Synthesis of Polysubstituted 2-Iodoindenes via Iodonium-Induced Cyclization of Arylallenes

Article abstract of DOI:10.1021/acs.orglett.5b03634

A new chemoselective iodocarbocyclization of allenyl arenes was developed leading to the formation of 2-iodoindenes. In acetonitrile or nitromethane, electrophilic sources of iodine cations react selectively with the C₂-C₃ double bond of 1-arylallenes to give, after anti nucleophilic attack of the aromatic ring, 2-iodoindene products in high yields. Variations of the allenic skeletons revealed the high 5-endo selectivity and some competitive pathways of cyclization. Postfunctionalization reactions of the carbon-iodine bond, via Pd- and Cu-cross-couplings, gave rise to substituted indenes in good to excellent yields. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b03634

Letter
pubs.acs.org/OrgLett
Synthesis of Polysubstituted 2‑Iodoindenes via Iodonium-Induced
Cyclization of Arylallenes
Charlotte Grandclaudon, Veronique Michelet,* and Patrick Y. Toullec*,†
́
PSL Research University, Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, F-75005 Paris, France
S
* Supporting Information
ABSTRACT: A new chemoselective iodocarbocyclization of allenyl arenes
was developed leading to the formation of 2-iodoindenes. In acetonitrile or
nitromethane, electrophilic sources of iodine cations react selectively with
the C2−C3 double bond of 1-arylallenes to give, after anti nucleophilic attack
of the aromatic ring, 2-iodoindene products in high yields. Variations of the
allenic skeletons revealed the high 5-endo selectivity and some competitive
pathways of cyclization. Postfunctionalization reactions of the carbon−
iodine bond, via Pd- and Cu-cross-couplings, gave rise to substituted indenes in good to excellent yields.
olysubstituted indene derivatives are an important class of
compounds which is found in a number of biologically
Scheme 1. Approaches to 2-Iodoindenes
P
active molecules.1 This structural unit also serves as building
blocks for the synthesis of optoelectronic devices in material
sciences2 and as ligand precursors in homogeneous catalysis.3
Considering the interest for this scaffold and the need for
synthetic methodologies enabling the introduction of sub-
stituent diversity upon postfunctionalization, some effort has
been devoted to the synthesis of 2- and 3-haloindenes.4−7
Among the various routes developed, the strategies based on
the electrophilic activation of a C−C unsaturation followed by
the intramolecular attack of a carbon nucleophile play a pivotal
role as they allow the formation of complex, polysubstituted
structures from simple precursors in one step using an efficient
and atom-economical protocol.8 So far, much attention has
been paid to methodologies involving the activation of an
alkyne function either in the presence of protic5 or halogen6
electrophiles delivering the 3-iodoindene isomer. More
recently, methodologies involving iodonium-induced activation
of propargylic alcohol substrates have offered the opportunity
to synthesize functionalized 2-iodoindenyl products via a
tandem reaction7 in the presence of a second nucleophile
(Scheme 1, eq 1). The mechanism of such transformations
involves the initial formation of a propargylic carbocation A
upon reaction between an electrophilic iodine reagent or boron
trifluoride diethyl etherate and the propargylic alcohol
substrate. Isomerization of A to the allenyl cation B followed
by nucleophilic addition of a variety of nucleophiles including
halides,7a,c esters,7d and sulfonamides,7b,e delivers the arylallene
C. Formation of an iodonium ion D upon further reaction of C
with a second equivalent of cationic iodine atom followed by
anti 5-endo nucleophilic attack of the aryl group gives the
functionalized 2-iodoindene 2. Considering the versatility of the
carbocyclization reactions promoted by halogen electrophiles9
and prior reports in the literature illustrating the possibility to
activate allene unsaturations with halogen electrophiles toward
anti nucleophilic arylation reactions,10 we decided to investigate
the formation of 2-iodoindenes 4 using an unprecedented
methodology based on the electrophilic iodocarbocyclization of
tri- and tetrasubstituted arylallenes11 3 (Scheme 1, eq 2).
Based on these considerations, the iodocarbocyclization of
3a, which possesses a phenyl substituent, was investigated in
the presence of an iodonium source using a variety of
conditions. Results are reported in Table 1. Treatment of the
allene 3a with N-iodosuccinimide 6a in dichloromethane at
room temperature provided a mixture of the desired cyclized
iodoindene 4a along with the undesired 2-iodo-1,3-diene 5a in
24% and 72% yields respectively (entry 1). When the reaction
was performed in toluene, a lower conversion of 3a (77%) and
the exclusive formation of the diene 5a were monitored (entry
2). Interestingly, using polar solvents such as nitromethane and
acetonitrile, a reversal of selectivity was observed, leading to the
formation of the halogenated indene product 4a in 69% and
74% respectively (entries 3−4). In contrast, the use of DMF as
Received: December 22, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b03634
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a
Table 1. Optimization of Reaction Conditions
Scheme 2. Synthesis of Arylallenes 3
groups. Modifications on R3/R4 positions were also performed,
as exemplified by the synthesis of 3h−l.
We then studied the scope of the iodocarbocyclization under
the optimized conditions. The reaction proceeded in good
yields for a large spectrum of primary and secondary alkyl
substituents on position 1 (Scheme 3, products 4a−f). The
a
All reactions were run under the following conditions, unless
otherwise indicated: 0.1 mmol of 3a, 0.12 mmol of the halogen source
6 were placed in a tube with 1 mL of solvent at room temperature for
5 min. The reaction mixture is then treated with 1 mL of aq saturated
b
Na2S2O3. Yields were determined by 1H NMR using acenaphthene as
a standard. 77% conversion. Reaction run at −30 °C. Degradation
of 3a. 1 equiv instead of 1.2 equiv of 6a was used.
Scheme 3. Substrate Scope of the Iodonium-Induced
Carbocyclization of Arylallenes 3a−l
c
d
e
f
solvent gave only trace amounts of 4a and 58% of the diene 5a
(entry 5). Decreasing the temperature had a detrimental effect
on the yield of the cyclized product (entry 6). Other sources of
electrophilic iodine were also tested: when employing I2, only
degradation was observed (entry 7), whereas, in the presence of
the diiodohydantoin 6b, a good yield of the iodoindene (69%)
4a was obtained (entry 8). The concentration of the substrate
did not show any significant impact on the yield or selectivity of
the transformation (entries 9, 10). Finally, diminishing the
quantity of halogenating agent 6a resulted in a slightly lower
yield (entry 11).
We prepared a set of variously substituted arylallenes by a
two-step methodology starting from terminal alkynes (Scheme
2). Formation of propargylic alcohols 7 occurred upon
nucleophilic attack of the alkynyl lithium intermediates on
carbonyl derivatives. Introduction of the aryl substituent was
conducted via a Li2CuCl4-catalyzed SN2′ attack of aryl or
heteroaryl Grignard reagents on the in situ formed mesylates
derived from 7.12 Variation of the allenyl skeleton was
envisaged on the 4 positions, starting from R1. Alkyl as well
as functionalized alkyl groups were tolerated during the starting
material preparation process and led to 3a−d, 3f, 3g, and 3o−r
in good yields (see Supporting Information). In order to
evaluate the influence of the substitution on the aromatic
moiety during the cyclization process, we prepared several
diaryl-functionalized allenes 3t−w, bearing electron-withdraw-
ing and electron-donating groups. Considering the importance
of organofluorine and heterocycle compounds in various areas
including pharmaceuticals and agrochemicals, we prepared 3e,
3m, and 3n bearing fluoroaryl, pyridinyl, and thiophenyl
formation of the 2-iodo-1,3-diene byproduct 5 was only
observed in the case of substrates 3a, 3e, and 3f (14% and
5% yield for 5e and 5f respectively). The presence of an
electron-withdrawing halogen atom on the aromatic ring
nucleophile had a negative influence on the yield (83%, 77%,
and 61% products 4d, 4f, and 4e respectively). Cyclization of
allenes bearing an aromatic heterocycle hardly occurred; we
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observed only decomposition of substrates 3m under the
reaction conditions, and only traces of 4n could be monitored
in the case of thienylallene 3n. The variation of the substitution
pattern on the 3 position of the allene (R3 and R4 groups) was
also studied. With a substrate bearing a tetrahydropyranyl
substituent instead of the dimethyl group, the reaction provided
the spirocycle 4h in 67% yield. The allene 3i with a methyl-
cyclopropyl combination of substituents was cleanly converted
to 4i in good yield (74%). The reaction also took place for
substrates bearing a single substituent on position 3 (alkyl or
aryl); the cyclized products 4j and 4k were isolated in 77% and
66% yields, respectively. Finally, the terminal allene 3l was also
submitted to the intramolecular iodocyclization conditions.
Decomposition was observed in this case, the 2-iodoindene 4l
being isolated with a very low yield.
regioselectivity in favor of the 2-iodoindenes 4v′ and 4w′
resulting from the attack of the more electron-rich aryl moiety
was observed in both cases. Very interestingly, substrate 3r also
cleanly reacted via a 5-endo attack of the phenyl nucleophile to
give the iodoindene 4r, whereas the competitive 5-exo
cyclization of the electron-rich trimethoxyaniline nucleophile
to give the iodovinylindoline 9 was not observed (Scheme 4, eq
3). Based on the experimental evidence, we proposed a
mechanism for the formation of 4a and 5a, involving the initial
formation of an iodonium cation upon reaction between the
cationic iodine atom and a carbon−carbon double bond of the
allene 3a. Depending on the reaction conditions used,
iodonium E and F may be formed (Scheme 5). Anti
Scheme 5. Postulated Mechanism
To further investigate the scope of this reaction, we decided
to study the iodocyclization of arylallene substrates bearing a
second nucleophile able to react via a 5-endo mode of
cyclization. In the case of substrates 3o−q, exclusive formation
of the 3-iododihydrofurane 8, resulting from the attack of the
oxygen nucleophile, occurred in 54−70% yield, whereas the
corresponding iodoindenes 4o−q, resulting from the attack of
the phenyl nucleophile, could not be monitored (Scheme 4, eq
1).
Scheme 4. Regio- and Chemoselectivity Issues of the
Iodocarbocyclization of Arylallenes 3o−w
nucleophilic attack of the phenyl group on iodonium E delivers
the cyclized 2-iodoindene 4a, whereas proton elimination from
intermediate F leads to the formation of diene 5a. The
stereochemistry of 5a has been confirmed by a 2D NOE NMR
experiment.
The benefit of the 2-iodoindene scaffolds was finally
demonstrated by conducting relevant postfunctionalization
reactions on iododerivative 4u (Scheme 6).
Scheme 6. Derivatization of 4u
The length of the tether between the allene function and the
oxygen nucleophile therefore had a crucial impact on the
chemoselectivity, as no product resulting from the attack of the
oxygen nucleophile was detected in the case of substrates 3a−c
and 3h−l. We also challenged the iodonium-induced cyclization
on 1,1-diarylallenes in order to evaluate the importance of the
nucleophilicity of the aromatic substituent on the course of the
reaction (Scheme 4, eq 2). In the case of the symmetric
diphenyl-substituted substrate 3s, the reaction proceeded with
an excellent yield of 95%. For substrates where the phenyl
group was placed in competition with an aromatic ring bearing
an electron-withdrawing substituent, the chemoselectivity was
excellent and only the products 4t and 4u resulting from the
attack of the phenyl ring was observed. When electron-donating
groups were placed in competition with the phenyl, a moderate
Halogen−metal exchange13 followed by trapping with an
aldehyde allowed the formation of the indene 10 bearing an
alcohol moiety in 61% yield. Palladium-catalyzed Sonogashira14
and Suzuki−Miyaura7c cross-couplings were performed, and
compounds 11 and 12 were isolated in 98% and 75% yields,
respectively. A copper-catalyzed C−N coupling15 involving
pyrrolidin-2-one enabled the formation of the indenylamide 13
in 55% yield.
In conclusion, a new and mild protocol for the synthesis of 2-
iodoindenes has been developed. In the presence of N-
iodosuccinimide, the iodonium-induced carbocyclization of a
wide set of functionalized allenes proceeded rapidly in good to
excellent yields, tolerating a wide range of substituents.
Variations of the allenic skeletons revealed the high 5-endo
selectivity and some competitive pathways of cyclization.
C
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2009, 36, 5406. (f) Zhou, F.; Han, X.; Lu, X. J. Org. Chem. 2011, 76,
1491. (g) Akbar, S.; Srinivasan, K. RSC Adv. 2015, 5, 5542.
(5) Saito, S.; Homma, M.; Gevorgyan, V.; Yamamoto, Y. Chem. Lett.
2000, 722.
Moreover, 2-iodoindene products can be used as key synthons
for the synthesis of substituted derivatives upon functionaliza-
tion of the reactive Csp −iodine bond.
2
(6) (a) Khan, Z. A.; Wirth, T. Org. Lett. 2009, 11, 229. (b) Sanz, R.;
Martínez, A.; García-García, P.; Fernandez-Rodríguez, M. A.; Rashid,
́
ASSOCIATED CONTENT
■
S
* Supporting Information
M. A.; Rodríguez, F. Chem. Commun. 2010, 46, 7427.
(7) (a) Zhu, H.-T.; Ji, K.-G.; Yang, F.; Wang, L.-J.; Zhao, S.-C.; Ali,
S.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2011, 13, 684. (b) Zhu, Y.; Yin,
G.; Hong, D.; Lu, P.; Wang, Y. Org. Lett. 2011, 13, 1024. (c) Zhou, C.;
Chen, X.; Lu, P.; Wang, Y. Tetrahedron 2012, 68, 2844. (d) Zhu, H.-
T.; Dong, X.; Wang, L.-J.; Zhong, M.-J.; Liu, X.-Y.; Liang, Y.-M. Chem.
Commun. 2012, 48, 10748. (e) Sun, L.; Zhu, Y.; Wang, J.; Lu, P.;
Wang, Y. Org. Lett. 2015, 17, 242.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03634.
Experimental procedures, characterization data and
spectra of new compounds (PDF)
(8) (a) Larock, R. C. In Acetylene Chemistry. Chemistry, Biology, and
Material Science; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.;
Wiley-VCH: New York, 2005; Chapter 2, pp 51−99. (b) Modern
Alkyne Chemistry, Trost, B. M., Li, C.-J., Eds.; Wiley-VCH: New York,
2015.
(9) For reviews, see: (a) Rousseau, G.; Homsi, F. Chem. Soc. Rev.
1997, 26, 453. (b) Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T.
Chem. Commun. 2009, 34, 5075. (c) Godoi, B.; Schumacher, R. F.;
Zeni, G. Chem. Rev. 2011, 111, 2937. (d) Palisse, A.; Kirsch, S. F. Org.
Biomol. Chem. 2012, 10, 8041. (e) Hummel, S.; Kirsch, S. F. Beilstein J.
Org. Chem. 2011, 7, 847.
(10) For examples of iodoarylation of allenes, see: (a) Barluenga, J.;
Campos-Gomez, E.; Minatti, A.; Rodriguez, D.; Gonzalez, J. M. Chem.
- Eur. J. 2009, 15, 8946. (b) Wang, M.; Li, J.; Fu, C.; Ma, S. Org. Lett.
2014, 16, 4976.
(11) For a single example of bromocarbocyclization of xanthenyl- and
thioxanthenylallenes, see: Abdul-Malik, N. F.; Awad, S. B.; Sakla, A. B.
Helv. Chim. Acta 1979, 62, 1872. No indication of yield for the
transformation is given in this publication.
AUTHOR INFORMATION
■
Corresponding Authors
*veronique.michelet@chimie-paristech.fr
*patrick.toullec@u-bordeaux.fr
Present Address
†Univ. Bordeaux, Institute of Molecular Sciences, UMR 5255,
F-33400 Talence, France.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the Centre National de la Recherche
Scientifique (CNRS) and the Minister
Recherche for financial support. C.G. is grateful to the Agence
Nationale de la Recherche (ANR-13-JS07-0010) for a PhD
grant. Dr. M.-N. Rager (Chimie ParisTech) is kindly acknowl-
edged for 2D NMR experiments on compound 5a.
̀
e de l’Education et de la
(12) Fouquet, G.; Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974, 13,
82.
(13) Nowrouzi, F.; Janetzko, J.; Batey, R. A. Org. Lett. 2010, 12, 5490.
(14) Barluenga, J.; Palomas, D.; Rubio, E.; Gonzal
2007, 9, 2823.
̀
ez, J. M. Org. Lett.
REFERENCES
■
(15) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003,
5, 3667.
(1) (a) Witiak, D. T.; Kakodkar, S. V.; Brunst, G. E.; Baldwin, J. R.;
Rahwan, R. G. J. Med. Chem. 1978, 21, 1313. (b) Korach, K. S.;
Metzler, M.; McLachlan, J. A. J. Biol. Chem. 1979, 254, 8963.
(c) Anstead, G. M.; Peterson, C. S.; Pinney, K. G.; Wilson, S. R.;
Katzenellenbogen, J. A. J. Med. Chem. 1990, 33, 2726. (d) Palm, J.;
Boegesoe, K. P.; Liljefors, T. J. Med. Chem. 1993, 36, 2878. (e) Huang,
H.-C.; Chamberlain, T. S.; Selbert, K.; Koboldt, C. M.; Isakson, P. C.;
Reitz, D. B. Bioorg. Med. Chem. Lett. 1995, 5, 2377. (f) Hagishita, S.;
Yamada, M.; Shirahase, K.; Okada, T.; Murakami, Y.; Ito, Y.; Matsuura,
T.; Wada, M.; Kato, T. J. Med. Chem. 1996, 39, 3636. (g) Gao, H.;
Katzenellenbogen, J. A.; Garg, R.; Hansch, C. Chem. Rev. 1999, 99,
723. (h) Korte, A.; Legros, J.; Bolm, C. Synlett 2004, 2397. (i) Wang,
Y.; Mo, S.-Y.; Wang, S.-J.; Li, S.; Yang, Y.-C.; Shi, J.-G. Org. Lett. 2005,
7, 1675. (j) Clegg, N. J.; Paruthiyil, S.; Leitman, D. C.; Scanlan, T. S. J.
Med. Chem. 2005, 48, 5989. (k) Huffman, J. W.; Padgett, L. W. Curr.
Med. Chem. 2005, 12, 1395. (l) Alcalde, E.; Mesquida, N.; Lop
́
ez-
Perez, S.; Frigola, J.; Merce, R. J. Med. Chem. 2009, 52, 675.
́
́
(2) (a) Grimsdale, A. C.; Mulllen, K. Angew. Chem., Int. Ed. 2005, 44,
5592. (b) Levi, Z. U.; Tilley, T. D. J. Am. Chem. Soc. 2010, 132, 11012.
(c) Zeng, X.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011, 133,
17638.
(3) (a) Halterman, R. L. Chem. Rev. 1992, 92, 965. (b) Cadierno, V.;
Diez, J.; Pilar Gamasa, M.; Gimeno, J.; Lastra, E. Coord. Chem. Rev.
1999, 193−195, 147. (c) Alt, H. G.; Koppl, A. Chem. Rev. 2000, 100,
̈
1205. (d) Zargarian, D. Coord. Chem. Rev. 2002, 233−234, 157.
(4) For selected examples, see: (a) Roussel, C.; Rajoharison, H. G.;
Bizzari, S. L. J. Org. Chem. 1988, 53, 683. (b) Ivchenko, N. B.;
Ivchenko, P. V.; Nifant’ev, I. E.; Kotov, V. V. Russ. Chem. Bull. 2000,
49, 942. (c) Tutar, A.; Cakmak, O.; Balci, M. Tetrahedron 2001, 57,
9759. (d) Zhou, X.; Zhang, H.; Xie, X.; Li, Y. J. Org. Chem. 2008, 73,
3958. (e) Ye, S.; Gao, K.; Zhou, H.; Yang, X.; Wu, J. Chem. Commun.
D
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