Azetidine-derived bifunctional organocatalysts for Michael reactions

Article abstract of DOI:10.1016/j.tetasy.2010.08.003

2-Cyano azetidines, easily accessible from β-amino alcohols, are precursors of stereodefined homochiral azetidinic or pyrrolidinic 1,2-diamines. A small library of these original diamines was screened as precatalysts for the enantioselective addition of 1,3-dicarbonyl compounds onto β-nitro styrenes. An azetidinic diamine derived from (-)-ephedrine and derivatized as a thiourea was found to catalyze the conjugate addition of acetylacetone with good levels of enantioselectivities (up to 84% ee). Interestingly, the absolute configuration of the Michael adduct depends on the nature of the 1,3 dicarbonyl nucleophile (diethyl malonate or acetylacetone), which is indicative of a different mechanism involved in the reaction of these two nucleophiles.

Full text of DOI:10.1016/j.tetasy.2010.08.003

Tetrahedron: Asymmetry 21 (2010) 2385–2389
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Azetidine-derived bifunctional organocatalysts for Michael reactions
*
Laurence Menguy, François Couty
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles St-Quentin en Yvelines, 45, av. des Etats-Unis, 78035 Versailles Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Cyano azetidines, easily accessible from b-amino alcohols, are precursors of stereodefined homochiral
azetidinic or pyrrolidinic 1,2-diamines. A small library of these original diamines was screened as precat-
alysts for the enantioselective addition of 1,3-dicarbonyl compounds onto b-nitro styrenes. An azetidinic
diamine derived from (ꢀ)-ephedrine and derivatized as a thiourea was found to catalyze the conjugate
addition of acetylacetone with good levels of enantioselectivities (up to 84% ee). Interestingly, the abso-
lute configuration of the Michael adduct depends on the nature of the 1,3 dicarbonyl nucleophile (diethyl
malonate or acetylacetone), which is indicative of a different mechanism involved in the reaction of these
two nucleophiles.
Received 26 July 2010
Accepted 9 August 2010
Available online 18 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
We also demonstrate herein that efficient catalysts can be discov-
ered starting from commercially available amino alcohols, such as
Since the seminal work of Takemoto1 who first reported thio-
ureas acting as very efficient bifunctional organocatalysts for the
enantioselective addition of 1,3-dicarbonyl compounds onto nitro-
olefins, this reaction has become a standard for the evaluation of
newly designed organocatalysts.2 Thus, continuous efforts have
been made to synthesize new ureas or other hydrogen bond donors
from accessible members of the chiral pool, such as amino acids,3
carbohydrates,4 cinchona-derived alkaloids,5 or other more sophis-
ticated scaffolds.6 The basic subunit found in the majority of these
organocatalyst is a chiral 1,2-diamine in which one of the amino
moieties will be part of a urea, which activates the electrophile
through a hydrogen bond, while the other one, as a tertiary amine,
will concomitantly act as a base for nucleophile activation.7 There-
fore, new classes of chiral and stereodefined 1,2-diamines readily
available from the chiral pool are important for the screening of
such new catalysts. We have reported that 2-cyano azetidines 1,
easily accessible from b-amino alcohols8 are ideal precursors for
a wide range of 1,2-diamines either by simple LiAlH4 reduction,
to give primary amines 2 or through a one pot two-step procedure
leading to anti-diamine 3.9,10 Furthermore, these strained 2-alkyl-
amino azetidines can be rearranged into 3-amino pyrrolidines
4.10 Thus, starting from readily available amino alcohols, a library
of stereodefined 1,2-diamines can be easily synthesized and
screened in this reaction (Fig. 1).
(1R,2S)-ephedrine 5 and (1S,2S)-pseudoephedrine 6, and that the
direction of the enantioselectivity of this reaction can be reversed
according to the nature of the 1,3-dicarbonyl nucleophile, which at
first sight is unexpected.
R3
R2
N
NH2
2
3
R1
R3
R3
R2
LiAlH4
R3
OH
R4
NH2
R2
CN
R2
N
R1
1
1) R4M
2) NaBH4
MeOH
NH
R1
N
R1
BF3(OEt)2
NH2
R3
R2
R4
N
4
R1
Figure 1. Azetidinic and pyrrolidinic 1,2-diamines are accessible from b-amino
alcohols.
As part of our program directed toward the development of
azetidines,11 we herein report the screening of thioureas derived
from these heterocyclic diamines as new organocatalysts for the
conjugate addition of 1,3-dicarbonyl compounds onto nitroolefins.
2. Results and discussion
2.1. Synthesis of catalysts
As previously described, 2-cyano azetidines 7–8 and 9–10 are
easily prepared8 in gram quantities from 5 and 6, respectively.
* Corresponding author.
E-mail address: couty@chimie.uvsq.fr (F. Couty).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.003

2386
L. Menguy, F. Couty / Tetrahedron: Asymmetry 21 (2010) 2385–2389
Table 1
Screening of the catalyst
Reduction of the cyano group with LiAlH4 gave 11–14, while addi-
tion of PhMgBr followed by reduction gave anti-diamine 15–18.
Three of the latter were also rearranged into 3-aminopyrrolidines
19–21.10 These amines were then transformed in quantitative
yields, as judged by NMR into their urea derivatives by reaction
with 3,5-bis trifluoromethyl isothiocyanate in toluene at room
temperature for 15mn. These ureas were isolated in the case of
azetidine 12 and pyrrolidine 20 (see Section 4) but it was shown
that in situ generation of the urea prior to the Michael reaction in-
stead of external addition of the catalyst was equally efficient in
terms of yield and enantioselectivity. Therefore, the above amines
can be considered as ‘pre-catalysts’ and have been used as such in
this work (see Fig. 2).
EtOOC
Ph
COOEt
NO2
cat. (10 mol%)
Toluene, rt
NO2
*
Ph
EtOOC
COOEt
1a
Entry
Pre-catalyst
Time (h)
Yielda (%)
er (S:R)b
1
2c
3
4
5
6
7
8
9
11
12
13
14
15
16
17
18
19
20
21
192
20
72
192
192
192
192
192
48
63
77
71
33:67
68:32
35:65
nd
d
—
—
d
nd
38
26
38:62
61:39
nd
—
—
d
—
No reaction
No reaction
No reaction
Ph
Ph
OH
NH
OH
NH
10
11
48
48
—
a
b
c
Yield of isolated product.
Determined by HPLC (see Section 4).
The same results were obtained with in situ generated, or externally added
5
6
catalyst.
d
Ph
N
Ph
Ph
N
Ph
N
Conversion was below 20%.
R
R
R
R
N
activity, and produced the Michael adduct in reasonable time
and yield, albeit with moderate enantioselectivity. Pyrrolidinic dia-
mines 19–21 proved completely inefficient in this reaction. The
enantioselectivity of the reaction appeared to be governed by the
configuration of the C-2 center of the azetidine (compare entries
1/2 and 6/7).
R = CN
7
8
9
10
14
R = CH2NH2 11
12
13
Ph
Ph
Ph
Ph
NH2
Ph
NH2
Ph
17
NH2
Ph
NH2
Ph
N
N
N
N
2.3. Optimization with catalyst 12
15
16
NH2
Ph
18
Thus we focused on diamine 12 to optimize its catalytic activity
by varying the nature of the solvent and of the nucleophile. These
experiments appear in Table 2.
Ph
Ph
NH2
Ph
NH2
Ph
This second set of experiments showed that toluene was indeed
the best solvent for this reaction. In this solvent, variation of the
nature of the nucleophile showed more contrasting results: malon-
onitrile gave a racemic adduct, and Meldrum’s acid reacted slug-
gishly and produced the adduct with low ee; but both rates and
enantioselectivity were nicely improved when acetylacetone was
used as the nucleophile (entry 5). In this case, the Michael reaction
was completed in 6 h, giving the adduct with 76% ee. Unexpect-
edly, the absolute configuration of the major Michael adduct was
reversed compared to the experiment with diethylmalonate
(Table 1, entry 2). Finally, a last set of experiments was conducted
by varying the nature of the b-nitrostyrene, using precatalyst 12,
and acetylacetone as the nucleophile. These experiments are
shown in Table 3, and they demonstrate the scope of this reaction,
which remains unaffected by the electronic effects on the aromatic
ring. However, a slight decrease in enantioselectivity was noticed
for meta- and para-substituted benzene rings.
Ph
N
N
N
19
21
20
Ph
H
H
N
F3C
N
CF3
N
NCS
S
22
CF3
F3C
or
12 or 20
quant.
H
H
N
Ph
N
CF3
S
Ph
N
CF3
23
Figure 2. Structure of ephedrine-derived azetidinic and pyrrolidinic 1,2-diamines
screened in this work.
Table 2
2.2. Screening of the catalyst
Screening of solvent and nucleophile with precatalyst 12
Entry
Solvent/nucleophile
Time (h)
Yielda (%)
er (S:R)b
Having a small library of diamines in hand, these compounds
were evaluated in the standard reaction of diethyl malonate react-
ing with b-nitrostyrene in toluene at room temperature to give ad-
duct 1a. The results are shown in Table 1.
This first set of experiments demonstrates that both the nature
of the aza-heterocycle (azetidine or pyrrolidine), and relative con-
figurations of the substituents on these scaffolds have a profound
influence on the efficiency of this reaction. Only azetidinic diamine
12, (entry 2) derived from (ꢀ)-ephedrine displayed high catalytic
1
2
3
4
5
6
Diethyl malonate/DCM
Diethyl malonate/diethyl ether
Diethyl malonate/MeCN
Malononitrile/toluene
Acetylacetone/toluene
Meldrum’s acid/toluene
72
72
168
6
6
144
61
69
26
57
63
40
70:30
71:29
65:35
50:50
12:88
40:60c
a
b
c
Yield of isolated product.
Determined by HPLC (see Section 4).
Determined after chemical correlation to diethylmalonate adduct.1b

L. Menguy, F. Couty / Tetrahedron: Asymmetry 21 (2010) 2385–2389
2387
Table 3
Scope for different b-nitrostyrene with precatalyst 12 and acetylacetone
precat. 12
S
N
+
3,5-bis-trifluoromethyl isothiocyanate
(10 mol%)
N
N
NO2
MeOC
Ar
COMe
NO2
H
Ar
EtO2C
Ph
CO2Et
NO2
Ar
Si Face
O
H
H
+
attack
N
Toluene, rt
O
O
MeOC
COMe
O
1b-i
(S)
EtO
OEt
Entry
Ar
Time (h)
6
Yielda (%)
er (S:R)b
1
2
63 1b
12:88
3A: Takemoto's Model
24
74 1c
10:90
OMe
NO2
S
N
3
4
5
24
24
24
78 1d
79 1e
67 1f
8:92
17:83
7:93
N
H
N Ar
MeOC
Ph
COMe
NO2
O
H
O
Re Face
H
O
O
attack
N
MeO
(R)
O N
2
3B: Pápai's Model
6
24
79 1g
17:83
Figure 3. Takemoto (3A) and Pápai’s (3B) models account for our observed reversal
of enantioselectivity.
7
8
Cl
Br
24
3
65 1h
62 1i
15:85
13:87
S
not the case in Pápai’s calculation). Thus, our experimental results
provide indirect suspicion that these different mechanisms are in-
deed operating in our case and demonstrate that the nature of the
1,3-dicarbonyl nucleophile can have a profound influence on the
enantioselectivity of the related reactions. It should be noted that
the same direction of enantioselection is observed for acetylace-
tone (pKa 9), and Meldrum’ acid (pKa 4.97) (Table 2, entry 6), which
is also indicative of the same mechanism operating with these two
acidic nucleophiles compared to diethylmalonate (pKa 13).
Work is currently in progress in our group in order to screen
other members of this class of heterocycles in organocatalyzed
reactions.
a
Yield of isolated product.
Determined by HPLC (see Section 4).
b
3. Conclusion
In this study, we have demonstrated that efficient catalysts can
be discovered by screening a library of 1,2-diamines prepared from
2-cyano azetidines.11 These azetidines are easily accessed from
commercially available b-amino alcohols, and they are convenient
scaffolds for molecular diversity.12 An interesting finding in this
study is the reversal of the absolute configuration in the Michael
adduct produced, when diethylmalonate or acetylacetone is used.
To the best of our knowledge, this observation is unprecedented
since Takemoto1 first reported that his cyclohexylamine-derived
catalyst induced the same absolute configuration in the Michael
adduct with diethyl malonate and acetylacetone.13 In our case, this
inversion suggests that a completely different mode of activation is
operating depending on the nature of these nucleophiles. As a mat-
ter of fact, experimental, theoretical, and mechanistical studies of
this reaction have witnessed the emergence of two possible mech-
anisms: Takemoto initially proposed that (with malonate as a
nucleophile), the ternary complex leading to the more favorable
transition state involves binding of the nitrostyrene with the urea
through H-bonding, and concommitent deprotonation of the enol
form of the malonate by the proximate tertiary amine, as schema-
tized in Figure 3A, with catalyst derived from 12. This route was la-
ter confirmed by Liu et al.14 by DFT calculations. The same year,
Pápai15 proposed an alternative route (with acetylacetone), involv-
ing an inverted scenario, that is, binding of the nitrostyrene to the
ammonium resulting from the enolization of the 1,3-diketone, and
binding of the enolate to the urea (Fig. 3B). This change in scenario,
which is logical, considering the differences of pKa values for these
nucleophiles can of course induce a change in enantioselectivity if
the prochiral face of the electrophile remains the same (which was
4. Experimental
4.1. General
Amino azetidines and pyrrolidines 11–21 were prepared fol-
lowing our previously reported procedures (see Section 1). All
chemicals were used as received unless otherwise noted. Toluene
was dried by a dehydrating system MB-SPS 800 (Mbraun). 1H
and 13C NMR spectra were collected on a Bruker Avance 300
NMR spectrometer. High resolution mass spectra (HR-MS) were
obtained on a Waters Micromass Q-Tof Micro instrument. Optical
rotations were determined on a Perkin Elmer 341 polarimeter.
Enantiomeric excesses were measured by HPLC at room tempera-
ture using Jasco PU-2089 pump equipped with UV detector and
Chiralpak AD-H (4.6 mm ꢁ 250 mm), AD (4.6 mm ꢁ 250 mm), AS-
H (4.6 mm ꢁ 250 mm).
4.2. Synthesis of catalysts
4.2.1. 1-((2R,3S,4S)-3-Phenyl-1,2,4-trimethylazetidinic)-3-(3,5-
bis(trifluoromethyl)phenyl) thiourea 22
Under an argon atmosphere, to a solution of (2R,3S,4S)-2-(1-amino-
methyl)-1,4-dimethyl-3-phenyl-azetidine 12 (160 mg, 0.84 mmol)

2388
L. Menguy, F. Couty / Tetrahedron: Asymmetry 21 (2010) 2385–2389
in dry toluene (9.5 mL) was added 3,5-bis-(trifluoromethyl)phenyl
isothiocyanate (1.0 equiv, 228 mg). After the reaction mixture was
stirred for 30 min at room temperature, the reaction mixture was
concentrated in vacuo. The residue was purified by preparative
TLC (10:90, MeOH/CH2Cl2, Rf = 0.46) to give the desired thiourea
22 as pale yellow amorphous solid (169 mg, 41%); mp 84–86 °C.
mo-2-(2-nitro-vinyl)-thiophene (150 mg, 0.6 mmol) in dry toluene
(0.5 mL) and acetylacetone (2 equiv, 128 mg) under an argon atmo-
sphere. Upon consumption of the nitroolefin substrate after 6 h
(monitored by TLC), the reaction mixture was concentrated and
purified by preparative TLC (25:75, AcOEt/pentane, Rf = 0.10) to
yield a brown powder 1i (132 mg, 62%). mp 67 °C; ½a D25
¼ ꢀ30:0
ꢂ
½
a 2D5
ꢂ
¼ þ12:7 (c 1.2, CH2Cl2); FTIR mmax 3250, 3097, 2927, 2852,
1594, 1472, 1373, 1274, 1167, 1123, 881, 840, 726, 702,
681 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.42–7.09 (m, 8H), 5.22
(c 0.2, CH2Cl2); FTIR mmax 3080, 2922, 1726, 1547, 1430, 1361,
1251, 1142, 963, 795 cmꢀ1 1H NMR (300 MHz, CDCl3) d 6.89–6.87
.
.
(d, J = 4 Hz, 1H), 6.67–6.65 (d, J = 4 Hz, 1H), 4.65–4.62 (m, 2H),
4.41 (m, 1H), 4.34 (d, J = 10 Hz, 1H), 2.30 (s, 3H), 2.14 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 201.2, 200.4, 140.1, 130.1, 127.6, 112.6,
78.0, 70.4, 38.5, 30.6, 29.9; HRMS (ESI) m/z calcd for C11H12BrNO4S
[M+Na]+: 355.9568, found: 355.9573. HPLC [CHIRALPAKÒ AD, 2-
propanol/heptane = 20/80, 0.8 mL/min, k = 244 nm, retention times:
(minor) 10.2 min, (major) 12.8 min].
(br s, 2H), 4.12 (m, 1H), 3.28 (dd, J = 10.9 Hz, J = 6.8 Hz, 1H), 3.10
(dd, J = 10.9 Hz, J = 8.8 Hz, 1H), 2.97 (dd, J = 6.6 Hz, J = 10.7 Hz
1H), 2.87 (m, 1H), 2.36 (s, 3H), 0.88 (d, J = 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 164.1, 150.2, 137.7, 132.6, 132.2, 131.8, 129.2,
128.9, 128.8, 127.8, 125.1, 122.0, 116.2, 58.5, 54.8, 52.6, 50.8,
32.9, 15.5; HRMS (ESI) m/z calcd for
C
21H21F6N3S [M+H]+:
462.1439, found: 462.1432.
4.3.3. (S)-Ethyl-2-(carboxyethyl)-4-nitro-3-phenylbutyrate 1a
Colorless needles.1a 1H NMR (300 MHz, CDCl3) d 7.42–7.10 (m,
5H), 4.93 (dd, J = 4.6, 13.1 Hz, 1H), 4.86 (dd, J = 9.2, 13.1 Hz, 1H),
4.33–4.15 (m, 3H), 4.00 (q, J = 7.2 Hz, 2H), 3.82 (d, J = 9.5 Hz, 1H),
1.25 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H); HPLC [CHIRALPAKÒ
AD-H, 2-propanol/heptane = 20/80, 0.8 mL/min, k = 213 nm, reten-
tion times: (major) 12.6 min, (minor) 34.8 min].
4.2.2. 1-((2R,3S,4R,5R)-1,5-Dimethyl-2,4-diphenylpyrrolidinic)-
3-(3,5-bis(trifluoromethyl)phenyl) thiourea 23
Under an argon atmosphere, to a solution of (2R,3S,4R,5R)-3-amino-
1,5-dimethyl-2,4-diphenyl-pyrrolidine 20 (118 mg, 0.45 mmol) in
toluene (6.6 mL) was added 3-(-bis(trifluoromethyl)phenyl
isothiocyanate (1.0 equiv, 122 mg). After the reaction mixture
was stirred for 30 min at room temperature, the reaction mixture
was concentrated in vacuo. The residue was purified by prepara-
tive TLC (30:70, AcOEt/pentane, Rf = 0.68) to give a viscous yellow
4.3.4. (R)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione 1b
White solid;6a mp 114–116 °C. 1H NMR (300 MHz, CDCl3): d
7.37–7.18 (m, 5H), 4.58–4.67 (m, 2H), 4.36–4.40 (d, J = 10.8 Hz,
1H), 4.21–4.28 (m, 1H), 2.30 (s, 3H), 1.94 (s, 3H); HPLC [CHIR-
ALPAKÒ AS-H, 2-propanol/heptane = 20/80, 0.8 mL/min, k = 215
nm, retention times: (minor) 15.0 min, (major) 24.9 min].
oil 23 (133 mg, 61%). ½a D25
ꢂ
¼ þ68:5 (c 0.2, CH2Cl2); FTIR
mmax 3300,
3031, 2932, 2780, 1525, 1380, 1171, 1125, 884, 846, 762, 699,
681 cmꢀ1 1H NMR (300 MHz, CDCl3) d 8.16 (br s, 1H), 7.49–7.15
.
(m, 13H), 5.80 (br s, 1H), 5.23 (br s, 1H), 4.08 (br s, 1H), 3.73 (br
s, 1H), 3.64 (m, 1H), 2.02 (s, 3H), 0.86 (d, 3H); 13C NMR (75 MHz,
CDCl3) d 180.1, 130.4, 128.7, 123.8, 119.1, 72.6, 65.1, 61.4, 51.8,
4.3.5. (R)-3-(1-Naphthalen-1-yl)-2-nitroethyl)pentane-2,4-
dione 1c
34.5, 15.1; HRMS (ESI) m/z calcd for
C
27H25F6N3S [M+H]+:
538.1752, found: 538.1732.
Yellow viscous oil.4a 1H NMR (300 MHz, CDCl3,) d 8.18–7.27 (m,
7H), 5.20 (m, 1H), 4.81 (dd, J = 12.0, J = 6.6 Hz, 1H), 4.75–4.68 (m,
2H), 2.31 (s, 3H), 1.86 (s, 3H); HPLC [CHIRALPAKÒ AS-H, 2-propa-
nol/heptane = 20/80, 0.8 mL/min, k = 215 nm, retention times:
(minor) 17.1 min, (major) 23.4 min].
4.3. General procedure for enantioselective Michael addition of
1,3 dicarbonyl compounds to nitroolefins
4.3.1. (R)-3-(1-(3-Nitrophenyl)-2-nitroethyl)pentane-2,4-dione
1g
4.3.6. (R)-3-(1-(2-Methoxyphenyl)-2-nitroethyl)pentane-2,4-
dione 1d
To a stirred solution of (2R,3S,4S)-2-(1-amino-methyl)-1,4-di-
methyl-3-phenyl-azetidine 12 (0.1 equiv, 12 mg) and 3,5-bis(tri-
fluoromethyl)phenyl isothiocyanate (0.1 equiv, 17 mg) in dry
toluene (0.9 mL) were added after 30 min a solution of (E)-1-ni-
tro-3-(2-nitro-vinyl)-benzene (123 mg, 0.6 mmol) in dry toluene
(0.5 mL) and acetylacetone (2 equiv, 128 mg) under an argon atmo-
sphere. Upon consumption of nitroolefin substrate in 24 h (moni-
tored by TLC), the reaction mixture was concentrated and purified
by preparative TLC (25:75, AcOEt/pentane, Rf = 0.20) to yield 1g as
Orange viscous oil.6d 1H NMR (300 MHz, CDCl3) d 7.29–7.25 (m,
1H), 7.09–7.07 (m, 1H), 6.88–6.92 (m, 2H), 4.82–4.75 (m, 1H),
4.61–4.49 (m, 3H), 3.89 (s, 3H)), 2.28 (s, 3H), 1.94 (s, 3H); HPLC
[CHIRALPAKÒ AS-H, 2-propanol/heptane = 20/80, 0.8 mL/min,
k = 215 nm, retention times: (minor) 14.7 min, (major) 15.0 min].
4.3.7. (R)-3-(1-(4-Methoxyphenyl)-2-nitroethyl)pentane-2,4-
dione 1e
an orange oil (147 mg, 79%). ½a D25
¼ ꢀ21:7 (c 1.3, CH2Cl2); FTIR mmax
ꢂ
Pale yellow solid;4a mp 117 °C. 1H NMR (300 MHz, CDCl3) d 7.10
(d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 4.61–4.57 (m, 2H), 4.35
(d, J = 11.0 Hz, 1H), 4.24–4.18 (m, 1H), 3.78 (s, 3H), 2.29 (s, 3H;
CH3), 1.95 (s, 3H); HPLC [CHIRALPAKÒ AD, 2-propanol/heptane =
20/80, 0.8 mL/min, k = 215 nm, retention times: (minor) 13.6 min,
(major) 19.9 min].
3069, 2963, 2919, 1716, 1548, 1527, 1349, 1250, 1171, 1142, 912,
738, 692 cmꢀ1 1H NMR (300 MHz, CDCl3) d 8.17–8.13 (m, 2H),
.
7.60–7.51 (m, 2H), 4.77–4.65 (m, 2H), 4.47 (d, J = 12 Hz, 1H), 4.40
(m, 1H), 2.33 (s, 3H), 2.05 (s, 3H); 13C NMR (75 MHz, CDCl3) d
200.9, 200.1, 148.5, 138.5, 134.5, 130.3, 123.5, 122.7, 77.4, 69.9,
42.2, 30.5, 30.1; HRMS (ESI) m/z calcd for C13H14N2O6 [M+Na]+:
317.0750, found: 317.075. HPLC [CHIRALPAKÒAS-H, 2-propanol/
heptane = 20/80, 0.8 mL/min, k = 215 nm, retention times: (minor)
31.0 min, (major) 50.2 min].
4.3.8. (R)-3-(1-(2-Nitrophenyl)-2-nitroethyl)pentane-2,4-dione
1f
Pale yellow solid;6c mp 112–114 °C. 1H NMR (300 MHz, CDCl3) d
7.93 (dd, J = 8.0, J = 1.4 Hz, 1H), 7.58–7.36 (m, 3H), 4.97 (dd,
J = 13.3, J = 7.1 Hz, 1H), 4.84 (dd, J = 13.3, J = 3.7 Hz, 1H), 4.73
(ddd, J = 8.7, J = 7.2, J = 3.7 Hz, 1H), 4.67 (d, J = 8.7 Hz, 1H), 2.31 (s,
3H), 2.13 (s, 3H); HPLC [CHIRALPAKÒ AS-H, 2-propanol/heptane =
20/80, 0.8 mL/min, k = 215 nm, retention times: (minor) 27.3 min,
(major) 28.4 min].
4.3.2. (R)-3-(1-(5-Bromothienyl)-2-nitroethyl)pentane-2,4-
dione 1i
To a stirred solution of (2R,3S,4S)-2-(1-amino-methyl)-1,4-di-
methyl-3-phenyl-azetidine 12 (0.1 equiv, 12 mg) and 3,5-bis-
(trifluoromethyl)phenyl isothiocyanate (0.1 equiv, 17 mg) in dry
toluene (0.9 mL) were added after 30 min a solution of (E)-5-bro-

L. Menguy, F. Couty / Tetrahedron: Asymmetry 21 (2010) 2385–2389
2389
Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4932–4933; (e) Song, J.; Wang, Y.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 6048–6049.
4.3.9. (R)-3-(1-(4-Chlorophenyl)-2-nitroethyl)pentane-2,4-
dione 1h
6. (a) Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4713–4716; (b)
Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454–1455; (c)
Malerich, J.; Hagihara, K.; Rawal, H. J. Am. Chem. Soc. 2008, 130, 14416–14417;
(d) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chem. Commun. 2008, 1431–
1433; (e) Peng, F.-Z.; Shao, Z.-H.; Fan, B.-M.; Song, H.; Li, G.-P.; Zhang, H.-B. J.
Org. Chem. 2008, 73, 5202–5205; (f) Jiang, X.; Zhang, Y.; Liu, X.; Zhang, G.; Lai,
L.; Wu, L.; Zhang, J.; Wang, R. J. Org. Chem. 2009, 74, 5562–5567; (g) Almasi, D.;
Alonso, D. A.; Gómez-Bengoa, E.; Nàjera, C. J. Org. Chem. 2009, 74, 6163–6168;
(h) McGarraugh, P. G.; Brenner, S. E. Tetrahedron 2009, 65, 449–455; (i) Thai, K.;
Gravel, M. Tetrahedron: Asymmetry 2010, 21, 751–755.
Pale yellow solid;4a mp 121 °C. 1H NMR (300 MHz, CDCl3) d 7.30
(d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.60 (d, J = 5.7 Hz, 2H), 4.32
(d, J = 10.8 Hz, 1H), 4.26–4.18 (m, 1H), 2.29 (s, 3H), 1.97 (s, 3H);
HPLC [CHIRALPAKÒ AD, 2-propanol/heptane = 20/80, 0.8 mL/min,
k = 215 nm, retention times: (minor) 12.9 min, (major) 30.6 min].
Acknowledgments
7. For selected reviews on this topic, see: (a) Almaßsi, D.; Alonso, D. A.; Nájera, C.
Tetrahedron: Asymmetry 2007, 18, 299–365; (b) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713–5743; (c) Dondoni, A.; Massy, A. Angew. Chem., Int.
Ed. 2008, 47, 4638–4660; (d) Zhang, Z. G.; Schreiner, P. R. Chem. Soc. Rev. 2009,
38, 1187–1198.
CNRS and University of Versailles St-Quentin-en-Yvelines are
acknowledged for financial support.
8. Agami, C.; Couty, F.; Evano, G. Tetrahedron: Asymmetry 2002, 13, 297–302.
9. Couty, F.; Evano, G.; Prim, D.; Marrot, J. Eur. J. Org. Chem. 2004, 3893–3897.
10. Vargas-Sanchez, M.; Couty, F.; Evano, G.; Prim, D.; Marrot, J. Org. Lett. 2005, 7,
5861–5864.
11. For other applications of azetidines as ligands in enantioselective catalysis, see:
Couty, F.; Evano, G.; Prim, D. Mini-Rev. Org. Chem. 2004, 1, 133–148. and
references cited therein.
12. Couty, F.; Evano, G. Synlett 2009, 3053–3064.
13. In the initial report of Takemoto (Ref. 1b), the absolute configuration of the
acetylacetone adduct on b-nitrostyrene was not determined. It was later on
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