Organolithium-induced alkylative ring opening of aziridines: Synthesis of unsaturated amino alcohols and ethers

Article abstract of DOI:10.1021/jo0615201

Organolithium-induced alkylative ring opening of N-sulfonyl-protected aziridinyl ethers is described. The reactions were efficiently carried out with a variety of organolithiums, providing a promising new strategy to unsaturated amino alcohols and ethers.

Full text of DOI:10.1021/jo0615201

Organolithium-Induced Alkylative Ring Opening of Aziridines:
Synthesis of Unsaturated Amino Alcohols and Ethers
David M. Hodgson,*,† Bogdan Sˇtefane,† Timothy J. Miles,† and Jason Witherington‡
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford
OX1 3TA, United Kingdom, and Neurology & GI Centre of Excellence for Drug DiscoVery,
GlaxoSmithKline, New Frontiers Science Park, Third AVenue, Harlow, Essex CM19 5AW, United Kingdom
daVid.hodgson@chem.ox.ac.uk
ReceiVed July 21, 2006
Organolithium-induced alkylative ring opening of N-sulfonyl-protected aziridinyl ethers is described.
The reactions were efficiently carried out with a variety of organolithiums, providing a promising new
strategy to unsaturated amino alcohols and ethers. Cis- and trans-1,4-dimethoxybut-2-ene-derived aziridines
were prepared, and their propensity to undergo organolithium- induced alkylative desymmetrization is
detailed. Use of a single enantiomer of the latter aziridine provides a route to enantiopure unsaturated
amino ethers.
SCHEME 1. Aziridine r-Lithiation
Introduction
On exposure to strong bases, suitably N-protected aziridines
1 (Scheme 1, PG ) protecting group) can, like their more
thoroughly investigated epoxide cousins, undergo R-metalation
(typically lithiation) of the three-membered ring.1 In the absence
of an additional anion-stabilizing substituent, the resulting ring-
metalated (carbenoid) species 22 are rather unstable, although
under certain conditions they can be trapped with electrophiles.3
The instability of these species mainly arises from the fact that
they possess a nitrogen (or oxygen) leaving group at the site of
metalation, whose R-elimination would also relieve ring strain.
Some cycloalkene-derived 2,3-disubstituted aziridines have
previously been shown on lithiation to preferentially react by
intramolecular C-H insertion,4 and we have recently utilized
the carbenoid character of lithiated terminal aziridines in
synthetically useful dimerizations5 and (with unsaturated sub-
strates) intramolecular cyclopropanations.6
The electrophilicity2 of R-lithiated aziridines (and epoxides)
also makes them potentially susceptible to insertion by an
organolithium (typically, but not always, by an excess of the
base used in the initial deprotonation). With epoxides 3 this is
now a reasonably well-studied pathway to alkenes 4 (Scheme
2),7 and as originally demonstrated by Mioskowski and co-
workers, loss of the oxygen atom (as Li2O) derived from the
* To whom correspondence should be addressed. Phone: 44-(0)1865-275697.
Fax: 44-(0)1865-285002.
† University of Oxford.
‡ GlaxoSmithKline.
(1) (a) Rubottom, G. M.; Stevenson, G. R.; Chabala, J. C.; Pascucci, V.
L. Tetrahedron Lett. 1972, 3591-3594. For recent reviews on aziridinyl
and oxiranyl anions, see: (b) Oxiranyl and aziridinyl anions as reactive
intermediates in synthetic organic chemistry. Florio, S., Ed.; Tetrahedron
2003, 59, 9683-9864. (c) Hodgson, D. M.; Bray, C. D. In Aziridines and
Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim,
2006; pp 145-184. (d) Hodgson, D. M.; Bray, C. D.; Humphreys, P. G.
Synlett. 2006, 1-22.
(2) Boche, G.; Lohrenz, J. C. W. Chem. ReV. 2001, 101, 697-756.
(3) (a) Beak, P.; Wu, S.; Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994,
59, 276-277. (b) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org.
Lett. 2005, 7, 1153-1156.
(4) (a) Arjona, O.; Menchaca, R.; Plumet, J. Heterocycles 2001, 55, 5-7.
(b) Mu¨ller P.; Nury, P. HelV. Chim. Acta 2001, 84, 662-677. (c) O’Brien,
P.; Rosser, C. M.; Caine, D. Tetrahedron 2003, 59, 9779-9791. (d) Mu¨ller,
P.; Riegert, D.; Bernardinelli, G. HelV. Chim. Acta 2004, 87, 227-239.
(5) Hodgson, D. M.; Miles, S. M. Angew. Chem., Int. Ed. 2006, 45, 935-
938.
(6) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2006, 8,
995-998.
(7) (a) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4527-
4528. (b) Doris, E.; Dechoux, L.; Mioskowski, C. Tetrahedron Lett. 1994,
35, 7943-7946. (c) Hodgson, D. M.; Fleming, M. J.; Stanway, S. J. J. Am.
Chem. Soc. 2004, 126, 12250-12251.
10.1021/jo0615201 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/05/2006
8510
J. Org. Chem. 2006, 71, 8510-8515

Organolithium-Induced AlkylatiVe Ring Opening of Aziridines
4) could not be directly prepared by Sharpless aziridination15
of commercially available 2,5-dihydrofuran, it could be obtained
in three steps by ring opening of the corresponding epoxide
1316 using aqueous ammonium hydroxide to give the amino
alcohol 1417 (95%), which was subsequently N-tosylated (89%)
and the resulting hydroxy sulfonamide 15 cyclized (92%) under
Mitsunobu conditions18 with diisopropyl azodicarboxylate (DIAD).
A more concise (two-step) approach, which also used a cheaper
starting material, proceeded from cis-but-2-ene-1,4-diol (17) by
aziridination15 (54%),19 followed by Mitsunobu ring closure of
the resulting aziridine diol 1820 (68%).
SCHEME 2. Alkenes from Epoxides Using Organolithiums
SCHEME 4. Synthesis of NTs Aziridine 16a
three-membered heterocycle can be avoided if a suitably
positioned (and better) leaving group is present in the substrate
(e.g., 5 f 6).8 We have previously developed this process further
with epoxides of 2,5-dihydro-pyrrole (and -furan) 7 (PG )
protecting group), in which the leaving group involved in alkene
formation is not lost from the product, resulting in routes to
3-substituted 1-aminobut-3-en-2-ols (and but-3-ene-1,2-diols)
8.9
Arising from these latter studies, we considered whether the
corresponding dihydrofuranyl aziridines 9 might react similarly
to provide synthetically valuable10 unsaturated 1,2-amino alco-
hols 10 (Scheme 3); the latter are regioisomeric to the amino
alcohols 8 (X ) NPG) previously obtainable, with the additional
potential of accessing R-amino acids following oxidation.11 In
the present paper, we detail our studies on the scope of this
process, which provides a versatile route to unsaturated 1,2-
amino alcohols. At the outset of our investigations there was a
single example of insertion of an organolithium into an
R-lithiated (tosyl-protected) aziridine (Scheme 3).4c However,
in that case alkene generation occurred from aziridine 11 with
concomitant loss of the valuable amino functionality (as TsNH2)
to give cyclopentene 12. Following our initial communication
in this area,12 O’Brien and co-workers subsequently reported
related chemistry to give substituted cyclic unsaturated amines,
following adaptation of the Mioskowski-type process to aziri-
dines.13
a Reagents and conditions: (a) NH4OH (35% in H2O, 13 equiv), i-PrOH,
80 °C, 12 h (95%); (b) TsCl (1.1 equiv), Et3N (2 equiv), MeCN, 0 °C, 2 h
(89%); (c) DIAD (1.5 equiv), Ph3P (1.5 equiv), THF, -78 °C, 1 h, then
-30 °C, 5 h (92%); (d) TsNClNa (1.1 equiv), PhMe3NBr3 (0.1 equiv),
MeCN, 25 °C, 24 h (54%); (e) DIAD (1.5 equiv), Ph3P (1.5 equiv), THF,
-78 °C 1 h, then 25 °C, 7 d (68%).
As direct aziridination of diol 17 could not be achieved using
BusNClNa,21 the Bus-protected aziridine 20 was synthesized
as shown in Scheme 5. Sulfinylation of amino alcohol 14 using
(8) (a) Dechoux, L.; Doris, E.; Mioskowski, C. Chem. Commun. 1996,
549-550. (b) Doris, E.; Dechoux, L.; Mioskowski, C. Synlett 1998, 337-
343.
(9) (a) Hodgson, D. M.; Stent, M. A. H.; Wilson, F. X. Org. Lett. 2001,
3, 3401-3403. (b) Hodgson, D. M.; Miles, T. J.; Witherington, J. Synlett
2002, 310-312. (c) Hodgson, D. M.; Stent, M. A. H.; Wilson, F. X.
Synthesis 2002, 1445-1453. (d) Hodgson D. M.; Maxwell, C. R.; Miles,
T. J.; Paruch, E.; Stent, M. A. H.; Matthews, I. R.; Wilson, F. X.;
Witherington, J. Angew. Chem., Int. Ed. 2002, 41, 4313-4316. (e) Hodgson
D. M.; Stent M. A. H.; Sˇtefane B.; Wilson F. X. Org. Biomol. Chem. 2003,
1, 1139-1150. (f) Hodgson, D. M.; Miles, T. J.; Witherington, J.
Tetrahedron 2003, 59, 9729-9742. (g) Hodgson, D. M.; Maxwell, C. R.;
Miles, T. J.; Paruch, E.; Matthews, I. R.; Witherington, J. Tetrahedron 2004,
60, 3611-3624.
(10) (a) Kunieda, T.; Ishizuka, T. In Studies in Natural Products
Chemistry; Rahman, A., Ed.; Elsevier: Amsterdam, 1993; Vol. 12, pp 411-
445. (b) Ager, D. J.; Prakash,.I.; Schaad, D. R. Chem. ReV. 1996, 96, 835-
875. (c) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576.
(11) Flock, S.; Frauenrath, H. Synlett 2001, 839-841.
(12) Hodgson, D. M.; Sˇtefane, B.; Miles, T. J.; Witherington, J. Chem.
Commun. 2004, 2234-2235.
SCHEME 3. Alkenes from Aziridines Using Organolithiums
(13) Rosser, C. M.; Coote, S. C.; Kirby, J. P.; O’Brien, P.; Caine, D.
Org. Lett. 2004, 6, 4817-4819.
(14) Sun, P.; Weinreb, S. M.; Shang, M. Y. J. Org. Chem. 1997, 62,
8604-8608.
(15) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844-6845.
(16) Barili, P. L.; Berti, G.; Mastrorilli, E. Tetrahedron 1993, 49, 6263-
6265.
Results and Discusion
(17) Reppe, W. Liebigs Ann. Chem. 1955, 596, 1-224.
(18) Smith, P. W.; Whittington, A. R.; Cobley, K. N.; Jaxa-Chamiec,
A.; Finch, H. J. Chem. Soc., Perkin Trans. 1 2001, 21-25.
(19) No improvement in yield was observed using TsNBrNa (Chanda,
B. M.; Vyas, R.; Bedekar, A. V. J. Org. Chem. 2001, 66, 30-34) instead
of TsNClNa.
(20) Fuji, K.; Kawabata, T.; Kiryu, Y.; Sugiura, Y.; Taga, T.; Miwa, Y.
Tetrahedron Lett. 1990, 31, 6663-6666.
(21) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1,
783-786.
To begin to examine our above strategy to unsaturated amino
alcohols 10, we required access to suitably protected aziridines
9. Both tosyl and acid-labile tert-butylsulfonyl (Bus)14 nitrogen
protection have proven useful in many of our other base-induced
transformations of epoxides and aziridines,3b,5,6,9 and the cor-
responding protected aziridines were examined in the current
chemistry. Although the tosyl-protected aziridine 16 (Scheme
J. Org. Chem, Vol. 71, No. 22, 2006 8511

Hodgson et al.
SCHEME 5. Synthesis of NBus Aziridine 20a
cessful reaction with aziridine 16. With 4,5-dihydrofuran-2-
yllithium, a subsequent spirocyclization occurred presumably
during workup to give spiroketal 27a as a 1.7:1 mixture of
diastereomers. Given the utility of allylsilanes in synthesis,23
the direct formation of allylsilane 31a using commercially
available Me3SiCH2Li is noteworthy. Formation of allylsilane
32a makes use of the addition of organolithiums to vinylsilane
to give substituted R-silyl anions,24 and in the present case
allows a straightforward approach for the preparation of more
substituted allylsilanes.
a Reagents and conditions: (a) t-BuSOCl (2.2 equiv), Et3N (2.5 equiv),
MeCN-DMF (5:1), 0 °C, 5 h; (b) MCPBA (2.2 equiv), CH2Cl2, 0 to 25 °C,
1 h (63% over two steps); (c) K2CO3 (12 equiv), MeCN, 25 °C, 24 h (86%).
t-BuSOCl21 gave, following oxidation (MCPBA) of the crude
N,O-bis-tert-butylsulfinyl intermediate, the N,O-Bus-protected
amino alcohol 19 (63% from 14). Cyclization of the latter using
K2CO3 gave the N-Bus-protected aziridine 20 (86%). An
alternative three-step procedure to Bus-protected aziridine 20
that proceeds by ring opening of epoxide 13 with BusNH2 has
recently been reported.22
Initially, addition of tosyl-protected aziridine 16 to n-BuLi
(3 equiv) was examined in three different solvents (Et2O, THF,
and toluene) at -78 °C (1 h, followed by warming to 0 °C
over 3 h). In all three cases the desired amino alcohol 21a was
observed, in 66%, 82%, and 38% yields, respectively (Scheme
6); TsNH2 was also detected as a minor (<20%) side product.4c
The amount of TsNH2 observed was not reduced if either the
order of addition was reversed, i.e., by dropwise addition of
n-BuLi to a solution of the aziridine 16, or if only 2 equiv of
n-BuLi was used. The scope of the reaction was then investi-
gated using a variety of organolithiums under the initial
conditions in THF (Scheme 6). Although reaction of aziridine
16 with MeLi gave mainly rearranged N-tosyl 2,3-dihydro-furan-
3-amine (45%), along with some of the desired amino alcohol
22a (28%, Scheme 6), no rearranged allylic amine was isolated
from reactions with other organolithiums. Secondary, tertiary,
vinyl, aryl, and heteroaryl organolithiums all underwent suc-
Reaction of organolithiums with Bus-protected aziridine 20
showed a reaction profile similar to that observed with the tosyl-
protected aziridine 16 (Scheme 6), although the yields were more
sensitive to the reaction conditions. With less basic and more
nucleophilic organolithiums (e.g., TMSCH2Li), complete con-
sumption of aziridine 20 required longer reaction times as well
as warming to higher reaction temperatures (-78 to -30 °C).
To investigate the effect of the structure of the achiral
aziridine on the alkylative ring-opening process, we also
examined a non-ring-fused aziridine 33 (prepared by methylation
of aziridine diol 18, Scheme 7).
cis-Aziridine 33 displayed a useful reactivity profile, provid-
ing access to a range of unsaturated amino ethers 34-40. Et2O
is the preferred solvent, as reactions in THF did not always
proceed to completion. Interestingly, no loss of alkene geometry
was observed in the formation of diene 38 from Z-1-propenyl-
lithium. This suggests that the putative tertiary organolithium
intermediate 42 (R ) Z-CdCHMe) generated from the lithiated
aziridine 41 (possibly by a 1,2-metalate shift,2,25 as shown in
Scheme 8) undergoes elimination with loss of MeOLi to the
alkene 43 more rapidly than isomerization by allylic Li
transposition.
SCHEME 6. Organolithium-Induced Alkylative Ring Opening of Aziridines 16 and 20
8512 J. Org. Chem., Vol. 71, No. 22, 2006

Organolithium-Induced AlkylatiVe Ring Opening of Aziridines
SCHEME 7. Preparation and Alkylative Ring Opening of
cis-Aziridine 33
these conditions also resulted in recovery of 16. With sparteine
44, prolonged reaction time (48 h at -78 °C) did result in
consumption of aziridine 16, to give TsNH2 (41%) and
isomerization27 to (S)-N-Ts 2-amino-3-butyn-1-ol (45)28 (29%,
31% ee, Scheme 9). Under the same conditions, Bus-protected
aziridine 20 did give some of the desired unsaturated amino
alcohol (R)-21b29 (30% yield, 25% ee), along with alkyne 46
(43%, 8% ee); compared to sparteine, the use of other ligands
gave amino alcohol 21b in significantly improved yields but
lower ee’s.29 With n-BuLi and sparteine 44, cis-aziridine 33
gave only 6% of unsaturated amino ether (S)-34 (30% ee).29
Interestingly, with sparteine the sense of asymmetric induction
in the R-deprotonation of tosyl-protected aziridines 16 and 33
is the same as that observed by Mu¨ller with other tosyl-protected
achiral aziridines,4 whereas the opposite sense of induction seen
for Bus-protected aziridine 20 is the same as that found using
16 (when Ts ) 2,4,6-triisopropylbenzenesulfonyl).27
SCHEME 8. Possible Reaction Pathway for Alkylative Ring
Opening Process
Due to the limitations found above for enantioselective
synthesis with an external chiral ligand induction strategy, we
considered an alternative asymmetric entry using desymmetri-
zation of C2-symmetric aziridines. First, we established the
viability of alkylative ring opening of such a trans aziridine,
49, in the racemic sense, obtaining unsaturated amino ethers
34, 39, and 40 in good yields (Scheme 10).
The results with cis-aziridine 33 are noteworthy given that
the corresponding epoxides of acyclic allylic ethers have been
reported not to undergo organolithium-induced alkylative ring
opening.9a,c It is evident that the aziridine does not need to be
fused to a (five-membered) ring to allow the chemistry to
proceed satisfactorily.
In seeking to extend the above alkylative ring-opening
reaction of aziridines to provide enantioenriched unsaturated
amino alcohols and ethers, we initially investigated enantiose-
lective desymmetrization of aziridines 16 and 20 in the presence
of (-)-sparteine 44 as an external chiral ligand (Scheme 9).26
However, application of typical conditions [dropwise addition
of a solution of aziridine 16 to a preformed complex of n-BuLi
and sparteine 44 (3 equiv each) at -78 °C in Et2O for 1 h,
followed by slow warming over 3 h to 0 °C] gave no amino
alcohol 21a; instead, starting aziridine 16 was recovered (60-
70% yield), along with a small amount of TsNH2 (∼10%). Using
the (achiral) diamine TMEDA (3 equiv) as an additive under
Encouraged by the results with racemic trans aziridine 49,
we undertook syntheses of enantiopure aziridines (S,S)-49 and
(S,S)-53 (Scheme 11). L-Tartaric acid was converted to cyclic
sulfate 50 in 54% overall yield, following literature precedent.30
Shi et al.30d described the formation of aziridine 51 from cyclic
sulfate 50 by a two-step procedure involving ring opening with
LiN3, followed by LiAlH4 reduction-cyclization in a moderate
40% overall yield. The low yield for this transformation, together
with the use of LiN3, prompted us to develop an alternative
method. Thus, treatment of cyclic sulfate 50 with i-PrOH-NH4-
OH solution (sealed tube, 80 °C, 8 h) resulted in the formation
of an aminosulfate, which was subsequently cyclized using
31
LiAlH4 to aziridine 51 in excellent yield. Protection of
aziridine 51 resulted in the formation of aziridines (S,S)-49 and
(S,S)-53, and the latter underwent alkylative ring opening in
good yields (Scheme 11). Chiral HPLC analyses of unsaturated
SCHEME 9. Influence of (-)-Sparteine (44) with Aziridines 16 and 20
SCHEME 10. Preparation and Alkylative Ring Opening of trans-Aziridine 49a
a Reagents and conditions: (a) MeI (5 equiv), NaH (2.4 equiv), THF, 0 °C 1 h, then 25 °C 24 h, 86%; (b) TsNClNa (1.1 equiv), PhMe3NBr3 (0.1 equiv),
MeCN, 25 °C, 3 d, 42%; (c) RLi (3 equiv), Et2O, -78 °C, 1 h, then -78 to 0 °C, 3 h.
J. Org. Chem, Vol. 71, No. 22, 2006 8513

Hodgson et al.
SCHEME 11. Synthesis of Enantiopure Unsaturated Amino
Ethersa
trans-4-Aminotetrahydro-3-furanol (14).17 A solution of 3,6-
dioxabicyclo[3.1.0]hexane (13)16 (1.50 g, 17.5 mmol) in i-PrOH
(5 mL) was added to NH4OH (25 mL, 35% in water, 0.23 mol).
The mixture was then heated with stirring in a sealed tube at 80
°C. After 12 h, the mixture was cooled and evaporated under
reduced pressure, to give amino alcohol 14 (1.72 g, 95%), which
was used without further purification: νmax/cm-1 (film) 3345br,
2952w, 28882w, 1601m, 1472m, 1069m, 1045m, 973m, 893m; 1H
NMR (400 MHz, CDCl3) δ 3.86-3.79 (m, 3H), 3.44 (dd, 1H, J )
8.5, 1.5 Hz), 3.31 (dd, 1H, J ) 8.5, 2.5 Hz), 3.14-3.12 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 77.7, 73.5, 73.1, 59.1.
trans-N-(4-Hydroxytetrahydrofuran-3-yl)-4-methylbenzene-
sulfonamide (15). To a solution of amino alcohol 14 (1.88 g, 18.3
mmol) in dry MeCN (50 mL) was added TsCl (3.83 g, 20.1 mmol).
The resulting solution was cooled to 0 °C, and then Et3N (5.0 mL,
35.6 mmol) was added. After 2 h, the mixture was evaporated under
reduced pressure, and the residue diluted with water (40 mL) and
extracted with EtOAc (6 × 30 mL). The combined organic extracts
were dried (MgSO4), evaporated under reduced pressure, and
recrystallized (EtOAc-petroleum ether) to give the hydroxy
sulfonamide 1522 as a white solid (3.87 g, 89%): Rf 0.20 (EtOAc-
petroleum ether, 3:2); mp 98-99 °C (lit.22 80-82 °C); νmax/cm-1
(KBr) 3303br, 3164br, 2887m, 1596w, 1469m, 1338s, 1277m,
1217m, 1160s, 1088s, 1063s, 995s, 972m, 884s, 812s, 736br, 657m,
a Reagents and conditions: (a) NH4OH, (25%, H2O, 13.5 equiv), THF,
80 °C, 8 h, 94%; (b) LiAlH4 (1.1 equiv), THF, 25 °C, 12 h, 85%; (c) TsCl
1.1 equiv), Et3N (1.5 equiv), MeCN, 25 °C, 18 h, 82%; (d) t-BuSOCl (1.1
equiv), Et3N (1.5 equiv), THF, 0 °C 1 h, then 25 °C, 12 h, 61%; (e) MCPBA
(1.1 equiv), CH2Cl2, 0 to 25 °C, 3 h, 89%; (f) RLi (3 equiv), Et2O, -78
°C, 1 h, then -78 to 0 °C, 3 h, HCl (1 M) (5 equiv).
1
565s; H NMR (400 MHz, DMSO-d6) δ 7.84 (bd, 1H, J ) 6.0
Hz), 7.71-7.69 (m, 2H), 7.41-7.39 (m, 2H), 5.21 (bd, 1H, J )
4.0 Hz), 3.99-3.97 (m, 1H), 3.76 (dd, 1H, J ) 4.5, 9.5 Hz), 3.69
(dd, 1H, J ) 5.0, 9.0 Hz), 3.43 (dd, 1H, J ) 1.5, 9.5 Hz), 3.40-
3.33 (m, 2H), 2.39 (s, 3 H); 13C NMR (100 MHz, DMSO-d6) δ
142.7, 137.9, 129.6, 126.5, 74.8, 73.0, 70.5, 60.6, 20.9; m/z [CI +
(NH3)] 275 (M + NH4+, 100%), 240 (M + H+ - H2O, 90), 86
(30). Found: M + H+ - H2O, 240.0694; C11H14NO3S requires
240.0694.
amino ethers (S)-34 and (S)-39 established that no loss of
enantiopurity occurred during the alkylative ring-opening
process.
Conclusions
Alkylative and arylative double ring opening of 2,5-dihydro-
furan-derived aziridines is shown to proceed by intermolecular
C-C bond-forming reaction with co-generation of unsaturation
and the reorganization of two functional groups, leading to
nucleophile incorporation at a vinylic position as well as the
synthetically valuable 1,2-amino alcohol functionality. Extension
of this methodology to acyclic examples broadens the synthetic
applicability and with enantiomerically pure C2-symmetric
aziridines provides access to substituted allylic amino ethers in
enantiopure form.
(Z)-2,3-Bis(hydroxymethyl)-1-[(4-methylbenzene)sulfonyl]-
aziridine (18). To a solution of commercial (Z)-2-butene-1,4-diol
(17) (0.530 g, 6.02 mmol) and anhydrous chloramine-T (1.50 g,
6.60 mmol) in dry MeCN (30 mL) was added PTAB (0.23 g, 0.60
mmol) at room temperature. After stirring for 24 h, the reaction
mixture was filtered, concentrated to ∼1/3 volume, then cooled in
a refrigerator (at 0 °C for 24 h), and filtered to give a white solid,
aziridine diol 1820 (0.70 g, 45%). The filtrate was evaporated under
reduced pressure and purified by column chromatography (EtOAc)
yielding additional aziridine diol 18 (0.16 g, 9%): Rf 0.27 (EtOAc);
mp 119-121 °C; νmax/cm-1 (KBr) 3335br, 3232br, 3051w, 2931w,
1596m, 1452m, 1395w, 1325s, 1237m, 1162s, 1091m, 1046s, 947s,
863w, 815m, 730s, 675s, 572s, 544s; 1H NMR (400 MHz, CDCl3)
δ 7.68-7.62 (m, 2H), 7.25-7.21 (m, 2H), 4.05 (bs, 2H), 3.87-
3.66 (m, 4H), 3.17-3.06 (m, 2H), 2.46 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 144.5, 134.4, 129.6, 127.8, 58.3, 43.8, 21.5; m/z
[CI + (NH3)] 275 (M + NH4+, 15%), 258 (M + H+, 35), 108
(100), 104 (40), 91 (50), 86 (45), 72 (60). Found: MH+, 258.0800;
C11H16NO4S requires 258.0799. Anal. Calcd for C11H15NO4S: C,
51.35; H, 5.88; N, 5.44. Found: C, 51.31; H, 5.93; N, 5.48.
6-[(4-Methylbenzenel)sulfonyl]-3-oxa-6-azabicyclo[3.1.0]-
hexane (16). Procedure A: To a stirred solution of PPh3 (3.06 g,
11.7 mmol, 1.5 equiv) in THF (50 mL) at -78 °C under argon
was added DIAD (2.30 mL, 11.7 mmol, 1.5 equiv) dropwise over
30 min. The reaction mixture was stirred for 30 min until a pale
yellow suspension formed. A solution of hydroxy sulfonamide 15
(2.00 g, 7.8 mmol) in THF (10 mL) was added dropwise, and the
reaction mixture was stirred at -78 °C for 1 h and then at -30 °C
for 6 h. The reaction mixture was then filtered and evaporated under
reduced pressure, and the residue was purified by column chro-
matography (petroleum ether-EtOAc, 3:2) to give the N-Ts
aziridinyltetrahydrofuran 1622 (1.71 g, 92%): Rf 0.37 (petroleum
ether-EtOAc, 1:1); mp 117-117.5 °C (lit.22 96-98 °C); νmax/cm-1
(KBr) 2956w, 2868w, 1323m, 1159s, 1093m, 1077m, 10007w,
962m, 897m, 876m, 848w, 816w, 716m; 1H NMR (400 MHz,
CDCl3) δ 7.86-7.84 (m, 2H), 7.36-7.34 (m, 2H), 4.00 (s, 1H),
Experimental Section
General experimental details are described in Supporting Infor-
mation.
(22) Huang, J.; O’Brien, P. Synthesis 2006, 425-434.
(23) Fleming, I.; Dunogue`s, J.; Smithers, R. Org. React. 1989, 37, 57-
575.
(24) Ager, D. J. Org. React. 1990, 38, 1-223.
(25) Kasatkin, A. N.; Whitby, R, J. Tetrahedron Lett. 2000, 41, 5275-
5280.
(26) For a review, see: Topics in Organometallic Chemistry: Organo-
lithiums in EnantioselectiVe Synthesis; Hodgson, D. M., Ed.; Springer:
Heidelberg, 2003; Vol. 5.
(27) Huang, J.; O’Brien, P. Chem. Commun. 2005, 5696-5697.
(28) Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T. J.
Am. Chem. Soc. 2004, 126, 8744-8754.
(29) See Supporting Information for details.
(30) (a) Seebach, D.; Kalinowski, H.-O.; Bastani, B.; Crass, G.; Daum,
H.; Doerr, H.; DuPreez, N. P.; Ehrig, V.; Langer, W.; Nussler, C.; Oei,
H.-A.; Schmidt, M. HelV. Chim. Acta 1977, 60, 301-325. (b) Mash, E. A.;
Nelson, K. A.; Van Deusen, S.; Hemperly, S. B. Organic Syntheses;
Wiley: New York, 1993; Collect. Vol. VIII, pp 155-158. (c) Hoshino, J.;
Hiraoka, J.; Hata, Y.; Sawada, S.; Yamamoto, Y. J. Chem. Soc., Perkin
Trans. 1 1995, 693-697. (d) Shi, M.; Jiang, J.-K.; Feng, Y.-S. Tetrahe-
dron: Asymmetry 2000, 11, 4923-4933.
(31) Lohray, B. B.; Gao Y.; Sharpless, K. B. Tetrahedron Lett. 1989,
30, 2623-2626.
8514 J. Org. Chem., Vol. 71, No. 22, 2006

Organolithium-Induced AlkylatiVe Ring Opening of Aziridines
3.98 (s, 1H), 3.72-3.69 (m, 2H), 3.66 (s, 2H), 2.44 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 144.7, 135.1, 129.7, 127.8, 67.8, 44.8,
21.6; m/z [CI + (NH3)] 257 (M + NH4+, 100%), 240 (M + H+,
90), 204 (15), 86 (30). Found: MH+, 240.0694; C11H14NO3S
requires 240.0694. Anal. Calcd for C11H13NO3S: C, 55.21; H, 5.48;
N, 5.85. Found: C, 55.10; H, 4.98; N, 6.10. Procedure B: To a
stirred solution of PPh3 (1.53 g, 5.84 mmol, 1.5 equiv) in THF (15
mL) at -78 °C under argon was added DIAD (1.18 g, 5.84 mmol,
1.5 equiv) dropwise over 15 min. The reaction mixture was stirred
for a further 30 min until a pale yellow suspension formed. A
solution of aziridine diol 18 (1.00 g, 3.89 mmol) in THF (5 mL)
was then added dropwise, and the reaction mixture was stirred at
-78 °C for 1 h and then allowed to attain room temperature. After
7 d, the reaction mixture was then filtered and evaporated under
reduced pressure, and the residue purified by column chromatog-
raphy (petroleum ether-EtOAc, 3:2) to give the N-Ts aziridinyltet-
rahydrofuran 16 (0.63 g, 68%). Data as for procedure A above.
trans-4-[(tert-Butylsulfonyl)amino]tetrahydrofuran-3-yl 2-me-
thylpropane-2-sulfonate (19). To an ice-cold solution of amino
alcohol 14 (1.00 g, 9.71 mmol) and Et3N (2.35 g, 23.3 mmol) in
MeCN (50 mL) and DMF (10 mL) was added dropwise tert-
butylsulfinyl chloride21 (3.00 g, 21.4 mmol). After 5 h at 0 °C, the
mixture was diluted with saturated aqueous NaHCO3 (100 mL).
The aqueous layer was extracted with CH2Cl2 (5 × 50 mL). The
combined organic extracts were dried (Mg2SO4) and concentrated
under reduced pressure. To a solution of the residue (1.93 g) in
CH2Cl2 (100 mL) at 0 °C was added MCPBA (6.14 g, 60% w/w,
21.4 mmol) in five portions, and the reaction mixture was then
allowed to reach room temperature over 1 h. The reaction mixture
was then diluted with a mixture of saturated aqueous NaHSO3 (50
mL) and saturated aqueous NaHCO3 (50 mL), and the aqueous layer
extracted with CH2Cl2 (5 × 50 mL). The combined organic layers
were dried (Mg2SO4) and concentrated under reduced pressure. The
residue was slurried in Et2O (20 mL) and filtered, giving the N,O-
Bus-protected amino alcohol 19 (2.10 g, 63%): mp 153-154 °C;
ν
max/cm-1 (KBr) 2982w, 2869w, 1478w, 1383w, 1305s, 1191w,
1
1128s, 1076m, 1009w, 956m 895m, 715m; H NMR (400 MHz,
CDCl3) δ 4.07-4.05 (m, 2H), 3.77-3.74 (m, 2H), 3.62 (bs, 2H),
1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 67.8, 59.5, 44.2, 24.0;
m/z [CI + (NH3)] 223 (M + NH4+, 100%), 86 (30). Found: M +
NH4+, 223.1111; C8H19N2O3S requires 223.1115.
General Procedure for Organolithium-Induced Alkylative
Double Ring Opening of N-Ts Aziridinyltetrahydrofuran 16 in
THF. A solution of aziridine 16 (0.096 g, 0.40 mmol) in THF (4
mL) was added dropwise to a stirred solution of an organolithium
(3 equiv) at -78 °C. After 1 h at -78 °C, the reaction mixture
was allowed to warm to 0 °C over a period of 3 h and then quenched
by addition of aqueous HCl (5 mL, 1 mol dm-3) or, in the cases of
[(trimethylsilyl)methyl]lithium and [1-(trimethylsilyl)hexyl]lithium,
by addition of saturated aqueous NH4Cl (3 mL). The reaction
mixture was extracted with Et2O (5 × 15 mL), and the combined
organic layers were dried (MgSO4) and evaporated under reduced
pressure. The residue was then purified by column chromatography
(SiO2).
N-[2-Butyl-1-(hydroxymethyl)prop-2-enyl]-4-methylbenzene-
sulfonamide (21). Following the general procedure above using
n-BuLi (0.75 mL, 1.6 mol dm-3 in pentane, 1.2 mmol) gave after
purification by column chromatography (EtOAc-petroleum ether,
2:3) a colorless oil, the amino alcohol 21 (98 mg, 82%): Rf 0.22
(EtOAc-petroleum ether, 2:3); νmax/cm-1 (film) 3502br, 3277br,
2953m, 2929m, 1647w, 1598w, 1326m, 1159s, 1093m, 956w,
1
901w, 814m; H NMR (400 MHz, CDCl3) δ 7.76-7.74 (m, 2H),
7.30-7.28 (m, 2H), 5.33 (d, 1H, J ) 7.5 Hz), 4.91 (s, 1H), 4.85
(s, 1H), 3.80-3.75 (m, 1H), 3.59-3.58 (m, 2H), 2.42 (s, 3H), 2,-
26 (bs, 1H), 1.83-1.79 (m, 2H), 1.26-1.13 (m, 4H), 0.82 (t, 3H,
J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 145.6, 143.5, 137.2,
129.6, 127.3, 112.4, 64.1, 59.3, 33.1, 29.6, 22.3, 21.5, 13.8; m/z
[CI + (NH3)] 315 (M + NH4+, 45%), 189 (100), 144 (52), 112
(30). Found: M + NH4+, 315.1747; C15H27N2O3S requires 315.1742.
ν
max/cm-1 (KBr) 3266br, 2992m, 2942m, 1482m, 1458m, 1338s,
Acknowledgment. We thank the EPSRC for a Research
Grant (GR/M72340), the EPSRC and GlaxoSmithKline for a
CASE award (to T.J.M.), and the European Community for a
Marie Curie Fellowship (to B.Sˇ.; program TMR under contract
number HPMF-CT-2002201589). We also thank the EPSRC
National Mass Spectrometry Service Center Swansea for mass
spectra, Dr. A. Cowley for X-ray crystallographic analyses and
Dr. P. O’Brien (York) for a sample of ligand (+)-L2.
1309s, 1212w, 1146s, 1112s, 1081s, 1045m, 1011m, 958s 895s,
818m, 767m, 672s; 1H NMR (400 MHz, CDCl3) δ 5.13-5.11 (m,
1H), 4.69 (bd, 1H, J ) 9.0 Hz), 4.20-4.16 (m, 2H), 4.09 (dd, 1H,
J ) 9.5, 5.0 Hz), 3.94 (dd, 1H, J ) 11.0, 2.5 Hz), 3.79 (dd, 1H, J
) 9.5, 2.5 Hz), 1.48 (s, 9H), 1.42 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 82.8, 72.5, 71.7, 60.4, 60.2, 59.7, 24.3, 24.2; m/z [CI +
(NH3)] 361 (M + NH4+, 80%), 223 (100), 206 (70). Found: M +
NH4+, 361.1463; C12H29N2O6S2 requires 361.1462.
6-(tert-Butylsulfonyl)-6-aza-3-oxabicyclo[3.1.0]hexane (20). To
a solution of N,O-Bus-protected amino alcohol 19 (0.10 g, 0.30
mmol) in MeCN (10 mL) was added K2CO3 (0.5 g, 3.6 mmol) at
room temperature. After 24 h, the reaction mixture was filtered
and evaporated under reduced pressure. The residue was dissolved
in EtOAc (10 mL) and washed with water (2 × 20 mL). The organic
layer was dried (Mg2SO4) and evaporated under reduced pressure,
giving N-Bus aziridinyltetrahydrofuran 2022 (52 mg, 86%): Rf 0.35
(petroleum ether-EtOAc, 1:1); mp 59-61 °C (lit.22 64-66 °C);
Supporting Information Available: Full experimental details
of syntheses and characterization of azridine substrates and amino
alcohols/ethers not described in the Experimental Section, data for
ligand screening reactions, X-ray data for aziridine 16 and spiroketal
27b in CIF format, and copies of 1H and 13C spectra for all
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0615201
J. Org. Chem, Vol. 71, No. 22, 2006 8515