Rh(II)-catalysed room temperature aziridination of homoallyl-carbamates

Article abstract of DOI:10.1039/b611662k

Rhodium(II) catalysts and PhIO in benzene convert homoallylic carbamates into the corresponding aziridines at room temperature. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b611662k

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Rh(II)-catalysed room temperature aziridination of
homoallyl-carbamates{
Christopher J. Hayes,*a Peter W. Beavisa and Lesley A. Humphriesb
Received (in Cambridge, UK) 14th August 2006, Accepted 26th September 2006
First published as an Advance Article on the web 12th October 2006
DOI: 10.1039/b611662k
carbamates, but no significant improvement was observed. During
Rhodium(II) catalysts and PhIO in benzene convert homoallylic
carbamates into the corresponding aziridines at room
temperature.
further optimization studies we found that replacing CH2Cl2 with
benzene led to a significant improvement in aziridination (entries 1
and 5, Table 1) and these conditions were used on a range of other
homoallyl-carbamates. We were pleased to see that the expected
aziridines were formed as the major products in all cases (entries 9,
12, 14, 16, Table 1). The stereochemistry of the aziridine products
was determined from the magnitude of the vicinal coupling
constant between the two aziridine protons in the 1H NMR
spectrum.7 We did not observe any aziridination under thermal
There has been a recent resurgence of interest in transition metal-
catalysed amination reactions and it is now possible to effect
efficient and highly selective 1,5- or 1,6-CH insertions under mild
conditions using carbamate or sulfamate ester precursors respec-
tively.1 Du Bois’ recent total syntheses of tetrodotoxin and
manzacidin A2 serve as excellent illustrations of what can be
achieved using this new synthetic tool. Aziridination has also
developed at a fast pace, with homoallyl-sulfamate esters being
excellent precursors for this transformation.3 Padwa,3d,e Rojas4
and Lebel5 have all reported studies on the catalytic aziridination
and subsequent ring opening of allylic carbamates but the
equivalent aziridination and ring opening of homoallyl-carbamates
has been somewhat overlooked. Lebel et al. attempted this
transformation on two substrates, but they found that 1,5-CH
insertion was the only reaction pathway on one example and the
second gave equal amounts of CH-insertion and aziridination. In
this communication we wish to report reaction conditions for the
room temperature aziridination of homoallylic carbamates, along
with studies on regioselective aziridine-ring openings.
Table 1 Rh(II)-mediated aziridination of homoallyl-carbamatesa
Entry Catalyst
% Yield Products
1
2
3
4
Rh2(OAc)4
Rh2(Oct)4
Rh2(S-TBSP)4 66 : 12
Rh2(S-MEOX)4 0 : 40
68 : 14
71 : 6
5
6
7
8
Rh2(OAc)4
Rh2(Oct)4
Rh2(S-TBSP)4 71 : 13
Rh2(S-MEOX)4 31 : 30
58 : 18
70 : 13
We first prepared the E- and Z-homoallyl-carbamates 1 and 3,
from the corresponding alcohols according to the procedure of
Kocovsky,6 and then subjected them to the previously developed
CH-insertion conditions of Du Bois (Rh2(OAc)4, PhI(OAc)2,
CH2Cl2) (Scheme 1). Encouragingly, aziridination was favoured
over the competing CH-insertion reaction pathway, and the
transformation was stereospecific. We next examined the use of
Padwa’s iodosylbenzene-based conditions (Rh2(OAc)4, PhIO,
CH2Cl2) that had been developed for aziridination of allylic
9
Rh2(OAc)4
39 : 17
10
11
Rh2(S-TBSP)4 78 : 0
Rh2(S-MEOX)4 0 : 33
12
13
Rh2(OAc)4 31 : 8
Rh2(S-TBSP)4 66 : 0
14
15
Rh2(OAc)4 26 : 5
Rh2(S-TBSP)4 60 : 0
Scheme 1
16
Rh2(OAc)4
35 : 5
aSchool of Chemistry, University of Nottingham, University Park,
Nottingham, UK NG7 2RD. E-mail: Chris.Hayes@nottingham.ac.uk;
Fax: +44 (0)115 951 3564; Tel: +44 (0)115 951 3045
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road,
Stevenage, UK SG1 2NY
{ Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for all new compounds. See DOI: 10.1039/
b611662k
a
2 equiv. PhIO, 0.05 equiv. Rh(II)-catalyst in benzene at 23 uC over
˚
3 A mol. sieves for 24 h.
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Chem. Commun., 2006, 4501–4502 | 4501

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the course of the reactions. The regioselectivity observed in the
[4,1,0]-carbamate-tethered aziridine ring opening reactions was the
same as that observed for the related [3,1,0]-carbamate-tethered
aziridine series (equation 1),8,3d but is complementary to that
observed for [4,1,0]-sulfamate tethered aziridines (equation 2).1b,e,3c
Table 2 Nucleophilic ring openings of aziridines
Starting
Entry Material Conditions
% Yield Product
1
2
3
4
2a
4a
2a
4a
HOAc, THF
HOAc, THF
88
74
ð1Þ
ð2Þ
HCl, 1,4-dioxan, H2O 62
Our efforts are now directed towards the development of
enantioselective variants of these transformations, and the results
of these studies will be reported in due course.
PhSH, CH2Cl2
91
Notes and references
{ The commercially available catalysts Rh2(Oct)4, Rh2(S-TBSP)4 and
Rh2(S-MEOX)4 have the following structures:
conditions (40–80 uC) in the absence of the Rh(II) catalyst, thus
proving that this is a metal-catalysed process, and this is contrary
to Padwa’s observations in the allylic carbamate series.3d,e
We speculated that the heterogeneous nature of the reaction
conditions contributed to the variability in isolated yield of the
aziridines. In order to test this hypothesis we examined the use of
Rh2(Oct)4 and Rh2(S-TBSP)4 as catalysts due to their improved
solubility in benzene.{ Pleasingly, both catalysts gave reproducibly
good yields of aziridines (entries 2, 3, 6, 7, Table 1), but
Rh2(S-TBSP)4 proved to be the better catalyst over a wider range
of substrates (entries 3, 7, 10, 13, 15, Table 1). Enantiomeric
excesses of between 1 and 23% were observed in the reactions
using Rh2(S-TBSP)4 and Rh2(S-MEOX)4 as catalysts (please see
supporting information for individual values), and work is
underway to try and improve the asymmetric induction in these
transformations. It is interesting to note that during our catalyst
screen, we found that Rh2(S-MEOX)4 tended to catalyse the
competitive 1,5-CH-insertion reaction (entries 4 and 11, Table 1),
thus demonstrating that the nature of the ligand is crucial in
controlling the chemoselectivity of the reaction. Although most di-
and tri-substituted alkenes underwent aziridination, we did find
that terminal alkenes were generally poor substrates (e.g. entry 16,
Table 1) and that a,b-unsaturated ketones failed to cyclise under
any form of Rh(II)-catalysis.
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7 As with other reported aziridine products, the trans-isomers have
smaller coupling constants (J = 3–3.5 Hz) than the corresponding cis-
isomers (J = 5–5.5 Hz).
8 S. C. Bergmeier and D. M. Stanchina, J. Org. Chem., 1997, 62,
4456.
In order to assess their future synthetic potential, a selection of
the previously formed aziridines was exposed to a range of hetero-
atom nucleophiles, and the results are summarized in Table 2.
Complete regioselectivity was observed in all ring-opening
reactions, and stereochemical integrity was maintained during
4502 | Chem. Commun., 2006, 4501–4502
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