Highly substituted lactone/ester-containing furan library by the palladium-catalyzed carbonylation of hydroxyl-substituted 3-iodofurans

Article abstract of DOI:10.1021/co100088q

Highly substituted lactone- and ester-containing furans have been prepared by the efficient palladium-catalyzed intramolecular cyclocarbonylation or intermolecular carboalkoxylation, respectively, of hydroxyl-containing 3-iodofurans, readily prepared by t

Full text of DOI:10.1021/co100088q

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Highly Substituted Lactone/Ester-Containing Furan Library by the
Palladium-Catalyzed Carbonylation of Hydroxyl-Substituted
3-Iodofurans
Chul-Hee Cho and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S Supporting Information
b
ABSTRACT:
Highly substituted lactone- and ester-containing furans have been prepared by the efficient palladium-catalyzed intramolecular
cyclocarbonylation or intermolecular carboalkoxylation, respectively, of hydroxyl-containing 3-iodofurans, readily prepared by the
iodocyclization of 2-(1-alkynyl)-2-alken-1-ones in the presence of various diols.
KEYWORDS: iodocyclization, nucleophile, carboalkoxylation, cyclocarbonylation, furan
’ INTRODUCTION
palladium-catalyzed intramolecular lactonization using an acetoxy
group as the nucleophile (eq 3).21
Furans represent an important class of heterocyclic com-
pounds as they are prevalent in many biologically active natural
products, as well as numerous pharmacologically interesting
compounds.1À3 Among these, heteroatom-substituted furans
represent an important subclass, both as synthons and as func-
tionalized heterocycles of biological interest. Thus, the design
and discovery of synthetic methods that provide access to highly
substituted furans is an active area of investigation.4À9
Transition metal-catalyzed carbonylation reactions are of broad
applicability, in terms of both basic research and commercial
applications.10,11 This chemistry has been widely employed in
organic synthesis, because it can be utilized on a wide variety of
substrates to produce a wide range of carbonyl products and it
generally proceeds smoothly under low pressures of carbon mon-
oxide (eq 1).12,13 Similarly, the palladium-catalyzed cyclocarbonyla-
tion/lactonization of organic halides is very useful synthetic metho-
dology that has become an important tool in organic synthesis.14À18
For example, we have reported that the coupling of o-iodophenols,
internal alkynes, and carbon monoxide efficiently affords 3,4-
disubstituted coumarins (eq 2).19,20 Similarly, we have prepared
coumestans and coumestrol by iodocyclization and subsequent
Received: December 14, 2010
Revised:
February 6, 2011
Published: March 24, 2011
r
2011 American Chemical Society
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|

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RESEARCH ARTICLE
Scheme 1
Scheme 2
Recently, we have developed an efficient synthesis of tetrasub-
stituted 3-iodofurans through the electrophile-induced cyclization of
2-(1-alkynyl)-2-alken-1-ones in the presence of various nucleophiles
(eq 4).5,22 These multisubstituted 3-iodofurans provide an ideal
intermediate for further useful structure elaborations by a variety of
CÀC, CÀO, CÀN and CÀS bond forming processes.22À29 Thus,
the carbonÀhalogen bond can be utilized for a variety of palladium-
catalyzed reactions, including SuzukiÀMiyaura,30 Sonogashira,31
BuchwaldÀHartwig,32,33 and Heck12 reactions to name just a few.
As a continuation of our interest in the development of
attractive strategies for the synthesis of highly substituted
furans,22 we envisioned that hydroxyl-substituted 3-iodofurans,
readily available by iodocyclization in the presence of diols,
should prove valuable as building blocks for combinatorial
chemistry by intramolecular cyclocarbonylation, as well as inter-
molecular carboalkoxylation (Scheme 1).
Table 1. Library Data for Compounds 1{1À12}
Herein, we report an efficient method for the palladium-
catalyzed intramolecular cyclocarbonylation and intermolecular
carboalkoxylation of various hydroxyl-substituted 3-iodofurans
to give lactone- and ester-containing furan products, respectively.
The hydroxyl substituents present in the latter substrates can be
critical for receptor binding in vitro because of their hydrophi-
licity and, thus, lipophobic nature.34 According to calculations
using Lipinski’s rules,35 terminal hydroxyl-containing furans
should be good drug candidates. Intramolecular cyclocarbonyla-
tion would also appear to provide an interesting set of lactones of
potential biological interest. We anticipate that this chemistry
should find broad applications in synthetic organic chemistry, as
well as the pharmaceutical sciences.
’ RESULTS AND DISCUSSION
We hypothesized that our previously described iodocycliza-
tion process should readily afford the requisite iodofurans for
intramolecular cyclocarbonylation and intermolecular carboalk-
oxylation processes,22 resulting in a diverse library of lactone- and
ester-containing furans, respectively. A convenient two-step
approach to various hydroxyl-containing 3-iodofurans 2 has been
developed, which involves (i) the Sonogashira coupling of
2-iodo-2-alken-1-ones36 with terminal alkynes and (ii) electro-
philic cyclization by I2 (Scheme 2).5 The alkynes 1 were prepared
by the palladium/copper-catalyzed Sonogashira coupling of
appropriate 2-iodo-2-alken-1-ones with terminal alkynes. The
results are summarized in Table 1.
a All yields are isolated yields after column chromatography. The desired
products 1 have been characterized by 1H and 13C NMR spectroscopy.
cyclization of the corresponding alkynes 1 with various alcohols
as nucleophiles using I2 for only 0.5 h at room temperature. The
results of this iodocyclization process are summarized in Table 2
and Figure 1. All of the reactions were monitored by thin
layer chromatography and the products purified by column
chromatography.
The scope of this iodocyclization has been briefly examined.
Alkynes bearing a phenyl substituent exhibited broad generality
As the key step in our library synthesis, various hydroxyl-
substituted 3-iodofurans 2 were efficiently prepared by electrophilic
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Table 2. Library Data for Hydroxyl-Containing 3-Iodofurans 2a
a Unless otherwise noted, all of the reactions have been carried out using NaHCO3 (2.0 equiv), the nucleophile (4.0 equiv), and I2 (2.0 equiv) in MeCN
(0.1 M conc.) at room temperature for 0.5 h. b Isolated yields after column chromatography. All hydroxyl-containing 3-iodofurans 2 have been
characterized by 1H and 13C NMR spectroscopy. c Starting material 1{1} decomposed.
Figure 1. Hydroxyl-containing 3-iodofurans 2 synthesized by iodocyclization.
with a range of diols. With 1,2-ethanediol as the nucleophile, a
high yield of iodocyclization product is obtained (Table 2, entry 1).
However, when longer chain diols, such as 1,3-propanediol,
1,4-butanediol and 1,5-pentanediol, were used, somewhat lower
yields were obtained (Table 2, entries 2À4). Unfortunately, none
of the desired cyclized products were obtained when employing
secondary diols, e.g. 1,4-cyclohexanediol and 2,3-butanediol
(Table 2, entries 5 and 6). Water is a suitable nucleophile,
affording the cyclized product 2{7} in a high yield (Table 2,
entry 7). 2-Arylethynyl-2-cyclohexen-1-ones bearing an electron-
rich aromatic ring, such as those containing a methoxy group
or a dimethylamino group reacted well with I2, affording the
corresponding iodofurans in good yields (Table 2; entries
8À10 and 12). Placing an electron-donating methoxy group in
the position meta to the alkyne gave a 76% yield of the cyclized
product 2{11} (Table 2, entry 11). When the terminus of the
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alkynyl moiety contained an aryl group bearing an electron-
withdrawing group, such as a cyano group, the yield was even
better (Table 2, entry 13). Products from a heterocyclic
thiophenyl group and a cyclohexenyl group were also isolated
in modest yields (Table 2, entries 14 and 15). Similarly,
cyclized products from 2-arylethynyl-2-cyclopenten-1-ones
and acyclic substrates have also been obtained in good yields
(Table 2, entries 16À20).
In preliminary studies, we examined the carboalkoxylation of
hydroxyl-containing 3-iodofuran 2{1} with ethylene glycol under
various conditions, including various catalysts and ligands.22 As we
previously communicated, our brief ligand survey indicated that
reaction efficiencies are highest when monodentate ligands, such as
tricyclohexylphosphine (PCy3), are used as the ligand and Pd-
(OAc)2 is used as the catalyst. A 74% isolated yield of the desired
product 4{1} can be obtained when 20 mol % of PCy3 is employed
(Scheme 4). When optimizing the reaction, the base and solvent
were held constant, while the palladium-catalyst and ligand were
varied. 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], intermolecular carboalkoxylation of the
hydroxyl-containing 3-iodofurans 2{1} to the corresponding ester-
containing furans 4{1} is favored.
During our investigation of the intramolecular cyclocarbony-
lation and intermolecular carboalkoxylation processes, we chose
as our model system to examine the palladium-catalyzed reaction
of hydroxyl-containing 3-iodofuran 2{1} under one atmosphere
of carbon monoxide pressure (Scheme 3). As predicted, hydro-
xyl-containing 3-iodofuran 2{1} smoothly underwent intra-
molecular cyclocarbonylation using dppf as the ligand and
triethylamine as the base in the presence of Pd(OAc)2 as the
catalyst and using a balloon (1 atm) of carbon monoxide to give
the desired lactone 3{1} in a 71% yield. Unfortunately, the
carboalkoxylation of 2{1} with 3.0 equiv of ethylene glycol and
the same reagents at 110 °C for 12 h did not prove suitable for
preparation of the desired diol 4{1}, as only a 31% yield was
obtained, alongside the cyclized byproduct 3{1} (43% yield).
Having optimized the reaction conditions for the intramolecular
cyclocarbonylation and intermolecular carboalkoxylation of various
hydroxyl-containing 3-iodofurans 2, we have further determined the
scope of these two processes (Scheme 5 and Table 3). Neither
electron-donating nor electron-deficient groups on the furan skele-
ton seriously affect the efficiency of these processes. The reaction
has good substrate scope and tolerates a broad range of functional
groups. The ability to readily accommodate Ph, MeOC6H4,
Me2NC6H4, NCC6H4, thiophenyl, and cyclohexenyl groups should
allow one to further functionalize these products by employing
standard organic synthetic methods. During the carboalkoxylation, a
trace amount of cyclized lactone byproduct 3, the intramolecular
cyclocarbonylation product, have been observed. All of the struc-
Scheme 3
tures of the compounds 3/4 have been confirmed by 1H and 13
C
NMR spectroscopy after purification by flash chromatography (see
the Supporting Information).
As mentioned earlier, the carboalkoxylation product 4{1}
from 2{1} and 1,2-ethanediol was obtained in a 74% yield
(Table 3, entry 1). The carbomethoxylation of 2{1} using methyl
alcohol afforded the corresponding methyl ester in a 73% yield,
but required a much longer reaction time (Table 3, entry 2). Use
of a longer alkyl chain-containing monoalcohol, 1-pentanol,
produced a 38% yield of the corresponding coupling product
4{3}, which was also accompanied by the cyclized lactone 3{1}
in a 35% yield (Table 3, entry 3). The carboalkoxylation of 2{1}
using phenol afforded the desired product 4{4} but in a some-
what lower yield, and this reaction required a longer reaction time
(Table 3, entry 4). Similarly, using benzyl alcohol, the desired
product 4{5} was isolated in a 36% yield (Table 3, entry 5).
Unfortunately, the product 4{6} could not be isolated upon
treatment with 1,4-cyclohexanediol (Table 3, entry 6). Only a
small amount of the cyclized byproduct 3{1} was observed.
We have also examined the effect of different alkyl-containing
3-iodofurans 2{1À4} on the intramolecular cyclocarbonylation/
lactonization process (Table 3, entries 7À10). 3-Iodofuran-
containing alcohol 2{1} gave the fastest lactonization, reaching
Scheme 4
Scheme 5
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Table 3. Intramolecular Cyclocarbonylation to 3 and Intermolecular Carboalkoxylation to 4a
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Table 3. Continued
a Representative procedures: (i) Intramolecular cyclocarbonylation. The 3-iodofuran 2 (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. (ii) Intermolecular carboalkoxylation. The 3-iodofuran 2 (0.20 mmol), 10 mol % Pd(OAc)2, 20 mol % PCy3, TEA
(0.80 mmol), and R4OH (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 All yields are isolated yields after column chromatography. The desired products 3 and/
1
c
or 4 have been characterized by H and 13C NMR spectroscopy. 10.0 equiv of the desired alcohol were used. d The cyclized byproduct 3{1} was
observed in 35% yield. e None of the desired carboalkoxylation product was observed. The starting material 2{1} decomposed. f Some starting material
remained. g The starting material remained. h An inseparable mixture was obtained.
completion in 9 h (Table 3, entry 7). The longer chain containing
3-iodofuran 2{2} afforded a slightly lower yield of the desired
product 3{2} than 2{1} and some starting material 2{2}
remained (Table 3, entry 8). Unfortunately, none of the desired
products 3{3} and 3{4} could be obtained using longer reaction
times, when starting from 2{3} and 2{4} (Table 3, entries 9 and
10). Noteworthy is the fact that the formation of long chain-
containing 2{3} and 2{4} is more difficult than formation of 2{1}.
We next employed this chemistry on 3-iodofurans 2{8}, 2{9}, 2{10},
and 2{11} containing electron-donating substituents (Table 3, entries
11À22). Hydroxyl-containing 3-iodofurans bearing an electron-rich
methoxyphenyl ring, such as 2{8}, 2{9}, and 2{11}, smoothly
reacted by cyclocarbonylation to give the desired lactone pro-
ducts 3{5}, 3{6}, and 3{8}, respectively (Table 3; entries 11, 17,
and 21). As predicted, the long chain-containing 3-iodofuran
2{10} provided only a trace of 3{7}, and the reaction suffered
from low conversion (Table 3, entry 19). The products 4{7À14}
have been produced in modest yields by carboalkoxylation using
various alcohols, including methanol, 1,2-ethanediol, 1,3-propa-
nediol, 1,4-butanediol, and 1,5-pentanediol (Table 3; entries
12À16, 18, 20, and 22). 3-Iodofurans 2{12} and 2{13} bearing
electron-deficient aromatic rings have also provided the desired
intramolecular cyclization products (Table 3, entries 23 and 27)
and intermolecular carboalkoxylation products (Table 3, entries
24À26 and 28). Furthermore, both the thiophene-substituted
iodofuran 2{14} and the cyclohexenyl-substituted iodofuran
2{15} afforded the expected products in modest yields using
our standard procedures (Table 3, entries 29À33). The carbo-
nylation of 3-iodofuran 2{7} by both the intramolecular cyclo-
carbonylation and intermolecular carboalkoxylation processes
has been investigated (Table 3, entries 34À36). Compound 2{7}
cannot form the lactone-containing furan 3{13} because of the
ring strain (Table 3, entry 34). However, the carboalkoxylation of
2{7} with two different alcohols produced the desired products
4{22} and 4{23} (Table 3, entries 35 and 36). The intramolecular
cyclocarbonylation and intermolecular carboalkoxylation of the cyclo-
pentane-containing 3-iodofurans 2{16}, 2{17}, and 2{18} smoothly
proceeded to the desired products in modest yields (Table 3, entries
37À44). Aliphatic-substituted 3-iodofurans 2{19} and 2{20} have
also been employed in this chemistry. As expected, the desired
products were produced exclusively in near quantitative yields
(Table 3, entries 45À49).
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Scheme 6
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S
Supporting Information. Detailed experimental proce-
b
dures and characterization data for all new compounds and
copies of H and 13C NMR spectra. This material is available
1
free of charge via the Internet at http://pubs.acs.org.
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Corresponding Author
*E-mail: larock@iastate.edu. Phone: (515) 294-4660. Fax: (515)
294-0105.
Funding Sources
Financial support of this work was provided by the National
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