MeOTf-Induced Carboannulation of Isothiocyanates and Aryl Alkynes with C=S Bond Cleavage: Access to Indenones

Article abstract of DOI:10.1021/acs.orglett.5b02201

MeOTf-induced carboannulation of alkyl isothiocyanates and aryl alkynes for the synthesis of indenones in good yields under metal-free conditions with C=S bond cleavage is described. The thioalkoxy group at the 3-position of the indenone can also be converted into other functional groups, such as phenyl, methylsulfonyl, amino, and ethoxy groups.

Full text of DOI:10.1021/acs.orglett.5b02201

Letter
pubs.acs.org/OrgLett
MeOTf-Induced Carboannulation of Isothiocyanates and Aryl
Alkynes with CS Bond Cleavage: Access to Indenones
Peng Zhao,† Yu Liu,† and Chanjuan Xi*,†,‡
†Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: MeOTf-induced carboannulation of alkyl iso-
thiocyanates and aryl alkynes for the synthesis of indenones in
good yields under metal-free conditions with CS bond
cleavage is described. The thioalkoxy group at the 3-position of
the indenone can also be converted into other functional
groups, such as phenyl, methylsulfonyl, amino, and ethoxy
groups.
sothiocyanates possess the chemical group −NCS,
with the aryl isothiocyanate to form methylthio-substituted
Iwhich represents versatile reactivity in the synthesis of carbenium ion A, which is followed by the reaction with the
nitrogen- or sulfur-containing heterocycles,1 including thio-
alkyne to form intermediate B and subsequent electrophilic
annulation to give the quinoline C (Scheme 2). During the
hydantoins, thiopyrimidones, thioquinazolones, mercaptoimi-
dazoles, benzoimidazolethiols, benzothiazolamines, and benzo-
thiazines, which are valuable skeletons in synthetic chemistry,
biology, and materials.2 Nevertheless, to the best of our
knowledge there has been no report of exhaustive cleavage of
the CS bond of isothiocyanates for the construction of
carbocyclic compounds (Scheme 1).
Scheme 2. MeOTf-Induced Reactions of Isothiocyanates
and Alkynes
Scheme 1. Annulation of Isothiocyanates
course of our studies of the MeOTf-triggered annulation,6,7
we found a new reaction of alkyl isothiocyanates, alkynes, and
MeOTf with CS bond cleavage to form ketamine D, which
affords an indenone after workup (Scheme 2).
On the basis of our former research work on triflate-
triggered annulation,6,7 we initially explored the reaction of
ethyl isothiocyanate (1a), MeOTf (2a), and diphenylacetylene
(3a) in a 1.5:3:1 ratio in dichloroethane (DCE) at different
temperatures for 1.5 h (Table 1, entries 1−5), and 100 °C
was found to be the best temperature for this reaction, with
an isolated yield of 75% (entry 4). Then different solvents
were screened, such as CH3CN, dimethylformamide (DMF),
Indenones are important carbocycles that are ubiquitous in
pharmaceutical and material sciences.3 A variety of method-
ologies for their synthesis have been reported.4,5 Among these
methods, transition-metal-catalyzed annulation of function-
alized arenes with alkynes has been widely achieved for the
construction of indenones.5 Nonetheless, annulation of
functionalized arenes with alkynes under metal-free conditions
has rarely been reported.6a Herein we describe the methyl
triflate (MeOTf)-induced intermolecular carboannulation of
alkyl isothiocyanates and aryl alkynes with CS bond
cleavage to provide access to indenones.
We recently reported MeOTf-triggered annulation of aryl
isothiocyanates and alkynes leading to multiply substituted
quinolines.7 In this process, MeOTf as an electrophile reacts
Received: August 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02201
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Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions for the
Formation of 4a
Table 2. Synthesis of Indenones from Various Symmetrical
Diarylacetylenes
a
a
b
entry
T/°C
t/h
solvent
yield/%
1
2
rt
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.2
0.5
1
DCE
NR
42
65
75
69
NR
NR
55
45
28
32
56
63
69
58
60
DCE
3
80
DCE
4
100
120
100
100
100
100
100
100
100
100
100
100
DCE
5
DCE
6
CH3CN
DMF
CH2Cl2
CHCl3
CCl4
7
8
9
10
11
12
13
14
15
DCE
DCE
DCE
2
DCE
6
DCE
a
Reaction conditions: 0.5 mmol of 3a, 0.75 mmol of 1a, and 1.5 mmol
of MeOTf in 2 mL of solvent in a sealed tube under nitrogen.
b
Isolated yields.
dichlomethane (CH2Cl2), chloroform (CHCl3), and tetra-
chloromethane (CCl4) (entries 6−10). DCE was found to be
the superior solvent for this reaction (entry 4). Furthermore,
the effect of the reaction time was also examined (entries 4
and 11−15), and the best time for improving the yield was
1.5 h (entry 4). On the basis of the above results, the optimal
conditions are shown in entry 4.
Having identified the optimized reaction conditions, we first
tested various symmetrical diarylacetylenes (Table 2). Diary-
lacetylenes having various electron-donating and electron-
withdrawing groups at the para positions of the benzene rings
reacted without incident to give indenone derivatives in good
yields (entries 1−6), except for p-trifluoromethyl-substituted
diphenylacetylene 3g, wherein the strong electron-withdraw-
ing group largely inhibited the reaction (entry 7). Other
functional groups such as methyl and halides, including fluoro,
chloro, and bromo groups, were tolerated (entries 2 and 4−
6). When 1,2-bis(4-methoxyphenyl)ethyne (3c) was used, the
product 4c was formed in modest yield (entry 3), which may
be due to the interaction of MeOTf and the methoxy group.
To our delight, the structure of 4b was confirmed by single-
crystal X-ray diffraction (see the Supporting Information).
The reactions of o-fluoro- and o-methyl-substituted dipheny-
lacetylenes gave the desired products in moderate yields
(entries 8 and 9, respectively). The reaction of m-methyl-
substituted diarylacetylene 3j gave a mixture of two
regioisomers in a 3:1 ratio. A substrate with a naphthalene
nucleus, 1,2-bis(naphthalen-1-yl)acetylene (3k), afforded the
corresponding indenone 4k in 56% yield. Crystals of 4k
suitable for X-ray analysis were obtained (see the Supporting
Information), and this result further confirmed the formation
of indenone with the CS bond cleavage.
a
Reaction conditions: 0.5 mmol of alkyne, 0.75 mmol of 1a, and 1.5
b
mmol of MeOTf in 2 mL of DCE at 100 °C for 1.5 h. Isolated yields.
c
d
Yield for gram scale. At 120 °C for 12 h.
substrate, a single regioisomer was obtained in modest yield
(entries 1 and 2). The annulation occurred selectively in the
electron-rich benzene ring. This may occur because the
electron-rich benzene ring is more stable for formation of
intermediate B. When 1-(phenylethynyl)naphthalene (3n)
was employed, a single product 4n was obtained in 60% yield,
with the annulation occurring in the naphthalenyl group. To
our delight, the reaction could also proceed with aryl alkyl
alkynes. The reactions of 1-phenyl-1-propyne (3o), 1-phenyl-
1-butyne (3p), and 1-phenyl-1-hexyne (3q) afforded inden-
ones 4o, 4p, and 4q in 57%, 50%, and 55% yield, respectively,
Next, we tried a range of unsymmetrical diaryl alkynes with
1a and MeOTf (Table 3). When asymmetric diaryl alkynes
such as (4-methoxyphenyl)phenylacetylene (3l) or (4-
trifluoromethylphenyl)phenylacetylene (3m) was used as the
B
DOI: 10.1021/acs.orglett.5b02201
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Organic Letters
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Table 3. Synthesis of Indenones from Various
Unsymmetrical Alkynes
Scheme 3. Transformations of 4a into Other Substituted
Indenones
a
Scheme 4. Plausible Reaction Mechanism
a
Reaction conditions: 0.5 mmol of alkyne, 0.75 mmol of 1a, and 1.5
b
mmol of MeOTf in 2 mL of DCE at 100 °C for 1.5 h. Isolated yields.
c
At 120 °C for 12 h.
with the alkyl group at the 2-position. 1-Phenylacetylene failed
to undergo the desired reaction. When trimethylsilyl- or
bromo-substituted phenylacetylene was employed, the reac-
tion did not proceed.
It is noteworthy that there is a methylthio group at the 3-
position of the indenone, and it could be transformed into
other functional groups.8,9 As illustrated in Scheme 3, 3-
methylthio-2-phenyl-1H-inden-1-one (4a) could be trans-
formed into indenone 5 by treatment with Raney Ni in
refluxing ethanol. The 3-methylthio group could also be
converted into a phenyl group to give 3-phenylindenone 6 in
60% yield upon treatment with phenylmagnesium bromide
using Ni(PPh3)2Cl2 as a catalyst. The oxidation of 4a with m-
chloroperoxybenzoic acid (m-CPBA) afforded 3-methylsulfon-
yl-2-phenylindenone (7) in 75% yield. The 3-methylsulfonyl
group on the indenone ring could be easily replaced not only
by ethanol to generate 3-ethoxyindenone 8 in 66% yield but
also by morpholine to produce 3-aminoindenone 9 in 95%
yield.
intermediate 11. Finally, intramolecular Friedel−Crafts re-
action of 12 affords indenone imine 13, which undergoes
hydrolysis to form indenone 4.
To probe the reaction mechanism, mesityl isothiocyanate
(1b) instead of 1a was employed under the same reaction
conditions (Scheme 5). Indenone 4a was not obtained, but
instead indenone imine 13ba was isolated in 60% yield, which
indicates indenone imine 13 as the intermediate before
hydrolysis.
Scheme 5. Reaction of Mesityl Isothiocyanate with Alkyne
3a
On the basis of the above results and related precedents, a
plausible mechanism is proposed as follows (Scheme 4): First,
methylation of the isothiocyanate by MeOTf affords
carbenium ion A.7,10 Then the alkyne attacks the carbon
atom of A to afford intermediate B.11 Next, the strongly
nucleophilic sulfur atom attacks the carbenium in B to form
four-membered thiete 10,12 which is followed by ring opening
with C−S bond cleavage to form carbenium 12 via
C
DOI: 10.1021/acs.orglett.5b02201
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Tsutsumi, K.; Kagawa, N.; Kakiuchi, K.; Harada, Y.; Fukumoto, Y.;
Chatani, N.; Nishioka, T. Org. Lett. 2009, 11, 1777. (j) Chen, S.; Yu,
J.; Jiang, Y.; Chen, F.; Cheng, J. Org. Lett. 2013, 15, 4754. (k) Qi, Z.;
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(6) (a) Yan, X.; Zou, S.; Zhao, P.; Xi, C. Chem. Commun. 2014, 50,
2775. (b) Yan, X.; Yi, X.; Xi, C. Org. Chem. Front. 2014, 1, 657.
(7) Zhao, P.; Yan, X.; Yin, H.; Xi, C. Org. Lett. 2014, 16, 1120.
(8) Panda, K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H.
Synlett 2004, 449.
In conclusion, we have developed a MeOTf-induced
carboannulation between alkyl isothiocyanates and aryl
alkynes. This annulation represents the first example of
cleavage of the isothiocyanate CS bond for construction of
the carbocyclic compound. This reaction provides access to a
range of synthetically useful indenone derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
S
(9) Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Junjappa, H. J. Org.
Chem. 2006, 71, 1280.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02201.
(10) (a) Alder, R. W.; Phillips, J. G. E.; Huang, L.; Huang, X.
Methyltrifluoromethanesulfonate. In Encyclopedia of Reagents for
Organic Synthesis; John Wiley & Sons: Chichester, U.K., 2005.
(b) Murai, T.; Mutoh, Y.; Kato, S. Org. Lett. 2001, 3, 1993.
(c) Meyers, A. I.; Flanagan, M. E. Org. Synth. 1998, 9, 258.
(11) Wang, Y.; Chen, C.; Peng, J.; Li, M. Angew. Chem., Int. Ed.
2013, 52, 5323. (b) Su, X.; Chen, C.; Wang, Y.; Chen, J.; Lou, Z.; Li,
M. Chem. Commun. 2013, 49, 6752. (c) Wang, Y.; Chen, C.; Zhang,
S.; Lou, Z.; Su, X.; Wen, L.; Li, M. Org. Lett. 2013, 15, 4794.
(12) (a) Bur, S. K. Top. Curr. Chem. 2007, 274, 125. (b) Fang, Z.;
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(c) Fang, G.; Li, J.; Wang, Y.; Gou, M.; Liu, Q.; Li, X.; Bi, X. Org.
Lett. 2013, 15, 4126.
Experimental procedures, full characterization including
1H and 13C NMR data and spectra for all new
compounds, and X-ray structures of products 4b and 4k
(PDF)
Crystallographic data for 4b (CIF)
Crystallographic data for 4k (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cjxi@tsinghua.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21272132 and 21472106) and the
National Key Basic Research Program (973 Program) of
China (2012CB933402).
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DOI: 10.1021/acs.orglett.5b02201
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