Triflic acid-promoted cycloisomerization of 2-alkynylphenyl isothiocyanates and isocyanates: A novel synthetic method for a variety of indole derivatives

Article abstract of DOI:10.1039/c4ob00825a

A new approach towards the synthesis of indole derivatives via triflic acid-promoted cycloisomerization with rearrangement of 2-(alkyn-1-yl)phenyl isothiocyanates and 2-(alkyn-1-yl)phenyl isocyanates has been achieved. By this methodology, structurally di

Full text of DOI:10.1039/c4ob00825a

Volume 12 Number 42 14 November 2014 Pages 8356–8563
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
ISSN 1477-0520
PAPER
Takao Saito, Takashi Otani et al.
Triflic acid-promoted cycloisomerization of 2-alkynylphenyl
isothiocyanates and isocyanates: a novel synthetic method for a
variety of indole derivatives

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Triflic acid-promoted cycloisomerization of
2-alkynylphenyl isothiocyanates and isocyanates:
a novel synthetic method for a variety of
indole derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 8398
Takao Saito,*a Yoshihiko Sonoki,a Takashi Otani*a and Noriki Kutsumuraa,b
Received 22nd April 2014,
Accepted 19th June 2014
A new approach towards the synthesis of indole derivatives via triflic acid-promoted cycloisomerization
with rearrangement of 2-(alkyn-1-yl)phenyl isothiocyanates and 2-(alkyn-1-yl)phenyl isocyanates has
been achieved. By this methodology, structurally diverse types of indole derivatives such as thieno- and
furo-indoles, spiro-indolethiones, spiro-oxindoles, and 3-alkylidene-oxindoles were synthesized.
DOI: 10.1039/c4ob00825a
www.rsc.org/obc
1. Introduction
The indole ring system is probably the most important and
common heterocyclic core found in nature and in many bio-
logically active compounds and pharmaceuticals,1 and various
synthetic methods for producing structurally diverse indole
derivatives have been developed.2–4 By contrast, functionalized
heterocumulenes such as carbodiimides, isocyanates, isothio-
cyanates, and ketenimines are useful synthetic building blocks
for nitrogen-containing heterocycles, because they often take
part in a variety of synthetic transformations with high reactiv-
ity, especially in ring-forming reactions, by incorporating both
the heterocumulene moiety and other available functional
group(s) in the molecule.5 In this context, we recently reported
In(III)-promoted cycloaddition of 2-(alkyn-1-yl)phenyl isothio-
cyanates with arenes at 150 °C giving 4-aryl- or 4-arylthio-
quinoline-2-thiones, which were involved in the tandem regio-
selective Friedel–Crafts-type alkenylation–6π-electrocyclization
mode process (Scheme 1-(a)).6 Triflic acid (TfOH) was also
found to efficiently accelerate the same reaction even at a
lower temperature of 0 °C to produce 4-arylquinoline-2-
Scheme 1 In(III)- and triflic acid-promoted Friedel–Crafts-type reaction
of alkynyl isothiocyanates to produce quinolinethiones and indolethiones.
thiones.7
Alternatively,
3-(arylmethylene)indole-2-thiones
absence of an arene (a Friedel–Crafts-type nucleophile) in the
reaction system. A not completely unexpected, but nevertheless
somewhat surprising, result was obtained when 2-(3,3-
dimethylbutyn-1-yl)phenyl isothiocyanate (1a) was treated with
TfOH at −40 to 0 °C; predominantly 2,2,3-trimethyl-2H-thieno-
[2,3-b]indole (5)9 was formed (Scheme 2). This observation
suggests that a methyl group in the t-Bu group must migrate in
the process of the thieno-indole formation from alkynylphenyl
isothiocyanate 1a. Thus far, to our knowledge, no precedent
involving such a tandem cycloisomerization/rearrangement
sequence reaction of alkyne-heterocumulene species has been
reported.8c,10 Since we became interested in revealing this
highly unique reaction and the potential for a new entry to the
were predominantly formed at −40 °C via a tandem 5-dig-
mode cyclization and Friedel–Crafts-type alkenylation
(Scheme 1-(b)).7,8 With these results in mind, we wondered
what would happen when the reaction was performed in the
aDepartment of Chemistry, Faculty of Science, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan. E-mail: tsaito@rs.kagu.tus.ac.jp,
totani@rs.tus.ac.jp
bInternational Institute for Integrative Sleep Medicine (WPI-IIIS), University of
Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
†Electronic supplementary information (ESI) available: Experimental details.
CCDC 995430 and 995431. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c4ob00825a
8398 | Org. Biomol. Chem., 2014, 12, 8398–8407
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
(R = t-Bu) as a model substrate. Representative results shown
in Table 1 suggest that triflic acid is the most effective of the
acids used (entry 3 vs. entries 11–15); three equivalents of
triflic acid are necessary and sufficient to obtain a good yield
(78%) of the expected product 59 when the reaction is con-
ducted for only 10 min in dichloromethane at 0 °C (entry 3 vs.
entries 1, 2 and 4); and the reactions in the other solvents
except 1,2-dichloroethane or at rt or −40 °C (entry 3 vs. entries
5–10) bring less efficiency. The solvent effect is consistent with
the consideration that polar solvents with more coordination
ability tend to reduce the practical acidity of triflic acid to acti-
vate the substrate transforming to the cyclized product 5.
A possible reaction pathway is illustrated in Scheme 4. Pro-
tonation at the nitrogen and subsequent nucleophilic attack
Scheme 2 Triflic acid-promoted cycloisomerization of 1a to produce
thieno-indole 5.
synthesis of indole derivatives, we started to investigate this
reaction in more depth to examine its scope and limitations.
Here, we report the triflic acid-promoted cycloisomerization
reaction of 2-(alkyn-1-yl)phenyl isothiocyanates and isocya-
nates as a novel synthetic method for structurally diverse types
of indole derivatives (thieno- and furo-fused indoles, spiro-
indolethiones, spiro-oxindoles, and 3-alkylidene-oxindoles).
Characteristic and unique features of this tandem reaction are
that it involves the triflic acid-promoted indole-forming
process and the Wagner–Meerwein-type rearrangement11 of
the hydrogen or the substituent to the α-sp2 carbocation ([1,2]-
shift) arising from the substituted ethynyl group.
Table 1 Screening of Brønsted acids and optimization of stoichiometry
and reaction conditionsa
2. Results and discussion
2.1. Preparation of starting materials
Entry Acid (equiv.)
Solvent
Temp./°C Time
Yieldb,c/%
48 (27)
1
2
3
4
5
6
7
8
TfOH (1.0)
TfOH (2.0)
TfOH (3.0)
TfOH (4.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
H2SO4 (3.0)
HCl (3.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Dioxane
THF
ClCH2CH2Cl
MeNO2
CH2Cl2
CH2Cl2
0
0
0
24 h
10 min 69 (6)
10 min 78
First, the key substrates, 2-(alkyn-1-yl)phenyl isothiocyanates 1
and isocyanates 4, were prepared from 2-alkynylanilines 2 as
outlined in Scheme 3.6,12,13 2-Alkynylanilines 2, which were
readily synthesized from commercially available 2-iodoaniline
and alkynes via a Sonogashira coupling, were converted to the
corresponding iminophosphoranes 3, followed by the aza-Wittig
reaction of 3 with carbon disulfide to give 2-(alkyn-1-yl)-phenyl
isothiocyanates 1a–1k. Isothiocyanate 1l was conveniently pre-
pared from the reaction of 2l with di(1H-imidazol-1-yl)methane-
thione.13 2-(Alkyn-1-yl)phenyl isocyanates 4 were prepared by
the reaction of anilines 2 with triphosgene (see ESI†).
0
10 min 78
10 min 69
10 min 54 (17)
10 min NR (ca. 100)
10 min NR (90)
10 min 70
rt
−40
0
0
0
9
10
11
12
13
14
15
0
0
0
0
0
0
10 h
54
10 min NR (ca. 100)
10 min NR (ca. 100)
10 min NR (96)
10 min NR (91)
10 min 7 (80)
TsOH–H2O (3.0) CH2Cl2
TFA (3.0)
CH2Cl2
CH2Cl2
Tf2NH (3.0)
a Each reaction was performed such that a solution of 1a was added
dropwise to a solution of triflic acid or the other acids because when
triflic acid was added to a solution of 1a, 1a partially deteriorated and/
or dimerized leading to a decreased yield of 5. b Isolated yield. c NR: no
reaction; no trace of 5 was detected by TLC. In parentheses, yield of
2.2. Triflic acid-promoted reaction of 2-(alkyn-1-yl)phenyl
isothiocyanates (1)
Initially, we screened Brønsted acids with optimization of their
stoichiometry and reaction conditions using isothiocyanate 1a the recovered starting material 1a.
Scheme 3 Preparation of 2-(alkyn-1-yl)phenyl isothiocyanates 1 and isocyanates 4. Reagents and conditions: (i) PPh3 (1.2 equiv.), C2Cl6 (1.2 equiv.),
Et3N (2.4 equiv.), CH2Cl2, rt, 4 h; (ii) CS2, rt, 12 h; (iii) triphosgene (0.37–1.1 equiv.), Et3N (2.0 equiv.), toluene, 0 °C → rt.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8398–8407 | 8399

View Article Online
Paper
Organic & Biomolecular Chemistry
We next conducted the reaction of 1b–1l with a variety of
substituents R on the ethyne carbon to determine the scope
and limitations of this type of reaction. The reaction of 1b con-
taining a noncyclic secondary substituent of R = i-Pr under
optimal reaction conditions produced 2,3-dimethyl-8H-thieno-
[2,3-b]indole (6) in 45% yield (Scheme 5). Similar to the reac-
tion pathway illustrated in Scheme 4, protonation of 1b,
5-endo-dig-mode cyclization of A and rearrangement of the
methyl group at the key intermediate B (Path a) occurred to
afford C. The nucleophilic cyclization of C and deprotonation
from D gave the thieno[2,3-b]indole 6. Alternatively, the for-
mation of 2,2-dimethyl-2H-thieno[2,3-b]indole (6′) from the
cation B via hydrogen migration (Path b) occurred, and the
post-migration of the methyl group in 6′ gave 6.14a
Scheme 4 A possible reaction pathway via rearrangement leading to
thieno-indole 5.
The reactions of isothiocyanates 1c–1e and 1h–1k with
various substituents in R failed; intractable product mixtures
were formed. However, isothiocyanates 1f and 1g having a
by the inner acetylenic π-bond in a 5-endo-dig mode7,8 give cyclic secondary substituent [R = c-Hex (n = 2) and c-Pent
cation B. Anionotropic rearrangement of the methyl group in B (n
= 1)] produced the ring-expanded cycloalkane-fused
affords the allylic cation intermediate C, followed by the 8H-thieno[2,3-b]indoles 7 and 8 in 34% and 37% yields,
nucleophilic cyclization and deprotonation from D to produce respectively (Scheme 6). At the cation B, the methylene group
2,2,3-trimethyl-2H-thieno[2,3-b]indole (5) as the final product.
of the cycloalkane (Path a) should rearrange (B → C) leading to
Scheme 5 Possible reaction pathways via rearrangement leading to thieno-indoles 6/6’.
Scheme 6 Possible reaction pathways via rearrangement leading to thieno-indoles 7 and 8/7’ and 8’.
8400 | Org. Biomol. Chem., 2014, 12, 8398–8407
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 7 Possible reaction pathways via rearrangement leading to indoles 9/9’.
compounds 7 and 8 via the cyclization (C → D) with deproto-
nation. Possible spiro-thieno[2,3-b]indole products 7′ and 8′
via a hydrogen migration (Path b) were not detected.
In the present cycloisomerization of the o-alkynylphenyl
isothiocyanate 1, a tertiary or a secondary substituent R on the
acetylenic terminal seems to be necessary for the rearrange-
ment in which its branching alkyl substituent migrates suc-
cessfully onto the alkylidene sp2-carbocation in B to form the
target thieno[2,3-b]indole derivative (Schemes 4–6). Therefore,
we next conducted the reaction of isothiocyanate 1l having a
trityl substituent with high migrating ability (Scheme 7).
However, the expected thieno[2,3-b]indole 9′ was not formed.
Instead, the spiro-indolethione 9 was obtained in good yield
(58%). In the second cyclization step after the migration of the
phenyl group (B → C/D), the intramolecular Friedel–Crafts-
type reaction15 of D must take place at the ortho position of
the proximal benzene ring (D → 9) in preference to the thio-
phene ring-forming cyclization (C → 9′). The structure of 9 was
established unambiguously by X-ray crystallographic analysis
(Fig. 1).16
Fig. 1 Molecular structure for compound 9 as an ORTEP plot. All
hydrogen atoms have been omitted for clarity. Thermal ellipsoids are
shown at 50% probability levels.
conditions of 0 °C → rt for 25 h in dichloromethane, the furo-
[2,3-b]indole 10 was obtained quantitatively. The E geometry of
11 was determined by nOe using 1H NMR spectroscopy.
A possible reaction pathway is illustrated in Scheme 9. Pro-
tonation of 4a and 5-endo-dig-mode cyclization of A, and sub-
sequent methyl group migration at B give the allylic cation
intermediate C. The following nucleophilic cyclization by
O-attack with deprotonation via Path a produces 2,2,3-tri-
methyl-2H-furo[2,3-b]indole (10) as the major product. This
process is very similar to the reaction of the corresponding
isothiocyanate 1a leading to the exclusive formation of
2,2,3-trimethyl-2H-thieno[2,3-b]indole (5) (see Scheme 4). An
alternative, Path b, with deprotonation from the methyl group
of the intermediate C occurs at a lower temperature of 0 °C to
give oxindole 11 as the minor product. The fact that transform-
2.3. Triflic acid-promoted reaction of 2-(alkyn-1-yl)phenyl
isocyanates (4)
When isocyanate 4a (R = t-Bu) was similarly treated with triflic
acid (3.0 equiv.) at 0 °C for 10 min in dichloromethane, 2,2,3-
trimethylfuro[2,3-b]indole (10) was obtained in 85% yield
together with 3-(prop-3-en-2-ylidene)oxindole (11) in 9% yield
(Scheme 8). The same reaction in one pot from 4a for 25 h
afforded furo[2,3-b]indole 10 in 99% yield. When the isolated
oxindole 11 was treated with triflic acid (3.0 equiv.) under the
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8398–8407 | 8401

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 8 Triflic acid-promoted cycloisomerization of 4a to produce indoles 10 and 11.
Scheme 9 Possible reaction pathways via rearrangement leading to indoles 10 and 11.
ation of 11 to 10 proceeds exclusively at a higher temperature oxindole 13, while the O-attack cyclization at C via Path d pro-
(rt) in the presence of triflic acid suggests that this reaction is duces spiro-furo[2,3-b]indole 14.
thermodynamically controlled via the intermediate C.
Alternatively, rearrangement of the methylene group at B
The reaction of isocyanate 4b (R = i-Pr) under the optimal via Path b formed the ring-expanded oxindole intermediate D,
reaction conditions [TfOH (3.0 equiv.) at 0 °C for 10 min in which gave furo-indole 15 via Path f. Probable compound 16
CH2Cl2] afforded the furo[2,3-b]indole 12 in 70% yield was not obtained, but the formation of 15 from 16 is possible.
(Scheme 10). This compound 12 can be formed by H-migration
When the reaction of o-(cyclohexylethynyl)phenyl isocyanate
from the cation B via Path b, and cyclization of D. Neither the (4f) was conducted under optimal conditions, (1-cyclohexenyl-
Me-migrated product 12′ nor 12″ was obtained. The selectivity methylene)oxindole 17 (Z) and allenyloxindole 18, which were
of the migrating group (H) of 4b is in contrast to that (Me) of probably formed via Path b with H-migration and deprotona-
the corresponding isothiocyanate 1b (R = i-Pr) (Scheme 5).14b
tion, were obtained in 26% and 20% yields, respectively
From the reaction of isocyanate 4e (R = 1-methyl-1-cyclo- (Scheme 13, entry 1). Neither the ring-expanded compound 19
hexyl) under the optimal reaction conditions, three indole nor 20 was formed. The reaction of 4f at a lower temperature
derivatives 13, 14, and 15 were obtained in 10%, 30%, and 6% of −40 °C or −78 °C for 10 min gave the allenic oxindole 18 as
yields, respectively (Scheme 11). As shown in Scheme 12, the a sole product (entries 2 and 3). When the reaction was con-
protonated cationic intermediate A cyclizes to give the inter- ducted at −78 °C for 10 min, followed by standing at room
mediate B, from which the methyl group migration (Path a) temperature for a day, 3-methylene-oxindoles 17 (E) and 17 (Z)
and following deprotonation via Path c produces 3-methylene- were obtained in 27% and 67% yields, respectively, in place of
8402 | Org. Biomol. Chem., 2014, 12, 8398–8407
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 10 Possible reaction pathways via rearrangement leading to indoles 12/12’ or 12’’.
Scheme 11 Triflic acid-promoted cycloisomerization of 4e to produce indoles 13, 14 and 15.
Scheme 12 Possible reaction pathways via rearrangement leading to indoles 13, 14, and 15.
18 (entry 4). The isolated allene 18 was isomerized by treating graphic analysis (Fig. 2).17 The reaction at a lower temperature
it with TfOH to give 17 (E) and 17 (Z) in 20% and 62% yields, of −40 °C or −78 °C for 10 min did not give the allenic oxi-
respectively.
ndole of the cyclopentylidene analogue corresponding to 18.
In contrast to the above reaction (Scheme 13), the ring-
In the reaction of o-(cyclopropylethynyl)phenyl isocyanate
expanded product 21 (25%, Z : E = 8 : 2) and the H-migrated (4h), only the geometrically pure cis-oxindole 23 was isolated
product 22 (Z) (42%) were both obtained in the reaction of 4g as an identified product in 12% yield (Scheme 15). The cycliza-
under optimal reaction conditions (Scheme 14). The structure tion (A → B) and cyclopropane ring-expansion by the methy-
of 22 (Z) was established unambiguously by X-ray crystallo- lene rearrangement formed the cation C.10a–c Subsequent
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8398–8407 | 8403

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 13 Possible reaction pathways via rearrangement leading to indoles 17 and 18/19 and 20.
Scheme 14 Possible reaction pathways via rearrangement leading to indoles 21 and 22.
Fig. 2 Molecular structure for compound 22 as an ORTEP plot.
Thermal ellipsoids are shown at 30% probability levels.
cyclization of C and hydrolysis of the formed cyclobuta-furo-
Scheme 15 A possible reaction pathway via rearrangement leading to
indole 23.
fused oxindole D gave 23. This pathway is consistent with the
observation that cis-compound 23 was formed during purifi-
cation/isolation by silica gel chromatography.
In the reaction of trityl-substituted isocyanate 4l the spiro-
oxindole 24 was obtained in 78% yield, no formation of tri-
phenylfuro[2,3-b]indole 24′ was observed (Scheme 16). The
pathway is very similar to the reaction of the corresponding
isothiocyanate 1l (Scheme 7).
3. Conclusions
In conclusion, we have developed a new and unique, metal-
free approach to the synthesis of structurally diverse types of
indole derivatives such as thieno- and furo-indoles, spiro-indo-
8404 | Org. Biomol. Chem., 2014, 12, 8398–8407
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 16 Possible reaction pathways via rearrangement leading to indoles 24/24’.
lethiones, spiro-oxindoles, and 3-alkylidene-oxindoles. The CDCl3): δ 11.99 (CH3), 26.5 (2CH3), 72.2 (C), 117.8 (CH), 121.6
methodology involves triflic acid-promoted cycloisomerization (CH), 122.1 (CH), 125.6 (C), 128.3 (CH), 137.9 (C), 158.3 (C),
with anionotropic rearrangement of a substituent or hydrogen 162.7 (C), 180.0 (C); HRMS–ESI (m/z): [M + H]+ calcd for
in R of 2-(alkyn-1-yl)phenyl isothiocyanates and isocyanates, C13H14NS: 216.0841, found: 216.0834.
although, as anticipated, the substituents R are limited to
those having rich migrating ability.
4.1.2. 2,3-Dimethyl-8H-thieno[2,3-b]indole (6). Colorless
solid; mp 159.7–161.2 °C; IR (KBr): 1635.3, 2908 cm−1
;
1H NMR (500.0 MHz, CDCl3): δ 1.72 (s, 3H), 2.22 (s, 3H), 6.43
(d, J = 7.9 Hz, 1H), 6.84 (dd, J = 7.3, 7.9 Hz, 1H), 7.06 (dd, J = 7.3,
7.6, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.40–7.46 (br. s, 1H); 13C NMR
(125.7 MHz, CDCl3): δ 22.5 (CH3), 23.3 (CH3), 110.2 (CH), 114.0
(C), 115.9 (CH), 117.1 (C), 120.2 (CH), 121.6 (CH), 128.3 (C),
129.4 (C), 135.6 (C), 140.4 (C); Anal. calcd for C12H11NS: C 71.60,
H 5.51, N 6.96, found: C 71.38, H 5.89, N 7.31.
4. Experimental
4.1. Typical procedure for reaction of 2-(alkyn-1-yl)phenyl
isothiocyanates 1
In an oven-dried flask equipped with a septum and a magnetic
stirring bar, trifluoromethanesulfonic acid (123.7 µL,
1.41 mmol) was dissolved in dry dichloromethane (3 mL) and
the solution was cooled to 0 °C under an argon atmosphere.
4.2. Typical procedure for reaction of 2-(alkyn-1-yl)phenyl
isocyanates 4
Then, a solution of isothiocyanate 1a (101.2 mg, 0.470 mmol) In an oven-dried flask equipped with a septum and a magnetic
in dichloromethane (3 mL) was slowly added through a syringe stirring bar, trifluoromethanesulfonic acid (134.3 μL,
and the mixture was stirred at 0 °C for 10 min. The reaction 1.53 mmol) was dissolved in dry dichloromethane (3 mL) and
was quenched with saturated aq. NaHCO3 solution and the the solution was cooled to 0 °C under an argon atmosphere.
reaction mixture was extracted with dichloromethane (3 mL × A solution of isocyanate 4a (102 mg, 0.513 mmol) in dichloro-
3) and dried (Na2SO4). After evaporation of the solvent, the methane (3 mL) was slowly added through a syringe and the
residue was purified by flash column chromatography on silica mixture was stirred at 0 °C for 10 min. The reaction was con-
gel with hexane–ethyl acetate (4 : 1) as an eluant to give thieno- tinued at room temperature for 25 h and quenched with satu-
indole 5 (79 mg, 78%).
4.1.1. 2,2,3-Trimethyl-2H-thieno[2,3-b]indole
yellow oil; IR (neat): 3401.8, 2969.8, 1666.2 cm−1
rated aq. NaHCO3 solution. The reaction mixture was extracted
(5). Pale with dichloromethane (3 mL × 3) and dried (Na2SO4). After
1H NMR evaporation of the solvent, the residue was purified by flash
;
(500.0 MHz, CDCl3): δ 1.59 (s, 6H), 2.19 (s, 3H), 7.04 (dd, J = column chromatography on silica gel with hexane–ethyl
7.1, 7.3 Hz, 1H), 7.26 (dd, J = 7.1, 7.6 Hz, 1H), 7.40 (d, J = acetate (4 : 1) as an eluant to give furoindole 10 (101 mg, 99%)
7.6 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H); 13C NMR (125.7 MHz, as pale yellow needles (crystallized from CH2Cl2–hexane).
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8398–8407 | 8405

View Article Online
Paper
Organic & Biomolecular Chemistry
When the reaction at 0 °C was quenched after 10 min, furo-
indole 10 (86.7 mg, 85%) and oxindole 11 (9.2 mg, 9%) were
obtained.
2003, 2209 (Spiro-oxindoles); (l) T. L. Gilchrist, J. Chem.
Soc., Perkin Trans. 1, 2001, 2491; (m) G. W. Gribble, J. Chem.
Soc., Perkin Trans. 1, 2000, 1045.
4.2.1. 2,2,3-Trimethyl-2H-furo[2,3-b]indole
(10). Pale
3 For functionalization of indoles: (a) G. Bartoli,
G. Bencivennia and R. Dalpozzob, Chem. Soc. Rev., 2010,
39, 4449 (Organocatalytic, asymmetric); (b) L. Joucla,
L. Djakovitch and M. Bandini, Adv. Synth. Catal., 2009, 351,
673 (Transition metal-catalyzed arylation); (c) M. Bandini
and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608
(catalytic).
yellow needles; mp 262–264 °C; IR (KBr): 3448, 2854, 1666,
1
1435, 748 cm−1; H NMR (300.4 MHz, CDCl3): δ 1.54 (s, 6H),
2.22 (s, 3H), 7.02 (dd, J = 7.4, 7.5 Hz, 1H), 7.27 (dd, J = 7.5, 7.8
Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H);
13C NMR (75.5 MHz, CDCl3): δ 12.0 (CH3), 23.8 (2CH3), 103.1
(C), 118.5 (CH), 121.7 (CH), 122.4 (CH), 122.7 (C), 127.5 (C),
129.1 (CH), 155.0 (C), 162.4 (C), 181.4 (C); HRMS–ESI (m/z):
[M + H]+ calcd for C13H14NO: 200.1070, found: 200.1062.
4.2.2. (E)-3-(3-Methylbut-3-en-2-ylidene)-1,3-dihydroindol-2-
one (11). Yellow solid; mp 115.9–117.0 °C; IR (KBr): 3185.8,
4 For recent reports on synthesis of indoles, see:
(a) D. B. Ramachary, M. S. Prasad, S. V. Laxmi and
R. Madhavachary, Org. Biomol. Chem., 2014, 12, 574;
(b) A. Palmieri, S. Gabrielli, R. Maggi and R. Ballini, Synlett,
2014, 128 (indole-2-carboxylates); (c) G. Liu, G. Xu, J. Li,
D. Ding and J. Sun, Org. Biomol. Chem., 2014, 12, 1387
(C2-functionalized); (d) Y. Fang, C. Wang, S. Su, H. Yu and
Y. Huang, Org. Biomol. Chem., 2014, 12, 1061; (e) H. Gao,
J. Sun and G.-G. Yan, Synthesis, 2013, 489 (spiro-oxindoles);
(f) K. Inamoto, N. Asano, Y. Nakamura, M. Yonemoto and
Y. Kondo, Org. Lett., 2012, 14, 2622; (g) F. Zhu, F. Zhou,
Z.-Y. Cao, C. Wang, Y.-X. Zhang, C.-H. Wang and J. Zhou,
Synthesis, 2012, 3129 (3-Alkoxy- & alkylthio-oxindoles);
(h) J. H. Kim and S.-G. Lee, Synthesis, 2012, 1464; (i) Z. Xia,
K. Wang, J. Zheng, Z. Ma, Z. Jiang, X. Wang and X. Lv, Org.
Biomol. Chem., 2012, 10, 1602; ( j) B. Liu, X. Hong, D. Yan,
S. Xu, X. Huang and B. Xu, Org. Lett., 2012, 14, 4398;
(k) X. Ju, Y. Liang, P. Jia, W. Li and W. Yu, Org. Biomol.
Chem., 2012, 10, 498 (oxindoles); (l) Z. Chen, D. Zheng and
J. Wu, Org. Lett., 2011, 13, 848; (m) J. McNulty and
K. Keskar, Eur. J. Org. Chem., 2011, 6902; (n) H.-A. Du,
R.-Y. Tang, C.-L. Deng, Y. Liu, J.-H. Li and X.-G. Zhang, Adv.
Synth. Catal., 2011, 353, 2739; (o) B. Tan, G. Hernandez-
Torres and C. F. Barbas III, J. Am. Chem. Soc., 2011, 133,
12354 (Spiro); (p) L. Liu, N. Ishida, S. Ashida and
M. Murakami, Org. Lett., 2011, 13, 1666; (q) S. Cacchi,
G. Fabrizi, A. Goggiamani, A. Perboni, A. Sferrazza and
P. Stabile, Org. Lett., 2010, 12, 3279; (r) P. Kothandaraman,
W. Rao, S. J. Foo and P. W. H. Chan, Angew. Chem., Int. Ed.,
2010, 49, 4619; (s) J. M. Finefield and P. M. Williams,
J. Org. Chem., 2010, 75, 2785; (t) A. Pews-Davtyan, A. Tillack,
A.-C. Schmöle, S. Oritinau, M. J. Frech, A. Rolfs and
M. Beller, Org. Biomol. Chem., 2010, 8, 1149; (u) X. Wang,
B. Han, J. Wang and W. Yu, Org. Biomol. Chem., 2010, 8,
3865; (v) Y.-X. Jia, D. Katayev, G. Bernardinelli, T. M. Seidel
and E. P. Kündig, Chem. – Eur. J., 2010, 16, 6300;
(w) T. Toyoshima, Y. Mikano, T. Miura and M. Murakami,
Org. Lett., 2010, 12, 4584; (x) M. Bararjanian, S. Balalaie,
F. Rominger, B. Movassagh and H. R. Bijanzadeh, J. Org.
Chem., 2010, 75, 2806; (y) T. Miura, T. Toyoshima,
O. Kozawa and M. Murakami, Chem. Lett., 2010, 39, 1132;
(z) D. M. D’Souza, C. Muschelknautz, F. Rominger and
T. J. J. Müller, Org. Lett., 2010, 12, 3364; and many refer-
ences cited therein.
3085.6, 2923.6, 1689.3, 1612.2 cm−1 1H NMR (600.1 MHz,
;
CDCl3): δ 2.04 (dd, J = 1.4, 1.4 Hz, 3H), 2.59 (s, 3H), 4.67 (dq, J =
1.0, 1.4 Hz, 1H), 5.15 (dq, J = 1.0, 1.4 Hz, 1H), 6.84 (d, J = 7.7 Hz,
1H), 6.92 (dd, J = 7.7, 7.8 Hz, 1H), 7.16 (dd, J = 7.7, 7.8 Hz, 1H),
7.65 (d, J = 7.7 Hz, 1H), 8.15–8.23 (br. s, 1H); 13C NMR
(150.9 MHz, CDCl3): δ 20.45 (CH3), 20.48 (CH3), 109.2 (CH),
113.0 (CH2), 121.1 (C), 121.5 (CH), 123.1 (C), 123.5 (CH), 128.0
(CH), 139.4 (C), 146.7 (C), 157.8 (C), 168.0 (C); HRMS–ESI (m/z):
[M + Na]+ calcd for C13H13NNaO: 222.0889, found: 222.0886.
Notes and references
1 For reviews (Natural): (a) K. Higuchi and T. Kawasaki, Nat.
Prod. Rep., 2007, 24, 843; (b) S. E. O’Connor and J. Maresh,
Nat. Prod. Rep., 2006, 23, 532; (c) M. Somei and F. Yamada,
Nat. Prod. Rep., 2004, 21, 278; (d) A. Brancale and
R. Silvestri, Med. Res. Rev., 2007, 27, 209. For reviews (Med-
icinal and general): (e) D. St. C. Black, R. J. Sundberg and
G. W. Gribble, in Comprehensive Heterocyclic Chemistry II,
ed. A. R. Katritzky, C. R. Rees, E. F. V. Scriven and
C. W. Bird, Pergamon, Oxford, 1996, vol. 2; (f) M. d’Ischia,
A. Napolitano, A. Pezzella, B. A. Trofimov, N. A. Nedolya,
J. Bergman, T. Janosik, M. d’Ischia, A. Napolitano and
A. Pezzella, in Comprehensive Heterocyclic Chemistry III, ed.
A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K.
Taylor, Elsevier, New York, 2008, vol. 3.
2 For reviews (Synthesis): (a) K. Shen, X. Liu, L. Lin and
X. Feng, Chem. Sci., 2013, 3, 327 (Oxindoles, enantiomeric);
(b) M. Shiri, Chem. Rev., 2012, 112, 3508; (c) D. Zhang,
H. Song and Y. Qin, Acc. Chem. Res., 2011, 44, 447 (Indoline
alkaloids); (d) A. Millemaggi and R. J. K. Taylor, Eur. J. Org.
Chem., 2010, 4527 (3-Alkenyl-oxindoles); (e) F. Zhou,
Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381
(Oxindoles, asymmetric); (f) J. Barluenga, F. Rodrîguez and
F. J. Fañanås, Chem. – Asian J., 2009, 4, 1036; (g) K. Krüger,
A. Tillack and M. Beller, Adv. Synth. Catal., 2008, 350, 2153
(Catalytic synthesis); (h) C. V. Galliford and K. A. Scheidt,
Angew. Chem., Int. Ed., 2007, 46, 8748 (Spiro-oxindoles);
(i) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106,
2875; ( j) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105,
2873; (k) C. Marti and E. M. Carreira, Eur. J. Org. Chem.,
5 For reviews: (a) F. Palacios, C. Alonso, D. Aparicio,
G. Rubiales and J. M. de los Santos, Tetrahedron, 2007, 63,
8406 | Org. Biomol. Chem., 2014, 12, 8398–8407
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
523; (b) S. Eguchi, Top. Heterocycl. Chem., 2006, 6, 113;
(c) S. Eguchi, ARKIVOC, 2005 (ii), 98; (d) P. M. Fresneda and
P. Molina, Synlett, 2004, 1; (e) P. Molina and
M. J. Vilaplana, Synthesis, 1994, 1197; (f) A. K. Mukerjee
and R. Ashare, Chem. Rev., 1991, 91, 1; (g) V. I. Gorbatenko,
Tetrahedron, 1993, 49, 3227; (h) N. Kutsumura and T. Saito,
J. Synth. Org. Chem. Jpn., 2011, 69, 926 See also our reports
N. Jiao, Chem. Commun., 2009, 6842; (c) B. M. Trost, J. Xie
and N. Maulide, J. Am. Chem. Soc., 2008, 130, 17258 See
also: (d) J. Huan and A. J. Frontier, J. Am. Chem. Soc., 2007,
129, 8060 (Nazarov cyclization/Wagner–Meerwein rearrange-
ment, 100 mol% Cu(OTf)2); (e) M. C. Elliott, N. N. E. El Sayed
and J. S. Paine, Eur. J. Org. Chem., 2007, 792 (Tandem Prins
cyclization/rearrangement, 225 mol% TiCl4).
on this subject; for isothiocyanates: (i) T. Saito, H. Nihei, 11 For a review, see: J. R. Hanson, in Comprehensive Organic
T. Otani, T. Suyama, N. Furukawa and M. Saito, Chem.
Commun., 2008, 172; ( j) T. Otani, S. Katsurayama, T. Ote
and T. Saito, J. Sulfur Chem., 2009, 30, 250; for ketenimines:
Synthesis, ed. B. M. Trost, I. Fleming and G. Pattenden,
Pergamon Press, Oxford, 1991, vol. 3, ch. 3.1, pp. 705–
720.
(k) T. Saito, K. Sugizaki, H. Osada, N. Kutsumura and 12 For preparation and reaction of alkynyl isothiocyanates:
T. Otani, Heterocycles, 2010, 80, 207; for carbodiimides:
(l) T. Otani, T. Saito, R. Sakamoto, H. Osada, A. Hirahara,
N. Furukawa, N. Kutsumura, T. Matsuo and K. Tamao,
Chem. Commun., 2013, 6206; (m) H. Nakano, N. Kutsumura
and T. Saito, Synthesis, 2012, 3179; (n) T. Saito, H. Nakano,
H. Terada, N. Kutsumura and T. Otani, Heterocycles, 2012,
84, 893; (o) S. Hirota, T. Sakai, N. Kitamura, K. Kubokawa
and N. Kutsumura, Tetrahedron, 2010, 66, 653; (p) T. Saito,
N. Furukawa and T. Otani, Org. Biomol. Chem., 2010, 8,
1126; (q) T. Saito, T. Ote, M. Shiotani, H. Kataoka, T. Otani
and N. Kutsumura, Heterocycles, 2010, 82, 305; (r) S. Hirota,
R. Kato, M. Suzuki, Y. Soneta, T. Otani and T. Saito,
Eur. J. Org. Chem., 2008, 2075; (s) T. Saito, K. Sugizaki,
T. Otani and T. Suyama, Org. Lett., 2007, 9, 1239; and other
reports cited therein.
(a) L. Benati, G. Calestani, R. Leardini, M. Minozzi,
D. Nanni, P. Spagnolo, S. Strazzari and G. Zanardi, J. Org.
Chem., 2003, 68, 3454; (b) M. Minozzi, D. Nanni,
G. Zanardi and G. Calestani, ARKIVOC, 2006, 6, 6. For
preparation and reaction of alkynyl isocyanates:
(c) S. Kamijo, Y. Sasaki, C. Kanazawa, T. Schüßeler and
Y. Yamamoto, Angew. Chem., Int. Ed., 2005, 44, 7718;
(d) S. Kamijo and Y. Yamamoto, J. Org. Chem., 2003, 68,
4764; (e) S. Kamijo and Y. Yamamoto, Angew. Chem., Int.
Ed., 2002, 41, 3230; (f) T. Miura, Y. Takahashi and
M. Murakami, Org. Lett., 2007, 9, 5075; (g) T. Miura,
T. Toyoshima, Y. Takahashi and M. Murakami, Org. Lett.,
2008, 10, 4887; (h) X. Lu, J. L. Peterson and K. K. Wang,
J. Org. Chem., 2002, 67, 7797.
13 (a) H. A. Staab and G. Walther, Liebigs Ann. Chem., 1962,
657, 104; (b) P. de Tullio, B. Pirotte, F. Somers, S. Boverie,
F. Lacan and J. Delargo, Tetrahedron, 1998, 54, 4935.
6 T. Otani, S. Kunimatsu, H. Nihei, Y. Abe and T. Saito, Org.
Lett., 2007, 9, 5513.
7 T. Otani, S. Kunimatsu, T. Takahashi, H. Nihei and 14 (a) The authors thank the referee for this suggestion; (b) In
T. Saito, Tetrahedron Lett., 2009, 50, 3853.
general, an order of the migratory aptitudes of the groups
for an anionotropic (nucleophilic) rearrangement is:
CH3OC6H4 > p-tolyl > phenyl > tert-alkyl > primary-alkyl >
H, and hence Me > H. (“Organic Chemistry”, 5th edn,
Stanley H. Pine, McGraw-Hill, International Editions 1987).
The migratory deference between isothiocyanate 1b and
isocyanate 4b can be explained by the following consider-
ation. In the former case of 1b (Scheme 5), the cation B is
softer and highly stabilized by conjugation with the CvS
sulfur atom, so prefers the softer methyl group for the
migration rather than the hydrogen (HSAB theory). In con-
trast, the harder cation B conjugated with the CvO oxygen
atom prefers the harder hydrogen (Scheme 10). See:
X. Creary, H. N. Hatoum, A. Barton and T. E. Aldridge,
J. Org. Chem., 1992, 57, 1887.
8 The product selectivity [quinoline-2-thiones (via 6-dig mode)
versus indole-2-thiones (via 5-dig mode)] seemed to be
largely dependent on the alkyne-substituent and the reac-
tion mode and conditions as well as the promoters. TfOH-
promoted cycloaddition of 2-alkynylphenyl isocyanates with
arenes showed similar results. Regioselective cyclizations
(via 5-exo-dig mode vs. 6-endo-dig mode) of o-alkynylphenols
promoted by either TfOH or 4-(dimethylamino)pyridine to
afford γ-benzopyranones or flavones, respectively, were
reported recently. (a) M. Yoshida, Y. Fujino and T. Doi, Org.
Lett., 2011, 13, 4526; (b) M. Yoshida, Y. Fujino, K. Saito and
T. Doi, Tetrahedron, 2011, 67, 9993. For discussion, see:
(c) Y. Yamamoto, I. D. Gridnev, N. T. Patil and T. Jin, Chem.
Commun., 2009, 5075.
9 For several other synthetic methods of thieno[2,3-b]indoles, 15 The synthesis of indene-spiro-oxindoles, which involves
see: H. Z. Boeini, Helv. Chim. Acta, 2009, 92, 1268;
K. C. Majumdar and S. Alam, J. Chem. Res., 2006, 289;
J. Levy, D. Royer, J. Guilhem, M. Cesario and C. Pascard,
Bull. Soc. Chim. Fr., 1987, 193; P. Olesen, J. Hansen and
M. Engelstoft, J. Heterocycl. Chem., 1995, 32, 1641.
TiCl4-mediated tandem Prins reaction–intramolecular
Friedel–Crafts reaction between isatins and 1,1-diarylethy-
lenes has been reported. D. Basavaiah and K. R. Reddy,
Org. Lett., 2007, 9, 57.
16 The structure of 9 was determined spectroscopically and
finally confirmed by X-ray crystallographic analysis. CCDC
995430.
10 TfOH-catalyzed tandem transformation of (cyclopropyl-
ethynyl)arenes + 1,3-diketones involving ring expansion
(rearrangement) to cyclobutane-fused dihydrofurans has 17 The structure of 22 (Z) was determined spectroscopically
been reported recently. (a) S. Ye and Z.-X. Yu, Chem.
Commun., 2011, 47, 794; (b) A. Chen, R. Lin, Q. Liu and
and finally confirmed by X-ray crystallographic analysis.
CCDC 995431.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 8398–8407 | 8407