Intermolecular radical addition and addition/cyclization reactions of alkoxyamines onto nonactivated alkenes

Article abstract of DOI:10.1021/ol034994k

(Matrix presented) Alkoxyamines A, which are readily prepared from commercially available starting materials, undergo efficient thermal radical carboaminoxylations onto various nonactivated alkenes to provide 1,4-functionalized malonates B in good to exce

Full text of DOI:10.1021/ol034994k

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2899-2902
Intermolecular Radical Addition and
Addition/Cyclization Reactions of
Alkoxyamines onto Nonactivated
Alkenes
Christian Wetter, Katja Jantos, Katharina Woithe, and Armido Studer*
Department of Chemistry, Philipps-UniVersity Marburg, 35032 Marburg, Germany
studer@mailer.uni-marburg.de
Received June 4, 2003
ABSTRACT
Alkoxyamines A, which are readily prepared from commercially available starting materials, undergo efficient thermal radical carboaminoxylations
onto various nonactivated alkenes to provide 1,4-functionalized malonates B in good to excellent yields. The experiments are very easy to
conduct. The carboaminoxylations can be combined with radical cyclization and fragmentation processes.
Recently, we published our first results on environmentally
benign radical alkoxyamine isomerization reactions.1 These
processes are controlled by the so-called Persistent Radical
Effect (PRE).2 For example, alkoxyamine 1 was readily isom-
erized to the corresponding cyclized alkoxyamines 2 (70%)
and 3 (13%) upon simple heating in t-BuOH (Scheme 1).
as intramolecular carbohydroxylations (without N-O cleav-
age as intramolecular carboaminoxylations).
Transition-metal-catalyzed3 or ionic additions4 of alcohols
onto C-C double bonds are well established in organic
synthesis. However, alcohol additions, where the C-O bond
inserts into the multiple bond (carbohydroxylation), have
rarely been investigated to date.5 Herein we present our first
results on intermolecular radical alkoxyamine additions onto
nonactivated double bonds.
Scheme 1. PRE in Radical Cyclization Reactions
Alkoxyamines have found widespread application as
regulators/initiators for living radical polymerizations.6 To
circumvent polymerization in our planned bimolecular
processes, the stability of the starting and the product
alkoxyamine has to be tuned carefully. We have previously
(2) (a) Studer, A. Chem. Eur. J. 2001, 7, 1159. (b) Fischer, H. Chem.
ReV. 2001, 101, 3581.
(3) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. J. Org.
Chem. 2001, 66, 270 and references therein.
Since the N-O bond can be cleaved with various methods,
these alkoxyamine isomerizations can formally be regarded
(4) Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry;
Oxford University Press: New York, 2001.
(1) Studer, A. Angew. Chem., Int. Ed. 2000, 39, 1108. See also: Allen,
D. A.; Fenwick, M. F.; Henry-Riyad, H.; Tidwell, T. T. J. Org. Chem.
2001, 66, 5759. Leroi, C.; Fenet, B.; Couturier, J.-L.; Guerret, O.; Ciufolini,
M. A. Org. Lett. 2003, 5, 1079.
(5) (a) Nakamura, H.; Sekido, M.; Ito, M.; Yamamoto, Y. J. Am. Chem.
Soc. 1998, 120, 6838. (b) Monteiro, N.; Balme, G. Synlett 1998, 746. (c)
Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785.
(6) Hawker, C. J.; Bosman, A. W.; Hart, E. Chem. ReV. 2001, 101, 3661.
10.1021/ol034994k CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/10/2003

shown that the C-O bond dissociation energy correlates with
the C-radical stability.7 Alkoxyamines derived from nonsta-
bilized C-radicals have strong C-O bonds and are therefore
prevented from undergoing C-O bond homolysis. Thus,
thermal reversible homolysis of an alkoxyamine 4 derived
from a stabilized radical R1 will generate R1, which in turn
can react with an olefin CH2dCHR2 to afford radical adduct
5 (Scheme 2). If 5 is a nonstabilized radical, irreversible
prepared via enolate oxidation using CuCl2 in the presence
of TEMPO (see Supporting Information). Pleasingly, reaction
of 10 with 1-octene (5 equiv) in t-BuOH at 135 °C for 3
days afforded 12 in 35% yield (Table 1, run 1). As a side
Table 1. Reaction of 10 and 11 with Various Olefins (5 equiv)
at 135 °C for 3 days
Scheme 2. PRE in Intermolecular Addition Reactions
run
R1
R2
compd
solvent
t-BuOH
MeOH
CH3CO2Et
DMF
yield (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
12
12
12
12
12
12
12
13
13
13
14
15
16
17
18
19
20
35a
25
55
46
63
64
66
54
72b
76c
49
78
69b
C6H5Cl
trapping with TEMPO will eventually provide 6. Since the
generation of radical R1 is a reversible process, it has a longer
formal lifetime, and the method should particularly be useful
for slow intermolecular radical additions.8
C6H5CF3
ClCH2CH2Cl
t-BuOH
t-BuOH
t-BuOH
ClCH2CH2Cl
ClCH2CH2Cl
t-BuOH
ClCH2CH2Cl
t-BuOH
t-Bu C6H13
t-Bu C6H13
The first experiments were performed using 1-octene as a
radical acceptor. The reactions were conducted in t-BuOH
(1 M, sealed tube) at 135 °C with a 5-fold excess of the
olefin. However, none of the desired products were obtained
using the alkoxyamines 7 and 8. The intermolecular addition
of the stable radicals derived from 7 and 8 to 1-octene is
too slow to compete with TEMPO trapping. We therefore
studied the intermolecular addition of the more reactive
tertiary butyl radical using alkoxyamine 9. Tertiary alkyl
radicals react with 1-octene about 2 orders of magnitude
faster than secondary benzylic radicals.9 However, addition
did not occur. The activation energy for efficient C-O bond
homolysis in 9 is too large.7 Furthermore, tertiary alkyl-
TEMPO compounds are not sufficiently stable under the
applied conditions (see below). Malonic ester derivatives
10 t-Bu C6H13
11 Me
12 Me
13 t-Bu OBu
14 Me
15 t-Bu (CH2)3OCO2Me
16 Me
17 t-Bu (CH2)3OTBDMS
CH2CH2Ph
OBu
(CH2)3OCO2Me
42
38b
70
(CH2)3OTBDMS
ClCH2CH2Cl
t-BuOH
55b
a Transesterification product formed in 36%; see text. b Reaction for 5
days. c Performed with 10 equiv of 1-octene.
product the corresponding tert-butyl methylmalonate derived
from monotransesterification of 12 with t-BuOH was formed
in 36% yield (see Supporting Information). To circumvent
the transesterification, the experiment was repeated in MeOH;
however, a lower yield was obtained (25%, run 2). Experi-
ments in ethyl acetate, DMF, trifluorotoluene, chlorobenzene,
and dichloroethane provided good results (runs 3-7). We
further studied the reaction using di-tert-butyl malonate 11
in t-BuOH as a solvent. Product 13 was isolated in 54% yield
along with 40% yield of 11 (run 8). Reaction for 5 days
under otherwise identical conditions afforded 13 in an
excellent yield (72%, run 9). Reaction time can be decreased
if 10 equiv of 1-octene is used (3 days, 76%, run 10). Thus,
the best results were obtained using malonate 10 in ClCH2-
CH2Cl or 11 in t-BuOH. These two protocols were used for
the following studies.
Figure 1. Various alkoxyamines studied.
have successfully been used in atom transfer reactions.10
Malonyl radicals are reactive in intermolecular addition
reactions9 and, due to their stability, should be readily
generated with our method. TEMPO-derivative 10 was easily
The reaction with 4-phenyl-1-butene (f 14), butyl vinyl
ether (f 15,16), CH2dCH(CH2)3OCO2Me (f 17,18), and
CH2dCH(CH2)3OTBDMS (f 19,20) provided the corre-
sponding addition products in moderate to good yields,
(7) Marque, S.; Fischer, H.; Baier, E.; Studer, A. J. Org. Chem. 2001,
66, 1146. See also: Marque, S.; Fischer, H.; LeMercier, C.; Tordo, P.
Macromolecules 2000, 33, 4403.
(8) Formal long-lived radicals due to degenerate processes: Zard, S. Z.
Angew. Chem., Int. Ed. Engl. 1997, 36, 672.
(10) Curran, D. P.; Chen, M.-H.; Spletzer, E.; Seong, C. M.; Chang,
C.-T. J. Am. Chem. Soc. 1989, 111, 8872. Review: Byers, J. In Radicals
in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 1, 72
(9) Fischer, H.; Radom, L. Angew. Chem., Int. Ed. 2001, 40, 1341.
2900
Org. Lett., Vol. 5, No. 16, 2003

documenting the generality of our method (runs 11-17). It
is not surprising that the highest yields were obtained with
the most nucleophilic olefin (butyl vinyl ether), since the
malonyl radical is electrophilic in nature.9 Starting TEMPO-
malonate could not be recovered in these experiments. Some
decomposition of 10 and 11 occurs under the applied
conditions.
Carboaminoxylations onto terminally substituted olefins
can also be performed, as shown for the reaction of 10 with
cyclohexene to provide 21 (Scheme 3, 58%).
known that the reaction of TEMPO with a C-centered radical
is slower in polar protic solvents.13 Therefore, in t-BuOH,
telomerization can compete with TEMPO trapping of the
primary C-radical formed after cyclization.
We also investigated reactions leading to tertiary alkoxy-
amines. We found that the product alkoxyamines always un-
dergo elimination of TEMPOH under the reaction conditions.14
The elimination products are also useful compounds for
further synthetic manipulations. For example, reaction of 11
with 2-methyl-1-nonene provided 35 in 56% yield, unfor-
tunately, as a mixture of regioisomers (Scheme 5).15 Simi-
Scheme 3. Thermal Addition of 10 to Cyclohexene
Scheme 5. Addition/Elimination Reactions
We next studied intermolecular additions followed by
cyclization reactions. Various dienes 22-25 (3 equiv) were
reacted with malonates 10 and 11 under slightly modified
conditions (f 26-33, Scheme 4, Table 2).11
Scheme 4. Addition/Cyclization Reactions
larly, 34 was isolated in 37% yield. However, regioselective
elimination can also be obtained. For example, addition/
cyclization of 10 using acceptor 36 provided cyclization/
regioselective elimination product 37 (42%, cis/trans ) 2.4:
1). We also studied an example comprising an addition/
fragmentation sequence. Thus, reaction of â-pinene with 11
afforded the addition/fragmentation/regioselective elimination
product 39 in good yields (75%). In analogy, 38 was prepared
starting from malonate 10 (55%).
Finally, for a single case, we also conducted the reductive
C-O bond cleavage (“deprotection”). Carboaminoxylation
product 12 was treated with activated Zn in AcOH/THF/
H2O (Scheme 6). As expected, the secondary alcohol
Addition/cyclizations with 10 in ClCH2CH2Cl afforded 26,
28, 30, and 32 in moderate to good yields as a cis/trans
mixture of isomers.12 In t-BuOH with 11, we always
observed telomerization as a side reaction (n ) 2). It is
Table 2. Intermolecular Addition/Cyclization Reactions
starting
material
product
(n ) 1) (%) cis:transa
Scheme 6. Reductive N-O Bond Cleavage with Subsequent
X
R
Lactonization
22
22
23
23
24
24
25
25
C(CO2Me)2
C(CO2Me)2
Me
t-Bu
Me
t-Bu
Me
t-Bu
26
27
28
29
30
31
32
33
68
40b
33c
37d
49
2.2:1
1.8:1
1.7:1
1.3:1
1.5:1
2.3:1
2.1:1
O
O
NTos
NTos
42e
36
34f
C(CH2CH2O)2CMe2 Me
C(CH2CH2O)2CMe2 t-Bu
liberated underwent lactonization under the reaction condi-
tions to provide lactone 40 in 73% yield as a 1:1 mixture of
isomers.
a Determined by HPLC or NMR. b Consisted of 10% telomer was isolated
as a side product. c Performed with 6 equiv of 23. d Consisted of 12%
telomer was isolated as a side product. e Consisted of 23% telomer was
isolated as a side product. f Consisted of 12% telomer was isolated as a
side product.
(11) Reactions under the above-described optimized conditions provided
lower yields.
Org. Lett., Vol. 5, No. 16, 2003
2901

In conclusion, we have presented efficient radical car-
boaminoxylations of various nonactivated C-C double bonds
to provide synthetically useful functionalized malonates. It
is important to note that the malonyl radical precursors can
be readily prepared in one step in high yield starting from
commercially aVailable TEMPO and dialkyl malonates.
Furthermore, the reactions are Very easy to conduct. Simple
mixing of the starting materials and heating allows the
preparation of functionalized malonates in a single operation.
The carboaminoxylations can be combined with radical
cyclization and fragmentation reactions. N-O bond cleavage
can be performed under standard conditions to provide
γ-butyrolactones.
(12) Diastereoisomers could not be separated. The relative configuration
was assigned on the basis of literature reports on similar cyclizations:
Amrein, S.; Studer, A. HelV. Chim. Acta 2002, 85, 3559.
(13) Beckwith, A. L. J.; Bowry, V. W.; Ingold, K. U. J. Am. Chem. Soc.
1992, 114, 4983.
(14) We currently believe that elimination occurs via an ionic-type
process from the corresponding tertiary alkoxyamines. Since C-O bond
homolysis in these tertiary alkoxyamines is not efficient, radical dispro-
portionation is less likely. For a discussion, see: Ananchenko, G. S.; Fischer,
H. J. Polym. Sci. Part A: Polym. Chem. 2001, 39, 3604.
(15) For 34, exomethylene:âγ-unsaturated:γδ-unsaturated ) 3.9:1:1.2.
For 35, exomethylene:âγ-unsaturated:γδ-unsaturated ) 1.1:1:0.4. The âγ-
and γ,δ-unsaturated compounds were obtained as a trans/cis mixture of
isomers.
Acknowledgment. We thank the Fonds der Chemischen
Industrie (Ph.D. stipend to C.W.) and the Swiss Federal
Office for Education and Science (D12/0005/98) for funding.
Supporting Information Available: Experimental pro-
cedures and analytical data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034994K
2902
Org. Lett., Vol. 5, No. 16, 2003