Proline-Catalyzed Cyclization Reaction for the Synthesis of Naphthostyrils: Application to the Total Synthesis of Prioline

Article abstract of DOI:10.1002/adsc.201500367

A new method for the synthesis of naphthostyrils is described. In this method, a sequential Stille coupling and proline-catalyzed cyclization procedure is employed for the reaction of 4-bromooxindoles and β-tributylstannyl-α,β-unsaturated ketones. The uti

Full text of DOI:10.1002/adsc.201500367

FULL PAPERS
DOI: 10.1002/adsc.201500367
Proline-Catalyzed Cyclization Reaction for the Synthesis of
Naphthostyrils: Application to the Total Synthesis of Prioline
Kyeong-Yong Park,a,b Ha-Jeong Song,a,b and Jung-Nyoung Heoa,b,*
a
Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Daejeon
305-600, Korea
b
Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Daejeon
305-764, Korea
Fax: (+82)-42-860-7160; e-mail: heojn@krict.re.kr
Received: April 14, 2015; Revised: July 1, 2015; Published online: October 14, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500367.
Abstract: A new method for the synthesis of naph- the first total synthesis of prioline from a simple 2-
thostyrils is described. In this method, a sequential isopropylphenol.
Stille coupling and proline-catalyzed cyclization pro-
cedure is employed for the reaction of 4-bromooxin-
doles and b-tributylstannyl-a,b-unsaturated ketones. Keywords: naphthostyrils; organocatalysts; prioline;
The utility of this methodology is demonstrated in proline; Stille reaction
Introduction
ficient for the synthesis of naphthostyrils, significant
challenges still remain for the introduction of aliphat-
Organocatalysts play an important role in the modern ic substituents at the aromatic ring. Based on a retro-
organic synthesis of natural products and pharmaceut- synthetic analysis, we hypothesized that a sequential
icals. Among them, the proline-based catalytic aldol- Stille coupling and cyclization reaction for the synthe-
type reaction via enamines and imines as key inter- sis of naphthostyrils could be performed by simply
mediates has offered an attractive tool for synthetic using 4-bromooxindole 7 and b-stannyl ketones 8
applications.[1] As part of our ongoing efforts to devel- (Scheme 1).
op structurally unique motifs for potential use in
Although the Stille coupling step would be an obvi-
pharmaceuticals, we focused on the total synthesis of ous candidate based on the literature methods, the
natural products derived from 2-oxoindoles cyclization of (E)-a,b-unsaturated enones 6 should
(Figure 1).[2,3] In particular, prioline (1), which pos-
sesses a tricyclic naphthostyril core, was isolated in
2000 from the roots of Salvia prionitis.[4] This plant is
used in traditional Asian herbal medicines for treating
tonsillitis, pharyngitis, pulmonary tuberculosis, and ba-
cillary dysentery.[5] Recently, a new class of naphthos-
tyrils 2 rationally designed by Liu and co-workers was
synthesized, and their kinase inhibitory activity
against CDK2 was evaluated.[6] Additionally, ammosa-
mide B (3)[7] and piperumbellactam A (4),[8] which
possess a similar oxindole core, exhibited significant
in vitro cytotoxicity against HCT-116 colon cancer
cells and moderate a-glucosidase enzyme inhibition,
respectively.
The classical methods for synthesizing naphthostyr-
ils generally involve either the Lossen rearrangement
of naphthalimides[9] or the base-catalyzed intramolec-
ular cyclization of a,b-unsaturated ketones.[10] Al-
though these approaches have proven to be highly ef- Figure 1. Structures of prioline and naphthostyril analogues.
Adv. Synth. Catal. 2015, 357, 3197 – 3205
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3197

FULL PAPERS
Kyeong-Yong Park et al.
formed using the Oppenauer protocol as modified by
Nguyen,[12] which proved to be superior to MnO2-
based methods, even with low catalyst loadings. After
obtaining the b-stannyl enones 8a–c, the synthesis of
a,b-unsaturated enones 6a–g via a key Stille coupling
reaction was investigated.[13] Using Pd(PPh3)4, effi-
cient coupling reactions of 4-bromooxindoles 7a–
c with b-stannyl enones 8a–c were achieved. For ex-
ample, the reaction of 7a with 8a afforded the corre-
sponding b-stannyl enone 6a in 93% yield. Notably,
the coupling of 7a with cis-8a[14] afforded a mixture of
the (Z) and (E) isomers of 6a under the same condi-
tions. In most cases, substituted 4-bromooxindoles 7b
and 7c[3h] underwent smooth coupling with 8a–c to
generate the corresponding products 6c–f in good to
Scheme 1. Retrosynthetic analysis for naphthostyrils.
proceed via isomerization to the Z-isomer under the high yields.
reaction conditions to afford the desired naphthostyr-
In our preliminary experiments, 2-oxindole 6a was
ils 5. Additionally, this particular transformation is selected as a model substrate. From a mechanistic
difficult not only due to the isomerization step, but perspective, the challenge lies in the isomerization of
also to the steric hindrance of the R5 alkyl group. the E-enone to the Z-isomer, which allows for the for-
Herein, we report our recent investigation of this new mation of naphthostyril via intramolecular cyclization.
protocol for the construction of naphthostyrils and Although we initially hypothesized that an aldol-type
the application of this method to the first total synthe- condensation reaction could be employed for such
sis of the natural product prioline (1).
a one-step isomerization–cyclization at elevated tem-
perature, preliminary attempts under acidic or basic
conditions in a polar solvent were unsuccessful
(Table 1, entries 1 and 2). Eventually, we determined
that the use of piperidine afforded only trace amounts
Results and Discussion
The synthesis of b-stannyl enones 8a–c began from of the desired cyclized product (entry 3). Even using
propargyl alcohols 9a–c (Scheme 2). The palladium- the Liuꢁs protocol with NaH in MeOH, only a 15%
catalyzed hydrostannylation of alkynes afforded the yield of product was obtained (entry 4). Consequently,
desired trans-isomer of 10a–c after silica gel separa- we envisioned that a proline-promoted Knoevenagel-
tion.[11] Subsequent oxidation of the alcohol was per- or Mannich-type reaction could facilitate the isomeri-
zation–cyclization process.[15] Indeed, the use of
1 equiv. of l-proline afforded the naphthostyril 5a in
a better 24% yield (entry 5). After screening a variety
of solvents with different reaction temperatures, we
discovered that o-dichlorobenzene at 2008C afforded
the cyclized product in 57% yield (entries 6–9). Next,
we examined various commercially available proline
analogues L2–L5 (entries 10–13). With the exception
of L3, which possesses a neighboring tertiary carbon,
all of the proline analogues afforded similar-to-better
results compared with the original l-proline (L1). L5
was identified as the most effective proline analogue
for this cyclization (entry 13). At this point, we hy-
pothesized that the presence of an additional acid
could be beneficial for the cyclization due to the ac-
celerated formation of enamine or iminium inter-
mediates. The addition of acids, including benzoic
acid (PhCO2H), acetic acid, camphorsulfonic acid,
and para-toluenesulfonic acid, allowed the process to
occur more efficiently, with improved yields (en-
tries 14–17). The result with PhCO2H was superior to
that with the other acids. Benzoic acid also proved to
be an excellent acid additive in this type of cycliza-
Scheme 2. Generation of a,b-unsaturated enones.
tion, in combination with piperidine or l-proline (L1)
3198
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3197 – 3205

FULL PAPERS
Proline-Catalyzed Cyclization Reaction for the Synthesis of Naphthostyrils
Table 1. Optimization of the cyclization reaction.[a]
Entry
Reagent
Additive
Solvent
Temperature [oC]
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
p-TsOH
Cs2CO3
piperidine
NaH
l-proline (L1)
l-proline (L1)
l-proline (L1)
l-proline (L1)
l-proline (L1)
L2
L3
L4
L5
L5
–
–
–
–
–
–
–
–
–
–
–
–
toluene/EtOH
pyridine
toluene
MeOH
toluene
o-xylene
DMF
DMSO
o-dichlorobenzene
toluene
150
150
150
reflux
150
180
180
200
200
150
150
150
150
200
200
200
200
200
200
200
200
180
150
200
22
22
22
24
12
48
48
48
4
4
4
4
4
4
4
4
4
4
4
4
4
NR
NR
trace
15
24
49
42
34
57
34
3
22
49
84
76
66
73
80
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
toluene
toluene
toluene
–
PhCO2H
AcOH
CSA
o-dichlorobenzene
o-dichlorobenzene
o-dichlorobenzene
o-dichlorobenzene
o-dichlorobenzene
o-dichlorobenzene
o-dichlorobenzene
o-dichlorobenzene
o-dichlorobenzene
o-dichlorobenzene
o-dichlorobenzene
L5
L5
L5
p-TsOH
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
piperidine
l-proline (L1)
L5 (0.5 equiv.)
L5 (0.2 equiv.)
L5 (0.2 equiv.)
L5 (0.2 equiv.)
–
69
81
76
81
56
trace
24
24
4
[a]
Reaction conditions: 6a (0.3 mmol), reagent, additive (1 equiv.), molecular sieves (4Š, 200 mg), solvent (12 mL).
Isolated yield.
[b]
(entries 18 and 19). Moreover, the cyclization employ- ieved in synthetically valuable yields to provide naph-
ing catalytic amounts of proline L5 provided the de- thostyrils 5c–f. However, 6g with phenyl ketone af-
sired product in good yields (entries 20–23). Notably, forded the cyclized product 5g in only 15% yield, po-
the catalytic use of L5 (0.2 equiv.) with PhCO2H in o- tentially due to the enhanced steric encumbrance.
dichlorobenzene at 1808C for 24 h provided a respect-
able 81% yield (entry 22). In the absence of proline, stituted oxindole 17 was first prepared by Sandmey-
no reaction occurred (entry 24). erꢁs isatin synthesis followed by Wolff–Kishner reduc-
For the total synthesis of prioline (1), the fully sub-
After determining the optimal catalytic conditions tion from the commercially available 2-isopropylphe-
(Table 1, entry 22), we explored the substrate scope nol (11) (Scheme 4). Thus, the known phenol 12 was
with various a,b-unsaturated enones 6a–g (Scheme 3). readily prepared by sequential bromination and nitra-
Enone 6b, which contains ethyl ketone, reacted tion in 81% yield.[16] O-Methylation with iodome-
smoothly to provide the corresponding naphthostyril thane followed by reduction in the presence of iron
5b in 85% yield. Further diversification of the 2-oxin- afforded the corresponding aniline 13 in excellent
dole ring with 5-methyl and 7-fluoro groups was ach- yield. Aniline 13 was subsequently subjected to modi-
Adv. Synth. Catal. 2015, 357, 3197 – 3205
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3199

FULL PAPERS
Kyeong-Yong Park et al.
Scheme 3. Scope of the proline-catalyzed cyclization.
fied Sandmeyerꢁs conditions using chloral hydrate and
hydroxylamine to afford isonitrosoacetanilide 14.[17]
The acid-catalyzed cyclization of 14 provided isatin
15, which was protected with PMB-Cl to provide the
N-PMB-protected isatin 16 in excellent yield. The
Wolff–Kishner reduction of 16 with hydrazine pro-
ceeded cleanly to provide the required 4-bromooxin-
dole 17 in 87% yield.[18] Using the optimal procedure,
we examined the feasibility of the Stille coupling/pro-
line-catalyzed cyclization protocol for the total syn-
thesis of prioline. Stille cross-coupling between 4-bro-
mooxindole 17 and b-stannyl enones 8a and 8b with
Pd(PPh3)4 afforded the corresponding a,b-unsaturated
enones 18a and 18b in good yields. Next, the treat-
ment of 18a and 18b with trans-4-hydroxy-l-proline
(L5) in the presence of benzoic acid in o-dichloroben-
zene with heating at 1808C afforded the desired naph-
thostyrils 19a and 19b in 78% and 88% yields, respec-
tively. The structure of the prioline precursor 19a was
confirmed by X-ray crystallography[19] (Figure 2). Fi-
nally, the global deprotection of 19a with HBr in
acetic acid provided prioline (1); the NMR spectro-
Scheme 4. Total synthesis of prioline.
scopic data were in good agreement with the reported cyclization step: (i) thermal 6p-electrocyclization and
data for the natural product.
(ii) a Mannich-type reaction.[20] For the electrocyclic
Based on the above results, a catalytic cyclization process to occur, s-cis-21 provides a suitable planar
pathway using proline L5 is proposed in Scheme 5. delocalized 6p system with increased steric interac-
First, treatment of the a,b-unsaturated enone 6a with tions to afford the tertiary amine 23. In the case of
L5 in the presence of benzoic acid generates the imi- a Mannich-type reaction, the enolate of 22 attacks the
nium ion 20, which leads to the formation of the tri- carbon on the iminium ion to generate the intermedi-
enamine 21 from the abstraction of the a-hydrogen of ate 23. The two potential mechanisms proposed for
the 2-oxindole core. This formation of trienamine 21 this cyclization cannot currently be distinguished
allows for the interconversion between the s-cis-21 based on the reaction outcome. Finally, a subsequent
and the s-trans-21 isomers. At this stage, we hypothe- aromatization of 23 will provide the desired naphtho-
sized that there were two possible pathways for the styril 5a and catalytic proline L5.
3200
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3197 – 3205

FULL PAPERS
Proline-Catalyzed Cyclization Reaction for the Synthesis of Naphthostyrils
Further biological evaluations of the natural product
prioline and its analogues are currently in progress.
Experimental Section
Preparation of b-Tributylstannyl a,b-Unsaturated
Ketones (8a–8c)
To a solution of alkynyl alcohol 9a–9c (20 mmol) and
Pd(PPh3)2Cl2 (10 mol%) in THF (60 mL) at À788C was
added Bu3SnH (26 mmol, 1.3 equiv.) dropwise over 5 min.
The mixture was stirred for 3 h at À788C and then allowed
to warm at room temperature. The solvent was removed by
rotary evaporation and the residue purified by silica gel
flash column chromatography (1–5% EtOAc/hexanes) to
provide stannyl compound 10a–10c as colorless oils.
Figure 2. X-ray crystal structure of naphthostyril 19a.
(E)-4-(Tributylstannyl)but-3-en-2-ol (10a):[21] Colorless
1
oil; yield: 67%; H NMR (300 MHz, CDCl3): d=6.18–5.93
(m, 2H), 4.25–4.18 (m, 1H), 1.49–1.41 (m, 6H), 1.35–1.21
(m, 12H), 1.01–0.85 (m, 12H).
(E)-1-(Tributylstannyl)pent-1-en-3-ol (10b): Colorless oil;
1
yield. 57%; H NMR (300 MHz, CDCl3): d=6.17–5.94 (m,
2H), 4.01–3.98 (m, 1H), 1.61–1.44 (m, 8H), 1.36–1.24 (m,
6H), 0.88–0.83 (m, 18H); 13C NMR (125 MHz, CDCl3): d=
150.8, 127.8, 77.4, 29.8, 29.1 (3), 27.2 (3), 13.6 (3), 9.6 (3),
9.4; HR-MS (EI): m/z=376.1769, calcd. for C17H36OSn
[M+]: 376.1788.
(E)-1-Phenyl-3-(tributylstannyl)prop-2-en-1-ol (10c): Col-
orless oil; yield: 48%, 1H NMR (300 MHz, CDCl3): d=
7.37–7.24 (m, 5H), 6.34–6.11 (m, 2H), 5.18–5.15 (m, 1H),
1.59–1.43 (m, 6H), 1.34–1.22 (m, 6H), 0.95–0.78 (m, 15H);
13C NMR (125 MHz, CDCl3): d=149.5, 142.9, 128.5, 128.4,
127.5, 126.4, 77.6, 29.2, 27.3, 13.7, 9.5; HR-MS (EI): m/z=
424.1809, calcd. for C21H36OSn [M+]: 424.1788.
To a solution stannyl compound 10a–10c (10 mmol) in dry
toluene (40 mL) was added AlMe3 (0.5 mL, 2M in toluene,
0.1 equiv.) via syringe. After stirring for 30 min at room tem-
perature, 3-nitrobenzaldehyde (30 mmol, 3 equiv.) was
added. The resulting mixture was stirred for 1 h, and the sol-
vent was removed under reduced pressure. The residue was
purified by silica gel chromatography (1–3% EtOAc/hex-
anes) to afford b-tributylstannyl a,b-unsaturated ketones
8a–8c as colorless oils.
(E)-4-(Tributylstannyl)but-3-en-2-one (8a):[22] Colorless
1
oil; yield: 84%; H NMR (300 MHz, CDCl3): d=7.55 (d, J=
Scheme 5. Possible reaction pathway.
19.8 Hz, 1H), 6.53 (d, J=19.8 Hz, 1H), 2.27 (s, 3H), 1.57–
1.46 (m, 6H), 1.37–1.25 (m, 6H), 1.01–0.87 (m, 15H).
(E)-1-(Tributylstannyl)pent-1-en-3-one (8b): Colorless oil;
yield: 66%; 1H NMR (300 MHz, CDCl3): d=7.57 (d, J=
19.8 Hz, 1H), 6.55 (d, J=19.8 Hz, 1H), 2.63 (q, J=7.32,
7.35 Hz, 2H), 1.57–1.45 (m, 6H), 1.37–1.25 (m, 6H), 1.11 (q,
J=7.29, 7.26 Hz, 3H), 1.00–0.87 (m, 15H); 13C NMR
(125 MHz, CDCl3): d=199.8, 149.4, 145.4, 32.0, 28.9 (3),
27.2 (3), 13.6 (3), 9.6 (3), 8.1; HR-MS (EI): m/z=374.1628,
calcd. for C17H34OSn [M+]: 374.1632.
Conclusions
In summary, we have developed an efficient approach
for synthesizing naphthostyrils that is based on a se-
quential Stille coupling and proline-catalyzed cycliza-
tion/aromatization process. Notably, we have success-
fully demonstrated the first total synthesis of prioline
(1) in 11 steps (overall 20% yield), with the naphtho-
styril intermediate being confirmed by X-ray crystal-
lography. In particular, two plausible pathways for the
proline-catalyzed cyclization were proposed: a thermal
(E)-1-Phenyl-3-(tributylstannyl)prop-2-en-1-one (8c): Col-
1
orless oil; yield: 63%; H NMR (300 MHz, CDCl3): d=7.92
(d, J=7.0 Hz, 2H), 7.80 (d, J=19.3 Hz, 1H), 7.56 (t, J=7.3,
7.5 Hz, 1H), 7.49 (d, J=7.7 Hz, 2H), 7.30 (d, J=19.4 Hz,
1H), 1.60–1.50 (m, 6H), 1.39–1.27 (m, 6H), 1.05–0.88 (m,
6p-electrocyclic process and a Mannich-type reaction. 15H); 13C NMR (125 MHz, CDCl3): d=189.7, 153.4, 141.4,
Adv. Synth. Catal. 2015, 357, 3197 – 3205
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3201

FULL PAPERS
Kyeong-Yong Park et al.
137.7, 132.5, 128.9 (2), 128.5 (2), 29.0 (3), 27.2 (3), 13.7 (3),
9.81 (3); HR-MS (EI): m/z=422.1618, calcd. for C21H34OSn
[M+]: 422.1632.
(m, 1H), 7.05 (dd, J=8.9, 11.1 Hz, 1H), 6.67 (d, J=16.0 Hz,
1H), 3.63 (s, 2H), 3.44 (d, J=2.7 Hz, 3H), 2.68 (q, J=
7.1 Hz, 2H), 1.17 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=200.2, 173.6, 148.1 (J=246.3 Hz), 137.1, 132.1
(J=8.8 Hz), 127.3 (J=3.8 Hz), 127.1, 126.9 (J=4.5 Hz),
121.6 (J=7.5 Hz), 116.8 (J=20.0 Hz), 35.4, 34.8, 28.6 (J=
6.3 Hz), 8.1; HR-MS (EI): m/z=247.0991, calcd. for
C14H14FNO2 [M+]: 247.1009.
(E)-1-Methyl-4-(3-oxo-3-phenylprop-1-en-1-yl)oxindole
(6g): Pale yellow solid; yield: 50%; mp 1688C; 1H NMR
(300 MHz, CDCl3): d=8.03 (d, J=7.0 Hz, 2H), 7.78 (d, J=
15.7, 1H), 7.64–7.51 (m, 4H), 7.41–7.33 (m, 2H), 6.87 (d, J=
5.8 Hz, 1H), 3.68 (s, 2H), 3.24 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=189.9, 174.3, 145.9, 140.9 (2), 137.9, 133.1, 130.9,
128.7 (2), 128.5 (2), 124.8, 123.9, 121.4, 109.5, 35.3, 26.4;
HR-MS (EI); m/z=277.1104, calcd. for C18H15NO2 [M+]:
277.1103.
Preparation of a,b-Unsaturated Enones (6a–6g)
To a solution of oxindole 7a–7c (0.5 mmol) and b-tributyl-
stannyl a,b-unsaturated ketone 8a–8c (0.6 mmol, 1.2 equiv.)
in toluene (3 mL) was added Pd(PPh3)4 (5 mol%). The reac-
tion vial was sealed and heated at 1508C for 1 h. The solu-
tion was concentrated under reduced pressure and purified
by silica gel flash column chromatography (50% EtOAc/
hexanes) to afford a,b-unsaturated enones 6a–6g.
(E)-1-Methyl-4-(3-oxobut-1-en-1-yl)oxindole (6a): Pale
brown solid; yield: 93%; mp 1428C; 1H NMR (300 MHz,
CDCl3): d=7.48 (d, J=16.0 Hz, 1H), 7.34 (t, J=7.8 Hz,
1H), 7.27 (d, J=7.0 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 6.71
(d, J=16.3 Hz, 1H), 3.62 (s, 2H), 3.23 (s, 3H), 2.40 (s, 3H);
13C NMR (125 MHz, CDCl3): d=197.9, 174.1, 145.8, 139.3,
130.5, 128.8, 128.5, 124.6, 121.1, 109.4, 35.1, 28.1, 26.3; HR-
MS (EI): m/z=215.0946, calcd. for C13H13NO2 [M+]:
215.0946.
(E)-1-Methyl-4-(3-oxopent-1-en-1-yl)oxindole (6b): Pale
brown solid; yield; 92%; mp 1508C; 1H NMR (300 MHz,
CDCl3): d=7.52 (d, J=16.0 Hz, 1H), 7.33 (t, J=7.8 Hz,
1H), 7.28 (d, J=6.0 Hz, 1H), 6.84 (d, J=7.1 Hz, 1H), 6.74
(d, J=16.4 Hz, 1H), 3.61 (s, 2H), 3.23 (s, 3H), 2.70 (q, J=
7.2 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=200.5, 174.2, 145.8, 138.2, 130.6, 128.5, 127.6,
124.6, 121.0, 109.3, 35.1, 34.7, 23.3, 8.1; HR-MS (EI): m/z=
229.1096, calcd. for C14H15NO2 [M+]: 229.1103.
Preparation of Naphthosytrils (5a–5g)
A nitrogen-flushed glass vial (20 mL) was charged with 4 Š
molecular sieves (200 mg). The vial was flame-dried for
10 min under high vacuum. After cooling to room tempera-
ture, the vial was charged with a,b-unsaturated enone 6a–6g
(0.3 mmol), trans-4-hydroxy-l-proline L5 (0.06 mmol,
0.2 equiv.), benzoic acid (0.3 mmol, 1 equiv.) in an argon-
charged dry-box, and then the mixture was dissolved in dry
toluene (12 mL). The reaction vessel was sealed and the
mixture heated at 1808C. After 24 h, the mixture was cooled
to room temperature, filtered through a Celite pad. The so-
lution was concentrated under reduced pressure and puri-
fied by silica gel flash column chromatography (30%
EtOAc/hexanes) to afford naphthostyrils 5a–5g.
1,3-Dimethylbenzo[cd]indol-2(1H)-one (5a): Yellow solid;
yield: 81%; mp 1108C; 1H NMR (300 MHz, CDCl3): d=
7.87 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.43 (d, J=
6.8 Hz, 1H), 7.40 (d, J=7.0 Hz, 1H), 6.88 (d, J=6.9 Hz,
1H), 3.44 (s, 3H), 2.84 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=168.6, 139.3, 131.8, 130.3, 127.4, 127.3, 125.0,
123.2, 120.0, 119.9, 104.1, 26.1, 17.6; HR-MS (EI): m/z=
197.0836, calcd. for C13H11NO [M+]: 197.0841.
(E)-1,5-Dimethyl-4-(3-oxobut-1-en-1-yl)oxindole
(6c):
Pale brown solid; yield: 92%; mp 1668C; 1H NMR
(300 MHz, CDCl3): d=7.71 (d, J=16.0 Hz, 1H), 7.17 (d, J=
7.9 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.52 (d, J=16.5 Hz,
1H), 3.59 (s, 2H), 3.21 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H);
13C NMR (125 MHz, CDCl3): d=197.9, 174.2, 143.8, 139.2,
131.9, 130.8, 130.1 (2), 123.4, 109.1, 36.7, 28.1, 26.2, 20.1;
HR-MS (EI): m/z=229.1100, calcd. for C14H15NO2 [M+]:
229.1103.
(E)-1,5-Dimethyl-4-(3-oxopent-1-en-1-yl)oxindole
(6d):
Pale brown solid; yield: 94%; mp 1558C; 1H NMR
(300 MHz, CDCl3): d=7.75 (d, J=16.0 Hz, 1H), 7.17 (d, J=
7.9 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 6.54 (d, J=16.4 Hz,
1H), 3.59 (s, 2H), 3.21 (s, 3H), 2.69 (q, J=7.2 Hz, 2H), 2.41
(s, 3H), 1.18 (t, J=7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=200.5, 174.3, 143.8, 138.1, 132.0, 130.3, 130.0,
129.6, 123.3, 109.0, 36.7, 34.9, 26.2, 20.1, 8.1; HR-MS (EI):
m/z=243.1258, calcd. for C15H17NO2 [M+]: 243.1259.
(E)-7-Fluoro-1-methyl-4-(3-oxobut-1-en-1-yl)oxindole
(6e): Pale brown solid; yield: 72%; mp 1808C; 1H NMR
(300 MHz, CDCl3): d=7.42 (d, J=16.0 Hz, 1H), 7.27–7.20
(m, 1H), 7.07 (t, J=10.1 Hz, 1H), 6.65 (d, J=16.2 Hz, 1H),
3.64 (s, 2H), 3.44 (d, J=2.8 Hz, 3H), 2.38 (s, 3H); 13C NMR
(125 MHz, CDCl3): d=197.7, 173.5, 148.3 (J=246.4 Hz),
138.2, 132.2 (J=9.0 Hz), 128.2, 127.3 (J=4.3 Hz), 126.8 (J=
3.3 Hz), 121.7 (J=6.7 Hz), 116.8 (J=20.1 Hz), 35.4, 28.6 (J=
5.9 Hz), 28.2; HR-MS (EI): m/z=233.0847, calcd. for
C13H12FNO2 [M+]: 233.0852.
3-Ethyl-1-methylbenzo[cd]indol-2(1H)-one (5b): Yellow
solid; yield: 85%; mp 988C; 1H NMR (300 MHz, CDCl3):
d=7.90 (t, J=8.0 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.42 (d,
J=6.8 Hz, 1H), 7.39 (d, J=6.8 Hz, 1H), 6.87 (d, J=6.8 Hz,
1H), 3.43 (s, 3H), 3.26 (q, J=7.6 Hz, 2H), 1.36 (t, J=
7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=168.4, 145.8,
139.4, 130.7, 130.2, 127.4, 127.3, 125.1, 122.5, 119.9, 104.4,
26.1, 24.7, 15.1; HR-MS (EI): m/z=211.0989, calcd. for
C14H13NO [M+]: 211.0997.
1,3,6-Trimethylbenzo[cd]indol-2(1H)-one (5c): Yellow
solid; yield: 89%; mp 878C; 1H NMR (300 MHz, CDCl3):
d=7.92 (d, J=9.0 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.15 (d,
J=7.1 Hz, 1H), 6.73 (d, J=7.1 Hz, 1H), 3.39 (s, 3H), 2.82
(s, 3H), 2.62 (s, 3H); 13C NMR (125 MHz, CDCl3); d=
168.6, 138.9, 137.5, 131.3, 128.4, 127.8, 127.2, 126.7, 125.2,
123.5, 104.5, 26.0, 17.5 (2); HR-MS (EI): m/z=211.1004,
calcd. for C14H13NO [M+]: 211.0997.
3-Ethyl-1,6-dimethylbenzo[cd]indol-2(1H)-one
(5d):
(E)-7-Fluoro-1-methyl-4-(3-oxopent-1-en-1-yl)oxindole
(6f): Pale brown solid; yield: 81%; mp 1618C; 1H NMR
(300 MHz, CDCl3): d=7.46 (d, J=16.0 Hz, 1H), 7.24–7.20
Yellow solid; yield: 91%; mp 1168C; 1H NMR (300 MHz,
CDCl3): d=7.98 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H),
7.16 (d, J=7.1 Hz, 1H), 6.74 (d, J=7.1 Hz, 1H), 3.41 (s,
3202
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3197 – 3205

FULL PAPERS
Proline-Catalyzed Cyclization Reaction for the Synthesis of Naphthostyrils
1
3H), 3.26 (q, J=7.6 Hz, 2H), 2.63 (s, 3H), 1.36 (t, J=
7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=168.4, 145.4,
137.7, 129.8, 128.4, 128.2, 127.4, 126.7, 125.4, 122.8, 104.5,
26.1, 24.6, 17.5, 15.2; HR-MS (EI): m/z=225.1158, calcd. for
C15H15NO [M+]: 225.1154.
yield: 6.08 g (84%). H NMR (300 MHz, CDCl3): d=10.97
(s, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H),
3.45–3.36 (m, 1H), 1.26 (d, J=6.9 Hz, 6H); 13C NMR
(125 MHz, CDCl3): d=152.1, 141.9, 136.9, 133.9, 124.5,
111.5, 27.1, 22.1 (2); MS (EI): m/z=260 (M+ +2, 72), 258
(M+, 73), 245 (90), 243 (98), 197 (99), 195 (100), 146 (99).
8-Fluoro-1,3-dimethylbenzo[cd]indol-2(1H)-one
(5e):
Yellow solid; yield: 78%; mp 1548C; 1H NMR (300 MHz,
CDCl3): d=7.85 (d, J=8.0 Hz, 1H), 7.47–7.41 (m, 2H),
7.23–7.16 (m, 1H), 3.60 (d, J=1.0 Hz, 3H), 2.84 (s, 3H);
13C NMR (125 MHz, CDCl3): d=168.0, 143.7 (J=247.4 Hz),
140.6, 131.0, 130.2, 127.2 (J=7.7 Hz), 124.4, 122.8 (J=
5.4 Hz), 122.3 (J=8.2 Hz), 121.9 (J=6.7 Hz), 118.8 (J=
23.8 Hz), 28.2 (J=2.8 Hz), 17.5; HR-MS (EI): m/z=
215.0754, calcd. for C13H10FNO [M+]: 215.0746.
3-Ethyl-8-fluoro-1-methylbenzo[cd]indol-2(1H)-one (5f):
Yellow solid; yield: 83%; mp 928C; 1H NMR (300 MHz,
CDCl3): d=7.90 (d, J=8.0 Hz, 1H), 7.51–7.44 (m, 2H), 7.20
(dd, J=9.1, 11.2 Hz, 1H), 3.61 (d, J=1.2 Hz, 3H), 3.27 (q,
J=7.6 Hz, 2H), 1.36 (t, J=7.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=167.6, 147.1, 143.6 (J=247.5 Hz),
130.6, 129.4, 127.2 (J=7.5 Hz, 1H), 124.5, 122.3 (J=8.7 Hz),
122.1 (J=5.0 Hz), 121.89 (J=6.2 Hz), 118.8 (J=23.7 Hz),
28.2, 24.6, 15.1; HR-MS (EI): m/z=229.0883, calcd. for
C14H12FNO [M+]: 229.0903.
1-Methyl-3-phenylbenzo[cd]indol-2(1H)-one (5g): Yellow
solid; yield: 15%; mp 858C; 1H NMR (300 MHz, CDCl3):
d=8.04 (d, J=8.0 Hz, 1H), 7.85 (d, J=6.6 Hz, 2H), 7.75 (d,
J=8.3 Hz, 1H), 7.55–7.42 (m, 5H), 6.92 (d, J=6.8 Hz, 1H),
3.43 (s, 3H); 13C NMR (125 MHz, CDCl3): d=167.6, 141.5,
139.8, 136.8, 130.9 (2), 129.7 (2), 128.7, 128.2 (2), 128.1,
125.6, 121.8, 120.0, 119.9, 104.6, 26.2; HR-MS (EI): m/z=
259.0962, calcd. for C18H13NO [M+]: 259.0997.
5-Bromo-3-isopropyl-2-methoxyaniline (13)
To a solution of nitrophenol 12 (5.98 g, 23 mmol) in DMF
(100 mL) was added K2CO3 (4.77 g, 34.5 mmol, 1.5 equiv.).
After stirring for 10 min, iodomethane (9.79 g, 69 mmol,
3 equiv.) was added. The resulting mixture was heated at
808C for 2 h, and the solvent was removed under reduced
pressure. The residue was diluted with H2O and extracted
with EtOAc. The organic layer was washed with brine, dried
over MgSO4, and concentrated under vacuum. The residue
was purified by silica gel chromatography to afford 5-
bromo-1-isopropyl-2-methoxy-3-nitrobenzene as a clear col-
1
orless oil; yield: 6.19 g (98%). H NMR (300 MHz, CDCl3):
d=7.77 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 3.88 (s,
3H), 3.41–3.32 (m, 1H), 1.25 (d, J=6.9 Hz, 6H); 13C NMR
(125 MHz, CDCl3): d=149.9, 147.2, 144.5, 134.4, 125.4,
116.4, 63.1, 26.8, 23.3 (2); MS (EI): m/z=275 (M+ +2, 70),
273 (M+, 72), 260 (24), 258 (33), 230 (22), 228 (34), 147
(100).
To a solution of 5-bromo-1-isopropyl-2-methoxy-3-nitro-
benzene (6.03 g, 22 mmol) in THF/H2O (1:1, 120 mL) were
added NH4Cl (4.71 g, 88 mmol, 4 equiv.) and Fe (4.91 g,
88 mmol, 4 equiv.). The resulting mixture heated at 808C for
5 h and cooled to room temperature and filtered through
a Celite pad. The filtrate was removed under reduced pres-
sure and the resulting mixture extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4,
and concentrated under vacuum. The residue was purified
by silica gel chromatography to afford 2-methoxyaniline 13
4-Bromo-2-isopropyl-6-nitrophenol (12)
1
To a solution 2-isopropylphenol 11 (4.08 g, 30 mmol) in
chloroform (200 mL) was added tetra n-butyl ammonium
tribromide (17.36 g, 36 mmol, 1.0 equiv.) at room tempera-
ture. The resulting mixture was stirred for 3 h and then the
solvent was removed by rotary evaporation. The crude prod-
uct was partitioned between ether and water. The organic
layer was washed with H2O and brine, then dried over
MgSO4. The solution was evaporated and purified by silica
gel flash column chromatography to afford 4-bromo-2-iso-
propylphenol as a clear colorless oil; yield: 6.29 g (97%).
1H NMR (300 MHz, CDCl3): d=7.27 (d, J=2.0 Hz, 1H),
7.15 (dd, J=2.5, 8.5 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.88
(s, 1H), 3.21–3.11 (m, 1H), 1.23 (d, J=7.0 Hz, 6H);
13C NMR (125 MHz, CDCl3): d=151.8, 136.9, 129.4, 129.3,
116.9, 113.1, 27.1, 22.3 (2); MS (EI): m/z=215 (M+ +2, 40),
213 (M+, 42), 200 (82), 198 (87), 120 (10), 102 (22), 91 (21).
as a red oil; yield: 5.3 g (98%). H NMR (300 MHz, CDCl3):
d=6.73 (d, J=2.0 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 3.81 (s,
2H), 3.71 (s, 3H), 3.29–3.20 (m, 1H), 1.19 (d, J=6.9 Hz,
6H); 13C NMR (125 MHz, CDCl3): d=143.8, 143.4, 141.2,
118.9, 117.6, 115.9, 60.1, 26.4, 23.6 (2); MS (EI): m/z=245
(M+ +2, 34), 243 (M+, 35), 230 (42), 228 (43), 215 (4), 213
(4), 149 (100).
(E)-N-(5-Bromo-3-isopropyl-2-methoxyphenyl)-2-
(hydroxyimino)acetamide (14)
To
a solution of chloral hydrate (4.17 g, 25.2 mmol,
1.2 equiv.) in water (90 mL) and EtOH (30 mL) were added
Na2SO4 (32.51 g, 178.5 mmol, 8.5 equiv.), 2-methoxyaniline
13 (5.12 g, 21 mmol) and 37% HCl (1.4 mL) solution. After
5 min, hydroxylamine sulfate (5.17 g, 31.5 mmol, 1.5 equiv.)
was added to the mixture solution. The resulting mixture
was heated at 1008C for 2 h and then allowed to cool to
room temperature. EtOH was removed under reduced pres-
sure and the residue was extracted with EtOAc. The organic
layers were washed with brine, dried over Na2SO4, and con-
centrated under vacuum. The residue was purified by silica
gel column chromatography to afford 2-(hydroxylimino)ace-
tamide 14 as a pale red solid; yield: 4.2 g (63%); mp 1608C;
1H NMR (300 MHz, CDCl3): d=8.87 (s, 1H), 8.39 (d, J=
2.0 Hz, 1H), 8.34 (s, 1H), 7.60 (s, 1H), 7.12 (d, J=2.4 Hz,
1H), 3.75 (s, 3H), 3.30–3.21 (m, 1H), 1.22 (d, J=6.9 Hz,
To
a mixture of 4-bromo-2-isopropylphenol (6.02 g,
28 mmol) and sodium nitrite (6.18 g, 89.6 mmol, 3.2 equiv.)
in n-hexane (45 mL), isopropyl ether (20 mL) and water
(30 mL) was added 4.5N sulfuric acid (65 mL) dropwise
over 10 min. The mixture was stirred at room temperature
for 2 h and quenched with saturated aqueous sodium bicar-
bonate. The resulting two phases were separated and the or-
ganic layer was washed brine, and dried over anhydrous
sodium sulfate, and concentrated under vacuum. The resi-
due was purified by silica gel chromatography to afford 4-
bromo-2-isopropyl-6-nitrophenol 12 as a clear yellow oil;
Adv. Synth. Catal. 2015, 357, 3197 – 3205
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3203

FULL PAPERS
Kyeong-Yong Park et al.
6H); 13C NMR (125 MHz, CDCl3): d=159.5, 145.3, 145.1,
143.3, 131.6, 125.2, 120.8, 118.0, 61.7, 26.6, 23.5 (2); HR-MS
(EI); m/z=314.0273, calcd. for C12H15BrN2O3 [M+]:
314.0266.
158.8, 145.2, 141.5, 136.9, 129.5, 128.5 (2), 124.4, 123.3, 114.2,
113.9 (2), 63.1, 55.2, 44.6, 37.3, 26.2, 23.9 (2); HR-MS (EI):
m/z=403.0776, calcd. for C20H22BrNO3 [M+]: 403.0783.
(E)-6-Isopropyl-7-methoxy-1-(4-methoxybenzyl)-4-(3-
oxobut-1-enyl)indolin-2-one (18a)
4-Bromo-6-isopropyl-7-methoxyindoline-2,3-dione
(15)
To a thick-well glass vial (20 mL) was added oxindole 17
(202 mg, 0.5 mmol), (E)-4-(tributylstannyl)but-3-en-2-one
(8a) (215 mg, 0.6 mmol, 1.2 equiv.), and Pd(PPh3)4 (29 mg,
5 mol%) in toluene (3 mL). The reaction vial was sealed
and heated at 1508C for 1 h. After being cooled to room
temperature, the mixture was diluted with EtOAc and fil-
tered through a short Celite pad. The solution was concen-
trated under reduced pressure and purified by silica gel
chromatography to afford (3-oxobut-1-en-1-yl)indolin-2-one
18a as a pale brown solid; yield: 163 mg (83%); mp 1188C.
1H NMR (300 MHz, CDCl3): d=7.43 (d, J=16.0 Hz, 1H),
7.28 (d, J=6.0 Hz, 2H), 7.16 (s, 1H), 6.82 (d, J=8.7 Hz,
2H), 6.64 (d, J=16.3 Hz, 1H), 5.10 (s, 2H), 3.76 (s, 3H),
3.64 (s, 2H), 3.54 (s, 3H), 3.33–3.24 (m, 1H), 2.39 (s, 3H),
1.24 (d, J=6.8 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=
198.0, 175.1, 158.8, 143.8, 143.7, 139.5, 136.5, 129.6, 128.5 (2),
127.7, 126.6, 124.2, 119.6, 113.8 (2), 63.1, 55.2, 44.6, 35.2,
27.9, 26.1, 24.0 (2); HR-MS (EI): m/z=393.1936, calcd. for
C24H27NO4 [M+]: 393.1940.
Isonitrosoacetanilide 14 (4.1 g, 13 mmol) was added to rap-
idly stirred concentrated sulfuric acid (30 mL). The resulting
solution was stirred at 508C for 1 h and allowed to cool to
room temperature. The cooled mixture was poured carefully
onto crushed ice and the residue was extracted with EtOAc.
The organic layers were washed with NaHCO3 and brine,
dried over Na2SO4, and concentrated under vacuum. The
residue was purified by silica gel column chromatography to
afford methoxyindoline-2,3-dione 15 as an orange solid;
1
yield: 3.5 g (90%); mp 2138C. H NMR (300 MHz, CDCl3):
d=8.47 (s, 1H), 7.09 (s, 1H), 3.83 (s, 3H), 3.36–3.27 (m,
1H), 1.25 (d, J=6.8 Hz, 6H); 13C NMR (125 MHz, CDCl3):
d=179.7, 158.6, 155.4, 143.7, 141.5, 126.1, 116.4, 115.7, 61.9,
27.5, 22.9 (2); HR-MS (EI): m/z=296.9992, calcd. for
C12H12BrNO3 [M+]: 297.0001.
4-Bromo-6-isopropyl-7-methoxy-1-(4-methoxybenzyl)
indoline-2,3-dione (16)
(E)-6-Isopropyl-7-methoxy-1-(4-methoxybenzyl)-4-(3-oxo-
pent-1-yl)indolin-2-one (18b): Pale brown solid; yield: 84%;
mp 1168C; 1H NMR (300 MHz, CDCl3): d=7.48 (d, J=
16.0 Hz, 1H), 7.27 (d, J=7.0 Hz, 2H), 7.16 (s, 1H), 6.82 (d,
J=9.0 Hz, 2H), 6.65 (d, J=16.0 Hz, 1H), 5.10 (s, 2H), 3.76
(s, 3H), 3.64 (s, 2H), 3.54 (s, 3H), 3.33–3.24 (m, 1H), 2.70
(q, J=7.3 Hz, 2H), 1.24 (d, J=7.0 Hz, 6H), 1.17 (t, J=
7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=200.6, 175.1,
158.8, 143.8, 143.7, 138.4, 136.4, 129.6, 128.5 (2), 126.8, 126.6,
124.2, 119.6, 113.8 (2), 63.1, 55.2, 44.6, 35.3, 34.5, 26.1, 24.0
(2), 8.2; HR-MS (EI): m/z=407.2154, calcd. for C25H29NO4
[M+]: 407.2097.
A
solution of methoxyindoline-2,3-dione 15 (3.28 g,
11 mmol) in DMF (120 mL) at 08C were added K2CO3
(1.82 g, 13.2 mmol, 1.2 equiv.) and KI (0.37 g, 2.2 mmol,
0.2 equiv.). After stirring for 1 h at 08C, p-methoxybenzyl
chloride (1.64 mL, 12.1 mmol, 1.1 equiv.) was added slowly.
The resulting mixture was heated at 1008C for 2 h, and the
solvent was removed under reduced pressure. The residue
was treated with aqueous 1N HCl and extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and concentrated under vacuum. The residue was
purified by silica gel chromatography to afford (4-methoxy-
benzyl)indoline-2,3-dione 16 as an orange solid; yield: 4.3 g
1
(93%); mp 1548C. H NMR (300 MHz, CDCl3): d=7.28 (d,
J=9.0 Hz, 2H), 7.08 (s, 1H), 6.83 (d, J=8.7 Hz, 2H), 5.08
(s, 2H), 3.76 (s, 3H), 3.58 (s, 3H), 3.34–3.25 (m, 1H), 1.23
(d, J=6.8 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=180.2,
159.2, 158.9, 156.6, 144.1, 142.5, 128.9 (2), 128.2, 126.8, 116.9,
116.4, 114.0 (2), 63.1, 55.2, 45.1, 27.2, 23.2 (2); HR-MS (EI):
m/z=417.0599, calcd. for C20H20BrNO4 [M+]: 417.0576.
7-Isopropyl-8-methoxy-1-(4-methoxybenzyl)-3-
methylbenzo[cd]indol-2(1H)-one (19a)
The reaction was performed on 118 mg (0.3 mmol) of 18a,
following the standard procedure described for the synthesis
of naphthostyrils 5a–f. The product was purified by silica gel
flash column chromatography (15% EtOAc/hexanes) to
afford methylbenzo[cd]indol-2(1H)-one 19a as a yellow
4-Bromo-6-isopropyl-7-methoxy-1-(4-
methoxybenzyl)oxindole (17)
1
solid; yield: 88 mg (78%); mp 1108C. H NMR (300 MHz,
CDCl3): d=7.80 (d, J=8.0 Hz, 1H), 7.39 (d, J=7.6 Hz, 2H),
7.35 (d, J=8.7 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 5.26 (s,
2H), 3.74 (s, 3H), 3.63 (s, 3H), 3.42–3.33 (m, 1H), 2.84 (s,
3H), 1.32 (d, J=7.0 Hz, 6H); 13C NMR (125 MHz, CDCl3):
d=168.9, 158.7, 145.6, 140.2, 138.9, 130.7, 130.5, 129.8, 128.6
(2), 127.4, 125.9, 125.0, 122.3, 118.0, 113.8 (2), 63.4, 55.2,
44.3, 26.9, 24.4 (2), 17.5; HR-MS (EI): m/z=375.1826, calcd.
for C24H25NO3 [M+]: 375.1834.
To a solution of indoline-2,3-dione 16 (4.18 g, 10 mmol) in
ethanol (144 mL) was added hydrazine hydrate (98%,
36 mL). It was stirred for 24 h at 908C. After completion of
the reaction, the reaction solution was concentrated. The
residue was diluted with H2O and extracted with ethyl ace-
tate. The organic layer was washed with brine, dried over
Na2SO4, and concentrated under vacuum. The residue was
purified by silica gel chromatography to afford indolin-2-
one 17 as a pale yellow solid; yield: 3.52 g (87%); mp
3-Ethyl-7-isopropyl-8-methoxy-1-(4-methoxybenzyl)ben-
zo[cd]indol-2(1H)-one (19b): Yellow solid; yield: 88%; mp
1
1
1238C; H NMR (300 MHz, CDCl3): d=7.26 (d, J=9.0 Hz,
1318C; H NMR (300 MHz, CDCl3): d=7.84 (d, J=8.0 Hz,
2H), 7.02 (s, 1H), 6.82 (d, J=8.7 Hz, 2H), 5.06 (s, 2H), 3.76
(s, 3H), 3.51 (s, 3H), 3.48 (s, 2H), 3.30–3.21 (m, 1H), 1.21
(d, J=6.8 Hz, 6H); 13C NMR (125 MHz, CDCl3): d=174.6,
1H), 7.45 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.36 (d, J=
9.0 Hz, 2H), 6.81 (d, J=9.0 Hz, 2H), 5.25 (s, 2H), 3.74 (s,
3H), 3.64 (s, 3H), 3.43–3.34 (m, 1H), 3.27 (q, J=7.6 Hz,
3204
asc.wiley-vch.de
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 3197 – 3205

FULL PAPERS
Proline-Catalyzed Cyclization Reaction for the Synthesis of Naphthostyrils
2H), 1.38–1.31 (m, 9H); 13C NMR (125 MHz, CDCl3): d=
168.6, 158.7, 145.7, 145.4, 140.2, 130.6, 130.1, 129.1, 128.6 (2),
127.5, 125.9, 125.1, 121.6, 118.0, 113.8 (2), 63.4, 55.2, 44.3,
26.9, 24.6, 24.4 (2), 15.2; HR-MS (EI): m/z=389.1987, calcd.
for C25H27NO3 [M+]: 389.1991.
[6] J.-J. Liu, A. Dermatakis, C. Lukacs, F. Konzelmann, Y.
Chen, U. Kammlott, W. Depinto, H. Yang, X. Yin, Y.
Chen, A. Schutt, M. E. Simcox, K.-C. Luk, Bioorg.
Med. Chem. Lett. 2003, 13, 2465.
[7] a) C. C. Hughes, J. B. MacMillan, S. P. GaudÞncio, P. R.
Jensen, W. Fenical, Angew. Chem. 2009, 121, 739;
Angew. Chem. Int. Ed. 2009, 48, 725; b) C. C. Hughes,
J. B. MacMillan, S. P. GaudÞncio, P. R. Jensen, W. Feni-
cal, J. J. La Clair, Angew. Chem. 2009, 121, 742; Angew.
Chem. Int. Ed. 2009, 48, 728.
[8] T. K. Tabopda, J. Ngoupayo, J. Liu, A.-C. Mitaine-
Offer, S. A. K. Tanoli, S. N. Khan, M. S. Ali, B. T. Ngad-
jui, E. Tsamo, M.-A. Lacaille-Dubois, B. Luu, Phyto-
chemistry 2008, 69, 1726.
[9] a) G. Marzoni, M. D. Varney, Org. Process Res. Dev.
1997, 1, 81; b) A. A. Gryshchenko, K. V. Levchenko,
V. G. Bdzhola, T. P. Ruban, L. L. Lukash, S. M. Yarmo-
luk, J. Enzyme Inhib. Med. Chem. 2014, 1475; c) V. L.
Plakidin, V. N. Vostrova, P. P. Gnatyuk, N. M. Zador-
ozhnyi, Zh. Org. Khim. 1977, 13, 2194.
8-Hydroxy-7-isopropyl-3-methylbenzo[cd]indol-
2(1H)-one (Prioline, 1)
To
a solution of methylbenzo[cd]indol-2(1H)-one 19a
(150.2 mg, 0.4 mmol) in acetic acid (3 mL) was added HBr
(48% in H2O, 6 mL). The reaction mixture was stirred at
1208C for 3 h. The reaction mixture was cooled to room
temperature and diluted with dichloromethane, washed with
brine, dried over Na2SO4, and concentrated under vacuum.
The crude material was purified by flash column chromatog-
raphy (25% EtOAc/dichloromethane) to afford prioline
1
1 as a yellow solid; yield: 85 mg (88%); mp 2328C. H NMR
(300 MHz, CDCl3); d=10.89 (s, 1H), 10.11 (s, 1H), 7.75 (d,
J=8.0 Hz, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 3.49–3.40 (m,
1H), 2.84 (s, 3H), 1.34 (d, J=6.8 Hz, 6H); 13C NMR
(125 MHz, CDCl3): d=170.5, 141.7, 139.8, 139.5, 130.8,
128.6, 126.8, 123.0, 121.1, 118.6, 117.3, 28.4, 22.6 (2), 18.3;
HR-MS (EI): m/z=241.1098, calcd. for C15H15NO2 [M+]:
241.1103.
[10] a) J.-J. Liu, F. Konzelmann, K.-C. Luk, Tetrahedron
Lett. 2003, 44, 2545; b) J.-J. Liu, F. Konzelmann, K.-C.
Luk, Tetrahedron Lett. 2003, 44, 3901.
[11] T. Lee, S. Kim, Tetrahedron: Asymmetry 2003, 14, 1951.
[12] C. R. Graves, B. S. Zeng, S. T. Nguyen, J. Am. Chem.
Soc. 2006, 128, 12596.
[13] T. D. Michels, J. U. Rhee, C. D. Vanderwal, Org. Lett.
Acknowledgements
2008, 10, 4787.
[14] K. Miura, D. Wang, Y. Matsumoto, A. Hosomi, Org.
Lett. 2005, 7, 503.
We thank KRICT for financial support.
[15] a) K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J.
Am. Chem. Soc. 2001, 123, 5260; b) Q. Pan, B. Zou, D.
Ma, Org. Lett. 2004, 6, 1009.
[16] A. B. Williams, P. T. Weiser, R. N. Hanson, J. R. Gunth-
er, J. A. Katzenellenbogen, Org. Lett. 2009, 11, 5370.
[17] a) S. J. Garden, J. C. Torres, A. A. Ferreira, R. B. Silva,
A. C. Pinto, Tetrahedron Lett. 1997, 38, 1501; b) T. Lei,
J.-H. Dou, Z.-J. Ma, C.-H. Yao, C.-J. Liu, J.-Y. Wang, J.
Pei, J. Am. Chem. Soc. 2012, 134, 20025.
References
[1] For selected reviews, see; a) B. List, Acc. Chem. Res.
2004, 37, 548; b) W. Notz, F. Tanaka, C. F. Barbas III,
Acc. Chem. Res. 2004, 37, 580; c) M. J. Gaunt, C. C. C.
Johansson, A. McNally, N. T. Vo, Drug Discovery
Today 2007, 12, 8; d) D. W. C. MacMillan, Nature 2008,
455, 304; e) V. Bisai, A. Bisai, V. K. Singh, Tetrahedron
2012, 68, 4541.
[18] T. Kosuge, H. Ishida, A. Inaba, H. Nukaya, Chem.
Pharm. Bull. 1985, 33, 1414.
[2] a) S. R. S. Rudrangi, V. K. Bontha, V. R. Manda, S.
Bethi, Asian. J. Res. Chem. 2011, 4, 335; b) A. Mille-
maggi, R. J. K. Taylor, Eur. J. Org. Chem. 2010, 4527.
[3] a) J. K. Kim, Y. H. Kim, H. T. Nam, B. T. Kim, J.-N.
Heo, Org. Lett. 2008, 10, 3543; b) Y. H. Kim, H. Lee,
Y. J. Kim, B. T. Kim, J.-N. Heo, J. Org. Chem. 2008, 73,
495; c) Y. L. Choi, C.-M. Yu, B. T. Kim, J.-N. Heo, J.
Org. Chem. 2009, 74, 3948; d) Y.-H. Goh, G. Kim, B. T.
Kim, J.-N. Heo, Heterocycles 2010, 80, 669; e) Y. L.
Choi, H. Lee, B. T. Kim, K. Choi, J.-N. Heo, Adv.
Synth. Catal. 2010, 352, 2041; f) Y. L. Choi, H. S. Lim,
H. J. Lim, J.-N. Heo, Org. Lett. 2012, 14, 5102; g) H. S.
Lim, Y. L. Choi, J.-N. Heo, Org. Lett. 2013, 15, 4718;
h) K.-Y. Park, B. T. Kim, J.-N. Heo, Eur. J. Org. Chem.
2014, 164.
[19] Crystallographic data (excluding structure factors) for
the structure 19a reported in this paper have been de-
posited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC
1058959. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[20] a) E. E. Maciver, S. Thompson, M. D. Smith, Angew.
Chem. 2009, 121, 10164; Angew. Chem. Int. Ed. 2009,
48, 9979; b) M. D. Pierce, R. C. Johnston, S. Mahapatra,
H. Yang, R. G. Carter, P. H.-Y. Cheong, J. Am. Chem.
Soc. 2012, 134, 13625; c) L. Bianchi, C. Dell’Erba, M.
Maccagno, G. Petrillo, E. Rizzato, F. Sancassan, E.
Severi, C. Tavani, J. Org. Chem. 2005, 70, 8734.
[21] A. Darwish, A. Lang, T. Kim, J. M. Chong, Org. Lett.
2008, 10, 861.
[4] M. Li, J.-S. Zhang, Y.-M. Ye, J.-N. Fang, J. Nat. Prod.
2000, 63, 139.
[22] C. R. Johnson, J. F. Kadow, J. Org. Chem. 1987, 52,
1493.
[5] Y.-B. Wu, Z.-Y. Ni, Q.-W. Shi, M. Dong, H. Kiyota, Y.-
C. Gu, B. Cong, Chem. Rev. 2012, 112, 5967.
Adv. Synth. Catal. 2015, 357, 3197 – 3205
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3205