Directed ortho lithiation of N-alkylphenylaziridines

Article abstract of DOI:10.1021/ol051412l

(Chemical Equation Presented) The ortho lithiation-trapping sequence of phenylaziridines is described. This methodology, which counts on the ability of the aziridino group to act as a directed metalation group (DMG), provides an easy access to functionali

Full text of DOI:10.1021/ol051412l

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3749-3752
Directed Ortho Lithiation of
N-Alkylphenylaziridines
Vito Capriati, Saverio Florio,* Renzo Luisi, and Biagia Musio
Dipartimento Farmaco-Chimico, UniVersity of Bari, Via E. Orabona 4, I-70126 Bari,
C.N.R., Istituto di Chimica dei Composti Organometallici “ICCOM”,
Sezione di Bari, Italy
florio@farmchim.uniba.it
Received June 17, 2005
ABSTRACT
The ortho lithiation−trapping sequence of phenylaziridines is described. This methodology, which counts on the ability of the aziridino group
to act as a directed metalation group (DMG), provides an easy access to functionalized arylaziridines as well as to phthalans and phthalides.
The importance of the aziridine N-substituent in this DoM reaction is stressed as well.
In the directed ortho metalation (DoM) reaction, a useful
strategy for regioselective functionalization of arenes, the
directed metalation group (DMG) plays an extremely im-
portant role.1 Substrate coordination capability alone for the
metalating agent is in some cases sufficient to allow ortho
deprotonation, and, indeed, benzylamines are rapidly ortho
lithiated upon treatment with organolithiums.2 However, good
DMGs must have ideal basic properties for the organolithium
precomplexation, a good electron-withdrawing effect for a
rapid and efficient deprotonation, and a stabilizing ability
for the resulting ortho-lithiated species.3 Mechanisms have
been proposed to account for the DoM reaction.4
and alkylamino), aziridino groups have never previously been
considered in this capacity, as far as we are aware. This is
a surprising omission considering that the aziridino moiety
has an electron pair that can be used for the precomplexation
of the metalating agent and/or for coordination to the
corresponding ortho-lithiated species. The fact that aziridines
are amenable to synthetic manipulation makes this even more
surprising.
Data from the literature indicate that lithiation of aziridines
occurs at the R-position.5 Indeed, N-alkyloxazolinyl- and
thiazolylaziridines undergo aziridine ring hydrogen abstrac-
tion upon treatment with organolithiums, and the resulting
lithiated intermediates can be trapped with electrophiles.6
Moreover, diastereomeric N-sulfonyloxazolinyl phenylaziri-
Among the various nitrogen-containing DMGs (carbox-
amido, O- and N-carbamate, sulfonamido, oxazolino, imino
(3) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356-363. (b)
Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int.
Ed. 2004, 43, 2206-2225.
(1) For extensive reviews on ortho lithiation and for various DMGs,
see: (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1-360.
(b) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306-312. (c) Klumpp,
G. W. Recl. TraV. Chim. Pays-Bas 1986, 105, 1-21. (d) Snieckus, V. Chem.
ReV. 1990, 90, 879-933. (e) Clayden, J. Organolithium: SelectiVity for
Synthesis; Baldwin, J., E., Williams, R., M., Eds.; Pergamon: Oxford, GB,
2002; Vol. 23, pp 28-109.
(2) (a) Jones, F. N.; Vaulks, R.; Hauser, C. R. J. Org. Chem. 1963, 28,
3461-3465. (b) Klein, K. P.; Hauser, C. R. J. Org. Chem. 1967, 32, 1479-
1483. (c) Ludt, R. E.; Hauser, C. R. J. Org. Chem. 1971, 36, 1607-1613.
(d) Simig, G.; Schlosser, M. Tetrahedron Lett. 1988, 29, 4277-4280.
(4) (a) von Eikema-Hommes, N. J. R.; von Rague´ Schleyer, P. Angew.
Chem. 1992, 104, 768-771; Angew. Chem., Int. Ed. Engl. 1992, 31, 755-
758. (b) Beak, P.; Kerrick, S. T.; Gallagher, D. J. J. Am. Chem. Soc. 1993,
115, 10628-10636. (c) Saa´, J. M.; Martorell, G.; Frontera, A. J. Org. Chem.
1996, 61, 5194-5195. For recent spectroscopic investigations on DoM
reactions, see also: (d) Gossage, R. A.; Jastrzebski, J. T. B. H.; van Koten,
G. Angew. Chem., Int. Ed. 2005, 44, 1448-1454. (e) Chadwick, S. T.;
Rennels, R. A.; Rutheford, J. L.; Collum, D. B. J. Am. Chem. Soc. 2000,
122, 8640-8647.
10.1021/ol051412l CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/23/2005

dines undergo benzylic deprotonation upon treatment with
s-BuLi/TMEDA.7 The N-substituent effect in the lithiation
of oxazolinylphenylaziridines has also been investigated.8 In
no case was ortho lithiation observed. In addition, it had been
reported that lithiation of N-tosylphenylaziridine occurs at
the benzylic position and that the resulting lithio derivative
adds to the aryl group of the N-tosyl substituent with
subsequent dearomatization.9
Herein, we report for the first time that some N-alkyl
phenylaziridines can be cleanly and very efficiently ortho
lithiated upon treatment with organolithiums. Treatment of
aziridine 1a, which was easily prepared from styrene and
Br2/Me2S/MeNH2,10 with s-BuLi (1.5 equiv) in THF at -78
°C produced a yellow solution that turned colorless upon
quenching with D2O to furnish N-methyl (ortho-deuterio-
phenyl)aziridine 3a (>98%), with no trace of the R-deuterio-
phenylaziridine.11 The ortho-lithiated phenylaziridine 2a
likely intervenes in the conversion of 1a into 3a (Scheme 1,
Table 1).
Table 1. Reaction of Ortho-Lithiated Phenylaziridine 2a with
Electrophiles
aziridine 3
phthalan 5
electrophile
D2O
(% yield)
(% yield)
dr
3a (>98)a,b
3b (85)a
3c (63)a
3d (81)a
3e (80)c
3f (98)a
3g (50)a,d
3he
3i (76)f
3j (47)f
3k (52)a
3l (55)f
CH3I
1,2-dibromoethane
hexachloroethane
I2
DMF
PhCONMeOMe
(CH3)2CO
CH3CHO
PhCHO
Ph2CO
CH3(CH2)2COPh
CO2
ClCOOCH2CH3
ClCOOCH3
5a (>95)a
5bg
50/50h
60/40h,i
5c (>95)f
5d (>95)a
5e (>95)f
5f (73)a
5g (25)f
5h (55)f
50/50i,j
3m (25)f
50/50h
50/50h
a Isolated yields. b >98% D. c Yield calculated by weighing the crude
reaction product, after washing it with Et2O and 1H NMR analysis; this
product tends to decompose very quickly over time. d Yield decreases to
26% with DMB. e Not isolated. f Overall isolated yields in both diastere-
omers. g Aminomethylphthalan 5b could not be isolated. h Inseparable
mixture of diastereomers. i Relative configuration ascertained as described
in ref 15. j Diastereomers separated by column chromatography on silica
gel (see Supporting Information for details).
Scheme 1
that ortho lithiation competes only in the case of trans-
stilbene oxides.12d,e The lower kinetic acidity of hydrogens
R to nitrogen compared with hydrogens R to oxygen may
be playing a role.13 Therefore, we conclude that in the
lithiation of 1a, the N-methyl aziridino group acts as an ortho-
directing group. This has no literature precedent, although
it is known that benzylamines undergo ortho lithiation upon
treatment with organolithiums.2
Ortho-lithiated phenylaziridine 2a proved to be extra-
ordinarily stable: once generated at low temperature it could
be warmed to room temperature without undergoing any
transformation, and addition of D2O furnished 3a almost
quantitatively. Support of the hypothesis that the aziridine
nitrogen coordinates to the ortho-lithiated species 2a comes
from the observation that the aziridine 1a is configurationally
stable14 and puts the nitrogen lone-pair on the same side of
the phenyl group with respect to the N-C bond, as clearly
established by two-dimensional NOESY correlations (Scheme
1).
By way of comparison, it is worth noting that styrene
oxide12a,b,e and derivatives12c,e undergo clean R-lithiation and
(5) (a) Satoh, T. Chem. ReV. 1996, 96, 3303-3326. (b) Vedejs, E.;
Kendall, J. T. J. Am. Chem. Soc. 1997, 119, 6941-6942. (c) Satoh, T.;
Ozawa, M.; Takano, K.; Kudo, M. Tetrahedron Lett. 1998, 39, 2345-2348.
(d) Bisseret, P.; Bouis-Peter, C.; Jacques, O.; Henriot, S.; Eustache, J. Org.
Lett. 1999, 1, 1181-1182. (e) Alezra, V.; Bonin, M.; Mivouin, L.; Policar,
C.; Husson, H. P. Eur. J. Org. Chem. 2001, 2589-2594. (f) Hayes, J. F.;
Prevost, N.; Proket, I.; Shipman, M.; Slawin, A. M. Z.; Twin, H. Chem.
Commun. 2003, 1344-1345. (g) O’Brien, P.; Rosser, C. M.; Caine, D.
Tetrahedron 2003, 49, 9779-9791. (h) Vedejs, E.; Bhaun Prasad, S. A.;
Kendall, J. T.; Russel, J. S. Tetrahedron 2003, 49, 9849-9856. (i)
Concello´n, J. M.; Sua´rez, J. R.; Garc´ıa-Granda, S.; D´ıaz, M. R. Angew.
Chem., Int. Ed. 2004, 43, 4333-4336. (j) Hodgson, D. M.; Humphreys, P.
G.; Ward, J. G. Org. Lett. 2005, 7, 1153-1156.
(11) Addition of a ligand such as TMEDA (up to 3.0 equiv) has no effect
on the final result.
(12) (a) Capriati, V.; Florio, S.; Luisi, R.; Salomone, A. Org. Lett. 2002,
4, 2445-2448. (b) Capriati, V.; Degennaro, L.; Favia, R.; Florio, S.; Luisi,
R. Org. Lett. 2002, 4, 1551-1554. (c) Capriati, V.; Florio, S.; Luisi, R.;
Nuzzo, I. J. Org. Chem. 2004, 69, 3330-3335. (d) Florio, S.; Aggarwal,
V.; Salomone, A. Org. Lett. 2004, 6, 4191-4194. (e) Capriati, V.; Florio,
S.; Luisi, R. Synlett 2005, 9, 1359-1369.
(13) (a) Sawyer, J. S.; Macdonald, T. L.; McGarvey, G. J. J. Am. Chem.
Soc. 1984, 106, 3376-3377. (b) Kessar, S. V.; Singh, P. Chem. ReV. 1997,
97, 721-737.
(14) (a) Pierre, J.-L.; Baret, P.; Arnaud, P. Bull. Soc. Chim. Fr. 1971,
10, 3619-3628. (b) Martino, R.; Lopez, A.; Mathis, R.; Lattes, A. Bull.
Soc. Chim. Fr. (Chim. Mol.) 1976, 1849-1850. (c) Lopez, A.; Gauthier,
M. M.; Martino, R.; Lattes, A. Org. Magn. Reson. 1979, 12, 418-428.
(6) (a) Florio, S.; Troisi, L.; Capriati, V.; Ingrosso, G. Tetrahedron Lett.
1999, 40, 6101-6104. (b) De Vitis, L.; Florio, S.; Granito, C.; Ronzini,
L.; Troisi, L.; Capriati, V.; Luisi, R.; Pilati, T. Tetrahedron 2004, 60, 1175-
1181.
(7) Luisi, R.; Capriati, V.; Florio, S.; Ranaldo, R. Tetrahedron Lett. 2003,
44, 2677-2681.
(8) Luisi, R.; Capriati, V.; Florio, S.; Di Cunto, P.; Musio, B. Tetrahedron
2005, 61, 3251-3260.
(9) Breternitz, H. J.; Schaumann, E. Tetrahedron Lett. 1991, 32, 1299-
1302.
(10) Chow, Y. L.; Bakker, B. H.; Iwai, K. J. Chem. Soc., Chem. Commun.
1980, 521-522.
3750
Org. Lett., Vol. 7, No. 17, 2005

The ortho-directing ability of the aziridino group of 1a
was confirmed by its lithiation and trapping with electrophiles
other than D2O. Addition of MeI to the solution of 2a
provided ortho-tolylaziridine 3b in very good yield, while
the reaction with 1,2-dibromoethane, hexachloroethane, I2,
and DMF led to the formation of ortho-bromophenylaziridine
3c, ortho-chlorophenylaziridine 3d, ortho-iodophenylaziri-
dine 3e, and ortho-formylphenylaziridine 3f in very good to
excellent yields, respectively (Scheme 1, Table 1). The
reaction of 2a with N,N-dimethylbenzamide (DMB) gave a
chromatographically separable mixture of ortho-benzoyl-
phenylaziridine 3g (26%) and ortho-benzoyl-N,N-dimethyl-
benzamide 4 (34%), very likely derived from ortho-depro-
tonated DMB and subsequent debenzoylation of its precursor
(Scheme 2). A better yield of 3g (50%) was obtained when
the Weinreb amide (PhCONMeOMe) was used as the
benzoylating agent.
of TFA caused cyclization to aminomethylphthalans 5c-e
quantitatively,15 while bubbling CO2 into the solution of 2a
generated aminomethylphthalide 5f (Table 1, Scheme 3).
Interestingly, the capture of 2a with ethyl chloroformate
afforded the ethoxycarbonylaziridine 3m (25%) together with
the chloroethoxyphthalan 5g (25%). The latter was probably
formed as a result of a cascade reaction initiated with the
nucleophilic addition of 2a to ClCO2C2H5, followed by
aziridine ring-opening-promoted phthalan formation, and
N-ethoxycarbonylation. It is worth noting that the aziridine
ring-opening proceeds much faster than chlorine elimination.
Phthalan 5h (55%) was formed when 2a was reacted with
ClCO2CH3 (Table 1, Scheme 4).
Scheme 4
Scheme 2
To check the importance of the aziridine N-substituent in
the aforementioned ortho lithiation, we prepared some other
N-alkylaziridines and compared them with the N-methyl
derivative 1a. N-Ethyl-, N-propyl-, and N-butylaziridines
1b-d behaved like aziridine 1a undergoing ortho lithiation
with s-BuLi to give 2b-d but required a longer reaction
time, thus confirming that probably the N-substituent plays
an important role in the lithiation process. Quenching with
D2O after 4 h for 1b and 1c and after 6 h for 1d, at -78 °C,
furnished ortho-deuterated aziridines 3n-p (98%, >98% D)
(Scheme 5).
The addition of acetone to 2a gave the aminomethyl-
phthalan 5a: the probable intermediate 3h could not be
intercepted. In contrast, the reaction of 2a with acetaldehyde,
benzaldehyde, benzophenone, and butyrophenone furnished
aziridinylphenyl carbinols 3i-l as almost 1:1 diastereomeric
mixtures (yields ranging from 47 to 76%, see Table 1).
However, treatment of carbinols 3j-l in THF with few drops
Scheme 5
Scheme 3
In contrast, N-isopropylaziridine 1e could not be ortho-
lithiated under the conditions that caused lithiation of 1a-d
(15) Relative configuration to aminomethylphthalans 5c and 5e could
be assigned on the basis of two-dimensional NOESY correlations. In the
case of the cis isomers, NOE interactions between the two benzylic-type
protons on C1 and C3 were diagnostic of a proximity relationship.
Org. Lett., Vol. 7, No. 17, 2005
3751

even after a longer reaction time (10 h). No lithiation
occurred also when t-BuLi was used. One possible explana-
tion for the different behavior between 1e and 1a-d is that
the above ortho lithiation requires a preliminary complexation
of s-BuLi (or t-BuLi) on the nitrogen of the starting aziridine.
This probably is not allowed in the case of the sterically
hindered aziridine 1e. For the same reason, cis- and trans-
N-isopropyl-2,3-diphenylaziridines 1f and 1g were recovered
substantially unchanged upon treatment with s-BuLi followed
by D2O quenching. We also investigated the lithiation
reaction of N-Boc-phenylaziridine 1h.16 Its treatment with
s-BuLi, even at short reaction time (less than 5 min),
followed by addition of D2O and aqueous workup gave
2-phenyl-2-Boc-aziridine 6. This is likely the result of a [1,2]
aza-Wittig rearrangement in which R-lithiation followed by
Boc group migration from the nitrogen to the R-carbon atom
presumably takes place through transition state TS-A (Scheme
6).
isopropyldiphenylaziridines 1f and 1g do not. This seems to
suggest that a precomplexation between the aziridine and
s-BuLi en route to ortho lithiation is necessary for the
reaction to occur. This precomplexation could take place with
N-alkylaziridines 1a-d but not with 1e-g. The involvement
of the nitrogen lone pair in the ortho-lithiated intermediate
coordination also has to be considered. The ortho lithiation
of 1a-d appears to be particularly appealing, as the trapping
of 2a-d allows for the regioselective ortho functionalization
of phenylaziridines.17 Moreover, the reactivity of the aziridine
ring adds synthetic utility to the ortho-lithiated species 2.
Accordingly, systems such as phthalans and phthalides,
interesting classes of compounds owing to their promising
pharmacological potential,18 can be prepared by the above
methodology. More work is in progress to this end in our
laboratory.
Acknowledgment. This work was carried out under the
framework of the National Project “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” and the FIRB
Project “Progettazione, preparazione e valutazione biologica
e farmacologica di nuove molecole organiche quali potenziali
farmaci innovativi” supported by the MIUR (Rome), by the
University of Bari, and by the Interuniversities Consortium
CINMPIS.
Scheme 6
Supporting Information Available: Full experimental
details and copies of 1H and 13C NMR spectra for compounds
3a (S16, S17), 3b-g (S24-S34), 3i-m (S35-S46), 3n-p
(S18-S23), 5a (S47, S48), 5c-h (S49-S62), and 6 (S63,
S64). This material is available free of charge via the Internet
at http://pubs.acs.org.
OL051412L
(17) For some recent reviews on the synthesis of aziridines and their
reactions, see: (a) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry
1997, 8, 1693-1715. (b) McCoull, W.; Davis, F. A. Synthesis 2000, 10,
1347-1365. (c) Hu, X. E. Tetrahedron 2004, 60, 2701-2743.
(18) For some recent syntheses of phthalans and phthalides, their
pharmacological activity, and their uselfulness as intermediates in obtaining
other bioactive compounds, see: (a) DeBernardis, J. F.; Arendsen, D. L.;
Kyncl, J. J.; Kerkman, D. J. J. Med. Chem. 1987, 30, 178-184. (b) Zemolka,
S.; Lex, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2002, 41, 2525-2528.
(c) Yus, M.; Foubelo, F.; Ferra´ndez, J. V. Tetrahedron 2003, 59, 2083-
2092. (d) Yurovskaya, M. A. Chem. Heterocycl. Comp. 2005, 41, 24-78.
In conclusion, we have discovered that N-substituted
phenylaziridines, never studied before as DMGs, undergo
smooth ortho lithiation depending upon the steric hindrance
of the N-substituent: N-methyl- 1a, N-ethyl- 1b, N-propyl-
1c, and N-butylaziridine 1d undergo ortho lithiation quan-
titatively, whereas N-isopropylphenylaziridine 1e and N-
(16) Wessig, P.; Schwarz, J. Synlett 1997, 893-894.
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Org. Lett., Vol. 7, No. 17, 2005