Terminal aziridines by α-deprotonation/electrophile trapping of N-protected aziridine

Article abstract of DOI:10.1021/ol801224g

(Figure Presented) N-tert-Butylsulfonyl and N-tert-butylsulfinyl aziridine undergo α-lithiation/electrophile trapping providing a new entry to terminal aziridines. With N-tert-butylsulfinyl aziridine complete asymmetric induction is observed α; to nitrogen.

Full text of DOI:10.1021/ol801224g

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3453-3456
Terminal Aziridines by r-Deprotonation/
Electrophile Trapping of N-Protected
Aziridine
David M. Hodgson,* Steven P. Hughes, Amber L. Thompson, and
Tom D. Heightman†
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
daVid.hodgson@chem.ox.ac.uk
Received May 30, 2008
ABSTRACT
N-tert-Butylsulfonyl and N-tert-butylsulfinyl aziridine undergo r-lithiation/electrophile trapping providing a new entry to terminal aziridines.
With N-tert-butylsulfinyl aziridine complete asymmetric induction is observed r to nitrogen.
Aziridines are an important class of heterocycle currently
receiving increased research interest.1 Terminal aziridines
are particularly useful owing to the ease, generality, and
predictable regioselectivity of their ring-opening reactions
with nucleophiles.2 Currently, there are four conceptually
different synthetic routes to produce N-protected terminal
aziridines 1 (Scheme 1):1b,3 (a) ring-closure of 2-substituted
amines;4 (b) (formal) nitrene transfer to alkenes; (c) (formal)
carbene transfer to imines; and (d) additions to azirines.
Another potentially powerful strategy to terminal aziridines
1 involves R-metalation/electrophile trapping of N-protected
aziridine (strategy e, Scheme 1). One isolated example of
this latter process was described in 1994 by Beak and co-
workers, which involved silylation of N-Boc aziridine using
s-BuLi;5 however, this method was “successful only if the
electrophile, Me3SiCl, was present during the lithiation” – a
major limitation.
Scheme 1. Synthetic Strategies to Terminal Aziridines 1
† Department of Medicinal Chemistry & DMPK, Neurology & GI Centre
of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science
Park, Third Avenue, Harlow, Essex CM19 5AW, U.K.
(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.
(2) (a) Tanner, D. Angew. Chem., Int. Ed. 1994, 33, 599–619. (b)
McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365. (c) Hu, X. E.
Tetrahedron 2004, 60, 2701–2743. (d) Olsen, C. A.; Franzyk, H.; Jarosze-
wski, J. W. Eur. J. Org. Chem. 2007, 1717–1724.
Following our investigations into the direct R-deprotona-
tion/electrophile trapping of nonstabilized N-Bus (Bus ) tert-
butylsulfonyl)-protected terminal aziridines,6 we considered
whether further N-protected variants of aziridine itself could
(3) (a) Sweeney, J. B. In ref 1a, pp 117-144. (b) Osborn, H. M. I.;
Sweeney, J. B. Tetrahedron: Asymmetry 1997, 8, 1693–1715
.
(4) For a recent example, see: Hodgson, D. M.; Kloesges, J.; Evans, B.
(5) Beak, P.; Wu, S.; Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994, 59,
276–277.
Org. Lett. 2008, 10, 2781–2783.
10.1021/ol801224g CCC: $40.75
Published on Web 07/10/2008
2008 American Chemical Society

be lithiated and electrophile trapped.7 In the present paper,
we communicate our promising preliminary results on this
theme.
Table 1. Terminal Aziridines 5 by R-Lithiation of N-Bus
Aziridine 4
Initially, lithiation of N-Ts, N-Tris, and N-Boc aziridine
were investigated but, not unexpectedly, these unhindered
(C-unsubstituted) systems underwent mainly dimerization,
ring-opening, or in the N-Boc aziridine case, N-to-C migra-
tion.8 Using N-Bus aziridine 4 (readily accessed on a
multigram scale by tert-butylsulfinylation of 2-chloroethyl-
amine hydrochloride 2, followed by oxidation of the resulting
chlorosulfinamide 3 and ring-closure, Scheme 2) in combina-
Scheme 2. Synthesis of N-Bus Aziridine 4
tion with s-BuLi/TMEDA9 at low temperature did, however,
produce the first direct external electrophile trapping (deu-
teration) of a simple N-protected, C-unsubstituted aziridine,7
giving deuterated aziridine 5a (90% yield, >95% D, Table
1).
To examine the scope of this process, a range of other
electrophiles were then reacted with lithiated N-Bus aziridine
4-Li (Table 1). Me3SiCl, Bu3SnCl, and PhSO2F gave the
corresponding C-heteroatom-substituted aziridines10 5b-d
in 81%, 86%, and 51% yields, respectively (Table 1, entries
2-4). The structure of aziridinylsulfone 5d was confirmed
with single-crystal X-ray diffraction data.11 Pleasingly, both
nonenolizable and enolizable aldehydes and ketones proved
viable electrophiles to generate a range of aziridinyl alcohols
5e-j (56-96% yield). Aziridinyl ester and ketone structural
motifs 5k,l could also be accessed using methyl cyanoformate
and benzoyl cyanide as electrophiles (entries 11 and 12).12
Reactions illustrating the use of the N-Bus terminal
aziridines 5 in subsequent ring-opening chemistry giving
sulfonamides 6a-d are shown in Scheme 3. Using Grignard
and heteroatomic nucleophiles, ring-opening of aziridinyl
alcohol 5j occurred selectively at the less-hindered ring
carbon, whereas with aziridinyl ketone 5l, ring-opening took
place at the more substituted ring carbon (likely due to
transition-state stabilization by the adjacent CdO group).13
For the asymmetric synthesis of terminal aziridines by the
above strategy, we first considered modifying the chemistry
by attempting enantioselective deprotonation.7 Enantio-
selective chiral ligand-induced lithiation/electrophile trapping
of saturated N-protected heterocycles is currently well-
established only for N-Boc pyrrolidine.14 In our hands,14c
addition of N-Boc aziridine to premixed s-BuLi and (-)-
sparteine in ethereal solvents at low temperature, followed
by an electrophile, consistently resulted only in isolation of
(6) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2005, 7,
1153–1156.
(7) For (enantioselective) deprotonation-electrophile trapping of N-alkyl
aziridine borane (where the N-alkyl group can be removed by a four-step
procedure), see: (a) Vedejs, E.; Bhanu Prasad, A. S.; Kendall, J. T.; Russel,
J. S. Tetrahedron 2003, 59, 9849–9856.
(8) (a) Hodgson, D. M.; Miles, S. M. Angew. Chem., Int. Ed. 2006, 45,
935–938. (b) Hodgson, D. M.; Humphreys, P. G.; Xu, Z.; Ward, J. G.
Angew. Chem., Int. Ed. 2007, 46, 2245–2248. (c) Hodgson, D. M.;
Humphreys, P. G.; Miles, S. M.; Brierley, C. A. J.; Ward, J. G. J. Org.
Chem. 2007, 72, 10009–10021.
(9) Dimerization of R-lithiated epoxides is known to be inhibited by
TMEDA, see: (a) Lohse, P.; Loner, H.; Acklin, P.; Sternfeld, F.; Pfaltz, A.
Tetrahedron Lett. 1991, 32, 615–618.
(10) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. ReV. 2007, 107,
2080–2135.
(13) For examples of nucleophilic ring opening of aziridinyl ketones
occurring at the internal carbon, see: Kim, Y.; Ha, H.-J.; Han, K.; Ko, S. W.;
Yun, H.; Yoon, H. J.; Kim, M. S.; Lee, W. K. Tetrahedron Lett. 2005, 46,
4407–4409.
(11) See the Supporting Information for details.
(12) Attempted trapping with other electrophiles, such as allyl bromide,
BnBr, BuOTf, and MeI, has so far been unsuccessful.
3454
Org. Lett., Vol. 10, No. 16, 2008

Scheme 3
.
Ring-Opening of N-Bus Terminal Aziridines 5
Scheme 4.
Studies with N-tert-Butylsulfinyl Aziridine (RS)-723
3,5-dimethylheptan-4-one, arising from reaction of s-BuLi
at the Boc group. Adding a mixture of N-Bus aziridine 4
and Me3SiCl (1.2 equiv) dropwise via cooled cannula to a
premixed solution of s-BuLi/(-)-sparteine (1.2 equiv) in THF
at -105 °C did form aziridinylsilane 5b in 38% yield, but
with a negligible er.11 We therefore considered using a chiral
N-protecting group that might activate and bias the ring to
(highly) diastereoselective deprotonation.15 Aware of the high
levels of diastereocontrol often observed during the addition
of nucleophiles to N-tert-butylsulfinyl imines,4,16 we felt that
the tert-butylsulfinyl group might fulfill such a role.
First, a direct synthesis of N-tert-butylsulfinyl aziridine 7
in either enantiomeric form and in one step from commercial
starting materials was developed (Scheme 4).17 Deprotona-
tion of (RS)-7 using s-BuLi/TMEDA in THF at -98 °C and
trapping with CD3OD gave the anticipated 2-deuteroaziridine
8a; however, yields proved to be variable under these
conditions (potentially due to attack at the sulfinyl group by
the organolithium).18 Moving to the less nucleophilic base
LTMP (lithium 2,2,6,6-tetramethylpiperidide) in combination
with TMEDA19 improved the yields, and after a 25 min
lithiation time at -98 °C the desired 2-deuteroaziridine 8a
was generated in 81% yield with >90% D-incorporation.
Using the symmetrical ketone pentan-3-one as the electro-
phile gave aziridinyl alcohol 8b in 53% yield and, signifi-
cantly, only a single diastereomer was observed in the crude
1H and 13C NMR spectra. Analysis of single-crystal X-ray
diffraction data for aziridinyl alcohol 8b allowed the deter-
mination of the absolute configuration (RS,R), as shown in
Scheme 4.11,20 Confirmation of the highly diastereoselective
nature of the lithiation/electrophile trapping was obtained by
m-CPBA-mediated oxidation of crude aziridinyl alcohol 8b
to the N-Bus aziridinyl alcohol 5j (>99:1 er, by chiral HPLC
analysis of the 2-thionaphthalene ring-opened derivative
6c).11
Several other electrophiles were successfully trapped out
using (RS)-7-Li giving adducts 8c-g with similarly complete
control at the newly generated aziridine stereocenter (Scheme
(20) X-ray diffraction data was determined by refinement of the Flack
enantiopole parameter, see: Flack, H. D.; Bernardinelli, G. J. Appl.
(14) (a) Beak, P.; Johnson, T. A.; Kim, D. D.; Lim, S. H. In
Organolithiums in EnantioselectiVe Synthesis, Topics in Organometallic
Chemistry; Hodgson, D. M., Ed.; Springer: Berlin, 2003; Vol. 5, pp
139-176. (b) Gawley, R. E.; O’Connor, S.; Klein, R. In Science of Synthesis;
Snieckus, V., Majewski, M., Eds.; Thieme: Stuttgart, 2006; Vol. 8a, pp
677-757. (c) For a patent claiming enantioselective lithiation/trapping of
3-8-ring saturated N-Boc azacycles, see: Deng, X.; Mani, N. (Johnson &
Johnson) U.S. Pat. Appl 20060069250, 2006. For recent enantioselective
lithiation/trapping of N-Boc piperidines, see: (d) Coldham, I.; O’Brien, P.;
Patel, J. J.; Raimbault, S.; Sanderson, A. J.; Stead, D.; Whittaker, D. T. E.
Tetrahedron: Asymmetry 2007, 18, 2113–2119.
Crystallogr. 2000, 33, 1143–1148.
(21) The aziridinyl methanol motif found in 8b,d-g is currently of
interest in organocatalysts, see: (a) Bonini, B. F.; Capito`, E.; Comes-
Franchini, M.; Fochi, M.; Riccia, A.; Zwanenburg, B. Tetrahedron:
Asymmetry 2006, 17, 3135–3143. (b) Braga, A. L.; Paixa˜o, M. W.;
Westermann, B.; Schneider, P. H.; Wessjohann, L. A. J. Org. Chem. 2008,
73, 2879–2882
.
(22) Terminal aziridinyl ketone functionality is present in antimalarial
agents, see: (a) Schulz, F.; Gelhaus, C.; Degel, B.; Vicik, R.; Heppner, S.;
Breuning, A.; Leippe, M.; Gut, J.; Rosenthal, P. J.; Schirmeister, T.
ChemMedChem 2007, 2, 1214–1224
.
(15) Montagne, C.; Pre´vost, N.; Shiers, J. J.; Prie´, G.; Rahman, S.; Hayes,
J. F.; Shipman, M. Tetrahedron 2006, 62, 8447–8457.
(23) Representative procedure for lithiation/electrophile trapping of
sulfinyl anion (RS)-7-Li: n-BuLi (0.56 mL, 1.6 M in hexanes, 0.90 mmol)
was added dropwise to a stirring solution of 2,2,6,6-tetramethylpiperidine
(0.15 mL, 0.90 mmol) in THF (7 mL) at -78 °C. The solution was then
warmed to 25 °C for 20 min and then cooled to -98 °C. TMEDA (0.13
mL, 0.90 mmol) was added, followed by a solution of N-tert-butylsulfinyl
aziridine (RS)-7 (44 mg, 0.30 mmol) in THF (1 mL). After 25 min, pentan-
3-one (95 µL, 0.90 mmol) was added. After 1 h, MeOH (1 mL) was added.
The solution was warmed to 25 °C over 15 min and saturated aq NH4Cl
(15 mL) and Et2O (20 mL) added. The organic phase was separated and
the aqueous phase re-extracted with Et2O (3 × 10 mL). The combined
organic extracts were dried (MgSO4) and concentrated under reduced
pressure. The resulting residue was purified by column chromatography
(petroleum ether/Et2O, 70:30) to give (RS,R)-aziridinyl pentan-3-ol 8b as a
white solid (37 mg, 53%).
(16) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984–995. (b) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869–
8905.
(17) For a related synthesis of N-(diethoxyphosphoryl)aziridine, see:
Osowska-Pacewicka, K.; Zwierzak, A. Synthesis 1996, 333–335. The less
nucleophilic tert-butylsulfonylamide did not allow a synthesis of 4 by this
route.
(18) (a) Davis, F. A.; Liu, H.; Liang, C. -H.; Reddy, G. V.; Zhang, Y.;
Fang, T.; Titus, D. D. J. Org. Chem. 1999, 64, 8929–8935. (b) Luisi, R.;
Capriati, V.; Florio, S.; Di Cunto, P.; Musio, B. Tetrahedron 2005, 61,
´
3251–3260. (c) Arroyo, Y.; Meana, A.; Rodr´ıguez, J. F.; Santos, M.; Sanz-
Tejedor, M. A.; Garc´ıa-Ruano, J. L. Tetrahedron 2006, 62, 8525–8532.
(19) Collum, D. B. Acc. Chem. Res. 1992, 25, 448–454.
Org. Lett., Vol. 10, No. 16, 2008
3455

4).12,21 While low asymmetric induction was seen at the
carbinol carbon in the aziridinyl alcohols 8d,e arising from
addition of (RS)-7-Li to prochiral aldehydes, Swern oxidation
of 8d could be used to subsequently generate the corre-
sponding diasteromerically pure sulfinyl ketone11 in 78%
yield.22
Scheme 6
.
Ring-Opening of N-tert-Butylsulfinyl Terminal
Aziridines 8
A tentative explanation of the diastereoselectivity observed
in lithiation/electrophile trapping with N-tert-butylsulfinyl
aziridine (RS)-7 is indicated in Scheme 5. LTMP may
coordinate to the sulfinyl oxygen of (RS)-7 and form a
prelithiation complex in which a pro-R hydrogen on the
aziridine is closer than a pro-S hydrogen to the lithium amide,
thereby minimizing nonbonded interactions between the tert-
butyl group and the sterically demanding base. Following
deprotonation, the lithiated aziridine undergoes electrophile
trapping with retention of configuration.
trophile trapping of N-tert-butylsulfinyl aziridine 7 to provide
terminal aziridines 8 is notable not only for overcoming the
ring-opening and sulfenic acid elimination pathways previ-
ously observed in related systems,18a but also for the
controlled stereocenter generation adjacent to nitrogen by
electrophile incorporation. The latter suggests further op-
portunities for sulfinamide group utilization in asymmetric
synthesis beyond its current importance in sulfinyl imines
for stereocontrolled nucleophile incorporation R to nitro-
gen.16,24
Scheme 5. Possible Origin of Diastereoselectivity in the
Lithiation/Electrophile Trapping of N-tert-Butylsulfinyl Aziridine
(RS)-7
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for a CASE award (to S.P.H.), the EPSRC
National Mass Spectrometry Service Centre (Swansea) for
mass spectra, and Dr. A. Cowley (Oxford) for assistance with
the X-ray crystallography.
Reaction of aziridinyl alcohols 8b,g with 2-thionaphthalene
and PhMgBr gave secondary sulfinamides 9a,b, respectively,
illustrating regioselective ring-opening and also demonstrat-
ing that preoxidation to the more electron-withdrawing N-Bus
group is not required for such chemistry (Scheme 6). Sulfinyl
deprotection of the Grignard-derived adduct 9b using HCl
in dioxane generates 1,2-amino alcohol 10 in which the
potentially acid-sensitive tertiary alcohol functionality is
preserved.
In summary, this work demonstrates a new access to
terminal aziridines by ring-lithiation of N-sulfonyl and
N-sulfinyl protected aziridine, and the products have been
shown to undergo a range of synthetically useful ring-
opening reactions with nucleophiles. The R-lithiation/elec-
Supporting Information Available: Preparation and
characterization data for aziridines 4, 5, 7, and 8 and amines
1
6, 9, and 10, including H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801224G
(24) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z. -H.; Han, Z.; Gallou,
I. Aldrichim. Acta 2005, 38, 93–104
.
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