Influence of the acetylenic substituent on the intramolecular carbolithiation of alkynes

Article abstract of DOI:10.1002/ejoc.201101777

The intramolecular carbolithiation of a series of propargylic ethers has been performed to evaluate the influence of the terminal substituent on the efficiency and the stereochemical outcome of the cyclization. Our results show that only 5-exo-dig cyclizations are observed, and dihydrobenzofurans are obtained exclusively. Depending on the nature of the terminal substituent, two cases can be considered. If the terminal substituent carried by the acetylenic carbon atom is itself a carbon atom, the cyclization can occur provided the terminal propargylic position bears a coordinating element and is at least disubstituted. When the cyclization occurs, it follows an anti-carbolithiation pathway and thus leads to the E isomer of the exocyclic double bond. Only in one case (Ph) was a mixture of the E and Z isomers of the resulting olefin recovered. The cyclization can also take place if the alkyne is directly substituted by S or Si, provided the cyclization conditions are tuned. In the case of the trimethylsilyl substituent, a syn-carbolithiation was observed. If the double bond is recovered, in most cases, in the exocyclic position, the products can aromatize directly for SPh-substituted substrate 24. Furthermore, in the two latter cases, when alkylation of the vinyllithium intermediate is performed, isomerization of the double bond seems instantaneous. Copyright

Full text of DOI:10.1002/ejoc.201101777

Job/Unit: B11777
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FULL PAPER
DOI: 10.1002/ejoc.201101777
Influence of the Acetylenic Substituent on the Intramolecular Carbolithiation
of Alkynes
Anne-Lise Girard,[a][‡] Rudy Lhermet,[a] Catherine Fressigné,[a] Muriel Durandetti,*[a] and
Jacques Maddaluno*[a]
Keywords: Alkynes / Metalation / Lithium / Cyclization / Substituent effects
The intramolecular carbolithiation of a series of propargylic
ethers has been performed to evaluate the influence of the
terminal substituent on the efficiency and the stereochemical
outcome of the cyclization. Our results show that only 5-exo-
dig cyclizations are observed, and dihydrobenzofurans are
obtained exclusively. Depending on the nature of the ter-
minal substituent, two cases can be considered. If the ter-
minal substituent carried by the acetylenic carbon atom is
itself a carbon atom, the cyclization can occur provided the
terminal propargylic position bears a coordinating element
and is at least disubstituted. When the cyclization occurs, it
follows an anti-carbolithiation pathway and thus leads to the
E isomer of the exocyclic double bond. Only in one case (Ph)
was a mixture of the E and Z isomers of the resulting olefin
recovered. The cyclization can also take place if the alkyne
is directly substituted by S or Si, provided the cyclization con-
ditions are tuned. In the case of the trimethylsilyl substituent,
a syn-carbolithiation was observed. If the double bond is re-
covered, in most cases, in the exocyclic position, the products
can aromatize directly for SPh-substituted substrate 24.
Furthermore, in the two latter cases, when alkylation of the
vinyllithium intermediate is performed, isomerization of the
double bond seems instantaneous.
(Scheme 1). The origin of this phenomenon was rational-
ized through a series of DFT computations run on a model
including two explicit molecules of THF.[5] The results
showed that the terminal acetal moiety played a key role in
this stereocontrol, a strong and persistent Li–O coordina-
tion forcing the triple bond into a pro-E bending even be-
fore the transition state is reached.
Introduction
Carbometalations of alkynes attract continuous attention
because they constitute an unconventional way to create,
often in a regio- and stereoselective manner, carbon–carbon
bonds.[1] Intramolecular versions are particularly attractive,
for they afford (poly)carbo- and heterocyclic systems that
can be further functionalized from the intermediate vin-
ylmetals.[2] Zinc, lithium, magnesium, indium, titanium,
and palladium are efficient metals for such applications,
sometime employed in the presence of another metal.
In this field, we have focused on intramolecular carbo-
lithiation and carbonickelation reactions. We have shown
previously that propargylic ether 1 cyclizes efficiently and
stereoselectively into 3-vinylbenzofuran 4 using either lith-
ium[3] or nickel[4] chemistry. The carbolithiation occurs in
THF through a 5-exo-dig process and affords exocyclic
vinyllithium 3, of which derivatives exhibit an unexpected E
configuration. Furthermore, a one-pot cascade is observed
when an excess amount of nBuLi is employed, and 3-vinyl-
benzofuran 4 is recovered in good yield as a single E isomer
Scheme 1.
[a] CNRS UMR 6014 & FR 3038,
IRCOF – Université de Rouen and INSA de Rouen,
76821 Mont St. Aignan Cedex, France
Fax: +33-2-35522971
The major influence of the propargylic group on the
carbolithiation prompted us to evaluate the scope of this
reaction by modifying the propargylic substituent on aryl
ethers of type 1 and study their propensity to cyclize under
carbanionic conditions, as well as the configuration of the
resulting double bond.
E-mail: muriel.durandetti@univ-rouen.fr
jmaddalu@crihan.fr
[‡] Current address: Universidade Federal do Rio Grande do Sul
(UFRGS) – Institute of Chemistry, Laboratory of Molecular
Catalysis – LAMOCA,
Av. Bento Gonçalves, 9500 Porto Alegre 91501-970-RS, Brazil
Eur. J. Org. Chem. 0000, 0–0
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A.-L. Girard, R. Lhermet, C. Fressigné, M. Durandetti, J. Maddaluno
FULL PAPER
Results and Discussion
The importance of the role played by the oxygen atoms
of the diethyl acetal has been already evidenced: when this
function was replaced by a simple methyl group no cycliza-
tion was observed.[3a] We thus swapped the acyclic acetal
with functions likely to coordinate the lithium, such as
amines, ethers, alcohols, dioxolanes/dioxepanes, or, less or
not, chelating such as a thiophenyl, a phenyl, or a trimethyl-
silyl appendage.
Scheme 3.
Synthesis of the Substrates of the Study
Let us first begin with the preparation of propargylic and
homopropargylic amines 8a, 8b, 12a, and 14. Several routes
based on commercially available propynol and but-3-ynol
were evaluated. A simple three-step (amination–hydroxy-
methylation–Mitsunobu condensation[6]) procedure was op-
timized (Scheme 2). Unfortunately, the early introduction
of the amine revealed difficulties with cyclic amines; the
route was thus adapted (swapping the hydroxymethylation
and amination steps) or advantageously replaced by a cop-
per-catalyzed Mannich aminomethylation[7] in these cases.
Alcohols 15 and ethers 16 and 17 were prepared similarly
from intermediate 11 by using standard methods
(Scheme 2).
Figure 1. Structure of other propargylic substrates tested in this
work.
Phenylacetylene 22 was obtained by Mitsunobu conden-
Branched ethers 20 were obtained from the lithium acet- sation between 2-iodophenol and commercially available 3-
ylide derived from alkyne 18 (Scheme 3), itself obtained by phenylprop-2-yn-1-ol. Silylacetylene 23 was prepared by the
quantitative addition of potassium 2-iodophenolate onto same way from 3-(trimethylsilyl)prop-2-yn-1-ol in 96%
propargyl bromide.
yield. On the other hand, the lithium acetylide derived from
Simple cyclic acetals were also tested (dioxolanes 21a and alkyne 18 (Scheme 3) was treated with S-phenylbenzene
21b and dioxepane 21c, Figure 1). They were prepared by sulfonothioate (PhS-SO2Ph), itself prepared by a simple
trans-acetalization of dimethyl acetal 1a (X = Br, Scheme 1) oxidation of diphenyl disulfide following a known pro-
in toluene by using an excess amount of the corresponding cedure[9] and afforded thiophenylether derivative 24 in 68%
diols in the presence of catalytic amounts of PTSA.[8]
yield.
Scheme 2.
2
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Intramolecular Carbolithiation of Alkynes
In addition to this series of model substrates, we pre-
pared olefin 27 in an attempt to compare the behavior of a
double bond with respect to the acetylenic triple bond in
these carbolithiations. This has been easily achieved by di-
rect condensation of potassium 2-iodophenolate with allylic
bromide 26, made as a single E isomer in a single step from
silyldienol ether 25 (itself prepared from crotonalde-
hyde).[10] Allylic acetal 27 was thus obtained in 63% overall
from crotonaldehyde (Scheme 4).
Scheme 6.
We tried to force the deprotonation of the acetylenic pro-
ton by replacing the 2 equiv. of nBuLi by 1 equiv. of LDA
then 1 equiv. of nBuLi. However, the outcome of the reac-
tion was exactly the same, suggesting that deprotonated 31–
Li does not carbometalate, leaving time for the aryllithium
to protonate the diisopropylamine formed during the first
step.
We next moved to amines 8, 12, and 14 to take advantage
of a N–Li chelation effect, studied in detail in relatively sim-
ilar cases.[13] None of these substrates cyclized under the
conditions defined above (Scheme 1), and the ArH re-
duction product was systematically obtained. This sug-
gested that the Br–Li exchange is efficient but that the re-
sulting aryllithium is not sufficiently reactive to add across
the triple bond. Extensive modulation of the “classical” pa-
Scheme 4.
Cyclization by Carbolithiation
This study started with true alkyne 18, an interesting case rameters such as temperature (–78 °C to r.t.), solvents
that, we thought, would first undergo deprotonation of the [THF, ether, toluene, pentane/ether (3:2),[14] MTBE[15]],
acetylenic proton, leading to lithium acetylide 28. This lat- amount of added nBuLi (1 to 3 equiv.), use of tBuLi instead
ter was expected to provide, upon carbolithiation, vinylic of nBuLi (3.4 equiv.), or various additives (HMPA,
gem-dilithio derivative 29 susceptible to react differentially TMEDA,[16] LiCl,[17] or even FeCl3[18]) did not improve
with two (similar or different) electrophiles,[11] thus opening these results (Scheme 7). It thus appears that the carbolithi-
a route to a large variety of disubstituted olefins 30 ation of these (homo)propargylic amines is difficult, if not
(Scheme 5).
impossible. We proceeded and considered corresponding
alcohols 15 and ethers 16 and 17. The same disappointing
results were obtained, even with 17, which can be regarded
as an “isomer” of acetal 1, and the ArH derivative was the
only identified product (sometime contaminated with the
allenes corresponding to the isomerization of the triple
bond, Scheme 7).
Scheme 5.
However, iodine–lithium exchange seems to be more ra-
pid than deprotonation.[12] It thus affords aryllithium 31,
which undergoes intramolecular deprotonation to yield
acetylide 32, improper for cyclization (Scheme 6). This lat-
ter was evidenced by quenching the reaction medium with
iodine or bromine: the iodo- or bromoacetylenic derivatives
33a or 33b were isolated in high yields (100% 33a with I2,
57% 33b + 29% 33a with Br2).
Scheme 7.
These measly data pointed the finger at a possible influ-
ence of the substitution level of the propargylic position:
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A.-L. Girard, R. Lhermet, C. Fressigné, M. Durandetti, J. Maddaluno
FULL PAPER
1 bears a secondary terminal propargylic carbon atom in occurs, a lithium alkoxide tethered to an exocyclic allene is
contrast to all compounds tested above which exhibit a pri- expected, which could in turn undergo back additions or
mary carbon atom in this position. We therefore moved to isomerizations, leading to multiple byproducts. Attempts to
ethers 20a and 20b, for which the terminal propargylic car- dodge these uncontrolled reactions by trapping the lithium
bon atom is secondary and tertiary, respectively. First, un- alkoxide in situ with trimethylsilyl chloride were unsuccess-
der the regular cyclization conditions 20a led to expected ful.
dihydrobenzofuran 34 but in low yield (Scheme 8). The E
Phenyl-substituted substrate 22 was next investigated. In
character of the resulting exocyclic double bond (estab- good agreement with Bailey’s results,[20] treating 22 with
lished by careful NOE experiments) suggested that an anti- 1 equiv. of nBuLi triggered smooth carbolithiation and led
carbolithiation of the triple bond takes place, comparable to expected dihydrobenzofuran 40 in 60–65% isolated yield
to that observed with acetal 1 (Scheme 1).
(Scheme 10). The anti addition remains predominant, but
significant amounts of the Z isomer could be detected. Ac-
tually, the E/Z ratio turned out to be directly influenced by
the temperature. The data suggest a possible post-carbo-
lithiation isomerization of vinyllithium 39, a phenomenon
previously observed in the case of other α-lithiated
styrenes.[21]
Scheme 8.
By contrast, these same experimental conditions did not
trigger the cyclization of 20b. We had to resort to an excess
amount of nBuLi (3 equiv. at –78 °C) to trigger the cycliza-
tion of the substrate, as determined by TLC and GC. A
cascade process was observed under these harsher condi-
tions, the cyclization being followed by conjugate elimi-
nation of lithium methoxide, leading to 3-isobutenylbenzo-
furan 37 in moderate yield (Scheme 9). We previously hy-
pothesized that the use of an excess amount of nBuLi in
this reaction was likely to trigger deprotonation of the 2-
position of the newly created dihydrobenzofuran.[19] This
dilithiation would afford 35, then vinyllithium 36 after
lithiotropy and β-elimination of lithium methoxide. This
putative compound could be trapped with acetone, leading,
albeit in poor yield, to expected carbinol 38.
Scheme 10.
The important role played by the propargylic substituent
led us to consider two cases in which a heteroelement (Si,
S) is directly attached to the triple bond, keeping in mind
of course that the substituent would influence the polariza-
tion and the charge density on the alkyne and thus likely
to change the course of the carbometalation.
First, trimethylsilylacetylenic derivative 23 was tested un-
der the above conditions by using 1 equiv. of nBuLi
(Scheme 11). Bailey[20] and Negishi[22] have shown in pre-
vious work that silicon-substituted alkynes undergo clean
5-exo-dig intramolecular carbolithiation. Here also, 23
underwent cyclization, but dihydrobenzofuran 42 was reco-
vered only as a side product, and cyclization–isomeriza-
tion–butylation product 41 was the major product (67% in
the crude mixture). This well-recognized side reaction often
occurs when the reaction mixture is warmed, particularly in
THF.[23] In our hands, 41 and 42 could not be separated.
The butylating agent being most likely the nBuI generated
in situ during the iodine–lithium exchange process, we per-
formed the I–Li exchange with 2 equiv. of tBuLi. However,
allene 43 was recovered, contaminated with some reduction
Scheme 9.
Keeping in mind the importance of the tertiary nature of Ar–H product 44. This suggests that a competitive depro-
the propargylic carbon atom, we moved to cyclic acetals 21. tonation of the propargylic position, of which acidity is en-
In these cases again, the reaction proved unfruitful what- hanced by the silicon in β-position, in 23 occurs first, fol-
ever the conditions evaluated. Complex mixtures of com- lowed by the I–Li exchange promoted by the remaining
pounds were obtained, even using only 1 equiv. of nBuLi. equivalent of tBuLi. Finally, PhLi was revealed to be the
This suggests that not only does the Br–Li exchange take best reagent to promote the I–Li exchange (Scheme 11).
place but either the Ar–Li intermediate or the carbolithi- The driving force pushing the 23 + Ph–Li h 23-Li + Ph–
ation product is (are) unstable. If a putative β-elimination I equilibrium on the right is probably the intramolecular
4
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Intramolecular Carbolithiation of Alkynes
coordination resulting from the ortho O–Li interaction in
23-Li. The irreversible character of the cyclization process
(23 Ǟ 42-Li) is also expected to favor the I–Li exchange.
Scheme 12.
tained in 54% yield as a single E isomer (Scheme 13). Note
that the reaction is stereospecific: starting from a sample of
27 with E/Z = 9:1, product 49 was obtained with exactly
the same isomeric ratio.
Scheme 11.
Using an excess amount of PhLi as the organolithium,
dihydrobenzofuran 42 was obtained as the main product
(59% isolated yield) and as a single Z isomer, contaminated
by a small amount of allene 43. It is worth underlining that
the absence of a Li–Si interaction triggers a syn-carbolithi-
ation, in contrast to the above examples but as expected on
a theoretical basis. Note also that the intermediate vinyllith-
ium can be directly alkylated: it was trapped by benzyl
bromide but led to benzofuran 45 in medium yield. It thus
seems that the alkylation of the terminal vinylic position
sets off the isomerization of the double bond.
Scheme 13.
Conclusions
In conclusion, this study addresses several important is-
sues regarding the intramolecular carbolithiation of substi-
Next, thiophenylether 24 was submitted to our reaction tuted alkynes: (i) The 5-exo-dig cyclization is always ob-
conditions, using 1 equiv. of nBuLi. Little is known about served, and the 6-endo-dig product was not observed in any
the carbolithiation of ynol thioethers.[24] The cyclization case studied here. (ii) A necessary, but not sufficient, condi-
proceeded smoothly but here again the main product, ob- tion for the cyclization to occur is that the terminal propar-
tained in 31% yield, was butylated benzofuran 46 gylic carbon atom, if there is one, is at least disubstituted
(Scheme 12, path a), following a sequence probably similar and bears a coordinating element. (iii) When the cyclization
to that operating for 41. Using 2 equiv. of tBuLi led, this occurs, it seems to follow an anti-carbolithiation pathway,
time led to benzofuran 47 in good yield, suggesting a lower even if, in one case (Ph), a mixture of the E and Z isomers
acidity of the propargylic position in 24. An attempt to trap of the resulting olefin is recovered, possibly because of a
the intermediate vinyllithium, of which putative carbenoid post-cyclization isomerization. (iv) The cyclization can also
character could hamper the reactivity,[25] by benzyl bromide take place if the alkyne is directly substituted by a heteroele-
afforded disubstituted benzofuran 48 in 58% yield. No all- ment (S or Si) but in the latter case (at least) a syn-carbo-
enyl isomer could be observed this time. Thus, the double lithiation is observed, suggesting the absence of Li–Si inter-
bond isomerization seems to take place at an early stage of action. (v) The double bond is recovered, in most cases, in
the cascade and seems to be difficult to avoid in this case. the exocyclic position even though the benzofurans where
Consequently, we could not determine if an anti- or a syn- observed in the cases of the SPh substituent. If alkylation
carbolithiation occurs in this case.
of the intermediate vinyllithium is performed, the isomer-
Finally, we focused on the carbolithiation of (E)-alkene ization of the double bond can even be instantaneous (see
27, which is substituted by a diethylacetal and is, therefore, products 41, 45, 46, and 48). Note that all the products with
analogous to 1. The standard conditions failed to provide exocyclic double bonds tend to slowly aromatize, particu-
the expected dihydrobenzofuran. However, under condi- larly after repeated purifications by chromatography on sil-
tions inspired from Bailey’s protocol, viz. in the presence of ica gel. (vi) The iodine–lithium exchange can be efficiently
2 equiv. of TMEDA in Et2O, an addition–elimination pro- performed by using PhLi instead of nBuLi to avoid Wurtz–
cess took place, in complete accord with our own theoreti- Fittig side products (as in the 23 Ǟ 41 + 42 transformation,
cal assessment. Dihydrobenzofuran 49 was therefore ob- Scheme 11).
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A.-L. Girard, R. Lhermet, C. Fressigné, M. Durandetti, J. Maddaluno
FULL PAPER
brown liquid was purified by column chromatography (30% ethyl
Experimental Section
acetate in cyclohexane) to give pure product 8a (1.68 g, 4.0 mmol,
1
General Considerations: THF was dried from sodium/benzophen-
one. All reagents were of reagent grade and were used as such or
distilled prior to use. Reactions were monitored by TLC carried
out on 0.25 mm E. Silica gel coated aluminum plates (60 F254)
using UV light as visualizing agent and 7% ethanolic phosphomo-
lybdic acid and heat as developing agents or by GC 24-m HP-
methyl silicon capillary collumn. E. silica gel (60, particle size 0.04–
58%) as a yellow liquid. H NMR (300 MHz, CDCl3): δ = 3.25 (s,
2 H), 3.59 (s, 4 H), 4.90 (s, 2 H), 6.90 (dt, J = 7.9, 1.5 Hz, 1 H),
6.90 (dd, J = 7.9, 1.5 Hz, 1 H), 7.12–7.47 (m, 11 H), 7.59 (dd, J =
7.9, 1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.7, 57.6,
57.9 (2 C), 80.3, 83.7, 113.0, 114.9, 123.5, 127.5 (2 C), 128.7, 128.8
(4 C), 129.6 (4 C), 134.0, 139.1 (2 C), 154.5 ppm. MS (EI): m/z (%)
= 419–421 [M]+, 248, 156 (4), 91 [base]. IR: ν = 2085, 1241 cm–1.
˜
0.063 mm) was used for flash chromatography. H and 13C NMR
1
C24H22BrNO (420.35): calcd. C 68.58, H 5.28, N 3.33; found C
68.09, H 5.48, N 3.46.
spectra were recorded at room temperature at 300 and 75 MHz,
respectively, and calibrated by using residual undeuterated solvent
as an internal reference. The solvent was deuteriochloroform. The
mass spectra were obtained under electron impact conditions (EI)
at 70 eV ionizing potential or under positive chemical ionization
with methane.
N,N-Dibenzyl-5-(2-bromophenoxy)pent-3-yn-1-amine (8b): Ether 8b
was obtained from alcohol 7b (2.00 g, 7.2 mmol), 2-bromophenol
(0.85 mL, 7.2 mmol), triphenylphosphane (1.88 g, 1.0 equiv.,
7.2 mmol), and diisopropyl azodicarboxylate (1.42 mL, 1.0 equiv.,
7.2 mmol) following the same procedure. Filtration gave pure 8b
Compounds 5a,[26] 5b,[27] 6a,[28] 6b,[29] 9a,[30] 9b,[31] 10a,[32] 10b,[33]
18,[34] 22,[4a] 23,[35] 25,[10] 26,[10] 33b,[36] 40,[4a] and 42[35] have been
described previously.
1
(1.71 g, 3.94 mmol, 55%) as a yellow liquid. H NMR (300 MHz,
CDCl3): δ = 2.34 (t, J = 7.2 Hz, 2 H), 2.61 (t, J = 7.2 Hz, 2 H),
3.55 (s, 4 H), 4.68 (s, 2 H), 6.80 (dt, J = 7.9, 1.5 Hz, 1 H), 6.98 (dd,
J = 7.9, 1.5 Hz, 1 H), 7.10–7.48 (m, 11 H), 7.59 (dd, J = 7.9, 1.5 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.8, 52.1, 57.7, 58.3
(2 C), 75.4, 87.6, 112.5, 114.4, 122.7, 127.2 (2 C), 128.5 (4 C),
128.7;129.0 (4 C), 133.7, 139.7 (2 C), 154.5 ppm.
4-(Dibenzylamino)but-2-yn-1-ol (7a): To a solution of compound 6a
(2.0 g, 8.5 mmol) in THF (10 mL) under an atmosphere of argon
at –78 °C was added dropwise nBuLi (2.3 m in hexane, 4.8 mL,
1.3 equiv., 11 mmol) by an addition funnel. At the end of the ad-
dition, the mixture was stirred for 30 min at –78 °C before the ad-
dition of paraformaldehyde (0.8 g, 3.0 equiv., 25.5 mmol). The re-
action was slowly warmed to room temperature overnight and hy-
drolyzed at 0 °C with water. The mixture was extracted, and the
organic layer was washed with saturated NaCl solution
(2ϫ10 mL), dried with anhydrous MgSO4, and concentrated. The
resulting brown liquid was purified by column chromatography
(30% ethyl acetate in cyclohexane) to give 7a as a light yellow li-
quid (2.17 g, 8.2 mmol, 96%). 1H NMR (300 MHz, CDCl3): δ =
3.04 (s, 1 H), 3.35 (s, 2 H), 3.72 (s, 4 H), 4.38 (s, 2 H), 7.19–7.51
(m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 42.1, 51.4, 57.9
(2 C), 80.8, 84.5, 127.6 (2 C), 128.8 (4 C), 129.6 (4 C), 139.0 (2
[4-(2-Bromophenoxy)but-2-ynyloxy](tert-butyl)dimethylsilane (11a):
Ether 11a was obtained from alcohol 10a (3.00 g, 14.98 mmol), 2-
bromophenol (1.78 mL, 14.98 mmol), triphenylphosphane (3.93 g,
1.0 equiv., 14.98 mmol), and diisopropyl azodicarboxylate
(2.97 mL, 1.0 equiv., 14.98 mmol) following the same procedure.
Filtration gave pure 11a (4.55 g, 12.8 mmol, 85%) as a light yellow
1
liquid. H NMR (300 MHz, CDCl3): δ = 0.02 (s, 6 H), 0.82 (s, 9
H), 4.27 (t, J = 1.9 Hz, 2 H), 4.73 (t, J = 1.9 Hz, 2 H), 6.79 (td, J
= 7.9, 1.5 Hz, 1 H), 6.97 (dd, J = 7.9, 1.5 Hz, 1 H), 7.18 (td, J =
7.9, 1.5 Hz, 1 H), 7.56 (dd, J = 7.9, 1.5 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 4.8 (2 C), 18.7, 26.2 (3 C), 52.1, 57.4, 79.5,
87.0, 112.7, 114.5, 123.0, 128.7, 133.9, 154.5 ppm. C16H23BrO2Si
(355.35): calcd. C 54.08, H 6.52; found C 54.18, H 6.46.
C) ppm. MS (CI+, CH ): m/z = 266 [M + H+, base], 248. IR: ν =
˜
4
3390, 2360, 1242, 1027 cm–1. C18H19NO (265.35): calcd. C 81.47,
[5-(2-Bromophenoxy)pent-3-ynyloxy](tert-butyl)dimethylsilane
(11b): Ether 11b was obtained from alcohol 10b (21.6 g, 0.125 mol),
2-bromophenol (14.85 mL, 0.125 mol), triphenylphosphane (32.7 g,
0.125 mol), and diisopropyl azodicarboxylate (24.71 mL,
0.125 mol) following the same procedure. Filtration gave pure 11b
(41.6 g, 0.113 mmol, 90%) as a brown oil. 1H NMR (300 MHz,
CDCl3): δ = 0.00 (s, 6 H), 0.83 (s, 9 H), 2.37 (tt, J = 7.1, 2.0 Hz, 2
H), 3.64 (t, J = 7.1 Hz, 2 H), 4.67 (t, J = 2.0 Hz, 2 H), 6.78 (td, J
= 7.9, 1.5 Hz, 1 H), 6.98 (dd, J = 7.9, 1.5 Hz, 1 H), 7.18 (td, J =
7.9, 1.5 Hz, 1 H), 7.56 (dd, J = 7.9, 1.5 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = –4.9 (2 C), 18.7, 23.6, 26.2 (3 C), 57.7, 62.0,
75.9, 86.2, 112.7, 114.5, 122.8, 128.7, 133.8, 154.6 ppm.
H 7.22, N 5.28; found C 81.17, H 7.23, N 5.56.
5-(Dibenzylamino)pent-2-yn-1-ol (7b): Alcohol 7b was obtained
from amine 6b (2.2 g, 8.8 mmol), nBuLi (2.3 m in hexane, 5.0 mL,
1.3 equiv., 11.5 mmol) and paraformaldehyde (0.8 g, 3.0 equiv.,
26.4 mmol) following the same procedure. The resulting brown li-
quid was purified by column chromatography (30% ethyl acetate
in cyclohexane) to give 7b as a light yellow liquid (2.38 g, 8.5 mmol,
1
97%). H NMR (300 MHz, CDCl3): δ = 1.88 (s, 1 H), 2.30 (t, J =
7.2 Hz, 2 H), 2.67 (t, J = 7.2 Hz, 2 H), 3.61 (s, 4 H), 4.18 (s, 2 H),
7.12–7.47 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.7,
51.5, 52.5, 58.5 (2 C), 79.8, 84.9, 127.5 (2 C), 128.7 (4 C), 129.2 (4
C), 139.7 (2 C) ppm. MS (EI): m/z = 279 [M]+, 210 [base], 181, 91.
4-(2-Bromophenoxy)but-2-yn-1-ol (15a): Protected alcohol 11a
(17.01 g, 47.87 mmol) was diluted in a solution of 1% HCl in eth-
IR: ν = 3465, 2362, 1241 cm–1.
˜
N,N-Dibenzyl-4-(2-bromophenoxy)but-2-yn-1-amine (8a) (Mitsu- anol (100 mL). After stirring for 2 h, the alcohol was completely
nobu Condensation): To a solution of alcohol 7a (1.85 g, 6.9 mmol),
2-bromophenol (0.83 mL, 1.0 equiv., 6.9 mmol), and tri-
phenylphosphane (1.80 g, 1.0 equiv., 6.9 mmol) in THF (30 mL) at
0 °C under an atmosphere of argon was added dropwise di-
isopropyl azodicarboxylate (1.37 mL, 1.0 equiv., 6.9 mmol). The
solution was warmed to room temperature, stirred for 3 h, and
deprotected. A saturated NaHCO3 solution was added (60 mL),
then water (60 mL), and this mixture was extracted with EtOAc
(2ϫ150 mL). The combined organic layers were dried with anhy-
drous MgSO4 and concentrated to provide 15a (11.43 g,
47.41 mmol, 99%) as an orange-brown liquid. 1H NMR (300 MHz,
CDCl3): δ = 2.01 (s, 1 H), 4.30 (s, 2 H), 4.81 (s, 2 H), 6.88 (td, J =
washed by adding 0.4 m NaOH (10 mL). The mixture was diluted 7.9, 1.5 Hz, 1 H), 7.03 (dd, J = 7.9, 1.5 Hz, 1 H), 7.27 (td, J = 7.9,
by Et2O (15 mL) and washed again with 0.4 m NaOH (2ϫ10 mL).
The combined organic layers were dried with anhydrous MgSO4
and concentrated. Pentane (30 mL) was added to the residue to
precipitate triphenylphosphane oxide. After filtration, the resulting
1.5 Hz, 1 H), 7.55 (dd, J = 7.9, 1.5 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 51.2, 57.4, 80.3, 86.6, 112.6, 114.4, 123.2,
128.9, 133.9, 154.4 ppm. C10H9BrO2 (241.08): calcd. C 49.82, H
3.76; found C 49.75, H 3.78.
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: B11777
/KAP1
Date: 05-03-12 11:17:16
Pages: 12
Intramolecular Carbolithiation of Alkynes
5-(2-Bromophenoxy)pent-3-yn-1-ol (15b): Alcohol 15b was obtained
from protected alcohol 11b (41.64 g, 0.113 mol.) following the same
procedure. The combined organic layers were dried with anhydrous
MgSO4 and concentrated to provide 15b (22.60 g, 0.089 mol, 78%)
= 7.9, 1.5 Hz, 1 H), 7.07 (dd, J = 7.9, 1.5 Hz, 1 H), 7.26 (td, J =
7.9, 1.5 Hz, 1 H), 7.54 (dd, J = 7.9, 1.5 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 24.1, 26.1 (2 C), 48.1 (2 C), 53.6, 57.5, 79.6,
84.1, 112.7, 114.7, 122.9, 128.6, 133.8, 154.4 ppm. MS (EI): m/z =
307–309 [M]+, 228, 135 [base].
1
as an orange oil. H NMR (300 MHz, CDCl3): δ = 2.19 (s, 1 H),
2.46 (tt, J = 6.4, 2.3 Hz, 2 H), 3.68 (t, J = 6.4 Hz, 2 H), 4.75 (t, J
= 2.3 Hz, 2 H), 6.86 (td, J = 7.9, 1.5 Hz, 1 H), 7.03 (dd, J = 7.9,
1.5 Hz, 1 H), 7.26 (td, J = 7.9, 1.5 Hz, 1 H), 7.53 (dd, J = 7.9,
1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.5, 57.8,
61.2, 76.7, 85, 112.8, 114.6, 123.1, 128.7, 133.9, 154.5 ppm. MS
(EI): m/z = 254–256 [M]+, 174 [M – Br, base], 157, 145. C11H11BrO2
(255.11): calcd. C 51.79, H 4.35; found C 51.52, H 4.36.
1-Bromo-2-(4-methoxy-but-2-ynyloxy)benzene (16a): At 0 °C,
a
solution of alcohol 15a (0.723 g, 3.0 mmol) in THF (9 mL) was
added dropwise to a suspension of sodium hydride (60% in oil,
0.144 g, 1.2 equiv., 3.6 mmol) in THF (6 mL). After stirring at
room temperature for 30 min, methyl iodide (0.93 mL, 5 equiv.,
15 mmol) was added, and the resulting mixture was stirred for 1 h.
The solution was then diluted with Et2O and washed with a satu-
rated solution of ammonium chloride and brine. The combined
organic layers were dried with anhydrous MgSO4 and concentrated.
Purification of the residue by column chromatography (20% ethyl
acetate in cyclohexane) gave 16a (0.592 g, 2.3 mmol, 77%) as a light
1-[4-(2-Bromophenoxy)but-2-ynyl]pyrrolidine (12a): The mesylate
product was obtained from propargyl alcohol 15a (2.4 g,
9.95 mmol), triethylamine (2.24 mL, 2 equiv., 19.90 mmol), and dis-
tilled methanesulfonyl chloride (0.92 mL, 1.2 equiv., 11.95 mmol).
Without purification, the pure mesylated product (2.6 g,
1
yellow liquid. H NMR (300 MHz, CDCl3): δ = 3.35 (s, 3 H), 4.13
a
yellow oil. 1H NMR
(t, J = 1.9 Hz, 2 H), 4.83 (t, J = 1.9 Hz, 2 H), 6.88 (td, J = 7.9,
1.5 Hz, 1 H), 7.06 (dd, J = 7.9, 1.5 Hz, 1 H), 7.27 (td, J = 7.9,
1.5 Hz, 1 H), 7.55 (dd, J = 7.9, 1.5 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 57.4, 58.1, 60.2, 81.2, 84.3, 112.8, 114.5,
123.1, 128.7, 133.9, 154.4 ppm.
8.15 mmol, 82%) was obtained as
(300 MHz, CDCl3): δ = 2.93 (s, 3 H), 4.74 (t, J = 1.5 Hz, 2 H),
4.77 (t, J = 1.5 Hz, 2 H), 6.81 (td, J = 7.9, 1.5 Hz, 1 H), 6.91 (dd,
J = 7.9, 1.5 Hz, 1 H), 7.20 (td, J = 7.9, 1.5 Hz, 1 H), 7.46 (dd, J =
7.9, 1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 39.2, 57.1,
57.9, 80.4, 84.8, 112.7, 114.4, 123.5, 128.9, 134.1, 154.1 ppm.
C11H11BrO4S (319.17): calcd. C 41.39, H 3.47, S 10.05; found C
41.37, H 3.48, S 9.98. To a solution of the mesylate (0.140 g,
0.44 mmol) in ethanol (5 mL) was added dropwise pyrrolidine
(0.05 mL, 1.2 equiv., 0.87 mmol). After stirring 22 h at reflux, the
resultant mixture was concentrated, and the residue was diluted
with CH2Cl2 (5 mL). HCl was then added (5 mL). The organic
layer was washed by water (5 mL), dried with anhydrous MgSO4,
and concentrated to provide pure 12a (0.064 g, 0.22 mmol, 50%)
1-Bromo-2-[4-(methoxymethoxy)but-2-ynyloxy]benzene (17a): To a
solution of alcohol 15a (0.482 g, 1.9 mmol) and freshly distilled
diisopropylamine (2.44 mL, 7 equiv., 14 mmol) in CH2Cl2 (5 mL)
was added dropwise methoxymethyl chloride (0.45 mL, 3 equiv.,
6 mmol) at room temperature. After stirring for 18 h, the mixture
was concentrated. The residue was then diluted with Et2O and
washed with hydrogen carbonate solution. The combined organic
layers were dried with anhydrous MgSO4 and concentrated. Purifi-
cation of the residue by column chromatography (30% ethyl acetate
and 1% of triethylamine in cyclohexane) gave 17a (0.375 g,
1
as an orange oil. H NMR (300 MHz, CDCl3): δ = 1.72 (m, 4 H),
2.52 (m, 4 H), 3.38 (t, J = 1.8 Hz, 2 H), 4.75 (t, J = 1.8 Hz, 2 H),
6.86 (td, J = 8.4, 1.4 Hz, 1 H), 7.02 (dd, J = 8.4, 1.4 Hz, 1 H), 7.21
(dt, J = 8.4, 1.4 Hz, 1 H), 7.49 (dd, J = 8.4, 1.4 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 24.1 (2 C), 43.5, 52.8 (2 C), 78.9,
1
1.3 mmol, 69%) as a pink liquid. H NMR (300 MHz, CDCl3): δ
= 3.35 (s, 3 H), 4.25 (t, J = 1.9 Hz, 2 H), 4.67 (s, 2 H), 4.82 (t, J =
1.9 Hz, 2 H), 6.86 (td, J = 7.9, 1.5 Hz, 1 H), 6.91 (dd, J = 7.9,
1.5 Hz, 1 H), 7.27 (td, J = 7.9, 1.5 Hz, 1 H), 7.55 (dd, J = 7.9,
1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 54.6, 55.9,
57.4, 80.8, 84.0, 95.1, 112.7, 114.4, 123.0, 128.7, 133.9, 154.4 ppm.
84.6, 112.7, 114.6, 122.9, 128.6, 133.8, 154.4 ppm. IR: ν = 2085,
˜
1241 cm–1.
1-Bromo-2-(prop-2-ynyloxy)benzene (13): Ether 13 was obtained
from prop-2-yn-1-ol (0.648 g, 11.56 mmol), 2-bromophenol
(1.38 mL, 1.0 equiv., 11.56 mmol), triphenylphosphane (3.030 g,
5-(2-Iodophenoxy)pent-3-yn-2-ol (19a): To a solution of 18 (2.45 g,
9.5 mmol) in anhydrous THF (15 mL) under an atmosphere of ar-
gon at 0 °C was added dropwise LDA [freshly prepared from diiso-
propylamine (1.60 mL, 11.4 mmol) and nBuLi (1.6 m in hexanes,
6.53 mL, 10.5 mmol) in THF (15 mL)]. The dark brown mixture
was stirred for 30 min at 0 °C before acetaldehyde (1.60 mL,
28.5 mmol) was added, and the mixture was then stirred for 12 h
at room temperature. The solution was hydrolyzed with water
(10 mL), and the aqueous layer was extracted with Et2O
(3ϫ10 mL). The combined organic layers were washed with brine,
dried with MgSO4, and then concentrated. Pure 19a (2.33 g,
7.7 mmol, 81%) was obtained after purification by column
chromatography (40% of Et2O in n-pentane) as a pale yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.42 (d, J = 6.6 Hz, 3 H), 2.40
(s, 1 H), 4.53 (qd, J = 6.6, 1.6 Hz, 1 H), 4.77 (d, J = 1.6 Hz, 2 H),
6.74 (td, J = 7.6, 1.3 Hz, 1 H), 6.96 (dd, J = 8.3, 1.3 Hz, 1 H), 7.30
(ddd, J = 8.3, 7.6, 1.6 Hz, 1 H), 7.77 (dd, J = 7.6, 1.6 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 24.1, 57.3, 58.4, 78.5, 86.7, 89.8,
113.2, 123.5, 129.5, 139.8, 156.4 ppm. MS (EI, 70 eV): m/z = 302
[M]+, 287 [M – CH3], 220 (base) [2-iodophenol], 175 [M – I]. IR:
1.0 equiv.,
11.56 mmol),
and
diisopropylazodicarboxylate
(2.29 mL, 1.0 equiv., 11.56 mmol) following the above procedures
for the Mitsunobu condensation. The resulting brown oil was puri-
fied by column chromatography (20% ethyl acetate in cyclohexane)
to give 13 (2.171 g, 10.29 mmol, 89%) as a brown liquid. 1H NMR
(300 MHz, CDCl3): δ = 2.54 (t, J = 2.3 Hz, 1 H), 4.78 (d, J =
2.3 Hz, 2 H), 6.89 (td, J = 7.9, 1.1 Hz, 1 H), 7.07 (dd, J = 7.9,
1.1 Hz, 1 H), 7.28 (td, J = 7.9, 1.1 Hz, 1 H), 7.56 (dd, J = 7.9,
1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 57.1, 76.5,
78.3, 112.7, 114.5, 123.2, 128.7, 133.9, 154.4 ppm.
1-[4-(2-Bromo-phenoxy)-but-2-ynyl]piperidine (14): To a solution of
acetylene 13 (0.197 g, 0.93 mmol) in dioxane (5 mL) was added
piperidine (0.46 mL, 5 equiv., 4.67 mmol) followed by solid cop-
per(I) iodide (0.178 g, 1 equiv., 0.93 mmol) and lastly paraformal-
dehyde (0.280 g, 10 equiv., 9.33 mmol). The reaction mixture was
stirred for 3 h at reflux. The mixture was cooled, filtered through
a pad of Celite, and concentrated. The resulting liquid was purified
by column chromatography (20% ethyl acetate in cyclohexane) to
give 14 (0.244 g, 0.79 mmol, 85%) as a brown oil. 1H NMR
(300 MHz, CDCl3): δ = 1.39 (m, 2 H), 1.57 (m, 4 H), 2.43 (m, 4
H), 3.28 (t, J = 1.9 Hz, 2 H), 4.81 (t, J = 1.9 Hz, 2 H), 6.86 (td, J
ν = 3347, 2981, 1582, 1470, 1439, 1224, 1151, 1017 cm–1. HRMS
˜
(EI): calcd. for C11H11IO2 [M]+ 301.9805; found 301.9804.
5-(2-Iodophenoxy)-2-methylpent-3-yn-2-ol (19b): Compound 19b
was obtained from 18 (2.42 g, 9.4 mmol), diisopropylamine
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: B11777
/KAP1
Date: 05-03-12 11:17:16
Pages: 12
A.-L. Girard, R. Lhermet, C. Fressigné, M. Durandetti, J. Maddaluno
FULL PAPER
(1.65 mL, 11.7 mmol), nBuLi (1.5 m hexanes, 7.20 mL, 10.8 mmol),
and acetone (2.07 mL, 28.2 mmol) in anhydrous THF (30 mL) fol-
lowing the procedure for 19a. Pure 19b (2.50 g, 7.9 mmol, 84%)
2-[3-(2-Bromophenoxy)prop-1-ynyl]-4,4,5,5-tetramethyl[1,3]di-
oxolane (21b): Acetal 21b (0.274 g, 0.807 mmol, 97%) was obtained
as
a
yellow solid from ethyl acetal 1a (0.313 g, 1.2 equiv.,
2,3-dimethylbutan-2,3-diol (0.098 g, 1 equiv.,
was obtained after purification by column chromatography (30% 1.0 mmol),
of Et2O in n-pentane) as a pale yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 1.48 (s, 6 H), 2.29 (s, 1 H), 4.76 (s, 2 H), 6.74 (td, J =
7.6, 1.3 Hz, 1 H), 6.97 (dd, J = 8.2, 1.3 Hz, 1 H), 7.30 (td, J = 8.2,
0.833 mmol), and p-toluenesulfonic acid monohydrate (0.032 g,
0.2 equiv., 0.167 mmol) following the same procedure of transace-
1
talization. H NMR (300 MHz, CDCl3): δ = 1.17 (s, 6 H), 1.25 (s,
1.6 Hz, 1 H), 7.77 (dd, J = 7.6, 1.6 Hz, 1 H) ppm. 13C NMR 6 H), 4.82 (s, 2 H), 5.62 (s, 1 H), 6.87 (td, J = 7.9, 1.5 Hz, 1 H),
(75 MHz, CDCl3): δ = 31.2 (2 C), 57.5, 65.2, 76.6, 86.9, 92.6, 113.5, 7.05 (dd, J = 7.9, 1.5 Hz, 1 H), 7.25 (td, J = 7.9, 1.5 Hz, 1 H), 7.55
123.4, 129.4, 139.7, 156.5 ppm. MS (EI, 70 eV): m/z = 316 [M]+,
301 [M – CH3], 258 [M – (CH3)2COH], 220 (base) [iodophenol],
(dd, J = 7.9, 1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
22.3 (2 C), 23.3 (2 C), 57.3, 79.8, 85.7, 83.5 (2 C), 89.8, 112.7, 114.7,
123.1, 128.7, 133.8, 154.3 ppm. MS (EI): m/z = 338–340 [M]+, 109,
83, 67 [base]. M.p. 76–79 °C.
189 [M – I], 96 [M – iodophenol]. IR: ν = 3356, 2981, 1582, 1471,
˜
1223, 1164, 1017 cm–1. HRMS (EI): calcd. for C12H13IO2 [M]+
315.9965; found 315.9960.
2-[3-(2-Bromophenoxy)prop-1-ynyl][1,3]dioxepane (21c): Acetal 21c
1-Iodo-2-(4-methoxypent-2-ynyloxy)benzene (20a): To a solution of (0.207 g, 0.67 mmol, 67%) was obtained as a yellow liquid from
19a (2.26 g, 7.5 mmol) in anhydrous THF (25 mL) under an atmo-
sphere of argon at 0 °C was slowly added 60% NaH (897 mg,
22.4 mmol), followed by methyl iodide (1.40 mL, 22.4 mmol). After
stirring for 2 h at room temperature, the reaction was carefully
quenched with water (10 mL), and the aqueous layer was extracted
with Et2O (2ϫ15 mL). The combined organic layers were washed
with brine (10 mL), dried with MgSO4, and concentrated. Pure 20a
(2.20 g, 6.9 mmol, 93%) was obtained after purification by column
chromatography (20% of Et2O in n-pentane) as a pale yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.40 (d, J = 6.6 Hz, 3 H), 3.34
(s, 3 H), 4.09 (qt, J = 6.6, 1.6 Hz, 1 H), 4.81 (d, J = 1.6 Hz, 2 H),
6.75 (td, J = 7.6, 1.3 Hz, 1 H), 7.00 (dd, J = 8.3, 1.3 Hz, 1 H), 7.31
(ddd, J = 8.3, 7.6, 1.6 Hz, 1 H), 7.78 (dd, J = 7.6, 1.6 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.8, 56.5, 57.3, 66.9, 79.5, 86.8,
87.8, 113.3, 123.4, 129.4, 139.7, 156.5 ppm. MS (EI, 70 eV): m/z =
316 [M+, base], 284 [M – OMe], 220 (2-iodophenol), 189 [M – I],
ethyl acetal 1a (0.313 g, 1 equiv., 1.0 mmol), butane-1,4-diol
(0.135 g, 1.5 equiv., 1.5 mmol), and p-toluenesulfonic acid monohy-
drate (0.095 g, 0.5 equiv., 0.5 mmol) following the same procedure
1
of transacetalization. H NMR (300 MHz, CDCl3): δ = 1.65–1.70
(m, 4 H), 3.68–3.91 (m, 4 H), 4.82 (d, J = 1.5 Hz, 2 H), 5.39 (t, J
= 1.5 Hz, 1 H), 6.88 (td, J = 7.9, 1.5 Hz, 1 H), 7.06 (dd, J = 7.9,
1.5 Hz, 1 H), 7.27 (td, J = 7.9, 1.5 Hz, 1 H), 7.54 (dd, J = 7.9,
1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 29.4 (2 C),
57.3, 65.8 (2 C), 80.1, 83.2, 91.2, 112.8, 114.7, 123.1, 128.7, 133.9,
154.4 ppm.
[3-(2-Iodophenoxy)prop-1-ynyl](phenyl)sulfane (24): To a solution of
phenyl disulfide (4.37 g, 20 mmol) in glacial acetic acid (20 mL)
under an atmosphere of argon was added dropwise hydrogen perox-
ide (30% in water, 4.19 mL, 41 mmol) over 30 min. After stirring
for 24 h at room temperature, the reaction was carefully quenched
at 0 °C with water (20 mL) followed by CH2Cl2 (20 mL). The aque-
ous layer was extracted with CH2Cl2 (20 mL), and the combined
organic layers were washed with a saturated aqueous solution of
sodium carbonate (2ϫ10 mL), water (2ϫ10 mL), and brine
(10 mL), dried with anhydrous MgSO4, and concentrated. A mix-
ture of the sulfone and the sulfoxide (95:5, 2.71 g, ≈11 mmol) was
obtained and engaged without further purification in a sulfon-
ylation reaction following the procedure for 19a. Half of the crude
material (1.38 g, ≈5 mmol) was used as the electrophile with 18
(1.29 g, 5 mmol), diisopropylamine (740 μL, 5.3 mmol), and nBuLi
(1.6 m in hexanes, 3.13 mL, 5 mmol) in anhydrous THF (25 mL).
Compound 24 (1.25 g, 3.4 mmol, 68%) was obtained after purifica-
157 [M – I – OMe]. IR: ν = 3061, 2985, 2934, 1582, 1472, 1225,
˜
1113, 1017 cm–1. HRMS (EI): calcd. for C12H13IO2 [M]+ 315.9965;
found 315.9960.
1-Iodo-2-(4-methoxy-4-methylpent-2-ynyloxy)benzene (20b): Com-
pound 20b was obtained from 19b (2.47 g, 7.8 mmol), 60% NaH
(936 mg, 23.4 mmol), and methyl iodide (1.46 mL, 23.4 mmol) in
anhydrous THF (25 mL) following the procedure for 20a. Pure 20b
(2.34 g, 7.1 mmol, 91%) was obtained after purification by column
chromatography (20% of Et2O in n-pentane) as a pale yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.42 (s, 6 H), 3.29 (s, 3 H), 4.80
(s, 2 H), 6.75 (td, J = 7.6, 1.3 Hz, 1 H), 7.01 (dd, J = 8.2, 1.3 Hz,
1 H), 7.30 (ddd, J = 8.2, 7.6, 1.5 Hz, 1 H), 7.78 (dd, J = 7.6, 1.6 Hz,
tion by column chromatography (2% of Et2O in n-pentane) in a
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.1 (2 C), 51.8, 57.4, mixture with 18 (261 mg, 1.0 mmol, 20%) as a pale yellow oil. H
1
70.5, 78.6, 86.9, 90.0, 113.5, 123.4, 129.3, 139.7, 156.5 ppm. MS
NMR (300 MHz, CDCl3): δ = 5.00 (s, 2 H), 6.78 (td, J = 7.7,
1.3 Hz, 1 H), 7.02 (dd, J = 8.3, 1.3 Hz, 1 H), 7.20–7.42 (m, 6 H),
7.81 (dd, J = 7.7, 1.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 58.1, 75.9, 86.9, 93.6, 113.4, 123.6, 126.7, 127.0 (2 C), 129.4,
129.5 (2 C), 132.0, 139.9, 156.4 ppm. MS (EI, 70 eV): m/z = 367
(EI, 70 eV): m/z = 330 [M]+, 203 [M – I], 111 [base], 96, 79. IR: ν
˜
= 2983, 2934, 1582, 1471, 1224, 1172, 1073 cm–1. HRMS (EI):
calcd. for C13H15IO2 [M]+ 330.0128; found 330.0116.
2-[3-(2-Bromophenoxy)prop-1-ynyl]-1,3-dioxolane (21a) (Transace-
talization Procedure): A mixture of ethyl acetal 1a (0.313 g,
1.0 mmol), ethylene glycol (0.093 g, 1.5 equiv., 1.5 mmol), p-tolu-
enesulfonic acid monohydrate (0.095 g, 0.5 equiv., 0.125 mol), and
anhydrous MgSO4 in toluene (6 mL) was heated at reflux for 1 h.
Water (10 mL) was added, and the mixture was diluted with Et2O
(10 mL). The aqueous layer was extracted with Et2O (3ϫ10 mL).
The combined organic layers were dried with anhydrous MgSO4
and concentrated to give 21a (0.274 g, 0.97 mmol, 97%) as a yellow
[M + H+, base], 239 [M – I]. IR: ν = 3059, 2914, 2184, 1581, 1470,
˜
1440, 1401, 1222, 1018 cm–1. HRMS (ESI+): calcd. for C15H12IOS
[M + H] 366.9654; found 366.9645.
(E)-1-(4,4-Dimethoxybut-2-enyloxy)-2-iodobenzene (27): To a solu-
tion of crotonaldehyde (1.40 mL, 17.2 mmol) in anhydrous Et2O
(5 mL) under an atmosphere of argon was added Et3N (4.80 mL,
34.4 mmol), followed by zinc chloride (1 m in Et2O, 170 μL,
0.17 mmol) and TMSCl (1.67 mL, 20.6 mmol) dropwise. The
orange solution was heated at reflux for 26 h, then cooled to room
temperature, diluted with n-pentane, filtered through Celite, and
1
liquid. H NMR (300 MHz, CDCl3): δ = 3.97 (m, 4 H), 4.81 (s, 2
H), 5.69 (s, 1 H), 6.89 (td, J = 7.9, 1.5 Hz, 1 H), 7.04 (dd, J = 7.9,
1.5 Hz, 1 H), 7.26 (td, J = 7.9, 1.5 Hz, 1 H), 7.52 (dd, J = 7.9, concentrated. The crude as obtained was diluted in a mixture of
1.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 57.2 (2 C),
64.9, 80.0, 83.9, 93.1, 112.8, 114.7, 123.3, 128.8, 134.0, 154.4 ppm.
2,2-dimethoxypropane (15 mL), THF (7.5 mL), and MeOH
(7.5 mL) and cooled to –20 °C. NBS (3.20 g, 18 mmol) was slowly
8
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Intramolecular Carbolithiation of Alkynes
added to the reaction media, which was stirred for 30 min at this
temperature and then for 1 h at room temperature. After hydrolysis
with saturated aqueous solution of NaHCO3, the aqueous layer
was extracted with Et2O (2ϫ10 mL), and the combined organic
layers were washed with water (15 mL) and brine (15 mL), dried
with MgSO4, and concentrated. The crude obtained was diluted
in DMF (10 mL) and engaged in the o-alkylation without further
purification. K2CO3 (3.57 g, 25.8 mmol) and 2-iodophenol (3.78 g,
17.2 mmol) were added to the reaction mixture, which was stirred
for 2 h at room temperature and then hydrolyzed with 1 m HCl
(3 mL) and water (10 mL). The aqueous layer was extracted with
Et2O (2ϫ20 mL), and the combined organic layers were washed
with 1 m HCl (2ϫ10 mL), water (2ϫ20 mL), and brine (20 mL),
dried with MgSO4, and concentrated. Pure 27 (3.62 g, 10.3 mmol,
63%) was obtained after purification by column chromatography
(10% of Et2O in n-pentane) as a pale yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 3.35 (s, 6 H), 4.65 (d, J = 4.4 Hz, 2 H),
4.87 (d, J = 4.4 Hz, 1 H), 5.97 (dd, J = 15.8, 4.4 Hz, 1 H), 6.08 (dt,
J = 15.8, 4.4 Hz, 1 H), 6.73 (td, J = 7.6, 1.3 Hz, 1 H), 6.81 (dd, J
= 8.2, 1.2 Hz, 1 H), 7.29 (ddd, J = 8.2, 7.6, 1.6 Hz, 1 H), 7.79 (dd,
J = 7.6, 1.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 52.7
(2 C), 68.3, 86.7, 102.0, 112.4, 122.8, 129.0, 129.3, 129.4, 139.6,
156.9 ppm. MS (EI, 70 eV): m/z = 334 [M]+, 303 [M – OMe], 271
122.4, 124.6, 125.1, 130.5, 137.0, 165.0 ppm. NMR 2D NOESY
correlation between 3.34 (s, 3 H) and 7.48 (d, J = 7.6 Hz, 1 H) ppm.
MS (EI, 70 eV): m/z = 190 [M]+, 175 [M – Me, base], 159 [M –
OMe]. HRMS (EI): calcd. for C12H14O2 [M]+ 190.0994; found
190.0990.
3-(2-Methylprop-1-enyl)benzofuran (37): Compound 37 was ob-
tained from 20b (165 mg, 0.50 mmol) and nBuLi (1.3 m in hexanes,
1.15 mL, 1.5 mmol) in anhydrous THF (5 mL) following the car-
bolithiation procedure. Pure 37 (40 mg, 0.23 mmol, 46%) was ob-
tained after purification by column chromatography (in n-pentane)
as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ = 1.90 (d, J =
0.8 Hz, 3 H), 1.99 (d, J = 1.3 Hz, 3 H), 6.19–6.23 (m, 1 H), 7.21–
7.35 (m, 2 H), 7.48 (dd, J = 7.2, 1.3 Hz, 1 H), 7.57 (s, 1 H), 7.57–
7.60 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.6, 26.8,
111.4, 112.9, 118.4, 119.9, 122.5, 124.4, 128.1, 137.7, 141.7,
154.7 ppm. MS (EI, 70 eV): m/z = 172 [M+, base], 157 [M – Me],
131. HRMS (EI): calcd. for C12H12O [M]+ 172.0882; found
172.0890.
3-(Benzofuran-3-yl)-2,4-dimethylpent-3-en-2-ol (38): To a solution
of 20b (165 mg, 0.5 mmol) in anhydrous THF (5 mL) under an
atmosphere of argon at –78 °C was slowly added nBuLi (1.6 m in
hexanes, 0.94 mL, 1.5 mmol). After 15 min, acetone (110 μL,
15 mmol) was added dropwise, and the reaction media was stirred
for 30 min at –78 °C and then 15 min at room temperature. The
mixture was hydrolyzed with water (5 mL), and the aqueous layer
was extracted with Et2O (2ϫ5 mL). The combined organic layers
were washed with brine (10 mL), dried with MgSO4, and concen-
trated. Pure 38 (21 mg, 0.091 mmol, 18%) was obtained after puri-
fication by column chromatography (30% of Et2O in n-pentane) as
a colorless oil. 1H NMR (300 MHz, CDCl3): δ = 1.38 (s, 3 H), 1.40
(s, 3 H) 1.49 (s, 1 H), 1.64 (s, 3 H), 2.16 (s, 3 H), 7.19–7.31 (m, 2
H), 7.32 (s, 1 H), 7.41 (d, J = 7.8 Hz, 1 H), 7.48 (d, J = 7.8 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.1, 25.0, 31.1, 31.2,
73.8, 111.6, 120.7, 121.8, 122.8, 124.3, 128.9, 130.3, 135.9, 141.4,
155.0 ppm. MS (EI, 70 eV): m/z = 230 [M]+, 212 [M – H2O], 197,
172 [base]. HRMS (EI): calcd. for C15H18O2 [M]+ 230.1310; found
230.1307.
[M – 2OMe], 220, 115 [base]. IR: ν = 3060, 2888, 2838, 1682, 1475,
˜
1279, 1078 cm–1. C12H15IO3 (334.15): calcd. C 43.13, H 4.52; found
C 43.22, H 4.59.
Carbolithiation Procedure: To a solution of the halogenoaryl com-
pound (1 equiv.) in anhydrous THF (10 mL/mmol of halogenoaryl
compound) at –78 °C is added dropwise BuLi (x equiv.). After dis-
appearance of the starting material (TLC or GC), the mixture is
hydrolyzed with water and extracted with Et2O. The resulting or-
ganic phase is then dried with anhydrous MgSO4 and concentrated.
Tandem Procedure: To a solution of the halogenoaryl compound
(1 equiv.) in anhydrous THF (10 mL/mmol of halogenoaryl com-
pound) at –78 °C is added dropwise BuLi (x equiv.). After disap-
pearance of the starting material (TLC or GC), the electrophile is
added (x equiv.) before hydrolysis.
Trimethyl(3-phenoxypropa-1,2-dienyl)silane (43): Compound 43 was
obtained from 23 (165 mg, 0.5 mmol) and tBuLi (1.6 m in hexanes,
625 μL, 1.0 mmol) in anhydrous THF (5 mL) following the carbo-
lithiation procedure. The crude provided a mixture of 43 and re-
duction product 44 and was purified by preparative chromatog-
raphy (n-pentane). Compound 43 was obtained as a colorless oil
(3-Iodoprop-2-ynyloxy)benzene (33a): To a solution of 18 (258 mg,
1 mmol) in anhydrous THF (5 mL) under an atmosphere of argon
at –78 °C was slowly added nBuLi (1.45 m in hexanes, 1.38 mL,
2 mmol). After 15 min, iodine (254 mg, 1 mmol) in THF (2 mL)
was added dropwise, and the reaction media was stirred for 20 min
and then hydrolyzed at –78 °C with EtOH (3 mL). The mixture was
washed with saturated aqueous solution of Na2S2O3 (5 mL), and
the aqueous layer was extracted with Et2O (2ϫ5 mL). The com-
bined organic layers were washed with brine (10 mL), dried with
MgSO4, and concentrated. Pure 33a (258 mg, 1 mmol, quantita-
tive) was obtained without further purification as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 4.83 (s, 2 H), 6.95–7.02 (m, 3
H), 7.29–7.34 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 5.3,
57.2, 89.1, 114.8 (2 C), 121.6, 129.5 (2 C), 157.4 ppm.
1
(75 mg, 0.37 mmol, 74%). H NMR (300 MHz, CDCl3): δ = 0.21
(s, 9 H), 5.92 (d, J = 6.3 Hz, 1 H), 6.71 (d, J = 6.3 Hz, 1 H), 7.02
(t, J = 7.5 Hz, 1 H), 7.07 (d, J = 8.5 Hz, 2 H), 7.31 (t, J = 7.5 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = –1.2 (3 C), 101.9,
115.0, 116.5 (2 C), 122.3, 129.6 (2 C), 158.0, 206.4 ppm. MS (EI,
70 eV): m/z = 204 [M]+, 189 (base) [M – Me], 161. IR: ν = 3040,
˜
2959, 1945, 1592, 1489, 1365, 1237, 836 cm–1.
Trimethyl(3-phenoxyprop-1-ynyl)silane (44): Obtained with 43, see
above (24 mg, 0.12 mmol, 24%). 1H NMR (300 MHz, CDCl3): δ =
0.20 (s, 9 H), 4.69 (s, 2 H), 6.99 (d, J = 7.8 Hz, 2 H), 7.02 (t, J =
7.8 Hz, 1 H), 7.31 (t, J = 7.8 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = –0.3 (3 C), 56.7, 92.6, 100.1, 114.9 (2 C), 121.4, 129.4
(2 C), 158.7 ppm. MS (EI, 70 eV): m/z = 204 [M+, base].
(E)-3-(2-Methoxypropylidene)-2,3-dihydrobenzofuran (34): Com-
pound 34 was obtained from 20a (316 mg, 1 mmol) and nBuLi
(1.6 m in hexanes, 656 μL, 1.1 mmol) in anhydrous THF (5 mL)
following the carbolithiation procedure. Pure 34 (71 mg,
0.37 mmol, 37%) was obtained after purification by column
chromatography (5% of Et2O in n-pentane) as a pale yellow oil.
1H NMR (300 MHz, CDCl3): δ = 1.35 (d, J = 6.3 Hz, 3 H), 3.34
(s, 3 H), 4.54–4.67 (m, 1 H), 5.02–5.16 (m, 2 H), 5.41 (dt, J = 8.5,
2.6 Hz, 1 H), 6.87 (d, J = 8.1 Hz, 1 H), 6.92 (t, J = 7.6 Hz, 1 H),
7.21 (dd, J = 8.1, 7.6 Hz, 1 H), 7.48 (d, J = 7.6 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 20.7, 56.2, 73.1, 75.5, 111.0, 120.9,
[1-(Benzofuran-3-yl)-2-phenylethyl]trimethylsilane (45): Compound
45 was obtained from 23 (330 mg, 1.0 mmol), PhLi (2.2 mmol), and
benzyl bromide (416 μL, 3.5 mmol) following the tandem pro-
cedure. Pure 43 (130 mg, 0.44 mmol, 44%) was obtained after puri-
fication by column chromatography (n-pentane then 2% of Et2O
1
in n-pentane) as a pale yellow oil. H NMR (300 MHz, CDCl3): δ
Eur. J. Org. Chem. 0000, 0–0
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A.-L. Girard, R. Lhermet, C. Fressigné, M. Durandetti, J. Maddaluno
FULL PAPER
= 0.17 (s, 9 H), 3.26 (dd, J = 13.6, 6.7 Hz, 2 H), 4.89 (t, J = 6.7 Hz,
1 H), 6.77–6.91 (m, 4 H), 7.07–7.13 (m, 1 H), 7.15–7.25 (m, 5
1 H), 6.78 (d, J = 7.9 Hz, 1 H), 6.87 (t, J = 7.1 Hz, 1 H), 7.08–7.11
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 42.0, 56.2, 77.6,
H) ppm. 13C NMR (75 MHz, CDCl3): δ = –0.2 (3 C), 42.3, 69.7, 103.0, 109.7, 120.7, 124.9, 128.4, 130.6, 149.0, 159.9 ppm. MS (EI,
92.6, 103.4, 116.2, 121.5, 126.9, 128.1, 128.3 (2 C), 129.4 (2 C), 70 eV): m/z = 176 [M]+, 161 [M – Me], 144 [M – OMe, base]. IR:
130.0, 130.5, 136.8, 157.7 ppm. MS (EI, 70 eV): m/z = 294 [M]+,
ν = 3048, 2951, 2892, 1720, 1596, 1482, 1460, 1233 cm–1.
˜
200 [base], 185. IR: ν = 3063, 3030, 2953, 1493, 1229, 838 cm–1.
˜
HRMS (EI): calcd. for C19H22OSi [M]+ 294.1440; found 294.1449.
Acknowledgments
3-[1-(Phenylthio)pentyl]benzofuran (46): Compound 46 was ob-
tained from 24 (183 mg, 0.5 mmol) and nBuLi (1 m in hexanes,
525 μL, 0.53 mmol) in anhydrous THF (5 mL) following the
carbolithiation procedure. Pure 46 (46 mg, 0.16 mmol, 31%) was
obtained after purification by column chromatography (1% of
Et2O in n-pentane) as a colorless oil. 1H NMR (300 MHz, CDCl3):
δ = 0.87 (t, J = 7.0 Hz, 3 H), 1.23–1.49 (m, 4 H), 1.97–2.12 (m, 2
H), 4.31 (t, J = 7.4 Hz, 1 H), 7.15–7.35 (m, 8 H), 7.46 (d, J =
8.1 Hz, 1 H), 7.77 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.1, 22.5, 30.0, 34.4, 44.6, 111.7, 120.9, 121.2, 122.5,
124.5, 126.5, 127.5, 128.8 (2 C), 133.0 (2 C), 134.7, 142.4,
155.8 ppm. MS (EI, 70 eV): m/z = 296 [M]+, 187 [M – SPh], 131
A. L. G. acknowledges the Pôle Universitaire Normand de Chimie
Organique (PUNCHorga) Interregional Network for a PhD fellow-
ship. R. L. is grateful to the Région de Haute-Normandie and Cen-
tre National de la Recherche Scientifique (CNRS) for a joint PhD
stipend. We also acknowledge the Centre de Recherche Uni-
versitaire Normand de Chimie (CRUNCh) Interregional Program
for its financial support of our research projects. We finally thank
Dr. Angéline Chanu for her careful contribution to the amine
chemistry.
[base]. IR: ν = 3058, 2938, 2858, 1582, 1452, 1105 cm–1. HRMS
˜
[1] See, for instance: a) J.-F. Normant, A. Alexakis, Synthesis 1981,
841–870; b) A. G. Fallis, P. Forgione, Tetrahedron 2001, 57,
5899–5913; c) M. J. Mealy, W. F. Bailey, J. Organomet. Chem.
2002, 646, 59–67; d) J. Clayden, Organolithium: Selectivity for
Synthesis, Pergamon, Amsterdam, 2002; e) I. Marek, N. Chin-
kov, D. Banon-Tenne in Metal-Catalyzed Cross-Coupling Reac-
tions (Eds.: F. Diederich, A. de Meijere), Wiley-VCH, Stutt-
gart, 2004, ch. 7, pp. 395–478; f) F. J. Fañanás, R. Sanz in The
Chemistry of Organolithium Compounds (Eds.: Z. Rappoport,
I. Marek), Wiley, Chichester, 2006, vol. 2 ch. 4, pp. 295–379;
g) A.-M. L. Hogan, D. F. O’Shea, Chem. Commun. 2008, 3839–
3851; h) S. Ma, Handbook of Cyclization Reactions, Wiley-
VCH, Weinheim, 2010, vol. 1.
[2] See, for representative examples: a) W. F. Bailey, T. V. Ovaska,
T. K. Leipert, Tetrahedron Lett. 1989, 30, 3901–3904; b) W. F.
Bailey, T. V. Ovaska, Tetrahedron Lett. 1990, 31, 627–630; c)
J. M. Nuss, M. M. Murphy, R. A. Rennels, M. H. Heravi, R. J.
Mohr, Tetrahedron Lett. 1993, 34, 3079–3082; d) Y. Liu, B.
Shen, M. Kotora, T. Takahashi, Angew. Chem. 1999, 111, 966–
968; Angew. Chem. Int. Ed. 1999, 38, 949–952; e) D. Bouyssi,
G. Balme, Synlett 2001, 1191–1193; f) G. Zhu, Z. Zhang, Org.
Lett. 2003, 5, 3645–3648; g) R. Yanada, S. Obika, T. Inokuma,
K. Yanada, M. Yamashita, S. Ohta, Y. Takemoto, J. Org.
Chem. 2005, 70, 6972–6975; h) R. N. Richey, H. Yu, Org. Pro-
cess Res. Dev. 2009, 13, 315–320.
[3] a) F. Le Strat, J. Maddaluno, Org. Lett. 2002, 4, 2791–2793; b)
F. Le Strat, H. Vallette, L. Toupet, J. Maddaluno, Eur. J. Org.
Chem. 2005, 5296–5305.
[4] a) M. Durandetti, L. Hardou, M. Clément, J. Maddaluno,
Chem. Commun. 2009, 4753–4755; b) M. Durandetti, L. Har-
dou, R. Lhermet, M. Rouen, J. Maddaluno, Chem. Eur. J.
2011, 17, 12773–12783.
[5] a) C. Fressigné, A.-L. Girard, M. Durandetti, J. Maddaluno,
Angew. Chem. 2008, 120, 905–907; Angew. Chem. Int. Ed. 2008,
47, 891–893; b) Fressigné, A.-L. Girard, M. Durandetti, J.
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(EI): calcd. for C19H20OS [M]+ 296.1234; found 296.1235.
3-(Phenylthiomethyl)benzofuran (47): Compound 47 was obtained
from 24 (183 mg, 0.5 mmol) and tBuLi (1.7 m in hexanes, 618 μL,
1.05 mmol) in anhydrous THF (5 mL) following the carbolithiation
procedure. Pure 47 (95 mg, 0.39 mmol, 78%) was obtained after
purification by column chromatography (1% of Et2O in n-pentane)
as a colorless oil. 1H NMR (300 MHz, CDCl3): δ = 4.19 (d, J =
1.0 Hz, 2 H), 7.16–7.35 (m, 7 H), 7.42 (t, J = 1.0 Hz, 1 H), 7.46
(dd, J = 7.5, 1.6 Hz, 1 H), 7.65 (dd, J = 6.8, 1.7 Hz, 1 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 28.4, 111.7, 116.8, 120.1, 122.7, 124.7,
126.8, 127.2, 129.1 (2 C), 130.5 (2 C), 136.0, 142.9, 155.6 ppm. MS
(EI, 70 eV): m/z = 240 [M]+, 131 (base) [M – SPh]. IR: ν = 3058,
˜
2923, 1583, 1452, 1232, 1182, 1098 cm–1. HRMS (EI): calcd. for
C15H12OS [M]+ 240.0609; found 240.0598.
3-[2-Phenyl-1-(phenylthio)ethyl]benzofuran (48): Compound 48 was
obtained from 24 (183 mg, 0.5 mmol), tBuLi (1.7 m in hexanes,
618 μL, 1.05 mmol), and benzyl bromide (119 μL, 1 mmol) follow-
ing the tandem procedure. Pure 48 (96 mg, 0.29 mmol, 58%) was
obtained after purification by column chromatography (2% of
Et2O in n-pentane) as a pale yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 3.34 (d, J = 7.6 Hz, 2 H), 4.56 (t, J = 7.6 Hz, 1 H),
7.01–7.32 (m, 13 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.77 (d, J = 6.5 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.1, 46.2, 111.8,
120.3, 121.0, 122.6, 124.5, 126.5, 126.7, 127.6, 128.4 (2 C), 128.9 (2
C), 129.2 (2 C), 133.0 (2 C), 134.6, 138.8, 142.8, 155.7 ppm. MS
(EI, 70 eV): m/z = 330 [M]+, 239 [M – Bn], 221 [M – SPh, base],
178. IR: ν = 3058, 2926, 2582, 1477, 1451, 1003 cm–1. HRMS
˜
(ESI+): calcd. for C22H19OS [M + H] 331.1157; found 331.1162.
(E)-3-(2-Methoxyvinyl)-2,3-dihydrobenzofuran (49): To a solution of
27 (167 mg, 0.5 mmol) in anhydrous Et2O (5 mL) under an atmo-
sphere of argon at –78 °C was slowly added nBuLi (1.4 m in hex-
anes, 430 μL, 0.6 mmol). The mixture was stirred for 30 min before
TMEDA (165 μL, 1.1 mmol) was added. The mixture was further
stirred for 15 min at –78 °C and then for 30 min at 0 °C. After
hydrolysis with water (5 mL), the aqueous layer was extracted with
Et2O (2ϫ10 mL). The combined organic layers were washed with
water (10 mL) and brine (10 mL), dried with MgSO4, and then con-
centrated. Pure 49 (48 mg, 0.27 mmol, 54%) was obtained after
purification by column chromatography (2% of Et2O in n-pentane)
as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ = 3.54 (s, 3
H), 4.05 (t, J = 8.6 Hz, 1 H), 4.11 (t, J = 8.6 Hz, 1 H), 4.70 (t, J =
8.6 Hz, 1 H), 4.78 (dd, J = 12.6, 8.6 Hz, 1 H), 6.48 (d, J = 12.6 Hz,
[7] G. Ebeling, M. R. Meneghetti, F. Rominger, J. Dupont, Orga-
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2000, 2, 3849–3852.
[9] H. W. Pinnick, M. A. Reynolds, R. T. McDonald Jr., W. D.
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Balma Tivola, C. Prandi, P. Venturello, Synlett 1999, 1841–
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[11] I. Marek, Chem. Rev. 2000, 100, 2887–2990.
10
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Intramolecular Carbolithiation of Alkynes
[12] The competition between these two reactions has been dis-
cussed before, albeit in a very different case: a) N. S. Narasim-
ham, R. Ammanamanchi, J. Chem. Soc., Chem. Commun.
1985, 1368–1369; b) P. Beak, T. J. Musick, C. W. Chen, J. Am.
Chem. Soc. 1988, 110, 3538–3542; c) N. S. Narasimham, N. M.
Sunder, R. Ammanamanchi, B. D. Bonde, J. Am. Chem. Soc.
1990, 112, 4431–4435; d) D. J. Gallagher, P. Beak, J. Am. Chem.
Soc. 1991, 113, 7984–7987.
[23] The addition of an aryllithium on the cogenerated butyl halide
is known as the Wurtz–Fittig addition. See, for instance:W. F.
Bailey, Chimica Oggi (Chemistry Today) 2001, 19, 28–32.
[24] a) R. L. Funk, G. L. Bolton, K. M. Brummond, K. E. Ellestad,
J. B. Stallman, J. Am. Chem. Soc. 1993, 115, 7023–7024; b) N. J.
Ashweek, I. Coldham, D. J. Snowden, G. P. Vennall, Chem.
Eur. J. 2002, 8, 195–207.
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1220; b) L. W. Pratt, N. V. Nguên, L. Th Le, J. Org. Chem.
2005, 70, 2294–2298; c) M. Braun, “Lithium Carbenoids”, in
The Chemistry of Organolithium Compounds, Patai Edition
(Ed.: Z. Rappoport), J. Wiley, Chichester, UK, 2004.
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Received: December 9, 2011
Published Online: ᭿
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11

Job/Unit: B11777
/KAP1
Date: 05-03-12 11:17:16
Pages: 12
A.-L. Girard, R. Lhermet, C. Fressigné, M. Durandetti, J. Maddaluno
FULL PAPER
Carbolithiation
A.-L. Girard, R. Lhermet, C. Fressigné,
M. Durandetti,* J. Maddaluno* ...... 1–12
Influence of the Acetylenic Substituent on
the Intramolecular Carbolithiation of Alk-
ynes
The intramolecular carbolithiation of prop-
argylic ethers has been studied. When the
alkyne is directly substituted by a Ph, SPh,
or SiMe3 group or if the propargylic pos-
ition is secondary, dihydrobenzofurans are
recovered selectively, resulting from anti-
Keywords: Alkynes / Metalation / Lithium /
Cyclization / Substituent effects
carbolithiation. Alkylation of the vinyllith-
ium intermediate can be performed, but it
triggers intracyclic isomerization of the
double bond.
12
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