Indium-mediated intermolecular alkyl radical addition to electron-deficient C=N bond and C=C bond in water

Article abstract of DOI:10.1021/ol017013h

(matrix presented) The intermolecular alkyl radical addition to imine derivatives was studied in aqueous media by using indium as a single-electron-transfer radical initiator. The one-pot reaction based on radical addition to glyoxylic hydrazone provided a convenient method for preparing the α-amino acids. The indium-mediated radical addition to an electron-deficient C=C bond also proceeded effectively to provide the new carbon-carbon bond-forming method in aqueous media.

Full text of DOI:10.1021/ol017013h

ORGANIC
LETTERS
2002
Vol. 4, No. 1
131-134
Indium-Mediated Intermolecular Alkyl
Radical Addition to Electron-Deficient
CdN Bond and CdC Bond in Water
Hideto Miyabe, Masafumi Ueda, Azusa Nishimura, and Takeaki Naito*
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe 658-8558, Japan
taknaito@kobepharma-u.ac.jp
Received November 8, 2001
ABSTRACT
The intermolecular alkyl radical addition to imine derivatives was studied in aqueous media by using indium as a single-electron-transfer
radical initiator. The one-pot reaction based on radical addition to glyoxylic hydrazone provided a convenient method for preparing the r-amino
acids. The indium-mediated radical addition to an electron-deficient CdC bond also proceeded effectively to provide the new carbon−carbon
bond-forming method in aqueous media.
Indium-mediated carbon-carbon bond-forming reactions in
aqueous media have been of great importance from both
economical and environmental points of view. Recently,
numerous and useful indium-mediated allylation reactions
of carbonyl compounds have been reported.1 However, the
corresponding reaction of imine derivatives has not been
widely studied because of the lower electrophilicity of
carbon-nitrogen double bond. Therefore, the development
of indium-mediated reactions of imines in aqueous media
has been a subject of current interest. Chan’s group reported
the first studies on the indium-mediated allylation of N-
sulfonylimines in aqueous media.2 These allylation reactions
proceeded through an allylindium(I) intermediate, which
reacts with the N-sulfonylimines, and thus, simple alkylation
reactions were not investigated. As a part of our program
directed toward the development of reactions of imines in
aqueous media,3,4 we now report the indium-mediated
alkylation reactions of imine derivatives based on the alkyl
radical addition to carbon-nitrogen double bond.
The carbon-nitrogen double bond has emerged as a
radical acceptor, and thus several intermolecular radical
addition reactions of imines were recently investigated in
organic solvents.5-7 Our recent studies show that imine
derivatives such as oxime ethers, hydrazones, and nitrones
are excellent water-resistant radical acceptors for the
aqueous-medium reactions using triethylborane as a radical
initiator.3a
On the basis of these results, we newly investigated the
intermolecular radical addition to imine derivatives by using
indium as a new radical initiator.8,9 As a preliminary experi-
(1) For a recent review, see: Li, C. J.; Chan, T. H. Tetrahedron 1999,
55, 11149. For some examples of indium-mediated reaction, see: (a) Yang,
Y.; Chan, T. H. J. Am. Chem. Soc. 2000, 122, 402. (b) Chan, T. H.; Yang,
Y. J. Am. Chem. Soc. 1999, 121, 3228. (c) Paquette, L. A.; Rothhaar, R. R.
J. Org. Chem. 1999, 64, 217. (d) Woo, S.; Sqires, N.; Fallis, A. G. Org.
Lett. 1999, 1, 573. (e) Engstrom, G.; Morelli, M.; Palomo, C.; Mitzel, T.
Tetrahedron Lett. 1999, 40, 5967. (f) Loh, T.-P.; Zhou, J. R. Tetrahedron
Lett. 1999, 40, 9115.
(3) (a) Miyabe, H.; Ueda, M.; Naito, T. J. Org. Chem. 2000, 65, 5043.
(b) Miyabe, H.; Fujii, K.; Goto, T.; Naito, T. Org. Lett. 2000, 2, 4071. We
recently reported that N-sulfonylimines have shown the excellent reactivity
toward nucleophilic carbon radical. See: (c) Miyabe, H.; Ueda, M.; Naito,
T. Chem. Commun. 2000, 2059.
(2) (a) Lu, W.; Chan, T. H. J. Org. Chem. 2001, 66, 3467. (b) Lu, W.;
Chan, T. H. J. Org. Chem. 2000, 65, 8589. (c) Chan, T. H.; Lu, W.
Tetrahedron Lett. 1998, 39, 8605. For examples of indium-mediated
allylation of imines in organic solvents, see: (d) Basile, T.; Bocoum, A.;
Savoia, D.; Umani-Ronichi, A. J. Org. Chem. 1994, 59, 7766. (e) Beuchet,
P.; Marrec, N. L.; Mosset, P. Tetrahedron Lett. 1992, 33, 5959.
(4) For some selected examples, see: (a) Yorimitsu, H.; Nakamura, T.;
Shinokubo, H.; Oshima, K. J. Org. Chem. 1998, 63, 8604. (b) Nakamura,
T.; Yorimitsu, H.: Shinokubo, H.: Oshima, K. Synlett 1998, 1351. (c) Kita,
Y.; Nambu, H.; Ramesh, N. G.; Anikumar, G.; Matsugi, M. Org. Lett. 2001,
3, 1157.
(5) For a recent review, see: Friestad, G. K. Tetrahedron 2001, 57, 5461.
10.1021/ol017013h CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/14/2001

ment, the substrates of choice were the glyoxylic oxime ether
1 and glyoxylic hydrazone 3 since they have shown excellent
reactivity toward nucleophilic carbon radicals in our previous
work on triethylborane-induced radical reactions.3a Addition-
ally, we also expected that the direct comparison of indium-
mediated reactions with triethylborane-induced reactions
would lead to informative and instructive suggestions regard-
ing indium as a single-electron-transfer radical initiator.
We first investigated the reaction of glyoxylic oxime ether
1 under several reaction conditions (Scheme 1). To a biphasic
was stirred at 20 °C for 22 h.10 As expected, glyoxylic oxime
ether 1 exhibits a good reactivity to give the desired
isopropylated product 2 in 76% yield without formation of
significant by-products such as a reduced product (Table 1,
Table 1. Indium-Mediated Reaction of Glyoxylic Oxime Ether
1
entry
solvent
time (h)
yield (%)
76
no reaction
74
1a
2a
3b
4c
H2O-CH2Cl2 4:1
CH2Cl2
H2O-MeOH 2:1
H2O-MeOH 2:1
22
24
0.5
0.5
Scheme 1
no reaction
a Reactions were carried out with i-PrI (5 equiv) and indium (7 equiv).
b Reaction was carried out with i-PrI (4 equiv × 2) and indium (7 equiv).
c Reaction was carried out with galvinoxyl free radical (2 equiv), i-PrI (4
equiv × 2), and indium (7 equiv).
entry 1). It is important to note that practically no reaction
of 1 occurred in the absence of water (entry 2). These results
suggest that water would be important for the activation of
indium and for the proton-donor to the resulting amide anion.
In the case of monophasic reaction in H2O-MeOH, the
formation of isopropylated product 2 was observed after
being stirred for only 0.5 h (entry 3).11 In the presence of
galvinoxyl free radical as a radical scavenger, the reaction
did not proceed effectively (entry 4); thus, this reaction would
proceed via the radical mechanism based on the single-
electron transfer (SET) process from indium. However, an
alternative mechanistic hypothesis involving addition of
alkylindium species to the CdN bond would not be rigor-
ously excluded, because it is possible that galvinoxyl free
radical inhibited the non-radical reaction by scavenging
radicals during the formation of the alkylindium species. In
general, free radical synthetic methods largely rely on toxic
organotin chemistry; therefore, the development of tin-free
reactions including SET processes or atom-transfer and
group-transfer processes has been of great importance in
radical chemistry.12 However, this indium-mediated reaction
of 1 was slightly slower than the triethylborane-induced
reaction of 1 in aqueous media shown in our recent report.3a
In our studies on the reactivity of several imine derivatives,
we have found that the indium-mediated alkyl radical
addition to glyoxylic hydrazone 3 is a highly promising
approach to the synthesis of R-amino acids (Scheme 2 and
Table 2). In the case of the aqueous-medium reactions of 3
solution of 1 and i-PrI (5 equiv) in H2O-CH2Cl2 (4:1, v/v)
was added indium (7 equiv), and then the reaction mixture
(6) For some examples, see: (a) Hart, D. J.; Seely, F. L. J. Am. Chem.
Soc. 1988, 110, 1631. (b) Kim, S.; Lee, I. Y.; Yoon, J.-Y.; Oh, D. H. J.
Am. Chem. Soc. 1996, 118, 5138. (c) Kim, S.; Yoon, J.-Y. J. Am. Chem.
Soc. 1997, 119, 5982. (d) Ryu, I.; Kuriyama, H.; Minakata, S.; Komatsu,
M.; Yoon, J.-Y.; Kim, S. J. Am. Chem. Soc. 1999, 121, 12190. (e) Bertrand,
M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998, 780. (f) Bertrand,
M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148. (g) Bertrand,
M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem. 1999, 64, 9189.
(h) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329. For some
examples of our studies, see: (i) Friestad, G. K.; Qin, J. J. Am. Chem. Soc.
2001, 123, 9922 (j) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun.
1997, 1789. (k) Miyabe, H.; Sibata, R.; Ushiro, C.; Naito, T. Tetrahedron
Lett. 1998, 39, 631. (l) Miyabe, H.; Fujishima, Y.; Naito, T. J. Org. Chem.
1999, 64, 2174. (m) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1,
569. (n) Miyabe, H.; Konishi C.; Naito, T. Org. Lett. 2000, 2, 1443. (o)
Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T. J. Org. Chem.
2000, 65, 176.
(7) For reviews on radical reactions, see: (a) Sibi, M. P.; Porter, N. A.
Acc. Chem. Res. 1999, 32, 163. (b) Renaud, P.; Gerster, M. Angew. Chem.,
Int. Ed. 1998, 37, 2563. (c) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut,
J.; Thoma, G.; Kulicke, K. J.; Trach, F. Org. React. (N.Y.) 1996, 48, 301.
(d) Curran, D. P.; Porter, N. A.; Giese, B. In Stereochemistry of Radical
Reactions: Concepts, Guidelines, and Synthetic Applications; VCH: Wein-
heim, 1996.
(8) Indium(I) iodide mediated radical cyclization was recently studied.
See: (a) Cook, G. R.; Erickson, S.; Hvinden, M. 221th ACS National
Meeting, San Diego, April 1-5, 2001. Indium as a reducing agent, see:
(b) Moody, C. J.; Pitts, M. R. Synlett 1998, 1028. (c) Ranu, B. C.; Guchhait,
S. K.; Sarkar, A. Chem. Commun. 1998, 2113. (d) Ranu, B. C.; Dutta, P.;
Sarkar, A. J. Chem. Soc., Perkin Trans. 1 1999, 1139. (e) Reddy, G. V.;
Rao, G. V.; Iyengar, D. S. Tetrahedron Lett. 1999, 40, 3937. (f) Yadav, J.
S.; Bandyopadhyay, A.; Reddy, B. V. S. Tetrahedron Lett. 2001, 42, 6385.
Indium-mediated coupling reactions, see: (g) Araki, S.; Butsugan, Y. Bull.
Chem. Soc. Jpn. 1991, 64, 727. (h) Ranu, B. C.; Dutta, P.; Sarkar, A.
Tetrahedron Lett. 1998, 39, 9557. The use of indium trichloride, see: (i)
Inoue, K.; Yasuda, M.; Shibata, I.; Baba, A. Tetrahedron Lett. 2000, 41,
113. (j) Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. Tetrahedron Lett. 2001,
42, 4661.
Scheme 2
(9) For the radical reaction using zinc as a radical initiator in water, see:
(a) Petrier, C.; Dupuy, C.; Luche, J. L. Tetrahedron Lett. 1986, 27, 3149.
(b) Giese, B.; Damm, W.; Roth, M.; Zehnder, M. Synlett 1992, 441. (c)
Erdmann, P.; Scha¨fer, J.; Springer, R.; Zeitz, H.-G.; Giese, B. HelV. Chim.
Acta 1992, 75, 638.
132
Org. Lett., Vol. 4, No. 1, 2002

Table 2. Alkyl Radical Addition to Glyoxylic Hydrazone 2a
Scheme 4
entry
RX
product
yield (%)
1
2
3
4
5
6
i-PrI
4a
4a
4b
4c
4d
4e
98
i-PrBr
s-BuI
c-pentyl I
t-BuI
no reaction
90
79
48
EtI
no reaction
a Reactions were carried out with RX (5 equiv × 2), indium (7 equiv),
and H2O in MeOH at 20 °C for 1 h.
using triethylborane, the undesired C- and N-dialkylated
products 5 were only obtained as a result of the additional
N-alkylation.3a In contrast, the indium-mediated alkyl radical
addition to 3 gave selectively the desired C-monoalkylated
products 4 with no detection of dialkylated products 5. Not
only a secondary alkyl but also the tert-butyl radical worked
well to give 4a-d in good yields after being stirred for 1 h
(entries 1-5). However, the alkyl bromide such as i-PrBr
and a less reactive primary ethyl iodide did not work (entries
2 and 6).
Integration of multi-step chemical reactions into one-pot
reactions is of great significance as an environmentally
benign method.13 We next extended the indium-mediated
reaction to the one-pot synthesis of R-amino acid derivatives
(Scheme 3). Condensation of 2-hydroxy-2-methoxyacetic
prepared from benzaldehyde (Scheme 4). Although the
reactivity of hydrazone 7 is not high, the biphasic reaction
of 9 in H2O-CH2Cl2 (4:1, v/v) proceeded to give 10 in 54%
yield after being stirred for 2 days. The monophasic reaction
of N-sulfonylimine 9 in H2O-MeOH (2:1, v/v) proceeded
effectively to give the desired isopropylated product 10 in
70% yield accompanied with 29% of TsNH2 as a hydrolysis
product after being stirred for only 1 h.3c
To test the utility of indium as a single-electron transfer
radical initiator, we next investigated the indium-mediated
alkyl radical addition to electron-deficient CdC bond
(Scheme 5). To a solution of phenyl vinyl sulfone 11 and
Scheme 5
Scheme 3
acid methyl ester 6 with N,N-diphenylhydrazine hydrochlo-
ride proceeded smoothly in MeOH to give 3 after being
stirred at 20 °C for 2 h. Subsequently, alkyl iodide, In, and
H2O were added to the reaction vessel to afford good yields
of R-amino acid derivatives 4a-c.
RI (5 equiv) in MeOH were added indium (7 equiv) and
H2O, and then the reaction mixture was stirred at 20 °C for
30 min. As expected, 11 exhibits a good reactivity to give
the desired alkylated products 12a-d in good yields with
no detection of by-products such as a reduced product. The
reaction would proceed via the single-electron transfer
process from indium as shown in Scheme 5.
To survey the scope and limitations of the present method,
we investigated the alkylation reaction of imines 7 and 9
(10) As a comparison, the triethylborane-induced reaction of 1 was
usually run by using a large amount of alkyl iodides (more than 30 equiv)
to suppress the competitive reaction with ethyl radical generated from
triethylborane. See ref 3a.
(11) See Supporting Information for detail on the experimental proce-
dures.
(12) We previously reported the radical reaction based on an iodine atom
transfer process. See: Miyabe, H.; Ueda, M.; Yoshioka, N.; Naito, T. Synlett
1999, 465.
(13) We previously investigated the one-pot reactions via radical addition
to oxime ethers. See: (a) Miyabe, H.; Ueda, M.; Yoshioka, N.; Yamakawa,
K.; Naito, T. Tetrahedron 2000, 56, 2413. (b) Miyabe, H.; Yamakawa, K.;
Yoshioka, N.; Naito, T. Tetrahedron 1999, 55, 11209. (c) Miyabe, H.;
Yoshioka, N.; Ueda, M.; Naito, T. J. Chem. Soc., Perkin Trans. 1 1998,
3659.
In conclusion, we have shown a new method for synthesis
of R-amino acid derivatives based on the indium-mediated
radical reaction of glyoxylic hydrazone. Since the known
examples of indium-mediated carbon-carbon bond-forming
reactions in aqueous media are mainly limited to allylation
reactions, it is noteworthy that the newly found reaction
involves the alkylation of imine derivatives. Additionally,
the indium-mediated carbon-carbon bond-forming reactions
Org. Lett., Vol. 4, No. 1, 2002
133

based on the radical addition to electron-deficient CdC bond
also proceeded smoothly in aqueous media.
tion was supported in part by The Mochida Memorial
Foundation for Medical and Pharmaceutical Research (to
H.M.).
Acknowledgment. We thank the Ministry of Education,
Science, Sports and Culture of Japan and the Science
Research Promotion Fund of the Japan Private School
Promotion Foundation for research grants. H.M. gratefully
acknowledges the financial support from Takeda Science
Foundation and Fujisawa Foundation, Japan. This investiga-
Supporting Information Available: General experi-
mental procedures and characterization data for obtained
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL017013H
134
Org. Lett., Vol. 4, No. 1, 2002