Chiral phosphoric acid catalyzed diastereo- and enantioselective 1,4- conjugate addition of β-ketoesters to nitroolefins

Article abstract of DOI:10.2174/157017810791112360

Chiral phosphoric acid as organocatalyst for the diastereo- and enantioselectivity 1,4-conjugate addition of a variety of P-ketoesters to nitroolefins was firstly developed, providing the corresponding adducts in high yield (up to 97%) with moderate diast

Full text of DOI:10.2174/157017810791112360

Letters in Organic Chemistry, 2010, 7, 219-225
219
Chiral Phosphoric Acid Catalyzed Diastereo- and Enantioselective 1,4-
Conjugate Addition of ꢀ-Ketoesters to Nitroolefins
Hui Zhanga,b, Lin-Feng Cuna, Xiao-Mei Zhanga and Wei-Cheng Yuan*,a
aKey Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
bGraduate School of Chinese Academy of Sciences, Beijing, 100049, P. R. of China
Received September 18, 2009: Revised January 08, 2010: Accepted January 14, 2010
Abstract: Chiral phosphoric acid as organocatalyst for the diastereo- and enantioselectivity 1,4-conjugate addition of a
variety of ꢀ-ketoesters to nitroolefins was firstly developed, providing the corresponding adducts in high yield (up to
97%) with moderate diastereoselectivities (up to 2.6:1 dr) and enantioselectivities (up to 58% ee).
Keywords: Chiral phosphoric acid, organocatalysis, asymmetric catalysis, 1,4-conjugate addition, ꢀ-ketoesters, nitroolefins.
INTRODUCTION
asymmetric reactions [6, 7]. In general, the chiral phosphoric
acid acts as a bifunctional catalyst, that is the acidic proton
as acid and the P=O moiety of the catalyst as a base [6].
Moreover, among the various asymmetric reactions
catalyzed by chiral phosphoric acids, most of them include
imine or iminium ion as electrophiles, whereas few of them
include some other electrophiles [8]. More recently,
Akiyama and co-workers reported the Friedel-Crafts
alkylation of indoles with nitroolefins catalyzed by chiral
phosphoric acid, and firstly disclosed the nitroolefins
The asymmetric 1,4-conjugate addition of ꢀ-ketoesters to
nitroolefins has proved to be one of the most powerful
carbon-carbon-forming strategies for the preparation of
valuable nitrogen-contained compounds in organic synthesis
[1]. The nitro functionality in the adducts can easily be
further transformed to amine [2a-e], nitrile oxide [2f], ketone
or carboxylic acid [2g] and hydrogen [2h]. Due to the
important synthetic potential, considerable efforts have been
devoted in recent years to develope chiral metal catalysts [3]
Akiyama's work (Ref. 9)
R1
Chiral phosphoric acid
NO2
NO2
+
R1
(1)
*
N
H
HN
O
O
This work
O
O
*
*
R2
OR3
NO2
Chiral phosphoric acid
(2)
NO2
+
R1
R2
OR3
R1
Scheme 1.
and chiral organocatalysts [4] for this class of 1,4-conjugate
addition reaction [5]. However, to the best of our knowledge,
despite all the significant progress made in this area, there is
no report about employing a chiral protonic acid as catalyst
for the asymmetric 1,4-conjugate addition of ꢀ-ketoesters to
nitroolefins.
activation catalyzed by chiral phosphoric acids (Scheme 1,
(1)) [9]. Prompted by this study, we recently found that
chiral phosphoric acids were efficient catalysts for the
asymmetric 1,4-conjugate addition of ꢀ-ketoesters to
nitroolefins (Scheme 1, (2)). It should be note that this
reaction is only another example about the nitroolefins
activation catalyzed by chiral phosphoric acids [10], except
Akiyama’s report [9]. Herein, we hope to report our
preliminary results.
The chiral phosphoric acids, derived from chiral BINOL
(BINOL
=
2,2'-dihydroxy-1,1'-binaphthyl), have been
developed as a class of versatile chiral protonic acids
catalysts and extensively applied to a variety of catalytic
RESULTS AND DISCUSSION
By using ethyl 3-oxo-3-phenylpropanoate (3a) and trans-
phenyl nitroolefin (2a) as the model compounds, a series of
chiral phosphoric acid catalysts derived from (R)-BINOL
*Address correspondence to this author at the Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu City, Sichuan Province,
610041, P. R. of China; Tel: +86-028-85257883; Fax: +86-028-85229250;
E-mail: yuanwc@cioc.ac.cn
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

220 Letters in Organic Chemistry, 2010, Vol. 7, No. 3
Zhang et al.
Ar
O
Ar
The product could be obtained in 94% yield using CH3OH as
a solvent, but the product was racemic (Table 2, entry 4).
With toluene as a solvent, further examining to molecular
sieves, resulted in MS 5 Å provided better results than MS 3
Å and 4 Å (Table 2, entries 7 vs 1 and 6) [11]. Interestingly,
decreasing the catalyst loading from 20 mol % to 5 mol %
with MS 5 Å as additive, the enantioselectivities of both
isomers were improved to 41% and 45%, and the chemical
yield was slightly decreased to 87% from 92% (Table 2,
entries 7 and 8). And then, carrying out the reaction with 5
mol % catalyst and MS 3 Å as additive, the reaction
provided 54% and 56% ee for the two isomers in 91%
chemical yield (Table 2, entry 9). Encouraged by these
results, examining the reaction by further decreasing the
catalyst loading to 2.5 mol %, the reaction also completed in
72 h and provided the desired product in 83% isolated yield,
however, the enantioselectivities of two diastereoisomers
were both slightly decreased (Table 2, entry 10).
O
O
O
P
P
OH
OH
O
O
Ar
Ar
1a-e
1f-h
1a, Ar = Ph
1f, Ar = 2,6-(CH3)2C6H3
1g, Ar = 4-CF3-C6H4
1h, Ar = ꢀ-naphthyl
1b, Ar =ꢀ-naphthyl
1c, Ar = 9-phenanthrenyl
1d, Ar = 2,4,6-(iPr)3C6H2
1e, Ar = 3,5-(F3C)2C6H3
Fig. (1). Catalysts Screened for the Michael Reactions.
and (R)-H8-BINOL (1a-h, Fig. 1) was screened at room
temperature in toluene, and the results were summarized in
Table 1. It was found that this Michael addition reaction
proceeded smoothly in 20 mol % catalyst loading with
molecular sieves (MS) 3 Å as additive and provided the
corresponding adducts in good yields with poor
diastereoselectivities and enantioselectivities (Table 1,
entries 8 vs 1-7) [11]. In general, among the catalysts
examined, catalyst 1h was slightly superior to other catalysts
(1a-g) in the enantioselectivity and yield (Table 1, entries 8
vs 1-7).
o
Unfortunately, try to decrease the temperature to 0 C led to
the reaction very sluggish, moreover, the corresponding
adduct was obtained with only trace amount even though
prolonging the reaction time to 7 days (Table 2, entry 11).
With the optimal reaction conditions in hand, we
determined the scope and limitations of this 1,4-conjugate
addition reactions. As shown in Table 3, for the nitroolefins
having electron-donating phenyl group 2b, electron-
withdrawing phenyl group 2c-g and heteroaromatic
substituent 2h, the chiral addition products 4b-h were well
formed in good to excellent chemical yields with moderate
stereoselectivities (Table 3, entries 2-8). Additionally, we
also found that the ꢀ-ketoesters 3b-d bearing electron-
withdrawing substituents in the phenyl group reacted
smoothly with 2a, giving the desired products 4i-k in range
from 90% to 96% yield with moderate stereoselectivities
With the best chiral catalyst 1h being identified, we next
carried out the Michael reaction of 2a with 3a for screening
the optimal reaction conditions. As shown in Table 2, the
screening of solvent with MS 3 Å as additive revealed that
the reaction proceeded smoothly in several solvent, and
toluene was the most favorable solvent (Table 2, entries 1-5).
Table 1. Catalyst Screeninga
O
O
O
O
catalyst
(20 mol %)
Ph
OEt
NO2
OEt
+
NO2
48 h, r.t.
3Å, toluene
3a
2a
4a
Entry
Catalytst
drb
ee(%)c
Yield(%)d
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1.4:1
1.6:1
1.5:1
1.5:1
1.5:1
1.4:1
1.5:1
1.5:1
7/2
14/15
8/6
71
81
87
82
86
67
84
91
16/13
5/4
2/1
1g
1h
5/5
24/23
aAll reactions were carried out with 2a (0.3 mmol) and 3a (0.1 mmol) in 0.5 mL toluene with molecular sieves (MS) 3 Å 10 mg.
bThe ratio of diastereoselectivities were determined by HPLC analysis.
cEnantioselectivity in ꢀ-position to nitro group for major (minor) diastereomer, the ee values were determined by HPLC analysis [3m].
dYields of isolated product.

Chiral Phosphoric Acid Catalyzed Diastereo
Letters in Organic Chemistry, 2010, Vol. 7, No. 3
221
Table 2. Optimizing the Reaction Conditions for the 1,4-Conjugate Addition of 3a to 2a Catalyzed by Chiral Phosphoric Acid 1ha
O
O
O
O
1h (x mol %)
additive
Ph
OEt
NO2
OEt
NO2
+
solvent
temperature (T)
3a
2a
4a
Entry
Solvent
1h(x mol %)
T(oC)
Additive
drb
ee(%)c
Yield(%)d
1
2
toluene
Et2O
20
20
20
20
20
20
20
5
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
3 Å
3 Å
3 Å
3 Å
3 Å
4 Å
5 Å
5 Å
3 Å
3 Å
3 Å
1.5:1
1.3:1
1.3:1
1.4:1
1.4:1
1.2:1
1.6:1
1.5:1
1.5:1
1.6:1
--
24/23
14/16
13/11
2/1
91
78
3
DCE
81
4
CH3OH
xylene
toluene
toluene
toluene
toluene
toluene
toluene
94
5
20/19
6/3
72
6
20
7
33/33
41/45
54/56
52/51
--
92
8
87
9
5
91
10
2.5
83
11
5
trace
aAll reactions were carried out with 2a (0 .3 mmol) and 3a (0.1 mmol) in 0.5 mL solvent with MS 10 mg for 72 h. DCE = 1,2-dichloroethane.
bThe ratio of diastereoselectivities were determined by HPLC analysis.
cEnantioselectivity in ꢀ-position to nitro group for major (minor) diastereomer, the ee values were determined by HPLC analysis [3m].
dYields of isolated product.
Table 3. Chiral Phosphoric Acid 1h Catalyzed 1,4-Conjugate Addition Reactions of ꢀ-Ketoesters to Nitroolefinsa
O
O
O
O
(5 mol %)
1h
NO2
+
Ar2
OEt
Ar1
Ar2
OEt
NO2
MS 3 Å, rt
Toluene
Ar1
3a-d
4a-k
2a-h
Entry
Ar1
Ar2
Products 4
drb
ee(%)c
Yield(%)d
1
2
Ph (2a)
p-Me-Ph (2b)
p-Cl-Ph (2c)
p-Br-Ph (2d)
m-Br-Ph (2e)
m-F3C-Ph (2f)
m-NO2-Ph (2g)
2-Furyl (2h)
Ph (2a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
4a
4b
4c
4d
4e
4f
1.4:1
2.0:1
1.3:1
1.2:1
1.5:1
1.4:1
1.9:1
1.3:1
2.6:1
2.0:1
1.6:1
54/56
34/34
58/56
56/56
53/55
51/53
49/37
31/28
55/45
45/27
55/40
91
91
95
91
97
97
89
84
96
93
90
3
4
5
6
7
4g
4h
4i
8
9
p-F-Ph (3b)
p-Cl-Ph (3c)
p-Br-Ph (3d)
10
11
Ph (2a)
4j
Ph (2a)
4k
aReactions were carried out with 2 (0.6 mmol), 3 (0.2 mmol), MS 3 Å 10 mg and 5 mol % catalyst 1h in 1.0 mL toluene for 72 h at room temperature.
bThe ratio of diastereoselectivities were determined by HPLC analysis.
cEnantioselectivity in ꢀ-position to nitro group for major (minor) diastereomer, the ee values were determined by HPLC analysis [3m].
dYields of isolated product.

222 Letters in Organic Chemistry, 2010, Vol. 7, No. 3
Zhang et al.
O
O
P
O
OH
O
O
OH
O
1h
Ar2
OEt
Ar2
OEt
3
O
O
NO2
Ar1
Ar2
OEt
2
NO2
Ar1
4
Ar2
O
O
OEt
H
O
O
O
O
P
N
O
O
Ar1
H
Ts-1
Scheme 2. Proposed catalytic cycle for the asymmetric 1,4-conjugated addition reaction of ꢀ-ketoesters to nitroolefins catalyzed by chiral
phosphoric acid.
(Table 3, entries 9-11). Generally, to this developed
methodology, moderate diastereo- and enantioselectivities in
very good chemical yields were observed for the addition of
different ꢀ-ketoesters to nitroolefins with 5 mol % chiral
phosphoric acid organocatalyst 1h (Table 3).
internal standard. Optical rotations were measured on a
Perkin-Elmer 241 Polarimeter. Melting points were recorded
on a Buchi Melting Point B-545 and this instrument was
without correction.
General Procedure for Chiral Phosphoric Acid 1h
Catalyzed
Asymmetric
1,4-Conjugated
Addition
This chiral phosphoric acid catalyzed asymmetric 1,4-
conjugated addition reaction of ꢀ-ketoesters to nitroolefins
for the synthesis of compound 4 can be explained by a
proposed mechanism cycle as outlined in Scheme 2. We
assume that the chiral phosphoric acid serves as bifunctional
catalysts in this reaction: i) the phosphoric acid activates the
nitroolefin 2 with the –OH group of acid 1h, and ii) the
phosphoryl oxygen atom of P=O acting as base forms a
hydrogen bond with the hydrogen atom of the enolate of ꢀ-
ketoesters 3. As a result, the transition state TS-1 is formed.
This rigid conformation likely contributes to the
stereoselectivity of this process. Subsequently, attack of the
ꢀ-position of nitroolefins by the ꢀ-ketoesters affords the
desired Michael addition product and releases the chiral
catalyst 1h (Scheme 2).
Reactions of ꢀ-Ketoesters to Nitroolefins [12]
A
mixture of activated powder MS 3Å (10mg),
nitroolefins 2 (0.6 mmol), catalyst 1h (6.1 mg, 0.01 mmol)
and ꢀ-ketoesters 3 (0.02 mmol) in 1 mL toluene was added
to an ordinary vial with a magnetic stirring bar at room
temperature. The stirring was maintained at room
temperature for 72 h and the crude reaction mixture was
directly charged onto silica gel and purified by flash
chromatography (petroleum ether/ethyl acetate, 10:1 to 5:1)
to afford products 4. The diastereo- and enantioselectivities
were determined by HPLC using a Chiracel AD-H column.
CONCLUSION
In summary, we have developed a chiral phosphoric
acids catalyzed asymmetric 1,4-conjugated addition reaction
of ꢀ-ketoesters to nitroolefins for the synthesis of
nitroalkanes compounds with molecular sieves 3 Å as
additive. The corresponding valuable adducts have been
isolated in high yields with moderate stereoselectivities [12].
This approach is the first example of Michael type reaction
of ꢀ-ketoester to nitroolefins catalyzed by a chiral protonic
acid organocatalyst. The further investigation into the
application of chiral phosphoric acids in catalytic
asymmetric reaction is currently underway in our laboratory.
EXPERIMENTAL SECTION
General
Flash column chromatography was performed using
silica gel. For thin-layer chromatography (TLC), silica gel
plates (HSGF-254) were used and compounds were
visualized by irradiation with UV light. All reactions were
conducted in a closed system with an atmosphere of air and
1
were monitored by TLC. H and 13C NMR spectra were
performed on a Brucker-300 MHz spectrometer for products
dissolved by CDCl3 with tetramethylsilane (TMS) as an

Chiral Phosphoric Acid Catalyzed Diastereo
Letters in Organic Chemistry, 2010, Vol. 7, No. 3
223
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ACKNOWLEDGEMENT
We are grateful for financial support from the National
Natural Science Foundation of China (No. 20802074 and
No. 20772122).
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Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Chiral brønsted acid
catalyzed enantioselective hydrophosphonylation of imines:
asymmetric synthesis of ꢀ-amino phosphonates. Org. Lett., 2005, 7,
2583. (d) Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K.
Enantioselective mannich-type reaction catalyzed by
a chiral
brønsted acid derived from TADDOL. Adv. Synth. Catal., 2005,
347, 1523. (e) Rowland, G. B.; Zhang, H.; Rowland, E. B.;
Chennamadhavuni, S.; Wang, Y. Antilla, J. C. Brønsted acid-
catalyzed imine amidation. J. Am. Chem. Soc., 2005, 127, 15696.
(f) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D.W. C.
Enantioselective organocatalytic reductive amination. J. Am. Chem.
Soc., 2006, 128, 84. (g) Seayad, J.; Seayad, A. M.; List, B.
Catalytic asymmetric pictet-spengler reaction. J. Am. Chem. Soc.,
2006, 128, 1086. (h) Rueping, M.; Sugiono, E.; Azap, C. A highly
enantioselective brønsted acid catalyst for the strecker reaction.
Angew. Chem. Int. Ed. Engl., 2006, 45, 2617. (i) Akiyama, T.;
Morita, H.; Fuchibe, K. chiral brønsted acid-catalyzed inverse
electron-demand Aza Diels-Alder reaction. J. Am. Chem. Soc.,
2006, 128, 13070. (j) Chen, X.-H.; Xu, X.-Y.; Liu, H.; Cun, L.-F.;
Gong, L.-Z. Highly enantioselective organocatalytic biginelli
reaction. J. Am. Chem. Soc., 2006, 128, 14802. (k) Itoh, J.;

224 Letters in Organic Chemistry, 2010, Vol. 7, No. 3
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Akiyama, T.; Fuchibe, K. Chiral brønsted acid catalyzed
enantioselective Aza-Diels-Alder reaction of brassard's diene with
imines. Angew. Chem. Int. Ed., 2006, 45, 4796. (l) Rueping, M.;
Azap, C. Cooperative coexistence: effective interplay of two
brønsted acids in the asymmetric synthesis of isoquinuclidines.
Angew. Chem. Int.ꢀ Ed., 2006, 45, 7832. (m) Li, G.; Liang, Y.;
Antilla, J. C. A Vaulted biaryl phosphoric acid-catalyzed reduction
of ꢀ-imino esters: the highly enantioselective preparation of ꢀ-
amino esters. J. Am. Chem. Soc., 2007, 129, 5830. (n) Yamanaka,
M.; Itoh, J.; Fuchibe, K.; Akiyama, T. Chiral brønsted acid
catalyzed enantioselective mannich-type reaction. J. Am. Chem.
Soc., 2007, 129, 6756. (o) Zhou, J.; List, B. Organocatalytic
asymmetric reaction cascade to substituted cyclohexylamines. J.
Am. Chem. Soc., 2007, 129, 7498. (p) Terada, M.; Machioka, K.;
Sorimachi, K. Chiral brønsted acid-catalyzed tandem aza-ene type
reaction/cyclization cascade for a one-pot entry to enantioenriched
piperidines. J. Am. Chem. Soc., 2007, 129, 10336. (q) Rueping, M.;
Antonchick, A. P.; Brinkmann, C. Dual catalysis: a combined
enantioselective brønsted acid and metal-catalyzed reaction - metal
catalysis with chiral counterions. Angew. Chem. Int. Ed., 2007, 46,
6903. (r) Akiyama, T.; Honma, Y.; Itoh, J.; Fuchibe, K.
Vinylogous mannich-type reaction catalyzed by an iodine-
substituted chiral phosphoric acid. Adv. Synth. Catal., 2008, 350,
399.
For selected examples, see: (a) Nakashima, D.; Yamamoto, H.
Design of chiral N-triflyl phosphoramide as a strong chiral brønsted
acid and its application to asymmetric DielsꢁAlder reaction. J. Am.
Chem. Soc., 2006, 128, 9626. (b) Rueping, M.; Ieawsuwan, W.;
Antonchick, A. P.; Nachtsheim, B. J. Chiral brønsted acids in the
catalytic asymmetric nazarov cyclization-the first enantioselective
organocatalytic electrocyclic reaction. Angew. Chem. Int. Ed.,
2007, 46, 2097. (c) Rowland, E. B.; Rowland, G. B.; Rivera-Otero,
E.; Antilla, J. C. Brønsted acid-catalyzed desymmetrization of
meso-aziridines. J. Am. Chem. Soc., 2007, 129, 12084. (d) Rueping,
M.; Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Asymmetric
brønsted acid catalysis: enantioselective nucleophilic substitutions
and 1,4-additions. Angew. Chem. Int. Ed., 2008, 47, 593. (e) Tang,
H.-Y.; Lu, A.-D.; Zhou, Z.-H.; Zhao, G.-F.; He, L.-N.; Tang, C.-C.
Chiral phosphoric acid catalyzed asymmetric friedel-crafts
alkylation of indoles with simple ꢀ,ꢁ-unsaturated aromatic ketones.
Eur. J. Org. Chem., 2008, 1406. (f) Jiao, P.; Nakashima, D.;
Yamamoto, H. Enantioselective 1,3-dipolar cycloaddition of
nitrones with ethyl vinyl ether: the difference between brønsted and
lewis acid catalysis. Angew. Chem. Int. Ed., 2008, 47, 2411.
Itoh, J.; Fuchibe, K.; Akiyama, T. Chiral phosphoric acid catalyzed
enantioselective friedel-crafts alkylation of indoles with
nitroalkenes: cooperative effect of 3 å molecular sieves. Angew.
Chem. Int. Ed., 2008, 47, 4016.
Ethyl 2-benzoyl-4-nitro-3-p-tolylbutanoate (4b): White solid,
25
yield 91%, ratio of diastereomers 2.0:1, Mp 126.9-128.3 oC, [ꢀ]D
-
0.76 (c 0.39, CHCl3). IR (KBr): 3056, 2981, 2922, 1734, 1681,
1596, 1580, 1548, 1516, 1450, 1381, 1262, 1158, 1117, 1014, 970,
1
824, 681, 560 cm-1; H NMR (300 MHz, CDCl3): major isomer, ꢂ
8.06 (d, J = 7.2 Hz, 2H), 7.85-7.42 (m, 4H), 7.16-7.13 (m, 1H),
7.13-7.10 (m, 2H), 4.93-4.90 (m, 1H), 4.77-4.73 (m, 2H), 4.43-4.40
(m, 1H), 3.86 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 0.89 (t, J = 7.2 Hz,
3H); minor isomer, ꢂ 7.87 (d, J = 7.2 Hz, 2H), 7.85-7.42 (m, 1H),
7.16-7.13 (m, 2H), 7.13-7.10 (m, 2H), 7.07-7.00 (m, 2H), 4.93-4.90
(m, 3H), 4.43-4.40 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.23 (s, 3H),
1.17 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): ꢂ 192.9,
192.7, 167.7, 167.0, 138.0, 137.8, 136.0, 135.9, 134.4, 133.7,
133.6, 133.1, 129.6, 129.5, 128.9, 128.8, 128.7, 128.6, 128.1,
127.8, 78.1, 62.1, 61.9, 57.1, 56.5, 42.8, 42.7, 21.0, 20.9, 13.9,
13.6. The ee was determined by HPLC with a Chiralcel AD-H
column (85:15 hexanes: isopropanol, 1 mL/min, 254 nm); First
(major) diastereomer: tr (major) = 8.21 min, tr (minor) = 13.93 min;
34% ee; Second (minor) diastereomer: tr (major) = 11.51 min, tr
(minor) = 17.17 min, 34% ee.
Ethyl
2-benzoyl-3-(4-chlorophenyl)-4-nitrobutanoate
(4c):
25
Colorless liquid, yield 95%, ratio of diastereomers 1.3:1, [ꢀ]D
-
1.30 (c 0.38, CHCl3). IR (neat): 3070, 2983, 2923, 1736, 1686,
1598, 1580, 1556, 1512, 1448, 1379, 1228, 1163, 1104, 1016, 979,
881, 837, 732, 560 cm-1; 1H NMR (300 MHz, CDCl3): major
isomer, ꢂ 8.04 (dd, J = 8.4, 1.2 Hz, 2H), 7.62-7.28 (m, 5H), 7.19 (d,
J = 8.4 Hz, 2H), 4.91-4.87 (m, 1H), 4.77-4.72 (m, 2H), 4.50-4.44
(m, 1H), 3.88 (q, J = 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H);minor
isomer, ꢂ 7.86 (dd, J = 8.4, 1.2 Hz, 2H), 7.62-7.42 (m, 3H), 7.20-
7.16 (m, 2H), 7.10 (d, J = 8.4 Hz, 2H), 4.91-4.87 (m, 3H), 4.50-
[8]
4.44 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H); 13
C
NMR (75 MHz, CDCl3): ꢂ 192.5, 167.5, 166.8, 135.9, 135.7, 134.3,
134.0, 132.5, 132.0, 130.1, 130.0, 129.8, 129.7, 129.0, 128.9,
128.8, 128.7, 128.5, 78.0, 62.3, 62.0, 57.0, 56.3, 42.4, 13.9, 13.6.
The ee was determined by HPLC with a Chiralcel AD-H column
(85:15 hexanes: isopropanol, 1 mL/min, 254 nm); First (major)
diastereomer: tr (major) = 9.03 min, tr (minor) = 16.32 min; 58% ee;
Second (minor) diastereomer: tr (major) = 14.64 min, tr (minor) =
22.77 min, 56% ee.
Ethyl 2-benzoyl-3-(4-bromophenyl)-4-nitrobutanoate (4d):
25
Colorless liquid, yield 91%, ratio of diastereomers 1.2:1, [ꢀ]D
-
2.98 (c 0.47, CHCl3). IR (neat): 3064, 2981, 1734, 1685, 1596,
1555, 1489, 1448, 1377, 1260, 1185, 1075, 912, 880, 826, 688, 555
1
cm-1; H NMR (300 MHz, CDCl3): major isomer, ꢂ 8.04 (dd, J =
[9]
8.4, 1.2 Hz, 2H), 7.60-7.40 (m, 3H), 7.29-7.26 (m, 2H), 7.04-7.01
(m, 2H), 4.92-4.87 (m, 1H), 4.77-4.73 (m, 2H), 4.50-4.44 (m, 1H),
3.89 (q, J = 7.2 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3H); minor isomer, ꢂ
7.85 (dd, J = 8.4, 1.2 Hz, 2H), 7.60-7.40 (m, 3H), 7.20-7.17 (m,
2H), 6.93-6.90 (m, 2H), 4.92-4.87 (m, 3H), 4.50-4.44 (m, 1H), 4.16
(q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3): ꢂ 192.4, 192.3, 167.4, 166.7, 135.9, 135.8, 135.7, 135.4,
134.3, 134.0, 132.1, 132.0, 130.0, 129.7, 129.0, 128.9, 128.8,
128.6, 122.4, 122.2, 77.7, 62.4, 62.1, 56.7, 56.1, 42.5, 42.3, 13.8,
13.6. The ee was determined by HPLC with a Chiralcel AD-H
column (85:15 hexanes: isopropanol, 1 mL/min, 254 nm); First
(major) diastereomer: tr (major) = 10.12 min, tr (minor) = 21.11
min; 56% ee; Second (minor) diastereomer: tr (major) = 14.66 min,
tr (minor) = 26.61 min, 56% ee.
[10]
In most of the Michael addition reaction of nitroolefins, the general
feature of this reaction is Michael donor activated by a base or
Lewis acid or Michael acceptor activated by a Lewis acid, but
Michael acceptor activated by a protonic acid have never seen
before. For reviews on Michael reactions, see: ref. (5).
The powdered molecular sieves used in this work must be activated
by placing the powder under vacuum and heating with the flame of
spirit lamp.
[11]
[12]
Spectral data for Michael addition products (Table 3, 4a-k) [3m]:
Ethyl 2-benzoyl-4-nitro-3-phenylbutanoate (4a): White solid,
25
yield 91%, ratio of diastereomers 1.4:1, Mp 78.9-80.6 oC, [ꢀ]D
-
Ethyl 2-benzoyl-3-(3-bromophenyl)-4-nitrobutanoate (4e):
25
1.13 (c 0.44, CHCl3). IR (KBr): 3064, 2982, 2924, 1725, 1686,
Colorless liquid, yield 97%, ratio of diastereomers 1.5:1, [ꢀ]D
-
1598, 1554, 1449, 1284, 1263, 1090, 1020, 981, 877, 700, 563 cm-
1.77 (c 0.45, CHCl3). IR (neat): 3063, 2981, 2923, 1735, 1685,
1
1. H NMR (300 MHz, CDCl3): major isomer, ꢂ 8.05 (dd, J = 8.4,
1596, 1555, 1476, 1448, 1377, 1282, 1186, 1076, 1022, 979, 880,
1
1.2 Hz, 2H), 7.62-7.60 (m, 1H), 7.41-7.30 (m, 2H), 7.30-7.22 (m,
5H), 4.96-4.91 (m, 1H), 4.80-4.76 (m, 2H), 4.50-4.44 (m, 1H), 3.86
(q, J = 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H);minor isomer, ꢂ 7.95
(dd, J = 8.4, 1.2 Hz, 2H), 7.52-7.47 (m, 1H), 7.41-7.30 (m, 2H),
7.22-7.19 (m, 5H), 4.96-4.91 (m, 3H), 4.50-4.44 (m, 1H), 4.18 (q, J
= 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3): ꢂ 192.7, 192.6, 167.7, 166.9, 136.8, 136.3, 136.0, 135.8,
134.2, 133.8, 129.0, 128.9, 128.8, 128.7, 128.5, 128.3, 128.2,
128.1, 128.0, 77.9, 62.2, 61.9, 57.0, 56.4, 43.1, 43.0, 13.9, 13.6.
The ee was determined by HPLC with a Chiralcel AD-H column
(85:15 hexanes: isopropanol, 1 mL/min, 254 nm); First (major)
diastereomer: tr (major) = 8.01 min, tr (minor) = 14.51 min; 54% ee;
Second (minor) diastereomer: tr (major) = 12.26 min, tr (minor) =
21.56 min, 56% ee.
787, 696, 588 cm-1; H NMR (300 MHz, CDCl3): major isomer ꢂ
8.05 (dd, J = 8.4, 1.2 Hz, 2H), 7.62-7.53 (m, 2H), 7.52-7.41 (m,
2H), 7.37-7.25 (m, 1H), 7.25-7.20 (m, 2H), 4.95-4.88 (m, 1H),
4.90-4.88 (m, 2H), 4.50-4.44 (m, 1H), 3.90 (q, J = 7.2 Hz, 2H),
0.89 (t, J = 7.2 Hz, 3H); minor isomer, ꢂ 7.86 (dd, J = 8.4, 1.2 Hz,
2H), 7.52-7.41 (m, 3H), 7.37-7.25 (m, 2H), 7.20-7.10 (m, 2H),
4.95-4.88 (m, 3H), 4.50-4.44 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H),
1.18 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): ꢂ 192.4,
192.3, 167.4, 166.7, 139.1, 138.6, 135.6, 134.4, 134.0, 131.5,
131.4, 131.3, 131.1, 130.4, 129.0, 128.9, 128.8, 128.6, 122.9,
122.8, 77.6, 62.4, 62.1, 56.7, 56.2, 42.6, 42.5, 13.9, 13.6. The ee
was determined by HPLC with a Chiralcel AD-H column (85:15
hexanes: isopropanol,
1 mL/min, 254 nm); First (major)
diastereomer: tr (major) = 8.36 min, tr (minor) = 12.82 min; 53% ee;

Chiral Phosphoric Acid Catalyzed Diastereo
Letters in Organic Chemistry, 2010, Vol. 7, No. 3
225
Second (minor) diastereomer: tr (major) = 10.41 min, tr (minor) =
14.32 min, 55% ee.
Ethyl 2-(4-fluorobenzoyl)-4-nitro-3-phenylbutanoate (4i): White
solid, yield 96%, ratio of diastereomers 2.6:1, Mp 74.8-92.8 oC,
[ꢀ]D25 -0.71 (c 0.28, CHCl3). IR (KBr): 3087, 2984, 2927, 1722,
1685, 1599, 1555, 1506, 1456, 1379, 1299, 1262, 1150, 1020, 983,
Ethyl 2-benzoyl-4-nitro-3-(2-(trifluoromethyl)phenyl)butanoate
(4f): Colorless liquid, yield 97%, ratio of diastereomers 1.4:1,
25
1
[ꢀ]D -2.22 (c 0.26, CHCl3). IR (neat): 3067, 2984, 2925, 1735,
849, 764, 561 cm-1, H NMR (300 MHz, CDCl3): major isomer, ꢀ
1686, 1697, 1580, 1557, 1449, 1378, 1330, 1285, 1167, 1127,
1023, 980, 910, 805, 547 cm-1; 1H NMR (300 MHz, CDCl3): major
isomer, ꢀ 8.05 (dd, J = 8.4, 1.2 Hz, 2H), 7.63-7.42 (m, 7H), 4.98-
4.91 (m, 1H), 4.90-4.78 (m, 2H), 4.50-4.44 (m, 1H), 3.86 (q, J =
7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H); minor isomer, ꢀ 7.83 (dd, J =
8.4, 1.2 Hz, 2H), 7.63-7.42 (m, 7H), 4.98-4.91 (m, 3H), 4.50-4.44
8.09 (dd, J = 8.4, 1.2 Hz, 2H), 7.29-7.25 (m, 3H), 7.22-7.08 (m,
4H), 4.94-4.88 (m, 1H), 4.78-4.76 (m, 2H), 4.50-4.44 (m, 1H), 3.88
(q, J = 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H); minor isomer, ꢀ 7.88
(dd, J = 8.4, 1.2 Hz, 2H), 7.29-7.25 (m, 4H), 7.22-7.08 (m, 3H),
4.94-4.88 (m, 3H), 4.50-4.44 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H),
1.18 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): ꢀ 192.7,
167.6, 166.9, 136.6, 136.1, 135.9, 135.7, 133.8, 128.9, 128.8,
128.7, 128.5, 128.3, 128.2, 128.1, 127.9, 77.9, 62.2, 61.9, 56.9,
56.2, 43.1, 43.0, 13.8, 13.5. The ee was determined by HPLC with
a Chiralcel AD-H column (85:15 hexanes: isopropanol, 1 mL/min,
254 nm); First (major) diastereomer: tr (major) = 8.53 min, tr
(minor) = 14.37 min; 55% ee; Second (minor) diastereomer: tr
(major) = 11.82 min, tr (minor) = 16.85 min, 45% ee.
(m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H); 13
C
NMR (75 MHz, CDCl3ꢀ: ꢀ 192.5, 192.2, 167.4, 166.7, 137.9,
137.5, 136.0, 135.5, 134.3, 134.0, 131.9, 131.7, 131.6, 129.4,
128.9, 128.8, 128.7, 128.4, 125.2, 125.1, 125.0, 124.7, 121.9, 77.5,
62.3, 62.0, 56.7, 56.0, 42.8, 42.7, 42.5, 13.7, 13.3. The ee was
determined by HPLC with a Chiralcel AD-H column (85:15
hexanes: isopropanol,
1 mL/min, 254 nm); First (major)
Ethyl
2-(4-chlorobenzoyl)-4-nitro-3-phenylbutanoate
(4j):
diastereomer: tr (major) = 6.14 min, tr (minor) = 9.30 min; 51% ee;
Second (minor) diastereomer: tr (major) = 7.95 min, tr (minor) =
10.79 min, 53% ee.
White solid, yield 93%, ratio of diastereomers 2.0:1, Mp 115.8-
118.6 oC, [ꢀ]D25 -10.1 (c 0.43, CHCl3). IR (KBr): 3066, 2961, 1736,
1687, 1590, 1561, 1425, 1401, 1377, 1281, 1231, 1212, 1090,
Ethyl
2-benzoyl-4-nitro-3-(2-nitrophenyl)butanoate
(4g):
1
1031, 988, 878, 832, 765, 586 cm-1; H NMR (300 MHz, CDCl3):
25
Colorless liquid, yield 89%, ratio of diastereomers 1.9:1, [ꢀ]D
-
major isomer, ꢀ 8.00 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H),
7.32-7.26 (m, 4H), 7.22-7.18 (m, 1H), 4.95-4.87 (m, 1H), 4.79-4.76
(m, 2H), 4.50-4.44 (m, 1H), 3.87 (q, J = 7.2 Hz, 2H), 0.87 (t, J =
7.2 Hz, 3H); minor isomer, ꢀ 7.79 (d, J = 8.4 Hz, 2H), 7.38 (d, J =
8.4 Hz, 2H), 7.32-7.26 (m, 3H), 7.22-7.18 (m, 2H), 4.95-4.87 (m,
3H), 4.50-4.44 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3): ꢀ 191.6, 191.5, 167.4, 166.8,
140.9, 140.4, 136.5, 136.1, 134.4, 134.1, 130.3, 129.9, 129.2,
129.1, 129.0, 128.9, 128.4, 128.2, 127.9, 78.0, 62.3, 62.1, 57.0,
56.2, 43.1, 43.0, 13.9, 13.6. The ee was determined by HPLC with
a Chiralcel AD-H column (85:15 hexanes: isopropanol, 1 mL/min,
254 nm); First (major) diastereomer: tr (major) = 9.24 min, tr
(minor) = 15.54 min; 45% ee; Second (minor) diastereomer: tr
(major) = 12.72 min, tr (minor) = 19.21 min, 27% ee.
1.30 (c 0.23, CHCl3). IR (neat): 3071, 2982, 2929, 1734, 1685,
1597, 1556, 1532, 1448, 1351, 1261, 1097, 1021, 978, 889, 809,
688, 582 cm-1; 1H NMR (300 MHz, CDCl3): major isomer, ꢀ 8.22-
8.20 (m, 2H), 8.06 (dd, J = 8.4, 1.2 Hz, 2H), 7.87-7.84 (m, 2H),
7.56-7.43(m, 4H), 5.00-4.93 (m, 1H), 4.84-4.80 (m, 2H), 4.60 (m,
1H), 3.87 (q, J = 7.2 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H); minor
isomer, ꢀ 8.22-8.20 (m, 3H), 7.86 (dd, J = 8.4, 1.2 Hz, 2H), 7.56-
7.43 (m, 4H), 5.00-4.93 (m, 3H), 4.60 (m, 1H), 4.20 (q, J = 7.2 Hz,
2H), 1.17 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): ꢀ 191.1,
168.0, 167.7, 167.4, 166.8, 164.6, 164.3, 136.6, 136.1, 132.4,
132.3, 132.2, 132.1, 131.7, 131.6, 131.3, 131.2, 128.8, 128.7,
128.3, 128.2, 128.0, 127.9, 116.1, 116.0, 115.8, 115.7, 77.9, 77.8,
62.2, 61.9, 56.9, 56.1, 43.1, 43.0, 13.8, 13.5. The ee was
determined by HPLC with a Chiralcel AD-H column (85:15
Ethyl 2-(4-bromobenzoyl)-4-nitro-3-phenylbutanoate (4k):
White solid, yield 90%, ratio of diastereomers 1.6:1, Mp 121.9-
123.8 oC, [ꢀ]D25 -10.1 (c 0.49, CHCl3). IR (KBr): 3031, 2986, 2926,
1725, 1685, 1584, 1556, 1496, 1455, 1384, 1294, 1260, 1166,
1070, 1024, 983, 882, 830, 700, 567 cm-1; 1H NMR (300 MHz,
CDCl3): major isomer, ꢀ 7.91 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4
Hz, 2H), 7.32-7.26 (m, 3H), 7.22-7.18 (m, 2H), 4.94-4.87 (m, 1H),
4.77-4.76 (m, 2H), 4.50-4.44 (m, 1H), 3.86 (q, J = 7.2 Hz, 2H),
0.89 (t, J = 7.2 Hz, 3H); minor isomer, ꢀ 7.71 (d, J = 8.4 Hz, 2H),
7.56 (d, J = 8.4 Hz, 2H), 7.32-7.26 (m, 3H), 7.22-7.18 (m, 2H),
4.94-4.87 (m, 3H), 4.50-4.44 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H),
1.18 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): ꢀ 191.9,
191.8, 167.4, 166.7, 136.5, 136.1, 134.8, 134.5, 132.2, 132.1,
130.3, 130.0, 129.7, 129.2, 129.0, 128.9, 128.2, 127.9, 125.9, 78.0,
62.4, 62.1, 57.0, 56.2, 43.1, 43.0, 13.9, 13.6. The ee was
determined by HPLC with a Chiralcel AD-H column (85:15
hexanes: isopropanol,
1 mL/min, 254 nm); First (major)
diastereomer: tr (major) = 13.08 min, tr (minor) = 20.98 min; 49%
ee; Second (minor) diastereomer: tr (major) = 17.22 min, tr (minor)
= 26.48 min, 37% ee.
Ethyl 2-benzoyl-3-(furan-2-yl)-4-nitrobutanoate (4h): Colorless
liquid, yield 84%, ratio of diastereomers 1.3:1, [ꢀ]D -1.32 (c 0.37,
25
CHCl3). IR (neat): 3063, 2984, 2937, 1736, 1686, 1597, 1556,
1449, 1377, 1262, 1096, 1079, 1016, 981, 885, 742, 532 cm-1, H
1
NMR (300 MHz, CDCl3): major isomer, ꢀ 8.00 (d, J = 7.2 Hz, 2H),
7.60-7.56 (m, 2H), 7.50-7.44 (m, 1H), 7.32 (s, 1H), 6.26-6.23 (m,
2H), 5.02-4.92 (m, 1H), 4.84-4.81 (m, 2H), 4.50-4.44 (m, 1H), 3.98
(q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H);minor isomer, ꢀ 7.92
(d, J = 7.2 Hz, 2H), 7.50-7.44 (m, 3H), 7.20 (s, 1H), 6.15-6.12 (m,
2H), 5.02-4.92 (m, 3H), 4.50-4.44 (m, 1H), 4.15 (q, J = 7.2 Hz,
2H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): ꢀ 192.7,
192.6, 167.3, 167.0, 149.7, 149.6, 142.6, 142.4, 135.6, 135.5,
134.1, 133.9, 128.8, 128.7, 128.6, 128.5, 110.4, 108.6, 108.5, 75.8,
62.1, 62.0, 54.8, 53.9, 37.0, 36.9, 13.7, 13.6. The ee was
determined by HPLC with a Chiralcel AD-H column (85:15
hexanes: isopropanol,
1 mL/min, 254 nm); First (major)
diastereomer: tr (major) = 10.09 min, tr (minor) = 17.56 min; 55%
ee; Second (minor) diastereomer: tr (major) = 13.73 min, tr (minor)
= 21.89 min, 40% ee.
hexanes: isopropanol,
1 mL/min, 254 nm); First (major)
diastereomer: tr (major) = 9.20 min, tr (minor) = 13.30 min; 31% ee;
Second (minor) diastereomer: tr (major) = 10.30 min, tr (minor) =
15.40 min, 28% ee.