A convenient synthetic route to furan esters and lactones by palladium-catalyzed carboalkoxylation or cyclocarbonylation of hydroxyl-substituted 3-iodofurans

Article abstract of DOI:10.1016/j.tetlet.2010.04.108

An effective palladium-catalyzed protocol for the intermolecular carboalkoxylation or intramolecular cyclocarbonylation of hydroxyl-substituted 3-iodofurans under carbon monoxide pressure has been developed. The 3-iodofurans are readily prepared by iodocy

Full text of DOI:10.1016/j.tetlet.2010.04.108

Tetrahedron Letters 51 (2010) 3417–3421
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A convenient synthetic route to furan esters and lactones
by palladium-catalyzed carboalkoxylation or cyclocarbonylation
of hydroxyl-substituted 3-iodofurans
*
Chul-Hee Cho, Richard C. Larock
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective palladium-catalyzed protocol for the intermolecular carboalkoxylation or intramolecular
cyclocarbonylation of hydroxyl-substituted 3-iodofurans under carbon monoxide pressure has been
developed. The 3-iodofurans are readily prepared by iodocyclization of 2-(1-alkynyl)-2-alken-1-ones in
the presence of various diols.
Received 23 March 2010
Revised 21 April 2010
Accepted 23 April 2010
Available online 28 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Iodocyclization
Carbonylation
Furan
Transition metal-catalyzed carbonylation is broadly applicable
for the preparation of carbonyl-containing substrates, particularly
the palladium-catalyzed carbonylation of organic halides.1–6 This
chemistry has found wide application in organic synthesis, because
it can be employed on a wide variety of substrates to produce a wide
range of carbonyl products and generally proceeds smoothly under
low pressures of carbon monoxide (Eq. (1)).7–9 Similarly, the palla-
dium-catalyzed cyclocarbonylation/lactonization of organic halides
with carbon monoxide insertion is a very useful synthetic method-
ology that has become an important tool in organic synthesis.10–14
We now wish to report an efficient method for the palladium-
catalyzed intermolecular carboalkoxylation and intramolecular
cyclocarbonylation of hydroxyl-substituted 3-iodofurans under
one atmosphere of pressure of carbon monoxide to give lactone-
and ester-containing furan products. To the best of our knowledge,
the study reported here is the first general exploration of the pal-
ladium-catalyzed carboalkoxylation and cyclocarbonylation of hy-
droxyl-substituted 3-iodofurans.
First of all, various hydroxyl-containing 3-iodofurans 116 have
been readily prepared by a two-step approach involving the Sono-
gashira coupling of 2-iodo-2-alken-1-ones with terminal alkynes,
followed by electrophilic cyclization by I2 in the presence of diols
(Scheme 1). The results of this iodocyclization process are summa-
rized in Table 1.
To develop a general process for preparing dihydroxyfuran esters
by intermolecular carboalkoxylation, we examined the carbonyl-
ation of hydroxyl-containing 3-iodofuran 1a with ethylene glycol
under various reaction conditions (Table 2). When optimizing the
reaction, the base TEA and the solvent DMF were held constant,
while the palladium-catalyst and ligand were varied. This decision
CO (1 atm)
O
cat. Pd(0)
base
+
(Het)Ar
X
NuH
ð1Þ
(Het)ArCNu
X = Br, I
Nu = OH, OR, NR'R''
Previously, we have developed an efficient synthesis of tetra-
substituted 3-iodofurans through the electrophile-induced cycliza-
tion of 2-(1-alkynyl)-2-alken-1-ones in the presence of various
nucleophiles (Scheme 1).15 We envisioned that hydroxyl-substi-
tuted 3-iodofurans, readily available by iodocyclization in the pres-
ence of diols, should prove valuable as building blocks for
combinatorial chemistry by intramolecular cyclocarbonylation, as
well as intermolecular carboalkoxylation (Scheme 2).
O
R1
R2
R3
O
I2
O
R3
HO(CH2)nOH
cat. Pd/Cu
R3
I
R1
R1
NaHCO3
MeCN, r.t.
I
R2
R2
O(CH2)nOH
1
* Corresponding author. Tel.: +1 515 294 4660.
E-mail address: larock@iastate.edu (R.C. Larock).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.108

3418
C.-H. Cho, R. C. Larock / Tetrahedron Letters 51 (2010) 3417–3421
Table 1
O
R1
R2
R3
Synthesis of hydroxyl-containing 3-iodofurans 1 by iodocyclizationa
Intermolecular
Carboalkoxylation
Entry
Substrate (R3)
3-Iodofuran 1
Yieldb (%)
CO2R4
R3
O
R1
R2
R3
O(CH2)nOH
O
R3
O
2
I
I
R3
O
O
R1
R2
O(CH2)nOH
1
Intramolecular
O(CH2)nOH
1a (n = 2)
Cyclocarbonylation
1
2
3
4
Ph
83
82
77
65
4-MeOC6H4
Ph
Ph
1b (n = 2)
1c (n = 3)
1d (n = 5)
O
O
n
3
PMP
OCH3
O
Scheme 2.
O
5
86
(PMP: 4-MeOC6H4)
I
was made, because TEA and DMF have previously proven quite use-
ful for such palladium-catalyzed carboalkoxylations.7,8 A small
amount of the desired product 2a (<5% yield) was obtained by
employing 10 mol % Pd(OAc)2 with no ligand, ethylene glycol
(5.0 equiv), and TEA (4.0 equiv) at 110 °C for 72 h. Under these con-
ditions, the lactone 3a (58%) was favored (Table 2, entry 1). We
subsequently added various bidentate phosphine ligands, such as
1,10-bis(diphenylphosphino)ferrocene (dppf, L1), bis(diphenylphos-
phino)methane (dppm, L2), and 1,4-bis(diphenylphosphino)butane
(dppb, L3), in the hope of stabilizing the anticipated cationic
palladium(II) intermediate. This significantly affected both intermo-
lecular carboalkoxylation, as well as the intramolecular cyclocarb-
onylation, with diol 2a now being the major product (Table 2,
entries 2-4). ( )-(1,10-Binaphthalene-2,20-diyl)bis(diphenyl-
phosphine) [( )-BINAP, L4] produced both the desired product 2a
and the by-product 3a in poor yields (Table 2, entry 5). Interestingly,
the addition of monodentate ligands, such as tricyclohexylphos-
O(CH2)2OH
1e
a
Unless otherwise noted, all the reactions have been carried out using NaHCO3
(2.0 equiv), the diol (4.0 equiv), and I2 (2.0 equiv) in MeCN (0.1 M concn) at room
temperature for 0.5 h.
b
Isolated yields after column chromatography.
phine (PCy3, L5), triphenylphosphine (PPh3, L6), and tris(2,6-dime-
thoxyphenyl)phosphine (L7), afforded an increase in the yields of
ester 2a (Table 2, entries 6–9). A 74% isolated yield of the desired
product 2a can be obtained when 20 mol % of PCy3 (L5) is employed
(Table 2, entry 7). Other phosphine ligands, such as 2-dicyclohexyl-
phosphino-20-(N,N-dimethylamino)biphenyl (DavePhos, L8) and
tri-tert-butylphosphine, introduced as the corresponding tetrafluo-
roborate salt (L9), produced both the desired product 2a and the
Table 2
Carboalkoxylation of 3-iodofuran 1a and 1,2-ethanediol: a survey of reaction conditionsa
O
O
CO (balloon)
O
Ph
Ph
10 mol % Pd cat.
ligand
Ph
+
I
O
O
O
O
HOCH2CH2OH (5.0 equiv)
Et3N (4.0 equiv)
O
O
O
DMF,110 oC
HO
HO
Pd cat
OH
1a
2a
3a
Entry
Ligand (mol %)
Time (h)
Yield of 2ab (%)
Yield of 3ab (%)
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
72
12
24
24
24
12
12
12
12
12
12
24
24
<5
38
58
48
<5
68
74
47
63
27
31
26
<5
58
27
13
21
17
7
<5
21
18
23
28
53
37
L1 (10)
L2 (10)
L3 (10)
L4 (10)
L5 (10)
L5 (20)
L6 (20)
L7 (20)
L8 (10)
L9 (10)
L5 (20)
—
4
5c
6
7
8
9
10c
11c
12
13c
PdCl2(PPh3)2
PdCl2(PPh3)2
PCy2
PPh2
PPh2
R
P
PPh2
PPh2
Ph2P(CH2)nPPh2
(t-Bu)3PH(BF4)
Fe
R
R
L5, R = Cy
L6, R = Ph
Me2N
L8
L2, n = 1
L3, n = 4
L1
L4
L7, R = 2,6-(MeO)2C6H3
L9
a
Reaction conditions: 3-iodofuran 1a (0.20 mmol), 10 mol % Pd catalyst, 20 mol % ligand, CO (1 atm), TEA (0.80 mmol), and ethylene glycol (1.00 mmol) were stirred in
DMF (2.0 mL) at room temperature. The vial was purged with CO for 2 min and then connected to a balloon of CO, and the reaction mixture was stirred at 110 °C.
b
Isolated yields based on 1a.
The starting material 1a was recovered.
c

C.-H. Cho, R. C. Larock / Tetrahedron Letters 51 (2010) 3417–3421
3419
cyclized lactone 3a (Table 2, entries 10 and 11). Another palladium
catalyst, PdCl2(PPh3)2, favored the cyclized lactone product 3a
(53%), alongside a 26% yield of the diol product 2a (Table 2, entry
12). Very little of the desired diol 2a was obtained in the absence
of added ligand (Table 2, entry 13).
Our brief ligand survey indicated that the yield of diol-containing
ester 2a is highest when PCy3 (L5) is used as the ligand and Pd(OAc)2
as the catalyst. Thus, under our optimized conditions [10 mol %
Pd(OAc)2, 20 mol % PCy3, TEA (4.0 equiv), and diol (5.0 equiv) in
DMF at 110 °C under 1 atm of CO], the carbonylation of hydroxyl-
containing 3-iodofuran 1a favors intermolecular carboalkoxylation
to give the corresponding ester-containing furan 2a.
Having optimized the reaction conditions for both intermolecu-
lar and intramolecular carbonylation, we have further determined
the scope of these processes (Scheme 2). However, lactone forma-
tion was not examined intensively. Formation of the carboalkoxy-
lation coupling product 2a from 1a and 1,2-ethanediol proceeded
in a 74% yield (Table 3, entry 1).17 During carboalkoxylation, a trace
Table 3
Intermolecular carboalkoxylation to 2 and intramolecular cyclocarbonylation to 3a
Entry
3-Iodofuran 1
R4OH
Time (h)
Product 2/3
Yieldb (%)
O
O
R3
I
O
O
O
O
R4
OH
HO
2a
2b
1
2
1a (R3 = Ph)
HO(CH2)2OH
CH3OHc
12
24
74
73
1a
c
3
4
1a
24
12
2c
2d
O
38
76
HO
HO(CH2)2OH
1b (R3 = 4-MeOC6H4)
5
6
1a
—
—
9
77
O
O
O
3a
O
O
47d
I
24
O
O
O
O
OH
3b
1c
O
O
I
Tracee
O
O
7
—
48
O
O
OH
1d
3c
O
O
OMe
OMe
O
I
O
O
8
—
9
63
O
OH
3d
1e
O
OMe
O
O
O
9
1e
HO(CH2)2OH
12
67
HO
OH
2e
Representative procedure: (i) Intermolecular carboalkoxylation: the 3-iodofuran 1 (0.20 mmol), 10 mol % Pd(OAc)2, 20 mol % PCy3, TEA (0.80 mmol), and R4OH (1.00 mmol)
a
were stirred in DMF (2.0 mL) at room temperature. The vial was purged with CO for 2 min and then connected to a balloon of CO, and the reaction mixture was stirred at
110 °C. (ii) Intramolecular cyclocarbonylation: the 3-iodofuran 1 (0.20 mmol), 10 mol % Pd(OAc)2, 20 mol % dppf, and TEA (0.80 mmol) were stirred in DMF (2.0 mL) at room
temperature. The vial was purged with CO for 2 min and then connected to a balloon of CO, and the reaction mixture was stirred at 80 °C.
b
All yields are isolated yields after column chromatography. The desired products 2 and 3 have been characterized by 1H and 13C NMR spectroscopy.
10.0 equiv of the desired alcohol were used.
Some starting material remained.
Starting materials remained.
c
d
e

3420
C.-H. Cho, R. C. Larock / Tetrahedron Letters 51 (2010) 3417–3421
amount of cyclized by-product 3, the intramolecular cyclocarbony-
lation product, was observed. The carbomethoxylation of 1a using
10 equiv of methyl alcohol was achieved in 73% yield, but required
a much longer reaction time (Table 3, entry 2). Use of a longer alkyl
chain-containing monoalcohol, 1-pentanol, produced 38% of the
corresponding ester 2c, which was also accompanied by the lac-
tone 3a in 35% yield (Table 3, entry 3). Hydroxyl-containing 3-
iodofurans bearing an electron-rich 4-methoxyphenyl ring, 1b,
smoothly react by carboalkoxylation to give the desired product
2d (Table 3, entry 4).
We have also examined the intramolecular cyclocarbonylation/
lactonization of different alkyl chain-containing 3-iodofurans 1a,
1c, and 1d (Table 3, entries 5–7). 3-Iodofuran 1a gave the fastest
lactonization, reaching completion in 9 h (Table 3, entry 5).18 Long-
er chain containing 3-iodofuran 1c afforded a slightly lower yield
of the desired lactone 3b than 1a and some starting material 1c re-
mained (Table 3, entry 6). Unfortunately, the desired lactone 3c
could not be obtained using longer reaction times, when starting
from 1d (Table 3, entry 7). The formation of long chain-containing
1d is also more difficult than the formation of 1a. The intramolec-
ular cyclocarbonylation of cyclopentane-containing 3-iodofuran 1e
afforded the desired lactone 3d in a decent yield (Table 3, entry 8).
Similarly, the intermolecular carboalkoxylation of cyclopentane-
containing 3-iodofuran 1e smoothly proceeded to the desired
product 2e in a modest yield (Table 3, entry 9).
On the other hand, base-catalyzed intramolecular cyclization of II
gives a palladacycle IV, which undergoes reductive elimination
affording cyclized product 3.
In summary, we have developed an effective Pd-catalyzed
protocol for the intermolecular carboalkoxylation of hydroxyl-
substituted 3-iodofurans 1 leading to the corresponding ester-con-
taining furans 2, as well as intramolecular cyclocarbonylation of 1
leading to the corresponding lactone-containing furans 3. The start-
ing iodine-containing furans 1 have proven to be very useful inter-
mediates for further diversification by known palladium-catalyzed
chemistry, and are thus valuable building blocks for combinatorial
chemistry.
Acknowledgments
We thank the National Institute of General Medical Sciences
(GM070620 and GM079593), the National Institutes of Health Kan-
sas University Chemical Methodologies, and the Library Develop-
ment Center of Excellence (GM069663) for their generous
financial support; Johnson Matthey, Inc. and Kawaken Fine Chem-
icals Co., Ltd for donations of palladium catalysts. We also thank
Mr. Patrick H. Hall for helpful discussions.
Supplementary data
The selectivity of these carbonylation processes suggests the
mechanism depicted in Scheme 3. Oxidative addition of the car-
bon–iodine bond of the 3-iodofuran 1 to Pd(0), generated in situ
from PdLn, results in the corresponding Pd(II) intermediate I. Car-
bon monoxide insertion into the carbon–palladium bond of I af-
fords the acylpalladium iodide complex II. When alcohols (R4OH)
are used, nucleophilic attack of the hydroxyl group from the alco-
hol on the acyl group of the acylpalladium intermediate II appar-
ently terminates the base-catalyzed cycle, affording the ester
products 2 with simultaneous regeneration of the Pd(0) catalyst.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.108.
References and notes
1. Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114.
2. Barnard, C. F. J. Organometallics 2008, 27, 5402.
3. Trzeciak, A. M.; Ziolkowski, J. J. Coord. Chem. Rev. 2005, 249, 2308.
4. El Ali, B.; Alper, H. Synlett 2000, 161.
5. Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev. 1996, 96, 635.
6. Vizer, S. A.; Yerzhanov, K. B.; Al Quntar, A. A. A.; Dembitsky, V. M. Tetrahedron
2004, 60, 5499.
7. McNulty, J.; Nair, J. J.; Robertson, A. Org. Lett. 2007, 9, 4575.
8. Chambers, R. J.; Marfat, A. Synth. Commun. 1997, 27, 515.
9. Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 7761.
10. Fernandes, T. A.; Carvalho, R. C. C.; Gonçalves, T. M. D.; da Silva, A. J. M.; Costa,
P. R. R. Tetrahedron Lett. 2008, 49, 3322.
Pd(OAc)2 + Ligand
11. Kreimerman, S.; Ryu, I.; Minakata, S.; Komatsu, M. Org. Lett. 2000, 2, 389.
12. Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda, M.; Suginome, H. J. Org. Chem.
1999, 64, 6583.
13. Negishi, E.; Copéret, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour, J. M. J. Am. Chem. Soc.
1996, 118, 5904.
14. El Ali, B.; Okuro, K.; Vasapollo, G.; Alper, H. J. Am. Chem. Soc. 1996, 118, 4264.
15. Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70, 7679.
16. General procedure for iodocyclization: The iodofurans 1 were prepared by a
modification of our earlier literature procedure.15 To a mixture of the 2-(1-
alkynyl)-2-alken-1-one (2.0 mmol), I2 (4.0 mmol), and NaHCO3 (4.0 mmol) was
added a solution of the appropriate diol (8.0 mmol) in MeCN (20 mL). The
resulting mixture was stirred at room temperature for 0.5 h, unless otherwise
specified. The reaction was monitored by TLC to establish completion. The
mixture was diluted with EtOAc (250 mL). The excess I2 was removed by
washing with satd aq Na2S2O3. The combined organic layers were dried over
Pd(0)
2
3
1
R1
R2
O
R3
O
O
R3
O
R1
R2
R1
R2
R3
O
Pd Ln
I
O
R
Pd
O
O
R
O
Pd
R O
anhydrous MgSO4 and concentrated under
a vacuum to yield the crude
OH
HO
R4
product, which was purified by flash chromatography on silica gel using EtOAc/
hexanes as the eluent system. Compound 1a: the product was obtained as a
yellow oil (83% yield); 1H NMR (400 MHz, CDCl3) d 1.51–1.63 (m, 1H), 1.78–
1.90 (m, 1H), 1.91–2.04 (m, 1H), 2.06–2.17 (m, 1H), 2.41–2.60 (m, 2H), 2.62–
2.76 (m, 1H), 3.61–3.71 (m, 1H), 3.69–3.82 (m, 3H), 4.26 (br s, 1H), 7.21–7.32
(m, 1H), 7.38 (t, J = 7.8 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d 18.4, 23.3, 27.2, 62.2, 64.9, 70.5, 71.3, 123.2, 126.2 (ꢀ2), 128.0, 128.4
(ꢀ2), 130.4, 150.3, 154.1; HRMS calcd for C16H17IO3 [M+], 384.0222, found
384.0228.
III
I
IV
CO
R1
.
.
.
Et3N HI
Et3N HI
R3
O
O
HOR4
Et3N
17. General procedure for intermolecular carboalkoxylation: A stirred mixture of the
Et3N
R2
appropriate hydroxyl-substituted 3-iodofuran
1
(0.10 mmol), 10 mol %
Pd(OAc)2, 20 mol % PCy3, TEA (0.40 mmol), and excess R4OH (0.50–1.0 mmol)
in DMF (2.0 mL) was charged into a 50 mL long flask at room temperature. The
mixture was flushed with CO gas for 2 min, and the flask was fitted with a
balloon of CO gas. The reaction mixture was heated at 110 °C with vigorous
stirring. Upon cooling to room temperature, the resulting reaction mixture was
extracted with EtOAc (2 ꢀ 20 mL). The separated organic layer was washed
with water and brine, dried over MgSO4, and concentrated in vacuo. The crude
Pd
O
R
Ln
I
OH
II
Scheme 3.

C.-H. Cho, R. C. Larock / Tetrahedron Letters 51 (2010) 3417–3421
3421
product was purified by column chromatography on silica gel using ethyl
acetate/hexanes as the eluent to afford the corresponding products 2.
Compound 2a: the product was obtained as a yellow oil (74% yield); 1H NMR
(400 MHz, CDCl3) d 1.59–1.70 (m, 1H), 1.81–1.93 (m, 1H), 1.96–2.10 (m, 1H),
2.12–2.22 (m, 1H), 2.48 (br s, 1H), 2.50–2.63 (m, 1H), 2.66–2.78 (m, 1H), 3.10
(br s, 1H), 3.59–3.66 (m, 1H), 3.69–3.83 (m, 5H), 4.20–4.30 (m, 1H), 4.33–4.42
(m, 1H), 4.84 (br s, 1H), 7.37–7.47 (m, 3H), 7.68–7.77 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 17.9, 23.3, 27.1, 61.1, 62.3, 66.7, 69.9, 70.4, 112.6, 119.1,
128.2 (ꢀ2), 128.9 (ꢀ2), 129.6, 130.6, 154.1, 157.5, 164.4; HRMS calcd for
C19H22O6 [M+], 346.1416, found 346.1423.
for 2 min, and the flask was fitted with a balloon of CO gas. The reaction
mixture was heated at 70–80 °C with vigorous stirring for 8 h. Upon cooling to
room temperature, the resulting reaction mixture was extracted with EtOAc
(2 ꢀ 20 mL). The separated organic layer was washed with water and brine,
dried over MgSO4, and concentrated in vacuo. The crude product was purified
by column chromatography on silica gel using ethyl acetate/hexanes as the
eluent to afford the corresponding lactone 3. Compound 3a: the product was
obtained as a pale yellow oil that solidified upon standing to afford an ivory
solid (77% yield); 1H NMR (400 MHz, CDCl3) d 1.65–1.77 (m, 1H), 1.90–2.00
(m, 1H), 2.03–2.15 (m, 2H), 2.55–2.66 (m, 1H), 2.73–2.83 (m, 1H), 3.98–4.06
(m, 1H), 4.09–4.17 (m, 1H), 4.29–4.38 (m, 2H), 4.53–4.61 (m, 1H), 7.33–7.47
(m, 3H), 7.90 (d, J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 18.0, 23.1, 30.9,
69.6, 71.3, 71.4, 111.4, 119.7, 126.9 (ꢀ2), 128.8 (ꢀ2), 129.3, 129.4, 152.7, 155.5,
166.8; HRMS calcd for C17H16O4 [M+], 284.1049, found 284.1053.
18. General procedure for intramolecular lactonization: A stirred mixture of the
appropriate hydroxyl-substituted 3-iodofuran
1
(0.10 mmol), 10 mol %
Pd(OAc)2, 20 mol % dppf, and TEA (0.40 mmol) in DMF (2.0 mL) was added to
a 50 mL long flask at room temperature. The mixture was flushed with CO gas