A hexafluorobenzene promoted ring-closing metathesis to form tetrasubstituted olefins

Article abstract of DOI:10.1016/j.tetlet.2008.07.161

Highly efficient formation of tetrasubstituted olefins is described by ring-closing metathesis (RCM) using catalyst 2 in presence of hexafluorobenzene. This combination with hexafluorobenzene shows an unexpected promoting effect, which requires low cataly

Full text of DOI:10.1016/j.tetlet.2008.07.161

Tetrahedron Letters 49 (2008) 5968–5971
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A hexafluorobenzene promoted ring-closing metathesis
to form tetrasubstituted olefins
Daniel Rost, Marta Porta, Simon Gessler, Siegfried Blechert *
TU Berlin—Berlin University of Technology, Institute of Chemistry, Strasse des 17. Juni 115, Sekr. C3, 10623 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly efficient formation of tetrasubstituted olefins is described by ring-closing metathesis (RCM) using
catalyst 2 in presence of hexafluorobenzene. This combination with hexafluorobenzene shows an
unexpected promoting effect, which requires low catalysts loadings and allows the conversion of
deficient olefins in high yields and very short reaction times.
Received 8 July 2008
Revised 25 July 2008
Accepted 29 July 2008
Available online 31 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Ring-closing metathesis
Tetrasubstituted olefins
Catalysis
With the advent of stable Ru-based catalyst that combines high
catalytic activity and excellent functional group tolerance olefin
metathesis reactions have emerged as one of the most attractive
and powerful tools for the formation of new carbon–carbon double
N-naphthyl group would also offer a less bulky environment
around the metal center than the mesityl moiety in the second
generation Grubbs catalyst. In addition, any potential deactivation
through intramolecular carbene–arene bond formation, reported
1
6
bonds. In particular ring-closing metathesis (RCM) to generate
by our group, would also be prevented. Recently, Dorta et al. have
functionalized cyclic olefins, which are very common synthetic
intermediates in organic synthesis, has received much attention.
reported a different synthetic route for catalyst 2 and found mod-
2
erate conversion of a standard substrate in the RCM to tetrasubsti-
7
Nevertheless, sterically demanding substrates leading to tetrasub-
stituted cyclic olefins are still challenging and typically require
tuted olefins with this catalyst.
Herein we report systematic studies of the employment of 2 in
the highly efficient generation of tetrasubstituted olefins in hexa-
fluorobenzene as the solvent, which shows an unexpected promot-
ing effect on the RCM reaction. In accordance with previous
observations we obtained higher yields in RCM reactions upon
changing the solvent from dichloromethane at 40 °C to toluene at
3
high loadings of second-generation catalysts. Recently, Grubbs
et al. have investigated the catalytic properties of novel ruthe-
nium-based catalysts in this particular RCM.4 They could demon-
strate the superior performance of complex 1 over the standard
Grubbs’ ‘second-generation’ catalyst. This finding has been attrib-
uted to a less crowded steric environment of 1 at the ruthenium
8
80 °C. Several other solvents with similar boiling points were also
4
b
center. Despite its high initiation rates complex 1 decomposes
readily under the reaction conditions, and the use of the corre-
sponding more stable phosphine-free isopropoxybenzylidene-
based catalyst is mandatory. Still transformations with these
ruthenium complexes require high catalyst loadings, and attempts
to form electron-deficient tetrasubstituted olefins have not shown
satisfactory results. In our search for stable catalysts for the forma-
tion of tetrasubstituted olefins, we focused our interest on the use
tested, including perfluorinated benzene derivatives, which had
already been successfully employed in metathesis reactions in our
9
group. During these studies we discovered a pronounced effect
of fluorinated benzene on the performance of 1 and 2 in the RCM
reactions. We then conducted several comparative studies with
catalyst 2 and the commercially available complex 1 to evaluate
their synthetic potential under these reaction conditions (Fig. 1).10
5
of catalyst 2, which was synthesized by our group a few years ago.
N
N
N
N
We anticipated that an enlargement of the p-system in the N-aryl
substituent of the NHC ligand would provide an increased stability
of the corresponding active catalytic complex. An ortho-substituted
Cl
Cl
Ru
Ru
Ph
Ph
Cl
Cl
PCy3
PCy3
1
2
*
Corresponding author. Tel.: +49 030 314 22255; fax: +49 030 314 23619.
E-mail address: blechert@chem.tu-berlin.de (S. Blechert).
Figure 1. Ru-catalysts for RCM to form tetrasubstituted olefins.
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.161

D. Rost et al. / Tetrahedron Letters 49 (2008) 5968–5971
5969
We first assessed the activity and stability of both catalysts in
the RCM of sulfonamide 3 in hexafluorobenzene (Fig. 2).
O
O
O
O
cat.
(
i)
The conversion over time to the desired reaction product 4 with
0.1 M C6F6, 80 °C, 12 h
1
0
.25 mol % catalyst in 0.1 M C
6
F
6
at 80 °C was measured by H NMR
analysis. Figure 2 clearly shows the superior catalytic activity of
catalyst 2 in the conversion of substrate 3. Catalyst 1 is less stable,
and fails to efficiently promote this reaction. After 5 min the activ-
ity of both catalysts breaks down, accounting for the short lifetimes
of the respective catalytic active species. In summary, complex 2
due to its rapid initiation and its higher stability catalyzes the con-
version of 3 more efficiently than catalyst 1. To compare the overall
performance of catalysts, studies of conversion versus catalyst
loading and the determination of the amount of product yielded
by a given amount of catalyst have to be carried out.11 We there-
fore investigated the lower catalyst loading limit for the RCM to
a tetrasubstituted olefin and determined the reactivity profile for
5
6
EtO C
CO Et
2
2
EtO C
CO Et
2
2
(
ii)
cat.
0
.1 M C6F6, 80 °C, 12 h
8
7
1
00
8
6
4
0
1
and 2 under the novel reaction conditions.
First, we focused on the transformation of 5 to the six-mem-
bered lactone 6. The presence of such lactones as structural sub-
units in numerous natural products makes electron-deficient
0
0
alkenes, such as
a,b-unsaturated esters, very attractive substrates
1
; (i)
1; (ii)
2; (i)
2; (ii)
12
for metathesis reactions. Catalyst 1 was reported to fail to pro-
mote this reaction in benzene at 60 °C. We found a conversion
4
20
0
of diene 5 to lactone 6 of 23% with 5 mol % of catalyst 1 in hexaflu-
orobenzene clearly demonstrating the strong promoting effect of
this solvent.
0
1
2
3
4
5
Catalyst [mol%]
The use of 2 under the same reaction conditions gave 83% of
conversion of substrate 5. Figure 3 again shows the superiority of
catalyst 2. Only 0.25 mol % of 2 is needed to obtain the same con-
version as found for 5 mol % of catalyst 1. Substrate 7 was then
chosen as a model for a RCM reaction for seven membered rings.
Once more, 2 was remarkably more efficient than catalyst 1. Quan-
titative conversion was found for 3 mol % of catalyst 2. Using com-
plex 1, only 72% of conversion was found with the same catalyst
loading. In fact, for full conversion more than 5 mol % of catalyst
Figure 3. Conversion versus catalyst loading.
In view of these results we were interested in comparing the
steric environment at the metal center of catalysts 1 and 2. Since
a crystal structure of the corresponding phosphine-free isoprop-
4
b
oxybenzylidene complex of 1 has been published we decided to
1
3
1
were needed in this reaction.
synthesize complex 9, assuming that the structural features of
the phosphine-free complexes reflect the situation in complexes
1 and 2. The X-ray crystal structure of 9 (Fig. 4) and the published
structure show similar characteristics. Both complexes have the
same open environment at the metal center.
These findings demonstrated the superior efficiency of catalyst
in hexafluorobenzene, and we decided to evaluate catalyst 2 in a
2
variety of RCM reactions with sterically challenging substrates (Ta-
ble 1). In all cases catalyst 2 in hexafluorobenzene showed faster
reactions and superior yields with lower catalyst loadings than cat-
Several factors may be responsible for the increased RCM effi-
ciency in the formation of tetrasubstituted olefins in hexafluoro-
benzene. Grubbs et al. suggested that the initiation rate was
roughly proportional to the dielectric constant of a given solvent.14
The dielectric constant of hexafluorobenzene is, however, consid-
erably lower than of benzene and of toluene at the same tempera-
4
b
alyst 1 in benzene.
Ts
N
Ts
N
15
cat. (0.25 mol%)
ture. Thus the effects seen in our investigations cannot be
attributed to the dielectric constant of the solvent. Further, the
0.1 M, C6F6, 80 °C
known intermolecular
p–p interaction between the N-aryl group
of the NHC ligand and the aromatic solvent may be a factor
explaining our findings. This interaction was suggested as a rea-
3
4
16
son for the increase in activity in metathesis reactions carried out
in toluene at 80 °C, since the same transformations in dichloroeth-
ane at the same temperature led to lower yields. In addition, this
1
00
8
6
4
2
0
0
0
0
0
p–p interaction would influence the intramolecular stabilizing
interaction between the N-aryl group and the benzylidene carbene
and consequently affect the initiation rate of the catalyst. In
addition, a potential influence on the donating capacity of the
NHC ligand through
p–p intermolecular interaction with hexa-
fluorobenzene can be discussed. Previous studies in different
cyclophane-based rhodium dicarbonyl complexes showed (by
measuring CO stretching frequencies) a decrease in the donor
1
2
17
capacity when fluorinated cyclophanes were used. Such a modi-
0
5
10
15
20
fication of the electron density around the ruthenium center could
also influence the reactivity of the catalyst. Finally, a fluorine–
ruthenium interaction could reduce the activation energy of the
Time [min]
Figure 2. RCM to form tetrasubstituted olefin 4.

5
970
D. Rost et al. / Tetrahedron Letters 49 (2008) 5968–5971
Table 1
be explained by the release of hexafluoro benzene from a ruthe-
nium catalyst—hexafluorobenzene complex.
Formation of tetrasubstituted olefins with catalyst 2
Product
Cat. (mol %)
Conversions
isolated yields) (%)
In conclusion, we have developed a new catalytic system for the
efficient formation of tetrasubstituted olefins, which requires low
catalyst loadings and even allows the conversion of electron defi-
cient olefins in high yields and very short reaction times. Detailed
studies on the influence of hexafluorobenzene in ruthenium com-
plex catalyzed metathesis reactions are currently ongoing in our
group.
(
Ts
N
1
1
5
>99 (99)
>99a
O
Acknowledgment
E
E
The authors acknowledge support from the Cluster of Excel-
lence ‘Unifying Concepts in Catalysis’ coordinated by the Techni-
sche Universität Berlin.
>99 (97)
E
E
References and notes
1
>99 (99)
1
.
.
Selected reviews: (a) Holub, N.; Blechert, S. Chem. An Asian J. 2007, 2, 1064–
1
4
082; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44,
490–4527; (c) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140; (d) Connon, S.;
Blechert, S. Angew. Chem. 2003, 115, 1944–1968; (e) Connon, S.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900–1923.
NTs
O
1
5
>99 (99)
83 (80)
2
Selected reviews: (a) Chattopadhyay, S.; Karmakar, S.; Biswas, T.; Majumdar,
K.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919–3952; (b) Villar, H.; Frings,
M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55–66; (c) Deiters, A.; Martin, S. Chem.
Rev. 2004, 104, 2199–2238; (d) McReynolds, M.; Dougherty, J.; Hanson, P.
Chem. Rev. 2004, 104, 2239–2258; (e) Meier, M. E. Angew. Chem., Int. Ed. 2000,
O
3
9, 2073–2077.
3.
(a) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dologonos, G.; Grela,
K. J. Am. Chem. Soc. 2004, 126, 9318–9325; (b) Andreana, P. R.; McLellan, J. S.;
Chen, Y.; Wang, P. G. Org. Lett. 2002, 4, 3875–3878; (c) Fürstner, A.; Ackermann,
L.; Beck, K.; Hori, H.; Koch, D.; Langemann, K.; Liebl, M.; Six, C.; Leitner, W. J.
Am. Chem. Soc. 2001, 123, 9000–9006; (d) Briot, A.; Bujard, M.; Gouverneur, V.;
Nolan, S. P.; Mioskowski, C. Org. Lett. 2000, 2, 1517–1519; (e) Scholl, M.; Trnka,
T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247–2250; (f)
Jafarpour, L.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18,
E
E
3
>99 (98)
5
416–5419; (g) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310–
6 6 2
Conditions: 0.1 M C F , 80 °C, 1 h, E = CO Et.
a
7318.
Isolated yield not determined due to product volatility.
4
.
(a) Berlin, J. M.; Campbell, K.; Ritter, T.; Funk, T. W.; Chlenov, A.; Grubbs, R. H.
Org. Lett. 2007, 9, 1339–1342; (b) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J.
M.; Grubbs, R. H.; Schrodi, J. Org. Lett. 2007, 9, 1589–1592.
Gessler, S. ‘Neue trägerfixierte und homogene Katalysatoren für die
Olefinmetathese’ Dissertation, TU Berlin, 2002.
Vehlow, K.; Gessler, S.; Blechert, S. Angew. Chem. 2007, 46, 8228–8231; Vehlow,
K.; Gessler, S.; Blechert, S. Angew. Chem., Int. Ed. 2007, 46, 8082–8085.
Luan, X.; Mariz, R.; Gatti, M.; Costabile, C.; Poater, A.; Cavallo, L.; Linden, A.;
Dorta, R. J. Am. Chem. Soc. 2008, 130, 6848–6858.
5
6
7
8
.
.
.
.
(a) Bieniek, M.; Michrowska, A.; Usanov, D. L.; Grela, K. Chem. Eur. J. 2008, 14,
806–818; (b) Fürstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P.
J. Org. Chem. 2000, 65, 2204–2207.
9.
Imhof, S.; Randl, S.; Blechert, S. Chem Commun 2001, 1692–1693.
1
0. General procedure for the ring-closing metathesis reactions: The corresponding
substrate and the catalyst were added in a tube under nitrogen atmosphere.
Hexafluorobenzene (0.1 M) was added, and the mixture was stirred at 80 °C.
The conversion progress was monitored by 1H NMR spectroscopy. For isolated
yields: The solution was concentrated, and the product was purified by column
chromatography in EtOAc/hexane.
1
1. (a) Maechling, S.; Zaja, M.; Blechert, S. Adv. Synth. Catal. 2005, 1413–1422; (b)
Zaja, M.; Connon, S.; Dunne, A.; Rivard, M.; Buschmann, N.; Jiricek, J.; Blechert,
S. Tetrahedron 2003, 59, 6545–6558.
12. (a) D’Annibale, A.; Ciaralli, L.; Bassetti, M.; Pasquini, C. J. Org. Chem. 2007, 72,
6
067–6074; (b) Eidman, K. F.; MacDougall, B. S. J. Org. Chem. 2006, 71, 9513–
Figure 4. ORTEP diagram of complex 9.
9516; (c) Mori, K. Tetrahedron 1989, 45, 3233–3298; (d) Bloch, R.; Gilbert, L.
J. Org. Chem. 1987, 52, 4603–4605; (e) Rao, Y. S. Chem. Rev. 1976, 76, 625–
694.
1
3. Synthesis of catalyst 9: Two hundred and forty milligrams of the complex 2
(0.34 mmol) and 33 mg CuCl (0.33 mmol) were dissolved under nitrogen
atmosphere in 20 ml dichloromethane followed by the addition of 160 mg
2-Isopropoxy styrene (0.68 mmol). The reaction mixture was stirred at 45 °C
for 1 h. Catalyst 3 was purified by silica chromatography (100% hexane to 100%
CH Cl ), to afford the product as a bright green solid after removal of the
rate-limiting phosphine dissociation. Such an interaction has
previously been described and discussed as a reason for the
increased efficiency observed for the corresponding complex.
To get more information about the role of hexafluorobenzene a
suspension of 2 in hexafluorobenzene was heated up to 80 °C until
dissolution of the catalyst. The solvent was then immediately
removed under reduced pressure, yielding a solid of light pink
color significantly differing from the color of complex 2. This
substance is stable at room temperature in solid form but unstable
1
8
2
2
solvent, which was recrystallized from hexane/CH
2
Cl
68%); mp > 230 °C, decomposition. H NMR (500 MHz, CDCl
ppm) = 16.32, 16.16 (s, 1H), 8.48–6.48 (m, 16H), 4.68–4.34 (m, 4H), 2.83, 2.75
2
(1:1). Yield: 155 mg
1
(
(
(
3
): (isomers) d
s, 6H), 0.93, 0.88 (d, J3 = 6.0 Hz 6H). C NMR (125 MHz, CDCl
13
3
): (isomers) d
(ppm) = 152.4, 144.8, 144.7, 133.3, 133.2, 131.7, 131.5 (C), 129.5, 129.3, 129.2,
1
7
3
29.1, 129.0, 127.8, 127.7, 127.6, 126.1, 126.0, 122.6, 122.6, 122.1, 112.7, 112.6,
À1
4.9, 74.8 (CH), 53.0, 52.9 (CH
2
), 20.8, 20.7 (CH
3
). IR (ATR):
m
(cm ) = 3470 (w),
in solution. The substance was dissolved in CDCl
3
, and after 10 min
050 (w), 2973 (m), 2926 (m), 2852 (w), 1701 (m), 1589 (m), 1476 (s), 1414 (s),
F NMR showed the presence of hexafluorobenzene, which can only
1375 (m), 1272 (vs), 1255 (vs), 1218 (m), 1113 (s), 936 (m), 814 (m), 780 (s),

D. Rost et al. / Tetrahedron Letters 49 (2008) 5968–5971
5971
+
7
45 (s). MS (EI, 70 °C): m/z (%) = 670 (<1) [M ], 488 (30), 97 (28), 81 (49), 69
16. Fürstner, A.; Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.;
Stelzer, F.; Thiel, O. R. Chem. Eur. J. 2001, 7, 3236–3253.
+
(
100). HR-MS (C35
H
34
2
N OCl
2
Ru, M ): Calcd: 670.1085, found: 670.1093.
1
1
4. Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 6543–6554.
5. (a) Laurence, C.; Nicolet, P.; Dalati, T.; Abboud, J.; Notario, R. J. Phys. Chem. 1994,
17. Fürstner, A.; Alcarazo, M.; Krause, H.; Lehmann, C. W. J. Am. Chem. Soc. 2007,
129, 12676–12677.
98, 5807–5816; (b) Cauwood, J. D.; Turner, W. E. S. J. Chem. Soc. 1915, 107, 276–
18. Ritter, T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 11768–11769.
2
81.