Palladium-catalyzed cascade annulation to construct functionalized β- And γ-lactones in ionic liquids

Article abstract of DOI:10.1002/anie.201403341

A highly efficient and mild palladium-catalyzed, one-pot, four-step cascade annulation has been developed to afford functionalized β- and γ-lactones in moderate to good yields with high regio- and diastereoselectivities in ionic liquids. The employment of ionic liquids under mild reaction conditions makes this transformation green and practical. Especially, this reaction provided a novel and convenient methodology for the construction of naturally occurring biologically active β- and γ-lactones.

Full text of DOI:10.1002/anie.201403341

Angewandte
Chemie
DOI: 10.1002/anie.201403341
Synthetic Methods
Palladium-Catalyzed Cascade Annulation To Construct Functionalized
b- and g-Lactones in Ionic Liquids**
Jianxiao Li, Wanfei Yang, Shaorong Yang,* Liangbin Huang, Wanqing Wu, Yadong Sun, and
Huanfeng Jiang*
Abstract: A highly efficient and mild palladium-catalyzed,
one-pot, four-step cascade annulation has been developed to
afford functionalized b- and g-lactones in moderate to good
yields with high regio- and diastereoselectivities in ionic
liquids. The employment of ionic liquids under mild reaction
conditions makes this transformation green and practical.
Especially, this reaction provided a novel and convenient
methodology for the construction of naturally occurring
biologically active b- and g-lactones.
T
ransition-metal-catalyzed carbon–carbon and carbon–het-
eroatom bond formations have attracted considerable atten-
tion over the past decades owing to its easy access to highly
functionalized and complex molecules in a rather efficient,
atom- and step-economical way.[1] Prominently, carbometala-
tion of carbon–carbon multiple bonds is a crucial process in
organometallic chemistry from both theoretical and practical
standpoints.[2] Among numerous successful representative
strategies, the carbometalation of alkenes provides an effi-
cient and versatile method to realize carbo- and heterofunc-
tionalization of alkenes.[3] Traditionally, the crucial intermedi-
Scheme 1. Alkene difunctionalization through carbometalation.
ral products,[8,9] many of which exhibit extraordinary biolog-
ical and pharmaceutical properties. Representative saturated
lactones are found in natural products and biologically active
molecules such as (+)-eldanolide,[10] (+)-harzialactone A,[11]
antimycinone,[12] salinosporamide A,[13] and an antibiotic
agent[14] as shown in Figure 1.
ate A of the carbometalation process is formed mainly
2
À
through the oxidative addition of C(sp ) X using low-valent
transition metals (Scheme 1a).[4] In recent years, impressive
achievements have been made in enhancing the efficiency of
À
transition-metal-catalyzed C H bond activation for the con-
struction of the indispensable intermediate B of the carbo-
metalation process (Scheme 1b).[5] Despite the significant
progress that has been achieved along these lines, the main
restrictive limitation is that the olefins are usually limited to
allenes, 1,3-dienes, and activated alkenes. Other polyfunc-
tionalized alkenes, such as an enoic acid, are highly desirable.
In addition, saturated lactones are found in a vast array of
synthetically challenging[6,7] and biologically significant natu-
Figure 1. Representative examples containing saturated lactone motifs.
[*] J. Li, W. Yang, Dr. S. Yang, L. Huang, Dr. W. Wu, Y. Sun,
Prof. Dr. H. Jiang
Consequently, the development of concise routes to the
construction of saturated lactones continues to be an active
area of research. However, these known pioneering methods
may, in some cases, suffer from certain limitations such as
multiple steps, troublesome operations, harsh reaction con-
ditions, or low yields. Recently, Smith and co-workers
discovered an elegant method for the stereoselective syn-
thesis of stereodefined b-lactones based on a [2+2] cyclo-
addition of alkylarylketenes with electron-deficient benzal-
dehydes or pyridinecarboxaldehydes.[15] However, complex
substrates and harsh reaction conditions are required in these
reactions. Very recently, we reported an intermolecular
School of Chemistry and Chemical Engineering, South China
University of Technology
Guangzhou 510640 (P. R. China)
E-mail: lisryang@scut.edu.cn
jianghf@scut.edu.cn
[**] This work was supported by the National Basic Research Program of
China (973 Program) (2011CB808600), the National Natural
Science Foundation of China (21172076 and 21102047), Guang-
dong Natural Science Foundation (10351064101000000), and the
Fundamental Research Funds for the Central Universities
(2014ZP0004).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403341.
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carboxylative annulation cascade to construct saturated
functionalized g-lactones in ionic liquids (ILs) through
palladium-catalyzed, one-pot, four-step cascade methods.[16]
As part of our research program in nucleopalladation[17] and
palladium-catalyzed cross-coupling reactions in ILs,[18] herein,
we present the first example of a palladium-catalyzed
intermolecular cascade annulation for the synthesis of
functionalized b- and g-lactones with high regio- and stereo-
selectivity in ILs (Scheme 1c).
instance, the bromoalkynes containing vinyl or thienyl groups
underwent the cascade reaction to give corresponding
products in good yields with high stereoselectivities (3s–u).
Unfortunately, 2-(bromoethynyl)pyridine (1v) failed to
afford the desired products. In terms of the stereoselectivity,
all of the products obtained in the presence of an excess of
chloride ions and acid in a polar solvent resulted from
trans addition.[19] The site of halogen addition to asymmetrical
acetylenes is controlled by the electronic factors.[20]
We optimized the reaction as follows: the haloalkyne
(0.25 mmol), enoic acid (0.30 mmol), PdCl2 (3 mol%),
AgNO3 (0.5 mmol), and [C2O2mim]Cl (0.5 mL) at room
temperature (see the Supporting Information for details).
Representative results are summarized in Scheme 2. Gratify-
Based on the results obtained, we were interested in
extending the method to bromoalkynes and but-3-enoic acid
(5) to prepare a variety of substituted b-lactones under similar
reaction conditions (Scheme 3).[21] To our delight, the chlor-
Scheme 3. Cascade annulation of bromoalkynes with 5 in
[C2OHmim]Cl. Reaction conditions: 1 (0.25 mmol), 5 (0.30 mmol),
PdCl2 (3 mol%), AgNO3 (0.5 mmol), [C2OHmim]Cl (0.5 mL), and
CH3CN (0.1 mL) at room temperature.
opalladation of bromoalkynes could also initiate this domino-
type reaction with but-3-enoic acid (5) to give functionalized
b-lactone products. Similarly, the bromoalkynes substituted
with electron-donating groups and electron-withdrawing
groups proceeded smoothly to give the products in moderate
to good yields.
Scheme 2. Substrate scope of the cascade annulation of haloalkynes
with 2 in [C2O2mim]Cl. Reaction conditions: 1 (0.25 mmol), 2
(0.30 mmol), PdCl2 (3 mol%), AgNO3 (0.5 mmol), and [C2O2mim]Cl
(0.5 mL) at room temperature.
The scope of the reaction at room temperature was
further expanded to a range of alkynoates (Scheme 4).
Gratifyingly, methyl, ethyl, and phenyl alkynoates were
reacted under the optimal reaction conditions, and good to
excellent yields of the desired products were obtained (8a–c).
Various functional groups, including alkyl, fluoro, chloro,
bromo, cyano, ester, acetyl, alkoxyl, thiol, and trifluoromethyl
groups, were compatible with the reaction conditions (8d–t).
Notably, a vinyl group was tolerated under the standard
reaction conditions, thus providing 8m in 79% yield with high
Z stereoselectivity. Substitution at the 4-, or 3-, or 2-position
of the aromatic ring had a slight impact (8d,f and 8j,k).
Moreover, the more bulky fused aryl alkynoate, such as 2-
naphthyl alkynoate (7w), could be converted into the
corresponding products 8w in moderate yield as well.
Furthermore, besides the aryl alkynoates, alkyl alkynoates
(7x and 7y) were also found to be suitable substrates under
the standard reaction conditions.
ingly, a series of para-substituted bromoalkynes, including
some with electron-donating groups (Me, Et, tBu, OMe,
ethylcyclohexyl, 4-propylphenyl) and some with electron-
withdrawing groups (F, Cl, Br, CN, Ac), were converted into
the corresponding g-lactones in excellent yields (3a–n).
Furthermore, the reaction was found to be applicable to
a chloroalkyne (1o), although the reaction was relatively
sluggish. As for the sterically hindered bromoalkynes 1g, 1h,
and 1i, the reaction furnished the corresponding products
(Z)-3g, (Z)-3h, and (Z)-3i in similar yields. Satisfied with the
above results, we then tried more challenging aliphatic
bromoalkynes. Delightfully, the g-lactones 3p, 3q, and 3r
were smoothly obtained in a highly stereoselective fashion
and with good yields. Besides the wide substrate scope,
another impressive feature of the current cascade annulation
reaction is its high tolerance for functional groups. For
To demonstrate the synthetic utility of this protocol, the
newly formed chlorinated acrylates were employed for
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Chemie
Scheme 6. Plausible reaction mechanism.
a reductive elimination gives the target product. Worthy of
note, a silver mirror reaction was observed after the reaction
was finished.[27] Hence, the resulting palladium(0) is addi-
tionally oxidized to palladium(II) to complete this catalytic
cycle.
Scheme 4. Cascade annulation of alkynoates with 5 in [C2OHmim]Cl.
Reaction conditions: 7 (0.25 mmol), 5 (0.30 mmol), PdCl2 (3 mol%),
AgNO3 (0.5 mmol), [C2OHmim]Cl (0.5 mL), and CH3CN (0.1 mL) at
room temperature.
In conclusion, we have successfully accomplished an
attractive strategy for the synthesis of functionalized b- and
g-lactones with high regio- and diastereoselectivities by
a palladium-catalyzed cascade annulation of alkynes with
olefins in ionic liquids. This cascade annulation process, is
a one-pot, four-step reaction which proceeds smoothly with
good functional-group tolerance. Most importantly, this
methodology provides a new tool for the construction of
diversely substituted b- and g-lactone derivatives from inex-
pensive starting materials.
further transformations to prepare a series of functionalized
products (Scheme 5). For instance, the Suzuki–Miyaura cross-
coupling reactions of 8b with phenylboronic acid delivered
the arylated compound 9a in moderate yield.[22] Furthermore,
Received: March 14, 2014
Published online: May 27, 2014
Keywords: alkynes · annulation · ionic liquids · lactones ·
.
palladium
Scheme 5. Synthetic transformations of 8b.
[1] For selected reviews, see: a) E. Negishi, C. Coperet, S. Ma, Y. S.
Liou, F. Liu, Chem. Rev. 1996, 96, 365; b) G. Zeni, C. R. Larock,
Chem. Rev. 2006, 106, 4644; c) N. P. Patil, Y. Yamamoto, Chem.
Rev. 2008, 108, 3395; d) B.-J. Li, Z.-J. Shi, Chem. Soc. Rev. 2012,
41, 5588; e) W. K. Chow, O. Y. Yuen, P. Y. Choy, C. M. So, C. P.
Lau, W. T. Wong, F. Y. Kwong, RSC Adv. 2013, 3, 12518; f) A. V.
Gulevich, A. S. Dudnik, N. Chernyak, V. Gevorgyan, Chem. Rev.
2013, 113, 3084.
[2] For selected reviews, see: a) W. Oppolzer, Angew. Chem. 1989,
101, 39; Angew. Chem. Int. Ed. Engl. 1989, 28, 38; b) P. Knochel
in Comprehensive Organometallic Chemistry II, Vol. 11 (Eds.:
E. W. Able, F. G. A. Stone, G. Wilkinson), Pergamon, Oxford,
1995, p. 159; c) Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93,
2207; d) E. Negishi, D. Y. Kondakov, Chem. Rev. 1996, 96, 417;
e) I. Marek, J. F. Normant in Metal-Catalyzed Cross-Coupling
Reactions (Eds.: F. Diederich, P. Stang), Wiley-VCH, New York,
1998, p. 271.
8b underwent the decarboxylative coupling to produce the
highly functionalized b-lactone 9b in 70% yield.[23] To our
satisfaction, the desulfitative coupling of 8b occurred
uneventfully as well, thus providing the stereodefined tetra-
substituted alkene 9c in 65% yield.[24]
Based on the current results and previous literature,[17,18,25]
the postulated mechanism is depicted in Scheme 6. A
palladium complex is initially formed in situ in ILs,[17,18] and
the vinylpalladium intermediate I is formed by trans-chlor-
opalladation of the alkyne in a polar solvent system[19] in the
presence of excess chloride ions.[26] Subsequently, I could
undergo alkene insertion. Simultaneously, the vinylpalladium
species coordinates to the oxygen atoms of the hydroxy group
to generate the palladium/alkyl intermediate II. Finally,
[3] For selected examples, see: a) X. Tong, M. Beller, M. K. Tse, J.
Am. Chem. Soc. 2007, 129, 4906; b) L. L. Welbes, T. W. Lyons,
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.
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Communications
K. A. Cychosz, M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 5836;
c) G. Yin, G. Liu, Angew. Chem. 2008, 120, 5522; Angew. Chem.
Int. Ed. 2008, 47, 5442; d) T. Wu, X. Mu, G. Liu, Angew. Chem.
2011, 123, 12786; Angew. Chem. Int. Ed. 2011, 50, 12578; e) Y. Li,
X. Liu, H. Jiang, B. Liu, Z. Chen, P. Zhou, Angew. Chem. 2011,
123, 6465; Angew. Chem. Int. Ed. 2011, 50, 6341; f) H. Liu, C. Li,
D. Qiu, X. Tong, J. Am. Chem. Soc. 2011, 133, 6187; g) X. Mu, T.
Wu, H. Wang, Y. Guo, G. Liu, J. Am. Chem. Soc. 2012, 134, 878;
h) R. Zhu, S. L. Buchwald, Angew. Chem. 2012, 124, 1962;
Angew. Chem. Int. Ed. 2012, 51, 1926; i) H. Wang, F. Glorius,
Angew. Chem. 2012, 124, 7430; Angew. Chem. Int. Ed. 2012, 51,
7318; j) T. Piou, L. Neuville, J. Zhu, Angew. Chem. 2012, 124,
11729; Angew. Chem. Int. Ed. 2012, 51, 11561.
Kokotos, Org. Lett. 2013, 15, 2406; g) C. C. Oliveira, R. A.
Angnes, C. R. D. Correia, J. Org. Chem. 2013, 78, 4373.
[8] For selective examples of b-lactones, see: a) B. D. Morris, R. R.
Smyth, S. P. Foster, M. P. Hoffmann, W. L. Roelofs, S. Franke, W.
Francke, J. Nat. Prod. 2005, 68, 26; b) D.-Z. Liu, F. Wang, T.-G.
Liao, J.-G. Tang, W. Steglich, H.-J. Zhu, J.-K. Liu, Org. Lett. 2006,
8, 5749; c) M. Groll, E. P. Balskus, E. N. Jacobsen, J. Am. Chem.
Soc. 2008, 130, 14981.
[9] For selective examples of g-lactones, see: a) R. Bandichhor, B.
Nosse, O. Reiser, Top. Curr. Chem. 2005, 243, 43; b) R. R. A.
Kitson, A. Millemaggi, R. J. K. Taylor, Angew. Chem. 2009, 121,
9590; Angew. Chem. Int. Ed. 2009, 48, 9426.
[10] D. A. Devalankar, P. U. Karabal, A. Sudalai, Org. Biomol.
Chem. 2013, 11, 1280.
[11] G. M. Tener, E. E. van Tamelen, F. M. Strong, J. Am. Chem. Soc.
1953, 75, 3623.
[4] a) R. V. Rozhkov, R. C. Larock, J. Org. Chem. 2003, 68, 6314;
b) R. V. Rozhkov, R. C. Larock, J. Org. Chem. 2010, 75, 4131;
c) M. Yamauchi, M. Morimoto, T. Miura, M. Murakami, J. Am.
Chem. Soc. 2010, 132, 54; d) T. Miura, M. Morimoto, M.
Yamauchi, M. Miurakami, J. Org. Chem. 2010, 75, 5359; e) T.
Miura, M. Yamauchi, A. Kosaka, M. Miurakami, Angew. Chem.
2010, 122, 5075; Angew. Chem. Int. Ed. 2010, 49, 4955.
[12] M. He, A. Lei, X. Zhang, Tetrahedron Lett. 2005, 46, 1823.
[13] L. R. Dick, A. A. Cruikshank, L. Grenier, F. D. Melandri, S. L.
Nunes, R. L. Stein, J. Biol. Chem. 1996, 271, 7273.
¯
[14] H. Tomoda, H. Kumagai, H. Tanaka, S. Omura, Biochim.
[5] For selected examples, see: a) G. L. J. Bar, G. C. Lloyd-Jones,
K. I. Booker-Milburn, J. Am. Chem. Soc. 2005, 127, 7308; b) S.
Rakshit, C. Grohmann, T. Besset, F. Glorius, J. Am. Chem. Soc.
2011, 133, 2350; c) N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am.
Chem. Soc. 2011, 133, 6449; d) B. Li, J. Ma, N. Wang, H. Feng, S.
Xu, B. Wang, Org. Lett. 2012, 14, 736; e) M. Presset, D. Oehlrich,
F. Rombouts, G. A. Molander, Org. Lett. 2013, 15, 1528.
[6] For representative preparation of b-lactones, see: a) F. Soucy, L.
Grenier, M. L. Behnke, A. T. Destree, T. A. McCormack, J.
Adams, L. Plamondon, J. Am. Chem. Soc. 1999, 121, 9967; b) R.
Tennyson, D. Romo, J. Org. Chem. 2000, 65, 7248; c) S. Ma, B.
Wu, X. Jiang, S. Zhao, J. Org. Chem. 2005, 70, 2568; d) L. R.
Reddy, E. J. Corey, Org. Lett. 2006, 8, 1717; e) J. W. Kramer,
E. B. Lobkovsky, G. W. Coates, Org. Lett. 2006, 8, 3709; f) Y. Li,
K. J. Jardine, R. Tan, D. Song, V. M. Dong, Angew. Chem. 2009,
121, 9870; Angew. Chem. Int. Ed. 2009, 48, 9690; g) K. A. Morris,
K. M. Arendt, S. H. Oh, D. Romo, Org. Lett. 2010, 12, 3764; h) I.
Shiina, Y. Umezaki, N. Kuroda, T. Iizumi, S. Nagai, T. Katoh, J.
Org. Chem. 2012, 77, 4885; i) L. Huang, Q. Wang, X. Liu, H.
Jiang, Angew. Chem. 2012, 124, 5794; Angew. Chem. Int. Ed.
2012, 51, 5696; j) N. Sun, Y. Li, G. Yin, S. Jiang, Eur. J. Org.
Chem. 2013, 2541.
Biophys. Acta. 1987, 922, 351.
[15] J. Douglas, J. E. Taylor, G. Churchill, A. M. Z. Slawin, A. D.
Smith, J. Org. Chem. 2013, 78, 3925.
[16] J. Li, S. Yang, W. Wu, H. Jiang, Chem. Commun. 2014, 50, 1381.
[17] W. Wu, H. Jiang, Acc. Chem. Res. 2012, 45, 1736.
[18] a) S. Yang, H. Jiang, Y. Li, H. Chen, W. Luo, Y. Xu, Tetrahedron
2008, 64, 2930; b) J. Li, S. Yang, L. Huang, H. Chen, H. Jiang,
RSC Adv. 2013, 3, 11529; c) J. Li, S. Yang, H. Jiang, W. Wu, J.
Zhao, J. Org. Chem. 2013, 78, 12477; d) J. Li, S. Yang, W. Wu, C.
Qi, Z. Deng, H. Jiang, Tetrahedron 2014, 70, 1516.
[19] a) Z. Wang, X. Lu, J. Org. Chem. 1996, 61, 2254; b) Q. Zhang, X.
Lu, X. Han, J. Org. Chem. 2001, 66, 7676; c) W. Wu, A. Kong, X.
Lu, J. Org. Chem. 2006, 71, 3854.
[20] K. Kaneda, T. Uchiyama, Y. Fujiwara, T. Imanaka, S. Teranishi,
J. Org. Chem. 1979, 44, 55.
[21] For details of the selection of the solvents, see the Supporting
Information.
[22] A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350; Angew.
Chem. Int. Ed. 2002, 41, 4176.
[23] J. Moon, M. Jang, S. Lee, J. Org. Chem. 2009, 74, 1403.
[24] F. Zhao, Q. Tan, F. Xiao, S. Zhang, G. J. Deng, Org. Lett. 2013, 15,
1520.
[7] For representative preparation of g-lactones, see: a) R. B.
Chhor, B. Nosse, S. Sçrgel, C. Bçhm, M. Seitz, O. Reiser,
Chem. Eur. J. 2003, 9, 260; b) G. Liu, X. Lu, Tetrahedron Lett.
2003, 44, 127; c) L. Huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem.
Soc. 2010, 132, 17652; d) L. Zhou, C. K. Tan, X. Jiang, F. Chen,
Y.-Y. Yeung, J. Am. Chem. Soc. 2010, 132, 15474; e) C. Shu, M.-
Q. Liu, Y.-Z. Sun, L.-W. Ye, Org. Lett. 2012, 14, 4958; f) C. G.
[25] A. Cowell, J. K. Stille, J. Am. Chem. Soc. 1980, 102, 4193.
[26] a) Z. Zhang, X. Lu, G. Zhu, J. Org. Chem. 1995, 60, 1087; b) X.
Lu, Z. Xu, Q. Zhang, X. Han, Organometallics 2001, 20, 3724;
c) Q. Zhang, W. Xu, X. Lu, J. Org. Chem. 2005, 70, 1505.
[27] D. R. Stuart, E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007,
129, 12072.
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