Unsaturated 1,2-amino alcohols and ethers from aziridines and organolithiums

Article abstract of DOI:10.1039/b409486g

Organolithium-induced ring-opening of aziridines of 2,5-dihydrofuran (5 and 8) and 1,4-dimethoxybut-2-ene (16, 17 and 23) gives 3-substituted 2-aminobut-3-en-1-ols 9-15 and amino ethers 18-20 and 24-26.

Full text of DOI:10.1039/b409486g

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Unsaturated 1,2-amino alcohols and ethers from aziridines and
organolithiums
a
David M. Hodgson,* Bogdan Stefane, Timothy J. Miles and Jason Witherington
a
a
b
ˇ
a Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road,
Oxford, UK OX1 3TA. E-mail: david.hodgson@chem.ox.ac.uk
b GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK CM19 5AW
Received (in Cambridge, UK) 24th June 2004, Accepted 20th July 2004
First published as an Advance Article on the web 24th August 2004
Organolithium-induced ring-opening of aziridines of 2,5-
steps from commercially available dihydrofuran epoxide (7),
according to Scheme 3.
dihydrofuran (5 and 8) and 1,4-dimethoxybut-2-ene (16, 17
and 23) gives 3-substituted 2-aminobut-3-en-1-ols 9–15 and
amino ethers 18–20 and 24–26.
The 1,2-amino alcohol motif is a common structural component in
bioactive natural products and many pharmaceutical agents; it is
also present in useful synthetic intermediates, auxiliaries, and
ligands in catalysis.1 Consequently, considerable importance is
attached to new methods to access this moiety. We recently
reported the reactions of organolithiums with 2,5-dihydro-pyrrole
(and -furan) epoxides 1 (X ~ NR1 or O) to give 3-substituted
1-aminobut-3-en-2-ols (and but-3-ene-1,2-diols) 2 (Scheme 1).2
Compared with epoxides, the reactions of aziridines with
organolithiums have been far less explored.3 However, tosyl-
protected aziridines have recently been shown to undergo
a-lithiation and subsequent rearrangement to give C–H insertion
products.4 The insertion of BusLi into an a-lithiated aziridine
(resulting in alkene generation, but with concomitant loss of the
amino functionality) has also been observed.5 In the present paper
we communicate the reactions of dihydrofuran aziridines (e.g. 5,
Scheme 2) with organolithiums, as a promising new strategy to
unsaturated 1,2-amino alcohols 6; the latter are regioisomeric to the
amino alcohols 2 (X ~ NR1) obtainable via Scheme 1, and offer
the additional potential of providing, after oxidation,6 access to
unsaturated a-amino acids.
Scheme 3 Reagents and conditions: i, NH4OH (35% in H2O, 13 equiv.),
PriOH, 80 uC, 12 h; ii, ButSOCl (2.2 equiv.), Et3N (2.5 equiv.), MeCN–
DMF (5 : 1), 0 uC, 5 h; iii, MCPBA (2.2 equiv.), CH2Cl2, 0 uC to 25 uC, 1 h;
iv, K2CO3 (12 equiv.), MeCN, 25 uC, 24 h.
With aziridinyltetrahydrofurans 5 and 8 in hand, a study was
undertaken of their propensity to undergo organolithium-induced
alkylative double ring-opening. Initially, addition of tosyl-protected
aziridine 5 to BunLi (3 equiv) was examined at 278 uC in three
different solvents (Et2O, THF and toluene), and pleasingly the
desired amino alcohol 9a (Scheme 4) was observed in all three cases
(in 66%, 82%,{ and 38% yields, respectively).11 The scope of the
reaction was then investigated using different types of organo-
lithiums in THF. Secondary, tertiary, aryl and heteroaryl organo-
lithiums all generated the corresponding unsaturated amino
alcohols 10a–13a in good yields. Versatile allylsilane functionality12
was also readily introduced using Me3SiCH2Li, or a combination
of an organolithium with a vinylsilane.13 Aziridine 8, bearing the
acid-labile Bus protecting group,14 also proved to be a viable
substrate with the same range of organolithiums, and in general the
yields were similar to those found with tosyl-protected aziridine 5.
Scheme 1
As both tosyl and tert-butylsulfonyl (Bus) nitrogen protection
proved useful in our earlier studies,2 the corresponding protected
aziridines were examined in the current chemistry. The tosyl-
protected aziridine 5 could not be directly prepared by Sharpless
aziridination7 of 2,5-dihydrofuran, but was readily accessed in two
steps from cis-but-2-ene-1,4-diol (3) by aziridination,7 followed by
ring-closure of the resulting aziridine diol 48 under Mitsunobu
conditions using diisopropyl azodicarboxylate (DIAD, Scheme 2).9
Since direct aziridination of diol 3 could not be achieved using
BusNClNa,10 the Bus-protected aziridine 8 was synthesised in four
Scheme 2 Reagents and conditions: i, TsNClNa (1.1 equiv.), PhMe3NBr3
(0.1 equiv.), MeCN, 25 uC, 3 d; ii, DIAD (1.5 equiv.), PPh3 (1.5 equiv.),
THF, 278 uC, 1 h, then 25 uC, 7 d; iii, RLi (see text).
Scheme 4
2 2 3 4
C h e m . C o m m u n . , 2 0 0 4 , 2 2 3 4 – 2 2 3 5
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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In contrast to dihydrofuran epoxide 1 (X ~ O), epoxides of
acyclic allylic ethers have been reported not to undergo
organolithium-induced alkylative ring-opening.2a,c This may be
due to comparatively reduced acidity at the oxiranyl carbon.15 It is
therefore also of significance that aziridines of such ethers were
found to successfully undergo this chemistry in Et2O (Scheme 5).
Both cis-aziridine 16 [prepared by methylation of aziridine diol 4
using Ag2O (3.5 equiv.), MeI (6 equiv.), Et2O, 25 uC, 2 d, 90%] and
trans-aziridine rac-17 (prepared in 42% yield by Sharpless
aziridination of trans-1,4-dimethoxybut-2-ene16) gave a range of
unsaturated amino ethers rac-18–20.
and the EPSRC National Mass Spectrometry Service Center for
mass spectra.
Notes and references
{ A solution of aziridine 5 (96 mg, 0.40 mmol) in THF (4 cm3) was added
dropwise to a stirred solution of BunLi (1.6 mol dm23 in pentane; 0.75 cm3,
1.2 mmol) at 278 uC. After 1 h at 278 uC, the reaction mixture was
allowed to warm to 0 uC over 3 h, then aq. HCl (1 mol dm3; 5 cm3) was
added. The reaction mixture was extracted with Et2O (3 6 10 cm3), the
combined organic layers dried (MgSO4) and concentrated under reduced
pressure. Purification of the residue by column chromatography [SiO2,
gradient elution 30% to 100% Et2O in light petroleum (bp 30–40 uC)] gave
amino alcohol 9a as a colourless oil (98 mg, 82%); Rf 0.15 (petrol–Et2O, 1 :
1); nmax/cm21 3502 brs, 3277 brs, 2953 m, 2929 m, 1647 w, 1598 w, 1326 m,
1159 s, 1093 m, 956 w, 901 w and 814 m; dH (400 MHz; CDCl3) 7.74 (2 H,
d, J 8.0, Ar), 7.36 (2 H, d, J 8.0, Ar), 5.59–5.30 (1 H, br, m, NH), 4.92 (1 H,
s, H of LCH2), 4.83 (1 H, s, H of LCH2), 3.81–3.75 (1 H, m, CHN), 3.62–
3.53 (2 H, m, CH2OH), 2.42 (3 H br, s, CMe and OH), 1.89–1.73 (2 H, m,
CH2), 1.29–1.05 (4 H, m, 2 6 CH2) and 0.84 (3 H, t, J 7.0, Me); dC
(100 MHz, CDCl3) 145.6 (CL), 143.5 (CSO2), 137.2 (CMe), 129.6 (CH),
127.3 (CH), 112.4 (LCH2), 64.1 (CH2OH), 59.3 (CHN), 33.1 (CH2), 29.6
(CH2), 22.3 (CH2), 21.5 (CMe) and 13.8 (CH2Me); m/z (CI1) 315 (M 1
NH41, 45%), 189 (100), 144 (52) and 112 (30); Found M 1 NH4, 315.1747.
C15H27N2O3S requires M 315.1742.
1 (a) T. Kunieda and T. Ishizuka, in Studies in Natural Product Chemistry,
ed. A. Rahman, Elsevier, Amsterdam, 1993, vol. 12, pp. 411–445;
(b) D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96, 835–
875; (c) S. C. Bergmeier, Tetrahedron, 2000, 56, 2561–2576.
2 (a) D. M. Hodgson, M. A. H. Stent and F. X. Wilson, Org. Lett., 2001,
3, 3401–3403; (b) D. M. Hodgson, T. J. Miles and J. Witherington,
Synlett, 2001, 310–312; (c) D. M. Hodgson, M. A. H. Stent and
F. X. Wilson, Synthesis, 2002, 1445–1453; (d) D. M. Hodgson,
C. R. Maxwell, T. J. Miles, E. Paruch, M. A. H. Stent,
I. R. Matthews, F. X. Wilson and J. Witherington, Angew. Chem.,
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Org. Biomol. Chem., 2003, 1, 1139–1150; (f) D. M. Hodgson,
T. J. Miles and J. Witherington, Tetrahedron, 2003, 59, 9729–9742;
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I. R. Matthews and J. Witherington, Tetrahedron, 2004, 60, 3611–3624.
3 For reviews, see: (a) T. Satoh, Chem. Rev., 1996, 96, 3303–3325;
(b) D. M. Hodgson and E. Gras, Synthesis, 2002, 1625–1642.
4 (a) O. Arjona, R. Menchaca and J. Plumet, Heterocycles, 2001, 55, 5–7;
(b) P. Mu¨ller and P. Nury, Helv. Chim. Acta, 2001, 84, 662–677;
(c) P. Mu¨ller, D. Riegert and G. Bernardinelli, Helv. Chim. Acta, 2004,
87, 227–239.
Scheme 5
Enantioselective desymmetrisation studies of aziridines 5, 8 and
16 in the presence of a chiral diamine ligand such as (2)-
sparteine2d,e,g,17 has so far only produced low levels of asymmetric
induction.18 However, tartaric acid-derived enantiopure trans-
aziridines (S,S)-17 and (S,S)-23 [both prepared by protection of
aziridine (S,S)-21]19 underwent ring-opening analogous to rac-17
(Scheme 6). Chiral HPLC analysis of (S)-18 established that no loss
of enantiopurity occurred during the alkylative ring-opening pro-
cess. This latter strategy has the potential for accessing a diverse
range of enantiopure unsaturated amino ethers.
5 P.O’Brien,C.M.RosserandD.Caine,Tetrahedron,2003,59, 9779–9791.
6 S. Flock and H. Frauenrath, Synlett, 2001, 839–841.
7 J. U. Jeong, B. Tao, I. Sagasser, H. Henniges and K. B. Sharpless, J. Am.
Chem. Soc., 1998, 120, 6844–6845.
8 K. Fuji, T. Kawabata, Y. Kiryu, Y. Sugiura, T. Taga and Y. Miwa,
Tetrahedron Lett., 1990, 31, 6663–6666.
9 D. L. Hughes, Org. React., 1992, 42, 335–656.
10 A.V.Gontcharov,H.LiuandK.B.Sharpless,Org.Lett.,1999,1,783–786.
11 p-Toluenesulfonamide was detected as a minor (v20%) side-product
(see also ref. 5).
12 T. K. Sarkar, in Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations, ed. I. Fleming, Thieme, Stuttgart, 2001,
vol. 4, pp. 837–925.
13 D. J. Ager, Org. React., 1990, 38, 1–223.
14 P. Sun, S. M. Weinreb and M. Shang, J. Org. Chem., 1997, 62,
8604–8608.
Scheme 6 Reagents and conditions: i, TsCl (1.5 equiv.), Et3N (1.5 equiv.),
MeCN, 25 uC, 18 h (83%); ii, RLi (3 equiv.), Et2O, 278 uC, 1 h, then
278 uC to 0 uC, 3 h; iii, ButSOCl (1.1 equiv.), Et3N (1.5 equiv.), THF, 0 uC,
12 h (61%); iv, MCPBA (1.1 equiv.), CH2Cl2, 0 uC, 1 h (89%).
In conclusion, we have demonstrated a new entry to acyclic
unsaturated 1,2-amino alcohols and ethers, based on the
organolithium-induced ring-opening of aziridines20 of 2,5-dihy-
drofuran and 1,4-dimethoxybut-2-enes. The work provides the first
examples of retention of the valuable amino functionality arising
from insertion of organolithiums into a-lithiated aziridines.
We thank the EPSRC for a Research Grant (GR/M72340), and
the EPSRC and GlaxoSmithKline for a CASE award (to T.J.M.),
15 K. M. Morgan and S. Gronert, J. Org. Chem., 2000, 65, 1461–1466.
16 M. Hojo, H. Aihara and A. Hosomi, J. Am. Chem. Soc., 1996, 118,
3533–3534.
17 Topics in Organometallic Chemistry: Organolithiums in Enantioselective
Synthesis, ed. D. M. Hodgson, Springer-Verlag, Heidelberg, 2003, vol. 5.
18 For example, reaction of NBus aziridine 8 with BunLi/(2)-sparteine in
Et2O at 278 uC gave amino alcohol (1)-9b (30%, 25% ee).
19 J. Hoshino, J. Hiraoka, Y. Hata, S. Sawada and Y. Yamamoto, J. Chem.
Soc., Perkin Trans. 1, 1995, 693–698.
ˇ
the European Community for a Marie Curie Fellowship (to B.S.;
program TMR under contract number HPMF-CT-2002201589),
20 For a recent review of nucleophilic ring-opening of aziridines, see:
X. E. Hu, Tetrahedron, 2004, 60, 2701–2743.
C h e m . C o m m u n . , 2 0 0 4 , 2 2 3 4 – 2 2 3 5
2 2 3 5