Synthesis of 2,6,7-Trisubstituted Prenylated indole

Article abstract of DOI:10.1021/acs.joc.7b03273

Prenylated indole alkaloids bearing more than one prenyl or reverse-prenyl group show various biological activities. Among them, synthesis of trisubstituted-type prenylated indoles have not been well explored because of the difficulty in regioselective introduction of multiple prenyl and reverse-prenyl groups due to steric hindrance problems. Herein, we describe a synthesis of 2,6,7-trisubstituted prenylated indole using aza-Claisen rearrangement under mild conditions to introduce a prenyl group at C7 in the presence of the prenyl group at C6.

Full text of DOI:10.1021/acs.joc.7b03273

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A synthesis of 2,6,7-trisubstituted prenylated indole
Motoki Shiozawa, Keisuke Iida, Minami Odagi, Masahiro Yamanaka, and Kazuo Nagasawa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03273 • Publication Date (Web): 08 Mar 2018
Downloaded from http://pubs.acs.org on March 8, 2018
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A synthesis of 2,6,7-trisubstituted prenylated indole
Motoki Shiozawa,[a] Keisuke Iida,[b] Minami Odagi,[a] Masahiro Yamanaka,[c] and Kazuo
Nagasawa*[a]
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[a]Department of Biotechnology and Life Science, Graduate Scholl of Technology, Tokyo University
of Agriculture and Technology, 2ꢀ24ꢀ16, Nakaꢀcho, Koganei city, 184ꢀ8588, Tokyo Japan
[b] Department of Chemistry, Graduate Scholl of Science, Chiba University, 1ꢀ33 Yayoi, Inage,
263ꢀ8522, Chiba Japan
[c]Department of Chemistry, Faculty of Science, Rikkyo University, 3ꢀ34ꢀ1 NishiꢀIkebukuro, Toshimaꢀku,
171ꢀ8501, Tokyo Japan
Abstract:
Prenylated indole alkaloids bearing more than one prenyl or reverseꢀprenyl group show
various biological activities. Among them, synthesis of trisubstitutedꢀtype prenylated indoles
have not been well explored because of the difficulty in regioselective introduction of multiple
prenyl and reverseꢀprenyl groups due to steric hindrance problems. Herein, we describe a
synthesis of 2,6,7ꢀtrisubstituted prenylated indole using azaꢀClaisen rearrangement under mild
conditions to introduce a prenyl group at C7 in the presence of the prenyl group at C6.
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Graphical Abstract
7
8
9
Me
Me
Me
Me
Me
"silica gel"
rt
Me
Me
Me
N
H
Me
Me
N
Me
Me
Me
Me
aza-Claisen
rearrangement
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Me Me
‡
Me Me
H
2
7
6
3
2
4
3
.
3
9
2
.
2
9
0
.
N
H
1
H
1
.
7
H
Me
Me
5
7
7
N
2,6,7ꢀtrisubstituted
prenylated indole
Me Me
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Prenylated indole alkaloids bearing one or more prenyl or reverseꢀprenyl groups at C2~C7
form a large structural family (Figure 1), and many of these analogs possess significant
biological activities, including antimicrobial activity.1 For example, cristatumin A (1),
tardioxopiperadine A (2) and echinulin (3) show moderate antimicrobial activity against E. coli
and S. aureus.2 Many syntheses of monoꢀ and disubstituted prenylated indole alkaloids have
been reported.3 On the other hand, trisubstituted prenylated indoles have remained
synthetically inaccessible due to the difficulty of selective introduction of multiple prenyl
groups into the indole core structure.4 In particular, synthesis of trisubstituted prenylated
indole alkaloids bearing neighboring prenyl motifs at C6 and C7, as seen in cristatin A (4)3,5ꢀ6
and arestrictins (5, 6),6 has not been reported. The only successful synthesis of a trisubstituted
prenylated alkaloid so far reported is a synthesis of echinulin (3), which has two prenyl groups
at C5 and C7, a sterically less hindered relationship compared to trisubstituted prenylated
indoles 4, 5, and 6.7
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Herein, we described a synthesis of indole derivative 7, which is the core structure of
critatin A (4) and arestrictins (5, 6), bearing three prenyl or reverseꢀprenyl groups at C2, C6, and
C7.
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Figure 1. Structures of prenylated indole alkaloids 1ꢀ6, and the synthetic target indole
7.
We planned two strategies for the synthesis of trisubstituted indole 7, i.e., routes A and B
(Scheme 1). In route A, introduction of the reverseꢀprenyl group at C2 into the bisprenylated
indole 8 was examined. On the other hand, in route B, we considered construction of the
bisprenylated structure from 10 via 9 through an azaꢀClaisen rearrangement reaction.8
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Me
Me
2
6
Me
7
8
9
Me
N
H
1
N
H
7
Me
Me
Route A
7
8
10
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Me Me
Me Me
Route B
Me
Me
Me
Me
Me
Me
1
Me
N1
H
N
7
Me
Me
Me
10
9
Scheme 1. Synthetic plan for trisubstituted prenylated indole 7
Firstly, route A was examined, starting from dibromoꢀnitrobenzene 11, which was readily
prepared from 1,2ꢀdibromobenzene by nitration (Scheme 2a). Thus, prenylation of 11 was
carried out by reaction with prenyltributyl stannane (12) under Stille coupling conditions,9 and
the product was used for the construction of indole structure by reaction with vinylmagnesium
bromide as developed by Bartoli.10 Under these conditions, bisprenylated indole 8 was
obtained in 28% yield from 11, and monoprenylated compounds were generated as byꢀproducts.
Next, we attempted that introduction of the reverseꢀprenyl group into 8. Then, introduction of
the reverseꢀprenyl group into 8 was examined under the Danishefsky’s condtions.2a,2b In 1999,
Danishefsky and coꢀworkers reported the introduction of reverseꢀprenyl group at C2 with
3ꢀchloro indole by reacting the prenyl boron reagent, such as 14 and 15.2a In this reaction,
firstly, prenyl boron reagent reacts with 3ꢀchlorinated indole to form the boronꢀindole complex,
and then the reverseꢀprenyl group was introduced at C2 via 3,3ꢀsigmatropic rearrangement and
loss of hydrogen chloride (Scheme 2b). Chlorination of 8 at C3 was carried out with
Nꢀchlorosuccinimide (NCS), and we attempted reverseꢀprenylation of the resulting
3ꢀchlorinated 13 with prenylꢀ[9BBN] (14). However, unfortunately, no reaction took place,
and the starting 13 was recovered quantitatively. Allyl pinacol boronate (15) was also
ineffective. We further examined various reaction conditions, including solvents, temperatures
and bases, with prenyl reagents 14 or 15, but no reaction took place. Although the reason for
the low reactivity of bisꢀprenylated indole 8 in the reverseꢀprenylation reaction at C2 under
Danishefsky’s conditions is unclear, it is likely to be related to the presence of the prenyl group
at C7.11
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SnnBu3
10
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a)
Me
1)
2)
3
12
Me
Pd(PPh3)4, DMF
100 °C
6
Me
N
H
7
Br
NO2
Me
MgBr
Br
8
THF, ꢀ40 °C
(28%, 2 steps)
11
Me Me
Me
NCS
DMF
(70%)
Me
O
Me
Me
Me
B
Me
B
O
Me
14
Me 15
Cl
Me
Me
14 or 15
Me
2
Me
N
N
X
H
H
Me
Me
13
7
Me Me
Me Me
b) Introduction of reverse-prenyl group at C2 to 3-chlorinated indole
‡
Cl
Me
B
Cl
Me
Me
Me
Me
– HCl
Me
N
B
N
H
N
H
H
Scheme 2. Attempts to synthesize trisubstituted indole 7 by introduction of a reverseꢀprenyl
group at C2 from bisꢀprenylated indole 13.
Next, route B was examined. Thus, introduction of the prenyl group at C7 was
investigated using the disubstituted indole 10, which was synthesized as follows (Scheme 3).
6ꢀBromoindole (16), obtained from 4ꢀbromoꢀ2ꢀnitrotoluene in accordance with the procedure
developed by Yamada,12 was treated with tributylallyltin in the presence of
tetrakis(triphenylphosphine) palladium catalyst, and the resulting allyl substituent was
converted into a prenyl group by reaction with 2ꢀmethylꢀ2ꢀbutene under crossꢀmetathesis
reaction conditions in the presence of Grubbs II catalyst to give indole 17 bearing a prenyl
group at C6, in 71% yield from 16.2b Then, introduction of the reverseꢀprenyl group at the C2
position was examined by reaction with NCS followed by treatment with prenylꢀ[9BBN] (14).
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7
In this case, the reverseꢀprenyl group was selectively introduced, and disubstituted indole 10
was obtained in two steps with 62% overall yield.
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nBu3Sn
1)
Pd(PPh3)4
DMF, 100 °C
2
6
Me
N
N
Br
2) Me
H
H
Me
Me
16
17
Me
Grubbs II, CH2Cl2
(71% ,2 steps)
Me
Me
2
1) NCS, DMF
Me
N
2) 14, NEt3, THF
H
Me
10
(62% ,2 steps)
Scheme 3. Synthesis of disubstituted prenylated indole 10
Then, introduction of the prenyl group at C7 was examined from
Nꢀreverseꢀprenylated indoline 9 via azaꢀClaisen rearrangement (Scheme 4). Thus,
selective reduction of the pyrrole ring at C2ꢀ3 in 10 was conducted with sodium
cyanoborohydride in acetic acid,13 followed by Nꢀalkylation of the resulting indoline
with 1,1ꢀdimethylꢀpropargyl chloride (18)14 in the presence of copper chloride (I) and
diisopropylethylamine to give Nꢀpropagylated indoline 19 in 70% yield from 10.2c
Then, selective hydrogenation of the alkyne in 19 with Pd/C(en) which is a palladium–
activated carbon ethylenediamine complex15 was performed to afford alkene 9 in
quantitative yield.
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Me
Me
1) NaBH3CN
AcOH
Me
Me
10
1
N
2)
Cl
Me
18
Me
19
Me Me
iꢀPr2NEt, CuCl
THF
H2
Pd/C(en)
THF
(99%)
(70%, 2 steps)
Me
Me
nOe
Me
H
Me
2
Me
Me
6
H
3
Me
H
Me
1
N
N
2
7
Me
Me
Me
anti-9
Me
9
‡
silica gel
25 °C
Me
H
(79%)
Me
N
Me
Me
TS
Me
Me
2
Me
Me
Me
Me
N
MnO2
N
H
7
H
Me
Me
CH2Cl2
(89%)
20
7
Me Me
Me Me
Scheme 4. Synthesis of trisubstituted prenylated indole 7 via azaꢀClaisen rearrangement
reaction of Nꢀreverseꢀprenylated indoline 9.
With the Nꢀreverseꢀprenylated indoline 9 in hand, we investigated introduction of a prenyl
group at C7 by means of azaꢀClaisen rearrangement reaction. To our surprise, the reaction
proceeded smoothly on treatment with silica gel (acid form) at room temperature, and the
azaꢀClaisen product, C7ꢀprenylated indoline 20, was obtained in 79% yield. Although the
azaꢀClaisen rearrangement reactions of Nꢀreverseꢀprenylated substrates usually require harsh
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8
conditions, such as strong Brønsted acids or microwave irradiation, especially in the case of
substrate 21 (Figure 2),2c,16 the reaction proceeded under quite mild conditions in the case of 9.
The unusual reactivity of 9 was suggested to be due to fixing of the indoline ring in the
antiꢀconformer (antiꢀ9, i.e., 9A in Figure 2) with respect to the two reverseꢀprenyl groups at N
and C2, based on NMR analysis (NOESY experiment), in spite of rapid nitrogen inversion.17
This experimental observation was further supported by DFT calculations (B3LYP/6ꢀ31G*) of
model compounds 9A, 9B and 21, which are antiꢀ and synꢀconformers of 9, and the conformer
of 21 lacking the reverseꢀprenyl group at C2, respectively (see the Supporting Information).
Indeed, antiꢀconformer 9A is 15 kcal/mol more stable than synꢀconformer 9B, which has a
steric interaction between the two reverseꢀprenyl groups at N and C2. Since the overlaps of
the orbitals in 9AꢀTS are favorable for the rearrangement reaction, azaꢀClaisen rearrangement
reaction should proceed via antiꢀ9. In addition, the reverseꢀprenyl group at C2 in 9 induces a
significant pyramidalization around the N atom, compared with 21. Thus, the totals of the
three CꢀNꢀC angles of 9A and 21 were found to be 340 and 348 degrees, respectively. This
structural distortion of 9 should also contribute to acceleration of the azaꢀClaisen rearrangement
reaction. Actually, the activation energy of the azaꢀClaisen rearrangement reaction of 9A was
calculated to be 7 kcal/mol lower than that of 21.
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Finally, oxidation of the indoline 20 was achieved with manganese dioxide to give indole 7
in 89% yield.
9A
9A-TS
9B
21
Figure 2. 3D structures of 9A, 9A-TS, 9B, and 21 optimized at the B3LYP/6ꢀ31G* level.
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In summary, we have synthesized C2,C6,C7ꢀtrisubstituted prenylated indole 7 as a
common synthetic key intermediate for the natural indoles 4ꢀ6, successfully introducing two
adjacent two prenyl groups and a reverse prenyl group. Notably, introduction of the prenyl
group at C7 was efficiently carried out by means of azaꢀClaisen rearrangement reaction of
Nꢀreverseꢀprenylated 9 under very mild conditions. This synthetic strategy should open up a
synthetic route to various prenylated indole alkaloids with sterically hindered substituents,
including triꢀsubstituted analogs.
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EXPERIMENTAL SECTION
General Experimental Methods.
Flash chromatography was performed on Silica Gel 60 (spherical, particle size 40ꢀ100
µm; Kanto) and CHROMATOREX NHꢀDM1020 (particle size 90.0ꢀ105.0 µm; Fuji
1
Silysia). H and 13C NMR spectra were recorded on JEOL JNMꢀAL 300, JNMꢀECX
400 and JNMꢀECX 500. The spectra are referenced internally according to a residual
solvent signal of CDCl3 (1H NMR; δ = 7.26 ppm, 13C NMR; δ = 77.0 ppm). High
resolution mass spectra (HRMS) were recorded on a JEOL JMSꢀT100LC spectrometer
with ESIꢀTOFꢀMS mode using methanol as solvent.
6,7-Bis(3-methylbut-2-en-1-yl)-1H-indole
(8).
To
a
solution
of
2,3ꢀdibromonitrobenzene (11) (100 mg, 0.356 mmol) in DMF (0.5 mL) was added
Pd(PPh3)4 (40 mg, 0.0356 mmol) and prenyltributylstannane (12) (280 mg, 0.785
mmol), and the resultant was heated to 100 °C for 24 h. The reaction mixture was
cooled to room temperature, and to the reaction mixture was added ethyl acetate and
10% KF aqueous solution. The organics were extracted with ethyl acetate, and the
organic phase was washed with 10% KF aqueous solution and brine, dried over MgSO4,
filtered and concentrated in vacuo. The residue was purified by column chromatography
on
silica
gel
(hexane/CH2Cl2
=
16:1)
to
give
1,2ꢀbis(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ3ꢀnitrobenzene as a liquid (40 mg, 0.160 mmol, 45%).
To a solution of 1,2ꢀbis(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ3ꢀnitrobenzene (5.37 g, 20.7 mmol) in
THF (200 mL) was added vinylmagnesium bromide (62 mL, 1 M in THF, 62.1 mmol)
at ꢀ40 °C under argon. The reaction mixture was stirred at ꢀ40 °C for 2 h, then quenched
with saturated NH4Cl, and the resultant was warmed to room temperature. The reaction
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mixture was extracted with ethyl acetate, and the extracts were washed with H2O and
brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (hexane/CH2Cl2 = 15:1 to 5:1) to give 8 as a
9
1
10
11
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colorless liquid (3.31 g, 13.1 mmol, 63%). Spectral data for 8: H NMR (300 MHz,
CDCl3) δ 8.09 (br s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.15 (dd, J = 3.1, 2.4 Hz, 1H), 6.98
(d, J = 7.9 Hz, 1H), 6.51 (dd, J = 3.1, 2.1 Hz, 1H), 5.34ꢀ5.20 (m, 2H), 3.60 (d, J = 6.2
Hz, 2H), 3.47 (d, J = 6.9 Hz, 2H), 1.89 (s, 3H), 1.80ꢀ1.69 (m, 9H); 13C NMR (75 MHz,
CDCl3) δ 135.9, 132.7, 132.3, 131.0, 126.2, 124.3, 123.6, 122.9, 122.1, 121.4, 118.4,
102.7, 31.8, 27.0, 25.8, 25.6, 18.1, 17.9; HRMS (ESI, MꢀHꢀ) calcd for C18H22N1
252.1752, found 252.1767.
6,7-Bis(3-methylbut-2-en-1-yl)-3-chloro-1H-indole (13). To
a
solution of
6,7ꢀbis(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ1Hꢀindole (8) (30 mg, 0.118 mmol) in DMF (0.6 mL)
was added Nꢀchlorosuccimide (17.4 mg, 0.13 mmol) at 0 °C under argon. The reaction
mixture was stirred at 0 °C for 15 min, then warmed to room temperature for 15 min.
The reaction mixture was quenched with brine and extracted with ethyl acetate. The
organic layer was washed with H2O and brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by column chromatography on silica
gel (hexane/CH2Cl2 = 16:1) to give 13 as a white solid (23.8 mg, 0.083 mmol, 70%).
1
Mp = 67–70 °C. Spectral data for 13: H NMR (300 MHz, CDCl3) δ 7.97 (br s, 1H),
7.41 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 5.29ꢀ5.14 (m,
2H), 3.55 (d, J = 6.5 Hz, 2H), 3.45 (d, J = 6.9 Hz, 2H), 1.85 (s, 3H), 1.75 (s, 3H), 1.73
(d, J = 1.0 Hz, 3H), 1.71 (d, J = 1.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 135.1, 134.0,
132.8, 131.5, 123.9, 123.8, 122.8, 122.4, 121.8, 120.2, 115.9, 106.6, 31.8, 26.6, 25.7,
25.6, 18.1, 17.9; HRMS (ESI, MꢀHꢀ) calcd for C18H21Cl1N1 286.1363, found 286.1376.
6-(3-Methylbut-2-en-1-yl)-1H-indole (17). To a solution of 6ꢀbromoindole (16)
(402 mg, 2.05 mmol) in DMF (4.1 mL) was added Pd(PPh3)4 (237 mg, 0.205 mmol)
and allyltributylstannane (14) (0.69 mL, 2.26 mmol) at room temperature. The resulting
mixture was heated to 100 °C for 9 h. The reaction mixture was cooled to room
temperature, and filtered through a pad of Celite. To the filtrate was added Et2O and
10% KF solution, and the mixture was extracted with Et2O. The organic layer was
washed with 10% KF solution and brine, dried over MgSO4, filtered and concentrated
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in vacuo. The residue was purified by column chromatography on silica gel
(hexane/CH2Cl2 = 10:1) to give 6ꢀallylꢀ1Hꢀindole as a colorless liquid (277 mg, 1.76
mmol, 86%). To a solution of 6ꢀallylꢀ1Hꢀindole (35.6 mg, 0.226 mmol) in CH2Cl2 (0.25
mL) was added 2ꢀmethylꢀ2ꢀbutene (0.72 mL, 6.79 mmol) and Grubbs’ 2nd generation
catalyst (13 mg, 0.0158 mmol) at room temperature, and the mixture was stirred for 2.5
h. The reaction mixture was concentrated in vacuo. The residue was purified by column
9
10
11
12
13
14
15
16
17
18
19
20
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chromatography on silica gel (hexane/CH2Cl2 = 10:1) to give 17 as a colorless liquid
1
(34.5 mg, 0.181 mmol, 82%). Spectral data for 17: H NMR (300 MHz, CDCl3)
δ 8.02
(br s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 7.15 (dd, J = 3.1, 2.4 Hz, 1H), 6.98 (d,
J = 7.9 Hz, 1H), 6.52 (dd, J = 3.1, 2.1 Hz, 1H), 5.41 (t, J = 7.6 Hz, 1H), 3.47 (d, J = 7.6
Hz, 2H), 1.77 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 136.1, 135.8, 132.0, 125.9, 124.0,
123.6, 120.9, 120.4, 110.2, 102.2, 34.5, 25.8, 17.8; HRMS (ESI, MꢀHꢀ) calcd for
C13H14N1 184.1126, found 184.1140.
2-(2-Methylbut-3-en-2-yl)-6-(3-methylbut-2-en-1-yl)-1H-indole (10). To
a
solution of 6ꢀ(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ1Hꢀindole (17) (229 mg, 1.10 mmol) in DMF (12
mL) was added Nꢀchlorosuccimide (165 mg, 1.24 mmol) at 0 °C under argon. The
resulting mixture was stirred at 0 °C for 15 min, then heated to room temperature for 15
min. The reaction mixture was quenched with brine and extracted with Et2O. The
organic layer was washed with brine, dried over MgSO4, filtered and concentrated in
vacuo. The residue was purified by column chromatography on silica gel
(hexane/CH2Cl2 = 16:1) to give 3ꢀchloroꢀ6ꢀ(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ1Hꢀindole as a
white amorphous (242 mg, 1.10 mmol, 89%). To
a
solution of
3ꢀchloroꢀ6ꢀ(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ1Hꢀindole (77.6 mg, 0.362 mmol) and Et3N (0.3
mL, 2.2 mmol) in THF (1.8 mL) was added prenylꢀ9ꢀBBN (14) (5 mL, 2.2 mmol) at
room temperature under argon, and the mixture was stirred at this temperature for 15 h.
The reaction mixture was quenched with saturated NaHCO3 and extracted with ethyl
acetate. The extracts were washed with H2O and brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by column chromatography on silica
gel (hexane/CH2Cl2 = 16:1 to 10:1) to give 10 as a yellow liquid (64.2 mg, 0.253, mmol,
1
70%). Spectral data for 10: H NMR (300 MHz, CDCl3) δ 7.77 (br s, 1H), 7.44 (d, J =
7.9 Hz, 1H), 7.10 (s, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.25 (d, J = 1.4 Hz, 1H), 6.02 (dd, J
= 17.5, 10.3 Hz, 1H), 5.37 (t, J = 7.6 Hz, 1H), 5.10 (d, J = 17.5 Hz, 1H), 5.09 (d, J =
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10.3 Hz, 1H), 3.42 (d, J = 7.6 Hz, 2H), 1.74 (s, 6H), 1.46 (s, 6H); C NMR (75 MHz,
CDCl3) δ 146.2, 145.2, 136.3, 135.1, 131.8, 126.5, 124.1, 120.6, 119.8, 112.0, 109.7,
97.6, 38.1, 34.5, 27.3, 25.8, 17.8; HRMS (ESI, MꢀHꢀ) calcd for C18H22N1 252.1752,
found 252.1765.
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1-(2-Methylbut-3-yn-2-yl)-2-(2-methylbut-3-en-2-yl)-6-(3-methylbut-2-en-1-yl)-1
H-indoline
(19).
To
a
solution
of
2ꢀ(2ꢀmethylbutꢀ3ꢀenꢀ2ꢀyl)ꢀ6ꢀ(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ1Hꢀindole (10) (106 mg, 0.417
mmol) in AcOH (2.1 mL) was added sodium cyanoborohydride (46 mg, 0.709 mmol) at
room temperature under argon, and the mixture was stirred at room temperature for 1 h.
The reaction mixture was quenched with 20% aqueous NaOH, and extracted with ethyl
acetate. The organic layer was washed with H2O and brine, dried over MgSO4, filtered
and concentrated in vacuo. The residue was purified by column chromatography on
silica
6ꢀ(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ2ꢀ(2ꢀmethylbutꢀ3ꢀenꢀ2ꢀyl)indoline as a yellow liquid (94.3
mg, 0.369 mmol, 89%). To solution of
gel
(hexane/CH2Cl2
=
16:1
to
12:1)
to
give
a
6ꢀ(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ2ꢀ(2ꢀmethylbutꢀ3ꢀenꢀ2ꢀyl)indoline (75.1 mg, 0.294 mmol)
and 1,1ꢀdimethylꢀpropargyl chloride (18) (66 µL, 0.586 mmol) in THF (0.59 mL) was
added CuCl (5.8 mg, 0.0588 mmol) and DIPEA (101 µL, 0.588 mmol) at 0 °C under an
argon. After 10 min, the resulting mixture was warmed to room temperature and stirred
for 1 h. The reaction mixture was filtered through a pad of NHꢀsilica gel
(CHROMATOREX NHꢀDM1020) and filtrates were concentrated in vacuo. The residue
was purified by column chromatography on NHꢀsilica gel (hexane) to give 19 as a
1
yellow liquid (74.3 mg, 0.231 mmol, 79%). Spectral data for 19: H NMR (400 MHz,
CDCl3) δ 6.96 (d, J = 7.3 Hz, 1H), 6.86 (s, 1H), 6.71 (d, J = 7.3 Hz, 1H), 5.75 (dd, J =
17.4, 10.5 Hz, 1H), 5.33 (t, J = 7.3 Hz, 1H), 4.89 (dd, J = 17.4, 1.8 Hz, 1H), 4.88 (dd, J
= 10.5, 1.8 Hz, 1H), 3.68 (d, J = 8.7 Hz, 1H), 3.30ꢀ3.21 (m, 3H), 2.53 (d, J = 16.0 Hz,
1H), 2.23 (s, 1H), 1.75 (s, 3H), 1.71 (s, 3H), 1.58 (s, 3H), 1.49 (s, 3H), 1.01 (s, 3H),
0.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.1, 146.5, 139.4, 135.1, 132.0, 123.7,
123.1, 122.7, 120.1, 111.2, 89.9, 70.4, 68.6, 55.7, 42.3, 34.4, 32.0, 31.3, 29.4, 25.8, 25.2,
21.8, 17.8; HRMS (ESI, M+H+) calcd. for C23H32N1 322.2535, found 322.2576.
1,2-Bis(2-methylbut-3-en-2-yl)-6-(3-methylbut-2-en-1-yl)-1H-indoline (9). To a
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solution
of
1ꢀ(2ꢀmethylbutꢀ3ꢀynꢀ2ꢀyl)ꢀ2ꢀ(2ꢀmethylbutꢀ3ꢀenꢀ2ꢀyl)ꢀ6ꢀ
(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ1Hꢀindoline (19) (31.3 mg, 0.097 mmol) in THF (1 mL) was
added Pd/C (en) (3 mg). The mixture was stirred at room temperature for 12 h under an
atmosphere of hydrogen gas (balloon). The reaction mixture was filtered through a
pad of Celite, and the filtrates were concentrated in vacuo to give 9 as a colorless liquid
(30.9 mg, 0.096 mmol, 99%). Spectral data for 9: 1H NMR (500 MHz, CDCl3) δ 6.91 (d,
J = 7.4 Hz, 1H), 6.80 (s, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.09 (dd, J = 17.8, 10.9 Hz, 1H),
5.72 (dd, J = 17.2, 10.9 Hz, 1H), 5.30 (t, J = 7.4 Hz, 1H), 5.00 (d, J = 17.8, 1H), 4.98 (d,
J = 10.9 Hz, 1H), 4.86 (d, J = 17.2, 1H), 4.86 (d, J = 10.9 Hz, 1H), 3.34 (d, J = 8.6 Hz,
1H), 3.24 (d, J = 7.4 Hz, 2H), 2.98 (dd, J = 16.0, 8.6 Hz, 1H), 2.53 (d, J = 16.0 Hz, 1H),
1.74 (s, 3H), 1.70 (s, 3H), 1.28 (s, 3H), 1.23 (s, 3H), 0.96 (s, 3H), 0.75 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 152.1, 147.4, 146.8, 139.3, 134.8, 131.8, 123.9, 122.9, 121.8,
119.7, 111.0, 111.0, 67.0, 61.1, 42.4, 34.5, 32.5, 26.7, 25.9, 25.8, 25.2, 22.0, 17.8;
HRMS (ESI, M+H+) calcd for C23H34N1 324.2691, found 324. 2520.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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2-(2-Methylbut-3-en-2-yl)-6,7-bis(3-methylbut-2-en-1-yl)-1H-indoline
(20).
1,2ꢀBis(2ꢀmethylbutꢀ3ꢀenꢀ2ꢀyl)ꢀ6ꢀ(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ1Hꢀindoline (9) was charged
with silica gel and stand for 15 min. To the reaction mixture was added an eluent
(hexane:Et2O = 50:1), and the mixture was filtered to give 20 as a colorless liquid (24.9
mg, 0.077 mmol, 79%). Spectral data for 20: 1H NMR (500 MHz, CDCl3) δ 6.84 (d, J =
6.9 Hz, 1H), 6.51 (d, J = 6.9 Hz, 1H), 5.85 (dd, J = 17.8, 10.9 Hz, 1H), 5.21 (t, J = 6.9
Hz, 1H), 5.09ꢀ4.97 (m, 3H), 3.80 (br s, 1H), 3.70 (t, J = 8.3 Hz, 1H), 3.27 (d, J = 6.9 Hz,
2H), 3.19 (d, J = 6.3 Hz, 2H), 2.95 (dd, J = 15.8, 8.3 Hz, 1H), 2.82 (dd, J = 15.8, 8.3 Hz,
1H), 1.78 (s, 3H), 1.70 (s, 9H), 1.01 (s, 3H), 0.97 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 150.6, 145.8, 138.1, 132.1, 131.3, 126.5, 124.0, 122.2, 121.9, 119.7, 119.1, 112.3, 67.3,
40.5, 31.9, 31.3, 26.9, 25.7, 25.7, 24.0, 21.5, 17.8; HRMS (ESI, M+H+) calcd for
C23H34N1 324.2691, found 324. 2676.
2-(2-Methylbut-3-en-2-yl)-6,7-bis(3-methylbut-2-en-1-yl)-1H-indole (7). To a
solution of 2ꢀ(2ꢀmethylbutꢀ3ꢀenꢀ2ꢀyl)ꢀ6,7ꢀbis(3ꢀmethylbutꢀ2ꢀenꢀ1ꢀyl)ꢀ1Hꢀindoline (20)
(24.9 mg, 0.077 mmol) in CH2Cl2 was added MnO2 (33 mg, 0.385 mmol) at room
temperature, and the mixture was heated at 50 °C for 5 h. To the mixture was added
additional MnO2 (33 mg x 4 times, 1.54 mmol) every hour. The reaction mixture was
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cooled to room temperature and filtered through a pad of Celite. The filtrates were
concentrated in vacuo, and the residue was purified by column chromatography on
NHꢀsilica gel (hexane) to give 7 as a yellow liquid (22 mg, 0.068 mmol, 89%). Spectral
data for 7: 1H NMR (500 MHz, CDCl3) δ 7.90 (br s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.90
(d, J = 8.0 Hz, 1H), 6.23 (d, J = 2.3 Hz, 1H), 6.01 (dd, J = 17.2, 10.3 Hz, 1H), 5.31ꢀ5.22
(m, 2H), 5.10 (d, J = 17.2 Hz, 1H), 5.09 (d, J = 10.3 Hz, 1H), 3.54 (d, J = 6.9 Hz, 2H),
3.43 (d, J = 6.9 Hz, 2H), 1.88 (s, 3H), 1.75 (s, 3H), 1.74 (s, 3H), 1.71 (s, 3H), 1.44 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 146.3, 144.8, 136.1, 132.0, 131.9, 130.8, 126.9,
124.5, 123.4, 121.8, 120.5, 117.9, 111.7, 97.7, 38.2, 32.0, 27.4, 27.2, 25.7, 25.6, 17.9;
HRMS (ESI, MꢀHꢀ) calcd. for C23H30N1 320.2378, found 320.2378.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publication website.
Copies of 1H and 13C NMR spectra for the compounds, and computational experimental data are
available.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: knaga@cc.tuat.ac.jp
ORCID
Kazuo Nagasawa: 0000ꢀ0002ꢀ0437ꢀ498X
Minami Odagi: 0000ꢀ0002ꢀ0334ꢀ3565
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENT
This work was supported in part by a GrantꢀinꢀAid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysts” (no. 23105013) and “Middle
Molecular Strategy” (no. JP16H01134) from The Ministry of Education, Culture, Sports,
Science and Technology, Japan, and the Japan Society for the Promotion of Science (JSPS)
KAKENHI Grant Number JP26282214, JP16K17897 and A3 foresight program.
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REFERENCES
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Scholz, U.; Winterfeldt, E. Nat. Prod. Rep. 2000, 17, 349ꢀ366. (c) Li, S. Nat. Prod. Rep.
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Avendano, C.; Menendez, J. C. J. Org. Chem. 2003, 68, 6944ꢀ6951. (g) Kuramochi, K.;
Aoki, T.; Nakazaki, A.; Kamisuki, S.; Takeno, M.; Ohnishi, K.; Kimoto, K.; Watanabe,
N.; Kamakura, T.; Arai, T.; Sugawara, F.; Kobayashi, S. Synthesis 2008, 3810ꢀ3818. (h)
Baran, P. S.; Guerrero, C. A.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 5628ꢀ5629. (i)
Grubbs, A. W.; Artman, III, G. D.; Tsukamoto, S.; Williams, R. M. Angew. Chem. Int. Ed.
2007, 46, 2257–2261.
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Venkateswarlu, Y. Phytochemistry 2001, 58, 1263ꢀ1266.
(4) Tanaka, S.; Shiomi, S.; Ishikawa, H. J. Nat. Prod. 2017, 80, 2371ꢀ2378.
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Kawai, K. Chem. Pharm. Bull. 2006, 54, 1639ꢀ1641.
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(7) (a) Inoue, S.; Takamatsu, N.; Kishi, Y.; Yakugaku Zasshi 1977, 97, 553ꢀ557; (b) Inoue,
S.; Takamatsu, N.; Kishi, Y. Yakugaku Zasshi 1977, 97, 558ꢀ563. (c) Takamatsu, N.;
Inoue, S.; Kishi, Y. Tetrahedron Lett. 1971, 12, 4665ꢀ4668.
(8) Review, see: Majumdar, K. C.; Bhattacharyya, T.; Synthesis 2009, 2117ꢀ2142.
(9) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508ꢀ524.
(10) Dappozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163ꢀ178.
(11) As shown in Scheme 3, reverseꢀprenylation took place under the same conditions
with another similar substrate, 17, which lacks the prenyl group at C7.
(12) Yamada, Y. K ; Okada, C.; Yoshida, K.; Umeda, Y.; Arima, S.; Sato, N.; Kai, T.;
Takayanagi, H.; Harigaya, Y. Tetrahedron 2002, 58, 7851ꢀ7861.
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(13) Direct Nꢀalkylation of indole 10 with 1,1ꢀdimethylꢀpropargyl chloride (18) did not
proceed due to its low nucleophilicity of N1 in indole. Thus, the reduction of indole 10
was carried out for increasing the nucleophilicity of N1 in 10.
9
(14) Chengebroyen, J.; Linke, M.; Robitzer, M.; Sirlin, C.; Pfeffer, M. J. Organomet. Chem.
2003, 687, 313ꢀ321.
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(15) Sajiki, H.; Hattori, K.; Hirota, K. J. Org. Chem. 1998, 63, 7990ꢀ7992.
(16) Xiong, X.; Pirrung, M. C. J. Org. Chem. 2007, 72, 5832ꢀ5834.
(17) nOes were observed between protons at C2, C3, and methyl groups on the nitrogen and
reverse prenyl group a by NOESY experiment. See Supporting Information for details.
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