Can the Ti(OiPr)4/nBuLi combination of reagents function as a catalyst for [2+2+2] alkyne cyclotrimerisation reactions?

Article abstract of DOI:10.1039/c8nj04931a

Catalysis of the cyclotrimerisation of alkynes with the Ti(OiPr)₄/nBuLi system was studied, leading to the development of a particularly convenient and reliable protocol. This method allows the [2+2+2] cycloaddition reaction to proceed within a few minutes under microwave conditions, with generally good selectivity from a variety of aromatic and aliphatic alkynes.

Full text of DOI:10.1039/c8nj04931a

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Can the Ti(OiPr)4/nBuLi combination of reagents
function as a catalyst for [2+2+2] alkyne
cyclotrimerisation reactions?†‡
Cite this: New J. Chem., 2018,
42, 20219
Gabriela Siemiaszko and Yvan Six
*
Received 28th September 2018,
Accepted 7th November 2018
Catalysis of the cyclotrimerisation of alkynes with the Ti(OiPr)4/nBuLi system was studied, leading to the
development of a particularly convenient and reliable protocol. This method allows the [2+2+2]
cycloaddition reaction to proceed within a few minutes under microwave conditions, with generally
good selectivity from a variety of aromatic and aliphatic alkynes.
DOI: 10.1039/c8nj04931a
rsc.li/njc
Introduction
Since the initial discoveries by the group of O. G. Kulinkovich,1,2 the
combined use of titanium(IV) isopropoxide and excess amounts of
Grignard reagents [42 equivalents (equiv.) vs. Ti(OiPr)4] has led to
the development of a family of powerful synthetic tools.3 Analogous
chemistry using organolithium reagents RLi only emerged in the
early 2000s, with reports by the group of J. J. Eisch,4 although earlier
studies on the mono-transmetallation of organolithium reagents
with Ti(OiPr)4 had been carried out from the mid-20th century.5,6
Using 2 equiv. of an organolithium reagent having a b-hydrogen
atom with 1 equiv. of Ti(OiPr)4, the behaviour of the organometallic
species generated is consistent with the titanacyclopropane struc-
ture 1 (Scheme 1). The conditions described by J. J. Eisch (ꢀ78 1C
then overnight, 25 1C) are in fact not applicable because of the low
thermal stability of 1 but subsequent work reported by several
groups has revealed the synthetic potential of the combination of
reagents.7–10 Moreover, using non-standard proportions, i.e. 2 equiv.
of Ti(OiPr)4 and 3 equiv. of nBuLi, we showed that 1 can be
conveniently and reproducibly generated at 0 1C in THF.11
It was also disclosed that terminal alkynes 2 undergo rapid
cyclotrimerisation when treated with a solution of 1 prepared in
this way (about 1.1 equiv., generated from 2.2 equiv. of Ti(OiPr)4 and
3.3 equiv. of nBuLi, Scheme 2).12 Excellent 1,2,4 regioselectivity is
observed in the case of aryl-substituted substrates. The mechanism
is likely to proceed via titanacyclopropene and titanacyclopentadiene
intermediates 3 and 4. To account for the eventual formation of the
Scheme 1 Generation of the active titanacyclopropane complex 1.
Scheme 2 Alkyne cyclotrimerisation mediated by 1: previous work and
tentative mechanism.
[2+2+2] product 5 (/50), several pathways can be put forward, for
instance a [4+2] cycloaddition reaction as shown in Scheme 2. Every
possibility formally involves extrusion of Ti(OiPr)2 and in principle,
the latter could then react with the alkyne starting material 2 to
regenerate species 3, thereby establishing a catalytic cycle.
´
`
Laboratoire de Synthese Organique (LSO), UMR 7652 CNRS/ENSTA/Ecole
´
Polytechnique, Universite Paris-Saclay, 91128 Palaiseau Cedex, France.
Results and discussion
Initial investigation
E-mail: yvan.six@polytechnique.edu
´
† Dedicated to Prof. Janusz Zakrzewski of the University of Łod´z, Poland, on the
occasion of his 70th birthday.
A preliminary study on this prospect was conducted with phenyl-
acetylene 2a. The first experiment, involving the generation of
‡ Electronic supplementary information (ESI) available: Detailed experimental
procedures and characterisation data. See DOI: 10.1039/c8nj04931a
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Table 1 Modification of the initial experimental procedure for the cyclo-
trimerisation of phenylacetylene 2aa
Table 2 Cyclotrimerisation studies performed with phenylacetylene 2a,
under microwave conditions
Ti(OiPr)4 nBuLi
Entry (equiv.) (equiv.) Solvent T (1C)
5a/6a/2a 5a
Time ratiob yieldc
Ti(OiPr)4 nBuLi
Time 5a/6a/2a 5a
yieldc
Entry (equiv.) (equiv.) Solvent Procedurea (min) ratiob
1d
2
3
4
5
0.20
0.20
0.20
0.14
0.10
0.10
0.070
0.30
0.30
0.30
0.21
0.15
0.15
0.105
THF
THF
THF
THF
THF
THF
THF
Ae
B
C
C
C
C
C
30
30
30
30
30
60
30
93 : 07 : 00 74%
100 : 0 : 0f
91 : 06 : 03 72%
95 : 05 : 00 71%
54 : 03 : 43
34 : 03 : 63
13 : 00 : 87
1
2
3
4
2.2
1.0
3.3
1.5
THF
THF
THF
THF
THF
THF
THF
20
20
20
20
20 min 94 : 06 : 00 84%
20 min 36 : 36 : 28
0.40
0.20
0.20
0.10
0.20
0.20
0.20
0.20
0.20
0.10
0.10
0.60
0.30
0.30
0.15
0.30
0.30
0.30
0.30
0.30
0.15
0.15
20 h
20 h
91 : 09 : 00
60 : 07 : 33
92 : 08 : 00 68%
27 : 02 : 71
5
66 (reflux) 20 h
66 (reflux) 20 h
66 (reflux) 20 h
6
6
7
7d
8
81 : 19 : 00 55%
72 : 04 : 24
tBuOMe 55 (reflux) 20 h
a
9
THF
THF
THF
THF
THF
70 (mW)e 45 min 91 : 09 : 00
Procedure A: a solution of 1 in dry THF, generated at 0 1C from
Ti(OiPr)4 and nBuLi, was added dropwise to a cold (0 1C) solution of 2a
in THF. The mixture was then heated with a microwave apparatus for 30
minutes. Procedure B: as Procedure A except nBuLi was added drop-
wise, at 0 1C, to a solution of 2a and Ti(OiPr)4 in dry THF. Procedure C:
2a was added to a solution of 1 in dry THF, generated at 0 1C from
Ti(OiPr)4 and nBuLi. The mixture was then heated with a microwave
10
11
12
13
70 (mW)e 30 min 93 : 07 : 00 74%
70 (mW)e 10 min 93 : 07 : 00
70 (mW)e 10 min 09 : 01 : 90
70 (mW)e 90 min 15 : 01 : 84
a
Experimental procedure, unless otherwise stated: a solution of 1 in the
dry solvent indicated, generated at 0 1C from Ti(OiPr)4 and nBuLi, was
added dropwise to a cold (0 1C) solution of 2a in the same solvent. The
b
apparatus for the time indicated. Qualitative estimation obtained by
13C NMR spectroscopy. Isolated yield. Entry 1 is taken from Table 1
c
d
b
e
mixture was then stirred at T 1C for the time indicated. Qualitative
(entry 10) for comparison purposes. Reaction performed at 70 1C.
estimation obtained by 13C NMR spectroscopy. Isolated yield. A sim-
c
d
f
Polymeric by-products were observed.
plified experimental procedure was applied, whereupon 1 was generated
in the presence of the alkyne. ‘‘mW’’ stands for heating by microwave
e
irradiation.
(Table 1, entry 7), or by adding 2a directly into the solution of
pre-formed 1 [Table 2, entry 3, (procedure C)]. When procedure B
ca. 0.5 equivalent of complex 1, was not encouraging (Table 1, was applied, comparatively large amounts of undesired polymer
entry 2 vs. entry 1). Conversion of 2a was not complete and large compounds were produced again. This problem was minimised
amounts of diene 6a were produced, presumably by hydrolysis with the convenient procedure C and little difference was
of unreacted intermediate 4a (structure 4 in Scheme 2 with observed with the results obtained with procedure A (Table 2,
R = Ph). Better results could be obtained by extending the reac- entry 3 vs. entry 1) (ESI‡). However, the amounts of Ti(OiPr)4 and
tion time to 20 h, even with decreased amounts of Ti(OiPr)4 and nBuLi could not be reduced further, even using freshly distilled
nBuLi (entry 3). Further decrease to 0.1 equiv. of 1 led to lower THF from sodium/benzophenone. Moreover, at times, we experi-
conversion of 2a (entry 4) but gratifyingly, heating the reaction enced difficulties reproducing our results. This is not surprising
mixture at reflux restored reactivity (entry 5). An attempt made since in practice, the septum on the reaction vial must be quickly
at simplifying the procedure by generating the active complex 1 replaced with a cap for the microwave apparatus, which causes
directly in the presence of the alkyne reactant led to a somewhat introduction of a small quantity of oxygen and traces of water.
inferior result (entry 7). Switching the solvent to tBuOMe was Eventually, our best result was obtained with 0.14 equiv. of
unsatisfactory, with lower conversion of 2a (entry 8), as well as Ti(OiPr)4 and 0.21 equiv. of nBuLi, corresponding to 0.07 equiv.
the production of polymeric material (ESI‡). We next investi- of complex 1 (Table 2, entry 4).
gated the effect of microwave irradiation (entries 9–13). Much
One experiment performed with Cp2TiCl2 instead of Ti(OiPr)4
faster production of the cyclotrimerisation product 5a was left 2a essentially unscathed, with the production of minor
observed (entry 11). Finally, attempts at further decreasing amounts of unidentified new compounds. More interestingly,
the amount of catalyst 1 down to less than 0.1 equiv. led to when Grignard reagents were used, the cyclotrimerisation of 2a
poor results (entries 6, 12 and 13).
proceeded with strikingly modified regioselectivity (Scheme 3).
Indeed, the 1,3,5-triphenyl isomer 50a, which had not been
observed so far, was now produced in comparatively large
amounts, suggesting the extensive formation of the titanacyclo-
Development of a better procedure, under microwave
conditions
This first set of experiments had established that complex 1 pentadiene intermediate complex 40a. Explanation for this
could catalyse the cyclotrimerisation of 2a but the experimental phenomenon is not straightforward, especially if one remem-
protocol remained somewhat tedious. Indeed, it involved pre- bers that when treated with Ti(OiPr)4 and a Grignard reagent in
formation of species 1 in a separate vessel (procedure A). We Et2O at low temperature, phenylacetylene 2a is transformed
sought to simplify this procedure in two ways, either by gene- selectively into (E,E)-1,4-diphenylbutadiene 6a.13 However,
rating 1 in the presence of 2a [Table 2, entry 2, (procedure B)], as similar selectivity in [2+2+2] cycloaddition reactions has been
had been attempted already under standard reflux conditions reported by the group of S. Okamoto using a reagent system
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Table
3
Titanium-mediated cyclotrimerisation reactions of terminal
alkynes, performed under simplified and reliable conditionsa
Scheme 3 Comparison of the uses of nBuLi and Grignard reagents in the
titanium-catalysed cyclotrimerisation of phenylacetylene 2a.
composed of Ti(OiPr)4 (1 equiv.), Mg powder (3 equiv.) and
Me3SiCl (2 equiv.).14
Optimised conditions and scope
To circumvent the reproducibility issues encountered at the
lowest loadings of Ti(OiPr)4 and nBuLi and even, occasionally, with
0.2 equiv. of Ti(OiPr)4 and 0.3 equiv. of nBuLi, one could consider
excluding water and oxygen more rigorously from the system. This,
of course, would be inconvenient, costly and hazardous, with the
routine use of a glove box and distillation of THF over sodium.
Given the low cost and wide availability of both Ti(OiPr)4 and
nBuLi, we chose a more practical solution consisting in increasing
their amounts to 0.6 and 0.9 equivalents respectively. The reaction
could not be considered truly catalytic any longer but became
more efficient (5a was isolated in 84% yield from 2a) and, more
importantly, perfectly reliable. The results of the reactions of several
terminal alkynes, under these conditions, are presented in Table 3.
Moderate to excellent yields and high regioselectivities in favour of
the 1,2,4 products 5a–d were achieved with arylacetylene derivatives
2a–d. The reactivity of 2e was non-typical (see next paragraph).
Enyne substrates 1-ethynylcyclohexene 2f and 2-methyl-1-buten-3-
yne 2g reacted with excellent regioselectivity as well but 5f and 5g
were produced in low yields, together with a number of unidenti-
fied by-products. More interestingly, hept-1-yne 2h was converted
into the [2+2+2] adduct 5h in 86% yield. This is remarkable, since
the same transformation had performed poorly under the pre-
viously developed conditions (2.2 equiv. of Ti(OiPr)4 and 3.3 equiv.
of nBuLi at room temperature), with large amounts of diene
by-products.12 These experimental results suggest that the reaction
of the third molecule of 2h with the titanacyclopentadiene inter-
mediates 4/40 is more difficult than in the case of 2a but can be
sufficiently accelerated upon heating. Another difference with the
reaction of 2a is the lower regioselectivity (5h/50h E 65 : 35),
indicating that the 1,3-disubstituted intermediate complex 40h is
produced in significant amounts. The reactions of the bulkier
substrates 3,3-dimethyl-but-1-yne 2i and cyclopropylacetylene 2j
proceeded with better selectivities (86 : 14 and 89 : 11 respectively)
but in somewhat lower yields, perhaps because of their volatility.
a
Unless indicated otherwise, all the yields are for isolated products.
b
5/50 regioisomeric ratios are indicated in parentheses. The starting
alkyne was added as a solution in THF. 5e was formed together with
c
a hydro-defluoro-substitution product (total yield 63%). The 39% yield
indicated is for 5e only. Yield estimated by 1H NMR spectroscopy (ESI).
d
The single hydro-dehalo-substitution products 7e, 7k and 7l are
formed predominantly (ESI‡), with remarkable selectivity in
the case of the fluoro substrates 2e and 2k. The hydro-dehalo-
substitution appears to be more facile with chloro derivatives,
as evidenced by the low yield (6%) of the trichloro product 5l
and the significant formation of mono-chloro by-products 8l
and 9l (ESI‡). Work-up of the reaction mixture with D2O did not
result in any deuterium atom incorporation into the products.
Interestingly, the phenomenon is significantly minimised when
only 0.3 equiv. of Ti(OiPr)4 and 0.6 equiv. of nBuLi are employed,
instead of 0.6 and 0.9 equiv. respectively (ESI‡). This suggests
that nBuTi(OiPr)3 might play a key role in the reduction process.
Moreover, when purified 5e is submitted to the reaction con-
ditions again, the defluorinated molecule 7e is formed in
significant amounts. This is consistent with a hydro-dehalo-
substitution reaction taking place after the alkyne cyclotrimer-
isation process. A tentative mechanistic proposal is presented
in Scheme 5.
Unexpected hydro-dehalo-substitution
According to this hypothesis, an aryltitanium intermediate
Intriguing hydro-dehalo-substitution processes were observed complex, e.g. 10e starting from 5e, would be generated by
when halophenylacetylene substrates were engaged (Scheme 4). oxidative addition of a C-halogen bond onto ‘‘Ti(OiPr)2’’.
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Table 4 Titanium-mediated cyclotrimerisation reactions of disubstituted
alkynes 12a
a
Typical experimental procedure as in Table 3 (ESI). Unless indicated
otherwise, all the yields are for isolated products. The 13d/130d ratio is
indicated in parentheses. Yield estimated by 1H NMR spectroscopy.
b
Only partial conversion took place and the production of (Z)-oct-4-ene,
in about 28% yield, was also observed.
Scheme 4 Reactions of haloarylacetylene substrates 2e, 2k and 2l.
addition of the most polarised carbon–halogen bonds. None-
theless, further work is still needed, and will be carried out,
in order to support this mechanistic picture more decisively or
rule it out.
Disubstituted alkyne substrates
Finally, the possibility to extend the titanium-mediated cyclotri-
merisation process to internal alkynes 12 was briefly examined
(Table 4). The reactions of but-2-yne 12a and 1-phenylprop-1-
yne 12d afforded the corresponding hexasubstituted benzene
derivatives 13a and 13d in satisfactory yields, 13d being obtained
with good selectivity (88 : 12). In contrast, oct-4-yne 12b, diphenyl-
acetylene 12c and 1-phenylpent-1-yne 12e gave poor results,
suggesting that the transformation does not tolerate internal
alkyne substrates having both substituents larger than a methyl
group. Interestingly, in the case of the reaction of 12b, which gave
hexapropylbenzene 13b in low yield (14%), no trace of diene
resulting from hydrolysis of the titanacyclopentadiene inter-
mediate of type 4 was observed. The only by-product is (Z)-oct-4-
ene, the presence of which presumably results from hydrolysis of
unreacted titanacyclopropene complex. The limiting factor thus
appears to be the reaction of the second molecule of 12b.
A similar situation is met starting from 12c and 12e, with
substantial amounts of cis-stilbene and (Z)-1-phenylpent-1-ene
being produced, while neither diene resulting from dimerisa-
tion nor cyclotrimerised product 13 are observed.
Scheme 5 Tentative mechanism for the formation of hydro-dehalo-
substitution products.
Subsequent reaction with nBuTi(OiPr)3, by s-bond metathesis,
would lead to the new complex 11e. Eventually, intramolecular
hydrogen atom transfer, analogous to the initial formation of 1
from nBu2Ti(OiPr)2, would produce 7e and regenerate 1. The
latter would thus function as a catalyst in this transformation
Conclusions
and the source of hydrogen atom would be nBuTi(OiPr)3. It is To conclude, our new results demonstrate that the Ti(OiPr)4/
interesting to note that in the 13C NMR spectra of 5e, 5k and 5l, nBuLi system can function as a catalyst for the cyclotrimerisa-
the most downfield C-halogen signals belong to the very aryl tion of alkynes. However, the use of 0.6 equiv. of Ti(OiPr)4 and
groups where the hydro-dehalo-substitution takes place prefer- 0.9 equiv. of nBuLi with respect to the alkyne substrate gives the
entially. This is reasonable, since it corresponds to oxidative most reliable results. Although these new conditions cannot be
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841 mL) was added dropwise, over 2.5 min, into a solution of
Ti(OiPr)4 (0.200 equiv., 1.20 mmol, 355 mL) in dry THF (8.0 mL),
under argon at 0 1C. After 5 min of stirring at 0 1C, the resulting
solution was added dropwise, over 2.5 min, into a solution
of phenylacetylene 2a (1.00 equiv., 6.00 mmol, 660 mL) in THF
(1.0 mL) at 15 1C. The mixture was then heated at reflux for
20 h. After cooling, 2 M HCl aqueous solution (15 mL) was
added. The mixture was stirred at r.t. for 15 min, then extracted
with Et2O (3 ꢁ 15 mL). The combined organic phases were
dried over MgSO4, filtered and concentrated under reduced
pressure to afford the crude product. Purification by flash
column chromatography on silica gel (EtOAc/petroleum ether,
gradient from 0 to 10%) afforded pure 1,2,4-triphenylbenzene
5a (418 mg, 1.36 mmol, 68%).
Catalytic reaction performed under microwave conditions,
with a simplified procedure (Table 2, entry 3 and Scheme 3,
top). nBuLi (2.34 M solution in hexanes, 0.300 equiv., 900 mmol,
385 mL) was added dropwise, over 1 min, into a solution of
Ti(OiPr)4 (0.200 equiv., 600 mmol, 178 mL) in dry THF (4.5 mL), in
a flame-dried 10 mL microwave vial, under argon at 0 1C. After
5 min of stirring at 0 1C, 2a (1.00 equiv., 3.00 mmol, 330 mL) was
added dropwise. The septum on the vial was quickly replaced
with the suitable sealed cap and the vial was immediately heated
with the microwave synthesis reactor (100 1C, 30 min). After
cooling, 2 M HCl aqueous solution (10 mL) was added. The
mixture was stirred at r.t. for 15 min, then extracted with Et2O
(3 ꢁ 10 mL). The combined organic phases were dried over
MgSO4, filtered and concentrated under reduced pressure to
afford the crude product. Purification by flash column chromato-
graphy on silica gel (EtOAc/petroleum ether, gradient from 0
to 2%) afforded pure 5a (222 mg, 725 mmol, 72%).
Scheme 6 Comparison of the two terminal alkyne cyclotrimerisation
methods developed by our group.
applied to the heterocyclotrimerisation reactions we developed
earlier, which require the stoichiometric preparation of titana-
cyclopropene complexes from internal alkynes,12 they represent
a dramatic improvement over our previously described alkyne
homocyclotrimerisation method, as summarised in Scheme 6.
In addition, comparison with the few other Ti-catalysed pro-
cesses reported in the literature15 reveals significant advan-
tages, notably the low cost and direct availability of the reagent
system, as well as the practicability of the experimental
procedure.
Experimental section
For general information, see the ESI.‡ Compounds 5a,12,16
Catalytic reaction performed under microwave conditions
50a,17 5b,12,15b,18 5c,19 5d,12,18a,20 5e,18a,21 5f, 50f,22 5g,23 50g,23a with iPrMgCl (Scheme 3, bottom). iPrMgCl (1.73 M solution in
5h,12,24 50h,24 5i,25 50i,26 5j, 50j,27 5l,18–20 9l,18b 13a,26 13b,28 THF, 0.300 equiv., 900 mmol, 520 mL) was added dropwise, over
13d29 and 130d29a have already been described and their 1 min, into a solution of Ti(OiPr)4 (0.200 equiv., 600 mmol,
analytical data are in good agreement with those reported in 178 mL) in dry THF (4.5 mL), in a flame-dried 10 mL microwave
the literature (ESI‡).
vial, under argon at 0 1C. After 5 min of stirring at 0 1C, 2a
(1.00 equiv., 3.00 mmol, 330 mL) was added dropwise. The
septum on the vial was quickly replaced with the suitable sealed
cap and the vial was immediately heated with the microwave
General procedure (GP) for the cyclotrimerisation reactions
under optimised conditions
nBuLi (E2.0 M solution in hexanes, 0.900 equiv., 2.70 mmol) was synthesis reactor (100 1C, 30 min). After cooling, 2 M HCl
added dropwise, over 1 min, into a solution of Ti(OiPr)4 (0.600 equiv., aqueous solution (10 mL) was added. The mixture was stirred
1.80 mmol) in dry THF (4.0 mL), in a flame-dried 10 mL microwave at r.t. for 15 min, then extracted with Et2O (3 ꢁ 10 mL). The
vial, under argon at 0 1C. After 5 min of stirring at 0 1C, the alkyne combined organic phases were dried over MgSO4, filtered and
substrate (1.00 equiv., 3.00 mmol) was then added dropwise. The concentrated under reduced pressure to afford the crude pro-
septum on the vial was quickly replaced with the suitable sealed cap duct (380 mg, brown sticky oil). 13C NMR analysis showed full
and the vial was immediately heated with the microwave synthesis conversion of the starting material and the production of 1,2,4-
reactor (100 1C, 15 min). After cooling, 2 M HCl aqueous solution and 1,3,5-triphenylbenzene 5a and 50a in 60 : 40 ratio. Purification
(10 mL) was added. The mixture was stirred at r.t. for 15 min, then by flash column chromatography on silica gel (EtOAc/petroleum
extracted with Et2O (3 ꢁ 10 mL). The combined organic phases were ether, gradient from 0 to 2%) afforded a 58 : 42 mixture of 5a and
dried over MgSO4, filtered and concentrated under reduced pressure 50a (197 mg, 642 mmol, 64%).
to afford the crude product.
Reaction performed under optimised conditions (Table 3).
General procedure GP was applied with 2a. Purification of the
crude product (420 mg, brown sticky oil) by flash column
Cyclotrimerisation of phenylacetylene 2a
Catalytic reaction performed at reflux (Table 1, entry 5). chromatography on silica gel (EtOAc/petroleum ether, gradient
nBuLi (2.14 M solution in hexanes, 0.300 equiv., 1.80 mmol, from 0 to 2%) afforded pure 5a (257 mg, 839 mmol, 84%).
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Cyclotrimerisation reactions of terminal alkynes 2b–j (Table 3) The total amount of triisopropenylbenzene isomers isolated is
thus 13.2 mg (66.6 mmol, 7%).
1,2,4-Tris(p-tolyl)benzene 5b. General procedure GP was applied
with 2b. Purification of the crude product by flash column
chromatography on silica gel (EtOAc/petroleum ether, gradient
from 0 to 2%) afforded pure 5b (273 mg, 783 mmol, 78%).
1,2,4-Tripentylbenzene 5h and 1,3,5-tripentylbenzene 50h.
General procedure GP was applied with 2h. Analysis of the
crude product by 1H NMR spectroscopy showed full conversion
of the starting material and the production of 5h and 50h in an
1,2,4-Tris(4-tert-butylphenyl)benzene 5c. General procedure
estimated 65 : 35 ratio. Minor diene by-products 4h and 40h
GP was applied with 2c. Purification of the crude product
made purification difficult and they were therefore destroyed by
(685 mg, brown sticky oil) by flash column chromatography
the following treatment: concentrated H2SO4 (0.5 mL) was
on silica gel (EtOAc/petroleum ether, gradient from 0 to 2%)
added dropwise to the crude product at 0 1C. After 15 min of
afforded pure 5c (436 mg, 918 mmol, 92%).
stirring at r.t., H2O (20 mL) was added dropwise at 0 1C and the
1,2,4-Tris(4-methoxyphenyl)benzene 5d. General procedure
mixture was extracted with Et2O (3 ꢁ 20 mL). The combined
GP was applied with 2d. Purification of the crude product
organic phases were dried over MgSO4, filtered and concen-
(685 mg, brown sticky oil) by flash column chromatography
trated under reduced pressure. Purification of the residue
on silica gel (EtOAc/petroleum ether, gradient from 1 to 10%)
afforded pure 5d (225 mg, 567 mmol, 57%).
1,2,4-Tris(4-fluorophenyl)benzene 5e and 1,2-bis(4-fluoro-
phenyl)-4-phenyl-benzene 7e. General procedure GP was applied
(351 mg, brown oil) by flash column chromatography on silica
gel (petroleum ether) afforded a 62 : 38 mixture of 5h and 50h
(247 mg, 530 and 330 mmol respectively). The yields obtained
for both compounds are thus 53% (5h) and 33% (50h).
with 2e [added into the reaction mixture as a solution in THF
1,2,4-Tri(tert-butyl)benzene 5i and 1,3,5-tri(tert-butyl)benzene 50i.
(0.5 mL)]. Analysis of the crude product (370 mg, brown sticky
oil) by 13C NMR spectroscopy showed full conversion of the
General procedure GP was applied with 2i. Purification of the crude
product (360 mg, orange oil) by flash column chromatography on
silica gel (petroleum ether) afforded a 90 : 10 mixture of 5i and 50i
(121 mg, 491 mmol, 49%).
1,2,4-Tricyclopropylbenzene 5j and 1,3,5-tricyclopropyl-
benzene 50j. General procedure GP was applied with 2j.
Purification by flash column chromatography on silica gel
(pentane) afforded pure 5j (28.1 mg, 142 mmol, 14%) and a
86 : 14 mixture of 5j and 50j (52.7 mg, 229 and 37, mmol
starting material and the production of 5e and 7e in an esti-
mated 65 : 35 ratio. Purification by flash column chromato-
graphy on silica gel (EtOAc/petroleum ether, gradient from 0
to 5%) afforded pure 5e (36.8 mg, 103 mmol, 10%) and a 55 : 45
mixture of 5e and 7e (187 mg, 292 and 239 mmol respectively).
The yields obtained for both compounds are thus 39% (5e) and
24% (7e).
1
7e. White solid. H NMR (CDCl3, 400 MHz): d 6.94 (2 H, br respectively). The yields obtained for both compounds are thus
dd, J 9.0, 8.5), 6.95 (2 H, br dd, J 9.0, 8.5), 7.09–7.16 (4 H, m), 37% (5j) and 4% (50j).
7.38 (1 H, br t, J 7.5), 7.47 (2 H, br t, J 7.5), 7.47 (1 H, d, J 8.0),
Cyclotrimerisation reactions of halo substrates 2k–l (Scheme 4)
7.62 (1 H, br d, J 2.0), 7.63 (1 H, br dd, J 8.0, 2.0), 7.66 (2 H, br d,
J 7.5). 13C NMR (CDCl3, 100.6 MHz): d 115.0 (4 C, br d, J 21.5),
126.3, 127.1, 127.6, 128.9, 129.3, 131.0, 131.33 (d, J 8.0),
131.38 (d, J 8.0), 136.8 (d, J 3.0), 137.2 (d, J 3.0), 138.4, 139.9,
1,2,4-Tris(2-fluorophenyl)benzene 5k and 1,2-bis(2-fluoro-
phenyl)-4-phenyl-benzene 7k. General procedure GP was applied
with 2k. Analysis of the crude product by 13C NMR spectroscopy
showed full conversion of the starting material and the produc-
tion of 5k and 7k in an estimated 55 : 45 ratio. Purification by flash
column chromatography on silica gel (EtOAc/petroleum ether,
gradient from 0 to 2%) afforded pure 5k (4.2 mg, 11.7 mmol, 1%)
and a 52 : 48 mixture of 5k and 7k (198 mg, 286 and 264 mmol
respectively). The yields obtained for both compounds are thus
30% (5k) and 26% (7k).
140.3, 140.6, 161.80 (d, J 246.5), 161.83 (d, J 246.5). HRMS
+
(EI): m/z 342.1209 (M+ C24H16F2 requires 342.1215). Note:
this compound was not obtained in pure form but as a mixture
with 5e.
ꢂ
ꢂ
1,2,4-Tri(cyclohexen-1-yl)benzene 5f and 1,3,5-tri(cyclohexen-
1-yl)benzene 50f. General procedure GP was applied with 2f but
the work-up was performed as follows: H2O (0.5 mL) was added
and the mixture was stirred at r.t. for 30 min, before being
filtered through a short pad of sand, MgSO4, celite and sand
1
5k. Colourless oil. H NMR (CDCl3, 400 MHz): d 6.94 (1 H,
(from bottom to top) (rinsing: Et2O). The combined organic ddd, J 10.0, 8.0, 1.0), 6.95 (1 H, ddd, J 10.0, 8.0, 1.0), 7.02 (2 H, br
phases were dried over MgSO4 and filtered. trans-Cinnamic acid d, J 7.5), 7.13–7.24 (5 H, m), 7.23 (1 H, br t, J 7.5), 7.34 (1 H, tdd,
(200 mmol, 29.6 mg) was added as an internal standard and the J 8.0, 5.0, 2.0), 7.52 (1 H, d, J 8.0), 7.54 (1 H, dd, J 8.0, 2.0), 7.64
solution was concentrated under reduced pressure to afford the (1 H, br s), 7.67 (1 H, ddd, J 8.0, 2.0, 1.5). 13C NMR (CDCl3, 100.6
1
crude product. H NMR analysis, with comparison of the inte- MHz): d 115.3 (2 C, d, J 22.5), 116.2 (d, J 22.5), 123.6 (d, J 3.0),
grals of relevant signals, showed that 5f and 50f had been 123.6 (d, J 3.0), 124.4 (d, J 3.5), 128.5, 129.02 (d, J 8.0), 129.03
produced in 19% yield (ratio 97 : 3).
(d, J 8.0), 129.2 (d, J 8.0), 130.8, 130.8, 131.3 (d, J 2.5), 131.8 (2 C,
1,2,4-Triisopropenylbenzene 5g and 1,3,5-triisopropenyl- br s), 135.0, 135.4, 135.8, 159.4 (d, J 247.0), 159.5 (d, J 246.5),
benzene 50g. General procedure GP was applied with 2g. 159.8 (d, J 248.0). The signals of carbons C3, C11 and C19 could
Purification of the crude product (278 mg) by flash column not be identified with certainty. 19F NMR (CDCl3, 282.4 MHz):
chromatography on silica gel (pentane) afforded pure 5g (11.2 mg) d ꢀ117.76 (1 F, br m), ꢀ115.32 (2 F, br m). HRMS (EI): m/z
+
and a 90 : 10 mixture of 5g and the 1,3,5 isomer 50g (3.0 mg). 360.1130 (M+ C24H15F3 requires 360.1120).
ꢂ
ꢂ
20224 | New J. Chem., 2018, 42, 20219--20226 This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018

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1
7k. Colourless oil. H NMR (CDCl3, 400 MHz): d 6.91–6.97 spectroscopy showed that it contained essentially only starting
(2 H, m), 6.98–7.04 (2 H, m), 7.36 (1 H, br t, J 7.5), 7.45 (2 H, br t, material 12c and cis-stilbene in 83 : 17 ratio. 13c was not
J 7.5), 7.52 (1 H, d, J 8.0), 7.12–7.24 (4 H, m), 7.63–7.70 (2 H, m), detected.
7.66 (2 H, br d, J 8.0). 13C NMR (CDCl3, 100.6 MHz): d 115.3 (2 C,
1,2,4-Trimethyl-3,5,6-triphenyl-benzene 13d and 1,3,5-tri-
d, J 22.5), 123.5 (d, J 3.0), 123.6 (d, J 3.0), 126.5, 127.2, 127.5, methyl-2,4,6-triphenyl-benzene 130d. General procedure GP was
128.8, 129.4, 128.9 (d, J 7.5), 129.0 (d, J 7.5), 131.1, 131.7 (2 C, applied with 12d. Purification of the crude product (412 mg,
br s), 134.5, 136.0, 140.3, 140.8, 159.4 (d, J 247.0), 159.4 (d, J 247.0). brown oil) by flash column chromatography on silica gel (EtOAc/
The signals of carbons C9 and C17 could not be identified with petroleum ether, gradient from 0 to 5%) afforded a 82 : 18
certainty. 19F NMR (CDCl3, 282.4 MHz): d ꢀ115.38 (2 F, br m). mixture of 13d and 130d (208 mg, 597 mmol, 60%).
+
HRMS (EI): m/z 342.1221 (M+ C24H16F2 requires 342.1215).
1,2,4-Triphenyl-3,5,6-tripropyl-benzene 13e and 1,3,5-triphenyl-
ꢂ
ꢂ
Note: this compound was not obtained in pure form but as a 2,4,6-tripropyl-benzene 130e. General procedure GP was applied
mixture with other reduction compounds in minor amounts with 12e. Analysis of the crude product by 1H and 13C NMR
and with 5k.
spectroscopy showed that it contained essentially only starting
1,2,4-Tris(4-chlorophenyl)benzene 5l, 1,2-bis(4-chlorophenyl)- material 12e and (Z)-1-phenyl-pent-1-ene in 61 : 39 ratio. Neither
4-phenyl-benzene 7l, 1-(4-chlorophenyl)-2,4-diphenyl-benzene 8l 13e nor 130e were detected.
and 1-(4-chlorophenyl)-2,5-diphenyl-benzene 9l. General proce-
dure GP was applied with 2l [added into the reaction mixture as a
Conflicts of interest
solution in THF (0.5 mL)]. Analysis of the crude product (422 mg,
orange oil) by 13C NMR spectroscopy showed full conversion of
There are no conflicts to declare.
the starting material and the presence of 7l as the major product
of the reaction. Purification by flash column chromatography on
silica gel (EtOAc/petroleum ether, gradient from 0 to 2%) afforded Acknowledgements
a 27 :73 mixture of 5l and 7l (78.7 mg, 55.3 and 149 mmol
´
We are grateful to Ecole Polytechnique for the PhD grant
respectively), pure 7l (6 mg, 16.0 mmol, 2%) and a mixture of 7l
with other reduced compounds (ratio dichloro/monochloro com-
pounds 28 : 72 as determined by MS; 75.5 mg, 60.3 and 155 mmol
respectively). Assuming 7l is the sole dichloro product, the yields
obtained are thus 6% (5l), 23% (7l) and 16% (9l and isomers).
awarded to G. S. We warmly thank Prof. Armin de Meijere from
¨
¨
Georg-August-Universitat Gottingen for a generous gift of cyclo-
propylacetylene, and Vincent Jactel for MS analyses. Y. S. also
wishes to thank Prof. S. Z. Zard for his constant support.
1
7l. Colourless oil. H NMR (CDCl3, 400 MHz): d 7.09 (2 H,
Notes and references
br d, J 8.5), 7.11 (2 H, br d, J 8.5), 7.23 (2 H, br d, J 8.5), 7.24 (2 H,
br d, J 8.5), 7.38 (1 H, br t, J 7.5), 7.47 (1 H, d, J 8.0), 7.47
(2 H, br dd, J 8.0, 7.5), 7.61 (1 H, br d, J 2.0), 7.66 (2 H, br d, J 8.0),
7.66 (1 H, br dd, J 8.0, 2.0). 13C NMR (CDCl3, 100.6 MHz): d 126.6,
127.1, 127.6, 128.32, 128.34, 128.9, 129.3, 131.03, 131.06, 131.10,
132.84, 132.92, 138.1, 139.2, 139.56, 139.64, 140.2, 140.9. HRMS
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ꢂ
ꢂ
8l. 13C NMR (CDCl3, 100.6 MHz), characteristic signals
(tentative proposal): d 126.2, 126.8, 129.5, 138.1, 140.9, 141.1.
Note: this compound was not obtained in pure form. It is
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Cyclotrimerisation reactions internal alkynes 12a–e (Table 4)
Hexamethylbenzene 13a. General procedure GP was applied
with 12a. Purification of the crude product (177 mg, yellow
solid) by flash column chromatography on silica gel (petroleum
ether) afforded pure 13a (97.8 mg, 603 mmol, 60%).
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¨
Chim. Acta, 1980, 63, 2451–2454; (c) T. Kauffmann, R. Konig,
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