Transition-Metal-Free Coupling of 1,3-Dipoles and Boronic Acids as a Sustainable Approach to C?C Bond Formation

Article abstract of DOI:10.1002/chem.202001590

The need for alternative, complementary approaches to enable C?C bond formation within organic chemistry is an on-going challenge in the area. Of particular relevance are transformations that proceed in the absence of transition-metal reagents. In the current study, we report a comprehensive investigation of the coupling of nitrile imines and aryl boronic acids as an approach towards sustainable C?C bond formation. In situ generation of the highly reactive 1,3-dipole facilitates a Petasis–Mannich-type coupling via a nucleophilic boronate complex. The introduction of hydrazonyl chlorides as a complementary nitrile imine source to the 2,5-tetrazoles previously reported by our laboratory further broadens the scope of the approach. Additionally, we exemplify for the first time the extension of this protocol into another 1,3-dipole, through the synthesis of aryl ketone oximes from aryl boronic acids and nitrile N-oxides.

Full text of DOI:10.1002/chem.202001590

Accepted Article
Accepted Article
Title: Transition Metal-Free Coupling of 1,3-Dipoles and Boronic Acids
as a Sustainable Approach to C-C Bond Formation
Authors: Keith Livingstone, Sophie Bertrand, Alan R. Kennedy, and
Craig Jamieson
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202001590
Link to VoR: https://doi.org/10.1002/chem.202001590
01/2020

10.1002/chem.202001590
Chemistry - A European Journal
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Transition Metal-Free Coupling of 1,3-Dipoles and Boronic Acids
as a Sustainable Approach to C-C Bond Formation
Keith Livingstone,[a] Sophie Bertrand,[b] Alan R. Kennedy[a] and Craig Jamieson*[a]
[a]
K. Livingstone, Dr. A. R. Kennedy, Dr. C. Jamieson
Department of Pure and Applied Chemistry
University of Strathclyde
Thomas Graham Building, 295 Cathedral St, Glasgow, United Kingdom G1 1XL
E-mail: craig.jamieson@strath.ac.uk
[b]
Dr. S. Bertrand
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, United Kingdom SG1 2NY
Supporting information for this article is given via a link at the end of the document.
Abstract: The need for alternative, complementary approaches to
enable C-C bond formation within organic chemistry is an on-going
challenge in the area. Of particular relevance are transformations
that proceed in the absence of transition metal reagents. In the
current study, we report a comprehensive investigation of the
coupling of nitrile imines and aryl boronic acids as an approach
towards sustainable C-C bond formation. In situ generation of the
highly reactive 1,3-dipole facilitates a Petasis-Mannich-type coupling
via a nucleophilic boronate complex. The introduction of hydrazonyl
chlorides as a complementary nitrile imine source to the 2,5-
tetrazoles previously reported by our laboratory further broadens the
scope of the approach. Additionally, we exemplify for the first time
the extension of this protocol into another 1,3-dipole, through the
synthesis of aryl ketone oximes from aryl boronic acids and nitrile N-
oxides.
variety of boronic acids and esters (Scheme 1a).9,10 In both
transformations, the key mechanistic step is the formation of a
nucleophilic boronate complex via coordination of the boronic
acid to a nucleophilic heteroatom of the substrate. This electron-
rich boronate facilitates migration of the pendant aryl group to
the electrophilic iminium moiety (or pseudo-iminium moiety, in
the case of the NI).
Introduction
The formation of the C-C bond is of unique importance within
synthetic organic chemistry.1 While a vast number of research
groups have reported a raft of different protocols to facilitate this
transformation, the overwhelming majority of these require harsh
reaction conditions, or the application of transition metals.2 As
research within the synthetic chemistry community gravitates
towards more sustainable and economical solutions to such
challenges,2b the development of complementary methodology
towards C-C bond formation that obviates the requirement for
expensive or toxic reagents is becoming increasingly important.
Recently, nitrile imines (NIs) have come to our attention as an
attractive reagent in this regard.3,4 The NI is a highly versatile
1,3-dipole, first reported by Huisgen in 1959.4a Due to its
substantial reactivity, the species normally exists as a transient
intermediate, generated in situ from a suitable precursor prior to
trapping with an appropriate reaction partner. As with most 1,3-
dipolar moieties, NI chemistry is dominated by 1,3-dipolar
Scheme 1. a) An overview of the Petasis-Mannich reaction, which features the
generation of the nucleophilic boronate complex in situ. b) Previous efforts
within our research group furnished a metal-free route towards aryl ketone
hydrazones employing the photolysis of 2,5-tetrazole derivatives. c) This work:
we introduce hydrazonyl chlorides as an alternative source of the NI 1,3-dipole,
which affords certain practical advantages over the previous methodology,
including extension to other 1,3-dipoles.
cycloaddition,
a
versatile transformation with diverse
applications in synthesis, bioorthogonal chemistry and materials
science.5,6 However, an additional aspect of this dipole is its
significant reactivity with soft nucleophiles, such as thiols and
carboxylic acids.4j,7
In a previous report, we disclosed that by exploiting the
pleiotropic reactivity profile of the NI, combination with aryl
boronic acids could facilitate C-C bond formation in the absence
of any exogenous reagents.8 This approach drew on mechanistic
inspiration from the work of Petasis, who demonstrated the
formation of a C-C bond between α-alkoxyiminium species and a
Our previous efforts in this field largely employed the 2,5-diaryl
tetrazole moiety as an NI precursor (Scheme 1b).4i,8,11 This
functionality has the advantage of direct and irreversible NI
generation through exposure to 300 nm ultraviolet (UV) light,
enabling reagent-free access to the dipole with only nitrogen gas
as a by-product. However, despite the utility of the method,
1
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some limitations with this approach remain. From a practical
perspective, the scale upon which photochemistry may be
performed is often limited by the size of the light source
available. Furthermore, the use of high-energy UV-B light carries
with it associated health risks, which are exacerbated at a larger
scale. Substitution of the NI is also restricted to aryl groups, to
ensure that the precursor possesses an appropriate HOMO
energy to enable photochemical activation.12
conversion were considered (Table 1, entries 4 and 5). The
introduction of toluene as a direct replacement of DCM within
the optimized conditions was found to be relatively
straightforward,
furnishing comparable
conversions
to
hydrazone 3a in only 1 hour (Table 2, entry 2). Furthermore, an
immediate improvement was observed in the conversion of
electron-deficient substrate 3b, with a 34% conversion after
heating at reflux for 2 hours (Table 2, entry 4). In parallel with
our previous report,8 the introduction of dry conditions and
increased boronic acid stoichiometry facilitated an improved
42% turnover to the desired reaction product (Table 2, entry 7).
These conditions were found to be directly comparable to those
previously developed in the case of boronic acid 2a, with a 75%
isolated yield of hydrazone 3a.
In a concurrent approach towards exemplifying the scope of this
procedure, and comparing the efficiency of the transformation to
our previously reported conditions, the scope of the boronic acid
component was explored by employing a similar palette of
substrates. In most cases, this offered a direct comparison
between the benefits of both methods of NI generation, with the
results shown in Table 3.
Based on all of the above, we sought to harness
a
complementary approach to NI generation to enhance the
applicability of this methodology. Preliminary efforts at the time
of our previous report highlighted the potential of hydrazonyl
chlorides to serve as such an alternative (Scheme 1c).4a,13,14 NI
production from this precursor differs to the 2,5-tetrazole in that
it is a reversible process,11a meaning that the introduction of this
method could modulate the extraneous decomposition of the
highly reactive dipole. Additionally, it is likely that such a
procedure would be more amenable to scale-up in comparison
to our initial protocol, owing to the absence of UV light.
Employing similar reasoning, NIs bearing alkyl substituents
should also now be compatible within such a manifold, thus
expanding the substrate scope. One final advantage of the
hydrazonyl chloride as an NI source is that it may hypothetically
facilitate extension of the protocol into other 1,3-dipolar species,
owing to the similarity of the precursors. For example, the
closely related hydroxamoyl chlorides, a common source of the
nitrile oxide (NO) 1,3-dipole.15
Table 1. Preliminary investigations into solvent and base selection[a]
Results and Discussion
Our optimization campaign commenced with the application of
hydrazonyl chloride 1a as an NI precursor, with the electron-rich
4-(methoxy)phenylboronic acid (2a) selected as an appropriate
reaction partner. Initial efforts proved to be encouraging,
affording 32% conversion to the desired reaction product (Table
1, entry 1). The reaction was found to be highly sensitive to both
solvent and base selection (see SI for further details), with DCM
and K3PO4 identified as a favorable combination (Table 1, entry
15). The pKa of the base employed was found to be of particular
importance,16 with a direct correlation evident in the region of 6
to 13 (Graph 1). Interestingly, negligible by-product formation
was observed throughout this optimization, with starting material
1a comprising the majority of the remaining mass balance.
A two level, five factor, half-fractional Design of Experiments
study17,18 further implicated the importance of the role of the
base. Increased stoichiometry of the base was found to
significantly improve reaction conversion, particularly when
present in greater proportions than the boronic acid (Scheme
2a). Increased temperature was also found to be a major
contributor to the overall conversion (Scheme 2b). The reaction
conditions developed through the application of this data
afforded an 80% yield of aryl hydrazone 3a in 3 hours, requiring
only 1.1 equivalents of boronic acid 2a (Scheme 2c).
ArB(OH)2
Stoichiometry
Conversion
(%)[b]
Entry
Solvent
Base
1
2
MeCN
THF
NEt3
NEt3
3
32
22
48
58
50
75
54
40
51
<1
10
20
55
55
71
15
3
3
EtOAc
1,4-dioxane
PhMe
DCM
NEt3
3
4
NEt3
3
5
NEt3
3
6
NEt3
3
7
DCM
NEt3
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
8
DCE
NEt3
9
CHCl3
DCM
NEt3
10
11
12
13
14
15
16
Pyridine
Collidine
K2CO3
Cs2CO3
DIPEA
K3PO4
KOtBu
DCM
DCM
DCM
Unfortunately, introduction of the more electron-deficient boronic
acid 2b highlighted certain limitations of the protocol, with
minimal conversion to the desired reaction product (Scheme 2d).
As a consequence, we sought to further modify the reaction
conditions to increase compatibility with a broad scope of
boronic acids. Due to the proven impact of temperature on
reaction conversion (Scheme 2b), alternative solvents with
higher boiling points that had previously demonstrated adequate
DCM
DCM
DCM
aReactions performed on a 0.1 mmol scale using 3 equiv. base at a concentration of 0.1 M.
bConversions were determined by 19F NMR with reference to an internal standard.
2
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Table 2. The introduction of toluene as a solvent and further optimization of
electron-deficient boronic acid substrates[a]
80
K3PO4
r2 = 0.9844
60
40
20
0
Cs2CO3
DIPEA
NEt3
Lutidine
K2CO3
Collidine
ArB(OH)2
Species
Temperature
(°C)
Conversion
(%)[b]
Entry
Time
NMM
6
8
10
pKa
12
1
2
2a
2a
2b
2b
2b
2b
2b
2a
3
1
50
80
75
81
Graph 1. The correlation between the pKa of bases employed and reaction
conversion is evident within the range of 6.5 to 12.5. The notable outlier,
K2CO3, is thought to possess limited solubility in the reaction solvent (c.f.
Cs2CO3).
3
2
80
17
4
2
110
110
110
110
110
34
5[c]
6[c.d]
7[c,d,e]
8[c,d,e]
16
16
16
16
35
41
The reaction conditions once again demonstrated an excellent
compatibility with electron-rich boronic acids, affording 3c, 3d
and 3e in good yield. In comparison to NI generation via
tetrazole photolysis, the conversion levels observed are slightly
lower. This correlation is exacerbated in the case of the
moderately electron-donating 3f and heterocyclic analogues 3g,
3h and 3i. This is understandable in the latter cases, when
considering the limited stability of the corresponding boronic
acids and the more forcing conditions necessitated by the
modified approach. Having stated this, one advantage afforded
by the hydrazonyl chloride NI source is the improved yields of
electron-neutral boronic acids (c.f. 3j and 3k). Electron-deficient
boronic acids 3l and 3m retained almost identical conversion
values, despite the change in reaction conditions. The yield of
indazole substrate 3n was also largely unaffected by the
alternative source of NI. Unfortunately, as was identified in our
previous report, moderate to strongly electron-deficient boronic
acids failed to furnish the desired C-C bond (c.f. 3o). The
modified protocol was also shown to be more sensitive to steric
occlusion, with the unanticipated negative result of ortho-
substituted substrate 3p. The failure of substrate 3q remains
unexplained.
42 (27[f])
75[f]
aReactions performed on a 0.1 mmol scale using 1.1 equiv. 2a/2b and 3 equiv. K3PO4 at a
concentration of 0.1 M. bConversions were determined by 19F NMR with reference to an
internal standard. cN2 atmosphere. d3Å mol. sieves (400 mgmmol-1) were added. e2 equiv.
ArB(OH)2 were used. fIsolated yield.
While the reaction itself is believed to be stereospecific,8 the
isolation of E:Z mixtures of the hydrazone was a consequence of
thermal isomerization during the reaction and the presence of
mildly
acidic
conditions
during
purification
(column
chromatography).The inability of the hydrazonyl chloride to
improve these yields relative to the 2,5-tetrazole as an NI source
was an unexpected result. While the reversibility of dipole
formation from this precursor should inhibit NI decomposition, it
is possible that the reaction conditions may induce degradation
of 1b via an alternative pathway, such as through formation of
the analogous carbonium ion.14b However, while it was
established that the yields from different boronic acids afforded
Scheme 2. a) A 3D response surface outlining the dependence of boronic and base stoichiometry on reaction conversion, showing that an excess of base relative
to the reaction partner is favored. b) A 3D response surface highlighting the impact of temperature on the yield of procedure, with raised temperatures resulting in
a higher conversion. c) The successful isolation of an 80% yield of 3a when employing the optimized reaction conditions. d) The introduction of electron-deficient
boronic acid substrates highlighted the drawbacks of the initially developed conditions.
3
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by the hydrazonyl chloride were largely unchanged in
source and negating the necessity of employing UV light greatly
improves the practicality of the procedure. To further exemplify
the benefits of the facile synthesis of 3c on scale (5 mmol), the
hydrazone was derivatized to afford a number of secondary and
tertiary products (Scheme 3). This demonstrates the wide-
ranging applicability of this methodology in the efficient and
transition metal-free synthesis of diverse heterocyclic motifs (c.f.
4 and 6), or in the introduction of masked aryl ketones and
hydrazines (c. f. 8 and 9). Of particular note is the synthesis of
deuterated ketone 10, where for the first time, an aryl hydrazone
was employed as a directing group using a hydrogen isotope
exchange (HIE) catalyst developed by Kerr.19 Site-selective
deuteration is achieved through iridium(III)-promoted C-H
activation.
comparison to NI generation via
a 2,5-tetrazole, other
advantages of the new procedure were evident. Repeating the
synthesis of 3c on a 5 mmol scale furnished the desired product
in a comparable yield of 72%. This scale would represent a
significant challenge if employing the pre-existing methodology,
however the introduction of hydrazonyl chlorides as an NI
Table 3. Investigation of the scope of aryl boronic acids compatible with the
reaction conditions[a]
Scheme 3. Applications of aryl hydrazone product 3c.
To further exemplify the utility of NI generation from two
complementary sources, we subsequently utilized hydrazonyl
chloride precursors in the synthesis of a small library of
substrates that would otherwise be inaccessible through
tetrazole photolysis (Table 4). This was preceded by the efficient
generation of hydrazone 3r, which established the proof-of-
concept that substitution of the NI precursor was well-tolerated.
Nitro-substituted hydrazone 3s and analogous derivatives 3t and
3u were all accessed in good to acceptable yields. These
compounds represent examples of substrates incompatible with
the route previously developed in our laboratory, due to the very
limited photochemical reactivity of the relevant nitro-substituted
tetrazole precursors.4i,20 Alkyl substitution of the NI, which was
similarly unsuited to the initial UV-promoted protocol, was also
aReactions performed on a 0.25 mmol scale using 2 equiv. 2, 3 equiv. K3PO4, and 400
mgmmol-1 3Å mol. sieves at a concentration of 0.1 M.
4
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accomplished (c.f. 3v and 3w). While increased steric bulk of the
C-terminus was shown to be relatively inconsequential, the
overall yields of these analogues were generally low. This is
thought to be attributable to the truncated π-system of the
corresponding NI increasing the reactivity of the intermediate,
leading to unwanted side-reactions. A similar phenomenon is
likely responsible for the failure of substrates 3x and 3y. While
diversification of the NI N-terminus is an attractive prospect from
a synthetic perspective, the significant role of the N-aryl ring in
stabilising the intermediate likely further accelerates
decomposition in these substrates.21
comparison to the analogous NI (see SI for further details), with
only two bases found to afford the product 12a in an appreciable
yield (Table 5, entries 2 and 3). N,N’-dimethylaniline (DMA) was
eventually identified as an appropriate choice of base. The
notably lower pKa of this compound in comparison to the bases
evaluated as part of the NI screen further emphasizes the
elevated reactivity of the NO species.
Table 5. The optimization of reaction conditions for the metal-free C-C bond
formation between nitrile oxides and aryl boronic acids[a]
Table 4. The synthesis of hydrazone systems containing aryl-nitro and alkyl
substituents.[a]
Temperature
(°C)
Conversion
(%)[b]
Entry
Base
Solvent
1[c]
2[c]
3
K3PO4
Cs2CO3
DMA
DCM
DCM
25
25
25
25
60
60
<1
17
DCM
43
4
DMA
CHCl3
CHCl3
CHCl3
37
5
DMA
63
6[d,e]
DMA
70 (62[f])
aReactions performed on a 0.1 mmol scale using 1.5 equiv. 2a and 3 equiv. base at a
concentration of 0.1 M. bConversions were determined by 19F NMR with reference to an
internal standard. c3 equiv. 2a and 5 equiv. base. d2 equiv. 2a and 5 equiv. base. e3 hours
reaction time. fIsolated yield.
While direct application of the reaction conditions identified for
the NI dipole was not possible, the conditions developed for the
corresponding NO species nevertheless exhibited similar
characteristics, with a dependence on base stoichiometry and
elevated temperatures. The identification of chloroform as an
alternative solvent (Table 5, entry 4) enabled operation at
elevated temperatures, ultimately furnishing a 62 % isolated
yield of oxime 12a with an unprotracted reaction time (Table 5,
entries 5 and 6).
aReactions performed on a 0.25 mmol scale using 2 equiv. 2, 3 equiv. K3PO4, and 400
mgmmol-1 3Å mol. sieves at a concentration of 0.1 M. bIsolated as the corresponding
ketone.
With optimized conditions in hand, a small selection of boronic
acids were reacted with phenyl hydroxamoyl chloride 11b in
order to further delineate the scope of the reaction (Table 6).
Particular attention was invested in the comparison of these
results with those generated when employing NI precursor 1b. In
general, the results obtained from this part of the study were
very similar to the isolated yields found in Table 3. Electron-rich
boronic acids were again shown to possess the most favorable
properties within the protocol, with oximes 12b and 12c isolated
in 68 and 71 % yields, respectively. The noted decrease in yield
observed for 12d is consistent with the reduced inductive
influence of the para-methyl group. Substrates 12e to 12h
highlight the comparability of NO and NI reactivity, as all four
oximes isolated under these conditions were furnished in very
similar yield in comparison to the corresponding NI substrate.
One interesting difference when employing the NO 1,3-dipole is
the compatibility of the N,N’-dimethylaniline moiety. While
hydrazone 3q was not successfully isolated, oxime 12i was
One of the principal benefits of the development of transition
metal-free C-C bond formation using hydrazonyl chlorides as an
NI source is the potential applicability of the method towards
other 1,3-dipole systems. In particular, the nitrile oxide (NO) 1,3-
dipole can be readily accessed from the closely related
hydroxamoyl chloride moiety.22 Accordingly, we reasoned that
appropriate adaption of the reaction conditions developed in the
current study could furnish an analogous protocol for C-C bond
formation from boronic acids and NOs.
Initial efforts using a similar base and solvent combination as
described above failed to furnish the desired ketone oxime from
hydroxamoyl chloride 11a, despite application of the more
reactive boronic acid 2a (Table 5, entry 1). Indeed, the NO 1,3-
dipole proved significantly more capricious in its reactivity in
5
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obtained in moderate yield. The procedure was, however, found
to be incompatible with ortho-substitution of the boronic acid (c.f.
12j), with the synthesis of electron-deficient substrate 12k also
unsuccessful. The increased stereoselectivity of oximes 12
relative to hydrazones 3 is likely symptomatic of the increased
hydrolytic stability of oximes under mildly acidic conditions, such
as silica chromatography,23 in addition to the lower reaction
temperature limiting thermal isomerization.
of the protocol following on from our initial communication.
Introduction of the hydrazonyl chloride as an alternative and
complementary source of the NI 1,3-dipole can achieve
comparable yields of aryl ketone hydrazones with respect to 2,5-
tetrazole photolysis, while negating some of the practical
shortcomings associated with UV light. The protocol was shown
to operate effectively on a larger scale, serving as a feedstock
for a diverse array of further transformations. A number of
hydrazones previously inaccessible through our earlier
conditions were also furnished in moderate to good yields by
adopting this methodology, providing a route towards alkyl
hydrazones through metal-free C-C bond formation.
Furthermore, mechanistic translation of the procedure into the
related NO 1,3-dipole family was accomplished via a relatively
straightforward optimization campaign, with exemplification of
Table 6. Investigation of the scope of aryl ketone oximes accessible from
hydroxamoyl chloride 11b.[a]
the protocol through
a substrate scope highlighting the
substantial similarities in reactivity between the NI and NO
dipoles. We anticipate that this transformation may serve as a
facile alternative towards traditional C-C bond formation, while
simultaneously aiding in furthering the understanding of the
complex reactivity profiles of NIs and related 1,3-dipoles.
Scheme 4. The summation of mechanistic evidence indicates an
aReactions performed on a 0.25 mmol scale using 2 equiv. 2 and 3 equiv. DMA at a
intramolecular, facially selective aryl group migration
concentration of 0.1 M.
As a final demonstration of its utility, the nitrile oxide procedure
was also shown to be compatible on large scale, with 1.5 g of
11b smoothly converted to oxime 12b in a 72 % yield (Scheme
4). Expedient purification of this sample afforded the desired
compound with complete Z-stereoselectivity, providing evidence
that the isomerization of 12b that was previously observed
(Table 6) was a consequence of extended exposure to silica
during column chromatography, rather than during the
transformation itself. An X-ray crystal structure of 12b also
added weight to our previous mechanistic proposal,8 indicating
that aryl migration occurs via an intramolecular process,
following prior coordination of the boronic acid moiety to the
anionic terminus of the NO. This C-C bond formation appears to
proceed with complete syn-selectivity, relative to the oxime
directing group. Given the similarity between the properties of
the dipoles, it is probable that this facial selectivity is also
implicated when employing the NI, although further studies are
required to corroborate this hypothesis.
Experimental Section
General procedure for the synthesis of ketone hydrazones 3: To
an oven-dried 5 mL microwave vial was added 3 Å molecular
sieves (400 mgmmol-1), hydrazonyl chloride (1 equiv.), and
boronic acid (2 equiv.). The mixture was dissolved in toluene
(0.1 M), and K3PO4 (3 equiv.) was added to initiate the reaction.
The solution was purged with N2, and heated at 110 °C for 16 h.
The reaction mixture was diluted with ethyl acetate, filtered
through Celite and rinsed with additional ethyl acetate. The
crude solution was concentrated under vacuum and purified by
column chromatography.
General procedure for the synthesis of aryl ketone oximes 12:
To an oven-dried 5 mL microwave vial was added hydroxamoyl
chloride (1 equiv.) and boronic acid (2 equiv.). The mixture was
dissolved in chloroform (0.1 M), and N,N’-dimethylaniline (5
equiv.) was added to initiate the reaction. The solution was
purged with N2, and heated at 60 °C for 3 h. The reaction
mixture was diluted with DCM, and washed with 1 M HCl
solution. The organic phase was separated, washed with brine,
passed through a phase separator and concentrated under
vacuum. The crude residue was purified by column
chromatography.
Conclusion
In summary, we have comprehensively investigated the
application of NIs and boronic acids in the metal-free synthesis
of C-C bonds. This expanded report greatly enhances the utility
6
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[12] a) E. Sato, Y. Kanaoka, A. Padwa, J. Org. Chem. 1982, 47, 4256-4260;
b) V. Lohse, P. Leihkauf, C. Csongar, G. Tomaschewski, J. Prakt.
Chem. 1988, 330, 406-414.
Acknowledgements
We are grateful for the financial support provided by the EPSRC
and GSK. We are also indebted to Professor W J Kerr for the gift
of the Ir-HIE catalyst system used in Scheme 3.
[13] A. Shawali, M. Mosselhi, J. Het. Chem. 2003, 40, 725-746 and
references therein.
[14] a) A. F. Hegarty, M. P. Cashman, F. L. Scott, J. Chem. Soc. D. 1971,
684-685; b) A. F. Hegarty, M. P. Cashman, F. L. Scott, J. Chem. Soc.,
Perkin Trans. 2 1972, 44-52.
Keywords: C-C coupling • 1,3-Dipole • Nitrile imines • Nitrile
oxides • Reactive intermediates
[15] a) L. I. Belen’kii in Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis, 2nd. Ed. (Ed.: H. Feuer), Wiley, Hoboken, 2008, pp. 1-128; b)
Y. Ukaji, T. Soeta in Methods and Applications of Cycloaddition
Reactions in Organic Syntheses (Ed.: N. Nishiwaki), Wiley, Hoboken,
2014, pp. 263-282.
[1]
[2]
W. Carruthers, I. Coldham, Modern Methods of Organic Synthesis, 4th
Ed., Cambridge University Press, Cambridge, 2004.
a) J. R. Ludwig, C. S. Schindler, Chem 2017, 2, 313-316; b) T. P. Umile,
Catalysts for Sustainability: Goals, Challenges and Impacts, CRC Press,
Boca Raton, 2015.
[16] pKa values in water were obtained from the following reports; a) E. A.
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10.1002/chem.202001590
Chemistry - A European Journal
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A scalable and metal-free approach to carbon-carbon bond formation using 1,3-dipole systems generated from hydrazonyl chloride or
hydroxamoyl chloride precursors and aryl boronic acid derivatives is reported. Generation of the 1,3-dipole results in activation of the
boronic acid, with migration of the pendant aryl group to forge a new C-C bond in yields up to 80%.
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