Radical cyclizations of carboxylic mixed anhydrides

Article abstract of DOI:10.1016/S0040-4039(00)01418-0

Carboxylic mixed anhydrides are moderately reactive toward alkyl radicals and can be used as radical acceptors in the radical cyclizations, although carboxylic esters and amides are generally unreactive toward alkyl radicals. (C) 2000 Elsevier Science Ltd

Full text of DOI:10.1016/S0040-4039(00)01418-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8127–8130
Radical cyclizations of carboxylic mixed anhydrides
a,
a
a
a
b,
Sunggak Kim, * Sang Yong Jon, Jung Yoon Do, Hyun Ji Song and Sung Soo Kim *
a
Department of Chemistry and Center for Molecular Design and Synthesis,
School of Molecular Science (BK21) Korea Advanced Institute of Science and Technology,
Taejon 305-701, South Korea
b
Department of Chemistry, Inha University, Inchon 402-752, South Korea
Received 13 July 2000; revised 16 August 2000; accepted 18 August 2000
Abstract
Carboxylic mixed anhydrides are moderately reactive toward alkyl radicals and can be used as radical
acceptors in the radical cyclizations, although carboxylic esters and amides are generally unreactive
toward alkyl radicals. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: radical cyclization; carboxylic mixed anhydride; radical acceptor.
Additions of alkyl radicals onto carbonyl groups are reversible and energetically unfavorable
due to strong p-bond strengths of carbonyl bonds. The reverse reactions (b-fragmentation1
reactions of alkoxy radicals) are faster than additions of alkyl radicals onto carbonyl groups.
Thus, it is anticipated that carbonyl derivatives can not be used as efficient radical acceptors.
The use of carboxylic acid derivatives as radical acceptors in intermolecular addition reactions
2
is uncommon and only several reports have appeared to date. Similarly, only several carbonyl
3
derivatives are effective in radical cyclizations to some extent.
Carboxylic esters and amides are generally unreactive toward carbon-centered radicals and
4
have not been used as radical acceptors although two exceptions have been reported to date.
We assumed that the low reactivity of carboxylic acid derivatives such as esters and amides
would be due to the p-bond delocalization of the carbonyl groups with non-bonding electrons
of heteroatoms such as oxygen and nitrogen. Thus, the CꢀO bonds of esters and amides would
be something less than the CꢀO bonds of aldehydes and ketones. If this idea might be true, one
can expect that resonance stabilization should be greatly reduced by introducing an electron-
*
Corresponding authors. Fax:+82-42-869-8370; e-mail: skim@mail.kaist.ac.kr
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01418-0

8128
withdrawing group. The introduction of an electron-withdrawing group should lower the energy
5
of the LUMO of a radical acceptor, thereby increasing the rate of addition. We have studied
this intriguing possibility of using carboxylic acid derivatives such as mixed anhydrides as
radical acceptors.
We initially studied the radical reaction of ester 1a with Bu SnH/AIBN in refluxing benzene
3
under a high dilution and direct reduction product 3a was isolated in 82% yield without yielding
b-cleavage product 6a as shown in Scheme 1. However, radical reaction of mixed anhydride 1b
with Bu SnH/AIBN under the same condition resulted in the formation of a mixture of 3b and
3
6
b. Since 3b and 6b were unstable on silica gel, the mixed anhydride products 3b and 6b were
treated with thiophenol and dicyclohexylcarbodiimide in the presence of a catalytic amount of
4
6
-dimethyl-aminopyridine to afford the thioester 3c and 6c in 20 and 65% yields, respectively.
Apparently, 1,4-migration product 6b was formed by the addition of the alkyl radical to mixed
anhydride 1b, subsequent b-cleavage and reduction by Bu SnH. We also briefly studied
3
1
,2-migration of mixed anhydride group via 3-exo cyclization (Scheme 2). Radical reaction of
mixed anhydride 7 under the same conditions followed by treatment with thiophenol and
DCC–DMAP provided a mixture of 8 and 9 in 15 and 61% yields, apparently resulting from
1
,2-migration and the direct reduction, respectively. As we anticipated, the results obtained here
clearly indicate that mixed anhydrides could be used as radical acceptors, although the efficiency
of this process would depend very much on the nature of the substrate.
Scheme 1.
Scheme 2.
In order to study the efficiency of several different types of carboxylic mixed anhydrides as
radical acceptors in the radical cyclizations, we prepared carboxylic mixed anhydride 10a,
carboxylic carbonic anhydride 10b, carboxylic phosphinic anhydride 10c, and carboxylic phos-

8129
phonic anhydride 10d. Radical cyclization of alkyl radical 11 would give rise to compound 15
via two consecutive b-cleavages of alkoxy radical 12 (Scheme 3). Treatment of mixed anhydride
1
0a with a catalytic amount of hexabutylditin (0.1 equiv.) in benzene at 300 nm for 7 h followed
by addition with thiophenol and DCC–DMAP afforded a mixture of 14a and 15a in 7 and 78%
yields, respectively. Experimental results are summarized in the Table 1. The mixed anhydride
7
products were converted into the corresponding thioesters due to instability of mixed anhydrides
on silica gel. Among four different mixed anhydrides, carboxylic carbonic anhydride 10b seems
to be the most efficient, although 10a is equally effective. 1,4-Migration (n=1) via 5-exo ring
closure was slightly more efficient than 1,5-migration (n=2) via 6-exo ring closure. Carboxylic
phosphinic anhydride 10c and phosphonic anhydride 10d were somewhat less efficient than 10a
and 10b but still gave 1,4- and 1,5-migration products as a major product.
Scheme 3.
Table 1
Intramolecular additions of alkyl radicals onto mixed anhydrides
Entry
Substrate
Time, h
n
Product (X=SPh), yield %
1
4
15
78
69
74
79
61
53
61
52
1
2
3
4
5
6
7
8
10a: X=OCOPh
9
6
1
2
1
2
1
2
1
2
7
18
5
10b: X=OCOOCH Ph
7
2
6
8
10c: X=OP(O)Ph2
13
8
21
16
29
20
10d: X=OP(O)(OPh)2
12
8

8130
Encouraged by the results obtained here, we next studied the possibility of using mixed
anhydrides as radical acceptors in the intermolecular radical carboxylation reaction. However,
our attempts were unsuccessful. When a benzene solution of mixed anhydride 16 was treated
with 4-phenoxybutyl iodide in the presence of hexabutylditin (0.1 equiv.) at 300 nm for 10 h, the
desired mixed anhydride 17 was not detected and a small amount of 4-phenoxybutane from the
direct reduction was isolated along with the starting iodide and several unidentified products.
In conclusion, we have demonstrated that carboxylic mixed anhydrides were much more
reactive than carboxylic esters toward alkyl radicals and could be utilized as radical acceptors in
the radical cyclizations.
Acknowledgements
This work was supported by grants from the Korea Research Foundation, BK21 Project, and
the Center for Molecular Design and Synthesis (CMDS).
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6
7
. A representative experimental procedure is as follows. A solution of 10a (n=1) (61 mg, 0.1 mmol) and
bis(tributyltin) (18 mg, 0.03 mmol) in benzene (2 mL) in a pyrex tube was degassed for 10 min and irradiated at
300 nm in a Rayonet photochemical reactor for 9 h. After the solution was concentrated under reduced pressure,
the residue was dissolved in methylene chloride (2 mL) and then thiophenol (20 mL, 0.2 mmol), DCC (42 mg, 0.2
mmol), and DMAP (2 mg) were added to the solution. After being stirred at room temperature for 2 h, the
reaction mixture was diluted with methylene chloride (20 mL), washed with 0.1 M HCl solution and Na CO3
2
solution, dried and concentrated to dryness. The residue was subjected to the flash silica gel column chromatogra-
phy to give 14a (n=1) (3.5 mg, 7%) and 15a (17 mg, 78%).
.