Efficient allyl to propenyl isomerization in functionally diverse compounds with a thermally modified Grubbs second-generation catalyst

Article abstract of DOI:10.1021/ol062167o

Heating compounds containing C-allylic appendages in MeOH in the presence of 10 mol % of Grubbs second-generation catalyst at 0.075 M substrate concentration leads to the corresponding 2-propenyl derivatives without further conjugation in the cases of ketones, esters, and lactams. The reaction is applicable to a large variety of functionally relevant terminal olefins, including O- and N-allyl ethers.

Full text of DOI:10.1021/ol062167o

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5481-5484
Efficient Allyl to Propenyl Isomerization
in Functionally Diverse Compounds
with a Thermally Modified Grubbs
Second-Generation Catalyst
Stephen Hanessian,* Simon Giroux, and Andreas Larsson
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128, Succursale Centre-Ville,
Montre´al, Que´bec H3C 3J7, Canada
stephen.hanessian@umontreal.ca
Received September 1, 2006
ABSTRACT
Heating compounds containing C-allylic appendages in MeOH in the presence of 10 mol % of Grubbs second-generation catalyst at 0.075 M
substrate concentration leads to the corresponding 2-propenyl derivatives without further conjugation in the cases of ketones, esters, and
lactams. The reaction is applicable to a large variety of functionally relevant terminal olefins, including O- and N-allyl ethers.
Alkene metathesis including the venerable ring-closure
metathesis (RCM) variant reactions, with ruthenium catalysts
such as I developed by Grubbs and co-workers,1 has
markedly influenced our thought process regarding strategic
C-C bond formation. Characterized by its compatibility with
a wide cross section of functionalities, this remarkable
internal olefin-forming reaction under mild and requisite
dilution conditions has been used as a key carbo- and
heterocyclization step in a large number of natural product
syntheses.2 Occasionally, and depending on the nature of the
reacting olefinic partners, isomerization to a 2-alkenyl-type
motif may occur with terminal olefins, thereby detracting
from the usually high-yielding metathesis reaction.3 To
address this problem, Grubbs and co-workers4 have devel-
oped methods that minimize the unwanted isomerization
reaction.
Olefin isomerization with ruthenium carbene catalysts in
conjunction with RCM reactions has been reported by several
groups.5 For example, Snapper and co-workers6 utilized a
N2/H2 atmosphere in a tandem RCM-isomerization sequence
for the syntheses of 2,3-dihydropyrans from terminal olefinic
precursors in the presence of I (Figure 1).7
(3) For selected observations of unwanted isomerizations during or
subsequent to RCM reactions, see: (a) Bourgeois, D.; Pancrazi, A.;
Nolan, S. P.; Prunet, J. J. Organomet. Chem. 2002, 643-644, 247-
254. (b) Fu¨rstner, A.; Theil, O. R.; Ackermann, L.; Schanz, H.-J.;
Nolan, S. P. J. Org. Chem. 2000, 65, 2204-2207. (c) Maynard, H.
D.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137-4140. (d) Joe,
D.; Overman, L. E. Tetrahedron Lett. 1997, 38, 8635-8638 (with
Mo-carbene).
(1) For an authoritative collection of relevant work in this area, see: (a)
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinhem,
Germany, 2003; Vols. 1, 2, & 3. See also pertinent reviews: (b) Grubbs,
R. H. Tetrahedron 2004, 60, 7117-7140. (c) Schmidt, B.; Hermanns, J.
Top. Organomet. Chem. 2004, 7, 223-267. (d) Connon, S. J.; Blechert, S.
Top. Organomet. Chem. 2004, 7, 93-124. (e) Connon, S. J.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900-1923. (f) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18-29. (g) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012-3043.
(4) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 17160-17161.
(5) Schmidt, B. Eur. J. Org. Chem. 2004, 1865-1880.
(6) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am.
Chem. Soc. 2002, 124, 13390-13391.
(2) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4490-4527. (b) Deiters, A.; Martin, S. F. Chem. ReV. 2004,
104, 2199-2238.
(7) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
10.1021/ol062167o CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/24/2006

grade, undistilled MeOH at 60 °C for 3-12 h depending on
the nature of the substrates. A catalyst loading of 10 mol %
and a concentration of 0.075 M in substrate is highly
effective.
Starting with simple allyl aromatics, isomerization is
complete with minimal self-dimerization taking place (Table
1). There is a high tolerance for a variety of aromatic
Figure 1. Ru carbene and hydride complexes I-V.
Table 1. Isomerization of C-Allyl Aromatic Derivatives
Bo¨rsch and Blechert8 utilized I in the presence of catalytic
amounts of NaBH4 to effect a tandem RCM-isomerization
reaction. Nishida and co-workers9 have achieved indole
syntheses in a tandem isomerization-RCM sequence with
I in the presence of excess TMS vinylether as an olefinic
reacting partner. Schmidt10 utilized a combination of the first-
generation catalyst II and ethyl vinylether to perform tandem
isomerization-Claisen rearrangements. Prunet and Nolan3a
observed isomerization in the presence of the IMes derivative
of I in their attempt to obtain a cyclooctene intermediate.
Wagener and co-workers11 have studied olefin isomerization
in conjunction with ADMET polymerization. Competing
olefin isomerization to the detriment of an intended RCM
reaction has also been noted by Fu¨rstner,3b Grubbs,3c and
Overman.3d
However, the intentional isomerization of a terminal
double bond to its internal counterpart with Ru catalysts can
also be of particular importance in natural product synthesis.12
To the best of our knowledge, there are no catalytic methods
of preparatiVe utility for the isomerization of unsubstituted
terminal olefins in polyfunctional compounds into their
2-alkenyl equivalents in the presence of I. The availability
of such a method that is compatible with the presence of
one or more polar substituents in polyfunctional substrates
bearing a C-allyl appendage, for example, would greatly
expand the repertoire of olefin chemistry.13
We report herein a mild, efficient, and versatile method
for the isomerization of unsubstituted terminal allyls to
their 2-propenyl counterparts, with minimal if any self-
dimerization or cross-metathesis products1e in the examples
studied. The method consists of heating a suspension of the
Grubbs second-generation catalyst and the olefin in reagent
a Only the E isomer is shown. b Yields of isolated olefins after chroma-
1
tography. c Determined by H NMR.
substituents. Pentafluoro allylbenzene (3a), which was
reported to isomerize with 50% conversion in the presence
of an Ir catalyst,14 was isomerized with 100% conversion
and 80% isolated yield under the present conditions (Table 1,
entry 3). Functionalized rings such as 4a and 5a (Table 1,
entry 4) were isomerized, whereas other catalysts failed to
react.15 A 2-allyl-indole analogue (6a) underwent isomer-
ization to afford the propenyl derivative 6b (Table 1, entry 5).
In general, these allyl aromatics were fully converted to their
2-propenyl counterparts in less than 3 h giving a preponder-
ance of the trans isomers.14
In Table 2 are listed the results from the isomerization of
a variety of C-allyl groups appended to functionally diverse
and preparatively useful substrates (7a-13a). Thus, N-
substituted amino acid esters and lactams (Table 2, entries
1-3), ketones, esters, and lactones (entries 4-6) harboring
C-allyl groups are smoothly isomerized to the corresponding
2-propenyl olefins in high yields, without further conjuga-
(8) Bo¨hrsch, V.; Blechert, S. Chem. Commun. 2006, 1968-1970.
(9) (a) Terada, Y.; Arisawa, M.; Nishida, A. Angew. Chem., Int. Ed.
2004, 43, 4063-4067. (b) Arisawa, M.; Terada, Y.; Takahashi, K.;
Nakagawa, M.; Nishida, A. J. Org. Chem. 2006, 71, 4255-4261.
(10) Schmidt, B. Synlett 2004, 1541-1544. See also: Ammar, H. B.;
Le Noˆtre, J.; Salem, M.; Kaddachi, M. T.; Dixneuf, P. H. J. Organomet.
Chem. 2002, 662, 63-69. For a similar approach to tandem isomerization-
Claisen using Ir-based catalysts, see: Nelson, S. G.; Bungard, C. J.; Wang,
K. J. Am. Chem. Soc. 2003, 125, 13000-13001. See also: Stevens, B. D.;
Bungard, C. J.; Nelson, S. G. J. Org. Chem. 2006, 71, 6397-6402.
(11) Lehman, S. E.; Schwendeman, J. E.; O’Donnell, P. M.; Wagener,
K. B. Inorg. Chim. Acta 2003, 345, 190-198.
(12) For recent isomerizations of terminal double bonds in total synthesis,
see: (a) Shen, X.; Wasmuth, A. S.; Zhao, J.; Zhu, C.; Nelson, S. G. J. Am.
Chem. Soc. 2006, 128, 7438-7439. (b) Wipf, P.; Spencer, S. R. J. Am.
Chem. Soc. 2005, 127, 225-235.
(13) For reviews on double-bond isomerizations with Ru hydride
catalysts, see: (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV.
2001, 101, 2067-2096. (b) Naota, T.; Takaya, H.; Murahashi, S.-I. Chem.
ReV. 1998, 98, 2599-2660.
(14) For a recent report on trans-selective isomerizations of allylbenzene
derivatives, see: Baxendale, I. R.; Lee, A.-L.; Ley, S.V. J. Chem. Soc.,
Perkin Trans. 1 2002, 1850-1857.
(15) Isomerizations were tried with 10 mol % of RhCl3·H2O, RhCl-
(PPh3)3, and RuH2(PPh3)4 in refluxing EtOH for 12 h.
5482
Org. Lett., Vol. 8, No. 24, 2006

Table 2. Isomerization of R-C-Allyl Carbonyl Derivatives
Table 3. Isomerization of Differently Functionalized C-, P-,
O-, and N-Allyl Compounds
a Only the E isomer is shown. b Yields of isolated olefins after chroma-
tography. c Determined by 1H NMR. d Run in the absence of light and with
12 mol % of I.
tion.16 Although these functionalized olefins with multiple
coordination sites were isomerized at lower rates than the
aromatic olefins, they were complete after 12 h at 60 °C
giving the trans isomers as major or exclusive products.
Again, when isomerization of substrates such as 9a was tried
with other well-known isomerization catalysts,15 only starting
material was recovered in each case.
The isomerizations listed in Table 3 were done following
the same simple protocol, and the results further validate
the generality of the method. Remarkably, benzylic acetates
and ethers (16a-20a) in a variety of aromatic and hetero-
aromatic substrates are not subject to methanolysis or
hydrolysis under these conditions (Table 3, entries 3 and 4).
Allyl diketone (15a) and allylphosphine oxide (21a) undergo
isomerization with high E/Z ratios (Table 3, entries 2 and
5). The isomerization of O-allyl ethers under mild conditions
(Table 3, entry 6) obviates the need to include excess
amounts of N-allylic reagents as in the commonly used
protocol.17 N-Allyl-indole derivatives are converted to the
N-2-propenyl counterparts in good yields (Table 3, entry 7).18
a Only the E isomer is shown. b Yields of isolated olefins after chroma-
1
d
1
tography. c Determined by H NMR. >90% conversion by H NMR.
We next studied the effect of solvents using 3,4-dimethoxy
allylbenzene 1a as a model substrate (Table 4). All four
expected products of isomerization, self-dimerization, and
cross-metathesis were prepared separately as controls. The
results are listed in Table 4. Clearly, the most efficient solvent
for isomerization of 1a was MeOH. Benzene, dichloro-
methane, and dichloroethane were the least efficient, afford-
ing mixtures due to the occurrence of cross-metathesis with
a still viable catalyst prior to isomerization. Alternatively,
heating the catalyst I in DME3a at 60 °C for 1 h, followed
by addition of 1a, gave 2a in 84% yield (NMR).
Mol19a and co-workers have reported the isomerization of
neat 1-nonene with V and the partial conversion of I to IV
and V in MeOH at 60 °C in the presence of NEt3.19b It has
(16) For a review of R-vinylic and related amino acids, see: Berkowitz,
D. B.; Charette, B. D.; Karukurichi, K. R.; McFadden, J. M. Tetrahedron:
Asymmetry 2006, 17, 869-882.
(17) Hu, Y.-J.; Dominique, R.; Das, S. K.; Roy, R. Can. J. Chem. 2000,
78, 838-845.
(18) Alcaide, B.; Almendros, P.; Alonso, J. M. Chem.-Eur. J. 2003, 9,
5793-5799.
(19) (a) Dinger, M. B.; Mol, J. C. Organometallics 2003, 22, 1089-
1095. (b) Dinger, M. B.; Mol, J. C. Eur. J. Inorg. Chem. 2003, 2827-
2883.
Org. Lett., Vol. 8, No. 24, 2006
5483

The complex nature of the prevailing Ru species formed from
the Grubbs catalyst I under the reaction conditions precludes
any speculations regarding a precise catalytic cycle.23
In conclusion, we have developed a simple, mild, and
efficient method for the isomerization of terminal unsubsti-
tuted olefins into their 2-alkenyl counterparts with minimal
if any self-dimerization products even at a concentration of
0.075 M in substrate.24 Applications to a diverse set of
C-allylic substrates, including amino acid derivatives, and
of O-allyl ethers demonstrate the versatility of the method.
Particularly useful are isomerizations of R-C-allyl carbonyl
compounds to their R-2-propenyl counterparts, which are
formally equivalent to a two-step R-propenylation of an
enolate, without further conjugation. Isomerization of 1-
butenyl benzylic acetates and O-TBS ethers to the corre-
sponding 2-butenyl isomers without solvolysis in MeOH is
noteworthy. The catalytic species are most likely Ru hydride
complexes generated during the initial heating period in
MeOH.21 The facile allyl to propenyl isomerizations reported
herein should find utility in a variety of synthetic applications.
Table 4. Isomerization vs Self-Dimerization/Cross-Metathesis
with 1a
entrya,b solvent 1a (%) 2a (%) 3a (%) 4a (%) 5a (%)
1
2
3
4
5
6c
C6H6
36
0
0
11
0
36
11
80
54
18
47
9
28
0
2
22
1
29
24
7
32
39
19
24
1
13
12
10
33
2
MeOH
i-PrOH
DCE
DME
CH2Cl2
a Substrate and catalyst heated at 60 °C for 90 min. b Ratios determined
by 1H NMR of crude reaction mixtures (400 MHz, CDCl3). c Reaction
performed at 40 °C.
Acknowledgment. We thank NSERC (Canada) and the
Wenner-Gren foundation (Sweden) for financial assistance
to A.L.
also been shown by Grubbs and co-workers20 that I could
be transformed in part to the hydrido-carbonyl complex IV
in the presence of MeOH, even at room temperature after
12 h. We surmised that the catalytic species in the isomeri-
zations reported herein involved the Ru hydrido-carbonyl
complex IV (and possibly V) formed in situ, although no
precautions were taken to avoid air or moisture in the
methanol used.21
Supporting Information Available: Experimental details
and characterization data for relevant new compounds.
1
Copies of selected H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL062167O
To gain evidence toward this assumption, we conducted
the isomerization of 24 with 1 equiV of I in MeOH-d4.
Deuterium incorporation (50%) was observed at CMe, CR,
and Câ as confirmed by H NMR spectroscopy and HRMS
analysis (Scheme 1).22 A Ru-D species generated in situ, as
(20) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.; Scholl,
M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 2546-2558.
(21) For a study of the Ru complexes formed from I in MeOH in the
presence of NEt3, see ref 19b. For the formation of IV in the presence of
TMS vinylether, see ref 9. For the formation of V in the presence of
ethylvinylether, see: Louie, J.; Grubbs, R. H. Organometallics 2002, 21,
2153-2164. For the synthesis of the IMes derivative of IV from V, see:
Lee, H. M.; Smith, D. C.; He, Z.; Stevens, E. D.; Y, C. S.; Nolan, S. P.
Organometallics 2001, 20, 794-797. See also: Dharmasena, U. L.;
Foucault, H. M.; dos Santos, E. N.; Fogg, D. E.; Nolan, S. P. Organo-
metallics 2005, 24, 1056-1058.
1
Scheme 1. Deuterium Incorporation
(22) For a related experiment in a Pd-catalyzed olefin isomerization,
see: Davies, N. R. Aust. J. Chem. 1964, 17, 212-218.
(23) Preliminary results showed that catalyst II was less efficient than I
for isomerization. As expected, the Hoveyda-Grubbs catalyst III led to
self-dimerization of 1a.
(24) Representative procedure: To a solution of the olefin (1 equiv) in
MeOH (0.075 M) was added I (10 mol %) at room temperature. The
suspension was then heated at 60 °C. After a few minutes, the insoluble
catalyst (purple) dissolved and the resulting orange-brown solution was
stirred for 3 h (Table 1) or 12 h (Tables 2 and 3) after which time the
solution was evaporated. The residue was purified by flash chromatography
to give the isomerized olefin. See Supporting Information for details.
observed by Grubbs20 and Mol19 for the protio equivalent,
could be responsible for such deuterium atom incorporation.
5484
Org. Lett., Vol. 8, No. 24, 2006