Nickel-catalyzed substitution reactions of propargyl halides with organotitanium reagents

Article abstract of DOI:10.1039/c4ob00677a

A simple and mild catalytic coupling reaction of propargyl halides with organotitanium reagents is reported. The reaction of propargyl bromide with organo-titanium reagents mediated by NiCl₂(2 mol%) and PCy₃(4 mol%) in CH₂

Full text of DOI:10.1039/c4ob00677a

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Biomolecular Chemistry
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Nickel-catalyzed substitution reactions of
propargyl halides with organotitanium reagents†
Cite this: Org. Biomol. Chem., 2014,
12, 7634
Qing-Han Li,*a,b Jung-Wei Liao,a Yi-Ling Huang,a Ruei-Tang Chianga and
Han-Mou Gau*a
A simple and mild catalytic coupling reaction of propargyl halides with organotitanium reagents is reported.
The reaction of propargyl bromide with organo-titanium reagents mediated by NiCl2 (2 mol%) and PCy3
(4 mol%) in CH2Cl2 afforded coupling product allenes in good to excellent yields (up to 95%) at room temp-
erature. However, NiCl2(PPh3)2 was the best catalyst for substituted propargyl halides to yield allenes or
alkynes preferentially. On the basis of the experimental results, a possible catalytic cycle has been proposed.
Received 31st March 2014,
Accepted 30th July 2014
DOI: 10.1039/c4ob00677a
www.rsc.org/obc
Introduction
Allenes and alkynes are important structural scaffolds found
in many natural and pharmaceutical products,1 and in
addition, they serve as building blocks for many organic trans-
formations.2 Owing to the importance of the framework of
allenes and alkynes, their synthesis and applications have
attracted considerable attention over the past decades.3 Syn-
thetic protocols for substituted allenes include elimination of
allylic compounds,4 isomerization of alkynes,5 a reaction of
aldehyde and terminal alkynes,6 and a few cases of metal-cata-
lyzed reactions of propargylic compounds.7,8 For the synthesis
of alkynes, numerous new synthetic methodologies have been
developed in recent years. Among the methods hitherto develo-
ped, Sonogashira coupling reactions, which are conducted in
general at elevated temperatures, have been a central focus in
recent years.9 In addition, metal-catalyzed coupling reactions
of electrophiles with alkynylmetallic reagents provide an
alternative route for the synthesis of alkyne compounds.10 For
metal-catalyzed reactions, the coupling reaction of propargyl
derivatives with organometallic nucleophiles is especially
interesting, since the reaction may proceed via either an SN2′
process for the formation of an allene 2, or an SN2 process to
give an alkyne 3 (Scheme 1).2b However, this type of reaction
has been less often explored due to the complication of two
competitive pathways. The success of this reaction relies
mainly on suitable catalytic systems and/or appropriate
Scheme 1 SN2’ and SN2 processes of the metal-catalyzed coupling
reactions of propargyl derivatives with organometallic nucleophiles.
organometallic reagents that can selectively produce either
compound 2 or 3.
Organotitanium reagents, which can be easily prepared
from the corresponding halides, are highly efficient nucleo-
philes for cross-coupling reactions with aromatic halides11 or
benzylic halides.12 To the best of our knowledge, there is no
report on the direct coupling of propargylic halide with
organotitanium reagents for the synthesis of allenes or
alkynes. Recent investigations have demonstrated that nickel is
a good catalyst for many cross-coupling reactions.13
To continue our effort to develop efficient coupling reac-
tions using reactive organometallic reagents,11d,14 we herein
report a novel nickel(II)-catalyzed substitution reaction of pro-
pargyl halides with organotitanium reagents, at ambient temp-
erature, on short timescales and with good yields, for the
synthesis of allenes or alkynes.
aDepartment of Chemistry, National Chung Hsing University, Taichung 402, Taiwan.
E-mail: hmgau@draagon.nchu.edu.tw; Fax: +886-4-22862547; Tel: +886-4-22878615
bCollege of Chemistry and Environmental Protection Engineering, Southwest
Results and discussion
University for Nationalities, Chengdu 610041, P. R. China.
Initially, the reaction of propargyl bromide HCuCCH2Br (1a)
with PhTi(O-i-Pr)3 (4a) was selected as the basis for the catalyst
screening study (eqn (1)). The primary metal screening was
E-mail: lqhchem@163.com; Fax: +86-28-85524382
†Electronic supplementary information (ESI) available: Characterization data of
titanium reagents and coupling products. See DOI: 10.1039/c4ob00677a
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performed with PCy3, and the results are listed in Table 1. 2 mol% NiCl2 and 4 mol% PCy3, conducted in CH2Cl2 at room
When 2 mol% NiCl2(PPh3)2 was used as the catalyst, the reac- temperature over 6 h (Table 1, entry 5).
tion smoothly proceeded via the SN2′ process to give the corres-
With the optimized conditions in hand, the scope of the
ponding product phenylallene 2aa, with 73% conversion in catalytic substitution reaction with organotitanium reagents of
CH2Cl2 at room temperature over 6 h (Table 1, entry 1). To our RTi(O-i-Pr)3 was then explored (eqn (2)), and the results are
delight, when 4 mol% PCy3 was used, the reaction conversion presented in Table 2 (entries 1–11). The reactions of aryltita-
was significantly elevated to 97% (Table 1, entry 2). Sub- nium reagents bearing electron-donating substituents on the
sequently, we surveyed other nickel(II) complexes with PCy3 aromatic ring gave mono-substituted allenes 2ab–2ag in good
and found that the NiCl2 (2 mol%)/PCy3 (4 mol%) complex
exhibited the best activity (Table 1, entry 5). Since the outcome
of each coupling reaction depends on the relative steric hin-
drance and electronic properties of the ligand, further optimi-
zation of the reaction conditions was then aimed at exploring
the efficacy of NiCl2 with other phosphine ligands (Table 1,
entries 6–9). It was found that the NiCl2/PPh3, NiCl2/
P(p-tolyl)3, NiCl2/P(o-tolyl)3, and NiCl2/dppm complexes were
also effective for the reaction, but the catalytic system of NiCl2
(2 mol%)/PCy3 (4 mol%) had the highest conversion capability
(>99%) among the NiCl2/phosphine complexes (Table 1, entry 5).
When Pd(OAc)2 was used as a metal source, a lower 68% con-
version of 2aa was obtained (Table 1, entry 10). Under the
above reaction conditions, phenyl boronic acid and phenyl pot-
assium fluoborate were also examined as a nucleophile source.
However, with or without 2 equiv. Cs2CO3, PhB(OH)2 was inert
for the coupling reaction (Table 1, entries 11 and 12). When
PhBF3K was used as a nucleophile source, a 13% conversion of
2aa was obtained with NiCl2/PCy3 and a 55% conversion of 2aa
was obtained with Pd(OAc)2/PCy3(Table 1, entries 13 and 14).
Therefore, the optimal reaction conditions were as follows:
Table 2 Monosubstituted allenes from coupling reactions of propargyl
bromide 1a with RTi(O-i-Pr)3
a
ð2Þ
Entry
1
4 (R)
Product 2
Yieldb (%)
87%
2
91%
3
4
92%
91%
5
6
93%
95%
Table 1 Optimization of the coupling reaction of propargyl bromide
(1a) and PhTi(O-i-Pr)3 (4a)a
ð1Þ
7
8
90%
94%
Entry
[Ni]
PR3
Nucleophile
Conv.b (%)
1
2
3
4
5
6
7
8
NiCl2(PPh3)2
NiCl2(PPh3)2
Ni(acac)2
NiBr2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
Pd(OAc)2
NiCl2
—
PCy3
PCy3
PCy3
PCy3
PPh3
P(p-tolyl)3
P(o-tolyl)3
dppmc
PCy3
PCy3
PCy3
PCy3
PCy3
4a
4a
4a
4a
4a
4a
4a
4a
73
97
97
97
>99
92
96
94
96
68
—
9c
91%
20%
9
4a
4a
10d
10
11d
12e
13
14
PhB(OH)2
PhB(OH)2
PhBF3K
PhBF3K
NiCl2
NiCl2
Pd(OAc)2
6
13
55
61%
a 1a/4a/M/L = 1.00/1.50/0.020/0.040 mmol; CH2Cl2, 2 mL. b Conversion
of 2aa is based on 1H NMR spectra. c dppm (1,1-bis-
(diphenylphosphino)methane) = 2 mol%. d 1.50 mmol PhB(OH)2.
e 1.50 mmol PhB(OH)2 and 3.00 mmol of Cs2CO3.
a 1/4/NiCl2/PCy3 = 1.00/1.50/0.020/0.040 mmol; CH2Cl2, 2 mL; room
temperature. b Isolated yield. c NiCl2/PCy3 = 0.060/0.120 mmol (6 mol%),
12 h. d >99% conversion, 2aj : 2aj′ = 38 : 62.
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to excellent isolated yields from 87 to 95% (Table 2, entries intermediate 10, which undergoes a reductive elimination
2–7). The catalytic system also works well for an aryl nucleo- process to produce the coupling product 2aj and regenerate
phile bearing an electron-withdrawing trifluoromethyl substi- the active species 5 for the next cycle of the reaction.
tuent, giving 2ah in a 94% yield (Table 2, entry 8). In contrast,
Encouraged by the good performance of the current catalyst
reactions employing an aliphatic cyclohexyl nucleophile system shown above, we subsequently investigated coupling
required a higher catalyst loading of 6 mol% and a longer reac- reactions of substituted propargyl bromide (eqn (3)). However,
tion time of 12 h to give the allene 2ai in a yield of 92% the reaction of 1-bromo-2-pentyne (1b) with PhTi(O-i-Pr)3,
(Table 2, entry 9). Unfortunately, we used other alkyltitanium employing the catalyst of 2 mol% NiCl2 and 4 mol% PCy3,
reagents, such as nBuTi(O-i-Pr)3 and sBuTi(O-i-Pr)3, without yielded both SN2′ and SN2 products of 1-phenyl-1-ethyl-allene
success. This may be due to the fact that the boiling point of (2ba) and 1-phenyl-2-pentyne (3ba) with only a 50% conversion
the corresponding allene products is too low and they cannot (Table 3, entry 1). The product ratio is about 3 : 1 in favor of
be separated.
the allene 2ba. Therefore, the reaction conditions were re-
It is worth noting that a reaction of 1a with (2,6-Me2C6H3)- tuned. We initially optimized the reaction of 1-bromo-
Ti(O-i-Pr)3 (4j) containing a sterically hindered 2,6-Me2C6H3 2-pentyne (1b) with PhTi(O-i-Pr)3 in CH2Cl2 at room tempera-
nucleophile produced a mixture of the two compounds 2aj ture, catalyzed by the NiCl2 (4 mol%)/PCy3 (8 mol%) complex.
and 2aj′ (Table 2, entry 10). The total conversion is >99% with The reaction proceeded smoothly to give the products 2ba and
a ratio of 38 : 62 in favor of 2aj′. The desired allene 2aj is a 3ba with a 77% conversion and a ratio of 82 : 18 in favor of
minor product in a 20% yield. The structure of 2aj′ that is in a 2ba. Then, the effect of solvents was investigated (Table 3,
61% yield was confirmed by 1H NMR and high-resolution entries 2–4). The results indicated that solvents played an
mass spectra. Compound 2aj′ is formed from two molecules of important role in adjusting the conversion and product ratio
1a and one 2,6-Me2C6H3 nucleophile.
of the reaction. THF was found to be the most suitable solvent
A likely catalytic cycle for the formation of 2aj′ is proposed for the reaction, affording the products 2ba and 3ba with 90%
as shown in Scheme 2. The first reaction involves the replace- conversion and a ratio of 86 : 14 in favor of 2ba (Table 3, entry 4).
ment of both chloride ions in NiCl2 with two 2,6-Me2C6H3 To further improve the conversion and product ratio of the
groups, followed by reductive elimination of two 2,6-Me2C6H3 reaction, various phosphine ligands were investigated (Table 3,
groups and coordination of PCy3 to give a Ni(0) active species entries 5–7). The results showed that PPh3 could produce 2ba
Ni(PCy3)2 (5). Oxidative addition of propargyl bromide (1a) to 5 and 3ba with product ratio of 94 : 6, but in 82% conversion
gives a Ni(II) species (Cy3P)2Ni(CH2CuCH)Br (6). Complex 6 (Table 3, entry 5). Pleasingly, the NiCl2(PPh3)2 complex signifi-
could also be isomerized to 9. However, (2,6-Me2C6H3)Ti(O- cantly improved the conversion and product ratio of the reac-
i-Pr)3 (4j) contains sterically hindered 2,6-Me2C6H3 groups, and tion. The coupling products 2ba and 3ba were obtained in a
its steric hindrance slows down the transmetallation reaction, 95% conversion and the best selectivity (2ba : 3ba = 95 : 5,
allowing the reaction of 6 with another molecule of propargyl Table 3, entry 8). Thus, the optimized catalytic system was
bromide. Then, the α-H of the propargyl group of 6 is attacked
by one molecule of 1a to give an intermediate 7. Transmetalla-
tion of 7 with (2,6-Me2C6H3)Ti(O-i-Pr)3 gives a Ni(II) intermedi-
ate 8, which undergoes a reductive elimination process to
produce the coupling product 2aj′ and regenerate the active
species 5 for the next cycle of the reaction. Meanwhile, trans-
metallation of 9 with (2,6-Me2C6H3)Ti(O-i-Pr)3 gives a Ni(II)
4 mol% NiCl2(PPh3)2, 1.0 mmol substituted propargyl
Table 3 Optimization of the reaction of 1-bromo-2-pentyne (1b) and
PhTi(O-i-Pr)3 (4a)a
ð3Þ
[Ni]
(4 mol%)
Ligand
(8 mol%)
Conv.b
(%)
Entry
Solvent
2ba : 3ba
1c
2
3
4
5
6
7
8
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2(PPh3)2
PCy3
PCy3
PCy3
PCy3
CH2Cl2
CH2Cl2
Et2O
THF
THF
THF
THF
THF
50
77
88
90
82
50
80
95
75 : 25
82 : 18
81 : 19
86 : 14
94 : 6
80 : 20
83 : 17
95 : 5
PPh3
PPh2Me
P(o-tolyl)3
—
a 1b/4a/“Ni”/L = 1.00/1.50/0.040/0.080 mmol; solvent, 2 mL, 6 h.
b Conversions were based on 1H NMR spectra. c 2 mol% NiCl2, 4 mol%
PCy3.
Scheme 2 The proposed catalytic cycle for the formation of 2aj’ and
2aj.
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bromide, and 1.5 mmol RTi(O-i-Pr)3 in THF at room tempera-
ture (eqn (3), Table 3, entry 8).
Table 4 (Contd.)
Under the optimized reaction conditions, the reaction
scope was further explored with the propargyl bromides 1b, 1c,
1d and propargyl chlorides 1e, 1f using a catalytic system of
NiCl2(PPh3)2 (eqn (4)), and results are summarized in Table 4.
Coupling reactions of 1b with the aryltitanium reagents 4a, 4c,
4f or 4j gave 1,1-disubstituted allenes 2ba, 2bc, 2bf and 2bj in
>90% selectivity with moderate to good isolated yields
ð4Þ
2 : 3
Product
Entry 1 X R1 R2
4 R
(conv., %)b (yield, %)c
11
Cl nPent H (1e)
2ec : 3ec =
1 : 99 (99)e
Table 4 Coupling reactions of substituted propargyl bromides or
chlorides with ArTi(O-i-Pr)a
12
13
Cl nPent H (1e)
Cl nPent H (1e)
2ef : 3ef =
10 : 90 (99)e
ð4Þ
2ej : 3ej =
86 : 14 (99)e
2 : 3
Product
Entry 1 X R1 R2
4 R
(conv., %)b (yield, %)c
14
15
Cl Ph H (1f)
Cl Ph H (1f)
2fa : 3fa =
3 : 97 (97)
1
Br Et H (1b)
2ba : 3ba =
95 : 5 (95)d
2fc : 3fc =
9 : 91 (87)
2
Br Et H (1b)
2bc : 3bc =
97 : 3 (86)
16
Br nPent H (1g)
2ga : 3ga =
1 : 99 (>99)e
3
4
Br Et H (1b)
Br Et H (1b)
2bf : 3bf =
93 : 7 (78)
a Propargyl halide/Ti reagent/Ni = 1.0/1.5/0.06 mmol, THF, 2 mL; room
temperature, 6 h. b Conversion represented in parenthesis is based on
1H NMR spectra. c Isolated yield is given in parentheses. d Propargyl
halide/Ti reagent/Ni = 1.0/1.5/0.04 mmol. e 12 h.
2bj : 3bj =
96 : 4 (74)
(68–84%; Table 4, entries 1–4). Coupling reactions of 1-bromo-
2-butyne (1c) with phenyl or 2-methylphenyl also gave predo-
minantly allene products 2ca and 2cc with excellent selectivity
(>90%) and good isolated yields (Table 4, entries 5 and 6). The
catalytic system also applies to the secondary propargyl
bromide 3-bromo-1-butyne (1d), giving 1,3-disubstituted pro-
ducts of 1-methyl-3-phenylallene (2da) and 1-methyl-3-(2-
methylphenyl)-allene (2dc) in >90% selectivity with isolated
yields of 81 and 64%, respectively (Table 4, entries 7 and 8).
In contrast, the coupling reaction of 1-chloro-2-octyne (1e)
with phenyl favoured the formation of an alkyne product 3ea
in 69% selectivity (Table 4, entry 9) over a reaction time of 6 h.
It was further found that the alkynes 3ea, 3ec and 3ef became
predominant products when the reaction time was extended to
12 h (Table 4, entries 10–12). Furthermore, in order to explain
the experimental results, the corresponding bromine derivate
1e was submitted to the reaction, and it was also found that
the alkyne product 3ga (that is, product 3ea) was the predomi-
nant product when 1-bromo-2-octyne (1g) coupled with the
5
6
Br Me H (1c)
Br Me H (1c)
2ca : 3ca =
92 : 8 (87)d
2cc : 3cc =
95 : 5 (95)d
7
8
Br H Me (1d)
Br H Me (1d)
2da : 3da =
95 : 5 (90)
2dc : 3dc =
95 : 5 (72)
9
Cl nPent H (1e)
Cl nPent H (1e)
2ea : 3ea =
31 : 69 (87)
2ea (22)
3ea (55)
10
2ea : 3ea =
1 : 99 (>99)e
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phenyl nucleophile (Table 4, entry 16). So, the reverse selecti-
vity for the coupling reactions of 1e and 1g is attributed to an
effect of the long-chain n-pentyl substituent at the sp carbon.
Similarly, coupling reactions of 1-phenyl-3-chloropropyne (1f)
with aryl also favoured the formation of alkyne products 3fa
and 3fc in >90% selectivity with yields of 90 and 70% (Table 4,
entries 14 and 15). However, the allene 2ej remained as the
major product when 1e coupled with the hindered 2,6-
dimethylphenyl nucleophile (Table 4, entry 13). This result
may be attributed to an effect of the different stability of the
intermediate from oxidative addition of propargyl halides to
(R′3P)2Ni, and the steric hindrance of the aryltitanium
reagents. (R′3P)2Ni(alkynyl)Cl from oxidative addition of pro-
pargyl chlorides to (R′3P)2Ni is more stable than from the iso-
merization of (R′3P)2Ni(allenyl)Cl. In the equilibrium mixture
of compounds of (R′3P)2Ni(allenyl)Cl and (R′3P)2Ni(alkynyl)Cl,
intermediate (R′3P)2Ni(alkynyl)Cl accounted for the major.
So, transmetallation of (R′3P)2Ni(alkynyl)Cl with aryltitanium
reagents gives intermediate (R′3P)2Ni(alkynyl)Ar, which under-
goes a reductive elimination process to produce the coupling
product alkynes 3ea, 3ec, 3ef, 3fa and 3fc. When 1e couples
with the 2,6-dimethylphenyl nucleophile, steric hindrance
slows down the transmetallation reaction, allowing the inter-
mediate (R′3P)2Ni(alkynyl)Ar to isomerize to (R′3P)2Ni(allenyl)-
Cl with smaller steric hindrance. Then, transmetallation of
(R′3P)2Ni(allenyl)Cl with aryltitanium reagents gives a Ni(II)
intermediate (R′3P)2Ni(allenyl)Ar, which undergoes a reductive
elimination process to produce the allene 2ej (see Scheme 3).
Substitution reactions of 1b, 1e, or 1f with a phenyl
Grignard reagent catalyzed by 6 mol% of NiCl2(PPh3)2 were
examined for the purpose of comparison (eqn (5)). Results
showed that a rough 1 : 1 ratio of 2 : 3 was obtained no matter
whether the R1 was an alkyl or an aryl group. This study
Table 5 Coupling reactions of substituted propargyl bromides or chlor-
ides with a Grignard reagenta
ð5Þ
Entry
1 (X R1 R2)
Conv.b (%)
2ba : 3ba
1
1b (Br Et H)
1e (Cl nPent H)
1f (Cl Ph H)
97
>99
>99
54 : 46
51 : 49
47 : 53
2c
3
a Propargyl halide/PhMgBr/NiCl2(PPh3)2 = 1.0/1.5/0.06 mmol, 2 mL
THF, room temperature, 6 h. b Conversion is based on 1H NMR
spectra. c 12 h.
NiCl2 with two aryl groups followed by reductive elimination of
two aryl groups and coordination of PR′3 to give a Ni(0) active
species of Ni(PR′3)2 (11). Then, oxidative addition of propargyl
halides to complex 11 gives a Ni(II) species of (R′3P)2Ni-
(CH2CuCH-R)X (12). Complex 12 could be isomerized to the
corresponding complex 14. Transmetalation of aryltitanium
with 12 or 14 gives aryl(propargyl)nickel(II) intermediate 13 or
aryl(allenyl)nickel(II) intermediate 15 and XTi(O-i-Pr)3. Finally
complex 13 or 15 undergoes reductive elimination giving the
desired product of an alkyne 3 or an allene 2, and regenerates
the active Ni(0) species for the next catalytic cycle.
Conclusions
demonstrates an advantage of organotitanium compounds as A nickel-catalyzed coupling reaction of propargyl bromides or
nucleophile sources over Grignard reagents in terms of substituted propargyl bromides or chlorides with organotita-
product selectivity (Table 5).
nium reagents is reported. Coupling reactions of aryl or alkyl
A proposed possible reaction process for the coupling reac- nucleophiles with the simple propargyl bromide 1a give mono-
tion, based on the above results and on previous mechanistic substituted allenes in high yields. Depending on the type of
studies on the coupling reaction of propargyl derivatives with substituents on the substituted propargyl bromides or chlor-
organometallic nucleophiles, is shown in Scheme 3. The first ides, 1,1-disubstituted allenes, 1,3-disubstituted allenes, or
reaction involves the replacement of both chloride ions in substituted alkynes are obtained in high to excellent selecti-
vity. Profound steric effects of bulk aryl nucleophiles or of pro-
pargyl chloride with a long chain n-pentyl substituent are
observed. The most sterically bulky 2,6-Me2C6H3 nucleophile
couples with propargyl bromide 1a, producing
a major
product 2aj′ which is derived from one 2,6-Me2C6H3 and two
molecules of 1a. Coupling reactions of 1e favoured alkyne pro-
ducts 3ef with conversions of up to >99%. However, the coup-
ling reaction of 1e with the 2,6-Me2C6H3 nucleophile shifts the
selectivity back to the allene product 2ej, with the ratio of
2ej : 3ej equal to 86 : 14. For coupling reactions of 3-phenyl pro-
pargyl chloride, the alkynes were obtained as the predominant
products. This methodology provides a useful procedure for
the synthesis of allenes and alkynes. Further studies on the
reaction mechanism and the application of this catalyst to
other coupling reactions are currently under way.
Scheme 3 The proposed catalytic cycle for the formation of 2 and 3.
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General procedures for the coupling reaction of propargyl
bromide with organotitanium reagents
Experimental section
General procedures
1H and 13C NMR spectra were obtained with a Varian Mercury- Under a dry nitrogen atmosphere, to a mixture of NiCl2
400 (1H, 400 MHz; 13C, 100 MHz) spectrometer, and chemical (0.0026 g, 0.020 mmol) and tricyclohexylphosphine (0.0112 g,
shifts were measured relative to tetramethylsilane (0.00 ppm) 0.0400 mmol) in a reaction vessel was added an organotita-
as an internal reference. Mass spectroscopy was performed nium compound (1.5 mmol) in 2 mL CH2Cl2 followed by an
using a Finnigan MAT 95 XL ThermoQuest Mass Spectrometer. addition of propargyl bromide (1a, 0.107 mL, 1.00 mmol). The
Elemental analyses were performed using a Heraeus CHN-O- resultant solution was stirred at room temperature for 6 h to
RAPID instrument. All syntheses and manipulations were give an orange–yellow solution which was quenched with 2 mL
carried out under a dry nitrogen atmosphere using standard of de-ionized water. The solution was extracted with CH2Cl2
Schlenk techniques or in a glovebox. Solvents were dried by (3 × 30 mL). The organic phase was dried over anhydrous
refluxing for at least 24 h over P2O5 (dichloromethane) or MgSO4 and concentrated. The coupling products were purified
sodium/benzophenone (THF, diethylether, n-hexane or by column chromatography.
toluene) and were freshly distilled prior to use. Nickel com-
Phenyl-1,2-propadiene (2aa).3e Colorless liquid, 0.101
g
pounds, phosphines, and propargyl halides were obtained (87.0%). 1H NMR (400 MHz, CDCl3): δ 7.33–7.28 (m, 4H),
commercially and used directly for coupling reactions. Organo- 7.23–7.17 (m, 1H), 6.17 (t, J = 6.8 Hz, 1H), 5.15 (d, J = 6.8 Hz,
titanium compounds of RTi(O-i-Pr)3 (R = Ph (4a),11d 4-MeC6H4 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 209.8, 133.9,
(4b),11d 2-MeC6H4 (4c),11d 4-MeOC6H4 (4d),12a 3,5-Me2C6H3 128.6, 126.9, 126.7, 93.93, 78.7 ppm.
(4f),11d 2-Naphthyl (4g),12a 4-CF3C6H4 (4 h),11d or c-C6H11
1-(4-Methylphenyl)-1,2-propadiene (2ab).5 Colorless liquid,
(4i)11e) were prepared according to literature procedures. Purifi- 0.118 g (91.0%). 1H NMR (400 MHz, CDCl3): δ 7.18 (d, J =
cation of the reaction products was carried out by flash 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.13 (t, J = 6.8 Hz, 1H),
chromatography.
5.11 (t, J = 6.8 Hz, 2H), 2.32 (s, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): δ 209.6, 136.6, 130.9, 129.3, 126.6, 93.7,
78.6, 21.1 ppm.
General procedures for the synthesis of organotitanium
reagents(4a–j)
1-(2-Methylphenyl)-1,2-propadiene (2ac).3f Colorless liquid,
1
To a three-necked round bottom flask containing magnesium 0.120 g (92.0%). H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 7.2
turnings (2.43 g, 0.100 mol) in 100 mL of THF and equipped Hz, 1H), 7.18–7.08 (m, 3H), 6.34 (t, J = 6.8 Hz, 1H), 5.11 (d, J =
with an addition funnel, a septum and a condenser, aryl 6.8 Hz, 2H), 2.35 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
bromide (0.100 mol) in 50 mL THF was slowly added over a δ 210.4, 134.9, 132.1, 130.4, 127.2, 126.8, 126.1, 91.1, 77.9,
period of 1 h under a dry nitrogen atmosphere. The reaction 19.8 ppm.
mixture was stirred for another 2 h to give a Grignard
1-(4-Methoxyphenyl)-1,2-propadiene (2ad).3f Colorless liquid,
solution. The above solution was transferred via a cannula to a 0.133 g (91.0%). 1H NMR (400 MHz, CDCl3): δ 7.22 (d, J =
solution of Ti(O-i-Pr)4 (22.4 mL, 0.0750 mol) and TiCl4 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.13 (t, J = 6.8 Hz, 1H),
(2.80 mL, 0.0250 mol) in 50 mL THF, cooling to 0 °C. The 5.13 (d, J = 6.8 Hz, 2H), 3.80 (s, 3H) ppm. 13C{1H} NMR
resultant solution was allowed to warm to room temperature (100 MHz, CDCl3): δ 209.3, 158.7, 127.7, 126.1, 114.1, 93.3,
and reacted for 3 h. The solvent was removed under reduced 78.7, 55.3 ppm.
pressure to give a solid. The residue was extracted with
1-(2-Methoxyphenyl)-1,2-propadiene (2ae).3e Colorless liquid,
hexane (3 × 100 mL), and the combined extract was concen- 0.136 g (93.0%). 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J =
trated and cooled at 4 or −18 °C to give a crystalline material 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 6.85
ArTi(O-i-Pr)3.
(d, J = 8.4 Hz, 1H), 6.57 (t, J = 6.8 Hz, 1H), 5.10 (d, J = 6.8 Hz,
(2-MeOC6H4)Ti(O-i-Pr)3 (4e). Pale yellow crystals, 19.8 g 2H), 3.83 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
1
(59.6%). H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 6.8 Hz, 1H), δ 210.2, 155.9, 127.9, 127.7, 122.3, 120.8, 110.9, 87.8, 78.0,
7.13 (t, J = 7.6 Hz, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.70 (d, J = 55.5 ppm.
8.0 Hz, 1H), 4.75 (s, br, 3H), 3.80 (s, 3H), 1.28 (d, J = 6.0 Hz,
1-(3,5-Dimethylphenyl)-1,2-propadiene (2af). Colorless liquid,
18H) ppm. 13C{1H} NMR (100 MHz, CDCl3): 174.1, 0.137 g (95.0%). 1H NMR (400 MHz, CDCl3): δ 6.92 (s, 2H),
δ
162.7, 135.2, 127.6, 119.4, 107.9, 77.3, 54.4, 25.7 ppm. Anal. 6.84 (s, 1H), 6.10 (t, J = 6.8 Hz, 1H), 5.12 (d, J = 6.8 Hz, 2H),
calcd for C16H28O4Ti: C, 57.84; H, 8.49%. Found: C, 57.69; 2.29 (s, 6H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 209.7,
H, 8.37%.
(2,6-Me2C6H3)Ti(O-i-Pr)3 (4j). Yellow crystals, 19.6 g (59.3%). calcd for C11H12: 144.0939. Found: 144.0930.
1H NMR (400 MHz, CDCl3): δ 7.03 (t, J = 7.6 Hz, 1H), 6.90 1-(2-Naphthyl)-1,2-propadiene (2ag).3g White solid, 0.150 g
138.1, 133.6, 128.7, 124.5, 93.9, 78.6, 21.2 ppm. HRMS (EI) m/z
1
(d, J = 7.6 Hz, 2H), 4.69 (sept, J = 6.0 Hz, 3H), 2.65 (s, 6H), (90.0%). H NMR (400 MHz, CDCl3): δ 7.82–7.75 (m, 3H), 7.66
1.35 (d, J = 6.0 Hz, 18 H) ppm. 13C{1H} NMR (100 MHz, (s, 1H), 7.53–7.39 (m, 3H), 6.34 (t, J = 6.8 Hz, 1H), 5.22 (d, J =
CDCl3): 184.1, 142.3, 128.1, 125.4, 77.9, 26.7, 26.1 ppm. 6.8 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 210.3,
Anal. calcd for C17H30O3Ti: C, 61.82; H, 9.16%. Found: 133.7, 132.6, 131.4, 128.2, 127.7, 127.6, 126.2, 125.6, 125.4,
C, 61.20; H, 8.88%.
124.6, 94.3, 79.0 ppm.
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1-(4-Trifluoromethylphenyl)-1,2-propadiene (2ah). Colorless (100 MHz, CDCl3): δ 208.4, 137.7, 136.4, 128.3, 123.8, 106.7,
liquid, 0.173 g (94.0%). 1H NMR (400 MHz, CDCl3): δ 7.55 78.4, 22.5, 21.3, 12.5 ppm. HRMS (EI) m/z calcd for C13H16:
(d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.19 (t, J = 6.8 Hz, 172.1252. Found: 172.1245.
1H), 5.21 (d, J = 6.8 Hz, 2H) ppm. 13C{1H} NMR (100 MHz,
3-(2,6-Dimethylphenyl)-1,2-pentadiene (2bj). Colorless liquid,
CDCl3): δ 210.4, 137.9, 128.8 (q, J = 32.0 Hz), 126.8, 125.5 0.122 g (71.0%). 1H NMR (400 MHz, CDCl3): δ 7.09–7.00 (m,
(q, J = 3.8 Hz), 124.2 (q, J = 270 Hz), 93.2, 79.3 ppm. HRMS (EI) 3H), 4.75 (t, J = 4.0 Hz, 2H), 2.29 (s, 6H), 2.13 (qt, J = 4.0,
m/z calcd for C10H7F3: 184.0500. Found: 184.0491.
7.6 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H) ppm. 13C{1H} NMR
1-Cyclohexyl-1,2-propadiene (2ai).3h Yellow liquid, 0.112 g (100 MHz, CDCl3): δ 205.3, 137.5, 135.9, 127.5, 126.8, 104.2,
(91.0%). 1H NMR (400 MHz, CDCl3): δ 5.13–5.06 (m, 1H), 75.2, 25.5, 19.9, 12.0 ppm. HRMS (EI) m/z calcd for C13H16:
4.72–4.66 (m, 2H), 2.04–1.92 (m, 1H), 1.80–1.68 (m, 4H), 172.1252. Found: 172.1254.
1.67–1.59 (m, 1H), 1.34–1.04 (m, 5H) ppm. 13C{1H} NMR
3-Phenyl-1,2-butadiene (2ca).3j Colorless liquid, 0.100
g
(100 MHz, CDCl3): δ 207.4, 96.1, 75.4, 36.6, 33.0, 26.1, (77.0%). 1H NMR (400 MHz, CDCl3): δ 7.43–7.38 (m, 2H),
26.0 ppm.
7.36–7.28 (m, 2H), 7.23–7.17 (m, 1H), 5.02 (q, J = 3.2 Hz, 2H),
1-(2,6-Dimethylphenyl)-1,2-propadiene (2aj). Colorless liquid, 2.10 (t, J = 3.2 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
0.029 g (20.0%). 1H NMR (400 MHz, CDCl3): δ 7.06–7.00 δ 209.0, 136.7, 128.3, 126.5, 125.6, 99.8, 76.9, 16.6 ppm.
(m, 3H), 6.24 (t, J = 7.2 Hz, 1H), 4.91 (d, J = 7.2 Hz, 2H), 2.36
3-(2-Methylphenyl)-1,2-butadiene (2cc).3k Colorless liquid,
(s, 6H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 210.3, 136.5, 0.127 g (88.0%). 1H NMR (400 MHz, CDCl3): δ 7.23–7.12
131.2, 128.1, 126.7, 89.5, 75.8, 21.1 ppm. HRMS (EI) m/z calcd (m, 4H), 4.75 (q, J = 3.2 Hz, 2H), 2.36 (s, 3H), 2.04 (t, J = 3.2 Hz,
for C11H12:144.0939. Found: 144.0945.
1-(2,6-Dimethylphenyl)-4-(bromomethyl)-1,2,4-pentatriene 135.8, 130.5, 127.5, 126.9, 125.8, 98.8, 74.2, 20.4, 20.3 ppm.
(2aj′). Colorless liquid, 0.081 g (61.0% based on 2 molecules of
1-Phenyl-1,2-butadiene (2da).3l Colorless liquid, 0.105
3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 207.6, 137.7,
g
the substrate). 1H NMR (400 MHz, CDCl3): δ 7.13–7.08 (m, 1H), (81.0%). 1H NMR (400 MHz, CDCl3): δ 7.30–7.27 (m, 4H),
7.05–7.00 (m, 2H), 6.61 (s, 1H), 5.54 (t, J = 6.8 Hz, 1H), 7.19–7.15 (m, 1H), 6.09 (dq, J = 3.2, 7.2 Hz, 1H), 5.53 (dq, J =
5.09–5.06 (m, 2H), 4.23 (s, 2H), 2.19 (s, 6H) ppm. 13C{1H} NMR 7.2, 7.2 Hz, 1H), 1.78 (dd, J = 3.2, 7.2 Hz, 3H) ppm. 13C{1H}
(100 MHz, CDCl3): δ 210.4, 136.3, 134.7, 132.8, 130.7, 127.4, NMR (100 MHz, CDCl3): δ 206.0, 135.0, 128.5, 126.6, 93.9, 89.6,
127.3, 89.7, 78.9, 33.3, 20.1 ppm. HRMS (EI) m/z calcd for 14.1 ppm.
C14H15Br: 262.0357. Found: 262.0351.
1-(2-Methylphenyl)-1,2-butadiene (2dc). Colorless liquid,
0.092 g (64.0%). 1H NMR (400 MHz, CDCl3): δ 7.35, (d, J =
7.6 Hz, 1H), 7.17–7.05 (m, 3H), 6.27 (dq, J = 3.2, 7.2 Hz, 1H),
5.48 (dq, J = 7.2, 7.2 Hz, 1H), 2.35 (s, 3H), 1.78 (dd, J = 3.2, 7.2
General procedures for the coupling reaction of substituted
propargyl halides with organotitanium reagents
Under a dry nitrogen atmosphere, to NiCl2(PPh3)2 (0.026 or Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 206.7, 134.8,
0.039 g, 0.0400 or 0.0600 mmol) was added an organotitanium 133.1, 130.4, 127.2, 126.5, 126.0, 91.3, 88.6, 19.8, 14.2 ppm.
compound (1.5 mmol) in 2 mL THF followed by an addition of HRMS (EI) m/z calcd for C11H12: 144.0939. Found: 144.0947.
substituted propargyl bromide or chloride (1.00 mmol). The
3-Phenyl-1,2-octadiene (2ea). Colorless liquid, 0.041
g
1
resultant solution was stirred at room temperature for a given (22.0%). H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.0 Hz, 2H),
period. The solution was quenched with 2 mL of de-ionized 7.32 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 5.06 (t, J = 3.2
water and extracted with CH2Cl2 (3 × 30 mL). The organic Hz, 2H), 2.44–2.37 (m, 2H), 1.60–1.51 (m, 2H), 1.42–1.30 (m,
phase was washed with brine (3 × 30 mL), dried over anhy- 4H), 0.90 (t, J = 6.8 Hz, 3H) ppm. 13C{1H} NMR (100 MHz,
drous MgSO4 and concentrated. The coupling products were CDCl3): δ 208.6, 136.5, 128.3, 126.5, 125.9, 105.0, 78.0, 31.7,
purified by column chromatography.
29.4, 27.5, 22.5, 14.1 ppm. HRMS (EI) m/z calcd for C14H18:
3-Phenyl-1,2-pentadiene (2ba).3i Colorless liquid, 0.121 g 186.1409. Found: 186.1410.
1
(84.0%). H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 7.6 Hz, 2H),
Phenyl-2-octyne (3ea).3m Colorless liquid, 0.168 g (90.0%).
7.32 (t, J = 7.6 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 5.10 (t, J = 1H NMR (400 MHz, CDCl3): δ 7.37–7.28 (m, 4H), 7.25–7.19
4.0 Hz, 2H), 2.43 (qt, J = 4.0, 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, (m, 1H), 3.63–3.57 (m, 2H), 2.26–2.19 (m, 2H), 1.58–1.49 (m,
3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 208.3, 136.5, 2H), 1.43–1.28 (m, 4H), 0.91(t, J = 7.2 Hz, 3H) ppm. 13C{1H}
128.3, 126.5, 125.9, 106.7, 78.8, 22.3, 12.4 ppm.
3-(2-Methylphenyl)-1,2-pentadiene (2bc).3i Colorless liquid, 31.1, 28.7, 25.1, 22.2, 18.8, 14.0 ppm.
0.130 g (82.0%). 1H NMR (400 MHz, CDCl3): δ 7.22–7.14 (3ec).3m Colorless
1-(2-Methylphenyl)-2-octyne
NMR (100 MHz, CDCl3): δ 137.6, 128.4, 127.8, 126.3, 82.7, 77.5,
liquid,
1
(m, 4H), 4.81 (t, J = 3.6 Hz, 2H), 2.33 (s, 3H), 2.31 (qt, J = 3.6, 0.190 g (95.0%). H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.2
7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR Hz, 1H), 7.22–7.12 (m, 3H), 3.49 (s, 2H), 2.31 (s, 3H), 2.24–2.18
(100 MHz, CDCl3): δ 206.4, 137.5, 136.0, 130.4, 127.9, 126.8, (m, 2H), 1.57–1.48 (m, 2H), 1.42–1.27 (m, 4H), 0.90 (t, J = 6.8
125.8, 105.4, 75.7, 26.5, 20.1, 12.3 ppm.
Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 135.9, 135.8,
3-(3,5-Dimethylphenyl)-1,2-pentadiene (2bf). Colorless liquid, 129.9, 128.1, 126.6, 126.1, 82.9, 77.1, 31.1, 28.7, 23.3, 22.2,
0.117 g (68.0%). 1H NMR (400 MHz, CDCl3): δ 7.03 (s, 2H), 19.2, 18.8, 14.0 ppm.
6.85 (s, 1H), 5.08 (t, J = 3.6 Hz, 2H), 2.41 (qt, J = 3.6, 7.6 Hz,
1-(3,5-Dimethylphenyl)-2-octyne (3ef). Colorless liquid,
2H), 2.31 (s, 6H), 1.14 (t, J = 7.6 Hz, 3H) ppm. 13C{1H} NMR 0.174 g (81.0%). 1H NMR (400 MHz, CDCl3): δ 6.96 (s, 2H),
7640 | Org. Biomol. Chem., 2014, 12, 7634–7642
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6.86 (s, 1H), 3.50 (s, 2H), 2.30 (s, 6H), 2.24–2.18 (m, 2H),
1.58–1.48 (m, 2H), 1.44–1.28 (m, 4H), 0.91 (t, J = 7.2 Hz, 3H)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 137.9, 137.5, 128.0,
125.6, 82.4, 77.7, 31.1, 28.7, 24.9, 22.2, 21.2, 18.8, 14.0 ppm.
HRMS (EI) m/z calcd for C16H22: 214.1722. Found: 214.1720.
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3-(2,6-Dimethyl)-1,2-octadiene
(2ej). Colorless
liquid,
0.161 g (75.0%). 1H NMR (400 MHz, CDCl3): δ 7.08–7.00
(m, 3H), 4.72 (t, J = 3.6 Hz, 2H), 2.30 (s, 6H), 2.13–2.06 (m, 2H),
1.53–1.48 (m, 2H), 1.38–1.30 (m, 4H), 0.90 (t, J = 6.4 Hz, 3H)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 205.3, 137.5, 135.8,
127.5, 126.8, 102.9, 74.8, 32.5, 31.7, 27.2, 22.6, 19.9, 14.1 ppm.
HRMS (EI) m/z calcd for C16H22: 214.1722. Found: 214.1727.
1-(2,6-Dimethyl)-2-octyne (3ej). Colorless liquid, 0.010 g
1
(4.6%). H NMR (400 MHz, CDCl3): δ 7.06–6.97 (m, 3H), 3.44
(t, J = 2.4 Hz, 2H), 2.39 (s, 6H), 2.09 (tt, J = 2.4, 6.8 Hz, 2H),
1.49–1.40 (m, 2H), 1.35–1.24 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 136.2, 135.0, 128.0,
126.4, 80.2, 76.9, 31.1, 28.7, 22.2, 19.9, 19.3, 18.8, 14.0 ppm.
HRMS (EI) m/z calcd for C16H22: 214.1722. Found: 214.1717.
1,3-Diphenylpropyne (3fa).3m Colorless liquid, 0.173
g
(90.0%). 1H NMR (400 MHz, CDCl3): δ 7.47–7.40 (m, 4H),
7.37–7.32 (t, J = 7.2 Hz, 2 H), 7.31–7.24 (m, 4H), 3.84 (s, 2H)
ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 136.7, 131.6, 128.5,
128.2, 127.9, 127.8, 126.6, 123.6, 87.5, 82.6, 25.7 ppm.
Phenyl-3-(2-methylphenyl)propyne (3fc).3n Colorless liquid,
0.145 g (70.0%). 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J =
6.4 Hz, 1H), 7.46–7.40 (m, 2H), 7.31–7.26 (m, 3H), 7.23–7.16
(m, 3H), 3.74 (s, 2H), 2.37 (s, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3): δ 136.0, 135.0, 131.6, 130.1, 128.3, 128.2,
127.7, 126.9, 126.2, 123.7, 87.2, 82.7, 23.9, 19.3 ppm.
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Phenyl-2-octyne (3ga).3m Colorless liquid, 0.169 g (91.0%).
1H NMR (400 MHz, CDCl3): δ 7.37–7.29 (m, 4H), 7.25–7.22
(m, 1H), 3.59–3.58 (m, 2H), 2.24–2.20 (m, 2H), 1.55–1.52
(m, 2H), 1.41–1.32 (m, 4H), 0.91(t, J = 7.2 Hz, 3H) ppm.
13C{1H} NMR (100 MHz, CDCl3): δ 137.6, 128.4, 127.6, 126.3,
82.7, 77.5, 31.1, 28.7, 25.1, 22.2, 18.8, 14.0 ppm.
Acknowledgements
Financial support under grant number NSC 99-113-M-005-005-
MY3 from the National Science Council of Taiwan is
appreciated.
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