Iodine/Palladium approaches to the synthesis of polyheterocyclic compounds

Article abstract of DOI:10.1021/jo902639f

Chemical Equation Represented A simple, straightforward strategy for the synthesis of polyheterocyclic compounds (PHCs) is reported, which involves iterative cycles of palladium-catalyzed Sonogashira coupling, followed by iodocyclization using I₂ or ICI. A variety of heterocyclic units, including benzofurans, benzothiophenes, indoles, and isocoumarins, can be efficiently incorporated under mild reaction conditions. In addition, variations of this strategy afford a variety of linked and fused PHCs.

Full text of DOI:10.1021/jo902639f

pubs.acs.org/joc
Iodine/Palladium Approaches to the Synthesis of Polyheterocyclic
Compounds
Saurabh Mehta and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received December 14, 2009
A simple, straightforward strategy for the synthesis of polyheterocyclic compounds (PHCs) is
reported, which involves iterative cycles of palladium-catalyzed Sonogashira coupling, followed by
iodocyclization using I2 or ICl. A variety of heterocyclic units, including benzofurans, benzothio-
phenes, indoles, and isocoumarins, can be efficiently incorporated under mild reaction conditions. In
addition, variations of this strategy afford a variety of linked and fused PHCs.
Introduction
dology (Scheme 1) for the synthesis of benzofurans,2
furans,3 benzothiophenes,4 thiophenes,5 benzopyrans,6 ben-
zoselenophenes,7 selenophenes,8 naphthols,9 indoles,10 qui-
nolines,11 isoquinolines,12 R-pyrones,13 isocoumarins,13
naphthalenes14 and polycyclic aromatics,15 isoxazoles,16
The iodocyclization of alkynes has emerged as an effi-
cient tool for the synthesis of important heterocycles
and carbocycles.1 We and others have utilized this metho-
(1) (a) Mehta, S.; Waldo, J. P.; Larock, R. C. J. Org. Chem. 2009, 74,
1141. (b) Larock, R. C. In Acetylene Chemistry. Chemistry, Biology, and
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1652 J. Org. Chem. 2010, 75, 1652–1658
Published on Web 02/03/2010
DOI: 10.1021/jo902639f
r
2010 American Chemical Society

Mehta and Larock
JOCArticle
SCHEME 1. Iodocyclization Reaction
transformations,28 the iodocyclization products are ideal
substrates for further functionalization and a rapid increase
in molecular diversity. These features prompted us to test the
applicability of this strategy for building more complex
systems containing multiple heterocyclic units. Polyhetero-
cyclic compounds (PHCs) of this type have found applica-
tions in biological29 as well as materials chemistry.30 We
here present several versatile synthetic strategies involving
iodocyclization and subsequent palladium-catalyzed trans-
formations for the synthesis of PHCs.
chromones,17 bicyclic β-lactams,18 cyclic carbonates,19
pyrroles,20 furopyridines,21 spiro[4.5]trienones,22 coumestrol
and coumestans,23 furanones,24 benzothiazine 1,1-dioxides,25
isochromenes,26 etc.27
Results and Discussion
The general scheme employed by us for polyheterocycle
synthesis involves the Sonogashira coupling31 of a function-
ally substituted haloarene with a functionalized alkyne
(Scheme 2). The alkyne is then subjected to iodocyclization,
and the resulting 3-iodoheterocycle is generally isolated in
good to excellent yields as reported previously. The resulting
iodine-containing heterocycle is then used as the starting
material for further iterative cycles of Sonogashira coupling
and iodocyclization to generate the desired polyheterocyclic
molecule.
In general, iodocyclization is a very efficient reaction,
proceeds under very mild reaction conditions, and exhibits
a very broad scope in terms of the functional group/
substituent compatibility. As iodine is known to be an excellent
handle for further elaboration through transition-metal-
catalyzed cross-couplings, especially palladium-catalyzed
(17) (a) Zhou, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2006,
71, 1626. (b) Likhar, P. R.; Subhas, M. S.; Roy, M.; Roy, S.; Kantam, M. L.
Helv. Chim. Acta 2008, 91, 259.
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Gonzalez, J.; Turos, E. J. Org. Chem. 1998, 63, 8898.
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Commun. 1998, 2207.
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Org. Lett. 2002, 4, 2409.
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Tang, B.-X.; Tang, D.-J.; Yu, Q.-F.; Zhang, Y.-H.; Liang, Y.; Zhong, P.; Li,
J.-H. Org. Lett. 2008, 10, 1063.
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(24) (a) Crone, B.; Kirsch, S. F. J. Org. Chem. 2007, 72, 5435. (b) Just,
Z. W.; Larock, R. C. J. Org. Chem. 2008, 73, 2662.
(25) Barange, D. K.; Batchu, V. R.; Gorja, D.; Pattabiraman, V. R.;
Tatini, L. K.; Babu, J. M.; Pal, M. Tetrahedron 2007, 63, 1775.
Repetitive cycles of Sonogashira coupling, followed by
iodocyclization, have proven quite efficient and lead to
PHCs bearing two or three linked heterocycles in moderate
to good yields. Representative heterocycles and the corre-
sponding intermediates prepared by this general strategy are
listed in Scheme 2. For preparation of the intermediate
alkynes, the usual Sonogashira coupling conditions have
been somewhat modified, as they have generally been per-
formed in DMF (see the Supporting Information). The
intermediate alkynes have generally been prepared in good
to excellent yields (Scheme 2). The iodocyclization reactions
have been performed using our previously published proce-
dures for the corresponding heterocycles.
Various 5- and 6-membered ring heterocycles linked
through different positions have been conveniently synthe-
sized by this general strategy. We believe that this basic
methodology can be extended to all other functional groups
and substituents that have previously been shown to undergo
facile iodocyclization.1-27 An interesting feature of this
approach is the fact that after starting the reaction sequence
using an o-haloarene, only one other type of building block,
namely a readily available functionalized terminal alkyne 5,
is required for polyheterocycle generation, and different
heterocyclic units can be successfully inserted at the desired
positions in the PHC by simply changing the sequence of
functionalized alkyne building blocks. The iterative nature
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SCHEME 2. Generation of Polyheterocyclic Compounds by the General Strategya
aConditions: All Sonogashira reactions were carried out on a 0.25-5.0 mmol scale, and the iodocyclization reactions were carried out on a 0.10-
4.0 mmol scale using I2 or ICl (see the Supporting Information).bThis compound was prepared from 4c by desilylation.
of this approach to linked PHCs lends itself well to the
automated synthesis of large heterocyclic sequences of vary-
ing complexity.32 The solubility issues in larger heterocyclic
systems should be resolved by adjusting the polarity of the
individual alkyne building blocks.
SCHEME 3. Simultaneous and Stepwise Diiodination
After successful implementation of this general strategy
for the efficient synthesis of PHCs, several variations in the
approach have been explored that further highlight the
versatility and scope of this methodology. First, iodocycliza-
tion can be carried out quite selectively affording a variety of
intermediates, which should prove quite versatile for further
elaboration (Scheme 3). For example, 2-silyl-3-alkynylben-
zothiophene derivative 6f can be converted to the benzothio-
phene-isocoumarin diheterocycle 11 in one step in excellent
yield or 6f can be very efficiently cyclized to the correspond-
ing silicon-containing iodoisocoumarin 10, allowing for
further selective functionalization and/or iodocyclization.
As noted previously, a variety of heterocyclic units are
readily accessible by this iodocyclization strategy. This app-
roach can be combined with other efficient transformations
to broaden the scope of the methodology and allow easy
access to heterocycles that are not presently accessible by
(32) Preliminary studies were performed to develop a one-pot procedure
for this Sonogashira/iodocyclization sequence. DCE, DCM, and DMF were
examined as the reaction solvents (single solvent or in combinations), and the
reactions were found to be relatively cleaner when performed in DCE.
However, at present additional work is necessary in order to find appropriate
reaction conditions for this potentially useful one-pot Sonogashira/iodocy-
clization sequence.
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SCHEME 4. Click Chemistry Followed by Iodo-desilylation
SCHEME 5. Double Sonogashira Coupling, Followed by Double Iodocyclization
SCHEME 6. Palladium-Catalyzed Ullmann Reaction
iodocyclization. For example, alkyne 12 has been subjected
to well-known click chemistry using benzyl azide, and the
desired triazole 13 was obtained in good yield (Scheme 4).33
Upon iodo-desilylation, the iodotriazole 14 was obtained,
providing avenues for the further introduction of hetero-
cycles using our Sonogashira coupling/iodocyclization
methodology or other coupling reactions, such as Suzuki-
Miyaura couplings.34
In an effort to synthesize fused polyheterocyclic compounds,
the benzothiophene derivative 4c was subjected to silyl-iodine
exchange (Scheme 5). The resulting 2,3-diiodobenzothiophene
(15) on double Sonogashira coupling with an appropriate
o-functionalized terminal alkyne, followed by double cycliza-
tion, quickly leads to a compound 17, having three linked
heterocyclic units and two iodine handles.
The diiodo compound 17 was then subjected to a
palladium-catalyzed Ullmann reaction leading to the
formation of fused heterocycle 18 (Scheme 6).35 Similar
fused heterocyclic systems have been shown to exhibit
interesting electronic and luminescent properties.36 This
approach can be conveniently extended to the synthesis of
symmetrical fused heterocycles as well. PHCs such as
these should prove useful as ligands in coordination and
organometallic chemistry.
The above variations in our basic strategy (Schemes 4
and 6) highlight the ability to couple our methodology with
other efficient methodologies to synthesize molecules with
diverse functionalities quickly and efficiently. In another
variation, the cyclization of 1,3-diynes has been explored.
Efficient examples of homo-1,3-diyne cyclization have been
reported (Scheme 7) previously by us and others.2b,3h,7a,13,37
In an effort to cover other functional groups and hetero-
atom-containing diynes, several additional 1,3-diynes have
been synthesized using our optimized Sonogashira condi-
tions (Scheme 8). The hetero-1,3-diynes were obtained in
only moderate yields as the cross-coupling suffers from for-
mation of homocoupling byproduct. Nonetheless, the homo-
and hetero-1,3-diynes were subjected to iodocyclization, and
SCHEME 7. Previously Reported Examples of 1,3-Diyne Cyclization
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SCHEME 8. Preparation of 1,3-Diynes
the two expected regioisomeric annulated products was
formed presumably due to the ring strain. Instead, the
reaction led to the corresponding carboxylic acid 38, whose
structure was confirmed by single crystal X-ray analysis, in
59% yield. Carboxylic acid formation probably happens
because of nucleophilic attack by the pivalate anion on the
initially formed acylpalladium intermediate, which leads to
the corresponding anhydride, followed by hydrolysis during
aqueous workup of the reaction mixture (Scheme 12).
On the other hand, the alkyne annulation of polyhetero-
cyclic compound 7b affords the fused ring heterocycle 39 in
52% yield (Scheme 13).41 The regioisomeric assignment is
based on X-ray crystallographic data. Such annulation
processes provide considerable scope in terms of the types
of heterocycles that can be included in different positions, the
ring size, etc., allowing one to introduce a wide variety of
heterocycles in desired positions.
SCHEME 9. Iodocyclization of Homo- and Hetero-1,3-diynes
the double-cyclized products 30-32 were obtained in good
to excellent yields (Scheme 9). Furthermore, in the case of
hetero-1,3-diyne 27, the reaction conditions were tuned to
achieve single or double cyclization (Scheme 10). Thus,
symmetrical, as well as unsymmetrical, bisheterocyclic units
with dihalide functionality are readily accessible using our
methodology. Recently, similar dihalo compounds have
been used as precursors for the synthesis of more complex
fused heterocycles exhibiting potential applications as or-
ganic field effect transistors (OFETs).38
As observed in all of the processes outlined above, the end
products contain iodine, an important handle for further
modifications. Thus, these heterocyclic iodides can either be
subjected to reductive hydrodehalogenation39 or they can be
used to introduce further diversity and polarity into the
molecules using conventional palladium-catalyzed transfor-
mations (Scheme 11), for example, Suzuki-Miyaura
couplings (Scheme 11, eqs 1 and 2) and Sonogashira alky-
nylation (Scheme 11, eq 3).
Conclusions
Several iodocyclization/palladium-catalyzed approaches
have been reported for the generation of linked and fused
polyheterocyclic compounds. The ability to quickly put
together multiple heterocyclic rings and accommodate var-
ious other subsequent transformations adds to the synthetic
utility and scope of the methodology, making this a very
practical approach for PHC synthesis. In some cases, the
potential exists for combinatorial automated synthesis. Con-
sidering the broad scope and considerable flexibility of this
methodology and the widespread potential applications of
the resulting products, rapid advances in this area of research
are anticipated.
Finally, palladium-catalyzed annulations have been exa-
mined in order to extend the scope of this methodology for
the generation of complex fused PHCs. For example, in an
attempt to perform the cyclocarbonylation reaction, bishe-
terocyclic compound 7b was subjected to our previously
published conditions (Scheme 12).40 However, neither of
Experimental Section
General Methods. The 1H NMR and 13C NMR spectra were
recorded at 25 °C at 300 or 400 MHz and 75 or 100 MHz,
SCHEME 10. Tuning of Reaction Conditions for Single or Double Cyclization
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SCHEME 11. Elaboration of the Iodine-Containing Products
SCHEME 12. Cyclocarbonylation Attempt
SCHEME 13. Alkyne Annulation Reaction Leading to a Fused
PHC
respectively, with Me4Si as an internal standard. The chemical
shifts (δ) and coupling constants (J) are given in ppm and Hz,
respectively. Thin-layer chromatography was performed using
commercially prepared 60-mesh silica gel plates and visualiza-
tion was effected with short wavelength UV light (254 nm).
Purification of the compounds has been performed by column
chromatography and/or recrystallization. All melting points are
uncorrected. HRMS data: the electron impact ionization experi-
ments were performed on a triple quadrupole mass spectrometer
fitted with a EI/CI ion source. The samples were introduced to
the mass spectrometer using a solids probe. The probe was
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JOCArticle
heated gradually from 100 to 400 °C. The instrument was used as
a single quadrupole and scanned from 50 to 1000 Da. Accurate
mass measurements were conducted using a manual peak
matching technique with the double focusing mass spectro-
meter. DCM was distilled over CaH2. Anhydrous MeCN and
DMF were used as received. All reagents were used directly as
obtained commercially unless otherwise noted.
General Procedure Used for the Sonogashira Coupling. To a
solution of haloarene starting material in DMF were added 3
mol % of PdCl2(PPh3)2 and 4 mol % of CuI. The reaction vial
was then sealed and flushed with argon. After the solution was
stirred for 5 min at room temperature, 4 equiv of DIPA was
added by syringe. The reaction mixture was then heated to
65 °C, a solution of the alkyne (1.2 equiv) in DMF (1 mL) was
added dropwise over 5-10 min, and the mixture was allowed to
stir at 65-80 °C for 2-3 h. After cooling, the reaction mixture
was diluted with EtOAc and washed with satd aq NH4Cl, water,
and brine. The combined organic extracts were dried over
MgSO4 and concentrated under vacuum to give the crude
product, which was purified by column chromatography on
silica gel using hexane-EtOAc as eluent.
General Procedure for Iodocyclization. To a solution of the
starting alkyne in DCM was added gradually the I2/ICl solution
(0.25 M) in DCM. The reaction mixture was allowed to stir at
25 °C, and the reaction was monitored by TLC for completion.
The excess I2 or ICl was removed by washing with satd aq
Na2S2O3. The mixture was then extracted by EtOAc or diethyl
ether. The combined organic layers were dried over anhydrous
MgSO4 and concentrated under vacuum to yield the crude
product, which was purified by flash chromatography on silica
gel using hexane-EtOAc as the eluent or by recrystallization.
3-(2-(Benzo[b]thiophen-3-yl)-5-methoxybenzofuran-3-yl)-4-
iodo-1H-isocoumarin (9e). The product was obtained (yield =
1
71%) as a yellow solid: mp 148-151 °C; H NMR (400 MHz,
CDCl3) δ 3.91 (s, 3H), 6.98 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H),
7.38-7.47 (m, 3H), 7.61 (t, J = 7.2 Hz, 1H), 7.70 (s, 1H),
7.76-7.83 (m, 2H), 7.87 (d, J = 7.6 Hz, 1H), 8.31-8.33 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 56.0, 81.4, 96.2, 113.0, 113.6,
120.6, 120.7, 121.0, 122.9, 124.1, 125.1, 125.2, 126.3, 127.7, 129.9,
130.1, 131.5, 135.9, 136.9, 138.0, 140.2, 149.6, 150.8, 155.0, 158.9,
161.9; HRMS calcd for C26H15IO4S 549.97359, found 549.97467.
Acknowledgment. We gratefully acknowledge the Na-
tional Institute of General Medical Sciences (GM070620
and GM079593) and the National Institutes of Health Kan-
sas University Center of Excellence for Chemical Methodol-
ogies andLibrary Development (P50GM069663) for support
of this research. We also thank Dr. Arkady Ellern and the
Molecular Structure Laboratory of Iowa State University for
providing X-raycrystallographic data forproducts38 and 39.
We also thank Dr. Shu Xu (Instrument Services) for his help
with NMR experiments. Thanks are also extended to John-
son Matthey, Inc., and Kawaken Fine Chemicals Co. for
donating the palladium catalysts and Frontier Scientific and
Synthonix for donating the boronic acids.
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Supporting Information Available: General experimental
methods, reaction procedures, characterization data, copies of 1H
and 13C NMR spectra for previously unreported compounds and
X-ray crystallographic data for compounds 38 and 39.Thismaterial
is available free of charge via the Internet at http://pubs.acs.org.
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1658 J. Org. Chem. Vol. 75, No. 5, 2010