Radical reactions with 2-bromobenzylidene group, a protecting/radical- translocating group for the 1,6-radical hydrogen transfer reaction

Article abstract of DOI:10.1021/ol061162o

The 2-bromobenzylidene group, designed as a novel protecting/radical- translocating (PRT) group, proved to be effective for an unusual 1,6-hydrogen transfer reaction. Using this PRT group, 4-branched ribose derivatives were stereoselectively prepared.

Full text of DOI:10.1021/ol061162o

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3291-3294
Radical Reactions with
2-Bromobenzylidene Group, a
Protecting/Radical-Translocating Group
for the 1,6-Radical Hydrogen Transfer
Reaction
Natsumi Sakaguchi, Shinpei Hirano, Akira Matsuda, and Satoshi Shuto*
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity, Kita-12, Nishi-6,
Kita-ku, Sapporo 060-0812, Japan
shu@pharm.hokudai.ac.jp
Received May 11, 2006
ABSTRACT
The 2-bromobenzylidene group, designed as a novel protecting/radical-translocating (PRT) group, proved to be effective for an unusual 1,6-
hydrogen transfer reaction. Using this PRT group, 4-branched ribose derivatives were stereoselectively prepared.
Protecting/radical-translocating (PRT) groups1 allow remote
functionalization of alcohols, amines, and amides.2 PRT
Scheme 1
groups should be easy to introduce and should function as
normal protecting groups for alcohols and/or amines before
the radical reaction, at which point they should effectively
generate a radical at the desired position via hydrogen transfer
(HT). After the radical reaction, they need to be easily re-
moved. PRT groups have the distinct advantage of homo-
lytically cleaving an inactive C-H bond.1,2 As shown in
Scheme 1, benzene derivatives are often used as PRT groups,
since aromatic radicals generated from them are active
enough to abstract a hydrogen on an aliphatic carbon.
few examples of radical 1,6-HT reactions,4 no report of a
PRT groups can generate a radical via homolytic cleavage
PRT group selectively abstracting a hydrogen at the position
of an inactive C-H bond (Scheme 1), in which the radical
â to the oxygen or nitrogen in a 1,6-HT reaction has appeared
adjacent to the oxygen or nitrogen atom is selectively formed
in the literature. We describe here radical reactions with a
via a 1,5-hydrogen transfer process.3 Although there are a
2-bromobenzylidene group, designed as a novel PRT group
for unusual 1,6-selective HT reactions.
(1) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem. Soc.
1988, 110, 5900-5902.
(2) For examples of PRT groups, see: Feray, L.; Kuznetsov, N.; Renaud,
P. Hydrogen Atom Abstraction. In Radicals in Organic Synthesis; Renaud,
P.; Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 246-278.
If the initially generated aromatic radical intermediate
could accommodate the stereoelectronic preference for 1,6-
hydrogen abstraction, where the radical orbital and the C-H
10.1021/ol061162o CCC: $33.50
© 2006 American Chemical Society
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bond of the hydrogen to be abstracted are linear or nearly
linear, we concluded that the 1,6-HT reaction with a PRT
group would likely take place. Thus, we chose the 2-bro-
mobenzylidene group as a novel PRT group, thinking that it
would be useful in protecting 1,2- or 1,3-diols similar to other
benzylidene groups and the reactive aryl radical generated
from it could abstract a hydrogen on an aliphatic carbon.
We anticipated that the regio- as well as stereoselective 1,6-
hydrogen abstraction might occur with the 2-bromoben-
zylidene PRT group, because the bromophenyl moiety
seemed to be conformationally constrained as a result of the
rigid 1,3-dioxo ring formed from a diol and 2-bromoben-
zaldehyde or its equivalent.
as precursors for 4′-branched nucleosides having considerable
biological importance,5,6 would be synthesized via radical
C-C bond formation at the 4-position.
Thus, 1-O-(3-fluorobenzoyl)-2,3-O-endo-2-bromoben-
zylidene-5-O-tert-butyl-diphenylsilyl (TBDPS)-R-D-ribose
(4) was synthesized as the substrate for examining the 1,6-
HT reaction (Scheme 3). Treatment of D-ribose with 2-Br-
Scheme 3
We decided to examine the potential of 2-bromoben-
zylidene group as a PRT group using ribose derivatives as
reaction substrates. Thus, 2,3-O-endo-benzylidene-R-D-ribose
derivative I was designed as a model substrate (Scheme 2).
Scheme 2
PhCH(OEt)2 and p-TsOH in DMF at room temperature gave
the desired endo-benzylidene product 2. After selective
protection of the 5-hydroxyl of 2 with a TBDPS group,
Mitsunobu reaction of the product 3 with a Ph3P/diisopropyl
azodicarboxylate (DIAD)/3-F-PhCO2H system in CH2Cl2
gave highly stereoselectively the R-riboside 4,7 the substrate
for the radical reaction. Deuterium-labeling experiments of
Scheme 4
Treatment of the substrate I under reductive radical reaction
conditions, such as a Bu3SnH/AIBN system, would generate
the aryl radical II. The 1,5-HT, i.e., abstraction of a hydrogen
at the 2- or 3-position of the ribose by the aryl radical, would
be impossible as a result of the steric demand of the endo-
benzylidene structure. Thus, we expected that, because of
the rigid ring system, the desired 1,6-HT might selectively
occur to generate the ribose 4-radical III. If, by this method,
the ribose 4-radical III could be effectively generated,
4-branched ribose derivatives, which are useful, for example,
4 with Bu3SnD were first investigated with the idea of
clarifying whether the desired 1,6-HT reaction had indeed
(3) For examples of HT reactions, see: (a) Curran, D. P.; Kim, D.; Liu,
H. T.; Shen, W. J. Am. Chem. Soc. 1988, 110, 5900-5902. (b) Lathbury,
D. C.; Parsons, P. J.; Pinto, I. J. Chem. Soc., Chem. Commun. 1988, 81-
82. (c) Wiedenfeld, D.; Breslow, R. J. Am. Chem. Soc. 1991, 113, 8977-
8978. (d) Brown, C. D. S.; Simpkins, N. S.; Clinch, K. Tetrahedron Lett.
1993, 34, 131-132. (e) Bosch, E.; Bachi, M. D. J. Org. Chem. 1993, 58,
5581-5582. (f) Robertson, J.; Peplow, M. A.; Pillai, J. Tetrahedron Lett.
1996, 37, 5825-5828. (g) Bertrand, M. P.; Crich, D.; Nouguier, R.; Samy,
R.; Stien, D. J. Org. Chem. 1996, 61, 3588-3589. (h) Kittaka, A.; Asakura,
T.; Kuze, T.; Tanaka, H.; Yamada, N.; Nakamura, K.; Miyasaka, T. J. Org.
Chem. 1999, 64, 7081-7093. (i) Chatgilialoglu, C.; Gimisis, T.; Spada, G.
P. Chem. Eur. J. 1999, 5, 2866-2876. (j) Robertson, J.; Pillai, J.; Lush, R.
K. Chem. Soc. ReV. 2001, 30, 94-103 and references therein.
(5) (a) Giese, B.; Erdmann, P.; Schafer, T.; Schwitter, U. Synthesis 1994,
1310-3112. (b) Hayakawa, H.; Kohgo, S.; Kitano, K.; Ashida, N.; Kodama,
E.; Mitsuya, H.; Ohrui, H. AntiViral Chem. Chemother. 2004, 15, 169-
187 and references therein.
(6) (a) Shuto, S.; Kanazaki, M.; Ichikawa, S.; Matsuda, A. J. Org. Chem.
1997, 62, 5676-5677. (b) Shuto, S.; Kanazaki, M.; Ichikawa, S.; Minakawa,
N.; Matsuda, A. J. Org. Chem. 1998, 63, 746-754. (c) Ueno, Y.; Nagasawa,
Y.; Sugimoto, I.; Kojima, N.; Kanazaki, M.; Shuto, S.; Matsuda, A. J. Org.
Chem. 1998, 63, 1660-1667. (d) Sugimoto, I.; Shuto, S.; Mori, S.; Shigeta,
S.; Matsuda, A. Bioorg. Med. Chem. Lett. 1999, 9, 385-388. (e) Kanazaki,
M.; Ueno, Y.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2000, 122, 2422-
2432. (f) Yamamoto, Y.; Shuto, S.; Tamura, Y.; Kodama, T.; Hoshika, S.;
Ichikawa, S.; Ueno, Y.; Ohtsuka, E.; Komatsu, Y.; Matsuda, A. Biochemistry
2004, 43, 8690-8699 and references therein.
(4) (a) Bosch, E.; Bachi, M. D. J. Org. Chem. 1993, 58, 5581-5582.
(b) Baldwin, J. E.; Adlington, R. M.; Robertson, J. Tetrahedron 1991, 47,
6795-6812.
3292
Org. Lett., Vol. 8, No. 15, 2006

occurred. When the substrate 4 (0.01 M) was heated in the
presence of Bu3SnD (3.0 equiv) and AIBN (0.6 equiv) in
benzene under reflux, the desired deuterium-labeled products
at the 4-position 5a and 5b7 were obtained in 66% yield in
a 1:1.1 ratio, along with the compound deuterium-labeled at
the phenyl moiety 6 (11%) and the unlabeled reduction
product 7 (2%). Thus, the desired 1,6-HT reaction did in
fact occur to generate the radical at the 4-position of the
ribose derivative.
In recent years, we have developed a regio- and a
stereoselective method for introducing C2-substituents at the
position â to the hydroxyl group in halohydrins or in
R-phenylselenoalkanols A using an intramolecular radical
cyclization reaction with a dimethyl- or a diphenylvinylsilyl
group as a temporary connecting radical-acceptor tether
(Scheme 5).6,8,9 Thus, the selective introduction of both the
reaction, the kinetically favored 5-exo-cyclized radical C,
formed from radical B, was trapped when the concentration
of Bu3SnH was high enough to give E. At lower concentra-
tions of Bu3SnH and higher reaction temperatures, the radical
C rearranged into the more thermodynamically stable ring-
enlarged radical D via a pentavalent-like silicon radical
transition state X, which was then trapped with Bu3SnH to
give F.8d
In this study, we planned to employ this temporary
connecting silicon tether in the intramolecular radical C-C
bond formation at the ribose 4-position via the 1,6-HT
reaction with a 2-bromobenzylidene group. Consequently,
the 2,3-O-(2-bromobenzylidene)ribose derivative 9 with a
diphenylvinylsilyl group at the 5-hydroxyl was designed as
the substrate, which was prepared from 4 via 8, as shown in
Scheme 6.
Scheme 5
Scheme 6
The radical reaction of 9 was performed with Bu3SnH (3.0
equiv)/AIBN (0.6 equiv) or Et3B (1.0 equiv), and the
products were obtained after Tamao oxidation. The results
are shown in Table 1. A mixture of 9 (0.01 M), Bu3SnH,
Table 1. Radical Reaction of the Substrate 9
1-hydroxyethyl and 2-hydroxyethyl groups can be achieved,
depending on the concentration of Bu3SnH in the reaction
system, via a 5-exo-cyclization intermediate E or a 6-endo-
cyclization intermediate F, respectively, after oxidative ring
cleavage by treating the cyclization products under Tamao
oxidation conditions,10 as shown in Scheme 5. In this
yield, %b
entry
methoda
temp, °C
10 + 11 (ratio)c
12
16
trace
0
1
2
3
4
A
B
B
A
80
80
130
rt
75 (2:1)
64 (1:3.9)
47 (only 11)
50 (only 10)
34
(7) Stereochemistries of the compounds were confirmed by NOE and/
or NOESY data: see Figure S1 in Supporting Information.
(8) (a) Sugimoto, I.; Shuto, S.; Matsuda, A. J. Org. Chem. 1999, 64,
7153-7157. (b) Yahiro, Y.; Ichikawa, S.; Shuto, S.; Matsuda, A. Tetra-
hedron Lett. 1999, 40, 5527-5531. (c) Sugimoto, I.; Shuto, S.; Matsuda,
A. Synlett 1999, 1766-1768. (d) Shuto, S.; Sugimoto, I.; Matsuda, A. J.
Am. Chem. Soc. 2000, 122, 1343-1351. (e) Sukeda, M.; Ichikawa, S.;
Matsuda, A.; Shuto, S. Angew. Chem., Int. Ed. 2002, 41, 4748-4750. (f)
Sukeda, M.; Ichikawa, S.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68,
3465-3475.
a Method A: a mixture of 9 (0.01 M) and Bu3SnH (3.0 equiv) was heated
with AIBN (0.6 equiv) under reflux (entry 1) or stirred with Et3B (1.0 equiv)
at room temperature (entry 4) in benzene. Method B: to a solution of 9
(0.01 M) in benzene (entry 2) or chlorobenzene (entry 3) was added slowly
a solution of Bu3SnH (3.0 equiv) and AIBN (0.6 equiv) in the same solvent.
b Isolated yield. c The ratio was based on the isolated yields.
(9) (a) Yahiro, Y.; Ichikawa, S.; Shuto, S.; Matsuda, A. Tetrahedron
Lett. 1999, 40, 5527-5531. (b) Shuto, S.; Yahiro, Y.; Ichikawa, S.; Matsuda,
A. J. Org. Chem. 2000, 65, 5547-5557. (c) Terauchi, M.; Yahiiro, Y.;
Abe, H.; Ichikawa, S.; Stephen, C.; Tovey, S. C.; Dedos, S. G.; Taylor, C.
W.; Potter, B. V. L.; Matsuda, A.; Shuto, S. Tetrahedron 2005, 61, 7865-
7873. (d) Terauchi, M.; Matsuda, A.; Shuto, S. Tetrahedron Lett. 2005,
46, 6555-6558.
and AIBN was first heated in benzene under reflux. The
reaction gave the 4-branched products 10 and 11 in 75%
yield in a 2:1 ratio, along with the reduction product 12 in
16% yield (entry 1). When a mixture of Bu3SnH and AIBN
in benzene was added slowly to a solution of 9 (0.01 M) in
refluxing benzene, the 4-branched products 10 and 11 were
(10) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694-1696.
Org. Lett., Vol. 8, No. 15, 2006
3293

obtained in 64% yield in a ratio of 1:3.9, and the reduction
product 12 was formed in trace amounts (entry 2). A similar
reaction using the slow addition method at 130 °C with
chlorobenzene as a solvent gave the 4-branched product 11
as the only isolated product in 47% yield. On the contrary,
treatment of 9 at room temperature with Bu3SnH using Et3B
as the initiator produced 10 in 50% yield as the only
4-branched product isolated, along with the reduction product
12 in 34% yield.
Scheme 7
In the 4-branched products 10 and 11, the stereochemistry
at the 4-position proved to be completely inverted.7 On the
other hand, the 4-stereochemistry of the reduction product
12 was completely retained, suggesting that 12 was produced
by the direct reduction of the phenyl radical before the 1,6-
HT reaction occurred.
Access of the vinylsilyl moiety to the 4-radical from the
R-face seems to be hampered as a result of the steric
repulsion of the bulky endo-benzylidene group, and accord-
ingly, addition from the â-face would be preferred to form
the exo-cyclized radical i highly stereoselectively, as
shown in Scheme 7. Under the kinetic conditions, i.e., higher
Bu3SnH concentration at a lower reaction temperature, the
radical i was trapped with Bu3SnH to form mainly 13. Under
the thermodynamic conditions, i.e., lower Bu3SnH concentra-
tion at a higher reaction temperature, the radical i rearranged
into the ring-enlarged radical ii to produce 14. It is interesting
to note that the stereochemistry of the 4-position was
completely controlled throughout the reaction. This high
stereoselectivity would be due to the steric demand of both
the rigid benzylidene moiety and the intramolecular 5-exo-
cyclization process.
1,6-HT reaction with the 2-bromobenzylidene group. Thus,
the 2-bromobenzylidene group has proved to be the first
effective PRT group for the 1,6-HT reaction.
Acknowledgment. We wish to acknowledge financial
support from Ministry of Education, Culture, Sports, Science
and Technology, Japan for Scientific Research 17659027 and
17390027.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of all new compounds, NOE
and NOESY data for determination of the stereochemistries,
In conclusion, the 2-bromobenzylidene group was designed
as a new PRT group to realize a selective 1,6-HT reaction.
Deuterium-labeling experiments with the 2,3-O-bromoben-
zylideneribose derivative 4 indicated that the 1,6-HT reaction
did indeed occur. The intramolecular C-C-bond formation
reaction with a silicon tether successfully proceeded via the
1
1
and H, 13C, and H-2D NMR spectra of key compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL061162O
3294
Org. Lett., Vol. 8, No. 15, 2006