Enantioselective and regioselective organocatalytic conjugate addition of malonates to nitroenynes

Article abstract of DOI:10.1002/asia.201000561

The first catalytic asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroenynes catalyzed by cinchona alkaloid-based thiourea organocatalysts has been developed. The 1,4-addition adducts were obtained solely, in moderate to good yields (up to

Full text of DOI:10.1002/asia.201000561

FULL PAPERS
DOI: 10.1002/asia.201000561
Enantioselective and Regioselective Organocatalytic Conjugate Addition of
Malonates to Nitroenynes
Xiao-Jiao Li, Fang-Zhi Peng, Xiang Li, Wen-Tao Wu, Zhong-Wen Sun, Ying-Mei Li,
Shao-Xiong Zhang, and Zhi-Hui Shao*[a]
Dedicated to Professor Albert S. C. Chan on the occasion of his 60th birthday
Abstract: The first catalytic asymmetric conjugate addition of 1,3-dicarbonyl com-
pounds to nitroenynes catalyzed by cinchona alkaloid-based thiourea organocata-
lysts has been developed. The 1,4-addition adducts were obtained solely, in moder-
ate to good yields (up to 93%) with good enantioselectivities (up to 99% ee). This
protocol affords a conceptually different entry to the precursors of pharmaceuti-
cally important chiral b-alkynyl acid derivatives and synthetically useful chiral ni-
troalkynes. Notably, the protocol worked well with both aryl- and alkyl-substituted
alkynyl substrates.
Keywords: asymmetric catalysis
conjugate addition · dicarbonyls ·
enantioselectivity · nitroenynes
·
Introduction
ceptors,[7] this is probably due to the competition between
1,4- and 1,6-addition of extended Michael acceptors,[8] and
the difficulties in controlling the regioselectivity. More re-
cently, Alexakis and co-workers demonstrated in the
copper-catalyzed conjugate addition of nitroenynes that the
regioselectively was largely dependent on the types of nucle-
ophilic reagents.[7f] Given the enormous potentials of nitroe-
nynes as a class of Michael acceptors and the interesting re-
gioselectivity issue, in combination with our interest in de-
veloping new catalytic methods to synthesize chiral mole-
cules that bear acetylene moieties, we have explored the
possibility of developing new types of catalytic asymmetric
reactions by using nitroenynes as a class of Michael accept-
ors. In the current research, we focused on the regioselec-
tive, catalytic asymmetric 1,4-conjugate addition of malo-
nates to nitroenynes as this would allow access to the pre-
cursors of chiral b-alkynyl acid derivatives and functional-
ized chiral nitroalkynes.
The asymmetric conjugate addition of carbon-centered nu-
cleophiles to nitroolefins is one of the most important and
useful carbon–carbon bond-forming reactions in modern or-
ganic synthesis.[1] The development of the corresponding cat-
alytic asymmetric variants has received growing attention
due to the diverse transformations of the nitro group.[2] On
the other hand, on account of the synthetic versatility and
modularity of the acetylene group,[3] tremendous efforts
have been devoted to the development of catalytic asym-
metric methods to access chiral molecules that bear acety-
lene moieties.[4] In this context, nitroenynes seem to be ideal
substrates for both such processes because this class of sub-
strates effectively merges the nitroolefin moiety and the
acetylene moiety. Despite a large body of literature on cata-
lytic asymmetric Michael addition of nitroolefins,[1,5,6] there
are few examples with nitroenynes as a class of Michael ac-
Chiral b-alkynyl acids constitute an important class of
pharmaceutical compounds with diverse biological activities
that include phosphodiesterase (PDE) IV inhibitors, tumor
necrosis factor (TNF) inhibitors, GPR40 receptor agonists,
and gene related peptide (GRP) receptor antagonists.[9]
However, their asymmetric synthesis remains a significant
challenge. The asymmetric methods that have been de-
scribed to date for access to this target class involve the
transition-metal-mediated asymmetric conjugate alkynyla-
tion of Meldrumꢀs acid-derived acceptors [Eq. (1)].[10–12] But
[a] X.-J. Li, F.-Z. Peng, X. Li, W.-T. Wu, Z.-W. Sun, Y.-M. Li,
S.-X. Zhang, Prof. Dr. Z.-H. Shao
Key Laboratory of Medicinal Chemistry for Natural Resources
Ministry of Education
School of Chemical Science and Technology
Yunnan University, Kunming, 650091 (China)
Fax : (+86)871-5035538
E-mail: zhihui_shao@hotmail.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000561.
220
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 220 – 225

bonyl compounds such as a-substituted malonate, 1,3-dike-
tone, and b-keto ester were also suitable substrates for the
1,4-conjugate addition.
these protocols have limitations such as the requirement of
use of aromatic alkynes,[10] sterically shielded trimethylsilyl
(TMS) acetylene,[11] or a stoichiometric chiral mediator.[12]
Scheme 1. Organocatalytic asymmetric conjugate addition of malonates
to nitroenynes.
Chiral nitroalkynes are potentially important chiral building
blocks in organic synthesis; however, there are few general
and asymmetric approaches to such compounds. Recently,
Tomioka and co-workers reported the highly enantioselec-
tive Michael addition of terminal arylalkynes to nitroolefins
mediated by diorganozinc and chiral amino alcohol [Eq. (2),
right].[13] But this protocol required the use of a stoichiomet-
ric chiral amino alcohol. Moreover, the use of a nonarylal-
kyne led to an almost racemic product (7% ee).
Results and Discussion
Chiral bifunctional thiourea organocatalysts have been
shown to be quite effective in asymmetric transforma-
tions.[17] Accordingly, our initial investigation began with
screening chiral-diamine-derived thiourea organocatalysts
1a–i. In the presence of catalyst 1a (RA,S,S), which possess-
À
In view of the diverse requirements of C C bond-forming
reactions, the development of a new, particularly conceptu-
ally different strategy that complements the metal-based
routes to the above-mentioned valuable molecules would be
highly desirable.
As part of our interest in developing new catalytic reac-
tions that involve terminal alkynes,[14] and in asymmetric or-
ganocatalysis,[15,16] herein we report the first catalytic asym-
metric conjugate addition of malonates to nitroenynes cata-
lyzed by chiral bifunctional thiourea organocatalysts. This
highly regioselective 1,4-conjugate addition affords a con-
ceptually different entry to the precursors of pharmaceuti-
cally important chiral b-alkynyl acid derivatives and synthet-
ically useful chiral nitroalkynes. Notably, this protocol
worked well with both aryl- and alkyl-substituted alkynyl
substrates (Scheme 1). In addition, other types of 1,3-dicar-
es both central and axial chiral elements,[5ac] the reaction of
phenylnitroeneyne 2a and diethyl malonate 3a in toluene at
room temperature afforded the desired 1,4-addition adduct
4a in 52% yield and 57% ee (Table 1, entry 1), whereas the
catalyst 1b (RA,R,R)[5ac] gave the product 4a in higher yield
(58%) and enantioselectivity (À79% ee, entry 2). These re-
sults seem to indicate that the two chiral elements in catalyst
1a (RA,S,S) are mismatched, whereas two chiral elements in
catalyst 1b (RA,R,R) are matched. Interestingly, in our pre-
vious enantioselective Michael reactions between 1,3-dicar-
Abstract in Chinese:
Chem. Asian J. 2011, 6, 220 – 225
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
221

Z.-H. Shao et al.
FULL PAPERS
Table 1. Optimization of reaction conditions for the enantioselective Mi-
an additional phenylnitroeneyne 2a, was observed. Howev-
er, it could be easily separated by flash column chromatog-
raphy. It is worth pointing out that almost no bisaddition
product was observed in the organocatalytic asymmetric ad-
dition of malonates to nitroolefins. On the other hand, 1,6-
diynes are valuable building blocks in organic synthesis.[19]
Therefore, the use of excess amounts of phenylnitroeneyne
2a (3 equiv) was examined, thereby providing the 1,6-diyne
4a’ as the major product (66% yield, 4a’/4a=68:32)
[Eq. (3)]:
chael addition of phenylnitroeneyne 2a with diethyl malonate 3a.[a]
Entry
Catalyst
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1g
1g
1g
1g
1g
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
64
64
39
39
18
28
16
24
18
48
48
44
26
48
52
58
62
64
58
58
68
62
60
60
56
65
63
75
57
À79
67
À68
69
À79
83
81
9
À82
10
11
12
13
14[d]
69
CH2Cl2
Et2O
DMF
79
84
0
90
toluene
[a] The reaction was performed with phenylnitroeneyne 2a (0.3 mmol)
and diethyl malonate 3a (2 equiv) in the presence of 10 mol% catalyst in
solvent (1 mL). [b] Isolated yields. [c] Enantiomeric excess (ee) was deter-
mined by chiral HPLC analysis (Chiralpak AD-H). [d] The reaction was
carried out at À108C.
Under the optimized experimental conditions, the general
utility of the reaction was examined. The results were sum-
marized in Table 2. Generally, the corresponding 1,4-addi-
tion products could be obtained in moderate to good yields
and with good enantioselectivities. Notably, the protocol
worked well not only with electron-neutral (Table 2,
entry 1), electron-rich (entries 2–4), and electron-deficient
arylalkynyl substrates (entry 5), but also with alkyl-substitut-
ed alkynyl substrates (entries 6–8). Importantly, the use of
“pseudoenantiomer” 1i derived from quinidine allowed
access to the opposite enantiomer of 4b with the same enan-
tioselectivity (entry 3).
bonyl compounds and nitroolefins,[5ac] two chiral elements of
the catalyst 1a (RA,S,S) were found to be matched, whereas
two chiral elements of the catalyst 1b (RA,R,R) were mis-
matched. The bifunctional thioureas 1c and 1d[5ad,ae] devel-
oped by us recently provided product 4a in 67% ee
(entry 3) and À68% ee (entry 4), respectively. Although
Takemotoꢀs catalyst 1e,[5a] which was an excellent catalyst in
the Michael addition of malonates to nitroolefins, was evalu-
ated, only 69% ee was obtained in the current reaction
(entry 5). Then, several cinchona alkaloid-based thiourea or-
ganocatalysts 1 f–i[18] were evaluated (entries 6–9). The re-
sults suggested that there was no big difference between
these catalysts, and the catalyst 1g derived from dihydroqui-
nine was the most effective in terms of both chemical yield
(68%) and enantioselectivity (83% ee; entry 7).
Table 2. Enantioselective Michael reactions of nitroenynes with malona-
tes.[a]
Entry R1
R2
t
Product
Yield
[%][b]
ee
Next, the influence of the solvents was investigated by
using the organocatalyst 1g. Although the use of Et2O af-
forded product 4a with similar yield and enantioselectivity,
a longer reaction time was needed (Table 1, entry 12). Inter-
estingly, DMF led to a complete racemic product (entry 13).
This is probably due to the destruction of hydrogen-bonding
interactions between the thiourea and the nitro group in the
substrate in strongly hydrogen-bonding-acceptor solvents.
To improve the yields and enantioselectivity further, we in-
vestigated lowering the reaction temperature. To our de-
light, the desired 1,4-addition product 4a was obtained in
good yield (75%) with high enantioselectivity (90% ee) at
À108C (entry 14).
[h]
[%][c]
1
2
Ph (2a)
p-MeOC6H4
(2b)
p-MeOC6H4
(2b)
Et (3a)
Et (3a)
48
23
4a
4b
75
61
90
92
3
Et (3a)
28 ent-4b
63
À92[d]
4
5
6
7
8
9
p-MeC6H4 (2c)
p-FC6H4 (2d)
Et (3a)
Et (3a)
23
60
38
4c
4d
4e
4 f
4g
4h
60
55
65
61
69
56
90
86
96
99
90
87
CH
CH
3A
CTHUNGTRENUN(GN CH2)2 (2 f) Et (3a) 100
PhCH2CH2 (2g) Et (3a)
Ph (2a)
72
52
Me
(3b)
10
Ph (2a)
tBu
(3c)
48
4i
trace
–
[a] The reaction was performed with nitroenynes (0.3 mmol) with diethyl
malonate (2 equiv) in the presence of 10 mol% catalyst in toluene
(1 mL) at À108C. [b] Isolated yields. [c] Enantiomeric excess (ee) was de-
termined by chiral HPLC analysis (Chiralpak AD-H and Chiralcel OD-
H or OJ-H). [d] The catalyst 1i was used.
Interestingly, no trace of the 1,6-addition adduct was ever
observed during the course of the whole study. However, it
was found that the bisaddition product 1,6-diyne 4a’ (cat.
10%), which resulted from the reaction of product 4a with
222
www.chemasianj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 220 – 225

Malonates to Nitroenynes
The asymmetric conjugate addition of other types of 1,3-
dicarbonyl compounds to nitroeneyne 2a by using 1g as the
catalyst was also investigated [Eq. (4)]. For a-monosubsti-
tuted malonate ester 3d, 1,3-diketone 3e, and b-ketoester
3 f, the corresponding adducts were obtained in good yields
(74–93%) and enantioselectivities (86–93% ee) at the b po-
sition to the nitro group. Interestingly, whereas the a-proton
acetylacetone 3e and ethyl acetoacetate 3 f were more
acidic than that of the malonates, respectively, their re
actions with nitroeneyne 2a did not give the bisaddition
adducts.
Scheme 3. Proposed transition-state model.
chiral nitroalkynes. Notably, the protocol worked well with
both aryl- and alkyl-substituted alkynyl substrates. The in-
vestigation of the reaction scope and mechanism as well as
the development of a new method for the synthesis of novel
types of chiral molecules that bear acetylene moieties is in
progress and will be reported in due course.
To determine the absolute configuration, product 4 f was
converted into compound 5 (Scheme 2). The R configuration
was established by comparison of the optical rotation of 5
with the previously reported value of this compound.[6f]
Experimental Section
General Procedure for Conjugate Addition of Nitroenynes with Diethyl
Malonate
Organocatalyst 1g (10 mol%) was added to a solution of diethyl malo-
nate 3a (96 mg, 0.6 mmol) and phenylnitroeneyne 2a (52 mg, 0.3 mmol)
in dry toluene (1 mL) at À108C. The resulting solution was stirred at
À108C for 48 h. The reaction mixture was quenched with aqueous
NH4Cl, extracted with EtOAc, and dried over Na2SO4. The crude product
was purified by flash column chromatography to give adduct 4a (75 mg,
75%).
Scheme 2. Determination of the absolute configuration of the product 4 f.
(R)-Diethyl 2-(1-nitro-4-phenylbut-3-yn-2-yl)malonate (4a):
[a]2D0 =+6.5 (c=0.8m, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.31 (m,
2H), 7.25 (m, 3H), 4.77 (m, 2H), 4.22 (q, J=6.9 Hz, 4H), 4.10 (m, 1H),
3.80 (d, J=7.7 Hz, 1H), 1.24 ppm (m, 6H); 13C NMR (75 MHz, CDCl3):
d=166.9, 166.7, 131.9, 128.9, 128.4, 122.1, 85.8, 83.4, 76.3, 62.4, 53.4, 30.9,
25.5, 14.2 ppm; HRMS (EI): m/z: calcd for C17H19NO6: 333.1212 [M]+;
found: 333.1186; HPLC (Chiralpak AD-H, isopropanol/hexane=10:90,
flow rate=1.0 mLminÀ1, l=254 nm): tmajor =11.7 min, tminor =13.7 min.
The observed absolute configuration (R) of the conjugate
adduct was explained by the transition-state assembly shown
in Scheme 3 in which the Re face of the nitroeneyne was
predominantly approached by the deprotonated malonate.[20]
However, we could not rule out the possibility that the nitro
group of nitroenyne was activated by the protonated tertiary
amine motif at this stage.[5s,20]
(R)-Diethyl 2-[4-(4-methoxyphenyl)-1-nitrobut-3-yn-2-yl]malonate (4b):
[a]2D0 =+7.6 (c=0.8m, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.25 (d,
J=8.7 Hz, 2H), 6.75 (d, J=8.7 Hz, 2H), 4.74 (m, 2H), 4.22 (q, J=7.2 Hz,
4H), 4.08 (m, 1H), 3.77 (d, J=8.1 Hz, 1H), 3.74 (s, 3H), 1.21 ppm (m,
6H); 13C NMR (75 MHz, CDCl3): d=166.8, 166.6, 159.9, 114.0, 113.9,
85.6, 81.8, 76.3, 62.2, 55.3, 53.4, 30.8, 14.0 ppm; HRMS (EI): m/z: calcd
for C18H21NO7: 363.1318 [M]+; found: 363.1316; HPLC (Chiralcel OD-H,
Conclusion
We have developed the first catalytic asymmetric conjugate
addition of 1,3-dicarbonyl compounds to nitroenynes in
moderate to good yields (up to 93%) and with good enan-
tioselectivities (up to 99% ee) by using easily accessible cin-
chona alkaloid-based thiourea organocatalysts. The reaction
is highly regioselective. This protocol provided a catalytic
and transition-metal-free method to the precursors of phar-
maceutically important chiral b-alkynyl acids. Furthermore,
it also offered a new catalytic route to synthetically useful
isopropanol/hexane=5:95, flow rate=0.5 mLminÀ1, l=254 nm): tmajor
38.8 min, tminor =43.1 min.
=
(R)-Diethyl 2-(1-nitro-4-p-tolylbut-3-yn-2-yl)malonate (4c):
[a]2D0 =+18.1 (c=0.3m, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.25 (d,
J=8.1 Hz, 2H), 7.08 (d, J=7.9 Hz, 2H), 4.80 (m, 2H), 4.26 (q, J=7.1 Hz,
4H), 4.14 (m, 1H), 3.82 (d, J=7.7 Hz, 1H), 2.33 (s, 3H), 1.29 ppm (m,
6H); 13C NMR (75 MHz, CDCl3): d=168.1, 166.8, 166.6, 159.9, 138.9,
131.7, 129.0, 118.8, 85.8, 82.5, 76.2, 62.3, 53.3, 30.8, 21.5, 14.1 ppm; HRMS
Chem. Asian J. 2011, 6, 220 – 225
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
223

Z.-H. Shao et al.
FULL PAPERS
(EI): m/z: calcd for C18H21NO6: 347.1369 [M]+; found: 347.1374; HPLC
isopropanol/hexane=5:95, flow rate=0.8 mLminÀ1, l=254 nm): tmajor
26.2 min, tminor =41.6 min.
=
(Chiralcel OJ-H, isopropanol/hexane=15:85, flow rate=0.8 mLminÀ1
l=254 nm): tmajor =18.3 min, tminor =20.8 min.
,
(2R)-Ethyl 2-acetyl-3-(nitromethyl)-5-phenylpent-4-ynoate (4l):
(R)-Diethyl 2-[4-(4-fluorophenyl)-1-nitrobut-3-yn-2-yl]malonate (4d):
The diastereomers could not be separated. [a]2D0 =+25.6 (c=0.8m,
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.27–7.18 (m, 5H), 4.67–4.63
(m, 2H), 4.21–4.16 (m, 2H), 4.03–3.92 (m, 2H), 2.30 (m, 3H), 1.24–
1.16 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=200.3, 200.1, 166.9,
166.7, 131.8, 128.8, 128.7, 128.3, 121.9, 121.8, 85.7, 85.6, 83.6, 76.3, 76.2,
62.3, 60.3, 59.6, 30.4, 30.1, 30.0, 21.0, 14.0 ppm; HRMS (EI): m/z: calcd
for C17H19NO6: 303.1107 [M+1]+; found: 303.1111; HPLC (Chiralpak
AD-H, isopropanol/hexane=5:95, flow rate=0.8 mLminÀ1, l=254 nm):
[a]2D0 =+1.1 (c=0.4m, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.28 (m,
2H), 6.91 (m, 2H), 4.75 (m, 2H), 4.20 (q, J=7.1 Hz, 4H), 4.09 (m, 1H),
3.77 (d, J=7.7 Hz, 1H), 1.22 ppm (m, 6H); 13C NMR (75 MHz, CDCl3):
d=166.7, 166.5, 164.3, 161.0, 133.8, 133.7, 118.0, 115.7, 115.4, 84.5, 83.2,
76.1, 62.2, 53.2, 30.7, 13.9 ppm; HRMS (EI): m/z: calcd for C17H18NO6F:
351.1118 [M]+; found: 351.1144; HPLC (Chiralpak AD-H, isopropanol/
hexane=10:90, flow rate 0.8 mLminÀ1
minor =19.3 min.
, l=254 nm): tmajor =16.0 min,
tmajor =17.6 min, tminor =25.8 min; tmajor =20.0 min, tminor =23.0 min.
t
(R)-Diethyl 2-(1-nitrooct-3-yn-2-yl)malonate (4e)
[a]2D0 =+2.5 (c=0.4m, CHCl3); 1H NMR (300 MHz, CDCl3): d=4.66 (m,
2H), 4.19 (q, J=7.2 Hz, 4H), 3.85 (m, 1H), 3.67 (d, J=7.7 Hz, 1H), 2.09
(m, 2H), 1.36–1.23 (m, 10H), 0.86 ppm (m, 3H); 13C NMR (75 MHz,
CDCl3): d=166.9, 166.6, 86.4, 74.1, 62.1, 61.5, 53.5, 41.6, 30.4, 30.3, 21.7,
18.1, 14.0, 13.5 ppm; HRMS: m/z: calcd for C15H24NO6: 314.1604 [M+1]+
; found: 314.1610; HPLC (Chiralcel OJ-H, isopropanol/hexane=0:100,
flow rate=0.8 mLminÀ1, l=210 nm): tmajor =39.0 min, tminor =43.9 min.
Acknowledgements
We thank the National Natural Science Foundation of China (20702044,
20962023) and the Program for New Century Excellent Talents in Uni-
versity (NCET-10-0907) for support of this research.
(R)-Diethyl 2-(1-nitrohept-3-yn-2-yl)malonate (4 f):
[1] For recent reviews on asymmetric Michael addition of nitroolefins,
see: a) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem.
2002, 1877; b) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; c) D.
Almas¸i, D. A. Alonso, C. Nꢂjera, Tetrahedron: Asymmetry 2007, 18,
299; d) S. Sulzer-Mossꢃ, A. Alexakis, Chem. Commun. 2007, 3123;
e) J. L. Vicario, D. Badia, L. Carrillo, Synthesis 2007, 2065.
[2] For the review or monograph, see: a) N. Ono, The Nitro Group in
Organic Synthesis, Wiley-VCH, New York, 2001; b) R. Ballini, M.
Petrini, Tetrahedron 2004, 60, 1017.
[3] Acetylene Chemistry: Chemistry, Biology, and Material Science
(Eds.: F. Diederich, P. J. Stang, R. R. Tykwinski), Wiley-VCH, Wein-
heim, 2005.
[4] For recent reviews, see: a) B. M. Trost, A. H. Weiss, Adv. Synth.
Catal. 2009, 351, 963; b) L. Zani, C. Bolm, Chem. Commun. 2006,
4263; c) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem.
2004, 4095.
[5] For recent selected examples of organocatalytic asymmetric conju-
gate addition of 1,3-dicarbonyl compounds to nitroolefins, see: a) T.
Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672;
b) H. Li, Y. Wang, L. Tang, L. Deng, J. Am. Chem. Soc. 2004, 126,
9906; c) J. Wang, H. Li, W. Duan, L. Zu, W. Wang, Org. Lett. 2005,
7, 4713; d) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto,
J. Am. Chem. Soc. 2005, 127, 119; e) S. H. McCooey, S. J. Connon,
Angew. Chem. 2005, 117, 6525; Angew. Chem. Int. Ed. 2005, 44,
6367; f) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo, B. M.
Foxman, L. Deng, Angew. Chem. 2005, 117, 107; Angew. Chem. Int.
Ed. 2005, 44, 105; g) J. Ye, D. J. Dixon, P. S. Hynes, Chem. Commun.
2005, 4481; h) M. Terada, H. Ube, Y. Yaguchi, J. Am. Chem. Soc.
2006, 128, 1454; i) A. Lattanzi, Tetrahedron: Asymmetry 2006, 17,
837; j) F. Chen, C. Shao, Q. Wang, P. Gong, D. Zhang, B. Zhang, R.
Wang, Tetrahedron Lett. 2007, 48, 8456; k) J. Lubkoll, H. Wennem-
ers, Angew. Chem. 2007, 119, 6965; Angew. Chem. Int. Ed. 2007, 46,
6841; l) J. M. Andrꢃs, R. Manzano, R. Pedrosa, Chem. Eur. J. 2008,
14, 5116; m) J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am. Chem.
Soc. 2008, 130, 14416; n) C. Wang, Z. Zhang, X. Dong, X. Wu,
Chem. Commun. 2008, 1431; o) X. Li, K. Liu, H. Ma, J. Nie, J. Ma,
Synlett 2008, 3242; p) P. Gao, C. Wang, Y. Wu, Z. Zhou, C. Tang,
Eur. J. Org. Chem. 2008, 4563; q) P. J. Chua, G. Zhong, Chem.
Commun. 2009, 779; r) J. Luo, L. Xu, R. A. S. Hay, Y. Lu, Org. Lett.
2009, 11, 437; s) D. Almas¸i, D. A. Alonso, E. Gomez-Bengoa, C.
Najera, J. Org. Chem. 2009, 74, 6163; t) H. Li, S. Zhang, C. Yu, X.
Song, W. Wang, Chem. Commun. 2009, 2136; u) H. Li, L. Zu, H.
Xie, W. Wang, Synthesis 2009, 1525; v) X. Han, J. Luo, C. Liu, Y.
Lu, Chem. Commun. 2009, 2044; w) Y. Oh, S. M. Kim, D. Y. Kim,
Tetrahedron Lett. 2009, 50, 4674; x) L. Zhang, M.-M. Lee, S.-M. Lee,
J. Lee, M. Cheng, B.-S. Jeong, H.-J. Park, S.-S. Jew, Adv. Synth.
[a]2D0 =+3.0 (c=0.7m, CHCl3); 1H NMR (300 MHz, CDCl3): d=4.68 (m,
2H), 4.24 (q, J=7.1 Hz, 4H), 3.88 (m, 1H), 3.69 (d, J=7.9 Hz, 1H), 2.10
(m, 2H), 1.47 (m, 2H), 1.28 (t, J=7.1 Hz, 6H), 0.94 ppm (t, J=7.4 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=166.9, 166.7, 86.3, 74.2, 62.1, 61.5,
53.5, 41.7, 30.3, 21.8, 20.5, 14.0, 13.2 ppm; HRMS (EI): m/z: calcd for
C14H21NO6: 299.1369 [M+1]+; found: 299.1319; HPLC (Chiralcel OJ-H,
isopropanol/hexane=0:100, flow rate=0.65 mLminÀ1
major =44.0 min, tminor (not found).
,
l=210 nm):
t
(R)-Diethyl 2-(1-nitro-6-phenylhex-3-yn-2-yl)malonate (4g):
1
[a]2D0 =+8.8 (c=0.3m, CHCl3); H NMR (300 MHz, CDCl3): d=7.24–7.08
(m, 5H), 4.58 (m, 2H), 4.15 (m, 4H), 3.81 (m, 1H), 3.60 (d, J=7.7 Hz,
1H), 2.68 (t, J=7.4 Hz, 2H), 2.34 (m, 2H), 1.20 (m, 6H), 0.86 ppm (m,
3H); 13C NMR (75 MHz, CDCl3): d=166.8, 166.6, 140.3, 128.4, 126.3,
85.5, 76.4, 75.0, 62.1, 53.4, 34.8, 30.2, 20.7, 14.0 ppm; HRMS (EI): m/z:
calcd for C19H23NO6: 361.1525 [M]+; found: 361.1549; HPLC (Chiralcel
OJ-H, isopropanol/hexane=10:90, flow rate=1.0 mLminÀ1, l=254 nm):
tmajor =26.6 min, tminor =37.9 min.
(R)-Dimethyl 2-(1-nitro-6-phenylhex-3-yn-2-yl)malonate (4h):
1
[a]2D0 =+8.6 (c=0.2m, CHCl3); H NMR (300 MHz, CDCl3): d=7.37–7.28
(m, 5H), 4.81 (m, 2H), 4.18 (m, 1H), 3.89 (m, 1H), 3.81 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=167.2, 167.0, 131.8, 128.8, 128.3, 121.8,
85.8, 83.0, 76.0, 53.1, 53.0, 30.8 ppm; HRMS (EI): m/z: calcd for
C17H19NO6: 305.0899 [M+1]+; found: 305.0872; HPLC (Chiralpak AD-
H, isopropanol/hexane=5:95, flow rate=1.0 mLminÀ1
major =20.8 min, tminor =24.7 min.
, l=254 nm):
t
(S)-Dimethyl 2-methyl-2-(1-nitro-4-phenylbut-3-yn-2-yl)malonate (4j):
[a]2D0 =À31.6 (c=0.6m, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.37–
7.28 (m, 5H), 4.88 (m, 1H), 4.67 (m, 1H), 4.29–4.22 (m, 5H), 1.65 (s,
3H), 1.28 ppm (t, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=169.6,
169.4, 131.8, 128.7, 128.2, 122.0, 85.9, 83.4, 62.3, 62.1, 55.9, 36.6, 19.1,
14.0 ppm; HRMS (EI): m/z: calcd for C17H19NO6: 347.1369 [M+1]+;
found: 347.1367; HPLC (Chiralcel OJ-H, isopropanol/hexane=5:95, flow
rate=0.8 mLminÀ1, l=254 nm): tmajor =18.0 min, tminor =24.4 min.
(R)-3-(1-Nitro-4-phenylbut-3-yn-2-yl)pentane-2,4-dione (4k):
[a]2D0 =+107.7 (c=0.9m, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.37–
7.28 (m, 5H), 4.62 (m, 1H), 4.54 (m, 1H), 4.25–4.22 (m, 2H), 2.36 ppm
(m, 6H); 13C NMR (75 MHz, CDCl3): d=200.9, 200.5, 131.8, 128.9, 128.4,
121.6, 86.4, 83.4, 76.3, 68.2, 30.7, 30.0 ppm; HRMS (EI): m/z: calcd for
C17H19NO6: 273.1001 [M+1]+; found: 273.1002; HPLC (Chiralcel OJ-H,
224
www.chemasianj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 220 – 225

Malonates to Nitroenynes
Catal. 2009, 351, 3063; y) Z. Zhang, X. Dong, D. Chen, C. Wang,
Chem. Eur. J. 2008, 14, 8780; z) P. S. Hynes, P. A. Stupple, D. J.
Dixon, Org. Lett. 2008, 10, 1389; aa) B. K. Kwon, S. M. Kim, D. Y.
Kim, J. Fluorine Chem. 2009, 130, 759; ab) P. Elsner, H. Jiang, J. B.
Nielsen, F. Pasi, K. A. Jørgensen, Chem. Commun. 2008, 5827; ac) F.
Peng, Z. Shao, B. Fan, H. Song, G. Li, H. Zhang, J. Org. Chem.
2008, 73, 5202; ad) X. Pu, P. Li, F. Peng, X. Li, H. Zhang, Z. Shao,
Eur. J. Org. Chem. 2009, 4622; ae) X. Pu, F. Peng, H. Zhang, Z.
Shao, Tetrahedron 2010, 66, 3655.
[11] E. Fillion, A. K. Zorzitto, J. Am. Chem. Soc. 2009, 131, 14608.
[12] S. Cui, S. D. Walker, J. C. S. Woo, C. J. Borths, H. Mukherjee, M. J.
Chen, M. M. Faul, J. Am. Chem. Soc. 2010, 132, 436.
[13] M. Yamashita, K. Yamada, K. Tomioka, Org. Lett. 2005, 7, 2369.
[14] For a Highlight on metal-mediated alkyne synthesis, see: a) Z. Shao,
F. Peng, Angew. Chem. Int. Ed. DOI:10.1002/anie.201003081. For se-
lected examples, see: b) B. Fan, X. Li, F. Peng, H. Zhang, A. S. C.
Chan, Z. Shao, Org. Lett. 2010, 12, 304; c) Z. Shao, J. Wang, K.
Ding, A. S. C. Chan, Adv. Synth. Catal. 2007, 349, 2375; d) J. Wang,
Z. Shao, K. Ding, W. Y. Yu, A. S. C. Chan, Adv. Synth. Catal. 2009,
351, 1250; e) F. Peng, Z. Shao, A. S. C. Chan, Tetrahedron: Asymme-
try 2010, 21, 465; f) Z. Shao, X. Pu, X. Li, B. Fan, A. S. C. Chan, Tet-
rahedron: Asymmetry 2009, 20, 225.
[6] For recent selected examples of metal-catalyzed asymmetric conju-
gate addition of 1,3-dicarbonyl compounds to nitroolefins, see: a) Q.
Zhu, H. Huang, D. Shi, Z. Shen, C. Xia, Org. Lett. 2009, 11, 4536;
b) D. A. Evans, D. Seidel, J. Am. Chem. Soc. 2005, 127, 9958;
c) D. A. Evans, S. Mito, D. Seidel, J. Am. Chem. Soc. 2007, 129,
11583; d) M. Watanabe, A. Ikagawa, H. Wang, K. Murata, T. Ikar-
iya, J. Am. Chem. Soc. 2004, 126, 11148; e) P. J. Nichols, J. A. De-
Mattei, B. R. Barnet, N. A. LeFur, T.-H. Chuang, A. D. Piscopio, K.
Koch, Org. Lett. 2006, 8, 1495; f) D. M. Barnes, J. Ji, M. G. Fickes,
M. A. Fitzgerald, S. A. King, H. E. Morton, F. A. Plagge, M. Preskill,
S. H. Wagaw, S. J. Wittenberger, J. Zhang, J. Am. Chem. Soc. 2002,
124, 13097; g) J. Ji, D. M. Barnes, J. Zhang, S. A. King, S. J. Witten-
berger, H. E. Morton, J. Am. Chem. Soc. 1999, 121, 10215.
[7] a) S. Belot, A. Massaro, A. Tenti, A. Mordini, A. Alexakis, Org.
Lett. 2008, 10, 4557; b) S. Belot, K. Vogt, C. Besnard, N. Krause, A.
Alexakis, Angew. Chem. 2009, 121, 9085; Angew. Chem. Int. Ed.
2009, 48, 8923; c) S. Belot, A. Quintard, N. Krause, A. Alexakis,
Adv. Synth. Catal. 2010, 352, 667; d) H. Ma, K. Liu, F. Zhang, C.
Zhu, J. Nie, J. Ma, J. Org. Chem. 2010, 75, 1402; e) B. M. Trost, S.
Hisaindee, Org. Lett. 2006, 8, 6003; f) M. Tissot, D. Muller, S. Belot,
A. Alexakis, Org. Lett. 2010, 12, 2770.
[15] For selected examples, see: a) F. Peng, Z. Shao, X. Pu, H. Zhang,
Adv. Synth. Catal. 2008, 350, 2199; b) Y. Wang, F. Peng, H. Zhang,
Z. Shao, Synlett 2009, 3287; see also references [5ac–ae].
[16] For selected recent reviews on organocatalysis, see: a) S. Bertelsen,
K. A. Jørgensen, Chem. Soc. Rev. 2009, 38, 2178; b) A. Dondoni, A.
Massi, Angew. Chem. 2008, 120, 4716; Angew. Chem. Int. Ed. 2008,
47, 4638; c) D. W. C. MacMillan, Nature 2008, 455, 304; d) P. I.
Dalko, Enantioselective Organocatalysis: Reactions and Experimen-
tal Procedures, Wiley-VCH, Weinheim, 2007; e) M. J. Gaunt,
C. C. C. Johansson, A. McNally, N. C. Vo, Drug Discovery Today
2007, 12, 8; f) H. Pellissier, Tetrahedron 2007, 63, 9267; g) B. List,
J. W. Yang, Science 2006, 313, 1584; h) F. Peng, Z. Shao, J. Mol.
Catal. A 2008, 285, 1.
[17] For selected recent reviews, see: a) S. J. Connon, Chem. Commun.
2008, 2499; b) X. Yu, W. Wang, Chem. Asian J. 2008, 3, 516; c) A. G.
Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713; d) Y. Takemoto,
H. Miyabe, Chimia 2007, 61, 269; e) P. R. Schreiner, Chem. Soc. Rev.
2003, 32, 289; f) Z. Zhang, P. R. Schreiner, Chem. Soc. Rev. 2009, 38,
1187; g) S. Tian, Y. Chen, J. Hang, L. Tang, P. McDaid, L. Deng,
Acc. Chem. Res. 2004, 37, 621; h) S. J. Connon, Synlett 2009, 354.
[18] For the seminal work on cinchona alkaloid-based thiourea organoca-
talysts, see: a) B. Li, L. Jiang, M. Liu, Y. Chen, L. Ding, Y. Wu, Syn-
lett 2005, 603; b) B. Vakulya, S. Varga, A. Csampai, T. Soos, Org.
Lett. 2005, 7, 1967; see also references [15e] and [15g].
[8] For reviews on the regioselectivity of conjugate addition reactions
of extended Michael acceptors, see: a) N. Krause, S. Thorand, Inorg.
Chim. Acta 1999, 296, 1; b) A. G. Csꢂkꢄ, G. de la Herrꢂn, M. C.
Murcia, Chem. Soc. Rev. 2010, 39, 4080.
[9] a) T. Shimada, H. Ueno, K. Tsutsumi, K. Aoyagi, T. Manabe, S.
Sasaki, S. Katoh, Int. Appl. PCT, WO 2009054479, 2009; b) J.
Houze, J. Liu, Z. Ma, J. C. Medina, M. J. Schmitt, R. Sharma, Y.
Sun, Y. Wang, L. Zhu, US Patent 7,465,804, 2008; c) S. P. Brown, P.
Dransfield, Z. Fu, J. Houze, X. Jiao, T. J. Kohn, V. Pattaropong, M.
Vimolratana, M. J. Schmitt, Int. Appl. PCT, WO 2008130514, 2008;
d) J. N. Xiang, J. M. Karpinski, S. B. , IV. Christensen, Int. Appl.
PCT, WO 0009116, 2000; e) S. B. , IV. Christensen, J. M. Karpinski,
J. S. Frazee, Int. Appl. PCT, WO 9703945, 1997; f) S. B. Bharate,
K. V. S. Nemmani, R. A. Vishwakarma, Expert Opin. Ther. Pat.
2009, 19, 237, and references therein.
[19] For selected examples, see: a) C. A. Sperger, A. Fiksdahl, J. Org.
Chem. 2010, 75, 4542; b) C. Gonzꢂlez-Rodriguez, J. A. Varela, L.
Castedo, C. Saꢂ, J. Am. Chem. Soc. 2007, 129, 12916; c) L. Yao, M.
Shi, Chem. Eur. J. 2009, 15, 3875; d) Y. Yamamoto, H. Takagishi, K.
Itoh, J. Am. Chem. Soc. 2002, 124, 28.
[20] A. Hamza, G. Schubert, I. Papai, J. Am. Chem. Soc. 2006, 128,
13151.
[10] T. F. Knçpfel, P. Zarotti, T. Ichikawa, E. M. Carreira, J. Am. Chem.
Soc. 2005, 127, 9682.
Received: August 12, 2010
Published online: November 12, 2010
Chem. Asian J. 2011, 6, 220 – 225
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
225