = 1.3, 3
H), 1.38 (s, 9 H). 13C NMR (75 MHz, CDCl3): δ 167.5, 165.6, 136.4,
121.7, 112.9, 51.0, 34.7, 28.5, 9.9. GC-MS (EI, 70 eV): m/z 196 (13)
[M+], 181 (38), 165 (9), 149 (100), 122 (6), 107 (5), 93 (8), 91 (19),
79 (12), 77 (24). Anal. Calcd for C11H16O3 (196.24): C, 67.32; H,
8.22. Found: C, 67.28; H, 8.23.
Methyl 2-tert-Butyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate
(2o). Yield: 243 mg, starting from 264 mg of 1o (76%) (Table 2,
entry 16). Yellow oil. IR (film): ν 2953 (w), 1717 (s), 1615 (w), 1500
1
(w), 1436 (m), 1291 (m), 1120 (m), 1076 (m), 822 (w) cm−1. H
NMR (300 MHz, CDCl3): δ 7.70−7.61 (m, 2 H), 7.28−7.13 (m, 3
H), 3.78 (s, 3 H), 2.36 (s, 3 H), 2.17 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ 165.0, 158.4, 139.1, 138.9, 128.7, 128.3, 127.7, 122.4, 113.5,
51.1, 21.4, 10.1. GC-MS (EI, 70 eV): m/z 230 (100) [M+], 199 (80),
170 (19), 159 (4), 141 (26), 128 (36), 115 (35), 91 (13). Anal. Calcd
for C14H14O3 (230.26): C, 73.03; H, 6.13. Found: C, 73.15; H, 6.12.
Methyl 2-(4-Bromophenyl)-4-methylfuran-3-carboxylate (2p).
Yield: 332 mg, starting from 355 mg of 1p (81%) (Table 2, entry
17). Yellow oil. IR (film): ν 2951 (w), 1719 (s), 1547 (w), 1490 (w),
1290 (m), 1213 (m), 1085 (m), 1066 (w), 766 (m), 693 (m) cm−1.
1H NMR (300 MHz, CDCl3): δ 7.65−7.25 (m, 5 H), 3.73 (s, 3 H),
2.23 (s, 3 H). GC-MS (EI, 70 eV): m/z 294 (absent) [M+], 216 (81),
185 (100), 156 (16), 129 (24), 128 (57), 127 (34), 115 (9), 102 (15),
Methyl 2-tert-Butyl-4,5-dimethylfuran-3-carboxylate (2i). Yield:
170 mg, starting from 237 mg of 1i (58%) (Table 2, entry 10). Yellow
oil. IR (film): ν 2960 (w), 2932 (w), 1714 (s), 1643 (w), 1436 (m),
1364 (m), 1222 (m), 1083 (m) cm−1. 1H NMR (300 MHz, CDCl3): δ
3.81 (s, 3 H), 2.16 (q, J = 1.0, 3 H), 1.98 (q, J = 1.0, 3 H), 1.36 (s, 9
H). 13C NMR (75 MHz, CDCl3): δ 166.0, 164.3, 144.4, 115.1, 113.3,
51.0, 34.4, 28.7, 11.0, 9.8. GC-MS (EI, 70 eV): m/z 210 (16) [M+],
195 (42), 179 (8), 163 (100), 135 (4), 121 (2), 107 (3), 91 (9), 77
(8), 65 (5). Anal. Calcd for C12H18O3 (210.27): C, 68.54; H, 8.63.
Found: C, 68.59; H, 8.61.
Methyl 2-tert-Butyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate
(2j). Yield: 246 mg, starting from 273 mg of 1j (75%) (Table 2,
entry 11). Colorless amorphous solid. Mp: 39−40 °C. IR (KBr): ν
I
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77 (31). Anal. Calcd for C13H11BrO3 (295.13): C, 52.91; H, 3.76; Br,
27.07. Found: C, 52.99; H, 3.75; Br, 27.09.
(12), 84 (100), 79 (11), 69 (59), 59 (52). Anal. Calcd for C11H20O2
(184.28): C, 71.70; H, 10.94. Found: C, 71.79; H, 10.93.
Methyl 4-Methyl-2-(thiophen-3-yl)furan-3-carboxylate (2q).
Yield: 272 mg, starting from 253 mg of 1q (88%) (Table 2, entry
18). Yellow oil. IR (film): ν 2953 (m), 1718 (s), 1619 (w), 1521 (w),
1438 (m), 1242 (m), 1075 (m), 864 (w), 806 (m), 784 (m) cm−1. 1H
NMR (300 MHz, CDCl3): δ 8.19 (d, J = 3.2, 1 H), 7.62 (d, J = 5.3, 1
H), 7.30 (dd, J = 5.3, 3.2, 1 H), 7.16 (s, 1 H), 3.85 (s, 3 H), 2.17 (s, 3
H). 13C NMR (75 MHz, CDCl3): δ 164.9, 154.6, 138.3, 131.2, 127.3,
125.9, 124.9, 122.3, 113.0, 51.2, 10.4. GC-MS (EI, 70 eV): m/z 222
(100) [M+], 207 (4), 191 (87), 179 (4), 165 (15), 162 (29), 151 (6),
135 (34), 134 (27), 121 (4), 111 (12), 91 (34), 89 (18). Anal. Calcd
for C11H10O3S (222.26): C, 59.44; H, 4.53; S, 14.43. Found: C, 59.51;
H, 4.54; S, 14.44.
2,3-Dimethyl-5-p-tolylpent-4-yne-2,3-diol (3c). Yield: 2.63 g,
starting from 1.74 g of 3-hydroxy-3-methylbutan-2-one (71%). Pale
yellow solid. Mp: 64−65 °C. IR (KBr): ν 3419 (s, br), 2985 (m), 2234
(w), 1665 (w), 1511 (m), 1370 (m), 1267 (w), 1121 (s), 940 (m), 903
(w), 816 (m) cm−1. 1H NMR (300 MHz, CDCl3): δ 7.35−7.27 (m, 2
H), 7.14−7.06 (m, 2 H), 2.93 (s, br, 1 H), 2.34 (s, 3 H), 2.25 (s, br, 1
H), 1.55 (s, 3 H), 1.45 (s, 3 H), 1.33 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ 138.6, 131.6, 129.1, 119.4, 90.6, 84.9, 75.5, 74.4, 25.8, 24.4,
23.1, 21.5. GC-MS (EI, 70 eV): m/z 218 (1) [M+], 185 (5), 160 (56),
159 (38), 145 (100), 142 (21), 141 (19), 128 (4), 117 (13), 115 (22),
91 (6), 59 (22). Anal. Calcd for C14H18O2 (218.29): C, 77.03; H, 8.31.
Found: C, 77.14; H, 8.30.
Methyl 2-Cyclohex-1-enyl-4-methylfuran-3-carboxylic Acid
Methyl Ester (2r). Yield: 285 mg, starting from 250 mg of 1r (93%)
(Table 2, entry 19). Yellow oil. IR (film): ν 2936 (s), 2862 (m), 1719
(s), 1602 (w), 1534 (m), 1436 (s), 1379 (w), 1286 (w), 1205 (w),
5-(4-Bromophenyl)-2,3-dimethylpent-4-yne-2,3-diol (3d). Yield:
2.84 g, starting from 1.74 g of 3-hydroxy-3-methylbutan-2-one (59%).
Yellow oil. IR (film): ν 3399 (s, br), 3302 (m, br), 2932 (w), 2230
(vw), 1484 (m), 1384 (m), 1249 (m), 1124 (m), 1048 (s), 948 (w),
1
1087 (s), 805 (w), 787 (m) cm−1. H NMR (300 MHz, CDCl3): δ
1
899 (m), 822 (m), 764 (m), 695 (m) cm−1. H NMR (300 MHz,
7.06 (s, 1 H), 6.42−6.34 (m, 1 H), 3.81 (s, 3 H), 2.42−2.29 (m, 2 H),
2.28−2.16 (m, 2 H), 2.11 (s, 3 H), 1.80−1.58 (m, 4 H). 13C NMR (75
MHz, CDCl3): δ 165.3, 160.3, 137.5, 131.5, 128.4, 121.7, 112.7, 51.2,
26.3, 25.6, 22.5, 21.8, 10.0. GC-MS (EI, 70 eV): m/z 220 (100) [M+],
205 (17), 188 (77), 187 (57), 173 (12), 166 (31), 161 (25), 160 (27),
159 (24), 145 (15), 133 (24), 132 (18), 131 (21), 117 (20), 115 (23),
105 (24), 103 (14), 91 (45), 79 (22), 77 (38), 65 (19). Anal. Calcd for
C13H16O3 (220.26): C, 70.89; H, 7.32. Found: C, 70.95; H, 7.30.
General Procedure for the Preparation of 2-Methyl-3-yne-
1,2-diols 3a−e. To a solution of BuLi in hexane (1.6 M; 25 mL, 40
mmol) was added anhydrous THF (6 mL) and hexane (25 mL) under
nitrogen. The resulting mixture was cooled to −40 °C and maintained
with stirring. A solution of the 1-alkyne (44.5 mmol: 1-hexyne, 3.66 g;
phenylacetylene, 4.54 g; 3-ethynylthiophene, 4.81 g; p-bromopheny-
lacetylene, 8.06 g; p-methylphenylacetylene, 5.17 g) in anhydrous
THF (6 mL) was added dropwise under nitrogen to the cooled
mixture followed by a solution of LiBr (1.56 g, 18.0 mmol) in
anhydrous THF (6 mL). After the mixture was stirred for 0.5 h at −40
°C, a solution of 3-hydroxy-3-methylbutan-2-one (1.74 g, 17 mmol) in
anhydrous THF (5 mL) was added under nitrogen. The mixture was
stirred at the same temperature for 2 h, and then it was warmed to
room temperature. Saturated aqueous NH4Cl (40 mL) was added,
followed by Et2O (50 mL). The phases were separated, and the
aqueous phase was extracted with Et2O (50 mL × 3). The collected
organic phases were washed with brine to neutral pH and dried over
Na2SO4. After filtration and evaporation of the solvent, products 3a−e
were purified by column chromatography on silica gel using the
following mixtures as eluent: 85/15 hexane/AcOEt (3a), 9/1 hexane/
AcOEt (3b,d), 95/5 hexane/AcOEt (3c), 8/2 hexane/AcOEt (3e).
2,3-Dimethyl-5-phenylpent-4-yne-2,3-diol (3a). Yield: 2.64 g,
starting from 1.74 g of 3-hydroxy-3-methylbutan-2-one (76%). Yellow
oil. IR (film): ν 3568 (m, br), 3301 (m, br), 2986 (m), 2231 (vw),
1598 (w), 1490 (w), 1443 (w), 1370 (m), 1338 (m), 1266 (w), 1123
(m), 1077 (m), 961 (w), 939 (w), 903 (w), 846 (w), 756 (m), 691
CDCl3): δ 7.47−7.37 (m, 2 H), 7.33−7.25 (m, 2 H), 3.15 (s, br, 1 H),
2.38 (s, br, 1 H), 1.56 (s, 3 H), 1.46 (s, 3 H), 1.34 (s, 3 H). 13C NMR
(75 MHz, CDCl3): δ 133.1, 131.7, 128.3, 122.5, 91.3, 84.7, 75.5, 74.4,
25.8, 24.4, 23.2. GC-MS (EI, 70 eV): m/z 282 (absent) [M+], 251 (6),
249 (6), 226 (58), 224 (60), 211 (63), 209 (72), 183 (8), 181 (7), 145
(37), 127 (19), 115 (9), 102 (13), 101 (10), 75 (9), 59 (100). Anal.
Calcd for C13H15BrO2 (283.16): C, 55.14; H, 5.34, Br, 28.22. Found:
C, 55.21; H, 5.33, 28.24.
2,3-Dimethyl-5-thiophen-3-ylpent-4-yne-2,3-diol (3e). Yield: 2.82
g, starting from 1.74 g of 3-hydroxy-3-methylbutan-2-one (79%).
Yellow oil. IR (film): ν 3410 (s, br), 2984 (m), 2936 (w), 2234 (w),
1634 (w), 1459 (m), 1370 (m), 1182 (m), 1122 (m), 1080 (m), 963
(m), 919 (m), 866 (w), 841 (w), 782 (m) cm−1. 1H NMR (300 MHz,
CDCl3): δ 7.43 (distorted dd, J = 3.0, 1.2, 1 H), 7.25 (distorted dd, J =
4.9, 3.0, 1 H), 7.09 (dd, J = 4.9, 1.2, 1 H), 2.42 (s, br, 2 H), 1.55 (s, 3
H), 1.45 (s, 3 H), 1.33 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 129.9,
129.0, 125.4, 121.5, 90.9, 80.0, 75.4, 74.5, 25.8, 24.4, 23.1. GC-MS (EI,
70 eV): m/z 210 (absent) [M+], 195 (1), 177 (6), 152 (97), 151 (38),
137 (100), 134 (30), 109 (30), 89 (5), 77 (3), 69 (5), 59 (54). Anal.
Calcd for C11H14O2S (210.29): C, 62.83; H, 6.71, S, 15.25. Found: C,
62.91; H, 6.70, S, 15.23.
General Procedure for the Synthesis of 4-Methylene-4,5-
dihydrofuran-3-carboxylic Esters 4a−e. A 250 mL stainless steel
autoclave was charged in the presence of air with PdI2 (5.0 mg, 1.39 ×
10−2 mmol), KI (11.5 mg, 6.93 × 10−2 mmol), anhydrous ROH (R =
Me, Et, 28 mL), and the 2-methyl-3-yne-1,2-diol 3a−e (1.39 mmol).
The autoclave was sealed and, while the mixture was stirred, the
autoclave was pressurized with CO (32 atm) and air (up to 40 atm).
After the mixture was stirred at 100 °C for the required time (see
Table 3), the autoclave was cooled, degassed, and opened. The solvent
was evaporated, and the products 4a−e were purified by column
chromatography on silica gel using 95/5 hexane/AcOEt as eluent.
Methyl 5,5-Dimethyl-4-methylene-2-phenyl-4,5-dihydrofuran-3-
carboxylate (4a). Yield: 228 mg, starting from 284 mg of 3a (67%)
(Table 3, entry 1). Pale yellow amorphous solid. Mp: 53−55 °C. IR
(KBr): ν 1699 (s), 1589 (m), 1436 (w), 1384 (s), 1273 (m), 1193
(w), 1160 (w), 1098 (w), 1072 (m), 859 (m), 763 (m), 694 (m) cm−1.
1H NMR (300 MHz, CDCl3): δ 7.70−7.62 (m, 2 H), 7.47−7.34 (m, 3
1
(m) cm−1. H NMR (300 MHz, CDCl3): δ 7.44−7.38 (m, 2 H),
7.32−7.26 (m, 3 H), 3.16 (s, br, 1 H), 2.42 (s, br, 1 H), 1.56 (s, 3 H),
1.45 (s, 3 H), 1.33 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 131.7,
128.4, 128.3, 122.6, 91.6, 84.8, 75.5, 74.4, 25.8, 24.5, 23.3. GC-MS (EI,
70 eV): m/z 204 (absent) [M+], 171 (8), 146 (93), 145 (84), 131
(100), 128 (42), 115 (13), 103 (29), 102 (19), 77 (17), 59 (53). Anal.
Calcd for C13H16O2 (204.26): C, 76.44; H, 7.90. Found: C, 76.51; H,
7.89.
2,3-Dimethylnon-4-yne-2,3-diol (3b). Yield: 2.16 g, starting from
1.74 g of 3-hydroxy-3-methylbutan-2-one (69%). Colorless oil. IR
(film): ν 3420 (s, br), 2963 (m), 2935 (m), 2242 (vw), 1636 (m),
1461 (m), 1368 (m), 1175 (m), 1084 (m), 960 (w), 917 (m) cm−1.
1H NMR (300 MHz, CDCl3): δ 2.87 (s, br, 1 H), 2.27 (s, br, 1 H),
2.22 (t, J = 7.0, 2 H), 1.56−1.32 (m, 4 H), 1.44 (s, 3 H), 1.37 (s, 3 H),
1.27 (s, 3 H), 0.91 (t, J = 7.3, 3 H). 13C NMR (75 MHz, CDCl3): δ
85.4, 82.4, 75.3, 74.0, 30.7, 25.7, 24.6, 22.9, 22.0, 18.3, 13.6. GC-MS
(EI, 70 eV): m/z 184 (absent) [M+], 151 (1), 125 (10), 109 (3), 97
H), 5.49 (s, 1 H), 4.68 (s, 1 H), 3.70 (s, 3 H), 1.50 (s, 6 H). 13C NMR
(75 MHz, CDCl3): δ 169.2, 165.2, 153.1, 130.7, 130.6, 129.1, 127.7,
105.4, 99.7, 89.3, 50.9, 28.5. GC-MS (EI, 70 eV): m/z 244 (92) [M+],
229 (42), 212 (19), 199 (18), 197 (23), 185 (24), 184 (20), 171 (15),
155 (13), 144 (23), 141 (20), 127 (17), 115 (18), 105 (84), 77 (100).
Anal. Calcd for C15H16O3 (244.29): C, 73.75; H, 6.60. Found: C,
73.82; H, 6.58.
Ethyl 5,5-Dimethyl-4-methylene-2-phenyl-4,5-dihydrofuran-3-
carboxylate (4a′). Yield: 198 mg, starting from 284 mg of 3a
(55%) (Table 3, entry 7). Pale yellow amorphous solid. Mp: 82−83
°C. IR (KBr): ν 1687 (s), 1589 (m), 1405 (w), 1383 (s), 1275 (m),
1190 (w), 1167 (w), 1095 (m), 1073 (s), 863 (m), 765 (w), 699 (m)
cm−1. 1H NMR (300 MHz, CDCl3): δ 7.70−7.63 (m, 2 H), 7.47−7.35
J
dx.doi.org/10.1021/jo301628n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(m, 3 H), 5.52 (s, 1 H), 4.67 (s, 1 H), 4.19 (q, J = 7.1, 2 H), 1.50 (s, 6
H), 1.20 (t, J = 7.1, 3 H). 13C NMR (75 MHz, CDCl3): δ 168.9, 164.8,
153.4, 131.0, 130.4, 129.2, 127.7, 105.7, 99.6, 89.2, 59.9, 28.5, 14.0.
GC-MS (EI, 70 eV): m/z 258 (58) [M+], 243 (8), 229 (7), 215 (21),
197 (17), 186 (22), 185 (17), 184 (13), 171 (25), 144 (18), 136 (12),
115 (8), 105 (100), 77 (63). Anal. Calcd for C16H18O3 (258.31): C,
74.39; H, 7.02. Found: C, 74.45; H, 7.01.
AUTHOR INFORMATION
Corresponding Author
*E-mail: b.gabriele@unical.it
Notes
■
The authors declare no competing financial interest.
Methyl 2-Butyl-5,5-dimethyl-4-methylene-4,5-dihydrofuran-3-
carboxylate (4b). Yield: 180 mg, starting from 256 mg of 3b (58%)
(Table 3, entry 3). Yellow oil. IR (film): ν 2957 (m), 2932 (m), 2872
(w), 1705 (s), 1598 (m), 1437 (m), 1383 (m), 1274 (m), 1198 (w),
ACKNOWLEDGMENTS
Financial support from the Ministero dell’Istruzione, dell’Uni-
■
versita
̀
e della Ricerca (MIUR, Rome, Italy) is gratefully
1
1172 (w), 1077 (m), 1032 (w), 866 (w) cm−1. H NMR (300 MHz,
acknowledged (Progetto di Ricerca d’Interesse Nazionale PRIN
2008A7P7YJ). Thanks are due to the European Commission,
FSE (Fondo Sociale Europeo), and Calabria Region for a
fellowship grant to R.M.
CDCl3): δ 5.37 (s, 1 H), 4.51 (s, 1 H), 3.78 (s, 3 H), 2.75 (t, J = 7.6, 2
H), 1.66−1.31 (m, 2 H), 1.47−1.24 (m, 2 H), 1.39 (s, 6 H), 0.92 (t, J
= 7.3, 3 H). 13C NMR (75 MHz, CDCl3): δ 177.6, 165.7, 152.4, 104.6,
97.7, 89.6, 50.7, 29.0, 28.8, 28.3, 22.4, 13.8. GC-MS (EI, 70 eV): m/z
224 (47) [M+], 209 (29), 195 (100), 177 (9), 167 (17), 149 (9), 135
(18), 107 (14), 79 (20). Anal. Calcd for C13H20O3 (224.30): C, 69.61;
H, 8.99. Found: C, 69.70; H, 8.97.
REFERENCES
■
(1) For reviews, see: (a) Gabriele, B.; Salerno, G. Cyclocarbonylation.
In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002; Vol. 2, pp
2623−2641. (b) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. J.
Organomet. Chem. 2003, 687, 219−228. (c) Gabriele, B.; Salerno, G.;
Costa, M.; Chiusoli, G. P. Curr. Org. Chem 2004, 8, 919−946.
(d) Gabriele, B.; Salerno, G.; Costa, M. Synlett 2004, 2468−2483.
(e) Gabriele, B.; Salerno, G.; Costa, M. Top. Organomet. Chem. 2006,
18, 239−272. (f) Gabriele, B.; Mancuso, R.; Salerno, G. Eur. J. Org.
Chem. 2012, in press (10.1002/ejoc.201200794). (g) Gabriele, B.;
Salerno, G. PdI2. In e-EROS (Electronic Encyclopedia of Reagents for
Organic Synthesis); Crich, D., Ed.; Wiley-Interscience: New York, 2006.
(2) For palladium iodide catalyzed heterocyclization−alkoxycarbo-
nylation or heterocyclization−aminocarbonylation reactions under
nonoxidative conditions, see: (a) Gabriele, B.; Mancuso, R.; Lupinacci,
E.; Salerno, G.; Veltri, L. Tetrahedron 2010, 66, 6156−6161.
(b) Gabriele, B.; Mancuso, R.; Salerno, G.; Plastina, P. J. Org. Chem.
2008, 73, 756−759. (c) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa,
M. J. Org. Chem. 2007, 72, 9278−9282. (d) Gabriele, B.; Mancuso, R.;
Salerno, G.; Costa, M. Adv. Synth. Catal. 2006, 348, 1101−1109.
(e) Gabriele, B.; Mancuso, R.; Salerno, G.; Veltri, L. Chem. Commun.
2005, 271−273.
Methyl 5,5-Dimethyl-4-methylene-2-p-tolyl-4,5-dihydrofuran-3-
carboxylate (4c). Yield: 230 mg, starting from 303 mg of 3c (64%)
(Table 3, entry 4). Yellow solid. Mp: 77−78 °C. IR (KBr): ν 2978
(w), 1699 (s), 1593 (m), 1505 (w), 1438 (m), 1383 (m), 1266 (m),
1192 (w), 1154 (w), 1093 (m), 1074 (m), 955 (w), 863 (m), 824 (m),
1
787 (m), 624 (w) cm−1. H NMR (300 MHz, CDCl3): δ 7.62−7.52
(m, 2 H), 7.24−7.12 (m, 2 H), 5.47 (s, 1 H), 4.65 (s, 1 H), 3.70 (s, 3
H), 2.37 (s, 3 H), 1.48 (s, 6 H). 13C NMR (75 MHz, CDCl3): δ 169.3,
165.3, 153.3, 140.9, 129.1, 128.4, 127.8, 104.9, 99.3, 89.1, 50.8, 28.5,
21.5. GC-MS (EI, 70 eV): m/z 258 (100) [M+], 243 (41), 227 (10),
211 (32), 199 (10), 185 (11), 183 (8), 169 (6), 158 (10), 155 (9), 141
(9), 119 (57), 91 (35), 65 (12). Anal. Calcd for C16H18O3 (258.31):
C, 74.39; H, 7.02. Found: C, 74.45; H, 7.01.
Methyl 2-(4-Bromophenyl)-5,5-dimethyl-4-methylene-4,5-dihy-
drofuran-3-carboxylate (4d). Yield: 284 mg, starting from 394 mg
of 3d (63%) (Table 3, entry 5). Yellow oil. IR (film): ν 2978 (w), 1709
(s), 1589 (m), 1485 (w), 1437 (m), 1383 (m), 1366 (w), 1277 (m),
1195 (w), 1153 (w), 1094 (m), 1072 (m), 865 (m), 831 (w), 766 (m),
1
694 (m) cm−1. H NMR (300 MHz, CDCl3): δ 7.70−7.64 (m, 1 H),
7.57−7.51 (m, 1 H), 7.45−7.35 (m, 2 H), 5.49 (s, 1 H), 4.68 (s, 1 H),
3.70 (s, 3 H), 1.50 (s, 6 H). 13C NMR (75 MHz, CDCl3): δ 169.1,
165.2, 153.2, 130.8, 130.5, 129.1, 127.7, 100.3, 99.7, 89.3, 50.9, 28.5.
GC-MS (EI, 70 eV): m/z 324 (99) [(M + 2)+], 322 (100) [M+], 309
(42), 307 (43), 291 (16), 277 (17), 264 (15), 224 (12), 222 (12), 211
(15), 202 (11), 185 (57), 183 (62), 169 (8), 157 (27), 155 (40), 143
(12), 141 (11), 126 (17), 76 (18). Anal. Calcd for C15H15BrO3
(323.18): C, 55.75; H, 4.68; Br, 24.72. Found: C, 55.82; H, 4.69; Br,
24.69.
(3) For recent examples of palladium iodide catalyzed heterocycliza-
tion−alkoxycarbonylation or heterocyclization−aminocarbonylation
reactions under oxidative conditions, see: (a) Gabriele, B.; Veltri, L.;
Mancuso, R.; Salerno, G.; Maggi, S.; Aresta, B. M. J. Org. Chem. 2012,
77, 4005−4016. (b) Gabriele, B.; Veltri, L.; Mancuso, R.; Salerno, G.;
Costa, M. Eur. J. Org. Chem. 2012, 2549−2559. (c) Gabriele, B.; Veltri,
L.; Maltese, V.; Spina, R.; Mancuso, R.; Salerno, G. Eur. J. Org. Chem.
2011, 5626−5635. (d) Gabriele, B.; Veltri, L.; Salerno, G.; Mancuso,
R.; Costa, M. Adv. Synth. Catal. 2010, 352, 3355−3363. (e) Della Ca,
̀
Methyl 5,5-Dimethyl-4-methylene-2-thiophen-3-yl-4,5-dihydro-
furan-3-carboxylate (4e). Yield: 245 mg, starting from 292 mg of
3e (70%) (Table 3, entry 6). Yellow oil. IR (film): ν 2978 (w), 1704
(s), 1579 (m), 1438 (m), 1364 (w), 1263 (m), 1192 (w), 1144 (w),
N.; Campanini, F.; Gabriele, B.; Salerno, G.; Massera, C.; Costa, M.
Adv. Synth. Catal. 2009, 351, 2423−2432. (f) Gabriele, B.; Mancuso,
R.; Salerno, G.; Lupinacci, E.; Ruffolo, G.; Costa, M. J. Org. Chem.
2008, 73, 4971−4977.
1
1098 (m), 1077 (m), 878 (m), 853 (m), 788 (m), 650 (w) cm−1. H
(4) A preliminary communication of this work was published
recently: Gabriele, B.; Veltri, L.; Mancuso, R.; Plastina, P.; Salerno, G.;
Costa, M. Tetrahedron Lett. 2010, 51, 1663−1665.
NMR (300 MHz, CDCl3): δ 8.26 (d, J = 3.0, 1 H), 7.60 (distorted d, J
= 5.5, 1 H), 7.29 (distorted dd, J = 5.5, 3.0, 1 H), 5.45 (s, 1 H), 4.66 (s,
1 H), 3.81 (s, 3 H), 1.48 (s, 6 H). 13C NMR (75 MHz, CDCl3): δ
165.5, 163.8, 153.1, 131.4, 130.7, 128.5, 124.5, 104.5, 99.7, 88.6, 51.0,
28.6. GC-MS (EI, 70 eV): m/z 250 (100) [M+], 235 (35), 218 (12),
205 (13), 203 (21), 190 (11), 177 (11), 161 (9), 150 (11), 147 (11),
134 (9), 111 (64), 97 (8), 83 (13). Anal. Calcd for C13H14O3S
(250.31): C, 62.38; H, 5.64; S, 12.81. Found: C, 62.44; H, 5.62; S,
12.80.
(5) Many molecules incorporating the furan-3-carboxylic ester core
have shown interesting pharmacological activities, including anti-
hypertensive, antimicriobial, and anticancer activity. For selected
recent examples, see: (a) Luo, Y.; Zhou, M.; Ye, Q.; Pu, Q.; Zhang, G.
J. Nat. Prod. 2012, 75, 98−102. (b) Lu, Z.; Chen, Y.-H.; Smith, C.; Li,
H.; Thompson, C. F.; Sweis, R.; Sinclair, P.; Kallashi, F.; Hunt, J.;
Adamson, S. E.; Dong, G.; Ondeuka, D. Qian, X.; Sun, W.; Vachal, P.;
Zhao, K. (Merck Sharp and Dohme Corp.) World Pat.
WO201258187A1, 2012. (c) El-Sayed, W. A.; Abbas, H.-A. S.;
Mohamed, A. M.; Abdel-Rahman, A. A.-H. J. Heterocycl. Chem. 2011,
48, 1006−1013. (d) Perestelo, N. R.; Limenez, I. A.; Bazzocchi, I. L.;
Sanchez-Canete, M. P.; Gamarro, F.; Castanys, S. Eur. J. Med. Chem.
2011, 46, 4915−4923. (e) Kato, M.; Takai, M.; Matsuyama, T.;
Kurose, T.; Hagiwara, Y.; Matsuda, M.; Mori, T.; Imoto, K.; Dota, A.
ASSOCIATED CONTENT
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S
* Supporting Information
1
Figures giving H and 13C NMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
K
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Khalil, Z.; Capon, R. J.; Lacey, E. Org. Biomol. Chem. 2011, 9, 1201−
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Eur. J. Med. Chem. 2011, 46, 4915−4923. (l) Jorgenes, C. G.; Frolund,
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(6) Several synthetic approaches to furan-3-carboxylic esters have
been developed to date; none of these methods, however, involve the
direct carbonylation of acyclic precursors. For very recent examples,
see: (a) Brucoli, F.; Marimuthu, P.; Borrello, M. T.; Stapleton, P.;
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́ ́
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L
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