Investigations into the effectiveness of deuterium as a protecting group for C-H bonds in radical reactions involving hydrogen atom transfer

Article abstract of DOI:10.1039/b810018g

Competition experiments have been carried out to determine the extent to which deuterium can be used as a protecting group for carbon-hydrogen bonds in radical-based intramolecular hydrogen atom transfer processes.

Full text of DOI:10.1039/b810018g

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Investigations into the effectiveness of deuterium as a “protecting group” for
C–H bonds in radical reactions involving hydrogen atom transfer
Mark E. Wood,*a Sabine Bissiriou,a Christopher Loweb and Kim M. Windeatta
Received 16th June 2008, Accepted 3rd July 2008
First published as an Advance Article on the web 22nd July 2008
DOI: 10.1039/b810018g
Competition experiments have been carried out to deter-
mine the extent to which deuterium can be used as a
protecting group for carbon–hydrogen bonds in radical-based
intramolecular hydrogen atom transfer processes.
tunneling.7 Whilst there are many examples of the exploitation
of the primary kinetic isotope effect in mechanistic studies, there
are relatively few in synthetic applications8 and hence, we initiated
the systematic studies described herein into the effectiveness of
deuterium as a “protecting group” for hydrogen atoms bonded to
a carbon atom a-to nitrogen. a-Aminoalkyl radicals are valuable
reactive intermediates in the preparation of a wide range of amine
and amino acid derivatives9 and their regioselective generation is
the key to their effective synthetic use.
Competition experiments using two heterocyclic systems were
chosen for these studies, in which protecting-radical translocating
(PRT) groups10 were positioned such that 1,5-transfer of hydrogen
or deuterium could occur after initial radical generation using
standard tin hydride-based methodology. Initial studies were
carried out with di-deuterated N-(2-iodobenzyl)pyrrolidine 1,
a modified analogue of the substrates originally used in a-
aminoalkyl radical alkylation procedures reported by Undheim
et al.11 After generation of the highly reactive radical intermediate
2, rapid 1,5-hydrogen or deuterium atom transfer would give rise to
a-aminoalkyl radicals 3 and 4 respectively for subsequent trapping
with either tributyltin hydride or unsaturated radicalphiles such
as acrylonitrile (Scheme 2).
Translocation of carbon-centred radicals via intramolecular hy-
drogen atom transfer, in particular from highly reactive aryl
and vinyl radicals, represents a popular and powerful method
for the remote functionalisation of positions in molecules which
would traditionally be regarded as unreactive.1 High regioselec-
tivity in the hydrogen atom removal/radical generation is of
prime importance for such a process to be of synthetic value,
and the stereoelectronic desirability for a linear transition state
often results in an overwhelming preference for 1,5-hydrogen
atom transfer over other possible modes of radical translocation
(Scheme 1).
Scheme 1 1,5-Hydrogen atom transfer.
In certain instances when using radical-based methodology
however, hydrogen atom transfer may occur as an unwanted side-
reaction. For example, in the total synthesis of the antitumour
agent fredericamycin A,2 Clive et al. found that 1,7-hydrogen
atom transfer from an aryl methoxy group (used as a protecting
group) to an intermediate vinyl radical occurred after a radical
spirocyclisation onto an alkyne. This led to the formation of
a substantial quantity of an undesired by-product with the
intramolecular hydrogen atom transfer process being found to be
competitive with the required quenching of the vinyl radical with
triphenyltin hydride.3 A solution to this problem was found in
deuteration of the methyl group, with the primary kinetic isotope
effect for deuterium vs. hydrogen atom transfer efficiently retarding
the competing side-reaction.3,4
Scheme 2 Hydrogen vs. deuterium atom transfer.
During our initial studies into the radical-based functionali-
sation of b-amino alcohols, via 1,5-hydrogen atom transfer,5 we
encountered a similar problem.6
The extent to which deuterium can be used to block intramolec-
ular hydrogen atom transfer is not straightforward to predict, as
extremely high kinetic isotope effects have been observed in cases
where the predominant mechanism involves quantum mechanical
In order to investigate the extent to which a more stabilised, later
transition state can override the primary kinetic isotope effect,
similar radical reactions of di-deuterated morpholinone derivative
5 were also examined. In this system, hydrogen atom transfer from
C-5 to intermediate aryl radical 6 would be expected to occur via an
earlier, less stable transition state (to give 7) than the corresponding
deuterium transfer process resulting in captodatively stabilised
radical 8 (Scheme 3). Hence, these experiments would give some
indication of the relative importance of kinetic vs. thermodynamic
control in determining the regioselectivity of 1,5-hydrogen atom
transfer.
aSchool of Biosciences (originally Department of Chemistry), University
of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, EX4 4QD, UK.
E-mail: m.e.wood@exeter.ac.uk; Tel: +44 1392 263450
bUCB Celltech, Granta Park, Great Abington, Cambridge, CB21 6GS, UK
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Table 1 Results for reduction of di-deuterated pyrrolidine 1
Entry
Bu3SnH/D
Temp/◦C
Products
Ratio
Yield (%)
1
2
3
4
5
6
H
H
H
D
D
D
80
25
11, 12
11, 12
11, 12
13, 14
13, 14
13, 14
3 : 1
12 : 1
49 : 1
1 : 2
7 : 1
7 : 1
55
58
66
58
70
55
−50
80
25
−50
All of the reduction experiments were carried out using
azobisisobutyronitrile as the initiator with either thermal or
photochemical radical generation, depending on the reaction
temperature required. The reactions were carried out in either
benzene (or fluorobenzene for experiments at −50 ◦C) in the
presence of 1.3 equiv. of tributyltin hydride or deuteride, at
a substrate concentration of 50–60 mM. In all of the radical
reactions carried out, the polar nature of the amine products,
combined with the use of tin-based reagents, resulted in significant
difficulties with product purification. Although these problems
could be alleviated to some extent by using chromatography with
silica gel containing potassium fluoride,13 the relatively low yields
can be partly attributed to the need for repeated chromatographic
purification. In all cases, 11, 12, 13 and 14 were the only isolable
pyrrolidine-containing products.
Scheme 3 Radical/transition state stability vs. kinetic isotope effect.
In addition, radical precursors 9 (a deuterated version of
the derivative used by Robertson in the preparation of ( )-
heliotridane12) and 10 (Fig. 1) were prepared, incorporating vinyl
groups suitably positioned for 5-exo-trig trapping of a-aminoalkyl
radical intermediates.
Products 11 and 14 could of course, result from either direct
aryl iodide reduction or 1,5-hydrogen (for 11) or deuterium (for 14)
transfer, followed bya-aminoalkyl radical trapping with tributyltin
hydride or deuteride respectively. It is therefore not possible to
determine accurate kH/kD values from these data, although it is
possible to make useful qualitative deductions. The results shown
in Table 1 (entries 1 to 3) suggest kH/kD values ranging between 3
and 49, depending on temperature, with entries 4 to 6 suggesting a
maximum kH/kD value of 7, although these values should clearly be
treated with appropriate caution. Most importantly, these results
suggested that the selectivity for hydrogen over deuterium atom
transfer increases, as expected, at lower temperatures.
Similar radical reactions were carried out using 1, in the presence
of acrylonitrile as an a-aminoalkyl radical trap (Scheme 6). The
optimal conditions used a 5-fold excess of acrylonitrile and
2 equiv. of tributyltin hydride, at a substrate 1 concentration of
60 mM. Table 2 summarises the results from these studies, with
the inseparable mixture of alkylated products 15 and 16 being the
only detectable/isolable pyrrolidine-containing material obtained.
Fig. 1 Radical cyclisation precursors.
Radical reactions were carried out firstly on pyrrolidine sub-
strate 1. Reduction reactions were performed using both trib-
utyltin hydride (Scheme 4) and tributyltin deuteride (Scheme 5),
in order to assess the efficiency of 1,5-hydrogen atom transfer in
intermediate aryl radical 2 and also the extent to which the primary
kinetic isotope effect could influence the regioselectivity of this
process. The results from these studies are shown in Table 1.†
Scheme 4 Reduction of di-deuterated pyrrolidine 1 with tributyltin
hydride. Reagents and conditions: Bu3SnH (1.3 equiv.), AIBN, C6H6 or
C6H5F, heat or UV irradiation.
Scheme 6 Intermediate radical trapping with acrylonitrile. Reagents and
=
conditions: Bu3SnH ( 2 equiv.), CH2 CHCN (5 equiv.), AIBN, C6H6 or
C6H5F, heat or UV irradiation.
In these experiments, both products 15 and 16 can only be
produced by 1,5-hydrogen (or deuterium) atom transfer, and hence
these results give a clearer estimate of the effectiveness of the
isotope protecting group in diverting the course of this process.
Scheme 5 Reduction of di-deuterated pyrrolidine 1 with tributyltin
deuteride. Reagents and conditions: Bu3SnD (1.3 equiv.), AIBN, C6H6 or
C6H5F, heat or UV irradiation.
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Table 2 Results for intermediate radical trapping with acrylonitrile
Entry
Temp/◦C
Products
Ratio
Yield (%)
1
2
3
80
25
−50
15, 16
15, 16
15, 16
3.2 : 1
4.4 : 1
5.5 : 1
15
23
56
The kinetic isotope effect (kH/kD) of 5.5, observed at −50 ◦C
(Table 2, entry 3) represents a significant and measurable increase
on the selectivity observed at 80 ◦C (entry 1).
Scheme 8 Reduction of di-deuterated morpholinone 5 with tributyltin
hydride. Reagents and conditions: Bu3SnH (1.5 equiv.), AIBN, C6H6 or
C6H5F, heat or UV irradiation.
Intramolecular trapping of the pyrrolidine-derived intermediate
a-aminoalkyl radicals was also investigated using substrate 9
(Scheme 7). A cascade process involving vinyl radical generation,
1,5-hydrogen (or deuterium) atom transfer and 5-exo-trig a-
aminoalkyl radical cyclisation, resulted in a mixture of products
17 and 18. Slow addition of tributyltin hydride (2.8 equiv.) at
80 ◦C and a substrate concentration of 12 mM gave rise to
a 20% overall isolated yield of the two products, in a 5.5 : 1
ratio,‡ favouring the product 17 from hydrogen atom transfer
and suggesting a kinetic isotope effect (kH/kD) of 5.5. (The
17/18 product mixture constituted the only isolable pyrrolidine-
containing material from this reaction with the low yield being
attributable, in part, to the well-documented problems associated
with product isolation.12) Analogous reactions conducted at 20
and −50 ◦C, with photochemical cleavage of AIBN, failed to give
any of the desired bicyclic product.
Table 3 Results for reduction of di-deuterated morpholinone 5
Entry
Temp/◦C
Yield (%)
1
2
3
80
25
−50
68
59
59
Scheme 9 Reduction of di-deuterated morpholinone 10 with tributyltin-
hydride. Reagents and conditions: (a) Bu3SnH (1.1 equiv.), AIBN, C6H6,
80 ◦C; (b) slow addition of Bu3SnH (1.1 equiv.), AIBN, C6H6, 80 ◦C or (c)
Bu3SnCl (0.1 equiv.), NaBH3CN (2.0 equiv.), tBuOH, 80 ◦C.
Table 4 Results for reduction of morpholinone 10 (for conditions a–c,
see Scheme 9)
Entry
Conditions
Yield (%)
Scheme 7 Intramolecular a-aminoalkyl radical trapping. Reagents and
conditions: (a) Bu3SnH (2.8 equiv.), AIBN, C6H6, 80 ◦C; (b) PhSH.
1
2
3
a
b
c
30
10
10
These experiments indicate that the primary kinetic isotope
effect can give rise to significant selectivity for hydrogen rather
than deuterium atom transfer to a highly reactive aryl radical
when the resulting intermediate radical, and hence its immediately
preceding transition state, is only partially stabilised. Analogous
radical reactions were therefore carried out using di-deuterated
morpholinone substrates 5 and 10, in order to assess the influence
of transition state stability on this process.
Under optimised conditions, 42 mM solutions of N-2-iodo-
benzyl morpholinone 5 (in benzene or fluorobenzene as appropri-
ate) were reduced with tributyltin hydride (1.5 equiv.) and AIBN
at 80, 20 and −50 ◦C (Scheme 8 and Table 3). (Photochemical
cleavage of AIBN was used for the experiments at 20 and −50 ◦C.)
In all cases, the only morpholinone-containing product obtained
was the symmetrical dimer 19,§ and attempts to favour monomeric
product formation, by increasing either the substrate 5 dilution or
the concentration of tributyltin hydride, gave the same result.
Attempts to intercept intermediate a-aminoalkyl radicals using
a 5-exo-trig cyclisation were made using N-2-bromobut-1-enyl
morpholinone 10 but again, only the dimeric product 20 could
be isolated from these reactions, all of which were carried out at
80 ◦C (Scheme 9). Standard approaches to obtaining monomeric
products were also investigated, but neither slow addition nor in
situ generation of tributyltin hydride resulted in the formation of
any other identifiable morpholinone-containing product and only
gave substantially lower isolated yields of 20 (Table 4).
The studies carried out on morpholinones 5 and 10 clearly
illustrate the fact that hydrogen atom transfer to a highly reactive
aryl or vinyl radical is not always a kinetically controlled process.
Atom transfer leading to a stabilised radical intermediate will
have a later, more “product-like” transition state, and the results
obtained here show that captodative stabilisation can completely
override the primary kinetic isotope effect in determining the
regioselectivity of such processes. (Curran et al. have previously
shown that hydrogen atom transfer is most efficient when a tertiary
alkyl radical is generated,14 and the radical dimerisation of amino
acids9 and related morpholinone-based systems15 has also been
observed.)
In summary, we have carried out fundamental, systematic
studies into the factors that can influence the regioselectivity of
hydrogen atom transfer in radical-based processes. Exploitation of
the primary kinetic isotope effect facilitates the use of deuterium
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as a “protecting group” for carbon–hydrogen bonds, unless the
atom transfer process has a highly stabilised, late transition state,
in which case, formation of the most stable radical intermediate
will be favoured. Reasonable selectivity of hydrogen vs. deuterium
atom transfer for a-aminoalkyl radical generation in pyrrolidine
systems such as 1, 5 and 9, even at elevated temperatures, suggests
that this methodology could be used for carbon–hydrogen bond
protection in synthetic schemes if the products arising from the
different transfer processes are separable. The radical dimerisation
of morpholinone systems such as 5 and 10 via exclusive deuterium
rather than hydrogen atom transfer adds support to the concept
of captodative radical stabilisation, and this system could offer
further opportunities for the study of this phenomenon, which
has seen recent interest in synthetic applications.16
‡ Product ratios were determined using 2H NMR spectroscopy.
§ Compunds 19 and 20 appeared to be produced in a single diastereoiso-
meric form, although the actual stereochemistry is, as yet, undetermined.
1 J. Robertson, J. Pillai and R. K. Lush, Chem. Soc. Rev., 2001, 30, 94.
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Acknowledgements
We thank EPSRC (DTA funding to K. M. W. and Project Stu-
dentship to S. B.) and UCB Celltech (CASE funding to K. M. W.)
for financial support, Dr Jeremy Robertson (Oxford, UK) for
invaluable advice concerning the preparation and isolation of
( )-heliotridane, the EPSRC National Mass Spectrometry Service
Centre (Swansea, UK) for mass spectra and Dr Stephen J. Simpson
(Exeter, UK) for NMR work.
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10 V. Snieckus, J.-C. Cuevas, C. P. Sloan, H. Liu and D. P. Curran, J. Am.
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12 J. Robertson, M. A. Peplow and J. Pillai, Tetrahedron Lett., 1996, 37,
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13 D. C. Harrowven and I. L. Guy, Chem. Commun., 2004, 1968.
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16 For example, see: S. K. Bagal, R. M. Adlington, R. A. B. Brown and
J. E. Baldwin, Tetrahedron Lett., 2005, 46, 4633.
Notes and references
† Product ratios were determined using a combination of 2H NMR
spectroscopy and mass spectrometry.
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Org. Biomol. Chem., 2008, 6, 3048–3051 | 3051
©