Asymmetric synthesis of terminal N-tert-butylsulfinyl aziridines from organoceriums and an α-chloroimine

Article abstract of DOI:10.1021/ol800961a

(Chemical Equation Presented) Addition of N-(2-chloroethylidene)-tert- butylsulfinamide to organocerium reagents in DMPU/THF (1:10) at -78°C followed by warming to 25°C provides terminal N-tert-butylsulfinyl aziridines in good yields (63-92%, nine examples) and diastereomeric ratios (85:15->99:1).

Full text of DOI:10.1021/ol800961a

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2781-2783
Asymmetric Synthesis of Terminal
N-tert-Butylsulfinyl Aziridines from
Organoceriums and an r-Chloroimine
David M. Hodgson,* Johannes Kloesges, and Brian Evans†
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
daVid.hodgson@chem.ox.ac.uk
Received April 25, 2008
ABSTRACT
Addition of N-(2-chloroethylidene)-tert-butylsulfinamide to organocerium reagents in DMPU/THF (1:10) at -78 °C followed by warming to 25 °C
provides terminal N-tert-butylsulfinyl aziridines in good yields (63-92%, nine examples) and diastereomeric ratios (85:15->99:1).
The synthetic value of aziridines conventionally resides in
their ability, usually when bearing a suitable activating/
electron-withdrawing group on nitrogen, to undergo ring-
opening with nucleophiles.1 Terminal aziridines (e.g., 3,
Scheme 1) are, arguably, the most useful aziridines of all
minal aziridines 3 (n ) 2).2 However, the use of terminal
aziridines in any of the above chemistry in the context of
asymmetric synthesis is limited because there is currently
no general, straightforward method to access highly enan-
tioenriched 2-substituted (particularly 2-alkyl-substituted)
aziridines in an efficient manner.3–6 Catalytic asymmetric
nitrene transfer to terminal alkenes may ultimately provide
one solution, but despite significant progress it is not yet a
viable route to 2-alkyl-substituted aziridines.3 Aziridination
by formal methylene transfer to imines bearing a chiral
N-activating group has been achieved using dimethylsulfo-
Scheme 1. Aziridines from Imines
(2) (a) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2005,
7, 1153–1156. (b) Hodgson, D. M.; Miles, S. M. Angew. Chem., Int. Ed.
2006, 45, 935–938. (c) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G.
Org. Lett. 2006, 8, 995–998. (d) Hodgson, D. M.; Humphreys, P. G.; Miles,
S. M.; Brierley, C. A. J.; Ward, J. G. J. Org. Chem. 2007, 72, 10009–
10021. For recent reviews, see: (e) Hodgson, D. M.; Bray, C. D.;
Humphreys, P. G. Synlett 2006, 1, 22. (f) Hodgson, D. M.; Humphreys,
because of the ease, generality, and predictable regioselec-
tivity with which they undergo such ring-openings. Recently,
our laboratory has reported several new transformations of
terminal aziridines that proceed by R-lithiation, including
trapping of electrophiles, dimerization, and intramolecular
cyclopropanation of N-Bus (Bus ) tert-butylsulfonyl) ter-
P. G.; Hughes, S. P. Pure Appl. Chem. 2007, 79, 269–280
(3) Kawabata, H.; Omura, K.; Uchida, T.; Katsuki, T. Chem. Asian J.
2007, 2, 248–256
.
.
(4) (a) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Synlett
2003, 1985, 1988. (b) For a recent review on chiral nonracemic sulfinimines,
see: Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869–8905
.
† GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road,
Stevenage, SG1 2NY, U.K.
(1) (a) Hu, X. E. Tetrahedron 2004, 60, 2701–2743. (b) Aziridines and
Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim,
2006. (c) Padwa, A. In ComprehensiVe Heterocyclic 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.
(5) For efficient resolution-based approaches to terminal aziridines from
epoxides, see: (a) Kim, S. K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2004,
43, 3952–3954. (b) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.;
Melchiorre, P.; Sambri, L. Org. Lett. 2004, 6, 3973–3975
.
(6) For a recent approach to terminal aziridines, see: Jamookeeah, C. E.;
Beadle, C. D.; Jackson, R. F. W.; Harrity, J. P. A. J. Org. Chem. 2008, 73,
1128–1130
.
10.1021/ol800961a CCC: $40.75
Published on Web 06/04/2008
2008 American Chemical Society

nium methylide (2); with N-tert-butylsulfinyl-substituted
aldimines 1, Stockman and co-workers’ observed <97.5:2.5
dr for an R-branched imine 1 (R1 ) cyclohexyl, 63% yield),
but dr fell to 90:10 for an unbranched case (1, R1 ) pentyl,
65% yield).4 De Kimpe and co-workers recently reported
an asymmetric synthesis of 2,2,3-trisubstituted aziridines by
addition of Grignard reagents to nonenolizable R-chloro
aldimines 4 (R2 ) alkyl),7 and in the present work we
describe adaptation of this chemistry using imine 4 (R2 )
H), which has resulted in a promising route to terminal
aziridines 3.
Table 1. Aziridines 7 from R-Chloroimine 5
Initial application of De Kimpe’s conditions (BuMgCl,
CH2Cl2, -78 °C) with imine 5 (Scheme 2, prepared in
Scheme 2. Organometallic Additions to R-Chloroimine 5
essentially quantitative yield from anhydrous chloroacetal-
dehyde8 and commercially available t-BuSONH2) led to
virtually no diastereoselectivity in the resulting chlorosulfi-
namide 6. Variation of the reaction conditions (solvent,
Grignard reagent)7,9,10 did not lead to a significant improve-
ment in diastereoselectivity, whereas reaction with BuLi
(THF, -78 °C) gave no discernible products.
Ellman and co-workers, in their seminal studies on
additions of organometallics to simple N-tert-butylsulfinyl-
substituted aldimines, noted in a single example (5, Me
instead of Cl) that MeCeCl2 (THF, -78 °C) was inferior to
MeMgBr (CH2Cl2, -48 °C) with respect to diastereoselec-
tivity (78:22 compared with 97:3, respectively).9 However,
encouraged by Denmark and co-workers’ earlier report on
organocerium additions to SAMP-hydrazones,11 we exam-
ined BuCeCl2 with imine 5 in THF or Et2O at -78 °C and
were pleased to observe dramatic rises in diastereoselectivity
(93:7 and 87:13, respectively). The diastereoselectivity in
THF could be further improved to >99:1 (GC analysis) by
addition of DMPU.12 Allowing a reaction under the latter
conditions to warm to room temperature led to ring-closure
and isolation of terminal aziridine 7a (Table 1, entry 1) in
86% yield and unchanged dr.
a By GC of crude reaction mixtures.
The scope of this reaction was then examined with a range
of organocerium reagents (Table 1).13 The organocerium
reagents were prepared from the corresponding organolithi-
ums and CeCl3. Alkyl and allyl cerium reagents added with
essentially complete diastereocontrol (entries 1-3).14 The
reaction was less diastereoselective for aryl, heteroaryl and
alkynyl cerium reagents (entries 4-7). Entries 3 and 5
illustrate the ability to carry additional functionality into the
aziridine 7. For entry 5, relative stereochemistry of the major
diastereomer was determined to be Rs*, R* by X-ray
crystallographic analysis.15 To demonstrate this reaction in
asymmetric synthesis, C10H21CeCl2 was added to imine (Rs)-5
(prepared as before, but using commercially available (Rs)-
t-BuSONH2) to give aziridine 7h in 78% yield and 97:3 dr
(Scheme 3). m-CPBA has previously been reported to oxidize
2,3-disubstituted N-tert-butylsulfinyl aziridines to N-Bus
(13) General Procedure. The organolithium (1.2 mmol) in THF (5 mL)
was added dropwise to a stirred slurry of CeCl3 (295 mg, 1.2 mmol) in
THF (7 mL) at -78 °C under argon. After 45 min DMPU (1.5 mL) was
added, followed after 15 min by a solution of imine 5 (181 mg, 1 mmol)
in THF (3 mL) and the reaction mixture was then allowed to warm to room
temperature overnight. Saturated aq NH4Cl (10 mL) and Et2O (5 mL) were
added, the reaction mixture filtered through a pad of Celite, and the filter
cake washed thoroughly with Et2O (3 × 10 mL). The combined organic
layers were washed with H2O (2 × 15 mL) and brine (15 mL), dried
(MgSO4) and evaporated under reduced pressure. Purification of the residue
by column chromatography (SiO2, petroleum ether/Et2O) gave the corre-
sponding aziridine 7.
(7) Denolf, B.; Mangelinckx, S.; To¨rnroos, K. W.; De Kimpe, N. Org.
Lett. 2006, 8, 3129–3132.
(8) Prepared in one-step from commercially available 4-chloro-1,3-
dioxolan-2-one, see:Gross, H.; Costisella, B. Org. Prep. Proced. Int. 1969,
1, 97–98.
(9) (a) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883–
8904. (b) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984–995
.
(10) During the course of our work, an isolated example of addition of
a Grignard reagent to imine 5 (mesitylMgBr, toluene, -78 °C) was reported
to give a single diastereomer of the corresponding chlorosulfinamide; this
might be attributable to steric effects with this particular reagent, see:
(14) Use of 10% DMPU in THF also improved the dr reported by Ellman
and co-workers in the addition of MeCeCl2 to imine 5 (Me instead of Cl)
from 78:22 (89% yield)9 to 96:4 (75% yield).
Crimmins, M. T.; Shamszad, M. Org. Lett. 2007, 9, 149–152
.
(11) (a) Denmark, S. E.; Weber, T.; Piotrowski, D. W. J. Am. Chem.
Soc. 1987, 109, 2223–2225. (b) For a review on organocerium reagents,
see: Liu, H.-J.; Shia, K.-S.; Shang, X.; Zhu, B.-Y. Tetrahedron 1999, 55,
3803–3830.
(15) For details, see Supporting Information.
ˇ
(16) (a) Hodgson, D. M.; Stefane, B.; Miles, T. J.; Witherington, J. Chem.
ˇ
Commun. 2004, 2234–2235. (b) Hodgson, D. M.; Stefane, B.; Miles, T. J.;
Witherington, J. J. Org. Chem. 2006, 71, 8510–8515. (c) Hanessian, S.;
Del Valle, J. R.; Xue, Y.; Blomberg, N. J. Am. Chem. Soc. 2006, 128,
10491–10495.
(12) Mukhopadhyay, T.; Seebach, D. HelV. Chim. Acta 1982, 65, 385–
391.
2782
Org. Lett., Vol. 10, No. 13, 2008

Scheme 3
.
Asymmetric Synthesis, Oxidation, and Deprotection
Scheme 4. Synthesis of Unsaturated N-Bus Aziridine 8i
of Aziridine 7h
(63% yield, 99:1 dr), and the latter underwent chemoselective
oxidation using cat. TPAP/NMO20 to give unsaturated N-Bus
aziridine 8i (72% yield), which has previously been converted
into the bicyclic N-Bus amine 10using LiNCy2.2c,d
In conclusion, we have developed an efficient and highly
diastereoselective access to terminal N-tert-butylsulfinyl
aziridines 7 from readily prepared t-BuSONH2-derived N-(2-
chloroethylidene)tert-butylsulfinamide (5) and a range of
organolithium-derived organoceriums. By using one of the
commercially available t-BuSONH2 enantiomers we have
also demonstrated that the chemistry provides an entry to
terminal N-Bus aziridine functionality in high er. Deprotec-
tion of a terminal N-tert-butylsulfinyl aziridine, and selective
oxidation to N-Bus aziridine functionality in the presence
of unsaturation are also noteworthy transformations which
expand the utility of the methodology.
aziridines,16 and in the present case efficient oxidation of
aziridine 7h to give known sulfonamide (R)-8h2d (87%, 96:4
er by chiral HPLC) illustrates asymmetric access to syntheti-
cally valuable terminal N-Bus aziridine functionality. The
sense of asymmetric induction found using imine 5 with both
aryl and alkyl cerium reagents parallels that observed in De
Kimpe’s study (and in other reports concerning N-sulfinyl
imines containing R-coordinating groups).7
Although deprotection of several tert-butylsulfinyl aziri-
dines have been reported, typically using HCl in dioxane,17
in our hands these methods did not prove viable with terminal
aziridines 7.18 After extensive screening, it was found that
the tert-butylsulfinyl group can be rapidly and cleanly
removed using aq HI in THF, followed by neutralization with
aq KOH (eg, 7h gave 9h in 84% yield, and 97:3 er by chiral
GC, Scheme 3).
Acknowledgment. We thank the EPSRC (DTA) and
GlaxoSmithKline for financial support of this work. We also
thank the EPSRC National Mass Spectrometry Service
Center (Swansea) for mass spectra, Dr. A. L. Thompson
(Oxford) for X-ray crystallographic analysis, Dr. C. J. R.
Bataille (Oxford) for chiral GC analysis and Dr. R. P. C.
Cousins (GlaxoSmithKline) and Prof. A. Fu¨rstner (Max-
Planck-Institut, Mu¨lheim) for useful discussions.
Finally, the chemistry can be extended to illustrate
preparation of an unsaturated N-Bus terminal aziridine
suitable for intramolecular cyclopropanation (Scheme 4).
Thus, addition of homoallylcerium dichloride (prepared from
homoallylithium)19 to imine 5 gave N-sulfinyl aziridine 7i
Supporting Information Available: Preparation and
characterization data for imine 5 and aziridines 7-9,
including 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) (a) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Org.
Lett. 2004, 6, 2377–2380. (b) Chemla, F.; Ferreira, F. J. Org. Chem. 2004,
69, 8244–3250. (c) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org. Chem.
2007, 72, 3211–3217. (d) Kokotos, C. G.; Aggarwal, V. K. Org. Lett. 2007,
9, 2099–2102.
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(19) (a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404–
5406. (b) Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990,
55, 5406–5409.
(18) The principal authors of refs 17a,c and d have accepted that their
published data for material obtained on deprotection are not consistent with
that expected for the deprotected aziridines (personal communications with
Profs. Stockman, De Kimpe, and Aggarwal).
(20) Guertin, K. R.; Kende, A. S. Tetrahedron Lett. 1993, 34, 5369–
5372.
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