Ruthenium-Catalyzed 1,6-Aromatic Enamide-Silylalkyne Cycloisomerization: Approach to 2,3-Disubstituted Indoles

Article abstract of DOI:10.1021/acs.joc.7b01288

Cycloisomerization is an atom economic procedure that converts dienes and enynes into cyclic molecules. To date, cycloisomerization between enamides and silylalkynes has not been explored. We found that N-acyl-N-vinyl-2-silylalkynylaniline derivatives und

Full text of DOI:10.1021/acs.joc.7b01288

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Note
Ruthenium-Catalyzed 1,6-Aromatic Enamide–Silylalkyne
Cycloisomerization: Approach to 2,3-Disubstituted Indoles
Kohei Takamoto, Shohei Ohno, Norimichi Hyogo, Hiromichi Fujioka, and Mitsuhiro Arisawa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01288 • Publication Date (Web): 21 Jul 2017
Downloaded from http://pubs.acs.org on July 21, 2017
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Ruthenium-Catalyzed 1,6-Aromatic Enamide–Silylalkyne Cycloisomerization:
Approach to 2,3-Disubstituted Indoles
Kohei Takamoto, Shohei Ohno, Norimichi Hyogo,
Hiromichi Fujioka, Mitsuhiro Arisawa*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita,
Osaka 565-0871, Japan
e-mail: arisaw@phs.osaka-u.ac.jp
Abstract
Cycloisomerization is an atom economic procedure that converts dienes and enynes into
cyclic molecules. To date, cycloisomerization between enamides and silylalkynes has
not been explored. We found that N-acyl-N-vinyl-2-silylalkynylaniline derivatives
undergo a cycloisomerization in the presence of a well-defined ruthenium hydride to
give a 2,3-disubstitued indole. The vinyl and silylmethyl substituents on the 2- and
3-positions of the indole can be easily converted to other functional groups.
Transition metal-catalyzed cycloisomerization of enynes is a powerful atom economic
method for accessing cyclic structures from acyclic precursors with substantially less
molecular complexity than that of their products.1, 2
Enamides are highly stable and commonly present in natural products and drugs, 3
making these compounds important building blocks in organic chemistry. The majority
of synthetic applications of enamides4 documented in the literature relate to their
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asymmetric reductions5, nucleophilic additions6, cycloadditions, radical reactions, and
oxidation reactions. Transition metal-catalyzed regioselective functionalization of
enamides can be used to rapidly construct nitrogen-containing heterocycles.7 For
example, the Mizoroki-Heck reaction has been applied to enamides8 and enamide-ene
ring-closing metathesis9 for various applications in the total synthesis of natural
products. Cyclization between an alkyne and enamide to give piperidine has been
catalyzed by a Pt or Au π-electrophilic Lewis acids.10 In addition, several groups have
reported pyrrole synthesis using Rh or Ru catalyzed oxidative annulations of
enamides.11 Fukuyama and Tokuyama reported Cu-catalyzed N-arylation of
enecarbamates to construct an indole. On the bases of these earlier studies, we
envisioned that cycloisomerization between an aromatic enamide and a silylalkyne
moiety could give a 2,3-disubstituted indole with synthetically useful vinyl and
trimethylsilylmethyl groups at the 2- and 3-positions, respectively. 12 Indole is present in
numerous bioactive natural products and pharmaceuticals.13
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SiMe3
N
1a
Ts
Figure 1. N-Toluenesulfonyl-N-vinyl-2-trimethylsilylethynylaniline (1a)
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Mes
N
N Mes
Mes
N
N Mes
Ru
Cl
Ru
Cl
Cl
Cl
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O
Ph
PCy3
I (Grubbs II)
II
PCy3
Cl
Cl
PCy3
Ru
Cl
Ru
Cl
O
Ph
PCy3
III (Grubbs I)
IV
Figure 2. Ruthenium carbene catalysts (I–IV)
OSiMe3
Mes
N
N Mes
Ru H
I
Cl
OC
A
PCy3
Scheme 1. Ruthenium hydride A with a nitrogen-containing heterocyclic carbene
ligand.
We prepared N-toluenesulfonyl-N-vinyl-2-trimethylsilylethynylaniline (1a, Figure 1)
from 2a and RuHCl(CO)(PPh3)3 quantitatively, and attempted cycloisomerization of 1a
under various conditions using a conventional catalyst system, including Pd12. However,
we obtained only trace amounts of the expected indole. Then, we treated 1a under
various conditions with commercially available ruthenium hydrides, RuHCl(CO)(PPh3)3
and RuH2(CO)(PPh3)3, and ruthenium hydride A,14 which contains a nitrogen-containing
heterocyclic carbene ligand (Figure 2, Scheme 1). When 1a was treated with 10% (mole
fraction) of RuHCl(CO)(PPh3)3 or RuH2(CO)(PPh3)3 under reflux in p-xylene, the
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expected indole 3a or 4a was obtained in low yield. The same reaction, with the use of
ruthenium hydride A, generated from ruthenium carbene catalyst I (Scheme 1),
followed by aromatization with (+)-10-camphorsulfonic acid, (+)-CSA, yielded the
corresponding 3-trimethylsilylmethyl-2-vinylindole 4a in 41% yield (Table 1, run 1).
Compound 4a could be a useful synthon, because it has functional groups allowing for
further chemical transformations at both the 2- and 3-positions of the indole. Before
examining these chemical transformations, we optimized the substrate and reaction
conditions for this cycloisomerization.
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Table 1. Cycloisomerization of 1 to give 3 and 4.
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SiMe3
N
R
N
R
2
4
RuHCl(CO)(PPh3)3
(10 mol%)
p-xylene, 100 °C, 1 h
(+) - CSA
(20 mol%)
reflux, 1 h
isomerization
aromatization
SiMe3
"Ru"
SiMe3
OTMS
(1 eq.)
N
N
reflux
see table
R
R
1 (E:Z = 1:1)
3 (E:Z = 1:1)
cycloisomerization
run substrate
R =
Ts
“Ru”
time isolated yield (%)
(mol%)
(h)
3
1
4
1
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
I (10)
54
75
90
-
41
2
Ts
Ts
RuHCl(CO)(PPh3)3 (10)
RuH2Cl(CO)(PPh3)2 (10)
3
trace
trace
92
3
3
4
CHO I (10)
0.5
2
5
CHO I (5)
-
80
6a)
CHO I (2)
12
1
-
83
7
CHO II (10)
-
80
8
CHO III (10)
3
-
61
9
CHO IV (10)
3
-
71
10
11
CHO RuHCl(CO)(PPh3)3 (10)
CHO RuH2Cl(CO)(PPh3)2 (10)
3
44
42
18
3
16
a) Performed in a glove box with oxygen and moisture levels less than 1 ppm.
We applied catalyst A to the cycloisomerization of 1a under various reaction conditions,
solvents, and temperatures in a conventional heating system. However, the yield of 4a
did not increase. These results suggested that cycloisomerization of 1a to 3a requires a
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high temperature. Thus, we reduced the size of the substituents on the aromatic amine to
promote the cyclization. Formyl derivative 1b was subjected to the same experimental
conditions as those used for run 1. As expected, 1b was converted to the cyclized
compound 4b in 92% yield (run 4). When the amount of catalyst I was reduced, the
yield of 4b decreased, even when the reaction time was increased (runs 5 and 6). In runs
7–9, we respectively used ruthenium carbene catalysts II, III, and IV instead of I.
Control experiments with commercially available ruthenium hydrides,
RuHClCO(PPh3)3 and RuH2CO(PPh3)2, showed no conversion of 1b to 3b or 4b. These
results indicate that the presence of a nitrogen-containing heterocyclic carbene ligand
might be necessary for this cycloisomerization to proceed quantitatively. We also tried
to catalyze the first two steps, i.e., the isomerization/cycloisomerization, with a single
catalytic system. Thus, 2b was treated with Grubbs II (10 mol%) and
vinyloxy-trimethylsilane (1 eq.) in refluxing p-xylene for 4 hours and we obtained the
corresponding 3b in only 14% yield. Furthermore, control experiments with the use of
Pd(OAc)2(PPh3)215 or [IrCl(cod)]216, which has been used in a previous 1,6-enyne
cycloisomerization, failed to convert 1b to 3b or 4b.
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Table 2. Effect of the alkyne substituent on the reaction yield.
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R
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N
2
CHO
RuHCl(CO)(PPh3)3 (10 mol%)
p-xylene, 100 °C, 1 h
R
I (10 mol%)
CH2=CHOSiMe3
( 1 eq.)
(+) - CSA
1
3
N
p-xylene
p-xylene
reflux, time 2
CHO
reflux, time 1
4
run
R =
time 1 (+)-CSA
(h) (mol%)
time 2 yield of 4 (%, 3 steps)
(h)
1
2
3
4
5
6
2b SiMe3
0.5
0.5
1
20
20
1
1
1
8
2
-
4b (92)
2c SiMe2Ph
2d SiMe2Bn
2e tBu
4c (83)
4d (89)
4e (70)
4f (24)
4g (0)
20
1
100
100
-
2f CH2OSii-Pr3
2
2g
H
0.5
On the basis of these results, we next examined the effect of alkyne substituents on the
yield (Table 2). A one-pot reaction starting from the trialkylsilyl derivatives 2b (SiMe3),
2c (SiMe2Ph), and 2d (SiMe2Bn) gave the corresponding cyclized products 4 in
respective yields of 92%, 83%, and 89%, via cycloisomerization of 1 to 3 (runs 1–3).
The differences among these yields were most likely the result of steric
effects. Derivatives with weaker electron donating groups on the alkyne (i.e., tert-butyl
derivative 1e, silyloxymethyl derivative 1f, and proton derivative 1g) prepared from the
corresponding compounds 2 did not participate in this reaction very well. Compound 1g
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gave a complex mixture (run 6), and 1e and 1f were converted to 4e and 4f in 70% and
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24% yields, respectively (runs 4 and 5).
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Table 3. Effect of benzene ring substituents on the reaction yield.
SiMe3
3
4
5
N
R
6
2
CHO
RuHCl(CO)(PPh3)3 (10 mol%)
p-xylene, 100 °C, 1 h
Me3Si
I (10 mol%)
(+) - CSA
CH2=CHOSiMe3
( 1 eq.)
3
1
N
R
p-xylene
reflux, time 1
p-xylene
reflux, time 2
CHO
4
run
R =
time 1 (+)-CSA time 2 yield of 4 (%, 3 steps)
(h)
0.5
3
(mol%)
20
(h)
1
1
2
3
4
5
6
7
8
9
2b
H
4b (92)
4h (60)
4i (73)
4j (85)
4k (62)
4l (75)
4m (78)
4n (84)
4o (64)
2h 3-Cl
20
12
6
2i
2j
4-Cl
5-Cl
3
20
2.5
3
20
6
2k 6-Cl
2l 4-Me
40
12
1
3
20
2m 5-Me
3
20
1
2n 4-OMe
2.5
20
1
2o
4-CO2Me 2
20
1
The effects of substituents on the benzene ring were used to investigate the scope and
mechanism of this cycloisomerization (Table 3). All of the substrates 2h–o were
subjected to the one-pot reaction conditions used in Table 1, entry 2 (Table 3).
Compounds 2i–n were converted to the cycloisomerized product 4 in good to excellent
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yields. However, 2h, with a substituent at the 3-position, and 2o with a methyl ester
substituent at the 4-position, were converted to 4h (60% yield) and 4o (64% yield),
respectively (Table 3, entries 2 and 9). These results and the structure of product 4
suggest that some ruthenium hydride species reacted with the silylalkyne moiety faster
than the vinyl ether moiety on 1 in this cycloisomerization.
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Chemical transformations of 4b were possible (Scheme 2). For example, the vinyl
group at the 2-position of indole 4b was converted to the corresponding formyl
derivative 5 via Lemieux–Johnson oxidation or to the hydroxyethyl derivative 6, by
deformylation and hydroboration-oxidation in good yield. The trimethylsilylmethyl
group at the 3-position of 4b reacted with benzaldehyde in the presence of fluoride ions,
and the deformydated carbon–carbon bond forming product 7 was obtained in 81%
yield. The dimethyl(phenyl)silyl group at the 3-position of 4c was converted to the
corresponding acetoxy derivative 8 in 47% yield.
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K2OsO4
NaIO4
SiMe3
8
2,6-lutidine
9
4b
N
CHO
71%
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CHO
5
1) NaOH
1) Bu4NF (0.1 eq.)
PhCHO, DMF
aq. THF
2) Cy2BH, THF
3) H2O2, NaOH aq.
83%
2) NaOH aq.
81% (2 steps)
Ph
OH
SiMe3
N
N
H
6
H
7
OH
KBr
NaOAc
AcOOH
OAc
4c
N
8
47%
CHO
Scheme 2. Chemical transformations of 4b and 4c.
Finally, we used NMR spectroscopy to detarmine the active ruthenium species in this
cycloisomerization. We compared the 1H- and 31P-NMR spectra of catalysts (I and A) in
p-xylene and the reaction mixture for the cycloisomerization. For catalyst I, we
1
observed signals for the benzylidene proton at 19.7 ppm in the H-NMR spectrum and
31
tricyclohexylphosphine at 29.8 ppm in the P-NMR spectrum. In the spectra of the
cycloisomerization reaction mixture, new catalyst A peaks appeared within 10 min
along with peaks for the cycloisomerized compound 3b; however, whereas the
ruthenium carbene catalyst I and substrate 1b peaks disappeared (Figure 3). Between
141 and 239 min, no peaks from catalyst A or peaks indication further generation of 3b
could be observed. These results together with those of our control experiments (Tables
2 and 3) suggest that the cycloisomerization proceeds via ruthenium hydride A, and a
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plausible reaction mechanism is given in Scheme 3. Ruthenium hydride A, generated in
situ from Grubbs II could selectively coordinate to silylalkyne moiety of 1 to gave
cycloisomerized product 3.
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Grubbs"2nd"
1b"
ruthenium"hydride"A"
3b"
120"
100"
80"
60"
40"
20"
0"
0"
7"
15"
29"
reaction time (min.) at 120 °Cꢀ
42"
66"
91"
141"
239"
Figure 3. NMR time course experiments.
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SiMe3
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SiMe3
N
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1
CHO
(E:Z = 1:1)
N
Ru-H A
3 (E:Z = 1:1)
CHO
SiMe3
Ru-H
SiMe3
Ru
N
CHO
N
CHO
Me3Si
H
Ru
N
CHO
Scheme 3. Proposed reaction mechanism.
In conclusion, our ruthenium hydride-catalyzed cycloisomerization of 1 with
trialkylsilylalkyne and enamide moieties, and subsequent aromatization gives a
2,3-disubstituted indole 4, with vinyl and trimethylsilylmethyl groups at the 2- and
3-positions, respectively. The functional groups of 4 can be efficiently converted to
other functional groups. This is an example of a non-metathesis reaction with the use of
a ruthenium carbene catalyst17, which will be of interest owing to the widespread
application of these catalysts in functional molecular synthesis.
Experimental Section
Preparation of 2
• Preparation of 2a
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To a stirring solution of 2-iodoaniline (664 mg, 3.03 mmol, 1.0 eq.) in THF (15 ml)
and iPr2NH (15 ml) was added trimethylsilylacetylene (500 μl, 3.63 mmol 1.2 eq.),
PdCl2(PPh3)2 (53 mg, 0.0758 mmol 2.5 mol%), CuI (14 mg, 0.0758 mmol 2.5 mol%),
and the mixture was stirred at 50 ℃ for 1 h. The mixture was filtered on celite pad and
concentrated. The residue was purified by column chromatography to give
2-[(trimethylsilyl)ethynyl]aniline. (n-hexane:AcOEt = 12:1) (516 mg, 2.73 mmol, 90%)
To a stirring solution of 2-[(trimethylsilyl)ethynyl]aniline (516 mg, 2.73 mmol 1.0 eq.)
in CH2Cl2 (27 ml, 0.1 M), was added pyridine (0.66 ml 8.19 mmol 3.0 eq.) and TsCl
(1.04 g, 5.46 mmol, 2.0 eq.). The mixture was stirred for 8 h. at room temperature. The
reaction was quenched by the addition of NaHCO3 and the organic compounds were
extracted with CH2Cl2. The organic layers were dried over Na2SO4 and the solvent was
removed under reduced pressure. The obtained residue was subjected to column
chromatography
(n-hexane:AcOEt
=
8:1)
to
give
N-tosyl-2-[(trimethylsilyl)ethynyl]aniline (938 mg, 2.73 mmol, quant.).
To a stirring solution of N-tosyl-2-[(trimethylsilyl)ethynyl]aniline (938 mg, 2.73 mmol,
1.0 eq.) in MeCN (5.5 ml, 0.50 M), was added K2CO3 (755 mg, 5.46 mmol 2.0 eq.)
and allyl bromide (1.9 ml 21.8 mmol, 8.0 eq.) and the mixture was refluxed for 9 h.
After the mixture was cooled to room temperature, the reaction was quenched by the
addition of H2O and the organic compounds were extracted with Et2O. The organic
layers were washed with brine, dried over Na2SO4 and the solvent was removed under
reduced pressure. The obtained residue was subjected to column chromatography
(n-hexane:AcOEt = 10:1) to give 2a (860 mg, 2.24 mmol, 82%).
2a; Pale yellow oil; 1H-NMR (CDCl3, 500 MHz): δ 7.63 (2H, d, J = 8.0 Hz), 7.45 (1H,
d, J = 7.5 Hz), 7.32-7.24 (5H, m), 5.86 (1H, ddt, J = 17.2, 10.3, 6.3 Hz), 5.08 (1H, d, J
= 17.2 Hz), 5.05 (1H, d, J = 10.3 Hz), 4.33 (2H, d, J = 6.3 Hz), 2.43 (3H, s), 0.17 (9H,
s) ppm; 13C-NMR (CDCl3, 125 MHz):δ: 143.3, 140.3, 137.4, 134.1, 133.5, 132.3, 129.7,
129.2, 128.1, 128.0, 123.8, 118.7, 101.9, 100.0, 53.2, 21.8, -0.1 ppm; HRMS
(MALDI-TOF) calcd for C21H25NO2NaSiS [M+Na]+ 406.1267, found 406.1267.; Anal
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calcd for C21H25NO2SiS: C, 65.76; H, 6.57; N, 3.65, found: C, 65.69; H, 6.68; N, 3.73.
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• General procedure A for preparation of 2b-2e, 2h-2o
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A solution of formic acid (3.0 eq.) and acetic anhydride (3.6 eq.) was stirred at 60 ℃
for 3 h. To the resulting mixture was added a 2-iodoaniline derivative (1.0 eq.) in THF
(0.1 M) at room temperature and the mixture was stirred for 1 h. Then the solvent was
removed in reduced pressure to give the corresponding N-formyl-2-iodoaniline
derivative.
To a stirred solution of above N-formyl-2-iodoaniline compound (1.0 eq.) in
THF-iPr2NH (1:1) was added a suitable acetylene derivative (1.2 eq.), CuI (5 mol%)
and PdCl2(PPh3)2 (2 mol%). The mixture was stirred at 50 ℃ for 1 h. The mixture was
filtered on celite pad and the mother liquor was concentrated to remove the solvent. The
residue was purified by column chromatography to give the corresponding
N-formyl-2-[(trialkylsilyl)ethynyl]aniline derivative.
To a stirred solution of N-formyl-2-[(trialkylsilyl)ethynyl]aniline (1.0 eq.) in THF
were added NaH (1.3 eq.) and allyl bromide (2.0 eq.). The mixture was stirred at 50 ℃
for 1.5 h. To the mixture, was added of sat. NH4Cl aq. The organic compounds were
extracted with Et2O, dried over Na2SO4 and the solvent was removed under reduced
pressure. The residue was purified by silica gel column chromatography to give 2.
Following the general procedure A , 2b (1.08 g, 4.18 mmol 46%) was prepared from
2-iodoaniline (2.00 g, 9.10 mmol) and trimethylsilylacetylene (1.5 ml, 10.9 mmol) after
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column chromatography on silica gel (n-hexane/AcOEt = 8:1). Colorless oil; H-NMR
(130 ℃, DMSO-d6, 500 MHz): δ 8.26 (1H, s), 7.53 (1H, d, J = 7.4 Hz), 7.46 (1H, dd, J
= 7.4, 7.4 Hz), 7.34 (2H, m), 5.81 (1H, br m), 5.17 (1H, d, J = 17 Hz), 5.08 (1H, d, J = 5
13
Hz), 4,37 (2H, d, J = 5.5 Hz), 0.24 (9H, s) ppm; C-NMR (70 ℃, DMSO-d6, 125
MHz): δ 161.7, 141.9, 132.63, 132.57, 129.8, 127.3, 127.2, 120.3, 117.2 101.6, 99.5,
47.0, -0.7 ppm; HRMS (MALDI-TOF) calcd for C15H20NOSi[M+H]+ 258.1309, found
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258.1307.; Anal calcd for C15H19NOSi: C, 69.99; H, 7.44; N, 5.44, found: C, 70.29; H,
7.46; N, 5.44.
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Following the general procedure A, 2c (176 mg, 0.551 mmol 27%) was prepared from
2-iodoaniline (442 mg, 2.02mmol) and dimethylphenylsilylacethlene (0.43 ml, 2.42
mmol) after column chromatography on silica gel (n-hexane/AcOEt = 8:1). Pale yellow
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oil; H-NMR (130 ℃, DMSO-d6, 500 MHz) δ: 8.13 (1H, s), 7.50-7.20 (9H, m), 5.62
(1H, br m), 4.99 (1H, d, J = 17.2 Hz) 4.90 (1H, d, J = 8.6 Hz), 4.21 (2H, br m), 0.32
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(6H, s) ppm; C-NMR (115 ℃, DMSO-d6, 125 MHz) δ: 162.5, 142.6, 136.4, 133.9,
133.7, 133.3, 130.8, 130.1, 128.4, 128.2, 128.1, 120.9, 118.1, 103.8, 98.2, 47.8, -0.8
ppm; HRMS (MALDI-TOF) calcd for C20H21NONaSi [M+Na]+ 342.1285, found
342.1272.; Anal calcd for C20H21NOSi: C, 75.19; H, 6.63; N, 4.38, found: C, 75.45; H,
6.76; N, 4.58.
Following the general procedure A, 2d (1.55 g, 4.64 mmol 70%) was prepared from
2-iodoaniline (1.44 g, 6.59 mmol) and benzyldimethylsilylacetylene18 (1.38 g, 7.91
mmol) after column chromatography on silica gel (n-hexane/AcOEt = 7:1). Pale yellow
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oil; H-NMR (CDCl3, 300 MHz): δ 8.43 (1H, s), 7.68 (1H, dd, J = 8.0, 1.7 Hz), 7.53
(1H, ddd, J = 7.7, 7.7, 1.7 Hz), 7.43 (1H, ddd, J = 7.7, 7.7, 1.7 Hz) 7.41-7.37 (3H, m),
7.33 (1H, d, J = 8.0), 7.25 (2H, d, J = 8.0), 5.93 (1H, ddd, J = 16.8, 10.3, 6.3 Hz), 5.31
(1H, dd, J = 16.8, 1.3 Hz), 5.25 (1H, dd, J = 10.3, 1.3 Hz), 4.55 (2H, d, J = 6.3 Hz),
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2.43 (2H, s), 0.36 (6H, s) ppm;13C-NMR (70 °C, DMSO-d6, 125 MHz) δ: 162.6, 142.1,
138.6, 133.7, 132.4, 129.6, 128.3, 128.2, 127.5, 127.5, 124.4, 121.6, 118.2, 102.2, 99.1,
48.2, 25.9, -2.3 ppm; HRMS (MALDI-TOF) calcd for C21H24NOSi [M+H]+ 334.1622,
found 334.1621.
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Following the general procedure A, 2e (460 mg, 1.91 mmol 94%) was prepared from
2-iodoaniline (442 mg, 2.02 mmol) and 3,3-Dimethyl-1-butyne (0.30 ml, 2.42 mmol)
after column chromatography on silica gel (n-hexane/AcOEt = 8:1). Pale yellow oil;
1H-NMR (110 ℃, DMSO-d6, 500 MHz) δ: 8.17 (1H, s), 7.40-7.25 (4H, m), 5.73 (1H,
ddt, J = 16.6, 10.3, 5.7 Hz), 5.12 (1H, d, J = 16.6 Hz), 5.02 (1H, d, J = 10.3 Hz), 4.31
(2H, d, J = 5.7 Hz), 1.24 (9H, s) ppm; 13C-NMR (110 ℃, DMSO-d6, 125 MHz) δ: 161.4,
141.1, 132.5, 132.0, 128.3, 127.0, 126.9, 121.3, 116.8, 103.2, 75.4, 46.8, 29.9, 27.2
ppm; HRMS (MALDI-TOF) calcd for C16H20NO[M+H]+ 242.1539, found 242.1539.
Following the general procedure A, 2h (483 mg, 1.66 mmol 42%) was prepared from
3-chloro-2-iodoaniline (1.00 g, 3.95 mmol) trimethylsilylacetylene (0.65 ml, 4.74
mmol) after column chromatography on silica gel (n-hexane/AcOEt = 8:1). Pale yellow
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oil; H-NMR (130 ℃, DMSO-d6, 500 MHz) δ: 8.28 (1H, s), 7.51 (1H, d, J = 8.0 Hz),
7.44 (1H, dd, J = 8.0, 4.0 Hz), 7.34-7.32 (1H, br m), 5.81-5.79 (1H, br m), 5.19 (1H, d,
J = 17.2 Hz), 5.10 (1H, d, J = 10.3 Hz), 4.36 (2H, d, J = 5.7 Hz), 0.26 (9H, s) ppm;
13C-NMR (DMSO-d6, 125 MHz) δ: 162.3, 143.9, 135.6, 132.6, 130.6, 128.2, 126.3,
120.6, 117.9, 105.6, 98.3, 47.2, -0.5 ppm; HRMS (MALDI-TOF) calcd for
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C15H18ClNONaSi[M+Na]+ 314.0738, found 314.0730.; Anal calcd for C15H18ClNOSi: C,
61.73; H, 6.22; N, 4.80, found: C, 61.79; H, 6.26; N, 4.80.
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Following the general procedure A, 2l (112 mg, 0.384 mmol 17%) was prepared from
4-chloro-2-iodoaniline (573 mg, 2.26 mmol) trimethylsilylacetylene (0.38 ml, 2.71
mmol) after column chromatography on silica gel (n-hexane/AcOEt = 8:1). Colorless
oil; 1H-NMR (130 ℃, DMSO-d6, 500 MHz): δ 8.26 (1H, s), 7.54 (1H, s), 7.49 (1H, d, J
= 8.5 Hz), 7.36 (1H, br m), 5.79 (1H, br m), 5.18 (1H, d, J = 17 Hz), 5.10 (1H, d, J =
13
9.5 Hz), 4,35 (2H, d, J = 6.0 Hz), 0.25 (9H, s) ppm; C-NMR (70 ℃ DMSO-d6, 125
MHz): δ 161.6, 140.8, 132.3, 131.8, 131.5, 129.8, 129.0, 122.1, 117.5, 101.1, 100.1,
46.9, -0.9 ppm; HRMS (MALDI-TOF) calcd for C15H19ClNOSi [M+H]+ 292.0919,
found 292.0921.; Anal calcd for C15H18ClNOSi: C, 61.73; H, 6.22; N, 4.80, found: C,
61.95; H, 6.33; N, 4.78.
Following the typical procedure A, 2j (112 mg, 0.384 mmol 17%) was prepared from
5-chloro-2-iodoaniline (573 mg, 2.26 mmol) trimethylsilylacetylene (0.38 ml, 2.71
mmol) after column chromatography on silica gel (n-hexane/AcOEt = 8:1). Colorless
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oil; H-NMR (130 ℃, DMSO-d6, 500 MHz): δ 9.32 (1H, s), 8.31 (1H, d, J = 8.5 Hz),
7.38 (1H, d, J = 1.5 Hz), 7.30 (1H, dd, J = 8.5, 1.5 Hz), 6.78 (1H, dd, J = 18.0, 12.0 Hz),
5.66 (1H, d, J = 12.0 Hz), 5.53 (1H, d, J = 18.0 Hz), 2.16 (2H, s), 0.05 (9H, s) ppm;
13C-NMR (70 ℃, DMSO-d6, 125 MHz): δ 161.7, 143.2, 133.94, 133.92, 132.4, 127.3,
127.1, 119.1, 117.4, 100.7, 100.6, 46.8, -0.8 ppm; HRMS (MALDI-TOF) calcd for
C15H19ClNOSi [M+H]+ 292.0919, found 292.0919.; Anal calcd for C15H18ClNOSi: C,
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61.73; H, 6.22; N, 4.80, found: C, 61.86; H, 6.27; N, 4.91.
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Following the general procedure A, 2k (377 mg, 1.29 mmol 33%) was prepared
from 6-chloro-2-iodoaniline (1.00 g, 3.95 mmol) trimethylsilylacetylene (0.65 ml, 4.74
mmol) after column chromatography on silica gel (n-hexane/AcOEt = 8:1). Colorless
oil; 1H-NMR (DMSO-d6, 500 MHz) δ: 8.38 (0.3H, s), 8.09 (0.7H, s), 7.65 (0.7H, dd, J =
8.0, 1.1 Hz), 7.59 (0.3H, dd, J = 8.0, 1.1 Hz), 7.55 (0.7H, dd, J = 8.0, 1.1 Hz), 7.50
(0.3H, dd, J = 8.0, 1.1 Hz), 7.43 (0.7H, dd, J = 8.0, 8.0 Hz), 7.38 (0.3H, dd, J = 8.0, 8.0
Hz), 5.94 (0.3H, ddt, J = 16.9, 9.7, 6.8 Hz), 5.84-5.76 (0.7H, ddt, J = 17.2, 10.3, 6.8 m),
5.18-5.04 (2H,m), 4.44 (0.7H, dd, J = 14.9, 6.8 Hz), 4.37 (0.3H, dd, J = 15.1, 6.8 Hz),
4.30 (0.3H, dd, J = 15.1, 6.8 Hz), 4.164 (0.7H, dd, J = 14.9, 6.8 Hz), 0.24 (3H, s), 0.23
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(6H, s) ppm; C-NMR (DMSO-d6, 125 MHz) δ: 161.9 161.5, 138.7, 138.3, 133.1,
132.9, 132.8, 132.0, 131.3, 131.2, 130.6, 130.2, 129.6, 129.1, 124.8, 124.2, 118.6, 118.5,
100.90, 100.87, 100.5, 99.9, 51.1, 47.0, -0.8, -0.9 ppm; HRMS (MALDI-TOF) calcd for
C15H19ClNOSi [M+H]+ 292.0919, found 292.0918.; Anal calcd for C15H18ClNOSi: C,
61.73; H, 6.22; N, 4.80, found: C, 62.03; H, 6.39; N, 4.83.
Following the general procedure A, 2l (611 mg, 2.25 mmol 55%) was prepared from
4-methyl-2-iodoaniline (1.00 g, 4.29 mmol) trimethylsilylacetylene (0.71 ml, 5.15
mmol) after column chromatography on silica gel (n-hexane/AcOEt = 8:1). Pale yellow
oil; 1H-NMR (110 ℃, DMSO-d6, 500 MHz) δ: 8.20 (1H, s), 7.35 (1H, s), 7.24 (2H, m),
5.77 (1H, br m), 5.16 (1H, d, J = 17.2 Hz), 5.06 (1H, d, J = 9.7 Hz), 4.33 (2H, d, J = 5.2
Hz), 2.31 (3H, s), 0.23 (9H, s) ppm; 13C-NMR (110 ℃, DMSO-d6, 125 MHz) δ: 161.4,
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139.2, 136.7, 132.7, 132.5, 130.1, 127.0, 120.2, 116.9, 101.5, 98.9, 46.8, 19.5, -1.0 ppm;
HRMS (MALDI-TOF) calcd for C16H22NOSi[M+H]+ 272.1465 found 272.1464.
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Following the general procedure A, 2m (421 mg, 1.55 mmol 36%) was prepared
4-methyl-2-iodoaniline (1.00 g, 4.29 mmol) trimethylsilylacetylene (0.71 ml, 5.15
mmol) after column chromatography on silica gel (n-hexane/AcOEt = 8:1). Pale yellow
oil; 1H-NMR (110 ℃, DMSO-d6, 500 MHz) δ: 8.23 (1H, s), 7.41 (1H, d, J = 8.2 Hz),
7.16 (2H, m), 5.78 (1H, br m), 5.18 (1H, d, J = 17.2 Hz), 5.07 (1H, d, J = 10.3 Hz), 4.36
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(2H, d, J = 5.2 Hz), 2.35 (3H, s), 0.22 (9H, s) ppm; C-NMR (110 ℃, DMSO-d6, 125
MHz) δ: 161.3, 141.6, 139.8, 132.5, 132.2, 127.6, 127.5, 117.3, 116.8, 101.6, 98.5, 46.8,
20.2, -1.0 ppm; HRMS (MALDI-TOF) calcd for C16H22NOSi [M+H]+ 272.1465 found
272.1465.
Following the general procedure A, 2n (251 mg, 0.872 mmol 30%) was prepared from
2-iodo-4-methoxyaniline (735 mg, 2.95 mmol) trimethylsilylacetylene (0.49 ml, 3.54
mmol) after column chromatography on silica gel (n-hexane/AcOEt = 8:1). Pale yellow
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oil; H-NMR (130 ℃, DMSO-d6, 500 MHz): δ: 8.15 (1H, s), 7.25 (1H, d, J = 8.0 Hz),
7.04-7.01 (2H, br m), 5.79 (1H, br m), 5.16 (1H, d, J = 17.2 Hz), 5.08 (1H, d, J = 9.7
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Hz), 4.29 (2H, d, J = 5.7 Hz), 3.81 (3H, s), 0.24 (9H, s) ppm; C-NMR (120 ℃,
DMSO-d6, 125 MHz) δ: 161.9, 157.9, 134.9, 132.7, 129.0, 121.8, 117.3, 116.6, 116.2,
101.5, 99.3, 55.4, 47.2, -0.7 ppm; HRMS (MALDI-TOF) calcd for C16H22NO2Si[M+H]+
288.1414, found 288.1415.; Anal calcd for C16H21NO2Si: C, 66.86; H, 7.36; N, 4.87,
found: C, 66.85; H, 7.49; N, 4.85.
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Following the general procedure A, 2o (90 mg, 0.285 mmol 17%) was prepared from
Methyl 4-amino-3-iodobenzoate (460 mg, 1.66 mmol) trimethylsilylacetylene (0.28 ml,
1.99 mmol) after column chromatography on silica gel (n-hexane/AcOEt = 8:1).
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Colorless plates; m.p.: 56-58 ℃ (from n-hexane); H-NMR (65 ℃, DMSO-d6, 500
MHz) δ: 8.37 (1H, s), 8.02 (1H, s), 7.98 (1H, d, J = 8.6 Hz), 7.55 (1H, d, J = 8.6 Hz)
5.75 (1H, ddt, J = 16.9, 10.6, 5.2 Hz), 5.18 (1H, d, J = 16.9 Hz), 5.08 (1H, d, J = 10.6
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Hz), 4.43 (2H, d, J = 5.2 Hz), 3.88 (3H, s), 0.23 (9H, s) ppm; C-NMR (65 ℃,
DMSO-d6, 125 MHz) δ: 164.0, 161.2, 145.2, 133.0, 131.8, 129.7, 127.7, 126.5, 119.4,
116.9, 100.14, 100.07, 51.6, 46.2, -1.3 ppm; HRMS (MALDI-TOF) calcd for
C17H22NO3Si[M+H]+316.1363 found 316.1363.
• Preparation of 2f
A solution of formic acid (0.23 ml, 6.06 mmol, 3.0 eq.) and acetic anhydride (0.69 ml,
7.27 mmol, 3.6 eq.) was stirred at 60 ℃ for 3 h. To the resulting mixture was added
2-iodoaniline (442 mg, 2.02 mmol, 1.0 eq.) in THF (20 ml, 0.1 M) at room temperature
and the mixture was stirred for 1 h. Then the solvent was removed in reduced pressure
to give N-formyl-2-iodoaniline (500 mg, 2.02 mmol, quant.)
To a stirred solution of above N-formyl-2-iodoaniline (500 mg, 2.02 mmol 1.0 eq.) in
THF-iPr2NH (1:1) (20 ml, 0.1 M) were added 3-propyn-1-ol (0.14 ml, 2.43 mmol, 1.2
eq.), CuI (19 mg, 0.101 mmol, 5 mol%) and PdCl2(PPh3)2 (28 mg, 0.0404 mmol, 2
mol%). The mixture was stirred at 50 ℃ for 1 h. The mixture was filtered on celite pad
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To a stirred solution of above residue (2.02 mmol, 1.0 eq.) in CH2Cl2 were added
Et3N (0.42 ml, 3.03 mmol, 1.5 eq.) and triisopropylsilyl chloride (0.52 ml, 2.43 mmol,
1.2 eq.). The mixture was refluxed for 6 h. To the resulting mixture was added
additional Et3N (0.42 ml, 3.03 mmol, 1.5 eq.) and triisopropylsilyl chloride (0.52 ml,
2.43 mmol, 1.2 eq.). The mixture was refluxed for 12 h. To the mixture, was added of
sat. NaHCO3 aq. The organic compounds were extracted with CH2Cl2. The organic
layers were dried over Na2SO4 and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (n-hexane/AcOEt = 1:2)
to give N-formyl-2-[(trialkylsilyl)ethynyl]aniline (329 mg, 0.99 mmol, 49% (2 steps)).
To a stirred solution of N-formyl-2-[(trialkylsilyl)ethynyl]aniline (329 mg, 0.99 mmol,
1.0 eq.) in THF (10 ml, 0.1 M) were added NaH (52 mg, 1.29 mmol, 1.3 eq.) and allyl
bromide (0.17 ml, 1.98 mmol, 2.0 eq.). The mixture was stirred at 50 ℃ for 1.5 h. To
the mixture, was added sat. NH4Cl aq. The organic compounds were extracted with
Et2O. The organic layers were dried over Na2SO4 and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column chromatography
(n-hexane/AcOEt = 4:1) to give 2f (315 mg, 0.846 mmol 42%).
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2f; Pale yellow oil; H-NMR (115 ℃, DMSO-d6, 500 MHz) δ: 8.24 (1H, s), 7.55-7.30
(4H, m) 5.77 (1H, br m), 5.14 (1H, d, J = 17.2 Hz), 5.06 (1H, d, J = 9.7 Hz), 4.64 (2H,
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s), 4.38 (2H, br m), 1.11-1.06 (21H, m) ppm; C-NMR (115 ℃, DMSO-d6, 125 MHz)
δ: 161.2, 141.1, 132.6, 132.4, 129.1, 127.3, 127.0, 120.2 116.9, 92.9, 80.4, 51.5, 46.7,
17.1, 11.1 ppm; HRMS (MALDI-TOF) calcd for C22H33NO2NaSi [M+Na]+ 394.2173,
found 394.2172.
• Preparation of 2g
To a stirred solution of 2b (91 mg, 0.354 mmol) in THF (3.5 mL) was added n-Bu4NF
(0.42 ml, 0.420 mmol, 1.0 M in THF). The mixture was stirred at 0 ℃ for 0.5 h. To the
mixture, was added of sat. NH4Cl aq. The organic compounds were extracted with Et2O.
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The organic layers were dried over Na2SO4 and the solvent was removed under reduced
pressure. The residue was purified by silica gel column chromatography
(n-hexane/AcOEt = 4:1) to give 2g (315 mg, 0.846 mmol 42%).
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2g; Pale yellow oil; 1H-NMR (CDCl3, 500 MHz) δ: 8.31 (1H, s), 7.59 (1H, dd, J = 7.4,
1.7 Hz), 7.40 (1H, ddd J = 7.7, 7.4, 1.7 Hz), 7.31 (1H, ddd, J = 7.4, 7.4, 1.1 Hz), 7.21
(1H, dd, J = 7.7, 1.1 Hz), 5.86-5.79 (1H, ddt, J = 16.9, 10.3, 3.9Hz), 5.15 (1H, dd, J =
16.9, 1.4 Hz), 5.10 (1H, dd, J = 10.3, 1.4 Hz), 4.43 (2H, d, J = 3.9 Hz), 3.30 (1H, s)
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ppm; C-NMR (CDCl3, 125 MHz) δ: 162.6, 142.2, 134.0, 132.3, 129.8, 127.6, 127.6,
120.7, 118.3, 82.8, 79.8, 48.2 ppm; HRMS (MALDI-TOF) calcd for C12H12NO[M+H]+
186.0913, found 186.0914.
General procedure B: One-pot isomerization/cycloisomerization/aromatization
from 2 to 4
To a stirred solution of 2 (1.0 eq.) in degassed p-xylene (0.0125 M) was added
RuHCl(CO)(PPh3)3 (10 mol%) under an Ar atmosphere and the mixture was stirred at
100 ℃ for 1 h. To the reaction mixture, was added vinyloxytrimethylsilane (1.0 eq.)
and Grubbs II (10 mol%) at room temperature. The mixture was refluxed until TLC
showed complete consumption of the isomerization product. Then to the reaction
mixture was added (+)-CSA (20 mol%) and the mixture was refluxed until TLC showed
complete consumption of the cycloisomerization product. The reaction mixture was
concentrated in vacuo to remove the solvent, and the obtained residue was purified by
flash column chromatography on silica gel to give 4.
Following the general procedure B, 4a (7 mg, 0.0193 mmol 41%) was obtained from
N-allyl-N-formyl-2-((trimethylsilyl)ethynyl)aniline
(18
mg
0.0474
mmol),
RuHCl(CO)(PPh3)3 (5 mg, 0.00474 mmol), Grubbs 2nd catalyst (4 mg, 0.00474 mmol),
trimethyl(vinyloxy)silane (7 μl, 0.0474 mmol) and (+)-10-canphorsulfonic acid (3 mg,
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0.0948 mmol) after column chromatography on silica gel (n-hexane/AcOEt = 20:1).
Reaction time in cyclization and aromatization are 3 h. and 1 h., respectively. Colorless
needles; m.p.:77-81 ℃ (from n-hexane); 1H-NMR (CDCl3, 500 MHz): δ 8.20 (1H, d, J
= 8.6 Hz), 7.51(2H, d, J = 8.1 Hz), 7.32-7.06 (6H, m), 5.53 (1H, dd, J = 11.5, 1.8 Hz),
5.37 (1H, dd, J = 17.8, 1.8 Hz), 2.27 (3H, s), 2.17 (2H, s), -0.13 (9H, s) ppm; 13C-NMR
(CDCl3, 125 MHz): δ 144.3, 136.9, 134.6, 132.2, 132.0, 129.2 128.6, 126.7, 125.1,
123.6, 123.4, 119.7, 117.8, 115.9, 21.4, 14.5, -0.8 ppm; HRMS (MALDI-TOF) calcd
for C21H25NO2NaSiS[M+Na]+ 406.1267, found 406.1253.
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Following the general procedure B, 4b (14 mg, 0.0554 mmol 92%) was obtained from
2b (16 mg 0.0602 mmol), RuHCl(CO)(PPh3)3 (6 mg, 0.00602 mmol), Grubbs 2nd
catalyst (5 mg, 0.00602 mmol), trimethyl(vinyloxy)silane (9 μl, 0.0602 mmol) and
(+)-10-canphorsulfonic acid (3 mg, 0.0120 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 25:1). Reaction time in cyclization and aromatization are
1
0.5 h. and 1 h., respectively. Pale yellow oil; H-NMR (55 ℃, CDCl3, 500 MHz): δ
9.37 (1H, s), 8.37 (1H, d, J = 8.0 Hz), 7.43 (1H, d, J = 7.5 Hz), 7.35 (1H, dd, J = 8.0,
7.5 Hz), 7.29 (1H, dd, J = 8.0, 7.5 Hz), 6.82 (1H, dd, J = 17.5, 11.5 Hz), 5.62 (1H, d, J
= 11.5 Hz), 5.51 (1H, d, J = 17.5 Hz), 2.22 (2H, s), 0.05 (9H, s) ppm; 13C-NMR (55 ℃,
CDCl3, 125 MHz): δ 159.4, 135.4, 131.0, 130.2, 125.6, 125.5, 124.1, 121.7, 120.2,
119.6, 115.7, 14.3, -0.6 ppm; HRMS (MALDI-TOF) calcd for C15H20NOSi [M+H]+
258.1309, found 258.1307.; Anal calcd for C15H19NOSi: C, 69.99; H, 7.44; N, 5.44,
found: C, 70.31; H, 7.55; N, 5.40.
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Following the general procedure B, 4c (171 mg, 0.535 mmol 83%) was obtained from
2c (206 mg 0.646 mmol), RuHCl(CO)(PPh3)3 (62 mg, 0.0646 mmol), Grubbs 2nd
catalyst (55 mg, 0.0646 mmol), trimethyl(vinyloxy)silane (96 μl, 0.646 mmol) and
(+)-10-canphorsulfonic acid (30 mg, 0.129 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 25:1). Reaction time in cyclization and aromatization are
0.5 h. and 1 h, respectively. Pale yellow oil; 1H-NMR (55 °C, CDCl3, 400 MHz) δ: 9.25
(1H, s), 8.31 (1H, d, J = 8.2 Hz), 7.40-7.14 (8H, m), 6.54 (1H, dd, J = 17.9, 11.9 Hz),
5.43 (1H, d, J = 11.9 Hz), 5.29 (1H, d, J = 17.9 Hz), 2.35 (2H, s), 0.25 (6H, s) ppm;
13C-NMR (55 °C, CDCl3, 100 MHz) δ: 159.3, 138.3, 135.3, 133.6, 130.9, 130.6, 129.3,
127.9, 125.5, 125.2, 124.0, 120.7, 120.4, 119.7, 115.6, 14.0, -2.4 ppm; HRMS
(MALDI-TOF) calcd for C20H21NONaSi [M+Na]+ 342.1285, found 342.1289.; Anal
calcd for C20H21NOSi: C, 75.19; H, 6.63; N, 4.38, found: C, 75.24; H, 6.59; N, 4.49.
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Following the general procedure B, 4d (29 mg, 0.0845 mmol 89%) was obtained from
2d (32 mg 0.965 mmol), RuHCl(CO)(PPh3)3 (9 mg, 0.00965 mmol), Grubbs 2nd
catalyst (8 mg, 0.00965 mmol), trimethyl(vinyloxy)silane (14 μl, 0.0965 mmol) and
(+)-10-canphorsulfonic acid (5 mg, 0.0193 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 25:1). Reaction time in cyclization and aromatization are
3 h. and 1 h, respectively. Pale yellow oil; 1H-NMR (CDCl3, 300 MHz) δ: 9.37 (1H, s),
8.41 (1H, d, J = 7.2 Hz), 7.40-7.01 (8H, m), 6.76 (1H, dd, J = 17.8, 11.8 Hz), 5.60 (1H,
dd, J = 11.8, 1.0 Hz), 5.45 (1H, dd, J = 17.8, 1.0 Hz), 2.26 (2H, s), 2.20 (2H, s), 0.00
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(6H, s) ppm; C-NMR (70 °C, DMSO-d6, 125 MHz) δ: 159.5, 139.4, 139.3, 135.1,
130.8, 130.2, 128.3, 128.1, 125.6, 125.0, 124.2, 124.1, 121.0, 120.5, 119.4, 26.1, 12.4,
-2.7 ppm; HRMS (MALDI-TOF) calcd for C21H24NOSi [M+H]+ 334.1622, found
334.1622.
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Following the general procedure B, 4e (38 mg, 0.157 mmol 70%) was obtained from
2e (54 mg 0.223 mmol), RuHCl(CO)(PPh3)3 (21 mg, 0.0223 mmol), Grubbs 2nd catalyst
(19 mg, 0.0223 mmol), trimethyl(vinyloxy)silane (33 μl, 0.223 mmol) and
(+)-10-canphorsulfonic acid (50 mg, 0.0223 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 25:1). Reaction time in cyclization and aromatization are
3 h. and 1 h, respectively. Pale yellow oil; 1H-NMR (CDCl3, 500 MHz) δ: 9.39 (1H, s),
8.44 (1H, d, J = 7.7 Hz), 7.55 (1H, dd, J = 7.7 Hz, 1.1Hz), 7.33 (1H, ddd, J = 7.7, 7.4,
1.1 Hz), 7.31 (1H, ddd, J = 7.7, 7.4, 1.1 Hz) 6.84 (1H, dd, J = 17.6, 12.2 Hz), 5.70 (1H,
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d, J = 12.2 Hz), 5.49 (1H, d, J = 17.6 Hz), 2.67 (2H, s), 0.99 (9H, s) ppm; C-NMR
(55 °C, CDCl3, 125 MHz) δ: 160.2, 135.1, 133.8, 131.6, 125.9, 125.2, 124.1, 122.2,
120.9, 120.3, 115.8, 37.1, 34.1, 30.3 ppm; HRMS (MALDI-TOF) calcd for C16H20NO
[M+H]+ 242.1539, found 242.1530.
Following the general procedure B, 4f (16 mg, 0.0431 mmol 24%) was obtained from
2f (66 mg 0.180 mmol), RuHCl(CO)(PPh3)3 (17 mg, 0.0180 mmol), Grubbs 2nd catalyst
(15 mg, 0.0180 mmol), trimethyl(vinyloxy)silane (27 μl, 0.180 mmol) and
(+)-10-canphorsulfonic acid (42 mg, 0.180 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 20:1). Reaction time in cyclization and aromatization are
1
2 h. and 4 h., respectively. Colorless oil; H-NMR (40 ℃, CDCl3, 500 MHz) δ: 9.33
(1H, s), 8.34 (1H, d, J = 7 Hz), 7.55 (1H, d, J = 7 Hz), 7.34 (1H, t, J = 7 Hz), 7.30 (1H, t,
J = 7 Hz), 6.85 (1H, dd, J = 17, 12 Hz), 5.68 (1H, d, J = 12 Hz), 5.67 (1H, d, J = 17 Hz),
13
3.95 (2H, t, J = 7 Hz), 3.02 (2H, t, J = 7 Hz)., 1.09-0.98 (21H, m); C-NMR (75 ℃,
DMSO-d6, 125 MHz) δ: 159.7, 134.0, 133.6, 130.1, 124.8, 124.6, 123.6, 121.4, 119.0,
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118.1, 114.3, 62.3, 27.3, 17.3, 11.1.; HRMS (MALDI-TOF) calcd for C22H33NO2Si[M]+
371.2275, found 371.2274.
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Following the general procedure B, 4h (35 mg, 0.119 mmol 60%) was obtained from
2h (58 mg 0.199 mmol), RuHCl(CO)(PPh3)3 (19 mg, 0.0199 mmol), Grubbs 2nd
catalyst (17 mg, 0.0199 mmol), trimethyl(vinyloxy)silane (30 μl, 0.199 mmol) and
(+)-10-canphorsulfonic acid (9 mg, 0.0398 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 25:1). Reaction time in cyclization and aromatization are
1
3 h. and 12 h., respectively. Colorless plates; m.p.:52-54 ℃ (from n-hexane); H-NMR
(55 ℃, CDCl3, 500 MHz) δ: 9.37 (1H, s), 8.41 (1H, d, J = 6.9 Hz), 7.28-7.24 (2H, m),
6.79 (1H, dd, J = 17.8, 12.0 Hz), 5.73 (1H, d, J = 12.0 Hz), 5.54 (1H, d, J = 17.8 Hz),
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2.62 (2H, s), 0.07 (9H, s) ppm; C-NMR (55 ℃, CDCl3, 125 MHz) δ: 159.6, 136.9,
131.2, 127.3, 126.9, 126.1, 125.9, 125.3, 121.9, 121.6, 114.6, 14.9, -0.7 ppm; HRMS
(MALDI-TOF) calcd for C15H19ClNOSi[M+H]+ 292.0919, found 292.0917.; Anal calcd
for C15H18ClNOSi: C, 61.73; H, 6.22; N, 4.80, found: C, 61.75; H, 6.41; N, 4.90.
Following the general procedure B, 4i (40 mg, 0.137 mmol 73%) was obtained from 2i
(55 mg 0.187 mmol), RuHCl(CO)(PPh3)3 (18 mg, 0.0187 mmol), Grubbs 2nd catalyst
(16 mg, 0.0187 mmol), trimethyl(vinyloxy)silane (28 μl, 0.187 mmol) and
(+)-10-canphorsulfonic acid (9 mg, 0.0374 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 40:1). Reaction time in cyclization and aromatization are
1
3 h. and 6 h, respectively. Colorless needles; m.p.:75-76 ℃ (from n-hexane); H-NMR
(55 ℃, CDCl3, 500 MHz): δ 9.32 (1H, s), 8.31 (1H, d, J = 8.5 Hz), 7.38 (1H, d, J = 1.5
Hz), 7.30 (1H, dd, J = 8.5, 1.5 Hz), 6.78 (1H, dd, J = 18.0, 12.0 Hz), 5.66 (1H, d, J =
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12.0 Hz), 5.53 (1H, d, J = 18.0 Hz), 2.16 (2H, s), 0.05 (9H, s) ppm; C-NMR (55 ℃,
CDCl3, 125 MHz): δ 159.3, 133.7, 132.6, 131.6, 130.0, 125.8, 125.2, 121.4, 121.0,
119.5, 117.0, 14.4, -0.5 ppm; HRMS (MALDI-TOF) calcd for C15H19ClNOSi [M+H]+
292.0919, found 292.0916.; Anal calcd for C15H18ClNOSi: C, 61.73; H, 6.22; N, 4.80,
found: C, 62.08; H, 6.43; N, 4.65.
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Following the general procedure B, 4j (34 mg, 0.116 mmol 85%) was obtained from 2j
(40 mg 0.136 mmol), RuHCl(CO)(PPh3)3 (13 mg, 0.0136 mmol), Grubbs 2nd catalyst
(12 mg, 0.0136 mmol), trimethyl(vinyloxy)silane (22 μl, 0.136 mmol) and
(+)-10-canphorsulfonic acid (6 mg, 0.0272 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 40:1). Reaction time in cyclization and aromatization
are 2.5 h. and 6 h, respectively. Colorless needles; m.p.:65-67 ℃ (from n-hexane);
1H-NMR (55 ℃, CDCl3, 500 MHz): δ 9.32 (1H, s), 8.48 (1H, s), 7.32 (1H, d, J = 8.3
Hz), 7.27 (1H, dd, J = 8.3, 2.0 Hz), 6.77 (1H, dd, J = 17.5, 11.8 Hz), 5.64 (1H, d, J =
13
11.8 Hz), 5.51 (1H, d, J = 17.5 Hz), 2.18 (2H, s), 0.04 (9H, s) ppm; C-NMR (55 ℃,
CDCl3, 125 MHz): δ 159.4, 135.7, 131.7, 130.9, 129.7, 125.3, 124.8, 121.4, 120.9,
120.4, 116.3, 14.5, -0.5 ppm; HRMS (MALDI-TOF) calcd for C15H19ClNOSi [M+H]+
292.0919, found 292.0917.; Anal calcd for C15H18ClNOSi: C, 61.73; H, 6.22; N, 4.80,
found: C, 61.92; H, 6.49; N, 4.73.
Following the general procedure B, 4k (23 mg, 0.0781 mmol 62%) was obtained from
2k (37 mg 0.125 mmol), RuHCl(CO)(PPh3)3 (12 mg, 0.0125 mmol), Grubbs 2nd
catalyst (11 mg, 0.0125 mmol), trimethyl(vinyloxy)silane (19 μl, 0.125 mmol) and
(+)-10-canphorsulfonic acid (12 mg, 0.050 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 25:1). Reaction time in cyclization and aromatization are
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3 h. and 12 h., respectively. Colorless plates; m.p.:56-57 ℃ (from n-hexane); H-NMR
(55 ℃, CDCl3, 500 MHz): 10.44 (1H, s), 7.37 (1H, d, J = 8.0 Hz), 7.32 (1H, d, J = 8.0
Hz), 7.19 (1H, dd, J = 8.0, 8.0 Hz), 7.15 (1H, dd, J = 17.8, 11.2 Hz), 5.52 (1H, d, J =
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11.2 Hz), 5.49 (1H, d, J = 17.8 Hz), 2.27 (2H, s), 0.03 (9H, s) ppm; C-NMR (55 ℃,
CDCl3, 125 MHz) δ: 159.9, 134.5, 133.0, 131.6, 129.0, 127.1, 124.0, 121.6, 119.2,
118.1, 117.9, 14.1 , -0.3 ppm; HRMS (MALDI-TOF) calcd for C15H19ClNOSi[M+H]+
292.0919, found 292.0918.; Anal calcd for C15H18ClNOSi: C, 61.73; H, 6.22; N, 4.80,
found: C, 61.85; H, 6.44; N, 4.74.
Following the general procedure B, 4l (50 mg, 0.181 mmol 75%) was obtained from 2l
(66 mg 0.240 mmol), RuHCl(CO)(PPh3)3 (23 mg, 0.0240 mmol), Grubbs 2nd catalyst
(20 mg, 0.0240 mmol), trimethyl(vinyloxy)silane (36 μl, 0.240 mmol) and
(+)-10-canphorsulfonic acid (11 mg, 0.0480 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 25:1). Reaction time in cyclization and aromatization are
3 h. and 1 h, respectively. Colorless needles; m.p.: 63-65 ℃ (from n-hexane); 1H-NMR
(55 ℃, CDCl3, 500 MHz) δ: 9.33 (1H, s), 8.24 (1H, d, J = 8.0 Hz), 7.21 (1H, s), 7.16
(1H, d, J = 8.0 Hz), 6.80 (1H, dd, J = 17.8, 11.8 Hz), 5.59 (1H, d, J = 11.8 Hz), 5.49
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(1H, d, J = 17.8 Hz), 2.46 (3H, s), 2.19 (2H, s), 0.06 (9H, s) ppm; C-NMR (55 ℃,
CDCl3, 125 MHz) δ: 159.1, 133.6, 133.5, 131.2, 130.3, 126.7, 125.5, 121.5, 119.8,
119.6, 115.3, 21.5, 14.3, -0.7 ppm; HRMS (MALDI-TOF) calcd for C16H22NOSi
[M+H]+ 272.1465 found 272.1464.
Following the general procedure B, 4m (53 mg, 0.194 mmol 78%) was obtained from
2m (68 mg 0.249 mmol), RuHCl(CO)(PPh3)3 (24 mg, 0.0249 mmol), Grubbs 2nd
catalyst (21 mg, 0.0249 mmol), trimethyl(vinyloxy)silane (37 μl, 0.249 mmol) and
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(+)-10-canphorsulfonic acid (12 mg, 0.0498 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 25:1). Reaction time in cyclization and aromatization are
3 h. and 1 h., respectively. Pale yellow oil; 1H-NMR (55 ℃, CDCl3, 500 MHz): δ: 9.35
(1H, s), 8.22 (1H, s), 7.30 (1H, d, J = 8.0 Hz), 7.12 (1H, d, J = 8.0 Hz), 6.80 (1H, dd, J
= 17.8, 12.0 Hz), 5.58 (1H, d, J = 12.0 Hz), 5.47 (1H, d, J = 17.8 Hz), 2.49 (3H, s), 2.19
10
11
12
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16
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24
25
26
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28
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48
49
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55
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58
59
60
13
(2H, s), 0.05 (9H, s) ppm; C-NMR (55 ℃, CDCl3, 125 MHz) δ: 159.4, 135.8, 135.7,
129.6, 128.8, 125.5, 125.4, 121.7, 119.4, 119.2, 116.0, 21.8, 14.4, -0.7 ppm; HRMS
(MALDI-TOF) calcd for C16H22NOSi[M+H]+ 272.1465 found 272.1460.
Following the general procedure B, 4n (37 mg, 0.128 mmol 81%) was obtained from
2n (45 mg 0.158 mmol), RuHCl(CO)(PPh3)3 (15 mg, 0.0158 mmol), Grubbs 2nd
catalyst (13 mg, 0.0158 mmol), trimethyl(vinyloxy)silane (24 μl, 0.158 mmol) and
(+)-10-canphorsulfonic acid (7 mg, 0.0316 mmol) after column chromatography on
silica gel (n-hexane/AcOEt = 25:1). Reaction time in cyclization and aromatization are
2.5 h. and 1 h., respectively. Colorless needles; m.p.:50-52 ℃ (from n-hexane);
1H-NMR (CDCl3, 500 MHz) δ: 9.31 (1H, s), 8.33 (1H, br s), 6.97 (1H, dd, J = 8.9, 2.3
Hz), 6.89 (1H, d, J = 2.3 Hz), 6.80 (1H, br m), 5.64 (1H, d, J = 11.5 Hz), 5.51 (1H, d, J
13
= 17.8 Hz), 3.89 (3H, s), 2.19 (2H, s), 0.07 (9H, s) ppm; C-NMR (CDCl3, 125 MHz)
δ: 159.5, 157.0, 132.2, 131.1, 130.0, 125.3, 125.3, 121.7, 120.6, 113.5, 103.2, 55.9, 14.5,
-0.4 ppm; HRMS (MALDI-TOF) calcd for C16H22NO2Si [M+H]+ 288.1414, found
288.1413.; Anal calcd for C16H21NO2Si: C, 66.86; H, 7.36; N, 4.87, found: C, 67.06; H,
7.57; N, 4.80.
Following the general procedure B, 4o (8 mg, 0.0263 mmol 64%) was obtained from 2o
29
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