Conjugated enyne synthesis by rearrangement of acetylenic epoxides mediated by low-valence organotitanium and organozirconium reagents

Article abstract of DOI:10.1055/s-0032-1316894

The rearrangement of acetylenic epoxides mediated by low-valence organotitanium and organozirconium reagents is -reported to give conjugated enynes. Moderate to good yields and high selectivities are obtained when using the organozirconium(II) Negishi rea

Full text of DOI:10.1055/s-0032-1316894

LETTER
▌1001
lCettoernjugated Enyne Synthesis by Rearrangement of Acetylenic Epoxides
Mediated by Low-Valence Organotitanium and Organozirconium Reagents
Conjugated Enyne Synthesis
Aurélien Denichoux, Mathieu Cyklinsky, Fabrice Chemla,* Franck Ferreira,* Alejandro Pérez-Luna
Université Pierre et Marie Curie-Paris 6, UMR CNRS 7201, Institut Parisien de Chimie Moléculaire, Institut de Chimie Moléculaire (FR 2769),
Case 183, 4 place Jussieu, 75252 Paris Cedex 05, France
Fax +33(144)277567; E-mail: fabrice.chemla@upmc.fr; E-mail: franck.ferreira@upmc.fr
Received: 10.01.2013; Accepted after revision: 17.03.2013
R1
Y = H (Sonogashira)
Y = TMS (Hiyama)
Y = ZnBr (Negishi)
Abstract: The rearrangement of acetylenic epoxides mediated by
low-valence organotitanium and organozirconium reagents is
reported to give conjugated enynes. Moderate to good yields and
high selectivities are obtained when using the organozirconium(II)
Negishi reagent in toluene at 20 °C; whereas only poor yields and
low selectivities are achieved with the organotitanium(II) Sato re-
agent. The process is stereospecific and involves formation of tita-
na- and zirconacyclopropenes by oxidative insertion of the low-
valence titanium and zirconium reagents into the carbon–carbon tri-
ple bond of the acetylenic epoxides. These metallacyclopropenes
then rearrange to afford stereodefined propargylmetals through the
epoxide ring-opening. Conjugated enynes are finally produced by
β-elimination of metal oxide.
X
+
+
R1
Y
R2
Pd(0)
Y = MgBr (Kumada–Corriu)
X = halide
R1
X
M
R2
M = SnBu3 (Stille)
M = BR2 (Suzuki)
R2
Cu
R2
+
X
(X = I, Br)
R1
+ R1CHO
MeO
CCl3
TBS
R1
Ph3P
HO
R2
I
Key words: elimination, enynes, rearrangement, titanium, zirconi-
um
R1
R1
R2
R2
Scheme 1 Common syntheses of conjugated enynes
The conjugated enyne motif is largely widespread in nat-
ural products and has been intensively exploited in syn-
thesis. The methods most commonly used for its synthesis
utilize palladium(0)-catalyzed C(sp2)–C(sp) cross-cou-
plings between vinylic and acetylenic partners (Scheme
1). All these methods generally involve the cross-coupling
of a vinyl halide with a terminal alkyne (Sonogashira cou-
pling),1,2 an alkynylsilane (Hiyama coupling),3 an al-
kynylzinc (Negishi coupling),1 or an alkynyl Grignard
reagent (Kumada–Corriu coupling).1,4 The cross-cou-
plings of a vinylstannane (Stille coupling)5 or a vinylbo-
rane (Suzuki coupling)6 with an alkynyl halide are also
efficient means to access conjugated enynes. Other less
employed metal-catalyzed cross-coupling reactions are
also described in the literature.7–10
During the past decade, we have developed a stereoselec-
tive route to acetylenic epoxides and aziridines by reac-
tion of allenylzinc reagents with carbonyl derivatives and
imines, respectively.15 Inspired by previous work on the
preparation of conjugated dienes by zirconocene-mediat-
ed deoxygenation of vinyl epoxides,16 we reasoned that
acetylenic epoxides and aziridines could be precursors to
conjugated enynes by reaction with low-valence metals
such as the organotitanium(II) Sato reagent [formally a
(i-PrO)2Ti·propylene complex]17 or the organozirconi-
um(II) Negishi reagent [formally a Cp2Zr·(1-butene) com-
plex].18 The oxidative insertion of these low-valence
metallic complexes into the carbon–carbon triple bond of
All these metal-catalyzed cross-couplings require the use acetylenic epoxides and aziridines was anticipated to give
of stereomerically pure vinylic precursors, constituting titana- and zirconacyclopropenes that could undergo het-
the main obstacle to their application in the stereoselective erocycle ring-opening.19 This would result in the forma-
synthesis of Z conjugated enynes. Alternative methods in- tion of allenyltitanium and allenylzirconium species that
clude the reaction of a Z-alkenylcopper reagent with an al- are in equilibrium with their respective propargylic
kynyl iodide or bromide,11 a sequence that combines the forms.20 Finally, β-elimination of metal oxo or imido
Wittig olefination reaction using 3,3,3-trichloropropyli- complexes was expected to afford the corresponding con-
dene-1-triphenylphosphorane with the Corey–Fuchs rear- jugated enynes (Scheme 2).
rangement,12 Peterson syn β-elimination of propargylic β-
We initiated our studies with prototypical trans-acetylenic
hydoxysilanes,13 and n-BuLi-induced syn β-elimination
epoxide 1a that was reacted with Sato reagent generated
of propargylic iodohydrin derivatives.14
in situ from (i-PrO)4Ti (1 equiv) and i-PrMgX (2 equiv)
for 30 minutes at –80 °C. Gratifyingly, regardless of the
reaction conditions employed, conjugated enyne 2a was
SYNLETT 2013, 24, 1001–1005
Advanced online publication: 28.03.2013
DOI: 10.1055/s-0032-1316894; Art ID: ST-2013-D0034-L
© Georg Thieme Verlag Stuttgart · New York
formed, albeit in moderate yields with poor E/Z selectivi-
ties (Scheme 3). In all cases, unidentified by-products
were observed. Their formation was explained by the re-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1002
A. Denichoux et al.
LETTER
X
(i-PrO)2Ti
(1 equiv)
R2
R1
X
O
O
R2
ref. 15
L2M(II)
R1
H
TMS
ZnBr
c-Hex
c-Hex
c-Hex
•
TMS
TMS
Cl
1a
Ti(Oi-Pr)2
TMS
OMgX
OMgX
H
X
H
R2
R1
X
anti
TMS
H
R2
R1
ML2
c-Hex
•
•
TMS
ring-opening
H
ML2
TMS
Ti(Oi-Pr)3
H
Ti(Oi-Pr)3
3
TMS
X
4
c-Hex
anti
R1
R2
ML2
β-elimination
– ML2X
R2
R1
β-elimination
– TiO(Oi-Pr)2
– MgX(Oi-Pr)
(E)-2a
TMS
TMS
TMS
4
X = O, NR
R1, R2 = H, alkyl, alkenyl, aryl
O
Ti(Oi-Pr)3MgCl
syn
β-elimination
L2M(II) = organotitanium(II) Sato or organozirconium(II)
Negishi reagents
c-Hex
c-Hex
– TiO(Oi-Pr)2
– MgX(Oi-Pr)
TMS
(Z)-2a
5
Scheme 2 Our work
TMS
Scheme 4 Mechanism of the reaction of 1a with Sato reagent
action of enyne 2a with the Sato reagent that is indeed re-
ported to be prone to react with conjugated enynes
through the formation of enyne–titanium complexes.21
thus undergo the syn β-elimination of titanium oxide to af-
ford conjugated enyne (Z)-2a.
Encouraged by the results obtained with the Sato reagent,
we next examined the use of the Negishi reagent. Under
optimized conditions, this reagent is preformed by adding
n-BuLi (2 equiv) at –80 °C to a solution of Cp2ZrCl2
(1 equiv). This first leads to Cp2Zr(n-Bu)2 then finally
gives the desired organozirconium(II) reagent after an ad-
ditional one hour stirring at –20 °C (Scheme 5).23
+
(i-PrO)4Ti
i-PrMgX (X = Cl, Br, I)
(2 equiv)
(1 equiv)
Et2O or CH2Cl2 or THF or toluene
–80 °C, 30 min
c-Hex
(i-PrO)2Ti
O
(1 equiv)
c-Hex
TMS
–45 °C or 20 °C
1a
TMS
2a, 29–73%
E/Z = 26:74 to 88:12
Cp2ZrCl2
(x equiv)
+
n-BuLi
(2x equiv)
solvent, –80 °C
then –20 °C, 1 h
Scheme 3 Reaction of 1a with Sato reagent
Although unsatisfactory both in terms of yield and selec-
tivity, the results obtained with the Sato reagent validated
our approach to conjugated enynes based on the rear-
rangement of acetylenic epoxides mediated by low-
valence metal species. The epoxide ring-opening thus
should occur in an anti manner subsequently to oxidative
addition of the organotitanium(II) reagent. This could af-
ford allenyltitanium 3 stereoselectively in equilibrium
with the propargylic isomer 4 (Scheme 4).
O
c-Hex
Cp2Zr
(x equiv)
c-Hex
TMS
solvent, –20 °C
then 20 °C, 1 h
(E)-2a
1a
TMS
TMS
OLi
O
ZrCp2⋅LiCl
H
c-Hex
through
TMS
H
c-Hex
ZrCp2Cl
7
6
The organotitanium species so formed should be configu-
rationally stable as previously reported in the analogous
reaction of substrates bearing leaving groups at the
propargylic position.22 At this point, the direct anti β-
elimination of titanium oxide could take place giving con-
jugated enyne (E)-2a. The β-elimination could be favored
in the presence of magnesium salts (MgX2) produced in
situ that could coordinate to the oxygen atom of the alkox-
ide moiety. On the other hand, because of the high oxophi-
licity of the titanium(IV) species, cyclic magnesium
organotitanate 5 may be produced through free rotation
around the σ carbon–carbon bond. Intermediate 5 could
Scheme 5 Reaction of 1a with Negishi reagent (see Table 1)
Thus, when reacting 1a with the preformed Negishi re-
agent (1 equiv) at 0 °C or below, conjugated enyne 2a was
isolated in very low yields regardless the solvent, even
though excellent stereoselectivities were achieved in fa-
vor of the E-isomer (Table 1, entries 1–3). Under these
conditions, degradation was observed to some extent. By
contrast, carrying out the reaction at 20 °C allowed 2a to
be produced in reasonable yields within one hour (Table
1, entries 4–6). Although in all cases excellent E/Z ratios
were attained, only the use of toluene as solvent afforded
Synlett 2013, 24, 1001–1005
© Georg Thieme Verlag Stuttgart · New York

LETTER
Conjugated Enyne Synthesis
1003
The optimized conditions in Table 1 [i.e., Negishi reagent
(0.8 equiv), toluene, 20 °C, 1 h], were next applied to a va-
riety of readily available trans-acetylenic epoxides 1
(Scheme 6).15
Table 1 Reaction of 1a with Negishi Reagent (See Scheme 5)
Entry Solvent
Temp (°C) Equiv (x) E/Za
Yield (%)b
1
2
3
4
5
6
7
8
9
THF
–20
0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
0.8
1.0
92:08
–
9 (23)
0 (47)
Et2O
toluene
THF
–20
20
20
20
20
20
20
>98:02
86:14
89:11
>98:02
>98:02
>98:02
87:13
6 (16)
Cp2Zr
R1
O
(0.8 equiv)
55 (83)
64 (97)
48 (96)
25 (62)
64 (84)c
63 (86)
R1
R2
TMS
R2
toluene, –20 °C
then 20 °C, 1 h
Et2O
1a–h
(E)-2a–h
TMS
toluene
toluene
toluene
Et2Od
Scheme 6 Synthesis of (E)-2a–h from 1a–h (see Table 2)
With all disubstituted epoxides, excellent E-selectivities
were observed. Yields of conjugated enynes 2 were good
with epoxides possessing alkyl substituents even though a
low yield was obtained in the case of the tert-butyl group
mainly due to the volatility of the product (Table 2, entries
1–4). Epoxides bearing ethenyl or aromatic substituents
afforded the corresponding conjugated enynes in slightly
lower yields (Table 2, entries 5 and 6). In contrast, when
trisubstituted epoxides were used, significantly lower iso-
lated yields were obtained (Table 2, entries 7 and 8).
a Selectivities were determined by 1H NMR analysis at 400 MHz of
the crude materials.
b Isolated yields. In parenthesis are given the conversions into 2a
based upon recovered 1a.
c Isolated yield and conversion relative to 0.8 equiv of Negishi re-
agent.
d Reaction was conducted with Cp2TiCl2.
complete selectivity in favor of the E-isomer. Increasing
the amount of Negishi reagent to 1.2 equivalents relative
to 1a resulted in a significantly lower yield (Table 1, entry
6 vs. entry 7). This result can be explained by the polym-
erization of 2a by the excess organozirconium(II) species
via carbozirconation of the carbon–carbon triple bond of
2a giving zirconacyclopentenes.24 Conversely, employing
only 0.8 equivalent of Negishi reagent furnished E-conju-
gated enyne 2a as the sole product and with an improved
isolated yield of 64% (Table 1, entry 8).
Table 2 Synthesis of (E)-2a–h from 1a–h (See Scheme 6)27
Entry Epoxide R1
R2
Enyne E/Za
Yield
(%)b
1
2
3
4
5
6
7
8
1a
1bc
1c
1d
1e
1f
c-Hex
n-Bu
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
>98:02
62
67
68
30d
55
45
37
30
93:07
>98:02
>98:02
>98:02
>98:02
–
Ph(CH2)2
t-Bu
Interestingly, in all cases better selectivities were ob-
served with the Negishi reagent than with the Sato re-
agent. This could be first rationalized by comparing the
hardness of the acidic metallic(IV) centers in 4 and 6. Ti-
tanium(IV) is intrinsically a harder Lewis acid than zirco-
nium(IV).25 Accordingly, zirconium(IV) in 6 could be
less likely to coordinate to the alkoxide (a hard base) as ti-
PhCH=CH
Ph
1g
1h
n-Pent
Ph
n-Pent 2g
Ph 2h
–
a Selectivities were determined by 1H NMR analysis at 400 MHz of
tanium(IV) in 4. As a consequence 6 should be less prone the crude materials.
b Isolated yields relative to 0.8 equiv of Negishi reagent.
to give the Z-isomer through cyclic zirconium intermedi-
ate 7. However, the nature of the ligands on the metals
could also play a role in these reactions.26 To gain insight
on the influence of both the metal and the ligand on the
stereochemical outcome of the rearrangement, the reac-
tion was thus performed with the titanium analogue of the
Negishi reagent [formally the Cp2Ti·(1-butene) complex]
generated from Cp2TiCl2. At 20 °C in Et2O the conjugated
enyne 2a was isolated in 63% yield and with an E/Z ratio
of 87:13 (Table 1, entry 9). This result was significantly
different from the ratio of 67:33 obtained with the Sato re-
agent under the same conditions, but very close to the
89:11 ratio obtained with the Negishi reagent. This result
suggests that it is not the metal as such, but the nature of
the ligand which is important in the stereochemical out-
come of the rearrangement.
c Ratio (trans/cis) = 92:08.
d Volatile product.
In order to gain further insight into the stereochemical
outcome of the rearrangement mediated by the Negishi re-
agent, we carried out the reaction starting from epoxide
cis-1a. Interestingly, under the optimized conditions, con-
jugated enyne (Z)-2a was isolated in good yield and with
a high selectivity of 93:7 perfectly reflecting the initial
92:8 cis/trans ratio of 1a (Scheme 7). All these results
suggest that the zirconium(II)-mediated rearrangement is
stereospecific, with acetylenic trans- and cis-epoxides
giving E- and Z-isomers, respectively. As in the case of
the Sato reagent, the ring-opening of the epoxide moiety
should thus occur in an anti-fashion affording configura-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1001–1005

1004
A. Denichoux et al.
LETTER
tionally stable propargylzirconiums 6 and 8 that undergo
the anti β-elimination of zirconium oxide.
Acknowledgment
The authors kindly thank the MESR for PhD grants to A.D. and
M.C.
Cp2Zr
References and Notes
O
(0.8 equiv)
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c-Hex
cis-1a
c-Hex
TMS
toluene, –20 °C
then 20 °C, 1 h
TMS
(Z)-2a
58%, Z/E = 93:7
cis/trans = 92:8
OLi
H
– ZrOCp2
– LiCl
1a
c-Hex
TMS
(E)-2a
(Z)-2a
H
ZrCp2Cl
6
Cp2Zr
(0.8 equiv)
OLi
– ZrOCp2
– LiCl
c-Hex
ZrCp2Cl
H
TMS
H
cis-1a
8
Scheme 7 Stereospecificity of the rearrangement
(7) For palladium(0)- and nickel(0)-catalyzed cross-couplings
of zinc reagents with 1,2-vinylic tellurides, see:
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The method was next applied to acetylenic aziridines. Us-
ing N-H or N-Bz aziridines with the Sato or Negishi re-
agents failed to produce conjugated enynes. With N-tert-
butylsulfinyl and N-tert-butylsulfonyl aziridines, the de-
sired products were isolated in moderate 32–39% yields
and with low E-selectivities of ≤70:30. In fact, only N-Bn
aziridines were found to give E-conjugated enynes with
high selectivities, albeit in very poor isolated yields, as il-
lustrated with 9 that furnished 10 in 20–26% yield and
with a selectivity of ≥94:6 under optimized conditions
(Scheme 8).
(10) For cobalt(II)-catalyzed cross-couplings of vinyltriflates
with alkynyl Grignard reagents, see: Shirakawa, E.; Sato, T.;
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1980, 36, 1215.
Ph
Bn
Cp2Zr
2
N
(0.8–1.2 equiv)
2
TMS
Ph
THF or toluene, –20 °C
then 20 °C, 1 h
TMS
9
10, 20–26%
E/Z = 94:6 to >98:2
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Xu, G.; Pierce, M. E.; Fortunak, J. M.; Confalone, P. N. J.
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Scheme 8 Reaction of 9 with Negishi reagent
In conclusion, the synthesis of conjugated enynes by the
reaction of acetylenic epoxides and aziridines with low-
valence organotitanium(II) and organozirconium(II) re-
agents has been investigated. Only the reaction employing
the Cp2Zr·(1-butene) complex (Negishi reagent) and acet-
ylenic epoxides has been fully satisfactory in producing
di- and trisubstituted aliphatic and aromatic conjugated
enynes, both in terms of reactivity and stereoselectivity.
Using 0.8 equivalent of the Negishi reagent for one hour
in toluene at 20 °C permitted stereospecific access to E- or
Z- conjugated enynes from trans- and cis-acetylenic epox-
ides, respectively, in good yields and with complete selec-
tivities.
Synlett 2013, 24, 1001–1005
© Georg Thieme Verlag Stuttgart · New York

LETTER
Conjugated Enyne Synthesis
1005
(18) (a) Negishi, E.; Huo, S. In Titanium and Zirconium in
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(25) Because the ionization potential of a reagent is usually
substantially larger than its electron affinity, the value of the
ionization potential makes the dominant contribution to the
hardness. Ti4+ is thus a harder Lewis acid than Zr4+ due to its
higher value of ionization potential (99 eV for Ti4+and 80 eV
for Zr4+).
(26) The hardness of metallic(IV) centers in 4 and 6 can be
influenced by the nature of their ligands, i.e. i-PrO– (a hard
base) for titanium(IV) and and Cp– (a soft base) for
zirconium(IV). The steric hindrance generated by Cp– could
also decrease the oxophilicity of the zirconium in 6. See:
Ayers, R. G.; Pearson, R. G. J. Chem. Phys. 2006, 124,
194107.
(27) Representative Procedure for the Preparation of 2a–h;
Preparation of 2e: To a solution of Cp2ZrCl2 (117 mg, 0.40
mmol) in anhyd toluene (4 mL) was added dropwise n-BuLi
(2.20 M in hexanes, 0.36 mL, 0.80 mmol) at –80 °C. The
resulting mixture was warmed to –20 °C and stirred for 1 h
at this temperature. Epoxide 1e (121 mg, 0.50 mmol) was
then added and the mixture was immediately warmed to 20
°C. After 1 h of stirring at 20 °C, the reaction was quenched
with aq 0.5 M HCl. The layers were separated, and the
aqueous phase was extracted with Et2O (2 ×). The combined
organic layers were washed with H2O, then brine, dried over
anhyd MgSO4 and filtered through a plug of silica gel.
Removal of the solvent and purification by flash
chromatography (silica gel, pentane) afforded conjugated
enyne 2e (50 mg, 55%) as a colorless oil. Analytical data
were in agreement with those reported (see ref. 28).
(28) Ni, Z.-H.; Luh, T.-Y. Org. Synth. 1992, 70, 240.
(24) Zhou, Y.; Chen, J.; Zhao, C.; Wang, E.; Liu, Y.; Li, Y.
J. Org. Chem. 2009, 74, 5326.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1001–1005

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