Organocatalytic enantioselective Michael addition of 2,4-pentandione to nitroalkenes promoted by bifunctional thioureas with central and axial chiral elements

Article abstract of DOI:10.1021/jo800774m

(Chemical Equation Presented) Two novel bifunctional amine-thiourea organocatalysts 1 and 2, which both bear central and axial chiral elements, have been developed to promote enantioselective Michael reaction between 1,3-dicarbonyl compounds and nitro ole

Full text of DOI:10.1021/jo800774m

reaction conditions.3 Recently, the development of organocata-
lytic asymmetric Michael addition reactions of nitro olefins has
received growing attention.4 Impressive progress has been made
in the development of metal-free bifunctional organic catalysts
for the enantioselective addition of aldehydes and ketones,5
malonate esters,6 and ketoesters7 to nitroalkenes. Nonetheless,
few successful organocatalysts have been demonstrated for the
enantioselective addition of 1,3-diketone compounds to nitro
olefins. Recently, Wang and co-workers have developed the first
highly enantioselective organocatalytic Michael addition of 2,4-
pentandione to aryl nitroalkenes.8 As part of our interest in
asymmetric organocatalysis,9 we want to describe a novel type
of bifunctional chiral amine-thiourea organocatalyst for promot-
ing the Michael reaction between 1,3-diketone compounds and
nitro olefins with good levels of enantioselectivity (up to 96%
ee). In addition, other types of 1,3-dicarbonyl compounds such
as malonate ester and ꢀ-ketoester were also briefly investigated.
In the past few years, chiral urea and thiourea derivatives
have emerged as new and efficient organocatalysts for various
enantioselective reactions.10 Among them, Takemoto’s amine-
thioureas,11 Jacobsen’s ureas/thioureas,12 and cinchona alkaloid-
Organocatalytic Enantioselective Michael
Addition of 2,4-Pentandione to Nitroalkenes
Promoted by Bifunctional Thioureas with Central
and Axial Chiral Elements
Fang-Zhi Peng, Zhi-Hui Shao,* Bao-Min Fan, He Song,
Gan-Peng Li, and Hong-Bin Zhang
Key Laboratory of Medicinal Chemistry for Natural
Resource (Yunnan UniVersity), Ministry of Education, School
of Chemical Science and Technology, Yunnan UniVersity,
Kunming, 650091, China
zhihui_shao@hotmail.com
ReceiVed April 8, 2008
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Two novel bifunctional amine-thiourea organocatalysts 1 and
2, which both bear central and axial chiral elements, have
been developed to promote enantioselective Michael reaction
between 1,3-dicarbonyl compounds and nitro olefins. The
catalyst 2 afforded the desired products with good levels of
enantioselectivity (up to 96% ee), showing clearly that two
chiral elements of 2 are matched, and enhance the stereo-
chemical control.
The nitroalkanes are important building blocks and intermedi-
ates in organic synthesis because the nitro group can be easily
transformed into other useful groups such as amines and
carbonyls.1 Michael addition of carbon-centered nucleophiles
to nitro olefins represents a direct and powerful approach to
chiral nitroalkanes. As a result, a considerable of effort has been
devoted to the development of catalytic enantioselective versions
of the process.2
(6) For selected examples, see: (a) Terada, M.; Ube, H.; Yaguchi, Y. J. Am.
Chem. Soc. 2006, 128, 1454. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (c) Li, Y.; Wang, H.; Tang,
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Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105.
(8) (a) Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7,
4713. (b) Cinchona alkaloids have also been employed for the process, but very
low enantioselectivities (26-29% ee) were achieved: (c) Brunner, H.; Kimel,
B. Monatsh. Chem. 1996, 127, 1063.
Although the catalytic asymmetric versions of this reaction
have been achieved, most required metal catalysts or strict
(9) Peng, F.; Shao, Z. J. Mol. Catal. A: Chem. 2008, 285, 1.
(1) For reviews, see: (a) Ono, N. The Nitro Group in Organic Synthesis;
Wiley-VCH: New York, 2001. (b) Ballini, R.; Petrini, M. Tetrahedron 2004,
60, 1017.
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Z.; Schreiner, P. R. Synthesis 2007, 2559.
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Org. Chem. 2002, 1877. (b) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron:
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5202 J. Org. Chem. 2008, 73, 5202–5205
10.1021/jo800774m CCC: $40.75 2008 American Chemical Society
Published on Web 06/11/2008

SCHEME 1. Synthesis of Organocatalysts 1 and 2a
FIGURE 1. Designed bifunctional catalysts 1 and 2 with both central
and axial chiral elements.
based thioureas13 are the most popular, and have been widely
used in many asymmetric reactions. In addition, other types of
thiourea catalysts such as imidazole-thioureas,5i guanidine-
thioureas,14 pyrrolidine-thioureas,15 and oxazoline-thioureas16
have been found to be useful for different asymmetric trans-
formations. It is noted, however, that most of them contain
central chirality as the only asymmetric element. Chiral urea
and thiourea organocatalysts bearing two different types of
stereogenic structures in the same molecule are few. We
envisioned that appropriately introducing a second chiral element
in a chiral urea/thiourea molecule could facilitate its tunability,
and would lead to finding an optimal chiral organocatalyst. To
achieve catalytic enantioselective Michael reaction into nitro
olefins with thioureas, we designed novel bifunctional organo-
catalysts 1 and 2 bearing both central and axial chiral elements
(Figure 1). The influence of these elements on the enantiose-
lectivity of Michael addition of 2,4-pentandione to nitroalkenes
was also studied. To the best of our knowledge, this is the first
highly enantioselective organocatalytic Michael reaction of nitro
olefins promoted by amine-thioureas containing both central and
axial chiral elements.
a Reagents and conditions: (a) Et3N, CH2Cl2, 35 °C, 5a 76%, 5b 74%;
(b) KOH, 96% EtOH, 50 °C, 6a 89%, 6b 90%; (c) 1-isothiocyanato-3,5-
bis(trifluoromethyl)benzene, THF, rt, 1 91%, 2 92%.
TABLE 1. Enantioselective Addition of 2,4-Pentandione (7) to
trans-ꢀ-Nitrostyrene (8a) Catalyzed by Amine-Thioureas 1 and 2a
The two bifunctional chiral amine-thioureas 1 and 2, carrying
the same absolute configuration of the binaphthyl unit, but
differing in the two stereogenic centers of the cyclohexyl
scaffold, were synthesized by following the procedure described
in Scheme 1. The reaction of (R)-2,2′-di(bromomethyl)-1,1′-
binaphthyl 317 with DAB (1,3-dimethyl-5-acetylbarbituric acid)-
monoprotected (1R,2R)- and (1S,2S)-cyclohexyldiamines 4a and
4b in CH2Cl2 in the presence of Et3N as the base gave the
corresponding tertiary amines 5a and 5b in 76% and 74% yield,
entry
catalyst
solvent
yield (%)
ee (%)b
1
2
3
4
5
6
1
2
2
2
2
2
toluene
toluene
DCM
THF
Et2O
DMSO
84
82
80
78
81
63
78(R)
93(S)
89(S)
84(S)
90(S)
28(S)
(12) For a review, see: Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2006, 45, 1520.
a The reaction was performed with trans-ꢀ-nitrostyrene (8a) and
2,4-pentandione (7) (2 equiv) in the presence of catalysts (10 mol %) at
room temperature for 16 h. b Enantiomeric excess (ee) was determined
by chiral HPLC analysis (Chiralpak AS-H).
(13) For selected examples, see: (a) Diner, P.; Nielsen, M.; Bertelsen, S.;
Niess, B.; Jorgensen, K. A. Chem. Commun. 2007, 3646. (b) Wang, J.; Zu, L.;
Li, H.; Xie, H.; Wang, W. Synthesis 2007, 2576. (c) Lubkoll, J.; Wennemers,
H. Angew. Chem., Int. Ed. 2007, 46, 6841. (d) Gu, C.; Liu, L.; Sui, Y.; Zhao, J.;
Wang, D.; Chen, Y. Tetrahedron: Asymmetry 2007, 18, 455. (e) Hynes, P. S.;
Stranges, D.; Stupple, P. A.; Guarna, A.; Dixon, D. J. Org. Lett. 2007, 9, 2107.
(f) Amere, M.; Lasne, M. C.; Rouden, J. Org. Lett. 2007, 9, 2621. (g) Liu, T.;
Cui, H.; Chai, Q.; Long, J.; Li, B.; Wu, Y.; Ding, L.; Chen, Y. Chem. Commun.
2007, 2228. (h) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Mazzanti,
A.; Sambri, L.; Melchiorre, P. Chem. Commun. 2007, 722. (i) McCooey, S. H.;
Connon, S. J. Org. Lett. 2007, 9, 599. (j) Song, J.; Shih, H. W.; Deng, L. Org.
Lett. 2007, 9, 603. (k) Zu, L.; Wang, J.; Li, H.; Xie, H.; Jiang, W.; Wang, W.
J. Am. Chem. Soc. 2007, 129, 1036. (l) Tillman, A. L.; Ye, J.; Dixon, D. J.
Chem. Commun. 2006, 1191. (m) Marcelli, T.; van der Haas, R. N. S.; van
Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929. (n) Wang,
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Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967.
respectively.18 Subsequent deprotection of 5a and 5b with KOH
in 96% EtOH solution at 50 °C afforded primary amines 6a
and 6b in 89% and 90% yield, respectively. Finally, condensa-
tion of 6a and 6b with 1 equiv of 1-isothiocyanato-3,5-
bis(trifluoromethyl)benzene in THF provided the chiral amine-
thiourea catalysts 1 and 2 in 91% and 92% yield, respectively.
The efficacy of bifunctional amine-thioureas 1 and 2 as chiral
organocatalysts was initially evaluated by using the reaction of
2,4-pentandione 7 with trans-ꢀ-nitrostyrene 8a in toluene at
room temperature (Table 1). Under the same conditions, catalyst
2 gave desired product 9a in higher enantioselectivity (93% ee,
(14) (a) Sohtome, Y.; Takemura, N.; Takada, K.; Takagi, R.; Iguchi, T.;
Nagasawa, K. Chem. Asian J. 2007, 2, 1150. (b) Sohtome, Y.; Hashimoto, Y.;
Nagasawa, K. AdV. Synth. Catal. 2005, 347, 1643.
(15) (a) Cao, C.; Ye, M.; Sun, X.; Tang, Y. Org. Lett. 2006, 8, 2901. (b)
Cao, Y.; Lai, Y.; Wang, X.; Li, Y.; Xiao, W. Tetrahedron Lett. 2007, 48, 21.
(16) Chang, Y.; Yang, J.; Dang, J.; Xue, Y. Synlett 2007, 2283.
(18) Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.; Yanagisawa, A.
Angew. Chem., Int. Ed. 2006, 45, 5978.
(17) Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679.
J. Org. Chem. Vol. 73, No. 13, 2008 5203

TABLE 2. Organocatalytic Enantioselective Addition of
2,4-Pentandione (7) to Various Nitro Olefins 8 Promoted by
Amine-Thioureas 2a
entry
R
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
9
Ph (8a)
82
86
84
81
78
83
80
85
83
80
93
94
94
91
96
96
93
92
90
76c
4-Cl-C6H4 (8b)
4-Br-C6H4 (8c)
2-CF3-C6H4 (8d)
2-BnO-C6H4 (8e)
2,3-(MeO)2-C6H3 (8f)
4-Me-C6H4 (8g)
4-MeO-C6H4 (8h)
4-BnO-C6H4 (8i)
i-Bu (8j)
FIGURE 2. Proposed catalytic reaction mode through double activation.
Other types of 1,3-dicarbonyl compounds 10 were also
applicable to the present catalytic system (eq 1). For R-mono-
substituted 1,3-diketone 10a, malonate ester 10b, and ꢀ-ketoester
10c, the corresponding adducts were obtained in good yields
(75-81%) and enantioselectivities (80-84%) at the ꢀ-position
to the nitro group.
10
a The reaction was performed with 2,4-pentandione (7) (2 equiv) and
nitro olefins 8 in the presence of catalyst 2 (10 mol %) at room
temperature. b Enantiomeric excess (ee) was determined by chiral HPLC
analysis (Chiralpak AS-H, OD-H, and AD/AD-H). c Absolute configura-
tion was not determined.
entry 2), whereas catalyst 1 afforded product 9a in lower
enantioselectivity (78% ee, entry 1), as well as a reversal of
the absolute configuration of product 9a. These results demon-
strate that the two chiral elements in chiral amine-thiourea
catalyst 2 are matched, enhancing the stereochemical control,
whereas the two chiral elements in chiral amine-thiourea catalyst
1 are mismatched. Furthermore, the central chiral element of
catalysts predominates the absolute configuration of product 9a.
Next, the influence of the solvents was investigated by using
the bifunctional organocatalyst 2. In polar solvents such as
DMSO (Table 1, entry 6), lower enantioselectivity for product
9a was observed. This is probably due to the destruction of
hydrogen bonding interactions between the thiourea and the nitro
group in the substrate in strongly H-bonding-acceptor solvents.
As expected, when reactions were conducted in less polar
solvents, higher enantioselectivities were obtained (entries 2-5,
Table 1). With toluene as the solvent, the Michael adduct 9a
was isolated with the highest ee (93%) in 82% yield (entry 2).
A plausible catalytic mode representing the prototypical addition
of 2,4-pentandione (7) to trans-ꢀ-nitrostyrene (8a) in the presence
of 2 as a catalyst is shown in Figure 2, in which a thiourea moiety
of the catalyst 2 interacts through hydrogen bonding with a nitro
group of the nitroalkene and enhances their electrophilicity while
the tertiary amine deprotonates an acidic proton of 2,4-pentandione
(7), generating a ternary complex. The synergistic steric hindrance
from the chiral dihydroazepine moiety of bifunctional catalyst 2
might be responsible for the increased stereocontrol of the Michael
addition reaction. Nevertheless, the real catalytic mechanism still
needs further investigation.
Experiments that probe the scope and limitations of the
nitroalkene substrates utilizing the bifunctional catalyst 2 are
summarized in Table 2. The Michael addition reactions of
aromatic nitro olefins 8a-i with 2,4-pentandione (7) proceeded
smoothly with good enantioselectivities (90-96% ee). It appears
that the position and the electronic property of the substituents
for aromatic rings of nitroalkenes are well tolerated by the
Michael addition reactions. Whether electron-withdrawing
(entries 2-4, Table 2), -donating (entries 5-9, Table 2), or
-neutral (entry 1, Table 2) groups on aromatic rings were used,
the reactions proceeded smoothly to give the desired adducts
in good yields (78-86%) with good enantioselectivities (90-96%
ee). The Michael reaction of aliphatic nitro olefin 8j reacted
with 2,4-pentandione 7 to afford the desired product 9j in 80%
yield and 76% ee value (entry 10, Table 2). Although the
enantioselectivity of the product with aliphatic nitro olefin is
not so high as the enantioselectivity with aromatic nitroalkenes,
this is the first example of enantioselective addition of 1,3-
diketone to aliphatic nitro olefin. Absolute configurations of
9a-i were determined by comparing the retention time of HPLC
of products with those of literature data.
In summary, we have developed two novel bifunctional
amine-thiourea organocatalysts 1 and 2, which both bear central
and axial chiral elements, for promoting the enantioselective
Michael reaction between 1,3-dicarbonyl compounds and nitro
olefins.19 Catalyst 2 afforded the desired products with levels
of enantioselectivity of up to 96% ee, showing clearly that two
chiral elements of 2 are matched, and enhance the stereochem-
ical control. Our research might have implications for the design
of novel chiral organocatalysts. Utilization of these bifunctional
amine-thiourea organocatalysts in other asymmetric reactions
is under way in our laboratory.
Experimental Section
Typical Procedure for Michael Addition Reaction Catalyzed
by Bifunctional Catalyst 2. The catalyst 2 (6.63 mg, 0.01 mmol,
10 mol %) was added to a vial containing 2,4-pentanedione 7 (20
(19) The catalysts can be recovered and reused after further purification. For
example, the Michael addition reaction of 2,4-pentandione (7) and trans-ꢀ-
nitrostyrene (8a) in the presence of recovered catalyst 2 (10 mol %) afforded
adduct 9a in 73% yield and 89% ee (1st run).
5204 J. Org. Chem. Vol. 73, No. 13, 2008

mg, 0.2 mmol) and trans-ꢀ-nitrostyrene 8a (14.9 mg, 0.1 mmol)
in dry toluene (1 mL) at room temperature. After 16 h of stirring,
the reaction mixture was quenched with 1 M aqueous HCl solution,
extracted with EtOAc, and dried over Na2SO4. The crude product
was purified by flash silica gel chromatography to give 20.4 mg
Acknowledgment. We thank National Natural Science
Foundation of China (20702044) for financial support.
Supporting Information Available: The synthesis of catalyst
2, Michael addition procedure, spectroscopic data of compounds
5b, 6b, and 2 adducts 9, 11, and chiral HPLC data for the
adducts 9, 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
(82%) of the adduct 9a as a white solid: H NMR (400 MHz,
CDCl3) δ 7.32-7.25 (m, 3H), 7.19-7.16 (m, 2H), 4.64-4.59 (m,
2H), 4.35 (d, J ) 10.8 Hz, 1H), 4.26-4.22 (m, 1H), 2.26 (s, 3H),
1.92 (s, 3H); HPLC (Chiralpak AS-H, isopropyl alcohol/hexane )
15/85, flow rate 1.0 mL/min, λ ) 210 nm) tmajor ) 14.1 min, tminor
) 20.2 min.
JO800774M
J. Org. Chem. Vol. 73, No. 13, 2008 5205