Tin-free radical alkylation of ketones via N-silyloxy enamines

Article abstract of DOI:10.1039/b606295d

The radical alkylation of ketones is achieved by their conversion into corresponding N-silyloxy enamines, followed by a radical reaction with alkyl halides bearing electron-withdrawing groups. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606295d

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Tin-free radical alkylation of ketones via N-silyloxy enamines
Hyun-Ji Song, Che Jo Lim, Sunggi Lee and Sunggak Kim*
Received (in Cambridge, UK) 4th May 2006, Accepted 17th May 2006
First published as an Advance Article on the web 1st June 2006
DOI: 10.1039/b606295d
The radical alkylation of ketones is achieved by their
conversion into corresponding N-silyloxy enamines, followed
by a radical reaction with alkyl halides bearing electron-
withdrawing groups.
Despite the synthetic importance of alkylating carbonyl com-
pounds, radical alkylations have not been well studied.1
Previously, we reported a novel radical alkylation of carboxylic
amides, involving a cleavage of the N–O bond along with a radical
rearrangement of a silyloxy radical into a silyl radical to achieve
tin-free conditions (eqn. 1).2 To extend our previous finding to the
alkylation of aldehydes and ketones, we initially prepared
Scheme 1
N-silyloxy unsaturated carbamate 2 (eqn. 2).3 When 2 was treated
with iodophenylsulfonyl methane (1) under various radical
transfer from an alkyl iodide to the ethyl radical, (ii) the addition
conditions, surprisingly, the desired product was not obtained,
of an alkyl radical onto 6, followed by the homolytic bond
and methyl phenyl sulfone was isolated, along with the recovery of
cleavage of the N–O bond to generate an imine to provide a
the starting material in most cases. At present, we have no
ketone product, and (iii) a radical rearrangement of a silyloxy
explanation as to why no reaction occurs.
radical into a silyl radical to propagate the radical chain reaction
(Scheme 2).7
ð1Þ
Experimental results, using diethyl bromomalonate as a radical
precursor, are listed in Table 1.{ N-Silyloxy enamines derived from
symmetrical ketones underwent clean radical reactions to give the
corresponding ketones in high yields (Table 1, entries 1–3).
Regioselective alkylation of unsymmetrical ketones is very
important and depends highly on the regioselective formation of
(2)
N-silyloxy enamines in this approach. Deprotonation of N-silyloxy
immonium salt 8, derived from 3-methyl-2-butanone, with
triethylamine occurred at the less substituted carbon, yielding 9
exclusively. A radical reaction using 9 under the same conditions
provided ketone 10 in a regioselective manner (eqn. 3). Similarly,
Our next approach involves the use of N-silyloxy enamine 6,
and is outlined in Scheme 1. Treatment of N-methyl nitrone 44
with tert-butyldiphenylsilyl chloride (TBDPSCl) and silver triflate5,
followed by the addition of triethylamine, afforded 6 via the
intermediate 5. As we expected, 6 was hydrolytically, thermally
and photochemically labile, undergoing extensive decomposition
upon chromatographic separation and with standing, requiring the
use of Et3B to initiate the radical reaction.6 Treatment of 6 with
ethyl iodoacetate in the presence of Et3B (0.5 equiv.) in benzene for
1 h at room temperature gave the corresponding ketone, 7a, in
80% yield. A similar result was also obtained with tert-butyl
iodoacetate.
regioselective alkylation was achieved with unsymmetrical ketones
(Table 1, entries 4–7). Furthermore, it is noteworthy that the
alkylation of 2-methylcyclohexanone was stereoselective, yielding
The present approach is based on three important steps
involving (i) initiation of the radical reaction by iodine atom
Department of Chemistry and Center for Molecular Design & Synthesis,
School of Molecular Science (BK-21), Korea Advanced Institute of
Science and Technology, Daejeon 305-701, Korea.
Scheme 2
E-mail: skim@kaist.ac.kr; Fax: +82 42 869 8370; Tel: +82 42 869 2820
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Table 1 Radical alkylation of carbonyl compounds with diethyl bromomalonatea
Entry
1
Substate
Enamine
Product
Yield (%)
76
2
3
84
95
4
72
5
6
n = 1: 90b
n = 2: 87c
7
84
8
60d
a
b
E = COOEt. syn : anti = 6 : 4. anti only. Solvent was CH2Cl2.
c
d
trans-disubstituted cyclohexanone exclusively (Table 1, entry 6),
whereas that of 2-methylcyclopentanone was not stereoselective
(Table 1, entry 5).
phenoxybutyl iodide under similar conditions gave a small amount
of the desired product, 14, along with recovery of most of the
starting material (71%) (eqn. 5). A similar result was also obtained
with tert-butyl iodide.
(3)
(4)
The reaction could be performed with N-acyloxy enamine 11
(eqn. 4). 11 was conveniently prepared by treatment of nitrone 5
with acetyl chloride and triethylamine. 11 was also thermally and
hydrolytically labile but photochemically quite stable. Thus, the
radical reaction could be performed under photochemically
initiated conditions. Irradiation of a benzene solution of 11, ethyl
iodoacetate and hexamethylditin at 300 nm for 3 h afforded ketone
12 in 75% yield. When the same reaction was repeated using Et3B
as an initiator for 1 h, the desired ketone was isolated in 89% yield.
Apparently, the methyl radical, generated from decarboxylation of
the acyloxy radical, abstracts an iodine atom from the alkyl iodide
to produce an alkyl radical.8 The present approach reaches a limit
with nucleophilic alkyl radicals due to the nature of electron-rich
enamine radical acceptors. The radical reaction of 11 with
(5)
In conclusion, we have developed a new tin-free radical
alkylation of aldehydes and ketones via N-silyloxy enamines.
Further extension of the present approach to secondary amines via
nitrones is under way. We thank the Center for Molecular Design
and Synthesis (CMDS) and the BK21 program for financial
support.
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Notes and references
{ Typical procedure (Table 1, entry 1): To a stirred solution of N-methyl
dimethyl nitrone (26 mg, 0.30 mmol) and AgOTf (85 mg, 0.33 mmol) in dry
benzene (1.5 mL) was added, successively, TBDPSCl (86 mL, 0.33 mmol)
and NEt3 (46 mL, 0.33 mmol) at room temperature under N2. After being
stirred for 30 min at room temperature, the reaction mixture separated into
a clear solution and a black precipitate. The clear solution was transferred
to another flask containing diethyl bromomalonate (48 mg, 0.20 mmol),
and then Et3B (1.0 M in THF, 100 mL, 0.10 mmol) was added. The
reaction mixture was exposed to open air and stirred at room temperature
for 3 h. The solvent was then evaporated and the residue purified by
column chromatography (silica gel, hexane/AcOEt = 5 : 1) to afford the
desired product (33 mg, 76%).
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