Copper catalyzed Heck-like cyclizations of oxime esters

Article abstract of DOI:10.1039/c4sc00652f

Copper catalyzed Heck-like cyclizations of oxime esters are described. Mechanistic studies indicate a reaction pathway that proceeds via the generation and cyclization of an intermediate that possesses iminyl radical character. To the best of our knowledge, this work encompasses the first examples of Cu-catalyzed aza-Heck reactions that proceed via oxidative initiation at nitrogen to generate products containing a new alkene. This new protocol is also an effective alternative to Pd-based systems and highlights the value of replacing precious metal catalysts with cheaper and more sustainable variants. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4sc00652f

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Copper catalyzed Heck-like cyclizations of oxime
esters†
Cite this: Chem. Sci., 2014, 5, 2416
a
a
b
a
*
Adele Faulkner,‡ Nicholas J. Race,‡ James S. Scott and John F. Bower
Copper catalyzed Heck-like cyclizations of oxime esters are described. Mechanistic studies indicate a
reaction pathway that proceeds via the generation and cyclization of an intermediate that possesses
iminyl radical character. To the best of our knowledge, this work encompasses the first examples of
Cu-catalyzed aza-Heck reactions that proceed via oxidative initiation at nitrogen to generate products
containing a new alkene. This new protocol is also an effective alternative to Pd-based systems and
highlights the value of replacing precious metal catalysts with cheaper and more sustainable variants.
Received 2nd March 2014
Accepted 24th March 2014
DOI: 10.1039/c4sc00652f
www.rsc.org/chemicalscience
our earlier work (e.g. b-hydride elimination selectivity to 3 vs. 4,
Scheme 1A).6a To the best of our knowledge, the present
Introduction
study also encompasses the rst examples of copper-catalyzed
aza-Heck reactions that furnish products containing a new
alkene by oxidative initiation at nitrogen (i.e. in terms of
The advent of catalysis based upon the oxidative generation and
capture of aryl-Pd(II) intermediates has had a profound impact
upon the eld of organic synthesis. Accordingly, it is estimated
that 20% of C–C bond forming reactions employed in the
pharmaceutical sector are reliant upon this technology.1 Given
the privileged position of nitrogen in drug discovery, it is
surprising that related processes involving the oxidative gener-
ation and capture of aza-Pd(II) species have been slow to
emerge.2 Seminal studies by Narasaka demonstrated that Pd(0)-
catalysts undergo oxidative addition into the N–O bond of
O-pentauorobenzoyl oximes 1 to generate imino-Pd(II) inter-
mediates 2 (Scheme 1A).3,4 The reactivity of these species
mirrors that of their aryl counterparts and migratory insertion
of pendant alkenes provides an aza-variant of the Heck reac-
tion.5 This reactivity manifold is heavily underdeveloped and
our studies have focused upon providing efficient catalysis
systems that generate synthetically versatile chiral N-heterocy-
clic scaffolds (e.g. 3 rather than 4).6,7
There is a growing interest in replacing Pd(0)-catalysts with
more abundant and isoelectronic Cu(I)-variants.2,8 Cu(I)-cata-
lyzed aza-Stille and aza-Suzuki cross-couplings involving oxime
esters have been reported by Liebeskind et al. but the corre-
sponding aza-Heck processes have not been developed.9,10 In
this report we detail the discovery and mechanism of a Cu-
catalyzed protocol for the aza-Heck cyclization of oxime esters.
This provides a direct and economic alternative to Pd-based
systems, and also addresses selectivity issues that hampered
aSchool of Chemistry, University of Bristol, Bristol, BS8 1TS, UK. E-mail: john.bower@
bris.ac.uk
bAstraZeneca, Alderley Park, Maccleseld, Cheshire, SK10 4TG, UK
† Electronic supplementary information (ESI) available: Experimental procedures
and characterisation data for all compounds are provided. See DOI:
10.1039/c4sc00652f
Scheme 1 Aza-Heck cyclizations of oxime esters and the develop-
ment of a Cu-catalyzed protocol. a Isolated yield (product ratios were
1
‡ These authors contributed equally.
determined by H NMR).
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Table 1 Cyclizations involving 1,2-disubstituted alkenes
substrate/product structure, the process is an exact aza-variant
of the conventional Heck reaction where the oxime ester takes
the place of the aryl halide).10,11
Results and discussion
At the outset of our studies, the prospect of replacing Pd-based
systems with Cu(I)-variants was considered tentative. The
generation of aza-copper intermediates by oxidative addition
into N–O bonds has been invoked in a range of amination
processes.9,10,11d,g–j However, reactions involving alkenes provide
1,2-difunctionalization processes and do not afford new alkene
containing products.11d,e,i Consequently, the viability of a
copper-catalyzed aza-Heck cycle that incorporates the key steps
of oxidative initiation and b-hydride elimination was unclear.
Our preliminary investigations involved exposing DMF solu-
tions of O-pentauorobenzoyl oxime 5 to a variety of commer-
cial Cu-salts (Scheme 1B). Gratifyingly, both CuOAc and
Cu(OAc)2 provided the desired product 8a with complete selec-
tivity over the alternative pyrrole product (entries 1 and 2; cf.
Scheme 1A). However, 8a was accompanied by signicant
quantities of adduct 9, which contains a saturated side chain.
Cu(acac)2 and Cu(OTf)2 both suppressed the formation of this
byproduct but provided only modest yields of the target 8a
(entries 3 and 4). However, good selectivity and yield was
obtained using the more soluble Cu(2-ethylhexanoate)2, which
provided adduct 8a in 79% yield and as the only observable
product when PhCN was used as solvent (entry 6). Pleasingly,
this protocol also tolerates less activated oxime esters and acetyl
and pivaloyl variants 6 and 7a cyclized efficiently to provide 8a
in 65% and 78% yield respectively (entries 7 and 8). This facet is
particularly striking and is in stark contrast to our work with Pd-
systems, where O-pentauorobenzoyl oximes are a requirement
for efficient cyclization.6
a
b
7j was dimethylated at C-2. Yield using optimized Pd-systems and
the corresponding O-pentauorobenzoyl oxime ester. The ratio of
product vs. alternative pyrrole is given in parentheses (see ref. 6a).
c
The reaction was run at 120 ꢀC.
The ability to use acetyl or pivaloyl oxime esters is benecial
from the viewpoint of cost, starting material stability and atom the option to modify further the initial scaffold using conven-
economy. Consequently, we elected to explore scope using a tional Pd(0)-catalyzed cross-coupling reactions. Certain limita-
range of pivaloyl oxime ester substrates 7a–l that possess tions are evident however, and alkynyl and aldoxime based
pendant 1,2-disubstituted alkenes (Table 1). In the majority of systems 7k and 7l did not cyclize efficiently. In the former case
cases cyclization proceeded smoothly to generate the target the issue was the sensitivity of the product 8k to conjugate
dihydropyrroles 8a–j in good to excellent yield and with complete addition by in situ generated pivalic acid. In the latter case (8l),
selectivity over the alternative pyrrole products (cf. Scheme 1A). decomposition of the oxime ester to the corresponding nitrile
A range of alkyl and aryl oxime esters can participate in this predominated.12
process and cyclization efficiency is not adversely affected by
We have also explored cyclizations of more heavily
sterically demanding oximes (e.g. 7d). The successful cyclization substituted 1,1-disubstituted alkenes 7m–r to provide
of 7c, which possesses a potentially problematic Lewis basic adducts 8m–r that possess challenging quaternary amino-
pyridyl moiety, is particularly noteworthy. For ease of compar- substituted stereocenters (Table 2). For 7m–q cyclization was
ison, and where determined, the results of the cyclization of the efficient independent of the nature of the alkene. For
analogous O-pentauorobenzoyl oxime esters with our best Pd- example, cyclization of 7m, which involves an electron de-
based systems are included.6a Note that in many cases (e.g. 8g cient acrylate, provided 8m in 76% yield. Notably, under our
and 8i) these Pd-catalyzed processes suffered from competing best palladium catalyzed conditions, the analogous O-penta-
formation of signicant quantities of pyrrole products (the uorobenzoyl oxime ester cyclized in only 31% yield.6b Some
ratios of dihydropyrrole to pyrrole products are given in limitations do exist with respect to the alkene and cyclization
parentheses). Another limitation of Pd-based systems is that of 7r, which generates a benzylic C–N bond, was not efficient.
aryl bromides are not well tolerated.6c For the copper catalyzed Here, competing formation of the corresponding ketone (the
protocol this is not an issue and cyclization of 7h provided 8h in formal hydrolysis product of the oxime ester) was
good yield and with Ar–Br bond still intact. This then opens up problematic.13
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Table 2 Cyclizations involving 1,1-disubstituted alkenes
a
b
The reaction was run at 120 ꢀC. Yield using optimized Pd-systems
and the corresponding O-pentauorobenzoyl oxime ester (see ref. 6b).
c
Isolated as a 5 : 1 mixture of alkene regioisomers.
Table 3 Cyclizations involving cyclic alkenes
a
7t was a 1 : 1 mixture of diastereomers at C-2. b Yield using optimized
Pd-systems and the corresponding O-pentauorobenzoyl oxime ester
(see ref. 6c).
Cyclizations onto pendant cyclohexenes provide a direct
entry to cis-congured heterobicycles 8s–u (Table 3). Here,
reaction efficiency is comparable to our best Pd-based systems.6c
In the case of 7t, cyclization of a 1 : 1 mixture of diastereomers
at C-2 provided 8t as a 10 : 1 mixture of diastereomers at C-2. By
analogy with our earlier work,6c we favor epimerization of the
C-2 stereocenter under the acidic reaction conditions aer
cyclization to provide the thermodynamically favored diaste-
reomer 8t.
Scheme 2 Mechanistic analysis and supporting studies.
triggers cyclization to alkyl radical 12. Pathways proceeding via
Our studies indicate that the copper-catalyzed processes either the generation of iminyl radical 10 or imino-Cu(III)
described here are distinct from Pd-catalyzed variants and most intermediate 11 can be envisaged; in the latter case cyclization
likely do not involve migratory insertion of the alkene compo- occurs by homolytic cleavage of the N–Cu bond.14,15 It is well
nent into an N–Cu bond. A working mechanistic hypothesis is established that alkyl radicals can undergo oxidative elimina-
outlined in Scheme 2A. In situ generation of Cu(I)-carboxylate tion upon exposure to cupric acetate.16 Accordingly, trapping of
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alkyl radical 12 with Cu(II)-carboxylate17 provides alkyl-Cu(III)
intermediate 13. Alkyl-Cu(III) species have signicant carboca-
tionic character and can undergo syn-elimination (as depicted)
to generate alkene 8i.16 This process is known to favor formation
of the less hindered alkene, which accounts for the observed
regioselectivities. The minor quantities of saturated product
(e.g. 9) obtained during optimization are presumably the result
of hydrogen atom abstraction by 12 from elsewhere in the
reaction system.18 Alkyl-Cu(III) carboxylates (i.e. 13) are mecha-
nistically promiscuous and undergo b-hydride elimination or
reductive elimination of carboxylate (to generate an alkyl-O(CO)
R bond) or solvolysis to a carbocation (which might lead to
Ritter-type products).16 It is noteworthy that the current protocol
gives high selectivity for alkene 8i over byproducts derived
either from these latter two pathways or from alkyl radical 12.
A series of experiments underpin the mechanism proposed
in Scheme 2A. Heating a PhCN solution of Cu(II)(2-ethyl-
hexanoate)2 in the presence of cuproin 15 resulted in the slow
evolution of a deep purple solution (Scheme 2B).19 This is
indicative of the formation of a Cu(I)–cuproin complex and is
supportive of either reduction or disproportionation of Cu(II)(2-
ethylhexanoate)2 under the reaction conditions.20 By way of
comparison, exposure of Cu(I)OAc to analogous conditions
resulted in the immediate formation of a similar purple solution
(see the ESI†). The generation of an intermediate with signi-
cant iminyl radical character is evidenced using estrone derived
oxime ester 16 (Scheme 2C). Upon exposure to Cu(II)(2-ethyl-
hexanoate)2 and subsequent hydrolysis (MeOH, aq. HCl) the
formation of adducts 20a–c was observed. The inversion of the
methyl substituted stereocenter in 20c is accounted for by
reversible b-scission from iminyl radical 17 (or an imino-Cu(III)
species with radical-like character; not depicted), which leads to
the thermodynamically favored diastereomer 19.21,22 Multiple
mechanistic pathways, including those based upon iminyl
radicals, can account for the formation of 20a/b.23
To gain insights into the sequence of events aer cyclization
we have prepared cyclopropyl substrates 21a–c (Scheme 2D).
The substituted cyclopropane moiety is based upon Newcomb's
design, which enables differentiation of radical vs. carbocation-
like intermediates;24 the latter would be indicative of pathways
involving either alkene imino-cupration16 or Lewis acid activa-
tion of the oxime ester.10 Because the mechanism proposed in
Scheme 2A involves both radical and carbocation-like interme-
diates, careful analysis of the products arising from cyclization
of all three substrates 21a–c was required. Cyclization of 21a
resulted in the formation of the unstable cis-congured vinyl
pyrrole 22a as the only observable product. This indicates that
alkyl radical 25 forms and then rearranges, via cleavage of bond
b, to the more stable benzylic radical 26. 1,5-Hydrogen atom
abstraction (cis-alkene isomer of 26 only)25 then leads, aer in
situ oxidation by Cu(II)(carboxylate)2, to pyrrole 22a. Alterna-
tively, benzylic oxidation of 26 followed by 1,5-hydride transfer
(not depicted) could also generate 22a. Cyclization of deuterio-
Scheme 3 Attempted 6-ring cyclization and mechanistic pathways to
allylic C–H functionalization products.
product 23c was observed. Presumably, at the stage of 26,
Cu(II)(carboxylate)2 promotes oxidation to benzylic carbocation
27 16 which undergoes ring-closure to cyclopropyl stabilized
carbocation 29.26 Methoxy-triggered cleavage of bond a gener-
ates an oxocarbenium ion which is trapped by carboxylate
ꢁ
(R1CO2 ¼ pivalate or 2-ethylhexanoate) to afford adduct 23b,c
(R ¼ D or Me).27 Overall, these results support initial cyclization
to an alkyl radical and subsequent Cu(II)-promoted oxidation to
an alkene. A pathway based upon migratory insertion of the
alkene into the N–Cu bond of an imino-Cu(III) intermediate is
discounted as this should lead solely to dihydropyrroles 23a–c.
An ionic mechanism, involving Lewis acid activation of the
oxime ester by Cu(II)(carboxylate)2, is not consistent with the
results presented here.
As further support for the mechanism outlined in Scheme
2A, it is pertinent to consider the results of an attempted 6-ring
cyclization (Scheme 3). Exposure of oxime ester 30 (the homo-
logue of 7s) to optimized conditions did not result in the
formation of Heck-type product 31. Instead, adducts 8n and 34
were generated in 46% and 31% yield respectively. The forma-
tion of these products can be accounted for by copper-catalyzed
generation of iminyl radical 32 (or an imino-Cu(III) species with
radical like character). 1,5-Hydrogen atom abstraction then
generates an allylic radical which undergoes copper-catalyzed
oxidation to the corresponding cation 33. This is trapped by
either the imine moiety or pivalate to provide 8n or 34. These
processes represent interesting approaches to allylic C–H ami-
nation or oxidation. The generation of 8n can be viewed as a
¨
copper-catalyzed variant of the Hofmann–Loffler–Freytag reac-
tion and further investigations into the scope of this process are
ongoing.28–30
Conclusions
variant 21b revealed full deuterium transfer from C-4 of the In summary, we demonstrate that simple copper salts can
starting material to C-9 of product 22b. In this case, the replace phosphine ligated palladium catalysts for aza-Heck
formation of adduct 23b, which results from cleavage of bond a, cyclizations of oxime esters. The Cu-catalyzed protocol proceeds
was also observed. For methyl-substituted analogue 21c, only via a mechanistically distinct pathway involving radical-based
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C–N bond formation and does not involve migratory insertion
of the alkene into the N–Cu bond of an imino-Cu(III) interme-
diate. The net result is an easy catalytic entry to a range of
synthetically exible pyrrolidine derivatives that seem well
suited to applications in medicinal chemistry. Key synthetic
benets of the current work include (a) the replacement of
expensive Pd-based systems with more economical Cu-variants,
(b) the use of cheap pivaloyl oxime esters instead of O-penta-
uorobenzoyl variants, (c) complete selectivity for chiral prod-
ucts over the corresponding pyrroles for processes involving
1,2-disubstituted alkenes and (d) a catalyst system that tolerates
aryl bromides. In a broader context, these studies also provide
unique examples of Cu-catalyzed aza-Heck reactions that
proceed via oxidative initiation at nitrogen to generate new
alkene containing products. Replacing precious metal catalysts
with cheaper and more sustainable variants is an important
goal and this study highlights a case where this can be achieved
in a particularly effective manner.
2013, 49, 1521; (c) A. Faulkner and J. F. Bower, Angew.
Chem., Int. Ed., 2012, 51, 1675.
7 There is a pressing demand for the development of efficient
methodologies that target low molecular weight (200–
350
Da),
3D
(sp3-rich)
scaffolds:
A.
Nadin,
C. Hattotuwagama and I. Churcher, Angew. Chem., Int. Ed.,
2012, 51, 1114.
8 Selected examples of copper catalyzed Heck-like couplings:
(a) R. J. Phipps, L. McMurray, S. Ritter, H. A. Duong and
M. J. Gaunt, J. Am. Chem. Soc., 2012, 134, 10773; (b)
V. Declerck, J. Martinez and F. Lamaty, Synlett, 2006, 3029;
(c) Y. Peng, J. Chen, J. Ding, M. Liu, W. Gao and H. Wu,
`
Synthesis, 2011, 213; (d) V. Calo, A. Nacci, A. Monopoli,
E. Ieva and N. Cioffi, Org. Lett., 2005, 7, 617; (e) J.-H. Li,
D.-P. Wang and Y.-X. Xie, Tetrahedron Lett., 2005, 46, 4941.
9 (a) S. Liu, Y. Yu and L. S. Liebeskind, Org. Lett., 2007, 9, 1947;
(b) S. Liu and L. S. Liebeskind, J. Am. Chem. Soc., 2008, 130,
6918. These processes are proposed to involve oxidative
addition of Cu(I) into the N–O bond. For mechanistically
similar processes that involve O-acyl hydroxylamine
derivatives, see: (c) Z. Zhang, Y. Yu and L. S. Liebeskind,
Org. Lett., 2008, 10, 3005. For examples of mechanistically
similar processes that involve N–Cl bonds, see: (d) C. He,
C. Chen, J. Cheng, C. Liu, W. Liu, Q. Li and A. Lei, Angew.
Chem., Int. Ed., 2008, 47, 6414 and references cited therein.
Copper can catalyze SN2 substitutions of N–O bonds. For
example, see: (e) M. J. Campbell and J. S. Johnson, Org.
Lett., 2007, 9, 1521.
Acknowledgements
A.F. thanks AstraZeneca and the University of Bristol for a Ph.D.
studentship. N.J.R. thanks the Bristol Chemical Synthesis
Doctoral Training Centre, funded by the EPSRC (EP/G036764/1),
for the provision of a Ph.D. studentship and the SCI for a
postgraduate scholarship. EPSRC (EP/J007455/1) are thanked
for support. J.F.B. is indebted to the Royal Society for a
University Research Fellowship.
10 Zard has reported recently two examples of cyclizations of
oxime esters that are stoichiometric in Cu(OAc)2 and
provide aza-Heck-type products by an ionic mechanism that
involves Lewis acid activation of the oxime ester:
M. Bingham, C. Moutrille and S. Z. Zard, Heterocycles, 2014,
88, 953.
Notes and references
1 (a) J. S. Carey, D. Laffan, C. Thomson and M. T. Williams,
Org. Biomol. Chem., 2006, 4, 2337; (b) S. D. Roughley and
A. M. Jordan, J. Med. Chem., 2011, 54, 3451.
2 Review: I. P. Beletskaya and A. V. Cheprakov, 11 Intramolecular copper-catalyzed alkene difunctionalization
Organometallics, 2012, 31, 7753. We refer specically to
processes that rely upon an internal oxidant (cf. oxidative
addition of Pd(0)-catalysts into aryl-halide bonds).
3 (a) H. Tsutsui and K. Narasaka, Chem. Lett., 1999, 45; (b)
H. Tsutsui, M. Kitamura and K. Narasaka, Bull. Chem. Soc.
Jpn., 2002, 75, 1451, For reviews, see: (c) M. Kitamura and
K. Narasaka, Chem. Rec., 2002, 2, 268; (d) K. Narasaka and
M. Kitamura, Eur. J. Org. Chem., 2005, 4505.
Pentauorobenzoyl oxime esters are usually employed for
these processes because they are stable to Beckmann
rearrangement.
4 Imino-Pd(II) intermediates have been characterized and
exploited in catalytic C–H amination: (a) Y. Tan and
J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 3676; see also:
(b) W. P. Hong, A. V. Iosub and S. S. Stahl, J. Am. Chem.
Soc., 2013, 135, 13664.
reactions that use external oxidants: (a) T. W. Liwosz and
S. R. Chemler, J. Am. Chem. Soc., 2012, 134, 2020; (b)
P. H. Fuller, J. W. Kim and S. R. Chemler, J. Am. Chem.
Soc., 2008, 130, 17638; (c) M. C. Paderas, J. B. Keister and
S. R. Chemler, J. Org. Chem., 2013, 78, 506, Intramolecular
copper-catalyzed alkene difunctionalization reactions that
use internal oxidants: (d) alkene amino-hydroxylation:
¨
M. Noack and R. Gottlich, Chem. Commun., 2002, 536; (e)
alkene amino-chlorination: G. Heuger, S. Kalsow and
¨
R. Gottlich, Eur. J. Org. Chem., 2002, 1848. Intermolecular
oxidative aza-Heck reactions that employ an external
oxidant and do not rely on oxidative initiation at nitrogen:
(f) T. W. Liwosz and S. R. Chemler, Chem.–Eur. J., 2013, 19,
12771. The activation of oxime ester N–O bonds with
catalytic Cu(I) to form new C–N bonds has been employed
in various contexts. For leading references, see: (g) aza-
copper enolate generation: Y. Wei and N. Yoshikai, J. Am.
Chem. Soc., 2013, 135, 3756; (h) aryl-C–H amination:
K. Tanaka, M. Kitamura and K. Narasaka, Bull. Chem. Soc.
Jpn., 2005, 78, 1659; (i) alkene imino-bromination:
Y. Koganemaru, M. Kitamura and K. Narasaka, Chem. Lett.,
2002, 784; For the activation of oxime ester N–O bonds
5 Previous studies are consistent the direct insertion of the
alkene component into the N–Pd(II) bond in a manner that
is analogous to the conventional Heck reaction (see ref. 6b
and c).
6 (a) N. J. Race and J. F. Bower, Org. Lett., 2013, 15, 4616; (b)
A. Faulkner, J. S. Scott and J. F. Bower, Chem. Commun.,
2420 | Chem. Sci., 2014, 5, 2416–2421
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with catalytic Cu(I) to form new N–N bonds, see: (j)
M.-N. Zhao, H. Liang, Z.-H. Ren and Z.-H. Guan, Synthesis,
2012, 44, 1501.
12 The mechanism for nitrile formation is not clear. Possible
Chemical Science
benzonitrile, see: R. C. Larson and R. T. Iwamoto, J. Am.
Chem. Soc., 1960, 82, 3239.
21 J. Boivin, A. M. Schiano and S. Z. Zard, Tetrahedron Lett.,
1992, 33, 7849.
pathways include (but are not limited to) Lewis acid 22 It is unclear whether the processes described here proceed
promoted Beckmann type-II rearrangement of the oxime
ester or b-hydride elimination from an imino-Cu(III)
intermediate (vide infra). See also ref. 9a.
via an imino-Cu(III) species or the direct formation of an
iminyl radical or, indeed, a radical anion of the oxime
ester. To date, all attempts to isolate an imino-Cu(III)
intermediate have been unsuccessful.
13 Addition of molecular sieves to the reaction mixture did not
suppress the formation of this byproduct. Consequently, we 23 20a,b are formally hydrolysis and Beckmann rearrangement
favor a pathway involving decomposition of the oxime ester
to the corresponding NH-imine and hydrolysis to the ketone
during work-up or chromatography. The NH-imine may
products of 16: C. Wang, X. Jiang, H. Shi, J. Lu, Y. Hu and
H. Hu, J. Org. Chem., 2003, 68, 4579. Both products may
arise also via an iminyl radical or imino-Cu(III) intermediate.
form via either an imino-Cu(III) intermediate or an iminyl 24 (a) M. Newcomb and D. L. Chestney, J. Am. Chem. Soc., 1994,
radical (vide infra).
116, 9753; (b) M. H. Le Tadic-Biadatti and M. Newcomb,
J. Chem. Soc., Perkin Trans. 2, 1996, 1467. For an
application of this type of probe to a copper catalyzed
Heck reaction, see ref. 8a.
14 For a review on the one electron reduction of oxime
derivatives, see: K. Narasaka and M. Kitamura, ARKIVOC,
2006, vii, 245.
15 Iminyl radical and imino-Cu(III) intermediates may exist in 25 The fate of trans-26 (R ¼ H) is unknown. For examples of
equilibrium as depicted in Scheme 2A. Imino-Cu(III)
intermediates have been proposed previously (for example,
see ref. 9a and b). An alternative possibility is that a
copper mediated additions of imines to alkenes that
generate alkyl radicals, see: S. Sanjaya, S. H. Chua and
S. Chiba, Synlett, 2012, 23, 1657.
radical anion of the oxime ester is generated which then 26 For the relative stabilities of benzyl and cyclopropyl
cyclizes, with concomitant loss of pivalate, to generate an
alkyl radical (see ref. 11i).
16 (a) J. K. Kochi, J. Am. Chem. Soc., 1962, 84, 3271; (b)
stabilized carbocations, see: J. P. Pezacki, D. Shukla,
J. Lusztyk and J. Warkentin, J. Am. Chem. Soc., 1999, 121,
6589.
J. K. Kochi, A. Bemis and C. L. Jenkins, J. Am. Chem. Soc., 27 A mixture of diastereomeric products arising from trapping
1968, 90, 4616; (c) J. K. Kochi and C. L. Jenkins, J. Am.
Chem. Soc., 1972, 94, 843; (d) J. K. Kochi and C. L. Jenkins,
J. Am. Chem. Soc., 1972, 94, 856.
of the oxocarbenium ion with pivalate or 2-ethylhexanoate
was observed (see the ESI†).
28 (a) A. W. Hofmann, Ber. Dtsch. Chem. Ges., 1883, 16, 558; (b)
A. W. Hofmann, Ber. Dtsch. Chem. Ges., 1885, 18, 5; (c)
A. W. Hofmann, Ber. Dtsch. Chem. Ges., 1885, 18, 109; (d)
M. E. Wolff, Chem. Rev., 1963, 63, 55.
17 “Carboxylate” refers to either pivalate or 2-ethylhexanoate.
18 Even though we propose a Cu(I)-initiated process, Cu(II)-salts
are preferred. Higher concentrations of Cu(II) may increase
the efficiency of oxidative elimination from secondary alkyl 29 For a mechanistically similar process that employs an
radical 12.
amidoxime ester, see: H. Chen and S. Chiba, Org. Biomol.
Chem., 2014, 12, 42.
19 J. Hoste, Anal. Chim. Acta, 1950, 4, 23. For an application of
this method as a mechanistic probe in Cu-catalysis, see: 30 Exposure of the analogous O-pentauorobenzoyl oxime ester to
T. P. Lockhart, J. Am. Chem. Soc., 1983, 105, 1940.
our optimized Pd-based systems (see ref. 6) did not result in the
formation of 8n or products related to 34 and only formal
hydrolysis to the corresponding ketone was observed. See ref.
6a for a discussion on mechanistic pathways to the ketone.
20 Based upon the considerations outlined in ref. 18, we favor
partial disproportionation to provide small quantities of
Cu(I). For the reduction potentials of copper ions in
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