Facile generation of alkoxy radicals from N-alkoxyphthalimides

Article abstract of DOI:10.1055/s-1998-1711

N-Alkoxyphthalimides, stable and readily accessible from alcohols and alkyl halides, are found to be very efficient alkoxy radical precursors.

Full text of DOI:10.1055/s-1998-1711

May 1998
SYNLETT
471
Facile Generation of Alkoxy Radicals from N-Alkoxyphthalimides
Sunggak Kim,* Tai Au Lee, and Yukwan Song
Department of Chemistry, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea
E-mail:skim@sorak.kaist.ac.kr
Received 27 February 1998
Abstract: N-Alkoxyphthalimides, stable and readily accessible from
alcohols and alkyl halides, are found to be very efficient alkoxy radical
precursors.
Alkoxy radicals have unique characteristic properties such as β-
1
2
fragmentation and hydrogen atom abstraction due to their high
reactivity, as compared with alkyl and aminyl radicals. Various
precursors for the generation of alkoxy radicals are normally prepared
3
4
5
from alcohols and include nitrites, nitrates, hypohalites, and sulfenyl
6
7
ethers, in which nitrates and certain sulfenyl ethers are relatively
stable to be isolated. However, their preparations often require acidic
conditions and/or reactive reagents which can not be compatible with
other labile functional groups in the molecule. N-Alkoxypyridine-2-
8
thiones have been developed as stable alkoxy radical precursors.
However, the selective O-alkylation of the sodium salt of 2-
mercaptopyridine-N-oxide with alkyl halides is still a problem due to
9
competing S-alkylation. Although a new procedure for the preparation
10
of N-alkoxypyridine-2-thiones has appeared recently, the yields are
not generally high.
During our studies on the functionalization of unactivated C-H bonds
via 1,5-hydrogen transfer from carbon to oxygen, a stable and efficient
11
alkoxy radical precursor was needed. Thus, we turned our attention to
the possibility of using N-alkoxyphthalimides as possible alkoxy radical
precursors because N-alkoxyphthalimides are very stable and easily
accessible from alkyl halides and alcohols (Figure 1). N-
Acyloxyphthalimides are known to generate alkyl radicals both under
12
photolysis and under the standard radical conditions using Bu SnH/
AIBN.
3
13
N-Alkoxyphthalimides were readily prepared from alkyl halides and
alcohols in high yield by routine operations. Experimental results for the
preparation of 3 and for the generation of alkoxy radicals from 3 are
shown in Table 1. Firstly, treatment of alkyl halide 1 with the sodium
salt of N-hydroxyphthalimide in DMF gave N-alkoxyphthalimide 3 in
14
high yields (method A) (eq 1). The reaction normally was complete
within 10 h at room temperature and the reaction time could be
o
considerably shortened by performing the reaction at 70 C. Secondly,
N-alkoxyphthalimides were prepared by treatment of alcohol 2 with N-
hydroxyphthalimide, diethyl azodicarboxylate, and triphenylphosphine
15,16
using the well-known Misunob procedure (method B) (eq 2).
Two
procedures were equally effective and worked well with primary and
secondary alkyl halide and alcohol 2. As we expected, N-
1
alkoxyphthalimides were very stable and could be kept for several
weeks without any decomposition.
We began our studies with N-alkoxyphthalimide 4. Radical reaction of 4
with Bu SnD/AIBN in refluxing benzene under a high dilution afforded
3
7 in 99% yield (95% deuterium exchange), resulting from the generation
of alkoxy radical 5 and the subsequent 1,5-hydrogen transfer from
carbon to oxygen (eq 3). Encouraged by this result, we carried out
several experiments to examine the reactivity of N-alkoxyphthalimides
relative to other radical precursors toward tributyltin radical. Treatment

472
LETTERS
SYNLETT
Soc., Perkin Trans. 1 1979, 1159. (c) Cekovic, Z.; Ilijev, D. Tetrahedron
Lett. 1988, 29, 1441.
of an equimolar amount of N-alkoxyphthalimide 8 and alkyl bromide 9a
with Bu SnH/AIBN afforded alcohol 10 (9%) and reduction product 11
3
(88%) (eq 4), indicating that 8 was much less reactive than bromide 9a.
However, 8 was more reactive than phenylselenide 9b. Table 1
summarizes experimental results and shows the clean generation of
(3) (a) Barton, D. H. R.; Beaton, J. M.; Geller. L. E.; Pechet, M. M. J. Am.
Chem. Soc. 1960, 82, 2640. (b) Akhtan, M. Adv. Photochem. 1964, 2,
263.
alkoxy radicals from the corresponding N-alkoxyphthalimides under the
(4) Vite, G. D.; Fraser-Reid, B. Synth. Commun. 1988, 18, 1339.
17
standard conditions (Bu SnH/ AIBN). The reaction was complete
3
(5) (a) Kraus, G. A.; Thurston, J. Tetrahedron Lett. 1987, 28, 4011. (b)
Furuta, K.; Nagata, T.; Yamamoto, H. Tetrahedron Lett. 1988, 29, 2215.
(c) Suginome, H.; Wang, J. J. Chem. Soc., Perkin Trans. 1 1990, 2825.
(d) Inanaga, J.; Sugimoto, Y.; Yokoyama, Y.; Hanamoto, T.
Tetrahedron Lett. 1992, 33, 8109
within 2 h in refluxing benzene and the yields were consistently high.
Radical cyclization of an alkoxy radical onto the double bond was
successfully carried out with 12 to afford 2-benzyltetrahydrofuran (13)
18
in 93% yield (eq 5). We also found that tris(trimethylsilyl)silane was
equally effective for the generation of alkoxy radicals from N-
alkoxyphthalimides (eq 6).
(6) Beckwith, A. L. J.; Hay, B. P; Willams, G. M. J. Chem. Soc., Chem.
Commun. 1989, 1202.
(7) (a) Pasto, D. J.; L'Hermine, G. J. Org. Chem. 1990, 55, 5815. (b) Pasto,
D. J.; Cottard, F. Tetrahedron Lett. 1994, 35, 4303.
(8) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1988, 110, 4415.
(9) Hay, B. P.; Beckwith, A. L. J. J. Org. Chem. 1989, 54, 4330.
(10) Hartung, J. Synlett 1996, 1206.
(11) Kim, S.; Lee, T. A. Synlett 1997, 950.
(12) Okada, K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1988, 110, 8736.
(13) Barton, D. H. R.; Blundell, P.; Jaszberenyi, J. C. Tetrahedron Lett. 1989,
30, 2341.
(14) Method A: To a solution of N-hydroxyphthalimide (200 mg, 1.2 mmol)
and sodium hydride (64 mg, 1.6 mmol) in DMF (4 ml) was added 5-
bromovaleronitrile (195 µl, 1.6 mmol) at 25 oC under N2. After being
stirred for 16 h at room temperature, the reaction mixture was diluted
with water and extracted with ether. The organic layer was dried over
anhydrous MgSO4, filtered and concentrated. The product was purified
by passing through a column of silica gel using an eluent (2:1, n-hexane-
ethyl acetate) to give N-alkoxy phthalimide 3 (RO=NC(CH2)4O, 242
mg, 81 %). 1H-NMR (200 MHz, CDCl3) δ 1.86-1.93 (m, 4H), 2.49 (t,
J=6.9 Hz, 2H), 4.20 (t, J=5.6 Hz, 2H), 7.69-7.81 (m, 4H); 13C-NMR (75
MHz, CDCl3) δ 16.6, 21.8, 26.8, 76.9, 119.4, 123.4, 128.6, 134.5, 163.4;
IR (KBr) 3098, 2952, 2239, 1789, 1727, 1462, 1130, 700 cm-1.
(15) Method B: To a solution of N-hydroxyphthalimide (40 mg, 0.26 mmol),
benzyl alcohol (38 µl, 0.38 mmol) and triphenyl-phosphine (74 mg, 0.28
mmol) in THF (1.5 ml) was added diethyl azodicarboxylate (45 µl, 0.28
mmol) in THF (0.6 ml) at 25 oC under N2. After being stirred for 18 h at
room temperature, the reaction mixture was diluted with water and
extracted with ether. The organic layer was dried over anhydrous
MgSO4, filtered and concentrated. The product was purified by passing
through a column of silica gel using an eluent (2:1, n-hexane-ethyl
acetate) to give N-alkoxyphthalimide 3 (RO=PhCH2O, 58 mg, 92 %).
1H-NMR (200 MHz, CDCl3) δ 5.19 (s, 2H), 7.34-7.77 (m, 9H); 13C-
NMR (75 MHz, CDCl3) δ 79.8, 123.4, 128.5, 128.8, 129.3, 129.8,
133.6, 134.3, 163.4; IR (KBr) 3076, 2954, 1789, 1730, 1382, 1131, 976,
698 cm-1.
(16) Mitsunobu, O. Synthesis 1981, 1.
(17) General procedure for the generation of alkoxy radicals from N-
Acknowledgement. We thank the Organic Chemistry Research Center
(KOSEF) for financial support.
alkoxyphthalimides 3. To
a solution of N-alkoxyphthalimide 3
(RO=PhCH2O, 60 mg, 0.24 mmol) and AIBN (6 mg) in benzene (4.8
ml, 0.05 M) was added Bu3SnH (72 µl, 0.26 mmol). The reaction
mixture was degassed for 20 min with nitrogen. After being refluxed in
refluxing benzene for 2 h, the reaction mixture was concentrated and
purified by silica gel column chromatography to give benzyl alcohol
(24.6 mg, 95 %).
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