Nickel-catalyzed cycloadditions of thiophthalic anhydrideswith alkynes

Article abstract of DOI:10.1021/ol200336c

Nickel-catalyzed cycloadditions have been developed where thiophthalic anhydrides reactwith alkynes to afford substituted sulfur-containing heterocyclic compounds. Selective formations of thioisocoumarins, benzothiophenes, and thiochromoneswre accomplishe

Full text of DOI:10.1021/ol200336c

ORGANIC
LETTERS
2011
Vol. 13, No. 8
1912–1915
Nickel-Catalyzed Cycloadditions of
Thiophthalic Anhydrides with Alkynes
Tasuku Inami, Yoko Baba, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto 615-8510, Japan
tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp; matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Received January 20, 2011
ABSTRACT
Nickel-catalyzed cycloadditions have been developed where thiophthalic anhydrides react with alkynes to afford
substituted sulfur-containing heterocyclic compounds. Selective formations of thioisocoumarins, benzothiophenes,
and thiochromones were accomplished with three different reaction conditions.
Recently, we have reported nickel-catalyzed cycloadditions
of phthalic anhydrides with alkynes to afford isocoumarins.1
Each reaction is supposed to proceed via oxidative addi-
tion of phthalic anhydride to nickel(0), decarbonylation,
and insertion of alkyne, followed by reductive elimination.
As a result, the reaction became equivalent to a substitu-
tion reaction by replacing a carbon monoxide with an
alkyne in a phthalic anhydride through the catalytic pro-
cess. The results prompted us to investigate the versatility
of such reactions to afford heterocyclic compounds. When
this method was examined with use of thiophthalic anhy-
dride as a starting compound, a mixture of three different
types of products was obtained (Scheme 1). Thus, we
envisioned that we might prepare three different heterocyclic
compounds selectively from a single starting heterocyclic
compound by tuning the nickel catalyst. Herein, we report
our results of the nickel-catalyzed selective synthesis of
sulfur-containing heterocyclic compounds from a thioph-
thalic anhydride using such an approach.2,3
Scheme 1. Nickel-Catalyzed Cycloaddition of a Thiophthalic
Anhydride with an Alkyne
Initially, it was found that the reaction of thiophthalic
anhydride 1with 4-octyne (2a) in the presence of Ni(0)/PMe3
catalyst in refluxing toluene afforded thioisocoumarin 3a
in 11% yield along with benzothiophene 4a in 11% yield and
thiochromone 5a in 26% yield (Table 1, entry 1). According
to our results of decarbonylative cycloaddition of phthalic
anhydrides with alkynes, in which the addition of a Lewis
acid promoted the reaction process,1 we presumed that an
addition of Lewis acid to the reaction would alsoaccelerate
the formation of thioisocoumarin 3a. Indeed, detailed
examination of the reaction conditions revealed that on
(1) Kajita, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2008,
130, 17226.
(2) Sulfur-containing heterocyclic compounds are widely distributed
in nature, and their biological and physiological effects are of interest.
Pharmaceutical drugs, such as Raloxifene, Zileuton, Sertaconazole,
Arzoxifene, Metizoline, and Sb-271046, contain benzothiophene
structures.
(3) (a) Tseng, N.-W.; Lautens, M. J. Org. Chem. 2009, 74, 1809. (b)
Benati, L.; Calestani, G.; Leardini, R.; Minozzi, M.; Nanni, D.; Spag-
nolo, P.; Strazzari, S.; Zanardi, G. J. Org. Chem. 2003, 68, 3454. (c) Yue,
D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (d) Nakamura, I.; Sato,
T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 4473. (e) Leardini,
R.; Franco Pedulli, G.; Tundo, A.; Zanardi, G. J. Chem. Soc., Chem.
Commun. 1985, 1390.
r
10.1021/ol200336c
Published on Web 03/07/2011
2011 American Chemical Society

addition of 10 mol % of Lewis acid (MAD: methylalumi-
num bis(2,6-di-tert-butyl-4-methylphenoxide), the reaction
proceeded smoothly to furnish 3a in 99% isolated yield
(entry 4). Among phosphine ligands examined, PPr3 gave
the best yield with a combination of MAD (entries 2-4).
Increasing or decreasing the amount of MAD (50 mol % or
1 mol %), or replacing it with another Lewis acid, such as
B(C6F5)3 or ZnCl2, gave inferior results from the points of
yield and selectivity (entries 5-8).
2e, 2f, and 2g also gave the cycloadducts in good yields
consisting of regioisomers in a range of 1/1 to 5/1 ratio. By
analogy to the mechanism of the previously reported nickel-
catalyzed reaction of phthalic anhydrides with alkynes to
form isocoumarins,1,4,5 it is reasonable to consider that the
catalytic cycle of the present reactions should consist of
oxidative addition of an anhydride S-CO bond to nickel.6
Subsequent decarbonylation and coordination of alkyne
affords five-membered nickelacycle. The alkyne would then
insert into the nickelacycle, which undergoes reductive
elimination to give 3 and regenerates the starting Ni(0).
We next turned our attention to the selective synthesis of
benzothiophenes 4 with reactions of 1 and 2. Thus, our
initial investigation involvedstudyingthe effectof different
ligands. The cycloaddition with PPr3 as a ligand afforded
4a in 23% yield as a major adduct (Table 2, entry 2). It was
found that sterically hindered trialkylphosphine PCy3 gave
the best result with respect to both yield of 4a and product
selectivity (entry 3). In other reaction solvents, such as
benzene, MeCN, and 1,4-dioxane, yields were even lower
(entries 4-6). Further examination of the reaction condi-
tions revealed that increasing the concentration of 1 in the
reaction mixture improved the yield of 4a. Consequently,
benzothiophene 4a was obtained as a sole product in 93%
isolated yield when the reaction was carried out in a 0.34 M
toluene solution of 1 (entry 7).
Table 1. Cycloaddition of 1 with 2a To Form 3aa
yield (%)
entry
ligand
additive (mol %)
3a
4a
5a
1
2
3
4
5
6
7
8
PMe3
PMe3
PCy3
PPr3
PPr3
PPr3
PPr3
PPr3
-
11
11
15
99
62
93
91
24
11
<1
<1
<1
12
<1
<1
28
26
10
10
<1
<1
<1
<1
13
MAD (10)
MAD (10)
MAD (10)
MAD (1)
MAD (50)
B(C6F5)3 (10)
ZnCl2 (10)
Table 2. Cycloaddition of 1 with 2a To Form 4aa
a All reactions were carried out with Ni(cod)2 (10 mol %), ligand
(40 mol %), 1 (0.2 mmol), and 2a (0.4 mmol) at 130 °C for 3 h.
Scheme 2. Scope of Cycloaddition To Form Thioisocoumarins 3
yield (%)
entry
ligand
solvent
3a
4a
5a
1
2
3
4
5
6
7
PMe3
PPr3
PCy3
PCy3
PCy3
PCy3
PCy3
toluene (0.17 M)
toluene (0.17 M)
toluene (0.17 M)
benzene (0.17 M)
MeCN (0.17 M)
1,4-dioxane (0.17 M)
toluene (0.34 M)
11
6
11
23
70
56
23
33
93
26
6
<1
<1
<1
5
<1
<1
<1
<1
<1
<1
a All reactions were carried out with Ni(cod)2 (10 mol %), ligand (40
mol %), 1 (0.2 mmol), and 2a (0.4 mmol) at 130 °C for 5 h.
(5) (a) Yoshino, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2009, 131, 7494. (b) Ooguri, A.; Nakai, K.; Kurahashi, T.; Matsubara, S.
J. Am. Chem. Soc. 2009, 131, 13194.
The cycloaddition is also compatible with aryl-substituted
alkyne 2b and afforded 3b in 99% isolated yield (Scheme 2).
The reaction of 1 with unsymmetrical alkynes such as 2c, 2d,
(6) For addition of the S-CO2R bond to alkynes, see: (a) Hua, R.;
Takeda, H.; Onozawa, S.; Abe, Y.; Tanaka, M. J. Am. Chem. Soc. 2001,
123, 2899. For addition of the S-C(O)R bond to alkynes, see:(b) Sugoh,
K.; Kuniyasu, H.; Sugae, T.; Ohtaka, A.; Takai, Y.; Tanaka, A.;
Machino, C.; Kambe, N.; Kurosawa, H. J. Am. Chem. Soc. 2001, 123,
5108. For addition of the S-C(O)NR2 bond to alkynes, see:(c)
Toyofuku, M.; Fujiwara, S.; Kuniyasu, H.; Kambe, N. J. Am. Chem.
Soc. 2005, 127, 9706.
(4) (a) Trost, B. M.; Chen, F. Tetrahedron Lett. 1971, 12, 2603. (b)
Sano, K.; Yamamoto, T.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1984, 57,
2741. (c) Yamamoto, T.; Sano, K.; Yamamoto, A. J. Am. Chem. Soc.
1987, 109, 1092. (d) Fischer, R.; Walther, D.; Kempe, R.; Sieler, J.;
€
Schonecker, B. J. Organomet. Chem. 1993, 447, 131.
Org. Lett., Vol. 13, No. 8, 2011
1913

With the optimized reaction conditions, the scope of the
reaction was briefly examined and the results are summar-
ized in Scheme 3. The reaction of 1 to tolane (2b) also
furnished 4b in 78% yield as a sole product. Unsymme-
trical alkynes, such as 2-octyne (2c) and 1-phenyl-1-pro-
pyne (2d), alsoreacted with1 toaffordthe correspondingly
substituted 4c and 4b consisting of regioisomers in a ratio
of 5/3 and 10/1. The reaction of 1tounsymmetricalalkynes,
containing sterically hindered substituents such as tBu and
SiMe3, gave adducts 4e and 4f in 99% and 60% yields,
respectively, with good regioselectivity, while the reaction
of 1 with not sterically but electronically differentiated
diaryl-substituted alkyne 2g afforded 4g in 72% yield, con-
sisting of regioisomers in a ratio of 1/1.
elimination of 3 from nickelacycle B and reoxidative
additionof3, afford intermediate C. Reductiveelimination
provides 4 and regenerates starting Ni(0) catalyst. The
regioselectivity of the reaction can be rationalized as due to
the direction of alkyne insertion, in which the steric
repulsive interaction is minimal between the bulkier RL
substituent on alkyne and the nickel/ligand complex.
Scheme 5. Plausible Reaction Mechanism for Formation of 4
Scheme 3. Scope of Cycloaddition To Form Benzothiophenes 4
Table 3. Cycloaddition of 1 with 2a To Form 5aa
Scheme 4. Decarbonylation of 3f
yield (%)
entry
solvent
reaction temp (°C)
3a
4a
5a
1
2
3
4
5
toluene
benzene
toluene
benzene
benzene
130
130
80
11
4
11
12
<1
<1
6
26
89
23
28
60
<1
<1
4
80
90
a All reactions were carried out with Ni(cod)2 (10 mol %), ligand (40
mol %), 1 (0.2 mmol), and 2a (0.4 mmol) for 5 h.
The formation 4 can be ascribed to additional decarbony-
lation of 3 with Ni catalyst. In fact, the treatment of 3a with
the reaction conditions for formation of benzothiophene 4
(Ni(0)/PCy3) afforded 4a in 98% yield (Scheme 4). The
result that decarbonylation of 3f affords 4f0 in 22% yield
suggests that 3f is more resistant to oxidative addition of
Ni(0) than the regioisomer 3f0, leading to the observation
of 4f0 as the minor product in the formation of benzothio-
phene 4. Thus, a plausible reaction pathway to account for
the formation of benzothiophenes 4 based on the observed
results is outlined in Scheme 5. The catalytic cycle for
formation of 4 may consist of the oxidative addition of
thiophthalic anhydride to Ni(0). The use of bulky ligand
PCy3 inhibits insertion of alkyne to a nickelacycle A, and
decarbonylation occurs prior to alkyne insertion. Subse-
quent carbonickelation of alkyne, followed by reductive
The results of selective synthesis of thioisocoumarins 3
and benzothiophenes 4 encouraged us to investigate the
selective synthesis of thiochromones 5. To our delight,
preferential formation of 5 was accomplished by changing
the reaction solvent. That is, the reaction of 1 with 2a in
benzene at 130 °C afforded 5a as a major product in 89%
yield (Table 3, entry 2). Attempts to lower the reaction
temperature to improve the selectivity decreased the yield
of 5a in 28% yield (80 °C, entry 4) and 60% yield (90 °C,
entry 5). We then examined the scope of the reaction to
form thiochromones; the results are summarized in
Scheme 6. Isolated yields ranged from 44% to 78% with
aryl-, alkyl-, and trimethylsilyl-substituted alkynes.
1914
Org. Lett., Vol. 13, No. 8, 2011

Lastly, we demonstrated accumulation of two different
types of sulfur heterocycle in one molecule by selective
stepwise reactions (Scheme 8). Thus, the reaction of 1 with
1,4-bis(trimethylsilyl)-1,3-butadiyne (6), which contains
two conjugated carbon-carbon triple bonds, gave the
corresponding benzothiophene 7 in 75% yield regioselec-
tively with reaction conditions of Ni(0)/PCy3. Subsequent
reaction of 7 with 1 in the presence of Ni(0)/PPr3/MAD
gave the adduct 8 in 36% yield.
Scheme 6. Scope of Cycloaddition To Form Thiochromones 5
Scheme 8. Accumulative Reaction of 1 to 1,3-Butadiyne 8
Scheme 7. Plausible Reaction Mechanism for Formation of 5
In conclusion, cycloadditions of thiophthalic anhydride
with alkynes to afford sulfur-containing heterocyclic com-
pounds were successfully developed by using nickel
catalysts.8 It was demonstrated that the nickel-catalyzed
reaction gave three types of compounds selectively
depending on the reaction conditions employed. The
use of Ni(0)/PPr3 catalyst in combination with Lewis
acid afforded thioisocoumarin 3. On the contrary, the
use of Ni(0)/PCy3 catalyst in the reaction afforded
benzothiophene 4, while the use of Ni(0)/PMe3 catalyst
furnished thiochromone 5.
Acknowledgment. This work was supported by Grants-
in-Aid from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan. T.K. also acknowledges
the Asahi Glass Foundation and Kansai Research Foun-
dation for the Promotion of Science.
The proposed catalytic cycle for formation of 5 is illu-
strated in Scheme 7. The reaction is initiated by oxidative
addition of thiophthalic anhydride to Ni(0). Sterically less
hindered PMe3 ligand allowed carbonickelation of alkyne
prior to decarbonylation to afford the eight-membered
nickelacycle E. Subsequent reductive elimination and re-
oxidative addition gives the eight-membered nickelacycle
F. Following decarbonylation and reductive elimination
furnishes 5. The observed regioselectivity in the reaction is
ascribed to the properties of substituted groups on alkenyl 2;
this stabilizes a developing positive charge on the alkyenyl
carbon atom adjacent to nickel in nickelacycle E.7 The effects
of benzene as reaction solvent are not clear at the moment;
however, we assumed that vigorous refluxing at 130 °C may
promote exhaust of CO from the reaction system efficiently.
Supporting Information Available. Experimental pro-
cedures including spectroscopic and analytical data of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Note Added after ASAP Publication. Due to a produc-
tion error this paper was published ASAP without the
Table corrections applied. The correct version reposted
March 10, 2011.
(8) Terminal alkynes, such as 1-octyne and phenylacetylene, failed to
participate in the reactions, presumably due to rapid oligomerization of
alkynes. For an example, see: Connor, D. T.; Cetenko, W. A.; Mullican,
M. D.; Sorenson, R. J.; Unangst, P. C.; Weikert, R. J.; Adolphson, R. L.;
Kennedy, J. A.; Thueson, D. O. J. Med. Chem. 1992, 35, 958.
(7) Fujiwara, K.; Kurahashi, T.; Matsubara, S. Org. Lett. 2010, 12,
4548.
Org. Lett., Vol. 13, No. 8, 2011
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