Generation and ring opening of aziridine N-carbonyl radicals

Article abstract of DOI:10.1039/b512956g

Aziridine N-carbonyl radicals, generated by irradiating the corresponding S-oxalyl xanthates, undergo ring opening to give 2-isocyanato radicals, which can be trapped by an external olefin. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b512956g

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COMMUNICATION
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Generation and ring opening of aziridine N-carbonyl radicals
Markus R. Heinrich,ab Ine´s Pe´rez-Mart´ına and Samir Z. Zard*a
Received (in Cambridge, UK) 13th September 2005, Accepted 6th October 2005
First published as an Advance Article on the web 3rd November 2005
DOI: 10.1039/b512956g
serendipitous finding to study the behaviour of aziridinyl
Aziridine N-carbonyl radicals, generated by irradiating the
corresponding S-oxalyl xanthates, undergo ring opening to give
2-isocyanato radicals, which can be trapped by an external
olefin.
N-carbonyls, a family of reactive intermediates that has not been
studied as far as we are aware.3
On the basis of previous related observations,4 it seemed
reasonable to assume that carbonyl radicals 6, produced upon
irradiation of xanthates 5,5 would rapidly lose carbon monoxide to
give carbamoyl radicals 7. Ring opening, encouraged by the
presence of the two stabilising ester groups, would lead to an
isocyanate radical 8, which could perhaps be captured by addition
to an external olefin 9. We believed that the adduct radical 10
would then add to the isocyanate group to furnish cyclic amidyl
radical 11, by analogy with the observations of Walton and
Minin,6 and the latter could possibly abstract a hydrogen from the
solvent to give finally lactam 12.
We recently found that cyclopropylacyl radicals add to external,
unactivated olefins in preference to extrusion of carbon mon-
oxide.1 In an extension to this work aimed at generating radical 1
(Scheme 1) and using it to produce unusual aziridinyl amino acid
derivatives such as 2 and 3, we isolated hemi-oxalamide chloride 4a
(R 5 iPr) and the corresponding xanthate 5a as a side product in
one reaction and were surprised to find this compound sufficiently
stable to be purified by chromatography. This was in contrast to
the difficulties recently reported for the synthesis of xanthates from
carbamoyl chlorides.2 We therefore decided to exploit this
The preparation of the requisite xanthates 5 involves first the
construction of the aziridine ring by reaction of
N,O-bis(trimethylsilyl) hydroxylamine with malonylidene deriva-
tives according to the recent procedure described by Cardillo et al.7
The resulting aziridine is then treated with a three-fold excess of
oxalyl chloride and the crude acid chloride 4, obtained by
evaporation of the solvent and unreacted oxalyl chloride, is
dissolved in ethyl acetate and cooled to 275 uC, whereupon
sodium O-neopentyl xanthate is added and the reaction allowed to
proceed at the same temperature for 30 min. The yellow xanthate
can be obtained pure by chromatography but this is not usually
necessary.
When xanthate 5a and trimethyl vinylsilane were dissolved in
1,2-dichloroethane and irradiated with a 250 W tungsten-halogen
lamp, a reasonably clean reaction ensued but we were surprised to
find that the main product was in fact isocyanate 13a, as indicated
by the strong band at 2269 cm21 in the IR spectrum (Scheme 2).{
It was isolated in 24% yield and consisted of a 1.3:1 mixture of
diastereoisomers. Clearly, compound 13a results from the
Scheme 1 Possible evolution of an aziridine N-carbonyl radical.
aOrganische Chemie 1, Technische Universita¨t Mu¨nchen, Lichtenbergstr.
4, D-85747 Garching, Germany. E-mail: Markus.Heinrich@ch.tum.de
bLaboratoire de Synthe`se Organique associe´ au C.N.R.S., Ecole
Polytechnique, F-91128 Palaiseau, France.
E-mail: zard@poly.polytechnique.fr; Fax: +33 169333851;
Tel: +33 169334872
Scheme 2 Fragmentation to an isocyanate.
5928 | Chem. Commun., 2005, 5928–5930
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premature capture of intermediate radical 10a (10, R 5 iPr) by the
starting xanthate 5a.
fairly complex structures, for example by adding an amine or an
alcohol at the end of the irradiation period. The first attempt using
aniline gave a disappointing yield of the corresponding urea 14a
(Scheme 2), but the more reactive and more useful ethyl glycinate
and aminoacetonitrile gave generally acceptable yields of the
desired product (Table 1).
As far as we are aware, this is the first observation of a ring
opening of an aziridine leading to an isocyanate. The absence of
ring closure of the intermediate radical 10a to the isocyanate group
is puzzling and contrasts with earlier findings of Walton and
Minin,6 and cyclisations involving ketenes.8 The possibility of a
reversible addition seems unlikely since there is no obvious driving
force to cause the amidyl radical to fragment into a strained
isocyanate and an unstabilised secondary radical.9 The radical
addition to the isocyanate must therefore be a relatively slow
process and does not occur in the present case, despite the presence
of the geminal ester groups exerting, in principle, a favourable
Thorpe–Ingold type effect.
All three components can be varied as indicated by the examples
collected in Table 1. The main limitations derive from a lack of
flexibility and difficulties associated with the synthesis of the
starting aziridines 5. The overall yields are modest, but it must be
remembered that the product arises following a complex sequence
involving a large number of individual steps and highly reactive
intermediates. It is also necessary to capture the isocyanate
selectively without partially cleaving the xanthate group or the
ester groups. Xanthates are known to be somewhat more labile
than esters with respect to aminolysis.10 Capture by an alcohol to
The unexpected formation of a reactive isocyanate opens up the
possibility of accomplishing a multicomponent sequence leading to
Table 1 Synthesis of ureas by a radical–ionic sequence
Entry
1
5
Nucleophile
Product (yield, %)
5a
R9 5 CH2OAc
R9 5 C6H13
R9 5 OPiv
R9 5 CH2OAc, 14b (41)
R9 5 C6H13, 14c (55)
R9 5 OPiv, 14d (54)
2
3
4
5
5a
R9 5 CH2NHBoc
R9 5 CH2OAc
R9 5 CH2OAc
R9 5 CH2SiMe3
MeOH
14e (34)
14f (24)
14g (34)
5b R 5 CO2Et
5c R 5 nBu
5c
R9 5 OPiv
R9 5 C4H9
R9 5 CH2SiMe3, 14h (22)
R9 5 OPiv, 14i (49)
R9 5 C4H9, 14j (33)
6
5c
PhNH2
14k (29)
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(CH3), 13.9 (CH3), 22.1 (CH2), 22.4 (CH2), 26.5 (3 6 CH3), 26.8 (3 6
give a urethane is illustrated by the transformation in entry 2 and
an addition–fragmentation sequence is exemplified by the reaction
with b-pinene (entry 6).
CH3), 27.6 (CH2), 28.4 (CH2), 28.6 (CH2), 28.8 (CH2), 31.5 (2 6 CH2,
D1 + D2), 31.8 (2 6 Cq, D1 + D2), 38.1 (CH2), 38.3 (CH2), 38.8 (2 6 Cq),
52.7 (CH3), 52.9 (CH3), 53.3 (CH3), 54.1 (CH3), 55.3 (CH), 55.4 (CH), 61.3
(Cq), 61.4 (Cq), 78.4 (CH), 78.6 (CH), 83.6 (2 6 CH2, D1 + D2), 158.1 (2 6
Cq, D1 + D2), 164.3 (Cq), 165.7 (Cq), 169.8 (Cq) 170.0 (Cq), 170.1 (Cq), 176.5
(Cq), 210.2 (Cq), 210.4 (Cq). HRMS calcd for C26H43O8N3S2; 589.24915,
found 589.24906.
In summary, this preliminary study has highlighted the ready
generation of isocyanate from aziridine derivatives. The scope of
this reaction, especially as concerns the nature of the substituents
on the aziridine ring and their influence on the ring opening step,
remains to be examined in more detail; nevertheless, the sequence
as it now stands allows an expedient access to otherwise not readily
available derivatives.
1 M. R. Heinrich and S. Z. Zard, Org. Lett., 2004, 6, 4969.
2 R. S. Grainger and P. Innocenti, Angew. Chem., Int. Ed., 2004, 43, 3445.
3 The closest process we have found is the fragmentation of N-acyl
aziridines upon electron transfer from a naphthalenide radical anion,
studied by the group of H. Stamm: T. Mall and H. Stamm, J. Chem.
Soc., Perkin Trans. 2, 1997, 2135; J. Werry, P.-Y. Lin, P. Assithianakis
and H. Stamm, J. Chem. Soc., Perkin Trans. 1, 1995, 3103, and earlier
references cited therein.
I. P.-M. thanks the M. E. C. y D. (Spain) and M. R. H., the
Alfred Kastler Foundation, for a postdoctoral fellowship.
Notes and references
4 For a review on acyl radicals, see: I. Ryu, N. Sonoda and D. P. Curran,
Chem. Rev., 1996, 96, 177.
{ General procedure for the synthesis of isocyanates and further derivatives:
A solution of xanthate 5 (1 mmol) and olefin (18 mmol) in CH2Cl2 (0.5 mL)
was irradiated under argon with a 250 W-lamp until all starting material
was consumed (4–8 h). The crude product was concentrated under reduced
pressure and added to a solution of the nucleophile (1 mmol) and iPr2NEt
(2 mmol) at 0 uC. Total consumption of the isocyanate was monitored by
IR spectroscopy. The solution was concentrated under reduced pressure
and the residue was submitted to column chromatography. Compound 14i,
as a mixture of diastereomers D1/D2 (1:1): IR (CCl4, cm21) 3401, 2958,
1743, 1698, 1539, 1275, 1231. 1H NMR (CDCl3, 400 MHz) 0.87 (3H, dd,
J 5 6.4, 6.4 Hz), 0.92 (3H, dd, J 5 7.2, 7.2 Hz), 1.03 (9H, s), 1.17 (9H, s),
1.19–1.65 (12H, m, D1 + D2), 2.62 (1H, dd, J 5 6.4, 15.2 Hz), 2.73 (1H, dd,
J 5 5.2, 15.0 Hz), 2.80 (2H, m), 3.75 (3H, s), 3.76 (3H, s), 3.78 (6H, s), 3.82
(2H, s), 3.90 (2H, s), 4.24 (2H, dd, J 5 4.4, 6.0 Hz, D1 + D2), 4.27 (4H, s),
5.70 (2H, br s, D1 + D2), 5.90 (2H, m, D1 + D2), 6.74 (1H, dd, J 5 6.7,
6.7 Hz), 6.80 (1H, dd, J 5 5.2, 8.4 Hz). 13C NMR (CDCl3, 100 MHz) 13.8
5 For general reviews see: S. Z. Zard, Angew. Chem., Int. Ed. Engl., 1997,
36, 672; S. Z. Zard, ‘‘Xanthates and Related Derivatives as Radical
Precursors’’ in Radicals in Organic Synthesis, ed. P. Renaud and M. P.
Sibi, Wiley-VCH, Weinheim, 2001, vol. 1, p. 90.
6 J. C. Walton and P. L. Minin, Org. Biomol. Chem., 2004, 2, 2471;
J. C. Walton and P. L. Minin, J. Org. Chem., 2003, 68, 2960. See also:
P. Kaushal and B. P. Roberts, J. Chem. Soc., Perkin Trans. 2, 1989,
1559.
7 G. Cardillo, L. Gentilucci, M. Gianotti, R. Perciaccante and
A. Tolomelli, J. Org. Chem., 2001, 66, 8657.
8 N. Herbert and G. Pattenden, Synlett, 1997, 69; B. De Boeck and
G. Pattenden, Tetrahedron Lett., 1998, 39, 6975; B. De Boeck,
N. Herbert and G. Pattenden, Tetrahedron Lett., 1998, 39, 6971.
9 E. Bacque´, M. El Qacemi and S. Z. Zard, Org. Lett., 2005, 7, 3817.
10 K. Mori and Y. Nakamura, J. Org. Chem., 1969, 34, 4170.
5930 | Chem. Commun., 2005, 5928–5930
This journal is ß The Royal Society of Chemistry 2005