A highly efficient olefin metathesis initiator: Improved synthesis and reactivity studies

Article abstract of DOI:10.1016/S0040-4039(03)00346-0

The synthesis of ligand 8, required for the preparation of catalyst 4c has been optimised. Ligand exchange studies indicate that biphenyl-based alkylidene 4c initiates considerably faster than its unsubstituted analogue 4a. The performance of 4c in ring-opening cross metathesis reactions involving substrates containing unprotected chelating atoms is also reported.

Full text of DOI:10.1016/S0040-4039(03)00346-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2733–2736
A highly efficient olefin metathesis initiator: improved synthesis
and reactivity studies
Aideen M. Dunne, Stefan Mix and Siegfried Blechert*
Institut fu¨r Chemie, Technische Universita¨t Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany
Received 5 December 2002; revised 3 February 2003; accepted 3 February 2003
Abstract—The synthesis of ligand 8, required for the preparation of catalyst 4c has been optimised. Ligand exchange studies
indicate that biphenyl-based alkylidene 4c initiates considerably faster than its unsubstituted analogue 4a. The performance of 4c
in ring-opening cross metathesis reactions involving substrates containing unprotected chelating atoms is also reported. © 2003
Elsevier Science Ltd. All rights reserved.
The olefin metathesis reaction is one of the most syn-
thetically useful carbonꢀcarbon bond forming reac-
tions.1 This is largely due to the discovery of active,
well-defined ruthenium alkylidenes such as 1–4 (Fig. 1),
which combine high catalytic activity with impressive
functional group tolerance.2
out an accompanying loss in stability. The chromato-
graphy-stable catalyst 4a initiates more slowly than the
phosphine-based 3, however its use can be advanta-
geous in certain situations, particularly in metathesis
reactions involving electron-deficient olefins.1g,3 Our
group has modified the isopropoxy benzylidene compo-
nent to give analogues of 4a (4b and 4c) which initiate
faster than benchmark catalyst 3, while retaining the
air- and moisture insensitivity characteristic of NHC-
based catalysts.2h,i Of particular interest is biphenyl
derivative 4c, which was shown to exhibit impressive
activity in ring-closing metathesis (RCM), cross
metathesis (CM), ring-opening cross metathesis (ROM-
CM) and ring-opening metathesis polymerisation
(ROMP) reactions.2i
The exchange of one phosphine ligand for a N-hetero-
cyclic carbene (NHC) moiety (2, 3 and 4) leads to
‘second generation’ alkylidenes possessing improved
activity relative to the parent Grubbs’ catalyst 1, with-
To explore the synthetic potential of 4c further, signifi-
cant amounts of catalyst were required. The original
synthetic route, while suitable for small scale laboratory
syntheses, was not practical for larger scale operations
and was heavily reliant on column chromatography
purification steps. We were thus encouraged to develop
a straightforward and convenient method ideal for
preparing this ligand efficiently on a large scale, using
inexpensive starting materials but without using expen-
sive and time-consuming separating techniques. With
this in mind, we first attempted to carry out the alkyla-
tion of 2-hydroxybiphenyl with paraformaldehyde
using the literature procedure.4 In our hands, this reac-
tion failed to give the desired products. We then turned
our attention toward more traditional methods
(Scheme 1). The oxidation of the sodium salt of 2-
hydroxybiphenyl (5), under Kolbe–Schmitt conditions,
lead to the formation, on acidic work-up, of the corre-
sponding carboxylic acid (40%) with recovery of 2-
Figure 1. Olefin metathesis catalysts.
* Corresponding author. Tel.: +49-30-314-22255; fax: +49-30-314-
23619; e-mail: blechert@chem.tu-berlin.de
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00346-0

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A. M. Dunne et al. / Tetrahedron Letters 44 (2003) 2733–2736
Scheme 3. Ligand exchange experiments.
Table 1. Ligand exchange conversions via Scheme 3
Scheme 1. Synthesis of ligand 8.
hydroxy biphenyl.5 The crude reaction mixture was
quantitatively alkylated with excess isopropylbromide,
which allows the formation of the isopropylether moi-
ety with concurrent esterification of the carboxylate
group. This is desirable, as the direct reduction of the
ester 6 rather than the precursor acid is thus facilitated.
At this stage the crude product was purified by distilla-
tion (twice) to furnish alcohol 7. The corresponding
benzaldehyde derivative was obtained after MnO2-oxi-
dation of 7, and could also be purified by distillation.
Subsequent Wittig olefination and filtration of the
crude product through a short silica-gel column gave
styrene 8 in good yield (Scheme 1) and in multi-gram
quantities. Catalyst 4c was then prepared using stan-
dard techniques.2i
Entry
Reaction
Time
Conversiona (%)
1
2
3
4
5
6
4a“14a
4a“14a
4a“14a
4b“14b
4b“14b
4b“14b
3 h
21 h
52 h
19 min
39 min
137 min
15
41
45b
33
41
53b
a Determined by NMR.
b Equilibrium reached.
Biphenyl-based catalyst 4c underwent much faster
exchange with 9 than 4a did with 10. Since the steric
and electronic effects of meta-phenyl group on the
benzylidene moiety are negligible, it is clear that in the
case of 4c, the energy barrier associated with sponta-
neous initiation at room temperature (i.e. dissociation
of the RuꢀO bond)7 is considerably lower than that of
4a. This can be reasonably attributed to a weakening of
the chelation bond of 4c as a result of steric crowding
by the adjacent phenyl substituent. Since the formation
of stilbenes, which would require the intermediacy of a
methylidene rather than a benzylidene intermediate,
was not observed on the time-scale of the experiments,
these results allow some insights to be obtained con-
cerning the relative ability of 4a and 4c to dissociate
their chelating isopropoxyether ligands.
With more workable quantities of 4c in hand, we
wanted to estimate the relative initiation efficiency of 4a
and 4c. Since direct observation of the intermediates in
1
metathesis reactions by H NMR spectroscopy is often
difficult due to their low concentration in solution, it
was decided to monitor the rates of exchange of added
isopropoxystyrenes with catalysts 4a,c in solution. This
necessitated the synthesis of ligands 9 and 10, which are
deuterated a- to the aromatic ring (Scheme 2).
The deuterium substituents were conveniently intro-
duced via reduction of 6 and 11 with lithium aluminium
deuteride. A subsequent oxidation/olefination sequence
then gave the required ligands in good overall yields.
Compounds 9 and 10 were reacted in equimolar quanti-
ties with 4c and 4a respectively in C6D6.6 As the
catalyst initiates the deuterated ligands are incorpo-
rated into the alkylidene over time, as indicated by the
disappearance of the alkylidene signal (l=ca. 16.6
ppm) and appearance of signals associated with the
corresponding non-deuterated styrenes (15 and 8)
(Scheme 3). Thus the relative initiation efficiency of 4a
and 4c can be assessed (Table 1).
We were also interested in testing the ability of the fast
initiator 4c to promote the metathesis of traditionally
challenging olefin substrates. It is known that unpro-
tected amines and sulphides8 are generally poor sub-
strates in olefin metathesis reactions due to their
tendency to coordinate to the ruthenium centre, thus
trapping the catalyst in an unreactive form. However,
we were pleased to find that ROM-CM reactions9
between flexible and readily prepared norbornene and
azanorbornene derivatives bearing either unprotected
Lewis-basic nitrogen or sulphur atoms (16–19) and
allyltrimethylsilane (22) proceeded with uniformly high
efficiency (Scheme 4, Table 2). Pyridine, indole, unhin-
dered sulphide and tertiary amine substituents were all
found to be compatible with 4c in these reactions, with
a maximum of 0.5 mol% of initiator required for quan-
titative conversion of 16–19. The products from these
reactions were formed as an expected mixture of
regioisomers,10,11 however, no attempt at separation
Scheme 2. Synthesis of deuterated ligands 9 and 10.

A. M. Dunne et al. / Tetrahedron Letters 44 (2003) 2733–2736
2735
Fu¨rstner, A. Angew. Chem. 2000, 112, 3140–3172; Angew.
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2. (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. J. Am. Chem.
Soc. 1993, 115, 9858–9859; (b) Nolan, S. P.; Huang, J.;
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5. Due to their similar pKa values, repeated attempts to
separate 5 and its corresponding acid non-chromato-
graphically were unsuccessful.
Scheme 4. ROM-CM promoted by 4c.
Table 2. Results of ROM-CM experiments
Substrate
CM Partner Product
4c (mol%)
Yield (%)a
16
17
18
19
16
17
18
19
16
17
18
19
20
20
20
20
21
21
21
21
22
22
22
22
23a,b
24a,b
25a,b
26a,b
27a,b
28a,b
29a,b
30a,b
31a,b
32a,b
33a,b
34a,b
0.3
0.5
0.3
0.4
3
1
1
3
1
72
96
90
82
39
46
50
39
55
72
68
46
0.5
0.5
1
a Refers to isolated yields after chromatography.
6. Use of CD2Cl2 resulted in significant catalyst decomposi-
tion. In C6D6, catalyst degradation in the absence of
added styrene was monitored and found to be insignifi-
cant on the time-scale of the experiments.
7. The steric effect which promotes ligand dissociation
would also be expected to hinder the catalyst deactivating
reassociation back reaction. For a discussion of the
mechanism of olefin metathesis catalysed by 3, see: San-
ford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 6543–6554.
8. For recent advances in the use of sulphur-containing
metathesis substrates, see: (a) Gan, Z.; Roy, R. Tetra-
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P.; Nolan, S. P. C.; Mioskowski, C. Org. Lett. 2002, 4,
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Tetrahedron Lett. 2002, 43, 209-211.
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108, 479–481; Angew. Chem., Int. Ed. Engl. 1996, 35,
411–413; (b) Schneider, M. F.; Lucas, N.; Velder, J.;
Blechert, S. Angew. Chem. 1997, 109, 257–258; Angew.
Chem., Int. Ed. Engl. 1997, 36, 257–258; (c) Randall, M.
L.; Tallarico, J. A.; Snapper, M. L. J. Am. Chem. Soc.
1995, 117, 9610–9611; (d) Snapper, M. L.; Tallarico, J.
A.; Randall, M. L. J. Am. Chem. Soc. 1997, 119, 1478–
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Commun. 2001, 1796–1797; (f) Lee, C. W.; Choi, T.-L.;
Grubbs, R. H. J. Am. Chem. Soc. 2002, 124, 3224–3225.
was made, as these experiments were designed only to
test the functional group tolerance of 4c in ROM-CM
processes. Less sterically encumbered CM partners 21
and 22 were not as effective as 20; isolated yields of
cross products were reduced due to the ability of 27a,b–
34a,b to participate in metathesis dimerisation and
oligimerisation (as opposed to selective CM) processes
under the reaction conditions.
Nevertheless, it is apparent that phosphine-free catalyst
4c possesses functional group tolerance towards Lewis-
basic potentially chelating functionality in ROM-CM
reactions. In summary, we have developed an efficient
and practical synthetic route to ligand 8, which allows
catalyst 4c to be readily prepared in reasonable quanti-
ties. Reactivity studies have shown that despite display-
ing relatively high rates of exchange with deuterated
ligand 9, 4c is a robust and synthetically useful catalyst
for the ROM-CM of substrates bearing Lewis-basic
chelating atoms.
References
1. For recent olefin metathesis reviews, see: (a) Trnka, T.
M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (b)

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A. M. Dunne et al. / Tetrahedron Letters 44 (2003) 2733–2736
The solution was stirred at rt for 24 h and the solvent
removed in vacuo. The residue was purified by column
chromatography to give 20 (0.22 mmol, 72%) as a light
yellow oil.
10. All products gave satisfactory analytical data.
11. Sample ROM-CM procedure: To a stirred solution of 16
(0.30 mmol) and allyltrimethylsilane (0.45 mmol) in
CH2Cl2 (6 mL) under N2 was added 4c (0.0009 mmol).