Novel methodology for the synthesis of n-alkoxyamines

Article abstract of DOI:10.1021/ol049271v

We report a new methodology for the synthesis of the N-alkoxyamines, which can be used as initiators in "living" free radical polymerization. Silyl radical abstraction from alkyl halides allows the synthesis of N-alkoxyamines inaccessible by other methods

Full text of DOI:10.1021/ol049271v

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2233-2235
Novel Methodology for the Synthesis of
N-Alkoxyamines
Rebecca Braslau,* Anna Tsimelzon, and Jennifer Gewandter
Department of Chemistry and Biochemistry, UniVersity of California-Santa Cruz,
Santa Cruz, California 95064
braslau@chemistry.ucsc.edu
Received April 20, 2004
ABSTRACT
We report a new methodology for the synthesis of the N-alkoxyamines, which can be used as initiators in “living” free radical polymerization.
Silyl radical abstraction from alkyl halides allows the synthesis of N-alkoxyamines inaccessible by other methods.
N-Alkoxyamines are commonly prepared by generating
carbon radicals from the corresponding alkyl halides followed
by trapping with nitroxides.1 Tris(trimethyl)silyl radicals
readily abstract halogen atoms from alkyl halides.2 In this
methodology, we now demonstrate the use of silyl radicals
to generate alkyl radicals from the corresponding alkyl
halides in the presence of a nitroxide trap, using a stoichio-
metric radical initiator.
The reaction to prepare N-alkoxyamines entails use of tert-
butyl hyponitrite5 1 as a thermal radical initiator, tris(tri-
methyl)silane, an alkyl halide, and a nitroxide. The proposed
mechanism for the reaction is outlined in Scheme 1. Upon
Scheme 1
This new methodology offers a number of potential
advantages over other methods. For instance, the use of toxic
reagents such as hydrazine3 or tin hydride4 is avoided. One
can readily prepare tert-butyl and i-propyl N-alkoxyamines,
which are not possible by other methods. Furthermore, the
method allows synthesis of N-alkoxyamines with hydroxyl
and carboxyl functionalities. Incorporation of functionality
on the N-alkoxyamine provides functional handles to allow
for pre- or postpolymerization modification, applications
including attachment of polymers to surfaces, or end-capping
with affinity labels or biomolecules.
(1) (a) Braslau, R.; Burill, L. C.; Siano, M.; Naik, N.; Howden, R.; Mahal,
L. K. Macromolecules 1997, 30, 6445. (b) Matyjaszewaki, K.; Woodworth,
B. E.; Zhang, X.; Gaynor, S. G.; Metzner Z. Macromolecules 1998, 31,
5955. (c) Benoit, D.; Chaplinsky, V.; Braslau, R.; Hawker, C. J. Am. Chem.
Soc. 1999, 121, 3904.
(2) For a review, see: Chatgilialoglu, C.; Ferreri, C.; Gimisis, T. In The
Chemistry of Organic Silicon Compounds; Rapport, S., Apeloig, Y., Eds.;
Wiley: Chichester, 1998; Vol.2, Chapter 25, pp 1539-1579.
(3) Braslau, R.; Burill, L. C.; Siano, M.; Naik, N.; Howden, R.; Mahal,
L. K. Macromolecules 1997, 30, 6445.
heating, the oxygen-nitrogen bond in tert-butyl hyponitrite
1 undergoes homolytic cleavage generating 2 equiv of
t-butoxy radical 2, which in turn abstracts hydrogen from
commercially available tris(trimethylsilyl)silane 36 to gener-
ate silicon-centered radical 4. The intermediate silyl radical
4 abstracts halogen from the alkyl halide to generate carbon
(4) (a) Nagashima, T.; Curran, D. P. Synlett 1996, 4, 331. (b) Marque,
S.; Fischer, H.; Baier, E.; Studer, A. J. Org. Chem. 2001, 66, 1146.
10.1021/ol049271v CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/04/2004

radical 5, which is then trapped by nitroxide to give
N-alkoxyamine 6. Since trapping of the carbon radical by
nitroxide terminates the radical sequence, a minimum of 0.5
equiv of tert-butyl hyponitrite is required for complete
conversion, as overall this is not a radical chain sequence.
The results are summarized in the Table 1. This new
methodology allows generation of a variety of carbon radicals
such as benzylic, allylic, tertiary, R-carbonyl, secondary, and
even primary alkyl radicals, which can be trapped with
various nitroxides to generate N-alkoxyamines. The reaction
is selective for bromides and iodides over chlorides as
demonstrated by entries 2, 6, and 11. Better yields were
obtained with iodides than bromides.
Table 1. Synthesis of N-Alkoxyamines
Of particular interest is entry 17 in Table 1, which gave
product 7. This N-alkoxyamine incorporates an ester func-
tionality and is made using the TIPNO nitroxide developed
by this lab in conjuction with the Hawker lab at IBM for
nitroxide-mediated polymerization.7 N-Alkoxyamine initia-
tors bearing this R-hydrogen nitroxide have been demon-
strated to give polymers with good control of both molecular
weight and low polydispersity. As compared to the use of
TEMPO, use of this less sterically demanding nitroxide in
this tris(trimethylsilyl)silane procedure suffers from competi-
tive reduction of the nitroxide to the corresponding amine.8
Thus, reasonable yields were obtained by using an excess
(2.0 equiv) of nitroxide. To provide evidence for nitroxide
reduction under the reaction conditions, 1.0 equiv of the
TIPNO nitroxide was mixed with 1.0 equiv of tert-butyl
hyponitrite 1 and 1.0 equiv of tris(trimethylsilyl)silane 3 in
benzene at 60 °C for 2 h. The formation of the corresponding
amine was supported by observation of a strong peak at 205
m/e in the mass spectrum of the crude reaction mixture.
Chemoselective reduction of the ester in compound 7
(Scheme 2) using lithium aminoborohydride reagent9 (LAB)
Scheme 2
8 produced compound 9 in 47% yield, which contains an
unprotected hydroxyl group. This free alcohol can be used
to append a variety of species onto the intiator or to anchor
the initiator onto a solid support.
(5) For the synthesis of tert-butyl-hyponitrite, see: Mendenhall, G. D.
Tetrahedron Lett. 1983, 24, 451.
(6) (a)Chatgilialoglu, C. Chem. ReV. 1995, 95, 1229. (b) Chatgilialoglu,
C.; Newcomb, M. AdV. Organomet. Chem. 1999, 44, 67.
(7) Benoit, D.; Chaplinsky, V.; Braslau, R.; Hawker, C. J. J. Am. Chem.
Soc. 1999, 121, 3904.
(8) Lucarini, M.; Marchesi, E.; Pedulli, G. F.; Chatgilialoglu, C. J. Org.
Chem. 1998, 63, 1687.
a Performed with 1.0 equiv of alkyl halide. b Performed with 2.0 equiv
of alkyl halide. c Ratio of alkyl halide to product was 5:1 as determined by
1H NMR of the crude product. d Performed with 2.0 equiv of nitroxide.
(9) Fisher, G. B.; Fuller J. C.; Harrison, J.; Alvarez, S. G.; Burkhardt,
E. R.; Goralski, C. T.; Singaram, B. J. Org. Chem. 1994, 59, 6378.
2234
Org. Lett., Vol. 6, No. 13, 2004

A typical reaction procedure is illustrated by the formation
of the tert-butyldimethylsiloxy-protected alcohol shown in
entry 14: 1-bromo-1-phenyl-2-(tert-butyldimethylsiloxy)-
ethane (241.5 mg, 0.77 mmol) was combined with tris(tri-
methylsilyl)silane (94.5 mg, 0.38 mmol), tert-butyl hypo-
nitrite (66.2 mg, 0.38 mmol), and TEMPO (0.38 mmol, 59.4
mg). The mixture was dissolved in 1.3 mL of benzene, and
the solution was heated to 65-70 °C for 2 h under N2. The
benzene was then removed by distillation. The crude material
was dissolved in 30 mL of ether and washed three times
with 30 mL of water. The organic phase was dried over
MgSO4 and filtered. Volatiles were removed in vacuo giving
222 mg of orange oil. Purification by flash chromatography
using 49:1 hexane/ethyl acetate gave 102 mg (68% yield)
of compound 14 as a colorless oil.
nitroxides. Both alkyl and functionalized groups can be in-
corporated, making available modified initiators for nitroxide-
mediated polymerization to prepare designed materials for
a variety of applications in nanotechnology.
Acknowledgment. This work was supported by the
National Science Foundation (CHE-0078852 and CHE-
0243786). We would like to thank Professor Bakthan
Singaram for helpful discussions on the use of the LAB
reagent.
Supporting Information Available: The characterization
of compounds in entries 1-17 of Table 1 as well as
characterization of compound 9. This material is available
free of charge via the Internet at http://pubs.acs.org.
In summary, this methodology provides access to primary,
secondary, and tertiary N-alkoxyamines from a variety of
OL049271V
Org. Lett., Vol. 6, No. 13, 2004
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