Intramolecular cyclopropanation of unsaturated terminal aziridines

Article abstract of DOI:10.1021/ol060101n

Regio- and stereoselective deprotonation of bishomoallylic terminal N-Bus (Bus = tert-butylsulfonyl)-protected aziridines generate aziridinyl anions that undergo diastereoselective Intramolecular cyclopropanation giving trans-2-aminobicyclo[3.1.0]hexanes in good to excellent yields.

Full text of DOI:10.1021/ol060101n

ORGANIC
LETTERS
2006
Vol. 8, No. 5
995-998
Intramolecular Cyclopropanation of
Unsaturated Terminal Aziridines
David M. Hodgson,* Philip G. Humphreys, and John G. Ward†
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
daVid.hodgson@chem.ox.ac.uk
Received January 13, 2006
ABSTRACT
Regio- and stereoselective deprotonation of bishomoallylic terminal N-Bus (Bus
) tert-butylsulfonyl)-protected aziridines generate aziridinyl
anions that undergo diastereoselective intramolecular cyclopropanation giving trans-2-aminobicyclo[3.1.0]hexanes in good to excellent yields.
Aziridine chemistry is currently seeing increasing research
interest.1 The widespread availability of terminal aziridines
(typically accessed from terminal alkenes2 or imines3) and
recent reports on the synthesis of enantiomerically pure
terminal aziridines from epoxides4 suggest that new methods
to utilize such aziridines would be of considerable value.5
With this in mind we recently reported the diastereoselective
lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced depro-
tonation-electrophile trapping of terminal N-Bus (tert-butyl-
sulfonyl)6-protected aziridines 1 to give trans-disubstituted
aziridines 2 (Scheme 1).7 We also recently demonstrated the
Scheme 1. Reactivity of R-Lithiated Aziridine 3a
† GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow,
Essex CM19 5AW, U.K.
(1) Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247-258.
(2) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. J.
Am. Chem. Soc. 1998, 120, 6844-6845.
(3) Aggarwal, V. K.; Stenson, R. A.; Jones, R. V. H.; Fieldhouse, R.;
Blacker, J. Tetrahedron Lett. 2001, 42, 1587-1589.
a See refs 7 and 8.
LTMP-induced dimerization of enantiopure terminal N-Bus-
protected aziridines to give enantiopure 2-ene-1,4-diamines
4.8 This latter work was the first report demonstrating
carbenoid reactivity of R-lithiated terminal aziridines 3,9
something that was perhaps surprising given the potential
for elimination leading to 2H-azirines 5 (Scheme 1).10,11
We recently revisited and advanced the LTMP-induced
intramolecular cyclopropanation of unsaturated terminal
(4) (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. Also, for reviews
on enantioselective aziridination, see: (c) Jacobsen, E. N. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, 1999; Vol. 2, pp 607-618. (d) Mu¨ller, P.; Fruit,
C. Chem. ReV. 2003, 103, 2905-2919.
(5) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619. (b)
McCoull, W. M.; Davis, F. A. Synthesis 2000, 1347-1365.
(6) Sun, P.; Weinreb, S. M.; Shang, M. J. J. Org. Chem. 1997, 62, 8604-
8608.
(7) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2005, 7,
1153-1156.
(8) Hodgson, D. M.; Miles, S. M. Angew. Chem., Int. Ed. 2006, 45, 935-
938.
10.1021/ol060101n CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/04/2006

epoxides12 to give trans-bicyclo[3.1.0]hexan-2-ols in excel-
lent yields and diastereoselectivity.13 In the present com-
munication, we report adaptation of this methodology with
unsaturated terminal aziridines to achieve access to 2-amino-
bicyclo[3.1.0]hexanes. The latter structural motif is found
in analgesics,14 antiviral agents,15 and antiobesity therapeu-
tics.16
Preliminary evaluation of our LTMP-mediated intramo-
lecular cyclopropanation protocol13 with terminal unsaturated
aziridines used N-tosyl aziridine 6,2,17 which on addition of
LTMP over 1 h gave bicyclic amine 8 as a single trans-
diastereomer,18 albeit in only 19% yield (Scheme 2). The
trisyl,23 mesitylsulfonyl, p-methoxybenzenesulfonyl, and
Bus6-8 N-protected variants of aziridine 6 were examined
under the cyclopropanation conditions using LTMP and also
LiNCy2. However, use of all of these protecting groups led
to <15% yields of the corresponding bicyclic amines, apart
from Bus, which after 16 h resulted in a 23% yield of amine
1024 when LTMP was used and a 38% yield with LiNCy2
(Table 1, entries 1 and 2).25 2-Ene-1,4-diamine 118 (as a
Table 1. Optimization of the Synthesis of Bicyclic Amine 10a
Scheme 2. Synthesis of Bicyclic Amine 8
yield (%)
entry
base
equiv solvent conc (M)
temp
10 11
base added to aziridine 9 over 1 h
1
2
LTMP
LiNCy2
2
2
t-BuOMe
t-BuOMe
0.07
0.07
0 °C to rt 23 44
0 °C to rt 38 35
aziridine 9 added to base over 1 h
3
4
5
6
7
8
9
LTMP
2
2
2
2
2
2
3
3
3
3
3
3
3
3
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
THF
0.07
0.07
0.07
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0 °C to rt 41 23
yield of bicyclic amine 8 could be increased to 37% by using
a slightly less hindered lithium amide in the reaction, lithium
dicyclohexylamide (LiNCy2, conditions otherwise as Scheme
2).19
On the basis that complications arising from competitive
ortho-lithiation of the tosyl group could be contributing to
the low yields of 8,20 other N-protecting groups not (or less)
susceptible to this process were screened. The t-Bu,21 Boc,22
LiNCy2
LiNCy2
LiNCy2
LiNCy2
LiNCy2
LiNCy2
0 °C to rt 54
6
6
0 °C
65
0 °C
68 <5
67
67 16
73 <5
69 10
-10 °C
-40 °C
0 °C
7
10 LTMP
11 LDA
0 °C
0 °C
63
9
12 LiNCy2
13 LiNCy2
14 LiNCy2
15b LiNCy2
16c LiNCy2
0 °C
0 °C
0 °C
0 °C
29 36
71 <5
68 <5
72 <5
75 <5
Hexane
Et2O
t-BuOMe
t-BuOMe
(9) For recent reviews on aziridinyl and oxiranyl anions, see: (a) Oxiranyl
and aziridinyl anions as reactive intermediates in synthetic organic chemistry.
Florio, S., Ed.; Tetrahedron 2003, 59, 9683-9864. (b) Hodgson, D. M.;
Bray, C. D. In Aziridines and Epoxides in Organic Synthesis; Yudin, A.
K., Ed.; Wiley-VCH: Weinheim, 2006; pp 145-184. (c) Hodgson, D. M.;
Bray, C. D.; Humphreys, P. G. Synlett 2006, 1-22.
(10) (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) Aggarwal,
V. K.; Alonso, E.; Ferrara, M.; Spey, S. E. J. Org. Chem. 2002, 67, 2335-
2344. (c) Luisi, R.; Capriati, V.; Florio, S.; Di Cunto, P.; Musio, B.
Tetrahedron 2005, 61, 3251-3260.
(11) Carbene reactivity has been observed for ring-fused aziridines, where
2H-azirine formation is less likely; see: Mu¨ller, P.; Riegert, D.; Bernar-
dinelli, G. HelV. Chim. Acta 2004, 87, 227-239. See also: Hodgson, D.
M.; Sˇtefane, B.; Miles, T. J.; Witherington, J. Chem. Commun. 2004, 2234-
2235.
0 °C
a 16 h reaction duration, unless otherwise indicated. b 1 h reaction
duration. c 2 h reaction duration.
mixture of diastereomers) was also isolated in these reactions
in 44% and 35% yields, respectively. It is noteworthy that
significant levels of cyclopropanation occur with N-Bus
aziridine 9, given the propensity of this and related N-Bus
aziridines to efficently dimerize under closely related condi-
tions (Scheme 1).8 Variation in the experimental conditions
with N-Bus aziridine 9 was then studied further, with the
aim of favoring cyclopropanation relative to dimerization
(Table 1).
(12) (a) Originally observed as minor reaction pathway; see: Crandall,
J. K.; Lin, L.-H. J. Am. Chem. Soc. 1967, 89, 4526-4527. (b) Apparu, M.;
Barelle, M. Tetrahedron 1978, 34, 1691-1697.
(13) (a) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. J. Am. Chem. Soc.
2004, 126, 8664-8665. (b) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M.
Synthesis 2005, 2264-2266.
(14) Moshe, A. Eur. J. Med. Chem. 1981, 16, 199-206.
Reversing the addition order, so that aziridine 9 was added
dropwise to the base, led to increased yields of bicyclic amine
(15) (a) Rodriquez, J. B.; Marquez, V. E.; Nicklaus, M. C.; Mitsuya,
H.; Barchi, Jr., J. J. J. Med. Chem. 1994, 37, 3389-3399. (b) Marquez, V.
E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.; Wang, J.; Wagner, R. W.;
Matteucci, M. D. J. Med. Chem. 1996, 39, 3379-3747. (c) Tchilibon, S.;
Joshi, B. V.; Kim, S.-K.; Duong, H. T.; Gao, Z.-G.; Jacobson, K. A. J.
Med. Chem. 2005, 48, 1745-1758. (d) Lee, J. A.; Moon, H. R.; Kim, H.
O.; Kim, K. R.; Lee, K. M.; Kim, B. T.; Hwang, K. J.; Chun, M. W.;
Jacobsen, K. A.; Jeong, L. S. J. Org. Chem. 2005, 70, 5006-5013.
(16) McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; P. A.;
Clader, J. W.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O’Neill, K.;
Spar, B.; Weig, B. J. Med. Chem. 2005, 48, 2274-2277.
(20) Huang, J.; O’Brien, P. Tetrahedron Lett. 2005, 46, 3253-3256.
(21) (a) Vedejs, E.; Kendall, J. T. J. Am. Chem. Soc. 1997, 119, 6941-
6942. (b) Vedejs, E.; Prasad, A. S. B.; Kendall, J. T.; Russel, J. S.
Tetrahedron 2003, 59, 9849-9857.
(22) Beak, P.; Wu, S.; Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994, 59,
276-277.
(23) Huang, J.; O’Brien, P. Chem. Commun. 2005, 5696-5698.
(24) Isolated as a single diastereomer. Structure supported by X-ray
crystallographic analysis: CCDC 292434 available at http://www.ccdc.
cam.ac.uk.
(17) Lapinsky, D. J.; Bergmeier, S. C. Tetrahedron 2002, 58, 7109-
7117.
(18) Determined by NOE analysis and by comparison with the analogous
epoxide cyclopropanation product; see ref 13a.
(19) Use of LDA under these conditions gave 30% yield of amine 8.
(25) With LiNCy2, quenching directly after addition of the aziridine 9
(1 h) indicated incomplete reaction; 9 (52%), amine 10 (10%), and dimer
11 (22%) were obtained.
996
Org. Lett., Vol. 8, No. 5, 2006

10 (Table 1, entries 3 and 4) and reduced dimer 11, the latter
reduction being particularly noticeable when using LiNCy2
(entries 2 and 4). Maintaining the reaction temperature at 0
°C further increased the yield of bicyclic amine 10 (entry
5). Halving the reaction concentration led to only a further
modest increase in yield, but no dimer was now isolated
(entry 6). Decreasing the reaction temperature to -10 or -40
°C maintained the yields of bicyclic amine 10, but the amount
of dimer 11 rose (entries 7 and 8). Increasing the quantity
of LiNCy2 to 3 equiv allowed a 73% yield of desired bicyclic
amine 10 to be obtained, with only trace amounts of 2-ene-
1,4,-diamine 11 detectable by 1H NMR analysis of the crude
reaction mixture (entry 9).26 Re-examination of LTMP and
LDA under these latter conditions resulted in only slightly
lower yields of amine 10; however, dimer formation was
more noticeable (entries 10 and 11). With LiNCy2 the process
was relatively insensitive to switching solvent from t-BuOMe
to ether or hexane (entries 13 and 14), but dimer formation
increased significantly when using THF8 (entry 12).
Finally, quenching the reaction in t-BuOMe directly after
addition of the aziridine 9 (1 h) and also 1 h after addition
indicated essentially complete reaction (entries 15 and 16);
this is in stark contrast to when LiNCy2 was added to the
aziridine.25 Deprotonation (and cyclopropanation) of the
aziridine 9 is therefore rapid when it is added to the base
over 1 h at 0 °C. Perhaps dimerization is minimized under
these latter conditions because deprotonation of more than
one aziridine is unlikely to occur from a single lithium amide
aggregate.27 In contrast, when the base is added to the
aziridine, this may create a localized high concentration of
lithiated aziridine (due to the aggregated nature of the lithium
amide), which allows dimerization to become competitive
with intramolecular cyclopropanation.
Table 2. Bicyclic Amines from Unsaturated Terminal
Aziridinesa
The optimized conditions (Table 1, entry 16) were
subsequently applied to a variety of other unsaturated
terminal aziridines to assess the scope of the method (Table
2).
No erosion of ee was observed for cyclopropanation of
an enantiopure terminal aziridine (Table 2, entry 1).29 The
process tolerates di- and trisubstituted alkenes (entries 2-5),
and the stereochemistry of the bicyclic amines 13b,c
demonstrates that cyclopropanation occurs stereospecifically
(entries 2 and 3).18 The lower yield with cis-alkene 12c was
associated with noticeably increased dimer signals in the 1H
NMR spectrum of the crude product; this suggests cyclo-
(26) Use of N-Ts aziridine 6 under these conditions gave a 47% yield of
amine 8.
(27) (a) Aubrecht, K. B.; Collum, D. B. J. Org. Chem. 1996, 61, 8674-
8676. (b) Remenar, J. F.; Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc.
1997, 119, 5567-5572.
a See ref 28.
(28) General Procedure. n-BuLi (1.6 M in hexanes, 0.94 mL, 1.5 mmol)
was added dropwise to a stirred solution of dicyclohexylamine (0.30 mL,
1.5 mmol) in t-BuOMe (5 mL) at -78 °C under argon. Following warming
to room temperature over 30 min, the reaction was cooled to 0 °C, a solution
of aziridine (0.5 mmol) in t-BuOMe (10 mL) at 0 °C was added via cannula
over 1 h, and the reaction left to stir at 0 °C. On completion of the reaction
(TLC monitoring), saturated aqueous NH4Cl (5 mL) and Et2O (5 mL) were
added. The phases were separated, and the aqueous layer was extracted
with Et2O (3 × 15 mL). The combined organic layers were dried (MgSO4)
and evaporated under reduced pressure. Purification of the residue by column
chromatography (SiO2, petroleum ether/Et2O) gave the bicyclic amine.
(29) Determined by chiral GC analysis.
propanation was slowed, which could be due to the ethyl
substituent residing axial in the proposed chairlike transition
state (cf. Scheme 2). Substitution on the link between the
aziridine and alkene functionality led to very efficient
cyclopropanation (entries 6-9). Similarly to observations
made with intramolecular cyclopropanation of epoxides,13
no competitive aromatic C-H insertion was observed (entry
7). Efficient selection between diastereotopic allyl groups
Org. Lett., Vol. 8, No. 5, 2006
997

occurred (entries 8 and 9) and synthesis of a tricyclic system
could also be achieved (entry 10). Aziridinyl-substituted
styrenes also underwent cyclopropanation (entries 11 and 12).
Access to 2-amino-5-aryl substituted bicyclo[3.1.0]hexanes
such as in entry 12 is of interest in the context of antiobesity
therapeutics.16
functionality was synthesized and subjected to the reaction
conditions (entry 2). Pleasingly, an 85% yield of a 2-amino
bicyclo[3.1.0]hexane 15b containing a potentially useful
vinyl cyclopropane moiety30 was obtained.
In conclusion, we have demonstrated a new facet of
aziridine chemistry, the ability of aziridines, following
lithiation, to undergo cyclopropanation. The scope of this
process has been examined, and a variety of synthetically
useful bicyclic amines14-16 have been synthesized as single
diastereomers in good to excellent yields. These amines retain
a useful nitrogen protecting group6 to enable further synthetic
transformations. Work is ongoing in the area of aziridine
cyclopropanation and the synthetic utility of the resulting
bicyclic amines.
We also investigated the cyclopropanation of trishomoal-
lylic aziridines (Table 3). Trishomoallylic aziridine 14a
Table 3. Cyclopropanation with Trishomoallylic Aziridines
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for a CASE award (to P.G.H.). We also thank
the EPSRC National Mass Spectrometry Service Center
(Swansea) for mass spectra, A. Collins for X-ray crystal-
lographic analysis, Dr. G. MacDonald for useful discussions,
and C. A. J. Brierley for supporting investigations.
underwent cyclopropanation in low yield (Table 3, entry 1),
although the bicyclic amine was isolated as a single diaste-
reomer that was assigned trans stereochemistry by compari-
son with the analogous trishomoallylic epoxide cyclopropa-
nation product.13 Significant quantities of 2-ene-1,4-diamine
were observed in the 1H NMR of the crude reaction mixture,
so the low yield of amine 15a probably reflects a slower
cyclopropanation rate compared to the corresponding ho-
moallylic aziridine 9.
Supporting Information Available: Characterization
data for aziridines 12 and 14 and amines 8, 10, 13, and 15,
including 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL060101N
(30) (a) Hudlicky, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985,
33, 247-335. (b) Hudlicky, T.; Reed, J. W. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon:
Oxford, 1992; Vol. 5, pp 899-970. (c) Oxgaard, J.; Wiest, O. Eur. J. Org.
Chem. 2003, 1454-1462. (d) Zuo, G.; Louie, J. Angew. Chem., Int. Ed.
2004, 43, 2277-2279.
Intrigued as to whether this result could be turned to our
advantage, an aziridine containing both bis- and trishomoallyl
998
Org. Lett., Vol. 8, No. 5, 2006