Organocatalyzed asymmetric Michael reaction of β-aryl-α- ketophosphonates and nitroalkenes

Article abstract of DOI:10.1016/j.tetlet.2013.08.015

The first enantioselective Michael reaction of β-aryl-α- ketophosphonates and nitroalkenes has been realized by using a new bifunctional Takemoto-type thiourea catalyst. The primary Michael adducts obtained were converted in situ to the corresponding amides through the aminolysis. High yields, excellent diastereoselectivities (>95:5 dr), and good enantioselectivities (up to 81% ee) have been achieved for the corresponding α,β-disubstituted γ-nitroamides. This reaction again demonstrated that α-ketophosphonates are interesting pronucleophiles that can be used as amide surrogates in organocatalyzed reactions.

Full text of DOI:10.1016/j.tetlet.2013.08.015

Tetrahedron Letters 54 (2013) 5703–5706
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalyzed asymmetric Michael reaction
of b-aryl- -ketophosphonates and nitroalkenes
a
⇑
Jie Guang, John Cong-Gui Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0689, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The first enantioselective Michael reaction of b-aryl-a-ketophosphonates and nitroalkenes has been real-
Received 2 July 2013
Revised 1 August 2013
Accepted 3 August 2013
Available online 12 August 2013
ized by using a new bifunctional Takemoto-type thiourea catalyst. The primary Michael adducts obtained
were converted in situ to the corresponding amides through the aminolysis. High yields, excellent diaste-
reoselectivities (>95:5 dr), and good enantioselectivities (up to 81% ee) have been achieved for the corre-
sponding
a,b-disubstituted c-nitroamides. This reaction again demonstrated that a-ketophosphonates
are interesting pronucleophiles that can be used as amide surrogates in organocatalyzed reactions.
Keywords:
Michael reaction
Organocatalysis
Ó 2013 Elsevier Ltd. All rights reserved.
a-Ketophosphonate
Nitroalkene
Enantioselective
Amide surrogate
The Michael reaction is one of the most important tools for the
carbon–carbon formation in organic chemistry and, therefore, it
has found extensive applications in the asymmetric synthesis of
chiral compounds.1 In the past decade, organocatalyzed Michael
reactions have been widely studied as one of the most economical
and environmentally friendly strategies in asymmetric catalyses.2
Among the various Michael acceptors, nitroalkenes attract particu-
lar attention owing to their high electrophilicity and the various
functional group transformations available for the nitro group.3 Be-
sides the enamine-mediated catalysis involving the more electro-
philic ketones and aldehydes as the pronucleophiles in the
organocatalyzed Michael reactions,4 a large number of reactive
Michael donors, such as 1,3-dicarbonyl compounds,5 1,2-dicar-
bonyl compounds,6 phosphites,7 and oxindoles8 have been applied
in the reactions with nitroalkenes using organic Brønsted base cat-
alysts. However, the direct use of an ester or an amide as the sub-
strate in both mechanisms remains very challenging due to their
poor electrophilic carbonyl groups (precluding the direct formation
of an enamine intermediate using an amine catalyst) and their high
pKa values (precluding the direct formation of an enolate interme-
diate using organic Brønsted bases). To circumvent this problem,
Wennemers and coworkers chose malonic acid half thioesters
and mono thiomalonate as the surrogates of esters/amides.9
Nonetheless, with these substrates it is difficult to generate a
substituent at the b-position of the ester/amide group in the Mi-
chael products. Most recently, Barbas and coworkers used a
pyrazoleamide as an ester surrogate and accomplished an organo-
catalyzed Michael reaction using a special amide as the donor.10
Despite the fact that excellent results were normally achieved,
the electronic nature of the substituent on the pyrazoleamide aro-
matic ring has a major influence on the reactivity of this reaction.
Whenever there is an electron-donating group, the yield of the
reaction is merely modest. Thus, the development of new ester/
amide surrogates that can be applied in organocatalyzed Michael
reactions with nitroalkenes is not only warranted but highly desir-
able. It should be also pointed out that the products of this Michael
reaction (
are analogues of
c
-nitroesters or
c-nitroamides) are very important: They
c
-aminobutyric acid (GABA).11 GABA is the chief
inhibitory neurotransmitter in the mammalian central nervous
system.12
It is known that the
converted into an ester or amide group.13 Previously, Jørgensen
and coworkers also used b, -unsaturated -ketophosphonates as
surrogates of ,b-unsaturated esters/amides in an organocatalyzed
a-ketophosphonate group can be easily
c
a
a
Michael reaction.14 Most recently, we successfully realized the first
direct application of acetylphosphonate as an enolate precursor15
in Brønsted base-catalyzed aldol reactions.16 The products ob-
tained in the aldol reactions were efficiently converted in situ into
the corresponding esters or amides. Thus, we demonstrated that
a
-ketophosphonate is an excellent surrogate for ester/amide
⇑
Corresponding author. Tel.: +1 210 458 5432; fax: +1 210 458 7428.
E-mail address: cong.zhao@utsa.edu (J.Cong-Gui Zhao).
that can be applied in organic Brønsted base-catalyzed
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.015

5704
J. Guang, J. Cong-Gui Zhao / Tetrahedron Letters 54 (2013) 5703–5706
enolate-mediated reactions. To further demonstrate the usefulness
of these compounds as surrogates of esters/amides in organocata-
lytic reactions, herein we wish to disclose the first organocatalyzed
bifunctional catalysts with the trans-cyclohexanediamine scaffold.
When the thiourea group in catalyst 4c is replaced by a squarea-
mide, as in catalyst 4d, there was no change in the dr of this
reaction; however, the ee value obtained for 3a dropped to 40%
(entry 4). Similarly, modification on the aryl group of the thiourea
moiety (to a phenyl group, catalyst 4e) or modification on both the
aryl group and the tertiary amine group (catalyst 4f) proved to be
unhelpful for improving the dr or the enantioselectivity of this
reaction (entries 5 and 6). To further improve the enantioselectiv-
ity of this reaction, the steric factors of the thiourea moiety were
finely tuned. Thus, we designed and synthesized two new catalysts
4g and 4h, which contain a more bulky 2,6-diisopropylphenyl
group on the thiourea moiety. To our pleasure, a slightly higher
ee value of 64% was obtained for 3a when catalyst 4g was applied,
without compromising the yield and the dr value (entry 7). When
4h was employed as the catalyst, an ee value of 57% was obtained
(entry 8). Thus, catalyst 4g was identified as the best catalyst for
this reaction. Next, the solvent used in the reaction was optimized.
It was found that the solvent did not have any major influence on
the reaction in terms of the product yield or ee value (entries
8–12); however, slightly higher dr values were obtained in methy-
lene chloride (entry 10), toluene (entry 11), and benzene (entry
12). Methylene chloride was selected as a solvent of choice since
a slightly better yield was also obtained in this solvent (entry
10). Lowering the reaction temperature to À10 °C led to a higher
yield for 3a (95%, entry 13). Under these conditions, product 3a
was obtained as a single diastereomer (dr >95:5) with an ee value
of 78% (entry13).
Once the reaction conditions were optimized, the scope of this
reaction was then established, and the results are summarized in
Table 2. As is evident from the data in Table 2, trans-b-nitrostyrene
derivatives with either an electron-donating or an electron-with-
drawing group on the phenyl ring all gave the desired formal
amide Michael adducts with excellent yields and diastereoselectiv-
ities (Table 2, entries 1–6). Slightly higher ee values were obtained
for trans-b-nitrostyrenes with an electron-donating group (entries
2 and 3), which also reacted slightly slower. trans-b-(1-Naph-
thyl)nitroethene (entry 7) also yielded the desired Michael adduct
3g in a high yield and excellent dr, albeit with a slightly lower ee
value of 67%. A high yield and good dr could also be obtained for
a trans-b-alkyl-substituted nitroethene (entry 7), which yielded
one of the highest ee values for the corresponding Michael product
asymmetric Michael reaction of b-aryl-
nitroalkenes using chiral bifunctional Brønsted base catalysts.
Once the Michael addition reactions were finished, the -keto-
phosphonate group was in situ converted to an amide group
through aminolysis to give the corresponding ,b-disubstituted
-nitroamides in high yields and good stereoselectivities.
a
-ketophosphonates17 with
a
a
c
On the basis of our previous findings in the Brønsted base-
catalyzed asymmetric aldol reaction of acetylphosphonates,15 we
chose dimethyl 2-phenylacetylphosphonate (1a) and trans-b-
nitrostyrene (2a) as the model substrates to screen several readily
available bifunctional Brønsted base catalysts (Fig. 1) for the de-
sired Michael reaction. Once the reaction was completed, the ami-
nolysis of the
methanamine in a one-pot fashion to give the corresponding
diphenyl- -nitroamide product 3a. The results of the screening
a
-ketophosphonate group was achieved with
a,b-
c
are summarized in Table 1. As the data in Table 1 show, when 9-
O-(1-naphthylmethyl)cupreidine (4a) was used as the catalyst in
THF at rt for 4 h, the desired product 3a was obtained in 61% yield
with a dr of 80:20. The major anti-diastereomer was obtained in a
low ee value of only 11% (Table 1, entry 1). In contrast, when the
quinidine-derived thiourea 4b was used under similar conditions,
product 3a was obtained in a high yield of 90%. The dr of the prod-
uct was 85:15 and the opposite enantiomer [(2S,3R)] of the major
anti-diastereomer was obtained in 51% ee (entry 2). Similarly,
when the Takemoto-type thiourea catalyst5a 4c was used, the dr
value of the reaction was slightly improved to 90:10 while the
enantioselectivity of this reaction remained at 50% ee (entry 3).
Encouraged by these results, we further screened some additional
CF3
S
N
H
NH
F3C
O
N
N
N
H
N
H
OMe
CF3
OH
3h (81% ee, entry 8). We also explored the scope of the b-aryl-a-
4a
4b
ketophosphonates using trans-b-nitrostyrene as the Michael
acceptor (entries 9–12). Apparently, the electronic nature of sub-
stituent on the phenyl ring has little influence on the reactivity,
diastereoselectivity, or the enantioselectivity of this reaction since
similar results were obtained for compounds with an electron-
donating group or an electron-withdrawing group at the para-po-
sition of the phenyl ring (entries 9–12).
The absolute configuration of the major enantiomer obtained in
this reaction was determined through the X-ray crystallographic
analysis using compound 3d.18 As shown in Figure 2, compound
3d has an absolute configuration of (2R,3S). The stereochemistry
of the other products was similarly assigned on the basis of the
reaction mechanism.
CF3
O
O
S
N
N
H
N
H
CF3
N
H
CF3
H
N
N
4c
4d
S
S
N
H
N
H
N
H
N
H
N
N
On the basis of the stereochemistry of the major stereoisomer
formed in this reaction, a plausible mechanism of this reaction
was proposed. As shown as in Scheme 1, the tertiary amine moiety
4e
4f
iPr
S
iPr
of catalyst 4g first deprotonates the b-aryl-a-ketophosphonate.
S
N
H
N
H
After deprotonation, the enolate associates closely with the cata-
lyst through ironic interactions and potentially also hydrogen
bonding between the ammonium and enolate. Simultaneously,
the nitroalkene is hydrogen-bonded to the thiourea moiety of the
catalyst. These hydrogen bonds not only help fix the orientation
of the nitroalkene but also activate the electrophile. Due to the
N
H
N
H
N
iPr
N
iPr
4g
4h
Figure 1. Catalysts screened in the Michael reaction.

J. Guang, J. Cong-Gui Zhao / Tetrahedron Letters 54 (2013) 5703–5706
5705
Table 1
Catalyst screening and optimization of the reaction conditionsa
Ph
NO2
1a
(1) Cat. (10 mmol %),
Solvent, rt, 4 h
(2) MeNH2 (2 M in THF)
O
Ph
NO2
+
O
N
H
Ph
3a
Ph
P(OMe)2
O
2a
Entry
Catalyst
Solvent
Yieldb (%)
drc
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13f
4a
4b
4c
4d
4e
4f
4g
4h
4g
4g
4g
4g
4g
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
61
90
85
80
83
88
90
80
73
82
80
80
95
80:20
85:15
90:10
90:10
90:10
90:10
90:10
90:10
90:10
95:5
11
51e
50
40
49
45
64
57
73
74
73
73
78
CH2Cl2
Toluene
Benzene
CH2Cl2
95:5
95:5
>95:5
a
Unless otherwise specified, all reactions were conducted with trans-b-nitrostyrene (1a, 0.10 mmol), dimethyl 2-phenylacetylphosphonate (2a, 0.20 mmol), and the
catalyst (10 mmol %) in the specified solvent (0.5 mL) at rt.
b
Combined yield of both diastereomers after column chromatography.
c
Determined by 1H NMR analysis of the crude product.
d
Determined by HPLC analysis using a ChiralPak IC column.
The opposite (2S,3R)-enantiomer was obtained as the major product.
The reaction was carried out at À10 °C.
e
f
Table 2
Substrate scope of the Michael reactiona
4g
(1)
(10 mmol%),
O
O
R
Ar
DCM, -10 oC
R
NO2
+
P(OMe)2
O
NO2
N
H
(2) MeNH2 (2M in THF)
Ar
1
2
3
Entry
R
Ar
3
Time (h)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
4
4
3
3
2
3
2
4
3
2
4
4
95
93
98
93
90
90
92
84f
95
93
95
98
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
90:10
>95:5
>95:5
>95:5
>95:5
78
81
78
78
73
74
67
81
80
79
76
78
4-MeOC6H4-
4-MeC6H4-
4-BrC6H4-
4-ClC6H4-
3-BrC6H4-
1-Nape
n-Pr
Ph
Ph
Ph
Ph
4-MeOC6H4-
4-MeC6H4-
4-ClC6H4-
4-FC6H4-
10
11
12
3j
3k
3l
a
All reactions were conducted with nitroalkene 1 (0.10 mmol), b-aryl-a-ketophosphonate 2 (0.20 mmol), and catalyst 4g (0.010 mmol, 10.0 mmol %) in CH2Cl2 (0.5 mL) at
À10 °C.
b
Yield of isolated product after column chromatography.
c
d
e
f
Determined by 1H NMR analysis of the crude product.
Determined by HPLC analyses.
1-Naphthyl.
Combined yield of both diastereomers.
unfavorable interactions between the large phosphoryl group and
the catalyst as well as those between the two aryl groups of the
substrates (Scheme 1, lower equation), the attack of the enolate
using its Si face to the Re face of the nitroalkene is disfavored. In-
stead, the attack of the Si-face of the nitroalkene using the enolate
Re face is favored (Scheme 1, upper equation), which leads to the
observed major (2R,3S)-diastereomer after aminolysis.
In summary, we have realized the first enantioselective
Michael reaction of b-aryl-a-ketophosphonates and nitroalkenes
by using a new Takemoto-type catalyst and demonstrated that

5706
J. Guang, J. Cong-Gui Zhao / Tetrahedron Letters 54 (2013) 5703–5706
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.08.015. These data include MOL
files and InChiKeys of the most important compounds described
in this article.
References and notes
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Figure 2. ORTEP drawing of compound 3d.
S
Ar
O
N
H
N
H
(MeO)2(O)P
H
NO2
N
H
favored
O
O
N
H
(MeO)2OP
O
Ar
Ph
Ar
Ph
O
Ph
O
Ph
MeNH2
NO2
NO2
(MeO)2(O)P
N
H
Ar
Ar
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S
N
Ar
N
H
O
P(O)(OMe)2
H
N
NO2
H
O
unfavored
H
H
O
N
O
P(O)(OEt)2
Ar
Ph
Ar
Ph
O
Ph
O
Ph
MeNH2
NO2
NO2
N
H
(MeO)2(O)P
Ar
Ar
Scheme 1. Proposed transition states of the Michael reaction of trans-b-nitrosty-
rene and b-aryl- -ketophosphonate.
a
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b-aryl-a-ketophosphonate may be used as an amide surrogate in
organocatalyzed Michael reactions. The corresponding formal
amide Michael adducts were obtained in excellent yields and dia-
stereoselectivities with good enantioselectivities (up to 81% ee).
Acknowledgments
The generous financial support of this project from the Welch
Foundation (grant No. AX-1593) and the NIH-NIGMS (grant No.
SC1-082718) is gratefully appreciated. The authors also thank Dr.
Hadi Arman for help with the X-ray analysis of compound 3d.
17. Afarinkia, K.; Echenique, J.; Nyburg, S. C. Tetrahedron Lett. 1997, 38, 1663–1666.
18. CSD No. 915465 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/Community/
Requestastructure/Pages/DataRequest.aspx.
Supplementary data
Supplementary data associated (detailed experimental proce-
dures and copies of 1H, 13C NMR spectra and HPLC chromatograms)