Chiral heterodisulfoxide ligands in rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to chromenones

Article abstract of DOI:10.1002/ejoc.201100387

A new family of benzene-based chiral heterodisulfoxide ligands L1-L5 was synthesized in a single step. These disulfoxide ligands were applied in the rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to chromenones. The addition of diverse arylboronic acids to chromenones proceeds smoothly in up to 70% yield with up to 95%ee. A new family of benzene-based chiralheterodisulfoxide ligands was synthesized in a single step. These disulfoxide ligands were applied in the rhodium-catalyzed asymmetric 1,4-addition of arylboronicacids to chromenones. The addition of diverse arylboronic acids to chromenones proceeds smoothly in up to 70% yield and with up to 95%ee.

Full text of DOI:10.1002/ejoc.201100387

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100387
Chiral Heterodisulfoxide Ligands in Rhodium-Catalyzed Asymmetric
1,4-Addition of Arylboronic Acids to Chromenones
Fuzhong Han,[a,b,c] Guihua Chen,[a,b,c] Xiangyang Zhang,[a,b,c] and Jian Liao*[a,b,c]
Keywords: Sulfur / Ligand design / Chromenones / Boron / Michael addition
A new family of benzene-based chiral heterodisulfoxide li-
gands L1–L5 was synthesized in a single step. These disulf-
oxide ligands were applied in the rhodium-catalyzed asym-
metric 1,4-addition of arylboronic acids to chromenones. The
addition of diverse arylboronic acids to chromenones pro-
ceeds smoothly in up to 70% yield with up to 95%ee.
Pioneered by Hayashi and Miyaura,[11] rhodium-cata-
lyzed 1,4-addition of organoboron reagents to electron-de-
ficient olefins is one of the most powerful strategies for
enantioselective C–C bond formation. Recently, we de-
scribed a new method to prepare chiral flavanones, which
proceeds through rhodium-catalyzed conjugate addition of
sodium tetraarylborates to chromenones when a C2-sym-
metric chiral disulfoxide is used as the ligand. Good reactiv-
ities (yields up to 75%) and excellent enantioselectivities (up
to Ͼ99%ee) were achieved.[12] Although sodium tetraaryl-
borates can promote the 1,4-addition because of high nu-
cleophilicity, there are still some limitations in their use:
lack of readily available functionalized sodium tetraarylbor-
ates,[13] and the byproducts are generally toxic.[14] Utilizing
commercially available arylboronic acids as the nucleophiles
is obviously an attractive and convenient way to make func-
tionalized chiral flavanones.[15]
Achieving rhodium-catalyzed 1,4-addition of arylboronic
acids to chromenones is significantly challenging work and
few reports describe this strategy for the synthesis of chiral
flavanones.[12,16] Undesirable reversibility of the reaction by
ring-opening/cyclization under the basic conditions of the
1,4-addition would lead to erosion of the enantiomeric ex-
cess and yield of the chiral flavanones [Equation (1)].[16c]
Introduction
Flavanones and their derivatives are a very important
class of natural products that possess many notable phar-
macological activities such as anti-inflammatory, antitumor,
and antibacterial properties.[1] Synthetic methods for the
construction of racemic flavanones have been extensively
developed.[2] However, approaches to the stereoselective
preparation of enantiomerically pure structural motifs are
limited, and much attention has been paid to the pro-
duction of a catalytic asymmetric strategy employing en-
zymes, organocatalysis, and metal-based catalysts.[3] En-
zyme-catalyzed biosynthesis can generate chiral flavanones
with very high enantioselectivity,[4] but other attempts, in-
cluding the use of amino acids,[5] tartaric acid, or N-benzyl-
1-phenylethylamine[6] and chiral cobalt–salen[7] complex
catalyzed asymmetric oxa-Michael-type cyclization, failed.
A recent breakthrough was achieved by Scheidt et al.[8] who
utilized chiral thioureas as organocatalysts in the asymmet-
ric intramolecular conjugate addition of phenols to unsatu-
rated ketones; the corresponding flavanones were generated
in yields and with excellent ee values. A similar approach
was reported by Hintermann; modest enantioselectivities
were observed (up to 64%ee) when quinine was used as a
catalyst.[9] On the other hand, Feng et al.[10] employed chi-
ral N,NЈ-dioxide nickel(II) catalysts in enantioselective in-
tramolecular oxa-Michael (IOM) additions and flavanones
were obtained with up to 99%ee.
[a] Key Laboratory of Asymmetric Synthesis and Chirotechnology
of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences,
(1)
Although (R)-BINAP gives an excellent ee value (97%),
a low yield (31%) was observed; our C2-symmetric disulfox-
ide ligand, [(R,R)-1,2-bis(tert-butylsulfinyl)benzene], also
demonstrated unsatisfactory reactivity (32% yield).[12]
Therefore, it was necessary to modify our chiral disulfoxide
ligand to improve the reactivity. In this way, good yields
and high ee values of the chiral flavanones might be
achieved.
Chengdu 610041, P. R. China
[b] Natural Products Center, Chengdu Institute of Biology, Chinese
Academy of Sciences,
Chengdu 610041, P. R. China
Fax: +86-28-8522-9250
E-mail: jliao@cib.ac.cn
[c] Graduate School of Chinese Academy of Sciences,
Beijing 100049, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100387.
2928
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2928–2931

Chiral Heterodisulfoxide Ligands in Rh-Catalyzed 1,4-Additions
In investigations performed by Dorta,[17] chiral aryl sulf- L1–L5 (6.0 mol-%), aqueous KOH (50 mol-%) was added
oxides acted as highly efficient ligands in the rhodium-cata- to a solution of chromenone 3a and phenylboronic acid
lyzed 1,4-addition of arylboronic acids to electron-deficient (3.0 equiv. with respect to 3a) in CH2Cl2, and the mixture
acceptors. In our recent work, tert-butyl sulfoxide ligands was heated at 40 °C for 3 h (Table 1). For ligand L1, the
showed encouraging results in asymmetric reactions.[12,18,19] enantioselectivity was poor (72%ee) but a moderate yield
We thus expected that combination of simple chiral tert- (45%) of flavanone 4a was obtained (Table 1, Entry 1). On
butyl and aryl sulfoxides, which would allow the advantages the contrary, diastereomer L2 gave a low yield (20%),
associated with each framework, in one framework would though the enantioselectivity was high (95%ee; Table 1, En-
provide a highly efficient ligand. Herein, we would like to try 2). Interestingly, ligand L3, which is similar to L1 except
report a new class of chiral heterodisulfoxide ligands con- for two ortho-methyl substituents, provided the best result
taining tert-butyl and aryl sulfoxides within a rigid benzene (56% yield and 91%ee; Table 1, Entry 3). However, bulky
scaffold, and we also evaluate these ligands in the rhodium- ligands L4 and L5 were not effective and low yields and low
catalyzed asymmetric 1,4-addition of arylboronic acids to enantioselectivities were observed (Table 1, Entries 4 and 5).
chromenones.
Moreover, diene catalyst [Rh(cod)Cl]2 was also tested, and
a poor yield (10%) was observed;[23] moreover, the 1,2-ad-
duct of the carbonyl group was not observed in the hetero-
disufoxide/RhI catalytic system.
Results and Discussion
The sequence of ligand synthesis is outlined in Scheme 1.
The preparation of new heterodisufoxide ligands L1–L5
was accomplished efficiently in one step from (R)-phenyl
tert-butyl sulfoxide (1).[17a,20] Sulfoxide 1 was submitted to
ortho-lithiation by using nBuLi (1.1 equiv.) in THF at
–78 °C for 1 h. Subsequent trapping of electrophilic sulfin-
ate ester 2a–e[21,22] at –78 °C followed by slow warming to
room temperature gave disulfoxide ligands L1–L5 in 52–
65% yield.
Table 1. Rh-catalyzed enantioselective 1,4-addition of phenylbor-
onic acid to chromenone 3a. Screening of ligands and solvents.[a]
Entry
Ligand
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L3
L3
L3
L3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
45
20
55
20
trace
70
60
trace
trace
72 (R)[d]
95
91
71
n.d.
91
86
toluene
cyclohexane
1,4-dioxane
EtOH
n.d.
n.d.
[a] The reaction was performed with 3a (0.2 mmol), phenylboronic
acid (0.6 mmol), [Rh(C2H4)2Cl]2 (5.0 mol-% Rh), and L (6.0 mol-
%) in solvent (1 mL) at 40 °C for 3 h. [b] Isolated yield. [c] The ee
values were determined by HPLC with a chiral column. [d] The
absolute configuration was determined by comparison to literature
data.[8]
To improve the reactivity and enantioselectivity of ligand
L3 further, a variety of solvents were examined. The reac-
tion proceeded well in nonpolar solvents (toluene and cy-
clohexane; Table 1, Entries 6 and 7), and a low activity of
ligand L3 was observed in polar solvents (dioxane and eth-
anol; Table 1, Entries 8 and 9). Toluene was found to be the
best solvent for this reaction (70% yield, 91%ee; Table 1,
Entry 6).
Encouraged by these results, the effect of the added base,
which plays an important role in the reactivity and enantio-
selectivity of rhodium-catalyzed 1,4-additions, was studied.
The rhodium-catalyzed asymmetric 1,4-addition to 3a was
optimized by using 0.5 equiv. of base in the presence of Rh/
Scheme 1. Synthesis of chiral heterodisulfoxide ligands L1–L5.
With chiral heterodisufoxide ligands L1–L5 in hand, our L3 (5.0 mol-% Rh) in toluene/H2O (10:1) at 40 °C for 3 h
initial efforts were focused on ligand screening and estab- (Table 2). When KOH and K2CO3 were used, about 70%
lishing optimal conditions. Using rhodium catalysts gener- yield and 90%ee were obtained (Table 2, Entries 1 and 2).
ated in situ from [Rh(C2H4)2Cl]2 (2.5 mol-%) and ligand Cs2CO3 and Et3N did not give better results (Table 2, En-
Eur. J. Org. Chem. 2011, 2928–2931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2929

F. Han, G. Chen, X. Zhang, J. Liao
SHORT COMMUNICATION
tries 3 and 4). It is interesting to note that increased
To improve the reactivity and maintain the high enantio-
enantioselectivity of 4a was observed (ee Ͼ95%) when selectivity of ligand L3, the amount of KHCO3 and KF
weak bases (KHCO3 and KF) were used, but the yields was increased, respectively. When 5.0 equiv. of KHCO3 was
were lower (Table 2, Entries 5 and 6).
added, the yield was increased (60%) and the enantio-
selectivity was still high (95%ee; Table 2, Entry 7). Similar
results were achieved by using 2.5 equiv. KF (Table 2, En-
try 8). Nevertheless, a higher loading of KF gave a yield of
80%, but the selectivity was lower (Table 2, Entry 9). The
latter was slightly improved by a combination of KHCO3
(5 equiv.) and KF (2.5 equiv.; Table 2, Entry 10), which
served as the best conditions for further studies. A pro-
longed reaction time (12 h) also did not improve the yield.
Under the optimal reaction conditions, the substrate
scope was evaluated. A variety of chromenones 3 and aryl-
boronic acids were well suited for this catalyst system. De-
sired 1,4-adducts 4 were well obtained in moderate to good
yield (53–70%) with excellent enantioselectivities (92–
95%ee, Table 3).
Table 2. Rh-catalyzed enantioselective 1,4-addition of phenylbor-
onic acid to chromenone 3a. Screening of bases.[a]
Entry Toluene/H2O
Base (equiv.)
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
10:1
10:1
10:1
10:1
10:1
10:1
1:1
2:1
2:1
2:3
KOH (0.5)
K2CO3 (0.5)
Cs2CO3 (0.5)
Et3N (0.5)
KHCO3 (0.5)
KF (0.5)
KHCO3 (5.0)
KF (2.5)
KF (12.0)
70
75
55
45
40
40
60
57
80
67
91
89
91
93
95
96
95
94
87
94
Conclusions
In conclusion, we have developed a novel class of chiral
hetero-disulfoxide ligands L1–L5, which are effective
KHCO3 (5.0) + KF (2.5)
[a] The reaction was performed with 3a (0.2 mmol), phenylboronic ligands for asymmetric rhodium-catalyzed 1,4-addition of
acid (0.6 mmol), [Rh(C2H4)2Cl]2 (5.0 mol-% Rh), and L3 (6.0 mol-
%) in toluene (1 mL) at 40 °C for 3 h. [b] Isolated yield. [c] The ee
dition process affords flavanones 4 in excellent enantio-
values were determined by HPLC with a chiral column.
arylboronic acids to chromenones. The enantioselective ad-
selectivities (92–95% ee) and up to 70% yield under mild
conditions. This paper represents a practical strategy to pre-
pare a series of chiral flavanones through rhodium-cata-
Table 3. Rh-catalyzed enantioselective 1,4-addition of arylboronic
lyzed 1,4-addition.
acids to chromenones 3.[a]
Experimental Section
General Procedure for the Preparation of Chiral Heterodisufoxide
Ligands L1–L5: At –78 °C, nBuLi (2.5 m in hexane, 1.8 mL,
4.4 mmol) was added dropwise to a solution of (R)-tert-Butylsulfin-
ylbenzene (1; 0.73 g, 4.0 mmol) in tetrahydrofuran (15 mL). The
resulting mixture was stirred for 1 h at –78 °C and optically pure
sulfinate ester 2[21,22] (4.4 mmol) was added to the mixture. After
0.5 h at –78 °C the reaction was warmed to room temperature. The
resulting mixture was quenched with water (10 mL), the organic
phase was separated, and the aqueous layer was extracted with
CH2Cl2 (3ϫ15 mL). The combined organic layer was dried with
Na2SO4 and concentrated to a small volume. Flash chromatog-
raphy (petroleum/EtOAc, 2:1) of the crude material afforded li-
gands L1–L5.
General Procedure for the Enantioselective Rhodium-Catalyzed Ad-
dition of Arylboronic Acids to Chromenones: Under an argon atmo-
sphere and at room temperature, to a 10-mL Schlenk tube with a
Teflon cap was added ligand L (6.0 mol-%), [RhCl(C2H4)2]2
(1.94 mg, 5.0 mol-% Rh), and CH2Cl2 (1.0 mL), and the mixture
was stirred at 25 °C. After 30 min, CH2Cl2 was evaporated. Then,
ArB(OH)2 (0.6 mmol, 3.0 equiv.), chromene 3 (0.2 mmol), toluene
(1.0 mL), and KHCO3 (1.0 mmol, 5.0 equiv.) + KF (5.0 mmol,
2.5 equiv.) in degassed H2O (1.5 mL) was added sequentially. The
mixture was stirred for 3 h at 40 °C and directly charged onto a
column (silica gel) and purified by flash chromatography (petro-
leum/EtOAc) to afford product 4.
[a] The reaction was performed with 3 (0.2 mmol), arylboronic acid
(0.6 mmol), [Rh(C2H4)2Cl]2 (5.0 mol-% Rh), and L3 (6.0 mol-%) in
toluene (1 mL) at 40 °C for 3 h. [b] Isolated yield. [c] The ee values
were determined by HPLC with a chiral column.
2930
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2928–2931

Chiral Heterodisulfoxide Ligands in Rh-Catalyzed 1,4-Additions
Pure Appl. Chem. 2004, 76, 465–475; d) E. M. Carreira, H.
Grutzmacher, C. Defieber, Angew. Chem. 2008, 120, 4558; An-
gew. Chem. Int. Ed. 2008, 47, 4482–4052; e) R. Shintani, Y.
Tsutsumi, M. Nagaosa, T. Nishimura, T. Hayashi, J. Am.
Chem. Soc. 2009, 131, 13588–13589.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization of the prepared
compounds, copies of the NMR spectra, and chiral HPLC spectra
of the Michael addition products.
[12] J. Chen, J. M. Chen, F. Lang, X. Y. Zhang, L. F. Cun, J. Zhu,
J. G. Deng, J. Liao, J. Am. Chem. Soc. 2010, 132, 4552–4553.
[13] R. Shintani, M. Takeda, T. Nishimura, T. Hayashi, Angew.
Chem. Int. Ed. 2010, 49, 3969–3971.
[14] a) S. Darses, J. P. Genet, Eur. J. Org. Chem. 2003, 4313–4327;
b) A. H. Stefani, R. Cella, A. S. Vieira, Tetrahedron 2007, 63,
3623–3658; c) G. A. Molander, N. Ellis, Acc. Chem. Res. 2007,
40, 275–286; d) S. Darses, J. P. Genet, Chem. Rev. 2008, 108,
288–325.
Acknowledgments
We are grateful for support from the National Natural Science
Foundation of China (NSFC) (21072186 and 20872139), the West
Light Foundation of CAS, the National Basic Research Program
of China (973 Program, 2010CB833300), and Chengdu Institute of
Biology, CAS (Y0B1051100).
[15] Recent report of rhodium-catalyzed 1,4-addition of aryl-
boronic acids to chromenones: T. Korenaga, K. Hayashi, Y.
Akaki, R. Maenishi, Y. Sakai, Org. Lett. 2011, 13, 2022–2025.
[16] a) J. Ramnauth, O. Poulin, S. S. Bratovanov, S. Rakhit, S. P.
Maddaford, Org. Lett. 2001, 3, 2571–2573; b) G. Kumaras-
wamy, G. Ramakrishna, P. Naresh, B. Jagadeesh, B. Sridhar, J.
Org. Chem. 2009, 74, 8468–8471; c) A. Cisak, C. Mielczarek,
J. Chem. Soc. Perkin Trans. 2 1992, 1603–1607.
[17] a) R. Mariz, X. J. Luan, M. Gatti, A. Linden, R. Dorta, J. Am.
Chem. Soc. 2008, 130, 2172–2173; b) J. J. Bürgi, R. Mariz, M.
Gatti, E. Drinkel, X. J. Luan, S. Blumentritt, A. Linden, R.
Dorta, Angew. Chem. 2009, 121, 2806; Angew. Chem. Int. Ed.
2009, 48, 2768–2771; c) R. Mariz, A. Poater, M. Gatti, E. Drin-
kel, J. J. Bürgi, X. J. Luan, S. Blumentritt, A. Linden, L. Cav-
allo, R. Dorta, Chem. Eur. J. 2010, 16, 14335–14347.
[18] a) J. M. Chen, D. Li, H. F. Ma, L. F. Cun, J. Zhu, J. G. Deng,
J. Liao, Tetrahedron Lett. 2008, 49, 6921–6923; b) P. Wang,
J. M. Chen, L. F. Cun, J. G. Deng, J. Zhu, J. Liao, Org. Biomol.
Chem. 2009, 7, 3741–3747; c) J. M. Chen, F. Lang, D. Li, L. F.
Cun, J. Zhu, J. G. Deng, J. Liao, Tetrahedron: Asymmetry 2009,
20, 1953–1956; d) F. Lang, D. Li, J. M. Chen, J. Chen, L. C.
Li, L. F. Cun, J. Zhu, J. G. Deng, J. Liao, Adv. Synth. Catal.
2010, 352, 843–846; e) F. Z. Han, J. Chen, X. Y. Zhang, J. B.
Liu, L. F. Cun, J. Zhu, J. G. Deng, J. Liao, Tetrahedron Lett.
2011, 52, 830–833; f) X. Y. Zhang, J. Chen, F. Z. Han, L. F.
Cun, J. Liao, Eur. J. Org. Chem. 2011, 1443–1446.
[1] a) J. B. Harborne (Ed.), The Flavonoids: Advances in Research
Since 1980, Chapman and Hall, New York, 1988; b) J. B. Har-
borne, C. A. Williams, Nat. Prod. Rep. 1995, 12, 639–642; c)
L. C. Chang, A. D. Kinghorn in Bioactive Compounds from
Natural Sources: Isolation, Characterisation and Biological
Properties (Ed.: C. Tringali), Taylor & Francis, London, 2001,
ch. 5; d) Ø. M. Andersen, K. R. Markham (Eds.), Flavonoids:
Chemistry, Biochemistry and Applications, Taylor & Francis,
London, 2006.
[2] Selected examples: a) K. Tanaka, T. Sugino, Green Chem. 2001,
3, 133–137; b) D. J. Macquarrie, R. Nazih, S. Sebti, Green
Chem. 2002, 4, 56–59; c) S. Sarvanamurugan, M. Palanichamy,
B. Arabindoo, V. Murugesan, J. Mol. Catal. A 2004, 218, 101–
105; d) B. M. Choudary, K. V. S. Ranganath, J. Yadav, M. L.
Kantam, Tetrahedron Lett. 2005, 46, 1369–1371.
[3] a) S. Ramadas, G. L. D. Krupadanam, Tetrahedron: Asym-
metry 2004, 15, 3381–3385; b) K. J. Hodgetts, Tetrahedron
2005, 61, 6860–3870; c) H. F. Wang, H. F. Cui, Z. Chai, P. Li,
C. W. Zheng, Y. Q. Yang, G. Zhao, Chem. Eur. J. 2009, 15,
13299–13303.
[4] R. A. Bednar, J. R. Hadcock, J. Biol. Chem. 1988, 263, 9582–
9588.
[5] S. Chandrasekhar, K. Vijeender, K. V. Reddy, Tetrahedron Lett.
2005, 46, 6991–6993.
[6] T. Patonay, R. S. Varma, A. Vass, A. Lévai, J. Dudás, Tetrahe-
dron Lett. 2001, 42, 1403–1406.
[19] R. Tokunoh, M. Sodeoka, K. Aoe, M. Shibasaki, Tetrahedron
Lett. 1995, 36, 8035–8038.
[20] N. L. Fur, L. Mojovic, N. Ple, A. Turck, V. Reboul, P. Metzner,
J. Org. Chem. 2006, 71, 2609–2616.
[21] Y. Watanabe, N. Mase, M. Tateyama, T. Toru, Tetrahedron:
Asymmetry 1999, 10, 737–745.
[7] K. Maruyama, K. Tamanaka, A. Nishinaga, A. Inada, T. Nak-
anishi, Tetrahedron Lett. 1989, 30, 4145–4158.
[8] M. M. Biddle, M. Lin, K. A. Scheidt, J. Am. Chem. Soc. 2007,
129, 3830–3831.
[9] C. Dittmer, G. Raabe, L. Hintermann, Eur. J. Org. Chem. 2007,
5886–5898.
[10] L. J. Wang, X. H. Liu, Z. H. Dong, X. Fu, X. M. Feng, Angew.
Chem. 2008, 120, 8798; Angew. Chem. Int. Ed. 2008, 47, 8670–
8673.
[11] Selected examples: a) S. Sakuma, M. Sakai, R. Itooka, N. Mi-
yaura, J. Org. Chem. 2000, 65, 5951–5955; b) T. Hayashi, K.
Yamasaki, Chem. Rev. 2003, 103, 2829–2844; c) T. Hayashi,
[22] Z. X. Han, D. Krishnamurthy, P. Grover, Q. K. Fang, C. H.
Senanayake, J. Am. Chem. Soc. 2002, 124, 7880–7881.
[23] Reaction conditions: 3a (0.2 mmol) and phenylboronic acid
(0.6 mmol) in 1,4-dioxane/H2O (10:1) at 60 °C for 12 h in the
presence of [Rh(cod)Cl]2 (5.0 mol-% Rh) and KOH (50 mol-
%).
Received: March 21, 2011
Published Online: May 2, 2011
Eur. J. Org. Chem. 2011, 2928–2931
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2931