Nickel(II)-Catalyzed Asymmetric Propargyl and Allyl Claisen Rearrangements to Allenyl- and Allyl-Substituted β-Ketoesters

Article abstract of DOI:10.1002/anie.201404643

Highly efficient catalytic asymmetric Claisen rearrangements of O-propargyl β-ketoesters and O-allyl β-ketoesters have been accomplished under mild reaction conditions. In the presence of the chiral N,N′-dioxide/Ni^II complex, a wide range of allenyl/allyl-substituted all-carbon quaternary β-ketoesters was obtained in generally good yield (up to 99 %) and high diastereoselectivity (up to 99:1 d.r.) with excellent enantioselectivity (up to 99 % ee).

Full text of DOI:10.1002/anie.201404643

Angewandte
Chemie
DOI: 10.1002/anie.201404643
Asymmetric Catalysis
Nickel(II)-Catalyzed Asymmetric Propargyl and Allyl Claisen
Rearrangements to Allenyl- and Allyl-Substituted b-Ketoesters**
Yangbin Liu, Haipeng Hu, Haifeng Zheng, Yong Xia, Xiaohua Liu, Lili Lin, and
Xiaoming Feng*
Dedicated to Professor Li-Xin Dai on the occasion of his 90th birthday
Abstract: Highly efficient catalytic asymmetric Claisen rear-
rangements of O-propargyl b-ketoesters and O-allyl b-ketoest-
ers have been accomplished under mild reaction conditions. In
the presence of the chiral N,N’-dioxide/NiII complex, a wide
range of allenyl/allyl-substituted all-carbon quaternary b-
ketoesters was obtained in generally good yield (up to 99%)
and high diastereoselectivity (up to 99:1 d.r.) with excellent
enantioselectivity (up to 99% ee).
tively, the enantioselective catalytic version of the propargyl
vinyl rearrangement[6] continues to be relatively rare although
it provides an useful route to synthetically valuable function-
alized allenes (Scheme 1B).[7] Modern strategies for the
stereoselective construction of the propargyl rearrangements
are primarily based on either auxiliary controlled versions at
high temperature[8] or using optically active propargyl alco-
hols in the presence of gold(I).[9] To date, only one group
made a breakthrough in the asymmetric catalytic propargyl
Claisen rearrangements, that is the group of Kozlowski
recently reported on the first asymmetric Saucy–Marbet
rearrangement for the synthesis of allenyl oxindoles and
spirolactones catalyzed by palladium(II)/binap.[10] The explo-
ration of cheap and efficient chiral Lewis acids instead of
precious metals is obviously expected to expand the avail-
ability and generality of the reaction. Herein, we disclosed
a general asymmetric propargyl vinyl rearrangement to
a series of allenyl-substituted cyclic b-ketoesters by an easily
available chiral N,N’-dioxide/nickel(II) complex. The method
also enables the asymmetric allyl vinyl rearrangement to give
a wide range of allyl-substituted b-ketoesters with vicinal
tertiary-quaternary stereocenters. Excellent diastereo- and
enantioselectivities were obtained at a good catalytic turn-
over under mild reaction conditions.
Claisen rearrangement and its variants have enjoyed
unparalleled value because of the utility of the products in
the synthesis of complex organic structures.[1] The develop-
ment of a general array of catalytic asymmetric rearrange-
ments represents a highly desirable goal. The classic Claisen
rearrangement of allyl vinyl ethers can give access to g,d-
unsaturated carbonyl compounds with contiguous stereogenic
centers (Scheme 1A). By relying on either chiral Lewis
acids,[2] Jacobsenꢀs guanidinium salts,[3] N-heterocyclic car-
benes,[4] or chiral transition metal systems,[5] the catalytic
asymmetric rearrangements of allyl vinyl ethers were ach-
ieved with an excellent level of enantioselectivity. Compara-
Initially, we synthesized the propargyl vinyl ethers
1 (PVEs) utilizing the Mitsunobu reaction[11] according to
the report from the group of Jacobsen.[3b] Low to moderate
yields of the isolated O-propargyl ketoesters were obtained in
a single step from the propargyl alcohol and b-ketoester. The
ester group was introduced into the substrate with the
anticipation that it could provide an additional binding site
for the Lewis acid catalysts and thus improve the enantio-
control.[12] Based on our previously established metal/N,N’-
dioxide complex,[13] we investigated the asymmetric Claisen
rearrangement of the O-propargyl b-ketoester 1a (Table 1,
entries 1–4). We were delighted to find that 1a engaged in the
rearrangement to afford the desired allenic derivative 2a in
84% yield and 91% ee when promoted by 5 mol% of the L1/
Ni(OTf)2 complex (Table 1, entry 4). Encouragingly, the
reactions proceeded with unanimously excellent enantiose-
lectivities (98% ee) when the N,N’-dioxides L2, L4, and L5,
containing 2,6-dimethylaniline subunits, served as the chiral
ligands (Table 1, entries 5, 7, and 8). However, performing the
reaction at 08C resulted in dramatic loss of reactivity (Table 1,
entry 9).
Scheme 1. Allyl vinyl rearrangment versus propargyl vinyl rearrange-
ment.
[*] Y. B. Liu, H. P. Hu, H. F. Zheng, Y. Xia, Prof. Dr. X. H. Liu,
Dr. L. L. Lin, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
E-mail: xmfeng@scu.edu.cn
Prof. Dr. X. M. Feng
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
[**] We thank the National Basic Research Program of China (973
Program: 2011CB808600), the National Natural Science Founda-
tion of China (21290182, 21321061 and 21172151), and the Ministry
of Education (20110181130014) for financial support.
Then, the substrate scope of the asymmetric propargyl
vinyl rearrangement was surveyed with various substituents at
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404643.
Angew. Chem. Int. Ed. 2014, 53, 11579 –11582
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11579

.
Angewandte
Communications
Table 1: Optimization of the reaction conditions.[a]
Entry
Ligand
Metal source
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
L1
L1
L1
L1
L2
L3
L4
L5
L2
Sc(OTf)3
Yb(OTf)3
Cu(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
14
91
57
84
88
85
70
73
trace
51
65
10
91
98
80
98
98
–
8
9[d]
[a] Unless otherwise noted, all reactions were performed with 1a
(0.10 mmol), ligand/metal (1:1, 5 mol%) in CH2Cl2 (1.0 mL) at 358C for
48 h. [b] Yield of isolated product. [c] Determined by HPLC analysis using
a chiral stationary phase. [d] At 08C for 48 h. Tf=trifluoromethanesul-
fonyl.
the propargyl group and b-ketoester unit (Scheme 2). Both
electron-donating and electron-withdrawing substituents on
the 1H-indone backbone of the substrate (1a–e) were
tolerated in the asymmetric rearrangement. Varying the
ester groups of the b-ketoesters (1 f,g) delivered the similar
levels of enantioselectivity to that of 1a. Aryl substituents
(R2) at the terminal position of the alkynyl group (1h–j) had
no obvious influence on the yields and enantioselectivities.
Meanwhile, the absolute configuration of the propargyl
Claisen rearrangement product 2j was unambiguously deter-
mined to be R on the basis of X-ray single-crystal diffrac-
tion.[14] Moreover, neither the simplest unsubstituted con-
gener 1k, nor aliphatic substituents in 1l,m, nor the TMS
group in 1n prevented the enantioselective rearrangement.
Notably, the THP-protected substrate 1o, generated from 1,4-
butanediol, gave the rearrangement product 2o in 90% yield,
and 95% and 73% ee for the two diastereomers, respectively.
Comparatively, the TBS-protected substrate 1p delivered the
allenic product 2p in higher enantioselectivity (97% ee).
Cyclic b-ketoesters of fused aromatic rings (1q,r) were as
effective as the simple saturated aliphatic ring (1s,t) and
a heterocycle (1u) with regard to the enantioselectivities (93–
98% ee). It is noteworthy that a substituent (R3) on the O-
propargyl units was also favorable for products (2v,w) with
vicinal a chiral allene and an all-carbon quaternary center in
satisfactory yields. High enantioselectivity was obtained for
one diastereomer, albeit moderate for the other. It indicates
that the catalyst has excellent facial discrimination of the b-
ketoesters, and the minor ee value for the other diastereomer
results from the competition of the instinctive diastereose-
lection of the racemic substrates. And no obvious resolution
Scheme 2. Substrate scope of the asymmetric propargyl Claisen rear-
rangement. The reactions were performed with 1 (0.10 mmol), L2/
Ni(OTf)2 (1:1, 5 mol%) in CH2Cl2 (1.0 mL) at 358C for 24–96 h (for
details, see the Supporting Information). Yields of the isolated
products were reported. The ee values were determined by HPLC
analysis using a chiral stationary phase. [a] Catalyst loading: 10 mol%.
[b] Reaction performed in CH2ClCH2Cl (1.0 mL) at 508C. Boc=tert-
butoxycarbonyl, TBS=tert-butyldimethylsilyl, THP=2-tetrahydropyr-
anyl, TMS=trimethylsilyl.
process occurred in the asymmetric rearrangement. More-
over, the Saucy–Marbet–Claisen rearrangement of the prop-
argyl-substituted indole 1x also proceeded smoothly with
high yield and moderate enantioselectivity.
To evaluate the potential of the allenic products of the
rearrangement for constructing interesting and useful chiral
building blocks, additional transformations were carried out
(Scheme 3). The carbonyl group of the allenyl-substituted b-
ketoester 2a was reduced by NaBH4, then the nucleophilic
hydroxy group attacked to allenyl motif in the presence of
Bi(OTf)3 to form the polycyclic product 5 in moderate yield,
and high diastereo- and enantioselectivity. Interestingly,
a cascade reaction occurred when 2p was treated with
PPTS, thus affording the sterically congested spirolactone 6.
11580 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 11579 –11582

Angewandte
Chemie
Scheme 3. Application of the catalytic asymmetric rearrangement reac-
tion. DCE=CH2ClCH2Cl, PPTS=pyridinium p-toluenesulfonate,
THF=tetrahydrofuran.
Upon investigation of the propargyl vinyl rearrangement,
we were glad to find that the catalyst system of N,N’-dioxide
L2/Ni(BF4)2 was capable of the asymmetric Claisen rear-
rangement of O-allyl b-ketoesters (Scheme 4). Remarkably,
a variety of allyl rearrangement products bearing continuous
tertiary-quaternary stereocenters was obtained in good to
excellent yields (90–99%), high diastereoselectivities (94:6–
99:1 d.r.), and enantioselectivities (91–98% ee). The catalyst
loading was lowered to 0.5 mol% without deterioration of the
yields and stereoselectivities. Neither the ester group of the b-
ketoesters nor the substituents at the allyl group had an
adverse effect on the yield and the stereoselectivity (4a–j).
Also of note, the reaction could be extended to heteroar-
omatic and condensed-ring substrates, thus affording the
Scheme 5. Investigating mechanism experiment. TEMPO=2,2,6,6-tet-
ramethyl-1-piperidinyloxy free radical.
corresponding products (4k–m) in excellent results. The
conjugated substituent was also well tolerated and gave the
desired [3,3]-rearrangement product 4n. The six-membered
and fused aromatic ring substrates 3o–q also coupled with
satisfied yields and stereoselectivities.[15]
To obtain information about the reaction mechanism,
some control experiments were carried out. The crossover
reaction of 1e and 1i indicates the propargyl rearrangement
proceeds in an intramolecular concerted manner (Sche-
me 5a). The radical pair intermediate is ruled out according
to the results that TEMPO had no effect on the reaction
outcome[16] (Scheme 5b). HRMS analysis of the mixture of
Ni(OTf)2, N,N’-dioxide L2, and 1a (1:1:1) confirmed the
coordination of the substrate to the catalyst. A peak at
m/z 1061.3521 was detected and corresponded to the complex
[Ni2+ + L2 + 1a + TfOÀ]+(cal. m/z 1061.3492). In line with the
X-ray structure of the chiral N,N’-dioxide/metal complexes[17]
and the product 2j,[14] the possible stereochemical model was
considered in Figure 1. The substrate 1j coordinates tightly to
the Lewis acid catalyst through the ether oxygen atom and the
carbonyl group of the auxiliary ester group. The propargyl
unit preferentially approaches the enolate ether from the
Scheme 4. Substrate scope of the asymmetric allyl Claisen rearrange-
ment. The reactions were performed with 3 (0.10 mmol), L2/Ni-
(BF4)2·6H2O (1:1, 0.5 mol%) in CH2Cl2 (1.0 mL) at 358C for 1–48 h
(for details, see the Supporting Information). Yields of isolated
products reported. The ee values and d.r. were determined by HPLC
analysis using a chiral stationary phase. [a] Catalyst loading: 2.0 mol%.
[b] Catalyst loading: 1.0 mol%.
Figure 1. Proposed stereochemical model of the propargyl rearrange-
ment.
Angew. Chem. Int. Ed. 2014, 53, 11579 –11582
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11581

.
Angewandte
Communications
Re face.[18] Therefore, the R-configurated product 2j was
generated in high enantioversion.
Y. Hanzawa, Angew. Chem. 2007, 119, 4005; Angew. Chem. Int.
Ed. 2007, 46, 3931; c) P. Mauleꢃn, J. L. Krinsky, F. D. Toste, J.
Am. Chem. Soc. 2009, 131, 4513; d) K. Tanaka, E. Okazaki, Y.
Shibata, J. Am. Chem. Soc. 2009, 131, 10822; e) H. Cao, H. Jiang,
W. Yao, X. Liu, Org. Lett. 2009, 11, 1931; f) H. Jiang, W. Yao, H.
Cao, H. Huang, D. Cao, J. Org. Chem. 2010, 75, 5347; g) A. Gille,
J. Rehbein, M. Hiersemann, Org. Lett. 2011, 13, 2122; h) E.
Okazaki, R. Okamoto, Y. Shibata, K. Noguchi, K. Tanaka,
Angew. Chem. 2012, 124, 6826; Angew. Chem. Int. Ed. 2012, 51,
6722; i) Y. Xiong, S. E. Schaus, J. A. Porco, Jr., Org. Lett. 2013,
15, 1962.
In summary, we have successfully developed highly
enantioselective Claisen rearrangement of both propargyl
and allyl vinyl ethers. The readily available chiral N,N’-
dioxide/nickel(II) complex accelerated the reaction in high
efficiency and stereoselectivity under mild reaction condi-
tions. High catalyst turnover was smoothly realized for the
asymmetric allyl vinyl rearrangement. Meanwhile, a wide
range of substrates was well tolerated with high yield and
enantioselectivity. The rearrangement products demonstrated
great potential for the rapid access to functionalized chiral
building blocks. Further studies on expanding the scope of
this reaction to the construction of useful chiral compounds
and on further elucidation of catalytic mechanism is in
progress.
[7] For reviews on allenes in organic synthesis, see: a) S. Ma, Acc.
Chem. Res. 2003, 36, 701; b) A. Hoffmann-Rçder, N. Krause,
Angew. Chem. 2004, 116, 1216; Angew. Chem. Int. Ed. 2004, 43,
1196; c) N. Krause, A. S. K. Hashimi, Modern Allene Chemistry,
Wiley-VCH, Weinheim, 2004; d) S. Ma, Chem. Rev. 2005, 105,
2829; e) B. J. Cowen, S. J. Miller, Chem. Soc. Rev. 2009, 38, 3102;
f) C. Aubert, L. Fensterbank, P. Garcia, M. Malacria, A.
Simonneau, Chem. Rev. 2011, 111, 1954; g) S. Yu, S. Ma,
Angew. Chem. 2012, 124, 3128; Angew. Chem. Int. Ed. 2012,
51, 3074; h) J. Ye, S. Ma, Acc. Chem. Res. 2014, 47, 989.
[8] For selected examples of auxiliary controlled diastereoselective
versions, see: a) M. O. Frederick, R. P. Hsung, R. H. Lambeth,
J. A. Mulder, M. R. Tracey, Org. Lett. 2003, 5, 2663; b) K. C. M.
Kurtz, M. O. Frederick, R. H. Lambeth, J. A. Mulder, M. R.
Tracey, R. P. Hsung, Tetrahedron 2006, 62, 3928.
[9] For selected examples of optical propargyl alcohols, see: a) B. D.
Sherry, F. D. Toste, J. Am. Chem. Soc. 2004, 126, 15978; b) B. D.
Sherry, L. Maus, B. N. Laforteza, F. D. Toste, J. Am. Chem. Soc.
2006, 128, 8132; c) R. A. Brawn, J. S. Panek, Org. Lett. 2007, 9,
2689; d) Y. Tang, L. Shen, B. J. Dellaria, R. P. Hsung, Tetrahe-
dron Lett. 2008, 49, 6404; e) B. Lꢄ, X. Jiang, C. Fu, S. Ma, J. Org.
Chem. 2009, 74, 438.
Experimental Section
General experimental procedure for the propargyl Claisen rearrange-
ment (for details, see the Supporting Information): Ni(OTf)2 (1.7 mg,
5 mol%) and the N,N’-dioxide ligand L2 (2.7 mg, 5 mol%) were
stirred in CH2Cl2 (1.0 mL) for 0.5 h at 358C. Subsequently, the
substrate 1 was added, and the resulting mixture was stirred at 358C
for the indicated time. The residue was purified by flash chromatog-
raphy on silica gel (1:10, Et2O/petroleum ether) to afford the desired
product 2.
Received: April 24, 2014
Published online: September 11, 2014
[10] a) T. Cao, J. Deitch, E. C. Linton, M. C. Kozlowski, Angew.
Chem. 2012, 124, 2498; Angew. Chem. Int. Ed. 2012, 51, 2448;
b) T. Cao, E. C. Linton, J. Deitch, S. Berritt, M. C. Kozlowski, J.
Org. Chem. 2012, 77, 11034.
[11] K. C. K. Swamy, N. N. B. Kumar, E. Balaraman, K. V. P. P.
Kumar, Chem. Rev. 2009, 109, 2551.
Keywords: allenic compounds · asymmetric catalysis ·
heterocycles · nickel · rearrangement
.
[1] For recent reviews, see; a) H. Ito, T. Taguchi, Chem. Soc. Rev.
1999, 28, 43; b) M. Hiersemann, L. Abraham, Eur. J. Org. Chem.
2002, 1461; c) U. Nubbemeyer, Synthesis 2003, 961; d) A. M.
Martꢁn Castro, Chem. Rev. 2004, 104, 2939; e) The Claisen
Rearrangment (Eds.: M. Hiersemann, U. Nubbemeyer), Wiley-
VCH, Weinheim, 2007; f) E. A. Ilardi, C. E. Stivala, A. Zakar-
ian, Chem. Soc. Rev. 2009, 38, 3133; g) J. Rehbein, M. Hier-
semann, Synthesis 2013, 1121.
[2] a) L. Abraham, R. Czerwonka, M. Hiersemann, Angew. Chem.
2001, 113, 4835; Angew. Chem. Int. Ed. 2001, 40, 4700; b) L.
Abraham, M. Kçrner, P. Schwab, M. Hiersemann, Adv. Synth.
Catal. 2004, 346, 1281; c) L. Abraham, M. Kçrner, M. Hierse-
mann, Tetrahedron Lett. 2004, 45, 3647; d) J. Troendlin, J.
Rehbein, M. Hiersemann, O. Trapp, J. Am. Chem. Soc. 2011,
133, 16444; e) J. Tan, C. H. Cheon, H. Yamamoto, Angew. Chem.
2012, 124, 8389; Angew. Chem. Int. Ed. 2012, 51, 8264.
[3] a) C. Uyeda, E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130, 9228;
b) C. Uyeda, A. R. Rçtheli, E. N. Jacobsen, Angew. Chem. 2010,
122, 9947; Angew. Chem. Int. Ed. 2010, 49, 9753.
[4] a) J. Kaeobamrung, J. Mahatthananchai, P. Zheng, J. W. Bode, J.
Am. Chem. Soc. 2010, 132, 8810; b) L. Candish, D. W. Lupton, J.
Am. Chem. Soc. 2013, 135, 58.
[5] a) M. E. Geherty, R. D. Dura, S. G. Nelson, J. Am. Chem. Soc.
2010, 132, 11875; b) E. C. Linton, M. C. Kozlowski, J. Am. Chem.
Soc. 2008, 130, 16162.
[6] For reviews on propargyl Claisen rearrangement, see: a) D.
Tejedor, G. Mꢂndez-Abt, L. Cotos, F. Garcꢁa-Tellado, Chem.
Soc. Rev. 2013, 42, 458. For selected examples of propargyl
rearrangement in organic synthesis, see: b) A. Saito, A. Kanno,
[12] When the ester group was replaced with CH2OTBS, the
rearrangement product was obtained only in less 20% yield
and 3% ee under the optimized reaction conditions.
[13] For reviews, see: a) X. H. Liu, L. L. Lin, X. M. Feng, Acc. Chem.
Res. 2011, 44, 574; b) X. H. Liu, L. L. Lin, X. M. Feng, Org.
Chem. Front. 2014, 1, 298; For recent examples, see: c) W. D.
Cao, X. H. Liu, R. X. Peng, P. He, L. L. Lin, X. M. Feng, Chem.
Commun. 2013, 49, 3470; d) M. S. Xie, X. H. Liu, X. X. Wu, Y. F.
Cai, L. L. Lin, X. M. Feng, Angew. Chem. 2013, 125, 5714;
Angew. Chem. Int. Ed. 2013, 52, 5604; e) W. Li, X. H. Liu, F. Tan,
X. Y. Hao, J. F. Zheng, L. L. Lin, X. M. Feng, Angew. Chem.
2013, 125, 11083; Angew. Chem. Int. Ed. 2013, 52, 10883; f) K.
Zheng, L. L. Lin, X. M. Feng, Acta Chim. Sinica 2012, 70, 1785;
g) M. S. Xie, X. X. Wu, G. Wang, L. L. Lin, X. M. Feng, Acta
Chim. Sinica 2014, 72, 856.
[14] CCDC 995994 (2j) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[15] The NO2 group was introduced for the other substrates that
could not be synthesized according to the general method.
[16] J. J. Gajewski, Acc. Chem. Res. 1997, 30, 219.
[17] K. Zheng, X. H. Liu, J. N. Zhao, Y. Yang, L. L. Lin, X. M. Feng,
Chem. Commun. 2010, 46, 3771.
[18] The steric hindrance between the propargyl unit and the bulky
aniline moiety of ligand might be disfavor for the enantioselec-
tive reaction, as shown in the lower right model.
11582 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 11579 –11582