Radical addition of ethers to terminal alkynes with high E-selectivity

Article abstract of DOI:10.1002/ejoc.200900858

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.200900858. Direct radical additions of ethers to terminal alkynes were investigated by using Me2Zn/O2 as radical initiator to afford 2-vinyl ether derivat

Full text of DOI:10.1002/ejoc.200900858

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900858
Radical Addition of Ethers to Terminal Alkynes with High E-Selectivity
Zili Chen,*[a] Yu-Xin Zhang,[b] Yan An,[a] Xin-Li Song,[a] Ya-Hui Wang,[a] Li-Li Zhu,[a] and
Lin Guo*[b]
Keywords: Radicals / Radical reactions / Hydrogen abstraction / Vinylzinc
Direct radical additions of ethers to terminal alkynes were
investigated by using Me2Zn/O2 as radical initiator to afford
2-vinyl ether derivatives with high E-selectivity, while re-
versed E/Z selectivity is obtained with Et3B/O2. Two competi-
tive pathways are suggested for the formation of vinyl radical
B: zinc-radical exchange (route a) followed by protonation
provides E-configuration products exclusively through Zn(II)
complexation. Hydrogen abstraction by vinyl radicals (route
b) yields mainly Z isomers.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
tion products after protonation, in which, Me2Zn plays
both as the mild radical initiator and as a Lewis acid com-
plexing ligand.[7] In the competitive minor pathway thereof,
the vinyl radical abstracts the ether α-hydrogen atom to
produce a mixture of low E/Z ratio products, which there-
fore, blemished otherwise perfect stereocontrol. To date, re-
ports upon intermolecular radical hydrogen abstraction
from sp3-hybrized C atoms by vinyl radical under the mild
conditions are very scarce to the best of our knowledge.[8]
Vinyl radical intermediates have been reported to react
with metallic reagents to give various metallic vinylides.[9]
However, only one recent result described of trapping vinyl
radicals with Me2Zn to provide vinylzinc derivatives for fur-
ther transformation.[4a] In this paper, we also demonstrate
that the in-situ generated vinylzinc intermediates can be
transformed into iodo-substituted analogs and Negishi cou-
pling products.
Introduction
Direct C–H functionalization via different synthetic
methods has been fruitfully developed in the past decades.
In this regard, radical approach has some significant advan-
tages in terms of its efficiency to transform saturated C–
H bonds and the mildness of the reaction conditions, and
therefore, is of particular importance in organic synthesis.[1]
α-Alkoxyalkyl radicals, generated through direct hydrogen
abstraction from ethers by a radical source, have been re-
ported to react with aldehydes, imines, amines, and elec-
tron-deficient alkenes to give heteroatom-containing com-
pounds of various structural characteristics and functional-
ities.[2–4] In the light of these achievements, we were inter-
ested to investigate the radical addition of ethers onto elec-
tron-deficient terminal alkynes, and to explore a potential
one-pot route leading to 2-vinyl ether derivatives.[3b,5]
To our delight, direct radical addition of ether onto ter-
minal alkynes afforded 2-vinyl ether derivatives with a high
degree of E-selectivity in Me2Zn/O2 condition.[6] When
Et3B/O2 was used as radical source, the corresponding
products were obtained with the reversed E/Z selectivities.
A series of deuteration experiments was then performed
to elucidate the reaction mechanism. Two competitive reac-
tion pathways, including routes a and b, ensued on the for-
mation of vinyl radical intermediate B. In the major path-
way (Me2Zn/O2 condition), vinylzinc intermediates, in-situ-
generated from vinyl radicals, gave exclusively E configura-
Results and Discussion
In preliminary studies, the reaction of THF and (3-chlo-
rophenyl)acetylene was chosen as model system to examine
various radical sources.[10] The optimal ratio of O2 to N2
(O2/N2 = 1:1000) was first identified. A series of experi-
ments was then performed,[11] and the results are shown in
Table 1.
It was found that 3 equiv. of dimethylzinc give mainly E-
3b in 24% yield (Table 1, entry 1) with a high E selectivity
(E/Z ≈ 13.5:1). 3 equiv. of diethylzinc provide E-3b in 18%
yield (Table 1, entry 2), along with small amounts of ethyl
adduct; 3 equiv. of triethylborane produce a mixture of E/
Z-3b (E/Z = 1:2.3) in 33% of yield (Table 1, entry 3). When
the amount of Me2Zn was increased to 5 equiv., the reac-
tion yield was improved to 41% (Table 1, entry 5). Pro-
[a] Department of Chemistry, Renmin University of China,
Beijing 100872, P. R. China
Fax: +86-10-62516660
E-mail: zilichen@ruc.edu.cn
[b] School of Chemistry and Environment, Beijing University of
Aeronautics and Astronautics,
Beijing 100083, P. R. China
E-mail: guolin@buaa.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900858.
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Radical Addition of Ethers to Terminal Alkynes
Table 1. Radical addition of THF onto (m-chlorophenyl)acetyl- chlorophenyl)acetylene with 8 mol-equiv. of dimethylzinc
ene.[a]
(added in three batches) in 4 mL of THF under a mixture
of O2/N2 atmosphere at room temperature for 8 h, to give
E-3b in 53% yield (Table 1, entry 6). Improving the equiva-
lent of Et3B, nevertheless, afforded the product in 60% yield
with reversed selectivity (Table 1, entry 4).
The scope and limitations of this reaction were then ex-
plored. As shown in Table 2, a series of aromatic alkynes
Entry Initiator (equiv.)[c] Temp./time [h]
Yield [%]
E/Z ratio[b]
readily reacts with several cyclic and acyclic ethers to pro-
vide the corresponding 2-vinyl ether derivatives. The reac-
tion of phenylacetylene with THF gives (E)-tetrahydro-2-
styrylfuran (3a) in 28% yield with E selectivity of 8.5:1
(Table 2, entries 1). The presence of electron-withdrawing
groups, such as chloro, bromo and fluoro attached to the
aromatic alkynes enhances the reactivity and improves the
yields somewhat (Table 2, entries 2–12). The products’ E/Z
selectivity varies with different substitution patterns on the
aryl groups.[12] For example: the E/Z selectivity for the reac-
tion of (p-bromophenyl)acetylene with THF is about 7:1
(Table 2, entries 6), while the reaction of THF with (m-chlo-
rophenyl)- and (p-fluorophenyl)acetylene gives products
1
2
3
4
Me2Zn (3)
Et2Zn (3)
Et3B (3)
Et3B (5)
Me2Zn (5)
Me2Zn (8)
r.t./5
r.t./5
r.t./5
r.t./5
r.t./5
r.t./8
24
18
33
60
41
53
13.5:1[f]
5.6:1
1:2.3
1:2.3
Nd[e]
20:1
5
6[d]
[a] Unless noted, all reactions were carried out at 0.2 mmol scale
in 4 mL of THF under a mixture of O2/N2 atmosphere at room
temp. [b] E/Z ratio was determined by H NMR spectrum of the
crude product. [c] Me2Zn was added in two batches. [d] Me2Zn was
added in three batches. [e] Nd = not determined. [f] E/Z ratio in
Me2Zn condition ranged from 25% to 10%.
1
longing the reaction time and lowering the reaction tem- with a selectivity of 20:1 and 29:1, respectively (Table 2, en-
perature turned out to be disadvantageous. Further studies tries 2, 10). However, the E/Z selectivity for the reaction of
then identified the optimal condition to be 0.2 mmol of (3- (3,4-dichlorophenyl)acetylene and (2,4-difluorophenyl)-
Table 2. Addition of cyclic and acyclic ethers onto the terminal aromatic alkynes initiated by Me2Zn.[a]
Entry
1
Ether 2
Product
Yield [%]
E/Z[b]
1
2
3
4
1a
1b
THF
THF
THP
1,3-dioxolane
3a
3b
4b
5b
6b
7b
3c
4c
5c
6c
7c
3d
3e
3f
28
53
39
8.5:1
20:1
13:1
13.5:1
9.5:1
Ͼ99:1
7:1
16.5:1
3:1
3.5:1
Ͼ99:1
29:1
14:1
8.5:1
63 (3.7:1)
5
6
7
8
diethyl ether
THF
THP
41
51
40
56 (4:1)
1c
1,3-dioxolane
9
diethyl ether
THF
THF
47
43
37
35
10
11
12
1d
1e
1f
THF
[a] Unless noted, all reactions were carried out at 0.2 mmol scale with 8 molar equiv. of dimethylzinc (added in three batches) in 4 mL
1
of THF under a mixture of O2/N2 atmosphere at room temperature (summer) for 8 h. [b] The E/Z ratio was determined by H NMR
spectrum of the crude products.
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Z. Chen, L. Guo et al.
SHORT COMMUNICATION
acetylene is only 8.5:1 and 14:1 (Table 2, entries 11, 12). It with less than 1% D into Z-3b (Scheme 1). In the reaction
was also found that the reaction of THF with (p-ni- of (3,4-dichlorophenyl)acetylene with THF, the deuterium
trophenyl)acetylene does not lead to desired products.[13]
atom ratio in E-3f was only 41%, and with 0% D incorpo-
Cyclic ethers other than THF and acyclic ether are also rated in Z-3f (E/Z = 8:1).
applicable in the reaction. 1,3-Dioxolane reacts with 1b to
The following plausible mechanism is proposed: as
afford 5b/6b (5b/6b = 3.7:1, Table 2, entries 4)[14] in a total shown in Scheme 2, a methyl radical, generated in-situ from
yield of 63%, and with a E/Z selectivity of 13.5:1 and 9.5:1, dimethylzinc by a trace amount of oxygen, abstracts the 2-
and with 1c to afford 5c/6c (5c/6c = 4:1, Table 2, entries 8) H of the ether reactant 2 to provide an α-alkoxy radical
in 56% yield with a E/Z selectivity of 3:1 and 3.5:1. THP intermediate A, which then undergoes a direct radical ad-
reacts with 1b to give 4b in 39% yield (E/Z = 13:1, Table 2, dition onto terminal alkyne 1 to form a new C–C bond and
entries 3), and with 1c to give 4c in 40% yield (E/Z = 16.5:1, a vinyl radical intermediate B. In the major reaction path-
Table 2, entries 7). Linear ethers were also investigated. For way, trapping of the intermediate B with Me2Zn produces
example, diethyl ether reacts with 1b and 1c to afford 7b in an alkenylzinc intermediate C (route a)[4a,15] and a methyl
41% yield and 7c in 47% yield with E selectivity up to 99:1 radical for further reaction. Quenching the reaction with
(no Z-isomer was detected in the reaction mixture, Table 2, water or possible zinc-proton exchange with terminal al-
entries 5, 9).
kyne 1 provides the desired 2-vinyl-substituted ether deriva-
Deuteration experiments were performed to probe the re- tive 3. The complexation of ZnII with the oxygen atom of
action mechanism. As shown in Scheme 1, when the reac- the ether in the intermediate C, as illustrated in Scheme 2,
tion of (m-chlorophenyl)acetylene (1b) in THF was leads to the formation of the E-alkenyl ether products.
quenched with 99% D2O, deuterated E/Z-3b was readily
The existence of the alkenylzinc intermediate C was
obtained in 50% yield (E/Z = 15:1). It was found that 87% partly proved by deuteration experiments (Scheme 1), in
deuterium atom was incorporated into E-3b at C2 position, which, intermediate C was eventually caught by D2O to af-
[a]
Scheme 1. Experiments of quenching the reaction with D2O.
corresponding products.
The deuterium ratio was determined by 1H NMR spectrum of the
Scheme 2. A plausible mechanism to afford E/Z configuration 2-vinyl ether derivatives.
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Radical Addition of Ethers to Terminal Alkynes
ford E configuration products with high deuterium content.
Experiments to trap intermediate C with other electro-
Interestingly, some of the C2-H remained in deuterated E- philes were also performed. When the reaction mixture of
3b and E-3f, maybe as a result of zinc-proton exchange of THF radical with (m-chlorophenyl)acetylene was treated
intermediate C with terminal alkyne 1, or with trace with iodine, an iodo-substituted analog 8 was obtained in
amounts of water in the reaction mixture.[16]
45% yield (Scheme 4).[19] Negishi coupling of intermediate
The results in Scheme 1 show that no deuterium atoms C with iodobenzene affords the corresponding product 9 in
are incorporated into Z configuration isomers, which im- 30% yield.[19,20]
plies that route b affords E-configuration products exclu-
sively. We speculate that Z-isomers might be generated from
the alternative route b. As shown in Scheme 2, abstraction
of a hydrogen atom of the ether reactant 2 by the vinyl
radical intermediate B regenerates the α-alkoxy radical A,
and provides the product 4 in low E/Z selectivity.[17] The
tendency of the reaction to take the minor pathway (route
Scheme 4. Experiments of trapping intermediate C with different
electrophiles.
b) would be enhanced by the high reactivity of the 2-posi-
tion hydrogen atom of the ether reactants 2. The existence
of route b was partly proved by deuterium experiments and
We then turn to investigate the reaction details of the
by the relative low E/Z selectivity in the reaction of dioxol- route b by using Et3B/O2 Radical source. The reaction of
ane, THF and the high E/Z selectivity in the reaction of (m-chlorophenyl)acetylene with THF in the condition of
ethyl ether.[18]
5 equiv. Et3B afforded 3b in 60% yield with a reversed E/Z
To evaluate the extent of the zinc-proton exchange be- selectivity (E/Z = 1:2.3, Scheme 5). Quenching the reaction
tween intermediate C and terminal alkyne 1, the reaction with I2 enhanced the Z/E ratio (E/Z = 1:3.8).[21] The reac-
of deuterated (3,4-dichlorophenyl)acetylene (over 99% deu- tion of (p-bromophenyl)acetylene in THF gave similar re-
terium atom attached to the terminal alkyne C atom) in sults. The major products – (Z) configuration vinyl ethers in
THF was carried out by using Me2Zn as radical source. this case, were primarily resulted from hydrogen-abstracting
The reaction was quenched by deuterated water. As shown route b. Addition of I2 quenched the E configuration vinyl-
in Scheme 3, about 79% deuterium was incorporated into borane intermediates generated in route a, and then im-
C2 position of E-3f-d, while no deuterium was detected in proved the Z isomer ratio. The reaction of diethyl ether with
C2 position of compound Z-3f-d. If the reaction was 1b, which gave no Z-isomer in Me2Zn/O2 condition, be-
quenched by H2O, 20% deuterium was attached to C2 posi- cause of low reactivity of its 2-position hydrogen, yielded a
tion of E-3f-d. These results suggest that the reaction of mixture of products in a low E/Z ratio with a reduced yield.
intermediate C with terminal alkyne 1 produces unreacted
zinc alkynylide in the reaction mixture and thus reduces the ture of 90% [D8]THF and 10% THF was performed by
yield. employing Et3B/O2 in order to determine the source of the
The reaction of (m-chlorophenyl)acetylene with a mix-
Scheme 3. The reaction of deuterated (3,4-dichlorophenyl)acetylene with THF.
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Z. Chen, L. Guo et al.
SHORT COMMUNICATION
[b]
Scheme 5. Experiments with Et3B/O2 as radical initiator. [a] Et3B was added in two batches; quenching the reaction with NH4Cl (aq.);
[c]
[d]
1
quenching the reaction with I2; The E/Z ratio was determined by H NMR spectrum of the crude products.
hydrogen atom abstracted by intermediate C in route b vinyl radicals in route b. Route b competes with route a, as
(Scheme 2).[22,23] It was found that 25% deuterium atom a minor pathway for the Me2Zn/O2 system and as a major
was incorporated into C2 position of E-3b-d, while about one for Et3B/O2 conditions.
27% percent deuterium into C2 position of compound Z-
We assume that ether reactants, as indicated in Scheme 7,
3b-d (Scheme 6). These results indicate that the ether reac- readily approach the vinyl radical intermediate B from the
tants can act as source for hydrogen atoms abstracted by opposite direction of the ether functionality in route b.[24,25]
This might explain why mainly Z configuration products
are observed for Et3B/O2 reaction conditions.
Conclusions
We have investigated the direct radical addition of a vari-
ety of cyclic and acyclic ethers onto terminal alkynes,
which, by using Me2Zn/O2 as radical initiator, afford a
series of 2-vinyl ether derivatives with a high degree of E-
selectivity. With Et3B/O2 as radical source the correspond-
ing products are obtained with reversed E/Z selectivity. Two
competitive reaction pathways ensue over the formation of
vinyl radical intermediate B. Zinc-radical exchange (route
a) produces the alkenylzinc intermediate C, in which ZnII
acts as a Lewis acid ligand, chelating with the ether oxygen
atom to control the alkene’s configuration, and to provide
E-configuration products exclusively after protonation.
However, hydrogen abstraction from the ether by the vinyl
radical (route b) would instead give mainly the Z configura-
tion isomers.
Scheme 6. The reaction of (m-chlorophenyl)acetylene with 90%
[a]
deuterated [D8]THF and 10% THF.
from Et3B (THF solution).
10% THF solvent come
Experimental Section
General Procedure for the Radical Addition of Ethers Onto Terminal
Alkynes: A 1.0  solution of dimethylzinc in hexane (0.6 mL,
0.6 mmol, 3.0 equiv.) was added to a solution of (m-chlorophenyl)
acetylene (1b) (27 mg, 0.20 mmol) in THF (4 mL, 50 mmol,
250 equiv.) under a mixture of O2/N2 atmosphere (O2/N2 = 1:1000)
at room temperature. 3 h later, another batch of dimethylzinc solu-
tion (0.6 mL, 0.6 mmol) was added. 6 h later, the third batch of
dimethylzinc solution (0.4 mL, 0.4 mmol) was added. After stirred
at room temp. for 8 h, the reaction mixture was quenched by the
addition of saturated NH4Cl solution, and then was extracted with
dichloromethane (3ϫ5 mL). Combined organic layer was washed
with saturated aqueous sodium hydrogen carbonate, brine, and
Scheme 7. Possible explanation for the observed Z-selectivity in
route b.
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Radical Addition of Ethers to Terminal Alkynes
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Prolonged reaction time resulted in low yields of products, so
small amounts of O2 was added to the system in order to accel-
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Although intermediate B can be stabilized by the electron-with-
drawing groups, the effect of different substitution on E/Z
selectivity is still unclear.
This might be owing to the formation the zinc alkynilide
through the zinc-proton exchange between (p-nitrophenyl)
acetylene and Me2Zn.
Position 2 in 1,3-dioxane is much more reactive than position
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Intermediate C can be decomposed by oxygen gas. Keeping the
reaction mixture in the dry air for 30 min, most of the formed
product was decomposed.
Alkyne 1 can not be consumed to the completion, might be-
cause of the zinc-proton exchange of alkyne 1 with intermedi-
ate C, or with Me2Zn; a) T. M. Bertrand, G. Courtois, L. Mig-
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Hydrogen abstraction by vinyl radical has been reported be-
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ides has been proposed; see ref. [4].
Ring size effects on alkyl radical reactivity: P. J. Kropp, J. Am.
Chem. Soc. 1969, 91, 5783.
A small amount of E/Z-3b were also detected in the reaction
mixture. See Supporting Information.
For reviews on Negishi coupling: a) E.-I. Negishi, J. Or-
ganomet. Chem. 2002, 34, 653; b) E.-I. Negishi, Acc. Chem.
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dried with sodium sulfate. After removal of the solvent, purification
of the resulting crude material by column chromatography (petro-
leum ether/ethyl acetate = 80:1) afforded the desired product E-3b
(22 mg, 53%).
Supporting Information (see also the footnote on the first page of
this article): All reaction procedures and spectroscopic data for the
products.
[7]
[8]
Acknowledgments
Support of this work by grants from the National Sciences Founda-
tion of China (20502033 and 20872176) is gratefully acknowledged.
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[22]
This reaction can not be quenched by D2O.
It was found that [D8]THF radical can not be generated di-
rectly by ethyl radical. However, this can be obtained by ad-
dition of a small amount of THF to the solvent [D8]THF.
Me2Zn/O2 system was also tested, but no Z-isomer was ob-
tained; see Supporting Information.
[23]
[6] For reviews on stereocontrol in radical reaction, see: a) D. P.
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Received: July 29, 2009
[25] It was suggested by a referee of this article that the preferential
formation of the Z adduct might as well involve two sp2-iso-
meric radicals (going through an sp intermediate). For some
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Trofimov, N. K. Gusarova, S. N. Arbuzova, N. I. Ivanova, A. V.
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Published Online: September 15, 2009
5152
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5146–5152