Synthesis of optically active arylaziridines by regio- and stereospecific lithiation of N-bus-phenylaziridine

Article abstract of DOI:10.1021/ol802487v

(Chemical Equation Presented) α,α-Disubstituted aziridines can be produced in good yields by selective lithiation of W-fert-butylsulfonyl-2- phenylaziridine (n-BuLi/TMEDA, Et₂O) at the benzylic position and subsequent trapping with a range of e

Full text of DOI:10.1021/ol802487v

ORGANIC
LETTERS
2009
Vol. 11, No. 2
325-328
Synthesis of Optically Active
Arylaziridines by Regio- and
Stereospecific Lithiation of
N-Bus-Phenylaziridine
Biagia Musio,†,‡ Guy J. Clarkson,† Michael Shipman,*,† Saverio Florio,*,‡ and
Renzo Luisi‡
Department of Chemistry, UniVersity of Warwick, Gibbet Hill Road, CoVentry CV4
7AL, U.K., and 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 October 29, 2008
ABSTRACT
r,r-Disubstituted aziridines can be produced in good yields by selective lithiation of N-tert-butylsulfonyl-2-phenylaziridine (n-BuLi/TMEDA,
Et2O) at the benzylic position and subsequent trapping with a range of electrophiles. Repetition of the lithiation/electrophilic trapping sequence
provides a stereocontrolled route to trisubstituted aziridines. Using (R)-N-tert-butylsulfonyl-2-phenylaziridine, the r,r-disubstituted aziridines
can be produced as single enantiomers (er >98:2), indicating that the intermediate organolithium is configurationally stable. Efficient aziridine
ring-opening reactions leading to 1,2-diamines and 1,4-diamines are also reported.
Aziridines are important compounds because of their wide-
spread use in organic synthesis and their presence in many
natural products and biologically active molecules.1 In recent
years, a variety of methods have been developed for the
synthesis of functionalized aziridines. Of these, aziridinyl
anion methodology (AAM), based on the metalation/elec-
trophile trapping of simple, readily available aziridines, has
become one of the most useful strategies to this class of
compounds.2 Normally, the presence of an electron-
withdrawing group (EWG) on the nitrogen or the carbon
atoms of the heterocyclic ring is crucial for successful
metalation.3
Recently, investigation of lithiation/electrophile trapping
of simple 2-arylaziridines4 established that N-alkyl pheny-
laziridines undergo predominantly ortho-lithiation5 upon
treatment with organolithiums, an outcome that is in stark
† University of Warwick
‡ Universita` di Bari
(1) (a) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, 2006. (b) Padwa, A. In ComprehensiVe Hetero-
cyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V.,
Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; Vol. 1, pp 1-104. (c) Hu,
X. E. Tetrahedron 2004, 60, 2701–2743. (d) McCoull, W.; Davis, F. A.
Synthesis 2000, 1347–1365.
(2) (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.
10.1021/ol802487v CCC: $40.75
Published on Web 12/16/2008
2009 American Chemical Society

contrast to phenyloxirane,6 which gives exclusively R-lithia-
tion (Scheme 1).
R-lithiation of N-Bus-2-phenylaziridine 1 and demonstrate
its use in the preparation of a range of functionalized
arylaziridines.
N-Bus-2-phenylaziridine 1, prepared as reported,10 was
initially subjected to deprotonation conditions reported for
similar aziridines (LTMP, 3 equiv, THF).3b Unfortunately,
under such conditions a competition between R- and ꢀ-lithia-
tion was observed as demonstrated by the trapping of
organolithiums 2and 3 with trimethylsilyl chloride (TMSCl)
to give 4 and 5a in a 50:50 ratio (Scheme 2).11 The trans
configuration of 4 was unambiguously established by single
crystal X-ray diffraction (see Supporting Information).12 The
poor selectivity observed in this reaction can be rationalized
in terms of a complex induced proximity effect13 whereby
the Bus group, positioned anti- to the Ph ring, directs
lithiation to both ring hydrogens that are located syn to it.
Scheme 1. Reactivity of Lithiated Arylaziridines
Other base/solvent combinations were explored to try and
improve the regioselectivity. Using LDA (3 equiv) in THF,
some preference for the required R-lithiated product was
observed (4/5a; 12:88). Similar results were achieved using
n-BuLi/TMEDA in THF (4/5a; 15:85). Finally, using n-BuLi/
TMEDA in Et2O facilitated almost exclusively lithiation at
the R-position. Capture of the corresponding lithiated
intermediate 3 with TMSCl gave aziridine 5a (86% yield;
5a/4 > 99:1) as the sole product (Scheme 2).
Aware of the considerable utility of R-lithiated aziridines,
we sought conditions for the lithiation at the benzylic position
of 2-arylaziridines. We envisaged that the presence of an
EWG on the aziridine ring nitrogen might help direct
lithiation to this site. Initial studies revealed that although
N-Boc-2-phenylaziridine undergoes the required R-lithiation,
fast N f C Boc migration leads to quenching of the initial
organolithium (Scheme 1).5 N-Tolylsulfonyl-2-phenylaziri-
dine also undergoes R-lithiation, but this is rapidly followed
by a 1,4-like addition of the carbanion to the phenyl ring of
the N-substituent resulting in dearomatization (Scheme 1).7
In a bid to counteract this, we turned our attention to the
N-tert-butylsulfonyl-2-phenylaziridine, driven by the aware-
ness that the tert-butylsulfonyl (Bus) group is strongly
electron-withdrawing, stable to a wide range of reaction
conditions, and easily removable under mild acidic condi-
tions.8 Recently, lithiation/electrophile trapping of unsub-
stituted and 2-alkylsubstituted N-Bus-aziridines has been
reported,3b,9 but no efficient methods for the R-lithiation of
N-Bus-substituted monoarylaziridines have been disclosed.
In this paper, we report conditions for the regioselective
Scheme 2. Regioselective Lithiation of N-Bus-2-Phenylaziridine
(3) (a) Luisi, R.; Capriati, V.; Di Cunto, P.; Florio, S.; Mansueto, R.
Org. Lett. 2007, 9, 3295–3298. (b) Hodgson, D. M.; Humphreys, P. G.;
Ward, J. G. Org. Lett. 2005, 7, 1153–1156. (c) Alezra, V.; Bonin, M.;
Mivouin, L.; Policar, C.; Husson, H. P. Eur. J. Org. Chem. 2001, 2589–
2594. (d) O’Brien, P.; Rosser, C. M.; Caine, D. Tetrahedron 2003, 59, 9779–
9791. (e) Montagne, C.; Prevost, N.; Shiers, J. J.; Prie, G.; Rahman, S.;
Hayes, J. F.; Shipman, M. Tetrahedron 2006, 62, 8447–8457. (f) Vedejs,
E.; Kendall, J. T. J. Am. Chem. Soc. 1997, 119, 6941–6942. (g) Bisseret,
P.; Bouis-Peter, C.; Jacques, O.; Henriot, S.; Eustache, J. Org. Lett. 1999,
1, 1181–1182. (h) Yamauchi, Y.; Kawate, T.; Katagiri, T.; Uneyama, K.
Tetrahedron 2003, 59, 9839–9847.
Having developed conditions for the regioselective depro-
tonation of 1, the scope of this chemistry was explored by
trapping lithiated intermediate 3 with a variety of electro-
philes. Thus, deuteration, methylation, tributylstannylation,
benzylation, and hydroxyalkylation provided 5b-f, respec-
tively, in moderate to good yields (Table 1). Trapping with
aldehydes gave hydroxyalkyl derivatives 5 g-i in good yields
(4) Examples of lithiation/substitution of polysubstituted arylaziridines
have been reported: (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.
(5) (a) Luisi, R.; Capriati, V.; Florio, S.; Musio, B. Org. Lett. 2005, 7,
3749–3752. (b) Hodgson, D. M.; Humphreys, P. G.; Xu, Z.; Ward, J. G.
Angew. Chem., Int. Ed. 2007, 46, 2245–2248.
(10) (a) Sharpless, K. B.; Gontcharov, A. V.; Liu, H. U.S. Patent
US6008376, 1999. (b) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org.
Lett. 1999, 1, 783–786.
(6) Capriati, V.; Florio, S.; Luisi, R.; Salomone, A. Org. Lett. 2002, 4,
2445–2448.
(11) The use of trimethylsilyl chloride allowed easy separation of the
regioisomeric products 4 and 5a.
(7) (a) Breternitz, H.-J.; Schaumann, E. Tetrahedron Lett. 1991, 32,
1299–1302. (b) Aggarwal, V.; Alonso, E.; Ferrara, M.; Spey, S. E. J. Org.
Chem. 2002, 67, 2335–2344.
(12) CCDC 706652 contains the supplementary crystallographic data
for compound 4. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(8) Sun, P.; Weinreb, S. M. J. Org. Chem. 1997, 62, 8604–8608.
(9) Hodgson, D. M.; Hughes, S. P.; Thompson, A. L.; Heightman, T. D.
(13) For a review, see: Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak,
P. Angew. Chem., Int. Ed. 2004, 43, 2206–2225.
Org. Lett. 2008, 10, 3453–3456
.
326
Org. Lett., Vol. 11, No. 2, 2009

and moderate diastereoselectivity.14,15 Aminomethyl triph-
enyloxirane 7, which is most likely the result of an aza-Payne
rearrangement16 of the intermediate aziridine 6, was obtained
when lithiation of 1 was followed by trapping with ben-
zophenone.
Scheme 3. Synthesis of Optically Active Arylaziridines
Table 1. Lithiation/Electrophile Trapping of Aziridine 1
aziridine 5
electrophile (E+)
yield (%)a
drb
PhCHO to give the corresponding products (R)-5c, (R)-5f,
and diastereoisomers (1R,2′R)-5g and (1S,2′R)-5g (Scheme
3).17,18
5a
5b
5c
5d
5e
5f
5g
5h
5i
TMSCl
D2O
MeI
Bu3SnCl
PhCH2Br
(Me)2CO
PhCHO
i-PrCHO
t-BuCHO
86
88c
80
90
36
To develop a stereoselective route to optically active
trisubstituted arylaziridines and to further assess the role of
the N-Bus group in the lithiation reaction, a second func-
tionalization of 5c was investigated. Lithiation/deuteration
and lithiation/silylation sequences resulted in the formation
of N-Bus phenylaziridine 9a,b as single diastereomers (dr
>99:1) (Scheme 4). This second lithiation involves stereo-
selective deprotonation of Ha cis to the aziridine methyl group
(Scheme 4), as deduced by analysis of 1D-selective NOESY
experiments conducted on aziridine 5c.19 Equally highly
regioselective was the silylation reaction leading to aziridine
9b, whose stereochemistry was also ascertained by low
temperature 1D-selective NOESY experiments conducted on
a slowly equilibrating mixture of two nitrogen invertomers.
56
80d
55d
60d
70:30
80:20
80:20
a Isolated yields. b Diastereomeric ratio with respect to the newly created
alcohol-bearing stereogenic center, ascertained by 1H NMR analysis of the
crude product. c 97% deuterium incorporation. d Combined yield of the
separated diastereoisomers.
With a view to developing an approach to stereodefined
R,R-disubstituted aziridines using the same lithiation/elec-
trophile trapping sequence, the preparation of enantiomeri-
cally enriched N-Bus-2-phenylaziridine (R)-1 was under-
taken. This compound was prepared from (-)-phenylglycinol
by a high-yielding sequence that involved N-sulfinylation,
oxidation, O-tosylation, and cyclization (Scheme 3).
Scheme 4. Double Functionalization of Aziridine 5c
Lithiation with n-BuLi/TMEDA in Et2O at -78 °C
resulted in the generation of (R)-3, which proved to be
configurationally stable as demonstrated by comparison of
optical rotation values and HPLC analysis of deuterated
compound (R)-5b (er >98:2) with the chiral aziridine (R)-
1. In a similar way, (R)-3 reacted with MeI, Me2CO, and
(14) The structure and relative configuration of the major diastereomer
of the trapping reaction with benzaldehyde was confirmed by X-ray analysis
To further demonstrate the utility of the R,R-disubstituted
aziridines, optically active aziridine (R)-5c was subjected to
two further transformations. When it was reacted with aniline
(see Supporting Information)
.
(15) CCDC 706653 contains the supplementary crystallographic data
for compound 5g. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(16) (a) Nakai, K.; Ibuka, T.; Otaka, A.; Tamamura, H.; Fujii, N.
Tetrahedron Lett. 1995, 36, 6247–6250. (b) Ibuka, T. Chem. Soc. ReV. 1998,
27, 145–154.
(17) The enantiomeric ratios were determined by comparison with a
1
racemic sample by using chiral HPLC analysis or by H NMR analysis in
the presence of a chiral solvating agent (see Supporting Information)
.
Org. Lett., Vol. 11, No. 2, 2009
327

under microwave irradiation, sulfonamide 10 (er >99:1) was
obtained as a result of a highly regioselective benzylic ring
opening.20 Sulfonamide 10 was further subjected to Bus-
deblocking with TfOH/anisole to furnish diamine 11. In order
to confirm the regioselectivity of the ring-opening reaction,
diamine 11 was transformed into the imidazolidinone 12
upon cyclization with N,N′-carbonyldiimidazole (CDI)
(Scheme 5).21 NOE measurements conducted on 12 estab-
obtained by lithiation of (R)-5c with LTMP, which underwent
ring-opening and dimerization upon warming to 0 °C.23
In conclusion, an efficient method for a regioselective
benzylic lithiation/functionalization of 2-phenylaziridines has
been established allowing access to di- and trisubstituted
aziridines with defined stereochemistry. The use of an N-Bus
group is critical for success. Moreover, it has been shown
that enantioenriched R-lithiated N-Bus-2-phenylaziridine is
configurationally stable so that reaction with electrophiles
occurs with complete retention of configuration, giving access
to chiral R,R-disubstituted aziridines. The synthetic utility
of these aziridines has been demonstrated by the transforma-
tion of (R)-5c into 1,2- and 1,4-diamines24 by ring opening
and eliminative dimerization reactions, respectively. Work
is ongoing on the development of new synthetic strategies
based on AAM and on clarifying the role of the Bus group
on the regiochemical outcome of the reactions reported
herein.
Scheme 5. Synthesis of 1,2- and 1,4-Diamines
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 thank EPSRC (EP/C007999/1) for the provision
of mass spectrometers at the University of Warwick, and
the EPSRC X-ray Crystallographic Service for recording the
crystallographic data.
lished that aziridine opening of 5c had occurred at the
benzylic carbon without loss of stereochemical integrity (see
Supporting Information). Alternatively, by exploiting the
known carbenoidic character of lithiated aziridines, chiral
diamino alkene 1322 bearing two quaternary centers was
Supporting Information Available: Experimental pro-
cedures and compound characterization data for aziridine
5a-1, 9a,b, 10, 11, 12, and 13. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802487V
(18) The absolute configuration of (R)-5c and (R)-5f was assigned
assuming that reaction proceeds with retention of configuration [cf. (R)-
5b]. For the two diastereoisomers (1R,2′R)-5g and (1S,2′R)-5g, the absolute
configuration of the major isomer was deduced by comparison with the
spectral data of the corresponding racemic compounds (5g) for which X-ray
analysis was available (see text).
(22) The (E)-configuration was ascertained by measurement of the 3JH-H
coupling constant on the 13C satellite signals in the 1H NMR spectrum; see
Supporting Information.
(23) This reaction is the result of the carbenoidic behavior of R-hetero-
substituted carbanion; see: (a) Boche, G.; Lohrenz, J. C. W. Chem. ReV.
2001, 101, 697–756. (b) Hodgson, D. M.; Miles, S. M. Angew. Chem., Int.
Ed. 2006, 45, 935–938.
(19) The 1H NMR spectrum of deuterated aziridine 9a (%D >95%) lacks
the signal corresponding to Ha. Strong reciprocal NOEs were seen within
5c between Ha and the aziridine Me group, confirming their syn relationship
(see Supporting Information).
(24) For the usefulness of diamino compounds, see: (a) Hems, W. P.;
Groarke, M.; Zanotti-Gerosa, A.; Grasa, G. A. Acc. Chem. Res. 2007, 40,
1340–1347. (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int.
Ed. 1998, 37, 2580–2627. (c) Lake, F.; Moberg, C. Eur. J. Org. Chem.
2002, 317, 9–3188.
(20) Low levels of regioselectivity were observed in the ring-opening
reactions using aliphatic amines.
(21) Wright, W. B., Jr J. Heterocycl. Chem. 1965, 41–43.
328
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