Improved chiral olefin metathesis catalysts: Increasing the thermal and solution stability via modification of a C1-symmetrical N-heterocyclic carbene ligand

Article abstract of DOI:10.1002/adsc.200900269

Four new ruthenium-based olefin metathesis catalysts that possess an N-heterocyclic carbene (NHC) ligand with benzyl (Bn) or or n-propyl (n-Pr) N-alkyl groups have been prepared. The synthetic routes developed for the synthesis of the required dihydroimid

Full text of DOI:10.1002/adsc.200900269

FULL PAPERS
DOI: 10.1002/adsc.200900269
Improved Chiral Olefin Metathesis Catalysts: Increasing the
Thermal and Solution Stability via Modification of a
C1-Symmetrical N-Heterocyclic Carbene Ligand
Jolaine Savoie,a Brice Stenne,a and Shawn K. Collinsa,*
a
Department of Chemistry, Universitꢀ de Montrꢀal, C.P. 6128 Station Downtown, Montrꢀal, Quꢀbec, Canada H3C 3J7
Fax : (+1)-514-343-7586; e-mail: shawn.collins@umontreal.ca
Received: April 17, 2009; Revised: June 5, 2009; Published online: July 21, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900269.
Abstract: Four new ruthenium-based olefin metathe- ring-closing metathesis is directly related to the in-
sis catalysts that possess an N-heterocyclic carbene creased steric bulk of the NHC ligand. The new cata-
(NHC) ligand with benzyl (Bn) or or n-propyl (n-Pr) lysts have been evaluated in desymmetrization reac-
N-alkyl groups have been prepared. The synthetic tions and the nature of the N-alkyl group of the
routes developed for the synthesis of the required di- NHC ligands has been shown to have an important
hydroimidazolium salts are general. Catalysts bear- effect on the observed enantioselectivities.
ing larger NHC ligands with larger N-alkyl groups
displayed improved thermal and solution state stabil- Keywords: asymmetric catalysis; desymmetrization;
ity up to 808C. The reactivity of the new catalysts in N-heterocyclic carbenes; olefin metathesis
Introduction
tive and unstable in solution, which is a drawback if
one wants to perform more challenging transforma-
The development of efficient asymmetric transforma- tions requiring longer reaction times.
tions using chiral Ru-based catalysts is an ongoing
As such, we sought to improve the stability of the
challenge in the field of olefin metathesis.[1] The fur- catalysts through varying the N-alkyl group in cata-
ther development and improvement of asymmetric lysts 4 and 6. It was hoped that this modification
metathesis transformations are inherently linked to
modification of catalyst structure. Both Mo-based and
Ru-based catalysts have been studied and while Ru-
based catalysts have not reached the levels of efficacy
provided by their Mo-based counterparts, the devel-
opment of chiral Ru-based catalysts such as 1 and 2
has continued to gain momentum due to their stabili-
ty to air and moisture and tolerance to functional
groups (Figure 1).[2–4] Recently, our group reported
the synthesis of catalyst 4, bearing a C1-symmetrical
N-heterocyclic carbene (NHC) unit, in which one of
the N-substituents (typically large aryl groups) was re-
placed by a sterically unencumbered Me group. Fur-
ther modification of the N-aryl group provided cata-
lysts that were highly reactive and afforded good
enantioselectivities in asymmetric desymmetrization
reactions.[5] Interestingly, olefin metathesis catalysts
bearing NHC ligands with N-alkyl groups are relative-
ly few in number[6–8] compared to the variety of cata-
lysts prepared with NHCs bearing various N-aryl
groups. Catalysts 4, 5 and 6 were both thermally sensi- Figure 1. Olefin metathesis catalysts.
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would improve catalyst stability (particularly their sta-
Although the yields were mediocre in some cases,
1
bility in solution) and allow for H NMR analysis of unreacted starting materials could easily be isolated
the NHCꢂs rotational behavior. In turn, we sought to and efficiently recycled. The activated electrophile
study the effects of N-alkyl substitution on catalyst re- benzyl bromide reacted relatively quickly (12 h), pro-
activity and selectivity in enantioselective desymmet- ducing the benzyl-substituted aminals 12-Bn and 14-
rization.
Bn in 79% and 47% isolated yield, respectively. The
unactivated electrophile n-PrBr required a much
longer reaction time (>36 h) and the n-Pr aminals 12-
Pr and 14-Pr were obtained in 63% and 44% isolated
yields, respectively. We believe the difficulties ob-
Results and Discussion
In order to study the effect of the N-alkyl substituents served in the functionalization of aminals 10 and 11
on their corresponding NHCs and Ru-based olefin may be due to the adjacent t-Bu group on the dihy-
metathesis catalysts, efficient synthetic protocols were droimidazoline ring. All attempts to alkylate with
required to prepare the dihydroimidazolium salt pre- bulkier branched electrophiles failed: N-alkylation
cursors. The aminals 10 and 11 were prepared from a using i-Pr halides or cyclopropyl bromide were unsuc-
Buchwald–Hartwig amination of diamine 7 and the cessful at installing branched functionality. Oxidation
aromatic bromides 8 and 9 (Scheme 1). Following the of the aminals could be carried out by treatment with
cross-coupling, the resulting diamine was cyclized in I2 and NaHCO3 in CH2Cl2. Following counter-ion ex-
the presence of paraformaldehyde to afford the ami- change, the salts 13-Pr (66%), 13-Bn (62%), 15-Pr
nals 10 and 11 in 82% and 68% yield over two steps, (63%) and 15-Bn (79%) could be isolated and charac-
respectively. The aminals 10 and 11 could be alkylated terized.
with alkyl bromides when subjected to K2CO3 in ace-
With the required dihydroimidazolium salts in
tone and high temperatures in
a
sealed tube hand, we proceeded to prepare the corresponding
Ru-based catalyst systems (Scheme 2). The first series
of catalysts prepared were from the series of dihydroi-
midazolium salts containing the 2-i-PrC6H4 group as
the N-aryl substituent. Dihydroimidazolium salts 13-
Pr, and 13-Bn were each treated with (CF3)2CH3COK
and Grubbs 1st generation catalyst 3 in toluene at
vessel.[9,10]
Scheme 1. Synthesis of new N-heterocyclic carbene ligands
via N-alkylation; reaction conditions: (a) Pd2A(dba)3
CTHUNGTRENNUNG
(5 mol%), (t-Bu)3PHBF4 (20 mol%), NaO-t-Bu (4 equiv.), 8
or 9, PhMe, 1008C, 24 h; (b) paraformaldehyde (1 equiv.),
CH2Cl2, 218C, 24 h; (c) R3CH2Br, K2CO3, acetone, 1008C,
sealed tube, 12–48 h; (d) I2, NaHCO3, CH2Cl2, 218C, 24 h;
(e) NaBF4, Na2SO3, 218C.
Scheme 2. Synthesis of new catalysts; reaction conditions:
(a) (CF3)2CH3COK (1.5 equiv.), PhMe then (PCy3)2Cl2Ru=
CHPh 3 (1 equiv.), 608C, 3 h. Only the major syn rotational
isomer is shown above.
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608C for 6 h to afford the corresponding catalysts 16- Blechert[13] and Grubbs.[14] However, 16-Bn and 17-Bn
Pr and 16-Bn in ~30% yield.[11] In an identical are stable over the same period of 4–5 months. Thus,
manner, the dihydroimidazolium salts 15-Pr and 15- even a relatively small alkyl group can increase the
Bn containing bulkier N-aryl groups were also treated steric bulk of the NHC ligand to such a point as to in-
with (CF3)2CH3COK and Grubbs 1st generation cata- crease the catalystꢀs thermal and solution stability.
lyst in toluene to afford the corresponding catalysts
In order to gain further understanding of the NHC
dynamics in these catalysts, 2D EXSY experiments
17-Pr and 17-Bn in ~30%% yield. respectively
All catalysts were isolated as a mixture of rotation- were undertaken on catalysts 16-Bn and 17-Bn to cal-
al isomers (syn: N-alkyl group syn to the benzylidene culate the rate of rotation of the NHC ligand. When
1
unit, see Scheme 2), where NOE and H NMR studies 16-Bn or 17-Bn was heated in an NMR tube in tolu-
were used to deduce the ratio of NHC rotational iso- ene-d8 at 40 or 508C, 2D EXSY experiments revealed
mers present in the precatalyst at room temperature. no rotation of the NHC in the precatalyst.
The ratio of syn and anti isomers for each catalyst is
Catalysts 4 and 6 were both previously observed to
indicated in Scheme 2. The n-Pr bearing catalyst 16- cyclize the meso-triene 18 at much faster rates than
Pr was obtained as almost exclusively syn, while cata- the corresponding catalyst 1a bearing a C2-symmetri-
lyst 16-Bn was isolated as a 1:1 mixture of syn:anti cal bulky NHC ligand. Gratifyingly, catalysts in which
isomers. Using a bulkier N-aryl group did not improve the N-alkyl group was modified were also highly
the preference for the syn isomer. The n-Pr catalyst active when compared to 1a over the same time
17-Pr was isolated in a 1:1.3 syn:anti ratio and catalyst period. When the cyclization of 18 using catalyst 16-
1
17-Bn, was isolated in a ratio of 1.4:1 syn:anti iso- Pr was monitored by H NMR, >90% conversion was
mers.
observed after only 10 min., which is similar to cata-
It was envisioned that the larger N-alkyl groups in lyst 4 (Figure 3). The substitution of the n-Pr group
catalysts 16-Pr, 16-Bn, 17-Pr and 17-Bn would impart for a Bn group again resulted in a highly active spe-
both a greater thermal stability and stability in solu- cies as catalyst 16-Bn achieved 80% conversion after
tion. Catalyst 6 decomposed in solution at ambient 12 min., although it was slightly less active than the
temperature in less than 10 min. Catalysts 16-Pr, 17- parent catalyst 4.[15]
Pr, 16-Bn and 17-Bn bearing the n-Pr and Bn groups
With the above results in hand, the efficacy of the
were all found to be stable for hours in solution in new catalysts in three desymmetrization reactions of
benzene, toluene, or THF at room temperature meso-trienes was studied (Table 1).[16] The cyclization
(Figure 2).[12] The benzyl catalyst 17-Bn was the most of 18 to form a five-membered ring gave ees for the
stable at higher temperatures. For example, 17-Bn
was stable in an NMR tube in toluene-d8 when heated
to 608C for up to 4 h before the solution slowly dark-
ened and the benzylidene peaks in the 1H NMR
slowly began to decrease in intensity. However, heat-
ing the toluene-d8 solutions of 17Bn to 808C rapidly
resulted in the formation of a brownish-black solution
and complete disappearance of any benzylidene
peaks. It should be noted that catalysts 16-Pr and 17-
Pr did decompose in the solid state over a period of
4–5 months. It was initially expected that catalysts 16-
Bn and 17-Bn might decompose through insertion
into the benzylidene unit as previously reported by
*
Figure 3. Ring-closing metathesis of 18 using catalysts 4 ( ),
~
&
*
Figure 2. Improved thermal and solution stability through
variation of the N-alkyl group of the NHC ligand.
16-Pr ( ), 16-Bn ( ) and 1a ( ). Conversions determined by
1H NMR spectrum of reaction mixture.
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Table 1. Comparison of new ARCM catalysts in enantioselective desymmetrizations.
Triene
Cat.
syn:anti ratio of cat.
ee [%][a]
Conv. [%][b], yield [%][c]
4
>95:5
>95:5
1:1
4:1
1:1.3
1.4:1
82
82
77
81
60
73
>98
>98
>98, 50
>98
>98, 40
>98, 45
16-Pr
16-Bn
6
17-Pr
17-Bn
4
>95:5
>95:5
1:1
4:1
1:1.3
1.4:1
6
>98
>98
>98
>98
>98, 77
60
16-Pr
16-Bn
6
17-Pr
17-Bn
40
25
94
90
33
4
>95:5
>95:5
1:1
4:1
1:1.3
1.4:1
60
>98
0
55
>98
>98, 71[d]
60
16-Pr
16-Bn
6
17-Pr
17-Bn
nd[e]
45
86
75
40
[a]
Enantiomeric excesses determined by chiral GC: see Supporting Information for chromatograms.
Determined from the H NMR spectrum of the crude reaction mixture.
Isolated yields after chromatography. Product loss is mainly due to their high volatility.
Conversion of 20 is >98%; only the products resulting from cyclization and dimerization are observed.
nd=not determined.
[b]
[c]
[d]
[e]
1
new N-alkyl-substituted catalysts 16-Pr (82% ee) and the desymmetrization, catalyst 16-Pr only succeeded
16-Bn (77% ee) that were similar to what was ob- in dimerizing 20 while 16-Bn afforded a lower ee of
tained for catalysts 4 and 6 (81–82% ee). When exam- 43% with only 55% conversion. Although Figure 2
ining the new catalysts that were derivatives of parent clearly shows that 16-Pr and 16-Bn are lower in reac-
catalyst 6, 17-Pr and 17-Bn afforded lower ees (60% tivity than the analogous catalyst 4, the inability to cy-
and 73%, respectively) in the cyclizations of 18.
clize 20 was surprising. Catalyst 6 had provided an
The cyclization of the triene 19 forms a six-mem- 86% ee in this reaction. Modification of the N-alkyl
bered ring and had provided low ees with catalyst 4. group in catalyst 6 slightly lowered the reactivity, but
The new catalysts 16-Pr and 16-Bn caused slight in- caused large drops in the levels of enantioselectivity.
creases in the ee in this transformation. While only The substitution of the N-Me group in catalyst 6 for
6% ee was observed with 4, 40% and 25% ee were an n-Pr group (catalyst 17-Pr) caused the ee in the
observed for catalyst 16-Pr and 16-Bn, respectively. cyclization of 20 to drop to 75% ee. An even larger
Although these results were encouraging, catalyst 6 change was observed when the cyclization was carried
still provided the highest ee in the cyclizations of 19. out with catalyst 17-Bn, where a 40% ee was ob-
Modification of the N-alkyl group in catalyst 6 had a served.
deleterious effect on the ee in the cyclization of 19.
The dramatic effects of the N-alkyl groups on the
Both catalysts bearing the larger N-alkyl groups but ee of the desymmetrization reactions are interesting.
with the identical N-aryl group as 6 (17-Pr and 17- Cavallo and co-workers have provided theoretical
Bn), produced lower ees in the cyclization of 19 (90 studies into the origin of stereoinduction in asymmet-
and 33% ee, respectively).
ric metathesis reactions using catalyst 1a.[17] These
Finally, all catalysts were surveyed in the more studies suggest a model where the N-aryl group of the
challenging cyclization of triene 20 to form a seven- NHC ligand exerts an influence over the propagating
membered ring. While catalyst 4 afforded 60% ee in alkylidene and the substrate is bound to the catalyst
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Figure 4. Possible intermediates in the cyclizations of meso-triene 18 with catalysts bearing C1-symmetrical NHC ligands.
in a “bottom-binding” arrangement (intermediate C, sis. The substitution of the N-Me group of the NHC
Figure 4). In this model, the effect of the N-aryl ligand of catalysts 4 and 6 for the Bn and n-Pr groups
group on the NHC of the catalyst opposite to the al- successfully improved thermal and solution state sta-
kylidene is not thought to influence the enantioselec- bility. Notably, the increase in the overall stability of
tivity of the ring closure. However, Grubbs and co- the catalysts allowed for NMR investigations which
workers have proposed a “side-binding” mechanism showed that no ligand rotation occurs in the precata-
where the propagating alkylidene is once again under lyst up to 808C, at which point the catalysts were ob-
the influence of the N-aryl group of the NHC ligand. served to degrade. The catalysts 16-Pr and 16-Bn
In this model, the substrate is bound so that the olefin both show lower reactivities in ring closing than the
involved in the ring closure occupies a binding site cis parent catalyst 4. This observation is in agreement
to the NHC and the Cl atom has isomerized trans to with those of Grubbs and co-workers, who have ob-
the NHC (intermediate B, Figure 4).[18] The reaction served large increases in reactivity in Ru-based cata-
between a triene such as 18 and the propagating spe- lysts bearing NHC ligands that are less sterically de-
cies A could therefore afford two intermediates B or manding.[14,20] The new catalysts have been evaluated
C (Figure 4). In these intermediates the alkylidene in desymmetrization reactions of meso-trienes and
has moved from underneath the N-alkyl group to un- have shown surprising results. The change of the N-
derneath the N-aryl group in accordance with recent alkyl group of the NHC ligands provided lower enan-
work by Chen and co-workers.[19]
tioselectivities in almost all cyclization reactions. This
It is difficult to say with any certainty whether in- suggests that C1-symmetrical NHCs such as those
termediate B or C (“side-binding” or “bottom-bind- present in catalysts 4 and 5 may be optimal for de-
ing” model) is actually responsible for the observed symmetrization reactions. These efforts should help
eeꢂs in the desymmetrization reactions. However, it is the design of future generations of chiral catalysts
clear that the N-alkyl group of the NHC ligand has a where increased lifetime is needed, such as in the syn-
direct effect on the ees of the desymmetrization. thesis of tetrasubstituted olefins. Future efforts to-
These effects are more easily explained with inter- wards discerning the decomposition pathways of
mediate B, where the “side-bound” alkene would olefin metathesis catalysts bearing NHC ligands with
more likely be influenced by the steric environment N-alkyl groups are currently underway.
provided by the N-alkyl group.
Experimental Section
Conclusions
Full experimental details for the synthesis of all ligands and
catalysts can be found in the Supporting Information.
In summary, we have prepared four new Ru-based
olefin metathesis catalysts that possess a chiral NHC
General Procedure for Asymmetric
Desymmetrization Reactions
ligand with Bn or n-Pr N-alkyl groups and are highly
active in desymmetrization reactions. The synthetic
routes developed for the synthesis of the dihydroimi-
dazolium salts 13-Pr, 13-Bn, 15-Pr and 15-Bn should
be applicable in the synthesis of other sterically de-
manding chiral dihydroimidazoliums for various ap-
Triene was added to a solution of catalyst (2.5 mol%) in
CH2Cl2 (0.055M), and the reaction stirred at 408C for 2 h.
The reaction was then quenched with ethyl vinyl ether (ap-
proximately 0.1 mL) and cooled down to room temperature.
plications in organometallic catalysis or organocataly- The reaction mixture was then filtered on neutral alumina
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and the solvent was evaporated. Further purification by
flash chromatography was performed if needed (1–5% Et2O
in pentane).
Boydston, Y. Xia, J. A. Kornfield, I. A. Gorodetskaya,
R. H. Grubbs, J. Am. Chem. Soc. 2008, 130, 12775–
12782.
[8] For other studies on N-alkyl-substituted NHCs in meta-
thesis see: a) A. Fꢃrstner, B. Gabor, R. Goddard, W. L.
Christian, R. Mynott, F. Stelzer, R. T. Oliver, Chem.
Eur. J. 2001, 7, 3236; b) A. Fꢃrstner, H. Krause, L. Ac-
kermann, C. W. Lehmann, Chem. Commun. 2001, 2240;
c) S. Pruhs, C. W. Lehmann, A. Fꢃrstner, Organometal-
lics 2004, 23 280; d) K. Velhlow, S. Maechling, S. Ble-
chert, Organometallics 2006, 25, 25.
[9] A reductive amination protocol was also investigated
but often produced a complex mixture of by-products
that were difficult to separate from the desired product,
resulting in unreproducible yields.
Acknowledgements
We thank the NSERC (Canada), FQRNT (Quꢁbec), CFI
(Canada), Boehringer Ingelheim (Canada) Ltd., Merck
Frosst Centre for Therapeutic Research and the Universitꢁ de
Montrꢁal for generous financial support.
References
[10] The N-alkylation was very sensitive. Both Na2CO3 and
Cs2CO3 were ineffective as bases and other polar sol-
vents (THF, DMF) were less effective.
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1826 – 1832