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

Fabrice Chemla, Florian Dulong, Franck Ferreira, Alejandro Pérez-Luna

► To cite this version:

Fabrice Chemla, Florian Dulong, Franck Ferreira, Alejandro Pérez-Luna. Radical zinc-atom-transfer-based carbozincation of haloalkynes with dialkylzincs. Beilstein Journal of Organic Chemistry, 2013, 9, pp.236-245. 10.3762/bjoc.9.28. hal-01543100

HAL Id: hal-01543100

https://hal.sorbonne-universite.fr/hal-01543100

Submitted on 20 Jun 2017

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

# 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:
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

Email:
Fabrice Chemla* - fabrice.chemla@upmc.fr; Alejandro Pérez-Luna* -
alejandro.perez_luna@upmc.fr

Keywords:
carbenoids; carbometallation; carbozincation; radicals; tandem
reaction

Beilstein J. Org. Chem. **2013**, *9*, 236–245.
doi:10.3762/bjoc.9.28

Received: 13 November 2012

Accepted: 08 January 2013

Published: 04 February 2013

This article is part of the Thematic Series "Carbometallation chemistry".

Guest Editor: I. Marek

© 2013 Chemla et al; licensee Beilstein-Institut.

License and terms: see end of document.

## 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 of organozinc reagents as nontoxic radical precursors or mediators [1-3]. As part of this development, the so-called radical-polar reactions in which alkylzinc reagents are used as mediators in a radical transformation that affords a new zincated species, have emerged as valuable tools in synthesis. Pivotal to the processes disclosed so far using alkylzinc derivatives is zinc atom radical transfer [4]. In general terms, the reaction involves a radical chain process initiated by the formation of an alkyl radical from the organozinc derivative in the presence of oxygen [5-14]. The newly formed radical then undergoes one or more radical transformations before being reduced by the alkylzinc reagent through homolytic substitution at zinc,

producing a new organozinc derivative along with an alkyl radical that sustains a radical chain. Overall, the in situ transformation of simple organozinc reagents into more elaborate ones is thus achieved, and subsequent reaction with electrophiles is possible [15-30].

More specifically, building on well-established addition reactions of carbon-centered radicals to carbon-carbon double and triple bonds, such reactivity has been advantageously employed in the context of carbozincation chemistry [31]. The intramolecular carbozincation of unactivated terminal alkenes following zinc atom transfer processes, including a 5-exo-trig cyclization step, has been reported. This is, for instance, the case in the for-

<footnote>* Corresponding author</footnote>
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-
proach to transition-metal-mediated carbozincations, which are
generally *syn*-selective [41-46].

To explore further the possibilities offered by zinc atom transfer
processes we considered the possibility to prepare alkyli-
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].

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
ideally suited (Scheme 1). On the one hand it would provide a
means to control totally the regioselectivity of the radical addi-
tion to the haloalkyne, and on the other hand the envisioned
zinc atom transfer to an α-halo vinylic radical should be favor-
able as a result of the presence of the ester moiety. Hereafter,
we disclose our findings concerning this reaction.

**Results and Discussion**

β-(Propargyloxy)enoates **3a** and **3b** having a pendant
bromoalkyne and an iodoalkyne moiety, respectively, were
prepared by condensation of propargylic alcohols **1** with methyl
2-(bromomethyl)acrylate (**2**) (Scheme 2). Enoate **3a** was readily
obtained by direct reaction of 3-bromopropargyl alcohol (**1a**).

<figure><img src="image_3.png" /><figcaption>**Scheme 1:** Anticipated formation of alkylidene zinc carbenoids by reaction of dialkylzincs with β-(propargyloxy)enoates having pendant haloalkynes.</figcaption></figure>

By contrast, the reaction of the iodo analogue **1b** with **2** proved
troublesome as it led to inseparable mixtures of the desired
enoate **3b** and non-iodinated enoate **3c**. Thus, **3b** was best
prepared by iodinating (AgNO₃/NIS) the terminal alkyne of
enoate **3c** prepared from propargyl alcohol (**1c**) and acrylate **2**.

<figure><img src="image_4.png" /><figcaption>**Scheme 2:** Preparation of β-(propargyloxy)enoates having pendant haloalkynes. Reagents and conditions: (a) **2** (1.4 equiv), Et₃N (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**).</figcaption></figure>

According to our previously optimized conditions for the 1,4-
addition/carbozincation reaction of dialkylzincs with β-(propar-
gyloxy)enoates [37,38], bromoalkyne **3a** was treated with Et₂Zn
at room temperature in Et₂O under an argon atmosphere
(Table 1, entry 1). To our delight, following acidic work-up, the
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
intermediate formation of an alkylidene zinc carbenoid as
deuterated **4aa-D** was produced (Table 1, entry 2). As previ-
ously noted in the case of similar 1,4-addition/carbozincation
sequences [37,38], deuterium incorporation was nearly quanti-
tative for the Z isomer, and much lower for the E one. More
<figure><img src="image_5.png" /><figcaption>**Table 1:** 1,4-addition/carbozincation of dialkylzincs with β-(propargyloxy)enoates 3 having pendant haloalkynes in the presence of traces of air.<sup>a</sup></figcaption></figure>

<table><thead><tr><th>Entry</th><th>Enoate</th><th>X</th><th>Solvent</th><th>R</th><th>Products (Yield<sup>b</sup> (%) [dr<sup>c</sup> (Z/E)])</th></tr></thead><tbody><tr><td>1</td><td><b>3a</b></td><td>Br</td><td>Et<sub>2</sub>O</td><td>Et</td><td><b>4aa</b> (43 [77:23]); <b>5a</b> (40 [79:21])</td></tr><tr><td>2</td><td><b>3a</b></td><td>Br</td><td>Et<sub>2</sub>O</td><td>Et</td><td><b>4aa-D<sup>d</sup></b> (44 [81(90% D):19(10% D)]);<br/><b>5a-D<sup>d</sup></b> (35 [84(85% D):16(40% D)])</td></tr><tr><td>3</td><td><b>3b</b></td><td>I</td><td>Et<sub>2</sub>O</td><td>Et</td><td><b>4ba</b> (40<sup>e</sup> [98:2]); <b>5a</b> (21<sup>e</sup> [82:18])</td></tr><tr><td>4</td><td><b>3a</b></td><td>Br</td><td>Et<sub>2</sub>O</td><td><i>n</i>-Bu</td><td><b>4ab</b> (76 [70:30]); <b>5b</b> (7 [nd<sup>f</sup>])</td></tr><tr><td>5</td><td><b>3b</b></td><td>I</td><td>Et<sub>2</sub>O</td><td><i>n</i>-Bu</td><td><b>4bb</b> (58 [98:2])</td></tr><tr><td>6</td><td><b>3a</b></td><td>Br</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td>Et</td><td><b>4aa</b> (39<sup>d</sup> [78:22]); <b>5a</b> (17<sup>d</sup> [91:9])</td></tr><tr><td>7</td><td><b>3a</b></td><td>Br</td><td>CH<sub>2</sub>Cl<sub>2</sub></td><td><i>n</i>-Bu</td><td><b>4ab</b> (37 [76:24]); <b>5b</b> (12 [nd]<sup>f</sup>)</td></tr></tbody></table>

<sup>a</sup>Reaction conditions: R<sub>2</sub>Zn (3 equiv), rt, 24 h under Ar atmosphere (see Experimental section).

<sup>b</sup>Combined yield of diastereomers after chromatography unless otherwise noted.

<sup>c</sup>Determined by ¹H NMR analysis of the crude material.

<sup>d</sup>The reaction mixture was quenched with D<sub>2</sub>O. The percentage of deuterium incorporation is given in parenthesis for each compound.

<sup>e</sup>Determined by ¹H NMR spectroscopy based on analysis of the crude mixture with biphenyl as internal standard.

<sup>f</sup>Not determined.

unexpectedly, however, 40% of alkylidenetetrahydrofuran **5a**, wherein the bromine atom had been substituted by an ethyl group, was also isolated as a 79:21 Z/E mixture. Deuterium labeled **5a-D** was produced following hydrolysis with D<sub>2</sub>O (Table 1, entry 2), thereby showing that an alkylidenezinc intermediate was being formed in the generation of this side-product under these reaction conditions.

When iodoalkyne **3b** was used, a similar 40% yield of vinylic 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*-Bu<sub>2</sub>Zn 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 CH<sub>2</sub>Cl<sub>2</sub> was used as the solvent instead of Et<sub>2</sub>O, even though this had little impact on the efficiency and diastereoselectivity of vinyl halide formation (Table 1, entries 6 and 7). Reaction of Et<sub>2</sub>Zn with **3a** provided

vinyl bromide **4aa** in 39% yield (78:22 Z/E ratio) and **5a** in 17% yield, while reaction of *n*-Bu<sub>2</sub>Zn gave **4ab** in 37% yield (76:24 Z/E ratio) and **5b** in 12% yield. It is worthy of note that no difference was observed between the different dialkylzincs in this case.

The formation of alkylidenezinc derivatives **7** leading to compounds **5** is intriguing (Scheme 3). A first possible mechanistic route could involve the reaction of zinc carbenoid **6** and the

<figure><img src="image_6.png" /><figcaption>**Scheme 3:** Possible reaction pathways to account for the formation of product **5**.</figcaption></figure>
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
place between pure 10 and Et₂Zn indicates that 12 is not formed
by carbozincation. Hence, most likely it is formed by the reac-
tion of Et₂Zn and carbenoid 13 arising from the carbozincation
of 11 (Scheme 4). Moreover, if 13 is indeed formed, it would
also lead to alkyne 10 following Fritsch–Buttenberg–Wieschell
(FBW) rearrangement [55-57]. Since the presence of the
oxygen atom in the propargylic position should facilitate the
carbometallation reaction [58], this mechanistic pathway
provides a plausible explanation for the fact that bromine
substitution occurs from α-oxgenated bromoalkyne 11 and not
from 9.

Regarding our 1,4 addition/carbocyclization sequence, these test
experiments provide two important pieces of evidence for the
behavior of **3a** in the presence of a dialkylzinc. First, β-alkoxy
bromoalkynes undergo direct substitution with Et₂Zn to some
extent. Second, alkylidenezinc carbenoids react with dialkyl-
zincs to afford the bromine substitution product. Thus, forma-
tion of alkylidenezinc compound **7** (and thereby **5**) most prob-
ably arises from both depicted mechanistic pathways (paths a
and b, Scheme 3). In such a situation, we reasoned that in both
possibilities, reducing the reaction time would limit the produc-
tion of the unwanted side-products by limiting the contact time
between the dialkylzinc reagent and either the starting
bromoalkyne or the generated zinc carbenoid. Thus, we consid-
ered adding air to the reaction media in order to accelerate the
oxidation of the dialkylzinc species and therefore radical
production (Table 2).

<figure><img src="image_7.png" /><figcaption>**Scheme 4:** Test experiments to gain insight into the mechanism of formation of alkylidene zinc intermediate **7**.</figcaption></figure>

A reduced amount of side-product **5** was indeed observed in the
reaction of enoate **3a** with Et₂Zn in CH₂Cl₂ at room tempera-
ture in the presence of added dry air (Table 2, entry 1). A mix-
ture of vinyl bromide **4aa** and alkene **5a** in a 84:16 ratio and in
69% overall yield was obtained. However the diastereoselectiv-
ity of the formation of **4aa** dropped significantly. Lowering the
reaction temperature had a highly beneficial impact on the
reaction outcome. At 0 °C, the formation of **5a** was totally
suppressed, and **4aa** was obtained with a much better diastereo-
selectivity, though remarkably in favor of the *E* isomer
(Table 2, entry 2). At –30 °C, the exclusive and totally diaste-
reoselective formation of (*E*)-**4aa** in excellent 89% isolated
yield was obtained (Table 2, entry 3). Hydrolysis with D₂O led
to (*E*)-**4aa-D** with 83% deuterium incorporation when either
CH₂Cl₂ or DCE were used as solvent (entries 4 and 5), there-
fore evidencing the intermediate stereoselective formation of an
alkylidene zinc carbenoid. Similar results were obtained by
using *n*-Bu₂Zn, indicating that the process is quite general
(Table 2, entry 6).

The diastereoselectivity of the formation of 4aa seemed to be
dependent not only on the reaction temperature, but also on the
total reaction time (compare Table 1, entry 6 and Table 2, entry
1). Suspecting a possible Z/E isomerization of the alkylid-
enezinc carbenoid intermediate, we conducted an experiment
wherein air was added to a mixture of enoate 3a and Et2Zn in
CH2Cl2 at -30 °C, and the reaction was first kept for 1 h at this
temperature and then for 23 h at room temperature (Table 2,
<figure><img src="image_8.png" /><figcaption>**Table 2:** 1,4-Addition/carbozincation of dialkylzincs on **3a** in the presence of added air.<sup>a</sup></figcaption></figure>

<table><thead><tr><th>Entry</th><th>R</th><th>Reaction conditions</th><th>Products [ratio]</th><th>Yield<sup>b</sup> (%)</th><th>dr<sup>c</sup> of product 4 (E/Z)</th></tr></thead><tbody><tr><td>1</td><td>Et</td><td>rt, 1 h</td><td>4aa/(Z)-5a [84:16]</td><td>69<sup>d</sup></td><td>54:46</td></tr><tr><td>2</td><td>Et</td><td>0 °C, 1 h</td><td>4aa</td><td>93</td><td>87:13</td></tr><tr><td>3</td><td>Et</td><td>-30 °C, 1 h</td><td>4aa</td><td>89</td><td>&gt;98:2</td></tr><tr><td>4</td><td>Et</td><td>-30 °C, 1 h</td><td>4aa-D<sup>e</sup></td><td>95<sup>d</sup></td><td>&gt;98(83% D):2</td></tr><tr><td>5</td><td>Et</td><td>-30 °C, 1 h, DCE<sup>f</sup></td><td>4aa-D<sup>e</sup></td><td>89</td><td>&gt;98(83% D):2</td></tr><tr><td>6</td><td>Bu</td><td>-30 °C, 1 h</td><td>4ab</td><td>93</td><td>&gt;98:2</td></tr><tr><td>7</td><td>Et</td><td>-30 °C, 1 h then rt, 24h</td><td>4aa/(Z)-5a [78:22]</td><td>78<sup>d</sup></td><td>44:56</td></tr><tr><td>8</td><td>Et</td><td>-30 °C, 1 h then rt, 24 h</td><td>4aa-D<sup>e</sup>/(Z)-5a-D<sup>g</sup> [78:22]</td><td>78<sup>d</sup></td><td>44(&lt;10% D):56(&lt;10% D)</td></tr></tbody></table>

<sup>a</sup>Reaction conditions: R<sub>2</sub>Zn (3 equiv), CH<sub>2</sub>Cl<sub>2</sub>, dry air was bubbled at once into the reaction mixture, which was then kept under Ar atmosphere (see Experimental section).

<sup>b</sup>Combined yield of products after chromatography unless otherwise noted.

<sup>c</sup>Determined by ¹H NMR analysis of the crude material.

<sup>d</sup>Determined by ¹H NMR spectroscopy based on analysis of the crude mixture with biphenyl as the internal standard.

<sup>e</sup>The reaction mixture was quenched with D<sub>2</sub>O. The percentage of deuterium incorporation is given in parenthesis for each isomer.

<sup>f</sup>DCE = 1,2-dichloroethane was used as solvent instead of CH<sub>2</sub>Cl<sub>2</sub>.

<sup>g</sup>30% deuterium incorporation was observed for product 5a-D.

entry 7). Following acidic quench, very similar results to those noted for the same reaction carried out at room temperature (Table 2, entry 1) were observed. **4aa** was recovered in 61% yield as a 56:44 mixture of isomers along with alkene (Z)-5a in 22% yield. It is worthy to note that very low levels of deuterium incorporation were observed in this case.

These results have a three-fold consequence. First, they indicate that Z/E isomerization of the alkylidenezinc carbenoid occurs between -30 °C and room temperature. Second, it demonstrates that alkene 5a can be formed by the reaction between the zinc carbenoid and Et<sub>2</sub>Zn (Scheme 3, path a), and that in such a case the transformation is stereoselective. Third, when oxygen is introduced into the reaction media, the alkylidenezinc carbenoid is eventually demetallated upon standing at room temperature.

The different results obtained for the 1,4-addition/carbozincation of enoates having pendant bromoalkynes are consistent with our anticipated zinc atom radical transfer mechanism (Scheme 1) and can be rationalized according to the following scenario (Scheme 5). The process involves the initial 1,4-addition of radical R to the starting enoate and the subsequent 5-exo-dig cyclisation of enoxy radical **14** to provide

α-bromovinyl radical **15** of E geometry. Substitution by electron-withdrawing groups slows down E to Z isomerization of vinylic radicals, and therefore, due to the presence of the bromine atom, interconversion of (E)-**15** into (Z)-**15** should not be fast. Thus, (E)-**15** reacts by Zn atom transfer prior to its equilibration to provide stereoselectively carbenoid (Z)-**6** [59] and to some extent by H-atom transfer to give reduced bromoalkene (E)-**4** [60]. Upon warming, (Z)-**6** isomerizes to its more stable isomer (E)-**6** wherein the zinc atom is coordinated intramolecularly to the adjacent ester. To a minor extent, reaction with the excess dialkylzinc present in the reaction media provides alkylidenezinc (E)-**7** stereoselectively. Note, however, that in the case where reactions are conducted at room temperature, E/Z equilibration of the intermediate radical **15** should be faster and zinc atom transfer from (Z)-**15** may also contribute to the formation of (E)-**6**.

Two situations are next to be distinguished. Under the conditions involving excess air, carbenoid **6** is protonated in the reaction media (even though we have not identified the proton source). It is possible that protonation occurs prior to full E to Z isomerization and vinyl bromide **4** is obtained in low diastereoselectivity. Under the conditions involving only a trace of air, after 24 h at room temperature, carbenoid **6** is still present and
<figure><img src="image_9.png" /><figcaption>**Scheme 5:** Mechanistic rationale for the reaction of dialkylzincs with β-(propargyloxy)enoate 3a.</figcaption></figure>

total Z to E isomerization has occurred. The reason why vinyl bromide **4** is only isolated with moderate diastereoselectivity following hydrolysis, is that (E)-**4**, formed from (E)-**15** by H-abstraction, is present from the start.

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
CH₂Cl₂ at 0 °C and under continuous introduction of dry air
over a period of 1 h (Table 3, entry 1). After acidic quench,
vinylic bromide (E)-**4ac** [61] was isolated in 77% yield as a
single diastereoisomer. The stereoselective formation of an
alkylidenezinc carbenoid intermediate was this time evidenced
by treating the reaction mixture with iodine (Table 3, entry 2).
Vinylic dihalide **16** was isolated in 64% yield, again as a single
Z diastereoisomer. Thus, Me₂Zn showed a similar reactivity to
its higher homologues Et₂Zn and n-Bu₂Zn, with the additional
advantage that no direct formation of vinyl bromide (E)-**4ac** by
hydrogen abstraction was observed.

In the presence of 5 equiv iPrI, a mixture of two (diastereomeri-
cally pure) compounds **4ad** and **4ac** in 87:13 ratio was
observed. Incorporation of the iPr moiety was therefore the

major reaction pathway. The competitive addition of a Me
group could be reduced by increasing the amount of iPrI to
10 equiv (Table 3, entries 3 and 4). However, in this case,
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.

Conclusion

In conclusion, we have shown that β-(propargyloxy)enoates
having pendant iodo- and bromoalkynes undergo a 1,4-addition/
carbozincation sequence by reaction with dialkylzincs or with
alkyliodides in the presence of dimethylzinc. The sequence
involves a radical chain mechanism initiated by air and provides
the proof of concept that alkylidenezinc carbenoids can be
prepared by carbozincation based on zinc atom transfer. In the
disclosed process, we have demonstrated that the formation of a
bromocarbenoid 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. In the absence of added
air, no decomposition of the carbenoid intermediate is observed
at room temperature for at least 24 h. Deuterium labeling and
iodolysis experiments evidence that the zinc carbenoids
<figure><img src="image_10.png" /><figcaption>**Table 3:** $Me_2Zn$-mediated 1,4-addition/carbozincation of alkyl iodides with **3a** in the presence of added air.<sup>a</sup></figcaption></figure>

<table><thead><tr><th>Entry</th><th>iPrl (equiv)</th><th>E-X</th><th>Yield<sup>b</sup> (%)</th><th>Products [ratio]</th></tr></thead><tbody><tr><td>1</td><td>0</td><td>H<sub>2</sub>O</td><td>77</td><td><b>4ac<sup>c</sup></b></td></tr><tr><td>2</td><td>0</td><td>I<sub>2</sub></td><td>64</td><td><b>16</b></td></tr><tr><td>3<sup>d</sup></td><td>5</td><td>H<sub>2</sub>O</td><td>59</td><td><b>4ad/4ac</b> [87:13]</td></tr><tr><td>4<sup>d</sup></td><td>10</td><td>H<sub>2</sub>O</td><td>87</td><td><b>4ad/4ac/17</b> [75:6:19]</td></tr><tr><td>5<sup>d</sup></td><td>10</td><td>D<sub>2</sub>O</td><td>75</td><td><b>4ad-D/4ac-D/17</b> [75 (95% D):6 (95% D):19]</td></tr></tbody></table>

prepared under such reactions can act as typical nucleophiles and should, thus, be well-suited for subsequent functionalization [47-51]. Furthermore, as indicated with the formation of some side-products observed during this work, they should also react readily as electrophiles toward organometallic nucleophiles and undergo intramolecular nucleophilic substitution reactions [47-51].

## Experimental

Experiments involving organometallic compounds were carried out in dried glassware under a positive pressure of dry Ar. All solvents were distilled to remove stabilizers and dried with a MBRAUN Solvent Purification System SPS-800. n-Bu₂Zn (Fluka, ~1 N in heptane), Et₂Zn (Aldrich, 1.0 M in hexanes), Me₂Zn (Aldrich, 1.0 M in heptane) and all other reagents were of commercial quality and were used without purification. ¹H NMR, ¹³C NMR spectra were recorded with a Bruker AVANCE 400 spectrometer fitted with BBFO probe with Z gradient. Chemical shifts are reported in δ relative to an internal standard of residual chloroform (δ 7.27 for ¹H NMR and 77.16 for ¹³C NMR). IR spectra were recorded with an ATR diamond spectrophotometer. High-resolution mass spectra (HRMS) were obtained on a Finnigan MAT 95.

**General Procedure 1. Reaction of n-Bu₂Zn and Et₂Zn with β-(propargyloxy)enoates 3a and 3b having pendant haloalkynes in the presence of a trace amount of air**
(Table 1): Under argon, to a stirred solution of β-(propargyl-

oxy)enoate (0.2 mmol) in Et₂O (1 mL) at room temperature was added R₂Zn (0.6 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction was hydrolyzed with an aqueous solution of HCl (1 M, 10 mL). The layers were separated, the aqueous one being extracted with Et₂O (2 × 15 mL). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure, and the residue was purified by flash chromatography (pentane/ether).

**General Procedure 2. Reaction of n-Bu₂Zn and Et₂Zn with β-(propargyloxy)enoate 3a in the presence of added air**
(Table 2): Under argon, to a stirred solution of β-(propargyl-oxy)enoate **3a** (0.2 mmol) in CH₂Cl₂ (2 mL) at -30 °C was added R₂Zn (0.6 mmol). Air (2 mL) was bubbled at once into the solution via a syringe fitted with a CaCl₂ guard and the reaction mixture was stirred at -30 °C for 1 h. CH₂Cl₂ (20 mL) and an aqueous solution of HCl (1 M, 10 mL) were added to quench the reaction. The layers were separated, the aqueous one being extracted with Et₂O (2 × 15 mL). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure to afford the crude product.

*(Z)-Methyl 4-(bromomethylene)-3-propyltetrahydrofuran-3-carboxylate ((Z)-4aa): Prepared according to general procedure 1 from enoate **3a** (50 mg, 0.2 mmol) and Et₂Zn (0.6 mL, 1.0 M in hexanes, 0.6 mmol). Purification by flash chromatography with pentane/ether (95:05) as eluent gave the title compound ((Z)-4aa) (19 mg, 33%) as a colorless oil. IR (neat):

<footnote><sup>a</sup>Reaction conditions: $Me_2Zn$ (5 equiv), iPrl (equiv), $CH_2Cl_2$, 0 °C, 20 mL dry air was bubbled during 1 h into the reaction mixture via a syringe pump.</footnote>

<footnote><sup>b</sup>Combined yield of isolated products after chromatography unless otherwise noted.</footnote>

<footnote><sup>c</sup>The product was contaminated with ~10% of product resulting from the addition of the dichloromethyl radical (4ae, R = $CHCl_2$).</footnote>

<footnote><sup>d</sup>3 equiv $Me_2Zn$ were used.</footnote>
2958, 1730, 1434, 1219, 1072, 938, 722 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.34 (t, *J* = 2.7 Hz, 1H), 4.42 (d(AB system), *J* = 9.1 Hz, 1H), 4.40 (d br, *J* = 2.9 Hz, 2H), 3.84 (d(AB system), *J* = 9.1 Hz, 1H), 3.74 (s, 3H), 1.90 (m, 1H), 1.68 (m, 1H), 1.24 (m, 2H), 0.91 (t, *J* = 7.3 Hz, 3H); ¹³C NMR (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 C₁₀H₁₅O₃BrNa: 285.00968; found: 285.00990.

(E)-Methyl 4-(bromomethylene)-3-propyltetrahydrofuran-3-carboxylate ((E)-4aa): Prepared according to general procedure 2 from enoate 3a (47 mg, 0.2 mmol) and Et₂Zn (0.6 mL, 1.0 M in hexanes, 0.6 mmol). The title compound ((E)-4aa) was isolated pure (47 mg, 89%) as a colorless oil and did not require further purification. IR (neat): 2960, 2873, 1769, 1730, 1433, 1217, 1122, 1074, 968, 938, 742 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.15 (t, *J* = 1.9 Hz, 1H), 4.39 (dd(ABX system), *J* = 12.7, 1.9 Hz, 1H), 4.32 (dd(ABX system), *J* = 12.7, 1.8 Hz, 1H), 4.12 (d(AB system), *J* = 8.9 Hz, 1H), 3.97 (d(AB system), *J* = 8.9 Hz, 1H), 3.74 (s, 3H), 2.13 (td, *J* = 13.5, 4.6 Hz, 1H), 1.90 (dt, *J* = 12.5, 4.4 Hz, 1H), 1.50–1.30 (m, 1H), 1.30–1.25 (m, 1H), 0.95 (t, *J* = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.3, 146.7, 98.5, 78.3, 73.8, 58.3, 52.7, 34.7, 17.9, 14.8; HRMS–ESI (*m/z*): [M + Na]⁺ calcd for C₁₀H₁₅O₃BrNa: 285.0097; found: 285.0091.

(Z)-Methyl 4-(iodomethylene)-3-pentyltetrahydrofuran-3-carboxylate ((Z)-4bb): Prepared according to general procedure 1 from enoate 3b (40 mg, 0.14 mmol) and Bu₂Zn (0.42 mL, ~1 N in heptane, 0.42 mmol). Purification by flash chromatography with pentane/ether (80:20) as eluent gave the title compound ((Z)-4bb) (28 mg, 58%) as a colorless oil. IR (neat): 2951, 2925, 2856, 1731, 1434, 1230, 1073, 939, 730 cm⁻¹. ¹H NMR (400 MHz, CDCl₃) δ 6.36 (t, *J* = 2.6 Hz, 1H), 4.49 (d(AB system), *J* = 9.1 Hz, 1H), 4.31 (d br, *J* = 2.6 Hz, 2H), 3.90 (d(AB system), *J* = 9.1 Hz, 1H), 3.74 (s, 3H), 1.90 (m, 1H), 1.66 (m, 1H), 1.40–1.20 (m, 6H), 0.91 (t, *J* = 6.9 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.3, 152.4, 76.5, 76.2, 71.3, 59.7, 52.7, 37.3, 32.0, 25.1, 22.5, 14.1.

(E)-Methyl 4-(bromomethylene)-3-pentyltetrahydrofuran-3-carboxylate ((E)-4ab): Prepared according to general procedure 2 from enoate 3a (47 mg, 0.2 mmol) and Bu₂Zn (0.6 mL, ~1 N in heptane, 0.6 mmol). The title compound ((E)-4ab) was isolated pure (55 mg, 93%) as a colorless oil and did not require further purification. IR (neat): 2955, 2927, 2856, 1771, 1733, 1433, 1260, 1230, 1217, 1122, 1074, 936, 910, 731 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.15 (t, *J* = 1.9 Hz, 1H), 4.39 (dd(ABX system), *J* = 12.7, 2.0 Hz, 1H), 4.32 (dd(ABX system), *J* = 12.7, 1.8 Hz, 1H), 4.12 (d(AB system), *J* = 8.9 Hz, 1H), 3.97 (d(AB system), *J* = 8.9 Hz, 1H), 3.74 (s, 3H), 2.15

(td, *J* = 13.7, 4.2 Hz, 1H), 1.91 (dt, *J* = 12.2, 4.4 Hz, 1H), 1.50–1.20 (m, 6H), 0.88 (t, *J* = 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.3, 146.7, 98.6, 78.3, 73.9, 58.2, 52.7, 32.5, 32.4, 24.1, 22.7, 14.3; HRMS–ESI (*m/z*): [M + Na]⁺ calcd for C₁₂H₁₉O₃BrNa: 313.0410; found: 313.0413.

(E)-Methyl 4-(bromomethylene)-3-ethyltetrahydrofuran-3-carboxylate ((E)-4ac) (Table 3, entry 1): Under argon, to a stirred solution of β-(propargyloxy)enoate 3a (46 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 introduced 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. CH₂Cl₂ (5 mL) was then added, and the reaction was hydrolyzed with an aqueous solution of HCl (1 M, 5 mL). The layers were separated, the aqueous one being extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated under reduced pressure. Purification by flash chromatography on silica gel (pentane/ether 80:20) afforded the title compound ((E)-4ac) (38 mg, 77%) as a colorless oil. IR (neat): 2953, 1767, 1731, 1638, 1229, 1138, 1034, 936, 786 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.17 (t, *J* = 1.9 Hz, 1H), 4.41 (dd(ABX system), *J* = 12.7, 1.9 Hz, 1H), 4.33 (dd(ABX 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 (m, 1H), 2.00 (m, 1H), 0.96 (t, *J* = 7.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.2, 146.4, 98.5, 77.9, 73.8, 58.5, 52.6, 25.2, 8.9; HRMS–ESI (*m/z*): [M + Na]⁺ calcd for C₉H₁₃O₃BrNa: 270.99403; found: 270.99477.

(E)-Methyl 4-(bromomethylene)-3-isobutyltetrahydrofuran-3-carboxylate ((E)-4ad) (Table 3, entry 4): Under argon, to a stirred solution of β-(propargyloxy)enoate 3a (47 mg, 0.2 mmol) and iPrI (0.2 mL, 2.0 mmol) in CH₂Cl₂ (1 mL) at 0 °C was added Me₂Zn (0.6 mL, 1.0 M in heptane, 0.6 mmol). Air (20 mL) was slowly introduced 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. CH₂Cl₂ (5 mL) was then added and the reaction was hydrolyzed with an aqueous solution of HCl (1 M, 5 mL). The layers were separated, the aqueous one being extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated under reduced pressure. Purification by flash chromatography on silica gel (pentane/ether 50:50) afforded the title compound ((E)-4ad) (36 mg, 65%) as a colorless oil. IR (neat): 2953, 2870, 1732, 1640, 1230, 1126, 1073, 937, 695 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.15 (t, *J* = 1.9 Hz, 1H), 4.40 (d, *J* = 1.9 Hz, 2H), 4.15 (d(AB system), *J* = 8.9 Hz, 1H), 4.02 (d(AB system), *J* = 8.9 Hz, 1H), 3.74 (s, 3H), 2.05 (m, 2H), 1.77 (m, 1H), 0.96 (d, *J* = 8.4 Hz,
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.

(Z)-Methyl 4-(bromoiodomethylene)-3-ethyltetrahydrofuran-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 introduced 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 chromatography 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.

(Z)-Methyl 4-(bromoiodomethylene)-3-isobutyltetrahydrofuran-3-carboxylate (17) (Table 3, entry 4): The title compound 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 characteristic 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.

References

1. Bazin, S.; Feray, L.; Bertrand, M. P. *Chimia* **2006**, *60*, 260–265.

2. Akindele, T.; Yamada, K.-i.; Tomioka, K. *Acc. Chem. Res.* **2009**, *42*, 345–355. doi:10.1021/ar800166q

3. Seyferth, D. *Organometallics* **2001**, *20*, 2940–2955. doi:10.1021/om010439f

4. Cohen, T.; Gibney, H.; Ivanov, R.; Yeh, E. A.-H.; Marek, I.; 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. doi:10.1002/anie.200601001

7. Lewiński, J.; Suwala, K.; Kubisiak, M.; Ochal, Z.; Justyniak, I.; Lipkowski, J. *Angew. Chem., Int. Ed.* **2008**, *47*, 7888–7889. doi:10.1002/anie.200803254

8. Lewiński, J.; Bury, W.; Dutkiewicz, M.; Maurin, M.; Justyniak, I.; Lipkowski, J. *Angew. Chem., Int. Ed.* **2008**, *47*, 573–576. doi:10.1002/anie.200703125

9. Lewiński, J.; Kościelski, M.; Suwala, K.; Justyniak, I. *Angew. Chem., Int. Ed.* **2009**, *48*, 7017–7020. doi:10.1002/anie.200902716

10. Lewiński, J.; Suwala, K.; Kaczorowski, T.; Gałęzowski, M.; Gryko, D. T.; Justyniak, I.; Lipkowski, J. *Chem. Commun.* **2009**, 215–217. doi:10.1039/b813315h

11. Jana, S.; Berger, R. J. F.; Fröhlich, R.; Pape, T.; Mitzel, N. W. *Inorg. Chem.* **2007**, *46*, 4293–4297. doi:10.1021/ic062438r

12. Mileo, E.; Benfatti, F.; Cozzi, P. G.; Lucarini, M. *Chem. Commun.* **2009**, 469–470. doi:10.1039/b818437b

13. Maury, J.; Feray, L.; Bazin, S.; Clément, J.-L.; Marque, S. R. A.; Siri, D.; Bertrand, M. P. *Chem.–Eur. J.* **2011**, *17*, 1586–1595. doi:10.1002/chem.201002616

14. Mukherjee, D.; Ellern, A.; Sadow, A. D. *J. Am. Chem. Soc.* **2012**, *134*, 13018–13026. doi:10.1021/ja303440n

15. Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. *J. Org. Chem.* **1999**, *64*, 9189–9193. doi:10.1021/jo9912404

16. Bazin, S.; Feray, L.; Siri, D.; Naubron, J.-V.; Bertrand, M. P. *Chem. Commun.* **2002**, 2506–2507. doi:10.1039/b206695e

17. Bazin, S.; Feray, L.; Vanthuyne, N.; Bertrand, M. P. *Tetrahedron* **2005**, *61*, 4261–4274. doi:10.1016/j.tet.2005.02.042

18. Bazin, S.; Feray, L.; Vanthuyne, N.; Siri, D.; Bertrand, M. P. *Tetrahedron* **2007**, *63*, 77–85. doi:10.1016/j.tet.2006.10.049

19. Maury, J.; Feray, L.; Perfetti, P.; Bertrand, M. P. *Org. Lett.* **2010**, *12*, 3590–3593. doi:10.1021/ol101519w

20. Maury, J.; Mouysset, D.; Feray, L.; Marque, S. R. A.; Siri, D.; Bertrand, M. P. *Chem.–Eur. J.* **2012**, *18*, 3241–3247. doi:10.1002/chem.201102366

21. Van der Deen, H.; Kellog, R. M.; Feringa, B. L. *Org. Lett.* **2000**, *2*, 1593–1595. doi:10.1021/ol005843+

22. Miyabe, H.; Asada, R.; Yoshida, K.; Takemoto, Y. *Synlett* **2004**, 540–542. doi:10.1055/s-2004-815407

23. Miyabe, H.; Asada, R.; Takemoto, Y. *Tetrahedron* **2005**, *61*, 385–393. doi:10.1016/j.tet.2004.10.104

24. Yamada, K.-i.; Umeki, M.; Maekawa, M.; Yamamoto, Y.; Akindele, T.; Nakano, M.; Tomioka, K. *Tetrahedron* **2008**, *64*, 7258–7265. doi:10.1016/j.tet.2008.05.069

25. Yamada, K.-i.; Konishi, T.; Nakano, M.; Fujii, S.; Cadou, R.; Yamamoto, Y.; Tomioka, K. *J. Org. Chem.* **2012**, *77*, 5775–5780. doi:10.1021/jo300944f

26. Cozzi, P. G. *Angew. Chem., Int. Ed.* **2006**, *45*, 2951–2954. doi:10.1002/anie.200504239

27. Cozzi, P. G. *Adv. Synth. Catal.* **2006**, *348*, 2075–2079. doi:10.1002/adsc.200606178

28. Cozzi, P. G.; Mignogna, A.; Vicennati, P. *Adv. Synth. Catal.* **2008**, *350*, 975–978. doi:10.1002/adsc.200700572
29. Fernández-Ibáñez, M. A.; Maciá, B.; Minnaard, A. J.; Feringa, B. L. *Angew. Chem., Int. Ed.* **2008**, *47*, 1317–1319.
doi:10.1002/anie.200704841

30. Cozzi, P. G.; Benfatti, F.; Guiteras Capdevila, M.; Mignogna, A. *Chem. Commun.* **2008**, 3317–3318. doi:10.1039/b805197f

31. Pérez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F. *New J. Chem.* **2008**, *32*, 594–606. doi:10.1039/b716292h

32. Denes, F.; Chemla, F.; Normant, J. F. *Angew. Chem., Int. Ed.* **2003**, *42*, 4043–4046. doi:10.1002/anie.200250474

33. Denes, F.; Cutri, S.; Pérez-Luna, A.; Chemla, F. *Chem.-Eur. J.* **2006**, *12*, 6506–6513. doi:10.1002/chem.200600334

34. Denes, F.; Pérez-Luna, A.; Chemla, F. *J. Org. Chem.* **2007**, *72*, 398–406. doi:10.1021/jo061603h

35. Giboulot, S.; Pérez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F. *Tetrahedron Lett.* **2008**, *49*, 3963–3966.
doi:10.1016/j.tetlet.2008.04.108

36. Feray, L.; Bertrand, M. P. *Eur. J. Org. Chem.* **2008**, 3164–3170.
doi:10.1002/ejoc.200800242

37. Pérez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F. *Chem.-Eur. J.* **2008**, *14*, 8784–8788. doi:10.1002/chem.200801451

38. Chemla, F.; Dulong, F.; Ferreira, F.; Nüllen, M.; Pérez-Luna, A. *Synthesis* **2011**, 1347–1360. doi:10.1055/s-0030-1259993

39. Chen, Z.; Zhang, Y.-X.; An, Y.; Song, X.-L.; Wang, Y.-H.; Zhu, L.-L.; Guo, L. *Eur. J. Org. Chem.* **2009**, 5146–5152.
doi:10.1002/ejoc.200900858

40. Maury, J.; Feray, L.; Bertrand, M. P. *Org. Lett.* **2011**, *13*, 1884–1887.
doi:10.1021/ol200419x

41. Stüdemann, T.; Knochel, P. *Angew. Chem., Int. Ed. Engl.* **1997**, *36*, 93–95. doi:10.1002/anie.199700931

42. Stüdemann, T.; Ibrahim-Ouali, M.; Knochel, P. *Tetrahedron* **1998**, *54*, 1299–1316. doi:10.1016/S0040-4020(97)10226-5

43. Gourdet, B.; Lam, H. W. *J. Am. Chem. Soc.* **2009**, *131*, 3802–3803.
doi:10.1021/ja900946h

44. Normant, J. F.; Alexakis, A. *Synthesis* **1981**, 841–870.
doi:10.1055/s-1981-29622

45. Chinkov, N.; Tene, D.; Marek, I. *In Metal-Catalyzed Cross Coupling Reactions*, 2nd ed.; Diederich, D.; de Meijere, A., Eds.; Wiley-VCH: New York, 2004; p 395.

46. Denès, F.; Pérez-Luna, A.; Chemla, F. *Chem. Rev.* **2010**, *110*, 2366–2447. doi:10.1021/cr800420x

47. Marek, I. *Chem. Rev.* **2000**, *100*, 2887–2900. doi:10.1021/cr990288e

48. Harada, T.; Katsuhira, T.; Oku, A. *J. Org. Chem.* **1992**, *57*, 5805–5807.
doi:10.1021/jo00048a002

49. Harada, T.; Katsuhira, T.; Hara, D.; Kotani, Y.; Maejima, K.; Kaji, R.; Oku, A. *J. Org. Chem.* **1993**, *58*, 4897–4907. doi:10.1021/jo00070a027

50. Harada, T.; Katsuhira, T.; Hattori, K.; Oku, A. *Tetrahedron* **1994**, *50*, 7987–8002. doi:10.1016/S0040-4020(01)85284-4

51. Creton, I.; Marek, I.; Normant, J.-F. *Synthesis* **1996**, 1499–1508.
doi:10.1055/s-1996-4422

52. Deng, C.-L.; Song, R.-J.; Liu, Y.-L.; Li, J.-H. *Adv. Synth. Catal.* **2009**, *351*, 3096–3100. doi:10.1002/adsc.200900588

The ZnCl₂ catalyzed Conia–ene reaction of iodoalkynes that in principle involves a vinylidene zinc carbenoid intermediate has been reported here.

53. The Z configuration for the major isomer was determined by NOE experiments on isolated pure (Z)-4aa. An NOE signal (3%) was observed between the vinylic proton and the protons of the methylene group of the propyl chain α to the ester.

54. Yeh, M. C. P.; Knochel, P. *Tetrahedron Lett.* **1989**, *30*, 4799–4802.
doi:10.1016/S0040-4039(01)80511-6

55. Creton, I.; Rezaei, H.; Marek, I.; Normant, J. F. *Tetrahedron Lett.* **1999**, *40*, 1899–1902. doi:10.1016/S0040-4039(99)00090-8

56. Rezaei, H.; Marek, I.; Normant, J. F. *Tetrahedron* **2001**, *57*, 2477–2483. doi:10.1016/S0040-4020(01)00069-2

57. Rezaei, H.; Yamanoi, S.; Chemla, F.; Normant, J. F. *Org. Lett.* **2000**, *2*, 419–421. doi:10.1021/ol991117z

58. Fallis, A. G.; Forgione, P. *Tetrahedron* **2001**, *57*, 5899–5913.
doi:10.1016/S0040-4020(01)00422-7

59. Takahashi, K.; Honda, T. *Org. Lett.* **2010**, *12*, 3026–3029.
doi:10.1021/ol101034s

Zn-atom radical transfer is facilitated by coordination to a Lewis base. In the present case, the bromine atom may be coordinated to the dialkylzinc reagent and thereby activates it towards homolytic substitution. For a similar proposed coordination involving Sml₂, see this reference.

60. Even though the H-donor has not been identified, competitive H-atom transfer is a frequent side-reaction in the 1,4-addition/cyclization reaction of dialkylzincs with β-(propargyloxy)enoates, see references [37] and [38].

61. The stereochemical assignment was done on the basis of the comparison of the NMR data of 4ac and 4aa. Among others, the chemical shift (δ = 6.17 ppm) and coupling constant of the vinylic proton (J = 1.9 Hz) are indicative of the E-configuration.

## License and Terms

This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The license is subject to the *Beilstein Journal of Organic Chemistry* terms and conditions:
(http://www.beilstein-journals.org/bjoc)

The definitive version of this article is the electronic one which can be found at:
doi:10.3762/bjoc.9.28