Transmetalation of Alkylzirconocenes in Copper-Catalyzed Alkyl–Alkynyl Cross-Coupling Reactions

Article abstract of DOI:10.1002/adsc.201700164

A simple copper-catalyzed alkyl–alkynyl cross-coupling strategy has been developed using the reaction between alkynyl bromides and alkylzirconocenes. The alkylzirconocenes were generated in situ via regioselective addition of Schwartz's reagent (ZrCp₂HCl) on to alkenes. The reaction has a broad scope, a range of functionalized bromoalkynes and alkylzirconium reagents were successfully coupled, resulting in moderate to good yields of the desired internal alkynes. (Figure presented.).

Full text of DOI:10.1002/adsc.201700164

Title: Transmetalation of Alkylzirconocenes in Copper-Catalyzed Alkyl–
Alkynyl Cross-Coupling Reactions
Authors: Kiran Indukuri and Olivier Riant
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10.1002/adsc.201700164
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Transmetalation of Alkylzirconocenes in Copper-Catalyzed
Alkyl–Alkynyl Cross-Coupling Reactions
Kiran Indukuria and Olivier Rianta*
a
Institute of Condensed Matter and Nanosciences, Molecules, Solids and Reactivity (IMCN/MOST), Universitꢀ
catholique de Louvain, Place Louis Pasteur 1, bte L4.01.02, 1348 Louvain-la-Neuve, Belgium.
Fax: +32 10 47 41 68; e-mail: olivier.riant@uclouvain.be
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A simple copper-catalyzed alkyl-alkynyl cross- bromoalkynes and alkylzirconium reagents were
coupling strategy has been developed by the reaction successfully coupled, resulting moderate to good yields of
between alkynyl bromides and alkylzirconocenes. The the desired internal alkynes.
alkylzirconocenes were generated in situ via regioselective
addition of Schwartz’s reagent (ZrCp2HCl) on alkenes. The
reaction has a broad scope, a range of functionalized
Keywords: Alkylzirconocenes; transmetalation; alkynes;
copper catalysis; cross-coupling
catalytic systems. In particular, Pd, Co, Fe, Ni, and
Cu catalyzed alkyl-alkynyl cross-coupling reactions
involving alkyl or alkynyl organometallic reagents
have attracted considerable interest in the past two
decades.[12],[13],[14] However, copper catalyzed alkyl-
alkynyl cross coupling reactions are very limited, as
less than a handful of reports found in the literature.
Recently, Cahiez et al. reported the use of Grignard
reagents in alkyl-alkynyl cross-coupling reaction
using catalytic CuI.[14a] Giri and co-workers
documented their findings about copper catalyzed
alkyl-alkynyl cross-coupling reactions of alkynylzinc
reagents with hetero aryliodides.[14b] Knochel[14c] and
Normant[14d] separately published copper mediated
cross-coupling reactions between alkylcuprates and
alkynyl halides. Despite the progress in this area,
poor yields, limited substrate scope, tedious reaction
conditions, toxicity, use of expensive metal catalysts
and less tolerance towards the reactive functional
groups such as esters or nitriles or imides still limit
their laboratory applications.
Introduction
Internal alkynes are ubiquitous molecules present
in a wide range of natural products as well as in
biologically important molecules and polymers.[1]
These units are often attractive precursors in the
total synthesis of complex natural products. For
example, several natural products such as
epithilone,
lactimidomycin,
citreofuran,
amphidinolide V, etc. have been synthesized via
alkyne-alkyne RCM of alkylated alkynes.[2]
Recently, they have also been used as essential
motifs in OLEDs,[3] liquid crystals[4] and dyes.[5]
In addition, a diverse range of products can be
obtained by functionalization of the triple bond
through electrophilic additions,[6] oxidative
cleavage,[7] C–C coupling,[8] reduction,[9] and
Diels-Alder reactions.[10] Internal alkynes can also
serve as key synthons for the synthesis of highly
substituted
triazoles
via
the
Huisgen
cycloaddition reaction.[11]
Alkyl-alkynyl coupling reactions are an important
class of reactions for the synthesis of alkylated
alkynes and they are some of the most challenging of
cross-coupling processes, due to involvement of
undesired β-hydride elimination and other side
reactions.[12],[13] There are two major pathways to
perform alkyl-alkynyl cross-coupling reactions; (i)
alkylation of metal acetylides with primary alkyl
halides (Scheme 1a)[12] and (ii) cross-coupling of
alkylmetal reagents with haloalkynes (Scheme
1b).[13],[14] Since the development of these methods,
numerous efforts have been made to develop efficient
Scheme 1. Different strategies of alkyl-alkynyl cross-
coupling reactions.
1
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10.1002/adsc.201700164
Advanced Synthesis & Catalysis
On the other hand, alkylzirconocenes are a unique
There was no noticeable change in the yield when
the reaction temperature was reduced to ambient
temperature (Table 1, entry 2). However, we
found a little increment in the yield (69%) upon
increasing the catalyst loading to 20 mol% (Table
1, entry 3). Other copper salts such as Cu(OAc)2,
CuTc and CuI were tested as well and the desired
alkyne 4a was obtained with a yield of 25%,
57%, and 59%, respectively (Table 1, entries 4-
6). To our surprise, the yield of the coupling
product was enhanced to 76% (entry 7) upon
switching the solvent to dichloromethane. The
use of 20 mol% of Cu2O and CuCN in
dichloromethane produced the desired product in
moderate yields (Table 1, entries 8 and 9).
Changes of the loading of Cu(MeCN)4PF6 did not
lead to better results (entries 10 and 11). Then,
we further evaluated the effect of ligands such as
class of synthetic intermediates and their chemistry
has been actively investigated in recent years because
of their high functional group tolerance and their
simple regioselective generation from alkenes.[15]
Moreover, they readily react with various
electrophiles to produce functionalized alkanes.[15],[16]
Over
the
years,
transmetalation
of
alkenylzirconocenes to various transition metals has
been well studied in cross-coupling reactions because
of the high binding capability of zirconium with π-
systems, which led to better transmetalation
compared to alkylzirconocenes.[15b],[17],[18] Since the
first report of Zr-Cu transmetalation reaction by
Schwartz in 1977,[19] only a few numbers of
innovations have been published to address the utility
of alkylzirconium reagents under copper catalysis.[20]
These examples include asymmetric allylic
alkylation,[20a,b] conjugate addition with enones,[20c,d]
acylation using acid chlorides,[20e] bisalkynylation of
bromoalkynes[20f]
and
phenanthroline
tetramethylethylenediamine
(Phen),
(TMEDA),
zirconacycles
carbometalation of nonactivated alkynes by
zirconacyclopentanes.[20g]
Recently, Giri and
with
pentamethyldiethyl-enetriamine (PMDTA) and
PPh3 to improve the rate of reaction.
coworkers reported first Cu-catalysed cross-coupling
of arylzirconocenes with aryl and heteroaryl
iodides.[21] Previously, Takahashi and co-workers
established a copper-mediated alkenyl-alkynyl cross
coupling reaction of alkenylzirconocenes with
bromoalkynes.[17a] More recently, Liu et al.
demonstrated oxidative cross-coupling between
alkenylzirconocenes and alkynylcopper reagents.[17b]
The above two methods require stoichiometric
amounts of copper, glove box conditions and only
few examples of bromoalkynes were explored. To the
best of our knowledge, hydrozirconation of alkenes
followed by transmetalation to copper and alkyl-
alkynyl cross coupling reaction has never been
reported in the literature.
Table 1. Optimization of the reaction.a
S.No. Catalyst/ligand
Mol%
Cu(MeCN)4PF6 10
Cu(MeCN)4PF6 10
Cu(MeCN)4PF6 20
Solvent Yield [%]b
1
2
3
THF
THF
THF
THF
THF
THF
CH2Cl2
64c (62)d
61
69 (65)d
25
4
5
Cu(OAc)2
CuTc
20
20
20
57
6
CuI
59
76 (72)d
7
Cu(MeCN)4PF6 20
8
9
10
11
12
Cu2O
CuCN
Cu(MeCN)4PF6 10
Cu(MeCN)4PF6 100
Cu(MeCN)4PF6/ 20
Phen
20
20
CH2Cl2 60
CH2Cl2 69 (64)d
CH2Cl2 64
CH2Cl2 31
CH2Cl2 12
Taking cues from the literature and continuing our
interest in copper catalyzed cross-coupling
reactions,[22]
we
postulated
that
similar
alkylzirconocenes could be transmetalated under
copper catalysis and would participate in alkyl-
alkynyl cross coupling reactions with alkynyl halides
(Scheme 1c). This method could address some of the
limitations of existing methodologies. Furthermore,
the wide range of readily available alkenes would
allow direct access to a diverse library of alkylated
alkynes.
13
14
Cu(MeCN)4PF6/ 20
TMEDA
Cu(MeCN)4PF6/ 20
PMDTA
CH2Cl2 35
CH2Cl2 29
15
16
17
18
CuI/Phen
CuI/TMEDA
CuI/PMDTA
20
20
20
CH2Cl2 38e
CH2Cl2 18f
CH2Cl2 16f
CH2Cl2 43
Cu(MeCN)4PF6/ 20
PPh3
19
---
---
CH2Cl2 13
Results and Discussion
a)All the reactions were performed at rt with 1a (0.24
mmol), ZrCp2HCl (0.24 mmol), solvent (0.6 mL), 3a (0.2
mmol), and copper catalyst (0.04 mmol) under argon
atmosphere; ligand (0.08 mmol) was added. b)Yield refers
to NMR yield, determined by 1H NMR spectroscopy of the
To test our hypothesis, we first generated
regioselective alkylzirconocene 2a in situ by the
treatment of allyl phenyl ether 1a with
Schwartz’s reagent in THF at room temperature
and then subjected it to cross-coupling reaction
with (bromoethynyl)benzene 3a using 10 mol%
of Cu(MeCN)4PF6 at 40 °C. The reaction
proceeded smoothly and gave the desired alkyne
crude
reaction
mixture
using
3,4,5-
c)
trimethoxybenzaldehyde as an internal standard. Reaction
was performed at 40 °C. d)Yields in the parenthesis refers
to isolated yield. e)8% of (3-iodopropoxy)benzene was also
observed.
iodopropoxy)benzene was observed.
f)Exclusive
formation
of
(3-
1
4a in 64% H NMR yield (Table 1, entry 1).
2
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10.1002/adsc.201700164
Advanced Synthesis & Catalysis
Table 2. Scope of the reaction with various alkenes.a
Disappointingly, Cu(MeCN)4PF6 with these
amine ligands afforded the desired alkyne in low
yields (entries 12-14). Notably, the use of CuI
with these amine ligands furnished either a
mixture of alkyne 4a and iodinated products
(Table 1, entry 15), or exclusively iodinated
products (Table 1, entries 16-17).[16] On the other
hand, Cu(MeCN) PF PPh3 system also failed to
/
4
6
improve the yield of the reaction (entry 18).
Moreover, the absence of catalyst in the reaction
led to the desired alkyne in lower yield (13%;
Table 1, entry 19).
With the optimized reaction conditions in
hand, we then explored the substrate scope of the
reaction with various alkylzirconium reagents,
generated in situ from alkenes and coupled them
directly with (bromoethynyl)benzene 3a. The
results are summarized in Table 2. In all cases,
internal alkynes 4a-h and 4k-n were observed in
moderate to good yields. Alkenes, possessing a
hetero atom (O, S, Si and N), furnished the
desired alkynes 4a, 4b, 4c and 4d in 72%, 67%,
61% and 57% yields, respectively (Table 2,
entries 1-4). The hydrozirconation/cross-coupling
of 1-chloro-5-hexene also afforded the desired
alkyne 4e in 76% yield. Simple alkylzirconocenes
derived from terminal alkenes such as, 1-
tetradecene 1f and vinylcyclohexane 1g were also
coupled with bromoalkyne 3a, to give the alkynes
4f and 4g in 93% and 83% yields, respectively.
Similarly,
the
allylbenzene
gave
the
corresponding alkyne 4h in 83% of yield when
(bromoethynyl)benzene 3a was used as coupling
partner. To test the reactivity of other haloalkynes
in this reaction, we performed the cross-coupling
reaction of zirconium reagent generated from
allylbenzene with (chloroethynyl)benzene and
(iodoethynyl)benzene, observed the formation of
pent-1-yne-1,5-diyldibenzene 4h in 34% and 92%
yields, respectively. The improvement of yield
from chloroalkyne to iodoalkyne is intriguing as
it indicates β- halogen elimination process (D4;
if X = I, see mechanism) is more favoured in case
of alkynyliodides, because of its good leaving
group character. In this protocol, the formation of
secondary alkylzirconocenes from internal
alkenes 1i-j took longer time (5h) and the formed
secondary zirconium reagents proved difficult to
undergo
cross-coupling
reactions
with
a)All the reactions were performed with 1a (0.2 mmol),
ZrCp2HCl (0.2 mmol), solvent (0.6 mL), 3a (0.2 mmol),
and Cu(MeCN)4PF6 (0.04 mmol) under argon atmosphere
b)Isolated yield. c)Inseparable mixture of diastereomers.
d)Mixture of regio isomeric alkynes. e)Reaction was
performed in THF. f)Decomposition of alkene was
observed. g)Dihydrocaveol (5; 53%) was isolated. h)2 equiv.
of ZrCp2HCl was used in the reaction.
bromoalkyne 3a. This might be due to the
difficulty of the formation of dialkylcuprate
species from sterically hindered secondary
alkylzirconocenes. We also observed that the
substrate limonene 1k bearing both internal and
terminal alkenes underwent a chemoselective
hydrozirconation on the terminal alkene and
coupled with (bromoethynyl)benzene 3a to afford
the alkyne 4k in 68% yield, as an inseparable
mixture of diastereomers with a ratio of 60:40.
From these observations, it can be concluded that,
the rate of hydrozirconation on terminal alkenes is
much faster, compared to internal alkenes, and the
3
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10.1002/adsc.201700164
Advanced Synthesis & Catalysis
secondary zirconium reagents could not be coupled
with bromoalkynes.
along with small amounts (9-13%) of unreacted
bromoalkynes. The higher reactivity of the electron-
deficient bromoalkynes indicates the enhancement of
the electrophilic nature of the bromoalkyne to
facilitate the cross-coupling reaction. It is noteworthy
to mention that, electronically diverse functional
groups such as chloro, bromo, trifluoromethyl, cyano,
ester, imide, silyl, sulfide, methyl, and methoxy
substituents were well tolerated under the reaction
conditions.
Under these reaction conditions, α-methylstyrene
produced an exclusive coupling product 4l in 87%
yield. Whereas, styrenes 1m-n under the similar
reaction conditions producing a mixture of regio
isomeric alkynes, which is due to addition of
Schwartz’s reagent on styrenes in Markovnikov and
anti-Markovnikov fashion. The reason for this
unusual formation of isomers is not clear. For
example, styrene 1m afforded a mixture of isomers in
84% yield, with a ratio of 89:11 having linear alkyne
4m as major one. The same reaction in THF gave a
mixture of isomers in 73% yield with 50:50 ratio.
Similarly, 4-methylstyrene 1n in CH2Cl2 underwent a
smooth coupling to form a mixture of isomers (79%,
92:8) having linear alkyne 4n as major one. These
results proved that dichloromethane plays a vital role
in deciding the selectivity of hydrozirconation on
styrenes. On the other hand, alkenes bearing ester,
nitrile and ketone groups (4o-q) were also examined.
In contrast to our previous results, decomposition of
alkene was observed when starting with methyl-5-
hexenoate (1o) or 5-hexenenitrile (1p). Whereas,
dihydrocarvone (1q) reduced to dihydrocarveol (5)
Table 3. Scope of different bromoalkynes in the reaction.a
exclusively in 53% yield as
a
mixture of
diastereomers (entry 17; see SI). When we used 2
equivalents of Schwartzs reagent on dihydrocarvone
under the reaction conditions, observed an alkyne 4q’
in 41% yield as aninseparable mixture of isomers.
The intolerance of these functional groups with
zirconium is due to strong coordination of Lewis
acidic Zr with the above mentioned functional groups,
which further results reduction products via hydride
transfer in some cases.[15b,23]
Having demonstrated the utility of the optimized
conditions on various alkenes, we turned our
attention to the scope of bromoalkynes. As expected,
a series of bromoalkynes reacted smoothly with 3-
phenylpropylzirconocene as robust model, providing
the internal alkynes 4r-4ac in moderate to good
yields. The results are depicted in Scheme 2. Simple
aliphatic alkynyl bromides such as 1-bromooct-1-yne
and (5- bromopent-4-yn-1-yl)benzene were converted
to the corresponding dialkylated alkynes 4r (89%)
and 4s (84%), respectively. Bromoalkyne derived
from 3-ethynylcyclohex-1-ene was also alkylated
under these conditions to furnish the enyne 4t in 66%
yield. Moreover, the substrates having imide and
ester groups are well tolerated affording the desired
alkynes 4u (56%) and 4v (82%), respectively. We
were also pleased to find that the substitution on the
benzene ring of bromophenylacetylenes play a crucial
role in the outcome of yield. For example,
aAll the reactions were performed with 1d (0.24 mmol),
ZrCp2HCl (0.24 mmol), CH2Cl2 (0.6 mL), 3 (0.2 mmol),
and Cu(MeCN)4PF6 (0.04 mmol) under argon atmosphere;
yields refers to isolated yield. Small amounts of unreacted
bromoalkyne was also recovered.
b
Although the mechanism for the copper-catalyzed
cross-coupling reaction of alkenyl/alkylzirconocenes
is unknown, we here propose a mechanism similar to
Cahiez’s alkyl-alkynyl cross coupling with Grignard
reagents.[14a] The alkylzirconocene generates the
alkynylbromides
bearing
electron-withdrawing
groups on the benzene ring led to alkynes 4w-4aa in
excellent yields. Here, the formation of 4w-x suggests
that the cross-coupling reaction is highly
chemoselective in favor of alkynylbromides over
haloarenes. The substrates having electron-donating
groups such as, methyl and methoxy were slower to
react and gave the corresponding alkynes 4ab-ac
4
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10.1002/adsc.201700164
Advanced Synthesis & Catalysis
1
petroleum ether) 0.47; H NMR (300 MHz, CDCl3) δ 1.92
(p, J = 6.0 Hz, 2 H), 2.15 (s, 3 H), 2.57 (t, J = 6.0 Hz, 2 H),
2.69 (t, J = 6.0 Hz, 2 H), 7.28−7.32 (m, 3 H), 7.40−7.43 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ 15.5, 18.5, 28.1, 33.2,
81.2, 89.1, 123.8, 127.6, 128.2 (2C), 131.5 (2C); IR (thin
film) 1596, 1488, 1440, 1429, 756, 692 cm−1; HRMS
(APCI) calcd for C12H14S (M + H)+ 191.0889, found
191.0889.
Scheme 2. Plausible reaction mechanism.
corresponding alkylcopper(I) species A in situ through
transmetalation. These species further react with another
molecule of alkylzirconium to give dialkylcuprate complex
B. This complex undergoes carbocupration with
bromoalkynes via a five coordinate, three-membered
cyclic organocopper species C to generate a β-halo-
vinylcopper(I) complex D. Finally, the β-halogen
elimination of complex D gives the cross-coupled
product 4 and regenerates the alkylcopper(I) species
(Scheme 2).
Trimethyl(5-phenylpent-4-yn-1-yl)silane (4c): Pale
yellow liquid; yield 27 mg, 61%; Rf (2% EtOAc in
1
petroleum ether) 0.55; H NMR (300 MHz, CDCl3) δ 0.08
(s, 9 H), 0.70−0.75 (m, 2 H), 1.59−1.73 (m, 2 H), 2.48 (t, J
= 6.0 Hz, 2 H), 7.32−7.38 (m, 3 H), 7.45−7.49 (m, 2 H);
13C NMR (75 MHz, CDCl3) δ -1.7 (3C), 16.5, 23.2, 23.8,
80.1, 90.5, 124.1, 127.5, 128.2 (2C), 131.6 (2C); IR (thin
film) 1599, 1488, 1442, 1247, 1164, 1070, 1026, 966, 862,
835, 752, 690 cm−1; HRMS (APCI) calcd for C14H20Si (M
+ Na)+ 239.1239, found 239.1239.
Conclusion
In summary, we have developed a two-step synthesis
of alkylated alkynes from alkenes via sequential
hydrozirconation with Schwartz’s reagent followed
by transmetalation to copper and cross-coupling with
bromoalkynes. The ‘ligandless’ and ‘base free’
conditions make this methodology more attractive
from the standpoints of cost, atom economy and ease
(R)-4-Methyl-N-(1-phenylethyl)-N-(5-phenylpent-4-
yn-1-yl)benzenesulfonamide (4d): Pale yellow liquid;
yield 47 mg, 57%; Rf (4% EtOAc in petroleum ether) 0.27;
1H NMR (300 MHz, CDCl3) δ 1.41 (d, J = 6.0, 3 H),
1.45−1.50 (m, 1 H), 1.67−1.79 (m, 1 H), 2.08−2.29 (m, 2
H), 2.42 (s, 3 H), 3.15−3.23 (m, 2 H), 5.22 (q, J = 6.0, 1 H),
7.22−7.34 (m, 12 H), 7.76 (d, J = 6.0, 2 H); 13C NMR (75
MHz, CDCl3) δ 16.7, 17.0, 21.5, 29.5, 43.3, 55.5, 81.2,
88.9, 123.8, 127.2 (2C), 127.63 (2C), 127.66, 127.70,
128.2 (2C), 128.4 (2C), 129.7 (2C), 131.5 (2C), 138.2,
140.2, 143.1; IR (thin film) 1598, 1490, 1450, 1334, 1159,
1147, 1091, 1028, 958, 859, 742 cm−1; HRMS (ESI) calcd
for C26H27NO2S (M + Na)+ 440.1655, found 440.1654.
of
purification.
Furthermore,
the
direct
hydrozirconation/transmetalation/cross-coupling
sequence from alkenes would be a reliable alternative
for the synthesis of dialkylated alkynes, which are
quite difficult to afford through known methods.
Experimental Section
(8-Chlorooct-1-yn-1-yl)benzene (4e): Pale yellow
liquid; yield 33 mg, 76%; Rf (2% EtOAc in petroleum
ether) 0.48; 1H NMR (300 MHz, CDCl3) δ 1.46−1.59 (m, 4
H), 1.58−1.64 (m, 2 H), 1.76−1.83 (m, 2 H), 2.42 (t, J =
6.0 Hz, 2 H), 3.55 (t, J = 6.0 Hz, 2 H),7.25−7.30 (m, 3 H),
7.37−7.41 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 19.3,
26.4, 28.1, 28.5, 32.5, 45.1, 80.8, 90.1, 124.0, 127.5, 128.2
(2C), 131.5 (2C); IR (thin film) 2937, 1599, 1489, 1444,
1388, 1246, 1159, 1070, 1028, 796, 690 cm−1; HRMS
(APCI) calcd for C14H17Cl (M + H)+ 221.1092, found
221.1092.
Alkene (0.24 mmol; 1.2 equiv.) was added slowly to a
solution of Schwartz’s reagent (0.24 mmol; 1.2 equiv.) in
dichloromethane (0.6 mL) under argon atmosphere at room
temperature. After stirring for 1 hr, the resulting clear
yellow solution was transferred via cannula to a mixture of
haloalkyne (0.2 mmol, 1 equiv.) and Cu(MeCN)4PF6 (0.04
mmol, 0.2 equiv.) under argon atmosphere. The resulting
mixture was stirred at ambient temperature for 18 hours.
The solution was diluted with diethyl ether (5 mL),
filtrated trough a short pad of silica and eluted with diethyl
ether (15 mL). The ethereal solution was evaporated under
reduced pressure to afford the crude product. The crude
product was purified by flash chromatography using
petroleum ether to afford the desired alkyne.
Hexadec-1-yn-1-ylbenzene (4f): Colorless liquid; yield
1
55 mg, 93%; Rf (2% EtOAc in petroleum ether) 0.50; H
NMR (300 MHz, CDCl3) δ 0.91 (t, J = 6.0 Hz, 3 H), 1.21
(s, 20 H), 1.42−1.50 (m, 2 H), 1.63 (p, J = 6.0 Hz, 2 H),
2.42 (t, J = 6.0 Hz, 2 H), 7.27−7.32 (m, 3 H), 7.40−7.43 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ 14.1, 19.4, 22.7, 28.8,
28.9, 29.2, 29.4, 29.6, 29.7 (5C), 31.9, 80.5, 90.5, 124.1,
127.4, 128.2 (2C), 131.5 (2C); IR (thin film) 2925, 2904,
2851, 1597, 1483, 1437, 1266, 1191, 1059, 1016, 912, 799,
756, 696 cm−1; HRMS (APCI) calcd for C22H34 (M + H)+
299.2733, found 299.2734.
(5-Phenoxypent-1-yn-1-yl)benzene (4a): Colorless
liquid; yield 34 mg, 72%; Rf (2% EtOAc in petroleum
ether) 0.43; 1H NMR (300 MHz, CDCl3) δ 2.08 (p, J = 6.0
Hz, 2 H), 2.63 (t, J = 6.0 Hz, 2 H), 4.12 (t, J = 6.0 Hz, 2 H),
6.92−6.97 (m, 3 H), 7.25−7.29 (m, 5 H), 7.37−7.40 (m, 2
H); 13C NMR (75 MHz, CDCl3) δ 16.2, 28.5, 66.3, 81.1,
89.1, 114.5 (2C), 120.7, 123.8, 127.7, 128.2 (2C), 129.5
(2C), 131.6 (2C), 158.9; IR (thin film) 1599, 1587, 1488,
1469, 1301, 1244, 1172, 1080, 1047, 754, 690 cm−1;
HRMS (APCI) calcd for C17H16O (M + H)+ 237.1274,
found 237.1273.
(4-Cyclohexylbut-1-yn-1-yl)benzene (4g): Colorless
liquid; yield 35 mg, 83%; Rf (2% EtOAc in petroleum
ether) 0.55; 1H NMR (300 MHz, CDCl3) δ 0.84−0.98 (m, 2
H), 1.13−1.54 (m, 6 H), 1.62−1.68 (m, 5 H), 2.41 (t, J =
Methyl(5-phenylpent-4-yn-1-yl)sulfane (4b): Pale
yellow liquid; yield 25 mg, 67%; Rf (2% EtOAc in
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700164
Advanced Synthesis & Catalysis
6.0 Hz, 2 H), 7.24−7.29 (m, 3 H), 7.43−7.46 (m, 2 H); 13C
NMR (75 MHz, CDCl3) δ 16.9, 26.3 (2C), 26.6, 33.0 (2C),
36.3, 36.9, 80.4, 90.7, 124.1, 127.4, 128.2 (2C), 131.5
(2C); IR (thin film) 2908, 2848, 1596, 1488, 1442, 1261,
1174, 1068, 1018, 912, 840, 798, 754, 690 cm−1; HRMS
(APCI) calcd for C16H20 (M + H)+ 213.1638, found
213.1637.
21.8, 34.8, 81.2, 89.6, 123.9, 127.6, 128.2 (2C), 128.4 (2C),
129.0 (2C), 131.5 (2C), 135.8, 137.7; IR (thin film) 2219,
1596, 1514, 1488, 1442, 1340, 1163, 1070, 916, 806, 754,
690 cm−1; HRMS (APCI) calcd for C17H16 (M + H)+
221.1325, found 221.1325.
2-Methyl-5-(5-phenylpent-4-yn-2-yl)cyclohexan-1-ol
(mixture of isomers, 4q’): Pale yellow liquid; yield 21 mg,
1
Pent-1-yne-1,5-diyldibenzene (4h): Pale yellow liquid;
yield 36 mg, 83%; Rf (2% EtOAc in petroleum ether) 0.52;
1H NMR (300 MHz, CDCl3) δ 1.93 (p, J = 6.0 Hz, 2 H),
2.42 (t, J = 6.0 Hz, 2 H), 2.80 (t, J = 6.0 Hz, 2 H),
7.17−7.33 (m, 8 H), 7.39−7.43 (m, 2 H); 13C NMR (75
MHz, CDCl3) δ 18.8, 30.3, 34.8, 81.1, 89.8, 124.0, 125.9,
127.6, 128.2 (2C), 128.4 (2C), 128.6 (2C), 131.6 (2C),
141.6; IR (thin film) 1598, 1488, 1454, 1070, 1027, 756,
692 cm−1; HRMS (APCI) calcd for C17H16 (M + H)+
221.1325, found 221.1325.
41%; Rf (4% EtOAc in petroleum ether) 0.29; H NMR
(300 MHz, CDCl3) δ 0.86−1.05 (m, 6 H), 1.25−1.79 (m, 8
H), 2.19−2.48 (m, 3 H), 3.87 (brs, 0.2 H), 4.06−4.10 (m,
0.6 H), 4.68−4.72 (m, 0.2 H), 7.25−7.30 (m, 3 H),
7.37−7.40 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 16.29,
16.37, 16.63, 16.67, 18.24, 18.31, 24.31, 24.43, 24.55,
27.14, 27.23, 28.13, 29.24, 29.94, 32.79, 34.52, 35.94,
36.02, 36.26, 36.32, 37.23, 37.53, 37.72, 38.51, 38.57,
40.27, 40.47, 70.98, 81.57, 81.84, 85.99, 86.08, 86.15,
86.24, 88.73, 88.80, 89.51, 123.94, 124.11, 127.45, 127.56,
128.20, 131.54; IR (thin film) 2929, 1596, 1498, 1379,
1296, 1058, 1021, 948, 861, 852, 800, 756, 692 cm−1;
HRMS (APCI) calcd for C18H24O (M + H)+ 257.1900,
found 257.1901.
(4-(4-Methylcyclohex-3-en-1-yl)pent-1-yn-1-
yl)benzene (inseparable mixture of diastereomers with
a ratio of 60 :40) (4k): Colorless liquid; yield 33 mg,
1
69%; Rf (2% EtOAc in petroleum ether) 0.42 ; H NMR
(300 MHz, CDCl3) δ 1.06 (d, J = 6.0 Hz, 1.8 H), 1.09 (d, J
= 6.0 Hz, 1.2 H), 1.22−1.39 (m, 1 H), 1.57−1.84 (m, 8 H),
1.97−2.04 (m, 3 H), 2.32−2.53 (m, 2 H), 7.27−7.31 (m, 3
Undec-4-yn-1-ylbenzene (4r): Pale yellow liquid;
yield 41 mg, 89%; Rf (2% EtOAc in petroleum ether)
0.47 ; 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J = 6.0 Hz, 3
H), 7.40−7.43 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 16.4, H), 1.29−1.57 (m, 8 H), 1.83 (p, J = 6.0 Hz, 2 H),
16.8, 23.5 (2C), 24.4, 24.5, 25.7, 27.0, 28.1, 29.7, 30.6,
30.7, 37.1, 37.3, 37.5, 37.7, 81.5 (2C), 89.5 (2C), 120.6
(2C), 124.1 (2C), 127.4 (2C), 128.2 (4C), 131.5 (4C),
134.0 (2C); IR (thin film) 2929, 1598, 1541, 1491, 1442,
1070, 1027, 912, 800, 756, 690 cm−1; HRMS (APCI) calcd
for C18H22 (M + H)+ 239.1794, found 239.1793.
2.17−2.22 (m, 4 H), 2.75 (t, J = 6.0 Hz, 2 H), 7.18−7.34 (m,
5 H); 13C NMR (75 MHz, CDCl3) δ 14.1, 18.2, 18.8, 22.6,
28.6, 29.1, 30.8, 31.4, 34.8, 79.7, 80.9, 125.8, 128.3 (2C),
128.5 (2C), 141.9; IR (thin film) 2927, 2916, 2856, 2063,
1602, 1496, 1454, 1377, 1330, 1078, 1029, 744, 691 cm−1;
HRMS (APCI) calcd for C17H24 (M + H)+ 229.1951, found
229.1951.
Pent-1-yne-1,4-diyldibenzene (4l): Colorless liquid;
yield 38 mg, 87%; Rf (2% EtOAc in petroleum ether)
0.52 ; 1H NMR (300 MHz, CDCl3) δ 1.44 (d, J = 5.4 Hz, 3
H), 2.57−2.74 (m, 2 H), 3.01−3.13 (m, 1 H), 7.22−7.37 (m,
10 H); 13C NMR (75 MHz, CDCl3) δ 20.7, 28.7, 39.2, 81.9,
88.8, 123.9, 126.4, 126.9 (2C), 127.6, 128.2 (2C), 128.3
(2C), 131.5 (2C), 145.8; IR (thin film) 1596, 1490, 1452,
1271, 1169, 1070, 1014, 912, 756, 692 cm−1; HRMS
(APCI) calcd for C17H16 (M + H)+ 221.1325, found
221.1325.
1,8-Diphenyloct-4-yne (4s): Pale yellow liquid; yield
44 mg, 84%; Rf (2% EtOAc in petroleum ether) 0.53 ; H
1
NMR (300 MHz, CDCl3) δ 1.83 (p, J = 6.0 Hz, 4 H), 2.21
(t, J = 6.0 Hz, 4 H), 2.71 (t, J = 6.0 Hz, 4 H), 7.16−7.31 (m,
10 H); 13C NMR (75 MHz, CDCl3) δ 18.3 (2C), 30.8 (2C),
34.9 (2C), 80.3 (2C), 125.9 (2C), 128.4 (4C), 128.6 (4C),
141.9 (2C); IR (thin film) 3022, 2921, 2896, 1947, 1602,
1494, 1452, 1332, 1080, 1029, 908, 744, 696 cm−1; HRMS
(APCI) calcd for C20H22 (M + H)+ 263.1794, found
263.1793.
But-1-yne-1,4-diyldibenzene (major isomer, 4m):
Colorless liquid; yield 35 mg, 84%; Rf (2% EtOAc in
petroleum ether) 0.51; H NMR (300 MHz, CDCl3) δ 2.73
(t, J = 6.0 Hz, 2 H), 2.95 (t, J = 6.0 Hz, 2 H), 7.28−7.34 (m, petroleum ether) 0.57 ; H NMR (300 MHz, CDCl3) δ
(5-(Cyclohex-1-en-1-yl)pent-4-yn-1-yl)benzene (4t):
1
Pale yellow liquid; yield 29 mg, 66%; Rf (2% EtOAc in
1
7 H), 7.38−7.42 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ
21.7, 35.2, 81.3, 89.5, 123.8, 126.3, 127.6, 128.2 (2C),
128.4 (2C), 128.5 (2C), 131.5 (2C), 140.7; IR (thin film)
2212, 1590, 1488, 1454, 1340, 1274, 1068, 756, 692 cm−1;
HRMS (APCI) calcd for C16H14 (M + H)+ 207.1168, found
207.1169.
1.53−1.67 (m, 4 H), 1.84 (p, J = 6.0 Hz, 2 H), 2.07−2.12
(m, 4 H), 2.31 (t, J = 6.0 Hz, 2 H), 2.73 (t, J = 5.7 Hz, 2 H),
6.02−6.04 (m, 1 H), 7.16−7.31 (m, 5 H); 13C NMR (75
MHz, CDCl3) δ 18.7, 21.6, 22.4, 25.6, 29.6, 30.5, 34.8,
82.9, 86.8, 121.0, 125.8, 128.3 (2C), 128.5 (2C), 133.3,
141.8; IR (thin film) 2937, 2931, 2860, 2212, 1730, 1716,
1670, 1600, 1452, 1348, 1259, 1172, 1078, 748, 700 cm−1;
HRMS (APCI) calcd for C17H20 (M + H)+ 225.1638, found
225.1637.
1-Methyl-4-(4-phenylbut-3-yn-1-yl)benzene (major
isomer, 4n): Colorless liquid; yield 35 mg, 79%; Rf (2%
EtOAc in petroleum ether) 0.52; 1H NMR (300 MHz,
CDCl3) δ 2.36 (s, 3 H), 2.70 (t, J = 5.7 Hz, 2 H), 2.92 (t, J
= 6.0 Hz, 2 H), 7.14−7.21 (m, 4 H), 7.28−7.32 (m, 3 H),
7.38−7.42 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 21.0,
2-(7-Phenylhept-3-yn-1-yl)isoindoline-1,3-dione (4u):
Colorless semi solid; yield 36 mg, 56%; Rf (10% EtOAc in
petroleum ether) 0.38 ; 1H NMR (300 MHz, CDCl3) δ 1.70
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700164
Advanced Synthesis & Catalysis
(p, J = 6.0 Hz, 2 H), 2.07−2.13 (m, 2 H), 2.57−2.65 (m, 4
H), 3.86 (t, J = 6.0 Hz, 2 H), 7.11−7.28 (m, 5 H), 7.69 (dd,
J = 3.0 and 4.5 Hz, 2 H), 7.83 (dd, J = 3.0 and 4.5 Hz, 2
H); 13C NMR (75 MHz, CDCl3) δ 18.1, 18.7, 30.3, 34.7,
37.1, 76.4, 81.9, 123.3 (2C), 125.8, 128.2 (2C), 128.5 (2C),
132.0 (2C), 133.9 (2C), 141.7, 168.1 (2C); IR (thin film)
1772, 1710, 1614, 1467, 1433, 1394, 1361, 1298, 1188,
1114, 1000, 869, 717 cm−1; HRMS (APCI) calcd for
C21H19NO2 (M + H)+ 318.1489, found 318.1489.
7.60 (d, J = 9.0 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ
18.9, 30.0, 34.8, 79.9, 95.0, 110.9, 118.6, 126.0, 128.4
(2C), 128.5 (2C), 129.0, 131.9 (2C), 132.1 (2C), 141.3; IR
(thin film) 2230, 1602, 1499, 831, 748 , 700 cm−1; HRMS
(APCI) calcd for C18H15N (M + H)+ 246.1277, found
246.1276.
1-(5-Phenylpent-1-yn-1-yl)-2-(trifluoromethyl)-
benzene (4aa): Pale yellow gum; yield 51 mg, 88%; Rf
(2% EtOAc in petroleum ether) 0.34 ; 1H NMR (300 MHz,
CDCl3) δ 1.98 (p, J = 6.0 Hz, 2 H), 2.51 (t, J = 6.0 Hz, 2
H), 2.86 (t, J = 6.0 Hz, 2 H), 7.22−7.42 (m, 6 H), 7.50 (dt,
J = 1.8 and 9.0 Hz, 1 H), 7.59 (d, J = 6.0 Hz, 1 H), 7.68 (d,
J = 9.0 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 19.0, 30.1,
Ethyl 6-phenylhex-2-ynoate (4v): Pale yellow gum;
yield 35 mg, 82%; Rf (5% EtOAc in petroleum ether)
0.53 ; 1H NMR (300 MHz, CDCl3) δ 1.31 (t, J = 6.0 Hz, 3
H), 1.90 (p, J = 6.0 Hz, 2 H), 2.33 (t, J = 6.0 Hz, 2 H), 2.73
(t, J = 6.0 Hz, 2 H), 4.22 (q, J = 6.0 Hz, 2 H), 7.17−7.32
(m, 5 H); 13C NMR (75 MHz, CDCl3) δ 14.1, 18.0, 29.1,
34.7, 61.8, 73.6, 88.8, 126.1, 128.47 (2C), 128.51 (2C),
140.8, 153.8; IR (thin film) 2233, 1704, 1496, 1454, 1365,
1247, 1070, 750, 700 cm−1; HRMS (APCI) calcd for
C14H16O2 (M + H)+ 217.1223, found 217.1223.
1
34.7, 77.3, 96.1, 122.3, 123.7 (q, JCF = 272 Hz), 125.7 (q,
3JCF = 5.2 Hz), 125.9, 127.3, 128.4 (2C), 128.6 (2C), 131.3,
131.5 (q, 2JCF = 30 Hz), 134.0, 141.7; 19F NMR (282 MHz,
CDCl3) δ -62.4; IR (thin film) 1611, 1415, 1325, 1249,
1167, 1070, 837, 751, 694 cm−1; HRMS (APCI) calcd for
C18H15F3 (M + H)+ 289.1199, found 289.1198.
1-Chloro-4-(5-phenylpent-1-yn-1-yl)benzene (4w):
Colorless gum; yield 40 mg, 78%; Rf (2% EtOAc in
petroleum ether) 0.43 ; 1H NMR (300 MHz, CDCl3) δ 1.92
(p, J = 6.0 Hz, 2 H), 2.41 (t, J = 6.0 Hz, 2 H), 2.78 (t, J =
6.0 Hz, 2 H), 7.20−7.34 (m, 9 H); 13C NMR (75 MHz,
CDCl3) δ 18.8, 30.2, 34.9, 80.1, 90.9, 122.5, 126.0, 128.4
(2C), 128.5 (2C), 128.6 (2C), 132.8 (2C), 133.5, 141.5; IR
(thin film) 1602, 1488, 1454, 1244, 1091, 1014, 827, 746,
698 cm−1; HRMS (APCI) calcd for C17H15Cl (M + H)+
255.0935, found 255.0934.
1-Methyl-4-(5-phenylpent-1-yn-1-yl)benzene (4ab):
Pale yellow liquid; yield 32 mg, 69%; Rf (2% EtOAc in
petroleum ether) 0.42 ; 1H NMR (300 MHz, CDCl3) δ 1.92
(p, J = 6.0 Hz, 2 H), 2.33 (s, 3 H), 2.41 (t, J = 6.0 Hz, 2 H),
2.79 (t, J = 6.0 Hz, 2 H), 7.09 (d, J = 9.0 Hz, 2 H),
7.18−7.32 (m, 7 H); 13C NMR (75 MHz, CDCl3) δ 18.9,
21.4, 30.4, 34.9, 81.2, 89.0, 120.9, 125.9, 128.4 (2C),
128.6 (2C), 129.0 (2C), 131.4 (2C), 137.5, 141.7; IR (thin
film) 2215, 1710, 1604, 1541, 1508, 1454, 1251, 1182,
1048, 815, 746, 698 cm−1; HRMS (APCI) calcd for C18H18
(M + H)+ 235.1481, found 235.1480.
1-Bromo-4-(5-phenylpent-1-yn-1-yl)benzene
(4x):
Pale yellow gum; yield 51 mg, 85%; Rf (2% EtOAc in
petroleum ether) 0.48 ; 1H NMR (300 MHz, CDCl3) δ 1.92
(p, J = 5.7 Hz, 2 H), 2.40 (t, J = 6.0 Hz, 2 H), 2.77 (t, J =
6.0 Hz, 2 H), 7.17−7.33 (m, 7 H), 7.41 (d, J = 6.0 Hz, 2 H);
13C NMR (75 MHz, CDCl3) δ 18.9, 30.2, 34.9, 80.2, 91.2,
121.7, 122.9, 126.0, 128.4 (2C), 128.6 (2C), 131.4 (2C),
133.0 (2C), 141.5; IR (thin film) 1601, 1491, 1449, 1384,
1251, 1139, 1071, 1008, 826, 749, 696 cm−1; HRMS
(APCI) calcd for C17H15Br (M + H)+ 299.0430, found
299.0431.
1-Methoxy-4-(5-phenylpent-1-yn-1-yl)benzene (4ac):
Pale yellow liquid; yield 25 mg, 51%; Rf (2% EtOAc in
petroleum ether) 0.38 ; 1H NMR (300 MHz, CDCl3) δ 1.95
(p, J = 6.0 Hz, 2 H), 2.44 (t, J = 6.0 Hz, 2 H), 2.82 (t, J =
6.0 Hz, 2 H), 2.83 (s, 3 H), 6.85 (d, J = 9.0 Hz, 2 H),
7.22−7.40 (m, 7 H); 13C NMR (75 MHz, CDCl3) δ 18.9,
30.4, 34.9, 55.3, 80.8, 88.2, 113.8 (2C), 116.1, 125.9,
128.4 (2C), 128.6 (2C), 132.9 (2C), 141.7, 159.0; IR (thin
film) 2933, 1604, 1508, 1454, 1288, 1245, 1172, 1105,
1031, 831, 744, 700 cm−1; HRMS (APCI) calcd for
C18H18O (M + H)+ 251.1430, found 251.1429.
Methyl 4-(5-phenylpent-1-yn-1-yl)benzoate (4y):
White solid, mp 89-91 °C; yield 46 mg, 82%; Rf (5%
EtOAc in petroleum ether) 0.44 ; H NMR (300 MHz,
Dihydrocaveol (5, mixture of isomers): Pale yellow
liquid; yield 17 mg, 53%; Rf (5% EtOAc in petroleum
ether) 0.31 ; 1H NMR (300 MHz, CDCl3) δ 0.97 (d, J = 6.0
Hz, 1.5 H), 1.03 (d, J = 6.0 Hz, 1.5 H), 1.11-1.28 (m, 2 H),
1.37-1.51 (m, 2 H), 1.67-1.80 (m, 5 H), 1.88-2.05 (m, 1.5
1
CDCl3) δ 1.94 (p, J = 6.0 Hz, 2 H), 2.45 (t, J = 6.0 Hz, 2
H), 2.79 (t, J = 6.0 Hz, 2 H), 3.91 (s, 3 H), 7.18−7.33 (m, 5
H), 7.46 (d, J = 9.0 Hz, 2 H), 7.96 (d, J = 9.0 Hz, 2 H); 13
C
NMR (75 MHz, CDCl3) δ 18.9, 30.1, 34.8, 52.2, 80.6, 93.4, H), 2.22-2.32 (m, 0.5 H), 3.15-3.23 (m, 0.5 H), 3.87-3.91
126.0, 128.4 (2C), 128.5 (2C), 128.8, 128.9, 129.4 (2C),
131.5 (2C), 141.4, 166.7; IR (thin film) 2229, 1720, 1604,
1434, 1307, 1293, 1107, 1018, 964, 858, 769, 744, 698
cm−1; HRMS (APCI) calcd for C19H18O2 (M + H)+
279.1380, found 279.1380.
(m, 0.5 H), 4.69 (brs, 2 H),; 13C NMR (75 MHz, CDCl3) δ
18.3, 20.9, 21.0, 28.1, 31.1, 31.4, 33.2, 36.0, 37.8, 38.6,
40.0, 40.5, 44.1, 71.0, 76.4, 108.4, 108.6, 149.4, 150.3;
HRMS (APCI) calcd for C18H18O (M + H)+ 155.1430,
found 155.1430.
4-(5-Phenylpent-1-yn-1-yl)benzonitrile (4z): Pale yellow
solid, mp 73-75 °C; yield 39 mg, 79%; Rf (5% EtOAc in
petroleum ether) 0.54 ; 1H NMR (300 MHz, CDCl3) δ 1.97
(p, J = 6.0 Hz, 2 H), 2.47 (t, J = 6.0 Hz, 2 H), 2.81 (t, J =
6.0 Hz, 2 H), 7.23−7.36 (m, 5 H), 7.49 (d, J = 9.0 Hz, 2 H),
Acknowledgements
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700164
Advanced Synthesis & Catalysis
H. Li, Eur. J. Org. Chem. 2014, 6769; c) T. Thaler,
L.-N. Guo, P. Mayer, P. Knochel, Angew. Chem. Int.
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Université catholique de Louvain and FNRS are gratefully
acknowledged for financial support. KI would like to
acknowledge the ‘MOVEIN Louvain’ Incoming post-doc
Fellowship programme for the financial support.
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10.1002/adsc.201700164
Advanced Synthesis & Catalysis
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Transmetalation of Alkylzirconocenes in Copper-
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Kiran Indukuria, Olivier Rianta*
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