Nitrogen dynamics and reactivity of chiral aziridines: Generation of configurationally stable aziridinyllithium compounds

Article abstract of DOI:10.1002/chem.201003424

Diastereomeric oxazolinylaziridines (R,R)-9 and (R,S)-9 have been regioselectively lithiated at the α-position with respect to the oxazolinyl ring. The resulting aziridinyllithium compounds proved to be chemically and configurationally stable under the ex

Full text of DOI:10.1002/chem.201003424

DOI: 10.1002/chem.201003424
Nitrogen Dynamics and Reactivity of Chiral Aziridines: Generation of
Configurationally Stable Aziridinyllithium Compounds
Leonardo Degennaro,[a] Rosmara Mansueto,[a] Elisa Carenza,[b] Rosanna Rizzi,[c]
Saverio Florio,[a] Lawrence M. Pratt,[d] and Renzo Luisi*[a]
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Chem. Eur. J. 2011, 17, 4992 – 5003

FULL PAPER
Abstract: Diastereomeric oxazolinyl-
ACHTUNGTRENNUNGaziridines (R,R)-9 and (R,S)-9 have
the basis of DFT calculations and the
observed dynamics of the aziridine ni-
trogen atom. The DFT analysis allowed
the disclosure of a solvent-dependent
differing stability of diastereomeric
lithiated aziridines (R,R)-9-Li and
(R,S)-9-Li, suggesting h3-coordinated
oxazolinylaziridinyllithium compounds
as likely intermediates. Such intermedi-
ates could be the result of a dynamical-
ly controlled lithiation that relies on
the preliminary formation of a complex
between the lithiating agent and the
oxazolinyl ring. According to this
model, the competing complexation of
the lithiating agent by the lone pair of
electrons on the aziridine nitrogen
would cause addition to the oxazoline
C=N bond, thus ending up with the for-
mation of oxazolidines, which are pre-
cursors of useful chiral ketoaziridines.
The proposed model has been also sup-
ported by estimating the nitrogen in-
version barrier by dynamic NMR spec-
troscopic experiments.
been regioselectively lithiated at the a-
position with respect to the oxazolinyl
ring. The resulting aziridinyllithium
compounds proved to be chemically
and configurationally stable under the
experimental conditions used, thus fur-
nishing, upon trapping with electro-
philes, chiral 2,2-disubstituted aziri-
dines, in contrast to the corresponding
a-lithiated oxazolinyloxiranes that have
been reported to be chemically stable
but configurationally unstable. This pe-
culiar behavior of the nitrogen-bearing
heterocycle has been rationalized on
Keywords: ketoaziridines · lithium ·
nitrogen dynamics · NMR spectros-
copy · stereoselectivity
Introduction
trogen atom) lithiation takes place at the b-trans position
with respect to the alkyl group.[6] Moreover, the lithiation/
trapping reactions meet the problem of the configurational
stability of the related aziridinyllithium compounds, so far
scarcely investigated but of great importance for planning
stereoselective synthesis of aziridines and derivatives.
Indeed, at least with reference to aziridines bearing an
EWG substituent on the lithiated carbon atom, studies on
the configurational stability of these compounds and the ste-
reochemistry of trapping them with electrophiles are rather
rare. In an early report, Seebach et al.[7] studied lithiated
aziridinyl thioesters (S,R)-1 and (S,S)-1, thus demonstrating
that their configurational stability depends on the configura-
tion of the starting aziridine (Figure 1). Moreover, Housson
and co-workers[8] reported that lithiated aziridinyl esters
(R,R)-2 and (R,S)-2 were configurationally stable under dif-
ferent reaction conditions and reacted with electrophiles
with retention of configuration (Figure 1).
Aziridines are widely used as versatile building blocks for
the synthesis of a variety of biologically and pharmaceutical-
ly important molecules.[1] Several methods of synthesis of
chiral aziridines have been developed and their use as chiral
building blocks has also emerged.[2] The synthesis of func-
tionalized aziridines based on the lithiation/trapping se-
quence of readily available parent aziridines has become
more and more useful over recent years.[3] The generation of
lithiated aziridines involved in such a methodology by de-
protonation (usually by using an organolithium or a lithio-
ACHTUNGTRENNUNGamide) clearly depends on several factors, including the
nature of the aziridine-ring substitution and the stereochem-
istry at the aziridine nitrogen atom.[4] As a matter of fact,
when an electron-withdrawing group (EWG) is on one of
the aziridine-ring carbon atoms, lithiation takes place nor-
mally at the a-position to that group,[5] whereas with alkyl-
substituted terminal aziridines (bearing an EWG on the ni-
[a] Dr. L. Degennaro, Dr. R. Mansueto, Prof. S. Florio, Prof. R. Luisi
Dipartimento Farmaco-Chimico
University of Bari, “Aldo Moro”
Via E. Orabona 4, 70125 - Bari (Italy)
Fax : (+39)080-5442539
E-mail: luisi@farmchim.uniba.it
[b] Dr. E. Carenza
Institut de Ciꢁncia de Materials de Barcelona
Campus de la Universitat Autꢂnoma de Barcelona
08193 Bellaterra, Catalunya (Spain)
[c] Dr. R. Rizzi
Istituto di Cristallografia (IC-CNR)
Via Amendola 122/o, 70125 - Bari (Italy)
[d] Prof. L. M. Pratt
Department of Chemistry
Fisk University
37208 - Nashville, TN (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003424.
Figure 1. Reported aziridinyl ester compounds.
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R. Luisi et al.
Finally, Patwardhan et al.[9] investigated the alkylation of
lithiated aziridine-2-carboxylate compounds bearing a benz-
hydryl group on the nitrogen atom and found high diaste-
reoselectivity only with aziridines of the type cis-3, whereas
the lithiated aziridine carboxylate compound (R)-3 under-
went racemization. Variable amounts of dimerization prod-
ucts 4, which decreased the yields of the trapping reactions,
were always observed in the reactions of all the studied lithi-
ated aziridine carboxylate compounds.
In our recent studies on the lithiation of N-alkyl oxazoli-
nylaziridines, we found that the regioselectivity depends on
the steric demand of the N-substituent. Indeed, chiral 1-
trityl-2-oxazolinylaziridine (S)-5 could be regioselectively b-
lithiated to give chemically and configurationally stable
(S,S)-5-Li, as proved by electrophilic trapping, and yield
Scheme 3. Preparation of chiral oxazolinylaziridines (R,R)-9 and (R,S)-9.
(R,S)-8 with diethylamino sulfurtrifluoride (Scheme 3).[13]
No epimerization at C2 was observed during all the synthet-
ic steps.
chiral cis-2,3-diACHTUNGTRENNUNG
substituted aziridine (S)-5a (Scheme 1).[10]
Once prepared, both the diastereomeric aziridines (R,R)-
9 and (R,S)-9 were subjected to the lithiation/deuteration se-
quence under varied reaction conditions. Both aziridines
(R,R)-9 and (R,S)-9 underwent highly regioselective lithia-
tion at the a-position to give (R,R)-9-Li and (R,S)-9-Li and,
in both cases, quenching with a deuterium source within
1 hour from their generation took place with complete re-
tention of configuration (Table 1, entries 1–3 and 6–8). Nev-
ertheless, at a closer look, some differences in the thermal
and configurational stability of (R,R)-9-Li and (R,S)-9-Li
were observed. In analogy with the work of Seebach and
Scheme 1. Regioselective b-lithiation of terminal oxazolinylaziridines.
TMEDA=tetramethylethylenediamine.
Table 1. Lithiation/deuteration (MeOD) sequence of aziridines (R,R)-9
and (R,S)-9.
Conversely, oxazolinylaziridines with a less sterically de-
manding N-substituent, such as 1-benzyl-2-oxazolinylaziri-
dine (ꢀ)-6, underwent exclusive a-lithiation to give 6-Li
and products derived upon its trapping (Scheme 2).
As the configurational stability of a-lithiated oxazolinyl-
ACHTUNGTRENNUNGaziridines is so far completely unexplored, we decided to un-
dertake a detailed investigation on this topic and were also
intrigued by the recent observation that a-lithiated oxazoli-
nyloxiranes generated from optically pure precursors have a
pronounced bias to epimerization.[11]
Entry
Aziridine
T
[8C]
t
D
Yield
[%][b]
Ratio
(R,R)/ACHTUNGTRENNUNG
(R,S)[c]
[%][a]
U
1
2
3
4
5
6
7
8
9
U
ꢁ98
ꢁ98
ꢁ98
ꢁ98
ꢁ78
ꢁ98
ꢁ98
ꢁ98
ꢁ98
ꢁ78
15 min
30 min
1 h
4 h
4 h
15 min
30 min
1 h
4 h
4 h
90
90
90
90
80
90
90
90
80
80
80
80
70
80
80
80
–
>98:2
98:2
98:2
98:2
>98:2
5:95
5:95
6:94
25:75
23:77
Scheme 2. Regioselective a-lithiation of terminal oxazolinylaziridines.
[d]
–
Results and Discussion
[d]
10
–
–
[a] Deuterium content established by 1H NMR spectroscopic and/or MS-
To begin the study, chiral 1-phenylethyl-2-oxazolinylaziri-
dines (R,R)-9 and (R,S)-9 were prepared starting from dia-
stereomeric esters (R,R)-7 and (R,S)-7[7,12] upon treatment
with 2-methyl-2-amino-1-propanol and nBuLi in toluene
and subsequent reaction of the resulting amides (R,R)-8 and
AHCTUNGTERG(NNUN ESI) analysis. [b] Yield of isolated products. [c] Diastereomeric ratio by
1H NMR spectroscopic and GC-MS analysis of the crude reaction mix-
ture. [d] Degradation occurred under these reaction conditions and only
traces of epimerized deuterated compounds were detected by GC-MS
analysis.
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Dynamically Controlled Lithiation of Chiral Aziridines
FULL PAPER
Housson, it was found that in some cases the reactions of
the (R,S)-9 diastereoisomer were less selective than those of
(R,R)-9. The lithiated intermediate (R,S)-9-Li proved to be
thermally and configurationally unstable for a longer reac-
tion time and at a higher temperature (Table 1, entries 9 and
10), thus leading to degradation products and appreciable
epimerization. Conversely, lithiated intermediate (R,R)-9-Li
was thermally and configurationally stable even at a temper-
ature higher than ꢁ988C and for a long reaction time
(Table 1, entry 5).
The same behavior was observed, as expected, also for
the enantiomeric aziridines (S,S)-9 and (S,R)-9, prepared by
using the corresponding aziridinyl esters obtained from (S)-
phenylethylamine (Scheme 3).
In view of this, the generation of the lithiated aziridines
from all the available stereoisomers and the stereoselective
trapping with electrophiles was investigated by using ꢁ988C
for 15 minutes as optimal reaction conditions. Under such
conditions, trapping with alkyl halides furnished enantiomer-
ically enriched 2,2-disubstituted aziridines (S,S)-10a,b,
(R,R)-10a,b, (R,S)-11a,b, and (S,R)-11a,b in good yields
(Table 2).
phy and the absolute configuration of the S,S,R isomer was
ascertained by X-ray analysis.[14] This stereochemical out-
come revealed that the aziridine ring in (S,S,R)-10c had the
same configuration at C2 of the starting aziridine (S,R)-9,
thus demonstrating that the transformation (S,R)-9!
ACHTUNGTRENNUNG(S,R)-
9-Li!
ACHTUNGTRENNUNG
tion. Because of the observed retention of configuration in
the deuteration and hydroxyalkylation reactions of all the
isomeric aziridines 9, the absolute configuration of alkylated
aziridines (S,S)-10a,b, (R,R)-10a,b, (R,S)-11a,b, and (S,R)-
11a,b was assigned by analogy.
Dynamics of the aziridine nitrogen atom: An interesting
aspect highlighted by the NMR spectroscopic analysis of a-
alkylated products was that they exist as a mixture of two
slowly equilibrating invertomers (as a consequence of the ni-
trogen inversion) in a ratio that depends on the a-substitu-
ent and on the configuration of the starting aziridine.[15]
Mindful of the importance of such a dynamic phenomenon
on the reactivity of aziridines[4,16,17] and on its potential ap-
plication at the molecular level for the development of mo-
lecular switches,[18] we decided to run a dynamic NMR spec-
troscopic investigation as well with the aim of obtaining in-
sight into the lithiation mechanism and the reasons for the
observed configurational stability.
Trapping of lithiated aziridine (S,R)-9-Li with para-
ClC6H4CHO occurred with low stereoselectivity with respect
to the newly created stereogenic centre, thus furnishing the
two diastereomeric aziridines (S,S,R)-10c and (S,S,S)-10c in
a 70:30 ratio and 55% overall yield. Fortunately, the two
diastereoisomers could be separated by flash chromatogra-
Several aziridines were investigated, including the already
reported N-benzyl aziridines 12a–c,[10] and the distribution
of the two invertomers was evaluated by NMR spectroscop-
ic analysis by varying the solvent and temperature (Table 3).
It is remarkable that the steric demand of the a-substituent
very much affects the A/B ratio. The stereochemistry of
each invertomer A and B, with reference to the configura-
Table 2. Lithiation/trapping sequence of aziridines 9 with electrophiles.
1
tion of the nitrogen atom, was first ascertained by H NMR
spectroscopic analysis under slow-exchange conditions by
using 1D selective NOESY experiments with the DPFGSE
sequence.[19]
Figure 2 reports the results of this stereochemical investi-
gation for oxazolinylaziridines 12b,c and (R,S)-11a,b in
Table 3. Distribution of invertomers of terminal oxazolinylaziridines.
Aziridine
Electrophile
Product
Yield
[%][a]
d.r.[b,c]
A
MeI
EtI
MeI
EtI
MeI
EtI
MeI
EtI
G
90
90
86
60
80
60
85
85
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
A
Aziridine
G
R
A/B[a]
A/B[b]
A
G
12a
A
PhCH2
H
H
H
Me
Me
Me
Et
Et
Et
>95:5
>95:5
>95:5
38:62
15:85
44:56
15:85
15:85
10:90
>95:5[c]
>95:5[c,d]
>95:5[c,d]
30:70[d]
17:83[d]
N
PhCHCH3
PhCHCH3
PhCH2
PhCHCH3
PhCHCH3
PhCH2
R
N
N
A
N
A
G
23:77[d]
10:90[d]
10:90[d]
10:90[d]
(S,R)-9
p-ClC6H4CHO
55[d]
>99:1[e]
AHCTUNGTRENNUNG
G
PhCHCH3
PhCHCH3
[a] Yield of the isolated products. [b] Epimerization would give a mixture
of diastereomers. [c] Diastereomeric ratio established by 1H NMR spec-
troscopic and/or GC-MS analyses. [d] Overall yield of two separable dia-
stereomers (d.r.=70:30). [e] Diastereomeric ratio for both (S,S,R)-10c
and (S,S,S)-10c.
AHCTUNGTRENNUNG
[a] Ratio at 298–233 K in CDCl3. [b] Ratio at 298–203 K in a different
solvent. [c] Ratio at 270 K in [D8]THF. [d] Ratio at 270–203 K in
[D8]toluene.
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R. Luisi et al.
Figure 2. Stereochemical analysis for oxazolinylaziridines 12b,c, (S,R)-11a, and (R,S)-11b: A–C) CDCl3, 270 K; D) CDCl3, 223 K. Main NOE interac-
tions are shown.
CDCl3 under slow-exchange conditions.[20] The aziridine pro-
tons Ha/aꢃ and Hb/bꢃ were used as probes to establish the spa-
tial relationship between the groups.[21] Either N-benzyl or
N-phenylethyl C2-substituted (R¼H) oxazolinylaziridines
preferentially set the N-substituent on the same side of the
oxazolinyl ring regardless of the steric demand of the C2
alkyl substituent. This preferred arrangement of the N-sub-
stituent was also demonstrated in a different solvent such as
[D8]toluene (see the Supporting Information) in which a
more marked imbalance between invertomers was observed
with respect to CDCl3 (Table 3).
In contrast, the same structural analysis (in CDCl3 or
[D8]toluene solution) performed on C2-unsubstituted (R=
H) oxazolinylaziridines 12a, (R,R)-9, and (R,S)-9 disclosed
that the almost exclusive invertomers (d.r.>95:5) set the N-
substituent in a trans relationship with respect to the oxazo-
linyl group (see the Supporting Information), thus leaving
the lone pair of electrons on the opposite side to the proton
to be removed. This evidence was also demonstrated by 1D
selective NOESY experiments in [D8]THF, which is the sol-
vent for the lithiation reaction.
Because it has been reported that nitrogen dynamics and
the availability of the lone pair of electrons play a pivotal
role in determining the regioselectivity of the lithiation in
N-alkyl-2-phenyl- and 2,3-diphenylaziridines[4b,c,17] and pro-
mote the formation of complexes with the lithiating
agent,[22] the question is whether the same factors could ac-
count for the lithiation of oxazolinylaziridines.
On the basis of the ratio between the two invertomers of
aziridines (R,R)-9 and (R,S)-9 (d.r. A/B>95:5), the lone
pair of electrons on the aziridine nitrogen atom could come
into play only if invertomer B is deprotonated much faster
than A (Scheme 4, path a). However, under the reaction
conditions (ꢁ988C), the inversion process is almost blocked
and the reaction of B is expected to be very slow. Moreover,
the two oxazoline heteroatoms in invertomer A could also
form complexes with the base competing with the aziridine
nitrogen atom (Scheme 4, path b).
With the aim of verifying our hypothesis, we decided to
estimate the nitrogen inversion barrier and to perform DFT
calculations on neutral and lithiated oxazolinylaziridines.
The nitrogen inversion barrier was first established for
aziridines 12b (d.r.=70:30 in [D8]toluene)[23] and (S,S)-10a
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Dynamically Controlled Lithiation of Chiral Aziridines
FULL PAPER
Table 4. Relative energies [kcalmolꢁ1] for lithiated oxazolinylaziridines
(R,R)-9-Li and (R,S)-9-Li.
Molecule
(R,S)-9-N-Li-inv
(R,S)-9-h3-N-Li
(R,S)-9-O-Li
(R,R)-9-N-Li-inv
(R,R)-9-h3-N-Li
(R,R)-9-O-Li
G MP2[a,b]
G M062X[a]
G
11.81
0.00
4.52
10.41
0.00
7.15
10.33
0.00
5.89
11.88
0.00
8.50
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] Relative energies in kcalmolꢁ1. [b] G MP2//M062X
Scheme 4. Possible pathways for the regioselective a-lithiation of oxazoli-
nylaziridines.
(d.r.=83:17 in [D8]toluene) by dynamic NMR spectroscopic
N double bond of the oxazoline ring and could likely benefit
from extra stabilization by the phenyl ring of the N-substitu-
ent (Figure 5). This type of h3-coordination has been already
observed by FTIR and NMR spectroscopic analysis on a-
lithiated oxazolinyloxiranes in THF solution.[29] The extra
stability from the interaction with the phenyl group is not
possible in the invertomer (R,S)-9-N-Li-inv.
The O-chelated structure (R,S)-9-O-Li was also found as
a local minimum, but was 5.9 kcalmolꢁ1 less stable than
(R,S)-9-h3-N-Li.[30] Optimization on the nitrogen invertomer
revealed that the equilibrium geometry (R,S)-9-N-Li-inv
was almost 10.3 kcalmolꢁ1 less stable than (R,S)-9-h3-N-Li
and that the Li ion could be chelated by the lone pair of
experiments and line-shape analysis[24] (Figure 3) by finding
¼
DG
values for the conversion of major into minor of
(298)
¼
DG (298) =16.8 and 16.3 kcalmolꢁ1, respectively. These
values were in the range expected for this type of N-alkyl-
substitued aziridine[25] and were used as a reference for the
estimation of the nitrogen inversion barrier of aziridines
(R,R)-9 and (R,S)-9, in which the very low intensity (<5%)
1
of the H NMR signals of the minor invertomers encumbers
an accurate analysis of the inversion process by dynamic
NMR analysis.[26]
Calculations with the modern M06-2X functional and post
HF MP2 method[27] were subsequently performed on neutral
and lithiated oxazolinylaziridines (R,R)-9, (R,S)-9, (R,R)-9-
Li, and (R,S)-9-Li. The search for the equilibrium geometry
was run for both the invertomers of the neutral aziridines
(R,R)-9 and (R,S)-9. According to 1D selective NOESY ex-
periments in CDCl3, [D8]THF, and [D8]toluene, even the
calculations demonstrated that for both (R,R)-9 and (R,S)-9
the most stable invertomer sets the N-substituent and the
oxazolinyl ring trans each other. In fact, it was found that
aziridines (R,R)-9 and (R,S)-9 were more stable than the
corresponding nitrogen invertomers (R,R)-9-inv and (R,S)-
9-inv of about 7.3 kcalmolꢁ1, respectively (Figure 4). The
difference in energy between (R,S)-9 and (R,R)-9 was only
ꢁ
electrons on the aziridine nitrogen atom (Li30 N4=
1.89 ꢄ). Similar conclusions were obtained from the analysis
with the MP2 method (Table 4).
The computed structures obtained in the analysis of
(R,R)-9-Li showed again that an h3-coordinated intermedi-
ate (R,R)-9-h3-N-Li (0 kcalmolꢁ1 rel. energy) was more
stable than (R,R)-9-O-Li and (R,R)-9-N-Li-inv by about 8.5
and 11.9 kcalmolꢁ1, respectively (Figure 6). A comparison
between neutral and lithiated aziridines (R,S)-9 and (R,S)-9-
ꢁ
ꢁ
h3-N-Li reveals that the C2 C5 and C5 N6 bond lengths
are 1.48 and 1.28 ꢄ, respectively, in the neutral aziridine
versus 1.43 and 1.31 ꢄ, respectively, in the lithiated inter-
mediate. Similar bond lengths have also been computed for
(R,R)-9 and (R,R)-9-h3-N-Li (1.48 and 1.28 ꢄ in the neutral
aziridine versus 1.43 and 1.30 ꢄ in the lithiated intermedi-
ate). These values suggest that the aziridine carbon atoms
likely do not change their hybridization upon lithiation and
that the negative charge could not be delocalized into the
oxazolinyl ring, which is in contrast with lithiated aziridine-
carboxylate compounds in which an enolate-like structure
has been taken into consideration.[8,9]
¼
DG (298) =0.26 kcalmolꢁ1.
On the basis of the computed structures obtained for the
neutral aziridines (R,R)-9 and (R,S)-9 and the estimated
value of the inversion barrier, it seems reasonable to assume
that the deprotonation reaction could involve invertomer A
(Scheme 4).
Computational analysis on lithiated oxazolinylaziridines
(R,R)-9 and (R,S)-9: With the aim of explaining the config-
urational stability observed with this type of lithiated oxazo-
linylaziridines, which is in striking contrast with the bias to
epimerization of lithiated oxazolinyloxiranes, a computa-
tional analysis with the hybrid GGA M06-2X functional
with the 6-31+G(d) basis set[28] was undertaken.
Gas-phase calculations on diastereoisomeric lithiated azir-
idines (R,S)-9-Li and (R,R)-9-Li were performed taking into
consideration also the corresponding nitrogen invertomers
(Table 4). The computational analysis of (R,S)-9-Li gave
(R,S)-9-h3-N-Li as equilibrium geometry (relative energy=
0 kcalmolꢁ1), in which the Li atom is coordinated to the C=
By considering the optimized structures (R,S)-9-h3-N-Li
and (R,R)-9-h3-N-Li, their energy difference was
5.4 kcalmolꢁ1, the former being more stable than the latter.
This result contrasts with the experimental evidence in THF
in which lithiated aziridine (R,R)-9-Li proved to be more
thermally stable than (R,S)-9-Li. Such a different stability
could be justified because these computed structures do not
take into account aggregation phenomena.[31]
Nevertheless, to validate the computational results in the
gas-phase experimentally, the lithiation of aziridines (R,S)-9
and (R,R)-9 was performed in a less polar and non-coordi-
Chem. Eur. J. 2011, 17, 4992 – 5003
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4997

R. Luisi et al.
The high configurational sta-
bility observed in toluene can
be explained by taking into ac-
count the epimerization process
depicted in Scheme 5 and the
equilibrium geometries found
computationally. If we consider
the epimerization of (R,S)-9-Li,
which would give (R,R)-9-Li,
and vice versa, it would occur
through two inversions: one in-
volving the lithiated carbon
ꢁ
atom (C Li inversion in
Scheme 5) and one involving
ꢁ
the aziridine nitrogen atom (N
R inversion in Scheme 5). Re-
gardless of the inversion that
occurs first, two intermediates
result that set the oxazolinyl
ring and substituent on the azir-
idine nitrogen atom in a cis re-
lationship. From calculations
such intermediates might corre-
spond to (R,S)-9-h3-N-Li-inv
and (R,R)-9-h3-N-Li-inv, which
are higher in energy (Table 4)
with respect to the correspond-
ing equilibrium geometries of
(R,S)-9-h3-N-Li and (R,R)-9-h3-
N-Li.
Therefore, it could be reason-
able to ascribe the high configu-
rational stability observed in
toluene to a high-energy barrier
associated with the inversion
processes involved in the epi-
merization mechanism.
For the sake of comparison,
the DFT computational analysis
of lithiated oxazolinylaziridines
(R,R)- and (R,S)-9-Li was also
performed on the correspond-
ing THF solvates (Table 5). The
structure of disolvated deriva-
Figure 3. Line-shape analysis on oxazolinylaziridines 12b and (S,S)-10a.
tives were analyzed by consid-
ering that just two THF ligands
nating solvent such as toluene. Surprisingly, lithiation of
aziridines (R,S)-9 and (R,R)-9 with nBuLi (1.5 equiv) in tol-
uene at ꢁ788C for 4 hours followed by trapping with a deu-
terium source gave (R,S)-9-D and (R,R)-9-D in 80% isolat-
ed yield and with 95% deuterium content and in both cases
without epimerization (d.r.>98:2). This result showed that
lithiated aziridines (R,S)-9-Li and (R,R)-9-Li were both
chemically and configurationally stable in toluene. Accord-
ing to the computational result in the gas phase, (R,S)-9-Li
was chemically stable in toluene but decomposes under the
same reaction conditions in THF (Table 1, entry 10).
could fill the coordination sphere of the lithium atom also
coordinated to two other atoms.
The disolvated (R,S)-9-N-Li·2THF, which again shows h3-
coordination for the lithium ion in addition to the two THF
ligands (Figure 7), was found as equilibrium geometry. How-
ever, comparison with the unsolvated (R,S)-9-N-Li showed a
ꢁ
ꢁ
ꢁ
slight lengthening of the C2 Li, C5 Li, and N6 Li bonds as
a consequence of the presence of the two THF molecules. A
comparison between (R,S)-9-N-Li-inv·2THF and (R,S)-9-N-
Li-inv discloses that the two THF molecules prevent the co-
ordination of the lithium ion by the aziridine ring nitrogen
4998
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Dynamically Controlled Lithiation of Chiral Aziridines
FULL PAPER
Regardless of the solvent and
aggregation effects, which are
difficult to demonstrate without
spectroscopic support,[33] the re-
sults of the DFT analysis reveal
that, in accord with a similar
study on oxazolinyloxiranes,[28]
the most stable intermediates
are
h3-coordinated
species,
which, in this case, set the oxa-
zoline group and the N-sub-
stituent in a trans relationship.
This computational evidence
combined with the structural
analyses of the neutral aziri-
dines (R,S)-9 and (R,R)-9 and
the reactivity observed in tolu-
ene, allows us to propose path b
in Scheme 4 as a likely mecha-
nism for the a-lithiation reac-
tion, which could be an exam-
ple of dynamically controlled
lithiation.[34] In addition, the
Figure 4. Optimized structure for (R,R)-9 and (R,S)-9 by using the M06-2X functional.
Table 5. Relative energies [kcalmolꢁ1] for disolvated lithiated oxazoliny-
laziridines (R,R)- and (R,S)-9-Li in THF.
atom, thus lowering the energy of this invertomer. The THF
solvation also prevents the additional coordination brought
by the phenyl ring (see the structure of (R,S)-9-N-Li for
comparison).
Molecule
(R,S)-9-Li-inv·2THF
(R,S)-9-N-Li·2THF
(R,S)-9-O-Li·2THF
(R,R)-9-Li-inv·2THF
(R,R)-9-N-Li·2THF
(R,R)-9-O-Li·2THF
G MP2[a,b]
G M062X[a]
G
3.45
0
3.30
0
AHCTUNGTRENNUNG
The disolvated (R,R)-9-N-Li·2THF (Figure 8) was found
as equilibrium geometry for the R,R diastereoisomer, and
the nitrogen invertomer that corresponds to (R,R)-9-N-Li-
inv·2THF was not found (Table 5). However, the analysis of
the disolvated species showed that for both diastereomeric
lithiated aziridines (R,R)- and (R,S)-9-Li·2THF, h3-coordi-
nated intermediates bearing the oxazolinyl ring and the N-
substituent in a trans relationship were predicted to be more
stable.[32] In addition, it was possible to assess the extra coor-
dination brought by the phenyl ring in (R,S)-9-Li in the gas
phase.
R
8.65
8.12
[c]
[c]
N
–
–
T
0.21
0
0
2.25
A
[a] Relative energies in kcalmolꢁ1. [b] G MP2//M062X. [c] Not found as
equilibrium geometry.
high barrier for nitrogen inversion (ca. 16 kcalmolꢁ1) and
the higher computed stability of (R,S)-9-h3-N-Li and (R,R)-
9-h3-N-Li, with respect to (R,S)-9-N-Li-inv and (R,R)-9-N-
Li-inv, could justify the configurational stability of this type
of aziridinyllithium compounds.[35]
Additional reactivity: From the reaction performed in tolu-
ene, useful insights were obtained that support the model
proposed in Scheme 4. Indeed, compounds (R,S)-13 and
(R,R)-13, likely formed by nucleophilic attack of nBuLi on
the oxazoline C=N bonds of (R,S)-9 and (R,R)-9, respective-
ly, were isolated in yields of 15% and as a mixture of two
diastereomers (d.r.=1:1 for (R,S)-13 and 70:30 for (R,R)-
13).[36] Because the addition of an organolithium species to
the oxazoline C=N double bond is not an easy event unless
favored by peculiar stereoelectronic requirements,[37] the for-
mation of (R,S)-13 and (R,R)-13 has to be explained. As re-
ported in Scheme 6 and in accord with the model depicted
in Scheme 4, the lone pair of electrons on the nitrogen atom
of the major invertomer A could form a complex with
Scheme 5. Epimerization mechanism of lithiated oxazolinylaziridines.
Chem. Eur. J. 2011, 17, 4992 – 5003
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4999

R. Luisi et al.
Figure 5. Computed equilibrium geometries (M06-2X) from the analysis
of (R,S)-9-Li.
Figure 6. Computed equilibrium geometries (M06-2X) from the analysis
of (R,R)-9-Li.
nBuLi, which as it is close to the oxazolinyl ring, could
attack the C=N bond.[38]
To unequivocally characterize (R,S)-13 and (R,R)-13, they
were subjected to acidic hydrolysis of the oxazolidinyl ring,
thus obtaining chiral ketoaziridines (R,S)-14 and (R,R)-14
(95% yield) and disclosing a new potentially useful transfor-
mation of chiral oxazolinylaziridines.
To further prove that the nitrogen dynamics and complex-
ation phenomena could likely be responsible of the unusual
C=N double-bond addition, the reactivity of a-functional-
ized aziridines (S,S)-10a and (S,R)-11a was investigated
(Scheme 7). When these aziridines were treated with nBuLi
at ꢁ788C for 4 h, before quenching with a proton source,
only the starting materials were recovered. A different
result was obtained in the reaction with nBuLi at 08C. In
this case, the C=N addition occurred, thus obtaining ketoa-
ziridines (S,S)-15 and (S,R)-15 in 75% yield with high enan-
tioenrichment (e.r.>98:2) after acidic hydrolysis of the
crude reaction mixture.
trogen dynamics and ultimately on the reactivity of oxazoli-
nylaziridines toward nBuLi.
If one consider the distribution of the invertomers for
(S,S)-10a and (S,R)-11a in toluene (Table 3), two equilibrat-
ing nitrogen invertomers in major/minor ratios of 83:17 and
77:23, respectively, can be found. Assuming that only the
minor invertomers possess the stereochemical requirements
(that is the cis relationship between the lone pairs of elec-
trons on the nitrogen atom and the oxazoline ring) for the
C=N addition, the reactivity of the corresponding complex
with nBuLi will be enhanced at a higher temperature. In
fact, the lack of reactivity observed at low temperature
(ꢁ788C) is likely to be a consequence of the low rate of ni-
trogen inversion and a slow rate of the reaction between the
minor invertomers and nBuLi.[39] In contrast, at a higher
temperature (08C) there is a faster nitrogen inversion and
faster reaction with nBuLi, which ends up with the C=N ad-
dition.
These results could be reasonably explained by taking
into consideration the effect of the temperature on the ni-
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Chem. Eur. J. 2011, 17, 4992 – 5003

Dynamically Controlled Lithiation of Chiral Aziridines
FULL PAPER
Figure 8. Computed equilibrium geometries (M06-2X) for THF-disolvat-
ed (R,R)-9-Li.
Figure 7. Computed equilibrium geometries (M06-2X) for THF-disolvat-
ed (R,S)-9-Li.
Scheme 7. Dynamically controlled reactivity of a-functionalized oxazoli-
nylaziridines.
Therefore, it could be argued that by controlling the nitro-
gen dynamics it could be possible to address the reactivity
of oxazolinylaziridines and prepare useful chiral 2,2-disubsti-
tuted ketoaziridines.
Conclusion
It has been demonstrated that enantiomerically enriched 1-
phenylethyloxazolinylaziridines undergo exclusive a-lithia-
tion and that the resulting lithiated species are generally
Scheme 6. Competitive addition reaction that leads to enantioenriched
ketoaziridines 14.
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R. Luisi et al.
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configurationally stable under the given experimental condi-
tions. This finding is in striking contrast with a-lithiated oxa-
zolinyloxiranes, which are quite prone to undergo fast race-
mization (or epimerization) when generated from optically
pure precursors. The reason for this different behavior has
been rationalized by considering the role of the aziridine ni-
trogen atom and its dynamics, which has been evaluated by
NMR spectroscopic experiments and DFT calculations,
which furnished h3-coordinated species for both diastereo-
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Acknowledgements
This work was carried out under the framework of the National Project
“FIRB - Futuro in Ricerca” (code: CINECA RBFR083M5N) and sup-
ported by the University of Bari. This work was supported in part by
NSF grant CHE-0643629 (L.M.P.). This research used resources from the
National Energy Research Scientific Computing Center, which is sup-
ported by the Office of Science of the US Department of Energy under
contract no. DE-AC03-76SF00098 (L.M.P.). We are grateful to Professor
Varinder Aggarwal of the University of Bristol for providing HRMS
analyses.
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Dynamically Controlled Lithiation of Chiral Aziridines
FULL PAPER
[26] Aziridine 12b and (S,S)-10a showed clear signals for both inverto-
[35] A double inversion has been also suggested for the epimerization of
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[36] It is likely that two diastereomers are obtained from the same com-
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oxazoline C=N bond; the 13C NMR spectrum shows the signals of
two quaternary carbons at d=96–97 ppm, which belong to the C2 of
the oxazolidine ring, and the absence of the oxazoline C=N signal
usually found at around d=160 ppm; examples of related structures
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[39] With reference to the C=N addition reaction, it is worth noting that
the major invertomer would produce unreactive complexes with
nBuLi because of the anti relationship between the oxazoline ring
and the lone pair of electrons on the aziridine nitrogen atom.
[40] The synthetic procedures and spectral characterization data for the
prepared compounds are given in the Supporting information for
this article, which is available on the WWW under http://www.
chemeurj.org/or from the author.
1
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[32] The roles of aggregation phenomena and solvation are being evalu-
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azolinylaziridines, and the results will be reported in due course.
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to provide structural insight.
[34] The proposed model assumes that oxazolinylaziridines can break
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Received: November 26, 2010
Published online: April 4, 2011
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