Microflow radical carboaminoxylations with a novel alkoxyamine

Article abstract of DOI:10.1021/ol900713d

Highly efficient thermal radical carboaminoxylations of various olefins by using the novel alkoxyamine A to give adducts of type B are described. It is reported that these radical addition reactions can be performed in a microflow reaction system. As comp

Full text of DOI:10.1021/ol900713d

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2457-2460
Microflow Radical Carboaminoxylations
with a Novel Alkoxyamine
Inga C. Wienho¨fer,† Armido Studer,*,† Md. Taifur Rahman,‡ Takahide Fukuyama,‡
and Ilhyong Ryu*,‡
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t, Corrensstrasse 40,
48149 Mu¨nster, Germany, and Department of Chemistry, Graduate School of Science,
Osaka Prefecture UniVersity, Sakai, Osaka 599-8531, Japan
studer@uni-muenster.de; ryu@c.s.osakafu-u.ac.jp
Received April 4, 2009
ABSTRACT
Highly efficient thermal radical carboaminoxylations of various olefins by using the novel alkoxyamine A to give adducts of type B are described.
It is reported that these radical addition reactions can be performed in a microflow reaction system. As compared to conventional batch
reaction setup, significantly higher yields are obtained by running carboaminoxylations using the microflow system under analogous conditions.
Microreactor technology has gained increased attention
during the past few years and has been used to conduct
different types of reactions.1-3 However, only few reports
on the use of microreactors to conduct radical chemistry have
appeared to date.4 Herein we present radical carboaminoxy-
lations5 by using either classical batch or microflow technol-
ogy. Importantly, these radical reactions are performed
without the need of toxic trialkyl tin compounds.6 Moreover,
we introduce a novel alkoxyamine for highly efficient radical
carboaminoxylation reactions.7
We have shown that various alkoxyamines undergo
thermal radical addition reactions to various unactivated
(2) For recent reports on microreactor-assisted organic syntheses, see:
(a) Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami, T.; Yoshida,
J. J. Am. Chem. Soc. 2007, 129, 3046. (b) Sahoo, H. R.; Kralj, J. G.; Jensen,
K. F. Angew. Chem., Int. Ed. 2007, 46, 5704. (c) Tanaka, K.; Motomatsu,
S.; Koyama, K.; Tanaka, S.; Fukase, K. Org. Lett. 2007, 9, 299. (d) Carrel,
F. R.; Geyer, K.; Code´e, J. D. C.; Seeberger, P. H. Org. Lett. 2007, 9,
2285. (e) Bogdan, A. R.; Mason, B. P.; Sylvester, K. T.; McQuade, D. T.
Angew. Chem., Int. Ed. 2007, 46, 1698. (f) Miller, P. W.; Long, N. J.; de
Mello, A. J.; Vilar, R.; Audrain, H.; Bender, D.; Passchier, J.; Gee, A.
Angew. Chem., Int. Ed. 2007, 46, 2875. (g) Uozumi, Y.; Yamada, Y. M. A.;
Beppu, T.; Fukuyama, N.; Ueno, M.; Kitamori, T. J. Am. Chem. Soc. 2006,
128, 15994.
† Westfa¨lische Wilhelms-Universita¨t.
‡ Osaka Prefecture University.
(1) Reviews: (a) Ehrfeld, W.; Hessel, V.; Lo¨we, H. Microreactors: New
Technology for Modern Chemistry; Wiley-VCH: Weinheim, 2000. (b)
Hessel, V.; Hardt, S.; Lo¨we, H. Chemical Micro Process Engineering;
Wiley-VCH: Weinheim, 2004. (c) Wirth, T. Microreactors in Organic
Synthesis and Catalysis; Wiley-VCH: Weinheim, 2008. (d) Hessel, V;
Renken, A.; Schouten, J. C.; Yoshida, J. Micro Process Engineering; Wiley-
VCH: Verlag, 2009. (e) Ja¨hnisch, K.; Hessel, V.; Lo¨we, H.; Baerns, M.
Angew. Chem., Int. Ed. 2004, 43, 406. (f) Geyer, K.; Code´e, J. D. C.;
Seeberger, P. H. Chem.sEur. J. 2006, 12, 8434. (g) Ahmed-Omer, B.;
Brandt, J. C.; Wirth, T. Org. Biomol. Chem. 2007, 5, 733. (h) Watts, P.;
Wiles, C. Chem. Commun. 2007, 443. (i) Mason, B. P.; Price, K. E.;
Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. ReV. 2007, 107,
2300. (j) Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008,
151. Also see a review on continuous flow reactions: (k) Jas, G.; Kirschning,
(3) (a) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org.
Lett. 2002, 4, 1691. (b) Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Org. Process
Res. DeV. 2004, 8, 477. (c) Rahman, M. T.; Fukuyama, T.; Kamata, N.;
Sato, M.; Ryu, I. Chem. Commun. 2006, 2236. (d) Fukuyama, T.; Hino,
Y.; Kamata, N.; Ryu, I. Chem. Lett. 2004, 33, 1430.
(4) (a) Sugimoto, A.; Sumino, Y.; Takagi, M.; Fukuyama, T.; Ryu, I.
Tetrahedron Lett. 2006, 47, 6197. (b) Fukuyama, T.; Kobayashi, M.;
Rahman, Md. T.; Kamata, N.; Ryu, I. Org. Lett. 2008, 10, 533. (c) Odedra,
A.; Geyer, K.; Gustafsson, T.; Gilmour, R.; Seeberger, P. H. Chem.
Commun. 2008, 3025. (d) Sugimoto, A.; Fukuyama, T.; Sumino, Y.; Takagi,
M.; Ryu, I. Tetrahedron 2009, 65, 1593.
A. Chem.sEur. J. 2003, 9, 5708
.
10.1021/ol900713d CCC: $40.75
Published on Web 05/07/2009
 2009 American Chemical Society

olefins. Radical generation occurs by C-O-bond homolysis
in these processes. The C-radical adds to the olefin, and the
thus formed adduct radical is eventually trapped by the
nitroxide (aminoxyl radical) to form the corresponding
alkoxyamine product (Scheme 1).5
from dimethylmalonate and 3 (see Supporting Information).
We were pleased to observe that 1c reacted as efficiently as
1b and product 2c was isolated in 83% yield (1.5 h, 125
°C). As previously shown, activation energy Ea for C-O-
bond homolysis of an alkoxyamine correlates well with the
reaction outcome of the corresponding radical carboami-
noxylation. For malonates 1a and 1b we reported activation
energies of 140.0 and 124.9 kJ/mol, respectively.7e For 1c
we measured (see Supporting Information) a value of 128.8
kJ/mol, which shows that the novel, readily available bulky
alkoxyamine 1c compares well with the highly efficient 1b.
Therefore, all further studies were performed by using
alkoxyamine 1c.
Scheme 1
.
Intermolecular Radical Alkoxyamine Additions by
Using TEMPO-Derived Alkoxyamines
To document substrate scope, various olefins were reacted
with 1c under optimized conditions. Results are summarized
in Figure 1. Reactions with unactivated olefins (f 4a-c),
Intermolecular reactions, which we call radical carboami-
noxylations, occurred efficiently by using alkoxyamines
derived from malonates.5,6 The structure of the nitroxide
moiety in the alkoxyamine heavily influenced reaction
outcome. Hence, alkoxyamine 1a bearing a TEMPO moiety
(TEMPO ) 2,2,6,6-tetramethylpiperidine-N-oxyl radical)8
reacted with 1-octene to give the corresponding adduct 2a
in 66% yield (3 d, 135 °C), whereas alkoxyamine 1b, bearing
a sterically more demanding nitroxide moiety, reacted far
more efficiently and 2b was isolated in 85% yield in far
shorter reaction time and lower temperature (1.5 h, 125 °C,
Scheme 2).7e Since the nitroxide of alkoxyamine 1b was
Scheme 2. Radical Carboaminoxylation of 1-Octene
Figure 1. Products of carboaminoxylations with 1c. Conditions:
olefin (5 equiv, 4i 1.05 equiv), ClCH2CH2Cl (1 M), 2 h, 125 °C.
vinylphthalimide (f 4d), and vinyl ethers (f 4e,f) occurred
with high yields. Interestingly, even tertiary sterically
difficult to prepare, we were looking for an alternative readily
accessible sterically highly demanding nitroxide. The bulky
nitroxide 3 has recently been introduced as a readily prepared
efficient regulator for nitroxide-mediated radical polymeri-
zation.9 We therefore decided to test 3 in radical carboami-
noxylation reactions. Alkoxyamine 1c was easily prepared
(7) (a) Studer, A. Angew. Chem., Int. Ed. 2000, 39, 1108. (b) Wetter,
C.; Jantos, K.; Woithe, K.; Studer, A. Org. Lett. 2003, 5, 2899. (c) Wetter,
C.; Studer, A. Chem. Commun. 2004, 174. (d) Teichert, A.; Jantos, K.;
Harms, K.; Studer, A. Org. Lett. 2004, 6, 3477. (e) Molawi, K.; Schulte,
T.; Siegenthaler, K. O.; Wetter, C.; Studer, A. Chem.sEur. J. 2005, 11,
2335. (f) Herrera, A. J.; Studer, A. Synthesis 2005, 1389. (g) Uenoyama,
Y.; Tsukida, M.; Doi, T.; Ryu, I.; Studer, A. Org. Lett. 2005, 7, 2985. (h)
Janza, B.; Studer, A. Org. Lett. 2006, 8, 1875. (i) Schulte, B.; Studer, A.
Synthesis 2006, 2129. (j) Vogler, T.; Studer, A. Synthesis 2006, 4257. (k)
Siegenthaler, K. O.; Scha¨fer, A.; Studer, A. J. Am. Chem. Soc. 2007, 129,
5826.
(5) Reviews: (a) Studer, A. Chem.sEur. J. 2001, 7, 1159. (b) Studer,
A. Chem. Soc. ReV. 2004, 33, 267. (c) Studer, A.; Schulte, T. Chem. Rec.
2005, 5, 27.
(6) (a) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37,
3072. (b) Studer, A.; Amrein, S. Synthesis 2002, 835.
(8) Vogler, T.; Studer, A. Synthesis 2008, 1979.
(9) Miele, S.; Nesvadba, P.; Studer, A. Macromolecules 2009, 42, 2419.
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Org. Lett., Vol. 11, No. 11, 2009

hindered stabilized radicals were efficiently trapped with 3
as shown in the synthesis of 4g and 4h.10 The electron-poor
n-butyl acrylate also underwent radical addition to give 4i
in 82% yield.11 Radical carboaminoxylation of ꢀ-pinene with
1c afforded adduct 4j resulting from malonyl radical addition,
fragmentation, and nitroxide trapping.12
all experiments by using conventional batch reaction tech-
nique under otherwise identical conditions (residence time
in flow reactor ) reaction time in batch system). Results
are summarized in Table 1.
Radical carboaminoxylations could also be performed in
water as a solvent.13 Mixing of 1-octene (5 equiv) with 1c
in H2O (1 M) for 2 h in a sealed tube at 125 °C afforded 2c
in 78% yield. By analogy, 4a (98%) and 4d (54%) were
successfully prepared in water. Interestingly, reaction also
worked under neat conditions. Hence, stirring of 1-octene
(5 equiv) and 1c at 125° for 2 h gave 2c in 82% isolated
yield, and heating a mixture of vinylphthalimide (5 equiv)
and 1c for 2 h at 125 °C afforded 4d in 50% yield.
Radical cascade reactions could be conducted as a one-
pot process. To this end, 1c was first allowed to react with
n-butyl acrylate (1 equiv) in ClCH2CH2Cl for 2 h (125 °C).
After evaporation of the solvent the reaction vessel was
charged with butyl vinyl ether (10 equiv), and heating was
continued for 8 h. Compound 5 was isolated in 58% yield
as a mixture of isomers (Scheme 3).14
Table 1. Batch and Microflow Radical Carboaminoxylations
time
batch
microflow
entry
alkene
[min] no. yield [%] yield [%]
1
2
3
4
5
6
7
8
1-octene
10
10
5
2c
2c
4a
4a
4j
4h
4e
4d
45
72
31
55
60
60
65
58
73
95
65
86
77
81
93
68b
1-octenea
4-phenyl-1-butene
4-phenyl-1-butene
ꢀ-pinene
2-methyl-1-nonene
butyl vinyl ether
vinylphthalimide
10
5
5
5
5
a 5 equiv. b Telomer resulting from addition of 2 equiv of vinyl
phthalimide was obtained as side product in 13% yield.
It turned out that carboaminoxylations proceeded very
efficiently in DMSO as a solvent. In the batch system,
reaction of 1-octene (2 equiv) with 1c for 10 min provided
2c in 45% yield (entry 1). Increasing the amount of 1-octene
Scheme 3. Cascade Reaction
Scheme 4. Batch and Microflow Carboaminoxylations with 1a
Importantly, all radical carboaminoxylations were per-
formed without addition of any reagents by mixing the two
reactants. Therefore, this chemistry should be well suited to
be conducted in a microflow system. As a typical solvent
for the microflow system we chose DMSO (Figure 2).
Figure 2. Setup of the microflow system (DMSO, 0.07 M).
Reactions were performed in a capillary microtube (stainless
steel) at 125 °C by feeding a mixture of alkoxyamine and
olefin in a flow system (2 equiv of olefin; 5 or 10 min
residence time in the reactor). For comparison, we repeated
Org. Lett., Vol. 11, No. 11, 2009
2459

to 5 equiv further increased yield (entry 2). To our delight,
yields were further improved upon switching to the flow
system. Thus 10 min residence time in the flow reactor
resulted in a 95% isolated yield of 2c (entry 2). Similar results
were achieved in the carboaminoxylation of 4-phenyl-1-
butene (entries 3 and 4). For the more reactive butyl vinyl
ether as a radical acceptor, a 93% isolated yield was achieved
with 5 min reactor residence time. Importantly, for all
reactions studied, yields were higher in the microflow system
as compared to yields achieved in the batch reaction under
comparable conditions (entries 1-8), documenting the power
of microflow technology to conduct these radical addition
reactions.
In summary, we presented a novel, readily available
alkoxyamine that underwent a highly efficient radical car-
boaminoxylation reaction to various olefins. Radical car-
boaminoxylations were for the first time conducted by using
microflow technology. Importantly, as compared to conven-
tional batch reaction setup, microflow technology delivered
substantially higher yields under comparable conditions.
Acknowledgment. A.S. and I.W. thank Novartis Pharma
AG (Young Investigator Award to A.S.) and the Fonds der
Chemischen Industrie for supporting our work. We thank S.
Miele (WWU Mu¨nster) for measuring Ea for the C-O-bond
homolysis of 1c. I.R., T.R., and T.F. thank JSPS/MEXT and
MCPT/NEDO for financial support of this work.
High thermal efficiency of a microflow system over a batch
system led us to reexamine TEMPO-malonate addition
chemistry,7c which requires higher temperatures to undergo
effective addition to alkenes. Scheme 4 shows results of both
batch and microflow reactions of 1a with three different
olefins, which were conducted at 180 °C. In all cases
examined, microflow reactions constantly gave better yields
of alkene addition products 2a, 7a, and 8a over batch
reactions. It is noteworthy that microflow reactions gave
negligible formation of byproducts 6, 7b, and 8b, which
would be obtained by further thermal decomposition reac-
tions of the initially obtained addition products. Thus, in turn
of microflow reactions, high-speed cooling down (fast
product removal from the reactor) would allow for such
selective reactions.
Supporting Information Available: Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900713D
(10) Along with 4h, olefins deriving from hydroxylamine elimination
were isolated in 32% as mixture of regioisomers and an unidentified side
product (see Supporting Information).
(11) Radical carboaminoxylation on electron-poor olefins, see: Dufils,
P.-E.; Chagneux, N.; Gigmes, D.; Trimaille, T.; Marque, S. R. A.; Bertin,
D.; Tordo, P. Polymer 2007, 48, 5219.
(12) Along with 4j, an olefin deriving from hydroxylamine elimination
was isolated in 8% (see Supporting Information).
(13) Reactions in water: (a) Chanda, A.; Fokin, V. V. Chem. ReV. 2009,
109, 725. (b) Li, C. J. Chem. ReV. 1993, 93, 2023. Radical chemistry in
water: (c) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 2002, 674.
(14) As a side product 4e was formed in 25% yield.
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