Uncovering the importance of proton donors in TmI2-promoted electron transfer: Facile C-N bond cleavage in unactivated amides

Article abstract of DOI:10.1002/anie.201303178

Nonclassical lanthanide(II) iodides are modern reagents for the development of challenging electron-transfer processes. It was demonstrated that alcohols are critical for the formation of a thermodynamically more powerful reductant from TmI₂ (thulium diiodide), the first nonclassical lanthanide(II) iodide in the series (TmI₂, DyI₂, NdI₂). The TmI₂(ROH)_n reagent promotes an unprecedented cleavage of the σ C-N bond in amides. Copyright

Full text of DOI:10.1002/anie.201303178

Angewandte
Chemie
DOI: 10.1002/anie.201303178
Thulium Diiodide
Uncovering the Importance of Proton Donors in TmI2-Promoted
ꢀ
Electron Transfer: Facile C N Bond Cleavage in Unactivated
Amides**
Michal Szostak,* Malcolm Spain, and David J. Procter*
The amide bond is one of the most ubiquitious functional
groups in chemistry and biology.[1] To date, the majority of
strategies to functionalize amide bonds have focused on
activation of the carbonyl group towards nucleophilic addi-
tion,[2] however only few examples of the selective activation
of s C–N bonds in amides have been reported. In this regard,
ꢀ
the cleavage of a s C N bond in amides was achieved in
several highly innovative but very specialized bridged lac-
ꢀ
tams, in which one of the C N bonds was sufficiently distorted
from planarity (Figure 1a).[3] Functionalization of the C N
ꢀ
bond in electronically activated phthalimides has also been
described.[4] However, a general method for the activation of
ꢀ
s C N bonds in amides is unknown despite its considerable
potential to advance the synthetic application of amide
linkages in chemistry and biology.
The discovery of new reactivity modes of underexplored
elements underpins major advancements in synthesis. In this
regard, the seminal discovery of Kagan and co-workers that
SmI2 acts as a strong electron donor[5] has resulted in one of
the most important single-electron transfer reagents in
organic chemistry.[6,7] However, the inherent limitation of
SmI2 is its relatively low redox potential (E8 (LnIII/II) = ꢀ1.5 V
vs. NHE),[8] especially when compared with the extremely
powerful, albeit less chemoselective, alkali metals in liquid
ammonia (i.e. Birch-type reductants).[9] Recently, nonclassical
lanthanide(II) iodides (TmI2, thulium diiodide; DyI2, dyspro-
sium diiodide; NdI2, neodymium diiodide) have emerged as
an attractive solution to the problem of insufficient redox
potential of SmI2 (Figure 1b).[10] In analogy to SmI2, these
extremely reducing lanthanide iodides (E8 (LnIII/II) = ꢀ2.2,
ꢀ2.5, ꢀ2.6 V vs. NHE,[8] respectively) have been fully
characterized in ethereal solvents[11] and can be easily
ꢀ
Figure 1. a) Cleavage of unactivated s C N bonds in amides. b) Clas-
sical and nonclassical lanthanide(II) iodides. c) This study.
obtained in multigram quantities.[12] Seminal work by Evans
et al. provided the first evidence that TmI2, DyI2, and NdI2
mediate challenging cross-coupling reactions beyond the
scope of SmI2.[13] Evans et al. also reported DyI2 as the first
lanthanide(II) reagent capable of promoting Birch reductions
under very mild conditions.[11b] However, the direct use of
nonclassical lanthanides(II) to generate ketyl radicals has not
been reported despite their significant potential to activate
=
C O groups that are typically resistant to open-shell reaction
pathways.
ꢀ
Herein, we demonstrate that the TmI2 ROH reagent
(R = H, Me), formed from the first nonclassical lantha-
nide(II) iodide in the series, promotes a highly unusual
[*] Dr. M. Szostak, M. Spain, Prof. Dr. D. J. Procter
School of Chemistry, University of Manchester
Oxford Road, Manchester M13 9PL (UK)
E-mail: michal.szostak@manchester.ac.uk
david.j.procter@manchester.ac.uk
Homepage: http://people.man.ac.uk/~mbdssdp2/
[**] We acknowledge the EPSRC and GSK for financial support.
ꢀ
cleavage of the s C N bond in planar amides. Moreover, we
ꢀ
report that TmI2 ROH is the first lanthanide(II) reagent to
selectively generate ketyl radicals from aliphatic esters.
Finally, we demonstrate that the presence of alcohols is
critical for the formation of thermodynamically more power-
ful reductants from TmI2 (TmI2(ROH)n, E8 = ꢀ2.6 V vs.
SCE).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303178.
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We recently developed approaches for the chemoselective
reduction of cyclic esters[14a] and 1,3-diesters[14b] by using
ꢀ
a SmI2 H2O reagent. These reactions were the first examples
of the activation of carbonyls that are traditionally unreactive
towards SmI2. On the basis of these results, we initiated efforts
to chemoselectively activate other types of carbonyl by using
lanthanide(II) reagents. We hypothesized that the use of the
more-reducing nonclassical lanthanide(II) iodides would
result in a chemoselective generation of acyl-type radicals
from carboxylic acid derivatives that lie beyond the scope of
SmI2. In particular, we considered that highly reducing
nonclassical lanthanide(II) iodides that are additionally
activated by proton donors, could potentially permit produc-
tive electron transfer to amide carbonyls, a functional group
that has been traditionally resistant to single-electron-transfer
reductants, as a result of nN!p* O conjugation.[1] With these
=
C
considerations in mind, we subjected N,N-dialkyl amide 1a to
several TmI2-mediated reaction conditions (Table 1). To our
ꢀ
Table 1: Optimization of the C N bond cleavage in unactivated amides
in the presence of LnI2(ROH)n.
ꢀ
Scheme 1. Cleavage of unactivated s C N bonds in amides in the
presence of TmI2(ROH)n at 238C.
ꢀ
tion of the scope of this transformation (Scheme 1). The C N
bond scission occurred for both unhindered and sterically
encumbered pyrrolidinyl amides (1a–1c). Moreover, the
reaction of the azetidinyl amide 1d demonstrated that the
reaction is applicable to other cyclic amides. In addition, two
acyclic amides (1e–1 f) were similarly cleaved, thus demon-
strating that the cyclic structure of amides is not necessary for
the scission. Importantly, secondary n-alkyl and n-aryl amides
did not undergo the cleavage reaction (see the Supporting
Information), thus indicating complete selectivity of the
reducing system for these tertiary amides. To gain a prelimi-
nary mechanistic insight, we subjected a sterically biased
aziridinyl amide 1g to the reaction conditions. The reaction
afforded an approximately 1.6:1.0 ratio of regioisomeric
amides, with the predominant product resulting from cleav-
age at the less substituted carbon center. On the basis of this
Entry LnI2 LnI2 (equiv) ROH
ROH (equiv)[a] t[b]
2 h
Yield [%][c]
1
2
3
TmI2
TmI2
TmI2
TmI2
TmI2
SmI2
SmI2
SmI2
3
3
3
3
3
3
3
3
–
–
<2
MeOH 10
MeOH 100
MeOH 100
H2O
–
3 min <2
3 min 48 (77)[d]
3 min <2
4[e]
5
150
–
3 min <2
6[f]
7[f]
8[f]
3 h
3 h
1 h
<2
<2
<2
MeOH 100
H2O 100
[a] With respect to LnI2. [b] Time elapsed until characteristic color change
from TmII to TmIII. [c] Determined by 1H NMR spectroscopy and/or GC–
MS. [d] In parentheses, yield based on the recovered starting material.
TmI2 (6 equiv) afforded 2a in 45% yield. [e] The corresponding amine
was used instead of the amide. [f] Azetidinyl amide 1d used instead of
the pyrrolidinyl amide. Reaction conditions: LnI2 (3 equiv), ROH (H2O,
150 equiv; MeOH, 100 equiv), THF, 238C. See the Supporting Informa-
tion for details.
experiment and the known propensity of nonclassical LnI2 to
[15]
ꢀ
cleave C O bonds in ethers, we propose that the mecha-
nism of the TmI2-mediated cleavage involves a direct inser-
tion of Tm into the C N amide bond; however, a mechanism
II
ꢀ
delight, with MeOH as the proton source, we observed
efficient formation of N-monoalkyl amide 2a, in which
a highly unusual cleavage of the s C N bond took place
involving fragmentation of an initially-formed ketyl-type
radical seems also to be operating in some cases as suggested
by the correlation of the reaction efficiency with thermo-
chemical stabilization energies (SE) of the fragmenting
radical in the series: tBu (71%, SE = 4.35 kcalmolꢀ1) > iPr
(29%, SE = 2.57 kcalmolꢀ1) > Me (< 2%, SE = ꢀ1.65 kcal
molꢀ1).[16]
ꢀ
(Table 1, entry 3; see the Supporting Information for reagent
stability studies). Control reactions demonstrated that the
reaction did not proceed in the absence of a proton source
(Table 1, entry 1), at low concentration of MeOH (Table 1,
entry 2), with H2O as an alternative additive (Table 1,
entry 5), and with a variety of SmI2 systems (Table 1,
entries 6–8; see also the Supporting Information). Further-
more, the corresponding aliphatic pyrrolidinyl amine was
inert to the reaction conditions (Table 1, entry 4), thus
demonstrating high levels of chemoselectivity imparted by
the TmI2 reagent.[15]
ꢀ
The mechanistic implications of the C N cleavage merit
further discussion. The present reaction with TmI2 represents
ꢀ
the first case of a general scission of unactivated s C N bonds
in planar amides, and compares favorably with the previous
ꢀ
examples of the cleavage of a s C N bond in distorted
lactams[3] (reagent vs. substrate control). Moreover, it strongly
suggests that the reactivity of nonclassical lanthanides(II)
extends beyond being the reagents that simply close the
energy gap between SmI2 and the Birch-type reductants.[11,13a]
With the optimized conditions in hand, a series of amides
was subjected to the reaction to provide an initial examina-
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ꢀ
Having established that TmI2 ROH is capable of an
(note that in both cases no reaction was observed with TmI2
efficient electron transfer to the amide carbonyl group but not
their reduction, the reagent system was applied to the
generation of ketyl radicals from esters (Table 2). In previous
alone, see the Supporting Information), we examined the
reactivity of TmI2 with a set of aromatic hydrocarbons with
gradually increasing redox potentials in the presence of
MeOH (Table 3).[17] In this study, the TmI2 MeOH complex
ꢀ
was found to reduce aromatic hydrocarbons with redox
Table 2: Reduction of aliphatic esters in the presence of TmI2(ROH)n at
238C.[a]
Table 3: Determination of the redox potential of TmI2(ROH)n by
reduction of aromatic hydrocarbons.
Entry
Ester/Acid
ROH
t [min][a]
Yield [%][b]
Entry
Hydrocarbon
ꢀE1/2 [V][a]
Reaction with TmI2
observed[c]
1
H2O
2–3
88
1
2
3
4
5
6
7
8
cyclooctatetraene[b]
anthracene
stilbene
1,4-diphenylbenzene
1,3,5-triphenylbenzene
naphthalene
1.83
1.98
2.21
2.40
2.51
2.61
2.65
3.42
+
+
+
+
+
+
+
ꢀ
2
3
MeOH
MeOH
2–3
2–3
99
96
4
MeOH
2–3
85
styrene
benzene
5
6
MeOH
MeOH
2–3
2–3
94
63
[a] In volts vs. SCE; E1/2 describes half-reduction potential; see Ref. [17].
[b] Ref. [13d]. [c] Determined by GC and/or 1H NMR spectroscopy.
potentials up to ꢀ2.6 V (vs. SCE); however, benzene was
inert under the reaction conditions. These results suggest that
the addition of MeOH to TmI2 results in an increase of the
reduction potential of TmI2 by approximately 0.6 V.[13d]
Furthermore, deuterium incorporation and kinetic iso-
tope effect studies in the reduction of stilbene, a reaction that
is known to proceed through an outer-sphere electron-
7
8
MeOH
MeOH
2–3
2–3
58
<5[c]
[a] Time elapsed until characteristic color change from TmII to TmIII.
[b] Determined by 1H NMR spectropscopy. [c] Decanoic acid recovered
in >95%. Reaction conditions: TmI2 (6–8 equiv), ROH (H2O, 150 equiv;
MeOH, 100 equiv), THF, 238C. See the Supporting Information for
details.
transfer mechanism,[18] using TmI2 ROH ([D4]methanol,
ꢀ
96.5% D2 incorporation, kH/kD = 1.13 ꢁ 0.1; D2O, 98.0% D2
incorporation, kH/kD = 1.27 ꢁ 0.1), suggest that the increase in
reduction potential of the reagent results from complexation
between the proton donor and TmI2.
work, we reported the reduction of lactones in the presence of
SmI2 H2O;
reaction times, was limited to unhindered substrates, and
could be applied only to six-membered lactones; other ring
systems and acyclic esters were unreactive under the reaction
[14a]
ꢀ
however, this reaction suffered from long
A detailed examination of different proton donors in the
model system (see the Supporting Information) revealed that
a much lower concentration of alcohols (10 equiv) is required
to enhance the redox potential of TmI2 in comparison with
SmI2 (100 equiv).[19] This result is consistent with the smaller
radial size of TmII and bodes well for the development of
catalytic cycles based on regeneration of the TmI2 reagent.[20]
Finally, to test whether in analogy to amides a bond
cleavage mechanism also contributes to the reduction of
esters with TmI2, we subjected decyl and 1-phenylethyl
ꢀ
conditions. In sharp contrast, TmI2 ROH reacted with a wide
range of substrates, including lactones (Table 2, entry 1),
aliphatic (Table 2, entries 2 and 3), aromatic (Table 2,
entries 3 and 4), alpha-substituted (Table 2, entries 4–6), and
sterically demanding (Table 2, entry 7) esters. In all cases
rapid (within 2–3 min) reduction to the corresponding
alcohols took place, clearly demonstrating the higher reac-
ꢀ
ꢀ
tivity of TmI2 ROH. Control reactions established that, in
acetate to the reaction conditions (Scheme 2). C O bond
the absence of proton donors, TmI2 does not reduce aliphatic
esters. Acids are not reduced under the reaction conditions
(Table 2, entry 8), thus opening the door for highly chemo-
selective reductions of carboxylic acid derivatives through
single-electron reaction pathways that are not possible with
the traditional alkali or transition metal hydrides.[9] Overall,
this study outlines the reactivity scale for the generation of
ꢀ
ketyl-type radicals with TmI2 ROH (see the Supporting
Information for comparison tables between TmI2 and SmI2),
demonstrates that useful levels of chemoselectivity are
ꢀ
possible with TmI2 ROH, and opens the door for the use of
TmI2-generated ketyls in radical bond-forming reactions.
To gain a preliminary mechanistic insight into the key
effect of protic additives on the properties of the TmI2 reagent
Scheme 2. Investigating the mechanism of ester reduction with TmI2-
(ROH)n.
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In summary, the highly unusual cleavage of unactivated
ꢀ
s C N bonds in amides in the presence of TmI2, the first
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NdI2), has been achieved. This method was also applied to the
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transfer processes based on nonclassical lanthanide(II)
iodides.
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Received: April 16, 2013
Published online: June 12, 2013
ꢀ
Keywords: amides · C N cleavage · electron transfer ·
lanthanides · thulium diiodide
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