Kinetic benchmarking reveals the competence of prenyl groups in ring-closing metathesis

Article abstract of DOI:10.1021/acs.orglett.7b02492

A series of prenyl-containing malonates are kinetically benchmarked against the standard allyl-containing congeners using a ruthenium benzylidene precatalyst for ringclosing metatheses. The prenyl grouping is found to be a superior acceptor olefin compared to an allyl group in RCM processes with ruthenium alkylidenes derived from terminal alkenes. The prenyl group is also found to be a highly competent acceptor for a ruthenium alkylidene derived from a 1, 1-disubstituted olefin in a RCM process.

Full text of DOI:10.1021/acs.orglett.7b02492

Letter
pubs.acs.org/OrgLett
Kinetic Benchmarking Reveals the Competence of Prenyl Groups in
Ring-Closing Metathesis
Karim A. Bahou,† D. Christopher Braddock,*,† Adam G. Meyer,‡ and G. Paul Savage‡
†Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, U.K.
‡CSIRO Manufacturing, Private Bag 10, Clayton South VIC 3169, Australia
S
* Supporting Information
ABSTRACT: A series of prenyl-containing malonates are
kinetically benchmarked against the standard allyl-containing
congeners using a ruthenium benzylidene precatalyst for ring-
closing metatheses. The prenyl grouping is found to be a
superior acceptor olefin compared to an allyl group in RCM
processes with ruthenium alkylidenes derived from terminal
alkenes. The prenyl group is also found to be a highly
competent acceptor for a ruthenium alkylidene derived from a
1,1-disubstituted olefin in a RCM process.
he advent of well-defined ruthenium benzylidene precata-
lysts for ring-closing metathesis (RCM) has revolutionized
with known malonates 1−3 using Grubbs’ second-generation
catalyst (GII)13 as the ruthenium benzylidene precatalyst. As
expected, malonates 1−3 behaved as previously described (Table
1, entries 1−3).2 Inspection of the results for malonates 4 and 6
T
organic synthesis, as showcased by countless examples of highly
successful acyclic diene RCM reactions.1 These possibilities are
perhaps best illustrated in Grubbs’ standard characterization
method2 which utilize diethylmalonate substrates 1−3, respec-
tively, as increasingly difficult RCM substrates as test beds for
new catalyst types. These substrates are all characterized by being
unsubstituted at the termini of the participating olefins. In
contrast, the RCM of terminal olefins with alkenes that are
geminally disubstituted at their terminus (e.g., the prenyl group)
in ruthenium benzylidene catalyzed RCM reactions have limited
literature precedent.3−12 While these examples have shown that
such olefin combinations are possible in RCM reactions, the
prenyl grouping is most often employed as a matter of synthetic
expediency to derive the RCM substrate from readily available
terpene building blocks5,9 or in RCM reactions demonstrated
directly on monoterpenes.4 It has also been employed as a
rational design feature to direct initiation to another olefin,8a,11,12
and it has certainly been noted that the prenyl group functions
surprisingly well in selected RCM reactions.3a,4a,7e However, to
the best of our knowledge, there have been no direct kinetic
comparison of RCM reactions using acyclic dienes with terminal
alkenes versus an acyclic diene where one of the alkenes is now
geminally disubstituted at its terminus. Herein, we report on such
activities, and experimentally demonstrate that prenyl groups are
excellent acceptor olefins in ring-closing metatheses.
Table 1. Ring-Closing Metatheses of Substrates 1−6 with GII
a
Catalyst
b
entry
substrate
time (h)
product
yield (%)
1
2
3
4
5
6
1
2
3
4
5
6
1
1
7
8
9
7
8
7
99
100
c
24
1
0
99
42
24
24
c
0
a
RCM were performed with 10 mol % GII catalyst in refluxing CH2Cl2
b
c
solution at 0.01 M. Isolated % yield after chromatography. RCM
runs were quenched with diethylene glycol vinyl ether to avoid false
positives on concentration.
reveals that although the (productive) initiation on a prenyl
group (entry 6) is evidently not possible under these conditions
(substrate 6 was completely unchanged), the prenyl group is a
perfectly competent acceptor olefin in ring-closing metathesis
reactions after initiation on an allyl group (entry 4). In the case of
methallylprenyl malonate 5 (entry 5), assuming that (produc-
tive) prenyl group initiation is still prohibited, initiation at the
Our investigations began by preparation of malonates 4−6 and
comparison of theirpreviously unexploredRCM reactivity
Received: August 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
methallyl unit followed by productive RCM onto the prenyl
grouping is evidently also possible, although the overall process is
considerably slower.
1H NMR plots of time vs conversion under Grubbs’ standard
conditions2 (1 mol % GII, 0.1 M CD2Cl2, 30 °C) for diallyl 1
versus allylprenyl 4 malonate substrates (Figure 1) showed that
Figure 3. Preorganization of prenyl group (left) in alkylidene A of
substrate 4 vs reduced preorganization of allyl group (right) in
alkylidene B of substrate 1.
We next questioned whether it was possible for a prenyl
grouping to competently accept a ruthenium alkylidene derived
from a 1,1-disubstituted olefin in a RCM process. Substrate 5
(Table 1, entry 5) partially answered this question (knowing that
productive initiation is prohibited at the prenyl group), but it
does not allow kinetic separation of the ring-closing event from
the expected slow initiation process at the methallyl group. The
very limited literature precedents for this ring-closing mode had
not previously addressed this issue.17 Accordingly, we targeted
relay ring-closing metathesis (RRCM)10 substrate 16 to
uncouple these two factors (Scheme 1).
Figure 1. Plot of time vs conversion for malonates 1 vs 4 into
disubstituted alkene 7 at 1 and 0.1 mol % GII loading.
Scheme 1. Synthesis of RRCM Substrate 16
although the latter showed a more pronounced induction period,
it reached quantitative conversion in less than 20 min whereas
the former did not quite reach quantitative conversion after 1 h.14
These differences were even more pronounced at 0.1 mol % GII
catalyst loading, with the RCM of 4 being complete in less than
40 min, and RCM of 1 reaching 68% conversion in 1 h (Figure
1).15
Thus, not only is the prenyl group a competent acceptor in this
RCM substrate, it is also beneficially allows reduced catalyst
loading and shorter reaction times. To the best of our knowledge,
this is a previously unrecognized benefit of using the prenyl
group in RCM reactions. However, a parallel study using diallyl
ether 10 versus allyl prenyl ether 1112 (Figure 2) did not reveal
Thus, methallyl malonate 12 was subject to a cross-metathesis
with prenyl acetate as inspired by the studies of Robinson
(Scheme 1).18 The resulting trisubstituted olefin 13 was
subsequently C-allylated, hydrolyzed and O-allylated to give
RRCM substrate 16.
With RRCM substrate 16 in hand, we were pleased to find that
the action of 10 mol % GII catalyst (refluxing CH2Cl2 solution,
0.01 M, 1 h) gave trisubstituted cyclic olefin 8 in 83% isolated
yield. This is a significant improvement on the previously
obtained 42% yield (in 24 h) obtained for methallyl substrate 5
under the same reaction conditions (Table 1, entry 5) and
confirms that the rate-determining step in the RCM of malonate
5 is initiation at the methallyl grouping (and where productive
initiation at the prenyl grouping is prohibited). To the best of our
knowledge, this is the first example of a RRCM utilizing a prenyl
group as the final acceptor olefin. Moreover, while it is to be
expected that the RRCM approach here facilitates the overall
conversion of 16 (compared to 5) into 8, by overcoming slow
initiation, this experiment also reveals that the inherent proclivity for
RCM of an alkylidene derived from a 1,1-disubstituted olefin onto a
prenyl group is surprisingly facile. However, 1H NMR monitoring,
under the standard conditions of Grubbs2 (1 mol % GII, 0.1 M
CD2Cl2, 30 °C), of methallylprenyl malonate 5 versus RRCM
substrate 16 revealed that both reactions were sluggish over the
course of 1 h, which could be partially ameliorated by the use of
10 mol % GII catalyst and an increase of temperature to 35 °C for
RRCM of substrate 16 (Figure 4).
Figure 2. Plot of conversion of diallyl ether 10 vs allyl prenyl ether 11
into dihydrofuran at 1 mol % GII loading.
such distinct differences, although a more pronounced induction
period was still observed for the prenyl containing substrate, and
a marginally faster subsequent rate ensued. We therefore
attribute the very fast RCM reaction of allylprenyl malonate 4
to a preorganization effect where the prenyl group preferentially
adopts a pseudoequatorial position avoiding detrimental
interactions with the malonate groupings (Figure 3).16 From
these experiments with the malonate substrates and their ether
analogues, the conclusion is that all things being equal, the prenyl
group is at least as competent as an allyl group in accepting a
ruthenium alkylidene derived from a terminal alkene.
We suspected that the malonate group was also influencing the
ring-closure of RRCM substrate 16, where intermediate
B
DOI: 10.1021/acs.orglett.7b02492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
once any other deleterious factors have been eliminated, the
prenyl group is also a highly competent acceptor for a ruthenium
alkylidene derived from a 1,1-disubstituted olefin in a RCM process.
The kinetic data obtained from the NMR monitoring
experiments (cf. Figures 1, 2, 4, and 6) can be manipulated to
extract rate constant (kobs) as previously described (Table 2).2
a,b
Table 2. Observed Rate Constants for RCM Substrates
entry
substrate
kobs (s−1
)
c
d
1
2
3
4
5
6
diallyl malonate 1
0.0015 (0.0020) [0.0002]
d
allyl prenyl malonate 4
diallyl ether 10
0.0070 [0.0031]
d
0.0023 [0.0004]
Figure 4. Plot of time vs conversion for malonates 5 vs 16 into
trisubstituted alkene 8 at 1 and 10 mol % GII loading.
d
allyl prenyl ether 11
monoester relay 17
allyl methallyl malonate 2
0.0033 [0.0004]
e
0.0020
c
0.0008 (0.0012)
isoalkylidene C (postrelay) cannot escape a detrimental
interaction with one or other of the ester groups in the presumed
envelope-like conformation necessary for RCM (Figure 5). We
therefore conjectured that a monoester substrate might alleviate
this interaction via one reactive conformation of isoalkylidene D.
a
Rate constants were extracted from ln([SM]) vs time plots as
b
previously described (ref 2). Data acquired conducted under the
standard conditions of Grubbs: 1 mol % of GII, 0.1 M CD2Cl2, 30 °C
(ref 2). Number in parentheses is the kobs reported by Grubbs for this
substrate (ref 2). Figure in square parentheses is the corresponding
kobs at 0.1 mol % GII loading. 35 °C, 0.01 M.
c
d
e
Thus, the diallyl vs allylprenyl substrates can be directly
compared, where the RCM of the prenyl containing compounds
proceed faster (entries 1−4). For monoester relay substrate 17
(entry 5), it is important to appreciate here that a direct control
experiment of a ruthenium alkylidene derived from a 1,1-
disubstituted olefin closing onto an allyl group is not possible,
since preferential initiation would occur instead at the allyl group
thereby compromising the comparison. However, notwithstand-
ing this, it is notable that the overall closure of substrate 17
leading to trisusbstituted olefin 20 (entry 5) is faster than the
RCM of the typically employed allylmethallyl malonate 2 to give
trisubstituted alkene 8 (entry 6), as well as faster than the RCM
of the simplest (and usually considered as the easiest) diallyl
malonate substrate 1 to give disubstituted olefin 7 (entry 1).
Thus, the prenyl moiety has been experimentally demon-
strated to be a perfectly competent or even superior acceptor
olefin compared to an allyl group in RCM processes with
ruthenium alkylidenes derived from terminal alkenes. In
addition, through the application of Hoye’s excellent RRCM
methodology, which allows uncoupling of slow initiation from
the subsequent RCM event, the prenyl group was also revealed to
be a highly competent acceptor for a ruthenium alkylidene
derived from a 1,1-disubstituted olefin in a RCM process. These
findings should aid in the rational design and incorporation of
prenyl groups in other olefin metathesis processes.21
Figure 5. Postulated detrimental interaction of isoalkylidene C with
malonate ester (left) vs potentially alleviated interaction in monoester
isoalkylidene D (right).
Accordingly, malonate 16 was subjected to Krapcho
decarboxylation19 yielding new monoester RRCM substrate
17, and nonrelay monoester 19 was prepared by alkylation of
1
ester 18 (Scheme 2). H NMR monitoring of the metathesis
Scheme 2. Synthesis of Monoesters 17 (Left) and 19 (Right)
reaction of the former (1 mol % GII, 0.01 M20 CD2Cl2, 35 °C)
now showed rapid conversion to the ring-closed product 20
(Figure 6). A comparison with the monoester 19 under the same
conditions, clearly demonstrates that once slow initiation has
been circumvented, andby comparison with malonate 16
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02492.
Experimental procedures, characterizing data and copies
of 1H and 13C NMR spectra for compounds 2−8, 13−17
and 19. See also ref 21 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: c.braddock@imperial.ac.uk.
ORCID
Figure 6. Plot of time vs conversion for malonates 17 vs 19 into
trisubstituted alkene 20 at 1 mol % GII loading.
D. Christopher Braddock: 0000-0002-4161-7256
C
DOI: 10.1021/acs.orglett.7b02492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(10) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J.
Am. Chem. Soc. 2004, 126, 10210−10211.
Notes
The authors declare no competing financial interest.
(11) For representative cascade metathesis reactions which employ
prenyl groupings as final acceptor olefins, see: (a) Boyer, F.-D.; Hanna, I.
Tetrahedron Lett. 2002, 43, 7469−7472. (b) Boyer, F.-D.; Hanna, I. Org.
Lett. 2007, 9, 2293−2295. (b1) Schubert, M.; Metz, P. Angew. Chem., Int.
Ed. 2011, 50, 2954−2956. (d) Chang, L.; Jiang, H.; Fu, J.; Liu, B.; Li, C.-
c.; Yang, Z. J. Org. Chem. 2012, 77, 3609−3614. (e) Li, K.; Wang, C.; Yin,
G.; Gao, S. Org. Biomol. Chem. 2013, 11, 7550−7558. (f) Ma, C.; Letort,
A.; Aouzal, R.; Wilkes, A.; Maiti, G.; Farrugia, L. J.; Ricard, L.; Prunet, J.
Chem. - Eur. J. 2016, 22, 6891−6898. (g) Letort, A.; Long, D.-L.; Prunet,
J. J. Org. Chem. 2016, 81, 12318−12331. (h) Han, J.-C.; Li, C.-C. Synlett
2015, 26, 1289−1304 and references cited therein.
ACKNOWLEDGMENTS
■
We thank CSIRO and Imperial College London for a studentship
(to K.B.) and Mr. Peter R. Haycock, Imperial College London,
for assistance with the 1H NMR studies.
REFERENCES
■
(1) Handbook of Metathesis, 2nd ed.; Grubbs, R. H., Wenzel, A. G.,
O’Leary, D. J., Khosravi, E., Eds.; Wiley-VCH: Weinheim, 2015; Vols.
1−3.
(2) Ritter, T.; Hejl, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H.
Organometallics 2006, 25, 5740−5745.
(12) Clark, J. R.; French, J. M.; Jecs, E.; Diver, S. T. Org. Lett. 2012, 14,
4178−4181.
(13) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953−956.
(14) Isobutylene was observed in solution as the expected byproduct in
the 1H NMR studies [CD2Cl2, 400 MHz, δH 4.69 (hept, J = 1.2 Hz, 2H),
1.27 (t, J = 7.1 Hz, 6H, isobutylene) ppm] of prenyl substrate 4 and was
found to be present throughout the experiment in the ratio that matched
substrate conversion to product. Trace quantities (0.25%) of ethylene
were also observed. For diallyl substrate 1, ethylene (CD2Cl2, 400 MHz
δH 5.44 ppm) was observed as the expected byproduct, but only at ca.
70% of the expected amount based on substrate conversion, meaning
that some has escaped from solution.
(15) Attempted RCM at 0.01 mol % GII for substrates 1 and 4 showed
no conversion for either substrate.
(16) One reviewer suggested that the expected propagating ruthenium
isopropylidene for substrates 4 and 11 may facilitate PCy3 dissociation,
thus enhancing the reaction rate after the first RCM cycle and providing
an explanation for the induction period.
(3) (a) Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.;
Mathison, C. J. N. J. Am. Chem. Soc. 2005, 127, 8872−8888.
(b) Vassilikogiannakis, G.; Margaros, I.; Tofi, M. Org. Lett. 2004, 6,
205−208.
(4) Terminal olefin-containing C10 terpenes into cyclopentenes.
Linalool: (a) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123−1125.
For other representative examples, see: (b) Meylemans, H. A.;
Quintana, R. L.; Goldsmith, B. R.; Harvey, B. G. ChemSusChem 2011,
4, 465−469 and references cited therein. Citronellene: (c) Borre,
Dinh, T. H.; Caijo, F.; Crevisy, C.; Mauduit, M. Synthesis 2011, 2011,
2125−2130. Myrcene: (d) Kobayashi, S.; Lu, C.; Hoye, T. R.; Hillmyer,
M. A. J. Am. Chem. Soc. 2009, 131, 7960−7961.
́
E.;
́
(5) Carbocycles. 5-Ring: (a) Tian, J.-M.; Zhao, X.; Tu, Y.-Q.; Gong,
W.; Zhang, F.-M.; Zhang, S.-Y.; Wang, S.-H. Chem. - Asian J. 2014, 9,
724−727. (b) Kingsbury, J. S.; Garber, S. B.; Giftos, J. M.; Gray, B. L.;
Okamoto, M. M.; Farrer, R. A.; Fourkas, J. T.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2001, 40, 4251−4256. (c) Donohoe, T. J.; Blades, K.;
Moore, P. R.; Waring, M. J.; Winter, J. J. G.; Helliwell, M.; Newcombe,
N. J.; Stemp, G. J. Org. Chem. 2002, 67, 7946−7956. 6-Ring: (d) Ferris,
G. E.; Hong, K.; Roundtree, I. A.; Morken, J. P. J. Am. Chem. Soc. 2013,
135, 2501−2504. 7-Ring: (e) Horeischi, F.; Guttroff, C.; Plietker, B.
Chem. Commun. 2015, 51, 2259−2261. Macrocycles: (f) Heidt, T.;
(17) (a) Dorrich, S.; Ulmer, A.; Mahler, C.; Burschka, C.; Baus, J. A.;
̈
Tacke, R.; Chai, A.; Ding, C.; Zou, Y.; Brunner, G.; Goeke, A.; Kraft, P.
Eur. J. Inorg. Chem. 2014, 2014, 4394−4407. (b) Ribaucourt, A.;
Hodgson, D. M. Org. Lett. 2016, 18, 4364−4367. (c) Chavan, S. P.;
Thakkar, M.; Jogdand, G. F.; Kalkote, U. R. J. Org. Chem. 2006, 71,
8986−8988. (d) Torres, A.; Gutierrez, P.; Alvarez-Manzaneda, R.;
Chahboun, R.; Alvarez-Manzaneda, E. Org. Biomol. Chem. 2016, 14,
9836−9845. See also refs 3a and 3b.
Baro, A.; Kohn, A.; Laschat, S. Chem. - Eur. J. 2015, 21, 12396−12404.
̈
(g) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312−11313. (h) Callejo, R.; Corr, M. J.; Yang, M.; Wang, M.;
Cordes, D. B.; Slawin, A. M. Z.; O’Hagan, D. Chem. - Eur. J. 2016, 22,
8137−8151. (i) Ito, M.; Kitahara, S.; Ikariya, T. J. Am. Chem. Soc. 2005,
127, 6172−6173.
(18) Wang, Z. J.; Jackson, W. R.; Robinson, A. J. Org. Lett. 2013, 15,
3006−3009.
(19) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G. E.;
Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978, 43, 138−147.
(20) Grubbs standard conditions at 0.1 M were found to lead to
competing homodimerization of the terminal olefin of allyl ether 17. At
0.01 M, homodimerization was not observed.
(6) RCM of homoprenylallyl diethylmalonate: Gatti, M.; Vieille-Petit,
L.; Luan, X.; Mariz, R.; Drinkel, E.; Linden, A.; Dorta, R. J. Am. Chem.
Soc. 2009, 131, 9498−9499.
(21) 1H NMR, 13C NMR, and RCM kinetic data are available via a data
repository as: Bahou, K. A.; Braddock, D. C. Imperial College HPC Data
Repository, 2017. DOI: 10.14469/hpc/2707 (accessed July 2017).
(7) N-Heterocycles. 5-Ring: (a) Urbina-Blanco, C. A.; Bantreil, X.;
Wappel, J.; Schmid, T. E.; Slawin, A. M. Z.; Slugovc, C.; Cazin, C. S. J.
Organometallics 2013, 32, 6240−6247. (b) Urbina-Blanco, C. A.;
Leitgeb, A.; Slugovc, C.; Bantreil, X.; Clavier, H.; Slawin, A. M. Z.;
Nolan, S. P. Chem. - Eur. J. 2011, 17, 5045−5053. (c) Pepe, A.;
Pamment, M.; Georg, G. I.; Malhotra, S. V. J. Org. Chem. 2011, 76,
3527−3530. (d) Broggi, J.; Urbina-Blanco, C. A.; Clavier, H.; Leitgeb,
A.; Slugovc, C.; Slawin, A. M. Z.; Nolan, S. P. Chem. - Eur. J. 2010, 16,
9215−9225. (e) Lipshutz, B. H.; Ghorai, S.; Aguinaldo, G. T. Adv. Synth.
Catal. 2008, 350, 953−956. 6-Ring: (f) Takahashi, M.; McLaughlin, M.;
Micalizio, G. C. Angew. Chem., Int. Ed. 2009, 48, 3648−3652. 7-Ring:
(g) Lamberto, M.; Kilburn, J. D. Tetrahedron Lett. 2008, 49, 6364−6367.
8-Ring: (h) Wan, B.; Ma, S. Angew. Chem., Int. Ed. 2013, 52, 441−445.
(8) O-Heterocycles. 5-Ring: (a) Wallace, D. J. J. Mol. Catal. A: Chem.
2006, 254, 78−84. 6-Ring: (b) da Rocha, D. R.; Mota, K.; da Silva, I. M.
C. B.; Ferreira, V. F.; Ferreira, S. B.; da Silva, F. Tetrahedron 2014, 70,
3266−3270. 7-Ring: (c) Lee, H.; Kim, H.; Yoon, T.; Kim, B.; Kim, S.;
Kim, H.-D.; Kim, D. J. Org. Chem. 2005, 70, 8723−8729.
(9) Macrolactones: (a) Furstner, A.; Dierkes, T.; Thiel, O. R.; Blanda,
̈
G. Chem. - Eur. J. 2001, 7, 5286−5298. (b) Furstner, A.; Thiel, O. R.;
Blanda, G. Org. Lett. 2000, 2, 3731−3734. (c) Fuse, S.; Sugiyama, S.;
Takahashi, T. Chem. - Asian J. 2010, 5, 2459−2462.
̈
D
DOI: 10.1021/acs.orglett.7b02492
Org. Lett. XXXX, XXX, XXX−XXX