Anchimeric assistance in hydrogen-atom transfer to bromine

Article abstract of DOI:10.1071/CH04058

The free-radical benzylic brominations of series of phenylalanine derivatives and O-phenylalkyi benzoates and N-phenylalkylamides with N-bromosuccinimide exhibit anchimeric assistance by neighbouring ester and amido groups. Rate enhancement occurs through

Full text of DOI:10.1071/CH04058

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Aust. J. Chem. 2004, 57, 651–654
∗
Anchimeric Assistance in Hydrogen-Atom Transfer to Bromine
Anna K. CroftA,B and Christopher J. EastonA,C
A
Research School of Chemistry, Institute of Advanced Studies, Australian National University,
Canberra ACT 0200, Australia.
Current address: Department of Chemistry, University of Wales, Bangor, Gwynedd LL57 2UW, UK.
Author to whom correspondence should be addressed (e-mail: easton@rsc.anu.edu.au).
B
C
The free-radical benzylic brominations of series of phenylalanine derivatives and O-phenylalkyl benzoates and
N-phenylalkylamides with N-bromosuccinimide exhibit anchimeric assistance by neighbouring ester and amido
groups. Rate enhancement occurs through electron donation to the electropositive carbon centre that develops in the
transition state of the hydrogen-atom transfer to bromine. The extent of the effect depends on the electron demand
at the benzylic position and the electron-donating ability of the neighbouring group.
Manuscript received: 2 March 2004.
Final version: 4 May 2004.
X–Ph
H
X–Ph
X–Ph
Br
Neighbouring-group participation and anchimeric assistance
CH
CH
CH•
CH
CH
CH
[1]
commonly occur in ionic processes. By contrast, only a
limited range of examples have been found in free-radical
reactions, and the majority of these involve 1,3-participation,
where the formation of an alkyl radical is affected by a
substituent on carbon adjacent to the incipient radical cen-
tre. Accordingly, anchimeric assistance has been observed in
hydrogen-atom abstractions, during the vicinal halogenation
PhthN
COR
PhthN
COR
PhthN
COR
1
2
3
a X ϭ H, R ϭ OMe
b X ϭ H, R ϭ NHBut
c X ϭ 4-OAc, R ϭ OMe
d X ϭ 4-OAc, R ϭ NHBut
e X ϭ 4-NO , R ϭ OMe
X ϭ 4-NO , R ϭ NHBu
2
[
2–4]
of alkyl halides
and in reactions of the tert-butoxy radical
t
f
2
[
5]
with tetraethyl-silane, -germanium, and -stannane, and in
g X ϭ 4-OMe, R ϭ OMe
h X ϭ 4-OMe, R ϭ NHBut
halogen-atom transfers in the reactions of β-haloalkylsilanes
i
j
X ϭ 3,4-(OMe) , R ϭ OMe
X ϭ 3,4-(OMe) , R ϭ NHBu
[4–6]
2
and vicinal dihalides with stannanes.
Neighbouring-
t
2
group participation is also reflected in the bridging of the
[
4]
product radicals as determined through product analyses
and EPR (electron paramagnetic resonance) spectroscopic
Scheme 1.
[7]
studies.
(a)
(b)
Several years ago we reported 1,4-neighbouring-group
participation by an amido substituent in hydrogen-atom trans-
fer reactions from the side chains of amino acid derivatives.
These studies stemmed from our earlier observations that
nucleophilic substitution reactions of the bromides 3a–3f
␦Ϫ•
ϩ•
␦
Br
Ph Sn
3
PhthN
␦
PhthN
H
H
Br
H
ϩ•
Ϫ•
[
8]
␦
Ar
␦
Ar
NHBut
H
H
ϩ•
t
NHBu
O
O
(
Scheme 1) to give alcohols are substantially affected by
Scheme 2.
neighbouring-group participation by the ester and amide
groups, particularly in the latter case where the more electron-
donating amido substituent can interact more extensively
with an electron-deficient carbon centre developing in a reac-
tion transition state. In analogous free-radical reactions of
the phenylalanines 1a–1f with N-bromosuccinimide to give
the bromides 3a–3f via the radicals 2a–2f, respectively, the
amides 1b, 1d, and 1f underwent reaction faster than the
corresponding esters 1a, 1c, and 1e. This enhanced reac-
tivity of the amides 1b, 1d, and 1f was attributed to the
greater electron-donating ability of an amido substituent,
relative to an ester group, to interact with and stabilize the
electron-deficient carbon centre developing in the transition
state of each hydrogen abstraction (Scheme 2a). No such
rate enhancement was observed in the reductions of the bro-
mides 3a–3f with triphenyltin hydride to give 1a–1f via the
radicals 2a–2f, respectively. This is as expected since the
transition state for halogen-atom transfer to a stannyl radical
[9]
∗
Dedicated to Professor Lew Mander on the occasion of his 65th birthday.
CSIRO 2004
©
10.1071/CH04058
0004-9425/04/070651

6
52
A. K. Croft and C. J. Easton
•
(CH ) CH Ph
2 n
X
(CH2) CH Ph
X
X
(CH ) CH Ph
Table 1. Relative rates of reactionA of the phenylalanine
n
2 n
H
Br
derivatives 1a–1j with N-bromosuccinimde
4
5
6
B
Compound
krel
a n ϭ 1, X ϭ OCOC H
6
5
b n ϭ 1, X ϭ OCOC6F5
c n ϭ 1, X ϭ NHCOCH3
d n ϭ 1, X ϭ NHCOCF3
e n ϭ 1, X ϭ NHCOC H
n ϭ 1, X ϭ NHCOC6F
g n ϭ 2, X ϭ NHCOC H
h n ϭ 2, X ϭ NHCOC6F5
n ϭ 3, X ϭ NHCOC H
n ϭ 3, X ϭ NHCOC6F5
1a
1b
1c
1d
1e
1f
1C
4.5
1.1
4.3
0.13
0.63
10
6
5
5
f
5
6
1
g
i
j
6 5
1
h
33
18
49
1
i
1
j
Scheme 3.
A
Reaction with N-bromosuccinimide in carbon tetrachloride
at reflux under nitrogen, initiated using a 250W mercury lamp.
Relative rates of reaction were determined as the average of
the results of at least duplicate experiments which varied by
involves the development of an electron-rich centre at the site
of halogen abstraction, which is unlikely to be facilitated by
B
[
8]
the presence of electron-donating groups (Scheme 2b).
less than 10%. Data obtained for compounds 1a–1f are derived
[10]
[8]
from the literature.
Hutton
has made good use of the nucleophilic sub-
C
Assigned as unity.
stitution reactions of β-bromophenylalanine derivatives in
the stereocontrolled synthesis of β-hydroxyphenylalanines.
He found that the stereoselectivity was reduced by electron-
donating substituents on the aryl ring, presumably because
these decreased the extent of neighbouring-group participa-
tion by lowering electron demand at the benzylic position.
Thispromptedustoinvestigatetheeffectofelectron-donating
substituents on the analogous free-radical processes, by
examining reactions of 1g–1j. We also studied reactions of
Ph
O
N
Ph
N
Ph
COPh
7
8
Scheme 4.
4
a–4j (Scheme 3) to determine if the anchimeric assistance
Table 2. Relative rates of reactionA of the esters 4a, 4b
seen in the radical reactions of 1a–1f is a more general
phenomenon.
and the amides 4c–4j with N-bromosuccinimde
B
Compound
krel
The esters 1g and 1i were obtained as reported
[10,11]
previously.
ment of O-methyltyrosine
then triethylamine, ethyl chloroformate, and tert-butylamine
The amide 1h was prepared by treat-
4a
4b
0.36
0.20
0.80
0.34
[12]
with phthalic anhydride and
4
c
4
d
(
see Accessory Materials). In a similar manner, 3,4-
C
4
e
1
[13]
dimethoxyphenylalanine
1
1
chloride at reflux under nitrogen, while the solutions were
irradiatedwitha250Wmercurylamp, togivethecorrespond-
ing bromides 3g–3j, each as a 1 : 1 mixture of diastereomers
was used to prepare the amide
4
4g
4h
4
4
f
0.60
4.5
2.9
6.1
3.8
j (see Accessory Materials). The amino acid derivatives
g–1jweretreatedwith N-bromosuccinimide in carbon tetra-
i
j
A
Reaction with N-bromosuccinimide in carbon tetrachloride
[10]
(
the esters 3g and 3i have been described previously;
the
at reflux under nitrogen, initiated using a 250W mercury lamp.
B
Relative rates of reaction were determined as the average of
amides3hand3jandthebrominationmethodaredescribedin
theAccessory Materials).As was previously observed for 3a–
the results of at least duplicate experiments which varied by
less than 10%.
3
f, the yields of the bromides 3g–3j were all greater than 90%.
C
Assigned as unity.
The relative rates of reaction of 1g–1j were determined in
standard competitive experiments (see Accessory Materials)
[8]
1
and compared to those of 1a–1f (Table 1), by measuring
the relative rates of consumption of the starting materials and
of formation of the products.
to be almost quantitative when measured by H NMR spec-
troscopy using N-tert-butylbenzamide as an internal standard
in the reaction mixtures, but some decomposition of the bro-
mides 6c, 6e, 6g, and 6i was observed during their isolation
and purification, particularly with 6e and 6i, which cyclized
The esters 4a, 4b and the amides 4c–4j were prepared
by acylation of the corresponding alcohol and amines, as
[14]
[15]
[16]
described previously for 4a, 4c–4g and 4i.
Characteri-
to give the oxazoline 7
and the pyrrolidine 8 (Scheme
zation data for 4b, 4h, and 4j are included as Accessory
Materials. Treatment of 4a–4j with N-bromosuccinimide,
as described above for the reactions of 1g–1j, afforded the
corresponding bromides 6a–6j (see Accessory Materials) in
yields ranging from 58 to 86%. The crude yields appeared
4), in yields of 75 and 55%, based on 4e and 4i, respectively.
The relative rates of reaction of 4a–4j (Table 2) were deter-
mined in standard competitive experiments, as performed
with1a–1j.Thepairsoffluorinatedandnon-fluorinatedcom-
pounds 4a and 4b, 4c and 4d, 4e and 4f, 4g and 4h, and 4i and

Anchimeric Assistance in Hydrogen-Atom Transfer to Bromine
653
4
j were always compared directly, so that the effects of the
corresponds to 1,4-participation through either the amide
oxygen or nitrogen. The reactions of 4a–4f, 4g, 4h, and 4i, 4j
could involve either 1,3- or 1,5-, 1,4- or 1,6-, and 1,5- or
1,7-participation, respectively. Although it is not practical to
distinguish between these possibilities, there is likely to be a
preference for 1,5-neighbouring-group effects. This is seen
by analogy in the decomposition of the bromides 6e and 6i,
to give the oxazoline 7 and the pyrrolidine 8, respectively.
In conclusion, all of the above evidence indicates that
anchimeric assistance in hydrogen-atom transfer to bromine
is a general phenomenon. The neighbouring-group effects
arise from stabilization of carbon-centred electron-deficient
transition states and do not necessarily reflect properties of
the intermediate radicals. Either way, the radical reactions
show polar characteristics similar to those of their ionic
counterparts.
electron-withdrawing fluorines could be accurately assessed.
The relative rates of reaction of the phenylalanine deriva-
tives 1a–1j correspond to the relative rates of formation of
the radicals 2a–2j, since this is the first committing step on
the pathway to give the bromides 3a–3j. Notably, the rates
do not reflect the stability of the radicals 2a–2j. Radical
stabilization energies calculated for model benzylic radicals
indicate that both nitro and methoxy substituents in the para
[17]
position increase radical stability.
However, in the reac-
tions of 1a–1j, the nitro substituents of 1e and 1f decrease
reactivity relative to that of 1a and 1b, respectively, while
the methoxyphenylalanines 1g and 1h are more reactive.
Thus, the relative reactivity of 1a–1j appears to be deter-
mined largely by the electron-donating and -withdrawing
ability of the aryl substituents, indicating that the hydrogen-
atom abstractions to give 2a–2j proceed by electron-deficient
carbon-centred transition states (Scheme 2). For the esters
Accessory Materials
1
a, 1c, 1e, 1g, and 1i, the ratios of the relative reaction rates
Experimental procedures for the individual and competitive
brominations and for the preparation of 1h and 1j and char-
acterization of compounds 1h, 1j, 3h, 3j, 4b, 4h, 4j, and
+
[18]
correlate with σ Hammett substituent parameters
with a
2
reliability coefficient (R ) of 0.9975 and a ρ value of −1.25.
The ρ value is reduced to −1.05 for the amides 1b, 1d, 1f,
6a–6j are available from the corresponding author or, until
1
h, and 1j, indicating that there is less electron demand at
July 2009, the Australian Journal of Chemistry.
the benzylic position in the transition states for the reac-
tions of these species. This is consistent with that demand
being decreased through neighbouring-group participation
by the amido substituents of these compounds. Conversely,
the extent of neighbouring-group participation by the amido
group is enhanced by electron-withdrawing substituents on
thearylringanddecreasedbyelectron-donatinggroups. Con-
sequently, the nitro-substituted amide 1f is almost five times
more reactive than the ester 1e, while the dimethoxyphenyl-
alaninamide 1j is less than three times more reactive than 1i.
Anchimeric assistance is also evident in the reactions of
Acknowledgment
This work was made possible through the support of the
Australian Research Council.
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