LDA-catalyzed cycloisomerization of 2-(2-propynyloxy)ethyl iodides leading to 3-(iodomethylene)tetrahydrofurans

Article abstract of DOI:10.1021/ol047570e

(Chemical Equation Presented) LDA catalyzes cycloisomerization of 2-(2-propynyloxy)ethyl iodides to give 3-(iodomethylene)tetrahydrofurans. The reaction is proposed to proceed through a mechanism involving exo-cyclization of an alkynyllithium intermediate

Full text of DOI:10.1021/ol047570e

ORGANIC
LETTERS
2005
Vol. 7, No. 5
779-781
LDA-Catalyzed Cycloisomerization of
2-(2-Propynyloxy)ethyl Iodides Leading
to 3-(Iodomethylene)tetrahydrofurans
Toshiro Harada,* Keiko Muramatsu, Takayuki Fujiwara, Hiroshi Kataoka, and
Akira Oku
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
harada@chem.kit.ac.jp
Received November 26, 2004
ABSTRACT
LDA catalyzes cycloisomerization of 2-(2-propynyloxy)ethyl iodides to give 3-(iodomethylene)tetrahydrofurans. The reaction is proposed to
proceed through a mechanism involving exo-cyclization of an alkynyllithium intermediate and protonation of the resulting alkylidene carbenoid
by the starting iodide.
Iodine-containing organic compounds are frequently utilized
as reactive carbon electrophiles in organic synthesis. In their
reactions, the substrate iodine atom is usually lost as an
iodide salt and not incorporated into the product. Carbon-
carbon bond forming reactions that give products with
incorporation of the iodine atom would provide a useful
means for constructing complex carbon frameworks through
a subsequent bond forming reaction of the iodine-containing
products. Indeed, the atom transfer radical cyclization of hex-
5-enyl and hex-5-ynyl halides leading to the formation of
the five-membered ring cycloisomerization product has been
the focus of recent research and several reagents mediating
this useful reaction have been developed.1-3
Alkynylmetal ate complexes such as alkynylboronates4,5
and -zincates6 are known to react at the â position with
simultaneous migration of the ate ligand to the R position.
That alkynylmetals (M ) Li, Na, K) also exhibit nucleophilic
reactivity at the â position was recently disclosed.7 Alkyn-
ylmetals 3 bearing a remote leaving group undergo facile
exo-cyclization at the â position to generate cycloalkylidene
carbenoids 4 (Scheme 1).8 A tandem cyclization of io-
(3) (a) Chakraborty, A.; Marek, I. Chem. Commun. 1999, 2375-2376.
(b) Yanada, R.; Koh, Y.; Nishimori, N.; Matsumura, A.; Obika, S.; Mitsuya,
H.; Fujii, N.; Takemoto, Y. J. Org. Chem. 2004, 69, 2417.
(4) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic
Press: London: 1988; 283.
(5) (a) Merril, R. E.; Allen, J. L.; Abramovitch, A.; Negishi, E.
Tetrahedron Lett. 1977, 1019. (b) Corey, E. J.; Seibel, W. L. Tetrahedron
Lett. 1986, 27, 909. (c) Negishi, E.; Nguyen, T.; Boardman, L. D.; Sawada,
H.; Morrison, J. A. Heteroatom Chem. 1992, 3, 293.
(6) (a) Harada, T.; Wada, I.; Oku, A. J. Org. Chem. 1995, 60, 5370. (b)
Harada, T.; Otani, T.; Oku, A. Tetrahedron Lett. 1997, 38, 2855.
(7) Harada, T.; Iwazaki, K.; Otani, T.; Oku, A. J. Org. Chem. 1998, 63,
9007.
(8) Some transition metal acetylides are known to react with electrophiles
at the â position to form vinylidene complexes: Bruce, M. I. Chem. ReV.
1991, 91, 197.
(1) (a) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1986,
108, 2489. (b) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc.
1989, 111, 6265. (c) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54,
3140-3157.
(2) (a) Ichinose, Y.; Matsunaga, S.; Fugami, K.; Oshima, K.; Utimoto,
K. Tetrahedron Lett. 1989, 30, 3155. (b) Yorimitsu, H.; Nakamura, T.;
Shinokubo, H.; Oshima, K. J. Org. Chem. 1998, 63, 8604. (c) Yorimitsu,
H.; Nakamura, T.; Shinokubo, H.; Oshima, K.; Omoto, K.; Fujimoto, H. J.
Am. Chem. Soc. 2000, 122, 11041.
10.1021/ol047570e CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/29/2005

of a reduced amount of the base resulted in lower conversion
of the reaction (entry 4) whereas an increased amount of
the base did not give a better result owing to the formation
of byproducts (entry 5).11 The formation of (E)-5a, albeit in
low yield, was also observed with NaN(TMS)2 (entry 6) but
not with KN(TMS)2. No reaction took place when the LDA-
catalyzed reaction of 1a was carried out in ether.
Scheme 1. Tandem Cyclization of Iodoalkynes 1
Under the optimized conditions using LDA (0.2 equiv)
as a base in THF at 0.5 M at room temperature, the reaction
of cyclohexyl derivative 1c gave stereoselectively (E)-5c
(Table 2, entry 3). On the other hand, iodoalkyne 1d with
the phenyl group â to the iodine atom was found to be less
reactive. The reaction using 0.4 equiv of LDA at 65 °C
afforded 5e as a mixture of stereoisomers in 30% yield (entry
4). Bromoalkyne 1b did not undergo similar cyclization
leading to bromide 5b even at 65 °C (entry 2).
doalkynes 1 leading to bicyclic products 2 was developed
by the use of regioselective intramolecular C-H insertion
of thus-generated cycloalkylidene carbenoids.9
The present cycloisomerization was found to be success-
fully applied to acetal derivatives 1e-j. Acetal 1e, not
bearing substituents at the propargylic position, was slightly
less reactive but the corresponding cycloisomerization prod-
uct 5e was obtained in 81% yield by carrying out the reaction
at 40 °C (entry 5). Efficient and E-selective cycloisomer-
ization was observed at 25-35 °C for acetal 1f-i bearing
substituents at the propargylic position (entries 6-10). A
smooth reaction took place for gem-disubstituted 1h even
in the presence of 0.1 equiv of LDA (entry 9). Although
extremely sluggish even at 65 °C, the reaction of the trans-
cyclic secondary iodide 1j selectively afforded cis-fused
bicyclic product (Z)-5j at (entry 11), albeit in only ca. 7%
conversion. The stereochemical outcome of the reaction may
imply that the exo-cyclization proceeds with the inversion
of the carbon attached by the iodine atom.
If the protonation of carbenoid intermediate 4 occurred
before decomposition to the reactive carbenic species,10 this
might produce the desired iodine-containing product 5. Such
a possibility was examined in the reaction of iodoalkynes 1
in the presence of a catalytic amount of a base with the
anticipation that the terminal alkyne moiety of 1 serves as a
proton source for intermediate 4. Herein is reported an
unusual LDA-catalyzed cyclization of iodoalkynes leading
to a product without the loss of the iodo functional group.
When iodoalkyne 1a was treated with 0.2 equiv of LDA
in THF at 0.1 M for 5 h at room temperature, cycloisomer-
ization product (E)-5a was obtained stereoselectively (E/Z
) 10:1) in 30% yield together with the recovery of 1a (60%)
(Table 1, entry 1). Similar reactions at higher concentration
Scheme 1 suggests a mechanism involving the protonation
of alkylidene carbenoid intermediate 4 by iodoalkyne 1 in
the catalytic cycle for the present cycloisomerization reaction
depicted in Scheme 2. Thus, alkynyllithium 3, generated by
Table 1. Cycloisomerization of 1a under Various Conditions
Scheme 2. Proposed Catalytic Cycle for Cycloisomerization
of 1
entry
base
LDA
LDA
LDA
LDA
LDA
NaN(TMS)2
equiv
conc (M)
yielda (%)
E/Zb
1
2
3
4
5
6
0.2
0.2
0.2
0.1
0.4
0.2
0.1
0.5
1.0
0.5
0.5
0.5
30
74
70
30
54
10
10:1
9.1:1
9.0:1
8.1:1
5.3:1
4.2:1
a Isolated as an E/Z mixture after flash chromatography. b Determined
by a capillary GC analysis. The structure of (E)-5a was determined by
NOESY analysis.
of 0.5 and 1.0 M gave (E)-5a in the improved yields of 74%
and 70%, respectively, demonstrating the catalytic nature of
the cycloisomerization reaction (entries 2 and 3). The use
the lithiation of 1 with LDA, undergoes exo-cyclization to
give carbenoid 4, which is basic enough to abstract the
(9) Harada, T.; Fujiwara, T.; Iwazaki, K.; Oku, A. Org. Lett. 2000, 2,
1855.
(10) Knorr, R. Chem. ReV. 2004, 104, 3795.
(11) The corresponding tandem cyclization product 2 (R ) Ph, X ) O,
n ) 1) was obtained in 10% yield.
780
Org. Lett., Vol. 7, No. 5, 2005

The atom transfer radical cyclization of analogous hex-
5-ynyl iodides giving rise to cycloisomerization products has
been reported.1-3 Alternatively, the present reaction may
proceed through the radical mechanism if LDA acts as an
initiator. However, such mechanism is less likely judging
from the following observations. Low stereoselectivity has
been reported for the radical cyclization of hex-5-hexynyl
iodides in general.1-3 When 1a was treated with radical
initiator Et3B in hexane at room-temperature according to
the procedure reported by Oshima et al.,2a 5a was obtained
with low stereoselectivity (E/Z ) 2.7:1) in 49% yield. The
result is in contrast to the high E selectivity (9.1:1) observed
in the LDA-catalyzed reaction. In the LDA-catalyzed reaction
of 1h possessing both hex-5-ynyl and hex-5-enyl iodide
structures (Table 2, entry 7), no product derived from
cyclization on the olefinic moiety was formed.
Table 2. LDA-Catalyzed Cycloisomerization of Iodoalkynes 1a
Further support for the proposed base-catalyzed mecha-
nism was provided by deuterium labeling experiments. The
reaction of 1a-d (98% d) with LDA (0.2 equiv) gave (E)-
5a-d (90%-d) in 70% yield. When a 1:1 mixture of 1a-d
and 1c were treated with LDA, deuterium incorporation was
observed not only into (E)-5a-d (48% d) (65% yield) but
also into (E)-5c-d (51% d) (58% yield) (eq 2). The result of
the deuterium scrambling experiment is well in accord with
an intermolecular deuterium (and proton) transfer during the
cycloisomerization process.
In summary, a LDA-catalyzed cycloisomerization of 2-(2-
propynyloxy)ethyl iodides 1 to give 3-(iodomethylene)-
tetrahydrofuran derivatives 5 has been discovered. The
carbocyclization took place with incorporation of iodine atom
into the products, which may serve as synthetically useful
intermediates for the construction of complex carbon frame-
works. In comparison with the radical mediated reactions,
the LDA-catalyzed reaction showed higher stereoselectivity
for the formation of sterically less hindered E products.
a Unless otherwise noted, the reactions were carried out by using 0.2
equiv of LDA in THF at 25-30 °C for 4-7 h. b Isolated as an E/Z mixture
after flash chromatography. c Unless otherwise noted, E/Z ratio was
determined by a capillary GC analysis. d The reaction was carried out at
65 °C. e LDA (0.4 equiv) was used. f The reaction was carried out at 40°
for 18 h. g A 1:1 mixture of diastereomers. h E and Z isomers were obtained
as a mixture of diastereomers. i Determined by 1H NMR analysis. j The
Supporting Information Available: Experimental pro-
cedure and spectra data for cycloisomerization products 5.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
geometrical isomer was not detected by H NMR analysis. k The reaction
was carried out by using 0.1 equiv of LDA.
terminal acetylenic proton of 1 to give cycloisomerization
product 5 with simultaneous generation alkynyllithium 3.
OL047570E
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