Palladium(II)-catalyzed stereospecific three-component domino reactions of diyne-enones, nucleophiles, and vinyl ketones

Article abstract of DOI:10.1002/asia.201100770

One thing leads to another: A novel palladium(II)-catalyzed three-component domino reaction of diyne-enones with nucleophiles and vinyl ketones or acrolein under mild conditions provides efficient, general, and atom-economical access to multifunctionalize

Full text of DOI:10.1002/asia.201100770

COMMUNICATION
DOI: 10.1002/asia.201100770
Palladium(II)-Catalyzed Stereospecific Three-Component Domino
Reactions of Diyne-enones, Nucleophiles, and Vinyl Ketones
Renrong Liu[a] and Junliang Zhang*[a, b]
Transition-metal-catalyzed multicomponent domino reac-
tions have received much attention due to their unrivaled
power in efficient construction of architecturally complex
molecules from relatively simple starting materials.[1] Furans
are a class of important subunits that appear in many bioac-
tive natural products and man-made drugs and are impor-
tant building blocks in organic synthesis.[2] Among those
methodologies available for synthesis of highly substituted
furans,[3] much recent attention has focused on the develop-
ment of metal-catalyzed single or two-component reactions
of cyclopropyl ketones,[4] cyclopropenyl ketones,[5] allenyl
ketones,[6] 3-alkyn-1-ones,[7] (Z)-2-en-4-yn-1-ols,[8] 1-(1-alkyn-
yl)-cyclopropyl ketones,[9] 2-(1-alkynyl)-2-alken-1-ones,[10,11]
and so forth.[12] However, methods for efficient synthesis of
2,3-cyclo[b]furans have been rarely reported.[13,14] We report
herein a novel atom-economical palladium(II)-catalyzed
three-component domino reaction of diyne-enones with nu-
cleophiles and vinyl ketones or acrolein, leading to multi-
functional 2,3-cyclo[b]furan along with a stereodefined tetra-
substituted olefin.
With the best conditions in hand, we tested different nu-
cleophiles (Table 1). The corresponding furans can be ob-
tained in high yields when different alcohols are used as nu-
Table 1. Variation of nucleophiles and vinyl ketones.[a]
Entry
NuH (3)
R=(2)
t [h]
Product
(Yield [%])[b]
AHCTUNGTRENNUNG
1
2
3
MeOH (3a)
iPrOH (3b)
BnOH (3c)
Me (2a)
2a
2a
8
12
12
4aaa (78)
4aba (59)
4aca (61)
4
(3d)
2a
8
4ada (73)
5
6
7
8
9
10
H2O (3e)
2a
Ph (2b)
4-ClC6H4 (2c)
4-MeOC6H4 (2d)
CH=CHPh (2e)
OMe (2 f)
5
8
8
8
8
4aea (58)
4aab (67)
4aac (81)
4aad (69)
4aae (80)
4aaf (0)
3a
3a
3a
3a
3a
Initially, we examined the palladium-catalyzed three-com-
ponent reaction of diyne-enone 1a with MeOH and vinyl
methyl ketone 2a under different reaction conditions. After
numerous attempts,[15] we obtained the best result at room
temperature in CH3CN with 10.0 equivalents MeOH as nu-
cleophile and 6.0 equivalents vinyl methyl ketone as electro-
20
[a] All reactions were carried out under the optimal conditions reported
in the text. The product 4aaa means that the starting materials were 1a,
2a, and 3a. [b] Yield of isolated product.
philic acceptor and 10 mol% [PdCl
respectively. Other catalyst such as Pd
(dba=dibenzylideneacetone), [Pd
(h3-C3H5)2Cl2], and CuI
are not effective at all. Reducing the catalyst loading or the
amount of nucleophile and electrophile would result in
slightly lower yields and longer reaction times.
(CH3CN)2] as catalyst,
A
E
cleophiles (Table 1, entries 2–4). Gratifyingly, water can act
as nucleophile to give the corresponding furan with a further
convertible alcohol in 58% yield (Table 1, entry 5). Further-
more, vinyl phenyl ketones 2b–2d can also be used as elec-
trophilic acceptors to afford the corresponding furans 4aab–
4aad in good yields (Table 1, entries 6–8), in which the
weakly electron-withdrawing chlorine substituent on the
aryl ring leads to higher yield. To our delight, ketone 2e
with olefinic double bonds can also act as the electrophilic
acceptor to afford 4aae selectively in high yield, in which
only the terminal alkene is involved in the transformation
(Table 1, entry 9). However, the acrylate 2 f cannot be ap-
plied to this transformation (Table 1, entry 10).
AHCTUNGTRENNUNG
[a] R. Liu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, Department of Chemistry
East China Normal University
3663 N. Zhongshan Road, Shanghai 200062 (P.R. China)
Fax : (+86)21-6223-3213
E-mail: jlzhang@chem.ecnu.edu.cn
[b] Prof. Dr. J. Zhang
We next examined the scope of the diyne-enone compo-
nent under optimal conditions (Table 2). Electron-deficient
and electron-rich aryl groups can be introduced to the
alkyne moiety R3 to give the corresponding products in high
yields (Table 2, entries 1–6). The convertible Br group is tol-
erated in this reaction, providing a convenience way to
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100770.
294
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 294 – 297

Table 2. Variation of diyne-enone components.
Entry
Ketone 1
t [h]
Product
(Yield [%])[b]
R1/R2/R3
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
Ph/Ph/4-MeC6H4 (1b)
Ph/Ph/4-MeOC6H4 (1c)
Ph/Ph/4-MeCOC6H4 (1d)
Ph/Ph/4-EtO2CC6H4 (1e)
Ph/Ph/3-CF3C6H4 (1 f)
Ph/Ph/4-BrC6H4 (1g)
Me/Ph/Ph (1h)
Ph/4-ClC6H4/Ph (1i)
Ph/Ph/4-NO2C6H4 (1j)
4-ClC6H4/Ph/Ph (1k)
Ph/Ph/H (1l)
8
8
8
8
8
8
6
8
8
10
20
20
16
4baa (71)
4caa (70)
4daa (76)
4eaa (71)
4 faa (75)
4gaa (72)
4haa (42)
4iaa (71)
4jaa (78)
4kaa (61)
4laa (44)
4maa (47)
4naa (32)
9
10
11[a]
12[a]
13[a]
Ph/Ph/n-C4H9 (1m)
Me/nBu/Ph (1n)
[a] 20 mol% [PdCl2ACHTUNGTRENNUNG(CH3CN)2] was used. [b] Yield of isolated product.
bring in other groups (Table 2, entry 6). It is noteworthy
that the terminal alkyne is compatible in this transforma-
tion. For example, diyne-enone 1l with a terminal alkyne
still affords the desired 4laa with a stereodefined trisubsti-
tuted alkene in a reasonable yield (Table 2, entry 11).
Diyne-enone 1n containing aliphatic R1 and R2 groups dis-
plays a relatively low reactivity and affords the correspond-
ing products in only 32% yield, because the substrate is un-
stable (Table 2, entry 13). It is also noteworthy that various
functional groups such as ester, ketone, nitro, and halogen
are also compatible in this PdII-catalyzed multicomponent
domino reaction, which provides an opportunity for further
modification.
To our delight, 4-methylbenzenesulfonamide (TsN) can
be used as the tether group to give the corresponding prod-
uct 4oaa in moderate yield [Eq. (1), DCE=1,2-dicholoro-
ethane]. Compound 1p with oxygen tether decomposed
under the reaction conditions and failed to give the corre-
sponding product [Eq. (2)]. Furthermore, when acrolein 2g
is used instead of vinyl ketone, the reaction produces an
acetal 5 in 48% yield along with a small amount of free al-
dehyde under the standard conditions owing to the HCl gen-
erated in the process [Eq. (3)]. The generality of this trans-
formation was further investigated by employing compound
6 with a terminal alkene instead of the alkyne as substrate
[Eq. (4)]. It is quite surprising to find that no reaction
occurs even at higher temperature, thus indicating that the
olefin shuts down the reaction.
A plausible mechanism of this palladium(II)-catalyzed
domino reaction is depicted in Scheme 1. According to our
previous results,[13] we believe that in this process, [PdCl2
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
coordinate to the two alkyne moieties of the diyne-enone 1
to form intermediate IA. This coordination would mediate a
tandem heterocyclization and nucleophilic addition to give
furanyl palladium intermediate IB and release one molecule
2
À
of HCl. The syn addition of sp C Pd bond of IB to the un-
conjugated alkyne would generate a bicyclic vinylpalladium
species IC, with subsequent conjugate addition of the vinyl-
Scheme 1. Plausible mechanism that accounts for the stereochemistry.
Chem. Asian J. 2012, 7, 294 – 297
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
295

J. Zhang and R. Liu
COMMUNICATION
palladium species to the vinyl ketone 2 to produce inter-
mediate ID with two interconvertible forms but with palladi-
um enolate as the major form, which would prefer protona-
tion by the HCl generated in situ to produce the final prod-
uct 4 rather than the Heck type product via b-H elimination
of ID. Lu and co-workers have established that the palladium
enolate prefers protonation in the presence of excess
halide.[16] The excess halide accelerates the protonation step,
which may explain why higher catalyst loading (10 mol%)
gives better results. Accordingly, the corresponding ID-type
intermediate generated from methyl acrylate 2 f would
prefer b-H elimination and generate Pd0, which would shut
down the reaction (Table 1, entry 10). The terminal olefin of
compound 6 may bind to the PdII species strongly, and the
Lewis acid PdII might not be strong enough to activate the
alkyne bond.
In summary, we have developed a novel palladium(II)-
catalyzed steroselective three-component domino reaction
of readily available diyne-enones with nucleophiles and
vinyl ketones under mild conditions, which provides a gener-
al, efficient, and atom-economical route to multifunctional-
ized 2,3-cyclo[b]furan with a stereodefined tri- or tetrasub-
stituted olefin. Further studies including the scope, mecha-
nism, and design of new reactions based on the diyne-
enones are ongoing.
[1] a) A. De Meijere, P. Von Zezschwitz, S. Brꢁse, Acc. Chem. Res.
2005, 38, 413; b) A. Dondoni, A. Massi, Acc. Chem. Res. 2006, 39,
451; c) A. Dçmling, Chem. Rev. 2006, 106, 17; d) D. M. D’Souza,
T. J. J. Mꢂller, Chem. Soc. Rev. 2007, 36, 1095; e) B. B. Toure, D. G.
Hall, Chem. Rev. 2009, 109, 4439; f) Multi-component Reactions
(Eds.: J. Zhu and H. Bienaymꢃ), Wiley-VCH, Weinheim, 2005;
g) L. F. Tietze, Chem. Rev. 1996, 96, 115; h) L. F. Tietze, H. Ila, H. P.
Bell, Chem. Rev. 2004, 104, 3453; i) T. Vlaar, E. Ruijter, R. V. A.
Orru, Adv. Synth. Catal. 2011, DOI:10.1002/adsc.201000979; j) S. M.
Abu Sohel, R.-S. Liu, Chem. Soc. Rev. 2009, 38, 2269.
[2] a) H. Heaney in Natural Products Chemistry (Ed.: K. Nakanishi,),
Kodansha, Toyko, 1974, p. 297; b) B. H. Lipshutz, Chem. Rev. 1986,
86, 795; c) M. Shipman, Contemp. Org. Synth. 1995, 2, 1.
[3] For recent reviews, accounts, and highlights dealing with the synthe-
sis of furans, see: a) D. M. D’Souza, T. J. J. Mꢂller, Chem. Soc. Rev.
2007, 36, 1095; b) N. T. Patil, Y. Yamamoto, ARKIVOC. 2007, x,
121; c) G. Balme, D. Bouyssi, N. Monteiro, Heterocycles 2007, 73,
87; d) K-S. Yeung, Z. Yang, X.-S. Peng, X. L. Hou in Progress in
Heterocyclic Chemistry, Vol. 22 (Eds.: G. W. Gribble, J. A. Joule),
Pergamon, Oxford, 2011, p. 186; e) A. Dudnik, N. Chernyak, V. Ge-
vorgyan, Aldrichimica Acta 2010, 43, 37.
[4] a) S. Ma, J. Zhang, Angew. Chem. 2003, 115, 193; Angew. Chem. Int.
Ed. 2003, 42, 183; b) S. Ma, L. Lu, J. Zhang, J. Am. Chem. Soc.
2004, 126, 9645.
[5] a) A. Padwa, J. M. Kassir, S. L. Xu, J. Org. Chem. 1991, 56, 6971;
b) S. Ma, J. Zhang, J. Am. Chem. Soc. 2003, 125, 12386.
[6] a) J. A. Marshall, E. D. Robinson, J. Org. Chem. 1990, 55, 345;
b) J. A. Marshall, G. S. Bartley, J. Org. Chem. 1994, 59, 7169;
c) A. S. K. Hashmi, Angew. Chem. 1995, 107, 1749; Angew. Chem.
Int. Ed. Engl. 1995, 34, 1581; d) A. S. K. Hashmi, T. L. Ruppert, T.
Knçfel, J. W. Bats, J. Org. Chem. 1997, 62, 7295; e) A. S. K. Hashmi,
L. Schwarz, J.-H. Choi, T. M. Frost, Angew. Chem. 2000, 112, 2382;
Angew. Chem. Int. Ed. 2000, 39, 2285; f) A. W. Sromek, M. Rubina,
V. Gevorgyan, J. Am. Chem. Soc. 2005, 127, 10500; g) C.-Y. Zhou,
P. W. H. Chan, C.-M. Che, Org. Lett. 2006, 8, 325; h) A. S. Dudnik,
V. Gevorgyan, Angew. Chem. 2007, 119, 5287; Angew. Chem. Int.
Ed. 2007, 46, 5195; i) A. S. Dudnik, A. W. Sromek, M. Rubina, J. T.
Kim, A. V. Kel’in, V. Gevorgyan, J. Am. Chem. Soc. 2008, 130, 1440;
j) A. S. K. Hashmi, L. Schwarz, J. W. Bats, J. Prakt. Chem. 2000, 342,
40; k) A. S. K. Hashmi, J.-H. Choi, J. W. Bats, J. Prakt. Chem. 1999,
341, 342.
[7] a) Y. Fukuda, H. Shiragami, K. Utimoto, H. Nozaki, J. Org. Chem.
1991, 56, 5816; b) A. Arcadi, S. Cacchi, R. C. Larock, F. Marinelli,
Tetrahedron Lett. 1993, 34, 2813; c) A. Sniady, A. Durham, M. S.
Morreale, K. A. Wheeler, R. Dembinski, Org. Lett. 2007, 9, 1175;
d) T. Schwier, A. W. Sromek, D. M. L. Yap, D. Chernyak, V. Ge-
vorgyan, J. Am. Chem. Soc. 2007, 129, 9868; e) A. S. Dudnik, Y. Xia,
Y. Li, V. Gevorgyan, J. Am. Chem. Soc. 2010, 132, 7645; f) A. S. K.
Hashmi, T. M. Frost, J. W. Bats, J. Am. Chem. Soc. 2000, 122, 11553.
[8] a) B. Seiller, C. Bruneau, P. H. Dixneuf, J. Chem. Soc. Chem.
Commun. 1994, 493; b) B. Gabriele, G. Salerno, E. Lauria, J. Org.
Chem. 1999, 64, 7687; c) Y. Liu, F. Song, Z. Song, M. Liu, B. Yan,
Org. Lett. 2005, 7, 5409; d) M. Egi, K. Azechi, S. Akai, Org. Lett.
2009, 11, 5002; e) C. C. Schneider, H. Caldeira, B. M. Gay, D. F.
Back, G. Zeni, Org. Lett. 2010, 12, 936.
Experimental Section
ACHTUNGTRENNUNG[PdCl2ACHTUNGTRENNUNG(CH3CN)2] (5.6 mg, 0.02 mmol) was added to a mixture of 1a
(98.0 mg, 0.2 mmol), MeOH (3a, 64.0 mg, 2.0 mmol), and vinyl methyl
ketone (2a, 84.0 mg, 1.2 mmol) in CH3CN (2.0 mL) at room temperature.
After the mixture was stirred for 8 h, 1a was completely consumed ac-
cording to TLC analysis. The reaction mixture was concentrated in
vacuo. The residue was purified by column chromatography on silica gel
(hexane/EtOAc=5:1) to give the desired product 4aaa (92.3 mg) in 78%
yield as colorless oil. 1H NMR (300 MHz, CDCl3): dH =7.61 (d, 2H, J=
7.8 Hz), 7.39 (d, 2H, J=6.6 Hz), 7.15–7.33 (m, 9H), 7.01 (d, 2H, J=
7.5 Hz), 5.46 (s, 1H), 3.65 (s, 3H), 3.59 (s, 3H), 3.55 (d, 1H, J=17.7 Hz),
3.36 (s, 3H), 3.14 (d, 1H, J=17.7 Hz), 2.98 (d, 1H, J=12.9 Hz), 2.67–2.77
(m, 1H), 2.65 (d, 1H, J=12.9 Hz), 2.48–2.59 (m, 1H), 2.04 (t, 2H, J=
7.8 Hz), 1.63 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): dC =207.55,
171.19, 170.68, 152.35, 149.24, 140.75, 140.08, 139.08, 130.62, 128.80,
128.21, 128.12, 128.02, 127.49, 127.44, 127.20, 127.12, 127.00, 122.54,
122.47, 117.03, 77.43, 56.79, 54.97, 52.80, 52.72, 41.45, 36.94, 29.77, 29.53,
29.25 ppm; MS (70 eV): m/z (%): 592 (0.88) [M+], 502 (100); HRMS
calcd for C37H36O7 (M)+: 592.2461, found: 592.2465.
[9] a) J. Zhang, H.-G. Schmalz, Angew. Chem. 2006, 118, 6856; Angew.
Chem. Int. Ed. 2006, 45, 6704; b) G. Zhang, X. Huang, G. Li, L.
Zhang, J. Am. Chem. Soc. 2008, 130, 1814; c) Y. Zhang, Z. Chen, Y.
Xiao, J. Zhang, Chem. Eur. J. 2009, 15, 5208; d) Y. Bai, J. Fang, J.
Ren, Z. Wang, Chem. Eur. J. 2009, 15, 8975; e) Y. Zhang, F. Liu, J.
Zhang, Chem. Eur. J. 2010, 16, 6146.
[10] For selected examples, see: a) T. Yao, X. Zhang, R. C. Larock, J.
Am. Chem. Soc. 2004, 126, 11164; b) N. T. Patil, H. Wu, Y. Yamamo-
to, J. Org. Chem. 2005, 70, 4531; c) T. Yao, X. Zhang, R. C. Larock,
J. Org. Chem. 2005, 70, 7679; d) Y. Liu, S. Zhou, Org. Lett. 2005, 7,
4609; e) C. H. Oh, V. R. Reddy, A. Kim, C. Y. Rhim, Tetrahedron
Lett. 2006, 47, 5307; f) X. Liu, Z. Pan, X. Shu, X. Duan, Y. Liang,
Synlett 2006, 1962.
Acknowledgements
We are grateful to the Natural Science Foundation of China (20972054)
and Science and Technology Commission of Shanghai Municipality and
Ministry of Education of China the Central Universities and 973 program
(2011CB808600)
Keywords: domino reactions · enynes · furans · palladium ·
stereoselectivity
296
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 294 – 297

Palladium(II)-Catalyzed Three-Component Domino Reactions
[11] The work from our group, see: a) Y. Xiao, J. Zhang, Angew. Chem.
2008, 120, 1929; Angew. Chem. Int. Ed. 2008, 47, 1903; b) R. Liu, J.
Zhang, Chem. Eur. J. 2009, 15, 9303; c) F. Liu, Y. Yu, J. Zhang,
Angew. Chem. 2009, 121, 5613; Angew. Chem. Int. Ed. 2009, 48,
5505; d) H. Gao, X. Zhao, Y. Yu, J. Zhang, Chem. Eur. J. 2010, 16,
456; e) F. Liu, D. Qian, L. Li, X, Zhao, J. Zhang, Angew. Chem.
2010, 122, 6819; Angew. Chem. Int. Ed. 2010, 49, 6669; f) W. Li, J.
Zhang, Chem. Commun. 2010, 46, 8839; g) H. Gao, X. Wu, J.
Zhang, Chem. Commun. 2010, 46, 8764; h) H. Gao, X. Wu, J.
Zhang, Chem. Eur. J. 2011, 17, 2838; i) G. Zhou, F. Liu, J. Zhang,
Chem. Eur. J. 2011, 17, 3101.
P. H. Dixneuf, Angew. Chem. 2009, 121, 1709; Angew. Chem. Int.
Ed. 2009, 48, 1681; g) C. H. Oh, S. J. Lee, J. H. Lee, Y. J. Na, Chem.
Commun. 2008, 5794; h) T. Wang, J. Zhang, Chem. Eur. J. 2011, 17,
86.
[13] a) C. H. Oh, H. M. Park, D. I. Park, Org. Lett. 2007, 9, 1191; b) H.
Yamamoto, I. Sasaki, H. Imagawa, M. Nishizawa, Org. Lett. 2007, 9,
1399.
[14] a) W. Zhao, J. Zhang, Chem. Commun. 2010, 46, 4384; b) W. Zhao,
J. Zhang, Chem. Commun. 2010, 46, 7816; c) R. Liu, J. Zhang, Adv.
Synth. Catal. 2011, 353, 36; d) W. Zhao, J. Zhang, Org. Lett. 2011,
13, 688.
[12] For examples from other substrates, see a) A. S. K. Hashmi, P.
Sinha, Adv. Synth. Catal. 2004, 346, 432; b) M. H. Suhre, M. Reif,
S. F. Kirsch, Org. Lett. 2005, 7, 3925; c) S. Kim, P. H. Lee, Adv.
Synth. Catal. 2008, 350, 547; d) A. Blanc, K. Tenbrink, J.-M. Weibel,
P. Pale, J. Org. Chem. 2009, 74, 5342; e) L. Peng, X. Zhang, M. Ma,
J. Wang, Angew. Chem. 2007, 119, 1937; Angew. Chem. Int. Ed.
2007, 46, 1905; f) M. Zhang, H.-F. Jiang, H. Neumann, M. Beller,
[15] See the Supporting Information.
[16] a) Z. Wang, X. Lu, J. Org. Chem. 1996, 61, 2254; b) A. Lei, X. Lu,
Org. Lett. 2000, 2, 2699; c) G. Liu, X. Lu, Org. Lett. 2001, 3, 3879;
d) L. Zhao, X. Lu, Org. Lett. 2002, 4, 3903.
Received: September 12, 2011
Published online: December 1, 2011
Chem. Asian J. 2012, 7, 294 – 297
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
297