The stereoselective addition of organocuprates to cyclopentenyl aziridine derivatives

Article abstract of DOI:10.1016/S0040-4039(00)02202-4

Various organocopper reagents were added in the expected anti-S_N2′ fashion to cyclopentenyl aziridines, which were derived from the photosolvolysis of pyridinium salts.

Full text of DOI:10.1016/S0040-4039(00)02202-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1179–1181
The stereoselective addition of organocuprates to cyclopentenyl
aziridine derivatives
Clive S. Penkett* and Iain D. Simpson
School of Chemistry, Physics and Environmental Science, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK
Received 5 October 2000; revised 15 November 2000; accepted 29 November 2000
Abstract—Various organocopper reagents were added in the expected anti-SN2% fashion to cyclopentenyl aziridines, which were
derived from the photosolvolysis of pyridinium salts. © 2001 Elsevier Science Ltd. All rights reserved.
Recent publications from our group,1 and others,2,3
have shown that the photosolvolysis of N-alkylpyri-
dinium salts in an alcohol solvent allows facile con-
struction of bicyclic cyclopentenyl aziridines such as 2
(Scheme 1).
organocuprates in the presence of BF3·OEt2.5 None of
the substrates investigated were 2-alkenyl aziridines,
and so no SN2% reactions were observed. Indeed, the few
examples of SN2% reactions between cuprates and
alkenyl aziridines so far reported have all involved
activated4 aziridines.6–8
Such molecules offer a wealth of potential for elabora-
tion into a wide range of highly substituted five-mem-
bered rings. Some interesting uses of these compounds
have so far been reported, such as the total synthesis of
mannostatin,2b however much of this potential remains
untapped. In particular, the ring-opening of the
aziridine moiety has so far only been reported with
heteroatomic nucleophiles. We were interested in seeing
how the formation of new carbonꢀcarbon bonds could
be effected on such a system.
Intrigued by this relatively unexplored area of chem-
istry we applied Ganem’s conditions5 to our substrates.
To our delight the simple N-alkyl aziridine 2 underwent
SN2% reactions to allow the formation of new car-
bonꢀcarbon bonds in a highly stereoselective manner.
The N-ethyl and N-allyl cyclopentenyl aziridines1 2 and
5 were reacted with a range of cuprates to give the
ring-opened products 3a–3f in moderate to good
yields.9 Moreover, the stereoselectivity of the reactions
was excellent, with only a single (anti-) diastereomer of
each product being observed (Table 1).
A challenge was posed by the poor reactivity of unacti-
vated aziridines (i.e. those lacking an electron-with-
drawing group on nitrogen)4 towards nucleophiles in
the absence of Lewis acids. Indeed the aziridine 2
showed no sign of reaction upon prolonged exposure to
MeLi. However, Ganem has reported that simple N-
alkyl aziridines can be opened in an SN2 fashion by
SN2% reactions of cuprates with a variety of leaving
groups generally show predominantly anti-stereoselec-
tivity, and Corey12 has suggested that this is due to the
fact that filled d-orbitals on the copper can interact
with both the p* antibonding orbital of the olefin and
the s* orbital of the carbon-leaving group bond. How-
ever, the strong preference for anti- attack in this case
may also be explained by the increased steric bulk
introduced about the aziridinyl nitrogen as a result of
coordination between the nitrogen lone pair and the
Lewis acid.
Scheme 1.
In entry (a) the reaction between 2 and the dimethyl
cuprate species produced a small amount of the by-
product 4a. Unfortunately we could not isolate it free
from the product 3a, hence its structure has only been
tentatively assigned from NMR studies, and more rig-
Keywords: photosolvolysis; heterocycle; vinyl; alkenyl; cyclopentenyl;
aziridine; organocuprate; stereoselective; SN2%.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02202-4

1180
C. S. Penkett, I. D. Simpson / Tetrahedron Letters 42 (2001) 1179–1181
Table 1. Reaction of N-ethyl and N-allyl cyclopentenyl aziridines 2 and 5 with various organocopper reagents
Entry
a10
Substrate
Reagents and conditions
Products
Yield (%)
40 and 13
Me2CuLi
BF3·OEt2, THF, −78°C
b
39
45
Bu2CuLi
BF3·OEt2, THF, −78°C
c
(Vinyl)2CuMgBr
BF3·OEt2, THF, −78°C
d11
51
Me2CuLi
BF3·OEt2, THF, −78°C
e
62
35
Bu2CuLi
BF3·OEt2, THF, −78°C
f
(Vinyl)2CuMgBr
BF3·OEt2, THF, −78°C
new alkyl groups in a stereoselective fashion. These
represent the first examples of SN2% reactions between
cuprates and unactivated alkenyl aziridines.
orous characterisation has so far been prevented. It
may be that 4a arises from competing SN2 opening of
the aziridine (which would be more favourable for
smaller cuprates), followed by elimination of MeOH
(Scheme 2).
Acknowledgements
It is unclear why methanol should be eliminated in the
case of SN2 attack (i.e. in the formation of 4a) and not
in the case of SN2% attack.
The authors are very grateful to the EPSRC and Tocris
Cookson Ltd for funding this project. C.S.P. would like
to thank the Royal Society for an equipment grant. We
would also like to thank Dr. A. Avent for NMR studies
In conclusion, we have shown how organocuprates can
be reacted with cyclopentenyl aziridines to incorporate

C. S. Penkett, I. D. Simpson / Tetrahedron Letters 42 (2001) 1179–1181
1181
Scheme 2.
and the EPSRC Service Centre in Swansea for mass
spectral analyses. Finally we thank Professor Philip
Parsons for his advice and support.
10. Ethyl - (5,5 - dimethoxy - 2,4 - dimethylcyclopent - 2 - enyl)-
amine 3a: lH (500 MHz, CDCl3) 1.02 (d, 3H, J 7.2 Hz,
(C-4)CH3), 1.08 (t, 3H, J 7.2 Hz, NCH2CH3), 1.7 (br s,
1H, NH), 1.71 (ddd, 1H, J 0.9, 1.5, 2.3 Hz, (C-2)CH3),
2.61 (dq, 1H, J 7.2, 10.9 Hz, NCHHCH3), 2.65 (dq, 1H,
J 7.2, 10.9 Hz, NCHHCH3), 2.82 (m, 1H, (C-4)H), 3.23
(s, 3H, (C-5)OCH3), 3.26 (s, 3H, (C-5)OCH3), 3.42 (m,
1H, (C-1)H), 5.22 (m, 1H, (C-3)H). If the proton signal
at 1.71 ppm is selectively decoupled, the three proton
signals on (C-1), (C-3) and (C-4) simplify to 2.82 (ddq,
1H, J 1.6, 2.0, 7.2 Hz, (C-4)H), 3.42 (dd, 1H, J 1.0, 1.6
Hz, (C-1)H), 5.22 (dd, 1H, J 1.0, 2.0 Hz, (C-3)CH). lC
(125 MHz, CDCl3) 15.15, 15.38, 15.78, 41.61, 45.08,
48.68, 49.77, 69.02, 107.61, 130.39, 138.11.
References
1. (a) Penkett, C. S.; Simpson, I. D. Synlett 1999, 93; (b)
Penkett, C. S.; Simpson, I. D. Tetrahedron 1999, 55, 6183.
2. (a) Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem.
1996, 61, 4439; (b) Ling, R.; Mariano, P. S. J. Org.
Chem. 1998, 63, 6072.
3. (a) Acar, E. A.; Glarner, F.; Burger, U. Helv. Chim. Acta
1998, 81, 1095; (b) Glarner, F.; Acar, B.; Etter, I.;
Damiano, T.; Acar, E. A.; Bernardinelli, G.; Burger, U.
Tetrahedron 2000, 56, 4311.
Ethyl-(3-methoxy-1,2-dimethyl-cyclopenta-2,4-dienyl)-
amine 4a: lH (500 MHz, CDCl3) 1.01 (t, 3H, J 7.2 Hz,
NCH2CH3), 1.16 (s, 3H, (C-1)CH3), 1.61 (s, 3H, (C-
2)CH3), 1.7 (br s, 1H, NH), 2.22 (dq, 1H, J 7.2, 11.3 Hz,
NCHHCH3), 2.25 (dq, 1H, J 7.2, 11.3 Hz, NCHHCH3),
3.71 (s, 3H, (C-3)OCH3), 6.11 (br d, 1H, J 5.9 Hz,
(C-5)H), 6.28 (d, 1H, J 5.9 Hz, (C-4)H). lC (125 MHz,
CDCl3) 7.00, 15.68, 22.44, 37.57, 57.40, 68.62, 119.05,
124.95, 141.62, 151.66.
4. Ham, G. E. J. Org. Chem. 1964, 29, 3052.
5. Eis, M. J.; Ganem, B. Tetrahedron Lett. 1985, 26, 1153.
6. Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4886.
7. (a) Fujii, N.; Nakai, K.; Tamamura, H.; Otaka, A.;
Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto, Y.; Ibuka,
T. J. Chem. Soc., Perkin Trans. 1 1995, 1359; (b)
Aoyama, H.; Mimura, N.; Ohno, H.; Ishii, K.; Toda, A.;
Tamamura, H.; Otaka, A.; Fujii, N.; Ibuka, T. Tetra-
hedron Lett. 1997, 38, 7383.
11. Allyl - (5,5 - dimethoxy - 2,4 - dimethyl - cyclopent - 2 - enyl)-
amine 3d: lH (500 MHz, C6D6) 1.18 (d, 3H, J 7.2 Hz,
(C-4)CH3), 1.6 (br s, 1H, NH), 1.82 (ddd, 3H, J 1.0, 1.5,
2.3 Hz, (C-2)CH3), 2.79 (m, 1H, (C-4)H), 3.08 (s, 3H,
(C-5)OCH3), 3.14 (s, 3H, (C-5)OCH3), 3.34 (ddt, 1H, J
1.7, 6.0, 14.1 Hz, NCHHCHꢁCH2), 3.49 (ddt, 1H, J 1.7,
5.4, 14.1 Hz, NCHHCHꢁCH2), 3.56 (br s, 1H, (C-1)H),
5.10 (ddt, 1H, J 1.7, 2.0, 10.2 Hz, NCH2CHꢁCHH), 5.18
(m, 1H, (C-3)CH), 5.33 (ddt, 1H, J 1.7, 2.0, 17.2 Hz,
NCH2CHꢁCHH), 6.05 (dddd, 1H, J 5.4, 6.0, 10.3, 17.2
Hz, NCH2CHꢁCHH). lC (125 MHz, CDCl3) 15.19,
15.40, 45.07, 48.79, 49.77, 50.10, 68.28, 107.80, 115.29,
130.48, 137.86, 138.10.
8. Cantrill, A. A.; Jarvis, A. N.; Osborn, H. M. I.; Ouadi,
A.; Sweeney, J. B. Synlett 1996, 847.
9. Typical experimental procedure: Vinyl magnesium bro-
mide (6.5 ml, 1.0 M solution in THF) was added drop-
wise to a suspension of copper(I) iodide (625 mg, 3.27
mmol) in tetrahydrofuran (10 ml) at −50°C. After 15
minutes the solution was cooled to −78°C and the
aziridine 2 (283 mg, 1.55 mmol) in THF (3 ml) was
added, followed by boron trifluoride diethyl etherate
(0.38 ml, 3.1 mmol). The reaction mixture was stirred at
−78°C for 4 h, then allowed to warm gradually to room
temperature over a further 4 h. The reaction mixture was
quenched with 2 M sodium hydroxide solution (5 ml) and
poured into concentrated ammonia (50 ml). The ammo-
nia solution was extracted with ethyl acetate (3×50 ml)
and the combined organic layers were washed with water
(30 ml), dried (MgSO4) and concentrated in vacuo to give
the crude product as a red oil. This was purified by flash
chromatography (SiO2, DCM:EtOH:NH3, 400:8:1) to
give the amine 3c as a colourless oil (148 mg, 0.70 mmol,
45%).
The relative stereochemistry of compound 3d was con-
firmed by the observation of the following NOE results.
12. Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25,
3063.
.