Solvent- and temperature-dependent functionalisation of enantioenriched aziridines

Article abstract of DOI:10.1002/chem.201002172

A highly stereo- and regioselective functionalisation of chiral non-racemic aziridines is reported. By starting from a parent enantioenriched aziridine and finely tuning the reaction conditions, it is possible to address the regio- and stereoselectivity of the lithiation/electrophile trapping sequence, thereby allowing the preparation of highly enantioenriched functionalised aziridines. From chiral N-alkyl trans-2,3-diphenylaziridines (S,S)-1 a,b, two differently configured chiral aziridinyllithiums could be generated (trans-1 a,b-Li in toluene and cis-1 a,b-Li in THF), thus disclosing a solvent-dependent reactivity that is useful for the synthesis of chiral tri-substituted aziridines with different stereochemistry. In contrast, chiral aziridine (S,S)-1 c showed a temperature-dependent reactivity to give chiral ortho-lithiated aziridine 1 c-ortho-Li at -78 °C and α-lithiated aziridine 1 c-α-Li at 0 °C. Both lithiated intermediates react with electrophiles to give enantioenriched ortho- and α-functionalised aziridines. The reaction of all the lithiated aziridines with carbonyl compounds furnished useful chiral hydroxyalkylated derivatives, the stereochemistry of which was ascertained by X-ray and NMR spectroscopic analysis. The usefulness of chiral non-racemic functionalised aziridines has been demonstrated by reductive ring-opening reactions furnishing chiral amines that bear quaternary stereogenic centres and chiral 1,2-, 1,3- and 1,5-aminoalcohols. It is remarkable that the solvent-dependent reactivity observed with (S,S)-1 a,b permits the preparation of both the enantiomers of amines (11 and ent-11) and 1,2-aminoalcohols (13 and ent-13) starting from the same parent aziridine. Interestingly, for the first time, a configurationally stable chiral α-lithiated aziridine (1 c-α-Li) has been generated at 0 °C. In addition, ortho- hydroxyalkylated aziridines have been easily converted into chiral aminoalkyl phthalans, which are useful building blocks in medicinal chemistry.

Full text of DOI:10.1002/chem.201002172

DOI: 10.1002/chem.201002172
Solvent- and Temperature-Dependent Functionalisation of Enantioenriched
Aziridines
Maria Carolina de Ceglie,[a] Biagia Musio,[a] Francesco Affortunato,[a] Anna Moliterni,[b]
Angela Altomare,[b] Saverio Florio,[a] and Renzo Luisi*[a]
Abstract: A highly stereo- and regiose-
lective functionalisation of chiral non-
racemic aziridines is reported. By start-
ing from a parent enantioenriched azir-
idine and finely tuning the reaction
conditions, it is possible to address the
regio- and stereoselectivity of the lith-
iation/electrophile trapping sequence,
thereby allowing the preparation of
highly enantioenriched functionalised
aziridines. From chiral N-alkyl trans-
2,3-diphenylaziridines (S,S)-1a,b, two
differently configured chiral aziridinyl-
lithiums could be generated (trans-
1a,b-Li in toluene and cis-1a,b-Li in
THF), thus disclosing a solvent-depen-
dent reactivity that is useful for the
synthesis of chiral tri-substituted aziri-
dines with different stereochemistry. In
contrast, chiral aziridine (S,S)-1c
showed a temperature-dependent reac-
tivity to give chiral ortho-lithiated aziri-
dine 1c-ortho-Li at À788C and a-lithi-
ated aziridine 1c-a-Li at 08C. Both
lithiated intermediates react with elec-
trophiles to give enantioenriched
ortho- and a-functionalised aziridines.
The reaction of all the lithiated aziri-
dines with carbonyl compounds fur-
nished useful chiral hydroxyalkylated
derivatives, the stereochemistry of
which was ascertained by X-ray and
NMR spectroscopic analysis. The use-
fulness of chiral non-racemic function-
alised aziridines has been demonstrat-
ed by reductive ring-opening reactions
furnishing chiral amines that bear qua-
ternary stereogenic centres and chiral
1,2-, 1,3- and 1,5-aminoalcohols. It is
remarkable that the solvent-dependent
reactivity observed with (S,S)-1a,b per-
mits the preparation of both the enan-
tiomers of amines (11 and ent-11) and
1,2-aminoalcohols (13 and ent-13) start-
ing from the same parent aziridine. In-
terestingly, for the first time, a configu-
rationally stable chiral a-lithiated aziri-
dine (1c-a-Li) has been generated at
08C. In addition, ortho-hydroxyalkylat-
ed aziridines have been easily convert-
ed into chiral aminoalkyl phthalans,
which are useful building blocks in me-
dicinal chemistry.
Keywords: asymmetric synthesis ·
molecular dynamics · organolithi-
ums · regioselectivity · stereoselec-
tivity
Introduction
optimisation of reactions that involve organolithium re-
agents discloses that several experimental parameters may
affect the outcome of such reactions.[2] In the case of hetero-
substituted organolithium reagents such as oxiranyllithiums,
the reaction conditions (i.e., solvent, temperature, presence
of ligands) should be carefully chosen to avoid undesired
side reactions and maximise the yields. In addition, the ef-
fective use of chiral hetero-substituted organolithiums re-
quires information about their stereochemical integrity.[3]
The above considerations continue to be true also for aziri-
dines, which are now well established as useful and versatile
building blocks in organic synthesis and medicinal chemis-
try.[4]
Organolithium-mediated stereoselective syntheses gained
great importance in the modern synthetic chemistry of the
last two decades and are nowadays also central to important
industrial processes.[1] Nevertheless, research directed at the
[a] Dr. M. C. de Ceglie, Dr. B. Musio, Dr. F. Affortunato, Prof. S. Florio,
Prof. Dr. R. Luisi
Dipartimento Farmaco Chimico
Universitꢀ degli Studi di Bari “A. Moro”
Via E. Orabona, 4 70125 Bari (Italy)
Fax : (+39)0805442539
E-mail: luisi@farmchim.uniba.it
Among the available methodologies for the preparation
of functionalised aziridines, the lithiation/trapping sequence
of simple parent aziridines is growing in importance.[5] Sev-
eral research efforts have shed light on the structural factors
that allow for an easy and stereoselective decoration of azir-
[b] Dr. A. Moliterni, Dr. A. Altomare
Istituto di Cristallografia: IC-CNR sezione di Bari
Via Amendola, 122/O 70126 Bari (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002172.
286
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Chem. Eur. J. 2011, 17, 286 – 296

FULL PAPER
idines in their lithiated form, and recent mechanistic investi-
gations have demonstrated that in N-alkyl arylaziridines the
reaction conditions and aziridine nitrogen substitution can
greatly affect the regio- and stereoselectivity of the lithiation
reaction.[6]
For example, the a versus ortho competition observed in
the lithiation of N-alkyl arylaziridines has been explained by
a dynamically controlled reactivity that depends on the rate
of the aziridine nitrogen inversion and complexation phe-
nomena (Scheme 1). It has been found that starting from
the same parent aziridine two different lithiated intermedi-
ates could be generated by finely tuning the reaction tem-
perature.
Interestingly, the above-described evidence suggests that a
single starting material can serve for the preparation of
completely different functionalised aziridines, thereby in-
creasing the synthetic efficiency of such organolithium-medi-
ated stereoselective transformations. Because we are aware
of the importance of developing more efficient synthetic
methodologies for the preparation of chiral molecules, and
to assess both the efficiency and usefulness of temperature-
and solvent-dependent reactivity, we wish to report here the
results achieved in the lithiation/trapping of chiral enan-
tioenriched aziridines.
Results and Discussion
For this study, two kinds of chiral non-racemic N-alkyl aziri-
dines have been employed: an N-alkyl monophenylaziridine
(to prove the temperature-dependent reactivity) and an N-
alkyl 2,3-diphenylaziridine (to prove the solvent-dependent
reactivity). Highly enantioenriched trans-N-alkyl-2,3-diphe-
nylaziridines (S,S)-1a,b were easily obtained by starting
from the commercially available chiral hydrobenzoin and
using a reported protocol developed by Sharpless and co-
workers.[9] Reaction of hydrobenzoin with SOCl2 followed
by oxidation furnished the cyclic sulfate (R,R)-2, which un-
derwent a stereospecific ring-opening/ring-closing sequence
in the presence of a primary amine and nBuLi (Scheme 3).
Chiral N-methyl-2-phenylaziridine (S,S)-1c could be pre-
pared from commercially available (+)-ephedrine by cyclisa-
tion under Mitsunobu conditions (Scheme 3).[10]
Scheme 1. Dynamically controlled reactivity.
Moreover, in addition to the nitrogen dynamics and com-
plex induced proximity effect, it has been also demonstrated
that the reaction solvent could affect the stereoselectivity of
the lithiation/trapping sequence of trans-N-alkyl-2,3-diphe-
nylaziridines.[7]
In particular, in a polar solvent such as THF, a complete
inversion of configuration occurs upon quenching with an
electrophile, whereas complete retention of the configura-
tion is observed in a less polar solvent such as toluene. This
opposite stereochemical outcome has been explained by a
multinuclear magnetic resonance investigation and ascribed
to two differently configured lithiated intermediates: a mon-
omeric cis-configured lithiated aziridine in THF and a ho-
mochiral dimeric trans-configured lithiated aziridine in tolu-
ene (Scheme 2).[8]
In this latter case, a solvent-dependent reactivity oc-
curred, and two stereochemical pathways (retentive or in-
vertive) could be followed simply by starting from the same
parent aziridine and just changing the reaction medium.
Scheme 3. Synthesis of enantioenriched N-alkyl arylaziridines (DEAD=
diethyl azodicarboxylate).
With chiral aziridines (S,S)-1a–c in hand (e.r.>98:2), the
lithiation/electrophile trapping sequence was explored by
finely tuning the reaction conditions (i.e., reaction solvent
for (S,S)-1a,b and the temperature for (S,S)-1c).
The lithiation of both trans-aziridines (S,S)-1a,b with
sBuLi in THF occurred with complete inversion of configu-
ration to furnish, upon trapping with electrophiles, chiral tri-
substituted aziridines 3a–e (e.r.>98:2). Conversely, the lith-
iation/electrophile trapping performed in toluene furnished
highly enantioenriched (e.r.>98:2) aziridines 4a–d with
complete retention of the configuration as a consequence of
Scheme 2. Solvent-dependent reactivity (TMEDA=N,N,N’,N’-tetrame-
thylenediamine).
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287

R. Luisi et al.
Table 2. Temperature-dependent reactivity: lithiation/electrophile-trap-
ping sequence.
a retentive pathway (Table 1). The two differently config-
ured intermediates trans-1a,b-Li and cis-1a,b-Li are most
likely involved in this highly stereoselective solvent-depen-
dent transformation.[11]
Table 1. Solvent-dependent reactivity: lithiation/electrophile trapping se-
quence.
Product[a,b]
T [8C]
t [h]
E
Yield [%][c]
5a
5b
0
0
0
3.5
3.5
3.5
3.5
4
4
4
4
Me
Et
SiMe3
SnBu3
Me
Br
SiMe3
SnBu3
85
60
65
37
85
65
88
75
cis-5c[d]
5d
0
6a
6b
6c
6d
À78
À78
À78
À78
Product
R
T [8C]
t [h]
E
Yield [%][a]
3a
4a
3b
4b
3c
4c
3d
4d
3e
nPr
nPr
Bn
Bn
nPr
nPr
Bn
Bn
Bn
À78
À78
À78
À84
À78
À78
À78
À84
À78
3
4
1.5
1
3
4
1.5
1
Et
Et
Et
Et
Me
Me
nPr
nPr
SiMe3
92[b]
95[b]
91[b]
68[b]
98[c]
64[c]
90[c]
78[c]
50[c,d]
[a] Enantiomeric ratios evaluated by 1H NMR spectroscopy in the pres-
ence of Mosherꢂs acid or by chiral HPLC (see the Supporting Informa-
tion). [b] Any epimerisation was observed by 1H NMR spectroscopic
analysis of the crude reaction mixture. [c] Isolated yields. [d] An inver-
sion of configuration occurred with this electrophile. Such an inversion
was verified by NOESY experiments.
1.5
[a] Isolated yields. [b] Enantiomeric ratios ascertained by 1H NMR spec-
troscopy (see the Supporting Information). [c] Enantiomeric ratios were
assigned by analogy; no epimerisation was detected by H NMR spectro-
scopic analysis of the crude reaction mixtures. [d] Silylation in toluene
occurs with inversion of configuration to furnish 3e (see ref. [7]).
(À788C), the nitrogen inversion is slower with respect to the
deprotonation reaction and the kinetic position becomes
preferred.[14] In both cases, highly enantioenriched lithiated
intermediates could be generated.
1
By reasoning that the trapping with carbonyl compounds
would have provided hydroxyalkylated aziridines, which are
useful in synthesis and catalysis,[15] this kind of lithiation/
trapping sequence was then investigated on aziridines (S,S)-
1a–c.
The solvent-dependent reactivity was first evaluated with
aziridines (S,S)-1a,b to obtain the results reported in
Table 3.
By running the lithiation/trapping sequence in toluene,
the reactions with aldehydes occurred with complete reten-
tion of the configuration at the lithiated carbon but low ste-
reoselectivity with reference to the newly created carbinolic
carbon. Moreover, the almost equimolar mixtures of diaste-
reomeric hydroxyalkylated aziridines 7a–f and diast-7a–f
could be easily separated by flash chromatography. The
pure separated diastereomers were found to be highly enan-
tioenriched (e.r.>98:2).
As expected, when using THF as the reaction solvent, the
lithiation/trapping with aldehydes occurred with complete
inversion of the configuration at the lithiated carbon and,
almost surprisingly, with a good to high level of stereocon-
trol at the newly created stereogenic centre, thereby furnish-
ing highly enantioenriched hydroxyalkyl aziridines 8 and
diast-8.
Next we turned our attention to aziridine (S,S)-1c to
prove its temperature-dependent reactivity. When the lithia-
tion was performed at 08C, the a-lithiated intermediate 1c-
a-Li was obtained and its trapping with electrophiles fur-
nished highly enantioenriched (e.r.>98:2) aziridines 5a–d
(Table 2).[12] It is remarkable that for the first time a config-
urationally stable enantioenriched aziridinyllithium has been
generated at a relatively high temperature (08C), which is
unusual for this kind of “fleeting” intermediates. It was also
verified that 1c-a-Li reacted with electrophiles with com-
plete retention of the configuration with the exception of
the silylation reaction.[13]
According to the model reported in Scheme 1, when per-
forming the lithiation/trapping sequence at lower tempera-
ture (À788C), a complete switch of the regioselectivity was
observed to obtain mainly ortho-lithiated intermediate 1c-
ortho-Li, which, upon reaction with electrophiles, gave
chiral (e.r.>98:2) aziridines 6a–d (Table 2).
The regioselectivity switch (a/ortho) can be explained by
taking into account the effect of the temperature on the rate
of nitrogen inversion and complex induced proximity effect.
At higher temperature (08C), the nitrogen inversion most
likely occurs faster with respect to the rate of the deproto-
nation reaction, and the thermodynamically favoured ben-
zylic position is lithiated. Conversely, at lower temperature
The reason for this different stereoselectivity upon switch-
ing from toluene to THF has been tentatively ascribed to
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Chem. Eur. J. 2011, 17, 286 – 296

Enantioenriched Aziridines
FULL PAPER
1H NMR spectra revealed for the almost single isomer of
diast-8e (d.r. 98:2) broad signals, which could likely be as-
cribed to a hindered rotation of the aryl groups induced by
the two ortho-methyl substituents of the mesityl ring. In
contrast, a 90:10 diastereomeric mixture of 8a showed clear
and sharp signals for the major isomer and featureless
lumps for the minor isomer, thus suggesting the change of
stereochemistry at the carbinolic carbon as responsible for
this phenomenon. The presence of broad signals was also
Table 3. Solvent-dependent reactivity: hydroxyalkylation reactions.
1
verified by H NMR spectroscopic analysis of the crude re-
action mixtures for the minor isomer of derivatives 8b (d.r.
88:12) and 8d (d.r. 87:13).[21] However, to prove the influ-
ence of the ortho substitution of the aldehyde on the stereo-
selectivity of the reaction, o-tolualdehyde was used for the
trapping of cis-1a-Li in THF. Surprisingly, a modest degree
of stereoselectivity was observed and two diastereomers, 8g
and diast-8g (d.r. 40:60), were isolated. This result seems to
prove that the ortho substitution on the aromatic ring of the
aldehyde could induce a switch on the stereoselectivity of
the addition reaction.
Product[a]
R
R1CHO
Yield [%][b]
d.r.
7a/diast-7a
7b/diast-7b
7c/diast-7c
7d/diast-7d
7e/diast-7e
7 f/diast-7 f
8a
8b
8c
8d
nPr
nPr
nPr
nPr
Bn
PhCHO
2-furylCHO
2,4,6-(CH3)3C6H2CHO
tBuCHO
PhCHO
2,4,6-(CH3)3C6H2CHO
PhCHO
2-furylCHO
tBuCHO
PhCHO
77
59
49
65
48
45
68
77
62
56
54
49
69
49:51[c,d]
48:52[c]
48:52[c]
44:56[c,d]
47:53[c]
57:43[c]
90:10[d,e]
88:12[f]
98:2[e]
Bn
nPr
nPr
nPr
Bn
nPr
Bn
Being unable to obtain suitable crystals, we decided to
assign the stereochemistry of 8g and diast-8g by comparison
of their 1H NMR spectra with that of compounds 8a and
diast-8e with known stereochemistry. Such a comparative
1H NMR spectroscopic analysis was performed in
[D8]toluene at two different temperatures (298 and 348 K)
on derivatives 8a (as a 90:10 mixture of two diastereomers),
diast-8e, 8g and diast-8g (Figure 1). As depicted in Figure 1,
more sharp signals were seen at 298 K for 8a and 8g (Fig-
ure 1a and b), whereas the minor isomer of 8a (diast-8a)
gave broad signals under the same conditions. In contrast,
87:13[d,e]
2:98[d,e]
2:98[d,e]
40:60[e]
diast-8e
diast-8 f
8g/diast-8g
2,4,6-(CH3)3C6H2CHO
2,4,6-(CH3)3C6H2CHO
2-CH3-C6H4CHO
nPr
[a] Enantiomeric ratios (>98:2) ascertained by 1H NMR spectroscopic
analysis (see the Supporting Information). [b] Overall isolated yields.
[c] (S,S,S)/
tive stereochemistry ascertained by X-ray analysis (see the Supporting In-
formation). [e] (S,R,R)/(S,R,S) diastereomeric ratio (see text). [f] (S,R,S)/
(S,R,R) diastereomeric ratio because of the higher priority of the 2-furyl
group.
ACHTUNGTRENNUNG(S,S,R) diastereomeric ratio (see text). [d] Absolute and rela-
G
ACHTUNG-
TRENNUNG
1
the H NMR spectra of diast-8e and diast-8g showed broad
the different aggregation state of the lithiated aziridines
(i.e., monomeric in THF and dimeric in toluene).[16] It is
likely that complexation and aggregation phenomena could
be responsible for the low stereoselectivity observed in tolu-
ene.
signals at 298 K, which could likely be ascribed to a ham-
pered rotation of the aryl groups due to their “similar” ste-
reochemistry (Figure 1c and d).[22] When recording the
1H NMR spectra at 348 K to overcome the rotational barri-
er, sharp signals were observed for all four hydroxyalkylated
derivatives. Upon closer inspection, such spectra showed a
similarity in chemical shifts for the pair 8a and 8g as well as
for the pair diast-8e and diast-8g. In fact, the aziridinyl pro-
tons Ha (ꢀd=3.10 ppm) in both 8a and 8g are more shield-
ed with respect to Ha’ (ꢀd=3.5 ppm) of diast-8e and diast-
8g; in addition, methylenic protons Hb/Hc in both 8a and 8g
showed similar chemical shifts, and a large Dd (ꢀd=
0.7 ppm) as well as similar chemical shifts were found for
Hb’/Hc’ of diast-8e and diast-8g that were associated with a
smaller Dd (ꢀd=0.35 ppm). All this evidence prompted us
to assign the (S,R,R) configuration to 8g and the (S,R,S)
configuration to diast-8g.
Once the stereochemistry of the hydroxyalkylated aziri-
dines obtained in THF was established, a model that ac-
counted for the stereoselectivity was needed. The observed
stereochemistry has been tentatively rationalised by consid-
ering the monomeric tri-solvated structure of cis-1a-Li,
demonstrated by NMR spectroscopy,[8] and the empirical
model proposed by Bassindale and Taylor et al. for the reac-
tion of chiral anions with carbonyl compounds.[23] In this
The relative and absolute stereochemistry of hydroxyalky-
lated aziridines of the kind 7, diast-7 and 8 were ascertained
1
on the basis of H NMR spectra, chromatographic evidence
and by single-crystal X-ray analysis of some derivatives.
For derivatives 7a and 7d, both with a lower chromato-
graphic Rf,[17] the crystallographic analysis furnished an
(S,S,S) absolute configuration. In addition, it was found that
all the diastereomers 7a–f with a lower chromatographic Rf,
showed a more shielded carbinolic methinic proton and a
less shielded aziridine methinic proton with respect to the
diastereomers with major Rf (see the Supporting Informa-
tion). On the basis of this evidence, the (S,S,S) configuration
was similarly assigned also to 7b,c and 7e,f. Consequently,
compounds diast-7a–f should have an (S,S,R) configura-
tion.[18,19]
The stereochemical analysis of hydroxyalkyl aziridines 8,
obtained in THF, was a little more complicated. The X-ray
analyses of 8a, 8d, diast-8e and diast-8 f assigned the
(S,R,R) and (S,R,S) absolute configurations to 8a,d and
diast-8e,f, respectively.[20]
A careful inspection of the
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289

R. Luisi et al.
Figure 1. 1H NMR spectroscopic analysis of hydroxyalkylated aziridines 8.
model, the large-, medium- and small-sized groups were as-
signed as depicted in Scheme 4. The nitrogen substituent
was chosen as the large group, the lone pair being trans-con-
À
figured with respect to the C Li bond and the phenyl ring
directly bonded to the lithiated carbon as medium group
pointing away from the N substituent. The remaining proton
was chosen as the small group.[24] It is reasonable to assume
that the aldehyde approaches the anionic carbon by pointing
its large substituent (L’) between the medium- and small-
sized groups M and S. With the hypothesis that a complex
between the carbonyl oxygen and the lithium (complexes A
or B) could direct the approach of the aldehyde, two possi-
ble transition states could be proposed: TS-A in the reaction
with unhindered aldehydes (i.e., benzaldehyde, 2-furfural
and pivalaldehyde) that leads to derivatives 8, and TS-B in
the reaction with hindered aldehydes (i.e., mesityl aldehyde)
that leads to derivatives diast-8. It is likely that with o-tolyl
aldehyde both pathways could be followed, thereby leading
to a modest stereoselectivity.[25]
The reactions of lithiated aziridines cis-1a-Li and trans-
1a-Li with ketones were also explored but, unfortunately,
Scheme 4. Proposed model for the stereoselective synthesis of hydroxyal-
kylated aziridines 8.
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Enantioenriched Aziridines
FULL PAPER
Table 4. Temperature-dependent reactivity: hydroxyalkylation reactions.
they were found to be more problematic. They occurred
with very low yields and recovery of unreacted aziridines. In
the reaction with cyclohexanone, for example, hydroxyalky-
lated products 7g,h and 8h,i were always obtained with vari-
able amounts of protonated aziridines (cis-1a in THF and
trans-1a in toluene) as the result of an acid–base reaction
(Scheme 5). This hypothesis was confirmed by treating cis-
Product[a]
R1R2CO
(CH2)5CO
(CH2)3CO
p-ClC6H4CHO
(CH2)5CO
t [h]
Yield [%][b]
d.r.[c]
9a
9b
G
3.5
3.5
3.5
4
4
4
82
84
70
54
50
51
–
–
E
9c/diast-9c[f]
10a[e]
50:50[d]
A
–
–
10b
Ph2CO
p-ClC6H4CHO
10c/diast-10c[g]
50:50[d]
[a] Enantiomeric ratios evaluated by 1H NMR spectroscopy in the pres-
ence of Mosherꢂs acid or by chiral HPLC (see the Supporting Informa-
tion). [b] Isolated yields. [c] Evaluated by 1H NMR spectroscopy on the
crude reaction mixture. [d] Configuration at the newly created stereogen-
ic centre assigned by X-ray analysis (see the Supporting Information).
[e] Product 10a underwent, upon flash chromatography, an intramolecu-
lar cyclisation reaction to furnish phthalan 17b (see text). [f] The (S,S,R)
configuration was assigned to 9c based on crystallographic X-ray analysis
(see the Supporting Information). [g] The (S,S,S) configuration was as-
signed to 10c by crystallographic X-ray analysis (see the Supporting In-
formation).
Scheme 5. Solvent-dependent reactivity: reaction with ketones.
1a-Li and trans-1a-Li with deuterium-labelled acetophe-
none. The main reaction products were deuterated aziridines
[D]cis-1a and [D]trans-1a (in THF and toluene, respective-
ly) together with traces of the corresponding hydroxyalky-
lated products. This different reactivity observed with ke-
tones is still unclear and it is currently under investigation.
The hydroxyalkylation reaction was also investigated with
aziridine (S,S)-1c to further prove its temperature-depen-
dent reactivity. As expected, on the basis of the results re-
ported in Table 2, the lithiation/trapping sequence per-
formed at 08C gave a-functionalisation again to furnish
enantioenriched derivatives 9a–c. In contrast, when working
at À788C, exclusive ortho-hydroxyalkylation was observed
to achieve enantioenriched derivatives 10a–c (Table 4).
In this case, the reaction of 1c-a-Li occurred with com-
plete retention of the configuration at the lithiated carbon
atom, and was successful also with enolisable ketones. The
reaction with aldehydes occurred with poor stereoselectivity,
with reference to the newly created stereogenic centre, for
both 1c-a-Li and 1c-ortho-Li.
According to the above results, we were able to conclude
that by using the same chiral scaffold and by just tuning
finely the reaction parameters (i.e., solvent or temperature),
it would be possible to prepare different chiral molecules by
a simple lithiation/trapping sequence.
In fact, with functionalised aziridines in hand, we rea-
soned that they could be suitable starting materials for the
preparation of chiral amines or aminoalcohols by using a
simple reductive ring-opening reaction.[26]
Scheme 6. Reductive ring opening of aziridines: synthesis of chiral
amines.
dines 4,[28] it is noteworthy that both enantiomers of chiral
amines could be obtained by using this methodology and
both derived from the same chiral parent aziridine.[29]
The chance to apply the same synthetic protocol to the
preparation of chiral aminoalcohols was also verified. Re-
duction of hydroxyalkylated aziridines 7a, diast-7a and 8a
gave, respectively, aminoalcohols 12, 13 and ent-13 without
loss of their optical purity (Scheme 7).[30] The enantiomeric
relationship found between 13 and ent-13 was also evidence
of the correct stereochemistry assigned to diast-7a.[31]
We were pleased to find that diastereomeric 2,3-dipheny-
laziridines 3a–e and 4a–d underwent a regioselective ring
opening at the less-substituted benzylic carbon to furnish
chiral amines 11a–e and ent-11a–d, which bore quaternary
stereogenic centres (Scheme 6).[27] Even if lower yields were
observed in the reductive ring opening of some trans-aziri-
For sake of comparison, the usefulness of hydroxyalkylat-
ed aziridines obtained in the temperature-dependent reac-
tivity studies was also proven. Reductive ring opening of a-
hydroxyalkylated aziridines 9a–c provided chiral 1,3-amino-
alcohol 14a–c with good yields and high regioselectivity
(Scheme 8). The stereochemistry of 14c was assigned by
Chem. Eur. J. 2011, 17, 286 – 296
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291

R. Luisi et al.
Conclusion
This work reports a highly stereo- and regioselective func-
tionalisation of chiral aziridines.
With chiral N-alkyl trans-2,3-diphenylaziridines (S,S)-1a,b,
it has been demonstrated that the solvent is able to induce a
complete inversion of the stereochemical course of the reac-
tion between the a-lithiated intermediates and the electro-
philes. An invertive pathway is followed in THF in which
monomeric cis-configured aziridinyllithiums cis-1a,b-Li are
present, whereas a retentive pathway is observed in toluene,
which can likely be ascribed to dimeric trans-configured
aziridinyllithiums trans-1a,b-Li. This solvent-dependent re-
activity has been nicely exploited for the preparation of op-
tically active hydroxyalkylated aziridines 7, diast-7, 8 and
diast-8, the stereochemistry of
Scheme 7. Reductive ring opening of aziridines: synthesis of chiral 1,2-
aminoalcohols.
which has been deeply investi-
gated by X-ray and NMR spec-
troscopic analyses to assign
their absolute configurations.
An interesting switch of the ste-
reoselectivity, with reference to
the newly created stereogenic
centre, has been observed in
the addition of cis-1a,b-Li to ar-
omatic aldehydes depending on
the substitution at the ortho po-
sition of the aromatic ring of
the aldehyde. A model for the
stereoselectivity observed in
THF as been also proposed. A
temperature-dependent regiose-
lective lithiation has been dem-
onstrated with aziridine (S,S)-
1c. The lithiation performed at
low temperature (À788C) fur-
nished ortho-lithiated aziridine
Scheme 8. Synthesis of chiral 1,5-aminoalcohols and phthalans and crystal structure of 14c·HCl.
single-crystal X-ray analysis on its chloridrate, and the same
configuration was assigned by analogy to 14a,b (see the
Supporting Information).
1c-ortho-Li, which reacted with electrophiles to furnish
enantioenriched ortho-functionalised aziridines 10. By per-
forming the lithiation reaction at higher temperature (08C),
the a-lithiated aziridine 1c-a-Li formed almost exclusively
and gave chiral non-racemic tri-substituted aziridines upon
quenching with electrophiles. In summary, it has been dem-
onstrated that just by finely tuning the reaction conditions it
is possible to address the regio- and stereoselectivity of the
lithiation/electrophile trapping sequence of two chiral
parent aziridines, which can serve as an efficient preparation
of highly enantioenriched functionalised aziridines.
Remarkably, the reductive ring-opening reactions of such
functionalised aziridines furnished chiral amines, 1,2-, 1,3-
and 1,5-aminoalcohols, and in some cases in both enantio-
meric forms simply starting from the same parent aziridine.
In addition, chiral aminoalkyl phthalans, which are useful
building blocks in medicinal chemistry, could derive from
ortho-hydroxyalkylated aziridines. Moreover, for the first
time a configurationally stable aziridinyllithium (1c-a-Li)
has been generated at relatively high temperature (08C),
Finally, it was realised that ortho-hydroxyalkylated aziri-
dines could serve as starting materials for the preparation of
two kinds of derivatives depending on the reaction condi-
tions. Upon reduction, ortho-functionalised derivative 10b
furnished chiral non-racemic 1,5-aminoalcohol 15. In addi-
tion, derivatives 10a–c can serve also as useful starting ma-
terials for the preparation of enantioenriched phthalans
16a–c by an acid-promoted intramolecular cyclisation reac-
tion.[32]
It is worth pointing out again that by starting from the
same chiral aziridine (S,S)-1c, useful chiral molecules with
different structures can be obtained.
292
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 286 – 296

Enantioenriched Aziridines
FULL PAPER
CDCl3, 298 K): d=142.4, 137.5, 134.5, 131.7, 128.2, 127.6, 127.5, 127.4,
126.93, 126.91, 126.6, 126.4, 74.3, 58.9, 55.5, 52.8, 24.0, 12.4 ppm; IR
(KBr): n˜ =698, 760, 784, 846, 915, 940, 1008, 1047, 1076, 1200, 1250, 1403,
1455, 1495, 1603, 2869, 2932, 2962, 3029, 3056, 3429 cmÀ1; ESI-MS: m/z
(%): 344 (100) [M+H]+; elemental analysis calcd (%) for C24H25NO: C
83.93, N 4.08, H 7.34; found: C 83.73, N 4.21, H 7.31; enantiomeric purity
(e.r.>98:2) ascertained by 1H NMR spectroscopy in the presence of
Mosherꢂs acid (see the Supporting Information).
thus paving the way for new applications of such reactive in-
termediates in organometallic chemistry.
Experimental Section
General: THF was freshly distilled under a nitrogen atmosphere over
sodium/benzophenone ketyl. Petroleum ether refers to the 40–608C boil-
ing fraction. For the 1H and 13C NMR spectra (1H NMR: 400, 600 MHz;
13C NMR: 150, 100 MHz), CDCl3, CD3OD and [D8]toluene were used as
the solvent. GC–MS spectrometry analyses were performed using a gas
chromatograph (dimethylsilicon capillary column, 30 m, 0.25 mm i.d.)
equipped with a mass selective detector operating at 70 eV (EI). Optical
rotation values were measured using a polarimeter with a cell of 1 dm
path length at 258C; the concentration (c) is expressed in g per 100 mL.
Melting points were uncorrected. Analytical thin-layer chromatography
(TLC) was carried out on pre-coated 0.25 mm thick plates of Kieselgel
60 F254; visualisation was accomplished by UV light (254 nm) or by
spraying with a solution of 5% (w/v) ammonium molybdate and 0.2%
General procedure for the lithiation–trapping sequence of aziridines
(S,S)-1a,b in toluene: sBuLi (1.5 mmol for 1a and 2 mmol for 1b, 1.4m
cyclohexane solution) was added dropwise to a solution of aziridine
(S,S)-1a or (S,S)-1b (1 mmol) and TMEDA (1.5 mmol for 1a and
2 mmol for 1b) in dry toluene (10 mL) at the temperature indicated in
Table 1 and under an N2 atmosphere. The resulting brown mixture was
stirred for the time reported in Table 1 and the electrophile was added
(neat if liquid or diluted in toluene (2 mL) if solid). Stirring was contin-
ued at the reported temperature until consumption of the starting aziri-
dine (TLC-GC monitoring), then the mixture was warmed up to room
temperature and quenched with
a saturated solution of aq. NH4Cl
(3 mL). The mixture was poured into water (20 mL) and extracted with
Et2O (3ꢃ10 mL). The combined organic layers were dried (Na2SO4) and
the solvent evaporated in vacuo. The crude was purified by flash chroma-
tography on silica gel (EtOAc/petroleum ether).
(w/v) ceriumACHTUNGTRENNUNG(III) sulfate in 100 mL 17.6% (w/v) aq. sulfuric acid and
heating to 473 K for some time until blue spots appeared. All reactions
that involved air-sensitive reagents were performed under nitrogen in
oven-dried glassware using a syringe/septum cap technique. Lithiation/
electrophile trapping sequences were performed using a methanol/liquid
N2 (À848C) or acetone/dry ice (À788C) cold bath. The enantiomeric
ratios were determined by HPLC analysis using a Daicel Chiralcel OD-H
column (250ꢃ4.6 mm) or a Cellulose Lux-2 column (250ꢃ4.6 mm), and
by 1H NMR spectroscopy in the presence of Mosherꢂs acid (1.5 equiv in
CDCl3).
AHCTUNGTERG(NNUN 2S,3S)-1-Benzyl-2-ethyl-2,3-diphenylaziridine (4b): Flash chromatogra-
phy (petroleum ether/EtOAc 95:5), yellow oil, 68%. [a]2D0 =À14 (c=0.5
in CHCl3); 1H NMR (400 MHz, CDCl3, 298 K): d=7.38–7.40 (m, 2H;
ArH), 7.32–7.35 (m, 2H; ArH), 7.20–7.30 (m, 7H; ArH), 7.07–7.16 (m,
4H; ArH), 3.64 (d, 2J
2.92 (d, 2J
1.26–1.35 (m, 1H; CH3CHH), 0.34 ppm (t, 3J
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
13C NMR (100 MHz, CDCl3, 298 K): d=140.0, 138.2, 137.8, 130.5, 128.12,
128.1, 127.9, 127.84, 127.8, 127.5, 126.6, 126.5, 58.9, 56.7, 51.2, 28.4,
9.5 ppm; IR (film): n˜ =698, 800, 868, 1027, 1074, 1096, 1261, 1399, 1455,
1495, 1602, 2964, 3027, 3062 cmÀ1; MS (70 eV): m/z (%): 313 (4) [M+],
312 (4) [M+ÀH], 223 (18), 222 (100) [M+ÀC7H7], 194 (13), 167 (17), 165
(9), 115 (7), 91 (44) [C7H7+]; enantiomeric purity (e.r.>98:2) ascertained
by 1H NMR spectroscopy in the presence of Mosherꢂs acid (see the Sup-
porting Information).
General procedure for the lithiation-trapping sequence of aziridines
(S,S)-1a,b in THF: sBuLi (1.5 mmol for 1a and 2 mmol for 1b, 1.4m cy-
clohexane solution) was added dropwise to a solution of aziridine (S,S)-
1a or (S,S)-1b (1 mmol) in dry THF (10 mL) at À788C under an N2 at-
mosphere. The resulting brown mixture was stirred at À788C for the
time indicated in Table 1 before adding the electrophile (neat if liquid or
diluted in 2 mL of THF if solid). Then the reaction mixture was stirred at
À788C until consumption of the starting aziridine (TLC-GC monitoring),
warmed up to room temperature and quenched with a saturated solution
of aq. NH4Cl (3 mL). The resulting mixture was poured in water (20 mL)
and extracted with Et2O (3ꢃ10 mL). The combined organic layers were
dried (Na2SO4) and the solvent evaporated in vacuo. The crude was puri-
fied by flash chromatography on silica gel (EtOAc/petroleum ether).
(1S,2’S,3’S)-(2,3-Diphenyl-1-propylaziridin-2-yl)phenylmethanol
(7a):
Flash chromatography (petroleum ether/EtOAc 95:5), white solid, 38%.
M.p. 114.6–115.08C; [a]D20 =À4 (c=1 in CHCl3); 1H NMR (400 MHz,
CDCl3, D2O exchange, 298 K): d=7.55 (d, 3J
ACTHNUTRGNEUNG(H,H)=7.3 Hz, 2H; ArH);
7.41 (t, 3J
ACTHNUTRGNEUNG(H,H)=7.7 Hz, 2H; ArH), 7.17–7.34 (m, 6H; ArH), 6.87–6.97
ACHTUNGTRENNUNG(2R,3S)-1-Benzyl-2-ethyl-2,3-diphenylaziridine (3b): Flash chromatogra-
3
(m, 3H; ArH), 6.40 (d, J=6.4 Hz, 2H; ArH), 4.42 (s, 1H; CHOH), 3.15
(s, 1H; NCH), 2.86–2.91 (m, 1H; CHH), 1.63–1.76 (m, 2H; CH2), 1.51–
phy (petroleum ether/EtOAc 95:5), yellow solid, 91%. M.p. 77.8–78.28C;
[a]2D0 =+35 (c=1 in CHCl3); 1H NMR (400 MHz, CDCl3, 298 K): d=
7.51–753 (m, 2H; ArH), 7.30–7.36 (m, 2H; ArH), 7.21–7.25 (m, 1H;
ACTHNUTRGNEUNG
1.61 (m, 1H; CHH), 0.90 ppm (t, 3J(H,H)=7.2 Hz, 3H; CH3); 13C NMR
(150 MHz, CDCl3, 298 K): d=139.9, 137.4, 134.4, 131.7, 128.2, 127.9,
127.5, 127.3, 127.2, 127.1, 126.6, 126.0, 75.4, 59.8, 57.9, 53.5, 23.3,
12.0 ppm; IR (KBr): n˜ =700, 714, 766, 1043, 1450, 1495, 1602, 2836, 2861,
2926, 2955, 3057, 3481 cmÀ1; ESI-MS: m/z (%): 344 (100) [M+H]+; ele-
mental analysis calcd (%) for C24H25NO: C 83.93, N 4.08, H 7.34; found:
C 83.66, N 4.07, H 7.30; enantiomeric purity (e.r.>98:2) ascertained by
1H NMR spectroscopy in the presence of Mosherꢂs acid (see the Support-
ing Information).
ArH), 6.96–7.11 (m, 10H; ArH), 4.27 (d, 2J
ACHTUNGTRENNUNG
NCHH), 3.94 (d, 2J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
140.3, 139.5, 138.2, 129.3, 128.2, 128.0, 127.3, 127.2, 126.7, 126.02, 126.0,
56.3, 56.1, 53.5, 25.9, 11.3 ppm; IR (KBr): n˜ =698, 733, 754, 1028, 1073,
1125, 1356, 1452, 1495, 1602, 2875, 2965, 3027, 3060 cmÀ1; MS (70 eV):
m/z (%): 313 (4) [M+], 312 (3) [M+ÀH], 223 (18), 222 (100)
[M+ÀC7H7], 194 (7), 167 (16), 165 (9), 115 (7), 91 (33) [C7H7+]; elemen-
tal analysis calcd (%) for C23H23N: C 88.13, N 4.47, H 7.40; found: C
87.75, N 4.51, H 7.37; enantiomeric purity (e.r.>98:2) ascertained by
1H NMR spectroscopy in the presence of Mosherꢂs acid (see the Support-
ing Information).
(1R,2’S,3’S)-(2,3-Diphenyl-1-propylaziridin-2-yl)phenylmethanol (diast-
7a): Flash chromatography (petroleum ether/EtOAc 95:5), colourless oil,
39%. [a]2D0 =À12 (c=1 in CHCl3); 1H NMR (500 MHz, CDCl3, 298 K):
d=7.55 (d, 3J=7.1 Hz, 2H; ArH), 7.37 (t, 3J
ACHTUNGTRENNUNG
7.28–7.33 (m, 4H; ArH), 7.09–7.20 (m, 5H; ArH), 6.94 (d, 3J
ACHTUNGTRENNUNG
7.1 Hz, 2H; ArH), 4.69 (s, 1H; CHOH), 3.12 (s, 1H; NCH), 2.73–2.76
(m, 1H; NCHH), 1.55–1.73 (m, 3H; CH3CH2 and NCHH), 0.99 ppm (t,
(1R,2’R,3’S)-(2,3-Diphenyl-1-propylaziridin-2-yl)phenylmethanol
(8a):
Flash chromatography (petroleum ether/EtOAc 90:10), white solid, 68%.
M.p. 89.8–90.28C; [a]D20 =+42 (c=1 in CHCl3); 1H NMR (400 MHz,
CDCl3, 298 K): d=7.16–7.28 (m, 5H; ArH), 6.86–7.04 (m, 8H; ArH),
ACTHNUTRGNEUNG
3J(H,H)=7.1 Hz, 3H; CH3); 13C NMR (150 MHz, CDCl3, 298 K): d=
141.2, 137.1, 135.1, 132.0, 128.1, 127.9, 127.7, 127.3, 127.0, 126.7, 126.2,
74.6, 59.0, 56.7, 51.5, 23.3, 12.1 ppm; IR (film): n˜ =703, 712, 754, 1027,
1044, 1072, 1110, 1198, 1242, 1376, 1448, 1495, 1601, 2849, 2872, 2931,
2958, 3028, 3058, 3469 cmÀ1; ESI-MS: m/z (%): 344 (100) [M+H]+;
HRMS: m/z: calcd for C24H26NO [M+H]+: 344.2014; found: 344.2019.
6.54 (d, 3J(H,H)=7.3 Hz, 2H; ArH), 5.13 (d, 3J
ACHTUNGTRENNUNG ACHTUNTGREN(NUGN H,H)=7.3 Hz, 1H;
CHOH), 3.41–3.47 (m, 1H; NCHH), 3.17 (s, 1H; NCH), 2.82–2.88 (m,
1H; NCHH), 2.00 (d, 3J
A
3
CH3CH2), 1.05 ppm (t, J
A
Chem. Eur. J. 2011, 17, 286 – 296
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
293

R. Luisi et al.
1
Enantiomeric purity (e.r.>98:2) ascertained by H NMR spectroscopy in
ACHTUNGTRENNUNG
the presence of Mosherꢂs acid (see the Supporting Information).
General procedure for the lithiation–trapping sequence of aziridines
(S,S)-1c at 08C: sBuLi (1.5 mmol, 1.4m cyclohexane solution) was added
dropwise to a solution of aziridine (1 mmol) and TMEDA (1.5 mmol) in
Et2O (10 mL) at 08C and under an N2 atmosphere. The resulting orange
mixture was stirred for 3.5 h before adding the electrophile (neat if liquid
or diluted in 2 mL of Et2O if solid). Then a solution of sat. aq. NH4Cl
(3 mL) was added and the mixture poured into water (20 mL) and ex-
tracted with Et2O (3ꢃ10 mL). The combined organic layers were dried
(Na2SO4) and the solvent evaporated in vacuo. The crude was purified by
flash chromatography on silica gel (EtOAc/petroleum ether).
3J
major; ArH), 7.29–7.35 (m, 1 H major + 2 H minor; ArH), 7.18–7.21
(m, 2H, major; ArH), 7.14 (d, 3J
(H,H)=7.0 Hz, 1H, minor; ArH), 2.96
(d, 3J
(H,H)=2.9 Hz, 1H, minor; ArCHN), 2.56 (s, 3H, major; NCH3),
2.28 (d, J
NCHCH3), 2.03–2.06 (m, 1H, major; NCHCH3), 2.01 (s, 3H, minor;
NCH3), 1.39 (d, 3J
(H,H)=5.8 Hz, 3H, major; CHCH3), 1.34 (d,
3J
ACTHNGUTREN(NUG H,H)=5.3 Hz, 3H, minor; CHCH3), 0.40 (s, 9H, minor; 3ꢃCH3),
(H,H)=7.0 Hz, 1H, minor; ArH), 7.46 (d, 3J
ACHUTGTNRENNUG ACHUTNTGREN(NUGN H,H)=7.2 Hz, 1H,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
3
AHCTUNGTREG(NNNU H,H)=2.8 Hz, 1H, major; ArCHN), 2.17–2.21 (m, 1H, minor;
AHCTUNGTRENNUNG
0.36 ppm (s, 9H, major; 3ꢃCH3); 13C NMR (spectra description for the
major invertomer, 150 MHz, CDCl3, 263 K): d=145.9, 137.5, 133.8, 129.6,
125.7, 123.7, 49.4, 43.5, 38.4, 11.0, 0.4 ppm; IR (film): n˜ =620, 741, 837,
ACHTUNGTRENNUNG(2R,3S)-1,3-Dimethyl-2-trimethylsilyl-2-phenylaziridine (cis-5c): Flash
chromatography (petroleum ether/EtOAc 40:60), colourless oil, 65%.
[a]2D0 =À66 (c=1, CHCl3); 1H NMR (400 MHz, CDCl3, 298 K): d=7.17–
7.21 (m, 2H; ArH); 7.06–7.11 (m, 3H; ArH), 2.74 (s, 3H; NCH3), 1.88
1087, 1121, 1249, 1398, 1438, 1466, 2955, 3053 cmÀ1
; MS (70 eV):
m/z (%): 219 (19) [M+], 218 (81) [M+ÀH], 205 (15), 204 (87), 147 (16),
146 (100) [M+ÀSiCH3], 145 (24), 144 (14), 131 (19), 73 (41) [SiCH3+];
ESI-MS: m/z (%): 220 (100) [M+H]+. Enantiomeric purity (e.r.>98:2)
ascertained by 1H NMR spectroscopy in the presence of Mosherꢂs acid
(see the Supporting Information).
(q, 3J(H,H)=5.6 Hz, 1H; CHCH3), 0.92 (d, 3J
ACHTUNGTRENNUNG ACHTUNTGREN(NUGN H,H)=5.6 Hz, 3H;
CHCH3), 0.03 ppm (s, 9H; 3ꢃCH3); 13C NMR (100 MHz, CDCl3, 298 K):
d=141.6, 129.4, 127.5, 125.3, 44.4, 43.5, 16.2, 0.2 ppm; IR (film): n˜ =702,
837, 884, 1249, 1453, 1488, 2952, 3024, 3056 cmÀ1; MS (70 eV): m/z (%):
219 (24) [M+], 218 (100) [M+ÀH], 204 (14), 135 (18), 105 (27), 73 (37).
Enantiomeric purity determined by HPLC analysis (Daicel Chiralcel
OD-H column, hexane/iPrOH 99:1, flow rate 0.4 mLminÀ1, l=220 nm;
for racemic aziridine, t1 =10.33 min, t2 =10.85 min; for enantioenriched
aziridine, t=10.49 min).
(1R,2’S,3’S)-4-Chlorophenyl-[2-(1,3-dimethylaziridin-2-yl)phenyl]metha-
nol (diast-10c): Flash chromatography (petroleum ether/EtOAc 20:80),
colourless oil, 23% as inseparable mixture of invertomers (d.r.=87:13,
CDCl3, 298 K). [a]2D0 =+99 (c=2 in CHCl3); 1H NMR (400 MHz, CDCl3,
298 K): d=7.17–7.29 (m, 8H, major; ArH), 7.07–7.16 (m, 7H, minor;
ArH), 6.87–6.89 (m, 1H, minor; ArH), 6.17 (s, 1H, minor; CHOH), 5.60
(1R,2’S,3’S)-4-Chlorophenyl-(1,3-dimethyl-2-phenylaziridin-2-yl)methanol
(9c): Flash chromatography (petroleum ether/EtOAc 80:20), white solid,
35%. M.p. 113.0–114.08C; [a]2D0 =+22 (c=0.9 in CHCl3); 1H NMR
(600 MHz, CDCl3, 298 K): d=7.32–7.33 (m, 3H; ArH), 7.14–71.5 (m,
(s, 1H, major; CHOH), 3.28 (d, 3J
2.04 (d, 3J
(H,H)=3.3 Hz, 1H, major; ArCHN), 1.94–2.00 (m, 1H
major+1H minor; 2ꢃCH3CHN), 1.90 (s, 3H, major; NCH3), 1.67 (s, 3H,
minor; NCH3), 1.31 (d, 3J
(H,H)=4.4 Hz, 3H, minor; CHCH3), 1.20 ppm
(d, 3J(H,H)=6.0 Hz, 3H, major; CHCH3); 13C NMR (spectra description
ACHTUNGTRNE(NUNG H,H)=4.0 Hz, 1H, minor; ArCHN),
AHCTUNGTRENNUNG
4H; ArH), 7.01 (d, 3J
2.13 (s, 3H; NCH), 2.00 (q, J
3J(H,H)=6.0 Hz, 3H; CHCH3); 13C NMR (100 MHz, CDCl3, 298 K): d=
ACHTUNGTRENNUNG(H,H)=8.3 Hz, 2H; ArH), 5.07 (s, 1H; CHOH),
AHCTUNGTRENNUNG
3
AHCTUNGTERG(NUNN H,H)=6.0 Hz, 1H; CHCH3), 1.35 ppm (d,
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
for both the invertomers, 100 MHz, CDCl3, 298 K): d=143.3, 142.3,
140.9, 138.3, 137.9, 132.5, 130.0, 129.45, 129.4, 128.7, 128.2, 128.1, 127.94,
127.92, 127.8, 127.1, 122.3, 121.3, 84.4, 84.2, 75.8, 57.8, 48.6, 39.9, 36.7,
29.7, 14.6, 10.9 ppm; IR (film): n˜ =759, 1013, 1032, 1088, 1171, 1263,
1377, 1402, 1457, 1488, 1601, 2850, 2920, 2957, 3413 cmÀ1; ESI-MS: m/z
(%): 288 (100) [M+H]+.
139.8, 136.7, 132.4, 131.6, 128.2, 128.1, 127.7, 74.2, 54.8, 45.2, 40.9,
14.0 ppm; IR (KBr): n˜ =704, 730, 828, 1014, 1075, 1090, 1131, 1405, 1446,
1490, 2870, 2924, 2956, 3059, 3368 cmÀ1; ESI-MS: m/z (%): 288 (100)
[MÀH]+; elemental analysis calcd (%) for C17H18ClNO: C 70.95, N 4.87,
H 6.30; found: C 70.54, N 4.85, H 6.28. Enantiomeric purity determined
by HPLC analysis (Cellulose Lux-2, hexane/iPrOH 90:10, flow rate
0.8 mLminÀ1
, l=260 nm; for racemic aziridine, t1 =6.13 min, t2 =
7.18 min; for enantioenriched aziridine, t=6.17 min).
(1S,2’S,3’S)-4-Chlorophenyl-[2-(1,3-dimethylaziridin-2-yl)phenyl]metha-
nol (10c): Flash chromatography (petroleum ether/EtOAc 20:80), white
solid, 28% as inseparable mixture of invertomers (d.r.=77:23, CDCl3,
298 K). M.p. 140.0–141.08C; [a]2D0 =+23 (c=1.2 in CHCl3); 1H NMR
(400 MHz, CDCl3, 298 K): d=7.10–7.35 (m, 15H, major+minor; ArH),
7.03–7.06 (m, 1H, major; ArH), 6.08 (s, 1H, major; CHOH), 5.86 (s, 1H,
(1S,2’S,3’S)-4-Chlorophenyl-(1,3-dimethyl-2-phenylaziridin-2-yl)methanol
(diast-9c): Flash chromatography (petroleum ether/EtOAc 80:20),white
solid, 35%. M.p. 184.0–185.08C; [a]2D0 =+39 (c=1.9 in CHCl3); 1H NMR
(600 MHz, CDCl3, 298 K): d=7.19–7.28 (m, 5H; ArH), 7.11 (d,
minor; CHOH), 2.78 (d, 3J
3H, major; NCH3), 2.31 (d, 3J
(s, 3H, minor; NCH3), 2.00–2.06 (m, 1H major+1H minor; NCHCH3),
1.38 (d, 3J(H,H)=5.5 Hz, 3H, minor; CHCH3), 1.32 ppm (d, 3J
(H,H)=
ACHTUNGTRENNUNG
3J(H,H)=8.4 Hz, 2H; ArH), 6.99 (d, 3J
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
CHCH3); 13C NMR (100 MHz, CDCl3, 298 K): d=140.1, 134.5, 132.3,
132.0, 127.7, 127.5, 127.4, 74.3, 56.9, 47.2, 42.2, 14.6 ppm; IR (KBr): n˜ =
704, 730, 1014, 1050, 1066, 1090, 1404, 1447, 1490, 2852, 2921, 2955,
3086 cmÀ1; ESI-MS: m/z (%): 288 (100) [M+H]+; elemental analysis
calcd (%) for C17H18ClNO: C 70.95, N 4.87, H 6.30; found: C 70.54, N
4.85, H 6.28. Enantiomeric purity determined by HPLC analysis (Cellu-
lose Lux-2, hexane/iPrOH 90:10, flow rate 0.8 mLminÀ1, l=260 nm; for
racemic aziridine, t1 =6.53 min, t2 =7.01 min; for enantioenriched aziri-
dine, t=6.94 min).
A
ACHTUNGTRENNUNG
6.0 Hz, 3H, major; CHCH3); 13C NMR (spectra description for both the
invertomers, 100 MHz, CDCl3, 298 K): d=145.2, 143.3, 143.2, 141.1,
137.6, 132.8, 132.6, 130.5, 130.1, 128.6, 128.4, 128.3, 128.2, 128.1, 127.8,
127.5, 127.3, 127.24, 127.2, 126.8, 71.9, 69.8, 48.1, 45.6, 40.8, 39.1, 39.0,
37.8, 17.6, 10.8 ppm; ESI-MS: m/z (%): 288 (100) [M+H]+; IR (KBr):
n˜ =759, 1014, 1033, 1089, 1457, 1488, 2850, 2920, 3420 cmÀ1. Enantiomeric
purity determined by HPLC analysis (Cellulose Lux-2, hexane/iPrOH
90:10, flow rate 0.8 mLminÀ1, l=260 nm; for racemic aziridine, t1 =
10.53 min, t2 =15.42 min; for enantioenriched aziridine, t=10.42 min).
General procedure for the lithiation–trapping sequence of aziridines
(S,S)-1c at À788C: sBuLi (1.5 mmol of a 1.4m cyclohexane solution) was
added dropwise to a solution of aziridine (1 mmol) in dry THF (10 mL)
at À788C and under an N2 atmosphere. The resulting brown mixture was
stirred for 4 h before adding the electrophile (neat if liquid or diluted in
2 mL of THF if solid). The mixture was stirred at À788C until consump-
tion of the starting aziridine (TLC-GC monitoring) and then warmed up
to room temperature. A solution of sat. aq. NH4Cl (3 mL) was added, the
mixture poured into water (20 mL), and then extracted with Et2O (3ꢃ
10 mL). The combined organic layers were dried (Na2SO4) and the sol-
vent evaporated in vacuo. The crude was purified by flash chromatogra-
phy on silica gel (EtOAc/petroleum ether) or by crystallisation.
General procedure for the reductive ring-opening of substituted aziri-
dines: Pd(OH)2 (20mol%) was added to a solution of aziridine (1 mmol)
in EtOAc or MeOH (1 mL). The mixture was connected with a cannula
to a balloon filled with hydrogen at room temperature and stirred until
consumption of the starting aziridine (TLC-GC monitoring). The reac-
tion mixture was filtered on a celite pad and concentrated in vacuo. The
crude was purified by chromatography on silica gel or by crystallisation.
(R)-1,2-Diphenyl-N-propylbutan-2-amine (11a): Flash chromatography
(petroleum ether/EtOAc, 90:10), pale yellow oil, 81%. [a]2D0 =+14 (c=1
in CHCl3); 1H NMR (400 MHz, CDCl3, 298 K): d=7.23–7.29 (m, 4H;
ArH), 7.16–7.19 (m, 1H; ArH), 7.09–7.10 (m, 3H; ArH), 6.70–6.72 (m,
294
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Chem. Eur. J. 2011, 17, 286 – 296

Enantioenriched Aziridines
FULL PAPER
2H; ArH), 2.97 (s, 2H; ArCH2), 2.30–2.41 (m, 2H; NCH2), 1.66–1.81 (m,
concentrated in vacuo. The crude reaction mixture was purified by flash
chromatography.
2H; CH2), 1.40–1.49 (m, 2H; CH2), 0.89 (t, 3J
ACHTUNGTRENNUNG
0.83 ppm (t, 3J
ACHTUNGTRENNUNG
AHCTUNGTERG(NNUN 1R,1’S)-3,3-Diphenyl-1-(methylaminoethyl)-1,3-dihydroisobenzofuran
298 K): d=145.5, 137.7, 130.3, 127.7, 126.6, 127.1, 126.0, 125.95, 61.8,
43.9, 43.7, 28.5, 23.8, 12.0, 7.8 ppm; IR (film): n˜ =703, 751, 765, 1030,
1075, 1151, 1379, 1455, 1496, 1599, 2872, 2927, 2962, 3024, 3052, 3080,
3336 cmÀ1; ESI-MS: m/z (%): 268 (100) [M+H]+; elemental analysis
calcd (%) for C19H25N·HCl: C 75.10, N 4.61, H 8.62; found: C 75.41, N
4.67, H 8.57. Enantiomeric purity determined by HPLC analysis (Cellu-
lose Lux-2, hexane/iPrOH 99.5:0.5, flow rate 0.6 mLminÀ1, l=260 nm;
for racemic amine, t1 =5.75 min, t2 =6.00 min; for enantioenriched amine,
t=5.77 min).
(16a): Flash chromatography (CH2Cl2/MeOH 95:5), yellow oil, 76%.
1
[a]2D0 =+19 (c=1 in CHCl3); H NMR (600 MHz, CDCl3, 298 K): d=7.40
(d, J=7.6 Hz, 2H; ArH), 7.20–7.31 (m, 12H; ArH), 5.46 (d, 3J=2.0 Hz,
1H; ArCHO), 3.11–3.13 (m, 1H; NCHCH3), 2.51 (s, 3H; NCH3),
ACTHNUTRGNEUNG
0.97 ppm (d, 3J(H,H)=6.5 Hz, 3H; CHCH3); 13C NMR (100 MHz,
CDCl3, 298 K): d=145.0, 144.9, 144.8, 140.4, 127.91, 127.9, 127.8, 127.7,
127.5, 127.4, 127.0, 126.7, 123.9, 121.5, 92.1, 83.5, 57.8, 33.7, 14.5 ppm; IR
(film): n˜ =699, 758, 999, 1446, 1490, 2796, 2874, 2969, 3026, 3058,
3326 cmÀ1; ESI-MS: m/z (%): 330 (100) [M+H]+. Enantiomeric purity
(e.r.>98:2) ascertained by 1H NMR spectroscopy in the presence of
Mosherꢂs acid (see the Supporting Information).
(S)-1,2-Diphenyl-N-propylbutan-2-amine (ent-11a): Colourless oil, 55%.
[a]2D0 =À14 (c=1 in CHCl3). Enantiomeric purity was determined by
HPLC analysis (Cellulose Lux-2, hexane/iPrOH 99.8:0.2, flow rate
1.0 mLminÀ1, l=260 nm; for racemic amine, t1 =4.50 min, t2 =5.50 min;
for enantioenriched amine, t=5.54 min).
Acknowledgements
ACHTUNGTRENNUNG(1R,2S)-1,2,3-Triphenyl-2-(propylamino)propan-1-ol (ent-13): Flash chro-
matography (hexane/CH2Cl2 30:70), white oil, 65%. [a]2D0 =+70 (c=0.5
in CHCl3); 1H NMR (400 MHz, CDCl3, 298 K): d=7.02–7.27 (m, 13H;
This work was carried out under the framework of the national project
“Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni” and
financially supported by the University of Bari and by the Interuniversi-
ties Consortium C.I.N.M.P.I.S. The authors would like to acknowledge
Professor Varinder Aggarwal of the University of Bristol for providing
some high-resolution mass analyses, and Giuseppe Chita and Caterina
Chiarella of the Istituto di Cristallografia of CNR in Bari for their techni-
cal assistance.
ArH), 6.81 (d, 3J
3.39 (2ꢃd, AB system, 2J
2H; NCH2), 1.38–1.55 (m, 2H; CH2), 0.92 ppm (t, 3J
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CH3); 13C NMR (100 MHz, CDCl3, 298 K): d=139.8, 139.3, 137.0, 130.1,
128.9, 128.4, 128.2, 127.4, 127.1, 127.05, 126.9, 126.4, 76.9, 66.2, 43.2, 37.4,
23.7, 11.8 ppm; IR (KBr): n˜ =700, 1032, 1051, 1263, 1396, 1453, 1495,
1602, 2873, 2929, 2960, 3029, 3060, 3087, 3400 cmÀ1; ESI-MS: m/z (%):
346 (100) [M+H]+.
A
[1] For leading references on organolithium-mediated stereoselective
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0.5 in CHCl3). Enantiomeric purity of 13 and ent-13 was determined by
HPLC analysis (Cellulose Lux-2, hexane/iPrOH 95:5, flow rate
1.0 mLminÀ1, l=260 nm; for racemic amino alcohol, t1 =6.09 min, t2 =
9.49 min; for ent-13, t=5.98 min; for 13, t=9.45).
ACHTUNGTRENNUNG(1S,2R,3S)-3-(Methylamino)-1,2-diphenylbutan-1-ol (14c): Crystallised
from Et2O, white solid, 70%. M.p. 194.5–195.08C; [a]2D0 =À48.5 (c=0.2 in
EtOH(abs)); 1H NMR (400 MHz, CD3OD, 298 K): d=7.18 (brs, 5H;
ArH), 7.02–7.09 (m, 5H; ArH), 5.34 (d, 3J
ACHTUNGTRENNUNG
ArCHOH), 3.91 (quintet, 3J
3J
3J
d=142.6, 134.3, 130.4, 128.0, 127.4, 127.2, 126.5, 125.5, 74.0, 58.6, 55.1,
30.0, 13.7 ppm; IR (KBr): n˜ =704, 1057, 1453, 1602, 2851, 2924, 3028,
3350 cmÀ1; ESI-MS: m/z (%): 256 (100) [M+H]+; elemental analysis
calcd (%) for C17H21NO·HCl: C 69.97, N 4.80, H 7.60; found: C 70.11, N
5.15, H 8.02. Enantiomeric purity determined by HPLC analysis (Daicel
Chiralcel OD-H column, hexane/iPrOH 95:5, flow rate 0.8 mLminÀ1, l=
210 nm; for racemic amino alcohol, t1 =15.67 min, t2 =19.41 min; for
enantioenriched amino alcohol, t=19.70 min).
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[11] The structure and configuration of cis-1a-Li and trans-1a-Li have
been ascertained by a multinuclear magnetic resonance investiga-
(S)-2-[2-(methylamino)propylphenyl]diphenylmethanol (15): Flash chro-
matography (EtOAc), white solid, 75%. M.p. 124.0–125.08C; [a]D20
=
+143.3 (c=1.3 in CHCl3); 1H NMR (400 MHz, CDCl3, 298 K): d=7.18–
7.30 (m, 12H; ArH), 6.97–7.02 (m, 1H; ArH), 6.62 (d, 3J
(H,H)=7.8 Hz,
1H; ArH), 2.71–2.79 (m, 1H; NCHCH3), 2.65 (dd, 2,3J
(H,H)=13.3,
9.1 Hz, 1H; ArCHH), 2.50 (dd, 2,3J
(H,H)=13.3, 4.0 Hz, 1H; ArCHH),
2.05 (s, 3H; NCH3), 1.10 ppm (d, 3J
(H,H)=6.4 Hz, 3H; CHCH3);
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
13C NMR (100 MHz, CDCl3, 298 K): d=149.8, 148.9, 147.1, 139.0, 132.1,
130.4, 128.2, 127.5, 127.48, 127.46, 127.4, 126.3, 126.2, 125.3, 81.2, 56.7,
42.1, 34.7, 21.1 ppm; IR (KBr): n˜ =701, 759, 1036, 1445, 1486, 2797, 2962,
3021, 3056, 3306 cmÀ1; MS (70 eV): m/z (%): 331 (5) [M+], 313 (3) [M+
ÀH2O], 298 (6), 254 (9), 236 (39), 178 (12), 165 (8), 77 (8), 58 (100); ele-
mental analysis calcd (%) for C23H25NO: C 83.34, N 4.23, H 7.60; found:
C 83.22, N 4.26, H 7.57.
General procedure for the synthesis of aminoalkylphthalans: A solution
of ortho-hydroxyalkylated phenylaziridine 10 (1 mmol) in acetic acid
(3.0 mL) was stirred at room temperature until the substrate disappeared
(TLC-GC monitoring). The reaction mixture was poured into aq. NaOH
(20 mL, 10%), extracted with CH2Cl2 (3ꢃ10 mL), dried (Na2SO4), and
Chem. Eur. J. 2011, 17, 286 – 296
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R. Luisi et al.
tion, (see ref. [8]). It is worth pointing out that the same solvent-de-
pendent reactivity has been observed with N-benzylaziridine (S,S)-
1b, reported here for the first time.
[25] It cannot be ruled out that a different stability of the products 8 and
diast-8 could be responsible for the stereoselectivity switch. Never-
theless, it could be also considered that the ortho-substituent on the
aromatic ring of the aldehyde could induce a steric inhibition of res-
onance, thereby giving a non-planar conformer and thus favouring
complex B. For a recent paper on this possibility, see: D. Hnyk, S.
Samdal, O. Exner, D. A. Wann, D. W. H. Rankin, J. Org. Chem.
2010, 75, 4939–4943. The irreversibility of the addition reaction has
been also verified by quenching the reaction between cis-1a-Li and
benzaldehyde at short (5 min) and long (2 h) reaction times. In both
experiments, the same diastereomeric ratio has been observed
(90:10). See Table 3.
[12] The reaction needs to be performed in Et2O to avoid the competi-
tive deprotonation of THF under these conditions. However, it has
been demonstrated that the solvent does not affect the regioselectiv-
ity (see ref. [6]).
[13] The retention of configuration has been demonstrated by NOESY
experiments on derivatives 5 (see the Supporting Information).
[14] A reported solvent-dependent ortho/a-benzylic competition showed
that the ortho position is kinetically favoured, see: M. Linnert, C.
Bruhn, T. Ruffer, H. Schmidt, D. Steinborn, Organometallics 2004,
23, 3668–3673.
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Y. Arata, K. Okamura, T. Date, K. Koga, Tetrahedron 1997, 53,
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[17] It is worth pointing out that two diastereomers were always ob-
tained in toluene. The Rf refers to the use of hexane/AcOEt (95:5)
as mobile phase for flash chromatography on silica gel.
[18] The retention of configuration and preservation of the enantiomeric
purity have been demonstrated on both diastereoisomers 7 and
diast-7 by comparison of spectral data with that of known com-
pounds, by NOESY experiments and by analysis of the enantiomeric
composition against a racemic sample.
[19] It is worth pointing out that in the case of the 2-furyl substituent,
the absolute configuration should be (S,S,R) for 7b and (S,S,S) for
diast-7b because of a change in the priority order of the 2-furyl
group.
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[28] The lower yields that were observed when starting from trans-aziri-
dines 4 should be ascribed to a competing ring opening that involves
the more substituted benzylic carbon.
[29] The enantiomeric relationship between amines 11a–d and ent-11a–d
was demonstrated on the basis of chiral HPLC analyses and the
values of optical rotation. It was also verified that no loss of optical
purity occurred during the lithiation/trapping/reduction sequence
(see the Supporting Information).
[30] The enantiomeric relationship between 13 and ent-13 has been dem-
onstrated by chiral HPLC analysis (see the Supporting Informa-
tion).
[31] It is worth pointing out that X-ray analysis provided the configura-
tion of 8a and 7a but not for diast-7a.
[20] The X-ray analysis furnished either relative or absolute configura-
tion of hydroxyalkyl derivatives 8a,d and diast-8e,f. See the Sup-
porting Information.
[21] Attempts to isolate an analytically pure sample of the minor isomer
failed.
[22] This interesting phenomenon could allow the establishment of some
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À
C C bond rotation barriers and is currently under investigation by
dynamic NMR spectroscopy. The results will be reported in due
course.
[23] a) A. R. Bassindale, R. J. Ellis, J. C.-Y. Lau, P. G. Taylor, J. Chem.
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[24] These assignments seem to be the better choice in terms of fitting
with the observed stereochemistry.
Received: July 29, 2010
Published online: November 12, 2010
296
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Chem. Eur. J. 2011, 17, 286 – 296