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L. Zeng et al. / Tetrahedron Letters 47 (2006) 7911–7914
EtO2C
R
O
Cl
H3C
CH2Cl
H3C
CH3
H3C
CH3
SO2Cl2
N
+
CF3SO2NH
CO2Me
CF3SO2NH
CO2Me
CF3SO2NH
CO2Me
O
H
H
H
6
5
Scheme 1.
initial success utilizing a-bromoamino acids,14 this
chemistry suffered from serious drawbacks that included
the instability of the radical precursors, as well as diffi-
culties in their synthesis. Indeed, Easton reported that
some substituted amino acids (e.g., 5) undergo preferen-
tial free-radical halogenation in the alkyl side-chain
rather than at the a-position (Scheme 1).15 This has been
attributed to both steric repulsion between the amide
carbonyl and the side-chain in structures such as Naph-
thaloyl substituted (and other) amides 6, themselves
mimics of peptide residues, as well as the lower p-donat-
ing ability of amides and triflamides.15,16
O
O
X
O
R
Cl
OMe
R
OMe
NH
NH2
Et3N
48 - 80%
O
X
Boc2O
NaH
O
9a: R = H
b: R = Me
c: R = iBu
d: R = tBu
e: R = Ph
R
OMe
OtBu
N
O
O
X
1,5-Hydrogen transfer chemistry has been used on a
number of occasions to translocate a radical centre to
a desired, but inaccessible location, so that further
chemistry can be carried out. When used to generate
a-amidyl radicals, Curran and Snieckus demonstrated
the importance of influencing amide rotamer popula-
tions through the judicious choice a of nitrogen substit-
utent,17 since 1,5-hydrogen transfers are faster than the
rotation about the amide C–N bonds.18
50 - 83%
Scheme 3.
with 2-iodobenzoyl chloride (X = I) in the presence of
triethylamine to afford the N-(2-iodobenzoyl)amino acid
methyl esters in moderate yield. These amides were fur-
ther reacted with sodium hydride and bis(tert-butyloxy-
carbonyl) anhydride (Boc2O) to afford the precursors (9,
X = I). An analogous procedure, utilizing benzoyl chlo-
ride, was used to prepare the ‘reduced’ compounds (9,
X = H) as NMR standards.
With this in mind, together with an understanding that a
knowledge of rate constant data is crucial to the design
of free-radical reactions of synthetic significance, we set
about determining kinetic data for 1,5-hydrogen trans-
fer from the a-carbon in substituted Boc-protected ami-
no acid radicals 7 to afford the a-centred radicals 8. We
reasoned that the bulky protecting group would ensure
that the correct rotamer of 7 was available for reaction,
and that, unlike the intermolecular radical chemistry
described by Easton,15 entropy would work in our
favour (Scheme 2). During this work we discovered that
while radicals 8 were able to be generated for these
amino acids, competition with 1,6- and 1,7-abstractions
by the radical centre in 7 are significant competing
processes.
With iodides (9, X = I) in hand, we next turned our
attention to the determination of translocation rate
data. Absolute rate constants for the 1,5-hydrogen
transfer reactions in benzene were determined under
pseudo first-order conditions (5 equiv Bu3SnD) through
the use of competition kinetics as depicted in Scheme 4.
Initial experiments were conducted using the leucine
derivative. When 9c (X = I) was reacted with Bu3SnD
(0.1 M) as described above, 2H NMR spectroscopy
revealed three main signals. Two of these corresponded
to the directly reduced product (9c, X = D) and the
translocated product (10c) at 7.6 and 5.2 ppm, respec-
tively.19 The third peak (1.5 ppm) corresponded to the
product 11 of 1,7-hydrogen transfer, while the fourth
peak (0.9 ppm) was consistent with small amounts of
the product arising from 1,6-H transfer and too small
for a value of k1,6 to be determined in this system.
Aryl iodides 9 were prepared as precursors for 7 using
standard synthetic methodology (Scheme 3). Accord-
ingly, the required amino acid (glycine, alanine, leucine,
tert-leucine, phenylglycine) methyl ester was treated
Given a best estimate for kD of 6.7 · 108 Mꢀ1 sꢀ1 at
80 ꢀC,20,21 integration of these signals and application
of the appropriate integrated rate equation (Eq. 1) pro-
vided an estimate for the rate constant for 1,5-hydrogen
MeO2C
MeO2C
R
H
1,5-H
N
N
O
O
R
O
O
O
O
transfer and formation of the a-leucinyl radical 8c (k1,5
)
of 3.1 · 107 sꢀ1 at 80 ꢀC, while applying analogous prin-
ciples, k1,7 in this system is estimated to be 1.9 · 107 sꢀ1
at 80 ꢀC.
7
8
Scheme 2.