Ruthenium(II)-Catalyzed Synthesis of Spirobenzofuranones by a Decarbonylative Annulation Reaction

Article abstract of DOI:10.1002/anie.201710049

The first decarbonylative insertion of an alkyne through C?H/C?C activation of six-membered compounds is reported. The Ru-catalyzed reaction of 3-hydroxy-2-phenyl-chromones with alkynes works most efficiently in the presence of the ligand PPh₃ to provide spiro-indenebenzofuranones. Unlike previously reported metal-catalyzed decarbonylative annulation reactions, in the present decarbonylative annulation reaction, the annulation occurs before extrusion of carbon monoxide.

Full text of DOI:10.1002/anie.201710049

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Accepted Article
Title: Ru(II)-Catalyzed Synthesis of Spiro Benzofuranones via
Decarbonylative Annulation Reaction
Authors: Partha P. P Kaishap, Gauri Duarah, Bipul Sarma, Dipak
Chetia, and Sanjib Gogoi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710049
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10.1002/anie.201710049
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Ru(II)-Catalyzed Synthesis of Spiro Benzofuranones via
Decarbonylative Annulation Reaction
P. P. Kaishapa, G. Duaraha, B. Sarmab, D. Chetiac and S. Gogoia*
Abstract: The first decarbonylative insertion of alkyne through C-
H/C-C activation of six membered compounds is reported. This Ru-
catalyzed reaction of 3-hydroxy-2-phenyl-chromones with alkynes
works most efficiently in the presence of ligand PPh3 to provide
spiro-indenebenzofuranones. Unlike the previously reported metal-
catalyzed decarbonylative annulation reactions, in the present
decarbonylative annulation reaction, the annulation occurs before
extrusion of carbon monoxide.
reported the first example of intermolecular decarbonylative
addition reaction of strained cyclobutenediones and
cyclobutenones with norbornene and ethylene.[3e-f] Concurrently,
the low valent metal complex Ni(COD)2 has been used for the
decarbonylative activation of C-N/C-O/C-C bonds of carbonyl
containing cyclic compounds and subsequent annulation
reactions with alkynes (Scheme 1, eqn 2).[4] While the
decarbonylative addition reactions with higher valent metals are
mainly limited to strained rings,[3] very recently, G. Dong and co-
workers have reported
a
directing group assisted
Cycloaddition reaction of π-systems is the most common
strategy to synthesize cyclic compounds.[1] In recent years, the
transition-metal-catalyzed activation of inert C-H/C-C bonds,
followed by insertion of π-systems has grown as the method of
choice to synthesize complex carbacycles and heterocycles.[2] In
particular, the metal-catalyzed decarbonylative activation of C-C
bonds of strained four membered cyclobutanones and insertion
of π-systems have been usually used for the synthesis of ring
structures (Scheme 1, eqn 1).[3] Kondo and Mitsudo have
decarbonylative cyclization reaction of less strained five-
membered isatins with alkynes for the synthesis of 2-quinolinone
derivatives (Scheme 1, eqn 3).[5] Nevertheless, the less strained
six-membered rings, to the best of our knowledge, have never
been studied for the decarbonylative C-C/C-H activation and π-
insertion reaction. In all the above mentioned, reported metal-
catalyzed decarbonylative cyclization reactions, insertion of the
π-systems occur after the extrusion of carbon monoxide via C-
C/C-N/C-O activations. Herein, in continuation of our studies on
metal-catalyzed novel transformations,[6] we describe an
unprecedented decarbonylative alkyne insertion reaction, where
insertion of the π-system occur before the extrusion of carbon
monoxide via C-H/C-C activations. Notably, this decarbonylative
cycloaddition reaction of 3-hydroxy-2-phenylchromones with
alkynes provides a discrete procedure for the synthesis of spiro-
indenebenzofuranones. Spiro-benzofuranones are the important
motifs that are widely distributed in bioactive compounds,
pharmaceuticals and natural products.[7] In particular, spiro-
cyclopentanebenzofuranone
and
spiro-
dihydroindenebenzofuranone are the substructures of some of
the recently isolated bioactive natural products (Figure 1).[7c-d]
Therefore, an efficient method to synthesize this substructure is
very essential.
Scheme 1. Examples of decarbonylative annulation reactions
[*]
P. P. Kaishap, G. Duarah and Dr. S. Gogoi
Chemical Sciences & Technology Division, CSIR-North East Institute of
Science and Technology, Jorhat-785006, AcSIR, India, Fax:
+913762370011 Tel.: +91 3762372948; skgogoi1@gmail.com;
sanjibgogoi@neist.res.in
.
Dr. B. Sarma, Department of Chemical Sciences, Tezpur University,
Napaam, Tezpur–784028, India
Figure 1. Representative examples of related natural products
Prof. Dr. D. Chetia, Department of Pharm. Sciences, Dibrugarh
University, Dibrugarh
Supporting information for this article can be found under:
Initially, the reaction conditions for the decarbonylative
annulation reaction were optimized using hydroxychromone 1a
and alkyne 2a (Table 1 and SI). Among the catalysts screened
1
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Table 1. Optimization of the reaction conditions for 3aa[a]
3aa in 85% yield (entries 5-8 & SI). This optimized condition was
then first utilized to study the scope of various 2-aryl-3-
hydroxychromones 1b-q for this annulation reaction with 2a. As
shown in Table 2, different electron-donating and electron-
withdrawing para-substituents such as methyl, methoxy, fluoro
and chloro on the 2-phenyl ring of 1b-e, tolerate the reaction
condition to afford good yields of spiro compounds 3ba-ea.
Similarly, methoxy substituent present at both meta and para
position of the 2-phenyl ring of 1f provided good yield of 3fa. The
substrates that have electron withdrawing substituents such as F,
Cl, CN and CF3 at meta position of 2-phenyl ring of 1g-j, were
also found to be good substrates for this reaction to provide
spiro compounds 3ga-ja. Then, the scope of 2-aryl-3-hydroxy
chromones that have substituents on the fused aromatic ring 1k-
m was studied. All the representative chromone derivatives
substituted with a methyl, methoxy and fluoro substituent 1k-m
turned out to be good substrates to afford 3ka-ma. The
disubstituted chromones substituted on the fused aryl ring 1n-o
Entry
Catalyst
Additive
Cu(OAc)2
CsOAc
AgOAc
CuBr2
Ligand
3aa (%)[b]
1
2
3
4
5
6
7
8
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
[RuCl2(p-cymene)2]
-
21
56
34
0
-
-
-
CsOAc
CsOAc
CsOAc
CsOAc
P(Cy)3
PPh3
76
85
56
62
Dppe[c]
(±)-BINAP[d]
Table 3: Scope of alkynes 2a-n with 1a[a]
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), catalyst (5.0 mol %),
additive (1.0 mmol), ligand (10 mol %) and tAmOH (5.0 mL) at 85 °C under air
for 10 h; unless otherwise mentioned. [b] Isolated yields. [c] 1,4-
Bis(diphenylphosphino)ethane.
binaphthalene.
[d]
(±)-2,2′-Bis(diphenylphosphino)-1,1′-
Table 2: Scope of chromones 1b-q with 2a[a]
[a] Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), Ru-catalyst (5.0 mol %),
t
PPh3 (10 mol %), CsOAc (1.0 equiv) in AmOH (5.0 mL) was heated at 85 oC
for 10 h under air.
[a] Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), Ru-catalyst (5.0 mol %),
t
PPh3 (10 mol %) and CsOAc (1.0 equiv) in AmOH (5.0 mL) was heated at 85
or substituted both on the fused phenyl ring and 2-phenyl ring 1p
were also found to be good substrates for the reaction to provide
3na-pa. The 2-heteroaryl substituted chromone 1q also
tolerated the reaction condition well to afford 3qa in good yield.
However, other 2-heteroaryl substituted chromones such as 2-
oC for 10 h under air.
to perform this reaction, [RuCl2(p-cymene)2] provided the highest
yield of the annulated product 3aa in the presence of additive
CsOAc (entry 2). Screening of some monodented and bidented
phosphine ligands revealed PPh3 as the best ligand to afford
(furan-2-yl)-3-hydroxy-4H-chromen-4-one
and
3-hydroxy-2-
2
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(pyridin-4-yl)-4H-chromen-4-one, tested for this annulation
reaction were not found to be good substrates. The annulation
reactions of 1g-j,1p with 2a were highly regioselective. Next, the
scope of alkynes 2a-n for this annulation reaction was studied
with 1a (Table 3). The diaryl substituted alkynes substituted with
electron-donating and electron-withdrawing groups such as
methyl, methoxy and fluoro on the phenyl rings 2b-d provided
very good yields of 3ab-ad. The diheteroaryl substituted alkyne
1e also tolerated the reaction condition to provide 3ae. The
unsymmetrical diaryl substituted and arylheteroaryl substituted
alkynes 2f-h provided a mixture of isomers 3af-ah. The
annulation reactions of unsymmetrical arylalkyl substituted
alkynes 2i-m with 2a were highly regioselective to provide single
isomers of the spiro compounds 3ai-am. Similarly, the aryl and
ester group containing alkyne 2n also turned out to be very good
substrate for this reaction to afford regioselective product 3an
(10:1). However, under the standard reaction condition, attempts
to synthesize the spiro compounds with dialkyl substituted
symmetrical and unsymmetrical alkynes met with failure. The
structure of the compounds were determined by spectroscopic
studies and finally confirmed by single X-ray crystallographic
studies of compound 3fa.[8] Previous studies on the transition-
metal-catalyzed annulation reactions showed that the alkyne
insertion phenomenon was mainly controlled by electronic effect
rather than steric effect.[2f-h] Thus, similar to the previous reports,
it is difficult to envisage the regioselectivity of the unsymmetrical
diaryl substituted alkynes in the present reaction, though with
some of the unsymmetrical diaryl alkynes good regioselectivity
was observed.[2f-h] Nevertheless, the annulation pattern of
unsymmetrical arylalkyl substituted alkynes in the present
reaction is similar to the previously reported transition-metal-
catalyzed annulation reactions, where the electron rich carbon
center of the alkyne favorably binds with the metal to furnish
regioselectivity into the final annulated products.[2f-i][5]
(Scheme 3, eqn 1), which indicates a nonreversible Ru-C bond
formation. To determine the kH/kD, the intermolecular competitive
experiment between 1a and 1a-D5 with 2a was performed which
provided kH/kD = 3 (Scheme 3, eqn 2). The competitive parallel
experiments, performed using substrates 1a and 1a-D5 with 2a
provided kH/kD = 2.6 (Scheme 3, eqn 3).[9] These results indicate
the Ru-C bond formation step might be the rate determining step
of this reaction. Furthermore, the elimination of CO from the
reaction mixture was proved by phosphomolibdic acid-PdCl2 test
(Figure SI-1, SI).[10] In this test, the evolved CO is oxidized to
CO2 in the presence of phosphomolibdic acid [H3PO4(MoVIO3)12]
Scheme 3. Isotopically labeled experiments
and PdCl2. During this process, phosphomolibdic acid which is
yellow in color gets reduced into mixed valence molybdate
complex (MoV MoVI), which is blue-green in color. To
demonstrate the synthetic utility of this method, some other
transformations of spiro benzofuranone 3da were carried out
(Scheme 4). Hydrogenation of 3da in the presence of Pd/C
provided a mixture of spiro benzofurans 4a and 4b which were
separated by silica gel column chromatography. The Wittig
reaction of 3da and methyltriphenylphosphonium bromide
provided good yield of spiro benzofuran 4c. Similarly, selective
reduction of keto functionality of 3da with NaBH4 afforded spiro
benzofuran 4d.
Scheme 2. Competitive experiments
The competitive experiment performed between the electron-
rich alkyne 2c and electron-poor alkyne 2d with 1a showed that
2d reacted faster than 2c (3ac:3ad = 1:1,8, Scheme 2). Similarly,
another competitive reaction between electron-rich chromone 1l
and electron-poor chromone 1m with 2a displayed preferential
conversation of 1l into its corresponding product 3la (3la:3ma =
1.5:1, Scheme 2). The reaction of 1a alone in CD3OD under
standard condition could not afford the D/H exchanged product
Scheme 4. Transformation of spiro benzofuranone
3
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Based on these studies as well as literature evidences,[4,5,11]
a
Wang, Y. Wang, Chem. Asian J. 2010, 5, 1072-1088; (d) B. Heller, M.
Hapke, Chem. Soc. Rev. 2007, 36, 1085-1094.
possible mechanism is proposed in Scheme 5. The active
catalyst A first forms Ru(II) complex B by eliminating two
molecules of acetic acid which might be the rate determining
step. Insertion of alkyne 2a in between C-Ru bond of complex B
affords complex C. Reductive elimination of the metal from C,
followed by carbonyl group assisted oxidative addition of the
eliminated Ru(0) into C(4o)-C(carbonyl) bond might afford
complex D.11b-c Next, decarbonylation and reductive elimination
of the metal in the presence of acetic acid affords 3aa and
regenerates the active catalyst A.
[2]
For selected recent reviews and articles on C-H activation, see: (a) S.
Santoro, S. I. Kozhushkov, L. Ackermann, L. Vaccaro, Green Chem.
2016, 18, 3471-3493; (b) Y. Segawa, T. Maekawa, K. Itami, Angew.
Chem. Int. Ed. 2015, 54, 66-81; Angew. Chem. 2015, 127, 68-83; (c) J.
Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369-375; (d) L.
Ackermann, Chem. Rev. 2011, 111, 1315-1345; (e) J. Wencel-Delord,
T. Droge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740-4761; (f)
M. P. Huestis, L. Chan, D. R. Stuart, K. Fagnou, Angew. Chem. Int. Ed.
2011, 50, 1338-1341; Angew. Chem. 2011, 123, 1374-1377; (g) D. R.
Stuart, P. Alsabeh, M. Kuhn, K. Fagnou, J. Am. Chem. Soc. 2010, 132,
18326-18339; (h) G. Zhang, H. Yu, G. Qin, H. Huang, Chem. Commun.
2014, 50, 4331-4334; (i) A. Seoane, N. Casanova, N. Quiñones, J. L.
Mascareñas, M. Gulías, J. Am. Chem. Soc. 2014, 136, 834-837.
(a) T. Xu, N. A. Savage, G. Dong, Angew. Chem. Int. Ed. 2014, 53,
1891-1895; Angew. Chem. 2014, 126, 1922-1926; (b) P.-h. Chen, T. Xu,
G. Dong, Angew. Chem. Int. Ed. 2014, 53, 1674-1678; Angew. Chem.
2014, 126, 1700-1704; (c) G. Lu, C. Fang, T. Xu, G. Dong, P. Liu, J.
Am. Chem. Soc. 2015, 137, 8274-8283; (d) R. Zeng, P.-h. Chen, G.
Dong, ACS Catal. 2016, 6, 969-973; (e) T. Kondo, A. Nakamura, T.
Okada, N. Suzuki, K. Wada, T. A. Mitsudo, J. Am. Chem. Soc. 2000,
122, 6319-6320; (f) T. Kondo, Y. Taguchi, Y. Kaneko, M. Niimi, T.-A.
Mitsudo, Angew. Chem. Int. Ed. 2004, 43, 5369-5372; Angew. Chem.
2004, 116, 5483-5486.
[3]
[4]
(a) Y. Kajita, S. Matsubara, T. Kurahashi, J. Am. Chem. Soc. 2008, 130,
6058-6059; (b) Y. Kajita, T. Kurahashi, S. Matsubara, J. Am. Chem.
Soc. 2008, 130, 17226-17227; (c) T. Shiba, T. Kurahashi, S. Matsubara,
J. Am. Chem. Soc. 2013, 135, 13636-13639.
[5]
[6]
R. Zeng, G. Dong, J. Am. Chem. Soc. 2015, 137, 1408-1411.
(a) P. P. Kaishap, B. Sarma, S. Gogoi, Chem. Commun. 2016, 52, 9809-
9812; (b) S. Baruah, S. Borthakur, S. Gogoi, Chem. Commun. 2017, 53,
9133-9135.
Scheme 5. Possible reaction mechanism
In summary, we have developed a novel Ru(II)-catalyzed
decarbonylative π-insertion reaction of less strained six-
membered ring compound. This annulation reaction of 3-
hydroxy-2-phenyl chromones and di-substituted alkynes
proceeds via C-H/C-C activation, alkyne insertion and
decarbonylation reactions, providing good yields of spiro-
indenebenzofuranones which are the key skeleton of some of
the recently isolated bioactive natural products.
[7]
(a) C. Guo, M. Schedler, C. G. Daniliuc, F. Glorius, Angew. Chem. Int.
Ed. 2014, 53, 10232-10236; Angew. Chem. 2014, 126, 10397-10401;
(b) H. Ni, Z. Yu, W. Yao, Y. Lan, N. Ullah, Y. Lu, Chem. Sci. 2017, 8,
5699-5704; (c) Q. Luo, L. Di, W.-F. Dai, Q. Lu, Y.-M. Yan, Z.-L. Yang,
R.-T. Li; Y.-X. Cheng, Org. Lett. 2015, 17, 1110-1113; (d) Q.-M. Li, J.-G.
Luo, Y.-M. Zhang, Z.-R. Li, X.-B. Wang, M.-H. Yang, J. Luo, H.-B. Sun,
Y.-J. Chen, L.-Y. Kong, Chem. Eur. J. 2015, 21, 13206-13209; (e) Y.-M.
Yan, X.-L. Wang, Q. Luo, L.-P. Jiang, C.-P. Yang, B. Hou, Z.-L. Zuo, Y.-
B. Chen, Y.-X. Cheng, Phytochemistry, 2015, 114, 155-162; (f) D.
Magdziak, S. J. Meek, T. R. R. Pettus, Chem. Rev. 2004, 104, 1383-
1430.
Experimental Section
Typical experimental procedure:
A solution of 3-hydroxy-2-phenyl-
[8]
[9]
CCDC 1574292 contains the crystallographic data of 3fa.
chromone (1, 0.3 mmol), alkyne (2, 0.3 mmol), [RuCl2(p-cymene)]2 (5.0
mol %), PPh3 (10 mol %) and CsOAc (1.0 equiv) in tAmOH (5.0 mL) was
stirred at 85 oC under open air for 10 hours. The solvent was removed
under vacuo and the crude reaction mixture was poured into water and
extracted with dichloromethane (20 mL x 2). The organic layer was then
washed with brine and dried over anhydrous Na2SO4. The solvent was
removed under vacuo and the crude product obtained was purified by
silica gel (100-200 mesh) column chromatography using EtOAc/Hexane
(1:9) as the eluant to afford spiro benzofuranone 3.
(a) E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51,
3066–3072; Angew. Chem. 2012, 124, 3120–3126; (b) J. Mo, L. Wang,
X. Cui, Org. Lett. 2015, 17, 4960–4963.
[10] (a) A. Verma, S. Kumar, Org. Lett. 2016, 18, 4388-4391; (b) F. Feigl, V.
Anger, Spot Tests in Inorganic Analysis, 6th ed.; Elsevier: Amsterdams,
1972; pp 168-169.
[11] (a) J. Wu, W. Xu, Z.-X. Yu, J. Wang, J. Am. Chem. Soc. 2015, 137,
9489−9496; (b) T. Kondo, A. Nakamura, T. Okada, N. Suzuki, K. Wada,
T.-a. Mitsudo, J. Am. Chem. Soc. 2000, 122, 6319–6320; (c) Y.
Yamamoto, S. Kuwabara, H. Hayashi, H. Nishiyama, Adv. Synth. Catal.
2006, 348, 2493–2500; (d) T. Inami, T. Kurahashi, S. Matsubara, Org.
Lett. 2014, 16, 5660−5662.
Acknowledgements
Authors thank SERB, New Delhi, for financially supporting us
with GPP-0303 (YSS/2014/001018) project. P. P. Kaishap
thanks UGC for the fellowship. We are grateful to the Director,
CSIR-NEIST for his keen interests.
Keywords: Decarbonylation • annulation reaction • spiro-
benzofuranone • C-H activation • ruthenium catalysis
[1]
For selected books and reviews on cycloaddition reaction, see: (a)
Advances in Cycloaddition; D. P. Curran, M. Lautens, M. Harmata,
Eds.; JAI, Press Inc: Stamford, CT, 1988-1999; Vol. 1-6; (b) K. E. O.
Ylijoki, J. M. Stryker, Chem. Rev. 2013, 113, 2244-2266; (c) Z.-X. Yu, Y.
4
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Entry for the Table of Contents
COMMUNICATION
P. P. Kaishap, G. Duarah, B. Sarma, D.
Chetia and S. Gogoi*
Page 1 – Page 4
Ru(II)-Catalyzed Synthesis of Spiro
Benzofuranones via Decarbonylative
Annulation Reaction
Ru(II)-Catalyzed C-H/C-C activation, alkyne insertion and decarbonylation reaction
of 3-hydroxy-2-phenyl chromones and di-substituted alkynes afforded good yields
of spiro-indenebenzofuranones.
5
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