Radical zinc-atom-transfer-based carbozincation of haloalkynes with dialkylzincs

Article abstract of DOI:10.3762/bjoc.9.28

The formation of alkylidenezinc carbenoids by 1,4-addition/carbozincation of dialkylzincs or alkyl iodides based on zinc atom radical transfer, in the presence of dimethylzinc with β-(propargyloxy)enoates having pendant iodo- and bromoalkynes, is disclosed. Formation of the carbenoid intermediate is fully stereoselective at -30 °C and arises from a formal anti-selective carbozincation reaction. Upon warming, the zinc carbenoid is stereochemically labile and isomerizes to its more stable form.

Full text of DOI:10.3762/bjoc.9.28

Radical zinc-atom-transfer-based carbozincation
of haloalkynes with dialkylzincs
Fabrice Chemla*, Florian Dulong, Franck Ferreira
and Alejandro Pérez-Luna*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 236–245.
Institut Parisien de Chimie Moléculaire (UMR 7201), FR 2769, UPMC
Univ Paris 06, CNRS, Bâtiment F 2ème et., Case 183, 4 place
Jussieu, F-75005 Paris, France
doi:10.3762/bjoc.9.28
Received: 13 November 2012
Accepted: 08 January 2013
Published: 04 February 2013
Email:
Fabrice Chemla* - fabrice.chemla@upmc.fr; Alejandro Pérez-Luna* -
alejandro.perez_luna@upmc.fr
This article is part of the Thematic Series "Carbometallation chemistry".
Guest Editor: I. Marek
* Corresponding author
Keywords:
© 2013 Chemla et al; licensee Beilstein-Institut.
License and terms: see end of document.
carbenoids; carbometallation; carbozincation; radicals; tandem
reaction
Abstract
The formation of alkylidenezinc carbenoids by 1,4-addition/carbozincation of dialkylzincs or alkyl iodides based on zinc atom
radical transfer, in the presence of dimethylzinc with β-(propargyloxy)enoates having pendant iodo- and bromoalkynes, is
disclosed. Formation of the carbenoid intermediate is fully stereoselective at −30 °C and arises from a formal anti-selective carbo-
zincation reaction. Upon warming, the zinc carbenoid is stereochemically labile and isomerizes to its more stable form.
Introduction
The last few years have witnessed a gaining interest in the use producing a new organozinc derivative along with an alkyl
of organozinc reagents as nontoxic radical precursors or media- radical that sustains a radical chain. Overall, the in situ transfor-
tors [1-3]. As part of this development, the so-called radical- mation of simple organozinc reagents into more elaborate ones
polar reactions in which alkylzinc reagents are used as media- is thus achieved, and subsequent reaction with electrophiles is
tors in a radical transformation that affords a new zincated possible [15-30].
species, have emerged as valuable tools in synthesis. Pivotal to
the processes disclosed so far using alkylzinc derivatives is zinc More specifically, building on well-established addition reac-
atom radical transfer [4]. In general terms, the reaction involves tions of carbon-centered radicals to carbon–carbon double and
a radical chain process initiated by the formation of an alkyl triple bonds, such reactivity has been advantageously employed
radical from the organozinc derivative in the presence of in the context of carbozincation chemistry [31]. The intramolec-
oxygen [5-14]. The newly formed radical then undergoes one or ular carbozincation of unactivated terminal alkenes following
more radical transformations before being reduced by the zinc atom transfer processes, including a 5-exo-trig cyclization
alkylzinc reagent through homolytic substitution at zinc, step, has been reported. This is, for instance, the case in the for-
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Beilstein J. Org. Chem. 2013, 9, 236–245.
mation of (pyrrolidylmethyl)zinc and (tetrahydrofuranyl-
methyl)zinc derivatives by reaction of dialkylzinc, organozinc
and copper–zinc mixed reagents with (N-allyl)aminoenoates
[32-34] and β-(allyloxy)enoates [35], in the formation of
(pyrrolidonylmethyl)zinc by condensation of dialkylzincs with
N,N-diallylpropiolamide [36], and also in the cyclization of
alkenylzinc iodides to cyclopentylmethylzinc iodides, formerly
believed to be anionic in nature [4]. Carbozincations of alkynes
based on zinc atom transfer have also been disclosed. The reac-
tion of dialkylzincs or of alkyl iodides in the presence of
Me2Zn/O2 with β-(propargyloxy)enoates entails the intramolec-
ular carbometallation of the pendant alkynes substituted by
silyl, alkyl, aryl, alkenyl or amino groups by a 5-exo dig radical
cyclization step [37,38]. Intermolecular carbozincation of
terminal arylacetylenes [39] and of diethyl acetylenedicarboxy-
late [40] has been achieved by dialkylzinc-mediated radical
additions. Worthy of note is that in some cases the zinc-atom-
transfer-based carbozincation of alkynes can occur with anti
selectivity [38,40], and thereby represents a complementary ap-
Scheme 1: Anticipated formation of alkylidene zinc carbenoids by
reaction of dialkylzincs with β-(propargyloxy)enoates having pendant
haloalkynes.
proach to transition-metal-mediated carbozincations, which are By contrast, the reaction of the iodo analogue 1b with 2 proved
generally syn-selective [41-46].
troublesome as it led to inseparable mixtures of the desired
enoate 3b and non-iodinated enoate 3c. Thus, 3b was best
To explore further the possibilities offered by zinc atom transfer prepared by iodinating (AgNO3/NIS) the terminal alkyne of
processes we considered the possibility to prepare alkyli- enoate 3c prepared from propargyl alcohol (1c) and acrylate 2.
denezinc carbenoids by radical-based carbozincation of
haloalkynes. Such carbenoids are multipurpose reagents [47]
that are typically prepared from 1,1'-dihaloalkenes, either by
lithium/halogen exchange followed by transmetallation with
zinc salts or by direct zinc/halogen exchange [48-50]. Alter-
natively, they can also be prepared efficiently by selective
monohalogenation of alkylidene gem-bismetallic intermediates
[51].
Scheme 2: Preparation of β-(propargyloxy)enoates having pendant
haloalkynes. Reagents and conditions: (a) 2 (1.4 equiv), Et3N
To the best of our knowledge, the preparation of alkylidenezinc
carbenoids by the direct carbozincation of haloalkynes has not
been reported [52]. As a starting point to develop such an ap-
proach, we reasoned that the reaction of dialkylzincs with
β-(propargyloxy)enoates bearing pendant haloalkynes would be
(4 equiv), NaI (10 mol %), CH2Cl2, 50 °C, sealed tube, 74% (3a), 87%
(3c); (b) AgNO3 (1.5 equiv), N-iodosuccinimide (1.5 equiv), acetone, rt,
53% (3b).
ideally suited (Scheme 1). On the one hand it would provide a According to our previously optimized conditions for the 1,4-
means to control totally the regioselectivity of the radical addi- addition/carbozincation reaction of dialkylzincs with β-(propar-
tion to the haloalkyne, and on the other hand the envisioned gyloxy)enoates [37,38], bromoalkyne 3a was treated with Et2Zn
zinc atom transfer to an α-halo vinylic radical should be favor- at room temperature in Et2O under an argon atmosphere
able as a result of the presence of the ester moiety. Hereafter, (Table 1, entry 1). To our delight, following acidic work-up, the
we disclose our findings concerning this reaction.
expected methylenetetrahydrofuranyl bromide 4aa was
obtained in 43% isolated yield as a mixture of diastereoisomers
in a 77:23 Z/E ratio [53]. Hydrolysis with D2O evidenced the
Results and Discussion
β-(Propargyloxy)enoates 3a and 3b having a pendant intermediate formation of an alkylidene zinc carbenoid as
bromoalkyne and an iodoalkyne moiety, respectively, were deuterated 4aa-D was produced (Table 1, entry 2). As previ-
prepared by condensation of propargylic alcohols 1 with methyl ously noted in the case of similar 1,4-addition/carbozincation
2-(bromomethyl)acrylate (2) (Scheme 2). Enoate 3a was readily sequences [37,38], deuterium incorporation was nearly quanti-
obtained by direct reaction of 3-bromopropargyl alcohol (1a). tative for the Z isomer, and much lower for the E one. More
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Beilstein J. Org. Chem. 2013, 9, 236–245.
Table 1: 1,4-addition/carbozincation of dialkylzincs with β-(propargyloxy)enoates 3 having pendant haloalkynes in the presence of traces of air.a
Entry
Enoate
X
Solvent
R
Products (Yieldb (%) [drc (Z/E)])
4aa (43 [77:23]); 5a (40 [79:21])
1
2
3a
3a
Br
Br
Et2O
Et2O
Et
Et
4aa-Dd (44 [81(90% D):19(10% D)]);
5a-Dd (35 [84(85% D):16(40% D)])
3
4
5
6
7
3b
3a
3b
3a
3a
I
Et2O
Et
4ba (40e [98:2]); 5a (21e [82:18])
4ab (76 [70:30]); 5b (7 [ndf])
4bb (58 [98:2])
Br
I
Et2O
n-Bu
n-Bu
Et
Et2O
Br
Br
CH2Cl2
CH2Cl2
4aa (39d [78:22]); 5a (17d [91:9])
4ab (37 [76:24]); 5b (12 [nd]f)
n-Bu
aReaction conditions : R2Zn (3 equiv), rt, 24 h under Ar atmosphere (see Experimental section).
bCombined yield of diastereomers after chromatography unless otherwise noted.
cDetermined by 1H NMR analysis of the crude material.
dThe reaction mixture was quenched with D2O. The percentage of deuterium incorporation is given in parenthesis for each compound.
eDetermined by 1H NMR spectroscopy based on analysis of the crude mixture with biphenyl as internal standard.
fNot determined.
unexpectedly, however, 40% of alkylidenetetrahydrofuran 5a, vinyl bromide 4aa in 39% yield (78:22 Z/E ratio) and 5a in 17%
wherein the bromine atom had been substituted by an ethyl yield, while reaction of n-Bu2Zn gave 4ab in 37% yield (76:24
group, was also isolated as a 79:21 Z/E mixture. Deuterium Z/E ratio) and 5b in 12% yield. It is worthy of note that no
labeled 5a-D was produced following hydrolysis with D2O difference was observed between the different dialkylzincs in
(Table 1, entry 2), thereby showing that an alkylidenezinc inter- this case.
mediate was being formed in the generation of this side-prod-
The formation of alkylidenezinc derivatives 7 leading to com-
pounds 5 is intriguing (Scheme 3). A first possible mechanistic
uct under these reaction conditions.
When iodoalkyne 3b was used, a similar 40% yield of vinylic route could involve the reaction of zinc carbenoid 6 and the
iodide 4ba was obtained, but this time exclusively as the Z
isomer (Table 1, entry 3). 5a was also produced, but in a lower
21% yield and similar diastereoselectivity (82:18 Z/E ratio).
Significantly lower levels of side-product formation arising
from halogen substitution were observed when n-Bu2Zn was
used, thus leading to improved results (Table 1, entries 4 and 5).
The reaction with bromoalkyne 3a provided vinylic bromide
4ab in 76% yield and 70:30 Z/E ratio and only 7% of 5b.
Better, the reaction with iodoalkyne 3b afforded exclusively
iodide 4bb in 58% yield and complete diastereoselectivity in
favor of the (Z) isomer. Formation of substitution side-products
was also diminished when CH2Cl2 was used as the solvent
instead of Et2O, even though this had little impact on the effi-
Scheme 3: Possible reaction pathways to account for the formation of
product 5.
ciency and diastereoselectivity of vinyl halide formation
(Table 1, entries 6 and 7). Reaction of Et2Zn with 3a provided
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Beilstein J. Org. Chem. 2013, 9, 236–245.
excess of dialkylzinc reagent via the intermediate formation of a
zincate [48-51] (Scheme 3, path a). The stereoselectivity of
such rearrangements is often dependent on the substrate struc-
ture, so the diastereopurity of 5 is not necessarily informative
about that of 6 [48-51]. An alternative possibility to account for
the formation of 7 could be the reaction of the dialkylzinc
reagent with enoate 8 arising from a prior substitution of
bromoalkyne 3a with the dialkylzinc reagent (Scheme 3, path
b). Both the diastereoselectivity and the levels of deuterium
incorporation are very close to those obtained for the reaction of
diethylzinc with pure 8 [37], which argues in favor of this
mechanistic scenario.
To try to discriminate between these possibilities we conducted
some additional test experiments (Scheme 4). In agreement with
the general consideration that dialkylzinc reagents do not
undergo uncatalyzed cross-coupling reactions with bromo-
alkynes, no reaction was observed between Et2Zn and 1-bromo-
hexyne (9) [54]. By contrast, bromoalkyne 11 having a silyloxy
group at the propargylic position reacted smoothly to afford
ethyl-substituted alkyne 10 along with alkene 12, which had
incorporated two ethyl groups. 12 was isolated as a mixture of
diastereoisomers in 70:30 dr. The fact that no reaction takes
Scheme 4: Test experiments to gain insight into the mechanism of for-
mation of alkylidene zinc intermediate 7.
place between pure 10 and Et2Zn indicates that 12 is not formed A reduced amount of side-product 5 was indeed observed in the
by carbozincation. Hence, most likely it is formed by the reac- reaction of enoate 3a with Et2Zn in CH2Cl2 at room tempera-
tion of Et2Zn and carbenoid 13 arising from the carbozincation ture in the presence of added dry air (Table 2, entry 1). A mix-
of 11 (Scheme 4). Moreover, if 13 is indeed formed, it would ture of vinyl bromide 4aa and alkene 5a in a 84:16 ratio and in
also lead to alkyne 10 following Fritsch–Buttenberg–Wieschell 69% overall yield was obtained. However the diastereoselectiv-
(FBW) rearrangement [55-57]. Since the presence of the ity of the formation of 4aa dropped significantly. Lowering the
oxygen atom in the propargylic position should facilitate the reaction temperature had a highly beneficial impact on the
carbometallation reaction [58], this mechanistic pathway reaction outcome. At 0 °C, the formation of 5a was totally
provides a plausible explanation for the fact that bromine suppressed, and 4aa was obtained with a much better diastereo-
substitution occurs from α-oxgenated bromoalkyne 11 and not selectivity, though remarkably in favor of the E isomer
from 9.
(Table 2, entry 2). At −30 °C, the exclusive and totally diaste-
reoselective formation of (E)-4aa in excellent 89% isolated
Regarding our 1,4 addition/carbocyclization sequence, these test yield was obtained (Table 2, entry 3). Hydrolysis with D2O led
experiments provide two important pieces of evidence for the to (E)-4aa-D with 83% deuterium incorporation when either
behavior of 3a in the presence of a dialkylzinc. First, β-alkoxy CH2Cl2 or DCE were used as solvent (entries 4 and 5), there-
bromoalkynes undergo direct substitution with Et2Zn to some fore evidencing the intermediate stereoselective formation of an
extent. Second, alkylidenezinc carbenoids react with dialkyl- alkylidene zinc carbenoid. Similar results were obtained by
zincs to afford the bromine substitution product. Thus, forma- using n-Bu2Zn, indicating that the process is quite general
tion of alkylidenezinc compound 7 (and thereby 5) most prob- (Table 2, entry 6).
ably arises from both depicted mechanistic pathways (paths a
and b, Scheme 3). In such a situation, we reasoned that in both The diastereoselectivity of the formation of 4aa seemed to be
possibilities, reducing the reaction time would limit the produc- dependent not only on the reaction temperature, but also on the
tion of the unwanted side-products by limiting the contact time total reaction time (compare Table 1, entry 6 and Table 2, entry
between the dialkylzinc reagent and either the starting 1). Suspecting a possible Z/E isomerization of the alkyli-
bromoalkyne or the generated zinc carbenoid. Thus, we consid- denezinc carbenoid intermediate, we conducted an experiment
ered adding air to the reaction media in order to accelerate the wherein air was added to a mixture of enoate 3a and Et2Zn in
oxidation of the dialkylzinc species and therefore radical CH2Cl2 at −30 °C, and the reaction was first kept for 1 h at this
production (Table 2).
temperature and then for 23 h at room temperature (Table 2,
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Beilstein J. Org. Chem. 2013, 9, 236–245.
Table 2: 1,4-Addition/carbozincation of dialkylzincs on 3a in the presence of added air.a
Entry
R
Reaction conditions
Products [ratio]
Yieldb (%)
drc of product 4 (E/Z)
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Bu
Et
Et
rt, 1 h
4aa/(Z)-5a [84:16]
69d
93
54:46
0 °C, 1 h
4aa
87:13
−30 °C, 1 h
4aa
89
>98:2
−30 °C, 1 h
4aa-De
95d
89
>98(83% D):2
>98(83% D):2
>98:2
−30 °C, 1 h, DCEf
−30 °C, 1 h
4aa-De
4ab
93
−30 °C, 1 h then rt, 24h
−30 °C, 1 h then rt, 24 h
4aa/(Z)-5a [78:22]
4aa-De/(Z)-5a-Dg [78:22]
78d
78d
44:56
44(<10% D):56(<10% D)
aReaction conditions : R2Zn (3 equiv), CH2Cl2, dry air was bubbled at once into the reaction mixture, which was then kept under Ar atmosphere (see
Experimental section).
bCombined yield of products after chromatography unless otherwise noted.
cDetermined by 1H NMR analysis of the crude material.
dDetermined by 1H NMR spectroscopy based on analysis of the crude mixture with biphenyl as the internal standard.
eThe reaction mixture was quenched with D2O. The percentage of deuterium incorporation is given in parenthesis for each isomer.
fDCE = 1,2-dichloroethane was used as solvent instead of CH2Cl2.
g30% deuterium incorporation was observed for product 5a-D.
entry 7). Following acidic quench, very similar results to those α-bromovinyl radical 15 of E geometry. Substitution by elec-
noted for the same reaction carried out at room temperature tron-withdrawing groups slows down E to Z isomerization of
(Table 2, entry 1) were observed. 4aa was recovered in 61% vinylic radicals, and therefore, due to the presence of the
yield as a 56:44 mixture of isomers along with alkene (Z)-5a in bromine atom, interconversion of (E)-15 into (Z)-15 should not
22% yield. It is worthy to note that very low levels of deuterium be fast. Thus, (E)-15 reacts by Zn atom transfer prior to its equi-
incorporation were observed in this case.
libration to provide stereoselectively carbenoid (Z)-6 [59] and to
some extent by H-atom transfer to give reduced bromoalkene
These results have a three-fold consequence. First, they indi- (E)-4 [60]. Upon warming, (Z)-6 isomerizes to its more stable
cate that Z/E isomerization of the alkylidenezinc carbenoid isomer (E)-6 wherein the zinc atom is coordinated intramolecu-
occurs between −30 °C and room temperature. Second, it larly to the adjacent ester. To a minor extent, reaction with the
demonstrates that alkene 5a can be formed by the reaction excess dialkylzinc present in the reaction media provides alkyli-
between the zinc carbenoid and Et2Zn (Scheme 3, path a), and denezinc (E)-7 stereoselectively. Note, however, that in the case
that in such a case the transformation is stereoselective. Third, where reactions are conducted at room temperature, E/Z equili-
when oxygen is introduced into the reaction media, the alkyli- bration of the intermediate radical 15 should be faster and zinc
denezinc carbenoid is eventually demetallated upon standing at atom transfer from (Z)-15 may also contribute to the formation
room temperature.
of (E)-6.
The different results obtained for the 1,4-addition/carbozinca- Two situations are next to be distinguished. Under the condi-
tion of enoates having pendant bromoalkynes are consistent tions involving excess air, carbenoid 6 is protonated in the reac-
with our anticipated zinc atom radical transfer mechanism tion media (even though we have not identified the proton
(Scheme 1) and can be rationalized according to the following source). It is possible that protonation occurs prior to full E to Z
scenario (Scheme 5). The process involves the initial 1,4-addi- isomerization and vinyl bromide 4 is obtained in low diastereo-
tion of radical R to the starting enoate and the subsequent selectivity. Under the conditions involving only a trace of air,
5-exo-dig cyclisation of enoxy radical 14 to provide after 24 h at room temperature, carbenoid 6 is still present and
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Beilstein J. Org. Chem. 2013, 9, 236–245.
Scheme 5: Mechanistic rationale for the reaction of dialkylzincs with β-(propargyloxy)enoate 3a.
total Z to E isomerization has occurred. The reason why vinyl major reaction pathway. The competitive addition of a Me
bromide 4 is only isolated with moderate diastereoselectivity group could be reduced by increasing the amount of iPrI to
following hydrolysis, is that (E)-4, formed from (E)-15 by 10 equiv (Table 3, entries 3 and 4). However, in this case,
H-abstraction, is present from the start.
significant amounts of vinylic dihalide 17 were also isolated.
Thus, if large amounts of iodide are used, radical iodine atom
transfer between iPrI and the α-bromovinylic radical 15
resulting from the cyclization step (Scheme 5) becomes compet-
itive with the desired zinc atom transfer and hampers the carbo-
zincation process.
We finally considered the prospect to carry out the carbozinca-
tion of bromoalkynes using a combination of an alkyl iodide
and dimethylzinc (Table 3). Towards this end, we first treated
enoate 3a with Me2Zn, following our previously reported opti-
mized conditions for the 1,4-addition/carbozincation of
β-(propargyloxy)enoates with Me2Zn [38], which proceeds in Conclusion
CH2Cl2 at 0 °C and under continuous introduction of dry air In conclusion, we have shown that β-(propargyloxy)enoates
over a period of 1 h (Table 3, entry 1). After acidic quench, having pendant iodo- and bromoalkynes undergo a 1,4-addition/
vinylic bromide (E)-4ac [61] was isolated in 77% yield as a carbozincation sequence by reaction with dialkylzincs or with
single diastereoisomer. The stereoselective formation of an alkyliodides in the presence of dimethylzinc. The sequence
alkylidenezinc carbenoid intermediate was this time evidenced involves a radical chain mechanism initiated by air and provides
by treating the reaction mixture with iodine (Table 3, entry 2). the proof of concept that alkylidenezinc carbenoids can be
Vinylic dihalide 16 was isolated in 64% yield, again as a single prepared by carbozincation based on zinc atom transfer. In the
Z diastereoisomer. Thus, Me2Zn showed a similar reactivity to disclosed process, we have demonstrated that the formation of a
its higher homologues Et2Zn and n-Bu2Zn, with the additional bromocarbenoid intermediate is fully stereoselective at −30 °C
advantage that no direct formation of vinyl bromide (E)-4ac by and arises from a formal anti-selective carbozincation reaction.
hydrogen abstraction was observed.
Upon warming, the zinc carbenoid is stereochemically labile
and isomerizes to its more stable form. In the absence of added
In the presence of 5 equiv iPrI, a mixture of two (diastereomeri- air, no decomposition of the carbenoid intermediate is observed
cally pure) compounds 4ad and 4ac in 87:13 ratio was at room temperature for at least 24 h. Deuterium labeling and
observed. Incorporation of the iPr moiety was therefore the iodolysis experiments evidence that the zinc carbenoids
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Beilstein J. Org. Chem. 2013, 9, 236–245.
Table 3: Me2Zn-mediated 1,4-addition/carbozincation of alkyl iodides with 3a in the presence of added air.a
Entry
iPrI (equiv)
E-X
Yieldb (%)
Products [ratio]
1
0
H2O
I2
77
64
59
87
75
4acc
2
0
16
3d
4d
5d
5
H2O
H2O
D2O
4ad/4ac [87:13]
10
10
4ad/4ac/17 [75:6:19]
4ad-D/4ac-D/17 [75 (95% D):6 (95% D):19]
aReaction conditions: Me2Zn (5 equiv), iPrI (equiv), CH2Cl2, 0 °C, 20 mL dry air was bubbled during 1 h into the reaction mixture via a syringe pump.
bCombined yield of isolated products after chromatography unless otherwise noted.
cThe product was contaminated with ~10% of product resulting from the addition of the dichloromethyl radical (4ae, R = CHCl2).
d3 equiv Me2Zn were used.
prepared under such reactions can act as typical nucleophiles oxy)enoate (0.2 mmol) in Et2O (1 mL) at room temperature was
and should, thus, be well-suited for subsequent functionaliza- added R2Zn (0.6 mmol). The reaction mixture was stirred at
tion [47-51]. Furthermore, as indicated with the formation of room temperature for 24 h. The reaction was hydrolyzed with
some side-products observed during this work, they should also an aqueous solution of HCl (1 M, 10 mL). The layers were sep-
react readily as electrophiles toward organometallic nucleo- arated, the aqueous one being extracted with Et2O (2 × 15 mL).
philes and undergo intramolecular nucleophilic substitution The combined organic layers were washed with brine, dried
reactions [47-51].
over MgSO4, and concentrated under reduced pressure, and the
residue was purified by flash chromatography (pentane/ether).
Experimental
Experiments involving organometallic compounds were carried General Procedure 2. Reaction of n-Bu2Zn and Et2Zn with
out in dried glassware under a positive pressure of dry Ar. All β-(propargyloxy)enoate 3a in the presence of added air
solvents were distilled to remove stabilizers and dried with a (Table 2): Under argon, to a stirred solution of β-(propargyl-
MBRAUN Solvent Purification System SPS-800. n-Bu2Zn oxy)enoate 3a (0.2 mmol) in CH2Cl2 (2 mL) at −30 °C was
(Fluka, ~1 N in heptane), Et2Zn (Aldrich, 1.0 M in hexanes), added R2Zn (0.6 mmol). Air (2 mL) was bubbled at once into
Me2Zn (Aldrich, 1.0 M in heptane) and all other reagents were the solution via a syringe fitted with a CaCl2 guard and the reac-
of commercial quality and were used without purification. tion mixture was stirred at −30 °C for 1 h. CH2Cl2 (20 mL) and
1H NMR, 13C NMR spectra were recorded with a Bruker an aqueous solution of HCl (1 M, 10 mL) were added to quench
AVANCE 400 spectrometer fitted with BBFO probe with Z the reaction. The layers were separated, the aqueous one being
gradient. Chemical shifts are reported in δ relative to an internal extracted with Et2O (2 × 15 mL). The combined organic layers
standard of residual chloroform (δ 7.27 for 1H NMR and 77.16 were washed with brine, dried over MgSO4, and concentrated
for 13C NMR). IR spectra were recorded with an ATR diamond under reduced pressure to afford the crude product.
spectrophotometer. High-resolution mass spectra (HRMS) were
obtained on a Finnigan MAT 95.
(Z)-Methyl 4-(bromomethylene)-3-propyltetrahydrofuran-
3-carboxylate ((Z)-4aa): Prepared according to general proce-
General Procedure 1. Reaction of n-Bu2Zn and Et2Zn with dure 1 from enoate 3a (50 mg, 0.2 mmol) and Et2Zn (0.6 mL,
β-(propargyloxy)enoates 3a and 3b having pendant 1.0 M in hexanes, 0.6 mmol). Purification by flash chromatog-
haloalkynes in the presence of a trace amount of air raphy with pentane/ether (95:05) as eluent gave the title com-
(Table 1): Under argon, to a stirred solution of β-(propargyl- pound ((Z)-4aa) (19 mg, 33%) as a colorless oil. IR (neat):
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Beilstein J. Org. Chem. 2013, 9, 236–245.
2958, 1730, 1434, 1219, 1072, 938, 722 cm−1; 1H NMR (td, J = 13.7, 4.2 Hz, 1H), 1.91 (dt, J = 12.2, 4.4 Hz, 1H),
(400 MHz, CDCl3) δ 6.34 (t, J = 2.7 Hz, 1H), 4.42 (d(AB 1.50–1.20 (m, 6H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR
system), J = 9.1 Hz, 1H), 4.40 (d br, J = 2.9 Hz, 2H), 3.84 (100 MHz, CDCl3) δ 173.3, 146.7, 98.6, 78.3, 73.9, 58.2, 52.7,
(d(AB system), J = 9.1 Hz, 1H), 3.74 (s, 3H), 1.90 (m, 1H), 32.5, 32.4, 24.1, 22.7, 14.3; HRMS–ESI (m/z): [M + Na]+ calcd
1.68 (m, 1H), 1.24 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR for C12H19O3BrNa: 313.0410; found: 313.0413.
(100 MHz, CDCl3) δ 172.3, 146.6, 100.4, 75.7, 72.8, 58.5, 52.6,
39.5, 18.8, 14.2; HRMS–ESI (m/z): [M + Na]+ calcd for (E)-Methyl 4-(bromomethylene)-3-ethyltetrahydrofuran-3-
C10H15O3BrNa: 285.00968; found: 285.00990.
carboxylate ((E)-4ac) (Table 3, entry 1): Under argon, to a
stirred solution of β-(propargyloxy)enoate 3a (46 mg,
(E)-Methyl 4-(bromomethylene)-3-propyltetrahydrofuran- 0.2 mmol) in CH2Cl2 (1 mL) at 0 °C was added Me2Zn (1 mL,
3-carboxylate ((E)-4aa): Prepared according to general proce- 1.0 M in heptane, 1.0 mmol). Air (20 mL) was slowly intro-
dure 2 from enoate 3a (47 mg, 0.2 mmol) and Et2Zn (0.6 mL, duced over 1 h into the solution via a syringe pump by using a
1.0 M in hexanes, 0.6 mmol). The title compound ((E)-4aa) was syringe fitted with a CaCl2 guard. The reaction mixture was
isolated pure (47 mg, 89%) as a colorless oil and did not require then stirred at 0 °C for 1 h. CH2Cl2 (5 mL) was then added, and
further purification. IR (neat): 2960, 2873, 1769, 1730, 1433, the reaction was hydrolyzed with an aqueous solution of HCl
1217, 1122, 1074, 968, 938, 742 cm−1; 1H NMR (400 MHz, (1 M, 5 mL). The layers were separated, the aqueous one being
CDCl3) δ 6.15 (t, J = 1.9 Hz, 1H), 4.39 (dd(ABX system), J = extracted with CH2Cl2 (3 × 10 mL). The combined organic
12.7, 1.9 Hz, 1H), 4.32 (dd(ABX system), J = 12.7, 1.8 Hz, layers were washed with brine, dried over MgSO4 and concen-
1H), 4.12 (d(AB system), J = 8.9 Hz, 1H), 3.97 (d(AB system), trated under reduced pressure. Purification by flash chromatog-
J = 8.9 Hz, 1H), 3.74 (s, 3H), 2.13 (td, J = 13.5, 4.6 Hz, 1H), raphy on silica gel (pentane/ether 80:20) afforded the title com-
1.90 (dt, J = 12.5, 4.4 Hz, 1H), 1.50–1.30 (m, 1H), 1.30–1.25 pound ((E)-4ac) (38 mg, 77%) as a colorless oil. IR (neat):
(m, 1H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) 2953, 1767, 1731, 1638, 1229, 1138, 1034, 936, 786 cm−1;
δ 173.3, 146.7, 98.5, 78.3, 73.8, 58.3, 52.7, 34.7, 17.9, 14.8; 1H NMR (400 MHz, CDCl3) δ 6.17 (t, J = 1.9 Hz, 1H), 4.41
HRMS–ESI (m/z): [M + Na]+ calcd for C10H15O3BrNa: (dd(ABX system), J = 12.7, 1.9 Hz, 1H), 4.33 (dd(ABX
285.0097; found: 285.0091.
system), J = 12.7, 1.9 Hz, 1H), 4.13 (d(AB system), J = 8.9 Hz,
1H), 3.98 (d(AB system), J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.21
(Z)-Methyl 4-(iodomethylene)-3-pentyltetrahydrofuran-3- (m, 1H), 2.00 (m, 1H), 0.96 (t, J = 7.5 Hz, 3H); 13C NMR
carboxylate ((Z)-4bb): Prepared according to general proce- (100 MHz, CDCl3) δ 173.2, 146.4, 98.5, 77.9, 73.8, 58.5, 52.6,
dure 1 from enoate 3b (40 mg, 0.14 mmol) and Bu2Zn 25.2, 8.9; HRMS–ESI (m/z): [M + Na]+ calcd for
(0.42 mL, ~1 N in heptane, 0.42 mmol). Purification by flash C9H13O3BrNa: 270.99403; found: 270.99477.
chromatography with pentane/ether (80:20) as eluent gave the
title compound ((Z)-4bb) (28 mg, 58%) as a colorless oil. IR (E)-Methyl 4-(bromomethylene)-3-isobutyltetrahydrofuran-
(neat): 2951, 2925, 2856, 1731, 1434, 1230, 1073, 939, 3-carboxylate ((E)-4ad) (Table 3, entry 4): Under argon, to a
730 cm−1. 1H NMR (400 MHz, CDCl3) δ 6.36 (t, J = 2.6 Hz, stirred solution of β-(propargyloxy)enoate 3a (47 mg,
1H), 4.49 (d(AB system), J = 9.1 Hz, 1H), 4.31 (d br, 0.2 mmol) and iPrI (0.2 mL, 2.0 mmol) in CH2Cl2 (1 mL) at
J = 2.6 Hz, 2H), 3.90 (d(AB system), J = 9.1 Hz, 1H), 3.74 (s, 0 °C was added Me2Zn (0.6 mL, 1.0 M in heptane, 0.6 mmol).
3H), 1.90 (m, 1H), 1.66 (m, 1H), 1.40–1.20 (m, 6H), 0.91 (t, J = Air (20 mL) was slowly introduced over 1 h into the solution
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.3, 152.4, 76.5, via a syringe pump by using a syringe fitted with a CaCl2 guard.
76.2, 71.3, 59.7, 52.7, 37.3, 32.0, 25.1, 22.5, 14.1.
The reaction mixture was then stirred at 0 °C for 1 h. CH2Cl2
(5 mL) was then added and the reaction was hydrolyzed with an
(E)-Methyl 4-(bromomethylene)-3-pentyltetrahydrofuran-3- aqueous solution of HCl (1 M, 5 mL). The layers were sep-
carboxylate ((E)-4ab): Prepared according to general proce- arated, the aqueous one being extracted with CH2Cl2 (3 ×
dure 2 from enoate 3a (47 mg, 0.2 mmol) and Bu2Zn (0.6 mL, 10 mL). The combined organic layers were washed with brine,
~1 N in heptane, 0.6 mmol). The title compound ((E)-4ab) was dried over MgSO4 and concentrated under reduced pressure.
isolated pure (55 mg, 93%) as a colorless oil and did not require Purification by flash chromatography on silica gel (pentane/
further purification. IR (neat): 2955, 2927, 2856, 1771, 1733, ether 50:50) afforded the title compound ((E)-4ad) (36 mg,
1433, 1260, 1230, 1217, 1122, 1074, 936, 910, 731 cm−1; 65%) as a colorless oil. IR (neat): 2953, 2870, 1732, 1640,
1H NMR (400 MHz, CDCl3) δ 6.15 (t, J = 1.9 Hz, 1H), 4.39 1230, 1126, 1073, 937, 695 cm−1; 1H NMR (400 MHz, CDCl3)
(dd(ABX system), J = 12.7, 2.0 Hz, 1H), 4.32 (dd(ABX δ 6.15 (t, J = 1.9 Hz, 1H), 4.40 (d, J = 1.9 Hz, 2H), 4.15 (d(AB
system), J = 12.7, 1.8 Hz, 1H), 4.12 (d(AB system), J = 8.9 Hz, system), J = 8.9 Hz, 1H), 4.02 (d(AB system), J = 8.9 Hz, 1H),
1H), 3.97 (d(AB system), J = 8.9 Hz, 1H), 3.74 (s, 3H), 2.15 3.74 (s, 3H), 2.05 (m, 2H), 1.77 (m, 1H), 0.96 (d, J = 8.4 Hz,
243

Beilstein J. Org. Chem. 2013, 9, 236–245.
4. Cohen, T.; Gibney, H.; Ivanov, R.; Yeh, E. A.-H.; Marek, I.;
3H), 0.95 (d, J = 8.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.1, 146.9, 98.6, 78.0, 73.6, 58.1, 52.5, 40.5, 24.9, 24.5, 24.4;
HRMS–ESI (m/z): [M + Na]+ calcd for C11H17O3BrNa:
299.02533; found: 299.02606.
Curran, D. P. J. Am. Chem. Soc. 2007, 129, 15405–15409.
doi:10.1021/ja076554k
5. Lewiński, J.; Marciniac, W.; Lipkowski, J.; Justyniak, I.
J. Am. Chem. Soc. 2003, 125, 12698–12699. doi:10.1021/ja036020t
6. Lewiński, J.; Śliwiński, W.; Dranka, M.; Justyniak, I.; Lipkowski, J.
Angew. Chem., Int. Ed. 2006, 45, 4826–4829.
(Z)-Methyl 4-(bromoiodomethylene)-3-ethyltetrahydro-
furan-3-carboxylate (16) (Table 3, entry 2): Under argon, to a
stirred solution of β-(propargyloxy)enoate 3a (45 mg,
0.2 mmol) in CH2Cl2 (1 mL) at 0 °C was added Me2Zn (1 mL,
1.0 M in heptane, 1.0 mmol). Air (20 mL) was slowly intro-
duced over 1 h into the solution via a syringe pump by using a
syringe fitted with a CaCl2 guard. The reaction mixture was
then stirred at 0 °C for 1 h. A solution of I2 (330 mg, 1.3 mmol)
in THF (1 mL) was then added at the same temperature, and the
mixture was stirred for 1 h. CH2Cl2 (10 mL) followed by an
aqueous solution of Na2S2O3 (10%) were added. The layers
were separated, the aqueous one being extracted with CH2Cl2
(2 × 10 mL). The combined organic layers were washed with
HCl (1 M) (10 mL) and brine (10 mL), dried over MgSO4, and
concentrated under reduced pressure. Purification by flash chro-
matography on silica gel (pentane/ether 80:20) afforded the title
compound 16 (46 mg, 64%) as a pale yellow oil. IR (neat):
2947, 2878, 1730, 1630, 1432, 1236, 1081, 941 cm−1; 1H NMR
(400 MHz, CDCl3) δ 4.32 (d(AB system), J = 14.0 Hz, 1H),
4.27 (d(AB system), J = 14.0 Hz, 1H), 4.24 (d(AB system), J =
8.8 Hz, 1H), 4.15 (d(AB system), J = 8.8 Hz, 1H), 3.75 (s, 3H),
2.21 (m, 1H), 1.95 (m, 1H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.4, 152.4, 80.1, 79.5, 60.9, 52.8, 41.2,
25.5, 9.0; HRMS–ESI (m/z): [M + Na]+ calcd for
C9H12O3BrINa: 396.89067; found: 396.89159.
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(Z)-Methyl 4-(bromoiodomethylene)-3-isobutyltetrahydro-
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pound was obtained as a side-product following the above-
described procedure for the preparation of (E)-4ad. It could not
be isolated pure after column chromatography, but character-
istic NMR spectroscopic data were obtained. 1H NMR
(400 MHz, CDCl3) δ 4.32 (d(AB system), J = 14.0 Hz, 1H),
4.29 (d(AB system), J = 14.0 Hz, 1H), 4.24 (d(AB system), J =
8.9 Hz, 1H), 4.21 (d(AB system), J = 8.9 Hz, 1H), 3.75 (s, 3H),
2.10 (dd, J = 14.5, 6.8 Hz, 1H), 1.95 (dd, J = 14.5, 5.0 Hz, 1H),
1.81 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 172.5, 152.9, 80.3, 79.8, 58.3,
52.7, 41.9, 40.7, 24.7, 24.5, 23.8.
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