Regioselective functionalization of 2-arylazetidines: Evaluating the ortho-directing ability of the azetidinyl ring and the α-directing ability of the N-substituent

Article abstract of DOI:10.1039/c3cc48555b

The regioselective lithiation-functionalization of 2-arylazetidines has been explored. The nature of the N-substituent is mainly responsible for a regioselectivity switch. ortho-Lithiation occurred, using hexyllithium as a greener base, in N-alkylazetidines, while α-benzylic lithiation has been observed with N-Boc azetidines.

Full text of DOI:10.1039/c3cc48555b

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Regioselective functionalization of
2-arylazetidines: evaluating the ortho-directing
ability of the azetidinyl ring and the a-directing
ability of the N-substituent†‡
Cite this: Chem. Commun., 2014,
50, 1698
Received 8th November 2013,
Accepted 3rd December 2013
Leonardo Degennaro,*a Marina Zenzola,a Piera Trinchera,a Laura Carroccia,a
DOI: 10.1039/c3cc48555b
Arianna Giovine,a Giuseppe Romanazzi,b Aurelia Falcicchioc and Renzo Luisi*a
www.rsc.org/chemcomm
The regioselective lithiation–functionalization of 2-arylazetidines pyrrolidines and piperidines, bearing an electron-donating group, such
has been explored. The nature of the N-substituent is mainly as an alkyl group as the N-substituent, to the best of our knowledge, has
responsible for a regioselectivity switch. ortho-Lithiation occurred, not been reported. However, it has been reported that N-alkyl-2-phenyl
using hexyllithium as a greener base, in N-alkylazetidines, while a- pyrrolidines could generate a stable ortho-lithiated intermediate by
benzylic lithiation has been observed with N-Boc azetidines.
bromine–lithium exchange6 or lithiation could occur by Lewis acid
activation.7 Some examples of regioselective lithiation on 2-aryl
Regioselectivity represents a very important aspect in planning a substituted nitrogen-bearing heterocycles are presented in Table 1.
synthetic strategy. Within synthetic protocols involving lithiated inter- However, to our surprise, we noticed that some systems were not
mediates, usually generated by deprotonation of suitable starting covered. We focused our attention to the almost unexplored four-
materials, this aspect is particularly relevant. In fact, several factors membered ring azetidine. This aza-heterocycle is appealing because
could affect the regioselectivity of a lithiation reaction such as the of its occurrence in several biologically active natural molecules and
nature of the functional groups already installed into the molecule, or drug candidates.8
the presence of special functional groups able to direct the lithiation
It is worth mentioning that, despite the large amount of work on
itself.1 For example, it has been demonstrated that the regioselectivity the metalation–electrophile trapping on aza-heterocycles, there are
of the lithiation of some N-benzyl amine derivatives is dependent on only few examples concerning the metalation (lithiation) of azetidines.
the nature of the N- and ring-substituent, as well as the reaction Pioneering work by Seebach et al.9 and recent reports by Hodgson
conditions.2 In a research project aimed at developing new meth- et al. deal with the a-lithiation of azetidines bearing an electron-
odologies for the functionalization of nitrogenated small heterocycles, withdrawing group as the N-substituent.10 To the best of our knowl-
the importance of such factors in the regioselective lithiation of edge there are no reports on the lithiation of 2-arylazetidines bearing
2-arylaziridines was highlighted.3 It was demonstrated that N-alkyl-2- either an EWG or EDG as the N-substituent (Table 1).
aryl aziridines could give ortho-lithiation, while 2-arylaziridines bearing
Herein, we wish to report the first successful use of the
an electron-withdrawing group, such as Boc (tBuOCO) or Bus (tBuSO2), azetidinyl ring as an effective ortho-directing group for the
as the N-substituent, almost exclusively undergo a-lithiation.4 Similarly, regioselective functionalization, under very mild conditions,
other 2-aryl substituted nitrogenated heterocycles such as N-Boc-2-aryl of 2-aryl derivatives, and preliminary results on the effect of
pyrrolidines and piperidines, extensively studied by Coldham, O’Brien,
Gawley et al.,5 undergo exclusive a-lithiation. In striking contrast, the
Table 1 Regioselective lithiation of nitrogenated 2-aryl heterocycles
regioselectivity of the hydrogen–lithium exchange reaction in 2-aryl
a Department of Pharmacy – Drug Sciences, University of Bari,
‘‘A. Moro’’ Via E. Orabona 4, Bari 70125, Italy. E-mail: renzo.luisi@uniba.it,
leonardo.degennaro@uniba.it
b DICATECh, Polytechnic of Bari, Via E. Orabona 4, Bari 70125, Italy
Heterocycle
n
a-Lithiation
ortho-Lithiation
c Istituto di Cristallografia (IC-CNR), Via Amendola 122/o, 70125 Bari, Italy
† This work is dedicated to the memory of Prof. Robert (Bob) Gawley.
‡ Electronic supplementary information (ESI) available: Experimental proce-
dures, spectroscopic data and copies of 1H–13C NMR spectra of new compounds.
CCDC 969537 and 969538. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3cc48555b
3
4
Aziridine
0
1
2
3
O
O
Azetidine
Pyrrolidine
Piperidine
X
X
5
a, 6
O
O
5
O
X
a
O = reported; X = not reported. Generated by Br–Li exchange.
1698 | Chem. Commun., 2014, 50, 1698--1700
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Scheme 1 Synthesis of 2-arylazetidines.
the N-substituent on the regioselectivity of the lithiation. As a first
step, we embarked in the preparation of N-methyl-2-arylazetidines.
Two main routes were employed for the preparation of azetidines
3a–c: the reduction of 2-azetidinones 1 and the cyclization of
dichloro derivatives 2 with MeNH2 (Scheme 1).11
Scheme 2 Examples of regioselective functionalization of azetidines.
conditions (entry 6, Table 2). Nevertheless, gratifyingly a regioselective
lithiation ortho to the azetidinyl ring was observed without using
TMEDA (entry 3, Table 2). In this latter case, the directing ability of the
azetidinyl ring over the OMe group is worth noting.
Next, we tested the scope of the methodology in the ortho C–H
functionalization of azetidines 3a–c with a variety of representative
electrophiles (Scheme 3). Functionalized azetidines 4a–l were regio-
selectively prepared in high yields.
In order to optimize the lithiation reaction, 1-methyl-2-phenyl-
azetidine 3a was chosen as a model substrate, and reacted under the
conditions provided in Table 2 using MeI as the electrophile and
n-hexyllithium (n-HexLi) as the base.12 We were pleased to find
exclusively ortho-methylated azetidine 4a in 43% yield by using
n-HexLi in Et2O at 20 1C for 1 h (entry 1). Better yields (up to 93%)
were observed upon prolonging the lithiation time (entries 2 and 3).
With the aim to get high conversion with a reduced reaction time, the
role of TMEDA was investigated (entries 4–6). As expected, the use of
TMEDA accelerates the lithiation reaction and higher conversions could
be obtained even with an amount of 20% (entries 4–6).13 However,
conditions of entry 6 were chosen as a good time–yield compro-
mise. The observed ortho-directing ability of the azetidine ring
could be explained assuming the coordinating role of the nitro-
gen, just as seen in the case of aziridines.3 NOESY experiments
on 3a and X-ray analysis on 4h confirmed a trans arrangement
between the N-methyl group and the phenyl ring (see ESI‡).14
With the optimized conditions in hand, we applied this protocol to
2-arylazetidines 3b and c. In these cases, we envisaged two possible sites
of deprotonation (Ha and Hb in Scheme 2). Quite surprisingly, in the
case of naphthylazetidine 3b, where the peri lithiation might be
considered, product 4b was isolated in 96% yield as the result of a
very selective ortho-lithiation (Scheme 2). The result is, in our opinion,
remarkable because it reveals an opposite regiochemistry with respect
to that reported for the open-chain analogue a-dimethylaminomethyl
naphthalene. In this latter case peri lithiation predominates
upon treatment with n-BuLi in ether–hexane.15
Interestingly, combining the azetidine-assisted ortho-lithiation with
the Li–B exchange with boropinacolate (iPrOBpin), arylboronates 6a,b
were prepared (Scheme 3). Encouraged by these results, we envisioned
further synthetic applications for ortho-lithiated 2-arylazetidines. The
directing ability of the azetidinyl ring was exploited in a double
functionalization of 3a. First 3a was converted into the ortho-
chloro derivative 4d which was subjected, after isolation, to another
regioselective lithiation–electrophile trapping sequence affording
2,6-disubstituted azetidines 7a,b in excellent yields (Scheme 4A). The
stereoselectivity was also addressed using enantioenriched azetidine
(S)-3a. The lithiation–trapping sequence furnished azetidine (S)-4h,
without loss of the optical purity (Scheme 4B). The inherent ring strain
of the azetidine was exploited for an acid-catalyzed cyclization promoted
by the azetidinyl carbinol (S)-4h. Highly enantioenriched (er 95 : 5)
phthalan (R)-8 was obtained in 70% yield.16
In order to confirm our initial expectations (see Table 1) on the
ability of the N-substituent in directing the regioselectivity of the
lithiation, we prepared azetidine 9 bearing an electron-withdrawing
group, such as the Boc group, as the nitrogen substituent. In this case,
because of the poor coordinating ability of the azetidine nitrogen, the
ortho-lithiation would not be expected. In fact, when azetidine 9 was
subjected to deprotonation reactions under the optimized conditions
(entries 3 and 6, Table 2), only complex reaction mixtures were obtained
(Scheme 5). However, performing the reaction at low temperature
(À84 1C), using n-HexLi in a coordinating solvent (2-MeTHF), under
in situ quench conditions, we were happy to isolate (although in
In the case of azetidine 3c bearing a ‘‘competitor’’ directing group,
a mixture of regioisomers 4c and 5 was observed under the optimized
Table 2 Optimization of the ortho-lithiation of 3a
Entry Base (equiv.)/ligand (equiv.) Solvent T (1C) Time (h) Yielda (%)
1
2
3
4
5
6
n-HexLi (1.5)
n-HexLi (1.5)
n-HexLi (2)
n-HexLi (1.3) TMEDA (0.2) Et2O
n-HexLi (1.3)/TMEDA (0.2) Et2O
n-HexLi (1.3) TMEDA (1.3) Et2O
Et2O
Et2O
Et2O
20
20
20
20
20
20
1
4
16
1
4
1
43
71
93
60
83
95
a
Yield of isolated product.
Scheme 3 Scope of the azetidine-directed ortho-aryl C–H functionalization.
Chem. Commun., 2014, 50, 1698--1700 | 1699
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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.
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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,
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9 W. Wykypiel, J. J. Lohmann and D. Seebach, Helv. Chim. Acta, 1981,
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10 (a) D. M. Hodgson, C. I. Pearson and A. L. Thompson, J. Org. Chem.,
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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
This journal is ©The Royal Society of Chemistry 2014