Electrophilic cyclization of 1,6-enynes

Article abstract of DOI:10.1055/s-0030-1259938

The NIS-mediated iodocyclization of 1,6-enynes is described. While 1,6-enynes with a cation-stabilizing substituent at C2 position undergo 6-exo cyclization in poor yields, 1,6-enynes with donor substituents at C1 position favor the 5-exo mode of cyclizat

Full text of DOI:10.1055/s-0030-1259938

LETTER
1151
Electrophilic Cyclization of 1,6-Enynes
Iodocyclizationobias Harschneck, Stefan F. Kirsch,* Michael Wegener
Department Chemie, Catalysis Research Center, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: stefan.kirsch@ch.tum.de
Received 25 January 2011
was reported as an alternative mode of cyclization.7b,c
Here we show that 1,6-enynes are also substrates in iodo-
nium-induced carbocyclizations yielding both six-mem-
bered and five-membered carbocycles depending on the
Abstract: The NIS-mediated iodocyclization of 1,6-enynes is de-
scribed. While 1,6-enynes with a cation-stabilizing substituent at
C2 position undergo 6-exo cyclization in poor yields, 1,6-enynes
with donor substituents at C1 position favor the 5-exo mode of cy-
clization. The resulting five-membered carbocycles are obtained in position of cation-stabilizing substituents.
moderate to good yields, thus demonstrating another facet in the
iodocyclization of enynes.
As transition-metal-catalyzed cycloisomerizations of 1,6-
enynes are of exceptionally broad use to construct various
carbocycles,9,10 we expected that the corresponding io-
docyclization also has the potential to deliver carbocyclic
products of high complexity.11 Due to the incorporation of
I rather than H at the final product, further functionaliza-
tion is made easy by use of classical cross-coupling meth-
odologies.12 To this end, 1,6-enyne 1 bearing a methyl
donor at C2 position was treated with of N-iodosuccinim-
ide (NIS) in CH2Cl2. The initial attempt employing three
equivalents of NIS at room temperature produced only
18% of the desired six-membered ring system 2, along
with a large number of trace products not further analyzed
(Scheme 2). The yield was slightly improved to 38% by
using 1.1 equivalents of NIS at 50 °C in a sealed tube. As
shown through NOESY studies, diene 2 was obtained as a
single diastereoisomer resulting from anti addition onto
the iodonium-activated triple bond. Other iodonium
sources (e.g., I2/K3PO4, IBr) did not provide better yields
neither did other solvents (EtOAc, MeCN, toluene, THF,
DMF). Notably, the 6-exo cyclization mode proved re-
stricted to 1,6-enynes with a terminal alkyne moiety as as-
sessed by reacting internal alkyne 3 with NIS to give
lactone 4.13
Key words: enynes, cyclizations, iodine, alkynes, carbocycles
The electrophilic iodocyclization of alkynes has emerged
as a powerful tool to efficiently synthesize small molecule
targets. In particular, the iodonium-induced cyclization of
heteroatom nucleophiles with tethered alkynes is useful to
accomplish direct carbon–heteroatom bond formation for
the synthesis of a variety of carbo- and heterocycles.1,2
Despite a groundbreaking report by Barluenga et al. in
1988,3 the analogous iodonium-induced cyclization of
carbon nucleophiles remained mostly restricted to arenes4
and malonates.5 In 2010, we6 and others7 then showed
how simple olefins can act as internal carbon nucleophiles
in the iodocyclization of 1,5-enynes. In the presence of
carbocation-stabilizing substituents at the C2 position,
we6a and Shin7a et al. observed exclusive 6-endo cycliza-
tion converting 1,5-enynes into six-membered cyclic
products of high value including highly substituted ben-
zenes, 1,4-cyclohexadienes, and 4-fluoro cyclohexenes8
(Scheme 1). For 1,5-enynes with carbocation-stabilizing
substituents at the C1-alkenyl terminus, a 5-endo mode
R1'
1
R2
R2
2
R1
I+
R
R
R1
R
I+
R
I
6-endo
5-endo
I
R1'
O
O
n-Bu
Ph
OSit-BuMe2
O
Ph
Ph
I
I
I
I
C6H4(4-OMe)
Ph
I
Ph
(Kirsch et al.)
(Shin et al.)
(Michelet et al.)
(Sanz et al.)
Scheme 1 Iodocyclization modes of 1,5-enynes
SYNLETT 2011, No. 8, pp 1151–1153
x
x.
x
x.
2
0
1
1
Advanced online publication: 07.04.2011
DOI: 10.1055/s-0030-1259938; Art ID: B02411ST
© Georg Thieme Verlag Stuttgart · New York

1152
T. Harschneck et al.
LETTER
NOE
MeO2C
MeO2C
MeO2C
MeO2C
O
2
1
O
O
O
CH2Cl2
H
CH2Cl2
H
I
H
H
NOE
1
I
2
18%
38%
H
6a
5a
NIS (3 equiv), 23 °C
NIS (1.1 equiv), 50 °C
NIS (3 equiv), 0 °C, 22 h
NIS (3 equiv), 23 °C, 6 h
NIS (3 equiv), AcOH, 23 °C, 1.5 h
I2, K3PO4, 0 °C, 1 h
58%
68%
65%
MeO2C
MeO2C
decomp.
2
O
I
NIS (1.1 equiv), CH2Cl2
O
50 °C
49%
NIS, CH2Cl2
23 °C or 50 °C
MeO2C
Ph
X
Ph
X
3
4
H
Scheme 2 6-Exo cyclization of 1,6-enynes
H
I
5b X = (MeO2C)2C
5c X = (PhO2S)2C
5d X = O
6b 55%
6c 47%
6d 40%
6e 46%
In order to investigate the alternative 5-exo cyclization,
we sought to examine the reactivity of 1,6-enynes that
possess two donor substituents at the C1-alkenyl termi-
nus. We were pleased to find that acetonide 5a indeed
gave the expected cyclization product 6a in up to 68%
yield when employing NIS as the iodonium source in
CH2Cl2 (Scheme 3). To rapidly convert the starting 1,6-
enyne 5a, heating to 50 °C was not required; the highest
yield was obtained at room temperature after six hours.
Surprisingly, significantly faster reaction times were real-
ized when adding stoichiometric amounts of acetic acid.
The origin of this effect, and why acetic acid was not in-
corporated under the reaction conditions,6a,7c is currently
under investigation. Most likely, the Brønsted acid en-
hances the halogenating ability by activation of the suc-
cinimide carbonyl.14 In the presence of other iodonium
sources (e.g., I2/K3PO4), we mostly observed rapid and
complete decomposition to untraceable products.
5e X = NTs
EtO2C
EtO2C
NIS, CH2Cl2
EtO2C
EtO2C
23 °C
67%
H
I
H
6f
5f
Scheme 3 5-Exo cyclization of 1,6-enynes
uents at the alkene, was not converted at all when NIS was
employed at various temperatures (Scheme 4).
O
NIS, CH2Cl2
0 °C to 50 °C
O
no conversion
The substrate scope was briefly examined utilizing NIS in
dichloromethane at either 23 °C or at 50 °C. As shown in
Scheme 3, a variety of 1,6-enynes with two substituents at
C1 position underwent iodonium-induced cyclization to
afford the five-membered carbocycles 6b–f in moderate
yields.15 Notably, in all cases 5-exo carbocyclization oc-
curred selectively over competing modes of cyclization. A
major limitation stems again from the fact that internal
alkynes do not react in the expected way.16
7
Scheme 4 Attempted reaction of unsubstituted alkene 7
In summary, we have investigated the reactivity of 1,6-
enynes in the presence of electrophilic iodine sources. It
was shown that the carbocyclization favors a pathway that
proceeds through the more stabilized carbocation. A 6-exo
process was realized in poor yields when enynes with a
stabilizing substituent at the C2 position were reacted in
the presence of NIS. In the case of 1,6-enynes with car-
bocation-stabilizing substituents at the C1-alkenyl termi-
nus, the more rapid 5-exo cyclization yields the
corresponding five-membered carbocycles in moderate to
good yields. The transition-metal-free processes are ex-
perimentally simple to perform and demonstrate another
facet of the still underdeveloped potential of electrophilic
enyne cyclizations for the synthesis of diverse carbocyclic
scaffolds.
A plausible mechanism accounting for the observations
reported herein is based on the intermediacy of cyclic car-
bocations. Accordingly, iodonium activation of the triple
bond initiates the nucleophilic attack in an anti fashion.
Since the reaction favors the carbon–carbon bond forma-
tion that, upon cyclization, leads to the more stable cation-
ic intermediate, a substituent at C2 renders the C1 carbon
of the alkene moiety more nucleophilic (6-exo cycliza-
tion). In sharp contrast, a disubstituted C1-alkenyl termi-
nus generates five-membered cyclic cations via bond
formation between the alkynyl C6 and the alkenyl C2 (5-
exo cyclization). In both cases, proton abstraction (by the
succinimide anion) finally delivers the diene product con-
taining a vinyl iodide moiety. In accordance with this
consideration, 1,6-enyne 7, not bearing additional substit-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 8, 1151–1153 © Thieme Stuttgart · New York

LETTER
Iodocyclization
1153
(7) (a) Lim, C.; Rao, S.; Shin, S. Synlett 2010, 368. (b) Pradal,
A.; Nasr, A.; Toullec, P. Y.; Michelet, V. Org. Lett. 2010,
12, 5222. (c) Sanz, R.; Martínez, A.; García-García, P.;
Fernández-Rodríguez, M. A.; Rashid, M. A.; Rodríguez, F.
Chem. Commun. 2010, 46, 7427.
Acknowledgment
This project was supported by the Deutsche Forschungsgemein-
schaft (DFG), the Fonds der Chemischen Industrie (FCI), and the
TUM Graduate School.
(8) For fluorination using Py2IBF4, see: (a) Ref. 3 (b) Huang,
K.-T.; Winssinger, N. Eur. J. Org. Chem. 2007, 1887.
(c) Barluenga, J.; Campos, P. J.; González, J. M.; Suárez,
J. L. J. Org. Chem. 1991, 56, 2234.
(9) For leading reviews, see: (a) Fürstner, A.; Davies, P. W.
Angew. Chem. Int. Ed. 2007, 46, 3410. (b) Hashmi, A. S. K.
Chem. Rev. 2007, 107, 3180. (c) Jiménez-Núñez, E.;
Echavarren, A. M. Chem. Commun. 2007, 333.
References and Notes
(1) For selected examples, see: Benzofurans: (a) Arcadi, A.;
Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999,
1432. (b) Furans: Yue, D.; Yao, T.; Larock, R. C. J. Org.
Chem. 2005, 70, 10292. (c) Yao, T.; Zhang, X.; Larock,
R. C. J. Org. Chem. 2005, 70, 7679. (d) Benzothiophenes:
Sniady, A.; Morreale, M. S.; Wheeler, K. A.; Dembinski, R.
J. Org. Chem. 2008, 73, 3449. (e) Hessian, K.; Flynn, B. L.
Org. Lett. 2003, 5, 4377. (f) Benzopyrans: Sanz, R.;
Guilarte, V.; Hernando, E.; Sanjuán, A. M. J. Org. Chem.
2010, 75, 7443. (g) indoles: Worlikar, S. A.; Kesharwani,
T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007, 72, 1347.
(h) Barluenga, J.; Trincado, M.; Rubio, E.; González, J. M.
Angew. Chem. Int. Ed. 2003, 42, 2406. (i) Isoquinolines:
Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71, 62.
(j) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem.
2002, 67, 3437. (k) Isochromenes: Fischer, D.; Tomeba, H.;
Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem. Int.
Ed. 2007, 46, 4764. (l) Barluenga, J.; Vázquez-Villa, H.;
Ballesteros, A.; González, J. M. J. Am. Chem. Soc. 2003,
125, 9028. (m) Yue, D.; Della, C. N.; Larock, R. C. J. Org.
Chem. 2006, 71, 3381. (n) Naphthalenes: Barluenga, J.;
Vázquez-Villa, H.; Merino, H.; Ballesteros, A.; González,
J. M. Chem. Eur. J. 2006, 12, 5790. (o) Barluenga, J.;
Vázquez-Villa, H.; Ballesteros, A.; González, J. M. Org.
Lett. 2003, 5, 4121. (p) Furanones: Barluenga, J.; Vázquez-
Villa, H.; Ballesteros, A.; González, J. M. Adv. Synth. Catal.
2005, 347, 526. (q) Crone, B.; Kirsch, S. F. J. Org. Chem.
2007, 72, 5435. (r) Just, Z. W.; Larock, R. C. J. Org. Chem.
2008, 73, 2662. (s) Binder, J. T.; Crone, B.; Kirsch, S. F.;
Liébert, C.; Menz, H. Eur. J. Org. Chem. 2007, 1636.
(2) For a leading reference, see: Mehta, S.; Waldo, J. P.; Larock,
R. C. J. Org. Chem. 2009, 74, 1141.
(d) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008,
108, 3326. (e) Michelet, V.; Toullec, P. Y.; Genêt, J.-P.
Angew. Chem. Int. Ed. 2008, 47, 4268. (f) Crone, B.;
Kirsch, S. F. Chem. Eur. J. 2008, 14, 3514.
(10) For previous work from our group, see: Baskar, B.; Bae,
H. J.; An, S. E.; Cheong, J. Y.; Rhee, Y. H.; Duschek, A.;
Kirsch, S. F. Org. Lett. 2008, 10, 2605.
(11) For a comprehensive review, see: Yamamoto, Y.; Gridnev,
I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075.
(12) (a) Miyaura, N.; Yanagi, T.; Suzuki, K. Synth. Commun.
1981, 11, 513. (b) Suzuki, A. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998, Chap. 2.
(13) For a related lactone formation through iodocyclization, see:
Kim, K. M.; Ryu, E. K. Tetrahedron Lett. 1996, 37, 1441.
(14) For NXS activation, see inter alia: (a) Goldberg, Y.; Alper,
H. J. Org. Chem. 1993, 58, 3072. (b) Shibatomi, K.; Zhang,
Y.; Yamamoto, H. Chem. Asian J. 2008, 3, 1581.
(15) Representative Experimental Procedure for 6f
Enyne 5f (32.0 mg, 105 mmol) was dissolved in CH2Cl2 (1
mL) and NIS (47.0 mg, 209 mmol, 2 equiv) were added. The
solution was stirred at r.t. in the dark until TLC indicated full
consumption of the starting material. The reaction mixture
was diluted with CH2Cl2 (10 mL), and a sat. aq Na2S2O3
solution (10 mL) was added. The phases were separated, and
the aqueous phase was extracted with CH2Cl2 (2 × 10 mL).
The combined organic phases were washed with brine and
dried over Na2SO4. The solvent was evaporated, and the
residue was purified by flash chromatography on silica gel
(pentane–Et2O = 98:2). Carbocycle 6f was obtained as a
yellow oil (30.4 mg, 70.3 mmol, 67%); Rf = 0.18 (pentanes–
EtOAc = 95:5) [UV, CAM]. 1H NMR (500 MHz, CDCl3):
d = 1.26 (t, J = 7.1 Hz, 6 H), 1.48–1.56 (m, 2 H), 1.59–1.69
(m, 2 H), 1.81–1.86 (m, 2 H), 1.98–2.05 (m, 2 H), 2.23 (t,
J = 12.5 Hz, 1 H), 2.57 (dd, J = 12.8, 7.4 Hz, 1 H), 2.78 (dt,
J = 18.1, 2.4 Hz, 1 H), 3.08 (d, J = 18.1 Hz, 1 H), 3.17–3.21
(m, 1 H), 4.20 (virt. pent, J = 6.7 Hz, 4 H), 5.53–5.57 (s, 1
H), 5.79–5.83 (m, 1 H). 13C NMR (91 MHz, CDCl3):
d = 14.2, 22.6, 23.1, 24.3, 25.5, 39.2, 44.9, 53.5, 58.0, 61.8,
71.9, 126.2, 135.6, 153.5, 171.3, 171.5. LRMS (EI): m/z (%)
= 432 (5) [M+], 387 (5), 305 (21), 231 (100), 157 (39).
HRMS (EI): m/z calcd for C18H25O4I [M+]: 432.0792; found:
432.0788.
(3) Barluenga, J.; González, J. M.; Campos, P. J.; Asensio, G.
Angew. Chem., Int. Ed. Engl. 1988, 27, 1546.
(4) For selected examples, see: (a) Goldfinger, M. B.;
Crawford, K. B.; Swager, T. M. J. Am. Chem. Soc. 1997,
119, 4578. (b) Yao, T.; Campo, M. A.; Larock, R. C. Org.
Lett. 2004, 6, 2677. (c) Barluenga, J.; Trincado, M.; Marco-
Arias, M.; Ballesteros, A.; Rubio, E.; González, J. M. Chem.
Commun. 2005, 2008. (d) Barluenga, J.; Trincado, M.;
Rubio, E.; González, J. M. Angew. Chem. Int. Ed. 2006, 45,
3140. (e) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem.
2006, 71, 236. (f) Worlikar, S. A.; Kesharwani, T.; Yao, T.;
Larock, R. C. J. Org. Chem. 2007, 72, 1347.
(5) (a) 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.
(b) Barluenga, J.; Palomas, D.; Rubio, E.; González, J. M.
Org. Lett. 2007, 9, 2823. (c) Khan, Z. A.; Wirth, T. Org.
Lett. 2009, 11, 229. (d) Kitagawa, O.; Inoue, T.; Hirano, K.;
Taguchi, T. J. Org. Chem. 1993, 58, 3106.
(16) When 2,2-dimethyl-5-(3-methylbut-2-en-1-yl)-5-(3-
phenylprop-2-yn-1-yl)-1,3-dioxane (as an internal alkyne
derived from 5a) was reacted with NIS in CH2Cl2 at r.t., the
cyclization product was not observed. Instead, at least two
compounds were formed that could not be unequivocally
identified while, after 24 h, the bulk was unreacted starting
material.
(6) (a) Crone, B.; Kirsch, S. F.; Umland, K.-D. Angew. Chem.
Int. Ed. 2010, 49, 4661. (b) Kummerlöwe, G.; Crone, B.;
Kretschmer, M.; Kirsch, S. F.; Luy, B. Angew. Chem. Int.
Ed. 2011, 50, 2643. (c) For related work on dienynes, see:
Matsumoto, S.; Takase, K.; Ogura, K. J. Org. Chem. 2008,
73, 1726.
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