Tandem RCM-lsomerization-cyclopropanation reactions

Article abstract of DOI:10.1021/ol702766h

A new triple tandem process has been discovered in which simple acyclic substrates can be transformed into bicyclic compounds via RCMdouble bond isomerization-cyclopropanation. This process is catalyzed by second generation Grubb's catalyst without the re

Full text of DOI:10.1021/ol702766h

ORGANIC
LETTERS
2008
Vol. 10, No. 4
597-600
Tandem RCM
−Isomerization−
Cyclopropanation Reactions
AÄ lvaro Mallagaray, Gema Dom´ınguez, Ana Gradillas, and Javier Pe´rez-Castells*
Facultad de Farmacia, Dpto. Qu´ımica, UniVersidad San Pablo CEU, Urb.
Montepr´ıncipe, ctra. Boadilla km 5,300 Boadilla del Monte, 28668 Madrid, Spain
jpercas@ceu.es
Received December 3, 2007
ABSTRACT
A new triple tandem process has been discovered in which simple acyclic substrates can be transformed into bicyclic compounds via RCM
double bond isomerization cyclopropanation. This process is catalyzed by second generation Grubb’s catalyst without the requirement of
other reactives or additives. In addition, a one-pot RCM isomerization reaction followed by cyclopropanation with CHCl3/NaOH allows the
synthesis of products related to iNOS (nitric oxide synthase) inhibitors, which are currently under clinical evaluation.
−
−
−
Ruthenium alkylidene catalysts have triggered the utility of
metathesis reactions in synthesis.1 Many groups have ob-
served non-methatetic transformations as side reactions
during their studies using these complexes.2 If these alterna-
tive reactions are combined with metathesis, the synthetic
potential of ruthenium catalysts is enhanced. The ability of
one species to mediate or catalyze sequentially several
transformations adopts several names although the term
concurrent tandem transformation expresses conveniently this
concept.3
Recently, Snapper’s group has made interesting contribu-
tions in tandem transformations involving ruthenium alkyl-
idene compounds. In particular, they have described an enyne
metathesis-cyclopropanation sequence leading to alkenyl
cyclopropanes using first generation Grubbs’ catalysts [Ru]-
I.4 This group and others have accounted for the ability of
second generation complex [Ru]-II to isomerize emerging
with double bonds after a RCM. Heteroatoms which are
suitably located within the substrate facilitate the isomer-
ization process. Thus, Fustero has described the synthesis
of unsaturated lactams via RCM-double bond shift, a
process in which the presence of fluoro atoms improves the
results of the isomerization step.5
Synthesis of highly functionalized cyclopropanes is a
challenge as there are many biologically active compounds
containing this motif.6 In addition, many cyclopropane-
containing non-natural products have been prepared to study
enzyme mechanism or inhibition.7 Transition metal-catalyzed
decomposition of diazocompounds is a convenient procedure
to synthesize cyclopropanes. The use of ruthenium carbenes
to catalyze cyclopropanations via decomposition of diazo-
compounds would increase their use, particularly if the
reaction is combined with a metathesis. In particular, a new
(1) For reviews on olefin metathesis, see: (a) Katz, T. J. Angew. Chem.,
Int. Ed. 2005, 44, 3010-3019. (b) Schrock, R. R. J. Mol. Catal. A: Chem.
2004, 213, 21-30. (c) Hoveyda, A. H.; Schrock, R. R. Compr. Asymmetric
Catal. 2004, 1, 207-233. (d) Grubbs, R. H. Tetrahedron 2004, 60, 7117-
7140. (e) Grubbs, R. H.; Trnka, T. M. In Ruthenium in Organic Synthesis;
Murahashi, S.-I., Ed.; Wiley-VCH: Weinheim, Germany, 2004; Chapter
6.
(2) Reviews on non-metathetic behavior of Ru catalysts: (a) Schmidt,
B. Eur. J. Org. Chem. 2004, 1865-1880. (b) Alcaide, B.; Almendros, P.
Chem. Eur. J. 2003, 9, 1258-1262.
(3) Wasilke, J. C.; Obrey, S. J.; Baker, T.; Bazan, G. C. Chem. ReV.
2005, 105, 1001-1022.
(4) Kim, B. G.; Snapper, M. L. J. Am. Chem. Soc. 2006, 128, 52-53.
(5) Fustero, S.; Sa´nchez-Rosello´, M.; Jime´nez, D.; Sanz-Cervera, J. F.;
Pozo, C.; Acen˜a, J. L. J. Org. Chem. 2006, 71, 2706-2714. See also:
Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem.
Soc. 2002, 124, 13390-13391.
(6) Recent review: Donalson, W. A. Tetrahedron 2001, 57, 8589-8627.
10.1021/ol702766h CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/24/2008

one-step entry to [n.1.0] systems can be envisioned. We
discuss herein a new approach to the formation of bicyclic
compounds using a novel RCM-isomerization-cyclopro-
panation reaction catalyzed by [Ru]-II.
Our initial aim was the synthesis of compound 4 via RCM
and subsequent double bond isomerization (Scheme 1). This
Next, we combined this tandem process with a cyclopro-
panation reaction with dichlorocarbene. This reaction was
achieved by adding a 50% solution of NaOH in water,
CHCl3, and Aliquat 336 to the reaction mixture once the
RCM-isomerization reaction had been completed. The
overall yield of compound 5 was 21% from 1. This result
was improved by applying sonication to the cyclopropanation
step, reaching a yield of 55% (Scheme 2). A different attempt
Scheme 1. RCM-Isomerization of Compound 1
Scheme 2. RCM-Isomerization-Cyclopropanation of 1 with
Dichlorocarbene
involved using catalysts [Ru]-I for the RCM reaction and
adding NaH to perform the isomerization following Schmidt’s
conditions.8 The cyclopropanation was effected by subse-
quent addition of CHCl3 and gave 5 with a yield of only
11%. Compound 5 is structurally related to a recently
disclosed selective inhibitor of the human inducible isoform
of nitric oxide synthase (iNOS).9
strategy is advisable as a simple RCM reaction on enamides
would imply their synthesis, which is not trivial, and the
possibility that non-metathetic competitive reactions would
take place as described previously.2 Thus, substrate 1 was
reacted with ruthenium complexes [Ru]-I or [Ru]-II under
different conditions summarized in Table 1. After completion
To tune up a triple tandem process involving a cyclopro-
panation step with a diazocompound, we first checked the
ability of catalyst [Ru]-II to cyclopropanate with ethyl
diazoacetate (EDA). Thus, addition of EDA to compound 4
afforded bicyclic compounds 6 (mixture of cis:trans isomers)
along with insertion product 7 (Scheme 3). As indicated in
Table 1.
yield
3a
catalyst
temp
(°C)
time
(h)
entry (5 mol %)
solvent
2a
4a
1
2
3
4
5
6
7
8
[Ru]-I
toluene
CHCl3
toluene
toluene
p-cymene rt/∆
toluene
CHCl3
rt/∆
rt/∆
rt/70
rt/∆
3-22 80 n.d. n.d.
3-12 95 n.d. n.d.
3-12 90 n.d n.d.
[Ru]-II
[Ru]-II
[Ru]-II
[Ru]-II
[Ru]-II
[Ru]-II
[Ru]-II
Scheme 3. RCM-Isomerization-Cyclopropanation of 1
3-12 11 21
3-12 16 27
57
50
48
13
64
rt/200b 3-12 15 22
rt/140b 3-12 17 36
∆
toluene
12
10 17
a Percent of pure product. b In a sealed tube.
of the RCM reaction, the mixture was heated to favor the
double bond shift. [Ru]-I was unable to isomerize the double
bond (entry 1). With [Ru]-II, no isomerization was observed
in chloroform (entry 2), whereas in refluxing toluene the
reaction reached acceptable results, yielding 4 as the major
product (entry 4). However, at rt or 70 °C this solvent only
produced 2, and no double bond shift products such as 3 or
4 were observed (entry 3). This observation prompted us to
carry out the reaction in p-cymene (entry 5) and in sealed
tubes (entries 6 and 7). These conditions allowed the
formation of 4 in chloroform but with low yields. Finally
the best results were achieved by performing the reaction in
refluxing toluene for the RCM and the isomerization steps
(entry 8), which gave a 64% yield of the desired compound,
4.
Table 2 the results are similar in terms of yields as for
classical cyclopropanation methods (with rhodium acetate,
entry 3). The reaction in chloroform or at room temperature
did not take place. Results are similar at 70 °C (entry 2) and
(8) Schmidt, B. J. Org. Chem. 2004, 69, 7672-7687.
(9) (a) Kawanaka, Y.; Kobayashi, K.; Kusuda, S.; Tatsumi, T.; Murota,
M.; Nishiyama, T.; Hisaichi, K.; Fujii, A.; Hirai, K.; Naka, M.; Komeno,
M.; Odagaki, Y.; Nakai, H.; Toda, M. Bioorg. Med. Chem. 2003, 11, 1723-
1743. (b) Kawanaka, Y.; Kobayashi, K.; Kusuda, S.; Tatsumi, T.; Murota,
M.; Nishiyama, T.; Hisaichi, K.; Fujii, A.; Hirai, K.; Naka, M.; Komeno,
M.; Nakai, H.; Toda, M. Eur. J. Med. Chem. 2003, 38, 277-288.
(7) (a) Salau¨n, J. Top. Curr. Chem. 2000, 207, 1-67. (b) Faust, R. Angew.
Chem., Int. Ed. 2001, 40, 2251-2253.
598
Org. Lett., Vol. 10, No. 4, 2008

ization (12 h), EDA was slowly added over 8 h to the reaction
mixture and yielded 40% of the two isomeric cyclopropanes
6 (entry 4). A 52% yield of both cyclopropanes was obtained
from the initial ethyl diazoacetate (EDA) addition over 8 h
(entry 5).
Table 2.
yield
starting
temp
time
(h)
entry compd (mol %) cat. (°C)
trans-6a cis-6a 7a
1
2
3
4
5
6
4
4
4
1
1
4
(10) [Ru]-II
(10) [Ru]-II
∆
70
8b
36
40
40
25
34
19
25
21
10
15
18
10
17
10
5
<5
<5
<5
From the results shown in Table 1, a thermal modification
of the ruthenium complex seems to be essential for the
isomerization process.10 Fustero has explained the mechanism
of the double bond shift by the formation of a ruthenium
hydride from catalyst [Ru]-II, without the aid of any reactive.
This hydride would add to the double bond and then
eliminate to form the isomeric unsaturated lactam. The
regioselectivity of the process would be due to stabilization
of a positive charge by the electron lone pair of the nitrogen
in its contiguous position. If the ruthenium complex is
transformed into a hydride the question would be the identity
of the catalyst in the cyclopropanation step. We have shown
that Grubbs’ catalyst [Ru]-II is able to cyclopropanate
substrate 4 at temperatures where isomerization does not take
place, i.e., Ru-H species are not formed (entry 2, Table 2).11
8b + 48
8b
(5) Rh(OAc)2 rt
(15) [Ru]-II
(15) [Ru]-II
(10) [Ru]-IIc
∆
12 + 8b
8b
∆
70
8b
a Percent of pure product. b EDA was added over 8 h with a pump
syringe. c Thermally modified prior to reaction.
Scheme 4. RCM-Cyclopropanation of 10
The methodology was extended to other starting materials,
precursors of cycles of 5 and 7 members. Thus, diene 8 was
reacted with EDA in refluxing toluene in the presence of
[Ru]-II, giving 10 as a mixture of isomers in 58% combined
yield (Scheme 4). The RCM alone gave conjugated enone 9
(95%), which did not isomerized in any of the previously
used conditions.
When applied to substrate 11, the RCM-isomerization
phase gave a mixture of all the possible regioisomers of the
seven-membered lactam although the desired compound 12
was isolated in 62% yield (Scheme 5). The other three
isomers, 13-15, could be characterized. This result was
in refluxing toluene (entry 1), although the first reaction
needed a supplementary time for completion. Next, we
performed the three reactions from 1 in a one-pot fashion.
Thus, after verifying the completion of the RCM-isomer-
Scheme 5. RCM, Isomerization, Cyclopropanation, and Tandem Reactions from 11
a Obtained as a mixture of isomers. A small amount of major compounds trans-16, trans-18, and trans-19 was isolated for characterization.
Org. Lett., Vol. 10, No. 4, 2008
599

achieved by performing the RCM at rt and heating to reflux
temperature after completion. The reaction in a sealed tube
gave better selectivity for compound 12 but overall yield
was lower (58%). Compound 12 was cyclopropanated at 70
°C, giving products 16 (60%) as a 4:1 mixture of diastereo-
isomers. The major isomer (trans-16) was separated and
characterized whereas we were unable to obtain the minor
isomer pure. Insertion product 17 was detected in the crude
mixture. Interestingly, when performing the tandem process,
starting from 11 (conditions from Table 2, entry 5), we
obtained a mixture of cyclopropanes 18 and 19 with good
global yield. In each mixture, the diastereomers could not
be separated by MPLC. Major compounds trans-18 and
trans-19 were characterized. This latter result shows that after
the isomerization step there is equilibrium between the
isomers 12-15 and the composition of the mixture may
change with subtle variation of the conditions. For an
unknown reason, compounds 13 and 15 react better than 12
under these conditions. This result shows that [Ru]-II is able
to catalyze the cyclopropanation of non-activated olefins like
13 or 15. The identity of cyclopropanes 18 and 19 was
checked by performing two independent cyclopropanation
reactions from 13 and 15 using catalyst [Ru]-II at 70 °C.
In conclusion, we have described a new concurrent tandem
catalyzed triple process including RCM-isomerization and
cyclopropanation. The second generation Grubb’s catalyst
was able to catalyze the three processes without requiring
other reactives. The identity of the catalytic species and the
mechanism of this transformation needs further study, but
we presume that the complex mediating in the isomerization
step is a ruthenium hydride formed by thermal modification
of the initial carbene. RCM-isomerizations can be combined
with classical cyclopropanations with dichlorocarbenes giving
products related to bioactive compounds.
Acknowledgment. Funding of this project by the Spanish
MEC (No. CTQ2006-00601/BQU) is acknowledged. A.M.
thanks FUSP-CEU for a predoctoral fellowship.
(10) (a) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc.
2004, 126, 7414-7415. (b) Hong, S. H.; Grubbs, R. H. Org. Lett. 2007, 9,
1955-1957. (c) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J.
Am. Chem. Soc. 2005, 127, 17160-17161. (d) Hong, S. H.; Wenzel, A.
G.; Salguero, T. T.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2007,
129, 7961-7968.
(11) In addition, it is known that Grubbs’ catalysts activate diazo
compounds, maintaining their metathesis activity. See: (a) Hodgson, D.
M.; Angrish, D. Chem. Commun. 2005, 4902-4904. (b) Hodgson, D. M.;
Angrish, D. AdV. Synth. Catal. 2006, 348, 2509-2514. (c) Hodgson, D.
M.; Angrish, D. Chem. Eur. J. 2007, 13, 3470-3479. (d) Hodgson, D. M.;
Angrish, D.; Labande, A. H. Chem. Commun. 2006, 627-628.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702766H
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Org. Lett., Vol. 10, No. 4, 2008