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fingerprints’’ Code: 68, Interuniversity Consortium CINMPIS;
we are grateful to Giovanna Parisi, Ivana Cavaliere and Dr
Angelo Lovece of the University of Bari ‘‘A. Moro’’, for analysis
and preparation of some reported compounds.
Notes and references
1 (a) G. W. Gribble, Aryllithium and Hetaryllithium Compounds,
Science of Synthesis, Section 8.1.14, Thieme, Stuttgart, 2006, p. 357;
(b) C. Hartung and V. Snieckus, in Modern Arene Chemistry, ed.
D. Astruc, WILEY, New York, 2002, p. 330; (c) T. K. Macklin and
V. Snieckus, in Handbook of C-H Transformations, ed. G. Dyker,
WILEY-VCH, Weinheim, 2005, vol. 1, pp. 106–118.
2 For early seminal studies see: (a) G. Simig and M. Schlosser, Tetrahedron
Lett., 1988, 29, 4277; (b) K. Katsoulos and M. Schlosser, Tetrahedron Lett.,
1993, 34, 6263. For recent investigations see: (c) A. M. Kanazawa,
A. Correa, J.-N. Denis, M.-J. Luche and A. E. Greene, J. Org. Chem.,
1993, 58, 255; (d) K. Smith, G. A. El-Hiti, A. S. Hegazy and B. Kariuki,
Beilstein J. Org. Chem., 2011, 7, 1219 and reference therein.
Scheme 4 Applications of the azetidine-directed ortho-aryl C–H
functionalization.
3 (a) V. Capriati, S. Florio, R. Luisi and B. Musio, Org. Lett., 2005, 7, 3749;
(b) R. Luisi, V. Capriati, S. Florio and B. Musio, Org. Lett., 2007, 9, 1263;
(c) F. Affortunato, S. Florio, R. Luisi and B. Musio, J. Org. Chem., 2008,
73, 9214; (d) M. C. de Ceglie, B. Musio, F. Affortunato, A. Moliterni,
A. Altomare, S. Florio and R. Luisi, Chem.–Eur. J., 2011, 17, 286.
4 (a) B. Musio, G. J. Clarkson, M. Shipman, S. Florio and R. Luisi, Org.
Lett., 2009, 11, 325; (b) R. Luisi, V. Capriati, P. Di Cunto, S. Florio
and R. Mansueto, Org. Lett., 2007, 9, 3295; (c) R. Luisi and S. Florio,
Chem. Rev., 2010, 110, 5128.
5 (a) T. K. Beng, J. S. Woo and R. E. Gawley, J. Am. Chem. Soc., 2012,
134, 14764; (b) N. S. Sheikh, D. Leonori, G. Barker, J. D. Firth,
K. R. Campos, A. J. H. M. Meijer, P. O’Brien and I. Coldham, J. Am.
Chem. Soc., 2012, 134, 5300.
Scheme 5 Regioselective a-lithiation of N-Boc azetidine.
6 (a) H. J. Reich, W. S. Goldenberg and A. W. Sanders, ARKIVOC, 2004,
13, 97; (b) A. T. Hansson and M. Nilsson, Tetrahedron, 1982, 38, 389.
7 S. V. Kessar and P. Singh, Chem. Rev., 1997, 97, 721.
moderate yields) exclusively a-functionalized azetidines 10a,b. It is
worth mentioning that this is the first case of successful trapping
of an a-lithiated N-Boc-2-phenylazetidine. Previous attempts on
C-unsubstituted N-Boc-azetidine resulted in complex mixtures
and decomposition.10b The structure of 10a was confirmed by
X-ray analysis which also revealed a quasi-planar arrangement of
the azetidine ring according to a poor availability of the N-lone
pair.17 A different arrangement of the 4-membered ring is recog-
nizable for ortho-functionalized azetidine 4h (see ESI‡). All the
attempts to capture the lithiated intermediate 9-Li by external
quenching failed. Decomposition was always observed, while the
expected N to C [1,2]-migration product,18 obtained in the case of
lithiated N-Boc-aziridines,3a was never found.
In conclusion, our preliminary results demonstrate that 2-aryl-
azetidines could be lithiated regioselectively depending on the nature
(EWG or EDG) of the N-substituent. The ortho-lithiation appears to be
a simple method for the regioselective ortho-C–H functionalization of
aryls mediated by the azetidinyl ring. In addition, the directing role of
the azetidinyl ring, likely related to a preferential conformation, is
responsible for the high regioselectivity observed in the lithiation of
8 (a) Y. Han, M. Han, D. Shin, C. Song and H.-G. Hahn, J. Med. Chem., 2012,
¨
55, 8188; (b) H. Brauner-Osborne, L. Bunch, N. Chopin, F. Couty,
G. Evano, A. A. Jensen, M. Kusk, B. Nielsen and N. Rabasso, Org. Biomol.
Chem., 2005, 3, 3926; (c) D. Honcharenko, C. Zhou and J. Chattopadhyaya,
J. Org. Chem., 2008, 73, 2829.
9 W. Wykypiel, J. J. Lohmann and D. Seebach, Helv. Chim. Acta, 1981,
64, 1337.
10 (a) D. M. Hodgson, C. I. Pearson and A. L. Thompson, J. Org. Chem.,
2013, 78, 1098; (b) D. M. Hodgson and J. Kloesges, Angew. Chem., Int.
Ed., 2010, 49, 2900.
11 A. Brandi, S. Cicchi and F. M. Cordero, Chem. Rev., 2008, 108, 3988.
12 We believe that n-HexLi is a safer substitute of n-BuLi having several
advantages: (1) it gives more stable and safer solutions decompos-
ing slowly with respect to n-BuLi; (2) it is a non-pyrophoric strong
base; (3) the deprotonation reaction gives n-hexane which is less
volatile and has a higher flash point than butane generated with n-
BuLi. NMR investigation on the aggregation state of n-HexLi, which
is expected to be similar to n-BuLi, is underway.
13 For the use of catalytic amount of TMEDA see: D. W. Slocum, T. K.
Reinscheld, C. B. White, M. D. Timmons, P. A. Shelton, M. G. Slocum, R. D.
Sandlin, E. G. Holland, D. Kusmic, J. A. Jennings, K. C. Tekin, Q. Nguyen,
S. J. Bush, J. M. Keller and P. E. Whitley, Organometallics, 2013, 32, 1674.
14 X-ray analysis on adduct 4h (see text) disclosed a trans relationship
between the N-methyl group and the ortho-functionalized aromatic
ring (see ESI‡). CCDC 969537.
the 1-naphthyl derivative 3b, and for the double functionalization of 15 (a) R. L. Gay and C. R. Hauser, J. Am. Chem. Soc., 1967, 89, 2297;
(b) J. Clayden, C. S. Frampton, C. McCarthy and N. Westlund,
Tetrahedron, 1999, 55, 14161.
16 We propose that the high stereocontrol observed in the formation of
3a never proved in the case of 2-arylaziridines. A regioselectivity switch
(ortho vs. a) could be realized simply by using an electron-withdrawing
group as the N-substituent although the in situ quench was mandatory
using the Boc group. Further studies focused on the synthetic
application of the methodology to more challenging systems, as well
(R)-8 is consistent with a stereospecific cyclization via an SN2-type
mechanism (inversion of configuration). For related example on
aziridines see: M. Dammacco, L. Degennaro, S. Florio, R. Luisi,
B. Musio and A. Altomare, J. Org. Chem., 2009, 74, 6319.
as on the search for a more suitable N-substituent for the a-benzylic 17 X-ray analysis on adduct 10a revealed a planar arrangement of the
azetidine ring (see ESI‡). CCDC 969538.
18 (a) D. M. Hodgson, P. G. Humphreys, Z. Xu and J. G. Ward, Angew.
lithiation are underway.
We thank National Project ‘‘FIRB – Futuro in Ricerca’’ (code:
Chem., Int. Ed., 2007, 46, 2245; (b) R. Luisi, V. Capriati, S. Florio,
CINECA RBFR083M5N); Regional project ‘‘Apulian food
P. Di Cunto and B. Musio, Tetrahedron, 2005, 61, 3251.
1700 | Chem. Commun., 2014, 50, 1698--1700
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