Stereoselective synthesis of substituted 1,2-ethylenediaziridines and their use as ligands in palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1016/j.tet.2009.11.062

The double addition of organometallic reagents to fused oxazino-oxazines prepared from glyoxal and (S)-phenylglycinol afforded C₂- or C₁-symmetric 1,2-ethylenebis(β-aminoalcohols), depending on the nature of the organometallic reagent. This route was modified by the use of (S)-valinol and phenylglyoxal as starting materials, and by reduction of the oxazino-oxazines by diborane. Cyclization of the β-aminoalcohol moieties gave 1,2-ethylenediaziridines bearing one substituent/stereocenter on the ring carbon and one, two or no substituents/stereocenters in the ethylene tether. These bis(aziridines) were used as ligands in the Pd-catalyzed allylic alkylation of dimethyl malonate. It was established that the substituent(s) in the carbon tether and the configuration of the corresponding stereocenters have limited influence on the enantioselectivity.

Full text of DOI:10.1016/j.tet.2009.11.062

Tetrahedron 66 (2010) 715–720
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of substituted 1,2-ethylenediaziridines and their use
as ligands in palladium-catalyzed asymmetric allylic alkylation
*
Andrea Gualandi, Francesco Manoni, Magda Monari, Diego Savoia
Dipartimento di Chimica ‘‘G. Ciamician’’, Universita’ di Bologna, via Selmi 2, 40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2009
Received in revised form 23 October 2009
Accepted 12 November 2009
Available online 5 December 2009
The double addition of organometallic reagents to fused oxazino-oxazines prepared from glyoxal and
(S)-phenylglycinol afforded C2- or C1-symmetric 1,2-ethylenebis(
of the organometallic reagent. This route was modified by the use of (S)-valinol and phenylglyoxal as starting
materials, and by reduction of the oxazino-oxazines by diborane. Cyclization of the -aminoalcohol moieties
b-aminoalcohols), depending on the nature
b
gave 1,2-ethylenediaziridines bearing one substituent/stereocenter on the ring carbon and one, two or no
substituents/stereocenters in the ethylene tether. These bis(aziridines) were used as ligands in the Pd-cata-
lyzed allylic alkylation of dimethyl malonate. It was established that the substituent(s) in the carbon tether
and the configuration of the corresponding stereocenters have limited influence on the enantioselectivity.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric allylic alkylation
Aziridine
Diastereoselective organometallic reaction
Oxazine
Palladium
1. Introduction
MeO2C
CO2Me
Ph
CH2(CO2Me)2
OCOR
Ph
Chiral non-racemic 1,2-diamines are valuable auxiliaries and
ligands in asymmetric synthesis and metal-mediated enantiose-
lective catalysis.1 Among them, bis(aziridines) have found only
a limited number of applications. Tanner and Andersson reported
the preparation of bis(aziridines) starting from enantiopure
stilbene epoxide and used them in a number of asymmetric
transformations.2 The best results were obtained in the palla-
dium-catalyzed asymmetric allylic alkylation (AAA) of dimethyl
malonate with the allylic acetate 1a, affording the product (S)-2
with complete stereocontrol when the bis(aziridine) 3 was used
in a sub-stoichiometric amount (Scheme 1).3 Less satisfactory
results were obtained in cyclopropanation, aziridination, and
dihydroxylation of alkenes and in the addition of organolithium
reagents to imines.2 More recently, we have described the
diastereoselective synthesis of pyridine-aziridines and pyridine-
Ph
BSA, (allylPdCl)2,
AcOK, L*, CH2Cl2
*
Ph
2
1, a: R = Me
b: R = OEt
Ph
N
Ph
N
N
N
N
Ph
Ph
Ph
Ph
4
3
Scheme 1. Pd-catalyzed asymmetric allylic alkylation of dimethyl malonate using
bis(aziridines) as ligands.
The ligands 3 and 4 differ for their skeleton and the substitution
patterneitherintheaziridineringsandthetetherlinking thenitrogen
atoms. Whereas the ligand 3 has C2-symmetric 2,3-disubstituted
aziridine rings and nosubstituent/stereocenter in the ethylenetether,
the ligand 4, although being C2-symmetric, features mono-
substituted aziridine rings and two substituents/stereocenters in the
2,6-dimethynepyridine tether. The lack of C2-symmetry of the azir-
idine rings in 4 can affect the configuration of the nitrogen atoms in
diaziridines by
additions to the imines derived from 2-pyridinecarboxyaldehyde
and 2,6-pyridinedicarboxyaldehyde and enantiopure -amino-
-aminoalcohol
a short route involving: (a) organometallic
b
alcohols; (b) Mitsunobu cyclization of the two
b
moieties.4 In particular, we obtained the compound (R)-2 with
99% ee from the allylic carbonate 1b using the bis(aziridine) 4 as
the ligand.4d
the catalytically active (h
3-allylic)L*Pdþ species, where the metal is
involved in bidentate chelation to the pyridine and one of the azir-
idine nitrogen atoms. However, homochirality was observed in all the
crystal structures of the cationic h3-allylic complexes we prepared
from several ligands analogous to 4: as a matter of fact, all the Pd-
coordinated aziridine nitrogen atoms had the same configuration, the
one allowing to reduce the steric interactions of the benzylic and
* Corresponding author. Tel.: þ39 051 2099571; fax: þ39 051 2099456.
E-mail address: diego.savoia@unibo.it (D. Savoia).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.062

716
A. Gualandi et al. / Tetrahedron 66 (2010) 715–720
aziridine substituents. Moreover, the aziridine analogous to 4 but
lacking a substituent at the tether methine carbons displayed minor
enantioselectivity. From this stereochemical outcome, we deduced
that the substituents/stereocenters in the tether were necessary to
achieve the best level of stereocontrol.
Considering the simplicity and the convenience of the synthetic
route to bis(aziridines) from di(aldimines), we envisioned the
possibility to prepare C2-symmetric ligands analogous to 3, i.e.,
having the same skeleton but a different substitution pattern, and
then investigate their enantioselectivity in the AAA reaction.
2. Results and discussion
We prepared the known compound 57 by a modified procedure,
i.e., by treatment of glyoxal trimer dihydrate with a stoichiometric
amount of (S)-phenylglycinol in dichloromethane at room tem-
perature in the presence of magnesium sulfate. 1H NMR spectro-
scopic analysis of the crude compound showed the presence of only
one diastereomer and some unreacted (S)-phenylglycinol. The
compound 5 was then obtained pure by crystallization from
methanol. Then, we carried out the addition of different organo-
metallic reagents in order to check their reactivity and diastereo-
selectivity. In principle, three diastereomers could be formed by the
double organometallic addition, having S,S-, R,R- and R,S-configu-
ration of the newly formed stereocenters. The results of the per-
formed reactions are reported in Table 1. In the first experiment
carried out with allylzinc bromide, the desired 1,2-diallylated 1,2-
diamine 6a was obtained with high yield and high diastereo-
selectivity (entry 1). The main diastereomer was easily isolated
from the crude reaction mixture by crystallization from methanol,
and its C2-symmetry was apparent in the 1H NMR spectrum. Re-
crystallization from methanol allowed the separation of crystals
suitable for X-ray structure determination (Fig. 1), which showed
the S configuration of the newly formed stereocenters. The
Glyoxal and optically pure
b-aminoalcohols are the required
starting material for the envisioned route.5,6 The reactions of 1,2-
dicarbonyl compounds including glyoxal with diversely C- and
N-substituted
b-aminoalcohols gave fused oxazino-oxazines or
2,20-bis(oxazolidines) or other products, depending on the solvent
and experimental conditions used.5 In particular, the reaction with
phenylglycinol afforded a fused oxazino-oxazine 5, rather than the
open chain, 1,2-diimine tautomer 50, as confirmed by X-ray crystal
diffraction studies.7 Our first studies were directed to the addition
of organometallic reagents to compound 5 (Scheme 2).8,9
Ph
OH
H
N
H
O
Ph
N
Ph
Ph
Ph
N
H
O
N
H
5
HO
Ph
Ph 5'
RM
R
S
R
S
R
R
R
R
Ph
Ph
Ph
NH HN
NH HN
OH
HO
HO
OH
HO
(S,S)-6
(R,R)-6
a:
b:
c:
d:
e:
R
S
R
R = Allyl
R = Ph
R = Me
R = n-Bu
R = t-Bu
R
NH HN
OH
(S,R)-6
Scheme 2. Addition of organometallic reagents to the oxazino-oxazine 5 derived from
glyoxal and (S)-phenylglycinol.
Figure 1.
Table 1
Organometallic reactionsa and borane-dimethylsulfide reductionb of oxazino-oxazines and preparation of 1,2-ethylenediaziridines from bis( -aminoalcohols)c
b
Entry
Starting compound
Reagent
Crude product
Yield (%), drd (%)
Pure products,
Bis(aziridines),
Yield (%)e
Yield (%)e
1
2
3
5
5
5
AllylZnBr
PhMgBr
PhLig
6a
6b
6b
91, 80:20
87, 85:15
95, 73:27
(S,S)-6a, 68
(S,S)-7a, 88
(S,S)-8, 91f
(S,R)-7b, 82
(S,R)-6b, 72
(S,S)-6b, 9
(S,R)-6b, 64
(S,S)-6b, 22
(S,R)-7b, 82
(S,S)-7b, 84
4
5
6
7
8
9
5
5
5
5
11
14
MeLi
n-BuLi
t-BuLi
BH3-SMe2
BH3-SMe2
PhMgBr
6c
6d
6e
9j
91h
90, 54:46i
97h
74
88, 100:0
93, 95:5
10, 68
(R)-13, 78
(S,S)-16, 81
12j
15
(S,S)-15, 69
a
The reactions were performed by adding the organometallic reagent (6 M equiv) to the compound 5 dissolved in THF at ꢀ78 ꢁC while stirring and allowing
the temperature to reach 20 ꢁC overnight.
b
Borane-dimethylsulfide (4 M equiv) was added to the stirred solution of compound 5 in THF and the mixture was stirred at the reflux temperature during 8 h.
c
Compound 6 dissolved in THF was treated with a 40% toluene solution of DEAD and then with triphenylphosphine (2.2 M equiv each).
d
The dr was determined by GC–MS or 1H NMR spectroscopic analysis of the crude product.
e
After column chromatography.
Overall yield after hydrogenation and cyclization steps.
The reaction was performed in Et2O.
A complex mixture of products was obtained and no compound could be isolated in a pure state by column chromatography.
The diastereomers could not be separated by column chromatography (SiO2).
The compound was not purified.
f
g
h
i
j

A. Gualandi et al. / Tetrahedron 66 (2010) 715–720
717
Table 2
stereochemical outcome is in agreement with the sense of asym-
metric induction observed in the allylation of the 2-pyridineimines
derived from (S)-valinol and (S)-phenylglycinol.
Asymmetric allylic alkylation of dimethyl malonate using bis(aziridines) as ligands.a
Entry
Bis(aziridine)
Yield (%) of 2
Configuration
eeb (%)
Surprisingly, much lower diastereoselectivity was observed in
the addition of either phenylmagnesium chloride and phenyl-
lithium to 5. Two main diastereomers were observed by 1H NMR
spectroscopy of the crude products coming from both reactions and
the prevalent one lacked C2-symmetry. Consequently the (R,S)-
configuration of the tether stereocenters was assigned. This was
surprising since in all the organometallic reactions of chiral 1,2-
diimines reported so far, the (R,S)-diastereomer was by far the less
abundant one, if ever observed.5 Moreover, poor diaster-
eoselectivities and/or complex reaction mixtures were obtained in
the addition of methyl-, n-butyllithium and t-butyllithium to
compound 5.
1
2
3
4
5
6
7
(S,S)-7a
(S,S)-8
(S,S)-7b
(S,R)-7b
10
69
88
86
R
R
R
R
R
R
R
55
70
91
85
92
82
86
76
86
91
(R)-13
(S,S)-16
a
The reactions were performed in CH2Cl2 at room temperature: 0.24 mmol of
carbonate 1b, 0.60 mmol of dimethyl malonate, 0.72 mmol of BSA and 0.01 mmol of
[(allyl)PdCl]2.
b
The ee was determined by HPLC analysis of the crude product on Chiralpak AD
column (n-hexane:i-PrOH 90:10, 1 mL/min,
l 254 nm).
The 1,2-disubstituted-1,2-ethylenediaziridines (S,S)-7a, (S,R)-7b,
and (S,S)-7b were prepared with good yields from the corre-
sponding bis(b-aminoalcohols) (S,S)-6a, (S,R)-6b, and (S,S)-6b, re-
spectively, by treatment with triphenylphosphine and diethyl
azodicarboxylate (DEAD) and were purified by column chroma-
tography (Scheme 3). The dipropyl-substituted bis(aziridine) (S,S)-
8 was similarly obtained by hydrogenation of the unsaturated
chains of the precursor (S,S)-6a.
That supposition was later confirmed by the experiments car-
ried out with two newly synthesized aziridines (Scheme 4). The
first one, 10, lacking substituents in the tether, was easily prepared
with 50% overall yield by borane reduction of 5 to give 9, followed
by Mitsunobu cyclization. The other one, (R)-13, was obtained as
a single diastereomer by a similar sequence starting from the
oxazino-oxazine 11 derived from phenylglyoxal and (S)-phenyl-
glycinol through the intermediate (R)-12. The structure and hence
the configuration of the newly formed stereocenters in compound
11 was determined by X-ray crystallography (Fig. 2). The
(R)-configuration of compound 13 was assumed considering that
the reduction of chiral ketimines generally occurs with opposite
diastereoselectivity with respect to the organometallic addition to
the corresponding chiral aldimines. Successively, we confirmed
the correctness of this hypothesis by an alternative synthesis of
(R)-13 exploiting (R)- and (S)-phenylglycinol without affecting the
configuration of the stereocenters .11 Unexpectedly, the ligand 10,
despite lacking stereocenters in the tether, gave the best level of
enantioselectively (92% ee, Table 2, entry 5) in the formation of the
substituted malonate 2, and also the ligand (R)-13, having the
opposite configuration of the phenyl-substituted stereocenter in
the tether with respect to (S,S)-5b, gave a good performance
maintaining the same sense of asymmetric induction (82% ee,
entry 6).
PPh3,
DEAD
Ph
S
Ph
S
S
S
NH HN
N
N
THF,
20 °C
Ph
Ph
OH
(S,S)-6a
HO
(S,S)-7a, 88%
1) H2, Pd/C, MeOH
S
S
2) PPh3, DEAD,
THF, 20 °C
N
N
Ph
Ph
(S,S)-8, 91%
Ph
Ph
PPh3,
DEAD
Ph
Ph
S
S
R
R
Ph
Ph
Ph
Ph
NH HN
N
N
THF,
20 °C
Ph
Ph
OH HO
(S,R)-6b
(S,R)-7b, 82%
5
Ph
S
Ph
S
PPh3,
DEAD
Ph
S
Ph
THF
BH3-SMe2
S
NH HN
N
N
Ph
Ph PPh3, DEAD
THF, 20 °C
THF,
20 °C
Ph
Ph
NH HN
OH HO
N
N
OH HO
(S,S)-6b
(S,S)-7b, 84%
Ph
Ph
Scheme 3. Synthesis of C2- and C1-symmetric 1,2-ethylenediaziridines from
bis( -aminoalcohols).
9, 74%
10, 68%
b
H
H
The bis(aziridine) bearing different substituents and stereo-
O
N
Ph
chemistry in the tether were used as ligands10 in the standard Pd-
catalyzed asymmetric allylic alkylation of dimethyl malonate with
ethyl 1,3-diphenyl-3-propen-1-yl carbonate 1b leading to compound
2. When the allyl-substituted ligand (S,S)-7a was used, the product 2
was obtained with moderate yield (69%) and enantiomeric excess
(55%) (Table 2, entry1). The correspondingsaturatedcompound (S,S)-
8 gave better performance (70% ee, entry 2). Then, the ee of 2 raised to
91% when the reaction was carried out with the phenyl-substituted
ligand (S,S)-7b (entry 3). On the other hand, using (S,R)-7b a lower
level of enantioselectivity (85% ee, entry 4) was obtained. This out-
come is in agreement with the hypothesis that the C2-symmetry of
the chiral tether enables a better/complete control of the configura-
tion of the nitrogen stereocenters in the intermediate Pd cationic
complexes when the aziridine rings are mono-substituted.
Ph
Ph
N
H
O
Ph
11
THF
Ph
BH3-SMe2
Ph
R
R
Ph
PPh3, DEAD
THF, 20 °C
NH HN
N
N
Ph
(R)-13, 78%
Ph
OH
HO
(R)-12, 88%
Scheme 4. Synthesis of 1,2-ethylenediaziridines unsubstituted and mono-substituted
in the ethylene tether linking the nitrogen atoms.

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A. Gualandi et al. / Tetrahedron 66 (2010) 715–720
tether linking the nitrogen atoms. Up to 92% ee has been achieved
using the bis(aziridine) bearing only one phenyl substituents in
both the aziridine rings, that is, only slightly inferior to the opti-
mum enantioselectivity displayed by the previously described
analogous ligands. The shortness, simplicity and convenience of the
described route make it worth investigating the new ligands in
other asymmetric catalytic reactions.
4. Experimental section
4.1. General information
Optical rotations were measured on a digital polarimeter in
a 1-dm cell and [
a
]D-values are given in 10ꢀ1 deg cm3 gꢀ1. 1H NMR
spectra were recorded on Varian Mercury and Gemini instruments
for samples in CDCl3, which was stored over Mg: 1H chemical shifts
are reported in ppm relative to CHCl3 (dH 7.27), J-values are given in
Hertz. Infrared spectra were recorded on a Nicolet FT-380 spec-
trometer and IR assignments are reported in wave numbers (cmꢀ1).
MS spectra were taken at an ionizing voltage of 70 eV on a Hewlett-
Packard 5975 spectrometer with GLC injection (using HP-5 column,
30 m, ID 0.25 mm). Molecular weights were determined on an
Agilent Technologies MS 1100 instrument. Chromatographic sepa-
rations were performed on columns of SiO2 (Merck, 230–400 mesh)
at medium pressure. All the organic, inorganic and organometallic
reagents and anhydrous solvents were purchased from Aldrich.
Compounds 5 and 9 were previously described.7
Figure 2.
Finally, we investigated the importance of steric properties of
the aziridine substituent on the enantioselectivity of the AAA re-
action. This was achieved by using a different 2-aminoalcohol in the
initial step. Eventually, we prepared the diaziridine (S,S)-16 by the
same reactions sequence previously described, from the fused
oxazino-oxazine 14 derived from glyoxal trimer dihydrate and
(S)-valinol (Scheme 5).
H
N
H
O
N
H
O
H
14, dr 75:25
4.1.1. Preparation of oxazino-oxazines: general procedure. To
a solution of (S)-phenylglycinol (0.600 g, 4.4 mmol) in dry CH2Cl2
(40 mL) was added anhydrous MgSO4 (3.0 g) and phenylglyoxal
monohydrate (0.333 g, 2.2 mmol) and the mixture was stirred
overnight. The solid was filtered off through a pad of Celite and the
organic phase was concentrated at reduced pressure to leave a pink
PhMgBr, THF, 78 °C
Ph
Ph
Ph
N
Ph
N
PPh3, DEAD
NH HN
THF, 20 °C
solid, which was crystallized from Et2O to give 11 as white powder:
OH
HO
25
0.781 g (96%): mp¼145.8–146.5 ꢁC; [
a
]
þ100.6 (c 1.0, CHCl3); IR
D
(S,S)-15, 69%
(S,S)-16, 81%
(KBr): v¼3461, 3342, 3023, 2962, 2904, 2860, 1450, 1336, 1176,
1070, 956, 923, 743, 698, 530; 1H NMR (200 MHz, CDCl3):
d¼7.66–
Scheme 5. Synthesis of the C2-symmetric bis(aziridine) (S,S)-16 from the oxazino-
oxazine 14 derived from (S)-valinol.
7.69 (m, 2H), 7.25–7.50 (m, 13H), 5.20 (s, 1H), 4.70 m (2H), 4.04 (dd,
J¼3.4, J¼11.0 Hz, 1H), 3.78 (dd, J¼3.8, J¼11.3 Hz, 1H), 3.73 (app. t,
J¼11.0 Hz, 1H), 3.50 (app. t, J¼11.3 Hz, 1H), 2.21 (br s, 2H); 13C NMR
The 1H NMR spectroscopy and GC–MS analyses of the crude
product showed it was a 3:1 mixture of two diastereoisomers, both
having C2-symmetry, as was shown by the absorptions of the
aminoacetal (N–CH–O) protons, which appeared as a singlet for both
diastereoisomers. Separation of the diastereomers proved to be dif-
ficult, so that their mixture was used in reaction with phenyl-
magnesium chloride. Surprisingly, this reaction cleanly afforded the
C2-symmetric product (S,S)-17 with very high diastereoselectivity (dr
95:5 by 1H NMR spectroscopy), in marked contrast to the
corresponding reaction of oxazino-oxazine 5. Avoiding separation of
the diastereomers, the ring-closure to bis(aziridine) occurredwithout
event by the routine procedure, and the pure diastereomer (S,S)-16
was isolated by column chromatography. The AAA of dimethyl mal-
onate with the carbonate 1b and the ligand (S,S)-16 again gave
compound 2 with an enantioselectivity falling in the usual range (86%
ee), although slightly lower to that displayed by (S,S)-7b (entry 7).
(50 MHz, CDCl3):
d
¼141.8, 140.1, 139.6, 128.4, 128.3, 128.2, 127.8,
127.7, 127.4, 125.9, 83.5, 83.0, 72.5, 70.1, 53.8, 52.2; MS (ES) m/z¼
373.1 [MþH]þ; Anal. Calcd for C24H24N2O2: C, 77.39; H, 6.49; N, 7.52.
Found C, 77.75; H, 6.51; N, 7.50.
Compound 14 was obtained starting from glyoxal trimer
dihydrate and (S)-valinol in 65% yield: colorless oil; dr 75:25
(GC–MS, 1H NMR); IR (neat): v¼3335, 2960, 2873, 1466, 1339,
1288, 1184, 1085, 905, 798, 765, 601; MS (ES) m/z¼229.1 [MþH]þ;
MS (EI) m/z¼114 (100), 127 (58), 84 (45), 69 (27), 185 (13), 197 (9),
167 (6), 228 (1). Major diastereoisomer: 1H NMR (200 MHz,
CDCl3):
d
¼4.26 (s, 2H), 3.92 (dd, J¼3.1, J¼10.9, 2H), 3.39 (app t,
J¼10.9, 2H), 2.97 (m, 2H), 2.12 (br s, 2H), 1.44 (m, 2H), 0.92 (d,
J¼6.9, 3H), 0.88 (d, J¼6.9, 3H). Minor diastereoisomer: 1H NMR
(200 MHz, CDCl3), relative signals:
d
¼4.64 (s, 2H), 3.22 (app t,
J¼10.5, 2H), 1.63 (m, 2H), 1.08 (d, J¼6.6, 3H). This compound was
not purified.
3. Conclusions
4.1.2. Organometallic additions to oxazino-oxazines: typical proce-
dure. Phenyllithium (0.5 M in Et2O, 16 mL, 8.0 mmol) was added to
a magnetically stirred solution of the oxazino-oxazine 3 (0.918 g,
3.1 mmol) in THF (10 mL) cooled at ꢀ78 ꢁC. After 30 min the reaction
mixture was slowly warmed up until room temperature was reached
and stirring was continued for 24 h. The mixture was quenched with
a saturated aqueous solution of NH4Cl (10 mL) and 30% NH4OH
(10 mL) at 0 ꢁC, then the organic material was extracted with diethyl
The study herein described on the AAA of dimethyl malonate
using a number of 1,2-ethylenediaziridines has demonstrated that
the sense of asymmetric induction and the degree of enantiose-
lectivity is mainly controlled by the chirality and the substitution
pattern of the aziridine rings, and only to a limited extent by the
presence of substituents and the relative chirality in the ethylene

A. Gualandi et al. / Tetrahedron 66 (2010) 715–720
719
25
ether (3ꢂ20 mL). The collected ethereal layers were dried over
mp¼139.4–140.1 ꢁC; [
a]
D
þ76.1 (c 4.0, CHCl3); IR (KBr): v¼3084,
Na2SO4 and concentrated to leave the crude product as yellow oil.
Flash column chromatography (SiO2) eluting with cyclohexane to
cyclohexane/ethyl acetate 8:2 mixtures gave the products (S,R)-6b
(0.897 g, 64%) and then (S,S)-6b (0.308 g, 22%) as yellow oils.
3060, 3029, 2956, 2926, 2851, 1452, 1261, 1105, 1028, 759, 698; 1H
NMR (400 MHz, CDCl3):
d
¼7.63–6.93 (m, 20H), 3.14 (d, J¼6.7 Hz,1H),
2.98 (d, J¼6.7 Hz, 1H), 2.32–2.16 (m, 2H), 1.70 (d, J¼2.2 Hz, 1H), 1.67
(d, J¼8.7 Hz, 1H), 1.57 (d, J¼6.4 Hz, 1H), 1.42 (d, J¼6.4 Hz, 1H); 13C
Compound (S,R)-6b: [
a
]D25 þ158.3 (c 1.0, CHCl3); IR (neat):
NMR (100 MHz, CDCl3):
d
¼141.0, 140.7, 128.5, 128.5, 128.4, 128.3,
v¼3425, 3327, 3284, 3074, 3021, 2908, 1455, 1348, 1104, 1027, 918,
128.3,127.9,127.8,127.7,127.6,127.3,127.2,127.1, 66.4, 66.1, 65.3, 64.1,
756, 699; 1H NMR (400 MHz, CDCl3):
d¼7.37–7.14 (m, 14H), 7.00
61.7, 61.0; MS (ES): m/z¼417.5 [MþH]þ; Anal. Calcd for C30H28N2: C,
(dd, J¼1.3, J¼7.4 Hz, 2H), 6.92 (dd, J¼3.9, J¼7.5 Hz, 2H), 6.84 (dd,
J¼2.0, J¼3.8 Hz, 2H), 3.76 (d, J¼7.7 Hz, 1H), 3.66 (d, J¼7.7 Hz, 1H),
3.55–3.43 (m, 3H), 3.40–3.26 (m, 3H), 2.19 (br s, 4H); 13C NMR
86.50; H, 6.78; N, 6.72. Found C, 86.48; H, 6.80; N, 6.71.
25
Compound (S,S)-7a: White solid; mp¼49.7–50.8 ꢁC; [
a]
þ227.3
D
(c 1.0, CHCl3); IR (KBr): v¼3062, 2976, 2912, 2814, 1497, 1450, 1438,
(100 MHz, CDCl3):
d
¼141.1, 140.7, 128.5, 128.5, 128.4, 128.4, 128.3,
1313, 1207, 1088, 1028, 999, 741, 696; 1H NMR (400 MHz, CDCl3):
128.0,127.8,127.8,127.7,127.3,127.3,127.1, 66.4, 66.1, 65.3, 64.1, 61.7,
d
¼7.34–7.20 (m, 10H), 5.98–5.84 (m, 2H), 4.98 (m, 4H), 2.78 (dd,
60.9; MS (ES) m/z¼453.2 [MþH]þ; Anal. Calcd for C30H32N2O2: C,
J¼6.36, J¼13.9 Hz, 2H), 2.50–2.39 (m, 2H), 2.25 (dd, J¼3.3, J¼6.3 Hz,
2H), 1.94 (d, J¼3.3, 2H), 1.82 (d, J¼6.3 Hz, 2H), 1.76 (d, J¼9.9 Hz, 2H);
79.61; H, 7.13; N, 6.19. Found C, 79.98; H, 7.15; N, 6.17.
25
Compound (S,S)-6b: [
a
]
þ178.2 (c 1.0, CHCl3); IR (neat):
13C NMR (50 MHz, CDCl3):
d
¼140.2, 137.5, 128.2, 126.7, 126.2, 116.1,
D
v¼3428, 3318, 3278, 3079, 3028, 2915, 1451, 1340, 1109, 1028, 915,
758, 699; 1H NMR (400 MHz, CDCl3):
¼7.35–7.25 (m, 6H), 7.15–7.10
(m, 10H), 6.91 (dd, J¼3.6, J¼7.3 Hz, 4H), 3.64–3.50 (m, 8H), 2.76 (br
s, 4H); 13C NMR (100 MHz, CDCl3):
73.6, 39.1, 38.7, 34.9; MS (ES): m/z¼345.2 [MþH]þ. Anal. Calcd for
d
C24H28N2: C, 83.68; H, 8.19; N, 8.13. Found C, 83.81; H, 8.18; N, 8.10.
25
Compound (S,S)-7b: White solid; mp¼139.1–139.8 ꢁC; [
a]
D
d¼140.3, 140.0, 128.6, 128.1,
þ97.4 (c 1.0, CHCl3); IR (KBr): v¼3085, 3058, 3021, 2958, 2921, 2842,
127.9, 127.6, 127.4, 127.1, 67.3, 65.2, 61.3; MS (ES): m/z¼453.2
[MþH]þ; Anal. Calcd for C30H32N2O2: C, 79.61; H, 7.13; N, 6.19.
Found C, 79.81; H, 7.15; N, 6.17.
1451, 1269, 1100, 1024, 759, 697; 1H NMR (400 MHz, CDCl3):
d
¼7.38–7.26 (m, 16H), 7.08 (t, J¼14.7 Hz, 2H), 7.01 (d, J¼7.5 Hz, 2H),
3.07 (s, 2H), 2.64 (dd, J¼2.6, J¼6.2 Hz, 2H), 1.72 (d, J¼2.6 Hz, 2H),
Compound (S,S)-6a: Colorless crystals; mp¼93.0–93.9 ꢁC
1.60 (d, J¼6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
¼140.5, 139.3,
d
25
(MeOH); [
a
]
þ145.7 (c 1.0, CHCl3); IR (KBr): v¼3432, 3324, 3264,
129.3, 128.2, 126.8, 126.7, 126.1, 79.2, 43.1, 38.1; MS (ES): m/z¼417.2
D
3076, 3030, 2928, 1453, 1348, 1106, 1022, 915, 756, 699; 1H NMR
(200 MHz, CDCl3):
[MþH]þ; Anal. Calcd for C30H28N2: C, 86.50; H, 6.78; N, 6.72. Found
d
¼7.46–7.23 (m, 10H), 5.66–5.43 (m, 2H), 5.00–
C, 86.71; H, 6.76; N, 6.69.
25
4.82 (m, 4H), 3.80 (dd, J¼4.1, J¼9.0 Hz, 2H), 3.66 (dd, J¼4.3,
J¼10.4 Hz, 2H), 3.51 (dd, J¼9.0, J¼10.4 Hz, 2H), 2.37 (m, 2H), 2.27–
Compound 10: Colorless oil; [
a
]
þ24.1 (c 1.0, CHCl3); IR (neat):
D
v¼3065, 3038, 2926, 2924, 2852, 1561, 1501, 1459, 1259, 974; 1H
2.03 (m, 4H), 2.01 (br s, 4H); 13C NMR (50 MHz, CDCl3):
d¼140.8,
NMR (200 MHz, CDCl3):
d
¼7.18–7.25 (m, 10H), 2.73 (s, 4H), 2.38 (dd,
134.9, 128.6, 127.6, 117.0, 67.1, 62.3, 56.0, 34.2; MS (ES): m/z¼381.2
J¼3.2, J¼6.6 Hz, 2H), 1.94 (d, J¼3.2 Hz, 2H), 1.76 (d, J¼6.6 Hz, 2H);
[MþH]þ; Anal. Calcd for C24H32N2O2: C, 75.75; H, 8.48; N, 7.36.
13C NMR (50 MHz, CDCl3):
d
¼140.2, 128.2, 126.8, 126.1, 61.0, 41.0,
Found C, 75.70; H, 8.50; N, 7.33.
38.3; MS (ES): m/z¼265.1 [MþH]þ; Anal. Calcd for C18H20N2: C,
25
Compound (S,S)-15: [
a]
þ198.6 (c 1.0, CHCl3); IR (neat): v 3412,
81.78; H, 7.63; N, 10.60. Found C, 81.72; H, 7.58; N, 10.57.
D
25
3305, 3081, 3056, 3023, 2954, 2921, 2868, 1467, 1454, 1389, 1364,
Compound (R)-13: Colorless oil; [
a]
þ39.2 (c 1.0, CHCl3); IR
D
1103,1042, 907, 731, 691; 1H NMR (200 MHz, CDCl3):
d¼7.30–7.39 (m,
(neat): v¼3068, 3035, 2927, 2922, 2858, 1560, 1547, 1451, 1268, 972;
1H NMR (200 MHz, CDCl3): 7.13–7.37 (m, 15H), 3.19 (dd, J¼7.4,
J¼11.7 Hz,1H), 2.97 (dd, J¼5.1, J¼7.4 Hz,1H), 2.59(dd, J¼5.1, J¼11.7 Hz,
1H), 2.38 (dd, J¼3.5, J¼6.5 Hz,1H), 2.20 (dd, J¼3.3, J¼6.5 Hz,1H), 2.17
(d, J¼3.5 Hz, 1H), 2.11 (d, J¼6.5 Hz,1H), 2.04 (d, J¼3.3 Hz, 1H),1.91 (d,
2H), 7.02–7.18 (m, 8H), 3.75 (s, 2H), 3.40 (dd, J¼4.3, J¼10.6 Hz, 2H),
3.27 (dd, J¼8.0, J¼10.6 Hz, 2H), 2.56 (br s, 4H), 2.36 (dd, J¼4.0, J¼4.3,
J¼8.0 Hz, 2H), 1.86–2.01 (m, 2H), 0.91 (d, J¼7.0 Hz, 12H); 13C NMR
(50 MHz, CDCl3);
d
¼141.4, 128.0, 127.7, 126.9, 67.3, 61.4, 61.2, 28.2,
19.2, 17.3; MS (ES): m/z¼385.1 [MþH]þ; Anal. Calcd for C24H36N2O2:
J¼6.5 Hz, 1H); 13C NMR (50 MHz, CDCl3):
¼141.8, 141.2, 140.0, 128.1,
d
C, 74.96; H, 9.44; N, 7.28. Found C, 75.11; H, 9.40; N, 7.26.
128.1, 127.9, 127.5, 127.1, 126.7, 126.5, 126.2, 126.0, 75.1, 68.6, 41.5, 39.8,
39.2, 38.5; MS (ES): m/z¼341.1 [MþH]þ; Anal. Calcd for C24H24N2: C,
4.1.3. Reduction of oxazino-oxazines by BH3$SMe2. To a solution of
11 (0.150 g, 0.4 mmol) in dry THF (15 mL) was added BH3–SMe2
84.67; H, 7.11; N, 8.23. Found C, 84.75; H, 7.13; N, 8.20.
25
Compound (S,S)-16: Colorless oil; [
a
]
þ72.8 (c 1.0, CHCl3); IR
D
(0.153
mL, 0.123 g, 1.6 mmol) and the mixture was heated at the
(neat): v 3062, 3032, 2956, 2871, 2833, 1469, 1452, 1353, 1285,
reflux temperature for 8 h. Water (5 mL), was slowly added at 0 ꢁC
and the solvent was removed at reduce pressure. Water (10 mL) was
again added and the organic material was extracted with CH2Cl2
(3ꢂ20 mL). The collected organic layers were dried over Na2SO4 and
concentrated to leave (R)-12 as a yellow oil: 0.132 g (88%). Similarly,
1162, 1040, 699; 1H NMR (200 MHz, CDCl3):
d¼7.14 (m, 10H), 2.85
(s, 2H), 1.62 (ddd, J¼5.4, J¼6.6, J¼7.0 Hz, 2H), 1.45 (m, 2H), 1.31
(d, J¼7.0 Hz, 2H), 1.27 (d, J¼7.0 Hz, 6H), 1.17 (d, J¼6.6 Hz, 2H), 1.07
(d, J¼7.0 Hz, 6H); 13C NMR (50 MHz, CDCl3):
¼139.6, 128.7, 126.8,
d
126.4, 79.6, 49.2, 32.0, 31.0, 21.3, 19.7; MS (ES): m/z¼349.2
[MþH]þ; Anal. Calcd for C24H32N2: C, 82.71; H, 9.25; N, 8.04. Found
C, 82.93; H, 9.26; N, 8.01.
9 was prepared from 5 in 74% yield. The b-aminoalcohols 9 and (R)-
12 were used in the next step avoiding purification.
Compound (R)-12: 1H NMR (200 MHz, CDCl3):
(m, 15H), 3.61–3.84 (m, 7H), 3.01 (br s, 4H), 2.82 (m, 2H).
d
¼7.05–7.20
4.1.5. Preparation of diaziridine (S,S)-8. To a solution of (S,S)-6a
(0.200 g, 0.5 mmol) in MeOH (5 mL) and Et2O (5 mL) was added
anhydrous 10% Pd/C (0.020 g) and the mixture was stirred under an
atmosphere of H2 (1 atm, ballon) for 1 h. The solid was filtered off
through a pad of Celite and the organic phase was concentrated at
reduced pressure to leave the saturated compound as a white solid
(0.198 g, 98%). To this compound (0.190 g, 0.5 mmol) dissolved in
THF (20 mL) was added PPh3 (0.574 g, 2.19 mmol) and then DEAD
(40% in toluene,1.0 mL, 2.19 mmol) dropwise. After stirring for 24 h,
2 M aq KOH (10 mL) was added and the mixture was stirred for 1 h.
The organic material was extracted with diethyl ether (3ꢂ20 mL)
and the collected ethereal layers were dried over Na2SO4 and
4.1.4. Preparation of 1,2-ethylenediaziridines: typical procedure. To
a solution of the aminoalcohol (S,R)-6b (0.150 g, 0.3 mmol) in THF
(20 mL) was added PPh3 (0.191 g, 0.73 mmol) and then DEAD (40%
solution of in toluene, 0.668 mL, 0.73 mmol) dropwise. After stirring
for 24 h, 2 M aq KOH (10 mL) was added and the mixture was stirred
for 1 h. The organic material was extracted with diethyl ether
(3ꢂ20 mL) and the collected ethereal layers were dried over Na2SO4
and concentrated to leave a yellow oil. Flash column chromatogra-
phy (SiO2) eluting with cyclohexane to cyclohexane/ethyl acetate 9:1
mixtures gave the product (S,R)-7b as a white powder: 0.102 g (82%);

720
A. Gualandi et al. / Tetrahedron 66 (2010) 715–720
concentrated to leave a yellow oil. Flash column chromatography
(SiO2) eluting with cyclohexane to cyclohexane/ethyl acetate 9:1
References and notes
1. (a) Chiral Diaza Ligands for Asymmetric Synthesis; Lemaire, M., Mangeney, P.,
Eds.; Springer: Berlin, 2005; (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2580; (c) Kizirian, J.-C. Chem. Rev. 2008, 108, 140.
2. Tanner, D.; Harden, A.; Johansson, F.; Wyatt, P.; Andersson, P. G. Acta Chem.
Scand. 1996, 50, 361.
3. Andersson, P. G.; Harden, A.; Tanner, D.; Somfai, P.-O. Chem.dEur. J. 1995, 1, 12.
4. (a) Alvaro, G.; Martelli, G.; Savoia, D. J. Chem. Soc., Perkin Trans. 1 1998, 775;
(b) Fiore, K.; Martelli, G.; Monari, M.; Savoia, D. Tetrahedron: Asymmetry 1999,
10, 4803; (c) Ferioli, F.; Fiorelli, C.; Martelli, G.; Monari, M.; Savoia, D.;
Tobaldin, C. Eur. J. Org. Chem. 2005, 1016; (d) Savoia, D.; Alvaro, G.; Di Fabio,
R.; Fiorelli, C.; Gualandi, A.; Monari, M.; Piccinelli, F. Adv. Synth. Catal. 2006,
348, 1883.
5. The diimines derived from glyoxal and the commercially available, cheap en-
antiomers of 1-phenylethylamine have been extensively used to prepare C2-
symmetric 1,2-diamines: Martelli, G.; Savoia, D. Curr. Org. Chem. 2003, 7, 1049.
6. More recently, the highly diastereoselective addition of organolithium reagents
in the presence of Lewis acids and the Barbier-type addition of allylzinc bro-
mide to the diimine derived from glyoxal and (S)- t-butanesulfinamide has
been reported: Sun, X.; Wang, S.; Sun, S.; Zhu, J.; Deng, J. Synlett 2005, 2776.
7. Santes, V.; Go´mez, E.; Za´rate, V.; Santillan, R.; Farfa´n, N.; Rojas-Lima, S. Tetra-
hedron: Asymmetry 2001, 12, 241.
mixtures gave (S,S)-8 as a white powder: 0.182 g (91%); mp¼91.8–
25
92.4 ꢁC; [
a
]
þ231.1 (c 1.0, CHCl3); IR (KBr): v 3063, 3038, 2955,
D
2925, 2863, 2815, 1497, 1466, 1347, 1315, 1204, 1089, 1028, 753, 727,
694; 1H NMR (400 MHz, CDCl3):
d
¼7.19–7.31 (m, 10H), 2.24 (dd,
J¼3.3, J¼6.5 Hz, 2H), 1.96 (d, J¼3.3 Hz, 2H), 1.94–1.93 (m, 2H), 1.80
(d, J¼6.5 Hz, 2H), 1.63–1.73 (m, 4H), 1.52–1.6 (m, 2H), 1.27–1.36
(m, 2H), 0.82 (t, J¼7.3 Hz, 6H); 13C NMR (50 MHz, CDCl3):
¼140.2,
d
128.2, 126.7, 126.2, 73.3, 39.1, 39.0, 32.6, 20.8, 14.5; MS (ES):
m/z¼349.2 [MþH]þ; Anal. Calcd for C24H32N2: C, 82.71; H, 9.25; N,
8.04. Found C, 82.39; H, 9.28; N, 8.02.
4.1.6. Palladium-catalyzed allylic alkylation: typical procedure. To
a solution of aziridine (S,S)-4b (0.010 g, 0.02 mmol) in CH2Cl2 (2 mL)
was added (allylPdCl)2 (0.004 g, 0.01 mmol) and the solution was
deaerated by a slow stream of Ar and then stirred for 1 h. 1,3-
Diphenyl-2-propenyl ethyl carbonate 1b (0.068 g, 0.24 mmol) was
added to the mixture, followed by dimethyl malonate (0.069 mL,
0.60 mmol), BSA (0.176 mL, 0.721 mmol), and KOAc (0.002 g,
0.02 mmol). The reaction was monitored by TLC analysis and, when
complete, quenched with 1 N HCl solution (1 mL) and the organic
phase was extracted with diethyl ether (3ꢂ10 mL). The organic layer
was dried over Na2SO4 and the solvents were evaporated to dryness.
Column chromatography (SiO2, cyclohexane/AcOEt, 75:5) gave (R)-
2: 0.071 g (91%); ee 91% as determined by chiral HPLC (Chiralpak
AD; 2-propanol/hexane 1:9, 1.0 mL/min; 250 nm): retention times
10.7 min (major enantiomer) and 14.9 min (minor enantiomer).
8. (a) The reaction of Grignard reagents with the oxazolidine-acetal prepared
from glyoxal, (R)-phenylglycinol and 2,4-dimethylpentane-2,4-diol, followed
by hydrolysis of the acetal function, produced a-aminoaldehydes with excellent
stereocontrol: Muralidharan, K. R.; Mokhallati, M. K.; Pridgen, L. N. Tetrahedron
Lett. 1994, 35, 7489.
9. For reviews on the organometallic reactions of imines/oxazolidines, see Ref. 5
and: (a) Pridgen, L. N. In Organometallic Reagents in Organic Synthesis; Bateson,
J. H., Mitchell, M. B., Eds.; Academic: London, 1994; (b) Enders, D.; Reinholdt, U.
Tetrahedron: Asymmetry 1997, 8, 1895; (c) Bloch, R. Chem. Rev. 1998, 98, 1407; (d)
Alvaro, G.; Savoia, D. Synlett 2002, 651.
10. 1-Phenylpropanol was produced with low enantiomeric excess (ee 20%) in the
addition of diethylzinc to benzaldehyde in the presence of a catalytic amount of
(S,S)- 7a.
11. The addition of dimethylsulfonium methylide to (R)- N-benzylidenephenyl-
glycinol 17 gave the aziridine 18 by Re-face attack at the imine group, by
analogy with the stereochemical outcomes of the analogous reaction of the
corresponding imine-methyl ether12 and the organometallic reactions of the
same imine.9 In the successive step, the double intermolecular–intramolecular
Mitsunobu reaction using (S)-phenylglycinol afforded in low yield the desired
bis(aziridine), which was identical to the previously prepared (R)-13.
Acknowledgements
This work was carried out in the field of the Prin Project: ‘Sintesi
e stereocontrollo di molecole organiche per lo sviluppo di meto-
dologie innovative’. Fundamental contribution by Fondazione del
Monte di Bologna e Ravenna is also acknowledged.
Ph
OH
H2N
Ph
N
Ph
N
Ph
N
Me3SI, n-BuLi
(2 equiv.)
OH
OH
N
Ph
Ph
PPh3 ( 3 equiv.),
DEAD ( 3 equiv.),
toluene, 110 °C
THF/HMPA, 0 °C
Ph
(R)-13, 18%
Ph
17
18, 73%
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2009.11.062.
12. Higashiyama, K.; Matsumura, M.; Shiogama, A.; Yamauchi, T.; Ohmiya, S. Het-
erocycles 2002, 58, 85.