Regio- and stereoselective lithiation of terminal oxazolinylaziridines: The aziridine N-substituent and the oxazolinyl group effect

Article abstract of DOI:10.1021/ol071264u

The regioselective lithiation of terminal oxazolinylaziridines has been investigated. The steric hindrance of the nitrogen substituent in 1-trityl-2-oxazolinylaziridine 3a, combined with the coordinating ability of the oxazolinyl group, causes β-lithiatio

Full text of DOI:10.1021/ol071264u

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3295-3298
Regio- and Stereoselective Lithiation of
Terminal Oxazolinylaziridines: The
Aziridine N-Substituent and the
Oxazolinyl Group Effect†
Renzo Luisi, Vito Capriati, Peppino Di Cunto, Saverio Florio,* and
Rosmara Mansueto
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
Received May 29, 2007
ABSTRACT
The regioselective lithiation of terminal oxazolinylaziridines has been investigated. The steric hindrance of the nitrogen substituent in 1-trityl-
2-oxazolinylaziridine 3a, combined with the coordinating ability of the oxazolinyl group, causes -lithiation, whereas a completely regioselective
-lithiation is observed with the much less sterically demanding 1-benzyl-2-oxazolinylaziridine 3c and a competition between - and -lithiation
â
r
r
â
occurs with 1-cumyl-2-oxazolinylaziridine 3b in which the N-substituent has a steric hindrance in between the trityl and the benzyl groups. The
application of the lithiation-trapping sequence for the preparation of enantioenriched 2,3-cis-disubstituted oxazolinylaziridines and aziridino-
γ
-lactones is also reported.
Lithiation-induced functionalization of simple and easily
available aziridines has become a very useful synthetic
strategy for the preparation of more functionalized aziridines
and products that can be derived from them.1
(Figure 1).2 Moreover, it occurs that with an electron-
withdrawing group (EWG) on one of the aziridine ring
atoms, lithiation takes place normally R to that group,3
whereas with alkyl-substituted terminal aziridines (bearing
Regioselectivity of the lithiation reaction of aziridines is
dramatically dependent upon the aziridine ring substitution:
e.g., 1-alkyl-2-phenyl aziridines are smoothly ortho-lithiated,
trans-1-alkyl-2,3-diphenylaziridines are cleanly R-lithiated,
and the corresponding cis isomers are not lithiated at all
(2) (a) Capriati, V.; Florio, S.; Luisi, R.; Musio, B. Org. Lett. 2005, 7,
3749-3752. (b) Luisi, R.; Capriati, V.; Florio, S.; Musio, B. Org. Lett.
2007, 9, 1263-1266.
(3) (a) Troisi, L.; Granito, C.; Carlucci, C.; Bona, F.; Florio, S. Eur. J.
Org. Chem. 2006, 775-781. (b) Alezra, V.; Bonin, M.; Mivouin, L.; Policar,
C.; Husson, H. P. Eur. J. Org. Chem. 2001, 2589-2594. (c) O’Brien, P.;
Rosser, C. M.; Caine, D. Tetrahedron 2003, 59, 9779-9791. (d) Montagne,
C.; Pre`vost, N.; Shiers, J. J.; Prie´, G.; Rahman, S.; Hayes, J. F.; Shipman,
M. Tetrahedron, 2006, 62, 8447-8457. (e) Vedejs, E.; Kendall, J. T. J.
Am. Chem. Soc. 1997, 119, 6941-6942. (f) Bisseret, P.; Bouis-Peter, C.;
Jacques, O.; Henriot, S.; Eustache, J. Org. Lett. 1999, 1, 1181-1182. (g)
Yamauchi, Y.; Kawate, T.; Katagiri, T.; Uneyama, K. Tetrahedron 2003,
59, 9839-9847.
† Dedicated to the memory of Professor Yoshihiko Ito of the University
of Kyoto for his outstanding contribution in the fields of synthetic and
organometallic chemistry.
(1) (a) Satoh, T. Chem. ReV. 1996, 96, 3303-3325. (b) Hodgson, D.
M.; Bray, C. D.; Humphreys P. G. Synlett 2006, 1-22. (c) For a special
issue on Oxiranyl and Aziridinyl Anions (Florio, S. Ed.), see: Florio, S.
Tetrahedron 2003, 59, 9693.
10.1021/ol071264u CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/26/2007

mercially available (S)-1-trityl-2-methoxycarbonyl aziridine
1 (er: 98/2) (Scheme 1) upon treatment with 2-methyl-2-
amino-1-propanol and n-BuLi in toluene6 and subsequent
reaction of the resulting amide (S)-2 with diethylamino
sulfurtrifluoride (DAST),7 whereas the corresponding racemic
aziridine (()-3a was prepared starting from racemic aziridine
(()-1, which in turn was obtained from the commercially
available methylaziridine-2-carboxylate (()-4 upon alkyla-
tion with tritylbromide (Scheme 1).8
Aziridine (S)-3a was spectroscopically characterized: dy-
namic NMR proved that, under the used reaction conditions
(THF, -70 °C), (S)-3a is present as one main invertomer,
the one that sets the oxazolinyl and trityl groups trans to
each other (Figure 2), as ascertained by NOESY experi-
ments.9
Figure 1. Regioselective lithiation of aziridines: the ring substit-
uents effect.
an EWG on the nitrogen), lithiation takes place at the
â-position trans to the alkyl group (Figure 1).4
The oxazolinyl group has proven to be an extraordinary
good stabilizing group either for oxiranyl or aziridinyl
anions.3a,5 In its presence, lithiation occurs always R to it if
there is an R hydrogen; it occurs â only when there is no R
hydrogen. We report here the first example of a stereo-
selective lithiation taking place â to the electron-withdrawing
aziridine ring substituent as in the case of 1-trityl-2-
oxazolinylaziridine 3a (Scheme 1).
Figure 2. Selective NOEs interactions.
With the aziridine (S)-3a in hand, we subjected it to
deprotonation, making use of strong bases. It was found that
the best conditions of deprotonation are: s-BuLi (2 equiv),
TMEDA (2 equiv), THF, 2h, -70 °C. Under these condi-
tions, the aziridine (S)-3a gave a deep-red solution likely
containing the lithiated species (S,S)-3a-Li, which decolorized
upon quenching with excess D2O; usual workup furnished
almost quantitatively 3-deuterio aziridine 5a (Table 1), as
ascertained by ESI-MS and NMR analysis.
Scheme 1a
It is remarkable that lithiation occurs at the â position cis
with respect to the oxazolinyl group although in the presence
of the more acidic R hydrogen. This result can be explained
with the strong stabilizing effect of the oxazolinyl group10
which chelates the â-lithiated species (S,S)-3a-Li and the
presence of the sterically demanding N-trityl group which
protects the other two aziridine-ring hydrogens from lithiation
by creating a sort of “umbrella” on them. This hypothesis is
a Key: i: (a) 2-methyl-2-amino-1-propanol (2.5 equiv); (b) n-
BuLi (2.2 equiv), toluene, LaCl3, 100 °C. ii: DAST (1 equiv),
CH2Cl2, -78 °C. iii: Ph3CBr, NaH, THF, 25 °C.
(6) Zhou, P.; Blubaum, J. E.; Burns, C. T.; Natale, N. R. Tetrahedron
Lett. 1997, 38, 7019-7022.
(7) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org.
Lett. 2000, 2, 1165-1168.
Optically active 1-trityl-2-oxazolinylaziridine (S)-3a [enan-
tiomeric ratio (er): 98/2] was prepared from the com-
(8) Ahman, J.; Somfai, P. Synth. Comm. 1994, 1121-1127.
(9) Dynamic 1H NMR experiments performed in THF-d8 on aziridine
3a revealed only one set of signals for the aziridine protons in the range
293-195 K.
(10) (a) Chadwick, S.; Ramirez, A.; Gupta, L.; Collum, D. B. J. Am.
Chem. Soc. 2007, 129, 2259-2268. (b) Jantzi, K. L.; Guzei, I. A.; Reich,
H. J. Organometallics 2006, 25, 2259-2268. (c) Capriati, V.; Degennaro,
L.; Florio, S.; Luisi, R.; Punzi, P. Org. Lett. 2006, 8, 4803-4806.
(4) (a) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2005,
7, 1153-1156. (b) Hodgson, D. M.; Miles S. Angew. Chem., Int. Ed. 2006,
45, 949-952.
(5) (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) Capriati, V.; Florio, S.;
Luisi, R. Synlett 2005, 9, 1359-1369.
3296
Org. Lett., Vol. 9, No. 17, 2007

1
determined by an H NMR analysis, to give hydroxyalkyl-
aziridines 6b-f, whereas very poor or no diastereoselectivity
Table 1. Lithiation-Trapping Sequence of Aziridine (S)-3a
with Electrophiles
was observed with acetophenone to give 6g (Table 2).12
Table 2. Lithiation-Trapping Sequence of Aziridine (S)-3a
with Carbonyl Compounds
electrophiles
D2O
Me3SiCl
MeI
aziridine 5
yield (%)a
er
R
R1
aziridine 6 yield (%)a
dr b
er
b
5a
5b
5c
5d
5e
5f
5g
5h
5i
90
70
75
55
75
70
60
66
70
50
-
-
d
Et
Et
H
H
H
H
6a
6b
6c
6d
6e
6f
60
80
80
70
70
75
50
-
-
b
4-BrC6H4
Ph
4-MeOC6H4
2-Furyl
t-Bu
90/10 > 99:1c
>99:1c
>99:1c
>99:1c
>99:1c
90/10 > 99:1c
BnBr
d
95/5
90/10
75/25 > 99 :1c
-
-
Bu3SnCl
Allyl Me2SiCl
EtI
AllylBr
PhCON(Me)OMe
PhSSPh
d
H
Me
b
-
-
-
d,e
Ph
6g
50/50
-
b
b
a Isolated yields. b Diastereomeric ratio (dr) calculated on the basis of
1H NMR spectrum of the crude reaction mixture. c Enantiomeric ratio
established by HPLC analysis on a Chiracel OD-H column or by 1H NMR
(see Supporting Information). d Enantiomeric ratio not determined. e Stereo-
chemistry not established for the two diastereomers.
5j
>99:1c
a Isolated yields. b Enantiomeric ratio not determined. c Enantiomeric ratio
established by HPLC analysis on Chiracel OD-H or by 1H NMR (see
Supporting Information).
Interestingly, treatment of racemic aziridines 6a,b with
trifluoroacetic acid (TFA) in dioxane/water at r.t. for 48 h
resulted in the formation of 2,3-aziridino-γ-lactones 7a,b,
which are useful buiding blocks in the synthesis of analogues
of L-glutamic acid, an important neurotransmitter of the
central nervous system (Scheme 2).
supported by the evidence that cis-2-(oxazolin-2-yl)-3-
trimethylsilyl-1-tritylaziridine 5b, prepared by capturing
(S,S)-3a-Li with Me3SiCl, could be neither â- nor R-lithiated
under varied conditions (s-BuLi, t-BuLi, MeLi). Therefore,
the lithiation-deuteration sequence carried out on (S)-3a
proceeds regio and stereospecifically affording the aziridine
5a. The role of the oxazolinyl group for the above-described
regio- and stereoselectivity seems to be crucial as its
precursor, the 1-trityl-2-methoxycarbonyl aziridine 1, un-
dergoes addition to the ester functionality upon treatment
with s-BuLi or LDA.
Scheme 2
The synthetic utility of lithiated aziridine (S,S)-3a-Li was
then checked by its trapping with several electrophiles.
Reactions with halides (MeI, Bu3SnCl, Me3SiCl, AllylMe2-
SiCl, AllylBr, EtI, BnBr) and other electrophiles led to the
formation of highly enantiomerically enriched cis-2,3-
disubstituted aziridines 5b-j in good yields (Table 1): in
all cases a SEret mechanism is likely to occur.11 It might be
useful to point out that while lithiation/trapping of a terminal
aziridine such as (S)-3a leads to cis-configured oxazolinyl-
aziridines, the reported lithiation/trapping of terminal N-tert-
butylsulfonyl-2-alkylaziridines leads to trans-configured
aziridines.4
The reaction of (S,S)-3a-Li, with carbonyl compounds
(aldehydes and ketones) was successively studied. In all
cases, the reactions with aldehydes proceeded with very high
diastereoselectivity at the newly created stereocentre, as
Stereochemistry of 7b was determined by comparing the
two vicinal coupling constant values found between HA and
HB (see Scheme 2) for the two diastereomers 7b and diast-
(11) The cis stereochemistry to aziridines 5 and 6 was assigned on the
basis of the JHH coupling constants between the two aziridinyl protons
ranging from 5.5 to 7.0 Hz, (see Supporting Information); see also:
Yonezawa, T.; Morishima, I. J. Mol. Spectrom. 1968, 27, 210-217.
3
(12) In two cases (6a and 6b), the configuration of the major diastereomer
was unambiguously determined by further conversion into 7a,b whose
stereochemistry was deduced by NMR analysis (vide infra).
Org. Lett., Vol. 9, No. 17, 2007
3297

Scheme 3a
a Key: i: RNH2, EtOH, Et3N; ii: (a) 2-methyl-2-amino-1-propanol (2.5 equiv); (b) n-BuLi (2.2 equiv), toluene, LaCl3. iii: Et2NSF3 (1
equiv), CH2Cl2, -98 °C (3b: R ) PhC(CH3)2, 35%; 3c: R ) PhCH2, 40%). iv: s-BuLi/TMEDA, 2h, THF -98 °C. v: Electrophile (D2O,
EtI, PhCHO). vi: n-BuLi, THF, 2h, -98 °C. vii: Electrophile (D2O, MeI, EtI).
7b, as similarly reported for 2,3-aziridino-γ-lactones of the
same configuration.13
In summary, 1-alkyl-2-oxazolinylaziridines undergo smooth
R- and/or â-lithiation depending upon the steric demand of
the nitrogen substituent, thus giving access to cis-configured
2,3-disubstituted and 2,2-disubstituted aziridines. It is quite
remarkable that, for steric reasons, 1-trityl-2-oxazolinylaziri-
dine 3a undergoes exclusive â-lithiation despite the presence
of a much more acidic hydrogen at the R-position, whereas
1-benzyl-2-oxazolinyaziridine 3c gives only R-lithiation. The
utility of the reported methodology resides in the stereo-
selectivity of the reaction of configurationally stable â-lithi-
ated intermediates and also in the fact that the oxazolinyl
group is amenable to synthetic eleboration as shown in the
preparation of 2,3-aziridino-γ-lactones 7. Further investiga-
tion will focus on the synthetic application of the above
lithiated aziridines.
For the sake of comparison and to get more insight about
the role of the nitrogen substituent with reference to the steric
demand, N-cumyl- and N-benzyl oxazolinylaziridines (()-
3b and (()-3c14 were prepared, as reported in Scheme 3,
and investigated.
A competition between R and â lithiation (with respect to
the oxazolinyl ring) occurred with the N-cumylaziridine (()-
3b as proved by the trapping of the lithiated intermediates
R-3b-Li and â-3b-Li with D2O, PhCHO, and EtI (Scheme
1
3). A careful examination of the H NMR spectrum of the
crude obtained in the deuteration reaction revealed that the
R/â ratio (8a/9a, 94% D both) was 1:2 being the â product
the most favored one. The same preference for the â product
was observed in the reaction with EtI (8b/9b ) 1/2) and
with PhCHO (8c/9c ) 1/2).15
Interestingly, the n-BuLi mediated lithiation of N-benzyl-
oxazolinylaziridine (()-3c occurred exclusively at the R
position and the corresponding intermediate R-3c-Li could
be trapped with electrophiles to furnish 2,2-disubstituted
aziridines 10a-c.16
Acknowledgment. This work was carried out under the
framework of the National Project “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” and supported by
the University of Bari.
Supporting Information Available: Experimental pro-
cedures and compound characterizations. This material is
available free of charge via the Internet at http://pubs.acs.org
(13) (a) Kale, A. S.; Deshmukh, A. R. Synlett 2005, 2370-2372. (b)
Saint-Fuscien, C.; Tarrade, A.; Dauban, P.; Dodd, R. H. Tetrahedron Lett.
2000, 41, 6393-6397.
(14) Trost, B. M.; Fandrick, D. R. Org. Lett. 2005, 7, 823-826.
(15) Compounds 8b and 9b were isolated in 18 and 36% yield,
respectively. The reaction with PhCHO gave 8c in 22% yield as 1:1 mixture
of diastereomers and 9c in 44% yield as a single diastereomer whose
stereochemistry, at the newly created stereogenic centre, has not been
determined yet.
OL071264U
(16) Compound 10a was obtained with 97% of deuterium incorporation;
compounds 10b (50% yield) and 10c (70% yield) show two slowly
1
equilibrating invertomers in the H NMR spectra.
3298
Org. Lett., Vol. 9, No. 17, 2007