Highly enantioselective organocatalytic Michael addition of 2-hydroxy- 1,4-naphthoquinone to β,γ-unsaturated α-oxo esters

Article abstract of DOI:10.1002/ejoc.201000885

An organocatalytic enantioselective Michael addition of 2- hydroxy-1,4-naphthoquinone to β,γ-unsaturated α-oxo esters has been developed. The process was promoted by bifunctional chiral amine derived squaramides according to a hydrogen- bonding mediated activation mechanism and af forded the chiral adducts in high yields (up to 88%) and excellent enantioselectivity (up to 98% ee) under mild conditions. This organocatalytic asymmetric Michael addition provides an efficient route toward the synthesis of optically active functionalized naphthoquinones.

Full text of DOI:10.1002/ejoc.201000885

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000885
Highly Enantioselective Organocatalytic Michael Addition of 2-Hydroxy-
1,4-naphthoquinone to β,γ-Unsaturated α-Oxo Esters
Yi-Feng Wang,[a] Wei Zhang,[a] Shu-Ping Luo,[a] Guang-Cun Zhang,[a] Ai-Bao Xia,[a]
Xiang-Sheng Xu,[a] and Dan-Qian Xu*[a]
Keywords: Asymmetric catalysis / Organocatalysis / Hydrogen-bonding catalysis / Michael addition / Squaramide
An organocatalytic enantioselective Michael addition of 2-
hydroxy-1,4-naphthoquinone to β,γ-unsaturated α-oxo esters
has been developed. The process was promoted by bifunc-
tional chiral amine derived squaramides according to a hy-
drogen-bonding mediated activation mechanism and af-
forded the chiral adducts in high yields (up to 88%) and ex-
cellent enantioselectivity (up to 98% ee) under mild condi-
tions. This organocatalytic asymmetric Michael addition pro-
vides an efficient route toward the synthesis of optically
active functionalized naphthoquinones.
through double hydrogen-bonding interaction with nitro al-
kenes. To the best of our knowledge there are no organocat-
alytic asymmetric process reported in which β,γ-unsatu-
rated α-oxo esters are employed as electron-deficient al-
kenes to react with naphthoquinone cores.[6] Nevertheless,
β,γ-unsaturated α-oxo esters are very attractive Michael ac-
ceptors,[7] since the α-oxo ester moiety is a strong electron-
withdrawing group that can be readily transformed into a
range of different functionalities. Herein we present our re-
sults on the use of simply obtainable tertiary amine–thio-
urea/squaramide[8] organocatalysts for the first catalytic
enantioselective Michael addition of 2-hydroxy-1,4-
naphthoquinone to β,γ-unsaturated α-oxo esters (Figure 1).
This is also a broadening of the strategy employed in our
first paper on the application of chiral squaramides in or-
ganocatalysis.[8b]
Introduction
With respect to an increasing need for efficient and new
catalytic synthetic methods, organocatalysis represents a
powerful field and has found widespread application over
the past decade.[1] As a subfield of organocatalysis, hydro-
gen-bonding catalysis has emerged as an especially impor-
tant tool for enantioselective synthesis.[2] This is probably
attributed to some privileged hydrogen-bonding motifs,
such as ureas, thioureas, guanidiniums and squaramides,
but is also associated with the compatibility of these hydro-
gen-bond donators with a range of Brønsted bases or Lewis
bases, which allow the development of bifunctional sys-
tems,[3] providing new opportunities for simultaneous acti-
vation of both the electrophile and the nucleophile. Despite
this, further explorations of new asymmetric reactions to-
ward the synthesis of chiral bioactive compounds with use
of this activation strategy are still demanding research
areas.
Quinones and naphthoquinones have attracted much at-
tention due to the broad scope of their biological activi-
ties.[4] The organocatalytic additions of these valuable skel-
etons to electron-deficient alkenes, which benefited from
using secondary amine or tertiary amine–thiourea catalysts,
have been investigated in order to provide an alternative
process for some novel optically active chemicals with po-
tent pharmacological properties.[5] Both these applied catal-
ysis systems are capable of activating electron-deficient al-
kenes, either through the formation of an iminium ion inter-
mediate with α,β-unsaturated carbonyl compounds, or
Results and Discussion
The addition of 2-hydroxy-1,4-naphthoquinone (1) to
β,γ-unsaturated α-oxo ester 2a was used as the test reaction
to explore the feasibility of the enantioselective Michael ad-
dition catalyzed by chiral amine derived thioureas and
squaramides at room temperature in CH2Cl2 as the solvent
(Table 1). Gratifyingly, preliminary results showed that
good yields and enantioselectivities were obtained when di-
aminocyclohexane-derived thioureas/squaramides were
used as catalysts (Entries 1–2). Whereas thiourea I gave a
higher enantioselectivity than squaramide II did, the reac-
tion rate was higher with squaramide II. These results moti-
vated us to optimize these two catalysts simultaneously by
screening the catalysts III–IV. Apparently, these two kinds
of bifunctional catalysts were distinctly different in their
performance. No improvement in terms of reaction yields
and enantioselectivities was observed by using cinchona-de-
View this journal online at
[a] State Key Laboratory Breeding Base of Green Chemistry –
Synthesis Technology, Zhejiang University of Technology
Hangzhou 310014, China
Fax: +86-0571-88320066
E-mail: chrc@zjut.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000885.
wileyonlinelibrary.com
Eur. J. Org. Chem. 2010, 4981–4985
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4981

D.-Q. Xu et al.
SHORT COMMUNICATION
Figure 1. Screened chiral thiourea- and squaramide-based catalysts.
rived thioureas III (Entries 3–7). To our delight, promising Table 1. Organocatalytic enantioselective Michael addition of 2-hy-
droxy-1,4-naphthoquinone 1 to β,γ-unsaturated α-oxo ester 2a.[a]
enantioselectivity and especially high efficiency was
achieved when cinchona-derived squaramides IVa and IVb
were employed, which provided 78–81% yields and 80–83%
ee values after 3 h (Entries 8–9). The pseudo-enantiomers
of IVa and IVb exhibited similar catalytic activity, but the
asymmetric inductions were slightly lower (Entries 10–11).
Upon further varation of the substituent on one end of the
squaramide, catalyst IVc afforded an excellent level of
Entry
Cat.
t [h]
Yield[b] [%]
ee[c] [%]
enantioselectivity (94% ee) and yield (87%) (Entries 12–13).
The potential of the catalyst IVc was also demonstrated by
reducing the catalyst loading in the asymmetric Michael ad-
dition; the efficiency was almost maintained even when the
amount of the catalyst was decreased to 2.5 mol-% (En-
tries 14–16). Above observations confirmed that the type of
the hydrogen-bond donor motif has a dramatic impact on
the catalytic activity.
Subsequently, the solvent effect on the Michael addition
reaction was investigated. As shown in Table 2, the reaction
proceeded smoothly in most aprotic solvents probed, and
encouraging results were obtained with dichloromethane
and dioxane as solvents, which afforded 83–85% yields and
94–96% ee (Entries 1–7). Nevertheless, protic solvents such
as EtOH retarded this process, and both yield and enantio-
1
2
3
4
5
6
7
8
9
10
11
12
13
14[d]
15[e]
16[f]
I
12
6
81
84
78
82
80
86
77
81
78
79
80
87
79
83
85
76
88
72
77
59
30
53
21
80
83
–76
–78
94
84
93
94
92
II
IIIa
IIIb
IIIc
IIId
IIIe
IVa
IVb
Va
12
12
12
12
12
3
3
3
3
3
3
7
12
24
Vb
IVc
IVd
IVc
IVc
IVc
[a] Unless otherwise specified, all reactions were carried out with 2-
selectivity dropped (Entry 8). Its relatively weak polar hydroxy-1,4-naphthoquinone (0.125 mmol), β,γ-unsaturated α-oxo
ester 2a (0.125 mmol), catalyst (0.025 mmol, 20 mol-%) in CH2Cl2
homologue iPrOH afforded the products with high selectiv-
(1.0 mL) at room temperature. [b] Isolated yield. [c] Determined by
ity, but the yield was low (Entry 9). The lower efficiency
chiral HPLC analysis (Daicel Chiralpak AD-H, hexane/iPrOH =
70:30 containing 0.15% TFA); a minus sign before the ee signifies
the enantiomer opposite that obtained in all other entries in this
table. [d] With 10 mol-% catalyst loading. [e] With 5 mol-% catalyst
loading. [f] With 2.5 mol-% catalyst loading.
of the protic solvents can be attributed to the competitive
hydrogen-bond interaction between the alcohols and the or-
ganocatalyst or substrates.
The asymmetric Michael addition of 2-hydroxy-1,4-
naphthoquinone (1) to various β,γ-unsaturated α-oxo esters
2 in the presence of organocatalyst IVc was investigated un- ters 2a–i, which bear electron-rich, electron-neutral and
der the optimized experimental conditions. As shown in electron-withdrawing groups, reacted smoothly with 2-hy-
Table 3, a wide array of aromatic β,γ-unsaturated α-oxo es- droxy-1,4-naphthoquinone (1) to afford the corresponding
4982
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4981–4985

Michael Addition of 2-Hydroxy-1,4-naphthoquinone to β,γ-Unsaturated α-Oxo Esters
Table 2. Screening of the solvents for the enantioselective Michael tively with only 2.5 mol-% catalyst loading (Entries 4–10).
addition reaction catalyzed by squaramide IVc.[a]
Other aromatic oxo esters, derived from naphthalene, furan
and thiophene, could also be applied in this reaction to pro-
vide 81–86% yields and 93–96% ee (Entries 11–13). More-
over, aliphatic oxo esters react also in this catalytic system
and give rise to the corresponding products in good yield
and high enantioselectivity (Entry 14).
The products were found to exist in solution in a rapid
equilibrium with their pseudo-diastereomeric hemiketal
Entry
Solvent
Yield[b] [%]
ee[c] [%]
forms, which could be converted into tetrahydrobenzo-
quinolines by a simple one-step treatment. Therefore, reac-
tion of 3a with ammonium acetate yielded tetrahydrobenzo-
quinoline 4a (Scheme 1). The hemiketal of compound 3fЈ
was crystallized, and its absolute configuration was deter-
mined to be (R) on the basis of a single-crystal X-ray analy-
sis[9] (Figure 2).
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
DCE[d]
Et2O
85
51
81
50
78
83
77
66
35
94
84
92
93
94
96
91
76
94
THF
dioxane
PhMe
EtOH
iPrOH
[a] All reactions were carried out with 2-hydroxy-1,4-naphtho-
quinone (0.125 mmol), β,γ-unsaturated α-oxo ester 2a (0.125
mmol), catalyst IVc (0.0625 mmol, 5 mol-%) in the solvent
(1.0 mL) at room temperature for 12 h. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis (Daicel Chiralpak AD-H, hexane/
iPrOH = 70:30 containing 0.15% TFA). [d] DCE: 1,2-dichloro-
ethane.
products 3a–i with high levels of yield (73–88%) and
enantioselectivity (90–98% ee) (Entries 1–10). It is noted
that oxo esters with an electron-neutral or electron-with-
drawing group at the aromatic ring could react quite effec-
Scheme 1. Conversion of 3a into tetrahydrobenzoquinoline 4a.
Table 3. Squaramide IVc promoted enantioselective Michael ad-
dition of 2-hydroxy-1,4-naphthoquinone (1) to β,γ-unsaturated α-
oxo ester 2.[a]
Entry
R
Product Yield[b] [%] ee[c] [%]
1
2
3
Ph (2a)
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-ClC6H4 (2d)
2-ClC6H4 (2e)
4-BrC6H4 (2f)
3-BrC6H4 (2g)
2,4-Cl2C6H3 (2h)
4-CF3C6H4 (2i)
4-NO2C6H4 (2j)
naphthalen-2-yl (2k)
furan-2-yl (2l)
thien-2-yl (2m)
Me (2n)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
83
88
82
87
86
81
85
86
73
83
86
81
83
78
96
91
94
95
91
94
93
90
93
98
93
93
96
87
4[d]
5[d]
6[d]
7[d]
8[d]
9[d]
10[d]
11
Figure 2. X-ray crystal structure of adduct 3f in its hemiketal form.
12
13
14
According to above experimental results and previous re-
ported dual activation model, the two substrates involved
in the reaction are activated by catalyst IVc as proposed in
Figure 3. The α-oxo ester 2a has been assumed to interact
with the squaramide moiety of IVc through two hydrogen
bonds, which activates the γ-carbon atom of the substrate
[a] Unless otherwise specified, all reactions were carried out with 2-
hydroxy-1,4-naphthoquinone (0.125 mmol), β,γ-unsaturated α-oxo
ester 2 (0.125 mmol), catalyst IVc (0.0625 mmol, 5 mol-%) in diox-
ane (1.0 mL) at room temperature for 12 h. [b] Isolated yield. [c]
Determined by chiral HPLC analysis (Daicel Chiralpak AD-H). [d]
With 2.5 mol-% catalyst loading.
Eur. J. Org. Chem. 2010, 4981–4985
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4983

D.-Q. Xu et al.
SHORT COMMUNICATION
but also constrains it to a well-defined orientation, which is
furthermore enhanced by the two chiral substituted ends of
the squaramide. The deprotonated form of 2-hydroxy-1,4-
Acknowledgments
This work was supported by the National Natural Science Founda-
naphthoquinone (1) is assumed to interact with the tertiary tion of China (No. 20772110).
amine group of the catalyst through the hydrogen bonds
between the protonated amine and the two vicinal oxygen
[1] a) A. Berkessel, H. Gröger, Asymmetric Organocatalysis, Wiley-
atoms of 1, which is also activated and fixed by a bidentate
interaction. The well-induced transition state facilitates the
nucleophile 1 to attack the oxo ester 2a from the re face
and to form the (R) product.
VCH, Weinheim 2005; b) P. I. Dalko, Enantioselective Organo-
catalysis, Wiley-VCH, Weinheim, 2007.
[2] For recent selected reviews of hydrogen-bonding activation,
see: a) Z. G. Zhang, P. R. Schreiner, Chem. Soc. Rev. 2009, 38,
1187–1198; b) S. J. Connon, Chem. Commun. 2008, 2499–2510;
c) X. H. Yu, W. Wang, Chem. Asian J. 2008, 3, 516–532; d)
A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–5743;
e) S. J. Connon, Chem. Eur. J. 2006, 12, 5418–5427; f) M. S.
Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550; Angew.
Chem. Int. Ed. 2006, 45, 1520–1543; g) T. Akiyama, J. Itoh, K.
Fuchibe, Adv. Synth. Catal. 2006, 348, 999–1010.
[3] For recent selected examples of this bifunctional system, see:
a) B. Tan, Y. Lu, X. Zeng, P. J. Chua, G. Zhong, Org. Lett.
2010, 12, 2682–2685; b) X. Han, J. Kwiatkowski, F. Xue, K. W.
Huang, Y. X. Lu, Angew. Chem. 2009, 121, 7740–7741; Angew.
Chem. Int. Ed. 2009, 48, 7604–7607; c) G. Dickmeiss, V. De Sio,
J. Udmark, T. B. Poulsen, V. Marcos, K. A. Jørgensen, Angew.
Chem. 2009, 121, 6778–6781; Angew. Chem. Int. Ed. 2009, 48,
6650–6653; d) W. J. Nodes, D. R. Nutt, A. M. Chippindale,
A. J. A. Cobb, J. Am. Chem. Soc. 2009, 131, 16016–16017; e)
T. Bui, S. Syed, C. F. Barbas, J. Am. Chem. Soc. 2009, 131,
8758; f) D. R. Li, A. Murugan, J. R. Falck, J. Am. Chem. Soc.
2008, 130, 46–48; g) J. Wang, H. X. Xie, H. Li, L. S. Zu, W.
Wang, Angew. Chem. 2008, 120, 4245–4247; Angew. Chem. Int.
Ed. 2008, 47, 4177–4179; h) C. Gioia, A. Hauville, L. Bernardi,
F. Fini, A. Ricci, Angew. Chem. 2008, 120, 9376–9379; Angew.
Chem. Int. Ed. 2008, 47, 9236–9239; i) Y. Q. Fang, E. N. Ja-
cobsen, J. Am. Chem. Soc. 2008, 130, 5660–5661; j) C. J. Wang,
X. Q. Dong, Z. H. Zhang, Z. Y. Xue, H. L. Teng, J. Am. Chem.
Soc. 2008, 130, 8606–8607; k) C. Rabalakos, W. D. Wulff, J.
Am. Chem. Soc. 2008, 130, 13524–13525.
[4] a) V. K. Tandon, D. B. Yadav, R. V. Singh, A. K. Chaturvedi,
P. K. Shukla, Bioorg. Med. Chem. Lett. 2005, 15, 5324–5328;
b) I. Gomez-Monterrey, G. Santelli, P. Campiglia, D. Califano,
F. Falasconi, C. Pisano, L. Vesci, T. Lama, P. Grieco, E. Nov-
ellino, J. Med. Chem. 2005, 48, 1152–1157; c) M. Glänzel, R.
Bültmann, K. Starke, A. W. Frahm, Eur. J. Med. Chem. 2005,
40, 1262–1276; d) V. K. Tandon, R. B. Chhor, R. V. Singh, S. J.
Rai, D. B. Yadav, Bioorg. Med. Chem. Lett. 2004, 14, 1079–
1083; e) A. G. Ravelo, A. Estevez-Braun, H. Chavez-Orellana,
E. Perez-Sacau, D. Mesa-Siverio, Curr. Top. Med. Chem. 2004,
4, 241–265; f) V. F. de Andrade-Neto, M. O. F. Goulart, J. F.
da Silva, M. J. da Silva, M. D. Pinto, A. V. Pinto, M. G. Zalis,
L. H. Carvalho, A. U. Krettli, Bioorg. Med. Chem. Lett. 2004,
14, 1145–1149; g) M. Glänzel, R. Bültmann, K. Starke, A. W.
Frahm, Eur. J. Med. Chem. 2003, 38, 303–312.
[5] a) M. Rueping, E. Sugiono, E. Merino, Angew. Chem. 2008,
120, 3089–3092; Angew. Chem. Int. Ed. 2008, 47, 3046–3049;
b) W. M. Zhou, H. Liu, D. M. Du, Org. Lett. 2008, 10, 2817–
2820.
[6] For the chiral copper(II) complex catalyzed one, see: N. Hal-
land, T. Velgaard, K. A. Jørgensen, J. Org. Chem. 2003, 68,
5067–5074.
[7] For recent selected examples of using β,γ-unsaturated α-oxo
esters as substrates, see: a) S. L. Zhao, C. W. Zheng, H. F.
Wang, G. Zhao, Adv. Synth. Catal. 2009, 351, 2811–2816; b)
C. W. Zheng, Y. W. Li, Y. Q. Yang, H. F. Wang, H. F. Cui, J. K.
Zhang, G. Zhao, Adv. Synth. Catal. 2009, 351, 1685–1691; c)
M. A. Calter, J. Wang, Org. Lett. 2009, 11, 2205–2208; d) S. L.
Zhao, C. W. Zheng, G. Zhao, Tetrahedron: Asymmetry 2009,
20, 1046–1051; e) H. F. Wang, C. W. Zheng, Y. Q. Yang, Z.
Chai, G. Zhao, Tetrahedron: Asymmetry 2008, 19, 2608–2615;
f) X. S. Wang, C. W. Zheng, S. L. Zhao, Z. Chai, G. Zhao, G. S.
Figure 3. Proposed transition state of the organocatalytic enantio-
selective Michael reaction.
Conclusions
We have developed a novel highly enantioselective organo-
catalytic Michael addition of 2-hydroxy-1,4-naphthoquin-
one to β,γ-unsaturated α-oxo esters catalyzed by readily
available cinchona-derived squaramides with low catalyst
loading (2.5–5 mol-%) to provide an expeditious access to-
ward highly functionalized naphthoquinone derivatives in
good yields (73–88%) and with excellent enantioselectivities
(87–98% ee). Considering the high efficiency of the potent
transformations, further investigation on the application of
chiral squaramides in organocatalysis is in progress in our
laboratory.
Experimental Section
Typical Procedure for the Organocatalytic Asymmetric Michael Re-
action: To a solution of catalyst IVc (0.0625 mmol, 5 mol-%) in
dioxane (1.0 mL), 2-hydroxy-1,4-naphthoquinone (1) (0.125 mmol)
and β,γ-unsaturated α-oxo ester 2a (0.125 mmol) were added se-
quentially. The reaction mixture was then stirred at room tempera-
ture (about 25 °C) for 12 h. The crude mixture was purified by flash
chromatography to furnish a yellow solid in 83% yield. The process
was clear and no 1,2-addition or oxa-Michael addition product
formed. The enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column [hexane/iPrOH = 70:30 containing 0.15%
TFA; flow rate 1.0 mL/min; tR(major isomer) = 9.9 min, tR(minor
isomer) = 13.6 min].
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra, mass spectra, HPLC analysis data.
4984
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4981–4985

Michael Addition of 2-Hydroxy-1,4-naphthoquinone to β,γ-Unsaturated α-Oxo Esters
Yang, Tetrahedron: Asymmetry 2008, 19, 2699–2704; g) R. P.
Herrera, D. Monge, E. Martín-Zamora, R. Fernández, J. M.
Lassaletta, Org. Lett. 2007, 9, 3303–3306; h) C. L. Cao, X. L.
Sun, Y. B. Kang, Y. Tang, Org. Lett. 2007, 9, 4151–4154.
[8] a) Y. Zhu, J. P. Malerich, V. H. Rawal, Angew. Chem. 2010, 122,
157–160; Angew. Chem. Int. Ed. 2010, 49, 153–156; b) D. Q.
Xu, Y. F. Wang, W. Zhang, S. P. Luo, A. G. Zhong, A. B. Xia,
Z. Y. Xu, Chem. Eur. J. 2010, 16, 4177–4180; c) J. P. Malerich,
K. Hagihara, V. H. Rawal, J. Am. Chem. Soc. 2008, 130,
14416–14417.
[9] CCDC-759808 (3fЈ) contains the supplementary crystallo-
graphic 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.
Received: June 21, 2010
Published Online: August 16, 2010
Eur. J. Org. Chem. 2010, 4981–4985
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4985