α- vs ortho-lithiation of N-alkylarylaziridines: Probing the role of the nitrogen inversion process

Article abstract of DOI:10.1021/jo8016549

(Chemical Equation Presented) The lithiation reaction of monophenyl- and diphenylaziridines has been investigated in detail in an effort to understand why the former undergo exclusively or mainly ortho-lithiation while the latter are lithiated exclusively at the α-position. Evidence is reported that ruled out the possibility that the α-lithiation, observed for the diphenylaziridines, is the result of an ortho- to α-translocation phenomenon, thus substantiating a direct α-deprotonation process. The role of the aziridine nitrogen lone-pair has been considered: dynamics at the aziridine nitrogen as well as complex-induced proximity effects seem to be responsible for the observed regioselectivity in both monophenyl and diphenylaziridines. It turns out that, by tuning the reaction conditions for the lithiation of trans-1-alkyl-2-methyl-3-phenylaziridines, it is possible to generate with high regioselectivity α- and/or ortho-lithiated aziridines, which can be stereoselectively functionalized by electrophilic trapping. A regioselective ortho-functionalization of diphenylaziridines is made possible by halogen- or tin-lithium exchange and by deprotonation of bis-deuterated aziridines.

Full text of DOI:10.1021/jo8016549

r- vs Ortho-Lithiation of N-Alkylarylaziridines: Probing the Role of
the Nitrogen Inversion Process†
Francesco Affortunato, Saverio Florio,* Renzo Luisi,* and Biagia Musio
Dipartimento Farmaco-Chimico, UniVersita` di Bari, Consorzio InteruniVersitario Nazionale Metodologie e
Processi InnoVatiVi di Sintesi C.I.N.M.P.I.S., Via E. Orabona 4, I-70125, Bari, Italy
florio@farmchim.uniba.it; luisi@farmchim.uniba.it
ReceiVed July 25, 2008
The lithiation reaction of monophenyl- and diphenylaziridines has been investigated in detail in an effort
to understand why the former undergo exclusively or mainly ortho-lithiation while the latter are lithiated
exclusively at the R-position. Evidence is reported that ruled out the possibility that the R-lithiation,
observed for the diphenylaziridines, is the result of an ortho- to R-translocation phenomenon, thus
substantiating a direct R-deprotonation process. The role of the aziridine nitrogen lone-pair has been
considered: dynamics at the aziridine nitrogen as well as complex-induced proximity effects seem to be
responsible for the observed regioselectivity in both monophenyl and diphenylaziridines. It turns out
that, by tuning the reaction conditions for the lithiation of trans-1-alkyl-2-methyl-3-phenylaziridines, it
is possible to generate with high regioselectivity R- and/or ortho-lithiated aziridines, which can be
stereoselectively functionalized by electrophilic trapping. A regioselective ortho-functionalization of
diphenylaziridines is made possible by halogen- or tin-lithium exchange and by deprotonation of bis-
deuterated aziridines.
Introduction
inversion). Indeed, while with an electron-withdrawing group
[i.e., R(Ar)SO2, Boc] as the N-substituent deprotonation at the
aziridine carbon atoms is always observed,4 a more complex
situation results, instead, when the nitrogen substituent is an
electron-releasing group (i.e., alkyl, benzyl).5
Lithiation of simpler and easily available aziridines followed
by trapping with electrophiles is undoubtedly an appealing
methodology for making more functionalized aziridines, which
are useful building blocks in stereoselective synthesis.1,2 The
regioselectivity of the lithiation step substantially depends upon
the nature of the aziridine ring substituents3 as well as on the
stereochemistry at the nitrogen atom (related to the rate of
(1) (a) Satoh, T. Chem. ReV. 1996, 96, 3303–3325. (b) Hodgson, D. M.;
Bray, C. D.; Humphreys, P. G. Synlett 2006, 1–22. For a special issue on oxiranyl
and aziridinyl anions (Florio, S., Ed.), see: (c) Florio, S. Tetrahedron 2003, 59,
9693. (d) Hodgson, D. M.; Bray, C. D. In Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006, p 145.
† Dedicated to Prof. Peter Beak of the Department of Chemistry of the
University of Illinois at Urbana-Champaign.
9214 J. Org. Chem. 2008, 73, 9214–9220
10.1021/jo8016549 CCC: $40.75 2008 American Chemical Society
Published on Web 10/15/2008

RegioselectiVe Lithiation of Aziridines
SCHEME 1
SCHEME 2
Thus, while 1-alkyl-2-arylaziridines are smoothly ortho-
lithiated, surprisingly trans-1-alkyl-2,3-diphenylaziridines are
regioselectively R-lithiated with a stereochemistry that is
controlled by the reaction medium (i.e., inversion in THF and
retention in toluene). Yet, unexpectedly, cis-1-alkyl-2,3-diphe-
nylaziridines are not lithiated at all (Scheme 1).6
TABLE 1. Lithium-Bromine Exchange of Aziridine 4
Additionally, further studies in this context (a detailed
multinuclear magnetic resonance investigation) proved that
lithiated species derived from trans-1-alkyl-2,3-diphenylaziri-
dines are cis configured in THF and trans in toluene.7
Having proved the synthetic utility and ascertained the
structural features of such lithiated aziridines, we became
successively concerned with the lithiation mechanism and the
R- vs ortho competition observed in the lithiation of monophe-
nyl- and trans-diphenylaziridines. The results of this investiga-
tion are reported herein.
aziridine 6
ratio
entry
t
RLi
E
(% yield)a
6/trans-1ab
1
2
3
4
5
6
1 h
1 h
4 h
1 h
4 h
n-BuLi
n-BuLi
n-BuLi
t-BuLi
t-BuLi
n-BuLi
D
Me
Me
Me
Me
Bu3Sn
6a (53)
6b (70)
6b (50)
6b (60)
6b (0)
53/47
80/20
45/55
60/40
1/99
Results and Discussion
In principle, there are two possibilities that could be envisaged
in the R-lithiation of the trans-2,3-diphenylaziridines trans-1
(Scheme 2), (a) direct R-deprotonation and (b) ortho-lithiation,
giving 2-Li, followed by an ortho/R-translocation (a kinetically
favored ortho deprotonation and subsequent thermodynamically
more acidic benzylic proton removal). The latter possibility has
to be taken into consideration because the four-center transition
state TS-A (assumable exclusively for 2-Li) would explain the
different regioselectivity observed in the lithiation of the N-alkyl-
2-phenylaziridines, where, due to the presence of only one
benzylic hydrogen, exclusive ortho-lithiation takes place.
In order to get more insight on the lithiation mechanism of
arylaziridines, some solving experiments were conducted on
d
20 min
6c (56)c
-
a Estimated by 1H NMR and GC-MS analysis. b From 1H NMR of
the crude. c Isolated yield. d By GC-MS analysis less than 10% of
trans-1a can be estimated.
SCHEME 3
alternatively generated ortho-lithiated aziridines and on deuterium-
labeled aziridines.
(2) (a) Lowden, P. A. S. In Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006, p 399. (b) Singh, G. S.;
D’hooghe, M.; De Kimpe, N. Chem. ReV. 2007, 107, 2080–2135. (c) Sweeney,
J. B. Chem. Soc. ReV. 2002, 31, 247–258. (d) McCoull, W. M.; Davis, F. A.
Synthesis 2000, 134, 7–1365. (e) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994,
33, 599–619.
(3) Because of the electronic effect of the N-substituent on the reactivity of
the aziridines, it could be useful to classify as activated those aziridines bearing
an electron-withdrawing group and as nonactivated the ones with an electron-
releasing group as the nitrogen substituent.
(4) (a) Luisi, R.; Capriati, V.; Florio, S.; Ranaldo, R. Tetrahedron Lett. 2003,
44, 2677–2681. (b) Luisi, R.; Capriati, V.; Florio, S.; Di Cunto, P.; Musio, B.
Tetrahedron 2005, 61, 3251–3260. (c) Hodgson, D. M.; Humphreys, P. G.; Ward,
J. G. Org. Lett. 2005, 7, 1153–1156. (d) Hodgson, D. M.; Miles, S. Angew.
Chem., Int. Ed. 2006, 45, 949–952. (e) O’Brien, P.; Rosser, C. M.; Caine, D.
Tetrahedron 2003, 59, 9779–9791. (f) Breternitz, H. J.; Schaumann, E.;
Adiwidjaja, G. Tetrahedron Lett. 1991, 32, 1299–1302.
(5) (a) Luisi, R.; Capriati, V.; Di Cunto, P.; Florio, S.; Mansueto, R. Org.
Lett. 2005, 9, 3925–3928. (b) Capriati, V.; Florio, S.; Luisi, R.; Musio, B. Org.
Lett. 2005, 7, 3749–3752.
In the first of these experiments, the o-bromoaziridine 4,
prepared from o-bromostilbene oxide,8 was subjected to lithium/
bromine exchange with organolithiums (n-BuLi, t-BuLi) to give
the ortho-lithiated aziridine 5-Li (Table 1), which furnished,
upon deuteration or methylation, ortho-substituted products 6a,b
and aziridine trans-1a, which likely originates from the depro-
tonation, by 5-Li, of the resulting alkyl bromide (n-BuBr or
t-BuBr) formed in the reaction medium in the Li-Br exchange.
In order to optimize this reaction, several conditions were
verified (Table 1).
All the attempts to quantitatively generate 5-Li and capture
it by deuteration or methylation using the standard time of the
(6) Luisi, R.; Capriati, V.; Florio, S.; Musio, B. Org. Lett. 2007, 9, 1263–
1266.
(7) Capriati, V.; Florio, S.; Luisi, R.; Mazzanti, A.; Musio, B. J. Org. Chem.
2008, 73, 3197–3204.
(8) (a) Akguen, E.; Glinski, M. B.; Dhawan, K. L.; Durst, T. J. Org. Chem.
1981, 46, 2730–2734. (b) Anderson, W. K.; Milowsky, A. S. J. Med. Chem.
1986, 29, 2241–2249.
J. Org. Chem. Vol. 73, No. 23, 2008 9215

Affortunato et al.
SCHEME 4
SCHEME 5
deprotonation reaction (3-4 h) failed, giving mainly trans-1a.
The intermediate 5-Li could be efficiently trapped with elec-
trophiles only within 1 h (Table 1, entries 1, 2, 4) or less (entry
6). In any case, under the above conditions, no trace of the
R-functionalized derivatives was observed, suggesting that no
translocation occurs. In the second experiment, the aziridine 6c
was subjected to the tin-lithium exchange reaction in order to
avoid the formation of trans-1a (Scheme 3). The resulting ortho-
lithiated aziridine 5-Li was kept at low temperature up to 4 h
and then quenched with MeI to furnish exclusively the ortho-
methylated aziridine 6b (57% isolated yield), once more
suggesting that no translocation had taken place.
easily removable protons for proximity reasons, namely, the
ortho position for the invertomer D and the R-position for C.14
Accordingly, R-lithiation of C, occurring after the complex
formation between s-BuLi and starting aziridine, followed by
trans to cis isomerization (in THF), would generate cis-1-D-Li
and then, after trapping with D2O, cis-1-D2. On the other hand,
invertomer D would undergo either ortho-deprotonation or
R-dedeuteration, the ortho-deprotonation being preferred likely
because of a kinetic isotope effect.15
The different result obtained in toluene, that is, exclusive
R-lithiation, could be tentatively ascribed to the different
aggregation state of the lithiating agent16 and/or to a more
marked difference in kinetic and thermodynamic acidity between
the protons to be removed in this solvent.
Other experiments were executed on deuterated aziridine
trans-1-D (Scheme 4), which was subjected to lithiation in THF9
under standard conditions (s-BuLi, -78 °C, 4 h), giving bis-
deuterated compounds cis-1-D2 (32% isolated yield) and 6a-
D2 (50% isolated yield) upon quenching with D2O (ratio R/ortho
1
55:45 from H NMR of the crude). Compound cis-1-D2 likely
originates from cis-1-D-Li (the expected lithiated species in
THF), while 6a-D2, unexpectedly for diphenylaziridines, should
derive from ortho-lithiated intermediate 5-D-Li.10 By contrast,
deprotonation of trans-1-D in toluene furnished, upon quenching
with D2O or MeI, R-functionalized aziridines trans-1-D2 and
aziridine trans-7-D with complete retention of configuration.
It must be pointed out that, in all the reactions in Scheme 4,
there is some deuterium erosion with respect to the starting
material, testifying that a kinetic isotope effect is operative and
a competitive R-dedeuteration occurs.11
To explain the formation of 5-D-Li in THF, the role of the
aziridine ring nitrogen and complexation phenomena must be
considered.12 It has been proved that aziridines like trans-1-D
exist as an equilibrating mixture of the two invertomers C and
D (Scheme 5) in a 50:50 ratio.6 Therefore, with the assumption
that a precomplexation to the base is a prerequisite for the
deprotonation to occur and that a kinetic isotope effect is
operative,13 the deprotonation should take place at the more
To definitely prove that no translocation occurs, aziridine
trans-1-D2 was subjected to deprotonation in THF under
standard conditions (Scheme 6).
Upon quenching with MeI, R-methylated aziridine cis-7-D
and ortho-methylated aziridine 6b-D2 were the only products
identified in the 1H NMR of the crude products in a 20:80 ratio,
respectively. This outcome clearly demonstrates that no trans-
location occurs because the expected R-methylated aziridine cis-
7-D2 that would result from the trapping of 8-Li was not found.
Moreover, a comparison of the R/ortho ratios observed in the
deprotonation/trapping sequences of trans-1-D and trans-1-D2
(13) The kinetic isotope effect could suggest if the deprotonation step is rate-
determining and a precomplexation could be involved. See related studies: (a)
Resek, J. E.; Beak, P. J. Am. Chem. Soc. 1994, 116, 405–406. (b) Meyers, A. I.;
Dickman, D. A. J. Am. Chem. Soc. 1987, 109, 1263–1265.
(9) R-Lithiation in this coordinating solvent would give an isomerized cis
aziridine (see ref 7).
(10) On the basis of the model depicted in Scheme 5, we assume that the
phenyl group linked to the CH of the aziridine ring is ortho-lithiated, because of
a concomitance of a kinetic isotope effect and a proximity effect. It is worth
noting that ortho-lithiation has never been observed with undeuterated aziridines
trans-1 (see ref 6).
(11) A value of kH/kD > 5 can be estimated for the R-deprotonation
considering the loss of deuterium in aziridine cis-1-D2 (87% D), trans-7-D (83%
D), and trans-1-D2 (80% D) with respect to the starting aziridine trans-1-D (95%
D).
(12) For examples of assisted deprotonation, see: (a) Bertini Gross, K. M.;
Beak, P. J. Am. Chem. Soc. 2001, 123, 315–321. (b) Itami, K.; Kamei, T.;
Mitsudo, K.; Nokami, T.; Yoshida, J. J. Org. Chem. 2001, 66, 3970–3976.
(14) This could be an example of complex-induced proximity effect as
exhaustively reported: Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P.
Angew. Chem., Int. Ed. 2004, 43, 2206–2225.
(15) Related mechanistic studies on deuterium-labeled systems have been
reported. See: (a) Fernandez, I.; Gonzalez, J.; Lopez-Ortiz, F. J. Am. Chem.
Soc. 2004, 126, 12551–12564. (b) Florio, S.; Aggarwal, V.; Salomone, A. Org.
Lett. 2004, 6, 4191–4194. (c) Clayden, J.; Pink, J. H.; Westlund, N.; Wilson,
F. X. Tetrahedron Lett. 1998, 39, 8377–8380. (d) Faibish, N. C.; Park, Y. S.;
Lee, S.; Beak, P. J. Am. Chem. Soc. 1997, 119, 11561–11570.
(16) (a) Hay, D. R.; Song, Z.; Smith, S. G.; Beak, P. J. Am. Chem. Soc.
1988, 110, 8145–8153. (b) Thomas, R. D.; Jensen, R. M.; Young, T. C.
Organometallics 1987, 6, 565–571. (c) Bauer, W.; Winchester, W. R.; Schleyer,
P. v. R. Organometallics 1987, 6, 2371–2379. (d) Fraenkel, G.; Henrichs, M.;
Hewitt, M.; Su, B. M. J. Am. Chem. Soc. 1984, 106, 255–256.
9216 J. Org. Chem. Vol. 73, No. 23, 2008

RegioselectiVe Lithiation of Aziridines
SCHEME 6
TABLE 2. Lithiation/Electrophile Trapping Sequence of Aziridine
trans-9a,b
(55:45 and 20:80, respectively) clearly show that a kinetic
isotope effect is responsible for the increased ortho regioselec-
tivity obtained in the lithiation of trans-1-D2, accordingly with
the model shown in Scheme 5.13
The questions that rise at this point are the following: if no
ortho/R-translocation process intervenes, why are N-alkyl-
monophenylaziridines regioselectively ortho-lithiated, whereas
trans-N-alkyl-2,3-diphenylaziridines are regioselectively R-lithi-
ated? If we assume that the ortho-lithiation is a kinetically
favored process and that the R-lithiation is the thermodynamic
one, because of the higher acidity of the benzylic protons, which
factors should be considered to address the regioselectivity?
In order to answer these questions and give an explanation
to the experimental results, the deprotonation/trapping sequence
of the aziridines trans-9a,b was investigated under several
conditions (Table 2).
Lithiation of trans-9a, at low temperature and in different
solvents (entries 1-6), occurred mainly at the ortho position
giving ortho-9a-Li, which furnished aziridines 11a,b as the main
products upon reaction with electrophiles.17 Upon raising the
temperature to 0 °C, a complete inversion of regioselectivity
was observed (entries 7, 8) and the R-functionalized aziridines
10a,b, resulting from the trapping of R-9a-Li, were obtained.18
In order to verify if, for instance, the observed change in
regioselectivity was due to a temperature-induced ortho/R-
translocation, trans-9a was deprotonated in Et2O at low tem-
perature (-78 °C) and then warmed up to 0 °C before quenching
with MeI: the same result as entry 6 was obtained, thus
excluding once more the translocation.
Similar results were obtained in the deprotonation/electro-
philic trapping sequence of trans-9b; once more the reactions
performed at low temperature (-70 °C)19 (entries 10-12) led
mainly to ortho-functionalized aziridines 11c,d, likely deriving
from the quenching of ortho-9b-Li. On the contrary, the same
sequence conducted at higher temperature (0 °C) furnished, as
the main products, R-functionalized aziridines 10c,d.17
A reduced reactivity with respect to that of the aziridine trans-
9a was observed when the isomer cis-9a was subjected to
deprotonation (s-BuLi/TMEDA in THF at -78 °C) followed
by trapping with D2O and MeI. Only 30% of ortho-function-
alized products 13a,b was recovered together with unreacted
starting material (Scheme 7).
aziridine
aziridine aziridine ratio
entry trans-9 solvent T (°C) t (h)
E
10
10a
Me cis-10be
10a
Me 10b
10a
Me 10b
10a
11
10/11
a b
,
1
2
3
4
5
6
7
8
9
trans-9a THF
trans-9a THF
trans-9a toluene -78
trans-9a toluene -78
trans-9a Et2O
trans-9a Et2O
trans-9a Et2O
trans-9a Et2O
trans-9a Et2O
-78
-78
4
4
4
4
4
4
3.5
D
11a
11b
11a
11b
11a
11b
11a
11b
11b
11c
11d
11d
11c
11d
-
14/86c
a, b
D
-
13/87c
a, b
-78
-78
0
D
-
10/90c
a d
,
D
-
0
3.5 Me 10b
97/3c
-40
-70
-70
-70
0
4
6
6
6
4
4
Me 10b
10c
Me 10d
Me 10d
10c
Me 10d
34/66c
a b
,
10 trans-9b THF
11 trans-9b THF
12 trans-9b Et2O
13 trans-9b Et2O
14 trans-9b Et2O
D
-
10/90c
20/80c
a d
,
D
-
0
97/3c
a Deuterium incorporation
> 92%. Aziridines 10a and 11a are
undistinguishable by 1H NMR analysis. The ortho/R ratio can be
estimated from the integral values between the aromatic and benzylic
protons. b Under these conditions, the main product is the
ortho-deuterated derivative. c From 1H NMR and GC-MS analyses of
the crude. d Under these conditions the main product is the R-deuterated
derivative. e An inversion of configuration occurs in this solvent upon
quenching with MeI.
SCHEME 7
(17) Compounds 11a-d and 10a-d have been isolated and fully character-
ized (see the Supporting Information).
(18) Under these conditions, an undesired deprotonation of THF and toluene
intervenes, making Et2O the solvent of choice.
(19) The reaction is slower at-78 °C, likely because of a nitrogen substituent
effect.
This result is not surprising considering that it has been
reported that cis-N-alkyl-2,3-diphenylaziridines are not lithiated
at all under the same conditions, likely due to a steric interaction
between the cis positioned substituents.6
J. Org. Chem. Vol. 73, No. 23, 2008 9217

Affortunato et al.
1
FIGURE 1. Comparison of H NMR spectra of aziridines trans-9a,b and cis-9 in toluene-d8 at 223 K under slow exchange conditions.
In order to find an explanation for the different reactivity and
regioselectivity between aziridines trans-9a,b and cis-9a, again
the role of the aziridine ring nitrogen configuration should be
considered. 1H NMR experiments unequivocally demonstrated
that aziridines trans-9a,b exist, at low temperature, as a mixture
of two slowly equilibrating invertomers20 (dr ≈ 88:12 to 90:
10), whereas aziridine cis-9a shows the signals of one main
invertomer (dr > 99:1) under the same conditions (Figure 1).21
k2 . k3 > k4. Similar conclusion can be drawn for aziridine
trans-9b (entries 11, 12, 14).25
In the case of aziridine cis-9a, the only detectable invertomer,
at -78 °C, is the one that puts the lone pair on the same side
of the phenyl ring; therefore, the interaction with the lithiating
agent would give complex F and then ortho-lithiation, as
experimentally observed (here again likely k1, k2 , k4 and k3).
The cis relationship between the methyl group and the phenyl
ring could cause steric hindrance and reduce the reactivity.
Accordingly, 1-methyl-2-phenylaziridine, existing as the sole
invertomer that puts the lone pair on the same side of the phenyl
ring, is exclusively ortho-lithiated.
To further support this hypothesis, we decided to perform
some more experiments at higher temperature on aziridines cis-
9a and 1426 with the idea that an enhancement of the
interconversion rate (k1, k2) between the two invertomers could
promote the thermodynamically favored benzylic deprotonation,
which actually proved to be favored at 0 °C in the case of trans-
9a,b.
The nitrogen configuration has been ascertained by selective
NOESY experiments under slow exchange conditions for both
trans-9a,b and cis-9a (Figure 2).22 In all cases the main
invertomers are those that set the lone pairs from the same side
of the phenyl ring.
According to the proposed model reported in Scheme 5 and
assuming a precomplexation between the base and the aziridine
prior to the deprotonation, the regioselectivity can be explained
by considering the relative rates of the deprotonation reactions
(k3, k4) with respect to the rate of nitrogen inversion (k1, k2)
(Scheme 8).23
The lithiation/trapping sequence of aziridines cis-9a and 14
(Scheme 9) led to a mixture of R-functionalized aziridines 10b
If we assume that the proximity effect complex F in Scheme
8 should give ortho-lithiation and complex E R-lithiation, we
can answer all the questions above. In the lithiation of trans-
9a,b carried out at low temperature, where the rate of nitrogen
inversion is low (two invertomers can be detected under the
NMR time scale) and likely k1 and k2 are much lower than k4
and k3, the major invertomer, that is, the one that puts the lone
pair on the same side of the phenyl ring, would form complex
F and then undergo ortho-lithiation. Examining the data in Table
2, at -78 °C, we note an ortho/R ratio ranging from 86:14 to
90:10 in the lithiation trapping sequence of trans-9a (entries 2,
4, 6), likely reflecting the ratio between the two invertomers,
that is, 88:12 in toluene-d8 and 90:10 in THF-d8.24 When the
temperature is raised to 0 °C, a complete inversion of regiose-
lectivity is observed (ortho/R ratio 3:97, entry 8) that can be
justified with the Curtin-Hammett principle by assuming k1,
(20) For some studies on the aziridine nitrogen inversion, see: (a) Johnston,
E. R. Magn. Reson. Chem. 1995, 33, 664–668. (b) Kessler, H. Angew. Chem.,
Int. Ed. 1970, 9, 219–235. (c) Jennings, W. B. In Cyclic Organonitrogen
Stereodynamics; Lambert, J. B., Takeuchi, Y., Eds.; VCH: New York, 1992, p
105.
(21) The same diastereomeric ratio was observed at lower temperature and
in a different solvent, such as THF-d8.
(22) Neuhaus, D.; Williamson, M. In The Nuclear OVerhauser Effect in
Structural and Conformational Analysis; VCH: New York, 1989, p 264.
(23) For examples of reactivity in conformationally mobile systems, see: (a)
Seeman, J. I.; Secor, H. V.; Hartung, H.; Galzerano, R. J. Am. Chem. Soc. 1980,
102, 7741–7747. (b) Oki, M. Acc. Chem. Res. 1984, 17, 154–159. (c) Seeman,
J. I. Chem. ReV. 1983, 83, 83–134.
(24) On the basis of the experimental results, it is likely that a similar
invertomer distribution could be also present in Et2O.
(25) It seems that the nitrogen substituent could affect significantly only the
reactivity (longer reaction times) and not the regioselectivity.
(26) It has been already reported that aziridine 14 exists as one main
invertomer, analogously to cis-9a, (dr > 99:1), which puts the lone pair on the
same side of the phenyl ring (see ref 5b).
9218 J. Org. Chem. Vol. 73, No. 23, 2008

RegioselectiVe Lithiation of Aziridines
FIGURE 2. NOESY-1D spectra of aziridines trans-9a,b and cis-9 in toluene-d8 at 223 K under slow exchange conditions.
SCHEME 8
SCHEME 9
and 15 (13% and 16% yield, respectively) and ortho-function-
alized aziridines 13b and 16 (61% and 63% yield, respectively),
and the ortho/R ratio in both cases was around 80/20. Bis-
functionalized derivatives 17 and 18 were also detected (24%
and 19% yield, respectively), likely derived from a double
lithiation.27
The presence of R-functionalized aziridines 10b and 15 in
the reaction mixture could be ascribed to R-lithiated intermedi-
ates resulting from complexes of the kind E (Scheme 8), which
are favored under thermodynamic conditions.
From the above results, it seems that the rate of the nitrogen
inversion is responsible for the observed regioselectivity; we
reasoned that performing the lithiation/trapping sequence of
trans-9a at an intermediate temperature (i.e., -40 °C) where
likely k1, k2 ≈ k4 and k3, both the ortho- and R-functionalized
aziridines should be obtained. An ortho/R ratio of 66/34 was
observed (Table 2, entry 9) upon quenching with MeI, proving
once more the role of the nitrogen inversion.
J. Org. Chem. Vol. 73, No. 23, 2008 9219

Affortunato et al.
Conclusion
without isomerization in the case of the R-lithiated species)
to give the corresponding R- or ortho-substituted aziridines.
Further studies are actually underway in order to exploit the
above results for planning stereoselective syntheses and
unravel the role of the aziridine nitrogen.
To summarize, all the above results seem to exclude that
the R-lithiation of trans-2,3-diphenylaziridine 1 arises from
an ortho- to R-translocation phenomenon, while they sub-
stantiate the crucial role of the aziridine nitrogen dynamics
in controlling the R- vs ortho-lithiation competition. For both
the R- and ortho-lithiation a model can be proposed on the
basis of a complex-induced proximity effect (CIPE), where
the first event is the precomplexation of the lithiating agent
at the nitrogen lone-pair and then, if the proximity arrange-
ment is realized, R or ortho or both deprotonations occur. It
is remarkable that controlling the rate of the nitrogen
inversion could make the lithiation site predictable and also
that for the first time an R-lithiated aziridine has been
generated at relatively high temperature (0 °C). Finally, the
resulting lithiated species react with electrophiles (with or
Acknowledgment. This work was carried out under the
framework of the National Project “Stereoselezione in Sintesi
Organica Metodologie ed Applicazioni” by the University of
Bari. We are also grateful to Prof. Ted Cohen of the Department
of Chemistry of the University of Pittsburgh for useful
suggestions.
Supporting Information Available: General procedures,
spectral data, and copies of NMR spectra for all the compounds
prepared. This material is available free of charge via the Internet
at http://pubs.acs.org.
(27) Attempts to isolate compounds 17 and 18 failed. They were recognized
by GC-MS analysis and by 1H NMR of the crude.
JO8016549
9220 J. Org. Chem. Vol. 73, No. 23, 2008