Carbocyclization reaction of ω-iodo- and 1,ω-diiodo-1-alkynes without the loss of iodine atoms through a carbenoid-chain process

Article abstract of DOI:10.1021/jo7021179

(Chemical Equation Presented) Atom-economical carbocyclization reactions of ω-iodo-1-alkynes and 1,ω-diiodo-1-alkynes to give products with incorporation of iodine atoms is described. Cycloisomerization of 2-(2-propynyloxy)ethyl iodides is initiated by a catalytic amount of LDA to give 3-(iodomethylene)tetrahydrofurans in high yields. Upon treatment of with a catalytic amount of 1-hexynyllithium, 1ω-diiodo-1-alkynes efficiently undergo cycloisomerization to give (diiodomethylene)cycloalkanes. The diiodomethylene products are also obtained by iodine atom-transfer-type cyclization of ω-iodo-1-alkynes, using 1-iodo-1-hexyne as an external iodine atom source. Bromine atom-transfer and proton-transfer cyclization proceed as well by employing 1-bromo-1-octyne and 1-octyne, respectively. These reactions are proposed to proceed through a carbenoid-chain process involving exo-cyclization of the lithium acetylide intermediates to give Li,I-alkylidene carbenoids. It is shown that the exo-cyclization proceeded stereospecifically through inversion of the stereochemistry at the electrophilic carbon.

Full text of DOI:10.1021/jo7021179

Carbocyclization Reaction of ω-Iodo- and 1,ω-Diiodo-1-alkynes
without the Loss of Iodine Atoms through a Carbenoid-Chain
Process
Toshiro Harada,* Keiko Muramatsu, Kenta Mizunashi, Chie Kitano, Daisuke Imaoka,
Takayuki Fujiwara, and Hiroshi Kataoka
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
harada@chem.kit.ac.jp
ReceiVed September 28, 2007
Atom-economical carbocyclization reactions of ω-iodo-1-alkynes and 1,ω-diiodo-1-alkynes to give products
with incorporation of iodine atoms is described. Cycloisomerization of 2-(2-propynyloxy)ethyl iodides
is initiated by a catalytic amount of LDA to give 3-(iodomethylene)tetrahydrofurans in high yields. Upon
treatment of with a catalytic amount of 1-hexynyllithium, 1,ω-diiodo-1-alkynes efficiently undergo
cycloisomerization to give (diiodomethylene)cycloalkanes. The diiodomethylene products are also obtained
by iodine atom-transfer-type cyclization of ω-iodo-1-alkynes, using 1-iodo-1-hexyne as an external iodine
atom source. Bromine atom-transfer and proton-transfer cyclization proceed as well by employing 1-bromo-
1-octyne and 1-octyne, respectively. These reactions are proposed to proceed through a carbenoid-chain
process involving exo-cyclization of the lithium acetylide intermediates to give Li,I-alkylidene carbenoids.
It is shown that the exo-cyclization proceeded stereospecifically through inversion of the stereochemistry
at the electrophilic carbon.
Introduction
1-Alkynyl organometallics, or acetylides, are efficient carbon
nucleophiles, frequently used in organic syntheses. They react
with a variety of electrophiles generally at the carbon R to the
metal atom.1 Although being less exploited in organic synthesis,
some alkynylmetals are known to react at the â position.
Alkynylmetal ate complexes 1 such as alkynylboronates2,3 and
-zincates4 are known to react at the â position with simultaneous
migration of the ate ligand to the R position (eq 1). Transition
metal acetylides 2 such as M ) Fe, W, Mo, and Rh are known
to react with electrophiles at the â position to form vinylidene
complexes (eq 2).5
(1) (a) Pu, L. Tetrahedron 2003, 59, 9873. (b) Cozzi, P. G.; Hilgraf, R.;
Zimmermann, N. Eur. J. Org. Chem. 2004, 4095. (c) Wei, C.; Li, Z.; Li,
C.-J. Synlett 2004, 1472.
(2) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic
Press: London, UK, 1988; p 283.
We have recently disclosed that alkaline metal acetylides 3
(M ) Li, Na, K) also exhibit nucleophilic reactivity at the â
10.1021/jo7021179 CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/04/2007
J. Org. Chem. 2008, 73, 249-258
249

Harada et al.
SCHEME 1
SCHEME 3
iodo-acetylide 9 (M ) Li, X ) I, Y ) O, n ) 1), (iodometh-
ylene)tetrahydrofuran 12 was obtained as a minor byproduct.
The iodine-containing product was assumed to be formed by
protonation of unstable Li,I-alkylidene carbenoid 10 before
decomposing into reactive carbene 11.
SCHEME 2
Organoiodine compounds are one of the most reliable
electrophiles in organic synthesis. In their reactions, however,
the iodine atom is usually not retained in the product but lost
as an iodide salt, making them less attractive from an atom
economy point of view.10 Carbon-carbon bond-forming reac-
tions 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.11
Byproduct formation of 12 in the tandem cyclization reaction
suggested that, in spite of the notorious instability, carbenoids
10 can be trapped before decomposing into carbene 11. The
alkylidene carbenoids12,13 generated through the exo-cyclization
are more reactive as a nucleophile than the starting acetylides.
We envisaged that the enhanced reactivity of the carbenoids
can be exploited as a driving force in atom-economical
cycloisomerization of iodoalkynes 13 and diiodoalkynes 14 to
give methylene-cycloalkanes 15 and 16, respectively (Scheme
3): Acetylides 17 would cyclize to form carbenoids 18, which
are reactive enough to be trapped by substrate 13 or 14 to give
product 15 or 16, respectively, with concurrent generation of
the acetylides.
position in an intramolecular reaction (eq 3).6-8 Lithium
acetylides 4 bearing a remote leaving group undergo facile exo-
cyclization at the â position to generate cycloalkylidene
carbenoids 5, which decompose to carbenes 6, undergoing
cyclopropanation, Si-H insertion, and addition by acetylides
(Scheme 1).6,9 A tandem cyclization of alkynes 7 leading to
bicyclic products 8 was developed by the use of regioselective
intramolecular C-H insertion of cycloalkylidene carbenes 11
generated by the exo-cyclization (Scheme 2).7 Lithium, sodium,
and potassium acetylides bearing tosyloxy and iodo leaving
groups underwent the tandem cyclization. In the reaction of
Herein, we wish to report cycloisomerization of iodoalkynes
and diiodoalkynes to afford (iodomethylene)- and (diiodometh-
ylene)cycloalkanes through a novel carbenoid-chain process
(10) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
(11) For iodine transfer radical cyclization of hex-5-enyl and hex-5-ynyl
iodides, see: (a) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc.
1989, 111, 6265. (b) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54,
3140. (c) Ichinose, Y.; Matsunaga, S.; Fugami, K.; Oshima, K.; Utimoto,
K. Tetrahedron Lett. 1989, 30, 3155. (d) Yorimitsu, H.; Nakamura, T.;
Shinokubo, H.; Oshima, K. J. Org. Chem. 1998, 63, 8604. (e) Yorimitsu,
H.; Nakamura, T.; Shinokubo, H.; Oshima, K.; Omoto, K.; Fujimoto, H. J.
Am. Chem. Soc. 2000, 122, 11041. (f) Chakraborty, A.; Marek, I. Chem.
Commun. 1999, 2375. (g) Yanada, R.; Koh, Y.; Nishimori, N.; Matsumura,
A.; Obika, S.; Mitsuya, H.; Fujii, N.; Takemoto, Y. J. Org. Chem. 2004,
69, 2417.
(12) (a) Ko¨brich, G. Angew. Chem., Int. Ed. Engl. 1965, 4, 49. (b)
Ko¨brich, G. Angew. Chem., Int. Ed. Engl. 1967, 6, 41. (c) Ko¨brich, G.
Angew. Chem., Int. Ed. Engl. 1972, 11, 473. (d) Stang, P. J. Chem. ReV.
1978, 78, 383. (e) Taber, D. F. Methods of Organic Chemistry (Houben
Weyl); Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.;
Georg Thieme Verlag: New York, 1995; Vol. E21a, p 1127. (f) Kirmse,
W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1164. (g) Braun, M. Angew.
Chem., Int. Ed. Engl. 1998, 37, 430. (h) Boche, G.; Lohrenz, J. C. W. Chem.
ReV. 2001, 101, 697. (i) Knorr, R. Chem. ReV. 2004, 104, 3795.
(13) For Li,I-alkylidene carbenoids, see: (a) Barluenga, J.; Rodriguez,
M. A.; Campos, P. J.; Asensio, G. J. Am. Chem. Soc. 1988, 110, 5567-
5568. (b) Barluenga, J.; Gonzalez, J. M.; Llorente, I.; Campos, P. J.;
Rodriguez, M. A.; Thiel, W. J. Organomet. Chem. 1997, 548, 185-189.
(3) (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.
(4) (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.
(5) (a) Bruce, M. I. Chem. ReV. 1991, 91, 197. (b) Bruneau, C.; Dixneuf,
P. H. Angew. Chem., Int. Ed. 2006, 45, 2176. (c) Joo, J. M.; Yuan, Y.;
Lee. C. J. Am. Chem. Soc. 2006, 128, 14818 and references cited therein.
(6) Harada, T.; Iwazaki, K.; Otani, T.; Oku, A. J. Org. Chem. 1998, 63,
9007.
(7) Harada, T.; Fujiwara, T.; Iwazaki, K.; Oku, A. Org. Lett. 2000, 2,
1855.
(8) Harada, T.; Oku, A. J. Synth. Org. Chem. Jpn. 2001, 59, 101.
(9) In contrast to the nucleophilic nature of acetylides in the exo-
cyclization, addition of nucleophiles to the electrophilic â-carbon of
alkynyliodonium salts has been exploited as a versatile and efficient method
of generating alkylidene carbenes. For reviews with leading references,
see: (a) Ochiai, M. Reviews on Heteroatom Chemistry; Oae, S., Ed.;
MYU: Tokyo, Japan, 1989; Vol. 2, p 92. (b) Stang, P. J. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 274. (c) Varvoglis, A. Tetrahedron 1997, 53, 1179.
(d) Stang, P. J.; Zhdankin, V. V. Tetrahedron 1998, 54, 10927. (e) Stang,
P. J. J. Org. Chem. 2003, 68, 2997.
250 J. Org. Chem., Vol. 73, No. 1, 2008

Carbocyclization Reaction
TABLE 1. Cycloisomerization of Iodoalkyne 13a
TABLE 2. LDA-Catalyzed Cycloisomeriztion of Iodoalkynes 13
entry
base
equiv
concn (M)
yielda (%)
E:Zb
1
2
3
LDA
LDA
LDA
LDA
LDA
NaN(TMS)2
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
4
5c
6
a Isolated as an E-Z mixture after flash chromatography. b Determined
by a capillary GC analysis. The structure of (E)-15a was determined by
NOESY analysis. c 20 was also obtained in 10% yield.
involving exo-cyclization of the acetylide intermediate. The
extension of the reactions to an atom-transfer-type cyclization
of 13 (eq 4) as well as some mechanistic aspects in exo-
cyclization of acetylides are also described.14
Results and Discussion
Cycloisomerization of Iodoalkynes. Treatment of iodoalkyne
13a with 0.2 equiv of LDA in THF at 0.1 M for 5 h at room
temperature gave cycloisomerization product (E)-15a stereose-
lectively in 30% yield together with the recovery of 13a (60%)
(Table 1, entry 1). Reactions at higher concentrations of 0.5
and 1.0 M gave (E)-15a in the improved yields of 74% and
70%, respectively, demonstrating the catalytic nature of the
cycloisomerization reaction (entries 2 and 3). It should be noted
that, in these reactions, any products derived from the inter-
molecular substitution reaction of an acetylide intermediate were
not observed.15 The use of a reduced amount of LDA gave rise
to lower conversion of the reaction (entry 4), whereas an
increased amount of the base did not give a better result and
tandem-cyclization product 20 (10%) was obtained as a byprod-
uct (entry 5). The formation of (E)-15a, albeit in low yield,
was also observed with NaN(TMS)2 (entry 6) but not with
KN(TMS)2. No reaction was observed when the reaction with
LDA was carried out in ether. Bromoalkyne 21 did not undergo
similar cyclization even at 65 °C.
The scope of LDA-initiated carbocyclization of iodoalkynes
13 is summarized in Table 2. The reaction of cyclohexyl
derivative 13b also proceeded with LDA (0.2 equiv) at room
temperature to give (E)-15b stereoselectively (entry 2). On the
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, the 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 °C
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
1
geometrical isomer was not detected by H NMR analysis. k The reaction
was carried out by using 0.1 equiv of LDA.
successfully applied to acetal derivatives 13d-i. Acetal 13d,
not bearing substituents at the propargylic position, was slightly
less reactive but the corresponding cycloisomerization product
other hand, iodoalkyne 13c bearing phenyl group â to the iodine
atom was found to be less reactive. The reaction with 0.4 equiv
of LDA at 65 °C afforded 15c as a mixture of stereoisomers in
30% yield (entry 3). The present cycloisomerization was
(15) Intermolecular reactions of lithium acetylides with primary iodoal-
kanes are slow in THF at room temperature and generally carried out in
the presence of polar additives such as HMPA. (a) Fletcher, S.; Ahmad,
A.; Perouzel, E.; Heron, A.; Miller, A. D.; Jorgensen, M. R. J. Med. Chem.
2006, 49, 349. (b) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.
Tetrahedron 2006, 62, 5126. (c) Narayan, R. S.; Borhan, B. J. Org. Chem.
2006, 71, 1416.
(14) For a preliminary report of the work described here, see: (a) Harada,
T.; Muramatsu, K.; Fujiwara, T.; Kataoka, H.; Oku, A. Org. Lett. 2005, 7,
779. (b) Harada, T.; Mizunashi, K.; Muramatsu, K. Chem. Commun. 2006,
638. (c) Harada, T.; Kitano, C.; Mizunashi, K. Synlett 2007, 1130.
J. Org. Chem, Vol. 73, No. 1, 2008 251

Harada et al.
TABLE 3. Cycloisomerization of Diiodoalkyne 14g To Give 16g
15d was obtained in 81% yield by carrying out the reaction at
40 °C (entry 4). E-selective cycloisomerization was observed
for acetals 13e-h bearing substituents at the propargylic position
(entries 5-9). A smooth reaction took place for gem-disubsti-
tuted 13g even with 0.1 equiv of LDA (entry 9). Although
extremely sluggish even at 65 °C, the reaction of the trans-
cyclic secondary iodide 13i afforded cis-fused bicyclic product
(Z)-15i (entry 10). The substrate for the LDA-initiated cyclo-
isomerization is limited to 2-(2-propynyloxy)ethyl iodide deriva-
tives 13 (Y ) O, n ) 1). Attempted reaction of iodoalkynes 22
and 23 did not give the anticipated cyclopentane and tetrahy-
dropyran derivatives.
temp time yield recovery
entry
base
BuLi
equiv solvent (°C)
(h)
(%)
(%)a
1
2
3
4
5
6
7
8
0.2
0.4
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.4
THF
THF
THF
THF
THF
40
40
40
40
0
2
2
22
2
22
2
22
4
69
48
61
85
86
65
80
0
BuLi
BuC≡CLi
BuC≡CLi
BuC≡CLi
BuC≡CLi
BuC≡CLi
BuC≡CLi
BuC≡CLi
BuC≡CNa
EtMgCl
16 (5)
DME 40
DME
Et2O
Et2O
THF
THF
0
30
30
0-40
0-40
90 (10)
43 (14)
42 (15)
66 (26)
9b
10
11
4
4
4
13
0
0
a The yield of iodoalkyne 13g is shown in parentheses. b The reaction
was carried out in the presence of TMEDA (1.0 equiv).
for 2 h gave 3-(diiodomethylene)tetrahydrofuran 16g in 69%
(eq 7, Table 3, entry 1). An increase in the amount of
According to our supposition, the cycloisomerization reaction
of iodoalkynes 13 proceeds through a chain mechanism depicted
in Scheme 3 (Z ) H). Thus, lithium acetylide 17, generated by
the lithiation of 13 with LDA, undergoes exo-cyclization to give
alkylidene carbenoid 18, which is basic enough to abstract the
terminal acetylenic proton of 13 to give cycloisomerization
product 15 with simultaneous generation of 17. The atom
transfer radical cyclization of analogous hex-5-ynyl iodides
giving rise to cycloisomerization products has been reported.11
Alternatively, the cycloisomerization reaction may proceed
through the radical mechanism if LDA acts as a radical
initiator.16 However, such a mechanism is quite unlikely judging
from the following observations. In the reaction of 13f pos-
sessing both hex-5-ynyl and hex-5-enyl iodide structures (Table
2, entry 6), no product derived from cyclization on the olefinic
moiety was formed. Low stereoselectivity has been reported
for the radical cyclization of hex-5-hexynyl iodides.11 Indeed,
when 13a was treated with radical initiator Et3B in hexane at
room temperature under air according to the procedure reported
by Oshima et al.,11c-e 15a was obtained with low stereoselec-
tivity (E:Z ) 2.7:1) in 49% yield. To the contrary, high E
selectivity (9.1:1) was observed in the reaction with LDA (Table
1, entry 2).
butyllithium resulted in the lower yield of 16g (entry 2). An
improvement in the yield of 16g was obtained by the use of
1-hexynyllithium as an initiator. Thus, in the presence of 0.2
equiv of 1-hexynyllithium in THF at 40 °C, 14g cyclized to
give 16g in 85% yield (entry 3). Decreasing further the amount
of the initiator decreased the product yield together with the
recovery of the starting diiodide (16%) and formation of
iodoalkyne 13g (5%) (entry 3). At 0 °C, the cycloisomerization
reaction proceeded slowly (33% conversion after 2 h) but
steadily, reaching full conversion of 14g after 22 h, to give 16g
in 86% yield (entry 5). The cycloisomerization proceeded also
in DME with a slightly lower efficiency (entries 6 and 7). No
reaction was observed in less polar diethyl ether (entry 8).
However, in the presence of TMEDA (1.0 equiv), low-yield
formation of 16g was observed (entry 9). Neither 1-hexynyl-
sodium nor EtMgCl was effective as an initiator (entries 10 and
11). In these reactions, the formation of iodoalkyne 13g was
observed, indicating generation of the corresponding sodium
and magnesium acetylide intermediates.
The scope of the cycloisomerization was investigated for other
diiodoalkynes (Table 4). A variety of 2-(3-iodo-2-propynyloxy)-
ethyl iodides underwent cycloisomerization in the presence of
1-hexynyllithium (0.2 equiv) at 40 °C in THF to give 3-(di-
iodomethylene)tetrahydrofurans (entries 1-10). The efficiency
of the reaction was influenced by substituents on a parent mole-
cule. The reaction of gem-disubstituted derivatives 14g,h,j-l,
irrespective of the ethoxy group R to the oxygen atom, gave
the corresponding cycloisomerization products 16g,h,j-l in high
yield (entries 1-5). Parent nonsubstituted diiodoalkyne 14m
underwent cyclization to give 16m in 50% yield (entry 8). While
a relatively high yield formation of 16a,e was observed for 14a,e
bearing a substituent at the propargylic position (entries 6 and
7), the reaction of 2-phenyl derivative 14c resulted in low-yield
formation of the corresponding product 16c (entry 9). The
reaction of secondary iodide 14n took place at 60 °C to give
16n in low yield (entry 10). With 0.2 equiv of 1-hexynyllithium,
A support for the proposed carbenoid-chain mechanism was
provided by deuterium-labeling experiments. The reaction of
13a-d (98% d) with LDA (0.2 equiv) gave (E)-15a-d (90% d)
in 70% yield. When a 1:1 mixture of 13a-d and 13b was treated
with LDA, deuterium incorporation was observed not only into
(E)-15a-d (48%-d) (65% yield) but also into (E)-15b-d (51%-
d) (58% yield) (eq 6). The observation of deuterium scrambling
is well in accord with an intermolecular deuterium (and proton)
transfer during the cycloisomerization process (Scheme 3).
Cycloisomerization of Diiodoalkynes. Treatment of di-
iodoalkyne 14g with butyllithium (0.2 equiv) in THF at 40 °C
(16) Ashby, E. C.; Sun, X.; Duff, J. L. J. Org. Chem. 1994, 59, 1270.
252 J. Org. Chem., Vol. 73, No. 1, 2008

Carbocyclization Reaction
TABLE 4. Cycloisomerization of Diiodoalkynes 14 with
Hexynyllithiuma
the reaction of homologous 2-(3-iodo-2-propynyloxy)propyl
iodides 14o,p was sluggish at 40 °C. However, by using 0.4
equiv of the initiator, 3-(diiodomethylene)tetrahydropyrans 16o,p
were obtained in moderate yields (entries 11 and 12).
Treatment of 1,6-diiodo-1-hexyne (14q) with 1-hexynyl-
lithium (0.2 equiv) at 40 °C gave cycloisomerization product
16q in 11% yield (entry 13). Again, an improvement in the
product yield was obtained by the increase of the amount of
the initiator (entries 14 and 15). In these reactions, byproduct
formation of enyne 24 and/or 25 was observed.17 By using 0.4
equiv of 1-hexynyllithium, (diiodomethylene)cyclopentanes
16r,s were obtained in moderate yield in the reaction of the
substituted derivatives 14r,s (entries 16 and 17).
It should be noted that the cycloisomerization of diiodo-
alkynes 14 could not be achieved through a radical chain
reaction. Thus, for example, treatment of 14g with radical
initiator Et3B (0.2 equiv) in hexane at room temperature for 8
h resulted in the recovery of 14g (69%) without the formation
of cycloisomerization product 16g.
The cycloisomerization of diiodoalkynes 14 is rationalized
by a carbenoid-chain mechanism analogous to that proposed
for the reaction of iodoalkyne 13 (Scheme 3, Z ) I). The
initiation step involves selective iodine/lithium exchange of
diiodoalkyne 14 at the acetylenic carbon by the organolithium
compounds (RLi) (eq 8). Lithium acetylide 17, thus generated,
undergoes exo-cyclization to give carbenoid 18, which, in turn,
undergoes iodine/lithium exchange with 14 to give product 16
with concurrent generation of 17. According to this chain
mechanism, stoichiometric conversion of 14 into the product
would be achieved only when carbenoid 18 undergoes iodination
not only by 14 but also by RI, which is formed in the initiation
step (eq 9). The observation that the yield of 16g decreased
with the increase of the amount of butyllithium (Table 3, entries
1 and 2) implies that 1-iodobutane (R ) Bu) does not serve as
an iodine donor toward carbenoid 20. On the other hand, when
1-hexynyllithium was employed as an initiator, 1-iodo-1-hexyne
(R ) BuCtC) could participate in iodination of carbenoid 4,
thus leading to the high-yield formation of 16g.
In comparison with the cycloisomerization reaction of iodo-
alkynes 13, the reaction of diiodoalkynes 14 proceeded more
efficiently, realizing higher yields of the products. The less
efficient nature of the reaction of iodoalkynes 13 is most
probably owing to the competing decomposition of carbenoid
a Unless otherwise noted, the reactions were carried out with 0.2 equiv
of 1-hexynyllithium in THF at 40 °C for 2-4 h. b 0.4 equiv of 1-hexynyl-
lithium was used. c The reaction was carried out at 60 °C. d Enyne 24 was
obtained in 11% (entry 13), 33% (entry 14), and 36% yield (entry 15).e 0.3
equiv of 1-hexynyllithium was used. f Enyne 25 was obtained in 21% yield.
(17) Boatman, R. J.; Whitlock, B. J.; Whitlock, H. W., Jr. J. Am. Chem.
Soc. 1977, 99, 4822.
J. Org. Chem, Vol. 73, No. 1, 2008 253

Harada et al.
SCHEME 4
SCHEME 5
intermediate 18 before undergoing proton abstraction to form
the cycloisomerization product 15. Halogen/lithium exchange
by organolithium compounds is known to be much faster than
proton abstraction.17 A rapid transformation of labile carbenoid
18 by iodine/lithium exchange to the product might be respon-
sible for the higher efficiency of the cycloisomerization reaction
of diiodoalkynes.
It is most probable that the exo-cyclization of acetylide 17 is
a rate-determining step of the cycloisomerization reaction,
considering from a fast rate of iodine/lithium exchange to
generate 17 and high reactivity of the resulting carbenoid 18.
The advantageous effect of gem-disubstitution18 observed in
tetrahydrofuran-ring formation (Table 4, entries 1-5) is ratio-
nalized by the acceleration of the exo-cyclization step. The exo-
cyclization to form a tetrahydropyran ring was slower and
required a prolonged reaction at 40 °C, resulting in the chain
termination through the decomposition of the corresponding
carbenoid with elimination of LiI. This might be the reason why
a larger amount of the initiator was required in the reaction of
2-(3-iodo-2-propynyloxy)propyl iodides 14o,p.
In the cycloisomerization reaction of 1,6-diiodo-1-hexyne
(14q), formation of enyne 24 and/or 25 was also observed.
Cyclopentylidene carbenoid 18q is prone to undergo Fritsch-
Buttenberg-Wiechell rearrangement19 to form cyclohexyne
(Scheme 4).20,12i, Enynes 24 and 25 were most probably
produced through carbolithiation of thus generated cyclohexyne
with lithium acetylide 17q and 1-hexynyllithium6a,21 followed
by iodination of the resulting alkenyllithium 26 and 27,
respectively. In the reaction of oxa-derivatives 14a-n, no such
byproduct was detected. The result implies that the rearrange-
ment of cyclopentylidene carbenoids to cyclohexynes, which
proceeds fast enough to complete the rapid lithium/iodine
exchange reaction, is considerably retarded by the introduction
of the oxygen atom in the ring.
of the resulting cycloalkylidene carbenoids. The cycloisomer-
ization of diiodoalkynes, especially that of 2-(3-iodo-2-propy-
nyloxy)ethyl iodides, would afford us indirect but reliable
information on the exo-cyclization judging from the observed
high efficiency in trapping the carbenoid intermediate through
the facile lithium/iodine exchange reaction.
There are two plausible pathways for the exo-cyclization
(Scheme 5). π-Electrons of acetylide 17′ attack on the electro-
philic carbon (π-type cyclization)22 with simultaneous transfer
of the departed iodide anion to the carbon bearing the lithium
atom, leading to the formation of carbenoid 18′ in a concerted
manner (path a). Alternatively, the exo-cyclization proceeds
through a stepwise mechanism involving initial π-type cycliza-
tion followed by the internal return of the resulting intimate
ion pair 28 (path b). The two pathways could be discriminated
by the stereochemistry of the reaction: Cyclization through
concerted path a and stepwise path b would give retention
product 18′ and inversion product 18′′, respectively.
Although inversion product (Z)-15i was obtained in the
cycloisomerization of secondary iodide 13i (Table 2, entry 10),
the reaction was extremely sluggish and the structures of the
substrate and the product were relatively constrained. We
therefore examined the cycloisomerization of diiodoalkyne anti-
14t and syn-14t (eq 11). Iodoetherification of 1-ethoxy-1-
Stereochemistry. A major difficulty in a detailed study on
the unprecedented exo-cyclization of acetylides is the instability
(18) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080. (b) Lightstone, F. C.; Bruice, T. C. J. Am. Chem. Soc. 1994,
116, 10789. (c) Schleyer, P. v. R. J. Am. Chem. Soc. 1961, 83, 1368. (d)
Milstein, S.; Cohan, L. A. J. Am. Chem. Soc. 1972, 94, 9166.
(19) (a) Fritsch, P. Liebigs Ann. Chem. 1894, 279, 319. (b) Buttenberg,
W. P. Liebigs Ann. Chem. 1894, 279, 324. (c) Wiechell, H. Liebigs Ann.
Chem. 1894, 279, 337. (d) Rezaei, H.; Yamanoi, S.; Chemla, F.; Normant,
J. F. Org. Lett. 2000, 2, 419. (e) Luu, T.; Tykwinski, R. R. J. Org. Chem.
2006, 71, 8982 and references cited therein.
(20) (a) Meier, H. AdV. Strain Org. Chem. 1991, 1, 215. (b) Erickson,
K. L.; Wolinsky, J. J. Am. Chem. Soc. 1965, 87, 1143. (c) Fitjer, L.;
Kliebisch, U.; Wehle, D.; Modaressi, S. Tetrahedron Lett. 1982, 23, 1661.
(d) Gilbert, J. C.; Baze, M. E. J. Am. Chem. Soc. 1983, 105, 664. (e) Gilbert,
J. C.; Baze, M. E. J. Am. Chem. Soc. 1984, 106, 1885. (f) Tseng, J.; McKee,
M. L.; Shevlin, P. B. J. Am. Chem. Soc. 1987, 109, 5474.
propene (Z:E ) 74:26) with iodoalkynol 29 and NIS gave anti-
and syn-14t as an inseparable 25:75 mixture (eq 10). Treatment
of the mixture at 40 °C for 21 h in the presence of 1-hexynyl-
254 J. Org. Chem., Vol. 73, No. 1, 2008

Carbocyclization Reaction
TABLE 5. Cycloisomerization of anti- and syn-14t
products yield (%)a
entry
14t anti:syn
BuCtCLi (equiv)
temp (°C)
time (h)
trans-16t
cis-16t
syn-13t
syn-14t
1
2
3
25:75
38:62
2:98
0.2
0.3
0.3
40
40
50
21
2
22
15 (60)
32 (84)
2 (100)
trace
7 (11)
18 (18)
7 (9)
20 (32)
3 (3)
47 (63)b
23 (37)
16 (16)
1
a Determined by H NMR analysis. Yields based on anti- and syn-14t are shown in parentheses. b anti-14t was recovered in 3% yield.
SCHEME 6
lithium (0.2 equiv) gave cycloisomerization product trans-16t
in 15% yield together with a trace amount of cis-16t (Table 5,
entry 1). Stereochemistry of the cycloisomerization products was
determined by 1H NMR NOESY analysis. In this reaction, anti-
14t was almost consumed while syn-14t was recovered in 47%
yield and iodoalkyne syn-13t was formed in 7% yield. The result
suggests that anti-14t reacted smoothly to give trans-16t (60%
yield based on the anti-14t) and that syn-14t is less reactive
resulting in the recovery (63% based on the syn-14t) and in the
formation of syn-13t (9% yield based on the syn-14t).
When a 38:62 mixture of anti- and syn-14t was treated with
0.3 equiv of 1-hexynyllithium at 40 °C for 2 h, a product
distribution similar to that in the previous experiment was
observed with an increased yield of minor cis-16t (7%) (entry
2). Taking advantage of the less reactive nature of syn-14t, we
could obtain a syn-enriched 2:98 mixture of the diiodoalkyne
by recovering the starting material from the reaction mixture
of the cycloisomerization. Upon treatment with 0.3 equiv of
1-hexynyllithium at 50 °C, for 22 h, syn-14t underwent slow
cyclization to give cis-16t in 18% yield (entry 3).
The cycloisomerization of anti-14t proceeded rapidly and
iodide (R-I), which affords 16 together with RLi, the latter
serving as a base to undergo lithiation of 13 (eq 13).
efficiently to give trans-16t. On the other hand, the reaction of
syn-14t was slower and less efficient to give cis-16t. These
stereochemical results clearly showed that the exo-cyclization
proceeded stereospecifically through inversion of the stereo-
chemistry at the electrophilic carbon. Accordingly, the stepwise
mechanism (path b), involving a π-type cyclization and the
internal return of the resulting intimate ion pair 28, is most
probable for the exo-cyclization of lithium acetylides 17.
The likely origin of difference in reactivity between the anti
and syn isomers can be seen by comparing SN2-type trigonal-
bipyramidal transition state structures TS-A and -B (Scheme
6). Assuming the pseudoaxial orientation of the ethoxy group
by anomeric effect, anti-14t cyclized through TS-A ()TS-A′).
Note that the reaction of syn-14t leads to an eclipsing interaction
in TS-B ()TS-B′) between the ethoxy group and the methyl
group adjacent to the reacting center, which is absent in TS-A.
To circumvent the eclipsing interaction, anti-14t is required to
cyclize through TS-C ()TS-C′) with the sacrifice of the
anomeric stabilization.23
Indeed, treatment of iodoalkyne 13k with 1-iodo-1-hexyne
(1.1 equiv) in the presence of 1-hexynyllithium (0.4 equiv) in
THF at 40 °C for 2 h gave anticipated diiodo product 16k in
80% yield (eq 14) (entry 2 in Table 6). When an amount of
Atom-Transfer-Type Carbocyclization. Since mono-iodo-
alkynes 13 are synthetically more accessible than diiodides 14,24
the reaction of 13 leading to the same diiodo products 16 by
using an external iodine atom source would be more useful (eq
12). Such iodine atom-transfer-type cyclization can be realized
through iodination of the carbenoid intermediate 18 with an
1-hexynyllithium was reduced to 0.2 equiv, essentially no
cyclization was observed (entry 1). With 1.0 equiv of 1-hexy-
nyllithium, the yield of 16k was decreased and byproduct
formation of enyne 30 (8%) was observed (entry 3). When
iodobenzene or 2-iodothiophene was employed as an iodine
atom source in combination with phenyllithium or 2-thienyl-
lithium, respectively, monoiodo product 15k was obtained in
moderate yield without formation of diiodo product 16k (entries
4 and 5).
(21) (a) Nakagawa, M. Cyclic Acetylenes. In The Chemistry of Carbon-
Carbon Triple Bond; Patai, S., Ed.; J. Wiley & Sons: New York, 1978; p
635. (b) Roberts, J. D. J. Am. Chem. Soc. 1960, 82, 4750. (c) Wittig, G.;
Pohlke, R. Chem. Ber. 1961, 94, 3276. (d) Gassman, P. G.; Valcho, J. J. J.
Am. Chem. Soc. 1975, 97, 4768.
(22) (a) Negishi, E.; Boardman, L. D.; Sawada, H.; Bagheri, V.; Stoll,
A. T.; Tour, J. M.; Rand, C. L. J. Am. Chem. Soc. 1988, 110, 5383. (b)
Liu, F.; Negishi, E. Tetrahedron Lett. 1997, 38, 1149.
J. Org. Chem, Vol. 73, No. 1, 2008 255

Harada et al.
TABLE 6. Iodine Atom-Transfer-Type Cyclization of 13k with
RI/RLia
TABLE 8. Bromine Atom-Transfer-Type Carbocyclization of
Iodoalkynes 13a
yield (%)
iodoalkyne
products: yieldb (%)
R-Li
(equiv)
entry
R-I
16k
15k
entry
R1
R2
Y
19
31
1
BuCtCI
0.2
0.4
1.0
0.4
0.2
trace
80
69
0
0
0
0
43
30
1
13k
-(CH2)5-
H
19k: 45
19k: 46
19h: 42
19l: 36
31k: 40
31k: 17
31h: 46
31l: 47
2c
3
2
3b
4
13h
13l
-(CH2)5-
OEt
OEt
C6H5I
2-ThIc
4
i-Bu
Me
5
0
a Reactions were carried out with 1-bromo-1-octyne (1.7 equiv) and
1-octynyllithium (0.4 equiv) in THF (0.5 M) at 0 °C for 14-20 h. b The
yield was based on a 1H NMR analysis of a mixture of 31 and 32 obtained
by column chromatography. c Diiodo product 16k was obtained in 26%.
a Unless otherwise noted, reactions were carried out in THF (0.5 M) at
40 °C for 2-6 h. b Enyne 30 was obtained in 8% yield. c 2-Iodothiophene.
TABLE 7. Iodine Atom-Transfer-Type Carbocyclization of
Iodoalkynes 13a
furans 19 were obtained along with 3-(dibromomethylene)-
tetrahydrofurans 31 (eq 16). Thus, treatment of iodoalkyne 13k
iodoalkyne
yield
entry
Y
n
R1
R2
R3
product (%)b
1
2
3
4
5
6
7
8
9
13k
13h
13j
13g
13l
13a
13m
13q
13o
O
O
O
O
O
O
O
CH2
O
1
1
1
1
1
1
1
1
2
-(CH2)5-
-(CH2)5-
H
EtO
H
16k
16h
16j
16g
16l
16a
16m
16q
16o
80
77
78
81
78
71
55
13c
20c
Me
Me
Me
Me EtO
i-Bu
PhCH2CH2
Me
H
H
H
H
H
H
H
H
H
H
H
PhCH2CH2
a Reactions were carried out with 1-iodo-1-hexyne (1.1 equiv) and
1-hexynyllithium (0.4 equiv) in THF (0.5 M) at 40 °C in for 1-2 h.
b Isolated yield unless otherwise noted. c Yields were determined by 1H
NMR.
with 1-bromo-1-octyne (1.7 equiv) in the presence of 0.4 equiv
of 1-octynyllithium (0.4 equiv) at 0 °C for 14 h gave 19k and
31k in 45% and 40% yield, respectively (Table 8, entry 1).
Bromoiodo product 19k was obtained as a single diastereomer,
whose E geometry was assigned tentatively by analogy to the
selective formation of E-cycloisomerization products in the
reaction of iodoalkynes 13 (Table 2). When a limited amount
of 1-bromo-1-octyne (0.9 equiv) was used under otherwise the
same conditions, byproduct formation of dibromo product 31k
was reduced (entry 2). However, diiodo product 16k was also
produced in 26% yield. No improvement was observed for the
yield of 19k. The reaction of iodoalkyne 13h and 13l with
1-bromo-1-octyne also gave a mixture of the corresponding
bromoiodomethylene products 19h,l and dibromomethylene
products 31h,l in comparable yields (entries 3 and 4).
In the cycloisomerization of iodoalkynes 13 initiated by LDA,
unstable carbenoid intermediate is trapped with the terminal
acetylenic proton of the substrates (Scheme 3, Z ) H). The use
of alkynyllithium, instead of LDA, as an initiator, in combination
with the corresponding terminal alkyne, would improve the
efficiency of the cycloisomerization by an increased rate in
protonation of the unstable carbenoid intermediate. When
iodoalkynes 13a,g,k were treated with 1-octynyllithium (0.4
equiv) and 1-octyne (0.4 equiv) at 0 °C for 12 h, the anticipated
cycloisomerization reaction proceeded to give cycloisomeriza-
tion products 15a,g,k (eq 17). However, the product yields were
The scope of the iodine atom-transfer-type carbocyclization
was investigated under the conditions using 1-iodo-1-hexyne
(1.1 equiv) with 1-hexynyllithium (0.4 equiv) at 40 °C (eq 15,
Table 7). 2-(2-Propynyloxy)ethyl iodides 13a-m underwent a
smooth cyclization to give the corresponding 3-(diiodomethyl-
ene)tetrahydrofurans 16a-m. Of these, 4,4′-disubstituted de-
rivatives 13g,h,j,k,l, irrespective of the ethoxy substitution â
to the iodine atom, gave the corresponding products in high
yields (entries 1-5). On the other hand, the efficiency of the
reaction was steadily lowered for monosubstituted derivative
13a (entry 6) and for nonsubstituted derivative 13m (entry 7).
Cyclopentane ring-formation of 6-iodo-1-hexyne (13q) as well
as tetrahydropyran ring-formation of the homologous substrate
13o also proceeded under these conditions, albeit with low
product yields (entries 8 and 9).
When 1-bromo-1-octyne was used instead of 1-iodo-1-
hexyne, the corresponding 3-(bromoiodomethylene)tetrahydro-
(23) Low yields of cycloisomerization products were observed in the
reaction of 13c and 14c, bearing a phenyl group â to the leaving iodine
atom (entry 2 in Table 2 and entry 9 in Table 4). The observation is also
rationalized by the SN2-type transition state (TS-D), where unfavorable
interaction exists between the iodine atom and the phenyl group.
not much improved, being comparable to those in the LDA-
initiated reactions (entries 1 and 7 in Table 2).
(24) For the preparation of 13 and 14, see the Supporting Information.
256 J. Org. Chem., Vol. 73, No. 1, 2008

Carbocyclization Reaction
SCHEME 7
and bromoiodo products 19 may undergo iodine/lithium ex-
change reaction with 1-alkynyllithiums in a reversible manner
(eq 18). Indeed, when 3-(diiodomethylene)tetrahydrofuran 16k
was treated with 1-bromo-1-octyne (1.7 equiv) in the presence
of 1-octynyllithium (0.4 equiv) at 0 °C for 2 h, bromoiodo-
methylene derivative 19k was obtained in 72% yield along with
31k (10%) and 16k (7%) (eq 19). The result indicates that 16k
underwent the iodine/lithium exchange reaction with 1-octy-
nyllithium to give carbenoid 18, which reacted with 1-bromo-
1-octyne to give 19k. Minor formation of dibromomethylene
derivative 31k is rationalized by the iodine/lithium exchange
of 19k followed by bromination of the resulting Li,Br carbenoid
33.
In the cycloisomerization of diiodoalkynes 14 (eq 4, Z ) I)
and the iodine atom-transfer-type cyclization of iodoalkynes 13
(eq 15), it is very likely that the iodine/lithium exchange reaction
of the product 16 with alkynyllithiums (eq 18, Z ) I) takes
place reversibly as a nonproductive pathway. The reversible
exchange reaction (eq 18, Z ) Br) is responsible for the
formation of dibromo derivative 31 in the reaction of 13 with
1-bromo-1-octyne (eq 16). 1-Iodo-1-octyne concurrently pro-
duced in this reaction may serve as an iodine atom donor to
give diiodo derivative 16k as another byproduct in the reaction
with 0.9 equiv of 1-bromo-1-octyne (Table 8, entry 2).
According to our initial supposition, the iodine and bromine
atom-transfer-type cyclization might proceed through a chain
mechanism in which alkylidene carbenoid 18 is trapped by
1-halo-1-alkynes (RCtCZ; Z ) I, Br) with concurrent formation
of the 1-alkynyllithium (RCtCLi), serving as a base to generate
acetylide 17 under equilibrium conditions (Scheme 7, path a).
When 13k was treated at -20 °C with 1-iodohexyne (1.1 equiv)
and 1-hexynyllithium (0.4 equiv) for 2 h, a 39:61 mixture of
diiodoalkyne 14k and 13k was obtained without the formation
of 16k. The observation suggests an alternative mechanism (path
b) for the cyclization: The starting alkyne 13 is first converted
into diiodoalkyne 14 or bromoiodoalkyne 32 via lithium/halogen
exchange of acetylide 17 with RCtCZ (Z ) I, Br) and then
undergoes cycloisomerization through a carbenoid chain mech-
anism. It is most probable that both pathways are operating
concurrently in the present cyclization.
In the iodine atom-transfer-type cyclization of 13k with 1.0
equiv of 1-hexynyllithium, enyne 30 was obtained as a minor
byproduct (Table 6, entry 3). The enyne might be formed by
the addition of 1-hexynyllithium to carbenoid intermediate 18
followed by iodination of the resulting alkenyllithium.6 The
cyclization reaction leading to diiodo product 16 did not occur
with iodobenzene/phenyllithium or 2-iodothiophene/2-thienyl-
lithium (Table 6, entries 4 and 5). It has been shown, by a
combination of theoretical studies with NMR and crystal
structure investigations, that the C-Li bonds of lithium car-
benoids have high s-character, causing a higher p-character of
the C-X bond.12h,25 The C-Li bond of alkylidene carbenoids
is close to sp hybridized and stabilized.25c Accordingly, the
reaction of the iodoarenes either with carbenoid 18 (path a) or
with acetylide 17 (path b) to form relatively unstable sp2-
hybridized aryllithiums is an unfavorable process. Under these
conditions, carbenoid 18 rather underwent proton abstraction
from 13 leading to the formation of cycloisomerization product
15.
Conclusion
We have described new carbocyclization reactions of iodo-
and diiodoalkynes to give products with incorporation of iodine
atoms through a novel carbenoid-chain process. In the presence
of a catalytic amount of LDA, 2-(2-propynyloxy)ethyl iodides
13 underwent cycloisomerization to give 3-(iodomethylene)-
tetrahydrofurans 15 in high yields. By the use of 1-hexynyl-
lithium as an initiator, cycloisomerization of 1,ω-diiodo-1-
alkynes 14 proceeded in an efficient manner to furnish
diiodomethylene products 16. Diiodomethylene products 16
were also obtained in high yield by the reaction of iodoalkynes
13 and 1-iodo-1-hexyne in the presence of a catalytic amount
of the corresponding 1-alkynyllithium. A relevant bromine atom-
and proton-transfer-type cyclization proceeded as well by
employing 1-bromo-1-octyne and 1-octyne, respectively, in
place of 1-iodo-1-hexyne. The stereochemical outcome in the
cycloisomerization of secondary diiodoalkyne 14t clearly
showed that the exo-cyclization proceeded stereospecifically
through inversion of the stereochemistry at the electrophilic
carbon, providing support for a stepwise mechanism involving
a π-type cyclization of the acetylide moiety followed by the
internal return of the resulting intimate ion pair. The enhanced
reactivity of the lithium alkylidene carbenoids generated by the
exo-cyclization of the lithium acetylide serves as a driving force
Considering the relatively high s-character of the C-Li bond
of alkylidene carbenoids and its stability, diiodo products 16
(25) (a) Seebach, D.; Ha¨ssig, R.; Gabriel, J. HelV. Chim. Acta 1983, 66,
308. (b) Boche, G.; Marsch, M.; Mu¨ller, A.; Harms, K. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1032. (c) Boche, G.; Bosold, F.; Hermann, H.; Marsch,
M.; Harms, K.; Lohrenz, J. C. W. Chem. Eur. J. 1998, 4, 814.
J. Org. Chem, Vol. 73, No. 1, 2008 257

Harada et al.
(Na2SO4) and concentrated in vacuo. The residue was purified by
flash chromatography (SiO2, 7% ethyl acetate in hexane) to give
0.165 g (81% yield) of 16g.
in the present carbenoid-chain reactions and can be exploited
further in the development of atom-economical carbon-carbon
bond-forming reactions.
4-Bromoiodomethylene-1-oxaspiro[4.5]decane (19k) and 4-Di-
bromomethylene-1-oxaspiro[4.5]decane (31k): Typical Proce-
dure for Bromine Atom-Transfer-Type Cyclization of Iodo-
alkynes 13. To a solution of 1-octyne (0.030 mL, 0.20 mmol) in
THF (1 mL) under argon atmosphere at 0 °C was added BuLi (1.6
M solution in hexane) (0.125 mL, 0.200 mmol). The resulting
solution was stirred at 0 °C for 30 min. To the resulting solution
of 1-octynyllithium in THF was added 1-bromo-1-octyne (0.160
g, 0.846 mmol). The resulting solution was stirred at 0 °C for 30
min. To this was then added iodoalkyne 13k (0.139 g, 0.500 mmol).
The resulting solution was stirred at 0 °C for 14 h. The mixture
was poured into water and extracted three times with ethyl acetate.
The combined organic layers were dried (Na2SO4) and concentrated
in vacuo. The residue was purified by flash chromatography (SiO2,
4% ethyl acetate in hexane) to give 0.142 g of a mixture of 19k
(45% yield) and 31k (40% yield). The products were isolated by a
preparative recycling GPC (JAI LC-908 equipped with JAIGEL-
1H and -2H columns, chloroform as an eluent). 19k: 1H NMR
(500 MHz, CDCl3) δ 1.22 (1H, m), 1.50-1.67 (8H, m), 2.16-
2.25 (2H, m), 2.66 (2H, t, J ) 6.8 Hz), 3.82 (2H, t, J ) 6.8 Hz);
13C NMR (125.8 MHz, CDCl3) δ 22.0, 25.0, 30.8, 39.7, 45.1, 62.4,
85.6, 157.5; MS (EI), m/z (rel intensity) 358, 356 (M+, 27, 28),
315, 313 (100, 98), 231, 229 (76, 78); HRMS (EI) calcd for
C10H14O81BrI 357.9252, found 357.9261, calcd for C10H14O79BrI
355.9273, found 355.9282. 31k: 1H NMR (500 MHz, CDCl3) δ
1.21 (1H, m), 1.52-1.69 (8H, m), 2.09-2.18 (2H, m), 2.71
(2H, t, J ) 6.8 Hz), 3.83 (2H, t, J ) 6.8 Hz); 13C NMR
(125.8 MHz, CDCl3) δ 22.0, 25.0, 30.7, 40.3, 62.9, 78.4, 85.4,
151.9; MS (EI), m/z (rel intensity) 312, 310, 308 (M+, 13, 28,
15), 269, 267, 265 (54, 100, 52), 231, 229 (54, 57); HRMS (EI)
calcd for C10H14O81Br2 311.9370, found 311.9395, calcd for
C10H14O81Br79Br 307.9411, found 309.9399, calcd for
C10H14O79Br2 307.9411, found 307.9413.
4-Iodomethylene-1-oxaspiro[4.5]decane (15k): Typical Pro-
cedure for Proton Transfer-Type Cyclization of Iodoalkynes
13. To a solution of 1-octyne (0.059 mL, 0.40 mmol) in THF (1
mL) under argon atmosphere at 0 °C was added BuLi (1.6 M
solution in hexane) (0.13 mL, 0.20 mmol). The resulting solution
was stirred at 0 °C for 30 min. To the resulting solution of
1-octynyllithium (0.20 mmol) and 1-octyne (0.20 mmol) in THF
was added iodoalkyne 13k (0.139 g, 0.50 mmol). The resulting
solution was stirred at 0 °C for 12 h. The mixture was poured into
water and extracted twice with ethyl acetate. The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The residue
was purified by flash chromatography (SiO2, 3% ethyl acetate in
hexane) to give 0.107 g (77% yield) of 15k: 1H NMR (500 MHz,
CDCl3) δ 1.19 (1H, m), 1.32 (2H, m), 1.53-1.61 (4H, m), 1.67
(1H, m), 1.73 (2H, m), 2.61 (2H, dt, J ) 2.6 and 7.0 Hz), 3.91
(2H, t, J ) 7.0 Hz), 5.93 (1H, t, J ) 2.6 Hz); 13C NMR (125.8
MHz, CDCl3) δ 22.3, 25.3, 35.6, 38.2, 63.1, 68.8, 84.2, 160.2; MS
(EI), m/z (rel intensity) 278 (M+, 12), 235 (36), 151 (100); HRMS
calcd for C10H15OI 278.0168, found 278.0174.
Experimental Section
3-Iodomethylene-2-phenylethyltetrahydrofuran (15a): Typi-
cal Procedure for Cycloisomerization of Iodoalkynes 13. To a
solution of iodoalkyne 13a (157 mg, 0.5 mmol) in THF (1 mL)
under argon atmosphere at 0 °C was added LDA (1 M solution in
THF, 0.10 mL, 0.1 mmol). The resulting solution was stirred at
room temperature for 5 h. The mixture was poured into water and
extracted twice with ether. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The residue was purified
by flash chromatography (SiO2, 2-3% ether in hexane) to afford
116 mg (74% yield) of 15a (E:Z ) 9.0:1) as an oil. (E)-15a: 1H
NMR (500 MHz, CDCl3) δ 1.85-2.00 (2H, m), 2.56-2.66 (2H,
m), 2.73 (1H, ddd, J ) 6.9, 10.0, and 13.8 Hz), 2.82 (1H, ddd, J
) 5.2, 10.2, and 13.8 Hz), 3.86 (1H, dt, J ) 7.2 and 8.1 Hz), 4.11
(1H, ddd, J ) 5.1, 7.1, and 8.7 Hz), 4.29 (1H, m), 6.00 (1H, q, J
) 2.7 Hz), 7.20-7.36 (5H, m); NOESY experiment showed a cross-
peak between Ha (δ 6.00) and Hb (δ 1.9); 13C NMR (125.8 MHz)
δ 31.5, 36.1, 38.3, 65.6, 68.4, 80.6, 125.9, 128.35, 128.38, 141.6,
155.5. (Z)-15a: 1H NMR (500 MHz, CDCl3) δ 1.91 (1H, m), 2.15
(1H, m), 2.65 (2H, m), 2.70-2.82 (2H, m), 3.87 (1H, q, J ) 7.4
Hz), 4.12 (1H, m), 4.35 (1H, br d, J ) 8.7 Hz), 6.06 (1H, q, J )
1.7 Hz), 7.17-7.30 (5H, m); NOESY experiment showed a cross-
peak between Ha (δ 6.06) and Hb (δ 2.65); 13C NMR (125.8 MHz)
δ 31.5, 33.8, 36.1, 67.3, 67.5, 82.7, 125.8, 128.3, 128.5, 141.8,
153.3. (E)- and (Z)-15a: IR (liquid film) 3050, 1640, 1250, 740,
700 cm-1. Anal. Calcd for C13H15IO: C, 49.70; H, 4.81. Found:
C, 49.78; H, 4.82.
5-Ethoxy-3-diiodomethylene-2,2-dimethyltetrahydrofuran
(16g): Typical Procedure for Cycloisomerization of Di-
iodoalkynes 14. To a solution of 1-hexyne (23 µL, 0.20 mmol) in
THF (2 mL) under argon atmosphere at 0 °C was added BuLi (1.6
M solution in hexane) (0.14 mL, 0.22 mmol). The resulting solution
was stirred at 0 °C for 30 min. To the resulting solution of
1-hexynyllithium in THF was added diiodoalkyne 14g (0.408 g,
1.00 mmol). The resulting solution was stirred at 40 °C for 4 h.
The mixture was poured into water and extracted three times with
ethyl acetate. The combined organic layers were dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash
chromatography (SiO2, 2-5% ethyl acetate in hexane) to give 0.346
g (85% yield) of 16g: 1H NMR (500 MHz, C6D6) δ 1.11 (3H, t,
J ) 7.0 Hz), 1.54 (1H, s), 1.71 (1H, s), 2.62 (1H, dd, J ) 5.5 and
17.4 Hz), 2.88 (1H, d, J ) 17.4 Hz), 3.24 (1H, qd, J ) 7.1 and 9.4
Hz), 3.75 (1H, qd, J ) 7.1 and 9.4 Hz), 4.76 (1H, d, J ) 5.4 Hz);
13C NMR (125.8 MHz, C6D6) δ -2.6, 15.2, 26.7, 27.0, 52.5, 62.4,
85.2, 99.0, 161.3. Anal. Calcd for C9H14O2I2: C, 26.49; H, 3.46.
Found: C, 26.53; H, 3.59.
Preparation of (Diiodomethylene)tetrahydrofuran 16g from
Iodoalkyne 13g: Typical Procedure for Iodine Atom-Transfer-
Type Cyclization of Iodoalkynes 13. To a solution of 1-iodo-1-
hexyne (0.12 mL, 0.75 mmol) in THF (1 mL) under argon
atmosphere at 0 °C was added BuLi (1.6 M solution in hexane)
(0.13 mL, 0.20 mmol). The resulting solution was stirred at 0 °C
for 30 min. To the resulting solution of 1-hexynyllithium (0.2 mmol)
and 1-iodo-1-hexyne (0.55 mmol) in THF was added iodoalkyne
13g (0.141 g, 0.50 mmol). The resulting solution was stirred at 40
°C for 1.5 h. The mixture was poured into water and extracted
twice with ethyl acetate. The combined organic layers were dried
Supporting Information Available: Preparation of starting
materials 13 and 14, experimental procedure, and spectra data for
carbocyclization products 15, 16, 19, and 31. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO7021179
258 J. Org. Chem., Vol. 73, No. 1, 2008