Ruthenium-catalyzed cycloisomerization and its application to the synthesis of (±)-cinchonaminone

Article abstract of DOI:10.1002/ejoc.201200260

Ru-catalyzed cycloisomerization of a 1,3-diene and the alkene of an N-dienyl-2-vinylaniline substrate proceeded smoothly, leading to a 3-exomethylene-2-vinylindole derivative in good yield. This useful synthon was successfully applied to the total synthes

Full text of DOI:10.1002/ejoc.201200260

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200260
Ruthenium-Catalyzed Cycloisomerization and Its Application to the Synthesis
of (؎)-Cinchonaminone
Takao Ogawa,[a] Tomonori Nakamura,[b] Takuya Araki,[b] Koujirou Yamamoto,[b]
Satoshi Shuto,*[a] and Mitsuhiro Arisawa*[a]
Keywords: Heterocycles / Cyclization / Ruthenium / Natural products / Total synthesis
Ru-catalyzed cycloisomerization of a 1,3-diene and the alk-
ene of an N-dienyl-2-vinylaniline substrate proceeded
smoothly, leading to a 3-exomethylene-2-vinylindole deriva-
tive in good yield. This useful synthon was successfully ap-
plied to the total synthesis of (Ϯ)-cinchonaminone.
plex A[2c] showed high catalytic activity in selective ter-
minalolefin isomerization (from I to II)[2a,3] and/or cyclo-
Introduction
Indole derivatives are important cyclic structures in organic isomerization of 1,7-dienes (from I to III)[2b] depending on
synthesis, as they can serve as building blocks for functional the reaction temperature.[4] This was most notable in the
materials and as key components in a myriad of bioactive case of 2,3-disubstituted indole derivatives III obtained by
compounds. Consequently, new and more efficient synthetic cycloisomerization, which are important synthons for bio-
methods are being actively pursued to prepare this class of logically active natural products.[5] However, substituents at
nitrogen-containing heterocycles, with selective control of the 2-position of the indoles obtained by this method are
substitution patterns, from readily available and simple sub- limited to non-functionalized ethyl or longer alkyl groups.
strates.[1]
Therefore, the synthesis of biologically active 2,3-disubsti-
Previously, we found that ruthenium hydride complex A tuted indole derivatives, including cinchonaminone (Fig-
with an N-heterocyclic carbene ligand could be generated ure 1) could be difficult.
in pure form by reaction of the second generation Grubbs
In this article, we report the ruthenium-catalyzed cyclo-
catalyst with vinyloxytrimethylsilane (Scheme 1).[2] Com- isomerization of a 1,3-diene and the alkene of an N-dienyl-
Scheme 1. Reported Ru-catalyzed cycloisomerization to yield substituted indole derivatives.
[a] Faculty of Pharmaceutical Sciences
2-vinylaniline substrate, leading to a substituted, syntheti-
cally useful indole derivative with 3-exomethylene and 2-
vinyl substituents. The vinyl functionality in the indole
would be useful for further transformations, such as hydro-
boration, ozonolysis, and metathesis. Thus, the synthesis of
the naturally occurring 2,3-disubstituted indole compound
(Ϯ)-cinchonaminone (1) was achieved.
Hokkaido University
Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan
Fax: +81-11-706-3769
E-mail: arisawa@pharm.hokudai.ac.jp
[b] Department of Clinical Pharmacology,
Gunma University Graduate School of Medicine,
3-39-22 Showa-machi, Maebashi 371-8511, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200260.
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T. Ogawa, T. Nakamura, T. Araki, K. Yamamoto, S. Shuto, M. Arisawa
SHORT COMMUNICATION
2-vinylaniline, which could undergo intramolecular olefin
insertion into the Ru–C bond. On the basis of our pre-
viously reported reaction of A with N-allyl-2-vinylaniline
derivatives I, syn β-H elimination would afford the desired
cycloisomerization product, namely, the 3-exomethylene-2-
vinylindole derivatives.
The reaction catalyzed by A was investigated with deriva-
tive 2, which has a 1,3,8-triene structure, and the results are
summarized in Table 1. First, a solution of 2, Grubbs sec-
ond generation catalyst (10 mol-%), and vinyloxytrimethyl-
silane (1 equiv.) in xylene was heated at reflux for 1 h. The
reaction gave desired cycloisomerized product 3-exometh-
ylene-2-vinylindole derivative 3 in 35% yield (Table 1, En-
try 1). When the reaction was carried out at lower tempera-
tures (110–80 °C), the yield of 3 increased (Table 1, En-
tries 1–4). At 60 °C, the reaction proceeded slowly, and
most of the starting material was recovered (Table 1, En-
try 5). Consequently, 87% of 3 was isolated when a mixture
of 2, the Grubbs catalyst (5 mol-%), and vinyloxytrimethyl-
silane (1 equiv.) was heated at reflux in benzene for 1 h
(Table 1, Entry 6). In these reactions, none of the Diels–
Alder product was obtained.
Figure 1. An example of biologically active 2,3-disubstituted ind-
ole.
Results and Discussion
Transition-metal catalyzed carbon–carbon bond-forming
reactions have found exceptional utility in organic synthesis.
Of particular note are the applications of organotransition
metal chemistry in the construction of carbocyclic rings. Al-
though various transition-metal-catalyzed [4+2] cycload-
ditions (Diels–Alder reaction) of substrates having the
1,3,8- or 1,3,9-triene structure have been reported
(Scheme 2a), there are apparently only two examples of the
cycloisomerization between a 1,3-diene and the alkene of
1,3,8- or 1,3,9-trienes to form a cyclopentane structure,
those catalyzed by Fe or Rh (Scheme 2b and c).[6] In the
RhI-catalyzed reaction, the existence of a heteroatom in the
tether between the 1,3-diene moiety and the alkene changed
the course of the reaction. Namely, although the reaction
with the carbon-tethered substrate gave the cycloisomeriza-
tion product (Scheme 2b), the reaction with the corre-
sponding nitrogen- or oxygen-tethered substrates provided
none of the expected cycloisomerization product, but only
the Diels–Alder cycloadduct (Scheme 2c).[6b] The synthesis
of heterocycles, including that of indoles, by cycloisomeriza-
tion of a 1,3-diene and the alkene of 1,3,8- or 1,3,9-triene
substrates has not been reported until now. As described
above, recently we found that the reaction of I with A gave
2,3-disubstituted indole derivatives III by cycloisomeriza-
tion of the 1,7-diene structure of N-allyl-2-vinylanilines
(Scheme 1). Thus, we envisioned that A might catalyze the
reaction of the 1,3,8- or 1,3,9-triene structures of N-dienyl-
Table 1. Reaction of the N-butadienyl-2-vinylaniline derivative.
Entry
Grubbs cat.
[mol-%]
Solvent
T
t
Yield [%]
3 SM
[°C] [h]
1
2
3
4
5
6
10
10
10
10
10
5
xylene
toluene
toluene
benzene
benzene
benzene
140
110
80
80
60
1
1
2
1
2
1
35[a]
0
0
68[a]
62[b] 25[b]
86[a]
12[b] 62[b]
87[a]
0
80
0
[a] Isolated yield. [b] NMR yield.
The reaction with the corresponding derivative 4 with a
1,3,9-triene structure was next investigated, and the results
are summarized in Table 2. A refluxing solution of 4, the
Grubbs catalyst (10 mol-%), and vinyloxytrimethylsilane
(1 equiv.) in xylene did not give any of expected cycloiso-
merized product 5, but instead, cycloisomerized quinoline
derivative 6[7] and Diels–Alder adduct 7 were obtained in
32 and 31% yield, respectively (Table 2, Entry 1). Although
several reaction conditions were examined, that is, changing
the solvent, reaction temperature, and catalyst, we could
not synthesize 5 (Table 2, Entries 2–4), and we found that
at higher reaction temperatures, the Diels–Alder reaction of
4 proceeded smoothly to give 7 in 88% isolated yield
(Table 2, Entry 5).
Having expected 3-exomethylene-2-vinylindole derivative
3 in hand, we then applied it to the synthesis of indole alka-
loid (Ϯ)-cinchonaminone (1). This alkaloid was isolated
from Cinchonae Cortex (the cortex of Cinchona succirubra
PAV., Rubiaceae) in 1989 (Figure 1).[8] Although (+)-cin-
Scheme 2. Reported reaction of a 1,3-diene and an alkene.
2
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Ruthenium-Catalyzed Cycloisomerization
Table 2. Reaction of the N-pentadienyl-2-vinylaniline derivative.
Entry
Catalyst
[mol-%]
CH2=CHOTMS
[equiv.]
Solvent
T
[°C]
t
[h]
Yield [%][a]
5
6
7
SM 4
1
2
3
4
5
Grubbs 2nd (10)
Grubbs 2nd (10)
Grubbs 2nd (10)
Ru(CO)HCl(PPh3)3 (5)
–
1
1
1
–
–
xylene
toluene
benzene
toluene
xylene
140
110
80
110
140
0.5
2
2
4
1
0
0
0
0
0
32
24
7
10
0
31
17
26
0
0
57
0
51
88[b]
0
[a] NMR yield. [b] Isolated yield.
chonaminone is reported to have an inhibitory activity
Piperidine 15 was prepared from known 13[9] in four
against monoamine oxidase (MAO) from bovine plasma steps (Scheme 4). The methyl ester and benzoyl groups on
(IC50 = 31.7 μm), the total synthesis of 1 has not been re- 14 were simultaneously reduced with LiAlH4 to give the
ported.
corresponding amino alcohol, which was treated with
Thus, we decided to synthesize this indole alkaloid and Boc2O and then subjected to iodination to afford 15.
examine its effects on human MAOs. As shown in
Scheme 3, regioselective hydroboration of 3 and subsequent
TEMPO oxidation led to 3-formyl derivative 9, which was
treated with the Wittig reagent to afford 2,3-divinyl indole
10. Another regioselective hydroboration of 10 by using
Cy2BH followed by methoxy methyl ether protection of the
generated alcohol provided 2-vinylindole derivative 11. Oxi-
dative cleavage of the olefin moiety of 11 by using a combi-
nation of osmium tetroxide and sodium periodate gave 2-
formyl indole 12.
Scheme 4. Synthesis of the piperidine unit. Reagents and condi-
tions: (a) MeOH, EDC·HCl, DMAP, THF, 91%. (b) 1. LiAlH4,
THF, –30 to –5 °C. 2. Boc2O, Et3N, CH2Cl2. 3. I2, PPh3, imidazole,
PhH, reflux, 44% (3 steps).
The coupling of building blocks 12 and 15 leading to
the total synthesis of (Ϯ)-1 is shown in Scheme 5. Thus,
generation of the corresponding zinc reagent from 15 with
Zn followed by reaction with aldehyde 12 resulted in the
desired coupling product, which was oxidized with Dess–
Martin periodinane to give 16. Removal of both the meth-
oxymethyl and Boc groups furnished (Ϯ)-1. The synthe-
sized racemic cinchonaminone [(Ϯ)-1] exhibited spectro-
scopic data identical to those reported previously (1H NMR
and 13C NMR and HRMS).[8]
Scheme 3. Synthesis of indole unit. Reagents and conditions: (a) 9-
BBN, THF, –20 to 0 °C; then, H2O2, NaOH, H2O, 86 %.
(b) TEMPO (10 mol-%), NCS, Bu4NCl (10 mol-%), CH2Cl2, H2O
(pH 9), 66% (yield based on recovered starting material: 81%).
(c) Ph3PMeBr, NaN(TMS)2, THF, –78 to r.t., 82%. (d) 1. Cy2BH,
THF, 0 °C to r.t.; then, H2O2, NaOH, H2O. 2. MOMCl, iPr2NEt,
CH2Cl2. 3. NaOH, aq. MeOH, reflux. 4. Boc2O, Et3N, DMAP,
Scheme 5. Synthesis of (Ϯ)-1. Reagents and conditions: (a) Zn,
THF, 40 °C. (b) CuCN, LiCl, BF3·OEt2, THF, –78 to –30 °C.
(c) Dess–Martin periodinane, CH2Cl2, 11% (2 steps, yield based on
CH2Cl2, 62% (4 steps). (e) OsO4 (5 mol-%), NaIO4, aq. dioxane, recovered starting material: 30%). (d) 3 m HCl, MeOH, 40 °C,
45%.
76%.
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T. Ogawa, T. Nakamura, T. Araki, K. Yamamoto, S. Shuto, M. Arisawa
SHORT COMMUNICATION
126.45, 121.11, 120.48, 119.51, 116.91, 112.02, 63.19, 51.39, 46.19,
43.90, 43.06, 34.40, 29.06, 28.89 ppm. LRMS (EI): m/z = 312
[M]+. HRMS (EI): calcd. for C19H25N2O2 [M + H]+ 313.1911;
found 313.1913.
Conclusions
The chemistry described in this communication shows
the first example of the Ru-catalyzed cycloisomerization re-
action between a 1,3-diene and an alkene leading to a syn-
thetically useful 3-exomethylene-2-vinylindole derivative
and its application to the synthesis of racemic cinchon-
aminone [(Ϯ)-1]. Synthesis of cinchonaminone analogues
by this method and their effects on human MAOs are under
investigation to study the structure–activity relationship.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and full characterization of com-
pounds 2–4, 6–12, 14–16, and (Ϯ)-1.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research
on Innovative Areas “Molecular Activation Directed toward
Straightforward Synthesis” from the Ministry of Education, Cul-
ture, Sports, Science and Technology.
Experimental Section
Preparation of N-Methoxycarbonyl-3-methylene-2-(1-propenyl)-
indoline (3): Under an Ar atmosphere, to a solution of 2 (591 mg,
2.58 mmol) in benzene (210 mL) was added Grubbs 2nd generation
catalyst (109 mg, 0.13 mmol, 5 mol-%) and vinyloxytrimethylsilane
(385 μL, 2.58 mmol), and the mixture was heated at reflux for 1 h.
Solvents were partially removed under reduced pressure, and the
obtained residue was subjected to column chromatography (SiO2,
hexane/AcOEt = 20:1) to give 3 (510 mg, 2.23 mmol, 87%, E/Z =
[1] For recent reviews, see: a) J. Barluenga, F. Rodríguez, F. J.
Faáanás, Chem. Asian J. 2009, 4, 1036–1048; b) O. Miyata, N.
Takeda, T. Naito, Heterocycles 2009, 78, 843–871; c) K. Krüger
(née Alex), A. Tillack, M. Beller, Adv. Synth. Catal. 2008, 350,
2153–2167; d) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006,
106, 2875–2911; e) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105,
2873–2920.
[2] a) M. Arisawa, Y. Terada, M. Nakagawa, A. Nishida, Angew.
Chem. 2002, 114, 4926; Angew. Chem. Int. Ed. 2002, 41, 4732–
4734; b) Y. Terada, M. Arisawa, A. Nishida, Angew. Chem.
2004, 116, 4155; Angew. Chem. Int. Ed. 2004, 43, 4063–4067;
c) M. Arisawa, Y. Terada, K. Takahashi, A. Nishida, J. Org.
Chem. 2006, 71, 4255–4261.
1
7:3) as a colorless oil. H NMR (400 MHz, CDCl3, 50 °C, E iso-
mer): δ = 7.81 (br., 1 H), 7.41 (d, J = 7.7 Hz, 1 H), 7.25 (dd, J =
7.7, 7.7 Hz, 1 H), 6.99 (dd, J = 7.7, 7.7 Hz, 1 H), 5.74 (dd, J = 6.8,
15.0 Hz, 1 H), 5.51 (d, J = 2.7 Hz, 1 H), 5.45 (ddq, J = 1.8, 7.7,
14.9 Hz, 1 H), 5.18 (d, J = 7.2 Hz, 1 H), 4.97 (d, J = 2.3 Hz, 1 H),
3.82 (s, 3 H), 1.71 (dd, J = 1.8, 6.8 Hz, 3 H) ppm. 1H NMR
(400 MHz, CDCl3, 50 °C, Z isomer): δ = 7.81 (br., 1 H), 7.41 (d, J
= 7.7 Hz, 1 H), 7.25 (dd, J = 7.7, 7.7 Hz, 1 H), 6.99 (dd, J = 7.7,
7.7 Hz, 1 H), 5.70–5.61 (m, 2 H), 5.47 (d, J = 2.7 Hz, 1 H), 5.34
(ddq, J = 1.8, 9.5, 10.9 Hz, 1 H), 4.93 (d, J = 2.3 Hz, 1 H), 3.81 (s,
3 H), 1.71 (dd, J = 1.8, 6.8 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3, E isomer): δ = 153.13, 144.71, 143.70, 129.93, 129.51,
128.10, 127.55, 122.80, 120.57, 115.66, 103.31, 66.03, 52.45,
17.60 ppm. LRMS (EI): m/z = 229 [M]+. HRMS (EI): calcd. for
C14H15NO2 [M]+ 229.1103; found 229.1098. C14H15NO2·0.25H2O
(233.8): calcd. C 71.93, H 6.68, N 5.99; found C 71.99, H 6.48, N
5.90.
[3] For a review on metal-catalyzed isomerizations, see: S. Krom-
piec, M. Krompiec, R. Penczek, H. Ignasiak, Coord. Chem.
Rev. 2008, 252, 1819–1841.
[4] For reviews on non-metathesis reactions, see: a) B. Alcaide, P.
Almendros, Chem. Eur. J. 2003, 9, 1258–1262; b) B. Schmidt,
Eur. J. Org. Chem. 2004, 9, 1865–1880; c) M. Arisawa, Y. Ter-
ada, K. Takahashi, M. Nakagawa, A. Nishida, Chem. Rec.
2007, 7, 238–253; d) B. Alcaide, P. Almendros, A. Luna, Chem.
Rev. 2009, 109, 3817–3858.
[5] Y. Terada, M. Arisawa, A. Nishida, J. Org. Chem. 2006, 61,
1269–1272.
[6] a) J. M. Takacs, L. G. Anderson, J. Am. Chem. Soc. 1987, 109,
2200–2202; b) Y. Sato, Y. Oonishi, M. Mori, Organometallics
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c) J. M. Takacs, J. Zhu, Tetrahedron Lett. 1990, 31, 117–1120;
d) J. M. Takacs, J. Zhu, S. Chandramouli, J. Am. Chem. Soc.
1992, 114, 773–774; e) J. M. Takacs, F. Clement, J. Zhu, S. V.
Chandramouli, X. Gong, J. Am. Chem. Soc. 1997, 119, 5804–
5817.
[7] Although it is known that Ru-catalyzed diene cycloisomeriza-
tion usually leads to five-membered rings, in this case a six-
membered ring cyclization is probably the result of 1,3-diene
conjugation.
Preparation of (؎)-3-(2-Hydroxyethyl)-2-[2-(3-vinylpiperidin-4-yl)-
acetyl]indole (1): A solution of 16 (35 mg, 63 μmol) in 3 m HCl in
MeOH (2 mL) was stirred at 40 °C overnight. The solvent was re-
moved under reduced pressured, and the obtained residue was sub-
jected to column chromatography (SiO2, CHCl3/MeOH = 100:0–
97:3) to give (Ϯ)-1 (15 mg, 48 μmol, 76%) as a white amorphous
1
solid. H NMR (500 MHz, CDCl3): δ = 9.11 (s, 1 H), 7.70 (d, J =
8.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.35 (dd, J = 8.6, 8.6 Hz,
1 H), 7.15 (dd, J = 8.0, 8.0 Hz, 1 H), 6.14 (dt, J = 9.7, 17.2 Hz, 1
H), 5.13 (dd, J = 2.3, 10.3 Hz, 1 H), 5.03 (dd, J = 1.7, 17.2 Hz, 1
H), 3.94 (t, J = 6.3 Hz, 2 H), 3.37 (t, J = 6.3 Hz, 2 H), 3.04 (dt, J
= 4.0, 12.6 Hz, 1 H), 2.97–2.91 (m, 3 H), 2.80–2.69 (m, 2 H), 2.45
(m, 1 H), 2.38 (m, 1 H), 1.55–1.44 (m, 2 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 192.83, 137.62, 136.01, 132.88, 128.40,
[8] N. Mitsui, T. Noro, M. Kuroyanagi, T. Miyase, K. Umehara,
A. Ueno, Chem. Pharm. Bull. 1989, 37, 363–366.
[9] R. L. Funk, M. M. Abelman, J. D. Munger Jr., Tetrahedron
1986, 42, 2831–2846.
Received: March 3, 2012
Published Online: ᭿
4
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Date: 25-04-12 15:15:36
Pages: 5
Ruthenium-Catalyzed Cycloisomerization
Natural Products
Ru-catalyzed cycloisomerization of a 1,3-
diene and the alkene of an N-dienyl-2-vin-
ylaniline substrate proceeded smoothly,
leading to a 3-exomethylene-2-vinylindole
derivative in good yield. This useful syn-
thon was successfully applied to the total
synthesis of (Ϯ)-cinchonaminone.
T. Ogawa, T. Nakamura, T. Araki,
K. Yamamoto, S. Shuto,*
M. Arisawa* ..................................... 1–5
Ruthenium-Catalyzed Cycloisomerization
and Its Application to the Synthesis of (Ϯ)-
Cinchonaminone
Keywords: Heterocycles
/ Cyclization /
Ruthenium / Natural products / Total syn-
thesis
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