Synthesis of heterocycles through a ruthenium-catalyzed tandem ring-closing metathesis/isomerization/N-acyliminium cyclization sequence

Article abstract of DOI:10.1002/anie.201100417

Tandem bicycle: In the title reaction double bonds created during ring-closing metathesis isomerize to generate reactive iminium intermediates that undergo intramolecular cyclization reactions with tethered heteroatom and carbon nucleophiles. In this way, a series of biologically interesting heterocyclic compounds can be made, including a known precursor for the total synthesis of the antiparasitic natural product harmicine. Copyright

Full text of DOI:10.1002/anie.201100417

Communications
DOI: 10.1002/anie.201100417
Tandem Reactions
Synthesis of Heterocycles through a Ruthenium-Catalyzed Tandem
Ring-Closing Metathesis/Isomerization/N-Acyliminium Cyclization
Sequence**
Erhad Ascic, Jakob F. Jensen, and Thomas E. Nielsen*
Olefin metathesis is an extremely powerful and
general method for carbon–carbon bond formation
in organic synthesis.[1] For example, ruthenium
alkylidene catalyzed metathesis has been widely
used to construct a variety of alkenes for applica-
tions in chemistry, materials science, and chemical
biology. A key asset of the metathesis process is the
unique olefin functional group selectivity mediated
by robust and well-defined catalytic systems.
Over the years, however, unexpected non-
metathetic reactions have been observed under
metathesis conditions.[2] Although these reactions
typically are highly substrate dependent, associ-
ated with specific reaction conditions, and possibly
caused by ill-defined metal-catalytic species, they
represent a unique opportunity for the develop-
ment of tandem processes.[3] It is well recognized
Figure 1. Ruthenium alkylidene catalysts commonly used in metathesis. Cy=cyclo-
that tandem reactions offer major advantages in
the synthesis of valuable target compounds. In this
context, metathesis mediated by ruthenium alkyli-
dene catalysts 1e and 1k (Grubbs first- and second-gener-
ation catalysts; Figure 1) has successfully been coupled to
nonmetathetic transformations, such as double-bond isomer-
ization,[4–6] hydrogenation,[7–9] cyclopropanation,[10] dihydrox-
ylation,[11,12] keto-hydroxylation,[12] and Kharasch addition
reactions.[13]
hexyl, Mes=2,4,6-trimethylphenyl.
(RCM/isomerization/cyclopropanation),[15] we speculated
that enamides generated in the event of a RCM/isomerization
sequence could be further isomerized into reactive N-
acyliminium intermediates (Scheme 1).[16] The presence of a
suitably tethered nucleophile could then bring about a second
cyclization step.
Only a few reports have dealt with the tandem ring-
closing metathesis (RCM)/ double-bond isomerization. Nota-
ble works by the groups of Snapper[4] and Schmidt[5] have
independently shown how cyclic allyl ethers can isomerize
into 2,3-dihydropyrans. Schmidt and co-workers have also
shown the beneficial effect of added hydride to favor the
isomerization step. Inspired by the work of Fustero et al.
(RCM/isomerization),[14] and Pꢀrez-Castells and co-workers
Scheme 1. Tandem RCM/isomerization/N-acyliminium cyclization.
[*] E. Ascic, Dr. J. F. Jensen, Dr. T. E. Nielsen
Department of Chemistry, Technical University of Denmark
2800 Kgs. Lyngby (Denmark)
Initial investigations were focused on substrate 2 (see,
Table 1), which contains an indole moiety as a potentially
reactive p nucleophile. The resulting product has a tetracyclic
indolizinoindole core that is present in a range of pharmaco-
logically interesting compounds, such as GPCR antago-
nists,[17] antibacterial,[18] and antiparasitic agents.[19] Access
to enantiopure indolizinoindole derivatives has also been
widely pursued in recent efforts in asymmetric catalysis.[20] We
started out by screening ruthenium catalysts 1a–k (Figure 1),
in toluene at reflux (Table 1). The reactions were generally
Fax: (+45)4593-3968
E-mail: ten@kemi.dtu.dk
Homepage: http://www.thomasenielsen.org
[**] This work was supported by the Technical University of Denmark,
the Danish Council for Strategic Research, the Danish Council for
Independent Research, Natural Sciences, Technology and Produc-
tion Sciences, the Lundbeck Foundation, the Carlsberg Foundation,
and the Torkil Holm Foundation. We thank Prof. David Tanner for
valuable discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100417.
1
very clean, as indicated by UPLC-MS and H NMR spec-
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Angew. Chem. Int. Ed. 2011, 50, 5188 –5191

Table 1: Screening of catalysts for RCM/isomerization/N-acyliminium
cyclization.
Entry
Catalyst
Solvent
2/3a/3b[a]
1
2
3
1a
1b
1b
1b
1c
1c
1c
1d
1e
1 f
1 f
1 f
1g
1g
1g
1h
1i
toluene
toluene
m-xylene
m-xylene
toluene
m-xylene
m-xylene
toluene
toluene
toluene
m-xylene
m-xylene
toluene
m-xylene
m-xylene
toluene
toluene
toluene
m-xylene
m-xylene
toluene
100:0:0
0:2:98
0:0:100
0:5:95
4[b]
5
0:26:74
0:0:100
0:10:90
83:3:14
54:6:40
36:0:64
0:0:100
38:0:62
0:12:88
0:0:100
0:5:95
61:4:35
25:38:37
3:14:83
0:0:100
7:13:80
0:70:30
6
7[b]
8
9
10
11
12[b]
13
14
15[b]
16
17
18
19
20[b]
21
1j
1j
1j
1k
Scheme 2. a) Optimized reaction conditions, and b) proposed mecha-
nism for formation of N-acyliminium intermediate. TFA=trifluoro-
acetic acid.
[a] With the exception of entry 17, product mixtures were generally clean
(>85% of 2/3a/3b in the reaction mixture as indicated by RP-HPLC
analysis). [b] The reaction was carried out with 5 mol% of catalyst.
tion events during the isomerization (Scheme 2b). In addi-
tional experiments, we also noted that the conversion of 2 into
3b can be catalyzed cleanly with 1b in the presence of 1–2%
TFA or BF3·Et2O (added at the beginning of the reaction) in
m-xylene heated at reflux, thus shortening the reaction times
to less than 1 hour but giving slightly lower yields (70–75%;
Scheme 2a).
troscopy, and the proposed enamide intermediate was never
detected.[21] Notably, with 15 mol% of catalyst in m-xylene at
reflux, several catalysts brought about clean conversion into
the desired product 3b (entries 3, 6, 11, 14, and 19). When the
amount of catalyst was lowered to 5 mol%, the Hoveyda–
Grubbs catalyst 1b gave the cleanest and highest conversion
(95%) of 2 into 3b (entry 4). When the catalyst loading was
raised to 6 mol%, the reaction was complete in 17 hours
(Scheme 2a), and gave 3b in 81% yield. When 2 was
subjected to the same reaction conditions at lower temper-
ature (608C), the metathesis product 3a could be isolated in
75% yield. After careful removal of trace amounts of
ruthenium,[22] the conversion of 3a into 3b was investigated
under various reaction conditions. When 3a was treated with
catalyst 1b, the desired product formed quantitatively in less
than 5 hours. The same experiment without catalyst led to a
1:1 mixture of 3a and 3b, thus indicating a thermal back-
ground reaction, but also unambiguously demonstrating the
beneficial effect of the catalyst in the nonmetathetic part of
the tandem sequence. The synthesis of 3b represents a formal
total synthesis of the antiparasitic natural product harmi-
cine.[19,20b] The homologous substrates 4 and 5 were not
converted into the tetracycles 4b and 5b under the optimized
conditions (although they still underwent RCM reactions)
and TFA rapidly converted 3a into 3b (Scheme 2a); together
these findings suggest to us that the nonmetathetic role of the
ruthenium does not necessarily involve a ruthenium hydride
intermediate, but somehow promotes favorable tautomeriza-
The reaction using the N-methylated indole 6 gave an
increased yield of 86% (Scheme 3). The introduction of a
substituent, as present in the tryptophan (8) and benzothi-
enylalanine (10) derivatives, effectively directed the forma-
tion of the new stereocenter with excellent trans diastereose-
lectivity at the ring junction. The trimethoxybenzene deriv-
ative 12 also underwent the tandem reaction sequence to give
the tetrahydroisoquinoline derivative 13 in good yield (64%).
The methodology was also extended to an intermolecular
variant, wherein indole acted as the nucleophile in the
reaction with the N-acyliminium intermediate that was
derived from 14, in good yield (57%). Under these reaction
conditions, however, the reaction required the addition of
4 equivalents of indole. If 14 was instead treated with 1b at
reflux for 1 hour, followed by the addition of indole (1 equiv)
and TFA (1 equiv) and additionally reacted for 1 hour, then
15 could be isolated in 84% yield. The nucleophilicity of the
aromatic ring is highly important, as evident for substrates 16,
18, and 20 (Scheme 4), which were not converted into the
corresponding tricycles under reaction conditions similar to
those used in Scheme 3. Ring-closing metathesis occurred
smoothly for these substrates but further conversion was
better mediated by the subsequent addition of 1–4 equiva-
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Communications
substrates 22a–c, and, rewardingly, hemiaminals 23a–c were
formed in good yield and with excellent diastereoselectivity
(Scheme 5).
Scheme 5. Tandem RCM/somerization/N-acyliminium cyclization reac-
tions of alcohols.
The tandem methodology presented herein, presumably
involves the generation of an N-acyliminium species. There-
fore, it was natural to also investigate whether N-alkylimi-
nium ions could be formed during a similar tandem process. In
a preliminary study on amino alcohol 24, treatment with
10 mol% of the Grubbs second-generation catalyst 1k
resulted in a tandem metathesis/isomerization/cyclization
sequence to give the bicyclic product 26 in good yield
(Scheme 6). Notably, carefully purified cyclic alkene 25 does
not convert into 26 under thermal conditions whereas the
addition of 1k rapidly effects the isomerization steps.
Scheme 3. Tandem RCM/isomerization/N-acyliminium reactions.
Scheme 6. Ruthenium-catalyzed tandem RCM/isomerization/N-acyl-
iminium cyclization.
In summary, an efficient ruthenium-catalyzed tandem
ring-closing metathesis/isomerization/N-acyliminium cycliza-
tion sequence has been developed. In this tandem process,
two new rings are formed in a single synthetic operation,
which proceeds through a metathesis reaction and attack of
tethered carbon and heteroatom nucleophiles on iminium
intermediates. The resulting bi-, tri-, and tetracylic ring
systems are generally formed in good to excellent yields
with excellent diasteroselectivities. We believe that our
findings point in a promising direction for future metathesis
research.
Scheme 4. RCM and acid-mediated isomerization/N-acyliminium cycli-
zation.
Received: January 18, 2011
Published online: April 21, 2011
lents of TFA to the reaction mixture. In this way, tricyclic
compounds 17, 19 and 21 were obtained in good to excellent
yields.
Furthermore, the extension of the methodology to
heteroatom nucleophiles was briefly examined by using
Keywords: cyclization · isomerization · metathesis · ruthenium ·
tandem reactions
.
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