Activation of 1,2-keto esters with Takemoto's catalyst toward michael addition to nitroalkenes

Article abstract of DOI:10.1002/adsc.201100739

When activated with Takemoto's catalyst, 1,2-keto esters constitute versatile nucleophiles in the Michael addition reaction with nitroalkenes affording synthetically valuable, optically active anti-adducts in very good yields and high enantiomeric excesses. Copyright

Full text of DOI:10.1002/adsc.201100739

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DOI: 10.1002/adsc.201100739
Activation of 1,2-Keto Esters with Takemotoꢀs Catalyst toward
Michael Addition to Nitroalkenes
Wilfried Raimondi,a Olivier Baslꢀ,a Thierry Constantieux,a Damien Bonne,a,*
and Jean Rodrigueza,*
a
Aix-Marseille Universitꢀ, UMR CNRS 7313 iSm2, Centre Saint Jꢀrꢁme, service 531, 13397 Marseille, France
Fax : (+33)-491-289-187; phone: (+33)-491-288-933; e-mail: damien.bonne@univ-cezanne.fr or
jean.rodriguez@univ-cezanne.fr
Received: September 22, 2011; Revised: December 15, 2011; Published online: February 23, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100739.
Abstract: When activated with Takemotoꢂs catalyst,
1,2-keto esters constitute versatile nucleophiles in
the Michael addition reaction with nitroalkenes af-
fording synthetically valuable, optically active anti-
adducts in very good yields and high enantiomeric
excesses.
prompted us to disclose our preliminary contributions
to this emerging field.
To accomplish this goal, we envisioned a simple
methodology involving activation by a bifunctional or-
ganocatalyst with nitroalkenes as reactive acceptors.
We reasoned that these olefins would act as more
powerful electrophiles compared to 1,2-keto esters[13]
which should then behave as pronucleophiles. The
competitive self-condensation reaction would then be
disfavored.[14] Besides, the final Michael adducts
would possess very high synthetic potential given
their dense and diverse functionalities.
Keywords: asymmetric organocatalysis; 1,2-keto
esters; Michael addition; pronucleophiles; Takemo-
toꢂs catalyst
We first selected b-nitrostyrene (1a) and ethyl 2-
oxoACTHUNRTGNEUNGbutanoate (2a) as model substrates to examine the
The Michael addition is one of the most important role of the organocatalyst and the best activation
[1]
À
ways to create C C bonds in organic synthesis. The mode (Table 1, entries 1–5).
last ten years have witnessed the emergence of orga-
Catalyst I[15] proved to be unsuitable for this trans-
nocatalysis which is now often employed to develop formation affording the product in very low yield
new stereoselective Michael additions.[2] Nitroalkenes (10%) although a good diastereomeric ratio was ob-
are particularly attractive acceptors because of their tained (entry 1). The use of (S)-diphenylprolinol II[16]
high reactivity and thanks to the nitro group, qualified with an extra H-bonding site gave the product in low
as the “synthetic chameleon”,[3] which can be easily yield with good diastereoselectivity (entry 2). Catalyst
transformed into various functionalities.[4] Hence, III, which was efficient in organocatalyzed enantiose-
functionalized Michael adducts represent very useful lective Michael additions with malonate nucleo-
building blocks[5] or may also be involved in subse-
philes,[8c,17] gave a low yield and a low selectivity
ACHTUNGTRENNUNG
quent transformations allowing the development of (entry 3). More elaborated Cinchona-alkaloid derived
complex domino processes.[6,7] catalysts IV and V bearing either the thiourea[18] or
In continuation to our ongoing studies on conjugate the squaramide[19] subunits proved to be efficient pro-
additions to nitroolefins,[8] we became interested in viding the product in good yield and acceptable selec-
the challenging reactivity of a-keto esters as pronu- tivities (entries 4 and 5). Finally, we found that the
cleophiles in organocatalyzed Michael reactions since Takemotoꢂs catalyst VI,[20] when used in EtOAc was
no example of such a transformation has been report- the most efficient (entry 7), and it was chosen for the
ed so far.[9,10] Our own interest in the activation of following optimization experiments.[21] While the tert-
1,2-dicarbonyl compounds[11] and the very recent butyl ester 2b afforded the product 3b in lower diaste-
report from Terada and co-workers on an unprece- reoselectivity (entry 8), the use of the benzyl ester 2c
dented enantioselective organocatalyzed amination of allowed the formation of 3c in a promising 7:1 anti:-
a-keto esters using an axially chiral guanidine base,[12] syn ratio and 88% ee (entry 9). Finally, decreasing the
temperature to 08C (entry 10) had a positive impact
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Temperature
Solvent
2
3
Yield[b] [%]
dr[c,d] (anti/syn)
ee[e,f] [%]
1
2
3
4
5
6
7
8
I
II
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
toluene
toluene
toluene
toluene
toluene
toluene
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2c
3a
3a
3a
3a
3a
3a
3a
3b
3c
3c
3c
10
15
18
82
75
77
91
95
90
85
75
7:1
nd
nd
nd
77
87
89
80 [87]
93 [96]
88
10:1
2:1
4:1
9:1
2:1
3.5:1
2:1
7:1
III
IV
V
VI
VI
VI
VI
VI
VI
9
10
11
r.t.
08C
À358C
9:1
8:1
92
93
[b]
b-Nitrostyrene (1a) (0.2 mmol), keto ester 2 (0.4 mmol), solvent (0.4 mL) for 18 h.
Isolated yield after column chromatography.
Determined by H NMR analysis of the crude reaction product.
[b]
[c]
[d]
1
The relative and absolute stereochemistries of the Michael adducts were determined by comparison with reported litera-
ture data.[9e,f]
[e]
[f]
Determined by chiral HPLC analysis.
Values in brackets are for the minor enantiomer.
on selectivities albeit in slightly lower yield which was tries 6–8), the reaction proceeded with very good
yields and selectivities with no significant effect of the
confirmed by reaction at À358C (entry 11).
Our methodology was then tested by varying both substitution although a longer reaction time was re-
the nitroalkene 1 and the benzyl keto ester 2 using quired when 3-indolyl-substituted nitroalkene 1h was
the optimized reaction conditions (Table 2). With an employed.
extra carbon on the keto ester (2d, R2 =Et instead of
Interestingly, and in sharp contrast with other Mi-
R2 =Me in 2c) the diastereoselectivity was greatly im- chael additions,[22] aliphatic nitroalkenes including io-
proved (>20:1, entry 1) with equally excellent yield doalkane 1k, are suitable substrates affording the Mi-
and enantioselectivity.
chael adducts with comparable selectivities although a
In the case of aromatic compounds (entries 1–5) in- lower yield was generally obtained (entries 9 and 13)
cluding ortho-substituted phenylnitroalkenes (en- and longer reaction times were required.[23] Hindering
tries 4 and 5) and heteroaromatic nitroalkenes (en- the nucleophilic carbon of the keto ester by using
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Activation of 1,2-Keto Esters with Takemotoꢂs Catalyst toward Michael Addition to Nitroalkenes
Table 2. Scope of the conjugate addition.[a]
Entry
R1
1
2
3
Time [h]
Yield[b] [%]
dr[c] (anti/syn)
ee[d] [%]
1
2
3
4
5
6
7
8
Ph
1a
1b
1c
1d
1e
1f
1g
1h
1i
1a
1j
1a
1k
1a
2d
2d
2d
2d
2d
2d
2d
2d
2d
2e
2e
2f
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
18
18
18
18
18
18
18
72
18
36
72
18
96
18
89
84
88
98
99
88
72
89
55
36
41
70
44
87
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
94
94
94
97
98
95
94
94
94
91
90
80
90
93
4-MeOC6H4
4-O2NC6H4
2-BrC6H4
2-O2NC6H4
2-thienyl
3-furanyl
3-indolyl
PhCH2CH2
Ph
4-BrC6H4
Ph
ICH2CH2
Ph
9
10
11
12
13
14[e]
2f
2g
[a]
Standard conditions: nitroalkene 1 (0.2 mmol), keto ester 2 (0.4 mmol) in EtOAc (0.4 mL) at 08C.
[b]
[c]
[d]
[e]
Isolated yield after column chromatography.
1
Determined by H NMR analysis of the crude reaction product.
Determined by chiral HPLC analysis.
Reaction performed with 1 mmol of 1a.
branched keto ester 2e (entries 10 and 11) or phenyl-
substituted keto ester 2f (entries 12 and 13) slowed
down the reaction and had a detrimental effect on the
reaction yield. However, in these four cases, both the
diastereoselectivity and the enantioselectivity remain
excellent.[24] Finally, the use of the benzyl 2-oxo-hex-
5-enoate (2g) led to the clean formation of the ex-
pected allylic functionalized Michael adduct 3q
(entry 14) with very good yield and excellent stereose-
lectivities.
The present methodology was then applied to two
challenging a-substituted nitroalkenes 1l and 1m as
electrophiles (Scheme 1). The use of a-substituted ni-
troalkenes is relatively limited in organocatalyzed
enantioselective Michael addition probably due to the
facile retro-Michael reaction.[25] Usually, the Michael
adducts are not isolated but “siphoned” in subsequent
domino transformations. Gratifyingly, in the first case
we were pleased to obtained the desired adduct 3r
Scheme 1. Michael addition of a-keto esters onto a-substi-
bearing an anti:anti stereo-triad in 80% yield with a tuted nitroalkenes.
total diastereocontrol and 97% ee.[26] The a-chloroni-
troolefin 1m was also very reactive leading to a 3/1
mixture of only two diastereomers of 3s in 94% yield observed in the Michael adducts. Following Pꢄpaiꢂs
and high enantiomeric excess for both diastereomers. model,[27] the protonated tertiary amine of catalyst VI
The transition states depicted in Scheme 2 could ac- binds to the nitro function, hence enhancing the elec-
count for both relative and absolute stereochemistries trophilic character of the nitroalkene, whereas the
Adv. Synth. Catal. 2012, 354, 563 – 568
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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565

Wilfried Raimondi et al.
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Scheme 3. Transformations of Michael adducts into hetero-
and carbocycles.
been demonstrated with the easy transformation of
the Michael adducts to five-membered carbo- and
heterocyles with the creation and control of addition-
al stereocenters.
Scheme 2. Proposed transition states for the Michael addi-
tion.
thioACHTUNGTRENNUNGurea moiety binds to the strongly polarized eno-
late. In the resulting conformationally restrained envi- Experimental Section
ronment, the Si face of the thermodynamic (Z)-eno-
late[28] preferentially attacks the Re face of the nitroal- General Procedure for the Enantioselective Michael
kene accounting for the formation of the anti-(R,R)- Addition
Michael adduct. The formation of the syn Michael
Catalyst VI (10 mol%) was added to a solution of nitroal-
adduct 3c which would come from the Re face attack
kene (0.2 mmol, 1.0 equiv.) and a-keto ester (0.4 mmol,
of the (Z)-enolate is minor (syn:anti<1:20). In this
2.0 equiv.) in EtOAc (0.4 mL) at 08C. The reaction mixture
transition state, the binding of the thiourea moiety to
the enolate is disfavored because of the strong steric
interaction between the benzylic ester function and
the catalyst.[29]
was stirred until complete conversion of the starting materi-
als (monitored by TLC). Purification by flash column chro-
matography (silica gel, petroleum ether/AcOEt) afforded
the pure Michael adduct. The anti/syn diastereomeric ratio
was determined by 1H NMR spectroscopic analysis of the
crude mixture and the enantiomeric excess (ee) was deter-
mined by HPLC analysis on a chiral phase.
In order to prove the synthetic usefulness of our
methodology, we carried out several transformations
of the Michael adducts allowing the formation of vari-
ous interesting building blocks with increased molecu-
lar complexity (Scheme 3). It has already been shown
in the literature that these Michael adducts could be
easily reduced to the corresponding pyrrolidines.[9e–g]
Alternatively, under basic conditions, the Michael
adduct 3s was cleanly converted to the trans dihydro-
AHCTUNGTREG(NNUN 3R,4R)-Benzyl 3-Ethyl-5-nitro-2-oxo-4-phenyl-
pentanoate (3d)
This compound was isolated as a white solid; yield: 63 mg
(89%); mp 75–778C; Rf =0.47 (ethyl acetate/petroleum
ether=1:4); dr anti/syn>20:1; HPLC (Chiralpak IC,
furan 4 with a total chirality transfert.[30,31] Finally, hexane/i-PrOH=80/20, flow rate=1.0 mLminÀ1, l=
254 nm): tmajor =12.47 min, tminor =7.83 min, ee=94%; [a]2D2:
using the conditions we developed previously,[8a,c] 3q
was converted to the highly functionalized five-mem-
bered carbocycle 5 bearing three stereogenic centers
with good yield and excellent diastereocontrol.
1
+13.2 (c=1, CHCl3); H NMR (400 MHz, CDCl3): d=7.38–
7.34 (3H, m, ArH), 7.29–7.27 (2H, m, ArH), 7.23–7.20 (3H,
m, ArH), 5.14 (1H, d, J=12.1 Hz, CH2Ph), 5.10 (1H, d, J=
12.1 Hz, CH2Ph), 4.71 (1H, dd, J=12.8, 5.4 Hz, CH2NO2),
4.66 (1H, dd, J=12.8, 9.4 Hz, CH2NO2), 3.85 (1H, ddd, J=
9.4, 9.4, 5.4 Hz, PhCH), 3.74 (1H, ddd, J=9.4, 9.4, 3.7 Hz,
CHC=O), 1.84 (1H, ddq, J=13.5, 9.4, 7.4 Hz, CH2CH3),
1.73 (1H, dqd, J=13.5, 7.4, 3.7 Hz, CH2CH3), 0.88 (3H, t,
J=7.4 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3): d=
In conclusion, we have developed the first efficient
Takemotoꢂs catalyst-promoted activation of 1,2-keto
esters in an enantioselective Michael addition with ni-
troalkenes. The method is simple and can be applied
to many substrates with excellent yields and selectivi-
ties. Moreover the versatility of the condensation has 195.1, 160.6, 136.8, 134.1, 129.0 (2C), 128.8, 128.7 (2C),
566
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Adv. Synth. Catal. 2012, 354, 563 – 568

Activation of 1,2-Keto Esters with Takemotoꢂs Catalyst toward Michael Addition to Nitroalkenes
128.6 (2C), 128.1, 128.0 (2C), 77.7, 68.1, 51.5, 44.7, 22.2,
11.3; MS (ES+): m/z=373.1759, calcd. for C20H25N2O5 [M+
NH4]+: 373.1758].
Guillaume, P.-Y. Roger, R. Faure, J.-M. Pons, G. Herb-
ette, J.-P. Dulcꢈre, D. Bonne, J. Rodriguez, Chem. Eur.
J. 2009, 15, 12470; c) W. Raimondi, G. Lettieri, J.-P.
Dulcꢈre, D. Bonne, J. Rodriguez, Chem. Commun.
2010, 46, 7247.
[9] For examples where 1,2-dicarbonyl compounds act as
pronucleophiles in metal catalyzed transformations,
see: a) K. Juhl, N. Gathergood, K. A. Jørgensen,
Angew. Chem. 2001, 113, 3083; Angew. Chem. Int. Ed.
2001, 40, 2995; b) K. Juhl, K. A. Jørgensen, J. Am.
Chem. Soc. 2002, 124, 2420; c) G. Lu, H. Morimoto, S.
Matsunaga, M. Shibasaki, Angew. Chem. 2008, 120,
6953; Angew. Chem. Int. Ed. 2008, 47, 6847; d) Y. Xu,
G. Lu, S. Matsunaga, M. Shibasaki, Angew. Chem.
2009, 121, 3403; Angew. Chem. Int. Ed. 2009, 48, 3353;
e) A. Nakamura, S. Lectard, D. Hashizume, Y. Hama-
shima, M. Sodeoka, J. Am. Chem. Soc. 2010, 132, 4036;
f) A. Nakamura, S. Lectard, R. Shimizu, Y. Hamashi-
ma, M. Sodeoka, Tetrahedron: Asymmetry 2010, 21,
1682; g) Y. Xu, S. Matsunaga, M. Shibasaki, Org. Lett.
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[10] For an highlight on organocatalytic activation of 1,2-di-
carbonyl compounds, see: W. Raimondi, D. Bonne, J.
Rodriguez, Angew. Chem. 2012, 124, 40; Angew. Chem.
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[11] O. Baslꢀ, W. Raimondi, M. M. Sanchez Duque, D.
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Acknowledgements
This research was supported by the French Research Minis-
try, the Agence Nationale pour la Recherche (ANR-07-
CP2D-06), the Universitꢀ Paul Cꢀzanne and the CNRS
(ism2-UMR 7313). We thank Dr. N. Vanthuyne (iSm2-UMR
7313) for chiral HPLC analysis, Dr. Y. Coquerel (iSm2-UMR
7313) for theoretical calculations and Dr. D. Dauzonne (In-
stitut Curie – UMR 176) for providing a sample of 1m.
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[29] See the Supporting Information for additional discus-
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Adv. Synth. Catal. 2012, 354, 563 – 568