Enantioselective Nucleophilic β-Carbon-Atom Amination of Enals: Carbene-Catalyzed Formal [3+2] Reactions

Article abstract of DOI:10.1002/anie.201606571

An enantioselective β-carbon amination for enals is disclosed. The nitrogen atom from a protected hydrazine with suitable electronic properties readily behaves as a nucleophile. Addition of the nitrogen nucleophile to a catalytically generated N-heterocyclic-carbene-bound α,β-unsaturated acyl azolium intermediate constructs a new carbon–nitrogen bond asymmetrically. The pyrazolidinone products from our catalytic reactions are common scaffolds in bioactive molecules, and can be easily transformed into useful compounds such as β³-amino-acid derivatives.

Full text of DOI:10.1002/anie.201606571

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201606571
German Edition: DOI: 10.1002/ange.201606571
Heterocycle Synthesis
Enantioselective Nucleophilic b-Carbon-Atom Amination of Enals:
Carbene-Catalyzed Formal [3+2] Reactions
Xingxing Wu+, Bin Liu+, Yuexia Zhang, Martin Jeret, Honglin Wang, Pengcheng Zheng,
Song Yang,* Bao-An Song, and Yonggui Robin Chi*
Abstract: An enantioselective b-carbon amination for enals is
disclosed. The nitrogen atom from a protected hydrazine with
suitable electronic properties readily behaves as a nucleophile.
Addition of the nitrogen nucleophile to a catalytically gen-
erated N-heterocyclic-carbene-bound a,b-unsaturated acyl
azolium intermediate constructs a new carbon–nitrogen bond
asymmetrically. The pyrazolidinone products from our cata-
lytic reactions are common scaffolds in bioactive molecules,
and can be easily transformed into useful compounds such as
b3-amino-acid derivatives.
À
C
arbon–nitrogen (C N) bonds are ubiquitous in natural
products, pharmaceutical compounds, and other functional
molecules which include polymeric materials. The develop-
À
ment of efficient methods for asymmetric construction of C
N bonds continues to be an important objective in organic
synthesis. In particular, the direct installation of a nitrogen
atom at the b-carbon atom of aldehydes and esters can
provide a most efficient access to useful b-amino acids and
their derivatives.[1,2] N-heterocyclic carbene (NHC) organic
catalysts have been explored to activate aldehydes and
carboxylic esters to generate intermediates with reactive b-
carbon atoms. For example, the NHC-mediated reaction of
enals[3] or saturated esters[4] can generate a homoenolate
intermediate (I) with a nucleophilic b-carbon atom (Fig-
ure 1a). The nucleophilic b-carbon atom of I has been widely
studied with regard to the formation of new carbon–carbon
Figure 1. NHC-catalyzed b-carbon-atom functionalization of enals and
carboxylic acid derivatives. Ts=4-methylbenzenesulfonyl.
an NHC catalyst to a,b-unsaturated esters[8] or oxidation of
the NHC-bound homoenolate intermediate[9] can effectively
generate an a,b-unsaturated acyl azolium intermediate[10] II
(Figure 1b). This activation mode (via II) provides a compli-
mentary approach for b-carbon-atom functionalizations of
aldehydes or esters, as the electrophilic b-carbon atom (of II)
can in principle react with a large set of nucleophiles.
Somewhat unfortunately, to date, nearly all reactions involv-
ing the electrophilic b-carbon atom of II are limited to
carbon–carbon bond formation. To the best of our knowledge,
there is only one example of the addition of an aryl amine unit
to II in a cascade reaction, as reported by Hui and co-
workers.[11] Some of the intrinsic challenges for the b-
amination of II include: 1) the relatively weak electrophilicity
of the b-carbon atom of II,[9g] and 2) the competing amide
bond formation between a nitrogen nucleophile and the acyl
azolium moiety of II.
Herein we report the addition of a nucleophilic nitrogen
center of hydrazide to the catalytically generated a,b-
unsaturated acyl azolium intermediate (Figure 1c). The
reactivity of the nitrogen nucleophile is tuned by using
hydrazines with proper protecting groups. Our reaction
installs a nitrogen atom at the b-carbon atom of an enal and
affords a pyrazolidinone adduct with good yield and excellent
enantioselectivity. The pyrazolidinone adduct with a nitro-
bonds.[5] The formation of C N and C O bonds using the
homoenolate intermediate has also appeared in several
studies. Specifically, reaction of I with electrophilic nitrogen
À
À
À
atoms to form C N bonds has been reported by the groups of
Scheidt,[6a] Ying,[6b] Zhong,[6c] Ma,[6d] and She.[6e] The group of
À
Rovis as well as our group have realized b-carbon C O bond
formation of I by radical pathways.[7] In contrast, addition of
[*] X. Wu,[+] Y. Zhang, M. Jeret, Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry
School of Physical & Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
E-mail: robinchi@ntu.edu.sg
B. Liu,[+] H. Wang, P. Zheng, Prof. S. Yang, Prof. B.-A. Song,
Prof. Dr. Y. R. Chi
Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University
Huaxi District, Guiyang 550025 (China)
E-mail: jhzx.msm@gmail.com
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201606571.
À
gen–nitrogen (N N) bond in a five-membered ring is widely
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found as a core scaffold in natural products and bioactive
molecules[12] such as azapropazone[12a] and phendione.[12c]
Notably, similar compounds in optically enriched forms
were previously obtained by either chiral resolutions or an
additional oxidation step of the optical pyrazolidin-3-ols.13
model reaction could be easily scaled up without affecting the
enantioselectivity (entry 12).
With optimized reaction conditions in hand (Table 1,
entry 11), the generality of the reaction was explored
(Tables 2 and 3). We first examined b-aryl enals reaction
with hydrazides (Table 2). With tosyl-protected hydrazide 2a
À
The N N bond of our products can be readily cleaved, thus
leading to b3-amino-acid derivatives with high optical purity.
Our initial studies used the enal 1a as the substrate to
generate an a,b-unsaturated acyl azolium intermediate under
oxidative NHC catalysis utilizing quinone (DQ) as the
oxidant (Table 1).[9a–c] A survey of potential nitrogen nucle-
Table 2: Formal [3+2] annulations of the aromatic-enal with hydrazide.[a]
Table 1: Screening of reaction conditions for the reaction of 1a with 2a.[a]
Entry
NHC
Base
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
A
B
C
D
E
B
B
B
B
B
B
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
DIEA
DBU
45
71
66
61
61
45
53
51
88:12
97:3
95:5
96:4
92:8
88:12
96:4
94:6
92:8
95:5
97:3
97:3
9
25
42
10
11
12
DABCO
K2CO3 (2.0 equiv. 2a)[d]
92 (88)[e]
78 (2.9 g)[f]
B (12 mol%), K2CO3, 2.0 equiv. 2a
[a] Reaction conditions: 1a (0.05 mmol, 1.0 equiv), 2a (0.075 mmol,
1.5 equiv), NHC (20 mol%), base (2 equiv) and DQ (1.2 equiv), 4 ꢀ M.S.
(50 mg) in THF(0.05m) at RT for 16 h. [b] Yield determined by NMR
spectroscopy, based on 1a, by using 1,3,5-trimethoxybenzene as an
internal standard. [c] Determined by chiral-phase HPLC analysis.
[d] 2 equiv of 2a was used. [e] Yield of isolated product given within
parentheses. [f] Prepared on 2.9 gram scale. DABCO=1,4-diazabicyclo-
[2.2.2]octane, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DIEA=diiso-
propylethylamine, M.S.=molecular sieves.
ophiles revealed that tosyl-protected hydrazine (2a) could
react effectively, thus leading to the b-amination product 3a
in an encouraging yield and e.r. value (entry 1). The high
acidity of the NH proton (pKa around 17.1 in DMSO from
Bordwell pKa table) of 2a promotes the aza-Michael addition
step under basic conditions. Several amino-acid-derived
triazolium NHC precatalysts (B–E; entries 2–5) were found
to be effective in this reaction, and B proved to be superior in
terms of both yield and enantioselectivity (entry 2). The
effects of bases were also examined (entries 6–10). Under the
influence of strong bases such as Cs2CO3 (entry 6) and DBU
(entry 9), unproductive consumption of 2a, because of
decomposition,[14] led to lower yields. We finally found that
by increasing the amount of 2a from 1.5 to 2.0 equivalents, 3a
could be obtained in 88% yield and 97:3 e.r. (entry 10). The
[a] Reaction conditions as in Table 1, entry 11. Yields (after SiO2
chromatography purification) based on the enal 1. PG=protecting
group, Ns=4-nitrobenzenesulfonyl, PMP=p-methoxyphenyl.
as a model nitrogen nucleophile, different substituents and
substituent patterns on the b-aryl group of enals were well
tolerated (3a–j). Replacing the b-phenyl group of 1a with
a pyridine unit also led to the product 3k with excellent yield
and e.r. value. When enals with either a b-furyl or thienyl
group were used, the corresponding products were obtained
with excellent e.r. values, albeit with moderate yields (3l,m).
Readily convertible functional groups on the enal substrates,
such as ester and allyl units, are compatible with the reaction
conditions (3n,o). The tosyl protecting group of 2a could be
2
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replaced with other sulfonyl units (3p,q). When Boc-pro-
tected (Boc = tert-butyloxycarbonyl) hydrazide was used, no
b-amination product was obtained and most of the two
substrates remained unreacted. The hydrazide with Ns (4-
nitrobenzenesulfonyl) as the protecting group tended to
decompose easily under basic reaction conditions and no b-
amination adduct was observed.
We next examined enals having a b-alkyl substituent
(Table 3). When the standard reaction conditions (Table 1,
entry 11) were used for b-aryl enals, the corresponding
product 3r, from a b-alkyl enal, was obtained in 63% yield
and 87:13 e.r. (Table 3). With a slight modification of the
Scheme 1. Synthetic transformations of the pyrazolidinone 3a.
DCM=dichloromethane, DIBAL-H=diisobutylaluminum hydride
Table 3: Formal [3+2] annulations of the alkyl-enal with 2a.[a]
Raney Ni. b3-Amino acids and their derivatives have been
widely found in drugs,[16] bioactive molecules,[17] and building
blocks for non-natural peptidic foladmers.[18]
In summary, we have developed a highly efficient
approach for the b-carbon amination of unsaturated alde-
hydes. Our method involves the addition of a nucleophilic
nitrogen atom to the catalytically generated a,b-unsaturated
acyl azolium intermediate, having an electrophilic b-carbon
À
atom, as the key step. This C N bond-forming reaction
enabled by NHC catalysts readily provides pyrazolidinone
products with good to excellent yields and enantioselectiv-
ities. The products, easily prepared on gram scale, can be
converted into useful molecules, such as b-amino amides.
Most of the reactions mediated by NHC organocatalysts have
focused on carbon–carbon bond formations. We expect that
this study and future developments on carbon–heteroatom
bond constructions shall significantly expand the utility of
NHC organocatalysis.
[a] 1 (0.10 mmol), 2a (0.20 mmol), NHC D (20 mol%), K2CO3
(0.2 mmol), DQ (1.2 equiv) and 4 ꢀ M.S. (100 mg) in toluene (2 mL) at
RT for 16 h. Yields (after SiO2 chromatography purification) based on the
enal 1. [b] Reaction conditions as in Table 1, entry 11. [c] Catalyst E was
used instead of D.
Experimental Section
General procedure for the b-amination of enals: A dry 10 mL Schlenk
tube with stir bar was charged with hydrazide
2 (0.20 mmol,
2.0 equiv), NHC B (7.6 mg, 20 mol%), K2CO3 (27.6 mg, 0.2 mmol,
2 equiv), DQ (48.9 mg, 0.12 mmol, 1.2 equiv) and molecular sieves
(100 mg). The tube was evacuated, and refilled with nitrogen. Then
enal 1 (0.10 mmol, 1.0 equiv) was added and the mixture was
dissolved with newly distilled solvent THF (2.0 mL). The mixture
was stirred at room temperature for 16 h when the substrate was
consumed completely (monitored by TLC). The reaction mixture was
concentrated under vacuum and purified by column chromatography
on silica gel (hexane/ethyl acetate) to afford desired product 3.
reaction conditions by using D as the NHC precatalyst and
toluene as the solvent, the reaction enantioselectivities could
be improved to 91:9 e.r. We then used the modified reaction
conditions to examine the generality of the b-alkyl enal
reactions. Notably, enals bearing relatively bulky alkyl sub-
stituents led to better stereoselectivities (e.g., 3v). When an
a,b-disubstituted enal (1w) was used, both the standard and
modified reaction conditions with catalyst D were not
effective (only trace amounts of product were observed).
Additional investigations revealed that the precatalyst E led
to 3w in 71% yield with 6:1 d.r. and 91:9 e.r.
Acknowledgements
The optically enriched pyrazolidinone products prepared
in our catalytic reaction can readily undergo further trans-
formations, as illustrated in Scheme 1. The carbonyl group of
3a can be reduced to the corresponding alcohol to give the
pyrazolidin-3-ol 4 in 81% yield without erosion of the
e.r. value. The compound 4 could be further reduced to the
pyrazolidine 5. Both 4 and 5 are privileged heterocyclic
structures in natural and synthetic bioactive compounds.[15]
Deprotection of 3a with Mg/MeOH furnishes the compound
6, which was further converted into the b3-amino-acid
We acknowledge financial support by the Singapore National
Research Foundation, the Ministry of Education of Singa-
pore, Nanyang Technological University (NTU, Singapore),
Chinaꢀs Ministry of Education, National Key program for
Basic Research (No. 2010CB 126105), Thousand Talent Plan,
National Natural Science Foundation of China (No.
21132003; No. 21472028). Guizhou Province Returned Over-
sea Student Science and Technology Activity Program,
Science and Technology Department of Guizhou Province,
and Guizhou University.
À
derivative 7 by reductive cleavage of the N N bond using
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74, 1744; d) W. Yao, M. Bian, G. Wang, C. Ma, Synthesis 2011,
1998; e) R. Han, J. Qi, J. Gu, D. Ma, X. Xie, X. She, ACS Catal.
2013, 3, 2705; For g-amination of enals, please see: f) X.-Y. Chen,
F. Xia, J.-T. Cheng, S. Ye, Angew. Chem. Int. Ed. 2013, 52, 10644;
Angew. Chem. 2013, 125, 10838.
Keywords: cycloaddition · heterocycles ·
N-heterocyclic carbene · organocatalysis · reaction mechanisms
[7] a) N. A. White, T. Rovis, J. Am. Chem. Soc. 2014, 136, 14674;
b) Y. Zhang, Y. Du, Z. Huang, J. Xu, X. Wu, Y. Wang, M. Wang,
S. Yang, R. D. Webster, Y. R. Chi, J. Am. Chem. Soc. 2015, 137,
2416.
[1] For examples on the synthesis of b-amino acids and derivatives,
see: a) A. Landa, R. Lꢁpez, A. Mielgo, M. Oiarbide, C. Palomo
in Stereoselective Organocatalysis: Bond Formation Method-
ologies and Activation Modes (Eds.: R. R. Torres), Wiley,
Hoboken, 2013, p. 381; b) H. J. Drexler, J. You, S. Zhang, C.
Fisher, W. Baumann, A. Spannenberg, D. Heller, Org. Process
Res. Dev. 2003, 7, 355; c) Y. Chi, S. H. Gellman, J. Am. Chem.
Soc. 2006, 128, 6804; d) Y. K. Chen, M. Yoshida, D. W. C.
MacMillan, J. Am. Chem. Soc. 2006, 128, 9328; e) N. J. A.
Martin, X. Cheng, B. List, J. Am. Chem. Soc. 2008, 130, 13862;
f) P. Galzerano, D. Agostino, G. Bencivenni, L. Sambri, G.
Bartoli, P. Melchiorre, Chem. Eur. J. 2010, 16, 6069; g) J. Xu, X.
Chen, M. Wang, P. Zheng, B.-A. Song, Y. R. Chi, Angew. Chem.
Int. Ed. 2015, 54, 5161; Angew. Chem. 2015, 127, 5250.
[2] b-amino acids as building blocks for peptidic foldamers, see:
a) E. A. Porter, X. Wang, H.-S. Lee, B. Weisblum, S. H. Gellman,
Nature 2000, 404, 565; b) G. Lelais, D. Seebach, Biopolymers
2004, 76, 206; c) D. Seebach, J. Gardiner, Acc. Chem. Res. 2008,
41, 1366; d) S. J. Miller, Acc. Chem. Res. 2004, 37, 601; e) R. S.
Erdmann, H. Wennemers, J. Am. Chem. Soc. 2010, 132, 13957;
f) Y. Tal-Gan, M. Ivancic, G. Cornilescu, C. C. Cornilescu, H. E.
Blackwell, J. Am. Chem. Soc. 2013, 135, 18436.
[3] For selected examples on homoenolate chemistry: a) C. Bur-
stein, F. Glorius, Angew. Chem. Int. Ed. 2004, 43, 6205; Angew.
Chem. 2004, 116, 6331; b) S. S. Sohn, E. L. Rosen, J. W. Bode, J.
Am. Chem. Soc. 2004, 126, 14370; c) V. Nair, S. Vellalath, M.
Poonoth, E. Suresh, J. Am. Chem. Soc. 2006, 128, 8736; d) M. He,
J. R. Struble, J. W. Bode, J. Am. Chem. Soc. 2006, 128, 8418; e) A.
Chan, K. A. Scheidt, J. Am. Chem. Soc. 2007, 129, 5334;
f) D. E. A. Raup, B. Cardinal-David, D. Holte, K. A. Scheidt,
Nat. Chem. 2010, 2, 766; g) X. Zhao, D. A. DiRocco, T. Rovis, J.
Am. Chem. Soc. 2011, 133, 12466; h) H. Lv, W.-Q. Jia, L.-H. Sun,
S. Ye, Angew. Chem. Int. Ed. 2013, 52, 8607; Angew. Chem. 2013,
125, 8769; i) N. A. White, D. A. DiRocco, T. Rovis, J. Am. Chem.
Soc. 2013, 135, 8504; j) C. Guo, B. Sahoo, C. G. Daniliuc, F.
Glorius, J. Am. Chem. Soc. 2014, 136, 17402; k) A. Lee, K. A.
Scheidt, Angew. Chem. Int. Ed. 2014, 53, 7594; Angew. Chem.
2014, 126, 7724; l) G. Guo, M. Fleige, D. Janssen-Mꢂller, C. G.
Daniliuc, F. Glorius, Nat. Chem. 2015, 7, 842.
[8] a) S. J. Ryan, L. Candish, D. W. Lupton, J. Am. Chem. Soc. 2009,
131, 14176; b) J. Cheng, Z. Huang, Y. R. Chi, Angew. Chem. Int.
Ed. 2013, 52, 8592; Angew. Chem. 2013, 125, 8754; c) J. Xu, Z.
Jin, Y. R. Chi, Org. Lett. 2013, 15, 5028; d) Z. Zhang, X. Zeng, D.
Xie, L. Ding, A. Wang, L. Yang, G. Zhong, Org. Lett. 2015, 17,
5052; For carboxylic acid as substrates: e) A. Lee, A. Younai,
C. K. Price, J. Izquierdo, R. K. Mishra, K. A. Scheidt, J. Am.
Chem. Soc. 2014, 136, 10589; f) X.-Y. Chen, Z.-H. Gao, C.-Y.
Song, C.-L. Zhang, Z.-X. Wang, S. Ye, Angew. Chem. Int. Ed.
2014, 53, 11611; Angew. Chem. 2014, 126, 11795.
[9] a) J. Guin, S. De Sarkar, S. Grimme, A. Studer, Angew. Chem.
Int. Ed. 2008, 47, 8727; Angew. Chem. 2008, 120, 8855; b) S.
De Sarkar, A. Studer, Angew. Chem. Int. Ed. 2010, 49, 9266;
Angew. Chem. 2010, 122, 9452; c) S. De Sarkar, S. Grimme, A.
Studer, J. Am. Chem. Soc. 2010, 132, 1190; d) Z.-Q. Rong, M.-Q.
Jia, S.-L. You, Org. Lett. 2011, 13, 4080; e) A. G. Kravina, J.
Mahatthananchai, J. W. Bode, Angew. Chem. Int. Ed. 2012, 51,
9433; Angew. Chem. 2012, 124, 9568; f) J. Mo, L. Shen, Y. R. Chi,
Angew. Chem. Int. Ed. 2013, 52, 8588; Angew. Chem. 2013, 125,
8750; g) S. Bera, R. C. Samanta, C. G. Daniliuc, A. Studer,
Angew. Chem. Int. Ed. 2014, 53, 9622; Angew. Chem. 2014, 126,
9776; h) Z.-Q. Liang, D.-L. Wang, H.-M. Zhang, S. Ye, Org. Lett.
2015, 17, 5140; i) S. Bera, C. G. Daniliuc, A. Studer, Org. Lett.
2015, 17, 4940; j) S. R. Yetra, S. Mondal, S. Mukherjee, R. G.
Gonnade, A. T. Biju, Angew. Chem. Int. Ed. 2016, 55, 268;
Angew. Chem. 2016, 128, 276; For reviews, also see: k) S. D.
Sarkar, A. Biswas, R. C. Samanta, A. Studer, Chem. Eur. J. 2013,
19, 4664; l) J. Mahatthananchai, J. W. Bode, Acc. Chem. Res.
2014, 47, 696.
[10] For other methodes, please see: a) K. Zeitler, Org. Lett. 2006, 8,
637; b) S. J. Ryan, L. Candish, D. W. Lupton, J. Am. Chem. Soc.
2011, 133, 4694; c) L. Candish, D. W. Lupton, J. Am. Chem. Soc.
2013, 135, 58; d) F.-G. Sun, L.-H. Sun, S. Ye, Adv. Synth. Catal.
2011, 353, 3134; e) S. R. Yetra, A. Bhunia, A. Patra, M. V. Mane,
K. Vanka, A. T. Biju, Adv. Synth. Catal. 2013, 355, 1089.
[11] H.-R. Zhang, Z.-W. Dong, Y.-J. Yang, P.-L. Wang, X.-P. Hui, Org.
Lett. 2013, 15, 4750.
[12] a) G. Mixich, Helv. Chim. Acta 1972, 55, 1031; b) D. Hadjipav-
lou-Litina, Med. Res. Rev. 1998, 18, 91; c) E. Couloigner, D.
Cartier, R. Labia, Bioorg. Med. Chem. Lett. 1999, 9, 2205;
d) T. H. Schroeder, W. A. Krueger, H.-J. Dieterich, B. Nohe,
Biologics. Mar. 2008, 2, 151.
[4] a) Z. Fu, J. Xu, T. Zhu, W. W. Y. Leong, Y. R. Chi, Nat. Chem.
2013, 5, 835; b) Z. Fu, K. Jiang, T. S. Zhu, J. Torres, Y. R. Chi,
Angew. Chem. Int. Ed. 2014, 53, 6506; Angew. Chem. 2014, 126,
6624.
[5] Selected reviews on NHC catalysis: a) D. Enders, O. Niemeier,
A. Henseler, Chem. Rev. 2007, 107, 5606; b) N. Marion, S. Dꢃez-
Gonzꢄlez, S. P. Nolan, Angew. Chem. Int. Ed. 2007, 46, 2988;
Angew. Chem. 2007, 119, 3046; c) V. Nair, S. Vellalath, B. P.
Babu, Chem. Soc. Rev. 2008, 37, 2691; d) A. T. Biju, N. Kuhl, F.
Glorius, Acc. Chem. Res. 2011, 44, 1182; e) V. Nair, R. S. Menon,
A. T. Biju, C. R. Sinu, R. R. Paul, A. Jose, V. Sreekumar, Chem.
Soc. Rev. 2011, 40, 5336; f) J. Douglas, G. Churchill, A. D. Smith,
Synthesis 2012, 2295; g) J. Izquierdo, G. E. Hutson, D. T. Cohen,
K. A. Scheidt, Angew. Chem. Int. Ed. 2012, 51, 11686; Angew.
Chem. 2012, 124, 11854; h) S. J. Ryan, L. Candish, D. W. Lupton,
Chem. Soc. Rev. 2013, 42, 4906; i) M. N. Hopkinson, C. Richter,
M. Schedler, F. Glorius, Nature 2014, 510, 485; j) D. M. Flanigan,
F. Romanov-Michailidis, N. A. White, T. Rovis, Chem. Rev. 2015,
115, 9307.
[13] a) A. Suꢄrez, C. W. Downey, G. C. Fu, J. Am. Chem. Soc. 2005,
127, 11244; b) M. P. Sibi, K. Kawashima, L. M. Stanley, Org. Lett.
2009, 11, 3894; c) E. Gould, M. Reid, A. M. Z. Slawin, A. D.
Smith, Tetrahedron 2010, 66, 8892; d) M. Wang, Z. Huang, J. Xu,
Y. R. Chi, J. Am. Chem. Soc. 2014, 136, 1214; For amine
catalyzed synthesis of pyrazolidin-3-ol, see: e) M. Fernꢄndez, E.
Reyes, J. L. Vicario, D. Badia, L. Carrꢃllo, Adv. Synth. Catal.
2012, 354, 371; f) Z.-C. Geng, J. Chen, N. Li, X.-F. Huang, Y.
Zhang, Y.-W. Zhang, X.-W. Wang, Beilstein J. Org. Chem. 2012,
8, 1710.
[14] U. Ragnarsson, L. Grehn, Tetrahedron Lett. 2012, 53, 1045.
[15] a) D. E. Wilkinson, Bioorg. Med. Chem. 2003, 11, 4815; b) H. G.
Cheon, S. S. Kim, K. R. Kim, S. D. Rhee, S. D. Yang, J. H. Ahn,
S. D. Park, J. M. Lee, W. H. Jung, H. S. Lee, H. Y. Kim, Biochem.
Pharmacol. 2005, 70, 22.
[6] a) A. Chan, K. A. Scheidt, J. Am. Chem. Soc. 2008, 130, 2740;
b) J. Seayad, P. K. Patra, Y. Zhang, J. Y. Ying, Org. Lett. 2008, 10,
953; c) L. Yang, B. Tan, F. Wang, G. Zhong, J. Org. Chem. 2009,
4
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[16] Top 200 pharmaceutical drugs by sales in 2014 includes Focalin
Sadowsky, M. Scalf, W. A. Frund, L. M. Smith, J. Chem, S. H.
XR and Concerta.
Gellman, J. Am. Chem. Soc. 2005, 127, 13271.
[17] a) P. R. Cheng, S. H. Gellman, W. F. DeGrado, Chem. Rev. 2001,
101, 3219; b) D. Seebach, A. K. Beck, D. J. Bierbaum, Chem.
Biodiversity 2004, 1, 1111.
[18] a) R. F. Epand, T. L. Raguse, S. H. Gellman, R. M. Epand,
Biochemistry 2004, 43, 9527; b) J. K. Murray, B. Farooqi, J. D.
Received: July 7, 2016
Published online: && &&, &&&&
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Communications
Heterocycle Synthesis
X. Wu, B. Liu, Y. Zhang, M. Jeret, H. Wang,
P. Zheng, S. Yang,* B.-A. Song,
Y. R. Chi*
&&&& — &&&&
Enantioselective Nucleophilic b-Carbon-
Atom Amination of Enals: Carbene-
Catalyzed Formal [3+2] Reactions
Focus on the b-C: The aza-Michael addi-
tion of protected hydrazine to a catalyti-
cally generated unsaturated acyl azolium
intermediate provides a highly efficient
approach for enantioselective b-carbon-
atom amination of enals. The heterocyclic
products, prepared by using this method,
are common scaffolds found in bioactive
molecules, and can be readily trans-
formed into b3-amino-acid derivatives.
NHC=N-heterocyclic carbene.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!