Room-temperature metal-free electrophilic 5-endo -selective iodocarbocyclization of 1,5-enynes

Article abstract of DOI:10.1021/ol102257z

A highly efficient NIS-promoted iodocarbocyclization reaction of various functionalized 1,5-enynes is described via a 5-endo diastereoselective process. The cyclizations are conducted in the presence of 1.2 equiv of N-iodosuccinimide in dichloromethane at

Full text of DOI:10.1021/ol102257z

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5222-5225
Room-Temperature Metal-Free
Electrophilic 5-endo-Selective
Iodocarbocyclization of 1,5-Enynes
Alexandre Pradal, Alexandre Nasr, Patrick Y. Toullec,* and Veronique Michelet*
E.N.S.C.P., Chimie ParisTech, UMR 7223, Laboratoire Charles Friedel 11 rue P. et
M. Curie, 75231 Paris Cedex 05, France
patrick-toullec@chimie-paristech.fr; Veronique-michelet@chimie-paristech.fr
Received September 20, 2010
ABSTRACT
A highly efficient NIS-promoted iodocarbocyclization reaction of various functionalized 1,5-enynes is described via a 5-endo diastereoselective
process. The cyclizations are conducted in the presence of 1.2 equiv of N-iodosuccinimide in dichloromethane at room temperature. The
reaction conditions are compatible with several functional groups and lead to original iodo-functionalized carbocycles in good to excellent
yields.
Electrophilic iodocyclization of alkynes represents a useful
methodology for the synthesis of a variety of carbo- and
heterocycles.1 Although a broad scope of oxygen, nitrogen,
sulfur, or selenium nucleophiles has been used with success,
much fewer studies have been reported with carbon nucleo-
philes. The first seminal contribution in 1988 by Barluenga
et al. reported a unique example of intramolecular io-
doarylation of alkynes in the presence of bis(pyridine)-
iodonium tetrafluoroborate.2 Since then, several groups
have studied the iodocarbocyclization reactions employing
carbon nucleophiles such as aromatic rings3 or enol and
enolates.4 At the initial stage of our study, we wondered
if alkenes may act as nucleophiles toward iodonium-
activated alkynes. We anticipated that 1,n-enynes might
be good candidates for such investigations, considering
their fascinating reactivity5 and the recent theoretical
investigations highlighting the analogy between halonium
chemistry and π-Lewis acid catalysis.6 In the course of
our investigations, Shin, Kirsch, and co-workers indepen-
dently described the iodocarbocyclization of 1,5-enynes
in the presence of IBr and NIS (Scheme 1).7
(3) For selected references, see: (a) Zhang, X.; Larock, R. C. J. Am.
Chem. Soc. 2005, 127, 12230. (b) Barluenga, J.; Trincado, M.; Marco-
Arias, M.; Ballesteros, A.; Rubio, E.; Gonza´lez, J. M. Chem. Commun.
2005, 2008. (c) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006,
71, 236. (d) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C. J.
Org. Chem. 2007, 72, 1437. (e) Tang, B.-X.; Tang, D.-J.; Tang, S.; Yu,
Q.-F.; Zhang, Y.-H.; Liang, Y.; Zhong, P.; Li, J.-H. Org. Lett. 2008, 10,
1063. (f) Rahman, M. A.; Kitamura, T. Tetrahedron Lett. 2009, 50, 4759.
(4) (a) Kitagawa, O.; Inoue, T.; Hirano, K.; Taguchi, T. J. Org. Chem.
1993, 58, 3106. (b) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou, F.-R.; Huang,
S.-H.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2007, 9, 397. (c) Barluenga, J.;
Palomas, D.; Rubio, E.; Gonza´lez, J. M. Org. Lett. 2007, 9, 2823. (d) Ali,
Z.; Wirth, T. Org. Lett. 2009, 11, 229.
(5) (a) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 35, 6075. (b)
Lee, S. I.; Chatani, N. Chem. Commun. 2009, 371. (c) Jimenez-Nunez, E.;
Echavarren, A. M. Chem. ReV. 2008, 108, 3326. (d) Gorin, D. J.; Sherry,
B. D.; Toste, F. D. Chem. ReV. 2008, 108, 3351. (e) Michelet, V.; Toullec,
P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 45, 7427. (f) Fu¨rstner, A.;
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
(1) (a) Larock, R. C. In Acetylene Chemistry. Chemistry, Biology and
Material Science; Diederich, F., Stang, P. J., Tykwinsky, R. R., Eds; Wiley-
VCH: New York, 2005; Chapter 2, pp51-99. (b) Rodriguez, J.; Dulcere,
J.-P. Synthesis 1993, 1177. (c) Togo, H.; Iida, S. Synlett 2006, 2159. (d)
Mehta, S.; Waldo, J. P.; Larock, R. C. J. Org. Chem. 2009, 74, 1141.
(2) Barluenga, J.; Gonza´lez, J. M.; Campos, J. M.; Asensio, G. Angew.
Chem., Int. Ed. 1988, 27, 1546.
(6) For a recent review and seminal examples: Yamamoto, Y.; Gridnev,
I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075.
(7) For recent examples of iodonium-mediated 6-endo-dig cycloisomer-
ization of 1,5-enynes, see: (a) Lim, C.; Rao, S.; Shin, S. Synlett 2010, 368.
(b) Crone, B.; Kirsch, S. F.; Umland, K.-D. Angew. Chem., Int. Ed. 2010,
49, 4661.
10.1021/ol102257z  2010 American Chemical Society
Published on Web 10/28/2010

Scheme 1
.
Examples of Iodocyclization Reactions
Table 1. Optimization of the Reaction Conditions on 1a
[I]+ source
entry
1.1 equiv
solvent
convn (yield %)a
1
2
3
4
5
6
7
8
9b
NIS
NIS
NIS
NIS
NIS
NIS
I2
ICl
toluene
AcOEt
THF
CH3CN
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
42
75
100 (6)
100 (19)
100 (96)
100 (/)
100 (18)
100 (8)
IPy2BF4/HBF4
In both cases, a 6-endo mode of cyclization is observed.
Upon addition of the alkene function, the carbocation A
formed either reacts by elimination to give the 1,3-diene B
or is trapped by nucleophilic attack of a carbonate to give
the corresponding bicyclic heterocycle C. Targeting the rare
5-endo mode of cyclizations8 and considering the regiose-
lectivity observed in carbophilic Lewis acid-catalyzed cy-
cloisomerization of 1,5-enynes,9,5 we anticipated that the
introduction of carbocation-stabilizing substituents at the
alkenyl terminal position would promote the desired cycliza-
tion and, hence, lead to the formation of a cyclopentenyl
structure. We wish therefore to report our preliminary
investigations allowing the synthesis of iodo-functionalized
cyclopentenes under mild conditions. The iodocyclization of
1,5-enyne 1a was conducted in various solvents and in the
presence of electrophilic iodine sources (Table 1). We were
delighted to find that the iodocyclopentene 2a was obtained
selectively at room temperature in the presence of 1.1 equiv
of N-iodosuccinimide in dichloromethane (entry 6). No
conversion was observed in toluene, whereas lower reac-
tivities were detected in ethyl acetate or tetrahydrofuran
(entries 1-3). When the reaction was conducted in aceto-
nitrile (entry 4), the iodo derivative 2a was isolated in only
6% yield, whereas compound 3 was obtained in 42% yield.
The formation of amide 3 resulted from a domino
iodocyclization/Ritter reaction.10 A similar side reaction was
observed in MeOH (entry 5). Indeed, a methoxyiodocar-
a Isolated yields, dr > 95:5. b Reaction performed at 0 °C.7b
bocyclization reaction allowed the formation of the ether 4
in 22% yield, along with formation of product 2a in 19%
isolated yield (entry 5). The influence of other iodonium
sources was then investigated: iodine, iodochloride, and
bis(pyridine) iodonium tetrafluoroborate (entries 7-9) al-
lowed the consumption of starting material but afforded
mainly degradation products or very low yield of the desired
product.11 In the latter case, the fluoro compound 5 was also
isolated in 37% yield. The reaction was found to be totally
diastereoselective, which was demonstrated by high-field
NOESY 1H NMR experiment on the acetate-protected
bicyclic analogue of 2b (see Supporting Information).
Remarkably, electrophilic activation by iodonium species
takes place selectively at the carbon-carbon triple bond
rather than at the alkenyl moiety.12 This behavior seems to
be strongly affected by the spatial positioning of the alkene
nucleophile during the cyclization event (Scheme 2). Indeed,
treatment of enyne 6 that does not possess a substituent on
the 4-position of the enyne with N-iodosuccinimide in
dichloromethane led to the formation of product 7 in
moderate yield. Moreover, in the presence of an external
nucleophile, the activation of the substrate took place
chemoselectively at the alkenyl unsaturation. The reaction
allowed the formation of 8 that results from the iodoetheri-
fication of the carbon-carbon bond of higher electronic
density, in quantitative yield.
(8) For a recent paper, which appeared during the submission process:
Sanz, R.; Martinez, A.; Garcia-Garcia, P.; Fernandez-Rodriguez, M. A.;
Rashid, M. A.; Rodriguez, F. Chem. Commun. 2010, 46, 7427. For a single
example using Br2, see: Schreiner, P. R.; Prall, M.; Lutz, V. Angew. Chem.,
Int. Ed. 2003, 42, 5757.
(9) For Hg-, Pt-, and Au-catalyzed carbocyclization of 1,5-enynes, see:
(a) Imagawa, H.; Iyenaga, T.; Nishizawa, M. Synlett 2005, 703. (b) Imagawa,
H.; Iyenaga, T.; Nishizawa, M. Org. Lett. 2005, 7, 451. (c) Zhang, L.;
Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962. (d) Staben, S. T.;
Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste,
F. D. Angew. Chem., Int. Ed. 2006, 45, 5991. (e) Buzas, A. K.; Istrate,
F. M.; Gagosz, F. Angew. Chem., Int. Ed. 2007, 46, 1141. (f) Nelsen, D. L.;
Gagne´, M. R. Organometallics 2009, 28, 950. (g) Toullec, P. Y.; Blarre,
T.; Michelet, V. Org. Lett. 2009, 11, 2888. (h) Martinez, A.; Garcia-Garcia,
P.; Fernandez-Rodriguez, M. A.; Rodriguez, F.; Sanz, R. Angew. Chem.,
Int. Ed. 2010, 49, 4633. For a W-catalyzed example of 5-endo cyclization,
see: (i) Iwasawa, N.; Miura, T.; Kiyota, K.; Kusama, K. L.; Ho Lee, P.
Having in hand an optimized system, the iodocarbocy-
clization was then applied to several 1,5-enynes (Table 2
(10) Uemura, S.; Fukuzawa, S.-I.; Toshimitsu, A.; Okano, M. J. Org.
Chem. 1983, 48, 270.
(11) In the case of iodine and ICl, the use of an additional base, e.g.,
K3PO4,3a did not lead to any improvement of the yield.
(12) For the reactivity of the ene-ynamide mediated by electrophilic
oxene transfer reagents, see: (a) Couty, S.; Meyer, C.; Cossy, J. Synlett
2007, 2819. (b) Al-Rashid, Z. F.; Hsung, H. P. Org. Lett. 2008, 10, 661.
Org. Lett. 2002, 4, 4463, and references cited therein
.
Org. Lett., Vol. 12, No. 22, 2010
5223

the formation of the desired products in low yield or as a
free alcohol (entries 10 and 11).14 The influence of the nature
and position of the protected alcohol was also investigated
and was found to be critical for the outcome of the reaction.
In the case of enyne 1m and 1n, the iodocarbocyclization
reactions allowed the formation of the cyclopentenyl deriva-
tives 2m and 2n in modest yields (29% and 41%) and as
mixtures of syn and anti diastereomers (entries 12 and 13).
The reactivities of 1,5-enynes 1o-1q possessing tetrasub-
stituted alkenyl moieties were much more gratifying (Scheme
3), as the bicyclic iodo-functionalized derivatives were obtained
in good yields. The diastereoselectivity of the process was
demonstrated by NOESY experiments on 2q and X-ray analysis
of 2o (Figure 1, see Supporting Information).15
Scheme 2
.
Chemoselectivity of the NIS-Promoted Reaction of
1,5-Enyne 6
Table 2. NIS-Promoted Iodocarbocyclization of 1,5-Enynes in
Dichloromethane at Room Temperature
time yield
entry 1,5-enyne
R1
R2
Ar
(h) (%)a
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
OTBDMS H
OTBDMS H
OTBDMS H
OTBDMS H
Ph
2b 26
86
64
85
67
98
66
64
2-naphtyl
2-thienyl
2-tolyl
2c
2d
2e
9
3
5
OBz
OBz
OBz
OBz
OTES
OBn
OPMB
H
H
H
H
H
H
H
H
Ph
2f 21
2g 27
2h 21
2-naphtyl
2-thienyl
4-MeOC6H4 2i
Ph
Ph
Ph
5.5 88
60
9
2j 20
10
11b
12
13
2k 20
14
2l
2m
2n
3
3
1
45b
29c
41d
OTBDMS Ph
n-Pr Ph
H
Figure 1. X-ray analysis of 2o.
a Isolated yields, dr >95:5. b Deprotected alcohol is isolated. c 2:1 mixture
of diastereomers. d 1:1 mixture of diastereomers.
A mechanistic rationale accounting for the observed
products and selectivities is proposed in Scheme 4. At the
initial stage of the reaction, the iodonium ion would activate
the alkynyl function through π-coordination to give inter-
mediate D.
Upon nucleophilic attack of the alkenyl moiety in an anti
fashion, an iodocyclization reaction would lead to the
formation of a carbocation (intermediate E). In the absence
of an external nucleophile, proton abstraction by the suc-
cinimide anion would allow the formation of the 1,3-dienic
product. When an external nucleophile is present, nucleo-
philic attack of the carbocation would give products such as
3, 4, or 5.
and Scheme 3). Various aromatic and heteroaromatic rings
(phenyl, napthyl, tolyl, and thienyl) were introduced and
compatible with the reaction conditions (entries 1-4).13 The
corresponding iodocyclopentenes 2b-2e were isolated in
67-86% yields. Other protected alcohols were also cleanly
cyclized and functionalized, such as benzoyl or triethylsilyl-
substituted 1,5-enynes. The resulting adducts 2f-2j were
obtained in moderate to excellent yields (entries 5-9). The
benzyl or para-methoxybenzyl-protected 1,5-enynes allowed
Scheme 3
In conclusion, we have demonstrated that functionalized
1,5-enynes may be cyclized under extremely mild conditions,
(13) The reactivity of 1,5-enyne bearing an electron-deficient aryl group
on the alkyne moiety was sluggish, and traces of the desired product were
detected.
(14) For iodine-mediated PMB deprotection, see: Vaino, A. R.; Szarek,
W. A. Synlett 1995, 1157.
(15) For the iodine-mediated formation of bicyclic spiro structures, see:
(a) Ref 3a. Ref 3c . (c) Okitsu, T.; Nakazawa, D.; Kobayashi, A.; Mizohata,
M.; In, Y.; Ishida, T.; Wada, A. Synlett 2010, 203.
5224
Org. Lett., Vol. 12, No. 22, 2010

efficient access to highly valuable building blocks of natural
products or biologically active compounds.
Scheme 4. Mechanistic Rationale
Acknowledgment. This work was supported by the Centre
National de la Recherche Scientifique (CNRS) and the
Ministe`re de l’Education et de la Recherche for financial
support. A.P. is grateful to the National Research Agency
(ANR-09-JCJC-0078) for a grant. The authors thank Dr.
M.-N. Rager (Chimie ParisTech) for 2D and NOESY
experiments and Lise-Marie Chamoreau (UMR 7071, Labo-
ratoire de Chimie Inorganique et Mate´riaux Mole´culaires,
Paris) for X-ray structure analysis.
Supporting Information Available: Experimental pro-
cedures, full analyses of 1,5-enynes and iodocarbocycles, and
cif file for X-ray structure 2o. This material is available free
of charge via the Internet at http://pubs.acs.org.
at room temperature in the presence of NIS and without
additives according to an unprecedented 5-endo process. The
iodocarbocyclization was found to be totally diastereoselec-
tive, and the corresponding 1-iodopentenes were isolated in
good to high yields. This process constitutes an easy and
OL102257Z
Org. Lett., Vol. 12, No. 22, 2010
5225