Regioselective copper-mediated synthesis of thieno[2,3- c ]pyrane-7-one, Indolo[2,3- c ]pyrane-1-one, and indolo[3,2- c ]pyrane-1-one

Article abstract of DOI:10.1021/jo201528u

In the presence of copper(I) iodide, heteroaromatic Β-iodo-α, Β-unsaturated carboxylic acid systems opposed to terminal alkyne afford selectively 6-endo-dig cyclization products via a tandem coupling oxacyclization reaction.

Full text of DOI:10.1021/jo201528u

ARTICLE
pubs.acs.org/joc
Regioselective Copper-Mediated Synthesis of Thieno[2,3-c]pyrane-
7-one, Indolo[2,3-c]pyrane-1-one, and Indolo[3,2-c]pyrane-1-one
Samuel Inack Ngi, Vincent Guilloteau, Mohamed Abarbri, and Jꢀer^ome Thibonnet*
Laboratoire de Physicochimie des Matꢀeriaux et des Biomolꢀecules, EA 4244, Facultꢀe des Sciences et Techniques de Tours,
Parc de Grandmont, 37200 Tours, France
S Supporting Information
b
ABSTRACT:
In the presence of copper(I) iodide, heteroaromatic β-iodo-α,β-unsaturated carboxylic acid systems opposed to terminal alkyne
afford selectively 6-endo-dig cyclization products via a tandem coupling oxacyclization reaction.
’ INTRODUCTION
in favor of the 6-endo-dig cyclization. We report here a valuable
synthetic extension of this method onto heterocyclic substrates
such as indole and thiophene bearing a β-iodo-α,β-unsaturated
carboxylic acid system.
Pyranones are an important class of molecules, and indeed these
lactones are structural subunits in a wide variety of naturally
occurring substances that have an extensive range of biological
and pharmacological uses as, for example, antibiotic,1a,b phytotoxic,1c
or antifungal agents.1dÀf This may also be said of indole and
thiophene moieties. Combining a pyranone structure with the latter
may lead to potentially bioactive molecules (Figure 1). Indeed
thieno[2,3-c]pyrane derivatives are considered to be tumor cell
growth inhibitors,2 while indolo[2,3-c]pyrane derivatives are known
to inhibit the hepatitis C virus NS5B polymerase.3
In this study, we focused on the synthesis of thieno[2,3-c]-
pyran-7-one (1), indolo[2,3-c]pyrane-1-one (3), and indolo-
[3,2-c]pyrane-1-one (4) from easily available β-iodo-α,β-unsa-
turated carboxylic acid systems (Figure 1). It is interesting to
note that 3 and 4 may constitute interesting precursors to β- and
γ-carbolinone alkaloids, respectively. β-Carbolinones act on the
central nervous system4 and are recognized as HeLa and HLE
cell inhibitors,5 while some γ-carbolinones are serotonin 5-HT3
receptor antagonists.4d A certain number of methods to access
these molecules have been reported in the literature. To the best
of our knowledge, compounds 3 and 4 can be accessed from
γ-cetoester cyclization,6 anhydride rearrangement,4a,b,7 metal-
catalyzed enyne cyclization,8 or metal-catalyzed coupling,9
while compounds 1 can be obtained via enyne cyclization,10
Sonogashira-like cross-coupling,2,11 or metal-catalyzed oxidative
condensation.9b
’ RESULTS AND DISCUSSION
Synthesis of Thieno[2,3-c]pyran-7-one. The previously
published process involved was 20 mol % of CuI with 2 equiv
of alkyne and the same amount of potassium carbonate for
1 equiv of 2-iodo benzoic acid in DMF at 55À60 °C.12 While the
use of the same process with 2-iodobenzoic acid led to a mixture
of phthalides and isocoumarines, the effect on commercially
available 3-iodo-thiophene-2-carboxylic acid opposed to pheny-
lacetylene as a reference system resulted in a single product. In
fact, we only obtained 6-endo-dig cyclization, whatever the alkyne
used. A study similar to that already reported13 performed on our
reference system brought us to the same conclusions. We found
that the best base was K2CO3 instead of Cs2CO3, NaOH, or
K3PO4, while the best copper salt was still CuI instead of CuCN,
CuBr, Cu2O, or CuBr2. The solvent of choice was still the DMF
or DMSO. On the other hand, the yield was satisfactory only
when we used at least 0.4 equiv of CuI instead of 0.2 equiv. Four
hours was required to achieve the reaction from 4 mmol of the
acid. Increasing the temperature to 100 °C did not improve yield
nor change the regiochemistry. Decreasing the temperature to
room temperature lowered the yields to traces. We were able to
react alkynes bearing electron-withdrawing groups (aryl, acetal)
or an electron-donating group (alkyl) with average isolated yields
without losing regioselectivity. Functional groups like malonyl
(Table 1, entry 3) or acetal (Table 1, entry 4) were well tolerated.
The results obtained are set out in Table 1.
We have recently published an easy and mild palladium-free
process for rapid access to isocoumarines from a β-iodo-α,
β-unsaturated carboxylic acid system (Scheme 1).12 Indeed, o-iodo-
substituted benzoic acid is able to undergo a tandem couplingÀ
heterocyclization sequence in the presence of copper(I) iodide and
an alkaline carbonate.
Although the transformation suffered from a lack of selectivity,
we obtained phthalide and isocoumarin mixtures with the balance
Received: July 22, 2011
Published: September 01, 2011
r
2011 American Chemical Society
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Figure 1. Pyranone and indole or thiophene fused cycles of interest.
and 13). Various other functional groups were well tolerated
whether directly connected to the triple bond or not (such as
alkenyl, dienyl, alkynyl, methoxyl, hydroxyl, malonyl, and even
ferrocenyl), providing average to good yields of only the corre-
sponding pyranones. Although the use in the case on indole and
thiophene of a diyne derived from diethylmalonate provided a
moderate yield (Table 1, entry 3 and Table 3, entry 11), only one
alkynyl function was used. Only traces of the double coupling of
the alkyne were detected in the case of indole. This alkyne
provided original indole which may afford a pentacyclic molecule
with expedient conditions. Inversion of the iodine and carboxylic
acid function positions had no effect on the selectivity or yields,
as can be seen in the case of the indole moiety.
The stereochemistry observed with aromatic and heteroaro-
matic substrates could be explained by the preferential formation
of the thermodynamic product in our conditions due to the
temperature and the structure of our starting materials. It is
accepted that Baldwin’s rules13 predict that 5-exo-dig and 6-endo-
dig cyclization are almost equally favorable, making selective
synthesis difficult in practice. In the case of 2-iodobenzoic acid,12
we obtained a mixture of isocoumarin and phthalides at an
average ratio of 70/30 in favor of 6-endo-dig cyclization, while
with the five-membered heterocyclic starting material the cycli-
zation was totally regioselective. Experiments performed at room
temperature in the case of 2-iodobenzoic acid and 3-iodothio-
phen-2-carboxylic acid showed the preferential formation of
products from the 5-exo-dig cyclization with 2-iodobenzoic acid,
while only traces were detected after 72 h with 2-iodothiophene
carboxylic acid. On the other hand, reactions performed at
110 °C with the same material afforded the 6-endo-dig cyclization
product and up to 10% of the regioisomer in the case of
2-iodobenzoic acid and only the thienopyranone in the case of
2-iodothiophene carboxylic acid. This indicates that the 5-exo-dig
product is actually the kinetic product but is not favorable in the
case of 2-iodothiophene carboxylic acid, probably due to the
structure of the latter substrate. Indeed, it appears that building a
five-membered cycle over another five-membered cycle is more
unfavorable than building the same cycle over a six-membered
cycle. Moreover, the pH of the medium has no effect on the
regiochemistry of the cyclization. According to Rao and Saka-
moto et al.,14 if we consider an enyne intermediate, the regio-
chemistry of the cyclization may be influenced by the pH of the
medium. A basic medium may lead to the 5-exo-dig product,
Scheme 1. Copper-Catalyzed Preparation of Isocoumarins
Synthesis of Indolo[2,3-c]pyrane-1-one and Indolo[3,2-c]-
pyrane-1-one. To achieve our aims, 2a and 2b were synthesized
in good yields from the corresponding commercial indoles
(Scheme 2). Indole 2a was obtained in four steps from (1H)-
indole-2-carboxylic acid. After esterification of the starting indole
and halogenation of the ester with N-chlorosuccinimide/sodium
iodide (NCS/NaI) in DMF, the resulting indole was reacted with
benzylbromide and saponified into 2a in good yields. It was
impossible to obtain indole 2b in the same way. Methylindole-
3-carboxylate was benzylated prior to halogenation and saponi-
fication. The NCS/NaI system in DMF was unable to halogenate
position 2 of the indole. Treatment with t-BuLi and molecular
iodine permitted us to achieve our goals in good yields, while
n-BuLi and s-BuLi led to moderate or poor yields.
The conditions used with 3-iodothiophene carboxylic or
2-iodobenzoic acid12 could not be applied to indole derivatives.
With 2a and phenylacetylene as reference system, only traces of
cyclization product were detected with 0.2À0.4 equiv of CuI at
60 °C (Table 2, entries 3 and 4). Increasing the temperature to
100 °C with the same amount of copper iodide afforded only 5%
yield (Table 2, entry 5). The best result was obtained when using
1 equiv of CuI at 120 °C for about 12À14 h for 2 mmol of acid
(Table 2, entries 6 and 7). As with thiophene acid, we obtained
only 6-endo-dig cyclization. Assays using indole 2b provided the
same type of transformation. Various alkynes were used to inves-
tigate the scope of these reaction conditions. The results obtained
from 2a and 2b are summarized in Table 3. In addition, a study
similar to that performed for the thiophene moiety about the
copper source, the base, and the solvent gave the same conclusions.
Various alkynes bearing electron-withdrawing groups (aryl,
pyridinyl, thiophenyl) or an electron-donating group (alkyl)
were reacted with good yields on average. In contrast to non-
aromatic starting materials,12 the presence of an electron-donating
group on the terminal alkyne did not affect the regioselectivity of
the couplingÀoxacyclization process at all (Table 3, entries 7, 12,
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Table 1. Scope of Copper-Catalyzed Preparation of Thieno[2,3-c]pyran-7-one
Scheme 2. Preparation of Iodo-indole Carboxylic Acids 2a and 2b
Table 2. Optimization of Indolo[2,3-c]pyrane-1-one
Preparation
In the case of indoles, difficulties revealed in the transforma-
tion regarding the amount of catalyst may have resulted from
trapping of the copper by the nitrogen, making the metal
unavailable for the transformation and thus slowing the reaction.
This reactivity was greatly decreased when indole was reacted
unprotected. Assays with indole 2c (Scheme 3), obtained follow-
ing the method used by Merour et al.,15 led to full recovery of the
starting material. Similar results were obtained while unsuccess-
fully trying to couple alkynes bearing primary, secondary, and
tertiary amine function on nonaromatic and aromatic substrates.
On the other hand, Gaussian16 was employed to optimize and
visualize the 3D conformation of selected molecules presented
herein. For each studied compound, a DFT calculation was
performed using the B3LYP-DZVP basic set to compare xyz
coordinates for each atom in generated compounds. From this
work, we observed that the oxygens of the carboxylate group on
2a were oriented away from the halogen (or the triple bond) with
the comparisons of dihedral angles (Table 4). We consider this
was also a cause of the lengthening of the reaction time and
increase in temperature when compared with 2-iodobenzoic or
3-iodothiophene-2-carboxylic acid starting materials where the
carboxylate function is in the sameplane asiodine (or triple bond).
Although the mechanism of this reaction has not yet been fully
elucidated, we propose it could take place through the formation
of copper carboxylate 1 (Figure 2) followed by the oxidative
insertion of the copper in the carbon iodide bond, creating a
copper(III) intermediate 2. This intermediate, which reminds of
the CuTC structure used in Ullmann biaryl coupling,17 would
then allow the insertion of the alkyne followed by 6-endo-dig
entry
CuI (equiv)
T (°C)
yield %
1
2
3
4
5
6
7
0.2
0.4
0.2
0.4
0.4
1
20
20
0
0
60
traces
traces
5
60
100
100
120
30
1
40
while an acidic medium should yield 6-endo-dig. In our study, we
worked under basic conditions but obtained only 6-endo-dig
cyclization. This evidence points to the crucial role of the
thermodynamic control on the regiochemistry of the cycliza-
tion, instead of pH or the nature of the alkyne substituent.
As previously reported,12 the presence of the copper salt and
the base are also very critical; indeed, starting materials were
fully recovered after assays performed between 3-iodothiophene-
2-carboxylic acid and phenylacetylene without copper or
potassium carbonate.
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Table 3. Scope of Copper-Mediated Preparation of Indolo[2,3-c]pyrane-1-one and Indolo[3,2-c]pyrane-1-one
cyclization and reductive elimination. Copper(I) would be
regenerated after hydrolysis of the CÀCu bond of intermediate
5 by water released after the formation of the carboxylate with
potassium carbonate.
these structures from aromatic and heteroaromatic substrates
containing a β-iodo-α,β-unsaturated acid moiety. We were able
to prepare several variously substituted thiophene and indole
derivatives in average to good yields. The reactions were mild in
the case of 2-iodo-thiophenecarboxylic acid and needed high
temperatures and stoichiometric amounts of copper(I) in the case
of an indole starting material. This approach constitutes a cheap
alternativetotheexpensivepalladium cross-coupling generally used
to access this kind of molecule and to be sure to obtain β- and
γ-carbolinones at the same time.
’ CONCLUSION
In summary, we describe a copper-mediated regioselective route
to original thieno[2,3-c]pyrane-7-one, indolo[2,3-c]pyrane-1-ones,
and indolo[3,2-c]pyrane-1-ones. The reactions were very versatile
and constitute an effective methodology for the preparation of
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1
’ EXPERIMENTAL SECTION
2939, 1736. H NMR (300 MHz, CDCl3): 1.18 (t, 6H, J = 7.0), 3.10
(d, 2H, J = 7.5), 3.84 (t, 1H, J = 7.5), 4.00À4.20 (m, 4H), 6.51 (s, 1H),
7.07 (d, 1H, J = 5.1), 7.77 (d, 1H, J = 5.1). 13C NMR (75 MHz, CDCl3):
13.9, 32.6, 49.6, 61.9, 102.4, 122.6, 124.4, 136.9, 147.0, 156.0, 158.5,
168.1. LRMS (ESI) 325 (M+H). HRMS (ESI): Anal. calcd for C15H16O6S
(M+H) 325.0740, found 325.0753.
5-(Diethoxymethyl)thieno[2,3-c]pyran-7(7H)-one (1d). Yield:
59%; light yellow solid. Mp: 56À58 °C. IR (KBr): 3085, 2978, 2929, 2895,
1763, 1714, 1633. 1H NMR (300 MHz, CDCl3): 1.23 (t, 6H, J = 7.0), 3.62
(q, 2H, J=7.5), 3.68 (q, 2H, J= 7.5), 5.24 (s, 1H), 6.90 (s, 1H), 7.17 (d, 1H,
J = 5.5), 7.81 (d, 1H, J =5.5). 13CNMR (75 MHz, CDCl3): 15.2, 62.5, 97.7,
101.1, 123.8, 124.9, 136.8, 146.4, 155.7, 158.1. LRMS (ESI) 255 (M+H),
277 (M+Na). HRMS (ESI): Anal. calcd for C12H14O4S (M+H) 255.0613,
found 255.0615.
Synthesis of 1-Benzyl-3-iodo-indole-2(1H)-carboxylic Acid
(2a). 2a was synthesized in four steps from indole-2-carboxylate. In a
round-bottomed flask fitted with a condenser and containing 20 g of
indole-2(1H)-carboxylic acid (124 mmol, 1 equiv) are added 200 mL of
absolute ethanol and a few drops of concentrated sulfuric acid. The
mixture is refluxed for 24 h. The ethanol is removed under vacuum, and
the residue is dissolved in 200 mL of Et2O. The mixture is washed
successively with NaHCO3 (3 Â 40 mL), brine (40 mL), and water (2 Â
40 mL). After treatment with MgSO4, the solvent was removed under
vacuum. The desired ester obtained in 89% yield was pure enough for
General Procedure for the Preparation of Thieno[2,3-c]-
pyrane-7-ones. A dry Schlenk tube equipped with a Teflon-coated
magnetic stirrer was charged with 1.4 g of K2CO3 (10 mmol, 2 equiv)
and 1.2 g of 3-iodothiophene carboxylic acid (5 mmol, 1 equiv).
Anhydrous DMF (20 mL) was added, and the suspension was stirred for
15 min. The mixture was evacuated cold for 10 min and backfilled with
Argon. After reaching room temperature, alkyne (10.0 mmol, 2 equiv)
was added, and finally 0.384 g of CuI (2.0 mmol, 0.2 equiv) was added.
The Schlenk tube was placed in an oil bath preheated at 65 °C for 4 h
stirring. The temperature inside the Schlenk tube should be between 55
and 60 °C. The reaction mixture was then allowed to reach room
temperature and was hydrolyzed at 0 °C with a saturated NH4Cl
aqueous solution (15 mL). Et2O (50 mL) was added in the Schlenk
tube, and the mixture was filtered over a Celite pad. The pad was washed
with additional Et2O (50 mL). The aqueous phase was removed, and the
organic layer was washed several times with water (6 Â 15 mL). The
organic layer was dried over MgSO4 and concentrated under vacuum.
The raw material obtained was purified by flash chromatography on
silica gel to give the desired thieno[2,3-c]pyrane-7-one.
5-Phenylthieno[2,3-c]pyran-7(7H)-one (1a). Yield: 65%; gray
solid. Mp: 121À123 °C. IR (KBr): 3120, 2923, 2846, 1848, 1728, 1710,
1607. 1H NMR (300 MHz, CDCl3): 7.12 (s, 1H), 7.24 (d, 1H, J = 5.1),
7.35À7.55 (m, 3H), 7.78À7.95 (m, 3H). 13C NMR (75 MHz, CDCl3):
99.2, 123.1, 124.8, 125.5, 129.0, 130.3, 132.0, 136.9, 147.6, 156.6, 158.5.
MS (70 eV, EI) m/z (%) = 228 (M+, 100), 201 (10), 200 (100), 172
(15), 171 (100), 151 (10), 95 (30), 77 (35). HRMS (ESI): Anal. calcd
for C13H8O2S (M+H) 229.0318, found 228.0317.
5-Pentylthieno[2,3-c]pyran-7(7H)-one (1b). Yield: 49%; light
yellow gum. IR (NaCl): 3084, 2955, 2928, 2859, 1720, 1626. 1H NMR
(300 MHz, CDCl3): 0.87 (t, 3H, J = 7.4), 1.27À1.35 (m, 4H),
1.60À1.76 (m, 2H), 2.52 (t, 2H, J = 7.4), 6.42 (s, 1H), 7.08 (d, 1H,
J = 5.1), 7.76 (d, 1H, J = 5.1). 13C NMR (75 MHz, CDCl3): 13.9, 22.4,
26.9, 31.6, 33.5, 100.5, 122.0, 124.2, 136.7, 147.7, 159.4, 161.1. LRMS
(ESI) 223 (M+H). HRMS (ESI): Anal. calcd for C12H14O2S (M+H)
223.0787, found 223.0789.
Diethyl 2-((7-oxothieno[2,3-c]pyran-5(7H)-yl)methyl)-
malonate (1c). Yield: 68%; orange gum. IR (NaCl): 3285, 2984,
Scheme 3. Assay of Copper-Mediated Reaction with Un-
protected Indole
Figure 2. Proposed mechanism for the tandem coupling oxacyclization
reaction.
Table 4. Comparison of Dihedral Angles of Different β-Iodo-α,β-unsaturated Carboxylic Acid Bearing Systems
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further reaction. The 1H NMR characteristics matched with those found
in the literature.18
In a two-necked round-bottomed flask is placed 16.44 g of methyl
indole-3-carboxylate (1.0 equiv, 62 mmol) dissolved in 50 mL of THF.
The solution is brought to À78 °C before the addition drop by drop of
47 mL of tBuLi (1.2 equiv, 1.6 M in hexanes). The temperature is then
set to À50 °C, and 17.32 g of iodine is rapidly added. The mixture is
allowed to reach room temperature and stirred for 2 h. The medium is
then hydrolyzed with a 10% aqueous solution of sodium thiosulfate until
discoloration. The organic phase is isolated and washed with water
(40 mL). After treatment with MgSO4, the organic phase is evaporated.
The methyl 2-iodo-indole-3(1H)-carboxylate is obtained pure after
recrystallization in methylene chloride.
Methyl-2-iodo-indole-3(1H)-carboxylate. Yield: 96%; light
yellow solid. Mp: 96À98 °C. IR (KBr): 3030, 2950, 1697, 1492, 1451,
1173. 1H NMR (300 MHz, CDCl3): 4.00 (s, 3H), 5.55 (s, 2H),
7.00À7.08 (m, 2H), 7.12À7.34 (m, 6H), 8.13À8.22 (m, 1H). 13C
NMR (75 MHz, CDCl3): 51.4, 60.5, 95.3, 110.7, 112.1, 121.8, 122.3,
123.4, 126.4, 127.2, 127.7, 127.9, 129.0, 136.0, 138.5. LRMS (ESI) 392
(M+H). HRMS (ESI): Anal. calcd for C10H8INO2 (M+H) 392.0069,
found 392.0069.
In a round-bottomed flask is placed 20.0 g of methyl 1-benzyl-2-iodo-
indole-3(1H)-carboxylate (1 equiv, 51.1 mmol), 80 mL of ethanol, and
63.1 mL of KOH (12% aq. sol., 3 equiv). The mixture is refluxed for 24 h.
Ethanol is removed, and the residue is acidified with HCl 1 M to pH 2.
The aqueous phase is extracted with Et2O (2 Â 30 mL). The organic
phase is washed with brine (20 mL) and water (20 mL), treated with
MgSO4, and evaporated under vacuum. 1-Benzyl-3-iodo-indole-2(1H)-
carboxylic acid (2a) is obtained pure after recrystallization in methylene
chloride.
In a three-necked round-bottomed flask, containing 16.74 g of
N-chlorosuccinimide (74 mmol, 1.2 equiv) and 100 mL of DMF is added
11.15 g of NaI (74 mmol, 1.2 equiv) in small portions. The mixture is
stirred for 30 min at room temperature. An amount of 11.75 g of
previously prepared ethyl indole-2-carboxylate (62 mmol, 1 equiv) is
then added drop by drop at 0 °C, and the mixture is stirred for 1 h at
room temperature. The medium is hydrolyzed by sodium thiosulfate
(10% aq Sol., 60 mL). An amount of 40 mL of water is then added, and
the mixture is stirred for 30 min. The precipitate formed is filtered and
washed with petroleum spirit and dried under vacuum. The ethyl
3-iodoindole-2(1H)-carboxylate obtained in 95% yield was pure enough
for further use. The analytical characteristics matched with those in the
literature.19
In a three-necked round-bottomed flask containing 19.55 g of ethyl
3-iodoindole-2(1H)-carboxylate (62 mmol, 1 equiv) in 80 mL of DMF is
gently added 2.73 g of sodium hydride (60% in oil, 68.2 mmol, 1.1 equiv)
at 0 °C. After the end of evolution of hydrogen, 9.39 mL of benzyl-
bromide (80.6 mmol, 1.3 equiv) is added drop by drop at 0 °C, and the
mixture is left for stirring for 2 h at room temperature. The medium is
hydrolyzed with 100 mL of water and extracted with ethyl acetate (2 Â
30 mL). After treatment of the organic phase with MgSO4, the solvent is
evaporated under vacuum. Ethyl 1-benzyl-3-iodo-indole-2(1H)-carbox-
ylate was obtained sufficiently pure for further reaction.
Ethyl-1-benzyl-3-iodo-indole-2(1H)-carboxylate. Yield: 97%;
light yellow solid. Mp: 139À139 °C. IR (KBr): 3062, 2980, 1701, 1610.
1H NMR (300 MHz, CDCl3): 1.43 (t, 3H, J = 7.1), 4.46 (q, 2H, J = 7.1),
5.86 (s, 2H), 7.20À7.50 (m, 8H), 7.64 (d, 1H, J = 7.9). MS (70 eV, EI)
m/z (%) = 405 (M•+, 65), 360 (10), 269 (15), 248 (5), 232 (20), 205
(20), 204 (40), 91 (100). HRMS (ESI): Anal. calcd for C18H16INO2
(M+H) 405.0226, found 405.0228.
In a round-bottomed flask is placed 25.11 g of ethyl 1-benzyl-3-iodo-
indole-2(1H)-carboxylate (1 equiv, 62 mmol), 80 mL of ethanol, and
76.5 mL of KOH (12% aq. sol., 3 equiv). The mixture is refluxed for 24 h.
Ethanol is removed, and the residue is acidified with HCl 1 M to pH 2.
The aqueous phase is extracted with Et2O (2 Â 30 mL). The organic
phase is washed with brine (20 mL) and water (20 mL), treated with
MgSO4, and evaporated under vacuum. The 1-benzyl-3-iodo-indole-
2(1H)-carboxylic acid (2a) is obtained pure after recrystallization in
methylene chloride.
1-Benzyl-3-iodo-indole-2(1H)-carboxylic acid (2a). Yield:
96%; light yellow solid. Mp: 202À203 °C. IR (KBr): 3200À2500,
3028, 1672, 1608, 1276, 742, 724. 1H NMR(300 MHz, CDCl3): 5.72 (s,
2H), 6.90 (dd, 2H, J = 1.2), 7.00À7.12 (m, 4H), 7.13À7.22 (m, 2H),
7.44 (d, 1H, J = 8.1). 13C NMR (75 MHz, CDCl3): 48.9, 67.6, 111.0,
121.5, 123.8, 126.0, 126.2, 127.1, 128.4, 129.2, 130.4, 138.0, 138.7, 162.7.
MS (70 eV, EI) m/z (%) = 377 (M•+, 29), 127 (10), 91 (100), 77 (5).
HRMS (ESI): Anal. calcd for C16H12INO2 (M+H) 377.9986, found
377.9990.
Synthesis of 1-Benzyl-3-iodo-indole-2(1H)-carboxylic acid
(2b). 2b was synthesized in three steps from methyl indole-3(1H)-
carboxylate. In a three-necked round-bottomed flask containing 19.53 g
of methyl indole-3(1H)-carboxylate (111.5 mmol, 1 equiv) in 80 mL of
DMF is gently added 4.90 g of sodium hydride (60% in oil, 122.65 mmol,
1.1 equiv) at 0 °C. After the end of evolution of hydrogen, 17.24 mL
of benzylbromide (144.95 mmol, 1.3 equiv) is added drop by drop at
0 °C, and the mixture is left for stirring for 2 h at room temperature.
The medium is hydrolyzed with 100 mL of water and extracted with ethyl
acetate (2 Â 75 mL). After treatment of the organic phase with MgSO4,
the solvent is evaporated under vacuum. Ethyl 1-benzyl-2-iodo-indole-
3(1H)-carboxylate obtained in 64% was sufficiently pure for further
reaction. The analytical characteristics matched with those found in the
literature.20
1-Benzyl-2-iodoindole-3(1H)-carboxylic Acid (2b). Yield:
93%; Light yellow solid. Mp: 226À228 °C. IR (KBr): 3200À2300,
1
1662, 1495, 1451, 1282, 1186. H NMR (300 MHz, CDCl3): 5.37
(s, 2H), 6.84À7.15 (m, 8H), 8.03À8.10 (m, 1H). 13C NMR (75 MHz,
CDCl3): 50.8, 94.9, 110.2, 112.1, 121.5, 121.6, 122.7, 126.0, 127.3, 127.6,
128.4, 135.7, 138.0, 165.7. MS (70 eV, EI) m/z (%) = 378 (M•+, 29), 360
(15), 204 (10), 127 (10), 91 (100), 77 (5). HRMS (ESI): Anal. calcd for
C16H12INO2 (M+H) 377.9986, found 377.9995.
General Procedure for the Preparation of Indolo Pyrane-
1-one. A dry Schlenk tube equipped with a Teflon-coated magnetic
stirrer was charged with 552 mg of K2CO3 (4 mmol, 2 equiv) and 750
mg of iodoindole carboxylic acid (2 mmol, 1 equiv). Anhydrous DMF
(15 mL) was added, and the suspension was stirred for 15 min. The
mixture was evacuated cold for 10 min and backfilled with Argon. After
reaching room temperature, alkyne (4.0 mmol, 2 equiv) was added and
finally 381 mg of CuI (2.0 mmol, 1 equiv). The Schlenk tube was placed
in an oil bath preheated at 126 °C for 48 h stirring. The temperature
inside the tube should be between 120 and 123 °C. The reaction mixture
was then allowed to reach room temperature and was hydrolyzed at 0 °C
with a saturated NH4Cl aquaeous solution (15 mL). Et2O (50 mL) was
added in the Schlenk tube, and the mixture was filtered over a Celite pad.
The pad was washed with additional Et2O (50 mL). The aqueous layer
was removed, and the organic layer was washed several times with water
(6 Â 15 mL). The organic phase was dried over MgSO4 and concen-
trated under vacuum. The raw material obtained was purified by flash
chromatography on silica gel to give the desired indolopyranones. In the
case of product 3j, 5 equiv of methoxypropargylic alkyne was used. In the
case of products 3g and 4a, 10 equiv of hexyne and heptyne was used.
9-Benzyl-3-phenylindolo[2,3-c]pyrane-1(9H)-one (3a). Yield:
40%; yellow solid. Mp: 160À161 °C. IR (KBr): 3025, 2939, 1716, 1616,
1605, 1526. 1H NMR (300 MHz, CDCl3): 5.97 (s, 2H), 7.20À7.53
(m, 12H), 7.92À8.00 (m, 3H). 13C NMR (75 MHz, CDCl3): 48.2, 97.3,
100.1, 111.6, 121.0, 121.4, 121.8, 125.1, 126.5, 127.2, 127.7, 128.3, 128.8,
129.0, 129.3, 132.7, 137.5, 141.2, 153.0, 156.8. MS (70 eV, EI) m/z(%) = 351
(M•+, 100), 260 (59), 232 (23), 204 (18), 105 (12), 91, 45, 77 (14). HRMS
(ESI): Anal. calcd for C24H17NO2 (M+H) 352.1332, found 352.1322.
8352
dx.doi.org/10.1021/jo201528u |J. Org. Chem. 2011, 76, 8347–8354

The Journal of Organic Chemistry
ARTICLE
9-Benzyl-3-o-tolylindolo[2,3-c]pyrane-1(9H)-one (3b). Yield:
40%; brown gum. IR (NaCl): 3063, 3031, 1714, 1544. 1H NMR (300 MHz,
CDCl3): 2.61 (s, 3H), 5.33 (s, 2H), 7.13À7.37 (m, 11H), 7.42 (s, 1H),
7.52À7.57 (m, 1H), 7.82À7.91 (m, 1H). 13C NMR (75 MHz, CDCl3):
21.1, 50.5, 87.1, 90.3, 98.2, 110.2, 120.4, 120.7, 123.0, 124.1, 125.7, 127.1,
127.6, 128.0, 129.0, 129.5, 131.5, 136.0, 136.7, 139.6. LRMS (ESI) 366
(M+H). HRMS (ESI): Anal. calcd for C25H19 NO2 (M+H) 365.1416,
found 365.1419.
9-Benzyl-3-p-tolylindolo[2,3-c]pyrane-1(9H)-one (3c). Yield:
60%; yellow solid. Mp: 184À185 °C. IR (KBr): 3087, 3061, 3032, 1696,
1615, 1515. 1H NMR (300 MHz, CDCl3): 2.43 (s, 3H), 5.97 (s, 2H),
7.22À7.33 (m, 8H), 7.38 (s, 1H), 7.46À7.54 (m, 2H), 7.83 (d, 2H, J =
8.2), 7.98 (d, 1H, J = 8.0). 13C NMR (75 MHz, CDCl3): 21.5, 48.2, 96.6,
111.6, 120.8, 121.2, 121.8, 125.0, 126.7, 127.2, 127.6, 128.2, 128.8, 129.6,
129.9, 137.5, 139.5, 141.1, 153.2, 156.9. MS (70 eV, EI) m/z (%) = 365
(M•+, 100), 274 (63), 246 (21), 218 (27), 119 (12), 91 (44), 65 (12).
HRMS (ESI): Anal. Calcd for C25H19NO2 (M+H) 366.1489, found
366.1485.
9-Benzyl-3-(pyridin-2-yl)indolo[2,3-c]pyrane-1(9H)-one (3d).
Yield: 75%; yellow solid. Mp: 183À184 °C. IR (KBr): 3033, 1717, 1616,
1582, 1526. 1H NMR (300 MHz, CDCl3): 5.98 (s, 2H), 7.23À7.35 (m,
7H), 7.48À7.51 (m, 2H), 7.83 (td, 1H, J = 7.7,1.7), 9.90À8.10 (m, 2H),
8.16 (s, 1H), 8.68 (dq, 1H, J = 4.7,0.8). 13C NMR (75 MHz, CDCl3): 48.2,
99.7, 111.6, 119.8, 121.7, 121.8, 122.1, 123.6, 126.3, 127.2, 127.7, 128.4,
128.8, 137.4, 141.2, 149.5, 150.0, 151.3, 156.4. MS (70 eV, EI) m/z (%) =
352 (M•+, 100), 261 (51), 233 (26), 204 (10), 106 (10), 91 (54), 78 (19).
HRMS (ESI): Anal. calcd for C23H16N2O2 (M+H) 353.1285, found
353.1273.
9-Benzyl-3-(thiophen-3-yl)indolo[2,3-c]pyrane-1(9H)-one
(3e). Yield: 69%; yellow solid. Mp: 177À179 °C. IR (KBr): 3102, 3032,
2932, 1693, 1612. 1H NMR (300 MHz, CDCl3): 5.91 (s, 2H), 7.19 (s,
1H), 7.24À7.32 (m, 6H), 7.39 (dd, 1H, J = 5.1, 3.0), 7.45À7.50 (m, 3H),
7.82 (dd, 1H, J = 3.0, 1.1), 7.92 (d, 1H, J = 8.0). 13C NMR (75 MHz,
CDCl3): 48.1, 96.9, 111.5, 120.5, 121.2, 121.6, 121.7, 122.7, 124.3, 126.4,
126.8, 127.2, 127.6, 128.2, 128.7, 134.8, 137.5, 141.0, 149.8, 156.5. MS
(70 eV, EI) m/z (%) = 357 (M•+, 92), 267 (18), 266 (100), 238 (34),
210 (11), 111 (24), 91 (50), 65 (12). HRMS (ESI): Anal. calcd for
C22H15NO2S (M+H) 358.0896, found 358.0887.
9-Benzyl-3-(ferrocenyl)indolo[2,3-c]pyrane-1(9H)-one (3f).
Yield: 70%; orange solid. Mp: 230À232 °C. IR (KBr): 3084, 3031, 1700,
1617, 1606. 1H NMR (300 MHz, CDCl3): 4.12 (s, 5H), 4.34 (s, 2H), 4.77
(s, 2H), 5.86 (s, 2H), 6.93 (s, 1H), 7.21 (s, 6H), 7.39 (s, 2H), 7.86 (d, 1H,
J = 8.0). 13C NMR (75 MHz, CDCl3): 47.9, 65.9, 69.7, 77.82, 95.1, 111.3,
119.8, 120.9, 121.1, 121.7, 126.9, 127.1, 127.4, 128.1, 128.6, 137.5, 141.0,
155.0, 157.0. MS (70 eV, EI) m/z (%) = 459 (M•+, 100), 368 (30), 340
(14), 274 (24), 91 (14). HRMS (ESI): Anal. calcd for C28H21FeNO2
(M+H) 460.0995, found 460.0900.
9-Benzyl-3-butylindolo[2,3-c]pyrane-1(9H)-one (3g). Yield:
79%; orange solid. Mp: 90À91 °C. IR (KBr): 3079, 3025, 1700, 1624,
1532. 1H NMR (300 MHz, CDCl3): 0.98 (t, 3H, J = 7.3), 1.44 (sext, 2H,
J = 7.4), 1.76 (q, 2H, J = 7.8), 2.65 (t, 2H, J = 7.5), 5.93 (s, 2H), 6.72
(s, 1H), 7.10À7.31 (m, 6H), 7.41À7.48 (m, 2H), 7.88 (d, 1H, J = 8.0).
13C NMR (75 MHz, CDCl3): 13.9, 22.3, 29.6, 33.4, 48.0, 98.2, 111.4,
120.2, 120.9, 121.3, 121.7, 126.5, 127.2, 127.6, 128.0, 128.7, 137.7, 141.0,
157.5, 157.8. LRMS (ESI) 332 (M+H), 370 (M+Na). HRMS (ESI):
Anal. calcd for C22H21NO2 (M+H) 332.1645, found 332.1650.
(E)-9-Benzyl-3-[2-(2,6,6-trimethylcyclohex-2-enyl)vinyl]-
indolo[2,3-c]pyrane-1(9H)-one (3h). Yield: 70%; orange solid.
Mp: 86À88 °C. IR (KBr): 3060, 3031, 1710, 1640, 1593. 1H NMR (300
MHz, CDCl3): 0.92 (s, 3H), 0.97 (s, 3H), 1.20À1.28 (m, 1H), 1.49À1.60
(m, 1H), 1.65 (d, 3H, J = 1.3), 2.02À2.12 (m, 2H), 2.30 (d, J = 9.5, 1H),
5.50 (bs, 1H), 5.92 (s, 2H), 6.12 (d, 1H, J = 15.4), 6.46 (dd, 1H, J = 15.4/
9.5), 6.76 (s, 1H), 7.24À7.30 (m, 6H), 7.45À7.53 (m, 2H), 7.87 (d, 1H,
J = 8.0). 13C NMR (75 MHz, CDCl3): 23.2, 23.2, 27.1, 28.1, 31.4, 32.8,
48.1, 54.8, 99.3, 111.5, 120.8, 121.2, 121.6, 121.8, 121.9, 123.3, 126.6, 127.2,
127.6, 128.1, 128.8, 133.3, 135.8, 137.6, 141.0, 152.0, 156.9. MS (70 eV, EI)
m/z (%) = 423 (M•+, 41), 368 (12), 367 (40), 331 (24), 301 (20), 289
(10), 288 (39), 91 (100). HRMS (ESI): Anal. calcd for C29H29NO2
(M+H) 424.2271, found 424.2279.
(E)-9-Benzyl-3-[2-(2,6,6-trimethylcyclohex-1-enyl)vinyl]-
indolo[2,3-c]pyrane-1(9H)-one (3i). Yield: 72%; dark brown solid.
1
Mp: 153À155 °C. IR (KBr): 3057, 3015, 1700, 1565. H NMR (300
MHz, CDCl3): 1.10 (s, 6H), 1.48À1.53 (m, 2H), 1.62À1.68 (m, 2H),
1.81 (s, 3H), 2.07 (t, 2H, J = 5.8), 5.92 (s, 2H), 6.13 (d, 1H, J = 15.9),
6,77 (s, 1H), 7.02 (d, 1H, J = 15.9), 7.25 (s, 6H), 7.42À7.50 (m, 2H),
7.87 (d, 1H, J = 7.9). 13C NMR (75 MHz, CDCl3): 19.3, 21.9, 29.1, 33.3,
34.4, 39.8, 48.1, 99.6, 111.5, 120.7, 121.2, 121.6, 121.8, 124.2, 126.7,
127.2, 127.6, 128.1, 128.7, 131.0, 131.5, 137.3, 137.6, 141.0, 152.4, 156.8.
LRMS (ESI) 424 (M+H), 446 (M+Na). HRMS (ESI): Anal. calcd for
C29H29NO2 (M+H) 424.2271, found 424.2275.
9-Benzyl-3-methoxyindolo[2,3-c]pyrane-1(9H)-one (3j).
Yield: 77%; colorless solid. Mp: 121À122 °C. IR (KBr): 3069, 1698,
1626, 1615, 1212, 1084. 1H NMR (300 MHz, CDCl3): 3.50 (s, 3H), 4.36
(d, 2H, J = 0.7), 5.90 (s, 2H), 7.00 (s, 1H), 7.20À7.32 (m, 6H), 7.45À7.50
(m, 2H), 7.90 (d, 1H, J = 8.0). 13C NMR (75 MHz, CDCl3): 48.0, 58.9,
71.0, 99.9, 111.5, 120.7, 121.3, 121.4, 121.7, 125.4, 127.1, 127.6, 128.1,
128.7, 137.4, 140.8, 152.3, 156.9. MS (70 eV, EI) m/z (%) = 319 (M•+,
68), 288 (27), 260 (8), 168 (11), 91 (100). HRMS (ESI): Anal. calcd for
C20H17NO3 (M+H) 320.1281, found 320.1276.
Diethyl-2-[(9-benzyl-1,9-dihydroindolo[2,3-c]pyrane-3-yl)-
methyl]-2-(prop-2-ynyl)malonate (3k). Yield: 30%; white solid.
Mp: 165À166 °C. IR (KBr): 3256, 1735, 1709, 1628. 1H NMR
(300 MHz, CDCl3): 1.31 (t, 6H, J = 7.1), 2.15 (t, 1H, J = 2.5), 2.87 (d, 2H,
J = 2.5), 3.44 (s, 2H), 4.25À4.37 (m, 4H), 5.89 (s, 2H), 6.90 (s, 1H),
7.01À7.34 (m, 6H), 7.40À7.50 (m, 2H), 7.89 (d, 1H, J = 8.0). 13C NMR
(75 MHz, CDCl3): 14.1, 22.9, 36.3, 48.1, 56.3, 62.3, 72.2, 79.0, 102.0,
111.5, 121.2, 121.3, 121.8, 125.6, 126.4, 127.1, 127.6, 128.1, 128.8, 137.5,
140.9, 151.2, 156.7, 169.3. MS (70 eV, EI) m/z (%) = 485 (M•+, 19), 441
(40), 368 (17), 367 (33), 294 (11), 288 (17), 91 (100). HRMS (ESI):
Anal. calcd for C29H27NO6 (M+H) 486.1911, found 486.1914.
5-Benzyl-3-pentylindolo[3,2-c]pyrane-1(5H)-one (4a). Yield:
76%; colorless solid. Mp: 123À125 °C. IR (KBr): 3155, 3034À2872,
1793, 1713, 1626, 1608. 1H NMR (300 MHz, CDCl3): 0.88 (t, 3H, J =
6.4), 1.27À1.35 (m, 4H), 1.65À1.80 (m, 2H), 2.57 (t, 2H, J = 7.9), 5.38
(s, 2H), 6.29 (s, 1H), 7.03À7.12 (m, 3H), 7.27À7.35 (m, 6H), 7.97À8.03
(m, 1H). 13C NMR (75 MHz, CDCl3): 14.1, 22.5, 27.1, 31.3, 34.6, 47.7,
92.7, 99.6, 109.9, 121.4, 122.8, 124.5, 126.3, 128.2, 129.2, 135.7, 138.4,
146.7, 160.2, 164.5. LRMS (ESI) 346 (M+H). HRMS (ESI): Anal. calcd
for C23H23NO2 (M+H) 346.1729, found 346.1736.
5-Benzyl-3-(3-hydroxypropyl)indolo[3,2-c]pyrane-1(5H)-
one (4b). Yield: 63%; orange solid. Mp: 149À151 °C. IR (KBr): 3413,
2930À2860, 1694, 1559. 1H NMR (300 MHz, CDCl3): 1.71 (bs, 1H),
1.92À2.05 (m, 2H), 2.73 (t, 2H, J = 7.3), 3.71 (t, 2H, J = 6.1), 5.38
(s, 2H), 6.36 (s, 1H), 7.03À7.10 (m, 2H), 7.23À7.39 (m, 6H),
8.18À8.26 (m, 1H). 13C NMR (75 MHz, CDCl3): 30.3, 31.0, 47.3,
61.7, 93.2, 99.7, 110.0, 121.4, 122.9, 124.5, 124.7, 126.4, 128.2, 129.2,
135.7, 138.5, 146.6, 160.2, 163.6. LRMS (ESI) 333 (M+H), 356 (M+Na),
372 (M+K). HRMS (ESI): Anal. calcd for C21H19NO3 (M+H) 333.1365,
found 333.1367.
5-Benzyl-3-(2-hydroxypropan-2-yl)indolo[3,2-c]pyrane-
1(5H)-one (4c). Yield: 58%; colorless solid. Mp: 156À158 °C. IR (KBr):
3590, 3449, 3110À2920, 1698, 1682. 1H NMR (300 MHz, CDCl3): 1.63
(s, 6H), 3.07 (bs, 1H), 5.29 (s, 2H), 6.80 (s, 1H), 7.01À7.07 (m, 2H),
7.25À7.37 (m, 6H), 8.19À8.25 (m, 1H). 13C NMR (75 MHz, CDCl3):
28.7, 47.1, 71.8, 89.7, 99.4, 110.0, 121.3, 122.8, 124.2, 124.7, 126.3, 128.1,
129.1, 135.5, 138.4, 146.5, 159.6, 168.4. LRMS (ESI) 333 (M+H). HRMS
(ESI): Anal. calcd for C21H19NO3 (M+H) 333.1365, found 333.1361.
8353
dx.doi.org/10.1021/jo201528u |J. Org. Chem. 2011, 76, 8347–8354

The Journal of Organic Chemistry
ARTICLE
’ ASSOCIATED CONTENT
(13) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(b) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.
(14) (a) Rao, Y. S.; Filler, R. Tetrahedron Lett. 1975, 1457.
(b) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.; Yonehara,
M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8, 5517.
(15) Chacun-Lefevre, L.; Joseph, B.; Merour, J.-Y. Synlett 2001, 848.
(16) Frisch, M. J. et al. Gaussian 09, revision B.01; Gaussian, Inc.:
Wallingford, CT, 2010.
Supporting Information. Copies of H NMR and 13C
1
S
b
NMR of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(17) (a) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997,
62, 2312. (b) Hassan, J.; Sꢀevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
(18) Sudhakara, A.; Jayadevappa, H.; Mahadevan, K. M.; Hulikal, V.
Synth. Commun. 2009, 39, 2506.
Corresponding Author
*Tel.: +33(2)47367041. Fax: +33(2)47367073. E-mail: jerome.
thibonnet@univ-tours.fr
(19) Poriel, C.; Lachia, M.; Wilson, C.; Davies, J. R.; Moody, C. J.
J. Org. Chem. 2007, 72, 2978.
’ ACKNOWLEDGMENT
(20) Melkonyan, F. S.; Karchava, A. V.; Yurovskaya, M. A. J. Org.
Chem. 2008, 73, 4275.
We thank the “Dꢀepartement d'analyses chimiques et mꢀedicale”
(Tours, France) and Dr. Johan Jacquemin for calculs and com-
parison of dihedral angles.
’ REFERENCES
(1) (a) Abraham, W. R.; Arfmann, H. A. Phytochemistry 1988,
27, 3310. (b) Barrero, A. F.; Oltra, J. E.; Herrador, M. M.; Sanchez,
J. F.; Quilez, J. F.; Rojas, F. J.; Reyes, J. F. Tetrahedron 1993, 49, 141.
(c) Sato, H.; Konoma, K.; Sakamura, S. Agric. Biol. Chem. 1981, 45, 1675.
(d) Simon, A.; Dunlop, R. W.; Ghisalberti, E. L.; Sivasithamparam, K.
Soil Biol. Biochem. 1988, 20, 263. (e) Claydon, N.; Asllan, M.; Hanson,
J. R.; Avent, A. G. Trans. Br. Mycol. Soc. 1987, 88, 503. (f) Culter, H. G.;
Cox, R. H.; Crumley, F. G.; Cole, P. O. Agric. Biol. Chem. 1986, 50, 2943.
(2) Queiroz, M.-J. R. P.; Calhelha, R. C.; Vale-Silva, L. A.; Pinto, E.;
S~ao-Jose, N. M. Eur. J. Med. Chem. 2009, 44, 1893.
(3) (a) Gopalsamy, A.; Lim, K.; Ciszewski, G.; Park, K.; Ellingboe,
J. W.; Bloom, J.; Insaf, S.; Upeslacis, J.; Mansour, T. S.; Krishnamurthy,
G.; Damarla, M.; Pyatski, Y.; Ho, D.; Howe, A. Y. M.; Orlowski, M.; Feld,
B.; O’Connell, J. J. Med. Chem. 2004, 47, 6603. (b) LaPorte, M. G.;
Draper, T. L.; Miller, L. E.; Blackledge, C. W.; Leister, L. K.; Amparo, E.;
Hussey, A. R.; Young, D. C.; Chunduru, S. K.; Benetatos, C. A.; Rhodes,
G.; Gopalsamy, A.; Herbertz, T.; Burns, C. J.; Condon, S. M. Bioorg. Med.
Chem. Lett. 2010, 20, 2968.
(4) (a) Mashelkar, U. C.; Usgaonkar, R. N. Indian J. Chem., Sect. B
1978, 16B, 782. (b) Mashelkar, U. C.; Thakur, P. A.; Walavalkar, K. V.
Indian J. Heterocycl. Chem. 1992, 1, 201. (c) Mali, R. S.; Manekar-Tilve,
A. Org. Prep. Proced. Int. 1994, 26, 573. (d) Shi, Z.; Cui, Y.; Jiao, N. Org.
Lett. 2010, 12, 2908.
(5) (a) Veale, C. A.; Damewood, J. R., Jr.; Steelman, G. B.; Bryant,
C.; Gomes, B.; Williams, J. J. Med. Chem. 1995, 38, 86.(b) Wang, S. PhD
Dissertation, Nanjing University, 2002.
(6) Freter, K. J. Org. Chem. 1972, 37, 2010.
(7) (a) Mashelkar, U. C.; Usgaonkar, R. N. Indian J. Chem., Sect. B
1979, 17B, 407. (b) Kita, Y.; Mohri, S.; Tsugoshi, T.; Maeda, H.;
Tamura, Y. Chem. Pharm. Bull. 1985, 33, 4723.
(8) (a) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (b)
Hellal, M.; Bourguignon, J.-J.; Bihel, F. J. J. Tetrahedron Lett. 2007,
49, 62.
(9) (a) Zhang, H.; Larock, R. C. J. Org. Chem. 2003, 68, 5132. (b)
Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74,
3478.
(10) Peuchmaur, M.; Lisowski, V.; Gandreuil, C.; Maillard, L. T.;
Martinez, J.; Hernandez, J.-F. J. Org. Chem. 2009, 74, 4158.
(11) (a) Raju, S.; Batchu, V. R.; Swamy, N. K.; Dev, R. V.; Babu,
J. M.; Kumar, P. R.; Mukkanti, K.; Pal, M. Tetrahedron Lett. 2005, 47, 83.
(b) Raju, S.; Batchu, V. R.; Swamy, N. K.; Dev, R. V.; Sreekanth, B. R.;
Babu, J. M.; Vyas, K.; Kumar, P. R.; Mukkanti, K.; Annamalai, P.; Pal, M.
Tetrahedron 2006, 62, 9554.
(12) Inack-Ngi, S.; Rahmani, R.; Commeiras, L.; Chouraqui, G.;
Thibonnet, J.; Duchene, A.; Abarbri, M.; Parrain, J.-L. Adv. Synth. Catal.
2009, 351, 779.
8354
dx.doi.org/10.1021/jo201528u |J. Org. Chem. 2011, 76, 8347–8354