Radical-mediated γ-functionalizations of α,β-unsaturated carboxylic amides

Article abstract of DOI:10.1002/anie.200460820

Highly successful tin-free, radical-mediated alkylations of α,β-unsaturated carboxylic amides have been carried out. Alkyl iodides and bromides bearing α-electron-withdrawing groups undergo selective γ-additions to diene O,N-acetals (see scheme). This app

Full text of DOI:10.1002/anie.200460820

Communications
Radical Reactions
alkylation of a,b-unsaturated carboxylic amides. Our idea to
effect g-alkylation relies on the stability of the radical
intermediates derived from a and g attackof an alkyl radical
onto diene O,N-acetal 3 (Scheme 2). The g-alkylation would
be feasible because it is evident that intermediate 5 should be
more stable than intermediate 4 owing to the allylic nature of
5.
Radical-Mediated g-Functionalizations of a,b-
Unsaturated Carboxylic Amides**
Sunggak Kim* and Chae Jo Lim
a,b-Unsaturated carbonyl compounds are important inter-
mediates in organic synthesis.[1] Reaction of their enolate
anions with various electrophiles generally affords a-func-
tionalized products. Despite their versatility in synthetic
manipulations, g-functionalization of a,b-unsaturated carbon-
yl compounds, including g-alkylation, has been often a very
difficult and unresolved problem. Several methods to effect
this operation have been developed over the years and
include the use of g-arylsulfonyl groups as regiospecific
control elements,[2] copper dienolates,[3] and zinc bromide
catalyzed alkylation of O-silylated dienolates.[4,5] However,
these methods have their limitations in that they, most
importantly, depend on the nature of the alkylation agents
and dienolates. Thus, the g-functionalization of a,b-unsatu-
rated carbonyl compounds has been a very challenging
problem.
Scheme 2. Radical approach to the g-functionalization of a,b-unsatu-
rated carboxylic amides via 3.
Three diene O,N-acetals 9a, 9b, and 9c were prepared
(Scheme 3). The coupling of acid chloride 6a with 7 and
triethylamine in the presence of a catalytic amount of 4-
We recently reported a radical alkylation method based
on the addition of an alkyl radical to ketene O,N-acetal 1
À
followed by the cleavage of the N O bond to afford the
alkylated carboxylic amide
2
after aqueous workup
(Scheme 1).[6,7] In this approach, the rearrangement of a
Scheme 1. Tin-free radical alkylation of carboxylic amides. Cbz=benzyl-
oxycarbonyl, TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldimethyl-
silyl.
Scheme 3. Preparation of diene O,N-acetals. AIBN=azobisisobutyroni-
trile, DMAP=4-(dimethylamino)pyridine, LHMDS=lithium hexame-
thyldisilazide, TBSOTf=tert-butyldimethylsilyl trifluoromethanesulfo-
nate, V-70=2,2’-azobis(4-methoxy-2,4-dimethylvaleronitrile).
silyloxy radical to a silyl radical was utilized effectively in tin-
free alkylation.[8] A radical-mediated g-functionalization
approach has not, to the best of our knowledge, been reported
to date and seems to be a conceptual advance to our previous
finding. Therefore, we initially studied the radical-mediated g-
(dimethylamino)pyridine (DMAP) in dichloromethane at
room temperature for 30 minutes gave amide 8a in 78%
yield. The amide 8a was treated with lithium hexamethyldi-
silazide (LHMDS) in THF at À408C in the presence of tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) to
afford 9a in 95% yield. Similarly, diene O,N-acetals 9b and
9c were prepared in high yields. They were observed to be
fairly stable to purification by silica gel column chromatog-
raphy.
[*] Prof. Dr. S. Kim, C. J. Lim
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
Irradiation of a solution of 9a (1.5 equiv), iodoacetophe-
none (1.0 equiv) and hexamethylditin (1.1 equiv) in benzene
at 300 nm for 3 h gave 10a in 79% yield after isolation by
silica gel column chromatography without the formation of
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.
5378
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DOI: 10.1002/anie.200460820
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Angewandte
Chemie
the a-alkylation product (Scheme 4). Encouraged by this
result, we studied the tin-free g-alkylation of 9a based on the
previously reported rearrangement of a silyloxy radical into a
silyl radical.[9] Reaction of 9a with iodoacetophenone with
reactions were also carried out with 9c, derived from
senecioic acid, similar results were obtained, which confirms
the generality of the present method (Scheme 5).[10] We
consider the exclusive formation of g-alkylation products
Scheme 5. g-Functionalization of senecioic acid derivative 9c.
under tin-free radical conditions with no indication of the
formation of a-alkylation products to be of synthetic impor-
tance. However, this method proved to be limited with
respect to nucleophilic alkyl radicals. Irradiation of a benzene
solution of 9b with an equimolar mixture of 4-phenoxybutyl
iodide and hexamethylditin at 300 nm for 10 h gave the
desired g-alkylation product (25%) together with the dimer-
ized product (31%) and the starting iodide (11%), thus
indicating that the addition of a nucleophilic alkyl radical
onto electron-rich 9b is slow and inefficient.
Subsequently, the possibility of the g-addition of several
synthetically useful hetero groups, such as phenylsulfanyl and
phenylsulfonyl, to 9a was examined. It is known that the
phenylsulfenylation and phenylselenylation of a,b-unsatu-
rated carbonyl compounds occurs exclusively at the a posi-
tion,[11] whereas trimethylsilylation of a,b-unsaturated aldi-
mines occurs at the g position.[12] Based on our previous
rationale, the addition of the phenylsulfanyl radical to 9a at
the g position could be anticipated. When the radical-
mediated reaction was carried out with 9a and thiophenol
under the same conditions, phenylsulfenylation occurred
exclusively at the g position. Reaction of 9a with 2 equiv-
alents of thiophenol in dichloromethane in the presence of V-
70 as the initiator gave 15 in 67% yield because of further
addition of the phenylsulfanyl radical to 13, whereas a 63:15
mixture of 14 and 15 was isolated when 1 equivalent of
thiophenol was used. The reaction of phenylsulfonyl bromide,
diphenyl diselenide, and tris(trimethylsilyl)silane gave g-
addition products in high yields (Scheme 6).
Scheme 4. Formation of g-functionalized products 10a and 10b.
azobisisobutyronitrile (AIBN) as the initiator in benzene at
808C for 3 h afforded 10a in 57% yield. Apparently, the low
yield resulted from thermal decomposition of 9a to some
extent. When the reaction was carried out with V-70 (2,2’-
azobis(4-methoxy-2,4-dimethylvaleronitrile)) as the initiator
in dichloromethane at 308C for 10 h, the reaction cleanly
afforded 10a in 86% yield. Also, employing 9b in the reaction
under the same conditions gave 10b in 72% yield. To
determine the efficiency and scope of the present method,
we performed additional experiments with several different
alkyl iodides and bromides and with 9a and 9b as substrates.
As shown in Table 1, alkyl iodides and bromides bearing an a-
electron-withdrawing group underwent clean g-alkylations
under tin-free conditions. Notably, the monosubstituted diene
O,N-acetal 9b gave comparable results to 9a. When further
Table 1: Tin-free radical g-alkylations.[a]
Entry
Substrate
Product
Yield [%][b]
10a 10b
1
2
3
4
5
6
77
64
75
77
79
85
74
71
In conclusion, we have developed the first radical-
mediated g-functionalization of a,b-unsaturated carboxylic
amides via diene O,N-acetals under tin-free conditions to give
a synthetically useful process. Further studies to expand this
strategy to the a,b-unsaturated aldehydes and ketones are
underway.
82
73
Experimental Section
65[c]
74[d]
Typical procedure:
A solution of iodoacetophenone (49 mg,
0.2 mmol), 9a (176 mg, 0.3 mmol), and V-70 (12 mg, 0.04 mmol) in
dichloromethane (1 mL; 0.2m in iodide) was degassed with nitrogen
for 10 min, and the solution was then stirred at 308C under nitrogen
for 10 h. The solvent was evaporated under reduced pressure and the
residue was purified by silica-gel column chromatography with
EtOAc/hexane (1:3) as the eluant to give 10a (58 mg, 86%).
1H NMR (CDCl3, 400 MHz): d = 2.65–2.71 (m, 2H), 3.15 (t, J =
[a] The reaction was carried out with V-70 as the initiator in CH2Cl2 at
308C for 10 h. [b] Yield of isolated product. [c] syn/anti=2.5:1. [d] syn/
anti=1:1.
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Communications
Wang, A. Hosomi, Org. Lett. 2001, 3, 2591 – 2594; d) M. G.
Roepel, Tetrahedron Lett. 2002, 43, 1973 – 1976; e) Y. Cai, B. P.
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1
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Scheme 6. g-Addition of hetero groups to diene O,N-acetal 9a.
7.1 Hz, 2H), 5.16 (s, 2H), 6.89 (d, J = 15.4 Hz, 1H), 7.21 (dt, J =
15.4 Hz, 6.9 Hz, 1H), 7.34–7.95 ppm (m, 11H); 13C NMR (CDCl3,
100 MHz): d = 26.7, 36.6, 67.9, 122.0, 128.0, 128.4, 128.7 (C 2), 133.3,
134.3, 134.9, 136.6, 149.5, 151.5, 165.5, 198.1 ppm; IR (polymer): n˜ =
3292, 1764, 1687, 1648, 1523, 1204, 1049, 746, 698 cmÀ1; HRMS: calcd
for C20H19NO4: 337.1314, found: 337.1324.
Received: May 28, 2004
Keywords: alkenes · alkylation · carboxylic amides · radicals ·
.
synthetic methods
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www.angewandte.org
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