Regio- and stereoselective synthesis of 2-cyclopentenones via a hydrogenolysis-terminated Heck cyclization of β-alkylthio dienones

Article abstract of DOI:10.1039/c3cc37571d

Palladium-catalyzed cyclization of β-alkylthio dienone derivatives affords 2-cyclopentenones in a regio- and stereoselective manner in the presence of silane. C-S activation, intramolecular carbopalladation and hydrogenolysis construct the cascade process

Full text of DOI:10.1039/c3cc37571d

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Regio- and stereoselective synthesis of
2-cyclopentenones via a hydrogenolysis-terminated
Heck cyclization of b-alkylthio dienones†
Bangyu Liu,a Gang Zheng,a Xiaocui Liu,a Cong Xu,a Jingxin Liua and
Mang Wang*ab
Cite this: Chem. Commun., 2013,
49, 2201
Received 17th October 2012,
Accepted 30th January 2013
DOI: 10.1039/c3cc37571d
www.rsc.org/chemcomm
Palladium-catalyzed cyclization of b-alkylthio dienone derivatives ketones with terminal gem-dialkylthio substituents,10 are
affords 2-cyclopentenones in a regio- and stereoselective manner selected as the substrates. We report herein a novel and reason-
in the presence of silane. C–S activation, intramolecular carbo- ably designed hydrogenolysis-terminated Heck-type cyclization
palladation and hydrogenolysis construct the cascade process.
based on Pd-catalyzed C–S activation of b-alkylthio dienones,
leading to polysubstituted 2-cyclopentenones efficiently.
To test our hypothesis, we initially investigated the cyclization of
The widespread occurrence of cyclopentenones in natural products
and bioactive molecules1 has led to the development of a variety of 1a in dried DMF at different temperatures by using 5 to 20 mol% of
diverse methods for their synthesis.2ꢀ4 In general, 2-cyclopente- Pd catalyst, including Pd(PPh3)2Cl2, PdCl2, Pd(PPh3)4, and
nones can be synthesized by the Pauson–Khand reaction involving Pd(OAc)2. However, the Heck cyclization product, cyclopenta-
a [2+2+1] cycloaddition between an alkyne, an alkene and carbon 2,4-dienone 3a, was not obtained. Interestingly, an unexpected
monoxide,2 and Nazarov cyclization of dienones via a pericyclic product was isolated in 20% yield when the reaction time was
reaction.3 On the other hand, Heck reaction provides a powerful prolonged to 36 h with Pd(PPh3)2Cl2 as catalyst (Scheme 1). This
and reliable tool for C–C bond formation.5 In this field, the product was identified as 3-(ethylthio)-2-(4-methoxyphenyl)-
intramolecular version holds an indispensable position due to 4-phenyl cyclopent-2-enone 2a by NMR, MS and further by
the high efficiency, regio- and stereoselectivity in the synthesis of X-ray.13 The formation of 2a should be due to a reductive Heck
cyclic structures.6 In particular, the carbopalladation–termination reaction in which solvent DMF acted as the hydride donor.14
tandem process has accomplished strategic construction in a set of
important carbo- and heterocyclic molecules.7 However, the Heck- might provide a straightforward and selective synthesis of cyclo-
type cyclizations based on dienone derivatives are rare.
pentenones starting from dienones3 via a new reductive Heck
After consideration of these possibilities, we surmised that it
Most Heck reactions consist of the Pd(0)-catalyzed reaction of cyclization. Toward this end, we sought to screen the hydride
organic halides with alkenes. Additionally, the use of thioorganics donor reagents. As described in Table 1, entries 1–5, triphenyl-
as the coupling partners, such as sulfonates or sulfonyl chlorides, silane is the most suitable reductant.7 Upon treatment of 1a with
significantly extends the impact of these versatile processes. 2 equivalents of triphenylsilane in dried DMF at 90 1C for 10 h in
Recently, we focused on developing desulfitative C–C formation the presence of 10 mol% of Pd(PPh3)2Cl2, 2a could be isolated in
reaction8,9 and found an aerobic, Cu-catalyzed cross-coupling of 92% yield (entry 4). Decreasing the amount of Pd(PPh3)2Cl2 led to
boronic acids and a-oxo ketene dithioacetals.10 Just a little later, lower reaction yields (entries 6 and 7). Among various Pd cata-
the Pd(0)-catalyzed C–S bond activation was also reported to allow lysts tested, Pd(PPh3)2Cl2 gave the best result (entries 8–15).
this cross-coupling process.11 Accordingly, we envisioned that Pd
catalysis for C–S activation may be key to develop a striking
cyclization in the construction of functionalized cyclic
compounds12 if a-alkenoyl ketene dithioacetals 1 (for example,
compound 1a in Scheme 1), a kind of readily available divinyl
a Faculty of Chemistry, Northeast Normal University, Changchun 130024,
P. R. China. E-mail: wangm452@nenu.edu.cn; Fax: +86-431-85099759
b State Key Laboratory of Fine Chemicals, Dalian University of Technology,
Dalian 116012, P. R. China
† Electronic supplementary information (ESI) available: All the relevant synthetic
details as well as NMR spectra for all new compounds. CCDC 901005. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc37571d
Scheme 1 Heck cyclization of b-alkylthio dienone 1a.
c
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Table 1 Optimization of the reaction conditionsa
Table 2 Hydrogenolysis-terminated Heck cyclization of 1a
Yieldb
Solvent (1C) t (h) (%)
Entry
1/R, R1, R2
t (h)
2/Yieldb (%)
Hydride
donor (eq.)
T
Entry Pd-catalyst (%)
1
2
3
4
5
6
7
8
1a/Et, 4-MeOC6H4, Ph
10
11
18
5
20
12
14
11
10
8
20
10
20
22
14
15
20
20
18
12
20
7
2a/92
2b/85
2c/82
2d/92
2e/76
2f/77
2g/76
2h/56
2i/80
2j/85
2k/72
2l/91
2m/81
2n/80
2o/80
2p/90
2q/77
2r/72
2s/75
2t/70
2u/69
2v/85
2w/94
2x/88
2y/25
—
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2 (10) HCO2Hc
DMF 90 12 35
1b/Et, 4-MeOC6H4, 4-MeOC6H4
1c/Et, 4-MeOC6H4, 4-MeC6H4
1d/Et, 4-MeOC6H4, 2,3-CH2O2C6H3
1e/Et, 4-MeOC6H4, 4-ClC6H4
1f/Et, 4-MeOC6H4, 2-ClC6H4
1g/Et, 4-MeOC6H4, 2-furyl
1h/Et, 4-MeOC6H4, tBu
1i/Et, 2-MeOC6H4, Ph
1j/Et, 2-MeOC6H4, 2,3-CH2O2C6H3
1k/Et, 2-MeOC6H4, 4-ClC6H4
1l/Et, 4-ClC6H4, Ph
1m/Et, 4-ClC6H4, 2,3-CH2O2C6H3
1n/Et, 4-ClC6H4, 4-ClC6H4
1o/Et, 4-ClC6H4, 2-furyl
1p/Et, 4-FC6H4, Ph
1q/Et, 4-FC6H4, 2,3-CH2O2C6H3
1r/Et, 4-FC6H4, 4-ClC6H4
1s/Et, 4-FC6H4, 2-furyl
1t/Me, 4-ClC6H4, Ph
1u/Me, 4-ClC6H4, 4-ClC6H4
1v/Me, Me, Ph
Pd(PPh3)2Cl2 (10) HCO2Na (1.5) DMF
90 4 (12) 15 (—d)
Pd(PPh3)2Cl2 (10) Ph3SiH (1.5)
Pd(PPh3)2Cl2 (10) Ph3SiH (2)
Pd(PPh3)2Cl2 (10) tBuMe2SiH (2) DMF
Pd(PPh3)2Cl2 (8) Ph3SiH (2)
Pd(PPh3)2Cl2 (5) Ph3SiH (2)
DMF
DMF
90
90
90
90
90
90
90
90
90
90
90
10 58
10 92
10 80
12 73
18 70
18 65
12 nre
12 nre
12 15
12 Trace
10 86
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Pd(PPh3)4 (10)
Pd(OAc)2 (10)
Pd(dba)3 (10)
Ph3SiH (2)
Ph3SiH (2)
Ph3SiH (2)
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
10
11
12
13
Pd(dppe)Cl2 (10) Ph3SiH (2)
Pd(dppp)Cl2 (10) Ph3SiH (2)
PdCl2 (10)
PPh3 (30)
Pd(OAc)2 (10)
PPh3 (30)
PdCl2 (10)
PCy3 (30)
Ph3SiH (2)
Ph3SiH (2)
Ph3SiH (2)
14
15
DMF
DMF
90
90
10 35
24 30
16
17
18
19
Pd(PPh3)2Cl2 (10) Ph3SiH (2)
Pd(PPh3)2Cl2 (10) Ph3SiH (2)
Pd(PPh3)2Cl2 (10) Ph3SiH (2)
Pd(PPh3)2Cl2 (10) Ph3SiH (2)
DMF
DMF
DMSO
Dioxane 90
110
130
90
10 90
10 90
10 50
10 15
1w/Me, Me, 2,3-CH2O2C6H3
1x/Me, nBu, Ph
1y/Et, COPh, 4-ClC6H4
24
10
11
24
a
b
Reaction conditions: 1a (0.5 mmol), solvent (5 mL), N2. Isolated
c
d
yield. 0.5 mL of HCO2H was used. Complex mixture was obtained.
1z/Et, H, 4-ClC6H4
e
No reaction was observed.
a
b
Reaction conditions: 1 (0.5 mmol), DMF (5 mL). Isolated yield.
The combination of PdCl2 (10%) with PPh3 (30%) also afforded
2a in 86% yield (entry 13). No significant effect was found for
It is noteworthy that we isolated compounds 2 as the sole
the reaction upon increasing the reaction temperature (entries 16 products in the above experiments. Therefore, we provide an easily
and 17). In addition, DMSO and 1,4-dioxane were less effective regioselective access to polysubstituted 2-cyclopentenones from
than DMF in the solvent tested (entries 18 and 19).
dienone derivatives based on Pd-catalyzed C–S activation. When
With an optimized set of reaction conditions (Table 1, entry 4) we selected a cyclic ketene dithioacetal 1aa as the substrate, product
in hand, we examined the scope of this hydrogenolysis-terminated 2aa0, in which a CQC bond of the a-alkenoyl moiety was reduced by
Heck cyclization process. As described in Table 2, a variety of silane,15 was isolated in 18% yield after reacting for 10 h.16 Addi-
a-alkenoyl ketene dithioacetals 1 were prepared for the Pd-catalyzed tionally, 1ab bearing b0,b0-diphenyls also proved to be an unsuitable
cyclization. On the one hand, aromatic R2 substituents (including substrate in the Pd-catalyzed cyclization. The desulfurization pro-
heteroaromatic R2) at the b0-position of 1, bearing either an duct 20ab was obtained in 76% yield under the same conditions.17
electron-donating or an electron-withdrawing group at the
On the basis of the experimental results and the proposed
different position of the phenyl ring, are compatible with the process of the Heck reaction,5,6 the reaction mechanism is under-
reaction (entries 1–7). 1h with aliphatic b0-tBu can also afford 2h stood in terms of the Pd-catalytic cycle shown in Scheme 2. The C–S
in 56% yield (entry 8). On the other hand, various aromatic and bond in 1 undergoes the oxidative addition to a Pd(0) complex to
aliphatic R1 groups at the a-position of 1 are also well-tolerated in give intermediate A. Then, syn-carbopalladation takes place in a
the reaction (entries 1–24). Among them, 2-cyclopentenones 2t–x selective 4-endo-trig manner to give Pd(II) species B. Interestingly, no
were successfully prepared in 69–94% yields, respectively, from b-hydrogen being syn-coplanar with Pd of the rigid cyclic inter-
1t–x bearing methylthio groups (entries 20–24). However, 1y with mediate B blocks the usual b-elimination which leads to products 3.
a benzoyl group at the a-position afforded the desired product in Thus it provides an exclusive opportunity for the next transmetala-
low yield (entry 25). We also attempted to optimize the reaction tion in the presence of silane15 and gives intermediate C by releasing
with substrate 1y by increasing the amount of the catalyst but the (ethylthio)trialkylsilane18 smoothly. Additionally, the energy is
reaction yield could not be improved. Finally, we found that the unfavorable to the formation of cyclopentadienone 3 bearing semi
reaction is sensitive to the ketene dithioacetal substrate without antiaromaticity. Finally, the catalytically active Pd(0) complex is
any substituent at the a-position. A complex mixture was often regenerated through the reductive elimination of C to afford 2-cyclo-
obtained by using the present protocol (entry 26) even when the pentenones 2. If the carbopalladation of A is inefficient, transmetala-
reaction temperature is decreased to room temperature.
tion will take place at first to afford the desulfurization product 20.17
c
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N. Chaichit, C. Mahidol, S. Ruchirawat and P. Kittakoop, J. Nat. Prod.,
2006, 69, 1351; (c) S.-H. Luo, L.-H. Weng, M.-J. Xie, X.-N. Li, J. Hua,
X. Zhao and S.-H. Li, Org. Lett., 2011, 13, 1864; (d) H. B. Park, Y.-J. Kim,
J. K. Lee, K. R. Lee and H. C. Kwon, Org. Lett., 2012, 14, 5002.
2 (a) S. E. Gibson and N. Mainolfi, Angew. Chem., Int. Ed., 2005, 44, 3022;
(b) M. R. Rivero, J. Adrio and J. C. Carretero, Synlett, 2005, 26; (c) S. Laschat,
A. Becheanu, T. Bell and A. Baro, Synlett, 2005, 2547; (d) H.-W. Lee and
F.-Y. Kwong, Eur. J. Org. Chem., 2010, 789; (e) R. Rios Torres and J. Vesely,
Other Transition Metal-Mediated Cyclizations Leading to Cyclopente-
nones, in Pauson–Khand Reaction: Scope, Variations and Applications,
ed. R. Rios Torres, John Wiley & Sons, Ltd, Chichester, UK, 2012.
3 (a) H. Pellisier, Tetrahedron, 2005, 61, 6479; (b) A. J. Frontier and
C. Collison, Tetrahedron, 2005, 61, 7577; (c) M. A. Tius, Eur. J. Org.
Chem., 2005, 2193; (d) M. J. Fuchter, Nazarov Cyclization, in Name
Reactions for Carbocyclic Ring Formations, ed. J. J. Li, John Wiley &
Sons, Inc., Hoboken, NJ, USA, 2010, p. 122; (e) T. Vaidya,
R. Eisenberg and A. J. Frontier, ChemCatChem, 2011, 3, 1531.
4 Selected examples of alternative cyclopentenone synthesis, (a) T. Varea,
´
A. Alcalde, C. L. de Dicastillo, C. R. de Arellano, F. P. Cossıo and
G. Asensio, J. Org. Chem., 2012, 77, 6327; (b) C. B. Jacobsen, K. L.
Jensen, J. Udmark and K. A. Jørgensen, Org. Lett., 2011, 13, 4790;
(c) A. D. Jenkins, A. Herath, M. Song and J. Montgomery, J. Am. Chem.
Soc., 2011, 133, 14460; (d) Y. Xu, M. McLaughlin, C.-Y. Chen,
R. A. Reamer, P. G. Dormer and I. W. Davies, J. Org. Chem., 2009, 74, 5100.
5 (a) J. Le Bras and J. Muzart, Chem. Rev., 2011, 111, 1170;
(b) J. W. Ruan and J. L. Xiao, Acc. Chem. Res., 2011, 44, 614.
6 (a) A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945;
(b) E. Negishi, C. Coperet, S. Ma, S.-Y. Liou and F. Liu, Chem. Rev.,
1996, 96, 365; (c) S. Ma, Chin. J. Org. Chem., 1991, 11, 561.
7 (a) T. Vlaar, E. Ruijter and R. V. A. Orru, Adv. Synth. Catal., 2011,
353, 809; (b) A. de Meijere, P. von Zezschwitz, H. Nuske and
B. Stulgies, J. Organomet. Chem., 2002, 653, 129.
Scheme 2 Proposed mechanism for the Pd-catalyzed cyclization of 1.
8 (a) S. R. Dubbaka and P. Vogel, J. Am. Chem. Soc., 2003, 125, 15292;
(b) S. R. Dubbaka and P. Vogel, Org. Lett., 2004, 6, 95;
(c) S. R. Dubbaka and P. Vogel, Angew. Chem., Int. Ed., 2005,
44, 7674; (d) S. R. Dubbaka and P. Vogel, Chem.–Eur. J., 2005,
11, 2633; (e) H. Prokopcov and C. O. Kappe, Angew. Chem.,
Int. Ed., 2009, 48, 2276.
9 Y. Dong, M. Wang, J. Liu, W. Ma and Q. Liu, Chem. Commun., 2011,
47, 2080.
10 L. Pan and Q. Liu, Synlett, 2011, 1073, and references therein.
11 W. Jin, W. Du, Q. Yang, H. Yu, J. Chen and Z. Yu, Org. Lett., 2011,
13, 4272.
12 (a) M. Wang, F. Han, H. Yuan and Q. Liu, Chem. Commun., 2010,
46, 2247; (b) S. Hara, S. Okamoto, M. Narahara, T. Fukuhara and
N. Yoneda, Synlett, 1999, 411; (c) C. V. Asokan, S. Bhattacharji, H. Ila
and H. Junjappa, Synthesis, 1988, 281.
13 Crystal data for 2a: C20H20O2S, colorless, M = 324.42, monoclinic,
space group P21/c, a = 19.0155(8) Å, b = 8.2100(3) Å, c = 11.6450(5) Å,
V = 1735.83(12) Å3, a = 90.001, b = 107.291(4)1, g = 90.001, Z = 4, T =
293(2) K, F(000) = 688, 6642 reflections collected, 3048 unique with
Rint = 0.0206, R1 = 0.0427, wR2 = 0.1047 (I > 2s(I)).
14 (a) A. M. Zawisza and J. Muzart, Tetrahedron Lett., 2007, 48, 6738;
(b) H. S. Kim, S. Gowrisankar, S. H. Kim and J. N. Kim, Tetrahedron
Lett., 2008, 49, 3858.
15 Y. Sumida, H. Yorimitsu and K. Oshima, J. Org. Chem., 2009,
74, 7986.
Scheme 3 Reductive Heck cyclization of 1ac–ae.
To test the stereoselectivity of the reaction, we next investigated
the Pd-catalyzed cyclizations of ketene dithioacetals 1ac–ae with
a0-phenyl groups. Accordingly, 2-cyclopentenones 2ac–ae were
obtained in good yields by using 10 mol% of Pd(PPh3)2Cl2 as
the catalyst and 3 equivalents of nBuMe2SiH as the hydride
donor (Scheme 3). Each cyclopentenone 2 was isolated as a
regio- and diastereoisomer with a trans relationship between
the R2 and a0-phenyl on the alkenoyl moiety. Stereochemical
assignments were made based on the coupling constant
between the a0- and the b0-proton of 2 (2.0 Hz) and the
assumption of the syn-carbopalladation process. No cis-isomers
1
were observed in the H NMR spectra of the crude products.
In conclusion, we have developed a hydrogenolysis-terminated
Heck cyclization of divinyl ketone derivatives based on C–S activation
for the first time. The intramolecular carbopalladation of a-alkenoyl
ketene dithioacetals, a kind of readily available b-alkylthio dienones,
occurs smoothly under the catalysis of Pd(PPh3)2Cl2 and is sub-
sequently trapped by a hydrogen in the presence of silane. The
reaction provides an efficient entry to 2-cyclopentenones in high
yields with excellent regio- and diastereoselectivities via a mecha-
nistically unique catalytic process which complements the existing
methods. Further investigations focused on its asymmetric version.
We acknowledge NNSFC-21172031/20972029 and the State
Key Laboratory of Fine Chemicals (KF1003) for funding support
of this research.
16
17
Notes and references
1 (a) D. S. Straus and C. K. Glass, Med. Res. Rev., 2001, 21, 185;
(b) P. Chomcheon, N. Sriubolmas, S. Wiyakrutta, N. Ngamrojanavanich, 18 M.-K. Chung and M. Schlaf, J. Am. Chem. Soc., 2004, 126, 7386.
c
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Chem. Commun., 2013, 49, 2201--2203 2203