Alkylative carbocyclization of ω-iodoalkynyl tosylates with alkynyllithium compounds through a carbenoid-chain process leading to (1-iodoprop-2-ynylidene)tetrahydrofurans and-cyclopropanes

Article abstract of DOI:10.1002/chem.201001105

Alkylative carbocyclization reactions of ω-iodoalkynyl tosylates with alkynyllithium compounds to give products with incorporated iodine atoms are described. Slow addition of 2-(3-iodoprop-2-ynyloxy)ethyl tosylates to 1-alkynyllithium compounds in tetrahy

Full text of DOI:10.1002/chem.201001105

DOI: 10.1002/chem.201001105
Alkylative Carbocyclization of w-Iodoalkynyl Tosylates with Alkynyllithium
Compounds Through a Carbenoid-Chain Process Leading to (1-Iodoprop-2-
ynylidene)tetrahydrofurans and -cyclopropanes
Toshiro Harada,* Daisuke Imaoka, Chie Kitano, and Takahiro Kusukawa[a]
Abstract: Alkylative carbocyclization
reactions of w-iodoalkynyl tosylates
with alkynyllithium compounds to give
products with incorporated iodine
atoms are described. Slow addition of
2-(3-iodoprop-2-ynyloxy)ethyl tosylates
to 1-alkynyllithium compounds in tet-
rahydrofuran at 408C followed by addi-
tional stirring at this temperature gives
(Z)-3-(1-iodoprop-2-ynylidene)tetrahy-
drofurans stereoselectively in good to
moderate yields. Under similar condi-
tions at 08C, 4-iodobut-1-ynyl tosylates
react with 1-alkynyllithium compounds
to give (1-iodoprop-2-ynylidene)cyclo-
propanes. The carbocyclization reac-
tions are proposed to proceed through
a new carbenoid-chain process involv-
ing the exo cyclization of a lithium ace-
tylide intermediate and the vinylic sub-
stitution of the resulting TsO,Li-cyclo-
alkylidenecarbenoids (Ts=tosyl) by 1-
alkynyllithium compounds.
Keywords: alkynes · carbenoids ·
cyclization · iodine · lithium
Introduction
Carbenoids carrying both a metal cation and a nucleofugal
group on the same carbon exhibit characteristic ambiphilic
reactivities.[1] They have been exploited extensively in syn-
thetic transformations as reactive intermediates.[2–6] Recent-
ly, the scope of carbenoid-mediated reactions has been
broadened further by the development of carbon–carbon
bond-forming reactions that proceed through a novel carbe-
noid-chain mechanism.[7,8]
Knorr and co-workers reported a facile and clean reaction
of 2-(halomethylidene)indanes 1 (X=Cl, Br, Y=H, Cl, Br)
with organolithium compounds, which led to a formal substi-
tution product 2 (Scheme 1).[7] It was shown clearly that the
reaction occurs through an alkylidenecarbenoid-chain mech-
anism (type 1), which involves generation of carbenoid 3
(either by deprotonation (Y=H) or by halogen/lithium ex-
change (Y=Cl, Br) with RLi (initiation step)), followed by
a fast vinylic substitution of 3 by RLi to form alkenyllithium
Scheme 1. Vinylic substitution 2-(halomethylidene)indanes through
type 1 carbenoid-chain process.
a
4,[9] and the rate-limiting transfer of Y (=H, Cl, Br) from
substrate 1 to 4 with formation of product 2, and with regen-
eration of carbenoid 3 to close the chain cycle.
Recently, we reported an efficient, atom-economical car-
bocyclization reaction of w-iodo- and 1,w-diiodo-1-alkynes
5a,b, which led to cycloisomerization products 6a,b
(Scheme 2).[8] For example, treatment of iodoalkyne 5a (Y=
H, Z=O, n=1) with a catalytic amount of LDA affords the
6a (Y=H, Z=O, n=1). The cycloisomerization reaction
proceeds through a carbenoid-chain mechanism (type 2)
that is different from Knorrꢀs type 1 process. Iodoalkyne 5a
[a] Prof. Dr. T. Harada, D. Imaoka, C. Kitano, Prof. Dr. T. Kusukawa
Department of Chemistry and Materials Technology
Kyoto Institute of Technology
Matsugasaki, Sakyo-ku, Kyoto 606-8585 (Japan)
Fax : (+81)75-724-7580
E-mail: harada@chem.kit.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001105.
9164
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9164 – 9174

FULL PAPER
leaving group X. Exo cyclization of 11 followed by vinylic
substitution of the resulting cycloalkylidene carbenoid 12
with RLi would produce alkenyllithium intermediate 13,
which would then be iodinated by 9 to give product 10 to-
gether with regeneration of acetylide intermediate 11.
Herein, we report the alkylative carbocyclization of w-io-
doalkynyl tosylates with alkynyllithium compounds to afford
3-(1-iodoprop-2-ynylidene)tetrahydrofurans and (1-iodo-
prop-2-ynylidene)cyclopropanes. The reaction is proposed to
proceed through a new carbenoid-chain process involving
the exo cyclization of a lithium acetylide intermediate and
the vinylic substitution of the resulting TsO,Li-cycloalkylide-
necarbenoids by the alkynyllithium compounds.
Scheme 2. Cycloisomerization through a type 2 carbenoid-chain process.
LDA=lithium diisopropylamide.
Results and Discussion
is deprotonated by LDA to give lithium acetylide 7 (initia-
tion step). In the chain cycle, acetylide 7 undergoes facile
exo cyclization at the b position of the acetylide moiety to
generate I,Li-alkylidenecarbenoid 8,[10] which is protonated
by 5a to give product 6a, with simultaneous regeneration of
acetylide 7. The type 2 carbenoid-chain process is also re-
sponsible for the cycloisomerization of diiodoalkyne 5b
(Y=I, Z=O, CH2, n=1,2) to give diiodomethylene deriva-
tives 6b (Y=I, Z=O, CH2, n=1,2). The reaction is initiated
by the I/Li exchange reaction of 5b with 1-hexynyllithium
(0.2–0.4 equiv) to give acetylide 7. The chain cycle, in this
case, closes by iodination of carbenoid 8 by 5b to produce
6b.
Reaction of 2-(3-iodoprop-2-ynyloxy)ethyl iodide 14 with al-
kynyllithium compounds: We reported recently that diio-
doalkyne 14 undergoes
a cycloisomerization reaction
through a type 2 carbenoid-chain process upon treatment
with 1-hexynyllithium (15a; 0.2 equiv) in THF at 408C for
2 h or at 08C for 22 h to give 3-(diiodomethylene)tetrahy-
drofuran 16 in high yield (Scheme 4).[8d] In anticipation that
There might be many variants of the carbenoid-chain pro-
cess, other than type 1 and 2, that could be exploited to
bring about unprecedented synthetic transformations. It oc-
curred to us that the combination of the type 1 and 2 carbe-
noid-chain processes would provide a novel alkylative car-
bocyclization reaction of iodoalkyne 9 with organolithium
compounds, which would afford the iodine-atom-retained
product 10 (Scheme 3). Thus, the I/Li exchange reaction of
iodoalkyne 9 with RLi generates lithium acetylide 11 with a
Scheme 4.
an alkylidenecarbenoid intermediate could be trapped by
15a before undergoing iodination by 14, reactions were car-
ried out by slowly adding a solution of 14 (0.5 mmol, 1.0m)
in THF to 15a (1.1–6 equiv), which was prepared from 1-
hexyne and nBuLi (1.6m in hexane) in THF (1 mL)
(Table 1). Reactions at 408C gave 17 diastereoselectively in
moderate yields together with cycloisomerization product 16
(Table 1, entries 1, 2, 4, and 5). Neither the rate at which 14
was added nor the concentration of 15a had a significant in-
fluence on the yield of 17, or on the 17/16 ratio. Prolonged
reaction time led to the disappearance of 16, but resulted in
a decreasing yield of 17 (Table 1, entry 3). The reaction at
08C gave cycloisomerization product 16 in high yield with-
out the formation of 17 (Table 1, entry 6). When the reac-
tion was carried out with phenylethynyllithium (15b), prod-
uct 16 was obtained as a sole product even at 408C (Table 1,
entry 7).
It is likely that the reactions at 408C proceeded mainly
through an initial type 2 process followed by the conversion
of the resulting product 16 to 17 through an independent
type 1 process. It was demonstrated previously that 3-(diio-
domethylene)tetrahydrofurans such as 16 undergo a reversi-
ble iodine/lithium exchange reaction with 15a at 08C to gen-
Scheme 3. Possible alkylative carbocyclization through a type 2/1 carbe-
noid-chain process.
Chem. Eur. J. 2010, 16, 9164 – 9174
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9165

T. Harada et al.
Table 1. Reaction of diiodoalkyne 14 with 1-hexynyllithium (15a).[a]
Table 2. Alkylative carbocyclization of 2-(3-iodoprop-2-ynyloxy)ethyl to-
sylate 18a with 1-hexynyllithium (15a).[a]
Entry
15 ([equiv])
T [8C]
t [h]
Products; yield [%]
17
[b]
[c]
Z/E[d]
16
Entry
15a [equiv]
T [8C]
t [h]
Products; yield [%]
[b]
[c]
19aa
Z/E[d]
21
1
2
3
4
5
6
7
15a (1.1)
15a (2)
15a (2)
15a (2)
15a (6)
15a (2)
15b (2)
40
40
40
40
40
0
0.5
0.5
0.5
2
4
2
1
1.5
19
0.5
0.5
0.5
0.5
53
57
28
48
60
0
4.8:1
2.3:1
10:1
2.8:1
3.6:1
–
21
31
<1
19
3
85
85
1[e]
2
3
4
5
2
2
4
4
6
0 to RT
40
40
RT
40
2
2
4
4
4
4
0.5
1
3
0.5
17
31
66
58
69
3.2:1
4.8:1
5.7:1
6.1:1
8.4:1
25
20
5
10
<1
40
2
0
–
[a] Reactions were carried out by slowly adding
a solution of 18a
[a] Reactions were carried out by slowly adding
a
solution of 14
(0.5 mmol, 1.0m) in THF to 15a prepared by treatment of 1-hexyne with
nBuLi (1.6m in hexane) in THF (1 mL). [b] Time for slow addition.
[c] Time for further stirring after the slow addition. [d] Determined by a
capillary GC analysis. [e] After the addition of 18a at 08C, the reaction
mixture was stirred for 2 h at 08C and then for 2 h at room temperature.
(0.5 mmol, 1.0m) in THF to 15a,b prepared by treatment of the corre-
sponding 1-alkyne with nBuLi (1.6m in hexane) in THF (1 mL). [b] Time
for slow addition. [c] Time for further stirring after the slow addition.
[d] Determined by a capillary GC analysis.
erate the corresponding I,Li-alkylidenecarbenoids.[8d] Judg-
ing from the exclusive formation of 16 in recorded in en-
tries 6 and 7 in Table 1, the I,Li-carbenoid derived from 16
did not undergo vinylic substitution by 15a at 08C or by
15b and 408C.
vinyl tosylate 22a, which would arise from a type 2 carbe-
noid process, was not detected.
The formation of 20a indicates the formation of a lithium
acetylide derived from 18a that is stable at 08C, but slowly
undergoes exo cyclization at room temperature. To facilitate
the exo cyclization step, the reaction was examined at 408C.
Thus, the addition of 18a to 15a (2 equiv) at 408C for 2 h
followed by further stirring for 0.5 h afforded 19aa (31%)
and 21 (20%) (Table 2, entry 2). When the addition time
was extended to 4 h, and the concentration of 15a was in-
creased to 4 equiv, the yield of 19aa increased with a con-
comitant decrease of 21 (Table 2, entry 3). Under similar
conditions, the reaction at room temperature did not im-
prove the result (Table 2, entry 4). By using 6 equiv of 15a,
the optimum yield of 19aa (69%) was obtained with good
selectivity (Z/E=8.4:1), and with very little formation of 21
(Table 2, entry 5).
Reaction of 2-(3-iodoprop-2-ynyloxy)ethyl tosylates 18 with
alkynyllithium compounds: We expected that TsO,Li-alkyli-
denecarbenoid 12 (X=OTs), with the more electronegative
TsO group, would be more reactive toward organolithium
compounds than I,Li-carbenoid 12 (X=I) (Scheme 3). We
therefore turned our attention to the reaction of iodoalkynyl
tosylate 9 (X=OTs).
2-(3-Iodoprop-2-ynyloxy)ethyl tosylate 18a was chosen as
a substrate (Scheme 5). Reactions were carried out with 15a
under conditions similar to those used for 14. A solution of
To clarify the scope of the alkylative carbocyclization, re-
actions were carried out between iodoalkynyl tosylates 18a–
d and alkynyllithium 15a–d under the optimal conditions
(Scheme 6, Table 3). The 1-(iodoethynyl)cyclohexyl deriva-
Scheme 6.
Scheme 5.
tive 18b reacted with 15a to give spirocyclic product 19ba
in 65% yield with high Z selectivity (Table 3, entry 3). Reac-
tion of 18b with phenylethynyllithium (15b), 1-naphthyle-
thynyllithium (15c), and trimethylsilylethynyllithium (15d)
also afforded the corresponding spirocyclic products 19 with
Z selectivity in good to moderate yields (Table 3, entries 4–
6). In the reaction with 15d, a partial desilylation of the ini-
tial product 19bd’ (R3 =SiMe3) was observed (Table 3,
entry 6). The crude products were treated with K2CO3 in
methanol at reflux and isolated as 19bd (R3 =H). The effi-
ciency of the alkylative carbocyclization reaction was influ-
enced by the substitution pattern of the substrates. In com-
18a (0.5 mmol, 1m) in THF was added over 2 h to 15a
(2 equiv) at 08C. GC analysis of quenched aliquots of the
reaction mixture, taken immediately after the slow addition
as well as after stirring for a further 2 h, showed only the
formation of alkynyl tosylate 20a. However, stirring for an
additional 2 h at room temperature led to 3-(1-iodoprop-2-
ynylidene)tetrahydrofuran 19aa (Z/E=3.2:1) in 17% yield
(entry 1 in Table 2). In this reaction, bicyclic product 21
À
(25%), derived from intramolecular 1,5-C H insertion of
the corresponding alkylidenecarbenoid,[10b] and alkynyl tosy-
late 20a (24%) were also formed. The formation of a-iodo-
9166
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9164 – 9174

Alkylative Carbocyclization of w-Iodoalkynyl Tosylates
FULL PAPER
Table 3. Alkylative carbocyclization of 2-(3-iodoprop-2-ynyloxy)ethyl tosylates 18 with alkynyllithium com-
pounds 15.[a]
The formation of alkylative
carbocyclization products 19
from iodohexynyl tosylates 18
and 1-alkynyllithium 15 can be
Entry
Iodoalkyl
tosylate
Alkynyllithium
Product
Yield
[%]
Z/E[b]
1
2
15a; R3 =Bu
15b; R3 =Ph
19aa
19ab
69
63
8.4:1
5.1:1
rationalized by invoking
mechanism involving a type 2/1
carbenoid-chain process
a
(Scheme 7). An acetylide inter-
mediate 25, first formed by
iodine–lithium exchange reac-
tion of 18 with 15, undergoes
exo cyclization at 408C to gen-
erate TsO,Li-alkylidenecarbe-
noid 26. Then, carbenoid 26 un-
dergoes vinylic substitution by
15 to give alkenyllithium 27,
which is iodinated by substrate
18 to give product 19, with con-
current regeneration of acety-
lide 25. Compound 19 is also
produced by the iodination of
alkenyllithium 27 with iodoal-
kyne 24, formed by the reaction
of 18 and 15. Concurrently,
compound 24 is converted into
15, the reaction of which with
18 leads to the regeneration of
25.
3
4
15a; R3 =Bu
19ba
19bb
19bc
19bd
65
72
72
60
14:1
15b; R3 =Ph
7.8:1
7.9:1
>20:1
5
15c; R3 =1-naph
15d; R3 =Me3Si
6[c]
A
7[d]
8[d]
15a; R3 =Bu
15b; R3 =Ph
19ca
19cb
50
35
7.3:1
4.1:1
9[d]
15a; R3 =Bu
19da
24
1.9:1
[a] Reactions were carried out at 408C by adding a solution of 18 (0.5 mmol, 1.0m) in THF for 4 h to 15
(6.0 equiv) prepared by treatment of the corresponding alkyne with nBuLi (1.6m in hexane) in THF (1 mL).
The reaction mixture was stirred further for 0.5 h before workup. [b] Determined by a capillary GC or
1H NMR spectroscopic analysis. [c] The crude products were treated with K2CO3 in MeOH. [d] The corre-
sponding diynes 23 were obtained in 25, 5, and 40% yield in entries 7, 8, and 9, respectively.
parison with gem-disubstituted derivatives 18a,b, mono-sub-
stituted 18c reacted with 15a,b to give the corresponding
products 19 in lower yields (Table 3, entries 7 and 8). The
reaction of a nonsubstituted tosylate (18d) was much less ef-
ficient (Table 3, entry 9). In these reactions, the formation of
diyne by-product 23 was observed .
In all reactions examined, Z isomers of 19 were formed as
the major diastereomers. The degree of selectivity was influ-
Scheme 7. Type 2/1 carbenoid chain mechanism for alkylative carbocycli-
enced both by the substitution pattern of tosylates 18 and by
the structure of alkynyllithium compounds 15. In general,
higher Z selectivity was observed for tosylates with sterically
demanding substituents R1 and R2. The selectivity in the re-
action with 15a decreased in the order of 18b, 18a, 18c, and
18d (Table 3, entries 3, 1, 7, and 9). As illustrated in en-
tries 3–6 in Table 3, arylethynyllithium 15b and 15c exhibit-
ed lower selectivity than 15a and 15d.
zation of iodohexynyl tosylates 18.
In contrast to the reaction of diiodoalkyne 14 (Scheme 4),
formation of the cycloisomerization by-product 22 was not
detected in the reaction of iodoalkynyl tosylate 18. Since 22
was not accumulated in the reaction, it is unlikely that 19
was produced through an independent type 1 chain process
Chem. Eur. J. 2010, 16, 9164 – 9174
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9167

T. Harada et al.
Table 4. Reaction of 1,4-diiodobut-1-yne 28 with 1-hexynyllithium
(15a).[a]
via 22. However, this does not necessarily exclude the possi-
bility that a portion of carbenoid 26 is reversibly converted
into 22 through iodination by 18 and/or 20 (Scheme 7).
While exo cyclization of lithium acetylide 25, with a TsO
group, was less facile than that with an iodine atom (see
above), the resulting TsO,Li-alkylidenecarbenoid 26 is more
reactive in the vinylic substitution reaction by alkynyllithium
15 than I,Li-alkylidenecarbenoids. Thus, phenylethynyllithi-
um 15b reacted smoothly with iodoalkynyl tosylates 18 to
give the corresponding products 19 (Table 3, entries 2, 4,
and 8) whereas it did not afford alkylative cyclization prod-
uct 17 in the reaction with 14 (Table 1, entry 7). The en-
hanced reactivity of carbenoid 26 can be understood by con-
sidering that the carbenoid carbon becomes more electron
deficient with the attachment of the electronegative TsO
group. The electron-deficient character of 26 might also be
Entry
T [8C]
Products; yield [%]
29
30[b,c]
31aa[b]
1
2
0
À20
À80
À20
23
20
0
49
62
20
72
3
8
0
4
3[d,e]
4[f]
5
[a] Unless otherwise noted, reactions were carried out with 28 (1 mmol)
and 15a (0.4 equiv) in THF (2 mL) for 4 h. [b] Z/E> 10:1. [c] The yields
were calculated by dividing the molar amounts of 29 by 0.5 mmol, or 1/2
of the molar amount of substrate 28. [d] The reaction was carried out for
23 h. [e] Iodoalkyne 32 and starting material 28 were obtained in 25 and
45% yield, respectively. [f] The reaction was carried out in DME.
Even at À208C, compound 28 was consumed completely
within 4 h (Table 4, entry 2). The relative yield of methyl-
enecyclopropane products (30+31aa) increased from 69%
(Table 4, entry 1) to 78% under these conditions. Although
the reaction became sluggish at À808C, compound 30 was
produced selectively in 20% yield after 23 h together with
iodoalkyne 32 (25%). In addition, 45% of the starting mate-
rial 28 was recovered (Table 4, entry 3). Reaction in dime-
thoxyethane (DME) at À208C afforded 30 as the major
product in relatively high yield (Table 4, entry 4).
The formation of methylenecyclopropanes 30 and 31aa
implies the generation of I,Li-cyclopropylidenecarbenoid 35
through the exo cyclization of lithium acetylide 34
(Scheme 9). Thus, the vinylic substitution of 35 by 34 and
15a gave alkenyllithium intermediates 37 and 38, which
were subsequently iodinated with 28 and/or 1-iodo-1-hexyne
(24a) to give 30 and 31aa, respectively. The formation of
diiodocyclobutene 29 could conceivably occur through the
Fritsch–Buttenberg–Wiechell rearrangement[11,1e] of carbe-
noid 35 and subsequent iodination of the resulting b-iodocy-
À
responsible for the formation of 1,5-C H insertion by-prod-
uct 21 in the reaction of 18a at the lower concentrations of
15a (Table 2, entries 1 and 2). In the reaction of 18c,d,
diynes 23 were obtained as by-products (Table 3, entries 7–
9). As shown in our previous work,[8d] the exo cyclization of
lithium acetylide 25 is accelerated by gem-disubstitution at
the propargylic position. Without the geminal substituents,
acetylides derived from 18c,d underwent the cyclization
more slowly than those derived from gem-disubstituted
18a,b. For these substrates, substitution by lithium acetylides
15 occurred concurrently to give by-products 23.
Reaction of 1,4-diiodobut-1-yne 28 with a catalytic amount
of 1-hexynyllithium (15a): Upon treatment with 15a (0.2–
0.4 equiv) at 408C in THF, diiodoalkynes 5b (Y=I, Z=O,
CH2, n=1,2) undergo cycloisomerization reactions through
a type 2 carbenoid-chain mechanism to afford diiodomethy-
lene derivatives 6b (Y=I, Z=O, CH2, n=1,2)
(Scheme 2).[8d] On the other hand, attempted cycloisomeri-
zation of 1,4-diiodobut-1-yne 28 with 15a (0.4 equiv) did not
afford the anticipated (diiodomethylene)cyclopropane 33
(Scheme 8, Table 4). Reaction at 08C for 4 h in THF afford-
ed 1,2-diiodocyclobutene 29 (23%), dimeric methylenecy-
clopropane 30 (49%), and (1-iodoprop-2-ynylidene)cyclo-
propane 31aa (3%) (Table 4, entry 1). Methylenecyclopro-
panes 30 and 31aa were obtained with high Z selectivity.
Scheme 9. Plausible mechanism for formation of 29, 30, and 31aa from
diiodobutyne 28.
Scheme 8.
9168
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9164 – 9174

Alkylative Carbocyclization of w-Iodoalkynyl Tosylates
FULL PAPER
Table 5. Alkylative carbocyclization of iodobutynyl tosylate 39a with 1-
hexynyllithium (15a).[a]
clobutenyllithium intermediates 36 and/or 36’ with 28 and/or
24a.[12,13] Alternatively, compounds 36 and/or 36’ would be
formed directly from 34 by endo cyclization,[14] although
such a pathway is less likely because the formation of 29
was totally suppressed in the reaction at À808C (Table 4,
entry 3).
In contrast to the efficient five- and six-membered ring
cycloisomerization reactions observed for diiodoalkynes 5b
(Y=I, Z=O, CH2, n=1,2), the reaction of diiodobutyne 28
under similar conditions afforded a mixture of 29, 30, and
31aa without the formation of (diiodomethylene)cyclopro-
pane 33. The high reactivity of I,Li-cyclopropylidenecarbe-
noid 35 might be responsible for the unsuccessful cycloiso-
merization of 28 to give 33 through a type 2 chain process.
Judging from the selective formation of 30 reported in
Table 4, entry 3, carbenoid 35 underwent vinylic substitution
by 34 even at À808C. At higher temperature, compound 35
also underwent Fritsch–Buttenberg–Wiechell rearrange-
ment.
Entry
T [8C]
Products; yield [%]
31aa
Z/E[b]
40[c,d]
1
2
40
0
57
63
5
39
52
10:1
16:1
17:1
8.0:1
10:1
24
8
–
45
12
3[e,f]
4[g]
5[h]
À20
0
0
[a] Unless otherwise noted, reactions were carried out by slowly adding a
solution of 39a (0.5 mmol, 0.5m) in THF to 15a (6 equiv) prepared by
treatment of 1-hexyne with nBuLi (1.6m in hexane) in THF (2 mL). The
reaction mixture was stirred further for 1.5 h before workup. [b] Deter-
mined by 1H NMR spectroscopic analysis. [c] Z/E>10:1. [d] The yields
were calculated by dividing the molar amounts of 40 by 0.25 mmol, or 1/2
of the molar amount of substrate 39a. [e] The reaction mixture was
stirred for 2.5 h before workup. [f] Alkynyl tosylate 41a was obtained in
76% yield. [g] The reaction was carried out in DME. [h] TMEDA
(6 equiv) was added to 15a in THF.
ethylenediamine (TMEDA; 6 equiv) did not affect the ratio
of 31aa and 40 (Table 5, entry 5).
Reaction of 4-iodobut-1-ynyl tosylates 39 with alkynyllithi-
um compounds 15: The high reactivity of cyclopropylidene-
carbenoids observed in the attempted cycloisomerization re-
action of 28 prompted us to examine the alkylative carbo-
cyclization of iodoalkynyl tosylate 39a (Scheme 10). The re-
Methylenecyclopropanes have broad utility for the rapid
construction of complex molecular frameworks by virtue of
their high strain energy.[15] To clarify the scope of the alkyla-
tive carbocyclization reaction, which leads to the synthetical-
ly useful methylenecyclopropane derivatives,[16,7] the reac-
tions of several iodobutynyl tosylates 39a–d with alkynyl-
lithium compounds 15a–c were examined under the condi-
tions of entry 2 in Table 5 (Scheme 11).
Scheme 11.
Scheme 10.
As summarized in Table 6, iodobutynyl tosylates 39a–c
with gem-disubstitution at the propargyl position reacted
smoothly at 08C with 15 a–c to give the corresponding
(prop-2-ynylidene)cyclopropanes 31 in good to moderate
yields. On the other hand, the reaction of mono-substituted
39d with 15a afforded butynyl tosylate 41d without the for-
mation of a carbocyclization product, which indicates that
the exo cyclization of the corresponding mono-substituted
acetylide intermediate is slow at 08C (Table 6, entry 11).
In the reaction of 39a with 15a–d, the Z isomers of 31
were obtained as the major products (Table 6, entries 1–3).
The Z selectivity was higher for the reaction with alkynyl-
lithium 15a than with arylethynyllithium 15b,c. The trend in
stereoselectivity is similar to that observed in the reaction of
iodohexynyl tosylates 14 (Table 2). Z selectivity was also ob-
served (albeit somewhat diminished) for dimethyl derivative
39b (Table 6, entries 6 and 7). While moderate Z selectivity
was observed in the reaction of diphenyl derivative 39c with
action was first examined under the conditions optimized
for iodoalkynyl tosylates 18. Thus, addition of 39a over 4 h
to 1-hexynyllithium (15a) (6 equiv) in THF at 408C followed
by further stirring for 1.5 h afforded alkylative carbocycliza-
tion product 31aa in 57% yield with high Z selectivity (Z/
E=10:1) along with dimeric by-product 40 (24%) (Table 5,
entry 1). By carrying out the reaction at 08C, the yield of
31aa was improved to 63% with considerable suppression
of 40 (Table 5, entry 2). Reaction at À208C, however, result-
ed in the formation of butynyl tosylate 41a as the major
product (76%), indicating that the exo cyclization of the
corresponding acetylide intermediate became sluggish at
this temperature (Table 5, entry 3). As was observed in the
reaction of diiodoalkyne 28 (Table 3, entry 4), the yield of
40 increased noticeably by using DME as a solvent (Table 5,
entry 4). On the other hand, the addition of tetramethyl-
Chem. Eur. J. 2010, 16, 9164 – 9174
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9169

T. Harada et al.
Table 6. Alkylative carbocyclization reaction of iodobutynyl tosylates 39 with 15.[a]
by carrying out a separate iso-
merization experiment on the
pure Z isomer: upon treatment
with 15c (6 equiv) in THF at
08C for 2 h, compound (Z)-
31ac underwent isomerization
to give a 1.2:1 mixture of (Z)-
and (E)-31ac in 77% yield.
Isomerization between (Z)-
and (E)-31ac most probably oc-
curred via alkenyllithium (E)-
and (Z)-43 (R3 =1-naphthyl),
which are formed by I/Li ex-
change of 31ac with 15c
(Scheme 13).[8d] Butatrienyllithi-
um 44 (R3 =1-naphthyl), or the
more delocalized structure 45,
might be responsible for the in-
terconversion between (E)- and
(Z)-43 (R3 =1-naphthyl).
Entry
Iodoalkyl
tosylate
Alkynyllithium
Product
Yield
[%]
Z/E[b]
1
2
15a
15b
15c
15c
15c
31aa; R3 =Bu
31ba; R3 =Ph
31ac; R3 =1-naph
31ac
63
54
80
73
59
16:1
4.9:1
3.0:1
1:1.1
1.0:1
3[c]
4[c,d]
5[c,e]
31ac
6[f]
7
15a
15c
31ba; R3 =Bu
37
75
1.4:1
1.4:1
31bc; R3 =1-naph
8
9
10
15a
15b
15c
31ca; R3 =Bu
31cb; R3 =Ph
31cc; R3 =1-naph
45
69
65
1.7:1
1:2.4
1.3.0
11
15a
41d
35
–
The observed decrease in Z
selectivity in order from 31aa
to 31ab to 31ac (Table 6, en-
tries 1–3) can be rationalized by
assuming a relatively high ki-
netic selectivity for Z, which is
[a] Unless otherwise noted, reactions were carried out by adding a solution of 39a--d (0.5 mmol) in THF
(1 mL) to a solution of 1-alkynyllithium 15a--d (3 mmol) in THF (2 mL) during 4 h at 08C. The reaction mix-
ture was stirred for a further 1.5 h before workup. [b] Determined by 1H NMR spectroscopy. [c] Enediyne 42
was obtained in 9, 13, and 30% yield in entries 3, 4, and 5, respectively. [d] Further stirring for 3 h. [e] Further
stirring for 4 h. [f] Slow addition over 1 h.
15a (Table 6, entry 8), reactions with arylethynyllithium
15b,c afforded the E isomers as major products (Table 6, en-
tries 10 and 11).
In the reaction of 39a with 15c, the Z/E ratio of product
31ac varied with reaction times. Thus, under the standard
reaction conditions, in which the reaction mixture was
stirred for a further 1.5 h after the slow addition of 39a, a
3.0:1 mixture of (Z)- and (E)-31ac was obtained (Table 6,
entry 3). Extension of the additional stirring time to 3 or 4 h
resulted in the formation of a approximately 1:1 mixture of
the isomers (Table 6, entries 4 and 5), which suggests that
isomerization occurs between (Z)- and (E)-31ac. In these
reactions, formation of by-product enediyne 42 was ob-
served. The by-product is most probably produced by the
ring-opening reaction of 31ac, which itself is induced by de-
protonation of the cyclopropane-ring proton by 15c
(Scheme 12). The yield of 42 increased with longer reaction
Scheme 13. Isomerization of (Z)- and (E)-31ac via alkenyllithium (E)-
and (Z)-43.
times, counterbalancing the decrease in yield of 31ac
(Table 6, entries 3–5). Isomerization between (Z)- and (E)-
31ac under the present reaction conditions was confirmed
reduced to varying degrees by isomerization. In the reaction
with 15a, high Z selectivity was observed even at 408C
(Table 5, entry 1), which indicates that isomerization is slow,
if not negligible. Interconversion between (E)- and (Z)-43
(R3 =Bu) is less favorable due to the instability of butatrie-
nyllithium 44 (R3 =Bu), which is devoid of aromatic conju-
gation. In the reaction with 15b, reduction in the initial ki-
netic Z selectivity of 31ab via 44 (R3 =Ph) might be less ex-
tensive than that of 31ac, which results in a Z/E ratio in be-
Scheme 12.
9170
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9164 – 9174

Alkylative Carbocyclization of w-Iodoalkynyl Tosylates
FULL PAPER
tween those of 31aa and 31ac. Reaction of diphenyl deriva-
tive 39c with arylethynyllithium 15b,c gave the correspond-
ing products 31cb and 31cc with moderate E selectivity
(Table 6, entries 9 and 10). The E selectivity might be the
result of extensive isomerization of the kinetically favorable
Z isomers to the E isomers. Support for the thermodynamic
preference for the E isomer was obtained by ab initio mo-
lecular orbital calculations (HF/3-21G*)[18,19] of (E)- and
(Z)-31cb, which showed that the E isomer is 1.25 kcalmolÀ1
more stable than the Z isomer.[20,21] In the alkylative carbo-
cyclization of iodohexynyl tosylates 18, Z selectivities were
slightly lower with arylethynyllithium 15b,c than with alky-
nyllithium 15a. It is possible that initial kinetic Z selectivi-
ties would be reduced to some extent by the analogous iso-
merization.
Figure 1. ORTEP diagram of (Z)-19bc.
The reactions with 1-hexynyllithium 15a provide us with
information on the stereochemistry of nucleophilic substitu-
tion of the alkylidenecarbenoid intermediate[9d,1e] with mini-
mum influence of the subsequent isomerization. In the reac-
tions of both 18 and 39, compound 15a exhibited higher Z
selectivity for the substrates with sterically more demanding
groups at the propargylic position. Irrespective of the E,Z
geometry of TsO,Li-alkylidenecarbenoids 26 and 46, for
which no experimental information is available, the general
trend in stereoselectivity is consistent with the preferential
attack of 15a from the less hindered side of alkylidenecarbe-
noids 26 and 46 or, more probably, their dissociated forms,
26’ and 46’ (Scheme 14).
Figure 2. ORTEP diagram of (Z)-31cb.
Conclusion
We have described a new alkylative carbocyclization reac-
tion of w-iodoalkynyl tosylates with alkynyllithium com-
pounds to give products with incorporated iodine atoms.
Treatment of 2-(3-iodoprop-2-ynyloxy)ethyl tosylates with 1-
alkynyllithium compounds in THF at 408C provided (Z)-3-
(1-iodoprop-2-ynylidene)tetrahydrofurans stereoselectively
in good to moderate yields. 4-Iodobut-1-ynyl tosylates un-
derwent alkylative carbocyclization with 1-alkynyllithium
compounds at 08C to give (1-iodoprop-2-ynylidene)cyclo-
propanes. In this reaction, high Z selectivity was observed
when the kinetically favorable Z isomers were not prone to
isomerizing to the thermodynamically more stable E iso-
mers. We propose that these reactions proceed through a
new carbenoid-chain process involving exo cyclization of a
lithium acetylide intermediate and vinylic substitution of the
resulting TsO,Li-cycloalkylidenecarbenoid by 1-alkynyllithi-
um compounds.
Scheme 14. Possible rationale for the Z selectivity.
Determination of E,Z-stereochemistry: Although most of
the 3-(1-iodoprop-2-ynylidene)tetrahydrofurans 19 were ob-
tained as oils, the major isomer (Z)-19bc was recrystallized
from hexane to give suitable crystals for X-ray crystallo-
graphic analysis, which showed unequivocal Z geometry
(Figure 1). The stereochemistry of other products (19), as
well as that of 17, was assigned based on consistent trends in
13C NMR chemical-shift differences between Z and E iso-
mers (Table 7 in the Supporting Information). Stereochemi-
cal assignments for the 3-(1-iodoprop-2-ynylidene)cyclopro-
panes 31 were also based on X-ray analysis and consistent
trends in 13C NMR chemical-shift differences between Z and
E isomers (Table 8 in the Supporting Information). Recrys-
tallization of a 1:2.4 mixture of (Z)- and (E)-31cb from
hexane gave crystals of the minor Z isomer suitable for X-
ray analysis, which allowed Z geometry to be unambiguous-
ly established (Figure 2).
Experimental Section
General: NMR spectra were recorded on a Bruker DRX-500 spectrome-
ter (500 MHz for 1H and 125.8 MHz for 13C). Proton chemical shifts are
reported in ppm (d) using residual CHCl3 (d=7.26 ppm) or C6D6 (d=
Chem. Eur. J. 2010, 16, 9164 – 9174
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9171

T. Harada et al.
7.24 ppm) in deuterated solvents as the internal standard. Carbon chemi-
cal shifts are reported relative to the internal standard CDCl3 (d=
77.0 ppm) or C6D6 (d=128.0 ppm). MS measurements were conducted
with a JEOL JMS-700 instrument. X-ray analysis was conducted with a
Rigaku AFC7R diffractometer with filtered CuKa radiation and a rotating
anode generator at 213 K. GC analyses were performed with a capillary
column (OV-1, 30 m). Flash column chromatography was performed by
using silica gel (Wakogel C-300). THF, DME, and toluene were dried
and distilled over sodium benzophenone ketyl. CH2Cl2 and triethylamine
were dried and distilled over CaH2. Acetone was dried and distilled over
K2CO3. 1-Hexyne, phenylacetylene, 1-ethynylnaphthalene, trimethylsilyl-
acetylene, and BF3·OEt2 were distilled before use. Other commercially
available reagents were used without further purification. Reactions were
performed under an argon atmosphere unless otherwise noted.
td, J=8.5 and 17.0 Hz), 2.92 (1H for Z isomer, ddd, J=4.2, 6.7, and
17.0 Hz), 3.74 (1H for Z isomer, dt, J=6.8 and 8.6 Hz), 3.75–3.95 (2H
for Z and E isomer, m), 3.85 ppm (1H for Z isomer, dt, J=4.2 and
8.6 Hz); 13C NMR (125.8 MHz, CDCl3) d 13.6, 19.2, 21.9, 23.0, 24.0, 24.3,
24.7, 30.7, 38.7, 44.9, 60.6, 63.1, 82.9, 86.4, 95.1, 159.6 ppm for Z isomer,
13.5, 19.4, 22.1, 23.5, 23.9, 24.5, 24.6, 30.3, 43.5, 45.5, 62.7, 64.5, 80.9, 85.7,
97.7, 161.8 ppm for E isomer; MS (EI): m/z (%): 361 (<1) [M]+, 349
(54), 303 (100), 58 (85); HRMS (EI): calcd for C16H25OI: 360.0950;
found: 360.0960.
Typical procedure for reaction of 1,4-diiodobut-1-yne 28 with a catalytic
amount of 1-hexynyllithium (15a)
1,2-Diiodospiro
ACHTUNGTRENNUNG
hexane; 0.48 mL, 0.77 mmol) was added to
a
(0.082 mL, 0.71 mmol) in THF (2.1 mL) at 08C. The resulting solution
was stirred at 08C for 15 min to give a 0.27m solution of 15a. Compound
5-Ethoxy-3-(1-iodohept-2-ynylidene)-2,2-dimethyltetrahydrofuran
(17)
(Table 1, entry 5): nBuLi (1.6m in hexane; 1.94 mL, 3.1 mmol) was added
to a solution of 1-hexyne (0.34 mL, 3.0 mmol) in THF (1 mL) at 08C.
The reaction mixture was stirred at 08C for 15 min. Compound 14[8d]
(0.204 g, 0.50 mmol) in THF (0.5 mL) was added to the resulting mixture
of 15a in THF at 408C over 4 h with a syringe pump. After stirring for a
further 0.5 h at 408C, the reaction mixture was poured into water and ex-
tracted with ethyl acetate (3ꢂ30 mL). The combined organic layers were
dried (Na2SO4) and concentrated in vacuo. The residue was purified by
flash chromatography (3–5% diethyl ether in hexane) to give, in order of
elution, 17 (0.109 g, 65%) and 16 (5.7 mg, 3%) (Z/E=3.6:1).[8d] The Z
isomer was isolated by recycling gel permeation chromatography (JAI
LC-908 equipped with JAIGEL-1H and À2H columns, toluene as an
eluent). (Z)-17: 1H NMR (500 MHz, C6D6): d=0.82 (3H, t, J=7.1 Hz),
1.13 (3H, t, J=7.1 Hz), 1.26–1.35 (4H, m), 1.63 (3H, s), 1.82 (3H, s),
2.17 (2H, brt, J=6.4 Hz), 2.91 (1H, dd, J=5.4 and 17.4 Hz), 3.24–3.34
(2H, m), 3.81 (1H, m), 4.90 ppm (1H, d, J=5.4 Hz); 13C NMR
(125.8 MHz, C6D6): d=13.6, 15.2, 19.2, 22.1, 26.5, 27.0, 30.8, 44.8, 60.9,
62.3, 83.5, 84.7, 95.5, 100.5, 158.9 ppm; MS (EI), m/z (%): 362 (31) [M]+,
250 (68), 99 (100); HRMS (EI): calcd for C15H23IO2: 362.0743; found
362.0748. (Z)- and (E)-17 (1:1): 1H NMR (500 MHz, C6D6): d=0.81 (3H
for Z and E isomer, t, J=7.1 Hz), 1.13 (3H for Z isomer, t, J=7.1 Hz),
1.15 (3H for E isomer, t, J=7.1 Hz), 1.28–1.33 (4H for Z and E isomer,
m), 1.63 (3H for Z isomer, s), 1.73 (3H for E isomer, s), 1.82 (3H for Z
isomer, s), 1.88 (3H for E isomer, s), 2.12 (2H for E isomer, t, J=
6.6 Hz), 2.17 (2H for Z isomer, brt, J=6.4 Hz), 2.76 (1H for E isomer,
dd, J=5.5 and 18.2 Hz), 2.91 (1H for Z isomer, dd, J=5.4 and 17.4 Hz),
2.96 (1H for E isomer, d, J=18.2 Hz), 3.25–3.32 (1H for E isomer and
2H for Z isomer, m), 3.81 (1H for Z and E isomer, m), 4.90 (1H for Z
15a (0.74 mL, 0.20 mmol) was added to
a solution of 28 (185 mg,
0.495 mmol) in THF (0.7 mL) at 08C. The resulting solution was stirred
at 08C for 4 h. The mixture was poured into water (10 mL) and extracted
with diethyl ether (3ꢂ30 mL). The combined organic layers were washed
with brine, dried (Mg2SO4), and concentrated in vacuo. The residue was
purified by flash chromatography (hexane) to give, in order of elution, 29
1
(43 mg, 23%) and 30 (53 mg, 49%). 29: H NMR (500 MHz, CDCl3): d=
1.17 (1H, m), 1.25–1.39 (4H, m), 1.50–1.53 (2H, m), 1.62 (1H, m), 1.74–
1.77 (2H, m), 2.81 ppm (2H, s); 13C NMR (125.8 MHz, CDCl3): d=23.7,
25.1, 34.4, 52.9, 59.4, 99.4, 117.6 ppm; MS (EI): m/z (%): 374 (4) [M]+,
247 (5), 120 (3), 58 (100); HRMS (EI): calcd for C9H12I2; 373.9028;
1
found: 373.9022. 30: H NMR (500 MHz, CDCl3): d=1.11 (1H, m), 1.25–
1.32 (4H, m), 1.32 (2H, s), 1.40–1.48 (3H, m), 1.58–1.67 (6H, m), 1.71–
1.79 (4H, m), 1.87 (2H, brd, J=12.1 Hz), 3.27 ppm (2H, s); 13C NMR
(125.8 MHz, CDCl3): d=20.2, 23.1, 23.5, 25.2, 25.7, 25.9, 30.4, 32.1, 37.6,
38.0, 55.0, 84.7, 92.2, 151.4 ppm; MS (EI), m/z (%): 494 (2) [M]+, 367
(16), 240 (100); HRMS (EI): calcd for C18H24I2: 493.9967; found:
493.9970.
Typical procedure for alkylative carbocyclization of iodobutynyl tosylates
39 with alkynyllithium compounds 15
1-(1-Iodohept-2-ynylidene)spiroACTHNUTRGENUGN[2.5]octane (31aa) (Table 6, entry 1):
nBuLi (1.6m in hexane; 1.94 mL, 3.1 mmol) was added to a solution of 1-
hexyne (0.34 mL, 3.0 mmol) in THF (2 mL) at 08C. The resulting solu-
tion was stirred at 08C for 15 min. Iodobutynyl tosylate 39a (209 mg,
0.50 mmol) in THF (1 mL) was added to the resulting solution of 15a in
THF at 08C over 4 h with a syringe pump. The resulting solution was
stirred at 08C for 1.5 h. The mixture was poured into water (10 mL) and
extracted with Et2O (3ꢂ30 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. The residue was purified by flash
chromatography (0–20% ethyl acetate in hexane) to give, in order of elu-
tion, 31aa (103 mg, 63% yield, Z/E=16:1) and 40 (11 mg, 8%). 31aa:
1H NMR (500 MHz, CDCl3): d=0.92 (3H for Z and E isomer, t, J=
7.3 Hz), 1.03 (2H for E isomer, s), 1.26 (2H for Z and E isomer, m), 1.31
(2H for Z isomer, s), 1.35–1.82 (12H for Z and E isomer, m), 2.37 ppm
(2H for Z and E isomer, t, J=7.1 Hz). 13C NMR (125.8 MHz, CDCl3):
d=13.6, 19.18, 21.96, 23.0, 25.2, 25.85, 30.2, 30.5, 32.0, 55.8, 81.0, 90.6,
150.3 for Z isomer, 13.6, 19.16, 21.92, 24.2, 25.91, 26.00, 30.5, 34.6, 37.1,
59.9, 81.4, 90.4, 153.2 ppm; MS (EI), m/z (%): 328 (7) [M]+, 201 (22), 58
(100); HRMS (EI): calcd for C15 H21I: 328.0688; found: 328.0684. 40:
1H NMR (500 MHz, CDCl3): d=0.91 (1H, m), 1.14 (1H, m), 1.25–1.80
(20H, m, including s (2H) at 1.29), 2.45 (3H, s), 3.84 (2H, s), 7.34 (2H,
d, J=8.2 Hz), 7.81 ppm (2H, d, J=8.2 Hz); 13C NMR (125.8 MHz,
CDCl3) d 21.7, 22.4, 23.1, 25.2, 25.5, 25.8, 30.3, 32.0, 33.6, 38.0, 54.7, 76.0,
84.6, 90.5, 128.0, 129.8, 132.8, 144.7, 151.7 ppm; MS (EI): m/z (%): 538
(<1) [M]+, 239 (38), 149 (100); HRMS (EI): calcd for C25H31O3SI:
538.1039; found: 538.1055.
isomer, d, J=5.4 Hz), 4.97 ppm (1H for
E isomer, d, J=5.4 Hz);
13C NMR (125.8 MHz, C6D6): d=13.52, 15.20, 19.34, 22.18, 26.8, 27.6,
30.5, 49.9, 62.33, 65.0, 81.5, 83.8, 97.9, 100.3, 161.3 ppm for E isomer,
13.58, 15.18, 19.22, 22.08, 26.5, 27.0, 30.8, 44.8, 60.9, 62.29, 83.5, 84.7, 95.5,
100.5, 158.9 ppm for Z isomer; MS (EI): m/z (%): 362 (14) [M]+, 58
(100); HRMS (EI): calcd for C15H23IO2: 362.0743; found: 362.0748.
Typical procedure for alkylative carbocyclization of iodohexynyl tosylates
18 with alkynyllithium compounds 15
3-(1-Iodohept-2-ynylidene)-2-isobutyl-2-methyltetrahydrofuran
(19aa)
(Table 3, entry 1): nBuLi (1.6m in hexane; 1.94 mL, 3.1 mmol) was added
to a solution of 1-hexyne (0.34 mL, 3.0 mmol) in THF (1 mL) at 08C.
The reaction mixture was stirred at 08C for 15 min. Iodoalkynyl tosylate
18a (0.224 g, 0.50 mmol) in THF (0.5 mL) was added to the resulting
mixture of 15a in THF at 408C over 4 h with a syringe pump. After stir-
ring for 30 min at 408C, the reaction mixture was poured into water and
extracted three times with ethyl acetate (3ꢂ30 mL). The combined or-
ganic layers were dried (Na2SO4) and concentrated in vacuo. The residue
was purified by flash chromatography (1–2% diethyl ether in hexane) to
give 19aa (0.117 g, 65%; Z/E=8.4:1): 1H NMR (500 MHz, CDCl3): d=
0.94 (9H for E and Z isomer, m), 1.37 (3H for Z isomer, s), 1.38 (3H for
E isomer, s), 1.38–1.57 (5H for Z and E isomer, m), 1.64 (1H for E
isomer, dd, J=5.3 and 14.8 Hz), 1.74 (1H for Z and E isomer, sept, J=
ca. 6.3 Hz), 1.93 (1H for E isomer, dd, J=5.3 and 14.8 Hz), 2.02 (1H for
Z isomer, dd, J=5.3 and 14.7 Hz), 2.43 (2H for Z and E isomer, t, J=
7.0 Hz), 2.62–2.75 (2H for Z and E isomer, m), 2.80 (1H for Z isomer,
X-ray analysis of (Z)-19b,c: Single crystals suitable for X-ray analysis
were obtained by recrystallization from hexane as colorless prisms. Crys-
tal dimensions: 0.60ꢂ0.50ꢂ0.50 mm3. Crystal data: C22H21OI; M=428.31;
monoclinic; space group P21/a (no. 14); a=17.523(8), b=7.512(2), c=
14.123(4) ꢃ; b=96.42(3)8; V=1847.5(10) ꢃ3; Z=4; 1calcd =1.540 gcmÀ3
;
FACHTUNGTRENNUNG
9172
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9164 – 9174

Alkylative Carbocyclization of w-Iodoalkynyl Tosylates
FULL PAPER
full-matrix least-squares methods on F2 with 188 parameters. R1 =0.0651
(I>2s(I)), wR2 =0.1786, goodness of fit (GOF)=1.159; max./min. residu-
al density 2.66/À2.55 eꢃ3.
X-ray analysis of (Z)-31cb: Single crystals suitable for X-ray analysis
were obtained by recrystallization from hexane as colorless prisms. Crys-
tal dimensions: 0.30ꢂ0.20ꢂ0.20 mm3. Crystal data: C24H17I; M=432.30;
monoclinic; space group P21/n (no. 14); a=12.708(8), b=27.602(15), c=
6.251(3) ꢃ; b=95.44(4)8; V=2182.7(20) ꢃ3; Z=4; 1calcd =1.315 gcmÀ3; F-
9622–9629; c) Y. Li, L. Lu, X. Zhao, Org. Lett. 2004, 6, 4467–4470;
d) F. Kopp, G. Sklute, K. Polborn, I. Marek, P. Knochel, Org. Lett.
2005, 7, 3789–3791; e) D. C. Kapeller, F. Hammerschmidt, J. Am.
Chem. Soc. 2008, 130, 2329–2335.
[7] a) R. Knorr, C. Pires, C. Behringer, T. Menke, J. Freudenreich, E. C.
Rossmann, P. Bçhrer, J. Am. Chem. Soc. 2006, 128, 14845–14853;
b) R. Knorr, C. Pires, J. Freudenreich, J. Org. Chem. 2007, 72, 6084–
6090.
[8] a) T. Harada, K. Muramatsu, T. Fujiwara, H. Kataoka, A. Oku, Org.
Lett. 2005, 7, 779–781; b) T. Harada, K. Mizunashi, K. Muramatsu,
Chem. Commun. 2006, 638–639; c) T. Harada, C. Kitano, K. Mizu-
nashi, Synlett 2007, 1130–1132; d) T. Harada, K. Muramatsu, K.
Mizunashi, C. Kitano, D. Imaoka, T. Fujiwara, H. Kataoka, J. Org.
Chem. 2008, 73, 249–258.
[9] a) H. Gꢄnther, A. A. Bothner-By, Chem. Ber. 1963, 96, 3112–3119;
b) M. Duraisamy, H. M. Walborsky, J. Am. Chem. Soc. 1984, 106,
5035–5037; c) A. Oku, T. Harada, K. Hattori, Y. Nozaki, Y. Ya-
maura, J. Org. Chem. 1988, 53, 3089–3098; d) M. Topolski, M.
Rachꢅ, J. J. Gawronski, K. Gawronska, V. Goedken, H. M. Walbor-
sky, J. Org. Chem. 1993, 58, 546–555; e) T. Harada, T. Katsuhira, D.
Hara, Y. Kotani, K. Maejima, R. Kaji, A. Oku, J. Org. Chem. 1993,
58, 4897–4907; f) M. Topolski, J. Org. Chem. 1995, 60, 5588–5594.
[10] a) T. Harada, K. Iwazaki, T. Otani, A. Oku, J. Org. Chem. 1998, 63,
9007–9012; b) T. Harada, T. Fujiwara, K. Iwazaki, A. Oku, Org.
Lett. 2000, 2, 1855–1857; c) T. Harada, A. Oku, J. Synth. Org.
Chem. Jpn. 2001, 59, 101–108.
ACHTUNGTRENNUNG(000)=856; reflections collected/unique 5380/3872 (Rint =0.388). The
structure was solved by direct methods (SHELXL-97) and refined by
full-matrix least-squares methods on F2 with 224 parameters. R1 =0.1444
(I > 2s(I)), wR2 =0.3228, GOF=1.243; max./min. residual density 0.93/
À3.54 eꢃ3.
CCDC-774472 (19b,c) and 774473 (31b,c) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We thank Professor N. Krause for providing the procedure for preparing
2,2-diphenyl-4-trimethylsilylbut-3-yn-1-ol.
[11] a) P. Fritsch, Liebigs Ann. Chem. 1894, 279, 319–323; b) W. P. But-
tenberg, Liebigs Ann. Chem. 1894, 279, 324–337; c) H. Wiechell,
Liebigs Ann. Chem. 1894, 279, 337–344.
[12] b-Iodocyclobutenyllithium 36 and 36’ are considered to be relatively
stable because elimination of LiI would give a highly strained cyclo-
butyne, the existence of which is controversial, even theoretical
ly.[1e, 13]
[13] R. P. Johnson, K. J. Daoust, J. Am. Chem. Soc. 1995, 117, 362–367.
[14] For the competitive exo and endo cyclization of lithium acetylides
derived from hex-5-ynyl tosylates, see reference [10a].
[1] a) G. Kçbrich, Angew. Chem. 1965, 77, 75–94; Angew. Chem. Int.
Ed. Engl. 1965, 4, 49–68; b) G. Kçbrich, Angew. Chem. 1972, 84,
557–570; Angew. Chem. Int. Ed. Engl. 1972, 11, 473–485; c) P. J.
Stang, Chem. Rev. 1978, 78, 383–405; d) G. Boche, J. C. W. Lohrenz,
Chem. Rev. 2001, 101, 697–756; e) R. Knorr, Chem. Rev. 2004, 104,
3795–3850.
[2] a) Houben–Weyl, Methoden der organischen Chemie, Vols. 1 and 2
(Ed: M. Regitz), Thieme, Stuttgart, 1989; b) M. Braun, Angew.
Chem. 1998, 110, 444–465; Angew. Chem. Int. Ed. 1998, 37, 430–
451; c) I. Marek, Tetrahedron 2002, 58, 9463–9475; d) M. Braun in
The Chemistry of Alkyllithium Compounds (Eds: Z. Rappoport, I.
Marek), Wiley, New York, 2004, Chapter 13, pp. 829–900; e) T.
Harada in The Chemistry of Organozinc Compounds, Part 2 (Eds:
Z. Rappoport, I. Marek), Wiley, New York, 2006, Chapter 15,
pp. 685–711.
[3] For recent work on nucleophilic substitution, see: a) H. Yanagisawa,
K. Miura, M. Kitamura, K. Narasaka, K. Ando, Bull. Chem. Soc.
Jpn. 2003, 76, 2009–2026; b) M. Watanabe, M. Nakamura, T. Satoh,
Tetrahedron 2005, 61, 4409–4418; c) B. A. Pearlman, S. R. Putt, J. A.
Fleming, J. Org. Chem. 2006, 71, 5646–5657; d) J. Sakurada, T.
Satoh, Tetrahedron 2007, 63, 3806–3817; e) T. Ohbayashi, S. Mitsu-
naga, T. Satoh, Tetrahedron Lett. 2007, 48, 7829–7833; f) N. Mori, K.
Obuchi, T. Katae, J. Sakurada, T. Satoh, Tetrahedron 2009, 65, 3509–
3517; g) S. Mitsunaga, T. Ohbayashi, S. Sugiyama, T. Saitou, M. Ta-
dokoro, T. Satoh, Tetrahedron: Asymmetry 2009, 20, 1697–1708.
[4] For recent work on homologation of ate-type carbenoids, see: a) A.
Abramovitch, J. P. Varghese, I. Marek, Org. Lett. 2004, 6, 621–623;
b) P. R. Blakemore, S. P. Marsden, H. D. Vater, Org. Lett. 2006, 8,
773–776; c) Q. Pu, E. Wilson, C. K. Zercher, Tetrahedron 2008, 64,
8045–8051; d) A. Abramovitch, I. Marek, Eur. J. Org. Chem. 2008,
4924–4931.
[5] For recent work on magnesium carbenoids, see: a) T. Satoh, Chem.
Soc. Rev. 2007, 36, 1561–1572; b) S. Ogata, S. Masaoka, K. Sakai, T.
Satoh, Tetrahedron Lett. 2007, 48, 5017–5021; c) S. Tanaka, T. Anai,
M. Tadokoro, T. Satoh, Tetrahedron 2008, 64, 7199–7210; d) T.
Satoh, T. Noguchi, T. Miyagawa, Tetrahedron Lett. 2008, 49, 5689–
5692; e) T. Satoh, Y. Awata, S. Ogata, S. Sugiyama, M. Tanaka, M.
Tori, Tetrahedron Lett. 2009, 50, 1961–1964; f) N. Nakaya, S. Sugiya-
ma, T. Satoh, Tetrahedron Lett. 2009, 50, 4212–4216.
[15] For reviews, see: a) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996,
96, 49–92; b) M. S. Baird, T. Schmidt in Carbocyclic Three-Mem-
bered Ring Compounds (Ed.: A. de Meijere), Thieme, Stuttgart,
1996, p. 114; c) A. Brandi, A. Goti, Chem. Rev. 1998, 98, 589–635;
d) I. Nakamura, Y. Yamamoto, Adv. Synth. Catal. 2002, 344, 111–
129; e) A. Brandi, S. Cicchi, F. M. Cordero, A. Goti, Chem. Rev.
2003, 103, 1213–1270; f) M. Rubin, M. Rubina, V. Gevorgyan,
Chem. Rev. 2007, 107, 3117–3179; for recent reports, see: g) H. Ta-
niguchi, T. Ohmura, M. Suginome, J. Am. Chem. Soc. 2009, 131,
11298–11299; h) J. Terao, M. Tomita, S. P. Singh, N. Kambe, Angew.
Chem. 2010, 122, 148–151; Angew. Chem. Int. Ed. 2010, 49, 144–
147; i) S. Simaan, A. F. G. Goldberg, S. Rosset, I. Marek, Chem. Eur.
J. 2010, 16, 774–778;.
[16] For recent reports on the synthesis of methylenecyclopropanes, see:
a) T. Satoh, S. Saito, Tetrahedron Lett. 2004, 45, 347–350; b) Z.
Yang, X. Xie, J. M. Fox, Angew. Chem. 2006, 118, 4064–4066;
Angew. Chem. Int. Ed. 2006, 45, 3960–3962; c) A. Masarwa, A.
Stanger, I. Marek, Angew. Chem. 2007, 119, 8185–8188; Angew.
Chem. Int. Ed. 2007, 46, 8039–8042.
[17] For the preparation of (prop-2-ynylidene)cyclopropanes, see: a) J.
Salaun, F. Bennani, J.-C. Compain, A. Fadel, J. Ollivier, J. Org.
Chem. 1980, 45, 4129–4135; b) T. Lange, V. Gramlich, W. Amrein,
F. Diederich, M. Gross, C. Boudon, J.-P. Gisselbrecht, Angew. Chem.
1995, 107, 898–901; Angew. Chem. Int. Ed. Engl. 1995, 34, 805–809.
[18] The calculations were performed by using the Gaussian 98 program
package, see reference [19].
[19] Gaussian 98, Revision A.7, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
M. A. Scuseria, P. M. W. Gill, B. G. Johnson, M. A. Robb, J. R.
Cheeseman, T. A. P. Keith, G. A. Petersson, J. A. Montgomery, Jr..
J. C. Burant, S. Dapprich, J. M. Millam, A. D. Daniels, K. N. Kudin,
M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi,
B. Mennuci, C. Pomelli, C. Adamo, S. Clifford, G. Ochterski, Q. Cui,
K. Morokuma, D. K. Malick, A. D. Rabuck, K. Raghavachari, M. A.
[6] For other applications, see: a) J.-F. Fournier, S. Mathieu, A. B. Char-
ette, J. Am. Chem. Soc. 2005, 127, 13140–13141; b) T. Luu, Y. Mori-
saki, N. Cunningham, R. R. Tykwinski, J. Org. Chem. 2007, 72,
Chem. Eur. J. 2010, 16, 9164 – 9174
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9173

T. Harada et al.
Al-Laham, V. G. Zakrzewski, J. V. Ortiz, J. B. Foresman, J. Cioslow-
ski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi,
A. Nanayakkara, M. Challacombe, C. Y. Peng, P. A. Ayala, W.
Chen, M. W. Wong, J. L. Andres, E. S. Reprogle, R. Gomperts, R. L.
Martin, D. J. Fox, J. S. Binkley, D. J. Defrees, J. Baker, J. P. Stewart,
M. Head-Gordon, C. Gonzalez and J. A. Pople, Gaussian, Inc., Pitts-
burgh PA, 1998.
mers. The calculations showed that two stable structures, with re-
spect to the conformation of the cyclohexane ring, exist for each
isomer. Calculated relative energies are 0 and 0.33 kcalmolÀ1 for
conformers 1 and 2 of (E)-31ab, respectively, and 0.40 and 1.30 kcal
molÀ1 for conformers 1 and 2 of (Z)-31ab, which corresponds to a
calculated thermodynamic E/Z ratio of 2.7:1 at 08C.
[20] The calculated relative energy (1.25 kcalmolÀ1) corresponds to a
thermodynamic E/Z ratio of 10:1 at 08C.
[21] Calculations were also performed for spirocyclic product 31ab to
gain information on the thermodynamic stability of the E and Z iso-
Received: April 27, 2010
Published online: July 19, 2010
9174
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9164 – 9174