Radical alkylation of bis(silyloxy)enamine derivatives of organic nitro compounds

Article abstract of DOI:10.1002/anie.200601461

(Chemical Equation Presented) Alkylation β to a nitro group by radical chemistry is made possible by initial conversion of the organic nitro compound into a bis(silyloxy)enamine (see scheme; TBSOTf=tert-butyldimethylsilyl trifluoromethanesulfonate). An advantage of the method is the simultaneous conversion of the nitro group into a synthetically useful oxime ether group.

Full text of DOI:10.1002/anie.200601461

Communications
Radicals in Synthesis
DOI: 10.1002/anie.200601461
Radical Alkylation of Bis(silyloxy)enamine
Derivatives of Organic Nitro Compounds**
Jin Young Lee, Young-Taek Hong, and Sunggak Kim*
Organic nitro compounds are valuable intermediates in
organic synthesis that undergo a variety of carbon–carbon
bond-forming reactions. The alkylation of primary and
secondary alkyl nitro compounds proceeds via dianion species
to yield a- and b-alkylated nitro compounds, respectively.[1]
The conjugate addition and nitroaldol reaction of organic
nitro compounds have also found wide application in syn-
thesis.[2] Despite the great synthetic importance of the nitro
[*] J. Y. Lee, Y.-T. Hong, Prof. Dr. S. Kim
Center for Molecular Design & Synthesis and
Department of Chemistry
School of Molecular Science
Korea Advanced Institute of Science and Technology
Daejeon 305-701 (Korea)
Fax: (+82)42-869-8370
E-mail: skim@kaist.ac.kr
[**] We thank the CMDS and BK21 programs for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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group, radical-mediated reactions of this functional group
have not been well studied. Previously reported chain
processes via radical anion intermediates nicely complement
standard enolate alkylations, as they give good results with
tertiary alkyl and aryl halides.[3,4] The nitroalkylation of alkyl
iodides via silyl nitronates[5] has also been described, as well as
the previously known reduction of tertiary nitro groups with
Bu3SnH/2,2’-azobisisobutyronitrile (AIBN).[6]
Our approach for the radical alkylation of organic nitro
compounds is outlined in Scheme 1. It involves the addition of
an alkyl radical to a bis(silyloxy)enamine 3 and subsequent
À
homolytic cleavage of one N O bond to yield an oxime ether
6. Thus, this approach would enable alkylation at the
b position to the nitro group together with the conversion of
the nitro group into the synthetically important oxime ether
group. We began our study with 2-nitropropane (1b). The
treatment of 1b with tert-butyldimethylsilyl trifluorometh-
anesulfonate (TBSOTf; 2.0 equiv) and triethylamine
(2.2 equiv) afforded the bis(silyloxy)enamine 3b via 2.[7]
Since 3b underwent rearrangement into 4b when passed
through a column of silica gel,[7c] the remaining reactions were
carried out with the crude product after an aqueous workup.
Irradiation of a solution of 3b, iodomethyl phenyl sulfone,
and hexamethylditin in benzene at 300 nm for 9 h afforded
Scheme 1. Radical alkylation of the organic nitro compound 1.
the oxime ether 6b in 71% yield. The hydrolysis of 6b with 1m
HCl then gave the ketone 7b in 91% yield. Furthermore, the
oxime ether group can be converted into an amino[8] or nitro
group.[9] When 1c was treated with TBSOTf and triethyl-
amine under similar conditions, the deprotonation of 2c by
triethylamine occurred at the less-substituted carbon atom,
thereby yielding 3c in a regioselective manner.
Our experimental results are summarized in Table 1. The
radical reaction of the conjugated bis(silyloxy)enamine 3e,
Table 1: Radical alkylation of organic nitro compounds.[a]
Nitro compound
Enamine
Oxime ether
Yield [%]
Carbonyl compound
Yield [%]
1a
R=H
3a
3b
3c
3d
R=H
6a
6b
6c
6d
R=H
R’=CH2SO2Ph
R=CH3
R’=CH2SO2Ph
R=n-C3H7
R’=CH2CO2Et
R=Ph
85
71
70
82
7a
R=H
R’=CH2SO2Ph
R=CH3
R’=CH2SO2Ph
R=n-C3H7
R’=CH2CO2Et
R=Ph
86
91
85
93
1b
1c
1d
R=CH3
R=n-C3H7
R=Ph
R=CH3
7b
7c
7d
R=n-C3H7
R=Ph
R’=CH2CO2Et
R’=CH2CO2Et
1e
1 f
3e
3 f
6e
6 f
R=CH2SO2Ph
R=CH2CO2Et
79
72
7e
7 f
85
93
6g
6h
R=CH2CO2Et
R=CH2SO2Ph
65
62
1g
3g
6i
6j
R=CH2CO2Et
R=CH2SO2Ph
76
79
7g
7h
73
88
1h
3h
6k
R=CH2CO2Et
70
[a] Reaction conditions: (Me3Sn)2 (1 equiv), benzene, 300 nm.
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derived from the allylic nitro compound 1e, with
iodomethyl phenyl sulfone gave the conjugated oxime
ether 6e in 79% yield. When a benzene solution of
ethyl iodoacetate and the conjugated enamine 3 f,
derived from 4-nitro-1-butene (1 f), was subjected to
the standard reaction conditions, 7 f was isolated after
acidic hydrolysis of the oxime ether 6g. The successful
synthesis of 7 f indicates that the procedure is useful
for the preparation of g-alkylated enals from g,d-
unsaturated nitro compounds.
This method can be further extended to other a-
substituted nitro compounds to yield several types of
synthetically useful carbonyl derivatives. For example,
the radical reaction of 3g under the same conditions,
followed by acidic hydrolysis, afforded the thiol ester
7g in good yield. Furthermore, the radical reaction of
3h afforded the oxime ester 6k, which underwent
Scheme 3. Synthesis of isoxazoles by radical reactions of 16.
Tin-based reagents are not always convenient because of
acidic hydrolysis to give the synthetically important a-
ketoester 7h.
the inherent toxicity of organotin derivatives and the
difficulties often encountered in removing tin residues from
the product.[12] For a tin-free approach,[13] we implemented
the findings of our previous studies on the radical rearrange-
ment of silyloxy radicals into the corresponding silyl radi-
cals.[14] Thus, the treatment of 1d with tert-butyldiphenylsilyl
chloride (TBDPSCl) and triethylamine in the presence of
silver triflate in dichloromethane afforded the bis-
(silyloxy)enamine 22 in 92% yield. When the radical reaction
was carried out with 22 and ethyl iodoacetate in the presence
of 2,2’-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) as
the initiator in dichloromethane at 308C for 9 h, the oxime
ether 23 was isolated in 83% yield (Scheme 4). To determine
the efficiency and the scope of the present method, additional
experiments were carried out with 22 and several different
alkyl halides. As shown in Table 2, alkyl iodides with an
electron-withdrawing substituent at the a position underwent
clean radical alkylation reactions under tin-free conditions.
In conclusion, we have developed a novel radical alkyla-
tion reaction of organic nitro derivatives via bis-
(silyloxy)enamines. The method enables not only alkylation
Oxime ether 10 was obtained by radical alkylation of the
bromo-substituted enamine 9 under similar conditions. The
acidic hydrolysis of 10 in methanolic HCl at reflux gave the
corresponding methyl ester 11 in 93% yield, whereas the
radical reaction of 10 with Bu3SnH/AIBN in refluxing
benzene provided the nitrile 12 in 84% yield. Furthermore,
10 underwent 1,3-dipolar cycloaddition upon treatment with
potassium fluoride in N,N-dimethylformamide (DMF) in the
presence of polarophiles via the nitrile oxide 13 generated in
situ. An acrylic ester, a vinyl sulfone, and phenylacetylene
underwent smooth 1,3-dipolar cycloadditions with 13 to give
the corresponding isoxazolines 14a and 14b, and isoxazole
14c (Scheme 2).[10]
Scheme 2. Radical alkylation of 9 followed by 1,3-dipolar cycloaddition.
Isoxazole derivatives can also be prepared by the radical
alkylation of 15. The radical reaction of 16 with phenyl
sulfonyl bromide under similar conditions afforded the oxime
ether 17 in 50% yield. When 17 was subjected to hydrolysis in
HCl/MeOH at reflux for 1 h, the isoxazole 19 was obtained in
79% yield.[11] Similarly, the use of ethyl iodoacetate as an
alkylating agent provided the isoxazole 21 after transesteri-
fication of 20 under acidic conditions (Scheme 3).
Scheme 4. Tin-free radical alkylation of 1d via 22.
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1732, 2859, 2934 cmÀ1; HRMS: calcd for C28H33NO3Si [M+]: 459.2230;
Table 2: Tin-free radical alkylation of the organic nitro compound 1d.[a]
found: 459.2231.
Entry
Substrate
Product
Yield [%]
Received: April 13, 2006
Revised: May 23, 2006
1
61
Published online: August 14, 2006
2
3
4
5
63
68
72
75
Keywords: alkylation · ketones · nitro compounds · radicals ·
synthetic methods
.
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Experimental Section
Typical procedure A: A solution of iodomethyl phenyl sulfone
(56 mg, 0.2 mmol), 3b (95 mg, 0.3 mmol), and hexamethylditin
(65 mg, 0.2 mmol) in benzene (1 mL; 0.2m in iodide) was purged
with nitrogen for 10 min and then irradiated in a photochemical
reactor at 300 nm for 9 h. The solvent was then evaporated under
reduced pressure, and the residue was purified by column chroma-
tography on silica gel with EtOAc/hexane (1:5) as the eluent to give
6b (49 mg, 71%, E/Z 5:1 (ratio calculated from the 1H NMR
spectrum)). 1H NMR (CDCl3, 400 MHz): d(E isomer) = 0.04 (s,
6H), 0.79 (s, 9H), 1.85 (s, 3H), 2.61–2.66 (m, 2H), 3.22–3.26 (m,
2H), 7.53–7.57 (m, 2H), 7.62–7.64 (m, 1H), 7.87–7.90 ppm (m, 2H);
d(Z isomer) = 0.07 (s, 6H), 0.86 (s, 9H), 1.80 (s, 3H), 2.52–2.57 (m,
2H), 3.30–3.35 (m, 2H), 7.53–7.57 (m, 2H), 7.62–7.64 (m, 1H), 7.87–
7.90 ppm (m, 2H); 13C NMR (CDCl3, 100 MHz): d(E isomer) = À5.3
(2C), 17.8, 20.2, 23.5, 25.9 (3C), 51.7, 128.1, 129.3, 133.8, 138.6,
157.4 ppm; IR (polymer): n˜ = 784, 839, 938, 1155, 1253, 1309, 1654,
2859, 2933 cmÀ1; HRMS: calcd for C16H27NO3SSi [M+]: 341.1481;
found: 341.1430.
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Typical procedure B (tin-free conditions): A solution of ethyl
iodoacetate (45 mg, 0.2 mmol), 22 (188 mg, 0.3 mmol), and V-70
(12 mg, 0.04 mmol) in dichloromethane (1 mL; 0.2m in iodide) was
purged with nitrogen for 10 min and then stirred at 308C under
nitrogen for 9 h. The solvent was then evaporated under reduced
pressure, and the residue was purified by column chromatography on
silica gel with EtOAc/hexane (1:20) as the eluent to give 23 (82 mg,
83%, E/Z 3.3:1 (ratio calculated from the 1H NMR spectrum)).
1H NMR (CDCl3, 400 MHz): d(E isomer) = 1.14 (s, 9H), 1.21 (t, J =
7.1 Hz, 3H), 2.66–2.70 (m, 2H), 3.23–3.27 (m, 2H), 4.11 (q, J = 7.1 Hz,
2H), 7.31–7.40 (m, 10H), 7.61–7.62 (m, 2H), 7.71–7.73 ppm (m, 3H);
d(Z isomer) = 1.00 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H), 2.50–2.54 (m,
2H), 2.84–2.88 (m, 2H), 3.91 (q, J = 7.1 Hz, 2H), 7.31–7.40 (m, 10H),
7.61–7.62 (m, 2H), 7.71–7.73 ppm (m, 3H); 13C NMR (CDCl3,
100 MHz): d(E isomer) = 14.1, 19.4, 22.2, 27.2 (3C), 31.0, 60.6, 126.4,
127.4, 127.5 (2C), 127.9, 128.4, 129.3, 129.6, 133.7, 135.1, 135.5 (2C),
161.5, 172.6 ppm; IR (polymer): n˜ = 704, 744, 1114, 1528, 1566, 1690,
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