Organocatalyzed aziridination of α-branched enals: Enantioselective synthesis of aziridines with a quaternary stereocenter

Article abstract of DOI:10.1002/ejoc.201100437

Organocatalytic access to N-tosylaziridines catalyzed by diarylprolinol trimethylsilyl ether [Ar = 3,5-(CF₃)₂C₆H ₃] starting from different α-substituted-α,β- unsaturated aldehydes is described. The products wer

Full text of DOI:10.1002/ejoc.201100437

FULL PAPER
DOI: 10.1002/ejoc.201100437
Organocatalyzed Aziridination of α-Branched Enals: Enantioselective Synthesis
of Aziridines with a Quaternary Stereocenter
Alaric Desmarchelier,[a] Danilo Pereira de Sant’Ana,[b] Vincent Terrasson,[b]
Jean Marc Campagne,[b] Xavier Moreau,[a] Christine Greck,*[a] and
Renata Marcia de Figueiredo*[b]
Keywords: Aldehydes / Nitrogen heterocycles / Domino reactions / Organocatalysis / Chirality
Organocatalytic access to N-tosylaziridines catalyzed by di-
arylprolinol trimethylsilyl ether [Ar = 3,5-(CF3)2C6H3] start-
ing from different α-substituted-α,β-unsaturated aldehydes is
described. The products were obtained in good yields (up to
86%) and enantioselectivities (up to 90%ee) and could
rapidly be transformed under various conditions, including
ring opening, to afford useful small molecules possessing not
only the aziridine and aldehyde moieties but also other func-
tionalities such as alcohol, acid, ester, or amino alcohol.
Introduction
The use of chiral secondary amines as organocatalysts to
activate α,β-unsaturated aldehydes has, over the last few
years, witnessed considerable development[1,2] and numer-
ous nucleophiles (electron-rich aromatics; malonates; hy-
drides; nitrogen, oxygen, and sulfur nucleophiles) have been
successfully used in these asymmetric Michael-type ad-
ditions [Scheme 1, Equation (1)]. Moreover, in the presence
of a suitable electrophile, the intermediate enamine can also
be trapped, intra- or intermolecularly, in a tandem imin-
ium–enamine domino process [Scheme 1, Equation (2)].[3,4]
This concept has initially been illustrated by developing
highly efficient cyclopropanation,[5] epoxidation,[6] and azir-
idination[7] reactions.
Scheme 1. Tandem iminium–enamine domino process.
Paradoxically, until very recently,[8] the use of α-branched
α,β-unsaturated aldehydes (Scheme 2) in these reactions has
been scarcely described, and sluggish enamine activation
rates or even inert capacities are generally observed for sec-
ondary amino catalysts, which usually results in moderate
stereoselectivity at the α-position.[9] Stimulated by a seminal
paper by Melchiorre[8b] on the intermolecular aryl amin-
ation and thioamination of α-branched α,β-unsaturated al-
dehydes, we thus embarked on a program dealing with the
functionalization of these α-branched enals in the presence
of ambiphilic (bearing both nucleophilic and electrophilic
parts) substrates such as bromomalonates, activated hy-
droxylamines, or hydrogen peroxide (Scheme 2).
[a] Institut Lavoisier de Versailles, UMR CNRS 8180, Université
de Versailles-Saint-Quentin-en-Yvelines,
45, Avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax: +33-1-39254452
E-mail: greck@chimie.uvsq.fr
[b] Institut Charles Gerhardt Montpellier, UMR 5253 CNRS-
UM2-UM1-ENSCM, Ecole Nationale Supérieure de Chimie,
8 Rue de l’Ecole Normale
Scheme 2. Functionalization of α-branched enals with ambiphilic
A-LG substrates. P = protecting group.
34296 Montpellier Cedex 5, France
Fax: +33-4-67144322
We first examined the use of bromomalonates in these
reactions with the aim to construct cyclopropanes bearing
a chiral quaternary center.[8c] Previously described catalytic
E-mail: renata.marcia_de_figueiredo@enscm.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100437.
4046
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4046–4052

Organocatalyzed Aziridination of α-Branched Enals
systems[5a,5b] proved in this case inefficient, leading to either carbamate-protected aziridines either by NaBH4 reduction
low enantioselectivity (Córdova’s conditions in the presence or Horner–Wadsworth–Emmons reactions also proved to
of triethylamine) or no conversion (Wang’s conditions using give, in our hands, extensive decomposition. Indeed, it has
2,6-lutidine in dichloromethane). However, moving to eth- been previously shown that carbamate N-protected carb-
anol at room temperature, in the presence of 2,6-lutidine, oxylate aziridines are sensitive towards ring-opening reac-
the corresponding cyclopropanes could be obtained in good tions in the presence of different nucleophiles,[12] which
yields and enantioselectivities. It should also be emphasized could be explained through anchimeric assistance of the
that replacing 2,6-lutidine with N-methylimidazole resulted carbamate.[13] To avoid this problem of stability, other nitro-
in a considerably shorter reactions time (144 and 3 h, gen protecting groups were explored.
respectively; Scheme 3).
Scheme 4. Aziridination using different N-protected-O-(p-tolu-
enesulfonyl)hydroxylamines 2.
Fortunately, moving from carbamates to sulfonamide
(TsNHOTs) afforded stable carbaldehyde 3a in excellent
yield (95%) and moderate enantioselectivity (67%). On the
basis of this preliminary result, we then decided to screen
different catalysts and solvents to optimize the reaction
conditions and to improve the selectivities (Table 1). As an-
ticipated, the enantioselectivity was very poor when proline
(II) or trifluoromethyl-substituted diaryl prolinol III was
used as the catalyst (Table 1, Entries 2 & 3). Hayashi–
Jørgensen catalyst IV did not improve the result in terms
of selectivity (Table 1, Entry 4). Diaryl prolinol silyl ether I
was found to be the most efficient catalyst (Table 1, En-
Scheme 3. Cyclopropanation of α-branched enals.[8c]
try 1). The reaction was not efficient in either polar solvents
such as MeCN, THF, or DMF (Table 1, Entries 6–8) or in
Starting from these initial results, we next planned to ex-
protic polar solvent such as iPrOH (Table 1 as observed
plore other ambiphilic substrates such as activated hydrox-
when the reaction was conducted in toluene (60% yield,
ylamines. A recent publication by Córdova[8g] describing re-
70%ee; Table 1, Entry 11). We then tried to catalyze the
lated experiments prompts us to disclose our findings in this
reaction with sterically hindered catalyst V,[14] but we did
area. Thus, in this paper, we report our efforts towards the
not observe any enhancement in terms of reactivity or selec-
enantioselective aziridination of α-substituted α,β-unsatu-
tivity (Table 1, Entry 12). Finally, the best result was ob-
rated aldehydes 1 with N-protected-O-(p-toluenesulfonyl)-
tained when the reaction was run at 0 °C in toluene. In this
hydroxylamines 2.
case, carbaldehyde 3a was isolated in 72% yield and 80%ee
(Table 1, Entry 13).
With these conditions in hand, we then turned our atten-
tion to the scope of the aziridination reaction using various
Results and Discussion
Our investigations started by exploring the capacity of 2- aldehydes[15] (Table 2). All reactions were very clean and N-
benzylpropenal (1a) to undergo aziridination in the pres- tosylaziridines were obtained in good yields (69–86%) and
ence of different N-protected-O-(p-toluenesulfonyl)hydrox- acceptable enantioselectivities (up to 90%ee). Different
ylamines 2 by using the conditions described by Jørgensen alkyl groups at the α-position of the aldehyde (R = Bn, Me,
(Scheme 4).[10] When the nitrogen was protected as a carb- Pent, and iPr) were well tolerated (Table 2, Entries 1–4).
amate such as Cbz, Boc, or Alloc,[11] the reaction proved to Functionalized aldehydes can also efficiently participate in
be very efficient as judged by a clean and complete conver- these reactions (Table 2, Entries 5 & 6). A terminal olefin
sion (the crude product was checked by 1H NMR spec- side chain at the α-position can take part in the transforma-
troscopy) to aziridines. However, we were unable to purify tion with a good 84%ee and 82% yield (Table 2, Entry 5).
these compounds on silica gel (even if the silica gel was A bromide-substituted chain was also a suitable substrate
pretreated with Et3N) or alumina, as any attempt led to to afford the corresponding N-tosylaziridine 3f in 78% yield
extensive decomposition. Further transformations of crude and 79%ee (Table 2, Entry 6).
Eur. J. Org. Chem. 2011, 4046–4052
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Table 1. Catalyst and solvent screening.[a]
Table 2. Aldehyde scope of organocatalytic aziridination.[a]
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13[d]
I
II
III
IV
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CH3CN
THF
95
56
56
82
95
82
66
63
69
63
60
55
72
67
7
9
37
67
28
26
17
38
63
70
70
80
I
I
I
DMF
I
iPrOH
hexane
toluene
toluene
toluene
I
I
V
I
[a] Reaction conditions: 2-benzylpropenal (0.50 mmol), TsNHOTs
(0.25 mmol), NaOAc (0.75 mmol), catalyst (0.05 mmol), and sol-
vent (1.25 mL) at r.t. for 4.5 h. See the Experimental Section for
details. Ar = 3,5-(CF3)2C6H3. [b] Isolated yield after column
chromatography. [c] The ee was determined by chiral-phase HPLC
analysis after conversion of the aldehyde into its corresponding un-
saturated ester. [d] Reaction run at 0 °C over 15 h.
Our next goal was to determine the absolute configura-
tion of aziridines 3. Aziridine 3b was thus converted into
known aziridine 4 by first converting the aldehyde into the
primary alcohol and then protecting it as a TBDPS silyl
[a] Reaction conditions: aldehyde (0.50 mmol), TsNHOTs
(0.25 mmol), NaOAc (0.75 mmol), catalyst (0.05 mmol), and sol-
vent (1.25 mL) at 0 °C for 15 h. See the Experimental Section for
details. [b] Isolated yield after column chromatography. [c] The ee
ether (Scheme 5). The optical rotation of compound 4 was determined by chiral-phase HPLC analysis. [d] The ee was de-
{[α]2D0 = –28 (c = 1, CH2Cl2)} was found to be in good
termined by chiral-phase HPLC analysis after conversion of the
aldehyde into its corresponding unsaturated ester (see the Experi-
mental Section for details).
agreement with that reported value {[α]2D6 = –25.8 (c = 1.1,
CH2Cl2)}.[16] The absolute configuration of the quaternary
stereocenter formed during this sequence was determined
to be (S), in agreement with the absolute configuration ob-
served with cyclopropanes (Scheme 3).
To illustrate the synthetic scope of this methodology, we
modified resulting N-tosylaziridine aldehyde 3a, as shown
in Scheme 6. The aldehyde moiety was oxidized under
smooth conditions to afford N-protected cyclic amino acid
5 (91% yield), or it was transformed into compound 6
through Wittig olefination (78% yield), or it was reduced
Scheme 5. Determination of the absolute configuration.
and protected as a silyl enol ether to give rise to fully pro-
tected cyclic amino alcohol 7 (77% yield from 3a). To syn-
thesize quaternary α-amino acids,[17] aziridine 5 was treated cuprate Bu2CuCNLi2, and opening product 8 (29% yield
with the higher order cuprate Bu2CuCNLi2. Unfortunately, from 3a) was obtained. The ring opening of aziridine 7 was
the corresponding amino acid was not observed. In a sec- also effective with a nitrogen nucleophile to give protected
ond attempt, aziridine 7 was treated with the higher order diamino alcohol 9 (66% yield from 3a).[16]
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Organocatalyzed Aziridination of α-Branched Enals
traces were compared with racemic samples obtained by using a
mixture of (R)- and (S)-diphenylprolinol trimethylsilyl ether as cat-
alyst. The α-methylene aldehydes were prepared according to the
procedure described by Pihko.[15] 4-Methyl-N-(tosyloxy)benzene-
sulfonamide (TsNHOTs) was synthesized following Jørgensen’s
procedure.[10a]
General Procedure for the Organocatalyzed Asymmetric Aziridin-
ation: To a solution of α-substituted α,β-unsaturated aldehyde 1
(0.50 mmol, 2.00 equiv.) in toluene (1.25 mL) was successively
added TsNHOTs (85.4 mg, 0.25 mmol, 1.00 equiv.), NaOAc
(262 mg, 0.75 mmol, 3.00 equiv.), and organocatalyst I (30.0 mg,
0.05 mmol, 20 mol-%). The reaction mixture was rapidly cooled to
0 °C and stirred for 15 h. The reaction mixture was then filtered
through a pad of Celite (EtOAc), and the solvent was evaporated.
Purification was performed by column chromatography on silica
gel (pentane/Et2O, 6:1) to afford aziridines 3a–f.
(S)-2-Benzyl-1-tosylaziridine-2-carbaldehyde (3a): Yield: 61.0 mg
(72%); HPLC analysis was not performed on the aldehyde but on
its corresponding unsaturated ester (see below, compound 6). [α]2D0
1
= +56 (c = 1, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 9.46 (s,
1 H), 7.78 (d, J = 8.3 Hz, 2 H), 7.33 (d, J = 8.1 Hz, 2 H), 7.25–
7.18 (m, 5 H), 3.28 (s, 2 H), 3.19 (s, 1 H), 2.64 (s, 1 H), 2.45 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.2, 145.0, 136.0,
135.5, 130.0, 129.9, 128.4, 127.7, 127.0, 56.0, 38.1, 33.8, 21.8 ppm.
Scheme 6. Reagents and conditions: (a) KH2PO4, NaClO2, H2O2,
MeOH/MeCN/H2O (1:1:1), 0 °C to r.t., 2 h, 91%;
(b) Ph3PCHCO2Me, THF, 0 °C to r.t., 2 h, 78%; (c) 1. NaBH4,
EtOH, 0 °C, 15 min, 89%; 2. TBDMSCl, imidazole, CH2Cl2, 0 °C
to r.t., overnight, 87%; (d) Bu2CuCNLi2, THF, –78 °C to r.t., over-
night, 38%; (e) BnNH2, reflux, 42 h, 85%. See the Experimental
Section for details.
FTIR: ν = 2927, 2856, 1724, 1593, 1313, 1274, 1156, 1093, 986,
˜
876, 812, 690 cm–1. HRMS: calcd. for C17H17NO3SNa [M + Na]+
338.0827; found 338.0818.
(S)-2-Methyl-1-tosylaziridine-2-carbaldehyde (3b): Yield: 42.0 mg
(70%); HPLC analysis was not performed on the aldehyde but on
its corresponding unsaturated ester (see below). [α]2D0 = +36 (c = 1,
Conclusions
We have described straightforward organocatalytic access
to N-tosylaziridines derived from α-branched enals. The
transformation takes place through iminium/enamine catal-
ysis in the presence of diarylprolinol trimethylsilyl ether I
[Ar = 3,5-(CF3)2C6H3] and gives rise to aziridines bearing
1
CH2Cl2). H NMR (200 MHz, CDCl3): δ = 9.07 (s, 1 H), 7.85 (d,
J = 8.2 Hz, 2 H), 7.36 (d, J = 8.2 Hz, 2 H), 2.88 (s, 1 H), 2.83 (s,
1 H), 2.45 (s, 3 H), 1.68 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 195.6, 145.1, 136.4, 129.9, 127.8, 52.1, 37.9, 21.8, 12.8 ppm.
FTIR: ν = 2919, 2848, 1720, 1590, 1321, 1160, 1120, 880, 832,
˜
a quaternary stereocenter in good yields (up to 86%) and 686 cm–1. HRMS: calcd. for C11H14NO3S [M + H]+ 240.0694;
found 240.0685.
enantioselectivities (up to 90%ee). Preliminary and promis-
ing studies on the ring opening of the obtained aziridines
were realized, which allowed us to prepare useful small mo-
lecules possessing not only the aziridine and aldehyde moie-
ties but also other functionalities (Scheme 6). Undoubtedly,
all these possibilities provide versatile synthetic tools for the
asymmetric synthesis of more complex molecules, and fur-
ther work is aimed to this purpose within our research
groups.
(R,E)-Methyl 3-(2-Benzyl-1-tosylaziridin-2-yl)acrylate: To a stirred
solution of 3b (30.0 mg, 0.12 mmol) in THF (1.20 mL) at 0 °C was
added methyl (triphenylphosphoranylidene)acetate (50.0 mg,
0.15 mmol). The mixture was warmed to room temperature and
stirred for 2 h. The reaction was then quenched with a saturated
aqueous solution of NH4Cl and extracted with EtOAc (3ϫ). The
combined organic phases were washed with brine, dried with
MgSO4, filtered, and concentrated under reduced pressure. Purifi-
cation was performed by column chromatography on silica gel
(pentane/Et2O, 6:1) to afford the desired compound. Yield: 76%;
90%ee; HPLC (AD-H column, heptane/iPrOH = 80:20, flow rate
= 0.8 mL/min, 30 °C, λ = 260 nm): tR = 9.1 (minor), 10.1
(major) min. [α]2D0 = –26 (c = 1, CH2Cl2). 1H NMR (200 MHz,
CDCl3): δ = 7.82 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H),
6.90 (d, J = 15.7 Hz, 1 H), 6.07 (d, J = 15.7 Hz, 1 H), 3.74 (s, 3
Experimental Section
General Information: Unless otherwise stated all commercial mate-
rials were used without further purification. TLC analysis of all
reactions was performed on silica gel 60 F254 TLC plates and re-
vealed at 254 nm UV light and/or with phosphomolybdic acid
stain. Flash chromatography was carried out on silica gel 60 A (35–
70 μm). 1H and 13C NMR spectra were recorded at 200 and
50 MHz or 300 and 75 MHz, respectively. Chemical shifts (δ) for
1H and 13C are given in ppm relative to residual signal of the sol-
vent (CHCl3). The following abbreviations are used to indicate the
multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br. s, broad signal. High-resolution mass spectra were obtained
with a Waters XevoQTOF. HPLC analysis was performed by using
chiral AS-H columns with iPrOH/heptane as the eluent. HPLC
H), 2.74 (s, 1 H), 2.61 (s, 1 H), 2.43 (s, 3 H), 1.72 (s, 3 H) ppm. 13
NMR (50 MHz, CDCl3): δ = 166.1, 146.5, 144.5, 137.1, 129.7,
C
127.6, 123.5, 51.9, 47.9, 42.4, 21.7, 18.1 ppm. FTIR: ν = 2923,
˜
1724, 1653, 1592, 1323, 1277, 1161, 822, 706, 674 cm–1. HRMS:
calcd. for C14H18NO4S [M + H]+ 296.0957; found 296.0970.
(S)-2-Pentyl-1-tosylaziridine-2-carbaldehyde (3c): Yield: 68.4 mg
(86%); 87%ee; HPLC (AS-H column, heptane/iPrOH = 95:5, flow
rate = 0.9 mL/min, 30 °C, λ = 260 nm): tR = 13.8 (minor), 16.8
(major) min. [α]2D0 = +32 (c = 1, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 9.35 (s, 1 H), 7.84 (d, J = 8.3 Hz, 2 H), 7.35 (d, J =
Eur. J. Org. Chem. 2011, 4046–4052
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C. Greck, R. Marcia de Figueiredo et al.
FULL PAPER
8.3 Hz, 2 H), 3.12 (s, 1 H), 2.69 (s, 1 H), 2.45 (s, 3 H), 2.10–2.00
(m, 1 H), 1.74–1.64 (m, 1 H), 1.46–1.37 (m, 2 H), 1.30–1.25 (m, 4
NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 8.2 Hz, 2 H), 7.66–7.62
(m, 4 H), 7.44–7.26 (m, 8 H), 3.72 (d, J = 10.9 Hz, 1 H), 3.59 (d,
H), 0.89–0.84 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = J = 10.9 Hz, 1 H), 2.61 (s, 1 H), 2.42 (s, 3 H), 2.27 (s, 1 H), 1.76
194.8, 144.9, 136.3, 129.9, 127.7, 56.6, 38.7, 31.8, 28.7, 25.5, 22.5,
(s, 3 H), 1.02 (s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 143.9,
137.9, 135.7, 135.7, 133.2, 129.9, 129.9, 129.6, 127.9, 127.5, 68.0,
50.5, 38.6, 26.8, 21.7, 19.4, 15.5 ppm. Data are in accordance with
those previously reported.[16]
21.8, 14.0 ppm. FTIR: ν = 2954, 2927, 2860, 1716, 1321, 1278,
˜
1156, 1136, 1081, 841, 809, 706, 679 cm–1. HRMS: calcd. for
C15H21NO3SNa [M + Na]+ 318.1140; found 318.1137.
(S)-2-Isopropyl-1-tosylaziridine-2-carbaldehyde (3d): Yield: 50.0 mg
(69%); 76%ee; HPLC (AS-H column, heptane/iPrOH = 95:5, flow
rate = 0.9 mL/min, 30 °C, λ = 260 nm): tR = 18.3 (minor), 20.9
(major) min. [α]2D0 = +64 (c = 1, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 9.50 (s, 1 H), 7.84 (d, J = 8.3 Hz, 2 H), 7.35 (d, J =
8.1 Hz, 2 H), 3.20 (s, 1 H), 2.66 (s, 1 H), 2.45 (s, 3 H), 2.40 (quint.,
J = 6.9 Hz, 1 H), 1.01 (d, J = 6.9 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.6, 144.9, 136.4,
(S)-2-Benzyl-1-tosylaziridine-2-carboxylic Acid (5): To a stirred
solution of 3a (219 mg, 0.69 mmol) in MeOH/MeCN/H2O (1:1:1,
10.5 mL) at 0 °C was added successively KH2PO4 (376 mg,
2.76 mmol), NaClO2·1H2O (240 mg, 2.21 mmol), and H2O2 (30%
w/w in H2O, 3.50 mL). The mixture was allowed to warm to room
temperature and stirred for 2 h. The reaction was then acidified to
pH 3 with HCl (1 n), cooled to 0 °C, and treated with a saturated
aqueous solution of Na2SO3. The mixture was then re-acidified to
pH 3 with HCl (1 n) and extracted with EtOAc. The combined
organic layers were washed with brine, dried with MgSO4, filtered,
and concentrated under reduced pressure to afford desired com-
129.9, 127.7, 60.6, 38.0, 26.9, 21.8, 18.8, 17.4 ppm. FTIR: ν = 2967,
˜
2923, 2872, 1716, 1317, 1160, 1085, 836, 702, 651 cm–1. HRMS:
calcd. for C13H17NO3SNa [M + Na]+ 290.0827; found 290.0821.
1
pound 5 (208 mg, 91%). [α]2D0 = +17.7 (c = 1, MeOH). H NMR
(S)-2-(Non-8-enyl)-1-tosylaziridine-2-carbaldehyde
(3e):
Yield:
(300 MHz, CDCl3): δ = 7.85 (d, J = 8.3 Hz, 2 H), 7.35 (d, J =
8.1 Hz, 2 H), 7.29–7.23 (m, 5 H), 3.70 (d, J = 14.6 Hz, 1 H), 3.35
(d, J = 14.6 Hz, 1 H), 3.03 (s, 1 H), 2.83 (s, 1 H), 2.46 (s, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 171.9, 144.9, 136.6, 135.8, 129.9,
82.8 mg (82%); 79%ee; HPLC (AS-H column, heptane/iPrOH =
80:20, flow rate = 0.8 mL/min, 30 °C, λ = 260 nm): tR = 7.8
(minor), 8.7 (major) min. [α]2D0 = +21 (c = 1, CH2Cl2). 1H NMR
(200 MHz, CDCl3): δ = 9.35 (s, 1 H), 7.84 (d, J = 8.3 Hz, 2 H),
7.35 (d, J = 8.1 Hz, 2 H), 5.90–5.70 (m, 1 H), 5.03–4.90 (m, 2 H),
3.13 (s, 1 H), 2.68 (s, 1 H), 2.45 (s, 3 H), 2.13–1.98 (m, 3 H), 1.76–
1.62 (m, 1 H), 1.28 (m, 10 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 194.8, 144.9, 139.2, 136.4, 129.9, 127.7, 114.3, 56.6, 38.7, 33.9,
129.5, 128.7, 127.9, 127.3, 50.8, 37.6, 35.2, 21.8 ppm. FTIR: ν =
˜
3283, 3029, 2957, 2926, 1747, 1719, 1595, 1449, 1321, 1286, 1154,
1082, 905 cm–1. HRMS: calcd. for C17H17NO4SNa [M + Na]+
354.0776; found 354.0771.
29.6, 29.3, 29.1, 29.0, 28.7, 25.8, 21.8 ppm. FTIR: ν = 2927, 2855,
˜
(R,E)-Methyl 3-(2-Benzyl-1-tosylaziridin-2-yl)acrylate (6): To
a
1724, 1331, 1305, 1161, 1088, 845, 814, 707, 687 cm–1. HRMS:
calcd. for C20H31NO4SNa [M + MeOH + Na]+ 404.1871; found
404.1864.
stirred solution of 3a (70.0 mg, 0.22 mmol) in THF (2.20 mL) at
0 °C was added methyl (triphenylphosphoranylidene)acetate
(90.0 mg, 0.26 mmol). The mixture was warmed to room tempera-
ture and stirred for 2 h. The reaction was then quenched with a
saturated aqueous solution of NH4Cl and extracted with EtOAc
(3ϫ). The combined organic phases were washed with brine, dried
with MgSO4, filtered, and concentrated under reduced pressure.
Purification was performed by column chromatography on silica
gel (pentane/Et2O, 6:1) to afford desired compound 6. Yield: 78%;
80%ee; HPLC (AS-H column, heptane/iPrOH = 80:20, flow rate
= 0.8 mL/min, 30 °C, λ = 260 nm): tR = 16.4 (minor), 19.6
(major) min. [α]2D0 = +4.3 (c = 1, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 7.83 (d, J = 8.3 Hz, 2 H), 7.32 (d, J = 7.9 Hz, 2 H),
7.28–7.19 (m, 5 H), 7.08 (d, J = 15.8 Hz, 1 H), 6.07 (d, J = 15.6 Hz,
1 H), 3.71 (s, 3 H), 3.36–3.24 (m, 2 H), 2.76 (s, 1 H), 2.72 (s, 1 H),
2.44 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.0, 144.6,
143.5, 136.9, 135.7, 129.8, 129.5, 128.7, 127.8, 127.2, 124.7, 51.9,
(S)-2-(4-Bromobutyl)-1-tosylaziridine-2-carbaldehyde (3f): Yield:
81.1 mg (78%); 79%ee; HPLC (AS-H column, heptane/iPrOH =
80:20, flow rate = 0.8 mL/min, 30 °C, λ = 260 nm): tR = 16.4
(minor), 19.6 (major) min. [α]2D0 = +9 (c = 1, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 9.36 (s, 1 H), 7.86 (d, J = 8.3 Hz, 2 H),
7.37 (d, J = 8.3 Hz, 2 H), 3.39 (t, J = 6.7 Hz, 2 H) 3.17 (s, 1 H),
2.70 (s, 1 H), 2.46 (s, 3 H), 2.19–2.11 (m, 1 H), 1.94–1.85 (m, 2 H),
1.71–1.56 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.6,
145.1, 136.1, 130.0, 127.7, 56.2, 38.9, 33.3, 32.5, 27.9, 24.5,
21.8 ppm. FTIR: ν = 2923, 2860, 1720, 1321, 1282, 1156, 1128,
˜
844, 809, 682 cm–1. HRMS: calcd. for C15H22BrNO4SNa [M +
MeOH + Na]+ 414.0351; found 414.0346.
(S)-2-tert-Butyldiphenylsilanylmethyl-2-methyl-1-(toluene-4-sulfon-
yl)aziridine (4): To a stirred solution of 3b (70.0 mg, 0.29 mmol) in
EtOH (2.90 mL) at 0 °C was added NaBH4 (10.0 mg, 0.26 mmol).
The reaction mixture was stirred for 15 min, quenched with a satu-
rated aqueous solution of NH4Cl and extracted with EtOAc. The
combined organic layers were washed with brine, dried with
MgSO4, filtered, and concentrated under reduced pressure. The
crude alcohol was used in the next step without further purifica-
tion. To a stirred solution of crude (S)-(2-methyl-1-tosylaziridin-2-
50.9, 41.0, 38.8, 21.8 ppm. FTIR: ν = 3061, 2943, 2907, 2848, 1704,
˜
1657, 1591, 1491, 1436, 1317, 1271, 1148, 978, 848, 809, 674,
643 cm–1. HRMS: calcd. for C20H21NO4SNa [M + Na]+ 394.1089;
found 394.1081.
(S)-2-Benzyl-2-[(tert-butyldimethylsilyloxy)methyl]-1-tosylaziridine
(7): To a stirred solution of 3a (218 mg, 0.69 mmol) in EtOH
(6.90 mL) at 0 °C was added NaBH4 (26.0 mg, 0.69 mmol). The
yl)methanol (70.0 mg, 0.29 mmol) in CH2Cl2 (1.50 mL) at 0 °C was reaction mixture was stirred for 15 min, quenched with a saturated
added, successively, imidazole (30.0 mg, 0.44 mmol), DMAP
(7.00 mg, 0.06 mmol), and TBDPSCl (150 μL, 0.58 mmol). The
mixture was stirred for 3 h at 0 °C. Then, the reaction mixture was
treated with a saturated aqueous solution of NH4Cl and extracted
with CH2Cl2. The combined organic layers were washed with brine,
dried with MgSO4, filtered, and concentrated under reduced pres-
sure. Purification was performed by column chromatography on
silica gel (pentane/EtOAc, 95:5) to afford desired compound 4
(33.0 mg, 24% over two steps). [α]2D0 = –28 (c = 1, CH2Cl2). 1H
aqueous solution of NH4Cl and extracted with EtOAc. The com-
bined organic layers were washed with brine, dried with MgSO4,
filtered, and concentrated under reduced pressure. Purification was
performed by column chromatography on silica gel (pentane/
EtOAc, 3:1) to afford the desired alcohol (195 mg, 89%). [α]2D0
=
1
+86 (c = 1, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 7.84 (d, J
= 8.5 Hz, 2 H), 7.34 (d, J = 8.1 Hz, 2 H), 7.30–7.21 (m, 5 H), 3.98
(dd, J = 13.3, 9.4 Hz, 1 H), 3.80 (d, J = 13.1, 5.2 Hz, 1 H), 3.48
(d, J = 14.1 Hz, 1 H), 2.94 (d, J = 14.1 Hz, 1 H), 2.77–2.72 (m, 1
4050
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4046–4052

Organocatalyzed Aziridination of α-Branched Enals
H), 2.72 (s, 1 H), 2.52 (s, 1 H), 2.45 (s, 3 H) ppm. 13C NMR gel (pentane/Et2O, 4:1) to afford desired compound 9 (32.0 mg,
(50 MHz, CDCl3): δ = 144.4, 137.3, 136.3, 129.8, 129.8, 128.7, 85%). [α]2D0 = +12.4 (c = 1, CH2Cl2). 1H NMR (300 MHz, CDCl3):
127.4, 127.1, 62.5, 55.7, 38.4, 38.0, 21.8 ppm. FTIR: ν = 3514,
δ = 7.74 (d, J = 8.1 Hz, 2 H), 7.32–7.18 (m, 12 H), 5.30 (br. s, 1
H), 3.58 (s, 2 H), 3.53 (d, J = 9.8 Hz, 1 H), 3.45 (d, J = 9.8 Hz, 1
˜
3026, 2918, 1598, 1495, 1453, 1317, 1304, 1148, 1082, 978,
843 cm–1. HRMS: calcd. for C17H19NO3SNa [M + Na]+ 340.0983; H), 3.05 (d, J = 13.3 Hz, 1 H), 2.92 (d, J = 13.3 Hz, 1 H), 2.65 (s,
found 340.1000. To a stirred solution of (S)-(2-benzyl-1-tosylazir-
idin-2-yl)methanol (181 mg, 0.57 mmol) in CH2Cl2 (5.70 mL) at
2 H), 2.38 (s, 3 H), 1.58 (br. s, 1 H), 0.87 (s, 9 H), 0.01 (s, 3 H),
0.00 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 143.2, 140.7,
0 °C was added, successively, imidazole (155 mg, 2.28 mmol) and 140.1, 136.4, 130.8, 129.7, 128.4, 128.3, 128.1, 127.0, 126.8, 126.8,
TBDMSCl (103 mg, 0.68 mmol). The mixture was allowed to warm
to room temperature and stirred for 15 h. The reaction mixture was
treated with a saturated aqueous solution of NH4Cl and extracted
with CH2Cl2. The combined organic layers were washed with brine,
dried with MgSO4, filtered, and concentrated under reduced pres-
sure. Purification was performed by column chromatography on
silica gel (pentane/Et2O, 10:1) to afford desired compound 7
65.5, 63.3, 54.2, 52.1, 39.8, 26.0, 21.6, 18.2, –5.4, –5.4 ppm. FTIR:
ν = 3270, 2954, 2926, 2853, 1599, 1492, 1320, 1252, 1154, 1091,
˜
983, 835, 775, 701, 663 cm–1. HRMS: calcd. for C30H43N2O3SSi [M
+ H]+ 539.2764; found 539.2786.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR spectra of new compounds and chiral
HPLC traces for determination of the enantiomeric excess values
for aziridines 3a–f.
1
(214 mg, 87%). [α]2D0 = +6.0 (c = 1, CH2Cl2). H NMR (300 MHz,
CDCl3): δ = 7.83 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 8.1 Hz, 2 H),
7.28–7.22 (m, 5 H), 3.80 (d, J = 11.0 Hz, 1 H), 3.61 (d, J = 11.0 Hz,
1 H), 3.28 (d, J = 14.1 Hz, 1 H), 3.20 (d, J = 14.0 Hz, 1 H), 2.59
(s, 1 H), 2.49 (s, 1 H), 2.43 (s, 3 H), 0.87 (s, 9 H), 0.02 (s, 3 H),
–0.01 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 144.0, 137.8,
137.1, 129.8, 129.6, 128.5, 127.6, 126.9, 63.3, 54.7, 37.4, 36.5, 25.9,
Acknowledgments
The authors are grateful for the financial support of the Agence
Nationale de la Recherche (ANR) Program “Chimie et Procédés
pour le Développement Durable (CP2D)”.
21.7, 18.4, –5.3, –5.3 ppm. FTIR: ν = 3029, 2952, 2925, 2883, 1598,
˜
1495, 1232, 1250, 1157, 1093, 983, 832, 773, 702, 683, 561 cm–1.
HRMS: calcd. for C23H33NO3SSiNa [M + Na]+ 454.1848; found
454.1826.
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(R)-N-[2-Benzyl-1-(tert-butyldimethylsilyloxy)heptan-2-yl]-4-meth-
ylbenzenesulfonamide (8): All glassware and equipment were oven-
dried and flushed with argon prior to use. In a 15-mL Schlenk
tube, CuICN (32.0 mg, 0.36 mmol) was introduced and heated un-
der vacuum to thoroughly and then purged with argon. Freshly
distilled THF (0.40 mL) was added, and the solution was cooled
to –78 °C. nBuLi (1.60 m in hexanes, 490 μL, 0.78 mmol) was added
dropwise to the solution. The resulting mixture was stirred at
–78 °C for 30 min and warmed to room temperature over 30 min.
The reaction mixture was cooled to –78 °C, and a solution of 7
(65.0 mg, 0.15 mmol) in THF (0.40 mL) was added dropwise. The
solution was stirred for 4 h at –78 °C and slowly warmed to room
temperature overnight. The reaction was quenched with H2O
(2.00 mL), filtered through a pad of Celite (EtOAc), acidified to
pH 3 with an aqueous solution of citric acid (5%), and extracted
with EtOAc. The combined organic layers were washed with brine,
dried with MgSO4, filtered, and concentrated under reduced pres-
sure. Purification was performed by column chromatography on
silica gel (pentane/Et2O, 8:1) to afford desired compound 8
(28.0 mg, 38%). [α]2D0 = +3.4 (c = 1, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 7.73 (d, J = 8.3 Hz, 2 H), 7.30–7.21 (m, 7 H), 4.61 (s,
1 H), 3.36 (d, J = 9.8 Hz, 1 H), 3.32 (d, J = 9.6 Hz, 1 H), 2.95 (d,
J = 13.5 Hz, 1 H), 2.90 (d, J = 13.5 Hz, 1 H), 2.41 (s, 3 H), 1.65–
1.57 (m, 1 H), 1.50–1.41 (m, 1 H), 1.21–0.98 (m, 6 H), 0.92 (s, 9
H), 0.80 (t, J = 6.7 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 143.0, 140.8, 136.7, 130.9, 129.5,
128.3, 127.0, 126.8, 65.3, 63.7, 41.3, 33.6, 32.3, 26.0, 23.3, 22.7,
21.6, 18.3, 14.2, –5.3, –5.4 ppm. FTIR: ν = 3276, 2953, 2925, 2854,
˜
1597, 1462, 1321, 1250, 1155, 1092, 832, 774, 754, 699, 660 cm–1.
HRMS: calcd. for C27H44NO3SSi [M + H]+ 490.2811; found
490.2814.
(S)-N-[2-Benzyl-1-(benzylamino)-3-(tert-butyldimethylsilyloxy)-
propan-2-yl]-4-methylbenzenesulfonamide (9): To a stirred solution
of 7 (30.0 mg, 0.07 mmol) in THF (2.30 mL) at 0 °C was added
benzylamine (40.0 μL, 0.35 mmol). The resulting mixture was
heated at reflux for 42 h, and the solvent was evaporated in vacuo.
Purification was performed by column chromatography on silica
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Eur. J. Org. Chem. 2011, 4046–4052