Addition of electrophilic and heterocyclic carbon-centered radicals to glyoxylic oxime ethers

Article abstract of DOI:10.1021/ol049671i

Equation presented. Stabilized primary radicals can be formed from alkyl halides in an atom transfer process with Et₃B. This process depends on the strength of the carbon-halogen bond and the stability of the resulting primary radical. Radicals

Full text of DOI:10.1021/ol049671i

ORGANIC
LETTERS
2004
Vol. 6, No. 12
1911-1914
Addition of Electrophilic and
Heterocyclic Carbon-Centered Radicals
to Glyoxylic Oxime Ethers
Stephen B. McNabb, Masafumi Ueda, and Takeaki Naito*
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe 658-8558, Japan
taknaito@kobepharma-u.ac.jp
Received February 24, 2004
ABSTRACT
Stabilized primary radicals can be formed from alkyl halides in an atom transfer process with Et3B. This process depends on the strength of
the carbon−halogen bond and the stability of the resulting primary radical. Radicals formed from benzyl iodide and ethyl iodoacetate add to
glyoxylic oxime ethers; however, more electrophilic radicals do not. Glyoxylic oxime ethers are also good radical acceptors for heterocyclic
carbon-centered secondary radicals, giving novel r-amino acid derivatives.
The carbon-nitrogen double bonds of imine derivatives are
of great interest as radical acceptors in synthetic organic
chemistry.1 The reductive radical addition to CdN bonds is
important due to the prevalence of organic compounds in
nature that contain the amine functional group. The use of
environmentally benign conditions, especially aqueous media
for radical reactions, is of increasing importance.2-4 Trieth-
ylborane has proved to be a good reagent for radical reactions
in water or aqueous media via an atom transfer process.2,3
We have been interested in the intermolecular radical addition
to glyoxylic oxime ethers using Et3B in aqueous conditions.2
So far, the studies of reductive radical additions to
glyoxylic oxime ethers have focused on the use of simple
alkyl halides such as i-PrI, s-BuI, c-PenI, and c-HexI (2,
Scheme 1).5 A few alkyl halides containing ethers or a
halogen have also been used.6,7
A number of factors are known to influence the addition
of carbon radicals to glyoxylic imine derivatives.7 These
include the reactivity of the imine derivative, which can be
increased through the addition of Lewis acids7,8 and the
nucleophilicity of the radical. Another factor governing the
reaction is the efficiency of the atom transfer process between
the ethyl radical formed from Et3B and the alkyl halide. This
same factor is also involved in the Et2Zn-mediated radical
additions to glyoxylic imines.9 The efficiency of the atom
transfer process is dependent on the stability of the radical
formed from the alkyl halide. For this reason, secondary and
tertiary alkyl halides are most commonly used.9 It has also
been noted that isopropyl bromide does not undergo the atom
transfer process with Et3B effectively.7
Scheme 1. Alkyl Radical Additions to Oxime Ethers
(1) (a) Friestad, G. K. Tetrahedron 2001, 57, 5461. (b) Fallis, A. G.;
Brinza, I. M. Tetrahedron 1997, 53, 17543.
(2) (a) Ueda, M.; Miyabe, H.; Nishimura, A.; Miyata, O.; Takemoto,
Y.; Naito, T. Org. Lett. 2003, 5, 3835. (b) Miyabe, H.; Nishimura, A.;
Fujishima, Y.; Naito, T. Tetrahedron 2003, 59, 1901. (c) Miyabe, H.; Ueda,
M.; Naito, T. J. Org. Chem. 2000, 65, 5043.
(3) Yorimitsu, H.; Shinokubo, H.; Oshima, K. Synlett 2002, 674.
(4) Nambu, H.; Anilkumar, G.; Matsugi, M.; Kita, Y. Tetrahedron 2003,
59, 77.
(5) Miyabe, H.; Ueda, M.; Yoshioka, N.; Yamakawa, K.; Naito, T.
Tetrahedron 2000, 56, 2413.
10.1021/ol049671i CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/12/2004

Table 1. Primary or Secondary Alkyl Radical Additions to
Table 2. Bond Strengths of Selected Alkyl Halides
Glyoxylic Oxime Ethers
bond
atom
strengtha
transfer radical addition
entry
alkyl halide
(kJ mol-1
)
process
yield (%)
1
2
3
4
5
6
7
8
9
i-Pr-I
i-Pr-Br
Br-CH2CO2H
I-CH2CO2H
Bn-I
Bn-Br
Me-I
allyl iodide
CCl3-Br
C6F5CH2-Br
(CF3)2CF-I
234
298
25710
19810
215
256
239
19111
231
++
- - -
+
99
10 (ethyl ester)
76 (ethyl ester)
62
++
++
- - -
++
++
++
++
++
15
10
11
225
215
a Unless indicated otherwise obtained from: CRC Handbook of Chemistry
and Physics, 83rd ed.; Lide, D. R., Ed.; CRC Press Springer: Berlin, 2003.
assumption was based on some unpublished work within our
group that had shown that methyl 2-bromoacetate did not
react under the same conditions. To our surprise, 4 was
formed in 49% yield along with 5% of 3 (Table 1) under
standard conditions.2c We carried out the reaction of R-bromo-
γ-butyrolactone to see if this was a suitable radical precursor.
However, only the ethyl adduct, 3, was produced (82%).
Clearly the atom transfer process does not take place. This
result suggested to us that the carbon-halogen bond strength
of methyl 2-bromoacetate might have prevented the atom
transfer process from occurring. We decided to test this by
carrying out the radical addition reaction with ethyl 2-bro-
moacetate and ethyl 2-iodoacetate. The results of these two
reactions can be seen in entries 3 and 4 of Table 1. Ethyl
2-iodoacetate reacted to give the aspartic acid derivative 5
in 76% yield. In contrast, ethyl 2-bromoacetate only gave 5
in 10% yield, with 80% of 3 also being formed. This
indicates that the atom transfer process is inefficient due to
the strength of the carbon-halogen bond.
a Determined by 1H NMR of the crude diastereomeric mixtures. b 3 was
also formed in entries 1, 3, 4, and 7 in 8-49%. c Reaction carried out in
dichloromethane. d Starting material was recovered.
We also decided to investigate the reactions of benzyl
iodide and benzyl bromide. As can be seen by entries 5 and
6 of Table 1, the iodide reacted to give the phenylalanine
derivative 6 in 62% yield, while the benzyl bromide only
gave 3 in 50% yield.
We were interested in extending the range of alkyl halides
used in the radical addition reaction to include primary and
heterocyclic alkyl halides. The addition of heterocyclic
carbon-centered radicals to 1 would provide a route for the
synthesis of novel R-amino acid derivatives. The first
heterocyclic alkyl halide that we chose to investigate was
R-iodo-γ-butyrolactone.
R-Iodo-γ-butyrolactone is known to add to alkenes in
aqueous conditions using Et3B.3 However, it was expected
that this radical might be too electrophilic to add to 1. This
The carbon-halogen bond dissociation energies for a
number of different alkyl halides are shown in Table 2. It
was decided to attempt the radical addition reactions of the
alkyl halides shown in entries 8-11 of Table 1 which are
all commercially available. The bond strengths of these
compounds were expected to be low enough to allow the
radicals to form when reacted with Et3B (entries 8-11 of
Table 2).
(6) Miyabe, H.; Yoshioka, N.; Ueda, M.; Naito, T. J. Chem. Soc., Perkin
Trans. 1 1998, 3659.
(7) Jorgensen, K. A.; Halland, N. J. Chem. Soc., Perkin Trans. 1 2001,
1290.
(8) Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro, C.; Naito, T.
Tetrahedron 1998, 54, 11431.
(9) (a) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999,
1148. (b) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem.
1999, 64, 9189.
As can be seen in entry 7 (Table 1) the reaction of methyl
iodide only gave 15% yield of the alanine derivative 7 and
49% of the ethyl adduct 3. The lower stability of the resulting
methyl radical compared to the ethyl radical is likely to be
the reason for the low yield. Allyl iodide did not react with
1 in the presence of Et3B. This is probably due to polym-
1912
Org. Lett., Vol. 6, No. 12, 2004

Table 3. Synthesis of Heterocyclic R-amino Acids
1
a Determined by H NMR of the crude diastereomeric mixtures.
erization, and starting material was recovered (entry 8, Table
1). Bromo trichloromethane is known to undergo the atom
transfer reaction with Et3B and react with alkenes.3 In our
case, no reaction occurred (entry 9, Table 1). The absence
of any ethyl adduct may indicate that the bromine atom
transfer process occurs efficiently reducing the amount of
ethyl radical present in the reaction. The radical is presum-
ably too electrophilic to react. Pentafluorobenzyl bromide
and 2-iodoperfluoro propane have not been reacted with Et3B,
to the best of our knowledge. Again no product was formed
from the resulting radicals (entries 10 and 11, Table 1).
Starting material was again recovered indicating that the atom
transfer reaction with Et3B had occurred. We believe that
the radicals formed from these halides are too electrophilic
to react.
Having investigated the addition of electrophilic radicals,
we turned to the reaction of heterocyclic radicals. The
addition of heterocyclic carbon-centered radicals to 1 would
provide a route for the synthesis of novel R-amino acids
derivatives. Several alkyl halides containing heterocycles
were synthesized using literature procedures.12 The radical
addition reactions were carried out following the standard
procedure.2c A minor modification was made in that a smaller
number of equivalents of the alkyl halide were used. A large
excess of alkyl halide has been generally used to minimize
the amount of 3 produced. As the excess alkyl halide is
generally not recovered after the reaction this is not efficient
for alkyl halides that have to be synthesized in several steps.
In an attempt to keep the amount of ethyl adduct 3 to a
minimum, the Et3B was added in portions of 0.5 equiv over
the course of the reaction to maintain a high ratio of alkyl
halide to ethyl radical.
The reactions of 8, 10, 12, 14, and 16 all took place
although the yields ranged from poor to good (Table 3). The
radical addition reaction of 8 gave the amino acid derivative
9 in 75% yield along with 20% of the ethyl adduct 3. The
related iodide 10 also reacted well to give 11 in 63% and 3
in 33% yield. Although compound 12 does not have the
iodide directly attached to the heterocyclic ring it was of
interest as it opens up the possibility of utilizing the masked
aldehyde functionality for further functionalization. When
12 was used in the radical addition reaction, 13 was isolated
in 72% yield with only 5% of 3 isolated. Piperidine-based
amino acid derivatives have been shown to be inhibitors of
matrix metalloproteinases.13 Compound 14 was synthesized
(12) 4 according to: Perrier, M. J. Am. Chem. Soc. 1947, 69, 3148. 8
according to: Bartlett, P. A.; McQuaid, L. A. J. Am. Chem. Soc. 1984,
106, 7854. 10 according to: Clive, D. L. J.; Kale, V. N. J. Org. Chem.
1981, 46, 231. 12 according to: Weyerstahl, P.; Brendel, J. Liebigs Ann.
Chem. 1992, 669. 14 from the tosylate using NaI. 16 according to: Gervay,
J.; Nguyen, T. N.; Hadd, M. J. Carbohydr. Res. 1997, 300, 119.
(10) Lagoa, A. L. C.; Diogo, H. P.; Dias, M. P.; Minas da Piedade, M.
E.; Amaral, L. M. P. F.; Ribeiro da Silva, M. A. V.; Martino Simoes, J. A.;
Guedes, R. C.; Costa Cabral, B. J.; Schwarz, K.; Epple, M. Chem. Eur. J.
2001, 7, 483.
(11) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.
Org. Lett., Vol. 6, No. 12, 2004
1913

from the tosylate and used without purification. The piperi-
dine containing amino acid 15 was isolated in 43% yield
along with 3 in 49%. The reasons for the moderate yield of
15 are not clear at this stage. Finally the sugar iodide 16
was used to synthesize the glycopyranosyl glycine derivative
17 in 16% yield. The conditions for the reaction had to be
changed from a 1:1 mixture of methanol/water to a 1:1
mixture of acetonitrile/water. This change was needed to
prevent the iodide 16 reacting with methanol to give the
1-methoxy derivatives, which were inseparable from any
product. The low yield of 17 compared to the high yield of
3 (63%) may be due to steric hindrance preventing the
approach of the radical to the oxime ether. The stability of
the alkyl halide in the aqueous conditions is also a problem,
with hydrolysis to the glucopyranose derivative likely.
and therefore the reaction is inefficient even though the bond
strength is low (entry 7, Table 2). This is also the case with
the pentafluorobenzyl, trichloromethyl and perfluoropropane
radicals, which are all too electrophilic to react. On the other
hand, radicals formed from benzyl iodide and ethyl iodoac-
etate reacted well.
We have established that complex and interesting alkyl
halides can be used in the radical addition reaction to
glyoxylic oxime ethers. The success of the reactions depends
on the wise choice of the alkyl halide. This is to maximize
the atom transfer process and match the nucleophilicity of
the resulting radical to the oxime ether.
Acknowledgment. We acknowledge Grant-in-Aids for
Scientific Research (B) (T.N.) and for Young Scientists (B)
(M.U.) from the Ministry of Education, Culture, Sports,
Science and Technology of Japan. Support from the Japan
Society for the Promotion of Science for a Postdoctoral
Fellowship for Foreign Researchers (S.B.M) and the Science
Research Promotion Fund of the Japan Private School
Promotion Foundation for research grants is also greatly
appreciated.
In conclusion, there are two factors to be considered when
thinking about the use of alkyl halides for the addition to
oxime ethers. The first is the efficiency of the atom transfer
process. This is related to the stability of the radical formed
compared to the ethyl radical from Et3B, as well as the
strength of the carbon-halogen bond. The second factor is
the electrophilicity or nucleophilicity of the radical and
whether this is compatible with the oxime ether. Thus, the
methyl radical formed from methyl iodide reacts too slowly
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 4, 5, 9, 11,
13, 15, and 17. 1H NMR spectra of compounds 4-7, 9, 11,
13, 15, and 17. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) (a) Shieh, W.-C.; Xue, S.; Reel, N.; Wu, R.; Fitt, J.; Repic. O.
Tetrahedron: Asymmetry 2001, 12, 2421. (b) Pikul, S.; Ohler, N. E.;
Ciszewski, G.; Laufersweiler, M. C.; Almstead, N. G.; De, B.; Natchus,
M. G.; Hsieh, L. C.; Janusz, M. J.; Peng, S. X.; Branch, T. M.; King, S. L.;
Taiwo, Y. O.; Mieling, G. E. J. Med. Chem. 2001, 44, 2499.
OL049671I
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Org. Lett., Vol. 6, No. 12, 2004